PMID- 22916069 TI - Novel therapy for idiopathic pulmonary arterial hypertension: Can hepatocyte growth factor be beneficial? PMID- 22916070 TI - Metastatic seeding of glioblastoma along image-guided biopsy tract with successful treatment with re-irradiation: a case report. AB - Metastatic seeding along image-guided brain biopsy tracts is an uncommon phenomenon. We report a case of meningeal glioblastoma (GBM) metastasis at the site of a previous image-guided biopsy site, which developed 14 months after completing concurrent chemo-radiotherapy. This is the first reported case of successful treatment of an intracranial GBM metastasis with resection followed by radiotherapy. PMID- 22916071 TI - A rare adverse reaction of sorafenib. AB - Sorafenib is a multikinase inhibitor thought to target vascular endothelial growth factor and its receptor. The European Medicines Agency (EAMA) and Food and Drug Administration (FDA) approved the use of sorafenib in late-stage hepatic cellular cancer (HCC) on October 30, 2007, and November 19, 2007, respectively. It is the only drug approved for use in the systematic treatment of primary HCC, and it offers renewed hope for middle- and late-stage liver cancer patients. Conventional use of sorafenib is 400 mg orally, twice daily, until tumor progression or patient death. The following is a report of a serious episode of skin rash in a liver cancer patient at our hospital subsequent to treatment with sorafenib. PMID- 22916073 TI - The Invasion and Reproductive Toxicity of QDs-Transferrin Bioconjugates on Preantral Follicle in vitro. AB - The toxicity of QD has been extensively studied over the past decade. However, the potential toxicity of QDs impedes its use for clinical research. In this work, we established a preantral follicle in vitro culture system to investigate the effects of QD-Transferrin (QDs-Tf) bioconjugates on follicle development and oocyte maturation. The preantral follicles were cultured and exposed to CdTe/ZnTe QDs-Tf bioconjugates with various concentrations and the reproductive toxicity was assessed at different time points post-treatment. The invasion of QDs-Tf for oocytes was verified by laser scanning confocal microscope. Steroid production was evaluated by immunoassay. C-band Giemsa staining was performed to observe the chromosome abnormality of oocytes. The results showed that the QDs-Tf bioconjugates could permeate into granulosa cells and theca cells, but not into oocyte. There are no obvious changes of oocyte diameter, the mucification of cumulus-oocyte-complexes and the occurrence of aneulpoidy as compared with the control group. However, delay in the antrum formation and decrease in the ratio of oocytes with first polar body were observed in QDs-Tf-treated groups. The matured oocytes with first polar body decreased significantly by ~16% (from 79.6+/-10 % to 63+/-2.9 %) when the concentration of QDs-Tf bioconjugates exceeded 2.89 nmol.L(-1) (P < 0.05). Our results implied that the CdTe/ZnTe QDs Tf bioconjugates were reproductive toxic for follicle development, and thus also revealed that this in vitro culture system of preantral follicle is a highly sensitive tool for study on the reproductive toxicity of nanoparticles. PMID- 22916072 TI - Quantum dot enabled molecular sensing and diagnostics. AB - Since its emergence, semiconductor nanoparticles known as quantum dots (QDs) have drawn considerable attention and have quickly extended their applicability to numerous fields within the life sciences. This is largely due to their unique optical properties such as high brightness and narrow emission band as well as other advantages over traditional organic fluorophores. New molecular sensing strategies based on QDs have been developed in pursuit of high sensitivity, high throughput, and multiplexing capabilities. For traditional biological applications, QDs have already begun to replace traditional organic fluorophores to serve as simple fluorescent reporters in immunoassays, microarrays, fluorescent imaging applications, and other assay platforms. In addition, smarter, more advanced QD probes such as quantum dot fluorescence resonance energy transfer (QD-FRET) sensors, quenching sensors, and barcoding systems are paving the way for highly-sensitive genetic and epigenetic detection of diseases, multiplexed identification of infectious pathogens, and tracking of intracellular drug and gene delivery. When combined with microfluidics and confocal fluorescence spectroscopy, the detection limit is further enhanced to single molecule level. Recently, investigations have revealed that QDs participate in series of new phenomena and exhibit interesting non-photoluminescent properties. Some of these new findings are now being incorporated into novel assays for gene copy number variation (CNV) studies and DNA methylation analysis with improved quantification resolution. Herein, we provide a comprehensive review on the latest developments of QD based molecular diagnostic platforms in which QD plays a versatile and essential role. PMID- 22916074 TI - Dynamic PET and Optical Imaging and Compartment Modeling using a Dual-labeled Cyclic RGD Peptide Probe. AB - PURPOSE: The aim of this study is to determine if dynamic optical imaging could provide comparable kinetic parameters to that of dynamic PET imaging by a near infrared dye/(64)Cu dual-labeled cyclic RGD peptide. METHODS: The integrin alpha(v)beta(3) binding RGD peptide was conjugated with a macrocyclic chelator 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) for copper labeling and PET imaging and a near-infrared dye ZW-1 for optical imaging. The in vitro biological activity of RGD-C(DOTA)-ZW-1 was characterized by cell staining and receptor binding assay. Sixty-min dynamic PET and optical imaging were acquired on a MDA-MB-435 tumor model. Singular value decomposition (SVD) method was applied to compute the dynamic optical signal from the two-dimensional optical projection images. Compartment models were used to quantitatively analyze and compare the dynamic optical and PET data. RESULTS: The dual-labeled probe (64)Cu-RGD-C(DOTA)-ZW-1 showed integrin specific binding in vitro and in vivo. The binding potential (Bp) derived from dynamic optical imaging (1.762 +/- 0.020) is comparable to that from dynamic PET (1.752 +/- 0.026). CONCLUSION: The signal un-mixing process using SVD improved the accuracy of kinetic modeling of 2D dynamic optical data. Our results demonstrate that 2D dynamic optical imaging with SVD analysis could achieve comparable quantitative results as dynamic PET imaging in preclinical xenograft models. PMID- 22916075 TI - Gold Nanorods Conjugated with Doxorubicin and cRGD for Combined Anticancer Drug Delivery and PET Imaging. AB - A multifunctional gold nanorod (GNR)-based nanoplatform for targeted anticancer drug delivery and positron emission tomography (PET) imaging of tumors was developed and characterized. An anti-cancer drug (i.e., doxorubicin (DOX)) was covalently conjugated onto PEGylated (PEG: polyethylene glycol) GNR nanocarriers via a hydrazone bond to achieve pH-sensitive controlled drug release. Tumor targeting ligands (i.e., the cyclo(Arg-Gly-Asp-D-Phe-Cys) peptides, cRGD) and (64)Cu-chelators (i.e., 1,4,7-triazacyclononane-N, N', N''-triacetic acid (NOTA)) were conjugated onto the distal ends of the PEG arms to achieve active tumor targeting and PET imaging, respectively. Based on flow cytometry analysis, cRGD conjugated nanocarriers (i.e., GNR-DOX-cRGD) exhibited a higher cellular uptake and cytotoxicity than non-targeted ones (i.e., GNR-DOX) in vitro. However, GNR DOX-cRGD and GNR-DOX nanocarriers had similar in vivo biodistribution according to in vivo PET imaging and biodistribution studies. Due to the unique optical properties of GNRs, this multifunctional GNR-based nanoplatform can potentially be optimized for combined cancer therapies (chemotherapy and photothermal therapy) and multimodality imaging (PET, optical, X-ray computed tomography (CT), etc.). PMID- 22916076 TI - In vivo cancer targeting and imaging-guided surgery with near infrared-emitting quantum dot bioconjugates. AB - Early detection and subsequent complete surgical resection are among the most efficient methods for treating cancer. However, low detection sensitivity and incomplete tumor resection are two challenging issues. Nanoparticle-based imaging guided surgery has proven promising for cancer-targeted imaging and subsequent debulking surgery. Particularly, the use of near infrared (NIR) fluorescent probes such as NIR quantum dots (QDs) allows deep penetration and high sensitivity for tumor detection. In this study, NIR-emitting CdTe QDs (maximum fluorescence emission peak at 728 nm) were synthesized with a high quantum yield (QY) of 38%. The tumor-specific QD bioconjugates were obtained by attaching cyclic Arg-Gly-Asp peptide (cRGD) to the surface of synthesized QDs, and then injected into U87 MG tumor-bearing mice via tail veins for tumor-targeted imaging. The tumor and its margins were visualized and distinguished by NIR QD bioconjugates, and tumor resection was successfully accomplished via NIR guidance using a Fluobeam-700 NIR imaging system. Our work indicates that the synthesized tumor-specific NIR QDs hold great promise as a potential fluorescent indicator for intraoperative tumor imaging. PMID- 22916077 TI - The MUC1 Ectodomain: A Novel and Efficient Target for Gold Nanoparticle Clustering and Vapor Nanobubble Generation. AB - MUC1 is a large, heavily glycosylated transmembrane glycoprotein that is proposed to create a protective microenvironment in many adenocarcinomas. Here we compare MUC1 and the well studied cell surface receptor target, EGFR, as gold nanoparticle (AuNP) targets and their subsequent vapor nanobubble generation efficacy in the human epithelial cell line, HES. Although EGFR and MUC1 were both highly expressed in these cells, TEM and confocal images revealed MUC1 as a superior target for nanoparticle intracellular accumulation and clustering. The MUC1-targeted AuNP intracellular clusters also generated significantly larger vapor nanobubbles. Our results demonstrate the promising opportunities MUC1 offers to improve the efficacy of targeted nanoparticle based approaches. PMID- 22916078 TI - Multimodality imaging evaluation of functional and clinical benefits of percutaneous coronary intervention in patients with chronic total occlusion lesion. AB - AIMS: To determine the effects of percutaneous coronary intervention (PCI) on cardiac perfusion, cardiac function, and quality of life in patients with chronic total occlusion (CTO) lesion in left anterior descending (LAD) coronary artery. METHODS AND RESULTS: Patients (n=99) with CTO lesion in the LAD coronary artery who had successfully undergone PCI were divided into three groups based on the SPECT/CTCA fusion imaging: (a) no severe cardiac perfusion defects (n=9); (b) reversible cardiac perfusion defects (n=40); or (c) fixed cardiac perfusion defects (n=50). No statistical difference of perfusion abnormality was observed at 6 months and 1 year after PCI in group (a). In group (b), SPECT/CTCA fusion imaging demonstrated that cardiac perfusion abnormality was significantly decreased 6 month and 1 year after PCI. Left ventricular ejection fraction (LVEF) increased significantly at 6 months and 1 year follow up. Quality of life improved at 6 months and 1 year after PCI procedure. Moreover, patients in group (c) also benefited from PCI therapy: a decrease in cardiac perfusion abnormality, an increase in LVEF, and an improvement in quality of life. PCI of coronary arteries in addition to LAD did not significantly affect cardiac function and quality of life improvement in each group. CONCLUSIONS: PCI exerts functional and clinical benefits in patients with CTO lesion in LAD coronary artery, particularly in patients with reversible cardiac perfusion defects. SPECT/CTCA fusion imaging may serve as a useful tool to evaluate the outcomes of patients with CTO lesion in LAD coronary artery. PMID- 22916079 TI - Therapeutic angiogenesis for treating cardiovascular diseases. AB - Cardiovascular disease is the leading cause of death worldwide and is often associated with partial or full occlusion of the blood vessel network in the affected organs. Restoring blood supply is critical for the successful treatment of cardiovascular diseases. Therapeutic angiogenesis provides a valuable tool for treating cardiovascular diseases by stimulating the growth of new blood vessels from pre-existing vessels. In this review, we discuss strategies developed for therapeutic angiogenesis using single or combinations of biological signals, cells and polymeric biomaterials. Compared to direct delivery of growth factors or cells alone, polymeric biomaterials provide a three-dimensional drug-releasing depot that is capable of facilitating temporally and spatially controlled release. Biomimetic signals can also be incorporated into polymeric scaffolds to allow environmentally-responsive or cell-triggered release of biological signals for targeted angiogenesis. Recent progress in exploiting genetically engineered stem cells and endogenous cell homing mechanisms for therapeutic angiogenesis is also discussed. PMID- 22916080 TI - Job requirements compared to dental school education: impact of a case-based learning curriculum. AB - INTRODUCTION: Case-based learning (CBL) is suggested as a key educational method of knowledge acquisition to improve dental education. The purpose of this study was to assess graduates from a patient-oriented, case-based learning (CBL)-based curriculum as regards to key competencies required at their professional activity. METHODS: 407 graduates from a patient-oriented, case-based learning (CBL) dental curriculum who graduated between 1990 and 2006 were eligible for this study. 404 graduates were contacted between 2007 and 2008 to self-assess nine competencies as required at their day-to-day work and as taught in dental school on a 6-point Likert scale. Baseline demographics and clinical characteristics were presented as mean +/- standard deviation (SD) for continuous variables. To determine whether dental education sufficiently covers the job requirements of physicians, we calculated the mean difference ? between the ratings of competencies as required in day-to-day work and as taught in medical school by subtracting those from each other (negative mean difference ? indicates deficit; positive mean difference ? indicates surplus). Spearman's rank correlation coefficient was calculated to reveal statistical significance (statistical significance p<0.05). RESULTS: 41.6% recipients of the questionnaire responded (n=168 graduates). A homogeneous distribution quantity of the graduate groups concerning gender, graduation date, professional experience and average examination grade was achieved.Comparing competencies required at work and taught in medical school, CBL was associated with benefits in "Research competence" (?+0.6) "Interdisciplinary thinking" (?+0.47), "Dental medical knowledge" (?+0.43), "Practical dental skills" (?+0.21), "Team work" (?+0.16) and "Independent learning/working" (?+0.08), whereas "Problem-solving skills" (? 0.07), "Psycho-social competence" (?-0.66) and "Business competence" (?-2.86) needed improvement in the CBL-based curriculum. DISCUSSION: CBL demonstrated benefits with regard to competencies which were highly required in the job of dentists. Psycho-social and business competence deserve closer attention in future curricular development. PMID- 22916081 TI - Frequency and perceived severity of negative experiences during medical education in Germany--results of an online-survery of medical students. AB - AIMS: Negative experiences during the course of medical education have been reported in many countries, but little is known about the perceived severity of these experiences. We studied for the first time how often students at a medical university in Germany have had negative experiences, and how severe they perceive these to be. METHOD: We asked medical students in an online survey whether they felt adequately appreciated, had experienced peer rivalry, verbal abuse by their mentors, physical abuse or mistreatment, sexual harassment, racial or ethnic discrimination, or any other kind of mistreatment. RESULTS: Of 391 students, 56% stated that they felt insufficiently appreciated, 51% had experienced rivalry, and 34% had suffered verbal abuse. Fifty-nine percent of the students felt highly aggrieved because of verbal abuse, while 46% were aggrieved by the ongoing rivalry and 32% by the lack of appreciation. Significantly fewer students felt upset because they were passed over or ignored (21%). Generally, female students felt more often aggrieved by these negative experiences than their male colleagues. CONCLUSION: Of the possible negative experiences, the less prominent ones such as lack of appreciation or verbal abuse are not only frequent, they are also perceived as very upsetting. Medical teachers should reflect this more in their day-to-day dealings with students and aim to improve on their contact with the students accordingly. PMID- 22916082 TI - Novice medical students: individual patterns in the use of learning strategies and how they change during the first academic year. AB - BACKGROUND: Adequate use of different learning strategies is one of the most important prerequisites of academic success. The actual use of learning strategies is the result of an interaction between individual and situational variables. Against this background we conducted a longitudinal study with first year medical students to investigate whether individuals show different patterns in their use of learning strategies and whether these patterns change during the first academic year. METHODS: Medical students (N=175, 58% female) were surveyed three times in their first academic year regarding their use of learning strategies. A hierarchical cluster analysis (Ward) was conducted in order to identify groups of students with different patterns of learning strategies. RESULTS: We identified four different patterns in approaches to learning among novice medical students ("easy-going", "flexible", "problematic" and "hardworking" learners). Compared to their peers, the problematic learners had the worst final school grades. In addition changes in the use of learning strategies were identified, most of them occurred during the first term. CONCLUSION: Students start their academic studies with different patterns of learning strategies; the characteristics of these patterns change during the first academic year. Further research is necessary to better understand how individual and situational variables determine students' learning. PMID- 22916083 TI - Comparison of collegial individual and group reviews of general practice multiple choice questions. AB - AIMS: In most German medical faculties, credits in general practice can be earned via exams using multiple-choice questions (MCQ). Measures such as peer-reviews may help assure the quality of these exams. In order to use time and personnel intensive peer reviews effectively and efficiently, the procedures used are key. Therefore, we wanted to find out whether there are differences between group and individual reviews regarding defined parameters. METHODS: We conducted a controlled cross-over study with three GP reviewers from four different German universities. Each reviewed 80 MCQs, 40 individually and 40 within a group, including external assessments by a panel of experts. Furthermore all reviewers were asked to evaluate the review process and the time spent carrying out these reviews. OUTCOMES: We found no significant differences between the reliability and the validity of individual reviews versus group reviews. On average slightly more time was spent on group reviews compared with the individual reviews. The subjective assessments of the study participants regarding their satisfaction with the process and the efficiency and effectiveness of the reviews suggest a preference for group reviews. CONCLUSIONS: Based on this study, there are no definite recommendations for or against either approach. When choosing between the two, the specific work structures and organisation at the local faculty should be taken into account. PMID- 22916084 TI - The practial use of the consensus statement on practical skills in medical school -a validation study. AB - OBJECTIVE: The importance of the acquisition of practical medical skills during medical school is increasing. With the consensus statement "Practical Skills," developed by the GMA as part of the National Competency-Based Learning Objective Catalogue for Medicine (NKLM), a reference frame was created for the procurement of such skills. This frame consists of 290 learning objectives divided by "organ system," type (core or elective learning objective), current stage of medical education and level of instruction. By comparing a large and well evaluated range of student tutorials with the consensus statement, one can analyze the practical benefit of the statement, as well as evaluate the tutorial program for completeness. METHODS: In the first stage, four evaluators in two groups independently classified all consensus statement's learning objectives by each of the 48 tutorials currently offered. The inter-rater reliability among the evaluators of each group was calculated both collectively, and according to each organ system. In the second stage, disagreements in the classification were resolved through discussion and consensus decision-making. The coverage of the learning objectives by the tutorials, in the required level of instruction, was then analyzed separately by learning objective type and organ system. Reasons for any initial dissent were recorded and grouped thematically. RESULTS: The correlation between the classifications of the two evaluators was moderately significant. The strength of this correlation, and thus the precision of individual learning goals wording, varied according to organ system. After a consensus was reached, the results show that the offered tutorials covered 66% of all learning objectives, as well as 74% of the core objectives. The degree of coverage differed according to organ system and stage of medical education. CONCLUSION: The consensus statement is suitable to systematically analyze and develop teaching units. The comparison with established curricula also offers possibilities for further development of the consensus statement, and therefore also of the NKLM. PMID- 22916085 TI - Homepages of German medical faculties--an overview. AB - INTRODUCTION: The Internet represents a central communication medium for patients and physicians. Some national information is available regarding the design of physicians' homepages and patient requirements regarding homepages of physicians in private practice. To date, no data are available for homepages of medical faculties and their users' needs. METHODS: In 2008 the homepages of the 36 German medical faculties were analyzed according to a catalogue of 128 criteria assigned to five domains which had been developed from the literature. Structure, content and extent were compared. RESULTS: The homepages covered the criteria to a very different extent. The best homepage reached 80%, the worst only 26% of the achievable points. The mean was slightly above 50% . Faculties addressed mainly applicants and students as their target groups, less frequently lecturers and alumni. CONCLUSION: This study shows differences in quality and quantity of the "teaching section" on websites of medical faculties. The results allow faculties to use the criteria to adjust their websites with regard to addressing the relevant target groups of students, applicants, lecturers and alumni comprehensively. PMID- 22916086 TI - The GMA Journal for Medical Education--recent achievements and future goals. PMID- 22916087 TI - VARIABLE SELECTION AND REGRESSION ANALYSIS FOR GRAPH-STRUCTURED COVARIATES WITH AN APPLICATION TO GENOMICS. AB - Graphs and networks are common ways of depicting information. In biology, many different biological processes are represented by graphs, such as regulatory networks, metabolic pathways and protein-protein interaction networks. This kind of a priori use of graphs is a useful supplement to the standard numerical data such as microarray gene expression data. In this paper, we consider the problem of regression analysis and variable selection when the covariates are linked on a graph. We study a graph-constrained regularization procedure and its theoretical properties for regression analysis to take into account the neighborhood information of the variables measured on a graph, where a smoothness penalty on the coefficients is defined as a quadratic form of the Laplacian matrix associated with the graph. We establish estimation and model selection consistency results and provide estimation bounds for both fixed and diverging numbers of parameters in regression models. We demonstrate by simulations and a real dataset that the proposed procedure can lead to better variable selection and prediction than existing methods that ignore the graph information associated with the covariates. PMID- 22916089 TI - Missed Opportunities: barriers to HIV testing during pregnancy from a population based cohort study in rural Uganda. AB - The aim was to assess population-level HIV-testing uptake among pregnant women, key for access to prevention-of mother to child transmission (PMTCT) services, and to identify risk factors for not being HIV tested,The study was conducted May 2008-May 2010 in the Iganga/Mayuge Health and Demographic Surveillance Site (HDSS), Eastern Uganda, during regular surveillance of 68,000 individuals. All women identified to be pregnant May-July 2008 (n=881) were interviewed about pregnancy-related issues and linked to the HDSS database for socio-demographic data. Women were followed-up via antenatal care (ANC) register reviews at the health facilities to collect data related to ANC services received, including HIV testing. Adjusted relative risk (aRR), and 95% confidence intervals (CI) for not being HIV tested were calculated using multivariable binomial regression among the 544 women who remained after record review.Despite high ANC attendance (96%), the coverage of HIV testing was 64%. Only 6% of pregnant women who sought ANC at a facility without HIV testing services were referred for testing and only 20% received counseling regarding HIV. At ANC facilities with HIV testing services, 85% were tested. Only 4% of the women tested had been couple tested for HIV. Living more than three kilometers away from a health facility with HIV testing services was associated with not being tested both among the poorest (aRR,CI; 1.44,1.02-2.04) and the least poor women (aRR,CI;1.72,1.12-2.63).The lack of on site HIV testing services and distant ANC facilities lead to missed opportunities for PMTCT, especially for the poorest women. Referral systems for HIV testing need to be improved and testing should be expanded to lower level health facilities. This is in order to ensure that the policy of HIV testing during pregnancy is implemented more effectively and that testing is accessible for all. PMID- 22916088 TI - Transcriptional programs controlling perinatal lung maturation. AB - The timing of lung maturation is controlled precisely by complex genetic and cellular programs. Lung immaturity following preterm birth frequently results in Respiratory Distress Syndrome (RDS) and Broncho-Pulmonary Dysplasia (BPD), which are leading causes of mortality and morbidity in preterm infants. Mechanisms synchronizing gestational length and lung maturation remain to be elucidated. In this study, we designed a genome-wide mRNA expression time-course study from E15.5 to Postnatal Day 0 (PN0) using lung RNAs from C57BL/6J (B6) and A/J mice that differ in gestational length by ~30 hr (B60.9 mm was found in 4%, 45.9% and 20% of diabetic subjects at the common, bulb or internal carotid, respectively. Only 25% of patients had an HbA1c<7%, while over 41.6% presented with marked hyperglycemia (HbA1c>9%). The prevalence of diabetic subjects with abnormal levels of LDL cholesterol, triglycerides, HDL-cholesterol or blood pressure was 45%, 16.6%, 15% and 65.7%, respectively. CONCLUSIONS: Carotid thickness is increased in subjects with diabetes from a rural area of Cameroon, despite the relatively recent diagnosis. These findings and the high rate of uncontrolled diabetes in this population support the increasing concern of diabetes and cardiovascular diseases in African countries and indicate the need for multifaceted health interventions in urban and rural settings. PMID- 22916107 TI - The acute phase reactant orosomucoid-1 is a bimodal regulator of angiogenesis with time- and context-dependent inhibitory and stimulatory properties. AB - BACKGROUND: Tissues respond to injury by releasing acute phase reaction (APR) proteins which regulate inflammation and angiogenesis. Among the genes upregulated in wounded tissues are tumor necrosis factor-alpha (TNFalpha) and the acute phase reactant orosomucoid-1 (ORM1). ORM1 has been shown to modulate the response of immune cells to TNFalpha, but its role on injury- and TNFalpha induced angiogenesis has not been investigated. This study was designed to characterize the role of ORM1 in the angiogenic response to injury and TNFalpha. METHODS AND RESULTS: Angiogenesis was studied with in vitro, ex vivo, and in vivo angiogenesis assays. Injured rat aortic rings cultured in collagen gels produced an angiogenic response driven by macrophage-derived TNFalpha. Microarray analysis and qRT-PCR showed that TNFalpha and ORM1 were upregulated prior to angiogenic sprouting. Exogenous ORM1 delayed the angiogenic response to injury and inhibited the proangiogenic effect of TNFalpha in cultures of aortic rings or isolated endothelial cells, but stimulated aortic angiogenesis over time while promoting VEGF production and activity. ORM1 inhibited injury- and TNFalpha-induced phosphorylation of MEK1/2 and p38 MAPK in aortic rings, but not of NFkappaB. This effect was injury/TNFalpha-specific since ORM1 did not inhibit VEGF-induced signaling, and cell-specific since ORM1 inhibited TNFalpha-induced phosphorylation of MEK1/2 and p38 MAPK in macrophages and endothelial cells, but not mural cells. Experiments with specific inhibitors demonstrated that the MEK/ERK pathway was required for angiogenesis. ORM1 inhibited angiogenesis in a subcutaneous in vivo assay of aortic ring-induced angiogenesis, but stimulated developmental angiogenesis in the chorioallantoic membrane (CAM) assay. CONCLUSION: ORM1 regulates injury-induced angiogenesis in a time- and context dependent manner by sequentially dampening the initial TNFalpha-induced angiogenic response and promoting the downstream stimulation of the angiogenic process by VEGF. The context-dependent nature of ORM1 angioregulatory function is further demonstrated in the CAM assay where ORM1 stimulates developmental angiogenesis without exerting any inhibitory activity. PMID- 22916108 TI - Cell cycle regulation by the PRMT6 arginine methyltransferase through repression of cyclin-dependent kinase inhibitors. AB - PRMT6 belongs to the family of Protein Arginine Methyltransferase (PRMT) enzymes that catalyze the methylation of guanidino nitrogens of arginine residues. PRMT6 has been shown to modify the tail of histone H3, but the in vivo function of PRMT6 is largely unknown. Here, we show that PRMT6 regulates cell cycle progression. Knockdown of PRMT6 expression in the human osteosarcoma cell line U2OS results in an accumulation of cells at the G2 checkpoint. Loss of PRMT6 coincides with upregulation of p21 and p27, two members of the CIP/KIP family of cyclin-dependent kinase (CDK) inhibitors. Gene expression and promoter analysis show that p21 and p27 are direct targets of PRMT6, which involves methylation of arginine-2 of histone H3. Our findings imply arginine methylation of histones by PRMT6 in cell cycle regulation. PMID- 22916109 TI - Activation of the canonical bone morphogenetic protein (BMP) pathway during lung morphogenesis and adult lung tissue repair. AB - Signaling by Bone Morphogenetic Proteins (BMP) has been implicated in early lung development, adult lung homeostasis and tissue-injury repair. However, the precise mechanism of action and the spatio-temporal pattern of BMP-signaling during these processes remains inadequately described. To address this, we have utilized a transgenic line harboring a BMP-responsive eGFP-reporter allele (BRE eGFP) to construct the first detailed spatiotemporal map of canonical BMP-pathway activation during lung development, homeostasis and adult-lung injury repair. We demonstrate that during the pseudoglandular stage, when branching morphogenesis progresses in the developing lung, canonical BMP-pathway is active mainly in the vascular network and the sub-epithelial smooth muscle layer of the proximal airways. Activation of the BMP-pathway becomes evident in epithelial compartments only after embryonic day (E) 14.5 primarily in cells negative for epithelial lineage markers, located in the proximal portion of the airway-tree, clusters adjacent to neuro-epithelial-bodies (NEBs) and in a substantial portion of alveolar epithelial cells. The pathway becomes activated in isolated E12.5 mesenchyme-free distal epithelial buds cultured in Matrigel suggesting that absence of reporter activity in these regions stems from a dynamic cross-talk between endoderm and mesenchyme. Epithelial cells with activated BMP-pathway are enriched in progenitors capable of forming colonies in three-dimensional Matrigel cultures.As lung morphogenesis approaches completion, eGFP-expression declines and in adult lung its expression is barely detectable. However, upon tissue injury, either with naphthalene or bleomycin, the canonical BMP-pathways is re activated, in bronchial or alveolar epithelial cells respectively, in a manner reminiscent to early lung development and in tissue areas where reparatory progenitor cells reside. Our studies illustrate the dynamic activation of canonical BMP-pathway during lung development and adult lung tissue-repair and highlight its involvement in two important processes, namely, the early development of the pulmonary vasculature and the management of epithelial progenitor pools both during lung development and repair of adult lung tissue injury. PMID- 22916110 TI - Mutation discovery in regions of segmental cancer genome amplifications with CoNAn-SNV: a mixture model for next generation sequencing of tumors. AB - Next generation sequencing has now enabled a cost-effective enumeration of the full mutational complement of a tumor genome-in particular single nucleotide variants (SNVs). Most current computational and statistical models for analyzing next generation sequencing data, however, do not account for cancer-specific biological properties, including somatic segmental copy number alterations (CNAs) which require special treatment of the data. Here we present CoNAn-SNV (Copy Number Annotated SNV): a novel algorithm for the inference of single nucleotide variants (SNVs) that overlap copy number alterations. The method is based on modelling the notion that genomic regions of segmental duplication and amplification induce an extended genotype space where a subset of genotypes will exhibit heavily skewed allelic distributions in SNVs (and therefore render them undetectable by methods that assume diploidy). We introduce the concept of modelling allelic counts from sequencing data using a panel of Binomial mixture models where the number of mixtures for a given locus in the genome is informed by a discrete copy number state given as input. We applied CoNAn-SNV to a previously published whole genome shotgun data set obtained from a lobular breast cancer and show that it is able to discover 21 experimentally revalidated somatic non-synonymous mutations in a lobular breast cancer genome that were not detected using copy number insensitive SNV detection algorithms. Importantly, ROC analysis shows that the increased sensitivity of CoNAn-SNV does not result in disproportionate loss of specificity. This was also supported by analysis of a recently published lymphoma genome with a relatively quiescent karyotype, where CoNAn-SNV showed similar results to other callers except in regions of copy number gain where increased sensitivity was conferred. Our results indicate that in genomically unstable tumors, copy number annotation for SNV detection will be critical to fully characterize the mutational landscape of cancer genomes. PMID- 22916111 TI - Multiple regression methods show great potential for rare variant association tests. AB - The investigation of associations between rare genetic variants and diseases or phenotypes has two goals. Firstly, the identification of which genes or genomic regions are associated, and secondly, discrimination of associated variants from background noise within each region. Over the last few years, many new methods have been developed which associate genomic regions with phenotypes. However, classical methods for high-dimensional data have received little attention. Here we investigate whether several classical statistical methods for high-dimensional data: ridge regression (RR), principal components regression (PCR), partial least squares regression (PLS), a sparse version of PLS (SPLS), and the LASSO are able to detect associations with rare genetic variants. These approaches have been extensively used in statistics to identify the true associations in data sets containing many predictor variables. Using genetic variants identified in three genes that were Sanger sequenced in 1998 individuals, we simulated continuous phenotypes under several different models, and we show that these feature selection and feature extraction methods can substantially outperform several popular methods for rare variant analysis. Furthermore, these approaches can identify which variants are contributing most to the model fit, and therefore both goals of rare variant analysis can be achieved simultaneously with the use of regression regularization methods. These methods are briefly illustrated with an analysis of adiponectin levels and variants in the ADIPOQ gene. PMID- 22916112 TI - Molecular epidemiology of influenza A(H1N1)pdm09 viruses from Pakistan in 2009 2010. AB - BACKGROUND: In early 2009, a novel influenza A(H1N1) virus that emerged in Mexico and United States rapidly disseminated worldwide. The spread of this virus caused considerable morbidity with over 18000 recorded deaths. The new virus was found to be a reassortant containing gene segments from human, avian and swine influenza viruses. METHODS/RESULTS: The first case of human infection with A(H1N1)pdm09 in Pakistan was detected on 18(th) June 2009. Since then, 262 laboratory-confirmed cases have been detected during various outbreaks with 29 deaths (as of 31(st) August 2010). The peak of the epidemic was observed in December with over 51% of total respiratory cases positive for influenza. Representative isolates from Pakistan viruses were sequenced and analyzed antigenically. Sequence analysis of genes coding for surface glycoproteins HA and NA showed high degree of high levels of sequence identity with corresponding genes of regional viruses circulating South East Asia. All tested viruses were sensitive to Oseltamivir in the Neuraminidase Inhibition assays. CONCLUSIONS: Influenza A(H1N1)pdm09 viruses from Pakistan form a homogenous group of viruses. Their HA genes belong to clade 7 and show antigenic profile similar to the vaccine strain A/California/07/2009. These isolates do not show any amino acid changes indicative of high pathogenicity and virulence. It is imperative to continue monitoring of these viruses for identification of potential variants of high virulence or drug resistance. PMID- 22916113 TI - Efficacy and safety of telavancin in clinical trials: a systematic review and meta-analysis. AB - INTRODUCTION: The epidemiology and antibiotic resistance of Staphylococcus aureus have evolved, underscoring the need for novel antibiotics, particularly against methicillin-resistant S. aureus (MRSA). Telavancin is a bactericidal lipoglycopeptide with potent activity against Gram-positive pathogens. OBJECTIVE: To systematically review and synthesize the available evidence from randomized controlled trials (RCTs) evaluating telavancin in the treatment of patients with infections due to Gram-positive organisms with the methodology of meta-analysis. RESULTS: Six RCTs comparing telavancin with vancomycin were included; 4 (2229 patients) referred to complicated skin and soft tissue infections (cSSTIs) and 2 (1503 patients) to hospital-acquired pneumonia (HAP). Regarding cSSTIs, telavancin and vancomycin showed comparable efficacy in clinically evaluable patients (odds ratio [OR] =1.10 [95% confidence intervals: 0.82-1.48]). Among patients with MRSA infection, telavancin showed higher eradication rates (OR=1.71 [1.08-2.70]) and a trend towards better clinical response (OR=1.55 [0.93-2.58]). Regarding HAP, telavancin was non-inferior to vancomycin in terms of clinical response in two Phase III RCTs; mortality rates for the pooled trials were comparable with telavancin (20%) and vancomycin (18.6%). Pooled data from cSSTIs and HAP studies on telavancin 10 mg/kg indicated higher rates of serum creatinine increases (OR=2.22 [1.38-3.57]), serious adverse events (OR=1.53 [1.05-2.24]), and adverse event-related withdrawals (OR=1.49 [1.14-1.95]) among telavancin recipients. CONCLUSION: Telavancin might be an alternative to vancomycin in cases of difficult-to-treat MRSA infections. The potent antistaphylococcal activity of telavancin should be weighted against the potential for nephrotoxicity. PMID- 22916114 TI - Distance walked and run as improved metrics over time-based energy estimation in epidemiological studies and prevention; evidence from medication use. AB - PURPOSE: The guideline physical activity levels are prescribed in terms of time, frequency, and intensity (e.g., 30 minutes brisk walking, five days a week or its energy equivalence) and assume that different activities may be combined to meet targeted goals (exchangeability premise). Habitual runners and walkers may quantify exercise in terms of distance (km/day), and for them, the relationship between activity dose and health benefits may be better assessed in terms of distance rather than time. Analyses were therefore performed to test: 1) whether time-based or distance-based estimates of energy expenditure provide the best metric for relating running and walking to hypertensive, high cholesterol, and diabetes medication use (conditions known to be diminished by exercise), and 2) the exchangeability premise. METHODS: Logistic regression analyses of medication use (dependent variable) vs. metabolic equivalent hours per day (METhr/d) of running, walking and other exercise (independent variables) using cross-sectional data from the National Runners' (17,201 male, 16,173 female) and Walkers' Health Studies (3,434 male, 12,384 female). RESULTS: Estimated METhr/d of running and walking activity were 38% and 31% greater, respectively, when calculated from self-reported time than distance in men, and 43% and 37% greater in women, respectively. Percent reductions in the odds for hypertension and high cholesterol medication use per METhr/d run or per METhr/d walked were >= 2-fold greater when estimated from reported distance (km/wk) than from time (hr/wk). The per METhr/d odds reduction was significantly greater for the distance- than the time-based estimate for hypertension (runners: P<10(-5) for males and P=0.003 for females; walkers: P=0.03 for males and P<10(-4) for females), high cholesterol medication use in runners (P<10(-4) for males and P=0.02 for females) and male walkers (P=0.01 for males and P=0.08 for females) and for diabetes medication use in male runners (P<10(-3)). CONCLUSIONS: Although causality between greater exercise and lower prevalence of hypertension, high cholesterol and diabetes cannot be inferred from these cross-sectional data, the results do suggest that distance-based estimates of METhr/d run or walked provide superior metrics for epidemiological analyses to their traditional time-based estimates. PMID- 22916115 TI - Impact of chromosomal inversions on the yeast DAL cluster. AB - Chromosomal rearrangements occur readily in nature and are a major reshaping force during genome evolution. Such large scale modifications are usually deleterious causing several fitness defects, but sometimes can confer an advantage and become adaptive. For example the DAL metabolic cluster in yeast was assembled in recent evolutionary times in the Hemiascomycetes lineage, through a set of rearrangements that brought together the genes involved in the allantoin degradation pathway. In eukaryotes, the existence of physical clustering of genes with related functions supports the notion that neighbouring ORFs tend to be co expressed and that the order of genes along the chromosomes may have biological significance, rather than being random as previously believed. In this study, we investigate the phenotypic effect that inversions have on the DAL gene cluster, expressed during nitrogen starvation. In all Saccharomyces "sensu stricto" species the order of the DAL cluster is conserved, while in the "sensu lato" species Naumovia castellii, which grows significantly worse than S. cerevisiae on allantoin, the cluster includes two nested inversions encompassing three DAL genes. We constructed several inverted and non-inverted S. cerevisiae strains possessing different inversions including those to mimic the configuration of the N. castellii DAL cluster. We showed that the inversion of DAL2 lower its own expression and reduces yeast fitness during nitrogen starvation. This rearrangement also altered the expression of the neighbouring genes DAL1 and DAL4. Moreover, we showed that the expression of the DAL4 anti-sense transcript (SUT614) does not change upon inversions of DAL2 and therefore is unlikely to be involved in its regulation. These results show that the order of the DAL cluster has an impact on the phenotype and gene expression, suggesting that these rearrangements may have been adaptive in the "sensu stricto" group in relation to the low availability of nitrogen in the environment. PMID- 22916116 TI - Evidence of multiple inseminations in the field in Aedes albopictus. AB - Studies on the biology and mating behaviour of male mosquitoes are of major importance in a frame of a Sterile Insect Technique which could be used against mosquito vector species. Most particularly, the assumption of possible multiple inseminations in mosquito species must be investigated in order to optimize alternative mosquito control methods (Sterile Insect Techniques with genetically modified mosquitoes, cytoplasmic incompatibility, radiation...). The occurrence of multiple insemination events was investigated after 2 field samplings of Aedes albopictus (Diptera: Culicidae) in La Reunion Island using microsatellite markers. Respectively, 14 and 13 females after the first and the second sampling laid eggs. Seven wild females out of the 27 laying females were found with a progeny involving more than one father. This result is important for the new alternative mosquito control methods and raises the importance of pre- and post copulatory competition. PMID- 22916117 TI - High-resolution melting molecular signatures for rapid identification of human papillomavirus genotypes. AB - BACKGROUND: Genotyping of human papillomarvirus (HPV) is crucial for patient management in a clinical setting. This study accesses the combined use of broad range real-time PCR and high-resolution melting (HRM) analysis for rapid identification of HPV genotypes. METHODS: Genomic DNA sequences of 8 high-risk genotypes (HPV16/18/39/45/52/56/58/68) were subject to bioinformatic analysis to select for appropriate PCR amplicon. Asymmetric broad-range real-time PCR in the presence of HRM dye and two unlabeled probes specific to HPV16 and 18 was employed to generate HRM molecular signatures for HPV genotyping. The method was validated via assessment of 119 clinical HPV isolates. RESULTS: A DNA fragment within the L1 region was selected as the PCR amplicon ranging from 215-221 bp for different HPV genotypes. Each genotype displayed a distinct HRM molecular signature with minimal inter-assay variability. According to the HRM molecular signatures, HPV genotypes can be determined with one PCR within 3 h from the time of viral DNA isolation. In the validation assay, a 91% accuracy rate was achieved when the genotypes were in the database. Concomitantly, the HRM molecular signatures for additional 6 low-risk genotypes were established. CONCLUSIONS: This assay provides a novel approach for HPV genotyping in a rapid and cost effective manner. PMID- 22916118 TI - Kinetics of bulge bases in small RNAs and the effect of pressure on it. AB - Due to their self-catalytic properties, small RNAs with bulge bases are hypothesized to be primordial molecules which could form elementary translation systems. Using molecular dynamics simulations, we study the binding propensity of small RNAs by calculating the free energy barrier corresponding to the looped out conformations of bulge bases, which presumably act as the binding sites for ligands in these small RNAs. We find that base flipping kinetics can proceed at atmospheric pressure but with a very small propensity. Furthermore, the free energy barrier associated with base flipping depends on the stacking with neighboring bases. Next, we studied the base flipping kinetics with pressure. We find that the free energy associated with base looping out increases monotonically as the pressure is increased. Furthermore, we calculate the mean first-passage time of conformational looping out of the bulge base using the diffusion of reaction coordinate associated with the base flipping on the underlying free energy surface. We find that the mean first-passage time associated with bulge looping out increases slowly upon increasing pressures P up to 2000 atm but changes dramatically for P>2000 atm. Finally, we discuss our results in the light of the role of hydration shell of water around RNA. Our results are relevant for the RNA world hypothesis. PMID- 22916119 TI - Developing a gene expression model for predicting ventilator-associated pneumonia in trauma patients: a pilot study. AB - BACKGROUND: Ventilator-associated pneumonia (VAP) carries significant mortality and morbidity. Predicting which patients will become infected could lead to measures to reduce the incidence of VAP. METHODOLOGY/PRINCIPAL FINDINGS: The goal was to begin constructing a model for VAP prediction in critically-injured trauma patients, and to identify differentially expressed genes in patients who go on to develop VAP compared to similar patients who do not. Gene expression profiles of lipopolysaccharide stimulated blood cells in critically injured trauma patients that went on to develop ventilator-associated pneumonia (n=10) was compared to those that never developed the infection (n=10). Eight hundred and ten genes were differentially expressed between the two groups (ANOVA, P<0.05) and further analyzed by hierarchical clustering and principal component analysis. Functional analysis using Gene Ontology and KEGG classifications revealed enrichment in multiple categories including regulation of protein translation, regulation of protease activity, and response to bacterial infection. A logistic regression model was developed that accurately predicted critically-injured trauma patients that went on to develop VAP (VAP+) and those that did not (VAP-). Five genes (PIK3R3, ATP2A1, PI3, ADAM8, and HCN4) were common to all top 20 significant genes that were identified from all independent training sets in the cross validation. Hierarchical clustering using these five genes accurately categorized 95% of patients and PCA visualization demonstrated two discernable groups (VAP+ and VAP-). CONCLUSIONS/SIGNIFICANCE: A logistic regression model using cross validation accurately predicted patients that developed ventilator-associated pneumonia and should now be tested on a larger cohort of trauma patients. PMID- 22916121 TI - A small molecule agonist of EphA2 receptor tyrosine kinase inhibits tumor cell migration in vitro and prostate cancer metastasis in vivo. AB - During tumor progression, EphA2 receptor can gain ligand-independent pro oncogenic functions due to Akt activation and reduced ephrin-A ligand engagement. The effects can be reversed by ligand stimulation, which triggers the intrinsic tumor suppressive signaling pathways of EphA2 including inhibition of PI3/Akt and Ras/ERK pathways. These observations argue for development of small molecule agonists for EphA2 as potential tumor intervention agents. Through virtual screening and cell-based assays, we report here the identification and characterization of doxazosin as a novel small molecule agonist for EphA2 and EphA4, but not for other Eph receptors tested. NMR studies revealed extensive contacts of doxazosin with EphA2/A4, recapitulating both hydrophobic and electrostatic interactions recently found in the EphA2/ephrin-A1 complex. Clinically used as an alpha1-adrenoreceptor antagonist (Cardura(r)) for treating hypertension and benign prostate hyperplasia, doxazosin activated EphA2 independent of alpha1-adrenoreceptor. Similar to ephrin-A1, doxazosin inhibited Akt and ERK kinase activities in an EphA2-dependent manner. Treatment with doxazosin triggered EphA2 receptor internalization, and suppressed haptotactic and chemotactic migration of prostate cancer, breast cancer, and glioma cells. Moreover, in an orthotopic xenograft model, doxazosin reduced distal metastasis of human prostate cancer cells and prolonged survival in recipient mice. To our knowledge, doxazosin is the first small molecule agonist of a receptor tyrosine kinase that is capable of inhibiting malignant behaviors in vitro and in vivo. PMID- 22916120 TI - De novo sequencing and characterization of the floral transcriptome of Dendrocalamus latiflorus (Poaceae: Bambusoideae). AB - BACKGROUND: Transcriptome sequencing can be used to determine gene sequences and transcript abundance in non-model species, and the advent of next-generation sequencing (NGS) technologies has greatly decreased the cost and time required for this process. Transcriptome data are especially desirable in bamboo species, as certain members constitute an economically and culturally important group of mostly semelparous plants with remarkable flowering features, yet little bamboo genomic research has been performed. Here we present, for the first time, extensive sequence and transcript abundance data for the floral transcriptome of a key bamboo species, Dendrocalamus latiflorus, obtained using the Illumina GAII sequencing platform. Our further goal was to identify patterns of gene expression during bamboo flower development. RESULTS: Approximately 96 million sequencing reads were generated and assembled de novo, yielding 146,395 high quality unigenes with an average length of 461 bp. Of these, 80,418 were identified as putative homologs of annotated sequences in the public protein databases, of which 290 were associated with the floral transition and 47 were related to flower development. Digital abundance analysis identified 26,529 transcripts differentially enriched between two developmental stages, young flower buds and older developing flowers. Unigenes found at each stage were categorized according to their putative functional categories. These sequence and putative function data comprise a resource for future investigation of the floral transition and flower development in bamboo species. CONCLUSIONS: Our results present the first broad survey of a bamboo floral transcriptome. Although it will be necessary to validate the functions carried out by these genes, these results represent a starting point for future functional research on D. latiflorus and related species. PMID- 22916122 TI - Reduced set of virulence genes allows high accuracy prediction of bacterial pathogenicity in humans. AB - Although there have been great advances in understanding bacterial pathogenesis, there is still a lack of integrative information about what makes a bacterium a human pathogen. The advent of high-throughput sequencing technologies has dramatically increased the amount of completed bacterial genomes, for both known human pathogenic and non-pathogenic strains; this information is now available to investigate genetic features that determine pathogenic phenotypes in bacteria. In this work we determined presence/absence patterns of 814 different virulence related genes among more than 600 finished bacterial genomes from both human pathogenic and non-pathogenic strains, belonging to different taxonomic groups (i.e: Actinobacteria, Gammaproteobacteria, Firmicutes, etc.). An accuracy of 95% using a cross-fold validation scheme with in-fold feature selection is obtained when classifying human pathogens and non-pathogens. A reduced subset of highly informative genes (120) is presented and applied to an external validation set. The statistical model was implemented in the BacFier v1.0 software (freely available at http : ==bacfier:googlecode:com=files=Bacfier v1 0:zip), that displays not only the prediction (pathogen/non-pathogen) and an associated probability for pathogenicity, but also the presence/absence vector for the analyzed genes, so it is possible to decipher the subset of virulence genes responsible for the classification on the analyzed genome. Furthermore, we discuss the biological relevance for bacterial pathogenesis of the core set of genes, corresponding to eight functional categories, all with evident and documented association with the phenotypes of interest. Also, we analyze which functional categories of virulence genes were more distinctive for pathogenicity in each taxonomic group, which seems to be a completely new kind of information and could lead to important evolutionary conclusions. PMID- 22916123 TI - Associations between purine metabolites and clinical symptoms in schizophrenia. AB - BACKGROUND: The antioxidant defense system, which is known to be dysregulated in schizophrenia, is closely linked to the dynamics of purine pathway. Thus, alterations in the homeostatic balance in the purine pathway may be involved in the pathophysiology of schizophrenia. METHODOLOGY/PRINCIPAL FINDINGS: Breakdown products in purine pathway were measured using high-pressure liquid chromatography coupled with a coulometric multi-electrode array system for 25 first-episode neuroleptic-naive patients with schizophrenia at baseline and at 4 weeks following initiation of treatment with antipsychotic medication. Associations between these metabolites and clinical and neurological symptoms were examined at both time points. The ratio of uric acid and guanine measured at baseline predicted clinical improvement following four weeks of treatment with antipsychotic medication. Baseline levels of purine metabolites also predicted clinical and neurological symtpoms recorded at baseline; level of guanosine was associated with degree of clinical thought disturbance, and the ratio of xanthosine to guanosine at baseline predicted degree of impairment in the repetition and sequencing of actions. CONCLUSIONS/SIGNIFICANCE: Findings suggest an association between optimal levels of purine byproducts and dynamics in clinical symptoms and adjustment, as well as in the integrity of sensory and motor processing. Taken together, alterations in purine catabolism may have clinical relevance in schizophrenia pathology. PMID- 22916125 TI - ASSIST applicability scoring of surgical trials. an investigator-reported assessment tool. AB - CONTEXT: We aimed to develop a new tool for assessing and depicting the applicability of the results of surgical randomized controlled trials (RCTs) from the trial investigators' perspective. METHODS: We identified all items related to applicability by a systematic methodological review, and then a sample of surgeons used these items in a web-based survey to evaluate the applicability of their own trial results. For each applicability item, participants had to indicate on a numerical scale that was simplified as a three-item scale: 1) items essential to consider, 2) items requiring attention, and 3) items inconsequential to the applicability of the results of their own RCT to clinical practice. For the final tool, we selected only items that were rated as being essential or requiring attention for at least 25% of the trials evaluated. We propose a specific process to construct the tool and to depict applicability in a graph. We identified all investigators of published and registered ongoing RCTs assessing surgery and invited them to participate in the web-based survey. RESULTS: 148 surgeons assessed applicability for their own trial and participated in the process of item selection. The final tool contains 22 items (4 dedicated to patients, 5 to centers, 5 to surgeons and 8 to the intervention). We proposed a straightforward process of constructing the graphical tool: 1) a multidisciplinary team of investigators or other care providers participating in the trial could independently assess each item, 2) a consensus method could be used, and 3) the investigators could depict their assessment of the applicability of the trial results in 4 graphs related to patients, centers, surgeons and the intervention. CONCLUSIONS: This investigator-reported assessment tool could help readers define under what conditions they could reasonably apply the results of a surgical RCT to their clinical practice. PMID- 22916124 TI - HTLV-I tax increases genetic instability by inducing DNA double strand breaks during DNA replication and switching repair to NHEJ. AB - BACKGROUND: Appropriate responses to damaged DNA are indispensible for preserving genome stability and preventing cancer. Tumor viruses often target DNA repair machinery to achieve transformation. The Human T-cell leukemia virus type I (HTLV I) is the only known transforming human retrovirus and the etiological agent of Adult T-cell Leukemia (ATLL). Although HTLV-I-transformed leukemic cells have numerous genetic lesions, the precise role of the viral tax gene in this process is not fully understood. RESULTS: Our results show a novel function of HTLV-I oncoprotein Tax as an inducer of genomic DNA double strand breaks (DDSB) during DNA replication. We also found that Tax acts as a potent inhibitor of homologous recombination (HR) DNA repair through the activation of the NF-kB pathway. These results were confirmed using HTLV-I molecular clones expressing Tax at physiological levels in a natural context. We further found that HTLV-I- and Tax transformed cells are not more susceptible to DNA damaging agents and repair DNA lesions at a rate similar to that of normal cells. Finally, we demonstrated that during S phase, Tax-associated DDSB are preferentially repaired using the error prone non-homologous end joining (NHEJ) pathway. CONCLUSIONS: This study provides new insights in Tax effects on DNA repair and genome instability. Although it may not be self sufficient, the creation of DNA breaks and subsequent abnormal use of the non-conservative NHEJ DNA repair during the S phase in HTLV-I-infected Tax expressing cells may cooperate with other factors to increase genetic and genome instability and favor transformation. PMID- 22916126 TI - Inference of causal networks from time-varying transcriptome data via sparse coding. AB - Temporal analysis of genome-wide data can provide insights into the underlying mechanism of the biological processes in two ways. First, grouping the temporal data provides a richer, more robust representation of the underlying processes that are co-regulated. The net result is a significant dimensional reduction of the genome-wide array data into a smaller set of vocabularies for bioinformatics analysis. Second, the computed set of time-course vocabularies can be interrogated for a potential causal network that can shed light on the underlying interactions. The method is coupled with an experiment for investigating responses to high doses of ionizing radiation with and without a small priming dose. From a computational perspective, inference of a causal network can rapidly become computationally intractable with the increasing number of variables. Additionally, from a bioinformatics perspective, larger networks always hinder interpretation. Therefore, our method focuses on inferring the simplest network that is computationally tractable and interpretable. The method first reduces the number of temporal variables through consensus clustering to reveal a small set of temporal templates. It then enforces simplicity in the network configuration through the sparsity constraint, which is further regularized by requiring continuity between consecutive time points. We present intermediate results for each computational step, and apply our method to a time-course transcriptome dataset for a cell line receiving a challenge dose of ionizing radiation with and without a prior priming dose. Our analyses indicate that (i) the priming dose increases the diversity of the computed templates (e.g., diversity of transcriptome signatures); thus, increasing the network complexity; (ii) as a result of the priming dose, there are a number of unique templates with delayed and oscillatory profiles; and (iii) radiation-induced stress responses are enriched through pathway and subnetwork studies. PMID- 22916127 TI - Dominant negative effect of mutated thyroid stimulating hormone receptor (P556L) causes hypothyroidism in C.RF-Tshr(hyt/wild) mice. AB - C.RF-Tshr(hyt/hyt) mice have a mutated thyroid stimulating hormone receptor (P556L-TSHR) and these mice develop severe hypothyroidism. We found that C.RF Tshr(hyt/wild) heterozygous mice are also in a hypothyroid state. Thyroid glands from C.RF-Tshr(hyt/wild) mice are smaller than those from wild-type mice, and (125)I uptake activities of the former are significantly lower than those in the latter. When TSHR (TSHR(W)) and P556L-TSHR (TSHR(M)) cDNAs were cloned and co transfected into HEK 293 cells, the cells retained (125)I-TSH binding activity, but cAMP response to TSH was decreased to about 20% of HEK 293 cells transfected with TSHR(W) cDNA. When TSHR(W) and TSHR(M) were tagged with eCFP or eYFP, we observed fluorescence resonance energy transfer (FRET) in HEK 293 cells expressing TSHR(W)-eCFP and TSHR(W)-eYFP in the absence of TSH, but not in the presence of TSH. In contrast, we obtained FRET in HEK 293 cells expressing TSHR(W)-eCFP and TSHR (M)-eYFP, regardless of the presence or absence of TSH. These results suggest that P556L TSHR has a dominant negative effect on TSHR(W) by impairing polymer to monomer dissociation, which decreases TSH responsiveness and induces hypothyroidism in C.RF-Tshr(hyt/wild) mice. PMID- 22916128 TI - Prenatal ethanol exposure alters synaptic plasticity in the dorsolateral striatum of rat offspring via changing the reactivity of dopamine receptor. AB - Prenatal exposure to high-level ethanol (EtOH) has been reported to produce hyperlocomotion in offspring. Previous studies have demonstrated synaptic plasticity in cortical afferent to the dorsolateral (DL) striatum is involved in the pathogensis of hyperlocomotion. Here, prenatal EtOH-exposed rat offspring were used to investigate whether maternal EtOH exposure affected synaptic plasticity in the DL striatum. We found high-frequency stimulation (HFS) induced a weaker long-term potentiation (LTP) in EtOH rats than that in control rats at postnatal day (PD) 15. The same protocol of HFS induced long-term depression (LTD) in control group but still LTP in EtOH group at PD 30 or PD 40. Furthermore, enhancement of basal synaptic transmission accompanied by the decrease of pair-pulse facilitation (PPF) was observed in PD 30 EtOH offspring. The perfusion with D1-type receptors (D1R) antagonist SCH23390 recovered synaptic transmission and blocked the induction of abnormal LTP in PD 30 EtOH offspring. The perfusion with D2-type receptors (D2R) agonist quinpirole reversed EtOH induced LTP into D1R- and metabotropic glutamate receptor-dependent LTD. The data provide the functional evidence that prenatal ethanol exposure led to the persistent abnormal synaptic plasticity in the DL striatum via disturbing the balance between D1R and D2R. PMID- 22916129 TI - Recombinant interferon-gamma lentivirus co-infection inhibits adenovirus replication ex vivo. AB - Recombinant interferon-gamma (IFNgamma) production in cultured lentivirus (LV) was explored for inhibition of target virus in cells co-infected with adenovirus type 5 (Ad5). The ability of three different promoters of CMV, EF1alpha and Ubiquitin initiating the enhanced green fluorescence protein (GFP) activities within lentiviruses was systematically assessed in various cell lines, which showed that certain cell lines selected the most favorable promoter driving a high level of transgenic expression. Recombinant IFNgamma lentivirus carrying CMV promoter (LV-CMV-IFNgamma) was generated to co-infect 293A cells with a viral surrogate of recombinant GFP Ad5 in parallel with LV-CMV-GFP control. The best morphologic conditions were observed from the two lentiviruses co-infected cells, while single adenovirus infected cells underwent clear pathologic changes. Viral load of adenoviruses from LV-CMV-IFNgamma or LV-CMV-GFP co-infected cell cultures was significantly lower than that from adenovirus alone infected cells (P=0.005 0.041), and the reduction of adenoviral load in the co-infected cells was 86% and 61%, respectively. Ad5 viral load from LV-CMV-IFNgamma co-infected cells was significantly lower than that from LV-CMV-GFP co-infection (P=0.032), which suggested that IFNgamma rather than GFP could further enhance the inhibition of Ad5 replication in the recombinant lentivirus co-infected cells. The results suggest that LV-CMV-IFNgamma co-infection could significantly inhibit the target virus replication and might be a potential approach for alternative therapy of severe viral diseases. PMID- 22916130 TI - Giving the giggles: prediction, intervention, and young children's representation of psychological events. AB - Adults recognize that if event A predicts event B, intervening on A might generate B. Research suggests that young children have difficulty making this inference unless the events are initiated by goal-directed actions [1]. The current study tested the domain-generality and development of this phenomenon. Replicating previous work, when the events involved a physical outcome, toddlers (mean: 24 months) failed to generalize the outcome of spontaneously occurring predictive events to their own interventions; toddlers did generalize from prediction to intervention when the events involved a psychological outcome. We discuss these findings as they bear on the development of causal concepts. PMID- 22916131 TI - Use of national and international growth charts for studying height in European children: development of up-to-date European height-for-age charts. AB - BACKGROUND: Growth charts based on data collected in different populations and time periods are key tools to assess children's linear growth. We analyzed the impact of geographic factors and the secular trend on height-for-age charts currently used in European populations, developed up-to-date European growth charts, and studied the effect of using different charts in a sample of growth retarded children. METHODS AND FINDINGS: In an international survey we obtained 18 unique national height-for-age charts from 28 European countries and compared them with charts from the World Health Organization (WHO), Euro-Growth reference, and Centers of Disease Control and Prevention (CDC). As an example, we obtained height data from 3,534 children with end-stage renal disease (ESRD) from 13 countries via the ESPN/ERA-EDTA registry, a patient group generally suffering from growth retardation. National growth charts showed a clear secular trend in height (mean height increased on average 0.6 cm/decade) and a North-South height gradient in Europe. For countries without a recent (>1990) national growth chart novel European growth charts were constructed from Northern and Southern European reference populations, reflecting geographic height differences in mean final height of 3.9 cm in boys and 3.8 cm in girls. Mean height SDS of 2- to 17-year old ESRD patients calculated from recent national or derived European growth charts (-1.91, 95% CI: -1.97 to -1.85) was significantly lower than when using CDC or WHO growth charts (-1.55, 95% CI: -1.61 to -1.49) (P<0.0001). CONCLUSION: Differences between height-for-age charts may reflect true population differences, but are also strongly affected by the secular trend in height. The choice of reference charts substantially affects the clinical decision whether a child is considered short-for-age. Therefore, we advocate using recent national or European height-for-age charts derived from recent national data when monitoring growth of healthy and diseased European children. PMID- 22916132 TI - The transmembrane domains of TNF-related apoptosis-inducing ligand (TRAIL) receptors 1 and 2 co-regulate apoptotic signaling capacity. AB - TNF-related apoptosis-inducing ligand (TRAIL) is a member of the tumor necrosis factor (TNF) ligand family that exerts its apoptotic activity in human cells by binding to two transmembrane receptors, TRAILR1 and TRAILR2. In cells co expressing both receptors the particular contribution of either protein to the overall cellular response is not well defined. Here we have investigated whether differences in the signaling capacities of TRAILR1 and TRAILR2 can be attributed to certain functional molecular subdomains. We generated and characterized various chimeric receptors comprising TRAIL receptor domains fused with parts from other members of the TNF death receptor family. This allowed us to compare the contribution of particular domains of the two TRAIL receptors to the overall apoptotic response and to identify elements that regulate apoptotic signaling. Our results show that the TRAIL receptor death domains are weak apoptosis inducers compared to those of CD95/Fas, because TRAILR-derived constructs containing the CD95/Fas death domain possessed strongly enhanced apoptotic capabilities. Importantly, major differences in the signaling strengths of the two TRAIL receptors were linked to their transmembrane domains in combination with the adjacent extracellular stalk regions. This was evident from receptor chimeras comprising the extracellular part of TNFR1 and the intracellular signaling part of CD95/Fas. Both receptor chimeras showed comparable ligand binding affinities and internalization kinetics. However, the respective TRAILR2 derived molecule more efficiently induced apoptosis. It also activated caspase-8 and caspase-3 more strongly and more quickly, albeit being expressed at lower levels. These results suggest that the transmembrane domains together with their adjacent stalk regions can play a major role in control of death receptor activation thereby contributing to cell type specific differences in TRAILR1 and TRAILR2 signaling. PMID- 22916133 TI - Genetic and environmental factors influencing the Placental Growth Factor (PGF) variation in two populations. AB - Placental Growth Factor (PGF) is a key molecule in angiogenesis. Several studies have revealed an important role of PGF primarily in pathological conditions (e.g.: ischaemia, tumour formation, cardiovascular diseases and inflammatory processes) suggesting its use as a potential therapeutic agent. However, to date, no information is available regarding the genetics of PGF variability. Furthermore, even though the effect of environmental factors (e.g.: cigarette smoking) on angiogenesis has been explored, no data on the influence of these factors on PGF levels have been reported so far. Here we have first investigated PGF variability in two cohorts focusing on non-genetic risk factors: a study sample from two isolated villages in the Cilento region, South Italy (N=871) and a replication sample from the general Danish population (N=1,812). A significant difference in PGF mean levels was found between the two cohorts. However, in both samples, we observed a strong correlation of PGF levels with ageing and sex, men displaying PGF levels significantly higher than women. Interestingly, smoking was also found to influence the trait in the two populations, although differently. We have then focused on genetic risk factors. The association between five single nucleotide polymorphisms (SNPs) located in the PGF gene and the plasma levels of the protein was investigated. Two polymorphisms (rs11850328 and rs2268614) were associated with the PGF plasma levels in the Cilento sample and these associations were strongly replicated in the Danish sample. These results, for the first time, support the hypothesis of the presence of genetic and environmental factors influencing PGF plasma variability. PMID- 22916134 TI - Rho GTPase expression in human myeloid cells. AB - Myeloid cells are critical for innate immunity and the initiation of adaptive immunity. Strict regulation of the adhesive and migratory behavior is essential for proper functioning of these cells. Rho GTPases are important regulators of adhesion and migration; however, it is unknown which Rho GTPases are expressed in different myeloid cells. Here, we use a qPCR-based approach to investigate Rho GTPase expression in myeloid cells.We found that the mRNAs encoding Cdc42, RhoQ, Rac1, Rac2, RhoA and RhoC are the most abundant. In addition, RhoG, RhoB, RhoF and RhoV are expressed at low levels or only in specific cell types. More differentiated cells along the monocyte-lineage display lower levels of Cdc42 and RhoV, while RhoC mRNA is more abundant. In addition, the Rho GTPase expression profile changes during dendritic cell maturation with Rac1 being upregulated and Rac2 downregulated. Finally, GM-CSF stimulation, during macrophage and osteoclast differentiation, leads to high expression of Rac2, while M-CSF induces high levels of RhoA, showing that these cytokines induce a distinct pattern. Our data uncover cell type specific modulation of the Rho GTPase expression profile in hematopoietic stem cells and in more differentiated cells of the myeloid lineage. PMID- 22916135 TI - Usual populations, unusual individuals: insights into the behavior and management of Asian elephants in fragmented landscapes. AB - BACKGROUND: A dearth in understanding the behavior of Asian elephants (Elephas maximus) at the scale of populations and individuals has left important management issues, particularly related to human-elephant conflict (HEC), unresolved. Evaluation of differences in behavior and decision-making among individual elephants across groups in response to changing local ecological settings is essential to fill this gap in knowledge and to improve our approaches towards the management and conservation of elephants. METHODOLOGY/PRINCIPAL FINDINGS: We hypothesized certain behavioral decisions that would be made by Asian elephants as reflected in their residence time and movement rates, time activity budgets, social interactions and group dynamics in response to resource availability and human disturbance in their habitat. This study is based on 200 h of behavioral observations on 60 individually identified elephants and a 184 km(2) grid-based survey of their natural and anthropogenic habitats within and outside the Bannerghatta National Park, southern India during the dry season. At a general population level, the behavioral decisions appeared to be guided by the gender, age and group-type of the elephants. At the individual level, the observed variation could be explained only by the idiosyncratic behaviors of individuals and that of their associating conspecific individuals. Recursive partitioning classification trees for residence time of individual elephants indicated that the primary decisions were taken by individuals, independently of their above-mentioned biological and ecological attributes. CONCLUSIONS/SIGNIFICANCE: Decision-making by Asian elephants thus appears to be determined at two levels, that of the population and, more importantly, the individual. Models based on decision-making by individual elephants have the potential to predict conflict in fragmented landscapes that, in turn, could aid in mitigating HEC. Thus, we must target individuals, in addition to populations, in our efforts to manage and conserve this threatened species, particularly in human-dominated landscapes. PMID- 22916137 TI - Predictors and prevalence of latent tuberculosis infection in patients receiving long-term hemodialysis and peritoneal dialysis. AB - BACKGROUND: Tuberculosis is a common infectious disease in long-term dialysis patients. The prevalence of latent tuberculosis infection (LTBI) in this population is unclear, particularly in those receiving peritoneal dialysis (PD). This study investigated the prevalence of LTBI in patients receiving either hemodialysis (HD) or PD to determine predictors of LTBI and indeterminate results of interferon-gamma release assay. METHODS: Patients receiving long-term (>= 3 months) HD or PD from March 2011 to February 2012 in two medical centers were prospectively enrolled. QuantiFERON-Gold in tube (QFT) test was used to determine the status of LTBI after excluding active tuberculosis. The LTBI prevalence was determined in patients receiving different dialysis modes to obtain predictors of LTBI and QFT-indeterminate results. RESULTS: Of 427 patients enrolled (124 PD and 303 HD), 91 (21.3%) were QFT-positive, 316 (74.0%) QFT-negative, and 20 (4.7%) QFT-indeterminate. The prevalence of LTBI was similar in the PD and HD groups. Independent predictors of LTBI were old age (OR: 1.034 [1.013-1.056] per year increment), TB history (OR: 6.467 [1.985-21.066]), and current smoker (OR: 2.675 [1.061-6.747]). Factors associated with indeterminate QFT results were HD (OR: 10.535 [1.336-83.093]), dialysis duration (OR: 1.113 [1.015-1.221] per year increment), anemia (OR: 8.760 [1.014-75.651]), and serum albumin level (OR: 0.244 [0.086-0.693] per 1 g/dL increment). CONCLUSION: More than one-fifth of dialysis patients have LTBI. The LTBI prevalence is similar in PD and HD patients but is higher in the elderly, current smokers, and those with prior TB history. Such patients require closer follow-up. Repeated or alternative test may be required for malnutrition patients who received long length of HD. PMID- 22916136 TI - Comparative analysis of zinc finger proteins involved in plant disease resistance. AB - A meta-analysis was performed to understand the role of zinc finger domains in proteins of resistance (R) genes cloned from different crops. We analyzed protein sequences of seventy R genes of various crops in which twenty six proteins were found to have zinc finger domains along with nucleotide binding sites - leucine rice repeats (NBS-LRR) domains. We identified thirty four zinc finger domains in the R proteins of nine crops and were grouped into 19 types of zinc fingers. The size of individual zinc finger domain within the R genes varied from 11 to 84 amino acids, whereas the size of proteins containing these domains varied from 263 to 1305 amino acids. The biophysical analysis revealed that molecular weight of Pi54 zinc finger was lowest whereas the highest one was found in rice Pib zinc finger named as Transposes Transcription Factor (TTF). The instability (R(2) =0.95) and the aliphatic (R(2) =0.94) indices profile of zinc finger domains follows the polynomial distribution pattern. The pairwise identity analysis showed that the Lin11, Isl-1 & Mec-3 (LIM) zinc finger domain of rice blast resistance protein pi21 have 12.3% similarity with the nuclear transcription factor, X-box binding-like 1 (NFX) type zinc finger domain of Pi54 protein. For the first time, we reported that Pi54 (Pi-k(h)-Tetep), a rice blast resistance (R) protein have a small zinc finger domain of NFX type located on the C-terminal in between NBS and LRR domains of the R-protein. Compositional analysis depicted by the helical wheel diagram revealed the presence of a hydrophobic region within this domain which might help in exposing the LRR region for a possible R-Avr interaction. This domain is unique among all other cloned plant disease resistance genes and might play an important role in broad-spectrum nature of rice blast resistance gene Pi54. PMID- 22916138 TI - Role of structure and glycosylation of adsorbed protein films in biolubrication. AB - Water forms the basis of lubrication in the human body, but is unable to provide sufficient lubrication without additives. The importance of biolubrication becomes evident upon aging and disease, particularly under conditions that affect secretion or composition of body fluids. Insufficient biolubrication, may impede proper speech, mastication and swallowing, underlie excessive friction and wear of articulating cartilage surfaces in hips and knees, cause vaginal dryness, and result in dry, irritated eyes. Currently, our understanding of biolubrication is insufficient to design effective therapeutics to restore biolubrication. Aim of this study was to establish the role of structure and glycosylation of adsorbed protein films in biolubrication, taking the oral cavity as a model and making use of its dynamics with daily perturbations due to different glandular secretions, speech, drinking and eating, and tooth brushing. Using different surface analytical techniques (a quartz crystal microbalance with dissipation monitoring, colloidal probe atomic force microscopy, contact angle measurements and X-ray photo-electron spectroscopy), we demonstrated that adsorbed salivary conditioning films in vitro are more lubricious when their hydrophilicity and degree of glycosylation increase, meanwhile decreasing their structural softness. High molecular-weight, glycosylated proteins adsorbing in loops and trains, are described as necessary scaffolds impeding removal of water during loading of articulating surfaces. Comparing in vitro and in vivo water contact angles measured intra-orally, these findings were extrapolated to the in vivo situation. Accordingly, lubricating properties of teeth, as perceived in 20 volunteers comprising of equal numbers of male and female subjects, could be related with structural softness and glycosylation of adsorbed protein films on tooth surfaces. Summarizing, biolubrication is due to a combination of structure and glycosylation of adsorbed protein films, providing an important clue to design effective therapeutics to restore biolubrication in patients with insufficient biolubrication. PMID- 22916139 TI - Abnormal neural responses to social exclusion in schizophrenia. AB - Social exclusion is an influential concept in politics, mental health and social psychology. Studies on healthy subjects have implicated the medial prefrontal cortex (mPFC), a region involved in emotional and social information processing, in neural responses to social exclusion. Impairments in social interactions are common in schizophrenia and are associated with reduced quality of life. Core symptoms such as delusions usually have a social content. However little is known about the neural underpinnings of social abnormalities. The aim of this study was to investigate the neural substrates of social exclusion in schizophrenia. Patients with schizophrenia and healthy controls underwent fMRI while participating in a popular social exclusion paradigm. This task involves passing a 'ball' between the participant and two cartoon representations of other subjects. The extent of social exclusion (ball not being passed to the participant) was parametrically varied throughout the task. Replicating previous findings, increasing social exclusion activated the mPFC in controls. In contrast, patients with schizophrenia failed to modulate mPFC responses with increasing exclusion. Furthermore, the blunted response to exclusion correlated with increased severity of positive symptoms. These data support the hypothesis that the neural response to social exclusion differs in schizophrenia, highlighting the mPFC as a potential substrate of impaired social interactions. PMID- 22916140 TI - Defensive medicine in Israel - a nationwide survey. AB - BACKGROUND: Defensive medicine is the practice of diagnostic or therapeutic measures conducted primarily as a safeguard against possible malpractice liability. We studied the extent, reasons, and characteristics of defensive medicine in the Israeli health care system. METHODS AND FINDINGS: Cross-sectional study performed in the Israeli health care system between April and July 2008 in a sample (7%) of board certified physicians from eight medical disciplines (internal medicine, pediatrics, general surgery, family medicine, obstetrics and gynecology, orthopedic surgery, cardiology, and neurosurgery). A total of 889 physicians (7% of all Israeli board certified specialists) completed the survey. The majority [60%, (95%CI 0.57-0.63)] reported practicing defensive medicine; 40% (95%CI 0.37-0.43) consider every patient as a potential threat for a medical lawsuit; 25% (95%CI 0.22-0.28) have previously been sued at least once during their career. Independent predictors for practicing defensive medicine were surgical specialty [OR=1.6 (95%CI 1.2-2.2), p=0.0004], not performing a fellowship abroad [OR=1.5 (95%CI 1.1-2), p=0.027], and previous exposure to lawsuits [OR=2.4 (95%CI 1.7-3.4), p<0.0001]. Independent predictors for the risk of being sued during a physician's career were male gender [OR=1.6 (95%CI 1.1 2.2), p=0.012] and surgery specialty [OR=3.2 (95%CI 2.4-4.3), p<0.0001] (general surgery, obstetrics and gynecology, orthopedic surgery, and neurosurgery). CONCLUSIONS: Defensive medicine is very prevalent in daily physician practice in all medical disciplines. It exposes patients to complications due to unnecessary tests and procedures, affects quality of care and costs, and undermines doctor patient relationships. Further studies are needed to understand how to minimize defensive medicine resulting from an increased malpractice liability market. PMID- 22916142 TI - Growth decline linked to warming-induced water limitation in hemi-boreal forests. AB - Hemi-boreal forests, which make up the transition from temperate deciduous forests to boreal forests in southern Siberia, have experienced significant warming without any accompanying increase in precipitation during the last 80 years. This climatic change could have a profound impact on tree growth and on the stability of forest ecosystems in this region, but at present evidence for these impacts is lacking. In this study, we report a recent dramatic decline in the growth of hemi-boreal forests, based on ring width measurements from three dominant tree-species (Pinus sylvestris, Larix sibirica and Larix gmelinii), sampled from eight sites in the region. We found that regional tree growth has become increasingly limited by low soil water content in the pre- and early growing season (from October of the previous year to July of the current year) over the past 80 years. A warming-induced reduction in soil water content has also increased the climate sensitivity of these three tree species. Beginning in the mid-1980s, a clear decline in growth is evident for both the pine forests and the larch forests, although there are increasing trends in the proxy of soil water use efficiencies. Our findings are consistent with those from other parts of the world and provide valuable insights into the regional carbon cycle and vegetation dynamics, and should be useful for devising adaptive forest management strategies. PMID- 22916141 TI - Human neural stem cell replacement therapy for amyotrophic lateral sclerosis by spinal transplantation. AB - BACKGROUND: Mutation in the ubiquitously expressed cytoplasmic superoxide dismutase (SOD1) causes an inherited form of Amyotrophic Lateral Sclerosis (ALS). Mutant synthesis in motor neurons drives disease onset and early disease progression. Previous experimental studies have shown that spinal grafting of human fetal spinal neural stem cells (hNSCs) into the lumbar spinal cord of SOD1(G93A) rats leads to a moderate therapeutical effect as evidenced by local alpha-motoneuron sparing and extension of lifespan. The aim of the present study was to analyze the degree of therapeutical effect of hNSCs once grafted into the lumbar spinal ventral horn in presymptomatic immunosuppressed SOD1(G93A) rats and to assess the presence and functional integrity of the descending motor system in symptomatic SOD1(G93A) animals. METHODS/PRINCIPAL FINDINGS: Presymptomatic SOD1(G93A) rats (60-65 days old) received spinal lumbar injections of hNSCs. After cell grafting, disease onset, disease progression and lifespan were analyzed. In separate symptomatic SOD1(G93A) rats, the presence and functional conductivity of descending motor tracts (corticospinal and rubrospinal) was analyzed by spinal surface recording electrodes after electrical stimulation of the motor cortex. Silver impregnation of lumbar spinal cord sections and descending motor axon counting in plastic spinal cord sections were used to validate morphologically the integrity of descending motor tracts. Grafting of hNSCs into the lumbar spinal cord of SOD1(G93A) rats protected alpha-motoneurons in the vicinity of grafted cells, provided transient functional improvement, but offered no protection to alpha-motoneuron pools distant from grafted lumbar segments. Analysis of motor-evoked potentials recorded from the thoracic spinal cord of symptomatic SOD1(G93A) rats showed a near complete loss of descending motor tract conduction, corresponding to a significant (50-65%) loss of large caliber descending motor axons. CONCLUSIONS/SIGNIFICANCE: These data demonstrate that in order to achieve a more clinically-adequate treatment, cell replacement/gene therapy strategies will likely require both spinal and supraspinal targets. PMID- 22916143 TI - Autotaxin-lysophosphatidic acid axis is a novel molecular target for lowering intraocular pressure. AB - Primary open-angle glaucoma is the second leading cause of blindness in the United States and is commonly associated with elevated intraocular pressure (IOP) resulting from diminished aqueous humor (AH) drainage through the trabecular pathway. Developing effective therapies for increased IOP in glaucoma patients requires identification and characterization of molecular mechanisms that regulate IOP and AH outflow. This study describes the identification and role of autotaxin (ATX), a secretory protein and a major source for extracellular lysophosphatidic acid (LPA), in regulation of IOP in a rabbit model. Quantitative proteomics analysis identified ATX as an abundant protein in both human AH derived from non-glaucoma subjects and in AH from different animal species. The lysophospholipase D (LysoPLD) activity of ATX was found to be significantly elevated (by ~1.8 fold; n=20) in AH derived from human primary open angle glaucoma patients as compared to AH derived from age-matched cataract control patients. Immunoblotting analysis of conditioned media derived from primary cultures of human trabecular meshwork (HTM) cells has confirmed secretion of ATX and the ability of cyclic mechanical stretch of TM cells to increase the levels of secreted ATX. Topical application of a small molecular chemical inhibitor of ATX (S32826), which inhibited AH LysoPLD activity in vitro (by >90%), led to a dose-dependent and significant decrease of IOP in Dutch-Belted rabbits. Single intracameral injection of S32826 (~2 uM) led to significant reduction of IOP in rabbits, with the ocular hypotensive response lasting for more than 48 hrs. Suppression of ATX expression in HTM cells using small-interfering RNA (siRNA) caused a decrease in actin stress fibers and myosin light chain phosphorylation. Collectively, these observations indicate that the ATX-LPA axis represents a potential therapeutic target for lowering IOP in glaucoma patients. PMID- 22916144 TI - The genus Cecropia: a biological clock to estimate the age of recently disturbed areas in the Neotropics. AB - Forest successional processes following disturbance take decades to play out, even in tropical forests. Nonetheless, records of vegetation change in this ecosystem are scarce, increasing the importance of the chronosequence approach to study forest recovery. However, this approach requires accurate dating of secondary forests, which until now was a difficult and/or expensive task. Cecropia is a widespread and abundant pioneer tree genus of the Neotropics. Here we propose and validate a rapid and straightforward method to estimate the age of secondary forest patches based on morphological observations of Cecropia trees. We found that Cecropia-inferred ages were highly correlated with known ages of the forest. We also demonstrate that Cecropia can be used to accurately date disturbances and propose twenty-one species distributed all over the geographical range of the genus as potential secondary forest chronometer species. Our method is limited in applicability by the maximal longevity of Cecropia individuals. Although the oldest chronosequence used in this study was 20 years old, we argue that at least for the first four decades after disturbance, the method described in this study provides very accurate estimations of secondary forest ages. The age of pioneer trees provides not only information needed to calculate the recovery of carbon stocks that would help to improve forest management, but also provides information needed to characterize the initial floristic composition and the rates of species remigration into secondary forest. Our contribution shows how successional studies can be reliably and inexpensively extended without the need to obtain forest ages based on expensive or potentially inaccurate data across the Neotropics. PMID- 22916145 TI - Efficacy of a novel class of RNA interference therapeutic agents. AB - RNA interference (RNAi) is being widely used in functional gene research and is an important tool for drug discovery. However, canonical double-stranded short interfering RNAs are unstable and induce undesirable adverse effects, and thus there is no currently RNAi-based therapy in the clinic. We have developed a novel class of RNAi agents, and evaluated their effectiveness in vitro and in mouse models of acute lung injury (ALI) and pulmonary fibrosis. The novel class of RNAi agents (nkRNA(r), PnkRNATM) were synthesized on solid phase as single-stranded RNAs that, following synthesis, self-anneal into a unique helical structure containing a central stem and two loops. They are resistant to degradation and suppress their target genes. nkRNA and PnkRNA directed against TGF-beta1mRNA ameliorate outcomes and induce no off-target effects in three animal models of lung disease. The results of this study support the pathological relevance of TGF beta1 in lung diseases, and suggest the potential usefulness of these novel RNAi agents for therapeutic application. PMID- 22916146 TI - Iron status predicts malaria risk in Malawian preschool children. AB - INTRODUCTION: Iron deficiency is highly prevalent in pre-school children in developing countries and an important health problem in sub-Saharan Africa. A debate exists on the possible protective effect of iron deficiency against malaria and other infections; yet consensus is lacking due to limited data. Recent studies have focused on the risks of iron supplementation but the effect of an individual's iron status on malaria risk remains unclear. Studies of iron status in areas with a high burden of infections often are exposed to bias. The aim of this study was to assess the predictive value of baseline iron status for malaria risk explicitly taking potential biases into account. METHODS AND MATERIALS: We prospectively assessed the relationship between baseline iron deficiency (serum ferritin <30 ug/L) and malaria risk in a cohort of 727 Malawian preschool children during a year of follow-up. Data were analyzed using marginal structural Cox regression models and confounders were selected using causal graph theory. Sensitivity of results to bias resulting from misclassification of iron status by concurrent inflammation and to bias from unmeasured confounding were assessed using modern causal inference methods. RESULTS AND CONCLUSIONS: The overall incidence of malaria parasitemia and clinical malaria was 1.9 (95% CI 1.8 2.0) and 0.7 (95% CI 0.6-0.8) events per person-year, respectively. Children with iron deficiency at baseline had a lower incidence of malaria parasitemia and clinical malaria during a year of follow-up; adjusted hazard ratio's 0.55 (95% CI:0.41-0.74) and 0.49 (95%-CI:0.33-0.73), respectively. Our results suggest that iron deficiency protects against malaria parasitemia and clinical malaria in young children. Therefore the clinical importance of treating iron deficiency in a pre-school child should be weighed carefully against potential harms. In malaria endemic areas treatment of iron deficiency in children requires sustained prevention of malaria. PMID- 22916147 TI - Applying microsatellite multiplex PCR analysis (MMPA) for determining allele copy number status and percentage of normal cells within tumors. AB - The study of somatic genetic alterations in tumors contributes to the understanding and management of cancer. Genetic alterations, such us copy number or copy neutral changes, generate allelic imbalances (AIs) that can be determined using polymorphic markers. Here we report the development of a simple set of calculations for analyzing microsatellite multiplex PCR data from control-tumor pairs that allows us to obtain accurate information not only regarding the AI status of tumors, but also the percentage of tumor-infiltrating normal cells, the locus copy-number status and the mechanism involved in AI. We validated this new approach by re-analyzing a set of Neurofibromatosis type 1-associated dermal neurofibromas and comparing newly generated data with results obtained for the same tumors in a previous study using MLPA, Paralog Ratio Analysis and SNP-array techniques.Microsatellite multiplex PCR analysis (MMPA) should be particularly useful for analyzing specific regions of the genome containing tumor suppressor genes and also for determining the percentage of infiltrating normal cells within tumors allowing them to be sorted before they are analyzed by more expensive techniques. PMID- 22916148 TI - Alcohol intake in pregnancy increases the child's risk of atopic dermatitis. the COPSAC prospective birth cohort study of a high risk population. AB - BACKGROUND: Atopic dermatitis has increased four-fold over the recent decades in developed countries, indicating that changes in environmental factors associated with lifestyle may play an important role in this epidemic. It has been proposed that alcohol consumption may be one contributing risk factor in this development. OBJECTIVE: To analyze the impact of alcohol intake during pregnancy on the development of atopic dermatitis during the first 7 years of life. METHOD: The COPSAC cohort is a prospective, longitudinal, birth cohort study of 411 children born to mothers with a history of asthma, followed up for 7 years with scheduled visits every 6 months as well as visits for acute exacerbations of atopic dermatitis. Risk of atopic dermatitis from any alcohol consumption during pregnancy was analyzed as time-to-diagnosis and adjusted for known risk factors. RESULTS: 177 of 411 children developed atopic dermatitis before age 7 years. We found a significant effect of alcohol intake during pregnancy on atopic dermatitis development (HR 1.44, 95% CI 1.05-1.99 p=0.024). This conclusion was unaffected after adjustment for smoking, mother's education and mother's atopic dermatitis. LIMITATIONS: The selection of a high-risk cohort, with all mothers suffering from asthma, and all children having a gestational age above 35 weeks with no congenital abnormality, systemic illness, or history of mechanical ventilation or lower airway infection. CONCLUSION: Alcohol intake by pregnant women with a history of asthma, is significantly associated with an increased risk for the child for developing atopic dermatitis during the first 7 years of life. PMID- 22916149 TI - Sex-specific regulation of mitochondrial DNA levels: genome-wide linkage analysis to identify quantitative trait loci. AB - Altered mitochondrial DNA (mtDNA) levels have been associated with common diseases in humans. We investigated the genetic mechanism that controls mtDNA levels using genome-wide linkage analyses in families from the Genetic Analysis of Idiopathic Thrombophilia Project (GAIT). We measure mtDNA levels by quantitative real-time PCR in 386 subjects from 21 extended Spanish families. A variance component linkage method using 485 microsatellites was conducted to evaluate linkage and to detect quantitative trait loci (QTLs) involved in the control of mtDNA levels. The heritalibility of mtDNA levels was 0.33 (p=1.82e 05). We identified a QTL on Chromosome 2 (LOD=2.21) using all of the subjects, independently on their sex. When females and males were analysed separately, three QTLs were identified. Females showed the same QTL on Chromosome 2 (LOD=3.09), indicating that the QTL identified in the analysis using all of the subjects was a strong female QTL, and another one on Chromosome 3 (LOD=2.67), whereas in males a QTL was identified on Chromosome 1 (LOD=2.81). These QTLs were fine-mapped to find associations with mtDNA levels. The most significant SNP association was for the rs10888838 on Chromosome 1 in males. This SNP mapped to the gene MRPL37, involved in mitochondrial protein translation. The rs2140855 on Chromosome 2 showed association in the analysis using all of the subjects. It was near the gene CMPK2, which encodes a mitochondrial enzyme of the salvage pathway of deoxyribonucleotide synthesis. Our results provide evidence of a sex-specific genetic mechanism for the control of mtDNA levels and provide a framework to identify new genes that influence mtDNA levels. PMID- 22916150 TI - Drosophila EYA regulates the immune response against DNA through an evolutionarily conserved threonine phosphatase motif. AB - Innate immune responses against DNA are essential to counter both pathogen infections and tissue damages. Mammalian EYAs were recently shown to play a role in regulating the innate immune responses against DNA. Here, we demonstrate that the unique Drosophila eya gene is also involved in the response specific to DNA. Haploinsufficiency of eya in mutants deficient for lysosomal DNase activity (DNaseII) reduces antimicrobial peptide gene expression, a hallmark for immune responses in flies. Like the mammalian orthologues, Drosophila EYA features a N terminal threonine and C-terminal tyrosine phosphatase domain. Through the generation of a series of mutant EYA fly strains, we show that the threonine phosphatase domain, but not the tyrosine phosphatase domain, is responsible for the innate immune response against DNA. A similar role for the threonine phosphatase domain in mammalian EYA4 had been surmised on the basis of in vitro studies. Furthermore EYA associates with IKKbeta and full-length RELISH, and the induction of the IMD pathway-dependent antimicrobial peptide gene is independent of SO. Our data provide the first in vivo demonstration for the immune function of EYA and point to their conserved immune function in response to endogenous DNA, throughout evolution. PMID- 22916151 TI - Feasibility of intensity-modulated and image-guided radiotherapy for functional organ preservation in locally advanced laryngeal cancer. AB - PURPOSE: The study aims to assess the feasibility of intensity-modulated and image-guided radiotherapy (IMRT, and IGRT, respectively) for functional preservation in locally advanced laryngeal cancer. A retrospective review of 27 patients undergoing concurrent chemoradiation for locally advanced laryngeal cancers (8 IMRT, 19 IGRT) was undertaken. In addition to regular clinical examinations, all patients had PET imaging at 4 months and 10 months after radiotherapy, then yearly. Loco-regional control, speech quality and feeding-tube dependency were assessed during follow-up visits. RESULTS: At a median follow-up of 20 months (range 6-57 months), four out of 27 patients (14.8%) developed local recurrence and underwent salvage total laryngectomy. One patient developed distant metastases following salvage surgery. Among the 23 patients who conserved their larynx with no sign of recurrence at last follow-up, 22 (95%) reported normal or near normal voice quality, allowing them to communicate adequately. Four patients (14.8%) had long-term tube feeding-dependency because of severe dysphagia (2 patients) and chronic aspiration (2 patients, with ensuing death from aspiration pneumonia in one patient). CONCLUSIONS AND CLINICAL RELEVANCE: Functional laryngeal preservation is feasible with IMRT and IGRT for locally advanced laryngeal cancer. However, dysphagia and aspiration remain serious complications, due most likely to high radiation dose delivery to the pharyngeal musculatures. PMID- 22916152 TI - Effect of acupuncture in mild cognitive impairment and Alzheimer disease: a functional MRI study. AB - We aim to clarify the mechanisms of acupuncture in treating mild cognitive impairment (MCI) and Alzheimer disease (AD) by using functional magnetic resonance imaging (fMRI). Thirty-six right-handed subjects (8 MCI patients, 14 AD patients, and 14 healthy elders) participated in this study. Clinical and neuropsychological examinations were performed on all the subjects. MRI data acquisition was performed on a SIEMENS verio 3-Tesla scanner. The fMRI study used a single block experimental design. We first acquired the baseline resting state data in the initial 3 minutes; we then acquired the fMRI data during the procession of acupuncture stimulation on the acupoints of Tai chong and Hegu for the following 3 minutes. Last, we acquired fMRI data for another 10 minutes after the needle was withdrawn. The preprocessing and data analysis were performed using the statistical parametric mapping (SPM8) software. Then the two-sample t tests were performed between each two groups of different states. We found that during the resting state, brain activities in AD and MCI patients were different from those of control subjects. During the acupuncture and the second resting state after acupuncture, when comparing to resting state, there are several regions showing increased or decreased activities in MCI, AD subjects compared to normal subjects. Most of the regions were involved in the temporal lobe and the frontal lobe, which were closely related to the memory and cognition. In conclusion, we investigated the effect of acupuncture in AD and MCI patients by combing fMRI and traditional acupuncture. Our fMRI study confirmed that acupuncture at Tai chong (Liv3) and He gu (LI4) can activate certain cognitive related regions in AD and MCI patients. PMID- 22916153 TI - Morphological correlates of a combat performance trait in the forked fungus beetle, Bolitotherus cornutus. AB - Combat traits are thought to have arisen due to intense male-male competition for access to females. While large and elaborate weapons used in attacking other males have often been the focus of sexual selection studies, defensive traits (both morphological and performance) have received less attention. However, if defensive traits help males restrict access to females, their role in the process of sexual selection could also be important. Here we examine the morphological correlates of grip strength, a defensive combat trait involved in mate guarding, in the tenebrionid beetle Bolitotherus cornutus. We found that grip strength was repeatable and differed between the sexes. However, these differences in performance were largely explained by body size and a non-additive interaction between size and leg length that differed between males and females. Our results suggest that leg size and body size interact as part of an integrated suite of defensive combat traits. PMID- 22916154 TI - Analysis of MDM2 and MDM4 single nucleotide polymorphisms, mRNA splicing and protein expression in retinoblastoma. AB - Retinoblastoma is a childhood cancer of the developing retina that begins in utero and is diagnosed in the first years of life. Biallelic RB1 gene inactivation is the initiating genetic lesion in retinoblastoma. The p53 gene is intact in human retinoblastoma but the pathway is believed to be suppressed by increased expression of MDM4 (MDMX) and MDM2. Here we quantify the expression of MDM4 and MDM2 mRNA and protein in human fetal retinae, primary retinoblastomas, retinoblastoma cell lines and several independent orthotopic retinoblastoma xenografts. We found that MDM4 is the major p53 antagonist expressed in retinoblastoma and in the developing human retina. We also discovered that MDM4 protein steady state levels are much higher in retinoblastoma than in human fetal retinae. This increase would not have been predicted based on the mRNA levels. We explored several possible post-transcriptional mechanisms that may contribute to the elevated levels of MDM4 protein. A proportion of MDM4 transcripts are alternatively spliced to produce protein products that are reported to be more stable and oncogenic. We also discovered that a microRNA predicted to target MDM4 (miR191) was downregulated in retinoblastoma relative to human fetal retinae and a subset of samples had somatic mutations that eliminated the miR-191 binding site in the MDM4 mRNA. Taken together, these data suggest that post transcriptional mechanisms may contribute to stabilization of the MDM4 protein in retinoblastoma. PMID- 22916155 TI - Sputum biomarkers and the prediction of clinical outcomes in patients with cystic fibrosis. AB - Lung function, acute pulmonary exacerbations (APE), and weight are the best clinical predictors of survival in cystic fibrosis (CF); however, underlying mechanisms are incompletely understood. Biomarkers of current disease state predictive of future outcomes might identify mechanisms and provide treatment targets, trial endpoints and objective clinical monitoring tools. Such CF specific biomarkers have previously been elusive. Using observational and validation cohorts comprising 97 non-transplanted consecutively-recruited adult CF patients at the Intermountain Adult CF Center, University of Utah, we identified biomarkers informative of current disease and predictive of future clinical outcomes. Patients represented the majority of sputum producers. They were recruited March 2004-April 2007 and followed through May 2011. Sputum biomarker concentrations were measured and clinical outcomes meticulously recorded for a median 5.9 (interquartile range 5.0 to 6.6) years to study associations between biomarkers and future APE and time-to-lung transplantation or death. After multivariate modeling, only high mobility group box-1 protein (HMGB-1, mean=5.84 [log ng/ml], standard deviation [SD] =1.75) predicted time-to first APE (hazard ratio [HR] per log-unit HMGB-1=1.56, p-value=0.005), number of future APE within 5 years (0.338 APE per log-unit HMGB-1, p<0.001 by quasi Poisson regression) and time-to-lung transplantation or death (HR=1.59, p=0.02). At APE onset, sputum granulocyte macrophage colony stimulating factor (GM-CSF, mean 4.8 [log pg/ml], SD=1.26) was significantly associated with APE-associated declines in lung function (-10.8 FEV(1)% points per log-unit GM-CSF, p<0.001 by linear regression). Evaluation of validation cohorts produced similar results that passed tests of mutual consistency. In CF sputum, high HMGB-1 predicts incidence and recurrence of APE and survival, plausibly because it mediates long term airway inflammation. High APE-associated GM-CSF identifies patients with large acute declines in FEV(1)%, possibly providing a laboratory-based objective decision-support tool for determination of an APE diagnosis. These biomarkers are potential CF reporting tools and treatment targets for slowing long-term progression and reducing short-term severity. PMID- 22916156 TI - Epilepsy is a risk factor for sudden cardiac arrest in the general population. AB - BACKGROUND: People with epilepsy are at increased risk for sudden death. The most prevalent cause of sudden death in the general population is sudden cardiac arrest (SCA) due to ventricular fibrillation (VF). SCA may contribute to the increased incidence of sudden death in people with epilepsy. We assessed whether the risk for SCA is increased in epilepsy by determining the risk for SCA among people with active epilepsy in a community-based study. METHODS AND RESULTS: This investigation was part of the Amsterdam Resuscitation Studies (ARREST) in the Netherlands. It was designed to assess SCA risk in the general population. All SCA cases in the study area were identified and matched to controls (by age, sex, and SCA date). A diagnosis of active epilepsy was ascertained in all cases and controls. Relative risk for SCA was estimated by calculating the adjusted odds ratios using conditional logistic regression (adjustment was made for known risk factors for SCA). We identified 1019 cases of SCA with ECG-documented VF, and matched them to 2834 controls. There were 12 people with active epilepsy among cases and 12 among controls. Epilepsy was associated with a three-fold increased risk for SCA (adjusted OR 2.9 [95%CI 1.1-8.0.], p=0.034). The risk for SCA in epilepsy was particularly increased in young and females. CONCLUSION: Epilepsy in the general population seems to be associated with an increased risk for SCA. PMID- 22916157 TI - Morphology and viscoelasticity of actin networks formed with the mutually interacting crosslinkers: palladin and alpha-actinin. AB - Actin filaments and associated actin binding proteins play an essential role in governing the mechanical properties of eukaryotic cells. Even though cells have multiple actin binding proteins (ABPs) that exist simultaneously to maintain the structural and mechanical integrity of the cellular cytoskeleton, how these proteins work together to determine the properties of actin networks is not clearly understood. The ABP, palladin, is essential for the maintenance of cell morphology and the regulation of cell movement. Palladin coexists with alpha actinin in stress fibers and focal adhesions and binds to both actin and alpha actinin. To obtain insight into how mutually interacting actin crosslinking proteins modulate the properties of actin networks, we characterized the micro structure and mechanics of actin networks crosslinked with palladin and alpha actinin. We first showed that palladin crosslinks actin filaments into bundled networks which are viscoelastic in nature. Our studies also showed that composite networks of alpha-actinin/palladin/actin behave very similar to pure palladin or pure [Formula: see text]-actinin networks. However, we found evidence that palladin and alpha-actinin synergistically modify network viscoelasticity. To our knowledge, this is the first quantitative characterization of the physical properties of actin networks crosslinked with two mutually interacting crosslinkers. PMID- 22916158 TI - Evaluating the ribosomal internal transcribed spacer (ITS) as a candidate dinoflagellate barcode marker. AB - BACKGROUND: DNA barcoding offers an efficient way to determine species identification and to measure biodiversity. For dinoflagellates, an ancient alveolate group of about 2000 described extant species, DNA barcoding studies have revealed large amounts of unrecognized species diversity, most of which is not represented in culture collections. To date, two mitochondrial gene markers, Cytochrome Oxidase I (COI) and Cytochrome b oxidase (COB), have been used to assess DNA barcoding in dinoflagellates, and both failed to amplify all taxa and suffered from low resolution. Nevertheless, both genes yielded many examples of morphospecies showing cryptic speciation and morphologically distinct named species being genetically similar, highlighting the need for a common marker. For example, a large number of cultured Symbiodinium strains have neither taxonomic identification, nor a common measure of diversity that can be used to compare this genus to other dinoflagellates. METHODOLOGY/PRINCIPAL FINDINGS: The purpose of this study was to evaluate the Internal Transcribed Spacer units 1 and 2 (ITS) of the rDNA operon, as a high resolution marker for distinguishing species dinoflagellates in culture. In our study, from 78 different species, the ITS barcode clearly differentiated species from genera and could identify 96% of strains to a known species or sub-genus grouping. 8.3% showed evidence of being cryptic species. A quarter of strains identified had no previous species identification. The greatest levels of hidden biodiversity came from Scrippsiella and the Pfiesteriaceae family, whilst Heterocapsa strains showed a high level of mismatch to their given species name. CONCLUSIONS/SIGNIFICANCE: The ITS marker was successful in confirming species, revealing hidden diversity in culture collections. This marker, however, may have limited use for environmental barcoding due to paralogues, the potential for unidentifiable chimaeras and priming across taxa. In these cases ITS would serve well in combination with other markers or for specific taxon studies. PMID- 22916159 TI - Studies of ribonucleotide reductase in crucian carp-an oxygen dependent enzyme in an anoxia tolerant vertebrate. AB - The enzyme ribonucleotide reductase (RNR) catalyzes the conversion of ribonucleotides to deoxyribonucleotides, the precursors for DNA. RNR requires a thiyl radical to activate the substrate. In RNR of eukaryotes (class Ia RNR), this radical originates from a tyrosyl radical formed in reaction with oxygen (O(2)) and a ferrous di-iron center in RNR. The crucian carp (Carassius carassius) is one of very few vertebrates that can tolerate several months completely without oxygen (anoxia), a trait that enables this fish to survive under the ice in small ponds that become anoxic during the winter. Previous studies have found indications of cell division in this fish after 7 days of anoxia. This appears nearly impossible, as DNA synthesis requires the production of new deoxyribonucleotides and therefore active RNR. We have here characterized RNR in crucian carp, to search for adaptations to anoxia. We report the full length sequences of two paralogs of each of the RNR subunits (R1i, R1ii, R2i, R2ii, p53R2i and p53R2ii), obtained by cloning and sequencing. The mRNA levels of these subunits were measured with quantitative PCR and were generally well maintained in hypoxia and anoxia in heart and brain. We also report maintained or increased mRNA levels of the cell division markers proliferating cell nuclear antigen (PCNA), brain derived neurotrophic factor (BDNF) and Ki67 in anoxic hearts and brains. Electron paramagnetic resonance (EPR) measurements on in vitro expressed crucian carp R2 and p53R2 proteins gave spectra similar to mammalian RNRs, including previously unpublished human and mouse p53R2 EPR spectra. However, the radicals in crucian carp RNR small subunits, especially in the p53R2ii subunit, were very stable at 0 degrees C. A long half-life of the tyrosyl radical during wintertime anoxia could allow for continued cell division in crucian carp. PMID- 22916160 TI - Well-being and social capital on planet earth: cross-national evidence from 142 countries. AB - High levels of social trust and social support are associated with life satisfaction around the world. However, it is not known whether this association extends to other indicators of social capital and of subjective well-being globally. We examine associations between three measures of social capital and three indicators of subjective well-being in 142 low-, middle- and high-income countries. Furthermore, we explore whether positive and negative feelings mirror each other or if they are separate constructs that behave differently in relation to social capital. Data comes from the Gallup World Poll, an international cross sectional comparable survey conducted yearly from 2005 to 2009 for those 15 years of age and over. The poll represents 95% of the world's population. Social capital was measured with self-reports of access to support from relatives and friends, of volunteering to an organization in the past month, and of trusting others. Subjective well-being was measured with self-reports of life satisfaction, positive affect, and negative affect. We first estimate random coefficient (multi-level) models and then use multivariate (individual-level) Ordinary Least Square (OLS) regression to model subjective well-being as a function of social support, volunteering and social trust, controlling for age, gender, education, marital status, household income and religiosity. We found that having somebody to count on in case of need and reporting high levels of social trust are associated with better life evaluations and more positive feelings and an absence of negative feelings in most countries around the world. Associations, however, are stronger for high- and middle-income countries. Volunteering is also associated with better life evaluations and a higher frequency of positive emotions. There is not an association, however, between volunteering and experiencing negative feelings, except for low-income countries. Finally, we present evidence that the two affective components of subjective well being behave differently in relation to different indicators of social capital and social support across countries. PMID- 22916161 TI - Characterization of multisugar-binding C-type lectin (SpliLec) from a bacterial challenged cotton leafworm, Spodoptera littoralis. AB - BACKGROUND: Various proteins that display carbohydrate-binding activity in a Ca(2+)-dependent manner are classified into the C-type lectin family. They have one or two C-type carbohydrate-recognition domains (CRDs) composed of 110-130 amino acid residues in common. C-type lectins mediate cell adhesion, non-self recognition, and immuno-protection processes in immune responses and thus play significant roles in clearance of invaders, either as cell surface receptors for microbial carbohydrates or as soluble proteins existing in tissue fluids. The lectin of Spodoptera littoralis is still uncharacterized. METHODOLOGY: A single orf encoding a deduced polypeptide consisting of an 18-residue signal peptide and a 291-residue mature peptide, termed SpliLec, was isolated from the haemolymph of the cotton leafworm, S. littoralis, after bacterial challenge using RACE-PCR. Sequence analyses of the data revealed that SpliLec consists of two CRDs. Short form CRD(1) and long-form CRD(2) are stabilized by two and three highly conserved disulfide bonds, respectively. SpliLec shares homology with some dipteran lectins suggesting possible common ancestor. The purified SpliLec exhibited a 140-kDa molecular mass with a subunit molecular mass of 35 kDa. The hemagglutination assays of the SpliLec confirmed a thermally stable, multisugar-binding C-type lectin that binds different erythrocytes. The purified SpliLec agglutinated microorganisms and exhibited comparable antimicrobial activity against gram (+) and gram (-) bacteria too. CONCLUSIONS: Our results suggested an important role of the SpliLec gene in cell adhesion and non-self recognition. It may cooperate with other AMPs in clearance of invaders of Spodoptera littoralis. PMID- 22916162 TI - Compositional stability of a salivary bacterial population against supragingival microbiota shift following periodontal therapy. AB - Supragingival plaque is permanently in contact with saliva. However, the extent to which the microbiota contributes to the salivary bacterial population remains unclear. We compared the compositional shift in the salivary bacterial population with that in supragingival plaque following periodontal therapy. Samples were collected from 19 patients with periodontitis before and after periodontal therapy (mean sample collection interval, 25.8 +/- 2.6 months), and their bacterial composition was investigated using barcoded pyrosequencing analysis of the 16S rRNA gene. Phylogenetic community analysis using the UniFrac distance metric revealed that the overall bacterial community composition of saliva is distinct from that of supragingival plaque, both pre- and post-therapy. Temporal variation following therapy in the salivary bacterial population was significantly smaller than in the plaque microbiota, and the post-therapy saliva sample was significantly more similar to that pre-therapy from the same individual than to those from other subjects. Following periodontal therapy, microbial richness and biodiversity were significantly decreased in the plaque microbiota, but not in the salivary bacterial population. The operational taxonomic units whose relative abundances changed significantly after therapy were not common to the two microbiotae. These results reveal the compositional stability of salivary bacterial populations against shifts in the supragingival microbiota, suggesting that the effect of the supragingival plaque microbiota on salivary bacterial population composition is limited. PMID- 22916163 TI - Identification of additional trials in prospective trial registers for Cochrane systematic reviews. AB - BACKGROUND: Publication and selective outcome reporting bias are a threat to the validity of systematic reviews. Extensive searching for additional trials in prospective trial registers could reduce this problem. We have evaluated how authors of Cochrane systematic reviews currently make use of trial registers as an additional source for the identification of potentially eligible trials. METHODOLOGY/PRINCIPAL FINDINGS: We included 210 systematic Cochrane reviews of interventions published between 2008 and 2010 of which the protocol was first published in 2008. When prospective trial registers were searched we recorded the names of the register(s), the authors' motive(s) and if they yielded any extra trials. In 80 reviews (38.1%) the authors had searched in one or more prospective trial register(s) of which 55% had searched in overlapping search portals and individual registers. Most frequently assessed were the MetaRegister (66.3%) and Clinicaltrials.gov (60%) which is in sharp contrast of other registers or portals like the WHO ICTRP Search Portal (20%). Reported motives to use registers were to identify ongoing trials (83.3%), to identify unpublished outcomes or trials (23.5%), to identify recently published trials (11.8%), or to identify any relevant trial (3.9%).In 28 reviews (35%) the authors had selected (ongoing) trials identified in trial registers as potentially eligible. DISCUSSION: Trial registers as an additional source of information are gaining acknowledgement amongst Cochrane reviewers. Nevertheless, searches seem to be inefficient as overlapping databases are frequently consulted, while the WHO ICTRP Search Portal that includes the data from all approved registers worldwide is being underused. Moreover, the emphasis is now on the identification of ongoing trials, although the prospective registers offer a broader potential. Further familiarity of registers and guidance how to search and to report will help to implement this as a common method and utilize the full potential of prospective trial registers for systematic reviews. PMID- 22916164 TI - Suppression of peroxiredoxin 4 in glioblastoma cells increases apoptosis and reduces tumor growth. AB - Glioblastoma multiforme (GBM), the most common and aggressive primary brain malignancy, is incurable despite the best combination of current cancer therapies. For the development of more effective therapies, discovery of novel candidate tumor drivers is urgently needed. Here, we report that peroxiredoxin 4 (PRDX4) is a putative tumor driver. PRDX4 levels were highly increased in a majority of human GBMs as well as in a mouse model of GBM. Reducing PRDX4 expression significantly decreased GBM cell growth and radiation resistance in vitro with increased levels of ROS, DNA damage, and apoptosis. In a syngenic orthotopic transplantation model, Prdx4 knockdown limited GBM infiltration and significantly prolonged mouse survival. These data suggest that PRDX4 can be a novel target for GBM therapies in the future. PMID- 22916165 TI - Androgen concentrations in umbilical cord blood and their association with maternal, fetal and obstetric factors. AB - The aim of this study was to measure umbilical blood androgen concentrations in a birth cohort using a highly specific liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay and assesses the effects of sex, labor, and gestational age on fetal androgen levels at birth. We performed a prospective cohort study of androgen concentrations in mixed arterial and venous umbilical cord serum from 803 unselected singleton pregnancies from a general obstetric population in Western Australia. Total testosterone (TT), Delta4-androstenedione, and dehydroepiandrosterone were extracted from archived cord serum samples and measured using LC-MS/MS. SHBG was measured by ELISA; free testosterone (FT) and bioavailable testosterone (BioT) values were also calculated. Median values for all three androgens were generally lower than previously published values. Levels of TT, FT, BioT, and SHBG were significantly higher in male verses female neonates (P<0.0001), while dehydroepiandrosterone levels were higher in females (P<0.0001). Labor was associated with a significant (~15-26%) decrease in median cord blood TT and FT levels (both sexes combined), but a modest (~16-31%) increase in SHBG, Delta4-androstenedione, and dehydroepiandrosterone concentrations. TT and FT were significantly negatively correlated with gestational age at delivery, while SHBG, Delta4-androstenedione, and dehydroepiandrosterone were positively correlated. Antenatal glucocorticoid administration also had a significant effect in the multiple regression models. This is the first study to report umbilical cord androgen levels in a large unselected population of neonates using LC-MS/MS. Our findings suggest that previous studies have over-estimated cord androgen levels, and that fetal, maternal, and obstetric factors influence cord androgen levels differentially. Caution should be exercised when interpreting previously-published data that have not taken all of these factors into account. PMID- 22916166 TI - Maiden outbreak of chikungunya in Dongguan city, Guangdong province, China: epidemiological characteristics. AB - BACKGROUND: This study was conducted to identify epidemiological characteristics of the first documented CHIK fever outbreak in China and evaluate the effect of the preventive measures taken. METHODOLOGY/PRINCIPAL FINDINGS: From September 1 to October 29, 2010, China's first documented outbreak of CHIK fever occurred in the Xincun community of Wanjiang District of Dongguan city, Guangdong province; 253 case-patients were recorded, of which 129 were laboratory confirmed, with an attack rate of 1%. Before September 18(th) the number of CHIK fever cases remained relatively low in the Xincun community; from September 19(th) onwards, the number of cases increased drastically, with an outbreak peak on October 4(th). Cases were distributed across nine small village groups in the Xincun community, with an attack rate of 0-12% at the village level. The household attack rates ranged between 20% and 100%. No significant difference was found in the attack rate between males and females. There was a significant difference in the attack rate in different age groups (chi-square=18.35, p=0.005); highest in patients aged 60 years or older and the lowest in patients aged under 10. The major clinical characteristics of patients are fever (100%), joint pain (79%) and rash (54%). Phylogenetic analysis of the E1 gene on the five earliest confirmed cases showed that the strains of CHIKV isolated from their sera were highly homologous (up to 99%) with isogeneic strains isolated in Thailand in 2009. After control measures were taken, including killing adult mosquitoes and cleaning breeding habitats of Aedes mosquitoes, the Breteau index and Mosq-ovitrap index decreased rapidly, and the outbreak ended on October 29. CONCLUSION/SIGNIFICANCE: The infection source of the outbreak was imported. Cases showed obvious temporal, spatial, and population aggregation during the outbreak. Comprehensive control measures based on reducing the density of Aedes mosquitoes were effective in controlling the epidemic. PMID- 22916167 TI - Selection and validation of endogenous reference genes for qRT-PCR analysis in leafy spurge (Euphorbia esula). AB - Quantitative real-time polymerase chain reaction (qRT-PCR) is the most important tool in measuring levels of gene expression due to its accuracy, specificity, and sensitivity. However, the accuracy of qRT-PCR analysis strongly depends on transcript normalization using stably expressed reference genes. The aim of this study was to find internal reference genes for qRT-PCR analysis in various experimental conditions for seed, adventitious underground bud, and other organs of leafy spurge. Eleven candidate reference genes (BAM4, PU1, TRP-like, FRO1, ORE9, BAM1, SEU, ARF2, KAPP, ZTL, and MPK4) were selected from among 171 genes based on expression stabilities during seed germination and bud growth. The other ten candidate reference genes were selected from three different sources: (1) 3 stably expressed leafy spurge genes (60S, bZIP21, and MD-100) identified from the analyses of leafy spurge microarray data; (2) 3 orthologs of Arabidopsis "general purpose" traditional reference genes (GAPDH_1, GAPDH_2, and UBC); and (3) 4 orthologs of Arabidopsis stably expressed genes (UBC9, SAND, PTB, and F-box) identified from Affymetrix ATH1 whole-genome GeneChip studies. The expression stabilities of these 21 genes were ranked based on the C(T) values of 72 samples using four different computation programs including geNorm, Normfinder, BestKeeper, and the comparative DeltaC(T) method. Our analyses revealed SAND, PTB, ORE9, and ARF2 to be the most appropriate reference genes for accurate normalization of gene expression data. Since SAND and PTB were obtained from 4 orthologs of Arabidopsis, while ORE9 and ARF2 were selected from 171 leafy spurge genes, it was more efficient to identify good reference genes from the orthologs of other plant species that were known to be stably expressed than that of randomly testing endogenous genes. Nevertheless, the two newly identified leafy spurge genes, ORE9 and ARF2, can serve as orthologous candidates in the search for reference genes from other plant species. PMID- 22916168 TI - An efficient computational method for calculating ligand binding affinities. AB - Virtual compound screening using molecular docking is widely used in the discovery of new lead compounds for drug design. However, the docking scores are not sufficiently precise to represent the protein-ligand binding affinity. Here, we developed an efficient computational method for calculating protein-ligand binding affinity, which is based on molecular mechanics generalized Born/surface area (MM-GBSA) calculations and Jarzynski identity. Jarzynski identity is an exact relation between free energy differences and the work done through non equilibrium process, and MM-GBSA is a semimacroscopic approach to calculate the potential energy. To calculate the work distribution when a ligand is pulled out of its binding site, multiple protein-ligand conformations are randomly generated as an alternative to performing an explicit single-molecule pulling simulation. We assessed the new method, multiple random conformation/MM-GBSA (MRC-MMGBSA), by evaluating ligand-binding affinities (scores) for four target proteins, and comparing these scores with experimental data. The calculated scores were qualitatively in good agreement with the experimental binding affinities, and the optimal docking structure could be determined by ranking the scores of the multiple docking poses obtained by the molecular docking process. Furthermore, the scores showed a strong linear response to experimental binding free energies, so that the free energy difference of the ligand binding (DeltaDeltaG) could be calculated by linear scaling of the scores. The error of calculated DeltaDeltaG was within ~ +/- 1.5 kcal.mol(-1) of the experimental values. Particularly, in the case of flexible target proteins, the MRC-MMGBSA scores were more effective in ranking ligands than those generated by the MM-GBSA method using a single protein-ligand conformation. The results suggest that, owing to its lower computational costs and greater accuracy, the MRC-MMGBSA offers efficient means to rank the ligands, in the post-docking process, according to their binding affinities, and to compare these directly with the experimental values. PMID- 22916169 TI - Neural correlates of individual performance differences in resolving perceptual conflict. AB - Attentional mechanisms are a crucial prerequisite to organize behavior. Most situations may be characterized by a 'competition' between salient, but irrelevant stimuli and less salient, relevant stimuli. In such situations top down and bottom-up mechanisms interact with each other. In the present fMRI study, we examined how interindividual differences in resolving situations of perceptual conflict are reflected in brain networks mediating attentional selection. Doing so, we employed a change detection task in which subjects had to detect luminance changes in the presence and absence of competing distractors. The results show that good performers presented increased activation in the orbitofrontal cortex (BA 11), anterior cingulate (BA 25), inferior parietal lobule (BA 40) and visual areas V2 and V3 but decreased activation in BA 39. This suggests that areas mediating top-down attentional control are stronger activated in this group. Increased activity in visual areas reflects distinct neuronal enhancement relating to selective attentional mechanisms in order to solve the perceptual conflict. Opposed to good performers, brain areas activated by poor performers comprised the left inferior parietal lobule (BA 39) and fronto parietal and visual regions were continuously deactivated, suggesting that poor performers perceive stronger conflict than good performers. Moreover, the suppression of neural activation in visual areas might indicate a strategy of poor performers to inhibit the processing of the irrelevant non-target feature. These results indicate that high sensitivity in perceptual areas and increased attentional control led to less conflict in stimulus processing and consequently to higher performance in competitive attentional selection. PMID- 22916170 TI - Attentive and pre-attentive processes in change detection and identification. AB - In studies of change blindness, observers often have the phenomenological impression that the blindness is overcome all at once, so that change detection, localization and identification apparently occur together. Three experiments are described that explore dissociations between these processes using a discrete trial procedure in which 2 visual frames are presented sequentially with no intervening inter-frame-interval. The results reveal that change detection and localization are essentially perfect under these conditions regardless of the number of elements in the display, which is consistent with the idea that change detection and localization are mediated by pre-attentive parallel processes.In contrast, identification accuracy for an item before it changes is generally poor, and is heavily dependent on the number of items displayed. Identification accuracy after a change is substantially better, but depends on the new item's duration. This suggests that the change captures attention, which substantially enhances the likelihood of correctly identifying the new item. However, the results also reveal a limited capacity to identify unattended items. Specifically, we provide evidence that strongly suggests that, at least under these conditions, observers were able to identify two items without focused attention. Our results further suggest that spatial pre-cues that attract attention to an item before the change occurs simply ensure that the cued item is one of the two whose identity is encoded. PMID- 22916171 TI - A typical hospital-acquired methicillin-resistant Staphylococcus aureus clone is widespread in the community in the Gaza strip. AB - Epidemiological data on community acquired methicillin-resistant-Staphylococcus aureus (CA-MRSA) carriage and infection in the Middle-East region is scarce with only few reports in the Israeli and Palestinian populations. As part of a Palestinian-Israeli collaborative research, we have conducted a cross-sectional survey of nasal S. aureus carriage in healthy children and their parents throughout the Gaza strip. Isolates were characterized for antibiotic susceptibility, mec gene presence, PFGE, spa type, SCCmec-type, presence of PVL genes and multi-locus-sequence-type (MLST). S. aureus was carried by 28.4% of the 379 screened children-parents pairs. MRSA was detected in 45% of S. aureus isolates, that is, in 12% of the study population. A single ST22-MRSA-IVa, spa t223, PVL-gene negative strain was detected in 64% of MRSA isolates. This strain is typically susceptible to all non-beta-lactam antibiotics tested. The only predictor for MRSA carriage in children was having an MRSA carrier-parent (OR=25.5, P=0.0004). Carriage of the Gaza strain was not associated with prior hospitalization. The Gaza strain was closely related genetically to a local MSSA spa t223 strain and less so to EMRSA15, one of the pandemic hospital-acquired MRSA clones, scarcely reported in the community. The rapid spread in the community may be due to population determinants or due to yet unknown advantageous features of this particular strain. PMID- 22916172 TI - Unique prokaryotic consortia in geochemically distinct sediments from Red Sea Atlantis II and discovery deep brine pools. AB - The seafloor is a unique environment, which allows insights into how geochemical processes affect the diversity of biological life. Among its diverse ecosystems are deep-sea brine pools - water bodies characterized by a unique combination of extreme conditions. The 'polyextremophiles' that constitute the microbial assemblage of these deep hot brines have not been comprehensively studied. We report a comparative taxonomic analysis of the prokaryotic communities of the sediments directly below the Red Sea brine pools, namely, Atlantis II, Discovery, Chain Deep, and an adjacent brine-influenced site. Analyses of sediment samples and high-throughput pyrosequencing of PCR-amplified environmental 16S ribosomal RNA genes (16S rDNA) revealed that one sulfur (S)-rich Atlantis II and one nitrogen (N)-rich Discovery Deep section contained distinct microbial populations that differed from those found in the other sediment samples examined. Proteobacteria, Actinobacteria, Cyanobacteria, Deferribacteres, and Euryarchaeota were the most abundant bacterial and archaeal phyla in both the S- and N-rich sections. Relative abundance-based hierarchical clustering of the 16S rDNA pyrotags assigned to major taxonomic groups allowed us to categorize the archaeal and bacterial communities into three major and distinct groups; group I was unique to the S-rich Atlantis II section (ATII-1), group II was characteristic for the N-rich Discovery sample (DD-1), and group III reflected the composition of the remaining sediments. Many of the groups detected in the S-rich Atlantis II section are likely to play a dominant role in the cycling of methane and sulfur due to their phylogenetic affiliations with bacteria and archaea involved in anaerobic methane oxidation and sulfate reduction. PMID- 22916174 TI - Adoptive immunotherapy in postoperative hepatocellular carcinoma: a systemic review. AB - PURPOSE: The effectiveness of immunotherapy for postoperative hepatocellular carcinoma patients is still controversial. To address this issue, we did a systemic review of the literatures and analyzed the data with emphasis on the recurrence and survival. METHODS: We searched six randomized controlled trials that included adoptive immunotherapy in the postoperative management of hepatocellular carcinoma and compared with non-immunotherapy postoperation. A meta-analysis was carried out to examine one- and 3-year recurrence and survival. RESULTS: The overall analysis revealed significantly reduced risk of 1-year recurrence in patients receiving adoptive immunotherapy (OR=0.35; 95% CI, 0.17 to 0.71; p=0.003), in that the risk of 3-year recurrence with a pooled OR estimated at 0.31 (95% CI 0.16 to 0.61; p=0.001). However, no statistically significant difference was observed for 3-year survival between groups with adoptive immunotherapy and without adjuvant treatment (OR=0.91; 95% CI, 0.45 to 1.84; P=0.792). CONCLUSIONS: Adjuvant immunotherapy with cytokine induced killer cells or lymphokine activated killer cells may reduce recurrence in postoperative hepatocellular carcinoma patients, but may not improve survival. PMID- 22916173 TI - Developmental alterations in motor coordination and medium spiny neuron markers in mice lacking pgc-1alpha. AB - Accumulating evidence implicates the transcriptional coactivator peroxisome proliferator activated receptor gamma coactivator 1alpha (PGC-1alpha) in the pathophysiology of Huntington Disease (HD). Adult PGC-1alpha (-/-) mice exhibit striatal neurodegeneration, and reductions in the expression of PGC-1alpha have been observed in striatum and muscle of HD patients as well as in animal models of the disease. However, it is unknown whether decreased expression of PGC-1alpha alone is sufficient to lead to the motor phenotype and striatal pathology characteristic of HD. For the first time, we show that young PGC-1alpha (-/-) mice exhibit severe rotarod deficits, decreased rearing behavior, and increased occurrence of tremor in addition to the previously described hindlimb clasping. Motor impairment and striatal vacuolation are apparent in PGC-1alpha (-/-) mice by four weeks of age and do not improve or decline by twelve weeks of age. The behavioral and pathological phenotype of PGC-1alpha (-/-) mice can be completely recapitulated by conditional nervous system deletion of PGC-1alpha, indicating that peripheral effects are not responsible for the observed abnormalities. Evaluation of the transcriptional profile of PGC-1alpha (-/-) striatal neuron populations and comparison to striatal neuron profiles of R6/2 HD mice revealed that PGC-1alpha deficiency alone is not sufficient to cause the transcriptional changes observed in this HD mouse model. In contrast to R6/2 HD mice, PGC-1alpha (-/-) mice show increases in the expression of medium spiny neuron (MSN) markers with age, suggesting that the observed behavioral and structural abnormalities are not primarily due to MSN loss, the defining pathological feature of HD. These results indicate that PGC-1alpha is required for the proper development of motor circuitry and transcriptional homeostasis in MSNs and that developmental disruption of PGC-1alpha leads to long-term alterations in motor functioning. PMID- 22916175 TI - Using detection dogs to conduct simultaneous surveys of northern spotted (Strix occidentalis caurina) and barred owls (Strix varia). AB - State and federal actions to conserve northern spotted owl (Strix occidentalis caurina) habitat are largely initiated by establishing habitat occupancy. Northern spotted owl occupancy is typically assessed by eliciting their response to simulated conspecific vocalizations. However, proximity of barred owls (Strix varia)-a significant threat to northern spotted owls-can suppress northern spotted owl responsiveness to vocalization surveys and hence their probability of detection. We developed a survey method to simultaneously detect both species that does not require vocalization. Detection dogs (Canis familiaris) located owl pellets accumulated under roost sites, within search areas selected using habitat association maps. We compared success of detection dog surveys to vocalization surveys slightly modified from the U.S. Fish and Wildlife Service's Draft 2010 Survey Protocol. Seventeen 2 km * 2 km polygons were each surveyed multiple times in an area where northern spotted owls were known to nest prior to 1997 and barred owl density was thought to be low. Mitochondrial DNA was used to confirm species from pellets detected by dogs. Spotted owl and barred owl detection probabilities were significantly higher for dog than vocalization surveys. For spotted owls, this difference increased with number of site visits. Cumulative detection probabilities of northern spotted owls were 29% after session 1, 62% after session 2, and 87% after session 3 for dog surveys, compared to 25% after session 1, increasing to 59% by session 6 for vocalization surveys. Mean detection probability for barred owls was 20.1% for dog surveys and 7.3% for vocal surveys. Results suggest that detection dog surveys can complement vocalization surveys by providing a reliable method for establishing occupancy of both northern spotted and barred owl without requiring owl vocalization. This helps meet objectives of Recovery Actions 24 and 25 of the Revised Recovery Plan for the Northern Spotted Owl. PMID- 22916176 TI - FTY720 protects cardiac microvessels of diabetes: a critical role of S1P1/3 in diabetic heart disease. AB - BACKGROUND: Diabetes is associated with an increased risk of cardiac microvascular disease. The mechanisms by which this damage occurs are unknown. However, research suggests that signaling through the sphingosine-1-phosphates receptor 1 and 3 (S1P1/3) by FTY720, a sphiongolipid drug that is structually similar to SIP, may play a role in the treatment on cardiac microvascular dysfunction in diabetes. We hypothesized that FTY720 might exert the cardioprotective effects of S1P1 and S1P3 viaprotein kinase C-beta (PKCbeta II) signaling pathway. METHODOLOGY/PRINCIPAL FINDINGS: Transthoracic echocardiography was performed to detect the change of cardiac function. Scanning and transmission electron microscope with lanthanum tracer were used to determine microvascular ultrastructure and permeability in vivo. Apoptosis was detected by TUNEL and CD31 dual labeling in paraffin-embedded sections. Laser capture miscrodissection was used to assess cardiac micovascular endothelial cells (CMECs) in vivo. RT-PCR and Western blot analysis were used to determine the mRNA levels and protein expression of S1P1, S1P3, and PKCbeta II. In the diabetic rats vs. controls, cardiac capillaries showed significantly higher density; CD31 positive endothelial cells were significantly reduced; the apoptosis index of cardiac endothlial cells was significantly higher. And FTY720 could increase the expressional level of S1P1 and boost S1P3 trasnslocation from membrane to nuclear, then ameliorate cardiac microvascular barrier impairment and pathologic angiogenesis induced by diabetes. In addition, overexpression of PKCbeta II significantly decreased the protective effect of FTY720. CONCLUSIONS: Our study represents that the deregulation of S1P1 and S1P3 is an important signalresponsible for cardiac microvascular dysfunction in diabetes. FTY720 might be competent to serve as a potential therapeutic approach for diabetic heart disease through ameliorating cardiac microvascular barrier impairment and pathologic angiogenesis, which might be partly dependent on PKCbetaII-mediated signaling pathway. PMID- 22916177 TI - Transformation with oligonucleotides creating clustered changes in the yeast genome. AB - We have studied single-strand oligonucleotide (oligo) transformation of yeast by using 40-nt long oligos that create multiple base changes to the yeast genome spread throughout the length of the oligos, making it possible to measure the portions of an oligo that are incorporated during transformation. Although the transformation process is greatly inhibited by DNA mismatch repair (MMR), the pattern of incorporation is essentially the same in the presence or absence of MMR, whether the oligo anneals to the leading or lagging strand of DNA replication, or whether phosphorothioate linkages are used at either end. A central core of approximately 15 nt is incorporated with a frequency of >90%; the ends are incorporated with a lower frequency, and loss of the two ends appears to be by different mechanisms. Bases that are 5-10 nt from the 5' end are generally lost with a frequency of >95%, likely through a process involving flap excision. On the 3' end, bases 5-10 nt from the 3' end are lost about 1/3 of the time. These results indicate that oligos can be used to create multiple simultaneous changes to the yeast genome, even in the presence of MMR. PMID- 22916178 TI - Life form and life history explain variation in population processes in a grassland community invaded by exotic plants and mammals. AB - The existence of general characteristics of plant invasiveness is still debated. One reason we may not have found these characteristics is because we do not yet understand how processes underlying population dynamics contribute to community composition in invaded communities. Here I modify Ricker stock-recruitment models to parameterize processes important to community dynamics in an invaded grassland community: immigration, maximum intrinsic growth rate, self-regulation, and limitation by other species. I then used the parameterized models in a multi species stochastic simulation to determine how processes affected long-term community dynamics. By parameterizing the models using the frequency of the 18 most common species in the grassland, I determined that life history and life form are stronger predictors of underlying processes than is native status. Immigration maintains exotic annual grasses and the dominant native perennial grass in the community. Growth rate maintains other perennial species. While the model mirrors the frequency of native species well, exotic species have lower observed than parameterized frequencies, suggesting that they are not reaching their potential frequency. These results, combined with results from past research, suggest that disturbance may be key to maintaining exotic species in the community. Here I showed that a continuous modified Ricker model fit discrete grassland frequency data well. This allowed me to model the dominant species in the community simultaneously and gain insight into the processes that determine community composition. PMID- 22916180 TI - Exploring trade-offs between fisheries and conservation of the vaquita porpoise (Phocoena sinus) using an Atlantis ecosystem model. AB - BACKGROUND: Minimizing fishery bycatch threats might involve trade-offs between maintaining viable populations and economic benefits. Understanding these trade offs can help managers reconcile conflicting goals. An example is a set of bycatch reduction measures for the Critically Endangered vaquita porpoise (Phocoena sinus), in the Northern Gulf of California, Mexico. The vaquita is an endemic species threatened with extinction by artisanal net bycatch within its limited range; in this area fisheries are the chief source of economic productivity. METHODOLOGY/PRINCIPAL FINDINGS: We analyze trade-offs between conservation of the vaquita and fisheries, using an end-to-end Atlantis ecosystem model for the Northern Gulf of California. Atlantis is a spatially-explicit model intended as a strategic tool to test alternative management strategies. We simulated increasingly restrictive fisheries regulations contained in the vaquita conservation plan: implementing progressively larger spatial management areas that exclude gillnets, shrimp driftnets and introduce a fishing gear that has no vaquita bycatch. We found that only the most extensive spatial management scenarios recovered the vaquita population above the threshold necessary to downlist the species from Critically Endangered. The scenario that excludes existing net gear from the 2008 area of vaquita distribution led to moderate decrease in net present value (US$ 42 million) relative to the best-performing scenario and a two-fold increase in the abundance of adult vaquita over the course of 30 years. CONCLUSIONS/SIGNIFICANCE: Extended spatial management resulted in the highest recovery of the vaquita population. The economic cost of proposed management actions was unequally divided between fishing fleets; the loss of value from finfish gillnet fisheries was never recovered. Our analysis shows that managers will have to confront difficult trade-offs between management scenarios for vaquita conservation. PMID- 22916179 TI - The FRIABLE1 gene product affects cell adhesion in Arabidopsis. AB - Cell adhesion in plants is mediated predominantly by pectins, a group of complex cell wall associated polysaccharides. An Arabidopsis mutant, friable1 (frb1), was identified through a screen of T-DNA insertion lines that exhibited defective cell adhesion. Interestingly, the frb1 plants displayed both cell and organ dissociations and also ectopic defects in organ separation. The FRB1 gene encodes a Golgi-localized, plant specific protein with only weak sequence similarities to known proteins (DUF246). Unlike other cell adhesion deficient mutants, frb1 mutants do not have reduced levels of adhesion related cell wall polymers, such as pectins. Instead, FRB1 affects the abundance of galactose- and arabinose containing oligosaccharides in the Golgi. Furthermore, frb1 mutants displayed alteration in pectin methylesterification, cell wall associated extensins and xyloglucan microstructure. We propose that abnormal FRB1 action has pleiotropic consequences on wall architecture, affecting both the extensin and pectin matrices, with consequent changes to the biomechanical properties of the wall and middle lamella, thereby influencing cell-cell adhesion. PMID- 22916182 TI - Solving the problem of building models of crosslinked polymers: an example focussing on validation of the properties of crosslinked epoxy resins. AB - The construction of molecular models of crosslinked polymers is an area of some difficulty and considerable interest. We report here a new method of constructing these models and validate the method by modelling three epoxy systems based on the epoxy monomers bisphenol F diglycidyl ether (BFDGE) and triglycidyl-p-amino phenol (TGAP) with the curing agent diamino diphenyl sulphone (DDS). The main emphasis of the work concerns the improvement of the techniques for the molecular simulation of these epoxies and specific attention is paid towards model construction techniques, including automated model building and prediction of glass transition temperatures (T(g)). Typical models comprise some 4200-4600 atoms (ca. 120-130 monomers). In a parallel empirical study, these systems have been cast, cured and analysed by dynamic mechanical thermal analysis (DMTA) to measure T(g). Results for the three epoxy systems yield good agreement with experimental T(g) ranges of 200-220 degrees C, 270-285 degrees C and 285-290 degrees C with corresponding simulated ranges of 210-230 degrees C, 250-300 degrees C, and 250-300 degrees C respectively. PMID- 22916181 TI - Anticonvulsive effect of paeoniflorin on experimental febrile seizures in immature rats: possible application for febrile seizures in children. AB - Febrile seizures (FS) is the most common convulsive disorder in children, but there have been no clinical and experimental studies of the possible treatment of FS with herbal medicines, which are widely used in Asian countries. Paeoniflorin (PF) is a major bioactive component of Radix Paeoniae alba, and PF-containing herbal medicines have been used for neuromuscular, neuropsychiatric, and neurodegenerative disorders. In this study, we analyzed the anticonvulsive effect of PF and Keishikashakuyaku-to (KS; a PF-containing herbal medicine) for hyperthermia-induced seizures in immature rats as a model of human FS. When immature (P5) male rats were administered PF or KS for 10 days, hyperthermia induced seizures were significantly suppressed compared to control rats. In cultured hippocampal neurons, PF suppressed glutamate-induced elevation of intracellular Ca(2+) ([Ca(2+)](i)), glutamate receptor-mediated membrane depolarization, and glutamate-induced neuronal death. In addition, PF partially suppressed the elevation in [Ca(2+)](i) induced by activation of the metabotropic glutamate receptor 5 (mGluR5), but not that mediated by alpha-amino-3-hydroxy-5 methyl-4-isoxazolpropionic acid (AMPA) or N-methyl-D-aspartate (NMDA) receptors. However, PF did not affect production or release of gamma-aminobutyric acid (GABA) in hippocampal neurons. These results suggest that PF or PF-containing herbal medicines exert anticonvulsive effects at least in part by preventing mGluR5-dependent [Ca(2+)](i) elevations. Thus, it could be a possible candidate for the treatment of FS in children. PMID- 22916183 TI - Outcomes in registered, ongoing randomized controlled trials of patient education. AB - BACKGROUND: With the increasing prevalence of chronic noncommunicable diseases, patient education is becoming important to strengthen disease prevention and control. We aimed to systematically determine the extent to which registered, ongoing randomized controlled trials (RCTs) evaluated an educational intervention focus on patient-important outcomes (i.e., outcomes measuring patient health status and quality of life). METHODS: On May 6, 2009, we searched for all ongoing RCTs registered in the World Health Organization International Clinical Trials Registry platform. We used a standardized data extraction form to collect data and determined whether the outcomes assessed were 1) patient-important outcomes such as clinical events, functional status, pain, or quality of life or 2) surrogate outcomes, such as biological outcome, treatment adherence, or patient knowledge. PRINCIPAL FINDINGS: We selected 268 of the 642 potentially eligible studies and assessed a random sample of 150. Patient-important outcomes represented 54% (178 of 333) of all primary outcomes and 46% (286 of 623) of all secondary outcomes. Overall, 69% of trials (104 of 150) used at least one patient important outcome as a primary outcome and 66% (99 of 150) as a secondary outcome. Finally, for 31% of trials (46 of 150), primary outcomes were only surrogate outcomes. The results varied by medical area. In neuropsychiatric disorders, patient important outcomes represented 84% (51 of 61) of primary outcomes, as compared with 54% (32 of 59) in malignant neoplasm and 18% (4 of 22) in diabetes mellitus trials. In addition, only 35% assessed the long-term impact of interventions (i.e., >6 months). CONCLUSIONS: There is a need to improve the relevance of outcomes and to assess the long term impact of educational interventions in RCTs. PMID- 22916184 TI - Taurine induces proliferation of neural stem cells and synapse development in the developing mouse brain. AB - Taurine is a sulfur-containing amino acid present in high concentrations in mammalian tissues. It has been implicated in several processes involving brain development and neurotransmission. However, the role of taurine in hippocampal neurogenesis during brain development is still unknown. Here we show that taurine regulates neural progenitor cell (NPC) proliferation in the dentate gyrus of the developing brain as well as in cultured early postnatal (P5) hippocampal progenitor cells and hippocampal slices derived from P5 mice brains. Taurine increased cell proliferation without having a significant effect on neural differentiation both in cultured P5 NPCs as well as cultured hippocampal slices and in vivo. Expression level analysis of synaptic proteins revealed that taurine increases the expression of Synapsin 1 and PSD 95. We also found that taurine stimulates the phosphorylation of ERK1/2 indicating a possible role of the ERK pathway in mediating the changes that we observed, especially in proliferation. Taken together, our results demonstrate a role for taurine in neural stem/progenitor cell proliferation in developing brain and suggest the involvement of the ERK1/2 pathways in mediating these actions. Our study also shows that taurine influences the levels of proteins associated with synapse development. This is the first evidence showing the effect of taurine on early postnatal neuronal development using a combination of in vitro, ex-vivo and in vivo systems. PMID- 22916185 TI - High prevalence of HIV, HCV, HBV and co-infection and associated risk factors among injecting drug users in Yunnan province, China. AB - OBJECTIVE: To estimate the prevalence of HIV, HCV, HBV and co-infection with 2 or 3 viruses and evaluate risk factors among injecting drug users (IDUs) in Yunnan province, China. METHODS: 2080 IDUs were recruited from 5 regions of Yunnan Province, China to detect the infection status of HIV, hepatitis B virus (HBV) and hepatitis C virus (HCV). Statistical analysis was performed to evaluate risk factors related to HIV, HCV and HBV infections. RESULTS: The infection rates among all participants were 25.5% for HIV, 77.7% for HCV, 19.2% for HBV, 15% for HIV/HCV, 0.3% for HIV/HBV, 7.8% for HCV/HBV and 7.1% for HIV/HCV/HBV. The prevalence of virus infection varied widely by region in Yunnan of China. Statistical analyses indicated that high prevalence of HIV and HCV among IDUs was positively associated with the duration of drug injection and sharing needles/syringes; besides, HCV infection was associated with the frequency of drug injection. CONCLUSIONS: HIV, HCV, HBV infections and co-infections were still very prevalent among IDUs in Yunnan province because of drug use behaviors. PMID- 22916186 TI - ATXN2 and its neighbouring gene SH2B3 are associated with increased ALS risk in the Turkish population. AB - Expansions of the polyglutamine (polyQ) domain (>= 34) in Ataxin-2 (ATXN2) are the primary cause of spinocerebellar ataxia type 2 (SCA2). Recent studies reported that intermediate-length (27-33) expansions increase the risk of Amyotrophic Lateral Sclerosis (ALS) in 1-4% of cases in diverse populations. This study investigates the Turkish population with respect to ALS risk, genotyping 158 sporadic, 78 familial patients and 420 neurologically healthy controls. We re assessed the effect of ATXN2 expansions and extended the analysis for the first time to cover the ATXN2 locus with 18 Single Nucleotide Polymorphisms (SNPs) and their haplotypes. In accordance with other studies, our results confirmed that 31 32 polyQ repeats in the ATXN2 gene are associated with risk of developing ALS in 1.7% of the Turkish ALS cohort (p=0.0172). Additionally, a significant association of a 136 kb haplotype block across the ATXN2 and SH2B3 genes was found in 19.4% of a subset of our ALS cohort and in 10.1% of the controls (p=0.0057, OR: 2.23). ATXN2 and SH2B3 encode proteins that both interact with growth receptor tyrosine kinases. Our novel observations suggest that genotyping of SNPs at this locus may be useful for the study of ALS risk in a high percentage of individuals and that ATXN2 and SH2B3 variants may interact in modulating the disease pathway. PMID- 22916187 TI - Long-term occupational exposure to organic solvents affects color vision, contrast sensitivity and visual fields. AB - The purpose of this study was to evaluate the visual outcome of chronic occupational exposure to a mixture of organic solvents by measuring color discrimination, achromatic contrast sensitivity and visual fields in a group of gas station workers. We tested 25 workers (20 males) and 25 controls with no history of chronic exposure to solvents (10 males). All participants had normal ophthalmologic exams. Subjects had worked in gas stations on an average of 9.6 +/ 6.2 years. Color vision was evaluated with the Lanthony D15d and Cambridge Colour Test (CCT). Visual field assessment consisted of white-on-white 24-2 automatic perimetry (Humphrey II-750i). Contrast sensitivity was measured for sinusoidal gratings of 0.2, 0.5, 1.0, 2.0, 5.0, 10.0 and 20.0 cycles per degree (cpd). Results from both groups were compared using the Mann-Whitney U test. The number of errors in the D15d was higher for workers relative to controls (p<0.01). Their CCT color discrimination thresholds were elevated compared to the control group along the protan, deutan and tritan confusion axes (p<0.01), and their ellipse area and ellipticity were higher (p<0.01). Genetic analysis of subjects with very elevated color discrimination thresholds excluded congenital causes for the visual losses. Automated perimetry thresholds showed elevation in the 9 degrees , 15 degrees and 21 degrees of eccentricity (p<0.01) and in MD and PSD indexes (p<0.01). Contrast sensitivity losses were found for all spatial frequencies measured (p<0.01) except for 0.5 cpd. Significant correlation was found between previous working years and deutan axis thresholds (rho = 0.59; p<0.05), indexes of the Lanthony D15d (rho=0.52; p<0.05), perimetry results in the fovea (rho= -0.51; p<0.05) and at 3, 9 and 15 degrees of eccentricity (rho= 0.46; p<0.05). Extensive and diffuse visual changes were found, suggesting that specific occupational limits should be created. PMID- 22916188 TI - Low bone turnover and low BMD in Down syndrome: effect of intermittent PTH treatment. AB - Trisomy 21 affects virtually every organ system and results in the complex clinical presentation of Down syndrome (DS). Patterns of differences are now being recognized as patients' age and these patterns bring about new opportunities for disease prevention and treatment. Low bone mineral density (BMD) has been reported in many studies of males and females with DS yet the specific effects of trisomy 21 on the skeleton remain poorly defined. Therefore we determined the bone phenotype and measured bone turnover markers in the murine DS model Ts65Dn. Male Ts65Dn DS mice are infertile and display a profound low bone mass phenotype that deteriorates with age. The low bone mass was correlated with significantly decreased osteoblast and osteoclast development, decreased bone biochemical markers, a diminished bone formation rate and reduced mechanical strength. The low bone mass observed in 3 month old Ts65Dn mice was significantly increased after 4 weeks of intermittent PTH treatment. These studies provide novel insight into the cause of the profound bone fragility in DS and identify PTH as a potential anabolic agent in the adult low bone mass DS population. PMID- 22916189 TI - Comparative analysis of three brevetoxin-associated bottlenose dolphin (Tursiops truncatus) mortality events in the Florida Panhandle region (USA). AB - In the Florida Panhandle region, bottlenose dolphins (Tursiops truncatus) have been highly susceptible to large-scale unusual mortality events (UMEs) that may have been the result of exposure to blooms of the dinoflagellate Karenia brevis and its neurotoxin, brevetoxin (PbTx). Between 1999 and 2006, three bottlenose dolphin UMEs occurred in the Florida Panhandle region. The primary objective of this study was to determine if these mortality events were due to brevetoxicosis. Analysis of over 850 samples from 105 bottlenose dolphins and associated prey items were analyzed for algal toxins and have provided details on tissue distribution, pathways of trophic transfer, and spatial-temporal trends for each mortality event. In 1999/2000, 152 dolphins died following extensive K. brevis blooms and brevetoxin was detected in 52% of animals tested at concentrations up to 500 ng/g. In 2004, 105 bottlenose dolphins died in the absence of an identifiable K. brevis bloom; however, 100% of the tested animals were positive for brevetoxin at concentrations up to 29,126 ng/mL. Dolphin stomach contents frequently consisted of brevetoxin-contaminated menhaden. In addition, another potentially toxigenic algal species, Pseudo-nitzschia, was present and low levels of the neurotoxin domoic acid (DA) were detected in nearly all tested animals (89%). In 2005/2006, 90 bottlenose dolphins died that were initially coincident with high densities of K. brevis. Most (93%) of the tested animals were positive for brevetoxin at concentrations up to 2,724 ng/mL. No DA was detected in these animals despite the presence of an intense DA-producing Pseudo-nitzschia bloom. In contrast to the absence or very low levels of brevetoxins measured in live dolphins, and those stranding in the absence of a K. brevis bloom, these data, taken together with the absence of any other obvious pathology, provide strong evidence that brevetoxin was the causative agent involved in these bottlenose dolphin mortality events. PMID- 22916191 TI - Spatio-temporal patterns of pancreatic cancer cells expressing CD44 isoforms on supported membranes displaying hyaluronic acid oligomers arrays. AB - In this paper, we designed a quantitative model of biological membranes by the deposition of planar lipid membranes on solid substrates (called supported membranes), and immobilized biotinylated oligomers of hyaluronic acid (oligo-HA, 6-8 disaccharide units in length) to the membrane surface via neutravidin cross linkers. By controlling the self-assembly of biotinylated lipid anchors, the mean distance between the oligo-HA molecules on the membrane could be controlled to nm accuracy. The adhesion and motility of pancreatic adenocarcinoma cells expressing different splice variants of the HA-binding cell surface receptor CD44 on these surfaces were investigated quantitatively. The combination of label-free, time lapse imaging of living cells and statistical analysis suggests that the static morphology (global shape and cytoskeleton remodeling) of cells, their stochastic morphological dynamics, and the probability of directed motion reflect the metastatic behaviour of the cancer cells. PMID- 22916190 TI - Neuron-specific deletion of peroxisome proliferator-activated receptor delta (PPARdelta) in mice leads to increased susceptibility to diet-induced obesity. AB - Central nervous system (CNS) lipid accumulation, inflammation and resistance to adipo-regulatory hormones, such as insulin and leptin, are implicated in the pathogenesis of diet-induced obesity (DIO). Peroxisome proliferator-activated receptors (PPAR alpha, delta, gamma) are nuclear transcription factors that act as environmental fatty acid sensors and regulate genes involved in lipid metabolism and inflammation in response to dietary and endogenous fatty acid ligands. All three PPAR isoforms are expressed in the CNS at different levels. Recent evidence suggests that activation of CNS PPARalpha and/or PPARgamma may contribute to weight gain and obesity. PPARdelta is the most abundant isoform in the CNS and is enriched in the hypothalamus, a region of the brain involved in energy homeostasis regulation. Because in peripheral tissues, expression of PPARdelta increases lipid oxidative genes and opposes inflammation, we hypothesized that CNS PPARdelta protects against the development of DIO. Indeed, genetic neuronal deletion using Nes-Cre loxP technology led to elevated fat mass and decreased lean mass on low-fat diet (LFD), accompanied by leptin resistance and hypothalamic inflammation. Impaired regulation of neuropeptide expression, as well as uncoupling protein 2, and abnormal responses to a metabolic challenge, such as fasting, also occur in the absence of neuronal PPARdelta. Consistent with our hypothesis, KO mice gain significantly more fat mass on a high-fat diet (HFD), yet are surprisingly resistant to diet-induced elevations in CNS inflammation and lipid accumulation. We detected evidence of upregulation of PPARgamma and target genes of both PPARalpha and PPARgamma, as well as genes of fatty acid oxidation. Thus, our data reveal a previously underappreciated role for neuronal PPARdelta in the regulation of body composition, feeding responses, and in the regulation of hypothalamic gene expression. PMID- 22916192 TI - Pneumococcal antibody concentrations of subjects in communities fully or partially vaccinated with a seven-valent pneumococcal conjugate vaccine. AB - BACKGROUND: A recent trial with PCV-7 in a rural Gambian community showed reduced vaccine-type pneumococcal carriage in fully vaccinated compared with control communities. We measured pneumococcal polysaccharide antibody concentrations in this trial to understand further the mechanisms underlying the observed changes. METHODS: A single-blind, cluster-randomized (by village) trial was conducted in 21 Gambian villages. In 11 villages, all residents received PCV-7 (Vaccine group); in 10 control villages only children <30 months old or those born during the study received PCV-7. Subjects over the age of 30 months resident in vaccine villages received a single dose of PCV-7 whilst those in control villages received a single dose of a serogroup C meningococcal conjugate vaccine. Serum antibody concentrations against specific pneumococcal polysaccharides were measured in approximately 200 age-stratified subjects before, 4-6, 12 and 24 months following vaccination. RESULTS: Baseline pneumococcal antibody concentrations were generally high and increased with age up to 10 years. One dose of PCV-7 increased geometric mean antibody concentrations (GMC) in vaccinated versus control villages for vaccine serotypes 6B and 18C, and 4 and 18C, in the young (under 5 years) and older age groups (5+ years) respectively. There were significantly higher proportions of subjects in the vaccinated than in the control communities with an antibody concentration believed to protect against carriage (>5.0 ug/mL) for all but serotype 9V of the PCV-7 serotypes in the older group, but not in the younger age group. CONCLUSION: Higher antibodies in vaccinated communities provide an explanation for the lower pneumococcal carriage rates in fully vaccinated compared to control communities. TRIAL REGISTRATION: Controlled-Trials.com ISRCTN51695599 51695599. PMID- 22916193 TI - The trajectories and correlation between physical limitation and depression in elderly residents of Beijing, 1992-2009. AB - BACKGROUND: Physical limitation and psychological distress have been reported to be related, but studies describing the change of instrumental activities of daily living (IADLs) and depression syndrome over time or exploring the link pattern for their development are limited. The study was to assess distinctive patterns for the development of physical limitation and depression and to explore their correlation to form a proper prevention strategy. METHODS: Dual trajectory analysis was conducted using data from the Beijing Longitudinal Study of Aging (BLSA) 1992-2009 hosted by Xuanwu hospital for subjects with full information on depression and physical limitation for all available visits. Physical limitation was measured by the Instrumental Activities of Daily Living (IADL) scale and depression by the Center for Epidemiological Studies Depression scale (CES-D). The covariates were gender, age at baseline and number of chronic conditions. RESULTS: Three heterogeneous trajectories for physical limitation and two distinct groups for an increase in depression were detected. Among them, 10.13% of subjects experienced an increase in physical limitation, while 13.22% demonstrated a high, stable level of depressive mood. In all, 80.4% of the subjects enjoyed a relatively low, stable level of IADL and CES-D scores. People in the late increase group for IADL score were more likely to have depressive mood when adjusted for gender, age and number of chronic conditions (OR=3.900, 95%CI=1.347-11.290). CONCLUSIONS: The development of physical limitation among the elderly may significantly increase the risk for depressive symptoms. PMID- 22916194 TI - (S)-alpha-chlorohydrin inhibits protein tyrosine phosphorylation through blocking cyclic AMP - protein kinase A pathway in spermatozoa. AB - alpha-Chlorohydrin is a common contaminant in food. Its (S)-isomer, (S)-alpha chlorohydrin (SACH), is known for causing infertility in animals by inhibiting glycolysis of spermatozoa. The aim of present work was to examine the relationship between SACH and protein tyrosine phosphorylation (PTP), which plays a critical role in regulating mammalian sperm capacitation. In vitro exposure of SACH 50 uM to isolated rat epididymal sperm inhibited PTP. Sperm-specific glyceraldehyde 3-phosphate dehydrogenase (GAPDS) activities, the intracellular adenosine 5'-triphosphate (ATP) levels, 3'-5'-cyclic adenosine monophosphate (cAMP) levels and phosphorylation of protein kinase A (PKA) substrates in rat sperm were diminished dramatically, indicating that both glycolysis and the cAMP/PKA signaling pathway were impaired by SACH. The inhibition of both PTP and phosphorylation of PKA substrates by SACH could be restored by addition of cAMP analog dibutyryl-cAMP (dbcAMP) and phosphodiesterase inhibitor 3-isobutyl-1 methylxanthine (IBMX). Moreover, addition of glycerol protected glycolysis, ATP levels, phosphorylation of PKA substrates and PTP against the influence of SACH. These results suggested SACH inhibited PTP through blocking cAMP/PKA pathway in sperm, and PTP inhibition may play a role in infertility associated with SACH. PMID- 22916195 TI - Identifying the hotspots on the top faces of WD40-repeat proteins from their primary sequences by beta-bulges and DHSW tetrads. AB - The analysis of 36 available crystal structures of WD40 repeat proteins reveals widespread existence of a beta-bulge formed at the beginning of strand a and the end of strand b, termed as WD(b-a) bulge: among a total of 259 WD40 blades, there are 243 such beta-bulges. The R(1) positions in these WD(b-a) bulges have fair distributions of Arg, His, Ile, Leu, Lys, Met, Phe, Trp, Tyr and Val residues. These residues protrude on the top face of the WD40 proteins and can serve as hotspots for protein-protein interactions. An analysis of 29 protein complexes formed by 17 WD proteins reveals that these R(1) residues, along with two other residues (R(1)-2 and D-1), are indeed widely involved in protein-protein interactions. Interestingly, these WD(b-a) bulges can be easily identified by the 4-amino acid sequences of (V, L, I), R(1), R(2), (V, L, I), along with some other significant amino acids. Thus, the hotspots of WD40 proteins on the top face can be readily predicted based on the primary sequences of the proteins. The literature-reported mutagenesis studies for Met30, MDV1, Tup11, COP1 and SPA1, which crystal structures are not available, can be readily understood based on the feature-based method. Applying the method, the twelve potential hotspots on the top face of Tup11 from S. japonicas have been identified. Our ITC measurements confirm seven of them, Tyr382, Arg284, Tyr426, Tyr508, Leu559, Lys575 and Ile601, are essential for recognizing Fep1. The ITC measurements further convinced that the feature-based method provides accurate prediction of hotspots on the top face. PMID- 22916196 TI - Novel method for isolation of murine clara cell secretory protein-expressing cells with traces of stemness. AB - Clara cells are non-ciliated, secretory bronchiolar epithelial cells that serve to detoxify harmful inhaled substances. Clara cells also function as stem/progenitor cells for repair in the bronchioles. Clara cell secretory protein (CCSP) is specifically expressed in pulmonary Clara cells and is widely used as a Clara cell marker. In addition CCSP promoter is commonly used to direct gene expression into the lung in transgenic models. The discovery of CCSP immunoreactivity in plasma membranes of airway lining cells prompted us to explore the possibility of enriching Clara cells by flow cytometry. We established a novel and simple method for the isolation of CCSP-expressing cell Clara cells using a combination of mechanical and enzymatic dissociation followed by flow cytometry sorting technology. We showed that ~25% of dissociated cells from whole lung expressed CCSP. In the resulting preparation, up to 98% of cells expressed CCSP. Notably, we found that several common stem cell markers including CD44, CD133, Sca-1 and Sox2 were expressed in CCSP(+) cells. Moreover, CCSP(+) cells were able to form spheroid colonies in vitro with 0.970/00 efficiency. Parallel studies in vivo confirmed that a small population of CCSP(-)expressing cells in mouse airways also demonstrates stem cell-like properties such as label retention and harboring rare bronchioalveolar stem cells (BASCs) in terminal bronchioles (TBs). We conclude that CCSP(+) cells exhibit a number of stem cell like features including stem cell marker expression, bronchosphere colony formation and self-renewal ability. Clara cell isolation by flow cytometry sorting is a useful method for investigating the function of primary Clara cells in stem cell research and mouse models. PMID- 22916197 TI - TB screening in Canadian health care workers using interferon-gamma release assays. AB - BACKGROUND: While many North American healthcare institutions are switching from Tuberculin Skin Test (TST) to Interferon-gamma release assays (IGRAs), there is relatively limited data on association between occupational tuberculosis (TB) risk factors and test positivity and/or patterns of test discordance. METHODS: We recruited a cohort of Canadian health care workers (HCWs) in Montreal, and performed both TST and QuantiFERON-TB Gold In Tube (QFT) tests, and assessed risk factors and occupational exposure. RESULTS: In a cross-sectional analysis of baseline results, the prevalence of TST positivity using the 10 mm cut-off was 5.7% (22/388, 95%CI: 3.6-8.5%), while QFT positivity was 6.2% (24/388, 95%CI: 4 9.1%). Overall agreement between the tests was poor (kappa=0.26), and 8.3% of HCWs had discordant test results, most frequently TST-/QFT+ (17/388, 4.4%). TST positivity was associated with total years worked in health care, non occupational exposure to TB and BCG vaccination received after infancy or on multiple occasions. QFT positivity was associated with having worked as a HCW in a foreign country. CONCLUSIONS: Our results suggest that LTBI prevalence as measured by either the TST or the QFT is low in this HCW population. Of concern is the high frequency of unexplainable test discordance, namely: TST-/QFT+ subjects, and the lack of any association between QFT positivity and clear-cut recent TB exposure. If these discordant results are indeed false positives, the use of QFT in lieu of TST in low TB incidence settings could result in overtreatment of uninfected individuals. PMID- 22916198 TI - Generalization of stochastic visuomotor rotations. AB - Generalization studies examine the influence of perturbations imposed on one movement onto other movements. The strength of generalization is traditionally interpreted as a reflection of the similarity of the underlying neural representations. Uncertainty fundamentally affects both sensory integration and learning and is at the heart of many theories of neural representation. However, little is known about how uncertainty, resulting from variability in the environment, affects generalization curves. Here we extend standard movement generalization experiments to ask how uncertainty affects the generalization of visuomotor rotations. We find that although uncertainty affects how fast subjects learn, the perturbation generalizes independently of uncertainty. PMID- 22916199 TI - Design and synthesis of potent N-acylethanolamine-hydrolyzing acid amidase (NAAA) inhibitor as anti-inflammatory compounds. AB - N-acylethanolamine-hydrolyzing acid amidase (NAAA) is a lysosomal enzyme involved in biological deactivation of N-palmitoylethanolamide (PEA), which exerts anti inflammatory and analgesic effects through the activation of nuclear receptor peroxisome proliferator-activated receptor-alpha (PPAR-alpha). To develop selective and potent NAAA inhibitors, we designed and synthesized a series of derivatives of 1-pentadecanyl-carbonyl pyrrolidine (compound 1), a general amidase inhibitor. Structure activity relationship (SAR) studies have identified a compound 16, 1-(2-Biphenyl-4-yl)ethyl-carbonyl pyrrolidine, which has shown the highest inhibition on NAAA activity (IC(50) =2.12 +/- 0.41 uM) and is characterized as a reversible and competitive NAAA inhibitor. Computational docking analysis and mutagenesis study revealed that compound 16 interacted with Asparagine 209 (Asn(209)) residue flanking the catalytic pocket of NAAA so as to block the substrate entrance. In vitro pharmacological studies demonstrated that compound 16 dose-dependently reduced mRNA expression levels of iNOS and IL-6, along with an increase of intracellular PEA levels, in mouse macrophages with lipopolysaccharides (LPS) induced inflammation. Our study discovered a novel NAAA inhibitor, compound 16, that could serve as a potential anti-inflammatory agent. PMID- 22916200 TI - Avoiding pitfalls of internal controls: validation of reference genes for analysis by qRT-PCR and Western blot throughout rat retinal development. AB - BACKGROUND: Housekeeping genes have been commonly used as reference to normalize gene expression and protein content data because of its presumed constitutive expression. In this paper, we challenge the consensual idea that housekeeping genes are reliable controls for expression studies in the retina through the investigation of a panel of reference genes potentially suitable for analysis of different stages of retinal development. METHODOLOGY/PRINCIPAL FINDINGS: We applied statistical tools on combinations of retinal developmental stages to assess the most stable internal controls for quantitative RT-PCR (qRT-PCR). The stability of expression of seven putative reference genes (Actb, B2m, Gapdh, Hprt1, Mapk1, Ppia and Rn18s) was analyzed using geNorm, BestKeeper and Normfinder software. In addition, several housekeeping genes were tested as loading controls for Western blot in the same sample panel, using Image J. Overall, for qRT-PCR the combination of Gapdh and Mapk1 showed the highest stability for most experimental sets. Actb was downregulated in more mature stages, while Rn18s and Hprt1 showed the highest variability. We normalized the expression of cyclin D1 using various reference genes and demonstrated that spurious results may result from blind selection of internal controls. For Western blot significant variation could be seen among four putative internal controls (beta-actin, cyclophilin b, alpha-tubulin and lamin A/C), while MAPK1 was stably expressed. CONCLUSION: Putative housekeeping genes exhibit significant variation in both mRNA and protein content during retinal development. Our results showed that distinct combinations of internal controls fit for each experimental set in the case of qRT-PCR and that MAPK1 is a reliable loading control for Western blot. The results indicate that biased study outcomes may follow the use of reference genes without prior validation for qRT-PCR and Western blot. PMID- 22916201 TI - Altered serotonin, dopamine and norepinepherine levels in 15q duplication and Angelman syndrome mouse models. AB - Childhood neurodevelopmental disorders like Angelman syndrome and autism may be the result of underlying defects in neuronal plasticity and ongoing problems with synaptic signaling. Some of these defects may be due to abnormal monoamine levels in different regions of the brain. Ube3a, a gene that causes Angelman syndrome (AS) when maternally deleted and is associated with autism when maternally duplicated has recently been shown to regulate monoamine synthesis in the Drosophila brain. Therefore, we examined monoamine levels in striatum, ventral midbrain, frontal cerebral cortex, cerebellar cortex and hippocampus in Ube3a deficient and Ube3a duplication animals. We found that serotonin (5HT), a monoamine affected in autism, was elevated in the striatum and cortex of AS mice. Dopamine levels were almost uniformly elevated compared to control littermates in the striatum, midbrain and frontal cortex regardless of genotype in Ube3a deficient and Ube3a duplication animals. In the duplication 15q autism mouse model, paternal but not maternal duplication animals showed a decrease in 5HT levels when compared to their wild type littermates, in accordance with previously published data. However, maternal duplication animals show no significant changes in 5HT levels throughout the brain. These abnormal monoamine levels could be responsible for many of the behavioral abnormalities observed in both AS and autism, but further investigation is required to determine if any of these changes are purely dependent on Ube3a levels in the brain. PMID- 22916202 TI - Overexpression of ORCA3 and G10H in Catharanthus roseus plants regulated alkaloid biosynthesis and metabolism revealed by NMR-metabolomics. AB - In order to improve the production of the anticancer dimeric indole alkaloids in Catharanthuse roseus, much research has been dedicated to culturing cell lines, hairy roots, and efforts to elucidate the regulation of the monoterpenoid indole alkaloid (MIA) biosynthesis. In this study, the ORCA3 (Octadecanoid-derivative Responsive Catharanthus AP2-domain) gene alone or integrated with the G10H (geraniol 10-hydroxylase) gene were first introduced into C. roseus plants. Transgenic C. roseus plants overexpressing ORCA3 alone (OR lines), or co overexpressing G10H and ORCA3 (GO lines) were obtained by genetic modification. ORCA3 overexpression induced an increase of AS, TDC, STR and D4H transcripts but did not affect CRMYC2 and G10H transcription. G10H transcripts showed a significant increase under G10H and ORCA3 co-overexpression. ORCA3 and G10H overexpression significantly increased the accumulation of strictosidine, vindoline, catharanthine and ajmalicine but had limited effects on anhydrovinblastine and vinblastine levels. NMR-based metabolomics confirmed the higher accumulation of monomeric indole alkaloids in OR and GO lines. Multivariate data analysis of (1)H NMR spectra showed change of amino acid, organic acid, sugar and phenylpropanoid levels in both OR and GO lines compared to the controls. The result indicated that enhancement of MIA biosynthesis by ORCA3 and G10H overexpression might affect other metabolic pathways in the plant metabolism of C. roseus. PMID- 22916204 TI - Computational identification and functional predictions of long noncoding RNA in Zea mays. AB - BACKGROUND: Computational analysis of cDNA sequences from multiple organisms suggests that a large portion of transcribed DNA does not code for a functional protein. In mammals, noncoding transcription is abundant, and often results in functional RNA molecules that do not appear to encode proteins. Many long noncoding RNAs (lncRNAs) appear to have epigenetic regulatory function in humans, including HOTAIR and XIST. While epigenetic gene regulation is clearly an essential mechanism in plants, relatively little is known about the presence or function of lncRNAs in plants. METHODOLOGY/PRINCIPAL FINDINGS: To explore the connection between lncRNA and epigenetic regulation of gene expression in plants, a computational pipeline using the programming language Python has been developed and applied to maize full length cDNA sequences to identify, classify, and localize potential lncRNAs. The pipeline was used in parallel with an SVM tool for identifying ncRNAs to identify the maximal number of ncRNAs in the dataset. Although the available library of sequences was small and potentially biased toward protein coding transcripts, 15% of the sequences were predicted to be noncoding. Approximately 60% of these sequences appear to act as precursors for small RNA molecules and may function to regulate gene expression via a small RNA dependent mechanism. ncRNAs were predicted to originate from both genic and intergenic loci. Of the lncRNAs that originated from genic loci, ~20% were antisense to the host gene loci. CONCLUSIONS/SIGNIFICANCE: Consistent with similar studies in other organisms, noncoding transcription appears to be widespread in the maize genome. Computational predictions indicate that maize lncRNAs may function to regulate expression of other genes through multiple RNA mediated mechanisms. PMID- 22916203 TI - C. elegans BLOC-1 functions in trafficking to lysosome-related gut granules. AB - The human disease Hermansky-Pudlak syndrome results from defective biogenesis of lysosome-related organelles (LROs) and can be caused by mutations in subunits of the BLOC-1 complex. Here we show that C. elegans glo-2 and snpn-1, despite relatively low levels of amino acid identity, encode Pallidin and Snapin BLOC-1 subunit homologues, respectively. BLOC-1 subunit interactions involving Pallidin and Snapin were conserved for GLO-2 and SNPN-1. Mutations in glo-2 and snpn-1,or RNAi targeting 5 other BLOC-1 subunit homologues in a genetic background sensitized for glo-2 function, led to defects in the biogenesis of lysosome related gut granules. These results indicate that the BLOC-1 complex is conserved in C. elegans. To address the function of C. elegans BLOC-1, we assessed the intracellular sorting of CDF-2::GFP, LMP-1, and PGP-2 to gut granules. We validated their utility by analyzing their mislocalization in intestinal cells lacking the function of AP-3, which participates in an evolutionarily conserved sorting pathway to LROs. BLOC-1(-) intestinal cells missorted gut granule cargo to the plasma membrane and conventional lysosomes and did not have obviously altered function or morphology of organelles composing the conventional lysosome protein sorting pathway. Double mutant analysis and comparison of AP-3(-) and BLOC-1(-) phenotypes revealed that BLOC-1 has some functions independent of the AP-3 adaptor complex in trafficking to gut granules. We discuss similarities and differences of BLOC-1 activity in the biogenesis of gut granules as compared to mammalian melanosomes, where BLOC-1 has been most extensively studied for its role in sorting to LROs. Our work opens up the opportunity to address the function of this poorly understood complex in cell and organismal physiology using the genetic approaches available in C. elegans. PMID- 22916205 TI - NRFL-1, the C. elegans NHERF orthologue, interacts with amino acid transporter 6 (AAT-6) for age-dependent maintenance of AAT-6 on the membrane. AB - The NHERF (Na(+)/H(+) exchanger regulatory factor) family has been proposed to play a key role in regulating transmembrane protein localization and retention at the plasma membrane. Due to the high homology between the family members, potential functional compensations have been a concern in sorting out the function of individual NHERF numbers. Here, we studied C. elegans NRFL-1 (C01F6.6) (nherf-like protein 1), the sole C. elegans orthologue of the NHERF family, which makes worm a model with low genetic redundancy of NHERF homologues. Integrating bioinformatic knowledge of C. elegans proteins into yeast two-hybrid scheme, we identified NRFL-1 as an interactor of AAT-6, a member of the C. elegans AAT (amino acid transporter) family. A combination of GST pull-down assay, localization study, and co-immunoprecipitation confirmed the binding and characterized the PDZ interaction. AAT-6 localizes to the luminal membrane even in the absence of NRFL-1 when the worm is up to four-day old. A fluorescence recovery after photobleaching (FRAP) analysis suggested that NRFL-1 immobilizes AAT-6 at the luminal membrane. When the nrfl-1 deficient worm is six-day or older, in contrast, the membranous localization of AAT-6 is not observed, whereas AAT-6 tightly localizes to the membrane in worms with NRFL-1. Sorting out the in vivo functions of the C. elegans NHERF protein, we found that NRFL-1, a PDZ interactor of AAT-6, is responsible for the immobilization and the age-dependent maintenance of AAT-6 on the intestinal luminal membrane. PMID- 22916206 TI - Origins of albino and hooded rats: implications from molecular genetic analysis across modern laboratory rat strains. AB - Albino and hooded (or piebald) rats are one of the most frequently used laboratory animals for the past 150 years. Despite this fact, the origin of the albino mutation as well as the genetic basis of the hooded phenotype remained unclear. Recently, the albino mutation has been identified as the Arg299His missense mutation in the Tyrosinase gene and the hooded (H) locus has been mapped to the ~460-kb region in which only the Kit gene exists. Here, we surveyed 172 laboratory rat strains for the albino mutation and the hooded (h) mutation that we identified by positional cloning approach to investigate possible genetic roots and relationships of albino and hooded rats. All of 117 existing laboratory albino rats shared the same albino missense mutation, indicating they had only one single ancestor. Genetic fine mapping followed by de novo sequencing of BAC inserts covering the H locus revealed that an endogenous retrovirus (ERV) element was inserted into the first intron of the Kit gene where the hooded allele maps. A solitary long terminal repeat (LTR) was found at the same position to the ERV insertion in another allele of the H locus, which causes the so called Irish (h(i)) phenotype. The ERV and the solitary LTR insertions were completely associated with the hooded and Irish coat patterns, respectively, across all colored rat strains examined. Interestingly, all 117 albino rat strains shared the ERV insertion without any exception, which strongly suggests that the albino mutation had originally occurred in hooded rats. PMID- 22916207 TI - Relationships between PrPSc stability and incubation time for United States scrapie isolates in a natural host system. AB - Transmissible spongiform encephalopathies (TSEs), including scrapie in sheep (Ovis aries), are fatal neurodegenerative diseases caused by the misfolding of the cellular prion protein (PrP(C)) into a a-rich conformer (PrP(Sc)) that accumulates into higher-order structures in the brain and other tissues. Distinct strains of TSEs exist, characterized by different pathologic profiles upon passage into rodents and representing distinct conformations of PrP(Sc). One biochemical method of distinguishing strains is the stability of PrP(Sc) as determined by unfolding in guanidine hydrochloride (GdnHCl), which is tightly and positively correlated with the incubation time of disease upon passage into mice. Here, we utilize a rapid, protease-free version of the stability assay to characterize naturally occurring scrapie samples, including a fast-acting scrapie inoculum for which incubation time is highly dependent on the amino acid at codon 136 of the prion protein. We utilize the stability methodology to identify the presence of two distinct isolates in the inoculum, and compare isolate properties to those of a host-stabilized reference scrapie isolate (NADC 13-7) in order to assess the stability/incubation time correlation in a natural host system. We demonstrate the utility of the stability methodology in characterizing TSE isolates throughout serial passage in livestock, which is applicable to a range of natural host systems, including strains of bovine spongiform encephalopathy and chronic wasting disease. PMID- 22916208 TI - Copepods in turbid shallow soda lakes accumulate unexpected high levels of carotenoids. AB - Carotenoids are protective pigments present in many aquatic organisms that reduce the photooxidative stress induced by short-wavelenght solar radiation, yet increase their susceptibility to predators. Arctodiaptomus spinosus, a calanoid copepod typically found in many fishless shallow soda lakes, shows large between lake differences in pigmentation. Here, we attribute these differences to the environmental state of these ecosystems, namely, 'dark water' lakes with submersed vegetation and turbid 'white' lakes lacking macrophytes. Copepod carotenoid concentration in the turbid 'white' lakes was significantly (about 20 fold) higher than in the 'dark water' ones, although the latter systems were characterized by higher transparency. In addition, males had on a dry weight basis around three times higher carotenoid concentrations than females. Mycosporine-like amino acids (direct UV screening substances) were found in all cases, but in low concentration. The environmental conditions in these ecosystems were largely shaped by the presence/absence of submersed macrophytes Thus, in the turbid lakes, the strong wind-driven mixis allows for copepods to be brought to the surface and being exposed to solar radiation, whereas in 'dark water' ones, macrophytes reduce water turbulence and additionally provide shelter. Our results explain the counter-intuitive notion of strong red pigmentation in copepods from a turbid ecosystem and suggest that factors other than high UV transparency favor carotenoid accumulation in zooplankton. PMID- 22916209 TI - Reduced costs for Staphylococcus aureus carriers treated prophylactically with mupirocin and chlorhexidine in cardiothoracic and orthopaedic surgery. AB - BACKGROUND: A multi centre double-blind randomised-controlled trial (M-RCT), carried out in the Netherlands in 2005-2007, showed that hospitalised patients with S. aureus nasal carriage who were treated prophylactically with mupirocin nasal ointment and chlorhexidine gluconate medicated soap (MUP-CHX), had a significantly lower risk of health-care associated S. aureus infections than patients receiving placebo (3.4% vs. 7.7%, RR 0.42, 95% CI 0.23-0.75). The objective of the present study was to determine whether treatment of patients undergoing elective cardiothoracic or orthopaedic surgery with MUP-CHX (screen and-treat strategy) affected the costs of patient care. METHODS: We compared hospital costs of patients undergoing cardiothoracic or orthopaedic surgery (n=415) in one of the participating centres of the M-RCT. Data from the 'Planning and Control' department were used to calculate total hospital costs of the patients. Total costs were calculated including nursing days, costs of surgery, costs for laboratory and radiological tests, functional assessments and other costs. Costs for personnel, materials and overhead were also included. Mean costs in the two treatment arms were compared using the t-test for equality of means (two-tailed). Subgroup analysis was performed for cardiothoracic and orthopaedic patients. RESULTS: An investigator-blinded analysis revealed that costs of care in the treatment arm (MUP-CHX, n=210) were on average ?1911 lower per patient than costs of care in the placebo arm (n=205) (?8602 vs. ?10513, p=0.01). Subgroup analysis showed that MUP-CHX treated cardiothoracic patients cost ?2841 less (n=280, ?9628 vs ?12469, p=0.006) and orthopaedic patients ?955 less than non-treated patients (n=135, ?6097 vs ?7052, p=0.05). CONCLUSIONS: In conclusion, in patients undergoing cardiothoracic or orthopaedic surgery, screening for S. aureus nasal carriage and treating carriers with MUP-CHX results in a substantial reduction of hospital costs. PMID- 22916210 TI - A single locus is responsible for salinity tolerance in a Chinese landrace barley (Hordeum vulgare L.). AB - INTRODUCTION: Salinity and waterlogging are two major abiotic stresses severely limiting barley production. The lack of a reliable screening method makes it very hard to improve the tolerance through breeding programs. METHODS: This work used 188 DH lines from a cross between a Chinese landrace variety, TX9425 (waterlogging and salinity tolerant), and a Japanese malting barley, Naso Nijo (waterlogging and salinity sensitive), to identify QTLs associated with the tolerance. RESULTS: Four QTLs were found for waterlogging tolerance. The salinity tolerance was evaluated with both a hydroponic system and in potting mixture. In the trial with potting mixture, only one major QTL was identified to associate with salinity tolerance. This QTL explained nearly 50% of the phenotypic variation, which makes it possible for further fine mapping and cloning of the gene. This QTL was also identified in the hydroponic experiment for different salt-related traits. The position of this QTL was located at a similar position to one of the major QTLs for waterlogging tolerance, indicating the possibility of similar mechanisms controlling both waterlogging and salinity tolerance. CONCLUSION: The markers associated with the QTL provided a unique opportunity in breeding programs for selection of salinity and waterlogging tolerance. PMID- 22916211 TI - High hepatitis B surface antigen levels predict insignificant fibrosis in hepatitis B e antigen positive chronic hepatitis B. AB - INTRODUCTION: There is no data on the relationship between hepatitis B surface antigen (HBsAg) levels and liver fibrosis in hepatitis B e antigen (HBeAg) positive patients with chronic hepatitis B (CHB). METHODS: Serum HBsAg and HBV DNA levels in HBeAg-positive CHB patients with liver biopsies were analyzed. The upper limit of normal (ULN) of alanine aminotransferase (ALT) was 30 and 19 U/L for men and women respectively. Histologic assessment was based on Ishak fibrosis staging for fibrosis and Knodell histologic activity index (HAI) for necroinflammation. RESULTS: 140 patients (65% male, median age 32.7 years) were recruited. 56 (40%) had ALT <=2*ULN. 72 (51.4%) and 42 (30%) had fibrosis score <= 1 and necroinflammation grading <= 4 respectively. Patients with fibrosis score <= 1, when compared to patients with fibrosis score >1, had significantly higher median HBsAg levels (50,320 and 7,820 IU/mL respectively, p<0.001). Among patients with ALT <=2*ULN, serum HBsAg levels achieved an area under receiver operating characteristic curve of 0.869 in predicting fibrosis score <= 1. HBsAg levels did not accurately predict necroinflammation score. HBsAg >= 25,000 IU/mL was independently associated with fibrosis score <= 1 (p=0.025, odds ratio 9.042).Using this cut-off HBsAg level in patients with ALT <=2*ULN, positive and negative predictive values for predicting fibrosis score <= 1 were 92.7% and 60.0% respectively. HBV DNA levels had no association with liver histology. CONCLUSION: Among HBeAg-positive patients with ALT <=2*ULN, high serum HBsAg levels can accurately predict fibrosis score <= 1, and could potentially influence decisions concerning treatment commencement and reduce the need for liver biopsy. PMID- 22916212 TI - Exploring overlapping functional units with various structure in protein interaction networks. AB - Revealing functional units in protein-protein interaction (PPI) networks are important for understanding cellular functional organization. Current algorithms for identifying functional units mainly focus on cohesive protein complexes which have more internal interactions than external interactions. Most of these approaches do not handle overlaps among complexes since they usually allow a protein to belong to only one complex. Moreover, recent studies have shown that other non-cohesive structural functional units beyond complexes also exist in PPI networks. Thus previous algorithms that just focus on non-overlapping cohesive complexes are not able to present the biological reality fully. Here, we develop a new regularized sparse random graph model (RSRGM) to explore overlapping and various structural functional units in PPI networks. RSRGM is principally dominated by two model parameters. One is used to define the functional units as groups of proteins that have similar patterns of connections to others, which allows RSRGM to detect non-cohesive structural functional units. The other one is used to represent the degree of proteins belonging to the units, which supports a protein belonging to more than one revealed unit. We also propose a regularizer to control the smoothness between the estimators of these two parameters. Experimental results on four S. cerevisiae PPI networks show that the performance of RSRGM on detecting cohesive complexes and overlapping complexes is superior to that of previous competing algorithms. Moreover, RSRGM has the ability to discover biological significant functional units besides complexes. PMID- 22916213 TI - Role of the dopaminergic system in the acquisition, expression and reinstatement of MDMA-induced conditioned place preference in adolescent mice. AB - BACKGROUND: The rewarding effects of 3,4-methylenedioxy-metamphetamine (MDMA) have been demonstrated in conditioned place preference (CPP) procedures, but the involvement of the dopaminergic system in MDMA-induced CPP and reinstatement is poorly understood. METHODOLOGY/PRINCIPAL FINDINGS: In this study, the effects of the DA D1 antagonist SCH 23390 (0.125 and 0.250 mg/kg), the DA D2 antagonist Haloperidol (0.1 and 0.2 mg/kg), the D2 antagonist Raclopride (0.3 and 0.6 mg/kg) and the dopamine release inhibitor CGS 10746B (3 and 10 mg/kg) on the acquisition, expression and reinstatement of a CPP induced by 10 mg/kg of MDMA were evaluated in adolescent mice. As expected, MDMA significantly increased the time spent in the drug-paired compartment during the post-conditioning (Post-C) test, and a priming dose of 5 mg/kg reinstated the extinguished preference. The higher doses of Haloperidol, Raclopride and CGS 10746B and both doses of SCH 23390 blocked acquisition of the MDMA-induced CPP. However, only Haloperidol blocked expression of the CPP. Reinstatement of the extinguished preference was not affected by any of the drugs studied. Analysis of brain monoamines revealed that the blockade of CPP acquisition was accompanied by an increase in DA concentration in the striatum, with a concomitant decrease in DOPAC and HVA levels. Administration of haloperidol during the Post-C test produced increases in striatal serotonin, DOPAC and HVA concentrations. In mice treated with the higher doses of haloperidol and CGS an increase in SERT concentration in the striatum was detected during acquisition of the CPP, but no changes in DAT were observed. CONCLUSIONS/SIGNIFICANCE: These results demonstrate that, in adolescent mice, the dopaminergic system is involved in the acquisition and expression of MDMA-induced CPP, but not in its reinstatement. PMID- 22916214 TI - Grey matter alterations co-localize with functional abnormalities in developmental dyslexia: an ALE meta-analysis. AB - The neural correlates of developmental dyslexia have been investigated intensively over the last two decades and reliable evidence for a dysfunction of left-hemispheric reading systems in dyslexic readers has been found in functional neuroimaging studies. In addition, structural imaging studies using voxel-based morphometry (VBM) demonstrated grey matter reductions in dyslexics in several brain regions. To objectively assess the consistency of these findings, we performed activation likelihood estimation (ALE) meta-analysis on nine published VBM studies reporting 62 foci of grey matter reduction in dyslexic readers. We found six significant clusters of convergence in bilateral temporo-parietal and left occipito-temporal cortical regions and in the cerebellum bilaterally. To identify possible overlaps between structural and functional deviations in dyslexic readers, we conducted additional ALE meta-analyses of imaging studies reporting functional underactivations (125 foci from 24 studies) or overactivations (95 foci from 11 studies ) in dyslexics. Subsequent conjunction analyses revealed overlaps between the results of the VBM meta-analysis and the meta-analysis of functional underactivations in the fusiform and supramarginal gyri of the left hemisphere. An overlap between VBM results and the meta-analysis of functional overactivations was found in the left cerebellum. The results of our study provide evidence for consistent grey matter variations bilaterally in the dyslexic brain and substantial overlap of these structural variations with functional abnormalities in left hemispheric regions. PMID- 22916215 TI - Three decades of farmed escapees in the wild: a spatio-temporal analysis of Atlantic salmon population genetic structure throughout Norway. AB - Each year, hundreds of thousands of domesticated farmed Atlantic salmon escape into the wild. In Norway, which is the world's largest commercial producer, many native Atlantic salmon populations have experienced large numbers of escapees on the spawning grounds for the past 15-30 years. In order to study the potential genetic impact, we conducted a spatio-temporal analysis of 3049 fish from 21 populations throughout Norway, sampled in the period 1970-2010. Based upon the analysis of 22 microsatellites, individual admixture, F(ST) and increased allelic richness revealed temporal genetic changes in six of the populations. These changes were highly significant in four of them. For example, 76% and 100% of the fish comprising the contemporary samples for the rivers Vosso and Opo were excluded from their respective historical samples at P=0.001. Based upon several genetic parameters, including simulations, genetic drift was excluded as the primary cause of the observed genetic changes. In the remaining 15 populations, some of which had also been exposed to high numbers of escapees, clear genetic changes were not detected. Significant population genetic structuring was observed among the 21 populations in the historical (global F(ST) =0.038) and contemporary data sets (global F(ST) =0.030), although significantly reduced with time (P=0.008). This reduction was especially distinct when looking at the six populations displaying temporal changes (global F(ST) dropped from 0.058 to 0.039, P=0.006). We draw two main conclusions: 1. The majority of the historical population genetic structure throughout Norway still appears to be retained, suggesting a low to modest overall success of farmed escapees in the wild; 2. Genetic introgression of farmed escapees in native salmon populations has been strongly population-dependent, and it appears to be linked with the density of the native population. PMID- 22916216 TI - A multiple-choice task with changes of mind. AB - The role of changes of mind and multiple choices has recently received increased attention in the study of perceptual decision-making. Previously, these extensions to standard two-alternative tasks have been studied separately. Here we explored how changes of mind depend on the number of choice-alternatives. To this end, we tested 14 human subjects on a 2- and 4-alternative direction discrimination task. Changes of mind in the participants' movement trajectories could be observed for two and for four choice alternatives. With fewer alternatives, participants responded faster and more accurately. The frequency of changes of mind, however, did not significantly differ for the different numbers of choice alternatives. Nevertheless, mind-changing improved the participants' final performance, particularly for intermediate difficulty levels, in both experimental conditions. Moreover, the mean reaction times of individual participants were negatively correlated with their overall tendency to make changes of mind. We further reproduced these findings with a multi-alternative attractor model for decision-making, while a simple race model could not account for the experimental data. Our experiment, combined with the theoretical models allowed us to shed light on: (1) the differences in choice behavior between two and four alternatives, (2) the differences between the data of our human subjects and previous monkey data, (3) individual differences between participants, and (4) the inhibitory interaction between neural representations of choice alternatives. PMID- 22916217 TI - The ACTN3 R577X polymorphism across three groups of elite male European athletes. AB - The ACTN3 R577X polymorphism (rs1815739) is a strong candidate to influence elite athletic performance. Yet, controversy exists in the literature owing to between studies differences in the ethnic background and sample size of the cohorts, the latter being usually low, which makes comparisons difficult. In this case:control genetic study we determined the association between elite athletic status and the ACTN3 R577X polymorphism within three cohorts of European Caucasian men, i.e. Spanish, Polish and Russian [633 cases (278 elite endurance and 355 power athletes), and 808 non-athletic controls]. The odds ratio (OR) of a power athlete harbouring the XX versus the RR genotype compared with sedentary controls was 0.54 [95% confidence interval (CI): 0.34-0.48; P=0.006]. We also observed that the OR of an endurance athlete having the XX versus the RR genotype compared with power athletes was 1.88 (95%CI: 1.07-3.31; P=0.028). In endurance athletes, the OR of a "world-class" competitor having the XX genotype versus the RR+RX genotype was 3.74 (95%CI: 1.08-12.94; P=0.038) compared with those of a lower ("national") competition level. No association (P>0.1) was noted between the ACTN3 R577X polymorphism and competition level (world-class versus national-level) in power athletes. Our data provide comprehensive support for the influence of the ACTN3 R577X polymorphism on elite athletic performance. PMID- 22916218 TI - The Methylococcus capsulatus (Bath) secreted protein, MopE*, binds both reduced and oxidized copper. AB - Under copper limiting growth conditions the methanotrophic bacterium Methylococcus capsulatus (Bath) secrets essentially only one protein, MopE*, to the medium. MopE* is a copper-binding protein whose structure has been determined by X-ray crystallography. The structure of MopE* revealed a unique high affinity copper binding site consisting of two histidine imidazoles and one kynurenine, the latter an oxidation product of Trp130. In this study, we demonstrate that the copper ion coordinated by this strong binding site is in the Cu(I) state when MopE* is isolated from the growth medium of M. capsulatus. The conclusion is based on X-ray Near Edge Absorption spectroscopy (XANES), and Electron Paramagnetic Resonance (EPR) studies. EPR analyses demonstrated that MopE*, in addition to the strong copper-binding site, also binds Cu(II) at two weaker binding sites. Both Cu(II) binding sites have properties typical of non-blue type II Cu (II) centres, and the strongest of the two Cu(II) sites is characterised by a relative high hyperfine coupling of copper (A(||) =20 mT). Immobilized metal affinity chromatography binding studies suggests that residues in the N-terminal part of MopE* are involved in forming binding site(s) for Cu(II) ions. Our results support the hypothesis that MopE plays an important role in copper uptake, possibly making use of both its high (Cu(I) and low Cu(II) affinity properties. PMID- 22916219 TI - Modern lineages of Mycobacterium tuberculosis exhibit lineage-specific patterns of growth and cytokine induction in human monocyte-derived macrophages. AB - BACKGROUND: Strains of Mycobacterium tuberculosis vary in virulence. Strains that have caused outbreaks in the United States and United Kingdom have been shown to subvert the innate immune response as a potential immune evasion mechanism. There is, however, little information available as to whether these patterns of immune subversion are features of individual strains or characteristic of broad clonal lineages of M. tuberculosis. METHODS: Strains from two major modern lineages (lineage 2 [East-Asian] and lineage 4 [Euro-American]) circulating in the Western Cape in South Africa as well as a comparator modern lineage (lineage 3 [CAS/Delhi]) were identified. We assessed two virulence associated characteristics: mycobacterial growth (in liquid broth and monocyte derived macrophages) and early pro-inflammatory cytokine induction. RESULTS: In liquid culture, Lineage 4 strains grew more rapidly and reached higher plateau levels than other strains (lineage 4 vs. lineage 2 p=0.0024; lineage 4 vs. lineage 3 p=0.0005). Lineage 3 strains were characterized by low and early plateau levels, while lineage 2 strains showed an intermediate growth phenotype. In monocyte derived macrophages, lineage 2 strains grew faster than lineage 3 strains (p<0.01) with lineage 4 strains having an intermediate phenotype. Lineage 2 strains induced the lowest levels of pro-inflammatory TNF and IL-12p40 as compared to other lineages (lineage 2: median TNF 362 pg/ml, IL-12p40 91 pg/ml; lineage 3: median TNF 1818 pg/ml, IL-12p40 123 pg/ml; lineage 4: median TNF 1207 pg/ml, IL-12p40 205 pg/ml;). In contrast, lineage 4 strains induced high levels of IL-12p40 and intermediate level of TNF. Lineage 3 strains induced high levels of TNF and intermediate levels of IL-12p40. CONCLUSIONS: Strains of M. tuberculosis from the three major modern strain lineages possess distinct patterns of growth and cytokine induction. Rapid growth and immune subversion may be key characteristics to the success of these strains in different human populations. PMID- 22916220 TI - alphaA crystallin may protect against geographic atrophy-meta-analysis of cataract vs. cataract surgery for geographic atrophy and experimental studies. AB - BACKGROUND: Cataract and geographic atrophy (GA, also called advanced "dry" age related macular degeneration) are the two major causes of visual impairment in the developed world. The association between cataract surgery and the development of GA was controversial in previous studies. METHODS/PRINCIPAL FINDINGS: We performed a meta-analysis by pooling the current evidence in literature and found that cataract is associated with an increased risk of geographic atrophy with a summary odds ratio (OR) of 3.75 (95% CI: 95% CI: 1.84-7.62). However, cataract surgery is not associated with the risk of geographic atrophy (polled OR=3.23, 95% CI: 0.63-16.47). Further experiments were performed to analyze how the alphaA crystallin, the major component of the lens, influences the development of GA in a mouse model. We found that thealphaA-crystallin mRNA and protein expression increased after oxidative stress induced by NaIO(3) in immunohistochemistry of retinal section and western blot of posterior eyecups. Both functional and histopathological evidence confirmed that GA is more severe in alphaA-crystallin knockout mice compared to wild-type mice. CONCLUSIONS: Therefore, alphaA crystallin may protect against geographic atrophy. This study provides a better understanding of the relationship between cataract, cataract surgery, and GA. PMID- 22916221 TI - A novel nonsense mutation of the GPR143 gene identified in a Chinese pedigree with ocular albinism. AB - BACKGROUND: The purpose of this study was to elucidate the molecular basis of ocular albinism type I in a Chinese pedigree. METHODOLOGY/PRINCIPAL FINDINGS: Complete ophthalmologic examinations were performed on 4 patients, 7 carriers and 17 unaffected individuals in this five-generation family. All coding exons of four-point-one (4.1), ezrin, radixin, moesin (FERM) domain-containing 7 (FRMD7) and G protein-coupled receptor 143 (GPR143) genes were amplified by polymerase chain reaction (PCR), sequenced and compared with a reference database. Ocular albinism and nystagmus were found in all patients of this family. Macular hypoplasia was present in the patients including the proband. A novel nonsense hemizygous mutation c.807T>A in the GPR143 gene was identified in four patients and the heterozygous mutation was found in seven asymptomatic individuals. This mutation is a substitution of tyrosine for adenine which leads to a premature stop codon at position 269 (p.Y269X) of GPR143. CONCLUSIONS/SIGNIFICANCE: This is the first report that p.Y269X mutation of GPR143 gene is responsible for the pathogenesis of familial ocular albinism. These results expand the mutation spectrum of GPR143, and demonstrate the clinical characteristics of ocular albinism type I in Chinese population. PMID- 22916222 TI - Role of TRPM2 in H(2)O(2)-induced cell apoptosis in endothelial cells. AB - Melastatin-like transient receptor potential channel 2 (TRPM2) is an oxidant sensitive and cationic non-selective channel that is expressed in mammalian vascular endothelium. Here we investigated the functional role of TRPM2 channels in hydrogen peroxide (H(2)O(2))-induced cytosolic Ca(2+) ([Ca(2+)](i)) elavation, whole-cell current increase, and apoptotic cell death in murine heart microvessel endothelial cell line H5V. A TRPM2 blocking antibody (TM2E3), which targets the E3 region near the ion permeation pore of TRPM2, was developed. Treatment of H5V cells with TM2E3 reduced the [Ca(2+)](i) rise and whole-cell current change in response to H(2)O(2). Suppressing TRPM2 expression using TRPM2-specific short hairpin RNA (shRNA) had similar inhibitory effect. H(2)O(2)-induced apoptotic cell death in H5V cells was examined using MTT assay, DNA ladder formation analysis, and DAPI-based nuclear DNA condensation assay. Based on these assays, TM2E3 and TRPM2-specific shRNA both showed protective effect against H(2)O(2) induced apoptotic cell death. TM2E3 and TRPM2-specific shRNA also protect the cells from tumor necrosis factor (TNF)-alpha-induced cell death in MTT assay. In contrast, overexpression of TRPM2 in H5V cells resulted in an increased response in [Ca(2+)](i) and whole-cell currents to H(2)O(2). TRPM2 overexpression also aggravated the H(2)O(2)-induced apoptotic cell death. Downstream pathways following TRPM2 activation was examined. Results showed that TRPM2 activity stimulated caspase-8, caspase-9 and caspase-3. These findings strongly suggest that TRPM2 channel mediates cellular Ca(2+) overload in response to H(2)O(2) and contribute to oxidant-induced apoptotic cell death in vascular endothelial cells. Down-regulating endogenous TRPM2 could be a means to protect the vascular endothelial cells from apoptotic cell death. PMID- 22916223 TI - Protease-activated receptor 2 mediates mucus secretion in the airway submucosal gland. AB - Protease-activated receptor 2 (PAR2), a G protein-coupled receptor expressed in airway epithelia and smooth muscle, plays an important role in airway inflammation. In this study, we demonstrated that activation of PAR2 induces mucus secretion from the human airway gland and examined the underlying mechanism using the porcine and murine airway glands. The mucosa with underlying submucosal glands were dissected from the cartilage of tissues, pinned with the mucosal side up at the gas/bath solution interface of a physiological chamber, and covered with oil so that secretions from individual glands could be visualized as spherical bubbles in the oil. Secretion rates were determined by optical monitoring of the bubble diameter. The Ca(2+)-sensitive dye Fura2-AM was used to determine intracellular Ca(2+) concentration ([Ca(2+)](i)) by means of spectrofluorometry. Stimulation of human tracheal mucosa with PAR2-activating peptide (PAR2-AP) elevated intracellular Ca(2+) and induced glandular secretion equal to approximately 30% of the carbachol response in the human airway. Porcine gland tissue was more sensitive to PAR2-AP, and this response was dependent on Ca(2+) and anion secretion. When the mouse trachea were exposed to PAR2-AP, large amounts of secretion were observed in both wild type and DeltaF508 cystic fibrosis transmembrane conductance regulator mutant mice but there is no secretion from PAR-2 knock out mice. In conclusion, PAR2-AP is an agonist for mucus secretion from the airway gland that is Ca(2+)-dependent and cystic fibrosis transmembrane conductance regulator-independent. PMID- 22916226 TI - Integrating fasciolosis control in the dry cow management: the effect of closantel treatment on milk production. AB - The liver fluke Fasciola hepatica is a parasite of ruminants with a worldwide distribution and an apparent increasing incidence in EU member states. Effective control in dairy cattle is hampered by the lack of flukicides with a zero withdrawal time for milk, leaving the dry period as the only time that preventive treatment can be applied. Here, we present the results of a blinded, randomized and placebo-controlled trial on 11 dairy herds (402 animals) exposed to F. hepatica to 1) assess the effect of closantel treatment at dry-off (or 80-42 days before calving in first-calving heifers) on milk production parameters and 2) evaluate if a number of easy-to-use animal parameters is related to the milk production response after treatment. Closantel treatment resulted in a noticeable decrease of anti-F. hepatica antibody levels from 3-6 months after treatment onwards, a higher peak production (1.06 kg) and a slightly higher persistence (9%) of the lactation, resulting in a 305-day milk production increase of 303 kg. No effects of anthelmintic treatment were found on the average protein and fat content of the milk. Milk production responses after treatment were poor in meagre animals and clinically relevant higher milk production responses were observed in first-lactation animals and in cows with a high (0.3-0.5 optical density ratio (ODR)), but not a very high (>= 0.5 ODR) F. hepatica ELISA result on a milk sample from the previous lactation. We conclude that in dairy herds exposed to F. hepatica, flukicide treatment at dry-off is a useful strategy to reduce levels of exposure and increase milk production in the subsequent lactation. Moreover, the results suggest that treatment approaches that only target selected animals within a herd can be developed based on easy-to-use parameters. PMID- 22916224 TI - Endothelin B receptors contribute to retinal ganglion cell loss in a rat model of glaucoma. AB - Glaucoma is an optic neuropathy, commonly associated with elevated intraocular pressure (IOP) characterized by optic nerve degeneration, cupping of the optic disc, and loss of retinal ganglion cells which could lead to loss of vision. Endothelin-1 (ET-1) is a 21-amino acid vasoactive peptide that plays a key role in the pathogenesis of glaucoma; however, the receptors mediating these effects have not been defined. In the current study, endothelin B (ET(B)) receptor expression was assessed in vivo, in the Morrison's ocular hypertension model of glaucoma in rats. Elevation of IOP in Brown Norway rats produced increased expression of ET(B) receptors in the retina, mainly in retinal ganglion cells (RGCs), nerve fiber layer (NFL), and also in the inner plexiform layer (IPL) and inner nuclear layer (INL). To determine the role of ET(B) receptors in neurodegeneration, Wistar-Kyoto wild type (WT) and ET(B) receptor-deficient (KO) rats were subjected to retrograde labeling with Fluoro-Gold (FG), following which IOP was elevated in one eye while the contralateral eye served as control. IOP elevation for 4 weeks in WT rats caused an appreciable loss of RGCs, which was significantly attenuated in KO rats. In addition, degenerative changes in the optic nerve were greatly reduced in KO rats compared to those in WT rats. Taken together, elevated intraocular pressure mediated increase in ET(B) receptor expression and its activation may contribute to a decrease in RGC survival as seen in glaucoma. These findings raise the possibility of using endothelin receptor antagonists as neuroprotective agents for the treatment of glaucoma. PMID- 22916225 TI - Development and characterization of a caprine aerosol infection model of melioidosis. AB - Infection with Burkholderia pseudomallei causes the disease melioidosis, which often presents as a serious suppurative infection that is typically fatal without intensive treatment and is a significant emerging infectious disease in Southeast Asia. Despite intensive research there is still much that remains unknown about melioidosis pathogenesis. New animal models of melioidosis are needed to examine novel aspects of pathogenesis as well as for the evaluation of novel therapeutics. The objective of the work presented here was to develop a subacute to chronic caprine model of melioidosis and to characterize the progression of disease with respect to clinical presentation, hematology, clinical microbiology, thoracic radiography, and gross and microscopic pathology. Disease was produced in all animals following an intratracheal aerosol of 10(4) CFU delivered, with variable clinical manifestations indicative of subacute and chronic disease. Bronchointerstitial pneumonia was apparent microscopically by day 2 and radiographically and grossly apparent by day 7 post infection (PI). Early lesions of bronchopneumonia soon progressed to more severe bronchointerstitial pneumonia with pyogranuloma formation. Extrapulmonary dissemination appeared to be a function of pyogranuloma invasion of pulmonary vasculature, which peaked around day 7 PI. Histopathology indicated that leukocytoclastic vasculitis was the central step in dissemination of B. pseudomallei from the lungs as well as in the establishment of new lesions. While higher doses of organism in goats can produce acute fatal disease, the dose investigated and resulting disease had many similarities to human melioidosis and may warrant further development to provide a model for the study of both natural and bioterrorism associated disease. PMID- 22916227 TI - CLEARPOND: cross-linguistic easy-access resource for phonological and orthographic neighborhood densities. AB - Past research has demonstrated cross-linguistic, cross-modal, and task-dependent differences in neighborhood density effects, indicating a need to control for neighborhood variables when developing and interpreting research on language processing. The goals of the present paper are two-fold: (1) to introduce CLEARPOND (Cross-Linguistic Easy-Access Resource for Phonological and Orthographic Neighborhood Densities), a centralized database of phonological and orthographic neighborhood information, both within and between languages, for five commonly-studied languages: Dutch, English, French, German, and Spanish; and (2) to show how CLEARPOND can be used to compare general properties of phonological and orthographic neighborhoods across languages. CLEARPOND allows researchers to input a word or list of words and obtain phonological and orthographic neighbors, neighborhood densities, mean neighborhood frequencies, word lengths by number of phonemes and graphemes, and spoken-word frequencies. Neighbors can be defined by substitution, deletion, and/or addition, and the database can be queried separately along each metric or summed across all three. Neighborhood values can be obtained both within and across languages, and outputs can optionally be restricted to neighbors of higher frequency. To enable researchers to more quickly and easily develop stimuli, CLEARPOND can also be searched by features, generating lists of words that meet precise criteria, such as a specific range of neighborhood sizes, lexical frequencies, and/or word lengths. CLEARPOND is freely-available to researchers and the public as a searchable, online database and for download at http://clearpond.northwestern.edu. PMID- 22916228 TI - The PLOS ONE synthetic biology collection: six years and counting. AB - Since it was launched in 2006, PLOS ONE has published over fifty articles illustrating the many facets of the emerging field of synthetic biology. This article reviews these publications by organizing them into broad categories focused on DNA synthesis and assembly techniques, the development of libraries of biological parts, the use of synthetic biology in protein engineering applications, and the engineering of gene regulatory networks and metabolic pathways. Finally, we review articles that describe enabling technologies such as software and modeling, along with new instrumentation. In order to increase the visibility of this body of work, the papers have been assembled into the PLOS ONE Synthetic Biology Collection (www.ploscollections.org/synbio). Many of the innovative features of the PLOS ONE web site will help make this collection a resource that will support a lively dialogue between readers and authors of PLOS ONE synthetic biology papers. The content of the collection will be updated periodically by including relevant articles as they are published by the journal. Thus, we hope that this collection will continue to meet the publishing needs of the synthetic biology community. PMID- 22916229 TI - Atrial natriuretic peptide and adiponectin interactions in man. AB - Reduced circulating natriuretic peptide concentrations are independently associated with insulin resistance and type 2 diabetes, while increased natriuretic peptide levels appear to be protective. Observations in vitro and in heart failure patients suggest that atrial natriuretic peptide (ANP) promotes adiponectin release, an adipokine with insulin sensitizing properties. We tested the hypothesis that ANP acutely raises adiponectin levels in 12 healthy men. We infused ANP intravenously over 135 minutes while collecting venous blood and adipose tissue microdialysates at baseline and at the end of ANP-infusion. We obtained blood samples at identical time-points without ANP infusion in 7 age and BMI matched men. With infusion, venous ANP concentrations increased ~10 fold. Systemic and adipose tissue glycerol concentrations increased 70% and 80%, respectively (P<0.01). ANP infusion increased total adiponectin 14 +/- 5% and high molecular-weight (HMW)-adiponectin 13 +/- 5% (P<0.05). Adiponectin did not change in the control group (P<0.05 vs. infusion). ANP-induced changes in HMW adiponectin and adipose tissue lipolysis were directly correlated with each other, possibly suggesting a common mechanism. Our data show that ANP acutely increases systemic total and HMW-adiponectin concentrations in healthy subjects. Our study could have implications for the physiological regulation of adiponectin and for disease states associated with altered natriuretic peptide availability. PMID- 22916231 TI - The ability of PVX p25 to form RL structures in plant cells is necessary for its function in movement, but not for its suppression of RNA silencing. AB - The p25 triple gene block protein of Potato virus X (PVX) is multifunctional, participating in viral movement and acting as a suppressor of RNA silencing. The cell-to-cell movement of PVX is known to depend on the suppression function of p25. GFP-fused p25 accumulates in rod-like (RL) structures with intense fluorescence in cells. By monitoring the location of fluorescence at different times, we have now shown that the RL structure is composed of filaments. P25 mutants without the conditional ability to recover movement function could not form RL structures while the mutants that had the ability did form the structure, suggesting that the ability of p25 to form RL structures is necessary for its function in cell-to-cell movement, but not for its suppressor function. Moreover, chemical inhibition of microfilaments in cells destroyed the formation of the complete RL structure. Additionally, TGBp2 and TGBp3 were recruited into the RL structure, suggesting a relationship between the TGBps in virus movement. PMID- 22916230 TI - Combined species identification, genotyping, and drug resistance detection of Mycobacterium tuberculosis cultures by MLPA on a bead-based array. AB - The population structure of Mycobacterium tuberculosis is typically clonal therefore genotypic lineages can be unequivocally identified by characteristic markers such as mutations or genomic deletions. In addition, drug resistance is mainly mediated by mutations. These issues make multiplexed detection of selected mutations potentially a very powerful tool to characterise Mycobacterium tuberculosis. We used Multiplex Ligation-dependent Probe Amplification (MLPA) to screen for dispersed mutations, which can be successfully applied to Mycobacterium tuberculosis as was previously shown. Here we selected 47 discriminative and informative markers and designed MLPA probes accordingly to allow analysis with a liquid bead array and robust reader (Luminex MAGPIX technology). To validate the bead-based MLPA, we screened a panel of 88 selected strains, previously characterised by other methods with the developed multiplex assay using automated positive and negative calling. In total 3059 characteristics were screened and 3034 (99.2%) were consistent with previous molecular characterizations, of which 2056 (67.2%) were directly supported by other molecular methods, and 978 (32.0%) were consistent with but not directly supported by previous molecular characterizations. Results directly conflicting or inconsistent with previous methods, were obtained for 25 (0.8%) of the characteristics tested. Here we report the validation of the bead-based MLPA and demonstrate its potential to simultaneously identify a range of drug resistance markers, discriminate the species within the Mycobacterium tuberculosis complex, determine the genetic lineage and detect and identify the clinically most relevant non-tuberculous mycobacterial species. The detection of multiple genetic markers in clinically derived Mycobacterium tuberculosis strains with a multiplex assay could reduce the number of TB-dedicated screening methods needed for full characterization. Additionally, as a proportion of the markers screened are specific to certain Mycobacterium tuberculosis lineages each profile can be checked for internal consistency. Strain characterization can allow selection of appropriate treatment and thereby improve treatment outcome and patient management. PMID- 22916232 TI - Modeling of arylamide helix mimetics in the p53 peptide binding site of hDM2 suggests parallel and anti-parallel conformations are both stable. AB - The design of novel alpha-helix mimetic inhibitors of protein-protein interactions is of interest to pharmaceuticals and chemical genetics researchers as these inhibitors provide a chemical scaffold presenting side chains in the same geometry as an alpha-helix. This conformational arrangement allows the design of high affinity inhibitors mimicking known peptide sequences binding specific protein substrates. We show that GAFF and AutoDock potentials do not properly capture the conformational preferences of alpha-helix mimetics based on arylamide oligomers and identify alternate parameters matching solution NMR data and suitable for molecular dynamics simulation of arylamide compounds. Results from both docking and molecular dynamics simulations are consistent with the arylamides binding in the p53 peptide binding pocket. Simulations of arylamides in the p53 binding pocket of hDM2 are consistent with binding, exhibiting similar structural dynamics in the pocket as simulations of known hDM2 binders Nutlin-2 and a benzodiazepinedione compound. Arylamide conformations converge towards the same region of the binding pocket on the 20 ns time scale, and most, though not all dihedrals in the binding pocket are well sampled on this timescale. We show that there are two putative classes of binding modes for arylamide compounds supported equally by the modeling evidence. In the first, the arylamide compound lies parallel to the observed p53 helix. In the second class, not previously identified or proposed, the arylamide compound lies anti-parallel to the p53 helix. PMID- 22916233 TI - Optimal therapy for adults with Langerhans cell histiocytosis bone lesions. AB - BACKGROUND: There is little data on treatment of Langerhans cell histiocytosis (LCH) in adults. Available data is on small numbers of patients with short follow up times and no comparison of results from different treatment regimens. We analyzed the responses of adult LCH patients with bone lesions to three primary chemotherapy treatments to define the optimal one. METHODS AND FINDINGS: Fifty eight adult patients with bone lesions, either as a solitary site or as a component of multisystem disease, were analyzed for disease location and response to surgery, curettage, steroids, radiation, vinblastine/prednisone, 2 Chlorodeoxyadenosine (2-CdA), or cytosine arabinoside (ARA-C). The mean age of patients was 32 years, with equal gender distribution. Twenty-nine patients had 1 lesion; 16, 2 lesions; 5, 3 lesions; and 8 had 4 or more. Most bone lesions were in the skull, spine, or jaw. Chemotherapy, surgery, curettage, or radiation, but not steroids alone, achieved improvement or resolution of lesions in a majority of patients. Comparison of the three chemotherapy regimens revealed 84% of patients treated with vinblastine/prednisone either did not respond or relapsed within a year, whereas 59% of patients treated with 2-CdA and 21% treated with ARA-C failed. Toxicity was worse with the vinblastine/prednisone group as 75% had grade 3-4 neuropathy. Grade 3-4 cytopenias occurred in 37% of the 2-CdA -treated patients and 20% of the ARA-C-treated patients. The major limitation of this study is it is retrospective and not a clinical trial. CONCLUSIONS: ARA-C is an effective and minimally toxic treatment for LCH bone lesions in adults. In contrast, vinblastine/prednisone results in poor overall responses and excessive toxicity. PMID- 22916234 TI - Pediatric vancomycin use in 421 hospitals in the United States, 2008. AB - BACKGROUND: Recommendations to prevent the spread of vancomycin resistance have been in place since 1995 and include guidelines for inpatient pediatric use of vancomycin. The emergence of large databases allows us to describe variation in pediatric vancomycin across hospitals. We analyzed a database with hospitalizations for children under 18 at 421 hospitals in 2008. METHODOLOGY/PRINCIPAL FINDINGS: The Premier hospital 2008 database, consisting of records for 877,201 pediatric hospitalizations in 421 hospitals, was analyzed. Stratified analyses and logistic mixed effects models were used to calculate the probability of vancomycin use while considering random effects of hospital variation, hospital fixed effects and patient effects, and the hierarchical structure of the data. Most hospitals (221) had fewer than 10 hospitalizations with vancomycin use in the study period, and 47 hospitals reported no vancomycin use in 17,271 pediatric hospitalizations. At the other end of the continuum, 21 hospitals (5.6% of hospitals) each had over 200 hospitalizations with vancomycin use, and together, accounted for more than 50% of the pediatric hospitalizations with vancomycin use. The mixed effects modeling showed hospital variation in the probability of vancomycin use that was statistically significant after controlling for teaching status, urban or rural location, size, region of the country, patient ethnic group, payor status, and APR-mortality and severity codes. CONCLUSIONS/SIGNIFICANCE: The number and percentage of pediatric hospitalizations with vancomycin use varied greatly across hospitals and was not explained by hospital or patient characteristics in our logistic models. Public health efforts to reduce vancomycin use should be intensified at hospitals with highest use. PMID- 22916235 TI - Eco-geographical diversification of bitter taste receptor genes (TAS2Rs) among subspecies of chimpanzees (Pan troglodytes). AB - Chimpanzees (Pan troglodytes) have region-specific difference in dietary repertoires from East to West across tropical Africa. Such differences may result from different genetic backgrounds in addition to cultural variations. We analyzed the sequences of all bitter taste receptor genes (cTAS2Rs) in a total of 59 chimpanzees, including 4 putative subspecies. We identified genetic variations including single-nucleotide variations (SNVs), insertions and deletions (indels), gene-conversion variations, and copy-number variations (CNVs) in cTAS2Rs. Approximately two-thirds of all cTAS2R haplotypes in the amino acid sequence were unique to each subspecies. We analyzed the evolutionary backgrounds of natural selection behind such diversification. Our previous study concluded that diversification of cTAS2Rs in western chimpanzees (P. t. verus) may have resulted from balancing selection. In contrast, the present study found that purifying selection dominates as the evolutionary form of diversification of the so-called human cluster of cTAS2Rs in eastern chimpanzees (P. t. schweinfurthii) and that the other cTAS2Rs were under no obvious selection as a whole. Such marked diversification of cTAS2Rs with different evolutionary backgrounds among subspecies of chimpanzees probably reflects their subspecies-specific dietary repertoires. PMID- 22916236 TI - AID enzymatic activity is inversely proportional to the size of cytosine C5 orbital cloud. AB - Activation induced deaminase (AID) deaminates cytosine to uracil, which is required for a functional humoral immune system. Previous work demonstrated, that AID also deaminates 5-methylcytosine (5 mC). Recently, a novel vertebrate modification (5-hydroxymethylcytosine - 5 hmC) has been implicated in functioning in epigenetic reprogramming, yet no molecular pathway explaining the removal of 5 hmC has been identified. AID has been suggested to deaminate 5 hmC, with the 5 hmU product being repaired by base excision repair pathways back to cytosine. Here we demonstrate that AID's enzymatic activity is inversely proportional to the electron cloud size of C5-cytosine - H > F > methyl >> hydroxymethyl. This makes AID an unlikely candidate to be part of 5 hmC removal. PMID- 22916237 TI - Deep sequencing reveals complex spurious transcription from transiently transfected plasmids. AB - Transient plasmid transfection is a common approach in studies in cultured mammalian cells. To examine behavior of transfected plasmids, we analyzed their transcriptional landscape by deep sequencing. We have found that the entire plasmid sequence is transcribed at different levels. Spurious transcription may have undesirable effects as some plasmids, when co-transfected, inhibited expression of luciferase reporters in a dose-dependent manner. In one case, we attributed this effect to a Kan/Neo resistance cassette, which generated a unique population of edited sense and antisense small RNAs. The unexpected complexity of expression from transiently transfected plasmids underscores the importance of appropriate experimental controls. PMID- 22916238 TI - Validating serum S100B and neuron-specific enolase as biomarkers for the human brain - a combined serum, gene expression and MRI study. AB - INTRODUCTION: Former studies have investigated the potential of serum biomarkers for diseases affecting the human brain. In particular the glial protein S100B, a neuro- and gliotrophin inducing plasticity, seems to be involved in the pathogenesis and treatment of psychiatric diseases such as major depression and schizophrenia. Neuron-specific enolase (NSE) is a specific serum marker for neuronal damage. However, the specificity of these biomarkers for cell type and brain region has not been investigated in vivo until now. METHODS: We acquired two magnetic resonance imaging parameters sensitive to changes in gray and white matter (T(1)-weighted/diffusion tensor imaging) and obtained serum S100B and NSE levels of 41 healthy subjects. Additionally, we analyzed whole brain gene expressions of S100B in another male cohort of three subjects using the Allen Brain Atlas. Furthermore, a female post mortal brain was investigated using double immunofluorescence labelling with oligodendrocyte markers. RESULTS: We show that S100B is specifically related to white matter structures, namely the corpus callosum, anterior forceps and superior longitudinal fasciculus in female subjects. This effect was observed in fractional anisotropy and radial diffusivity - the latest an indicator of myelin changes. Histological data confirmed a co-localization of S100B with oligodendrocyte markers in the human corpus callosum. S100B was most abundantly expressed in the corpus callosum according to the whole genome Allen Human Brain Atlas. In addition, NSE was related to gray matter structures, namely the amygdala. This effect was detected across sexes. CONCLUSION: Our data demonstrates a very high S100B expression in white matter tracts, in particular in human corpus callosum. Our study is the first in vivo study validating the specificity of the glial marker S100B for the human brain, and supporting the assumption that radial diffusivity represents a myelin marker. Our results open a new perspective for future studies investigating major neuropsychiatric disorders. PMID- 22916239 TI - Luteolin induces microRNA-132 expression and modulates neurite outgrowth in PC12 cells. AB - Luteolin (3',4',5,7-tetrahydroxyflavone), a food-derived flavonoid, has been reported to exert neurotrophic properties that are associated with its capacity to promote neuronal survival and neurite outgrowth. In this study, we report for the first time that luteolin induces the persistent expression of microRNA-132 (miR-132) in PC12 cells. The correlation between miR-132 knockdown and a decrease in luteolin-mediated neurite outgrowth may indicate a mechanistic link by which miR-132 functions as a mediator for neuritogenesis. Furthermore, we find that luteolin led to the phosphorylation and activation of cAMP response element binding protein (CREB), which is associated with the up-regulation of miR-132 and neurite outgrowth. Moreover, luteolin-induced CREB activation, miR-132 expression and neurite outgrowth were inhibited by adenylate cyclase, protein kinase A (PKA) and MAPK/ERK kinase 1/2 (MEK1/2) inhibitors but not by protein kinase C (PKC) or calcium/calmodulin-dependent protein kinase II (CaMK II) inhibitors. Consistently, we find that luteolin treatment increases ERK phosphorylation and PKA activity in PC12 cells. These results show that luteolin induces the up regulation of miR-132, which serves as an important regulator for neurotrophic actions, mainly acting through the activation of cAMP/PKA- and ERK-dependent CREB signaling pathways in PC12 cells. PMID- 22916240 TI - Natural iminosugar (+)-lentiginosine inhibits ATPase and chaperone activity of hsp90. AB - Heat shock protein 90 (Hsp90) is a significant target in the development of rational cancer therapy due to its role at the crossroads of multiple signaling pathways associated with cell proliferation and cell viability. The relevance of Hsp90 as a therapeutic target for numerous diseases states has prompted the identification and optimization of novel Hsp90 inhibitors as an emerging therapeutic strategy. We performed a screening aimed to identify novel Hsp90 inhibitors among several natural compounds and we focused on the iminosugar (+) lentiginosine, a natural amyloglucosidases inhibitor, for its peculiar bioactivity profile. Characterization of Hsp90 inhibition was performed using a panel of chemical and biological approaches, including limited proteolysis, biochemical and cellular assays. Our result suggested that the middle domain of Hsp90, as opposed to its ATP-binding pocket, is a promising binding site for new classes of Hsp90 inhibitors with multi-target anti-cancer potential. PMID- 22916241 TI - The honey bee parasite Nosema ceranae: transmissible via food exchange? AB - Nosema ceranae, a newly introduced parasite of the honey bee, Apis mellifera, is contributing to worldwide colony losses. Other Nosema species, such as N. apis, tend to be associated with increased defecation and spread via a fecal-oral pathway, but because N. ceranae does not induce defecation, it may instead be spread via an oral-oral pathway. Cages that separated older infected bees from young uninfected bees were used to test whether N. ceranae can be spread during food exchange. When cages were separated by one screen, food could be passed between the older bees and the young bees, but when separated by two screens, food could not be passed between the two cages. Young uninfected bees were also kept isolated in cages, as a solitary control. After 4 days of exposure to the older bees, and 10 days to incubate infections, young bees were more likely to be infected in the 1-Screen Test treatment vs. the 2-Screen Test treatment (P=0.0097). Young bees fed by older bees showed a 13-fold increase in mean infection level relative to young bees not fed by older bees (1-Screen Test 40.8%; 2-Screen Test 3.4%; Solo Control 2.8%). Although fecal-oral transmission is still possible in this experimental design, oral-oral infectivity could help explain the rapid spread of N. ceranae worldwide. PMID- 22916242 TI - Influence of galloyl moiety in interaction of epicatechin with bovine serum albumin: a spectroscopic and thermodynamic characterization. AB - The health benefits stemming from green tea are well known, but the exact mechanism of its biological activity is not elucidated. Epicatechin (EC) and epicatechin gallate (ECG) are two dietary catechins ubiquitously present in green tea. Serum albumins functionally carry these catechins through the circulatory system and eliminate reactive oxygen species (ROS) induced injury. In the present study ECG is observed to have higher antioxidant activity; which is attributed to the presence of galloyl moiety. The binding affinity of these catechins to bovine serum albumin (BSA) will govern the efficacy of their biological activity. EC and ECG bind with BSA with binding constants 1.0 * 10(6) M(-1) and 6.6 * 10(7) M(-1), respectively. Changes in secondary structure of BSA on interaction with EC and ECG have been identified by circular dichroism (CD) and Fourier transform infrared (FT-IR) spectroscopy. Thermodynamic characterization reveals the binding process to be exothermic, spontaneous and entropy driven. Mixed binding forces (hydrophobic, electrostatic and hydrogen bonding) exist between ECG and BSA. Binding site for EC is primarily site-II in sub-domain IIIA of BSA and for ECG; it is site-I in sub-domain IIA. ECG with its high antioxidant activity accompanied by high affinity for BSA could be a model in drug designing. PMID- 22916243 TI - Plexin-B2 and Plexin-D1 in dendritic cells: expression and IL-12/IL-23p40 production. AB - Plexins are a family of genes (A,B,C, and D) that are expressed in many organ systems. Plexins expressed in the immune system have been implicated in cell movement and cell-cell interaction during the course of an immune response. In this study, the expression pattern of Plexin-B2 and Plexin-D1 in dendritic cells (DCs), which are central in immune activation, was investigated. Plexin-B2 and Plexin-D1 are reciprocally expressed in myeloid and plasmacytoid DC populations. Plasmacytoid DCs have high Plexin-B2 but low Plexin-D1, while the opposite is true of myeloid DCs. Expression of Plexin-B2 and Plexin-D1 is modulated upon activation of DCs by TLR ligands, TNFalpha, and anti-CD40, again in a reciprocal fashion. Semaphorin3E, a ligand for Plexin-D1 and Plexin-B2, is expressed by T cells, and interestingly, is dramatically higher on Th2 cells and on DCs. The expression of Plexins and their ligands on DCs and T cells suggest functional relevance. To explore this, we utilized chimeric mice lacking Plxnb2 or Plxnd1. Absence of Plexin-B2 and Plexin-D1 on DCs did not affect the ability of these cells to upregulate costimulatory molecules or the ability of these cells to activate antigen specific T cells. Additionally, Plexin-B2 and Plexin-D1 were dispensable for chemokine-directed in-vitro migration of DCs towards key DC chemokines, CXCL12 and CCL19. However, the absence of either Plexin-B2 or Plexin D1 on DCs leads to constitutive expression of IL-12/IL-23p40. This is the first report to show an association between Plexin-B2 and Plexin-D1 with the negative regulation of IL-12/IL-23p40 in DCs. This work also shows the presence of Plexin B2 and Plexin-D1 on mouse DC subpopulations, and indicates that these two proteins play a role in IL-12/IL-23p40 production that is likely to impact the immune response. PMID- 22916244 TI - Spatial genetic structure in natural populations of Phragmites australis in a mosaic of saline habitats in the Yellow River Delta, China. AB - Determination of spatial genetic structure (SGS) in natural populations is important for both theoretical aspects of evolutionary genetics and their application in species conservation and ecological restoration. In this study, we examined genetic diversity within and among the natural populations of a cosmopolitan grass Phragmites australis (common reed) in the Yellow River Delta (YRD), China, where a mosaic of habitat patches varying in soil salinity was detected. We demonstrated that, despite their close geographic proximity, the common reed populations in the YRD significantly diverged at six microsatellite loci, exhibiting a strong association of genetic variation with habitat heterogeneity. Genetic distances among populations were best explained as a function of environmental difference, rather than geographical distance. Although the level of genetic divergence among populations was relatively low (F'(ST) =0.073), weak but significant genetic differentiation, as well as the concordance between ecological and genetic landscapes, suggests spatial structuring of genotypes in relation to patchy habitats. These findings not only provided insights into the population dynamics of common reed in changing environments, but also demonstrated the feasibility of using habitat patches in a mosaic landscape as test systems to identify appropriate genetic sources for ecological restoration. PMID- 22916245 TI - Nanostructured synthetic carbons obtained by pyrolysis of spherical acrylonitrile/divinylbenzene copolymers. AB - Novel carbon materials have been prepared by the carbonization of acrylonitrile (AN)/divinylbenzene (DVB) suspension porous copolymers having nominal crosslinking degrees in the range of 30-70% and obtained in the presence of various amounts of porogens. The carbons were obtained by pre-oxidation of AN/DVB copolymers at 250-350 degrees C in air followed by pyrolysis at 850 degrees C in an N(2) atmosphere. Both processes were carried out in one furnace and the resulting material needed no further activation. Resulting materials were characterized by XPS and low temperature nitrogen adsorption/desorption. It was found that maximum pyrolysis yield was ca. 50% depending on the oxidation conditions but almost independent of the crosslinking degree of the polymers. Porous structure of the carbons was characterized for the presence of micropores and macropores, when obtained from highly crosslinked polymers or polymers oxidized at 350 degrees C and meso- and macropores in all other cases. The latter pores are prevailing in the structure of carbons obtained from less porous AN/DVB resins. Specific surface area (BET) of polymer derived carbons can vary between 440 m(2)/g and 250 m(2)/g depending on the amount of porogen used in the synthesis of the AN/DVB polymeric precursors. PMID- 22916246 TI - Genomic instability and telomere fusion of canine osteosarcoma cells. AB - Canine osteosarcoma (OSA) is known to present with highly variable and chaotic karyotypes, including hypodiploidy, hyperdiploidy, and increased numbers of metacentric chromosomes. The spectrum of genomic instabilities in canine OSA has significantly augmented the difficulty in clearly defining the biological and clinical significance of the observed cytogenetic abnormalities. In this study, eight canine OSA cell lines were used to investigate telomere fusions by fluorescence in situ hybridization (FISH) using a peptide nucleotide acid probe. We characterized each cell line by classical cytogenetic studies and cellular phenotypes including telomere associated factors and then evaluated correlations from this data. All eight canine OSA cell lines displayed increased abnormal metacentric chromosomes and exhibited numerous telomere fusions and interstitial telomeric signals. Also, as evidence of unstable telomeres, colocalization of gamma-H2AX and telomere signals in interphase cells was observed. Each cell line was characterized by a combination of data representing cellular doubling time, DNA content, chromosome number, metacentric chromosome frequency, telomere signal level, cellular radiosensitivity, and DNA-PKcs protein expression level. We have also studied primary cultures from 10 spontaneous canine OSAs. Based on the observation of telomere aberrations in those primary cell cultures, we are reasonably certain that our observations in cell lines are not an artifact of prolonged culture. A correlation between telomere fusions and the other characteristics analyzed in our study could not be identified. However, it is important to note that all of the canine OSA samples exhibiting telomere fusion utilized in our study were telomerase positive. Pending further research regarding telomerase negative canine OSA cell lines, our findings may suggest telomere fusions can potentially serve as a novel marker for canine OSA. PMID- 22916247 TI - Refined mapping of a quantitative trait locus on chromosome 1 responsible for mouse embryonic death. AB - Recurrent spontaneous abortion (RSA) is defined as the loss of three or more consecutive pregnancies during the first trimester of embryonic intrauterine development. This kind of human infertility is frequent among the general population since it affects 1 to 5% of women. In half of the cases the etiology remains unelucidated. In the present study, we used interspecific recombinant congenic mouse strains (IRCS) in the aim to identify genes responsible for embryonic lethality. Applying a cartographic approach using a genotype/phenotype association, we identified a minimal QTL region, of about 6 Mb on chromosome 1, responsible for a high rate of embryonic death (~30%). Genetic analysis suggests that the observed phenotype is linked to uterine dysfunction. Transcriptomic analysis of the uterine tissue revealed a preferential deregulation of genes of this region compared to the rest of the genome. Some genes from the QTL region are associated with VEGF signaling, mTOR signaling and ubiquitine/proteasome protein degradation pathways. This work may contribute to elucidate the molecular basis of a multifactorial and complex human disorder as RSA. PMID- 22916248 TI - Transcript and protein analysis reveals better survival skills of monocyte derived dendritic cells compared to monocytes during oxidative stress. AB - BACKGROUND: Dendritic cells (DCs), professional antigen-presenting cells with the unique ability to initiate primary T-cell responses, are present in atherosclerotic lesions where they are exposed to oxidative stress that generates cytotoxic reactive oxygen species (ROS). A large body of evidence indicates that cell death is a major modulating factor of atherogenesis. We examined antioxidant defence systems of human monocyte-derived (mo)DCs and monocytes in response to oxidative stress. METHODS: Oxidative stress was induced by addition of tertiary butylhydroperoxide (tert-BHP, 30 min). Cellular responses were evaluated using flow cytometry and confocal live cell imaging (both using 5-(and-6)-chloromethyl 2,7-dichlorodihydrofluorescein diacetate, CM-H(2)DCFDA). Viability was assessed by the neutral red assay. Total RNA was extracted for a PCR profiler array. Five genes were selected for confirmation by Taqman gene expression assays, and by immunoblotting or immunohistochemistry for protein levels. RESULTS: Tert-BHP increased CM-H(2)DCFDA fluorescence and caused cell death. Interestingly, all processes occurred more slowly in moDCs than in monocytes. The mRNA profiler array showed more than 2-fold differential expression of 32 oxidative stress related genes in unstimulated moDCs, including peroxiredoxin-2 (PRDX2), an enzyme reducing hydrogen peroxide and lipid peroxides. PRDX2 upregulation was confirmed by Taqman assays, immunoblotting and immunohistochemistry. Silencing PRDX2 in moDCs by means of siRNA significantly increased CM-DCF fluorescence and cell death upon tert-BHP-stimulation. CONCLUSIONS: Our results indicate that moDCs exhibit higher intracellular antioxidant capacities, making them better equipped to resist oxidative stress than monocytes. Upregulation of PRDX2 is involved in the neutralization of ROS in moDCs. Taken together, this points to better survival skills of DCs in oxidative stress environments, such as atherosclerotic plaques. PMID- 22916249 TI - Why did bluetongue spread the way it did? Environmental factors influencing the velocity of bluetongue virus serotype 8 epizootic wave in France. AB - Understanding where and how fast an infectious disease will spread during an epidemic is critical for its control. However, the task is a challenging one as numerous factors may interact and drive the spread of a disease, specifically when vector-borne diseases are involved. We advocate the use of simultaneous autoregressive models to identify environmental features that significantly impact the velocity of disease spread. We illustrate this approach by exploring several environmental factors influencing the velocity of bluetongue (BT) spread in France during the 2007-2008 epizootic wave to determine which ones were the most important drivers. We used velocities of BT spread estimated in 4,495 municipalities and tested sixteen covariates defining five thematic groups of related variables: elevation, meteorological-related variables, landscape-related variables, host availability, and vaccination. We found that ecological factors associated with vector abundance and activity (elevation and meteorological related variables), as well as with host availability, were important drivers of the spread of the disease. Specifically, the disease spread more slowly in areas with high elevation and when heavy rainfall associated with extreme temperature events occurred one or two months prior to the first clinical case. Moreover, the density of dairy cattle was correlated negatively with the velocity of BT spread. These findings add substantially to our understanding of BT spread in a temperate climate. Finally, the approach presented in this paper can be used with other infectious diseases, and provides a powerful tool to identify environmental features driving the velocity of disease spread. PMID- 22916250 TI - Beta-adrenergic receptor 1 selective antagonism inhibits norepinephrine-mediated TNF-alpha downregulation in experimental liver cirrhosis. AB - BACKGROUND: Bacterial translocation is a frequent event in cirrhosis leading to an increased inflammatory response. Splanchnic adrenergic system hyperactivation has been related with increased bacterial translocation. We aim at evaluating the interacting mechanism between hepatic norepinephrine and inflammation during liver damage in the presence of bacterial-DNA. ANIMALS AND METHODS: Forty-six mice were included in a 16-week protocol of CCl(4)-induced cirrhosis. Laparotomies were performed at weeks 6, 10, 13 and 16. A second set of forty mice injected with a single intraperitoneal dose of CCl(4) was treated with saline, 6 hydroxidopamine, Nebivolol or Butoxamine. After 5 days, mice received E. coli-DNA intraperitoneally. Laparotomies were performed 24 hours later. Liver bacterial DNA, norepinephrine, TNF-alpha, IL-6 and beta-adrenergic receptor levels were measured. RESULTS: Bacterial-DNA translocation was more frequent in CCl(4) treated animals compared with controls, and increased as fibrosis progressed. Liver norepinephrine and pro-inflammatory cytokines were significantly higher in mice with vs without bacterial-DNA (319.7 +/- 120.6 vs 120.7 +/- 68.6 pg/g for norepinephrine, 38.4 +/- 6.1 vs 29.7 +/- 4.2 pg/g for TNF-alpha, 41.8 +/- 7.4 vs 28.7 +/- 4.3 pg/g for IL-6). Only beta-adrenergic receptor-1 was significantly increased in treated vs control animals (34.6 +/- 7.3 vs 12.5 +/- 5.3, p=0.01) and correlated with TNF-alpha, IL-6 and norepinephrine hepatic levels in animals with bacterial-DNA. In the second set of mice, cytokine levels were increased in 6-hydroxidopamine and Nebivolol (beta-adrenergic receptor-1 antagonist) treated mice compared with saline. Butoxamine (beta-adrenergic receptor-2 antagonist) didn't inhibit liver norepinephrine modulation of pro-inflammatory cytokines. CONCLUSIONS: Beta-adrenergic receptor-1 mediates liver norepinephrine modulation of the pro-inflammatory response in CCl(4)-treated mice with bacterial-DNA. PMID- 22916251 TI - Celecoxib and GABA cooperatively prevent the progression of pancreatic cancer in vitro and in xenograft models of stress-free and stress-exposed mice. AB - Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis and is associated with high levels of psychological distress. We have shown that beta-adrenergic receptors (beta-ARs), which are activated by stress neurotransmitters, regulate PDAC cells via cyclic AMP (cAMP)-dependent signaling in vitro, that social stress promotes PDAC progression in mouse xenografts and that gamma-aminobutyric acid (GABA) inhibits these responses in vitro and in vivo. The targeted inhibition of stress-induced regulatory pathways may abolish the potentially negative impact of psychological stress on clinical outcomes. Our current data show that chronic exposure of PDAC cell lines Panc-1 (activating point mutations in K-ras) and BXPC 3 (no mutations in K-ras) in vitro to the stress neurotransmitter epinephrine at the concentration (15 nM) previously measured in the serum of mice exposed to social stress significantly increased proliferation and migration. These responses were inhibited in a concentration-dependent manner by celecoxib. The effects of celecoxib alone and in combination with gamma-aminobutyric acid (GABA) on the progression of subcutaneous mouse xenografts from the cell line (BXPC-3) most responsive to epinephrine were then investigated in the presence and absence of social stress. Cancer-stimulating factors (VEGF & prostaglandin E(2) [PGE(2)]) and levels of cAMP were measured by immunoassays in blood and xenograft tissue. Phosphorylation of the signaling proteins ERK, CREB, Src, and AKT was assessed by ELISA assays and Western blotting. Expression of COX-2, 5-lipoxygenase, and p-5 LOX were determined by semi-quantitative Western blotting. Celecoxib alone significantly inhibited xenograft progression and decreased systemic and tumor VEGF, PGE2, and cAMP as well as phosphorylated signaling proteins in stress exposed and stress-free mice. These responses were significantly enhanced by co treatment with GABA. The celecoxib-induced downregulation of COX-2 protein and p 5-LOX was also significantly enhanced by GABA under both experimental conditions. Our findings identify the targeted inhibition of stress-induced pathways as a promising area for more effective cancer intervention in pancreatic cancer. PMID- 22916252 TI - Urinary bisphenol a concentration and angiography-defined coronary artery stenosis. AB - BACKGROUND: Bisphenol A is widely used in food and drinks packaging. There is evidence of associations between raised urinary bisphenol A (uBPA) and increased incidence of reported cardiovascular diagnoses. METHODOLOGY/PRINCIPAL FINDINGS: To estimate associations between BPA exposure and angiographically graded coronary atherosclerosis. 591 patients participating in The Metabonomics and Genomics in Coronary Artery Disease (MaGiCAD) study in Cambridgeshire UK, comparing urinary BPA (uBPA) with grades of severity of coronary artery disease (CAD) on angiography. Linear models were adjusted for BMI, occupational social class and diabetes status. Severe (one to three vessel) CAD was present in 385 patients, 86 had intermediate disease (n=86) and 120 had normal coronary arteries. The (unadjusted) median uBPA concentration was 1.28 ng/mL with normal coronary arteries, and 1.53 ng/mL with severe CAD. Compared to those with normal coronary arteries, uBPA concentration was significantly higher in those with severe CAD (OR per uBPA SD=5.96 ng/ml OR=1.43, CI 1.03 to 1.98, p=0.033), and near significant for intermediate disease (OR=1.69, CI 0.98 to 2.94, p=0.061). There was no significant uBPA difference between patients with severe CAD (needing surgery) and the remaining groups combined. CONCLUSIONS/SIGNIFICANCE: BPA exposure was higher in those with severe coronary artery stenoses compared to those with no vessel disease. Larger studies are needed to estimate true dose response relationships. The mechanisms underlying the association remain to be established. PMID- 22916253 TI - Characterization of chicken thrombocyte responses to Toll-like receptor ligands. AB - Thrombocytes are the avian equivalent to mammalian platelets. In addition to their hemostatic effects, mammalian platelets rely in part on pattern recognition receptors, such as the Toll-like receptors (TLR), to detect the presence of pathogens and signal the release of certain cytokines. Ligands for TLRs include lipopolysaccharide (LPS), which is bound by TLR4, as well as unmethylated CpG DNA motifs, which are bound by TLR9 in mammals and TLR21 in chickens. Similar to mammalian platelets, avian thrombocytes have been shown to express TLR4 and secrete some pro-inflammatory cytokines in response to LPS treatment. However, the full extent of the contributions made by thrombocytes to host immunity has yet to be elucidated. Importantly, the mechanisms by which TLR stimulation may modulate thrombocyte effector functions have not been well characterized. As such, the objective of the present study was to gain further insight into the immunological role of thrombocytes by analyzing their responses to treatment with ligands for TLR4 and TLR21. To this end, we quantified the relative expression of several immune system genes at 1, 3, 8 and 18 hours post-treatment using real time RT-PCR. Furthermore, production of nitric oxide and phagocytic activity of thrombocytes was measured after their activation with TLR ligands. We found that thrombocytes constitutively express transcripts for both pro- and anti inflammatory cytokines, in addition to those associated with anti-viral responses and antigen presentation. Moreover, we found that both LPS and CpG oligodeoxynucleotides (ODN) induced robust pro-inflammatory responses in thrombocytes, as characterized by more than 100 fold increase in interleukin (IL) 1beta, IL-6 and IL-8 transcripts, while only LPS enhanced nitric oxide production and phagocytic capabilities. Future studies may be aimed at examining the responses of thrombocytes to other TLR ligands. PMID- 22916254 TI - Effects of rs7903146 variation in the Tcf7l2 gene in the lipid metabolism of three different populations. AB - BACKGROUND: TCF7L2 rs7903146 is an important genetic factor predicting type 2 diabetes (T2DM) which has also been linked to higher cardiovascular risk. To date, there is little information about the additional impact of this single nucleotide polymorphism (SNP) beyond glucose metabolism. METHODOLOGY/PRINCIPAL FINDINGS: We studied whether rs7903146 influenced postprandial lipid metabolism in three different populations (healthy young men, metabolic syndrome (MetS) patients and elderly persons). Eighty-eight healthy males were submitted to a single saturated fatty acid-rich test meal. Additionally, 110 middle-aged MetS patients and 20 healthy elderly persons (>= 65 years) were submitted to three different dietary models followed by test meals. Minor allele homozygotes for rs7903146 showed a worse postprandial lipemia profile in young males, as seen by a lower HDL-cholesterol and Apo A1 concentration during the postprandial lipemia and a trend towards higher triglycerides (TG), than the other genotypes. In healthy elderly persons, carriers of the minor allele showed higher total cholesterol, LDL-cholesterol, Apo B and TG in the fasting state, and a higher postprandial area under the curve for total cholesterol, Apo B, small triglyceride rich lipoprotein (TRL) cholesterol and small-(TRL) triglycerides. These results were accompanied by differential changes in adipokines. We did not observe any influence of rs7903146 on the postprandium of MetS patients. CONCLUSIONS/SIGNIFICANCE: Healthy young males and elderly persons who are carriers of the mutant allele for rs7903146 have an impaired postprandial lipid metabolism that may be mediated by an alteration in adipokine regulation, and may be related to the higher cardiovascular risk observed in these persons. TRIAL REGISTRATION: ClinicalTrials.gov NCT00429195. PMID- 22916255 TI - Exploiting the MDM2-CK1alpha protein-protein interface to develop novel biologics that induce UBL-kinase-modification and inhibit cell growth. AB - Protein-protein interactions forming dominant signalling events are providing ever-growing platforms for the development of novel Biologic tools for controlling cell growth. Casein Kinase 1 alpha (CK1alpha) forms a genetic and physical interaction with the murine double minute chromosome 2 (MDM2) oncoprotein resulting in degradation of the p53 tumour suppressor. Pharmacological inhibition of CK1 increases p53 protein level and induces cell death, whilst small interfering RNA-mediated depletion of CK1alpha stabilizes p53 and induces growth arrest. We mapped the dominant protein-protein interface that stabilizes the MDM2 and CK1alpha complex in order to determine whether a peptide derived from the core CK1alpha-MDM2 interface form novel Biologics that can be used to probe the contribution of the CK1-MDM2 protein-protein interaction to p53 activation and cell viability. Overlapping peptides derived from CK1alpha were screened for dominant MDM2 binding sites using (i) ELISA with recombinant MDM2; (ii) cell lysate pull-down towards endogenous MDM2; (iii) MDM2-CK1alpha complex based competition ELISA; and (iv) MDM2-mediated ubiquitination. One dominant peptide, peptide 35 was bioactive in all four assays and its transfection induced cell death/growth arrest in a p53-independent manner. Ectopic expression of flag tagged peptide 35 induced a novel ubiquitin and NEDD8 modification of CK1alpha, providing one of the first examples whereby NEDDylation of a protein kinase can be induced. These data identify an MDM2 binding motif in CK1alpha which when isolated as a small peptide can (i) function as a dominant negative inhibitor of the CK1alpha-MDM2 interface, (ii) be used as a tool to study NEDDylation of CK1alpha, and (iii) reduce cell growth. Further, this approach provides a technological blueprint, complementing siRNA and chemical biology approaches, by exploiting protein-protein interactions in order to develop Biologics to manipulate novel types of signalling pathways such as cross-talk between NEDDylation, protein kinase signalling, and cell survival. PMID- 22916256 TI - Leveraging rapid community-based HIV testing campaigns for non-communicable diseases in rural Uganda. AB - BACKGROUND: The high burden of undiagnosed HIV in sub-Saharan Africa limits treatment and prevention efforts. Community-based HIV testing campaigns can address this challenge and provide an untapped opportunity to identify non communicable diseases (NCDs). We tested the feasibility and diagnostic yield of integrating NCD and communicable diseases into a rapid HIV testing and referral campaign for all residents of a rural Ugandan parish. METHODS: A five-day, multi disease campaign, offering diagnostic, preventive, treatment and referral services, was performed in May 2011. Services included point-of-care screening for HIV, malaria, TB, hypertension and diabetes. Finger-prick diagnostics eliminated the need for phlebotomy. HIV-infected adults met clinic staff and peer counselors on-site; those with CD4 <= 100/uL underwent intensive counseling and rapid referral for antiretroviral therapy (ART). Community participation, case finding yield, and linkage to care three months post-campaign were analyzed. RESULTS: Of 6,300 residents, 2,323/3,150 (74%) adults and 2,020/3,150 (69%) children participated. An estimated 95% and 52% of adult female and male residents participated respectively. Adult HIV prevalence was 7.8%, with 46% of HIV-infected adults newly diagnosed. Thirty-nine percent of new HIV diagnoses linked to care. In a pilot subgroup with CD4 <= 100, 83% linked and started ART within 10 days. Malaria was identified in 10% of children, and hypertension and diabetes in 28% and 3.5% of adults screened, respectively. Sixty-five percent of hypertensives and 23% of diabetics were new diagnoses, of which 43% and 61% linked to care, respectively. Screening identified suspected TB in 87% of HIV infected and 19% of HIV-uninfected adults; 52% percent of HIV-uninfected TB suspects linked to care. CONCLUSIONS: In an integrated campaign engaging 74% of adult residents, we identified a high burden of undiagnosed HIV, hypertension and diabetes. Improving male attendance and optimizing linkage to care require new approaches. The campaign demonstrates the feasibility of integrating hypertension, diabetes and communicable diseases into HIV initiatives. PMID- 22916259 TI - Sleep supports selective retention of associative memories based on relevance for future utilization. AB - An outstanding question is whether memory consolidation occurs passively or involves active processes that selectively stabilize memories based on future utility. Here, we differentially modulated the expected future relevance of two sets of picture-location associations after learning. Participants first studied two sets of picture-location associations. After a baseline memory test, they were instructed that only one set of associations would be retested after a 14 hour delay. For half of the participants, this test-retest delay contained a night of sleep; for the other half the delay included a normal working day. At retest, participants were re-instructed and against their expectations tested on both sets of associations. Our results show that post-learning instruction about subsequent relevance selectively improves memory retention for specific associative memories. This effect was sleep-dependent; it was present only in the group of subjects for which the test-retest delay contained sleep. Moreover, time spent asleep for participants in this sleep group correlated with retention of relevant but not irrelevant associations; participants who slept longer forgot fewer associations from the relevant category. In contrast, participants that did not sleep forgot more relevant than irrelevant associations across the test retest delay. In summary, our results indicate that it is possible to modulate the retention of selected memories after learning with simple verbal instructions on their future relevance. The finding that this effect depends on sleep demonstrates this state's active role in memory consolidation and may have utility for educational settings. PMID- 22916260 TI - Larval tolerance to salinity in three species of Australian anuran: an indication of saline specialisation in Litoria aurea. AB - Recent anthropogenic influences on freshwater habitats are forcing anuran populations to rapidly adapt to high magnitude changes in environmental conditions or face local extinction. We examined the effects of ecologically relevant elevated salinity levels on larval growth, metamorphosis and survival of three species of Australian anuran; the spotted marsh frog (Limnodynastes tasmaniensis), the painted burrowing frog (Neobatrachus sudelli) and the green and golden bell frog (Litoria aurea), in order to better understand the responses of these animals to environmental change. Elevated salinity (16% seawater) negatively impacted on the survival of L. tasmaniensis (35% survival) and N sudelli (0% survival), while reduced salinity had a negative impact on L. aurea. (16% seawater: 85% survival; 0.4% seawater: 35% survival). L. aurea tadpoles survived in salinities much higher than previously reported for this species, indicating the potential for inter-populations differences in salinity tolerance. In L. tasmaniensis and L. aurea, development to metamorphosis was fastest in low and high salinity treatments suggesting it is advantageous for tadpoles to invest energy in development in both highly favourable and developmentally challenging environments. We propose that this response might either maximise potential lifetime fecundity when tadpoles experience favourable environments, or, facilitate a more rapid escape from pond environments where there is a reduced probability of survival. PMID- 22916257 TI - Placental transfer of maternally-derived IgA precludes the use of guthrie card eluates as a screening tool for primary immunodeficiency diseases. AB - There is a need for neonatal screening tools to improve the long-term clinical outcome of patients with primary immunodeficiency diseases (PID). Recently, a PCR based screening method for both TRECs and KRECs using Guthrie card samples has been developed. However, the applicability of these excision circle assays is limited to patients with severe T or B cell lymphopenia (SCID, XLA and A-T), whereas the most common forms of PID are not detected. Absence of serum IgA is seen in a major fraction of patients with immunological defects. As serum IgA in newborns is considered to be of fetal origin, eluates from routinely collected dried blood spot samples might thus be suitable for identification of children with PID. To assess the applicability of such screening assays, stored Guthrie card samples were obtained from 47 patients with various forms of primary immunodeficiency diseases (SCID, XLA, A-T, HIGM and IgAD), 20 individuals with normal serum IgA levels born to IgA-deficient mothers and 51 matched healthy newborns. Surprisingly, normal serum IgA levels were found in all SCID, XLA, A-T and HIGM patients and, additionally, in all those IgAD patients born to IgA sufficient mothers. Conversely, no serum IgA was found in any of the 16 IgAD patients born by IgA-deficient mothers. Moreover, half of the IgA-sufficient individuals born by IgA-deficient mothers also lacked IgA at birth whereas no IgA deficient individuals were found among the controls. IgA in neonatal dried blood samples thus appears to be of both maternal and fetal origin and precludes its use as a reliable marker for neonatal screening of primary immunodeficiency diseases. PMID- 22916258 TI - Reactive oxygen species-inducible ECF sigma factors of Bradyrhizobium japonicum. AB - Extracytoplasmic function (ECF) sigma factors control the transcription of genes involved in different cellular functions, such as stress responses, metal homeostasis, virulence-related traits, and cell envelope structure. The genome of Bradyrhizobium japonicum, the nitrogen-fixing soybean endosymbiont, encodes 17 putative ECF sigma factors belonging to nine different ECF sigma factor families. The genes for two of them, ecfQ (bll1028) and ecfF (blr3038), are highly induced in response to the reactive oxygen species hydrogen peroxide (H(2)O(2)) and singlet oxygen ((1)O(2)). The ecfF gene is followed by the predicted anti-sigma factor gene osrA (blr3039). Mutants lacking EcfQ, EcfF plus OsrA, OsrA alone, or both sigma factors plus OsrA were phenotypically characterized. While the symbiotic properties of all mutants were indistinguishable from the wild type, they showed increased sensitivity to singlet oxygen under free-living conditions. Possible target genes of EcfQ and EcfF were determined by microarray analyses, and candidate genes were compared with the H(2)O(2)-responsive regulon. These experiments disclosed that the two sigma factors control rather small and, for the most part, distinct sets of genes, with about half of the genes representing 13% of the members of H(2)O(2)-responsive regulon. To get more insight into transcriptional regulation of both sigma factors, the 5' ends of ecfQ and ecfF mRNA were determined. The presence of conserved sequence motifs in the promoter region of ecfQ and genes encoding EcfQ-like sigma factors in related alpha proteobacteria suggests regulation via a yet unknown transcription factor. By contrast, we have evidence that ecfF is autoregulated by transcription from an EcfF-dependent consensus promoter, and its product is negatively regulated via protein-protein interaction with OsrA. Conserved cysteine residues 129 and 179 of OsrA are required for normal function of OsrA. Cysteine 179 is essential for release of EcfF from an EcfF-OsrA complex upon H(2)O(2) stress while cysteine 129 is possibly needed for EcfF-OsrA interaction. PMID- 22916261 TI - Random mutagenesis reveals residues of JAK2 critical in evading inhibition by a tyrosine kinase inhibitor. AB - BACKGROUND: The non-receptor tyrosine kinase JAK2 is implicated in a group of myeloproliferative neoplasms including polycythemia vera, essential thrombocythemia, and primary myelofibrosis. JAK2-selective inhibitors are currently being evaluated in clinical trials. Data from drug-resistant chronic myeloid leukemia patients demonstrate that treatment with a small-molecule inhibitor generates resistance via mutation or amplification of BCR-ABL. We hypothesize that treatment with small molecule inhibitors of JAK2 will similarly generate inhibitor-resistant mutants in JAK2. METHODOLOGY: In order to identify inhibitor-resistant JAK2 mutations a priori, we utilized TEL-JAK2 to conduct an in vitro random mutagenesis screen for JAK2 alleles resistant to JAK Inhibitor-I. Isolated mutations were evaluated for their ability to sustain cellular growth, stimulate downstream signaling pathways, and phosphorylate a novel JAK2 substrate in the presence of inhibitor. CONCLUSIONS: Mutations were found exclusively in the kinase domain of JAK2. The panel of mutations conferred resistance to high concentrations of inhibitor accompanied by sustained activation of the Stat5, Erk1/2, and Akt pathways. Using a JAK2 substrate, enhanced catalytic activity of the mutant JAK2 kinase was observed in inhibitor concentrations 200-fold higher than is inhibitory to the wild-type protein. When testing the panel of mutations in the context of the Jak2 V617F allele, we observed that a subset of mutations conferred resistance to inhibitor, validating the use of TEL-JAK2 in the initial screen. These results demonstrate that small-molecule inhibitors select for JAK2 inhibitor-resistant alleles, and the design of next-generation JAK2 inhibitors should consider the location of mutations arising in inhibitor-resistant screens. PMID- 22916262 TI - 3-O-sulfated heparan sulfate recognized by the antibody HS4C3 contributes [corrected] to the differentiation of mouse embryonic stem cells via fas signaling. AB - Maintenance of self-renewal and pluripotency in mouse embryonic stem cells (mESCs) is regulated by the balance between several extrinsic signaling pathways. Recently, we demonstrated that heparan sulfate (HS) chains play important roles in the maintenance and differentiation of mESCs by regulating extrinsic signaling. Sulfated HS structures are modified by various sulfotransferases during development. However, the significance of specific HS structures during development remains unclear. Here, we show that 3-O-sulfated HS structures synthesized by HS 3-O-sulfotransferases (3OSTs) and recognized by the antibody HS4C3 increase during differentiation of mESCs. Furthermore, expression of Fas on the cell surface of the differentiated cells also increased. Overexpression of the HS4C3-binding epitope in mESCs induced apoptosis and spontaneous differentiation even in the presence of LIF and serum. These data showed that the HS4C3-binding epitope was required for differentiation of mESCs. Up-regulation of the HS4C3-binding epitope resulted in the recruitment of Fas from the cytoplasm to lipid rafts on the cell surface followed by activation of Fas signaling. Indeed, the HS4C3-binding epitope interacted with a region that included the heparin-binding domain (KLRRRVH) of Fas. Reduced self-renewal capability in cells overexpressing 3OST resulted from the degradation of Nanog by activated caspase 3, which is downstream of Fas signaling, and was rescued by the inhibition of Fas signaling. We also found that knockdown of 3OST and inhibition of Fas signaling reduced the potential for differentiation into the three germ layers during embryoid body formation. This is the first demonstration that activation of Fas signaling is mediated by an increase in the HS4C3-binding epitope and indicates a novel signaling pathway for differentiation in mESCs. PMID- 22916263 TI - Copper oxide nanoparticles induce autophagic cell death in A549 cells. AB - Metal oxide nanoparticles (NPs) are among the most highly produced nanomaterials, and have many diverse functions in catalysis, environmental remediation, as sensors, and in the production of personal care products. In this study, the toxicity of several widely used metal oxide NPs such as copper oxide, silica, titanium oxide and ferric oxide NPs, were evaluated In vitro. We exposed A549, H1650 and CNE-2Z cell lines to metal oxide NPs, and found CuO NPs to be the most toxic, SiO2 mild toxic, while the other metal oxide NPs had little effect on cell viability. Furthermore, the autophagic biomarker LC3-II significantly increased in A549 cells treated with CuO NPs, and the use of the autophagy inhibitors wortmannin and 3-methyladenin significantly improved cell survival. These results indicate that the cytoxicity of CuO NPs may involve the autophagic pathway in A549 cells. PMID- 22916265 TI - Accessing autonomic function can early screen metabolic syndrome. AB - BACKGROUND: Clinical diagnosis of the metabolic syndrome is time-consuming and invasive. Convenient instruments that do not require laboratory or physical investigation would be useful in early screening individuals at high risk of metabolic syndrome. Examination of the autonomic function can be taken as a directly reference and screening indicator for predicting metabolic syndrome. METHODOLOGY AND PRINCIPAL FINDINGS: The EZSCAN test, as an efficient and noninvasive technology, can access autonomic function through measuring electrochemical skin conductance. In this study, we used EZSCAN value to evaluate autonomic function and to detect metabolic syndrome in 5,887 participants aged 40 years or older. The EZSCAN test diagnostic accuracy was analyzed by receiver operating characteristic curves. Among the 5,815 participants in the final analysis, 2,541 were diagnosed as metabolic syndrome and the overall prevalence was 43.7%. Prevalence of the metabolic syndrome increased with the elevated EZSCAN risk level (p for trend <0.0001). Moreover, EZSCAN value was associated with an increase in the number of metabolic syndrome components (p for trend <0.0001). Compared with the no risk group (EZSCAN value 0-24), participants at the high risk group (EZSCAN value: 50-100) had a 2.35 fold increased risk of prevalent metabolic syndrome after the multiple adjustments. The area under the curve of the EZSCAN test was 0.62 (95% confidence interval [CI], 0.61-0.64) for predicting metabolic syndrome. The optimal operating point for the EZSCAN value to detect a high risk of prevalent metabolic syndrome was 30 in this study, while the sensitivity and specificity were 71.2% and 46.7%, respectively. CONCLUSIONS AND SIGNIFICANCE: In conclusion, although less sensitive and accurate when compared with the clinical definition of metabolic syndrome, we found that the EZSCAN test is a good and simple screening technique for early predicting metabolic syndrome. PMID- 22916264 TI - Early second trimester maternal plasma choline and betaine are related to measures of early cognitive development in term infants. AB - BACKGROUND: The importance of maternal dietary choline for fetal neural development and later cognitive function has been well-documented in experimental studies. Although choline is an essential dietary nutrient for humans, evidence that low maternal choline in pregnancy impacts neurodevelopment in human infants is lacking. We determined potential associations between maternal plasma free choline and its metabolites betaine and dimethylglycine in pregnancy and infant neurodevelopment at 18 months of age. METHODOLOGY: This was a prospective study of healthy pregnant women and their full-term, single birth infants. Maternal blood was collected at 16 and 36 weeks of gestation and infant neurodevelopment was assessed at 18 months of age for 154 mother-infant pairs. Maternal plasma choline, betaine, dimethylglycine, methionine, homocysteine, cysteine, total B12, holotranscobalamin and folate were quantified. Infant neurodevelopment was evaluated using the Bayley Scales of Infant Development-III. Multivariate regression, adjusting for covariates that impact development, was used to determine the associations between maternal plasma choline, betaine and dimethylglycine and infant neurodevelopment. RESULTS: The maternal plasma free choline at 16 and 36 weeks gestation was median (interquartile range) 6.70 (5.78 8.03) and 9.40 (8.10-11.3) umol/L, respectively. Estimated choline intakes were (mean +/- SD) 383 +/- 98.6 mg/day, and lower than the recommended 450 mg/day. Betaine intakes were 142 +/- 70.2 mg/day. Significant positive associations were found between infant cognitive test scores and maternal plasma free choline (B=6.054, SE=2.283, p=0.009) and betaine (B=7.350, SE=1.933, p=0.0002) at 16 weeks of gestation. Maternal folate, total B12, or holotranscobalamin were not related to infant development. CONCLUSION: We show that choline status in the first half of pregnancy is associated with cognitive development among healthy term gestation infants. More work is needed on the potential limitation of choline or betaine in the diets of pregnant women. PMID- 22916266 TI - Co-occurrence of TDP-43 mislocalization with reduced activity of an RNA editing enzyme, ADAR2, in aged mouse motor neurons. AB - TDP-43 pathology in spinal motor neurons is a neuropathological hallmark of sporadic amyotrophic lateral sclerosis (ALS) and has recently been shown to be closely associated with the downregulation of an RNA editing enzyme called adenosine deaminase acting on RNA 2 (ADAR2) in the motor neurons of sporadic ALS patients. Because TDP-43 pathology is found more frequently in the brains of elderly patients, we investigated the age-related changes in the TDP-43 localization and ADAR2 activity in mouse motor neurons. We found that ADAR2 was developmentally upregulated, and its mRNA expression level was progressively decreased in the spinal cords of aged mice. Motor neurons normally exhibit nuclear ADAR2 and TDP-43 immunoreactivity, whereas fast fatigable motor neurons in aged mice demonstrated a loss of ADAR2 and abnormal TDP-43 localization. Importantly, these motor neurons expressed significant amounts of the Q/R site unedited AMPA receptor subunit 2 (GluA2) mRNA. Because expression of unedited GluA2 has been demonstrated as a lethality-causing molecular abnormality observed in the motor neurons, these results suggest that age-related decreases in ADAR2 activity play a mechanistic role in aging and serve as one of risk factors for ALS. PMID- 22916267 TI - Cell-free circulating plasma hTERT mRNA is a useful marker for prostate cancer diagnosis and is associated with poor prognosis tumor characteristics. AB - BACKGROUND: Serum prostate-specific antigen (PSA) is the most widely used marker for diagnosing prostate cancer (PCa). It lacks specificity and predictive value, resulting in inaccurate diagnoses and overtreatment of the disease. The aim of this study was to assess the usefulness of plasma telomerase reverse transcriptase (hTERT) mRNA as a diagnostic and prognostic tool for PCa and its association with clinicopathological parameters of tumors. PRINCIPAL FINDINGS: Plasma hTERT mRNA levels were determined by qRT-PCR in 105 consecutive patients with elevated PSA levels and in 68 healthy volunteers. The diagnostic accuracy, the efficacy as a prognostic factor of biochemical recurrence and the association with tumor clinicopathological parameters of plasma hTERT mRNA and serum PSA tests were determined using univariate and multivariate analyses. The results show that plasma hTERT mRNA is a non-invasive biomarker for PCa diagnosis that shows higher sensitivity (85% vs. 83%), specificity (90% vs. 47%), positive predictive value (83% vs. 56%), and negative predictive value (92% vs. 77%) than serum PSA. Plasma hTERT mRNA is significantly associated with poor prognosis tumor clinicopathological parameters and is a significant independent predictor of PCa (p<0.0001). Univariate analysis identified plasma hTERT mRNA (but not serum PSA) as a significant prognostic factor of biochemical recurrence. Plasma hTERT mRNA Kaplan-Meier curves confirmed the significant differences between groups and patients with higher levels than the cut-off value showed diminished recurrence-free survival (p=0.004), whereas no differences were observed with serum PSA (p=0.38). Multivariate analysis indicated that plasma hTERT mRNA (but not serum PSA) and stage were significantly associated with biochemical recurrence. CONCLUSIONS: Overall, these findings indicate that hTERT mRNA is a useful non-invasive tumor marker for the molecular diagnosis of PCa, affording a greater diagnostic and prognostic accuracy than the PSA assay and may be of relevance in the follow-up of the disease. PMID- 22916268 TI - Projecting HIV transmission in Japan. AB - BACKGROUND: Little is known about the epidemiology of HIV in Japan, though newly identified cases amongst men who have sex with men (MSM) show an increasing trend. Predictions of future trends in the HIV epidemic are essential to identify suitable interventions. METHODS: A deterministic, compartmental model was developed that incorporated risk groups, disease stages, and treatment and testing parameters. This model was calibrated against current figures on new infections and run over 30 years to identify trends in prevalence amongst MSM, low-risk men and low-risk women. Multivariate sensitivity analysis was used to estimate sensitivity ranges for all outcomes. RESULTS: Without new interventions amongst MSM in Japan, HIV prevalence will climb from its current rate of 2.1% to 10.4% (sensitivity range 7.4% to 18.7%), while HIV prevalence among low-risk men and women will likely decline. With small changes in safer sex behavior and testing rates, HIV prevalence can remain stable or even decline amongst MSM. CONCLUSIONS: Japan is at risk of an epidemic of HIV amongst MSM unless significant changes are made to its current public health intervention framework. More research is necessary to understand the key drivers of the epidemic in Japan. PMID- 22916269 TI - PAPSS2 promotes alkaline phosphates activity and mineralization of osteoblastic MC3T3-E1 cells by crosstalk and Smads signal pathways. AB - Several studies have indicated that PAPSS2 (3'-phosphoadenosine-5'-phosphosulfate synthetase 2) activity is important to normal skeletal development. Mouse PAPSS2 is predominantly expressed during the formation of the skeleton and cartilaginous elements of the mouse embryo and in newborn mice. However, the role and mechanism of PAPSS2 in bone formation remains largely unidentified. By analyzing the expression pattern of the PAPSS2 gene, we have found that PAPSS2 is expressed in bone tissue and bone formation. PAPSS2 transcripts increase during osteoblast differentiation and are in less level in RANKL-induced osteoclast like cells. By using lentivirus-mediated RNA interference (RNAi) technology, we knocked down PAPSS2 expression in MC3T3-E1 osteoblast. Silencing of PAPSS2 expression significantly decreases ALP activity and cell mineralization, inhibits expression of osteoblast marker osteopontin (OPN) and collagen I. Conversely, overexpression of PAPSS2 promotes the MC3T3-E1 to differentiate into osteoblast and mineralization. Moreover, compared to that in the control cells, the mRNA level and protein expression of phosphorylated Smad 2/3, which is a key transcriptional factor in the Smad osteoblast differentiation pathway, showed significant decreases in PAPSS2-silenced cells and increases in PAPSS2-overexpression cells. These results suggest that PAPSS2 might regulate osteoblast ALP activity and cell mineralization, probably through Smads signal pathways. PMID- 22916270 TI - Anticancer properties and mechanisms of fucoidan on mouse breast cancer in vitro and in vivo. AB - BACKGROUND: Fucoidan is a sulfated polysaccharide derived from brown algae that has been reported to perform multiple biological activities, including antitumor activity. In this study, we examined the influence of crude fucoidan on mouse breast cancer in vitro and in vivo. MATERIALS AND METHODS: In vitro, fluorescent staining, flow cytometry and Western blot were performed to analyze apoptosis and vascular endothelial growth factor (VEGF) expression of mouse breast cancer 4T1 cells. In vivo, therapy experiments were conducted on Babl/c mice bearing breast cancer. The tumor volume and weight were measured. The number of apoptotic cells and microvascular density (MVD) in tumor tissues were assessed by TUNEL and CD34 immunostaining. Immunohistochemical assays and ELISA assay were used to detect the expression of VEGF in tissues. RESULTS: In vitro studies showed that crude fucoidan significantly decreased the viable number of 4T1 cells, induced apoptosis and down-regulated the expression of VEGF. The expression of Bcl-2 was decreased, and the ratio of Bcl-2 to Bax was significantly decreased. The expression of Survivin and phosphorylated extracellular signal regulated protein kinases (ERKs) was decreased. Cytochrome C was released from mitochondria into cytosol, and the cleaved Caspase-3 protein rose after fucoidan treatment. Intraperitoneal injection of fucoidan in breast cancer models reduced the tumor volume and weight. The enhanced antitumor efficacy was associated with decreased angiogenesis and increased induction of apoptosis. CONCLUSION: These findings indicated that crude fucoidan inhibited mouse breast cancer growth in vitro and in vivo. These data suggest that fucoidan may serve as a potential therapeutic agent for breast cancer. PMID- 22916271 TI - Human mesenchymal stem cell expression program upon extended ex-vivo cultivation, as revealed by 2-DE-based quantitative proteomics. AB - Human mesenchymal stem cells (MSC) have been on the focus of intense clinical oriented research due to their multilineage differentiation potential and immunomodulatory properties. However, to reach the clinically meaningful cell numbers for cellular therapy and tissue engineering applications, MSC ex-vivo expansion is mandatory but sequential cell passaging results in loss of proliferative, clonogenic and differentiation potential. To get clues into the molecular mechanisms underlying cellular senescence resulting from extended ex vivo cultivation of bone marrow (BM) MSC, we explored a two-dimensional gel electrophoresis (2-DE) based quantitative proteomics to compare the expression programs of Passage 3 cells (P3), commonly used in clinical studies with expanded MSC, and Passage 7 (P7) cells, which already demonstrated significant signs of culture-induced senescence. Proteins of the functional categories "Structural components and cellular cytoskeleton" and "Folding and stress response proteins" are less abundant in P7 cells, compared to P3, while proteins involved in "Energy metabolism", "Cell cycle regulation and aging" and "Apoptosis" are more abundant. The large number of multiple size and charge isoforms with an altered content that were identified in this study in P7 versus P3, namely the cytoskeleton components beta-actin (7 forms) and vimentin (24 forms), also emphasizes the importance of post-transcriptional modification upon long-term cultivation. The differential protein expression registered suggests that cellular senescence occurring during ex-vivo expansion of BM MSC is associated with the impairment of cytoskeleton remodeling and/or organization and the repair of damaged proteins resulting from cell exposure to culture stress. The genome-wide expression approach used in this study has proven useful for getting mechanistic insights into the observed decrease on the proliferative and clonogenic potential of P7 versus P3 cells and paves the way to set up a proteome profiling strategy for quality control to assure safe and clinically effective expanded MSC. PMID- 22916272 TI - Signature of a pre-human population decline in the critically endangered Reunion Island endemic forest bird Coracina newtoni. AB - The exceptional biodiversity of Reunion Island is threatened by anthropogenic landscape changes that took place during the 350 years of human colonization. During this period the human population size increased dramatically from 250 to 800,000. The arrival of humans together with the development of agriculture, invasive species such as rats and cats, and deforestation has lead to the extinction of more than half of the original vertebrate species of the island. For the remaining species, significant work is being carried out to identify threats and conservation status, but little genetic work has been carried on some of the most endangered species. In the last decade theoretical studies have shown the ability of neutral genetic markers to infer the demographic history of endangered species and identify and date past population size changes (expansions or bottlenecks). In this study we provide the first genetic data on the critically endangered species the Reunion cuckoo-shrike Coracina newtoni. The Reunion cuckoo-shrike is a rare endemic forest bird surviving in a restricted 12 km(2) area of forested uplands and mountains. The total known population consists of less than one hundred individuals out of which 45 were genotyped using seventeen polymorphic microsatellite loci. We found a limited level of genetic variability and weak population structure, probably due to the limited geographic distribution. Using Bayesian methods, we identified a strong decline in population size during the Holocene, most likely caused by an ancient climatic or volcanic event around 5000 years ago. This result was surprising as it appeared in apparent contradiction with the accepted theory of recent population collapse due to deforestation and predator introduction. These results suggest that new methods allowing for more complex demographic models are necessary to reconstruct the demographic history of populations. PMID- 22916273 TI - N-octanoyl-dopamine is an agonist at the capsaicin receptor TRPV1 and mitigates ischemia-induced [corrected] acute kidney injury in rat. AB - Since stimulation of transient receptor potential channels of the vanilloid receptor subtype 1 (TRPV1) mitigates acute kidney injury (AKI) and endogenous N acyl dopamine derivatives are able to activate TRPV1, we tested if synthetic N octanoyl-dopamine (NOD) activates TRPV1 and if it improves AKI. These properties of NOD and its intrinsic anti-inflammatory character were compared with those of dopamine (DA). TRPV1 activation and anti-inflammatory properties of NOD and DA were tested using primary cell cultures in vitro. The influence of NOD and DA on AKI was tested in a prospective, randomized, controlled animal study with 42 inbred male Lewis rats (LEW, RT1), treated intravenously with equimolar concentrations of DA or NOD one hour before the onset of warm ischemia and immediately before clamp release. NOD, but not DA, activates TRPV1 channels in isolated dorsal root ganglion neurons (DRG) that innervate several tissues including kidney. In TNFalpha stimulated proximal tubular epithelial cells, inhibition of NFkappaB and subsequent inhibition of VCAM1 expression by NOD was significantly stronger than by DA. NOD improved renal function compared to DA and saline controls. Histology revealed protective effects of NOD on tubular epithelium at day 5 and a reduced number of monocytes in renal tissue of DA and NOD treated rats. Our data demonstrate that NOD but not DA activates TRPV1 and that NOD has superior anti-inflammatory properties in vitro. Although NOD mitigates deterioration in renal function after AKI, further studies are required to assess to what extend this is causally related to TRPV1 activation and/or desensitization. PMID- 22916274 TI - Local variations in spatial synchrony of influenza epidemics. AB - BACKGROUND: Understanding the mechanism of influenza spread across multiple geographic scales is not complete. While the mechanism of dissemination across regions and states of the United States has been described, understanding the determinants of dissemination between counties has not been elucidated. The paucity of high resolution spatial-temporal influenza incidence data to evaluate disease structure is often not available. METHODOLOGY AND FINDINGS: We report on the underlying relationship between the spread of influenza and human movement between counties of one state. Significant synchrony in the timing of epidemics exists across the entire state and decay with distance (regional correlation=62%). Synchrony as a function of population size display evidence of hierarchical spread with more synchronized epidemics occurring among the most populated counties. A gravity model describing movement between two populations is a stronger predictor of influenza spread than adult movement to and from workplaces suggesting that non-routine and leisure travel drive local epidemics. CONCLUSIONS: These findings highlight the complex nature of influenza spread across multiple geographic scales. PMID- 22916275 TI - ARF6-dependent regulation of P2Y receptor traffic and function in human platelets. AB - Adenosine diphosphate (ADP) is a critical regulator of platelet activation, mediating its actions through two G protein-coupled receptors, the P2Y(1) and P2Y(12) purinoceptors. Recently, we demonstrated that P2Y(1) and P2Y(12) purinoceptor activities are rapidly and reversibly modulated in human platelets, revealing that the underlying mechanism requires receptor internalization and subsequent trafficking as an essential part of this process. In this study we investigated the role of the small GTP-binding protein ADP ribosylation factor 6 (ARF6) in the internalization and function of P2Y(1) and P2Y(12) purinoceptors in human platelets. ARF6 has been implicated in the internalization of a number of GPCRs, although its precise molecular mechanism in this process remains unclear. In this study we show that activation of either P2Y(1) or P2Y(12) purinoceptors can stimulate ARF6 activity. Further blockade of ARF6 function either in cell lines or human platelets blocks P2Y purinoceptor internalization. This blockade of receptor internalization attenuates receptor resensitization. Furthermore, we demonstrate that Nm23-H1, a nucleoside diphosphate (NDP) kinase regulated by ARF6 which facilitates dynamin-dependent fission of coated vesicles during endocytosis, is also required for P2Y purinoceptor internalization. These data describe a novel function of ARF6 in the internalization of P2Y purinoceptors and demonstrate the integral importance of this small GTPase upon platelet ADP receptor function. PMID- 22916276 TI - Enhanced anxiety observed in cocaine withdrawn rats is associated with altered reactivity of the dorsomedial prefrontal cortex. AB - Discontinuation of drug intake in cocaine abusers commonly produces a variety of adverse withdrawal symptoms among which anxiety and depression-related behavior are prevailing during the initial period of abstinence. The aim of this study was to provide further insight into the neurobiological dysregulations that might contribute to these pathological states. Rats were treated with cocaine or saline for 14 days (20 mg/kg; i.p) and anxiety-related behavior was assessed in different paradigms (elevated plus-maze (EPM), confinement to an open arm of the EPM and shock-probe burying tests) for up to 4 weeks after withdrawal. Depression like behavior was assessed by the forced swim test and sucrose preference test. Altogether our results demonstrated that cocaine withdrawal induced persistent heightened levels of anxiety that last for at least 28 days but did not affect depression-like behavior. We then used Fos immunohistochemistry to map neuronal activation patterns in withdrawn rats confined to one open arm of an EPM, and a double labeling procedure using Fos immunohistochemistry and in situ hybridization of glutamic acid decarboxylase or vesicular glutamate transporter mRNAs to identify the phenotype of the activated neurons. Our data showed that the exacerbated anxiety observed in cocaine withdrawn rats exposed to an elevated open arm was accompanied by an altered reactivity of the dorsal part of the medial prefrontal cortex (anterior cingulate and dorsal prelimbic cortices), the paraventricular thalamic nucleus and the lateral and anterior areas of the hypothalamus. In the medial prefrontal cortex, we evidenced a negative correlation between Fos expression in its dorsal part and open arm-induced freezing in NaCl-treated rats but not in cocaine withdrawn rats. We also found that more than 65% of activated neurons were glutamatergic projection neurons. The present study provides new insights into the neuroanatomical regions and neuronal cell types that may underlie pathological anxiety during cocaine withdrawal. PMID- 22916277 TI - FcepsilonR1-mediated mast cell reactivity is amplified through prolonged Toll like receptor-ligand treatment. AB - BACKGROUND: Mast cell-derived mediators mediate several of the pathological features of asthma. Microbial infections induce asthma exacerbations in which the contribution of mast cells remains incomprehensible. PRINCIPAL FINDINGS: In this study we have investigated the characteristic expression pattern of Toll-like receptors (TLRs) 1-9 and the effect of TLR ligand treatment on IgE-receptor mediated mast cell reactivity. For the studies we employed in vitro differentiated connective tissue like mast cells (CTLMC) and mucosal like mast cells (MLMC) from mice. Both phenotypes were treated for 24 h or 96 h with ligands for TLR1/2, TLR2/6, TLR3 and TLR4, before activation with IgE and antigen. Prolonged exposure (96 h) with TLR-ligands promoted mast cell reactivity following IgE-receptor activation. TLR4 activation with LPS generated the most pronounced effect, with an enhanced degranulation and secretion of leukotrienes, cytokines and chemokines, in both CTLMC and MLMC. The effect of LPS was mediated through a Myd88-dependent pathway and the increased effect involved JNK-dependent pathway. CONCLUSION: We find that prolonged exposure of mast cells to pathogens/TLR-ligands modulates their effector responses by priming them for increased release of several inflammatory mediators when subsequently activated by IgE-receptors. These data suggest that infections might exaggerate the severity of allergic reactions such as in asthma, by enhancing mediator release from mast cells. PMID- 22916278 TI - Hoxa11 and Hoxd11 regulate chondrocyte differentiation upstream of Runx2 and Shox2 in mice. AB - During limb development, posterior Hox genes of the Hoxa- and Hoxd cluster provide positional information along the limb axis. Here we report a new function for Hoxa11 and Hoxd11 in regulating the early steps of chondrocyte differentiation. We analyzed forelimbs of Hoxa11(-/-);d11(-/-) and Ulnaless mice, which are characterized by specifically shortened zeugopods. By detailed morphological and molecular analyses, we show that loss of Hoxa11 and Hoxd11 in the ulna of both mutants leads to an arrest of chondrocyte differentiation at a step before the separation into round and columnar cells takes place. Furthermore, we demonstrate that Hoxa11 and Hoxd11 act upstream of Runx2 and Shox2, two key regulators of chondrocyte differentiation. We hypothesize that Runx2 activates Shox2 in early chondrocytes, which at later stages induces Runx2 expression to regulate hypertrophic differentiation. These results give insight into mechanisms by which positional information might be translated into a specific bone pattern. PMID- 22916279 TI - Fractalkine is expressed in early and advanced atherosclerotic lesions and supports monocyte recruitment via CX3CR1. AB - Fractalkine (CX3CL1, FKN) is expressed in the inflamed vascular wall and absence of FKN reduces atherogenesis. Whether FKN is expressed throughout all stages of atherosclerotic disease and whether it directly contributes to monocyte recruitment to atherosclerotic lesions is not known. We collected human atherosclerotic plaque material and blood samples from patients with carotid artery disease undergoing endarterectomy. Plaques were analyzed by immunohistochemistry and qPCR. We found that FKN is expressed at all stages of atherosclerotic lesion formation, and that the number of FKN-expressing cells positively correlates with the number of CX3CR1-positive cells in human carotid artery plaques. In the circulation, soluble FKN levels are significantly elevated in the presence of high-grade (sub-occlusive) stenosis. To determine the role of the FKN-CX3CR1 axis for monocyte adhesion in vivo we then performed intravital videofluorescence microscopy of the carotid artery in ApoE(-/-) mice. Notably, FKN-CX3CR1 interactions are critical for recruitment of circulating monocytes to the injured atherosclerotic vascular wall. Thus, this chemokine dyad could represent an attractive target for anti-atherosclerotic strategies. PMID- 22916280 TI - Transcriptional and metabolic insights into the differential physiological responses of arabidopsis to optimal and supraoptimal atmospheric CO2. AB - BACKGROUND: In tightly closed human habitats such as space stations, locations near volcano vents and closed culture vessels, atmospheric CO(2) concentration may be 10 to 20 times greater than Earth's current ambient levels. It is known that super-elevated (SE) CO(2) (>1,200 umol mol(-1)) induces physiological responses different from that of moderately elevated CO(2) (up to 1,200 umol mol( 1)), but little is known about the molecular responses of plants to supra-optimal [CO(2)]. METHODOLOGY/PRINCIPAL FINDINGS: To understand the underlying molecular causes for differential physiological responses, metabolite and transcript profiles were analyzed in aerial tissue of Arabidopsis plants, which were grown under ambient atmospheric CO(2) (400 umol mol(-1)), elevated CO(2) (1,200 umol mol(-1)) and SE CO(2) (4,000 umol mol(-1)), at two developmental stages early and late vegetative stage. Transcript and metabolite profiling revealed very different responses to elevated versus SE [CO(2)]. The transcript profiles of SE CO(2) treated plants were closer to that of the control. Development stage had a clear effect on plant molecular response to elevated and SE [CO(2)]. Photosynthetic acclimation in terms of down-regulation of photosynthetic gene expression was observed in response to elevated [CO(2)], but not that of SE [CO(2)] providing the first molecular evidence that there appears to be a fundamental disparity in the way plants respond to elevated and SE [CO(2)]. Although starch accumulation was induced by both elevated and SE [CO(2)], the increase was less at the late vegetative stage and accompanied by higher soluble sugar content suggesting an increased starch breakdown to meet sink strength resulting from the rapid growth demand. Furthermore, many of the elevated and SE CO(2)-responsive genes found in the present study are also regulated by plant hormone and stress. CONCLUSIONS/SIGNIFICANCE: This study provides new insights into plant acclimation to elevated and SE [CO(2)] during development and how this relates to stress, sugar and hormone signaling. PMID- 22916281 TI - KIOM-79 protects AGE-induced retinal pericyte apoptosis via inhibition of NF kappaB activation in vitro and in vivo. AB - KIOM-79 is an herbal mixture of parched Puerariae radix, gingered Magnoliae cortex, Glycyrrhizae radix and Euphorbiae radix. In the present study, we determined the efficacy and possible mechanism of KIOM-79 on the advanced glycation end product (AGE)-modified bovine serum albumin (BSA)-induced apoptosis of cultured bovine retinal pericytes and rat retinal pericytes in Zucker diabetic fatty (ZDF) rats. Seven-week-old male ZDF rats were treated with KIOM-79 (50 mg/kg body weight) once a day orally for 13 weeks. KIOM-79 significantly inhibited pericyte apoptosis which were induced by the AGE-BSA treatment. The KIOM-79 treatment markedly suppressed the activation of nuclear factor-kappaB (NF kappaB) through the inhibition of inhibitory kappaB kinase complex. In addition, the oral administration of KIOM-79 inhibited the changes in retinal vasculature (vascular hyperpermeability, acellular capillary). KIOM-79 strongly inhibited pericyte apoptosis, NF-kappaB activation and the expression of pro-apoptotic Bax and tumor necrosis factor-alpha. Our results suggest that KIOM-79 may exert inhibitory effects on AGE-induced pericyte apoptosis by blocking NF-kappaB activation, thereby ameliorating retinal microvascular dysfunction. PMID- 22916283 TI - Light use efficiency over two temperate steppes in inner Mongolia, China. AB - Vegetation light use efficiency (LUE) is a key parameter of Production Efficiency Models (PEMs) for simulating gross primary production (GPP) of vegetation, from regional to global scales. Previous studies suggest that grasslands have the largest inter-site variation of LUE and controlling factors of grassland LUE differ from those of other biomes, since grasslands are usually water-limited ecosystems. Combining eddy covariance flux data with the fraction of photosynthetically active radiation absorbed by the plant canopy from MODIS, we report LUE on a typical steppe and a desert steppe in Inner Mongolia, northern China. Results show that both annual average LUE and maximum LUE were higher on the desert steppe (0.51 and 1.13 g C MJ(-1)) than on the typical steppe (0.34 and 0.88 g C MJ(-1)), despite the higher GPP of the latter. Water availability was the primary limiting factor of LUE at both sites. Evaporative fraction (EF) or the ratio of actual evapotranspiration to potential evapotranspiration (AET/PET) can explain 50-70% of seasonal LUE variations at both sites. However, the slope of linear regression between LUE and EF (or AET/PET) differed significantly between the two sites. LUE increased with the diffuse radiation ratio on the typical steppe; however, such a trend was not found for the desert steppe. Our results suggest that a biome-dependent LUE(max) is inappropriate, because of the large inter-site difference of LUE(max) within the biome. EF could be a promising down-regulator on grassland LUE for PEMs, but there may be a site-specific relationship between LUE and EF. PMID- 22916282 TI - Detection of simple and pattern regularity violations occurs at different levels of the auditory hierarchy. AB - Auditory deviance detection in humans is indexed by the mismatch negativity (MMN), a component of the auditory evoked potential (AEP) of the electroencephalogram (EEG) occurring at a latency of 100-250 ms after stimulus onset. However, by using classic oddball paradigms, differential responses to regularity violations of simple auditory features have been found at the level of the middle latency response (MLR) of the AEP occurring within the first 50 ms after stimulus (deviation) onset. These findings suggest the existence of fast deviance detection mechanisms for simple feature changes, but it is not clear whether deviance detection among more complex acoustic regularities could be observed at such early latencies. To test this, we examined the pre-attentive processing of rare stimulus repetitions in a sequence of tones alternating in frequency in both long and middle latency ranges. Additionally, we introduced occasional changes in the interaural time difference (ITD), so that a simple feature regularity could be examined in the same paradigm. MMN was obtained for both repetition and ITD deviants, occurring at 150 ms and 100 ms after stimulus onset respectively. At the level of the MLR, a difference was observed between standards and ITD deviants at the Na component (20-30 ms after stimulus onset), for 800 Hz tones, but not for repetition deviants. These findings suggest that detection mechanisms for deviants to simple regularities, but not to more complex regularities, are already activated in the MLR range, supporting the view that the auditory deviance detection system is organized in a hierarchical manner. PMID- 22916284 TI - Food intake is influenced by sensory sensitivity. AB - Wide availability of highly palatable foods is often blamed for the rising incidence of obesity. As palatability is largely determined by the sensory properties of food, this study investigated how sensitivity to these properties affects how much we eat. Forty females were classified as either high or low in sensory sensitivity based on their scores on a self-report measure of sensory processing (the Adult Sensory Profile), and their intake of chocolate during the experiment was measured. Food intake was significantly higher for high sensitivity compared to low-sensitivity individuals. Furthermore, individual scores of sensory sensitivity were positively correlated with self-reported emotional eating. These data could indicate that individuals who are more sensitive to the sensory properties of food have a heightened perception of palatability, which, in turn, leads to a greater food intake. PMID- 22916285 TI - Advances in linking wintering migrant birds to their breeding-ground origins using combined analyses of genetic and stable isotope markers. AB - An enduring problem in avian ecology and conservation is linking breeding and wintering grounds of migratory species. As migratory species and populations vary in the degree to which individuals from distinct breeding locales mix on stop over sites and wintering grounds, establishing migratory connectivity informs our understanding of population demography and species management. We present a new Bayesian approach for inferring breeding grounds of wintering birds of unknown origins in North America. We incorporate prior information from analysis of genetic markers into geographic origin assignment based upon stable-hydrogen isotope analysis of feathers (delta(2)H(f)), using the Loggerhead Shrike (Lanius ludovicianus). Likely geographic origins derived from analyses of DNA microsatellites were used as priors for Bayesian analyses in which birds were assigned to a breeding-ground origin using their delta(2)H(f) values. As with most applications of Bayesian methods, our approach greatly improved the results (i.e. decreased the size of the potential area of origin). Area of origin decreased by 3 to 5-fold on average, but ranged up to a 10-fold improvement. We recommend this approach in future studies of migratory connectivity and suggest that our methodology could be applied more broadly to the study of dispersal, sources of productivity of migratory populations, and a range of evolutionary phenomena. PMID- 22916286 TI - Bias in amputation research; impact of subjects missed from a prospective study. AB - For research findings to be generalized, a sample must be representative of the actual population of interest. Lower limb amputation is most frequently performed in older patients with vascular disease, a population that is often under represented in research. The aim of this study was to explore the impact of selection bias by comparing characteristics from a sample included in a prospective study of phantom pain with the actual population who underwent amputation. Only 27% of all potential patients were referred during the first year of the prospective study. The referred patients were 8 years younger (p<0.001) and less likely to have had amputation because of a vascular condition, diabetes or infection (p=0.003) than those not referred. There was also a significant difference in one year survival between the groups; 67% of referred patients survived compared with just 40% of non-referred patients (p=0.004). The biased population in the phantom pain study may have resulted in an underestimation of phantom pain in the original study and subsequent protective factors should be considered within the context of the younger population reported. Selection bias is common in amputation research, and research methods to minimize its impact must be given greater attention. PMID- 22916287 TI - Poor decision making is a consequence of cognitive decline among older persons without Alzheimer's disease or mild cognitive impairment. AB - OBJECTIVE: Decision making is an important determinant of health and well-being across the lifespan but is critical in aging, when many influential decisions are made just as cognitive function declines. Increasing evidence suggests that older adults, even those without dementia, often make poor decisions and are selectively vulnerable to scams. To date, however, the factors associated with poor decision making in old age are unknown. The objective of this study was to test the hypothesis that poor decision making is a consequence of cognitive decline among older persons without Alzheimer's disease or mild cognitive impairment. METHODS: Participants were 420 non-demented persons from the Memory and Aging Project, a longitudinal, clinical-pathologic cohort study of aging in the Chicago metropolitan area. All underwent repeated cognitive evaluations and subsequently completed assessments of decision making and susceptibility to scams. Decision making was measured using 12 items from a previously established performance-based measure and a self-report measure of susceptibility to scams. RESULTS: Cognitive function data were collected over an average of 5.5 years prior to the decision making assessment. Regression analyses were used to examine whether the prior rate of cognitive decline predicted the level of decision making and susceptibility to scams; analyses controlled for age, sex, education, and starting level of cognition. Among 420 persons without dementia, more rapid cognitive decline predicted poorer decision making and increased susceptibility to scams (p's<0.001). Further, the relations between cognitive decline, decision making and scams persisted in analyses restricted to persons without any cognitive impairment (i.e., no dementia or even mild cognitive impairment). CONCLUSIONS: Poor decision making is a consequence of cognitive decline among older persons without Alzheimer's disease or mild cognitive impairment, those widely considered "cognitively healthy." These findings suggest that even very subtle age-related changes in cognition have detrimental effects on judgment. PMID- 22916288 TI - Overexpression of CD157 contributes to epithelial ovarian cancer progression by promoting mesenchymal differentiation. AB - Epithelial ovarian carcinoma (EOC) is an aggressive tumor often diagnosed at an advanced stage, when there is little or no prospect of cure. Despite advances in surgical and chemotherapeutic strategies, only marginal improvements in patient outcome have been obtained. Hence, unraveling the biological mechanisms underpinning EOC progression is critical for improving patients' survival. Recently, we reported that CD157 (an ectoenzyme regulating leukocyte diapedesis) is expressed in EOC and that high expression of the molecule is negatively correlated with the disease outcome in patients. Here, we demonstrate that forced overexpression of CD157 in OVCAR-3, TOV-21G, A2780 and OV-90 ovarian cancer cell lines promotes morphological and phenotypic changes characterized by disruption of intercellular junctions, downregulation of epithelial markers and upregulation of mesenchymal ones. These changes in cell shape and phenotype bring to reduced sensitivity to anoikis, increased anchorage-independent growth, cell motility and mesothelial invasion. Conversely, knockdown of CD157 in OV-90 and OC314 cells reverts the mesenchymal phenotype and reduces the cells' migratory potential. Transcriptome profiling analysis highlighted 378 significantly differentially expressed genes, representing the signature of CD157-overexpressing OVCAR-3 and OV-90 cells. The modulation of selected genes translates into alteration of protein expression that give cells a highly malignant phenotype. The overall picture deduced from the analysis of the modulated transcripts is that high expression of CD157 strengthens a number of biological processes favoring tumor progression (including development and cell motility), and weakens several biological processes hindering tumor progression (such as apoptosis, cell death and response to stress). Together, these findings implicate CD157 in the progression of EOC to metastatic disease and suggest that CD157 may represent a valuable therapeutic target. PMID- 22916289 TI - A novel role of the PrpR as a transcription factor involved in the regulation of methylcitrate pathway in Mycobacterium tuberculosis. AB - Mycobacterium tuberculosis, the pathogen that causes tuberculosis, presumably utilizes fatty acids as a major carbon source during infection within the host. Metabolism of even-chain-length fatty acids yields acetyl-CoA, whereas metabolism of odd-chain-length fatty acids additionally yields propionyl-CoA. Utilization of these compounds by tubercle bacilli requires functional glyoxylate and methylcitrate cycles, respectively. Enzymes involved in both pathways are essential for M. tuberculosis viability and persistence during growth on fatty acids. However, little is known about regulatory factors responsible for adjusting the expression of genes encoding these enzymes to particular growth conditions. Here, we characterized the novel role of PrpR as a transcription factor that is directly involved in regulating genes encoding the key enzymes of methylcitrate (methylcitrate dehydratase [PrpD] and methylcitrate synthase [PrpC]) and glyoxylate (isocitrate lyase [Icl1]) cycles. Using cell-free systems and intact cells, we demonstrated an interaction of PrpR protein with prpDC and icl1 promoter regions and identified a consensus sequence recognized by PrpR. Moreover, we showed that an M. tuberculosis prpR-deletion strain exhibits impaired growth in vitro on propionate as the sole carbon source. Real-time quantitative reverse transcription-polymerase chain reaction confirmed that PrpR acts as a transcriptional activator of prpDC and icl1 genes when propionate is the main carbon source. Similar results were also obtained for a non-pathogenic Mycobacterium smegmatis strain. Additionally, we found that ramB, a prpR paralog that controls the glyoxylate cycle, is negatively regulated by PrpR. Our data demonstrate that PrpR is essential for the utilization of odd-chain-length fatty acids by tubercle bacilli. Since PrpR also acts as a ramB repressor, our findings suggest that it plays a key role in regulating expression of enzymes involved in both glyoxylate and methylcitrate pathways. PMID- 22916290 TI - The retrograde frequency response of passive dendritic trees constrains the nonlinear firing behaviour of a reduced neuron model. AB - Our goal was to investigate how the propagation of alternating signals (i.e. AC), like action potentials, into the dendrites influenced nonlinear firing behaviour of motor neurons using a systematically reduced neuron model. A recently developed reduced modeling approach using only steady-current (i.e. DC) signaling was analytically expanded to retain features of the frequency-response analysis carried out in multicompartment anatomically reconstructed models. Bifurcation analysis of the extended model showed that the typically overlooked parameter of AC amplitude attenuation was positively correlated with the current threshold for the activation of a plateau potential in the dendrite. Within the multiparameter space map of the reduced model the region demonstrating "fully-bistable" firing was bounded by directional DC attenuation values that were negatively correlated to AC attenuation. Based on these results we conclude that analytically derived reduced models of dendritic trees should be fit on DC and AC signaling, as both are important biophysical parameters governing the nonlinear firing behaviour of motor neurons. PMID- 22916291 TI - S-nitrosoglutathione acts as a small molecule modulator of human fibrin clot architecture. AB - BACKGROUND: Altered fibrin clot architecture is increasingly associated with cardiovascular diseases; yet, little is known about how fibrin networks are affected by small molecules that alter fibrinogen structure. Based on previous evidence that S-nitrosoglutathione (GSNO) alters fibrinogen secondary structure and fibrin polymerization kinetics, we hypothesized that GSNO would alter fibrin microstructure. METHODOLOGY/PRINCIPAL FINDINGS: Accordingly, we treated human platelet-poor plasma with GSNO (0.01-3.75 mM) and imaged thrombin induced fibrin networks using multiphoton microscopy. Using custom designed computer software, we analyzed fibrin microstructure for changes in structural features including fiber density, diameter, branch point density, crossing fibers and void area. We report for the first time that GSNO dose-dependently decreased fibrin density until complete network inhibition was achieved. At low dose GSNO, fiber diameter increased 25%, maintaining clot void volume at approximately 70%. However, at high dose GSNO, abnormal irregularly shaped fibrin clusters with high fluorescence intensity cores were detected and clot void volume increased dramatically. Notwithstanding fibrin clusters, the clot remained stable, as fiber branching was insensitive to GSNO and there was no evidence of fiber motion within the network. Moreover, at the highest GSNO dose tested, we observed for the first time, that GSNO induced formation of fibrin agglomerates. CONCLUSIONS/SIGNIFICANCE: Taken together, low dose GSNO modulated fibrin microstructure generating coarse fibrin networks with thicker fibers; however, higher doses of GSNO induced abnormal fibrin structures and fibrin agglomerates. Since GSNO maintained clot void volume, while altering fiber diameter it suggests that GSNO may modulate the remodeling or inhibition of fibrin networks over an optimal concentration range. PMID- 22916292 TI - Sites of glucose transporter-4 vesicle fusion with the plasma membrane correlate spatially with microtubules. AB - In adipocytes, vesicles containing glucose transporter-4 (GLUT4) redistribute from intracellular stores to the cell periphery in response to insulin stimulation. Vesicles then fuse with the plasma membrane, facilitating glucose transport into the cell. To gain insight into the details of microtubule involvement, we examined the spatial organization and dynamics of microtubules in relation to GLUT4 vesicle trafficking in living 3T3-L1 adipocytes using total internal reflection fluorescence (TIRF) microscopy. Insulin stimulated an increase in microtubule density and curvature within the TIRF-illuminated region of the cell. The high degree of curvature and abrupt displacements of microtubules indicate that substantial forces act on microtubules. The time course of the microtubule density increase precedes that of the increase in intensity of fluorescently-tagged GLUT4 in this same region of the cell. In addition, portions of the microtubules are highly curved and are pulled closer to the cell cortex, as confirmed by Parallax microscopy. Microtubule disruption delayed and modestly reduced GLUT4 accumulation at the plasma membrane. Quantitative analysis revealed that fusions of GLUT4-containing vesicles with the plasma membrane, detected using insulin-regulated aminopeptidase with a pH sensitive GFP tag (pHluorin), preferentially occur near microtubules. Interestingly, long-distance vesicle movement along microtubules visible at the cell surface prior to fusion does not appear to account for this proximity. We conclude that microtubules may be important in providing spatial information for GLUT4 vesicle fusion. PMID- 22916293 TI - Involvement of the CXCR7/CXCR4/CXCL12 axis in the malignant progression of human neuroblastoma. AB - Neuroblastoma (NB) is a typical childhood and heterogeneous neoplasm for which efficient targeted therapies for high-risk tumors are not yet identified. The chemokine CXCL12, and its receptors CXCR4 and CXCR7 have been involved in tumor progression and dissemination. While CXCR4 expression is associated to undifferentiated tumors and poor prognosis, the role of CXCR7, the recently identified second CXCL12 receptor, has not yet been elucidated in NB. In this report, CXCR7 and CXCL12 expressions were evaluated using a tissue micro-array including 156 primary and 56 metastatic NB tissues. CXCL12 was found to be highly associated to NB vascular and stromal structures. In contrast to CXCR4, CXCR7 expression was low in undifferentiated tumors, while its expression was stronger in matured tissues and specifically associated to differentiated neural tumor cells. As determined by RT-PCR, CXCR7 expression was mainly detected in N-and S type NB cell lines, and was slightly induced upon NB cell differentiation in vitro. The relative roles of the two CXCL12 receptors were further assessed by overexpressing CXCR7 or CXCR4 receptor alone, or in combination, in the IGR-NB8 and the SH-SY5Y NB cell lines. In vitro functional analyses indicated that, in response to their common ligand, both receptors induced activation of ERK1/2 cascade, but not Akt pathway. CXCR7 strongly reduced in vitro growth, in contrast to CXCR4, and impaired CXCR4/CXCL12-mediated chemotaxis. Subcutaneous implantation of CXCR7-expressing NB cells showed that CXCR7 also significantly reduced in vivo growth. Moreover, CXCR7 affected CXCR4-mediated orthotopic growth in a CXCL12-producing environment. In such model, CXCR7, in association with CXCR4, did not induce NB cell metastatic dissemination. In conclusion, the CXCR7 and CXCR4 receptors revealed specific expression patterns and distinct functional roles in NB. Our data suggest that CXCR7 elicits anti-tumorigenic functions, and may act as a regulator of CXCR4/CXCL12-mediated signaling in NB. PMID- 22916294 TI - Ethnic differences in cardiometabolic risk profile at age 5-6 years: the ABCD study. AB - BACKGROUND: To examine ethnic differences in cardiometabolic risk profile in early age, and explore whether such differences can be explained by differences in body mass index (BMI) or waist circumference (WC). METHOD: Anthropometric measurements, blood pressure and (in a subsample) fasting blood were collected during a health check of 2,509 children aged 5-6 years. Four ethnic groups were distinguished: Dutch (n=2,008; blood n=1,300), African descent (n=199; blood n=105), Turkish (n=108; blood n=57) and Moroccan (n=194; blood n=94). Ethnic differences in diastolic and systolic blood pressure (DBP/SBP), fasting glucose, low-density lipoprotein (LDL), high-density lipoprotein (HDL) and triglyceride levels were determined and the explanatory role of BMI and WC was examined with regression analysis. RESULTS: After adjustment for confounders, African descent children showed higher DBP (beta2.22 mmHg; 95%CI:1.09-3.36) and HDL levels (beta:0.09 mmol/l; 95%CI:0.03-0.16) compared to Dutch children (reference group). Turkish children showed higher SBP (beta:1.89 mmHg; 95%CI:0.25-3.54), DBP (beta:2.62 mmHg; 95%CI:1.11-4.13), glucose (beta:0.12 mmol/L; 95%CI:0.00-0.25) and triglyceride levels (beta:0.13 mmol/L; 95%CI:0.02-0.25). Higher BMI values were found in all non-Dutch groups (differences ranged from 0.53-1.03 kg/m(2)) and higher WC in Turkish (beta:1.68 cm; 95%CI:0.99-2.38) and Moroccan (beta:1.65 cm; 95%CI:1.11-2.19) children. BMI and WC partly explained the higher SBP/DBP and triglyceride levels in Turkish children. CONCLUSION: Ethnic differences in cardiometabolic profile exist early in life and are partly explained by differences in BMI and WC. African children showed favourable HDL levels and Turkish children the most unfavourable overall profile, whereas their Moroccan peers have less increased cardiometabolic risk in spite of their high BMI and WC. PMID- 22916295 TI - ING1 and 5-azacytidine act synergistically to block breast cancer cell growth. AB - BACKGROUND: Inhibitor of Growth (ING) proteins are epigenetic "readers" that recognize trimethylated lysine 4 of histone H3 (H3K4Me3) and target histone acetyl transferase (HAT) and histone deacetylase (HDAC) complexes to chromatin. METHODS AND PRINCIPAL FINDINGS: Here we asked whether dysregulating two epigenetic pathways with chemical inhibitors showed synergistic effects on breast cancer cell line killing. We also tested whether ING1 could synergize better with chemotherapeutics that target the same epigenetic mechanism such as the HDAC inhibitor LBH589 (Panobinostat) or a different epigenetic mechanism such as 5 azacytidine (5azaC), which inhibits DNA methyl transferases. Simultaneous treatment of breast cancer cell lines with LBH589 and 5azaC did not show significant synergy in killing cells. However, combination treatment of ING1 with either LBH589 or 5azaC did show synergy. The combination of ING1b with 5azaC, which targets two distinct epigenetic mechanisms, was more effective at lower doses and enhanced apoptosis as determined by Annexin V staining and cleavage of caspase 3 and poly-ADP-ribose polymerase (PARP). ING1b plus 5azaC also acted synergistically to increase gammaH2AX staining indicating significant levels of DNA damage were induced. Adenoviral delivery of ING1b with 5azaC also inhibited cancer cell growth in a murine xenograft model and led to tumor regression when viral concentration was optimized in vivo. CONCLUSIONS: These data show that targeting distinct epigenetic pathways can be more effective in blocking cancer cell line growth than targeting the same pathway with multiple agents, and that using viral delivery of epigenetic regulators can be more effective in synergizing with a chemical agent than using two chemotherapeutic agents. This study also indicates that the ING1 epigenetic regulator may have additional activities in the cell when expressed at high levels. PMID- 22916296 TI - Intra-amniotic inflammatory response in subgroups of women with preterm prelabor rupture of the membranes. AB - BACKGROUND: To evaluate the influence of microbial invasion of the amniotic cavity (MIAC) and histological chorioamnionitis (HCA) on the magnitude of intra amniotic inflammatory response in preterm prelabor rupture of membranes (PPROM). METHODOLOGY/PRINCIPAL FINDING: A prospective cohort study was performed in 107 women with PPROM between 23.0 and 36.6 weeks of gestational age. Twenty-six proteins were assayed by multiple immunoassay in amniotic fluid. The policy for PPROM in Czech Republic is active, and 90% of the women were delivered within 96 hours of membrane rupture. Histopathological placental findings were evaluated based on the Salafia classification. Data were analyzed in four subgroups of population according to the presence of MIAC and/or HCA. Results were stratified by gestational age at PPROM (< or >= 34.0 weeks). The rates of MIAC and HCA were 44% and 57%, respectively. Regardless of gestational age at PPROM, intra-amniotic inflammatory response was higher when MIAC and HCA were both present. There were no differences in the intra-amniotic inflammatory response between women with MIAC or HCA alone and women without infection. CONCLUSION: A higher intra amniotic inflammatory response was identified when both HCA and MIAC were detected. PMID- 22916297 TI - Acetylcholine-binding protein in the hemolymph of the planorbid snail Biomphalaria glabrata is a pentagonal dodecahedron (60 subunits). AB - Nicotinic acetylcholine receptors (nAChR) play important neurophysiological roles and are of considerable medical relevance. They have been studied extensively, greatly facilitated by the gastropod acetylcholine-binding proteins (AChBP) which represent soluble structural and functional homologues of the ligand-binding domain of nAChR. All these proteins are ring-like pentamers. Here we report that AChBP exists in the hemolymph of the planorbid snail Biomphalaria glabrata (vector of the schistosomiasis parasite) as a regular pentagonal dodecahedron, 22 nm in diameter (12 pentamers, 60 active sites). We sequenced and recombinantly expressed two ~25 kDa polypeptides (BgAChBP1 and BgAChBP2) with a specific active site, N-glycan site and disulfide bridge variation. We also provide the exon/intron structures. Recombinant BgAChBP1 formed pentamers and dodecahedra, recombinant BgAChBP2 formed pentamers and probably disulfide-bridged di pentamers, but not dodecahedra. Three-dimensional electron cryo-microscopy (3D EM) yielded a 3D reconstruction of the dodecahedron with a resolution of 6 A. Homology models of the pentamers docked to the 6 A structure revealed opportunities for chemical bonding at the inter-pentamer interfaces. Definition of the ligand-binding pocket and the gating C-loop in the 6 A structure suggests that 3D-EM might lead to the identification of functional states in the BgAChBP dodecahedron. PMID- 22916298 TI - Audience effect alters male mating preferences in zebra finches (Taeniopygia guttata). AB - The social environment of animals strongly influences the mating preferences of both the choosing and the observing individuals. Notably, there is recent evidence that polygamous males decrease their selectivity when being observed by competitors in order to direct their rivals' attention away from their true interest and, consequently, reduce sperm competition risk. Yet, other mechanisms, whose importance remains unexplored, could induce similar effects. In monogamous species with mutual choice, particularly, if males adjust their selectivity according to the risk of being rejected by their preferred mate, they should as well become less selective when potential rivals are present. Here, we investigated whether the presence of bystanders modifies male mating preferences when the risk of sperm competition is low, by carrying out mate-choice experiments with male zebra finches (Taeniopygia guttata) whose preferences for two females were measured twice: with and without an audience. We found that the presence of potential rivals had no effect on the males' choosiness. However, with an audience, they spent more time with the female that was considered as the less attractive one in the control condition. These findings support the hypothesis that monogamous males alter their mate choice decisions in the presence of a male audience to reduce the risk of remaining unpaired. Thus, our results indicate that several explanations can account for the changes in male preferences due to the presence of competitors and highlight the importance of assessing the relative role of each mechanism potentially involved, to be able to make conclusions about the effect of an audience on signal evolution. PMID- 22916299 TI - Vacuolar protein sorting receptor in Giardia lamblia. AB - In Giardia, lysosome-like peripheral vacuoles (PVs) need to specifically coordinate their endosomal and lysosomal functions to be able to successfully perform endocytosis, protein degradation and protein delivery, but how cargo, ligands and molecular components generate specific routes to the PVs remains poorly understood. Recently, we found that delivering membrane Cathepsin C and the soluble acid phosphatase (AcPh) to the PVs is adaptin (AP1)-dependent. However, the receptor that links AcPh and AP1 was never described. We have studied protein-binding to AcPh by using H6-tagged AcPh, and found that a membrane protein interacted with AcPh. This protein, named GlVps (for Giardia lamblia Vacuolar protein sorting), mainly localized to the ER-nuclear envelope and in some PVs, probably functioning as the sorting receptor for AcPh. The tyrosine-binding motif found in the C-terminal cytoplasmic tail domain of GlVps was essential for its exit from the endoplasmic reticulum and transport to the vacuoles, with this motif being necessary for the interaction with the medium subunit of AP1. Thus, the mechanism by which soluble proteins, such as AcPh, reach the peripheral vacuoles in Giardia appears to be very similar to the mechanism of lysosomal protein-sorting in more evolved eukaryotic cells. PMID- 22916300 TI - Deregulation of type I IFN-dependent genes correlates with increased susceptibility to cytomegalovirus acute infection of dicer mutant mice. AB - Regulation of gene expression by microRNAs (miRNAs) is now considered as an essential mechanism for cell development and homeostasis. Indeed, numerous studies have reported that modulating their expression, maturation, or activity can affect cell survival, identity or activation. In particular, miRNAs are key players in the tight regulation of signaling cascades, and as such, they appear as perfectly suited immunomodulators. Several immune-related processes, including inflammation, have recently been demonstrated to require specific miRNAs. In addition, the discovery of herpesvirus-encoded miRNAs has reinforced this assumption. To decipher the potential roles of miRNAs in innate antiviral immune response, we developed an in vivo model based on the inoculation of mouse cytomegalovirus (MCMV) in mice. Furthermore, we exploited a mouse line carrying a hypomorphic mutation in the Dicer gene to visualize the impact of impaired miRNA biogenesis upon the anti-MCMV response. Our data indicate that miRNAs are important actors in mounting an efficient response against herpesviruses. We suggest that a rapid and transient interferon response following viral infection requires miRNA-dependent repressor release. In addition, our in vivo efforts identified several miRNA targets, thus providing a conceptual framework for future analyzes on the regulation of specific actors involved in the Type I interferon pathway. PMID- 22916302 TI - Transcriptomics and comparative analysis of three antarctic notothenioid fishes. AB - For the past 10 to 13 million years, Antarctic notothenioid fish have undergone extraordinary periods of evolution and have adapted to a cold and highly oxygenated Antarctic marine environment. While these species are considered an attractive model with which to study physiology and evolutionary adaptation, they are poorly characterized at the molecular level, and sequence information is lacking. The transcriptomes of the Antarctic fishes Notothenia coriiceps, Chaenocephalus aceratus, and Pleuragramma antarcticum were obtained by 454 FLX Titanium sequencing of a normalized cDNA library. More than 1,900,000 reads were assembled in a total of 71,539 contigs. Overall, 40% of the contigs were annotated based on similarity to known protein or nucleotide sequences, and more than 50% of the predicted transcripts were validated as full-length or putative full-length cDNAs. These three Antarctic fishes shared 663 genes expressed in the brain and 1,557 genes expressed in the liver. In addition, these cold-adapted fish expressed more Ub-conjugated proteins compared to temperate fish; Ub conjugated proteins are involved in maintaining proteins in their native state in the cold and thermally stable Antarctic environments. Our transcriptome analysis of Antarctic notothenioid fish provides an archive for future studies in molecular mechanisms of fundamental genetic questions, and can be used in evolution studies comparing other fish. PMID- 22916301 TI - T cell receptor-like recognition of tumor in vivo by synthetic antibody fragment. AB - A major difficulty in treating cancer is the inability to differentiate between normal and tumor cells. The immune system differentiates tumor from normal cells by T cell receptor (TCR) binding of tumor-associated peptides bound to Major Histocompatibility Complex (pMHC) molecules. The peptides, derived from the tumor specific proteins, are presented by MHC proteins, which then serve as cancer markers. The TCR is a difficult protein to use as a recombinant protein because of production issues and has poor affinity for pMHC; therefore, it is not a good choice for use as a tumor identifier outside of the immune system. We constructed a synthetic antibody-fragment (Fab) library in the phage-display format and isolated antibody-fragments that bind pMHC with high affinity and specificity. One Fab, fE75, recognizes our model cancer marker, the Human Epidermal growth factor Receptor 2 (HER2/neu) peptide, E75, bound to the MHC called Human Leukocyte Antigen-A2 (HLA-A2), with nanomolar affinity. The fE75 bound selectively to E75/HLA-A2 positive cancer cell lines in vitro. The fE75 Fab conjugated with (64)Cu selectively accumulated in E75/HLA-A2 positive tumors and not in E75/HLA-A2 negative tumors in an HLA-A2 transgenic mouse as probed using positron emission tomography/computed tomography (PET/CT) imaging. Considering that hundreds to thousands of different peptides bound to HLA-A2 are present on the surface of each cell, the fact that fE75 arrives at the tumor at all shows extraordinary specificity. These antibody fragments have great potential for diagnosis and targeted drug delivery in cancer. PMID- 22916303 TI - Tertiary endosymbiosis in two dinotoms has generated little change in the mitochondrial genomes of their dinoflagellate hosts and diatom endosymbionts. AB - BACKGROUND: Mitochondria or mitochondrion-derived organelles are found in all eukaryotes with the exception of secondary or tertiary plastid endosymbionts. In these highly reduced systems, the mitochondrion has been lost in all cases except the diatom endosymbionts found in a small group of dinoflagellates, called 'dinotoms', the only cells with two evolutionarily distinct mitochondria. To investigate the persistence of this redundancy and its consequences on the content and structure of the endosymbiont and host mitochondrial genomes, we report the sequences of these genomes from two dinotoms. METHODOLOGY/PRINCIPAL FINDINGS: The endosymbiont mitochondrial genomes of Durinskia baltica and Kryptoperidinium foliaceum exhibit nearly identical gene content with other diatoms, and highly conserved gene order (nearly identical to that of the raphid pennate diatom Fragilariopsis cylindrus). These two genomes are differentiated from other diatoms' by the fission of nad11 and by an insertion within nad2, in frame and unspliced from the mRNA. Durinskia baltica is further distinguished from K. foliaceum by two gene fusions and its lack of introns. The host mitochondrial genome in D. baltica encodes cox1 and cob plus several fragments of LSU rRNA gene in a hugely expanded genome that includes numerous pseudogenes, and a trans-spliced cox3 gene, like in other dinoflagellates. Over 100 distinct contigs were identified through 454 sequencing, but intact full-length genes for cox1, cob and the 5' exon of cox3 were present as a single contig each, suggesting most of the genome is pseudogenes. The host mitochondrial genome of K. foliaceum was difficult to identify, but fragments of all the three protein coding genes, corresponding transcripts, and transcripts of several LSU rRNA fragments were all recovered. CONCLUSIONS/SIGNIFICANCE: Overall, the endosymbiont and host mitochondrial genomes in the two dinotoms have changed surprisingly little from those of free-living diatoms and dinoflagellates, irrespective of their long coexistence side by side in dinotoms. PMID- 22916304 TI - Sperm traits negatively covary with size and asymmetry of a secondary sexual trait in a freshwater crayfish. AB - In species where females mate promiscuously, the reproductive success of males depends both on their ability to acquire mates (pre-copulatory sexual selection) and ability of their ejaculates to outcompete those of other males (post copulatory sexual selection). Sperm competition theory predicts a negative relationship between investment in body traits favouring mate acquisition (secondary sexual characters, SSCs) and investment in ejaculate size or quality, due to the inherent costs of sperm production. In contrast, the phenotype-linked fertility hypothesis posits that male fertilizing efficiency is reliably reflected by the phenotypic expression of male SSCs, allowing females to obtain direct benefits by selecting more ornamented males as copulation partners. In this study, we investigated the relationships between male SSCs and size and quality (viability and longevity) of ejaculates allocated to females in mating trials of the freshwater crayfish Austropotamobius italicus. We showed that the relative size of male weapons, the chelae, was negatively related to ejaculate size, and that chelae asymmetry, resulting from regeneration of lost chelipeds, negatively covaried with sperm longevity. Moreover, males allocated more viable sperm to mates from their own rather than different stream of origin. Our findings thus suggest that, according to sperm competition theory, pre-copulatory sexual selection for large weapons used in male fighting may counteract post copulatory sperm competition in this crayfish species, and that investment in cheliped regeneration may impair ejaculate quality. PMID- 22916305 TI - One for all or all for one: heterogeneous expression and host cell lysis are key to gene transfer agent activity in Rhodobacter capsulatus. AB - The gene transfer agent (RcGTA) of Rhodobacter capsulatus is the model for a family of novel bacteriophage-related genetic elements that carry out lateral transfer of essentially random host DNA. Genuine and putative gene transfer agents have been discovered in diverse genera and are becoming recognized as potentially an important source of genetic exchange and microbial evolution in the oceans. Despite being discovered over 30 years ago, little is known about many essential aspects of RcGTA biology. Here, we validate the use of direct fluorescence reporter constructs, which express the red fluorescent protein mCherry in R. capsulatus. A construct containing the RcGTA promoter fused to mCherry was used to examine the single-cell expression profiles of wild type and RcGTA overproducer R. capsulatus populations, under different growth conditions and growth phases. The majority of RcGTA production clearly arises from a small, distinct sub-set of the population in the wild type strain and a larger sub-set in the overproducer. The most likely RcGTA release mechanism concomitant with this expression pattern is host cell lysis and we present direct evidence for the release of an intracellular enzyme accompanying RcGTA release. RcGTA ORF s is annotated as a 'cell wall peptidase' but we rule out a role in host lysis and propose an alternative function as a key contributor to RcGTA invasion of a target cell during infection. PMID- 22916306 TI - Zap1 regulates zinc homeostasis and modulates virulence in Cryptococcus gattii. AB - Zinc homeostasis is essential for fungal growth, as this metal is a critical structural component of several proteins, including transcription factors. The fungal pathogen Cryptococcus gattii obtains zinc from the stringent zinc-limiting milieu of the host during the infection process. To characterize the zinc metabolism in C. gattii and its relationship to fungal virulence, the zinc finger protein Zap1 was functionally characterized. The C. gattii ZAP1 gene is an ortholog of the master regulatory genes zafA and ZAP1 that are found in Aspergillus fumigatus and Saccharomyces cerevisiae, respectively. There is some evidence to support an association between Zap1 and zinc metabolism in C. gattii: (i) ZAP1 expression is highly induced during zinc deprivation, (ii) ZAP1 knockouts demonstrate impaired growth in zinc-limiting conditions, (iii) Zap1 regulates the expression of ZIP zinc transporters and distinct zinc-binding proteins and (iv) Zap1 regulates the labile pool of intracellular zinc. In addition, the deletion of ZAP1 reduces C. gattii virulence in a murine model of cryptococcosis infection. Based on these observations, we postulate that proper zinc metabolism plays a crucial role in cryptococcal virulence. PMID- 22916307 TI - Angiostatic factors in the pulmonary endarterectomy material from chronic thromboembolic pulmonary hypertension patients cause endothelial dysfunction. AB - Chronic thromboembolic pulmonary hypertension (CTEPH) is a rare disease with persistent thrombotic occlusion or stenosis of the large pulmonary arteries resulting in pulmonary hypertension. Surgical removal of the neointimal layer of these vessels together with the non-resolved thrombus consisting of organized collagen-rich fibrotic areas with partly recanalized regions is the treatment of choice (pulmonary endarterectomy, PEA). The present study investigates endothelial cells isolated from such material as well as factors present in the surgical PEA material, which may contribute to impairment of recanalization and thrombus non-resolution. We observed muscularized vessels and non-muscularized vessels in the PEA material. The isolated endothelial cells from the PEA material showed significantly different calcium homeostasis as compared to pulmonary artery endothelial cells (hPAECs) from normal controls. In the supernatant (ELISA) as well as on the tissue level (histochemical staining) of the PEA material, platelet factor 4 (PF4), collagen type I and interferon-gamma-inducible 10 kD protein (IP-10) were detected. CXCR3, the receptor for PF4 and IP-10, was particularly elevated in the distal parts of the PEA material as compared to human control lung (RT-PCR). PF4, collagen type I and IP-10 caused significant changes in calcium homeostasis and affected the cell proliferation, migration and vessel formation in hPAECs. The presence of angiostatic factors like PF4, collagen type I and IP-10, as recovered from the surgical PEA material from CTEPH patients, may lead to changes in calcium homeostasis and endothelial dysfunction. PMID- 22916308 TI - Filamins but not Janus kinases are substrates of the ASB2alpha cullin-ring E3 ubiquitin ligase in hematopoietic cells. AB - The ASB2alpha protein is the specificity subunit of an E3 ubiquitin ligase complex involved in hematopoietic differentiation and is proposed to exert its effects by regulating the turnover of specific proteins. Three ASB2alpha substrates have been described so far: the actin-binding protein filamins, the Mixed Lineage Leukemia protein, and the Janus kinases 2 and 3. To determine the degradation of which substrate drives ASB2alpha biological effects is crucial for the understanding of ASB2alpha functions in hematopoiesis. Here, we show that neither endogenous nor exogenously expressed ASB2alpha induces degradation of JAK proteins in hematopoietic cells. Furthermore, we performed molecular modeling to generate the first structural model of an E3 ubiquitin ligase complex of an ASB protein bound to one of its substrates. PMID- 22916310 TI - An evaluation of barrier repair foam on the molecular concentration profiles of intrinsic skin constituents utilizing confocal Raman spectroscopy. AB - For decades, transepidermal water loss and corneometry have been accepted as measures of skin barrier function. However, these tests are not capable of informing clinicians of the biochemical constituents and biophysical status of the stratum corneum. Knowledge of how the stratum corneum reacts to topical agents is important, as it reveals significant detail regarding the composition and function of this vital skin layer. Furthermore, transepidermal water loss and corneometry serve only as surrogate markers of barrier function. A more precise method of assessing stratum corneum hydration and lipid levels is emerging; in vivo confocal Raman spectroscopy is able to detect and quantify specific biochemical constituents in skin. This information then allows for assessment of the actual physiological status of this vital layer of the skin. This pilot study sought to elucidate a biophysical rationale for the clinical improvement achieved by hyaluronic acid/ceramide barrier repair foam in prior studies as measured by in vivo confocal Raman spectroscopy. Study results include increased lipid and hydration levels in the stratum corneum to depths of 25um and 40um, respectively, at the 2-hour, 48-hour, and 7-day time points. PMID- 22916309 TI - Beta adrenergic overstimulation impaired vascular contractility via actin cytoskeleton disorganization in rabbit cerebral artery. AB - BACKGROUND AND PURPOSE: Beta adrenergic overstimulation may increase the vascular damage and stroke. However, the underlying mechanisms of beta adrenergic overstimulation in cerebrovascular dysfunctions are not well known. We investigated the possible cerebrovascular dysfunction response to isoproterenol induced beta-adrenergic overstimulation (ISO) in rabbit cerebral arteries (CAs). METHODS: ISO was induced in six weeks aged male New Zealand white rabbit (0.8-1.0 kg) by 7-days isoproterenol injection (300 MUg/kg/day). We investigated the alteration of protein expression in ISO treated CAs using 2DE proteomics and western blot analysis. Systemic properties of 2DE proteomics result were analyzed using bioinformatics software. ROS generation and following DNA damage were assessed to evaluate deteriorative effect of ISO on CAs. Intracellular Ca(2+) level change and vascular contractile response to vasoactive drug, angiotensin II (Ang II), were assessed to evaluate functional alteration of ISO treated CAs. Ang II-induced ROS generation was assessed to evaluated involvement of ROS generation in CA contractility. RESULTS: Proteomic analysis revealed remarkably decreased expression of cytoskeleton organizing proteins (e.g. actin related protein 1A and 2, alpha-actin, capping protein Z beta, and vimentin) and anti-oxidative stress proteins (e.g. heat shock protein 9A and stress-induced-phosphoprotein 1) in ISO CAs. As a cause of dysregulation of actin-cytoskeleton organization, we found decreased level of RhoA and ROCK1, which are major regulators of actin cytoskeleton organization. As functional consequences of proteomic alteration, we found the decreased transient Ca(2+) efflux and constriction response to angiotensin II and high K(+) in ISO-CAs. ISO also increased basal ROS generation and induced oxidative damage in CA; however, it decreased the Ang II-induced ROS generation rate. These results indicate that ISO disrupted actin cytoskeleton proteome network through down-regulation of RhoA/ROCK1 proteins and increased oxidative damage, which consequently led to contractile dysfunction in CA. PMID- 22916311 TI - Borrelia burgdorferi Infections in the United States. AB - It is becoming increasingly evident that the clinical presentation of infection with Borrelia burgdorferi varies greatly between different parts of the world. A growing number of European and Asian isolates of Lyme borreliae, differing from the American strain of Borrelia burgdorferi, have been identified in several different disorders. In light of the increasing number of reports describing an association between various cutaneous disorders and infection with Borrelia burgdorferi and the controversy that still remains over where Borrelia burgdorferi is truly pathogenic in these diseases, this review of the literature assesses the significance of these reports in substantiating these hypotheses, as such associations are important both diagnostically and therapeutically. PMID- 22916312 TI - Treatment of xerosis with a topical formulation containing glyceryl glucoside, natural moisturizing factors, and ceramide. AB - OBJECTIVE: To assess the effects of Light Formulation, an oil-in-water emulsion, and Rich Formulation, a water-in-oil emulsion, for the treatment of xerosis. DESIGN: Two double-blind, vehicle-controlled trials (both formulations); a double blind, randomized regression study (Rich Formulation); and a single-blind tolerability study (Light Formulation). The two formulations were applied twice daily for two weeks, for five days in the regression study, and twice daily for two weeks in the tolerability study. SETTING: Studies were conducted during winter in Hamburg, Germany. PARTICIPANTS: A total of 169 subjects were enrolled and 154 completed the studies. The majority were between 50 and 80 years of age, women, all with very dry skin. One withdrew because of an incompatibility reaction that reoccurred with the subject's own body lotion after sun exposure. MEASUREMENTS: Skin hydration and skin barrier function with both formulations over two weeks, long-term moisturization effect after discontinuation of Rich Formulation, and symptom improvement and skin tolerability with Light Formulation. RESULTS: Vehicle-controlled studies of Light and Rich Formulations demonstrated significantly improved hydration at Weeks 1 and 2 versus the untreated site and vehicles, and significantly reduced transepidermal water loss versus untreated site and basic vehicle. Both products significantly decreased visible dryness and tactile roughness. In the regression study, Rich Formulation maintained significant moisturization six days after treatment discontinuation. Light Formulation reduced symptoms of itching, burning, tightness, tingling, and feeling of dryness. CONCLUSION: These formulations represent a new approach for the treatment of xerosis by addressing multiple key deficiencies in skin hydration. PMID- 22916313 TI - A Case of Palmoplantar Pustulosis Induced by Certolizumab Pegol: New Anti-TNF alpha Demonstrates the Same Class Effect. AB - The development of de novo psoriasis in patients treated with tumor necrosis factor-alpha antagonists is well recognized. The authors hereby report a case of palmplantar pustular psoriasis in a patient with rheumatoid arthritis treated with etanercept. The condition responded to topical steroids but re-occurred upon treating the patient with certolizumab pegol. This strongly suggests that the development of de novo psoriasis is a class effect. PMID- 22916314 TI - Generalized eruptive histiocytomas and rosai-dorfman disease presenting concurrently in a patient with myelodysplastic syndrome. AB - Non-Langerhans cell histiocytoses were originally described as individual diagnoses. However, evidence has been mounting that these entities are manifestations on a spectrum of the same disease. The authors present a patient who initially presented with lymphadenopathy, pancytopenia, splenomegaly, and high-grade fevers. A bone marrow biopsy was performed and she was diagnosed with myelodysplastic syndrome with trisomy 8. Several months later, her persistent pulmonary lymphadenopathy was biopsied revealing Rosai-Dorfman disease. Two years after her initial hospitalization, the patient presented with lesions consistent with generalized eruptive histiocytomas. This case highlights the difficulty that clinicians encounter when trying to separate generalized eruptive histiocytomas, Rosai-Dorfman disease, and the other non-Langerhans cell histiocytoses. While further research needs to be performed in the field of histiocytoses, this case provides clinical support that these diseases are closely linked. PMID- 22916315 TI - Pruritic annular patches with eosinophilia. PMID- 22916316 TI - NOSH-Aspirin: A Novel Nitric Oxide-Hydrogen Sulfide-Releasing Hybrid: A New Class of Anti-inflammatory Pharmaceuticals. AB - A series of new hybrids of aspirin (ASA), bearing both nitric oxide (NO) and hydrogen sulfide (H(2)S)-releasing moieties were synthesized and designated as NOSH compounds (1-4). NOSH-1 (4-(3-thioxo-3H-1,2-dithiol-5-yl) phenyl 2-((4 (nitrooxy)-butanoyl)oxy) benzoate); NOSH-2 (4-(nitrooxy)butyl (2-((4-(3-thioxo-3H 1,2-dithiol-5-yl)phenoxy)carbonyl)phenyl)); NOSH-3 (4-carbamothioylphenyl 2-((4 (nitrooxy)butanoyl)-oxy)benzoate); and NOSH-4 (4-(nitrooxy)butyl 2-(5-((R)-1,2 dithiolan-3-yl)pentanoyloxy)-benzoate). The cell growth inhibitory properties of compounds 1-4 were evaluated in eleven different human cancer cell lines of six different tissue origins. These cell lines are of adenomatous (colon, pancreatic, lung, prostate), epithelial (breast), and lymphocytic (leukemia) origin. All NOSH compounds were extremely effective in inhibiting the growth of these cell lines. NOSH-1 was the most potent, with an IC(50) of 48 +/- 3 nM in HT-29 colon cancer cells. This is the first NSAID-based compound with such potency. This compound was also devoid of any cellular toxicity, as determined by LDH release. NOSH-1 was comparable to aspirin in its anti-inflammatory properties, using the carrageenan rat paw edema model. PMID- 22916317 TI - Improved quality and quantity of written feedback is associated with a structured feedback proforma. AB - Facilitating the provision of detailed, deep and useful feedback is an important design feature of any educational programme. Here we evaluate feedback provided to medical students completing short transferable skills projects. Feedback quantity and depth were evaluated before and after a simple intervention to change the structure of the feedback-provision form from a blank free-text feedback form to a structured proforma that asked a pair of short questions for each of the six domains being assessed. Each pair of questions consisted of asking the marker 'what was done well?' and 'what changes would improve the assignment?' Changing the form was associated with a significant increase in the quantity of the feedback and in the amount and quality of feedback provided to students. We also observed that, for these double-marked projects, the marker designated as 'marker 1' consistently wrote more feedback than the marker designated 'marker 2'. PMID- 22916319 TI - Efforts for SCI Listing. PMID- 22916318 TI - 3D single molecule tracking of quantum-dot labeled antibody molecules using multifocal plane microscopy. AB - Single molecule tracking in three dimensions (3D) in a live cell environment promises to reveal important new insights into cell biological mechanisms. However, classical microscopy techniques suffer from poor depth discrimination which severely limits single molecule tracking in 3D with high temporal and spatial resolution. We introduced a novel imaging modality, multifocal plane microscopy (MUM) for the study of subcellular dynamics in 3D. We have shown that MUM provides a powerful approach with which single molecules can be tracked in 3D in live cells. MUM allows for the simultaneous imaging at different focal planes, thereby ensuring that trajectories can be imaged continuously at high temporal resolution. A critical requirement for 3D single molecule tracking as well as localization based 3D super-resolution imaging is high 3D localization accuracy. MUM overcomes the depth discrimination problem of classical microscopy based approaches and supports high accuracy 3D localization of singe molecule/particles. In this way, MUM opens the way for high precision 3D single molecule tracking and 3D super-resolution imaging within a live cell environment. We have used MUM to reveal complex intracellular pathways that could not be imaged with classical approaches. In particular we have tracked quantum dot labeled antibody molecules in the exo/endocytic pathway from the cell interior to the plasma membrane at the single molecule level. Here, we present a brief review of these results. PMID- 22916320 TI - Effects of Korean Red Ginseng on Cardiovascular Risks in Subjects with Metabolic Syndrome: a Double-blind Randomized Controlled Study. AB - BACKGROUND: This study investigated the effects of Korean red ginseng (KRG) supplementation on metabolic parameters, inflammatory markers, and arterial stiffness in subjects with metabolic syndrome. METHODS: We performed a randomized, double-blind, placebo-controlled, single-center study in 60 subjects who were not taking drugs that could affect metabolic and vascular functions. Subjects were randomized into either a KRG (4.5 g/d) group or a placebo group for a 12-week study. We collected anthropometric measurements, blood for laboratory testing, and brachial-ankle pulse wave velocity (baPWV) at the initial (week 0) and final (week 12) visits. RESULTS: A total of 48 subjects successfully completed the study protocol. Oral administration of KRG did not significantly affect blood pressure, oxidative or inflammatory markers, or baPWV. CONCLUSION: We found no evidence that KRG had an effect on blood pressure, lipid profile, oxidized low density lipoprotein, fasting blood glucose, or arterial stiffness in subjects with metabolic syndrome. These findings warrant subsequent longer-term prospective clinical investigations with a larger population. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00976274. PMID- 22916321 TI - Health-related Quality of Life and Related Factors in Full-time and Part-time Workers. AB - BACKGROUND: There has been a rapid increase in the number of part-time workers in Korea with little information available on associated changes in quality of life. This study was designed to compare part-time and full-time workers in terms of the quality of life and related factors. METHODS: Data were extracted from the 4th Korea National Health and Nutrition Examination Survey, conducted in 2008. Of the 1,284 participants selected, 942 were females (range, 20 to 64 years). Based on the information provided by self-administered questionnaire, subjects were categorized according to the working pattern (full-time and part-time) and working hours (<30 and >=30 hours). Differences in socio-demographic characteristics, health-related behaviors, and job characteristics were assessed by t-test and chi-square test. EuroQol-five dimensions (EQ-5D) index was implemented in order to measure the quality of life. Differences in the EQ-5D index scores between the groups were compared by t-test, stepwise multivariate logistic regression analyses. RESULTS: Quality of life did not differ by work patterns. In males, the Organization for Economic Cooperation and Development part-time group was associated with poorer quality of life (odds ratio [OR], 0.49; P = 0.028). For both sexes, the non-stress group was linked with superior quality of life in comparison to the stress group (OR, 2.64; P = 0.002; OR, 2.17; P < 0.001). Female employees engaged in non-manual labor had superior quality of life than those engaged in manual labor (OR, 1.40; P = 0.027). CONCLUSION: This study concludes that working less than 30 hours per week is related to lower quality of life in comparison to working 30 hours or more in male employees in Korea. PMID- 22916322 TI - Serum Ferritin Is Differentially Associated with Anti-oxidative Status and Insulin Resistance in Healthy Obese and Non-obese Women. AB - BACKGROUND: Ferritin is known to be associated with insulin resistance (IR) and oxidative stress; however, recent studies have shown that there is an association between ferritin and anti-oxidative status. To date, the biphasic response of ferritin to oxidative stress has not been fully evaluated. Thus, we investigated the association between ferritin and IR and anti-oxidative status in obese and non-obese women. METHODS: We evaluated the homeostasis model assessment of insulin resistance (HOMA-IR) and total anti-oxidant status (TAS) in a total of 111 healthy women between the ages of 32 and 68 years. RESULTS: In all of the study subjects, ferritin levels were positively correlated with age (r = 0.38, P < 0.001), body mass index (r = 0.24, P = 0.01), TAS (r = 0.38, P < 0.001) and HOMA-IR (r = 0.20, P = 0.04). In the subgroup analysis, ferritin levels were correlated with age (r = 0.39, P < 0.001) and TAS (r = 0.43, P < 0.001) in the non-obese group and with insulin (r = 0.50, P = 0.02) and HOMA-IR (r = 0.52, P = 0.01) levels in the obese group. On stepwise multiple linear regression analysis, ferritin was found to be independently associated with TAS (B = 177.16, P < 0.0001) in the non-obese group and independently associated with HOMA-IR (B = 30.36, P = 0.01) in the obese group. CONCLUSION: Our findings suggest ferritin is associated with IR in obese women and with anti-oxidative status in non-obese women. Further studies are warranted to elucidate the precise role of ferritin in obesity. PMID- 22916323 TI - Relationship between Alcohol Consumption and Metabolic Syndrome according to Facial Flushing in Korean Males. AB - BACKGROUND: The aim of the present study is to evaluate the risk of metabolic syndrome (MS) according to alcohol consumption for those subjects showing facial flushing, as well as the absence of facial flushing. METHODS: One thousand two hundred and one males were recruited in the health promotion center of a university hospital. Evaluation of alcohol consumption and facial flushing was assessed via questionnaires and interviews. The criteria for MS were defined according to the National Cholesterol Education Program Adult Treatment Panel III criteria with a modified waist circumference cutoff value (men >= 90 cm) for Korean subjects. Subjects were divided into three groups according to the amount of alcohol they consume: nondrinkers, moderate drinkers (<=14 standard drinks per week), and heavy drinkers (>14 standard drinks per week). They were also separated into two groups according to facial flushing: non-flushers (no occurrence) and flushers (steady occurrence). Factors related to MS were assessed by logistic regression analysis. RESULTS: In non-flushing moderate drinkers, the risk of MS did not significantly increase compared to non-drinkers. However in flushing moderate drinkers, there was significant increase (odds ratio [OR], 1.81; confidence interval [CI], 1.08 to 3.06) compared to non-drinkers. In non flushing and flushing heavy drinkers, significant increase (OR, 2.23; CI, 1.23 to 4.04; OR, 2.90; CI, 1.25 to 6.73, respectively) was evident compared to non drinkers. CONCLUSION: Non-flushing moderate drinkers did not show an increased risk of metabolic syndrome compared to the non-drinkers, but flushing moderate drinkers showed an increased risk of metabolic syndrome compared to non-drinkers. PMID- 22916324 TI - The Effect of Preparatory Education Program on Discomfort and Retching of Examinees during Upper Gastrointestinal Endoscopy. AB - BACKGROUND: Although upper gastrointestinal (UGI) endoscopy is highly sensitive for the detection of esophago-gastroduodenal lesions, pain and discomfort during the procedure cause examinees to experience stress and anxiety. Moreover, there have been only a few studies on relief of pain and discomfort during UGI endoscopy through preparatory interventions. Therefore, the aim of this study was to investigate the relationship between a preparatory education program and the discomfort and retching experienced by examinees during endoscopy. METHODS: A total of 306 examinees who visited a health promotion center and underwent non sedated endoscopy from May 13 to July 3, 2009 were included in this study. After they were assigned to experimental (n = 154) and control groups (n = 152), their discomfort and retching were measured with a visual analogue scale. The preparatory education program consisted of cognitive intervention, behavioral intervention and information. RESULTS: The preparatory education program relieved discomfort during endoscopy in male subjects, in subjects aged 60 and over, or in subjects with previous endoscopic experience with statistical significance (P < 0.05). It also relieved retching during endoscopy in subjects aged 60 and over with statistical significance (P = 0.023). Multiple logistic regression analysis showed that the preparatory education program significantly relieved the discomfort of examinees during endoscopy (P = 0.028). CONCLUSION: We found that the preparatory education program used in this study could significantly relieve the discomfort caused by endoscopy, particularly in subjects aged 60 and over, or in male subjects with a high incidence of stomach cancer in Korea. PMID- 22916325 TI - Association between Metabolic Components and Subclinical Atherosclerosis in Korean Adults. AB - BACKGROUND: Many studies have attempted to develop relatively simple and easy noninvasive measurements of atherosclerosis (NIMA), and each NIMA assesses different atherosclerotic properties. We, therefore, investigated the association between metabolic syndrome (MetS) components and different NIMAs. METHODS: This study included 1,132 Korean subjects over 20 years of age who had visited a Health Promotion Center in Korea. Carotid injury (increased carotid intima-media thickness or plaques) was evaluated by ultrasonography and arterial stiffness by brachial-ankle pulse wave velocity. The MetS components were assessed according to the Asian criteria of the American Heart Association/National Heart, Lung, and Blood Institute. RESULTS: Both arterial stiffness and carotid injury gradually deteriorated with increase in the number of MetS components. Arterial stiffness and carotid injury were associated with different MetS components, each of which had varying impact. After adjustment for all possible confounders such as age, sex, and lifestyle, elevated blood pressure (BP) was found to have the strongest association with arterial stiffness, whereas central obesity, impaired fasting plasma glucose, and elevated BP had comparable connection with carotid atherosclerosis. CONCLUSION: Individual MetS components were related with subclinical atherosclerosis in different ways. Elevated BP showed the strongest association with arterial stiffness, while central obesity, impaired fasting plasma glucose, and elevated BP showed good correlation with carotid atherosclerosis. PMID- 22916326 TI - Retention of the mother and child health handbook and additional immunization of Japanese encephalitis and tetanus vaccine. AB - BACKGROUND: Improvement of additional immunization rate is indicated as an important factor for effective immunization of diseases. In this study, the relationship between retention of mother and child health handbook and additional immunization rate of Japanese encephalitis and tetanus was examined. METHODS: A survey via questionnaire was performed against parents of students of middle schools in Gwangmyeong-si, Gyeonggi-do, and elementary schools in Seoul. Among 350 copies of the questionnaire delivered via post mail, 261 copies were collected and used in the analysis. The questionnaire included general features of subjects and their children, retention of the mother and child health handbook, and recognition of additional immunization of the Japanese encephalitis and tetanus vaccine. RESULTS: It was found that 80.8% of subjects answered affirmative to retaining the mother and child health handbook, and the group retaining the handbook had higher recognition rate of the need for additional immunization than the group that did not, for the Japanese encephalitis vaccine (83.2% vs. 51.2%, P < 0.001) and for the tetanus vaccine (66.5% vs. 31.7%, P < 0.001). Although the group retaining the handbook had a significantly higher additional immunization rate of the tetanus vaccine of 48.6% vs. 17.1% (P = 0.001), the immunization rate of the Japanese encephalitis vaccine did not show a significant difference (P = 0.231). The group recognizing the need for additional immunization of the Japanese encephalitis and tetanus vaccine had a significantly higher additional immunization rate than the counterpart (P < 0.001). CONCLUSION: It was considered that retention of the mother and child health handbook was related to recognition and execution of additional immunizations. PMID- 22916327 TI - A case of scrub typhus complicated by acute calculous cholecystitis. AB - We report a case of acute calculous cholecystitis through scrub typhus. A 69-year old woman presented with a history of general myalgia, fever, and right abdominal pain. She referred to our hospital for surgical treatment of clinically suspected acute cholecystitis. Physicians concluded the cause of cholecystitis as gall bladder (GB) stone and proper antibiotics treatment of scrub typhus was started later. The patient developed acute respiratory distress syndrome and multi organ failure through scrub typhus. Five days after admission, the patient was treated with proper antibiotics and discharged on the 13th day after starting doxycycline treatment without any sequelae. In areas endemic for tsutsugamushi disease, even though a patient with GB stone presents with symptoms of acute cholecystitis, careful history and physical examination are required to reveal the existence of eschars or skin eruptions. PMID- 22916328 TI - Comments on statistical issues in july 2012. PMID- 22916329 TI - Family Medicine as a Solution-oriented Medical Practice: A Letter from Kansai, Japan. PMID- 22916330 TI - Real-time analysis of sulfur-containing volatiles in Brassica plants infested with root-feeding Delia radicum larvae using proton-transfer reaction mass spectrometry. AB - BACKGROUND AND AIMS: Plants damaged by herbivores emit a variety of volatile organic compounds (VOCs). Here we used proton-transfer reaction mass spectrometry (PTR-MS) as a sensitive detection method for online analysis of herbivore-induced VOCs. Previously, it was found that Brassica nigra plants emit several sulfur containing VOCs when attacked by cabbage root fly (Delia radicum) larvae with m/z 60 as a marker for the formation of allylisothiocyanate from the glucosinolate sinigrin. We tested the hypothesis that m/z 60 emission occurs only in plants with sinigrin in their roots. Additionally, we tested the hypothesis that methanethiol, dimethylsulfide and dimethyldisulfide are only emitted after larval infestation. METHODOLOGY: Proton-transfer reaction mass spectrometry was used to track sulfur-containing VOCs from six different species of Brassica over time. The roots were either artificially damaged or infested with cabbage root fly larvae. Glucosinolate profiles of the roots were analysed using high-pressure liquid chromatography and compared with VOC emissions. PRINCIPAL RESULTS: Brassica nigra, B. juncea and B. napus primarily emitted m/z 60 directly after artificial damage or root fly infestation. Sulfide and methanethiol emissions from B. nigra and B. juncea also increased after larval damage but much later (6 12 h after damage). Brassica rapa, B. oleracea and B. carinata principally emitted methanethiol after artificial and after larval damage. Brassica oleracea and B. carinata showed some increase in m/z 60 emission after larval damage. Comparison with root glucosinolate profiles revealed that sinigrin cannot be the only precursor for m/z 60. CONCLUSIONS: The principal compound emitted after root damage is determined by the plant species, and not by damage type or root glucosinolate composition. Once determined, the principal compounds may be used as markers for identifying damaged or infested plants. Further analyses of plant enzymes involved in the breakdown of sulfur compounds is needed to reveal the origin of sulfur-containing VOCs from plants. PMID- 22916331 TI - Two-dimensional universal conductance fluctuations and the electron-phonon interaction of surface states in Bi2Te2Se microflakes. AB - The universal conductance fluctuations (UCFs), one of the most important manifestations of mesoscopic electronic interference, have not yet been demonstrated for the two-dimensional surface state of topological insulators (TIs). Even if one delicately suppresses the bulk conductance by improving the quality of TI crystals, the fluctuation of the bulk conductance still keeps competitive and difficult to be separated from the desired UCFs of surface carriers. Here we report on the experimental evidence of the UCFs of the two dimensional surface state in the bulk insulating Bi2Te2Se microflakes. The solely B?-dependent UCF is achieved and its temperature dependence is investigated. The surface transport is further revealed by weak antilocalizations. Such survived UCFs of the surface states result from the limited dephasing length of the bulk carriers in ternary crystals. The electron-phonon interaction is addressed as a secondary source of the surface state dephasing based on the temperature dependent scaling behavior. PMID- 22916332 TI - Spin-orbit density wave induced hidden topological order in URu2Si2. AB - The conventional order parameters in quantum matters are often characterized by 'spontaneous' broken symmetries. However, sometimes the broken symmetries may blend with the invariant symmetries to lead to mysterious emergent phases. The heavy fermion metal URu2Si2 is one such example, where the order parameter responsible for a second-order phase transition at Th=17.5 K has remained a long standing mystery. Here we propose via ab-initio calculation and effective model that a novel spin-orbit density wave in the f-states is responsible for the hidden-order phase in URu2Si2. The staggered spin-orbit order spontaneously breaks rotational, and translational symmetries while time-reversal symmetry remains intact. Thus it is immune to pressure, but can be destroyed by magnetic field even at T=0 K, that means at a quantum critical point. We compute topological index of the order parameter to show that the hidden order is topologically invariant. Finally, some verifiable predictions are presented. PMID- 22916333 TI - Quantum simulation of tunneling in small systems. AB - A number of quantum algorithms have been performed on small quantum computers; these include Shor's prime factorization algorithm, error correction, Grover's search algorithm and a number of analog and digital quantum simulations. Because of the number of gates and qubits necessary, however, digital quantum particle simulations remain untested. A contributing factor to the system size required is the number of ancillary qubits needed to implement matrix exponentials of the potential operator. Here, we show that a set of tunneling problems may be investigated with no ancillary qubits and a cost of one single-qubit operator per time step for the potential evolution, eliminating at least half of the quantum gates required for the algorithm and more than that in the general case. Such simulations are within reach of current quantum computer architectures. PMID- 22866241 TI - A proteasome inhibitor fails to attenuate dystrophic pathology in mdx mice. AB - Dystrophin deficiency leads to increased proteasome activity in skeletal muscle. Previous observations suggest short-term inhibition of the proteasome restores dystrophin expression. Contrary to our hypothesis, eight days of MG-132 administration to mdx mice increased susceptibility to contraction induced injury and Evan's blue dye penetration compared to controls. Following six weeks of MG 132 administration muscle function was similar to control animals. These data suggest that proteasome inhibition does not reduce the severity of muscle dysfunction caused by dystrophin-deficiency. PMID- 22916334 TI - The human transcriptome: an unfinished story. AB - Despite recent technological advances, the study of the human transcriptome is still in its early stages. Here we provide an overview of the complex human transcriptomic landscape, present the bioinformatics challenges posed by the vast quantities of transcriptomic data, and discuss some of the studies that have tried to determine how much of the human genome is transcribed. Recent evidence has suggested that more than 90% of the human genome is transcribed into RNA. However, this view has been strongly contested by groups of scientists who argued that many of the observed transcripts are simply the result of transcriptional noise. In this review, we conclude that the full extent of transcription remains an open question that will not be fully addressed until we decipher the complete range and biological diversity of the transcribed genomic sequences. PMID- 22916337 TI - Phospholipid-polyethylenimine conjugate-based micelle-like nanoparticles for siRNA delivery. AB - Gene silencing using small interfering RNA (siRNA) is a promising therapeutic strategy for the treatment of various diseases, in particular, cancer. Recently, our group reported on a novel gene carrier, the micelle-like nanoparticle (MNP), based on the combination of a covalent conjugate of phospholipid and polyethylenimine (PLPEI) with polyethylene glycol (PEG) and lipids. These long circulating MNPs loaded with plasmid DNA-mediated gene expression in distal tumors after systemic administration in vivo. In the current study, we investigated the potential of MNPs for siRNA delivery. MNPs were prepared by condensing siRNA with PLPEI at a nitrogen/phosphate ratio of 10, where the binding of siRNA is complete. The addition of a PEG/lipid coating to the PLPEI complexes generated particles with sizes of ca. 200 nm and a neutral surface charge compared with positively charged PLPEI polyplexes without the additional coating. MNPs protected the loaded siRNA against enzymatic digestion and enhanced the cellular uptake of the siRNA payload. MNPs carrying green fluorescent protein (GFP)-targeted siRNA effectively downregulated the gene in cells that stably express GFP. Finally, MNPs were non-toxic at a wide range of concentrations and for different cell lines. PMID- 22916338 TI - The use of mifepristone in the treatment of Cushing's syndrome. AB - Patients with endogenous hypercortisolism, Cushing's syndrome, have significant morbidity and increased mortality when inadequately treated. When surgical therapy has been unsuccessful other treatment modalities are necessary. Previously available therapies have limited effectiveness or significant toxicity. Mifepristone, a glucocorticoid receptor antagonist, provides a novel approach to the treatment of hypercortisolism. It is rapidly absorbed, highly protein bound and has a long plasma half-life. Since it also serves as a progesterone receptor antagonist, mifepristone has been used in several other medical conditions. A recently published prospective trial of mifepristone therapy for Cushing's syndrome resulted in its recent approval by the U.S. Food and Drug Administration for use in Cushing's syndrome. PMID- 22916336 TI - Adipose tissue signaling by nuclear receptors in metabolic complications of obesity. AB - In recent years white adipose tissue inflammation has been recognized to be associated with obesity. Adipocytes and adipose tissue associated macrophages (ATMs) secrete bioactive molecules, including adipokines, chemokines/cytokines and free fatty acids that modulate the development of low-grade inflammation and insulin resistance responsible for obesity-related metabolic and cardiovascular diseases. Nuclear receptors, notably peroxisome-proliferator-activated receptors, are sensors of dietary lipids and control transcriptional programs of key metabolic and inflammatory pathways in adipocytes and macrophages. This review focuses on mechanisms by which nuclear receptors maintain white adipose tissue homeostasis. The identification of ATMs as active players in the initiation of chronic inflammation and the links between inflammatory signaling and metabolic dysfunction will be presented, followed by discussion of recent evidence for nuclear receptors in ATM function, with an emphasis on the paracrine interaction between adipocytes and ATMs. PMID- 22916339 TI - Looking at ocriplasmin as a new option in eye disease. AB - Vitreomacular traction (VMT) syndrome and macular hole (MH) are disease processes that are caused by anomalous separation of the vitreous from the macula. Until now, management of these conditions has involved vitreoretinal surgery. Clinical trials have shown that a single intravitreal microplasmin (ocriplasmin) injection can induce separation of the vitreous from the macular surface and thereby relieve the tractional changes that contribute to vision loss from VMT and MH. Herein, we summarize the results of these trials which demonstrate that a significant number of intravitreal ocriplasmin-treated patients have resolution of their vitreoretinal interface abnormalities without the need for vitreoretinal surgery. PMID- 22916340 TI - Taliglucerase alfa for the treatment of Gaucher's disease. AB - Gaucher's disease is a rare inherited inborn error of metabolism caused by mutations in the gene encoding the lysosomal enzyme glucocerebrosidase, GBA. Glucocerebrosidase is involved in the metabolism of the lipid metabolism-derived substrate, glucocerebroside. Accumulation of glucocerebroside substrate in macrophages, as a result of loss of enzyme function, leads to the formation of Gaucher cells causing hypertrophy of the spleen and liver, hematological disorders, skeletal malformations and the neurological symptoms characteristic of Gaucher's disease. The disease is subdivided into three types that differ in their symptoms, severity and prognosis. Patients of any age can be affected but those of a younger age have a poor prognosis often dying in infancy. As a genetic disorder the incidence of the disease is variable on a global scale. Enzyme replacement therapy is the therapy of choice and has demonstrated good efficacy in treating the visceral and skeletal symptoms of Gaucher's disease. A cost effective plant-cell-derived human recombinant glucocerebrosidase, taliglucerase alfa, has been developed that demonstrated a promising safety and efficacy profile in phase I clinical trials and is currently in phase III and IV trials for the treatment of pediatric and adult patients with Gaucher's disease. PMID- 22916342 TI - Important drug interactions in patients with rheumatic disorders: interactions of glucocorticoids, immunosuppressants and antimalarial drugs. AB - Despite the fact that biological treatments are very promising, classical immunosuppressants, antimalarial drugs and glucocorticosteroids are still very important and widely used in practice. Although drug interactions can have fatal consequences, few studies have reviewed drug interactions of these classical drugs used in rheumatology, and very few guidelines are available on this subject. Therefore, this report summarizes important interactions of immunosuppressants, antimalarial drugs and glucocorticosteroids with drugs commonly used in internal medicine. In the present study, more than 300 interactions were retrieved from the Micromedex (r) database. The selection was reduced to the interactions rated as moderate, major or contraindicated. The selected interactions were further checked against PubMed (r), MEDLINE (r), InfoPharm Compendium of Drug Interactions and Summaries of Product Characteristics. For each interaction, its nature, mechanism, onset and clinical severity were indicated, documentation quality was rated and recommendations for clinical practice were formulated. Twenty significant interactions that we rated as moderate, severe and very severe were identified. Interacting drugs were warfarin, fluoroquinolones, azole antifungals, co-trimoxazole, proton pump inhibitors, amiodarone, cholestyramine, activated carbon, allopurinol, angiotensin-converting enzyme inhibitors, statins, digoxin, iron, aluminium and magnesium salts, and hepatotoxic and nephrotoxic agents. PMID- 22916341 TI - Tofacitinib for the treatment of moderate to severe rheumatoid arthritis. AB - The autoimmune disease rheumatoid arthritis (RA) causes severe disability through chronic and destructive inflammation of the synovial joints. Currently available therapeutic options, including disease-modifying antirheumatic drugs (DMARDs) and biologic agents, often fail to adequately prevent disease progression. Tofacitinib (CP-690550) is an inhibitor of the Janus kinase family; tyrosine kinase receptors expressed in lymphoid cells that are involved in the signaling of cytokines important for the production and function of various immune cells implicated in RA pathogenesis. Tofacitinib has been evaluated in phase II, phase III and long-term extension studies, as both monotherapy and in combination with methotrexate and other DMARDs, and demonstrates statistically significant and clinically meaningful improvements in the signs and symptoms of RA, patient health, physical functioning and quality of life, while having a manageable safety profile. It is currently under evaluation for approval for the treatment of adults with RA by several regulatory agencies around the world. PMID- 22916343 TI - A report from the 72nd Scientific Sessions of the American Diabetes Association (June 8-12, 2012 - Philadelphia, Pennsylvania, USA). AB - The 72nd Scientific Sessions of the American Diabetes Association were held this year in Philadelphia. Here, new findings with currently available drugs and drugs in advanced clinical research were reported during the meeting's oral and poster sessions and are summarized in the following report. PMID- 22916344 TI - Getting under-and through-the skin: ecological genomics of chytridiomycosis infection in frogs. AB - Amphibian species around the world are currently becoming endangered or lost at a rate that outstrips other vertebrates-victims of a combination of habitat loss, climate change and susceptibility to emerging infectious disease (Stuart et al. 2004). One of the most devastating such diseases is caused by the chytrid fungus Batrachochytrium dendrobatidis (Bd), which infects hundreds of amphibian species on multiple continents. While Bd itself has been characterized for some time, we still know little about the mechanisms that make it so deadly. In this issue of Molecular Ecology, Rosenblum et al. describe a genomic approach to this question, reporting the results of a genome-wide analysis of the transcriptional response to Bd in the liver, skin and spleen of mountain yellow-legged frogs (Rana mucosa and R. sierrae: Fig. 1) (Rosenblum et al. 2012). Their results indicate that the skin is not only the first, but likely the most important, line of defence in these animals. Strikingly, they describe a surprisingly modest immune response to infection in Rana, a result that may help explain variable Bd susceptibility across populations and species. PMID- 22916345 TI - Exploring symbiont management in lichens. AB - Lichens are unique among fungal symbioses in that their mycelial structures are compact and exposed to the light as thallus structures. The myriad intersections of unique fungal species with photosynthetic partner organisms (green algae in 90% of lichens) produce a wide variety of diverse shapes and colours of the fully synthesized lichen thallus when growing in nature. This characteristic complex morphology is, however, not achieved in the fungal axenic state. Even under ideal environmental conditions, the lichen life cycle faces considerable odds: first, meiotic spores are only produced on well-established thalli and often only after achieving considerable age in a stable environment, and second, even then in vivo resynthesis requires the presence of compatible algal strains where fungal spores germinate. Many lichen species have evolved a way around the resynthesis bottleneck by producing asexual propagules for joint propagation of symbionts. These different dispersal strategies ostensibly shape the population genetic structure of lichen symbioses, but the relative contributions of vertical (joint) and horizontal (independent) symbiont transmission have long eluded lichen evolutionary biologists. In this issue of Molecular Ecology, Dal Grande et al. (2012) close in on this question with the lung lichen, Lobaria pulmonaria, a flagship species in the conservation of old growth forests. By capitalizing on available microsatellite markers for both fungal and algal symbionts, they show that while vertical transmission is the predominant mode of reproduction, horizontal transmission is demonstrable and actively shapes population genetic structure. The resulting mixed propagation system is a highly successful balance of safe recruitment of symbiotic clones and endless possibilities for fungal recombination and symbiont shuffling. PMID- 22916346 TI - Intestinal microbiota composition in fishes is influenced by host ecology and environment. AB - The digestive tracts of vertebrates are colonized by complex assemblages of micro organisms, collectively called the gut microbiota. Recent studies have revealed important contributions of gut microbiota to vertebrate health and disease, stimulating intense interest in understanding how gut microbial communities are assembled and how they impact host fitness (Sekirov et al. 2010). Although all vertebrates harbour a gut microbiota, current information on microbiota composition and function has been derived primarily from mammals. Comparisons of different mammalian species have revealed intriguing associations between gut microbiota composition and host diet, anatomy and phylogeny (Ley et al. 2008b). However, mammals constitute <10% of all vertebrate species, and it remains unclear whether similar associations exist in more diverse and ancient vertebrate lineages such as fish. In this issue, Sullam et al. (2012) make an important contribution toward identifying factors determining gut microbiota composition in fishes. The authors conducted a detailed meta-analysis of 25 bacterial 16S rRNA gene sequence libraries derived from the intestines of different fish species. To provide a broader context for their analysis, they compared these data sets to a large collection of 16S rRNA gene sequence data sets from diverse free-living and host-associated bacterial communities. Their results suggest that variation in gut microbiota composition in fishes is strongly correlated with species habitat salinity, trophic level and possibly taxonomy. Comparison of data sets from fish intestines and other environments revealed that fish gut microbiota compositions are often similar to those of other animals and contain relatively few free living environmental bacteria. These results suggest that the gut microbiota composition of fishes is not a simple reflection of the micro-organisms in their local habitat but may result from host-specific selective pressures within the gut (Bevins & Salzman 2011). PMID- 22916347 TI - Artefacts, biology and bias in museum collection research. AB - Museum collections are increasingly subjected to scientific scrutiny, including molecular, isotopic and trace-element analyses. Recent advances have extended analyses from natural history specimens to historical artefacts. We highlight three areas of concern that can influence interpretation of data derived from museum collections: sampling issues associated with museum collection use, methods of analysis, and the value of cross-referencing data with historical documents and data sets. We use a case study that focuses on kiwi (Apteryx spp.) feather samples from valuable 19th century Maori cloaks in New Zealand to show how sampling and analysis challenges need to be minimized by careful design. We argue that aligning historical records with scientific data generated from museum collections significantly improves data interpretation. PMID- 22916348 TI - World conference: a watershed event? PMID- 22916349 TI - India: Court rules that nicotine is poison. PMID- 22916350 TI - [Dermatological side effects in cancer therapy]. PMID- 22916352 TI - Letter from the outgoing editor: Interpreting JAPA's mission. PMID- 22916351 TI - Cosmetic and dermatologic use of alpha hydroxy acids. AB - Alpha hydroxy acids (AHAs), in particular glycolic acid, are a class of chemical compounds frequently used in cosmetics and dermatology. This review summarizes the current knowledge regarding chemistry, mechanism of action as well as the different indications ranging from cosmetic skin hydration to acne proven by clinical trials. Overall AHAs depending on the concentration used present an ingredient for cosmetic products or medical devices with proven efficacy. PMID- 22916353 TI - Note from the editor-to-be: Continuing the dialogue on JAPA's mission. PMID- 22916354 TI - Promoting academic medicine to medical students. PMID- 22916355 TI - Hypertension-related but not necessarily age-related. PMID- 22916356 TI - Multidisciplinary team working. PMID- 22916357 TI - Implications of contemporary clinical trials series: the Placement of Aortic Transcatheter Valve trial (PARTNER). PMID- 22916358 TI - Health reform analysis: I.T. action now moves to Acos, HIX deployments, population health. PMID- 22916359 TI - What's next for HIT: challenges, changes despite the Supreme Court upholding. PMID- 22916360 TI - HIMSS analysis: I.T. a big winner, but lack of national ID will hamper efforts. PMID- 22916361 TI - Health I.T. Young bloods grow up fast. PMID- 22916362 TI - Fighting the internal I.T. threat. PMID- 22916363 TI - Carts push for a seat at the automation table. PMID- 22916370 TI - [Clinicopathologic conference. Sepsis with a pulmonary focus, morbid obesity and alcoholism]. PMID- 22916371 TI - An infectious origin for rheumatic disease? PMID- 22916372 TI - [What are the risk factors for delayed post-polypectomy bleeding?]. PMID- 22916373 TI - No grandfathers. PMID- 22916374 TI - Access to care! Missing the point. PMID- 22916375 TI - Moral decoupling. PMID- 22916376 TI - Oral robotic surgery successful for oropharyngeal cancer patients. PMID- 22916377 TI - Virtual dental home. PMID- 22916378 TI - The virtual dental home: bringing oral health to vulnerable and underserved populations. AB - Large and increasing oral health disparities in the U.S. population led the Institute of Medicine to call for expanded research and demonstration of delivery systems that test new methods and technologies. These new methods include delivering oral health services in nontraditional settings, using nondental professionals, expanded roles for existing dental professionals and new types of dental professionals, and incorporating telehealth technologies. The virtual dental home is a system that demonstrates the characteristics called for by the IOM. PMID- 22916379 TI - Using telehealth technologies to improve oral health for vulnerable and underserved populations. AB - Telehealth refers to the use of technology to provide health care at a distance. The important and increasing role of telehealth in the delivery of health care has been recognized for several decades. Although there are fewer reports on the use of telehealth to deliver oral health services, evidence is emerging that these technologies can enhance the ability of the oral health delivery system to reach vulnerable and underserved populations. PMID- 22916380 TI - In-person versus "virtual" dental examination: congruence between decision-making modalities. AB - This study evaluated the agreement of a dentist's conclusions reached through an in-person versus a virtual examination. The dentist determined whether a patient was healthy enough to be treated only by allied dental personnel in a community setting or whether the patient needed to be seen by a dentist. The study concludes that a virtual examination is a strong substitute for an in-person examination and validates the application of telehealth-enabled examinations. PMID- 22916381 TI - Community-based prevention and early intervention strategies. AB - Many people in California face significant barriers to obtaining dental care. Creation of a community-based oral health delivery system that could deliver preventive and simple therapeutic oral health services in community settings where these populations live or receive social and/or general health services has been one of the proposed strategies for improving access to oral health care. Two of the newer techniques are caries management by risk assessment and interim therapeutic restoration. PMID- 22916383 TI - The golden years: breaking dusk. PMID- 22916384 TI - [An evolution of the public health nurse]. PMID- 22916382 TI - The virtual dental home: implications for policy and strategy. AB - Widely recognized problems with the U.S. health care system, including rapidly increasing costs and disparities in access and outcomes also exist in oral health. If oral health systems are to meet the "Triple Aim" of improving the experience of care, improving the health of populations, and reducing per capita costs of health care, new and innovative strategies will be needed including new regulatory, delivery, and financing systems. The virtual dental home is one such system. PMID- 22916385 TI - [No health system can function without nurses]. PMID- 22916386 TI - [Discussion on emerging infectious diseases]. PMID- 22916387 TI - [The effect of resilience as a therapy of trauma]. PMID- 22916388 TI - [The roadmap of Marisol Touraine for the future of the public hospital]. PMID- 22916389 TI - [Sickle-cell anemia and pain]. AB - Sickle-cell anaemia is the most widespread genetic disease in the world. It manifests itself differently depending on the individual, but approximately 20% of patients affected suffer from very frequent and severe vaso-occlusive crises. The red blood cells, deformed into a sickle shape, obliterate the small blood vessels, reducing the oxygen supply to the organs. It is the main reason that patients with sickle-cell anaemia seek medical care in hospital emergency departments. Morphine is the basic treatment. PMID- 22916390 TI - [Care of the burn patient. From emergency treatment to education]. PMID- 22916391 TI - [Epidemiology of burns in France]. AB - As with most traumas, the epidemiology of the "burn" health-event has long been neglected by public health doctors and rarely considered by burns specialists. There were therefore few verified data and many approximations and preconceived ideas. The gathering of information recently undertaken in France enables the reliability of the data to be improved and the diagnostic and demographic elements relating to hospitalised patients with burns to be established. PMID- 22916392 TI - [Physiopathology and evolution of burns]. AB - The skin is an impermeable physical barrier which protects the organism from external aggressions.With a burn, the different layers which make up the skin can be partially or totally affected. Significant physiological disturbances can put the patient's life at risk. PMID- 22916393 TI - [Management of the patient with serious burns at admission]. AB - The first hours of care and treatment are determined by the quality of the preparation on a logistical, organisational and environmental level. The future of a patient with serious burns is at stake in these first few hours. The risk of threat to life is linked to potential vascular compressions, as well as cardio respiratory failure.The occurrence of these complications can be prevented by the setting up of codified instrumental and clinical monitoring. PMID- 22916394 TI - [Surgical management of acute severe burns]. AB - Surgical management of patients presenting severe burns begins from hospital admission. In association with intensive care, it preserves and improves patients' vital prognosis. Secondarily, excision and grafting surgery is used in second deep and third degree burns. PMID- 22916395 TI - [Intensive care and monitoring of patients with serious burns]. AB - A burn is a localised aggression which, in some circumstances, develops into a general pathology threatening the patient's life. Hydroelectrolytic, haemodynamic and respiratory intensive care is provided during the acute phase, with adapted monitoring in order to prevent infections. PMID- 22916396 TI - [Infections in burn patients]. AB - Infection in patients with serious burns is usually linked to care procedures. It occurs beyond the 48th hour and is the leading cause of mortality. The risk of infection is higher in certain elderly patients or those in a precarious situation. Its frequency can be controlled by high quality and well-organised care. PMID- 22916397 TI - [The treatment of pain in patients with serious burns]. AB - The assessment and treatment of pain in patients with serious burns concerns continuous pain and occasional pain provoked by care procedures.The patient must be included in this therapeutic project.The control of pain is a measure of the quality and effectiveness of the care provided. PMID- 22916398 TI - [Nursing care of the patient with serious burns]. AB - The care and monitoring of a patient with serious burns carried out by nurses are dominated by all the needs of an intensive care patient in addition to those relating to the burn.The future of these patients raises specific concerns with regard to functionality, aesthetics, work and family. PMID- 22916399 TI - [Skin allograft, from the donor to the burn patient]. AB - Severely burned patients are treated through the use of donor skin or skin allografts. It is a vital treatment. From the donor to the recipient, the process involves numerous procedures which are performed in accordance with ethical and medical safety rules. PMID- 22916400 TI - [The care of the burn patient in the rehabilitation center]. AB - The rehabilitation of a patient with serious burns involves several disciplines. The initial objective is to reduce the appearance or evolution of functional sequelae. The patient's future will depend on the quality of this rehabilitation. PMID- 22916401 TI - [The psychological care of patients with serious burns]. AB - Psychological disorganisation, identity disorders, grief, a patient with serious burns is a deconstructed being who must face a number of ordeals. How can the patient reconstruct and regain bodily integrity after such a violation? The role of the psychologist is to support and guide the patient on the path towards their new life. PMID- 22916402 TI - [Advances in the treatment of serious burns]. PMID- 22916403 TI - [Bibliography. Care of the burn patient]. PMID- 22916404 TI - [Defining a personalized patient education program]. PMID- 22916405 TI - The telltale teeth: psychodontia to sociodontia. PMID- 22916406 TI - Tongue and lip frenectomy in Spanish medical texts of the 16th-18th centuries. AB - The frena of the tongue and lip are normal structures of the buccal cavity, and surgical resection is only necessary in cases of hypertrophy. This article looks at medical texts of the Early Modern Era to analyze the origins and quality of our knowledge on this topic and examine any therapeutic measures proposed. This review shows that while the indications for carrying out tongue frenectomy are very similar to those today (speech and breastfeeding difficulties), those for carrying out a lip frenectomy are very different. Interestingly, apart from purely surgical or medicinal treatments, some authors indicated the need to complement such treatment with educational intervention and what can only be called basic speech therapy. PMID- 22916407 TI - The progress and social impact of dentistry in the Dominican Republic. PMID- 22916408 TI - History of the Oral and Maxillofacial Surgery Residency Program at Universidad el Bosque, Bogota, Colombia. AB - The formal training of oral and maxillofacial surgeons in Colombia started in 1958 at Hospital Sanjos6, thanks to the titanic work of Waldemar Wilhelm, a German-born surgeon who settled in BogotA in 1950. Today there are seven institutions in Colombia that offer residency programs in oral and maxillofacial surgery. The aim of this article is to describe the history of the Oral and Maxillofacial Surgery Residency Program at Universidad El Bosque in Bogota. PMID- 22916409 TI - Dental trade cards XXXVI. PMID- 22916410 TI - Dental postcards: 50th edition. "A swell time". PMID- 22916411 TI - Ethics and nursing. PMID- 22916412 TI - Our ethical responsibility in the transition to practice for new RNs. PMID- 22916413 TI - On the front line of the future: Rodney Abary, MSN, RN, FNP. PMID- 22916414 TI - A proactive approach to stress management in a neuroscience intensive care unit. PMID- 22916415 TI - Conversations or critical care beds? PMID- 22916416 TI - [Therapy traces on hands and feet in a patient with colon cancer]. PMID- 22916417 TI - [Ticks survive 40 degree C wash effortlessly. Masters of adaptation (interview by Dr. Christine Starostzik)]. PMID- 22916418 TI - [Suspected abuse by her own father. A case for child protection ambulatory service]. PMID- 22916419 TI - [Flaming red legs. Skin changes after urinary tract infection]. PMID- 22916420 TI - [Uric acid 8.4 in an asymptomatic patient. Does he need medication?]. PMID- 22916421 TI - [Which herbal drugs can be trusted? Herbal drugs increasingly from the supermarket (interview by Dr. med. Dirk Einecke)]. PMID- 22916422 TI - [Advanced education with MMW--30 CME credits at one swoop]. PMID- 22916423 TI - [After the tick bite: update borreliosis 2012]. PMID- 22916424 TI - [Chronified back pain]. PMID- 22916425 TI - [Oral antidiabetics: how you take the right choice]. PMID- 22916427 TI - [Teases at the scalp: ectoparasites]. PMID- 22916426 TI - [Antihypertensive therapy: individual concepts are required]. PMID- 22916428 TI - [Chronic hepatitis C: improved cure rates with new approved medications]. PMID- 22916429 TI - [Pain relief at the end of life. A genuine medical task within palliative medicine]. PMID- 22916430 TI - [Rational approach to the patient with diarrhea]. PMID- 22916431 TI - [Urinary incontinence: what women do not want to talk about]. PMID- 22916432 TI - [Erectile dysfunction: how can you help?]. PMID- 22916433 TI - Characterization of the olfactory impact around a wastewater treatment plant: optimization and validation of a hydrogen sulfide determination procedure based on passive diffusion sampling. AB - A monitoring program based on an indirect method was conducted to assess the approximation of the olfactory impact in several wastewater treatment plants (in the present work, only one is shown). The method uses H2S passive sampling using Palmes-type diffusion tubes impregnated with silver nitrate and fluorometric analysis employing fluorescein mercuric acetate. The analytical procedure was validated in the exposure chamber. Exposure periods ofat least 4 days are recommended. The quantification limit of the procedure is 0.61 ppb for a 5-day sampling, which allows the H2S immission (ground concentration) level to be measured within its low odor threshold, from 0.5 to 300 ppb. Experimental results suggest an exposure time greater than 4 days, while recovery efficiency of the procedure, 93.0+/-1.8%, seems not to depend on the amount of H2S collected by the samplers within their application range. The repeatability, expressed as relative standard deviation, is lower than 7%, which is within the limits normally accepted for this type of sampler. Statistical comparison showed that this procedure and the reference method provide analogous accuracy. The proposed procedure was applied in two experimental campaigns, one intensive and the other extensive, and concentrations within the H2S low odor threshold were quantified at each sampling point. From these results, it can be concluded that the procedure shows good potential for monitoring the olfactory impact around facilities where H2S emissions are dominant. PMID- 22916434 TI - Effectiveness and mechanisms of hydrogen sulfide adsorption by camphor-derived biochar. AB - The characteristics and mechanisms of hydrogen sulfide (H2S) adsorption on a biochar through pyrolysis at various temperatures (100 to 500 degrees C) were investigated. The biochar used in the current study was derived from the camphor tree (Cinnamomum camphora). The samples were ground and sieved to produceparticle sizes of 0.4 mm to 1.25 mm, 0.3 mm to 0.4 mm, and <0.3 mm. The H2S breakthrough capacity was measured using a laboratory-designed test. The surface properties of the biochar were characterized using pH and Fourier-transform infrared spectroscopy (FTIR) analysis. The results obtained demonstrate that all camphor derived biochars were effective in H2S sorption. Certain threshold ranges ofthepyrolysis temperature and surfacepH were observed, which, when exceeded, have dramatic effects on the H2S adsorption capacity. The sorption capacity ranged from 1.2 mg/g to 121.4 mg/g. The biochar with 0.3 mm to 0.4 mm particle size possesses a maximum sorption capacity at 400 degrees C. The pH and FTIR analysis results showed that carboxylic and hydroxide radical groups were responsible for H2S sorption. These observations will be helpful in designing biochar as engineered sorbents for the removal of H2S. PMID- 22916435 TI - Multiple-year black carbon measurements and source apportionment using delta-C in Rochester, New York. AB - Black carbon (BC), an important component ofthe atmospheric aerosol, has climatic, environmental, and human health significance. In this study, BC was continuously measured using a two-wavelength aethalometer (370 nm and 880 nm) in Rochester; New York, from January 2007 to December 2010. The monitoring site is adjacent to two major urban highways (I-490 and I-590), where 14% to 21% of the total traffic was heavy-duty diesel vehicles. The annual average BC concentrations were 0.76 microg/m3, 0.67 microg/m3, 0.60 microg/m3, and 0.52 microg/m3 in 2007, 2008, 2009, and 2010, respectively. Positive matrix factorization (PMF) modeling was performed using PM2.5 elements, sulfate, nitrate, ammonia, elemental carbon (EC), and organic carbon (OC) data from the US. Environmental Protection Agency (EPA) speciation network and Delta-C (UVBC370nm-BC880nm) data. Delta-C has been previously shown to be a tracer of wood combustion factor It was used as an input variable in source apportionment models for the first time in this study and was found to play an important role in separating traffic (especially diesel) emissions from wood combustion emissions. The result showed the annual average PM2.5 concentrations apportioned to diesel emissions in 2007, 2008, 2009, and 2010 were 1.34 microg/m3, 1.25 microg/m3, 1.13 microg/m3, and 0.97 microg/m3, respectively. The BC conditional probability function (CPF) plots show a large contribution from the highway diesel traffic to elevated BC concentrations. The measurements and modeling results suggest an impact of the US Environmental Protection Agency (EPA) 2007 Heavy-Duty Highway Rule on the decrease ofBC and PM2.5 concentrations during the study period. PMID- 22916436 TI - Bioethanol-gasoline fuel blends: exhaust emissions and morphological characterization of particulate from a moped engine. AB - This study was aimed at evaluating the effects of gasoline-ethanol blends on the exhaust emissions in a catalyst-equipped four-stroke moped engine. The ethanol was blended with unleaded gasoline in at percentages (10, 15, and 20% v/v). The regulated pollutants and the particulate matter emissions were evaluated over the European ECE R47 driving cycle on the chassis dynamometer bench. Particulate matter was characterized in terms of total mass collected on filters and total number ofparticles in the range 7 nm-10 microm measured by electrical low pressure impactor (ELPI). In addition, particle-phase polycyclic aromatic hydrocarbons (PAHs) emissions were evaluated to assess the health impact of the emitted particulate. Finally, an accurate morphological analysis was performed on the particulate by high-resolution transmission electron microscope (TEM) equipped with a digital image-processing/data-acquisition system. In general, CO emission reductions of 60-70% were obtained with 15 and 20% v/v ethanol blends, while the ethanol use did not reduce hydrocarbon (HC) and NOx emissions. No evident effect of ethanol on the particulate mass emissions and associated PAHs emissions was observed. Twenty-one PAHs were quantified in the particulate phase with emissions ranging from 26 to 35 microg/km and benzo[a]pyrene equivalent (BaPeq) emission factors from 2.2 to 4.1 microg/km. Both particulate matter and associated PAHs with higher carcinogenic risk were mainly emitted in the submicrometer size range (<0.1 microm). On the basis of the TEM observations, no relevant effect of the ethanol use on the particulate morphology was evidenced, showing aggregates composed ofprimary particles with mean diameters in the range 17.5-32.5 nm. PMID- 22916437 TI - Feasibility study on cross-linked biopolymeric concrete encapsulating selenium glass wastes. AB - Feasibility study was conducted to encapsulate the selenium (Se) contained in glass waste, using the biopolymer-modified concrete. Biopolymer has unique characteristics to provide the chemical sites to metals or toxic compounds through the three-dimensional cross-linked structure. Very minute amount of biopolymer enhanced the characteristics of cementitious material. The resulting biopolymeric composite with selenium glass waste showed 20% higher compressive strength than ordinary concrete and the lower leaching concentration than the equipment detection limit. For a qualitative measurement, X-ray diffraction (XRD; X-ray powder diffractogram) was used to characterize the biopolymeric concrete. The optimum waste content percentage with appropriate biopolymer concrete mixture ratio was identified for its possible commercial use. PMID- 22916438 TI - Integration of a nonmetallic electrostatic precipitator and a wet scrubber for improved removal of particles and corrosive gas cleaning in semiconductor manufacturing industries. AB - To remove particles in corrosive gases generated by semiconductor industries, we have developed a novel non-metallic, two-stage electrostatic precipitator (ESP). Carbon brush electrodes and grounded carbon fiber-reinforced polymer (CFRP) form the ionization stage, and polyvinyl chloride collection plates are used in the collection stage of the ESP The collection performance of the ESP downstream of a wet scrubber was evaluated with KC1, silica, and mist particles (0.01-10 pm), changing design and operation parameters such as the ESP length, voltage, and flow rate. A long-term and regeneration performance (12-hr) test was conducted at the maximum operation conditions of the scrubber and ESP and the performance was then demonstrated for 1 month with exhaust gases from wet scrubbers at the rooftop of a semiconductor manufacturing plant in Korea. The results showed that the electrical and collection performance of the ESP (16 channels, 400x400 mm2) was maintained with different grounded plate materials (stainless steel and CFRP) and different lengths of the ionization stage. The collection efficiency of the ESP at high air velocity was enhanced with increases in applied voltages and collection plate lengths. The ESP (16 channels with 100 mm length, 400x400 mm2x540 mm with a 10-mm gap) removed more than 90% of silica and mistparticles with 10 and 12 kV applied to the ESPat the air velocity of 2 m/s and liquid-to gas ratio of 3.6 L/m3. Decreased performance after 13 hours ofcontinuous operation was recovered to the initial performance level by 5 min of water washing. Moreover during the 1-month operation at the demonstration site, the ESP showed average collection efficiencies of 97% based on particle number and 92% based on total particle mass, which were achieved with a much smaller specific corona power of 0.28 W/m3/hr compared with conventional ESPs. PMID- 22916439 TI - The evolution and impact of testing baghouse filter performance. AB - In 1995, the US. Environmental Protection Agency (EPA) initiated the Environmental Technology Verification (ETV) program for the purpose of generating both independent and credible performance verification of innovative technologies and helping to accelerate acceptance of these products into the marketplace to further benefit the environment and protect public health. The EPA has approved a testing protocol under this program to verify the performance of commercially available filtration products for pulse-jet baghouses in removingfine particulate matter (aerodynamic diameter<2.5 microm; PM2.5). This verification testing protocol was later used as a basis for the development of the American Society for Testing and Materials (ASTM) Method D6830-02 and the International Organization for Standardization (ISO) Method 11057. The South Coast Air Quality Management District (SCAQMD) in California and the EPA s Office of Air Quality Planning and Standards (OAQPS) highly encourage the use of ETV/ASTM-verified filtration media. This paper highlights the evolution of the standard test methods, the EPA's and SCAQMD's regulatory activities, the benefits of using verified filtration media, and the importance of including the filter performance testing in future consideration of baghouse permitting, baghouse operation and maintenance (O&M) plans, quality assurance/quality control (QA/QC), and bag monitoring plans. PMID- 22916440 TI - Toluene vapor capture by activated carbon particles in a dual gas-solid cyclone system. AB - Capturing of odorous compounds such as toluene vapor by a particulate-activated carbon adsorbent was investigated in a gas-solid cyclone, which is one type of mobile beds. The test cyclone was early modified with the post cyclone (PoC) and a spiral flow guide to the vortex finder. The proposed process may contribute to the reduction of gases and dust from industrial exhausts, especially when dealing with a low concentration of odorous elements and a large volume ofdust flow. In this device, the toluene capturing efficiency at a 400 ppm concentration rose up to 77.4% when using activated carbon (AC) particles with a median size of 27.03 microm. A maximum 96% of AC particles could be collected for reuse depending on the size and flow rate. The AC regenerated via thermal treatment showed an adsorption potential up to 66.7% throughout repeated tests. PMID- 22916441 TI - NO2 and SO2 dispersion modeling and relative roles of emission sources over Map Ta Phut industrial area, Thailand. AB - Map Ta Phut industrial area (MA) is the largest industrial complex in Thailand. There has been concern about many air pollutants over this area. Air quality management for the area is known to be difficult, due to lack of understanding of how emissions from different sources or sectors (e.g., industrial, power plant, transportation, and residential) contribute to air quality degradation in the area. In this study, a dispersion study of NO2 and SO2 was conducted using the AERMOD model. The area-specific emission inventories of NOx and SO2 were prepared, including both stack and nonstack sources, and divided into 11 emission groups. Annual simulations were performed for the year 2006. Modeled concentrations were evaluated with observations. Underestimation of both pollutants was Jbund, and stack emission estimates were scaled to improve the modeled results before quantifying relative roles of individual emission groups to ambient concentration overfour selected impacted areas (two are residential and the others are highly industrialized). Two concentration measures (i.e., annual average area-wide concentration or AC, and area-wide robust highest concentration or AR) were used to aggregately represent mean and high-end concentrations Jbfor each individual area, respectively. For AC-NO2, on-road mobile emissions were found to be the largest contributor in the two residential areas (36-38% of total AC-NO2), while petrochemical-industry emissions play the most important role in the two industrialized areas (34-51%). For AR-NO2, biomass burning has the most influence in all impacted areas (>90%) exceptJor one residential area where on-road mobile is the largest (75%). For AC-SO2, the petrochemical industry contributes most in all impacted areas (38-56%). For AR SO2, the results vary. Since the petrochemical industry was often identified as the major contributor despite not being the largest emitter, air quality workers should pay special attention to this emission group when managing air quality for the MA. PMID- 22916442 TI - Breakthrough indicator for aromatic VOCs using needle trap samplers for activated carbon adsorbent. AB - Internal circulation cabinets equipped with granular activated carbon (GAC) for adsorbing volatile organic compounds (VOCs) are widely used to store bottles containing organic solvents in universities, colleges, and hospital laboratories throughout Taiwan. This work evaluates the VOC adsorption capacities of GAC using various adsorption times for gas stream mixtures of 100 ppm toluene and 100 ppm o xylene. Additionally, needle trap sampling (NTS) technology was used to indicate the time for renewing the GAC to avoid VOC breakthrough from adsorbents. Experimental results demonstrate that the proposed models can linearly express toluene and o-xylene adsorption capacities as the natural logarithm of adsorption time (ln(t)) and can accurately simulate the equilibrium adsorption capacities (Qe, g VOCs/g GAC) for gaseous toluene and o-xylene. The NTS, packed with 60-80 mesh divinylbenzene (DVB) particles, was compared in terms of extraction efficiency by simultaneously using the 75-microm Carboxen/polydimethylsiloxane solid-phase microextraction (Carboxen/PDMS-SPME) fiber for time-weighted average (TWA) sampling, and experimental results indicated that the packed DVB-NTS achieved higher toluene extraction rates. Additionally, the NTS installed in the outlet air stream for adsorbing toluene and o-xylene exhausted through GAC accurately indicated toluene and o-xylene breakthrough times of 4700-5000 min. The GAC-NTS operational instructions to indicate the replacing time of adsorbent in the internal circulation cabinets are also included in this paper. PMID- 22916443 TI - Fine particulate matter and visibility in the Lake Tahoe Basin: chemical characterization, trends, and source apportionment. AB - Speciated PM2.5 (particulate matter with an aerodynamic diameter8 km) downwind, once dilution overcomes ozone titration and inhibition by large flare emissions of NOx. The additional peak ozone from the hypothetical flare can briefly exceed 10 ppb about 16 km downwind. The enhancements of ambient ozone predicted by the model are significant, given that ozone control strategy widths are of the order of a few parts per billion. Degrading the horizontal resolution of the model to 1 km spuriously enhances the simulated ozone increases by reducing the effectiveness of ozone inhibition and titration due to artificial plume dilution. PMID- 22916445 TI - Near-source air quality impacts of large olefin flares. AB - Large petrochemicalflares, common in the Houston Ship Channel (the Ship Channel) and other industrialized areas in the Gulfof Mexico region, emit hundreds to thousands of pounds per hour of highly reactive volatile organic compounds (HRVOCs). We employedfine horizontal resolution (200 mx200 m) in a three dimensional (3D) Eulerian chemical transport model to simulate two historical Ship Channel flares. The model reasonably reproduced the observed ozone rise at the nearest monitoring stations downwind of the flares. The larger of the two flares had an olefin emission rate exceeding 1400 lb/hr. In this case, the model simulated a rate of increase in peak ozone greater than 40 ppb/hr over a 12 kmx12 km horizontal domain without any unusual meteorological conditions. In this larger flare, formaldehyde emissions typically neglected in official inventories enhanced peak ozone by as much as 16 ppb and contributed over 10 ppb to ambient formaldehyde up to approximately 8 km downwind of the flare. The intense horizontal gradients in large flare plumes cannot be simulated by coarse models typically used to demonstrate ozone attainment. Moreover even the relatively dense monitoring network in the Ship Channel may not be able to detect many transient high ozone events (THOEs) caused by industrial flare emissions in the absence of stagnant air recirculation or stalled sea breeze fronts, even though such conditions are unnecessary for the occurrence of THOEs. PMID- 22916446 TI - The impact of the earthquake and humanitarian assistance on household economies and livelihoods of earthquake-affected populations in Haiti. AB - OBJECTIVE: On January 12, 2010, one of the most destructive earthquakes in history struck the Haitian capital Port-au-Prince. This study aims to characterize the impact of the earthquake and humanitarian response on well being of the affected households as means of evaluating the effectiveness of response efforts. DESIGN: A stratified 60 x 20 cluster survey was conducted in Port-au Prince internally displaced persons camps (n = 600) and neighborhoods (n = 596) in January 2011. Clusters were assigned using probability proportional to size sampling and data were collected using interviewer-administered questionnaires. RESULTS: The earthquake affected incomes in 90 percent of camp and 73 percent of neighborhood households (p < 0.001); camp households were consistently worse off by most measures of economic and food security. As compared to camps, living in a neighborhood was associated with increased odds of better/same income status (Odds ratio, OR: 1.78, Confidence interval, CI: 1.25-2.53), employment (OR: 1.47, 1.01-2.14), and food access (OR: 1.83, CI: 1.33-2.52). With respect to earthquake impacts, damage to the home was associated with decreased odds of better/same food access (OR: 0.55, CI: 0.33-0.93) and injuries with decreased odds of better/same income status (OR: 0.57, CI: 0.37, 0.87). Within 1 month of the earthquake, 89 percent of camp and 46 percent in neighborhood households had received humanitarian assistance (p < or = 0.001); however, receipt of aid was not associated with improved income, employment, or food access at 1 year postearthquake. CONCLUSIONS: The immediate impacts of injury and mortality had marginal influences on long-term household economic security, whereas displacement into camps was stongly associated with negative outcomes for income, employment, and food access. PMID- 22916447 TI - Contribution of the administrative database and the geographical information system to disaster preparedness and regionalization. AB - OBJECTIVE: Public health emergencies like earthquakes and tsunamis underscore the need for an evidence-based approach to disaster preparedness. Using the Japanese administrative database and the geographical information system (GIS), the interruption of hospital-based mechanical ventilation administration by a hypothetical disaster in three areas of the southeastern mainland (Tokai, Tonankai, and Nankai) was simulated and the repercussions on ventilator care in the prefectures adjacent to the damaged prefectures was estimated. DESIGN, SETTING, AND PATIENTS: Using the database of 2010 including 3,181,847 hospitalized patients among 952 hospitals, the maximum daily ventilator capacity in each hospital was calculated and the number of patients who were administered ventilation on October xx was counted. INTERVENTIONS: Using GIS and patient zip code, the straight-line distances among the damaged hospitals, the hospitals in prefectures nearest to damaged prefectures, and ventilated patients' zip codes were measured. The authors simulated that ventilated patients were transferred to the closest hospitals outside damaged prefectures. OUTCOMES: The increase in the ventilator operating rates in three areas was aggregated. RESULTS: One hundred twenty-four and 236 patients were administered ventilation in the damaged hospitals and in the closest hospitals outside the damaged prefectures of Tokai, 92 and 561 of Tonankai, and 35 and 85 of Nankai, respectively. The increases in the ventilator operating rates among prefectures ranged from 1.04 to 26.33-fold in Tokai; 1.03 to 1.74-fold in Tonankai, and 1.00 to 2.67-fold in Nankai. CONCLUSION: Administrative databases and GIS can contribute to evidenced-based disaster preparedness and the determination of appropriate receiving hospitals with available medical resources. PMID- 22916449 TI - Pediatric patients in a disaster: part of the all-hazard, comprehensive approach to disaster management. AB - Disasters affect all ages of patients from the newborn to the elderly. Disaster emergency management includes all phases of comprehensive emergency management from preparedness to response and recovery. Disaster planning and management has frequently overlooked the unique issues involved in dealing with the pediatric victims of a disaster. The following will be addressed: disaster planning and management as related to pediatric patients and the integration of pediatric disaster management as part of an all-hazard, comprehensive emergency management approach. Key recommendations for dealing with children, infants, and special needs patients in a disaster are delineated. PMID- 22916448 TI - The impact of alternative diagnoses on the utility of influenza-like illness case definition to detect the 2009 H1N1 pandemic. AB - OBJECTIVE: To investigate the impact of excluding cases with alternative diagnoses on the sensitivity and specificity of the Centers for Disease Control and Prevention's (CDC) influenza-like illness (ILI) case definition in detecting the 2009 H1N1 influenza, using Geographic Utilization of Artificial Intelligence in Real-Time for Disease Identification and Alert Notification, a disease surveillance system. DESIGN: Retrospective cross-sectional study design. SETTING: Emergency department of an urban tertiary care academic medical center. PATIENTS: 1,233 ED cases, which were tested for respiratory viruses from September 5, 2009 to May 5, 2010. MAIN OUTCOME MEASURE: The main outcome measures were positive predictive value, negative predictive value, sensitivity, specificity, and accuracy of the ILI case definition (both including and excluding alternative diagnoses) to detect H1N1. RESULTS: There was a significant decrease in sensitivity (chi2 = 9.09, p < 0.001) and significant improvement in specificity (chi2 = 179, p < 0.001), after excluding cases with alternative diagnoses. CONCLUSION: When early detection of an influenza epidemic is of prime importance, pursuing alternative diagnoses as part of CDC's ILI case definition may not be warranted for public health reporting due to the significant decrease in sensitivity, in addition to the resources required for detecting these alternative diagnoses. PMID- 22916450 TI - Nursing homes' preparedness plans and capabilities. AB - OBJECTIVES: To assess nursing homes' capabilities to evacuate or shelter-in-place during a disaster and to determine their actual preparedness-related capacity. DESIGN: A 27-question survey assessing disaster preparedness plans and capabilities in nursing homes. Respondents and nonresponders were compared based on characteristics from the Nursing Home Compare Web site using t tests for continuous variables and chi2 test for categorical variables. Probit regression was used to estimate the relationships between nursing home characteristics and dichotomous measures of preparedness. SETTING: Web and paper surveys of nursing home administrators. PARTICIPANTS: Nursing home administrators in California, Florida, and Georgia. MAIN OUTCOME MEASURES: Number of disaster drills, days supply of emergency food and water, evacuation transportation and destination. RESULTS: All facilities reported conducting at least one disaster drill per year. Only 55 percent of facilities used a template to develop their disaster plans and 74 percent of facilities reported that they discuss their disaster plans with local or state emergency management officials. Most facilities (81 percent) have generators. All but 19 (7 percent) of nursing homes are able to shelter-in-place for 2 days or longer. Ambulance services are the most common form of transportation (76 percent). Most facilities (73 percent) plan to evacuate residents to nursing homes affiliated with their corporate group. DISCUSSION: Almost all respondents conducted disaster drills, discussed preparedness with local officials, and were able to shelter-in-place for at least 2 days. However, many facilities rely on resources that may not be available during a large disaster. PMID- 22916451 TI - Impact of Hurricane Ike on the call volumes of Houston Fire Department emergency medical services. AB - INTRODUCTION: Little is known about the capacity and activity of emergency medical services (EMS) during large-scale disasters. This article provides a case study of the role of EMS in one large urban city during a major hurricane. METHODS: The authors analyzed changes in call volume data from the City of Houston Fire Department's EMS during Hurricane Ike. Descriptive and statistical analyses are used to explain surges and statistical differences in volumes. RESULTS: Demand for EMS care can increase approximately 40 percent during surges in the disaster cycle, placing extreme burdens on system capacity and workload. The largest increase in demand came from respiratory problems, falls, and chest pains, with the largest decrease in calls from motor vehicle accidents. CONCLUSIONS: A strategy for managing surges in prehospital care from major disasters is a requirement for modern EMS. PMID- 22916452 TI - Games, simulations, and learning in emergency preparedness: a review of the literature. AB - Between 2007 and 2011, a comprehensive review of the literature was conducted to identify the usefulness of educational games and simulations in developing and evaluating the competency of public health professionals to prepare for, respond to, and recover from emergencies. This article presents an overview of the literature related to the use of games and simulations in education and training, summarizes key findings, identifies key features of gaming simulation design for educational effectiveness, and suggests that use of these emerging teaching and learning strategies be considered in the development of a comprehensive approach for creating and evaluating competency. PMID- 22916453 TI - Applying behavioral science to workforce challenges in the public health emergency preparedness system. AB - When disasters and other broad-scale public health emergencies occur in the United States, they often reveal flaws in the pre-event preparedness of those individuals and agencies charged with responsibility for emergency response and recovery activities. A significant contributor to this problem is the unwillingness of some public health workers to participate in the requisite planning, training, and response activities to ensure quality preparedness. The thesis of this article is that there are numerous, empirically supported models of behavior change that hold potential for motivating role-appropriate behavior in public health professionals. The models that are highlighted here for consideration and prospective adaptation to the public health emergency preparedness system (PHEPS) are the Transtheoretical Model of Intentional Behavior Change (TTM) and Motivational Interviewing (MI). Core concepts in TTM and MI are described, and specific examples are offered to illustrate the relevance of the frameworks for understanding and ameliorating PHEPS-based workforce problems. Finally, the requisite steps are described to ensure the readiness of organizations to support the implementation of the ideas proposed. PMID- 22916454 TI - Focus on integrated care fosters transformation in assisted living. PMID- 22916455 TI - Investments in direct-care staff a big win for everyone. PMID- 22916456 TI - Superior documentation means superior wound care. PMID- 22916457 TI - The CCRC conundrum. PMID- 22916458 TI - Unleash the power of supply chain control. PMID- 22916459 TI - Inflammatory bowel disease: diagnosis and research trends: the clinical lab is playing an increasingly important role. AB - IBD consists of ulcerative colitis and Crohn's disease and is characterized by recurrent and chronic inflammation of intestinal mucosa. In addition to patient's symptoms, history and physical examination, various techniques and tests help diagnose IBD. Endoscopy, histology, and imaging techniques such as CT-scan or MRI are used along with serological and hematological lab tests for its diagnosis. The likelihood of these procedures distinguishing between the diagnosis of ulcerative colitis or Crohn's disease is high. Various investigations are underway for better identification and management of IBD in the future. PMID- 22916461 TI - Interfacing the LIS. PMID- 22916460 TI - Tweaking the LIS: changes in technology offer new information system options for clinical labs. PMID- 22916462 TI - Labs speak out against additional Affordable Care Act cuts. PMID- 22916463 TI - Next generation sequencing and translational research: from bench to bedside. PMID- 22916464 TI - Next gen sequencing: its impact on transplant science. PMID- 22916465 TI - Platelet morphology: reliable technology doesn't require duplication. PMID- 22916467 TI - Alphabet soup: the who's who of transport regulations. PMID- 22916466 TI - Nucleic acid testing in oncology. PMID- 22916468 TI - [Realization of a compact mobile phone based wireless plantar pressure monitoring system and application]. AB - An improved compact mobile phone based wireless plantar pressure monitoring system and software are proposed based on former progress, which can collect pressure data by sensors and circuit board, transmit data through Bluetooth wirelessly, and display and calculate the data on the mobile terminal. Conceptual experiments carried out demonstrate the feasibility and accuracy of the new system The system is expected to be widely used in the future owing to its portability, ease of use, and cost-effectiveness PMID- 22916469 TI - [An automatic 3D brain segmentation based on improved level-set method in micro CT rat/mouse images]. AB - OBJECTIVE: In vivo Micro-PETICT imaging of mouse/rat brain has been widely used to non-invasively monitor brain and provides researchers a better understanding of therapeutic effects in models of human neurological disease. For the need of further processing, extraction of brain tissue from head is required and vital. METHODS: An automatic multistep combination methods was proposed based on an improved level set framework, which includes (1) Use Fuzzy-C-Means method together with threshold and morphology methods to get the initial level-set surface automatically. (2) Combine gradient vector flow to enhance the gradient contrast and enforce the surface move toward to the object's surface much faster, especially obtain a significantly improvement in the regions of forehead and the joint between brain and neck. (3) introduce an automatic stop condition based on average bandwidth energy maximization to overcome the leakage problem. RESULTS: 3 Micro-CT images of rat and 3 of mouse have been tested using the proposed methods and the average accuracy has increased by 33% for rat and 6.7% for mouse. The average processing duration for rat and mouse are about 8 minutes and 4 minutes, respectively. CONCLUSIONS: The proposed methods were proved that it can be effectively used for Micro-PET/CT imaging of mouse/rat brain segmentation and have a great improvement on accuracy and convenience. PMID- 22916470 TI - [Visualization study of SW atlases in neurosurgery navigation system]. AB - In this paper, we describe a study on visualization of SW atlases. Firstly, data structures in axial, coronal and sagittal directions are generated by SW atlases' raw data after pre-processing. Secondly, we produce 3D SW atlases through setting gray intensity and spaces between slices. Thirdly, we integrate the atlas into the neurosurgery navigation system and realize the visualization of SW atlases. Finally, we realize brain anatomy structures labeling and real-time display in neurosurgery navigation system. PMID- 22916471 TI - [The control method design of thermal treatment system via fuzzy logic]. AB - A novel system is proposed to control the liquid nitrogen cooling and radio frequency heating of tissue to achieve effective thermal ablation in the treatment using fuzzy logic controller and fuzzy logic PID type controller separately. Results of ex-vivo pig liver experiments demonstrate that this system is useful and could p control the desired treatment procedure. PMID- 22916472 TI - [Research on clone algorithm applied in edge detection of retinal vessels]. AB - Based on analyzing image edge cloning theory and algorithms, a marginal clone algorithm is proposed with a combination of edge connectivity and noise removal algorithm. Simulation results show that the edge image detected by the algorithm has solved problems of traditional edge discontinuities and tsereve noise. Moreover, it has better edge recognition performance. PMID- 22916473 TI - [Study and manufacture of a degradable bioactive glass]. AB - Refering to the successful experience from the foreign technology, a degradable bioactive glass is developed. This bioactive glasses composition can be used for filling bone defects. PMID- 22916474 TI - [The design of the static magnetic field testing coil for pacemaker]. AB - Based on the international standards about implantable pacemakers, designing the static magnetic field testing coil in accordance with the requirements of the standards. The testing result demonstrates that the designed coil could be used for the static magnetic field strength test of implantable pacemakers. PMID- 22916475 TI - [Design of hospital mobile clinical tablet PC]. AB - OBJECTIVE: Changing the current situation that doctors carry large amounts of paper medical records doctor's advice during clinical examination to improve the efficiency of examination. METHOD: Analysis of current business demand in doctor's clinical work, followed with a comprehensive improvement program. RESULT: Design a Tablet PC system comply with doctor's clinical demand in both software and hardware. CONCLUSION: By using the Tablet PC physicians improve the efficiency of work, realize the reengineering and optimization of traditional health services and management process. PMID- 22916476 TI - [Research of the clinical case knowledge based on ontology]. AB - Based on the idea of the ontology, knowledge representation and structure of knowledge base of clinical cases is proposed. The knowledge acquisition process of clinical cases is introduced, the methods of clinical case similarity calculation is proposed; and the experiments of case similarity calculation has been carried on using clinical data calculation is proposed; and the experiments of case similarity calculation has been carried on using clinical data from hospital. PMID- 22916477 TI - [Design of the chest belt wireless health monitoring terminal for the old based on MSP430]. AB - A real time monitoring terminal for the empty nest elderly based on extracting fabric type sensor and acceleration sensor combined with Bluetooth wireless communication technology is proposed. When the system detects arrhythmia and falls of the elderly, and then start the wireless bluetooth communication, complete the information interaction with mobile phone gateway device, so as to implement the rescue. PMID- 22916478 TI - [Design & development of orthopedics implants failure management system]. AB - The orthopedics implants failure management system has been put forward according to the present status. The function of the system and typical failure case reasoning route also have been described. Furthermore, the analysis process has been presented by illustrating a typical failure case analysis. PMID- 22916479 TI - [Research and design of an initiative lung simulator based on plunger]. AB - This article introduces the working principle and the structural design of an initiative lung simulator based on plunger. The lung simulator is intended to test the monitor parameter and trigger function of the ventilator. Lung simulator can ventilate initiatively by adjusting the parameters such as tidal volume(VT). frequency and inspiration time. PMID- 22916480 TI - [Point on consideration of the clinical trial design and evaluation on the dressing applied to burn wound]. AB - The relevant keypoints needed to be considered in clinical trials of dressing applied to burn wound when claiming for registration is discussed combining with the characteristics of burn wound and the dressing applied to wound surface in order to provide reference for development & clinical evaluation of dressing. PMID- 22916481 TI - [Study of the management of clinical trial in the registration of medical devices in China]. AB - The key factor responsible for the slowness of registration of medical devices in China is clinical trial. The clinical trial in European and U.S. is taken as an example to analyze the problems in clinical trials in China. Some suggestions are proposed to solve the problem. PMID- 22916482 TI - [A new solution for performance test of disposable syringe and other transfusion apparatus]. AB - The method and process for main performance test of regular medical apparatus is proposed based on test standards for medical package. This provides a comprehensive testing solution for the quality supervision, drug administration and major enterprises in medical industry. PMID- 22916483 TI - [The cytotoxicity study of sterile urethral catheter for single use]. AB - To further demonstrate the toxicity of the catheter, cytotoxicity evaluation was conducted in registration inspection products and the relationship between testing methods and materials were analyzed. This result showed that to strengthen cytotoxicity assay in registration inspection is important to choose catheter in clinic. PMID- 22916484 TI - [Preliminary discussion on the preparation of medical device standards adopting international standards]. AB - Conclude some specific problems in drafting the industry standards of medical devices which are adopted to international standards. Provide relevant suggestion and recommendation in accordance to GB/T 1.1-2009 and GB/T 20000.2-2009, some preliminary suggestions were accordingly proposed. PMID- 22916485 TI - [Discourse of requirement for facility & environment in medical device quality system]. AB - Requirement for facility and environment of FDA, regulation of China medical device Quality System, Europe medical device Directive and ISO13485 standard are introduced. The comparison is made to help domestic medical device industry understand the regulation requirement. PMID- 22916486 TI - [The practice and proposals for standardized management of neonatal insulation technology]. AB - In clinical practice, incubators can contribute to better diagnosis and treatment of diseases. Currently, insulation medical equipment used for the newborn are mainly warm-boxes. With the use popularity of warm-boxes in the country, medical accidents caused by improper use are on the increase. According to neonatal insulation technology and standardized management of practice, this article puts forward technical requirements of infant incubators with constant temperature and humidity, operation regulations and management specifications to better regulate the use of such devices. Meanwhile, it also suggests national related departments to formulate "incubator technology management norms" and "warm-box technology and practice", intending to standardize industry behaviors and ensure medical safety. PMID- 22916487 TI - [Low-field MRI: a quick scan based on the large field of view]. AB - To optimize the configuration of the conventional SE and FSE sequence parameters in low field MRI. With the combination of larger vision, relatively thinner slice thickness, small number of excitation (NEX = 1 or 2), the signal-to-noise ration and the spatial resolution on follow-up images are moderate, the scan time is significantly shorter along with fewer motion artifacts, the check success rate is improved. PMID- 22916488 TI - [Development of rapid determination of carbon dioxide combining power without mercury]. AB - A new type of instrument that called the rapid determination of carbon dioxide combining power without mercury is proposed. The performance of the instrument in accordance to the requirements in ISO15189 of laboratory accreditation has been evaluated. The results showed that, this instrument is safe, pollution-free, accurate and practical. PMID- 22916489 TI - [The applied research of a neotype medical drainage bag in clinical care]. AB - OBJECTIVE: To compare and evaluate the effectiveness of two kinds of medical drainage bag. METHODS: 206 patients were randomly divided into two groups each of which consisted of 103 patients. All the data including four indices, such as the time required to replace the drainage bags, the incidence of the bags detached, draining fluid splashing rates during the replacement of the bags, patient and medical staff satisfaction, were collected and analyzed statistically. RESULTS: The time required to replace the drainage bags, the incidence of the bags detached and draining fluid splashing rates during the replacement of the bags of the experimental group were significantly lower than those of the control group (P < 0.05), while the patient and medical staff satisfaction were significantly higher than those of the control group (P < 0.05). CONCLUSION: It is convenient, quick and time and effort saving to use the neotype medical drainage bags. Hence, the use of neotype medical drainage bags could help to improve the work efficiency, effectively prevent occupational injuries and protect health care workers. PMID- 22916490 TI - [RNA silencing, the fundamental security strategy of genomic immunity: a review]. AB - The 21-24 nucleotides small RNA that generated from double strands RNA can trigger two types of epigenetic gene silencing in plants. One is Post Transcriptional Gene Silencing (PTGS), characterized by cleavage of homologous mRNA in cytoplasm. Transcriptional Gene Silencing (TGS) is another one, in which transcription inhibition is obtained through small RNA-directed DNA methylation of homologous promoter region. Here we summarized the relationship and differences between PTGS and TGS, the current achievement in the study of RNA silencing spreading, as well as the discrepancy of exogenous and endogenous gene silencing, and discussed the underlying reasons in the end. PMID- 22916492 TI - [Essential genes, minimal genome and synthetic cell of bacteria: a review]. AB - Single-cell prokaryotes represent a simple and primitive cellular life form. The identification of the essential genes of bacteria and the minimal genome for the free-living cellular life could provide insights into the origin, evolution, and essence of life forms. The principles, methodology, and recent progresses in the identification of essential genes and minimal genome and the creation of synthetic cells are reviewed and particularly the strategies for creating the minimal genome and the potential applications are introduced. PMID- 22916491 TI - [Progress in the understanding of the function of atypical response regulators: a review]. AB - Two component system is a signal transduction system. It typically consists of a sensor histitine kinase and a cognate response regulator (RR) component. The activity of RR is regulated by a phosphorylation dependent mechanism. In recent years, the existence of atypical response regulators (ARRs), which rely on a phosphorylation independent mechanism to regulate their activity, have been recognized. ARRs are involved in the regulation of bacterial growth and development, antibiotic biosynthesis, iron transport, among others. Here we review the recent advances in the understanding of the structure and function of atypical response regulators, by using JadR1, a regulator in jadomycin biosynthesis in Streptomyces, as an example to elucidate the novel mechanism used by ARR to fine-tune its activity. PMID- 22916493 TI - [Progress in new vaccine strategies against influenza: a review]. AB - Influenza, caused by influenza virus, is a serious respiratory illness which poses a global public health threat. Vaccination is the primary strategy for the prevention and control of influenza. Although both inactivated vaccines and the live attenuated vaccines are effective in preventing influenza, the current vaccines have poor efficacy in the elderly and fail to provide protection against heterosubtype viruses. Development of a safer and more effective influenza vaccine that provides broad cross protection, overcoming the intrinsic limitation of the current vaccines, has been a scientific challenge. During the past decades, structural biology, reverse genetic and other virological technologies developed quickly and sped the progress of influenza vaccinology. Some new strategies for developing influenza vaccine have been generated, produced encouraging results, which showed great prospect as next-generation of influenza vaccines. PMID- 22916494 TI - [Expression and molecular evolution of recombinant acetylcholinesterase for detection of pesticide residues: a review]. AB - Acetylcholinesterase (AChE) plays a key role in the pesticide determination. However, the extraction of AChE from natural materials has the disadvantages of low yield, complex purification and poor stability. Therefore, the preparation of recombinant AChE with high performance becomes the hot topic of researchers in recent years. In this article we summarize the progress in the expression of recombinant AChE and the improvement of its analytical characteristic. Finally, we point out that the directed evolution strategy combined with surface display technology is the future trend on improving recombinant AChE activity. PMID- 22916495 TI - [Metabolic regulation of isocitrate lyase regulator in Escherichia coli based on metabolic flux information]. AB - Gene expression is regulated by different transcriptional regulators. The transcriptional regulator isocitrate lyase regulator (IclR) of Escherichia coli represses the expression of the aceBAK operon that codes for the glyoxylate pathway enzymes. In this study, physiological and metabolic responses of the deletion of the ic1R gene in E. coli BW25113 were investigated based on the quantification and analysis of intracellular metabolic fluxes. The knockout of the iclR gene resulted in a decrease in the growth rate, glucose uptake rate and the acetate secretion rate, but a slight increase in biomass yield. The latter could be attributed to the lowered metabolic fluxes through several CO2 generating pathways, including the redirection of 33% of isocitrate directly to succinate and malate without CO2 production as well as the reduced flux through the pentose phosphate pathway. Furthermore, although the glyoxylate shunt was activated in the iclR mutant, the flux through phosphoenolpyruvate (PEP) carboxykinase kept almost unchanged, implying an inactive PEP-glyoxylate cycle and no extra loss of carbon atoms in the mutant strain. Both the reduced glucose uptake rate and the active glyoxylate shunt were responsible for the minor decrease in acetate secretion in the ic1R knockout strain compared to that in the wild-type E. coli strain. PMID- 22916496 TI - [Construction and structural analysis of integrated cellular network of Corynebacterium glutamicum]. AB - Corynebacterium glutamicum is one of the most important traditional industrial microorganisms and receiving more and more attention towards a novel cellular factory due to the recently rapid development in genomics and genetic operation toolboxes for Corynebacterium. However, compared to other model organisms such as Escherichia coli, there were few studies on its metabolic regulation, especially a genome-scale integrated cellular network model currently missing for Corynebacterium, which hindered the systematic study of Corynebacterium glutamicum and large-scale rational design and optimization for strains. Here, by gathering relevant information from a number of public databases, we successfully constructed an integrated cellular network, which was composed of 1384 reactions, 1276 metabolites, 88 transcriptional factors and 999 pairs of transcriptional regulatory relationships. The transcriptional regulatory sub-network could be arranged into five layers and the metabolic sub-network presented a clear bow-tie structure. We proposed a new method to extract complex metabolic and regulatory sub-network for product-orientated study taking lysine biosynthesis as an example. The metabolic and regulatory sub-network extracted by our method was more close to the real functional network than the simplex biochemical pathways. The results would be greatly helpful for understanding the high-yielding biomechanism for amino acids and the re-design of the industrial strains. PMID- 22916497 TI - [Screening of food-grade microorganisms for biotransformation of D-tagatose and cloning and expression of L-arabinose isomerase]. AB - L-Arabinose isomerase (L-AI) is an intracellular enzyme that catalyzes the reversible isomerization of D-galactose and D-tagatose. Given the widespread use of D-tagatose in the food industry, food-grade microorganisms and the derivation of L-AI for the production of D-tagatose is gaining increased attention. In the current study, food-grade strains from different foods that can convert D galactose to D-tagatose were screened. According to physiological, biochemical, and 16S rDNA gene analyses, the selected strain was found to share 99% identity with Pediococcus pentosaceus, and was named as Pediococcus pentosaceus PC-5. The araA gene encoding L-AI from Pediococcus pentosaceus PC-5 was cloned and overexpressed in E. coli BL21. The yield of D-tagatose using D-galactose as the substrate catalyzed by the crude enzyme in the presence of Mn2+ was found to be 33% at 40 degrees C. PMID- 22916498 TI - [Subcellular localization and resistance to Botrytis cinerea of a new type lipid transfer protein AtDhyPRP1 from Arabidopsis thaliana]. AB - Genetic transformation was adopted to analyze the subcellular localization and the resistance to fungal pathogens of Arabidopsis lipid transfer protein AtDHyPRP1. The coding sequence of AtDHyPRP1 amplified by PCR from Ws ecotype was used to construct the plant binary expression vector pRI101-AN-AtDHyPRP1 and the fusion expression vector pCAMBIA1302-AtDHyPRP1-GFP. Transgenic tobacco and Arabidopsis plants were produced by leaf disc and floral dip protocols, respectively. AtDHyPRP1 could improve the resistance of tobacco to Botrytis cinerea remarkably and the infection sites on transgenic tobacco leaves accumulated large amounts of H2O2. Observation under laser scanning confocal microscope showed that AtDHyPRP1 was localized to cell surface. It suggested that AtDHyPRP1 might play special function after secretion to outside of the cell and was involved in plant defense system against pathogens. PMID- 22916499 TI - [Efficient delivery of siRNA into mouse preimplantation embryos by electroporation]. AB - We developed a detailed electroporation method to deliver efficiently siRNA into mouse preimplantation embryos. By introducing Cy3 labeled negative control small interfering RNA (siRNA) into mouse preimplantation embryos, we optimized conditions for the electroporation, including the voltage, pulse duration, pulse number, electroporation buffer and an important step to weaken the zona pellucida. Embryonic survival rate, transfection rate and blastocyst development rate were evaluated under the converted fluorescence microscope, by embryos counting and statistical analysis. The best transfection was achieved in opti-MEM under the conditions of 30 V, 1 ms, 3 pulses, and the duration of digestion in tyrode's solution was 10 s. In conclusion, the proposed electroporation approach here is a simple and efficient tool to deliver siRNA for RNA interference (RNAi) into mouse preimplantation embryos. PMID- 22916500 TI - [Construction of adenovirus carrying dual-target shRNA for Oct-4 and Survivin and its inhibitory effect on human hepatocellular carcinoma cells]. AB - The transcriptional factor Oct-4 and Survivin are the key regulatory factors in cancer cell proliferation and mitosis. A dual cancer-specific shRNA adenovirus vector, Ad5-Dual-shRNA, targeting Oct-4 and Survivin genes was constructed by molecular cloning and recombination. After cells were infected with virus, hepatocellular carcinoma cell line EHBH-H1 was used for detecting the expression of Oct-4 and Survivin proteins by Western blotting. The viral cytotoxic effect on cancer cells was detected by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) reduction assay in vitro, and the inhibition effect on tumor xenografts was observed in nude mice. The results showed that the expression of Oct-4 and Survivin in cancer cell line EHBH-H1 could be silenced markedly by Ad5-Dual-shRNA. In MTT and animal experiments, Ad5-Dual-shRNA also represented much stronger anti-tumor effect on tumor growth than Ad5-Surv-shRNA and Ad5-Oct4-shRNA. From this research we can draw a conclusion that the cancer specific adenovirus vector expressing dual-shRNA targeting Oct-4 and Survivin genes may provide us a more effective, specific and convenient gene therapy method. PMID- 22916502 TI - National pride: Walter Reed creates unified campus for country's wounded warriors. PMID- 22916501 TI - [Recombinant adenovirus expressing siRNA is generated to inhibit the expression of RARbeta in rat mesenchymal stem cells treated by all-trans retinoic acid]. AB - To construct the recombinant adenovirus vector expressing specific siRNA for rat retinoic acid receptor-beta (RARbeta) gene, and to detect its effect on RARbeta expression and neuronal differentiation of all-trans retinoic acid (ATRA) treated mesenchymal stem cells (MSCs). First, we designed four pairs of siRNA sequence for rat RARbeta gene and annealed complementary oligonucleotides in vitro, then cloned double-stranded DNA in pSES-HUS vector containing U6/H1 double-promoter and recombinated with the backbone vector to construct pAd-siRARbeta plasmid. We infected MSCs by using adenovirus Ad-siRARbeta which was packaged in HEK293 cell line, then performed Real-time, Western blotting and immunoflourencence to detect the expression of RARbeta. We used combination of ATRA and MNM to induce MSCs into neural-like cells, then performed Real-time PCR and immunoflourencence to detect neuronal specific markers of induced neural cells. By using PCR, endonuclease cutting and gene sequencing, we confirmed that the target genes were correctly cloned in adenovirus vector. We could observe more than 60% RFP positive MSCs at 24 h after adenovirus infection. The expression of RARbeta was significantly increased to 16.5 +/- 2.34 fold in ATRA treated MSCs (P < 0.05) and located in nucleus. Three of four pairs siRNA could effectively inhibit the expression of RARbeta with inhibition efficacy of (66.26 +/- 9.12)%, (48.70 +/- 5.78)%, (64.09 +/- 0.53)% (P < 0.05), especially siRNA-pool group with inhibition efficacy of (78.09 +/- 4.24)% (P < 0.01). Combination of ATRA and MNM induced MSCs into neural-like cells which expressed neuronal specific markers, Nestin, NSE, MAP-2, and Tau. Immunoflourencence result showed that about 50-88 present of cells were positive for Nestin, NSE, Tjul, however, adenovirus medicated expression of siRARbeta could effectively inhibit the expression level of neural specific proteins and the ratio of positive stained cells (P < 0.05). Therefore, we successfully constructed the recombinant adenovirus vector containing siRNA for rat RARP gene, adenovirus could effectively infect MSCs and inhibit the expression of induced RARbeta in ATRA treated MSCs, then inhibit neuronal differentiation of MSCs. PMID- 22916503 TI - Back in action: design considerations for safe patient handling. PMID- 22916504 TI - Risk + reward: assessing the need for electrical system shutdowns. PMID- 22916505 TI - It's about time: new disinfectants feature faster action against pathogens. PMID- 22916506 TI - Advice on educating front-line staff. PMID- 22916507 TI - All systems go: new resource provides commissioning support for health facility managers. PMID- 22916508 TI - Green guidance: gathering resources to launch sustainability initiatives. PMID- 22916509 TI - Longitudinal study on physical fitness parameters influencing bone mineral density reduction in middle-aged and elderly women: bone mineral density in the lumbar spine, femoral neck, and femur. AB - The prolongation of the average life span of women has been associated with the rapidly aging society. However, serious problem have arisen as a result, such as an increase in the number of bed-ridden elderly patients with osteoporosis associated femoral neck fracture. As preventive measures against osteoporosis for middle-aged to elderly women, 10,000 steps per day and intense exercise have been reported to inhibit bone mineral density (BMD) reduction. However, only a few studies have concretely reported on the type of physical fitness that is effective for BMD in particular parts of the body. In this study, a one-year longitudinal survey was performed involving generally healthy postmenopausal women to investigate physical fitness parameters influencing BMD in the lumbar spine, femoral neck, and femur. The subjects were 38 female residents of M City, aged 49-73 years. As physical fitness parameters, sit-ups, anteflexion in a sitting position, grip strength, mean amount of exercise (kcal), and area of outer body sway on standing straight with the eyes closed (m2) were measured. The BMD was measured in the lumbar spine (L2-L4), femoral neck, and femur. Logistic regression analysis was performed regarding the physical fitness parameters as explanatory variables and groups with and without BMD reduction over one year as those with and without risk as dependent variables. The number of sit-ups (odds ratio: 0.76, 95% CI: 0.61-0.96, p=0.022) was a preventive factor against BMD reduction of the lumbar spine, and ante flexion in a sitting position was a preventive factor against BMD reduction of the femoral neck (odds ratio: 0.88, 95% CI: 0.78-0.99, p=0.029). Regarding BMD reduction of the femur, the area of outer body sway on standing straight with the eyes closed tended to be not significant to the risk. It is suggested that physical fitness and local muscle strength are associated with BMD reduction in the lumbar spine, femoral neck, and femur. PMID- 22916510 TI - Cigarette smoking decreases dynamic inspiratory capacity during maximal exercise in patients with type 2 diabetes. AB - To investigate the influence of cigarette smoking on exercise capacity, respiratory responses and dynamic changes in lung volume during exercise in patients with type 2 diabetes. Forty-one men with type, 2 diabetes without cardiopulmonary disease were recruited and divided into 28 non-current smokers and 13 current smokers. All subjects received lung function tests and cardiopulmonary exercise testing using tracings of the flow-volume loop. Exercise capacity was compared using the percentage of predicted oxygen uptake at maximal workload (%VO2max). Respiratory variables and inspiratory capacity (IC) were compared between the two groups at rest and at 20%, 40%, 60%, 80% and 100% of maximum workload. Although there was no significant difference in lung function tests between the two groups, venous carboxyhemoglobin (CO-Hb) levels were significantly higher in current smokers. %VO2max was inversely correlated with CO Hb levels. Changing patterns in respiratory rate, respiratory equivalent and IC were significantly different between the two groups. Current smokers had rapid breathing, a greater respiratory equivalent and a limited increase in IC during exercise. Cigarette smoking diminishes the increase in dynamic IC in patients with type 2 diabetes. As this effect of smoking on dynamic changes in lung volume will exacerbate dynamic hyperinflation in cases complicated by chronic obstructive pulmonary disease, physicians should consider smoking habits and lung function when evaluating exercise capacity in patients with type 2 diabetes. PMID- 22916511 TI - Successful treatment of mesial temporal lobe epilepsy with bilateral hippocampal atrophy and false temporal scalp ictal onset: a case report. AB - Patients with bilateral hippocampal atrophy (BHA) in a subgroup suffering from mesial temporal lobe epilepsy represent a therapeutic challenge. We achieved successful surgical treatment in a case with BHA and false lateralized ictal onset on video-scalp electroencephalogram (EEG). A 27-year-old male patient with seizures since the age of 15 years showed current seizures consisting of an epigastric aura, a feeling of difficulty in breathing and oroalimentary automatism, which were frequently followed by secondary generalization with right arm tonic extension. MRI showed BHA with hyperintensity on FLAIR and a slightly smaller volume in the left hippocampus on volumetry. Ictal EEG started from the left anterior temporal and subtemporal regions, spreading to the right anterior to middle temporal region. Interictal EEG was not lateralized, and showed independent spikes in the bilateral anterior temporal and subtemporal regions. The patient underwent chronic intracranial EEG-monitoring, revealing that the seizure onset originated from the right hippocampus with a rapid spread to the hippocampus and lateral temporal cortex on the left side. We performed a right anterior temporal lobectomy with amygdalohippocampectomy. Histological diagnosis was classic hippocampal sclerosis. The patient has since been seizure-free for 4 years. In this case, false lateralization may have been caused by an atypical seizure-propagating route to the contralateral temporal region via the dorsal hippocampal commissure instead of the usual pathway to the ipsilateral temporal neocortex. The technique of bilateral intracranial EEG-monitoring is advantageous to lateralize the actual side, particularly in BHA patients even with clearly and falsely lateralized ictal onset on scalp-EEG. PMID- 22916512 TI - Benign papillary mesothelioma of the peritoneum associated with gastric cancer: report of a case. AB - Benign papillary mesothelioma of the peritoneum is an uncommon lesion that is usually discovered by chance during a surgical procedure. This lesion resembles metastatic carcinoma in gross appearance; therefore, intraoperative diagnosis can be difficult. This report presents a case of benign papillary mesothelioma concurrent with gastric cancer. The tumor was located on the hepatogastric ligament and resembled a metastatic peritoneal implant. A pathological review confirmed the diagnosis to be benign papillary mesothelioma. PMID- 22916513 TI - Ultrasound versus the landmark technique: a prospective randomized comparative study of internal jugular vein cannulation in an intensive care unit. AB - OBJECTIVE: The aim of this study is to find out if an ultrasound technique has advantages over the conventional landmark technique. METHODS: This is a prospective randomized comparative study on 120 patients requiring central venous cannulation of the right internal jugular vein. The study comprised of two groups: ultrasound and landmark groups, each consisting of 60 patients. The outcome measures were compared between the groups. RESULTS: Cannulation of the internal jugular vein was successful in 58 patients in the ultrasound group and in 53 in the landmark group. The number of attempts was 1.5 (1 - 3) and 2 (1 - 3) in the ultrasound and landmark group respectively (p = 0.001). The time taken for the successful cannulation was 4.9 +/- 1.7 minutes in the ultrasound approach and 8.0 +/- 2.8 minutes in the landmark approach (p = 0.00). The internal jugular vein diameter in the supine position was 11.2 +/- 1.5 mm which increased to 15.04 +/- 1.5 mm with a 15 degrees head-down position in the USG group (p = 0.001). The first attempt success rate was 39/60 (63%) in the ultrasound group and 19/60 (32%) with the landmark technique. The seven (12%) failure cases in the landmark group were rescued by the ultrasound technique. Inadvertent carotid artery puncture occurred in 2/60 (3%) and 6/60 (10%) of patients in the ultrasound and land mark group respectively. CONCLUSIONS: Ultrasound improves success rate, minimizes cannulation time and complications during internal jugular vein cannulation. It can be employed as a rescue technique in cases of a failed landmark technique. PMID- 22916514 TI - Clinical profile of patients with tetralogy of Fallot admitted for surgery at a cardiac surgical centre. AB - INTRODUCTION: Tetralogy of Fallot (TOF), a conotruncal defect, has been documented to be associated with chromosome abnormalities, single gene syndrome (22q11 microdeletion), known teratogens, with the rest associations being multifactorial. This study was carried out to determine the clinical profile and associated risk factors in patients with TOF admitted for surgical repairs. METHODS: Case files of all patients admitted for Tetralogy of Fallot over a period of one year were retrieved from the Medical Records Department and reviewed. Data on the patients' and their family history and associated cardiac anomalies were noted. RESULTS: There were 54 patients, 37 males and 17 females, with a mean age of 6.8 years +/- 7.1. Sixty percent were born between July and December, 81.5% as full term and 44% as first born. Twenty-six percent were born into consanguineous marriages. Five patients had dysmorphic features. Associated cardiac anomalies included right aortic arch, pulmonary atresia, dextrocardia and left superior vena cavae. CONCLUSION: The associated risk factors noted in this study were male sex, birthdates between July and December, first born and increased paternal age. Other risk factors were consanguinity and specific patterns of cardiovascular diseases associated with 22q 11 deletions. This suggests a multifactorial etiology for TOF. PMID- 22916515 TI - Open reduction and internal fixation of supracondylar fractures of the humerus: revival of the anterior approach. AB - INTRODUCTION: Supracondylar fractures of the humerus occur commonly in the paediatric age group. Gartland type III fractures are treated by closed manipulation and percutaneous pinning with K-wires. Open reduction is indicated in open fractures, failed closed reductions and in a dysvascular limb. There are various approaches that can be utilized to perform an open reduction. The approach of choice must be safe, surgeon and patient friendly and should provide a good access to the fracture and the important surrounding structures. The anterior approach has been described as the most versatile approach. The aim of the study was to review the advantages and drawbacks of the anterior approach and to assess the functional outcome of fractures treated via this approach. MATERIALS AND METHODS: Twenty five (15 male and 10 female) patients out of a hundred and twenty eight children with Gartland type III extension variety of supracondylar fractures of the humerus from underwent open reduction and internal fixation with K-wires via an anterior approach January 2007 to January 2011. The results were assessed at six months using Flynn's radiological and clinical criteria. RESULTS: Twenty five patients (19.53%) out of hundred and twenty eight patients underwent open reduction and internal fixation. According to Flynn's clinical and radiological criteria, 20 (80%) were found to have excellent and 5 (20%) good results. CONCLUSION: The anterior approach is safe, easy and provides direct exposure of the surrounding neurovascular structures with good to excellent results. PMID- 22916516 TI - Effect of submucosal injection of dexamethasone on post-operative sequelae of third molar surgery. AB - OBJECTIVE: This study was carried out to evaluate the effects of a single pre operative sub-mucosal injection of dexamethasone after third molar surgery to see the effects on post-operative discomfort. METHODS: This study was a prospective, double-blind, randomized, clinical trial. The subjects were forty patients who underwent surgical removal of the mandibular impacted third molar under local anesthesia and after being randomly assigned to receive either an 8 mg dexamethasone as submucosal injection or a normal saline injection into the lower buccal vestibule adjacent to the third molar. The maximum interincisal distance and facial contours were measured at the baseline and post-surgically on Day 2 and 7. Post-operative pain was evaluated subjectively using a visual analog scale and objectively by counting the number of analgesic tablets used. All subjects were operated upon by the same investigator to minimize the difference from inter operator variability. RESULTS: There was a significant difference in the measurements of the degree of swelling and trismus between the two groups on the 2nd post-operative day. In contrast, there was no statistically significant difference between the groups on the 7th post-operative day. The test group also used fewer analgesics post-operatively. CONCLUSIONS: Submucosal injection of dexamethasone after third molar surgery is effective in reducing postoperative swelling and trismus. It also delays the onset of post-operative pain. PMID- 22916517 TI - Luxation of eye ball following trauma--a rare case presentation. AB - Luxation of the eye globe is a rare event but it carries a risk of threat to permanent vision loss if appropriate intervention is not initiated on time. Although a rare presentation following minor trauma, it is usually associated with other ocular conditions like shallow orbital socket, floppy eyelid syndrome, and exophthalmos. Prompt reduction results in restoration of full anatomical and visual recovery in otherwise healthy eyes. We herein report a case of luxation of the eye ball following trauma in a 15-year-old girl, who recovered completely after the surgical correction and a review of the relevant literature. PMID- 22916518 TI - Rectosigmoid endometriosis causing an acute large bowel obstruction: a report of a case and a review of the literature. AB - Endometriosis is often seen in gynecology practice and is treated medically. However, intestinal involvement of endometriosis causing acute large bowel obstruction is uncommon and is difficult to differentiate from malignancy before surgery, owing to its similar colonoscopic and radiologic findings. We report a successfully-treated case of a 30-year-old woman in which endometrial infiltration of the large bowel caused acute obstruction, requiring emergency surgery to relieve the symptom and confirm the diagnosis. We present this unusual disease in general surgical practice and also review the literature. PMID- 22916519 TI - Vulvar endometrioma: a case report. AB - Endometriosis is a benign and common disorder that is characterized by ectopic endometrium outside the uterus. Extrapelvic endometriosis, like of the vulva, is rarely seen. We report a case of a 47-year-old woman referred to our clinic due to complaints of a vulvar mass and periodic swelling of the mass at the time of menstruation. During surgery, the cyst ruptured and a chocolate-colored liquid escaped onto the surgical field. The cyst was extirpated totally. Hipstopathological examination showed findings compatible with endometriosis. She was asked to follow-up after three weeks. The patient had no complaints and the incision field was clear at the follow-up. PMID- 22916520 TI - Bilateral, mirror-imaged, postero-inferior cerebellar artery aneurysms: report of a rare case. AB - A 60-year-old right-handed lady presented with the features of subarachnoid haemorrhage. The CT angiogram showed a pair of very rare bilateral, mirror-imaged distal postero-inferior cerebellar artery aneurysms. Both aneurysms were clipped via the midline posterior fossa craniectomy under general anaesthesia. The literatures is reviewed on the incidence, presentation, management and outcome of bilateral distal posterior-inferior cerebellar artery aneurysms. PMID- 22916521 TI - Approach to chronic hepatitis B virus infection. AB - Hepatitis B virus (HBV) infection constitutes one of the major global public health problems. Not only India and Nepal, East Asia is fighting with the same. About 30 percent of the world's population has serological evidence of current or past infection with HBV. By virtue of its different stage of presentation in different age groups of patients and the rapid mutation in the virus, the treatment of HBV requires thorough work-up and regular monitoring. Many new concepts have evolved in last decade in managing these patients, such as HBV Genotype, HBV DNA quantification and mutation analysis. The introduction of oral antivirals in the treatment of HBV infection has revolutionized the treatment. PMID- 22916522 TI - Time for elderly rehabilitation and nursing care center in the country. PMID- 22916523 TI - Health risks in oral piercings. PMID- 22916524 TI - Polymer burs remove less sound dentin and are as effective as carbide burs in caries removal (UT CAT #2206). PMID- 22916525 TI - Revascularization of immature permanent incisors after severe extrusive luxation injury. AB - Pulp necrosis is an uncommon sequel to extrusive luxation in immature teeth with incomplete apical closure. In this report, we describe the management of severely extruded immature maxillary incisors and the outcome of revascularization to treat subsequent pulp necrosis. An 8.5-year-old boy with severe dentoalveolar trauma to the anterior maxillary region as a result of a fall was provided emergency treatment consisting of reduction of the dislodged labial cortical bone and repositioning of the central incisors, which had suffered extrusive luxation. When he presented with spontaneous pain involving the traumatized incisors a week later, the teeth were treated via a revascularization protocol using sodium hypochlorite irrigation followed by 3 weeks of intracanal calcium hydroxide, then a coronal seal of mineral trioxide aggregate and resin composite. Complete periradicular healing was observed after 3 months, followed by progressive thickening of the root walls and apical closure. Follow-up observations confirmed the efficacy of the regenerative treatment as a viable alternative to conventional apexification in endodontically involved, traumatized immature teeth. PMID- 22916526 TI - Oral and maxillofacial pathology case of the month. Varix with phlebolith. PMID- 22916527 TI - Health considerations for oral piercing and the policies that influence them. AB - With the increase in popularity of piercings, the health care professional needs to be aware of the complications that can occur due to lack of regulations of the piercing establishments. Due to lack of training of piercing professionals and lack of enforcement of sterilization procedures, infection and life threatening complications can arise. Complications include, but are not limited to, hemorrhage, nerve damage, gingival recession, HIV, tongue swelling, tooth fracture, Bactermia, Ludwigs angina, increase salivary flow, jewelry aspiration, and localized infection. Texas requires an individual to be 18 years of age to receive a piercing. However, Texas does not regulate the piercing establishment or the artist providing the services. Oral health care providers should be aware of the lacking regulations of piercing studios so they can be more vigilant of oral complications that may occur. PMID- 22916528 TI - A custom-milled titanium complete-arch mandibular framework and a maxillary complete denture fabricated in 3 appointments: a dental technique. AB - BACKGROUND: When restoring multiple implants in the completely edentulous mandible, fabrication of a passive-fitting framework using traditional casting procedures is difficult. The introduction of computer-aided design and manufacturing techniques for fabricating custom 1-piece titanium frameworks simplifies this challenge and reduces time spent by the restorative dentist. PURPOSE: The aim of this case presentation is to explain how to fabricate a milled titanium framework using Procera technique step by step. MATERIALS AND METHODS: A 79-year-old woman with an edentulous maxilla and mandible received a maxillary complete denture in 3 appointments by duplicating her existing complete denture, and a mandibular screw-retained fixed dental prosthesis using a milled titanium framework. The patient did not have any problems regarding her implants and restorations in a year of service. CONCLUSION: This clinical report presents a complete oral rehabilitation, in which a custom-milled titanium complete-arch mandibular framework was fabricated with an overdenture, and a maxillary complete denture was fabricated using a denture duplication technique in 3 appointments. PMID- 22916529 TI - Late-breaking local news. PMID- 22916530 TI - Resources to help you build a drug kit. PMID- 22916531 TI - The interplay of health law and bioethics: a few thoughts on the practical implementation of scientific findings. PMID- 22916532 TI - Conscientious objection to sexual and reproductive health services: international human rights standards and European law and practice. AB - The practice of conscientious objection often arises in the area of individuals refusing to fulfil compulsory military service requirements and is based on the right to freedom of thought, conscience and religion as protected by national, international and regional human rights law. The practice of conscientious objection also arises in the field of health care, when individual health care providers or institutions refuse to provide certain health services based on religious, moral or philosophical objections. The use of conscientious objection by health care providers to reproductive health care services, including abortion, contraceptive prescriptions, and prenatal tests, among other services is a growing phenomena throughout Europe. However, despite recent progress from the European Court of Human Rights on this issue (RR v. Poland, 2011), countries and international and regional bodies generally have failed to comprehensively and effectively regulate this practice, denying many women reproductive health care services they are legally entitled to receive. The Italian Ministry of Health reported that in 2008 nearly 70% of gynaecologists in Italy refuse to perform abortions on moral grounds. It found that between 2003 and 2007 the number of gynaecologists invoking conscientious objection in their refusal to perform an abortion rose from 58.7 percent to 69.2 percent. Italy is not alone in Europe, for example, the practice is prevalent in Poland, Slovakia, and is growing in the United Kingdom. This article outlines the international and regional human rights obligations and medical standards on this issue, and highlights some of the main gaps in these standards. It illustrates how European countries regulate or fail to regulate conscientious objection and how these regulations are working in practice, including examples of jurisprudence from national level courts and cases before the European Court of Human Rights. Finally, the article will provide recommendations to national governments as well as to international and regional bodies on how to regulate conscientious objection so as to both respect the practice of conscientious objection while protecting individual's right to reproductive health care. PMID- 22916533 TI - The choice of child delivery is a European human right. AB - In a judgment of 14 December 2010, in the case of Madam Ternovszky v. Hungary, the European Court of Human Rights has considered that a State should provide an adequate regulatory scheme concerning the right to choose in matters of child delivery (at home or in a hospital). In the context of homebirth, regarded as a matter of personal choice of the mother, this implies that the mother is entitled to a legal and institutional environment that enables her choice. This contribution stresses in which sense the regulatory schemes in the Member States Belgium, Germany, the Netherlands, France and the UK concerning the choice of child delivery are in accordance with Article 8 ECHR, the right to respect for the private life. Do the Member States provide the legal certainty to a mother that the midwife can legally assist a homebirth? Or are restrictions made in interests of public health? PMID- 22916534 TI - Reshaping informed consent in the biobanking context. AB - In my article, I discuss the role of informed consent in the context of biobanking. I argue that the basic issue in understanding the role of the consent is one of identifying the interests at stake and determining which of these interests we intend to promote. The definition of the informational content represents only a consequential step. For this purpose, I analyse the legal status of human biological materials from three different perspectives: "material", "informational" and "relational". Informed consent produces different effects on each of these perspectives. From the material perspective, consent can influence the allocation of property rights over human tissue; from the informational point of view, consent is the legal instrument that permits control over personal data; while from the "relational" perspective, it is possible through consent to ensure that the person's personal beliefs are respected. The crucial point is that the legal effects that informed consent has on the three perspectives overlap. Therefore, in order to understand the role of informed consent holistically, in this article I analyse how these perspectives relate to each other. This analysis shows that the relationship between the perspectives can vary depending on the interests that we intend to promote. If we intend to promote the freedom of research, then the material dimension can prevail, whilst if we focus our attention on the interests of individuals then the informational and the relational dimensions will prevail. The challenge is to find a good balance between these two extremes. PMID- 22916535 TI - Acronyms of dying versus patient autonomy. AB - In medical practice in Germany and several other countries abbreviated orders linked to end-of-life decisions, such as DNR (do not resuscitate), are increasingly used. In order to investigate their legal status, this article gives an overview of the recently passed German law, which regulates the process of end of-life decision-making and the use of living wills, giving primacy to patient autonomy. Concerning the risk of misinterpretation of acronyms, the article describes the impacts of such orders on patient autonomy and safety and suggests a clear systematic classification of the different DNR orders in order to investigate their legal status under the German law. Their general binding force is to be acknowledged, depending on its origination and the fulfilment of certain requirements. PMID- 22916536 TI - ECHR 2012/8 Case of Stanev v. Bulgaria, 17 January 2012, no. 36760/06 (Grand Chamber). PMID- 22916537 TI - ECHR 2012/9 Case of Biziuk v. Poland (No. 2), 17 January 2012, no. 24580/06 (Fourth Section). PMID- 22916538 TI - ECHR 2012/10 Case of D.D. v. Lithuania, 14 February 2012, no. 13469/06 (Second Section). PMID- 22916539 TI - ECJ 2012/4, Centre hospitalier universitaire de Besancon v. Thomas Dutrueux and Caisse primaire d'assurance maladie du Jura, Judgement of 21 December (C-495/10). PMID- 22916540 TI - Promoting youth sexual and reproductive health in Africa: the need for a paradigm shift. PMID- 22916541 TI - Youth and HIV/AIDS in Africa: a call for effective policies and programs. PMID- 22916542 TI - HIV prevention for rural youth in Nigeria: background overview. AB - The negative impact of the HIV/AIDS epidemic has been a major challenge to sub Saharan Africa. Although the rate of new HIV infections in sub-continent has decreased, the total number of people living with HIV continues to rise. Most of the people infected with HIV/AIDS in sub-Saharan Africa are within the age bracket of 15 to 35 years. It has been estimated that about 80% of the infected group are aged 20-29 years. It is against the background of the challenges posed by HIV/AIDS to young people that the Canadian-Nigerian partnership Action Research on HIV Prevention for Rural Youth was conceived. This paper provides the background to the outcomes reported in this special edition of this journal by reviewing the HIV/AIDS situation in sub-Saharan Africa and the nature of the associated response; discussing the rationale for the Action Research which focuses on Nigeria; and outlining the key components of the research. PMID- 22916543 TI - Bridging theory and practice in HIV prevention for rural youth, Nigeria. AB - Thirty years into combating the spread of HIV through behaviour change interventions experience has grown in the application of multiple approaches from one-for-one counseling and small group workshops, information sessions, and activities to large-scale rallies and mass media campaigns with reducing the spread of HIV. These approaches have been variously guided by best field practice and theoretical frameworks developed to understand health-related behaviours and behaviour change. This article reviews the dominant theoretical approaches used to develop behaviour change interventions and strategies and presents the theoretical frameworks guiding the multi-level strategy to reduce youth vulnerability in Edo State, Nigeria known as HIV Prevention for Rural Youth (HP4RY). HP4RY is set within the multi-level Ecological Framework and specifically uses Sexual Scripting Theory and the AIDS Competent Community theoretical framework to guide an Action Research project that uses research to enhance the Family Life and HIV Education (FLHE) programme delivered in Junior Secondary Schools and a Community Mobilization programme led by members of the National Youth Service Corps. The benefits to using these theories and their fit with contemporary thinking in the field of HIV prevention through behaviour change are reviewed here. PMID- 22916544 TI - What does a decolonizing/decentralizing methodology in examining sexual lives entail? AB - This paper is based on an international study, HIV Prevention for Rural Youth (HP4RY) 2008-2012, designed to examine the state of, and teach about, sexual health and HIV/AIDS in Edo State, Nigeria. The paper focuses on the mixed methods used in this study, paying attention to the meaning of collaboration and participation in research in a cross-continental setting. Additionally, the paper considers the complexities of engaging in decolonizing and respectful methodological approaches in these settings. Drawing on specifics from the mixed methods and details from the relevant literature, this paper demonstrates the continued need for cross-continental decolonization and decentralized engagements, specifically when dealing with sensitive topics like sexuality and HIV/AIDS. . PMID- 22916545 TI - The use of National Youth Service Corp members to build AIDS competent communities in rural Edo State Nigeria. AB - This paper focuses on the community component of a larger action research project on HIV Prevention for Rural Youth (HP4RY), funded by the Global Health Research Initiative (Canada). It began with ethnographic research in 10 communities selected using geographic representative sampling and random assignment to one of three research arms. Using the AIDS Competent Community (ACC) model developed by Catherine Campbell, the ethnographic research identified factors in six domains that contributed to youth vulnerability to HIV infection. This was followed by recruitment, training and deployment of three overlapping cohorts of young adults (n = 40) serving in Nigeria's National Youth Service Corp (NYSC), to mobilize youth and adults in the communities to increase communities' AIDS competence over a nearly 2 year period. Monthly reports of these Corpers, observations of a Field Coordinator, and community feedback supported the conclusion that communities moved towards greater AIDS competence and reduction in youth vulnerability to HIV infection. PMID- 22916546 TI - Empowering teachers to change youth practices: evaluating teacher delivery and responses to the FLHE programme in Edo State, Nigeria. AB - School-based programming is one of the most common approaches to HIV/AIDS prevention among youth. This paper presents the history and development of the Family Life and HIV Education (FLHE) programme in Edo State, Nigeria and results of evaluation of teacher actions and responses to training in its delivery. Results indicate that teachers benefited from the training, were aware of new and/or existing teaching resources and began to teach about HIV/AIDS. Teachers expressed that the programme facilitated open dialogue about HIV/AIDS. However, given limited human resources, FLHE was viewed as additional work to already overloaded teaching schedules. It is recommended that the Ministry of Education channel resources to enhance teachers' efforts towards combating HIV/AIDS. To facilitate learning about sexual health and family life, it is recommended that FLHE-based training be viewed as the first rather than the only step towards teacher professional development in this area. PMID- 22916547 TI - Evaluation of school- and community-based HIV prevention interventions with junior secondary school students in Edo State, Nigeria. AB - This study examined the impact of two interventions delivered in rural communities and schools in Edo State, Nigeria designed to decrease youth vulnerability to HIV infection. The Ministry of Education approved Family Life and HIV Education (FLHE) programme delivered in Junior Secondary Schools and a community-based initiative to raise AIDS Competency of rural communities were evaluated using a clustered randomized control trial and mixed qualitative quantitative methods. Ten schools were assigned to each of three research arms: FLHE programme only, FLHE and community programme, and control. Results demonstrated positive effects on rejection of myths, attitudes related to abstinence and use of condoms, and sexual activity. Confidence in these results is supported by both levels of statistical significance and consistency in patterns of results across different levels of schooling. Results support expansion of delivery of the FLHE programme and development of community-based initiatives as effective methods of reducing youth vulnerability to HIV infection. PMID- 22916548 TI - Meeting the challenges of North-South collaboration: the case of HIV prevention for rural youth, Edo State, Nigeria. AB - Despite the significant contributions of the various North-South research partnerships during the past five decades to enhancing research capacity in the South, they have faced a number of challenges associated with the various partnerships. There have been limited attempts to critically examine the successes and challenges associated with these partnerships. Based on the experiences of implementing the 'HIV Prevention for Rural Youth' programme by a Canadian-Nigerian partnership during a four year period, this paper outlines the successes achieved and the challenges faced. The paper reviews the context of contemporary North-South research collaboration which provided the framework for the implementation of the HIV Prevention for Rural Youth. It then examines the benefits which the implementation of the programme have stimulated as well as the various challenges which confronted the partnership and how they were handled. The implications of the project's implementation experiences for future North South collaborative research programmes are highlighted. PMID- 22916549 TI - Influences of family structure dynamics on sexual debut in Africa: implications for research, practice and policies in reproductive health and social development. AB - There is no research on the timing, sequencing and number of changes in family environment and their influences on sexual and reproductive health outcomes in Africa. Using a population-based survey with data on family structure at three points in the life course, this paper examines the influences of these family structure dynamics on the timing of first sex among unmarried males and females aged 12-24 years in Cameroon. The number and timing of family transitions significantly impacted the timing of sexual debut for both males and females. The median age at first sex (18.7 years) is higher among young people without family transition than among those with one transition (18.2 years) or two transitions (17.7 years). Family transitions occurring during childhood were significantly associated with premature sexual initiation for females but not for males. Reproductive health and social development interventions for young people in Africa should integrate the changing contexts and transitions in family structure. PMID- 22916550 TI - Association between age at first sexual relation and some indicators of sexual behaviour among adolescents. AB - This study explores the relationship between age at first sexual intercourse and four indicators of sexual behaviour among adolescents aged 14 to 19 years in Burkina Faso, Malawi and Uganda. Analyses are conducted using data from National Surveys of Adolescents, organized in 2004. Multivariate analyses are performed using dichotomous logistic regression and ordered polychotomic logistic regression. Analyses show that initiation of sexual activity before age 14 is more likely to be associated with having a casual sex partner. It is less likely to be associated with condom use at first sexual relation or with systematic condom use in the past 12 months. These associations vary depending on adolescents' country and gender. Delaying onset of sexuality could be a surer and safer way to protect health during adolescence. However, sexual and reproductive health programs that advocate abstinence only are likely to have few positive effects on young people. To better implement this strategy, sexual education for adolescents should be integrated. PMID- 22916551 TI - From intervention to invitation: reshaping adolescent sexual health through story telling and games. AB - The University of Chicago and the University of Ibadan in Nigeria have partnered to exchange innovative insights into the sexual and reproductive health of disadvantaged populations in Chicago and Nigeria. Youth in both Chicago and Nigeria face disproportionately high rates of mortality and morbidity due to poor sexual and reproductive health. Traditional models have fallen short of the needs of these youth, so the University of Chicago is seeking to reframe and retool adolescent sexual health education. Game Changer Chicago is an initiative that incorporates digital storytelling, new media, and game design to conduct workshops with youth around issues of sexuality and emotional health. Based on the success of storytelling and digital media programs in Nigeria and the success of Game Changer Chicago, we believe this model holds promise for implementation in Nigeria and other sub-Saharan countries PMID- 22916552 TI - Application of information and communication technology for scaling up youth sexual and reproductive health. AB - The pervasive presence of the internet and the commonality of mobile devices for communication technology have changed modalities for information exchange. Recent developments in information and communication technology (ICT) have specific implications regarding dissemination of information among youth, as exemplified by the Arab spring. The opportunity of those emerging technologies should be seized upon. ICT platforms should be used to scale-up policies and programmes that promote the sexual and reproductive health of youth due to their low cost, increased access to remote populations, better efficiency and improved flexibility for programming. Successful models should be identified through programme evaluation. PMID- 22916553 TI - Online sexual activities and sexual risk-taking among adolescents and young adults in Lagos Metropolis, Nigeria. AB - As internet penetration surges in different parts of the world, access to a wide range of subject matters also increases. Matters of sexuality are no exceptions. While there is ample empirical evidence that youths seek knowledge about sexuality, and get involved in sexually stimulating and/or gratifying activities on the internet, the relationship between involvement in these online sexual activities (OSAs) and real life sexual behaviour remains a matter of polemic. Modelling theorists contend that exposure to sexuality related information propel acting out such information. Catharsis on the other hand holds the view that exposure to such information serves as safety valves for the peaceful release of imperfectly sublimated antisocial sexual drives. Using data gathered from adolescent internet users involved in OSAs as well as those not involved within the city of Lagos, this study concludes that OSA is associated with involvement in risk-bearing sexual behaviours. PMID- 22916554 TI - Opportunities and limitations for using new media and mobile phones to expand access to sexual and reproductive health information and services for adolescent girls and young women in six Nigerian states. AB - Reproductive health problems are a challenge affecting young people in Nigeria. Education as a Vaccine (EVA) implements the My Question and Answer Service, using mobile phones to provide sexual and reproductive health (SRH) information and services. Use of the service by adolescent girls and young women is low. Focus group discussions were held with 726 females to assess their access to mobile phones, as well as the barriers and limitations to the use of their phones to seek SRH information and services. Results demonstrate high mobile phone access but limited use of phones to access SRH information and services. Barriers to use of these services include cost of service for young female clients, request for socio-demographic information that could break anonymity, poor marketing and publicity, socio-cultural beliefs and expectations of young girls, individual personality and beliefs, as well as infrastructural/network quality. It is therefore recommended that these barriers be adequately addressed to increase the potential use of mobile phone for providing adolescent and young girls with SRH information and services. In addition, further initiatives and research are needed to explore the potentials of social media in meeting this need. PMID- 22916555 TI - Early marriage in Africa--trends, harmful effects and interventions. AB - This article explores the pattern of early marriage in Africa. It focuses on the sub-Saharan region as an area with the highest rates of early marriage in the world. The harmful effects of early marriage are explored in terms of impact on the health, education and economic well-being of young girls. The paper outlines a framework for analyzing global, regional and local initiatives to curb early marriage and examines the application of these interventions in sub-Saharan countries. Regional patterns are then examined and countries which have made progress in reducing age of marriage are compared to countries in which age of marriage amongst girls has reminded low. The paper concludes on the note that countries with the highest rates of early marriage are also the countries with the highest rates of poverty and highest population growth rates. The paper argues for a sub-regional strategy to address the problem of early marriage in the zone with the highest incidence. PMID- 22916556 TI - Community norms about youth condom use in Western Kenya: is transition occurring? AB - Most HIV prevention strategies for African youth have been ineffective in changing key behaviors like condom use, partly because community antagonism and structural barriers have rarely been addressed. Through qualitative research in rural Western Kenya, we sought to describe the attitudes of different segments of society towards youth condom use and to identify where transitions may be occurring. We found that about half of community members strongly opposed youth condom use, with many advocating punishment such as beatings and expulsion. Our research revealed significant differences in attitudes by gender, with females generally more opposed to youth condom use. Health providers, teachers and male students seemed to be transitioning to more permissive attitudes. They also had more accurate knowledge about the condom. Building on these transitional views, we would recommend that schools eliminate sanctions for students found with condoms and that clinics discourage providers from interrogating youths about their reasons for wanting condoms. Furthermore, we believe that health campaigns should portray condoms as "disaster preparedness" devices for responsible youths, and more efforts should be made to dispel myths about condoms' efficacy. PMID- 22916558 TI - Promoting healthy timing and spacing of pregnancy with young married women in Northern Nigeria: a short report. AB - The persistence of early and closely spaced pregnancies in Northern Nigeria contributes to maternal and child morbidity and mortality. A technical working group to WHO recommended that following a birth, a woman should space her next pregnancy by at least 24 months, and following a miscarriage or abortion, a woman space her next pregnancy by at least six months. UNICEF, UNFPA and WHO also recommend that a woman delay her first pregnancy until 18. These recommendations comprise the concept of Healthy Timing and Spacing of Pregnancy. The Extending Service Delivery Project (ESD) partnered with the Federation of Muslim Women Association of Nigeria and religious leaders to educate communities about the benefits of using family planning to practice HTSP in five local government areas. Informal discussions with 148 women and 28 men found high recall of the HTSP recommendations and favorable attitudes toward spacing and family planning although many remain concerned about the side effects of contraceptive methods. PMID- 22916557 TI - Reproductive health characteristics of young Malawian women seeking post-abortion care. AB - Abortion is illegal in Malawi except when the pregnancy endangers the mother's life, yet complications of abortion account for the majority of admissions to gynecological wards. This study collected data on all post-abortion care (PAC) cases reporting to all PAC-providing health facilities in Malawi over a 30-day period. Of a total of 2,028 PAC clients, 20.9% were adolescents (age 10-19) and 29.6% were young adults (age 20-24). More than half of adolescents and almost 80% of young adults were married. Less than 5% of adolescents and 22.5% of young adults reported using contraception when they became pregnant. Being unmarried was associated with previous abortion and contraceptive use among young adults. These statistics indicate a high proportion of unwanted pregnancy and lack of access to modern contraception among young women. Programs to increase access to pregnancy prevention services and protect young women from unsafe abortions are greatly needed. PMID- 22916559 TI - Perceptions of deaf youth about their vulnerability to sexual and reproductive health problems in Masvingo District, Zimbabwe. AB - This article examined the perceptions of deaf youth about their vulnerability to sexual and reproductive health problems in Masvingo District of Zimbabwe. A quasi survey was employed to carry out the field study. Therefore, a snowball sampling procedure was used to identify the respondents mainly because the target population constitutes one of the hard-to-reach groups. A sample of 50 deaf youth aged between 15 - 24 years was conveniently determined due to lack of comprehensive data of deaf population in the study area. Therefore, conclusions made in data analysis only referenced to the sampled population. Fifty questionnaires were administered among the deaf youth to collect quantitative data. Ten in-depth face-to-face interviews were carried out with deaf youth in order to qualify the magnitude of perceptions of deaf youth about their vulnerability to sexual and reproductive health problems. Sexual activity is taking place among the sampled deaf. The perceptions they had about vulnerability to sexual and reproductive health problems are mainly shaped by sexual socialization than their sensory conditions. Understanding the factors which influence the perceptions of deaf youth about sexual and reproductive health problems is significant mainly because the sexuality of people living with disabilities is poorly understood and neglected thereby putting them at risk of sexual and reproductive health problems as well as exposed to sexual violence. The study recommends that the government may adopt a human-rights approach to the provision of sexual and reproductive health services to ensure universal access information and inclusivity. PMID- 22916560 TI - Assessment of service availability and health care workers' opinions about young women's sexual and reproductive health in Soweto, South Africa. AB - Young women in South Africa experience high HIV and unintended pregnancy rates. Health care workers' (HCWs') opinions about sexual and reproductive health (SRH) issues impact young women's ability to access SRH services. We explored HCW opinions through interviews with a purposive sample of 29 HCWs in three primary health clinics in Soweto, South Africa and examined service availability through facility assessments. Most HCWs believed young women should not have sex before marriage and thought that young women ignore information they receive about HIV and pregnancy prevention. HCWs acknowledged outside factors influencing young women's ability to protect themselves. Most thought injectables were the most appropriate contraception for young women; all recognized the importance of condoms for dual protection. Some services were only reported to be provided to those over 18 years. HCWs may benefit from workshops providing technical and policy information and values clarification exercises highlighting the impact of opinions on service provision. PMID- 22916561 TI - [Regulation of innate immune responses by nucleic acid analogues]. AB - The activation of innate immune responses by nucleic acids is critical to host responses against pathogens, such as viruses; however, nucleic acids can also trigger the development and/or exacerbation of pathogenic responses such as autoimmunity. We previously demonstrated that the selective activation of nucleic acid-sensing cytosolic and Toll-like receptors is contingent on the promiscuous sensing of nucleic acids by high-mobility group box proteins (HMGBs). Basides these findings, we also found that nonimmunogenic nucleotide with high-affinity HMGB binding, termed ISM ODN, functions as suppressing agent for nucleic acid activated innate immune responses. In this review, we aim to summerize this novel feature of HMGB proteins in nucleic acid-mediated innate immune responses. In addition, we will discuss the inhibitory effect of nonimmunogenic oligodeoxynucleotides (ni-ODNs) targeting HMGB proteins. PMID- 22916562 TI - [Innate immune response to RNA virus infection]. AB - Viral RNA is recognized by RIG-I-like receptors and Toll-like receptors. RIG-I is a cytoplasmic viral RNA sensor. High Mobility Group Box (HMGB) proteins and DExD/H box RNA helicases, such as DDX3 and 60, associate with viral RNA. Those proteins promotes the RIG-I binding to viral RNA. RIG-I triggers the signal via IPS-1 adaptor molecule to induce type I IFN. RIG-I harbors Lys63-linked polyubiquitination by Riplet and TRIM25 ubiquitin ligases. The polyubiquitination is essential for RIG-I-mediated signaling. Toll-like receptors are located in endosome. TLR3 recognizes viral double-stranded RNA, and TLR7 and 8 recognize single-strand RNA. Virus has the ability to suppress these innate immune response. For example, to inhibit RIG-I-mediated signaling, HCV core protein suppresses the function of DDX3. In addition, HCV NS3-4A protein cleaves IPS-1 to inhibit the signal. Molecular mechanism of how viral RNA is recognized by innate immune system will make great progress on our understanding of how virus escapes from host immune system. PMID- 22916563 TI - [Chronic active Epstein-Barr virus infection]. AB - The ubiquitous Epstein-Barr virus (EBV), which establishes latency after primary infection, does not cause any symptomatic diseases as long as cellular immunity is intact. In apparently immunocompetent individuals, a chronic infection can develop, and this has been called as chronic active EBV infection (CAEBV). CAEBV is characterized by chronic or recurrent infectious mononucleosis-like symptoms, such as fever, extensive lymphadenopathy, and, hepatosplenomegaly. This disease is rare but severe with high morbidity and mortality. Recently, its pathophysiology is not an infection but a clonal expansion of EBV-infected T or natural killer NK cells. In this review, I discuss our current understanding of the pathogenesis of CAEBV and summarize its clinical features, therapies, and prognosis. PMID- 22916564 TI - [HTLV research 30th year]. AB - This year is 30th year since HTLV was first reported as a causative agent for ATL. From a series of extensive studies especially by Japanese researches, a variety of information is now available, such as characteristics of the virus, regulation of viral and/or cell gene expression by HTLV-encoded protein Tax and Rex, the pathway of activation machinery on cell growth, the mechanism of cell-to cell transmission, and prevalence of HTLV carries. However, it remains unsolved how HIV-1 invades and enters into human, how HIV-1 replicates in vivo, how the tumor cells are selected during course of infection, and which cellular molecules contribute disease onset and progression. It was thought the mechanism of HTLV related diseases, ATL and HAM, would be quickly revealed earlier time after HTLV discovery since the HTLV-related diseases show unique characteristics. Nevertheless, we do not have yet satisfied knowledge of the pathogenesis mechanism as well as the treatment. I describe the history and perspective. PMID- 22916565 TI - [Early steps of picornavirus infection]. AB - Picornaviridae is a large family of viruses that cause a variety of infectious diseases in humans and animals. It includes important viruses such as poliovirus, hepatisis A virus and foot and mouth disease virus. Early steps of infection play important roles in determining the host range and the target organs for each virus. Here, I review the recent advances in the studies of cellular receptors for picornaviruses, mechanisms of cell entry and viral uncoating. PMID- 22916566 TI - [Calicivirus]. AB - Caliciviruses represented by norovirus and sapovirus exist not only in human but also in other animal species. Clinical manifestations are gastroenteritis, respiratory infections, vesicles and hemorrhagic skin diseases and others symptoms depended on the viruses. Inapparent symptom of calicivirus infection is also recognized. Calicivirus is stable in the environment and found sometimes in contaminated food or water sources. In addition to intragenomic mutation, intragenomic recombination is the common phenomenon that usually found in calicivirus genome. The genomic recombinations have been reported among the strains within the same animal species. For diagnosis and molecular epidemiological study, several laboratory methods are available, such as genetic molecular analysis, enzyme immunoassay and immunochromatography, which developed by using the antibody against virus-like particles. The reactivity between virus and host immunity is type specific and the titer of cross reaction is not so high. There are evidences that the new variant strains are emerged and spread quickly year by year. Histo-blood group antigen (HBGA) is one of the specific host cells receptor for calicivirus. Infectivity of the virus depends on specificity of the HBGA on the host cells. Because of the inability to culture human norovirus and sapovirus, pathogenesis and immunological data are limited. So far, only feline calicivirus and mouse norovirus are cultivable. Animal model studies for calicivirus by gnotobiotic pigs with human calicivirus and mouse with mouse norovirus are mainly used for experiments of pathobiological study, treatment and vaccine development. PMID- 22916567 TI - [Coronaviruses]. AB - Coronaviruses contain positive-stranded RNA with ca. 30 kb as a genome, which is wrapped by the envelope, and constitute Nidovirales together with Arteriviridae. The feature of viruses in Nidovirales is the unique structure of the mRNA set, called 3' co-terminal nested set. Coronaviruses have several to more than 10 different species of subgenomic mRNA and generally only the OFR located in the 5' end of each mRNA is translated. The 5' 20 kb of the coronavirus genome or mRNA-1 consists of two ORFs, 1a and 1b, between that there is a unique RNA structure called pseudoknot. From mRNA-1, 1a as well as 1a+1b are translated; the latter 1a+1b results from the translation due to ribosomal frame-shifting facilitated by the pseudoknot structure. From those two proteins, totally 16 proteins are produced as a result of auto-cleavage by the proteases included in la protein. Those proteins exhibit different functions, such as RNA-dependent RNA polymerase, helicase, proteases and proteins that regulate cellular functions, mRNAs smaller than mRNA-2 translate in general the structural proteins, nucleocapsid (N) protein, spike (S) protein, integrated membrane (M) protein and envelope (E) proteins. Those proteins assemble to the vesicles located from ER to Golgi (ER Golgi intermediate compartment) and virions bud into the vesicles. Those virions are released from infected cells via exocytosis. PMID- 22916568 TI - [Virology of the family Togaviridae]. AB - Many pathogens important for medicine, veterinary medicine or public health belong to the genera alphavirus and rubivirus within the family Togaviridae. 29 species of alphaviruses have been reported, and most of them are arboviruses. Chikungnya virus re-emerged in Kenya in 2004 and the epidemics spread to the Indian Ocean islands and many countries in South Asia, South-East Asia and Europe. On the other hand, rubella virus, a sole member of the genus rubivirus, is the causative agent of rubella and congenital rubella syndrome (CRS). Because human is only a natural host of the virus and effective live attenuated vaccines are available, immunization activities are strengthened globally to eliminate rubella and CRS, together with measles. PMID- 22916569 TI - [Flaviviruses]. AB - Family Flaviviridae genus flavivirus contains numerous pathogenic viruses such as Japanese encephalitis virus, dengue virus, West Nile virus, etc, which cause public health problems in the world. Since many mammals and birds can act as amplifying hosts and reservoir hosts in nature and those viruses are transmitted by haematophagous mosquitoes or ticks, those viruses could not be eradicated from the nature. In the recent few decades, the viral replication mechanism and the ultrastructure of viral proteins as well as the viral immune evasion mechanism have been elucidated extensively, leading to develop novel types of antivirals and vaccines. In this review, the flavivirus nature and epidemiology, replication mechanism, immune response and immune evasion, and antivirals and vaccines against flaviviruses were described. PMID- 22916570 TI - [Pestivirus]. AB - Members of the genus Pestivirus, are causative agents of economically important diseases for livestock and wild animals that occur worldwide, such as bovine viral diarrhea, classical swine fever, and border disease of sheep. Pestivirus have novel insertions of host genes in the viral genome and functions of unique viral proteins, N(pro) and E(rns), related to the pathogenicity although genomic structure is closely related to the other viruses of Flaviviridae family, especially hepatitis C virus. In this review, recent studies on the molecular basis of pathogenicity of pestivirus infections were summarized. PMID- 22916571 TI - [Two different receptors for wild type measles virus]. AB - Measles is a highly contagious acute viral disease characterized by a maculopapular rash. It causes severe and temporary immune suppression and is often accompanied by secondary bacterial infections. In 2000, signaling lymphocyte activation molecule (SLAM) was identified as a receptor for measles virus (MV). Observations that SLAM is expressed on cells of the immune system provided a good explanation for the lymphotropic and immunosuppressive nature of MV. However, molecular mechanisms of highly contagious nature of MV have remained unclear. Previously we have demonstrated that MV has an intrinsic ability to infect polarized epithelial cells by using a receptor other than SLAM. Recently, nectin4, a cellular adhesion junction molecule, was identified as the epithelial cell receptor for MV. Understanding the molecular mechanisms of MV to infect both epithelial and immune cells provides a deep insight into measles pathogenesis. PMID- 22916572 TI - The structure of the American Nurses Association and how New Jersey State Nurses Association relates to it. PMID- 22916573 TI - Creating the professional nurses association for the future. PMID- 22916574 TI - Congress on Policy and Practice (COPP). PMID- 22916575 TI - RWJUH--New Brunswick wins quality award. PMID- 22916576 TI - Meet assemblywoman Munoz: a nurse in the state house. Interview by Suzanne Drake. PMID- 22916578 TI - End of life: policy, practice and pedagogy presented. PMID- 22916577 TI - Examining the concept of resilience. PMID- 22916579 TI - GPs' vital role in end of life care. PMID- 22916580 TI - Prompt treatment of acne improves quality of life. AB - Acne vulgaris is an inflammatory disorder of the pilosebaceous (hair follicle) units. It may be exacerbated by stress, topical greasy preparations that encourage blockage of the pores, trauma and humid climates. Certain medications may induce or exacerbate acne, including some oral and implanted contraceptives, and anabolic steroids. Occasionally, 'normal' acne can dramatically deteriorate: this may be due to a Gram-negative folliculitis superimposed on acne being treated with long-term antibiotics, or the development of one of the much more severe, destructive and aggressively scarring forms. Disfigurement from inflammation, pigmentation changes and scarring often causes embarrassment, and not infrequently undermines confidence and lowers self-esteem. Acne can also potentially induce much more serious psychological distress. It may take up to four to six months before the full benefit of treatment is apparent. Patients should be referred to a dermatologist if they: have a very severe variant; severe social or psychological problems; are at risk of scarring; have failed to respond to treatment or are suspected of having an underlying endocrinological cause. PMID- 22916581 TI - Identifying heritable connective tissue disorders in childhood. AB - Heritable connective tissue diseases are rare. Each disorder estimated at 1-10 per 100,000. However, as a group they are prevalent enough to constitute an important diagnostic challenge. Connective tissue disorders most significantly affect three systems: musculoskeletal, ocular and cardiovascular. The cardinal feature of the majority of these disorders is ligamentous laxity, or joint hypermobility. The joints show an increased range of movement, and the child may present with arthralgias, effusions and an increased risk of joint or soft tissue injury. Marfan syndrome is the most common heritable connective tissue disorder. It is an autosomal dominant condition with high penetrance but with striking pleiomorphism. In 25% of individuals there is no family history. The diagnosis is often not made until late childhood. Individuals are tall with a low upper: lower segment ratio and an arm span greater than height. Other skeletal characteristics include pectus deformity and scoliosis. Myopia and astigmatism are common. Cardiac abnormalities include mitral valve prolapse, mitral regurgitation and arrhythmias. Early diagnosis, meticulous echocardiographic follow-up and multidisciplinary assessment are essential. The Ehlers-Danlos syndromes share a triad of features: skin hyperextensibility, articular hypermobility, and tissue fragility. The abnormalities are caused by genetic defects resulting in the faulty synthesis or structure of collagen. There is a wide variety of phenotypes and mode of inheritance. Symptom management and joint protection are important to improve quality of life and prevent secondary complications. Osteogenesis imperfecta encompasses a group of rare heritable disorders associated with low bone mass and increased susceptibility to fractures. Increased bone fractures after minimal trauma is the cardinal feature. Other features include blue sclera, hearing loss, scoliosis, deafness, and hypermobility. PMID- 22916582 TI - Recent developments in the management of heart failure. AB - The typical presentation of heart failure in primary care is insidious, with progressive breathlessness on exertion, ankle swelling, orthopnoea or paroxysmal nocturnal dyspnoea. Not all patients will have all these symptoms, and in many patients there may be other causes. If a GP suspects heart failure, then the key blood test is B-type natriuretic peptide (BNP). If the BNP is normal then heart failure is unlikely and other diagnoses should be considered. If it is raised, or if there is a past history of myocardial infarction, the patient requires further assessment, which must include echocardiography and a specialist assessment. The underlying cardiac abnormality should be identified. An ECG is often very useful and if it is completely normal it makes heart failure less likely. Both the NICE and the ESC guidance emphasise the importance of lifestyle management (regular appropriate exercise, avoiding excessive salt and alcohol consumption). ACE inhibitors (or angiotensin receptor blockers) and beta-blockers licensed for heart failure (carvedilol, bisoprolol, nebivolol) remain the mainstay of treatment in addition to as small a dose of diuretic as possible to control any fluid retention. Aldosterone antagonism is recommended by the 2012 ESC guidance for all patients who remain symptomatic despite an ACE inhibitor and beta blocker. If the rhythm is sinus but the heart rate is 75 beats per minute, therapy needs to be optimised, perhaps by increasing the beta-blocker dose, if possible, or by the addition of ivabradine. PMID- 22916583 TI - Annular lesions. PMID- 22916584 TI - Epidemic gastro-enteritis. 1912. PMID- 22916585 TI - Lessons from DIY training for general practice. PMID- 22916586 TI - [AIDS diagnosis at a glance: 3 pathognomic opportunists in one glance]. PMID- 22916587 TI - [The magic word in AIDS research: "cure research". The keen hope for healing]. PMID- 22916588 TI - [While HIV-induced mortality decreases, cancer deaths on the rise: keeping an eye on taboo zones]. PMID- 22916589 TI - [AIDS pioneers remember: an affliction caused helplessness and hostility: in the pit of hell 30 years ago]. PMID- 22916590 TI - [Trends in research and clinical care: what will the future HIV therapy look like?]. PMID- 22916591 TI - [The ageing HIV-patient: what to do with comorbidities?]. PMID- 22916592 TI - [Fixed dose combinations and single tablet regimen for HIV therapy]. PMID- 22916593 TI - [HIV-infection and pregnancy: what is the best form of delivery?]. PMID- 22916594 TI - [HIV in elderly]. PMID- 22916595 TI - [Metabolic syndrome and cardiovascular diseases in HIV patients]. PMID- 22916596 TI - [Goal: a long-term successful HIV therapy. Nevirapine as sustained-release tablet offers good prospects]. PMID- 22916597 TI - [Management of dyslipidemia in HIV-infected patients]. PMID- 22916598 TI - [Osteoporosis, vitamin D deficiency and renale failure]. PMID- 22916599 TI - [The pillars of modern HIV therapy: effectiveness, tolerance, compatibility]. PMID- 22916600 TI - [CROI 2012: updates on raltegravir]. PMID- 22916601 TI - [Treatment of chronic hepatitis C in HIV coinfection]. PMID- 22916602 TI - [Case report: painful peripheral neuropathy in HIV-patient]. PMID- 22916603 TI - [HIV therapy of the next generation. Modern active drugs for long-term treatment]. PMID- 22916604 TI - [Kidney transplantation: consecutive one thousand transplants at National Institute of Medical Sciences and Nutrition Salvador Zubiran in Mexico City]. AB - INTRODUCTION: The National Institute of Medical Sciences and Nutrition Salvador Zubiran (INCMNSZ) is a specialty hospital for adults and a teaching hospital, which performed the first kidney transplant in 1967; in 1971 it began the formal program of renal transplantation. Recently, it was performed the kidney transplant number 1000, so this article presents the information of these thousand kidney transplants, with special emphasis on survival. MATERIAL AND METHODS: Retrospective cohort study which included 1000 consecutive transplants performed at the INCMNSZ between 1967 and June 2011. It describes the general characteristics of kidney transplant recipients, transplant-related variables, initial immunosuppression and complications. Descriptive statistics were used. The survival analysis was performed using the Kaplan-Meier method. It shows the patient survival, graft survival censored for death with functional graft and total graft survival (uncensored). RESULTS: Patient survival at 1, 3, 5, 10, 15, and 20 years was 94.9, 89.6, 86.8, 76.9, 66.1, and 62.2%, respectively. Graft survival censored for death with functional graft at 1, 3, 5, 10, 15, and 20 years was 93.1, 87.1, 83.5, 73.9, 62.7, and 52.5% respectively. Risk factors associated with poorer graft survival were younger age of the recipient, transplant during the first period (1967-1983), and a HLA mismatch. CONCLUSION: Patient and graft survival have improved over time through the use of better immunosuppression and use of induction therapy. Identification of risk factors affecting graft survival, allows each center to set their strategies to improve the patient's outcome. PMID- 22916605 TI - [Kidney transplant program at the Instituto Nacional de Cardiologia Ignacio Chavez]. AB - The first renal transplant was done on July 22, 1968 and until December, 2010 a total of 865 procedures have been performed. Immunosuppressive protocols have changing with time: from 1968 to 1984 azathioprine + prednisone plus total radiation in some cases; from 1985 to 1998 cyclosporine + azathioprine + prednisone; in 1998 tacrolimus is used for first time; Mofetil micofenolate was available at 2005 and practically has displaced to azathioprine. As far as possible we use some induction therapy. Primary ESRD etiologies were: unknown (74.9%), glomerulonephritis (9.7%) and diabetic nephropathy (4.2%). Recipient's mean age was 29.9 +/- 11.6 years (12-70) and 35 +/- 9.8 years (18-62) in donors. Analysis group for graft and patient survival included 292 transplants (censured for death with functional graft) with a follow-up of 103 months (CI 95%: 99-108). Survival at 1, 5 and 10 years were: 95, 85 and 60% for graft as well as 100, 94 and 90% for patient. In year 2000 we started to perform renal biopsies at transplant (time zero biopsies), those results have been published and at present are a worldwide reference. In September, 2005 laparoscopic donor nephrectomy is initiated, 180 procedures have been done with excellent results. In year 2006, training in renal transplant acquires the endorsement as a Medicine Posgrade recognized by the UNAM School of Medicine. We have participated in 9 national clinical trials and 6 international multicentric ones. Our renal transplant program offers a good choice for patients with low resources with similar results reported in the literature using current immunosuppressive schemes and surgical procedures. Institutional authorities and humanitarian associations support in addition to participation on investigation studies have been of vital importance. PMID- 22916606 TI - [Kidney transplant experience at the Specialty Hospital Bernardo Sepulveda National Medical Center Century XXI, Mexican Institute of Social Security]. AB - INTRODUCTION: The first kidney transplant in Mexico was done on October 22, 1963 at the General Hospital of National Medical Center (CMN) of the Mexican Institute of Social Security. After the earthquake in 1985, the transplantation activity was continued at the Specialty Hospital of National Medical Center Century XXI. Our program has a continue activity for almost 48 years and a total of 2019 kidney transplants from October 1963 to December 2010. We describe our experience in 20 years. MATERIAL AND METHODS: Retrospective cohort study that includes all kidney transplants performed in the period from January 1991 to December 2010. Descriptive statistics were used. The survival analysis was performed using the Kaplan Meier method. We show the patient survival, graft survival censored for death with functional graft and total graft survival (uncensored). RESULTS: We analyzed a total of 1544 kidney transplants. The percentage of living donor was 82.9 vs. deceased donor of 17.1%. Patient survival at 1, 5, 10, 15 and 20 years was 95.0, 91.8, 87.2, 81.1 and 70.1%, respectively; allograft survival rate censored for death with functional allograft at 1, 5, 10, 15 and 20 years was 93.0, 86.2, 76.2, 63.7 and 50.9%, respectively. Our Transplant center also take care of around 1300 living donors in the long term, looking for morbidities as risk factors for the unique kidney as metabolic syndrome, diabetes, hypertension and others. CONCLUSION: In our program, the main source of renal allografts was living donors. Our transplant center has to increase the organ procurement from deceased donors. An important contribution of our center has been the long follow up of living donors according to international consensus. PMID- 22916607 TI - [Kidney transplantation. Experience at the University Hospital Jose Gonzalez, UANL in Monterrey, Mexico]. AB - BACKGROUND: In patients with end-stage renal disease, successful renal allotransplantation improves the quality of life and increases survival as compared with long-term dialysis treatment. OBJECTIVE: To show our experience, effectiveness and results of renal transplantations at the University Hospital of UANL. MATERIAL AND METHODS: A retrospective study of renal transplantation performed at University Hospital of UANL was done. The transplant cases from 1967 to July 2001 and January 2003 to June 2011 were included. RESULTS: 280 kidney transplants were performed in 264 patients, 146 men and 118 women; 201 from deceased donor and 79 from living donor. The patient survival at 1, 3, and 5 years was 98.8, 85.9 and 85.9%, respectively. The graft survival at 1, 3, and 5 years, censored for death with functioning graft, was 98.8, 85.7 and 74.9%, respectively. CONCLUSIONS: Our results, in this population with unfavorable socioeconomic conditions, are comparable to those obtained in other institutions. PMID- 22916608 TI - [Renal transplantation program at the Centenario Hospital Miguel Hidalgo in Aguascalientes, Mexico]. AB - INTRODUCTION: Miguel Hidalgo Hospital in Aguascalientes is dependent from the Federal Secretary of Health and operates in integrity with State health system in Aguascalientes. It capacity is based on 132 censored beds and 71 no censored beds. Is considered a specialty hospital in the region of Bajio. Renal transplant program activity was initiated in 1990 and gives care for adult and pediatric population. MATERIAL AND METHODS: Retrospective, comparative and longitudinal study to describe and analyze our experience. Data base and clinical charts of renal transplant recipients were reviewed. Age, gender, date of transplant, etiology of renal disease, type of donor, HLA compatibility and PRA, immunosuppressive therapy, acute rejection, serum creatinina, graft loss and mortality were registered. Statistical analysis included 2, unpaired Student T test and Kaplan-Meier survival analysis with Log Rank test. Cox Analysis was also done. RESULTS: 1050 renal transplants were done from November 1990 to June 2011. 50 were excluded because follow-up was not longer than 3 months. 1000 consecutive renal transplant patients from January 1995 to June 2011 were included for analysis. Patients were divided in 2 groups: group A transplanted January 1995 to December 2004; group B transplanted January 2005 to June 2011. Etiology for end stage renal disease is unknown in 61% of cases, 11% developed renal disease to diabetes mellitus. 93% patient survival was observed at median follow-up and 84.9% graft survival at median follow-up (6 years). Biopsy proven acute rejection in group A 19.9 vs. 10% in group B. Two haplotype matching shows 92% graft survival. Diabetic patients exhibit 73% graft survival vs. other as hypertension (87%). PRA >0 and serum creatinine > 2.0 mg/dL increase risk for graft loss according to Cox analysis. CONCLUSION. Results are comparable to international data. Importance of developing regional transplant centers is emphasized. PMID- 22916609 TI - [Experience in kidney transplantation from 1999 to 2011 at the Hospital Central Dr. Ignacio Morones Prieto, San Luis Potosi]. AB - INTRODUCTION: In April 1991 was performed the first kidney transplant at the Hospital Central Dr. Ignacio Morones Prieto. In August 1999, formally started the kidney transplant program. OBJECTIVE: To describe the experience in kidney transplant at HCIMP. MATERIALS AND METHODS: Retrospective cohort study, which includes all kidney transplants performed during the period August 1999 to June 2011. We excluded patients whose medical record was eliminated or with incomplete data for analysis. It describes the general characteristics of kidney transplant recipients, transplant-related variables, initial immunosuppression and complications. The survival analysis was performed using the Kaplan-Meier method. The curves were compared using the log-rank test. RESULTS: From August 1999 to June 2011 were performed 517 kidney transplants at Central Hospital, of which 411 patients were analyzed. Ten years overall graft-survival was 73%. Both, the history of infection or acute rejection were associated with lower graft survival. The main cause of death, in our population, was infectious processes. CONCLUSION: Graft survival at 10 years was 73%, which is similar to that reported in the literature. A history of acute rejection and infection are factors associated with lower survival. PMID- 22916610 TI - [Kidney transplant program: Mexican Institute of Transplants. Model of synergy between private hospital and private assistance foundations]. AB - INTRODUCTION: The Mexican Institute of Transplantation (IMT) was created in 1999 in response to the need to meet the demand for transplants in the south of the country for patients with limited resources. Thanks to the synergy with private assistance foundations this task has been accomplished. OBJECTIVE: To describe the IMT experience in kidney transplants. RESULTS: From November 1999 to May 23,2011, 754 kidney transplants were performed in the IMT, of which 733 were from living donors and only 21 from deceased donors. In our experience, the 10-year patient and graft survival were 84.4 and 72.4%, respectively. The average follow up of patients was 44 months, it was during the first year after transplantation when most of patients were lost. More than 50% of patients have been supported by private assistance foundations. The IMT has participated in research protocols for phase II and phase III, for the development of new immunosuppressants. CONCLUSION: The synergy between our private medical institution and private assistance foundations has permitted to transplant low income patients, a similar association can be carried out in governmental health institutions that have overcharge in their transplant services. PMID- 22916611 TI - [Multiorgan transplantation program at the Hospital de Especialidades 71, Unidad Medica de Alta Especialidad 134, Instituto Mexicano del Seguro Social in Torreon]. AB - INTRODUCTION: This is the experience in a program of multiorgan transplant at the Hospital de Especialidades 71 in Torreon, Coahuila. It is a historical overview of the beginning and development of the transplant program. Describes the logistics of the study of patients for transplantation and the test to be carried out in the laboratory of histocompatibility. MATERIALS AND METHODS: We analyzed the records of the patients were transplanted in the period from January 1987 until June 2011. RESULTS: We found 2538 in total, of which 1940 were renal (76.4%). The 53% were male and 47% female. Average age of 37 +/- 15 years. The 82% was adult population and 18% pediatric. The most frequent cause of CRF was the chronic glomerulonephritis and 15% of the patients are diabetic. 73.5% were living donor and 26.5% were deceased donor. 7% of recipients of living donor have domino transplants. The incidence of acute rejection was 7.5%. 15% of the patients had infections and 60% was urinary. The immunosuppressive scheme most widely used is tacrolimus + mycophenolate mofetil + prednisone. The overall survival of the patient was 100, 90 and 87% to the first, third and fifth year after the transplant. The overall survival of the graft was 98, 87 and 83% in the first, third and fifth years post-transplant. CONCLUSIONS: It has been developed a multiple organ transplant program in Torreon that currently is one of the most important in Mexico with similar results to those obtained at the international level. PMID- 22916612 TI - [Pediatric liver transplant program at Hospital Infantil de Mexico Federico Gomez]. AB - This article reports the experience of the largest pediatric liver transplant (LT) program in Mexico. Between June 1998 and May 2011, 76 LT were performed in 74 recipients, including 80% cadaveric-whole organ grafts and 20% segmental grafts, 12% of those coming from live donors and 8% from cadaver reduced donors. The most common indication for LT was biliary atresia (43%), followed by metabolic disorders (13%) and fulminant hepatitis (12%). Most of the recipients were infants or toddlers weighing <15 kg (age range 0.7-17.2 years, weight range 6.5-66 kg), 73% had moderate to severe malnutrition and 72% had multiples surgeries previous to LT. There were 9 cases of hepatic artery thrombosis (11.8%) and 2 portal vein thrombosis (2.6%), however, 8 of these 10 grafts were rescued with early thrombectomy and reanastomosis. All biliary complications (19 cases, 25%) were solved with medical or surgical interventions and did not cause any graft loss. Acute cellular rejection (30 cases, 39%) required thymoglobulin in only 3 cases and chronic rejection (4 cases, 5%) has been retransplanted in 2 cases. CMV infection or reactivation occurred in 30% of cases and easily responded to preemptive therapy. Nine recipients developed postLT neoplasias (7 post-transplant lymphoproliferative disorders, one multivisceral Kaposi sarcoma and one systemic smooth muscle tumor). Five of them responded to decreasing or discontinuing immunosuppression, and 2 are completely tolerant to the graft. The one and five-year patient survival for those LT performed during 2001-2011 was 85 and 75%. The first successful live donor LT in the country was performed in 2001 at this program, as was the first simultaneous liver-kidney transplant in a child. This is the largest and most successful pediatric LT series in the country. Our results demonstrate that pediatric LT is a feasible undertaking in Mexico, with survival rates similar to those of foreign centers. PMID- 22916613 TI - [Experience in liver transplantation (1996-2011) at the UMAE, General Hospital Gaudencio Gonzalez Garza, National Medical Center La Raza, Mexican Institute of Social Security, Mexico City, D.F]. AB - We present the experience of General Hospital CMN La Raza from 1996 to 2011. In this period, we have made 40 liver transplants in adults and 22 pediatric liver transplants. A 100% of adult population received a graft from deceased donor; while in the pediatric age group, 60% were from deceased donor and 40% from living donor. The long-term follow-up is shown only for adult group due to lack of data in the pediatric group. The mean age for the adult group is 42 years old and 4.5 years for the pediatric group. The main indications for liver transplantation in adults were: cirrhosis due to chronic hepatitis C in 47.5% and cirrhosis due to alcohol abuse in 15% of the group. In the pediatric group was more likely the biliary atresia (60%) as an indication for liver transplantation followed by fulminant hepatitis (15%). We show the evolution of the hepatectomy's technique in the adult group: it was initially using conventional technique and later it changed to preservation of cava vein (Piggy Back). In the same way, the reconstruction of the bile-duct was initially made using a T-tube stenting and currently, we use end to end bile-duct reconstruction. The patient's survival at 1, 5, and 10 years was 41.5, 27.2, and 13.6%, respectively; with a median of global survival of 6.2 months. Long-term patient's survival has improved after 2004 compared to previous period. PMID- 22916614 TI - [Liver transplant at the UMAE 25 IMSS Monterrey]. AB - BACKGROUND: Liver transplantation is the best treatment for end stage liver diseases. In April 2003, our institution started a Liver Transplantation Program for both pediatric and adults population. OBJECTIVE: Shown the results of the Liver Transplantation Program in the UMAE 25 Monterrey N.L. MATERIALS AND METHODS: This is a retrospective cohort study of patients with liver transplantation. RESULTS: A total of 51 liver transplantations have been done in 49 patients with two retrasplantation, 15 in children and 36 in adults. The principal indication for liver transplantation in children was biliary atresia and hepatitis C cirrhosis in adults. The acute renal failure was the main early complication, the acute cellular rejection in the mediate period, and the cardiovascular diseases as late complication related to obesity, metabolic syndrome, diabetes mellitus and hypertension. Overall survival at 1 and 5 years was 57.1 and 54.2%, respectively. During the first three years post transplantation, the quality of life was good or very good. CONCLUSIONS: Although still a young and perfectible program, the effort of a multidisciplinary team has made possible to perform liver transplantation in two patient populations, pediatric and adults. PMID- 22916615 TI - [Twelve years of liver transplant at the San Jose-Tec De Monterrey Hospital]. AB - BACKGROUND: Liver transplantation is the only curative alternative for patients with end stage liver disease or acute liver failure. AIM: To report the experience of a single transplant center in Mexico. MATERIAL AND METHODS: Fifty five transplants in 54 adult patients were analyzed between 1999 and 2011 in a single private institution. All grafts were obtained from deceased donor. Surgical technique, donor and recipient demographics, complications, causes of death and overall survival are described. Results were expressed as range and percentages. A Kaplan-Meier survival curve was done to analyze patient and graft survival. RESULTS: Main cause of cirrhosis was hepatitis C virus infection followed by alcohol intake. A 16% of patients developed biliary complications without graft loss, and vascular complications were observed in 15%. Patient survival at one and five years was 83% and 76%, respectively. CONCLUSIONS: Complication rates and survival in our center are comparable to those in the United States and Europe. PMID- 22916616 TI - [Orthotopic liver transplantation. Experience in the University Hospital of Monterrey, N.L]. AB - INTRODUCTION: Several programs of organ and tissues transplantation have been developed for over a decade at the University Hospital. OBJECTIVE: To describe long term complications and survival in the liver transplant program at the University Hospital, UANL. MATERIAL AND METHODS: The long term complications and survival were analyzed in the liver transplant program at the University Hospital Dr. Jose Eleuterio Gonzalez in the period between 1991 and 2011. RESULTS: Ninety six liver transplants were performed during this period, four of them received one re-transplant and one patient received 2 retransplants. Most common long term complications were metabolic 62%, bony 31% and infectious 28%. Median survival was 78 months. CONCLUSIONS: Liver transplant program at the University Hospital UANL has grown, being the most active in the state of Nuevo Leon, with 1-, 5- and 10-years survival of 66.1, 53.3 and 46.2%, respectively. PMID- 22916617 TI - [Heart transplant program at the UMAE, General Hospital Dr. Gaudencio Gonzalez Garza, of the La Raza National Medical Center]. AB - BACKGROUND: The heart transplantation has modified the life expectancy of patients with terminal heart failure. OBJECTIVE: To present our experience in heart transplantation. MATERIAL AND METHODS: A retrospective cohort study was realized for heart transplant recipients between July 21, 1988 and May 30, 2011. We evaluated the procedure for evaluation and selection of heart donors and heart transplant recipients. Also we reviewed etiology of cardiomiopathy, age and gender of patients, surgical procedure, and postoperative evolution, immediate and long-term survival. RESULTS: Of all 233 heart transplants performed in Mexico, 64 were done in our hospital. Seven cases were excluded due to incomplete information. We present 57 heart transplantation performed in 56 patients (one retransplantation): 27 cases with dilated cardiomiopathy (47.35%), 23 with ischemic cardiomiopathy (40.35%), four patients with terminal heart valve disease (7.0%), two with restrictive cardiomiopathy (3.5%) and one retransplantation (1.8%). Forty-six male patients (82.1%), and 10 female cases (17.9%). The mean age was 40.9 +/- 15.6 years-old (8-66 years-old). In 22 years the immediate mortality was 30.3% and the main cause was primary graft failure. The longest survival has been 10 years. All survival recipients are in functional class I. CONCLUSION: It was concluded that heart transplantation is a feasible surgical option in our country for terminal heart disease. PMID- 22916618 TI - [Heart transplant in Monterrey, Nuevo Leon]. AB - Heart failure constantly increases its incidence and prevalence in our society, it was imperative to start a heart transplant program to improve the survival rates of patients with end stages of the disease. Legal issues made impossible to transplant patients out of Mexico City until recent years. Even with an acute hemodynamic and clinic improvement after the transplant, these patients frequently develop complications such as graft rejection or opportunistic infections due to the immunosuppressive schemes increasing the morbidity and mortality of the procedure. In the present article we report the experience acquired with 65 heart transplant patients from 4 transplant programs in Monterrey, Nuevo Leon, one of them from the socialized system and the other three from private hospitals. Our program not only has successfully transplanted patients with advanced age but, for the first time in Latin America we have transplanted patients assisted with the ambulatory Thoratec TLC II system. Even that we have faced obstacles like a newly started donation culture in our population and limited resources, our patient's survival rate push us to continue working with these very ill population. PMID- 22916619 TI - [Living-donor intestinal transplantation. First report in Latin-American]. AB - INTRODUCTION: Intestinal transplants as opposed to total parenteral nutrition is more physiological alternative to long term in patients with irreversible intestinal failure. According to the Intestinal Transplant Registry and the Organ Transplant Network there are 32 living-donor and 957 cadaveric-donor intestinal transplants worldwide. In Latin America there are no reports on this subject. We present the first successful case of intestinal transplantation from living donor in Latin America. CASE REPORT: Male patient, 20 years old, with short bowel, secondary to fire gun injuries that irreversibly affected mesenteric circulation so it was necessary to completely remove the small intestine, right and transverse colon. The patient needed ambulatory total parenteral nutrition and had hepatic failure related to it. The 44-year-old father of the patient was the intestinal living donor. Cold ischemia time was 16 min and warm ischemia time of 47 min. Immunosuppression was based on thymoglobulin, methylprednisolone, tacrolimus and mycophenolic acid. One month after the transplantation, the patient is well and the intestinal graft has adequate and functioning state, without evidence of rejection. CONCLUSION: Intestinal transplantation in our country is a procedure that can be performed with good outcome and offers a unique therapeutic alternative for a patient with irreversible intestinal failure. PMID- 22916620 TI - Dental implant stability and its measurement. PMID- 22916621 TI - Dental implant stability from placement to loading. PMID- 22916622 TI - Building faculty capacity in nursing education. PMID- 22916623 TI - What nurse educators can do to save patient safety from falling through the cracks. PMID- 22916624 TI - Teachers as researchers: a narrative pedagogical approach to transforming a graduate family and health promotion course. AB - Scholarship of teaching in nursing is illustrated by describing the development, implementation, evaluation, and revision of a family and health promotion course for graduate family nurse practitioner students. A narrative pedagogical approach that combines conventional pedagogy with action research is used. The work, an example of curriculum as dialogue, illustrates how teachers can incorporate research, evaluation, and reflection into their daily teaching practice. Given adequate support, these evaluation and research activities could constitute part of the scholarship of teaching, and, as such, would warrant allocation of time in faculty workloads and formal acknowledgment in annual performance evaluations and promotion and tenure decisions. The importance of increasing the clinical relevance of the scholarship of teaching in a practice discipline such as nursing is also emphasized. PMID- 22916625 TI - Implementing a change to a learner-centered philosophy in a school of nursing: faculty perceptions. AB - This qualitative study explores faculty experiences with their school of nursing's change to a learner-centered teaching philosophy. The primary research goals were to determine what change conditions faculty perceived as significant and how they viewed overall faculty progress and unity in adopting the philosophy. Nine nurse faculty members from a four-year public university were interviewed and also responded to two narrative questionnaires over a period of three months. Thematic analysis revealed five categories with a total of 20 themes. Certain conditions were found to be important to the process, such as availability of time and resources. Other conditions were found to be of lesser importance, such as dissatisfaction with the status quo and participation in the decision to make the change. This study provides an in-depth understanding of how one nursing faculty group experienced the implementation of change to a learner centered philosophy. PMID- 22916626 TI - Looking is not seeing and listening is not hearing: effect of an intervention to enhance auditory skills of graduate-entry nursing students. AB - Inspection/observation and listening/auscultation are essential skills for health care providers. Given that observational and auditory skills take time to perfect, there is concern about accelerated students' ability to attain proficiency in a timely manner. This article describes the impact of music auditory training (MAT) for nursing students in an accelerated master's entry program on their competence in detecting heart, lung, and bowel sounds. During the first semester, a two-hour MAT session with focused attention on pitch, timbre, rhythm, and masking was held for the intervention group; a control group received traditional instruction only. Students in the music intervention group demonstrated significant improvement in hearing bowel, heart, and lung sounds (p < .0001). The ability to label normal and abnormal heart sounds doubled; interpretation of normal and abnormal lung sounds improved by 50 percent; and bowel sounds interpretation improved threefold, demonstrating the effect of an adult-oriented, creative, yet practical method for teaching auscultation. PMID- 22916627 TI - Evidence for teaching: what are faculty using? AB - The benefit of engaging in evidence-based teaching practice (EBTP) is to identify and implement best practices in nursing education. Unfortunately, nursing education has made little forward movement in identifying the evidence upon which faculty base their teaching practices. A national online survey of 295 nurse educators from 86 programs revealed the evidence they use in their teaching practices as well as the facilitators and barriers to EBTP. The majority of participants indicated they used quantitative and qualitative research (94 percent) but also considered written course evaluations, conference information, class feedback, and student comments as evidence. Participants identified personal beliefs as the most frequent facilitator to EBTP with 25 percent indicating their institution as a barrier. As EBTP offers a guide to establishing best practices in nursing education, building a science of nursing education is the responsibility of all nurse educators. PMID- 22916628 TI - Faculty support for ESL nursing students: action plan for success. AB - Nursing students whose first language is not English have lower retention and NCLEX-RN pass rates. This review identifies four areas of difficulty and recommends strategies that can be employed by supportive faculty to assist these students and help ensure a more diverse nursing workforce to care for our increasingly diverse patient population. PMID- 22916629 TI - Focus on retention: Identifying barriers to nurse faculty satisfaction. AB - There has been a great deal of attention focused upon the professional and faculty nursing shortage. Retirement rates of seasoned nurse faculty, fewer nurses pursuing academic roles as nursing faculty, and insufficient numbers of nurses in doctoral programs hinder the ability to educate willing students to become professional nurses. The aim of this descriptive, quantitative study in the New England region was to determine barriers to job satisfaction as reported by nurse faculty. A 32-item survey was used with questions about workload, satisfaction, and identified barriers to satisfaction. Responses from 226 nurse faculty support findings regarding factors essential to job satisfaction, including work environment and workload. Implications for the study findings include the need for attention to the complexity of the academic work environment, specifically in nursing education. PMID- 22916630 TI - Transition to the tenure track for nurse faculty with young children: a case study. AB - Recent efforts to ease the nursing shortage focus on recruiting and retaining younger faculty. The first years in a tenure-track position are especially challenging for new faculty who struggle to negotiate demands of academia along with parenting young children. These struggles may influence retention and require further exploration. A case study using qualitative content analysis was conducted on the transitioning experiences of three assistant professors of nursing, who had young children, during their first two years on tenure track at a research-intensive public university. Three main content areas emerged: adapting to the academic role, negotiating work/life demands, and benefiting from mentoring. To help ease the nurse faculty shortage, colleges and universities should strive to implement family-friendly policies and mentoring programs to retain faculty with young children. PMID- 22916631 TI - Making it meaningful: Teaching public health nursing through academic-community partnerships in a baccalaureate curriculum. AB - Because of the importance, and difficulty, of providing public health clinical experiences for baccalaureate nursing students, a small midwestern school of nursing offered students a three-year assignment to agencies serving vulnerable populations. The program allowed for long-term placement of students, instilling in them an understanding of community health as a prime aspect of nursing care. Students mentored students, which enhanced continuity in the agencies. More than 2,000 community members have been served, and students' responses have been overwhelmingly positive. PMID- 22916632 TI - Using low-fidelity simulation with sophomore nursing students in a baccalaureate nursing program. AB - Opportunities to achieve competency in the psychomotor and cognitive outcomes required of the nursing profession are limited due to shortages of clinical sites and situations. One solution is to use simulation to replicate some of the essential aspects of a clinical situation so it may be readily understood and managed when it occurs in reality. A program developed for sophomore students integrated the pharmacology, health assessment, and pathophysiology theory courses using low-fidelity simulation and computer-assisted instruction. The objectives of the program were based on Quality and Safety Education for Nurses competencies. The simulation strategies were evaluated using the Educational Practice Scale for Simulation, the Student Satisfaction and Self-Confidence in Learning questionnaire, and the Simulation Design Scale. The initial findings are encouraging for promoting active and diverse methods of learning, high and positive expectations for students, self-confidence, and collaborative team building opportunities. PMID- 22916633 TI - The transition to online teaching as experienced by nurse educators. PMID- 22916634 TI - Shaping how graduate nursing students write. PMID- 22916635 TI - The nursing educational highway in action: results of a needs assessment and the formation of a collaborative workgroup. PMID- 22916636 TI - Findings from the Annual Survey of Schools of Nursing academic year 2010-2011: NLN survey finds unremitting demand for entry into programs while student demographics continue to shift. PMID- 22916637 TI - [Adverse perinatal outcomes in Mexican women with twin pregnancy achieved by assisted reproduction techniques vs. spontaneous twin pregnancies]. AB - BACKGROUND: Twin pregnancies (TP) have shown a greater risk of adverse perinatal outcomes than singletons have. However, there is still no consensus about whether the TP achieved by assisted reproduction techniques (ART) have worse perinatal outcomes compared with TP achieved spontaneously. OBJECTIVE: Compare the incidence of adverse perinatal outcomes (preterm birth, premature rupture of membranes, gestational diabetes, pregnancy-induced hypertension, anemia, weight and destination of the newborn) in Mexican women with TP achieved spontaneously vs those with TP achieved by ART. METHODS: Historical cohort study with two sample groups: group 1, women with TP achieved spontaneously, and group 2, women with TP achieved by ART. Women with TP achieved by TRA were matched 1:1 with women with EG achieved spontaneously for age, weeks of gestation, chorionicity and body mass index at admission to prenatal care. Adverse perinatal outcomes were compared between the two groups and the odds ratio (OR) had a 95% confidence interval. RESULTS: There were 57 women per group. Baseline characteristics were similar in both groups except for nulliparity (38.6% in group 1 vs 82.5% in group 2 (p < 0.0001)). In group 2 there was a higher incidence of pregnancy-induced hypertension (group 1 (19.3%) vs. group 2 (42.1%), OR 2.5 (95% CI 1.07-5.8)). Newborns in group 2 were admitted to nursery more often than those in group 1 (49.1% vs. 35.1% OR 1.7 IC 95% 1.04-3.04). There was no difference in other adverse perinatal outcomes. CONCLUSIONS: Mexican women with TP achieved by ART had higher risk of pregnancy-induced hypertension compared to women with TP achieved spontaneously. PMID- 22916638 TI - [Insulin sensitivity in patients not responding to ovulation induction using clomiphene citrate]. AB - BACKGROUND: The role of insulin resistance (IR) of infertile patients with chronic anovulation in their therapeutic failure to clomiphene citrate (CC) is not quite clear. OBJECTIVE: Determine the sensitivity to insulin in patients with chronic anovulation and failure to the treatment with clomiphene citrate. MATERIAL AND METHODS: A cross-sectional clinical study in infertile patients with clomiphene citrate resistance and in patients with adequate response to clomiphene citrate was carried out. In all patients insulin resistance was determined by the rate of glucose/insulin, HOMA (Homestatic Model Assessment) and the insulin sensitivity test. For the inferential statistical analysis, a Student's t test for independent samples was used. RESULTS: The average total basal insulin was 19.6 +/- 8.1 microU/mL. We observed higher concentrations in the clomiphene citrate resistance group (22.1 +/- 8.9 vs. 15.8 +/- 5.1 mU/mL p = 0.07). The glucose/insulin rate was statistically minor in patients with resistance to clomiphene citrate (4.2 +/- 1.9 versus 6.9 +/- 2.1 p = 0.02), but HOMA was not significantly different in both groups (4.3 +/- 1.4 vs. 3.9 +/- 1.3 p = 0.6). The total rate of glucose disappearance (KIIT) was 4.1 +/- 1.2. However, the statistical analysis did not show significant statistical differences between the two groups. CONCLUSIONS: Our preliminary results suggest that insulin resistance can be a mechanism involved in the pharmacologic response to ovulation induction in infertile patients, but coexisting pathophysiological mechanisms such as hyperandrogenism might also account for the lack of response to clomiphene citrate. PMID- 22916639 TI - [Factors associated with gestational hypertension and preeclampsia]. AB - BACKGROUND: Hypertensive complications in pregnancy are a cause of morbidity and mortality. Previous studies have identified similarities and differences in risk factors of hypertensive complications during pregnancy. OBJECTIVE: Determine factors associated with gestational hypertension (HTG) and those related to preeclampsia (PEE). PATIENTS AND METHODS: Case-control study. We included women who completed pregnancy without complications (n=260) and were diagnosed with HTG (n=65) and PEE (n=65). We excluded patients with gestational or pre-pregnancy diabetes, thyroid disease (hypo and hyperthyroidism), autoimmune diseases (lupus erythematosus, rheumatoid arthritis) or diagnosed with heart disease or neuropathy before pregnancy. RESULTS: There were similarities in the risk factors such as: age over 35 years (OR 8.8, 95% CI 2.91-22.40), previous HTG (OR 64.16 95% CI 13.04-315.57) in case of patients with PEE. But we found a difference in the magnitude of these associations as odds ratios (OR) estimates were higher than in patients with HTG, age over 35 years (OR 3.33, 95% CI 1.03-10.72), and previous HTG (OR 27.27 95% CI 5.60-132.87). First-time pregnant women showed similar associations (OR 3.11 95% CI 1.52-6.38) in case of PEE or HTG (OR 3.14 95% CI 1.65-5.97). CONCLUSION: There are similarities in risk factors: maternal age--35 years, previous gestational hypertension and first-time pregnancy, for the development of gestational hypertension and preeclampsia. PMID- 22916640 TI - [Consensus conference of the Mexican Association for the Study of Climateric on veralipride prescription for patients with vasomotor symptoms]. AB - Vasomotor symptoms are one of the main reasons for climateric women to consult a physician. Hormone therapy is the first treatment choice, but it is not indicated to all patients. Veralipride is an option for those who cannot or will not try hormone treatment. The Mexican Association for the Study of Climateric (AMEC) assembled an interdisciplinary group of medical experts so that they revised the medical literature on the subject and reached a consensus on veralipride indication, doses, counterindications and safety. The recommendations of the consensus conference on veralipride are: (1) Physicians must be familiar with its indication, side effects, pharmacokinetics and dosage. (2) Patients must be informed on other therapeutical options. (3) Patients' mental and neurological state must be evaluated, in particular to identify movement disorders, extrapyramidal symptoms (tremor or dystonia), anxiety and depression that can be mistaken for climateric symptoms. (4) Any adverse effect associated with the drug must be reported. (5) A random multicenter trial must be carried out in order to identify the frequency and severity of side effects, and (6) Written information on possible health risks when using the drug must be provided. PMID- 22916641 TI - [Mayer-Rokitansky-Kuster-Hauser syndrome. A case report and a review of the medical literature on its treatment]. AB - The Mayer-Rokitansky-Kuster-Hauser (MRKH) syndrome affects 1 out of 4500 women. It is characterized by the congenital absence of the upper third of the vagina, uterus and tubes; it is usually associated to renal malformations, and patients show normal phenotype and genotype. Age at diagnosis is between 15 and 18. A case is reported and a critical review of the information about the management alternatives of patients with MRKH syndrome available in medical literature is made. The paper is intended to help establish the best criteria and treatment options for a comprehensive therapeutic approach to MRKH patients. PMID- 22916642 TI - [Synchronous double primary ovarian tumor in situ]. AB - BACKGROUND: Afinding of primary malignancies of different histological nature in each ovary is a particularly interesting condition since the information available about it is scarce and because there is hardly any consensus about its definition, classification and proper diagnostic-therapeutic approach. CLINICAL CASE: A case of a 49-year-old female patient presenting an abdominal mass with irregular 10 x 10 cm edges that comprises the area between the left illiac fossa and the umbilical scar. An exploratory laparatomy revealed two masses; a 15 cm cystic one in the left ovary, and an 8 cm one in the right ovary. The following histopathological analysis revealed a bilateral papillary carcinoma. A full oncogy-necological surgical protocol for ovarian carcinoma was applied. The last histopathological analysis revealed a clear cell carcinoma in the left ovary, and a moderately differentiated endometrioid carcinoma in the right one. CONCLUSIONS: A rare case of a synchronous double primary ovarian tumor is reported. Its clinical presentation, diagnosis, treatment and follow-up pose a particular classification issue. PMID- 22916643 TI - [Transverse vaginal septum in the upper part of the vagina and pregnancy]. AB - Transverse vaginal septum is a congenital Mullerian malformation resulting from a failure of the fusion or canalization of the urogenital sinus and the Mullerian ducts. It may cause hematocolpos, dyspareunia and infertility in adult patients. In some cases, it is associated with congenital malformations such as coarctation of the aorta or atrial septal defects. A case of a transverse vaginal septum identified during a vaginal check-up of a 39-week pregnant patient during labour is reported. A cesarean surgery was performed with no complications. Septal defect was diagnosed due to heart murmur. It was decided to treat the transverse vaginal septum as soon as the puerperium was over. The patient left the hospital after proper response to treatment. PMID- 22916644 TI - [Uterine rupture of a cornual pregnancy: an obstetric emergency]. AB - Cornual pregnancy is a rare type of ectopic pregnancy. Its diagnosis is challenging as the fetus usually appears as being inside the uterus on ultrasound scanning. Cornual pregnancy is more dangerous than other forms of ectopic pregnancy since a severe maternal hemorrhage can result during a cornual rupture. A case of a uterine rupture in a 14-week cornual pregnancy is reported. PMID- 22916645 TI - [A case of female genital atrophy due to psychological distress. 1957]. PMID- 22916646 TI - [Psychological factors in a case of genital atrophy. 1957]. PMID- 22916647 TI - Nurses take centre stage at quirky London 2012 opening ceremony. PMID- 22916648 TI - Pay cartel ploy gaining traction as more trusts eye up ways to cut pay. PMID- 22916649 TI - Single patient-observation chart could save 6,000 lives a year. PMID- 22916650 TI - Input of nurses into A&E admission and discharge decisions explored. PMID- 22916651 TI - PM's care forum promises single national leadership programme. PMID- 22916653 TI - Take the right course. AB - Older patients and those with complex needs are at risk of medication error when they transfer between care settings. A Royal Pharmaceutical Society project is improving the information accompanying a transferring patient. Nurses are adopting the ideas, including use of a 'green bag' containing patients' medicines and medicines information. PMID- 22916652 TI - 'My daughter's experience proves the value of specialist nurses'. PMID- 22916654 TI - Doing away with doctors. AB - There is conflicting evidence about the benefits of replacing doctors with nurses. A leading nurse researcher says this illustrates the need always to review evidence with a critical eye. This is of particular importance at a time when NHS organisations are under extreme pressure to reduce their workforce costs. PMID- 22916655 TI - Regenerating liver care. AB - A free online toolkit has been launched to increase nurses's awareness of liver disease and provide them with the information they need to support patients. The toolkit reflects growing concern about the increasing numbers of people in the UK who are dying from a largely preventable disease. PMID- 22916656 TI - Genetics, mitosis and meiosis. AB - As part of the life sciences series, this article describes the role of deoxyribonucleic acid and ribonucleic acid, genes and chromosomes. The processes of mitosis and meiosis are discussed and some genetic disorders outlined. Possible strategies for future management of genetic disorders are introduced. PMID- 22916657 TI - Cancer pain part 2: assessment and management. AB - Pain is common in patients with cancer and may be caused by the disease itself or treatments. Part 1 of this article identified the causes and types of cancer pain to inform assessment and management of pain, which will be discussed in this article. Barriers to pain management and the non-medical prescribing role of the advanced practice nurse in treating patients with cancer pain will be explored. PMID- 22916658 TI - Portal hypertension and varices in patients with liver cirrhosis. AB - Portal hypertension is a complication seen in patients with liver cirrhosis and is characterised by high pressure in the portal vein. As portal hypertension worsens, varices can form, leading to increased morbidity and mortality if these rupture. Bleeding can be prevented with pharmacological agents and endoscopic therapy; however, some patients will experience variceal haemorrhage. Medical and nursing management of acute variceal haemorrhage is key to a successful outcome, and after initial resuscitation, endoscopic therapy should be undertaken. Long term management to prevent re-bleeding may involve surgery to implant shunts, which aim to reduce portal venous pressure. However, patients often require referral to specialist centres for transplant assessment. PMID- 22916659 TI - Meningococcal B disease. PMID- 22916660 TI - Journey of discovery. PMID- 22916661 TI - My rocky road to a new life. PMID- 22916662 TI - Keep calm and carry on. PMID- 22916663 TI - My journey from orthodontics to craniofacial pain and TMJ to movement disorders. PMID- 22916664 TI - The sea change in dentistry today. PMID- 22916665 TI - Letter to Clifton Simmons regarding his article published in CRANIO, 2012; 1(1):9 24. PMID- 22916666 TI - Comments on Dr. Simmons's Special Report, published in CRANIO, 2012; 1(1):9-24. PMID- 22916667 TI - Dr. Raman's patient, Dr. James K. Brannon, shares his personal experience with TMJ treatment. PMID- 22916668 TI - Are temporomandibular disorders and tinnitus associated? AB - The current study aimed to research the prevalence of temporomandibular disorders (TMD) in patients with subjective tinnitus, as compared to controls, and the association between symptoms of TMD, tinnitus, and chronic pain. Two hundred patients were divided into two groups, according to the presence (experimental) or not (control) of subjective tinnitus. The subgroups were determined according to the RDC/TMD criteria. The Pain Pressure Threshold (PPT) values of the masseter and temporalis muscles were recorded bilaterally, and a Visual Analog Scale (VAS) was used to address subjective pain. The most prevalent TMD subgroups in the tinnitus patients (p < 0.05) were myofascial pain with limited opening (39.0%), disc displacement with reduction (44.33%), and arthralgia (53.54%). The severity of tinnitus was significantly associated with the severity of chronic pain (p = .000). The PPT values were lower (p > 0.05), while the Visual Analog Scale (VAS) was statistically higher (p = .000) for the tinnitus patients. These results suggest that an association exists between TMD and subjective tinnitus. PMID- 22916669 TI - Approaching temporomandibular disorders from a new direction: a randomized controlled clinical trial of the TMDes ear system. AB - TMDes (Registered Trademark of Ascentia Health, Inc., Rockford, Illinois), custom fit ear inserts to aid in reducing temporomandibular disorder (TMD) pain, were evaluated in a prospective, three-month, open-label, three-arm, randomized, unblinded clinical trial, which included patients with TMD diagnoses (RDC/TMD) of myofascial pain, arthralgia, and/or disc displacement with reduction; and a screening VAS pain score of > 4. The three treatment groups included: TMDes (n = 60), stabilization splint (n = 64), and jaw exercise regimen (n = 28). The mean change in Craniomandibular Index (CMI) scores (reductions reflecting improvement) from baseline to one month were -27% (TMDes), -20% (stabilization splint), -12% (jaw exercise regimen), and from baseline to three months were -45%, -41%, -36%, reflecting statistically significant noninferiority (p = 0.0096) of the TMDes to the stabilization splint (primary efficacy endpoint). The TMDes produced significant (p < 0.0001) mean changes in VAS pain scores from baseline of -46% at one month and -58% at three months and demonstrated comparable efficacy and safety to the stabilization splint. PMID- 22916670 TI - Orofacial pain related to traumatic neuroma in a patient with multiple TMJ operations. AB - The diagnosis of orofacial pain associated with temporomandibular disorders after repeated temporomandibular joint (TMJ) surgeries can be quite difficult. This case report describes a 52-year-old woman who had previously undergone five TMJ surgeries and developed divergent pain caused by a trigger point in the left preauricular area. Computed tomography and magnetic resonance imaging could not be used to identify a lesion because of metallic artifacts from a TMJ prosthesis. However, sonography indicated the location of the suspected lesion. Moreover, a neurological examination performed with local anesthesia was clinically effective in ruling out other diagnoses of orofacial pain. Ultimately, a histopathological examination of a biopsy specimen from the painful site confirmed the lesion to be a traumatic neuroma. This case report suggests the value of including traumatic neuroma in the differential diagnosis of patients with a history of previous TMJ surgery who present with orofacial pain in the region of the TMJ. PMID- 22916671 TI - Spasmodic torticollis: the dental connection. AB - Spasmodic torticollis or cervical dystonia (CD) is the most common form of focal dystonia and is characterized by sustained abnormal muscle contractions in the head and neck area resulting in abnormal positioning or posturing of the head. The dystonic muscle spasms associated with spasmodic torticollis may affect any combination of neck muscles. Three cases are reported of spasmodic torticollis that were treated by a dental appliance with individual varying occlusal heights to open the maxillomandibular vertical dimension. Upon increasing the vertical dimension of occlusion, there was a slowing and/or discontinuance of the symptoms of cervical dystonia. The proposed hypothesis for this reversal is that there may be neuritis of the auriculotemporal branch of the trigeminal nerve, which has direct input into the reticular formation (RF), and it may activate the cells of the pontine region of the RF known for the control and deviation of head posture. There is growing clinical evidence that temporomandibular joint (TMJ) dysfunction may be a factor in this neurological and painful disorder when it coexists. PMID- 22916672 TI - Distribution of temporomandibular joint vibration transfer to the opposite side. AB - A vibration produced when a displaced temporomandibular disc reduces during opening can transfer some of its energy from the ipsilateral joint to the contralateral joint. The objective of this study was to measure what percentage of the ipsilateral vibration is transferred to the contralateral joint. The study included the temporomandibular joint (TMJ) vibrations of 144 (informed consent) subjects, (113 F, 31 M), with reducing displaced discs (DDR). Vibrations from 165 joints were recorded bilaterally with BioJVA (BioResearch Associates, Inc. Milwaukee, WI). In each case, any contralateral vibration was analyzed to verify that it was caused by the ipsilateral joint. The contralateral amplitude was divided by the ipsilateral amplitude and multiplied by 100 to produce a percentage of transfer. The percentage values (0-100%) were used to create a Relative Frequency Histogram with 20 classes (1-5%, 6-10%, 11-15%, etc.). The Relative Frequency Histogram graph revealed a three-mounded distribution of the percentage of transfer. One mound fell between 5 and 34 percent, one between 35 and 69 percent and the third between 70 and 98 percent. The appearance of a three mounded distribution suggests that there may be three different failure modes leading to TMJ intemal derangements. Alternatively, it may be that failure of the disc's stabilizing ligaments leads to three different internal derangement conditions that are in some way distinct. The evidence of apparent tri-modality in this vibration data distribution suggests that there may be three different failure modes of disc displacement with reduction (e.g., anterior, anteromedial, and medio-lateral disc displacement). If so, identifying them could allow for a more detailed description of DDR. Therefore, further investigation of this 'tri modal' distribution should be undertaken. PMID- 22916673 TI - An evaluation of horizontal jaw relations during standing and sitting with open or closed eyes. AB - When determining the horizontal jaw relation and mandibular movements, a question arises as to the appropriate choice of registration positions. The current study was carried out using 22 adults with full dentition who did not have any discomfort in their skeletal and craniomandibular systems. Occlusion and mandibular movements were investigated with open and closed eyes in standing and sitting positions using an electronic, central-bearing tracing device. The coordinates of the measured parameters are presented using a two-dimensional computer vector diagram. The non-parametric Friedman test was used for statistical data analysis. The measured data obtained for the initial habitual centric relation record (HR), centric relation record (CR), final habitual centric relation record (HR), and protrusion (P) did not significantly differ in the sitting and standing positions or with opened and closed eyes (p = 1.00). With closed eyes, the differences in the average values between the two condylar positions (initial HR/final HR, initial HR/CR, and final HR/CR) decreased in a manner that was independent of the registration position. The CR that was measured in a sitting position with closed eyes was 2.26 mm more retrusive than that measured with open eyes. Before and after CR measurements, only laterotrusion showed significant differences (p=0.02) in patients who were standing with closed eyes. It was concluded that the registration position and visual system could individually influence the measurements of condylar position and mandibular movements. From a clinical perspective, these measurements exhibited the smallest differences when they were conducted with patients in a sitting position with closed eyes. PMID- 22916674 TI - Bilateral supra- and infrahyoid EMG activity during eccentric jaw clenching and tooth grinding tasks in subjects with canine guidance or group function. AB - This study compares the effect of tooth clenching and grinding on supra- and infrahyoid electromyographic (EMG) activity during different laterotrusive jaw posture tasks. The study included 30 healthy subjects with natural dentition and bilateral molar support, 15 with bilateral canine guidance and 15 with bilateral group function. Bipolar surface electrodes were located on the left and right supra- and infrahyoid muscles. EMG activity was recorded during the following tasks: A. eccentric grinding from intercuspal position to the right lateral edge to-edge contact position; B. clenching in right edge-to-edge lateral contact position; C. concentric grinding from right lateral edge-to-edge contact position to intercuspal position. EMG activity was not significantly different between tasks on the working side, nonworking side, or between both sides, in subjects with canine guidance or group function (Wilcoxon rank-sum test). When comparing EMG activity by occlusal scheme, no significant differences were found either on the working side or the non-working side (Mann-Whitney U test). This result suggests that supra- and infrahyoid EMG activity in its predominant stabilizing role of the hyoid bone is not significantly modified by the type of laterotrusive occlusal scheme. PMID- 22916675 TI - Treatment for TMD with occlusal splint and electromyographic control: application of the FARC protocol in a Brazilian population. AB - The purpose of this study was to apply Functional Anatomy Research Center (FARC) Protocol of TMD treatment, which includes the use of a specific type of mandibular occlusal splint, adjusted based on the electromyographic index, in a group of 15 patients with disc displacement, classified according to the Research Diagnostic Criteria for Temporomandibular Disorders (RDC/TMD) and then analyzing the results compared with the control group. The clinical evaluations were completed both before and after the treatment. Electromyographic (EMG) data was collected and recorded on the day the splint was inserted (visit 1), after one week (visit 2) and after five weeks of treatment (visit 3). The control group consisted of 15 asymptomatic subjects, according to the same diagnostic criteria (RDC/TMD), who were submitted to the same evaluations with the same interval periods as the treatment group. Immediately after splint adjustment, masseter muscle symmetry and total muscular activity were significantly different with than without the splint (p < 0.05), showing an increased neuromuscular coordination. After treatment, significant variations (p < .05) were found in mouth opening and in pain remission. There were no significant differences among the three sessions, either with or without the splint. There were significant differences between the TMD and control groups for all analyzed indices of muscular symmetry, activity and torque, with the exception of total muscular activity. The use of the splint promoted balance of the EMG activities during its use, relieving symptoms. EMG parameters identified neuromuscular imbalance, and allowed an objective analysis of different phases of TMD treatment, differentiating individuals with TMD from the asymptomatic subjects. PMID- 22916676 TI - Intra-articular fracture of the mandibular condyle: a case report. AB - The authors describe a case of intra-articular fracture of the left mandibular condyle, successfully treated by the pumping technique in the upper and lower joint cavities, and show arthroscopic findings in these cavities. The patient was a 15-year-old boy whose maximum mouth opening was 30 mm. Computed tomography revealed a left intra-articular sagittal fracture of the condylar head. Aspiration of the hematoma in the upper and lower joint spaces was performed with ten pumping actions. In the upper and lower joint spaces, arthroscopic examination revealed the disappearance of the hematoma. The patient continued opening, protrusive, and lateral excursive exercises. One month after the surgery, the maximal interincisal distance was improved to 45 mm with straight opening. In the case presented, mouth-opening exercises, along with the pumping technique for treatment of an intraarticular fracture of the mandibular condyle, allowed satisfactory and stable results in the improvement of limited mouth movement. PMID- 22916677 TI - Relative preservation of the recognition of positive facial expression "happiness" in Alzheimer disease. AB - BACKGROUND: Positivity recognition bias has been reported for facial expression as well as memory and visual stimuli in aged individuals, whereas emotional facial recognition in Alzheimer disease (AD) patients is controversial, with possible involvement of confounding factors such as deficits in spatial processing of non-emotional facial features and in verbal processing to express emotions. Thus, we examined whether recognition of positive facial expressions was preserved in AD patients, by adapting a new method that eliminated the influences of these confounding factors. METHODS: Sensitivity of six basic facial expressions (happiness, sadness, surprise, anger, disgust, and fear) was evaluated in 12 outpatients with mild AD, 17 aged normal controls (ANC), and 25 young normal controls (YNC). To eliminate the factors related to non-emotional facial features, averaged faces were prepared as stimuli. To eliminate the factors related to verbal processing, the participants were required to match the images of stimulus and answer, avoiding the use of verbal labels. RESULTS: In recognition of happiness, there was no difference in sensitivity between YNC and ANC, and between ANC and AD patients. AD patients were less sensitive than ANC in recognition of sadness, surprise, and anger. ANC were less sensitive than YNC in recognition of surprise, anger, and disgust. Within the AD patient group, sensitivity of happiness was significantly higher than those of the other five expressions. CONCLUSIONS: In AD patient, recognition of happiness was relatively preserved; recognition of happiness was most sensitive and was preserved against the influences of age and disease. PMID- 22916678 TI - Comparison of adsorption probabilities of O2 and CO on copper cluster cations and anions. AB - Reactions of size-selected copper cluster cations and anions, Cu(n)(+/-), with O(2) and CO have been systematically investigated under single collision conditions by using a tandem-mass spectrometer. In the reactions of Cu(n)(+/-) (n = 3-25) with O(2), oxidation of the cluster is prominently observed with and without releasing Cu atoms at the collision energy of 0.2 eV. The reactivity of Cu(n)(+) is governed to some extent by the electronic shell structure; the relatively small reaction cross sections observed at n = 9 and 21 correspond to the electronic shell closings, and those at odd sizes in n <= 16 match with the clusters having no unpaired electron. On the other hand, the reactivity of Cu(n)( ) exhibits no remarkable decrease by the electronic shell closings and the even numbered electrons. These behaviors may be due to an influence of the electron detachment of the reaction intermediate, Cu(n)O(2)(-). Both the cations and anions show the dominant formation of Cu(n-1)O(2)(+/-) in n <= 16 and Cu(n)O(2)(+/-) in n >= 17 in the experimental time window. By contrast, Cu(n)(-) (n = 3-11) do not react with CO at the collision energy of 0.2 eV, while Cu(n)(+) (n = 3-19) adsorb CO though the cross sections are relatively small. The difference in the reactivity between the charge states can be understood in terms of the frontier orbitals of the Cu cluster and O(2) or CO. PMID- 22916679 TI - Probing dynamic conformations of the high-molecular-weight alphaB-crystallin heat shock protein ensemble by NMR spectroscopy. AB - Solution- and solid-state nuclear magnetic resonance (NMR) spectroscopy are highly complementary techniques for studying supra-molecular structure. Here they are employed for investigating the molecular chaperone alphaB-crystallin, a polydisperse ensemble of between 10 and 40 identical subunits with an average molecular mass of approximately 600 kDa. An IxI motif in the C-terminal region of each of the subunits is thought to play a critical role in regulating the size distribution of oligomers and in controlling the kinetics of subunit exchange between them. Previously published solid-state NMR and X-ray results are consistent with a bound IxI conformation, while solution NMR studies provide strong support for a highly dynamic state. Here we demonstrate through FROSTY (freezing rotational diffusion of protein solutions at low temperature and high viscosity) MAS (magic angle spinning) NMR that both populations are present at low temperatures (<0 degrees C), while at higher temperatures only the mobile state is observed. Solution NMR relaxation dispersion experiments performed under physiologically relevant conditions establish that the motif interchanges between flexible (highly populated) and bound (sparsely populated) states. This work emphasizes the importance of using multiple methods in studies of supra molecules, especially for highly dynamic ensembles where sample conditions can potentially affect the conformational properties observed. PMID- 22916680 TI - Development of a computational tool to rival experts in the prediction of sites of metabolism of xenobiotics by p450s. AB - The metabolism of xenobiotics--and more specifically drugs--in the liver is a critical process controlling their half-life. Although there exist experimental methods, which measure the metabolic stability of xenobiotics and identify their metabolites, developing higher throughput predictive methods is an avenue of research. It is expected that predicting the chemical nature of the metabolites would be an asset for designing safer drugs and/or drugs with modulated half lives. We have developed IMPACTS (In-silico Metabolism Prediction by Activated Cytochromes and Transition States), a computational tool combining docking to metabolic enzymes, transition state modeling, and rule-based substrate reactivity prediction to predict the site of metabolism (SoM) of xenobiotics. Its application to sets of CYP1A2, CYP2C9, CYP2D6, and CYP3A4 substrates and comparison to experts' predictions demonstrates its accuracy and significance. IMPACTS identified an experimentally observed SoM in the top 2 predicted sites for 77% of the substrates, while the accuracy of biotransformation experts' prediction was 65%. Application of IMPACTS to external sets and comparison of its accuracy to those of eleven other methods further validated the method implemented in IMPACTS. PMID- 22916681 TI - Estimation of reactive thiol concentrations in dissolved organic matter and bacterial cell membranes in aquatic systems. AB - Organic thiols are highly reactive ligands and play an important role in the speciation of several metals and organic pollutants in the environment. Although small thiols can be isolated and their concentrations can be estimated using chromatographic and derivatization techniques, estimating concentrations of thiols associated with biomacromolecules and humic substances has been difficult. Here we present a fluorescence-spectroscopy-based method for estimating thiol concentrations in biomacromolecules and cell membranes using one of the soluble bromobimanes, monobromo(trimethylammonio)bimane (qBBr). The fluorescence of this molecule increases significantly when it binds to a thiol. The change in the sample fluorescence due to thiols reacting with qBBr is used to determine thiol concentration in a sample. Using this method, small thiols such as cysteine and glutathione can be detected in clean solutions down to ~50 nM without their separation and prior concentration. Thiols associated with dissolved organic matter (DOM) can be detected down to low micromolar concentration, depending on the DOM background fluorescence. The charge on qBBr prevents its rapid diffusion across cell membranes, so qBBr is ideal for estimating thiol concentration at the cell membrane-water interface. This method was successfully used to determine the thiol concentration on the cell envelope of intact Bacillus subtilis to nanomolar concentration without any special sample preparation. Among the chemical species tested for potential interferences (other reduced sulfides methionine and cystine, carboxylate, salt (MgCl(2))), carboxylates significantly influenced the absolute fluorescence signal of the thiol-qBBr complex. However, this does not affect the detection of thiols in heterogeneous mixtures using the presented method. PMID- 22916682 TI - Predicting postoperative astigmatism using Scheimpflug keratometry (Pentacam) and automated keratometry (IOLMaster). AB - PURPOSE: To compare keratometry measurements obtained using an automated keratometer (AK, IOLMaster) and a Scheimpflug keratometer (Pentacam) in predicting residual astigmatism after cataract surgery. METHODS: Preoperative corneal astigmatism was calculated using preoperative refraction, an AK and a Scheimpflug keratometer (anterior corneal power [ACP] and true net power [TNP]) in 155 eyes of 107 Asian subjects. Phacoemulsification cataract removal and nontoric intraocular lens insertion (Akreos((r))MI-60TM, Bausch & Lomb, Rochester, NY, USA) were performed through a 2.8 mm temporal clear corneal incision. Six months later, postoperative astigmatism (postA) was calculated using manifest refraction. Error angle (EA) and error magnitude (EM) of above keratometries (AK, ACP, and TNP) in prediction of postA was calculated. The correlation between preoperative astigmatism and postA was analyzed using power vectors (J(0) and J(45)). RESULTS: AK resulted in the lowest EM and ACP resulted in the lowest EA. Preoperative astigmatism (preA) measured using AK, ACP, and TNP showed significant correlation with postA in both J(0) and J(45) components. (AK: rJ(0) = 0.554, rJ(45) = 0.559, ACP: rJ(0) = 0.346, rJ(45) = 0.281, TNP: rJ(0) = 0.409, rJ(45) = 0.231). Preoperative refractive astigmatism showed no significant correlation in any components. CONCLUSIONS: PreA determined using AK showed superior performance in prediction of postA than ACP and TNP. PMID- 22916683 TI - Cultural differences in emotion regulation during self-reflection on negative personal experiences. AB - Reflecting on negative personal experiences has implications for mood that may vary as a function of specific domains (e.g., achievement vs. interpersonal) and cultural orientation (e.g., interdependence vs. independence). This study investigated cultural differences in the social-cognitive and affective processes undertaken as Easterners and Westerners reflected on negative interpersonal and performance experiences. One hundred Asian Americans and 92 European-American college students were randomly assigned to one of three conditions: interpersonal rejection, achievement failure, or a control condition. Results revealed that Asian Americans experienced greater distress than European Americans after self reflecting over a failed interpersonal experience, suggesting cultural sensitivity in the relational domain. Consistent with theoretical predictions, analysis of the social cognitive and affective processes that participants engaged in during self-reflection provided some evidence that self-enhancement may buffer distress for European Americans, while emotion suppression may be adaptive for Asian Americans. PMID- 22916684 TI - Exhaled volatile organic compounds for phenotyping chronic obstructive pulmonary disease: a cross-sectional study. AB - BACKGROUND: Non-invasive phenotyping of chronic respiratory diseases would be highly beneficial in the personalised medicine of the future. Volatile organic compounds can be measured in the exhaled breath and may be produced or altered by disease processes. We investigated whether distinct patterns of these compounds were present in chronic obstructive pulmonary disease (COPD) and clinically relevant disease phenotypes. METHODS: Breath samples from 39 COPD subjects and 32 healthy controls were collected and analysed using gas chromatography time-of flight mass spectrometry. Subjects with COPD also underwent sputum induction. Discriminatory compounds were identified by univariate logistic regression followed by multivariate analysis: 1. principal component analysis; 2. multivariate logistic regression; 3. receiver operating characteristic (ROC) analysis. RESULTS: Comparing COPD versus healthy controls, principal component analysis clustered the 20 best-discriminating compounds into four components explaining 71% of the variance. Multivariate logistic regression constructed an optimised model using two components with an accuracy of 69%. The model had 85% sensitivity, 50% specificity and ROC area under the curve of 0.74. Analysis of COPD subgroups showed the method could classify COPD subjects with far greater accuracy. Models were constructed which classified subjects with >=2% sputum eosinophilia with ROC area under the curve of 0.94 and those having frequent exacerbations 0.95. Potential biomarkers correlated to clinical variables were identified in each subgroup. CONCLUSION: The exhaled breath volatile organic compound profile discriminated between COPD and healthy controls and identified clinically relevant COPD subgroups. If these findings are validated in prospective cohorts, they may have diagnostic and management value in this disease. PMID- 22916685 TI - Chirality and packing in small proline clusters. AB - The chiral composition of amino acid clusters may be related to the origin of chirality in biological systems. Here, we use ion mobility/mass spectrometry techniques to investigate the gas phase structures of singly charged proline clusters containing two to six monomers. Using deuterated L-proline (L(D7)) and different electrospray solution compositions varying from enantiopure (50:50 L:L(D7)) to racemic (50:50 L(D7):D), it is possible to study collision cross sections of L-, D-, and mixed xL:xD-proline clusters (where x refers to the number of monomers). These results show that [2Pro+H](+) and [3Pro+H](+) clusters, previously shown (Holliday et al. J. Phys. Chem. A 2012, DOI: 10.1021/jp302677n) to have a very small heterochiral preference, have similar collision cross sections for homochiral and heterochiral proline assemblies. The [4Pro+H](+) and [6Pro+H](+) clusters that exhibit homochiral preference have smaller collision cross sections for homochiral clusters and larger collision cross sections for heterochiral clusters. The [5Pro+H](+) cluster with heterochiral preference has a smaller collision cross section for its heterochiral compositions than for its homochiral compositions. These results suggest that the packing efficiency of subunits within each cluster influences the stability and prevalence of proline multimers as either homochiral or mixed L and D- clusters. PMID- 22916686 TI - Troglostrongylus brevior and Troglostrongylus subcrenatus (Strongylida: Crenosomatidae) as agents of broncho-pulmonary infestation in domestic cats. AB - BACKGROUND: Aelurostrongylus abstrusus is currently regarded as the main metastrongyloid infesting domestic cats, whereas the reports of Troglostrongylus spp. in domestic and wild felids largely remain anecdotic. This paper reports on pulmonary infestation caused by Troglostrongylus brevior and Troglostrongylus subcrenatus in two kittens and describes, for the first time, associated clinical presentations and pathological features. Morphometrical, molecular and phylogenetic analyses have also been conducted to differentiate here the examined Troglostrongylus species from A. abstrusus, towards a clearer delineation of metastrongyloids affecting cats. METHODS: Two kittens were referred for respiratory distress and hospitalized with a diagnosis of severe aelurostrongylosis, based on the presence of metastrongyloid larvae in the faeces. Despite prompt treatment, kittens died within 48 hours. Both kittens were submitted to necropsy to determine the cause of death. RESULTS: At necropsy, nematode specimens were found in the trachea, bronchi and bronchioles and were associated with respiratory signs (i.e., dyspnoea, polypnea, severe coughing and nasal discharge). Morphology and measurements of adult parasites found allowed the unequivocal identification of T. brevior and T. subcrenatus, even if first stage larvae were rather similar to those of A. abstrusus. Briefly, T. brevior and T. subcrenatus larvae were shorter in length and lacking the typical knob like terminal end of A. abstrusus. Molecular and phylogenetic analyses corroborated morphological identification and provided data on mitochondrial and ribosomal DNA genes of T. brevior. CONCLUSIONS: Data presented here indicate that T. brevior and T. subcrenatus may cause major respiratory distress in domestic cats. Consequently, these two species should be included, along with A. abstrusus, in the differential diagnosis of cat bronchopulmonary affections and treatment protocols need to be evaluated. Through research on the biology, epidemiology and control of Troglostrongylus spp. infestations in domestic cats are advisable to implement current knowledge on these neglected metastrongyloids. PMID- 22916689 TI - A 12 month review of a modified protocol using low dose Dabigatran Etexilate in postoperative thromboembolic prophylaxis in joint replacement surgery. AB - BACKGROUND: Venous Thrombo-embolic disease is currently a hot topic especially in the UK. 25,000 patients per year die of Pulmonary Emboli (PE) in the United Kingdom (UK). Hip and knee arthroplasty surgery is associated with an increased rate of deep vein thrombosis (DVT) and pulmonary embolus (PE). The National Institute for Clinical Excellence (NICE) guidelines introduced in January 2010 recommended use of subcutaneous heparin or an oral anticoagulant (Dabigatran or Rivaroxiban) for 10-14 days post knee and 28-35 days post hip arthroplasty. In our unit we were keen on the advantages of an oral anticoagulant post arthroplasty in terms of patient compliance, and avoiding the need for self administered injection in the community. METHODS: We analysed all the notes, blood results and imaging of patients undergoing total hip or knee arthroplasty and present 1 year's data using a regime of subcutaneous Dalteparin whilst an inpatient, followed by discharge on oral Dabigatran at a low dose (150 mg once daily). RESULTS: There were 337 patients over 1 year with hip and knee arthroplasty, with a 1.19% rate of DVT with no PEs and 1 death due to an unrelated cause. There was a transfusion rate of 11.57% with 1.19% patients taken back to theatre for evacuation of haematomas. There were no reported adverse effects of Dabigatran. CONCLUSION: Our treatment protocol is a novel practical approach for VTE prophylaxis in hip and knee replacement patients. This approach shows promising data but no definitive evidence to warrant wide-spread use of this new regime. This data can act as a foundation for larger randomised clinical trials. PMID- 22916687 TI - Reliability of the Multidimensional Pain Inventory and stability of the MPI classification system in chronic back pain. AB - BACKGROUND: This cross validation study examined the reliability of the Multidimensional Pain Inventory (MPI) and the stability of the Multidimensional Pain Inventory Classification System of the empirically derived subgroup classification obtained by cluster analysis in chronic musculoskeletal pain. Reliability of the German Multidimensional Pain Inventory was only examined once in the past in a small sample. Previous international studies mainly involving fibromyalgia patients showed that retest resulted in 33-38% of patients being assigned to a different Multidimensional Pain Inventory subgroup classification. METHODS: Participants were 204 persons with chronic musculoskeletal pain (82% chronic non-specific back pain). Subgroup classification was conducted by cluster analysis at 4 weeks before entry (=test) and at entry into the pain management program (=retest) using Multidimensional Pain Inventory scale scores. No therapeutic interventions in this period were conducted. Reliability was quantified by intraclass correlation coefficients (ICC) and stability by kappa coefficients (kappa). RESULTS: Reliability of the Multidimensional Pain Inventory scales was least with ICC = 0.57 for the scale life control and further ranged from ICC = 0.72 (negative mood) to 0.87 (solicitous responses) in the other scales. At retest, 82% of the patients in the Multidimensional Pain Inventory cluster interpersonally distressed (kappa = 0.69), 80% of the adaptive copers (kappa = 0.58), and 75% of the dysfunctional patients (kappa = 0.70) did not change classification. In total, 22% of the patients changed Multidimensional Pain Inventory cluster group, mainly into the adaptive copers subgroup. CONCLUSION: Test-retest reliability of the German Multidimensional Pain Inventory was moderate to good and comparable to other language versions. Multidimensional Pain Inventory subgroup classification is substantially stable in chronic back pain patients when compared to other diagnostic groups and other examiner-based subgroup Classification Systems. The MPI Classification System can be recommended for reliable and stable specification of subgroups in observational and interventional studies in patients with chronic musculoskeletal pain. PMID- 22916691 TI - Retraction - Candidate genes, small effects, and the prediction of atherosclerosis. Crit Rev Clin Lab Sci 1997; 34:343-67. PMID- 22916690 TI - Differential autonomic response to acupuncture at wood and metal of five-shu acupoints. AB - OBJECTIVES: The study examined differential autonomic nervous responses to acupuncture stimulation at the wood points ([Formula: see text]) and the metal points ([Formula: see text]) among the five-shu points of the Pericardium and Triple Energizer Meridian. DESIGN: This was a crossover study of different acupuncture points with randomized order. SUBJECTS: The study subjects were 30 healthy female volunteers (22.8 +/- 2.6 years old). INTERVENTIONS: The acupuncture sessions were carried out over four sessions at 2-5-day intervals at the same time of day with one of the four acupoints: the wood distal point (Zhongchong, PC9), metal distal point (Zhongzhu, TE3), wood proximal point (Jianshi, PC5), and metal proximal point (Guanchong, TE1) on the left hand. After 5 minutes' rest (Pre-Acup), acupuncture needles were inserted, manipulated promptly, and were retained for 20 minutes followed by 5 minutes' rest (Post Acup). MAIN OUTCOME MEASURES: Heart rate variability, skin conductance response, respiration rate, and peripheral skin temperature were measured. RESULTS: For the normalized low-frequency band of heart rate variability, there was a statistically significant increase during Acup and Post-Acup at the PC9 and TE3 wood points compared with Pre-Acup. Statistically significant decreases for PC5 and TE1 were evident at the metal points. Skin conductance response and peripheral skin temperature, which are indicative of sympathetic activity and blood flow, respectively, were significantly induced at PC9 during Acup compared to Pre-Acup. CONCLUSIONS: The wood points PC9 and TE3 increase sympathetic activity; and the metal points TE1 and PC5 increase the parasympathetic activity. The effect of acupuncture on the autonomic nervous system differs between the wood and the metal points. PMID- 22916692 TI - Outcome assessment alternatives for young children during the first 12 months after pediatric hearing-aid fittings. AB - OBJECTIVE: Perform longitudinal evaluations of young children during the first 12 months after initial hearing-aid fitting. Document evidence of early prelingual auditory development (EPLAD), identify factors that affect EPLAD, and define performance milestones that can guide best practices. DESIGN: Unblinded, prospective, within-subject, repeated-measures design. Audiological measures and measures of EPLAD were taken at baseline, 3, 6, and 12 months after hearing-aid fitting. STUDY SAMPLE: Subjects were 45 pediatric patients initially fitted with hearing aids between 1 and 5.5 years of age. Four groups were formed for analysis purposes based on severity of hearing loss (moderate-to-severe and profound) and initial fitting age (<= 30 months and > 30 months). RESULTS: All groups exhibited statistically significant increases in EPLAD within six months of hearing-aid fitting, and those with profound losses exhibited further statistically significant improvement between six and 12 months. Similar EPLAD levels were reached at 12 months regardless of severity of hearing loss. The EPLAD trajectory is similar to that following early cochlear implantation. CONCLUSIONS: Measures of EPLAD provide a means of evaluating outcomes following early pediatric hearing aid intervention, supplementing behavioral audiological measures. PMID- 22916693 TI - The effect of stimulus choice on cortical auditory evoked potentials (CAEP): consideration of speech segment positioning within naturally produced speech. AB - OBJECTIVE: Cortical auditory evoked potentials (CAEPs) can be elicited to stimuli generated from different parts of speech. The aim of this study was to compare the phoneme /?/ from word medial and word initial positions and its influence on the CAEP. DESIGN: Stimuli from word medial positions were found to have shorter rise times compared to the same phonemes from word initial positions. A repeated measures design was carried out with CAEPs elicited using /?/ from a word initial and a word medial position. STUDY SAMPLE: Sixteen individuals with audiometric thresholds within normal limits participated in the study. RESULTS: Stimuli /?/ from a word medial position elicited CAEPs with significantly larger amplitudes and shorter latencies compared to /?/ from a word initial position (p < 0.05). CONCLUSIONS: Findings from this study, incorporating naturally produced speech sounds, suggest the need to consider spectral and temporal variations when choosing stimuli to optimize the amplitude and latency characteristics of the CAEP. Overall, findings illustrate good test-retest reliability of CAEP measures using speech stimuli with clinical equipment. PMID- 22916694 TI - Preface. Proceedings of the Third Molar Multidisciplinary Conference. Washington, DC, October 19, 2010. PMID- 22916695 TI - Introduction. Proceedings of the Third Molar Multidisciplinary Conference. Washington, DC, October 19, 2010. PMID- 22916696 TI - Surveillance as a management strategy for retained third molars: is it desirable? AB - The purpose of the present report was to define and advocate active surveillance compared with follow-up as needed (prn follow-up), as the preferred management strategy for patients who elect to retain their third molars (M3s). Active surveillance, a nonoperative management strategy for retained M3s, is characterized as a prescribed, regularly scheduled set of follow-up visits that include both clinical and radiographic examinations. Given that the risk of complications with M3 removal are age related, the rationale for recommending active surveillance instead of "prn follow-up" is that the frequency of future disease among retained M3s is sufficiently high to warrant routine scheduled follow-up visits to detect and treat disease before it becomes symptomatic. Symptomatic disease is a late finding. Patients electing active surveillance as their preferred management strategy might not avoid operative treatment in the future, but it should increase their chances of being diagnosed at the youngest age possible, thus minimizing the age-related operative complications. The author recommends that the frequency of follow-up visits be approximately every 24 months and the examination be completed by a specialist or general dentist. Active surveillance as a management strategy is based on level 5 evidence (ie, expert opinion). PMID- 22916698 TI - How many patients have third molars and how many have one or more asymptomatic, disease-free third molars? AB - The purpose of this report was to summarize the frequencies of third molars (M3s) in general and asymptomatic, disease-free M3s specifically. Estimates of M3 prevalence range so widely (ie, 6.0% to 96%) as to be of little use. The estimates vary depending on definitions, age, clinical versus radiographic assessment, and patient versus population samples. For patient management, it may be more valuable to estimate the prevalence of M3s grouped by clinical rather than anatomic status. Many times, however, M3s are categorized simply as asymptomatic. In many pathologic processes, from cancer to cardiovascular disease, the term asymptomatic does not equal an absence of disease. As such, M3s should be categorized based on symptom and disease status. Subjects with all M3s asymptomatic and absent of disease ranged from 12% in a sample of patients referred for M3 evaluation to 29% in a nonpatient volunteer sample. In the patient sample, 37% of the M3s evaluated were asymptomatic and free of disease. PMID- 22916697 TI - What strategies are helpful in the operative management of third molars? AB - PURPOSE: The purpose of this review was to investigate and report strategies that might improve patient recovery after third molar (M3) surgery. MATERIALS AND METHODS: This was a literature review on various topics to identify the methods of improving outcomes after M3 removal. Numerous topics were reviewed, including patient age, flap design, effect of smoking, use of antibacterial rinses, pre emptive analgesia, and the role of antibiotics and corticosteroids in recovery. RESULTS: Increased patient age appears to be a factor in a higher complication rate, but the literature is sparse. The results of studies on flap design are contradictory, but there is no difference in long-term periodontal health. Systematic reviews clearly show that longer periods of smoking cessation decrease surgical complications, but few studies have addressed M3 surgery. Likewise, the role of pre-emptive analgesia, although beneficial in a general surgical setting, has not been studied thoroughly with regard to M3 surgery. The use of chlorhexidine rinses to prevent alveolar osteitis and surgical site infection has been studied extensively, but meta-analyses have not convincingly proved this effect. The evidence is convincing that antibiotics decrease alveolar osteitis and surgical site infection. Similarly, it is clear that corticosteroids decrease postoperative trismus and edema; however, the role of steroids in decreasing pain is not proved. CONCLUSION: This review found various factors associated with improving recovery and minimizing complications in M3 surgery. PMID- 22916699 TI - How often do asymptomatic, disease-free third molars need to be removed? AB - The preventive removal of third molars (M3s) should be based on evidence. To optimize the timing of removal of M3s, it is essential to predict the eruption of the tooth and, even more importantly, to recognize beforehand which teeth will become involved in pathologic conditions later in life. The first aim of this review was to determine how well physicians currently can predict the eruption of an M3. The second aim was to review how frequently impacted M3s are removed. The third aim was to summarize the indications for preventive removals as presented in the evidence-based Current Care Guideline for the management of M3s in Finland. The prediction of eruption can be made at accuracies from 80% to 97%. In addition, the decrease in the number of M3s is very rapid, with only 31% remaining at 38 years of age. According to the Current Care Guideline, preventive removals at a young age are justified for 3 groups of teeth in the mandible: partially impacted teeth in the horizontal position, partially erupted teeth in the vertical position, and incomplete roots growing close to the mandibular canal. In conclusion, one fourth of retained and disease-free M3s need to be removed preventively at a young age, whereas the rest should be treated according to signs and symptoms. PMID- 22916700 TI - What are the local and systemic implications of third molar retention? AB - PURPOSE: To establish a relationship between visible third molars (M3s) and increased periodontal probing depths on teeth other than M3s and to examine the hypothesis that the presence of M3s and/or increased probing depths and local inflammation associated with M3s was associated with increased levels of serum inflammatory markers. PATIENTS AND METHODS: The data from three previous population studies (Dental Atherosclerosis Risk In Communities [DARIC], Oral Conditions and Pregnancy [OCAP], and National Health and Nutrition Estimates Study [NHANES III]) and the third molar clinical trials of young adults (White et al) are summarized. A secondary analysis determined whether the presence or absence of visible M3s was associated with an increased prevalence of clinical signs of periodontal disease using adjusted logistic regression models. In addition, serum samples collected from the OCAP, DARIC, and White studies were used to measure the markers of systemic inflammation, C-reactive protein, interleukin-6, and soluble intracellular adhesion molecule-1. RESULTS: In young adults, asymptomatic M3s were associated with an increase in periodontal probing depths of at least 4 mm on second molars and an increase in probing depth of at least 2 mm in 24% of subjects after 2 years. Retention of asymptomatic M3s for 6 years led to a significant increase in the number of subjects with a probing depth of 4 mm or more in non-M3 regions of the mouth. Findings from the DARIC, OCAP, and NHANES III further confirmed the association between the M3 probing depth and periodontal inflammation on non-M3s. Retention of M3s in the presence of periodontal inflammation was associated with significant increases in the serum interleukin-6, soluble intracellular adhesion molecule-1, and C-reactive protein levels. CONCLUSION: Patients deciding to retain M3s should consider the potential long-term effects on their periodontal status and the potential for the retained M3s to serve as a chronic source of inflammation that stresses their systemic health. PMID- 22916701 TI - Summary of the proceeding of the Third Molar Multidisciplinary Conference. PMID- 22916702 TI - What costs are associated with the management of third molars? AB - PURPOSE: The purpose of this study was to estimate the treatment costs directly related to operative and nonoperative management of asymptomatic, disease-free, third molar (M3) teeth. MATERIALS AND METHODS: The data reviewed were limited to claims submitted by oral and maxillofacial surgeons. The data collected included charges for consultations, radiographs, surgical removal of bony impacted teeth, and general anesthesia, using the 2009 data extracts from Delta Dental of Virginia. The median charges were used as a proxy for the actual costs attributable to the removal or retention of M3 teeth. Three clinical scenarios were executed using the available claims data to calculate the treatment costs associated with nonoperative and operative M3 management. An assumption made in the computation of expenses was that for subjects who elected to retain their M3s, the recommended management strategy was active surveillance. Active surveillance is a prescribed treatment to monitor the retained M3s characterized by performing a clinical examination and panoramic imaging every 2 years. The author assumed a 3% increase in charges per annum. RESULTS: The 3 scenarios were as follows: scenario 1 (nonoperative management), retention of asymptomatic, disease-free M3s and monitoring for 20 years from age 18 to 38 years; scenario 2 (operative management), removal of 2 asymptomatic, disease-free, bony impacted M3s for 18-year-old patients using general anesthesia (30 minutes) in an office based ambulatory setting; and scenario 3 (failure of non-operative management), removal of 1 previously asymptomatic, disease-free, bony impacted M3 after 10 years of follow-up in a now 28-year-old patient using general anesthesia (30 minutes) in an office-based ambulatory setting. The estimated charges for managing M3s were $2,342, $1,184, and $1,997 for scenarios 1, 2, and 3, respectively. CONCLUSIONS: A simplified financial analysis derived from the dental claims data suggests that during the course of the patient's lifetime, the charges associated with non-operative management of asymptomatic, disease-free M3s will exceed the charges of operative management. The difference in costs might be important to patients when choosing between operative and non-operative management of their M3s. PMID- 22916703 TI - Fibre intake and evolution of BMI: from pre-pregnancy to postpartum. AB - OBJECTIVE: To evaluate the effect of fibre intake on the evolution of maternal BMI from pregnancy to postpartum and to identify dietary patterns associated with fibre intake. DESIGN: Cohort study. Food intake was obtained using an FFQ. Focused principal component analysis was used focusing on the variables: postpartum weight retention and total dietary fibre intake. Poisson regression models with robust variance were built in order to measure the effect of fibre intake during the postpartum period on obesity risk. SETTING: Primary care clinics in southern Brazil. SUBJECTS: Pregnant women (n 370) were followed until the 5th month postpartum. RESULTS: The highest contribution to fibre intake came from the consumption of beans. Consumption of bread and rice indicated a common Brazilian food pattern along with beans. Participants retained a median of 4.4 (interquartile range 0.6, 7.9) kg of weight gained during pregnancy. Obesity risk, defined as an unfavourable evolution of BMI during pregnancy and postpartum, was present in 189 (55.1%) women. Individual food items did not have an important effect on weight retention. In Poisson regression adjusting for maternal age, pre-pregnancy BMI and total gestational weight gain, inadequate postpartum fibre intake increased obesity risk by 24% (relative risk 51.24; 95% CI 1.05, 1.47). CONCLUSIONS: Important maternal weight retention occurred in these women. Adequate fibre intake may reduce obesity risk in the period following childbirth. PMID- 22916704 TI - Infant feeding practices and prevalence of obesity in eight European countries - the IDEFICS study. AB - OBJECTIVE: To assess the association between exclusive breast-feeding and childhood overweight. DESIGN: Cross-sectional data are from the baseline survey of the longitudinal cohort study IDEFICS. Exclusive rather than partial breast feeding is the focus of the study due to the theoretical relationship between exclusive breast-feeding and development of dietary self-regulation. Children's measured heights and weights were used to calculate weight status, while waist-to height ratio (WtHR) and skinfold measures were examined as alternative indicators of adiposity and fat patterning. SETTING: Examination centres in eight European countries (Italy, Estonia, Cyprus, Belgium, Sweden, Hungary, Germany and Spain). SUBJECTS: The analysis included 14 726 children aged 2-9 years for whom early feeding practices were reported by parents in standardized questionnaires. RESULTS: After controlling for education, income and other potential confounders, breast-feeding exclusively for 4-6 months was protective of overweight (including obesity) when compared with children never exclusively breast-fed (OR = 0.73; 95 % CI 0.63, 0.85) across all measures of overweight. Exclusively breast-feeding for 6 months offered slightly more protection than for 4 and 5 months combined (OR = 0.71; 95 % CI 0.58, 0.85). The associations could not be explained by socio economic characteristics or maternal overweight. CONCLUSIONS: This multi-country investigation indicated that exclusive breast-feeding for 4-6 months may confer protection against overweight in addition to other known benefits. There was no demonstrated benefit of exclusive breast-feeding for more than 6 months or combination feeding for any duration across all measures of overweight examined. PMID- 22916705 TI - Human food preferences and cultural identity: the case of Aragon (Spain). AB - This research aims to analyze the relationship between sociocultural values and human food preferences. The latter, as shown in this paper, are greatly influenced by cultural identity. This work stems from a theoretical context that originated in Europe and the United States towards the mid-twentieth century, within the field of the anthropology of food. A qualitative and quantitative analysis has been performed in the Comunidad Autonoma de Aragon (Spain). Research methods include focus groups, in-depth interviews, participant observation, and a questionnaire that was handed out to a representative sample of the Aragonese population (816 people over 21 years of age; confidence level of 95.5% and error margin of +/-3.5). Regarding the research outcome, a highly significant qualitative and quantitative connection has been found between food selection and cultural identity. In other words, people prefer to consume foods that are symbolically associated with their own culture, in order to reinforce their sense of belonging. Although this study has been carried out in Aragon, it is our belief that the results can be generalized to other areas. The originality and interest of our findings are notable considering that, to date, few works have analyzed the sociocultural factors motivating food behavior. Moreover, these results could be used by public and private organizations to meet objectives such as health promotion and product marketing. PMID- 22916706 TI - A basic study on molecular hydrogen (H2) inhalation in acute cerebral ischemia patients for safety check with physiological parameters and measurement of blood H2 level. AB - BACKGROUND: In animal experiments, use of molecular hydrogen ( H2) has been regarded as quite safe and effective, showing benefits in multiple pathological conditions such as ischemia-reperfusion injury of the brain, heart, kidney and transplanted tissues, traumatic and surgical injury of the brain and spinal cord, inflammation of intestine and lung , degenerative striatonigral tissue and also in many other situations. However, since cerebral ischemia patients are in old age group, the safety information needs to be confirmed. For the feasibility of H2 treatment in these patients, delivery of H2 by inhalation method needs to be checked for consistency. METHODS: Hydrogen concentration (HC) in the arterial and venous blood was measured by gas chromatography on 3 patients, before, during and after 4% (case 1) and 3% (case2,3) H2 gas inhalation with simultaneous monitoring of physiological parameters. For a consistency study, HC in the venous blood of 10 patients were obtained on multiple occasions at the end of 30-min H2 inhalation treatment. RESULTS: The HC gradually reached a plateau level in 20 min after H2 inhalation in the blood, which was equivalent to the level reported by animal experiments. The HC rapidly decreased to 10% of the plateau level in about 6 min and 18 min in arterial and venous blood, respectively after H2 inhalation was discontinued. Physiological parameters on these 3 patients were essentially unchanged by use of hydrogen. The consistency study of 10 patients showed the HC at the end of 30-min inhalation treatment was quite variable but the inconsistency improved with more attention and encouragement. CONCLUSION: H2 inhalation of at least 3% concentration for 30 min delivered enough HC, equivalent to the animal experiment levels, in the blood without compromising the safety. However, the consistency of H2 delivery by inhalation needs to be improved. PMID- 22916707 TI - 7-Alkyl-3-benzylcoumarins: a versatile scaffold for the development of potent and selective cannabinoid receptor agonists and antagonists. AB - A series of 7-alkyl-3-benzylcoumarins was designed, synthesized, and tested at cannabinoid CB(1) and CB(2) receptors in radioligand binding and cAMP accumulation studies. 7-Alkyl-3-benzylcoumarins were found to constitute a versatile scaffold for obtaining potent CB receptor ligands with high potency at either CB(1) or CB(2) and a broad spectrum of efficacies. Fine-tuning of compound properties was achieved by small modifications of the substitution pattern. The most potent compounds of the present series include 5-methoxy-3-(2-methylbenzyl) 7-pentyl-2H-chromen-2-one (19a, PSB-SB-1201), a selective CB(1)antagonist (K(i) CB(1) 0.022 MUM), 5-methoxy-3-(2-methoxybenzyl)-7-pentyl-2H-chromen-2-one (21a, PSB-SB-1202), a dual CB(1)/CB(2)agonist (CB(1)K(i) 0.032 MUM, EC(50) 0.056 MUM; CB(2)K(i) 0.049 MUM, EC(50) 0.014 MUM), 5-hydroxy-3-(2-hydroxybenzyl)-7-(2 methyloct-2-yl)-2H-chromen-2-one (25b, PSB-SB-1203), a dual CB(1)/CB(2) ligand that blocks CB(1) but activates CB(2) receptors (CB(1)K(i) 0.244 MUM; CB(2)K(i) 0.210 MUM, EC(50) 0.054 MUM), and 7-(1-butylcyclopentyl)-5-hydroxy-3-(2 hydroxybenzyl)-2H-chromen-2-one (27b, PSB-SB-1204), a selective CB(2) receptor agonist (CB(1)K(i) 1.59 MUM; CB(2)K(i) 0.068 MUM, EC(50) 0.048 MUM). PMID- 22916708 TI - Application and validation of an impedance-based real time cell analyzer to measure the toxicity of nanoparticles impacting human bronchial epithelial cells. AB - Nanomaterials are increasingly used in a variety of industrial processes and consumer products. There are growing concerns about the potential impacts for public health and environment of engineered nanoparticles. The aim of this work was to evaluate a novel impedance-based real time cell analyzer (RTCA) as a high throughput method for screening the cytotoxicity of nanoparticles and to validate the RTCA results using a conventional cytotoxicity test (MTT). A collection of 11 inorganic nanomaterials (Ag(0), Al(2)O(3), CeO(2), Fe(0), Fe(2)O(3), HfO(2), Mn(2)O(3), SiO(2), TiO(2), ZnO, and ZrO(2)) were tested for potential cytotoxicity to a human bronchial epithelial cell, 16HBE14o-. The data collected by the RTCA system was compared to results obtained using a more traditional methyl tetrazolium (MTT) cytotoxicity assay at selected time points following application of nanomaterials. The most toxic nanoparticles were ZnO, Mn(2)O(3) and Ag(0), with 50% response at concentrations lower than 75 mg/L. There was a good correlation in cytotoxicity measurements between the two methods; however, the RTCA method maintained a distinct advantage in continually following cytotoxicity over time. The results demonstrate the potential and validity of the impedance-based RTCA technique to rapidly screen for nanoparticle toxicity. PMID- 22916709 TI - Initial events in the degradation of hyaluronan catalyzed by hyaluronate lyase from Streptococcus [corrected] pneumoniae: QM/MM simulation. AB - Hyaluronate lyase from Spectrococcus pneumonia can degrade hyaluronic acid, which is one of the major components in the extracellular matrix. The major functions of hyaluronan are to regulate water balance and osmotic pressure and act as an ion-exchange resin. In this work, we focus on the prerequisite issue of the enzymatic reaction, i.e., the initial reactive conformer. Based on the quantum mechanical and molecular mechanical molecular dynamic simulations and free energy profiles, a near attack conformer was obtained for the degradation of hyaluronan catalyzed by the hyaluronate lyase. Along with the substrate binding, the phenylhydroxyl hydrogen atom of Tyr408 will transfer to nearby His399 via a near barrierless transition state, which results in a negatively charged Tyr408 and positively charged His399. The Tyr408, rather than the previously proposed His399, was suggested to act as the general base for the subsequent beta elimination reaction. The His399 was suggested to have the function of neutralizing the C5-carboxyl group. PMID- 22916710 TI - Science, democracy and emerging threats to scientific progress. AB - Can trustworthy science flourish in countries suffering from dictatorship? This is an increasingly relevant question. Many commercial publishers want to maximise their profits (as is to be expected in a capitalistic system) and are pushing into non-democratic countries with rapid economic growth like China. But how much can we trust the papers coming from countries with dictatorial regimes? PMID- 22916711 TI - Evaluation of the functional importance of organic cation transporters on the ocular disposition of its intravitreally injected substrate in rabbits. AB - PURPOSE: To evaluate the functional role of organic cation transporters (OCT) and ocular tissue distribution of intravitreally injected OCT substrate tetraethylammonium (TEA) in presence of OCT blocker (quinidine). METHODS: New Zealand albino rabbits of either sex were used. Intravitreal quinidine pretreatment was made 30 min before the administration of TEA. Modulation of vitreous and ocular tissue kinetics of OCT substrate was evaluated with or without blocker pretreatment. Gamma scintigraphy was also performed to visualize the vitreous residence of (99m)Tc-labelled TEA in the presence and absence of blocker. RESULTS: Intravitreally injected quinidine did not significantly alter the ocular disposition of TEA. TEA showed less significant posterior elimination kinetics and slow anterior elimination which resulted in longer residence time of TEA in eye after intravitreal administration. CONCLUSIONS: Intravitreally injected OCT substrates may follow an anterior elimination pathway and prolonged residence time in vitreous humor. The present study shows that OCT may not be active from vitreous-to-blood route in the blood-retinal barrier. PMID- 22916712 TI - Expression of cassini, a murine gamma-satellite sequence conserved in evolution, is regulated in normal and malignant hematopoietic cells. AB - BACKGROUND: Acute lymphoblastic leukemia (ALL) cells treated with drugs can become drug-tolerant if co-cultured with protective stromal mouse embryonic fibroblasts (MEFs). RESULTS: We performed transcriptional profiling on these stromal fibroblasts to investigate if they were affected by the presence of drug treated ALL cells. These mitotically inactivated MEFs showed few changes in gene expression, but a family of sequences of which transcription is significantly increased was identified. A sequence related to this family, which we named cassini, was selected for further characterization. We found that cassini was highly upregulated in drug-treated ALL cells. Analysis of RNAs from different normal mouse tissues showed that cassini expression is highest in spleen and thymus, and can be further enhanced in these organs by exposure of mice to bacterial endotoxin. Heat shock, but not other types of stress, significantly induced the transcription of this locus in ALL cells. Transient overexpression of cassini in human 293 embryonic kidney cells did not increase the cytotoxic or cytostatic effects of chemotherapeutic drugs but provided some protection. Database searches revealed that sequences highly homologous to cassini are present in rodents, apicomplexans, flatworms and primates, indicating that they are conserved in evolution. Moreover, CASSINI RNA was induced in human ALL cells treated with vincristine. Surprisingly, cassini belongs to the previously reported murine family of gamma-satellite/major satellite DNA sequences, which were not known to be present in other species. CONCLUSIONS: Our results show that the transcription of at least one member of these sequences is regulated, suggesting that this has a function in normal and transformed immune cells. Expression of these sequences may protect cells when they are exposed to specific stress stimuli. PMID- 22916713 TI - Rationale for the clinical application of flow cytometry in patients with myelodysplastic syndromes: position paper of an International Consortium and the European LeukemiaNet Working Group. AB - An international working group within the European LeukemiaNet gathered, aiming to determine the role of flow cytometry (FC) in myelodysplastic syndromes (MDS). It was agreed that FC has a substantial application in disease characterization, diagnosis and prognosis. FC may also be useful in predicting treatment responses and monitoring novel and standard therapeutic regimens. In this article the rationale is discussed that flow cytometry should be integrated as a part of diagnostic and prognostic scoring systems in MDS. PMID- 22916714 TI - Lunchtime food and nutrient intakes of secondary-school pupils; a comparison of school lunches and packed lunches following the introduction of mandatory food based standards for school lunch. AB - OBJECTIVE: To compare the key differences between school lunches and packed lunches as eaten in eleven secondary schools in England, 21 months after the food based standards for school lunch became mandatory, but before the introduction of nutrient-based standards. DESIGN: Data on 358 school lunches and 139 packed lunches were collected in May and June 2008 from pupils attending secondary schools in Sheffield, Manchester, Leicester City and Essex. Fieldwork was conducted over five consecutive school days at each school. Fieldworkers randomly selected five pupils taking a school lunch and five pupils bringing a packed lunch each day. All food and drink items chosen by pupils were weighed and recorded. Leftovers were also weighed. SETTING: Eleven state-maintained, co educational secondary schools from four local authorities in England. SUBJECTS: Four hundred and ninety-seven pupils aged 11-16 years. RESULTS: Pupils taking school lunches, on average, had significantly higher intakes of energy, protein, carbohydrate, NSP, vitamin C, folate, Fe and Zn than pupils bringing a packed lunch to school. Mean intakes of protein, fat and vitamin C from both types of lunch met the nutrient-based standards and school lunches also met standards for carbohydrate, NSP and energy. CONCLUSIONS: Nutrient intakes from school lunches were more favourable than those from packed lunches, but typically failed to meet nutrient-based standards for school food. A combination of continued improvements to school food, educating pupils to make healthier choices and policies to encourage pupils to eat at school or bring healthier packed lunches is needed. PMID- 22916715 TI - Abacavir/lamivudine versus tenofovir/emtricitabine in virologically suppressed patients switching from ritonavir-boosted protease inhibitors to raltegravir. AB - There are few clinical data on the combination abacavir/lamivudine plus raltegravir. We compared the outcomes of patients from the SPIRAL trial receiving either abacavir/lamivudine or tenofovir/emtricitabine at baseline who had taken at least one dose of either raltegravir or ritonavir-boosted protease inhibitors. For the purpose of this analysis, treatment failure was defined as virological failure (confirmed HIV-1 RNA >=50 copies/ml) or discontinuation of abacavir/lamivudine or tenofovir/emtricitabine because of adverse events, consent withdrawal, or lost to follow-up. There were 143 (72.59%) patients with tenofovir/emtricitabine and 54 (27.41%) with abacavir/lamivudine. In the raltegravir group, there were three (11.11%) treatment failures with abacavir/lamivudine and eight (10.96%) with tenofovir/emtricitabine (estimated difference 0.15%; 95% CI -17.90 to 11.6). In the ritonavir-boosted protease inhibitor group, there were four (14.81%) treatment failures with abacavir/lamivudine and 12 (17.14%) with tenofovir/emtricitabine (estimated difference -2.33%; 95% CI -16.10 to 16.70). Triglycerides decreased and HDL cholesterol increased through the study more pronouncedly with abacavir/lamivudine than with tenofovir/emtricitabine and differences in the total-to-HDL cholesterol ratio between both combinations of nucleoside reverse transcriptase inhibitors (NRTIs) tended to be higher in the raltegravir group, although differences at 48 weeks were not significant. While no patient discontinued abacavir/lamivudine due to adverse events, four (2.80%) patients (all in the ritonavir-boosted protease inhibitor group) discontinued tenofovir/emtricitabine because of adverse events (p=0.2744). The results of this analysis do not suggest that outcomes of abacavir/lamivudine are worse than those of tenofovir/emtricitabine when combined with raltegravir in virologically suppressed HIV-infected adults. PMID- 22916716 TI - Self-assembly of highly ordered peptide amphiphile metalloporphyrin arrays. AB - Long fibers assembled from peptide amphiphiles capable of binding the metalloporphyrin zinc protoporphyrin IX ((PPIX)Zn) have been synthesized. Rational peptide design was employed to generate a peptide, c16-AHL(3)K(3) CO(2)H, capable of forming a beta-sheet structure that propagates into larger fibrous structures. A porphyrin-binding site, a single histidine, was engineered into the peptide sequence in order to bind (PPIX)Zn to provide photophysical functionality. The resulting system indicates control from the molecular level to the macromolecular level with a high order of porphyrin organization. UV/visible and circular dichroism spectroscopies were employed to detail molecular organization, whereas electron microscopy and atomic force microscopy aided in macromolecular characterization. Preliminary picosecond transient absorption data are also reported. Reduced hemin, (PPIX)Fe(II), was also employed to highlight the material's versatility and tunability. PMID- 22916717 TI - An evidence-based approach to traumatic pain management in the emergency department. AB - Painful traumatic injuries account for a large portion of emergency department visits. Injuries may occur through various mechanisms, and many patient and provider factors affect the success of treatment. Not all injuries or patients should be treated in exactly the same fashion, and an understanding of these factors is important to providing optimal care. Medications, management strategies, and methods of evaluation have been studied with varying depth and success. Regional anesthetic techniques and nonpharmacologic means can help minimize the use of systemic agents that may have unwanted side effects. Diagnostic evaluation should not detract from symptomatic treatment. This evidence-based review summarizes the pathophysiology, historical factors, diagnostic strategies, and demographics that influence the experience of pain and provides recommendations for a variety of treatment options. PMID- 22916718 TI - Adaptive k-means algorithm for overlapped graph clustering. AB - The graph clustering problem has become highly relevant due to the growing interest of several research communities in social networks and their possible applications. Overlapped graph clustering algorithms try to find subsets of nodes that can belong to different clusters. In social network-based applications it is quite usual for a node of the network to belong to different groups, or communities, in the graph. Therefore, algorithms trying to discover, or analyze, the behavior of these networks needed to handle this feature, detecting and identifying the overlapped nodes. This paper shows a soft clustering approach based on a genetic algorithm where a new encoding is designed to achieve two main goals: first, the automatic adaptation of the number of communities that can be detected and second, the definition of several fitness functions that guide the searching process using some measures extracted from graph theory. Finally, our approach has been experimentally tested using the Eurovision contest dataset, a well-known social-based data network, to show how overlapped communities can be found using our method. PMID- 22916719 TI - Unsupervised markerless 3-DOF motion tracking in real time using a single low budget camera. AB - Motion tracking is a critical task in many computer vision applications. Existing motion tracking techniques require either a great amount of knowledge on the target object or specific hardware. These requirements discourage the wide spread of commercial applications based on motion tracking. In this paper, we present a novel three degrees of freedom motion tracking system that needs no knowledge on the target object and that only requires a single low-budget camera that can be found installed in most computers and smartphones. Our system estimates, in real time, the three-dimensional position of a nonmodeled unmarked object that may be nonrigid, nonconvex, partially occluded, self-occluded, or motion blurred, given that it is opaque, evenly colored, enough contrasting with the background in each frame, and that it does not rotate. Our system is also able to determine the most relevant object to track in the screen. Our proposal does not impose additional constraints, therefore it allows a market-wide implementation of applications that require the estimation of the three position degrees of freedom of an object. PMID- 22916720 TI - On the segmentation and classification of hand radiographs. AB - This research is part of a wider project to build predictive models of bone age using hand radiograph images. We examine ways of finding the outline of a hand from an X-ray as the first stage in segmenting the image into constituent bones. We assess a variety of algorithms including contouring, which has not previously been used in this context. We introduce a novel ensemble algorithm for combining outlines using two voting schemes, a likelihood ratio test and dynamic time warping (DTW). Our goal is to minimize the human intervention required, hence we investigate alternative ways of training a classifier to determine whether an outline is in fact correct or not. We evaluate outlining and classification on a set of 1370 images. We conclude that ensembling with DTW improves performance of all outlining algorithms, that the contouring algorithm used with the DTW ensemble performs the best of those assessed, and that the most effective classifier of hand outlines assessed is a random forest applied to outlines transformed into principal components. PMID- 22916721 TI - Tips and tricks in the dermoscopy of pigmented lesions. AB - Dermoscopy is a useful, widely used tool for examining pigmented lesions, especially helpful in cases of an uncertain nature. Nevertheless, doctors may experience diagnostic difficulties while using this method. An example of this may be found in the examination of subcorneal hematoma, dark nevi with black lamella or lesions of acral volar skin. In such cases, a few diagnostic tricks have proven to be helpful in achieving diagnostic accuracy. This paper reviews various methods of performing dermoscopy, suggesting a number of simple, yet helpful tests. These include the adhesive tape test, the skin scraping test and the ink furrow test. The adhesive tape test is helpful in differentiating between dark melanocytic nevi and melanoma. Hematoma may be more easily differentiated with the use of the so-called skin scraping test. The confirmation of benign and melanocytic lesions of acral volar skin, on the other hand, is more accurate when using the ink furrow test. These methods have been discussed here based upon a series of literature reviews, the authors' own experience and, also, iconography. The present article describes novel methods used in dermoscopy, helping to bring about a faster, more accurate diagnostics of those lesions which have proven to be more difficult to recognize. Helpful tricks, such as have been known to professional literature, as well as the authors' own experience (for instance, applying urea cream to hyperkeratotic lesions or using photographs of skin lesions taken with the aid of a mobile phone camera--all prior to surgery) will surely be considered beneficial to the practitioner, be it dermatologist or any other physician. PMID- 22916722 TI - Safety issues related to erythropoiesis-stimulating agents used to treat anemia in patients with chronic kidney disease. AB - INTRODUCTION: Erythropoiesis-stimulating agents (ESAs) have been the main therapy for anemia in CKD patients since the late eighties. Since then, treatment indications have progressively changed, together with a progressive increase in therapeutic targets, in terms of hemoglobin levels. AREAS COVERED: This paper discusses possible concerns about ESA use and increased cardiovascular risk (in particular stroke), hypertension, cancer progression and the development of pure red cell aplasia. A literature search was done on PubMed to obtain studies about the adverse effects of ESA in the CKD population. EXPERT OPINION: The publication of the TREAT study has largely contributed to the concerns about ESA use, indicating that complete anemia correction may not be safe in the CKD population. This may be particularly true in high-risk patients, especially if hyporesponsive to ESA treatment. However, there is a gray area of no evidence either way for intermediate levels (11.5 - 13 g/dl), in comparison with higher or lower levels. New recommendations about ESA use in the CKD population by the Food and Drug Administration seem to move toward treatment individualization. PMID- 22916723 TI - Fractalkine gene receptor polymorphism in patients with multiple sclerosis. AB - BACKGROUND: Although the immunopathogenesis of multiple sclerosis (MS) has been intensely investigated in recent years, some associated molecules still have not been examined. For instance, no study has been conducted to investigate a possible polymorphism in the fractalkine receptor gene. METHODS: In order to examine fractalkine gene receptor polymorphisms, 3 mL of serum from 92 MS patients and 91 controls were stored at -20 degrees C. DNA was extracted from the serum samples that were purified, and the gene regions in CX3CR1 (i.e., the fractalkine regions) containing the T280M and V294I fractalkine receptor haplotypes were amplified via the polymerase chain reaction (PCR) technique. The obtained fragments were then cut using restriction enzymes, and agarose gel electrophoresis was performed. RESULTS: In a comparison of the patients and controls, we found that the median values of the Expanded Disability Status Scale (EDSS) scores among genotypes of the V294I polymorphism in the fractalkine gene receptor were statistically higher in genotype II than genotype VI. Also, relapsing/remitting MS (RRMS) was statistically higher in genotype VI than in genotype II, whereas the frequency of secondary progressive MS (SPMS) was statistically higher in genotype VV than in the genotype VI for the same polymorphism. CONCLUSIONS: Although many polymorphism studies have focused on patients with MS, there is no polymorphism study about the fractalkine receptor which is a chemokine and plays an important role in neuroinflammation and neurodegeneration. Our results provide information about disease progression and may also be beneficial in developing new strategies for the treatment of the disease. PMID- 22916724 TI - Advances in the monitoring of anti-P2Y12 therapy. AB - Although there are many new and effective anti-P2Y(12) drugs available, clopidogrel in its original or generic forms will probably remain the most widely used and cheaper option. As clopidogrel is a pro-drug, there is marked heterogeneity in drug responsiveness between individuals and lack of responsiveness is associated with poorer clinical outcomes. Various platelet function and genetic tests are now available for potentially measuring whether clopidogrel effectively inhibits platelet function. Monitoring of P2Y(12) inhibition and/or identification of loss of function cytochrome P-450 genotypes could, therefore, offer the potential of tailoring therapy by identifying poor responders to clopidogrel and optimizing the levels of platelet inhibition using, for example, alternative drugs such as prasugrel or ticagrelor. The question remains whether any of these tests have prognostic utility with a defined therapeutic window to reliably identify hypo or hyper-responsive patients who may have an increased risk of thrombosis or bleeding, respectively? Once such patients are identified, can the tests then be subsequently used to demonstrate a change or improvement in platelet reactivity by using alternative therapies and equate this with improved clinical outcome? In this review, we describe an overview of the current platelet and genetic tests available and discuss whether these tests will ever become used routinely. PMID- 22916725 TI - Quantification of toxic metals derived from macroplastic litter on Ookushi Beach, Japan. AB - The potential risk of toxic metals that could leach into a beach environment from plastic litter washed ashore on Ookushi Beach, Goto Islands, Japan was estimated by balloon aerial photography, in situ beach surveys, and leaching experiments in conjunction with a Fickian diffusion model analysis. Chromium (Cr), cadmium (Cd), tin (Sn), antimony (Sb), and lead (Pb) were detected in plastic litter collected during the beach surveys. Polyvinyl chloride (PVC) fishing floats contained the highest quantity of Pb. Balloon aerial photography in conjunction with a beach survey gave an estimated mass of Pb derived from plastic litter of 313 +/- 247 g. Lead leaching experiments on collected PVC floats showed that Pb in the plastic litter could leach into surrounding water on the actual beach, and that plastic litter may act as a "transport vector" of toxic metals to the beach environment. Using the experimental data, the total mass of Pb that could leach from PVC plastic litter over a year onto Ookushi Beach was estimated as 0.6 +/- 0.6 g/year, suggesting that toxic metals derived from plastic beach litter are a potential "pathway" to contamination of the beach environment due to their accumulation in beach soil over time. PMID- 22916726 TI - Manipulating JNK signaling with (--)-zuonin A. AB - Recently, in a virtual screening strategy to identify new compounds targeting the D-recruitment site (DRS) of the c-Jun N-terminal kinases (JNKs), we identified the natural product (-)-zuonin A. Here we report the asymmetric synthesis of (-) zuonin A and its enantiomer (+)-zuonin A. A kinetic analysis for the inhibition of c-Jun phosphorylation by (-)-zuonin A revealed a mechanism of partial competitive inhibition. Its binding is proposed to weaken the interaction of c Jun to JNK by approximately 5-fold, without affecting the efficiency of phosphorylation within the complex. (-)-Zuonin A inhibits the ability of both MKK4 and MKK7 to phosphorylate and activate JNK. The binding site of (-)-zuonin A is predicted by docking and molecular dynamics simulation to be located in the DRS of JNK. (+)-Zuonin A also binds JNK but barely impedes the binding of c-Jun. (-)-Zuonin A inhibits the activation of JNK, as well as the phosphorylation of c Jun in anisomycin-treated HEK293 cells, with the inhibition of JNK activation being more pronounced. (-)-Zuonin A also inhibits events associated with constitutive JNK2 activity, including c-Jun phosphorylation, basal Akt activation, and MDA-MB-231 cell migration. Mutations in the predicted binding site for (-)-zuonin A can render it significantly more or less sensitive to inhibition than wild type JNK2, allowing for the design of potential chemical genetic experiments. These studies suggest that the biological activity reported for other lignans, such as saucerneol F and zuonin B, may be the result of their ability to impede protein-protein interactions within MAPK cascades. PMID- 22916727 TI - Design and synthesis of indomethacin analogues that inhibit P-glycoprotein and/or multidrug resistant protein without COX inhibitory activity. AB - We designed and synthesized conformationally restricted analogues and regioisomers of the nonsteroidal anti-inflammatory drug indomethacin. Evaluation of the inhibitory effects of these compounds on COX, P-glycoprotein, and multidrug resistance indicated that NSAIDS modulation of multidrug-resistant P glycoprotein and multidrug-resistant protein-1 is not associated with COX-1 and COX-2 inhibitory activities. PMID- 22916728 TI - Social gradients in child and adolescent antisocial behavior: a systematic review protocol. AB - BACKGROUND: The relationship between social position and physical health is well established across a range of studies. The evidence base regarding social position and mental health is less well developed, particularly regarding the development of antisocial behavior. Some evidence demonstrates a social gradient in behavioral problems, with children from low-socioeconomic backgrounds experiencing more behavioral difficulties than children from high-socioeconomic families. Antisocial behavior is a heterogeneous concept that encompasses behaviors as diverse as physical fighting, vandalism, stealing, status violation and disobedience to adults. Whether all forms of antisocial behavior show identical social gradients is unclear from previous published research. The mechanisms underlying social gradients in antisocial behavior, such as neighborhood characteristics and family processes, have not been fully elucidated. This review will synthesize findings on the social gradient in antisocial behavior, considering variation across the range of antisocial behaviors and evidence regarding the mechanisms that might underlie the identified gradients. METHODS: In this review, an extensive manual and electronic literature search will be conducted for papers published from 1960 to 2011. The review will include empirical and quantitative studies of children and adolescents (<=18 years old) recruited from the general population, which include measures of both social position and antisocial behavior. A standardized data extraction form and quality appraisal checklist will be used to retrieve essential information and critically appraise each study and the inter-rater reliability of the quality scores will be assessed. If practical, meta-analysis will be used to synthesize the data. However, it is expected that the selected studies will be heterogeneous, in which case narrative synthesis will be applied. Separate conclusions may be drawn for logically grouped studies on the basis of their quality score, scope or methodology. DISCUSSION: This systematic review has been proposed in order to synthesize cross-disciplinary evidence of the social gradient in antisocial behavior and mechanisms underlying this effect. The results of the review will inform social policies aiming to reduce social inequalities and levels of antisocial behavior, and identify gaps in the present literature to guide further research. PMID- 22916729 TI - Simulating a molecular machine in action. AB - Using QM/MM methods, we have simulated the action of a simple molecular machine, a cilium. It consists of a platform for surface mounting, a photochemical motor unit, and a tail-like effector that amplifies the small-scale conformational change of the motor unit into a larger-scale beating motion usable for molecular transport. In this proof-of-principle application, we show that the techniques used here make it possible to perform such simulations within reasonable real time, if the device action is sufficiently fast. Additionally, we show that this molecular device actually works as intended for one isomerization direction. For the other direction, results are inconclusive, possibly because the total propagation times we can afford are too short to capture the complete event. PMID- 22916731 TI - Effect of the anodization voltage on the pore-widening rate of nanoporous anodic alumina. AB - A detailed study of the pore-widening rate of nanoporous anodic alumina layers as a function of the anodization voltage was carried out. The study focuses on samples produced under the same electrolyte and concentration but different anodization voltages within the self-ordering regime. By means of ellipsometry based optical characterization, it is shown that in the pore-widening process, the porosity increases at a faster rate for lower anodization voltages. This opens the possibility of obtaining three-dimensional nanostructured nanoporous anodic alumina with controlled thickness and refractive index of each layer, and with a refractive index difference of up to 0.24 between layers, for samples produced with oxalic acid electrolytes. PMID- 22916730 TI - LIPID11: a modular framework for lipid simulations using amber. AB - Accurate simulation of complex lipid bilayers has long been a goal in condensed phase molecular dynamics (MD). Structure and function of membrane-bound proteins are highly dependent on the lipid bilayer environment and are challenging to study through experimental methods. Within Amber, there has been limited focus on lipid simulations, although some success has been seen with the use of the General Amber Force Field (GAFF). However, to date there are no dedicated Amber lipid force fields. In this paper we describe a new charge derivation strategy for lipids consistent with the Amber RESP approach and a new atom and residue naming and type convention. In the first instance, we have combined this approach with GAFF parameters. The result is LIPID11, a flexible, modular framework for the simulation of lipids that is fully compatible with the existing Amber force fields. The charge derivation procedure, capping strategy, and nomenclature for LIPID11, along with preliminary simulation results and a discussion of the planned long-term parameter development are presented here. Our findings suggest that LIPID11 is a modular framework feasible for phospholipids and a flexible starting point for the development of a comprehensive, Amber-compatible lipid force field. PMID- 22916733 TI - An update on bronchodilators in Phase I and II clinical trials. AB - INTRODUCTION: Inhaled bronchodilators are the mainstay of the current management of COPD at all stages of the disease, and are critical in the symptomatic management of asthma. Therefore, there is still considerable interest in finding novel classes of broncholytic drugs or, at least, in improving the existing classes of bronchodilator. AREAS COVERED: This review paper mainly focuses on bronchodilators that are in Phase I and II clinical trials. EXPERT OPINION: To date, finding new classes of bronchodilators has proved difficult. Consequently, many research groups have sought to improve the existing classes of bronchodytic drugs. The majority of programs in development for novel bronchodilators are focused on developing new ligands that interact with beta(2)-adrenoceptors and/or muscarinic acetylcholine receptors in a manner that enhances their bronchodilator effectiveness and duration of action, which allows only one administration per day, although the twice-daily dosing of bronchodilators is still considered a useful approach to the symptomatic treatment of COPD, and improving their safety profiles. Moreover, the current opinion is that it is advantageous to develop inhalers containing combinations of long-acting bronchodilator drugs in an attempt to simplify treatment regimes as much as possible. Another goal is to develop novel combinations of one or two classes of long-acting bronchodilators along with inhaled corticosteroids. PMID- 22916732 TI - Micro-computed tomography evaluation of human fat grafts in nude mice. AB - BACKGROUND: Although autologous fat grafting has revolutionized the field of soft tissue reconstruction and augmentation, long-term maintenance of fat grafts is unpredictable. Recent studies have reported survival rates of fat grafts to vary anywhere between 10% and 80% over time. The present study evaluated the long-term viability of human fat grafts in a murine model using a novel imaging technique allowing for in vivo volumetric analysis. METHODS: Human fat grafts were prepared from lipoaspirate samples using the Coleman technique. Fat was injected subcutaneously into the scalp of 10 adult Crl:NU-Foxn1(nu) CD-1 male mice. Micro computed tomography (CT) was performed immediately following injection and then weekly thereafter. Fat volume was rendered by reconstructing a three-dimensional (3D) surface through cubic-spline interpolation. Specimens were also harvested at various time points and sections were prepared and stained with hematoxylin and eosin (H&E), for macrophages using CD68 and for the cannabinoid receptor 1 (CB1). Finally, samples were explanted at 8- and 12-week time points to validate calculated micro-CT volumes. RESULTS: Weekly CT scanning demonstrated progressive volume loss over the time course. However, volumetric analysis at the 8- and 12 week time points stabilized, showing an average of 62.2% and 60.9% survival, respectively. Gross analysis showed the fat graft to be healthy and vascularized. H&E analysis and staining for CD68 showed minimal inflammatory reaction with viable adipocytes. Immunohistochemical staining with anti-human CB1 antibodies confirmed human origin of the adipocytes. CONCLUSIONS: Studies assessing the fate of autologous fat grafts in animals have focused on nonimaging modalities, including histological and biochemical analyses, which require euthanasia of the animals. In this study, we have demonstrated the ability to employ micro-CT for 3D reconstruction and volumetric analysis of human fat grafts in a mouse model. Importantly, this model provides a platform for subsequent study of fat manipulation and soft tissue engineering. PMID- 22916734 TI - Ruthenium-catalyzed transformation of aryl and alkenyl triflates to halides. AB - Aryl triflates were transformed to aryl bromides/iodides simply by treating them with LiBr/NaI and [Cp*Ru(MeCN)(3)]OTf. The ruthenium complex also catalyzed the transformation of alkenyl sulfonates and phosphates to alkenyl halides under mild conditions. Aryl and alkenyl triflates undergo oxidative addition to a ruthenium(II) complex to form eta(1)-arylruthenium and 1-ruthenacyclopropene intermediates, respectively, which are transformed to the corresponding halides. PMID- 22916735 TI - Transcriptomics in human blood incubation reveals the importance of oxidative stress response in Saccharomyces cerevisiae clinical strains. AB - BACKGROUND: In recent years an increasing number of yeast infections in humans have been related to certain clinical isolates of Saccharomyces cerevisiae. Some clinical strains showed in vivo and in vitro virulence traits and were able to cause death in mice whereas other clinical strains were avirulent. RESULTS: In this work, we studied the transcriptional profiles of two S. cerevisiae clinical strains showing virulent traits and two control non-virulent strains during a blood incubation model and detected a specific transcriptional response of clinical strains. This response involves an mRNA levels increase of amino acid biosynthesis genes and especially oxidative stress related genes. We observed that the clinical strains were more resistant to reactive oxygen species in vitro. In addition, blood survival of clinical isolates was high, reaching similar levels to pathogenic Candida albicans strain. Furthermore, a virulent strain mutant in the transcription factor Yap1p, unable to grow in oxidative stress conditions, presented decreased survival levels in human blood compared with the wild type or YAP1 reconstituted strain. CONCLUSIONS: Our data suggest that this enhanced oxidative stress response in virulent clinical isolates, presumably induced in response to oxidative burst from host defense cells, is important to increase survival in human blood and can help to infect and even produce death in mice models. PMID- 22916736 TI - Staphylococcus aureus infection of the rabbit cornea following topical administration. AB - PURPOSE: To determine the ability of diverse S. aureus strains to infect the rabbit cornea following topical inoculation, with special emphasis on a strain of unusual virulence. MATERIALS AND METHODS: S. aureus strains (5 * 10(5) colony forming units; CFU) were topically applied onto scarified rabbit corneas or 100 CFU were intrastromally injected into rabbit corneas. Eyes were scored by slit lamp examination (SLE) and corneas were cultured to determine the log CFU. Polymorphonuclear leukocytes (PMN) were quantified by myeloperoxidase assays and corneas underwent histopathological analysis. Hemolysin titers of S. aureus strains were determined and S. aureus interactions with rabbit tears or human corneal epithelial cells were investigated. RESULTS: All strains injected into the cornea produced high SLE scores and multi-log increases in CFU. Following topical inoculation, four strains produced low SLE scores with no bacterial replication. One strain (UMCR1) topically infected the cornea, causing high SLE scores, extensive PMN infiltration, and multi-log increases in CFU. Histopathologic analysis demonstrated a PMN influx into the UMCR1-infected cornea, destruction of the corneal epithelium, and severe edema. Strain UMCR1 did not demonstrate a high hemolysin titer or resistance to the bactericidal activity of rabbit tears, but did invade human corneal epithelial cells with relatively high efficiency. CONCLUSIONS: One S. aureus strain demonstrated the ability to topically infect the rabbit cornea. This strain was previously found to be unique in its ability to infect the anterior chamber and conjunctiva, suggesting that a key mechanism may be employed to overcome the host defenses of these three ocular sites. PMID- 22916738 TI - Molecular epidemiology of HIV type 1 infection in Iran: genomic evidence of CRF35_AD predominance and CRF01_AE infection among individuals associated with injection drug use. AB - To understand the molecular epidemiology of HIV-1 infection in Iran, we conducted the first study to analyze the genome sequence of Iranian HIV-1 isolates. For this cross-sectional study, we enrolled 10 HIV-1-infected individuals associated with injection drug use from Tehran, Shiraz, and Kermanshah. Near full-length genome sequences obtained from their plasma samples were used for phylogenetic tree and similarity plotting analyses. Among 10 isolates, nine were clearly identified as CRF35_AD and the remaining one as CRF01_AE. Interestingly, five of our Iranian CRF35_AD isolates made two clusters with 10 Afghan CRF35_AD isolates in a phylogenetic tree, indicating epidemiological connections among injection drug users in Iran and Afghanistan. In contrast, our CRF01_AE isolate had no genetic relationship with any other CRF01_AE isolates worldwide, even from Afghanistan. This study provides the first genomic evidence of HIV-1 CRF35_AD predominance and CRF01_AE infection among individuals associated with injection drug use in Iran. PMID- 22916737 TI - Adiposity indices in the prediction of insulin resistance in prepubertal Colombian children. AB - OBJECTIVE: To compare BMI with abdominal skinfold thickness (ASF), waist circumference and waist-to-height ratio in the prediction of insulin resistance (IR) in prepubertal Colombian children. DESIGN: We calculated age- and sex specific Z-scores for BMI, ASF, waist circumference, waist-to-height ratio and three other skinfold-thickness sites. Logistic regression with stepwise selection (P = 0.80 for entry and P = 0.05 for retention) was performed to identify predictors of IR and extreme IR, which were determined by age- and sex-specific Z scores to identify the >= 90th and >= 95th percentile of homeostasis model assessment (HOMAIR), respectively. We used receiver operating characteristic curves to compare the area under the curve between models. SETTING: Bucaramanga, Colombia. SUBJECTS: Children (n 1261) aged 6-10 years in Tanner stage 1 from a population-based study. RESULTS: A total of 127 children (seventy girls and fifty seven boys) were classified with IR, including sixty-three children (thirty-three girls and thirty boys) classified with extreme IR. Only ASF and BMI Z-scores were retained as predictors of IR by stepwise selection. Adding ASF Z-score to BMI Z score improved the area under the curve from 0.794 (95 % CI 0.752, 0.837) to 0.811 (95 % CI 0.770, 0.851; P for contrast = 0.01). In predicting extreme IR, the addition of ASF Z-score to BMI Z-score improved the area under the curve from 0.837 (95 % CI 0.790, 0.884) to 0.864 (95 % CI 0.823, 0.905; P for contrast = 0.01). CONCLUSIONS: ASF Z-score predicted IR independent of BMI Z-score in our population of prepubertal children. ASF and BMI Z-scores together improved IR risk stratification compared with BMI Z-score alone, opening new perspectives in the prediction of cardiometabolic risk in prepubertal children. PMID- 22916739 TI - Re: Results of accelerated postoperative rehabilitation using novel "suture frame" repair of Achilles tendon rupture. PMID- 22916741 TI - Postmenopausal unopposed estrogen and estrogen plus progestin use and risk of non Hodgkin lymphoma in the American Cancer Society Cancer Prevention Study-II Cohort. AB - Results of epidemiologic studies on postmenopausal hormone (PMH) use and non Hodgkin lymphoma (NHL) are inconsistent. To help clarify this issue, PMH and NHL incidence was examined in the Cancer Prevention Study-II Nutrition Cohort. Between 1992 and 2007, 616 cases of NHL were identified among 67 980 postmenopausal women who were cancer-free at baseline. PMH use was updated during follow-up. Using extended Cox regression, we observed a statistically significant 29% higher risk of NHL for ever unopposed estrogen use compared to never use, which was restricted to follicular lymphoma (current estrogen compared to never use, hazard ratio [HR] = 2.25, 95% confidence interval [CI]: 1.17-4.33) and diffuse large B-cell lymphoma (DLBCL, HR = 1.95, 95% CI: 1.13-3.35). There was no association between current estrogen plus progestin (E + P) use and NHL incidence overall, but a suggested positive association between current E + P use and DLBCL, as well as former E + P use and follicular lymphoma. These results suggest that postmenopausal hormones might play a role in NHL etiology, particularly for follicular lymphoma and DLBCL. PMID- 22916742 TI - Invited commentary. PMID- 22916743 TI - Invited commentary. PMID- 22916744 TI - Invited commentary. PMID- 22916745 TI - Invited commentary. PMID- 22916746 TI - Invited commentary. PMID- 22916747 TI - Invited commentary. PMID- 22916748 TI - Invited commentary. PMID- 22916749 TI - Invited commentary. PMID- 22916750 TI - Invited commentary. PMID- 22916751 TI - Invited commentary. PMID- 22916752 TI - Invited commentary. PMID- 22916753 TI - Percutaneous transcatheter closure of the aortic valve to treat cardiogenic shock in a left ventricular assist device patient with severe aortic insufficiency. AB - In this case report, we present a patient status post left ventricular assist device implantation complicated by de novo aortic insufficiency. At 8 months postimplant, the patient underwent a reoperative aortic valve repair, without complete closure of the valve. Three months after reoperation, the patient developed cardiogenic shock secondary to recurrent, severe aortic insufficiency. Ultimately, the patient underwent percutaneous, transcatheter closure of the aortic valve with an Amplatzer Cribiform device (AGA Medical Corp, Plymouth, MN). Two months post procedure, the patient remains stable with improved symptoms and functional status, and without evidence of further aortic insufficiency or device migration. PMID- 22916754 TI - Repair of a penetrating ascending aortic ulcer with localized resection and extracellular matrix patch aortoplasty. AB - Penetrating ascending aortic ulcers are rarely encountered, yet they present significant risk of hemorrhage and aortic dissection. Expedient recognition and repair is of vital importance. The current management of penetrating ulcer of the ascending aorta includes replacement of the ascending aorta with a prosthetic graft. We describe our technique of repairing a penetrating ulcer of the ascending aorta with localized ulcer resection and extracellular matrix patch aortoplasty. PMID- 22916755 TI - Proximal sano anastomosis aneurysm due to degeneration of bovine pericardial patch. AB - We report a 5-year-old girl with hypoplastic left heart syndrome who originally underwent a Norwood procedure with a Sano shunt. Subsequent procedures included a bidirectional Glenn and extracardiac Fontan with a Gore-Tex graft (W.L Gore and Associates, Flagstaff, AZ). The patient was found to have a heart murmur on a follow-up visit 3 years later. Echocardiography and computed tomography imaging showed an aneurysm of the proximal Sano anastomosis. The patient underwent successful surgical repair. PMID- 22916756 TI - Common carotid artery to internal jugular vein shunt for managing hypoxemia after a cavopulmonary shunt. AB - In the present report, we discuss a patient who developed persistent hypoxemia after an attempt at Fontan completion failed. As a bail-out procedure, a left common carotid artery to left internal jugular vein shunt was constructed, after which the hypoxemia was relieved. PMID- 22916758 TI - Lesson to be learned: beware of lusoria artery during transhiatal esophagectomy. AB - The presence of an aberrant right subclavian artery represents a potentially risky situation when high mediastinal surgery is planned. We report a case of a patient needing transhiatal esophagectomy for cancer; the presence of the abnormal anatomic arterial situation complicated the postoperative course, when a vascular- digestive fistula appears. We discuss the direct causes and consequences of a rare situation. PMID- 22916757 TI - Tracheal stent to repair tracheal laceration after a double-lumen intubation. AB - A 59-year-old woman was referred for a diagnostic video thoracoscopy under general anesthesia. At the end of the procedure, the patient presented with subcutaneous emphysema and cyanosis, abdominal distension, and bradycardia. A rigid bronchoscopy showed a longitudinal laceration in the pars membranacea of the trachea. A tracheal silicon stent was positioned on an emergency basis. She was intubated, positioning the tracheal tube cuff distal of the stent under bronchoscopic vision. A computed tomographic scan performed immediately after the procedure showed left pneumothorax, pneumoperitoneum, pneumopericardium, and diffuse subcutaneous emphysema. The subsequent course of the patient was uneventful. The patient was discharged home on postoperative day 4. After 1 year, the stent was removed with the evidence of complete trachel healing. PMID- 22916759 TI - Pulmonary embolization as the primary clinical manifestation of intravenous leiomyomatosis with intracardiac extension. PMID- 22916760 TI - Giant intravenous leiomyomatosis with intracardiac extension. PMID- 22916761 TI - Giant periosteal chondroma of the rib associated with mediastinum deviation. PMID- 22916762 TI - Branched graft inversion technique for distal anastomosis in total arch replacement. AB - Distal anastomosis during total arch replacement for thoracic aortic aneurysm is at times difficult, and bleeding from it is a serious problem because of its limited surgical exposure. We have modified a new procedure, the branched graft inversion (BGI) technique. We investigated the effectiveness of our technique by comparing it with the conventional stepwise technique. Between January 2008 and August 2011, 40 patients, divided into two groups of 20 each, underwent elective total arch replacement. One group underwent surgery using BGI; the stepwise technique was performed on the remaining 20 patients. Our modified BGI technique offers easy and secure distal anastomosis under good surgical procedure, resulting in shorter durations of operation, cardiopulmonary bypass, and circulatory arrest (455.1+/-101.3 min versus 354.7+/-49.3 min, p<0.001; 248.2+/ 46.6 min versus 199.7+/-28.2 min, p<0.001; 76.6+/-27.7 min versus 61.6+/-10.4 min, p=0.029, respectively). As a result, this technique could be a useful in performing total arch replacement. PMID- 22916763 TI - Giant sinus of valsalva aneurysm with severe aortic incompetence treated with a valve-sparing operation. AB - Typically, a sinus of Valsalva aneurysm with severe aortic incompetence is repaired with patch closure and aortic valve replacement. Here, we describe a very rare case of a giant nonruptured right Valsalva aneurysm, combined with severe aortic incompetence, treated with a valve-sparing aortic root replacement. During surgery we noted that the lengths of the free margin of the cusps and annuli were not uniform. As a result, we placed the first layer of sutures for the Valsalva graft in the same ratio as the annuli. It is difficult to preserve the geometry of the aortic annulus and position the commissures in the graft. One surgical tip for valve-sparing aortic root replacement for a sinus of Valsalva aneurysm with severe aortic incompetence is to suture the commissures inside the graft in the same ratio as the length of the cusp free margins. PMID- 22916764 TI - "Closed-vein" technique for primary sutureless repair of anomalous pulmonary venous connection. AB - Deep hypothermic circulatory arrest or low-flow bypass are commonly used in primary repair of total anomalous pulmonary venous connection, or individual veins may be dissected to allow clamp or snare application, in order to provide a bloodless field for anastomosis by the direct or sutureless marsupialization technique. In the described technical modification, the marsupialization of the opened atrium to the posterior pericardium is completed before opening the pulmonary venous confluence, allowing bloodless exposure during full-flow normothermic bypass. In addition, vein branch dissection is avoided. PMID- 22916765 TI - Double-barrel right ventricular outflow: tetralogy of Fallot annulus preservation technique. AB - In patients with tetralogy of Fallot (TOF) repair and a borderline pulmonary valve annulus (PVA) size, surgical repair often necessitates a transannular incision and subsequent placement of a patch with or without a monocusp or, alternatively, a right ventricle-to-pulmonary artery conduit. We discuss here a technique in which the pulmonary valve annulus can be safely preserved, with infrequent postoperative issues as well as the potential for less incidence of right ventricular outflow intervention in the long term. PMID- 22916767 TI - Double-barreled cannon stent grafting for dilated landing zones. PMID- 22916768 TI - Early diagnosis of perioperative myocardial infarction after coronary bypass grafting: why is the incidence so high? PMID- 22916770 TI - OPCAB technique for high-risk patients. PMID- 22916772 TI - Low-dose tranexamic acid use in isolated coronary artery bypass surgery. PMID- 22916774 TI - LeGoo and vascular injury: application is everything. PMID- 22916776 TI - What is the role of surgery in relapsed thymic tumors? An overview of a very debated issue. PMID- 22916778 TI - Cystic amyloidosis or lymphoid interstitial pneumonia associated with amyloidosis? A diagnostic challenge. PMID- 22916780 TI - Ascending, total arch, and descending thoracic aortic repair for acute DeBakey type I aortic dissection without circulatory arrest. AB - Complications may arise from the residual dissected arch and descending thoracic aorta after conventional ascending and hemiarch repair of acute DeBakey type I aortic dissection. To mitigate these complications, a total arch and elephant trunk procedure has been advocated. This case demonstrates a less invasive hybrid technique, performed in a single-stage fashion through a sternotomy without circulatory arrest or deep hypothermia, to achieve the benefits of the total arch and elephant trunk operation. PMID- 22916781 TI - Left ventricular aneurysm with herniation through the chest wall. AB - Cardiac herniation is a rare event associated with a high mortality rate. It is typically seen with blunt trauma to the chest or after a pneumectomy. Signs and symptoms include arrhythmia, myocardial ischemia, and hypotension. Diagnostic modalities, such as computed tomography scan, chest roentgenogram, magnetic resonance imaging, and transthoracic and transesophageal echocardiography, are key to diagnosis. Successful management requires timely recognition along with prompt surgical intervention. PMID- 22916782 TI - Hereditary esophageal-vulvar syndrome. AB - This article describes an esophageal leiomyomatosis in mother and daughter. A 33 year-old woman with cardiovascular symptoms was admitted to the hospital. Her mother at a young age had undergone an esophagectomy because of a leiomyosarcoma. The daughter received a diagnosis of diffuse leiomyomatosis of the esophagus and uterus. Because of its size, transthoracic esophagectomy with gastric reconstruction and a hysterectomy were performed. Histopathologic examination of the specimens confirmed the diagnosis of esophageal and uterine leiomyomatosis. These findings are characterized as the esophageal-vulvar syndrome, which is known to occur sporadically. PMID- 22916783 TI - Esophagobronchial fistula closure using a novel endoscopic over-the-scope-clip. AB - We report on a patient who presented with a symptomatic esophagobronchial fistula arising from an esophageal diverticulum with recurrent pulmonary infections despite prophylactic antibiotics. She was not an optimal candidate for esophageal stenting, bronchial stenting, or surgery and had refused a gastrostomy tube placement. We performed a successful endoscopic fistula closure using a novel endoscopic over-the-scope-clip device providing an effective seal of the fistula with durable resolution of symptoms. PMID- 22916784 TI - Masaoka approach for invasive aspergillosis: an aggressive approach for an aggressive disease. AB - Invasive pulmonary aspergillosis is a life-threatening infectious complication. The optimal management is still controversial, especially in cases of upper lobe lesions involving vascular structures. We report the case of a 24-year-old man with a granulocytic sarcoma of the left pulmonary apex, complicated by invasive pulmonary aspergillosis and false aneurysm of the left subclavian artery. A radical Masaoka anterior approach permitted left upper lobectomy and reconstruction of the artery. PMID- 22916785 TI - Endobronchial hypertrophic seromucous salivary gland: a rare bronchial occlusion. AB - A 41-year-old woman came to our clinics describing increased cough and shortness of breath. A chest roentgenogram revealed a loss of volume in her right lung. Computed tomography revealed a lesion at the level of the main carina, clogging the right main bronchus almost totally. The lesion underwent biopsy by use of flexible bronchoscopy. Histopathologic evaluation showed that the specimen was a hypertrophic seromucous salivary-type gland. Total excision of the mass was performed by bronchotomy through a right thoracotomy. We describe this case of a hypertrophic seromucous salivary gland in the tracheabronchial system. PMID- 22916786 TI - Pneumothorax: a classical presentation of metastatic scalp angiosarcoma. AB - Metastatic pulmonary angiosarcomas frequently present with pneumothorax, especially those arising from the scalp. The metastases on chest radiographs are initially subtle and easily missed. Computed tomographic scans can show a spectrum of diagnostic findings that may be misinterpreted because of a lack of awareness related to the rarity of the disease. We report a patient who presented with pneumothorax and lung cysts before his primary scalp angiosarcoma was diagnosed. This case highlights the sometimes ominous nature of innocuous looking, thin-walled cystic pulmonary lesions. PMID- 22916787 TI - The return of the left internal mammary artery after 11 years. PMID- 22916788 TI - Esophageal diverticulosis. PMID- 22916789 TI - Simplified technique of total aortic arch replacement with minimal circulatory and myocardial ischemia. AB - This manuscript describes the initial experience of 15 patients undergoing aortic arch replacement using a modification of the trifurcate arch technique described by Spielvogel and coworkers [1]. This technique provides continuous antegrade cerebral perfusion and minimal myocardial ischemia with mild hypothermia. PMID- 22916791 TI - State-selective vibrational excitation and dissociation of H2+ by strong infrared laser pulses: below-resonant versus resonant laser fields and electron-field following. AB - The quantum dynamics of vibrational excitation and dissociation of H(2)(+) by strong and temporally shaped infrared (IR) laser pulses has been studied on the femtosecond (fs) time scale by numerical solution of the time-dependent Schrodinger equation with explicit treatment of nuclear and electron motion beyond the Born-Oppenheimer approximation. Using sin(2)-shaped laser pulses of 120 fs duration with a peak intensity of I(0) > 10(14) W/cm(2), it has been found that below-resonant vibrational excitation with a laser carrier frequency of omega < omega(10)/2 (where omega(10) is the frequency of the |v = 0> -> |v = 1> vibrational transition) is much more efficient than a quasi-resonant vibrational excitation at omega ~ omega(10). In particular, at the below-resonant laser carrier frequency omega = 0.3641 * 10(-2) au (799.17 cm(-1)), dissociation probabilities of H(2)(+) (15.3% at the end of the 120 fs laser pulse and 21% at t = 240 fs) are more than 3 orders of magnitude higher than those obtained for the quasi-resonant laser frequency omega = 1.013 * 10(-2) au (2223.72 cm(-1)). Probabilities of state-selective population transfer to vibrational states |v = 1>, |v = 2>, and |v = 3> from the vibrational ground state |v = 0> of about 85% have been calculated in the optimal below-resonant cases. The underlying mechanism of the efficient below-resonant vibrational excitation is the electron field following and simultaneous transfer of energy to the nuclear coordinate. PMID- 22916790 TI - A set of dual promoter vectors for high throughput cloning, screening, and protein expression in eukaryotic and prokaryotic systems from a single plasmid. AB - BACKGROUND: The ability to produce the same recombinant protein in both prokaryotic and eukaryotic cells offers many experimental opportunities. However, the cloning of the same gene into multiple plasmids is required, which is time consuming, laborious and still may not produce soluble, stable protein in sufficient quantities. We have developed a set of expression vectors that allows for ligation-independent cloning and rapid functional screening for protein expression in both E. coli and S. cerevisiae. RESULTS: A set of expression vectors was made that can express the same open reading frame in E. coli (via the T7 phage promoter) and in S. cerevisiae (via the CUP1 or MET25 promoter). These plasmids also contain the essential elements for replication and selection in both cell types and have several advantages: they allow for cloning of genes by homologous recombination in yeast, protein expression can be determined before plasmid isolation and sequencing, and a GST-fusion tag is added to aid in soluble expression and purification. We have also included a TEV recognition site that allows for the specific cleavage of the fusion proteins to yield native proteins. CONCLUSIONS: The dual promoter vectors can be used for rapid cloning, expression, and purification of target proteins from both prokaryotic and eukaryotic systems with the ability to study post-translation modifications. PMID- 22916793 TI - Anti-inflammatory properties of a triterpenoidal glycoside from Momordica cochinchinensis in LPS-stimulated macrophages. AB - Two triterpenoidal saponins were isolated from the seeds of Momordica cochinchinensis Sprenger (Cucurbitaceae). Identification of chemical structures has been performed by (1)H- and (13)C-NMR spectroscopy and gas chromatography (GC). One of the saponins is a new gypsogenin glycoside, named as gypsogenin 3-O beta-D-galactopyranosyl(1->2)-[alpha-L-rhamnopyranosyl(1->3)]-beta-D glucuronopyranoside (compound 1), which is reported for the first time from natural resources. The other saponin is a quillaic acid glycoside (compound 2), which showed anti-inflammatory activities in RAW 264.7 cells. The mechanistic understanding of anti-inflammatory activities demonstrates that compound 2 inhibits lipopolysaccharide-induced expression of nitric oxide and IL-6 via NF kappaB pathway. PMID- 22916794 TI - Selenium in soil inhibits mercury uptake and translocation in rice (Oryza sativa L.). AB - A great number of studies have confirmed that mercury-selenium (Hg-Se) antagonism is a widespread phenomenon in microorganisms, fish, poultry, humans, and other mammals. However, by comparison, little attention has been paid to plants. To investigate the influence of Se on the uptake and translocation of methylHg/inorganic Hg (MeHg/IHg) in the rice-soil system, we determined the levels of Se, IHg, and MeHg in different parts of rice plants (including the root, stem, leaf, husk, and grain (brown rice)) and corresponding soils of root zones collected from a Hg mined area, where Hg and Se co-occur due to historic Hg mining and retorting activities. The results showed that, in general, the Se levels were inversely related to the levels of both IHg and MeHg in the grains. In addition, a consistent reduction in translocation of both IHg and MeHg in the aerial shoots (i.e., the stem, leaf, husk, and grain) with increasing Se levels in the soils was observed. Furthermore, the Se levels were positively correlated with the IHg levels in the soils and the roots. These results suggest that Se may play an important role in limiting the bioaccessibility, absorption, and translocation/bioaccumulation of both IHg and MeHg in the aerial rice plant, which may be related to the formation of an Hg-Se insoluble complex in the rhizospheres and/or roots. PMID- 22916792 TI - Sequencing and characterization of the FVB/NJ mouse genome. AB - BACKGROUND: The FVB/NJ mouse strain has its origins in a colony of outbred Swiss mice established in 1935 at the National Institutes of Health. Mice derived from this source were selectively bred for sensitivity to histamine diphosphate and the B strain of Friend leukemia virus. This led to the establishment of the FVB/N inbred strain, which was subsequently imported to the Jackson Laboratory and designated FVB/NJ. The FVB/NJ mouse has several distinct characteristics, such as large pronuclear morphology, vigorous reproductive performance, and consistently large litters that make it highly desirable for transgenic strain production and general purpose use. RESULTS: Using next-generation sequencing technology, we have sequenced the genome of FVB/NJ to approximately 50-fold coverage, and have generated a comprehensive catalog of single nucleotide polymorphisms, small insertion/deletion polymorphisms, and structural variants, relative to the reference C57BL/6J genome. We have examined a previously identified quantitative trait locus for atherosclerosis susceptibility on chromosome 10 and identify several previously unknown candidate causal variants. CONCLUSION: The sequencing of the FVB/NJ genome and generation of this catalog has increased the number of known variant sites in FVB/NJ by a factor of four, and will help accelerate the identification of the precise molecular variants that are responsible for phenotypes observed in this widely used strain. PMID- 22916795 TI - Identification of antitubercular benzothiazinone compounds by ligand-based design. AB - 1,3-Benzothiazin-4-ones (BTZs) are a novel class of TB drug candidates with potent activity against M. tuberculosis. An in silico ligand-based model based on structure-activity data from 170 BTZ compounds was used to design a new series. Compounds were tested against a panel of mycobacterial strains and were profiled for cytotoxicity, stability, and antiproliferative effects. Several of the compounds showed improved activity against MDR-TB while retaining low toxicity with higher microsomal, metabolic, and plasma stability. PMID- 22916796 TI - Toward multifunctional wet chemically functionalized graphene-integration of oligomeric, molecular, and particulate building blocks that reveal photoactivity and redox activity. AB - Many technological applications indispensable in our daily lives rely on carbon. By altering the periodic binding motifs in networks of sp(3), sp(2), and sp hybridized carbon atoms, researchers have produced a wide palette of carbon allotropes. Over the past two decades, the physicochemical properties of low dimensional nanocarbons, including fullerenes (0D), carbon nanotubes (1D), and, most recently, graphene (2D), have been explored systematically. An entire area of research has focused on the chemistry of 1D nanocarbons, particularly single wall carbon nanotubes. These structures exhibit unique electronic, mechanical, and optical properties. These properties are, however, only discernible for single-wall carbon nanotubes that are debundled, individualized, and stabilized, often in solution. Most prominently, they are small band gap, p-type semiconductors or metals with conductances that reach ballistic dimensions. These structures can have poor solubility in many media, and large bundles can originate from attractive interactions such as pi-pi stacking and London dispersion forces. Therefore, both covalent and noncovalent modifications of single-wall carbon nanotubes have emerged as powerful approaches to overcome some of these problems. Noncovalent functionalization is especially useful in improving the solubility without altering the electronic structure. We expect that many of the strategies that have recently been exploited and established in the context of 1D nanocarbons can be applied to the chemistry of 2D nanocarbons, especially graphene. Two-dimensional nanocarbons are currently attracting extensive attention due to their striking mechanical, optical, and electrical features. Nanocarbons that are a single atom thick are gapless semiconductors and exhibit electron mobilities reaching values of up to 15000 cm(2) V(-1) s(-1) at room temperature. Researchers have made rapid progress in the covalent and/or noncovalent functionalization of graphene with photoactive and or redox active building blocks. In this Account, we summarize our work on the integration of photoactive and/or redox active building blocks, including oligomers, molecules, and particulates, onto graphenoid materials to yield multifunctional electron donor-acceptor conjugates and hybrids. Intriguingly, we produce graphene in the form of single-layer, bilayer, and multilayer graphene through the exfoliation of graphite by surface active agents. The exfoliation occurs through pi-pi, hydrophobic, van der Waals, electrostatic, and charge transfer interactions, and the surface active agents also serve as versatile anchor groups. We studied the electronic interactions in terms of photoactivity and/or redox activity in depth by steady-state and time-resolved spectroscopy. Finally, we present examples of proof-of-principle solar energy conversion devices. PMID- 22916797 TI - Chloroplasts-mediated biosynthesis of nanoscale Au-Ag alloy for 2-butanone assay based on electrochemical sensor. AB - We reported a one-pot, environmentally friendly method for biosynthesizing nanoscale Au-Ag alloy using chloroplasts as reducers and stabilizers. The prepared nanoscale Au-Ag alloy was characterized by UV-visible spectroscopy, X ray diffraction (XRD) and high resolution transmission electron microscopy (HR TEM). Fourier transform infrared spectroscopy (FTIR) analysis was further used to identify the possible biomolecules from chloroplasts that are responsible for the formation and stabilization of Au-Ag alloy. The FTIR results showed that chloroplast proteins bound to the nanoscale Au-Ag alloy through free amino groups. The bimetallic Au-Ag nanoparticles have only one plasmon band, indicating the formation of an alloy structure. HR-TEM images showed that the prepared Au-Ag alloy was spherical and 15 to 20 nm in diameter. The high crystallinity of the Au Ag alloy was confirmed by SAED and XRD patterns. The prepared Au-Ag alloy was dispersed into multiwalled carbon nanotubes (MWNTs) to form a nanosensing film. The nanosensing film exhibited high electrocatalytic activity for 2-butanone oxidation at room temperature. The anodic peak current (Ip) has a linear relationship with the concentrations of 2-butanone over the range of 0.01% to 0.075% (v/v), when analyzed by cyclic voltammetry. The excellent electronic catalytic characteristics might be attributed to the synergistic electron transfer effects of Au-Ag alloy and MWNTs. It can reasonably be expected that this electrochemical biosensor provided a promising platform for developing a breath sensor to screen and pre-warn of early cancer, especially gastric cancer. PMID- 22916798 TI - The relationship between mean platelet volume and fasting plasma glucose differs with glucose tolerance status in a Korean general population: gender differences. AB - Mean platelet volume (MPV), which is used to measure platelet size, can reflect platelet activity. The objective of the present study was to evaluate the relationship between MPV and fasting plasma glucose (FPG) according to glucose tolerance (GT) status in a general population. We retrospectively studied 3098 Korean adults who underwent voluntary regular health check-ups at the Health Promotion Center of our hospital from January 2009 to December 2011. MPV was analysed within 2 hours of blood collection. A multiple linear regression analysis indicated that MPV had a significant negative correlation with FPG when the confounding variables of normal glucose tolerance (beta +/- SE, -0.112 +/- 0.033, R(2), 0.109, men; -0.102 +/- 0.034, 0.132, women) and intermediate hyperglycemia (-0.072 +/- 0.027, 0.130, men; -0.111 +/- 0.035, 0.100, women) were adjusted for. However, MPV had a significant positive relationship with FPG after adjusting for diabetes in women as a confounding factor (0.097 +/- 0.037, 0.442). We observed a contrasting relationship between MPV and FPG in the presence and absence of diabetes. This result suggests that the positive relationship between an increased glucose level and increased MPV is a unique phenomenon of diabetes itself. To our knowledge, this is the first study to demonstrate a different relationship between MPV and FPG according to glucose tolerance status in a general population. PMID- 22916799 TI - Cardiovascular effects of melatonin receptor agonists. AB - INTRODUCTION: Melatonin synchronizes circadian rhythms with light/dark period and it was demonstrated to correct chronodisruption. Several melatonin receptor agonists with improved pharmacokinetics or increased receptor affinity are being developed, three of them are already in clinical use. However, the actions of melatonin extend beyond chronobiology to cardiovascular and metabolic systems as well. Given the high prevalence of cardiovascular disease and their common occurrence with chronodisruption, it is of utmost importance to classify the cardiometabolic effects of the newly approved and putative melatoninergic drugs. AREAS COVERED: In the present review, the available (although very sparse) data on such effects, in particular by the approved (circadin, ramelteon, agomelatine) or clinically advanced (tasimelteon, piromelatine = Neu-P11, TIK-301) compounds are summarized. The authors have searched for an association with blood pressure, vascular reactivity, ischemia, myocardial and vascular remodeling and metabolic syndrome. EXPERT OPINION: The data suggest that cardiovascular effects of melatonin are at least partly mediated via MT(1)/MT(2) receptors and associated with its chronobiotic action. Therefore, despite the sparse direct evidence, it is believed that these effects will be shared by melatonin analogs as well. With the expected approval of novel melatoninergic compounds, it is suggested that the investigation of their cardiovascular effects should no longer be neglected. PMID- 22916801 TI - Melatonin in cardiovascular disease. AB - This editorial refers to "Cardiovascular effects of melatonin receptor agonists". The hormone melatonin is synthesized primarily in the pineal gland, retina, several peripheral tissues and organs. In the circulation, the concentration of melatonin follows a circadian rhythm, with high levels at night providing timing cues to target tissues endowed with melatonin receptors. Based on the data available, the last 18 years indicate that melatonin influences multiple factors of the cardiovascular function. Multiple evidences reveal that the rhythmicity of melatonin has a crucial role in a variety of cardiovascular pathophysiological processes including anti-inflammatory, antioxidant, anti-hypertensive and possibly as an antilipidemic function. Melatonin receptors receive and transduce melatonin's message to influence daily and seasonal rhythms of physiology. The melatonin message is translated through the interaction between the melatonin receptors (MT1 and MT2) and its coupling to G proteins, which are potential therapeutic targets in disorders ranging from insomnia, circadian sleep disorders, depression and cardiovascular diseases. Based on the data available, melatonin seems to have cardioprotective properties via its direct free radical scavenger activity. Melatonin efficiently interacts with several reactive oxygen species (receptor-independent actions). Collectively, these protective actions of melatonin may have potential clinical applicability for individuals with cardiovascular disease. PMID- 22916800 TI - Genomic arrangement of salinity tolerance QTLs in salmonids: a comparative analysis of Atlantic salmon (Salmo salar) with Arctic charr (Salvelinus alpinus) and rainbow trout (Oncorhynchus mykiss). AB - BACKGROUND: Quantitative trait locus (QTL) studies show that variation in salinity tolerance in Arctic charr and rainbow trout has a genetic basis, even though both these species have low to moderate salinity tolerance capacities. QTL were observed to localize to homologous linkage group segments within putative chromosomal regions possessing multiple candidate genes. We compared salinity tolerance QTL in rainbow trout and Arctic charr to those detected in a higher salinity tolerant species, Atlantic salmon. The highly derived karyotype of Atlantic salmon allows for the assessment of whether disparity in salinity tolerance in salmonids is associated with differences in genetic architecture. To facilitate these comparisons, we examined the genomic synteny patterns of key candidate genes in the other model teleost fishes that have experienced three whole-genome duplication (3R) events which preceded a fourth (4R) whole genome duplication event common to all salmonid species. RESULTS: Nine linkage groups contained chromosome-wide significant QTL (AS-2, -4p, -4q, -5, -9, -12p, -12q, 14q -17q, -22, and -23), while a single genome-wide significant QTL was located on AS-4q. Salmonid genomes shared the greatest marker homology with the genome of three-spined stickleback. All linkage group arms in Atlantic salmon were syntenic with at least one stickleback chromosome, while 18 arms had multiple affinities. Arm fusions in Atlantic salmon were often between multiple regions bearing salinity tolerance QTL. Nine linkage groups in Arctic charr and six linkage group arms in rainbow trout currently have no synteny alignments with stickleback chromosomes, while eight rainbow trout linkage group arms were syntenic with multiple stickleback chromosomes. Rearrangements in the stickleback lineage involving fusions of ancestral arm segments could account for the 21 chromosome pairs observed in the stickleback karyotype. CONCLUSIONS: Salinity tolerance in salmonids from three genera is to some extent controlled by the same loci. Synteny between QTL in salmonids and candidate genes in stickleback suggests genetic variation at candidate gene loci could affect salinity tolerance in all three salmonids investigated. Candidate genes often occur in pairs on chromosomes, and synteny patterns indicate these pairs are generally conserved in 2R, 3R, and 4R genomes. Synteny maps also suggest that the Atlantic salmon genome contains three larger syntenic combinations of candidate genes that are not evident in any of the other 2R, 3R, or 4R genomes examined. These larger synteny tracts appear to have resulted from ancestral arm fusions that occurred in the Atlantic salmon ancestor. We hypothesize that the superior hypo-osmoregulatory efficiency that is characteristic of Atlantic salmon may be related to these clusters. PMID- 22916802 TI - Novel origins of copy number variation in the dog genome. AB - BACKGROUND: Copy number variants (CNVs) account for substantial variation between genomes and are a major source of normal and pathogenic phenotypic differences. The dog is an ideal model to investigate mutational mechanisms that generate CNVs as its genome lacks a functional ortholog of the PRDM9 gene implicated in recombination and CNV formation in humans. Here we comprehensively assay CNVs using high-density array comparative genomic hybridization in 50 dogs from 17 dog breeds and 3 gray wolves. RESULTS: We use a stringent new method to identify a total of 430 high-confidence CNV loci, which range in size from 9 kb to 1.6 Mb and span 26.4 Mb, or 1.08%, of the assayed dog genome, overlapping 413 annotated genes. Of CNVs observed in each breed, 98% are also observed in multiple breeds. CNVs predicted to disrupt gene function are significantly less common than expected by chance. We identify a significant overrepresentation of peaks of GC content, previously shown to be enriched in dog recombination hotspots, in the vicinity of CNV breakpoints. CONCLUSIONS: A number of the CNVs identified by this study are candidates for generating breed-specific phenotypes. Purifying selection seems to be a major factor shaping structural variation in the dog genome, suggesting that many CNVs are deleterious. Localized peaks of GC content appear to be novel sites of CNV formation in the dog genome by non-allelic homologous recombination, potentially activated by the loss of PRDM9. These sequence features may have driven genome instability and chromosomal rearrangements throughout canid evolution. PMID- 22916803 TI - Circulating trends of non-B HIV type 1 subtypes among Kenyan individuals. AB - As the AIDS pandemic progresses, an increasingly broad range of genetic diversity continues to be reported within the main (M) group of HIV-1 viruses with viral subtype predominating in specific geographic areas. To determine the genetic diversity of HIV-1 subtypes among Kenyan individuals, the env-C2-V3 gene was successfully sequenced in samples from 176 patients. Analysis of the sequences showed that a majority of them belonged to subtype A1: 73.9% (130/176), followed by C: 10.8% (19/176), D: 10.2% (18/176), and 0.6% (1/176) for G and A2 as pure subtypes while the rest were recombinants of A1/U: 2.3% (4/176) and 0.6% (1/176) each for D/U, A/C/U, and AC. Similar to previous studies conducted in other parts of Kenya, HIV-1 subtype A1 still remains the most predominant subtype while subtype C continues to show an increasing prevalence. Continued surveillance of circulating subtypes of HIV-1 in Kenya is important in determining the evolution of the HIV/AIDS epidemic in Kenya. PMID- 22916804 TI - The nutritional value and health benefits of pulses in relation to obesity, diabetes, heart disease and cancer. PMID- 22916805 TI - A pulse-based diet is effective for reducing total and LDL-cholesterol in older adults. AB - Our purpose was to determine the effects of a pulse-based diet in individuals 50 years or older for reducing CVD risk factors. A total of 108 participants were randomised to receive pulse-based foods (two servings daily of beans, chickpeas, peas or lentils; about 150 g/d dry weight) or their regular diet for 2 months, followed by a washout of 1 month and a cross-over to the other diet for 2 months. Anthropometric measures, body composition and biochemical markers (i.e. serum LDL cholesterol (LDL-C), as the primary outcome, and other lipids, glucose, insulin and C-reactive protein) were assessed before and after each diet phase. A total of eighty-seven participants (thirty males and fifty-seven females; 59.7 (sd 6.3) years, body mass 76 (sd 16) kg) completed the study. Compared with the regular diet, the pulse-based diet decreased total cholesterol by 8.3 % (pulse, 4.57 (sd 0.93) to 4.11 (sd 0.91) mmol/l; regular, 4.47 (sd 0.94) to 4.39 (sd 0.97) mmol/l; P < 0.001) and LDL-C by 7.9 % (pulse, 2.93 (sd 0.84) to 2.55 (sd 0.75) mmol/l; regular, 2.96 (sd 0.86) to 2.81 (sd 0.83) mmol/l; P = 0.01). In a sub-analysis of individuals with high lipid levels at baseline (twenty individuals with high cholesterol), the pulse-based diet reduced cholesterol by 6 % compared with the regular diet (pulse, 5.62 (sd 0.78) to 5.26 (sd 0.68) mmol/l; regular, 5.60 (sd 0.91) to 5.57 (sd 0.85) mmol/l; P = 0.05). A pulse-based diet is effective for reducing total cholesterol and LDL-C in older adults and therefore reduces the risk of CVD. PMID- 22916806 TI - Nutritional quality and health benefits of chickpea (Cicer arietinum L.): a review. AB - Chickpea (Cicer arietinum L.) is an important pulse crop grown and consumed all over the world, especially in the Afro-Asian countries. It is a good source of carbohydrates and protein, and protein quality is considered to be better than other pulses. Chickpea has significant amounts of all the essential amino acids except sulphur-containing amino acids, which can be complemented by adding cereals to the daily diet. Starch is the major storage carbohydrate followed by dietary fibre, oligosaccharides and simple sugars such as glucose and sucrose. Although lipids are present in low amounts, chickpea is rich in nutritionally important unsaturated fatty acids such as linoleic and oleic acids. beta Sitosterol, campesterol and stigmasterol are important sterols present in chickpea oil. Ca, Mg, P and, especially, K are also present in chickpea seeds. Chickpea is a good source of important vitamins such as riboflavin, niacin, thiamin, folate and the vitamin A precursor beta-carotene. As with other pulses, chickpea seeds also contain anti-nutritional factors which can be reduced or eliminated by different cooking techniques. Chickpea has several potential health benefits, and, in combination with other pulses and cereals, it could have beneficial effects on some of the important human diseases such as CVD, type 2 diabetes, digestive diseases and some cancers. Overall, chickpea is an important pulse crop with a diverse array of potential nutritional and health benefits. PMID- 22916807 TI - Regular consumption of pulses for 8 weeks reduces metabolic syndrome risk factors in overweight and obese adults. AB - Pulses are low in energy density, supporting their inclusion in the diet for the management of risk factors of the metabolic syndrome (MetSyn). The aim of the present study was to describe the effects of frequent consumption (five cups/week over 8 weeks) of pulses (yellow peas, chickpeas, navy beans and lentils), compared with counselling to reduce energy intake by 2093 kJ/d (500 kcal/d), on risk factors of the MetSyn in two groups (nineteen and twenty-one subjects, respectively) of overweight or obese (mean BMI 32.8 kg/m2) adults. Body weight, waist circumference, blood pressure, fasting blood parameters and 24 h food intakes were measured at weeks 1, 4 and 8. Blood glucose, insulin, C-peptide, glucagon-like peptide-1 (GLP-1) and ghrelin were measured after a 75 g oral glucose load at weeks 1 and 8. At week 8, both groups reported reductions in energy intake, waist circumference, systolic blood pressure, glycosylated Hb (HbA1c) and glucose AUC and homeostasis model of insulin resistance (HOMA-IR) following the glucose load (P < 0.05). However, HDL, fasting C-peptide and insulin AUC responses were dependent on diet (P < 0.05). HDL and C-peptide increased by 4.5 and 12.3 %, respectively, in the pulse group, but decreased by 0.8 and 7.6 %, respectively, in the energy-restricted group. Insulin AUC decreased in both females and males on the energy-restricted diet by 24.2 and 4.8 %, respectively, but on the pulse diet it decreased by 13.9 % in females and increased by 27.3 % in males (P < 0.05). In conclusion, frequent consumption of pulses in an ad libitum diet reduced risk factors of the MetSyn and these effects were equivalent, and in some instances stronger, than counselling for dietary energy reduction. PMID- 22916808 TI - In vitro investigations of the potential health benefits of Australian-grown faba beans (Vicia faba L.): chemopreventative capacity and inhibitory effects on the angiotensin-converting enzyme, alpha-glucosidase and lipase. AB - The functional properties, including antioxidant and chemopreventative capacities as well as the inhibitory effects on angiotensin-converting enzyme (ACE), alpha glucosidase and pancreatic lipase, of three Australian-grown faba bean genotypes (Nura, Rossa and TF(Ic*As)*483/13) were investigated using an array of in vitro assays. Chromatograms of on-line post column derivatisation assay coupled with HPLC revealed the existence of active phenolics (hump) in the coloured genotypes, which was lacking in the white-coloured breeding line, TF(Ic*As)*483/13. Roasting reduced the phenolic content, and diminished antioxidant activity by 10-40 % as measured by the reagent-based assays (diphenylpicrylhydrazyl, 2,2'-azino-bis(3 ethylbenzthiazoline-6-sulphonic acid) and oxygen radical absorbance capacity) in all genotypes. Cell culture-based antioxidant activity assay (cellular antioxidant activity) showed an increase of activity in the coloured genotypes after roasting. Faba bean extracts demonstrated cellular protection ability against H2O2-induced DNA damage (assessed using RAW264.7 cells), and inhibited the proliferation of all human cancer cell lines (BL13, AGS, Hep G2 and HT-29) evaluated. However, the effect of faba bean extracts on the non-transformed human cells (CCD-18Co) was negligible. Flow cytometric analyses showed that faba bean extracts successfully induced apoptosis of HL-60 (acute promyelocytic leukaemia) cells. The faba bean extracts also exhibited ACE, alpha-glucosidase and pancreatic lipase inhibitory activities. Overall, extracts from Nura (buff coloured) and Rossa (red-coloured) were comparable, while TF(Ic*As)*483/13 (white coloured) contained the lowest phenolic content and exhibited the least antioxidant and enzyme inhibition activities. These results are important to promote the utilisation of faba beans in human diets for various health benefits. PMID- 22916809 TI - The anti-proliferative effect of TI1B, a major Bowman-Birk isoinhibitor from pea (Pisum sativum L.), on HT29 colon cancer cells is mediated through protease inhibition. AB - Bowman-Birk inhibitors (BBI) from legumes, such as soyabean, pea, lentil and chickpea, are naturally occurring plant protease inhibitors which have potential health-promoting properties within the mammalian gastrointestinal tract. BBI can survive both acidic conditions and the action of proteolytic enzymes within the stomach and small intestine, permitting significant amounts to reach the large intestine in active form to exert their reported anti-carcinogenic and anti inflammatory properties. In a previous study, we reported the ability of a recombinant form of TI1B (rTI1B), representing a major BBI isoinhibitor from pea, to influence negatively the growth of human colorectal adenocarcinoma HT29 cells in vitro. In the present study, we investigate if this effect is related directly to the intrinsic ability of BBI to inhibit serine proteases. rTI1B and a novel engineered mutant, having amino acid substitutions at the P1 positions in the two inhibitory domains, were expressed in the yeast Pichia pastoris. The rTI1B proved to be active against trypsin and chymotrypsin, showing K i values at nanomolar concentrations, whereas the related mutant protein was inactive against both serine proteases. The proliferation of HT29 colon cancer cells was significantly affected by rTI1B in a dose-dependent manner (IC50 = 31 (sd 7) MUm), whereas the inactive mutant did not show any significant effect on colon cancer cell growth. In addition, neither recombinant protein affected the growth of non-malignant colonic fibroblast CCD-18Co cells. These findings suggest that serine proteases should be considered as important targets in investigating the potential chemopreventive role of BBI during the early stages of colorectal carcinogenesis. PMID- 22916810 TI - Non-digestible fraction of beans (Phaseolus vulgaris L.) modulates signalling pathway genes at an early stage of colon cancer in Sprague-Dawley rats. AB - Colorectal cancer is one of the most common causes of morbidity and mortality in Western countries, the second cause of cancer mortality in the USA and a major public health problem in Mexico. A diet rich in legumes is directly related to the prevention of colon cancer, showing an inverse relationship with the development of colorectal adenomas in human subjects. The present study shows the results of molecular changes involved in the Tp53 pathway at an early stage in the distal colon tissue of azoxymethane (AOM)-induced colon cancer in rats evaluated by PCR array after exposure to diets containing the non-digestible fraction (NDF) of cooked bean (cultivar Bayo Madero). Significant differences were detected in seventy-two genes of the Tp53-mediated signalling pathway involved in apoptosis, cell-cycle regulation and arrest, inhibition of proliferation and inflammation, and DNA repair. Tp53, Gadd45a, Cdkn1a and Bax were highly expressed (9.3-, 18.3-, 5.5- and 3.5-fold, respectively) in the NDF+AOM group, whereas Cdc25c, Ccne2, E2f1 and Bcl2 were significantly suppressed ( - 9.2-, - 2.6-, - 18.4- and - 3.5-fold, respectively), among other genes, compared with the AOM group, suggesting that chemoprevention of aberrant crypt foci results from a combination of cell-cycle arrest in G1/S and G2/M phases and cell death by apoptotic induction. We demonstrate that the NDF from common bean modulates gene expression profiles in the colon tissue of AOM-induced rats, contributing to the chemoprotective effect of common bean on early-stage colon cancer. PMID- 22916811 TI - Metabolomic analysis of the effects of edible dry beans (Phaseolus vulgaris L.) on tissue lipid metabolism and carcinogenesis in rats. AB - Metabolite profiling using liquid chromatography-time-of-flight MS was undertaken to identify candidate metabolic processes that account for dry bean effects on disease risk with a specific focus on the development of breast cancer. Normal mammary gland and mammary carcinomas from previously reported experiments were evaluated. Principal component analysis (PCA) of mass spectral data revealed that tissue of both types from control-fed v. bean-fed rats could be distinguished by their metabolomic profiles. Candidate ion identification using MassTRIX analysis software revealed that alterations in eicosanoid, fatty acid, TAG and steroid metabolism partially accounted for the differences observed in both PCA. In addition, evidence was obtained consistent with the hypothesis that the varying inhibitory effects on mammary carcinogenesis of genetically distinct dry bean types were mirrored by differential patterns of lipid metabolites in mammary carcinoma. The use of MassTRIX provided links for metabolite profile enrichment with metabolic pathways in the Kyoto Encyclopedia of Genes and Genomes. Implicated pathways included a linkage between diacylglycerol and protein kinase C and eicosanoid metabolites and inducible cyclo-oxygenase-2 and/or eicosanoid degradation mediated via 15-PG dehydrogenase. These pathways have been reported to be misregulated during the development of cancer. The differences observed between control-fed and bean-fed rats in lipid metabolism require validation using targeted analytical methods and detailed analyses of how bean bioactive food components regulate genes that control lipid biosynthesis, interconversion and catabolism. PMID- 22916812 TI - Pulse consumption in Canadian adults influences nutrient intakes. AB - Pulses (dry beans, peas, lentils) are nutrient-dense foods that are recommended as good choices in either the vegetable or meat and alternative food groups in Canada's Food Guide. To examine the prevalence and the effect of pulse consumption on nutrient intake in Canadian adults ( >= 19 years), we analysed cross-sectional data (n 20,156) from the 2004 Canadian Community Health Survey, Cycle 2.2. Participants were divided into non-consumers and quartiles of pulse intake. Sample weights were applied and logistic regression analysis was used to explore the association of nutrient intakes and pulse consumption, with cultural background, sex, age and economic status included as covariates. On any given day, 13 % of Canadians consume pulses, with the highest consumption in the Asian population. The pulse intake of consumers in the highest quartile was 294 (se 40) g/d and, compared with non-consumers, these individuals had higher intakes of carbohydrate, fibre and protein. As well, the micronutrient intake of pulse consumers was enhanced, resulting in fewer individuals who were below the estimated average requirement for thiamin, vitamin B6, folate, Fe, Mg, P and Zn, compared with non-consumers. Although pulses are generally low in Na, its intake also was higher in pulse consumers. Among the higher quartiles of pulse consumers, fruit and vegetable intake was one serving higher. These data indicate that pulse consumption supports dietary advice that pulses be included in healthful diets. Further studies elucidating the sources of increased Na in pulse consumers will be necessary so that dietary advice to increase consumption of pulses will maximise their nutritional benefits. PMID- 22916813 TI - Review of the health benefits of peas (Pisum sativum L.). AB - Pulses, including peas, have long been important components of the human diet due to their content of starch, protein and other nutrients. More recently, the health benefits other than nutrition associated with pulse consumption have attracted much interest. The focus of the present review paper is the demonstrated and potential health benefits associated with the consumption of peas, Pisum sativum L., specifically green and yellow cotyledon dry peas, also known as smooth peas or field peas. These health benefits derive mainly from the concentration and properties of starch, protein, fibre, vitamins, minerals and phytochemicals in peas. Fibre from the seed coat and the cell walls of the cotyledon contributes to gastrointestinal function and health, and reduces the digestibility of starch in peas. The intermediate amylose content of pea starch also contributes to its lower glycaemic index and reduced starch digestibility. Pea protein, when hydrolysed, may yield peptides with bioactivities, including angiotensin I-converting enzyme inhibitor activity and antioxidant activity. The vitamin and mineral contents of peas may play important roles in the prevention of deficiency-related diseases, specifically those related to deficiencies of Se or folate. Peas contain a variety of phytochemicals once thought of only as antinutritive factors. These include polyphenolics, in coloured seed coat types in particular, which may have antioxidant and anticarcinogenic activity, saponins which may exhibit hypocholesterolaemic and anticarcinogenic activity, and galactose oligosaccharides which may exert beneficial prebiotic effects in the large intestine. PMID- 22916814 TI - Dietary dry bean effects on hepatic expression of stress and toxicity-related genes in rats. AB - Dry bean (Phaseolus vulgaris L.) consumption is associated with reduced risk for a number of chronic diseases. In westernised societies, dry bean consumption is particularly low (approximately 2-4 kg/capita per year) and little information is available about the safety of increasing dietary intake in humans to achieve levels that prevent and control chronic diseases. In anticipation of a human intervention study to address the safety and efficacy of increasing bean consumption, a dose-response study with dietary beans was conducted to establish whether increased bean consumption in rats exhibits changes indicative of hepatic stress or toxicity. Transcript levels from a panel of stress and toxicity-related genes were analysed in female Sprague-Dawley rats fed a dose range of dietary beans that bracketed amounts relevant to human consumption globally. Cooked red bean was incorporated into a purified diet formulation at 0, 7.5, 15, 30 or 60 % w/w for the assessment of adaptive patterns of gene expression using quantitative PCR array. Of the eighty-four genes evaluated, the expressions of Cyp3a11, Cyp7a1, Fmo1, Gstm1, Mif and Ugt1a6 were elevated, whereas the expression of Hspa8 was down-regulated. Liver gene expression was not modulated in a manner indicative of an adverse response. Only the expression of the cholesterol 7alpha hydoxylase and UDP-glucuronosyltransferase genes increased in a dose-dependent manner at nutritionally relevant dietary bean concentrations. These candidate genes may contribute to the health benefits attributed to increased bean consumption. PMID- 22916815 TI - Pulse grain consumption and obesity: effects on energy expenditure, substrate oxidation, body composition, fat deposition and satiety. AB - Pulses have been identified as important components of a healthy diet. Assessment of pulse grains' nutritional composition alongside data from available preclinical and clinical trials suggests that pulses can modulate biological processes that lead to obesity. Components of pulse grains, including pulse derived fibre and resistant starch, have been shown to alter energy expenditure, substrate trafficking and fat oxidation as well as visceral adipose deposition. Although mechanistic studies are scarce, studies have indicated that fibres found in pulses can have an impact on the expression of genes that modulate metabolism. Arginine and glutamine may produce thermogenic effects as major components of pulse grain proteins. Finally, evidence suggests that pulse-derived fibres, trypsin inhibitors and lectins may reduce food intake by inducing satiety via facilitating and prolonging cholecystokinin secretion. Nonetheless, the aforementioned data remain controversial and associations between dietary pulse grains and energy intake require further study. Given the available evidence, it can be concluded that pulses could be useful as functional foods and food ingredients that combat obesity. PMID- 22916816 TI - Phaseolus beans: impact on glycaemic response and chronic disease risk in human subjects. AB - Consumption of Phaseolus vulgaris bean species such as pinto, black, navy or kidney may be beneficial in the prevention and treatment of chronic diseases. In particular, conditions that are promoted by increased glycaemic stress (hyperglycaemia and hyperinsulinaemia) including diabetes, CVD and cancer seem to be reduced in individuals who eat more of these beans. The present paper discusses the influence of P. vulgaris species on glycaemic response and the impact that relationship may have on the risk of developing diabetes, CVD and cancer. PMID- 22916817 TI - Edible dry bean consumption (Phaseolus vulgaris L.) modulates cardiovascular risk factors and diet-induced obesity in rats and mice. AB - Pulses are grain legumes that have sustained the civilisations of the world throughout their development; yet this staple food crop has fallen into disuse, particularly in Westernised societies, and decreased consumption parallels increased prevalence of CVD. The objective of the present study was to identify mechanisms that account for the cardioprotective activity of dry bean (Phaseolus vulgaris L.), one of the four primary pulse crops, which is widely produced and consumed globally. Laboratory assays that can be used for in vivo screening of dry beans and other pulses to identify those with the greatest potential to benefit human health are also reported. Sprague-Dawley rats and a diet-induced obesity model in C57Bl/6 mice were used to assess the effect of cooked dry bean incorporated into a purified diet formulation on plasma lipids and hepatic proteins involved in the regulation of lipid biosynthesis. In both animal species, short-term feeding of a bean-containing diet reduced plasma total cholesterol and LDL-cholesterol without affecting HDL-cholesterol or total TAG. Mechanisms associated with cholesterol catabolism and excretion are the likely targets of the bean effect. Unexpectedly, bean-fed obese mice experienced weight loss as well as an improved plasma lipid profile within a 12 d time frame. These findings support the use of short-term (7-14 d) assays to investigate mechanisms that account for the cardioprotective and weight regulatory effects of dry bean and to screen dry bean germplasm resources for types of bean with high protective activity. These same assays can be used to identify the bioactive components of bean that account for the observed effects. PMID- 22916818 TI - The effect of yellow pea protein and fibre on short-term food intake, subjective appetite and glycaemic response in healthy young men. AB - Pulses are low-glycaemic foods rich in protein (20-25 %), resistant starch and fibre that suppress appetite and glycaemia. The objective of the present study was to elucidate the component(s) of yellow peas responsible for these benefits and assess their efficacy as value-added food ingredients. We investigated the effects of 10 or 20 g of isolated yellow pea protein (P10 and P20) or fibre (F10 and F20) on food intake (FI) at an ad libitum pizza meal served at 30 min (Expt 1, n 19) or 120 min (Expt 2, n 20) and blood glucose (BG) and appetite in young, healthy males (20-30 years). In Expt 1, P20 led to lower FI than control (4937 (sem 502) v. 5632 (sem 464) kJ (1180 (sem 120) v. 1346 (sem 111) kcal)) and all other treatments (P < 0.01) and lower cumulative FI (pizza meal kcal+treatment kcal; CFI) compared to F10 (5460 (sem 498) v. 6084 (sem 452) kJ (1305 (sem 119) v. 1454 (sem 108) kcal); P = 0.033). Both protein treatments suppressed mean pre meal (0-30 min) BG compared to control (P < 0.05), whereas only P20 suppressed mean post-meal (50-120 min) BG (P < 0.01). There was no effect of treatment on pre-meal or post-meal appetite. In Expt 2, there was no effect of treatment on FI, CFI, or pre- or post-meal BG or appetite. In conclusion, protein is the component responsible for the short-term effects of yellow peas in the regulation of glycaemia and FI, but its second-meal effects disappear by 2 h post consumption. PMID- 22916819 TI - Metabolism and performance during extended high-intensity intermittent exercise after consumption of low- and high-glycaemic index pre-exercise meals. AB - The metabolic and performance benefits of prior consumption of low-glycaemic index (GI) meals v. high-GI meals were determined in extended high-intensity intermittent exercise. Participants (ten males and four females, aged 25.8 (sd 7.3) years) completed two testing days (each consisting of back-to-back 90-min intermittent high-intensity treadmill running protocols separated by 3 h) spaced by at least 7 d. Using a randomised counterbalanced cross-over design, low-GI, lentil-based meals (GI about 42) or high-GI, potato-based meals (GI about 78) matched for energy value were consumed 2 h before, and within 1 h after, the first exercise session. Performance was measured by the distance covered during five 1-min sprints (separated by 2.5 min walking) at the end of each exercise session. Peak postprandial blood glucose was higher by 30.8 % in the high-GI trial compared with the low-GI trial, as was insulin (P = 0.039 and P = 0.003, respectively). Carbohydrate oxidation was lower by 5.5 % during the low-GI trials compared with the high-GI trials at the start of the first exercise session (P < 0.05). Blood lactate was significantly higher (6.1 v. 2.6 mmol/l; P = 0.019) and blood glucose significantly lower (4.8 v. 5.4 mmol/l; P = 0.039) at the end of the second exercise session during the high-GI trial compared with the low-GI trial. Sprint distance was not significantly different between conditions. A low GI meal improved the metabolic profile before and during extended high-intensity intermittent exercise, but did not affect performance. Improvements in metabolic responses when consuming low-GI meals before exercise may be beneficial to the long-term health of athletes. PMID- 22916820 TI - Assessment of the mechanisms exerting glucose-lowering effects of dried peas in glucose-intolerant rats. AB - The present study compared the effects of feeding uncooked pea fractions (embryo v. seed coat) on glucose homeostasis in glucose-intolerant rats and examined potential mechanisms influencing glucose homeostasis. Rats were made glucose intolerant by high-fat feeding, after which diets containing both high-fat and pea fractions were fed for 4 weeks. Rats fed diets containing uncooked pea seed coats low (non-coloured seed coat; NSC) or high (coloured seed coat; CSC) in proanthocyanidins but not embryos had improved oral glucose tolerance (P < 0.05). NSC also lowered fasting and glucose-stimulated insulin secretion (P < 0.05), decreased beta-cell mass by 50 % (P < 0.05) and lowered levels of malondialdehyde, a marker of oxidative stress. Furthermore, NSC decreased the mucosal thickness of the colon by 25 % (P < 0.05), which might affect fibre fermentation and other gut functions. Small but statistically significant (P < 0.05) effects consistent with enhanced glucose transport or metabolism were observed in the skeletal muscle of rats fed NSC or CSC, for example, increased levels of AMP-dependent kinase or akt. We conclude that pea seed coats are the fraction exerting beneficial effects on glucose tolerance. Most of the changes were small in amplitude, suggesting that additive effects on multiple tissues may be important. NSC content appeared to have the most beneficial effects in improving glucose homeostasis but our ability to detect the effect of flavonoids may have been limited by their low concentration in the diet. PMID- 22916821 TI - Monofunctionalized gold nanoparticles stabilized by a single dendrimer form dumbbell structures upon homocoupling. AB - The assembly of dumbbell structures as organic-inorganic hybrid materials is presented. Gold nanoparticles (NPs) with a mean diameter of 1.3 nm were synthesized in very good yields using a stabilizing dendrimer based on benzylic thioether subunits. The extended dendritic ligand covers the NP surface and contains a peripheral protected acetylene, providing coated and monofunctionalized NPs. These NPs themselves can be considered as large molecules, and thus, applying a wet-chemical deprotection/oxidative acetylene coupling protocol exclusively provides dimers of NPs interlinked by a diethynyl bridge. The concept not only enables access to novel organic/inorganic hybrid architectures but also promises new approaches in labeling technology. PMID- 22916822 TI - Sensitive equilibrium sampling to study polychlorinated biphenyl disposition in Baltic Sea sediment. AB - An equilibrium sampling approach using glass jars with MUm thin coatings of the silicone polydimethylsiloxane (PDMS) was validated and applied to background sediment samples from a >50 km transect in the Stockholm Archipelago. Equilibrium between the sediment and the PDMS was demonstrated using different coating thicknesses. From the concentrations of polychlorinated biphenyls (PCBs) in the PDMS, we assessed (i) freely dissolved concentrations in the sediment interstitial porewater (C(Sediment_free)); (ii) the equilibrium status between sediment and water; (iii) the equilibrium status between sediment and biota; and (iv) site-specific sediment/water distribution ratios (K(D)). The results showed that (i) Stockholm was a source of PCBs to the Baltic Sea as evidenced by significantly higher C(Sediment_free) in Stockholm Harbor; (ii) the fugacity in sediment exceeded that in water (monitoring samples collected in February) by an average factor of 4.0; (iii) the fugacity in sediment exceeded that in herring by an average factor of 5.2; and (iv) K(D) near Stockholm Harbor was 0.3-1.7 log units greater than in the outer archipelago. The coated glass jar method with its high precision and built-in QA/QC opens new possibilities to study the disposition of hydrophobic chemicals at trace levels (C(Sediment_free) down to 1.06 fg/L) in background environments. PMID- 22916823 TI - Spontaneous formation of cluster array of gold particles by convective self assembly. AB - Cluster arrays composed of metal nanoparticles are promising for application in sensing devices because of their interesting surface plasmon characteristics. Herein, we report the spontaneous formation of cluster arrays of gold colloids on flat substrates by vertical-deposition convective self-assembly. In this technique, under controlled temperature, a hydrophilic substrate is vertically immersed in a colloid suspension. Cluster arrays form when the particle concentration is extremely low (in the order of 10(-6)-10(-8) v/v). These arrays are arranged in a hierarchically ordered structure, where the particles form clusters that are deposited at a certain separation distance from each other, to form "dotted" lines that are in turn aligned with a constant spacing. The size of the cluster can be controlled by varying the particle concentration and temperature while an equal separation distance is maintained between the lines formed by the clusters. Our technique thus demonstrates a one-step, template-free fabrication method for cluster arrays. In addition, through the direct observation of the assembly process, the spacing between the dotted lines is found to result from the "stick-and-slip" behavior of the meniscus tip, which is entirely different from the formation processes observed for the striped patterns, which we reported previously at higher particle concentrations. The difference in the meniscus behavior possibly comes from the difference in colloidal morphology at the meniscus tip. These results demonstrate the self regulating characteristics of the convective self-assembly process to produce colloidal patterns, whose structure depends on particle concentration and temperature. PMID- 22916824 TI - Doubly hydrogen bonded dimer of delta-valerolactam: infrared spectrum and intermode coupling. AB - We report here the vibrational analysis of the infrared spectrum of doubly hydrogen bonded dimer of delta-valerolactam measured in CCl4 solution at room temperature (22 degrees C). The compound shows an equilibrium of population distributed over the monomer and doubly hydrogen bonded dimer, which is manifested by the isosbestic point in the normalized spectra for solutions of different concentrations. Dimerization induced changes in transition frequencies and intensities have been measured and compared with the computed results. Our results suggest doubling of the intensity of the amide-I (predominantly nuC?O) band by double hydrogen bonding at the amide (-C(O)-N(H)-) interface. The amide-A (nuN-H) spectral region appears broad and is featured with quite a few numbers of substructures. These substructures are theoretically reproduced by incorporating electrical anharmonicity to the vibrational states. Computational results at the MP2/6-311++G(d,p) level of theory are seen to nicely agree with the measured spectral data. PMID- 22916825 TI - Fusarium verticillioides from finger millet in Uganda. AB - Finger millet (Eleusine coracana) is a subsistence crop grown in Sub-Saharan Africa and the Indian Sub-continent. Fusarium species occurring on this crop have not been reported. Approximately 13% of the Fusarium isolates recovered from finger millet growing at three different locations in eastern Uganda belong to Fusarium verticillioides, and could produce up to 18,600 ug/g of total fumonisins when cultured under laboratory conditions. These strains are all genetically unique, based on AFLP analyses, and form fertile perithecia when crossed with the standard mating type tester strains for this species. All but one of the strains is female-fertile and mating-type segregates 13:20 Mat-1:Mat-2. Three new sequences of the gene encoding translation elongation factor 1-alpha were found within the population. These results indicate a potential health risk for infants who consume finger millet gruel as a weaning food, and are consistent with the hypothesis that F. verticillioides originated in Africa and not in the Americas, despite its widespread association with maize grown almost anywhere worldwide. PMID- 22916827 TI - Raman scattering of InAs/AlAs quantum dot superlattices grown on (001) and (311)B GaAs surfaces. AB - We present a comparative analysis of Raman scattering by acoustic and optical phonons in InAs/AlAs quantum dot superlattices grown on (001) and (311)B GaAs surfaces. Doublets of folded longitudinal acoustic phonons up to the fifth order were observed in the Raman spectra of (001)- and (311)B-oriented quantum dot superlattices measured in polarized scattering geometries. The energy positions of the folded acoustic phonons are well described by the elastic continuum model. Besides the acoustic phonons, the spectra display features related to confined transverse and longitudinal optical as well as interface phonons in quantum dots and spacer layers. Their frequency positions are discussed in terms of phonon confinement, elastic stress, and atomic intermixing. PMID- 22916826 TI - Emergence of carbapenem-resistant Enterobacteriaceae as causes of bloodstream infections in patients with hematologic malignancies. AB - Carbapenem-resistant Enterobacteriaceae (CRE) are increasingly prevalent pathogens. However, little is known about their emergence in patients with hematologic malignancies. We identified 18 patients with hematologic malignancies over 3.5 years who developed bloodstream infections (BSIs) caused by CRE. Fourteen BSIs were caused by Klebsiella pneumoniae, three by Enterobacter cloacae, and one was polymicrobial. Initial empirical antimicrobial therapy was active in two patients (11%), and a median of 55 h elapsed between culture collection and receipt of an active agent. Ten patients (56%) died, including nine (69%) of 13 neutropenic patients, with a median of 4 days from culture collection until death. CRE isolates were analyzed for carbapenemase production, beta-lactamase genes and outer membrane porin deletions and characterized by multilocus sequence typing and pulsed-field gel electrophoresis (PFGE). Carbapenem resistance mechanisms included Klebsiella pneumoniae carbapenemase production and CTX-M-15 production with an absent outer membrane porin protein. No isolate had >=95% homology on PFGE, indicating a heterogeneous, non-outbreak population of isolates. CRE BSIs are emerging in patients with hematologic malignancies and are associated with ineffective initial empirical therapy, long delays in administration of active antimicrobials and high mortality rates. New diagnostic, therapeutic and preventive strategies for CRE infections in this vulnerable population are needed. PMID- 22916828 TI - Regional hypothermia inhibits spinal cord somatosensory-evoked potentials without neural damage in uninjured rats. AB - Both the therapeutic effects of regional hypothermia (RH) and somatosensory evoked potentials (SSEP) have been intensively studied; however, the in vivo relationship between the two remains unknown. The primary focus of the current study was to investigate the impact of RH on SSEP in uninjured rats, as well as the neural safety of RH on neuronal health. An epidural perfusion model was used to keep local temperature steady by adjusting perfusion speed at 30 degrees C, 26 degrees C, 22 degrees C, and 18 degrees C for 30 min, respectively. Total hypothermic duration lasted up to 3 h. Neural signals were recorded at the end of each hypothermic period, as well as before cooling and after spontaneous rewarming. In addition, the Basso, Beattie, and Bresnahan (BBB) Locomotor Rating Scale was used to evaluate the effects of RH pre- and post-operative, combined with hematoxylin and eosin (H&E) and Fluoro-Jade C (FJC) staining. The results showed a marked declining trend in SSEP amplitude, as well as a significant prolongation in latency only during profound hypothermia (18 degrees C). The BBB scale remained consistent at 21 throughout the entire process, signifying that no motor function injury was caused by RH. In addition, H&E and FJC staining did not show obvious histological injury. These findings firmly support the conclusion that RH, specifically profound RH, inhibits spinal cord SSEP in both amplitude and latency without neural damage in uninjured rats. PMID- 22916829 TI - N-octanoyl-dopamine is a potent inhibitor of platelet function. AB - Dopamine (DA) is a co-agonist for platelet activation; yet, donor DA treatment is associated with improved transplantation outcome in renal and heart recipients. Recently, N-octanoyl-dopamine (NOD) was developed which displays superior effects compared to DA in terms of graft protecting properties. Whereas DA is a known platelet co-agonist, the effect of NOD on platelet function is unknown. This is a hypothesis generating study with the aim to assess the effects and molecular mechanisms of NOD and NOD-like compounds on platelet function. The influence of DA, NOD, and NOD-like compounds on platelet responses to classical agonists (adenosine 5'-diphosphate (ADP), U46619) was investigated in six healthy donors by applying whole blood aggregometry (Multiplate(r)) and flow cytometry for Pac 1, CD62P, and CD63 expression. Changes in platelet cAMP concentrations were assessed by ELISA. While DA showed synergy in platelet activation by ADP and U46619, NOD caused significant inhibition of platelet function both in whole blood aggregometry and flow cytometry. The inhibitory effect of NOD was not mediated via cAMP levels. The nonredox-active NOD-analog N-octanoyl-tyramine had no effects on platelet function. Acetylated NOD conferred to NOD by intracellular esterases showed similar inhibitory effects as NOD. In contrast to DA, NOD is a potent inhibitor of platelet function most likely through intracellular redox active processes. This adds to the overall protective effect of NOD on pre transplantation injury and makes NOD an attractive candidate compound for donor or organ conditioning prior to transplantation. PMID- 22916831 TI - Cloud parallel processing of tandem mass spectrometry based proteomics data. AB - Data analysis in mass spectrometry based proteomics struggles to keep pace with the advances in instrumentation and the increasing rate of data acquisition. Analyzing this data involves multiple steps requiring diverse software, using different algorithms and data formats. Speed and performance of the mass spectral search engines are continuously improving, although not necessarily as needed to face the challenges of acquired big data. Improving and parallelizing the search algorithms is one possibility; data decomposition presents another, simpler strategy for introducing parallelism. We describe a general method for parallelizing identification of tandem mass spectra using data decomposition that keeps the search engine intact and wraps the parallelization around it. We introduce two algorithms for decomposing mzXML files and recomposing resulting pepXML files. This makes the approach applicable to different search engines, including those relying on sequence databases and those searching spectral libraries. We use cloud computing to deliver the computational power and scientific workflow engines to interface and automate the different processing steps. We show how to leverage these technologies to achieve faster data analysis in proteomics and present three scientific workflows for parallel database as well as spectral library search using our data decomposition programs, X!Tandem and SpectraST. PMID- 22916830 TI - Cloning and characterization of a novel 2-ketoisovalerate reductase from the beauvericin producer Fusarium proliferatum LF061. AB - BACKGROUND: The ketoisovalerate reductase (EC 1.2.7.7 ) is required for the formation of beauvericin via the nonribosomal peptide synthetase biosynthetic pathway. It catalyzes the NADPH-specific reduction of ketoisovaleric acid to hydroxyisovalerate. However, little is known about the bioinformatics' data about the 2-Kiv reductase in Fusarium. To date, heterologous production of the gene KivRFp from Fusarium has not been achieved. RESULTS: The KivRFp gene was subcloned and expressed in Escherichia coli BL21 using the pET expression system. The gene KivRFp contained a 1,359 bp open reading frame (ORF) encoding a polypeptide of 452 amino acids with a molecular mass of 52 kDa. Sequence analysis indicated that it showed 61% and 52% amino acid identities to ketoisovalerate reductase from Beauveria bassiana ATCC 7159 (ACI30654) and Metarhizium acridum CQMa 102 (EFY89891), respectively; and several conserved regions were identified, including the putative nucleotide-binding signature site, GXGXXG, a catalytic triad (Glu405, Asn184, and Lys285). The KivRFp exhibited the highest activity at 35 degrees C and pH 7.5 respectively, by reduction of ketoisovalerate. It also exhibited the high level of stability over wide temperature and pH spectra and in the presence of metal ions or detergents. CONCLUSIONS: A new ketoisovalerate reductase KivRFp was identified and characterized from the depsipeptide-producing fungus F. proliferatum. KivRFp has been shown to have useful properties, such as moderate thermal stability and broad pH optima, and may serve as the starting points for future protein engineering and directed evolution, towards the goal of developing efficient enzyme for downstream biotechnological applications. PMID- 22916832 TI - Sequential coupling approach to the synthesis of nickel(II) complexes with N-aryl 2-amino phenolates. AB - A sequential multicomponent coupling approach is a powerful method for the construction of combinatorial libraries because structurally complex and diverse molecules can be synthesized from simple materials in short steps. In this paper, an efficient synthesis of nickel(II) complexes with N-aryl-2-amino phenols via a sequential three-step coupling approach is described, for potential use in nonlinear optical materials, bioinspired catalytic systems, and near-infrared absorbing filters. Seventeen N-aryl-2-amino phenolates were successfully synthesized in high yields based on the coupling of 3,5-di-tert-butylbenzene-1,2 diol with a pivotal aromatic scaffold, 4-bromo-2-iodo-aniline, followed by sequential Suzuki-Miyaura coupling with aryl boronates. A total of 16 analytically pure nickel(II) complexes with N-aryl-2-amino phenolates were obtained from 17 complexation trials. The procedure allowed us to assemble 4 components in high yields without protection, deprotection, oxidation or reduction steps. Various building blocks that included electron-donating, electron-withdrawing, and basic were used, and readily available, nontoxic and environmentally benign substrates and reagents were employed with no generation of toxic compounds. No strict anhydrous or degassed conditions were required. Absorption spectroscopic measurement of the synthesized nickel(II) complexes revealed that the ortho-substituent Ar(1) exerted more influence on the absorption wavelength of the complexes than the para-substituent Ar(2). On the other hand, both substituents Ar(1) and Ar(2) influenced the molar absorptivity values. These observations should be useful for the design of new and useful nickel(II) complexes as near-infrared chromophores. PMID- 22916834 TI - Multiresonant broadband optical antennas as efficient tunable nanosources of second harmonic light. AB - We report the experimental realization of efficient tunable nanosources of second harmonic light with individual multiresonant log-periodic optical antennas. By designing the nanoantenna with a bandwidth of several octaves, simultaneous enhancement of fundamental and harmonic fields is observed over a broad range of frequencies, leading to a high second harmonic conversion efficiency, together with an effective second order susceptibility within the range of values provided by widespread inorganic crystals. Moreover, the geometrical configuration of the nanoantenna makes the generated second harmonic signal independent from the polarization of the fundamental excitation. These results open new possibilities for the development of efficient integrated nonlinear nanodevices with high frequency tunability. PMID- 22916833 TI - Synthesis and biological investigations of nitric oxide releasing nateglinide and meglitinide type II antidiabetic prodrugs: in-vivo antihyperglycemic activities and blood pressure lowering studies. AB - A new group of hybrid nitric oxide-releasing type II antidiabetic drugs possessing a 1-(pyrrolidin-1-yl)diazen-1-ium-1,2-diolate (13 and 18), 1-(N,N diethylamino)diazen-1-ium-1,2-diolate (14 and 19), or nitrooxyethyl (15 and 20) moiety attached to the carboxylic acid group of the type II antidiabetic drugs nateglinide and meglitinide were synthesized. These prodrugs, based on the beneficial properties of nitric oxide (NO), were designed to reduce the risk of adverse cardiovascular events in diabetic patients. Ester prodrugs (13-15 and 18 20) exhibited appreciable oral antihyperglycemic activity comparable to the parent drugs in nonfasted diabetic rats. Systolic and diastolic blood pressure profiles validated the beneficial hypotensive properties of these prodrugs. These prodrugs released NO (1.3-72.2% range) upon incubation with either phosphate buffer solution at pH 7.4 or in the presence of serum. This new type of hybrid NO donor prodrug represents an attractive approach for the rational design of type II antidiabetic drugs with a reduced risk of contraindicated cardiovascular events. PMID- 22916835 TI - Binding by the hepatitis C virus NS3 helicase partially melts duplex DNA. AB - Binding of NS3 helicase to DNA was investigated by footprinting with KMnO(4), which reacts preferentially with thymidine residues in single-stranded DNA (ssDNA) compared to those in double-stranded DNA (dsDNA). A distinct pattern of reactivity was observed on ssDNA, which repeated every 8 nucleotides (nt) and is consistent with the known binding site size of NS3. Binding to a DNA substrate containing a partial duplex was also investigated. The DNA contained a 15 nt overhang made entirely of thymidine residues adjacent to a 22 bp duplex that contained thymidine at every other position. Surprisingly, the KMnO(4) reactivity pattern extended from the ssDNA into the dsDNA region of the substrate. Lengthening the partial duplex to 30 bp revealed a similar pattern extending from the ssDNA into the dsDNA, indicating that NS3 binds within the duplex region. Increasing the length of the ssDNA portion of the partial duplex by 4 nt resulted in a shift in the footprinting pattern for the ssDNA by 4 nt, which is consistent with binding to the 3'-end of the ssDNA. However, the footprinting pattern in the dsDNA region was shifted by only 1-2 bp, indicating that binding to the ssDNA dsDNA region was preferred. Footprinting performed as a function of time indicated that NS3 binds to the ssDNA rapidly, followed by slower binding to the duplex. Hence, multiple molecules of NS3 can bind along a ssDNA-dsDNA partial duplex by interacting with the ssDNA as well as the duplex DNA. PMID- 22916836 TI - Predictors of treatment failure and time to detection and switching in HIV infected Ethiopian children receiving first line anti-retroviral therapy. AB - BACKGROUND: The emergence of resistance to first line antiretroviral therapy (ART) regimen leads to the need for more expensive and less tolerable second line drugs. Hence, it is essential to identify and address factors associated with an increased probability of first line ART regimen failure. The objective of this article is to report on the predictors of first line ART regimen failure, the detection rate of ART regime failure, and the delay in switching to second line ART drugs. METHODS: A retrospective cohort study was conducted from 2005 to 2011. All HIV infected children under the age of 15 who took first line ART for at least six months at the four major hospitals of Addis Ababa, Ethiopia were included. Data were collected, entered and analyzed using Epi info/ENA version 3.5.1 and SPSS version 16. The Cox proportional-hazard model was used to assess the predictors of first line ART failure. RESULTS: Data of 1186 children were analyzed. Five hundred seventy seven (48.8%) were males with a mean age of 6.22 (SD = 3.10) years. Of the 167(14.1%) children who had treatment failure, 70 (5.9%) had only clinical failure, 79 (6.7%) had only immunologic failure, and 18 (1.5%) had both clinical and immunologic failure. Patients who had height for age in the third percentile or less at initiation of ART were found to have higher probability of ART treatment failure [Adjusted Hazard Ratio (AHR), 3.25 95% CI, 1.00-10.58]. Patients who were less than three years old [AHR, 1.85 95% CI, 1.24 2.76], chronic diarrhea after initiation of antiretroviral treatment [AHR, 3.44 95% CI, 1.37-8.62], ART drug substitution [AHR, 1.70 95% CI, 1.05-2.73] and base line CD4 count below 50 cells/mm3 [AHR, 2.30 95% CI, 1.28-4.14] were also found to be at higher risk of treatment failure. Of all the 167 first line ART failure cases, only 24 (14.4%) were switched to second line ART with a mean delay of 24 (SD = 11.67) months. The remaining 143 (85.6%) cases were diagnosed to have treatment failure retrospectively by the authors based on their records. Hence, they were not detected and these patients were not offered second line ARTs. CONCLUSIONS: Having chronic malnutrition, low CD4 at base line, chronic diarrhea after initiation of first line ART, substitution of ART drugs and age less than 3 years old were found to be independent predictors of first line ART failure in children. Most of the first line ART failure cases were not detected early and those that were detected were not switched to second line drugs in a timely fashion. Children with the above risk factors should be closely monitored for a timely switch to second line highly active anti-retroviral therapy. PMID- 22916837 TI - Analysis of microsatellite instability in gastric mucosa-associated lymphoid tissue lymphoma. AB - In Helicobacter pylori gastritis, constant antigenic stimulation triggers a sustained B-cell proliferation. Errors made during this continuous DNA replication are supposed to be corrected by the DNA mismatch repair mechanism. Failure of this mismatch repair mechanism has been described in hereditary non polyposis colorectal cancer (HNPCC) and results in a replication error phenotype. Inherent to their instability during replication, microsatellites are the best markers of this replication error phenotype. We aimed to evaluate the role of defects in the DNA mismatch repair (MMR) mechanism and microsatellite instability (MSI) in relation to the most frequent genetic anomaly, translocation t(11;18)(q21;q21), in gastric mucosa-associated lymphoid tissue (MALT) lymphoma. Therefore, we examined 10 microsatellite loci (BAT25, BAT26, D5S346, D17S250, D2S123, TGFB, BAT40, D18S58, D17S787 and D18S69) for instability in 28 patients with MALT lymphomas. In addition, these tumors were also immunostained for MLH1, MSH2, MSH6 and PMS2, as well as screened for the presence of t(11;18)(q21;q21) by real-time polymerase chain reaction (RT-PCR). We found MSI in 5/28 (18%) lymphomas, with MSI occurring in both t(11;18)(q21;q21)-positive and -negative tumors. One tumor displayed high levels of instability, and, remarkably, this was the only case displaying features of a diffuse large B-cell lymphoma. All microsatellite unstable lymphomas showed a loss of MSH6 expression. In conclusion, our data suggest that a MMR-defect may be involved in the development of gastric MALT lymphomas, and that a defect of MSH6 might be associated with those MSI-driven gastric lymphomas. PMID- 22916838 TI - Efficient long-range stereochemical communication and cooperative effects in self assembled Fe4L6 cages. AB - A series of large, optically active Fe(4)L(6) cages was prepared from linear 5,5' bis(2-formylpyridines) incorporating varying numbers (n = 0-3) of oligo-p-xylene spacers, chiral amines, and Fe(II). When a cage was constructed from the ligand bridged by one p-xylene spacer (n = 1) and a bulky chiral amine, both a homochiral Fe(2)L(3) helicate and Fe(4)L(6) cage were observed to coexist in solution due to a delicate balance between steric factors. In contrast, when a less bulky chiral amine was used, only the Fe(4)L(6) cage was observed. In the case of larger cages (n = 2, 3), long-range (>2 nm) stereochemical coupling between metal centers was observed, which was minimally diminished as the ligands were lengthened. This communication was mediated by the ligands' geometries and rigidity, as opposed to gearing effects between xylene methyl groups: the metal centered stereochemistry was not observed to affect the axial stereochemistry of the ligands. PMID- 22916839 TI - Synthesis and physicochemical properties of metallobacteriochlorins. AB - Access to metallobacteriochlorins is essential for investigation of a wide variety of fundamental photochemical processes, yet relatively few synthetic metallobacteriochlorins have been prepared. Members of a set of synthetic bacteriochlorins bearing 0-4 carbonyl groups (1, 2, or 4 carboethoxy substituents, or an annulated imide moiety) were examined under two conditions: (i) standard conditions for zincation of porphyrins [Zn(OAc)(2).2H(2)O in N,N dimethylformamide (DMF) at 60-80 degrees C], and (ii) treatment in tetrahydrofuran (THF) with a strong base [e.g., NaH or lithium diisopropylamide (LDA)] followed by a metal reagent MX(n). Zincation of bacteriochlorins that bear 2-4 carbonyl groups proceeded under the former method whereas those with 0-2 carbonyl groups proceeded with NaH or LDA/THF followed by Zn(OTf)(2). The scope of metalation (via NaH or LDA in THF) is as follows: (a) for bacteriochlorins that bear two electron-releasing aryl groups, M = Cu, Zn, Pd, and InCl (but not Mg, Al, Ni, Sn, or Au); (b) for bacteriochlorins that bear two carboethoxy groups, M = Ni, Cu, Zn, Pd, Cd, InCl, and Sn (but not Mg, Al, or Au); and (c) a bacteriochlorin with four carboethoxy groups was metalated with Mg (other metals were not examined). Altogether, 15 metallobacteriochlorins were isolated and characterized. Single-crystal X-ray analysis of 8,8,18,18 tetramethylbacteriochlorin reveals the core geometry provided by the four nitrogen atoms is rectangular; the difference in length of the two sides is ~0.08 A. Electronic characteristics of (metal-free) bacteriochlorins were probed through electrochemical measurements along with density functional theory calculation of the energies of the frontier molecular orbitals. The photophysical properties (fluorescence yields, triplet yields, singlet and triplet excited state lifetimes) of the zinc bacteriochlorins are generally similar to those of the metal-free analogues, and to those of the native chromophores bacteriochlorophyll a and bacteriopheophytin a. The availability of diverse metallobacteriochlorins should prove useful in a variety of fundamental photochemical studies and applications. PMID- 22916840 TI - Nanostructures formed by displacement of porous silicon with copper: from nanoparticles to porous membranes. AB - The application of porous silicon as a template for the fabrication of nanosized copper objects is reported. Three different types of nanostructures were formed by displacement deposition of copper on porous silicon from hydrofluoric acid based solutions of copper sulphate: (1) copper nanoparticles, (2) quasi continuous copper films, and (3) free porous copper membranes. Managing the parameters of porous silicon (pore sizes, porosity), deposition time, and wettability of the copper sulphate solution has allowed to achieve such variety of the copper structures. Elemental and structural analyses of the obtained structures are presented. Young modulus measurements of the porous copper membrane have been carried out and its modest activity in surface enhanced Raman spectroscopy is declared. PMID- 22916841 TI - Intermittent HIV-1 viremia (blips) and virological failure in a cohort of people living with HIV from Sao Paulo, Brazil. PMID- 22916843 TI - Malignant acanthosis nigricans associated with ileocecal adenocarcinoma. AB - Malignant acanthosis nigricans (MAN) is a cutaneous sign of internal malignancy, usually an adenocarcinoma. With this report, we aim to present a rare case of concomitant colon cancer and acanthosis nigricans (AN). A 62-year-old woman with hyperpigmentation, velvety cutaneous thickening and verrucous excrescences involving the axillary, inframammar, and inguinal regions with a history of 10 years is presented. Hyperpigmentation and thickening existed also on the nape, umbilicus, and periorbital regions. Histopathological findings of skin lesions were consistent with AN. Computed tomography of the abdomen revealed cecal wall thickening and multiple enlarged lymph nodes in pericolic fat tissue. The tumor was resected surgically and the diagnosis of poor differentiated adenocarcinoma of the colon with lymphatic metastasis was established. Although MAN is mostly reported in the course of abdominal malignancies, this is a very rare case report of MAN associated with adenocarcinoma of the colon. PMID- 22916844 TI - High frequency of CYP2C19*2 carriers in PCI-treated patients switched over from clopidogrel to prasugrel based on platelet function monitoring. PMID- 22916845 TI - Theoretical investigation of selenium interferences in inductively coupled plasma mass spectrometry. AB - Structures, heats of formation, ionization energies, and proton affinities of selenium, argon dimer, argon-chlorine, and their hydrides (Se, SeH, SeH2, ArH, ArH2, Ar2, Ar2H, Ar2H2, ArCl, and ArHCl) are estimated by quantum chemistry calculations using G3, G4, and W1 composite methods and coupled cluster approach at the CCSD(T)/aug-cc-pVTZ levels. Thermochemistry of the reactions between ions A(+) = Se(*+), SeH(+), SeH2(*+), SeH3(+), Ar2(*+), Ar2H(+), Ar2H2(*+), Ar2H3(+), ArCl(+), ArClH(*+), and ArClH2(+) with various neutral gas G commonly used in dynamic reaction chamber-inductively coupled plasma-mass spectrometry (DRC-ICP MS) (G = H2, CH4, NH3, O2, CO, CO2, NO, and N2O) has been investigated. PMID- 22916846 TI - Antiarrhythmic properties of ranolazine--from bench to bedside. AB - INTRODUCTION: Pharmacological management of cardiac arrhythmias is limited by the reduced availability of safe and effective antiarrhythmic agents. AREAS COVERED: Ranolazine is an agent currently used for the treatment of angina, which inhibits transmembrane ionic currents involved in several phases of the action potential in both the atrial and the ventricular cells. Due to its mechanism of action, ranolazine has been shown to exhibit antiarrhythmic properties that have been validated in the experimental models. This article recapitulates the mechanism of antiarrhythmic action of ranolazine, the existing clinical data, and the ongoing relevant clinical trials. EXPERT OPINION: The combination of the antiischemic properties of ranolazine with its antiarrhythmic potency and minimal proarrhythmia provides a promising background that could expand its therapeutic role in the management of atrial fibrillation and ventricular tachyarrhythmias. Data derived from adequately powered randomized clinical trials will determine whether the door to a new indication will open for ranolazine in the near future. PMID- 22916849 TI - Letters to the editor. Pursuing nonclinical practice in the veterinary profession. PMID- 22916850 TI - What is your diagnosis? Uroperitoneum. PMID- 22916851 TI - What is your diagnosis? Severe osteochondritis dissecans (OCD). PMID- 22916852 TI - Anesthesia case of the month. Cecal or large colon impaction. PMID- 22916853 TI - Pathology in practice. Proliferative and necrotizing otitis externa. PMID- 22916854 TI - Field Epidemiology and Laboratory Training Programs in West Africa as a model for sustainable partnerships in animal and human health. AB - The concept of animal and human health experts working together toward a healthier world has been endorsed, but challenges remain in identifying concrete actions to move this one health concept from vision to action. In 2008, as a result of avian influenza outbreaks in West Africa, international donor support led to a unique opportunity to invest in Field Epidemiology and Laboratory Training Programs (FELTPs) in the region that engaged the animal and human health sectors to strengthen the capacity for prevention and control of zoonotic diseases. The FELTPs mixed 25% to 35% classroom and 65% to 75% field-based training and service for cohorts of physicians, veterinarians, and laboratory scientists. They typically consisted of a 2-year course leading to a master's degree in field epidemiology and public health laboratory management for midlevel public health leaders and competency-based short courses for frontline public health surveillance workers. Trainees and graduates work in multidisciplinary teams to conduct surveillance, outbreak investigations, and epidemiological studies for disease control locally and across borders. Critical outcomes of these programs include development of a cadre of public health leaders with core skills in integrated disease surveillance, outbreak investigation, vaccination campaigns, laboratory diagnostic testing, and epidemiological studies that address priority public health problems. A key challenge exists in identifying ways to successfully scale up and transform this innovative donor-driven program into a sustainable multisectoral one health workforce capacity development model. PMID- 22916855 TI - Evaluation of cognitive learning, memory, psychomotor, immunologic, and retinal functions in healthy puppies fed foods fortified with docosahexaenoic acid-rich fish oil from 8 to 52 weeks of age. AB - OBJECTIVE: To assess effects of foods fortified with docosahexaenoic acid (DHA) rich fish oil on cognitive, memory, psychomotor, immunologic, and retinal function and other measures of development in healthy puppies. DESIGN: Evaluation study. ANIMALS: 48 Beagle puppies. PROCEDURES: Puppies were assigned to 3 groups after weaning (n = 16/group) and received 1 of 3 foods (low-DHA, moderate-DHA, or high-DHA food) as their sole source of nutrition until 1 year of age. Visual discrimination learning and memory tasks, psychomotor performance tasks, and physiologic tests including blood and serum analysis, electroretinography, and dual-energy x-ray absorptiometry were performed at various time points. Anti rabies virus antibody titers were evaluated 1, 2, 4, and 8 weeks after vaccination at 16 weeks of age. RESULTS: Foods had similar proximate analysis results but varied in concentration of DHA from fish oil; the high-DHA food also contained higher concentrations of vitamin E, taurine, choline, and l-carnitine than did other foods. The high-DHA group had significantly better results for reversal task learning, visual contrast discrimination, and early psychomotor performance in side-to-side navigation through an obstacle-containing maze than did the moderate-DHA and low-DHA groups. The high-DHA group had significantly higher anti-rabies antibody titers 1 and 2 weeks after vaccination than did other groups. Peak b-wave amplitudes during scotopic electroretinography were positively correlated with serum DHA concentrations at all evaluated time points. CONCLUSIONS AND CLINICAL RELEVANCE: Dietary fortification with fish oils rich in DHA and possibly other nutrients implicated in neurocognitive development following weaning improved cognitive, memory, psychomotor, immunologic, and retinal functions in growing dogs. PMID- 22916857 TI - Use of fluoroscopically guided percutaneous antegrade urethral catheterization for the treatment of urethral obstruction in male cats: 9 cases (2000-2009). AB - OBJECTIVE: To describe the technique and determine outcome for male cats with urethral obstruction treated with fluoroscopically guided percutaneous antegrade urethral catheterization (PAUC). DESIGN: Retrospective case series. ANIMALS: 9 client-owned neutered male cats with urethral obstruction and inability to pass a retrograde urinary catheter. PROCEDURES: Information regarding the procedure and hospitalization was obtained from medical records. Long-term follow-up was obtained via medical record review or telephone interview. RESULTS: Diagnoses included iatrogenic urethral tear (n = 6), obstructive urethral calculi (1), urethral ulceration (1), and urethral stricture (1). Seven of the 9 procedures were successful. The 2 patients in which PAUC failed had mechanical obstructions preventing guide wire access across the urethral obstruction. Procedure times ranged from 25 to 120 minutes. No complications were noted in any patients during the procedure. One patient was euthanized because of unrelated disease. Follow-up information was available for 6 of 8 surviving patients. No complications that could be directly attributed to the procedure were noted. All 6 patients had a perineal urethrostomy performed 0 days to 6 weeks following the procedure because of reobstruction of the lower urinary tract. None of these patients had documented urethral strictures and none had recurrence of clinical signs following perineal urethrostomy. CONCLUSIONS AND CLINICAL RELEVANCE: Results suggested that PAUC can be a simple, rapid, minimally invasive, and safe technique to facilitate transurethral catheterization in select cases. Patients with iatrogenic urethral tears may be good candidates. Patients with impacted urethral calculi, severe strictures or ulcerations, or a nondistended urinary bladder may be less amenable to PAUC. PMID- 22916856 TI - Comparative vaccine-specific and other injectable-specific risks of injection site sarcomas in cats. AB - OBJECTIVE: To compare associations between vaccine types and other injectable drugs with development of injection-site sarcomas in cats. DESIGN: Case-control study. ANIMALS: 181 cats with soft tissue sarcomas (cases), 96 cats with tumors at non-vaccine regions (control group I), and 159 cats with basal cell tumors (control group II). PROCEDURES: Subjects were prospectively obtained from a large pathology database. Demographic, sarcoma location, basal cell tumor, and vaccine and other injectable history data were documented by use of a questionnaire and used to define case, control, and exposure status. Three control groups were included: cats with sarcomas at non-vaccine sites, cats with basal cell tumors, and a combined group of cats with sarcomas at non-vaccine sites and cats with basal cell tumors. chi(2) tests, marginal homogeneity tests, and exact logistic regression were performed. RESULTS: In the broad interscapular region, the frequency of administration of long-acting corticosteroid injections (dexamethasone, methylprednisolone, and triamcinolone) was significantly higher in cases than in controls. In the broad rear limb region, case cats were significantly less likely to have received recombinant vaccines than inactivated vaccines; ORs from logistic regression analyses equaled 0.1, with 95% confidence intervals ranging from 0 to 0.4 and 0 to 0.7, depending on control group and time period of exposure used. CONCLUSIONS AND CLINICAL RELEVANCE: This case-control study measuring temporal and spatial exposures efficiently detected associations between administrations of various types of vaccines (recombinant vs inactivated rabies) and other injectable products (ie, long-acting corticosteroids) with sarcoma development without the need to directly measure incidence. These findings nevertheless also indicated that no vaccines were risk free. The study is informative in allowing practitioners to weigh the relative merits and risks of commonly used pharmaceutical products. PMID- 22916858 TI - Evaluation of a single subcutaneous infusion of carboplatin as adjuvant chemotherapy for dogs with osteosarcoma: 17 cases (2006-2010). AB - OBJECTIVE: To evaluate adverse effects and survival times in dogs with osteosarcoma that received a single SC infusion of carboplatin as adjunctive chemotherapeutic treatment following limb amputation or limb-sparing surgery. DESIGN: Retrospective case series. ANIMALS: 17 client-owned dogs with spontaneously occurring osteosarcoma. PROCEDURES: Medical records of dogs that underwent limb amputation or limb-sparing surgery followed by a single continuous SC infusion of carboplatin (total dose, 300 mg/m(2) infused over 3, 5, or 7 days) were evaluated. Signalment, tumor location, type of surgery (amputation or limb sparing), duration of carboplatin infusion, results of hematologic and serum biochemical analyses, and adverse effects were recorded. Kaplan-Meier survival analysis was performed. RESULTS: Median survival time for all dogs was 365 days. Nine dogs had adverse bone marrow-related (hematologic) effects, 1 had adverse gastrointestinal effects, and 7 had infections at the surgical site. No significant differences were detected in survival times of dogs grouped according to tumor location, type of surgery, duration of carboplatin infusion, or development of postoperative infection. CONCLUSIONS AND CLINICAL RELEVANCE: Median survival time and adverse effects in dogs with osteosarcoma that received a single SC infusion of carboplatin over a 3-, 5-, or 7-day period as adjunctive treatment following limb amputation or limb-sparing surgery were comparable to those of previously reported chemotherapy protocols requiring IV drug administration over several weeks. Further investigation is needed to evaluate the efficacy of this protocol as adjunctive treatment for osteosarcoma and other tumors in dogs. PMID- 22916859 TI - Liver lobe torsion in six horses. AB - CASE DESCRIPTION: 6 horses were determined to have torsion of a liver lobe at 4 referral institutions over a 21-year period. CLINICAL FINDINGS: Clinical findings were nonspecific but often included signs of marked inflammation. Two of the 6 horses were examined because of colic, and 2 were assessed because of peritonitis that failed to respond to treatment; the remaining 2 horses were examined because of nonspecific clinical signs that included inappetence, lethargy, and weight loss. The results of laboratory tests were widely variable, and values for liver enzyme activities were typically within reference limits or only mildly increased. Most affected horses had markedly increased peritoneal nucleated cell counts. TREATMENT AND OUTCOME: Exploratory laparotomy and resection of the affected liver lobe was performed in 5 horses. Three of those patients survived to discharge. CLINICAL RELEVANCE: Results suggested that diagnosis of liver lobe torsion in horses may be difficult because clinical signs and results of laboratory testing are nonspecific and variable. Most affected horses had markedly abnormal peritoneal fluid. The prognosis for hepatic lobe torsion can be good, and early surgical correction is expected to improve outcome. PMID- 22916860 TI - Duodenal obstruction caused by duodenal sigmoid flexure volvulus in dairy cattle: 29 cases (2006-2010). AB - OBJECTIVE: To characterize duodenal sigmoid flexure volvulus (DSFV) and determine the prognosis for affected cattle undergoing surgery. DESIGN: Retrospective case series. ANIMALS: 29 dairy cattle. PROCEDURES: The medical records were analyzed for history, signalment, clinical signs, medical management, surgical findings, and outcome. RESULTS: 29 cattle were determined to have DSFV between December 2006 and August 2010. Twenty cattle had had an omentopexy or pyloropexy performed 1 day to 2 years before initial evaluation. Cattle were afebrile, tachycardic, and moderately dehydrated, with a small zone of percussion with a ping at the 10th to 12th right intercostal spaces and associated succussion. Biochemical changes were a severe hypokalemic (mean +/- SD, 2.9 +/- 0.5 mmol/L; median, 3.1 mmol/L; range, 2.08 to 3.92 mmol/L), hypochloremic (mean, 69.7 +/- 11.1 mmol/L; median, 71.7 mmol/L; range, 49.1 to 94.1 mmol/L) metabolic alkalosis (mean total CO(2), 44.5 +/- 7.4 mmol/L; median, 45.3 mmol/L; range, 31.5 to 59.6 mmol/L) and hyperbilirubinemia (mean, 32.4 +/- 29.0 MUmol/L; median, 20.5 MUmol/L; range, 7.8 to 107 MUmol/L). Surgical findings for DSFV included an empty descending duodenum adjacent to a dorsally displaced and dilated cranial segment of the duodenum, distended abomasum and gallbladder, and a tight volvulus at the base of the duodenal sigmoid flexure. Manual reduction was considered successful if the descending duodenum filled after cranial duodenal massage. Twenty-two patients were successfully treated; the remaining 7 died or were euthanized within 4 days after surgery. CONCLUSIONS AND CLINICAL RELEVANCE: A condition clinically resembling abomasal volvulus but affecting the duodenal sigmoid flexure has been recognized in dairy cattle. When a focal, dorsal right-sided ping and succussion are present combined with severe hypokalemic, hypochloremic metabolic alkalosis and high bilirubin concentration, DSFV should be suspected, especially when there is a history of prior abomasal fixation. After surgical correction, the prognosis is fair to good. PMID- 22916861 TI - Drying mechanism of poly(N-isopropylacrylamide) microgel dispersions. AB - The drying mechanism of poly(N-isopropylacrylamide) (pNIPAm) microgel dispersions was investigated. The microgels were synthesized by temperature-programmed aqueous free radical precipitation polymerization using NIPAm, N,N' methylenebis(acrylamide), and water-soluble initiator. Drying processes of the microgel dispersions were observed with a digital camera and an optical microscope, and the resultant dried structures were observed by scanning electron microscopy. We found that the presence of the microgels changed the behavior of the drying process of water. In particular, the microgels were adsorbed at the air/water interface selectively within a few minutes irrespective of the microgel concentration. The relationship between the drying mechanism and structure of the resultant microgel thin film has been clarified by changing the microgel concentration of the dispersions. PMID- 22916862 TI - Kinetics of fumonisin B1 formation in maize ears inoculated with Fusarium verticillioides. AB - The kinetics of fumonisin B1 (FB1) biosynthesis have been examined in ears of four botanical varieties Zea mays var. indentata, Zea mays var. indurata, Zea mays var. saccharata and Zea mays var. everta inoculated with F. verticillioides isolates at silking stage. The level of mycotoxin accumulated in kernels was correlated with sample harvest time (r = 0.73) and ergosterol content (r = 0.70). FB1 biosynthesis was influenced by amylose, starch and moisture contents, which undergo dynamic changes during grain formation. A comparative analysis of ear infection rates and efficiency of FB1 biosynthesis showed that these are separate characters and their expression could be independent. PMID- 22916864 TI - A prospective, randomized comparison of 3 types of proximal interphalangeal joint arthroplasty. AB - PURPOSE: For surface replacement arthroplasty in proximal interphalangeal joint osteoarthritis, titanium-polyethylene (TI) and pyrocarbon (PY) implants are frequently used. However, their superiority in comparison to the silicone (SI) spacer has not been established. The purpose of this study was to compare these 3 types of implants with regard to outcome. METHODS: A prospective, randomized, multicenter trial was performed. A total of 43 patients (62 proximal interphalangeal joints) had surgery in the 3 participating centers, and each patient was randomly allocated to one of the 3 groups (TI, PY, SI). Range of motion (ROM) and strength were measured before surgery; pain and disability self assessment and radiographic analysis were also completed. The same examination protocol was planned for 3 months, 6 months, and 1, 2, and 3 years after surgery, but some follow-up visits did not take place due to patient death or poor compliance. RESULTS: The mean follow-up time at the final follow-up was 35 +/- 3 months (range, 30-41 mo). All implant types led to significant pain reduction at rest and at load. Tip pinch strength was slightly improved by all 3 devices at the 3-year follow-up. No significant improvement in ROM for silicone or resurfacing implants was found. However, when comparing the highest ROM values reached after surgery, the resurfacing devices tended to show superior joint motility compared to silicone spacers, albeit only temporarily and not significantly. Sixteen explantations were necessary: 2 of 18 SI (11%), 7 of 26 TI (27%) and 7 of 18 PY (39%) implants had to be removed. An additional 4 secondary surgical procedures were performed in group TI. CONCLUSIONS: Surface replacement arthroplasty devices showed a tendency for a temporarily superior maximum postoperative ROM, but markedly higher postoperative complication and explantation rates were observed compared to the silicone spacer implantation. PMID- 22916865 TI - Hand surgery's research dilemma: a lesson from Philip Hench. PMID- 22916866 TI - Scaphoid excision and 4-bone arthrodesis versus proximal row carpectomy: a comparison of contact biomechanics. AB - PURPOSE: We compare scaphoid excision and 4-bone arthrodesis (FBA) with proximal row carpectomy (PRC) in terms of contact pressure, area, and location. METHODS: Six cadaveric forearms underwent simulated FBA with K-wires. We measured pressures in the radiocarpal joint with Fuji contact film after we applied a 200 N load via the wrist tendons with the wrist in neutral, flexion, and extension. We repeated the experiment after excising the lunate and triquetrum, to create a PRC in the same specimens. RESULTS: Contact pressure in the PRC wrist was significantly greater, by 25%, compared with the FBA wrist for all wrist positions. The PRC wrist had a significantly smaller contact area, by 43%, compared with the FBA wrist. In the FBA wrist, lunate contact was more dorsal in flexion but more volar in extension. In the PRC wrist, capitate contact was more dorsal and radial in flexion, whereas the contact was more volar and ulnar in extension. Comparing contact location, FBA contact was significantly more ulnar than PRC contact in wrist flexion. We found no significant difference in contact translation (the distance between the contact locations in the positions of wrist flexion and extension) for the lunate in FBA or the capitate in PRC. CONCLUSIONS: The FBA wrist has significantly lower contact pressure (P < .001), greater contact area (P < .001), and equal contact translation compared with the PRC wrist. These qualities may make FBA less susceptible to degeneration over time. By advancing our understanding of the biomechanics of both wrist procedures, we may better tailor them to the individual patient. CLINICAL RELEVANCE: Current biomechanical evidence is lacking for common motion-preserving procedures for wrist arthritis. Comparing contact pressure, area, and location provides a biomechanical basis of our clinical understanding of these surgeries. PMID- 22916867 TI - Current innovations in wrist arthroscopy. AB - It has become clear that the stability of the scapholunate joint does not depend wholly on the scapholunate interosseous ligament, but rather on both primary and secondary stabilizers, which form a scapholunate ligament complex. Each case of scapholunate instability is unique and should be treated with tissue-specific repairs, which may partly explain why one procedure cannot successfully restore joint stability in every case. Wrist arthroscopy has a pivotal role in both the assessment and treatment of the scapholunate ligament complex derangements. Tears of the foveal attachment of the triangular fibrocartilaginous complex can be an underdiagnosed cause of distal radioulnar joint instability, because the foveal fibers cannot be visualized using the standard radiocarpal arthroscopy portals. Distal radioulnar joint arthroscopy allows for direct visualization and assessment of these fibers, which in turn has spawned a number of open and arthroscopic repair methods. Wrist arthroscopy has gained wider acceptance as a method to fine-tune articular reduction during open and percutaneous fixation of distal radius fractures, and simplifies intra-articular osteotomies for malunion. It can facilitate percutaneous bone grafting of scaphoid nonunions and has a role in the diagnosis and treatment of associated soft tissue lesions. These and other recent developments will be discussed in the following article. PMID- 22916868 TI - Kienbock disease. AB - Kienbock disease, or osteonecrosis of the lunate, is a progressive disease process that can lead to wrist pain and dysfunction. Although it was described over 100 years ago, and advances have been made in understanding this disease, the precise etiology remains uncertain. Anatomic, mechanical, vascular, and traumatic factors have been suggested to contribute to the disease. The natural history is unknown, and radiographic and clinical findings do not always correlate. Progress has been made in recognizing the progression of the avascular process and its deleterious effects on wrist mechanics. Initial treatment is nonsurgical, and it remains unclear whether surgical intervention results in improved outcomes over nonoperative treatment. Traditional surgical procedures such as radial shortening osteotomy and proximal row carpectomy have been shown to be reliable treatment options for relieving pain and improving function. Newer procedures such as pedicled bone grafts from the distal radius may improve direct revascularization of the lunate in earlier stages of the disease, potentially arresting the progression of collapse. Additional data are necessary to determine with certainty whether this type of procedure represents an improvement over the traditional treatment alternatives. Kienbock disease remains a challenging problem for hand surgeons. PMID- 22916869 TI - Southern California Society for Surgery of the Hand (SCSSH) award for the Journal of Hand Surgery 2011 article of the year. PMID- 22916870 TI - Letter regarding "Isolated displaced olecranon fracture". PMID- 22916872 TI - Letter regarding "Optimal fixation of oblique scaphoid fractures: a cadaver model". PMID- 22916874 TI - Letter regarding "Effects of tension across the tendon repair site on tendon gap and ultimate strength". PMID- 22916877 TI - Invited review: strategies for promoting productivity and health of dairy cattle by feeding nonforage fiber sources. AB - High-fiber byproducts are generated by several industries, and the supplies of some of these nonforage fiber sources (NFFS) are increasing. Although NFFS generally have limited utility in nonruminant diets, dairy cattle nutritionists can use these products to partially replace both forages and concentrates in lactation diets. Research has shown that production responses vary, but under certain conditions, NFFS-based diets can maintain or improve performance of dairy cattle. Traditional dietary formulation strategies are not ideal when formulating diets to contain large concentrations of NFFS. When feeding high levels of NFFS (>=15% inclusion rates, dry matter basis), less physically effective fiber is required; however, determining if this requirement has been met can be challenging, mainly because of the lack of a broadly applicable method for quantifying effective fiber in the field. Nutritionists must also be conscious of the nutrient variation that exists among many NFFS. Strategies to reduce risks associated with this variability include purchasing feed from a sole supplier who demonstrates product consistency and combining multiple NFFS at lower inclusion rates. A targeted approach whereby nonforage fiber primarily replaces some forage fiber for higher-producing cows but partially replaces some starch for lower producing cows can optimize nutrient utilization without sacrificing animal health. In summary, the judicious use of NFFS represents an opportunity to improve the productivity and health of cattle in all stages of lactation while potentially controlling feed costs. PMID- 22916876 TI - High yield expression of catalytically active USP18 (UBP43) using a Trigger Factor fusion system. AB - BACKGROUND: Covalent linkage of the ubiquitin-like protein ISG15 interferes with viral infection and USP18 is the major protease which specifically removes ISG15 from target proteins. Thus, boosting ISG15 modification by protease inhibition of USP18 might represent a new strategy to interfere with viral replication. However, so far no heterologous expression system was available to yield sufficient amounts of catalytically active protein for high-throughput based inhibitor screens. RESULTS: High-level heterologous expression of USP18 was achieved by applying a chaperone-based fusion system in E. coli. Pure protein was obtained in a single-step on IMAC via a His6-tag. The USP18 fusion protein exhibited enzymatic activity towards cell derived ISG15 conjugated substrates and efficiently hydrolyzed ISG15-AMC. Specificity towards ISG15 was shown by covalent adduct formation with ISG15 vinyl sulfone but not with ubiquitin vinyl sulfone. CONCLUSION: The results presented here show that a chaperone fusion system can provide high yields of proteins that are difficult to express. The USP18 protein obtained here is suited to setup high-throughput small molecule inhibitor screens and forms the basis for detailed biochemical and structural characterization. PMID- 22916878 TI - The effect of NaCl substitution with KCl on Akawi cheese: chemical composition, proteolysis, angiotensin-converting enzyme-inhibitory activity, probiotic survival, texture profile, and sensory properties. AB - The effect of partial substitution of NaCl with KCl on Akawi cheese with probiotic bacteria was investigated during 30 d of storage at 4 degrees C. Chemical composition, the survival of probiotic and lactic acid bacteria, proteolytic activity, and texture profile analysis were analyzed and sensory analysis was carried out to determine the effects of substitution. No significant differences were observed in moisture, protein, fat, and ash contents among the experimental Akawi cheeses at the same storage period. Significant differences were observed in water-soluble nitrogen and phosphotungstic-soluble nitrogen between experimental cheeses at the same of storage period. No significant difference was observed in the growth of Lactobacillus delbrueckii ssp. bulgaricus between experimental cheeses at the same storage period. However, the growth of Streptococcus thermophilus, Lactobacillus casei, and Lactobacillus acidophilus was significantly affected among experimental cheeses. A significant difference was observed in soluble Ca among experimental cheeses at the same storage period. In general, no significant differences existed in hardness and adhesiveness among experimental cheeses at the same storage period. No significant differences existed in sensory attributes, including creaminess, bitterness, saltiness, sour-acid, and vinegar taste among experimental Akawi cheeses at the same storage period. PMID- 22916879 TI - The evolution of chemical and microbiological properties of fresh goat milk cheese during its shelf life. AB - This study investigated the changes in chemical and microbiological properties of fresh goat milk cheese stored in an open deck refrigerated display cabinet (6 +/- 2 degrees C) or in a dark cold room (4 +/- 1 degrees C). The effects of partial vacuum packaging and fluorescent lighting were studied during the cheese shelf life (45 d) and 15 d after. Storage conditions did not affect the pH values (4.3), whereas a slight decrease in moisture (ca. 1%) and in water activity (<0.01 units) was recorded. Proteolysis monitored by Kjeldahl determination increased significantly during storage of all samples. The highest increase from 8.5 to 13.0% of soluble nitrogen (expressed as percentage of total nitrogen) was measured in cheese packaged in the presence of air and stored in a lighted cabinet. The proteolytic trend was also studied through capillary zone electrophoresis by monitoring the degradation of the main casein fractions and the formation of new peptides. In particular, 2 indices, based on peak area ratio of new-formed peptides and casein fractions were related to cheese age. Lipolysis, measured by solid-phase microextraction gas chromatography coupled to mass spectrometry of volatile fatty acids, was unaffected by air or light and did not proceed through storage. As expected, hexanal formed mainly in cheeses stored under light and packaged in air. Evaluation of sensorial quality, performed using a hedonic scale, showed significantly lower scores of cheeses kept under light compared with those kept in the dark, both at 45 and 60 d storage. Overall, the microbiological and chemical results suggested that the shelf life of soft goat milk cheese would be extended from 45 to 60 d. Such conclusion was supported also by the sensory quality evaluation. PMID- 22916880 TI - Fortification of cheese with vitamin D3 using dairy protein emulsions as delivery systems. AB - Vitamin D is an essential vitamin that is synthesized when the body is exposed to sunlight or after the consumption of fortified foods and supplements. The purpose of this research was to increase the retention of vitamin D(3) in Cheddar cheese by incorporating it as part of an oil-in-water emulsion using a milk protein emulsifier to obtain a fortification level of 280 IU/serving. Four oil-in-water vitamin D emulsions were made using sodium caseinate, calcium caseinate, nonfat dry milk (NDM), or whey protein. These emulsions were used to fortify milk, and the retention of vitamin D(3) in cheese curd in a model cheesemaking system was calculated. A nonemulsified vitamin D(3) oil was used as a control to fortify milk. Significantly more vitamin D(3) was retained in the curd when using the emulsified vitamin D(3) than the nonemulsified vitamin D(3) oil (control). No significant differences were observed in the retention of vitamin D(3) when emulsions were formulated with different emulsifiers. Mean vitamin D(3) retention in the model system cheese curd was 96% when the emulsions were added to either whole or skim milk compared with using the nonemulsified oil, which gave mean retentions of only 71% and 64% when added to whole and skim milk, respectively. A similar improvement in retention was achieved when cheese was made from whole and reduced-fat milk using standard manufacturing procedures on a small scale. When sufficient vitamin D(3) was added to produce cheese containing a target level of approximately 280 IU per 28-g serving, retention was greater when the vitamin D(3) was emulsified with NDM than when using nonemulsified vitamin D(3) oil. Only 58+/-3% of the nonemulsified vitamin D(3) oil was retained in full-fat Cheddar cheese, whereas 78+/-8% and 74+/-1% were retained when using the vitamin D(3) emulsion in full-fat and reduced-fat Cheddar cheese, respectively. PMID- 22916881 TI - Antibiotic resistance of lactic acid bacteria isolated from Chinese yogurts. AB - The aim of this study was to evaluate the susceptibility of 43 strains of lactic acid bacteria, isolated from Chinese yogurts made in different geographical areas, to 11 antibiotics (ampicillin, penicillin G, roxithromycin, chloramphenicol, tetracycline, chlortetracycline, lincomycin, kanamycin, streptomycin, neomycin, and gentamycin). The 43 isolates (18 Lactobacillus bulgaricus and 25 Streptococcus thermophilus) were identified at species level and were typed by random amplified polymorphic DNA analysis. Thirty-five genotypically different strains were detected and their antimicrobial resistance to 11 antibiotics was determined using the agar dilution method. Widespread resistance to ampicillin, chloramphenicol, chlortetracycline, tetracyclines, lincomycin, streptomycin, neomycin, and gentamycin was found among the 35 strains tested. All of the Strep. thermophilus strains tested were susceptible to penicillin G and roxithromycin, whereas 23.5 and 64.7% of Lb. bulgaricus strains, respectively, were resistant. All of the Strep. thermophilus and Lb. bulgaricus strains were found to be resistant to kanamycin. The presence of the corresponding resistance genes in the resistant isolates was investigated through PCR, with the following genes detected: tet(M) in 1 Lb. bulgaricus and 2 Strep. thermophilus isolates, ant(6) in 2 Lb. bulgaricus and 2 Strep. thermophilus isolates, and aph(3')-IIIa in 5 Lb. bulgaricus and 2 Strep. thermophilus isolates. The main threat associated with these bacteria is that they may transfer resistance genes to pathogenic bacteria, which has been a major cause of concern to human and animal health. To our knowledge, the aph(3')-IIIa and ant(6) genes were found in Lb. bulgaricus and Strep. thermophilus for the first time. Further investigations are required to analyze whether the genes identified in Lb. bulgaricus and Strep. thermophilus isolates might be horizontally transferred to other species. PMID- 22916882 TI - Accelerated ripening of Caciocavallo Pugliese cheese with attenuated adjuncts of selected nonstarter lactobacilli. AB - The nonstarter lactic acid bacteria Lactobacillus plantarum CC3M8, Lactobacillus paracasei CC3M35, and Lactobacillus casei LC01, previously isolated from aged Caciocavallo Pugliese cheese or used in cheesemaking, were used as adjunct cultures (AC) or attenuated (by sonication treatment) adjunct cultures (AAC) for the manufacture of Caciocavallo Pugliese cheese on an industrial scale. Preliminary studies on the kinetics of growth and acidification and activities of several enzymes of AAC were characterized in vitro. As shown by the fluorescence determination of live versus dead or damaged cells and other phenotype features, attenuation resulted in a portion of the cells being damaged and a portion of the cells being capable of growing with time. Compared with the control cheese (without adjunct cultures) and the cheese with AAC, the addition of AC resulted in a lower pH after manufacture, which altered the gross composition of the cheese. As shown by plate count and confirmed by random amplification of polymorphic DNA-PCR, the 3 species of nonstarter lactobacilli persisted during ripening but the number of cultivable cells varied between AC and AAC. Slight differences were found between cheeses regarding primary proteolysis. The major differences between cheeses were the accumulation of free amino acids and the activity levels of several enzymes, which were highest in the Caciocavallo Pugliese cheeses made with the addition of AAC. As shown by triangle test, the sensory properties of the cheese made with AAC at 45 d did not differ from those of the control Caciocavallo Pugliese cheese at 60 d of ripening. In contrast, the cheese made with AC at 45 d differed from both the Caciocavallo Pugliese cheese without adjuncts and the cheese made with AAC. Attenuated adjunct cultures are suitable for accelerating the ripening of Caciocavallo Pugliese cheese without modifying the main features of the traditional cheese. PMID- 22916883 TI - Effect of fat content and homogenization under conventional or ultra-high pressure conditions on interactions between proteins in rennet curds. AB - The objective of this study was to investigate the influence of conventional and ultra-high-pressure homogenization on interactions between proteins within drained rennet curds. The effect of fat content of milk (0.0, 1.8, or 3.6%) and homogenization treatment on dissociation of proteins by different chemical agents was thus studied. Increasing the fat content of raw milk increased levels of unbound whey proteins and calcium-bonded caseins in curds; in contrast, hydrophobic interactions and hydrogen bonds were inhibited. Both homogenization treatments triggered the incorporation of unbound whey proteins in the curd, and of caseins through ionic bonds involving calcium salts. Conventional homogenization-pasteurization enhanced interactions between caseins through hydrogen bonds and hydrophobic interactions. In contrast, ultra-high-pressure homogenization impaired hydrogen bonding, led to the incorporation of both whey proteins and caseins through hydrophobic interactions and increased the amount of unbound caseins. Thus, both homogenization treatments provoked changes in the protein interactions within rennet curds; however, the nature of the changes depended on the homogenization conditions. PMID- 22916884 TI - Strain-level characterization of nonstarter lactic acid bacteria in Norvegia cheese by high-resolution melt analysis. AB - The nonstarter lactic acid bacteria (NSLAB) constitute an important microbial group found during cheese ripening and they are thought to be fundamental to the quality of cheese. Rapid and accurate diagnostic tests for NSLAB are important for cheese quality control and in understanding the cheese ripening process. Here, we present a novel rapid approach for strain-level characterization through combined 16S rRNA gene and repetitive sequence-based high-resolution melt analysis (HRM). The approach was demonstrated through the characterization of 94 isolates from Norvegia, a Gouda-type cheese. The HRM profiles of the V1 and V3 variable regions of the 16S rRNA gene of the isolates were compared with the HRM profiles of 13 reference strains. The HRM profile comparison of the V1 and V3 regions of the 16S rRNA gene allowed discrimination of isolates and reference strains. Among the cheese isolates, Lactobacillus casei/paracasei (62 isolates) and Lactobacillus plantarum/Lactobacillus pentosus (27 isolates) were the dominant species, whereas Lactobacillus curvatus/Lactobacillus sakei were found occasionally (5 isolates). The HRM profiling of repetitive sequence-based PCR using the (GTG)(5) primer was developed for strain-level characterization. The clustering analysis of the HRM profiles showed high discriminatory power, similar to that of cluster analysis based on the gel method. In conclusion, the HRM approach in this study may be applied as a fast, accurate, and reproducible method for characterization of the NSLAB microflora in cheese and may be applicable to other microbial environments following selective plate culturing. PMID- 22916885 TI - Fermented milk supplemented with probiotics and prebiotics can effectively alter the intestinal microbiota and immunity of host animals. AB - Fermented milk supplemented with 2 probiotic strains, Bifidobacterium lactis Bi 07 and Lactobacillus acidophilus NCFM, and a prebiotic, isomaltooligosaccharide, was orally administered to 100 healthy adults at 480 g/d for 2 wk in a randomized controlled trial. The fecal bacterial compositions of these subjects were examined by culture before and after the intervention. The same fermented milk was also orally fed to BALB/c mice, and immune as well as fecal bacteria analyses were conducted using the same culturing methods. After the intervention, increases in fecal bifidobacteria and lactobacilli were observed among the subjects compared with the subjects in the control group. In contrast, after the intervention, fecal enterobacilli were significantly decreased in the test group compared with the control group. The same effects on the composition of the intestinal microbiota were observed in mice. Furthermore, the tested mice were found to have significantly increased delayed-type hypersensitivity, plaque forming cells, and half-hemolysis values after the intervention with the fermented milk. In summary, the synbiotic fermented milk containing probiotics and a prebiotic may contribute to improve intestinal health and may have a positive effect on the humoral and cell-mediated immunity of host animals. PMID- 22916886 TI - Effect of emulsifying salts on the physicochemical properties of processed cheese made from Mozzarella. AB - The aim of this study was to investigate the effect of different types and concentrations of emulsifying salts (trisodium citrate, tetrasodium pyrophosphate, sodium tripolyphosphate, sodium hexametaphosphate, and disodium orthophosphate) on the physicochemical properties of processed cheese. The physicochemical composition, texture profile, degree of casein dissociation, fat particle size, color, and nuclear magnetic resonance profile (NMR) of processed cheese were determined. Hardness, degree of casein dissociation, and pH increased as the concentration of emulsifying salts increased. The fat particle size of processed cheese was significantly influenced by the type of emulsifying salts, with processed cheese made with sodium hexametaphosphate having larger particles (4.68 um) than cheeses made with the other salts (from 2.71 to 3.30 um). The processed cheese prepared with trisodium citrate was whiter than those prepared with the other emulsifying salts. The NMR analysis showed that the relaxation time of processed cheese of 10 to 100 ms accounted for a major proportion, indicating that the moisture in processed cheese was mainly bound water combined with the fat globule and hydrated casein. PMID- 22916887 TI - Bovine milk contains microRNA and messenger RNA that are stable under degradative conditions. AB - We previously reported that microRNA (miRNA) is present in human breast milk. Recently, other groups have reported that bovine milk also contains miRNA; however, these reports are few. We therefore investigated bovine milk miRNA using microarray and quantitative PCR analyses to identify the differences between colostrum and mature milk. The RNA concentration in a colostrum whey fraction was higher than that in a mature milk whey fraction. In total, 102 miRNA were detected in bovine milk by microarray analysis (100 in colostrum and 53 in mature milk; 51 were common to both). Among these miRNA, we selected several immune- and development-related miRNA, including miR-15b, miR-27b, miR-34a, miR-106b, miR 130a, miR-155, and miR-223. These miRNA were detected in bovine milk by quantitative PCR, and each of these miRNA was significantly more highly expressed in colostrum than in mature milk. We also confirmed the presence of some mRNA in bovine milk. Nevertheless, synthesized miRNA spiked in the raw milk whey were degraded, and naturally existing miRNA and mRNA in raw milk were resistant to acidic conditions and RNase treatment. The RNA molecules in milk were stable. We also detected miRNA and mRNA in infant formulas purchased from Japanese markets. It is still unknown whether milk-derived RNA molecules play biological roles in infants; however, if milk-derived RNA do show functions in infants, our data will help guide future studies. PMID- 22916888 TI - Reduced fat and sugar vanilla ice creams: sensory profiling and external preference mapping. AB - The aims of this study were (1) to map sensory attributes of vanilla ice cream with reduced fat and sugar, and (2) to determine drivers of liking by applying external preference mapping and reveal the relationship between descriptive attributes and hedonic judgments using the partial least squares method. Descriptive sensory profiles (n=11) and consumer test (n=117) of 6 samples of vanilla ice cream (3 traditional and 3 with reduced fat and sugar) were determined. The attributes brightness and sweet aftertaste for sample and creaminess (appearance and texture) and sweet aroma contributed positively to the acceptance of ice cream samples. The attributes aeration, powdered milk aroma and flavor, and white chocolate aroma and flavor contributed positively to the acceptance of the ice creams. The attributes hydrogenated fat aroma and flavor were responsible for the lower acceptance of samples. The reduction in fat and sugar did not necessarily cause a decrease in acceptance. The most important factors were selection of the appropriate sweetener system and the use of good quality raw material. PMID- 22916889 TI - High-pressure processing inactivates Listeria innocua yet compromises Queso Fresco crumbling properties. AB - The objective of this study was to determine the effectiveness of high-pressure processing to inactivate Listeria innocua (a Listeria monocytogenes surrogate) in Queso Fresco, and to study the effects of the high-pressure treatment on cheese crumbling properties. Queso Fresco was made with pasteurized, homogenized milk, lactic acid bacterial starter culture, chymosin, and flake salt. Cheeses were pressed (0.1 MPa) for 1h before crumbling and inoculation with a cocktail of 3 strains of L. innocua, and then pressed for 12 h (0.1 MPa). High-pressure processing treatments of sliced cheese rounds included pressure from 400 to 600 MPa for 1 to 25 min. Cheese sample temperatures, initially approximately 21 degrees C, increased during pressurization and decreased gradually during the holding time. The highest temperature increase was to 23.6 degrees C at 600 MPa. Greater than 5-log reductions occurred at set-point pressures of 500, 550, or 600 MPa when held for at least 15, 3, or 1 min, respectively. However, because inactivation was neither complete nor permanent and crumbling properties were not maintained under the conditions tested in this study, high-pressure processing is not recommended for Queso Fresco applications. PMID- 22916890 TI - Short communication: evaluation of Brucella infection of cows by PCR detection of Brucella DNA in raw milk. AB - The collection of serum samples from cows is frequently difficult to implement in large-scale surveys, and may involve a high risk of occupational infection. This study assessed the potential of using raw milk sampling as a suitable method for use in a pilot survey of Brucella abortus infection status in cattle. Raw milk samples from 816 cows were examined. Polymerase chain reaction assays of raw milk, with primers derived from the IS711 element of the Brucella genome, were used. Of the cows, 55 were Brucella positive based on serum agglutination test (SAT) results. Polymerase chain reaction amplified Brucella DNA in 25 (45%) of the 55 SAT-positive cows. All of the 689 SAT-negative cows were found to be negative in PCR assays of their milk. Brucella infection status based on PCR results was then predicted for 72 cows from private h erds in which the brucellosis status was unknown. Subsequently, SAT verification of Brucella status was performed. There was no significant difference between predicted and actual SAT-positive rates in those 72 cows. This study indicates a relationship between Brucella detection levels obtained using milk-based PCR results and SAT results. The specific, rapid, and easy sampling procedure within milk-based PCR assaying for brucellosis detection makes the milk PCR method an attractive alternative for evaluation of B. abortus infection in cows, particularly if used as a routine screening and surveillance tool to reduce brucellosis outbreaks. PMID- 22916891 TI - Technical note: development of a quantitative PCR method for monitoring strain dynamics during yogurt manufacture. AB - Yogurt starter cultures may consist of multiple strains of Lactobacillus delbrueckii ssp. bulgaricus (LB) and Streptococcus thermophilus (ST). Conventional plating methods for monitoring LB and ST levels during yogurt manufacture do not allow for quantification of individual strains. The objective of the present work was to develop a quantitative PCR method for quantification of individual strains in a commercial yogurt starter culture. Strain-specific primers were designed for 2 ST strains (ST DGCC7796 and ST DGCC7710), 1 LB strain (DGCC4078), and 1 Lactobacillus delbrueckii ssp. lactis strain (LL; DGCC4550). Primers for the individual ST and LB strains were designed to target unique DNA sequences in clustered regularly interspersed short palindromic repeats. Primers for LL were designed to target a putative mannitol-specific IIbC component of the phosphotransferase system. Following evaluation of primer specificity, standard curves relating cell number to cycle threshold were prepared for each strain individually and in combination in yogurt mix, and no significant differences in the slopes were observed. Strain balance data was collected for yogurt prepared at 41 and 43 degrees C to demonstrate the potential application of this method. PMID- 22916892 TI - Evaluation of milk yield losses associated with Salmonella antibodies in bulk tank milk in bovine dairy herds. AB - The effect of Salmonella on milk production is not well established in cattle. The objective of this study was to investigate whether introduction of Salmonella into dairy cattle herds was associated with reduced milk yield and determine the duration of any such effect. Longitudinal data from 2005 through 2009 were used, with data from 12 mo before until 18 mo after the estimated date of infection. Twenty-eight case herds were selected based on an increase in the level of Salmonella-specific antibodies in bulk-tank milk from <10 corrected optical density percentage (ODC%) to >=70 ODC% between 2 consecutive three-monthly measurements in the Danish Salmonella surveillance program. All selected case herds were conventional Danish Holstein herds. Control herds (n=40) were selected randomly from Danish Holstein herds with Salmonella antibody levels consistently <10 ODC%. A date of herd infection was randomly allocated to the control herds. Hierarchical mixed effect models with the outcome test-day yield of energy corrected milk (ECM)/cow were used to investigate daily milk yield before and after the estimated herd infection date for cows in parities 1, 2, and 3+. Control herds were used to evaluate whether the effects in the case herds could be reproduced in herds without Salmonella infection. Herd size, days in milk, somatic cell count, season, and year were included in the models. Yield in first parity cows was reduced by a mean of 1.4 kg (95% confidence interval: 0.5 to 2.3) of ECM/cow per day from 7 to 15 mo after the estimated herd infection date, compared with that of first-parity cows in the same herds in the 12 mo before the estimated herd infection date. Yield for parity 3+ cows was reduced by a mean of 3.0 kg (95% confidence interval: 1.3 to 4.8) of ECM/cow per day from 7 to 15 mo after herd infection compared with that of parity 3+ cows in the 12 mo before the estimated herd infection. We observed minor differences in yield in second-parity cows before and after herd infection and observed no difference between cows in control herds before and after the simulated infection date. Milk yield decreased significantly in affected herds and the reduction was detectable several months after the increase in bulk tank milk Salmonella antibodies. It took more than 1 yr for milk yield to return to preinfection levels. PMID- 22916893 TI - Routine detection of hyperketonemia in dairy cows using Fourier transform infrared spectroscopy analysis of beta-hydroxybutyrate and acetone in milk in combination with test-day information. AB - The objective of this study was to assess the quality of a diagnostic model for the detection of hyperketonemia in early lactation dairy cows at test days. This diagnostic model comprised acetone and beta-hydroxybutyrate (BHBA) concentrations in milk, as determined by Fourier transform infrared (FTIR) spectroscopy, in addition to other available test-day information. Plasma BHBA concentration was determined at a regular test day in 1,678 cows between 5 and 60 d in milk, originating from 118 randomly selected farms in the Netherlands. The observed prevalence of hyperketonemia (defined as plasma BHBA >=1,200 umol/L) was 11.2%. The value of FTIR predictions of milk acetone and milk BHBA concentrations as single tests for hyperketonemia were found limited, given the relatively large number of false positive test-day results. Therefore, a multivariate logistic regression model with a random herd effect was constructed, using parity, season, milk fat-to-protein ratio, and FTIR predictions of milk acetone and milk BHBA as predictive variables. This diagnostic model had 82.4% sensitivity and 83.8% specificity at the optimal cutoff value (defined as maximum sum of sensitivity and specificity) for the detection of hyperketonemia at test days. Increasing the cutoff value of the model to obtain a specificity of 95% increased the predicted value of a positive test result to 56.5%. Confirmation of test-positive samples with wet chemistry analysis of milk acetone or milk BHBA concentrations (serial testing) improved the diagnostic performance of the test procedure. The presented model was considered not suitable for individual detection of cows with ketosis due to the length of the test-day interval and the low positive predictive values of the investigated test procedures. The diagnostic model is, in our opinion, valuable for herd-level monitoring of hyperketonemia, especially when the model is combined with wet chemistry analysis of milk acetone or milk BHBA concentrations. By using the diagnostic model in combination with wet chemistry milk BHBA analysis, 84% of herds were correctly classified at a 10% alarm-level prevalence. As misclassification of herds may particularly occur when only a limited number of fresh cows are sampled, we suggest using prevalence estimates over several consecutive test days to evaluate feeding and management practices in smaller dairy farms. PMID- 22916894 TI - Transmission dynamics of intramammary infections with coagulase-negative staphylococci. AB - A field trial was conducted on 2 US dairy herds to evaluate the transmission dynamics of coagulase-negative staphylococci (CNS) during the lactation period. Quarter milk cultures positive for CNS were classified as intramammary infection (IMI) or incidental isolation (transient colonization). The average proportion of quarters with CNS IMI was 0.114 in farm 1 and 0.09 in farm 2, and corresponding estimates for quarters with transient colonization of CNS were 0.122 and 0.088 throughout the 13-mo study period. Transmission parameters were obtained both for IMI caused by CNS and for CNS-positive quarters classified as the combination of transient colonization and IMI. Transmission between cows and between quarters in the same cow was assessed. The transmission parameters (beta) for IMI caused by CNS were 0.0066 (farm 1) and 0.0111 (farm 2). Corresponding estimates of beta when IMI and transient colonization of CNS were assessed jointly were 0.0256 (farm 1) and 0.0253 (farm 2). On farm 1, risk of transmission for CNS IMI between quarters in the same cow was 2 times greater than that between quarters from cow to cow. Transmission of CNS was considered contagious in one farm but no distinction between contagious and environmental transmission could be made in the other. We hypothesize that between-farm variation may be related to diversity between prevailing CNS species or by differences in management. In the current study, estimates of the basic reproduction number (R(0)) at the farm level for CNS IMI were 0.59 and 0.84 in farms 1 and 2, respectively. This shows that the transmission of CNS from IMI during the lactation period would to be too low to maintain the observed herd prevalence of CNS IMI. The R(0) values for the combination of transient colonization and IMI by CNS were 1.13 and 1.17 in farms 1 and 2, respectively. This indicates potential for sustained endemic infection of CNS throughout lactation. However, prevailing CNS species may also differ between transient colonization and IMI. Therefore, not only CNS originating from IMI or incidental isolation events, but also CNS IMI occurring from the period outside the lactation pen are essential for maintenance of the observed herd prevalence of CNS IMI throughout lactation in this study. The effect of IMI originating outside the lactation pen was verified in simulations with reduced entry of infectious quarters to the lactation pens. Measures against CNS IMI would probably increase in efficiency if prevention of infection during the dry period and early lactation were further emphasized in herd health programs. PMID- 22916895 TI - Protein and fat mobilization and associations with serum beta-hydroxybutyrate concentrations in dairy cows. AB - The objective of this study was to obtain information on variation between dairy cows in muscle and fat tissue mobilization around parturition and to study the association between protein and fat mobilization and serum beta-hydroxybutyrate (BHBA) concentrations (hyperketonemia) in this period. Thirty-four cows kept under similar conditions at a university dairy farm (no experimental treatments) were monitored from 4 wk before until 8 wk after calving. Mobilization of muscle protein was investigated by analysis of plasma 3-methylhistidine concentrations (3-MH, analyzed by a recently developed HPLC tandem mass spectrometry method) and ultrasound measurements of longissimus muscle thickness. Mobilization of fat tissue was monitored by serum nonesterified fatty acid (NEFA) concentrations and ultrasound measurements of backfat thickness. Large variation was observed between cows in onset and duration of periparturient protein and fat mobilization. Plasma 3-MH concentrations and muscle thickness profiles indicated that protein mobilization started, on average, before parturition and continued until approximately wk 4 of lactation. Serum NEFA concentrations and backfat thickness profiles showed that fat mobilization occurred from parturition until the end of the study. Thus, muscle protein mobilization occurred in advance of fat mobilization in most cows from this study. We hypothesized that this might be due to a prepartum amino acid deficiency in the absence of negative energy balance. The incidence of hyperketonemia in this study was 16/34 = 47%. With the exception of 3 cows defined as having severe hyperketonemia, cows with lower 3-MH concentrations had higher serum BHBA concentrations. A possible explanation for this observation might be that higher mobilization of protein around calving might restrict ketone body production due to the higher availability of glucogenic precursors in the period of most severe negative energy balance and highest fat mobilization. The validity of this hypothesis needs to be confirmed, but data from this study indicate that further research on the role of protein mobilization in the etiology of hyperketonemia in dairy cows is needed. PMID- 22916896 TI - Molecular epidemiology of Staphylococcus aureus mastitis in dairy heifers. AB - The specific purpose was to investigate the possible interrelationships of genotypes of Staphylococcus aureus found in mammary glands, horn flies, and extramammary sites on 3 southeastern US dairies. A total of 1,228 samples were obtained from various sources on the 3 dairy herds, each of which had a history of Staph. aureus mastitis. Dairy herds studied had access to pasture, and samples were collected during the summer when horn flies (Haematobia irritans) were active. Samples collected included milk samples from all lactating herd cows, colostrum samples from heifers calving during the study period, heifer body sites (mouth, nostrils, and teats), the heifer environment (water, feed, and soil/vegetation/pasture), horn flies, and humans (hands and nostrils). Isolation of Staph. aureus was attempted from all samples, with isolates subjected to genotypic analysis using pulsed-field gel electrophoresis. A total of 244/1228 (or 19.9%) of all samples were positive for Staph. aureus. For milk samples, 52/383 (or 13.6%) of samples were Staph. aureus positive, and 70/411 (or 17.0%) of heifer quarter colostrum samples were positive. Horn fly samples were frequently positive, with over one-half (29/52, or 55.8%) of samples positive for Staph. aureus. Staphylococcus aureus obtained during the study comprised isolates from 12 different genotype groups as defined in this study. Identical genotypes were obtained from horn flies, heifer colostrum samples, and cow milk samples. Group B genotypes were shared among flies, heifer colostrum samples, body sites, and cow milk samples, whereas group A genotypes were common to the same sample locations and body sites but rarely (once) found in horn flies. We conclude, based upon the finding of identical pulsed-field gel electrophoresis genotypes in flies, heifer body sites, and heifer colostrum samples, that flies and heifer body sites could be important sources of Staph. aureus for heifer intramammary infections. PMID- 22916897 TI - Effect of an automated dipping and backflushing system on somatic cell counts. AB - Postmilking teat disinfection is an effective management practice to prevent transmission of contagious mastitis pathogens from cow to cow. With farms increasing in size and an increase in the number of rotary milking parlors, the need for automation of postmilking teat disinfection is mounting. Automated teat dipping and backflushing (ADB) systems have existed for some years, but their effect on udder health was never examined in a field study on commercial dairy farms. The objectives of this study were, therefore, to evaluate the effect of introducing an ADB system in a herd on (1) bulk milk somatic cell count (SCC), (2) individual cow SCC, and (3) the proportion of newly elevated SCC. Dairy herd improvement data were collected over a 30-mo period on 25 sets of 3 farms. Each set of 3 farms contained a farm that installed an ADB system, one that disinfected teats using dipping after milking, and one that sprayed teats after milking. Data were analyzed using linear mixed models. Bulk milk SCC on farms that sprayed or dipped before installing an ADB system were 16,000 and 30,000 cells/mL lower in the period 6 to 18 mo after installation, respectively, than on farms that continued spraying or dipping the teats after milking. In the same period after installing an ADB system, proportions of cows with elevated SCC were 4.3 and 1.2% lower, respectively, compared with spraying and with dipping. Similarly, proportions of cows that had newly elevated SCC were 1.5% lower and 0.3% higher, respectively, compared with farms that sprayed or dipped. Installing an ADB system had a beneficial effect on bulk milk SCC, individual cow SCC, and the proportion of newly elevated SCC. The effect was most prominent in the period 6 to 18 mo after installation of an ADB system. PMID- 22916898 TI - The effects of experimentally induced Escherichia coli mastitis and flunixin meglumine administration on activity measures, feed intake, and milk parameters. AB - The use of flunixin meglumine (FM), a nonsteroidal antiinflammatory drug, during experimentally induced Escherichia coli mastitis was evaluated. Twenty-four primiparous and multiparous lactating dairy cows were challenged with 1*10(2) cfu of E. coli 727 in 1 uninfected quarter. Of the 24 E. coli-challenged animals, 12 were administered FM [ECF; 100mg (2 cc)/45.5 kg of body weight) at the onset of clinical mastitis signs. The remaining 12 challenged cows were untreated (EC). An additional 11 cows were infused with 1 mL of sterile phosphate-buffered saline and served as the nonchallenged control (CTL) group. Activity measures, dry matter intake (DMI), milk production, milk bacterial counts from challenged mammary glands, and somatic cell score (SCS) were collected on all animals. Activity measurements were collected using both a behavior-monitoring system and data loggers. Activity was summarized by day (behavior-monitoring system) and in 3-h time periods (data loggers). An examination of animal activity indicated that EC and ECF cows stood more and lay less as compared with the CTL animals in the first 6h after FM administration. When DMI was analyzed, CTL and ECF animals had greater DMI than the EC animals on d 1 postchallenge. However, by d 2 postchallenge, DMI for ECF and EC cows was significantly less than for the CTL cows. The ECF cows had greater milk yield than did EC animals by d 3 and 4 postchallenge, and no significant difference in yield was observed between the ECF and CTL animals. No differences in SCS were observed between the parity groups. Yet, bacterial counts in milk were greater in multiparous animals compared with the primiparous cows. Therefore, it can be concluded that E. coli mastitis does alter animal activity and may have a negative effect on animal well being. However, the improvement in DMI and milk production for ECF animals provides evidence for using a nonsteroidal antiinflammatory drug as supportive therapy in alleviating the adverse effects associated with E. coli mastitis. PMID- 22916899 TI - The effect of respiratory disease and a preventative antibiotic treatment on growth, survival, age at first calving, and milk production of dairy heifers. AB - Bovine respiratory disease complex (BRD) is a common disease in weaned dairy calves that incurs economic and welfare costs. This study was an extension of a randomized clinical trial in which a single injection of tulathromycin (TUL) or oxytetracycline (TET) was administered at first movement to group housing for the prevention of BRD in the 60 d following antimicrobial treatment (BRD60). Calves treated with TUL were 0.5 times [95% confidence interval (CI): 0.4 to 0.7] as likely to be treated for BRD60 as calves treated with TET. The objectives of the current study were to evaluate the long-term effects of BRD and antibiotic treatment on growth of heifers until breeding age, age at first calving, incidence of dystocia, milk production, and mortality before first calving and mortality before 120 d in milk. At entry to the breeding barn (382 d of age), calves that experienced BRD60 weighed 16.0+/-2.3 kg less than calves that did not. Survival to first calving was recorded for 98% (1,343/1,392) of the heifers on this trial. For TET and TUL heifers with BRD60, 63% (94/150) and 73% (64/88) survived to first lactation, respectively. For TET and TUL calves without BRD60, 84% (436/517) and 84% (494/588) survived to first lactation, respectively. The median age at first calving for heifers with and without BRD60 was 714 (95% CI: 705-723) and 702 (95% CI: 699-705) days, respectively. Heifers with BRD60 were 1.5 (95% CI: 1.1-2.2) times more likely to have a calving ease score >=2 at their first calving compared with heifers without BRD60. The administration of TUL at movement to group housing may have a role in the prevention of BRD and in mitigating some of the long-term effects of this disease. PMID- 22916900 TI - The welfare of dairy cows is improved in relation to cleanliness and integument alterations on the hocks and lameness when sand is used as stall surface. AB - Lying down is a highly prioritized behavior in dairy cattle, and previous studies have shown that the type of stall surface has a great effect on the health and welfare of the cow. The objective of this study was to examine the effect of stall surface (rubber mats, mattresses, or sand) on cleanliness, integument alterations on the hocks, lameness, and milk yield of loosely housed dairy cows. Thirty-seven Danish dairy farms with Danish Holstein-Friesian cows were included in the study, and 2,593 cows were examined. Twelve of the farms used rubber mats, 17 of the farms used mattresses, and 8 used sand as the stall surface. Cows housed in facilities with sand in the freestalls were at lower risk of being dirty, had fewer integument alterations on the hocks (e.g., hairless patches, lesions, and swellings), and were less likely to be lame. The cows in facilities with sand in the freestalls also had a significantly higher milk yield compared with cows housed in facilities with mattresses. No differences in milk yield were found between cows housed in facilities with mattresses and rubber mats. Cleanliness, integument alterations, lameness, and milk yield are important indicators of cow welfare; this study showed that, compared with other stall surfaces, sand had a positive effect on these indicators. We therefore conclude that the use of sand as a stall surface is associated with improved welfare. PMID- 22916901 TI - Sampling cows to assess lying time for on-farm animal welfare assessment. AB - The time that dairy cows spend lying down is an important measure of their welfare, and data loggers can be used to automatically monitor lying time on commercial farms. To determine how the number of days of sampling, parity, stage of lactation, and production level affect lying time, electronic data loggers were used to record lying time for 10 d consecutively, at 3 stages of lactation [early: when cows were at 10-40 d in milk (DIM), mid: 100-140 DIM, late: 200-240 DIM] of 96 Holstein cows in tiestalls (TS) and 127 in freestalls (FS). We calculated daily duration of lying, bout frequency, and mean bout duration. We observed complex interactions between parity and stage of lactation, which differed somewhat between tiestalls and freestalls. First-parity cows had higher bout frequency and shorter lying bouts than older cows but bout frequency decreased and mean bout duration increased as DIM increased. We found that individual cows were not consistent in time spent lying between early and mid lactation (Pearson coefficient, TS: r = 0.1, FS: r = 0.2), whereas cows seemed to be more consistent in time spent lying between mid and late lactation (TS: r = 0.7, FS: r = 0.3). For both TS and FS cows, daily milk production was significantly, but slightly negatively, correlated with lying time across the lactation (range, r: -0.2 to -0.4), whereas parity was slightly to moderately positively correlated with mean bout duration across the lactation (r: +0.2 to +0.6) and negatively with bout frequency (r: -0.2 to -0.5). To estimate how the duration of the time sample affected the estimates of lying time subsets of data subsets consisting of 1, 2, 3, 4, 5, 6, 7, 8, and 9 d per cow were created, and the relationship between the overall mean (based on 10 d) and the mean of each subset was tested by regression. For both TS and FS, lying time based on 4 d of sampling provided good estimates of the average 10-d estimate (90% of accuracy). Automated monitoring of lying time has potential as a measure of dairy cow welfare on commercial farms but cows differ greatly in lying time. To obtain a representative measure for the herd, it is necessary to sample cows based on their parity and stage of lactation but probably not milk production level. PMID- 22916902 TI - Variance components of teat dimensions in dairy cows and associated factors. AB - Traditionally, all cows within a herd are milked with the same teat cup liner, although it is hypothesized that considerable variation in teat dimensions exists between cows and quarters within cows. To study at which level (herd, cow, or quarter) most variation in teat dimensions resides, and to identify factors explaining (part of) this variation, both a cross-sectional (n=2,715) and a longitudinal study (n=8,678) were conducted. Using an objective and easy-to-use measuring device, teat length and teat diameters were determined. In both studies, most variation in teat dimensions was present at the cow or within-cow level, and not at the herd level, indicating that choosing a teat cup liner that is identical for all cows in a herd is far from optimal. Quarter position (front versus hind), parity and lactation stage were identified as factors associated with teat length and teat diameters. Generally, front teats were longer and broader than hind teats. Teat length and diameters increased with parity, although the increase in teat length was not significant from second parity onwards in front teats, based on observations from the longitudinal study. After the first 30 d in milk, teat length substantially and significantly increased, whereas teat diameters decreased. We conclude that better results in teat condition, and eventually in udder health, might be yielded when different teat cup liners are chosen for front versus hind teats or for cows of different parity or lactation stage, with special attention to the first 30 d in milk. However, the biological relevance of these differences should be examined first. PMID- 22916903 TI - Pleiotropic effects of polymorphism of the gene diacylglycerol-O-transferase 1 (DGAT1) in the mammary gland tissue of dairy cows. AB - Microarray analysis was used to identify genes whose expression in the mammary gland of Holstein-Friesian dairy cows was affected by the nonconservative Ala to Lys amino acid substitution at position 232 in exon VIII of the diacylglycerol-O transferase 1 (DGAT1) gene. Mammary gland biopsies of 9 homozygous Ala cows, 13 heterozygous cows (Ala/Lys), and 4 homozygous Lys cows in midlactation were taken. Microarray ANOVA and factor analysis for multiple testing methods were used as statistical methods to associate the expression level of the genes present on Affymetrix bovine genome arrays (Affymetrix Inc., Santa Clara, CA) with the DGAT1 gene polymorphism. The data was also analyzed at the level of functional modules by gene set enrichment analysis. In this small-scale experimental setting, DGAT1 gene polymorphism did not modify milk yield and composition significantly, although expected changes occurred in the yields of C14:0, cis-9 C16:1, and long-chain fatty acids. Diacylglycerol-O-transferase 1 gene polymorphism affected the expression of 30 annotated genes related to cell growth, proliferation, and development, remodeling of the tissue, cell signaling and immune system response. Furthermore, the main affected functional modules were related to energy metabolism (lipid biosynthesis, oxidative phosphorylation, electron transport chain, citrate cycle, and propanoate metabolism), protein degradation (proteosome-ubiquitin pathways), and the immune system. We hypothesize that the observed differences in transcriptional activity reflect counter mechanisms of mammary gland tissue to respond to changes in milk fatty acid concentration or composition, or both. PMID- 22916904 TI - A cohort study of the associations between udder conformation, milk somatic cell count, and lamb weight in suckler ewes. AB - A cohort study of 67 suckler ewes from 1 farm was carried out from January to May 2010 to investigate associations between udder conformation, udder half milk somatic cell count (SCC), and lamb weight. Ewes and lambs were observed at lambing. Ewe health and teat condition and lamb health and weight were recorded on 4 to 5 further occasions at 14-d intervals. At each observation, a milk sample was collected from each udder half for somatic cell counting. Two weeks after lambing, ewe udder conformation and teat placement were scored. Low lamb weight was associated with ewe SCC >400,000 cells/mL (-0.73 kg), a new teat lesion 14 d previously (-0.91 kg), suboptimal teat position (-1.38 kg), rearing in a multiple litter (-1.45 kg), presence of diarrhea at the examination (-1.19 kg), and rearing by a 9-yr-old ewe compared with a 6-yr-old ewe (-2.36 kg). High lamb weight was associated with increasing lamb age (0.21 kg/d), increasing birth weight (1.65 kg/kg at birth), and increasing number of days the ewe was given supplementary feed before lambing (0.06 kg/d). High udder half SCC was associated with pendulous udders (9.6% increase in SCC/cm of drop) and greater total cross sectional area of the teats (7.2% increase of SCC/cm(2)). Low SCC were associated with a heavier mean litter weight (6.7% decrease in SCC/kg). Linear, quadratic, and cubic terms for days in lactation were also significant. We conclude that poor udder and teat conformation are associated with high levels of intramammary infection, as indicated by increased SCC and that both physical attributes of the udder and SCC are linked to lamb growth, suggesting that selection of suckler ewes with better udder and teat conformation would reduce intramammary infection and increase lamb growth rate. PMID- 22916905 TI - Nonesterified fatty acids modify inflammatory response and eicosanoid biosynthesis in bovine endothelial cells. AB - Intense lipid mobilization during the transition period in dairy cows is associated with increased disease susceptibility. The potential impact of altered plasma nonesterified fatty acids (NEFA) concentrations and composition on host inflammatory responses that may contribute to disease incidence and severity are not known. The objective of this study was to evaluate if increased NEFA concentrations could modify vascular inflammatory responses in vitro by changing the expression of important inflammatory mediators that are important in the pathogenesis of infectious diseases of transition cows such as mastitis and metritis. Bovine aortic endothelial cells (BAEC) were cultured with different concentrations of a NEFA mixture that reflected the plasma NEFA composition during different stages of lactation. The expression of cytokines, adhesion molecules, and eicosanoids were measured to assess changes in BAEC inflammatory phenotype. Addition of NEFA mixtures altered the fatty acid profile of BAEC by increasing the concentration of stearic acid (C18:0) and decreasing the content of arachidonic acid (C20:4n6c) and other long-chain polyunsaturated fatty acids in the phospholipid fraction. A significant increase also occurred in mRNA expression of cytokine and adhesion molecules that are associated with increased inflammatory responses during the transition period. Expression of cyclooxygenase 2, an important enzyme associated with eicosanoid biosynthesis, was increased in a NEFA concentration-dependent manner. The production of linoleic acid-derived eicosanoids 9- and 13-hydroxyoctadecadienoic acids also was increased significantly after treatment with NEFA mixtures. This research described for the first time specific changes in vascular inflammatory response during in vitro exposure to NEFA mixtures that mimic the composition and concentration found in cows during the transition period. These findings could explain, in part, alterations in inflammatory responses observed during intense lipid mobilization stages such as in the transition period of dairy cows. Future studies should analyze specific mechanisms by which high NEFA concentrations induce a vascular proinflammatory phenotype including the effect of 9 and 13-hydroxyoctadecadienoic acids and other lipid mediators. PMID- 22916906 TI - Nitrogen metabolism and rumen microbial enumeration in lactating cows with divergent residual feed intake fed high-digestibility pasture. AB - Dairy cattle selected for negative residual feed intake (n-RFI; efficient) should maintain production while reducing dry matter intake over a lactation because of improvements in feed digestion and efficient use of nutrients. The objective of this study was to measure nitrogen (N) digestibility and rumen microbial community composition over a short period during early lactation in lactating Holstein-Friesian cows selected previously for divergent RFI. It was proposed that n-RFI cows would have greater apparent digestibility of N than the positive RFI (p-RFI; inefficient) animals, to compensate for the lower dry matter intake determined during selection for divergence. Sixteen 3-yr-old rumen-cannulated, lactating cows (56 +/- 10d in milk) selected for n-RFI (n = 8) and p-RFI (n = 8) were housed in metabolism stalls and fed fresh vegetative ryegrass (Lolium perenne L.) pasture ad libitum as a sole diet during an 8-d digestibility study. Intake of nutrients and outputs of milk, feces, and urine were determined. Rumen parameters were determined by removing, weighing, and sampling digesta, and by cobalt-EDTA dilution. Intakes of N, dry matter, organic matter, or its components did not differ with RFI. Compared with p-RFI cows, n-RFI cows had a greater apparent N digestibility (77.2 vs. 75.5%), and a tendency toward greater dry matter and organic matter digestibilities. The n-RFI cows had a lower fecal N output (126 vs. 138 g/d) and a lower partition of feed N to fecal N (23.1 vs. 24.7%) compared with p-RFI animals. We found no differences between phenotypes in the partition of N to urinary N or milk crude protein but did observe a trend for n-RFI cows to partition less N to milk casein (16.8 vs. 17.9%). Rumen digesta mass was similar for both groups, despite differences in calculated fractional liquid outflow rates, and most bacterial, archaeal, protozoal, and fungal communities were similar for both phenotype groups. In conclusion, dry matter intake and rumen function were similar for both phenotypes when the animals were fed highly digestible fresh ryegrass, but apparent digestibility of dietary N was higher in the efficient (n-RFI) cows. Future research should measure digestion parameters in cows with divergent RFI when fed diets differing in chemical composition (e.g., divergent crude protein contents). PMID- 22916907 TI - Effect of cooling heat-stressed dairy cows during the dry period on insulin response. AB - Heat stress (HT) during the dry period affects hepatic gene expression and adipose tissue mobilization during the transition period. In addition, it is postulated that HT may alter insulin action on peripheral tissues. Our objective was to evaluate the effect of cooling heat-stressed cows during the dry period on insulin effects on peripheral tissues during the transition period. Cows were dried off 46 d before expected calving and assigned to 1 of 2 treatments: HT (n = 16) or cooling (CL, n = 16). During the dry period, the average temperature humidity index was 78, but CL cows were cooled with sprinklers and fans, whereas HT cows were not. After calving, all cows were housed and managed under the same conditions. Rectal temperatures were measured twice daily (0730 and 1430 h) and respiration rate recorded 3 times weekly during the dry period. Dry matter intake was recorded daily from dry-off to 42 d relative to calving (DRC). Body weight and body condition score were measured weekly from dry-off to 42 DRC. Milk yield and composition were recorded daily to 42 wk postpartum. Glucose tolerance tests (GTT) and insulin challenges (IC) were performed at dry-off, -14, 7, and 28 DRC in a subset of cows (HT, n = 8; CL, n = 8). Relative to HT, CL cows had lower rectal temperatures (39.3 vs. 39.0 degrees C) in the afternoon and respiration rate (69 vs. 48 breath/min). Cows from the cooling treatment tended to consume more feed than HT cows prepartum and postpartum. Compared with HT, CL cows gained more weight before calving but lost more weight and body condition in early lactation. Cows from the cooling treatment produced more milk than HT cows (34.0 vs. 27.7 kg/d), but treatments did not affect milk composition. Treatments did not affect circulating insulin and metabolites prepartum, but CL cows had decreased glucose, increased nonesterified fatty acid, and tended to have lower insulin concentrations in plasma postpartum compared with HT cows. Cooling prepartum HT cows did not affect the insulin responses to GTT and IC during the transition period and glucose responses to GTT and IC at -14 and 28 DRC were not affected by treatments. At 7 DRC, CL cows tended to have slower glucose clearance to GTT and weaker glucose response to IC relative to HT cows. Cows from the cooling treatment had stronger nonesterified fatty acid responses to IC postpartum but not prepartum compared with HT. In conclusion, cooling heat stressed dairy cows in the dry period reduced insulin effects on peripheral tissues in early lactation but not in the dry period. PMID- 22916908 TI - Bioavailability of the flavonol quercetin in cows after intraruminal application of quercetin aglycone and rutin. AB - The bioavailability of quercetin has been intensively investigated in monogastric species, but knowledge about its bioavailability in ruminants does not exist. Thus, the aim of the present study was to determine the bioavailability of quercetin in nonlactating cows equipped with indwelling catheters placed in one jugular vein after intraruminal and additionally after i.v. application, respectively. Quercetin was administered intraruminally in equimolar amounts, either in the aglycone form or as its glucorhamnoside rutin, each at 2 dosages [10 and 50 mg of quercetin/kg of body weight (BW)]. In a second trial, 0.8 mg of quercetin aglycone/kg of BW was applied i.v. Blood samples were drawn 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, and 24 h after intraruminal application and every 5 min (first hour), every 10 min(second hour), and at 3 and 6h after i.v. bolus application, respectively. Quercetin and quercetin metabolites with an intact flavonol structure (isorhamnetin, tamarixetin, and kaempferol) in plasma samples were analyzed by HPLC with fluorescence detection. After intraruminal application of quercetin and rutin, respectively, quercetin and its methylated (isorhamnetin, tamarixetin) and dehydroxylated (kaempferol) derivatives were present in plasma mainly as conjugated forms, whereas free quercetin and its derivatives were scarcely detected. For rutin, the relative bioavailability of total flavonols (sum of conjugated and nonconjugated quercetin and its conjugated and nonconjugated derivatives after intake of 50 mg/kg of BW) was 767.3% compared with quercetin aglycone (100%). Absolute bioavailability of total flavonols was only 0.1 and 0.5% after quercetin aglycone and rutin applications, respectively. Our data demonstrate that bioavailability of quercetin from rutin is substantially higher compared with that from quercetin aglycone in cows after intraruminal (or oral) application, unlike in monogastric species. PMID- 22916909 TI - Epidemiology of subclinical ketosis in early lactation dairy cattle. AB - The purpose of this study was to describe the epidemiology of subclinical ketosis (SCK) in dairy cows in early lactation and determine the association of (1) days in milk (DIM) at onset of SCK, and (2) blood beta-hydroxybutyrate (BHBA) concentration at onset of SCK with development of displaced abomasum (DA) and removal from herd in the first 30 DIM, conception to first service, days to conception within 150 DIM, and early lactation milk yield. Cows from 4 freestall dairy herds (2 in New York and 2 in Wisconsin) were each tested 6 times for SCK from 3 to 16 DIM using the Precision Xtra meter (Abbott Laboratories, Abbott Park, IL). Subclinical ketosis was defined as a BHBA concentration of 1.2 to 2.9 mmol/L. Mixed-effects multivariable Poisson regression was used to assess DA, removal from herd, and conception to first service. Semiparametric proportional hazards models were used to evaluate days to conception, and repeated-measures ANOVA was used to evaluate milk yield in the first 30 DIM. A total of 741 of 1,717 (43.2%) eligible cows had a least one BHBA test of 1.2 to 2.9 mmol/L. Peak incidence of SCK occurred at 5 DIM, when 22.3% of cows had their first SCK positive test. Peak prevalence of SCK occurred at 5 DIM, when 28.9% of cows had a SCK-positive test. Median time from first positive SCK test until BHBA test <1.2 mmol/L was 5d. Cows first testing SCK positive from 3 to 5 DIM were 6.1 times more likely [95% confidence interval (CI) = 2.3 to 16.0] to develop a DA than cows first testing SCK positive at 6 DIM or later. Cows first testing SCK positive from 3 to 7 DIM were 4.5 times more likely (95% CI = 1.7 to 11.7) to be removed from the herd, were 0.7 times as likely (95% CI = 0.6 to 0.8) to conceive to first service, and produced 2.2 kg less milk per day for the first 30 DIM than cows first testing positive at 8 DIM or later. Each 0.1 mmol/L increase in BHBA at first SCK-positive test increased the risk of developing a DA by a factor of 1.1 (95% CI = 1.0 to 1.2), increased the risk of removal from herd by a factor of 1.4 (95% CI = 1.1 to 1.8), and was associated with a decrease in milk production by 0.5 kg/d for the first 30 DIM. These results show that time of onset and BHBA concentration of first SCK-positive test are important indicators of individual cow performance. PMID- 22916910 TI - Effect of enterotoxigenic Escherichia coli vaccine on innate immune function of bovine mammary gland infused with lipopolysaccharide. AB - The effects of using an enterotoxigenic Escherichia coli vaccine on innate immune responses following intramammary infusion of lipopolysaccharide (LPS) were investigated in midlactation Holstein-Friesian cows. Seven out of 14 cows were inoculated with E. coli vaccine. Three weeks later, 100 MUg of LPS dissolved in 10 mL of saline was infused into 1 quarter of all cows. Milk was collected every hour from infusion to 12 h after infusion, and twice daily (at 0900 and 1600 h) for 4 d. Blood samples were collected 0, 4, 8, 24, 48, 72, and 96 h after infusion. Rectal temperatures and milk yields were measured. The somatic cell count (SCC), lingual antimicrobial peptide concentration, lactoperoxidase (LPO) activity, and lactoferrin (LF) concentration in milk, and haptoglobin concentration in serum were determined. The mean rectal temperature in vaccinated cows was higher than in control cows at 10 h. The mean milk yield was decreased significantly in the infused quarter of control cows at 24 h compared with pretreatment, but not in vaccinated cows. The mean SCC in milk from vaccinated cows at 12 and 55 h was significantly lower than that of control cows. The lingual antimicrobial peptide and LF concentrations were significantly lower at 8 h and 55 h, respectively, in vaccinated cows than in control cows. The mean antibody titer in the serum against the vaccine at the time of LPS infusion into vaccinated cows was significantly higher than in control cows. These antibody titers were positively correlated with the peak concentrations of LPO and LF in milk following challenge; therefore, cows with a high antibody titer were accompanied by high LPO activity and LF concentration in milk. These results suggest that vaccination suppresses the innate immune reaction after intramammary LPS infusion; however, the elevated antibody titer was unlikely to be responsible for the modification of the innate immune reaction. PMID- 22916911 TI - Differences between coagulase-negative Staphylococcus species in persistence and in effect on somatic cell count and milk yield in dairy goats. AB - Coagulase-negative staphylococci (CNS) are the most commonly isolated bacteria from goat milk. The goal of this study was to explore and describe differences between CNS species in persistence of intramammary infection (IMI) and in effect on somatic cell count (SCC) and milk yield (MY). Milk samples were collected from 530 does from 5 Dutch dairy goat herds on 3 occasions during 1 lactation. Coagulase-negative staphylococci species were identified at the species level by transfer RNA-intergenic spacer PCR (tDNA-PCR) followed by capillary electrophoresis. The most prevalent CNS species were Staphylococcus caprae, Staphylococcus epidermidis, Staphylococcus simulans, and Staphylococcus xylosus, but large differences were seen in species distribution between herds. Staphylococcus caprae and Staph. xylosus appeared to be more persistent than other species, but confidence intervals were overlapping. The effect of IMI caused by the 4 most prevalent CNS species on SCC and on MY was determined with linear regression models, and Staph. aureus and Corynebacterium bovis were included in the analyses as reference organisms. Most species were associated with a significantly higher SCC than noninfected udder halves, but the effect of CNS species on SCC was much smaller than the effect of Staph. aureus on SCC. We found a significant positive association between infection with Staph. caprae and MY. Intramammary infection caused by Staph. xylosus, on the other hand, had a negative association with milk yield, comparable to the effect of Staph. aureus, but these effects were not significantly different from zero. Intramammary infections with CNS species have a high prevalence in goats and are persistent, but have a limited effect on SCC compared with IMI with Staph. aureus. The effect of CNS species on MY differed between species, but differences were nonsignificant because limited numbers per species were available for analysis. Therefore, CNS species appear to behave as minor pathogens in goats, but larger studies are needed to give better estimates for the effect on MY. PMID- 22916912 TI - Short communication: characterization of early postpartum estrous behavior and ovulation in lactating dairy cows using radiotelemetry. AB - The objective of this study was to describe early postpartum estrous behavior and ovulation in lactating dairy cows using radiotelemetry. Cows (n=50) were continuously monitored for behavioral estrus with a radiotelemetric system, HeatWatch II (CowChips LLC, Manalapan, NJ), from d 14 to approximately d 49 postpartum. Blood collection for analysis of progesterone and ovarian ultrasonography were performed once weekly starting on d 14. First ovulation was associated with behavioral estrus in 5 cows and occurred at 28.2+/-10.8 d (mean+/ SD; range 17 to 40 d). The average duration of estrus was 6.0+/-4.9 h (range 3 to 12.2 h), and the mean number of standing events was 18.4+/-8.9 (range 4 to 26). Based on progesterone concentrations of >=1 ng/mL, estimated first postpartum ovulation occurred at 25.1+/-10.4 d (range 10 to 49 d) for 38 animals without evidence of behavioral estrus. The interval to estimated first ovulation without behavioral estrus was not different from the interval to first ovulation associated with behavioral estrus. Level of milk production and body condition score loss did not affect the interval to estimated first ovulation without estrus or first ovulation associated with estrus. Six animals did not show evidence of ovulation based on progesterone concentration, whereas 1 cow showed evidence of estrous behavior on the day before removal from the study. The majority of first postpartum ovulations (38/43; 88.4%) were not associated with behavioral estrus. PMID- 22916913 TI - Short communication: expression of peptide YY, proglucagon, neuropeptide Y receptor Y2, and glucagon-like peptide-1 receptor in bovine peripheral tissues. AB - The role of distal gut signals in control of feed intake and metabolism in cattle has received scant attention. Peptide YY (PYY) and glucagon-like peptide-1, which are secreted from enteroendocrine cells of the distal gut in monogastrics have several functions, including regulation of energy balance. However, little is known of the tissue expression of these peptides and their receptors in cattle. The aim of the current study was to characterize the tissue distribution of PYY, neuropeptide Y receptor Y2 (Y2), proglucagon (GCG), and glucagon-like peptide-1 receptor (GLP1R) in various peripheral tissues of cattle. Four male 7-wk-old dairy calves were euthanized and 16 peripheral tissues were collected. Conventional PCR and quantitative real-time PCR were performed to confirm tissue expression and quantify the transcript abundance in various tissues. The results of conventional PCR revealed that mRNA for both PYY and Y2 was detectable in the rumen, abomasum, duodenum, jejunum, ileum, and colon but not in other tissues. Quantitative real-time PCR data demonstrated that PYY mRNA was 2- to 3-fold greater in the pancreas, kidney, and heart relative to the liver. By conventional PCR, GCG mRNA was detected in the abomasum, duodenum, jejunum, ileum, and colon and GLP1R mRNA was expressed in all gut segments, pancreas, spleen, and kidney. Quantitative real-time PCR data demonstrated that, relative to transcript abundance in the liver, GCG mRNA was 4- to 40-fold higher from abomasum to colon, and GLP1R mRNA was 50- to 300-fold higher from the rumen to colon, 14-fold greater in the pancreas, 18-fold higher in the spleen, and 166-fold greater in the kidney. The tissue distribution of PYY, GCG, and their receptors observed in the current study is, in general, consistent with expression patterns in monogastrics. The predominant expression of PYY, Y2, and GCG in the gut, and the presence of GLP1R in multiple peripheral tissues suggest a role for PYY in controlling gut functions and for GLP-1 in regulating multiple physiological functions in cattle. PMID- 22916914 TI - Short communication: glucose and fructose concentrations and expression of glucose transporters in 4- to 6-week pregnancies collected from Holstein cows that were either lactating or not lactating. AB - Glucose is an essential nutrient for the conceptus. The objective was to determine if lactation affected the amount of glucose crossing the placenta by measuring glucose and fructose in placental fluids in lactating and nonlactating cows. Holstein cows were assigned to one of 2 treatments immediately after parturition [lactating (n=23) or nonlactating (dried off immediately after calving; n=20)]. Pregnant cows were slaughtered at one of 3 d of pregnancy (d 28, 35, or 42) and tissues were collected. Plasma glucose and insulin were less in lactating cows. Pregnancies collected from lactating cows had less glucose and fructose in placental fluids compared with those from nonlactating cows. Relative to endometrium, the placenta expressed greater amounts of the glucose transporters SLC2A1 (Glut1), SLC2A3 (Glut3) and SLC2A4 (Glut4) mRNA. The mRNA for SLC2A1 decreased whereas the mRNA for SLC2A4 increased from d 28 to d 42 of pregnancy. Stepwise regression analyses for fetal and placental weight (dependent variable) retained day of pregnancy and maternal plasma insulin concentrations in the final model. The conclusion is that lower blood glucose and insulin in lactating cows may lead to less glucose crossing the placenta and slower fetal development during lactation. The slower fetal development may predispose lactating cows to fetal loss if developmental milestones are not reached. PMID- 22916915 TI - Short communication: presynchronization for timed artificial insemination in grazing dairy cows by using progesterone for 14 days with or without prostaglandin F2alpha at the time of progesterone withdrawal. AB - Progesterone-containing devices can be inserted intravaginally for 14 d to presynchronize the estrous cycle for timed artificial insemination (TAI) in beef heifers ("14-day CIDR-PG" or "Show-Me-Synch" program). The progesterone treatment is effective for presynchronization because cattle develop a persistent dominant follicle during treatment that ovulates within 3 d after progesterone removal. The subsequent estrous cycle can be effectively used for a TAI program. Some cattle will retain a functional corpus luteum (CL) for the entire 14-d treatment period and will not be synchronized effectively because the interval to ovulation depends on the lifespan of their existing CL. The objective was to test the effect of a luteolytic dose of PGF(2alpha) at progesterone removal for improving synchrony of estrus after treatment and increasing conception rate to a subsequent TAI in dairy cows. Postpartum cows (n = 1,021) from 2 grazing dairy herds were assigned to 1 of 2 presynchronization programs that used a controlled internal drug releasing (CIDR) device containing progesterone: 14dCIDR (CIDR in, 14 d, CIDR out; n = 523) or 14dCIDR+PGF(2alpha) (CIDR in, 14 d, CIDR out, and PGF(2alpha); n = 498). Cows were body condition scored (BCS; 1 to 5, thin to fat) and tail painted at CIDR removal. Paint score (PS) was recorded after CIDR removal [PS = 0 (all paint removed, indication of estrus), PS = 3 (paint partially removed), or PS = 5 (no paint removed; indication of no estrus)]. At 19 d after CIDR removal, all cows were treated with PGF(2alpha), 56 h later treated with GnRH, and then 16 h later were TAI. Treating cows with PGF(2alpha) at CIDR removal increased the percentage with PS = 0 within 5 d (58.1% vs. 68.9%; 14dCIDR vs. 14dCIDR+PGF(2alpha)). We found no effect of treatment, however, on conception rate at TAI (41.1% vs. 43.6%; respectively). The TAI conception rate increased with increasing BCS and was greater for cows that had PS = 0 within 5 d after CIDR removal. In summary, treating cows with PGF(2alpha) at CIDR removal increased the percentage of cows with all tail paint removed but did not increase percentage of pregnant cows after TAI. PMID- 22916916 TI - Hot topic: apparent total-tract nutrient digestibilities measured commercially using 120-hour in vitro indigestible neutral detergent fiber as a marker are related to commercial dairy cattle performance. AB - Measuring individual feed nutrient concentration is common practice for field dairy nutritionists. However, accurately measuring nutrient digestibility and using digestion values in total digestible nutrients models is more challenging. Our objective was to determine if in vivo apparent total-tract nutrient digestibility measured with a practical approach was related to commercial milk production parameters. Total mixed ration and fecal samples were collected from high-producing cows in pens on 39 commercial dairies and analyzed at a commercial feed and forage testing laboratory for nutrient concentration and 120-h indigestible NDF (iNDF) content using the Combs-Goeser in vitro digestion technique. The 120-h iNDF was used as an internal marker to calculate in vivo apparent nutrient digestibilities. Two samples were taken from each dairy and were separated in time by at least 3 wk. Samples were targeted to be taken within 7d of Dairy Herd Improvement (DHI) herd testing. Approved DHI testers measured individual cow milk weights as well as fat and protein concentrations. Individual cow records were averaged by pen corresponding to the total mixed ration and fecal samples. Formulated diet and dry matter intake (DMI) records for each respective pen were also collected. Mixed model regression analysis with dairy specified as a random effect was used to relate explanatory variables (diet nutrient concentrations, formulated DMI, in vivo apparent nutrient digestibilities, and fecal nutrient concentrations) to milk production measures. Dry matter intake, organic matter (OM) digestibility, fecal crude protein (CP) concentration, and fecal ether extract concentration were related to milk, energy corrected milk, and fat yields. Milk protein concentration was related to CP digestibility, and milk protein yield was related to DMI, OM digestibility, CP digestibility, and ether extract digestibility. Although many studies have related DMI and OM digestibility to milk production under controlled experimental settings, very few have related practical in vivo measures to milk production. By documenting the practical OM digestibility relationship with milk production, nutritionists and scientists may have confidence in this approach for measuring diet performance and collecting nutritional data for commercial dairies. PMID- 22916917 TI - The effects of hybrid, maturity, and length of storage on the composition and nutritive value of corn silage. AB - The objective of this study was to evaluate the effect of hybrid, maturity at harvest [dry matter (DM) content], and length of storage on the composition and nutritive value of corn silage. The plants used in this study included a normal (NORM) and a brown midrib (BMR) hybrid, harvested at 32 or 41% DM and ensiled for various lengths of time (0 to 360 d) without inoculation. Measurements included nutrient analysis, fermentation end products, in vitro digestion of NDF (NDF-D, 30 h), and in vitro digestion of starch (7h). The concentration of acetic acid increased with length of storage for all treatments, specifically increasing as much as 140% between d 45 to 360 for 32% DM BMR silage. Small changes in lactic acid and ethanol were noted but varied by DM and hybrid. When averaged across maturities and length of storage, compared with NORM, BMR silage was lower in concentrations of lignin, crude protein, neutral detergent fiber, and acid detergent fiber, but higher in starch. On average, NDF-D of both hybrids was not affected by length of storage between 45 and 270 d. The NDF-D was markedly greater for BMR than NORM after all times of storage. Increasing maturity at harvest generally did not affect the NDF-D of NORM, with the exception that it was slightly lower for the more mature plants at 270 and 360 d. In contrast, the NDF-D of BMR was lower in more mature silage by approximately 5 percentage units from 45 to 360 d. The concentration of starch for 32% DM NORM was lower (21%) than other treatments (31+/-3%; mean+/-SD) at harvest. This finding was probably the cause for starch digestibility to be highest in 32% DM NORM samples atd 0 (about 80%) and lower (65 to 68%) for other treatments. Concentrations of soluble N and ammonia-N increased with length of storage, indicating that proteolytic mechanisms were active beyond 2 to 3 mo of storage. The in vitro digestion of starch generally increased with length of storage, probably as a result of proteolysis. Although active fermentation occurs for only a relatively short time in the silo, many metabolic processes remain active during long-term storage. Changes in the nutritive value of corn silage during storage should be accounted for during ration formulations. PMID- 22916918 TI - Effects of different sources and levels of dietary gossypol on gossypol residues in plasma and milk of lactating cows. AB - Free gossypol residues in tissues or milk from feeding whole cottonseed and cottonseed meal were measured for their effect on health of dairy cows and humans. Forty lactating cows were randomly assigned to 5 treatments in a 60-d experiment to investigate the effects of sources and dietary level of gossypol on plasma and milk gossypol concentrations in lactating cows. Five experimental diets had identical net energy for lactation and crude protein content on a dry matter (DM) basis. Soybean meal was the main protein ingredient used in the control diet. Cottonseed meal (CSM) or whole cottonseed (WCS) substituted for part of the soybean meal in the other 4 diets. Gossypol levels in the 5 diets were 0 (control), 91.15 mg/kg of DM in CSM1, 117.31mg/kg of DM in CSM2, 385.43 mg/kg of DM in WCS1, and 611.13 mg/kg in WCS2. Yields of 3.5% fat-corrected milk were significantly higher for cows in the WCS2 group; cows in the CSM1 and WCS1 groups showed no differences but both were numerically higher than the control and CSM2 groups. Milk protein concentration was lower for cows consuming WCS1 compared with the control group. Lactose concentration was lower for cows in the CSM2 group compared with the WCS2 group, but no differences were observed among other diets. Aspartate aminotransferase in serum was significantly higher for the WCS2 group compared with the control and WCS1 groups, but no difference was observed with the CSM1 and CSM2 groups. Concentrations of gossypol in plasma and milk of cows in the WCS1 and WCS2 groups were both higher than those of the other groups. No adverse effects were observed on cows fed diets containing 12.0% CSM, and no gossypol was found in plasma and milk. When WCS comprised 15% of the diet DM, yields of 3.5% fat-corrected milk were increased in cows and gossypol was detected in plasma and milk but not at harmful levels. PMID- 22916919 TI - Nutrient demand interacts with grass maturity to affect milk fat concentration and digestion responses in dairy cows. AB - Effects of grass maturity on dry matter intake (DMI), milk production, ruminal fermentation and pool sizes, digestion and passage kinetics, and chewing activity and the relationship of these effects with preliminary DMI (pDMI) were evaluated using 13 ruminally and duodenally cannulated Holstein cows in a crossover design with a 14-d preliminary period and two 18-d treatment periods. During the preliminary period, pDMI of individual cows ranged from 23.5 to 28.2 kg/d (mean=26.1 kg/d) and 3.5% fat-corrected milk (FCM) yield ranged from 30.8 to 57.2 kg/d (mean=43.7 kg/d). Experimental treatments were diets containing orchardgrass silage harvested either (1) early-cut, less mature (EC) or (2) late-cut, more mature (LC) as the sole forage. Early- and late-cut orchardgrass contained 44.9 and 54.4% neutral detergent fiber (NDF) and 20.1 and 15.3% crude protein, respectively. Forage:concentrate ratio was 58:42 and 46:54 for EC and LC, respectively; both diets contained approximately 25% forage NDF and 30% total NDF. Preliminary DMI, an index of nutrient demand, was determined during the last 4d of the preliminary period when cows were fed a common diet and used as a covariate. Main effects of grass maturity and their interaction with pDMI were tested by ANOVA. The EC diet decreased milk yield and increased milk fat concentration compared with the LC diet. Grass maturity and its interaction with pDMI did not affect FCM yield, DMI, rumen pH, or microbial efficiency. The EC diet increased rates of ruminal digestion of potentially digestible NDF and passage of indigestible NDF (iNDF) compared with the LC diet. The lower concentration and faster passage rate of iNDF for EC resulted in lower rumen pools of iNDF, total NDF, organic matter, and dry matter for EC than LC. Ruminal passage rates of potentially digestible NDF and starch were related to level of intake (quadratic and linear interactions, respectively) and subsequently affected ruminal digestibility of these nutrients. The EC diet decreased eating, ruminating, and total chewing time per unit of forage NDF intake compared with the LC diet. When grass silage was the only source of forage in the diet, cows supplemented with additional concentrate to account for decreasing protein and increasing fiber concentrations associated with more mature grass had similar feed intake and produced similar FCM yields as cows fed less mature grass. PMID- 22916920 TI - Effects of the early social environment on behavioral responses of dairy calves to novel events. AB - Providing young animals the opportunity to engage in more complex social interactions is hypothesized to improve their capacity to cope with changing environments. To test the effects of the early social environment on the behavioral responses of dairy calves to novelty we compared (1) individual with pair housing and (2) group housing with companions of similar age with group housing with a more experienced conspecific. Fifty-four dairy calves were separated from the cow soon after birth and housed individually (n=6 calves) or in pairs (n=6 pairs), or in pens composed of groups of 3 young calves (n=6 groups) or groups of 2 young calves and an older calf (n=6 groups). At 65 to 69 d of age, calf responses were tested in an environmental novelty test and a social novelty test. Individually housed calves were more active [i.e., spent less time standing (means +/- SEM): 201.4 vs. 280.3+/-30.5 s/test; and more time running: 83.2 vs. 57.3+/-19.1 s/test] and more reactive (i.e., defecated more frequently; 1.3 vs. 0.6+/-0.2 events/test) when tested in the novel arena, compared with pair housed calves. During the social novelty test, individually housed calves spent less time running (51.8 vs. 96.4+/-11.6 s/test), showed a longer latency to socially interact (111.1 vs. 20.4+/-21.7 s/test), and spent more time involved in social interactions (130.7 vs. 79.7+/-19.0 s/test) with the unfamiliar calf than did pair-housed calves. Individually housed calves were also more reactive to the presence of an unfamiliar calf as indicated by increased rates of defecation (2.3 vs. 0.7+/-0.5 events/test) and kicking (2.2 vs. 0.7+/-0.4 events/test) compared with pair-housed calves. Calves housed in groups with an older companion were more reactive to the novel environment than were calves housed in groups of similar age: they defecated (1.0 vs. 0.6+/-0.2 events/test) and vocalized (23.6 vs. 15.3+/-3.8 events/test) more during the test. These calves also spent less time exploring (266.3 vs. 355.0+/-27.4 events/test) and had a lower frequency of kicking (0.1 vs. 2.0+/-0.5 events/test) when tested with an unfamiliar calf. We conclude that calves housed individually are more reactive to environmental and social novelty when compared with calves housed in pairs and that calves housed with an older companion are less reactive to a novel calf when compared with calves housed in groups of similar age. PMID- 22916921 TI - Review of the relationship between milk urea nitrogen and days in milk, parity, and monthly temperature mean in Iranian Holstein cows. AB - The objectives of this study were to determine the relationships between milk urea N and days in milk, parity, and season in Iranian Holstein cows. Twelve Iranian commercial dairy herds participated in a 13-mo study from December 1, 2008, to December 31, 2009. All cows were milked 3 times daily, housed in freestalls, and fed a total mixed ration twice a day. Mean milk urea N over the study period was 16.0mg/dL. Mean milk urea N, categorized by 30-d increments of days in milk, paralleled changes in milk values and followed a curvilinear shape. However, milk urea N concentration reached a maximum at the fifth month of days in milk, but milk production reached a maximum at the third month. The concentration of milk urea N was lower during the first 30 d in milk category compared with all other days in milk categories. Overall mean milk urea N concentration of Holstein cows in the third and greater lactations was lower than in the first or second lactation. Milk urea N was at its lowest level in December (13 mg/dL), increased in the spring and summer months, and reached a maximum in July (18.8 mg/dL). From that point, milk urea N concentration progressively diminished to the autumn-winter level. In this study, milk urea N concentration was positively correlated with monthly temperature mean and may be a reason for the lower reproductive performance during the summer months. It has been recommended that milk urea N concentration should be evaluated in association with parity, days in milk, and season (or month). These variables should be considered potential sources of misinterpretation when exploring the relationship between milk urea N and nutritional management or measures of performance. PMID- 22916922 TI - Life-cycle assessment of greenhouse gas emissions from dairy production in Eastern Canada: a case study. AB - The objective of this study was to conduct a life-cycle assessment (LCA) of greenhouse gas (GHG) emissions from a typical nongrazing dairy production system in Eastern Canada. Additionally, as dairying generates both milk and meat, this study assessed several methods of allocating emissions between these coproducts. An LCA was carried out for a simulated farm based on a typical nongrazing dairy production system in Quebec. The LCA was conducted over 6 yr, the typical lifespan of dairy cows in this province. The assessment considered 65 female Holstein calves, of which 60 heifers survived to first calving at 27 mo of age. These animals were subsequently retained for an average of 2.75 lactations. Progeny were also included in the analysis, with bulls and heifers in excess of replacement requirements finished as grain-fed veal (270 kg) at 6.5 mo of age. All cattle were housed indoors and fed forages and grains produced on the same farm. Pre-farm gate GHG emissions and removals were quantified using Holos, a whole-farm software model developed by Agriculture and Agri-Food Canada and based on the Intergovernmental Panel for Climate Change Tier 2 and 3methodologies with modifications for Canadian conditions. The LCA yielded a GHG intensity of 0.92 kg of CO(2) Eq/kg of fat- and protein-corrected milk yield. Methane (CH(4)) accounted for 56% of total emissions, with 86% originating from enteric fermentation. Nitrous oxide accounted for 40% of total GHG emissions. Lactating cows contributed 64% of total GHG emissions, whereas calves under 12 mo contributed 10% and veal calves only 3%. Allocation of GHG emissions between meat and milk were assessed as (1) 100% allocation to milk, (2) economics, (3) dairy versus veal animals, and (4) International Dairy Federation equation using feed energy demand for meat and milk production. Comparing emissions from dairy versus veal calves resulted in 97% of the emissions allocated to milk. The lowest allocation of emissions to milk (78%) was associated with the International Dairy Federation equation. This LCA showed that greatest reductions in GHG emissions would be achieved by applying mitigation strategies to reduce enteric CH(4) from the lactating cow, with minimal reductions being achievable in young stock. Choice of coproduct allocation method can also significantly affect the relative allocation of GHG emissions to milk and meat. PMID- 22916923 TI - Glycerol inhibition of ruminal lipolysis in vitro. AB - Supplemental glycerol inhibits rumen lipolysis, a prerequisite for rumen biohydrogenation, which is responsible for the saturation of dietary fatty acids consumed by ruminant animals. Feeding excess glycerol, however, adversely affects dry matter digestibility. To more clearly define the effect of supplemental glycerol on rumen lipolysis, mixed populations of ruminal bacteria were incubated with 6 or 20% glycerol (vol/vol). After 48-h anaerobic incubation of mixed culture rumen fluid, rates of free fatty acid production (nmol/mL per h) for the 6 and 20% glycerol-supplemented samples were decreased by 80 and 86%, respectively, compared with rates from nonsupplemented control cultures (12.4+/ 1.0; mean +/- SE). Conversely, assay of the prominent ruminal lipase-producing bacteria Anaerovibrio lipolyticus 5S, Butyrivibrio fibrisolvens 49, and Propionibacterium species avidum and acnes revealed no effect of 2 or 10% (vol/vol) added glycerol on lipolytic activity by these organisms. Supplementing glycerol at 6% on a vol/vol basis, equivalent to supplementing glycerol at approximately 8 to 15% of diet dry matter, effectively reduced lipolysis. However, the mechanism of glycerol inhibition of ruminal lipolysis remains to be demonstrated. PMID- 22916924 TI - Effect of conventional and intensified milk replacer feeding programs on performance, vaccination response, and neutrophil mRNA levels of Holstein calves. AB - This study compared conventional and intensified milk replacer feeding regimens on growth, intake, respiratory and fecal scores, vaccination response, and neutrophil mRNA levels. Holstein calves were randomly assigned to a 10-wk study on d 2 of life. Treatments were conventional (CON; n=8) and intensified (INT; n=7) milk replacer feeding programs. Conventional calves were fed a 20.8% crude protein and 21.0% fat milk replacer at 1.25% of birth body weight (BW) from wk 1 to 6 of life and 0.625% of birth BW during wk 7. A 29.3% crude protein and 16.2% fat milk replacer was fed to INT calves at 1.5% of birth BW during wk 1, 2% of current BW from wk 2 to 6, and 1% of current BW during wk 7. All calves were given milk replacer twice daily during wk 1 to 6, once daily during wk 7, and were weaned completely during wk 8. Calf starter intake was measured daily through wk 8. Body weight and withers height were measured weekly. Fecal and respiratory scores were recorded twice daily at feeding. Calves were vaccinated against ovalbumin at the end of wk 1, 3, and 5. Blood samples were collected at the end of wk 1, 3, 5, and 8 for analysis of serum anti-ovalbumin IgG concentration and for isolation of neutrophils. Quantitative PCR was used to measure neutrophil mRNA levels of 7 functionality genes. Treatment did not affect total DMI or anti-ovalbumin IgG response. Intensified milk replacer feeding increased average daily gain, protein intake, fat intake, and feed efficiency compared with the CON feeding program. Compared with CON calves, INT calves had greater fecal scores, indicating looser feces and greater respiratory scores, indicating more respiratory problems. Calves assigned to the INT treatment had increased neutrophil mRNA levels of L-selectin, and at wk 8, neutrophil cytosolic factor 1 was increased and toll-like receptor 4 tended to be increased compared with CON calves. This suggests greater activation of neutrophils in INT calves postweaning, but differences were relatively small and levels of the other 4 genes were unaffected. An INT milk replacer feeding program increased growth, fecal scores, and respiratory scores preweaning, increased mRNA levels of 2 neutrophil genes postweaning, and did not affect vaccination response. PMID- 22916925 TI - Milk fat responses to dietary supplementation of short- and medium-chain fatty acids in lactating dairy cows. AB - Short-and medium-chain fatty acids (SMCFA), which are synthesized de novo in the mammary gland, are reduced to a much greater extent than the long-chain fatty acids during diet-induced milk fat depression. Our hypothesis was that SMCFA are limiting for milk fat synthesis even under conditions when milk fat is not depressed. Our objective was to test the potential limitation of SMCFA on milk fat synthesis via dietary supplementation. Sixteen lactating Holstein cows (107+/ 18 d in milk) were fed a corn silage-based total mixed ration. Cows were randomly assigned to groups of 4 per pen and supplemented with 1 of 4 dietary fat supplements (600 g/d) supplied in a 4*4 Latin square design with 21-d experimental periods. Treatments consisted of fat supplements containing mixtures of calcium salts of long-chain fatty acids (Megalac; Church & Dwight Co. Inc., Princeton, NJ) and an SMCFA mixture (S; 3.3% C8, 7.6% C10, 9.85% C12, 32.12% C14, and 47.11% C16) that contained 0, 200, 400, and 600 g/d of S substituted for Megalac (S0, S200, S400, and S600, respectively). No treatment effects were observed for dry matter and fat-corrected milk. However, milk yield was decreased with S600. Milk fat increased linearly by 0.17, 0.25, and 0.33 percentage units for the respective S treatments. However, fat yield peaked at S200 and milk protein concentration and yield was significantly decreased at the higher S levels because of a linear trend toward decreased milk yield in the S600 treatment. In conclusion, SMCFA supplementation linearly increased milk fat concentration but decreased milk production at the higher levels of supplementation. The dietary inclusion of SMCFA had no effects on total milk fat yield. PMID- 22916926 TI - The effects of fermented soybean meal on immunophysiological and stress-related parameters in Holstein calves after weaning. AB - The present experiment was conducted to investigate the effects of partial substitution of soybean meal (SBM) with fermented SBM (FSBM) on immunophysiological and stress-related parameters in Holstein calves after weaning. Eighteen Holstein calves were randomly assigned to receive either SBM or FSBM (5% of SBM was replaced with FSBM) calf starter and calves were weaned at 42 d of age. It was noted that FSBM contained a lower content of trypsin inhibitor but higher crude protein, amino acids, and small-sized peptides than those of SBM. The group fed FSBM calf starter significantly increased body weight gain and intakes of both feed and milk, when compared with those fed SBM calf starter at 4 wk of age. Calves fed the FSBM calf starter had significantly lower fecal scores than those fed the SBM calf starter during both pre- and postweaning periods. Calves also had better health scores when fed the FSBM calf starter than those fed SBM during the preweaning period. Weaning challenge significantly increased proinflammatory cytokines, tumor necrosis factor alpha, IL-1beta, and IL-6 levels at 1d postweaning (DPW). The TNF-alpha and IL-6 levels of the SBM group were significantly higher compared with those of the FSBM group at 3 DPW. Acute phase proteins (serum amyloid A and haptoglobin) in the serum were increased after weaning. Concentrations of serum amyloid A and haptoglobin in calves fed FSBM calf starter were significantly lower than those fed the SBM calf starter at 3 and 5 DPW, respectively. The concentration of cortisol was significantly lower in the FSBM group than that of the SBM group at 3 DPW. Weaning stress did not cause drastic changes in the total serum immunoglobulin levels and composition of peripheral lymphocytes. Our results indicate that FSBM may not only improve growth performance, feed intake, and health conditions during the preweaning period, but also alleviate stress responses, which was indicated by reduced induction of stress hormone, proinflammatory cytokines, and acute phase proteins in Holstein calves after weaning. PMID- 22916927 TI - Effects of wet corn gluten feed on ruminal pH and productivity of lactating dairy cattle fed diets with sufficient physically effective fiber. AB - Wet corn gluten feed (WCGF), a byproduct of the wet-milling industry, is commonly substituted in lactating dairy rations for both forages and concentrates. Previous research has shown that increasing WCGF in the diet decreased ruminal pH, likely due in part to decreasing particle size as forage inclusion rate decreased. The objective of this study was to maintain at least 10% of ration particles >19 mm in length across diets while increasing WCGF inclusion in the diet. We hypothesized that as WCGF increased in this scenario, dry matter intake (DMI) and milk yield would increase and ruminal pH would be maintained. Seven ruminally cannulated, lactating Holstein cows (4 multiparous and 3 primiparous) were used in an incomplete 4*4 Latin square design. Treatments included 0, 12.4, 24.5, or 35.1% WCGF and used alfalfa hay to maintain particle size. Across treatments, crude protein and neutral detergent fiber concentrations were held relatively constant. Four 21-d periods were used with 17d of adaptation and 4d of sample collection. Indwelling ruminal pH probes were used during sampling periods and recorded pH every 5 min. Particle size of total mixed rations and orts were analyzed using a Penn State Particle Separator (The Pennsylvania State University, University Park). Results were analyzed with mixed models to test the fixed effect of treatment. All diets contained >=10% of particles >19 mm; however, as WCGF increased, the proportion of particles >19 mm decreased. Interestingly, with increasing WCGF, cows sorted for the particles >19 mm but against particles on the bottom screen and pan. With increasing WCGF, ruminal pH was not affected, but DMI and milk yield increased in a quadratic fashion, with the peak responses for the 24.5% WCGF diet. Milk protein, lactose, and fat concentrations were not affected by treatment; however, milk protein and lactose yields increased with the inclusion of WCGF because of the increased milk yield. Production efficiency was not affected by treatments. Thus, if adequate particle size is maintained when WCGF increases in the diet, DMI and milk yield increase while maintaining production efficiency and ruminal pH. PMID- 22916928 TI - Rapeseed or linseed supplements in grass-based diets: effects on milk fatty acid composition of Holstein cows over two consecutive lactations. AB - Persistency of changes in milk fatty acid (FA) composition to 4 different oilseed supplements rich in cis-9 18:1 or 18:3n-3 was determined over 2 consecutive lactations in 58 and 35 Holstein cows during the first and second years, respectively. During the initial 5 wk of the study, all experimental cows were fed the same diet. Thereafter, cows received 1 of 5 treatments for 2 consecutive lactations, including the prepartum period. Treatments comprised the basal diet with no additional lipid, or supplements of extruded linseeds (EL), extruded rapeseeds (ER), cold-pressed fat-rich rapeseed meal (FRM), or whole unprocessed rapeseeds (WR). Oilseeds were offered to provide between 2.5 to 3.0% of additional oil in diet dry matter. During indoor periods, cows received a mixture (3:1, wt/wt) of grass silage and grass hay, whereas cows were at pasture during outdoor periods. Over the entire study, oilseed supplements decreased the concentration of milk FA synthesized de novo and increased 18:0 and cis-9 18:1 content, with a ranking of treatment responses (highest to lowest) of FRM, EL, ER, and WR. Irrespective of period, both EL and FRM increased total milk trans FA content, whereas WR resulted in lower concentrations in milk from grazing cows. Relative to rapeseed, EL resulted in higher increases in milk cis-12,cis-15,trans 12 to -16 18:1, nonconjugated trans 18:2 (especially ?11,15), and 18:3n-3. In contrast, rapeseed supplements resulted in a greater enrichment of cis-11 18:1, trans-4 to -9 18:1, and cis 20:1 than EL. Changes in milk FA composition to oilseeds were of greater magnitude during indoor than outdoor periods, where oilseed supplements often decreased cis-9,trans-11 conjugated linoleic acid content. During the second indoor period, both EL and ER resulted in higher total trans FA content, trans-10 18:1 in particular, than during the first indoor period, consistent with an interaction between dietary starch content and oilseed supplement. Overall, the extent of changes in milk FA composition were related to the nature (rapeseed or linseed) and form of oilseed (extruded, cold-pressed fat rich meal or whole unprocessed), and their interactions with the composition of the basal diet (grass silage and hay or pasture; or dietary starch content). Milk FA responses were stable within each period and repeatable over both outdoor feeding periods, with extent of changes being comparable to reports from relatively short-term (1- to 3-mo) studies. PMID- 22916929 TI - Inhibition of ?9-desaturase activity with sterculic acid: effect on the endogenous synthesis of cis-9 18:1 and cis-9, trans-11 18:2 in dairy sheep. AB - This study was conducted in lactating ewes to examine the involvement of ?(9) desaturase in mammary lipogenesis, especially in the endogenous synthesis of cis 9, trans-11 18:2 and cis-9 18:1, because no information on this matter was available for dairy sheep. With this aim, 6 Assaf ewes were monitored in a 15-d experiment, which included a 5-d pretreatment period, a 5-d treatment period, and a 5-d posttreatment period. During the treatment period, ewes received 0.5 g/d of sterculic acid (a cyclopropene fatty acid that inhibits ?(9)-desaturase), delivered intravenously in 4 equal doses at 6-h intervals. Animals were fed pasture to supply mainly alpha-linolenic acid and minimize the amount of milk cis 9, trans-11 18:2 of ruminal origin. Sterculic acid administration was calculated to inhibit ?(9)-desaturase by 70% based on the milk content of cis-9 14:1. This inhibition resulted in decreases in the milk content of the enzyme products (e.g., cis-9 10:1, cis-9 14:1, cis-9 16:1, cis-9 18:1, and cis-9, trans-11 18:2) and increases in its substrates (e.g., 14:0, 18:0, and trans-11 18:1), as well as in reductions in the desaturase indexes. Some other milk fatty acids, further to previously reported products or substrates of ?(9)-desaturase (e.g., cis-15 18:1 and cis-9, cis-15 18:2, or trans-11, trans-15 18:2, and cis-9, trans-11, trans-15 18:3), were also affected by sterculic acid administration. Endogenous synthesis was the major source of cis-9 18:1 and cis-9, trans-11 18:2, accounting for 63 and 74% of its content in milk fat, respectively. To our knowledge, the present study provides the first estimates of endogenous synthesis of these 2 bioactive fatty acids in ovine milk fat. PMID- 22916930 TI - Effects of metabolizable protein supply and amino acid supplementation on nitrogen utilization, milk production, and ammonia emissions from manure in dairy cows. AB - Two experiments were conducted with the objective of investigating the effects of rumen-protected methionine (RPMet) supplementation of metabolizable protein (MP) deficient or MP-adequate but Met-deficient diets on dairy cow performance. Experiment (Exp.) 1 utilized 36 Holstein dairy cows blocked in 12 blocks of 3 cows each. Cows within block were assigned to one of the following dietary treatments: (1) MP-adequate diet [AMP; positive MP balance according to the National Research Council (2001) dairy model]; (2) an MP-deficient diet supplemented with 100g of rumen-protected Lys (RPLys)/cow per day (DMPL); and (3) DMPL supplemented with 24 g of RPMet/cow per day (DMPLM). Experiment 2 utilized 120 Holstein cows assigned to 6 pens of 20 cows each. Pens (3 per treatment) were assigned to one of the following dietary treatments: (1) AMP diet supplemented with 76 g of RPLys/cow per day (AMPL); and (2) AMPL (74 g of RPLys/cow per day) supplemented with 24 g of RPMet/cow per day (AMPLM). Each experiment lasted for 10 wk (2-wk adaptation and 8-wk experimental periods) following a 2-wk covariate period (i.e., a total of 12 wk). In Exp. 1, the MP-deficient diets decreased apparent total-tract nutrient digestibility but had no statistical effect on dry matter intake (DMI), milk yield, or milk fat percentage and yield. Compared with AMP, DMPL decreased milk protein content; both DMPL and DMPLM diets decreased milk protein yield. Urinary N losses and milk urea-N concentration were decreased by the MP-deficient diets compared with AMP. The ammonia emitting potential of manure from the MP-deficient diets was decreased by about 37% compared with that of AMP manure. Plasma Lys and Met concentrations were not affected by treatment, but concentrations of His, Thr, and Val were lower for the MP-deficient diets compared with AMP. In Exp. 2, the AMPLM diet had lower milk yield than AMPL due to numerically lower DMI; no other effects were observed in Exp. 2. In conclusion, feeding MP-deficient diets supplemented with RPLys and RPMet did not statistically decrease milk yield in dairy cows in Exp. 1. However, without RPMet supplementation, milk protein content was decreased compared with the MP-adequate diet. Other amino acids, possibly His, may limit milk production in MP-deficient, corn or corn silage-based diets. A summary of 97 individual cow data from trials in which MP-deficient diets were fed suggested the National Research Council (2001) model under-predicts milk yield in cows fed MP-deficient diets (MP balance of -20 to -666 g/d) in a linear manner: milk yield under-prediction [National Research Council (2001) MP-allowable milk yield, kg/d - actual milk yield, kg/d] = 0.0991 (+/-0.0905) + 0.0230 (+/-0.0003) * MP balance, g/d (R(2)=0.99). PMID- 22916931 TI - Use of algae or algal oil rich in n-3 fatty acids as a feed supplement for dairy cattle. AB - Fish oil is used as a ration additive to provide n-3 fatty acids to dairy cows. Fish do not synthesize n-3 fatty acids; they must consume microscopic algae or other algae-consuming fish. New technology allows for the production of algal biomass for use as a ration supplement for dairy cattle. Lipid encapsulation of the algal biomass protects n-3 fatty acids from biohydrogenation in the rumen and allows them to be available for absorption and utilization in the small intestine. Our objective was to examine the use of algal products as a source for n-3 fatty acids in milk. Four mid-lactation Holsteins were assigned to a 4*4 Latin square design. Their rations were supplemented with 1* or 0.5* rumen protected (RP) algal biomass supplement, 1* RP algal oil supplement, or no supplement for 7 d. Supplements were lipid encapsulated (Balchem Corp., New Hampton, NY). The 1* supplements provided 29 g/d of docosahexaenoic acid (DHA), and 0.5* provided half of this amount. Treatments were analyzed by orthogonal contrasts. Supplementing dairy rations with rumen-protected algal products did not affect feed intake, milk yield, or milk component yield. Short- and medium chain fatty acid yields in milk were not influenced by supplements. Both 0.5* and 1* RP algae supplements increased daily milk fat yield of DHA (0.5 and 0.6+/-0.10 g/d, respectively) compared with 1* RP oil (0.3+/-0.10 g/d), but all supplements resulted in milk fat yields greater than that of the control (0.1+/-0.10g/d). Yield of trans-18:1 fatty acids in milk fat was also increased by supplementation. Trans-11 18:1 yield (13, 20, 27, and 15+/-3.0 g/d for control, 0.5* RP algae, 1* RP algae, and 1* RP oil, respectively) was greater for supplements than for control. Concentration of DHA in the plasma lipid fraction on d 7 showed that the DHA concentration was greatest in plasma phospholipid. Rumen-protected algal biomass provided better DHA yield than algal oil. Feeding lipid-encapsulated algae supplements may increase n-3 content in milk fat without adversely affecting milk fat yield; however, preferential esterification of DHA into plasma phospholipid may limit its incorporation into milk fat. PMID- 22916932 TI - Transfer rate of alpha-linolenic acid from abomasally infused flaxseed oil into milk fat and the effects on milk fatty acid composition in dairy cows. AB - The objectives of the present study were to evaluate the transfer efficiency of alpha-linolenic acid (ALA) from the abomasum into milk fat, its interaction with milk fat content and yield, and the relationship between ALA and C16:0 in milk fat. Three rumen-fistulated multiparous Holstein cows at midlactation were used in a 3*3 Latin square design. Treatments consisted of abomasal infusion of (1) 110 mL of water/d (control), (2) 110 mL of flaxseed oil/d (low flaxseed oil, LFO), and (3) 220 mL of flaxseed oil/d (high flaxseed oil, HFO). Experimental periods were continued for 2 wk and fat supplements were infused abomasally during the last 7 d of each period. Average dry matter intake and milk yield were not affected by oil infusion. Milk fat and lactose content tended to be greater with flaxseed infusion compared with the control. Plasma ALA was 2.9- and 4.0 fold greater with LFO and HFO, respectively. The apparent transfer efficiency of ALA to milk was 44.8 and 45.7% with LFO and HFO, respectively. The C16:0 content in milk fat was decreased by 3.59 and 5.25 percentage units, whereas the ALA content was increased by 1.68 and 3.09 percentage units with LFO and HFO, respectively. Similarly, C18:2n-6 was increased by 0.95 and 1.31 percentage units with LFA and HFO, respectively, without changes in other fatty acids (FA). Total polyunsaturated FA was 4.4 and 2.7% lower in the HFO and LFO, respectively, than in the control. Furthermore, C16:0 content in the milk fat was reduced to a greater extent than the increase in ALA content, as a 1.68 and 3.09 percentage unit increase occurred in ALA compared with a 3.6 and 5.25 percentage unit decrease in C16:0 for LFO and HFO, respectively, such that a negative correlation existed between ALA and C16:0 (r=-0.72). In conclusion, abomasal infusion of flaxseed oil dramatically increased the ALA content in plasma and milk fat. Because the replacement of C16:0 with ALA and C18:2n-6 occurred without changes in other FA presumed to be synthesized de novo in the mammary gland, this suggests that the preformed C16:0 was replaced, rather than being caused, by an overall suppression of de novo FA synthesis in the mammary gland. PMID- 22916933 TI - Effect of treatment with a mixture of bacteria and fibrolytic enzymes on the quality and safety of corn silage infested with different levels of rust. AB - This project aimed to determine if a dual-purpose bacterial inoculant could mitigate potential adverse effects of increasing levels of rust infestation on the quality, aerobic stability, and safety of corn silage. Corn plants with no rust infestation (NR), or medium (all leaves on the lower half of the plant affected, MR), or high (all leaves affected, HR) levels of southern rust infestation were harvested at random locations on a field, chopped, and ensiled without (control, CON) or with a dual-purpose inoculant applied at a rate that supplied 1*10(5) cfu/g of Pediococcus pentosaceus 12455 and 4*10(5) cfu/g of Lactobacillus buchneri 40788. Each treatment was prepared in quadruplicate in 20 L mini silos and ensiled for 97 d. As the level of rust infestation increased, the concentrations of dry matter (DM) and neutral detergent fiber increased, whereas DM digestibility decreased by up to 16%. Control HR silages also had lower 24-h neutral detergent fiber digestibility (NDFD; 36.2% of DM) than CON MR (39.8%) or NR silages (38.1%). Inoculation increased the NDFD of NR (43.4%) and MR silages (45.7%) but not HR silages (33.0%). Concentrations of lactate and volatile fatty acids decreased with increasing rust infestation in CON silages, but this trend was absent in inoculated silages. In HR silages, inoculation increased aerobic stability by 75% (77.3 vs. 44 h), and prevented production of aflatoxin (5.2 vs. 0 mg/kg). The concentration of aflatoxin in uninoculated HR silages exceeded action levels stipulated by the US Food and Drug Administration. In conclusion, increasing rust infestation was associated with reductions in the nutritive value and fermentation of corn silage. Inoculation reduced adverse effects of rust infestation on the fermentation, increased 24-h NDFD of NR and MR silages, and decreased aerobic spoilage and aflatoxin production in HR silages. PMID- 22916934 TI - Adjusting the weaning age of calves fed by automated feeders according to individual intakes of solid feed. AB - When weaned at the ages typical of commercial dairy production, dairy calves usually show reduced growth rates, lowered energy intake, and increased behavioral signs of hunger, reflecting their difficulty in switching from a milk diet to solid feed. However, large differences exist between calves in their ability to adapt to solid feed, and automated feeders allow the age of weaning to be adjusted to an individual calf's intake of solid feed. We examined the effects of weaning according to solid feed intake on age at weaning, feed intake, and behavioral signs of hunger. In a 2*2 factorial design, 60 female Holstein calves in groups of 8 and fed milk, grain starter, and hay from automated feeders began to be weaned when their voluntary intake of grain starter was either 400 g/d (high start) or 200 g/d (low start), with weaning completed when their voluntary intakes of starter were either 1,600 g/d (high end) or 800 g/d (low end). Digestible energy intakes were calculated from milk, starter and hay intakes, corrected for body weights, calves were weighed, and the frequency of visits to the milk feeders were measured each day. The main effects and interactions between treatments were tested with ANOVA. Large differences were observed between calves in the age at which weaning was complete, with weaning completed earlier for low-end calves compared with high-end calves. No treatment effects (either of start amount or end amount) on intakes of milk, starter, or hay or on weight gains occurred. However, the calves that began weaning earlier had longer durations of weaning, greater growth rates from d 20 to 87, and were heavier on d 87, and had lower milk intakes, higher starter intakes, higher hay intakes, and a greater digestible energy intake, but showed more unrewarded visits to the milk feeder. Adjusting the age at which individual calves are weaned off milk according to their ability to eat solid feed can reduce the age at which weaning occurs while reducing the negative effects of weaning on energy intake and weight gain, although the increased visits to the milk feeder during weaning suggest that calves remain motivated to drink milk. PMID- 22916935 TI - A meta-analysis of variability in continuous-culture ruminal fermentation and digestibility data. AB - A meta-analysis was conducted to compare ruminal fermentation and digestibility data and variability between continuous-culture (CC) experiments and in vivo data. One hundred eighty CC studies representing 1,074 individual treatments, published in refereed journals between 1980 and 2010 were used in this analysis. Studies were classified into 2 groups based on the type of CC used: CC systems specified as rumen simulation techniques (RUSITEC) and non-RUSITEC CC systems (non-RUSITEC). The latter was a diverse group of systems, all of which were termed CC by the investigators. The CC data were compared with a data set of in vivo trials with ruminally cannulated lactating dairy cows (data from a total of 366 individual cows). The reported neutral detergent fiber (NDF) concentration of the diets fed in the 3 data sets was, on average (dry matter basis), 44, 34, and 32%, respectively. The average total volatile fatty acid (VFA) concentration for the RUSITEC and non-RUSITEC data sets was 67 and 80% (respectively) of the total VFA concentration in vivo. The average concentration of acetate was also lower for the CC data sets compared with in vivo and that of propionate was considerably lower for RUSITEC compared with in vivo, but butyrate concentrations were similar between the CC and in vivo data sets. Variability in the VFA data was generally the highest (higher coefficients of variation and variance) for the non-RUSITEC data set, followed by RUSITEC, and was the lowest for in vivo. Digestibilities of NDF and particularly organic matter were lower in the CC data sets compared with in vivo; the average NDF digestibility was 34.2, 45.5, and 53.0% for RUSITEC, non-RUSITEC, and in vivo, respectively. Variability in nutrient digestibility data followed the pattern of variability of the VFA data: highest variability for the non-RUSITEC data set, followed by RUSITEC, and the lowest for in vivo. This analysis showed that CC systems are generally characterized by lower total VFA and acetate concentrations, extremely low counts or lack of ruminal protozoa, and lower organic matter and NDF digestibilities than in vivo. Overall, variability was much greater for CC than for in vivo experimental data. PMID- 22916936 TI - Mitigation of methane production from cattle by feeding cashew nut shell liquid. AB - The effects of cashew nut shell liquid (CNSL) feeding on methane production and rumen fermentation were investigated by repeatedly using 3 Holstein nonlactating cows with rumen fistulas. The cows were fed a concentrate and hay diet (6:4 ratio) for 4 wk (control period) followed by the same diet with a CNSL-containing pellet for the next 3 wk (CNSL period). Two trials were conducted using CNSL pellets blended with only silica (trial 1) or with several other ingredients (trial 2). Each pellet type was fed to cows to allow CNSL intake at 4 g/100 kg of body weight per day. Methane production was measured in a respiration chamber system, and energy balance, nutrient digestibility, and rumen microbial changes were monitored. Methane production per unit of dry matter intake decreased by 38.3 and 19.3% in CNSL feeding trials 1 and 2, respectively. Energy loss as methane emission decreased from 9.7 to 6.1% (trial 1) and from 8.4 to 7.0% (trial 2) with CNSL feeding, whereas the loss to feces (trial 1) and heat production (trial 2) increased. Retained energy did not differ between the control and CNSL periods. Digestibility of dry matter and gross energy decreased with CNSL feeding in trial 1, but did not differ in trial 2. Feeding CNSL caused a decrease in acetate and total short-chain fatty acid levels and an increase in propionate proportion in both trials. Relative copy number of methyl coenzyme-M reductase subunit A gene and its expression decreased with CNSL feeding. The relative abundance of fibrolytic or formate-producing species such as Ruminococcus flavefaciens, Butyrivibrio fibrisolvens, and Treponema bryantii decreased, but species related to propionate production, including Prevotella ruminicolla, Selenomonas ruminantium, Anaerovibrio lipolytica, and Succinivibrio dextrinosolvens, increased. If used in a suitable formulation, CNSL acts as a potent methane-inhibiting and propionate-enhancing agent through the alteration of rumen microbiota without adversely affecting feed digestibility. PMID- 22916937 TI - Meta-analysis of the effect of pregrazing pasture mass on pasture intake, milk production, and grazing behavior of dairy cows strip-grazing temperate grasslands. AB - Grazing management is a key factor in pasture-based dairy systems, which can be improved given advanced knowledge of the effects of pregrazing pasture mass (PM) on the performance of dairy cows. The aim of this study was to quantify the effects of PM on the pasture intake, milk production, milk composition, and grazing behavior of strip- or rotational-grazing dairy cows, based on a meta analysis of published research papers. A database was created that included experiments in which the effects of PM on pasture intake and milk production of dairy cows were studied. Papers were selected only if at least 2 PM were compared under similar experimental conditions, particularly the same pasture allowance (SPA). The final database included 15 papers with 27 PM comparisons. For analytical purposes, the database was subdivided into 3 subsets that varied according to the estimation height at which pasture allowance was determined; that is, where PM were compared at the SPA above ground level (SPA(0) subset), above 2 to 3 cm (SPA(3) subset), and above 4 to 5 cm (SPA(5) subset). Statistical analyses were conducted on the entire database (global analysis) and within each subset using linear model procedures. An interaction between PM and estimation height was found for pasture intake and milk production in the global analysis. On the basis of the predictive equations, pasture intake increased by 1.58 kg of dry matter/d per tonne increase in PM when PM were compared at SPA(0), was not affected by PM when PM were compared at SPA(3), and decreased by 0.65 kg of dry matter/d per tonne increase in PM when PM were compared at SPA(5). This is consistent with the effect of PM on milk production, which was positive and negative (1.04 and -0.79 kg/t of PM, respectively) when PM were compared at SPA(0) and SPA(5), respectively. Grazing time was only slightly affected by PM, irrespective of estimation height, because the effect of PM on pasture intake was mainly dependent on the variation in pasture intake rate. Pasture intake rate increased with increasing PM at SPA(0) but decreased with increasing PM at SPA(5). This meta-analysis clearly demonstrates that the effects of PM on pasture intake, milk production, and behavior of strip-grazing dairy cows depend largely on the height at which the PM and pasture allowance are measured. These results have methodological implications for future grazing research because it can be recommended that PM be compared at similar levels of pasture availability (i.e., at the same pasture allowance above 2 to 3 cm) to avoid possible misinterpretations of results. They also reveal the benefits of improving grazing management and intake prediction through modeling in pasture-based dairy systems. PMID- 22916938 TI - Short communication: addition of sodium bicarbonate to maternal colostrum: effects on immunoglobulin G absorption and hematocrit in neonatal calves. AB - Twenty-six Holstein bull calves born from primiparous and multiparous cows without dystocia were assigned in a randomized complete block design to 1 of 2 treatments: pooled maternal colostrum (PMC) or PMC supplemented with 30 g of sodium bicarbonate (NaHCO(3)). Calves were fed PMC from 9 different batches containing (mean +/- SD) 82.05+/-8.45 g/L of IgG. Calves were fed 2.68 L of PMC at birth (referred to as 0 h) and 1.32 L of PMC 6h later. The total amount of IgG fed was 329.89+/-34.56 g. Calves were fed 2L of milk replacer at 24, 36, and 48 h postpartum. The addition of NaHCO(3) had no effect on IgG absorption. Serum IgG concentrations at 0, 6, 12, 24, and 48 h postpartum were not different between calves supplemented with or without 30 g of NaHCO(3) to colostrum. Area under the curve, apparent efficiency of absorption, and hematocrit were not affected by the NaHCO(3) treatment. PMID- 22916939 TI - Short communication: effect of difructose anhydride III on serum immunoglobulin G concentration in newborn calves. AB - Difructose anhydride (DFA) III is an indigestible disaccharide that promotes paracellular absorption of calcium, magnesium, and other minerals in the intestine by acting on epithelial tight junctions. This study aimed to elucidate the effect of DFA III on serum IgG concentration. One hundred and twenty Holstein and Holstein/Japanese Black crossbred calves were randomly divided into 4 groups of 30 to receive untreated colostrum (DFA0) or colostrum containing 3, 6, or 18 g of DFA III (DFA3, DFA6, or DFA18, respectively). At 24 h after birth, both serum IgG (ranging from 16.4 to 21.2 mg/mL) and apparent efficiency of absorption (26.0 to 37.2%) showed increases with the amount of DFA III intake. By multiple regression analysis, the standardized partial regression coefficient for DFA III was 0.25, the second highest following that for the colostrum IgG concentration (0.80), indicating a positive effect of DFA III on serum IgG. A positive linear regression was found between colostrum IgG and serum IgG concentrations at 24h of age. These results indicate that IgG absorption occurred as a nonsaturable process, which might be characteristic of gradient-dependent paracellular transport. Thus, it was concluded that DFA III improves not only minerals but IgG absorption in calves. PMID- 22916940 TI - Short communication: characterization of Shiga toxin-producing Escherichia coli isolated from newborn, milk-fed, and growing calves in Argentina. AB - Shiga toxin-producing Escherichia coli (STEC) cause foodborne pathogenic disease that is shed in the feces of cattle. The aim of this study was to evaluate how early young calves are colonized by STEC strains, potentially pathogenic for humans, and the prevalence in different calf categories. From 808 rectal swabs analyzed by PCR, 38% were stx positive. The prevalence in newborn (<24 h from birth), milk-fed (<2-mo-old), and growing calves (2-8 mo old) were 25, 43, and 58%, respectively. Forty different STEC serotypes were found among isolates from newborn, milk-fed, and growing calves that shed STEC strains potentially pathogenic for humans. The STEC strains could be acquired early from mothers, enabling the infection of other animal categories and confirming the risk to public health. PMID- 22916941 TI - Comparative evaluation of a new lactation curve model for pasture-based Holstein Friesian dairy cows. AB - Fourteen lactation models were fitted to average and individual cow lactation data from pasture-based dairy systems in the Australian states of Victoria and Tasmania. The models included a new "log-quadratic" model, and a major objective was to evaluate and compare the performance of this model with the other models. Nine empirical and 5 mechanistic models were first fitted to average test-day milk yield of Holstein-Friesian dairy cows using the nonlinear procedure in SAS. Two additional semiparametric models were fitted using a linear model in ASReml. To investigate the influence of days to first test-day and the number of test days, 5 of the best-fitting models were then fitted to individual cow lactation data. Model goodness of fit was evaluated using criteria such as the residual mean square, the distribution of residuals, the correlation between actual and predicted values, and the Wald-Wolfowitz runs test. Goodness of fit was similar in all but one of the models in terms of fitting average lactation but they differed in their ability to predict individual lactations. In particular, the widely used incomplete gamma model most displayed this failing. The new log quadratic model was robust in fitting average and individual lactations, and was less affected by sampled data and more parsimonious in having only 3 parameters, each of which lends itself to biological interpretation. PMID- 22916942 TI - Genome-wide association mapping of milk production traits in Braunvieh cattle. AB - A whole-genome association study of milk production traits: milk yield, protein yield, fat yield, protein percentage, and fat percentage, was performed on the population of Braunvieh cattle. Five hundred and fifty-four progeny-tested bulls and 36,219 autosomal single nucleotide polymorphism (SNP) markers on 29 Bos taurus autosomes (BTA) were included in the analysis. A principal component analysis was conducted to adjust for the effect of population stratification in the analyzed data set. For the principal component analysis, genome-wide relationships between individuals were calculated. Three different criteria (Horn's test, Kaiser's criterion, and Jolliffe's criterion) were tested to determine the number of significant principal components. Estimation of putative associations between SNP and milk production traits was carried out using a linear regression model in R software (R Foundation for Statistical Computing, Vienna, Austria). Significant principal components, adjusting for population stratification separately for each criterion and family relationships and genotypes at individual SNP were included as fixed effects in the model. The inflation factor lambda and quantile-quantile plots were calculated to compare how the different criteria deal with stratification in our mapping population. Based on the analyses on all of the aforementioned criteria, we can conclude that Jolliffe's criterion deals the best with population stratification. Furthermore, significance thresholds for a given genome-wide false discovery rate of 5% were estimated and used for specific traits. Three of the analyzed traits showed genome-wide significant association with SNP. Two SNP had an effect on milk yield on BTA4, 2 SNP affected fat yield on BTA14 and BTA23, and 1 SNP was associated with fat percent on BTA1. Single nucleotide polymorphisms identified in this study as associated with milk production traits will further contribute to the mapping of corresponding quantitative trait loci and investigation of the genes responsible for polymorphisms in milk production traits in dairy cattle. Described comparison of different criteria for determination of significant principal components can provide important information for similar studies in stratified populations. PMID- 22916943 TI - Estimation of genetic parameters for test-day records of dairy traits in a seasonal calving system. AB - Variance components for test-day milk yield were estimated for primiparous animals in a seasonal calving system where 80% of calvings occur within a 5-mo period in the spring. The objective was to investigate if the variance components of milk production were affected by seasonality via month in milk and test month (TM). These effects were, therefore, fitted for both the permanent environment effect and additive genetic effect. Estimates of heritability (0.14-0.27) were found to be lowest during early and late lactation for all calving months. The peak in heritability (0.22-0.27) occurred later in lactation for animals that calved toward the end of the spring calving season. Genetic variance of test day milk yield for all calving months was found to be highest at the beginning of the lactation (2.23-3.36 kg(2)), with a plateau toward the middle of the lactation. Genetic variance was found to be highest (2.98-3.36 kg(2)) for animals calving early in the season. Genetic correlations between corresponding stages of lactation were strongest (0.99-1.00) between consecutive calving months. Genetic correlations were slightly weaker when intervals between calving months increased; however, they remained above 0.96 in all cases. Akaike's information criterion values from models both inclusive and exclusive of TM, suggest that the model exclusive of TM is the preferred model. Estimated breeding values of lactation milk yield from bulls with 20 or more daughters, predicted for a full 305-d lactation, were used to compare the model with the standard test-day model (i.e., exclusive of TM), based on DIM. Correlations were higher than 0.995 for milk yield (and higher than 0.930 for persistency) between models inclusive and exclusive of TM, suggesting that given the straightforward approach taken in the current study, an apparent benefit for including seasonality in the evaluation of test-day milk yield was not found; however, there may be benefits of including it in the estimation of persistency. PMID- 22916944 TI - Multibreed genomic evaluations using purebred Holsteins, Jerseys, and Brown Swiss. AB - Multibreed models are currently used in traditional US Department of Agriculture (USDA) dairy cattle genetic evaluations of yield and health traits, but within breed models are used in genomic evaluations. Multibreed genomic models were developed and tested using the 19,686 genotyped bulls and cows included in the official August 2009 USDA genomic evaluation. The data were divided into training and validation sets. The training data set comprised bulls that were daughter proven and cows that had records as of November 2004, totaling 5,331 Holstein, 1,361 Jersey, and 506 Brown Swiss. The validation data set had 2,508 Holstein, 413 Jersey, and 185 Brown Swiss bulls that were unproven (no daughter information) in November 2004 and proven by August 2009. A common set of 43,385 single nucleotide polymorphisms (SNP) was used for all breeds. Three methods of multibreed evaluation were investigated. Method 1 estimated SNP effects separately within breed and then applied those breed-specific SNP estimates to the other breeds. Method 2 estimated a common set of SNP effects from combined genotypes and phenotypes of all breeds. Method 3 solved for correlated SNP effects within each breed estimated jointly using a multitrait model where breeds were treated as different traits. Across-breed genomic predicted transmitting ability (GPTA) and within-breed GPTA were compared using regressions to predict the deregressed validation data. Method 1 worked poorly, and coefficients of determination (R(2)) were much lower using training data from a different breed to estimate SNP effects. Correlations between direct genomic values computed using training data from different breeds were less than 30% and sometimes negative. Across-breed GPTA from method 2 had higher R(2) values than parent average alone but typically produced lower R(2) values than the within-breed GPTA. The across-breed R(2) exceeded the within-breed R(2) for a few traits in the Brown Swiss breed, probably because information from the other breeds compensated for the small numbers of Brown Swiss training animals. Correlations between within-breed GPTA and across-breed GPTA ranged from 0.91 to 0.93. The multibreed GPTA from method 3 were significantly better than the current within breed GPTA, and adjusted R(2) for protein yield (the only trait tested for method 3) were highest of all methods for all breeds. However, method 3 increased the adjusted R(2) by only 0.01 for Holsteins, <=0.01 for Jerseys, and 0.01 for Brown Swiss compared with within-breed predictions. PMID- 22916945 TI - Costs for health care of Holstein cows selected for large versus small body size. AB - The objective of the study was to compare Holstein cows selected for large versus small body size for health care cost. All health treatments were recorded for cows from 1983 to 2005, and treatments were assigned to 1 of 11 categories of health disorders. Actual cost for veterinary treatments, health supplies, and drugs, as well as the value of labor required by animal attendants, was recorded. Data were for 1,035 lactations of 486 cows, of which 199 cows were from the large line and 287 cows were from the small line. Large-line cows had significantly greater total health cost than small-line cows during first lactation and tended to have greater total health cost for the first 3 lactations of cows. During first lactation, large-line cows had a total health cost of $62.41, and small line cows had a total health cost of $41.41. Cows in the large line had significantly greater health cost for the individual categories of displaced abomasum and pneumonia than small-line cows during first lactation. Across the first 3 lactations, large-line cows had a total health cost per lactation of $54.15 and small-line cows had a total cost of $38.09. Cows in the large line had significantly greater health cost for the categories of locomotion and displaced abomasum across the first 3 lactations than small-line cows. Cost for displaced abomasum accounted for most the difference of health cost between the body size lines for both first lactation and for the first 3 lactations of cows. PMID- 22916946 TI - Genetic parameters for energy balance, feed efficiency, and related traits in Holstein cattle. AB - Objectives of the current study were to estimate genetic parameters in Holstein cows for energy balance (EB) and related traits including dry matter intake (DMI), body weight (BW), body condition score (BCS), energy-corrected milk (ECM) production, and gross feed efficiency (GFE), defined as the ratio of total ECM yield to total DMI over the first 150 d of lactation. Data were recorded for the first half of lactation on 227 and 175 cows in their first or later lactation, respectively. Random regression models were fitted to longitudinal data. Also, each trait was averaged over monthly intervals and analyzed by single and multivariate animal models. Heritability estimates ranged from 0.27 to 0.63, 0.12 to 0.62, 0.12 to 0.49, 0.63 to 0.72, and 0.49 to 0.53 for DMI, ECM yield, EB, BW, and BCS, respectively, averaged over monthly intervals. Daily heritability estimates ranged from 0.18 to 0.30, 0.10 to 0.26, 0.07 to 0.22, 0.43 to 0.67, and 0.25 to 0.38 for DMI, ECM yield, EB, BW, and BCS, respectively. Estimated heritability for GFE was 0.32. The genetic correlation of EB at 10d in milk (DIM) with EB at 150 DIM was -0.19, suggesting the genetic regulation of this trait differs by stage of lactation. Positive genetic correlations were found among DMI, ECM yield, and BW averaged over monthly intervals, whereas correlations of these traits with BCS depended upon stage of lactation. Total ECM yield for the lactation was positively correlated with DMI, but a negative genetic correlation between total ECM yield and EB was found. However, the genetic correlation between total ECM yield and EB in the first month of lactation was -0.02, indicating that total production is not genetically correlated with EB during the first month of lactation, when negative EB is most closely associated with diminished fitness. The genetic correlation between GFE and EB ranged from -0.73 to -0.99, indicating that selection for more efficient cows would favor a lower energy status. However, the genetic correlation between EB in the first month of lactation and GFE calculated from 75 to 150 DIM was not significant, indicating that the unfavorable correlation between GFE and EB in early lactation may be minimized with alternative definitions of efficiency. Thus, EB, GFE and related traits will likely respond to genetic selection in Holstein cows. However, the impact of selection for improved feed efficiency on EB must be carefully considered to avoid potential negative consequences of further reductions in EB at the onset of lactation. PMID- 22916947 TI - Reliability of genomic prediction for German Holsteins using imputed genotypes from low-density chips. AB - With the availability of single nucleotide polymorphism (SNP) marker chips, such as the Illumina BovineSNP50 BeadChip (50K), genomic evaluation has been routinely implemented in dairy cattle breeding. However, for an average dairy producer, total costs associated with the 50K chip are still too high to have all the cows genotyped and genomically evaluated. To study the accuracy of cheaper low-density chips, genotypes were simulated for 2 low-density chips, the Illumina Bovine3K BeadChip (3K) and BovineLD BeadChip (6K), according to their original marker maps. Simulated missing genotypes of the 50K chip were imputed using the programs Beagle and Findhap. Three genotype data sets were used to study imputation accuracy: the EuroGenomics data set, with 14,405 reference bulls (data set I); the smaller EuroGenomics data set, with 11,670 older reference bulls (data set II); and the data set of all genotyped German Holsteins, with 31,597 reference animals (data set III). Imputed genotypes were compared with their original ones to calculate allele error rate for validation animals in the 3 data sets. To evaluate the loss in accuracy of genomic prediction when using imputed genotypes, a genomic evaluation was conducted only for EuroGenomics data set II. Furthermore, combined genome-enhanced breeding values calculated from the original and imputed genotypes were compared. Allele error rate for EuroGenomics data set II was highest for the Findhap program on the 3K chip (3.3%) and lowest for the Beagle program on the 6K chip (0.6%). Across the data sets, Beagle was shown to be about 2 times as accurate as Findhap. Compared with the real 50K genotypes, the reduction in reliability of the genomic prediction when using the imputed genotypes was highest for Findhap on the 3K chip (5.3%) and lowest for Beagle on the 6K chip (1%) when averaged over the 12 evaluated traits. Differences in genome-enhanced breeding values of the original and imputed genotypes were largest for Findhap on the 3K chip, whereas Beagle on the 6K chip had the smallest difference. The low-density chip, 6K, gave markedly higher imputation accuracy and more accurate genomic prediction than the 3K chip. On the basis of the relatively small reduction in accuracy of genomic prediction, we would recommend the BovineLD 6K chip for large-scale genotyping as long as its costs are acceptable to breeders. PMID- 22916948 TI - The impact of genotyping different groups of animals on accuracy when moving from traditional to genomic selection. AB - Compared with traditional selection, the use of genomic information tends to increase the accuracy of estimated breeding values (EBV). The cause of this increase is, however, unknown. To explore this phenomenon, this study investigated whether the increase in accuracy when moving from traditional (AA) to genomic selection (GG) was mainly due to genotyping the reference population (GA) or the evaluated animals (AG). In it, a combined relationship matrix for simultaneous use of genotyped and ungenotyped animals was applied. A simulated data set reflected the dairy cattle population. Four differently designed (i.e., different average relationships within the reference population) small reference populations and 3 heritability levels were considered. The animals in the reference populations had high, moderate, low, and random (RND) relationships. The evaluated animals were juveniles. The small reference populations simulated difficult or expensive to measure traits (i.e., methane emission). The accuracy of selection was expressed as the reliability of (genomic) EBV and was predicted based on selection index theory using relationships. Connectedness between the reference populations and evaluated animals was calculated using the prediction error variance. Average (genomic) EBV reliabilities increased with heritability and with a decrease in the average relationship within the reference population. Reliabilities in AA and AG were lower than those in GG and were higher than those in GA (respectively, 0.039, 0.042, 0.052, and 0.048 for RND and a heritability of 0.01). Differences between AA and GA were small. Average connectedness with all animals in the reference population for all scenarios and reference populations ranged from 0.003 to 0.024; it was lowest when the animals were not genotyped (AA; e.g., 0.004 for RND) and highest when all the animals were genotyped (GG; e.g., 0.024 for RND). Differences present across designs of the reference populations were very small. Genomic relationships among animals in the reference population might be less important than those for the evaluated animals with no phenotypic observations. Thus, the main origin of the gain in accuracy when using genomic selection is due to genotyping the evaluated animals. However, genotyping only one group of animals will always yield less accurate estimates. PMID- 22916949 TI - Incidence validation and relationship analysis of producer-recorded health event data from on-farm computer systems in the United States. AB - The principal objective of this study was to analyze the plausibility of health data recorded through on-farm recording systems throughout the United States. Substantial progress has been made in the genetic improvement of production traits while health and fitness traits of dairy cattle have declined. Health traits are generally expensive and difficult to measure, but health event data collected from on-farm computer management systems may provide an effective and low-cost source of health information. To validate editing methods, incidence rates of on-farm recorded health event data were compared with incidence rates reported in the literature. Putative relationships among common health events were examined using logistic regression for each of 3 timeframes: 0 to 60, 61 to 90, and 91 to 150 d in milk. Health events occurring on average before the health event of interest were included in each model as predictors when significant. Calculated incidence rates ranged from 1.37% for respiratory problems to 12.32% for mastitis. Most health events reported had incidence rates lower than the average incidence rate found in the literature. This may partially represent underreporting by dairy farmers who record disease events only when a treatment or other intervention is required. Path diagrams developed using odds ratios calculated from logistic regression models for each of 13 common health events allowed putative relationships to be examined. The greatest odds ratios were estimated to be the influence of ketosis on displaced abomasum (15.5) and the influence of retained placenta on metritis (8.37), and were consistent with earlier reports. The results of this analysis provide evidence for the plausibility of on-farm recorded health information. PMID- 22916950 TI - Short communication: evaluation of bovine milk residues from routine milk testing programs as DNA source for genotyping. AB - Genome-wide association studies and genomic evaluation using a dense set of genetic markers both require a large number of genotyped individuals. Collection of the respective samples contributes substantially to the cost of the approach. In dairy cattle research, the use of residues from routine milk recording would be a cost-saving alternative to obtain samples for an appropriate number of individuals with specific phenotypes in a very short time. To assess the suitability of milk recording residues, we concurrently investigated milk residues obtained after standardized milk recording procedures and blood samples from 115 cows originating from 3 farms with different milking systems by genotyping 15 microsatellite markers. We found that 4% of the milk samples were possibly assigned to the wrong animal (i.e., conflicts) and that at least 27% of the milk residues were contaminated, as indicated by an extra allele not present in the blood sample. These additional alleles primarily originated from a sample with a higher somatic cell score that went through the milk sample analyzer in the milk laboratory before the target sample. Furthermore, additional allele carryover was observed across more than one sample, when the difference in somatic cell count between samples exceeded 100,000 cells/mL. Finally, in several samples, the extra allele could not be traced back to previous samples passing through the milk sample analyzer. One source of those contaminations might be sample collection on-farm due to milk traces from the previously milked cow in the hose. No correlation was found between the farm management and conflicts or contaminations. We conclude that residues from routine milk recording are not suitable for genomic evaluation or genome-wide association studies because of the high prevalence of contamination generated at several steps during the collection and processing of milk residual samples. PMID- 22916951 TI - A daily herd Markov-chain model to study the reproductive and economic impact of reproductive programs combining timed artificial insemination and estrus detection. AB - Our objective was to compare the economic and reproductive performance of programs combining timed artificial insemination (TAI) and different levels of AI after estrus detection (ED) using a daily Markov-chain model. A dairy herd was modeled with every cow following daily probabilistic events of aging, replacement, mortality, pregnancy, pregnancy loss, and calving. The probability of pregnancy depended on the combination of probability of insemination and conception rate (CR). All nonpregnant cows had a probability of pregnancy between the end of the voluntary waiting period and days in milk cutoff for AI. After the cutoff, cows were labeled as do not breed and replaced when milk production was below a minimum milk threshold. A similar model was created to represent a replacement heifer herd to simulate and adjust the supply and demand of replacements. The net value (NV) of a program was the sum of milk income over feed cost, replacement and mortality cost, income from newborns, and reproductive costs. The model was used to compare the NV of 19 programs. One program used 100% TAI (42% CR for first TAI and 30% for second-and-later services), whereas the other programs combined TAI with ED. The proportion of cows receiving AI after ED for the combined programs ranged from 30 to 80%, with levels of CR of 25, 30, and 35%. As the proportion of cows receiving AI after ED increased, the CR of cows receiving TAI decreased. The combined programs with CR of 35% for cows receiving AI after ED had the greatest NV and reproductive performance at all levels of ED. The program using 100% TAI had greater NV and better reproductive performance than all programs with 25% CR after ED inseminations, whereas it had very similar performance to combined programs with up to 60% of cows receiving AI after ED and 30% CR. The factor with the greatest relative contribution to the differences among programs was income over feed cost, followed by replacement and reproductive costs. Adjusting the days in milk cutoff for AI to match the supply and demand of heifer replacements improved the NV of all programs except for those with 25% CR after ED, which had either no change or a decrease in NV. In summary, the economic value of reproductive management programs combining TAI and ED depended on the proportion of cows receiving AI after ED and the resulting CR. Adjusting the heifer supply and demand increased the NV of programs with heifer surplus and decreased the NV of programs with heifer deficit. PMID- 22916952 TI - Transcriptomic and metabonomic profiling reveal synergistic effects of quercetin and resveratrol supplementation in high fat diet fed mice. AB - Dietary quercetin and resveratrol have been frequently used in treating various diseases, but the underlying mechanisms are not entirely clear. Here, we report combined transcriptomic and metabonomic profiling that showed that the combined supplementation with quercetin and resveratrol produced synergistic effects on a high-fat diet-induced metabolic phenotype in mice. Histological and phenotypic improvements in serum and hepatic total cholesterol, insulin, fasting blood glucose, and HbA1c were also observed in mice receiving combined quercetin and resveratrol supplementation. This combined quercetin and resveratrol supplementation resulted in significant restoration of gene sets in functional pathways of glucose/lipid metabolism, liver function, cardiovascular system, and inflammation/immunity, which were altered by high fat diet feeding. The integration of transcriptomic and metabonomic data indicated quercetin and resveratrol supplementation enhanced processes of glycolysis and fatty acid oxidation, as well as suppressed gluconeogenesis. These alterations discovered at both the transcriptional and metabolic levels highlight the significance of combined "omics" platforms for elucidating mechanistic pathways altered by dietary polyphenols, such as quercetin and resveratrol, in a synergistic manner. PMID- 22916953 TI - Molecular beacon aptamers for direct and universal quantitation of recombinant proteins from cell lysates. AB - Western blot, enzyme linked immunosorbent assay (ELISA), and fluorescent fusion proteins are currently the most common methods for detecting recombinant proteins. However, the former two are cumbersome and time-consuming, and the latter method may interfere with the trafficking and function of the fused recombinant proteins. We report here a rapid, inexpensive, and simple approach to detect and quantify recombinant proteins using an anti-His-tag molecular beacon aptamer (HMBA). We demonstrated the technique by detection and quantitation of expressed recombinant proteins directly from E. coli cell lysate. The amount of expressed P78-His was determined to be 1.49 MUg from the 20 MUg cell lysate proteins. To the best of our knowledge, this is the first example directly measuring the concentration and expression yield of recombinant proteins from cell lysate, and the entire procedure required only 5 min. PMID- 22916954 TI - Hepatoprotective iridoid glycosides from the roots of Rehmannia glutinosa. AB - Eleven new iridoid glycosides, rehmaglutosides A-K (1-11), together with 20 known analogues were isolated from the air-dried roots of Rehmannia glutinosa. The structures of these compounds were elucidated on the basis of spectroscopic data analysis and chemical evidence. Furthermore, in in vitro assays, compounds 3, 7, and 9-11 (10 MUM) exhibited moderate hepatoprotective activities against D galactosamine-induced HL-7702 cell damage. PMID- 22916955 TI - Plasmonic photoanodes for solar water splitting with visible light. AB - We report a plasmonic water splitting cell in which 95% of the effective charge carriers derive from surface plasmon decay to hot electrons, as evidenced by fuel production efficiencies up to 20-fold higher at visible, as compared to UV, wavelengths. The cell functions by illuminating a dense array of aligned gold nanorods capped with TiO(2), forming a Schottky metal/semiconductor interface which collects and conducts the hot electrons to an unilluminated platinum counter-electrode where hydrogen gas evolves. The resultant positive charges in the Au nanorods function as holes and are extracted by an oxidation catalyst which electrocatalytically oxidizes water to oxygen gas. PMID- 22916956 TI - Ultrashort electromagnetic pulse control of intersubband quantum well transitions. AB - : We study the creation of high-efficiency controlled population transfer in intersubband transitions of semiconductor quantum wells. We give emphasis to the case of interaction of the semiconductor quantum well with electromagnetic pulses with a duration of few cycles and even a single cycle. We numerically solve the effective nonlinear Bloch equations for a specific double GaAs/AlGaAs quantum well structure, taking into account the ultrashort nature of the applied field, and show that high-efficiency population inversion is possible for specific pulse areas. The dependence of the efficiency of population transfer on the electron sheet density and the carrier envelope phase of the pulse is also explored. For electromagnetic pulses with a duration of several cycles, we find that the change in the electron sheet density leads to a very different response of the population in the two subbands to pulse area. However, for pulses with a duration equal to or shorter than 3 cycles, we show that efficient population transfer between the two subbands is possible, independent of the value of electron sheet density, if the pulse area is Pi. PMID- 22916957 TI - Prognostic significance of IKZF1 alteration status in pediatric B-lineage acute lymphoblastic leukemia: a meta-analysis. PMID- 22916959 TI - Volumetrics of CO2 storage in deep saline formations. AB - Concern about the role of greenhouse gases in global climate change has generated interest in sequestering CO(2) from fossil-fuel combustion in deep saline formations. Pore space in these formations is initially filled with brine, and space to accommodate injected CO(2) must be generated by displacing brine, and to a lesser extent by compression of brine and rock. The formation volume required to store a given mass of CO(2) depends on the storage mechanism. We compare the equilibrium volumetric requirements of three end-member processes: CO(2) stored as a supercritical fluid (structural or stratigraphic trapping); CO(2) dissolved in pre-existing brine (solubility trapping); and CO(2) solubility enhanced by dissolution of calcite. For typical storage conditions, storing CO(2) by solubility trapping reduces the volume required to store the same amount of CO(2) by structural or stratigraphic trapping by about 50%. Accessibility of CO(2) to brine determines which storage mechanism (structural/stratigraphic versus solubility) dominates at a given time, which is a critical factor in evaluating CO(2) volumetric requirements and long-term storage security. PMID- 22916958 TI - Contribution of the serine kinase c-Jun N-terminal kinase (JNK) to oxidant induced insulin resistance in isolated rat skeletal muscle. AB - The specific and direct contribution of the stress-activated serine kinase c-Jun N-terminal kinase (JNK) in the development of oxidative stress-induced insulin resistance of the glucose transport system in mammalian skeletal muscle is not fully understood. We assessed the specific role of JNK in the development of insulin resistance caused by in vitro exposure of rat soleus muscle to low levels (30-40 uM) of the oxidant hydrogen peroxide (H(2)O(2)) for up to 6 h. Oxidant exposure caused significant (p < 0.05) decreases in insulin-stimulated glucose transport activity (up to 42%) and Akt Ser(473) phosphorylation (up to 67%), and increased (up to 74%) phosphorylation (Thr(183)/Tyr(185)) of JNK1 and JNK2/3 isoforms. Importantly, insulin-stimulated glucose transport activity in the presence of H(2)O(2) was moderately improved with the selective JNK inhibitor SP600125. These results indicate that activation of the serine kinase JNK contributes, at least in part, to oxidative stress-induced insulin resistance in isolated mammalian skeletal muscle. PMID- 22916961 TI - Vibrational solvatochromism in Vaska's complex adducts. AB - The vibrational solvatochromism of bis(triphenylphosphine) iridium(I) carbonyl chloride (Vaska's complex, VC) was investigated by FTIR spectroscopy. The carbonyl stretching frequency (nu(CO)) was measured in 16 different organic solvents with a wide range of Lewis acidities for VC and its dioxygen (VC-O(2)), hydride (VC-H(2)), iodide (VC-I(2)), bromide (VC-Br(2)), and sulfide (VC-S(X)) adducts. The nu(CO) of the VC-O(2) complex was sensitive to the solvent electrophilicity, whereas minimal correlation was found for VC and the other adducts. The stretching frequency of the trans-O(2) ligand on VC-O(2) was measured to be anticorrelated with nu(CO), supporting a model in which this ligand indirectly affects the carbonyl frequency by modulating the extent of metal-to-CO back-bonding. The nu(CO) values obtained from DFT calculations on VC adducts with solvent continua and explicit hydrogen bonds were used to aid the interpretations of the experimental results. The O(2) ligand is more susceptible to stronger specific solvent interactions and it binds in a fundamentally different mode from the monatomic ligands, providing a more direct communication channel with those metal d-orbitals that have the appropriate symmetry to back bond into the carbonyl pi*-orbital. PMID- 22916960 TI - Rapid measurement of pseudocontact shifts in metalloproteins by proton-detected solid-state NMR spectroscopy. AB - Pseudocontact shifts (PCSs) arise in paramagnetic systems in which the susceptibility tensor is anisotropic. PCSs depend upon the distance from the paramagnetic center and the position relative to the susceptibility tensor, and they can be used as structural restraints in protein structure determination. We show that the use of (1)H-detected solid-state correlations provides facile and rapid detection and assignment of site-specific PCSs, including resolved (1)H PCSs, in a large metalloprotein, Co(2+)-substituted superoxide dismutase (Co(2+) SOD). With only 3 mg of sample and a small set of experiments, several hundred PCSs were measured and assigned, and these PCSs were subsequently used in combination with (1)H-(1)H distance and dihedral angle restraints to determine the protein backbone geometry with a precision paralleling those of state-of-the art liquid-state determinations of diamagnetic proteins, including a well-defined active site. PMID- 22916962 TI - Effects of starting hemodialysis with an arteriovenous fistula or central venous catheter compared with peritoneal dialysis: a retrospective cohort study. AB - BACKGROUND: Although several studies have demonstrated early survival advantages with peritoneal dialysis (PD) over hemodialysis (HD), the reason for the excess mortality observed among incident HD patients remains to be established, to our knowledge. This study explores the relationship between mortality and dialysis modality, focusing on the role of HD vascular access type at the time of dialysis initiation. METHODS: A retrospective cohort study was performed among local adult chronic kidney disease patients who consecutively initiated PD and HD with a tunneled cuffed venous catheter (HD-TCC) or a functional arteriovenous fistula (HD-AVF) in our institution in the year 2008. A total of 152 patients were included in the final analysis (HD-AVF, n = 59; HD-TCC, n = 51; PD, n = 42). All cause and dialysis access-related morbidity/mortality were evaluated at one year. Univariate and multivariate analysis were used to compare the survival of PD patients with those who initiated HD with an AVF or with a TCC. RESULTS: Compared with PD patients, both HD-AVF and HD-TCC patients were more likely to be older (p<0.001) and to have a higher frequency of diabetes mellitus (p = 0.017) and cardiovascular disease (p = 0.020). Overall, HD-TCC patients were more likely to have clinical visits (p = 0.069), emergency room visits (p<0.001) and hospital admissions (p<0.001). At the end of follow-up, HD-TCC patients had a higher rate of dialysis access-related complications (1.53 vs. 0.93 vs. 0.64, per patient year; p<0.001) and hospitalizations (0.47 vs. 0.07 vs. 0.14, per patient-year; p = 0.034) than HD-AVF and PD patients, respectively. The survival rates at one year were 96.6%, 74.5% and 97.6% for HD-AVF, HD-TCC and PD groups, respectively (p<0.001). In multivariate analysis, HD-TCC use at the time of dialysis initiation was the important factor associated with death (HR 16.128, 95%CI [1.431-181.778], p = 0.024). CONCLUSION: Our results suggest that HD vascular access type at the time of renal replacement therapy initiation is an important modifier of the relationship between dialysis modality and survival among incident dialysis patients. PMID- 22916963 TI - Synthesis, structure, and characterization of new Li+-d0-lone-pair-oxides: noncentrosymmetric polar Li6(Mo2O5)3(SeO3)6 and centrosymmetric Li2(MO3)(TeO3) (M = Mo6+ or W6+). AB - New quaternary lithium-d(0) cation-lone-pair oxides, Li(6)(Mo(2)O(5))(3)(SeO(3))(6) (Pmn2(1)) and Li(2)(MO(3))(TeO(3)) (P2(1)/n) (M = Mo(6+) or W(6+)), have been synthesized and characterized. The former is noncentrosymmetric and polar, whereas the latter is centrosymmetric. Their crystal structures exhibit zigzag anionic layers composed of distorted MO(6) and asymmetric AO(3) (A = Se(4+) or Te(4+)) polyhedra. The anionic layers stack along a 2-fold screw axis and are separated by Li(+) cations. Powder SHG measurements on Li(6)(Mo(2)O(5))(3)(SeO(3))(6) using 1064 nm radiation reveal a SHG efficiency of approximately 170 * alpha-SiO(2). Particle size vs SHG efficiency measurements indicate Li(6)(Mo(2)O(5))(3)(SeO(3))(6) is type 1 nonphase-matchable. Converse piezoelectric measurements result in a d(33) value of ~28 pm/V and pyroelectric measurements reveal a pyroelectric coefficient of -0.43 MUC/m(2)K at 50 degrees C for Li(6)(Mo(2)O(5))(3)(SeO(3))(6). Frequency-dependent polarization measurements confirm that Li(6)(Mo(2)O(5))(3)(SeO(3))(6) is nonferroelectric, i.e., the macroscopic polarization is not reversible, or 'switchable'. Infrared, UV-vis, thermogravimetric, and differential thermal analysis measurements and electron localization function calculations were also done for all materials. PMID- 22916965 TI - Charge transport in nanochannels: a molecular theory. AB - We introduce a theoretical and numerical method to investigate the flow of charged fluid mixtures under extreme confinement. We model the electrolyte solution as a ternary mixture comprising two ionic species of opposite charge and a third uncharged component. The microscopy approach is based on kinetic theory and is fully self-consistent. It allows us to determine configurational properties, such as layering near the confining walls and the flow properties. We show that, under the appropriate assumptions, the approach reproduces the phenomenological equations used to describe electrokinetic phenomena, without requiring the introduction of constitutive equations to determine the fluxes. Moreover, we model channels of arbitrary shape and nanometric roughness, features that have important repercussions on the transport properties of these systems. Numerical simulations are obtained by solving the evolution dynamics of the one particle phase-space distributions of each species by means of a lattice Boltzmann method for flows in straight and wedged channels. Results are presented for the microscopic density, the velocity profiles, and the volumetric and charge flow rates. Strong departures from electroneutrality are shown to appear at the molecular level. PMID- 22916964 TI - Antimicrobial and antioxidant activities of the extracts and compounds from the leaves of Psorospermum aurantiacum Engl. and Hypericum lanceolatum Lam. AB - BACKGROUND: Psorospermun aurantiacum and Hypericum lanceolatum are plants locally used in Cameroon and other parts of Africa for the treatment of gastrointestinal and urinary tract infections, skin infections, venereal diseases, gastrointestinal disorder, infertility, epilepsy as well as microbial infections. The present study was designed in order to investigate the in vitro antimicrobial and radical scavenging activities of the extracts and isolated compounds from the leaves of these plants. METHODS: The plant extract was prepared by maceration in ethyl acetate and methanol and fractionated by column chromatography. The structures of isolated compounds were elucidated by spectroscopic analyses in conjunction with literature data. The broth microdilution method was used to evaluate the in vitro antimicrobial activity against bacteria, yeasts and dermatophytes. The antioxidant potentials of the extracts and their isolated compounds were evaluated using the DPPH radical scavenging method. RESULTS: Five known compounds: physcion (1), 1,8-dihydroxy-3-geranyloxy-6-methylanthraquinone (2), kenganthranol B (3), vismiaquinone (4), and octacosanol (5) were isolated from the leaves of P. aurantiacum while six compounds including friedelin (6), betulinic acid (7), 2,2',5,6'-tetrahydroxybenzophenone (8), allanxanthone A (9), 1,3,6- trihydroxyxanthone (10) and isogarcinol (11) were isolated from H. lanceolatum. Compound 8 and 4 exhibited the highest antibacterial and antifungal activities with MIC ranges of 2-8 MUg/ml and 4-32 MUg/ml respectively. P. aurantiacum crude extract (Rsa50 = 6.359 +/- 0.101) showed greater radical scavenging activity compared with H. lanceolatum extract (Rsa50 = 30.996 +/- 0.879). Compound 11 showed the highest radical scavenging activity (RSa50 = 1.012 +/- 0.247) among the isolated compounds, comparable to that of L-arscobic acid (RSa50 = 0.0809 +/- 0.045). CONCLUSIONS: The experimental findings show that the ethyl acetate and methanol extracts and isolated compounds from P. aurantiacum and H. lanceolatum stem bark possess significant antimicrobial and antioxidant activities justifying the use of these plants in traditional medicine, which may be developed as phytomedicines. PMID- 22916966 TI - Food-derived peptides stimulate mucin secretion and gene expression in intestinal cells. AB - In this study, the hypothesis that food-derived opioid peptides besides beta casomorphin 7 might modulate the production of mucin via a direct action on epithelial goblet cells was investigated in HT29-MTX cells used as a model of human colonic epithelium. Seven milk whey or casein peptides, a human milk peptide, and a wheat gluten-derived peptide with proved or probable ability to bind MU- or delta-opioid receptors were tested on the cell culture. Significantly increased secretion of mucins was found after exposure to six of the assayed peptides, besides the previously described beta-casomorphin 7, as measured by an enzyme-linked lectin assay (ELLA). Human beta-casomorphin 5 and alpha-lactorphin were selected to study the expression of mucin 5AC gene (MUC5AC), the HT29-MTX major secreted mucin gene. alpha-Lactorphin showed increased expression of MUC5AC from 4 to 24 h (up to 1.6-fold over basal level expression), although differences were statistically different only after 24 h of exposure. However, this increased expression of MUC5AC did not reach significance after cell treatment with human beta-casomorphin 5. In conclusion, six food-derived peptides have been identifed with described or probable opioid activity that induce mucin secretion in HT29 MTX cells. Concretely, alpha-lactorphin is able to up-regulate the expression of the major secreted mucin gene encoded by these cells. PMID- 22916967 TI - Insulin resistance is increased in alopecia areata patients. AB - Increased insulin resistance (IR) has been found in androgenetic alopecia in several studies. However, IR has not been investigated in alopecia areata (AA). We aimed to investigate IR in AA patients and the controls. Anthropometric and demographic data were obtained from 51 AA patients and 36 controls. We measured insulin, c-peptide and blood glucose and HOMA-IR. Demographic characteristics of the two groups were similar. AA group had higher insulin [12.5 +/- 7.01 vs. 8.3 +/- 3.9 uIU/mL, p = 0.001], c-peptide [2.7 +/- 1.07 vs. 2. +/- 0.6 ng/mL, p = 0.007] and HOMA-IR levels [2.8 +/- 1.6 vs. 1.9 +/- 0.9, p = .004] than the controls. Patient and control groups were also similar regarding lipid profiles. In this study, we found increased IR in AA patients for the first time in literature. Increased inflammatory cytokines and hypothalamic-pituitary-adrenal axis activation may be responsible for this finding. Further studies with larger sample sizes may give additional information for IR in AA. PMID- 22916968 TI - Molecular recognition of the Thomsen-Friedenreich antigen-threonine conjugate by adhesion/growth regulatory galectin-3: nuclear magnetic resonance studies and molecular dynamics simulations. AB - Nuclear magnetic resonance (NMR) spectroscopy and molecular modeling methods have been strategically combined to elucidate the molecular recognition features of the binding of threonine O-linked Thomsen-Friedenreich (TF) antigen to chimera type avian galectin-3 (CG-3). Saturation transfer difference (STD) NMR experiments revealed the highest intensities for the H4 protons of both the beta D-Galp and alpha-D-GalpNAc moieties, with 100 and 71% of relative STD, respectively. The methyl protons of the threonine residue exhibited a small STD effect, <15%, indicating that the interaction of the amino acid with the protein is rather transient. Two-dimensional transferred nuclear Overhauser effect spectroscopy NMR experiments and molecular modeling suggested some differences in conformer populations between the free and bound states. A dynamic binding mode for the TF antigen-CG-3 complex consisting of two poses has been deduced. In one pose, intermolecular interactions were formed between the terminal threonine residue and the receptor. In the second pose, intermolecular interactions involved the internal GalpNAc. The difference in the trend of some shifts in the heteronuclear single-quantum coherence titration spectra indicates some disparities in the binding interactions of CG-3 with lactose and TF antigen. The results obtained from this model of the avian orthologue of human galectin-3 will allow detailed interspecies comparison to give sequence deviations in phylogeny a structural and functional meaning. Moreover, the results indicate that the peptide scaffold presenting TF antigen could be relevant for binding and thus provides a possible route for the design of galectin-3 inhibitors with improved affinity and selectivity. PMID- 22916969 TI - Glutamine as a supplemental treatment in pediatric and adult oncology patients. AB - INTRODUCTION: This review summarizes the achievement and role of supplemental therapy in prevention of severe complications following anticancer treatment. AREAS COVERED: A promising supplemental therapy agent in the field is glutamine. Glutamine (Gln) is an amino acid that is produced in physiological conditions in human cells. However, in pathological states, glutamine production is often insufficient. In the clinical setting, glutamine has been shown to decrease metabolic side effects resulting from cancer treatment and to improve patient outcome. In clinical trials, the administration of glutamine was shown to benefit specific groups of patients, including oncology patients. The MEDLINE database PubMed search in English using the key words 'glutamine supplementation', 'parenteral and oral glutamine', 'glutamine in cancer' was performed. Only prospective randomized studies on cancer patients between 2005 and 2011 and ongoing researches from the US National Institute of Health trial database and EU Clinical Trials Register were taken into consideration. EXPERT OPINION: In the opinion of authors, the optimal dose and route of administration of glutamine needs to be determined in future studies. This review provides an overview of the use of glutamine as supplemental therapy in patients with cancer, including its use in pediatric patients. PMID- 22916970 TI - Department of Pediatrics Chair's Initiatives: promoting innovation and improvement through collaboration, accountability, and faculty development. PMID- 22916971 TI - 50 years ago in THE JOURNAL OF PEDIATRICS: growth disturbance in congenital heart disease. PMID- 22916972 TI - 50 years ago in the Journal of Pediatrics: smallpox and air travel: need for vigilance. PMID- 22916973 TI - 50 years ago in the Journal of Pediatrics: neuroblastoma. PMID- 22916974 TI - 50 years ago in the Journal of Pediatrics: mass screening for phenylketonuria. PMID- 22916975 TI - 50 years ago in the Journal of Pediatrics: identification of heterozygotes with phenylketonuria on basis of blood tyrosine responses. PMID- 22916976 TI - 50 years ago in the Journal of Pediatrics: comparison of serum phenylalanine levels with growth in Guthrie's inhibition assay in newborn infants. PMID- 22916977 TI - State-level policies can help reduce consumption of sugar-sweetened beverages in schools. PMID- 22916978 TI - Interrater reliability of history and physical examination is limited among children with possible appendicitis. PMID- 22916979 TI - Sleep-disordered breathing early in life predicts later behavioral problems in children. PMID- 22916980 TI - Zinc does not appear to have significant benefit in treatment of pneumonia. PMID- 22916981 TI - Text messaging increases receipt of influenza vaccine among low-income, urban children. PMID- 22916982 TI - Pulse oximetry is a cost-effective addition in screening newborns for congenital heart defects. PMID- 22916991 TI - The MBT Adherence and Competence Scale (MBT-ACS): development, structure and reliability. AB - The properties of the 17-item Mentalization-Based Treatment Adherence and Competence Scale (MBT-ACS) were investigated in a reliability study in which 18 psychotherapy sessions, comprising two sessions by nine different therapists, were rated by seven different raters. The overall reliabilities for adherence and competence for seven raters were high, .84 and .88 respectively. The level of reliability declined by number of raters but was still acceptable for two raters (.60 and .68). The reliabilities for the various items differed. The MBT-ACS was found to be an appropriate rating measure for treatment fidelity and useful for the purposes of quality control and supervision. The reliability may be enhanced by redefining some items and reducing their numbers. PMID- 22916992 TI - Evaluation of intact mass spectrometry for the quantitative analysis of protein therapeutics. AB - Implementation of modern analytical techniques, such as intact mass spectrometry, may allow for more detailed quality assessments of protein therapeutics. The complexity of the protein therapeutic manufacturing process as well as the sensitivity of these drugs to different storage conditions can lead to the presence of several undesired products, including truncations, degradation products, byproducts, and differentially modified protein variants that are difficult to detect by peptide mapping. Intact mass spectrometry can be used to identify the intact protein composition, inclusive of post-translational modifications (PTMs) but can also generate a chemical fingerprint of the different protein species present in a given sample. In this work, we systematically evaluated the influence of multiple charge states, multiple isotopes per charge state, and operating resolution on the suitability of intact mass spectrometry for quantitative analysis using insulin and somatotropin as model systems. Standard curves could be generated using absolute intensity data or using the relative ratio between the analyte and internal standard. These methods demonstrate the validity of quantitative intact mass spectrometry for the analysis of protein therapeutic drugs, thus providing a foundation for future comparative methods. PMID- 22916993 TI - Acoustic phonon modes and phononic bandgaps in GaN/AlN nanowire superlattices. AB - : We study numerically the phonon dispersion relations and corresponding displacement fields for a circular cross-section nanowire superlattices consisting of anisotropic GaN and AlN. We determine a set of parameters which gives complete phononic bandgaps. The results suggest the potential for manipulating phonons in the micro/nano electromechanical systems. PMID- 22916994 TI - Radiotherapy in the management of localized primary cutaneous B-cell lymphoma. AB - The optimal therapy and radiation dose for patients with localized primary cutaneous B-cell lymphoma (PCBCL) are unknown. We retrospectively identified 23 patients with localized (T1-T2) PCBCL treated with definitive radiation to doses ranging from 30 to 44 Gy (median, 36 Gy). With a median follow-up of 4.8 years, the 5-year overall survival rate was 100%, the relapse-free survival rate was 71% (95% confidence interval, 46-86%) and there were no local recurrences, suggesting that radiotherapy to a dose of 30 Gy may be sufficient for cure. PMID- 22916995 TI - Cost-effectiveness analysis of a community health worker intervention for low income Hispanic adults with diabetes. AB - INTRODUCTION: The objective of our study was to estimate the long-term cost effectiveness of a lifestyle modification program led by community health workers (CHWs) for low-income Hispanic adults with type 2 diabetes. METHODS: We forecasted disease outcomes, quality-adjusted life years (QALYs) gained, and lifetime costs associated with attaining different hemoglobin A1c (A1c) levels. Outcomes were projected 20 years into the future and discounted at a 3.0% rate. Sensitivity analyses were conducted to assess the extent to which our results were dependent on assumptions related to program effectiveness, projected years, discount rates, and costs. RESULTS: The incremental cost-effectiveness ratio of the intervention ranged from $10,995 to $33,319 per QALY gained when compared with usual care. The intervention was particularly cost-effective for adults with high glycemic levels (A1c > 9%). The results are robust to changes in multiple parameters. CONCLUSION: The CHW program was cost-effective. This study adds to the evidence that culturally sensitive lifestyle modification programs to control diabetes can be a cost-effective way to improve health among Hispanics with diabetes, particularly among those with high A1c levels. PMID- 22916996 TI - Accuracy of heart disease prevalence estimated from claims data compared with an electronic health record. AB - INTRODUCTION: We developed a decision support tool that can guide the development of heart disease prevention programs to focus on the interventions that have the most potential to benefit populations. To use it, however, users need to know the prevalence of heart disease in the population that they wish to help. We sought to determine the accuracy with which the prevalence of heart disease can be estimated from health care claims data. METHODS: We compared estimates of disease prevalence based on insurance claims to estimates derived from manual health records in a stratified random sample of 480 patients aged 30 years or older who were enrolled at any time from August 1, 2007, through July 31, 2008 (N = 474,089) in HealthPartners insurance and had a HealthPartners Medical Group electronic record. We compared randomly selected development and validation samples to a subsample that was also enrolled on August 1, 2005 (n = 272,348). We also compared the records of patients who had a gap in enrollment of more than 31 days with those who did not, and compared patients who had no visits, only 1 visit, or 2 or more visits more than 31 days apart for heart disease. RESULTS: Agreement between claims data and manual review was best in both the development and the validation samples (Cohen's kappa, 0.92, 95% confidence interval [CI], 0.87-0.97; and Cohen's kappa, 0.94, 95% CI, 0.89-0.98, respectively) when patients with only 1 visit were considered to have heart disease. CONCLUSION: In this population, prevalence of heart disease can be estimated from claims data with acceptable accuracy. PMID- 22916997 TI - The role of group 14 element hydrides in the activation of C-H bonds in cyclic olefins. AB - Formally, triple-bonded dimetallynes ArEEAr [E = Ge (1), Sn (2); Ar = C(6)H(3) 2,6-(C(6)H(3)-2,6-(i)Pr(2))(2)] have been previously shown to activate aliphatic, allylic C-H bonds in cyclic olefins, cyclopentadiene (CpH), cyclopentene (c C(5)H(8)) and 1,4-cyclohexadiene, with intriguing selectivity. In the case of the five-membered carbocycles, cyclopentadienyl species ArECp [E = Ge (3), Sn (4)] are formed. In this study, we examine the mechanisms for activation of CpH and c C(5)H(8) using experimental methods and describe a new product found from the reaction between 1 and c-C(5)H(8), an asymmetrically substituted digermene ArGe(H)Ge(c-C(5)H(9))Ar (5), crystallized in 46% yield. This compound contains a hydrogenated cyclopentyl moiety and is found to be produced in a 3:2 ratio with 3, explaining the fate of the liberated H atoms following triple C-H activation. We show that when these C-H activation reactions are carried out in the presence of tert-butyl ethylene (excess), compounds {ArE(CH(2)CH(2)tBu)}(2) [E = Ge(8), Sn(9)] are obtained in addition to ArECp; in the case of CpH, the neohexyl complexes replace the production of H(2) gas, and for c-C(5)H(8) they displace cyclopentyl product 5 and account for all the hydrogen removed in the dehydroaromatization reactions. To confirm the source of 8 and 9, it was demonstrated that these molecules are formed cleanly between the reaction of (ArEH)(2) [E = Ge(6), Sn(7)] and tert-butyl ethylene, new examples of noncatalyzed hydro-germylation and -stannylation. Therefore, the presence of transient hydrides of the type 6 and 7 can be surmised to be reactive intermediates in the production of 3 and 4, along with H(2), from 1 and 2 and CpH (respectively), or the formation of 3 and 5 from 1. The reaction of 6 or 7 with CpH gave 3 or 4, respectively, with concomitant H(2) evolution, demonstrating the basic nature of these low-valent group 14 element hydrides and their key role in the 'cascade' of C-H activation steps. Additionally, during the course of these studies a new polycyclic compound (ArGe)(2)(C(7)H(12)) (10) was obtained in 60% yield from the reaction of 1,6-heptadiene and 1 via double [2 + 2] cycloaddition and gives evidence for a nonradical mechanism for these types of reactions. PMID- 22916998 TI - Optical absorption engineering in stacked plasmonic Au-SiO2-Pd nanoantennas. AB - The nonradiative decay of a localized surface plasmon through absorption of a captured photon and excitation of an energetic electron-hole pair is a potentially very effective way to enhance chemical reactions on metal nanoparticle surfaces, so far limited to Ag (and Au). Here we explore the possibility of efficient and spectrally widely tunable optical absorption engineering based on heterometallic optical nanoantennas. They consist of an optimized antenna element made of Au (or Ag) and a catalytically active second metallic element separated by a thin SiO(2) layer. Specifically, we find that stacked Au-SiO(2)-Pd nanodisk antennas exhibit pronounced local absorption enhancement in the catalytic Pd particle. The effect is caused by efficient power transfer from the Au disk, exhibiting a narrow low-loss resonance and acting as an antenna collecting photons, to the Pd disk due to strong coupling between the two. The Pd element thus acts as receiver that efficiently dissipates energy into electron-hole pairs owing to efficient coupling to intra and interband transitions. In fact, the energy transfer is found to be so effective that the absorption efficiency at a given wavelength can be enhanced up to 6 to 9 times, and the total absorption integrated over a wide spectral range (400-900 nm) up to 2-fold, depending on the antenna dimensions. This finding suggests a novel route toward highly efficient plasmon-enhanced catalysis on widely selectable catalytic metal particle surfaces not limited to the "classic" plasmonic metals Au and Ag. PMID- 22916999 TI - Optimal intervention intensity. AB - Empirical evidence exists for many of the different interventions in speech language pathology. However, relatively little is known about the optimal intensity of those interventions. In order for speech-language pathology services to be both effective and efficient speech-language pathologists need to know how to faithfully administer ideal doses of the active ingredients of interventions, in what forms, how often and for how long. This is the lead paper to a scientific forum on this fundamental yet under-studied issue of clinical practice. Borrowing from the work of Warren, Fey, and Yoder, the concept of intervention intensity is described. Issues involved in establishing the optimal intensity of interventions are identified, including what and how intervention goals are targeted. Given that speech-language pathology interventions can involve the delivery of therapeutic inputs (e.g., conversational recasts, questions) and/or clients carrying out an act (e.g., speech production, voice production, comprehending, naming, swallowing), a framework is proposed for measuring all potential inputs and acts that might contribute to the calculation of an intervention intensity. Client-, clinician-, condition-, and service-related variables that could influence the investigation and practical application of an optimal intervention intensity are also discussed. PMID- 22917000 TI - Alkaloids from Narcissus serotinus. AB - Narcissus serotinus belongs to the Amaryllidaceae family, a group well known for an exclusive variety of alkaloids with interesting biological activities. This study was aimed at identifying the alkaloid constituents of N. serotinus collected in the Spanish region of Valencia, using a combination of chromatographic, spectroscopic, and spectrometric methods, including GC-MS and 2D NMR techniques. GC-MS analysis allowed for the direct identification of five known compounds. In addition, the isolation and structure elucidation of six new Amaryllidaceae alkaloids are described. PMID- 22917001 TI - Effect of botulinum toxin A on the intraocular pressure and the retina in an animal model. AB - OBJECTIVE: The purpose of our study was to investigate the effect of an inadvertent intravitreal injection of botulinum toxin A (BTA) on the intraocular pressure (IOP) and the retina in an animal model. METHODS: BTA was injected intravitreally in normotensive rats. IOP was measured preoperatively as well as 1, 2, and 4 weeks postoperatively. Retinas were stained in vivo using a retrograde labelling technique and the density of retinal ganglion cells (RGCs) was determined. Immunohistochemistry was performed for rhodopsin and retinal glial fibrillary acidic protein (GFAP). RESULTS: Significant temporary IOP elevation occurred in all groups in the immediate postoperative period (ANOVA, p < 0.05). IOP changes in the intermediate period were not statistically significant (ANOVA, p > 0.05). The differences in the density of RGCs after BTA injection were not statistically significant (ANOVA, p > 0.05). All retinas displayed the same immunostaining pattern for rhodopsin and GFAP. CONCLUSION: Our findings indicate that BTA has probably no severe impact on IOP and the retina after an inadvertent intravitreal injection. However, temporary rise of IOP may possibly occur in the immediate postoperative period due to a volume-effect. PMID- 22917003 TI - Silent brain injury after cardiac surgery: a review: cognitive dysfunction and magnetic resonance imaging diffusion-weighted imaging findings. AB - The appearance of cognitive dysfunction after cardiac surgery in the absence of focal neurologic signs, a poorly understood but potentially devastating complication, almost certainly results from procedure-related brain injury. Confirmation of the occurrence of perioperative silent brain injury has been developed through advances in magnetic resonance imaging (MRI) techniques. These techniques detect new brain lesions in 25% to 50% of patients after both coronary artery bypass graft and valve surgery. Use of post-operative cognitive dysfunction as a marker of brain injury is problematic because of potential difficulties in ascertainment. It can be hypothesized that post-operative appearance of MRI lesions may serve as a more objective marker of brain injury in research efforts. If MRI examination can be used in this way, then 2 vitally important questions can be addressed. 1) What is the frequency of important, but silent, brain injury during cardiac surgery? 2) Does long-term cognitive impairment ensue? This review briefly discusses clinical features of post operative cognitive dysfunction and reviews the evidence supporting a possible association with MRI evidence of perioperative brain injury and its potential for long-term dementia. We conclude that this association is plausible, but not yet firmly established. PMID- 22917002 TI - Effect of add-on direct renin inhibitor aliskiren in patients with non-diabetes related chronic kidney disease. AB - BACKGROUND: The renin-angiotensin-aldosterone system (RAAS) plays an important role in the progression of chronic kidney disease (CKD). Although dual RAAS inhibition results in worse renal outcomes than monotherapy in high risk type 2 diabetes patients, the effect of dual RAAS inhibition in patients with non-DM CKD is unclear. The aim of this study was to evaluate the potential renoprotective effect of add-on direct renin inhibitor in non-DM CKD patients. METHODS: We retrospectively enrolled 189 non-DM CKD patients who had been taking angiotensin II receptor blockers (ARBs) for more than six months. Patients were divided into an add-on aliskiren group and an ARB monotherapy group. The primary outcomes were a decline in glomerular filtration rate (GFR) and a reduction in urinary protein to-creatinine ratio at six months. RESULTS: The baseline characteristics of the two groups were similar. Aliskiren 150 mg daily reduced the urinary protein-to creatinine ratio by 26% (95% confidence interval, 15 to 37%; p < 0.001). The decline in GFR was smaller in the add-on aliskiren group (-2.1 vs. -4.0 ml/min, p = 0.038). Add-on aliskiren had a neutral effect on serum potassium in the non-DM CKD patients. In subgroup analysis, the proteinuria-reducing effect of aliskiren was more prominent in patients with a GFR less than 60 ml/min, and in patients with a urinary protein-to-creatinine ratio greater than 1.8. The effect of aliskiren in retarding the decline in GFR was more prominent in patients with hypertensive nephropathy than in those with glomerulonephritis. CONCLUSION: Add on direct renin inhibitor aliskiren (150 mg daily) safely reduced proteinuria and attenuated the decline in GFR in the non-DM CKD patients who were receiving ARBs. PMID- 22917004 TI - Risk of stroke with coronary artery bypass graft surgery compared with percutaneous coronary intervention. AB - OBJECTIVES: This study sought to determine whether coronary artery bypass graft (CABG) surgery is associated with an increased risk of stroke compared with percutaneous coronary intervention (PCI). BACKGROUND: Some, but not all, randomized trials have reported increased rates of stroke with CABG compared with PCI. However, all these studies were powered insufficiently to examine differences in the risk of stroke reliably. METHODS: We performed a meta-analysis of 19 trials in which 10,944 patients were randomized to CABG versus PCI. The primary end point was the 30-day rate of stroke. We also determined the rate of stroke at the midterm follow-up and investigated whether there was an interaction between revascularization type and the extent of coronary artery disease on the relative risk of stroke. RESULTS: The 30-day rate of stroke was 1.20% after CABG compared with 0.34% after PCI (odds ratio: 2.94, 95% confidence interval: 1.69 to 5.09, p < 0.0001). Similar results were observed after a median follow-up of 12.1 months (1.83% vs. 0.99%, odds ratio: 1.67, 95% confidence interval: 1.09 to 2.56, p = 0.02). The extent of coronary artery disease (single vessel vs. multivessel vs. left main) did not affect the relative increase in the risk of stroke observed with CABG compared with PCI at either 30 days (p = 0.57 for interaction) or midterm follow-up (p = 0.08 for interaction). Similar results were observed when the outcomes in 33,980 patients from 27 observational studies were analyzed. CONCLUSIONS: Coronary revascularization by CABG compared with PCI is associated with an increased risk of stroke at 30 days and at the mid-term follow-up. PMID- 22917005 TI - Family history of premature death and risk of early onset cardiovascular disease. AB - OBJECTIVES: The purpose of this study was to examine the effect of a family history of premature death, cardiovascular death in particular, on the risk of early cardiovascular disease. BACKGROUND: Studies suggest that fatal cardiovascular events and less severe cardiovascular diseases may co-occur in families. Consequently, a family history of premature death may indicate a familial cardiac frailty that predisposes to early cardiovascular disease. METHODS: We ascertained family history of premature death (age <60 years) in all individuals born in Denmark from 1950 to 2008 and followed this cohort for early cardiovascular disease (age <50 years). Using Poisson regression, we estimated incidence rate ratios (IRRs) reflecting the effect of premature death in the family on early cardiovascular disease risk. RESULTS: Among 3,985,301 persons followed up for 89,294,258 person-years, 129,825, 31,172, and 5,214 were diagnosed with any early cardiovascular disease, ischemic heart disease, and ventricular arrhythmia, respectively. IRRs for these conditions given a history of premature cardiovascular death in first-degree relatives were 1.72 (95% confidence interval [CI]: 1.68 to 1.77), 2.21 (95% CI: 2.11 to 2.31), and 1.94 (95% CI: 1.70 to 2.20), respectively. With >=2 cardiovascular deaths in a family, corresponding IRRs were 3.30 (95% CI: 2.77 to 3.94), 5.00 (95% CI: 3.87 to 6.45), and 6.18 (95% CI: 3.32 to 11.50). The IRR for any early cardiovascular disease given a family history of premature noncardiovascular death was significantly lower, 1.12 (95% CI: 1.10 to 1.14) (p(cardiac vs. noncardiac) < 0.0001). CONCLUSIONS: Family history of premature cardiovascular death was consistently and significantly associated with a risk of early cardiovascular disease, suggesting an inherited cardiac vulnerability. These results should be kept in mind when assessing cardiovascular disease risk in persons with a family history of premature cardiovascular death. PMID- 22917006 TI - Standardized reporting criteria for studies evaluating suspected acute heart failure syndromes in the emergency department. AB - Heart failure requiring urgent therapy represents a burgeoning health care burden. Although acute heart failure syndromes are commonly defined as a change in chronic heart failure signs and symptoms requiring urgent therapy, the presentation, development, and response to treatment is highly dependent on individual patient characteristics. This heterogeneity has led to challenges in interpreting widely differing study methods, including eligibility requirements and outcome measures. To improve interpretation of results and translate such information to better patient care, it is essential to present an accurate description of the patient population and study design. Based on existing recommendations and expert consensus, the authors present standardized reporting criteria to improve interpretability of research in this challenging cohort. PMID- 22917007 TI - Diagnosis of acute myopericarditis by delayed-enhancement multidetector computed tomography. PMID- 22917008 TI - Endothelial function in coronary chronic total occlusions: need for rigorous methodology. PMID- 22917012 TI - Multimodality imaging and transcatheter closure of a giant right pulmonary artery to left atrium communication: a rare cause of cyanosis. PMID- 22917011 TI - QRS morphology is equally important! PMID- 22917013 TI - Discontinued drugs 2011: endocrine and metabolic. AB - INTRODUCTION: This perspective summarizes key compounds from the endocrine and metabolic area that were discontinued during the calendar year 2011. Metabolic diseases continue to comprise some of the most important, but underserved areas of medical management. AREAS COVERED: The candidates covered in this summary were primarily being developed for treatment of type 2 and type 1 diabetes, obesity and inflammatory gastrointestinal disease. Candidates were identified from a search by informahealthcare including data available on TreasureTrove. EXPERT OPINION: Discontinuation of programs during this period include older and newer projects but apparently all suffer from inability to provide timely evidence of clear benefit in clinical trials in the face of growing costs of development. There is a key need for targets that when modulated clearly affect the pathophysiology of the disease in way that is evident early in clinical trials. PMID- 22917014 TI - Heteroaryl oxenium ions have diverse and unusual low-energy electronic states. AB - The electronic state orderings and energies of heteroaryl oxenium ions were computed using high-level CASPT2//CASSCF computations. We find that these ions have a number of diverse, low-energy configurations. Depending on the nature of the heteroaryl substituent, the lowest-energy configuration may be open-shell singlet, closed-shell singlet, or triplet, with further diversity found among the subtypes of these configurations. The 2- and 3-pyridinyl oxenium ions show small perturbations from the phenyl oxenium ion in electronic state orderings and energies, having closed-shell singlet ground states with significant gaps to an n,pi* triplet state. In contrast, the 4-pyridinyl oxenium ion is computed to have a low-energy nitrenium ion-like triplet state. The pyrimidinyl oxenium ion is computed to have a near degeneracy between an open-shell singlet and triplet state, and the pyrizidinyl oxenium ion is computed to have a near-triple degeneracy between a closed-shell singlet state, an open-shell singlet state, and a triplet state. Therefore, the ground state of these latter heteroaryl oxenium ions cannot be predicted with certainty; in principle, reactivity from any of these states may be possible. These systems are of fundamental interest for probing the spin- and configuration-dependent reactivity of unusual electronic states for this important class of reactive intermediate. PMID- 22917015 TI - Synthesis of graphene peroxide and its application in fabricating super extensible and highly resilient nanocomposite hydrogels. AB - Functionalized graphene has been considered as one of the most important materials for preparing polymer nanocomposites due to its unique physical structure and properties. To increase the interfacial interaction between polymer component and graphene oxide (GO) sheets, in situ grafting polymerization initiated by a free radical initiator immobilized on GO sheets is a better choice. We report a facile and effective strategy for preparing graphene peroxide (GPO) via the radiation-induced peroxidation of GO. The formation of peroxides on GO is proven by iodometric measurement and other characterizations. Using GPO as a polyfunctional initiating and cross-linking center, we obtained GO composite hydrogels exhibiting excellent mechanical properties, namely, very high tensile strength (0.2-1.2 MPa), extremely high elongations (2000-5300%), and excellent resilience. This work provides new insight into the fabrication of GO/polymer nanocomposites to fulfill the excellent mechanical properties of graphene. PMID- 22917016 TI - Resveratrol upregulates Nrf2 expression to attenuate methylglyoxal-induced insulin resistance in Hep G2 cells. AB - Oxidative stress can result in insulin resistance, a primary cause of type-2 diabetes. Methylglyoxal (MG), a highly reactive dicarbonyl metabolite generated during glucose metabolism, has also been confirmed to cause pancreatic injury and induce inflammation, thereby resulting in insulin resistance. Recently, resveratrol has been reported to exert antioxidant properties, protecting cells from the generation of reactive oxygen species (ROS). The aim of this study was to evaluate resveratrol activation of nuclear factor erythroid 2-related factor 2 (Nrf2) to attenuate MG-induced insulin resistance in Hep G2 cells. Therefore, the molecular signaling events affecting resveratrol-mediated heme oxygenase-1 (HO-1) and glyoxalase expression levels were further investigated in this study. Our findings indicated that resveratrol activated the extracellular signal-regulated kinase (ERK) pathway but not the p38 or c-Jun N-terminal kinase (JNK) pathways, subsequently leading to Nrf2 nuclear translocation and elevation of HO-1 and glyoxalase expression levels. Moreover, resveratrol significantly elevated glucose uptake and protected against MG-induced insulin resistance in Hep G2 cells. In contrast, depletion of Nrf2 by small interfering RNA (si-RNA) resulted in the abrogation of HO-1 and glyoxalase expression in the MG-treated resveratrol group in Hep G2 cells. Administration of an appropriate chemopreventive agent, such as resveratrol, may be an alternative strategy for protecting against MG induced diabetes. PMID- 22917017 TI - Pomalidomide and myeloma meningitis. PMID- 22917020 TI - Encapsulation and sensitization of UV-vis and near infrared lanthanide hydrate emitters for dual- and bimodal-emissions in both air and aqueous media based on a porous heteroatom-rich Cd(II)-framework. AB - A porous heteroatom-rich Cd(II)-polymeric framework which is generated from an ethylene glycol ether-bridging dicarboxylate ligand L, 4,4'-bipy and Cd(II) ion is reported. It contains one-dimensional tubes (9-11 A) which are able to trap cationic lanthanide hydrates such as Eu(H(2)O)(8)(3+), Tb(H(2)O)(8)(3+), and Nd(H(2)O)(8)(3+) under ambient conditions to generate Ln(H(2)O)(8)(3+)-loaded materials. In addition, the heteroatom-rich host material can effectively protect and sensitize the encapsulated Ln(3+) emitters in their hydrate form in both air and aqueous media. Furthermore, the dual- and bimodal-emissions are successfully realized by intercalation of the different Ln(3+)-hydrates based on a guest driven approach. PMID- 22917021 TI - Se-adenosyl-L-selenomethionine cofactor analogue as a reporter of protein methylation. AB - Posttranslational methylation by S-adenosyl-L-methionine(SAM)-dependent methyltransferases plays essential roles in modulating protein function in both normal and disease states. As such, there is a growing need to develop chemical reporters to examine the physiological and pathological roles of protein methyltransferases. Several sterically bulky SAM analogues have previously been used to label substrates of specific protein methyltransferases. However, broad application of these compounds has been limited by their general incompatibility with native enzymes. Here we report a SAM surrogate, ProSeAM (propargylic Se adenosyl-l-selenomethionine), as a reporter of methyltransferases. ProSeAM can be processed by multiple protein methyltransferases for substrate labeling. In contrast, sulfur-based propargylic SAM undergoes rapid decomposition at physiological pH, likely via an allene intermediate. In conjunction with fluorescent/affinity-based azide probes, copper-catalyzed azide-alkyne cycloaddition chemistry, in-gel fluorescence visualization and proteomic analysis, we further demonstrated ProSeAM's utility to profile substrates of endogenous methyltransferases in diverse cellular contexts. These results thus feature ProSeAM as a convenient probe to study the activities of endogenous protein methyltransferases. PMID- 22917023 TI - Detection limits of thin layer coulometry with ionophore based ion-selective membranes. AB - We report here on a significant improvement in lowering the low detection limit of thin layer coulometric sensors based on liquid ion-selective membranes, using a potassium-selective system as a model example. Various possible processes that may result in an elevated residual current reading after electrolysis were eliminated. Self-dissolution of AgCl on the Ag/AgCl inner element may result in a residual ion flux that could adversely affect the lower detection limit. It was here replaced with an Ag/AgI inner pseudoreference electrode where the self dissolution equilibrium is largely suppressed. Possible residual currents originating from a direct contact between inner element and ion-selective membranes were eliminated by introducing an inert PVDF separator of 50 MUm diameter that was coiled around the inner element by a custom-made instrument. Finally, the influence of electrolyte fluxes from the outer solution across the membrane into the sample was evaluated by altering its lipophilic nature and reducing its concentration. It was found that this last effect is most likely responsible for the observed residual current for the potassium-selective membranes studied here. For the optimized conditions, the calibration curves demonstrated a near zero intercept, thereby paving the way to the coulometric calibration-free sensing of ionic species. A linear calibration curve for the coulometric cell with valinomycin potassium-selective membrane was obtained in the range of 100 nM to 10 MUM potassium in the presence of a 10 MUM sodium background. In the presence of a higher (100 MUM) concentration of sodium, a reliable detection of 1-100 MUM of potassium was achieved. PMID- 22917022 TI - A method for the production of D-tagatose using a recombinant Pichia pastoris strain secreting beta-D-galactosidase from Arthrobacter chlorophenolicus and a recombinant L-arabinose isomerase from Arthrobacter sp. 22c. AB - BACKGROUND: D-Tagatose is a natural monosaccharide which can be used as a low calorie sugar substitute in food, beverages and pharmaceutical products. It is also currently being tested as an anti-diabetic and obesity control drug. D Tagatose is a rare sugar, but it can be manufactured by the chemical or enzymatic isomerization of D-galactose obtained by a beta-D-galactosidase-catalyzed hydrolysis of milk sugar lactose and the separation of D-glucose and D-galactose. L-Arabinose isomerases catalyze in vitro the conversion of D-galactose to D tagatose and are the most promising enzymes for the large-scale production of D tagatose. RESULTS: In this study, the araA gene from psychrotolerant Antarctic bacterium Arthrobacter sp. 22c was isolated, cloned and expressed in Escherichia coli. The active form of recombinant Arthrobacter sp. 22c L-arabinose isomerase consists of six subunits with a combined molecular weight of approximately 335 kDa. The maximum activity of this enzyme towards D-galactose was determined as occurring at 52 degrees C; however, it exhibited over 60% of maximum activity at 30 degrees C. The recombinant Arthrobacter sp. 22c L-arabinose isomerase was optimally active at a broad pH range of 5 to 9. This enzyme is not dependent on divalent metal ions, since it was only marginally activated by Mg2+, Mn2+ or Ca2+ and slightly inhibited by Co2+ or Ni2+. The bioconversion yield of D-galactose to D-tagatose by the purified L-arabinose isomerase reached 30% after 36 h at 50 degrees C. In this study, a recombinant Pichia pastoris yeast strain secreting beta-D-galactosidase Arthrobacter chlorophenolicus was also constructed. During cultivation of this strain in a whey permeate, lactose was hydrolyzed and D glucose was metabolized, whereas D-galactose was accumulated in the medium. Moreover, cultivation of the P. pastoris strain secreting beta-D-galactosidase in a whey permeate supplemented with Arthrobacter sp. 22c L-arabinose isomerase resulted in a 90% yield of lactose hydrolysis, the complete utilization of D glucose and a 30% conversion of D-galactose to D-tagatose. CONCLUSIONS: The method developed for the simultaneous hydrolysis of lactose, utilization of D glucose and isomerization of D-galactose using a P. pastoris strain secreting beta-D-galactosidase and recombinant L-arabinose isomerase seems to offer an interesting alternative for the production of D-tagatose from lactose-containing feedstock. PMID- 22917024 TI - Total synthesis of ripostatin A. AB - The first total synthesis of the bacterial RNA-polymerase inhibitor ripostatin A (1) was achieved. The route utilizes a cyclic methyl acetal intermediate and a sequence of a double Stille cross-coupling reaction followed by a ring-closing metathesis for the construction of the macrolactone ring. Additionally, an unprecedented formation of the 4-methoxy substituted tetrahydropyrans was observed during the acid catalyzed acetalization of the beta,delta dihydroxyketone. PMID- 22917026 TI - The primary cilium as a multiple cellular signaling scaffold in development and disease. AB - Primary cilia, single hair-like appendage on the surface of the most mammalian cells, were once considered to be vestigial cellular organelles for a past century because of their tiny structure and unknown function. Although they lack ancestral motility function of cilia or flagella, they share common ground with multiciliated motile cilia and flagella on internal structure such as microtubule based nine outer doublets nucleated from the base of mother centrioles called basal body. Making cilia, ciliogenesis, in cells depends on the cell cycle stage due to reuse of centrioles for cell division forming mitotic spindle pole (M phase) and assembling cilia from basal body (starting G1 phase and maintaining most of interphase). Ciliary assembly required two conflicting processes such as assembly and disassembly and balance between these two processes determines the length of cilia. Both process required highly conserved transport system to supply needed substance to grow tip of cilia and bring ciliary turnover product back to the base of cilia using motor protein, kinesin and dynein, and transport protein complex, IFT particles. Disruption of ciliary structure or function causes multiple human disorder called ciliopathies affecting disease of diverse ciliated tissues ranging from eye, kidney, respiratory tract and brain. Recent explosion of research on the primary cilia and their involvement on animal development and disease attracts scientific interest on how extensively the function of cilia related to specific cell physiology and signaling pathway. In this review, I introduce general features of primary cilia and recent progress in understanding of the ciliary length control and signaling pathways transduced through primary cilia in vertebrates. PMID- 22917025 TI - Physiopathology of intratendinous calcific deposition. AB - In calcific tendinopathy (CT), calcium deposits in the substance of the tendon, with chronic activity-related pain, tenderness, localized edema and various degrees of decreased range of motion. CT is particularly common in the rotator cuff, and supraspinatus, Achilles and patellar tendons. The presence of calcific deposits may worsen the clinical manifestations of tendinopathy with an increase in rupture rate, slower recovery times and a higher frequency of post-operative complications. The aetiopathogenesis of CT is still controversial, but seems to be the result of an active cell-mediated process and a localized attempt of the tendon to compensate the original decreased stiffness. Tendon healing includes many sequential processes, and disturbances at different stages of healing may lead to different combinations of histopathological changes, diverting the normal healing processes to an abnormal pathway. In this review, we discuss the theories of pathogenesis behind CT. Better understanding of the pathogenesis is essential for development of effective treatment modalities and for improvement of clinical outcomes. PMID- 22917027 TI - Human milk oligosaccharides: the novel modulator of intestinal microbiota. AB - Human milk, which nourishes the early infants, is a source of bioactive components for the infant growth, development and commensal formulation as well. Human milk oligosaccharide is a group of complex and diverse glycans that is apparently not absorbed in human gastrointestinal tract. Although most mammalian milk contains oligosaccharides, oligosaccharides in human milk exhibit unique features in terms of their types, amounts, sizes, and functionalities. In addition to the prevention of infectious bacteria and the development of early immune system, human milk oligosaccharides are able to facilitate the healthy intestinal microbiota. Bifidobacterial intestinal microbiota appears to be established by the unilateral interaction between milk oligosaccharides, human intestinal activity and commensals. Digestibility, membrane transportation and catabolic activity by bacteria and intestinal epithelial cells, all of which are linked to the structural of human milk oligosaccharides, are crucial in determining intestinal microbiota. PMID- 22917028 TI - Analysis and role of oligosaccharides in milk. AB - Milk is an important fluid in glycobiology because it contains a number of short carbohydrate chains either free or as glycoconjugates. These compounds as a class are the most abundant component and benefit the infant by developing and maintaining the infant's gut flora. New and emerging methods for oligosaccharide analysis have been developed to study milk. These methods allow for the rapid profiling of oligosaccharide mixtures with quantitation. With these tools, the role of oligosaccharide in milk is being understood. They further point to how oligosaccharide analysis can be performed, which until now has been very difficult and have lagged significantly those of other biopolymers. PMID- 22917029 TI - Functional roles of Tryptophan residues in diketoreductase from Acinetobacter baylyi. AB - Diketoreductase (DKR) from Acinetobacter baylyi contains two tryptophan residues at positions 149 and 222. Trp-149 and Trp-222 are located along the entry path of substrate into active site and at the dimer interface of DKR, respectively. Single and double substitutions of these positions were generated to probe the roles of tryptophan residues. After replacing Trp with Ala and Phe, biochemical and biophysical characteristics of the mutants were thoroughly investigated. Enzyme activity and substrate binding affinity of W149A and W149F were remarkably decreased, suggesting that Trp-149 regulates the position of substrate at the binding site. Meanwhile, enzyme activity of W222F was increased by 1.7-fold while W222A was completely inactive. In addition to lower thermostability of Trp-222 mutants, molecular modeling of the mutants revealed that Trp-222 is vital to protein folding and dimerization of the enzyme. PMID- 22917030 TI - Inhibition of glutamate dehydrogenase and insulin secretion by KHG26377 does not involve ADP-ribosylation by SIRT4 or deacetylation by SIRT3. AB - We investigated the mechanisms involved in KHG26377 regulation of glutamate dehydrogenase (GDH) activity, focusing on the roles of SIRT4 and SIRT3. Intraperitoneal injection of mice with KHG26377 reduced GDH activity with concomitant repression of glucose-induced insulin secretion. Consistent with their known functions, SIRT4 ribosylated GDH and reduced its activity, and SIRT3 deacetylated GDH, increasing its activity. However, KHG26377 did not affect SIRT4 mediated ADP-ribosylation/ inhibition or SIRT3-mediated deacetylation/activation of GDH. KHG26377 had no effect on SIRT4 protein levels, and did not alter total GDH, acetylated GDH, or SIRT3 protein levels in pancreatic mitochondrial lysates. These results suggest that the mechanism by which KHG26377 inhibits GDH activity and insulin secretion does not involve ADP-ribosylation of GDH by SIRT4 or deacetylation of GDH by SIRT3. PMID- 22917031 TI - MicroRNA let-7c inhibits Bcl-xl expression and regulates ox-LDL-induced endothelial apoptosis. AB - Endothelial cells (ECs) apoptosis induced by oxidized low-density lipoprotein (ox LDL) is thought to play a critical role in atherosclerosis. MicroRNAs (miRNAs) are a class of noncoding RNAs that posttranscriptionally regulate the expression of genes involved in diverse cell functions, including differentiation, growth, proliferation, and apoptosis. MiRNA let-7 family is known to be involved in the regulation of cell apoptosis. However, the function of let-7 in ox-LDL induced ECs apoptosis and atherosclerosis is still unknown. Here, we show that let-7c expression was markedly up-regulated in ox-LDL induced apoptotic human umbilical cord vein endothelial cells (HUVECs). Let-7c over-expression enhanced apoptosis in ECs whereas inhibition of let-7c could partly alleviate apoptotic cell death mediated by ox-LDL. Searching for how let-7c affected apoptosis, we discovered that antiapoptotic protein Bcl-xl was a direct target of let-7c in ECs. Our data suggest that let-7c contributes to endothelial apoptosis through suppression of Bcl-xl. PMID- 22917032 TI - The role of protein arginine-methyltransferase 1 in gliomagenesis. AB - Protein arginine methyltransferase 1 (PRMT1), a type-I arginine methyltransferase, has been implicated in diverse cellular events. We have focused on the role of PRMT1 in gliomagenesis. In this study, we showed that PRMT1 expression was up-regulated in glioma tissues and cell lines compared with normal brain tissues. The knock-down of PRMT1 resulted in an arrest in the G1-S phase of the cell cycle, proliferation inhibition and apoptosis induction in four glioma cell lines (T98G, U87MG, U251, and A172). Moreover, an in vivo study confirmed that the tumor growth in nude mouse xenografts was significantly decreased in the RNAi-PRMT1 group. Additionally, we found that the level of the asymmetric dimethylated modification of H4R3, a substrate of PRMT1, was higher in glioma cells than in normal brain tissues and decreased after PRMT1 knock-down. Our data suggest a potential role for PRMT1 as a novel biomarker of and therapeutic target in gliomas. PMID- 22917033 TI - Biochemical characterization of ferredoxin-NADP(+) reductase interaction with flavodoxin in Pseudomonas putida. AB - Flavodoxin (Fld) has been demonstrated to bind to ferredoxin- NADP(+) reductase A (FprA) in Pseudomonas putida. Two residues (Phe(256), Lys(259)) of FprA are likely to be important for interacting with Fld based on homology modeling. Sitedirected mutagenesis and pH-dependent enzyme kinetics were performed to further examine the role of these residues. The catalytic efficiencies of FprA Ala(259) and FprA-Asp(259) proteins were two-fold lower than those of the wild type FprA. Homology modeling also strongly suggested that these two residues are important for electron transfer. Thermodynamic properties such as entropy, enthalpy, and heat capacity changes of FprA-Ala(259) and FprA-Asp(259) were examined by isothermal titration calorimetry. We demonstrated, for the first time, that Phe(256) and Lys(259) are critical residues for the interaction between FprA and Fld. Van der Waals interactions and hydrogen bonding were also more important than ionic interactions for forming the FprA-Fld complex. PMID- 22917034 TI - Cyclosporine A and bromocriptine attenuate cell death mediated by intracellular calcium mobilization. AB - To identify the novel inhibitors of endoplasmic reticulum stress-induced cell death, we performed a high throughput assay with a chemical library containing a total of 3280 bioactive small molecules. Cyclosporine A and bromocriptine were identified as potent inhibitors of thapsigargiin-induced cell death (cut-off at 4sigma standard score) . However, U74389G, the potent inhibitor of lipid peroxidation had lower activity in inhibiting cell death. The inhibition effect of cyclosporine A and bromocriptine was specific for only thapsigargin-induced cell death. The mechanism of inhibition by these compounds was identified as modification of the expression of glucose regulated protein-78 (GRP-78/Bip) and inhibition of phosphorylation of p38 mitogen activated protein kinase (MAPK). However, these compounds did not inhibit the same events triggered by tunicamycin, which was in agreement with the cell survival data. We suggest that the induction of protective unfolded protein response by these compounds confers resistance to cell death. In summary, we identified compounds that may provide insights on cell death mechanisms stimulated by ER stress. PMID- 22917035 TI - Formation of amino acids and nucleotide bases in a Titan atmosphere simulation experiment. AB - The discovery of large (>100 u) molecules in Titan's upper atmosphere has heightened astrobiological interest in this unique satellite. In particular, complex organic aerosols produced in atmospheres containing C, N, O, and H, like that of Titan, could be a source of prebiotic molecules. In this work, aerosols produced in a Titan atmosphere simulation experiment with enhanced CO (N(2)/CH(4)/CO gas mixtures of 96.2%/2.0%/1.8% and 93.2%/5.0%/1.8%) were found to contain 18 molecules with molecular formulae that correspond to biological amino acids and nucleotide bases. Very high-resolution mass spectrometry of isotopically labeled samples confirmed that C(4)H(5)N(3)O, C(4)H(4)N(2)O(2), C(5)H(6)N(2)O(2), C(5)H(5)N(5), and C(6)H(9)N(3)O(2) are produced by chemistry in the simulation chamber. Gas chromatography-mass spectrometry (GC-MS) analyses of the non-isotopic samples confirmed the presence of cytosine (C(4)H(5)N(3)O), uracil (C(5)H(4)N(2)O(2)), thymine (C(5)H(6)N(2)O(2)), guanine (C(5)H(5)N(5)O), glycine (C(2)H(5)NO(2)), and alanine (C(3)H(7)NO(2)). Adenine (C(5)H(5)N(5)) was detected by GC-MS in isotopically labeled samples. The remaining prebiotic molecules were detected in unlabeled samples only and may have been affected by contamination in the chamber. These results demonstrate that prebiotic molecules can be formed by the high-energy chemistry similar to that which occurs in planetary upper atmospheres and therefore identifies a new source of prebiotic material, potentially increasing the range of planets where life could begin. PMID- 22917036 TI - Insights into the extremotolerance of Acinetobacter radioresistens 50v1, a gram negative bacterium isolated from the Mars Odyssey spacecraft. AB - The microbiology of the spacecraft assembly process is of paramount importance to planetary exploration, as the biological contamination that can result from remote-enabled spacecraft carries the potential to impact both life-detection experiments and extraterrestrial evolution. Accordingly, insights into the mechanisms and range of extremotolerance of Acinetobacter radioresistens 50v1, a Gram-negative bacterium isolated from the surface of the preflight Mars Odyssey orbiter, were gained by using a combination of microbiological, enzymatic, and proteomic methods. In summary, A. radioresistens 50v1 displayed a remarkable range of survival against hydrogen peroxide and the sequential exposures of desiccation, vapor and plasma phase hydrogen peroxide, and ultraviolet irradiation. The survival is among the highest reported for non-spore-forming and Gram-negative bacteria and is based upon contributions from the enzyme-based degradation of H(2)O(2) (catalase and alkyl hydroperoxide reductase), energy management (ATP synthase and alcohol dehydrogenase), and modulation of the membrane composition. Together, the biochemical and survival features of A. radioresistens 50v1 support a potential persistence on Mars (given an unintended or planned surface landing of the Mars Odyssey orbiter), which in turn may compromise the scientific integrity of future life-detection missions. PMID- 22917037 TI - Self-compassion and fear of self-compassion interact to predict response to eating disorders treatment: a preliminary investigation. AB - Gilbert (2005) proposed that the capacity for self-compassion is integral to overcoming shame and psychopathology. We tested this model among 74 individuals with an eating disorder admitted to specialized treatment. Participants completed measures assessing self-compassion, fear of self-compassion, shame, and eating disorder symptoms at admission and every 3 weeks during treatment. At baseline, lower self-compassion and higher fear of self-compassion were associated with more shame and eating disorder pathology. Multilevel modeling also revealed that patients with combinations of low self-compassion and high fear of self compassion at baseline had significantly poorer treatment responses, showing no significant change in shame or eating disorder symptoms over 12 weeks. Results highlight a new subset of treatment-resistant eating disorder patients. PMID- 22917038 TI - [Investigation of coagulation time: PT and APTT]. AB - The first case report describes an extremely prolonged activated partial thromboplastin time (APTT) in a patient with no history of increased bleeding tendency. Heparin use was excluded. The APTT mixing study combined with the medical history suggests a deficiency in one of the non-essential coagulation factors. This was confirmed by factor XII activity of <1%. The second case report describes a prolonged APTT in a patient with no history of increased bleeding tendency. The negative bleeding tendency in combination with a failure of the mixing study to correct the coagulation assay results suggests a factor inhibitor, most probably lupus anticoagulant. Indeed, the lupus anticoagulant was positive and the anti-cardiolipin antibody titre was also positive. Aberrations in the process of haemostasis can be efficiently screened using a platelet count, an APTT, a PT and a thorough physical examination combined with a thorough medical history taking. Common causes of prolonged PT and/or APTT are the use of oral anticoagulants or heparin, vitamin K deficiency and liver disease. Other causes include coagulation factor deficiencies, coagulation factor inhibitors and diffuse intravascular coagulation. PMID- 22917039 TI - [Summary of NHG practice guideline 'Acute cough']. AB - Coughing is usually caused by an uncomplicated respiratory tract infection for which antibiotics are not useful. Noscapine and codein are not advised. When the risk of complications is increased (because of age or relevant comorbidity), the decision to prescribe an antibiotic is based on the clinical presentation and any necessary additional investigations. Determination of the CRP value can assist in differentiating between pneumonia and a mild lower respiratory tract infection in moderately sick adults with several general and/or local symptoms. Patients with pneumonia should be prescribed antibiotics. Because of increasing resistance to doxycycline and macrolides, amoxicillin is the drug of first choice, and doxycycline of second choice. In the case of increased risk of severe pneumonia due to Coxiella burnetii (Q-fever) or Legionella, doxycycline remains first choice. In the case of whooping cough, additional investigation is advised if there are infants or third trimester pregnant women in the immediate environment. In moderately severe croup a single dose of glucocorticoids should be given; children with severe croup should be referred to a paediatrician. PMID- 22917041 TI - Invited commentary. PMID- 22917040 TI - A nationwide study on reproductive function, ovarian reserve, and risk of premature menopause in female survivors of childhood cancer: design and methodological challenges. AB - BACKGROUND: Advances in childhood cancer treatment over the past decades have significantly improved survival, resulting in a rapidly growing group of survivors. However, both chemo- and radiotherapy may adversely affect reproductive function. This paper describes the design and encountered methodological challenges of a nationwide study in the Netherlands investigating the effects of treatment on reproductive function, ovarian reserve, premature menopause and pregnancy outcomes in female childhood cancer survivors (CCS), the DCOG LATER-VEVO study. METHODS: The study is a retrospective cohort study consisting of two parts: a questionnaire assessing medical, menstrual, and obstetric history, and a clinical assessment evaluating ovarian and uterine function by hormonal analyses and transvaginal ultrasound measurements. The eligible study population consists of adult female 5-year survivors of childhood cancer treated in the Netherlands, whereas the control group consists of age matched sisters of the participating CCS. To date, study invitations have been sent to 1611 CCS and 429 sister controls, of which 1215 (75%) and 333 (78%) have responded so far. Of these responders, the majority consented to participate in both parts of the study (53% vs. 65% for CCS and sister controls respectively). Several challenges were encountered involving the study population: dealing with bias due to the differences in characteristics of several types of (non-) participants and finding an adequately sized and well-matched control group. Moreover, the challenges related to the data collection process included: differences in response rates between web-based and paper-based questionnaires, validity of self-reported outcomes, interpretation of clinical measurements of women using hormonal contraceptives, and inter- and intra-observer variation of the ultrasound measurements. DISCUSSION: The DCOG LATER-VEVO study will provide valuable information about the reproductive potential of paediatric cancer patients as well as long-term survivors of childhood cancer. Other investigators planning to conduct large cohort studies on late effects may encounter similar challenges as those encountered during this study. The solutions to these challenges described in this paper may be useful to these investigators. TRIAL REGISTRATION: NTR2922; http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=2922 PMID- 22917042 TI - Invited commentary. PMID- 22917043 TI - Bioengineered vascular access maintains structural integrity in response to arteriovenous flow and repeated needle puncture. AB - OBJECTIVE: Tissue-engineered blood vessels (TEBV) have been proposed as an alternative to prosthetic grafts for dialysis access. However, arteriovenous (AV) grafts must withstand extreme flow rates and frequent needle trauma. In a proof of-concept study, we sought to determine whether scaffold-based TEBV could withstand the hemodynamic and mechanical challenges of chronic dialysis access. METHODS: TEBV were constructed using decellularized arterial scaffolds seeded with autologous ovine endothelial cells (EC) derived from circulating endothelial progenitor cells (EPC) using a novel high-affinity capture approach. Seeded scaffolds were preconditioned to arterial pressure and flow in a bioreactor for 2 weeks prior to implantation to create carotid artery to jugular vein AV grafts in each animal. TEBV were healed for 1 month before initiating percutaneous needle puncture 3 days/week. TEBV wall geometry and patency were monitored using duplex imaging and were either explanted for histologic analysis at 2 months (n = 5) or followed for up to 6 months until venous outflow stenosis threatened AV graft patency (n = 6). RESULTS: Despite high flow, TEBV maintained stable geometry with only modest wall dilation (under 6%) by 4 months after implantation. Needle access was well tolerated with a single puncture site complication, a small pseudoaneurysm, occurring in the late group. Time-to-hemostasis at puncture sites averaged 4 +/- 2 minutes. Histologic analysis at 2 months demonstrated repopulation of the outer TEBV wall by host cells and healing of needle punctures by cellular ingrowth and new matrix deposition along the tract. TEBV followed beyond 2 months showed stable wall geometry but, consistent with the primary mode of clinical AV graft failure, all TEBV eventually developed venous anastomotic stenosis (mean, 4.4 +/- 0.9 months; range, 3.3-5.6 months postimplantation; n = 6). CONCLUSIONS: This pilot study supports the concept of creating dialysis access from scaffold-based autologous TEBV. Engineered AV grafts were created within a clinically relevant time frame and demonstrated stable wall geometry despite high flow and repeated puncture. Cellular ingrowth and puncture site healing may improve wall durability, but venous outflow stenosis remains the primary mode of TEBV graft failure in the ovine model. PMID- 22917044 TI - Invited commentary. PMID- 22917045 TI - Takayasu's arteritis and the utility of magnetic resonance imaging. PMID- 22917046 TI - Accidental introduction of a peel-away sheath during endovascular repair of an infrarenal abdominal aortic aneurysm. PMID- 22917047 TI - A contemporary perspective of the first aphorism of Hippocrates. PMID- 22917049 TI - Regarding "Remote and local ischemic preconditioning equivalently protects rat skeletal muscle mitochondrial function during experimental aortic cross clamping". PMID- 22917051 TI - Regarding "Factors affecting career choice among the next generation of academic vascular surgeons". PMID- 22917053 TI - Regarding "Long-term incidence of myocardial infarct, stroke, and mortality in patients operated on for abdominal aortic aneurysms". PMID- 22917055 TI - Regarding "Cost implications of more widespread carotid artery stenting consistent with the American College of Cardiology/American Heart Association guideline". PMID- 22917056 TI - Layered titanium disilicide stabilized by oxide coating for highly reversible lithium insertion and extraction. AB - The discovery of new materials has played an important role in battery technology development. Among the newly discovered materials, those with layered structures are often of particular interest because many have been found to permit highly repeatable ionic insertion and extraction. Examples include graphite and LiCoO(2) as anode and cathode materials, respectively. Here we report C49 titanium disilicide (TiSi(2)) as a new layered anode material, within which lithium ions can react with the Si-only layers. This result is enabled by the strategy of coating a thin (<5 nm) layer of oxide on the surface of TiSi(2). This coating helped us rule out the possibility that the measured capacity is due to surface reactions. It also stabilizes TiSi(2) to allow for the direct observation of TiSi(2) in its lithiated and delithiated states. In addition, this stabilization significantly improved the charge and discharge performance of TiSi(2). The confirmation that the lithium-ion storage capacity of TiSi(2) is a result of its layered structure is expected to have major fundamental and practical implications. PMID- 22917057 TI - Rpb4 and Rpb7: multifunctional subunits of RNA polymerase II. AB - The 12-subunit RNA polymerase II enzyme in yeasts and higher eukaryotic cells is important for transcription of protein-coding genes. Its fourth and seventh largest subunits named Rpb4 and Rpb7, respectively, display some unique features that distinguish them from the remaining subunits of this enzyme. These two subunits also bind to each other forming a complex in archaebacteria, yeasts, plants and humans. Our knowledge about the structure and functions of this complex has greatly advanced in recent years. These subunits were initially considered to be important only for initiation of transcription and stress response. However, recent evidence suggests that they are not only involved in transcription, but also in DNA repair, mRNA export and decay as well as translation, highlighting the roles of this heterodimer in diverse biological processes. In this article, we review the current status of these two subunits and discuss attributes of their structure and function across organisms. PMID- 22917058 TI - Antioxidant profile and in vitro cardiac radical-scavenging versus pro-oxidant effects of commercial red grape juices ( Vitis vinifera L. cv. Aglianico N.). AB - Several works have reported on the pharmaceutical usefulness of grape phytochemicals. Nevertheless, the scientific literature needs further studies to consider grape extracts as useful dietary supplements. The aim of the present work was to hypothesize for the first time the use of whole commercial red grape juices as food supplements potentially useful against both physiological and induced cardiac oxidative stress. First of all, the results indicated a good antioxidant stability of the juice sample to lyophilization that may be reasonably regarded as a suitable process for the formulation of food supplements. Then, the processed sample (lioRGJ) was tested on cardiac-derived H9C2 myocytes to ascertain its effects on reactive oxygen species (ROS) generation and caspase-3 activity incubating cardiomyocytes with lioRGJ at increasing doses (0.01-1 MUg). Experiments showed an appreciable direct radical scavenging activity at a maximum sample dose of 0.01 MUg that made the caspase-3 activity decrease by about 47% (P < 0.001). Cardiac cells were exposed to 1 MUM doxorubicin and its combination with different doses of lioRGJ. A maximum sample aliquot of 0.01 MUg seemed to effectively contrast the induced oxidant injury, decreasing the ROS levels by about 31% and depressing the caspase-3 activity by about 60% (P < 0.001). In both assays, pro-oxidant effects at higher sample concentrations were detected as indicated by the increase in both ROS generation and apoptotic activity. The data suggested the possible employment of the juice sample as a food supplement with prospective cardioprotective benefits, although further studies are needed to optimize its dosages to avoid harmful pro-oxidant effects. PMID- 22917059 TI - 5-HT2 ligands in the treatment of anxiety and depression. AB - INTRODUCTION: One third of depressed patients do not respond adequately to conventional antidepressants including the selective serotonin reuptake inhibitors (SSRIs). Therefore, multi-target drugs or augmentation strategies have been developed for the management of SSRIs-resistant patients. In this context, the 5-HT(2) receptor subtypes represent promising targets but their precise roles have yet to be determined. AREAS COVERED: The aim of this review is to shed some light on the preclinical evidence supporting the use of 5-HT(2A) and/or 5-HT(2C) receptor antagonists such as antipsychotics, as potential effective adjuncts in SSRIs-resistant depression. This review synthesizes the current literature about the behavioral, electrophysiological and neurochemical effects of 5-HT(2) receptors ligands on the monoaminergic systems but also on adult hippocampal neurogenesis. EXPERT OPINION: Although studies support the hypothesis that the inactivation of 5-HT(2A) and/or 5-HT(2C) receptors might be of interest to reinforce different facets of the therapeutic activity of SSRIs, this pharmacological strategy remains debatable notably because of the lack of chronic data in relevant animal models. Conversely, emerging evidence suggests that the activation of 5-HT(2B) receptor is required for antidepressant-like activity, opening the way to new therapeutic approaches. However, the potential risks related to the enhancement of monoaminergic neurotransmissions could represent a major concern. PMID- 22917060 TI - Absolute configuration of atropisomeric polychlorinated biphenyl 183 enantiomerically enriched in human samples. AB - Polychlorinated biphenyls (PCBs) are still of serious concern as a potential health hazard due to their persistency and bioacumulation. Of 209 possible PCB congeners, with varying number and position of chlorine atom(s), 19 are chiral. These are mostly highly chlorinated and tend to remain longer against the biological decompositions, suffering biological deracemization in the environment. In this work, we have unequivocally determined the absolute configurations of important chiral PCBs 183 and 171, as well as 132, through the combined theoretical and experimental investigations of the chiroptical properties (circular dichroism and optical rotation), which will be valuable in elucidating the mechanism of biological enantiomer enrichment of PCBs in the environment. PMID- 22917061 TI - Well-defined cholesterol polymers with pH-controlled membrane switching activity. AB - Cholesterol has been used as an effective component of therapeutic delivery systems because of its ability to cross cellular membranes. Considering this, well-defined copolymers of methacrylic acid and cholesteryl methacrylate, poly(methacrylic acid-co-cholesteryl methacrylate) P(MAA-co-CMA), were generated as potential delivery system components for pH-controlled intracellular delivery of therapeutics. Statistical copolymers with varying cholesterol contents (2, 4, and 8 mol %) were synthesized via reversible addition-fragmentation chain transfer (RAFT) polymerization. Dynamic light scattering (DLS) analysis showed that the hydrodynamic diameters of the copolymers in aqueous solutions ranged from 5 +/- 0.3 to 7 +/- 0.4 nm for the copolymers having 2 and 4 mol % CMA and 8 +/- 1.1 to 13 +/- 1.9 nm for the copolymer having 8 mol % CMA with increasing pH (pH 4.5-7.4). Atomic force microscopy (AFM) analysis revealed that the copolymer having 8 mol % CMA formed supramolecular assemblies while the copolymers having 2 and 4 mol % CMA existed as unimers in aqueous solution. The pH-responsive behavior of the copolymers was investigated via UV-visible spectroscopy revealing phase transitions at pH 3.9 for 2 mol % CMA, pH 4.7 for 4 mol % CMA, and pH 5.4 for 8 mol % CMA. Lipid bilayers and liposomes as models for cellular membranes were generated to probe their interactions with the synthesized copolymers. The interactions were determined in a pH-dependent manner (at pH 5.0 and 7.4) using surface plasmon resonance (SPR) spectroscopy and liposome leakage assay. Both the SPR analyses and liposome leakage assays indicated that the copolymer containing 2 mol % CMA displayed the greatest polymer-lipid interactions at pH 5.0, presenting the highest binding ability to the lipid bilayer surfaces, and also demonstrating the highest membrane destabilization activity. CellTiter-Blue assay showed that the copolymers did not affect the cell viability up to 30 MUM over a period of 72 h. PMID- 22917062 TI - An open real-time tele-stethoscopy system. AB - BACKGROUND: Acute respiratory infections are the leading cause of childhood mortality. The lack of physicians in rural areas of developing countries makes difficult their correct diagnosis and treatment. The staff of rural health facilities (health-care technicians) may not be qualified to distinguish respiratory diseases by auscultation. For this reason, the goal of this project is the development of a tele-stethoscopy system that allows a physician to receive real-time cardio-respiratory sounds from a remote auscultation, as well as video images showing where the technician is placing the stethoscope on the patient's body. METHODS: A real-time wireless stethoscopy system was designed. The initial requirements were: 1) The system must send audio and video synchronously over IP networks, not requiring an Internet connection; 2) It must preserve the quality of cardiorespiratory sounds, allowing to adapt the binaural pieces and the chestpiece of standard stethoscopes, and; 3) Cardiorespiratory sounds should be recordable at both sides of the communication. In order to verify the diagnostic capacity of the system, a clinical validation with eight specialists has been designed. In a preliminary test, twelve patients have been auscultated by all the physicians using the tele-stethoscopy system, versus a local auscultation using traditional stethoscope. The system must allow listen the cardiac (systolic and diastolic murmurs, gallop sound, arrhythmias) and respiratory (rhonchi, rales and crepitations, wheeze, diminished and bronchial breath sounds, pleural friction rub) sounds. RESULTS: The design, development and initial validation of the real-time wireless tele-stethoscopy system are described in detail. The system was conceived from scratch as open-source, low cost and designed in such a way that many universities and small local companies in developing countries may manufacture it. Only free open-source software has been used in order to minimize manufacturing costs and look for alliances to support its improvement and adaptation. The microcontroller firmware code, the computer software code and the PCB schematics are available for free download in a subversion repository hosted in SourceForge. CONCLUSIONS: It has been shown that real-time tele-stethoscopy, together with a videoconference system that allows a remote specialist to oversee the auscultation, may be a very helpful tool in rural areas of developing countries. PMID- 22917063 TI - Squaring the circle in peptide assembly: from fibers to discrete nanostructures by de novo design. AB - The design of bioinspired nanostructures and materials of defined size and shape is challenging as it pushes our understanding of biomolecular assembly to its limits. In such endeavors, DNA is the current building block of choice because of its predictable and programmable self-assembly. The use of peptide- and protein based systems, however, has potential advantages due to their more-varied chemistries, structures and functions, and the prospects for recombinant production through gene synthesis and expression. Here, we present the design and characterization of two complementary peptides programmed to form a parallel heterodimeric coiled coil, which we use as the building blocks for larger, supramolecular assemblies. To achieve the latter, the two peptides are joined via peptidic linkers of variable lengths to produce a range of assemblies, from flexible fibers of indefinite length, through large colloidal-scale assemblies, down to closed and discrete nanoscale objects of defined stoichiometry. We posit that the different modes of assembly reflect the interplay between steric constraints imposed by short linkers and the bulk of the helices, and entropic factors that favor the formation of many smaller objects as the linker length is increased. This approach, and the resulting linear and proteinogenic polypeptides, represents a new route for constructing complex peptide-based assemblies and biomaterials. PMID- 22917065 TI - Synthesis and assignment of the absolute configuration of indenotryptoline bisindole alkaloid BE-54017. AB - Synthesis of the indenotryptoline bisindole alkaloid, BE-54017, was accomplished using osmium-promoted cis-dihydroxylation of maleimide as a key step. After optical resolution, the absolute configuration of this molecule was determined by comparing its optical rotation and HPLC profile to those obtained for BE-54017 derived from enantiopure cladoniamide A, whose stereochemistry has been reported previously. BE-54017 with the correct absolute stereochemistry induced apoptosis of epidermal growth factor (EGF)-stimulated EGF receptor overexpressing A431 cells and inhibited vacuolar-type H(+)-ATPase (V-ATPase). PMID- 22917066 TI - [Achievements and challenges: an editorial management report]. PMID- 22917064 TI - Simultaneous RNA quantification of human and retroviral genomes reveals intact interferon signaling in HTLV-1-infected CD4+ T cell lines. AB - BACKGROUND: IFN-alpha contributes extensively to host immune response upon viral infection through antiviral, pro-apoptotic, antiproliferative and immunomodulatory activities. Although extensively documented in various types of human cancers and viral infections, controversy exists in the exact mechanism of action of IFN-alpha in human immunodeficiency virus type 1 (HIV-1) and human T lymphotropic virus type 1 (HTLV-1) retroviral infections. RESULTS: IFN-alpha displayed strong anti-HIV-1 effects in HIV-1/HTLV-1 co-infected MT-4 cells in vitro, demonstrated by the dose-dependent inhibition of the HIV-1-induced cytopathic effect (IC50 = 83.5 IU/ml, p < 0.0001) and p24 levels in cell-free supernatant (IC50 = 1.2 IU/ml, p < 0.0001). In contrast, IFN-alpha treatment did not affect cell viability or HTLV-1 viral mRNA levels in HTLV-1 mono-infected cell lines, based on flow cytometry and nCounter analysis, respectively. However, we were able to confirm the previously described post-transcriptional inhibition of HTLV-1 p19 secretion by IFN-alpha in cell lines (p = 0.0045), and extend this finding to primary Adult T cell Leukemia patient samples (p = 0.031). In addition, through microarray and nCounter analysis, we performed the first genome wide simultaneous quantification of complete human and retroviral transciptomes, demonstrating significant transcriptional activation of interferon-stimulated genes without concomitant decrease of HTLV-1 mRNA levels. CONCLUSIONS: Taken together, our results indicate that both the absence of in vitro antiproliferative and pro-apoptotic activity as well as the modest post transcriptional antiviral activity of IFN-alpha against HTLV-1, were not due to a cell-intrinsic defect in IFN-alpha signalisation, but rather represents a retrovirus-specific phenomenon, considering the strong HIV-1 inhibition in co infected cells. PMID- 22917067 TI - [Placental lesions in teenager's pregnancies of a public hospital of Argentina]. AB - INTRODUCTION: In Argentina, 18.3% of all births are related to adolescent mothers. Adolescent pregnancy has been associated with an increase of adverse perinatal outcomes. Placental examination helps to identify etiology and predict recurrence of perinatal pathologies. The aim of this study was to describe placental weight and placental lesions and to estimate the risks of adolescent pregnancies compared with young adults mothers. METHODS: We examined 50 placentas from adolescent mothers (greater than 16 yrs, n = 18 and 17-19 yrs, n = 32) and 101 placentas from adults mothers between 20 and 29 years old attending the Sarda' Maternity Hospital of Buenos Aires, Argentina. Conventional methods were used for macroscopic and histological examination. RESULTS: No differences were found in placental weights. In half of examined placenta one or more lesions were present, predominantly in adolescents (p = 0.327). In greater than 16 ys placental lesions represented 77.78 % (14/18, 95% CI 54 - 91), in older teenagers 34.3% (11/32, 95% CI 20 - 51) (OR 2.26, 95% CI 1.32 - 3.38, p = 0.003), whereas in young adults figure was 41.5% (42/101, [95% CI 32 - 51]), a 1.87 (IC 95% 1.33 2.62, p = 0.004) and 0.83 (IC 95% 0.49 - 1.41, p = 0.469) crude risks of both adolescents' groups compared with adults, respectively. Adjusted risk for placental lesions was four folds higher in adolescent at or below 16 years (p = 0.018). CONCLUSIONS: No differences were found in placental weights Younger teenagers (<= 16 year age) have an increased risk for having placental lesions. PMID- 22917068 TI - [Prescription errors in a neonatal intensive care unit from Buenos Aires]. AB - BACKGROUND: Although error could be present in almost every medical practice, they are more frequent and potentially more dangerous in neonatal intensive care units (NICU). OBJECTIVE: To determine prescription error rate of intravenous drugs in a Neonatal Intensive Care Unit (NICU), and to describe type of error (dose, dilution, and interval) and medication (antibiotics, inotropics, or analgesics). METHODS: Observational study including medical records of patients hospitalized in a NICU, receiving any of the above mentioned drugs. Each prescription was compared with one provided by a specific software. Prescription error was defined as >10% of difference between both values. RESULTS: 362 prescriptions from 82 patients were analyzed. An error was observed in 42.5% (95%CI 37.4 - 47.8) of all prescriptions, including 148 (96.1%; 95%CI: 91.3-98.4) antibiotics prescriptions, 5 (3.2%; 95%CI: 1.2-7.7) inotropics prescriptions and 1 (0.7%; 95%CI: 0.01-4.2) analgesics prescriptions. Prescription errors were due to frequency error in 53.8% 95%CI: 45.6-61.8 of cases and to volume error in 46.1% (95%CI: 38.1-54.3). CONCLUSION: Almost half of the intravenous drugs prescriptions included an error, being more frequently related to interval, followed by dosing; no errors in dilution were detected. Using prescription software could improve patient's safety. PMID- 22917069 TI - [Effects of anticoagulants on the immunological synapses of human autologous rosettes between macrophage and lymphocyte]. PMID- 22917070 TI - [Importance of the information systems in public health programs: diabetic patients databases]. AB - AIMS: To describe the characteristics of diabetic patients' population attended in the public health sector of Alta Gracia city. To analyze the use of amount of monthly dispensations as indicator of adherence to treatment, by comparing the results between settings. To assess the coordination of public facilities for patients attention. DESIGN: observational descriptive-analytical study. SETTINGS: Hospital Arturo Umberto Illia (HAUI) and Direccion de Salud Publica (DSP). Alta Gracia (province of Cordoba, Argentina). SUBJECTS: diabetic patients belonging to health programs at public facilities. MAIN MEASURES: demographic and epidemiological variables, amount of monthly dispensations, percentage of global adherence and coordination of settings. RESULTS: From diabetic patients' total (n=540): 52% were attended at HAUI, 39% at DSP, and 9% at both settings; 55% were female, and the average age was about 56 years old; 81% were type 2 Diabetes Mellitus (DM), 1% type 2 insulin-requiring DM, and 17% type 1 DM; the general mean of amount of monthly dispensations by patient was 4,9 in 12 months. Lack of trained personnel for information managing in both facilities was observed. CONCLUSIONS: The databases allowed knowing some demographic characteristics of diabetic population attended in the public sector of Alta Gracia. The dispensing frequency during 12 months was able to be used as an adherence to treatment indicator. The scarce coordination between care levels and jurisdictions (provincial and municipal) were confirmed. For decision making it is necessary to generate and maintain information systems. PMID- 22917071 TI - [Predictive models for complex diseases]. AB - The Non Communicable Complex Disease (NCCD) are the leading causes of death in the world, causing more deaths each year than all other combined causes. The approximately 80% of deaths were caused by NCCD and occured in low and middle income countries. However, NCCD deaths could be avoided by prevention programs and early diagnosis. The challenge of the multifactorial phenotypes is to achieve a valid strategy for identifying risk individuals at the population. These strategies may be addressed to screening population or generating causal predictive models for early detection, interpreting the root causes that create the condition. The aim of this paper is to describe the characteristic of complex chronic diseases and some of the current methods of study of these in the health area . CONCLUSIONS: Interdisciplinary work, a team of health professionals belonging to different areas allows for an adequate management of complex diseases. The application of graph models, such as DAG's, is a valuable tool for a better adjustment of the statistical model, which allows an appropriate correspondence with the actual health model of these illnesses. And the best methodological strategy for complex diseases is the early diagnosis and the monitoring of risk groups and therapy monitoring of patients diagnosed. PMID- 22917072 TI - [Chronic eosinophilic pneumonia]. AB - Chronic eosinophilic pneumonia. The chronic eosinophilic pneumonia is part of Pulmonary Eosinophilic Syndroms. It is presented a 33-years old man, Asmathic, with dry cough, fever, night sweats and fatigue of several weeks. The chest X-ray showed opacity in the right hemithorax. He was treated with antibiotics without response. A chest TC showed multifocal involvement. The patient refused bronchoalveolar lavage (BAL) so treatment antituberculostatic was started. Despite treatment the symptoms worsened. The Chest X-ray showed migration of the infiltrates and the blood smear marked eosinophilia. Finally, bronchoalveolar lavage was carried out and it showed a high percentage of eosinophils (over 50%). The patient was treated with inmmunosuppresive doses of corticosteroids with excellent response. The blood smear in Nonresolving pneumonia is key to consider eosinophilic pneumonia, an uncommon pathology but amenable to treatment. PMID- 22917073 TI - [Cryptococcal meningitis as initial presentation of systemic lupus erythematosus]. AB - INTRODUCTION: Infection is one of the most frequent etiology of morbidity and mortality in patients with systemic lupus erythematosus (SLE). Cryptococcal meningitis is a recognized complication of SLE with high mortality rates in those treated with immunosuppressive agents. We describe a patient with cryptoccoccal meningitis and SLE. This case suggests that intrinsic immunological abnormality related to SLE predisposed to opportunistic infections. CLINICAL CASE: A 25 years old woman was admitted because of Pelvic Inflammatory Disease. She had ascitis and abdominal pain and neurological examination was normal.. Laboratory findings showed mild anemia, leukocytes: 6350/mm(3). Total lymphocytes: 508/mm(3) (CD4 +: 75 cel/mm(3)). Erythrocyte sedimentation rate (ESR): 40mm/h, Coombs test (+). Abdominal CT scan showed ascites and pleural bilateral effusion. Two days after her admission, VDRL test was positive ( 1/64). Lumbar puncture was done and the r cerebrospinal fluid showed: normal glucose and protein level with normal cells. Fungi elements were found and Cryptococcus neoformans were identified. She received Anfotericin B treatment. HIV and TPHA test were negative. Antinuclear and anti-ds-DNA were positive in high levels and low levels of complement were found. Methylprednisolone pulses were s administered intravenously for three days. Cerebrospinal fluid was normal after 10 weeks of antifungical treatment. PMID- 22917074 TI - [Primary hydatid disease of the tibia. case report]. AB - Hydatidosis is an endemic disease in different parts of the world. Its causal agent is the cestode from the genus Echinococcus. The most commonly affected organs in humans are liver and lung. Bone hydatid disease is a very rare entity, accounting for 0.5 to 4% of total cases. We report a case of a 58 year-old woman from La Rioja, Argentina, who consulted for left infapatellar pain and walking disability of eight months duration. Imaging studies showed a cystic lesion which involved metaphysis and diaphysis of left proximal tibia. Surgical resection was performed and histopathological study confirmed that it was a hydatid cyst. The patient did well and completed three cycles of treatment with albendazole. Currently, she has no evidence of disease and she recovered motility of her left leg. Primary hydatid bone disease, where there is no evidence of systemic disease, is even more unusual. Tibia involvement occurs in up to 15% of the cases. These lesions clinically manifest when they suffer any type of complications. Preoperative diagnosis is mainly made by imaging studies. Lesions are usually osteolytic and can involve cortical bone and extend to soft tissues. Differential diagnosis with inflammatory processes and bone tumors should is mandatory. Treatment is surgical and prognosis is poor due to its high morbi mortality rate and recurrence risk from 70 to 80%. PMID- 22917075 TI - Sheep cheese naturally enriched in alpha-linolenic, conjugated linoleic and vaccenic acids improves the lipid profile and reduces anandamide in the plasma of hypercholesterolaemic subjects. AB - Intake of dairy fat has long been considered as a risk factor for CVD. Pasture and dietary lipid supplementation have been reported to be reliable strategies in ruminant nutrition, in order to increase the content of alpha-linolenic acid (ALA), conjugated linoleic acid (CLA) and vaccenic acid (VA), and decrease SFA in milk fat. In the present study, we aimed at verifying whether consumption of a sheep cheese, naturally enriched in ALA, CLA and VA, would modify the plasma lipid and endocannabinoid profiles in mildly hypercholesterolaemic subjects. A total of forty-two adult volunteers (nineteen males and twenty-three females) with diagnosed mildly hypercholesterolaemia (total cholesterol 5.68-7.49 mmol/l) were randomly assigned to eat 90 g/d of a control or enriched cheese for 3 weeks, with a cross-over after 3 weeks of washout. Plasma lipids, endocannabinoids, adipokines and inflammatory markers were measured. The intake of enriched cheese significantly increased the plasma concentrations of CLA, VA, the n-3 fatty acids ALA and EPA, and more remarkably decreased that of the endocannabinoid anandamide. LDL-cholesterol decreased significantly (7%). No changes were detected in the levels of inflammatory markers; however, a significant correlation was found between the plasma levels of anandamide and leptin. The control cheese modified none of the parameters measured. The results obtained do not support the view that intake of dairy fat is detrimental to hypercholesterolaemic subjects. Indeed, they show that a naturally enriched cheese possesses beneficial properties, since it ameliorates the plasma lipid profile, and more remarkably reduces endocannabinoid biosynthesis. PMID- 22917079 TI - Cell death and cytokine production induced by autoimmunogenic hydrocarbon oils. AB - Hydrocarbon oils such as pristane or hexadecane induce arthritis and lupus in rodents sharing clinical and pathological features with the human diseases rheumatoid arthritis and systemic lupus erythematosus, respectively. In pristane induced lupus in the mouse induction of apoptosis and augmentation of type-I Interferon signalling by pristane have been suggested to contribute to pathology, whereas in pristane-induced arthritis (PIA) in the rat the pathological mechanisms are still elusive. Here we show that pristane induces cell death in rat and human cells. Increased numbers of apoptotic cells were found in draining lymph nodes of pristane-injected rats and increased percentages of apoptotic and necrotic cells were observed in peripheral blood. In addition, neutrophil extracellular trap formation was triggered by pristane and hexadecane in neutrophils. Because levels of interleukin (IL)-1beta were elevated in sera of pristane-injected rats, with levels mirroring the course of PIA, we examined the effect of pristane at single cell level in vitro, using rat splenocytes and the human monocytic cell line THP-1. Pristane and other hydrocarbon oils induced IL 1beta secretion in THP-1 cells as well as in rat splenocytes. The potassium channel inhibitor glibenclamide partly inhibited IL-1beta induction, suggesting involvement of the inflammasome. Elevated levels of IL-1alpha were also found in supernatants of cells treated with pristane and hexadecane. In conclusion, autoimmunogenic hydrocarbon oils induce various forms of cell death in rat and human cells. The higher serum IL-1beta levels in pristane-injected animals might be caused by both inflammasome-dependent and -independent mechanisms, such as passive release from dying-cells and probably extracellular maturation of pro-IL 1beta. PMID- 22917081 TI - Structural changes of high-amylose rice starch residues following in vitro and in vivo digestion. AB - High-amylose cereal starch has a great benefit on human health through its resistant starch content. In this paper, starches were isolated from mature grains of high-amylose transgenic rice line (TRS) and its wild-type rice cultivar Te-qing (TQ) and digested in vitro and in vivo. The structural changes of digestive starch residues were characterized using DSC, XRD, (13)C CP/MAS NMR, and ATR-FTIR. TQ starch was very susceptible to digestion; its residues following in vitro and in vivo digestion showed similar structural characteristics with TQ control starch, which suggested that both amorphous and crystalline structures were simultaneously digested. Both amorphous and the long-range order structures were also simultaneously hydrolyzed in TRS starch, but the short-range order (double helix) structure in the external region of TRS starch granule increased with increasing digestion time. The A-type polymorph of TRS C-type starch was hydrolyzed more rapidly than the B-type polymorph. These results suggested that B type crystallinity and short-range order structure in the external region of starch granule made TRS starch resistant to digestion. PMID- 22917080 TI - Diabetes, glucose control, glucose lowering medications, and cancer risk: a 10 year population-based historical cohort. AB - BACKGROUND: Both diabetes and glucose-lowering medications have been associated with an increased risk of cancer incidence. This study will compare cancer incidence rates in individuals with and without diabetes; and will investigate, in individuals with diabetes, an association between glucose control and cancer incidence; and between the use of specific glucose-lowering medications, as well as no drug exposure, and cancer incidence. METHODS/DESIGN: This is a population based historical cohort study of all individuals aged 21 years or older (about 2,300,000) who were insured by Clalit Health Services, the largest health maintenance organization in Israel during a ten-year study period. Four study groups will be established according to the status of diabetes and cancer at study entry, Jan 1, 2002: cancer free, diabetes free; cancer free, diabetes prevalent; cancer prevalent, diabetes free; and cancer prevalent, diabetes prevalent. Individuals without diabetes at study entry will be followed for diabetes incidence, and all four groups will be followed for specific cancer incidence, including second primary neoplasms. Glucose control will be assessed by HbA1c and by fasting plasma glucose levels. Time dependent regression models for cancer incidence will account for glucose-lowering medications as they are added and changed over the follow-up period. A large number of demographic and clinical variables will be considered, including: age, gender, BMI, smoking status, concomitant medications, glucose control (assessed by HbA1c and by fasting plasma glucose) and cancer screening tests. DISCUSSION: Strengths of this study include the large population; high quality comprehensive data; comparison to individuals without diabetes, and to those with diabetes but not treated with glucose-lowering medications; and the extensive range of variables available for analysis. The great increases in diabetes prevalence and in treatment options render this study particularly relevant and timely. The Israeli national healthcare system, characterized by high standard and uniform healthcare, offers an advantageous environment for its conduct. PMID- 22917082 TI - The American Association of Hip and Knee Surgeons (AAHKS) is quickly becoming the world's leading organization for hip and knee arthroplasty. Introduction. PMID- 22917083 TI - Obstructive sleep apnea as a risk factor for postoperative complications after revision joint arthroplasty. AB - Although current evidence is limited, obstructive sleep apnea (OSA) has been suggested as a risk factor for morbidity after primary joint arthroplasty. Our objective was to determine if patients with OSA have a higher likelihood of postoperative in-hospital complications or increased costs after revision arthroplasty. The Nationwide Inpatient Sample was used to identify 258,455 patients who underwent revision total hip arthroplasty or revision total knee arthroplasty between 2006 and 2008. Of these patients, 16,608 (6.4%) had been diagnosed with OSA. Multivariate analysis with logistic regression modeling was used to compare patients with and without OSA. Obstructive sleep apnea was associated with increased in-hospital mortality (odds ratio, 1.9; P = .002), pulmonary embolism (odds ratio, 2.1; P = .001), wound hematomas or seromas (odds ratio, 1.36; P < .001), and increased postoperative charges ($61,044 vs $58,813; P < .001). Further research is warranted. PMID- 22917084 TI - Mucormycosis treated with posaconazole: review of 96 case reports. AB - Mucormycosis is an emerging invasive fungal infection, primarily affecting immunocompromised patients. The disease is difficult to diagnose and mortality reaches 40% even if treated adequately. Depending on site of infection and risk factors, surgical debridement in combination with systemically active antifungal drugs are the mainstay treatment strategies. Lipid-based amphotericin B is the treatment of choice for first-line therapy while posaconazole may be a promising alternative. We performed a PubMed search on reports of patients with mucormycosis treated with posaconazole. From 2003 to 2011, 96 cases have been published. Diagnosis was based on histology alone in 2 (2.1%) and microbiological evidence in 67 (69.8%), while no data on the diagnostic approach was reported in 27 (28.1%) patients. The most frequent pathogens were Rhizopus spp. (31.2%), followed by Mucor spp. (14.6%). The site of infection was predominantly rhino orbital (38.5%, of which 43% also had central nervous system [CNS] involvement), followed by disseminated disease (22.1%). A complete response was achieved in 62 (64.6%), partial response in 7 (7.3%) patients, and stable disease in 1 (1%). Overall mortality was 24% (lacking data for three patients). In published case reports on posaconazole treatment for mucormycosis, the drug was frequently and successfully used in combination or as second line therapy. PMID- 22917085 TI - Second pilot trials of the STAR-Liege protocol for tight glycemic control in critically ill patients. AB - BACKGROUND: Critically ill patients often present increased insulin resistance and stress-induced hyperglycemia. Tight glycemic control aims to reduce blood glucose (BG) levels and variability while ensuring safety from hypoglycemia. This paper presents the results of the second Belgian clinical trial using the customizable STAR framework in a target-to-range control approach. The main objective is reducing measurement frequency while maintaining performance and safety of the glycemic control. METHODS: The STAR-Liege 2 (SL2) protocol targeted the 100-140 mg/dL glycemic band and offered 2-hourly and 3-hourly interventions. Only insulin rates were adjusted, and nutrition inputs were left to the attending clinicians. This protocol restricted the forecasted risk of BG < 90 mg/dL to a 5% level using a stochastic model of insulin sensitivity to assess patient-specific responses to insulin and its future likely variability to optimize insulin interventions. The clinical trial was performed at the Centre Hospitalier Universitaire de Liege and included 9 patients. Results are compared to 24-hour pre-trial and 24-hour post-trial, but also to the results of the first pilot trial performed in Liege, STAR-Liege 1 (SL1). This trial was approved by the Ethics Committee of the Medical Faculty of the University of Liege (Liege, Belgium). RESULTS: During the SL2 trial, 91 measurements were taken over 194 hours. BG levels were tightly distributed: 54.9% of BG within 100-140 mg/dL, 40.7% were >= 140 mg/dL and 4.4% were < 100 mg/dL with no BG < 70 mg/dL. Comparing these results with 24-hour pre-trial and post-trial shows that SL2 reduced high and low BG levels and reduced glycemic variability. Nurses selected 3-hourly measurement only 5 of 16 times and overrode 12% of 91 recommended interventions (35% increased insulin rates and 65% decreased insulin rates). SL1 and SL2 present similar BG levels distribution (p > 0.05) with significantly reduced measurement frequency for SL2 (p < 0.05). CONCLUSIONS: The SL2 protocol succeeded in reducing clinical workload while maintaining safety and effectiveness of the glycemic control. SL2 was also shown to be safer and tighter than hospital control. Overall results validate the efficacy of significantly customizing the STAR framework. PMID- 22917086 TI - Post-assembly functionalization of organoplatinum(II) metallacycles via copper free click chemistry. AB - We describe the use of a strain-promoted copper-free click reaction in the post self-assembly functionalization of organoplatinum(II) metallacycles. The coordination-driven self-assembly of a 120 degrees cyclooctyne-tethered dipyridyl donor with 60 degrees and 120 degrees di-Pt(II) acceptors forms molecular rhomboids and hexagons bearing cyclooctynes. These species undergo post self-assembly [3+2] Huisgen cycloaddition with a variety of azides to give functionalized ensembles under mild conditions. PMID- 22917087 TI - In situ TEM study of lithiation behavior of silicon nanoparticles attached to and embedded in a carbon matrix. AB - Rational design of silicon and carbon nanocomposite with a special topological feature has been demonstrated to be a feasible way for mitigating the capacity fading associated with the large volume change of silicon anode in lithium ion batteries. Although the lithiation behavior of silicon and carbon as individual components has been well understood, lithium ion transport behavior across a network of silicon and carbon is still lacking. In this paper, we probe the lithiation behavior of silicon nanoparticles attached to and embedded in a carbon nanofiber using in situ TEM and continuum mechanical calculation. We found that aggregated silicon nanoparticles show contact flattening upon initial lithiation, which is characteristically analogous to the classic sintering of powder particles by a neck-growth mechanism. As compared with the surface-attached silicon particles, particles embedded in the carbon matrix show delayed lithiation. Depending on the strength of the carbon matrix, lithiation of the embedded silicon nanoparticles can lead to the fracture of the carbon fiber. These observations provide insights on lithium ion transport in the network structured composite of silicon and carbon and ultimately provide fundamental guidance for mitigating the failure of batteries due to the large volume change of silicon anodes. PMID- 22917088 TI - Water-soluble narrow-line radicals for dynamic nuclear polarization. AB - The synthesis of air-stable, highly water-soluble organic radicals containing a 1,3-bis(diphenylene)-2-phenylallyl (BDPA) core is reported. A sulfonated derivative, SA-BDPA, retains the narrow electron paramagnetic resonance linewidth (<30 MHz at 5 T) of the parent BDPA in highly concentrated glycerol/water solutions (40 mM), which enables its use as polarizing agent for solid effect dynamic nuclear polarization (SE DNP). A sensitivity enhancement of 110 was obtained in high-field magic-angle-spinning (MAS) NMR experiments. The ease of synthesis and high maximum enhancements obtained with the BDPA-based radicals constitute a major advance over the trityl-type narrow-line polarization agents. PMID- 22917089 TI - Impact of behavioural risk factors on death within 10 years for women and men in their 70s: absolute risk charts. AB - BACKGROUND: Estimates of the absolute risk of death based on the combined effects of sex, age and health behaviours are scarce for elderly people. The aim of this paper is to calculate population based estimates and display them using simple charts that may be useful communication tools for public health authorities, health care providers and policy makers. METHODS: Data were drawn from two concurrent prospective observational cohort studies of community-based older Australian women (N = 7,438) and men (N = 6,053) aged 71 to 79. The outcome measure was death within ten years. The predictor variables were: sex, age, smoking status, alcohol consumption, body mass index and physical activity. RESULTS: Patterns of risks were similar in men and women but absolute risk of death was between 9 percentage points higher in men (17 %) than in women (8 %) in the lowest risk group (aged 71-73 years, never smoked, overweight, physically active and consumed alcohol weekly) and 21 % higher in men (73-74 %) than women (51-52 %) in the highest risk group (aged 77-79 years, normal weight or obese, current smoker, physically inactive and drink alcohol less than weekly). CONCLUSIONS: These absolute risk charts provide a tool for understanding the combined effects of behavioural risk factors for death among older people. PMID- 22917090 TI - Exciton coupling analysis and enolization monitoring by vibrational circular dichroism spectra of camphor diketones. AB - The keto-enol tautomerization of (1R,3R,4R)-(+)-3-benzoylcamphor in solution was traced by the infrared (IR) and vibrational circular dichroism (VCD) spectra, reflecting the Boltzmann populations of the isomers. To investigate the exciton coupling of the carbonyl vibrations in the region 1800-1600 cm(-1), VCD spectra of a series of camphor derived beta-diketones were analyzed with the support of density functional theory (DFT) calculations. The results confirm the importance of the exciton chirality for VCD and manifest that the VCD spectroscopy is a convenient technique to investigate the keto-enol tautomerization equilibria in chiral diketones. PMID- 22917091 TI - Realising the dream of an AIDS-free generation. PMID- 22917092 TI - Lack of knowledge can anger patients with chronic diseases. PMID- 22917093 TI - Quantifying the efficacy of influenza vaccines. PMID- 22917094 TI - Quantifying the efficacy of influenza vaccines. PMID- 22917095 TI - Quantifying the efficacy of influenza vaccines. PMID- 22917096 TI - Quantifying the efficacy of influenza vaccines. PMID- 22917097 TI - Quantifying the efficacy of influenza vaccines. PMID- 22917099 TI - Antiretroviral therapy requires life-long adherence. PMID- 22917101 TI - Important steps for a reliable meta-analysis. PMID- 22917102 TI - Household transmission of meticillin-resistant Staphylococcus aureus and other staphylococci. AB - Although the role of pets in household transmission of meticillin-resistant Staphylococcus aureus (MRSA) has been examined previously, only minor attention has been given to the role of the abiotic household environment independent of, or in combination with, colonisation of pets and human beings to maintain transmission cycles of MRSA within the household. This report reviews published work about household transmission of S aureus and other staphylococci and describes contamination of household environmental surfaces and colonisation of pets and people. Household microbial communities might have a role in transfer of antimicrobial resistance genes and could be reservoirs for recolonisation of people, although additional research is needed regarding strategies for decontamination of household environments. Household-based interventions should be developed to control recurrent S aureus infections in the community, and coordination between medical and veterinary providers could be beneficial. PMID- 22917103 TI - Entamoeba histolytica infection in men who have sex with men. AB - Entamoeba histolytica infection (amoebiasis) is the second leading cause of death from parasitic diseases. Epidemiological studies from developed countries have reported an increasing prevalence of amoebiasis and of invasive infections, such as amoebic colitis, among men who have sex with men (MSM) who engage in oral-anal sex. Although most infections with E histolytica are asymptomatic, clinical manifestations of invasive amoebiasis mainly include amoebic colitis and amoebic liver abscess, which are associated with substantial morbidity and medical cost. Laboratory diagnosis of amoebiasis should be based on detection of E histolytica by use of tests with high sensitivity and specificity, such as specific amoebic antigen or PCR-based assays. Microscopy used in routine clinical laboratories is not sensitive or specific enough for detection of E histolytica. Metronidazole or tinidazole remains the mainstay of treatment for invasive amoebiasis, followed by treatment with luminal agents to prevent relapse and transmission of E histolytica to sexual partners or close contacts. PMID- 22917104 TI - Hypnotizability modulates the cardiovascular correlates of subjective relaxation. AB - Mean values and the spectral variability of heart rate (HRV), blood pressure, and skin blood flow were studied in high and low hypnotizable subjects during simple relaxation. Similar subjective relaxation was reported by highs and lows. A parasympathetic prevalence (indicated by a higher High-Frequency component of HRV and a lower High/Low-Frequency ratio) and lower renin-angiotensin activity (indicated by a lower Very-Low-Frequency component of HRV) could be attributed to highs with respect to lows. Hypnotizability did not affect blood pressure and its variability and modulated the skin blood flow across the session only in lows. The findings confirm that relaxation cannot be defined solely on cardiovascular parameters and also indicate that hypnotizability modulates cardiovascular activity during simple relaxation and suggest it may have a protective role against cardiovascular disease. PMID- 22917105 TI - Relational hypnosis. AB - This article provides a meta-theoretical framework, which can be applied to hypnosis, based on relational (intersubjective) psychoanalysis. The relationship between hypnosis and psychoanalysis is reviewed by describing three splits: (a) psychoanalysis split off from brain science; (b) psychoanalysis split off from hypnosis; and (c) splits within psychoanalysis itself. Reintegrations of these three splits are discussed from a meta-theoretical point of view--through neuropsychoanalysis and hypnodynamic hypnotherapy (or hypnoanalysis), which combines interpersonal and intrapersonal psychology. Evidence of the mutual adjustments of the hypnotist's style to the needs of the hypnotized is presented, including the unconscious interactional mechanisms that enable these adjustments in the context of relational hypnosis. PMID- 22917106 TI - Involuntary experiencing and the performance of hypnotic test suggestions. AB - This experimental study examined 2 questions: (a) Does the Harvard Group Scale of Hypnotic Susceptibility, Form A (HGSHS:A) tap the "classic suggestion effect" and (b) does the wording of postexperimental questions bias subjective reports of hypnotic subjects? Results indicated that a significant minority of individuals who "passed" test suggestions by objective behavioral criteria reported performance as occurring voluntarily, and participants who "failed" test suggestions reported performance of behaviors as occurring involuntarily. Participants' reports of the involuntariness of their experience during performance of hypnotic test suggestions were not significantly influenced by the wording of questions. Implications of these findings for experimental research and clinical practice are discussed. PMID- 22917107 TI - Hypnosis for the management of chronic and cancer procedure-related pain in children. AB - The aim of this study was to review published controlled trials of hypnotic treatments for chronic and cancer procedure-related pain in children. Trials were included if participants were 18 years of age or below, were randomized and had populations with chronic pain or cancer procedure-related pain. After the studies were assessed, 12 were selected for review. Although the evidence is limited, the findings indicate that hypnosis is an effective pain-control technique when used with children suffering from cancer procedure-related pain or chronic pain. Further research into the use of hypnosis to manage chronic pain in children should be a priority so that empirically based conclusions can be drawn about the effects of hypnosis on children. PMID- 22917108 TI - On the objectivity of the scoring of Harvard Group Scale of Hypnotic Susceptibility. AB - The authors analyzed the Harvard Group Scale of Hypnotic Susceptibility, Form A, scores of 1,887 subjects. In addition to the usual self-scoring, trained observers also scored the behavioral manifestations of the subjects according to the same standardized criteria during the sessions. Self- and observer-scoring proved to be internally consistent and highly correlated (r = .832). Item-by-item analysis, however, yielded notable differences. Subjects and observers scored items differently in about 20% of the cases; only 3 items showed no systematic bias toward pass or fail. Many subjects' hypnotizability level would be classified differently according to observer categorization (Cohen's Kappa = .563). We suggest reconsidering the "objectivity" of self-scoring. PMID- 22917110 TI - Arsenic exposure through drinking water is associated with longer telomeres in peripheral blood. AB - Inorganic arsenic is a strong carcinogen, possibly by interaction with the telomere length. The aim of the study was to evaluate how chronic arsenic exposure from drinking water as well as the arsenic metabolism efficiency affect the individual telomere length and the expression of telomere-related genes. Two hundred two women with a wide range in exposure to arsenic via drinking water (3.5-200 MUg/L) were recruited. Concentrations of arsenic metabolites in urine [inorganic arsenic (iAs), methylarsonic acid (MMA), and dimethylarsinic acid (DMA)] were measured. The relative telomere length in blood was measured by quantitative real-time polymerase chain reaction. Genotyping (N = 172) for eight SNPs in AS3MT and gene expression of telomere-related genes (in blood; N = 90) were performed. Urinary arsenic (sum of metabolites) was positively associated with telomere length (beta = 0.65 * 10(-4), 95% CI = 0.031 * 10(-4)-1.3 * 10(-4), adjusted for age and BMI). Individuals with above median fractions of iAs and MMA showed significantly longer telomeres by increasing urinary arsenic (beta = 1.0 * 10(-4), 95% CI = 0.21 * 10(-4)-1.8 * 10(-4) at high % iAs; beta = 0.88 * 10(-4) 95% CI = 0.12 * 10(-4)-1.6 * 10(-4) at high % MMA) than those below the median (p = 0.80 and 0.44, respectively). Similarly, carriers of the slow and more toxic metabolizing AS3MT haplotype showed stronger positive associations between arsenic exposure and telomere length, as compared to noncarriers (interaction urinary arsenic and haplotype p = 0.025). Urinary arsenic was positively correlated with the expression of telomerase reverse transcriptase (TERT, Spearman r = 0.22, p = 0.037), but no association was found between TERT expression and telomere length. Arsenic in drinking water influences the telomere length, and this may be a mechanism for its carcinogenicity. A faster and less toxic arsenic metabolism diminishes arsenic-related telomere elongation. PMID- 22917112 TI - Parasite epidemiology in a changing world: can molecular phylogeography help us tell the wood from the trees? AB - SUMMARY Molecular phylogeography has revolutionised our ability to infer past biogeographic events from cross-sectional data on current parasite populations. In ecological parasitology, this approach has been used to address fundamental questions concerning host-parasite co-evolution and geographic patterns of spread, and has raised many technical issues and problems of interpretation. For applied parasitologists, the added complexity inherent in adding population genetic structure to perceived parasite distributions can sometimes seem to cloud rather than clarify approaches to control. In this paper, we use case studies firstly to illustrate the potential extent of cryptic diversity in parasite and parasitoid populations, secondly to consider how anthropogenic influences including movement of domestic animals affect the geographic distribution and host associations of parasite genotypes, and thirdly to explore the applied relevance of these processes to parasites of socio-economic importance. The contribution of phylogeographic approaches to deeper understanding of parasite biology in these cases is assessed. Thus, molecular data on the emerging parasites Angiostrongylus vasorum in dogs and wild canids, and the myiasis causing flies Lucilia spp. in sheep and Cochliomyia hominovorax in humans, lead to clear implications for control efforts to limit global spread. Broader applications of molecular phylogeography to understanding parasite distributions in an era of rapid global change are also discussed. PMID- 22917113 TI - rgpA DNA vaccine induces antibody response and prevents alveolar bone loss in experimental peri-implantitis. AB - BACKGROUND: Peri-implantitis is one of many reasons for dental implant failure. This study is designed to prevent experimental peri-implantitis by arginine specific gingipain A (rgpA) DNA vaccine. METHODS: The bilateral mandibular second and third premolars from 15 male beagle dogs were extracted, and 60 implants were immediately implanted. Three months after implantation, the animals were randomly divided into groups A, B, and C and immunized with plasmid vector-rgpA, heat killed Porphyromonas gingivalis, and plasmid vector, respectively. Cotton ligatures infiltrated with P. gingivalis were placed in the submarginal position around the neck of the implants to induce peri-implantitis. Clinical measurements, including probing depth (PD) and bleeding on probing, were recorded every 2 weeks postoperatively, and P. gingivalis-specific immunoglobulin G (IgG) in serum and secretory IgA (sIgA) in saliva were quantitatively analyzed by enzyme-linked immunosorbent assay at the same time. Animals were sacrificed after 6 weeks, 50-MUm undecalcified histologic sections were prepared using methylene blue dye, and bone loss around implants was measured. RESULTS: Higher levels of IgG in serum and sIgA in saliva could be measured in groups A and B but not in group C after immunization. There were statistical differences (P <0.05) between, before, and after immunization, but no difference was found between groups A and B (P >0.05). Both peri-implant PD and bone loss in group A were significantly less than in groups B and C. CONCLUSIONS: IgG and sIgA could be generated by immunization with rgpA DNA vaccine, which could significantly slow down bone loss in the experimental peri-implantitis canine model. PMID- 22917111 TI - Adaptive trial designs: a review of barriers and opportunities. AB - Adaptive designs allow planned modifications based on data accumulating within a study. The promise of greater flexibility and efficiency stimulates increasing interest in adaptive designs from clinical, academic, and regulatory parties. When adaptive designs are used properly, efficiencies can include a smaller sample size, a more efficient treatment development process, and an increased chance of correctly answering the clinical question of interest. However, improper adaptations can lead to biased studies. A broad definition of adaptive designs allows for countless variations, which creates confusion as to the statistical validity and practical feasibility of many designs. Determining properties of a particular adaptive design requires careful consideration of the scientific context and statistical assumptions. We first review several adaptive designs that garner the most current interest. We focus on the design principles and research issues that lead to particular designs being appealing or unappealing in particular applications. We separately discuss exploratory and confirmatory stage designs in order to account for the differences in regulatory concerns. We include adaptive seamless designs, which combine stages in a unified approach. We also highlight a number of applied areas, such as comparative effectiveness research, that would benefit from the use of adaptive designs. Finally, we describe a number of current barriers and provide initial suggestions for overcoming them in order to promote wider use of appropriate adaptive designs. Given the breadth of the coverage all mathematical and most implementation details are omitted for the sake of brevity. However, the interested reader will find that we provide current references to focused reviews and original theoretical sources which lead to details of the current state of the art in theory and practice. PMID- 22917114 TI - Are short dental implants (<10 mm) effective? a meta-analysis on prospective clinical trials. AB - BACKGROUND: This study aims to compare the survival rate of short (<10 mm) and standard (>=10 mm) rough-surface dental implants under functional loading. METHODS: An electronic literature search using PubMed and Medline databases was conducted. Prospective clinical human trials, published in English from January 1997 to July 2011, that examined dental implants of <10 mm with a 12-month follow up were included in this meta-analysis. The following data were retrieved from the included articles: the number of implants, implant dimensions, implant locations, types of prostheses, follow-up periods, and implant survival rates. Kaplan-Meier survival estimates and the hazard rates were analyzed and compared between short and standard implants. RESULTS: Thirteen studies were selected, examining 1,955 dental implants, of which 914 were short implants. Short dental implants had an estimated survival rate of 88.1% at 168 months, when standard dental implants had a similar estimated survival rate of 86.7% (P = 0.254). The peak failure rate of short dental implants was found to occur between 4 and 6 years of function. This occurred at an earlier time point compared with standard dental implants, where the peak failure rate occurred between 6 and 8 years of function. CONCLUSIONS: This study shows that in the long term, implants of <10 mm are as predictable as longer implants. However, they fail at an earlier stage compared with standard implants. PMID- 22917115 TI - Emerging as leaders in autism research and practice: using the data-driven intervention process. PMID- 22917116 TI - Occupational therapy in primary health care: we should be there. PMID- 22917117 TI - Effect of classroom modification on attention and engagement of students with autism or dyspraxia. AB - Students with autism display sensory sensitivities to environmental stimuli that affect their attending and engagement in classroom learning activities. The purpose of the study was to determine whether attending of 4 male students, ages 13-20, increased after the installation of sound-absorbing walls and halogen lighting. The multiple single-subject, mixed-method design, AB(B+C), included a 2 wk baseline and two intervention phases: 2 wk after sound-absorbing wall installation using the Owens Corning Basement Finishing SystemTM (Owens Corning, Toledo, OH) and 2 wk after halogen light installation. We calculated nonattending frequencies from videotaped class sessions and used visual analysis to measure within-phase and between-phase characteristics. Results included increased frequency and stability of attending and engagement and improved classroom performance, comfort, and mood. Journaling provided students' perspective on the modifications and reflected overall increased sensory comfort and themes of improved classroom environment, positive emotional response (mood), and improved classroom performance. PMID- 22917118 TI - Impact of a contextual intervention on child participation and parent competence among children with autism spectrum disorders: a pretest-posttest repeated measures design. AB - OBJECTIVE. We tested an occupational therapy contextual intervention for improving participation in children with autism spectrum disorders and for developing parental competence. METHOD. Using a repeated-measures pretest posttest design, we evaluated the effectiveness of a contextually relevant reflective guidance occupational therapy intervention involving three components: authentic activity settings, family's daily routines, and the child's sensory processing patterns (Sensory Profile). We used these components to coach 20 parents in strategies to support their child's participation. Intervention sessions involved reflective discussion with parents to support them in identifying strategies to meet their goals and make joint plans for the coming week. We measured child participation (Canadian Occupational Performance Measure, Goal Attainment Scaling) and parent competence (Parenting Sense of Competence, Parenting Stress Index). RESULTS. Results indicated that parents felt more competent and children significantly increased participation in everyday life, suggesting that this approach is an effective occupational therapy intervention. PMID- 22917119 TI - Effect of a motor-based role-play intervention on the social behaviors of adolescents with high-functioning autism: multiple-baseline single-subject design. AB - OBJECTIVE. We examined the effect of a motor-based role-play intervention on the social skills of adolescents with high-functioning autism. METHOD. An ABA multiple-baseline design with three 3-mo phases occurring over 12 mo was used with 7 participants. Frequency of targeted verbal and nonverbal behaviors was tallied in each phase. Frequency data were analyzed using repeated-measures analyses of variance with post hoc comparisons to examine differences in targeted behaviors over the three phases. RESULTS. Three participants completed all three study phases, 2 completed Phase 2, and 2 completed Phase 1. All participants (N = 7) demonstrated improved social skill use in Phase 1. Participants completing Phase 2 (n = 5) further improved social skill use. Additional improvements were observed among participants (n = 3) who completed Phase 3. CONCLUSION. The intervention helped participants improve targeted social skill use. Further testing with larger samples and intervention modifications is warranted. PMID- 22917120 TI - Efficacy of the Get Ready to Learn yoga program among children with autism spectrum disorders: a pretest-posttest control group design. AB - Occupational therapists use school-based yoga programs, but these interventions typically lack manualization and evidence from well-designed studies. Using an experimental pretest-posttest control group design, we examined the effectiveness of the Get Ready to Learn (GRTL) classroom yoga program among children with autism spectrum disorders (ASD). The intervention group received the manualized yoga program daily for 16 wk, and the control group engaged in their standard morning routine. We assessed challenging behaviors with standardized measures and behavior coding before and after intervention. We completed a between-groups analysis of variance to assess differences in gain scores on the dependent variables. Students in the GRTL program showed significant decreases (p < .05) in teacher ratings of maladaptive behavior, as measured with the Aberrant Behavior Checklist, compared with the control participants. This study demonstrates that use of daily classroomwide yoga interventions has a significant impact on key classroom behaviors among children with ASD. PMID- 22917121 TI - Occupational therapy using sensory integration to improve participation of a child with autism: a case report. AB - In this case report, we describe the changes in adaptive behaviors and participation of 1 child with autism during a 10-wk program of intensive occupational therapy using a sensory integrative approach (OT-SI) following a manualized protocol. This case is part of a larger study examining the efficacy of the OT-SI approach. We found improvement in sensory processing, as measured by the Sensory Integration and Praxis Tests, as well as enhanced participation in home, school, and family activities, as indicated on parent-rated goal attainment scales. PMID- 22917122 TI - Sensory and motor behaviors of infant siblings of children with and without autism. AB - We compared the sensory and motor behaviors of typically developing infants with those of infant siblings of children with autism spectrum disorders (ASD), who are considered high risk for the disorder, to explore potential sensory and motor markers for use in early diagnosis of ASD. We compared frequencies of sensory and motor behaviors during 10-min, videotaped, infant-mother play sessions and during 5 min of spoon-feeding between groups of 12-mo-old infants. Data from standardized measures of development, sensory processing, and behaviors commonly associated with ASD were also analyzed descriptively for the high-risk group. The results indicated that high-risk infants demonstrated fewer movement transitions (t [23] = -2.4, p = .03) and less object manipulation (t [23] = -2.4, p = .03) than low-risk infants. The sensory and motor differences found between typical and high-risk infants suggest that early screenings for ASD should include the examination of sensory and motor behaviors. PMID- 22917123 TI - Autonomic and behavioral responses of children with autism to auditory stimuli. AB - OBJECTIVES. We examined whether children with and without autism spectrum disorder (ASD) differ in autonomic activity at rest and in response to auditory stimuli and whether behavioral problems related to sounds in everyday life are associated with autonomic responses to auditory stimuli. METHOD. We measured skin conductance (SC) at rest and in response to auditory stimuli as well as behavioral responses using the Sensory Processing Measure (SPM) Home Form. Participants were 25 children with ASD and 25 typically developing (TD) children, aged 5-12 yr. RESULTS. The ASD group had significantly higher resting SC and stronger SC reactivity to tones than the TD group. Correlations between SC and SPM indicated that more severe auditory behavioral difficulties were associated with higher sympathetic activation at rest and stronger sympathetic reactivity to sound. CONCLUSION. High sympathetic reactivity to sound may underlie the difficult behavioral responses to sound that children with ASD often demonstrate. PMID- 22917124 TI - Head lag in infants at risk for autism: a preliminary study. AB - OBJECTIVE.Poor postural control during pull-to-sit is a predictor of developmental disruption in cerebral palsy and preterm populations but has not been examined in infants at risk for autism. We examined the association between head lag during pull-to-sit at age 6 mo and autism risk status. METHOD.High-risk participants were siblings of children with autism. We studied one sample of 40 high-risk infants prospectively from 6-36 mo and obtained diagnostic classifications of autism or no autism. We conducted a subsequent between-group comparison with a new sample of 20 high-risk and 21 low-risk infants. RESULTS.Head lag was significantly associated with autism spectrum disorder at 36 mo (p = .020) and was more frequently observed in high-risk than in low-risk infants (p = .018). CONCLUSION.Head lag with other alterations in early development may be associated with autism risk and may serve as an early indicator of neurodevelopmental disruption. Results have clinical implications for occupational therapists in early intervention practice. PMID- 22917125 TI - Sensory processing, problem behavior, adaptive behavior, and cognition in preschool children with autism spectrum disorders. AB - OBJECTIVE. This retrospective study explored sensory processing characteristics in preschool-age children with autism spectrum disorders (ASD); the relationships between sensory processing and problem behavior, adaptive behavior, and cognitive function; and the differences in sensory processing between two subgroups (autism and pervasive developmental disorder-not otherwise specified). METHOD. Study measures included the Short Sensory Profile (SSP), Aberrant Behavior Checklist Community, Vineland Adaptive Behavior Scales, and Mullen Scales of Early Learning. RESULTS. Most of the children with ASD had sensory processing challenges, and a significant relationship was found between SSP total scores and problem behavior scores; however, no significant relationships were found between SSP total scores and adaptive behavior and cognitive functioning. Although all the children had low Vineland scores, approximately one-quarter of the children had typical SSP scores. No significant differences in SSP scores were found between the subgroups. CONCLUSION. The findings highlight the importance of comprehensive evaluations for children with ASD. PMID- 22917126 TI - Sensory overresponsivity and anxiety in typically developing children and children with autism and attention deficit hyperactivity disorder: cause or coexistence? AB - OBJECTIVE. To explore the relationship between sensory overresponsivity (SOR) and anxiety in children with autism, attention deficit hyperactivity disorder, and typical development. METHOD. Path analysis was used to examine the primary SOR model (Green & Ben-Sasson, 2010) using both physiological and behavioral data. RESULTS. The magnitude of physiological responses to sensory challenge was a mediator variable between predictors (baseline arousal and attention) and outcomes (anxiety and physiological recovery). Behavioral SOR was correlated with anxiety but not with physiological variables. CONCLUSION. The intensity or magnitude of sensory responsivity mediates the relationship between baseline arousal and attention and outcome anxiety and physiologic recovery from sensory challenge. Behavioral tools used to measure SOR do not reflect physiological responsiveness; this mismatch warrants further investigation. SOR can prevent children from participating in the occupations of childhood; the greater the understanding of SOR, the more successful occupational therapy practitioners will be in developing effective interventions. PMID- 22917127 TI - Comparing the functional performance of children and youths with autism, developmental disabilities, and no disability using the revised pediatric evaluation of disability inventory item banks. AB - OBJECTIVE. We compared the functional performance of children with autism spectrum disorders (ASD), intellectual and developmental disabilities (IDD), and without disabilities using the revised Pediatric Evaluation of Disability Inventory-Computer Adaptive Test (PEDI-CAT) Social/Cognitive, Daily Activities, and Responsibility domains. METHOD. A nationally representative sample of parents of children ages 0-21 without disabilities (n = 2,205), with ASD (n = 108), or with IDD (n = 150) completed an online survey. We obtained predicted PEDI-CAT scaled scores for three reference ages (5, 10, 15) from a modified analysis of covariance model and compared each group's scores using contrasts of the regression parameters. RESULTS. We found no significant differences between the ASD and IDD groups. The group with ASD demonstrated significantly lower performance than the group without disabilities across the three domains at ages 10 and 15. CONCLUSION. Scores on the PEDI-CAT differentiated the group with ASD from the group without disabilities. Children with ASD and IDD did not demonstrate different performance profiles. PMID- 22917128 TI - Test-retest reliability of Family L.I.F.E. (Looking Into Family Experiences): an occupation-based assessment. AB - OBJECTIVE. We examined the test-retest reliability of Family L.I.F.E. (Looking Into Family Experiences) for consistency in identifying occupations desired by families with a child with autism spectrum disorder (ASD), and we compared the perceived efficiency, effectiveness, and satisfaction ratings of those occupations for the families. METHOD. Family L.I.F.E. was administered initially and 1 wk later via interview to 13 families with a child with ASD. RESULTS. Ninety-two percent of the families identified the same occupations as important at test and retest. Wilcoxon signed-rank test indicated no change in the families' perceived efficiency and effectiveness of those occupations, and Spearman's correlations indicated strong relationships. A decrease in satisfaction was noted. CONCLUSION. For families with a child with ASD, desired family occupations and efficiency and effectiveness ratings are likely to remain consistent and are highly linked on retest using Family L.I.F.E. At second interview using this instrument, families with a child with ASD may report decreased satisfaction in desired family occupations. PMID- 22917129 TI - Proprioceptive processing difficulties among children with autism spectrum disorders and developmental disabilities. AB - OBJECTIVE. Sensory processing difficulties among children with autism spectrum disorders (ASD) have been extensively documented. However, less is known about this population's ability to process proprioceptive information. METHOD. We used the Comprehensive Observations of Proprioception (COP; Blanche, Bodison, Chang, & Reinoso, in press) to describe the proprioceptive difficulties experienced by children with ASD. A sample of 32 children with ASD, 26 children with developmental disabilities excluding ASD, and 28 typically developing control children were studied using the COP. RESULTS. Children with ASD present with proprioceptive processing difficulties that are different from those of children with developmental disabilities and their typically developing counterparts. Specific data, potential clinical applications, and directions for future research are described. CONCLUSION. Results suggest that the COP has useful clinical research applications. Further assessment of psychometric properties, clinical utility, and meaningful differences among diverse clinical populations are needed. PMID- 22917131 TI - Oral care and sensory concerns in autism. AB - We examined sensory-related aspects of oral care at home and the dentist's office in children with autism spectrum disorders (ASD) and their typically developing (TD) peers. Results from parent questionnaires (n = 196 ASD, n = 202 TD) and one focus group were analyzed to determine whether sensory experiences were different between groups. Significantly more parents of children with ASD reported difficulties with sensory-related oral care variables in the home and dental office; this finding was supported by qualitative data. Using sensory strategies to modify the environment may enhance the dental experience and improve quality of life for children with ASD and their families. PMID- 22917132 TI - Cross-cultural comparison of sensory behaviors in children with autism. AB - Parents of children with autism frequently report that their children exhibit unusual responses to sensory experiences. Little research is available, however, describing how parents' and children's culture and environment might influence parents' reports of their children's behaviors. This study compared the frequency of parent-reported responses to sensory experiences in children from two countries-Israel and the United States. We administered the Short Sensory Profile to primary caregivers of children with autism spectrum disorders (ASD) and typically developing peers. Results indicate that Israeli parents reported unusual responses to sensory experiences less frequently than U.S. parents for both ASD and typically developing children. U.S. children with ASD demonstrated significantly greater difficulty in the Auditory Filtering and Visual/Auditory Sensitivity domains than Israeli children with ASD. These findings indicate a need to further explore the influence of culture and environment on caregiver perceptions of the responses to sensory experiences of children with ASD. PMID- 22917134 TI - How do we change practice when we have the evidence? AB - Translating research findings into practice includes myriad pragmatic realities, including understanding the suitability of the data to a particular patient group, writing new guidelines for occupational therapy practitioners, facilitating adoption of the guidelines, and instituting new patterns of care for patients. The process is more than a matter of disseminating the information to practitioners and expecting immediate change in patient treatment. Indeed, the field of implementation science is devoted to the identification of the numerous barriers and supports that constrain or expedite practice change in response to research. Moving forward and adopting evidence-based findings will require a focused understanding of the particular setting where change is warranted. Among the issues to address are the health system levels involved in change (professional, legislative, administrative, practitioner, and patient and family members), the values and beliefs of the participants, and knowledge of the communication channels that exist in the setting and how information and new ideas make their way through the setting. PMID- 22917133 TI - Precursors and trajectories of sensory features: qualitative analysis of infant home videos. AB - OBJECTIVE. This study explored precursors and trajectories of extreme sensory patterns in children with autism spectrum disorders (ASD) compared with children with developmental delay (DD). METHOD. We conducted a retrospective analysis of home videos of 12 infants who later displayed extreme presence or absence of three sensory patterns at preschool and school age. RESULTS. In ASD, hyporesponsiveness was most evident in infancy, followed by sensory repetitions. Hyporesponsiveness appeared stable over time and also was a precursor of sensory seeking. Infants with DD had few sensory precursors. CONCLUSION. Precursors of extreme sensory features emerge early in children with ASD and appear relatively stable over time for a pattern of hyporesponsiveness but less stable for patterns of hyperresponsiveness and sensory seeking. These findings highlight the emergent nature of sensory features that may inform early identification and intervention. PMID- 22917135 TI - Seroepidemiological survey of Crimean-Congo hemorrhagic fever among sheep in Mazandaran province, northern Iran. AB - Crimean-Congo hemorrhagic fever (CCHF) is a disease prevalent among humans and animals and is endemic in Iran. Although CCHF has been reported in all of its neighboring provinces, in Mazandaran in northern Iran there have been no reports of any cases of human infection. This research has been carried out to clarify the epidemiological aspects of CCHF infection among sheep in various geographical regions of Mazandaran province. In this survey, 270 blood samples were collected from sheep in eastern, central, and western Mazandaran between 2010 and 2011, and the specific ELISA test for CCHF virus was carried out on the blood samples in the National Reference Laboratory in the Pasteur Institute, Tehran, Iran. The CCHF infection rate according to this study was 3.7%. A weak statistical relationship (p=0.063) was seen between the different geographical regions, with a gradual decrease in the infection rate noted, stretching from the eastern to the western portions of the province (eastern 6.8%, central 2.8%, and western 0%). Older sheep were 2.7 times more likely to be infected with the virus (OR 2.70; 95% CI 1.50,4.87; p<0.001). As the infection rate in Mazandaran is low among sheep, and as yet there have been no reports of human infection in this province, CCHF disease is not considered a serious health problem in Mazandaran. It is recommended that further research be carried out on other animals, high risk human groups, and ticks, in order to more completely reveal the status of the disease in this province. PMID- 22917136 TI - Fluid biomarkers for Alzheimer's disease: standardization and recent developments. PMID- 22917137 TI - Disclosure of Alzheimer's disease biomarker status in subjects with mild cognitive impairment. PMID- 22917138 TI - What is a certified reference material? PMID- 22917139 TI - Clinical use of cerebrospinal fluid biomarkers in Alzheimer's disease. AB - The cerebrospinal fluid is a valuable diagnostic fluid that is underutilized. A number of classical neurochemical tests and newer biomarkers of neuropathology may be performed on the cerebrospinal fluid from patients with clinical signs of progressive neurological disease to assist and complement diagnosis. Here, we discuss how they may be employed in the clinical evaluation of patients with memory problems. We argue for their proper application and use, and caution against common misinterpretations. PMID- 22917140 TI - Analytical aspects of molecular Alzheimer's disease biomarkers. AB - In general, a biomarker has multiple uses such as a diagnostic tool and a method to monitor therapy. The quality of a biomarker depends on how big the difference is between, for example, patients and healthy controls, but also on the capacity of the method used to measure it (the uncertainty in the method should be much less than the difference between the groups). A good biomarker should also be specific towards a disease, allowing for differentiation between clinically related syndromes. In addition, it is of importance that the stability of the methods used is high enough to establish cut-off levels both in individual laboratories and on a global scale. In the field of Alzheimer's disease, there are currently three cerebrospinal fluid markers that have been verified in multiple studies and the analytical aspects of measuring them will be discussed. PMID- 22917141 TI - Determining cut-points for Alzheimer's disease biomarkers: statistical issues, methods and challenges. AB - New proposed criteria for the clinical diagnosis of Alzheimer's disease increasingly incorporate biomarkers, most of which are normally measured on a continuous scale. Operationalizing such criteria thus requires continuous biomarkers to be dichotomized, which in turns requires the selection of a cut point at which to dichotomize. In this article, we review the statistical principles underlying the choice of cut-points, describe some of the most commonly adopted statistical approaches used to estimate cut-points, highlight potential pitfalls in some of the approaches and characterize in what sense the estimated cut-point from each approach is optimal. We also emphasize that how a cut-point is selected must be made in reference to how the resulting dichotomized biomarker is to be used, and in particular what actions will follow from a positive or negative test result. PMID- 22917142 TI - Proficiency testing programs for Alzheimer's disease cerebrospinal fluid biomarkers. AB - Cerebrospinal fluid (CSF) biomarkers are increasingly used for diagnosis of Alzheimer's disease in research, clinical trials and clinical settings. As for other biochemical measurements, variability between laboratories for these biomarkers may be monitored by proficiency testing programs, where participating laboratories use their local routine methods to analyze test samples shipped from a central laboratory. In this review, we summarize the results from the last years' pilot proficiency programs and describe the ongoing standardization efforts in this area. Global proficiency testing for CSF biomarkers is now fully established. It will continue to play an important part in the standardization of measurements that is a prerequisite for the broad-scale future implementation of CSF biomarkers. PMID- 22917143 TI - Reference measurement procedures for Alzheimer's disease cerebrospinal fluid biomarkers: definitions and approaches with focus on amyloid beta42. AB - Cerebrospinal fluid (CSF) biomarkers for Alzheimer's disease (AD) are increasingly used in clinical settings, research and drug trials. However, their broad-scale use on different technology platforms is hampered by the lack of standardization at the level of sample handling, determination of concentrations of analytes and the absence of well-defined performance criteria for in vitro diagnostic or companion diagnostic assays, which influences the apparent concentration of the analytes measured and the subsequent interpretation of the data. There is a need for harmonization of CSF AD biomarker assays that can reliably, across centers, quantitate CSF biomarkers with high analytical precision, selectivity and stability over long time periods. In this position paper, we discuss reference procedures for the measurement of CSF AD biomarkers, especially amyloid beta42 and tau. We describe possible technical approaches, focusing on a selected reaction monitoring mass spectrometry assay as a candidate reference method for quantification of CSF amyloid beta42. PMID- 22917144 TI - Recommendations to standardize preanalytical confounding factors in Alzheimer's and Parkinson's disease cerebrospinal fluid biomarkers: an update. AB - Early diagnosis of neurodegenerative disorders such as Alzheimer's (AD) or Parkinson's disease (PD) is needed to slow down or halt the disease at the earliest stage. Cerebrospinal fluid (CSF) biomarkers can be a good tool for early diagnosis. However, their use in clinical practice is challenging due to the high variability found between centers in the concentrations of both AD CSF biomarkers (Abeta42, total tau and phosphorylated tau) and PD CSF biomarker (alpha synuclein). Such a variability has been partially attributed to different preanalytical procedures between laboratories, thus highlighting the need to establish standardized operating procedures. Here, we merge two previous consensus guidelines for preanalytical confounding factors in order to achieve one exhaustive guideline updated with new evidence for Abeta42, total tau and phosphorylated tau, and alpha-synuclein. The proposed standardized operating procedures are applicable not only to novel CSF biomarkers in AD and PD, but also to biomarkers for other neurodegenerative disorders. PMID- 22917145 TI - Use of FDG PET as an imaging biomarker in clinical trials of Alzheimer's disease. AB - PET with the glucose analog FDG as a tracer is a mature and increasingly available clinical imaging technique that can improve the diagnostic accuracy for Alzheimer's disease, which is of particular value at an early stage of the disease when clinical symptoms are still mild and nonspecific. It can also monitor progression of Alzheimer's disease, and the findings are closely related to clinical symptoms. FDG PET, therefore, could also potentially be used as an imaging biomarker for selection of patients and assessment of outcome in clinical trials. Several published intervention studies indicate a good correspondence between clinical outcome and FDG PET findings, but study designs and methods used for data analysis vary widely. Recent developments towards standardization of largely user-independent methods for quantification of regional metabolic impairment on FDG PET scans will allow a new generation of studies that could provide the required evidence for full qualification of FDG PET as an imaging biomarker in clinical trials. PMID- 22917146 TI - Plasma biomarkers for Alzheimer's disease: much needed but tough to find. AB - Alzheimer's disease is a complex age-dependent neurodegenerative disease where definitive diagnosis is only possible after autopsy and where there is a long prodromal or preclinical phase. Biomarkers for both early diagnosis and prediction of disease progression are needed and extensive efforts to discover them have been undertaken. In this article, we have attempted to summarize the findings of current studies using proteomics and metabolomics approaches. We are also discussing how the use of emerging technologies and better study designs can support the identification of the much-needed Alzheimer's disease plasma biomarkers. PMID- 22917148 TI - Relationship between genetic risk factors and markers for Alzheimer's disease pathology. AB - Alzheimer's disease (AD) is a neurodegenerative disorder characterized by neuritic plaques (main constituent: beta-amyloid [Abeta]) and neurofibrillary tangles (hyperphosphorylated tau protein) in the brain. Abnormalities in Abeta and tau can be measured upon neuropathological examination, in cerebrospinal fluid or by PET. Etiologically, a growing body of evidence suggests that susceptibility to AD is genetically controlled. However, the precise nature of the underlying risk genes and their relation to AD biomarkers remains largely elusive. To this end, we performed a qualitative review of 17 studies (covering 47 polymorphisms in 26 genes) and investigated the potential relation between the most compelling AD risk genes and markers for Abeta and tau in cerebrospinal fluid, PET imaging and neuropathological examination. Of all covered genes, only APOE and PICALM showed consistent effects on Abeta but not on tau, while no obvious effects were observed for CLU, CR1, ACE, SORL and MAPT. PMID- 22917149 TI - Cells brainwashed by FOXM1: do they have potential as biomarkers of cancer? PMID- 22917150 TI - Biomarker testing for suspected autism spectrum disorder in early childhood: is such testing now feasible? PMID- 22917151 TI - Troponin T highlighted as a biomarker of mortality following noncardiac surgery. PMID- 22917152 TI - The role of serum oxidative stress biomarkers in the evaluation of colorectal cancer. PMID- 22917147 TI - Upcoming candidate cerebrospinal fluid biomarkers of Alzheimer's disease. AB - Dementia due to Alzheimer's disease (AD) is estimated to reach epidemic proportions by the year 2030. Given the limited accuracy of current AD clinical diagnosis, biomarkers of AD pathologies are currently being sought. Reductions in cerebrospinal fluid levels of beta-amyloid 42 (a marker of amyloid plaques) and elevations in tau species (markers of neurofibrillary tangles and/or neurodegeneration) are well-established as biomarkers useful for AD diagnosis and prognosis. However, novel markers for other features of AD pathophysiology (e.g., beta-amyloid processing, neuroinflammation and neuronal stress/dysfunction) and for other non-AD dementias are required to improve the accuracy of AD disease diagnosis, prognosis, staging and therapeutic monitoring (theragnosis). This article discusses the potential of several promising novel cerebrospinal fluid analytes, highlights the next steps critical for advancement in the field, and provides a prediction on how the field may evolve in 5-10 years. PMID- 22917153 TI - Functional MRI as a biomarker for evaluation and prediction of effectiveness of migraine prophylaxis. AB - Migraine is a neurological disorder characterized by episodic head pain and visual cortical phenomena. The pathogenesis of migraine is unknown and remains to be determined. Bright light, flickering light and certain visual patterns can trigger a migraine attack, and visual cortical hyperexcitability has been hypothesized to be responsible. Interictally, the brain of migraineurs functions normally under general conditions but abnormally only under some specific conditions, such as the observation of stressful visual patterns, suggesting studying the brain function could provide insights in migraine pathophysiology. The functional MRI technique is unique in probing specific cortical area activation under various stimulation conditions and studying the abnormal cortical activation associated with functional disorders in migraine. In this perspective, we discuss how a novel functional MRI technique can be used to identify those migraineurs suffering visual cortical hyperexcitability, and its potential as a biomarker to evaluate and possibly predict effectiveness of migraine-preventive treatments. PMID- 22917155 TI - Quantifying monocyte infiltration in response to intradermal tetanus toxoid injection. AB - AIMS: To characterize monocyte response in a delayed-type hypersensitivity reaction to intradermal tetanus toxoid (TT) injection. MATERIALS & METHODS: Men with positive serum anti-tetanus titers were stratified by last TT vaccination. Subjects were administered three intradermal injections of TT and one saline control on the same side of the back. Skin biopsies were taken post-injection. After 2 weeks, the procedure was repeated on the contralateral side. RESULTS: Men who received TT booster vaccination 1 month before the study showed greater reproducibility and lower variability in monocyte responses than those who were not revaccinated. Monocyte concentration in subjects re-vaccinated within 1 month of study start appeared maximal at 48 h post-injection. CONCLUSION: This assay represents a novel approach that allows for quantification of dermal monocyte/macrophage influx. This clinical methodology has potential utility in the pharmacodynamic evaluation of therapies targeting inflammatory disorders, which involve monocyte tissue recruitment, like the delayed-type hypersensitivity response. PMID- 22917156 TI - Alkaline phosphatase activity in human colostrum as a valuable predictive biomarker for lactational mastitis in nursing mothers. AB - AIMS: Biochemical investigations have shown that an indigenous milk enzyme - alkaline phosphatase (ALP) - which is detectable in the lactocytes, plays a very important diagnostic role in clinical medicine, since its activity varies in different tissues and serves as a specific indicator of disease states. The purpose of this study was to evaluate ALP activity in human colostrum as a possible early predictive biomarker for lactational mastitis in nursing mothers. PATIENTS & METHODS: During a period from May to July 2010, a total of 60 healthy nursing mothers were recruited for this study. RESULTS: The mean level of colostrum ALP activity from the affected breasts was significantly higher when compared with ALP activity from the contralateral asymptomatic as well as 'healthy' breasts (p < 0.01). CONCLUSION: Determining ALP activity in colostrum could be a valuable biochemical marker for an early prediction of mastitis in nursing mothers. PMID- 22917158 TI - Aryl amide derivatives of 4-(4-aminopiperidin-1-yl)-7H-pyrrolo[2,3-d]pyrimidine derivatives useful as ASK1 inhibitors, an evaluation of WO2012080735. AB - Novel 4-(4-aminopiperidin-1-yl)-7H-pyrrolo[2,3-d]pyrimidine derivatives and their salts, compositions containing them and their use as ASK1 inhibitors in the treatment of inflammation and pain are claimed. The compounds have a broad potential utility with osteoarthritis and neuropathic pain among the likely preferred indications. PMID- 22917154 TI - Personalized medicine: applying 'omics' to lung fibrosis. AB - Idiopathic pulmonary fibrosis (IPF), the most common fibrotic lung disease, is a chronic disease of unknown etiology with a very high mortality. Personalized medicine focuses on the use of the individual's molecular and 'omic' (i.e., genomic, epigenomic and proteomic) information to direct more efficient and cost effective strategies for prevention, diagnosis, outcome prediction and treatment of diseases. In this review, we describe the use and promise of applying 'omic' technologies to the familial and sporadic forms of IPF as a means to personalize diagnosis and outcome prediction in IPF. The validation and implementation of such approaches will be crucial to personalize IPF patient care, prioritize lung transplant and stratify patients for drug studies, as well as, in the future, predict response to therapies as they emerge. PMID- 22917159 TI - Using physiological data to predict future career progression in 14- to 17-year old Austrian soccer academy players. AB - The crux of any soccer-specific talent identification programme is to determine early predictors of future playing success (Williams & Reilly, 2000 ). We compare physiological characteristics among 14- to 17-year-old soccer academy players in terms of subsequent career progression ('drafted' vs. 'non-drafted'). In a longitudinal design (2001-2010), players passed through 10 fitness tests at four age levels: 14 (n = 410); 15 (n = 504); 16 (n = 456); and 17 years (n = 272). MANOVAs showed statistically significant (P < 0.05) superior performances for drafted players in all components ('speed', 'power and flexibility', 'coordination and endurance') and age categories. ANOVAs revealed significantly (P < 0.013) better performances for drafted players in almost all tests, with the largest effect sizes for shuttle sprint (eta2= 0.07-0.09), 20 m sprint (eta2= 0.04-0.05) and medicine ball throw (eta2=0.05-0.11). Follow up discriminant analyses confirmed that a combination of three variables correctly classified 62.7 to 66.2% of the players. Soccer-specific speed and power of upper limbs best discriminated future playing status, irrespective of age category. It is concluded that physiological measurements at adolescence can provide useful information in terms of predicting future career progression. PMID- 22917160 TI - Synthesis of bicyclic imidazoles via [2 + 3] cycloaddition between nitriles and regioselectively generated alpha-imino gold carbene intermediates. AB - The cyclic alpha-imino gold carbene intermediate B is most likely generated in situ via regioselective nitrene transfer from an azido group to a tethered terminal alkyne in the presence of a gold catalyst and at ambient temperature. This highly electrophilic intermediate can react with a weakly nucleophilic nitrile, which is used as the reaction solvent, to deliver a bicyclic imidazole rapidly in an overall bimolecular [2 + 2 + 1] cycloaddition and in mostly serviceable yield. The competing intramolecular Huisgen reaction, although likely also catalyzed by gold, is minimized by using AuCl(3) as the catalyst. PMID- 22917162 TI - Depth-dependent spin dynamics in thin films of TbPc2 nanomagnets explored by low energy implanted muons. AB - We present measurements of the magnetic properties of thin film TbPc(2) single molecule magnets evaporated on a gold substrate and compare them to those in bulk. Zero-field muon spin relaxation measurements were used to determine the molecular spin fluctuation rate of TbPc(2) as a function of temperature. At low temperature, we find that the fluctuations in films are much faster than in bulk and depend strongly on the distance between the molecules and the Au substrate. We measure a molecular spin correlation time that varies between 1.4 MUs near the substrate and 6.6 MUs far away from it. We attribute this behavior to differences in the packing of the magnetic cores, which change gradually on the scale of ~10 20 nm away from the TbPc(2)/Au interface. PMID- 22917161 TI - The discovery of [Ni(NHC)RCN]2 species and their role as cycloaddition catalysts for the formation of pyridines. AB - The reaction of Ni(COD)(2), IPr, and nitrile affords dimeric [Ni(IPr)RCN](2) in high yields. X-ray analysis revealed these species display simultaneous eta(1)- and eta(2)-nitrile binding modes. These dimers are catalytically competent in the formation of pyridines from the cycloaddition of diynes and nitriles. Kinetic analysis showed the reaction to be first order in [Ni(IPr)RCN](2), zeroth order in added IPr, zeroth order in nitrile, and zeroth order in diyne. Extensive stoichiometric competition studies were performed, and selective incorporation of the exogenous, not dimer bound, nitrile was observed. Post cycloaddition, the dimeric state was found to be largely preserved. Nitrile and ligand exchange experiments were performed and found to be inoperative in the catalytic cycle. These observations suggest a mechanism whereby the catalyst is activated by partial dimer-opening followed by binding of exogenous nitrile and subsequent oxidative heterocoupling. PMID- 22917163 TI - The practical value of comprehensive stool analysis in detecting the cause of idiopathic chronic diarrhea. AB - The practical diagnostic value of fecal analysis in the evaluation of patients with chronic nonbloody diarrhea is controversial. It is possible that variations in its value depend on how it is done and how the results are interpreted rather than on its intrinsic value. In the authors' city, stool analysis has been made easily accessible, with a commitment to quality assurance and interpretation. To evaluate its practical value, the results of stool analysis obtained on stool specimens submitted by gastroenterologists were retrospectively reviewed. The results indicate that stool analysis has substantial practical diagnostic value in patients with chronic diarrhea. PMID- 22917164 TI - Colorectal normal histology and histopathologic findings in patients with chronic diarrhea. AB - Collagenous and lymphocytic colitis are common causes of chronic watery diarrhea that are characterized by distinct histopathologic abnormalities without endoscopically visible lesions and are summarized as microscopic colitis. Several variants of microscopic colitis have been described, although their clinical significance still has to be defined. Preserved mucosal architecture is a histologic hallmark of microscopic colitis and distinguishes the disease from inflammatory bowel disease (IBD). In addition to architectural abnormalities, the diagnosis of IBD rests on characteristic inflammatory changes. Differential diagnosis of IBD mainly includes prolonged infection and diverticular disease associated colitis, also known as segmental colitis associated with diverticulosis. PMID- 22917165 TI - Bacterial flora as a cause or treatment of chronic diarrhea. AB - Intestinal microflora can be considered an organ of the body. It has several functions in the human gut, mostly metabolic and immunologic, and constantly interacts with the intestinal mucosa in a delicate equilibrium. Chronic diarrhea is associated with an alteration of gut microbiota when a pathogen invades the gut and also in several conditions associated with intestinal mucosal damage or bowel dysfunction, as in inflammatory bowel disease, irritable bowel syndrome, or small bowel bacterial overgrowth. This article discusses the basis of gut microbiota modulation. Evidence for the efficacy of gut microbiota modulation in chronic conditions is also discussed. PMID- 22917166 TI - Diarrhea caused by circulating agents. AB - Circulating agents cause intestinal secretion or changes in motility with decreased intestinal transit time, resulting in secretory-type diarrhea. Secretory diarrhea as opposed to osmotic diarrhea is characterized by large volume, watery stools, often more than 1 L per day; by persistence of diarrhea when patients fast; and by the fact that on analysis of stool-water, measured osmolarity is identical to that calculated from the electrolytes present. Although sodium plays the main role in water and electrolyte absorption, chloride is the major ion involved in secretion. PMID- 22917167 TI - Diarrhea caused by carbohydrate malabsorption. AB - This article will focus on the role of the colon in the pathogenesis of diarrhea in carbohydrate malabsorption or physiologically incomplete absorption of carbohydrates, and on the most common manifestation of carbohydrate malabsorption, lactose malabsorption. In addition, incomplete fructose absorption, the role of carbohydrate malabsorption in other malabsorptive diseases, and congenital defects that lead to malabsorption will be covered. The article concludes with a section on diagnostic tools to evaluate carbohydrate malabsorption. PMID- 22917168 TI - Functional diarrhea. AB - Chronic diarrhea is a frequent and challenging problem in clinical medicine. In a considerable subgroup of these, no underlying cause is identified and this is referred to as functional diarrhea. A consensus definition for functional diarrhea is based on loose stool consistency and chronicity and absence of coexisting irritable bowel syndrome. Underlying pathophysiology includes rapid intestinal transit, which may be worsened by stress or be triggered by a preceding infectious gastroenteritis. Diagnostic work-up aims at exclusion of underlying organic disease. Treatment starts with dietary adjustments, aiming at decreasing nutrients that enhance transit and stool and at identifying precipitating food items. PMID- 22917169 TI - Celiac disease. AB - Celiac disease is common, affecting approximately 1 in 100 people, yet it remains underdiagnosed. This article reviews our current understanding of celiac disease, diagnosis, and common pitfalls. Although the cornerstone of treatment is a gluten free diet, some patients may still have persisting symptoms and warrant further investigations. PMID- 22917170 TI - Diarrhea in chronic inflammatory bowel diseases. AB - Diarrhea is a common clinical feature of inflammatory bowel diseases and may be accompanied by abdominal pain, urgency, and fecal incontinence. The pathophysiology of diarrhea in these diseases is complex, but defective absorption of salt and water by the inflamed bowel is the most important mechanism involved. In addition to inflammation secondary to the disease, diarrhea may arise from a variety of other conditions. It is important to differentiate the pathophysiologic mechanisms involved in the diarrhea in the individual patient to provide the appropriate therapy. This article reviews microscopic colitis, ulcerative colitis, and Crohn's disease, focusing on diarrhea. PMID- 22917171 TI - Diarrhea in the immunocompromised patient. AB - Diarrhea is a common problem in patients with immunocompromising conditions. The etiologic spectrum differs from patients with diarrhea who have a normal immune system. This article reviews the most important causes of diarrhea in immunocompromised patients, ranging from infectious causes to noninfectious causes of diarrhea in the setting of HIV infection as a model for other conditions of immunosuppression. It also deals with diarrhea in specific situations, eg, after hematopoietic stem cell or solid organ transplantation, diarrhea induced by immunosuppressive drugs, and diarrhea in congenital immunodeficiency syndromes. PMID- 22917172 TI - Chronic diarrheal disorders. Preface. PMID- 22917174 TI - Stereoselective synthesis of 2,3-disubstituted indoline diastereoisomers by chemoenzymatic processes. AB - Racemic indolines including a variety of structural motifs such as C-2 and C-3 substitutions (alkyl or aryl), cis/trans relative stereochemistry and functionalization of the aromatic ring (fluoro, methyl or methoxy groups) have been efficiently prepared through Fischer indolization and subsequent diastereoselective reduction of the unprotected indoles. Combination of Candida antarctica lipase type A and allyl 3-methoxyphenyl carbonate has been identified as the best tandem for their kinetic resolutions, observing excellent stereodiscriminations for most of the tested indolines. PMID- 22917173 TI - Elevated levels of serum amyloid A indicate poor prognosis in patients with esophageal squamous cell carcinoma. AB - BACKGROUND: Increase of Serum amyloid A (SAA) level has been observed in patients with a variety of cancers. The objective of this study was to determined whether SAA level could be used as a prognostic parameter in patients with esophageal squamous cell carcinoma (ESCC). METHODS: SAA levels were measured by rate nephelometry immunoassay in 167 healthy controls and 167 ESCC patients prior to surgical resection. Statistical associations between clinicopathological observations and SAA levels were determined using the Mann-Whitney U test. The clinical value of SAA level as a prognostic parameter was evaluated using the Cox's proportional hazards model. RESULTS: SAA levels were significantly higher in patients with ESCC compared to levels in healthy controls (13.88 +/- 15.19 mg/L vs. 2.26 +/- 1.66 mg/L, P < 0.001). Elevation of SAA levels (>= 8.0 mg/L) was observed in 54.5% (91/167) of patients with ESCC but not in healthy controls. SAA levels were associated with tumor size (P < 0.001), histological differentiation (P = 0.015), T classification (P < 0.001), clinical stage (P < 0.001), lymph node metastasis (P < 0.001) and distant metastasis (P < 0.001), but not with the age and gender of the patients or tumor location. Multivariate analysis revealed that patients with an elevated level of SAA (>= 8.0 mg/L) had significantly lower 5-year survival rate than those with non-elevated SAA (< 8.0 mg/L, log-rank P < 0.0001). CONCLUSIONS: An elevated level of preoperative SAA was found to associate with tumor progression and poor survival in patients with ESCC. PMID- 22917175 TI - Clinical and molecular characterization of a Han Chinese family with high penetrance of essential hypertension. AB - Mutations in mitochondrial DNA are associated with cardiovascular diseases. We reported here molecular characterization of a three-generation Han Chinese family with maternally transmitted hypertension. Most strikingly, this family exhibited a high penetrance of hypertension. Sequence analysis of mitochondrial genome showed the presence of 12,338T>C mutation and 12,330A>G mutation and distinct sets of polymorphisms belonging to the Asian haplogroup F2b. Interestingly, the well-known 12,338T>C mutation, which caused a change of methionine in the translational initiation codon of ND5, also localized in two nucleotides adjacent to the 3' end of tRNA(Leu(CUN)), was implied to cause a decrease in ND5 mRNA level as well as to alter tRNA(Leu(CUN)) stability level. Moreover, the highly conserved 12,330A>G mutation, which disrupted the base pairing (6T-67A) in acceptor arm of tRNA(Leu(CUN)), may result in the failure of tRNA(Leu(CUN)) metabolism. Therefore, the combination of ND5 12,338T>C and tRNA(Leu(CUN)) 12,330A>G mutations may contribute to the high penetrance of hypertension in this Chinese family. PMID- 22917176 TI - Metabolic profiling assisted quality control of phorbolesters in Jatropha curcas seed by high-performance liquid chromatography using a fused-core column. AB - In this work, fast and sensitive high-performance liquid chromatography (HPLC) coupled with multivariate analysis was utilized to evaluate the metabolic profiling of Jatropha curcas seed and screen the marker compounds of phorbolesters (PEs), which significantly contributed to the metabolic profiling for quality control of PEs in J. curcas seed. Thirty-two peaks were separated and detected in J. curcas seed on a fused-core C(18) column between 2 and 25 min. Principal component analysis (PCA) and hierarchical cluster analysis (HCA) of the chromatographic data demonstrated that 12 batches of J. curcas seed could be well differentiated and categorized into 5 groups. Especially, one sample obtained from Lijiang Yunan was significantly different from the others. Partial least squares discriminant analysis (PLS-DA) showed that the metabolic profiling differentiation might be explained by 9 components including J.factors C(1)-C(5) of PEs, peak 21 (similar to J.factor C(1)) and 3 peaks (peaks 1, 9, and 10) significantly different in retention time from the PEs. The observation that the content levels of J.factors C(1) and C(2) plus peak 21 (equivalent to J.factor C(1)) were more relevant to the multivariate chromatographic data than the ones of J.factors C(3)-C(5) was confirmed by the PLS prediction models. The results of the present study indicated not only that J.factors C(1) and C(2) were the more rational markers representing the comprehensive quality of PEs in J. curcas seed but also that peak 21 (similar to J.factor C(1)) was a rational marker, too. PMID- 22917177 TI - Comparison between mechanical properties of human saphenous vein and umbilical vein. AB - BACKGROUND: As a main cause of mortality in developed countries, Coronary Artery Disease (CAD) is known as silent killer with a considerable cost to be dedicated for its treatment. Coronary Artery Bypass Graft (CABG) is a common remedy for CAD for which different blood vessels are used as a detour. There is a lack of knowledge about mechanical properties of human blood vessels used for CABG, and while these properties have a great impact on long-term patency of a CABG. Thus, studying these properties, especially those of human umbilical veins which have not been considered yet, looks utterly necessary. METHODS: Umbilical vein, as well as human Saphenous vein, are respectively obtained after cesarean and CABG. First, histological tests were performed to investigate different fiber contents of the samples. Having prepared samples carefully, force-displacement results of samples were rendered to real stress-strain measurements and then a fourth-order polynomial was used to prove the non-linear behavior of these two vessels. RESULTS: Results were analyzed in two directions, i.e. circumferentially and longitudinally, which then were compared with each other. The comparison between stiffness and elasticity of these veins showed that Saphenous vein's stiffness is much higher than that of umbilical vein and also, it is less stretchable. Furthermore, for both vessels, longitudinal stiffness was higher than that of circumferential and in stark contrast, stretch ratio in circumferential direction came much higher than longitudinal orientation. CONCLUSION: Blood pressure is very high in the region of aorta, so there should be a stiff blood vessel in this area and previous investigations showed that stiffer vessels would have a better influence on the flow of bypass. To this end, the current study has made an attempt to compare these two blood vessels' stiffness, finding that Saphenous vein is stiffer than umbilical vein which is somehow as stiff as rat aortic vessels. As blood vessel's stiffness is directly related to elastin and mainly collagen content, results showed the lower amount of these two contents in umbilical vein regarding Saphenous vein. PMID- 22917178 TI - 'Who's who' in renal sphaerosporids (Bivalvulida: Myxozoa) from common carp, Prussian carp and goldfish--molecular identification of cryptic species, blood stages and new members of Sphaerospora sensu stricto. AB - Myxozoans are a group of diverse, spore-forming metazoan microparasites bound to aquatic environments. Sphaerospora dykovae (previously S. renicola) causes renal sphaerosporosis and acute swim bladder inflammation (SBI) in juvenile Cyprinus carpio carpio, in central Europe. A morphologically similar species with comparably low pathogenicity, S. angulata has been described from C. c. carpio, Carassius auratus auratus and Carassius gibelio. To clarify uncertainties and ambiguities in taxon identification in these hosts we decided to re-investigate differences in spore morphology using a statistical approach, in combination with SSU and LSU rDNA sequence analyses. We found that developing spores of S. angulata and S. dykovae cannot be distinguished morphologically and designed a duplex PCR assay for the cryptic species that demonstrated S. dykovae is specific to C. c. carpio, whereas S. angulata infects C. a. auratus and C. gibelio. The molecular identification of myxozoan blood stages in common carp and goldfish, which had previously been ascribed to Sphaerospora spp. showed that approximately 75% of blood stages were from non-sphaerosporid coelozoic species infecting these cyprinids and more than 10% were from an alien species, Myxobilatus gasterostei, developing in sticklebacks. We hereby report non-selective myxozoan host invasion and multi-species infections, whose role in SBI still requires clarification. PMID- 22917180 TI - An interview with Yuichi Sugiyama. PMID- 22917179 TI - Is knee osteoarthritis a symmetrical disease? Analysis of a 12 year prospective cohort study. AB - BACKGROUND: The aim of this study was to document the development of bilateral knee osteoarthritis over a 12 year period using a middle-aged population-based cohort with knee pain at inclusion. METHODS: One hundred and forty three patients aged 35 to 54 were recruited from a population based cohort of 279 subjects who had knee pain at baseline and assessed with clinical and radiographic data, with 5 and 12 year follow up. The data was analysed with regard to the development and progression of uni- and bilateral knee osteoarthritis over 12 years. A definition of KL = 1 was used to define radiographic disease. RESULTS: 24 of the 30 (80%) patients with unilateral disease at baseline developed bilateral disease after 12 years. At baseline 37 patients (26%) had bilateral disease, whereas that number increased to 65 (52%) at 5 years and 100 (70%) at the 12 year follow up. The most common pattern was medial compartment involvement in both knees. Six patients had lateral compartment disease in one knee and medial in the other whereas only two had lateral compartment disease bilaterally. CONCLUSIONS: Bilateral knee osteoarthritis is very common with time, as the majority of sufferers will eventually develop radiographic disease in both knees. Clinicians need to be aware of the 'joint at risk' and researchers need to remember to account for both knees when assessing the relationship between physical function, pain and structural disease. The other knee should not be used for comparison, even if it appears to be normal at baseline. PMID- 22917181 TI - Poly-alpha,beta-DL-aspartyl-L-cysteine: a novel nanomaterial having a porous structure, special complexation capability for Pb(II), and selectivity of removing Pb(II). AB - Poly-alpha,beta-DL-aspartic acid is known as a green chelant of various metal ions. To provide a novel nanochelant for treating Pb(II) poisoning, poly alpha,beta-DL-aspartic acid was modified with L-Cys to form poly-alpha,beta-DL aspartyl-L-cysteine (PDC; MW, 27273). DL-Asp was converted into polysuccinimide through a thermal polycondensation, and the amidation of polysuccinimide with L Cys provided PDC. In water, PDC formed various porous nanospecies. In the mouse lead intoxication model, both intraperitoneal and oral administration of PDC (0.1, 1.0, and 10.0 nmol/kg) dose dependently removed Pb(II) accumulated in the organ, bone, and blood. PDC did not remove the essential metals including Cu(2+), Fe(2+), Mn(2+), Zn(2+), and Ca(2+) of the treated mice. The porous feature and size of the pH- and concentration-dependent nanospecies of PDC benefited the removal of Pb(II). PMID- 22917182 TI - Development of a fluorogenic probe with a transesterification switch for detection of histone deacetylase activity. AB - Histone deacetylases (HDACs) are key enzymatic regulators of many cellular processes such as gene expression, cell cycle, and tumorigenesis. These enzymes are attractive targets for drug development. However, very few simple methods for monitoring HDAC activity have been reported. Here, we have developed a fluorogenic probe, K4(Ac)-CCB, which consists of the histone H3 peptide containing acetyl-Lys and a coumarin fluorophore with a carbonate ester. By the simple addition of the probe to a HDAC solution, enzyme activity was clearly detected through spontaneous intramolecular transesterification, which renders the probe fluorescent. In addition, K4(Ac)-CCB can be applied to the evaluation of HDAC inhibitor activity. This is the first report to demonstrate the monitoring of HDAC activity by using a one-step procedure. Thus, our novel fluorogenic probe will provide a powerful tool for epigenetic research and the discovery of HDAC-targeted drugs. PMID- 22917184 TI - Life on two tracks. PMID- 22917185 TI - CDS: a fold-change based statistical test for concomitant identification of distinctness and similarity in gene expression analysis. AB - The problem of identifying differential activity such as in gene expression is a major defeat in biostatistics and bioinformatics. Equally important, however much less frequently studied, is the question of similar activity from one biological condition to another. The fold-change, or ratio, is usually considered a relevant criterion for stating difference and similarity between measurements. Importantly, no statistical method for concomitant evaluation of similarity and distinctness currently exists for biological applications. Modern microarray, digital PCR (dPCR), and Next-Generation Sequencing (NGS) technologies frequently provide a means of coefficient of variation estimation for individual measurements. Using fold-change, and by making the assumption that measurements are normally distributed with known variances, we designed a novel statistical test that allows us to detect concomitantly, thus using the same formalism, differentially and similarly expressed genes (http://cds.ihes.fr). Given two sets of gene measurements in different biological conditions, the probabilities of making type I and type II errors in stating that a gene is differentially or similarly expressed from one condition to the other can be calculated. Furthermore, a confidence interval for the fold-change can be delineated. Finally, we demonstrate that the assumption of normality can be relaxed to consider arbitrary distributions numerically. The Concomitant evaluation of Distinctness and Similarity (CDS) statistical test correctly estimates similarities and differences between measurements of gene expression. The implementation, being time and memory efficient, allows the use of the CDS test in high-throughput data analysis such as microarray, dPCR, and NGS experiments. Importantly, the CDS test can be applied to the comparison of single measurements (N=1) provided the variance (or coefficient of variation) of the signals is known, making CDS a valuable tool also in biomedical analysis where typically a single measurement per subject is available. PMID- 22917186 TI - Microarray analysis of ageing-related signatures and their expression in tumors based on a computational biology approach. AB - Ageing and cancer have been associated with genetic and genomic changes. The identification of common signatures between ageing and cancer can reveal shared molecular mechanisms underlying them. In this study, we collected ageing-related gene signatures from ten published studies involved in six different human tissues and an online resource. We found that most of these gene signatures were tissue-specific and a few were related to multiple tissues. We performed a genome wide examination of the expression of these signatures in various human tumor types, and found that a large proportion of these signatures were universally differentially expressed among normal vs. tumor phenotypes. Functional analyses of the highly-overlapping genes between ageing and cancer using DAVID tools have identified important functional categories and pathways linking ageing with cancer. The convergent and divergent mechanisms between ageing and cancer are discussed. This study provides insights into the biology of ageing and cancer, suggesting the possibility of potential interventions aimed at postponing ageing and preventing cancer. PMID- 22917187 TI - B-cell ligand processing pathways detected by large-scale comparative analysis. AB - The initiation of B-cell ligand recognition is a critical step for the generation of an immune response against foreign bodies. We sought to identify the biochemical pathways involved in the B-cell ligand recognition cascade and sets of ligands that trigger similar immunological responses. We utilized several comparative approaches to analyze the gene coexpression networks generated from a set of microarray experiments spanning 33 different ligands. First, we compared the degree distributions of the generated networks. Second, we utilized a pairwise network alignment algorithm, BiNA, to align the networks based on the hubs in the networks. Third, we aligned the networks based on a set of KEGG pathways. We summarized our results by constructing a consensus hierarchy of pathways that are involved in B cell ligand recognition. The resulting pathways were further validated through literature for their common physiological responses. Collectively, the results based on our comparative analyses of degree distributions, alignment of hubs, and alignment based on KEGG pathways provide a basis for molecular characterization of the immune response states of B-cells and demonstrate the power of comparative approaches (e.g., gene coexpression network alignment algorithms) in elucidating biochemical pathways involved in complex signaling events in cells. PMID- 22917188 TI - Overexpression of annexin A2 is associated with abnormal ubiquitination in breast cancer. AB - Abnormal expression of annexin A2 contributes to metastasis and infiltration of cancer cells. To elucidate the cause of abnormal expression of annexin A2, Western blotting, immunoproteomics and immunohistochemical staining were performed to analyze differentially ubiquitinated proteins between fresh breast cancer tissue and its adjacent normal breast tissue from five female volunteers. We detected an ubiquitinated protein that was up-regulated in the cancer tissue, which was further identified as annexin A2 by mass spectrometry. These results suggest that abnormal ubiquitination and/or degradation of annexin A2 may lead to presence of annexin A2 at high level, which may further promote metastasis and infiltration of the breast cancer cells. PMID- 22917189 TI - Computational analysis of position-dependent disorder content in DisProt database. AB - A bioinformatics analysis of disorder content of proteins from the DisProt database has been performed with respect to position of disordered residues. Each protein chain was divided into three parts: N- and C- terminal parts with each containing 30 amino acid (AA) residues and the middle region containing the remaining AA residues. The results show that in terminal parts, the percentage of disordered AA residues is higher than that of all AA residues (17% of disordered AA residues and 11% of all). We analyzed the percentage of disorder for each of 20 AA residues in the three parts of proteins with respect to their hydropathy and molecular weight. For each AA, the percentage of disorder in the middle part is lower than that in terminal parts which is comparable at the two termini. A new scale of AAs has been introduced according to their disorder content in the middle part of proteins: CIFWMLYHRNVTAGQDSKEP. All big hydrophobic AAs are less frequently disordered, while almost all small hydrophilic AAs are more frequently disordered. The results obtained may be useful for construction and improving predictors for protein disorder. PMID- 22917190 TI - A modified statistically optimal null filter method for recognizing protein coding regions. AB - Computer-aided protein-coding gene prediction in uncharacterized genomic DNA sequences is one of the most important issues of biological signal processing. A modified filter method based on a statistically optimal null filter (SONF) theory is proposed for recognizing protein-coding regions. The square deviation gain (SDG) between the input and output of the model is used to identify the coding regions. The effective SDG amplification model with Class I and Class II enhancement is designed to suppress the non-coding regions. Also, an evaluation algorithm has been used to compare the modified model with most gene prediction methods currently available in terms of sensitivity, specificity and precision. The performance for identification of protein-coding regions has been evaluated at the nucleotide level using benchmark datasets and 91.4%, 96%, 93.7% were obtained for sensitivity, specificity and precision, respectively. These results suggest that the proposed model is potentially useful in gene finding field, which can help recognize protein-coding regions with higher precision and speed than present algorithms. PMID- 22917191 TI - Evaluation of WO-2012085582 and WO-2012085583 two identified MABAs: backups to AZD-2115? AB - These two patent applications each claim combination formulations comprising a single dual-acting muscarinic antagonist/beta 2 agonist (MABA), as a free base or salt, with a second class of drug and the use of these formulations for the treatment of asthma and COPD. The two specified compounds are close analogues of each other and were originally disclosed in the same patent application. They are, respectively, 3-(2-chloro-3-((4-(2-ethylthiazole-4-carbonyl)-1-oxa-4,9 diazaspiro[5.5]undecan-9-yl)methyl)phenethoxy)-N-cyclopentyl-N-(2-(2-(5-hydroxy-3 oxo-3,4-dihydro-2H-benzo[b]{1,4] oxazin-8-yl)ethylamino)ethyl)propanamide and N butyl-N-(2-(2-(5-hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][l,4]oxazin-8 yl)ethylamino)ethyl)-3-(3-(2-(4-(2-isopropylthiazole-4-carbonyl)-1-oxa-4,9 diazaspiro[5.5]undecan-9-yl)ethyl)phenethoxy)propanamide. PMID- 22917192 TI - Ostwald's Rule of Stages and its role in CdSe quantum dot crystallization. AB - A century ago Ostwald described the "Rule of Stages" after deducing that crystal formation must occur through a series of intermediate crystallographic phases prior to formation of the final thermodynamically stable structure. Direct evidence of the Rule of Stages is lacking, and the theory has not been implemented to allow isolation of a selected structural phase. Here we report the role of Ostwald's Rule of Stages in the growth of CdSe quantum dots (QDs) from molecular precursors in the presence of hexadecylamine. It is observed that, by controlling the rate of growth through the reaction stoichiometry and therefore the probability of ion-packing errors in the growing QD, the initially formed zinc blende (ZB) critical nuclei representing the kinetic phase can be maintained at sizes >14 nm in diameter without phase transformation to the thermodynamic wurtzite (WZ) structure. An intermediate pseudo-ZB structure is observed to appear at intermediate reaction conditions, as predicted by Ostwald. The ZB and pseudo-ZB structures convert to the WZ lattice above a critical melting temperature. This study validates Ostwald's Rule of Stages and provides a phase diagram for growth of CdSe QDs exhibiting a specific crystallographic motif. PMID- 22917193 TI - Very high gravity ethanol fermentation by flocculating yeast under redox potential-controlled conditions. AB - BACKGROUND: Very high gravity (VHG) fermentation using medium in excess of 250 g/L sugars for more than 15% (v) ethanol can save energy consumption, not only for ethanol distillation, but also for distillage treatment; however, stuck fermentation with prolonged fermentation time and more sugars unfermented is the biggest challenge. Controlling redox potential (ORP) during VHG fermentation benefits biomass accumulation and improvement of yeast cell viability that is affected by osmotic pressure and ethanol inhibition, enhancing ethanol productivity and yield, the most important techno-economic aspect of fuel ethanol production. RESULTS: Batch fermentation was performed under different ORP conditions using the flocculating yeast and media containing glucose of 201 +/- 3.1, 252 +/- 2.9 and 298 +/- 3.8 g/L. Compared with ethanol fermentation by non flocculating yeast, different ORP profiles were observed with the flocculating yeast due to the morphological change associated with the flocculation of yeast cells. When ORP was controlled at -100 mV, ethanol fermentation with the high gravity (HG) media containing glucose of 201 +/- 3.1 and 252 +/- 2.9 g/L was completed at 32 and 56 h, respectively, producing 93.0 +/- 1.3 and 120.0 +/- 1.8 g/L ethanol, correspondingly. In contrast, there were 24.0 +/- 0.4 and 17.0 +/- 0.3 g/L glucose remained unfermented without ORP control. As high as 131.0 +/- 1.8 g/L ethanol was produced at 72 h when ORP was controlled at -150 mV for the VHG fermentation with medium containing 298 +/- 3.8 g/L glucose, since yeast cell viability was improved more significantly. CONCLUSIONS: No lag phase was observed during ethanol fermentation with the flocculating yeast, and the implementation of ORP control improved ethanol productivity and yield. When ORP was controlled at -150 mV, more reducing power was available for yeast cells to survive, which in turn improved their viability and VHG ethanol fermentation performance. On the other hand, controlling ORP at -100 mV stimulated yeast growth and enhanced ethanol production under the HG conditions. Moreover, the ORP profile detected during ethanol fermentation with the flocculating yeast was less fluctuated, indicating that yeast flocculation could attenuate the ORP fluctuation observed during ethanol fermentation with non-flocculating yeast. PMID- 22917195 TI - In this issue/abstract thinking: update your socioeconomic status. PMID- 22917194 TI - Synthesis of 5'-methylene-phosphonate furanonucleoside prodrugs: application to D 2'-deoxy-2'-alpha-fluoro-2'-beta-C-methyl nucleosides. AB - A new and facile synthetic pathway to metabolically stable 5'-methylene bis(pivaloyloxymethyl)(POM)phosphonate furanonucleoside prodrugs is reported. The key step involves a Horner-Wadsworth-Emmons reaction of a tetra(pivaloyloxymethyl) bisphosphonate salt with appropriately protected 5' aldehydic nucleosides. This efficient approach was applied for the synthesis HCV related 2'-deoxy-2'-alpha-fluoro-2'-beta-C-methyl nucleosides. PMID- 22917196 TI - Building a treatment safety net for children in child welfare programs. PMID- 22917197 TI - Boundary crossings and violations: time for child psychiatry to catch up. PMID- 22917198 TI - What we can all learn from the Treatment of Early Age Mania (TEAM) trial. PMID- 22917199 TI - Factors that contribute to caregiver burden for parents of children with autism spectrum disorder or attention-deficit/hyperactivity disorder. PMID- 22917201 TI - Caregiver burden as people with autism spectrum disorder and attention deficit/hyperactivity disorder transition into adolescence and adulthood in the United Kingdom. AB - OBJECTIVE: There is increasing recognition that autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD) are associated with significant costs and burdens. However, research on their impact has focused mostly on the caregivers of young children; few studies have examined caregiver burden as children transition into adolescence and young adulthood, and no one has compared the impact of ASD to other neurodevelopmental disorders (e.g., ADHD). METHOD: We conducted an observational study of 192 families caring for a young person (aged 14 to 24 years) with a childhood diagnosis of ASD or ADHD (n = 101 and n = 91, respectively) in the United Kingdom. A modified stress-appraisal model was used to investigate the correlates of caregiver burden as a function of family background (parental education), primary stressors (symptoms), primary appraisal (need), and resources (use of services). RESULTS: Both disorders were associated with a high level of caregiver burden, but it was significantly greater in ASD. In both groups, caregiver burden was mainly explained by the affected young person's unmet need. Domains of unmet need most associated with caregiver burden in both groups included depression/anxiety and inappropriate behavior. Specific to ASD were significant associations between burden and unmet needs in domains such as social relationships and major mental health problems. CONCLUSIONS: Adolescence and young adulthood are associated with high levels of caregiver burden in both disorders; in ASD, the level is comparable to that reported by persons caring for individuals with a brain injury. Interventions are required to reduce caregiver burden in this population. PMID- 22917200 TI - Treatment moderators and predictors of outcome in the Treatment of Early Age Mania (TEAM) study. AB - OBJECTIVE: Both the diagnosis and treatment of bipolar disorder in youth remain the subject of debate. In the Treatment of Early Age Mania (TEAM) study, risperidone was more effective than lithium or divalproex in children diagnosed with bipolar mania and highly comorbid with attention-deficit/hyperactivity disorder (ADHD). We searched for treatment moderators and predictors of outcome. METHOD: TEAM was a multi-site, 8-week, randomized clinical trial of risperidone, lithium, or divalproex in 279 medication-naive patients, aged 6 through 15 years, with a DSM-IV diagnosis of bipolar disorder currently in manic or mixed phase. Outcome measures included binary end-of-treatment responder status and change in the Kiddie Schedule for Affective Disorders and Schizophrenia (K-SADS) Mania Rating Scale (KMRS). Baseline demographics and clinical characteristics were tested as modifiers of treatment effect and as overall predictors of outcome. RESULTS: Moderator effects were detected for site, ADHD, and obesity. Across sites, the response ratio (RR) for risperidone versus lithium ranged from 1.2 (95% confidence interval [CI] = 0.8-1.7) to 8.3 (95% CI = 1.1-60.8), and for risperidone versus divalproex from 1.3 (95% CI = 0.8-2.2) to 10.5 (95% CI = 1.4 77.7). The RR for risperidone versus lithium was 2.1 for patients with ADHD, but 1.0 for those without ADHD, and 2.3 (95% CI = 1.6-3.3) for nonobese patients, but 1.1 (95% CI = 0.6-2.0) for obese ones. Older age and less severe ADHD symptoms were associated with greater improvement on the KMRS. CONCLUSIONS: Risperidone was more effective than lithium or divalproex across the demographics and clinical characteristics of the sample, but the magnitude of its effect was influenced by site-related characteristics and presence of ADHD. Clinical trial registration information--Treatment of Early Age Mania; http://clinicaltrials.gov/; NCT00057681. PMID- 22917202 TI - Relational aggression in children with preschool-onset psychiatric disorders. AB - OBJECTIVE: The role of preschool-onset (PO) psychiatric disorders as correlates and/or risk factors for relational aggression during kindergarten or first grade was tested in a sample of 146 preschool-age children (age 3 to 5.11 years). METHOD: Axis-I diagnoses and symptom scores were derived using the Preschool Age Psychiatric Assessment. Children's roles in relational aggression as aggressor, victim, aggressive-victim, or nonaggressor/nonvictim were determined at preschool and again 24 months later at elementary school entry. RESULTS: Preschoolers diagnosed with PO psychiatric disorders were three times as likely as the healthy preschoolers to be classified aggressors, victims, or aggressive-victims. Children diagnosed with PO disruptive, depressive, and/or anxiety disorders were at least six times as likely as children without PO psychiatric disorders to become aggressive-victims during elementary school after covarying for other key risk factors. CONCLUSIONS: Findings suggested that PO psychiatric disorders differentiated preschool and school-age children's roles in relational aggression based on teacher report. Recommendations for future research and preventative intervention aimed at minimizing the development of relational aggression in early childhood by identifying and targeting PO psychiatric disorders are made. PMID- 22917204 TI - Abnormal functional activation and connectivity in the working memory network in early-onset schizophrenia. AB - OBJECTIVE: Disruption within the working memory (WM) neural network is considered an integral feature of schizophrenia. The WM network, and the dorsolateral prefrontal cortex (DLPFC) in particular, undergo significant remodeling in late adolescence. Potential interactions between developmental changes in the WM network and disease-related processes for schizophrenia remain unclear. The aim of this study was to determine whether DLPFC activation and functional connectivity are impaired during WM in patients with early-onset schizophrenia (EOS; age of onset <18 years). METHOD: We used functional magnetic resonance imaging and psychophysiological interaction analysis to respectively measure blood oxygenation level-dependent signal and to derive functional connectivity estimates in response to the two-back WM task from 25 youths with EOS and 20 matched healthy adolescents. RESULTS: Compared with healthy adolescents, patients with EOS showed reduced engagement of the DLPFC, the anterior cingulate cortex (ACC), and frontal operculum, and had reduced DLPFC connectivity within the WM network. Patients with EOS showed abnormal reduction in the coupling of the DLPFC with the ACC, the inferior parietal lobule, and the middle occipital gyrus. In contrast to healthy adolescents, patients with EOS expressed age-related decrease in the activity of the DLPFC and an increase in its connectivity with the ACC. CONCLUSIONS: Patients with EOS show dysfunctional engagement and reduced integration within the WM neural network. The pattern of abnormal age-related correlations in DLPFC activity and connectivity suggests that schizophrenia related processes have an impact on brain regions that show significant late developmental changes. PMID- 22917203 TI - Error-related negativity and tic history in pediatric obsessive-compulsive disorder. AB - OBJECTIVE: The error-related negativity (ERN) is a negative deflection in the event-related potential after an incorrect response, which is often increased in patients with obsessive-compulsive disorder (OCD). However, the relation of the ERN to comorbid tic disorders has not been examined in patients with OCD. This study compared ERN amplitudes in patients with tic-related OCD, patients with non tic-related OCD, and healthy controls. METHOD: The ERN, correct response negativity, and error number were measured during an Eriksen flanker task to assess performance monitoring in 44 youth with a lifetime diagnosis of OCD and 44 matched healthy controls ranging in age from 10 to 19 years. Nine youth with OCD had a lifetime history of tics. RESULTS: ERN amplitude was significantly increased in patients with OCD compared with healthy controls. ERN amplitude was significantly larger in patients with non-tic-related OCD than in patients with tic-related OCD or controls. ERN amplitude had a significant negative correlation with age in healthy controls but not in patients with OCD. Instead, in patients with non-tic-related OCD, ERN amplitude had a significant positive correlation with age at onset of OCD symptoms. ERN amplitude in patients was unrelated to OCD symptom severity, current diagnostic status, or treatment effects. CONCLUSIONS: The results provide further evidence of increased error-related brain activity in pediatric OCD. The difference in the ERN between patients with tic-related and those with non-tic-related OCD provides preliminary evidence of a neurobiological difference between these two OCD subtypes. The results indicate the ERN is a trait-like measurement that may serve as a biomarker for non-tic-related OCD. PMID- 22917205 TI - Trajectories of early brain volume development in fragile X syndrome and autism. AB - OBJECTIVE: To examine patterns of early brain growth in young children with fragile X syndrome (FXS) compared with a comparison group (controls) and a group with idiopathic autism. METHOD: The study included 53 boys 18 to 42 months of age with FXS, 68 boys with idiopathic autism (autism spectrum disorder), and a comparison group of 50 typically developing and developmentally delayed controls. Structural brain volumes were examined using magnetic resonance imaging across two time points, at 2 to 3 and again at 4 to 5 years of age, and total brain volumes and regional (lobar) tissue volumes were examined. In addition, a selected group of subcortical structures implicated in the behavioral features of FXS (e.g., basal ganglia, hippocampus, amygdala) was studied. RESULTS: Children with FXS had larger global brain volumes compared with controls but were not different than children with idiopathic autism, and the rate of brain growth from 2 to 5 years of age paralleled that seen in controls. In contrast to children with idiopathic autism who had generalized cortical lobe enlargement, children with FXS showed specific enlargement in the temporal lobe white matter, cerebellar gray matter, and caudate nucleus, but a significantly smaller amygdala. CONCLUSIONS: This structural longitudinal magnetic resonance imaging study of preschoolers with FXS observed generalized brain overgrowth in children with FXS compared with controls, evident at age 2 and maintained across ages 4 to 5. In addition, different patterns of brain growth that distinguished boys with FXS from boys with idiopathic autism were found. PMID- 22917207 TI - Child and adolescent mental health research across the globe. PMID- 22917208 TI - Repetitive transcranial magnetic stimulation to treat early-onset auditory hallucinations. PMID- 22917206 TI - Blood-based gene expression signatures of infants and toddlers with autism. AB - OBJECTIVE: Autism spectrum disorders (ASDs) are highly heritable neurodevelopmental disorders that onset clinically during the first years of life. ASD risk biomarkers expressed early in life could significantly impact diagnosis and treatment, but no transcriptome-wide biomarker classifiers derived from fresh blood samples from children with autism have yet emerged. METHOD: Using a community-based, prospective, longitudinal method, we identified 60 infants and toddlers at risk for ASDs (autistic disorder and pervasive developmental disorder), 34 at-risk for language delay, 17 at-risk for global developmental delay, and 68 typically developing comparison children. Diagnoses were confirmed via longitudinal follow-up. Each child's mRNA expression profile in peripheral blood mononuclear cells was determined by microarray. RESULTS: Potential ASD biomarkers were discovered in one-half of the sample and used to build a classifier, with high diagnostic accuracy in the remaining half of the sample. CONCLUSIONS: The mRNA expression abnormalities reliably observed in peripheral blood mononuclear cells, which are safely and easily assayed in infants, offer the first potential peripheral blood-based, early biomarker panel of risk for autism in infants and toddlers. Future work should verify these biomarkers and evaluate whether they may also serve as indirect indices of deviant molecular neural mechanisms in autism. PMID- 22917209 TI - Could repetitive transcranial magnetic stimulation improve neurocognition in early-onset schizophrenia spectrum disorders? PMID- 22917211 TI - Practice parameter on gay, lesbian, or bisexual sexual orientation, gender nonconformity, and gender discordance in children and adolescents. AB - Children and adolescents who are growing up gay, lesbian, bisexual, gender nonconforming, or gender discordant experience unique developmental challenges. They are at risk for certain mental health problems, many of which are significantly correlated with stigma and prejudice. Mental health professionals have an important role to play in fostering healthy development in this population. Influences on sexual orientation, gender nonconformity, and gender discordance, and their developmental relationships to each other, are reviewed. Practice principles and related issues of cultural competence, research needs, and ethics are discussed. PMID- 22917212 TI - Efficacy of mesenchymal stem cells derived from human adipose tissue in inhibition of hepatocellular carcinoma cells in vitro. AB - Hepatocellular carcinoma (HCC) is often diagnosed at an advanced stage, and over the past several decades, many researchers have worked to develop novel effective therapies for HCC patients. The functional contributions of mesenchymal stem cells to human malignancies, including HCC growth and progression, are controversial, and the potential mechanisms underlying these effects are not clear. The aim of this study was to investigate the effect of adipose-derived mesenchymal stem cells (ADSCs) on the growth of HCC cells. In this study, a conditioned medium from ADSCs (ADSC-CM) efficiently inhibited HCC cell proliferation and division, and induced HCC cell death through the downregulation of Akt signaling. These findings indicated that the ADSC-CM could inhibit HCC growth. Thus, the ADSC-CM is a good candidate for the treatment of HCC patients for whom no effective therapy is available. PMID- 22917213 TI - 5-aza-2'-Deoxycytidine enhances the radiosensitivity of breast cancer cells. AB - PURPOSE: To investigate the effect of the DNA methyltransferase inhibitor, 5-aza 2'-deoxycytidine (DAC), on radiosensitivity in breast cancer cells. MATERIALS AND METHODS: Two breast cancer cell lines, MDA-MB-231 and MDA-MB-435, were evaluated. The methylation status and the mRNA expression of three genes (ER, PR, and HIC-1) that were frequently hypermethylated in these cell lines were determined as a function of DAC exposure. 3-(4,5)-dimethylthiahiazo-(-z-y1)-3,5-di phenytetrazoliumromide (MTT) absorbance and a colony-forming assay were used to estimate cell viability and radiosensitivity. Using cell-cycle analysis, gamma histone H2A (gamma-H2AX) formation assays and methylation-specific polymerase chain reaction (MSP) analysis of three genes correlated with radiosensitivity (BRCA1, 14-3-3sigma, and E-cadherin), the mechanism of DAC enhancement of radiosensitivity was explored. RESULTS: DAC induced the demethylation and reactivation of silent genes in both cell lines. The combination of DAC and irradiation induced growth suppression in vitro. DAC, 5 MUM, enhanced sensitivity to ionizing radiation. DAC followed by irradiation correlated with G2/M arrest and the retardation of repair of radiation-induced double strand breaks. DAC reversed the methylation status of genes connected with radiosensitization. The different radiosensitization effects observed with different breast cancers cells may correlate with the primary methylation status of radiosensitizing genes. CONCLUSIONS: Treatment strategies that include DAC present promising options for sensitizing breast cancer cells to irradiation. PMID- 22917214 TI - Identification of a new cytotoxic T-cell epitope p675 of human telomerase reverse transcriptase. AB - BACKGROUND: The identification of new tumor-associated antigens and epitopes is the prerequisite for cancer immunotherapy. The human telomerase catalytic subunit human telomerase reverse transcriptase (hTERT) is an attractive target for tumor therapy. The hTERT:540-548 peptide (p540, ILAKFLHWL) was previously identified as an HLA-A*0201-restricted T-cell epitope. However, other MHC-restricted epitopes in this antigen are urgently needed for an effective T-cell-based cancer treatment. The goal of this study was to identify other immunogenic peptides of hTERT restricted by HLA-A*0201 molecule, which accounts for about 15% of the Chinese population. METHODS: Computer algorithms were used for epitope prediction, followed by analyzation on the plate of Discovery Studio 2.5. The candidate peptides were verified by T2-cell-binding assay, ELISPOT analysis, flow cytometry examination, and in vitro and in vivo tumor inhibition assay. RESULTS: Six peptides were predicted by computer algorithms. Of these peptides, p540 and p675 (LLGASVLGL) were identified with lower binding free energies than the other four peptides, binding to HLA-A*02 more strongly, and elicited stronger IFN-gamma secretion of patients' peripheral blood mononuclear cells. The CTL clone against p675 elicited a significant cancer cell inhibition effect HLA-A*0201 restrictly. CONCLUSIONS: We identified p675 as a new HLA-A*0201-restricted T-cell epitope, and the CTL clone against it could suppress tumor growth effectively. PMID- 22917215 TI - Optochemogenetics (OCG) allows more precise control of genetic engineering in mice with CreER regulators. AB - New approaches that allow precise spatiotemporal control of gene expression in model organisms at the single cell level are necessary to better dissect the role of specific genes and cell populations in development, disease, and therapy. Here, we describe a new optochemogenetic switch (OCG switch) to control CreER/loxP-mediated recombination via photoactivatable ("caged") tamoxifen analogues in individual cells in cell culture, organoid culture, and in vivo in adult mice. This approach opens opportunities to more fully exploit existing CreER transgenic mouse strains to achieve more precise temporal- and location specific regulation of genetic events and gene expression. PMID- 22917217 TI - DNA barcoding of the ichthyofauna of Panuco-Tamesi complex: evidence for taxonomic conflicts in some groups. AB - The Panuco-Tamesi complex in eastern Mexico is globally recognized as an important ecoregion due to its high level of endemism. In this study, DNA barcodes were generated for 152 individuals of 31 species. Additionally, 170 DNA barcodes for the related species available in the Barcode of Life Database (BOLD) system were included to test the ability of barcoding technique to discriminate between the closely related species. DNA barcoding allowed the discrimination of 79.2% of the analyzed species; poor resolution was observed in four genera in which the levels of resolution ranged from 16.6% in the genus Herichthys to 77.7% in the genus Xiphophorus. The results of this study demonstrate that DNA barcoding is a useful exploratory tool but fails to discriminate between closely related species. PMID- 22917216 TI - Presence of three distinct genotypes within the Paragonimus westermani complex in northeastern India. AB - The name Paragonimus westermani (Kerbert, 1878) is commonly applied to members of a species complex that includes the well-known Asian lung fluke of medical and veterinary importance. Unambiguous molecular and morphological evidence showing the presence of a member of the complex in India has recently been published. In the present study we report the occurrence of 2 more members of the P. westermani complex in northeastern (NE) India. Surveys of the freshwater crabs Maydelliatelphusa lugubris in NE India revealed 2 morphologically distinct types of lung fluke metacercariae. Phylogenetic analyses, using DNA sequences from ITS2, 28S and cox1 gene regions indicate that these lung metacercariae belong to P. westermani complex. Type 1 metacercariae have a more basal position within the complex whereas type 2 metacercariae are closely related to the relatively derived forms of P. westermani from NE Asia (Japan, Korea, China) and Vietnam. A third type of metacercaria (type 3), detected in another crab host, Sartoriana spinigera in Assam, was phylogenetically close to P. siamensis, also a member of the P. westermani group. Molecular evidence has demonstrated the existence of 3 genotypes of lung flukes within the Paragonimus westermani complex in NE India. Two of these were previously unknown. PMID- 22917218 TI - Examining the ecological validity of the Talent Development Environment Questionnaire. AB - It is clear that high class expertise and effective practice exists within many talent development environments across the world. However, there is also a general consensus that widespread evidence-based policy and practice is lacking. As such, it is crucial to develop solutions which can facilitate effective dissemination of knowledge and promotion of evidence-based talent development systems. While the Talent Development Environment Questionnaire (Martindale et al., 2010 ) provides a method through which this could be facilitated, its ecological validity has remained untested. As such, this study aimed to investigate the real world applicability of the questionnaire through discriminant function analysis. Athletes across ten distinct regional squads and academies were identified and separated into two broad levels, 'higher quality' (n = 48) and 'lower quality' (n = 51) environments, based on their process quality and productivity. Results revealed that the Talent Development Environment Questionnaire was able to discriminate with 77.8% accuracy. Furthermore, in addition to the questionnaire as a whole, two individual features, 'quality preparation' (P < 0.01) and 'understanding the athlete' (P < 0.01), were found to be significant discriminators. In conclusion, the results indicate robust structural properties and sound ecological validity, allowing the questionnaire to be used with more confidence in applied and research settings. PMID- 22917219 TI - Change in health status (EQ-5D) over 5 years among individuals with and without type 2 diabetes mellitus in the SHIELD longitudinal study. AB - BACKGROUND: Health-related quality of life studies among adults with type 2 diabetes mellitus, using the EQ-5D, have been short term and have not assessed change over years. This study assessed the change in health status and health related quality of life over 5 years among individuals with and without diabetes. METHODS: Respondents to the US Study to Help Improve Early evaluation and management of risk factors Leading to Diabetes (SHIELD) completed the EuroQol-5D (EQ-5D) at baseline (2004) and 5 years later (2009). Visual analog scale (VAS) score and health index score were computed at baseline and year 5, and the change over 5 years was measured for individuals with type 2 diabetes mellitus (T2DM) and those without diabetes, and T2DM adults with and without diabetic complications. Linear regression models were used to determine change in EQ-5D score, controlling for age, gender, race, education, household income, and body mass index (BMI). RESULTS: There was significantly greater decline in the EQ-5D index score in the T2DM group (-0.031 [SD 0.158]), compared with those without diabetes (-0.016 [0.141], p = 0.001). Compared with respondents without diabetes, those with T2DM had a larger reduction in EQ-5D index score, after controlling for demographics (p = 0.001). EQ-5D VAS score declined over 5 years for both groups: -1.42 (18.1) for the T2DM group, and -0.63 (15.8) for the group without diabetes, but the between-group difference was not significant either before (p = 0.09) or after (p = 0.12), controlling for demographics. T2DM respondents with diabetic complications had a greater decline in EQ-5D scores than T2DM respondents without complications (p < 0.05). CONCLUSION: Over a 5-year period, health status of respondents with T2DM declined significantly compared with those with no diabetes, indicating that the burden of the disease has a long-term detrimental impact. This decline in health status is likely to impact utility scores (fewer quality-adjusted life years) for economic evaluations. PMID- 22917220 TI - Vaccinia virus-mediated intra-tumoral expression of matrix metalloproteinase 9 enhances oncolysis of PC-3 xenograft tumors. AB - BACKGROUND: Oncolytic viruses, including vaccinia virus (VACV), are a promising alternative to classical mono-cancer treatment methods such as surgery, chemo- or radiotherapy. However, combined therapeutic modalities may be more effective than mono-therapies. In this study, we enhanced the effectiveness of oncolytic virotherapy by matrix metalloproteinase (MMP-9)-mediated degradation of proteins of the tumoral extracellular matrix (ECM), leading to increased viral distribution within the tumors. METHODS: For this study, the oncolytic vaccinia virus GLV-1h255, containing the mmp-9 gene, was constructed and used to treat PC 3 tumor-bearing mice, achieving an intra-tumoral over-expression of MMP-9. The intra-tumoral MMP-9 content was quantified by immunohistochemistry in tumor sections. Therapeutic efficacy of GLV-1h255 was evaluated by monitoring tumor growth kinetics and intra-tumoral virus titers. Microenvironmental changes mediated by the intra-tumoral MMP-9 over-expression were investigated by microscopic quantification of the collagen IV content, the blood vessel density (BVD) and the analysis of lymph node metastasis formation. RESULTS: GLV-1h255 treatment of PC-3 tumors led to a significant over-expression of intra-tumoral MMP-9, accompanied by a marked decrease in collagen IV content in infected tumor areas, when compared to GLV-1h68-infected tumor areas. This led to considerably elevated virus titers in GLV-1h255 infected tumors, and to enhanced tumor regression. The analysis of the BVD, as well as the lumbar and renal lymph node volumes, revealed lower BVD and significantly smaller lymph nodes in both GLV 1h68- and GLV-1h255- injected mice compared to those injected with PBS, indicating that MMP-9 over-expression does not alter the metastasis-reducing effect of oncolytic VACV. CONCLUSIONS: Taken together, these results indicate that a GLV-1h255-mediated intra-tumoral over-expression of MMP-9 leads to a degradation of collagen IV, facilitating intra-tumoral viral dissemination, and resulting in accelerated tumor regression. We propose that approaches which enhance the oncolytic effect by increasing the intra-tumoral viral load, may be an effective way to improve therapeutic outcome. PMID- 22917221 TI - Wharton-fragmentation-based approach to the carbocyclic core of the phomoidrides. AB - The carbocyclic core of the phomoidrides has been synthesized efficiently and in high yield. Key steps include a phenolic oxidation/intramolecular Diels-Alder sequence, tandem radical cyclization, and a late-stage Wharton fragmentation of a densely functionalized isotwistane skeleton. PMID- 22917223 TI - Identification and location of hot and cold spots of treated prevalence of depression in Catalonia (Spain). AB - BACKGROUND: Spatial analysis is a relevant set of tools for studying the geographical distribution of diseases, although its methods and techniques for analysis may yield very different results. A new hybrid approach has been applied to the spatial analysis of treated prevalence of depression in Catalonia (Spain) according to the following descriptive hypotheses: 1) spatial clusters of treated prevalence of depression (hot and cold spots) exist and, 2) these clusters are related to the administrative divisions of mental health care (catchment areas) in this region. METHODS: In this ecological study, morbidity data per municipality have been extracted from the regional outpatient mental health database (CMBD-SMA) for the year 2009. The second level of analysis mapped small mental health catchment areas or groups of municipalities covered by a single mental health community centre. Spatial analysis has been performed using a Multi Objective Evolutionary Algorithm (MOEA) which identified geographical clusters (hot spots and cold spots) of depression through the optimization of its treated prevalence. Catchment areas, where hot and cold spots are located, have been described by four domains: urbanicity, availability, accessibility and adequacy of provision of mental health care. RESULTS: MOEA has identified 6 hot spots and 4 cold spots of depression in Catalonia. Our results show a clear spatial pattern where one cold spot contributed to define the exact location, shape and borders of three hot spots. Analysing the corresponding domain values for the identified hot and cold spots no common pattern has been detected. CONCLUSIONS: MOEA has effectively identified hot/cold spots of depression in Catalonia. However these hot/cold spots comprised municipalities from different catchment areas and we could not relate them to the administrative distribution of mental care in the region. By combining the analysis of hot/cold spots, a better statistical and operational-based visual representation of the geographical distribution is obtained. This technology may be incorporated into Decision Support Systems to enhance local evidence-informed policy in health system research. PMID- 22917224 TI - Generation of induced pluripotent stem cells from somatic cells. AB - The technology for generation of induced pluripotent stem cell (iPSC) from somatic cells emerged to circumvent the ethical and immunological limitations of embryonic stem cell (ESC). The recent progress of iPSC technology offers an unprecedented tool for regenerative medicine; however, integrating viral-driven iPSCs prohibits clinical applications by their genetic alterations and tumorigenicity. Various approaches including nonintegrating, nonviral, and nongenetic methods have been developed for generating clinically compatible iPSCs. In addition, approaches for using more clinically convenient or compatible source cells replacing fibroblasts have been actively pursued. While iPSC and ESC closely resemble in genomic, cell biologic, and phenotypic characteristics, these two pluripotent stem cells are not identical in terms of differentiation capacity and epigenetic features. In this chapter, we deal with the current techniques of generating iPSCs and their various characteristics. PMID- 22917222 TI - Association of differential gene expression with imatinib mesylate and omacetaxine mepesuccinate toxicity in lymphoblastoid cell lines. AB - BACKGROUND: Imatinib mesylate is currently the drug of choice to treat chronic myeloid leukemia. However, patient resistance and cytotoxicity make secondary lines of treatment, such as omacetaxine mepesuccinate, a necessity. Given that drug cytotoxicity represents a major problem during treatment, it is essential to understand the biological pathways affected to better predict poor drug response and prioritize a treatment regime. METHODS: We conducted cell viability and gene expression assays to determine heritability and gene expression changes associated with imatinib and omacetaxine treatment of 55 non-cancerous lymphoblastoid cell lines, derived from 17 pedigrees. In total, 48,803 transcripts derived from Illumina Human WG-6 BeadChips were analyzed for each sample using SOLAR, whilst correcting for kinship structure. RESULTS: Cytotoxicity within cell lines was highly heritable following imatinib treatment (h2 = 0.60-0.73), but not omacetaxine treatment. Cell lines treated with an IC20 dose of imatinib or omacetaxine showed differential gene expression for 956 (1.96%) and 3,892 transcripts (7.97%), respectively; 395 of these (0.8%) were significantly influenced by both imatinib and omacetaxine treatment. k-means clustering and DAVID functional annotation showed expression changes in genes related to kinase binding and vacuole-related functions following imatinib treatment, whilst expression changes in genes related to cell division and apoptosis were evident following treatment with omacetaxine. The enrichment scores for these ontologies were very high (mostly >10). CONCLUSIONS: Induction of gene expression changes related to different pathways following imatinib and omacetaxine treatment suggests that the cytotoxicity of such drugs may be differentially tolerated by individuals based on their genetic background. PMID- 22917225 TI - Induced pluripotent cells in cardiovascular biology: epigenetics, promises, and challenges. AB - Cardiovascular diseases are still the leading cause of death worldwide. Despite the improvement shown in the prognosis of patients with acute MI, there remains still a significant mortality risk. Since the main underlying problem after an MI is the loss of cardiomyocytes and microvasculature, treatment strategies aimed at preserving or regenerating myocardial tissue have been examined as potential therapeutic modalities. Toward this goal, many cell types are being investigated as potent sources of cardiomyocytes for cell transplantation. The progress made toward the generation of induced Pluripotent Stem (iPS) cells hold great potential for future use in myocardial repair. We review critical aspects of these cell's potential, such as their generation, their differentiating ability, the known epigenetic mechanisms that allow for their reprogramming, maintenance of pluripotency, their cardiovascular differentiation and therapeutic potential, and the possibility of an epigenetic memory. Understanding the molecular circuitry of these cells will provide a better understanding of their potential as well as limitations in future clinical use. PMID- 22917226 TI - Reprogramming of somatic cells. AB - Reprogramming of adult somatic cells into pluripotent stem cells may provide an attractive source of stem cells for regenerative medicine. It has emerged as an invaluable method for generating patient-specific stem cells of any cell lineage without the use of embryonic stem cells. A revolutionary study in 2006 showed that it is possible to convert adult somatic cells directly into pluripotent stem cells by using a limited number of pluripotent transcription factors and is called as iPS cells. Currently, both genomic integrating viral and nonintegrating nonviral methods are used to generate iPS cells. However, the viral-based technology poses increased risk of safety, and more studies are now focused on nonviral-based technology to obtain autologous stem cells for clinical therapy. In this review, the pros and cons of the present iPS cell technology and the future direction for the successful translation of this technology into the clinic are discussed. PMID- 22917227 TI - Induction of somatic cell reprogramming using the microRNA miR-302. AB - Since the discovery of pluripotent stem cells, scientists have envisioned their use in regenerative medicine. Unfortunately, such application of embryonic pluripotent stem cells has been impeded by ethical concerns as well as other obstacles. In light of this, the scientific community has begun to explore somatic cell reprogramming (SCR) as a means of producing induced pluripotent stem cells (iPSCs) from somatic cells. Although still far from being clinically applicable, SCR has become a hot research topic, with many groups working to understand its underlying mechanism. The standard method for inducing SCR is achieved by forced expression of four transcription factors defined by Yamanaka and Yu et al. Regrettably, iPSCs produced by the four-factor method tend to be tumorigenic, making them unsafe for clinical application. Recently, a new method has been identified to generate iPSCs through forced expression of an embryonic stem cell (ESC)-enriched microRNA, miR-302. This method holds a distinct advantage over the four-factor method because it can reprogram somatic cells to tumor-free iPSCs. Also, these miR-302-induced iPSCs, termed "mirPSCs," demonstrate a clear mechanism, which explains the process of reprogramming as a response to global DNA demethylation-the first sign of SCR. Nevertheless, miR-302 induced reprogramming is dose-dependent, and microRNA (miRNA) concentration must be within a specific range for the reprogramming to occur. In addition, excessive overexpression of miR-302 in mirPS cells must not occur; otherwise, they will undergo early senescence. mirPSCs represent a new source of pluripotent stem cells without the tumorigenicity traditionally attributed to iPSCs. Looking forward, the next challenge lies with surmounting senescence, an obstacle that often limits stem cell expansion and prevents researchers from growing the large quantities of iPSCs needed for therapeutic use. PMID- 22917228 TI - From ontogenesis to regeneration: learning how to instruct adult cardiac progenitor cells. AB - Since the first observations over two centuries ago by Lazzaro Spallanzani on the extraordinary regenerative capacity of urodeles, many attempts have been made to understand the reasons why such ability has been largely lost in metazoa and whether or how it can be restored, even partially. In this context, important clues can be derived from the systematic analysis of the relevant distinctions among species and of the pathways involved in embryonic development, which might be induced and/or recapitulated in adult tissues. This chapter provides an overview on regeneration and its mechanisms, starting with the lesson learned from lower vertebrates, and will then focus on recent advancements and novel insights concerning regeneration in the adult mammalian heart, including the discovery of resident cardiac progenitor cells (CPCs). Subsequently, it explores all the important pathways involved in regulating differentiation during development and embryogenesis, and that might potentially provide important clues on how to activate and/or modulate regenerative processes in the adult myocardium, including the potential activation of endogenous CPCs. Furthermore the importance of the stem cell niche is discussed, and how it is possible to create in vitro a microenvironment and culture system to provide adult CPCs with the ideal conditions promoting their regenerative ability. Finally, the state of clinical translation of cardiac cell therapy is presented. Overall, this chapter provides a new perspective on how to approach cardiac regeneration, taking advantage of important lessons from development and optimizing biotechnological tools to obtain the ideal conditions for cell-based cardiac regenerative therapy. PMID- 22917229 TI - Roles of microRNAs and myocardial cell differentiation. AB - As drug therapy is of limited efficacy in the treatment of heart diseases related to loss of cardiomyocytes, which have very poor division potential, regenerative medicine is expected to be a new strategy to address regenerative treatment in cardiac diseases. To achieve myocardial regeneration, elucidation of the mechanism of myocardial differentiation from stem cells is essential. Myocardial differentiation from embryonic pluripotent stem cells has been investigated worldwide, and remarkable developments such as establishment of induced pluripotent stem cells and transformation of somatic cells to cardiomyocytes have recently been made, markedly changing the strategy of regenerative medicine. At the same time, the close involvement of microRNA in the maintenance, proliferation, differentiation, and reprogramming of these stem cells has been revealed. In this report, microRNA is outlined, focusing on its role in myocardial differentiation. PMID- 22917230 TI - Wnt signaling and cardiac differentiation. AB - The Wnt family of secreted glycoproteins participates in a wide array of biological processes, including cellular differentiation, proliferation, survival, apoptosis, adhesion, angiogenesis, hypertrophy, and aging. The canonical Wnt signaling primarily utilizes beta-catenin-mediated activation of transcription, while the noncanonical mechanisms involve a calcium-dependent protein kinase C-mediated Wnt/Ca(2+) pathway and a dishevelled-dependent c-Jun N terminal kinase-mediated planar cell polarity pathway. Although both canonical and noncanonical Wnts have been implicated in cardiac specification, morphogenesis, and differentiation; the molecular events remain unclear and often depend on the cell type and biological context. In this regard, growing evidence indicates that Wnt11 is able to induce cardiogenesis not only during embryonic development but also in adult cells. The cardiogenic properties of Wnt11 may prove useful for preprogramming adult stem cells before myocardial transplantation. Further, elucidation of the molecular steps in Wnt11-induced cardiac differentiation will be necessary to enhance the outcomes of cardiac cell therapy. PMID- 22917231 TI - Cross talk between the Notch signaling and noncoding RNA on the fate of stem cells. AB - The Notch signal pathway directly controls stem cell survival, proliferation, and differentiation. Noncoding RNAs, including small microRNAs (miRNAs) and long noncoding RNAs (LncRNAs), are responsible for fine regulation of gene expression. It is also becoming increasingly evident that miRNAs have a profound impact on the Notch signaling pathway; conversely, Notch signaling can regulate a handful of miRNAs that are involved in the stem cell function. In this chapter, we summarize our current knowledge of Notch-mediated stem cell differentiation and the cross talk between miRNAs and the Notch signal pathway on determining the fate of stem cells. PMID- 22917232 TI - Myocardial regeneration: the role of progenitor cells derived from bone marrow and heart. AB - In animal models of myocardial infarction (MI), transplantation of various types of progenitor cells has been reported to (i) improve left ventricular (LV) function, (ii) decrease LV remodeling, (iii) limit fibrosis of noninfarcted LV regions, and (iv) in some cases, reduce infarct scar size. Moreover, in some reports these beneficial effects were present despite very low rates of long-term engraftment and transdifferentiation of transplanted cells into cardiomyocytes. In contrast, in other reports, significant numbers of transplanted cells do appear to have transdifferentiated into cardiomyocytes and vascular cells. Paracrine signals emanating from transplanted cells also appear to be very important because they protect injured cardiomyocytes and may activate endogenous cardiac progenitor cells (CPCs) to generate cardiomyocytes and vascular cells. Herein, we review evidence that transplanted bone-marrow- or cardiac-derived CPCs and/or in situ CPCs can be stimulated to propagate, differentiate, and partially replace cardiomyocytes damaged during AMI. The possibility that preexisting cardiomyocytes can be induced to reenter the cell cycle and regenerate replacement cardiomyocytes is also discussed. PMID- 22917233 TI - Role of GATA-4 in differentiation and survival of bone marrow mesenchymal stem cells. AB - Cell and tissue regeneration is a relatively new research field and it incorporates a novel application of molecular genetics. Combinatorial approaches for stem-cell-based therapies wherein guided differentiation into cardiac lineage cells and cells secreting paracrine factors may be necessary to overcome the limitations and shortcomings of a singular approach. GATA-4, a GATA zinc-finger transcription factor family member, has been shown to regulate differentiation, growth, and survival of a wide range of cell types. In this chapter, we discuss whether overexpression of GATA-4 increases mesenchymal stem cell (MSC) transdifferentiation into cardiac phenotype and enhances the MSC secretome, thereby increasing cell survival and promoting postinfarction cardiac angiogenesis. MSCs engineered with GATA-4 enhance their capacity to differentiate into cardiac cell phenotypes, improve survival of the cardiac progenitor cells and their offspring, and modulate the paracrine activity of stem cells to support their angiomyogenic potential and cardioprotective effects. PMID- 22917235 TI - Genetically manipulated progenitor/stem cells restore function to the infarcted heart via the SDF-1alpha/CXCR4 signaling pathway. AB - Progenitor/stem cells are a viable option to replace myocytes lost subsequent to myocardial infarction (MI). The stromal cell-derived factor-1alpha/CXC-chemokine receptor type 4 (SDF-1alpha/CXCR4) axis plays an important role in numerous biological processes including hematopoiesis, cardiogenesis, vasculogenesis, and neuronal development, as well as endothelial progenitor cell trafficking. The secretion of chemoattractants such as SDF-1alpha at the site of injury creates an environment facilitating the homing of circulating CXCR4 positive and other stem cells (such as mast/stem cell growth factor receptor kit-positive (c-kit(+)) and c-kit(+)/GATA binding protein 4 positive (GATA4(+)) cells) for organ regeneration and tissue repair. SDF-1alpha is also secreted by hematopoietic progenitor/stem cells and is involved in the autocrine/paracrine regulation of their development and survival. Hypoxic preconditioning activates SDF-1alpha/CXCR4 signaling and upregulates several vascular/angiogenic factors that cause mobilization of progenitor cells. The SDF-1alpha/CXCR4 signaling pathway can thus be effectively exploited for cell-based therapy. PMID- 22917236 TI - Genetic modification of stem cells for cardiac, diabetic, and hemophilia transplantation therapies. AB - Gene modification of stem cells prior to their transplantation enhances their survival and increases their function in cell therapy. Like the famous Trojan horse, the gene-modified cell has to gain entrance into the host's walls and survive to deliver its transgene products. Using cellular, molecular, and gene manipulation techniques, the transplanted cell can be protected in a hostile environment from immune rejection, inflammation, hypoxia, and apoptosis. Genetic engineering to modify cells involves construction of functional gene sequences and their insertion into stem cells. The modifications can be simple reporter genes or complex cassettes with gene switches, cell-specific promoters, and multiple transgenes. We discuss methods to deliver and construct gene cassettes with viral and nonviral delivery, siRNA, and conditional Cre/Lox P. We review the current uses of gene-modified stem cells in cardiovascular disease, diabetes, and hemophilia. PMID- 22917234 TI - Progenitor cell mobilization and recruitment: SDF-1, CXCR4, alpha4-integrin, and c-kit. AB - Progenitor cell retention and release are largely governed by the binding of stromal-cell-derived factor 1 (SDF-1) to CXC chemokine receptor 4 (CXCR4) and by alpha4-integrin signaling. Both of these pathways are dependent on c-kit activity: the mobilization of progenitor cells in response to either CXCR4 antagonism or alpha4-integrin blockade is impaired by the loss of c-kit kinase activity; and c-kit-kinase inactivation blocks the retention of CXCR4-positive progenitor cells in the bone marrow. SDF-1/CXCR4 and alpha4-integrin signaling are also crucial for the retention of progenitor cells in the ischemic region, which may explain, at least in part, why clinical trials of progenitor cell therapy have failed to display the efficacy observed in preclinical investigations. The lack of effectiveness is often attributed to poor retention of the transplanted cells and, to date, most of the trial protocols have mobilized cells with injections of granulocyte colony-stimulating factor (G-CSF), which activates extracellular proteases that irreversibly cleave cell-surface adhesion molecules, including alpha4-integrin and CXCR4. Thus, the retention of G CSF-mobilized cells in the ischemic region may be impaired, and the mobilization of agents that reversibly disrupt SDF-1/CXCR4 binding, such as AMD3100, may improve patient response. Efforts to supplement SDF-1 levels in the ischemic region may also improve progenitor cell recruitment and the effectiveness of stem cell therapy. PMID- 22917238 TI - Preconditioning approach in stem cell therapy for the treatment of infarcted heart. AB - Nearly two decades of research in regenerative medicine have been focused on the development of stem cells as a therapeutic option for treatment of the ischemic heart. Given the ability of stem cells to regenerate the damaged tissue, stem cell-based therapy is an ideal approach for cardiovascular disorders. Preclinical studies in experimental animal models and clinical trials to determine the safety and efficacy of stem cell therapy have produced encouraging results that promise angiomyogenic repair of the ischemically damaged heart. Despite these promising results, stem cell therapy is still confronted with issues ranging from uncertainty about the as-yet-undetermined "ideal" donor cell type to the nonoptimized cell delivery strategies to harness optimal clinical benefits. Moreover, these lacunae have significantly hampered the progress of the heart cell therapy approach from bench to bedside for routine clinical applications. Massive death of donor cells in the infarcted myocardium during acute phase postengraftment is one of the areas of prime concern, which immensely lowers the efficacy of the procedure. An overview of the published data relevant to stem cell therapy is provided here and the various strategies that have been adopted to develop and optimize the protocols to enhance donor stem cell survival posttransplantation are discussed, with special focus on the preconditioning approach. PMID- 22917239 TI - Preface. PMID- 22917237 TI - Role of heat shock proteins in stem cell behavior. AB - Stress response is well appreciated to induce the expression of heat shock proteins (Hsps) in the cell. Numerous studies have demonstrated that Hsps function as molecular chaperones in the stabilization of intracellular proteins, repairing damaged proteins, and assisting in protein translocation. Various kinds of stem cells (embryonic stem cells, adult stem cells, or induced pluripotent stem cells) have to maintain their stemness and, under certain circumstances, undergo stress. Therefore, Hsps should have an important influence on stem cells. Actually, numerous studies have indicated that some Hsps physically interact with a number of transcription factors as well as intrinsic and extrinsic signaling pathways. Importantly, alterations in Hsp expression have been demonstrated to affect stem cell behavior including self-renewal, differentiation, sensitivity to environmental stress, and aging. This chapter summarizes recent findings related to (1) the roles of Hsps in maintenance of stem cell dormancy, proliferation, and differentiation; (2) the expression signature of Hsps in embryonic/adult stem cells and differentiated stem cells; (3) the protective roles of Hsps in transplanted stem cells; and (4) the possible roles of Hsps in stem cell aging. PMID- 22917240 TI - Combined Poisson and soft-particle DLVO analysis of the specific and nonspecific adhesion forces measured between L. monocytogenes grown at various temperatures and silicon nitride. AB - Adhesion forces between pathogenic L. monocytogenes EGDe and silicon nitride (Si(3)N(4)) were measured using atomic force microscopy (AFM) under water and at room temperature for cells grown at five different temperatures (10, 20, 30, 37, and 40 degrees C). Adhesion forces were then decoupled into specific (hydrogen bonding) and nonspecific (electrostatic and Lifshitz-van der Waals) force components using Poisson statistical analysis. The strongest specific and nonspecific attraction forces were observed for cells grown at 30 degrees C, compared to those observed for cells grown at higher or lower temperatures, respectively. By combining the results of Poisson analysis with the results obtained through soft-particle Derjaguin-Landau-Verwey-Overbeek (DLVO) analysis, the contributions of the Lifshitz-van der Waals and electrostatic forces to the overall nonspecific interaction forces were determined. Our results showed that the Lifshitz-van der Waals attraction forces dominated the total nonspecific adhesion forces for all investigated thermal conditions. However, irrespective of the temperature of growth investigated, hydrogen bonding forces were always stronger than the nonspecific forces. Finally, by combining Poisson analysis with soft-particle analysis of DLVO forces, the closest separation distances where the irreversible bacterial adhesion takes place can be determined relatively easily. For all investigated thermal conditions, the closest separation distances were <1 nm. PMID- 22917241 TI - Therapeutic peptides. PMID- 22917242 TI - Ebselen could be used as anti-inflammatory Nox inhibitor. PMID- 22917243 TI - Interview with Loren D Walensky. AB - Loren D Walensky is an Associate Professor of Pediatrics at Harvard Medical School, faculty member in the Department of Pediatric Hematology/Oncology at Dana Farber Cancer Institute/Children's Hospital Boston, and Medical Director of Dana Farber's Program in Cancer Chemical Biology. He graduated as valedictorian from Princeton University in 1990, majoring in Chemistry and receiving a Certificate in Science Policy from the Woodrow Wilson School of Public and International Affairs. He went on to receive his MD and PhD from the Johns Hopkins University School of Medicine in 1997. Dr Walensky spoke to Isaac Bruce, Commissioning Editor of Future Medicinal Chemistry, about his career in therapeutic peptides, his involvement in collaborations and funding, and the future of peptides as therapy. PMID- 22917244 TI - Activity of short lipopeptides and conventional antimicrobials against planktonic cells and biofilms formed by clinical strains of Staphylococcus aureus. AB - BACKGROUND: The therapy for staphylococcal skin diseases is facing several difficulties caused by the growth of biofilms and development of resistant strains. Short synthetic lipopeptides designed on the basis of antimicrobial peptide structure seem to provide an alternative to conventional therapy. The purpose of this study was to synthesize a group of lipopeptides and evaluate their antistaphylococcal activity against biofilms formed by clinical strains of Staphylococcus aureus. RESULTS: The compounds exhibited a strong antibiofilm activity against all the isolates. The maturity of the biofilms has shown a well defined influence on antimicrobial activity of conventional antimicrobials. DISCUSSION: Results showed that the lipopeptides were promising agents as the time of the culture did not greatly affect their activity. PMID- 22917245 TI - Investigation of cytotoxicity of negative control peptides versus bioactive peptides on skin cancer and normal cells: a comparative study. AB - BACKGROUND: Resonant recognition model-myxoma virus (RRM-MV), a bioactive peptide analogue for myxoma virus MV-T5 protein, was computationally designed by the RRM. In this study, the anticancer effects of RRM-MV were assessed in vitro against four negative control peptides on human skin cancer and normal cells. RESULTS & DISCUSSION: The effects of RRM-MV versus negative control peptides on cells were evaluated by quantitative and qualitative assays. The RRM-MV treatment was able to induce cell death in cancer cells without triggering similar effects on normal cells. However, the negative control peptides produced no toxic effects on skin cancer and normal cells. No effects on human erythrocytes were detected when treated with all peptides. CONCLUSION: It is suggested that the RRM can be applied to design therapeutic anticancer peptides. PMID- 22917246 TI - Peptides and peptide conjugates: therapeutics on the upward path. AB - The main benefit of natural peptides, peptide analogs and newly designed peptides as therapeutics, lies in their high selectivity and affinity, which are frequently in the nanomolar range. New drugs targeting protein-protein interactions often require larger interaction sites than small molecules can offer. Thus, many peptidic drugs are already applied in therapy at the current state. The next generation of peptide-based therapeutic agents is currently on its way from basic research to clinical studies and eventually to the pharmaceutical market. Development of more robust and long-lasting drugs owing to well-known and new stabilization strategies is yielding novel and continuously improving peptide drugs. The introduction of smart linkers that exhibit stability towards blood plasma but intracellular lability will lead to target-oriented activity, which might successfully decrease side effects. In this review, peptidic therapeutics on the market, in clinical studies and some of those in basic research are characterized. Stabilization strategies and intelligent linkers are discussed with respect to their use in peptide drug therapy. PMID- 22917247 TI - Human cathelicidin LL-37 prevents bacterial biofilm formation. AB - Human pathogens often colonize their host by the formation of biofilms. These surface-attached aggregates of bacteria are characterized by a self-produced extracellular matrix, which makes them highly resistant towards antibiotic treatment. Their abilities to adhere to abiotic surfaces (e.g., catheters and other medical devices) also makes bacterial biofilm formation a challenge in modern medicine. Antimicrobial peptides have lately been introduced as a potential class of drug molecules for combating severe hospital-acquired infections. One of these peptides, human cathelicidin LL-37, has recently been demonstrated to bridge innate and adaptive host defence, in addition to facilitating a robust antibiofilm effect at sub-inhibitory concentrations. In this review we will discuss the evidence, potential and challenges for LL-37 as a candidate molecule for therapeutic use. PMID- 22917248 TI - Flexible or fixed: a comparative review of linear and cyclic cancer-targeting peptides. AB - Peptides can serve as versatile cancer-targeting ligands and have been used for clinically relevant applications such as cancer imaging and therapy. A current and long-standing focus within peptide research is the creation of structurally constrained peptides generated through cyclization. Cyclization is envisioned to enhance the selective binding, uptake, potency and stability of linear precursors. This review compares closely related linear and cyclic peptides in these respects. Peptide cyclization generally improves the selective binding and stability of linear precursors; however, not all cyclization strategies and constrained geometries enhance these properties to the same extent. In some instances, linear analogues actually have better cancer-targeting properties compared with their cyclic counterparts. Although cyclization does not necessarily improve the cancer-targeting properties of linear analogues, cyclic peptides may obtain properties that allow them to be used for additional applications. This review aims to convey the advantages and limitations of cyclic cancer-targeting peptides. PMID- 22917249 TI - Recent work in the development and application of protein-peptide docking. AB - Interest in the development of novel peptide-based drugs is growing. There is, thus, a pressing need for the development of effective methods to enable novel peptide-based drug discovery. A cogent case can be made for the development and application of computational or in silico methods to assist with peptide discovery. In particular, there is a need for the development of effective protein-peptide docking methods. Here, recent work in the area of protein-peptide docking method development is reviewed and several drug-discovery projects that benefited from protein-peptide docking are discussed. In the present review, special attention is given to the search and scoring problems, the use of peptide docking to enable hit identification, and the use of peptide docking to help rationalize experimental results, and generate and test structure-based hypotheses. Finally, some recommendations are made for improving the future development and application of protein-peptide docking. PMID- 22917251 TI - The best next drug in the course of generalized anxiety disorders: the "PN-GAD algorithm". AB - OBJECTIVE: Today, there are many pharmacotherapeutic options for generalized anxiety disorder (GAD). The question is, which is the best medication for a particular patient at a particular moment? This is especially challenging because GAD is by definition a chronic disorder and new interventions should learn from earlier experiences. An algorithm which can help to use pretreatment information for drug selection is the "Pretreatment - Next Treatment (PN) - Algorithm". This article introduces an PN-algorithm for GAD. METHODS AND RESULTS: For the development of a GAD-specific PN-algorithm, all possible pharmacological options for GAD are reviewed and brought into a rank order on the basis of scientific evidence regarding efficacy, tolerability, or price: (1) pregabalin, (2) venlafaxine XR, (3) selective serotonin reuptake inhibitors, (4) tricyclic antidepressants, (5) buspirone, (6) antipsychotics, (7) benzodiazepines, and (8) hydroxyzine. Based on this hierarchy and patient-specific information, a decision algorithm is derived, which allows to assess and evaluate pretreatment and to select the drug with no contraindications, limited negative or convincing positive effects, or the option which has not been used so far but which is the next compound in the hierarchy. CONCLUSIONS: The "PN-GAD-algorithm" can be easily translated into a checklist to support clinical decision-making. It can also help to increase patient empowerment and cooperation in long-term treatment. PMID- 22917253 TI - Characterization of polymethoxylated flavonoids (PMFs) in the peels of 'Shatangju' mandarin ( Citrus reticulata Blanco) by online high-performance liquid chromatography coupled to photodiode array detection and electrospray tandem mass spectrometry. AB - A sensitive HPLC-DAD-ESI-MS/MS method was established to screen and identify the polymethoxylated flavonoids (PMFs) in the peels of 'Shatangju' mandarin ( Citrus reticulata Blanco). Eight PMF standards, including four polymethoxylated flavones, two polymethoxylated flavanones, and two polymethoxylated chalcones, were first to be analyzed in positive mode by CID-MS/MS. On the basis of the ESI MS(n) characteristics of PMFs and the results of EIC-MS/MS experiment, 32 PMFs including 24 flavones and 8 flavanones or chalcones were screened from the complex extract of the peels of 'Shatangju' mandarin. Among them, 10 PMFs were hydroxylated polymethoxyflavonoids (OH-PMFs), and the rest were all permethoxylated PMFs. This was the first systematic report of the presence of PMFs in the peels of 'Shatangju' mandarin, especially for polymethoxylated flavanones and chalcones. Meanwhile, the contents of the three main PMFs and total flavonoids in the peels of 'Shatangju' were determined by HPLC and UV spectrophotometry, respectively. The results indicated that the developed analytical method could be employed as an effective technique for the characterization of PMFs. PMID- 22917254 TI - Charge inhomogeneity determines oxidative reactivity of graphene on substrates. AB - Single-layer graphene (SLG) supported on SiO(2) shows anomalously large chemical reactivity compared to thicker graphene, with charge inhomogeneity-induced potential fluctuations or topographic corrugations proposed as the cause. Here we systematically probe the oxidative reactivity of graphene supported on substrates with different surface roughnesses and charged impurity densities: hexagonal boron nitride (hBN), mica, thermally grown SiO(2) on Si, and SiO(2) nanoparticle thin films. SLG on low charge trap density hBN is not etched and shows little doping after oxygen treatment at temperatures up to 550 degrees C, in sharp contrast with oxidative etching under similar conditions of graphene on high charge trap density SiO(2) and mica. Furthermore, bilayer graphene shows reduced reactivity compared to SLG regardless of its substrate-induced roughness. Together the observations indicate that graphene's reactivity is predominantly controlled by charge inhomogeneity-induced potential fluctuations rather than surface roughness. PMID- 22917255 TI - Experimental and theoretical investigations of energy transfer and hydrogen-bond breaking in the water dimer. AB - The hydrogen bonding in water is dominated by pairwise dimer interactions, and the predissociation of the water dimer following vibrational excitation is reported here. Velocity map imaging was used for an experimental determination of the dissociation energy (D(0)) of (D(2)O)(2). The value obtained, 1244 +/- 10 cm( 1) (14.88 +/- 0.12 kJ/mol), is in excellent agreement with the calculated value of 1244 +/- 5 cm(-1) (14.88 +/- 0.06 kJ/mol). This agreement between theory and experiment is as good as the one obtained recently for (H(2)O)(2). In addition, pair-correlated water fragment rovibrational state distributions following vibrational predissociation of (H(2)O)(2) and (D(2)O)(2) were obtained upon excitation of the hydrogen-bonded OH and OD stretch fundamentals, respectively. Quasi-classical trajectory calculations, using an accurate full-dimensional potential energy surface, are in accord with and help to elucidate experiment. Experiment and theory find predominant excitation of the fragment bending mode upon hydrogen bond breaking. A minor channel is also observed in which both fragments are in the ground vibrational state and are highly rotationally excited. The theoretical calculations reveal equal probability of bending excitation in the donor and acceptor subunits, which is a result of interchange of donor and acceptor roles. The rotational distributions associated with the major channel, in which one water fragment has one quantum of bend, and the minor channel with both water fragments in the ground vibrational state are calculated and are in agreement with experiment. PMID- 22917256 TI - Why can't atrial fibrillation be more like a regular rhythm? PMID- 22917257 TI - Recording mitral annular motion: a discovery made while investigating the poor specificity of the mitral valve diastolic (E to F) slope. PMID- 22917258 TI - Deformation imaging: a new season for the athlete's heart. PMID- 22917262 TI - Innovative technology-transcatheter aortic valve implantation: cost and reimbursement issues. AB - OBJECTIVE: Transcatheter aortic valve implantation (TAVI) offers a new treatment option for patients with severe symptomatic aortic valve stenosis, classified as "inoperable". The purpose of the study was to reveal the association between ascertained hospital costs with the actual patient Diagnosis-Related Group (DRG). METHOD: We examined 50 consecutive patients who underwent either transapical TAVI, (TAVI-TA) or transfemoral TAVI (TAVI-TF) with the Edwards SAPIEN valve and CoreValve((r)) between September 2009 and August 2011. RESULTS: Fourty-nine patients had successful valve deployment. Seven patients died within 30 days of the operation. The mean length of hospital stay for TAVI-TA was 199 hours (range 77-362), and the mean costs for TAVI-TA were 55,690 US$. For TAVI-TF the mean length of hospital stay was 170 hours (range 49-276) and the mean costs were 52,087 US$. CONCLUSION: There was no significant difference between TAVI-TA and TAVI-TF patient characteristics. There was a significant discrepancy between actual hospital costs and the current Norwegian DRG reimbursement for the TAVI procedure. This discrepancy can be partly explained by excessive costs related to the introduction of a new program with new technology. Costly innovations should be considered in price-setting of reimbursement for novel technology. PMID- 22917263 TI - Crystal engineering: lattice inclusion based on O-H...O hydrogen-bonded self assembly and guest-induced structural mimicry. AB - Pyrene-tetraphenol TP2 constitutes a molecular system with inherent features for inclusion of two or more guest molecules that are complementary in terms of size and shape. Hydrogen-bonded self-assembly of TP2 in the solid state is shown to lead to voids within which the guest molecules are incorporated. A large aromatic expanse extant to the pyrene core in TP2 permits inclusion of two different types of guest species interchangeably. The robust association manifests in packing equivalence in all of the inclusion compounds of TP2 with the exception of the compound formed with pyridine and o-dichlorobenzene guests; in the latter, pyridine terminates the otherwise 3-dimensional hydrogen-bonded organization. The half-component of TP2, i.e., 4,6-bis(4-hydroxyphenyl)-m-xylene (BX), deduced by simple structural reduction, is shown to exhibit guest inclusion, but with considerably less guest accessible volume. The limited yet meaningful set of guests allows mimicry of the two expected patterns of molecular organization based on hydrogen bonding for both TP2 and BX in the solid state. PMID- 22917265 TI - Just enough, but not too much interactivity leads to better clinical skills performance after a computer assisted learning module. AB - BACKGROUND: Well-designed computer-assisted instruction (CAI) can potentially transform medical education. Yet little is known about whether specific design features such as direct manipulation of the content yield meaningful gains in clinical learning. We designed three versions of a multimedia module on the abdominal exam incorporating different types of interactivity. METHODS: As part of their physical diagnosis course, 162 second-year medical students were randomly assigned (1:1:1) to Watch, Click or Drag versions of the abdominal exam module. First, students' prior knowledge, spatial ability, and prior experience with abdominal exams were assessed. After using the module, students took a posttest; demonstrated the abdominal exam on a standardized patient; and wrote structured notes of their findings. RESULTS: Data from 143 students were analyzed. Baseline measures showed no differences among groups regarding prior knowledge, experience, or spatial ability. Overall there was no difference in knowledge across groups. However, physical exam scores were significantly higher for students in the Click group. CONCLUSIONS: A mid-range level of behavioral interactivity was associated with small to moderate improvements in performance of clinical skills. These improvements were likely mediated by enhanced engagement with the material, within the bounds of learners' cognitive capacity. These findings have implications for the design of CAI materials to teach procedural skills. PMID- 22917266 TI - Undergraduate medical education in Lebanon. AB - BACKGROUND: Lebanon, located on the eastern side of the Mediterranean Sea, is a multi-confessional, multi-cultural country with a long history of medical education. One of the first medical schools in the Middle East was established in Beirut, Lebanon's capital, in 1868. AIMS: The aim of this article is to provide an overview of the current status of undergraduate medical education in Lebanon. METHODS: The descriptive data were collected from the medical schools' institutional website and the analysis was performed by the authors. No statistical analysis was required. RESULTS: Currently, seven medical schools serve a population of 4 million people. Those schools adopt different curricular systems reflected in their admissions, study length, and language of instruction, mainly based on the French or the American model. CONCLUSION: Lebanon's diversity translates into medical education, with the various schools adopting different systems. PMID- 22917267 TI - Perceived medical school stress and the development of behavior and experience patterns in German medical students. AB - BACKGROUND: Longitudinal data about the development of health risks and resources in relation to the performance of medical students are limited. AIMS: To evaluate the development of study-related experience and the correlation to performance. METHOD: Medical students in the first (2006), second (2008), and fifth years (2011) of their studies were surveyed with standard instruments for quality of life, study-related behavior and experience, perceived medical school stress, anxiety and depression, and grades in their first major exam. RESULTS: The proportion of students with a healthy behavior and experience pattern decreased from 47.3% in the first year to 36.9% in the second year and 17.6% in the fifth year. This corresponded to an increase in the proportion of students at risk for burnout (7.1% first, 20% second, 19% fifth year). Students with a healthy behavior and experience pattern scored higher in self-perceived performance (p < 0.05) and objective grades. Stress and risk for burnout were important predictors for anxiety and depression. CONCLUSIONS: The decrease in health and the increase in risk patterns indicate a need for prevention and health promotion that should not only focus on individual behavior but also address the contextual factor of study organization within medical school. PMID- 22917268 TI - Profiling undergraduates' generic learning skills on entry to medical school; an international study. AB - BACKGROUND: Medical education faces challenges posed by widening access to training, a demand for globally competent healthcare workers and progress towards harmonisation of standards. AIM: To explore potential challenges arising from variation in diversity and educational background of medical school entrants. METHOD: This study investigated the reported experience and confidence, in a range of 31 generic skills underpinning learning, of 2606 medical undergraduates entering 14 medical schools in England and South Africa, using a validated questionnaire. RESULTS: Responses suggest that there is considerable similarity in prior educational experience and confidence skills profiles on entry to South African and English medical schools. South African entrants reported significantly more experience in 'Technical skills', 'Managing their own Learning', and 'Presentation', while English students reported increased experience in 'IT' skills. South African undergraduates reported more confidence in 'Information Handling', while English students were more confident in 'IT' skills. The most noticeable difference, in 'IT' skills, is probably due to documented differences in access to computer facilities at high school level. Differences between individual schools within each country are noticeable. CONCLUSIONS: Educators need to acquire a good understanding of their incoming cohorts, and ensure necessary tailored support for skills development. PMID- 22917269 TI - Fecal calprotectin levels are higher in rural than in urban Chinese infants and negatively associated with growth. AB - BACKGROUND: Fecal calprotectin (FC) is an established simple biomarker of gut inflammation. To examine a possible relationship between linear growth and gut inflammation, we compared fecal calprotectin levels in 6 month old infants from poor rural vs affluent urban families. METHODS: The project was a cross-sectional comparison of FC from rural and urban populations in China. The relationship between length-for-age Z-score (LAZ) and FC concentrations were also compared. Single fecal samples were assayed for FC using EK-CAL ELISA kits. RESULTS: The age of subjects for both locations was 6.1 +/- 0.2 mo; all were apparently healthy. The mean +/- SD of the LAZ for the rural and urban infants were -0.6 +/- 0.9 and 0.4 +/- 0.9, respectively. FC had a non-normal distribution. The median FC of 420.9 and 140.1 MUg/g for rural and urban infants, respectively, were significantly different (P < 0.0001). For the rural group, linear regression analysis showed that an increase in FC of 100 MUg/g was associated with a decrease of 0.06 in LAZ. CONCLUSION: FC levels were significantly elevated in the rural infants and high concentrations accounted for approximately one-third of the low LAZ scores of these infants. PMID- 22917270 TI - Comparative analysis of ITS1 nucleotide sequence reveals distinct genetic difference between Brugia malayi from Northeast Borneo and Thailand. AB - Brugia malayi is one of the parasitic worms which causes lymphatic filariasis in humans. Its geographical distribution includes a large part of Asia. Despite its wide distribution, very little is known about the genetic variation and molecular epidemiology of this species. In this study, the internal transcribed spacer 1 (ITS1) nucleotide sequences of B. malayi from microfilaria-positive human blood samples in Northeast Borneo Island were determined, and compared with published ITS1 sequences of B. malayi isolated from cats and humans in Thailand. Multiple alignment analysis revealed that B. malayi ITS1 sequences from Northeast Borneo were more similar to each other than to those from Thailand. Phylogenetic trees inferred using Neighbour-Joining and Maximum Parsimony methods showed similar topology, with 2 distinct B. malayi clusters. The first cluster consisted of Northeast Borneo B. malayi isolates, whereas the second consisted of the Thailand isolates. The findings of this study suggest that B. malayi in Borneo Island has diverged significantly from those of mainland Asia, and this has implications for the diagnosis of B. malayi infection across the region using ITS1-based molecular techniques. PMID- 22917271 TI - Atroposelective Heck macrocyclization: enantioselective synthesis of bis(bibenzylic) natural products. AB - The Heck protocol was applied for the first time to the atroposelective synthesis of macrocyclic natural products. As ring closure to bis(bibenzyls) of the isoplagiochin type leads to a configurationally stable biaryl axis in the molecule, cyclization could be conducted atroposelectively in the presence of a chiral BINAP ligand. PMID- 22917272 TI - Cytochrome c oxidase is activated by the oncoprotein Ras and is required for A549 lung adenocarcinoma growth. AB - BACKGROUND: Constitutive activation of Ras in immortalized bronchial epithelial cells increases electron transport chain activity, oxygen consumption and tricarboxylic acid cycling through unknown mechanisms. We hypothesized that members of the Ras family may stimulate respiration by enhancing the expression of the Vb regulatory subunit of cytochrome c oxidase (COX). RESULTS: We found that the introduction of activated H-Ras(V12) into immortalized human bronchial epithelial cells increased eIF4E-dependent COX Vb protein expression simultaneously with an increase in COX activity and oxygen consumption. In support of the regulation of COX Vb expression by the Ras family, we also found that selective siRNA-mediated inhibition of K-Ras expression in A549 lung adenocarcinoma cells reduced COX Vb protein expression, COX activity, oxygen consumption and the steady-state concentration of ATP. We postulated that COX Vb mediated activation of COX activity may be required for the anchorage-independent growth of A549 cells as soft agar colonies or as lung xenografts. We transfected the A549 cells with COX Vb small interfering or shRNA and observed a significant reduction of their COX activity, oxygen consumption, ATP and ability to grow in soft agar and as poorly differentiated tumors in athymic mice. CONCLUSION: Taken together, our findings indicate that the activation of Ras increases COX activity and mitochondrial respiration in part via up-regulation of COX Vb and that this regulatory subunit of COX may have utility as a Ras effector target for the development of anti-neoplastic agents. PMID- 22917274 TI - Using online learning and interactive simulation to teach spiritual and cultural aspects of palliative care to interprofessional students. AB - BACKGROUND: To meet the complex needs of patients with serious illness, health professional students require education in basics aspects of palliative care, including how to work collaboratively on an interprofessional team. OBJECTIVES: An educational program was created, implemented, and evaluated with students in medicine, nursing, chaplaincy, and social work. Five learning objectives emphasized spiritual, cultural, and interprofessional aspects of palliative care. DESIGN: The program blended two sequential components: an online interactive, case-based learning module, and a live, dynamic simulation workshop. MEASUREMENTS: Content analysis was used to analyze students' free-text responses to four reflections in the online case, as well as open-ended questions on students' postworkshop questionnaires, which were also analyzed quantitatively. RESULTS: Analysis of 217 students' free-text responses indicated that students of all professions recognized important issues beyond their own discipline, the roles of other professionals, and the value of team collaboration. Quantitative analysis of 309 questionnaires indicated that students of all professions perceived that the program met its five learning objectives (mean response values>4 on a 5-point Likert scale), and highly rated the program and its two components for both educational quality and usefulness for future professional work (mean response values approximately>4). CONCLUSIONS: This innovative interprofessional educational program combines online learning with live interactive simulation to teach professionally diverse students spiritual, cultural, and interprofessional aspects of palliative care. Despite the challenge of balanced professional representation, this innovative interprofessional educational program met its learning objectives, and may be transferable for use in other educational settings. PMID- 22917273 TI - Biotransformation of prim-O-glucosylcimifugin by human intestinal flora and its inhibition on NO production and DPPH free radical. AB - prim-O-Glucosylcimifugin (PGCN), a highest content chromone in the roots of Saposhnikovia divaricata, was incubated with human intestinal flora (HIF), and two biotransformation products were obtained from the incubated solution by chromatographic methods. The chemical structures of the two biotransformation products were elucidated as cimifugin (CN) and 5-O-methylvisamminol (MVL), respectively, on the basis of NMR and MS data. The biotransformation product CN was formed through a deglucosylation of PGCN by beta-glucosidase secreted from the HIF, and then the hydroxymethyl group of CN was reduced to lead to occurrence of MVL. All of these compounds were evaluated for their effect on the inhibition of nitric oxide production induced by lipopolysaccharide in macrophage cell line RAW 264.7 and for 1,1-diphenyl-2-picrylhydrazyl free-radical scavenging activity in cell-free bioassay system. PMID- 22917275 TI - A retrospective chart review of terminal patients with cancer with agitation and their risk factors. AB - BACKGROUND: Agitated delirium is often observed in terminal patients with cancer. To clarify the risk factors for agitated delirium in terminal patients with cancer, we conducted a retrospective chart review of 126 patients with cancer who died at a university hospital in 2008. METHOD: As a working definition, we define agitated delirium as a score of 2 or more in item 9 of the Memorial Delirium Assessment Scale with diurnal variation. RESULTS: The results were as follows: agitated delirium was observed in 49 (42%) of the 115 patients, and it occurred within the last week before death in 49% of the patients. Univariate analysis revealed older age, male gender, smoking history, lung cancer, diabetes, and high C-reactive protein (CRP) value as major risk factors, while dendritic analysis revealed lung cancer, high CRP value, diabetes, older age, and smoking history as key factors for predicting agitation. CONCLUSION: It is necessary to consider risk factors in order to categorize terminal patients with cancer into high- and low-risk groups and undertake possible counter-measures. PMID- 22917276 TI - CO2 sorption to subsingle hydration layer montmorillonite clay studied by excess sorption and neutron diffraction measurements. AB - Geologic storage of CO(2) requires that the caprock sealing the storage rock is highly impermeable to CO(2). Swelling clays, which are important components of caprocks, may interact with CO(2) leading to volume change and potentially impacting the seal quality. The interactions of supercritical (sc) CO(2) with Na saturated montmorillonite clay containing a subsingle layer of water in the interlayer region have been studied by sorption and neutron diffraction techniques. The excess sorption isotherms show maxima at bulk CO(2) densities of ~ 0.15 g/cm(3), followed by an approximately linear decrease of excess sorption to zero and negative values with increasing CO(2) bulk density. Neutron diffraction experiments on the same clay sample measured interlayer spacing and composition. The results show that limited amounts of CO(2) are sorbed into the interlayer region, leading to depression of the interlayer peak intensity and an increase of the d(001) spacing by ca. 0.5 A. The density of CO(2) in the clay pores is relatively stable over a wide range of CO(2) pressures at a given temperature, indicating the formation of a clay-CO(2) phase. At the excess sorption maximum, increasing CO(2) sorption with decreasing temperature is observed while the high-pressure sorption properties exhibit weak temperature dependence. PMID- 22917277 TI - Emtricitabine prodrugs with improved anti-HIV activity and cellular uptake. AB - Three fatty acyl conjugates of (-)-2',3'-dideoxy-5-fluoro-3'-thiacytidine (FTC, emtricitabine) were synthesized and evaluated against HIV-1 cell-free and cell associated virus and compared with the corresponding parent nucleoside and physical mixtures of FTC and fatty acids. Among all the compounds, the myristoylated conjugate of FTC (5, EC(50) = 0.07-3.7 MUM) displayed the highest potency. Compound 5 exhibited 10-24 and 3-13-times higher anti-HIV activity than FTC alone (EC(50) = 0.7-88.6 MUM) and the corresponding physical mixtures of FTC and myristic acid (14, EC(50) = 0.2-20 MUM), respectively. Cellular uptake studies confirmed that compound 5 accumulated intracellularly after 1 h of incubation and underwent intracellular hydrolysis in CCRF-CEM cells. Alternative studies were conducted using the carboxyfluorescein conjugated with FTC though beta-alanine (12) and 12-aminododecanoic acid (13). Acylation of FTC with a long chain fatty acid in 13 improved its cellular uptake by 8.5-20 fold in comparison to 12 with a short-chain beta-alanine. Compound 5 (IC(90) = 15.7-16.1 nM) showed 6.6- and 35.2 times higher activity than FTC (IC(90) = 103-567 nM) against multidrug resistant viruses B-NNRTI and B-K65R, indicating that FTC conjugation with myristic acid generates a more potent analogue with a better resistance profile than its parent compound. PMID- 22917438 TI - Physical activity is related to timing performance in older adults. AB - Physical activity has been linked to better cognitive function in older adults, especially for executive control processes. Researchers have suggested that temporal processing of durations less than 1 second is automatic and engages motor processes, while timing of longer durations engages executive processes. The purpose of this study was to determine whether a higher level of physical activity is associated with better reproduction performance in older adults, especially for durations in the "cognitive" range (i.e., longer than 1 s). Older right-handed adults completed a temporal reproduction task with five target durations (300, 650, 1000, 1350, and 1700 ms). Physical activity level was assessed via estimation of VO2 peak using a self-report activity scale. Results indicated that higher physical activity level was associated with better timing accuracy and that this effect was dependent on target duration. Namely, the relationship between physical activity and timing accuracy was strongest at the longest durations. Therefore, greater physical activity in older adults may have specific benefits linked to better executive functions. PMID- 22917439 TI - Fiber-reinforced resin coating for endocrown preparations: a technical report. AB - Coronal rehabilitation of endodontically treated posterior teeth is still a controversial issue. Although the use of classical crowns supported by radicular metal posts remains widespread in dentistry, their invasiveness has been largely criticized. New materials and therapeutic options based entirely on adhesion are available nowadays, from direct composite resins to indirect endocrowns. They allow for a more conservative, faster, and less expensive dental treatment. However, the absence of a metal or high-strength ceramic substructure as in full crown restorations can expose this kind of restoration to a higher risk of irreversible fracture in case of crack propagation. The aim of this case report is to present a technique to reinforce the cavity of an endodontically treated tooth by incorporating a fiber-reinforced composite (FRC) layer into the resin coating of the tooth preparation, before the final impressions of the cavity. This technique allows the use of FRCs in combination with any kind of restorative material for an adhesive overlay/endocrown. PMID- 22917440 TI - Effects of two in-office bleaching agents with different pH on the structure of human enamel: an in situ and in vitro study. AB - This study evaluated the effects of two in-office bleaching agents (Beyond and Opalescence Boost) with different pH on the structure and mechanical properties of human enamel in vitro and in situ. One hundred and eight enamel slabs were obtained from freshly extracted premolars. The specimens were randomly distributed into nine groups (n=12), and the human saliva (HS) in the volunteers' oral cavities was used to simulate the in situ condition: Beyond + HS, Opalescence Boost (O-Boost) + HS, Control + HS, Beyond + artificial saliva (AS), O-Boost + AS, Control + AS, Beyond + distilled water (DW), O-Boost + DW, and Control + DW. The bleaching treatments were performed on the first and eighth day, and the total bleaching time was 90 minutes. Baseline and final surface roughness (RMS), surface morphology, microhardness, and fracture toughness (FT) were measured before the treatment and on the fifteenth day, respectively. Compared with control groups, surface alterations on enamel were found in the Beyond + AS and Beyond + DW groups under atomic force microscopy evaluation. Two way analysis of variance and Tukey test revealed that the RMS showed significant intergroup differences for both storage condition and bleaching agent, whereas microhardness and FT revealed no significant alteration. The results indicated that in-office bleaching agents with low pH values could induce enamel morphology alterations under in vitro conditions. The presence of natural HS could eliminate the demineralization effect caused by low pH. PMID- 22917441 TI - The effect of polishing technique on 3-D surface roughness and gloss of dental restorative resin composites. AB - The aim of this study was to compare surface roughness and gloss of resin composites polished using different polishing systems. Five resin composites were investigated: Filtek Silorane (FS), IPS Empress Direct (IP), Clearfil Majesty Posterior (CM), Premise (PM), and Estelite Sigma (ES). Twenty-five disk specimens were prepared from each material, divided into five groups, each polished with one of the following methods: Opti1Step (OS), OptiDisc (OD), Kenda CGI (KD), Pogo (PG), or metallurgical polishing (ML). Gloss and roughness parameters (Sa, Sz, Sq, and St) were evaluated by 60 degrees -angle glossimetry and white-light interferometric profilometry. Two-way analysis of variance was used to detect differences in different materials and polishing techniques. Regression and correlation analyses were performed to examine correlations between roughness and gloss. Significant differences in roughness parameters and gloss were found according to the material, type of polishing, and material/polishing technique (p< 0.05). The highest roughness was recorded when KD was used (Sa: 581.8 [62.1] for FS/KD, Sq: 748.7 [55.6] for FS/KD, Sz: 17.7 [2.7] for CM/KD, and St: 24.6 [6.8] for FS/KD), while the lowest was recorded after ML (Sa: 133.6 [68.9] for PM/ML, Sq: 256.5 [53.5] for ES/ML, Sz: 4.0 [1.3] for ES/ML, and St: 7.1 [0.7] for ES/ML). The highest gloss was recorded for PM/ML (88.4 [2.3]) and lowest for FS/KD (30.3 [5.7]). All roughness parameters were significantly correlated with gloss (r= 0.871, 0.846, 0.713, and 0.707 for Sa, Sq, Sz, St, and gloss, respectively). It was concluded that the polishing procedure and the type of composite can have significant impacts on surface roughness and gloss of resin composites. PMID- 22917442 TI - The clinical effectiveness of various adhesive systems: an 18-month evaluation. AB - The aim of this clinical trial was to compare the clinical performance of three different adhesive systems over 18 months in noncarious cervical lesions (NCCLs). Thirty patients, with at least three noncarious cervical lesions, were enrolled in the study. One operator randomly restored a total of 90 lesions with resin composite (Herculite XRV). The restorations were bonded with either Optibond FL (OF), three-step total-etch; Optibond Solo Plus (OS), two-step total-etch; or Optibond All-In-One (OA), one step self-etch. The restorations were clinically evaluated at baseline and after six, 12, and 18 months using the eight United States Public Health Services criteria. Data were analyzed using Friedman and Wilcoxon signed ranks tests (p<0.05). After 18 months, the retention rate was (OF) 96.5%, (OS) 93.1%, and (OA) 89.7%. Differences among the three adhesive systems for evaluated criteria were not observed in comparison of the mean Alfa score percentages. There was a significant increase in marginal discoloration for (OA) adhesive after 18 months compared with baseline (p=0.011). Other restoration criteria had no statistically significant differences among the three adhesives (p>0.05). With the exception of marginal discoloration, the clinical effectiveness of three types of adhesive systems in NCCLs was acceptable after 18 months. However, using the one-step self-etch adhesive may lead to some marginal discolorations. PMID- 22917443 TI - Visibility of artificial buccal recurrent caries under restorations using different radiographic techniques. AB - The aim of the present study was to assess intraoral images and two cone beam computed tomography (CBCT) systems for detection of artificial buccal recurrent caries under restorations. Class V cavities were made for composite (30 teeth) and amalgam (30 teeth). Full restorations with thermoplastic polymer (30 teeth) and nickel-chromium metal crown (30 teeth) were constructed. In 60 teeth, artificial buccal recurrent caries were simulated; 60 other teeth served as controls. Intraoral film, intraoral digital, Veraviewepocs 3D, and Kodak 9000 images were scored twice. kappa Coefficients were calculated and Az values were compared using Z-tests, with a significance level of alpha=0.05. Higher interobserver agreement was obtained from the CBCT images compared with the intraoral images. The Az values of both readings of all three observers were highest for the Veraviewepocs 3D followed by Kodak 9000 except for the second reading of the third observer. CBCT outperformed intraoral radiography in detection of artificial buccal recurrent caries under restorations. PMID- 22917444 TI - Mesenchymal stem cells overexpressing PEDF decrease the angiogenesis of gliomas. AB - The present study is an exploration of a novel strategy to target a therapeutic gene to brain tumour tissues. In the present study, we evaluated the feasibility of using hMSCs (human mesenchymal stem cells) to deliver PEDF (pigment epithelium derived factor), a potent inhibitor of tumour angiogenesis, in a model of intracranial gliomas. To assess its potential of tracking gliomas, MSCs (mesenchymal stem cells) were injected into the cerebral hemisphere and it showed that MSCs infiltrated into the vessel beds and scattered throughout the tumour. In vitro migration assay showed that the VEGF (vascular endothelial growth factor) enhanced MSC migration. In contrast, the migratory activity of MSCs was significantly inhibited with the presence of PEDF. Systematic delivery of AAV (adeno-associated virus)-PEDF to established glioma xenografts resulted in increased apoptosis of gliomas. In addition, MSC-PEDF treatment prolonged the survival of mice bearing U87 gliomas. Taken together, these data validate that MSCs-PEDF can migrate and deliver PEDF to target glioma cells, which may be a novel and promising therapeutic approach for refractory brain tumour. PMID- 22917445 TI - Synthesis of 2,5-bis(spirocyclohexane)-substituted nitroxides of pyrroline and pyrrolidine series, including thiol-specific spin label: an analogue of MTSSL with long relaxation time. AB - The nitroxides of 7-azadispiro[5.1.5.2]pentadecane and 7 azadispiro[5.1.5.2]pentadeca-14-ene series have been prepared, including thiol specific methane thiosulfonate spin label for site-directed spin labeling. The effect of spirocyclohexane moieties on chemical and spectral properties has been studied. The obtained temperature dependencies of electron spin relaxation parameters demonstrate that new nitroxides may be suitable for PELDOR distance measurements at 80-120 K. Moreover, the new nitroxides demonstrated much higher stability toward reduction by ascorbate than spirocyclohexane-substituted nitroxides of piperidine series and showed 1.3-3.14 times lower reduction rates compared to corresponding 2,2,5,5-tetramethyl nitroxides. PMID- 22917446 TI - Legacy for ChildrenTM: a pair of randomized controlled trials of a public health model to improve developmental outcomes among children in poverty. AB - BACKGROUND: One in five Americans under age 18 lives in a family below the Federal poverty threshold. These more than 15 million children are at increased risk of a wide variety of adverse long-term health and developmental outcomes. The early years of life are critical to short- and long-term health and well being. The Legacy for ChildrenTM model was developed in response to this need and marries the perspectives of epidemiology and public health to developmental psychology theory in order to better address the needs of children at environmental risk for poor developmental outcomes. METHODS/DESIGN: The Legacy for ChildrenTM group-based parenting intervention model was evaluated as a pair of randomized controlled trials among low-income families in Miami and Los Angeles. The study was designed to allow for site-stratified analysis in order to evaluate each model implementation separately. Evaluation domains include comprehensive assessments of family, maternal, and child characteristics, process outcomes, and prospective programmatic cost. Data collection began prenatally or at birth and continues into school-age. DISCUSSION: The societal costs of poor developmental outcomes are substantial. A concerted effort from multiple sectors and disciplines, including public health, is necessary to address these societal concerns. Legacy uses a public health model to engage parents and promote overall child well-being in families in poverty through rigorous evaluation methodologies and evidence-based intervention strategies. This study collects rich and modular information on maternal and child outcomes, process, and cost that will enable a detailed understanding of how Legacy works, how it can be refined and improved, and how it can be translated and disseminated. Taken together, these results will inform public policy and help to address issues of health disparities among at risk populations. TRIAL REGISTRATION: NCT00164697. PMID- 22917448 TI - Novel approach to the lundurine alkaloids: synthesis of the tetracyclic core. PMID- 22917447 TI - Towards a new, ecologically targeted approach to monitoring wild bird populations for avian influenza viruses. AB - Prevalence monitoring of avian influenza in wild bird populations is important to estimate risks for the occurrence of potentially zoonotic and economically disastrous outbreaks of highly pathogenic avian influenza virus (AIV) in poultry worldwide. A targeted, cost-effective monitoring method for AIV in wild birds was developed, which is based on monitoring results for AIV in Germany and information on the distribution and abundance of wild bird species in selected habitat types. Spatial data were combined with virological and outbreak data for the period of 1 January 2006 to 31 December 2010. Using Germany as an example, we identified 11 indicator species. By concentrating monitoring efforts on these species in spatially confined locations, we propose a targeted and more cost effective risk-based AIV monitoring approach that can be adapted universally for the identification of wild bird indicator species worldwide with the perspective of reducing sample sizes (and costs) without impairing the validity of the results. PMID- 22917449 TI - Peripheral calcifying cystic odontogenic tumour of the maxillary gingiva. AB - BACKGROUND: Odontogenic tumors are lesions that are derived from remnants of the components of the developing tooth germ. The calcifying cystic odontogenic tumor or calcifying odontogenic cyst is a benign cystic neoplasm of odontogenic origin that is characterized by an ameloblastoma-like epithelium and ghost cells. Calcifying cystic odontogenic tumor may be centrally or peripherally located, and its ghost cells may exhibit calcification, as first described by Gorlin in 1962. Most peripheral calcifying cystic odontogenic tumors are located in the anterior gingiva of the mandible or maxilla. CASE PRESENTATION: Authors report a rare case of a peripheral calcifying cystic odontogenic tumor of the maxillary gingiva. A 39-year-old male patient presented with a fibrous mass on the attached buccal gingiva of the upper left cuspid teeth. It was 0.7-cm-diameter, painless and it was clinically diagnosed as a peripheral ossifying fibroma. After an excisional biopsy, the diagnosis was peripheric calcifying cystic odontogenic tumor. The patient was monitored for five years following the excision, and no recurrence was detected. CONCLUSIONS: All biopsy material must be sent for histological examination. If the histological examination of gingival lesions with innocuous appearance is not performed, the frequency of peripheral calcifying cystic odontogenic tumor and other peripheral odontogenic tumors may be underestimated. PMID- 22917450 TI - Labile hypertension: characteristics of a referred cohort. AB - From 88 subjects with labile high blood pressure (LHBP), we collected blood pressure variability (BPV) and assessed relationships with age, medications, and nocturnal pattern via ambulatory blood pressure monitoring. The average age of the subjects was 64 +/- 13 years and they were on 1.5 +/- 1.3 antihypertensives. BPV did not differ diurnally and was not influenced by medication. Aging associates with increasing daytime systolic but not diastolic BPV, with increasing nighttime systolic BP, and decreasing diastolic BP diurnally. Subjects had widened pulse pressure and abnormal diurnal pattern with age. Further studies are needed to stratify an individual's risk associated with LHBP. PMID- 22917451 TI - Kissing balloon inflation in percutaneous coronary interventions. AB - Bifurcation lesions are the most frequently approached complex coronary lesions in everyday interventional practice. Bifurcations complexity relies essentially on their very specific anatomy that is imperfectly handled by current coronary devices and, despite dedicated techniques and drug-eluting stents, percutaneous coronary interventions directed toward the treatment of bifurcations are technically demanding and require proper execution. Kissing balloon (KB) inflation was the first specific bifurcation technique to have been developed for percutaneous bifurcation interventions and continues to currently play an important role. Indeed, KB has been proposed to optimize stent apposition, improve side branch access while correcting stent deformation or distortion. Over the years, the KB technique has been deeply investigated by many different methods, from bench testing and computer simulations to in vivo intravascular imaging and clinical studies, producing a large amount of data pointing out the benefits and limitations of the technique. We sought to provide here a comprehensive overview of all those aspects. PMID- 22917452 TI - 3-Year clinical outcomes in the randomized SORT OUT III superiority trial comparing zotarolimus- and sirolimus-eluting coronary stents. AB - OBJECTIVES: This study sought to examine the 3-year clinical outcomes in patients treated with the Endeavor (Medtronic, Santa Rosa, California) zotarolimus-eluting stent (ZES) or the Cypher (Cordis, Johnson & Johnson, Warren, New Jersey) sirolimus-eluting stent (SES) in routine clinical practice. BACKGROUND: The long term clinical outcome in patients treated with ZES in comparison with SES is unclear. METHODS: The authors randomized 2,332 patients to ZES (n = 1,162) or SES (n = 1,170) implantation. Endpoints included major adverse cardiac events (MACE), a composite of cardiac death, myocardial infarction, or target vessel revascularization; the individual endpoints of MACE; and definite stent thrombosis. RESULTS: At 3-year follow-up, the MACE rate was higher in patients treated with ZES than in patients treated with SES (148 [12.9%] vs. 116 [10.1%]; hazard ratio [HR]: 1.33, 95% confidence interval [CI]: 1.04 to 1.69; p = 0.022). Target vessel revascularization was more frequent in the ZES group compared with the SES group (103 [9.1%] vs. 76 [6.7%]; HR: 1.40, 95% CI: 1.04 to 1.89; p = 0.025), whereas the occurrence of myocardial infarction (3.8% vs. 3.3%) and cardiac death (2.8% vs. 2.8%) did not differ significantly. Although the rate of definite stent thrombosis was similar at 3-year follow-up (1.1% vs. 1.4%), very late (12 to 36 months) definite stent thrombosis occurred in 0 (0%) patients in the ZES group versus 12 (1.1%) patients in the SES group (p = 0.0005). CONCLUSIONS: Although the 3-year MACE rate is higher in patients treated with ZES versus SES, our data highlight a late safety problem concerning definite stent thrombosis with the use of SES. This finding underscores the importance of long term follow-up in head-to-head comparisons of drug-eluting stents. (Randomized Clinical Comparison of the Endeavor and the Cypher Coronary Stents in Non selected Angina Pectoris Patients [SORT OUT III]; NCT00660478). PMID- 22917453 TI - Transradial versus transfemoral artery approach for coronary angiography and percutaneous coronary intervention in the extremely obese. AB - OBJECTIVES: This study sought to evaluate the safety and efficacy of transradial versus transfemoral access for coronary angiography and percutaneous coronary intervention in patients with a body mass index >= 40 kg/m(2). BACKGROUND: Coronary angiography is most commonly performed via femoral artery access; however, the optimal approach in extremely obese (EO) patients remains unclear. METHODS: Between January 2007 and August 2010, a cohort of consecutive EO patients who underwent coronary angiography was identified in our center's registry of angiography and percutaneous coronary intervention procedures. Of 21,103 procedures, 564 (2.7%) were performed in unique EO patients: 203 (36%) via the transradial approach; and 361 (64%) via the transfemoral approach. RESULTS: The primary outcome, a combined endpoint of major bleeding, access site complications, and nonaccess site complications, occurred in 7.5% of the transfemoral group and 2.0% of the transradial group (odds ratio [OR]: 0.30, 95% confidence interval [CI]: 0.10 to 0.88, p = 0.029), an endpoint driven by reductions in major bleeding (3.3% vs. 0.0%, OR: 0.12, 95% CI: 0 to 0.71, p = 0.015), as well as access site injuries (4.7% vs. 0.0%, OR: 0.08, 95% CI: 0 to 0.48, p = 0.002). There were no differences in nonaccess site complications (1.7% vs. 2.0%, OR: 1.50, 95% CI: 0.41 to 5.55), but transradial access procedures were associated with an increase in procedure time and patient radiation dose (p < 0.05). CONCLUSIONS: Transfemoral access for coronary angiography and percutaneous coronary intervention was associated with more bleeding and access site complications when compared with a transradial approach. Important reductions in procedural associated morbidity may be possible with a transradial approach in EO patients. PMID- 22917454 TI - The recanalization of chronic total occlusion leads to lumen area increase in distal reference segments in selected patients: an intravascular ultrasound study. AB - OBJECTIVES: This study sought to investigate the extent of and factors related to lumen and vessel area change in coronary arteries after total occlusion (TO) recanalization. BACKGROUND: TO of a coronary artery promotes negative remodeling in distal reference segments. Recanalization can restore blood flow, potentially leading to positive vascular remodeling. METHODS: From March 2005 to June 2008, 58 consecutive patients with de novo TO lesions of at least 1-month duration were enrolled. We performed intravascular ultrasound after successful percutaneous coronary intervention and at the 6-month follow-up, and we quantified changes in the distal reference segments. RESULTS: At the 6-month follow-up, there was a significant increase in the mean lumen diameter (+0.21 mm, p = 0.001), the mean external elastic membrane diameter (+0.13 mm, p = 0.010), the lumen area (+0.87 mm(2), p < 0.001), and the external elastic membrane area (+0.85 mm(2), p = 0.001) in the distal reference segments and an increase in the left ventricular ejection fraction (+2.77%, p = 0.010). Overall, 40 of 58 patients (69%) showed lumen area increase; these patients had increase in lumen diameter by 0.40 +/- 0.34 mm (p < 0.001) and increase in incomplete stent apposition rate (p = 0.006). A TO duration of longer than 3 months (odds ratio [OR]: 14.8; 95% confidence interval [CI]: 1.28 to 172.8, p = 0.032), a poor collateral flow (OR: 12.0; 95% CI: 1.92 to 74.2, p = 0.008), and statin use (OR: 7.4; 95% CI: 1.03 to 53.6, p = 0.047) were independent predictors of lumen area increase. CONCLUSIONS: Recanalization of TO led to lumen area increase in two-thirds of the patients. Independent predictors of lumen area increase were occlusion duration, a poor collateral flow, and statin use. These factors could be used as guides in choosing the optimal stent size during percutaneous coronary intervention to TO lesions and optimal medical therapy during follow-up. PMID- 22917456 TI - Vascular closure device failure: we are getting better but not there yet. PMID- 22917455 TI - Vascular closure device failure in contemporary practice. AB - OBJECTIVES: The goal of this study was to assess the frequency and predictors of vascular closure device (VCD) deployment failure, and its association with vascular complications of 3 commonly used VCDs. BACKGROUND: VCDs are commonly used following percutaneous coronary intervention on the basis of studies demonstrating reduced time to ambulation, increased patient comfort, and possible reduction in vascular complications as compared with manual compression. However, limited data are available on the frequency and predictors of VCD failure, and the association of deployment failure with vascular complications. METHODS: From a de-identified dataset provided by Massachusetts Department of Health, 23,813 consecutive interventional coronary procedures that used either a collagen plug based (n = 18,533), a nitinol clip-based (n = 2,284), or a suture-based (n = 2,996) VCD between June 2005 and December 2007 were identified. The authors defined VCD failure as unsuccessful deployment or failure to achieve immediate access site hemostasis. RESULTS: Among 23,813 procedures, the VCD failed in 781 (3.3%) procedures (2.1% of collagen plug-based, 6.1% of suture-based, 9.5% of nitinol clip-based VCDs). Patients with VCD failure had an excess risk of "any" (7.7% vs. 2.8%; p < 0.001), major (3.3% vs. 0.8%; p < 0.001), or minor (5.8% vs. 2.1%; p < 0.001) vascular complications compared with successful VCD deployment. In a propensity score-adjusted analysis, when compared with collagen plug-based VCD (reference odds ratio [OR] = 1.0), nitinol clip-based VCD had 2-fold increased risk (OR: 2.0, 95% confidence interval [CI]: 1.8 to 2.3, p < 0.001) and suture-based VCD had 1.25-fold increased risk (OR: 1.25, 95% CI: 1.2 to 1.3, p < 0.001) for VCD failure. VCD failure was a significant predictor of subsequent vascular complications for both collagen plug-based VCD and nitinol clip-based VCD, but not for suture-based VCD. CONCLUSIONS: VCD failure rates vary depending upon the type of VCD used and are associated with significantly higher vascular complications as compared with deployment successes. PMID- 22917457 TI - Reduction in treatment times through formalized data feedback: results from a prospective multicenter study of ST-segment elevation myocardial infarction. AB - OBJECTIVES: This study sought to evaluate the effect of systematic data analysis and standardized feedback on treatment times and outcome in a prospective multicenter trial. BACKGROUND: Formalized data feedback may reduce treatment times in ST-segment elevation myocardial infarction (STEMI). METHODS: Over a 15 month period, 1,183 patients presenting with STEMI were enrolled. Six primary percutaneous coronary intervention hospitals in Germany and 29 associated nonpercutaneous coronary intervention hospitals participated. Data from patient contact to balloon inflation were collected and analyzed. Pre-defined quality indicators, including the percentage of patients with pre-announced STEMI, direct handoff in the catheterization laboratory, contact-to-balloon time <90 min, door to-balloon time <60 min, and door-to-balloon time <30 min were discussed with staff on a quarterly basis. RESULTS: Median door-to-balloon time decreased from 71 to 58 min and contact-to-balloon time from 129 to 103 min between the first and the fifth quarter (p < 0.05 for both). Contributing were shorter stays in the emergency department, more direct handoffs from ambulances to the catheterization laboratory (from 22% to 38%, p < 0.05), and a slight increase in the number of patients transported directly to the percutaneous coronary intervention facility (primary transport). One-year mortality was reduced in the total group of patients and in the subgroup of patients with primary transport (p < 0.05). The sharpest fall in mortality was observed in patients with primary transport and TIMI (Thrombolysis In Myocardial Infarction) risk score >= 3 (n = 521) with a decrease in 30-day mortality from 23.1% to 13.3% (p < 0.05) and in 1-year mortality from 25.6% to 16.7% (p < 0.05). CONCLUSIONS: Formalized data feedback is associated with a reduction in treatment times for STEMI and with an improved prognosis, which is most pronounced in high-risk patients. (Feedback Intervention and Treatment Times in ST-Elevation Myocardial Infarction [FITT-STEMI]; NCT00794001). PMID- 22917458 TI - Impact of paravalvular leakage on outcome in patients after transcatheter aortic valve implantation. AB - OBJECTIVES: The aim of this study was to evaluate the performance of the aortic regurgitation (AR) index as a new hemodynamic parameter in an independent transcatheter aortic valve implantation (TAVI) cohort and validate its application. BACKGROUND: Increasing evidence associates more-than-mild periprosthetic aortic regurgitation (periAR) with increased mortality and morbidity; therefore precise evaluation of periAR after TAVI is essential. The AR index has been proposed recently as a simple and reproducible indicator for the severity of periAR and predictor of associated mortality. METHODS: The severity of periAR was evaluated by echocardiography, angiography, and periprocedural measurement of the dimensionless AR index = ([diastolic blood pressure - left ventricular end-diastolic pressure]/systolic blood pressure) * 100. A cutoff value of 25 was used to identify patients at risk. RESULTS: One hundred twenty two patients underwent TAVI by use of either the Medtronic CoreValve (Medtronic, Minneapolis, Minnesota) (79.5%) or the Edwards-SAPIEN bioprosthesis (Edwards Lifesciences, Irvine, California) (20.5%). The AR index decreased stepwise from 29.4 +/- 6.3 in patients without periAR (n = 26) to 28.0 +/- 8.5 with mild periAR (n = 76), 19.6 +/- 7.6 with moderate periAR (n = 18), and 7.6 +/- 2.6 with severe periAR (n = 2) (p < 0.001). Patients with AR index <25 had a significantly increased 1-year mortality rate compared with patients with AR index >= 25 (42.3% vs. 14.3%; p < 0.001). Even in patients with none/mild periAR, the 1-year mortality risk could be further stratified by an AR index <25 (31.3% vs. 14.3%; p = 0.04). CONCLUSIONS: The validity of the AR index could be confirmed in this independent TAVI cohort and provided prognostic information that was complementary to the severity of AR. PMID- 22917459 TI - Radiation dose reduction in the invasive cardiovascular laboratory: implementing a culture and philosophy of radiation safety. AB - OBJECTIVES: This paper investigates the effects of sustained practice and x-ray system technical changes on the radiation dose administered to adult patients during invasive cardiovascular procedures. BACKGROUND: It is desirable to reduce radiation dose associated with medical imaging to minimize the risk of adverse radiation effects to both patients and staff. Several clinical practice and technical changes to elevate radiation awareness and reduce patient radiation dose were implemented under the guidance of a cardiovascular invasive labs radiation safety committee. Practice changes included: intraprocedure radiation dose announcements; reporting of procedures for which the air-kerma exceeded 6,000 mGy, including procedure air-kerma in the clinical report; and establishing compulsory radiation safety training for fellows. Technical changes included establishing standard x-ray imaging protocols, increased use of x-ray beam spectral filters, reducing the detector target dose for fluoroscopy and acquisition imaging, and reducing the fluoroscopy frame rate to 7.5 s(-1). METHODS: Patient- and procedure-specific cumulative skin dose was calculated from air-kerma values and evaluated retrospectively over a period of 3 years. Data were categorized to include all procedures, percutaneous coronary interventions, coronary angiography, noncardiac vascular angiography and interventions, and interventions to treat structural heart disease. Statistical analysis was based on a comparison of the cumulative skin dose for procedures performed during the first and last quarters of the 3-year study period. RESULTS: A total of 18,115 procedures were performed by 27 staff cardiologists and 65 fellows-in-training. Considering all procedures, the mean cumulative skin dose decreased from 969 to 568 mGy (40% reduction) over 3 years. CONCLUSIONS: This work demonstrates that a philosophy of radiation safety, implemented through a collection of sustained practice and x-ray system changes, can result in a significant decrease in the radiation dose administered to patients during invasive cardiovascular procedures. PMID- 22917461 TI - First presentation of 3-dimensional reconstruction and centerline-guided assessment of coronary bifurcation by fusion of X-ray angiography and optical coherence tomography. PMID- 22917460 TI - Stem cell-based transcatheter aortic valve implantation: first experiences in a pre-clinical model. AB - OBJECTIVES: This study sought to investigate the combination of transcatheter aortic valve implantation and a novel concept of stem cell-based, tissue engineered heart valves (TEHV) comprising minimally invasive techniques for both cell harvest and valve delivery. BACKGROUND: TAVI represents an emerging technology for the treatment of aortic valve disease. The used bioprostheses are inherently prone to calcific degeneration and recent evidence suggests even accelerated degeneration resulting from structural damage due to the crimping procedures. An autologous, living heart valve prosthesis with regeneration and repair capacities would overcome such limitations. METHODS: Within a 1-step intervention, trileaflet TEHV, generated from biodegradable synthetic scaffolds, were integrated into self-expanding nitinol stents, seeded with autologous bone marrow mononuclear cells, crimped and transapically delivered into adult sheep (n = 12). Planned follow-up was 4 h (Group A, n = 4), 48 h (Group B, n = 5) or 1 and 2 weeks (Group C, n = 3). TEHV functionality was assessed by fluoroscopy, echocardiography, and computed tomography. Post-mortem analysis was performed using histology, extracellular matrix analysis, and electron microscopy. RESULTS: Transapical implantation of TEHV was successful in all animals (n = 12). Follow up was complete in all animals of Group A, three-fifths of Group B, and two thirds of Group C (1 week, n = 1; 2 weeks, n = 1). Fluoroscopy and echocardiography displayed TEHV functionality demonstrating adequate leaflet mobility and coaptation. TEHV showed intact leaflet structures with well-defined cusps without signs of thrombus formation or structural damage. Histology and extracellular matrix displayed a high cellularity indicative for an early cellular remodeling and in-growth after 2 weeks. CONCLUSIONS: We demonstrate the principal feasibility of a transcatheter, stem cell-based TEHV implantation into the aortic valve position within a 1-step intervention. Its long-term functionality proven, a stem cell-based TEHV approach may represent a next generation heart valve concept. PMID- 22917462 TI - Complete percutaneous obliteration of a post-infarction left ventricular inferior wall pseudoaneurysm. PMID- 22917465 TI - Integration not homogenization. PMID- 22917464 TI - Standing waves are not fibromuscular dysplasia. PMID- 22917466 TI - Short-cut under pressure: stenting the tortuous neonatal duct involves induced spasm. PMID- 22917468 TI - Puerarin stimulates osteoblasts differentiation and bone formation through estrogen receptor, p38 MAPK, and Wnt/beta-catenin pathways. AB - Puerarin is an isoflavone extracted from Radix Puerariae, a traditional Chinese herb used to treat many diseases such as osteoporosis. In this study, puerarin was shown to stimulate alkaline phosphatase (ALP) activity, type I collagen (Col I) secretion, and mineralized nodules formation of primary osteoblasts. Whereas the estrogen receptor (ER) antagonist ICI 182780 was able to reduce the increase in ALP activity and Col I secretion induced by puerarin. Furthermore, puerarin was shown to elevate levels of phospho-p38 mitogen-activated protein kinase (MAPK) and beta-catenin proteins in a time-dependent manner. Pretreatment of osteoblasts with ICI 182780 can reduce this elevation, whereas pretreatment with p38 MAPK inhibitor SB 203580 did not affect the increase of beta-catenin protein. Meanwhile, intragastric administration of puerarin protected against reduction in bone mineral density and bone mineral content in ovariectomized rats, and improved femur trabecular bone structure. Taken together, ER, p38 MAPK, and Wnt/beta-catenin pathways were involved in puerarin-stimulated osteoblasts differentiation and bone formation. PMID- 22917470 TI - Hydrostatic pressure effects on the fluorescence and FRET behavior of Cy3-labeled phycocyanin system. AB - FRET has been used as a powerful tool in biological fields as biosensors, bioimaging, protein folding/unfolding monitoring, biomolecular interactions, and so on. It is also important to applying FRET to high hydrostatic pressure studies on biosystems or biorelated systems. Herein, we construct a FRET system by labeling Cy3 on C-phycocyanin (C-PC) to investigate the effect of hydrostatic pressure on the fluorescence and FRET behavior between them. The fluorescence spectra of individual Cy3, C-PC, and integrated Cy3/C-PC system are measured separately under compression. An enhanced FRET efficiency under compression is concluded based on fluorescence behavior differences between them. To further reveal the origination of the enhanced FRET efficiency with pressure, the overlap integral between Cy3 emission and C-PC absorption is also calculated, and several possible explanations are proposed. PMID- 22917467 TI - Dichotomy effects of Akt signaling in breast cancer. AB - BACKGROUND: The oncogenic roles contributed by the Akt/PKB kinase family remain controversial and presumably depend on cell context, but are perceived to be modulated by an interplay and net balance between various isoforms. This study is intended to decipher whether distinct Akt kinase isoforms exert either redundant or unique functions in regulating neoplastic features of breast cancer cells, including epithelial-mesenchymal transition (EMT), cell motility, and stem/progenitor cell expansion. RESULTS: We demonstrate that overactivation of Akt signaling in nonmalignant MCF10A cells and in primary cultures of normal human mammary epithelial tissue results in previously unreported inhibitory effects on EMT, cell motility and stem/progenitor cell expansion. Importantly, this effect is largely redundant and independent of Akt isoform types. However, using a series of isogenic cell lines derived from MCF-10A cells but exhibiting varying stages of progressive tumorigenesis, we observe that this inhibition of neoplastic behavior can be reversed in epithelial cells that have advanced to a highly malignant state. In contrast to the tumor suppressive properties of Akt, activated Akt signaling in MCF10A cells can rescue cell viability upon treatment with cytotoxic agents. This feature is regarded as tumor-promoting. CONCLUSION: We demonstrate that Akt signaling conveys novel dichotomy effects in which its oncogenic properties contributes mainly to sustaining cell viability, as opposed to the its tumor suppressing effects, which are mediated by repressing EMT, cell motility, and stem/progenitor cell expansion. While the former exerts a tumor enhancing effect, the latter merely acts as a safeguard by restraining epithelial cells at the primary sites until metastatic spread can be moved forward, a process that is presumably dictated by the permissive tumor microenvironment or additional oncogenic insults. PMID- 22917471 TI - Combination of crossflow ultrafiltration, monolithic affinity filtration, and quantitative reverse transcriptase PCR for rapid concentration and quantification of model viruses in water. AB - We present a rapid and effective adsorption-elution method based on monolithic affinity filtration (MAF) for the concentration and purification of waterborne viruses. The MAF column consists of a hydrolyzed macroporous epoxy-based polymer. High recoveries were achieved by columns for the bacterial virus (bacteriophage) MS2 110 (+/-19)%, as model organism, as well as for human adenoviruses 42.4 (+/ 3.4)% and murine noroviruses 42.6 (+/-1.9)%. This new concentration and purification method was combined with crossflow ultrafiltration (CUF). Because of the adsorption of the examined viruses to the macroporous surface of the MAF column at pH 3, concentrated matrix components by CUF can be removed. Bacteriophages MS2 were spiked in tap water and concentrated with the new CUF-MAF concentration method by a volumetric factor of 10(4) within 33 min. Furthermore, the detection limit for quantification of bacteriophage MS2 by quantitative reverse transcriptase PCR (qRT-PCR) could be improved from 79.47 to 0.0056 GU mL( 1) by a factor of 1.4 * 10(4). In a first study, we have shown that this method could also be applied for river water containing naturally MS2 and MS2-like phages. PMID- 22917472 TI - 3D-QSAR based on quantum-chemical molecular fields: toward an improved description of halogen interactions. AB - Current 3D-QSAR methods such as CoMFA or CoMSIA make use of classical force-field approaches for calculating molecular fields. Thus, they can not adequately account for noncovalent interactions involving halogen atoms like halogen bonds or halogen-pi interactions. These deficiencies in the underlying force fields result from the lack of treatment of the anisotropy of the electron density distribution of those atoms, known as the "sigma-hole", although recent developments have begun to take specific interactions such as halogen bonding into account. We have now replaced classical force field derived molecular fields by local properties such as the local ionization energy, local electron affinity, or local polarizability, calculated using quantum-mechanical (QM) techniques that do not suffer from the above limitation for 3D-QSAR. We first investigate the characteristics of QM-based local property fields to show that they are suitable for statistical analyses after suitable pretreatment. We then analyze these property fields with partial least-squares (PLS) regression to predict biological affinities of two data sets comprising factor Xa and GABA-A/benzodiazepine receptor ligands. While the resulting models perform equally well or even slightly better in terms of consistency and predictivity than the classical CoMFA fields, the most important aspect of these augmented field-types is that the chemical interpretation of resulting QM-based property field models reveals unique SAR trends driven by electrostatic and polarizability effects, which cannot be extracted directly from CoMFA electrostatic maps. Within the factor Xa set, the interaction of chlorine and bromine atoms with a tyrosine side chain in the protease S1 pocket are correctly predicted. Within the GABA-A/benzodiazepine ligand data set, PLS models of high predictivity resulted for our QM-based property fields, providing novel insights into key features of the SAR for two receptor subtypes and cross-receptor selectivity of the ligands. The detailed interpretation of regression models derived using improved QM-derived property fields thus provides a significant advantage by revealing chemically meaningful correlations with biological activity and helps in understanding novel structure activity relationship features. This will allow such knowledge to be used to design novel molecules on the basis of interactions additional to steric and hydrogen-bonding features. PMID- 22917473 TI - Sex and gender differences in Alzheimer's disease: recommendations for future research. AB - Alzheimer's disease (AD) disproportionately affects women in both prevalence and severity; however, the biologic mechanisms underlying these sex differences are not fully understood. Sex differences in the brain, such as in brain anatomy, age related declines in brain volume, and brain glucose metabolism, have been documented and may be important in understanding AD etiology. The full impact of sex as a basic biologic variable on this neurodegenerative disease remains elusive. To address the evidence for sex differences in AD, the Society for Women's Health Research (SWHR) convened an interdisciplinary roundtable of experts from academia, clinical medicine, industry, and the government to discuss the state-of-the-science in sex and gender differences in AD. Roundtable participants were asked to address gaps in our knowledge and identify specific sex-based research questions for future areas of study. PMID- 22917474 TI - [The new advisory board of Gaceta Sanitaria is launched]. PMID- 22917475 TI - Popular perceptions of circumcision among Colombian men who have sex with men. AB - Male circumcision has received increased attention for its potential to reduce sexual transmission of HIV. Research on the acceptability of circumcision as a means of HIV prevention among men who have sex with men is limited. Men who have sex with men in Bogota, Colombia, either participated in a focus group in which they shared information regarding their perceptions of circumcision or completed a survey that assessed circumcision experiences, attitudes, beliefs and willingness. Few participants reported they were circumcised, yet most participants reported knowing something about the procedure. Overall, attitudes towards circumcision were mixed: although circumcision was viewed as safe, it was also viewed as unnatural and cruel to babies. Beliefs that circumcision could improve sexual functioning and protect against STIs and HIV were not widely endorsed by survey participants, although focus-group participants discussed the potential impacts of circumcision on the availability of sexual partners and sexual performance. Some focus-group participants and many survey participants reported a hypothetical willingness to get circumcised if strong evidence of its effectiveness could be provided, barriers removed and recovery time minimised. PMID- 22917476 TI - Evaluation of two outer membrane proteins, Aha1 and OmpW of Aeromonas hydrophila as vaccine candidate for common carp. AB - Aeromonas hydrophila is an important fish pathogen responsible for huge economic losses in aquaculture sector. The bacterial outer membrane proteins (OMPs), especially adhesins play a key role in the virulence of the bacteria and are considered potential vaccine candidates. We evaluated the immunogenicity of two important outer membrane proteins namely Aha1 and OmpW of A. hydrophila. These proteins were over-expressed in Escherichia coli, purified and used for the vaccination of common carp. Sequence analysis predicted that, Aha1 and OmpW are adhesins and antigenic. Common carp immunized with recombinant Aha1 and OmpW proteins showed significant antibody production and a relative percentage survival of 52 and 71 respectively indicating their protective efficacy against A. hydrophila infection. PMID- 22917477 TI - Change of Beclin-1 dependent on ATP, [Ca(2+)](i) and MMP in PC12 cells following oxygen-glucose deprivation-reoxygenation injury. AB - Autophagy is usually up-regulated to provide more ATP in response to starvation or OGD (oxygen-glucose deprivation), but the relationship between autophagy and ATP, [Ca2+]i (intracellular free Ca2+ concentration) or MMP (mitochondrial membrane potential) during reoxygenation is not yet fully clear. The role of autophagy is unknown in PC12 cells subjected to 2 h OGD with different time points of reoxygenation. In the present study, we showed that Beclin-1 was up regulated beginning at 0 h reoxygenation peaking at 24 h and lasting for 48 h. Cell viability was decreased from 0 to 48 h reoxygenation, reaching its minimum at 10 h reoxygenation. ATP was decreased from 0 to 10 h reoxygenation, reaching its minimum at 4 h reoxygenation. A significant negative correlation was observed between ATP and Beclin-1 (r = -0.61, P<0.05) at 0 h reoxygenation, but ATP was not significant related (r = 0.24, P>0.05) to Beclin-1 at 24 h reoxygenation. Besides, Nimodipine, a calcium antagonist, significantly reduced [Ca2+]i and Beclin-1, but increased MMP in OGD/R-treated cells. At 24 h reoxygenation, Beclin 1 expression reached its maximum, cell viability continued to increase, and ATP was higher than that before OGD. These results suggest that energy metabolism dysfunction can induce autophagy during OGD in PC12 cells. Increased [Ca2+]i and decreased MMP may induce autophagy during reoxygenation in PC12 cells. Autophagy may be a protective effect on PC12 cells treated with different time points of reoxygenation after 2 h OGD. PMID- 22917478 TI - Serum proteome changes in dengue virus-infected patients from a dengue-endemic area of India: towards new molecular targets? AB - The global burden of dengue continues to worsen, specifically in tropical and subtropical countries, and has evolved as a major public health problem. We investigated the changes in serum proteome in dengue fever (DF) patients from a dengue-endemic area of India to obtain mechanistic insights about the disease pathogenesis, the host immune response, and identification of potential serum protein biomarkers of this infectious disease. In this study, serum samples from DF patients, healthy subjects, and patients with falciparum malaria (an infectious disease control) were investigated by 2D-DIGE in combination with MALDI-TOF/TOF MS. The findings were validated with Western blotting. Functional clustering of the identified proteins was performed using PANTHER and DAVID tools. Compared to the healthy controls, we found significant changes in the expression levels of 48 protein spots corresponding to 18 unique proteins (7 downregulated and 11 upregulated) in DF patients (p<0.05). Among these differentially-expressed proteins, 11 candidates exhibited different trends in dengue fever compared to falciparum malaria. Importantly, our results suggest that dengue virus infection leads to alterations in expression levels of multiple serum proteins involved in diverse and vital physiological pathways, including acute phase response signaling, complement cascades, hemostasis, and blood coagulation. For the first time we report here that the serum levels of hemopexin, haptoglobin, serum amyloid P, and kininogen precursor, are altered in DF. This study informs the pathogenesis and host immune response to dengue virus infection, as well as the current search for new diagnostic and molecular drug targets. PMID- 22917479 TI - Predicting disease-related subnetworks for type 1 diabetes using a new network activity score. AB - In this study we investigated the advantage of including network information in prioritizing disease genes of type 1 diabetes (T1D). First, a naive Bayesian network (NBN) model was developed to integrate information from multiple data sources and to define a T1D-involvement probability score (PS) for each individual gene. The algorithm was validated using known functional candidate genes as a benchmark. Genes with higher PS were found to be more likely to appear in T1D-related publications. Next a new network activity metric was proposed to evaluate the T1D relevance of protein-protein interaction (PPI) subnetworks. The metric considered the contribution both from individual genes and from network topological characteristics. The predictions were confirmed by several independent datasets, including a genome wide association study (GWAS), and two large-scale human gene expression studies. We found that novel candidate genes in the T1D subnetworks showed more significant associations with T1D than genes predicted using PS alone. Interestingly, most novel candidates were not encoded within the human leukocyte antigen (HLA) region, and their expression levels showed correlation with disease only in cohorts with low-risk HLA genotypes. The results suggested the importance of mapping disease gene networks in dissecting the genetics of complex diseases, and offered a general approach to network-based disease gene prioritization from multiple data sources. PMID- 22917480 TI - A seven-gene signature aggregates a subgroup of stage II colon cancers with stage III. AB - Colorectal cancer is one of the most common cancers in the world. Histological staging is efficient, but combination with molecular markers may improve tumor classification. Gene expression profiles have been defined as prognosis predictors among stage II and III tumors, but their implementation in medical practice remains controversial. Stage II tumors have been recognized as a heterogeneous group, and high-risk morphologic features have been used to justify adjuvant chemotherapy. We propose here the investigation of clinical features and expression profiles from stage II and stage III colon carcinomas without DNA mismatch repair defects. Two series of 130 and 66 colon cancer samples were obtained. Expression profiles were established on oligonucleotide microarrays and processed in the R/Bioconductor environment. Hierarchical, then supervised, analyses were successively performed by applying a data-sampling approach. A molecular signature of seven genes was found to cluster stage III tumors with adjusted p values lower than 10(-10). A subgroup of stage II tumors aggregated this cluster in both series. No correlation was found with disease severity, but the function of the discriminating genes suggests that tumors have been classified according to their putative response to adjuvant targeted or classic therapies. Further pharmacogenetic studies might verify this observation. PMID- 22917481 TI - Prioritizing cancer therapeutic small molecules by integrating multiple OMICS datasets. AB - Drug design is crucial for the effective discovery of anti-cancer drugs. The success or failure of drug design often depends on the leading compounds screened in pre-clinical studies. Many efforts, such as in vivo animal experiments and in vitro drug screening, have improved this process, but these methods are usually expensive and laborious. In the post-genomics era, it is possible to seek leading compounds for large-scale candidate small-molecule screening with multiple OMICS datasets. In the present study, we developed a computational method of prioritizing small molecules as leading compounds by integrating transcriptomics and toxicogenomics data. This method provides priority lists for the selection of leading compounds, thereby reducing the time required for drug design. We found 11 known therapeutic small molecules for breast cancer in the top 100 candidates in our list, 2 of which were in the top 10. Furthermore, another 3 of the top 10 small molecules were recorded as closely related to cancer treatment in the DrugBank database. A comparison of the results of our approach with permutation tests and shared gene methods demonstrated that our OMICS data-based method is quite competitive. In addition, we applied our method to a prostate cancer dataset. The results of this analysis indicated that our method surpasses both the shared gene method and random selection. These analyses suggest that our method may be a valuable tool for directing experimental studies in cancer drug design, and we believe this time- and cost-effective computational strategy will be helpful in future studies in cancer therapy. PMID- 22917482 TI - Prenatal diagnosis of long QT syndrome with the superior vena cava-aorta Doppler approach. AB - We describe a fetus at 36 weeks with long QT syndrome presenting with variable types of atrioventricular blocks, ventricular premature beats, and torsades de pointes. All these diagnoses were made with the superior vena cava-aorta Doppler approach and confirmed with postnatal electrocardiography. PMID- 22917483 TI - Influence of religious beliefs in the professional practice of US gynecologists. PMID- 22917485 TI - Patient-centered care for antenatal depression. PMID- 22917484 TI - Use of topiramate in pregnancy and risk of oral clefts. AB - OBJECTIVE: The objective of this study was to evaluate the association between the use of monotherapy topiramate in pregnancy and cleft lip with or without cleft palate (CL/P) in the offspring. STUDY DESIGN: Data from the Slone Epidemiology Center Birth Defects Study (BDS) from 1997 to 2009 and the National Birth Defects Prevention Study (NBDPS) from 1997 to 2007 were analyzed. Conditional logistic regression was used to compare the first-trimester use of topiramate monotherapy to no antiepileptic drug use during the periconceptional period between the mothers of infants with CL/P and the mothers of controls for each study separately and in pooled data. RESULTS: The BDS contained 785 CL/P cases and 6986 controls; the NBDPS contained 2283 CL/P cases and 8494 controls. The odds ratios (exact 95% confidence intervals) for the association between topiramate use and CL/P were 10.1 (1.1-129.2) in the BDS, 3.6 (0.7-20.0) in the NBDPS, and 5.4 (1.5-20.1) in the pooled data. CONCLUSION: First-trimester use of topiramate may be associated with CL/P. PMID- 22917488 TI - Cu-catalyzed reaction of 1,2-dihalobenzenes with 1,3-cyclohexanediones for the synthesis of 3,4-dihydrodibenzo[b,d]furan-1(2H)-ones. AB - The Cu(I)-catalyzed reaction of 1-bromo-2-iodobenzenes and other 1,2 dihalobenzenes with 1,3-cyclohexanediones in DMF at 130 degrees C using Cs(2)CO(3) as a base and pivalic acid as an additive selectively delivers 3,4 dihydrodibenzo[b,d]furan-1(2H)-ones with yields ranging from 47 to 83%. The highly regioselective domino process is based on an intermolecular Ullmann-type C arylation followed by an intramolecular Ullmann-type O-arylation. Substituted products are accessible by employing substituted 1-bromo-2-iodobenzenes and substituted 1,3-cyclohexanediones as substrates. Reaction with an acyclic 1,3 diketone yields the corresponding benzo[b]furan. PMID- 22917487 TI - Recurrence risk of preterm birth in subsequent singleton pregnancy after preterm twin delivery. AB - OBJECTIVE: The purpose of this study was to investigate the recurrence risk of preterm birth (<37 weeks' gestation) in a subsequent singleton pregnancy after a previous nulliparous preterm twin delivery. STUDY DESIGN: We included 1957 women who delivered a twin gestation and a subsequent singleton pregnancy from the Netherlands Perinatal Registry. We compared the outcome of subsequent singleton pregnancy of women with a history of preterm delivery to the pregnancy outcome of women with a history of term twin delivery. RESULTS: Preterm birth in the twin pregnancy occurred in 1075 women (55%) vs 882 women (45%) who delivered at term. The risk of subsequent spontaneous singleton preterm birth was significantly higher after preterm twin delivery (5.2% vs 0.8%; odds ratio, 6.9; 95% confidence interval, 3.1-15.2). CONCLUSION: Women who deliver a twin pregnancy are at greater risk for delivering prematurely in a subsequent singleton pregnancy. PMID- 22917489 TI - A cross sectional assessment of knowledge, attitude and practice towards Hepatitis B among healthy population of Quetta, Pakistan. AB - BACKGROUND: Hepatitis B (HB) is a serious global public health problem. This study aims to evaluate Knowledge, Attitude and Practice (KAP) towards Hepatitis B (HB) among healthy population of Quetta city, Pakistan. METHODS: A cross sectional, descriptive study was undertaken. One thousand healthy individuals (aged 18 years and above) were approached for the study. KAP towards HB was assessed by using a pre validated questionnaire. Descriptive statistics were used for elaborating patients' demographic characteristics. Inferential statistics (Mann-Whitney U test and Kruskal Wallis test) were used for comparison while Spearman's rho correlation was used to identify association between the study variables. All analyses were performed using SPSS 16.0. RESULTS: Out of 1000 distributed questionnaires, 780 were returned with a response rate of 78.0%. Four hundred and twenty (53.8%) respondents were male with mean age of 32.76 +/- 9.40 year. Two hundred and eight (26.7%) had intermediate level of education and 354 (45.4%) were unemployed. Mean scores for knowledge, attitude and practice were 8.74 +/- 2.7, 3.72 +/- 1.2 and 2.76 +/- 1.1 respectively. Significant and positive linear correlations between knowledge-attitude (r = 0.296, p < 0.01) knowledge-practice (r = 0.324, p < 0.01) and attitude-practice (r = 0.331, p < 0.01) were observed. Area of residence (locality) was the only variables significantly associated with mean KAP of the study respondents. CONCLUSION: Results from the current study heighted poor KAP of healthy population towards HB. The positive linear correlations reaffirms that better knowledge can lead to positive attitude and subsequently in good practices. This will further help in prevention and management of HB. Therefore, extensive health educational campaign should be provided to general population and especially to the residents of rural areas. PMID- 22917490 TI - Systematic review and meta-analysis of Endostar (rh-endostatin) combined with chemotherapy versus chemotherapy alone for treating advanced non-small cell lung cancer. AB - BACKGROUND: Many studies have investigated the efficacy of Endostar combined with platinum-based doublet chemotherapy (PBDC) versus PBDC alone for treating advanced non-small cell lung cancer (NSCLC). This study is a meta-analysis of available evidence. METHODS: Fifteen studies reporting Endostar combined with PBDC versus PBDC alone for treating advanced NSCLC were reviewed. Pooled odds ratios and hazard ratio with 95% confidence intervals were calculated using either the fixed effects model or random effects model. RESULTS: The overall response rate (ORR) and disease control rate (DCR) of Endostar combined with PBDC for treating NSCLC were significantly higher than those of PBDC alone, with 14.7% and 13.5% improvement, respectively (P < 0.00001). In addition, the time to progression (TTP) and quality of life (QOL) were improved after the treatment of Endostar combined with PBDC (P < 0.00001). The main adverse effects found in this review were hematological reactions, hepatic toxicity, and nausea/vomiting. Endostar combined with PBDC had a similar incidence of adverse reactions compared with PBDC alone (P < 0.05). CONCLUSIONS: Endostar combined with PBDC was associated with higher RR, DCR, and TTP as well as superior QOL profiles compared with PBDC alone. Endostar combined with PBDC had a similar incidence of adverse reactions compared with PBDC alone. PMID- 22917491 TI - Generation of neuronal progenitor cells and neurons from mouse sleeping beauty transposon-generated induced pluripotent stem cells. AB - Mouse embryonic stem cells (ESCs) and induced pluripotent stem (iPS) cells can be used as models of neuronal differentiation for the investigation of mammalian neurogenesis, pharmacological testing, and development of cell-based therapies. Recently, mouse iPS cell lines have been generated by Sleeping Beauty (SB) transposon-mediated transgenesis (SB-iPS). In this study, we determined for the first time the differentiation potential of mouse SB-iPS cells to form neuronal progenitor cells (NPCs) and neurons. Undifferentiated SB-iPS and ES cells were aggregated into embryoid bodies (EBs) and cultured in neuronal differentiation medium supplemented with 5 MUM all-trans retinoic acid. Thereafter, EBs were dissociated and plated to observe further neuronal differentiation. Samples were fixed on days 10 and 14 for immunocytochemistry staining using the NPC markers Pax6 and Nestin and the neuron marker betaIII-tubulin/Tuj1. Nestin-labeled cells were analyzed further by flow cytometry. Our results demonstrated that SB-iPS cells can generate NPCs and differentiate further into neurons in culture, although SB-iPS cells produced less nestin-positive cells than ESCs (6.12 +/- 1.61 vs. 74.36 +/- 1.65, respectively). In conclusion, the efficiency of generating SB-iPS cells-derived NPCs needs to be improved. However, given the considerable potential of SB-iPS cells for drug testing and as therapeutic models in neurological disorders, continuing investigation of their neuronal differentiation ability is required. PMID- 22917492 TI - Effects of combined treatment of MG132 and scriptaid on early and term development of porcine somatic cell nuclear transfer embryos. AB - Although improving, the efficiency of producing offspring by somatic cell nuclear transfer (SCNT) is still low (<1.5%). Our laboratory has demonstrated that histone deacetylase inhibitor (Scriptaid) treatment of reconstructed embryos enhances blastocyst formation and cloning efficiency in pigs. It has also been shown that proteasomal inhibitor MG132 treatment for 2 h after activation of oocytes increases blastocyst rate and pregnancy rate. The current experiment was carried out to determine the effects of combined MG132 and Scriptaid treatment on early embryo development in vitro and on term development in vivo. Immediately after electrofusion and activation, SCNT oocytes were treated with 0, 1, or 10 MUM MG132 for 2 h in the presence of 500 nM Scriptaid, washed and treated with Scriptaid for an additional 14 to 15 h, then cultured in porcine zygote medium 3 (PZM3) until day 6. There was no difference in percent cleavage (58.1 +/- 7.2%, 62.7 +/- 7.2%, and 62.5 +/- 7.2%) on day 2, or total cell number (23.1 +/- 2.2, 24.0 +/- 2.0, and 24.5 +/- 2.3 for the 0, 1, and 10 MUM MG132 groups, respectively) on day 6 among the three groups. Interestingly, there was no difference in percentage of blastocysts between the 0 (18.5+/-4.7%) and 1 (25.1 +/- 4.7%) MUM MG132 treatment groups; however, compared with the 10 MUM MG132 group (14.0 +/- 4.7%), more embryos from the 1 MUM MG132 group developed into blastocysts (p<0.05). To determine the effects on term development in vivo, two MG132 groups were included (0 and 1 MUM MG132), and embryos were treated as above and transferred into synchronized surrogates after treatment. There was no difference in the oocyte-donor cell fusion rate, number of embryos transferred, pregnancy rate at days 28, 60, and at term, pigs delivered per embryo transfer, litter size, body weight at birth, nor cloning efficiency between the Scriptaid alone control and MG132+Scriptaid combined groups. In summary, the combined treatment of MG132 and Scriptaid did not improve term development compared to Scriptaid treatment alone. PMID- 22917494 TI - Textural properties and surface chemistry of lotus stalk-derived activated carbons prepared using different phosphorus oxyacids: adsorption of trimethoprim. AB - The preparation of activated carbons (AC-H(x)P(y)O(z)) by four kinds of oxyacids of phosphorus (H(3)PO(4), H(4)P(2)O(7), HPO(3) and H(3)PO(3)) activation of lotus stalk (LS) was studied, with a particular focus on the effect of these H(x)P(y)O(z) on both surface chemistry and porous texture. The XRD analysis of the samples after H(x)P(y)O(z) impregnation showed H(4)P(2)O(7) had the strongest influence on the crystallinity of LS. Thermo gravimetric studies of the pyrolysis of LS-H(x)P(y)O(z) indicated that these H(x)P(y)O(z) had a very different influence on the thermal degradation of LS. The prepared activated carbons were characterized by SEM, N(2) sorption/desorption isotherms, XRD, FTIR and Boehm's titration. Batched sorption studies were performed to compare adsorptive properties of the carbons toward trimethoprim (TMP). The surface area and pore volume of AC-H(3)PO(4) and AC-H(4)P(2)O(7) were much higher than AC-HPO(3) and AC H(3)PO(3). Boehm's titration results indicated that AC-H(4)P(2)O(7) and AC H(3)PO(3) possessed more acidic oxygen functionalities than AC-H(3)PO(4) and AC HPO(3). The structure of the AC-HPO(3) was kept as its starting material after activation. Activation with H(3)PO(3) would result in the aromatization of the carbon. The sorption affinities of TMP follows an order of AC-H(4)P(2)O(7)>AC H(3)PO(4)>AC-H(3)PO(3)>AC-HPO(3). PMID- 22917493 TI - Antagonism of the protein kinase R pathway by the guinea pig cytomegalovirus US22 family gene gp145. AB - Viral double-stranded RNA (dsRNA) activates protein kinase R (PKR), which phosphorylates eIF2alpha and inhibits translation. In response, viruses have evolved various strategies to evade the antiviral impact of PKR. We investigated whether guinea pig cytomegalovirus (GPCMV), a useful model of congenital CMV infection, encodes a gene that interferes with the PKR pathway. Using a proteomic screen, we identified several GPCMV dsRNA-binding proteins, among which only gp145 rescued replication of a vaccinia virus mutant that lacks E3L. gp145 also reversed the inhibitory effects of PKR on expression of a cotransfected reporter gene. Mapping studies demonstrated that the gp145 dsRNA-binding domain has homology to the PKR antagonists of other CMVs. However, dsRNA-binding by gp145 is not sufficient for it to block PKR. gp145 differs from the PKR antagonists of murine CMV in that it functions alone and from those encoded by human CMV in functioning in cells from both primates and rodents. PMID- 22917495 TI - Arsenate and arsenite exposure modulate antioxidants and amino acids in contrasting arsenic accumulating rice (Oryza sativa L.) genotypes. AB - Carcinogenic arsenic (As) concentrations are found in rice due to irrigation with contaminated groundwater in South-East Asia. The present study evaluates comparative antioxidant property and specific amino acid accumulation in contrasting rice genotypes corresponding to differential As accumulation during arsenate (As(V)) and arsenite (As(III)) exposures. The study was conducted on two contrasting As accumulating rice genotypes selected from 303 genotype accessions, in hydroponic conditions. Maximum As accumulation was up to 1181 MUg g(-1) dw in the roots of high As accumulating genotype (HARG), and 89 MUg g(-1) dw in low As accumulating genotype (LARG) under As(III) exposures. The inorganic As was correlated more significantly upon exposures to As(III) than As(V). In the presence of As(V) various antioxidant enzymes guiacol peroxidase (GPX), ascorbate peroxidase (APX) and superoxide dismutase (SOD) were highly stimulated in HARG. The stress responsive amino acids proline, cysteine, glycine, glutamic acid and methionine showed higher accumulation in HARG than LARG. A clear correlation was found between stress responsive amino acids, As accumulation and antioxidative response. The comparisons between the contrasting genotypes helped to determine the significance of antioxidants and specific amino acid response to As stress. PMID- 22917496 TI - Fe3+ and amino functioned mesoporous silica: preparation, structural analysis and arsenic adsorption. AB - Two novel adsorbents to remove excess arsenate and arsenite in the drinking water were prepared for the first time by grafting monoamine and diamine, respectively, and then coordinating Fe(3+) on silica gel that was obtained using sol-gel method with two-step acid-base catalysis. It was found that both adsorbents had mesoporous structure, large specific surface, and high amino and iron content according to N(2) adsorption isotherms, FTIR, XPS, and NMR analysis. The removal ability and adsorption rate of the adsorbents were very high for both As(V) and As(III). Langmuir and Freundlich models were used to fit the adsorption isotherm and investigate the adsorption mechanism. The effects of chloride and sulfate anion on the removal of arsenate and arsenite for the two adsorbents were also studied. PMID- 22917497 TI - Serum starvation activates NF-kappaB through G protein beta2 subunit-mediated signal. AB - Several cell stresses induce nuclear factor-kappaB (NF-kappaB) activation, which include irradiation, oxidation, and UV. Interestingly, serum-starving stress induced NF-kappaB activation in COS cells, but not in COS-A717 cells. COS-A717 is a mutant cell line of COS cells that is defective of the NF-kappaB signaling pathway. We isolated genes with compensating activity for the NF-kappaB pathway and one gene encoded the G protein beta2 (Gbeta2). Gbeta2 is one of the G protein coupled receptor signaling effectors. In COS-A717 cells, Gbeta2 expression is significantly reduced. In Gbeta2 cDNA-transfected COS-A717 cells, the NF-kappaB activity was increased along with the recovery of Gbeta2 expression. Furthermore, serum-starving stress induced the NF-kappaB activity in Gbeta2-transfected COS A717 cells. Consistently, the serum-starved COS cells with siRNA-reduced Gbeta2 protein expression showed decreased NF-kappaB activity. These results indicate that Gbeta2 is required for starvation-induced NF-kappaB activation and constitutive NF-kappaB activity. We propose that serum contains some molecule(s) that strongly inhibits NF-kappaB activation mediated through Gbeta2 signaling. PMID- 22917498 TI - Continued progress and an ambitious goal. PMID- 22917499 TI - Soft drink, 100% fruit juice, and vegetable juice intakes and risk of diabetes mellitus. AB - BACKGROUND & AIMS: Japan has experienced a jump in the diabetes prevalence rates. We want to examine whether increased intake of soft drink and juices have contributed to this jump. METHODS: Participants were 27,585 Japanese men and women aged 40-59 years who had no prior history of diabetes. Intakes of soft drink, 100% fruit juice and vegetable juice were measured by a validated food frequency questionnaire. Odds ratios of type 2 diabetes over 5 and 10 years were estimated by using logistic regression. RESULTS: A total of 484 men and 340 women reported newly diagnosed diabetes during 10 years. High soft drink intake was associated with increased risk of type 2 diabetes in women but not men; odds ratio (95% CI) for women with almost daily consumption versus non-consumers was 2.10 (1.23-3.59; P-trend = 0.004) and 1.79 (1.11-2.89; P-trend = 0.01) at 5 and 10 years, respectively. The association was evident in overweight, highly educated and premenopausal women, and women with blue collar job. Intakes of 100% fruit juice and vegetable juice were not associated with risk of type 2 diabetes for either gender (P-trend >0.05). CONCLUSIONS: Soft drink but not pure juices consumption was associated with increased risk of type 2 diabetes in Japanese women. PMID- 22917500 TI - 3D cerebrovascular segmentation combining fuzzy vessel enhancement and level-sets with anisotropic energy weights. AB - The aim of this work is to present and evaluate a level-set segmentation approach with vesselness-dependent anisotropic energy weights, which focuses on the exact segmentation of malformed as well as small vessels from time-of-flight (TOF) magnetic resonance angiography (MRA) datasets. In a first step, a vesselness filter is used to calculate the vesselness dataset, which quantifies the likeliness of each voxel to belong to a bright tubular-shaped structure and estimate the corresponding vessel directions from a given TOF dataset. The vesselness and TOF datasets are then combined using fuzzy-logic and used for initialization of a variational level-set method. The proposed level-set model has been extended in a way that the weight of the internal energy is locally adapted based on the vessel direction information. Here, the main idea is to weight the internal energy lower if the gradient direction of the level-set is similar to the direction of the eigenvector extracted by the vesselness filter. Furthermore, an additional vesselness force has been integrated in the level-set formulation. The proposed method was evaluated based on ten TOF MRA datasets from patients with an arteriovenous malformation. Manual segmentations from two observers were available for each dataset and used for quantitative comparison. The evaluation revealed that the proposed method yields significantly better segmentation results than four other state-of-the-art segmentation methods tested. Furthermore, the segmentation results are within the range of the inter observer variation. In conclusion, the proposed method allows an improved delineation of small vessels, especially of those represented by low intensities and high surface curvatures. PMID- 22917501 TI - Symptom attribution in first episode psychosis: a cortical thickness study. AB - One dimension of insight in psychosis is the ability to attribute correctly one's symptoms to a mental disorder. Recent work suggests that gray matter volumes of the orbitofrontal cortex (OFC) are correlated with aggregate symptom attribution scores in first-episode schizophrenia. Whether regions beyond the OFC are important for symptom attribution remains to be established. Further, whether common or separable neural systems underlie attribution of specific symptoms (e.g., delusions, asociality) has not been studied. In the current magnetic resonance imaging study, 52 people with a first-episode psychosis (FEP) were rated with the Scale for Assessment of Unawareness of Mental Disorder on attribution of hallucinations, delusions, flat affect and asociality. Attribution ratings were regressed on cortical thickness at 81,924 vertices. Mapping statistics revealed that delusion misattribution was associated with thickness in the OFC [Brodmann's area (BA) 11/47]. Delusion, flat affect and asociality misattribution were associated with cortical thinness in the dorsolateral prefrontal cortex (BA 9/46). Differential associations emerged between each attribution item and cortical thickness/thinness in a variety of frontal, temporal, parietal and occipital areas. The results imply a selective role for the OFC in delusion misattribution in FEP. Evidence for cortical thickness covariation in a variety of regions suggests partial independence in the neural architecture underlying attribution for different symptoms in FEP. PMID- 22917502 TI - Comprehensive segmentation of subcortical brain volumes in early onset schizophrenia reveals limited structural abnormalities. AB - Structural brain abnormalities are well documented in adult schizophrenia, but there are few studies of brain structures in early onset schizophrenia (EOS) and findings are inconsistent. Most previous EOS studies have been limited to global morphometric measures, such as whole gray matter (GM) or cerebrospinal fluid (CSF), or to single brain structures. The purpose of this study was to compare specific volumes and hemispheric lateralization in a large number of subcortical brain structures, between EOS patients and a healthy control group. High resolution structural magnetic resonance images (MRI) and automatic brain volume segmentation were performed on 18 EOS patients and 33 healthy controls (11-18 years). A total of 29 brain structures were studied. The patients showed marked bilateral enlargements of the lateral ventricles and of the fourth ventricle, and bilateral enlargement of the caudate nuclei compared to the controls. For all other subcortical brain structures, there were no significant differences between the EOS group and the healthy control group, contrary to findings from the majority of morphometric studies of childhood or adult onset schizophrenia. PMID- 22917504 TI - Candida albicans. PMID- 22917503 TI - A window into the brain: an in vivo study of the retina in schizophrenia using optical coherence tomography. AB - Retinal nerve fibre layer (RNFL) thickness and macular volume (MV) can be measured in vivo using optical coherence tomography (OCT) providing a "window into the brain". RNFL and MV are promising biomarkers in neurological diseases. This study explores the potential of RNFL and MV to detect axonal abnormalities in vivo in schizophrenia and their correlations with clinical features. OCT was performed in 49 patients (38 schizophrenia, 11 schizoaffective disorder) and 40 healthy controls matched for age and gender. Group comparisons were made between whole retina and quadrant RNFL thickness and MV using multi-level analyses. In patients, associations were sought between RNFL and MV with symptom severity (positive/negative). Patients and controls had similar whole retina RNFL thickness (p=0.86) and MV (p=0.64), but RNFL in the right nasal quadrant of the schizoaffective group was thinner than in the schizophrenia group (p=0.02). In patients, positive symptom severity was associated with smaller MV (right beta= 0.54, p=0.02; left beta=-0.49, p=0.04). Normal MV and RNFL thickness suggests unmyelinated axons in patients with schizophrenia/schizoaffective disorder remain unaffected. Longitudinal studies using higher resolution OCT will clarify whether progressive RNFL and MV changes occur and whether they can be used as state or trait markers in schizophrenia. PMID- 22917505 TI - Unfolded protein response. PMID- 22917506 TI - Silence resulting from the cessation of movement signals danger. PMID- 22917507 TI - By the teeth of their skin, cavefish find their way. PMID- 22917508 TI - Human genetics: message from the Mesolithic. AB - DNA extracted from the remains of two Mesolithic individuals reveals that they had genetically little in common with modern Europeans. The ancestors of most modern Europeans thus most likely entered Europe only with the advent of farming. PMID- 22917509 TI - Neuronal communication: firing spikes with spikes. AB - Spikes of single cortical neurons can exert powerful effects even though most cortical synapses are too weak to fire postsynaptic neurons. A recent study combining single-cell stimulation with population imaging has visualized in vivo postsynaptic firing in genetically identified target cells. The results confirm predictions from in vitro work and might help to understand how the brain reads single-neuron activity. PMID- 22917510 TI - Cell polarity: stretching prevents developmental cramps. AB - Initiation and successive development of organs induce mechanical stresses at the cellular level. Using the tomato shoot apex, a new study now proposes that mechanical strain regulates the plasma membrane abundance of the PIN1 auxin transporter, thereby reinforcing a positive feed-back loop between growth and auxin accumulation. PMID- 22917511 TI - Color vision: retinal blues. AB - Two complementary studies have resolved the circuitry underlying green-blue color discrimination in the retina. A blue-sensitive interneuron provides the inhibitory signal required for computing green-blue color opponency. PMID- 22917512 TI - Bacteriophage tubulins: carrying their own cytoskeleton key. AB - Cytoskeletal elements are well known to be widespread in eukaryotes and prokaryotes, providing important, diverse functions for cells large and small. Two new studies report that some bacteriophages encode their own tubulin homologs to facilitate phage reproduction within the host cell. PMID- 22917513 TI - Programmed genome rearrangements: in lampreys, all cells are not equal. AB - How can organisms silence deleterious gene loci? A recent study has shed light on a very brute mechanism in a jawless vertebrate: the irreversible deletion of massive chunks of genomic DNA. PMID- 22917514 TI - Actin cytoskeleton: a team effort during actin assembly. AB - Two recent studies highlight how tandems of previously described actin nucleators collaborate to produce new actin filaments. One key player in these collaborations is formin, which appears to function as a modulator of filament elongation. PMID- 22917515 TI - Plant development: should I stop or should I grow? AB - Plant growth is tightly controlled through the integration of environmental cues with the physiological status of the seedling. A recent study now proposes a model explaining how the plant hormone ethylene triggers opposite growth responses depending on the light environment. PMID- 22917517 TI - The functional importance of rhythmic activity in the brain. AB - Oscillations in brain activity have long been known, but many fundamental aspects of such brain rhythms, particularly their functional importance, have been unclear. As we review here, new insights into these issues are emerging from the application of intervention approaches. In these approaches, the timing of brain oscillations is manipulated by non-invasive brain stimulation, either through sensory input or transcranially, and the behavioural consequence then monitored. Notably, such manipulations have led to rapid, periodic fluctuations in behavioural performance, which co-cycle with underlying brain oscillations. Such findings establish a causal relationship between brain oscillations and behaviour, and are allowing novel tests of longstanding models about the functions of brain oscillations. PMID- 22917518 TI - Protecting the heart through delivering DNA encoding for heme oxygenase-1 into skeletal muscle. AB - AIM: To evaluate if remote gene delivery of HMOX-1 prior to myocardial infarction can prevent cardiac remodeling and preserve function, without causing general angiogenesis. MAIN METHODS: Right quadriceps muscles of mice were treated with DNA encoding for HMOX-1 or empty vector (pcDNA) and electroporated to enhance nuclear uptake, while a third group received saline. Transfection efficacy was evaluated by real time PCR and situ hybridization in transfected muscle, contralateral muscle, and heart. Seven days after transfection baseline echocardiography was performed. Myocardial infarction was induced by ligation of the left coronary artery. Six weeks later heart function was reassessed by echocardiography. Hearts were extracted for evaluation of infarct size. Immunoflorescent staining was used to evaluate angiogenesis using the endothelial marker CD31 in cross-sections of the transfected quadriceps muscle, the untreated muscle, and hearts. KEY FINDINGS: Gene delivery of HMOX-1 leads to a local expression of HMOX-1 in the treated muscle, but not in any other organ. HMOX-1 treated mice had reduced infarct size (p=0.03) and improved function evident as higher ejection fraction (p=0.001), improved fractional shortening (p<0.0001) and higher stroke volume (p=0.002). HMOX-1 did not cause angiogenesis in the heart or skeletal muscle. SIGNIFICANCE: Remote delivery of DNA encoding for HMOX-1 was cardioprotective, as evidenced by preserved cardiac structure and function. Angiogenesis was not induced by HMOX-1 treatment. PMID- 22917516 TI - Complexity in the wiring and regulation of plant circadian networks. AB - Endogenous circadian rhythms regulate many aspects of an organism's behavior, physiology and development. These daily oscillations synchronize with the environment to generate robust rhythms, resulting in enhanced fitness and growth vigor in plants. Collective studies over the years have focused on understanding the transcription-based oscillator in Arabidopsis. Recent advances combining mechanistic data with genome-wide approaches have contributed significantly to a more comprehensive understanding of the molecular interactions within the oscillator, and with clock-controlled pathways. This review focuses on the regulatory mechanisms within the oscillator, highlighting key connections between new and existing components, and direct mechanistic links to downstream pathways that control overt rhythms in the whole plant. PMID- 22917519 TI - Inhibitor scaffold for the histone lysine demethylase KDM4C (JMJD2C). AB - The human histone demethylases of the KDM4 (JMJD2) family have been associated to diseases such as prostate and breast cancer, as well as X-linked mental retardation. Therefore, these enzymes are considered oncogenes and their selective inhibition might be a possible therapeutic approach to treat cancer. Here we describe a heterocyclic ring system library screened against the histone demethylase KDM4C (JMJD2C) in the search for novel inhibitory scaffolds. A 4 hydroxypyrazole scaffold was identified as an inhibitor of KDM4C; this scaffold could be employed in the further development of novel therapeutics, as well as for the elucidation of the biological roles of KDM4C on epigenetic regulation. PMID- 22917520 TI - Discovery of liver selective non-steroidal glucocorticoid receptor antagonist as novel antidiabetic agents. AB - Series of benzyl-phenoxybenzyl amino-phenyl acid derivatives (8a-q) are reported as non-steroidal GR antagonist. Compound 8g showed excellent h-GR binding and potent antagonistic activity (in vitro). The lead compound 8g exhibited significant oral antidiabetic and antihyperlipidemic effects (in vivo), along with liver selectivity. These preliminary results confirm discovery of potent and liver selective passive GR antagonist for the treatment of T2DM. PMID- 22917521 TI - Highlights in basic autonomic neurosciences: exploring novel and atypical circuits. PMID- 22917522 TI - Adhesion molecule expression precedes brain damages of lupus-prone mice and correlates with kidney pathology. AB - Central nervous system (CNS) involvement is a frequent and potentially life threatening complication in systemic lupus erythematosus (SLE) yet the mechanisms of organ damage remain poorly understood. Upregulation of cellular adhesion molecules in kidney and other organs has been implicated in the expression of inflammation and tissue injury, but the relation between kidney pathology and altered brain function has not been studied. We therefore analyzed the expression of cellular adhesion molecules ICAM-1, VCAM-1, and E-selectin in brains from 6 to 14week old MRL/(lpr), MRL+/+ and C57BL/6 mice by real-time PCR and immunofluorescence. Adhesion molecule expression levels were compared to kidney pathology and adhesion molecule expression in the kidney. We found a significant upregulation of ICAM-1 and E-selectin mRNA in the kidneys from 14week-old MRL/(lpr) mice, which correlated with proteinuria and profound kidney damage. Moreover, despite the absence of marked brain histopathological changes, both ICAM-1 and E-selectin were also upregulated in brain tissue from these animals. There was a strong correlation of adhesion molecule expression levels in the kidney and the brain. Immunofluorescence studies revealed that ICAM-1 and E selectin upregulation localizes to blood vessel walls, astrocytes related to the blood-brain barrier, and microglial cells. Our data indicate that cellular adhesion molecules in the brain are upregulated without evidence of overt brain damage, and that a strong relation exists with the levels of kidney damage. Therefore, brain involvement, even subclinical, should be presumed when peripheral organs are inflamed. PMID- 22917523 TI - Neonatal levels of cytokines and risk of autism spectrum disorders: an exploratory register-based historic birth cohort study utilizing the Danish Newborn Screening Biobank. AB - The aim of the study was to analyze cytokine profiles in neonatal dried blood samples (n-DBSS) retrieved from The Danish Newborn Screening Biobank of children developing Autism Spectrum Disorders (ASD) later in life and controls. Samples of 359 ASD cases and 741 controls were analyzed using Luminex xMAP technology and clinical data were retrieved from nationwide registers. Findings showed that children developing ASD were more likely to have decreased levels of both T helper-1(Th-1)-like cytokines (i.e. IFN-gamma) and Th-2like cytokines (i.e. IL-4, IL-10) which may suggest a depressed or hypoactive immune cell activity during neonatal period in ASD. PMID- 22917524 TI - p-Hydroxybenzoate esters metabolism in MCF7 breast cancer cells. AB - Parabens are among the most frequently used preservatives to inhibit microbial growth and extend the shelf life of a range of consumer products. The objective of the present study was to gain insight into the metabolism of parabens in breast cancer cells (MCF7) since they have demonstrated estrogenic activity towards these cells and have been detected in breast cancer tissues. The toxicity of parabens to MCF7 cells was determined using MTT assays. Hydrolysis of methyl-, butyl and benzyl-paraben to p-hydroxybenzoic acid was analyzed in cultured MCF7 cells and in cellular homogenates. Glucuronidation and sulfoconjugation were studied in MCF7 homogenates, and parabens were analyzed by HPLC. Methyl-paraben was shown to be far less toxic than butyl and benzyl-paraben. Parabens were completely stable in MCF7 homogenates whereas p-nitrophenyl acetate, a substrate type, underwent hydrolysis. MCF7 cell homogenates did not express glucuronidation and sulfoconjugation activities toward parabens. The higher stability of parabens may explain their accumulation in breast cancer tissue as previously reported in the literature. PMID- 22917525 TI - Prevalence of blindness and low vision in a rural population in northern China: preliminary results from a population-based survey. AB - PURPOSE: To investigate the prevalence of visual impairment in a rural northern Chinese population. METHODS: A cross-sectional, population-based survey was conducted in 2010 in Ci County, Hebei Province in northern China. Residents aged 7 years and older in Lucunying Town, located within Ci County, underwent presenting visual acuity (VA) testing at home; those with presenting VA <20/60 were invited to participate in further examination at the local hospital. Population-weighted prevalences of blindness and low vision were determined according to World Health Organization definitions. RESULTS: Among the 24,539 residents aged older than 7 years, 20,298 (82.7%) participated in the study, and 20,072 (98.9%) of these had valid VA data. The population-weighted prevalence rates of presenting bilateral blindness and bilateral low vision were 0.3% and 2.4% for the entire population, 0% and 0.5% for residents 7-39 years of age, and 0.8% and 6.4% for residents 40 years and older, respectively. Based on best corrected VA, the corresponding prevalence rates of bilateral blindness and bilateral low vision were 0.2% and 1.4% for the entire population, 0% and 0.1% for residents 7-39 years, and 0.6% and 4.0% for residents 40 years and older, respectively. Prevalence rates of blindness and low vision were generally higher among women than men. Blindness and low vision increased with age among residents 40 years and older. CONCLUSION: Our findings highlight the need for eye healthcare services for visual impairment in rural China. PMID- 22917526 TI - Early life socioeconomic status, chronic physiological stress and hippocampal N acetyl aspartate concentrations. AB - OBJECTIVE: Early life socioeconomic deprivation has been associated with cognitive and behavioural changes that persist through towards adulthood. In this study, we investigated whether early life socioeconomic status is associated with changes in the hippocampus N-acetyl aspartate (NAA), using the non-invasive technique of magnetic resonance spectroscopy (MRS). METHODS: We performed proton magnetic resonance spectroscopy ((1)H-MRS) of the hippocampus at 3T in 30 adult males, selected from the PSOBID cohort. We conducted multiple regression analysis to examine the relationship between early socioeconomic status (SES) and concentration of N-acetyl-aspartate in the hippocampus. We also examined whether the relationship between these variables was mediated by markers of chronic physiological stress. RESULTS: Greater socioeconomic deprivation was associated with lower hippocampal NAA concentrations bilaterally. The relationship between early life SES and hippocampal NAA concentrations was mediated by allostatic load index - a marker of chronic physiological stress. CONCLUSIONS: Greater early life socioeconomic deprivation was associated with lower concentrations of NAA reflecting lesser neuronal integrity. This relationship was mediated by greater physiological stress. Further work, to better understand the biological processes underlying the effects of poverty, physiological stress on hippocampal metabolites is necessary. PMID- 22917527 TI - Fos expression in the prefrontal cortex and ventral striatum after exposure to a free-operant timing schedule. AB - It has been proposed that cortico-striato-thalamo-cortical circuits that incorporate the prefrontal cortex and corpus striatum regulate interval timing behaviour. In the present experiment regional Fos expression was compared between rats trained under an immediate timing schedule, the free-operant psychophysical procedure (FOPP), which entails temporally regulated switching between two operanda, and a yoked variable-interval (VI) schedule matched to the timing task for food deprivation level, reinforcement rate and overall response rate. The density of Fos-positive neurones (counts mm(-2)) in the orbital prefrontal cortex (OPFC) and the shell of the nucleus accumbens (AcbS) was greater in rats exposed to the FOPP than in rats exposed to the VI schedule, suggesting a greater activation of these areas during the performance of the former task. The enhancement of Fos expression in the OPFC is consistent with previous findings with both immediate and retrospective timing schedules. Enhanced Fos expression in the AcbS was previously found in retrospective timing schedules based on conditional discrimination tasks, but not in a single-operandum immediate timing schedule, the fixed-interval peak procedure. It is suggested that the ventral striatum may be engaged during performance on timing schedules that entail operant choice, irrespective of whether they belong to the immediate or retrospective categories. PMID- 22917528 TI - Post-transcriptional effects and interactions between chronic mild stress and acute sleep deprivation: regulation of translation factor and cytoplasmic polyadenylation element-binding protein phosphorylation. AB - Stress and restricted or disrupted sleep trigger adaptive responses in the brain at the level of gene transcription. We investigated the possible impact of chronic mild stress (CMS), acute sleep deprivation, and a combination of these in male rats on post-transcriptional mechanisms important for cognitive function and synaptic plasticity. Relationships between sleep architecture and translational regulators were also assessed. After four weeks of CMS, phosphorylation of two key translation factors, eukaryotic initiation factor 4E (eIF4E) and elongation factor 2 (eEF2), was enhanced in the prefrontal cortex, but unchanged in the hippocampus and dentate gyrus. Sleep deprivation decreased phosphorylated eIF4E in the dentate gyrus. In contrast, eEF2 phosphorylation was elevated in all brain regions after sleep deprivation. Thus, CMS and sleep deprivation, when given alone, have distinct region-specific effects. Furthermore, the combined treatment revealed striking interactions with eEF2 phosphorylation in which sleep deprivation counteracts the effect of CMS cortically and CMS modulates the effects of sleep deprivation in the hippocampus proper. Although CMS exposure alone had no effect in the hippocampus, it inhibited the sleep deprivation induced eIF4E phosphorylation, while inducing phosphorylation of a major regulatory RNA-binding protein, cytoplasmic polyadenylation element-binding protein (CPEB) in the combined treatment. CMS had no effect on plasma corticosterone, but led to disruption of sleep. Sleep quality and sleep quantity in non-stressed animals showed predictive changes in eIF4E and eEF2 phosphorylation cortically. Prior exposure to CMS abolishes this relationship. We conclude that CMS and acute sleep deprivation have interactive and brain region specific effects on translational regulators of relevance to mechanisms of stress responsiveness and sleep homeostasis. PMID- 22917529 TI - Unilateral angiokeratoma of Fordyce. PMID- 22917530 TI - IDH mutations in acute myeloid leukemia. AB - Acute myeloid leukemia is a heterogeneous group of diseases. Mutations of the isocitrate dehydrogenase (IDH) genes represent a novel class of point mutations in acute myeloid leukemia. These mutations prevent oxidative decarboxylation of isocitrate to alpha-ketoglutarate and confer novel enzymatic activity, facilitating the reduction of alpha-ketoglutarate to d-2-hydroxyglutarate, a putative oncometabolite. IDH1/IDH2 mutations are heterozygous, and their combined frequency is approximately 17% in unselected acute myeloid leukemia cases, 27% in cytogenetically normal acute myeloid leukemia cases, and up to 67% in acute myeloid leukemia cases with cuplike nuclei. These mutations are largely mutually exclusive. Despite many similarities of IDH1 and IDH2 mutations, it is possible that they represent distinct molecular or clinical subgroups of acute myeloid leukemia. All known mutations involve arginine (R), in codon 132 of IDH1 or codon 140 or 172 of IDH2. IDH1(R132) and IDH2(R140) mutations are frequently accompanied by normal cytogenetics and NPM1 mutation, whereas IDH2(R172) is frequently the only mutation detected in acute myeloid leukemia. There is increasing evidence that the prognostic impact of IDH1/2 mutations varies according to the specific mutation and also depends on the context of concurrent mutations of other genes. IDH1(R132) mutation may predict poor outcome in a subset of patients with molecular low-risk acute myeloid leukemia, whereas IDH2(R172) mutations confer a poor prognosis in patients with acute myeloid leukemia. Expression of IDH1/2 mutants induces an increase in global DNA hypermethylation and inhibits TET2-induced cytosine 5-hydroxymethylation, DNA demethylation. These data suggest that IDH1/2 mutations constitute a distinct mutational class in acute myeloid leukemia, which affects the epigenetic state, an important consideration for the development of therapeutic agents. PMID- 22917531 TI - Forests may need centuries to recover their original productivity after continuous intensive management: an example from Douglas-fir stands. AB - How long would it take for forests to recover their original productivity following continuous intensive management if they are left untouched? This issue was explored using the model FORECAST, calibrated and validated for coastal Douglas-fir stands on Vancouver Island (western Canada). Three types of forest management (production of timber, pulp, and biomass) were simulated, being different in utilization level and rotation length (stem-only and 75-year rotation for timber production, whole-tree and 30-year rotation for pulp/fiber, and whole-tree and 15-year rotations for biomass production). Management was simulated for 150 years, followed by several cycles of natural growth without management ending with a stand-replacing windstorm with a return time of 200 years. Productivity-related ecological variables in previously managed stands were compared to natural forests. Stands developed after management for timber would quickly reach values similar to non-managed forests for tree and understory total biomass, stored carbon, available nitrogen and soil organic matter (SOM). However, intensive management regimes designed for fiber and biomass production would cause a decrease in SOM and nutrient availability, increasing understory biomass. As a consequence, stands recovering from intensive management would need at least two stand-replacing events (400 years) to reach a productivity status similar to non-managed stands. Stands developed after management for biomass would take much longer, up to 600 or 800 years to recover similar values of SOM and understory biomass, respectively. Current fertilization prescriptions will likely be not enough to stop a quick drop in forest productivity associated with intensive management. Intensifying forest management to achieve short-term objectives could produce a reduction of stand productivity that would influence tree growth for very long time (up to several centuries), if such management is continuously implemented at the same stand. Some of these effects could be reduced if one rotation of intensive management (for pulp or bioenergy) is followed by a rotation of management for timber, or by leaving the forest without management for an equivalent time. PMID- 22917532 TI - Quaterpyridine ligands for panchromatic Ru(II) dye sensitizers. AB - A new general synthetic access to carboxylated quaterpyridines (qpy), of interest as ligands for panchromatic dye-sensitized solar cell organometallic sensitizers, is presented. The strategic step is a Suzuki-Miyaura cross-coupling reaction, which has allowed the preparation of a number of representative unsubstituted and alkyl and (hetero)aromatic substituted qpys. To bypass the poor inherent stability of 2-pyridylboronic acid derivatives, we successfully applied N methyliminodiacetic acid (MIDA) boronates as key reagents, obtaining the qpy ligands in good yields up to (quasi)gram quantities. The structural, spectroscopic (NMR and UV-vis), electrochemical, and electronic characteristics of the qpy have been experimentally and computationally (DFT) investigated. The easy access to the bis-thiocyanato Ru(II) complex of the parent species of the qpy series, through an efficient route which bypasses the use of Sephadex column chromatography, is shown. The bis-thiocyanato Ru(II) complex has been spectroscopically (NMR and UV-vis), electrochemically, and computationally investigated, relating its properties to those of previously reported Ru(II)-qpy complexes. PMID- 22917533 TI - Leptin-induced cardiomyocyte hypertrophy reveals both calcium-dependent and calcium-independent/RhoA-dependent calcineurin activation and NFAT nuclear translocation. AB - Leptin, a product of the obesity gene, has been shown to produce cardiac hypertrophy. Although leptin's mechanism of action is poorly understood activation of the RhoA/ROCK pathway has been proposed as a contributing mechanism. The Ca(2+)-dependent phosphatase calcineurin plays a critical role in the hypertrophic program although it is not known whether leptin can activate this signaling pathway or whether there is a relationship between RhoA activation and calcineurin. Accordingly, we determined the effect of leptin on calcineurin activation and assessed the possible role of RhoA. Experiments were performed using cultured neonatal rat ventricular myocytes exposed to 50 ng/ml leptin for 24h which resulted in a robust hypertrophic response. Moreover, leptin significantly increased intracellular Ca(2+) and Na(+) concentrations which was associated with significantly reduced activity of the 3Na(+)-2K(+)ATPase. The hypertrophic response to leptin were completely abrogated by both C3 exoenzyme (C3), a RhoA inhibitor as well as the reverse mode 3Na(+)-1Ca(2+) exchange inhibitor KB-R7943 ((2-[2-[4-(4-nitrobenzyloxy)phenyl] ethyl]isothiourea methanesulfonate), however only the effect of the latter was associated with attenuation of intracellular Ca(2+) concentrations whereas Ca(2+) concentrations were unaffected by C3. Similarly, C3 and KB-R7943 significantly attenuated early leptin-induced increase in calcineurin activity as well as the increase in nuclear translocation of the transcriptional factor nuclear factor of activated T cells. The hypertrophic response to leptin was also associated with increased p38 and ERK1/2 MAPK phosphorylation and increased p38, but not ERK1/2, translocation into nuclei. Both p38 responses as well as hypertrophy were abrogated by KB-R7943 as well as the calcineurin inhibitor FK-506 although ERK1/2 phosphorylation was unaffected. Our study therefore demonstrates a critical role for the calcineurin pathway in mediating leptin-induced hypertrophy. Moreover, we report a novel RhoA dependent leptin-induced calcineurin activation which acts independently of changes in intracellular Ca(2+) concentrations. PMID- 22917534 TI - The extracellular-regulated protein kinase 5 (ERK5) promotes cell proliferation through the down-regulation of inhibitors of cyclin dependent protein kinases (CDKs). AB - Activation of the extracellular-regulated protein kinase 5 (ERK5) has been associated with mitogenic signal transduction. However, conflicting findings have challenged the idea that ERK5 is a critical regulator of cell proliferation. We have addressed this issue by testing the effect of the conditional loss of ERK5 in primary fibroblasts. We have discovered that ERK5 suppressed the expression of the cyclin dependent protein kinase (CDKs) inhibitors, p21 and p27, by decreasing mRNA and protein stability, respectively. As a result, low level CDK2 activity detected in ERK5-deficient cells correlated with a defect in G1 to S phase transition of the cell cycle. Similarly, we found that the malignant MDA-MB-231 human breast cancer cell line was dependent on ERK5 to proliferate. We propose that ERK5 blocks p21 expression in MDA-MB-231 cells via a mechanism that implicates c-Myc-dependent transcriptional regulation of the miR-17-92 cluster. Together with evidence that cancer patients with poor prognosis display a high level of expression of components of the ERK5 signaling pathway, these findings support the hypothesis that ERK5 can be a potential target for cancer therapy. PMID- 22917536 TI - The local microenvironment instigates the regulation of mammary tetratricopeptide repeat domain 9A during lactation and involution through local regulation of the activity of estrogen receptor alpha. AB - Tetratricopeptide repeat domain 9A (TTC9A) belongs to a family of TTC9 proteins. Its induction by progesterone in breast cancer cells was associated with marked growth inhibition and induction of focal adhesion. TTC9A interacts specifically with actin-binding protein tropomyosin Tm5NM-1 which stabilizes actin filament and focal adhesion. However, the function of TTC9A is still obscure. This study exploited mice model to characterize the regulation of TTC9A gene expression during mammary development and explored possible mechanisms of TTC9A gene regulation. It was demonstrated that mammary TTC9A expression is distinctively down-regulated in gland undergoing functional differentiation (lactation) and up regulated during involution. Furthermore, TTC9A expression during lactation and involution is regulated by the factors in the local microenvironment. This is illustrated with teat sealing model in which the teat sealed glands (undergoing involution) expressed significantly higher levels of TTC9A protein and mRNA than the contralateral non-sealed lactating glands. Importantly, this local induction of TTC9A expression upon involution coincided with the re-activation of estrogen receptor alpha (ERalpha). Together with the observation that TTC9A is a direct ERalpha target gene, we propose that the fall and rise of TTC9A levels during lactation and involution is caused by the changes of ERalpha activity that is in turn regulated by the factors in the microenvironment. PMID- 22917535 TI - Responses of human embryonic stem cells and their differentiated progeny to ionizing radiation. AB - Human embryonic stem cells (hESCs) hold promise for the treatment of many human pathologies. For example, hESCs and the neuronal stem cells (NSCs) and neurons derived from them have significant potential as transplantation therapies for a variety of neurodegenerative diseases. Two concerns about the use of hESCs and their differentiated derivatives are their ability to function and their ability to resist neoplastic transformation in response to stresses that inevitably arise during their preparation for transplantation. To begin to understand how these cells handle genotoxic stress, we examined the responses of hESCs and derived NSCs and neurons to ionizing radiation (IR). Undifferentiated hESCs were extremely sensitive to IR, with nearly all the cells undergoing cell death within 5-7 h. NSCs and neurons were substantially more resistant to IR, with neurons showing the most resistant. Of interest, NSCs that survived IR underwent cellular senescence and acquired astrocytic characteristics. Unlike IR-treated astrocytes, however, the NSC-derived astrocytic cells that survived IR did not display the typical pro-inflammatory, pro-carcinogenic senescence-associated secretory phenotype. These findings suggest distinct genotoxic stress-responses of hESCs and derived NSC and neuronal populations, and suggest that damaged NSCs, while failing to function, may not cause local inflammation. PMID- 22917537 TI - Resveratrol effects on astrocyte function: relevance to neurodegenerative diseases. AB - Inflammatory molecules have been implicated in the pathogenesis of neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, and multiple sclerosis. Resveratrol is an anti-fungal compound found in the skins of red grapes and other fruits and nuts. We examined the ability of resveratrol to inhibit lipopolysaccharide (LPS)-induced production of inflammatory molecules from primary mouse astrocytes. Resveratrol inhibited LPS-induced production of nitric oxide (NO); the cytokines tumor necrosis factor-alpha (TNF-alpha), interleukin 1-beta (IL-1beta), and IL-6; and the chemokine monocyte chemotactic protein-1 (MCP-1), which play critical roles in innate immunity, by astrocytes. Resveratrol also suppressed astrocyte production of IL-12p40 and IL-23, which are known to alter the phenotype of T cells involved in adaptive immunity. Finally resveratrol inhibited astrocyte production of C-reactive protein (CRP), which plays a role in a variety of chronic inflammatory disorders. Collectively, these studies suggest that resveratrol may be an effective therapeutic agent in neurodegenerative diseases initiated or maintained by inflammatory processes. PMID- 22917538 TI - Fibrosis, myocardial crossings, disconnections, abrupt turns, and epicardial reflections: do they play an actual role in human permanent atrial fibrillation? A controlled necropsy study. AB - Atrial myocardium fibrosis and other alterations of fiber continuity and potential circuit reentrancy (disconnections, abrupt turns, crossings, and epicardial reflections) are thought to play an important role in permanent atrial fibrillation. However, few studies have been performed in human beings. Some of them are only descriptive, and controls were usually normal hearts; thus, differences between cases and controls could be related to the underlying disease rather than the arrhythmia. We quantified by histomorphometry the above characteristics in nine samples (three from the left atrium, three from around fat pads, one from the right atrium, one from the cavum-tricuspid isthmus, and one from the ventricular septum) from 13 necropsy hearts of patients with permanent atrial fibrillation and compared the findings with those from 13 control cases with the same diseases but without any atrial arrhythmia. Statistical analysis was performed using generalized estimating equations and a normal linear mixed model for repeated measures, with significance defined as P <=.05. No differences were found in fibrosis (estimated as collagen/(collagen+myocardium) ratio-0.26 vs. 0.23, P=.35), the presence of disconnections (70.1 vs. 61.5, P=.09), abrupt turns (43.6 vs. 45.3, P=.84), or epicardial reflections (9.4 vs. 14.5, P=.12). The only difference identified was that cases with permanent atrial fibrillation exhibited fewer crossings than those without (79.5 vs. 91.5, P=.02). In conclusion, alterations in myocardial fiber continuity, including fibrosis, seem to reflect a generalized myocardial disorganization of the atria in cardiac disease but are not specifically related to permanent atrial fibrillation. PMID- 22917539 TI - No association between IL-1beta -31 C/T polymorphism and the risk of duodenal ulcer: a meta-analysis of 3793 subjects. AB - The aim of this study was to perform a meta-analysis to investigate a more authentic association between IL-1beta -31 C/T polymorphism and duodenal ulcer (DU). Systematic searches of electronic databases Embase, PubMed and Web of Science were performed. Study selection, data abstraction and study quality evaluation were independently conducted in duplicate. Statistical analyses were conducted using software Stata 11.0. The pooled odds ratios (ORs) with 95% confidence intervals (95%CIs) were applied. Publication bias was tested by Begg's funnel plot and Egger's regression test. A total of 12 studies including 1151 cases and 2642 controls were included in our final meta-analysis. There was no evidence of significant association between IL-1beta -31 C/T polymorphism and DU (allelic model: OR=0.96, 95%CI=0.86-1.07; additive model: OR=0.85, 95%CI=0.67 1.07; dominant model: OR=0.95, 95%CI=0.81-1.13; and recessive model: OR=0.95, 95%CI=0.79-1.15). Significant association was found in additive model for PB subgroup (OR=0.65, 95%CI=0.44-0.96) and recessive model for non-Asian subgroup (OR=0.72, 95%CI=0.52-0.99). In conclusion, our meta-analysis suggested that there was no evidence of significant association between IL-1beta -31 C/T polymorphism and DU with or without Helicobacter pylori infection in overall population, whereas significant association was found by subgroup analyses which showed protective effect of C/C genotype against DU risk. PMID- 22917540 TI - Physicochemical and immunological studies on 4-hydroxynonenal modified HSA: implications of protein damage by lipid peroxidation products in the etiopathogenesis of SLE. AB - 4-Hydroxynonenal (HNE) is the most abundant and toxic aldehyde generated by the oxidation of plasma membrane polyunsaturated fatty acids. Systemic lupus erythematosus (SLE), a chronic autoimmune disease, is primarily characterized by increased levels of autoantibodies, predominantly against ds-DNA. However, the initial antigenic stimulus for the disease etiopathogenesis has remained elusive. HNE has been extensively used as a biomarker of oxidative stress. It can form adduct with proteins, making them highly immunogenic. Increased levels of such aldehyde-protein adducts have been reported in various pathological states, including autoimmune disorders like SLE and arthritis. In the present study, HNE mediated structural changes in human serum albumin (HSA) were characterized by UV, fluorescence, CD and FT-IR spectroscopy as well as by polyacrylamide gel electrophoresis. Furthermore, immunogenicity of native and HNE-modified HSA was probed in female rabbits. The HNE-modified HSA was highly immunogenic eliciting high titre immunogen specific antibodies. Binding of SLE anti-DNA antibodies was analyzed by direct binding and competition ELISA. The data show preferential binding of SLE autoantibodies to HNE-modified HSA as compared to native HSA or native DNA. Our results suggest that HNE modification generates neoepitopes on HSA causing enhanced autoantibodies production. The results point towards the possible role of HNE-modified HSA in SLE etiopathogenesis. PMID- 22917541 TI - Lack of association between the functional c-kit rs6554199 polymorphism and achalasia in a Spanish population. AB - A functional polymorphism (rs6554199) located in the c-kit gene was associated with achalasia in a Turkish cohort. Our aim was to replicate this result in a large cohort of Spanish patients and controls. A case-control study was performed with 282 Spanish white unrelated patients and 687 healthy controls. All were genotyped for SNP rs6554199 using a TaqMan Assay. No association was found in our study (T allele frequency in patients and controls: 47.3% vs. 49.4%; OR=0.92, p=0.41). The finding that the T allele of the c-kit rs6554199 polymorphism could be associated with achalasia as reported in a Turkish population could not be replicated in a Spanish cohort. Although ethnic differences might explain these data, the sample size that compromised the statistical power in the Turkish cohort and is higher in our study, led us to suggest that the reported association seems to be a false positive. PMID- 22917542 TI - Association of vitamin D receptor gene polymorphisms with clinical outcomes of dengue virus infection. AB - Vitamin D is known to affect pathogenesis of dengue through modulation of immune responses. Vitamin D exerts its effects through vitamin D receptor (VDR). The functioning of VDR is affected by the gene polymorphisms in the coding (rs2228570) and 3'untranslated region (UTR) (rs1544410, rs7975232 and rs731236). In the present study, VDR gene polymorphisms were investigated in 112 dengue infected patients (83 dengue fever (DF) and 29 dengue hemorrhagic fever cases (DHF)) and 105 apparently healthy controls (HCs) using polymerase chain reaction based restriction fragment length polymorphisms methods. HCs had no documented evidence of symptomatic dengue. Results revealed significantly lower frequency of 'C' allele of rs7975232 in all dengue patients (DEN) as compared to HCs [(P corrected (Pc)=0.014, Odds ratio (OR) 0.51]. The frequency of C/C genotype of rs7975232 was significantly lower in DEN and DF cases compared to HCs (DEN vs. HCs: Pc=0.0184, OR 0.24; DF cases vs. HCs: Pc=0.028, OR 0.21). The frequency of T allele of rs2228570 in a dominant mode was significantly higher in DHF cases as compared to DF cases (P=0.034 OR 2.58). A significantly lower frequency of the haplotype G-C-T (Pc=0.0135) and higher frequency of the haplotype G-A-T (Pc=0.000085) was observed in DEN and DF cases as compared to HCs. The results suggest that the 3'UTR haplotypes of VDR gene are differentially associated with risk of symptomatic dengue requiring hospitalization. The 'T' allele of rs2228570 polymorphism in a dominant mode of inheritance is associated with DHF. PMID- 22917543 TI - Management of bone tumours in paediatric oncology. AB - The management of bone tumours in paediatric oncology requires careful multidisciplinary planning due to the need for multimodal therapy approaches. The non-specific symptoms often lead to a delayed definitive diagnosis of a bone tumour. Imaging procedures are of major importance for an individualised and optimised treatment planning. They have to be carried out before any surgery, including biopsies. The introduction of multi-agent chemotherapy has led to a significant improvement in survival rates in patients suffering from Ewing's sarcomas and osteosarcomas. However, local therapy still remains indispensable in order to achieve long-term survival. For osteosarcoma, surgery remains the only adequate local therapy modality. Radiotherapy may be considered if surgery is not feasible. In these cases, high radiation doses need to be applied. The choice for local therapy modality is not as clear in patients with Ewing's sarcoma. Today, surgery is often preferred if a wide or at least marginal resection can be carried out. Additional radiotherapy is advised in patients with marginal/intralesional resection or poor histological response to induction chemotherapy. Definitive radiotherapy is recommended for inoperable lesions. In the future, new radiotherapy approaches, such as intensity-modulated radiotherapy or proton therapy, may yield better results with minor risks of late effects. PMID- 22917545 TI - Homologous recombination is facilitated in starving populations of Pseudomonas putida by phenol stress and affected by chromosomal location of the recombination target. AB - Homologous recombination (HR) has a major impact in bacterial evolution. Most of the knowledge about the mechanisms and control of HR in bacteria has been obtained in fast growing bacteria. However, in their natural environment bacteria frequently meet adverse conditions which restrict the growth of cells. We have constructed a test system to investigate HR between a plasmid and a chromosome in carbon-starved populations of the soil bacterium Pseudomonas putida restoring the expression of phenol monooxygenase gene pheA. Our results show that prolonged starvation of P. putida in the presence of phenol stimulates HR. The emergence of recombinants on selective plates containing phenol as an only carbon source for the growth of recombinants is facilitated by reactive oxygen species and suppressed by DNA mismatch repair enzymes. Importantly, the chromosomal location of the HR target influences the frequency and dynamics of HR events. In silico analysis of binding sites of nucleoid-associated proteins (NAPs) revealed that chromosomal DNA regions which flank the test system in bacteria exhibiting a lower HR frequency are enriched in binding sites for a subset of NAPs compared to those which express a higher frequency of HR. We hypothesize that the binding of these proteins imposes differences in local structural organization of the genome that could affect the accessibility of the chromosomal DNA to HR processes and thereby the frequency of HR. PMID- 22917544 TI - Quantitative analysis of the mutagenic potential of 1-aminopyrene-DNA adduct bypass catalyzed by Y-family DNA polymerases. AB - N-(Deoxyguanosin-8-yl)-1-aminopyrene (dG(AP)) is the predominant nitro polyaromatic hydrocarbon product generated from the air pollutant 1-nitropyrene reacting with DNA. Previous studies have shown that dG(AP) induces genetic mutations in bacterial and mammalian cells. One potential source of these mutations is the error-prone bypass of dG(AP) lesions catalyzed by the low fidelity Y-family DNA polymerases. To provide a comparative analysis of the mutagenic potential of the translesion DNA synthesis (TLS) of dG(AP), we employed short oligonucleotide sequencing assays (SOSAs) with the model Y-family DNA polymerase from Sulfolobus solfataricus, DNA Polymerase IV (Dpo4), and the human Y-family DNA polymerases eta (hPoleta), kappa (hPolkappa), and iota (hPoliota). Relative to undamaged DNA, all four enzymes generated far more mutations (base deletions, insertions, and substitutions) with a DNA template containing a site specifically placed dG(AP). Opposite dG(AP) and at an immediate downstream template position, the most frequent mutations made by the three human enzymes were base deletions and the most frequent base substitutions were dAs for all enzymes. Based on the SOSA data, Dpo4 was the least error-prone Y-family DNA polymerase among the four enzymes during the TLS of dG(AP). Among the three human Y-family enzymes, hPolkappa made the fewest mutations at all template positions except opposite the lesion site. hPolkappa was significantly less error-prone than hPoliota and hPoleta during the extension of dG(AP) bypass products. Interestingly, the most frequent mutations created by hPoliota at all template positions were base deletions. Although hRev1, the fourth human Y-family enzyme, could not extend dG(AP) bypass products in our standing start assays, it preferentially incorporated dCTP opposite the bulky lesion. Collectively, these mutagenic profiles suggest that hPolk and hRev1 are the most suitable human Y family DNA polymerases to perform TLS of dG(AP) in humans. PMID- 22917546 TI - High-performance liquid chromatographic assay for metamizol metabolites in rat plasma: application to pharmacokinetic studies. AB - In order to evaluate the pharmacokinetics of metamizol in the presence of morphine in arthritic rats, after subcutaneous administration of the drugs, an easy, rapid, sensitive and selective analytical method was proposed and validated. The four main metamizol metabolites (4-methylaminoantipyrine, 4 aminoantipyrine, 4-acetylaminoantipyrine and 4-formylaminoantipyrine) were extracted from plasma samples (50-100MUl) by a single solid-phase extraction method prior to reverse-phase high performance liquid chromatography with diode array detection. Standard calibration graphs for all metabolites were linear within a range of 1-100MUg/ml (r(2)>=0.99). The intra-day coefficients of variation (CV) were in the range of 1.3-8.4% and the inter-day CV ranged from 1.5 to 8.4%. The intra-day assay accuracy was in the range of 0.6-9.6% and the inter day assay accuracy ranged from 0.9 to 7.5% of relative error. The lower limit of quantification was 1MUg/ml for all metabolites using a plasma sample of 100MUl. Plasma samples were stable at least for 4 weeks at -20 degrees C. This method was found to be suitable for studying metamizol metabolites pharmacokinetics in arthritic rats, after simultaneous administration of metamizol and morphine, in single dose. PMID- 22917547 TI - Effects of renal sympathetic denervation on heart rate and atrioventricular conduction in patients with resistant hypertension. AB - BACKGROUND: Renal sympathetic denervation (RDN) reduces sympathetic activity and blood pressure (BP) in patients with resistant hypertension. The present study aimed to investigate the effects of RDN on HR and other electrocardiographic parameters. METHODS: 136 patients aged 62.2 +/- 0.8 years (58% male, BP 177 +/- 2/93 +/- 1 mmHg) with resistant hypertension underwent RDN. BP and a 12-lead electrocardiogram (ECG) were recorded before, 3 months (n=127), and 6 months (n=88) after RDN. RESULTS: After 3 months (3M) and 6 months (6M), systolic BP was reduced by 25.5 +/- 2.4 mmHg (p<0.0001) and 28.1 +/- 3 mmHg (p<0.0001). HR at baseline was 66.1 +/- 1 beats per minute (bpm) and was reduced by 2.6 +/- 0.8 bpm after 3 months (p=0.001) and 2.1 +/- 1.1 bpm after 6 months (p=0.046). Patients with HR at baseline between 60-71 bpm and >= 71 bpm had a reduction of 2.9 +/- 7.6 bpm (p=0.008) and 9.0 +/- 8.6 bpm (p<0.0001), respectively, whereas in patients with baseline HR<60 bpm HR slightly increased after 3 months (2.7 +/- 8.4 bpm; p=0.035). Neither baseline HR nor change of HR correlated with the reduction of systolic BP. The PR interval was prolonged by 11.3 +/- 2.5 ms (p<0.0001) and 10.3 +/- 2.5 ms (p<0.0001) at 3 and 6 months after RDN, respectively. CONCLUSIONS: Renal sympathetic denervation reduced heart rate and the PR interval as indicators of cardiac autonomic activity. PMID- 22917548 TI - A catalytic and non-catalytic role for the Yen1 nuclease in maintaining genome integrity in Kluyveromyces lactis. AB - Yen1 is a nuclease identified in Saccharomyces cerevisiae that cleaves the Holliday junction (HJ) intermediate formed during homologous recombination. Alternative routes to disjoin HJs are performed by the Mus81/Mms4- and Sgs1/Top3/Rmi1-complexes. Here, we investigate the role of the Yen1 protein in the yeast Kluyveromyces lactis. We demonstrate that both yen1 mus81 and yen1 sgs1 double mutants displayed negative genetic interactions in the presence of DNA damaging chemicals. To test if these phenotypes required the catalytic activity of Yen1, we introduced point mutations targeting the catalytic site of Yen1, which abolished the nuclease activity in vitro. Remarkably, catalytically inactive Yen1 did not exacerbate the hydroxyurea sensitivity of the sgs1Delta strain, which the yen1Delta allele did. In addition, overexpression of catalytically inactive Yen1 partially rescued the DNA damage sensitivity of both mus81 and sgs1 mutant strains albeit less efficiently than WT Yen1. These results suggest that Yen1 serves both a catalytic and non-catalytic role in its redundant function with Mus81 and Sgs1. Diploids lacking Mus81 had a severe defect in sporulation efficiency and crossover frequency, but diploids lacking both Mus81 and Yen1 showed no further reduction in spore formation. Hence, Yen1 had no evident role in meiosis. However, overexpression of WT Yen1, but not catalytically inactive Yen1 partially rescued the crossover defect in mus81/mus81 mutant diploids. Yen1 is a member of the RAD2/XPG-family of nucleases, but genetic analyses revealed no genetic interaction between yen1 and other family members (rad2, exo1 and rad27). In addition, yen1 mutants had normal nonhomologous end-joining efficiency. We discuss the similarities and differences between K. lactis Yen1 and Yen1/GEN1 from other organisms. PMID- 22917549 TI - Arginine deprivation as a new treatment strategy for head and neck cancer. AB - OBJECTIVES: Arginine is a nonessential amino acid which can regulate tumor growth. Argininosuccinate synthetase (ASS) is the rate-limiting enzyme for de novo arginine production. The expression pattern of ASS and the feasibility of arginine deprivation therapy in head and neck cancer have not been investigated. MATERIALS AND METHODS: The growth-inhibitory effect of arginine deprivation therapy was assessed either by proliferation assay with head and neck cancer cells cultured in arginine-free medium, or by tetrazolium/formazan dye assay with cells treated with an arginine-depleting drug (arginine deiminase, ADI). The tumor ASS status of 73 oral squamous carcinoma (OSCC) patients was then evaluated immunohistochemically and subsequently correlated with the corresponding clinicopathological parameters. RESULTS: Head and neck cancer cells cultured in arginine-free medium either completely stopped proliferating, or proliferated minimally. In addition, ADI treatment inhibited the growth of all 8 head and neck cancer cell lines to different degrees. Although cellular ASS level did not correlate well with ADI-sensitivity among these cell lines, knockdown of endogenous ASS potentiated the growth-inhibitory effect of ADI in each individual cell line (FaDu and OEC-M1). In multivariable analysis, high tumor ASS level independently predicted an unfavorable disease-free survival in OSCC patients. CONCLUSION: High tumor ASS status is an independent variable predicting a poor disease-free survival in OSCC patients. Arginine deprivation therapy may potentially be used as a new approach to treat head and neck cancer. PMID- 22917550 TI - Natural course of distant metastases following radiotherapy or chemoradiotherapy in HPV-related oropharyngeal cancer. AB - OBJECTIVES: To describe the natural course of distant metastases (DMs) following radiotherapy (RT) or chemoradiotherapy (CRT) in HPV(+) oropharyngeal carcinoma (OPC). METHODS: OPC treated with RT/CRT from 1/1/2000 to 5/31/2010 were reviewed. The natural course of DM were compared between HPV(+) and HPV(-) cohorts. RESULTS: Median follow-up was 3.9 years. The DM rate were similar (11% vs. 15% at 3-years, p=0.25) between the HPV(+) (n=457) vs. the HPV(-) (n=167) cases. While almost all (24/25) HPV(-) DM occurred within 2-years following RT (1 was at 2.1 years), 7/54 (13%) of HPV(+) DM were detected beyond 3 years (up to 5.3 years). Disseminating to >2 organs occurred in 18 (33%) HPV(+) vs. none in HPV(-). Post DM survival rates were 11% vs. 4% at 2-years (p=0.02) for the HPV(+) vs. HPV(-) cases respectively. 5/6 HPV(+) with lung oligo-metastasis were still alive with stable disease beyond 2-years after salvage procedures for DM (chemotherapy: 3; surgical resection: 2; radiotherapy: 1). CONCLUSIONS: Although DM rates are similar, the natural course of HPV(+) DM differs from that of HPV(-) patients: it may occur after a longer interval, often with a "disseminating" phenotype, and a small number may have prolonged survival after salvage for DM. PMID- 22917552 TI - Mitochondrial 'flashes': a radical concept repHined. AB - Mitochondrial free radicals and redox poise are central to metabolism and cell fate. Their measurement in living cells remains a major challenge and their in vivo dynamics are poorly understood. Reports of 'superoxide flashes' in single mitochondria have therefore been perceived as a major breakthrough: single mitochondria expressing the genetically encoded sensor circularly permuted yellow fluorescent protein (cpYFP) display spontaneous flashes of fluorescence that are responsive to metabolic changes and stressors. We critically review the evidence that underpins the interpretation of mitochondrial cpYFP flashes as bursts of superoxide production and conclude that flashes do not represent superoxide bursts but instead are caused by transient alkalinisation of the mitochondrial matrix. We provide a revised framework that will help to clarify the interpretation of mitochondrial flashes. PMID- 22917551 TI - Regulation from within: the cytoskeleton in transmembrane signaling. AB - There is mounting evidence that the plasma membrane is highly dynamic and organized in a complex manner. The cortical cytoskeleton is proving to be a particularly important regulator of plasmalemmal organization, modulating the mobility of proteins and lipids in the membrane, facilitating their segregation, and influencing their clustering. This organization plays a critical role in receptor-mediated signaling, especially in the case of immunoreceptors, which require lateral clustering for their activation. Based on recent developments, we discuss the structures and mechanisms whereby the cortical cytoskeleton regulates membrane dynamics and organization, and how the nonuniform distribution of immunoreceptors and their self-association may affect activation and signaling. PMID- 22917553 TI - Left ventricular mass in patients with a cardiomyopathy after treatment with anthracyclines. AB - We aimed to describe the cardiac magnetic resonance (CMR) findings and determine the prognostic variables in patients with a cardiomyopathy after treatment with anthracyclines. CMR imaging was performed in 91 patients (58% men, mean age 43 +/ 18 years, and mean anthracycline dose of 276 +/- 82 mg/m(2)) with a reduced ejection fraction after anthracycline-based chemotherapy. Major adverse cardiovascular events were defined as cardiovascular death, appropriate implantable cardioverter-defibrillator therapy, and admission for decompensated heart failure. Patients presented a median of 88 months (interquartile range 37 to 138) after chemotherapy and were followed for 27 months (interquartile range 22 to 38). Late gadolinium enhancement was an uncommon finding (5 patients, 6%) despite a reduced ejection fraction (36 +/- 8%). An inverse association was found between the anthracycline dose and the indexed left ventricular (LV) mass by CMR (r = -0.67, p <0.001). A total of 52 adverse cardiac events occurred (event rate of 22%/year). When the patients were grouped according to the presence or absence of a major adverse cardiovascular event, the indexed LV mass and glomerular filtration rate were lower and the anthracycline dose was greater among the patients who experienced an adverse event. In a multivariate model, the indexed LV mass demonstrated the strongest association with major adverse cardiovascular events (hazard ratio 0.89, chi-square 26, p <0.001). In conclusion, myocardial scar by late gadolinium enhancement-CMR is infrequent in patients with anthracycline-cardiomyopathy despite a reduced ejection fraction, the event rate in patients with established anthracycline-cardiotoxicity is high, and indexed LV mass by CMR imaging is a predictor of adverse cardiovascular events. PMID- 22917554 TI - Effectiveness and safety of inhaled treprostinil for the treatment of pulmonary arterial hypertension in children. AB - The introduction of prostanoid therapy has revolutionized the treatment of pulmonary arterial hypertension (PAH). However, continuous intravenous prostacyclin infusion poses significant risks and challenges, particularly in children. Inhaled treprostinil has been shown to be safe and efficacious in adults. This study describes the safety and efficacy of inhaled treprostinil in children with PAH. A retrospective analysis of 29 children treated with inhaled treprostinil for >=6 weeks was performed. Effects of inhaled treprostinil on exercise capacity, functional class, and echocardiographic and hemodynamic data were evaluated. Adverse events were documented. Patients received 3 to 9 breaths (6 MUg/breath) of inhaled treprostinil 4 times/day. All were receiving background PAH therapy; 12 had previously received parenteral prostanoid. Inhaled treprostinil was discontinued in 4 patients because of symptoms including cough and bronchospasm (n = 3) and progression of PAH (n = 1). Mild side effects including cough (n = 9) and sore throat (n = 6) did not require discontinuation of therapy. World Health Organization functional class improved in 19 and was unchanged in 10; exercise capacity significantly improved with the 6-minute walk distance, improving on follow-up from 455.7 +/- 71.5 to 498 +/- 70 m (p = 0.01) and peak oxygen consumption increasing from 25.5 +/- 10.2 to 27.4 +/- 10 (p = 0.04). In conclusion, inhaled treprostinil was associated with improvement in exercise capacity and World Health Organization functional class when added to background targeted PAH therapy in children and had an acceptable safety profile. Based on these early data, further study of inhaled treprostinil appears warranted in pediatric patients with PAH. PMID- 22917555 TI - Prognostic value of monocyte count in patients hospitalized for heart failure with reduced ejection fraction (from the EVEREST Trial). AB - Monocytes play a critical role in the pathophysiology of heart failure (HF), but few studies have evaluated the prognostic implications of an increased monocyte count in patients with HF and reduced ejection fraction (EF). The Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study with Tolvaptan (EVEREST) examined the effects of tolvaptan in patients with worsening HF and EF <=40%. This post hoc analysis evaluated the primary end points of all-cause mortality and cardiovascular mortality or HF hospitalization in 3,717 patients. At baseline, 265 (7.1%) had an increased monocyte count defined by >=800/MUl. Patients with increased monocyte count tended to have an increased EF and were less likely to have a history of diabetes mellitus, hypercholesterolemia, or coronary revascularization but were more likely to have higher HF functional class and to be taking HF therapies such as diuretics, angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers, and digoxin (p <0.05 for all comparisons). At median follow-up of 9.9 months, increased monocyte count was predictive of all-cause mortality (hazard ratio 1.27, 95% confidence interval 1.003 to 1.60, p = 0.047) but was not associated with cardiovascular mortality or HF hospitalization (hazard ratio 1.06, 95% confidence interval 0.87 to 1.30, p = 0.55). Similar results were seen when monocyte count was analyzed as a continuous variable. However, after adjustment for baseline clinical risk factors, monocyte count was not predictive of either primary end point. In conclusion, increased monocyte count occurs in a minority of patients hospitalized with HF and is associated with poor postdischarge prognosis. However, it does not contribute prognostic value above other more traditional risk factors. PMID- 22917556 TI - Ellipticine oxidation and DNA adduct formation in human hepatocytes is catalyzed by human cytochromes P450 and enhanced by cytochrome b5. AB - Ellipticine is an antineoplastic agent considered a pro-drug, the pharmacological and genotoxic effects of which are dependent on cytochrome P450 (CYP)- and/or peroxidase-mediated activation to covalent DNA adducts. We investigated whether ellipticine-DNA adducts are formed in human hepatic microsomes and human hepatocytes. We then identified which human CYPs oxidize ellipticine to metabolites forming DNA adducts and the effect of cytochrome b(5) on this oxidation. 13-Hydroxyellipticine, the metabolite forming the major ellipticine DNA adduct, was generated mainly by CYP3A4 and 1A1, followed by CYP2D6>2C19>1B1>1A2>2E1 and >2C9. Cytochrome b(5) increased formation of this metabolite by human CYPs, predominantly by CYP1A1, 3A4, 1A2 and 2C19. Formation of 12-hydroxyellipticine is generated mainly by CYP2C19, followed by CYP2C9>3A4>2D6>2E1 and >2A6. Other CYPs were less active (CYP2C8 and 2B6) or did not oxidize ellipticine to this metabolite (CYP1A1, 1A2 and 1B1). CYP2D6 was the most efficient enzyme generating ellipticine N(2)-oxide. CYP3A4 and 1A1 in the presence of cytochrome b(5) are mainly responsible for bioactivation of ellipticine to DNA adduct 1 (formed by ellipticine-13-ylium from 13 hydroxyellipticine), while 12-hydroxyellipticine generated during the CYP2C19 mediated ellipticine oxidation is the predominant metabolite forming ellipticine 12-ylium that generates ellipticine-DNA adduct 2. These ellipticine-DNA adducts were also generated by human hepatic microsomes and in primary human hepatocytes exposed to ellipticine. Ellipticine is toxic to these hepatocytes, decreasing their viability; the IC(50) value of ellipticine in these cells was 0.7 MUM. In liver CYP3A4 is the predominant ellipticine activating CYP species, which is expected to result in efficient metabolism after oral ingestion of ellipticine in humans. PMID- 22917558 TI - Oxidative stress and genotoxic effect of zinc oxide nanoparticles in freshwater snail Lymnaea luteola L. AB - Understanding the toxic effects of nanoparticles on aquatic organism is the biggest obstacle to the safe development of nanotechnology. However, little is known about the toxic mechanisms of zinc oxide nanoparticles (ZnONPs) in freshwater snail Lymnaea luteola (L. luteola). This study was designed to investigate the possible mechanisms of genotoxicity induced by ZnONPs in freshwater snail L. luteola. ZnONPs (32 MUg/ml) elicited a significant (p<0.01) reduction in glutathione (42.10% and 61.40%), glutathione-S-transferase (25.60% and 40.24%) and glutathione peroxidase (21.73% and 39.13%) with a concomitant increase in malondialdehyde level (54.50% and 57.14%; p<0.01) and catalase (34.88% and 52.56%; p<0.01) in digestive gland of L. luteola after 24 and 96 h exposure, respectively. However, a statistically significant (p<0.01) induction in DNA damage was observed by the comet assay in digestive gland cells treated with ZnONPs for 24 and 96 h. Thus, the results demonstrate that ZnONPs induce genotoxicity in digestive gland cells through oxidative stress. Freshwater snail L. luteola may be used as suitable test model for nanoecotoxicological studies in future. PMID- 22917557 TI - Cysteine protease involving in autophagosomal degradation of mitochondria during encystation of Acanthamoeba. AB - Using the microarray to identify encystation mediating factors, significantly higher expression of a cysteine protease gene was observed in cysts, compared with trophozoites. Results of real-time PCR analysis also showed a magnificent increase of cysteine protease levels during encystation of Acanthamoeba. We named the gene cyst specific cysteine protease (cscp) of Acanthamoeba. The purified recombinant protein of CSCP showed activities of papain and cathepsin B against the substrates. During encystation, EGFP fused CSCP showed colocalization with LysoTracker, an autophagosome marker, in transiently transfected amoeba. Amoeba transfected with siRNA against cscp was unable to form mature cysts. Undigested mitochondria in vacuole like structures were observed in cscp siRNA treated cells by transmission electron microscopy. These results provide evidence of the important role of CSCP in autophagosomal degradation of cell constituents, particularly mitochondria, during encystation of Acanthamoeba. PMID- 22917559 TI - Concerted actions of the catechol O-methyltransferase and the cytosolic sulfotransferase SULT1A3 in the metabolism of catecholic drugs. AB - Catecholic drugs had been reported to be metabolized through conjugation reactions, particularly methylation and sulfation. Whether and how these two Phase II conjugation reactions may occur in a concerted manner, however, remained unclear. The current study was designed to investigate the methylation and/or sulfation of five catecholic drugs. Analysis of the spent media of HepG2 cells metabolically labeled with [(35)S]sulfate in the presence of individual catecholic drugs revealed the presence of two [(35)S]sulfated metabolites for dopamine, epinephrine, isoproterenol, and isoetharine, but only one [(35)S]sulfated metabolite for apomorphine. Further analyses using tropolone, a catechol O-methyltransferase (COMT) inhibitor, indicated that one of the two [(35)S]sulfated metabolites of dopamine, epinephrine, isoproterenol, and isoetharine was a doubly conjugated (methylated and sulfated) product, since its level decreased proportionately with increasing concentrations of tropolone added to the labeling media. Moreover, while the inhibition of methylation resulted in a decrease of the total amount of [(35)S]sulfated metabolites, sulfation appeared to be capable of compensating the suppressed methylation in the metabolism of these four catecholic drugs. A two-stage enzymatic assay showed the sequential methylation and sulfation of dopamine, epinephrine, isoproterenol, and isoetharine mediated by, respectively, the COMT and the cytosolic sulfotransferase SULT1A3. Collectively, the results from the present study implied the concerted actions of the COMT and SULT1A3 in the metabolism of catecholic drugs. PMID- 22917560 TI - Compressive and flexural behaviour of fibre reinforced endodontic posts. AB - OBJECTIVES: The aim of this study was to investigate the mechanical properties of five types of fibre-reinforced composite (FRC) posts and compare them with traditional metal post. METHODS: Five FRC posts and a metallic post having different geometry and type of fibre (glass, carbon or quartz fibre) were loaded to failure in compression and bending. The transverse sections of FRC posts were observed using SEM to evaluate the fracture mode and the percentage of fibres (compared with burn-off test). Densities and voids content were also evaluated. RESULTS: Mechanical results were subjected to a one-way ANOVA and Tukey test (p<0.05). In compression, quartz fibre posts exhibited the greater maximum load and ultimate strength, carbon fibre posts showed a poor compressive behaviour. All posts had similar compressive moduli. Carbon posts showed the highest flexural properties (p<0.0001) while glass posts the greater maximum load. The fracture load values correlated to the diameters of posts showed a parabolic behaviour. The flexural strengths of all posts were four and seven times higher than dentine. The elastic moduli of almost all posts were similar to dentine. The compressive strengths were lower than flexural strengths. The fibre diameters ranged from 5.2 to 26 MUm, the volume percentage of fibres was about 64%. The content of voids of some posts lower their mechanical behaviour. CONCLUSIONS: Compressive properties of FRC posts were lower than in bending. The flexural properties of FRC posts were higher than the metal post and similar to dentine. The mechanical behaviour is influenced by voids. PMID- 22917561 TI - Efficacy of the stannous ion and a biopolymer in toothpastes on enamel erosion/abrasion. AB - OBJECTIVES: Sn(2+) has promising erosion-inhibiting properties in solutions, but little is known about respective effects in toothpastes. In addition, biopolymers might have protecting potential. Aim of this study was to investigate the effects of Sn(2+) in toothpastes and of a biopolymer (chitosan) added to a Sn(2+) formulation on erosion/abrasion. METHODS: Enamel samples were subjected to cyclic erosion procedures (10 days; 0.50% citric acid, pH 2.5; 6* 2 min/day), and brushing (2* 15s/day, load 200 g) during immersion in slurries (2 min). The toothpastes were NaF formulations (NaF/1, NaF/2, NaF/3) and Sn(2+) formulations (NaF/SnCl(2), AmF/SnF(2), AmF/NaF/SnCl(2)) and AmF/NaF/SnCl(2)+0.5% chitosan. Declared concentrations of active ingredients in toothpastes were 1400-1450 MUg/g F(-) and 3280-3500 MUg/g Sn(2+). Negative controls were erosion only and placebo, positive control was a SnF(2) gel. Tissue loss was quantified profilometrically, Sn on enamel surfaces was measured by energy dispersive X-ray spectroscopy. RESULTS: Loss values (MUm) for erosion only and placebo were 14.4 +/- 4.5 and 20.2 +/- 3.8, respectively, and 4.6 +/- 1.9 for the positive control (p <= 0.001 each compared to erosion only). The other loss values were: NaF/1 16.5 +/- 3.0, NaF/2 14.0 +/- 2.7, NaF/3 12.6 +/- 3.9, NaF/SnCl(2) 14.7 +/- 5.1, AmF/SnF(2) 13.5 +/- 4.8, AmF/NaF/SnCl(2) 12.4 +/- 4.2, AmF/NaF/SnCl(2)+chitosan 6.6 +/- 3.5 (except NaF/1 all p <= 0.01 compared to placebo). AmF/NaF/SnCl(2)/chitosan was more effective than all other toothpastes (p <= 0.01 each). Sn on the enamel surface ranged between 1.3 +/- 0.3 and 2.8 +/- 0.04 wt.% with no obvious relationship with efficacy. CONCLUSIONS: The NaF and Sn(2+) toothpastes without chitosan exhibited similar anti-erosion and abrasion-prevention effects. The experimental Sn(2+) formulation with chitosan revealed promising results similar to those of the positive control. CLINICAL SIGNIFICANCE: NaF toothpastes offer a degree of protection against erosion/abrasion, which is likely sufficient for most subjects with average acid exposures. For patients with initial erosive lesions, however, more effective toothpaste is desirable. The combination of Sn(2+) and a biopolymer appears promising in this context. PMID- 22917562 TI - Molecular analysis of microbiota associated with peri-implant diseases. AB - OBJECTIVES: The aim of this study was to identify bacteria associated with peri implant diseases using Denaturing Gradient Gel Electrophoresis (DGGE) as a method for microbiological assessment. METHODS: Subgingival plaque samples along with essential patient information and clinical indices were taken from 22 subjects showing signs of peri-implant diseases. Bacteria were detected from extracted DNA either by species specific PCR, or by using PCR coupled with DGGE and subsequent sequencing of resolved and excised bands. RESULTS: Altogether, approximately 26 different species were identified as components of peri-implant plaque, including non-culturable bacteria. Percentages of periodonto pathogenic bacterial species in plaque samples were: 82% of shallow pocket (<3mm), 51% of moderate pocket depth, and 63% of deep pocket (>7.5mm). A positive correlation was found between highly pathogenic bacteria and both Gingival Index score and pocket depth. CONCLUSION: DGGE in combination with sequence analysis is a comprehensive and sensitive microbiological method for detection and identification of multiple bacterial species in peri-implant disease conditions. This makes it a valuable microbiological diagnostic method to help the clinician to conduct a more accurate clinical diagnosis and to plan appropriate treatment for peri-implant diseases. Based on results, Fusobacterium and Prevotella species were most prevalent in early stages of disease whilst an increased diversity of species was present during more advanced stages of disease. PMID- 22917563 TI - Autophagy-dependent and -independent involvement of AMP-activated protein kinase in 6-hydroxydopamine toxicity to SH-SY5Y neuroblastoma cells. AB - The role of the main intracellular energy sensor adenosine monophosphate (AMP) activated protein kinase (AMPK) in the induction of autophagic response and cell death was investigated in SH-SY5Y human neuroblastoma cells exposed to the dopaminergic neurotoxin 6-hydroxydopamine (6-OHDA). The induction of autophagy in SH-SY5Y cells was demonstrated by acridine orange staining of intracellular acidic vesicles, the presence of autophagosome- and autophagolysosome-like vesicles confirmed by transmission electron microscopy, as well as by microtubule associated protein 1 light-chain 3 (LC3) conversion and p62 degradation detected by immunoblotting. 6-OHDA induced phosphorylation of AMPK and its target Raptor, followed by the dephosphorylation of the major autophagy inhibitor mammalian target of rapamycin (mTOR) and its substrate p70S6 kinase (S6K). 6-OHDA treatment failed to suppress mTOR/S6K phosphorylation and to increase LC3 conversion, p62 degradation and cytoplasmatic acidification in neuroblastoma cells in which AMPK expression was downregulated by RNA interference. Transfection of SH-SY5Y cells with AMPK or LC3beta shRNA, as well as treatment with pharmacological autophagy inhibitors suppressed, while mTOR inhibitor rapamycin potentiated 6-OHDA-induced oxidative stress and apoptotic cell death. 6-OHDA induced phosphorylation of p38 mitogen-activated protein (MAP) kinase in an AMPK-dependent manner, and pharmacological inhibition of p38 MAP kinase reduced neurotoxicity, but not AMPK activation and autophagy triggered by 6-OHDA. Finally, the antioxidant N-acetyl cysteine antagonized 6-OHDA-induced activation of AMPK, p38 and autophagy. These data suggest that oxidative stress-mediated AMPK/mTOR-dependent autophagy and AMPK/p38-dependent apoptosis could be valid therapeutic targets for neuroprotection. PMID- 22917564 TI - CpG-ODN, the TLR9 agonist, attenuates myocardial ischemia/reperfusion injury: involving activation of PI3K/Akt signaling. AB - BACKGROUND: Toll-like receptors (TLRs) have been implicated in myocardial ischemia/reperfusion (I/R) injury. The TLR9 ligand, CpG-ODN has been reported to improve cell survival. We examined effect of CpG-ODN on myocardial I/R injury. METHODS: Male C57BL/6 mice were treated with either CpG-ODN, control-ODN, or inhibitory CpG-ODN (iCpG-ODN) 1h prior to myocardial ischemia (60min) followed by reperfusion. Untreated mice served as I/R control (n=10/each group). Infarct size was determined by TTC straining. Cardiac function was examined by echocardiography before and after myocardial I/R up to 14days. RESULTS: CpG-ODN administration significantly decreased infarct size by 31.4% and improved cardiac function after myocardial I/R up to 14days. Neither control-ODN nor iCpG-ODN altered I/R-induced myocardial infarction and cardiac dysfunction. CpG-ODN attenuated I/R-induced myocardial apoptosis and prevented I/R-induced decrease in Bcl2 and increase in Bax levels in the myocardium. CpG-ODN increased Akt and GSK 3beta phosphorylation in the myocardium. In vitro data suggested that CpG-ODN treatment induced TLR9 tyrosine phosphorylation and promoted an association between TLR9 and the p85 subunit of PI3K. Importantly, PI3K/Akt inhibition and Akt kinase deficiency abolished CpG-ODN-induced cardioprotection. CONCLUSION: CpG ODN, the TLR9 ligand, induces protection against myocardial I/R injury. The mechanisms involve activation of the PI3K/Akt signaling pathway. PMID- 22917565 TI - PPARgamma ligand treatment inhibits cardiac inflammatory mediators induced by infection with different lethality strains of Trypanosoma cruzi. AB - Trypanosoma cruzi (T. cruzi), the etiological agent of Chagas' disease, causes cardiac alterations in the host. Although the main clinical manifestations arise during the chronic stage, the mechanisms leading to heart damage develop early during infection. In fact, an intense inflammatory response is observed from acute stage of infection. Recently, peroxisome proliferator-activated receptors (PPARs) have attracted research interest due to their participation in the modulation of inflammation. In this work we addressed the role of 15-Deoxy ?(12,14) ProstaglandinJ2 (15dPGJ2), a PPARgamma natural ligand in the regulation of inflammatory mediators, in acute and chronic experimental mouse models of Chagas' disease with the RA and K98 T. cruzi strains, respectively. This work demonstrates that 15dPGJ2 treatment inhibits the expression and activity of inducible nitric oxide synthase (NOS2) as well as TNF-alpha and IL-6 mRNA levels. Also, expression and activity of metalloproteinases 2 (MMP-2) and 9 (MMP9) were inhibited by 15dPGJ2. Moreover GW9662, a specific PPARgamma antagonist, revealed the participation of other signaling pathways since, in GW9662 presence, 15dPJG2 had a partial effect on the inhibition of inflammatory parameters in the acute model of infection. Accordingly, NF-kappaB activation was demonstrated, assessing p65 nuclear translocation in the hearts of infected mice with both T. cruzi strains. Such effect was inhibited after 15dPGJ2 treatment. Our findings support the concept that in vivo PPARgamma and NF-kappaB pathways are implicated in the inhibitory effects of 15dPGJ2 on inflammatory mediators at different times depending on whether the infection is caused by the lethal or non-lethal T. cruzi strain. PMID- 22917566 TI - Molecular genetics of preeclampsia and HELLP syndrome - a review. AB - Preeclampsia is characterised by new onset hypertension and proteinuria and is a major obstetrical problem for both mother and foetus. Haemolysis elevated liver enzymes and low platelets (HELLP) syndrome is an obstetrical emergency and most cases occur in the presence of preeclampsia. Preeclampsia and HELLP are complicated syndromes with a wide variety in severity of clinical symptoms and gestational age at onset. The pathophysiology depends not only on periconceptional conditions and the foetal and placental genotype, but also on the capability of the maternal system to deal with pregnancy. Genetically, preeclampsia is a complex disorder and despite numerous efforts no clear mode of inheritance has been established. A minor fraction of HELLP cases is caused by foetal homozygous LCHAD deficiency, but for most cases the genetic background has not been elucidated yet. At least 178 genes have been described in relation to preeclampsia or HELLP syndrome. Confined placental mosaicism (CPM) is documented to cause early onset preeclampsia in some cases; the overall contribution of CPM to the occurrence of preeclampsia has not been adequately investigated yet. This article is part of a Special Issue entitled: Molecular Genetics of Human Reproductive Failure. PMID- 22917567 TI - Error types and error positions in neglect dyslexia: comparative analyses in neglect patients and healthy controls. AB - Unilateral spatial neglect frequently involves a lateralised reading disorder, neglect dyslexia (ND). Reading of single words in ND is characterised by left sided omissions and substitutions of letters. However, it is unclear whether the distribution of error types and positions within a word shows a unique pattern of ND when directly compared to healthy controls. This question has been difficult to answer so far, given the usually low number of reading errors in healthy controls. Therefore, the present study compared single word reading of 18 patients with left-sided neglect, due to right-hemisphere stroke, and 11 age matched healthy controls, and adjusted individual task difficulty (by varying stimulus presentation times in participants) in order to reach approximately equal error rates between neglect patients and controls. Results showed that, while both omission and substitution errors were frequently produced in neglect patients and controls, only omissions appeared neglect-specific when task difficulty was adapted between groups. Analyses of individual letter positions within words revealed that the spatial distribution of reading errors in the neglect dyslexic patients followed an almost linear increase from the end to the beginning of the word (right-to-left-gradient). Both, the gradient in error positions and the predominance of omission errors presented a neglect-specific pattern. Consistent with current models of visual word processing, these findings suggest that ND reflects sublexical, visuospatial attentional mechanisms in letter string encoding. PMID- 22917568 TI - Suppression of aversive memories associates with changes in early and late stages of neurocognitive processing. AB - Unwanted memories, such as emotionally negative, can be intentionally suppressed through voluntary control in humans. Memory suppression is thought to be mediated by the interplay of a chain of neurocognitive processes. However, empirical data in support of this notion is lacking. Using high-temporal resolution event related potential (ERP) technique, we investigated the time course of ERPs associated with suppression of negative and neutral memories in a Think/No-Think paradigm in young, healthy participants. Results showed that participants had greater difficulty in suppressing emotionally negative memories than neutral ones. ERPs and source analyses demonstrated that memory suppression processing for negative and neutral memories were generally associated with changes during early components of a time window of 70-260 ms, such as P1 and N2, mainly at the right inferior frontal gyrus and occipital lobe; suppression of aversive memories was associated with two major late ERP components between 380 and 800 ms, with significantly smaller later negativity (LN) but larger late parietal positivity (LPP), primarily at the right medial and superior frontal gyri. These results suggest that differences in early components may reflect early stages of suppression processing including visual awareness, attention reallocation, and executive processing. Differences in late components between suppression of aversive and neutral memories may reflect a process of down-regulating conscious recollection of memory representations supported by prefrontal and parietal networks. A less effective control of this process, as evidenced by smaller LN and larger LPP, may explain the fact that emotionally negative memories were harder to be suppressed. Altogether, these findings suggest that suppression of aversive memories requires down-regulation of late conscious recollection, which can be dissociated from early visual and attention processing in memory suppression. PMID- 22917569 TI - [Implants with 32P-foils for LDR-brachytherapy of benign stenosis in urology and gastroenterology]. AB - For LDR-brachytherapy, a limited number of implant geometries and materials are available. To avoid wound healing related hyper-proliferation (stenosis, keloids) a novel radioactive foil system was developed based on beta emitting (32)P, which can be easily integrated in existing implants such as urethral catheters or bile duct stents. As substrate material for these foils PEEK (polyetherethercetone) was chosen because of its radiation hardness during neutron activation of (32)P. The activity was determined by liquid scintillation counting and gamma spectroscopy, dose distributions were measured with scintillation detectors and radiochromic films. The correlation between activity and dose was checked by Monte-Carlo-simulations (Geant4). Prototypes of the (32)P-implants have shown in wash-out tests the required tightness for sealed radioactive sources. In animal tests on urethra and bile duct, the uncomplicated and save application of (32)P foils mounted on standard implants has been demonstrated, which is almost unchanged due to the simple radiation protection with plexiglass. This concept of radioactive implants with integrated (32)P-foils could extend essentially the application possibilities of LDR-brachytherapy. PMID- 22917570 TI - Construct validity of two pain behaviour observation measurement instruments for young children with burns by Rasch analysis. AB - In this study, construct validity of 2 pain behaviour observation measurement instruments for young children aged 1 to 56 months (mean age was 20 months) with burns is assessed by using Rasch analysis. The Rasch model, wherein data should meet the model expectations, assumes that an instrument measures one unidimensional construct, and focuses on the items of measurement instruments. The Pain Observation Scale for Young Children (POCIS) and the COMFORT Behaviour Scale (COMFORT-B) measure background and procedural pain as unidimensional. Adequate measurements for scientific research and daily practice can now be obtained. PMID- 22917571 TI - Innate immunity in cystic fibrosis lung disease. AB - Chronic lung disease determines the morbidity and mortality of cystic fibrosis (CF) patients. The pulmonary immune response in CF is characterized by an early and non-resolving activation of the innate immune system, which is dysregulated at several levels. Here we provide a comprehensive overview of innate immunity in CF lung disease, involving (i) epithelial dysfunction, (ii) pathogen sensing, (iii) leukocyte recruitment, (iv) phagocyte impairment, (v) mechanisms linking innate and adaptive immunity and (iv) the potential clinical relevance. Dissecting the complex network of innate immune regulation and associated pro inflammatory cascades in CF lung disease may pave the way for novel immune targeted therapies in CF and other chronic infective lung diseases. PMID- 22917572 TI - Ganglioside-binding specificities of E. coli enterotoxin LT-IIc: Importance of long-chain fatty acyl ceramide. AB - Bacterial heat-labile (LT) enterotoxins signal through tightly regulated interactions with host cell gangliosides. LT-IIa and LT-IIb of Escherichia coli bind preferentially to gangliosides with a NeuAcalpha2-3Galbeta1-3GalNAc terminus, with key distinctions in specificity. LT-IIc, a newly discovered E. coli LT, is comprised of an A polypeptide with high homology, and a B polypeptide with moderate homology, to LT-IIa and LT-IIb. LT-IIc is less cytotoxic than LT IIa and LT-IIb. We theorized that LT-IIc-host cell interaction is regulated by specific structural attributes of immune cell ganglioside receptors and designed experiments to test this hypothesis. Overlay immunoblotting to a diverse array of neural and macrophage gangliosides indicated that LT-IIc bound to a restrictive range of gangliosides, each possessing a NeuAcalpha2-3Galbeta1-3GalNAc with a requisite terminal sialic acid. LT-IIc did not bind to GM1a with short-chain fatty acyl ceramides. Affinity overlay immunoblots, constructed to a diverse array of known ganglioside structures of murine peritoneal macrophages, established that LT-IIc bound to GM1a comprised of long-chain fatty acyl ceramides. Findings were confirmed with LT-IIc also binding to GM1a of RAW264.7 cells, comprised of a long-chain fatty acyl ceramide. Thus, LT-IIc-ganglioside binding differs distinctly from that of LT-IIa and LT-IIb. LT-IIc binding is not just dependent on carbohydrate composition, but also upon the orientation of the oligosaccharide portion of GM1a by the ceramide moiety. These studies are the first demonstration of LT-ganglioside dependence upon ceramide composition and underscore the contribution of long-chain fatty acyl ceramides to host cell interactions. PMID- 22917574 TI - Basic research in nephrology: are we in decline? PMID- 22917573 TI - Correlation of hyaluronan deposition with infiltration of eosinophils and lymphocytes in a cockroach-induced murine model of asthma. AB - Asthma is a chronic inflammatory disease that exhibits airway remodeling with changes in the extracellular matrix (ECM). The role of the ECM in mediating these changes is poorly understood. Hyaluronan (HA), a major component of the ECM, has been implicated in many biological processes in diseases. This study investigates the processes involved in HA synthesis, deposition and localization during the propagation of cockroach-induced asthma. Mice were sensitized and challenged with cockroach antigen, and sacrificed at various time points during an 8-week challenge protocol. Analysis of bronchoalveolar lavage (BAL) fluid revealed an increase in total nucleated cells as early as 6h, which peaked at 6 days. Histopathologic analysis of the lung tissue revealed an influx of inflammatory cells at the peribronchial and perivascular regions starting at 12 h, which peaked at 6 days and persisted to 8 weeks. Eosinophils predominated in the early time points while lymphocytes predominated during the late time points. Quantitative polymerase chain reaction (PCR) data showed that hyaluronan synthase 1 (HAS1) mRNA peaked within 6 h and then declined. HAS2 mRNA also peaked within 6 h but remained elevated throughout the 8-week exposure course. HA levels in lung tissue and BAL increased at 12 h and peaked by 6 and 8 days, respectively. Inflammatory cells and new collagen formation localized in areas of HA deposition. Taken together, these data support a role for HA in the pathogenesis in asthma. PMID- 22917576 TI - Attention control: relationships between self-report and behavioural measures, and symptoms of anxiety and depression. AB - Individual differences in attention control are proposed to contribute to anxiety and depression. However, self-reported attention control, assessed on the Attentional Control Scale (ACS), appears to be a heterogeneous construct with separate components of focusing (e.g., concentrating, resisting distraction) and shifting (e.g., flexible switching of attention between tasks). Moreover, these constructs are proposed to relate differently to anxiety and depression. Two studies are reported which investigated relationships between ACS focusing and shifting and (i) an objective behavioural measure of attention control from the Attention Network Task (ANT); and (ii) anxiety and depression symptoms in two separate non-clinical samples (Ns = 165 and 193). Results of Study 1 indicated that only ACS focusing was significantly associated with ANT attention control; with both measures reflecting resistance to distraction. In both studies, self reported ability to focus attention (ACS focusing) was associated with lower anxiety; and greater attentional flexibility (ACS shifting) was associated with fewer depression symptoms. PMID- 22917575 TI - Long-term outcomes of pre-emptive valganciclovir compared with valacyclovir prophylaxis for prevention of cytomegalovirus in renal transplantation. AB - Prevention of cytomegalovirus (CMV) is essential in organ transplantation. The two main strategies are pre-emptive therapy, in which one screens for and treats asymptomatic CMV viremia, and universal antiviral prophylaxis. We compared these strategies and examined long-term outcomes in a randomized, open-label, single center trial. We randomly assigned 70 renal transplant recipients (CMV seropositive recipient or donor) to 3-month prophylaxis with valacyclovir (n=34) or pre-emptive valganciclovir for significant CMV viremia detected at predefined assessments through month 12 (n=36). Among the 55 patients who had a protocol biopsy specimen available at 3 years to allow assessment of the primary outcome, 9 (38%) of 24 patients in the prophylaxis group and 6 (19%) of 31 patients in the pre-emptive therapy group had moderate to severe interstitial fibrosis and tubular atrophy (odds ratio, 2.50; 95% confidence interval, 0.74-8.43; P=0.22). The prophylaxis group had significantly higher intrarenal mRNA expression of genes involved in fibrogenesis. The occurrence of CMV disease was similar in both groups, but pre-emptive therapy improved 4-year graft survival (92% versus 74%; P=0.049) as a result of worse outcomes in patients with late-onset CMV viremia. In conclusion, compared with valacyclovir prophylaxis, pre-emptive valganciclovir therapy may lead to less severe interstitial fibrosis and tubular atrophy and to significantly better graft survival. PMID- 22917577 TI - Resistance to butyrate impairs bile acid-induced apoptosis in human colon adenocarcinoma cells via up-regulation of Bcl-2 and inactivation of Bax. AB - A critical risk factor in colorectal carcinogenesis and tumor therapy is the resistance to the apoptotic effects of different compounds from the intestinal lumen, among them butyrate (main regulator of colonic epithelium homeostasis). Insensitivity to butyrate-induced apoptosis yields resistance to other agents, as bile acids or chemotherapy drugs, allowing the selective growth of malignant cell subpopulations. Here we analyze bile acid-induced apoptosis in a butyrate resistant human colon adenocarcinoma cell line (BCS-TC2.BR2) to determine the mechanisms that underlay the resistance to these agents in comparison with their parental butyrate-sensitive BCS-TC2 cells. This study demonstrates that DCA and CDCA still induce apoptosis in butyrate-resistant cells through increased ROS production by activation of membrane-associated enzymes and subsequent triggering of the intrinsic mitochondrial apoptotic pathway. Although this mechanism is similar to that described in butyrate-sensitive cells, cell viability is significantly higher in resistant cells. Moreover, butyrate-resistant cells show higher Bcl-2 levels that confer resistance to bile acid-induced apoptosis sequestering Bax and avoiding Bax-dependent pore formation in the mitochondria. We have confirmed that this resistance is reverted using the Bcl-2 inhibitor ABT 263, thus demonstrating that the lower sensitivity of butyrate-resistant cells to the apoptotic effects of bile acids is mainly due to increased Bcl-2 levels. PMID- 22917578 TI - Mitophagy is triggered by mild oxidative stress in a mitochondrial fission dependent manner. AB - Mitochondrial dysfunction is linked to apoptosis, aging, cancer, and a number of neurodegenerative and muscular disorders. The interplay between mitophagy and mitochondrial dynamics has been linked to the removal of dysfunctional mitochondria ensuring mitochondrial quality control. An open question is what role mitochondrial fission plays in the removal of mitochondria after mild and transient oxidative stress; conditions reported to result in moderately elevated reactive oxygen species (ROS) levels comparable to physical activity. Here we show that applying such conditions led to fragmentation of mitochondria and induction of mitophagy in mouse and human cells. These conditions increased ROS levels only slightly and neither triggered cell death nor led to a detectable induction of non-selective autophagy. Starvation led to hyperfusion of mitochondria, to high ROS levels, and to the induction of both non-selective autophagy and to a lesser extent to mitophagy. We conclude that moderate levels of ROS specifically trigger mitophagy but are insufficient to trigger non selective autophagy. Expression of a dominant-negative variant of the fission factor DRP1 blocked mitophagy induction by mild oxidative stress as well as by starvation. Taken together, we demonstrate that in mammalian cells under mild oxidative stress a DRP1-dependent type of mitophagy is triggered while a concomitant induction of non-selective autophagy was not observed. We propose that these mild oxidative conditions resembling well physiological situations are thus very helpful for studying the molecular pathways governing the selective removal of dysfunctional mitochondria. PMID- 22917579 TI - Rapid detection of Cronobacter spp. with a method combining impedance technology and rRNA based lateral flow assay. AB - Cronobacter spp. is an important release test parameter for powered infant formula (PIF). An impedance method is proposed for the rapid detection of this pathogen in PIF. An impedance based method (BacTrac 4300 Microbiological Analyzer) combined with a RNA hybridisation assay (RiboFlowTM) was evaluated using 23 strains in PIF samples and compared to a culture based reference method (ISO/TS 22964). The influences of competitive flora, heat and dry stress on the reliability of the impedance method were investigated. Seven different Cronobacter species were included in the evaluation, among them are strains with high susceptibility to low pH and high temperatures. Compared to the reference method, a higher sensitivity (85%) and specificity (100%) was observed using the impedance method, combined with the commercial rRNA based lateral flow test kit as a confirmation tool. The detection time was substantially shortened by using the impedance technique and RiboFlowTM. Cronobacter could be detected within maximally 29 h, while the reference method takes up to five days when including confirmation of positive results. PMID- 22917580 TI - Quantification of the adult EEG background pattern. AB - OBJECTIVE: Visual interpretation of EEG is time-consuming and not always consistent between reviewers. Our objective is to improve this by introducing guidelines and algorithms to quantify various properties, focussing on the background pattern in adult EEGs. METHODS: Five common properties were evaluated: (i) alpha rhythm frequency; (ii) reactivity; (iii) anterio-posterior gradients; (iv) asymmetries; and (v) diffuse slow-wave activity. A formal description was found for each together with a guideline and proposed quantitative algorithm. All five features were automatically extracted from routine EEG recordings. Modified time-frequency plots were calculated to summarize spectral and spatial characteristics. Visual analysis scores were obtained from diagnostic reports. RESULTS: Automated feature extraction was applied to 384 routine EEGs. Inter rater agreement was calculated between visual and quantitative analysis using Fleiss' kappa: kappa={(i)0.60;(ii)0.35;(iii)0.19;(iv)0.12;(v)0.76}. The method is further illustrated with three representative examples of automated reports. CONCLUSIONS: Automated feature extraction of several background EEG properties seems feasible. Inter-rater agreement differed between various features, ranging from slight to substantial. This may be related to the nature of various guidelines and inconsistencies in visual interpretation. SIGNIFICANCE: Formal descriptions, standardized terminology, and quantitative analysis may improve inter-rater reliability in reporting of the EEG background pattern and contribute to more efficient and consistent interpretations. PMID- 22917582 TI - A pattern to regenerate through turnover. AB - Tissues of animals and plants are maintained through balanced cell growth, movement, and elimination. Although cells are exchanged perpetually, the whole structure of the tissue is maintained. This form of maintenance is called cell turnover. Here I propose a bio-inspired model of patterns that regenerate through turnover. This model is derived from the Dachsous-Fat system, which has recently attracted much attention because it is considered to facilitate regeneration in insect legs. In this model, I parameterized the manner of the redistribution of Dachsous and Fat during cell division, and then derived equations in the parameters that enable the patterns to regenerate and maintain themselves through turnover. I extended the equations derived in the one-dimensional model into a two-dimensional model. Finally, I discuss a possible relationship between regeneration and turnover. PMID- 22917581 TI - The effect of subcutaneous fat on electrical impedance myography when using a handheld electrode array: the case for measuring reactance. AB - OBJECTIVE: Recent developments in electrical impedance myography (EIM) have led to the use of handheld electrode arrays (HEAs) for data acquisition. Although preferable for several reasons, this approach tends to be more affected by subcutaneous fat (SF) than the original approach in which the impedance-measuring electrodes are widely spaced. In this study, we seek to identify the EIM parameter least impacted by subcutaneous fat (SF) when using an HEA. METHODS: 18 normal subjects underwent 50 kHz EIM and ultrasound of the medial gastrocnemius muscles on the dominant side. Coefficients of determination (R(2) values) were calculated for each of the three major EIM variables (reactance, resistance, and phase) and SF thickness. RESULTS: For both resistance and phase, a strong relationship to SF thickness was observed (R(2) = 0.64 and R(2) = 0.70, respectively, p < 0.001 for both). In contrast, for reactance, the relationship was non-significant, with R(2) = 0.07, p = 0.30. CONCLUSIONS: Unlike resistance and phase, both of which are highly impacted by SF thickness, the reactance shows no significant relationship. SIGNIFICANCE: Future clinical studies employing HEA's to perform EIM should evaluate alterations in reactance in addition to those in resistance and phase. PMID- 22917583 TI - Genotyping of C. psittaci in central area of Argentina. AB - In central area of Argentina, the epidemiologic and molecular characteristics of Chlamydophila psittaci infections are still unknown. Nested polymerase chain reaction of domains II, III, and IV of the omp A gene was used to detect Chlamydophila in 43 pharyngeal swab samples from patients with suspected human psittacosis (2010-2011); 9 (21%) of them yielded positive results. Molecular typing was performed by direct sequencing demonstrating the presence of C. psittaci genotypes A, E/B, and WC. PMID- 22917584 TI - Protein malnutrition modifies medullary neuronal recruitment in response to intermittent stimulation of the baroreflex. AB - Protein malnutrition after weaning changes the neurotransmission in neural pathways that organize cardiovascular reflexes in rats. The present study evaluates whether protein malnutrition alters the expression of c-fos protein (immediate-early gene expression) in central areas involved in the control of cardiovascular reflexes after intermittent stimulation of the baroreflex. The main nuclei we focused were paraventricular hypothalamus (PVH); nucleus tract solitarii (NTS); rostral ventromedial medulla (RVMM); rostral (RVLM) and caudal ventrolateral medulla (CVLM). Male Fisher rats at 28 days were submitted to two different isocaloric diets during the subsequent 35 days: control (CT) (15% protein) and malnourished (MN) (6% protein). thirtymin of intermittent (every 3 min) baroreflex stimulation was performed by infusing phenylephrine (Phe-0.25 mM) or, as control, 0.9% NaCl (Sal). Following ninety minutes, animals were anesthetized and perfused. The removed brains were sectioned (35 MUm) and used for c-fos immunohistochemistry. Images were analyzed using the software Leica Q Win. Despite not altering the baseline MAP, malnutrition increased baseline HR and expression of c-fos in RVMM. Increases in c-fos expression after intermittent stimulation of baroreflex were evident in the PVH, medial NTS and CVLM in both dietary protocols. Current data further revealed a differential neuronal recruitment to stimulation of baroreflex in the caudal commissural and rostral NTS and RVLM of MN. We conclude that protein malnutrition modifies the cardiovascular control and the pattern of central response to baroreflex stimulation. PMID- 22917585 TI - Comparative analyses of Purkinje cell gene expression profiles reveal shared molecular abnormalities in models of different polyglutamine diseases. AB - Polyglutamine (PolyQ) diseases have common features that include progressive selective neurodegeneration and the formation of protein aggregates. There is growing evidence to suggest that critical nuclear events lead to transcriptional alterations in PolyQ diseases such as spinocerebellar ataxia type 7 (SCA7) and Huntington's disease (HD), conditions which share a cerebellar degenerative phenotype. Taking advantage of laser capture microdissection technique, we compared the Purkinje cell (PC) gene expression profiles of two transgenic polyQ mouse models (HD: R6/2; SCA7: P7E) by microarray analysis that was validated by real time quantitative PCR. A large number of transcriptional alterations were detected in the R6/2 transgenic model of HD. Similar decreases in the same mRNAs, such as phospholipase C, beta 3, purkinje cell protein 2 (Pcp2) and aldolase C, were found in both models. A decrease in aldolase C and phospholipase C, beta 3, may lead to an increase in the vulnerability of PCs to excitotoxic events. Furthermore, downregulation of mRNAs mediated by the Pcp2-promoter is common in both models. Thus, our data reveal shared molecular abnormalities in different polyQ disorders. PMID- 22917586 TI - Sphenoid mucocele: an uncommon complication of a rare condition. AB - A 58-year-old white woman presented with sudden onset of diplopia, headache and vomiting with a history of tiredness and lethargy over the past four to six months. She had smooth, pale, hairless skin and on examination she was found to have left-sided third and sixth nerve palsy. Laboratory tests confirmed pan anterior hypopituitarism. Computerized tomography scan of head and magnetic resonance imaging appearances were consistent with those of a sphenoid sinus mucocoele. Following adequate replacement with hydrocortisone and thyroxine she underwent sphenoid mucocoele drainage and endoscopic left sphenoethmoidectomy. Her symptoms were relieved over the next few days and she had a near-total recovery of ophthalmoplegia over the following three months. Pituitary function tests showed partial resolution of hypopituitarism with recovery of hypothalamic pituitary-adrenal axis and hydrocortisone therapy was withdrawn, but she continued to require thyroxine. PMID- 22917587 TI - In vivo identification of essential nucleotides in tRNALeu to its functions by using a constructed yeast tRNALeu knockout strain. AB - The fidelity of protein biosynthesis requires the aminoacylation of tRNA with its cognate amino acid catalyzed by aminoacyl-tRNA synthetase with high levels of accuracy and efficiency. Crucial bases in tRNALeu to aminoacylation or editing functions of leucyl-tRNA synthetase have been extensively studied mainly by in vitro methods. In the present study, we constructed two Saccharomyces cerevisiae tRNALeu knockout strains carrying deletions of the genes for tRNALeu(GAG) and tRNALeu(UAG). Disrupting the single gene encoding tRNALeu(GAG) had no phenotypic consequence when compared to the wild-type strain. While disrupting the three genes for tRNALeu(UAG) had a lethal effect on the yeast strain, indicating that tRNALeu(UAG) decoding capacity could not be compensated by another tRNALeu isoacceptor. Using the triple tRNA knockout strain and a randomly mutated library of tRNALeu(UAG), a selection to identify critical tRNALeu elements was performed. In this way, mutations inducing in vivo decreases of tRNA levels or aminoacylation or editing ability by leucyl-tRNA synthetase were identified. Overall, the data showed that the triple tRNA knockout strain is a suitable tool for in vivo studies and identification of essential nucleotides of the tRNA. PMID- 22917589 TI - Efficacy and safety of multitarget therapy with mizoribine and tacrolimus for systemic lupus erythematosus with or without active nephritis. AB - The prognosis of lupus nephritis (LN) has improved since the introduction of immunosuppressant therapies, but the safety and effectiveness of treatments can also be improved. We retrospectively assessed the treatment courses of 12 patients with systemic lupus erythematosus who were treated with glucocorticoid, mizoribine (MZR) and tacrolimus. This regimen was used as initial therapy for active LN in six patients (mean glucocorticoid dose, 66.6 mg); four of these six patients also received pulse methylprednisolone therapy. The starting doses of MZR and tacrolimus were 150 and 3 mg, respectively, and they were titrated as required. Five of six patients achieved complete remission and one achieved partial remission at 6 months. Five patients who completed 12-month analysis achieved complete remission. Another six patients were given the combination regimen for treating minor flares or for steroid sparing. The mean prednisolone doses were reduced from 11.0 mg at baseline to 6.6 mg at 12 months. Six patients experienced minor adverse events, including three minor infections. One patient stopped tacrolimus because of suspected toxicity. All 12 patients were successfully treated, and none experienced severe adverse events. Multitarget therapy combining glucocorticoid, MZR and tacrolimus may have the potential to become a treatment option which is effective and safe. PMID- 22917588 TI - miR-182 inhibits Schwann cell proliferation and migration by targeting FGF9 and NTM, respectively at an early stage following sciatic nerve injury. AB - The regulation of Schwann cell (SC) responses to injury stimuli by microRNAs (miRNAs) remains to be explored. Here, we identified 17 miRNAs that showed dynamic expression alterations at five early time points following rat sciatic nerve resection. Then we analyzed the expression pattern of 17 miRNAs, and integrated their putative targets with differentially expressed mRNAs. The resulting 222 potential targets were mainly involved in cell phenotype modulation, including immune response, cell death and cell locomotion. Among 17 miRNAs, miR-182 expression was up-regulated. The enhanced expression of miR-182 was correlated with nerve injury-induced phenotype modulation of SCs. Further investigation revealed that fibroblast growth factor 9 (FGF9) and neurotrimin (NTM) were two direct targets of miR-182 in SCs, with miR-182 binding to the 3' untranslated region of FGF9 and NTM. Silencing of FGF9 and NTM recapitulated the inhibiting effect of miR-182 mimics on SC proliferation and migration, respectively, whereas enforced knockdown of FGF9 and NTM reversed the promoting effect of miR-182 inhibitor on SC proliferation and migration, respectively. Our data indicate that nerve injury inhibits SC proliferation and migration through rapid regulation of miR-182 by targeting FGF9 and NTM, providing novel insights into the roles of miRNAs in nerve injury and repair. PMID- 22917590 TI - Flavor and feeding: executive summary. PMID- 22917591 TI - People's experiences of being mechanically ventilated in an ICU: a qualitative study. AB - OBJECTIVES: In previous studies people receiving mechanical ventilation treatment have described experiencing distress over their inability to speak and feelings such as anxiety. More research is needed to improve their experience in the intensive care unit and promote recovery. The aim of this study was to describe the intensive care unit experiences of people undergoing mechanical ventilation. METHOD: Qualitative, personal interviews were conducted during 2011 with eight people who were mechanically ventilated in an intensive care unit in the northern part of Sweden. Interview transcripts were analysed using qualitative content analysis. FINDINGS: Two themes emerged, with four and three categories, respectively. Being dependent for survival on other people and technical medical equipment created a sense of being vulnerable in an anxious situation and a feeling of uncertainty about one's own capacity to breathe. Having lines and tubes in one's body was stressful. Being given a diary and follow-up visit to the intensive care unit after the stay were important tools for filling in the missing time, but there was also one participant who did not want to remember his stay in the intensive care unit. CONCLUSION: To be dependent on other people and technical medical equipment for survival creates a sense of being delivered into the hands of others, as the people being mechanically ventilated could not trust their body to function. PMID- 22917592 TI - Quantitative analysis of olanzapine in rat brain microdialysates by HPLC-MS/MS coupled with column-switching technique. AB - A rapid and sensitive liquid chromatography-tandem mass spectrometric (LC-MS/MS) method coupled with column-switching technique was developed for the determination of olanzapine in rat brain microdialysates. A C8 guard column was used to desalt the samples before analytical separation on a C18 column and detection with tandem mass spectrometry. The mobile phase consisted of methanol/acetonitrile/water (v/v/v, 22.5/22.2/55) was used for desalting and the mobile phase consisted of methanol/acetonitrile/water (v/v/v, 43/43/14) was for analytical separation, water in both mobile phases contained 0.1% ammonium acetate. The lower limit of quantification (LLOQ) for olanzapine was 0.085 ng/ml. The method was linear from LLOQ to 34 ng/ml with a coefficient of determination >0.998. Intra- and inter-day accuracy and precision were determined with variability less than 13.24% (R.S.D). This sensitive method was successfully applied to quantify the concentration of olanzapine in rat brain microdialysates. With this study, the effect of the alcohol extract of Schisandra sphenanthera Rehd. et Wils on the concentration of olanzapine in brain was investigated. PMID- 22917593 TI - Simultaneous quantification of Polyphyllin D and Paris H, two potential antitumor active components in Paris polyphylla by liquid chromatography-tandem mass spectrometry and the application to pharmacokinetics in rats. AB - Polyphyllin D and Paris H are two potential antitumor active components in Paris polyphylla, one of the Traditional Chinese Medicines (TCMs). The present study details the development and validation of a rapid, sensitive and accurate LC-ESI MS/MS method for the separation and simultaneous determination of Polyphyllin D and Paris H in rat plasma using Ginsenoside Rh(2) as the internal standard (IS). A simple protein precipitation method was used for the preparation of plasma sample. Chromatographic separation was successfully achieved on an Agilent Zorbax C(18) column using a step gradient program with the mobile phase of 10 mmol/L aqueous ammonium acetate and acetonitrile. Both analytes were detected by negative mode electrospray ionization mass spectrometry. Selected reaction monitoring (SRM) was applied for all monitored analytes. This method demonstrated good linearity and did not show any endogenous interference. The lower limits of quantification (LLOQs) of Polyphyllin D and Paris H were both 1.0 ng/mL using 100 MUL rat plasma. The average recoveries of Polyphyllin D and Paris H from rat plasma were both above 80%. The inter-day precisions (%RSD) of both analytes determined in five days were all below 15%. The developed and validated method has been successfully applied in the simultaneous quantification and pharmacokinetic studies of Polyphyllin D and Paris H in rats. PMID- 22917594 TI - Post acquisition data processing techniques for lipid analysis by quadrupole time of-flight mass spectrometry. AB - This study describes the effectiveness of post-acquisition data processing techniques in detecting the lipid species rapidly from the massive data generated by high resolution mass spectrometry. The filtering approaches by product ions or neutral losses enabled glycerophospholipids and sterol conjugates to be identified based on the investigation of their fragmentation patterns, and the filtration by mass defect facilitated the detection of fatty acyl residues and bile acids by limiting the range of mass defect values. After application of these filtering techniques to mass spectra, the background noise was significantly filtered out and characteristic peaks of lipid species were efficiently sorted out. Totally 145 individual lipids were identified and structurally elucidated. Validation results of the LCMS-Q-TOF-based quantitative performance for all the peaks showed that the accuracy, expressed as relative errors (RE%), was lower than +/-15%, and values (RSD%) of the inter-batch and intra-batch precision were lower than 15% in the assay. The developed method was integrated to the evaluation of plasma lipid profile from high fat diet versus energy restricted diet fed rats. A unique discrimination of the groups was successfully achieved through a principal component analysis (PCA). PMID- 22917595 TI - Liquid chromatography-tandem mass spectrometric assay for therapeutic drug monitoring of the tyrosine kinase inhibitor pazopanib in human plasma. AB - A quantitative bioanalytical liquid chromatography-tandem mass spectrometric assay for the tyrosine kinase inhibitor pazopanib was developed and validated. Plasma samples were pre-treated using protein precipitation with acetonitrile containing pazopanib-d(4) as internal standard. The extract was injected into the chromatographic system after dilution with water (1:9, v/v). The system consisted of a sub-2 MUm particle, trifunctional bonded octadecyl silica column with isocratic elution using 0.005% (v/v) of formic acid in a mixture of water (76%, v/v) and acetonitrile (24%, v/v). The analyte was quantified using the selected reaction monitoring mode of a triple quadrupole mass spectrometer with a heated electrospray interface. The assay was validated in a 0.1-100 MUg/ml calibration range. Within day precisions were 3.6-5.2%, between day precisions 4.0-8.3% and accuracies between 106% and 113% for the whole calibration range. The drug was sufficiently stable under all relevant analytical conditions. The assay has successfully been used to assess drug levels for therapeutic drug monitoring in patients treated with pazopanib. PMID- 22917596 TI - Highly sensitive and quantitative profiling of acidic phytohormones using derivatization approach coupled with nano-LC-ESI-Q-TOF-MS analysis. AB - In current study, we developed a highly sensitive method for the quantitative profiling of acidic phytohormones. Tandem solid-phase extraction (SPE) and liquid liquid extraction (LLE) was employed to efficiently purify acidic phytohormones, which were further derived by 3-bromoactonyltrimethylammonium bromide (BTA) to increase the ionization efficiency in electrospray ionization-mass spectrometry detection. Additionally, fifteen BTA-derived acidic phytohormones, including ten gibberellins (GAs), were well separated with a salt gradient on poly(methacrylic acid-co-ethylene glycol dimethacrylate) (MAA-co-EDMA) monolithic column. By employing online trapping system, the signal intensities of the analytes were significantly improved. The limits of detection (LODs, Signal/Noise=3) of targeted phytohormones ranged from 1.05 to 122.4 pg/mL, which allowed the highly sensitive determination of low abundant acidic phytohormones with tiny amount plant sample. Good reproducibility was obtained by evaluating the intra- and inter-day precisions with relative standard deviations (RSDs) less than 10.9 and 11.9%, respectively. Recoveries of the target analytes from spiked rice leave samples ranged from 88.3 to 104.3%. By employing the method developed here, we were able to simultaneously determine 11 endogenous acidic phytohormones from only 5mg of rice leave sample, which dramatically decreased the required sample amount (three orders of magnitude lower) for the profiling of low abundant acidic phytohormones compared to previous reports. Taken together, the method provided a good solution for the highly sensitive and quantitative profiling of endogenous acidic phytohormones. PMID- 22917597 TI - A gas chromatography-mass spectrometry assay to quantify camphor extracted from goat serum. AB - A sensitive gas chromatography-mass spectrometry (GC-MS) method was developed and validated for quantification and pharmacokinetics of camphor, a major monoterpene of juniper plant, in goat serum. Camphor and internal standard (terpinolene) eluates from solid phase extraction (SPE) with ethyl acetate yielded well resolved peaks and were clearly identified in total and selected ion chromatograms. The elution and injection volumes were optimized for improved detection and quantification of camphor based on peak shape, signal to noise ratio, recoveries, and repeatability. The matrix calibration curve with the good linearity (R(2)=0.998) and response in the range of 0.005-10.0 MUg/mL was used to determine camphor concentration in goat serum. The GC-MS method offered sufficiently low limits of detection (1 ng/mL) and quantitation (3 ng/mL) for camphor concentration in goat serum for the pharmacokinetic study. The proposed method showed good intra- and inter-day variation with relative standard deviation (RSD) of 0.2-7.7% and produced good recovery (96.0-111.6%) and reproducibility (1.6-6.1%) at all spiked levels. Using this method on serum samples obtained from two goats orally dosed with camphor confirmed that the method is suitable for camphor studies in animals. PMID- 22917598 TI - Learning and Developing Individual Exercise Skills (L.A.D.I.E.S.) for a better life: a physical activity intervention for black women. AB - Physical activity (PA) is low among African American women despite awareness of its positive impact on health. Learning and Developing Individual Exercise Skills for a Better Life (L.A.D.I.E.S.) compares three strategies for increasing PA among African American women using a cluster randomized, controlled trial. Underactive adult women from 30 churches (n=15 participants/church) were recruited. Churches were randomized to a faith-based intervention, a non-faith based intervention, or an information only control group. Intervention groups will meet 25 times in group sessions with other women from their church over a 10 month period. Control group participants will receive standard educational material promoting PA. All participants will be followed for an additional 12 months to assess PA maintenance. Data will be collected at baseline, 10, and 22 months. The primary outcome is PA (steps/day, daily moderate-to-vigorous PA). We expect treatment effects indicating that assignment to either of the active interventions is associated with greater magnitude of change in PA compared to the control group. In exploratory analyses, we will test whether changes in the faith-based intervention group are greater than changes in the non-faith-based intervention group. L.A.D.I.E.S. focuses on a significant issue-increasing PA levels-in a segment of the population most in need of successful strategies for improving health. If successful, L.A.D.I.E.S. will advance the field by providing an approach that is successful for initiating and sustaining change in physical activity, which has been shown to be a primary risk factor for a variety of health outcomes, using churches as the point of delivery. PMID- 22917599 TI - Efficacy and effectiveness as aspects of cluster randomized trials with nursing home residents: methodological insights from a pneumonia prevention trial. AB - This report discusses how methodological aspects of study efficacy and effectiveness combine in cluster randomized trials in nursing homes. Discussion focuses on the relationships between these study aspects in the Pneumonia Reduction in Institutionalized Disabled Elders (PRIDE) trial, an ongoing cluster randomized clinical trial of pneumonia prevention among nursing home residents launched in October 2009 in Greater New Haven, Connecticut. This clinical trial has enrolled long-term care nursing home residents, over 65years in age, who have either inadequate oral care or swallowing difficulty, previously identified risk factors for pneumonia. It has used a multicomponent intervention consisting of manual tooth/gum brushing, 0.12% chlorhexidine oral rinse administered twice daily by nurses, and upright feeding positioning at meals to reduce rates of radiographically documented pneumonia. Cluster randomization is attractive for nursing home intervention studies because physical proximity and administrative arrangements make it difficult to deliver different interventions to residents of the same nursing home. Implementing an intervention in an entire home requires integration into the daily life of residents and into the administrative procedures of the nursing home. This characteristic of nursing home cluster randomized trials makes them approximate "real-world" research contexts, but implementation can be challenging. The PRIDE trial of pneumonia prevention utilized specific methodological choices that include both efficacy and effectiveness elements. Cluster randomized trials in nursing homes having elements of both efficacy and effectiveness (i.e., hybrid designs) can address some of the methodological challenges of conducting clinical research in nursing homes; they have distinctive advantages and some limitations. PMID- 22917600 TI - Complementary feeding and non communicable diseases: current knowledge and future research needs. AB - Early diet and nutrition may set in place growth patterns and/or metabolic pathways that promote risk factors for later NCDs. Most relevant studies so far available have a cross-sectional or retrospective design and are thus of limited validity for evaluating the impact of early feeding on later disease. Standardised protocols for prospective research should be developed. The contribution of protein intake in early life to later NCD development has been the object of several studies; however future research should specifically target the effects of early protein intake on (a) how protein intake influences body composition, (b) how different body composition in infancy contributes to later NCDs, (c) whether there is an age 'window' when high protein intake is particularly associated with later overweight and obesity, (d) what levels of protein intake may protect against later overweight/obesity, (e) what level of cow milk intake in the first years of life minimises risk-inducing growth whilst meeting recommended calcium intakes. The role of the quality of fat and carbohydrate intakes at early ages should be better investigated. There is a dearth of data from many communities about the foods introduced as complementary feeds, the ages at which they are introduced and why mothers use these foods. Definitely more information is needed on how and to what extent mothers' behaviour is influenced by media, advertising and other commercial pressures and why formula fed infants are started on other foods much earlier than breast fed infants. Standardized protocols are needed to develop more data on complementary feeding in different regions, different countries and different socio-economic environments. PMID- 22917601 TI - Growth and complementary feeding in the Americas. AB - BACKGROUND AND AIMS: To describe growth patterns of young children in Latin America and the Caribbean, the types of nationally representative data available on complementary feeding practices and complementary feeding practices. METHODS AND RESULTS: Data on growth, timing of introduction of liquids and foods, and complementary feeding practices were abstracted from nationally representative surveys. The high prevalence of stunting relative to the low prevalence of underweight is striking, with the "average" child in the region, with the exception of the Haitian child, short and chubby. The focus of the demographic and health surveys continues to be on undernutrition with only one question, intake of sugary foods, related foods that may have consequences for adult health. The United States has more comprehensive information; Mexico has information on beverage consumption and Brazil on soft drink and biscuit or snack consumption. In 14 of 19 countries, fewer than half of infants are exclusively breastfed for the first 6 months of life, indicating an early introduction of liquids and complementary foods. Among the 5 countries with data on the intake of sugary foods, intake in the previous 24 h among children 6-23 months of age ranged from 14% to 79%. CONCLUSIONS: The absence of data to characterize complementary feeding diets as they relate to risk of overweight and chronic diseases in the Region of the Americas calls attention to the need to improve data collection frameworks and methods to address this important gap in knowledge. PMID- 22917602 TI - Relation of serum cortisol to delirium occurring after acute coronary syndromes. AB - BACKGROUND: Delirium can be associated with cardiac system disorders. Stress plays an important role in the pathogenesis of postoperative delirium. Cortisol is one of the most important stress hormones in humans. We aimed to investigate whether a relation exists between serum cortisol and the degree of delirium after acute coronary syndromes (ACS). METHODS: We enrolled 52 consecutive patients who presented with ACS and were hospitalized in the coronary care unit. Patients were examined daily by a single psychiatrist, and delirium was diagnosed by using the Delirium Rating Scale (DSR). Blood samples were obtained at 6:00 am of the next morning after admission. RESULTS: The mean age was 66 years (SD, +/-6 years), and 52% were men. Delirium occurred in 25 patients (48%). The median score on the DRS was 17 for the delirious patients and 5 for the nondelirious. Median cortisol levels were significantly different between the delirium and nondelirium groups (13.9 vs 6.2 MUg/dL; P < .01). There were significant correlations between the cortisol levels and the severity of the delirium based on DRS scores as well as between the cortisol levels and the presence of delirium (r = 0.65 and 0.74, respectively; P = .01). In a linear logistic regression model, cortisol predicted the occurrence of delirium (beta = .81; P < .01). In receiver operating characteristics analysis, the optimal cutoff value of cortisol to predict delirium was 10.8 MUg/dL, with 96% sensitivity and 89% specificity. CONCLUSION: Delirium was common after ACS, and serum cortisol levels correlated with the degree of delirium and the risk of delirium. PMID- 22917603 TI - Congenital long QT syndrome masked by atrial fibrillation and unmasked by hypokalemia. PMID- 22917605 TI - Mutation screening of the HTR2B gene in patients with Tourette syndrome. AB - Tourette syndrome (TS), a neurological disorder with a reported prevalence frequency ranging from 0.7% to 4.2%, is manifested by motor and phonic tics and associated with a variety of behavioral abnormalities including impulsivity. Clinical, neuroimaging and other studies support dysfunction of the dopamine and 5-hydroxytryptamine neurotransmitter systems in TS. To determine whether TS is associated with mutation in the 5-hydroxytryptamine receptor 2B gene (HTR2B), which has been also implicated in impulsivity, we screened 132 Caucasian and 128 Chinese Han patients with TS. Two novel (c.188T>G, Met63Arg; c.1346G>A, Arg449Gln) and three known (rs61731726, Gly51Gln; rs200541113, Lys324Asn; rs61731723, Asn438Asn) nucleotide variants were found. Further analysis of sex, age, and ethnically matched normal controls (138 Caucasians and 248 Chinese Han individuals), as well as an affected family member, indicated that these variants may not be pathogenically relevant, suggesting that variants in the HTR2B gene may play little or no role in the development of TS. PMID- 22917606 TI - Dexmedetomidine decreases hyperalgesia in neuropathic pain by increasing acetylcholine in the spinal cord. AB - The activation of alpha2-adrenoceptors has attracted attention as a therapeutic target for neuropathic pain, which remains a clinical challenge. In the present study, we examined the interaction between alpha2-adrenergic and cholinergic signaling in a rat model of neuropathic pain induced by spinal nerve ligation (SNL). Intrathecal administration of dexmedetomidine, which is a selective alpha2 adrenoceptor agonist (0.1-1.0 MUg), dose-dependently suppressed hyperalgesia in SNL rats but did not alter paw withdrawal thresholds in normal rats. The analgesic effect of dexmedetomidine was abolished by intrathecal pretreatment with idazoxan (30 MUg) and atropine (30 MUg), which antagonize the alpha2 adrenoreceptor and muscarinic receptor, respectively. In vivo microdialysis in the lumbar spinal dorsal horn revealed that acetylcholine concentrations increased after dexmedetomidine perfusion (1 MUM), but only in SNL rats. The combination of an ineffective dose of intrathecal dexmedetomidine with intraperitoneal donepezil, which is a cholinesterase inhibitor, decreased neuropathic hypersensitivity. These results suggest that plasticity of the spinal noradrenergic-cholinergic axis only occurs in neuropathic pain states. Thus, drug combinations that strengthen the noradrenergic-cholinergic interaction may provide therapeutic benefit in neuropathic pain. PMID- 22917607 TI - Neuroprotective effect of alpha-lipoic acid on hydrostatic pressure-induced damage of retinal ganglion cells in vitro. AB - BACKGROUND: Recently, alpha-lipoic acid (ALA) has been reported to afford protection against neurodegenerative disorders in humans and experimental animals, yet little study elucidates whether it works in glaucomatous optic neuropathy. OBJECTIVE: This study aims to investigate whether ALA possesses neuroprotection against hydrostatic pressure-induced damage and explore its possible protective mechanism in cultured retinal ganglion cells (RGCs) in vitro. METHODS: RGC-5 cells were differentiated using staurosporine and pre-treated with different concentrations of ALA, then subjected to 50mm Hg hydrostatic pressure for 6h. After elevated hydrostatic pressure, cell viability was measured using MTT assay and apoptosis was evaluated using flow cytometry with Annexin V/PI staining. Intracellular reactive oxygen species (ROS) changes were determined by flow cytometry based on 2',7'-dichlorofluorescein diacetate (DCFH-DA). The expression of manganese superoxide dismutase (MnSOD) was measured via quantitative real-time PCR and Western blotting analysis. RESULTS: Increases of apoptotic rate and ROS production were observed in pressure-treated RGC-5 cells compared to normal control cells. In contrast, pretreatment of ALA significantly reduced the production of ROS, increased the expression of MnSOD and prevented apoptosis in pressure-treated RGC-5 cells. CONCLUSIONS: These findings suggest that there are protective effects of ALA against elevated hydrostatic pressure induced damage in RGC-5 cells, indicating ALA might be a potential therapeutic agent for glaucomatous optic neuropathy. PMID- 22917608 TI - Effects of valproic acid on the expression of trophic factors in human bone marrow mesenchymal stromal cells. AB - The potential of human bone marrow-mesenchymal stromal cells (hBM-MSCs) to differentiate into diverse cell types and secrete a variety of trophic factors makes them an excellent cell therapy tool for intractable diseases. However, their therapeutic efficacy has not yet been satisfied in preclinical and/or clinical trials with autologous or allogenic stem cells. To improve the efficacy of stem cell therapy, optimized conditions for stem cells need to be defined. In this study, we evaluated the effects of valproic acid (VPA), an HDAC inhibitor, in human BM-MSCs and assessed the expression of trophic factors (ANG, BDNF, ECGF1, bFGF-2, GDNF, HGF, IGF-1, PIGF, TGF-beta1, and beta-Pix) in MSCs treated with 200MUg/ml VPA for 12h. Under these conditions the features of MSCs were not changed. The VPA-treated MSCs also showed an increased cell protective effect against oxidative injuries in MTT assays and improved migratory ability when examined by the Boyden chamber assay. This suggests that MSCs may be improved by treatment with an optimal VPA dose and incubation time, which may increase the efficacy of stem cell therapy. PMID- 22917609 TI - Neuroprotection of lipoic acid treatment promotes angiogenesis and reduces the glial scar formation after brain injury. AB - After trauma brain injury, a large number of cells die, releasing neurotoxic chemicals into the extracellular medium, decreasing cellular glutathione levels and increasing reactive oxygen species that affect cell survival and provoke an enlargement of the initial lesion. Alpha-lipoic acid is a potent antioxidant commonly used as a treatment of many degenerative diseases such as multiple sclerosis or diabetic neuropathy. Herein, the antioxidant effects of lipoic acid treatment after brain cryo-injury in rat have been studied, as well as cell survival, proliferation in the injured area, gliogenesis and angiogenesis. Thus, it is shown that newborn cells, mostly corresponded with blood vessels and glial cells, colonized the damaged area 15 days after the lesion. However, lipoic acid was able to stimulate the synthesis of glutathione, decrease cell death, promote angiogenesis and decrease the glial scar formation. All those facts allow the formation of new neural tissue. In view of the results herein, lipoic acid might be a plausible pharmacological treatment after brain injury, acting as a neuroprotective agent of the neural tissue, promoting angiogenesis and reducing the glial scar formation. These findings open new possibilities for restorative strategies after brain injury, stroke or related disorders. PMID- 22917611 TI - Perceived target-masker separation unmasks responses of lateral amygdala to the emotionally conditioned target sounds in awake rats. AB - In a (simulated) reverberant environment, both human listeners and laboratory rats are able to perceptually integrate the direct wave of a sound source with the reflections of the source, leading to a fused image as coming from the location around the source (the precedence effect). This perceptual grouping effect produces perceived spatial separation between sound sources and facilitates selective attention to the target source. However, the neural correlates of the unmasking effects of perceived spatial separation have not been reported in the literature. The lateral nucleus of the amygdala (LA) is critical for processing ecologically salient sensory signals (e.g., threatening sounds) and mediating auditory fear conditioning. LA neuronal responses to a sound increase if the sound is fear conditioned. This study investigated whether in awake rats the perceptual fusion-induced separation between a fear-conditioned target sound and a noise masker enhances LA responses to the target. The results show that frequency-following responses (FFRs, i.e., sustained potentials based on phase-locked firing of neuron populations to periodical sound waveforms) recorded in the LA to a tone-complex, which was masked by a wideband noise, were enhanced after the tone-complex became fear conditioned. More importantly, the fear-conditioned tone-complex, but not the pseudo-conditioned tone-complex, elicited further larger LA FFRs when it was perceived as separated from the masker than when it was perceived as co-located with the masker. The results suggest that in the LA there exists a neural correlate of selective attention to ecologically significant sounds with a high degree of stimulus specificity. PMID- 22917610 TI - Changes in response properties of rostral ventromedial medulla neurons during prolonged inflammation: modulation by neurokinin-1 receptors. AB - Activation of neurokinin-1 (NK-1) receptors in the rostral ventromedial medulla (RVM) can facilitate pain transmission in conditions such as inflammation, and thereby contribute to hyperalgesia. Since blockade of NK-1 receptors in the RVM can attenuate hyperalgesia produced by prolonged inflammation, we examined the role of NK-1 receptors in changes of response properties of RVM neurons following four days of hind paw inflammation with complete Freund's adjuvant. Recordings were made from functionally identified ON, OFF and NEUTRAL cells in the RVM. Spontaneous activity and responses evoked by a series of mechanical (10, 15, 26, 60, 100, and 180 g) and heat (34-50 degrees C) stimuli applied to the inflamed and non-inflamed hind paws were determined before and at 15 and 60 min after injection of the NK-1-antagonist L-733,060 or vehicle into the RVM. Prolonged inflammation did not alter the proportions of functionally-identified ON, OFF and NEUTRAL cells. ON cells exhibited enhanced responses to mechanical (60-100g) and heat (48-50 degrees C) stimuli applied to the inflamed paw, which were attenuated by L-733,060 but not by vehicle. Inhibitory responses of OFF cells evoked by mechanical stimuli applied to the inflamed paw were also inhibited by L 733,060, but responses evoked by stimulation of the contralateral paw were increased. Heat-evoked responses of OFF cells were not altered by L-733,060. Also, neither L-733,060 nor vehicle altered spontaneous ongoing discharge rate of RVM neurons. These data indicate that NK-1 receptors modulate excitability of ON cells which contribute to both mechanical and heat hyperalgesia, whereas NK-1 modulation of OFF cells contributes to mechanical hyperalgesia during prolonged inflammation. PMID- 22917612 TI - The ubiquitin ligase F-box/G-domain protein 1 promotes the degradation of the disease-linked protein torsinA through the ubiquitin-proteasome pathway and macroautophagy. AB - DYT1 dystonia is a dominantly inherited, disabling neurological disorder with low penetrance that is caused by the deletion of a glutamic acid (DeltaE) in the protein torsinA. We previously showed that torsinA(wt) is degraded through macroautophagy while torsinA(DeltaE) is targeted to the ubiquitin-proteasome pathway (UPP). The different catabolism of torsinA(wt) and (DeltaE) potentially modulates torsinA(wt):torsinA(DeltaE) stoichiometry. Therefore, gaining a mechanistic understanding on how the protein quality control machinery clears torsinA(DeltaE) in neurons may uncover important regulatory steps in disease pathogenesis. Here, we asked whether F-box/G-domain protein 1 (FBG1), a ubiquitin ligase known to degrade neuronal glycoproteins, is implicated in the degradation of torsinA(DeltaE) by the UPP. In a first set of studies completed in cultured cells, we show that FBG1 interacts with and influences the steady-state levels of torsinA(wt) and (DeltaE). Interestingly, FBG1 achieves this effect promoting the degradation of torsinA not only through the UPP, but also by macroautophagy. To determine the potential clinical significance of these findings, we asked if eliminating expression of Fbg1 triggers a motor phenotype in torsinA(DeltaE) knock in (KI) mice, a model of non-manifesting DYT1 mutation carriers. We detected differences in spontaneous locomotion between aged torsinA(DeltaE) KI Fbg1 knock out and control mice. Furthermore, neuronal levels of torsinA were unaltered in Fbg1 null mice, indicating that redundant systems likely compensate in vivo for the absence of this ubiquitin ligase. In summary, our studies support a non-essential role for FBG1 on the degradation of torsinA and uncover a novel link of FBG1 to the autophagy pathway. PMID- 22917614 TI - Discharge properties of presumed cholinergic and noncholinergic laterodorsal tegmental neurons related to cortical activation in non-anesthetized mice. AB - We have recorded, for the first time, in non-anesthetized, head-restrained mice, a total of 339 single units in and around the laterodorsal (LDT) and sublaterodorsal (SubLDT) tegmental nuclei, which are located, respectively, in, or beneath, the periaqueductal gray and contain cholinergic neurons. The recordings were made during the complete wake-sleep cycle including wakefulness (W), slow-wave sleep (SWS), and paradoxical (or rapid eye movement) sleep (PS). The tegmental neurons displayed either a biphasic narrow or triphasic broad action potential. Seventy-six LDT or SubLDT neurons characterized by their triphasic long-duration action potentials were judged to be cholinergic and this was verified in anesthetized mice using neurobiotin juxtacellular labeling combined with choline acetyltransferase immunohistochemistry of the recorded cell. The 76 presumed cholinergic neurons discharged tonically at the highest rate during W and PS (W/PS-active neurons) as either single isolated spikes or clusters of two to five spikes, and 26 of them discharged selectively during W and PS, these W/PS-selective neurons being found mainly in the SubLDT. The clustering discharge was particularly prominent during PS, when it was associated with an obvious phasic change in the cortical electroencephalogram (EEG), and during waking periods, when it was accompanied by abrupt body movements. During the transition from sleep to waking, the cholinergic W/PS-selective neurons and the LDT or SubLDT noncholinergic W-selective neurons showed firing before the onset of W, while, at the transition from waking to sleep, they ceased firing before sleep onset. At the transition from SWS to PS, all the cholinergic neurons exhibited a significant increase in discharge rate before the onset of PS. The present study in mice supports the view that cholinergic and noncholinergic LDT and SubLDT neurons play an important role in tonic and phasic processes of arousal and cortical EEG activation occurring during W or PS, as well as in the sleep/waking switch. PMID- 22917613 TI - Ultrastructural analysis of rat ventrolateral periaqueductal gray projections to the A5 cell group. AB - Stimulation of neurons in the ventrolateral periaqueductal gray (PAG) produces antinociception as well as cardiovascular depressor responses that are mediated in part by pontine noradrenergic neurons. A previous report using light microscopy has described a pathway from neurons in the ventrolateral PAG to noradrenergic neurons in the A5 cell group that may mediate these effects. The present study used anterograde tracing and electron microscopic analysis to provide more definitive evidence that neurons in the ventrolateral PAG form synapses with noradrenergic and non-catecholaminergic A5 neurons in Sasco Sprague Dawley rats. Deposits of anterograde tracer, biotinylated dextran amine, into the rat ventrolateral PAG labeled a significant number of axons in the region of the rostral subdivision of the A5 cell group, and a relatively lower number in the caudal A5 cell group. Electron microscopic analysis of anterogradely-labeled terminals in both rostral (n=127) and caudal (n=70) regions of the A5 cell group indicated that approximately 10% of these form synapses with noradrenergic dendrites. In rostral sections, about 31% of these were symmetric synapses, 19% were asymmetric synapses, and 50% were membrane appositions without clear synaptic specializations. In caudal sections, about 22% were symmetric synapses, and the remaining 78% were appositions. In both rostral and caudal subdivisions of the A5, nearly 40% of the anterogradely-labeled terminals formed synapses with non-catecholaminergic dendrites, and about 45% formed axoaxonic synapses. These results provide direct evidence for a monosynaptic pathway from neurons in the ventrolateral PAG to noradrenergic and non-catecholaminergic neurons in the A5 cell group. Further studies should evaluate if this established monosynaptic pathway may contribute to the cardiovascular depressor effects or the analgesia produced by the activation of neurons in the ventrolateral PAG. PMID- 22917616 TI - Differential lipopolysaccharide-induced immune alterations in the hippocampus of two mouse strains: effects of stress. AB - Immunological activation may result in the development of depressive-like symptoms in a large percentage of patients treated with cytokine-based therapies. The mechanisms underlying susceptibility to cytokine-induced depression are currently unknown; however activation of the tryptophan catabolising enzyme indoleamine 2,3-dioxygenase (IDO) is associated with the induction of cytokine induced depression. Peripheral administration of lipopolysaccharide (LPS) is one of the most commonly used immunological challenges in animal models of cytokine induced depression. Inbred mouse strains are useful tools in the investigation of the neurobiology of psychiatric illnesses. In this study we hypothesised that two strains which differ in stress susceptibility, namely the BALB/c and C57BL/6J mice, would respond differentially to LPS and swim-stress in cytokine profile, corticosterone concentrations and mRNA expression of genes coding for the tryptophan metabolising enzymes, IDO1, IDO2, Tph1 and Tph2. The stress-sensitive BALB/c strain exhibited increased depressive-like behaviour and enhanced corticosterone concentrations in response to LPS. Furthermore, swim-stress attenuated the LPS-induced corticosterone response in BALB/c mice only. LPS significantly increased plasma interleukin (IL)-1beta and tumour necrosis factor alpha (TNFalpha) concentrations to a greater extent in BALB/c mice. The LPS induced increase in IL-1beta mRNA expression was significantly attenuated by swim stress in the hippocampus of C57BL/6J but not in BALB/c mice. TNFalpha mRNA expression was significantly increased in BALB/c mice only; this increase was attenuated by swim-stress. Tph1 mRNA expression was upregulated in the brainstem of C57BL/6J mice post-LPS and following the combination of swim-stress and LPS in BALB/c mice. In the hippocampus Tph1 and Tph2 mRNA expression was increased in C57BL/6J but not BALB/c mice in response to LPS challenge and swim-stress. Conversely, IDO2 but not IDO1 mRNA expression was significantly altered following swim-stress and LPS, particularly in the hippocampus of BALB/c mice. These data indicate altered central mRNA expression of tryptophan metabolising enzymes and immune activation in BALB/c mice compared to the normo-sensitive C57BL/6J strain. PMID- 22917615 TI - Anterior thalamic nuclei lesions in rats disrupt markers of neural plasticity in distal limbic brain regions. AB - In two related experiments, neurotoxic lesions were placed in the anterior thalamic nuclei of adult rats. The rats were then trained on behavioral tasks, immediately followed by the immunohistochemical measurement of molecules linked to neural plasticity. These measurements were made in limbic sites including the retrosplenial cortex, the hippocampal formation, and parahippocampal areas. In Experiment 1, rats with unilateral anterior thalamic lesions explored either novel or familiar objects prior to analysis of the immediate-early gene zif268. The lesions reduced zif268 activity in the granular retrosplenial cortex and postsubiculum. Exploring novel objects resulted in local changes of hippocampal zif268, but this change was not moderated by anterior thalamic lesions. In Experiment 2, rats that had received either bilateral anterior thalamic lesions or control surgeries were exposed to novel room cues while running in the arms of a radial maze. In addition to zif268, measurements of c-AMP response element binding protein (CREB), phosphorylated CREB (pCREB), and growth associated protein43 (GAP-43) were made. As before, anterior thalamic lesions reduced zif268 in retrosplenial cortex and postsubiculum, but there were also reductions of pCREB in granular retrosplenial cortex. Again, the hippocampus did not show lesion-induced changes in zif268, but there were differential effects on CREB and pCREB consistent with reduced levels of hippocampal CREB phosphorylation following anterior thalamic damage. No changes in GAP-43 were detected. The results not only point to changes in several limbic sites (retrosplenial cortex and hippocampus) following anterior thalamic damage, but also indicate that these changes include decreased levels of pCREB. As pCREB is required for neuronal plasticity, partly because of its regulation of immediate early-gene expression, the present findings reinforce the concept of an 'extended hippocampal system' in which hippocampal function is dependent on distal sites such as the anterior thalamic nuclei. PMID- 22917617 TI - Essential role of brain-derived neurotrophic factor in the regulation of serotonin transmission in the basolateral amygdala. AB - Human and animal model studies have linked brain-derived neurotrophic factor (BDNF) with the etiology of anxiety disorders. This pleiotropic neurotrophin and its receptor, TrkB, promote neuronal survival, differentiation and synaptic plasticity. Here we interrogated the role of BDNF in serotonergic neurotransmission in the basolateral amygdala (BLA), a limbic brain region associated with the neurobiology of anxiety. We found that both GABAergic and pyramidal projection neurons in the wild-type BLA contained TrkB receptors. Examination of BDNF(2L/2LCk-Cre) mutant mice with brain-selective depletion of BDNF revealed mild decreases in serotonin content in the BLA. Notably, whole cell recordings in BLA pyramidal cells uncovered significant alterations in 5-HT(2) mediated regulation of GABAergic and glutamatergic transmission in BDNF(2L/2LCk Cre) mutant mice that result in a hyperexcitable circuit. These changes were associated with decreased expression of 5-HT(2) receptors. Collectively, the results indicate a required role of BDNF in serotonin transmission in the BLA. Furthermore, they suggest a mechanism underlying the reported increase in anxiety like behavior elicited by perturbed BDNF signaling. PMID- 22917618 TI - Role of sensory input distribution and intrinsic connectivity in lateral amygdala during auditory fear conditioning: a computational study. AB - We propose a novel reduced-order neuronal network modeling framework that includes an enhanced firing rate model and a corresponding synaptic calcium-based synaptic learning rule. Specifically, we propose enhancements to the Wilson-Cowan firing-rate neuron model that permit full spike-frequency adaptation seen in biological lateral amygdala (LA) neurons, while being sufficiently general to accommodate other spike-frequency patterns. We also report a technique to incorporate calcium-dependent plasticity in the synapses of the network using a regression scheme to link firing rate to postsynaptic calcium. Together, the single-cell model and the synaptic learning scheme constitute a general framework to develop computationally efficient neuronal networks that employ biologically realistic synaptic learning. The reduced-order modeling framework was validated using a previously reported biophysical conductance-based neuronal network model of a rodent LA that modeled features of Pavlovian conditioning and extinction of auditory fear (Li et al., 2009). The framework was then used to develop a larger LA network model to investigate the roles of tone and shock distributions and of intrinsic connectivity in auditory fear learning. The model suggested combinations of tone and shock densities that would provide experimental estimates of tone responsive and conditioned cell proportions. Furthermore, it provided several insights including how intrinsic connectivity might help distribute sensory inputs to produce conditioned responses in cells that do not directly receive both tone and shock inputs, and how a balance between potentiation of excitation and inhibition prevents stimulus generalization during fear learning. PMID- 22917619 TI - Treadmill training stimulates brain-derived neurotrophic factor mRNA expression in motor neurons of the lumbar spinal cord in spinally transected rats. AB - Brain-derived neurotrophic factor (BDNF) induces plasticity within the lumbar spinal circuits thereby improving locomotor recovery in spinal cord-injured animals. We examined whether lumbar spinal cord motor neurons and other ventral horn cells of spinally transected (ST) rats were stimulated to produce BDNF mRNA in response to treadmill training. Rats received complete spinal cord transections as neonates (n=20) and one month later, received four weeks of either a low (100 steps/training session; n=10) or high (1000 steps/training session; n=10) amount of robotic-assisted treadmill training. Using combined non radioactive in situ hybridization and immunohistochemical techniques, we found BDNF mRNA expression in heat shock protein 27-labeled motor neurons and in non motor neuron cells was greater after 1000 steps/training session compared to the 100 steps/training session and was similar to BDNF mRNA labeling in untrained Intact rats. In addition, there were significantly more motor neurons that contained BDNF mRNA labeling within processes in the ST rats that received the higher amount of treadmill training. These findings suggested that motor neurons and other ventral horn cells in ST rats synthesized BDNF in response to treadmill training. The findings support a mechanism by which postsynaptic release of BDNF from motor neurons contributed to synaptic plasticity. PMID- 22917620 TI - Cholesterol epoxide hydrolase and cancer. AB - Cholesterol epoxide hydrolase (ChEH) catalyzes the hydration of cholesterol-5,6 epoxides (5,6-EC) into cholestane-3beta,5alpha,6beta-triol. ChEH is a hetero oligomeric complex called the anti-estrogen binding site (AEBS) comprising 3beta hydroxysterol-Delta(8)-Delta(7)-isomerase (D8D7I) and 3beta-hydroxysterol Delta(7)-reductase (DHCR7). D8D7I and DHCR7 regulate cholesterol biosynthesis, fetal development and growth, tumor cell differentiation and death. The un reactivity of 5,6-EC toward nucleophiles has recently been demonstrated indicating that 5,6-EC are not alkylating and carcinogenic agents as first postulated. Here we discuss recent advances in the molecular characterization of ChEH, its potential role in cancer progression and resistance as well as the interest of inhibiting ChEH and to accumulate 5,6-EC which may contribute to the anti-tumor and chemopreventive action of ChEH inhibitors used in the clinic such as tamoxifen. PMID- 22917621 TI - The influence of puberty on stress reactivity and forebrain glucocorticoid receptor levels in inbred and outbred strains of male and female mice. AB - OBJECTIVE: To examine stress-induced corticosterone responses and forebrain glucocorticoid receptor (GR) levels in prepubertal and adult, male and female mice of three commonly used inbred (C57BL/6, BALB/c) and outbred (Swiss Webster) strains. METHODS: Prepubertal (30 days of age) and adult (75 days of age), male and female C57BL/6, BALB/c, and Swiss Webster mice were exposed to a 30 min session of restraint stress. Plasma corticosterone was measured before (basal), or 0, 30, or 60 min after termination of the stressor. GR protein levels of the medial prefrontal cortex, paraventricular nucleus of the hypothalamus, and hippocampus were also measured via tissue punches and western blots in the prepubertal and adult males and females at the basal time point. RESULTS: In response to acute stress, prepubertal males of both inbred strains showed greater hormonal responsiveness than their adult counterparts, while females of these strains displayed similar stress-induced corticosterone responses, independent of age. Conversely, only the females of the outbred Swiss Webster strain showed pubertal-related changes, with adult females showing greater hormonal reactivity compared to prepubertal females. Despite these significant differences in hormonal reactivity, we found little difference in GR protein levels in the brain regions examined. CONCLUSIONS: These data indicate that pubertal-dependent differences in stress reactivity can be significantly influenced by sex and genetic background. Moreover, these data provide points of departure for future studies investigating how puberty, sex, and genetic background interact to shape both short- and long-term effects of stress on mental and physical health. PMID- 22917622 TI - Examining the role of endogenous orexins in hypothalamus-pituitary-adrenal axis endocrine function using transient dual orexin receptor antagonism in the rat. AB - The orexin neuropeptide system regulates wakefulness and contributes to physiological and behavioral stress responses. Moreover, a role for orexins in modulating hypothalamus-pituitary-adrenal (HPA) axis activity has been proposed. Brain penetrating dual orexin receptor (OXR) antagonists such as almorexant decrease vigilance and have emerged as a novel therapeutic class for the treatment of insomnia. Almorexant was used here as a pharmacological tool to examine the role of endogenous orexin signaling in HPA axis endocrine function under natural conditions. After confirming the expression of prepro-orexin and OXR-1 and OXR-2 mRNA in hypothalamus, pituitary and adrenal glands, the effects of systemic almorexant were investigated on peripheral HPA axis hormone release in the rat under baseline, stress and pharmacological challenge conditions. Almorexant did not alter basal or stress-induced corticosterone release despite affecting wake and sleep stages (detected by radiotelemetric electroencephalography/electromyography) during the stress exposure. Moreover, almorexant did not affect the release of adrenocorticotropin (ACTH) and corticosterone at different time points along the diurnal rhythm, nor corticotrophin-releasing hormone (CRH)- and ACTH-stimulated neuroendocrine responses, measured in vivo under stress-free conditions. These results illustrate that dual OXR antagonists, despite modulating stress-induced wakefulness, do not interfere with endocrine HPA axis function in the rat. They converge to suggest that endogenous orexin signaling plays a minor role in stress hormone release under basal conditions and under challenge. PMID- 22917624 TI - Evidence for utilitarian motives in emotion regulation. AB - This investigation demonstrates that emotion regulation can be driven by considerations of utility per se. We show that as participants prepared for a negotiation, those who were motivated to confront (vs. collaborate with) another person believed that anger would be more useful to them. However, only participants who were motivated to confront another and expected to receive a monetary reward for their performance (i.e., high utility), were motivated to increase their anger in preparation for the negotiation. Participants who were motivated to confront another but did not expect their performance to be rewarded (i.e., low utility), did not try to increase their anger, even though they expected anger to be useful in the negotiation. Such patterns demonstrate that people are motivated to experience even unpleasant emotions to maximise utility. PMID- 22917623 TI - Incentive processing in Congenital Adrenal Hyperplasia (CAH): a reward-based antisaccade study. AB - Little is known about how steroid hormones contribute to the beneficial effect of incentives on cognitive control during adolescent development. In this study, 27 adolescents with Congenital Adrenal Hyperplasia (CAH, mean age 15.6 years, 12 female), a disorder of cortisol deficiency and androgen excess, and 36 healthy participants (mean age 16.3 years, 18 female) completed a reward-based antisaccade task. In this mixed-saccade task, participants performed eye movements towards (prosaccades) or away (antisaccades) from a peripherally occuring stimulus. On incentive trials, monetary reward was provided for correct performance, while no such reward was provided on no-incentive trials. Consistent with the hypothesis, the results showed that healthy, but not CAH adolescents, significantly improved their inhibitory control (antisaccade accuracy) during incentive trials relative to no-incentive trials. These findings were not driven by severity of CAH (salt wasters vs. simple virilizers), individual hormone levels, sex, age-at-diagnosis, or medication type (dexamethasone vs. hydrocortisone). In addition, no significant differences between groups were found on orienting responses (prosaccades). Additional analyses revealed an impact of glucocorticoid (GC) dosage, such that higher GC dose predicted better antisaccade performance. However, this effect did not impact incentive processing. The data are discussed within the context of steroid hormone mediated effects on cognitive control and reward processing. PMID- 22917625 TI - Mirror gait retraining for the treatment of patellofemoral pain in female runners. AB - BACKGROUND: Abnormal hip mechanics are often implicated in female runners with patellofemoral pain. We sought to evaluate a simple gait retraining technique, using a full-length mirror, in female runners with patellofemoral pain and abnormal hip mechanics. Transfer of the new motor skill to the untrained tasks of single leg squat and step descent was also evaluated. METHODS: Ten female runners with patellofemoral pain completed 8 sessions of mirror and verbal feedback on their lower extremity alignment during treadmill running. During the last 4 sessions, mirror and verbal feedback were progressively removed. Hip mechanics were assessed during running gait, a single leg squat and a step descent, both pre- and post-retraining. Subjects returned to their normal running routines and analyses were repeated at 1-month and 3-month post-retraining. Data were analyzed via repeated measures analysis of variance. FINDINGS: Subjects reduced peaks of hip adduction, contralateral pelvic drop, and hip abduction moment during running (P<0.05, effect size=0.69-2.91). Skill transfer to single leg squatting and step descent was noted (P<0.05, effect size=0.91-1.35). At 1 and 3 months post retraining, most mechanics were maintained in the absence of continued feedback. Subjects reported improvements in pain and function (P<0.05, effect size=3.81 7.61) and maintained through 3 months post retraining. INTERPRETATION: Mirror gait retraining was effective in improving mechanics and measures of pain and function. Skill transfer to the untrained tasks of squatting and step descent indicated that a higher level of motor learning had occurred. Extended follow-up is needed to determine the long term efficacy of this treatment. PMID- 22917627 TI - Acetyl salicylic acid induces damage to intestinal epithelial cells by oxidation related modifications of ZO-1. AB - Acetyl salicylic acid (ASA) is one of the most frequently prescribed medications for the secondary prevention of cardiovascular and cerebrovascular events. It has recently been reported to cause small intestinal mucosal injury at a considerably higher rate than previously believed. The aim of this study is to investigate the mechanism by which this occurs using an in vitro small intestine model focusing on the role of oxidative stress and cell permeability. Differentiated Caco-2 exhibits a phenotype similar to human small intestinal epithelium. We measured whether ASA induced the increase of differentiated Caco-2 permeability, the decrease of tight junction protein expression, the production of reactive oxygen species (ROS), and the expression of ROS-modified zonula occludens-1 (ZO-1) protein. In some experiments, Mn(III) tetrakis(1-methyl-4-pyridyl)porphyrin (MnTMPyP, a superoxide dismutase mimetic) was used. The nontoxic concentration of ASA decreased transepithelial electrical resistance and increased the flux of fluorescein isothiocyanate-conjugated dextran across Caco-2 in a time-dependent manner. The same concentration of ASA significantly decreased ZO-1 expression among TJ proteins as assessed by Western blot and immunocytochemistry and increased ROS production and the expression of oxidative stress-modified ZO-1 protein. However, MnTMPyP suppressed the ASA-induced increased intercellular permeability and the ASA-induced ROS-modified ZO-1 expression. Our findings indicate that ASA-induced ROS production can specifically modify the expression of ZO-1 protein and induce increased cell permeability, which may ultimately cause small intestinal mucosal injury. PMID- 22917626 TI - Biomechanical variables related to walking performance 6-months following post stroke rehabilitation. AB - BACKGROUND: Body-weight supported treadmill training has been shown to be effective in improving walking speed in post-stroke hemiparetic subjects, and those that have shown improvements generally maintain them after the completion of rehabilitation. However, currently no biomechanical variables are known to be related to those who will either continue to improve or regress in their self selected walking speed during the 6-month period following rehabilitation. The objective of this study was to identify those biomechanical variables that are associated with subjects who continue (or did not continue) to improve their self selected walking speed following the completion of rehabilitation. METHODS: Experimental kinematic and kinetic data were recorded from 18 hemiparetic subjects who participated in a 6-month follow-up study after completing a 12-week locomotor training program that included stepping on a treadmill with partial body weight support and manual assistance. Pearson correlation coefficients were used to determine which biomechanical variables evaluated during the post training session were related to changes in self-selected walking speed from post training to a 6-month follow-up session. FINDINGS: Following the completion of rehabilitation, the majority of subjects increased or retained (i.e., did not change) their self-selected walking speed from post-training to the follow-up session. Post-training step length symmetry and daily step activity were positively related to walking speed improvements. INTERPRETATION: Motor control deficits that lead to persistent step length asymmetry and low daily step activity at the end of rehabilitation are associated with poorer outcomes six months after completion of the program. PMID- 22917628 TI - Effects of Hange-shashin-to (TJ-14) and Keishi-ka-shakuyaku-to (TJ-60) on contractile activity of circular smooth muscle of the rat distal colon. AB - The Japanese Kampo medicines Hange-shashin-to (TJ-14) and Keishi-ka-shakuyaku-to (TJ-60) have been used to treat symptoms of human diarrhea on an empirical basis as Japanese traditional medicines. However, it remains unclear how these drugs affect smooth muscle tissues in the distal colon. The aim of the present study was to investigate the effects of TJ-14 and TJ-60 on the contractile activity of circular smooth muscle from the rat distal colon. TJ-14 and TJ-60 (both 1 mg/ml) inhibited spontaneous contractions of circumferentially cut preparations with the mucosa intact. Blockade of nitric oxide (NO) synthase or soluble guanylate cyclase activity abolished the inhibitory effects of TJ-60 but only attenuated the inhibitory effects of TJ-14. Apamin (1 MUM), a blocker of small-conductance Ca(2+)-activated K(+) channels (SK channels), attenuated the inhibitory effects of 5 mg/ml TJ-60 but not those of 5 mg/ml TJ-14. TJ-14 suppressed contractile responses (phasic contractions and off-contractions) evoked by transmural nerve stimulation and increased basal tone, whereas TJ-60 had little effect on these parameters. These results suggest that 1 mg/ml TJ-14 or TJ-60 likely inhibits spontaneous contractions of the rat distal colon through the production of NO. Activation of SK channels seems to be involved in the inhibitory effects of 5 mg/ml TJ-60. Since TJ-14 has potent inhibitory effects on myogenic and neurogenic contractile activity, TJ-14 may be useful in suppressing gastrointestinal motility. PMID- 22917629 TI - Mechanism and regulation of vitamin B2 (riboflavin) uptake by mouse and human pancreatic beta-cells/islets: physiological and molecular aspects. AB - Riboflavin (RF) is essential for the normal metabolic activities of pancreatic beta-cells and provides protection against oxidative stress. Very little is known about the mechanism of RF uptake by these cells and how the process is regulated. We addressed these issues using mouse-derived pancreatic beta-TC-6 cells and freshly isolated primary mouse and human pancreatic islets. Our results showed (3)H-RF uptake by beta-TC-6 cells is Na(+) independent, cis inhibited by RF related compounds, trans stimulated by unlabeled RF, and saturable as a function of concentration (apparent K(m) of 0.17 +/- 0.02 MUM). The latter findings suggest involvement of a carrier-mediated process. Similarly, RF uptake by primary mouse and human pancreatic islets was via carrier-mediated process. RF transporters 1, 2, and 3 (RFVT-1, -3, and -2) were all expressed in mouse and human pancreatic beta-cells/islets, with RFVT-1 being the predominant transporter expressed in the mouse and RFVT-3 in the human. Specific knockdown of RFVT-1 with gene-specific small interfering RNA leads to a significant inhibition in RF uptake by beta-TC-6 cells. RF uptake by beta-TC-6 cells was also found to be adaptively upregulated in RF deficiency via a transcriptional mechanism(s). Also, the process appears to be under the regulation of a Ca(2+)/calmodulin-mediated regulatory pathway. Results of these studies demonstrate, for the first time, the involvement of a carrier-mediated process for RF uptake by mouse and human pancreatic beta-cells/islets. Furthermore, the process appears to be regulated by extracellular and intracellular factors. PMID- 22917631 TI - Formation of tubules by p-tert-butylphenylamide derivatives of chenodeoxycholic and ursodeoxycholic acids in aqueous solution. AB - The formation of tubules by p-tert-butylphenylamide derivatives of chenodeoxycholic and ursodeoxycholic acids in aqueous solution is investigated. The critical aggregation concentrations of the new surfactants are much lower than those of ursodeoxycholate and chenodeoxycholate, indicating the enhanced surfactant properties resulting by the presence of the hydrophobic p-tert butylphenyl group. The molecular areas at the air-water interface suggest the formation of monolayer films with molecules upright oriented. The shape of the aggregates was investigated by TEM. The main structure present in solution corresponds to tubules. The estimated value for the wall thickness of tubules suggests that a bilayer structure is formed. Host of positively charged latex beads by tubules suggests that their inner and outer surfaces are negatively charged. The acid form of the chenodeoxycholate derivative was recrystallized from toluene and its crystal structure analyzed. PMID- 22917630 TI - Loss of MLK3 signaling impedes ulcer healing by modulating MAPK signaling in mouse intestinal mucosa. AB - Mixed-lineage kinase 3 (MLK3) activates multiple MAPK pathways and can initiate apoptosis, proliferation, migration, or differentiation in different cell types. However, whether MLK3 signaling regulates intestinal epithelial cell sheet migration in vivo is not known. We sought to investigate whether MLK3 signaling is important in intestinal mucosal healing and epithelial cell motility in vivo and in vitro. In vivo, we compared the healing of jejunal mucosal ulcers induced in MLK3 knockout (KO) mice with healing in wild-type (WT) mice. Ulcer healing was 20.8% less at day 3 (P < 0.05) and 18.9% less at day 5 (P < 0.05) in MLK3 KO than WT mice. Within the intestinal mucosa of MLK3 KO mice, ERK and JNK signaling were reduced, phosphatase and tensin homolog deleted on chromosome 10 (PTEN) level was increased, and p38 signaling was unchanged. Parallel in vitro studies using an MLK inhibitor assessed the role of MLK signaling in human Caco-2 intestinal epithelial migration across collagen substrates. The MLK inhibitor reduced closure of circular wounds in Caco-2 monolayers. MLK inhibition reduced ERK and JNK, but not p38, signaling in Caco-2 cells. Although PTEN is increased after MLK inhibition, it does not influence MLK-mediated cell migration. These findings indicate that disruption of MLK3 signaling impairs ulcer healing by suppressing ERK and JNK signaling in vitro and in mouse intestinal mucosa in vivo. These results reveal a novel role for MLK3 signaling in the regulation of intestinal epithelial migration in vivo and suggest that MLK3 may be an important target for the regulation of intestinal mucosal healing. PMID- 22917632 TI - Changes in steroid hormones during an international powerlifting competition. AB - The purpose of this study was to assess changes in the steroid hormone levels of elite athletes during an international powerlifting competition. Baseline cortisol, DHEA and testosterone were determined in saliva samples in 19 (8 men, 11 women) junior and sub-junior athletes on the day before competition, and then on the competition day during the official weighing and in the hour after competition. Performance was determined by total output and the Wilks formula. No change in saliva steroid concentrations was observed between samples collected on the day before competition and the weighing samples. There was no gender effect on cortisol concentrations but saliva testosterone levels were always significantly higher in men than in women (p<0.01), as was end-competition DHEA (p<0.05). Cortisol and DHEA were significantly increased in male and female athletes after the competition (respectively, p<0.01 and p<0.05), whereas end competition testosterone concentrations were only significantly increased in men (p<0.01). Significant relationships were demonstrated between performance and end competition cortisol levels in women and end-competition testosterone levels in men. These data indicate that workouts during an international powerlifting competition produce a significant increase in adrenal steroid hormones in both genders, with an increase in male gonadal steroid hormone. Further studies are necessary to examine the changes in oestradiol and progesterone in women and their potential impact on performance during international powerlifting competition. PMID- 22917633 TI - Biotransformation of 21-O-acetyl-deoxycorticosterone by cell suspension cultures of Digitalis lanata (strain W.1.4). AB - Cell cultures of Digitalis species are known to accept exogenous substrates for biotransformation reactions. We here report the biotransformation of 21-O-acetyl deoxycorticosterone (1) by cell suspension cultures of Digitalis lanata strain W.1.4. Nine derivatives of 1 were obtained and their chemical structures determined by spectroscopic methods. 2beta-Hydroxylation and C-21-glucosylation of the steroidal nucleus were described for the first time in suspension-cultured plant cells. Steroid 5alpha- and 5beta-reduction products were also observed. Among the compounds isolated and structures elucidated were 2beta,3beta,21 trihydroxy-4-pregnen-20-one, 2beta,3alpha,21-trihydroxy-4-pregnen-20-one and 3beta,21-dihydroxy-5alpha-pregnan-20-one-3beta-O-beta-glucoside. PMID- 22917634 TI - Estradiol receptors in breast cancer cells: associated co-factors as targets for new therapeutic approaches. AB - Estrogen receptors alpha (ERalpha) and beta (ERbeta) are nuclear receptors which transduce estradiol (E2) response in many tissues including the mammary gland and breast cancers (BC). They activate or inhibit specific genes involved in cell cycle progression and cell survival through multiple enzyme activities leading to malignant transformation. Hormone therapy (antiestrogens (AEs) and aromatase inhibitors (AIs) have been widely used to block the mitogenic action of E2 in patients with ER-positive BC. ERs act in concert with numerous other proteins outside and inside the nucleus where co-activators such as histone modifying enzymes help reaching optimum gene activation. Moreover, E2-mediated gene regulation can occur through ERs located at the plasma membrane or G protein coupled estrogen receptor (GPER), triggering protein kinase signaling cascades. Classical AEs as well as AIs are inefficient to block the cascades of events emanating from the membrane and from E2 binding to GPER, leading patients to escape anti-hormone treatments and hormone therapy resistance. Many pathways are involved in resistance, mostly resulting from over-expression of growth factor membrane receptors, in particular the HER2/ErbB2 which can be inhibited by specific antibodies or tyrosine kinases inhibitors. Together with the Hsp90 molecular chaperone machinery, a complex interplay between ERs, co-activators, co repressors and growth factor-activated membrane pathways represents potent targets which warrant to be manipulated alone and in combination to designing novel therapies. The discovery of new potential targets arising from micro array studies gives the opportunity to activate or inhibit different new ER-modulating effectors for innovative therapeutic interventions. PMID- 22917635 TI - Comment on "atorvastatin improves disease activity of nonalcoholic steatohepatitis partly through its tumour necrosis factor-alpha-lowering property". PMID- 22917636 TI - A new low-volume isosmotic polyethylene glycol solution plus bisacodyl versus split-dose 4 L polyethylene glycol for bowel cleansing prior to colonoscopy: a randomised controlled trial. AB - BACKGROUND: 4-L polyethylene glycol preparations are effective for colon cleansing before colonoscopy. However, large volume and unpleasant taste reduce tolerability and acceptability limiting patient compliance. A new isosmotic low volume polyethylene glycol preparation with citrates and simethicone plus bisacodyl has been developed to improve patient compliance and tolerability. AIM: To compare the efficacy of 2 different regimens of preparation vs a split-dose of polyethylene glycol solution. PATIENTS AND METHODS: In this randomised, blinded, comparative study, 153 patients were allocated to 3 arms. Arm 1 (n=52) received bisacodyl and 2-L polyethylene glycol with citrates and simethicone the day before the procedure. Arm 2 (n=50) received bisacodyl the day before and 2-L polyethylene glycol with citrates and simethicone on the day of colonoscopy. Control group (n=51) received a split-dose of 4-L polyethylene glycol. Cleansing was evaluated according to Ottawa scale. RESULTS: The mean Ottawa score was not different in the 3 groups. Excellent cleansing was observed more frequently in arm 2 (70%) than in controls (49%) (p<0.05). No serious adverse events were observed in the 3 regimens. The willingness to repeat the same bowel preparation was superior in arms 1 and 2 than in controls (p<0.001). CONCLUSIONS: New low volume preparations seem to be as effective as the split 4-L polyethylene glycol regimen, showing a better tolerability and acceptability. PMID- 22917638 TI - The current state of Indigenous and Aboriginal women with diabetes in pregnancy: a systematic review. AB - To undertake a systematic review of diabetes in pregnancy (DIP), determining prevalence and impact on maternal and child health outcomes for Indigenous and Aboriginal women. METHOD: Electronic searches of MEDLINE, Embase, CINAHL, ERIC, DARE, CDSR, PsycINFO, Austhealth and HealthInfoNet were undertaken. Changes in diagnostic criteria for DIP and variability in methodology meant a qualitative synthesis of the data was undertaken. RESULTS: From the 142 potential studies, 42 peer reviewed journal articles met the inclusion criteria. GDM prevalence in 65% of studies was greater for Indigenous and Aboriginal women than the comparison groups; Pacific Islander 8.1%, Canadian Aboriginal 11.5%, American Indian 7.9%, Australian Aboriginal 8.4% compared with 2-5% worldwide. Of studies reporting high birth weight (>4000 g) and DIP, 75% had a higher than expected prevalence, 86% had higher macrosomia prevalence and 63% had higher stillbirth rates. Studies with Alaskan, Australian Aboriginal and Pacific Islander women had GDM prevalence both greater and less than comparison groups. CONCLUSION: Correcting the health disparity for Indigenous and Aboriginal women with DIP is a health priority. DIP prevalence is not the same for all Indigenous and Aboriginal women. Inconsistent study design without robust data is interfering with accurate prevalence of DIP. New international consensus guidelines provide opportunities for high quality studies of DIP for Indigenous and Aboriginal women. PMID- 22917637 TI - Catalytic activities of a cocaine hydrolase engineered from human butyrylcholinesterase against (+)- and (-)-cocaine. AB - It can be argued that an ideal anti-cocaine medication would be one that accelerates cocaine metabolism producing biologically inactive metabolites via a route similar to the primary cocaine-metabolizing pathway, i.e., hydrolysis catalyzed by butyrylcholinesterase (BChE) in plasma. However, wild-type BChE has a low catalytic efficiency against naturally occurring (-)-cocaine. Interestingly, wild-type BChE has a much higher catalytic activity against unnatural (+)-cocaine. According to available positron emission tomography (PET) imaging analysis using [(11)C](-)-cocaine and [(11)C](+)-cocaine tracers in human subjects, only [(11)C](-)-cocaine was observed in the brain, whereas no significant [(11)C](+)-cocaine signal was observed in the brain. The available PET data imply that an effective therapeutic enzyme for treatment of cocaine abuse could be an exogenous cocaine-metabolizing enzyme with a catalytic activity against (-)-cocaine comparable to that of wild-type BChE against (+)-cocaine. Our recently designed A199S/F227A/S287G/A328 W/Y332G mutant of human BChE has a considerably improved catalytic efficiency against (-)-cocaine and has been proven active in vivo. In the present study, we have characterized the catalytic activities of wild-type BChE and the A199S/F227A/S287G/A328 W/Y332G mutant against both (+)- and (-)-cocaine at the same time under the same experimental conditions. Based on the obtained kinetic data, the A199S/F227A/S287G/A328 W/Y332G mutant has a similarly high catalytic efficiency (kcat/KM) against (+)- and (-)-cocaine, and indeed has a catalytic efficiency (k(cat/)K(M) = 1.84 * 10(9) M(-1) min(-1)) against (-)-cocaine comparable to that (k(cat)/K(M) = 1.37 * 10(9) M(-1) min(-1)) of wild-type BChE against (+)-cocaine. Thus, the mutant may be used to effectively prevent (-)-cocaine from entering brain and producing physiological effects in the enzyme-based treatment of cocaine abuse. PMID- 22917639 TI - Diabetes as a case study of chronic disease management with a personalized approach: the role of a structured feedback loop. AB - As non-communicable or chronic diseases are a growing threat to human health and economic growth, political stakeholders are aiming to identify options for improved response to the challenges of prevention and management of non communicable diseases. This paper is intended to contribute ideas on personalized chronic disease management which are based on experience with one major chronic disease, namely diabetes mellitus. Diabetes provides a pertinent case of chronic disease management with a particular focus on patient self-management. Despite advances in diabetes therapy, many people with diabetes still fail to achieve treatment targets thus remaining at risk of complications. Personalizing the management of diabetes according to the patient's individual profile can help in improving therapy adherence and treatment outcomes. This paper suggests using a six-step cycle for personalized diabetes (self-)management and collaborative use of structured blood glucose data. E-health solutions can be used to improve process efficiencies and allow remote access. Decision support tools and algorithms can help doctors in making therapeutic decisions based on individual patient profiles. Available evidence about the effectiveness of the cycle's constituting elements justifies expectations that the diabetes management cycle as a whole can generate medical and economic benefit. PMID- 22917640 TI - Pharmacokinetics of free mycophenolic acid and limited sampling strategy for the estimation of area under the curve in liver transplant patients. AB - Mycophenolate Mofetil (MMF) is widely used in preventing acute rejection in liver transplantation. Only free MPA (fMPA) can exert the pharmacological effect. In this study, we aimed to develop the new model which could be best fit to predict the fMPA area under the plasma concentration-time curve (AUC) by limited sampling strategy (LSS) in Chinese liver transplant patients. Fifty patients received MMF with the combination of tacrolimus. Free MPA concentrations were determined around day 7. Optimal subset regression analysis was used to establish the models for estimated fMPA AUC(0-12h). Three excellent better models were validated by Bootstrap analysis. Twenty-four models including four blood time point samplings were established. For the selected four models, 100% were successful and were not significantly different from the original dataset by Bootstrap analysis. The best model for prediction of fMPA AUC(0-12h) was by using C(1h), C(2h), C(4h) and C(6h). This model showed the minimal mean prediction error and the minimal mean absolute prediction error. In conclusion, the models for estimation of the fMPA AUC(0-12h) were established in liver transplant recipients and the best model for prediction of fMPA AUC was: estimated fMPA AUC=34.2+1.12C(1h)+1.29C(2h)+2.28C(4h)+3.95C(6h). PMID- 22917641 TI - Nanosponge-encapsulated camptothecin exerts anti-tumor activity in human prostate cancer cells. AB - Camptothecin (CPT) is a potent DNA Topoisomerase I inhibitor with anti-tumor activity in hematological and solid tumors. However, it did not reach clinical use because of its poor solubility and high degrability. beta-Cyclodextrin nanosponge (CN) have been demonstrated to be able to increase the solubility of lipophilic compounds and to protect them from degradation. In the present study, we evaluated whether beta-Cyclodextrin nanosponge carriers can overcome CPT chemical disadvantages and improve the in vitro anti-tumor efficacy in the androgen refractory models of prostate cancer DU145 and PC-3 and the androgen sensitive model LNCaP. Camptothecin-loaded beta-Cyclodextrin nanosponge (CN-CPT) showed sizes of about 400 nm, spherical shape and a drug loading of 38%. HPLC analysis, performed on the cell pellet after treatment with CN-CPT revealed that CPT concentration increased over time indicating a prolonged release of the drug. Moreover, CN-CPT inhibited Topoisomerase I activity, and induced DNA damage, and cell cycle arrest more effectively than CPT, indicating that the CN-CPT formulation does not affect activity of the drug. Moreover, Annexin V/Propidium Iodide staining showed an induction of cell death at low concentrations that were not effective for CTP. LNCaP cells were less sensitive to CPT than PC-3 and DU145 cells, but CN-CPT still exerted higher anti-proliferative activity and DNA damage ability than CPT. The experiments performed in LNCaP cells demonstrated that CN CPT treatment inhibited expression of the androgen receptor at doses where CPT was ineffective. Our results demonstrated the higher anti-tumor effectiveness of CN-CPT compare to CPT in prostate cancer cells, supporting the relevance of future studies for the use of the beta-Cyclodextrin nanosponge to deliver anticancer drugs in vivo. PMID- 22917642 TI - Semi-physiologically based pharmacokinetic modeling of paclitaxel metabolism and in silico-based study of the dynamic sensitivities in pathway kinetics. AB - PURPOSE: To build a semi-physiologically based pharmacokinetic model describing the uptake, metabolism and efflux of paclitaxel and its metabolites and investigate the effect of hypothetical genetic polymorphisms causing reduced uptake, metabolism or efflux in the pathway by model simulation and sensitivity analysis. METHODS: A previously described intracellular pharmacokinetic model was used as a starting point for model development. Kinetics for metabolism, transport, binding and systemic and output compartments were added to mimic a physiological model with hepatic elimination. Model parameters were calibrated using constraints postulated as ratios of concentrations and amounts of metabolites and drug in the systemic plasma and output compartments. The sensitivity in kinetic parameters was tested using dynamic sensitivity analysis. RESULTS: Predicted plasma concentrations of drug and metabolites were in the range of what has been observed in clinical studies. Given the final model, plasma concentrations of paclitaxel seems to be relatively little affected by changes in metabolism or transport, while its main metabolite may be largely affected even by small changes. If metabolites prove to be clinically relevant, genetic polymorphisms may play an important role for individualizing paclitaxel treatment. PMID- 22917643 TI - A simple and cheap alternative approach to administering continuous positive airway pressure in resource limited settings. AB - Continuous positive airway pressure (CPAP) is a valuable tool in managing infants requiring respiratory support. This article highlights a simple and economical alternative model to administer nasal CPAP using an infant feeding tube. PMID- 22917645 TI - Rectal prolapse in the elderly: trends in surgical management and outcomes from the American College of Surgeons National Surgical Quality Improvement Program database. AB - BACKGROUND: Full thickness rectal prolapse (FTRP) is managed with an abdominal or perineal operation. Traditionally, the approach has been determined by patient age and comorbidities. Our aim was to determine operative trends and outcomes for repair of FTRP in elderly patients using the American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP) database. STUDY DESIGN: We queried the ACS NSQIP database from 2006 to 2009 for patients with FTRP who were 70 years of age or older. Patients were grouped according to type of surgical repair: laparoscopic (LR), open (OR), or perineal (PR) technique. We reviewed demographics, operative trends of surgical technique, and short-term outcomes for each group. RESULTS: A total of 816 patients were analyzed; 596 (73%) PR, 130 (16%) OR, and 90 (11%) LR patients. Patients who received OR and LR had lower mean American Society of Anesthesiologists (ASA) scores than PR patients (2.6, 2.5, and 2.7, respectively, p < 0.001). The percentage of LR and OR procedures decreased as age increased by decade; the inverse was seen for PR (p < 0.001). The distribution of operative techniques has not changed from year to year. Length of stay was significantly shorter for LR (3.77 days) and PR (3.44 days) patients vs OR patients (6.23 days) (p = 0.01). Complication rates were 2.22%, 8.72%, and 12.31% for LR, PR, and OR, respectively (p = 0.021). Open surgery was the only factor associated with an increased complication rate, with an odds ratio of 6.29 (95% CI 1.38 to 28.6, p < 0.02). CONCLUSIONS: Despite the appeal of perineal proctectomy in the elderly and debilitated patient, the approach to FTRP is slowly evolving in the era of laparoscopic surgery. Laparoscopic repair of FTRP in the elderly is associated with improved short-term outcomes when compared with OR and PR. PMID- 22917646 TI - Optimal preoperative assessment of the geriatric surgical patient: a best practices guideline from the American College of Surgeons National Surgical Quality Improvement Program and the American Geriatrics Society. PMID- 22917644 TI - The role of extracellular signal-related kinase during abdominal aortic aneurysm formation. AB - BACKGROUND: It is hypothesized that activation of extracellular signal-related kinase (ERK) is critical in activating matrix metalloproteinases (MMPs) during abdominal aortic aneurysm (AAA) formation. STUDY DESIGN: C57BL/6 male mice underwent either elastase or heat-inactivated elastase aortic perfusion (n = 9 per group). Mouse aortic smooth muscle cells were transfected with ERK-1 and 2 siRNA along with or without elastase treatment. Mouse and human aortic tissue were analyzed by Western blots, zymograms, and immunohistochemistry, and statistical analysis was done using Graphpad and Image J softwares. RESULTS: Western blot and immunohistochemistry documented increased phospho-mitogen activated protein kinase kinase-1/2 (pMEK-1/2; 153%, p = 0.270 by Western) and pERK (171%, p = 0.004 by Western blot) in the elastase perfused aortas. Male ERK 1(-/-) mice underwent elastase perfusion, and aortic diameter was determined at day 14. ERK-1(-/-) mice failed to develop AAA, and histologic analysis depicted intact collagen and elastin fibers in the aortas. Zymography of aortas of elastase-treated ERK-1(-/-) mice showed lower levels of proMMP2 (p < 0.005) and active MMP2 (p < 0.0001), as well as proMMP9 (p = 0.037) compared with C57BL/6 mice. siRNA transfection of ERK-1 and -2 significantly reduced formation of pro- and active MMP2 (p < 0.01 for both isoforms) in aortic smooth muscle cells treated with elastase in vitro. Human AAA tissue had significantly elevated levels of pMEK-1/2 (150%, p = 0.014) and pERK (159%, p = 0.013) compared with control tissues. CONCLUSIONS: The MAPK (mitogen-activated protein kinase)/ERK pathway is an important modulator of MMPs during AAA formation. Targeting the ERK pathway by reagents that inhibit either the expression or phosphorylation of ERK isoforms could be a potential therapy to prevent AAA formation. PMID- 22917647 TI - Intention detection of gait initiation using EMG and kinematic data. AB - Gait initiation in transfemoral amputees (TFA) is different from non-amputees. This is mainly caused by the lack of stability and push-off from the prosthetic leg. Adding control and artificial push-off to the prosthesis may therefore be beneficial to TFA. In this study the feasibility of real-time intention detection of gait initiation was determined by mimicking the TFA situation in non-amputees. EMG and inertial sensor data was measured in 10 non-amputees. Only data available in TFA was used to determine if gait initiation can be predicted in time to control a transfemoral prosthesis to generate push-off and stability. Toe-off and heel-strike of the leading limb are important parameters to be detected, to control a prosthesis and to time push-off. The results show that toe-off and heel strike of the leading limb can be detected using EMG and kinematic data in non amputees 130-260 ms in advance. This leaves enough time to control a prosthesis. Based on these results we hypothesize that similar results can be found in TFA, allowing for adequate control of a prosthesis during gait initiation. PMID- 22917648 TI - Age and Parkinson's disease related kinematic alterations during multi directional gait initiation. AB - Previous literature suggests that older adults and persons with Parkinson's disease (PWP) exhibit impaired performance during gait initiation (GI) and turning while walking. While researchers have identified specific impairments during GI and turning separately in these populations, little is known about when these two tasks occur concurrently. Our objective was to determine how multi directional GI kinematics are affected by aging and Parkinson's disease. Kinematic data were collected on 12 healthy young adults (HYA), 11 healthy older adults (HOA) and 11 PWP during GI in four conditions: forward, medial 45 degrees , lateral 45 degrees , and lateral 90 degrees . Spatiotemporal characteristics and segmental angles were analyzed using separate 3 (group)*4 (condition) mixed ANOVA. Combined across all the conditions, HOA took a smaller (P=0.009) and slower (P=0.023) first step, and slower second step (P=0.021) compared to HYA. PWP took a slower first step (P=0.009), and longer time to initiate the second step (P=0.017) compared to HOA. Also, PWP had greater head rotation at the start of GI during the medial 45 degrees condition (P=0.043) and reduced overall segmental rotation before toe-off of the second step during the lateral 45 degrees condition (P=0.035), and at heel-strike of first step (P=0.031) and before toe-off of second step during lateral 90 degrees condition (P=0.035). For HOA, their general slowness of movement could be attributed to aging effects. For PWP, rigidity and bradykinesia could impair activities of daily living like multi directional GI and may be associated with an increased risk of falls. PMID- 22917649 TI - neo-Clerodane diterpenes from Ajuga decumbens and their inhibitory activities on LPS-induced NO production. AB - A phytochemical investigation of the whole plants of Ajuga decumbens led to the isolation of three new (1, 2a, and 2b) and three known (3a-3c) neo-clerodane diterpenes. Their structures were elucidated by spectroscopic data analysis (IR, ESIMS, HR-ESIMS, 1D and 2D NMR), and the structure of 1 was confirmed by X-ray crystallography. The inhibitory activities on LPS-induced NO production of the six diterpenes were evaluated and compounds 2a, 2b, and 3a showed inhibitory effects. PMID- 22917650 TI - Exploring metabolic pathways that contribute to the stem cell phenotype. AB - BACKGROUND: Stem cells must negotiate their surrounding nutritional and signaling environment and respond accordingly to perform various functions. Metabolic pathways enable these responses, providing energy and biosynthetic precursors for cell proliferation, motility, and other functions. As a result, metabolic enzymes and the molecules which control them are emerging as attractive targets for the manipulation of stem cells. To exploit these targets a detailed characterization of metabolic flux regulation is required. SCOPE OF REVIEW: Here we outline recent advances in our understanding of metabolism in pluripotent stem cells and adult progenitors. We describe the regulation of glycolysis, mitochondrial metabolism, and the redox state of stem cells, highlighting key enzymes and transcription factors involved in the control of these pathways. MAJOR CONCLUSIONS: A general description of stem cell metabolism has emerged, involving increased glycolysis, limited oxidative metabolism, and resistance to oxidative damage. Moving forward, the application of systems-based approaches to stem cells will help shed light on metabolic pathway utilization in proliferating and quiescent stem cells. GENERAL SIGNIFICANCE: Metabolic flux contributes to the unique properties of stem cells and progenitors. This review provides a detailed overview of how stem cells metabolize their surrounding nutrients to proliferate and maintain lineage homeostasis. This article is part of a Special Issue entitled Biochemistry of Stem Cells. PMID- 22917651 TI - Sending the right signal: Notch and stem cells. AB - BACKGROUND: Notch signaling plays a critical role in multiple developmental programs and not surprisingly, the Notch pathway has also been implicated in the regulation of many adult stem cells, such as those in the intestine, skin, lungs, hematopoietic system, and muscle. SCOPE OF REVIEW: In this review, we will first describe molecular mechanisms of Notch component modulation including recent advances in this field and introduce the fundamental principles of Notch signaling controlling cell fate decisions. We will then illustrate its important and varied functions in major stem cell model systems including: Drosophila and mammalian intestinal stem cells and mammalian skin, lung, hematopoietic and muscle stem cells. MAJOR CONCLUSIONS: The Notch receptor and its ligands are controlled by endocytic processes that regulate activation, turnover, and recycling. Glycosylation of the Notch extracellular domain has important modulatory functions on interactions with ligands and on proper receptor activity. Notch can mediate cell fate decisions including proliferation, lineage commitment, and terminal differentiation in many adult stem cell types. Certain cell fate decisions can have precise requirements for levels of Notch signaling controlled through modulatory regulation. GENERAL SIGNIFICANCE: We describe the current state of knowledge of how the Notch receptor is controlled through its interaction with ligands and how this is regulated by associated factors. The functional consequences of Notch receptor activation on cell fate decisions are discussed. We illustrate the importance of Notch's role in cell fate decisions in adult stem cells using examples from the intestine, skin, lung, blood, and muscle. This article is part of a Special Issue entitled Biochemistry of Stem Cells. PMID- 22917652 TI - Cervical spine injury: analysis and comparison of patients by mode of transportation. AB - BACKGROUND: Cervical spine injury (CSI) studies have identified different factors contributing to CSI, but none compares the incidence and pattern of injury of patients arriving at the Emergency Department (ED) by private vehicle (PV). OBJECTIVE: We compared the characteristics and injury patterns in CSI patients who were transported to the ED via Emergency Medical Services (EMS) versus PV. METHODS: We conducted a three-hospital retrospective review of patients with CSI from January 1, 2000 to December 31, 2007. We excluded transfers and follow-up visits. Using a standardized data collection form, we reviewed demographics, mode of transport, mechanism of injury, imaging results, injury type and level, and neurologic deficits. Means and proportions were compared using t-tests and chi squared as appropriate. RESULTS: Of 1174 charts identified, 718 met all study criteria; 671 arrived by EMS and 47 by PV. There was no difference between groups in age or gender. Ground-level fall was more likely in PV patients (32%, 95% confidence interval [CI] 20-46% vs. 6%, 95% CI 4-9%), whereas motor vehicle collision was less likely (32%, 95% CI 20-46% vs. 67%, 95% CI 63-70%). PV patients more often sustained a stable injury (66%, 95% CI 52-78% vs. 40%, 95% CI 36-44%), and were more often triaged to a lower-acuity area (25%, 95% CI 15-40% vs. 4%, 95% CI 3-6%). The incidence of neurologic deficit was similar (32%, 95% CI 20-46% vs. 24%, 95% CI 21-28%), though more PV patients had spinal cord injury without radiographic abnormality (21%, 95% CI 12-35% vs. 5%, 95% CI 4-7%). CONCLUSION: A small proportion of patients with CSI present to the ED by PV. Although most had stable injuries, a surprising number had unstable injuries with neurologic deficits, and were triaged to lower-acuity areas in the ED. PMID- 22917653 TI - Spontaneous coronary artery dissection in a 27-year-old woman. AB - BACKGROUND: Spontaneous coronary artery dissection (SCAD) causes acute coronary syndromes or sudden death in young patients who are often lacking classic coronary disease risk factors. Systemic inflammatory and connective tissue diseases have been suggested as risk factors for SCAD. OBJECTIVE: To review the risk factors, diagnosis, and management of this uncommon but life-threatening disease. CASE REPORT: We report a case of a 27-year-old woman with a history of an ill-defined inflammatory arthropathy who presented with an acute ST-elevation myocardial infarction. SCAD was diagnosed by coronary angiography. Percutaneous coronary intervention was attempted but was unsuccessful. The patient recovered uneventfully with medical management and was ultimately diagnosed with systemic lupus erythematosus. CONCLUSIONS: SCAD is a rare but important cause of acute coronary syndromes and sudden death. It commonly occurs in young women. Although pregnancy is the most well-established risk factor, systemic inflammatory and connective tissue diseases have also been suggested as risk factors. PMID- 22917654 TI - Traumatic tension gastrothorax and pneumothorax. PMID- 22917655 TI - Genetic characterization of UCS region of Pneumocystis jirovecii and construction of allelic profiles of Indian isolates based on sequence typing at three regions. AB - Pneumocystis jirovecii is an opportunistic pathogen that causes severe pneumonia in immunocompromised patients. To study the genetic diversity of P. jirovecii in India the upstream conserved sequence (UCS) region of Pneumocystis genome was amplified, sequenced and genotyped from a set of respiratory specimens obtained from 50 patients with a positive result for nested mitochondrial large subunit ribosomal RNA (mtLSU rRNA) PCR during the years 2005-2008. Of these 50 cases, 45 showed a positive PCR for UCS region. Variations in the tandem repeats in UCS region were characterized by sequencing all the positive cases. Of the 45 cases, one case showed five repeats, 11 cases showed four repeats, 29 cases showed three repeats and four cases showed two repeats. By running amplified DNA from all these cases on a high-resolution gel, mixed infection was observed in 12 cases (26.7%, 12/45). Forty three of 45 cases included in this study had previously been typed at mtLSU rRNA and internal transcribed spacer (ITS) region by our group. In the present study, the genotypes at those two regions were combined with UCS repeat patterns to construct allelic profiles of 43 cases. A total of 36 allelic profiles were observed in 43 isolates indicating high genetic variability. A statistically significant association was observed between mtLSU rRNA genotype 1, ITS type Ea and UCS repeat pattern 4. PMID- 22917656 TI - dbDiarrhea: the database of pathogen proteins and vaccine antigens from diarrheal pathogens. AB - Diarrhea occurs world-wide and is most commonly caused by gastrointestinal infections which kill around 2.2 million people globally each year, mostly children in developing countries. We describe here dbDiarrhea, which is currently the most comprehensive catalog of proteins implicated in the pathogenesis of diarrhea caused by major bacterial, viral and parasitic species. The current release of the database houses 820 proteins gleaned through an extensive and critical survey of research articles from PubMed. The major contributors to this compendium of proteins are Escherichia coli and Salmonella enterica. These proteins are classified into different categories such as Type III secretion system effectors, Type III secretion system components, and Pathogen proteins. There is another complementary module called 'Host proteins'. dbDiarrhea also serves as a repository of the research articles describing (1) trials of subunit and whole organism vaccines (2) high-throughput screening of Type III secretion system inhibitors and (3) diagnostic assays, for various diarrheal pathogens. The database is web accessible through an intuitive user interface that allows querying proteins and research articles for different organism, keywords and accession number. Besides providing the search facility through browsing, the database supports sequence similarity search with the BLAST tool. With the rapidly burgeoning global burden of the diarrhea, we anticipate that this database would serve as a source of useful information for furthering research on diarrhea. The database can be freely accessed at http://www.juit.ac.in/attachments/dbdiarrhea/diarrhea_home.html. PMID- 22917657 TI - Phylodynamics of HIV-1 unique recombinant forms in China-Myanmar border: implication for HIV-1 transmission to Myanmar from Dehong, China. AB - China-Myanmar border plays a crucial role in HIV-1 transmission in Asia. Here, we performed Bayesian phylodynamics analyses on p17 gene using BEAST to investigate HIV-1 transmission in this region. Maximum clade credibility trees of subtype C and CRF01_AE show that majority of unique recombinant forms (URFs) and pure subtype strains from Dehong and Myanmar cluster together, forming large clades with ancestral geographical states of Dehong. Bayes factor tests support the statistically significant geographic diffusion link between Dehong and Myanmar. The estimated time to the most recent common ancestor of Myanmar URFs_BC (1999.2) was later than that of Dehong URFs_BC (1998.0), but earlier than that of Myanmar URFs_01BC (2004.3). Since 1998, HIV-1 recombination between subtypes B, C and CRF01_AE has been continuously occurring in China-Myanmar border region. These results suggest that HIV-1 subtypes B, C and CRF01_AE were most likely transmitted from Dehong to Myanmar, and predict that URFs_01BC should be also prevalent in Dehong, Yunnan. PMID- 22917658 TI - A multidimensional model of psychobiological interactions in functional dyspepsia: a structural equation modelling approach. AB - OBJECTIVE: Gastric sensorimotor function, abuse history, 'trait' and 'state' psychological factors and 'somatisation' all play a role in functional dyspepsia (FD) and its associated impaired quality of life (QoL), but their interplay remains poorly understood. We aimed to test a comprehensive, a priori hypothesised model of interactions between these dimensions in FD. DESIGN: In 259 FD patients, we studied gastric sensitivity with a barostat. We measured abuse history (sexual/physical, childhood/adulthood), 'trait' (alexithymia, trait anxiety) and 'state' (positive/negative affect, depression, panic disorder) psychological factors, somatic symptom reporting (somatic symptom count, dyspepsia, irritable bowel syndrome and fatigue symptoms) and QoL (physical, mental) using validated questionnaires. Confirmatory factor analysis (CFA) was used to assess whether four a priori hypothesised latent variables ('abuse', 'trait affectivity', 'state affect' and 'somatic symptom reporting') were adequately supported by the data. Structural equation modelling (SEM) was used to test the a priori hypothesised relationships between these latent variables and the observed variables gastric sensitivity and QoL. RESULTS: Both the CFA and SEM models fitted the data adequately. Abuse exerted its effect directly on 'somatic symptom reporting', rather than indirectly through psychological factors. A reciprocal relationship between 'somatic symptom reporting' and 'state affect' was found. Gastric sensitivity influences 'somatic symptom reporting' but not vice versa. 'Somatic symptom reporting' and 'trait affectivity' are the main determinants of physical and mental QoL, respectively. CONCLUSIONS: We present the first comprehensive model elucidating the complex interactions between multiple dimensions (gastric sensitivity, abuse history, 'state' and 'trait' psychological factors, somatic symptom reporting and QoL) in FD. PMID- 22917659 TI - A global assessment of the oesophageal adenocarcinoma epidemic. AB - OBJECTIVE: About 20 years ago, the scientific community was first alerted to an enigmatic increase of oesophageal adenocarcinomas in the UK and USA. Subsequently, a virtual epidemic-still unexplained-was confirmed in several western countries. Detailed descriptive data might provide clues to its causes. DESIGN: We collected data on incident cases of oesophageal adenocarcinoma from population-based cancer registries in Australia, Europe, North America and Asia. We calculated age-standardised incidence rates and fitted log-linear Poisson models to assess annual rate of increase and to disentangle age-period-cohort effects, linear spine models to estimate rate of increase since 1985, and Joinpoint models to identify possible inflection points. RESULTS: With considerable between-registry variation in magnitude and timing, we found a consistent dramatic increase in incidence with an observed or estimated start between 1960 and 1990. The average annual increase ranged from 3.5% in Scotland to 8.1% in Hawaii with similar proportional increase among men and women in most registries and a maintained three to sixfold higher incidence among men. Generally, calendar period was a more important determinant of incidence trends than birth cohort. Where possible to conduct, Joinpoint analyses indicated that the onset of the epidemic varied considerably even between neighbouring countries. CONCLUSIONS: Given the preponderant period effect and the abrupt onset observed or inferred in most populations, the epidemic appears to be caused by some exposure that was first introduced around 1950. At least 30 years' variation in estimated time of onset opens prospects for hypothesis-generating ecological analyses. PMID- 22917660 TI - WITHDRAWN: A female autoimmunity gene exists: DDX3X. AB - This article has been withdrawn at the request of the author(s) and/or editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy. PMID- 22917662 TI - The endocannabinoid system in inflammatory bowel diseases: from pathophysiology to therapeutic opportunity. AB - Crohn's disease and ulcerative colitis are two major forms of inflammatory bowel diseases (IBD), which are chronic inflammatory disorders of the gastrointestinal tract. These pathologies are currently under investigation to both unravel their etiology and find novel treatments. Anandamide and 2-arachidonoylglycerol are endogenous bioactive lipids that bind to and activate the cannabinoid receptors, and together with the enzymes responsible for their biosynthesis and degradation [fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL)] constitute the endocannabinoid system (ECS). The ECS is implicated in gut homeostasis, modulating gastrointestinal motility, visceral sensation, and inflammation, as well as being recently implicated in IBD pathogenesis. Numerous subsequent studies investigating the effects of cannabinoid agonists and endocannabinoid degradation inhibitors in rodent models of IBD have identified a potential therapeutic role for the ECS. PMID- 22917664 TI - Positive affect improves working memory: implications for controlled cognitive processing. AB - This study examined the effects of positive affect on working memory (WM) and short-term memory (STM). Given that WM involves both storage and controlled processing and that STM primarily involves storage processing, we hypothesised that if positive affect facilitates controlled processing, it should improve WM more than STM. The results demonstrated that positive affect, compared with neutral affect, significantly enhanced WM, as measured by the operation span task. The influence of positive affect on STM, however, was weaker. These results suggest that positive affect enhances WM, a task that involves controlled processing, not just storage processing. Additional analyses of recall and processing times and accuracy further suggest that improved WM under positive affect is not attributable to motivational differences, but results instead from improved controlled cognitive processing. PMID- 22917663 TI - Recombinant viral vaccines for cancer. AB - Cancer arises from 'self' in a series of steps that are all subject to immunoediting. Therefore, therapeutic cancer vaccines must stimulate an immune response against tumour antigens that have already evaded the body's immune defences. Vaccines presenting a tumour antigen in the context of obvious danger signals seem more likely to stimulate a response. This approach can be facilitated by genetic engineering using recombinant viral vectors expressing tumour antigens, cytokines, or both, from an immunogenic virus particle. We overview clinical attempts to use these agents for systemic immunisation and contrast the results with strategies employing direct intratumoural administration. We focus on the challenge of producing an effective response within the immune-suppressive tumour microenvironment, and discuss how the technology can overcome these obstacles. PMID- 22917661 TI - Cobalt chloride decreases fibroblast growth factor-21 expression dependent on oxidative stress but not hypoxia-inducible factor in Caco-2 cells. AB - Fibroblast growth factor-21 (FGF21) is a potential metabolic regulator with multiple beneficial effects on metabolic diseases. FGF21 is mainly expressed in the liver, but is also found in other tissues including the intestine, which expresses beta-klotho abundantly. The intestine is a unique organ that operates in a physiologically hypoxic environment, and is responsible for the fat absorption processes including triglyceride breakdown, re-synthesis and absorption into the portal circulation. In the present study, we investigated the effects of hypoxia and the chemical hypoxia inducer, cobalt chloride (CoCl(2)), on FGF21 expression in Caco-2 cells and the consequence of fat accumulation. Physical hypoxia (1% oxygen) and CoCl(2) treatment decreased both FGF21 mRNA and secreted protein levels. Gene silence and inhibition of hypoxia-inducible factor alpha (HIFalpha) did not affect the reduction of FGF21 mRNA and protein levels by hypoxia. However, CoCl(2) administration caused a significant increase in oxidative stress. The addition of n-acetylcysteine (NAC) suppressed CoCl(2) induced reactive oxygen species (ROS) formation and completely negated CoCl(2) induced FGF21 loss. mRNA stability analysis demonstrated that the CoCl(2) administration caused a remarkable reduction in FGF21 mRNA stability. Furthermore, CoCl(2) increased intracellular triglyceride (TG) accumulation, along with a reduction in mRNA levels of lipid lipase, hormone sensitive lipase (HSL) and adipose triglyceride lipase (ATGL), and an increase of sterol regulatory element-binding protein-1c (SREBP1c) and stearoyl-coenzyme A (SCD1). Addition of both NAC and recombinant FGF21 significantly attenuated the CoCl(2) induced TG accumulation. In conclusion, the decrease of FGF21 in Caco-2 cells by chemical hypoxia is independent of HIFalpha, but dependent on an oxidative stress mediated mechanism. The regulation of FGF21 by hypoxia may contribute to intestinal lipid metabolism and absorption. PMID- 22917665 TI - Estimated strip wastage from glucose meter infection control recommendations. PMID- 22917667 TI - Selection of controls in kidney donor outcome studies: an admirable effort. PMID- 22917666 TI - Classification performance of instantaneous wave-free ratio (iFR) and fractional flow reserve in a clinical population of intermediate coronary stenoses: results of the ADVISE registry. AB - AIMS: To evaluate the classification agreement between instantaneous wave-free ratio (iFR) and fractional flow reserve (FFR) in patients with angiographic intermediate coronary stenoses. METHODS AND RESULTS: Three hundred and twelve patients (339 stenoses) with angiographically intermediate stenoses were included in this international clinical registry. The iFR was calculated using fully automated algorithms. The receiver operating characteristic (ROC) curve was used to identify the iFR optimal cut-point corresponding to FFR 0.8. The classification agreement of coronary stenoses as significant or non-significant was established between iFR and FFR and between repeated FFR measurements for each 0.05 quantile of FFR values, from 0.2 to 1. Close agreement was observed between iFR and FFR (area under ROC curve= 86%). The optimal iFR cut-off (for an FFR of 0.80) was 0.89. After adjustment for the intrinsic variability of FFR, the classification agreement (accuracy) between iFR and FFR was 94%. Amongst the stenoses classified as non-significant by iFR (>0.89) and as significant by FFR (<=0.8), 81% had associated FFR values located within the FFR "grey-zone" (0.75 0.8) and 41% within the 0.79-0.80 FFR range. CONCLUSIONS: In a population of intermediate coronary stenoses, the classification agreement between iFR and FFR is excellent and similar to that of repeated FFR measurements in the same sample. Vasodilator-independent assessment of intermediate stenosis seems applicable and may foster adoption of coronary physiology in the catheterisation laboratory. PMID- 22917668 TI - Airborne psychotropic substances in eight Italian big cities: burdens and behaviours. AB - Psychotropic substances were monitored in eight big cities of Italy over one year, starting in May 2010, in the frame of the Ariadrugs Project. Yearly average concentrations ranged from 0.02 +/- 0.01 to 0.26 +/- 0.11 ng/m(3) for cocaine, from 0.05 +/- 0.05 to 0.96 +/- 1.37 ng/m(3) for cannabinoids, from 16 +/- 6 to 61 +/- 28 ng/m(3) for nicotine, and from 1.0 +/- 0.8 to 8 +/- 7 ng/m(3) for caffeine. Palermo and Turin were the cities suffering the lowest and the highest psychotropic substance concentrations, respectively. Nicotine and cocaine exhibited trends less seasonally modulated than common air toxicants. Caffeine and cannabinoids peaked in winter dropping close to zero from May to August. In Rome, where various anthropic contours were investigated in February 2011, differences were observed both in net concentrations and ratios of psychotropic substances vs. regulated toxicants. Ambient drugs look as a consequence of addiction and their burdens give insights about the corresponding consumes. PMID- 22917669 TI - Does gastric volume in trauma patients identify a population at risk for developing pneumonia and poor outcomes? AB - BACKGROUND: Trauma patients may have full stomachs or impaired airway reflexes that place them at risk for aspiration and pneumonia. Our hypothesis was that trauma patients with larger gastric volumes as measured by abdominal computed tomography (CT) at admission have higher rates of pneumonia and worse outcomes. METHODS: We matched an initial cohort of 81 trauma patients with an admission CT of the abdomen and a diagnosis of pneumonia by Injury Severity Score and Abbreviated Injury Score of the head and chest with a control group of 81 trauma patients without pneumonia. We estimated gastric volumes on CT and compared variables using chi-square, t-tests, receiver operating curve analysis, and regression analysis. RESULTS: Patients with pneumonia had larger gastric volumes than those without pneumonia (879 cm(3)versus 704 cm(3); P = 0.04). Receiver operating curve analysis gave a gastric volume threshold value of 700 cm(3) as a predictor of pneumonia. Patients with a gastric volume >= 700 cm(3) had more pneumonia (61% versus 41%; P = 0.01), stayed longer in the hospital (27.6 versus 19.7 d; P < 0.05) and the intensive care unit (18.4 versus 12.5 d; P = 0.01), required more days on the ventilator (18.1 versus 12.0 d; P = 0.02), and had a trend toward increased mortality (17% versus 11%; P = 0.2). On multivariate analysis, nasogastric or orogastric tube (odds ratio 3.0; P = 0.004) and gastric volume >700 cm(3) (odds ratio 2.7; P = 0.004) were independent predictors of pneumonia. CONCLUSIONS: Trauma patients who developed pneumonia had larger initial gastric volumes. A straightforward estimate of gastric volume on admission abdominal CT may predict patients at risk for developing pneumonia and poor outcomes. Clinicians should be especially vigilant in taking precautions against pneumonia and have a lower threshold for suspecting pneumonia in patients with abdominal CT gastric volumes >= 700 cm(3). PMID- 22917670 TI - Differential susceptibility to motor impulsivity among functional subtypes of Parkinson's disease. AB - BACKGROUND AND OBJECTIVES: Parkinson's disease patients with predominant postural instability and gait difficulties (PIGD) may experience unique cognitive difficulties compared to patients with tremor predominant (TD) symptoms. PIGD patients are also at high risk for falling, and some of the worst fallers seem to react impulsively to their environment. We tested the hypothesis that PIGD patients show poorer control over motor impulses compared to TD patients. METHODS: 34 PD participants were divided into predominant PIGD (n=17) or TD (n=17) functional subtypes based on their presenting symptoms in their optimally treated motor state. All participants performed a speeded reaction task that quantified motor impulsivity and the proficiency of inhibiting prepotent motor impulses. RESULTS: The groups showed similar reaction times, but compared to TD patients, PIGD patients made significantly more impulsive motor errors. Notably, when the initial impulsive erroneous response was avoided, PIGD and TD groups were similar in their ability to suppress the incorrect motor impulse from further interfering with the selection of a correct action. CONCLUSIONS: PD patients with PIGD predominant symptoms show greater susceptibility to acting on prepotent motor impulses compared to TD patients. This finding may have direct implications for fall risk and also points to dissociable neurocognitive pathologies in TD and PIGD subtypes. Clinically, the use of specific cognitive instruments to assess the expression and inhibition of motor impulses may help identify PD patients who have difficulty 'thinking before they leap' and are at high risk of falling. PMID- 22917671 TI - Large scale brain models of epilepsy: dynamics meets connectomics. AB - The brain is in a constant state of dynamic change, for example switching between cognitive and behavioural tasks, and between wakefulness and sleep. The brains of people with epilepsy have additional features to their dynamic repertoire, particularly the paroxysmal occurrence of seizures. Substantial effort over decades has produced a detailed description of many human epilepsies and of specific seizure types; in some instances there are known causes, sometimes highly specific such as single gene mutations, but the mechanisms of seizure onset and termination are not known. A large number of in vivo animal models and in vitro models based on animal tissues can generate seizures and seizure-like phenomena. Although in some instances there is much known about the mechanism of seizure onset and termination, across the range of models there is a bewildering range of mechanisms. There is a pressing need to bridge the gap between microscale mechanisms in experimental models and mechanisms of human epilepsies. Computational models of epilepsy have advanced rapidly, allowing dynamic mechanisms to be revealed in a computer model that can then be tested in biological systems. These models are typically simplified, leaving a need to scale up these models to the large scale brain networks in which seizures become manifest. The emerging science of connectomics provides an approach to understanding the large scale brain networks in which normal and abnormal brain functions operate. The stage is now set to couple dynamics with connectomics, to reveal the abnormal dynamics of brain networks which allow seizures to occur. PMID- 22917672 TI - Assessment of cerebral small vessel disease predicts individual stroke risk. AB - BACKGROUND: Despite several known risk factors it is still difficult to foresee who will develop a stroke and who will not. Vascular brain damage, visualised with MRI, reflects how the brain tolerates the effects of vascular risk factors and may therefore be relevant in predicting individual stroke risk. OBJECTIVE: To examine whether the presence of small vessel disease on brain MRI could improve the prediction of stroke beyond the classic stroke risk factors from the 1991 Framingham Stroke Risk Function. METHODS: 1007 community-dwelling elderly people, free of stroke at baseline were included in the study. Small vessel disease--that is, the presence of silent brain infarcts (SBI) and white matter lesions (WML), was scored on MRI scans obtained in 1995-6. 10-Year stroke risk prediction was assessed by the C statistic and by reclassification adding SBI and WML to a risk model including the classic stroke risk factors. RESULTS: During 10-years of follow-up 99 strokes occurred. Individual stroke risk prediction significantly improved from 0.73 (95% CI 0.67 to 0.78) to 0.75 (0.69 to 0.80) in men and from 0.69 (0.64 to 0.75) to 0.77 (0.71 to 0.82) in women after inclusion of SBI and periventricular WML to the stroke risk factors. Reclassification occurred mainly in the intermediate stroke risk group (men 26%; women 61% reclassified). CONCLUSIONS: Assessment of small vessel disease with MRI beyond the classic stroke risk factors improved the prediction of subsequent stroke, especially in women with an intermediate stroke risk. These findings support the use of MRI as a possible tool for better identifying people at high risk of stroke. PMID- 22917673 TI - Early, equivalent ERP masked priming effects for regular and irregular morphology. AB - Converging evidence from behavioral masked priming (Rastle & Davis, 2008), EEG masked priming (Morris, Frank, Grainger, & Holcomb, 2007) and single word MEG (Zweig & Pylkkanen, 2008) experiments has provided robust support for a model of lexical processing which includes an early, automatic, visual word form based stage of morphological parsing that applies to all derivationally affixed words. The mechanisms by which regularly (walked, birds) and irregularly (gave, geese) inflected forms are processed are less well established. We combine the masked priming paradigm with EEG recording to directly compare the ERPs evoked by regularly and irregularly inflected forms. We find equivalent N250 priming effects for both types of morphological complexity, which argues for rapid, form based morphological parsing of all morphologically complex word forms. PMID- 22917674 TI - Endovascular treatment of infected aortic aneurysms. AB - OBJECTIVE: To report on the short- and long-term outcomes of patients with primary infected aortic aneurysm (IAA) treated by stent graft (SG) in two centers. MATERIAL AND METHOD: Over a period of 15 years, 32 patients with IAA underwent endovascular treatment. None had undergone previous aortic surgery. The causal relationship was gastrointestinal infection in 9 patients (28%), endovascular diagnostic/therapeutic procedures/resuscitation in 6 (19%), wound infection after previous surgeries in 5 (16%), urinary infection in 4 (13%), urology or gastroenterology procedures in 3 (9%), pancreatitis in 2 (6%), endocarditis in 1 (3%) and phlebitis in 1 (3%) patient. We implanted 11 bifurcated, 10 tubular thoracic, 4 aorto-uni-iliac, 4 tubular abdominal and 1 iliac SG. Two other surgeries were hybrid procedures. RESULTS: The etiological agent was identified in 28 (88%) patients. Twenty-six (81%) patients survived the 30-day postoperative period. Sixteen (50%) survived to 1-year follow-up and 13 (40.6%) survived to 3-year follow-up. Three patients have survived for less than 1 year and a further 3 for less than 3 years, so far. Among patients with aneurysms situated in central parts of the thoracic and infrarenal aorta there was a better death/survival ratio than among patients with a proximal or distal aneurysm location. CONCLUSION: The implantation of a SG may be an alternative to open surgery in selected groups of patients with primary IAA. Aneurysms of the central part of the thoracic or abdominal aorta have a more favorable prognosis with endovascular treatment. PMID- 22917676 TI - A simple and universal ligation mediated fusion of genes based on hetero staggered PCR for generating immunodominant chimeric proteins. AB - We developed a simple T4 DNA ligase mediated strategy for inframe splicing of two or more cohesive genes generated by hetero-staggered PCR and directionally cloning the spliced product bearing sticky overhangs in to a correspondingly cut vector. For this, two pairs of primers are used in two different parallel PCRs, for generation of each cohesive gene product. We exemplified this strategy by splicing two major super-antigen genes of Staphylococcus aureus, namely, staphylococcal enterotoxin A (sea), and toxic shock syndrome toxin (tsst-1) followed by its directional cloning into pre-digested pRSET A vector. The fusion gene encoding chimeric recombinant SEA-TSST protein (32kDa) was expressed in E. coli BL21(DE3) host strain. The recombinant chimeric protein retained the antigenicity of both toxins as observed by the strong immunoreactivity with commercial antibodies against both SEA and TSST-1 toxin components by Western blot analysis. We observed that the present method for gene splicing with cohesive ends is simple since it does not require elaborate standardization and a single fusion product is obtained consistently during nested PCR with forward primer of first gene and reverse primer of second gene. For comparison, we fused the same genes using splicing by overlap extension PCR (SOE-PCR) and consistently obtained DNA smearing and multiple non-specific bands even after several rounds of PCRs from gel excised product. Moreover, the newly described method requires only two to six complimentary sticky ends between the genes to be spliced, in contrast to long stretch of overlapping nucleotides in case of SOE-PCR. PMID- 22917675 TI - Prediction of gene network models in limb muscle precursors. AB - The ventrolateral dermomyotome gives rise to all muscles of the limbs through the delamination and migration of cells into the limb buds. These cells proliferate and form myoblasts, withdraw from the cell cycle and become terminally differentiated. The myogenic lineage colonizes pre-patterned regions to form muscle anlagen as muscle fibers are assembled. The regulatory mechanisms that control the later steps of this myogenic program are not well understood. The homeodomain transcription factor Pitx2 is expressed in the muscle lineage from the migration of precursors to adult muscle. Ablation of Pitx2 results in distortion, rather than loss, of limb muscle anlagen, suggesting that its function becomes critical during the colonization of, and/or fiber assembly in, the anlagen. Gene expression arrays were used to identify changes in gene expression in flow-sorted migratory muscle precursors, labeled by Lbx1(EGFP), which resulted from the loss of Pitx2. Target genes of Pitx2 were clustered using the "David Bioinformatics Functional Annotation Tool" to bin genes according to enrichment of gene ontology keywords. This provided a way to both narrow the target genes and identify potential gene families regulated by Pitx2. Representative target genes in the most enriched bins were analyzed for the presence and evolutionary conservation of Pitx2 consensus binding sequence, TAATCY, on the -20kb, intronic, and coding regions of the genes. Fifteen Pitx2 target genes were selected based on the above analysis and were identified as having functions involving cytoskeleton organization, tissue specification, and transcription factors. Data from these studies suggest that Pitx2 acts to regulate cell motility and expression of muscle specific genes in the muscle precursors during forelimb muscle development. This work provides a framework to develop the gene network leading to skeletal muscle development, growth and regeneration. PMID- 22917677 TI - Expression of common gamma chain signalling cytokines and their receptors distinguishes rejection from tolerance in a rat organ transplant model. AB - BACKGROUND: Signalling through the cytokine common gamma chain (gammac) is crucial for survival of activated T cells. In its absence, severe combined immunodeficiency ensues and transplanted tissues are not rejected. METHODS: To determine whether differences in the availability of gammac signalling cytokines correlate with rejection or acceptance, we examined expression of all gammac signalling components in organs transplanted between PVG donors and DA recipients. In this combination hearts or kidneys are rejected in <10 days while livers survive >100 days. Expression of the gammac cytokines IL-2, IL-4, IL-7, IL 9, IL-15 and IL-21 and their receptors gammac, IL-2Ralpha, IL-2Rbeta/IL-15Rbeta, IL-4Ralpha, IL-7Ralpha, IL-9Ralpha, IL-15Ralpha and IL-21Ralpha was determined by real-time PCR pre-transplant and on days 3, 5 and 7 after transplantation. RESULTS: Most increased after transplantation, although there were significantly lower levels of IL-2, IL-2Ralpha, IL-4 and IL-15Ralpha in tolerant livers compared to rejecting hearts or kidneys. IL-9 was only expressed in normal kidneys and decreased during rejection. IL-15 was constitutively expressed and did not change after transplantation. IL-21 and IL-21R increased in all transplanted organs to a similar extent. IL-7Ralpha in liver was considerably increased compared with heart or kidney, consistent with its known inverse relationship to global levels of gammac signalling. CONCLUSIONS: In transplanted livers, acceptance is associated with low levels of all gammac cytokines or receptors except IL-21. This is consistent with "dilution" of gammac cytokines from a finite clone size of alloreactive T cells in livers, which are ten times larger than kidneys or hearts. PMID- 22917678 TI - Spin echo functional MRI in bilateral auditory cortices at 7 T: an application of B1 shimming. AB - Ultra high fields (UHF) permit unprecedented explorations of functional organizations and insight into basic neuronal processes. Increases in the signal and contrast to noise ratios have allowed increases in the spatial resolution of T(2) weighted gradient echo (GE) echo planar imaging (EPI). Furthermore, while the use of T(2) weighted imaging methods at UHF (e.g. spin echo (SE) EPI, gradient and spin echo (GRASE) EPI) can also permit higher resolution images, they in addition allow for increased spatial specificity of functional responses, permitting the in-vivo study of functional organizations down to the columnar level of the cortex. The study of the visual cortex has, thus far, benefitted the most from higher resolution T(2) weighted studies as achieving the required transmit B(1) magnitude at 7T is more challenging in other brain regions, such as the auditory cortex. As such, auditory fMRI studies at UHF have been limited to T(2) weighted GE sequences. Recent advances in multi-channel RF transmission (e.g. B(1) shimming) have enabled procedures to efficiently address deficiencies in transmit B(1) profiles. However, these techniques, shown to be advantageous in anatomical imaging at UHF, are not generally utilized to facilitate T(2) weighted fMRI studies. Here we investigate the feasibility of applying B(1) shimming to achieve efficient RF transmission in the human auditory cortex. We demonstrate that, with B(1) shimming, functional responses to simple tones and to complex sounds (i.e. voices, speech, animal cries, tools and nature) can be efficiently measured with T(2) weighted SE-EPI in the bilateral human auditory cortex at 7T without exceeding specific absorption rate (SAR) limits. PMID- 22917680 TI - HTLV-1 infection: what determines the risk of inflammatory disease? AB - Human T-lymphotropic virus type 1 (HTLV-1) is an exogenous retrovirus that persists lifelong in the infected host. Infection has been linked to a spectrum of diverse diseases: adult T cell leukemia, encephalomyelopathy, and predisposition to opportunistic bacterial and helminth infections. Applications of new technologies and biological concepts to the field have provided new insights into viral persistence and pathogenesis in HTLV-1 infection. Here, we summarize the emerging concepts of dynamic HTLV-1-host interactions and propose that chronic interferon (IFN) production causes tissue damage in HTLV-1 associated inflammatory diseases. PMID- 22917679 TI - Evidence for alterations in central noradrenergic signaling in irritable bowel syndrome. AB - BACKGROUND/AIMS: Alterations in noradrenergic (NE) signaling have been implicated in the pathophysiology of irritable bowel syndrome (IBS), and adrenergic receptors are potential treatment targets. METHODS: To characterize central NE signaling in IBS, 11 patients and 11 healthy controls (HCs) were studied 3 times during an auditory oddball vigilance task after double-blind ingestion of the alpha2-adrenoreceptor (alpha2AR) antagonist yohimbine (YOH), the alpha2AR agonist clonidine (CLO), or placebo (PLA). Regional cerebral glucose metabolism was measured with [18F] fluorodeoxyglucose (FDG) positron emission tomography (PET). Measures of anxiety, early-life trauma, plasma NE and blood pressure were acquired. RESULTS: Patients had higher plasma NE levels than HCs before and after ingestion of all drugs (all p<0.05). YOH increased plasma NE and more anxiety in patients than in HCs. After YOH, NE levels directly correlated with drug-induced increases in anxiety in IBS patients (r=0.61), but not in HCs. IBS patients showed less YOH-mediated reduction of activity in a central arousal circuit, consistent with fewer functional presynaptic alpha2AR. In HCs, but not in patients, activation of amygdala and subgenual anterior cingulate cortex (sgACC) was inversely correlated with activation of anterior mid cingulate cortex (aMCC), and state anxiety covaried directly with activity in limbic and right frontotemporal cortices, but indirectly with activity in the left frontotemporal cortex. YOH-mediated reduction of activity in brainstem and amygdala inversely correlated with early life trauma. CONCLUSIONS: IBS patients showed evidence for increased noradrenergic activity consistent with downregulation of presynaptic inhibitory alpha2ARs. Activity within central arousal circuits was biased toward greater excitability and reduced corticolimbic inhibition in IBS. Early life trauma may be one mediator of these abnormalities. PMID- 22917682 TI - How do we use the past to predict the future in oculomotor search? AB - A variety of findings suggest that when conducting visual search, we can exploit cues that are statistically related to a target's location. But is this the result of heuristic mechanisms or an internal model that tracks the statistics of the environment? Here, connections are made between the two explanations, and four models are assessed to probe the mechanisms underlying prediction in search. Participants conducted a simple gaze-contingent search task with five conditions, each of which consists of different combinations of 1st and 2nd order statistics. People's exploration behaviour adapted to the statistical rules governing target behaviour. Behaviour was most consistent with a model that represents transitions from one location to another, and that makes the underlying assumption that the world is dynamic. This assumption that the world is changeable could not be overridden despite task instruction and nearly 1h of exposure to unchanging statistics. This means that while people may be suboptimal in some experimental contexts, it may be because their internal mental model makes assumptions that are adaptive in a complex, changeable world. PMID- 22917681 TI - Figure-ground discrimination in the avian brain: the nucleus rotundus and its inhibitory complex. AB - In primates, neurons sensitive to figure-ground status are located in striate cortex (area V1) and extrastriate cortex (area V2). Although much is known about the anatomical structure and connectivity of the avian visual pathway, the functional organization of the avian brain remains largely unexplored. To pinpoint the areas associated with figure-ground segregation in the avian brain, we used a radioactively labeled glucose analog to compare differences in glucose uptake after figure-ground, color, and shape discriminations. We also included a control group that received food on a variable-interval schedule, but was not required to learn a visual discrimination. Although the discrimination task depended on group assignment, the stimulus displays were identical for all three experimental groups, ensuring that all animals were exposed to the same visual input. Our analysis concentrated on the primary thalamic nucleus associated with visual processing, the nucleus rotundus (Rt), and two nuclei providing regulatory feedback, the pretectum (PT) and the nucleus subpretectalis/interstitio-pretecto subpretectalis complex (SP/IPS). We found that figure-ground discrimination was associated with strong and nonlateralized activity of Rt and SP/IPS, whereas color discrimination produced strong and lateralized activation in Rt alone. Shape discrimination was associated with lower activity of Rt than in the control group. Taken together, our results suggest that figure-ground discrimination is associated with Rt and that SP/IPS may be a main source of inhibitory control. Thus, figure-ground segregation in the avian brain may occur earlier than in the primate brain. PMID- 22917683 TI - Active learning as a path to critical thinking: are competencies a roadblock? AB - Nursing educators are called to graduate students who are critical thinkers able to face the challenge of negotiating increasingly complex health care systems (Candela, 2011; Cerullo and da Cruz, 2010). Active learning has been incited as a mechanism to foster critical thinking skills (Michel et al., 2009; Pascarella, 2005; Walker, 2003). Yet despite evidence and academic applause in favor of active pedagogies, passive pedagogies continue to dominant the nursing education landscape (Brown et al., 2009; Burbach et al., 2004; Schnell, 2005). Although, scholarly literature in nursing and education substantiate existence of various obstacles that inhibit faculty incorporation of active pedagogies, perhaps the insidious culture of competencies in nursing education is what truly engenders a milieu for the continued use of passive pedagogies. In this article, I aim to stimulate debate about the culture of competencies in nursing education as the overriding force which perpetuates use of passive pedagogies. PMID- 22917684 TI - Reconstruction of pulmonary artery with porcine small intestinal submucosa in a lamb surgical model: Viability and growth potential. AB - OBJECTIVES: This study investigated the time-dependent remodeling and growth potential of porcine small intestine submucosa as a biomaterial for the reconstruction of pulmonary arteries in a lamb model. METHODS: Left pulmonary arteries were partially replaced with small intestine submucosal biomaterial in 6 lambs. Two animals each were humanely killed at 1, 3, and 6 months. Computed tomographic angiography, macroscopic examination of the implanted patch, and microscopic analysis of tissue explants were performed. RESULTS: All animals survived without complications. Patency and arborization of the pulmonary arteries were detected 6 months after implantation. There was no macroscopic narrowing or aneurysm formation in the patch area. The luminal appearance of the patch was similar to the intimal layer of the adjacent native pulmonary artery. Scanning electron microscopy showed that the luminal surface of the patch was covered by confluent cells. Immunohistochemical examination confirmed endothelialization of the luminal side of the patch in all of the explanted patches. The presence of smooth muscle cells in the medial layer was confirmed at all time points; however, expression of elastin, growth of the muscular layer, and complete degradation of patch material were detectable only after 6 months. The presence of c-Kit-positive cells suggests migration of multipotent cells into the patch, which may play a role in remodeling the small intestine submucosal biomaterial. CONCLUSIONS: Our data confirmed that remodeling and growth potential of the small intestine submucosal biomaterial are time dependent. Additional experiments are required to investigate the stability of the patch material over a longer period. PMID- 22917686 TI - The "no-dissection" technique is safe for reoperative aortic valve replacement with a patent left internal thoracic artery graft. AB - OBJECTIVE: Management of a patent left internal thoracic artery graft during reoperation is controversial. The "no-dissection" technique avoids dissection and clamping of the left internal thoracic artery graft, and myocardial protection is achieved using adjunctive systemic hypothermia and hyperkalemia. We compared the postoperative outcomes after isolated reoperative aortic valve replacement in patients with previous coronary artery bypass grafting with a patent left internal thoracic artery graft using a no-dissection technique with the outcomes of patients with previous coronary artery bypass grafting without a left internal thoracic artery graft. METHODS: The outcomes were analyzed for patients who underwent isolated reoperative aortic valve replacement with previous coronary artery bypass grafting from January 1, 2002, to June, 30, 2011. Patency of the left internal thoracic artery was confirmed using either coronary angiography or computed tomography angiography. The patent left internal thoracic artery group did not undergo dissection or clamping of the left internal thoracic artery graft, and myocardial protection was obtained using systemic hypothermia and hyperkalemia. The no left internal thoracic artery group underwent isolated aortic valve replacement with previous coronary artery bypass grafting but had no left internal thoracic artery graft. RESULTS: A total 174 patients were identified for the patent left internal thoracic artery group and 26 for the no left internal thoracic artery group. The perfusion and crossclamp times were similar. No differences were seen between the 2 groups in operative mortality (6.9% vs 7.7%, P = 1.00). The complication rates were similar, and the peak creatine kinase-MB values within 24 hours of surgery were not significantly different between the 2 groups (median, 27.4 vs 29 MU/mL; P = .72). CONCLUSIONS: Reoperative aortic valve replacement in patients with previous coronary artery bypass grafting and a patent left internal thoracic artery graft can be performed safely without dissection or clamping of the left internal thoracic artery using systemic hyperkalemia and hypothermia. We believe this method prevents unnecessary injury during dissection of the left internal thoracic artery graft. PMID- 22917687 TI - Improving the productivity of elective surgery through a new 'package of care'. AB - In response to a need to improve the productivity and throughput of elective surgical services, one district health board (DHB) in New Zealand has introduced a 'package of care' (POC) in which incentive-based, risk-sharing contracts were developed collaboratively between DHB managers, surgeons and anaesthetists. The POC includes throughput targets and facilitates consistent surgical teams and the cohorting of patients. Whilst many staff are very supportive of the POC, some are of the view that it conflicts with the ideals and principles of working in a public health system, and creates inequities amongst the hospital staff. Analysis indicates that, after controlling for age, casemix and complexity the POC has resulted in shorter theatre times, shorter lengths of stay and lower average inpatient event costs compared with standard care at the public hospital. An unintended consequence could be that the POC may encourage throughput of less complex cases at the expense of more complex cases. The average complexity and range of cases performed publicly should be carefully monitored to ensure this does not occur. PMID- 22917688 TI - Expression of laminin-5 and integrins in actinic cheilitis and superficially invasive squamous cell carcinomas of the lip. AB - The progression of carcinogenesis entails the detachment of cells, invasion and migration of neoplastic cells. Alterations in epithelial adhesion and basement membrane proteins might mediate the early stages of carcinogenesis. This study investigated the expression of adhesion molecules and the basement membrane protein laminin-5 in actinic cheilitis (AC) and incipient squamous cell carcinoma of the lower lip to understand early photocarcinogenesis. Ln-5gamma2 chain as well as alpha3, beta1 subunits of alpha3beta1 heterodimer and beta4 subunit of integrin alpha6beta4 were evaluated by immunohistochemistry in 16 cases of AC and 16 cases of superficially invasive squamous cell carcinoma (SISCC). Most AC cases showed reduced expression of beta1, beta4 and alpha3 integrins, and SISCCs lacked beta1, beta4 and alpha3 integrins in the invasive front. AC cases were negative for the Ln-5gamma2 chain. Five cases of SISCC (31%) showed heterogeneous Ln 5gamma2 chain expression in the invasive front of the tumor. Integrin beta1, beta4 and alpha3 expression is lost during the early stages of lip carcinogenesis. Expression of Ln-5gamma2 in the invasive front in cases and its correlation with tumor progression suggest that it mediates the acquisition of the migrating and invading epithelial cell phenotype. PMID- 22917689 TI - CSF neurofilament and N-acetylaspartate related brain changes in clinically isolated syndrome. AB - BACKGROUND: Axonal damage is considered a major cause of disability in multiple sclerosis (MS) and may start early in the disease. Specific biomarkers for this process are of great interest. OBJECTIVE: To study if cerebrospinal fluid (CSF) biomarkers for axonal damage reflect and predict disease progression already in the earliest stages of the disease, that is, in clinically isolated syndrome (CIS). METHODS: We assessed CSF levels of neurofilament heavy (NFH), neurofilament light (NFL) and N-acetylaspartate (NAA) in 67 patients with CIS and 18 controls with neuropsychiatric diseases of non-inflammatory aetiology (NC). Patients with CIS underwent baseline magnetic resonance imaging (MRI) at 3T, and a follow-up MRI after 1 year was obtained in 28 of them. RESULTS: Compared with NC, patients with CIS had higher NFH (p=0.05) and NFL (p<0.001) levels. No significant group differences were found for NAA. Patients' NFH levels correlated with physical disability (r=0.304, p<0.05) and with change in brain volume over 1 year of follow-up (r=-0.518, p<0.01) but not with change in T2 lesion load. CONCLUSION: Our results confirm increased neurofilament levels already in CIS being related to the level of physical disability. The association of NFH levels with brain volume but not lesion volume changes supports the association of these markers with axonal damage. PMID- 22917690 TI - Setting a research agenda for progressive multiple sclerosis: the International Collaborative on Progressive MS. AB - Despite significant progress in the development of therapies for relapsing MS, progressive MS remains comparatively disappointing. Our objective, in this paper, is to review the current challenges in developing therapies for progressive MS and identify key priority areas for research. A collaborative was convened by volunteer and staff leaders from several MS societies with the mission to expedite the development of effective disease-modifying and symptom management therapies for progressive forms of multiple sclerosis. Through a series of scientific and strategic planning meetings, the collaborative identified and developed new perspectives on five key priority areas for research: experimental models, identification and validation of targets and repurposing opportunities, proof-of-concept clinical trial strategies, clinical outcome measures, and symptom management and rehabilitation. Our conclusions, tackling the impediments in developing therapies for progressive MS will require an integrated, multi disciplinary approach to enable effective translation of research into therapies for progressive MS. Engagement of the MS research community through an international effort is needed to address and fund these research priorities with the ultimate goal of expediting the development of disease-modifying and symptom relief treatments for progressive MS. PMID- 22917691 TI - Isoprostanes in clinically isolated syndrome and early multiple sclerosis as biomarkers of tissue damage and predictors of clinical course. AB - BACKGROUND: Isoprostanes (IsoP) are sensitive biomarkers of oxidative stress. Their cerebrospinal-fluid (CSF) level is increased in several neurological conditions, including multiple sclerosis (MS). In particular, in relapsing remitting MS, IsoP have been proposed as an index of neurodegenerative processes. The mechanisms leading to neuroaxonal damage in MS are not fully understood but oxidative mechanisms play a substantial role. Although axonal loss is present in MS patients since their first clinical symptoms, IsoP levels at this early stage have not been evaluated yet. OBJECTIVES: The objectives of this study were (a) to assess IsoP levels in CSF of patients with a first clinical attack suggestive of MS; (b) to correlate IsoP levels with magnetic resonance imaging (MRI) measures of brain damage and (c) to assess IsoP value in predicting disease clinical evolution. METHODS: Thirty-nine patients with a first clinical attack suggestive of MS underwent neurological examination, lumbar puncture with IsoP levels quantification and conventional/spectroscopic-MRI. Patients were followed up for 24 months. RESULTS: CSF IsoP levels were higher in patients than controls (mean +/- standard deviation (SD) 123.4 +/- 185.8 vs 4.5 +/- 2.9 pg/ml; p<0.0001) and inversely correlated to normalized brain volume (p=0.04) and N acetylaspartate/choline (NAA/Cho) (p=0.01). The risk of experiencing clinical relapses differed according to IsoP level: subjects with levels higher than 95 pg/ml (a cut-off value resulting from ROC analysis) were more likely to relapse than patients with levels equal or lower than 95 pg/ml (59% vs 27% respectively; p=0.03). CONCLUSIONS: CSF IsoP might be useful biomarkers of tissue damage in MS with a predictive value of disease course. PMID- 22917692 TI - Perceived changes and minimum clinically important difference of the Neurological Fatigue Index for multiple sclerosis (NFI-MS). AB - The determination of the minimum clinically important difference (MCID) is an important aspect of scale development. The Neurological Fatigue Index for multiple sclerosis (NFI-MS) was administered before and after expected change or stability in fatigue in 208 multiple sclerosis (MS) patients. The overall change scores of the NFI-MS accorded with perceived direction of change; importantly, no change was seen when none was perceived. Using the interval level NFI-MS scores, the largest MCID equated to 2.49 points on the Summary scale, 2.36 points on the Physical scale, 0.84 points on the Cognitive scale, 0.97 on the Diurnal Sleep scale and 1.95 on the Nocturnal Sleep scale. Our conclusion is that the NFI-MS responds as expected to changes in fatigue and has desirably small MCID scores. PMID- 22917693 TI - Effectiveness of gentamicin for gonorrhoea treatment: systematic review and meta analysis. AB - OBJECTIVES: The development of resistance to multiple antimicrobial agents has limited treatment options for gonorrhoea. The potential emergence of cephalosporin resistance in Neisseria gonorrhoeae and cephalosporin allergy in some patients make it necessary to evaluate the effectiveness of other available antimicrobial agents. Gentamicin is widely available in the USA and is used for gonorrhoea treatment in several countries. We conducted a systematic review of the medical literature to assess the effectiveness of gentamicin for treatment of uncomplicated urogenital gonococcal infections. METHODS: Two reviewers assessed relevant articles and independently selected studies that met prespecified selection criteria (including systematic enrolment and assignment to treatment and culture-confirmed diagnosis and outcome). Summary measures for selected studies were pooled using inverse variance-weighted averages with fixed effects. Heterogeneity was assessed using I(2), which estimates proportion (0-100%) of variability attributable to heterogeneity between studies. Pooled percentage with negative follow-up culture was compared with Centers for Disease Control and Prevention (CDC) criteria for selection of recommended therapy (lower 95% CI of efficacy >=95%). RESULTS: Twenty-nine potentially relevant studies were identified; three met inclusion criteria. Two studies used 240 mg intramuscular gentamicin and one used 280 mg. Percentages with negative culture after single dose treatment were 90.7% (n=86), 91.4% (n=220) and 95.0% (n=40). Pooled percentage with negative culture after single-dose treatment was 91.5% (95% CI 88.1% to 94.0%, I(2)=0%). CONCLUSIONS: Gentamicin does not meet current CDC criteria for recommended treatment of gonorrhoea. However, if cephalosporin resistance emerges, gentamicin may be a useful alternative agent. Evaluation of additional regimens, including combination therapy, is warranted. PMID- 22917694 TI - HIV and STI control in El Salvador: results from an integrated behavioural survey among men who have sex with men. AB - OBJECTIVE: This cross-sectional study investigates HIV, other sexually transmitted infections (STI), and risk behaviours among men who have sex with men (MSM) in two cities in El Salvador. METHODS: Respondent-driven sampling (RDS) was used to recruit MSM in the cities of San Salvador and San Miguel, El Salvador. Participants responded to questions about HIV risk behaviours; and blood, urine and anal swabs were collected. Blood samples were tested for herpes simplex type 2, syphilis and HIV infection. Urine and anal samples were tested by polymerase chain reaction (PCR) for Chlamydia trachomatis, Neisseria gonorrhoeae, Trichomonas vaginalis, and Mycoplasma genitalium. HIV-positive samples were tested with the BED capture enzyme immunoassay to distinguish recent from longstanding HIV infection. We estimated population-adjusted prevalence of behavioural variables, STI and HIV, and identified risk factors for HIV. RESULTS: The final sample included 596 and 195 MSM in San Salvador and San Miguel, respectively. Consistent condom use was low across all partner types as was recent HIV testing. RDS-adjusted HIV prevalence was 10.8% (95% CI 7.4% to 14.7%) in San Salvador, and 8.8% (95% CI 4.2% to 14.5%) in San Miguel. The proportion of recent testing among HIV-positive samples was 20%. Prevalence of any bacterial STI by PRC testing was 12.7% (95% CI 8.2% to 17.5%) in San Salvador, and 9.6% (95% CI 4.9% to 15.4%) in San Miguel. CONCLUSIONS: We found a high prevalence of HIV, high levels of recent infection, and low condom usage. In El Salvador, targeted interventions towards MSM are needed to promote condom use, as well as to diagnose, treat and prevent HIV and other STIs. PMID- 22917695 TI - A range of malar and masseteric hypoplasia exists in Treacher Collins syndrome. AB - BACKGROUND: Treacher Collins syndrome (TCS) is a facial dysostosis, the hallmark being bilateral malar hypoplasia. The purpose of this study is to morphologically classify the TCS malar deformity and to volumetrically characterise both the TCS zygoma and masseter muscle, including for left-right symmetry, compared to controls. We hypothesise that the TCS zygoma will be smaller than controls and zygomatic deficiency will portend masseteric hypoplasia. METHODS: Demographic and computed tomography (CT) data were recorded. The CT scans were converted into three-dimensional facial renderings, and the zygomatic morphology was grossly evaluated. A classification was reported based on malar structure and presence/absence of normal zygomaticomaxillary complex articulations. The zygoma and masseter muscles were then digitally isolated using 3-D planning software (Materialise, Leuven, Belgium). Volumes and sidedness ratios were calculated and compared using two-sided t-tests. RESULTS: 58 sides were identified (24 TCS: 34 controls), mean age of 60.0 months and normally distributed. The phenotypic dysmorphology was graded as mild, moderate or severe (I, II and III, respectively). TCS malar and masseteric volumes were significantly smaller than controls (p < 0.0001 in both cases). The TCS zygomatic side-side symmetry ratio was 0.66 +/- 0.28, compared to 0.97 +/- 0.02 for controls (p = 0.002). The TCS masseteric side-side ratio was 0.74 +/- 0.20, compared to 0.92 +/- 0.09 for controls (p = 0.001). CONCLUSIONS: A range of zygomatic hypoplasia exists in TCS (mild-severe). The decrease in malar volume occurs in concert with masseteric hypoplasia, and the left and right sides are not equally affected. PMID- 22917696 TI - Reconstruction of metatarsal bone defects with a free fibular osteomyocutaneous flap incorporating soleus muscle. AB - Severe traumatic bone and soft-tissue defects are often treated by lower leg amputation. The amputation level becomes a very important factor with respect to the patient's basic daily activities. We report the case of a 51-year-old man who was referred to us with severe traumatic metatarsal bone and dorsum pedis skin and soft-tissue defects. To avoid amputation, a free fibular osteomyocutaneous flap incorporating the soleus muscle was used to reconstruct the second and third metatarsal bones and the soft-tissue defect, respectively. Now, 2 years after the procedure, the patient is able to walk independently. To the best of our knowledge, this is the first report of use of such a composite transfer for a complex midfoot defect. PMID- 22917697 TI - Long-term follow-up of flaps for extensive Dupuytren's and Ledderhose disease in one family. AB - Dupuytren's and Ledderhose disease can be a cumbersome condition in patients with a severe diathesis with a very early onset. Two brothers are described with a reversed radial forearm flap on both hands and two upper lateral arm flaps on both feet with a long-term follow-up ranging from 14 to 25 years. They had multiple procedures of both hands before the flaps were considered. No recurrence occurred under the flap. In very severe diathesis flaps should be considered in an earlier phase to prevent multiple procedures and early recurrence. PMID- 22917698 TI - Obstetric nephrology: pregnancy in women with diabetic nephropathy--the role of antihypertensive treatment. AB - This review highlights factors of importance for the clinical care of pregnant women with pregestational diabetes and microalbuminuria or diabetic nephropathy with particular focus on the role of intensive antihypertensive treatment during pregnancy. Most information in the literature comes from women with type 1 diabetes and diabetic nephropathy, but this is probably also valid for women with type 2 diabetes. Careful counseling of women with diabetic nephropathy before pregnancy with estimation of the risk for the mother and fetus is important. Pregnancy does not result in worsening of kidney function in women with diabetic nephropathy and normal serum creatinine, but pregnancy complications such as pre eclampsia and preterm delivery are common. Intensive metabolic control before and during pregnancy, low-dose aspirin from 12 gestational weeks onward, and intensive antihypertensive treatment are important. Methyldopa, labetalol, and nifedipine are regarded safe in pregnancy, whereas angiotensin converting enzyme inhibitors, AngII antagonists, or statins should be paused before pregnancy. Case series and pathophysiological studies support the use of a stringent goal for BP and albumin excretion in pregnant women with diabetic nephropathy. Screening for diabetic retinopathy before and during pregnancy is mandatory and laser treatment should be performed if indicated. Pregnancy outcome in women with diabetic nephropathy has improved considerably with a take-home-baby rate of approximately 95%. Further research on the benefits and risks of intensive antihypertensive treatment in this population is needed. PMID- 22917699 TI - Parietal epithelial cell activation marker in early recurrence of FSGS in the transplant. AB - BACKGROUND AND OBJECTIVES: Podocyte loss is key in glomerulosclerosis. Activated parietal epithelial cells are proposed to contribute to pathogenesis of glomerulosclerosis and may serve as stem cells that can transition to podocytes. CD44 is a marker for activated parietal epithelial cells. This study investigated whether activated parietal epithelial cells are increased in early recurrent FSGS in transplant compared with minimal change disease. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: CD44 staining in renal allograft biopsies from 12 patients with recurrent FSGS was performed and compared with native kidneys with minimal change disease or FSGS and normal control native and transplant kidneys without FSGS. CD44+ epithelial cells along Bowman's capsule in the parietal epithelial cell location and over the glomerular tuft in the visceral epithelial cell location were assessed. RESULTS: Cases with early recurrent FSGS manifesting only foot process effacement showed significantly increased CD44+ visceral epithelial cells involving 29.0% versus 2.6% of glomeruli in minimal change disease and 0% in non-FSGS transplants. Parietal location CD44 positivity also was numerically increased in recurrent FSGS. In later transplant biopsies, glomeruli with segmental lesions had more CD44+ visceral epithelial cells than glomeruli without lesions. CONCLUSIONS: Parietal epithelial cell activation marker is significantly increased in evolving FSGS versus minimal change disease, and this increase may distinguish early FSGS from minimal change disease. Whether parietal epithelial cell activation contributes to pathogenesis of sclerosis in idiopathic FSGS or is a regenerative/repair response to replace injured podocytes awaits additional study. PMID- 22917700 TI - Association of smoking with cardiovascular and infection-related morbidity and mortality in chronic hemodialysis. AB - BACKGROUND AND OBJECTIVES: Smoking is common in the hemodialysis population and is associated with increased all-cause mortality and development of cardiovascular disease. Cause-specific outcomes have not yet been examined in detail. This study investigated the association of baseline smoking status with all-cause, cardiovascular, and infection-related morbidity and mortality in patients undergoing long-term hemodialysis. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Post hoc analysis of the HEMO Study in patients with available comorbidity, clinical, and nutritional data. Cox proportional hazards regression models were fit to estimate the association of smoking status with mortality. Poisson and negative binomial regression models were fit to estimate the association of smoking status with hospitalization rate. RESULTS: Complete data were available for 1842 individuals (44% male, 63% black, 45% diabetic). Mean age was 58 +/- 14 years. At baseline, 17% were current smokers and 32% were former smokers. After case-mix adjustment, compared with never smoking, current smoking was associated with greater infection-related mortality (hazard ratio [HR], 2.04; 95% confidence interval [CI], 1.32-3.10) and all-cause mortality (HR, 1.44; 95% CI, 1.16-1.79) and greater cardiovascular (incidence rate ratio [IRR], 1.49; 95% CI, 1.22-1.82), infection-related (IRR, 1.35; 95% CI, 1.11-1.64) and all-cause (IRR, 1.43; 95% CI, 1.24-1.65) hospitalization rates. The population attributable fraction (i.e., fraction of observed deaths that may have been avoided) was 5.3% for current smokers versus never-smokers and 2.1% for current versus former smokers. CONCLUSIONS: Active smoking is prevalent in the chronic hemodialysis population and is associated with greater all-cause, cardiovascular, and infection-related morbidity and mortality. PMID- 22917701 TI - Dialysis search filters for PubMed, Ovid MEDLINE, and Embase databases. AB - BACKGROUND AND OBJECTIVES: Physicians frequently search bibliographic databases, such as MEDLINE via PubMed, for best evidence for patient care. The objective of this study was to develop and test search filters to help physicians efficiently retrieve literature related to dialysis (hemodialysis or peritoneal dialysis) from all other articles indexed in PubMed, Ovid MEDLINE, and Embase. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: A diagnostic test assessment framework was used to develop and test robust dialysis filters. The reference standard was a manual review of the full texts of 22,992 articles from 39 journals to determine whether each article contained dialysis information. Next, 1,623,728 unique search filters were developed, and their ability to retrieve relevant articles was evaluated. RESULTS: The high-performance dialysis filters consisted of up to 65 search terms in combination. These terms included the words "dialy" (truncated), "uremic," "catheters," and "renal transplant wait list." These filters reached peak sensitivities of 98.6% and specificities of 98.5%. The filters' performance remained robust in an independent validation subset of articles. CONCLUSIONS: These empirically derived and validated high-performance search filters should enable physicians to effectively retrieve dialysis information from PubMed, Ovid MEDLINE, and Embase. PMID- 22917702 TI - The primary care perspective on routine urine dipstick screening to identify patients with albuminuria. AB - Proponents of routine urine dipstick screening to identify patients at risk for ESRD in the primary care setting have argued that urine dipsticks are inexpensive, low risk, acceptable to patients, and now, more accurate. Proponents believe that urine dipstick screening has the potential to improve outcomes for people with early disease and increase awareness of CKD. Most primary care physicians agree that populations who are at high risk for CKD should be tested and appropriately treated to decrease complications of ESRD. However, proponents of mass screening may not appreciate the challenges, limitations, and potential harms of screening. Urine dipstick testing does not meet all of the criteria for a good screening test. Screening the general population with urine dipsticks will generate many false positives--between 50% and 90% of positive tests--that will require follow-up, increase costs, and cause patient anxiety. Routine screening with urine dipsticks is not cost-effective on the order of $200,000 per quality adjusted life year. Most importantly, there is little evidence that early identification of microalbuminuria in unselected patients influences outcomes of CKD. Without proof of effectiveness, overdiagnosis, a problem for even well established screening tests, is risked. Finally, no specialty society or preventive services group currently recommends general screening. Instead of screening, primary care physicians and nephrologists should work together to identify patients at high risk for ESRD and optimize management to improve outcomes for patients with CKD. PMID- 22917703 TI - Physical exercise, fasting glucose, and renal hyperfiltration in the general population: the Renal Iohexol Clearance Survey in Tromso 6 (RENIS-T6). AB - BACKGROUND AND OBJECTIVES: Abnormally elevated GFR, or hyperfiltration, is a proposed mechanism for kidney injury in diabetes, prediabetes, and obesity. This study investigated whether lack of physical exercise is associated with hyperfiltration and whether exercise modifies the positive association between fasting glucose and measured GFR. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: The Renal Iohexol Clearance Survey in Tromso 6 measured GFR as single-sample plasma iohexol clearance in 1506 members of the general population (age 50-62 years) without diabetes, cardiovascular disease, or kidney disease. Leisure-time physical exercise was assessed by a self-administered questionnaire. Hyperfiltration was defined as GFR above the 90th percentile after adjustment for sex, age, weight, height, and use of renin-angiotensin system inhibitors. RESULTS: High-intensity exercise was associated with lower adjusted odds of hyperfiltration in men (odds ratio [OR], 0.47; 95% confidence interval [CI], 0.28 0.80) but not in women (OR, 1.02; 95% CI, 0.60-1.72). In both sexes, high intensity exercise modified the association between fasting glucose and GFR. A fasting glucose level 1 mmol/L higher was associated with a GFR that was 7.3 (95% CI, 4.0-10.6) and 6.2 (95% CI, 3.4-9.0) ml/min per 1.73 m(2) higher in men and women who never exercised or exercised with low intensity. There was no association between fasting glucose and GFR in men and women who exercised with high intensity (interaction, P<0.001). CONCLUSIONS: High-intensity exercise was associated with lower odds of hyperfiltration in men and modified the association between glucose and GFR of both sexes in a population without diabetes. PMID- 22917704 TI - Lupus nephritis: maintenance therapy for lupus nephritis--do we now have a plan? AB - Lupus nephritis (LN) increases the morbidity and mortality of patients with SLE. This review compares the randomized, controlled trials that examined various maintenance regimens available to treat LN. Currently, mycophenolate mofetil (MMF) and azathioprine (AZA) are the most popular therapeutic agents used for long-term maintenance of LN. Long-term maintenance with MMF is recommended as the first choice after achieving remission with cyclophosphamide or MMF induction. MMF is effective in consolidating remission and preventing relapse and CKD in patients of diverse races and ethnicities. Long-term maintenance with AZA is the recommended second choice, especially when patients develop intolerance of or contraindications to MMF. Azathioprine is particularly effective in consolidating remission and preventing relapse and CKD in patients who receive an induction regimen of cyclophosphamide. To date, there are no data on how rapidly maintenance therapies can be withdrawn; however, it is recommended that the immunosuppressive therapy be maintained indefinitely, unless it is contraindicated, in patients at high risk for progression to CKD. PMID- 22917705 TI - Attracting more residents into nephrology. PMID- 22917707 TI - Increased production of circulating soluble co-stimulatory molecules CTLA-4, CD28 and CD80 in patients with rheumatoid arthritis. AB - Co-stimulatory molecules are key immunoregulatory mediators in regulating T lymphocyte-mediated immune responses and inflammatory reactions. Here we investigated whether there is altered expression and the clinical significance of circulating soluble co-stimulatory molecules in rheumatoid arthritis (RA) patients. Serum concentrations of sCTLA-4, sCD28, sCD80 and sCD86 in 56 RA patients, and 32 sex- and age-matched control subjects were measured by enzyme linked immunosorbent assay (ELISA). Results showed that serum sCTLA-4, sCD28, and CD80 but not CD86 concentrations in all RA patients were significantly higher than concentrations in healthy control subjects. And there was significant and positive correlation between serum CTLA-4 and sCD28, sCD28 and sCD80, or sCTLA-4 and sCD80 in all RA patients. Serum sCTLA-4 concentration in all RA patients correlated significantly with disease activity score in 28 joints (DAS28). Moreover, immunosuppressant treatment with leflunomide could downregulate the increased levels of sCTLA-4, sCD28, and CD80 in RA patients. Therefore, the elevated production of circulating soluble T-cell co-stimulatory molecules should contribute to the pathogenesis of RA, and serum sCTLA-4 could potentially serve as a new marker of RA disease activity. PMID- 22917706 TI - The association of albumin/creatinine ratio with postoperative AKI in children undergoing cardiac surgery. AB - BACKGROUND AND OBJECTIVES: This study determined if preoperative and postoperative urine albumin/creatinine ratios (ACRs) predict postoperative AKI in children undergoing cardiac surgery (CS). DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This was a three-center, prospective study (2007-2009) of 294 children undergoing CS (n=145 aged <2 years). Urine ACR was measured preoperatively and 0-6 hours after intensive care unit arrival. AKI outcomes were based on the Acute Kidney Injury Network serum creatinine (SCr) criteria (stage 1 AKI, >=50% or 0.3 mg/dl SCr rise from baseline; and stage 2 or worse AKI, >=SCr doubling or dialysis). AKI was predicted using preoperative and postoperative ACRs and postoperative ACR performance was compared with other AKI biomarkers. RESULTS: Preoperative ACR did not predict AKI in younger or older children. In children aged <2 years, first postoperative ACR >=908 mg/g (103 mg/mmol) predicted stage 2 AKI development (adjusted relative risk, 3.4; 95% confidence interval, 1.2-9.4). In children aged >=2 years, postoperative ACR >=169 mg/g (19.1 mg/mmol) predicted stage 1 AKI (adjusted relative risk, 2.1; 95% confidence interval, 1.1-4.1). In children aged >=2 years, first postoperative ACR improved AKI prediction from other biomarker and clinical prediction models, estimated by net reclassification improvement (P<=0.03), but only when serum cystatin C was also included in the model. CONCLUSIONS: Postoperative ACR is a readily available early diagnostic test for AKI after pediatric CS that performs similarly to other AKI biomarkers; however, its use is enhanced in children aged >=2 years and in combination with serum cystatin C. PMID- 22917708 TI - Malabaricone C suppresses lipopolysaccharide-induced inflammatory responses via inhibiting ROS-mediated Akt/IKK/NF-kappaB signaling in murine macrophages. AB - Malabaricone C (MLB-C), isolated from nutmeg, is a phenolic diarylnonanoid that is known to exert a variety of pharmacological activities. In the present study, we investigated the molecular actions of MLB-C against lipopolysaccharide (LPS) induced inflammatory responses in RAW264.7 cells and murine peritoneal macrophages. MLB-C inhibited the production of nitric oxide (NO), prostaglandin E(2) (PGE(2)), interleukin-6 (IL-6), and interferon-gamma (INF-gamma) in a dose dependent manner. Consistent with NO and PGE(2) inhibition, MLB-C suppressed LPS induced inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) expression as well as the promoter activities of COX-2 and iNOS. MLB-C pretreatment prevented LPS-induced nuclear factor-kappa B (NF-kappaB) activation through the inhibition of phosphorylation of IkappaB kinase (IKK), phosphorylation and degradation of IkappaBalpha, and nuclear translocation of NF kappaB. In addition, MLB-C blocked LPS-induced serine 536 phosphorylation and transcriptional activity of RelA/p65 subunit of NF-kappaB. Further study demonstrated that MLB-C inhibited LPS-induced Akt phosphorylation, which is an upstream activator of NF-kappaB, by reducing reactive oxygen species (ROS) accumulation, without affecting phosphorylation of mitogen-activated protein kinases (MAPKs). These findings indicate that MLB-C exerts an anti-inflammatory effect through the inhibition of NF-kappaB activation by inhibiting interconnected ROS/Akt/IKK/NF-kappaB signaling pathways. PMID- 22917709 TI - Use of personalized decision analysis in decision making for Palliative vs. surgical management of the oldest-old patients with localized skin cancer in a culturally sensitive environment: a case study of a 96-year-old male Taiwanese patient. AB - Clinical management of older cancer patients is challenging, especially for those in the oldest-old age group. In the Chinese culture, the preference toward noninvasive care for patients in this age group may create a difficult situation for clinicians when the cancer is potentially curable. Palliative care may not always be the obvious choice, especially if patients suffer from quality-of-life impairment because of symptoms related to progression of the untreated cancer. Balancing between higher rates of toxicities and potential gains in quality of life from anticancer therapies among the oldest old presents a real challenge in clinical practice. Decision analysis is an analytical tool that has a long history of successful application in clinical decision making. In this case study of a 96-year-old male with localized skin cancer, we demonstrate that personalized decision analysis can be a helpful tool to assist decision making in the clinical management of cancer patients in the oldest-old age group, especially in situations in which the evidence-based literature provides little guidance. This was achieved by providing information to help the key decision makers to better understand the risk-benefit trade offs and make an informed decision. We found that the option of surgical management was associated with higher expected quality-adjusted life years (0.894) than best supportive care (0.853). Based on this finding and various scenarios explored in sensitivity analyses, the family members recommended surgery for the patient. The patient recovered well from surgery and there is no evidence of recurrence to date. PMID- 22917710 TI - Do community specialist palliative care services that provide home nursing increase rates of home death for people with life-limiting illnesses? A systematic review and meta-analysis of comparative studies. AB - CONTEXT: Systematic reviews and meta-analyses suggest that community specialist palliative care services (SPCSs) can avoid hospitalizations and enable home deaths. But more information is needed regarding the relative efficacies of different models. Family caregivers highlight home nursing as the most important service, but it is also likely the most costly. OBJECTIVES: To establish whether community SPCSs offering home nursing increase rates of home death compared with other models. METHODS: We searched MEDLINE, AMED, Embase, CINAHL, the Cochrane Database of Systematic Reviews, and CENTRAL on March 2 and 3, 2011. To be eligible, articles had to be published in English-language peer-reviewed journals and report original research comparing the effect on home deaths of SPCSs providing home nursing vs. any alternative. Study quality was independently rated using Cochrane grades. Maximum likelihood estimation of heterogeneity was used to establish the method for meta-analysis (fixed or random effects). Potential biases were assessed. RESULTS: Of 1492 articles screened, 10 articles were found eligible, reporting nine studies that yielded data for 10 comparisons. Study quality was high in two cases, moderate in three and low in four. Meta-analysis indicated a significant effect for SPCSs with home nursing (odds ratio 4.45, 95% CI 3.24-6.11; P<0.001). However, the high-quality studies found no effect (odds ratio 1.40, 95% CI 0.97-2.02; P=0.071). Bias was minimal. CONCLUSION: A meta analysis found evidence to be inconclusive that community SPCSs that offer home nursing increase home deaths without compromising symptoms or increasing costs. But a compelling trend warrants further confirmatory studies. Future trials should compare the relative efficacy of different models and intensities of SPCSs. PMID- 22917711 TI - Armodafinil for sarcoidosis-associated fatigue: a double-blind, placebo controlled, crossover trial. AB - CONTEXT: Fatigue has been identified in more than one-half of patients with sarcoidosis. Although fatigue is not synonymous with impaired quality of life, most studies of sarcoidosis identify fatigue as a major cause of impaired quality of life. OBJECTIVES: To test the hypothesis that stimulants may have a role in the treatment of fatigued sarcoidosis patients, even without objective evidence of daytime sleepiness. METHODS: This was a double-blind, placebo-controlled, crossover study of sarcoidosis patients followed up in one sarcoidosis clinic Sarcoidosis patients with fatigue received either armodafinil or placebo with eight weeks of therapy for each arm and a two week washout period before crossover to the other treatment. Initial armodafinil dose was 150mg and increased to 250mg after four weeks. Patients underwent polysomnography and multiple sleep latency testing (MSLT) the following day. Patients with an apnea/hypopnea index <6/hour received either armodafinil or placebo. Polysomnography with MSLT was repeated after each treatment arm. RESULTS: Fifteen patients received the study drug. Fatigue was assessed using the Fatigue Assessment Scale (the lower the score, the less the fatigue) and the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) (the higher the score, the less the fatigue). After eight weeks of therapy, there was a significant improvement in the Fatigue Assessment Scale during armodafinil treatment (median 4.5, range -20, 5) compared with placebo treatment (median 3.5, range -9, 14, P<0.05) and for the FACIT-F (armodafinil: median 9, range -12, 26 vs. placebo: median -5, range -17, 11, P<0.005). This improvement in fatigue was seen for both those with and without shortened sleep onset latency time during the MSLT. CONCLUSION: Armodafinil treatment led to a significant reduction in fatigue in sarcoidosis patients. This effect was seen even in patients who did not have excessive daytime somnolence. PMID- 22917713 TI - The relationship between spirituality, psychosocial adjustment to illness, and health-related quality of life in patients with advanced chronic kidney disease. AB - CONTEXT: Spirituality may promote psychosocial adjustment to illness, and this may be a mechanism by which patients with greater existential well-being (EWB) experience better health-related quality of life (HRQL) in the context of life limiting illness. OBJECTIVES: This study explored the relationship between psychosocial adjustment to illness, EWB, and HRQL in patients with advanced chronic kidney disease and sought to determine whether adjustment to illness mediates the relationship between EWB and HRQL. METHODS: This was a cohort study of 253 prevalent Stage 4 or 5 chronic kidney disease and dialysis patients. Participants completed the Spiritual Well-Being Scale, the Psychological Adjustment to Illness Scale (PAIS)-Self-Report, and the Kidney Dialysis Quality of Life Short Form. RESULTS: Psychosocial adjustment to illness was highly correlated with HRQL, accounting for 29% and 27% of the variance in physical and mental HRQL scores, respectively. Although PAIS domains were associated with EWB, EWB remained a significant predictor of HRQL after all PAIS domains were considered. Adjustment in the domains of psychological distress and extended family relationships did appear to mediate some of the relationship between EWB and HRQL. CONCLUSION: Adjustment in the domains of psychological distress and extended family relationships appears to mediate some of the beneficial effect of EWB on HRQL. Spirituality, however, provides unique variance in patients' HRQL, independent of their psychosocial adjustment. This study testifies to the importance of targeting both psychosocial adjustment to illness and spirituality as ways to preserve or enhance HRQL of predialysis and dialysis patients. PMID- 22917712 TI - Lack of energy: an important and distinct component of HIV-related fatigue and daytime function. AB - CONTEXT: Fatigue is a prevalent symptom among adults living with HIV. There is increasing evidence that fatigue and energy are related, yet distinct constructs. Although HIV-related fatigue has been well studied, little is known about perceived energy and how it relates to fatigue, individual characteristics, and other symptoms. OBJECTIVES: To describe the experience of perceived energy in adults with HIV and evaluate its relationship to demographic and clinical characteristics as well as symptoms of fatigue, sleep disturbance, anxiety, depression, and daytime function. METHODS: The design was descriptive, comparative, and correlational. The sample of 318 adults with HIV completed a demographic questionnaire; the Memorial Symptom Assessment Scale; and measures of fatigue, sleep disturbance, anxiety, depressive symptoms, and daytime function. Medical records were reviewed for disease and treatment data. Participants who reported a lack of energy were compared with those who did not on demographic, clinical, and symptom variables. Regression models of perceived energy and its interference with daytime function also were evaluated. RESULTS: Perceived lack of energy was highly prevalent (65%) and more strongly related to interference with daytime function than more general measures of fatigue severity, even when controlling for other characteristics and symptoms. Like other aspects of fatigue, lack of energy was associated with sleep disturbance, anxiety, and depressive symptoms. Lack of energy was more strongly related to morning fatigue than to evening fatigue. CONCLUSION: Lack of energy interferes with daytime function and is not just the inverse of fatigue but a distinct perception that differs from fatigue. PMID- 22917714 TI - Cross-cultural translation and adaptation to Brazilian Portuguese of the paediatric pain profile in children with severe cerebral palsy. AB - CONTEXT: Pain is a prevalent symptom in children with severe cerebral palsy (CSCP), mainly as a result of the progression of muscle contractures, bone deformities, gastroesophageal reflux, and recurrent infections. Considering the lack of verbal communication in this population, both pain diagnosis and assessment of the analgesic treatment are often neglected. Although the Paediatric Pain Profile (PPP), an instrument with 20 items, is used to assess behavior indicative of pain in CSCP, it is not validated in Brazil. OBJECTIVES: To translate, adapt, and evaluate the psychometric properties of the PPP to Brazilian Portuguese. METHODS: The study was carried out at a philanthropic institution for CSCP and a university hospital. The sample of CSCP unable to communicate through speech or any device, their respective parents or primary caregivers, and health professionals were included. First, the instrument was translated and then back translated, and its clarity was evaluated by parents, primary caregivers, and professionals. The psychometric properties of the final version were evaluated for internal consistency (Cronbach's alpha) and stability (test-retest). RESULTS: Forty-five children with a mean (SD) chronological age of 16 (8.69) years, 26 of whom were male, were included in the study. A total of 150 applications of PPP were carried out: 30 to assess clarity and 120 to assess the psychometric properties. Each item of the translated version showed a median between 3.00 and 4.00, considered to be clear and very clear, respectively. The internal consistency of the items was alpha=0.864, with no significant difference between test and retest (P=0.271). CONCLUSION: The adapted version of the PPP in Brazilian Portuguese demonstrated good internal consistency (similar to the original instrument) and stability over time, decisive for the next step of clinical validation for CSCP. PMID- 22917715 TI - Prevalence and severity of pruritus and quality of life in patients with cutaneous T-cell lymphoma. AB - CONTEXT: Cutaneous T-cell lymphoma (CTCL), although rare, is associated with a significant symptom burden. Pruritus appears to be one of the most prominent and disturbing symptoms. OBJECTIVES: To describe the prevalence and severity of pruritus and quality of life (QOL) in patients with CTCL. METHODS: Patients with CTCL able to complete two questionnaires were invited to complete a visual analogue scale for itch (VAS(itch)) and the Skindex-29. Prevalence of pruritus, mean score, and SD were estimated for the VAS(itch) and Skindex-29, and the Pearson's correlation coefficient was calculated to evaluate the relationship between severity of pruritus and QOL. RESULTS: One hundred patients were recruited (mean [SD] age 57.9 [12.9] years, range 30-86 years). Eighty-eight percent reported pruritus in the preceding four weeks, 46% indicating that it was often or always a problem. The mean (SD) of VAS(itch) (n=92) was 3.2 (3.2), range zero to 10. The mean (SD) total Skindex-29 score was 43.3 (27.7). More advanced disease stage was associated with poorer QOL. The Skindex-29 correlated strongly with the VAS(itch) (Pearson's correlation coefficient=0.72, P<0.001). CONCLUSION: All aspects of QOL are affected in CTCL. Pruritus is a common and troublesome symptom. A more advanced disease stage and more severe pruritus symptoms were associated with poorer QOL in this study. PMID- 22917717 TI - Advance care planning and dying in nursing homes in Flanders, Belgium: a nationwide survey. AB - CONTEXT: In Belgium, data on actual advance care planning (ACP) in nursing homes (NHs) are scarce. OBJECTIVES: To investigate the prevalence and characteristics of documented advance directives and physicians' orders for end-of-life care in NHs, and the authorization of a legal representative in relation to the residents' demographic and clinical characteristics and care received. METHODS: This was a retrospective cross-sectional study, including all NH residents deceased during September and October 2006 in all 594 NHs in Flanders, Belgium. Structured mail questionnaires about the resident's characteristics, hospital transfers, palliative care delivery, ACPs, and authorization of legal representatives were completed via the NH administrators and nurses involved in the care of the resident. RESULTS: Administrators of 318 NHs (53.5%) reported 1303 deaths. Nurses provided information about 1240 (95.2%) of these deaths. At the end of life, NH residents often had dementia (65.2%) and were severely dependent (76.1%). Almost half (43.1%) had at least one hospital transfer during the last three months of life and two-thirds received palliative care. Half had an ACP, predominantly a physician's order and less often an advance directive. Having advance directives or physician's orders was associated with receiving palliative care. Residents with a physician's order more often died in the NH. Nine percent had an authorized legal representative. CONCLUSION: Prevalence of ACPs and formal authorization of a legal representative was low among the deceased NH residents in Flanders, Belgium. There was a higher prevalence of physicians' orders, often established after the resident had lost capacity. Initiatives should be developed to stimulate more advance discussion on care options and making end-of-life decision with the residents while they retain capacity. PMID- 22917716 TI - Characteristics of advanced cancer patients with cancer-related fatigue enrolled in clinical trials and patients referred to outpatient palliative care clinics. AB - CONTEXT: Limited published data exist on whether characteristics of patients with advanced cancer enrolled in cancer-related fatigue clinical trials (CCTs) differ from patients in outpatient palliative care clinics (OPCs). OBJECTIVES: The primary aim of this study was to compare the characteristics of two groups of patients with advanced cancer and moderate-to-severe fatigue: patients in CCTs and patients at an OPC. METHODS: We retrospectively reviewed the records of 337 patients who were enrolled in one of five CCTs for advanced cancer patients at The University of Texas M. D. Anderson Cancer Center as well as the records of 1896 consecutive patients who were referred to our OPC from January 2003 through December 2010. Patients with fatigue scores of >=4/10 (measured by the Edmonton Symptom Assessment System [ESAS]) were eligible (1252 OPC patients and 337 CCT patients). Patient characteristics, ESAS scores, and survival times were compared using Chi-square tests, Wilcoxon rank sum tests, and the Kaplan-Meier method. RESULTS: Compared with the CCT patients, OPC patients were more likely to be older (58 vs. 59 years; P=0.009) and male (38% vs. 52%; P<0.001). The most common primary cancer type was breast cancer (22%) in the CCT patients and lung cancer (23%) in the OPC patients (P<0.001). The median ESAS scores in the OPC and CCT groups, respectively, were 6 and 4 for pain (P<0.001), 7 and 7 for fatigue (P=0.525), 3 and 2 for depression (P=0.004), 3 and 2 for anxiety (P<0.001), 3 and 2 for dyspnea (P<0.001), and 43 and 32 for the symptom distress score (P<0.001). The median overall survival times were 17.9 months (95% CI 13.5-22.3 months) in the CCT group and 3.8 months (95% CI 3.5-4.1 months) in the OPC group (P<0.001). CONCLUSION: Baseline characteristics and overall survival times significantly differed between patients enrolled in the CCT and OPC groups. Therefore, we conclude that the results of CCTs cannot be generalized to patients being treated in OPCs. PMID- 22917718 TI - Use of prophage free host for achieving homogenous population of bacteriophages: new findings. AB - We demonstrate that the prophage status of bacteria plays a critical role in achieving homogenous population of a phage preparation. When a lytic Staphylococcus bacteriophage 44AHJD was propagated in a Staphylococcus clinical isolate, the enriched phage showed 44AHJD phage virions along with the released prophages from the baiting host. The released prophage was identified as a siphophage by transmission electron microscopy. To obtain a phage preparation free of prophages, when we carried out multiplication of the 44AHJD phage in a prophage free Staphyloccoccus aureus host namely RN4220, we were surprised not to see any phage plaques in spite of the phage exhibiting >99.9% adsorption to such cells. Since RN4220 host is devoid of restriction modification system and prophages, we hypothesized that in spite of successful infection and multiplication, the phage virions might have failed to show plaques due to its insignificant release from the cell possibly due to insufficient endolysin expressed from phage virions during phage development and assembly. Our hypothesis was confirmed when we observed plaques of 44AHJD phage in RN4220 cells where additional phage endolysin protein was supplemented via a plasmid. Endolysin protein from various types of Staphylococcus phages showed plaques of 44AHJD in RN4220 cells confirming our hypothesis. Also, we demonstrate for the first time that propagation of 44AHJD phage with endolysin supplementation in prophage free RN4220 host yields pure phage preparation. PMID- 22917719 TI - A multiplex assay to detect variations in the CYP2C9, VKORC1, CYP4F2 and APOE genes involved in acenocoumarol metabolism. AB - OBJECTIVES: We have developed a genotyping system to determine the alleles of genes related to interindividual variability in acenocoumarol dosage requirements. This genotyping system is intended for routine clinical use and therefore it is essential that it be simple, fast and inexpensive. DESIGN AND METHODS: We developed a PCR multiplex SNaPshot reaction that targets 6 SNPs (single nucleotide polymorphisms) in CYP2C9, CYP4F2, VKORC1 and APOE genes, which are associated with acenocoumarol dose requirements. RESULTS: We tested the multiplex in 152 samples and found it to be 100% concordant with the results of other methods. CONCLUSIONS: We successfully produced a reliable multiplex system for simultaneously typing 6 SNPs. This system may be used as a model for accurate, simple and inexpensive genotyping of SNPs related to dose requirements. This information allows the prediction of drug efficiency in patients prior to treatment with acenocoumarol and the prevention of adverse drug reactions. PMID- 22917721 TI - In pursuit of perfection: "alive and better" as the measure of procedural success. PMID- 22917722 TI - Not all drug-eluting balloons are equally good for patients, not all patients are equally suitable for drug-eluting balloons. PMID- 22917723 TI - Multivessel versus culprit-only revascularisation in ST elevation acute myocardial infarction: facts and criticism. PMID- 22917724 TI - The latest news about the ESCeL Platform. PMID- 22917725 TI - Quality of life improvement is maintained up to two years after transcatheter aortic valve implantation in high-risk surgical candidates. AB - AIMS: The aim of the study was to investigate the changes in quality of life (QoL) following transcatheter aortic valve implantation (TAVI) up to two years' follow-up. METHODS AND RESULTS: One hundred consecutive patients (46 females, mean age 79.7 +/- 6.1 years) with at least two years' follow-up who underwent TAVI in our institution, between November 2007 and September 2009, were enrolled in this study. Peak and mean aortic gradients were 87.8 +/- 25.8 mmHg and 53.3 +/ 15.4 mmHg, respectively. Mean log EuroSCORE was 27.9 +/- 15.9. Patients had multiple comorbidities. All patients underwent a standardised prospective screening pathway, including QoL evaluation with the 36-item short-form health survey (SF-36v2((r))) and the Minnesota Living with Heart Failure Questionnaires (MLHFQ). The scores obtained preoperatively were compared with those obtained at two years' follow-up. An Edwards SAPIEN valve (Edwards Lifesciences, Irvine, CA, USA) was implanted in 67 patients (55 transfemoral and 12 transapical) and a CoreValve (Medtronic, Inc., Minneapolis, MN, USA) was implanted in 33 patients (26 transfemoral and seven transaxillary). Thirty-day mortality was 4%. Actuarial survival was 80.6 +/- 4.1%, 72.6 +/- 4.7% and 63.2 +/- 6.3% at one, two and three years, respectively. Mean SF36-physical improved from 31.9 +/- 8.8 to 51.5 +/- 9.5 (p<0.0001) and SF36-mental improved from 44.7 +/- 11.6 to 49.5 +/- 8.6 (p=0.0002). Mean MLHFQ decreased from 41.5 +/- 14.5 to 15.9 +/- 13.7 (p<0.0001). QoL score changes were not influenced by age or comorbidities. CONCLUSIONS: TAVI in high-risk surgical candidates is associated with favourable short and long term survival and with improvement of QoL up to two years after the procedure. PMID- 22917726 TI - Improvement of physical and mental health after transfemoral transcatheter aortic valve implantation. AB - AIMS: Transcatheter aortic valve implantation (TAVI) has emerged as a treatment alternative to surgical aortic valve replacement in elderly high-risk patients with symptomatic severe aortic stenosis. In this patient population, rapid improvement or restoration of quality of life (QoL) is at least as important as improved clinical outcomes. The purpose of the present study was to assess changes in QoL in response to TAVI. METHODS AND RESULTS: Between August 2007 and August 2010, 62 patients (39% females, age 83 +/- 5 years) underwent TAVI and were included in this QoL study. QoL was impaired at baseline and improved in all components of physical and mental health at nine months of follow-up: physical functioning (37.0 to 59.0, p<0.0001), physical role functioning (18.3 to 49.1, p<0.0001), general health (55.9 to 64.9, p=0.001), vitality (40.7 to 51.3, p<0.001), social functioning (67.4 to 76.8, p=0.049), emotional functioning (52.0 to 75.8, p<0.001) and mental health (66.6 to 75.8, p=0.05). The subscale bodily pain (60.7 to 70.4, p=0.058) showed a strong trend to improvement, but failed to reach statistical significance. Besides changes in health-related QoL, TAVI significantly improved symptoms (NYHA class 2.6 +/- 0.8 to 1.4 +/- 0.6, p<0.0001). CONCLUSIONS: TAVI leads to rapid and sustained restoration of all aspects of mental and physical health and effectively alleviates symptoms. PMID- 22917727 TI - Comparison of two drug-eluting balloons: a report from the SCAAR registry. AB - AIMS: Recently, drug-eluting balloons have received a guideline class IIa recommendation in the treatment of in-stent restenosis after bare metal stent implantation. It is not known if different balloons perform equally. Using a large real world registry, restenosis frequency was reported for two drug-eluting balloons. METHODS AND RESULTS: From April 2009 until September 2011, 1,129 patients were treated with paclitaxel-eluting balloons in Sweden. Mean follow-up was 328 +/- 210 days. Nine hundred and nineteen patients were treated with a balloon using a contrast agent as a drug-carrier and 217 with a balloon without a contrast agent as a drug-carrier. The indications were predominantly de novo (45.4%) or in-stent restenotic (51.8%) lesions. The overall incidence of restenosis at six months was 3.4% with the paclitaxel balloon using a contrast agent as carrier, compared with 12.5% with the paclitaxel-eluting balloon without a carrier (risk ratio: 0.42; 95% confidence interval [CI] [0.26-0.68]). After adjusting for indications, lesion types and procedural factors, the risk ratio was 0.39; 95% CI (0.24-0.65). CONCLUSIONS: This observational study from a large real world population shows a major difference between two paclitaxel-eluting balloons. The findings suggest that there are no class effects for drug-eluting balloons and factors other than the drug may be important for the clinical effect. PMID- 22917728 TI - Paclitaxcel-coated balloon plus bare metal stent vs. sirolimus-eluting stent in de novo lesions: an IVUS study. AB - AIMS: Restenosis after PCI and/or stent implantation is still one of the challenging problems in the field of interventional cardiology. Different approaches to prevent and to treat restenosis include the use of drug-eluting stents, which have shown to reduce restenosis. Another approach is the treatment with drug-coated balloons. This approach has been proven for different indications, e.g., in-stent restenosis and treatment of peripheral artery disease. METHODS AND RESULTS: Patients from the PEPCAD III multicentre randomised trial in two study centres (Homburg and Hannover, Germany) were asked to participate in this intravascular ultrasound (IVUS) study at nine-month follow up. At baseline (nine months before), patients were randomly assigned to receive either a paclitaxel-coated balloon (drug-coated balloon [DCB]) plus a premounted bare metal stent (DCB/BMS) or a sirolimus-eluting stent (drug-eluting stent [DES]) to treat de novo lesions. IVUS at follow-up was performed in order to analyse the restenosis for potential understanding of the mechanism leading to restenosis. IVUS data is available for 55 patients; 26 patients were treated with Cypher((r)) DES (Cordis, Miami Lakes, FL, USA) and 29 patients with DCB/BMS. A focal malapposition of the stent was seen in six patients; four after DES and two after DCB/BMS. Stent expansion, calculated as symmetric expansion index, was equal for both groups (0.89 and 0.90). Mean stent area was also equal for both groups (6.25 +/- 1.7 vs. 5.65 +/- 1.5 mm(2), p=n.s.). The neointimal hyperplasia (calculated as stent area minus lumen area) was significantly different between both groups (0.69 +/- 0.49 [DES] vs. 1.08 +/- 0.53 mm(2) [DCB/BMS], p<0.01). This resulted in a significantly higher in-stent restenosis in the DCB/BMS group (19.7 vs. 11 %, p<0.01). There is no evidence of geographical mismatch. CONCLUSIONS: First IVUS insights for the DCB/BMS showed a comparable, low incidence of malapposition for the combination of drug-coated balloon and premounted bare metal stent compared to the DES, and stent expansion was good and comparable to DES. However, at nine-month follow-up, the combination of drug-coated balloon and premounted bare metal stent showed higher in-stent restenosis compared to sirolimus DES. Geographical mismatch can be excluded as a reason for this result. PMID- 22917730 TI - Contemporary use and outcome of percutaneous coronary interventions in patients with acute coronary syndromes: insights from the 2010 ACSIS and ACSIS-PCI surveys. AB - AIMS: In patients with acute coronary syndromes (ACS), percutaneous coronary intervention (PCI) is the mainstay of treatment based on current guidelines. In this paper we describe contemporary management and outcomes of patients with ACS treated by PCI in the national ACS Israeli survey (ACSIS) performed in March and April 2010. METHODS AND RESULTS: The ACSIS 2010 registry was conducted in all 25 hospitals in Israel and included "all comers" admitted with ACS. In-hospital and 30-day outcome was assessed. The registry included 2,193 patients with ACS. Coronary angiography was performed in 86.1% and PCI in 75.1% of cases. The mean age was 62.5 years, the transradial approach was used in 32% of patients and overall use of drug-eluting stents was 34%. Procedural complications were extremely low at less than 1%. The thirty-day mortality rate was 2.1% and the repeated myocardial infarction (MI) rate was 2.5%. The major adverse cardiac and cerebral events (MACCE) rate was 5.6%. Multivariable analysis identified age, chronic renal failure, and hyperglycaemia on admission as independent predictors of 30-day mortality for all subsets of ACS, and Killip class >I on admission and prior MI for patients with ST-elevation ACS only. CONCLUSIONS: When evidence based medicine is applied in the treatment of patients with ACS, clinical outcome is favourable. Several clinical predictors identify high-risk patients who require special attention. PMID- 22917729 TI - Culprit only or multivessel percutaneous coronary interventions in patients with ST-segment elevation myocardial infarction and multivessel disease. AB - AIMS: In patients with ST-segment elevation myocardial infarction (STEMI), timely reperfusion with primary percutaneous coronary intervention (PPCI) is the preferred treatment. However, it remains unclear whether the optimal strategy is complete revascularisation or culprit vessel PPCI only. METHODS AND RESULTS: From January 2002 to June 2009 all patients treated with PPCI were identified from the Western Denmark Heart Registry. We examined mortality according to timing of multivessel PCI: acute procedure, staged procedure during the index hospitalisation, or staged procedure performed within 60 days. The hazard ratio (HR) for death was estimated using a time-dependent Cox regression model, with time of PCI for the non-culprit lesion as the time-dependent variable. The study cohort consisted of 5,944 patients, of whom 4,770 (80%) had single-vessel disease and 1,174 (20%) had multivessel PCI within 60 days. Among 354 (30.2%) patients with acute multivessel PCI, 194 (16.5%) patients with multivessel PCI during the index hospitalisation, and 626 (53.3%) patients with multivessel PCI within 60 days after the index hospitalisation, the adjusted HRs for one-year mortality were 1.53 (95% confidence interval (CI): 1.07-2.18), 0.60 (95% CI: 0.28-1.26), and 0.28 (95% CI: 0.14-0.54), respectively, compared to patients with single vessel disease. CONCLUSIONS: Acute multivessel PCI in patients with STEMI was associated with increased mortality. PMID- 22917731 TI - Time-related impact of distal embolisation on myocardial perfusion and survival among patients undergoing primary angioplasty with glycoprotein IIb-IIIa inhibitors: insights from the EGYPT cooperation. AB - AIMS: Considerable interest has been focused in recent years on the role of distal embolisation as a major determinant of impaired reperfusion after primary angioplasty for STEMI. The aim of the current study was to evaluate in a large cohort of STEMI patients undergoing primary angioplasty with glycoprotein (Gp) IIb-IIIa inhibitors, whether the impact of distal embolisation on myocardial perfusion and survival may depend on time-to-treatment. METHODS AND RESULTS: Our population is represented by 1,182 patients undergoing primary angioplasty for STEMI included in the EGYPT database. Patients were grouped according to time-to treatment (<3 hours, 3-6 hours, >6 hours). Distal embolisation was defined as an abrupt "cutoff" in the main vessel or one of the coronary branches of the infarct related artery, distal to the angioplasty site. Myocardial perfusion was evaluated by angiography or ST-segment resolution, whereas infarct size was estimated by using peak creatine kinase (CK) and CK-MB. Follow-up data were collected between 30 days and one year after primary angioplasty. Distal embolisation was observed in 132 patients (11.1%) and tended to occur more frequently in late presenters (p=0.067). Patients with distal embolisation less often had post-procedural Thrombolysis In Myocardial Infarction (TIMI) 3 flow (p<0.001), post-procedural myocardial blush grade (MBG) 2-3 (p<0.001), complete ST-segment resolution (p=0.021) and larger infarct size (p=0.012). Distal embolisation was associated with a significantly higher mortality (9.2% vs. 2.7%, heart rate [HR] [95% CI]=3.41 [1.73-6.71], p<0.0001). The impact of distal embolisation on myocardial perfusion and survival persisted for all time intervals. CONCLUSIONS: This study showed that among STEMI patients treated with Gp IIb-IIIa inhibitors, the negative impact of distal embolisation on myocardial perfusion and mortality is independent of the time from symptom onset to balloon angioplasty. PMID- 22917732 TI - Optical coherence tomography assessment of the spatial distribution of culprit ruptured plaques and thin-cap fibroatheromas in acute coronary syndrome. AB - AIMS: Plaque rupture and subsequent thrombosis is known to be the most important pathology leading to acute coronary syndrome (ACS). We investigated by optical coherence tomography (OCT) whether in ACS there is an association of the location of the culprit plaque in the coronary tree with plaque rupture and/or thin cap fibroatheroma (TCFA). METHODS AND RESULTS: We included 74 patients presenting with ACS that underwent OCT study of the culprit lesion. The distance of the culprit lesion from the ostium was measured angiographically, and the presence of rupture and/or TCFA was assessed by OCT. Sixty-seven patients were analysed. Forty-five ruptured plaques were identified by OCT (67.1%). The distance from the ostium was lower for culprit ruptured plaques versus culprit non-ruptured plaques (p<0.01), particularly in the left anterior descending (LAD) and the left circumflex (LCx) arteries. The majority of culprit ruptured plaques (68.9%) was located in the proximal 30 mm of the coronary arteries. A distance from the ostium of <=30.54 mm predicted plaque rupture with 71.1% sensitivity and 68.2% specificity. Culprit lesions in the proximal 30 mm are associated with rupture (p<0.05), TCFA (p<0.05), and lower minimal cap thickness (p<0.05). CONCLUSIONS: Culprit ruptured plaques in ACS seem to be predominately located in the proximal segments of the coronary arteries. PMID- 22917733 TI - Vasomotor function and re-endothelialisation after implantation of biodegradable abluminal polymer coated paclitaxel-eluting stents in rabbit iliac arteries: a time-course study. AB - AIMS: To evaluate the time-course of vasomotor function and re-endothelialisation after implantation of a novel platinum-chromium (PtCr) abluminal biodegradable polymer-coated paclitaxel-eluting stent (PES, Labcoat Element) in rabbit iliac arteries. METHODS AND RESULTS: Either PES (n=18) or an identical platform of bare metal stents (BMS, Element, n=18) were implanted in rabbit iliac arteries (six animals per time-point). At 14, 30, and 90 days, acetylcholine- and nitroglycerine-induced vasomotor reactivity at 5-10 mm distal to the stent was measured. Subsequently, the animals were terminated. The stented artery was bisected longitudinally for either SEM or en face CD31 immunochemistry examination. All arteries were patent with normal angiographic flow. Decreased endothelial-dependent vasomotion was found at both 14 and 30 days for PES compared to BMS (p<0.01, respectively); however, these differences resolved by 90 days. Endothelial-independent vasorelaxation was similar at all three time points. Both SEM and en face staining demonstrated equivalent endothelial coverage on the surface of the stented segments above and between struts at all time-points. CONCLUSIONS: This novel bioabsorbable polymer abluminal-coated PES demonstrated vasomotor function comparable to BMS within three months post deployment in the rabbit iliac model. Despite indistinguishable endothelial cell coverage on the stent surface between groups, earlier differences in vasomotion were detected: this finding suggests that the timing of restoration vasomotor function lags morphologic endothelial recovery. PMID- 22917734 TI - How should I treat a retrograde dissection of the aortic sinus of Valsalva during a percutaneous coronary intervention? PMID- 22917735 TI - Hepatic embolotherapy in interventional oncology: technology, techniques, and applications. AB - Embolotherapy continues to play a growing role in the management of primary and secondary hepatic malignancies. In this review article, we examine the basis of therapy with a focus on neovascularization, which makes treatments via the hepatic artery possible. An overview of the three generations of embolic and therapeutic agents follows. The techniques, technologies, and complications of bland embolization, transarterial chemoembolization, drug-eluting beads, and selective internal radiotherapy are covered to give the reader an overview of this exciting field in interventional radiology. PMID- 22917736 TI - Role of trapped air in the formation of cell-and-protein micropatterns on superhydrophobic/superhydrophilic microtemplated surfaces. AB - Air trapped within the interstices of TiO(2) nanotube surfaces bearing superhydrophobic/superhydrophilic microtemplated domains controls formation of protein micropatterns but not cell micropatterns. Protein binding from either bovine-serum albumin (BSA) or fetal-bovine serum (FBS) solutions to superhydrophobic domains is blocked in the presence of trapped air, leading to clear protein binding contrast between superhydrophilic and superhydrophobic domains. Protein binds to superhydrophobic domains when air is displaced by sonication, leading to more protein binding to superhydrophobic domains than to superhydrophilic, with concomitantly blurred protein binding contrast. The overall contrast obtained in formation of cell (hFOB1.19, MG63, and HeLa) micropatterns depends on the cell type and protein composition of the fluid phase. All cell types preferentially attach to superhydrophilic domains from each fluid phase tested (FBS, BSA, and basal media containing no protein). All cell types do not attach to superhydrophobic domains from FBS solutions, with-or without trapped air, creating a visually-obvious cell attachment pattern. However, cells attached to superhydrophobic domains from basal media suspensions, with-or-without trapped air, creating a blurred cell attachment pattern. Cell attachment from BSA-containing solutions gave mixed results depending on cell type. Thus, trapped air does not necessarily block cell attachment as has been suggested in the literature. Rather, cell attachment is controlled by interfacial tensions between cells, surfaces, and fluid phases in a manner that can be understood in terms of the Dupre work-of-adhesion formulation. Cell attachment patterns developed within the initial attachment phase persist for up to two days of continuous culture but overgrow thereafter, with-or-without trapped air, showing that trapped air does not block cell overgrowth over time of continuous culture. PMID- 22917737 TI - The effect of glycomimetic functionalized collagen on peripheral nerve repair. AB - Increasing evidence suggests that the improper synaptic reconnection of regenerating axons is a significant cause of incomplete functional recovery following peripheral nerve injury. In this study, we evaluate the use of collagen hydrogels functionalized with two peptide glycomimetics of naturally occurring carbohydrates-polysialic acid (PSA) and human natural killer cell epitope epitope (HNK-1)-that have been independently shown to encourage nerve regeneration and axonal targeting. Our novel biomaterial was used to bridge a critical gap size (5 mm) in a mouse femoral nerve injury model. Functional recovery was assessed using gait and hind limb extension, and was significantly better in all glycomimetic peptide-coupled collagen conditions versus non-functional scrambled peptide coupled collagen, native collagen, and saline controls. Analysis of cross sections of the regenerated nerve demonstrated that hydrogels coupled with the PSA glycomimetic, but not HNK, had significant increases in the number of myelinated axons over controls. Conversely, hydrogels coupled with HNK, but not PSA, showed improvement in myelination. Additionally, significantly more correctly projecting motoneurons were observed in groups containing coupled HNK-1 mimicking peptide, but not PSA mimicking peptide. Given the distinct morphological outcomes between the two glycomimetics, our study indicates that the enhancement of recovery following peripheral nerve injury induced by PSA- and HNK-functionalized collagen hydrogels likely occurs through distinct mechanisms. PMID- 22917738 TI - Polydopamine-mediated immobilization of multiple bioactive molecules for the development of functional vascular graft materials. AB - In this study, we introduced a simple method for polydopamine-mediated immobilization of dual bioactive factors for the preparation of functionalized vascular graft materials. Polydopamine was deposited on elastic and biodegradable poly(lactic acid-co-E-caprolactone) (PLCL) films, and a cell adhesive RGD containing peptide and basic fibroblast growth factor were subsequently immobilized by simple dipping. We used an enzyme-linked immunosorbent assay and fluorescamine assay to confirm that we had stably immobilized bioactive molecules on the polydopamine-coated PLCL film in a reaction time-dependent manner. When human umbilical vein endothelial cells (HUVEC) were cultured on the prepared substrates, the number of adherent cells and proliferation of HUVEC for up to 14 days were greatest on the film immobilized with dual factors. On the other hand, the film immobilized with RGD peptide exhibited the highest migration speed compared to the other groups. The expression of cluster of differentiation 31 and von Willebrand factor, which indicates maturation of endothelial cells, was highly stimulated in the dual factor-immobilized group, and passively adsorbed factors showed a negligible effect. The immobilization of bioactive molecules inspired by polydopamine was successful, and adhesion, migration, proliferation and differentiation of HUVEC were synergistically accelerated by the presence of multiple signaling factors. Collectively, our results have demonstrated that a simple coating with polydopamine enables the immobilization of multiple bioactive molecules for preparation of polymeric functionalized vascular graft materials. PMID- 22917740 TI - Moderators of working memory deficits in children with attention deficit/hyperactivity disorder (ADHD): a meta-analytic review. AB - Working memory has assumed a prominent role as a primary neurocognitive deficit or endophenotype in extant models of attention-deficit/hyperactivity disorder (ADHD). The current study updated previous reviews and employed meta-analytic techniques to examine a broad range of moderating variables of effect size heterogeneity across phonological and visuospatial working memory tasks. Collectively, results revealed large between-group effect sizes across both working memory domains. In addition, several sample (percent female) and task (number of experimental trials, recall vs. recognition tasks, and demands on the central executive) moderating variables explained significant effect size variability among phonological and visuospatial studies. These findings suggest that children with ADHD exhibit statistically significant, large magnitude working memory deficits relative to their typically developing peers. PMID- 22917741 TI - How related are hair pulling disorder (trichotillomania) and skin picking disorder? A review of evidence for comorbidity, similarities and shared etiology. AB - Hair pulling disorder (HPD; trichotillomania) and skin picking disorder (SPD) are relatively common and potentially severe psychiatric conditions that have received limited empirical attention. Researchers are increasingly recognizing the similarities and co-occurrence of HPD and SPD, and several authors have suggested that the two disorders should be categorized together in the DSM-5. In the present article, we critically examined the evidence for comorbidity of HPD and SPD, and reviewed a diverse literature pertaining to shared risk factors and similarities in clinical characteristics. Evidence suggests that the two disorders co-occur more often than can be expected by chance, have substantial similarities in a variety of clinical characteristics (e.g., symptom presentation and course of illness) and may have some distal risk factors in common (e.g., genetic vulnerabilities). Implications for classification in the DSM-5, clinical management and research on etiology were discussed. PMID- 22917739 TI - Iron-sulfur cluster synthesis, iron homeostasis and oxidative stress in Friedreich ataxia. AB - Friedreich ataxia (FRDA) is an autosomal recessive, multi-systemic degenerative disease that results from reduced synthesis of the mitochondrial protein frataxin. Frataxin has been intensely studied since its deficiency was linked to FRDA in 1996. The defining properties of frataxin - (i) the ability to bind iron, (ii) the ability to interact with, and donate iron to, other iron-binding proteins, and (iii) the ability to oligomerize, store iron and control iron redox chemistry - have been extensively characterized with different frataxin orthologs and their interacting protein partners. This very large body of biochemical and structural data [reviewed in (Bencze et al., 2006)] supports equally extensive biological evidence that frataxin is critical for mitochondrial iron metabolism and overall cellular iron homeostasis and antioxidant protection [reviewed in (Wilson, 2006)]. However, the precise biological role of frataxin remains a matter of debate. Here, we review seminal and recent data that strongly link frataxin to the synthesis of iron-sulfur cluster cofactors (ISC), as well as controversial data that nevertheless link frataxin to additional iron-related processes. Finally, we discuss how defects in ISC synthesis could be a major (although likely not unique) contributor to the pathophysiology of FRDA via (i) loss of ISC-dependent enzymes, (ii) mitochondrial and cellular iron dysregulation, and (iii) enhanced iron-mediated oxidative stress. This article is part of a Special Issue entitled 'Mitochondrial function and dysfunction in neurodegeneration'. PMID- 22917743 TI - Evaluation of the inflammatory response in experimentally induced synovitis in the horse: a comparison of recombinant equine interleukin 1 beta and lipopolysaccharide. AB - OBJECTIVE: To compare two transient models of synovitis-osteoarthritis (OA) in horses by characterizing biological changes in synovial fluid and joint tissue. METHOD: Twelve skeletally mature mares were utilized in a block design. Synovitis was induced by an intra-articular injection of 100 ng recombinant equine interleukin 1 beta (reIL-1beta) or 0.5 ng lipopolysaccharide (LPS) into a middle carpal joint in 1 ml volumes. One ml of saline was injected into the contra lateral control joint. Lameness evaluations were conducted through post-injection hour (PIH) 8 (at which time arthroscopic removal of synovium and articular biopsies was done), and at PIH 240. Arthrocentesis collection of synovial fluid occurred between PIH 0 and 48. An arthroscopic examination at PIH 8 included synovium and articular cartilage biopsies for gene expression analysis. RESULTS: Synovial fluid analysis indicated that single injections of reIL-1beta or LPS increased synovial white blood cell (WBC), neutrophil count, total protein, prostaglandin E(2) (PGE(2)) concentrations and general matrix metalloproteinase (MMP) activity relative to control joints through PIH 8. Injections of either reIL-1beta or LPS increased mRNA expression for MMP-1 and a disintegrin and metalloprotease with thrombospondin motifs (ADAMTS)-4 in synovium and for MMP-1, ADAMTS-4, ADAMTS-5 in articular cartilage collected at PIH 8 compared to saline injections. CONCLUSION: Injections of reIL-1beta into equine carpal joints resulted in a transient inflammatory response that was similar in severity to the LPS injection, causing increased expression of certain deleterious mediators in joint tissues at 8 h. Given that IL-1beta is a known critical mediator of traumatic arthritis and OA, this humane and temporary model may be useful in evaluating therapeutics that act against early stages of joint disease. PMID- 22917744 TI - Osteoarthritis year 2012 in review: genetics and genomics. AB - The field of genetics and genomics is a highly technological driven field that is advancing fast. The purpose of this year in review of genetics and genomics was to highlight the publications that apply these new technologies tools to improve understanding of the pathophysiology of osteoarthritis (OA). In addition, most recent developments in genetics and genomics research and their relevance to OA are discussed in this review. PMID- 22917742 TI - A consideration of select pre-trauma factors as key vulnerabilities in PTSD. AB - Posttraumatic stress disorder (PTSD) is a pathological response to a traumatic event. A number of risk and vulnerability factors predicting PTSD development have been identified in the literature. Many of these variables are specific factors occurring during and after exposure to a traumatic event or are not measured prospectively to assess temporal sequence. Recent research, however, has begun to focus on pre-trauma individual differences that could contribute to risk for developing PTSD. The present review proposes that a number of biological and cognitive vulnerability factors place individuals at risk for PTSD development prior to the actual experience of trauma. Accordingly, this review provides a summary of evidence for a select number of these factors as pre-trauma vulnerabilities to PTSD. Included is a discussion of biological factors, including molecular genetic studies of systems regulating serotonin, catecholamines, and glucocorticoids as well as aspects of the neuroendocrine system. Specific cognitive factors are also considered, including intelligence, neuropsychological functioning and cognitive biases such as negative attributional style and appraisals. For each factor, the present review summarizes evidence to date regarding PTSD vulnerability and highlights directions for future research in this area. PMID- 22917745 TI - Icariin: a potential promoting compound for cartilage tissue engineering. AB - OBJECTIVE: To investigate whether icariin, which is a widely used pharmacological constituent in traditional Chinese herbal medicine, can be a potential promoting compound for cartilage tissue engineering. DESIGN: Icariin was added into cell hydrogel constructs derived from neonatal rabbit chondrocytes and collagen type I. The chondrogenic gene expressions and the synthesis of cartilage matrix of the seeded cells were detected by quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and Biochemical assay. The effects of icariin-added cell hydrogel constructs on the restoration of supercritical-sized osteochondral defects of adult rabbit were investigated by histological observation. The cell hydrogel constructs without Icariin were set for controls. RESULTS: Icariin obviously up-regulate the expressions included aggrecan, sox9, and collagen type II of seeded chondrocytes from 99.7% to 248%. It increases the synthesis of glycosaminoglycan and collagen type II about fourfold to fivefolds from week 1 to week 4, and accelerates the formation of chondroid tissue in the cell-hydrogel constructs. Even, it improves the restoration efficiency of supercritical-sized osteochondral defects in adult rabbit model, and enhances the integration of new formed cartilage with subchondral bone. CONCLUSIONS: Icariin can be a potential promoting compound for cartilage tissue engineering, and it can be a substitute for the use of some growth factors. The long history and extensive cases of safe use in China, Japan and Korea make it more attractive. PMID- 22917746 TI - Design and production of gentamicin/dextrans microparticles by supercritical assisted atomisation for the treatment of wound bacterial infections. AB - In this work, the supercritical assisted atomisation (SAA) is proposed, for the first time, for the production of topical carrier microsystems based on alginate pectin blend. Gentamicin sulphate (GS) was loaded as high soluble and hygroscopic antibiotic model with poor flowability. Particularly, different water solutions of GS/alginate/pectin were processed by SAA to produce spherical microparticles (GAP) of narrow size (about 2 MUm). GS loading was varied between 20% and 33% (w/w) with an encapsulation efficiency reaching about 100%. The micronised powders also showed high flow properties, good stability and constant water content after 90 days in accelerated storage conditions. The release profiles of the encapsulated drug were monitored using vertical diffusion Franz cells to evaluate the application of GAP microsystems as self-consistent powder formulation or in specific fibres or gels for wound dressing. All formulations showed an initial burst effect in the first 6h of application (40-65% of GS loaded), and in particular GAP4 produced with a GS/alginate/pectin ratio of 1:3:1, exhibited the ability to release GS continuously over 6 days. Antimicrobial tests against Staphylococcus aureus indicated that GS antibiotic activity was preserved at 6 days and higher than pure GS at 12 and 24 days for all SAA formulations, especially for GAP1. PMID- 22917747 TI - Toward better understanding of powder avalanching and shear cell parameters of drug-excipient blends to design minimal weight variability into pharmaceutical capsules. AB - Powder flow of mixtures is complex and not properly understood. The selection of drug-excipient blends with inadequate powder flow can lead to quality issues of the final dosage form. Therefore, this work aims at a better understanding of how changes in powder flow of binary blends can lead to weight variability in pharmaceutical capsule filling. We used image-analysis-based powder avalanching and shear cell testing to study blends of paracetamol and microcrystalline cellulose. A pilot-scale machine with dosator principle was employed for encapsulation. As a result, the powder flow properties improved generally with rising amounts of microcrystalline cellulose. However, a negative correlation was observed between avalanche angle and angle of internal friction. Results were discussed and percolation theory was considered to explain abrupt changes in the observed flow properties. This was particularly helpful for analysis of the capsule-filling data, since capsule weight variability displayed a threshold behavior as a function of the mixture fraction. The capsule weight variability correlated with the angle of internal friction as well as with the angle and the energy of avalanches. Based on the results we proposed a strategy of how to design minimal weight variability into powder-filled capsules. PMID- 22917748 TI - Atrial remodeling in varying clinical substrates within beating human hearts: relevance to atrial fibrillation. AB - Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia in human beating hearts. AF initiates self-perpetuating changes in electrophysiology, structure and functional properties of the atria, a phenomenon known as atrial remodeling. Hypertension, heart failure, valvular heart disease, sleep apnea, congenital heart disease are well known risk factors for AF that contribute to the development of atrial substrate. There is some evidence that reversal of atrial remodeling is possible with correction of antecedent conditions, however the timing of the intervention or upstream therapy may be critical. This review will describe the pathophysiology of atrial remodeling as it pertains to AF. We will describe components of remodeling including changes in atrial refractoriness, conduction and atrial structure, in addition to autonomic changes and anatomic factors that predispose to remodeling. We will discuss our current understanding of the electrophysiological changes that contribute to AF persistence. We will describe nature of atrial and pulmonary vein remodeling in the context of different forms of AF, with and without predisposing risk factors. We will describe the nature of remodeling over time following therapeutic interventions such as AF ablation in order to show that it does not necessarily improve and may worsen. PMID- 22917749 TI - The 'blemish of place': stigma, geography and health inequalities. A commentary on Tabuchi, Fukuhara & Iso. PMID- 22917750 TI - Explaining suicide: identifying common themes and diverse perspectives in an urban Mumbai slum. AB - Rates, demographics and diagnostics, which are the focus of many studies of suicide, may provide an insufficient account without adequate consideration of psychological, social and cultural contexts and motives. Furthermore, reported explanations of suicide are shaped not only by events but also the relationship of survivor respondents explaining the suicide. An explanatory model interview for sociocultural autopsy has been used to assess underlying problems and perceived causes. This study in a low-income community of Mumbai in 2003-2004 compared accounts of the closest family survivors and more distant relationships. Our study design distinguished series-level agreement (i.e., consistency of accounts within a group) and case-level agreement for particular cases. Serious mental illness was the perceived cause reported by a respondent in either group for 22.0% of index suicides, but case-level agreement was only 6.0%. Regarding financial stressors, more closely related family respondents focused on acute stressors instead of enduring effects of poverty. Case-level agreement was high for marital problems, but low for other sources of family conflict. Tension was a feature of suicide reported in both groups, but case-level agreement on tension as a perceived cause was low (kappa = 0.14). The role of alcohol as a perceived cause of suicide had high series level agreement (46.0% in both groups) and case level agreement (kappa = 0.60), suggesting comparable community and professional views of its significance. The study shows that it is relevant and feasible to consider general community patterns and particular survivor interests. Findings from this study recommend an approach to sociocultural autopsy to assess reasons for suicide in community studies. Findings clarify diverse views of underlying problems motivating suicide that should be considered to make mental health care more effective in assessing risk and preventing suicide. PMID- 22917751 TI - In utero closure of myelomeningocele does not improve lower urinary tract function. AB - PURPOSE: Recent data comparing prenatal to postnatal closure of myelomeningocele showed a decreased need for ventriculoperitoneal shunting and improved lower extremity motor outcomes in patients who underwent closure prenatally. A total of 11 children whose spinal defect was closed in utero were followed at our spina bifida center. We hypothesized that in utero repair of myelomeningocele improves lower urinary tract function compared to postnatal repair. MATERIALS AND METHODS: Eleven patients who underwent in utero repair were matched to 22 control patients who underwent postnatal repair according to age, gender and level of spinal defect. Urological outcomes were retrospectively reviewed including urodynamic study data, need for clean intermittent catheterization, use of anticholinergic agents and prophylactic antibiotics, and surgical history. The need for ventriculoperitoneal shunting or spinal cord untethering surgery was also reviewed. RESULTS: Mean followup was 7.2 years for patients who underwent in utero repair and 7.3 years for those who underwent postnatal repair. Mean patient age at compared urodynamic studies was 5.9 years for in utero repair and 6.0 years for postnatal repair. The in utero repair group was comprised of 5 lumbar and 6 sacral level defects with equal matching (1:2) in the postnatal repair cohort. There were no differences between the groups in terms of need for clean intermittent catheterization, incontinence between catheterizations or anticholinergic/antibiotic use. Urodynamic parameters including bladder capacity, detrusor pressure at capacity, detrusor overactivity and the presence of detrusor sphincter dyssynergia were not significantly different between the groups. There was no difference in the rate of ventriculoperitoneal shunting (p = 0.14) or untethering surgery (p = 0.99). CONCLUSIONS: While in utero closure of myelomeningocele has been shown to decrease rates of ventriculoperitoneal shunting and improve motor function, it is not associated with any significant improvement in lower urinary tract function compared to repair after birth. PMID- 22917752 TI - The relative and unique contributions of emotion dysregulation and impulsivity to posttraumatic stress disorder among substance dependent inpatients. AB - BACKGROUND: Despite elevated rates of posttraumatic stress disorder (PTSD) among substance use disorder (SUD) patients, as well as the clinical relevance of this co-occurrence, few studies have examined psychological factors associated with a PTSD-SUD diagnosis. Two factors worth investigating are emotion dysregulation and impulsivity, both of which are associated with PTSD and SUDs. Therefore, this study examined associations between PTSD and facets of emotion dysregulation and impulsivity within a sample of trauma-exposed SUD inpatients. METHODS: Participants were an ethnically diverse sample of 205 SUD patients in residential substance abuse treatment. Patients were administered diagnostic interviews and completed a series of questionnaires. RESULTS: Patients with PTSD (n=58) reported significantly higher levels of negative urgency (i.e., the tendency to engage in impulsive behaviors when experiencing negative affect) and lower sensation seeking, as well as higher levels of emotion dysregulation and the specific dimensions of lack of emotional acceptance, difficulties engaging in goal directed behavior when upset, difficulties controlling impulsive behaviors when distressed, limited access to effective emotion regulation strategies, and lack of emotional clarity. Further, overall emotion dysregulation emerged as a significant predictor of PTSD status, accounting for unique variance in PTSD status above and beyond facets of impulsivity (as well as other relevant covariates). CONCLUSIONS: Results suggest that emotion dysregulation may contribute to the development, maintenance, and/or exacerbation of PTSD and highlight the potential clinical utility of targeting emotion dysregulation among SUD patients with PTSD. PMID- 22917753 TI - The 5-item Alcohol Use Disorders Identification Test (AUDIT-5): an effective brief screening test for problem drinking, alcohol use disorders and alcohol dependence. AB - AIMS: To identify an optimal brief version of the Alcohol Use Disorders Identification Test (AUDIT) and to evaluate its effectiveness as a screening test for problem drinking (PD), alcohol use disorders (AUD) and alcohol dependence (AD). METHODS: A multicenter trial was conducted from March, 2010, to January, 2012, in 101 normal comparison, 203 risky drinking, 92 alcohol abuse and 101 AD men aged below 65 years of age in a Korean population. For the purposes of screening, risky drinking, alcohol abuse and AD were grouped: all the three grouped as PD and the latter two grouped as AUD. Logistic regression analysis was used to determine the items among the 10-item AUDIT that provided information predictive of PD, AUD and AD. Receiver operating characteristic (ROC) curve analysis was performed to investigate the discrimination ability of the brief versions of AUDIT, 10-item AUDIT and Cut-down, Annoyed, Guilt, Eye-opener as a screen for PD, AUD and AD. Areas under the ROC curve were compared between tests according to the method suggested by Hanley and McNeil. RESULTS: The 5-item AUDIT (AUDIT-5: AUDIT items 2, 4, 5, 9 and 10) was obtained by stepwise multiple regression analyses for each screening. AUDIT-5 exhibited an AUD screening accuracy significantly superior to that of the 10-item AUDIT, but other brief versions of AUDIT and CAGE did not. Furthermore, AUDIT-5 had a high PD and AD screening accuracy equivalent to that of the 10-item AUDIT. CONCLUSION: These results strongly support the usefulness of AUDIT-5 for screening of PD, AUD and AD in clinical settings in Korean male populations. PMID- 22917754 TI - Widening access to treatment for alcohol misuse: description and formative evaluation of an innovative web-based service in one primary care trust. AB - AIMS: To describe the development and evaluation of an innovative web-based service for hazardous or harmful drinkers. METHODS: Patients were identified in General Practice and referred to the new service. Mixed methods were used for evaluation. RESULTS: The service was feasible and acceptable to patients, primary care professionals and commissioners. Users appeared to reduce their alcohol consumption. CONCLUSION: This model may be of interest to other primary care commissioners looking to increase access to alcohol treatments at low cost. PMID- 22917755 TI - Alcohol, tobacco and drug use as reasons for abortion. AB - AIMS: Concern about the effects of alcohol and drug use during pregnancy is intertwined with debates about abortion. There is concern that alcohol abstinence recommendations lead women using low levels of alcohol to terminate otherwise wanted pregnancies. This study examines how women describe alcohol, tobacco and/or drug use (ATOD) as reasons for deciding to have abortions and assesses the differences between women reporting and not reporting ATOD as reasons for deciding to have an abortion. METHODS: Data come from the UCSF Turnaway Study which recruited 956 women seeking an abortion at one of 30 US clinics between 2008 and 2010. Mixed methods were used and data were analyzed through thematic coding and logistic regression. RESULTS: Nearly 5% reported ATOD as a reason for abortion. Women worried that their ATOD had affected their baby's health and that their or their partner's ATOD would influence parenting. Most women (84%) who reported alcohol as a reason binge drank or had an alcohol-problem symptom in the month before discovering their pregnancy. Sixty-one percent who reported drugs as a reason used drugs, with 88% using more than once/week. Although two-thirds smoked tobacco, no woman reported tobacco alone as a reason. Ninety-eight percent of women reporting ATOD as a reason had unintended pregnancies. CONCLUSION: Women reporting ATOD as a reason drink at levels exceeding a low threshold and do not appear to be terminating otherwise wanted pregnancies. Thus, findings are inconsistent with hypotheses that abstinence recommendations and punitive policies lead women using low levels of alcohol or using drugs to terminate otherwise wanted pregnancies. PMID- 22917756 TI - Elevated D-dimer levels signify overlap between community-acquired pneumonia and pulmonary embolism. PMID- 22917758 TI - Hypochromia, microcytosis and iron deficiency. PMID- 22917757 TI - Computerised assistance for warfarin dosage--effects on treatment quality. AB - BACKGROUND: Well-managed warfarin treatment with a high time in therapeutic range (TTR) corresponds to fewer bleedings or thromboembolic complications. Many small centres manage their warfarin dosing manually, with little or no knowledge of their treatment quality as measured by TTR. AuriculA is a Swedish National web based anticoagulation dosing system. Our hypothesis was that the web based dosing system, compared to manual dosing, would improve the TTR. METHODS: Retrospective cohort study of medical records from patients with atrial fibrillation on warfarin treatment from two centres, with previously manual warfarin dosing regimens. Data for calculation of TTR was extracted manually from medical records from the time when using manual dosing and compared with the computerised regimen. RESULTS: In centre 1, the mean TTR was significantly increased after the introduction of AuriculA, from 64.3% (95% CI 58.8-69.8) to 71.3% (95% CI 67.7 74.8), p=0.03. In centre 2, a high TTR of 73.6% (95% CI 71.3-75.9) was maintained after the implementation, 74.0% (95% CI 71.6-76.3). INR tests were prescribed significantly more frequent after the introduction of AuriculA in both centres; 20% more often at centre 1 and 21% at centre 2. CONCLUSION: Computerised dosing assistance within the Swedish national quality registry AuriculA improves or maintains a high treatment quality with warfarin as measured by TTR. PMID- 22917759 TI - Embryos under surveillance! PMID- 22917760 TI - The historical evolution of the management of spinal cord injury. AB - The history of spinal cord injury (SCI) is long and fascinating. From Ancient Egypt to the current day, SCI has gradually shifted from being seen as an inevitably fatal condition, to one most amenable to treatment, albeit not yet cure. Several controversies have paved the path of this condition's history, from the question of whether to treat, to the optimal timing of surgical intervention, to the potential of recent novel therapies. This article traces the major developments in the management of SCI, in addition to many broader historical developments relating to SCI. PMID- 22917761 TI - Neurothrombectomy for the treatment of acute ischemic stroke in 1530 patients. AB - Neurothrombectomy is being used increasingly for the treatment of acute ischemic stroke. To assess the recanalization rates and clinical outcomes of patients treated with neurothrombectomy, we searched the CNKI (China National Knowledge Infrastructure), CBM (Chinese Biomedical Literature), MEDLINE and EMBASE databases to 2011 and summarized the outcome data of patients with acute ischemic stroke treated with neurothrombectomy. Forty-six studies (1530 patients) that reported recanalization rates were included in this analysis. Recanalization rates were recorded for the following neurothrombectomy techniques: endovascular thrombectomy (43-100%, median 86%), endovascular thromboaspiration (67-100%, median 83%), laser thrombolysis (41-50%, median 45.5%), and ultrasonification (62 71%, median 66.5%); the respective rates of symptomatic and asymptomatic intracranial hemorrhage were 20%, 22.5%, 12%, and 19% for each of the four types of neurothrombectomy. Clinical outcome data categorized by success or failure in achieving recanalization were available from 12 articles pertaining to 443 patients. At three months, patients in whom recanalization was achieved had better functional outcomes compared to non-recanalized patients (odds ratio [OR], 5.58; 95% confidence interval [CI], 2.98-10.45). In addition, the three-month mortality was lower in recanalized patients (OR, 0.37; 95% CI, 0.24-0.57). Among the various treatments for acute ischemic stroke, neurothrombectomy appears the most promising. Neurothrombectomy devices show great potential in improving functional outcomes and reducing mortality in patients with acute ischemic stroke, and meta-analysis confirms that successful recanalization was the most important indicator of predicting clinical benefit. PMID- 22917762 TI - A retrospective chart review of the perinatal period in 22 pregnancies of 16 women with Moyamoya disease. AB - Moyamoya disease (MMD) is characterized by severe stenoses of the arteries in the circle of Willis, which predispose the patient to brain ischemia and intracranial hemorrhage. We performed a retrospective chart review of 22 pregnancies in 16 patients with MMD at the Kyushu University Hospital. An uncomplicated Cesarean delivery was performed in nearly all patients. In the 20 pregnancies in patients with pre-existing MMD, two had transient ischemic symptoms in the postpartum period. Two patients not previously known to have MMD developed transient ischemic symptoms postpartum. One of these patients was initially diagnosed and managed as pre-eclampsia. For patients diagnosed with MMD, a good perinatal outcome can be expected with appropriate management. Neurological events, however, may still occur postpartum even in well-managed patients. MMD may mimic the signs and symptoms of other neurological or psychiatric disorders, thereby complicating diagnosis and management. PMID- 22917763 TI - Fast box-counting algorithm on GPU. AB - The box-counting algorithm is one of the most widely used methods for calculating the fractal dimension (FD). The FD has many image analysis applications in the biomedical field, where it has been used extensively to characterize a wide range of medical signals. However, computing the FD for large images, especially in 3D, is a time consuming process. In this paper we present a fast parallel version of the box-counting algorithm, which has been coded in CUDA for execution on the Graphic Processing Unit (GPU). The optimized GPU implementation achieved an average speedup of 28 times (28*) compared to a mono-threaded CPU implementation, and an average speedup of 7 times (7*) compared to a multi-threaded CPU implementation. The performance of our improved box-counting algorithm has been tested with 3D models with different complexity, features and sizes. The validity and accuracy of the algorithm has been confirmed using models with well-known FD values. As a case study, a 3D FD analysis of several brain tissues has been performed using our GPU box-counting algorithm. PMID- 22917764 TI - Blood and hair lead in children with different extents of iron deficiency in Karachi. AB - Childhood iron deficiency has a high incidence in Pakistan. Some but not all studies have shown that dietary iron deficiency may cause increased absorption of lead as both compete for the same transporters in the small intestine. Therefore, children in Pakistan, residing in heavily polluted cities like Karachi may be prone to lead poisoning. This hypothesis was tested by investigating blood and hair lead concentrations in children from Karachi who were divided into four groups of iron status; normal, borderline iron deficiency, iron deficiency and iron deficiency anaemia. A prospective observational study was conducted where 269 children were categorized into four groups of iron status using the World Health Organization criteria and one based on soluble transferrin receptor measurements. Blood iron status was determined using a full blood count, serum iron, ferritin, transferrin saturation and soluble transferrin receptor measurements. Blood lead was determined by graphite atomic absorption spectroscopy, whereas hair lead was assessed using an inductively coupled plasma atomic emission spectroscopy technique. Blood lead concentrations were significantly higher in children with iron deficiency anaemia (mean [95% confidence intervals] were 24.9 [22.6-27.2] MUg/dL) compared to those with normal iron status (19.1 [16.8-21.4] MUg/dL) using WHO criteria. In contrast, hair lead content was not significantly different in children of different iron status. Our findings reinforce the importance of not only reducing environmental lead pollution but also the development of national health strategies to reduce childhood iron deficiency in Pakistan. PMID- 22917765 TI - Polychlorinated biphenyls in coastal tropical ecosystems: distribution, fate and risk assessment. AB - Polychlorinated biphenyls (PCBs) though banned still find use in most developing countries including Ghana. PCB congener residues in sediments in the coastal regions of Ghana were determined. Sediment samples (n=80) were collected between June 2008 and March 2009, extracted by the continuous soxhlet extraction using (1:1) hexane-acetone mixture for 24h and analyzed with a CP 3800 gas chromatogram equipped with (65)Ni electron capture detector (GC-ECD) and a mixed PCBs standard of the ICES 7 as marker, after clean-up. Validation of the efficiency and precision of the extraction and analytical methods were done by extracting samples spiked with 2 ppm ICES PCB standard and a certified reference material 1941b for marine sediments from NIST, USA, and analyzed alongside the samples. Total PCBs detected in sediments during the dry and wet seasons were, respectively, 127 and 112 MUg/kg dry weight (dw), with a mean concentration of 120 MUg/kg (dw). The composition of PCB homologues in the sediments were dominated by tri-, penta- and tetra-PCBs. There was no correlation between organic carbon (OC) of the sediments and total PCBs content. Risk assessments conducted on the levels indicated that PCB levels in sediments along the coastal region of Ghana poses no significant health risk to humans. PMID- 22917766 TI - Intrathecal baclofen for progressive neurological disease in children. PMID- 22917767 TI - Clinical and cytogenetic characteristics of myelodysplastic syndrome in patients with HIV infection. AB - We report eight patients of myelodysplastic syndrome (MDS) with HIV infection. Compared to a historical cohort of HIV-uninfected MDS patients, HIV/MDS were younger (p=0.019), had more complex cytogenetics (p=0.015), and more often had 7q deletion or monosomy 7 (p=0.011). In five patients, HIV/MDS transformed to acute myeloid leukemia, with a median time to transformation of 7 months. Also, the median overall survival was shorter in the HIV/MDS than in their HIV-uninfected counterparts (8 vs. 22 months; p=0.003). These results suggest that HIV/MDS is a high-risk MDS necessitating thorough cytogenetic analysis and follow-up. PMID- 22917768 TI - Myeloproliferative neoplasms 2012: the John M. Bennett 80th birthday anniversary lecture. AB - Polycythemia vera, essential thrombocythemia and primary myelofibrosis constitute the BCR-ABL1-negative myeloproliferative neoplasms. In this communication, I will provide an overview on their histopathology, cytogenetic findings and associated mutations, as well as summarize recent advances that have changed our approach to their diagnosis and treatment. Also included in the current review are (i) indications for ordering JAK2 or MPL mutation analysis and result interpretation, (ii) new international prognostic scoring systems, and (iii) risk-adapted therapy including the therapeutic role of immunomodulatory drugs and JAK inhibitors. PMID- 22917769 TI - Recombinant human soluble thrombomodulin safely and effectively rescues acute promyelocytic leukemia patients from disseminated intravascular coagulation. AB - We treated individuals for disseminated intravascular coagulation (DIC) caused by acute promyelocytic leukemia (APL) (n=9) using human soluble thrombomodulin (rTM) in combination with all-trans retinoic acid (ATRA) and chemotherapy, and compared the clinical outcomes with historical control patients (n=8) treated with ATRA and/or chemotherapy. Two control patients developed intracranial vascular incidents. On the other hand, no bleeding related mortality was noted in rTM treated patients. Notably, treatment with rTM rescued patients from DIC earlier than historical controls (log rank test, p=0.019). These results suggest that administration of rTM should be considered for the treatment of individuals with DIC associated with APL. PMID- 22917771 TI - Generation and characterization of a novel multidrug resistance protein 2 humanized mouse line. AB - The multidrug resistance protein (MRP) 2 is predominantly expressed in liver, intestine, and kidney, where it plays an important role in the excretion of a range of drugs and their metabolites or endogenous compounds into bile, feces, and urine. Mrp knockout [Mrp2(-/-)] mice have been used recently to study the role of MRP2 in drug disposition. Here, we describe the first generation and initial characterization of a mouse line humanized for MRP2 (huMRP2), which is nulled for the mouse Mrp2 gene and expresses the human transporter in the organs and cell types where MRP2 is normally expressed. Analysis of the mRNA expression for selected cytochrome P450 and transporter genes revealed no major changes in huMRP2 mice compared with wild-type controls. We show that human MRP2 is able to compensate functionally for the loss of the mouse transporter as demonstrated by comparable bilirubin levels in the humanized mice and wild-type controls, in contrast to the hyperbilirubinemia phenotype that is observed in MRP2(-/-) mice. The huMRP2 mouse provides a model to study the role of the human transporter in drug disposition and in assessing the in vivo consequences of inhibiting this transporter by compounds interacting with human MRP2. PMID- 22917770 TI - The impact of hypomethylating agents on the cost of care and survival of elderly patients with myelodysplastic syndromes. AB - During 2004-2006, two hypomethylating agents (HMAs) were approved for the treatment of myelodysplastic syndromes (MDS) in the United States. We assessed the impact of HMAs on the cost of care and survival of MDS patients, by constructing a cohort of patients who were diagnosed during 2001-2007 (n=6556, age >=66.5 years) and comparable non-cancer controls. We assessed MDS patients' and controls' Medicare expenditures to derive MDS-related cost. We evaluated the two-year survival of patients as a group and by major subtypes. Taking into account the survival probabilities of MDS, the expected MDS-related 5-year cost was $63,223 (95% confidence interval: $59,868-66,432 in 2009 dollars), higher than the reported comparable cost for any of the 18 most prevalent cancers in the United States. Compared with MDS patients diagnosed in the earlier period (January 2001-June 2004) who received no HMAs, patients diagnosed later (July 2004-December 2007) who received HMAs had a significantly higher 24-month cost ($97,977 vs. $42,628 in 2009 dollars) and an improved 24-month survival (especially among patients with refractory anemia or refractory anemia with excess blasts). The magnitude of the cost of care underscores a need for comparative cost-effectiveness studies to reduce the clinical and economic burden of MDS. PMID- 22917772 TI - The use of mammalian two-hybrid technologies for high-throughput drug screening. AB - Developing agents that target protein-protein interactions (PPIs) is an emerging field in drug discovery. Although this target class has hitherto remained underexplored, it holds exceptional promise related to the large amount of potential PPI targets compared to single protein targets and it offers important opportunities to increase the specificity of therapeutic molecules. While several PPI modulating therapeutics have recently been reported and a number of these are in clinical trial, progress in the field has been hampered by the lack of efficient screening systems. Recently, a number of cellular approaches have been developed that complement classical in vitro screening methods and which exhibit a number of important assets related to the physiological context they provide. Here we discuss the utility of two-hybrid technologies towards high-throughput screening for PPI inhibitors, in particular those that operate in a mammalian cellular background. We review a number of cases where mammalian two-hybrids have been successfully applied to identify small molecule disruptors of PPIs and zoom in further on the MAPPIT (Mammalian Protein-Protein Interaction Trap) technology platform. The value of this approach for drug discovery is illustrated by recent data from MAPPIT-based screening projects. PMID- 22917773 TI - The human MSH5 (MutSHomolog 5) protein localizes to mitochondria and protects the mitochondrial genome from oxidative damage. AB - MutS homologs play a central role in maintaining genetic stability. We show that MSH5 (MutSHomolog 5) is localized into the mitochondria of germ and somatic cells. This protein binds to mtDNA and interacts with the Twinkle helicase and the DNA polymerase gamma. hMSH5 stimulates mtDNA repair in response to DNA damage induced by oxidative stress. Furthermore, we observed a subsarcolemmal accumulation of hMSH5 in COX negative muscle fibers of patients presenting a mitochondrial myopathy. We report a novel localization for hMSH5 suggesting that this protein may have functions other than those known in meiotic recombination. PMID- 22917774 TI - The astonishing hypothesis. PMID- 22917775 TI - The Balanced Scorecard as a management tool for assessing and monitoring strategy implementation in health care organizations. AB - Both prior literature and reported managerial practices have claimed that the Balanced Scorecard is a management tool that can help organizations to effectively implement strategies. In this article, we examine some of the contributions, dilemmas, and limitations of Balanced Scorecards in health care organizations. First, we describe the evolution of Balanced Scorecards from multidimensional performance measurement systems to causal representations of formulated strategies, and analyze the applicability of Balanced Scorecards in health care settings. Next, we discuss several issues under debate regarding Balanced Scorecard adoption in health care organizations. We distinguish between issues related to the design of Balanced Scorecards and those related to the use of these tools. We conclude that the Balanced Scorecard has the potential to contribute to the implementation of strategies through the strategically-oriented performance measurement systems embedded within it. However, effective adoption requires the adaptation of the generic instrument to the specific realities of health care organizations. Full English text available from:www.revespcardiol.org. PMID- 22917776 TI - Chondroitinase ABC promotes plasticity of spinal reflexes following peripheral nerve injury. AB - Peripheral nerve transection, even with optimal repair, can result in an extensive disruption of central connectivity, which can lead to long-lasting impairments in motor and sensory function. We hypothesised that removal of spinal cord chondroitin sulphate proteoglycans (CSPGs) would promote plasticity in the spinal cord, allowing compensation for inaccurate peripheral reinnervation. In adult rats, the median and radial nerves were cut and repaired, either correctly (median to median and radial to radial), or incorrectly (median to radial and vice versa). This produced two levels of inaccuracy of peripheral reinnervation. Whole nerve recordings from a third brachial plexus nerve, the ulnar, were made during median or radial nerve stimulation. Low and high threshold reflexes were characterised in uninjured animals and a clear difference in the pattern of ulnar response to flexor (median) or extensor (radial) stimulation was established. This included the phenomenon of wind-up, where repetitive median nerve stimulation at supramaximal C-fibre threshold leads to a progressive increase in the number of spikes recorded. To achieve digestion of CSPGs a lentiviral vector expressing ChABC was delivered to the spinal cord via intraspinal injection. Following ChABC treatment, we found several indicators of reorganisation of central connections. Firstly, we found that the amplitude of a low threshold, polysynaptic reflex could be increased after nerve injury, only following treatment with ChABC. Secondly, wind-up of motor responses in the ulnar nerve to supramaximal stimulation of afferents in the median nerve, which collapses after nerve injury (to ~25% of uninjured value), could be restored by ChABC after correct repair (to ~90% of uninjured value). Thirdly, wind-up in ulnar motor axons to stimulation of radial nerve afferents, which is minimal in the uninjured state, becomes significantly stronger after nerve injury and ChABC treatment (a 10 fold increase). We propose that application of a plasticity-promoting treatment to the spinal cord allows the amplification of adaptive changes in response to inaccurate wiring in the periphery. PMID- 22917777 TI - Comparison of the activation of somatostatin- and neuropeptide Y-containing neuronal populations of the rat amygdala following two different anxiogenic stressors. AB - Rats exposed to the odor of a predator or to the elevated plus maze express fear behaviors without a prior exposure to either stimulus. The expression of innate fear provides for an ideal model of anxiety which can aid in the elucidation of brain circuits involved in anxiety-related behaviors. The current experiments compared activation of neuropeptide-containing neuronal populations in the amygdala of rats exposed to either the elevated plus maze (EPM; 5 min) versus home cage controls, or predator ferret odor versus butyric acid, or no odor (30 min). Sections of the brains were prepared for dual-labeled immunohistochemistry and counts of c-Fos co-localized with somatostatin (SOM) or neuropeptide Y (NPY) were made in the basolateral (BLA), central (CEA), medial (MEA) nuclei of the amygdala. Ferret odor and butyric acid exposure significantly decreased the percentage of SOM-positive neurons also immunoreactive for c-Fos in the anterior BLA compared to controls, whereas EPM exposure yielded a significant increase in the activation of SOM-positive neurons versus home cage controls. In the CEA, ferret odor and butyric exposure significantly decreased the percentage of SOM positive neurons also immunoreactive for c-Fos compared to no-odor controls whereas EPM exposure yielded no change versus controls. In the MEA, both ferret odor exposure and EPM exposure resulted in increased SOM co-localized with c-Fos compared to control groups whereas NPY co-localized with c-Fos occurred following ferret odor exposure, but not EPM exposure. These results indicate that phenotypically distinct neuronal populations of the amygdala are differentially activated following exposure to different anxiogenic stimuli. These studies further elucidate the fundamental neurocircuitry of anxiety and could possibly explain the differential behavioral effects of predator versus novelty-induced stress. PMID- 22917778 TI - Immunomicelles for advancing personalized therapy. AB - Personalized medicine, which ultimately seeks to afford tailored therapeutic regimens for individual patients, is quickly emerging as a new paradigm in the diagnosis and treatment of diseases. The idea of casting aside generic treatments in favor of patient-centric therapies has become feasible owing to advances in nanotechnology and drug delivery coupled with an enhanced knowledge of genomics and an understanding of disease at the molecular level. This review highlights polymeric immunomicelles as a class of nanocarriers that have the potential to combine diagnosis, targeted drug therapy, as well as imaging and monitoring of therapeutic response, to render a personalized approach to the management of disease. Smart multi-functional immunomicelles, as the next generation of nanocarriers, are poised for facilitating personalized cancer treatment. This review provides an assessment of immunomicelles as tools for advancing personalized therapy of diseases, with cancer being the major focus. PMID- 22917780 TI - Stent for Life Initiative placed at the forefront in Egypt 2011. AB - AIMS: Myocardial infarction is a medical emergency in which 25 to 35% of patients will die before receiving medical attention. The Stent for Life registry was launched to access the current situation of the Egyptian population presenting with STEMI, and to determine what were the barriers to providing patients with cardiac problems appropriate care. METHODS AND RESULTS: This registry was conducted at 14 centres covered all the Egyptian regions including 1,324 consecutive patients presenting with STEMI during the period between January 1st, 2011 to November, 2011. Fourteen centres and 38 interventionalists participated in this registry; only six centres are Pilot Centres (fulfilling the criteria for a primary PCI centre) and were assigned at the end of 2011. Cardiovascular risk factors were mainly smoking (60.5%), dyslipidaemia (46.0%), diabetes (51.4%) and hypertension (56.0%). The mean age at presentation was 56.01+/-10.61years and 75.0% were male. Only 5% of the STEMI patients arrived via the emergency medical system. Thrombus aspiration was done in 42.7% of patients in primary PCI group and 25.9% in rescue PCI group. Bare metal stents (BMS) were used in 80.7% of the stented patients while drug eluting stents (DES) were used in 19.3% of the stented patients. In-hospital mortality was 2.9% (1.4% in primary PCI group, 1.1% in patients treated with thrombolysis and 0.4% in patients receiving no reperfusion therapy). CONCLUSION: Despite the logistical difficulties, excellent outcomes for acute interventional reperfusion strategy in STEMI can be achieved in our country, possibly similar to those seen in the West. There is a strong need for making the practice of PCI in STEMI more widespread in developing regions. PMID- 22917781 TI - STEMI guidelines: from formulation to implementation. PMID- 22917782 TI - Stent for Life Initiative--the Greek experience. AB - Primary percutaneous coronary intervention (p-PCI) is considered the gold standard reperfusion strategy for patients with ST-elevation myocardial infarction (STEMI). In the last two years, the Stent for Life (SFL) Initiative has aimed at expanding the use of p-PCI in Greece and several other European countries. During this short period of time, intensive efforts towards propagating the main objectives of the programme in Greece and important actions on the organisation and activation of two p-PCI networks in Athens, the Greek capital, and Patras in south-western Greece, have led to a dramatic nationwide increase of p-PCI rates among STEMI patients (from 9% to 32%). Especially in Athens, p-PCI is implemented in almost 60% of the cases with a diagnosis of STEMI. Recent data from the Greek national registry on acute coronary syndromes underscore the need to improve p-PCI time delays which are partially attributed to inter-hospital delays from hospitals with no p-PCI facilities to p-PCI hospitals. A national public campaign for the promotion of p-PCI is progressing very fast, while specific planning for the recruitment of additional hospitals in urban and rural areas to join old, or to form new p-PCI networks is still developing. PMID- 22917783 TI - Primary angioplasty in Portugal: door-to-balloon time is not a good performance index. AB - AIMS: Despite primary angioplasty being the recommended treatment for patients with acute myocardial infarction with ST-elevation, recent studies have shown a great heterogeneity in the access to this form of treatment in Europe. The project "Stent for Life", an initiative of the European Society of Cardiology which Portugal joined in February 2011, aims to improve this situation. METHODS AND RESULTS: The objective of this study was to re-evaluate the basic Portuguese performance indicators for primary angioplasty. A national survey called "Moment Zero" was implemented for a one-month period for this purpose. Nineteen Portuguese centres of interventional cardiology, where primary angioplasty is carried out, were invited to participate in this study. From 9th May to 8th June 2011, 14 centres participated in this study and 185 patients were included with a mean age of 62+/-14 years, of which 76.8% were male. 17.5% of the patients presented with a medical history of diabetes mellitus, 8.4% had previous percutaneous coronary intervention, 7.6% myocardial infarction and 1.1% coronary artery bypass surgery. Only 29% of the patients used the single national number for medical emergencies (112) to call for support. The median patient delay was 120 (73-240) minutes. The median pre-hospital transportation system delay was 104 (73-240) minutes. The median door-to-balloon delay (D2B) was 64 (30-110) minutes and was not significantly different between patients who contacted the National Institute for Medical Emergency (INEM) and patients who did not contact this service: 69 (30-109) minutes versus 60 (30-111) minutes. In 56% of the cases, patients entered a local hospital before transferring to a hospital with primary angioplasty facilities. The time between the admission to the local hospital and admission to a hospital with an interventional cardiology unit was 109 (73-173) minutes. CONCLUSIONS: The main barriers to a better performance of the primary angioplasty programme in Portugal, as revealed by "Moment Zero", are the low number of patients who contacted the INEM and the high number of patients who attended centres without interventional cardiology units, resulting in long delays spent in secondary transportation to the institutions with such services. The D2B delay, although close to the 90 minutes recommended by the guidelines, is not a good indicator of the overall performance of primary angioplasty in Portugal. PMID- 22917784 TI - Impact of the Romanian national programme for interventional therapy in ST elevation myocardial infarction. AB - A national programme for PPCI in STEMI patients was started in Romania in August 2010, based on an integrated and well-trained pre-hospital emergency medical system. Ten national centres experienced in PPCI were organised in a 24/7 system in five regional networks, in order to assist STEMI patients from areas offering PPCI within the first two hours after the first medical contact. For centres located further away, a strategy of local thrombolysis followed by transfer to the closest PCI centre was recommended. The total number of PPCI procedures increased from 1,289 in 2010 to 4,209 in 2011. The percentage of PPCI increased from 25.0% in 2010 to 49.32% in 2011. From 40 PPCI/million inhabitants in 2009, we reached 64/million in 2010 and 210/ million in 2011. In the Bucharest area there were 640 PPCI/ million in 2011. The global in-hospital mortality decreased from 13.5% in 2009 to 9.93% in 2011. In 2011 in-hospital mortality was 4.39%, 8.32% and 17.11% for PPCI, thrombolysis and no-reperfusion, respectively. In hospital mortality was 7.28% in the PCI centres but 14.20% in centres without PCI facilities. The national programme for PPCI had a major impact on STEMI in hospital mortality in Romania. PMID- 22917785 TI - Stent for Life project: present situation in Turkey. AB - The rate of percutaneous coronary intervention for acute ST-segment elevation myocardial infarction varies between European countries. The variations arise partly because of differences between countries in the primary percutaneous coronary intervention network system. The lack of an organised primary percutaneous coronary intervention network system in Turkey was the main reason for the low rate of primary percutaneous coronary intervention in Turkey. The Stent for Life project has increased the awareness of the importance of the prompt treatment of ST-segment elevation myocardial infarction in our country. Primary percutaneous coronary intervention has emerged as the preferred reperfusion strategy for patients with ST-segment elevation myocardial infarction in pilot cities after three years of Stent for Life project. In the present manuscript, we aim to summarise the current situation and the targets of the Stent for Life project in Turkey. PMID- 22917779 TI - Interactions of nanomaterials and biological systems: Implications to personalized nanomedicine. AB - The application of nanotechnology to personalized medicine provides an unprecedented opportunity to improve the treatment of many diseases. Nanomaterials offer several advantages as therapeutic and diagnostic tools due to design flexibility, small sizes, large surface-to-volume ratio, and ease of surface modification with multivalent ligands to increase avidity for target molecules. Nanomaterials can be engineered to interact with specific biological components, allowing them to benefit from the insights provided by personalized medicine techniques. To tailor these interactions, a comprehensive knowledge of how nanomaterials interact with biological systems is critical. Herein, we discuss how the interactions of nanomaterials with biological systems can guide their design for diagnostic, imaging and drug delivery purposes. A general overview of nanomaterials under investigation is provided with an emphasis on systems that have reached clinical trials. Finally, considerations for the development of personalized nanomedicines are summarized such as the potential toxicity, scientific and technical challenges in fabricating them, and regulatory and ethical issues raised by the utilization of nanomaterials. PMID- 22917786 TI - Variable penetration of primary angioplasty in Europe--what determines the implementation rate? AB - Primary percutaneous coronary intervention (PPCI) is the recommended treatment for patients with acute ST-segment elevation myocardial infarction (STEMI). A survey conducted in 2008 in the European Society of Cardiology (ESC) countries reported that the annual incidence of hospital admissions for acute STEMI is around 800 patients per million inhabitants. The survey also showed that STEMI patients' access to reperfusion therapy and the use of PPCI or thrombolytic therapy (TT) vary considerably among countries. Northern, Western and Central Europe already had well-developed PPCI services, offering PPCI to 60-90% of all STEMI patients. Southern Europe and the Balkans were still predominantly using TT and had a higher proportion of patients who were left without any reperfusion treatment. The survey concluded that a nationwide PPCI strategy results in more patients being offered reperfusion therapy. To address the inequalities in STEMI patients' access to life-saving PPCI and to support the implementation of the ESC STEMI treatment guidelines in Europe, the Stent for Life (SFL) Initiative was launched jointly by the European Association of Percutaneous Cardiovascular Interventions (EAPCI) and EuroPCR in 2008. The aim of the SFL Initiative is to improve the delivery of life-saving PPCI for STEMI patients. Currently, 10 national cardiac societies support the SFL Initiative in their respective countries. SFL national action programmes have been developed and are being implemented in several countries. The formation of regional PPCI networks involving emergency medical services, non-PPCI hospitals and PPCI centres is considered to be a critical factor in implementing PPCI services effectively. Better monitoring of STEMI incidence and prospective registration of PPCI in all countries is required to document improvements in health care and to identify areas where further effort is required. Furthermore, studies on potential factors or characteristics that explain the national penetration of PPCI are needed. Such knowledge will be necessary to increase the effectiveness and efficiency of the implementation, and will be the first step in ensuring equal access to PPCI treatment for STEMI patients in Europe. Establishing the delivery of PPCI in an effective, high-quality and timely manner is a great challenge. PMID- 22917787 TI - ACS and STEMI treatment: gender-related issues. AB - Cardiovascular disease is the leading cause of death amongst women, with acute coronary syndromes (ACS) representing a significant proportion. It has been reported that in women presenting with ACS there is underdiagnosis and consequent undertreatment leading to an increase in hospital and long-term mortality. Several factors have to be taken into account, including lack of awareness both at patient and at physician level. Women are generally not aware of the cardiovascular risk and symptoms, often atypical, and therefore wait longer to seek medical attention. In addition, physicians often underestimate the risk of ACS in women leading to a further delay in accurate diagnosis and timely appropriate treatment, including cardiac catheterisation and primary percutaneous coronary intervention, with consequent delayed revascularisation times. It has been acknowledged by the European Society of Cardiology that gender disparities do exist, with a Class I, Level of Evidence B recommendation that both genders should be treated in the same way when presenting with ACS. However, there is still a lack of awareness and the mission of Women in Innovation, in association with Stent for Life, is to change the perception of women with ACS and to achieve prompt diagnosis and treatment. PMID- 22917788 TI - Acute coronary syndromes: is there a place for a real pre-hospital treatment for patients "en route" to the coronary intensive care unit? AB - Acute initial management of patients with acute coronary syndrome (ACS) is based on a precise clinical and electrocardiographic diagnosis. Initial risk stratification in the pre-hospital phase is the key step. The last step, adequate patient routing, is decided based on emergency level and reperfusion strategies, considered right from the pre-hospital phase. The management of a patient with an ACS requires close collaboration between emergency physicians and cardiologists, according to simplified protocols for easier access to catheterisation. The next challenges for the pre-hospital management of ACS are based on: - precise knowledge of new antiplatelet and anticoagulant drugs by the emergency physicians, in order to adjust their prescriptions to the patient profile; - developing co-operation between hospitals, according to regional specificities (geographic considerations and distribution of PCI centres) in order to reduce access time to catheterisation rooms; - organising the healthcare network, where the SAMU has an essential role in coordinating the different medical actors; - regular analysis of the evolution of our professional practices, considering, e.g., the guidelines of the "HAS" (French official healthcare guidelines institute);- integrating pre-hospital medicine in health prevention programmes; - improving our understanding of the population's presentations of coronary artery disease, in order to encourage the patients and their families to call the EMS as soon as possible. The challenge of the emergency physician is to adapt the strategies to the patient's needs. PMID- 22917789 TI - STEMI treatment in areas remote from primary PCI centres. AB - In remote, sparsely populated areas with long transfer distances to percutaneous coronary intervention (PCI) centres it is impossible to deliver PCI within the recommended time limits, and fibrinolysis should be the treatment of choice in patients with ST-elevation myocardial infarction (STEMI). Fibrinolysis should preferably be administered in the pre-hospital setting. Patients with contraindications to fibrinolysis, late presenters and patients with cardiogenic shock should be transferred for primary PCI, even when the transfer delays are substantial. Fibrinolytic therapy is not the final step of reperfusion treatment, but should be followed by transfer to a PCI centre as soon as possible for rescue PCI or routine angiography with PCI if indicated. The optimal timing of routine angiography following fibrinolysis is not settled, but recent trials suggest a time window of two to 12 hours. A well-organised system of care with clear treatment protocols and coordinated transfer systems is necessary for identifying treatment-eligible patients for on-site fibrinolysis or transfer for primary PCI, and for ensuring that therapies are available in a timely manner 24 hours a day, seven days a week. A well-organised STEMI network is also necessary for early transfer of lytic treated patients for rescue PCI or routine angiography. PMID- 22917791 TI - From pharmacologically assisted early transfer to a universal primary angioplasty service: the experience of the Malopolska region. AB - The current article summarises more than 12 years' experience in the treatment of ST-segment elevation myocardial infarction in the Malopolska region (southern part of Poland). Data on the development phase of the STEMI treatment network, as well as the current status of interventional treatment of acute coronary syndromes in that region of Poland are provided. PMID- 22917792 TI - Changing management of acute MI--perspectives from India. AB - Management of acute myocardial infarction (AMI) in India essentially rests on the established reperfusion strategies with unique adaptations compelled by the socioeconomic structure of the country. Due to limited availability of trained interventionists coupled with financial limitations, thrombolysis remains the most utilised reperfusion therapy for AMI. Patient education through the active participation of physicians concerning the early detection of symptoms suggestive of AMI can enhance the impact of thrombolysis on the outcomes by narrowing the door-to-needle time. This article discusses some of these unique issues and possible solutions in the emerging economies to optimise outcomes in AMI. PMID- 22917793 TI - Stent for Life: an initiative reflecting the spirit of the European Community. PMID- 22917794 TI - The importance of audit to monitor applications of procedures and improve primary angioplasty results. AB - Although clinical trials have demonstrated that primary percutaneous coronary intervention (PPCI) provides better outcomes than thrombolysis for STEMI, it cannot be assumed that similar results can be obtained in day-to-day practice. To determine whether standards are being met, continuous audit of PPCI programmes is necessary, with appropriate feedback to participating centres and operators. Both the MINAP and BCIS national audit projects allow central electronic collection of data on consecutive patients presenting to every hospital involved in the acute management of these patients. Regular programmed feedback is provided to centres performing primary PCI that attempts to take account of statistical variation and differences in case mix between units by making use of funnel plots, statistical process control graphs and risk adjustment models. This reporting of "process" and "outcome" data, both confidentially and within the public domain, has been used to drive up clinical performance and has been associated with steady improvements and reduced inequalities of care. PMID- 22917795 TI - Economic evidence of interventions for acute myocardial infarction: a review of the literature. AB - AIMS: The aims of this review are to identify and evaluate studies exploring the cost-effectiveness of primary angioplasty (PPCI) vs. thrombolysis (TL) for treating acute myocardial infarction (AMI). METHODS AND RESULTS: A comprehensive free-text searching identified economic evaluation studies that were reviewed with respect to their effectiveness data, identification, measurement and valuation of resource data, measurement and valuation of health outcomes (clinical and QALYs) and uncertainty analysis. A total of 14 studies were included in the review: seven were economic evaluations alongside RCTs, two community-based studies or registries and five decision-analytical models. PPCI was found to be cost-effective when compared with TL in eight studies, cost saving in three, cost-neutral in one, and not significantly different in terms of both cost and benefits in two studies. CONCLUSIONS: The cost-effective evidence available is mainly derived from RCTs with stringent inclusion criteria using established catheter laboratories for providing PPCI treatment; these two components might restrict the generalisability of their "for managing patients with STEMI in hospital" settings. In order to aid policy makers on the real costs and benefits of the PPCI and TL, it is necessary to conduct more analyses with data from the real world in which there are more strategies evaluated for delivering PPCI than merely those in established catheter laboratories. PMID- 22917796 TI - Stent for Life in France. AB - France was chosen to be one of the six first pilot countries of the "Stent for Life" European initiative. First, a prospective registry was set up in five representative French regions, including all admissions within the first 48 hours of ST-elevated acute cardiac syndrome between 1st and 30th November 2010. The second step was to improve results. The main objective was to encourage members of the public experiencing chest pain to call immediately the SAMU's direct line (phone number "15"). Another action was to organise medical meetings in order to improve the management of these patients. Letters were also sent to general physicians to alert them to the issue and to the Stent for Life project. The third step consisted of creating a new registry, in November 2011, to assess the impact of the above actions on an area basis. It has resulted in streamlining the networks and bringing the rate of non-reperfusion down below the 10% threshold. Much remains to be done to improve public awareness of life-saving actions. PMID- 22917798 TI - Regional differences and Italian charter to expand the primary angioplasty service. AB - Italy was one of the first countries in Europe to perform primary percutaneous coronary intervention (p-PCI) and some regions are still a model for the ST elevation myocardial infarction (STEMI) network organisation. However, in Italy, as in other European countries, some regional disparities have emerged which are related to geographical, economic, organisational and structural issues. Although some regions have excellent STEMI networks, others still have to develop a model which will allow each STEMI patient to receive the best reperfusion treatment. Seven areas where patient clinical needs are not met were identified as primary "Stent for Life" targets in Italy: five main regions in the south of Italy, namely Campania, Sicilia, Puglia, Basilicata and Calabria, and two major areas in the north, the districts of Piemonte and Veneto. In this review we describe socio political issues and orographic barriers to implementation of STEMI guidelines that have been identified and some hints on what we have done in each target region in order to expand the p-PCI service. PMID- 22917797 TI - Stent for Life: how this initiative began? AB - The Stent for Life Initiative was founded in September 2008 as a coalition of the European Society of Cardiology, European Association for Percutaneous Cardiovascular Interventions and Eucomed. The aim is to promote the life-saving indications for percutaneous coronary interventions--especially in all forms of acute myocardial infarction. This article describes how this initiative began. PMID- 22917799 TI - Mentality and organisational changes are key to developing primary angioplasty. AB - At the moment of signing the Stent for Life (SFL) Initiative on August 31st, 2009, it was shown that, in Serbia during 2008, 48% of patients with ST-elevation myocardial infarction (STEMI) did not receive any reperfusion and only 19% and 33% received primary percutaneous coronary intervention (p-PCI) or hospital thrombolysis, respectively. However, during 2009, there was a trend towards a substantial increase in p-PCI procedures. This was the result of the commitment of cardiologists, the contract signed by the Health Insurance Fund (HIF) for remuneration of catheterisation laboratory (cathlab) staff for each p-PCI procedure (2005), and the provision of new cathlabs by the Ministry of Health (MOH). The number of PCI centres and trained cardiologists has been rising simultaneously. Direct mobile telephone contact with interventional cardiologists has facilitated the transport of patients directly to cathlabs (from 7.5% before 2009 to 34.2% in 2010 and 2011). Although the number of patients treated with p PCI is increasing (2006 - 647 p-PCIs; 2007 - 1,248 p-PCIs; 2008 -1,794 p-PCIs; 2009 - 2,468 p-PCIs; 2010 - 3,216 and 2011 - 3,498 p-PCIs), the percentage of patients who are treated within 120 minutes of establishing a diagnosis (first medical contact) is still not satisfactory (38%). PMID- 22917801 TI - Decreasing STEMI mortality by implementing a PPCI network in Bulgaria. AB - This article describes the development of the p-PCI network in Bulgaria. Even though interventional treatment of STEMI in the country was introduced around 1990, it was not performed on a regular basis which made it largely inefficient. The paper tracks the network evolution with all the problems encountered and the solutions undertaken until the present moment. Historically, all the important factors concerning the implementation, such as spreading of PCI centres, networks and infrastructure, training and certification, emergency medical service, public awareness campaigns, 24/7 work, reimbursement, etc., are reviewed. Finally, the current increase of the percentage of STEMI patients treated by p-PCI and the decrease of overall STEMI mortality rates are shown, clearly demonstrating the huge value of the SFL know-how and contribution. PMID- 22917800 TI - Primary percutaneous coronary intervention: models of intervention in Spain. AB - Early reperfusion of the occluded artery is the mainstay of the treatment of ST segment elevation myocardial infarction (STEMI), and the best way to coordinate the resources to deliver optimal care as soon as possible is through STEMI networks. Coordination of the healthcare system is the responsibility of each of the 17 different autonomous communities in Spain. Since 2002, when the first STEMI network in Spain was established, six other communities have developed regional networks, covering 39% of the population in Spain. In the autonomous communities, after implementing an intervention model, an improvement in the reperfusion times with an increase in the number of primary percutaneous coronary interventions has been observed. This optimisation of the system has resulted in a decrease in the mortality rate among STEMI patients treated in Spanish communities with a STEMI network. Despite the encouraging advances, the challenge remains of assuring equity of treatment for all of our patients regardless of their region of residence. PMID- 22917802 TI - Developing primary PCI as a national reperfusion strategy for patients with ST elevation myocardial infarction: the UK experience. AB - In 2004 in the United Kingdom (UK), the infrastructural and organisational changes required for implementation of primary PCI for treatment of STEMI were unclear, and the cost-effectiveness and sustainability of a changed reperfusion strategy had not been tested. In addition, any proposed change was to be made against the background of a previously successful in-hospital thrombolysis strategy, with plans for greater use of pre-hospital administration. A prospective study (the "National Infarct Angioplasty Project - NIAP") was set up to collect information on all patients presenting with STEMI in selected regions in the UK over a one year period (April 2005 - March 2006). The key findings from the NIAP project included that PPCI could be delivered within acceptable treatment times in a variety of geographical settings and that the shortest treatment times were achieved with direct admission to a PPCI-capable cardiac catheter laboratory. The transformation from a dominant lytic strategy to one of PPCI across the UK was achieved both swiftly and consistently with the help of 28 cardiac networks. By the second quarter of 2011, 94% of those STEMI patients in England who received reperfusion treatment were being treated by PPCI compared with 46% during the third quarter of 2008. PMID- 22917803 TI - Survival and structural evaluations of three-dimensional tissues fabricated by the hierarchical cell manipulation technique. AB - Mouse L929 fibroblasts and normal human dermal fibroblasts (NHDFs) were constructed into three-dimensional (3-D) multilayered tissues by directly coating them with nano-films consisting of fibronectin (FN) and gelatin (G) onto the surface of the cell layer using layer-by-layer assembly. The one-, two- and five layered (1L, 2L and 5L) tissues were cultured for 1 month in order to evaluate their long-term survival and structural changes. L929 cells in the 3-D tissues showed excessive proliferation throughout the culture period, regardless of the starting layer number. The cross-sectional images stained with hematoxylin and eosin revealed heterogeneous and random increases in the thickness of their layered structures, probably due to the immortalized property of L929 fibroblasts. On the other hand, NHDFs, which are primary cells, showed high stability in their amount of DNA in the multilayered structures, and their thicknesses were completely maintained even after 1 month of incubation. To evaluate the living cell density in each layer of 5L tissues during the culture period, 5L NHDFs were fluorescently labeled with LIVE/DEAD reagent and analyzed by confocal laser scanning microscopy. Although the upper layers did not show any dead cells, the bottom layers showed pieces of dead cell nuclei depending on culture time. However, the living cell densities in all layers were almost the same, even after 1 month of culture, suggesting that the 5L structures were completely filled with living cells. These findings from the multilayered tissue constructs will provide important information not only for the construction of 3 D engineered tissues in tissue engineering but also on 3-D cell culture in biological science generally. PMID- 22917804 TI - Multiarm cationic star polymers by atom transfer radical polymerization from beta cyclodextrin cores: influence of arm number and length on gene delivery. AB - Controlled beta-cyclodextrin (beta-CD) core-based cationic star polymers have attracted considerable attention as non-viral gene carriers. Atom transfer radical polymerization (ATRP) could be readily used to produce the star-shaped polymers. The precise control of the number of initiation sites on the multifunctional core was of crucial importance to the investigation of the structure-property relationship of the functional star gene carriers. Herein, the controlled multiarm star polymers consisting of a beta-CD core and various arm lengths of poly(2-(dimethylamino)ethyl methacrylate) (PDMAEMA) were prepared via ATRP from the chloroacetylated beta-CD with well-designed initiation sites. Generally, these star polycations can condense plasmid DNA into 100-150 nm nanoparticles with positive zeta potentials of 30-40 mV at N/P ratios (star polymer to DNA ratios) of 17 or higher. The effects of arm numbers and lengths on gene delivery were investigated in detail. With a fixed length of the PDMAEMA arm, the fewer the number of arms, the lower the toxicity. The star polycations with suitable arm numbers possess the best transfection ability. On the other hand, with the fixed molecular weights, the shorter the arms, the lower the toxicity. The polymers with 21 arms possess the lowest transfection efficiency. PMID- 22917806 TI - Epilepsy-associated stigma in Bolivia: a community-based study among the Guarani population: an International League Against Epilepsy/International Bureau for Epilepsy/World Health Organization Global Campaign Against Epilepsy Regional Project. AB - Epilepsy is associated with a significant burden of social stigma that appears to be influenced by psychosocial and cultural factors. Stigma has a negative effect on the management of people with epilepsy (PWE), representing one of the major factors that contribute to the burden of epilepsy. To assess stigma perception among the Guarani population, one hundred thirty-two people living in Guarani communities in Bolivia were invited to complete the Stigma Scale of Epilepsy questionnaire. The main determinants of stigma identified were: the fear linked to loss of control, the feelings of sadness and pity toward PWE, the difficulties faced by PWE in the professional and relationship fields, the level of education and type of seizure. Our study pointed out that, in this population, PWE face difficulties in everyday life because of epilepsy-associated stigma and the results attest to the importance of promoting community-based educational programs aimed at reducing the stigmatization process. PMID- 22917805 TI - Elastic discontinuity due to ectopic calcification in a human fibrous joint. AB - Disease can alter natural ramp-like elastic gradients to steeper step-like profiles at soft-hard tissue interfaces. Prolonged function can further mediate mechanochemical events that alter biomechanical response within diseased organs. In this study, a human bone-tooth fibrous joint was chosen as a model system, in which the effects of bacterial-induced disease, i.e. periodontitis, on natural elastic gradients were investigated. Specifically, the effects of ectopic biomineral, i.e. calculus, on innate chemical and elastic gradients within the cementum-dentin complex, both of which are fundamental parameters to load-bearing tissues, are investigated through comparisons with a healthy complex. Complementary techniques for mapping changes in physicochemical properties as a result of disease included micro X-ray computed tomography, microprobe micro X ray fluorescence imaging, transmission electron and atomic force microscopy (AFM) techniques, and AFM-based nanoindentation. Results demonstrated primary effects as derivatives of ectopic mineralization within the diseased fibrous joint. Ectopic mineralization with no cementum resorption, but altered cementum physicochemical properties with increasing X-ray attenuation, exhibited stratified concretion with increasing X-ray fluorescence counts of calcium and phosphorus elements in the extracellular matrix in correlation with decreased hygroscopicity, indenter displacement, and apparent strain-relieving characteristics. Disease progression, identified as concretion through the periodontal ligament (PDL)-cementum enthesis, and sometimes the originally hygroscopic cementum-dentin junction, resulted in a significantly increased indentation elastic modulus (3.16+/-1.19 GPa) and a shift towards a discontinuous interface compared with healthy conditions (1.54+/-0.83 GPa) (Student's t-test, P<0.05). The observed primary effects could result in secondary downstream effects, such as compromised mechanobiology at the mechanically active PDL cementum enthesis that can catalyze progression of disease. PMID- 22917807 TI - Primary leiomyosarcomas of the gastrointestinal tract in the post gastrointestinal stromal tumor era. AB - Most mesenchymal neoplasms of the gastrointestinal tract are currently classified as gastrointestinal stromal tumors (GIST). Gastrointestinal stromal tumors are diagnosed by immunopositivity for CD117, CD34, and DOG1.1, with or without molecular analyses. According to the World Health Organization classification, the diagnosis of primary leiomyosarcomas of the gastrointestinal tract is so rare that there are no significant data on demographic, clinical, or gross features of this tumor. A comprehensive literature search was performed to identify gastrointestinal leiomyosarcomas. Searches were limited to the past 12 years because definitive tools to differentiate leiomyosarcomas from GIST were introduced in the late 1990s. Cases were included only if convincing data were presented. Six cases of esophageal leiomyosarcoma and 5 cases of gastric leiomyosarcoma were confirmed. Furthermore, 26 cases of leiomyosarcoma of the small bowel, 11 cases of the colon, and 8 cases arising in the rectum were identified. Finally, 28 cases of infantile and adolescent leiomyosarcoma were reviewed. Although survival analysis is precluded by small case numbers and limited survival data availability, the trend identifies that increased size and mitotic activity portends to a worse prognosis in small bowel leiomyosarcomas. Colonic leiomyosarcomas appear to be aggressive tumors, regardless of tumor size and mitotic activity. Rectal leiomyosarcomas present as smaller tumors with favorable prognosis. Leiomyosarcomas in post-GIST era are rare tumors of the gastrointestinal tract with distinctive clinicopathologic characteristics. Owing to different treatment options, it is necessary to accurately differentiate these from GIST, using a combination of histologic appearance, presence of smooth muscle antigens, and absence of specific GIST immunomarkers. PMID- 22917808 TI - Guideline-concordant antibiotic therapy and clinical outcomes in healthcare associated pneumonia. AB - BACKGROUND: The 2005 ATS/IDSA guidelines defined healthcare-associated pneumonia (HCAP) as a novel category of pneumonia in patients with significant healthcare exposure in whom the risk of drug resistant bacteria may be higher. In this study, we compare clinical outcomes in patients with HCAP who were treated with guideline-concordant antibiotic regimens with those who were not. METHODS: Medical records of 100 patients meeting HCAP criteria admitted to an academic tertiary care hospital between January 2009 and January 2011 were retrospectively reviewed. Cases were divided into guideline-concordant and guideline-discordant groups based on antibiotic therapy. Demographic, microbiological and clinical outcome data were compared for both groups. RESULTS: Patients in this cohort had multiple co-morbidities, severe pneumonia (mean PSI score 124.1), and significant mortality (22%). 21 of the 100 cases (21.0%) were culture positive, of which 11 (53.8%) represented drug-resistant pathogens. No statistically significant differences for any of the four clinical outcome measures were detected between the guideline-concordant therapy group and guideline-discordant group. In multivariate regression analysis controlling for possible confounders, similar results were observed, with the exception that length of stay was significantly longer (3.99 days, p < 0.001) in the discordant group. Three or more HCAP criteria (OR 10.89) and wound care (OR 6.32) were characteristics found to be associated with increased risk for drug-resistant pathogens. CONCLUSION: In our cohort, the HCAP model identified a population with significant co-morbidities and increased risk for drug-resistant pathogens, severe pneumonia, and increased mortality. However, clinical outcomes were not significantly improved with guideline-concordant antibiotic therapy. PMID- 22917809 TI - The antimicrobial, antioxidative, anti-inflammatory activity and cytotoxicity of different fractions of four South African Bauhinia species used traditionally to treat diarrhoea. AB - ETHNOPHARMACOLOGICAL IMPORTANCE: Many Bauhinia species, including those indigenous to South Africa, are used in traditional medicine across the world for treating ailments such as gastrointestinal tract (GIT) disorders, diabetes, infectious diseases and inflammation. AIMS: Several relevant aspects of different fractions of leaf extracts of Bauhinia bowkeri (BAB), Bauhinia galpinii (BAG), Bauhinia petersiana (BAP), and Bauhinia variegata (BAV) used in South African traditional medicine to alleviate diarrhoea related symptoms were evaluated. MATERIALS AND METHODS: The antioxidative activities of the extracts were determined using the 2, 2-diphenyl-1-picrylhydrazyl (DPPH), 2, 2'-azino-bis (3 ethylbenzothiazoline-6-sulphonic acid (ABTS(+)) radical scavenging and ferric reducing antioxidant power (FRAP) methods. In vitro antimicrobial activities of the extracts were determined against bacterial strains (Staphylococcus aureus, Pseudomonas aeruginosa, Escherichia coli and Enterococcus faecalis) and clinical isolates of the opportunistic fungal strains (Aspergillus fumigatus, Candida albicans, and Cryptococcus neoformans) using a serial dilution microplate method. The polyphenolic contents were quantified using standard methods, and anti inflammatory activities of the crude extracts were determined using the cyclooxygenase and soybean 15-lipoxygenase enzyme inhibitory assays. The safety of the extracts was evaluated by determining the cytotoxicity against Vero cell lines. RESULTS: The acidified 70% acetone crude extract and their fractions had good antiradical potency against the DPPH and ABTS radicals. The methanol soluble portions of the butanol fractions were more potent (EC(50) ranges from 0.64 +/- 0.05 to 1.51 +/- 0.07 and 0.88 +/- 0.18 to 1.49 +/- 0.09 MUg/ml against DPPH and ABTS radical respectively) compared to the standard, trolox and ascorbic acid (EC(50) ranges from 1.47 +/- 0.24 to 1.70 +/- 0.27 MUg/ml) for both DPPH and ABTS. The crude extracts contained variable quantities of phenolic content. The crude extracts and their fractions had weak to good antimicrobial activities, inhibiting the growth of the organisms at concentrations ranging from 39 to 2500 MUg/ml. The BAG crude extract and its fractions were the most active against the fungi (MICs ranging from 39 to 625 MUg/ml) while the BAB extract and its fractions were the least active with the MICs ranging between 39 and 2500 MUg/ml. Aspergillus fumigatus was the least susceptible fungus while Cryptococcus neoformans was the most susceptible. The phenolic-rich crude extracts of BAB, BAG, and BAP had moderate to good dose-dependent cyclooxygenase-1 enzyme inhibitory activity with inhibitions between 22.8% and 71.4%. The extracts were however, inactive against cyclooxygenase-2. The extracts had some level of cytotoxicity towards Vero cell lines, reducing cell viability to less than 10% at concentrations more than 50 MUg/ml. CONCLUSION: The biological activities observed in Bauhinia species provide a scientific basis for the use of the plants in traditional medicines to treat diseases with multi-factorial pathogenesis such as diarrhoea, with each aspect of activity contributing to the ultimate therapeutic benefit of the plants. However, the use of the phenolic-rich extracts of these plants to treat diarrhoea or any other ailments in traditional medicine needs to be monitored closely because of potential toxic effects and selective inhibition of COX-1 with the associated GIT injury. PMID- 22917810 TI - In search of the perfect aphrodisiac: parallel use of bitter tonics in West Africa and the Caribbean. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Enslaved Africans in the Americas had to reinvent their medicinal flora in an unknown environment by adhering to plants that came with them, learning from Amerindians and Europeans, using their Old World knowledge and trial and error to find substitutes for their homeland herbs. This process has left few written records, and little research has been done on transatlantic plant use. We used the composition of aphrodisiac mixtures across the black Atlantic to discuss the adaptation of herbal medicine by African diaspora in the New World. Since Africans are considered relatively recent migrants in America, their healing flora is often said to consist largely of pantropical and cultivated species, with few native trees. Therefore, we expected Caribbean recipes to be dominated by taxa that occur in both continents, poor in forest species and rich in weeds and domesticated exotics. MATERIALS AND METHODS: To test this hypothesis, we compared botanical ingredients of 35 African and 117 Caribbean mixtures, using Dentrended Correspondence Analysis, Cluster Analysis, Indicator Species Analysis and Mann-Whitney U tests. RESULTS: Very few of the 324 ingredients were used on both continents. A slightly higher overlap on generic and family level showed that Africans did search for taxa that were botanically related to African ones, but largely selected new, unrelated plants with similar taste, appearance or pharmacological properties. Recipes from the forested Guianas contained more New World, wild and forest species than those from deforested Caribbean islands. We recorded few 'transatlantic genera' and weeds never dominated the recipes, so we rejected our hypothesis. CONCLUSIONS: The popularity of bitter tonics in the Caribbean suggests an African heritage, but the inclusion of Neotropical species and vernacular names of plants and mixtures indicate Amerindian and European influence. We show that enslaved Africans have reinvented their herbal medicine wherever they were put to work, using the knowledge and flora that was available to them with great creativity and flexibility. Our analysis reveals how transplanted humans adapt their traditional medical practises in a new environment. PMID- 22917811 TI - PCB concentrations in freshwater wild brown trouts (Salmo trutta trutta L) from Marche rivers, Central Italy. AB - The purpose of this study is to evaluate the degree of PCBs contamination of wild brown trouts (Salmo trutta trutta L) caught in Marche Region rivers and to study the percentage contribution of the sum of the six indicators PCBs with respect to the sum of eighteen congeners in wild brown trouts. The determination of eighteen PCBs was made on the edible portion (fillets) of trouts by GC-ECD analysis. Fish samples were collected from fourteen rivers, selected to represent the fluvial pollution in the Marche Region. The total sum of eighteen congener concentrations was 8.2+/-0.9 ng/g wet weight. All the analysed samples showed a high variability of their congener profile even though the six PCBs indicators stood for 49.8% of the total PCBs. In the muscle of brown trout the Sigma eighteen PCB and the Sigma six PCB concentrations were not statistically correlated with the length and the body mass of specimens. Total PCB (Sigma eighteen PCBs and Sigma six PCBs) concentrations measured in the different sampling sites showed significant statistical differences among districts and, in the same district, among rivers (p<0.01). In particular, the lowest PCB levels (p<0.01) were detected in fish caught in Pesaro-Urbino Province rivers with the mean total PCB concentrations of 102.4+/-6.3 ng/g fat weight while the highest PCB levels were measured in specimens coming from Macerata Province rivers (1147.8+/-456.6 ng/g fat weight). PMID- 22917812 TI - Production of meganucleases by cell-free protein synthesis for functional and structural studies. AB - Meganucleases are highly specific endonucleases that recognize and cleave long DNA sequences, making them powerful tools for gene targeting. We describe the production of active recombinant meganucleases suitable for functional and structural studies using a batch-based cell-free protein synthesis method. Isotopic labeling of the I-CreI meganuclease is demonstrated opening the way for structural and ligand binding studies in solution by nuclear magnetic resonance (NMR)(2) which was previously hampered by the problems associated with the toxicity of the enzyme for Escherichia coli limiting its growth. The method can be adapted for the synthesis of soluble engineered variants that are produced as inclusion bodies in bacterial cells, thus facilitating their purification as soluble proteins instead of using denaturing-refolding protocols. PMID- 22917813 TI - A placebo-controlled, randomized phase II study of maintenance enzastaurin following whole brain radiation therapy in the treatment of brain metastases from lung cancer. AB - INTRODUCTION: Enzastaurin is a protein kinase C inhibitor with anti-tumor activity. This study was designed to determine if maintenance enzastaurin improved the outcome of whole brain radiotherapy (WBRT) in lung cancer (LC) patients with brain metastases (BMs). METHODS: Patients with LC (any histology) who had received WBRT for BMs were randomized to receive oral maintenance enzastaurin (1125 mg on Day 1 followed by 500 mg daily) or placebo. The primary endpoint was time to progression (TTP) of BMs. RESULTS: Fifty-four patients received enzastaurin and 53 patients received placebo. The median TTP of BMs was (months) enzastaurin: 6.9 (95% confidence interval [CI]: 3.4-11.9); placebo: 4.9 (95% CI: 3.6-not assessable); p=0.82. Median overall survival (OS) was (months) enzastaurin: 3.8 (95% CI: 2.6-5.6); placebo: 5.1 (95% CI: 3.7-5.7); p=0.47. Median progression-free survival (PFS) was (months) enzastaurin: 2.2 (95% CI: 1.1 2.3); placebo: 2.0 (95% CI: 1.3-2.3); p=0.75. The overall response rate (ORR) for extracranial disease was enzastaurin: 0%; placebo: 4.5% (p=0.49) and for intracranial disease was enzastaurin: 9.3%; placebo 6.8% (p=0.71). Grade 4 hematologic treatment-emergent adverse events were (enzastaurin vs. placebo) thrombocytopenia (5.6% vs. 1.9%) and neutropenia (5.6% vs. 0%). There was 1 treatment-related death in each arm (enzastaurin: unknown cause; placebo: pulmonary embolism). No significant differences in health-related quality of life (HRQoL) were observed. CONCLUSIONS: Enzastaurin was well tolerated but did not improve TTP of BMs, ORR, OS, PFS, or HRQoL after WBRT in LC patients with BMs. PMID- 22917814 TI - Non-transcriptional oscillators in circadian timekeeping. AB - Circadian clocks have evolved as an adaptation to life on a rotating planet, and orchestrate rhythmic changes in physiology to match the time of day. For decades, cellular circadian rhythms were considered to solely result from feedback between the products of rhythmically expressed genes. These transcriptional/translational feedback loops (TTFLs) have been ubiquitously studied, and explain the majority of circadian outputs. In recent years, however, non-transcriptional processes were shown to be major contributors to circadian rhythmicity. These key findings have profound implications on our understanding of the evolution and mechanistic basis of cellular circadian timekeeping. This review summarises and discusses these results and the experimental and theoretical evidence of a possible relation between non-transcriptional oscillator (NTO) mechanisms and TTFL oscillations. PMID- 22917815 TI - Prevalence and persistence of male DNA identified in mixed saliva samples after intense kissing. AB - Identification of foreign biological material by genetic profiling is widely used in forensic DNA testing in different cases of sexual violence, sexual abuse or sexual harassment. In all these kinds of sexual assaults, the perpetrator could constrain the victim to kissing. The value of the victim's saliva taken after such an assault has not been investigated in the past with currently widely used molecular methods of extremely high sensitivity (e.g. qPCR) and specificity (e.g. multiplex Y-STR PCR). In our study, 12 voluntary pairs were tested at various intervals after intense kissing and saliva samples were taken from the women to assess the presence of male DNA. Sensitivity-focused assays based on the SRY (single-copy gene) and DYS (multi-copy gene) sequence motifs confirmed the presence of male DNA in female saliva after 10 and even 60min after kissing, respectively. For specificity, standard multiplex Y-STR PCR profiling was performed and male DNA was found in female saliva samples, as the entire Y-STR profile, even after 30min in one sample. Our study confirms that foreign DNA tends to persist for a restricted period of time in the victim's mouth, can be isolated from saliva after prompt collection and can be used as a valuable source of evidence. PMID- 22917816 TI - The 2011 GeFI collaborative exercise. Concordance study, proficiency testing and Italian population data on the new ENFSI/EDNAP loci D1S1656, D2S441, D10S1248, D12S391, D22S1045. AB - The 2011 collaborative exercise of the ISFG Italian Working Group GeFI was aimed at validating the five ENFSI/EDNAP miniSTR loci D1S1656, D2S441, D10S1248, D12S391 and D22S1045. The protocol required to type at least 50 multilocus profiles from locally resident individuals and two blind bloodstains in duplicate (i.e., using at least two different commercial kits), and to send the electropherograms to the Organizing Committee. Nineteen laboratories distributed across Italy participated, collecting a total of 960 samples. Full concordance was found for the five new miniSTRs as observed from the comparison of 13,150 alleles. The inspection of the electropherograms allowed the identification of a very limited number of mistypings in the miniSTR genotypes thus contributing to the establishment of an high quality Italian database of frequencies. PMID- 22917817 TI - The HIrisPlex system for simultaneous prediction of hair and eye colour from DNA. AB - Recently, the field of predicting phenotypes of externally visible characteristics (EVCs) from DNA genotypes with the final aim of concentrating police investigations to find persons completely unknown to investigating authorities, also referred to as Forensic DNA Phenotyping (FDP), has started to become established in forensic biology. We previously developed and forensically validated the IrisPlex system for accurate prediction of blue and brown eye colour from DNA, and recently showed that all major hair colour categories are predictable from carefully selected DNA markers. Here, we introduce the newly developed HIrisPlex system, which is capable of simultaneously predicting both hair and eye colour from DNA. HIrisPlex consists of a single multiplex assay targeting 24 eye and hair colour predictive DNA variants including all 6 IrisPlex SNPs, as well as two prediction models, a newly developed model for hair colour categories and shade, and the previously developed IrisPlex model for eye colour. The HIrisPlex assay was designed to cope with low amounts of template DNA, as well as degraded DNA, and preliminary sensitivity testing revealed full DNA profiles down to 63pg input DNA. The power of the HIrisPlex system to predict hair colour was assessed in 1551 individuals from three different parts of Europe showing different hair colour frequencies. Using a 20% subset of individuals, while 80% were used for model building, the individual-based prediction accuracies employing a prediction-guided approach were 69.5% for blond, 78.5% for brown, 80% for red and 87.5% for black hair colour on average. Results from HIrisPlex analysis on worldwide DNA samples imply that HIrisPlex hair colour prediction is reliable independent of bio-geographic ancestry (similar to previous IrisPlex findings for eye colour). We furthermore demonstrate that it is possible to infer with a prediction accuracy of >86% if a brown-eyed, black haired individual is of non-European (excluding regions nearby Europe) versus European (including nearby regions) bio-geographic origin solely from the strength of HIrisPlex eye and hair colour probabilities, which can provide extra intelligence for future forensic applications. The HIrisPlex system introduced here, including a single multiplex test assay, an interactive tool and prediction guide, and recommendations for reporting final outcomes, represents the first tool for simultaneously establishing categorical eye and hair colour of a person from DNA. The practical forensic application of the HIrisPlex system is expected to benefit cases where other avenues of investigation, including STR profiling, provide no leads on who the unknown crime scene sample donor or the unknown missing person might be. PMID- 22917818 TI - One hundred ten days of extracorporeal membrane oxygenation in a young woman with postpartum cerebral venous thrombosis and acute respiratory distress syndrome. AB - Extracorporeal membrane oxygenation (ECMO) is often the last resort for serious acute respiratory distress syndrome (ARDS) when all non-invasive treatment options have failed to improve the patient's pulmonary condition. We present a successful long-term therapy with ECMO over 110 days in a 28-year-old woman. She developed postpartum cerebral venous thrombosis with severe respiratory insufficiency. Veno-venous ECMO rescued this young patient, allowing for full recovery. PMID- 22917819 TI - A new form of coronary subclavian steal syndrome: a saphenous vein graft-coronary subclavian unidirectional steal syndrome. AB - Coronary subclavian steal syndrome refers to decreased or reversed internal mammary artery flow, which causes angina related to severe subclavian steno occlusive disease in patients with in situ internal mammary-to-coronary artery graft. We present a 48-year-old man with cerebrovascular and peripheral artery disease and the first case in the literature of a saphenous vein graft-coronary subclavian unidirectional steal syndrome. PMID- 22917820 TI - The Ross-Konno procedure as reoperative treatment in a young adult with congenital aortic stenosis. AB - Mechanical and biological prostheses are valid options when aortic valve replacement is necessary. The Ross procedure is also an alternative solution, especially for young patients. We describe the case of a young patient with congenital aortic stenosis and bicuspid aortic valve who presented with dyspnea on exertion. An open commissurotomy was performed, and within 8 months the patient developed recurrent symptoms of severe aortic stenosis. He underwent redo sternotomy and a Ross-Konno procedure with an uneventful recovery. PMID- 22917821 TI - Right ventricular dysfunction after coronary artery bypass grafting is a reality of unknown cause and significance. AB - OBJECTIVE: To evaluate the impact of coronary bypass surgery on the function of the right ventricle (RV) in patients with a pre-operative ejection fraction >= 35% who did not have any perioperative myocardial infarction. METHOD: We performed a prospective study of 30 patients who underwent uneventful isolated coronary artery bypass grafting (CABG). All patients had echocardiography prior to surgery and 3 months postoperatively. Myocardial tissue Doppler velocities were used to measure left and right ventricular function. The right ventricular myocardial performance index (Tei) and the ratio between the velocities of the RV and left ventricle (LV) were also calculated. RESULTS: There was a significant improvement in left ventricular ejection fraction before and after CABG (P = .046). The tissue Doppler imaging (TDI) velocities from the LV remained unchanged, but highly significant reductions in right ventricular TDI velocities were observed (P <.001). The TDI peak systolic (S), early diastolic (E), and late diastolic (A) velocities had a reduction of 30%, 34.5%, and 20%, respectively. Similarly, a fall in RV to LV ratios of various TDI velocities was also observed. This was also accompanied by a significant rise in the RV Tei index. All of these findings are suggestive of significant RV dysfunction. CONCLUSION: There is a marked impairment of RV function after CABG. PMID- 22917822 TI - Safety and efficacy of an ultrashort-acting beta1-blocker on left ventricular dysfunction. AB - Landiolol hydrochloride, an ultrashort-acting beta1-selective blocker, is a highly regulated drug. This study evaluated the safety and efficacy of this drug for cases of coronary artery bypass grafting (CABG) with left ventricular dysfunction. Between September 2006 and August 2009, 32 patients with a left ventricular ejection fraction of <40% underwent CABG. Two groups of patients, a group administered landiolol hydrochloride and a control group not administered this drug, were compared. The administration of landiolol hydrochloride was initiated at 1 MUg/kg per minute (gamma) after cardiopulmonary bypass in on-pump cases and after completion of all the distal anastomoses in off-pump cases. We observed no significant differences between the groups with respect to preoperative patient background or incidences of complications, except for postoperative atrial fibrillation. The heart rate decreased significantly 30 minutes after landiolol hydrochloride administration, but no change was observed in arterial pressure. No change was observed in other parameters; the hemodynamics were stable. The occurrence of atrial fibrillation during the intensive care unit stay (during landiolol hydrochloride administration) was significantly lower in the administration group. The difference remained significant after multiple logistic regression analysis; landiolol hydrochloride was the sole inhibitory factor. PMID- 22917823 TI - Can we identify risk factors for postoperative delirium in cardiac coronary patients? Our experience. AB - INTRODUCTION: Delirium is a temporary mental disorder that frequently occurs among elderly hospitalized patients. Patients who undergo cardiac operations have an increased risk of postoperative delirium, which is associated with higher mortality and morbidity rates, a prolonged hospital stay, and reduced cognitive and functional recovery. PATIENTS AND METHODS: In our prospective study, we included 370 consecutive adult patients who underwent on-pump coronary artery surgery between January 1, 2011, and July 1, 2011. We selected 21 potential risk factors and divided them into preoperative, intraoperative, and postoperative groups. Delirium was diagnosed with the Confusion Assessment Method. RESULTS: Postoperative delirium was diagnosed in 74 patients (20%). Four predictive factors were associated with postoperative delirium: diabetes mellitus, cerebrovascular disease, peripheral vascular disease, and prolonged intubation (P < .05). CONCLUSION: Three of the four predictive factors significantly associated with delirium are preoperative. They are relatively easy to measure and can be used to identify patients at higher risk. Fast extubation of these patients and preventive interventions can be taken to prevent negative consequences of this postoperative complication. PMID- 22917824 TI - Left atrial myxoma with neovascularization presenting as a sick sinus syndrome. AB - Myxoma is benign tumor of the heart. It is mostly located in the left atrium and revascularized by the left and right coronary artery in 30% to 40% of cases. Symptoms of these neovascularized cardiac myxomas are typically quite variable, from obstruction of mitral valve to coronary embolism resulting in acute myocardial infarction. In this case, left atrial myxoma that is revascularized by nodal branches of the right coronary artery presented as a sick sinus syndrome, which is rare in literature. PMID- 22917826 TI - Simple technique to verify CO(2) diffusion with the CarbonAidTM device. AB - It has become common practice in cardiac surgery to flood the operative field with CO(2) to facilitate deairing of the heart. However, CO(2) delivery is variable and verification of CO(2) delivery can be challenging. We report a simple, reliable method to confirm CO(2) delivery. This technique ensures that the benefits of CO(2) delivery are provided to the patient during the operation. PMID- 22917825 TI - Surgical myocardial revascularization versus percutaneous coronary intervention with drug-eluting stents in octogenarian patients. AB - OBJECTIVE: Our goal was to compare the clinical outcomes of octogenarian (or older) patients who are referred for either surgical or percutaneous coronary revascularization. METHODS: We retrospectively evaluated the outcomes of all patients 80 years of age who had undergone coronary artery bypass grafting (CABG) with an internal mammary artery or had undergone a percutaneous coronary intervention (PCI) with a sirolimus-eluting stent to the left anterior descending artery in our center between May 2002 and December 2006. RESULTS: Of the 301 patients, 120 underwent a PCI, and 181 underwent CABG. Surgical patients had higher rates of left main disease, triple-vessel disease, peripheral vascular disease, emergent procedures, and previous myocardial infarctions (39.7% versus 3.3% [P = .001], 76.1% versus 28.3% [P = .0001], 19.6% versus 7.5% [P = .004], 15.8% versus 2.5% [P = .0001], and 35.9% versus 25% [P = .04], respectively). CABG patients had a higher early mortality rate (9.9% versus 2.5%, P = .01). There were no differences in 1- and 4-year actuarial survival rates, with rates of 90% and 68%, respectively, for the PCI group and 85% and 71% for the CABG group (P = .85). The rates of actuarial freedom from major adverse cardiac events (MACEs) at 1 and 4 years were 83% and 75%, respectively, for the PCI group, and 86% and 78% for the CABG group (P = .33). The respective rates of freedom from reintervention were 87% and 83% for the PCI group, versus 99% and 97% for the CABG group (P < .001). The 4-year rate of freedom from recurring angina was 58% for the PCI group, versus 88% for CABG patients (P < .001). Revascularization strategy was not a predictor of adverse outcome in a multivariable analysis. CONCLUSION: Octogenarian CABG patients were sicker and experienced a higher rate of early mortality. The 2 strategies had similar rates of late mortality and MACEs, with fewer reinterventions and recurring angina occurring following surgery. PMID- 22917827 TI - Resection of Lambl's excrescence on the aortic valve in a patient with rheumatic mitral valve disease and a left atrial thrombus. AB - Lambl's excrescences (LEs) are filiform strands that form on heart valves and are associated with an increased risk of stroke due to embolization. Although resection of these strands is generally recommended in patients who present with a stroke and no other identifiable cause, the management of incidentally discovered LEs in patients without an adverse cardioembolic event is less clear. We report a case of a patient with severe mitral valve stenosis from rheumatic heart disease and a large left atrial thrombus who was incidentally found to have multiple LEs on her aortic valve. In addition to replacing her mitral valve and removing the left atrial thrombi, we resected the LEs from her aortic valve due to their potential to cause a stroke and the relatively low associated morbidity in resecting them while keeping the aortic valve leaflets and valve function intact. PMID- 22917828 TI - Calciphylaxis following coronary artery bypass surgery: an underappreciated cause of wound complications? AB - Wound complications following cardiac surgery are typically infectious and associated with a high morbidity and mortality. Calciphylaxis, vascular calcification of small and medium sized vessels, often associated with end-stage renal disease, can result in extensive tissue necrosis. We hypothesize that calciphylaxis is an under-recognized and under-reported precipitating wound and breast complication following coronary artery bypass surgery and thereby necessitates further study. PMID- 22917829 TI - Near-infrared spectroscopy-detected cerebral ischemia resolved by cannulation of an axillo-femoral graft during surgical repair of type A aortic dissection. AB - We report the case of a patient who experienced near-infrared spectroscopy (NIRS) detected transient regional cerebral desaturation during cardiopulmonary bypass for an operation to replace the aortic arch. Prompt institution of additional flow through an axillo-femoral graft was associated with restoration of regional cerebral saturation. The aortic surgery had no neurologic complications. Promptness in detecting and restoring cerebral perfusion appeared crucial in avoiding prolonged cerebral ischemia and reducing the likelihood of adverse neurologic events. PMID- 22917830 TI - Deep pericardial traction suture versus vacuum-assisted apical suction to expose the posterior wall of the heart in off-pump coronary artery bypass: a prospective, randomized study. AB - BACKGROUND: Displacement of the heart to expose the posterior vessels during off pump coronary artery bypass (OPCAB) may cause hemodynamic instability. Deep pericardial traction suture (DPTS) and vacuum-assisted apical suction (VAS) with the Starfish positioning device help to provide good exposure without relevant hemodynamic changes. Our aim was to compare these two methods in patients undergoing multivessel OPCAB. METHODS: We prospectively randomized 20 patients undergoing multivessel OPCAB to the use of VAS or DPTS. The Octopus device was used in both groups to stabilize the target vessel. Hemodynamic parameters, including venous oxygen content (SvO(2)), cardiac index (CI), central venous pressure (CVP), mean arterial pressure (MAP), pulmonary artery pressure (PAP), and pulmonary capillary wedge pressure (PCWP), were measured before grafting (baseline), after heart positioning, and during performance of peripheral anastomoses. RESULTS: Perioperative data for the two groups were similar. During exposure of the lateral wall, there were fewer hemodynamic changes in the DPTS group (increase in CVP) than in the VAS group (increases in CVP, PAP, and PCWP); the CVP was significantly higher in the DPTS group (P < .05). During exposure of the posterior wall, significant hemodynamic changes occurred only in the DPTS group (increase in PCWP). Values for all other parameters were similar, including anastomosis time, graft flow, postoperative myocardial enzymes, and inotropic support. CONCLUSIONS: Heart positioning during OPCAB with either VAS or DPTS is a safe and effective maneuver for exposure of coronary arteries. In our study, the use of the VAS device produced less hemodynamic impairment during exposure of the lateral and posterior walls. PMID- 22917831 TI - Spontaneous coronary artery dissections: three case reports and review of literature. AB - Primary spontaneous coronary artery dissection is one of the rare causes of acute myocardial infarction and is mostly fatal. Previous studies report that it is mostly seen in middle-aged women in the last trimester of pregnancy and early postpartum period. Clinical presentation of the disease is variable in pattern, and its severity is related to extent and development rate of dissection. Herein we present three cases of primary spontaneous left main coronary artery dissection. Two of the patients are men and the third patient is a non-pregnant 69-year-old woman. The cases were presented and discussed with review of the pertinent literature. PMID- 22917832 TI - Application of lower sternal incision with on-pump, beating heart intracardiac procedures in congenital heart disease. AB - BACKGROUND: The purpose of this study was to explore the application of lower sternal incision with on-pump, beating heart intracardiac procedures for the treatment of congenital heart disease. METHODS: A total of 106 cases with congenital heart disease were performed with lower sternal incision under the beating heart condition. The sternum was sawed open to the third sternocostal joint through a small incision in the lower sternum. Cardiopulmonary bypass was developed without aortic cross-clamping. The simultaneous left atrium and ventricle suction and integrating sequential deairing procedure was established to improve the exposure of the surgical field and intraoperative de-airing. We also randomly selected 100 patients with similar disease and age as controls. These control patients underwent middle sternal incision surgery with arresting heart. RESULTS: The results showed that all the patients were successfully completed with the surgery without death and serious complications, eg, air embolism, residual shunt, and complete atrioventricular block. The operative and cardiopulmonary bypass time in the experimental group was not significantly different from that in the control group. The length of the skin incision in the experimental group was shortened by 4.8 cm compared to that in the control group. The incidence of sternal deformity in patients under 3 years old in the experimental group was significantly lower than that in the control group. CONCLUSIONS: Lower sternal incision with beating heart can reduce the surgical injury, simplify the operation procedure, and improve the therapeutic efficacy. It is a safe and effective approach for the treatment of congenital heart disease. PMID- 22917833 TI - The unligated left internal mammary artery side branch as the cause of angina after coronary artery bypass grafting. AB - The left internal mammary artery (LIMA) is a widely used conduit during coronary artery bypass graft (CABG) surgery because of its excellent long-term patency. Although large LIMA side branches are typically ligated during the surgery, the occurrence of a coronary steal phenomenon related to these side branches following surgery remains controversial. Advocates for occlusion of LIMA side branches in the setting of left anterior descending artery (LAD) ischemia indicate that anginal symptoms often improve and that objective measures of LAD ischemia frequently resolve. We present a patient with ischemia in the LAD distribution secondary to coronary steal from a large LIMA side branch that was successfully treated using the Embolization Coil-IMWCE-3-PDA5 (Cook Medical, Bjaeverskov, Denmark). PMID- 22917835 TI - Laparoscopic fundoplication with double sided posterior gastropexy: a different surgical technique. AB - BACKGROUND: Laparoscopic Nissen Fundoplication has become the gold standard surgical procedure for management of gastroesophageal reflux disease. Nissen fundoplication provides an effective barrier against reflux. The aim of this study was to evaluate early postoperative outcomes of a different surgical technique, laparoscopic fundoplication with double sided posterior gastropexy. METHODS: Data of 46 patients who underwent laparoscopic fundoplication with double sided posterior gastropexy between February 2010 and December 2011 were collected. Surgically, after Nissen fundoplication was completed, 2-4 sutures were passed through the uppermost parts of the posterior and anterior wall of the gastric wrap and then passed gently 1 cm above the celiac artery from the denser fibers of uppermost part of the arcuate ligament. Demographic data, preoperative and postoperative assesments of sympthomatic and functional outcomes of patients were recorded. Length of hospital stay, operative time, early postoperative complications and complications at 1 year follow up, early recurrence rate were also recorded. RESULTS: This technique resulted in good symptomatic and clinical outcomes. Only one patient out of 45 patients was reoperated. The early recurrence rate was 2.2%. CONCLUSION: Laparoscopic Nissen fundoplication with double sided posterior gastropexy may prevent paraesophageal herniation. It is a reasonably feasible and effective method in surgical management of GERD. PMID- 22917836 TI - Surgical management of chronic subdural haematoma: one hole or two? AB - A best evidence topic in neurosurgery was written according to a structured protocol. The question addressed was: In patients undergoing craniostomy for the evacuation of chronic subdural haematoma, does the use of two burr-holes compared to one burr-hole improve clinical outcomes? A total of 238 papers were identified using the reported search protocol. Four of these articles represented the best evidence to answer the clinical question. The authors, date and country of publication, study type, patient group, outcomes and key results of these papers have been represented in a table. Three out of four studies showed that there was no significant difference in prevalence or rate of haematoma recurrence between two burr-hole craniostomy or one burr-hole craniostomy. Two studies demonstrated shorter hospital stay with two burr-hole craniostomy. Furthermore, one study showed increased rates of wound infection with one burr-hole craniostomy. Therefore, the clinical bottom line is that performing either two burr-hole craniostomy or one burr-hole craniostomy does not provide specific differences in patient outcome improvement following surgery for chronic subdural haematoma, however further research is required owing to the flawed methodology of existing studies. PMID- 22917834 TI - Postnatal choline levels mediate cognitive deficits in a rat model of schizophrenia. AB - In the present study, we investigated whether the essential nutrient choline may protect against schizophrenic-like cognitive deficits in a rat model. Theories regarding the etiology of schizophrenia suggest that early life events render an individual more vulnerable to adult challenges, and the combination may precipitate disease onset. To model this, the adult male offspring of dams who either experienced stress during late gestation or did not were given a 5 mg/kg dose of the NMDA antagonist,MK-801. The presence of both the prenatal challenge of stress and the adult challenge of MK-801 was expected to impair memory in these offspring. Memory was not expected to be impaired in rats that did not experience prenatal stress, but did receive MK-801 as adults. To study whether choline levels altered outcomes in these groups, rats were fed a choline supplemented, -deficient, or standard diet during the period between the two challenges: beginning at weaning and continuing for 25 days. All rats consumed regular rat chow thereafter. The efficacy of the model was confirmed in the standard fed rats in that only those that were prenatally stressed and received MK-801 as adults displayed impaired memory on a novelty preference test of object recognition. Contrary to this finding and consistent with our hypothesis, choline supplemented rats that were also both prenatally stressed and given MK-801 as adults showed intact memory. Choline deficiency impaired memory in rats that were just prenatally stressed, just given MK-801 as adults, and subjected to both. Thus, a choline deficient diet may render rats vulnerable to either challenge. Taken together, we offer evidence that developmental choline levels modulate the effects of prenatal stress and/or MK-801 and thereby alter the cognitive outcome in a rat model of schizophrenia. PMID- 22917837 TI - Investigating links between polychlorinated biphenyl (PCB) exposure and thymic involution and thymic cysts in harbour porpoises (Phocoena phocoena). AB - The associations between polychlorinated biphenyls (PCBs) exposure and involution of lymphoid tissue and development of epithelial-lined cysts in the thymus of UK stranded harbour porpoises (Phocoena phocoena) (n=170) were tested. Percentage of thymic lymphoid tissue (%TLT) was histologically quantified. Multiple regression analyses (n=169) demonstrated significant positive correlation between %TLT and nutritional status (p<0.001) and significant negative association between %TLT and onset of sexual maturity (p<0.001). However, in a subgroup of porpoises with total PCB levels above a proposed threshold of toxicity (>17mg/kg lipid weight) (n=109), the negative association between %TLT (as dependent variable) and summed blubber concentrations of 25 chlorobiphenyl congeners (?25CBs) remained significant (p<0.01) along with nutritional status (p<0.001) and onset of sexual maturity (p<0.001). These results suggest PCB-induced immuno suppression may be occurring in harbour porpoises in UK waters but only at concentrations that exceed proposed toxicity thresholds for marine mammals. In contrast, development of thymic cysts appears predominantly age-related. PMID- 22917838 TI - Gene test to elucidate the ETEC F4ab/F4ac receptor status in pigs. PMID- 22917839 TI - Changes to the electronic health records market in light of health information technology certification and meaningful use. AB - BACKGROUND: Health information technology (HIT) certification and meaningful use are interventions encouraging the adoption of electronic health records (EHRs) in the USA. However, these initiatives also constitute a significant intervention which will change the structure of the EHR market. OBJECTIVE: To describe quantitatively recent changes to both the demand and supply sides of the EHR market. MATERIALS AND METHODS: A cohort of 3447 of hospitals from the HIMSS Analytics Database (2006-10) was created. Using hospital referral regions to define the local market, we determined the percentage of hospitals using paper records, the number of vendors, and local EHR vendor competition using the Herfindahl-Hirschman Index. Changes over time were assessed using a series of regression equations and geographic information systems analyses. RESULTS: Overall, there was movement away from paper records, upward trends in the number of EHR vendors, and greater competition. However, changes differed according to hospital size and region of the country. Changes were greatest for small hospitals, whereas competition and the number of vendors did not change dramatically for large hospitals. DISCUSSION: The EHR market is changing most dramatically for those least equipped to handle broad technological transformation, which underscores the need for continued targeted support. Furthermore, wide variations across the nation indicate a continued role for states in the support of EHR utilization. CONCLUSION: The structure of the EHR market is undergoing substantial changes as desired by the proponents and architects of HIT certification and meaningful use. However, these transformations are not uniform for all hospitals or all the country. PMID- 22917840 TI - Prenatal zinc deficiency-dependent epigenetic alterations of mouse metallothionein-2 gene. AB - Zinc (Zn) deficiency in utero has been shown to cause a variety of disease states in children in developing countries, which prompted us to formulate the hypothesis that fetal epigenetic alterations are induced by zinc deficiency in utero. Focusing on metallothionein (MT), a protein that contributes to Zn transport and homeostasis, we studied whether and how the prenatal Zn status affects gene expression. Pregnant mice were fed low-Zn (IU-LZ, 5.0 MUg Zn/g) or control (IU-CZ, 35 MUg Zn/g) diet ad libitum from gestation day 8 until delivery, with a regular diet thereafter. Bisulfite genomic sequencing for DNA methylation and chromatin immunoprecipitation assay for histone modifications were performed on the MT2 promoter region. We found that 5-week-old IU-LZ mice administered cadmium (Cd) (5.0 mg/kg b.w.) have an elevated abundance of MT2 mRNA compared with IU-CZ mice. Alteration of histone modifications in the MT2 promoter region having metal responsive elements (MREs) was observed in 1-day-old and 5-week-old IU-LZ mice compared with IU-CZ mice. In addition, prolongation of MTF1 binding to the MT2 promoter region in 5-week-old IU-LZ mice upon Cd exposure is considered to contribute to the enhanced MT2 induction. In conclusion, we found for the first time that Zn deficiency in utero induces fetal epigenetic alterations and that these changes are being stored as an epigenetic memory until adulthood. PMID- 22917841 TI - Walnut diet reduces accumulation of polyubiquitinated proteins and inflammation in the brain of aged rats. AB - An increase in the aggregation of misfolded/damaged polyubiquitinated proteins has been the hallmark of many age-related neurodegenerative diseases. The accumulation of these potentially toxic proteins in brain increases with age, in part due to increased oxidative and inflammatory stresses. Walnuts, rich in omega fatty acids, have been shown to improve memory, cognition and neuronal effects related to oxidative stress (OS) and inflammation (INF) in animals and human trials. The current study found that feeding 19-month-old rats with a 6% or 9% walnut diet significantly reduced the aggregation of polyubiquitinated proteins and activated autophagy, a neuronal housekeeping function, in the striatum and hippocampus. Walnut-fed animals exhibited up-regulation of autophagy through inhibiting phosphorylation of mTOR, up-regulating ATG7 and Beclin 1, and turnover of MAP1BLC3 proteins. The clearance of polyubiquitinated protein aggregates such as p62/SQSTM1 was more profound in hippocampus, a critical region in the brain involved in memory and cognitive performance, than striatum. The clearance of ubiquitinated aggregates was in tandem with significant reductions in OS/INF, as indicated by the levels of P38-MAP kinase and phosphorylations of nuclear factor kappa B and cyclic AMP response element binding protein. The results demonstrate the effectiveness of a walnut-supplemented diet in activating the autophagy function in brain beyond its traditionally known antioxidant and anti inflammatory benefits. PMID- 22917842 TI - High multivitamin intakes during pregnancy and postweaning obesogenic diets interact to affect the relationship between expression of PPAR genes and glucose regulation in the offspring. AB - High multivitamin intake (HV) during pregnancy increases body fat and weight and alters glucose and fatty acid metabolism in Wistar rat offspring. This study investigated the expression of peroxisome-proliferator activated receptors (PPARs) genes involved in regulation of glucose and fatty acid metabolism in their tissues. Dams received the AIN-93G diet with either the regular (RV) or 10 fold multivitamins (HV) during pregnancy. Male offspring were weaned to either the RV diet (RV-RV and HV-RV) or an obesogenic diet (RV-Ob and HV-Ob). Gene expression of PPARs in tissues was analyzed by real-time reverse transcriptase polymerase chain reaction. Gestational diet (GD) did not affect PPARs gene expression in offspring at either birth or weaning. In liver, at 14 weeks postweaning, PPAR-gamma was 30% lower in the HV-RV and 30% higher in HV-Ob than in the RV-RV group [GD P=.76, postweaning diet (PD) P=.19, interaction P=.02, by two-way analysis of variance]. In muscle, PPAR-alpha expression was affected by GD and PD (GD P=.05, PD P<.01, interaction P=.07). In adipose tissue, PPAR-alpha expression was higher in all groups compared to RV-RV (GD P=.25, PD P=.85, interaction P=.03). PPAR-gamma mRNA levels correlated with abdominal fat (r=0.45, P<.05) and insulin resistance index (r=0.39, P<.05). In liver, PPAR-gamma expression correlated with insulin resistance index in offspring from RV (r= 0.62, P<.05), but not in those from HV dams (r=0.13, P>.05). In conclusion, the HV diet during pregnancy interacts with postweaning diets in determining the expression of PPARs genes in a tissue- and age-dependent manner and uncouples the relationship between these genes and glucose regulation and fat mass in the rat offspring. PMID- 22917843 TI - The association of quality of social relations, symptom severity and intelligence with anxiety in children with autism spectrum disorders. AB - Limited quality of social relations, milder symptom severity and higher intelligence were shown to account for higher anxiety levels in autism spectrum disorders. The current study replicated and extended earlier findings by combining these three determinants of anxiety in autism spectrum disorders in one study. The sample consisted of 134 school-aged children with autism spectrum disorders, of whom 58 (43%) had a co-morbid anxiety disorder according to the Diagnostic Interview Schedule for Children-Parent version. In this sample, we tested associations between these determinants and anxiety univariately and multivariately to clarify the unique contribution of all determinants. Since we hypothesized that the association between limited quality of social relations and anxiety would be amplified by low symptom severity and/or high intelligence, we additionally tested for moderating effects. We found that higher anxiety levels were associated with a lower quality of social relations and lower symptom severity. In this mainly high-functioning sample, intelligence was not related to anxiety levels. No moderation effects were found. Since lower quality of social relations and lower symptom severity are associated with higher anxiety levels in children with autism spectrum disorders, therapeutic interventions aimed at reducing anxiety in autism spectrum disorders should pay attention to improving social relations, and presumably children with a lower symptom severity could benefit most from such interventions. PMID- 22917844 TI - Priorities for autism spectrum disorder risk communication and ethics. AB - Autism spectrum disorders are an issue of increasing public health significance. The incidence of autism spectrum disorders has been increasing in recent years, and they are associated with significant personal and financial impacts for affected persons and their families. In recent years, a large number of scientific studies have been undertaken, which investigate genetic and environmental risk factors for autism, with more studies underway. At present, much remains unknown regarding autism spectrum disorder risk factors, but the emerging picture of causation is in many cases complex, with multiple genes and gene-environment interactions being at play. The complexity and uncertainty surrounding autism spectrum disorder risk factors raise a number of questions regarding the ethical considerations that should be taken into account when undertaking autism spectrum disorder risk communication. At present, however, little has been written regarding autism spectrum disorder risk communication and ethics. This article summarizes the findings of a recent conference investigating ethical considerations and policy recommendations in autism spectrum disorder risk communication, which to the authors' knowledge is the first of its kind. Here, the authors discuss a number of issues, including uncertainty; comprehension; inadvertent harm; justice; and the appropriate roles of clinicians, scientists, and the media in autism spectrum disorder risk communication. PMID- 22917845 TI - Predictors of quality-of-care processes in geriatric assessment units: toward a better organizational framework. AB - OBJECTIVES: To identify the structural and patient characteristics associated with better care processes in older vulnerable hospitalized patients. DESIGN: Retrospective study. SETTING: Forty-four Geriatric Assessment Units (GAU). PARTICIPANTS: Patients aged 65 and older who were admitted to a GAU for a fall with trauma. MEASUREMENTS: Three care processes (comprehensiveness, informational continuity, completion of advance health care directives) assessed through chart audit; 14 patient- and 23 GAU-related characteristics obtained from hospitalization records, national databases, and GAU managers. RESULTS: A total of 877 hospitalization records were included. Final models were based on multilevel modeling using stepwise variable selection. Strongest predictors of better comprehensiveness were longer hospital length of stay (LOS), higher clinical complexity (eg, higher mortality risk), and having a geriatrician as attending physician. Comprehensiveness score increased sharply up to 3 weeks LOS and then tended to plateau. Better informational continuity was associated with more comprehensive care, higher risk of mortality, acute rather than rehabilitation care, communication with community health care professionals within 48 hours after admission, and a target LOS of 3 weeks or longer. The completion of advance directives was more likely in the presence of advanced age, higher risk of mortality, cognitive impairment, discharge to another care facility, longer LOS, university-affiliated institution, and nonurban location. CONCLUSION: In GAUs, quality-of-care processes are related to both structural and patient characteristics. Our results pointed toward an organizational framework that may help to streamline the geriatric units and better use resources, notably by narrowing the admission criteria, targeting a proper LOS, improving communication with community organizations, and making systematic completion of advance directives. PMID- 22917846 TI - Reply to Bortolus: what's in a name? PMID- 22917847 TI - Obsession with quantity: a view from the south. PMID- 22917848 TI - Base composition, speciation, and barcoding. AB - Cryptic mutations producing no observable effect on phenotype can both spark divergence into species and assist species identification. Unlike most protein encoding sequences, a barcode sequence of great utility in phylogenetic analysis displays few interspecies differences at amino acid-determining codon positions (static conventional phenotype), but many at third codon positions (mobile genome phenotype). PMID- 22917849 TI - Strengths and weaknesses of experimental evolution. PMID- 22917850 TI - Type 1 Brugada ECG unmasked by intracoronary contrast media. PMID- 22917851 TI - Effect of smoke-free legislation on the incidence of sudden circulatory arrest in the Netherlands. Heart 2012;98:995-9. PMID- 22917853 TI - Effects of a supratherapeutic dose of investigational orally inhaled dihydroergotamine (MAP0004) on QT interval: a randomized, double-blind, active- and placebo-controlled crossover study in healthy volunteers. AB - BACKGROUND: MAP0004 is an orally inhaled investigational drug containing dihydroergotamine (DHE). Although DHE has been used for 60 years with no reported cardiac arrhythmias, a thorough QT study had not previously been performed with DHE. OBJECTIVE: The objective of this study was to assess the effects of MAP0004 on the QT interval as required for regulatory approval of a new product. METHODS: This randomized, double-blind, placebo-controlled, 3-period crossover study enrolled healthy volunteers. Subjects were assigned to receive, in randomized sequence, MAP0004 at a supratherapeutic dose (3-fold the clinically effective dose) (3.0 mg), moxifloxacin 400 mg, or inactive vehicle, each administered with 1 placebo capsule. Triplicate ECGs were performed continuously at baseline (day 0), before dosing, and over 24 hours after dosing in each treatment period. The effect on the QT interval was assessed using the Fridericia (QTcF) and individualized (QTcI) correction formulas. RESULTS: Fifty-four healthy adults (20 men, 34 women; mean age, 28 years) completed the trial and had measurable plasma levels of DHE after MAP0004 administration. The largest observed mean difference in QTcI between MAP0004 and placebo was 0.08 msec, and the largest 1-sided 95% upper confidence bound was 2.24 msec, both at 30 minutes after dosing. In contrast, moxifloxacin increased the mean QTcI between 9.57 and 11.28 msec relative to placebo, with a 1-sided lower 95% CL between 7.23 and 8.96 msec, confirming that the assay sensitivity was sufficient to detect MAP0004-related effects. Nausea (27.8%) was common following MAP0004 administration but apparently did not influence the QTc interval. CONCLUSIONS: A supratherapeutic dose of MAP0004 was not associated with prolonged QTc intervals. At the proposed clinical dose (1.0 mg), MAP0004 is unlikely to affect the QT interval. MAP0004 and its primary metabolite showed no evidence for prolongation of the QTc interval in healthy subjects according to the criteria required from regulatory agencies. ClinicalTrials.gov identifier: NCT01191723. PMID- 22917854 TI - Ezogabine (retigabine) and its role in the treatment of partial-onset seizures: a review. AB - BACKGROUND: Ezogabine, also known as retigabine, is a recently approved anticonvulsant medication with a novel mechanism of action. It activates low threshold voltage-gated potassium channels, leading to hyperpolarization of the membrane potential, stabilization of the resting membrane potential, and suppression of repetitive firing. OBJECTIVE: This review identified the efficacy and tolerability of ezogabine in the treatment of partial-onset seizures reported in randomized controlled trials. Additional characteristics of the medication, including mechanism of action, pharmacokinetic properties, drug interactions, and additional applications under investigation are also addressed. METHODS: MEDLINE and EMBASE were systematically searched, using the search terms retigabine and ezogabine, for randomized trials published from 1980 through February 8, 2012. Trials of the effects of adjunctive ezogabine in patients aged >=16 years with partial seizures were included for analysis of clinical efficacy and tolerability. Articles that did not pertain to clinical efficacy and that did not report on randomized controlled trials were excluded. Articles relating to additional properties were reviewed for inclusion in the review. RESULTS: One Phase IIb and 2 Phase III trials were identified. Ezogabine has reported dose dependent efficacy at doses of 600, 900, and 1200 mg/d. As with most anticonvulsant medications, the most common adverse events associated with ezogabine were central nervous system effects. Because potassium channels in the urothelium of the bladder are activated by ezogabine, a Risk Evaluation and Mitigation Strategy is in place regarding the risk for urinary retention and symptoms of acute urinary retention. There are limited drug interactions with ezogabine because it does not undergo metabolism by the cytochrome P450 system and is not highly protein bound. CONCLUSIONS: Ezogabine is a newly approved anticonvulsant for adjunctive therapy in partial-onset seizures in adults with a novel mechanism of action, activating low-threshold voltage-gated potassium channels. It has advantages over many of the available anticonvulsants in that it is not metabolized through the cytochrome P450 system and is not highly protein bound, therefore limiting its potential for drug-drug interactions. Unique to ezogabine compared with other anticonvulsants is its association with urinary retention due to its effect on potassium channels in the urothelium of the bladder. PMID- 22917855 TI - Inter-phylum structural conservation of the magnetosome-associated TPR-containing protein, MamA. AB - Magnetotactic bacteria enclose the magnetosome, a unique prokaryotic sub-cellular organelle that allows the biomineralization of magnetic nano-crystals. Membrane coated magnetosomes are arranged into a linear chain that permits magnetotactic bacteria to navigate geomagnetic fields. Magnetosome assembly and biomineralization are controlled by conserved magnetosome-associated proteins, including MamA, a tetra-trico-peptide repeat (TPR)-containing protein that was shown to coat the magnetosome membrane. In this study, two MamA structures from Candidatus Magnetobacterium bavaricum (Mbav) were determined via X-ray crystallography. These structures confirm that Mbav MamA folds as a sequential TPR protein and shares a high degree of structural similarity with homologous MamA proteins from Magnetospirillum species. Furthermore, the two TPR-containing domains of MamA are separated by an interphylum-conserved region containing a flexible hinge that is involved in ligand binding and recognition. Finally, substantial differences were found in the local stabilization of the MamA N terminal domain as a result of the loss of an evolutionary conserved salt bridge. PMID- 22917856 TI - Synthesis and SAR studies of 3-allyl-4-prenyloxyaniline amides as potent 15 lipoxygenase inhibitors. AB - 15-Lipoxygenases are one of the nonheme iron-containing proteins with ability of unsaturated lipid peroxidation in animals and plants. The critical role of the enzymes in formation of inflammations, sensitivities and some of cancers has been demonstrated in mammalians. Importance of the 15-lipoxygenases leads to development of mechanistic studies, products analysis and synthesis of their inhibitors. In this work new series of the 3-allyl-4-allyoxyaniline amides and 3 allyl-4-prenyloxyaniline amides were designed, synthesized and their inhibitory potency against soybean 15-lipoxygenase were determined. Among the synthetic amides, 3-allyl-4-(farnesyloxy)-adamantanilide showed the most potent inhibitory activity by IC(50) value of 0.69 MUM. SAR studies showed that in spite of prenyl length increases, the effects of the amide size and its electronic properties on the inhibitory potency became predominant. The SAR studies was also showed that the orientation of allyl and prenyloxy moieties toward Fe core of the SLO active site pocket is the most suitable location for enzyme inhibition. PMID- 22917857 TI - Synthesis and antiplasmodial activity of new heteroaryl derivatives of 7-chloro-4 aminoquinoline. AB - With the aim to investigate the effect of different heterocyclic rings linked to the 4-aminoquinoline nucleus on the antimalarial activity, a set of 7-chloro-N (heteroaryl)-methyl-4-aminoquinoline and 7-chloro-N-(heteroaryl)-4-aminoquinoline was synthesized and tested in vitro against D-10 (CQ-S) and W-2 (CQ-R) strains of Plasmodium falciparum. All compounds exhibited from moderate to high antiplasmodial activities. The activity was strongly influenced both by the presence of a methylenic group, as a spacer between the 4-aminoquinoline and the heterocyclic ring, and by the presence of a basic head. The most potent molecules inhibited the growth of both CQ-S and CQ-R strains of P. falciparum with IC(50)<30 nM and were not toxic against human endothelial cells. These results confirm that the presence of an heteroaryl moiety in the side chain of 7-chloro-4 aminoquinoline is useful for the design and development of new powerful antimalarial agents. PMID- 22917858 TI - Development of a bifunctional chelating agent containing isothiocyanate residue for one step F-18 labeling of peptides and application for RGD labeling. AB - We report herein a novel isothiocyanate active ligand for fluorine-18 labeling prepared by four step synthesis. It can be conjugated to a target molecule containing an amino functional group under weak basic conditions by way of thiourea bond formation. We explored the application of synthesized ligand by conjugating to well known alpha(v)beta(3) integrin targeting peptide, c(RGDyK). The conjugated peptide showed good radiochemical yield and efficiency with an excellent radiochemical purity (97.1 +/- 1.2%) in a short reaction time (10 min). Labeled peptide showed excellent in vitro and in vivo stability (>95%). alpha(v)beta(3) integrin specific tumor uptake was observed both in biodistribution and small animal microPET studies on alpha(v)beta(3)-positive U87MG (human glioma cells) xenograft bearing mice. In general, successful application of synthesized ligand for labeling of RGD peptide could facilitate the possibility of using this ligand for labeling peptides containing an amino functional group. PMID- 22917859 TI - On averaging force curves over heterogeneous surfaces in atomic force microscopy. AB - Atomic force microscopy (AFM) can be used to study mechanics at the nanoscale. Biological surfaces and nanocomposites have typically heterogeneous surfaces, both mechanically and chemically. When studying such surfaces with AFM, one needs to collect a large amount of data to make statistically sound conclusions. It is time- and resource-consuming to process each force curve separately. The analysis of an averaged raw force data is a simple and time saving option, which also averages out the noise and measurement artifacts of the force curves being analyzed. Moreover, some biomedical applications require just an average number per biological cell. Here we investigate such averaging, study the possible artifacts due to the averaging, and demonstrate how to minimize or even to avoid them. We analyze two ways of doing the averaging: over the force data for each particular distance (method 1, the most commonly used way), and over the distances for each particular force (method 2). We derive the errors of the methods in finding to the true average rigidity modulus. We show that both methods are accurate (the error is <2%) when the heterogeneity of the surface rigidity is small (<50%). When the heterogeneity is large (>100*), method 2 underestimates the average rigidity modulus by a factor of 2, whereas the error of method 1 is only 15%. However, when analyzing the different surface chemistry, which reveals itself in the changing long-range forces, the accuracy of the methods behave oppositely: method 1 can produce a noticeable averaging artifact in the deriving of the long-range forces; whereas method 2 can be successfully used to derive the averaged long-range force parameters without artifacts. We exemplify our conclusions by the study of human cervical cancer and normal epithelial cells, which demonstrate different degrees of heterogeneity. PMID- 22917860 TI - Editorial for the special issue: Biodemographic determinants of lifespan. PMID- 22917862 TI - Colonoscopy with polypectomy reduces colorectal cancer mortality in patients with adenomas. PMID- 22917861 TI - Standing down the guard: stellate cells leave quietly. PMID- 22917863 TI - Enhanced imaging technologies in detecting dysplasia in IBD: narrowing or widening our options? PMID- 22917864 TI - Endoscopic pancreatic necrosectomy: notes of excitement. PMID- 22917865 TI - Hepatocellular carcinoma surveillance: is a shorter interval better? PMID- 22917866 TI - Aspirin and chemoprevention of cancer: reaching beyond the colon. PMID- 22917867 TI - Is 325 mg of prevention worth a pound of cure? PMID- 22917868 TI - Are personal health records safe? A review of free web-accessible personal health record privacy policies. AB - BACKGROUND: Several obstacles prevent the adoption and use of personal health record (PHR) systems, including users' concerns regarding the privacy and security of their personal health information. OBJECTIVE: To analyze the privacy and security characteristics of PHR privacy policies. It is hoped that identification of the strengths and weaknesses of the PHR systems will be useful for PHR users, health care professionals, decision makers, and designers. METHODS: We conducted a systematic review using the principal databases related to health and computer science to discover the Web-based and free PHR systems mentioned in published articles. The privacy policy of each PHR system selected was reviewed to extract its main privacy and security characteristics. RESULTS: The search of databases and the myPHR website provided a total of 52 PHR systems, of which 24 met our inclusion criteria. Of these, 17 (71%) allowed users to manage their data and to control access to their health care information. Only 9 (38%) PHR systems permitted users to check who had accessed their data. The majority of PHR systems used information related to the users' accesses to monitor and analyze system use, 12 (50%) of them aggregated user information to publish trends, and 20 (83%) used diverse types of security measures. Finally, 15 (63%) PHR systems were based on regulations or principles such as the US Health Insurance Portability and Accountability Act (HIPAA) and the Health on the Net Foundation Code of Conduct (HONcode). CONCLUSIONS: Most privacy policies of PHR systems do not provide an in-depth description of the security measures that they use. Moreover, compliance with standards and regulations in PHR systems is still low. PMID- 22917870 TI - State of the iron: how to diagnose and efficiently treat iron deficiency anemia in inflammatory bowel disease. AB - Iron deficiency anemia (IDA) frequently occurs in patients suffering from inflammatory bowel disease (IBD) and negatively impacts their quality of life. Nevertheless, the condition appears to be both under-diagnosed and undertreated. Regular biochemical screening of patients with IBD for anemia by the gastroenterology community has to be advocated. Oral iron is a low cost treatment however its effectiveness is limited by low bioavailability and poor tolerability. Intravenous (IV) iron rapidly replenishes iron stores and has demonstrated its safe use in a number of studies in various therapeutic areas. A broad spectrum of new IV iron formulations is now becoming available offering improved tolerability and patient convenience by rapidly restoring the depleted iron status of patients with IBD. The following article aims to review the magnitude of the problem of IDA in IBD, suggest screening standards and highlight existing and future therapies. PMID- 22917871 TI - Assessment of tetrahydrobiopterin (BH(4))-responsiveness and spontaneous phenylalanine reduction in a phenylalanine hydroxylase deficiency population. AB - A BH(4) loading test was performed in 36 patients from 34 unrelated families. The patients had 29 different genotypes, and previous data on only eight of them were found in the BIOPKU database. Thirteen patients were classified as classic PKU (35.1%), 14 as mild PKU (37.8%) and 9 as MHP (27.0%). Blood Phe levels were shown to reach a plateau after three full days of increased natural protein ingestion. Measuring the 24-hour blood Phe levels (T(-24), T(-16), T(0)) on the fourth day of increased protein ingestion before BH(4) administration showed that within 24h Phe on average increased by 2.4% in MHP patients, decreased by 2.7% in mild PKU patients and increased by 9.7% in classic PKU patients (NS for all comparisons); Phe only slightly decreased in responders by 0.2% but increased in non-responders by 7.8% (P>0.05). Altogether, 16 of 36 (44.4%) patients represented by 12 of 29 (41.4%) different genotypes were proven to be BH(4) responders, and four (10.8%) were slow-responders. Responders were 6/9 (66.7%) MHP patients, 10/14 (71.4%) mild PKU patients and 0/13 classic PKU patients. Twenty of the 29 (68.9%) genotypes harbored at least one mutation with a known PRA of 10% or more but only 11 (55%) of them were BH(4)-responsive. Spontaneous reduction of blood Phe levels within 24h on the fourth day of natural protein loading was observed only in mild PKU patients and was shown not to be an important part of the BH(4)-response. 73.3% of genotypes containing at least one allele with a PRA of at least 30% were found to be BH(4) responsive; a PRA of at least 15.5% was needed for the responder genotype in our population. PMID- 22917872 TI - Screening tests for hazard classification of complex waste materials--selection of methods. AB - In this study we describe the development of an alternative methodology for hazard characterization of waste materials. Such an alternative methodology for hazard assessment of complex waste materials is urgently needed, because the lack of a validated instrument leads to arbitrary hazard classification of such complex waste materials. False classification can lead to human and environmental health risks and also has important financial consequences for the waste owner. The Hazardous Waste Directive (HWD) describes the methodology for hazard classification of waste materials. For mirror entries the HWD classification is based upon the hazardous properties (H1-15) of the waste which can be assessed from the hazardous properties of individual identified waste compounds or--if not all compounds are identified--from test results of hazard assessment tests performed on the waste material itself. For the latter the HWD recommends toxicity tests that were initially designed for risk assessment of chemicals in consumer products (pharmaceuticals, cosmetics, biocides, food, etc.). These tests (often using mammals) are not designed nor suitable for the hazard characterization of waste materials. With the present study we want to contribute to the development of an alternative and transparent test strategy for hazard assessment of complex wastes that is in line with the HWD principles for waste classification. It is necessary to cope with this important shortcoming in hazardous waste classification and to demonstrate that alternative methods are available that can be used for hazard assessment of waste materials. Next, by describing the pros and cons of the available methods, and by identifying the needs for additional or further development of test methods, we hope to stimulate research efforts and development in this direction. In this paper we describe promising techniques and argument on the test selection for the pilot study that we have performed on different types of waste materials. Test results are presented in a second paper. As the application of many of the proposed test methods is new in the field of waste management, the principles of the tests are described. The selected tests tackle important hazardous properties but refinement of the test battery is needed to fulfil the a priori conditions. PMID- 22917873 TI - Promoting lipid utilization with l-carnitine to improve oocyte quality. AB - Successful embryo and fetal development is dependent on the quality of the oocyte from which it was derived. Several studies to date have demonstrated the link between appropriate metabolism and sufficient ATP production with oocyte quality and preimplantation embryo development. Metabolism of fatty acids for the purpose of synthesizing ATP occurs within mitochondria via beta-oxidation and entry of fatty acids into this organelle is the rate-limiting step in this process. Transport of activated fatty acids into mitochondria is catalyzed by carnitine palmitoyl transferase-I (CPTI) which also requires the metabolite carnitine. Once inside the mitochondrial matrix, fatty acids are broken down into acetyl CoA molecules which are further metabolized via the TCA cycle and electron transport chain to produce ATP. The potential to improve oocyte quality by modulating fatty acid metabolism and beta-oxidation with carnitine in culture media formulations or via dietary supplementation has received little attention. This review summarizes studies to date investigating the developmental importance of beta oxidation through the use of metabolic inhibitors and whether regulation by carnitine, in vitro or in vivo, has beneficial effects on oocyte and embryo development. Overall, there is little evidence to date that dietary carnitine can improve oocyte quality or female fertility; however inclusion of l-carnitine to in vitro oocyte maturation and embryo growth media improves embryo outcomes, most likely by supplying the oocyte and embryo with an essential co-factor required to utilize fatty acids. PMID- 22917874 TI - The "closed loop model" in controlling mRNA translation during development. AB - Translational control is particularly important in situations where the correlation of a distinct mRNA and the abundance of the corresponding protein might be low. This is the case for instance during oocyte maturation, shortly before the GVBD when the chromatin is condensed, until the embryonic genome is activated. In these situations, gene expression relies on the activation of maternal mRNAs which were stored stably in a dormant form. The most sophisticated model for translational initiation at present is the so-called "closed loop" model, where a circularization of the mRNA is mediated by associated 5'-cap- and 3'-poly(A) binding proteins. Depending on differential interactions, this event can result in translational stimulation or repression. Several studies describe correlated regulation mechanisms in model organisms like mouse or Xenopus, but data addressing translational regulation in farm animals are rare. Cytoplasmic mRNA activating or repressing factors, however, might contribute to achieve developmental competence in bovine or porcine oocytes. Recently we showed that, in the pig, embryonic signals can modify essential components of the mRNA-5' translation initiation complex in the uterine luminal epithelium at the time of implantation. In accordance with the closed loop model of translational initiation, this review focuses on the regulatory impact of 5'-mRNA end associated proteins (components of the mRNA-cap binding complex) and 3'-end associated proteins (components of the poly(A) binding complex) during in vitro maturation of cattle and pig oocytes, early embryonic development and in the pig uterine epithelia. PMID- 22917875 TI - Transcriptome profile of early mammalian embryos in response to culture environment. AB - Early embryonic development, the period from maturation until blastocyst formation, is one of the most critical periods of mammalian development involves various morphological, cellular, and biochemical changes related to genomic activity. During the post-fertilization period, several major developmental events occur in the embryo which are regulating by a harmonized expression of genes and strongly influenced by culture conditions. The products of these genes are involved in various biological processes including metabolism, growth factor/cytokine signaling, stress adaptation, transcription and translation, epigenetic regulation of transcription, apoptosis, compaction and blastocyst formation. Post-fertilization culture environment is known to be the most important factor determining the quality of the resulting embryos as indicated in terms of cryo-tolerance and relative abundance of transcripts. However, the exact effect of culture conditions on gene expression and subsequent influences on molecular pathways controlling early development is still unknown. A number of culture environmental factors can influence the gene expression of produced embryos such as media composition, serum supplementation, number of embryos present in the culture drop and gas atmosphere. During the last ten years several studies were concerned with differences in the transcriptome profile of embryos produced under different environmental conditions and its subsequent influence on embryo developmental competence. From these studies, several genes have been determined as candidate genes controlling preimplantation embryo development and affecting its quality. Here we will discuss results of different experiments investigated the effect of different culture conditions on the transcriptome profile of bovine blastocyst. These experiments identified molecular mechanisms and pathways that influenced by culture conditions and this will enable to launch strategies to modify culture conditions to enhance the development of competent blastocyst. PMID- 22917876 TI - Transcriptome analyses of bovine, porcine and equine endometrium during the pre implantation phase. AB - Different reproductive strategies evolved in various mammalian groups to achieve recognition, establishment and maintenance of pregnancy. The complexity of these processes is reflected by a high incidence of embryonic loss during this critical period in many mammalian species. Besides studies in mice and humans a number of transcriptome studies of endometrial tissue samples and also of early embryos have been performed during the pre-implantation phase in cattle, swine and horse to identify genes associated with embryo-maternal interaction. Results of these studies are reviewed and compared between species. The comparison of data sets from different species indicated a general role of interferons for the establishment of pregnancy. In addition to many species-specific changes in gene expression, which may reflect different pregnancy recognition signals and mechanisms of embryo implantation, a number of transcriptome changes were found to be similar across species. These genes may have conserved roles during the establishment of pregnancy in mammals and reflect basic principles of mammalian reproduction. The relevance and strategies, but also the challenges of cross species comparisons of gene expression data are discussed. PMID- 22917877 TI - Quantitative proteomic analysis of pregnancy-related proteins from peripheral blood mononuclear cells during pregnancy in pigs. AB - Information obtained from peripheral blood could help us understand the underlying mechanisms in autoimmune diseases, cancer, pregnancy, and other conditions. In this paper, we present the protein map of porcine peripheral blood mononuclear cells (PBMC) to better understand the molecular expression changes that occur during pregnancy using proteomic analysis. We detected 94 differentially expressed proteins in pregnant vs. non-pregnant (NP) pigs, and a representative set of the proteins was subjected to LC-MS/MS analysis. Furthermore, the identified proteins were categorized according to their biological process and molecular function. By classifying the proteins according to their functions, a large number of differentially regulated proteins involved in anti-oxidant, detoxification and stress response pathways were found, including peroxiredoxin (PRX) 1, 2, and 6, glutathione-S-transferase (GST), annexin A2, and A6, and heat shock protein 27 (HSP 27) during pregnancy (pregnancy d of E40, embryonic day 40; E70, embryonic day 70; and E93, embryonic day 93) compared with non-pregnancy. In this study, a proteomic approach utilizing 2-DE and LC-MS/MS was applied to evaluate specific molecular expression changes during pregnancy compared with non-pregnancy. Together, these data offer new information about the proteome map and factors that are differentially regulated during maintenance of normal pregnancy. PMID- 22917878 TI - Factors influencing pregnancy per artificial insemination in repeat-breeder cows induced to ovulate with a CIDR-based protocol. AB - The aim of this study was to determine, using multiple logistic models, factors affecting pregnancy per AI (P/AI) following fixed-time artificial insemination (FTAI) in repeat breeders cows (RBC) treated with rbST throughout lactation. 498 RBC received a CIDR device and 100MUg of GnRH on day 0. CIDR removal and PGF(2alpha) (25mg) treatment were done concurrently on day 7. Estradiol benzoate (EB, 1mg) was injected on day 8 and GnRH on day 9; cows were inseminated 16-20h later. Cows with an average milk protein <3% were 43% more likely (P<0.05) to become pregnant at FTAI than cows with milk protein >=3%. Cows with <6 services had significantly increased chances of becoming pregnant than cows with >=6 services at FTAI (P/AI 36 vs. 27%; P<0.05). CIDR-treated cows with less than three lactations were 1.7 times more likely (P/AI 35 vs. 21%; P<0.05) to become pregnant than cows in third or greater lactation. Cows with peak milk yields lower than 55kg were 1.5 times more likely to get pregnant than cows with peak milk yields greater than 55kg (P/AI 37 vs. 28%; P<0.05). P/AI was lower (30 vs. 35%; P<0.01) for cows with dry periods <62 days than cows with dry periods >=62 days. Cows subjected to FTAI with a temperature-humidity index (THI) <76 were 45% more likely (P<0.05) to become pregnant than cows inseminated at a THI>=76. It was concluded that an acceptable proportion (32%) of RBC can become pregnant with the protocol used in the present study. Also, subfertility in CIDR-treated cows was associated with high peak yields, high milk protein, increased service, increased lactation, high THI at AI and short dry periods. PMID- 22917879 TI - Antimicrobial peptides from the skin of the Asian frog, Odorrana jingdongensis: de novo sequencing and analysis of tandem mass spectrometry data. AB - Eight intact antimicrobial peptides were identified from the skin of Odorrana jingdongensis by de novo sequencing following low energy ESI CID Q-TOF MS/MS in positive-mode with the help of Edman degradation and structural similarity analysis. We devised exact mass measurements to discriminate the K/Q amino acid residue in the peptides between 2.0 kDa to 3.8 kDa. Moreover, the cleavage at the CS bond at the side chain of Met was observed in all the spectra of the peptides containing Met residue. And we found unusual cleavages within the intramolecular disulfide loop with high frequency. Our data revealed that the cleavage pathways are significantly different from those reported previously which are similar to the cycle peptide cleavage mode followed by the secondary cleavage at the CS bond on oxidized Cys. Thus, our results highly suggest that ion series generated from the cleavages within the intramolecular disulfide loop should be considered in both the top-down sequencing and the disulfide bridge location with the presence of a relatively high intensity of MH(+)-28 ion marker. Furthermore, our activity data implied that different AMPs may use different strategies to kill microbes. PMID- 22917880 TI - Central administration of oxytocin reduces hyperalgesia in mice: implication for cannabinoid and opioid systems. AB - The neuropeptide oxytocin (OXT) contributes to the regulation of diverse cognitive and physiological functions including nociception. Indeed, OXT has been reported to be analgesic when administered directly into the brain, the spinal cord, or systemically. Although many authors have reported the analgesic effects of OXT, its mechanism has not been well elucidated. Recently, it has been also hypothesize that OXT, increasing intracellular concentration of calcium, could regulate the production of mediators, like endocannabinoids (eCB). It has been well documented that eCB are able to suppress pain pathways. The present study investigates the effect of OXT in paw carrageenan-induced pain. Intracerebroventricular (icv) administration of OXT, but neither intraperitoneal nor intraplantar route, induces an antihyperalgesic effect increasing paw withdrawal latency to mechanical or thermal stimuli. Our results clearly demonstrate that 3 and 6h following carrageenan challenge, central administration of OXT (30 ng/mouse) shows a significant antihyperalgesic activity. Moreover, for the first time, we demonstrate that CB1 receptor plays a key role in the antihyperalgesic effect of OXT. In fact our results show CB1 antagonist, but not the specific CB2 antagonist reduce OXT-induced antihyperalgesic effect. In addition, our data show that central OXT administration is able to reduce carrageenan-induced hyperalgesia but does not modify carrageenan-induced paw edema. Finally, using opioid antagonists we confirm an important role of opioid receptors. In conclusion, our experiments suggest that central administration of OXT reduces hyperalgesia induced by intraplantar injection of carrageenan, and this effect may work via cannabinoid and opioid systems. PMID- 22917881 TI - Pica in children with sickle cell disease: two case reports. AB - Children with sickle cell disease (SCD) are at greater risk for developing pica compared to other children. This comorbidity can result in harmful medical and nutritional, and neurodevelopmental consequences. This article will describe the medical, nutritional, and psychosocial functioning in two children with SCD and pica in order to illustrate the potential complications and correlates of this co morbidity. In addition, the clinical implications of pica in children with SCD will be discussed. PMID- 22917883 TI - Mapping tinnitus-related brain activation: an activation-likelihood estimation metaanalysis of PET studies. AB - In tinnitus, PET and other functional imaging modalities have shown functional changes not only in the auditory cortex but also in nonauditory regions such as the limbic, frontal, and parietal areas. Nonetheless, disparities in task dimension among studies, low statistical power due to small sample size, and the intrinsic uncertainty of a modality that measures activity indirectly limit the comprehensive understanding of the results from PET studies. These difficulties prompted us to undertake a metaanalysis of PET studies on tinnitus using a coordinate-based technique (activation-likelihood estimation) to retrieve the most consistent activation areas across different task dimensions and to compare the results with those from other imaging modalities. METHODS: We performed 2 activation-likelihood estimation metaanalyses on data from 10 studies with 56 foci in which we examined the contrast between tinnitus individuals and controls and the difference in activation between sound stimuli and resting state in tinnitus individuals. RESULTS: The studies show that the most consistently activated regions in tinnitus subjects, compared with controls, were the left primary and bilateral secondary auditory cortices, left middle and bilateral inferior temporal gyri, left parahippocampal area, left geniculum body, left precuneus, right anterior cingulate cortex, right claustrum, right middle and inferior frontal gyri, and right angular gyrus. The relatively activated area under sound stimuli, compared with resting state, in tinnitus subjects was the secondary auditory cortex. Our study reconfirms the findings of previous quantitative electroencephalography or magnetoencephalography studies because most of the 14 brain areas with significant activation found in our metaanalysis replicate these earlier data. Our results suggest that the areas described in the tinnitus network are solidly replicable regardless of the applied functional imaging technique. CONCLUSION: This study proves that PET is a useful modality for tinnitus research and solidifies human tinnitus research itself by confirming previously described brain areas involved in the generation and maintenance of tinnitus. PMID- 22917884 TI - Immuno-PET of the hepatocyte growth factor receptor Met using the 1-armed antibody onartuzumab. AB - The overexpression and overactivation of hepatocyte growth factor receptor (Met) in various cancers has been linked to increased proliferation, progression to metastatic disease, and drug resistance. Developing a PET agent to assess Met expression would aid in the diagnosis and monitoring of responses to Met-targeted therapies. In these studies, onartuzumab, the experimental therapeutic 1-armed monoclonal antibody, was radiolabeled with (76)Br or (89)Zr and evaluated as an imaging agent in Met-expressing cell lines and mouse xenografts. METHODS: (89)Zr desferrioxamine (df)-onartuzumab was synthesized using a df-conjugate; (76)Br onartuzumab was labeled directly. Met-binding studies were performed using the human tumor-derived cell lines MKN-45, SNU-16, and U87-MG, which have relatively high, moderate, and low levels of Met, respectively. Biodistribution and small animal PET studies were performed in MKN-45 and U87-MG xenografts. RESULTS: (76)Br-onartuzumab and (89)Zr-df-onartuzumab exhibited specific, high-affinity Met binding (in the nanomolar range) that was concordant with established Met expression levels. In MKN-45 (gastric carcinoma) xenografts, both tracers cleared slowly from nontarget tissues, with the highest uptake in tumor, blood, kidneys, and lungs. (76)Br-onartuzumab MKN-45 tumor uptake remained relatively constant from 18 h (5 percentage injected dose per gram of tissue [%ID/g]) to 48 h (3 %ID/g) and exhibited tumor-to-muscle ratios ranging from 4:1 to 6:1. In contrast, (89)Zr-df-onartuzumab MKN-45 tumor uptake continued to accumulate from 18 h (10 %ID/g) to 120 h (23 %ID/g), attaining tumor-to-muscle ratios ranging from 20:1 to 27:1. MKN-45 tumors were easily visualized in imaging studies with both tracers at 18 h, but after 48 h (89)Zr-df-onartuzumab image quality improved, with at least 2-fold-greater tumor uptake than nontarget tissues. MKN-45 tumor uptake for both tracers correlated significantly with tumor mass and Met expression and was not affected by the presence of plasma shed Met. CONCLUSION: (89)Zr-df onartuzumab and (76)Br-onartuzumab specifically targeted Met in vitro and in vivo; (89)Zr-df-onartuzumab achieved higher tumor uptake and tumor-to-muscle ratios than (76)Br-onartuzumab at later times, suggesting that (89)Zr-df onartuzumab would be better suited to image Met for diagnostic and prognostic purposes. PMID- 22917885 TI - PET prediction of response to trastuzumab in ErbB2-positive human xenograft model. PMID- 22917886 TI - Oncologic 18F-FDG PET/CT: referring physicians' point of view. AB - Oncologic (18)F-FDG PET/CT is rapidly gaining acceptance in clinical practice. However, the referring physician's attitude toward the usefulness of this diagnostic modality is unknown. This survey was undertaken to collect information regarding the current perspective of referring physicians on oncologic PET/CT. METHODS: We conducted a prospective worldwide, Web-based survey of physicians who manage cancer patients. A total of 963 referring physicians completed a 20 question survey focused on their experience with oncologic (18)F-FDG PET/CT. Attention was directed toward their confidence about indications, their satisfaction with related educational resources, the quality of interaction with interpreting physicians, and practical problems encountered. The respondents included oncologists (38.5%, n = 371), hematologists (16.4%, n = 158), radiation oncologists (9.0%, n = 87), surgeons (30.3%, n = 292), and other physicians (5.7%, n = 55). RESULTS: Only 25.2% of respondents considered the oncologic (18)F FDG PET/CT indications to be well established and defined. Frequent uncertainty about the need for a PET scan was indicated by 62.3% of the respondents. High cost and overinterpretation of findings were the most commonly reported concerns (47.0% and 40.9%, respectively). The experience and skill level of the interpreting physician was considered very important by 96.8% of the surveyed physicians. CONCLUSION: Referring physicians expressed considerable uncertainty about the appropriate use of oncologic PET/CT. Additional major concerns are procedure costs and quality of interpretation. The responses suggest a strong need for efforts to educate referring and interpreting physicians about the appropriate use of (18)F-FDG PET/CT in oncology. PMID- 22917887 TI - Five-year incidence of retinal microvascular abnormalities and associations with arterial hypertension: the Beijing Eye Study 2001/2006. AB - PURPOSE: To describe the 5-year incidence of retinal microvascular abnormalities and analyze their associations with arterial hypertension in nondiabetic elderly Chinese subjects in urban and rural Beijing in a follow-up of the original Beijing Eye Study 2001. DESIGN: Population-based study. PARTICIPANTS: The Beijing Eye Study 2006 included 3251 subjects who had participated in the Beijing Eye Study 2001 and returned for reexamination. METHODS: By using fundus photographs, we determined the 5-year incidence and change (progression or regression) of retinal microvascular abnormalities, including focal narrowing (FN) of retinal arterioles, arteriovenous nicking (AVN), and retinopathy. Arterial hypertension was graded as controlled treated arterial hypertension, uncontrolled treated arterial hypertension, and untreated arterial hypertension. MAIN OUTCOME MEASURES: Incidence of retinal microvascular abnormalities. RESULTS: After excluding patients with diabetes mellitus or any retinal or optic nerve disease, 2058 subjects (1409 women [68.5%]) were included in the study. The mean age of subjects was 53.8 +/- 9.5 years, and the mean refractive error was -0.24 +/- 2.04 diopters. The 5-year accumulated incidence of FN, AVN, and retinopathy was 4.1%, 1.4%, and 3.3%, respectively. Adjusted for age, gender, and region of habitation, the 5-year incidence of FN, AVN, and retinopathy increased 1.58 times (95% confidence interval [CI], 1.24-2.00; P<0.001), 1.55 times (95% CI, 1.04-2.32; P = 0.03), and 1.46 times (95% CI, 1.12-1.91; P = 0.005), respectively, for every 10 mmHg increase in mean arterial blood pressure. After adjusting for age, gender, and region of habitation, the rate of regression of FN decreased by 28% with every increase in the grade of the arterial hypertension classification. Correspondingly, the rate of regression of FN was significantly higher in the group with controlled arterial hypertension (44.4%) than in the uncontrolled (22.6%) and untreated (11.5%) groups (P = 0.01). CONCLUSIONS: Arterial hypertension was strongly associated with the incidence and longitudinal change of retinal microvascular abnormalities in nondiabetic subjects. Better control of arterial hypertension was correlated with a decreased incidence of retinal microvascular abnormalities and an increased rate of regression of FN. This suggests that retinal FN as potentially the first step of retinal microvascular abnormalities is reversible if arterial hypertension is controlled. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article. PMID- 22917888 TI - Corneal epithelial thickness mapping by Fourier-domain optical coherence tomography in normal and keratoconic eyes. AB - OBJECTIVE: To map the corneal epithelial thickness with Fourier-domain optical coherence tomography (OCT) and to develop epithelial thickness-based variables for keratoconus detection. DESIGN: Cross-sectional observational study. PARTICIPANTS: One hundred forty-five eyes from 76 normal subjects and 35 keratoconic eyes from 22 patients. METHODS: A 26,000-Hz Fourier-domain OCT system with 5-MUm axial resolution was used. The cornea was imaged with a Pachymetry + Cpwr scan pattern (6-mm scan diameter, 8 radials, 1024 axial-scans each, repeated 5 times) centered on the pupil. Three scans were obtained at a single visit in a prospective study. A computer algorithm was developed to map the corneal epithelial thickness automatically. Zonal epithelial thicknesses and 5 diagnostic variables, including minimum, superior-inferior (S-I), minimum-maximum (MIN-MAX), map standard deviation (MSD), and pattern standard deviation (PSD), were calculated. Repeatability of the measurements was assessed by the pooled standard deviation. The area under the receiver operating characteristic curve (AUC) was used to evaluate diagnostic accuracy. MAIN OUTCOME MEASURES: Descriptive statistics, repeatability, and AUC of the zonal epithelial thickness and diagnostic variables. RESULTS: The central, superior, and inferior epithelial thickness averages were 52.3 +/- 3.6 MUm, 49.6 +/- 3.5 MUm, and 51.2 +/- 3.4 MUm in normal eyes and 51.9 +/- 5.3 MUm, 51.2 +/- 4.2 MUm, and 49.1 +/- 4.3 MUm in keratoconic eyes. Compared with normal eyes, keratoconic eyes had significantly lower inferior (P = 0.03) and minimum (P<0.0001) corneal epithelial thickness, greater S-I (P = 0.013), more negative MIN-MAX (P<0.0001), greater MSD (P<0.0001), and larger PSD (P<0.0001). The repeatability of the zonal average, minimum, S-I, and MIN-MAX epithelial thickness variables were between 0.7 and 1.9 MUm. The repeatability of MSD was better than 0.4 MUm. The repeatability of PSD was 0.02 or better. Among all epithelial thickness-based variables investigated, PSD provided the best diagnostic power (AUC = 1.00). Using an PSD cutoff value of 0.057 alone gave 100% specificity and 100% sensitivity. CONCLUSIONS: High resolution Fourier-domain OCT mapped corneal epithelial thickness with good repeatability in both normal and keratoconic eyes. Keratoconus was characterized by apical epithelial thinning. The resulting deviation from the normal epithelial pattern could be detected with very high accuracy using the PSD variable. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references. PMID- 22917889 TI - Resection of intraocular tumors (partial lamellar sclerouvectomy) in the pediatric age group. AB - PURPOSE: To describe the outcome of intraocular tumor resection by partial lamellar sclerouvectomy (PLSU) in the pediatric age group. DESIGN: Retrospective, interventional case series. PARTICIPANTS: We included 37 patients who underwent PLSU for intraocular tumors under age 21 years. METHODS: Medical records were reviewed for clinical, operative, and histopathologic features. MAIN OUTCOME MEASURES: Globe salvage, visual acuity, surgical side effects, tumor control, and tumor-related metastasis and death. RESULTS: The mean patient age was 9 years (median, 10; range, 0.25-17) and there were 22 (59%) females and 15 (41%) males. The tumor involved mainly the iris (n = 27; 73%), ciliary body (n = 7; 19%), or choroid (n = 3; 8%). The mean tumor basal dimension was 7 mm (median, 6; range, 3 15) and thickness was 3.6 mm (median, 3; range, 0.2-9.6). The histopathologic diagnosis was melanoma (n = 19; 51%), cyst (n = 5; 14%), medulloepithelioma (n = 4; 10%), melanocytoma (n = 3; 8%), lacrimal gland choristoma (n = 2; 5%), gliosis (n = 1; 3%), nevus (n = 1; 3%), hemorrhage (n = 1; 3%), and leiomyoma (n = 1; 3%). Intraoperative adverse effects included vitreous loss in 19 (51%) and hyphema in 4 (11%). Postoperative side effects included early transient hyphema in 9 (24%) and late cataract in 12 (32%). Local tumor recurrence was detected in 5 cases (13%) at mean interval of 28 months, including melanoma (n = 3) and medulloepithelioma (n = 2). Enucleation was necessary in 9 (24%) cases for recurrence in 3 (8%), prophylactic in eyes with high-grade malignancy in 5 (13%), and for blind painful eye in 1 (3%). Of the 28 salvaged eyes, final visual acuity was >= 20/40 in 18 (64%), 20/50 to 20/100 in 5 (18%), and <20/200 in 5 (18%). There were no cases of metastasis or death at a mean of 51 months of follow-up. CONCLUSIONS: A surgically challenging procedure, PLSU can achieve control of selected intraocular tumors. Medulloepithelioma responds poorly to local resection and in most cases enucleation is required. If the globe is salvaged, visual acuity is >= 20/40 in 64% of children. FINANCIAL DISCLOSURE(S): The authors have no proprietary or commercial interest in any of the materials discussed in this article. PMID- 22917890 TI - Anti-vascular endothelial growth factor pharmacotherapy for diabetic macular edema: a report by the American Academy of Ophthalmology. AB - OBJECTIVE: To review the evidence regarding the safety and efficacy of current anti-vascular endothelial growth factor (VEGF) pharmacotherapies for the treatment of diabetic macular edema (DME). METHODS: Literature searches last were conducted in September 2011, in PubMed with no date restrictions, limited to articles published in English, and in the Cochrane Library without a language limitation. The combined searches yielded 532 citations, of which 45 were deemed clinically relevant for the authors to review in full text and to assign ratings of level of evidence to each of the selected studies with the guidance of the panel methodologists. RESULTS: At this time, there are 5 studies that provide level I evidence for intravitreal ranibizumab, alone or in combination with other treatments for DME. There is also 1 study that provides level I evidence for intravitreal pegaptanib sodium for DME. Nine studies reviewed were rated as level II, and 2 additional studies reviewed were graded as level III. Most studies do not provide information about long-term results (i.e., more than 2 years of follow-up) or the comparative efficacy of anti-VEGF pharmacotherapies. CONCLUSIONS: Review of the available literature indicates that anti-VEGF pharmacotherapy, delivered by intravitreal injection, is a safe and effective treatment over 2 years for DME. Further evidence is required to support the long term safety of these pharmacotherapies and their comparative efficacy. PMID- 22917891 TI - Identification of an RP1 prevalent founder mutation and related phenotype in Spanish patients with early-onset autosomal recessive retinitis. AB - OBJECTIVE: To identify the genetic causes underlying early-onset autosomal recessive retinitis pigmentosa (arRP) in the Spanish population and describe the associated phenotype. DESIGN: Case series. PARTICIPANTS: A total of 244 unrelated families affected by early-onset arRP. METHODS: Homozygosity mapping or exome sequencing analysis was performed in 3 families segregating arRP. A mutational screening was performed in 241 additional unrelated families for the p.Ser452Stop mutation. Haplotype analysis also was conducted. Individuals who were homozygotes, double heterozygotes, or carriers of mutations in RP1 underwent an ophthalmic evaluation to establish a genotype-phenotype correlation. MAIN OUTCOME MEASURES: DNA sequence variants, homozygous regions, haplotypes, best-corrected visual acuity, visual field assessments, electroretinogram responses, and optical coherence tomography images. RESULTS: Four novel mutations in RP1 were identified. The new mutation p.Ser542Stop was present in 11 of 244 (4.5%) of the studied families. All chromosomes harboring this mutation shared the same haplotype. All patients presented a common phenotype with an early age of onset and a prompt macular degeneration, whereas the heterozygote carriers did not show any signs of retinitis pigmentosa (RP). CONCLUSIONS: p.Ser542Stop is a single founder mutation and the most prevalent described mutation in the Spanish population. It causes early-onset RP with a rapid macular degeneration and is responsible for 4.5% of all cases. Our data suggest that the implication of RP1 in arRP may be underestimated. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article. PMID- 22917893 TI - CK2 and the regulation of the carbohydrate metabolism. AB - Protein kinase CK2 was originally identified by analyzing carbohydrate metabolism. Now it is clear that life without CK2 is impossible. Moreover, CK2 activity was found elevated in rapidly proliferating cells when compared to slowly proliferating or resting cells. Proliferating cells have an elevated need for energy which is generated from an elevated carbohydrate metabolism. From early observations and the emerging role of CK2 in cellular regulation, it is not surprising that CK2 plays a role in hormonal regulation of carbohydrate metabolism as well as modulating activities of enzymes directly involved in carbohydrate storage and metabolism. The aim of the present review is to summarize the knowledge about the role of CK2 in the regulation of the carbohydrate metabolism. PMID- 22917892 TI - Determinants of retinal venular diameter: the Beaver Dam Eye Study. AB - OBJECTIVE: To describe how retinal venular diameter changes over time for an individual and to examine differences in these changes among people with different risk profiles. DESIGN: Population-based cohort study. PARTICIPANTS: A total of 4600 persons aged 43 to 86 years from the Beaver Dam Eye Study (BDES) who participated in at least 1 examination and had venular diameter measured in the right eye. METHODS: Data from 4 examinations during a 15-year period were analyzed. Retinal venular diameter was measured from photographs at each examination by computer-assisted methods and summarized as the central retinal venular equivalent (CRVE). Associations of risk factors with concurrent CRVE measurements and changes in CRVE over time were determined using multivariate analyses. MAIN OUTCOME MEASURES: Central retinal venular equivalent. RESULTS: The CRVE tended to narrow with age. Mean CRVE was approximately 5 MUm smaller (225 vs. 230 MUm) for the average 70-year-old compared with the average 50-year-old, and was approximately 13 MUm smaller (217 vs. 230 MUm) for the average 85-year old compared with the average 50-year-old. Male sex (beta estimate [beta] = 5.24; 95% confidence interval [CI], 3.58-6.90), history of current cigarette smoking (beta = 9.38; 95% CI, 8.26-10.49), and higher white blood cell (WBC) count (per 1000/MUL: beta = 0.95; 95% CI, 0.74-1.16) were independently associated with larger concurrent CRVE, whereas higher mean arterial blood pressure (per 5 mmHg: beta = -0.36; 95% CI, -0.50 to -0.23) and higher serum high-density lipoprotein (HDL) cholesterol (per 10 mg/dl: beta = 0.89; 95% CI, -1.15 to -0.63) were independently associated with smaller concurrent CRVE. History of cardiovascular disease (CVD) (beta = -0.16; 95% CI, -0.26 to -0.06) and presence of chronic kidney disease (CKD) (beta = -0.20; 95% CI, -0.34 to -0.05) were associated with a greater decrease in CRVE over time. CONCLUSIONS: These data show that retinal venular diameter tends to narrow with age; concurrent venular diameter is independently associated with sex, blood pressure, serum HDL cholesterol, WBC count, and history of current cigarette smoking; and change in CRVE is independently associated with a history of CVD and presence of CKD. The different independent effects of these interrelated factors on CRVE highlight the complex relationship between CRVE and systemic diseases and conditions and the difficulty in determining specific causes of change in CRVE over time. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article. PMID- 22917894 TI - Onycholemmal carcinoma: a morphologic comparison of 6 reported cases. AB - BACKGROUND: We report 6 new cases of onycholemmal carcinoma, a rare, often misdiagnosed, subcategory of squamous cell carcinoma. All reported cases to date have been treated with amputation of the affected digit. OBJECTIVE: The purpose of this study was to present the clinical and pathological features of each new case and to discuss treatment options that spare digit functionality. METHODS: Hematoxylin-eosin stains were performed on tumor sections and examined using light microscopy. In situ hybridization using probes against human papillomavirus were examined in 1 case. RESULTS: The female to male ratio was 1:1 with involvement of fingers in 3, thumb in 1, and toe in 1. Among the symptoms were onycholysis, periungual erythema, and pain; symptom duration ranged from 6 months to 2 years. Histologically, all cases showed a well-differentiated atypical infiltrative squamous proliferative lesion exhibiting a lobulated and cystic pattern of growth in the dermis. Abrupt keratinization reminiscent of trichilemmal keratinization was noted. Mohs micrographic surgery and radiation therapy were used as primary treatment modalities, maintaining digit functionality and achieving remission. LIMITATIONS: Limitations of this study included the small number of cases, the infrequency with which this tumor has been reported in the literature, and the inability to obtain follow-up on an older archival case. CONCLUSIONS: Onycholemmal carcinoma is a distinct type of squamous cell carcinoma arising from the nail isthmus; its natural clinical course is indolent. In this regard less aggressive digit-sparing treatment modalities such as radiation or Mohs micrographic surgery should be considered. PMID- 22917895 TI - Acitretin for the treatment of cutaneous T-cell lymphoma. AB - BACKGROUND: Bexarotene is the only Food and Drug Administration-approved retinoid for the treatment of cutaneous T-cell lymphoma (CTCL) and is associated with a relatively high frequency of adverse effects. Acitretin has anecdotally been reported to be effective for CTCL. OBJECTIVE: We sought to determine the effectiveness and tolerability of acitretin as primary or adjuvant therapy for CTCL. METHODS: We conducted a retrospective chart review of patients with CTCL treated with acitretin at a single tertiary care center. RESULTS: A total of 32 patients with CTCL were included: 29 had mycosis fungoides, 2 had Sezary syndrome, and 1 had CTCL not otherwise specified. Median patient age was 55 years; 56% were male; 47% were white, 47% black, and 6% other. In all, 3% of patients were stage IA, 69% stage IB/IIA, 16% stage IIB, 6% stage III, and 6% stage IV. Six patients received acitretin alone; 26 received acitretin in addition to another CTCL therapy. The overall response rate was 59%. In all, 25% of patients had stable disease and 16% had progressive disease. Median duration of response was 28 months. Adverse effects were generally mild with 5 patients discontinuing therapy because of these. LIMITATIONS: In this small retrospective chart review, many patients were on other CTCL therapies while on acitretin; therefore precise assessment of response to acitretin alone was difficult. CONCLUSIONS: Acitretin is well tolerated and potentially effective for early stage CTCL. Response to acitretin, either as adjuvant therapy monotherapy, is comparable with the response to oral agents currently approved for this disease. PMID- 22917897 TI - Multiple jeopardy: poor, economically disconnected, and child welfare involved. AB - Although the welfare literature reveals a growing number of parents who are economically disconnected, meaning neither employed nor receiving cash assistance, little is known about the prevalence and impacts of disconnection among child welfare-involved parents. This study took advantage of a statewide survey of child welfare-involved parents to examine economic disconnection in this population and to explore the relationship between disconnection and parent engagement in child welfare. One fifth of the sample reported that they were economically disconnected, with several patterns differentiating disconnected caregivers from those who received benefits or earned income through employment. Disconnected caregivers were younger and more frequently had children in out-of home placements as opposed to receiving services in home than economically connected caregivers. They also reported higher unmet needs for basic services, such as housing and medical care, but were more likely to report financial help from their informal network. Finally, disconnected caregivers reported lower engagement in child welfare services even when controlling for demographic characteristics, chronic psychosocial risk factors, placement status, and maltreatment type. The findings document economic disconnection among child welfare-involved parents and raise important questions about the implications of disconnection for families and for child welfare outcomes. PMID- 22917896 TI - Grape seed extract neutralizes the effects of Cerastes cerastes cerastes post synaptic neurotoxin in mouse diaphragm. AB - This work was undertaken to investigate the toxic activity of the post-synaptic neurotoxic fraction isolated from the venom of the Egyptian sand viper (Cerastes cerastes cerastes), and the ability of grape seed extract to antagonize this effect produced in sublethally intoxicated mice, with an emphasis on ultrastructural features. Light and transmission electron microscopy of diaphragms of intoxicated mice showed myonecrosis, myofiber hypercontraction, sarcomere disorganization, and mitochondrial damage. Alterations in motor neurons and axon terminals were also observed. The toxic activities of C. cerastes cerastes neurotoxin were inhibited by administrating grape seed extract, either before or after intoxication, showing that grape seed extract has protective and therapeutic potential to be used as antivenom. PMID- 22917898 TI - [Nonsense-mediated mRNA decay and human monogenic disease]. AB - Nonsense-mediated mRNA decay (NMD) is a widespread quality control mechanism in eukaryotic cells. It can recognize and degrade aberrant transcripts harbouring a premature translational termination codon (PTC), and thereby prevent the production of C-terminally truncated proteins which might be deleterious. Approximately, 30% of human genetic diseases are caused by transcripts containing PTCs. These transcripts are potential targets of NMD. As for monogenic diseases, NMD has effects on the phenotype or mode of inheritance. Here, we explain the mechanism of this surveillance pathway, and take several neuromuscular disorders as examples to discuss its influence for human monogenic diseases. The deeper understanding for NMD will shed light on the nosogenesis and therapies of monogenic diseases. PMID- 22917899 TI - [The new function of p53 family and its pathway related proteins in female reproduction]. AB - p53 is an important tumor suppressor gene and one of the key genes in sensing and regulating responses to the environmental stress. Recent study showed that cold winter temperature naturally selected p53 Arg72 in eastern Asian population, suggesting that p53 plays a role in reproduction. It has also been reported that some SNPs of p53, Mdm2(Murine double minute 2), MdmX and Hausp (Herpes virus associated ubiquitin-specific protease) in p53 pathway are associated with the risk of the women's reproduction disorder. p53 regulates the LIF (leukaemia inhibitory factor) expression level by its DBD domain, and thus contributes to female reproduction by affecting the embryo implantation process. The MDM2, MDMX, and HAUSP proteins regulates the level and activity of p53 protein, which are critical for the appropriate p53 response in the embryo implantation process. The members of p53 family, p63 and p73, also play roles in female reproduction through other pathways. p63 has been implicated as a major regulator of oocyte death following treatment with irradiation and chemotherapeutic drugs, which prevents fetal malformation. p73 regulates the formation of spindle assembly complex(SAC). The dysfunction of SAC results in poor blastocyst quality and defects in kinetochore-microtubule associations, which leads to aneuploidy. This review summarized the function of p53 family and its pathway related proteins in female reproduction, pointed out a new method in improving the success rate in IVF-ET, and provided a new diagnosis idea for unexplained infertile women. It will facilitate personalized strategies in the infertility therapy. PMID- 22917900 TI - [DNA-binding profiles of mammalian transcription factors]. AB - The differential gene expression is the molecular base of development and responses to stimuli of organisms. Transcription factors (TFs) play important regulatory roles in this kind of differential gene expression. Therefore, to elucidate how these TFs regulate the complex differential gene expression, it is necessary to identify all target genes of them and construct the gene transcription regulatory network controlled by them. DNA binding is a key step for TFs regulating gene transcription. Therefore, in order to identify their target genes, it is indispensable to identify all possible DNA sequences that can be recognized and bound by TFs at the molecular level of their interactions with DNA, i.e., construction of the DNA-binding profiles of TFs. In recent years, along with the development of DNA microarray and high-throughput DNA sequencing techniques, there appeared some revolutionary new techniques for constructing DNA binding profiles of TFs, which greatly promotes studies in this field. These techniques include ChIP-chip and ChIP-Seq for constructing in vivo DNA-binding profiles of TFs, dsDNA microarray, SELEX-SAGE, Bind-n-Seq, MMP-SELEX, EMSA-Seq, and HiTS-FLIP for constructing in vitro DNA-binding profiles of TFs. This paper reviewed these techniques. PMID- 22917901 TI - [Effects of RFRP-3 on reproductive function and energy balance in mammals]. AB - The hypothalamo-pituitary-gonadal (HPG) axis integrates internal and external cues via a balance of stimulatory and inhibitory neurochemical systems to regulate reproductive function in mammals. However, RFRP-3 is a unique inhibitor of HPG axis at the hypothalamuic level in mammals to date. A large number of previous studies have confirmed that RFamide-related peptide (RFRP-3) suppresses gonadotropin-releasing hormone (GnRH) system and luteinizing hormone (LH) secretion, thereby affecting the reproduction. However, whether the inhibition of LH secretion by RFRP-3 occurs at the pituitary level or the hypothalamus level is not clear. It is interesting that RFRP-3 is also related to signal pathway of melatonin modulating mammal seasonal reproduction, but little is known about the effects of melatonin on the RFRP-3 neuron up to now. In addition, RFRP-3 also plays an important role in the regulation of energy balance and behavior. The regulatory mechanism of RFRP-3 in HPG axis and role of RFRP-3 in modulating mammalian energy balance, as well as behavior, are systematically elaborated and the remaining unsolved problems are also discussed in this paper. PMID- 22917902 TI - [Dosage compensation mechanism of X chromosome]. AB - Dosage compensation mechanism is crucial for the balance expression of X chromosome genes, which ensures the protein or enzyme encoded by the X chromosome to be equal or almost equal expression amounts between males and females. However, different organisms have evolved distinct dosage compensation strategies, and so far three kinds of dosage compensation strategies among organisms have been reported. The first strategy is that the single male X chromosome expression is doubly activated; the second one is to inactivate one female X chromosome by leaving both sexes with one active allele; and the third one is to reduce the expression to half activity in both X chromosomes of the female. The study of dosage compensation will be useful to reveal the mechanism of regulation of X-linked genes as well as the evolution and the differentiation progress of the sex chromosome, and it can also contribute to illustrate mutation and distortion of sex chromosome. Therefore, this paper briefly reviewed and discussed the progresses and prospects of the important mechanism of dosage compensation. PMID- 22917903 TI - [Cell fate switch: lineage reprogramming]. AB - It has been demonstrated that mature cells could switch their fate by the technologies for reprogramming, such as somatic cell nuclear transfer and induced pluripotent stem cells. Recently, this conclusion was further confirmed. It was found that mature differentiated cells could be directly converted into other somatic cells or progenitors with some defined transcription factors. This technology is called lineage reprogramming, which provides an attractive novel alternative to regenerative medicine and animal biotechnology. It is a more convenient and more effective system with less ethical issues. Moreover, lineage reprogramming technology could also facilitate researches on regulation of gene expression. This review highlights the procedures of reprogramming, its characteristics, and significant promise in biomedical applications. PMID- 22917904 TI - [Functions of NAC transcription factors in biotic and abiotic stress responses in plants]. AB - NAC transcription factors belong to a unique class of transcription factors in plants. The common characteristics of the NAC proteins are the presence of a conserved NAC domain, comprising of about 150 amino acids in N-terminals and a highly variable transcriptional regulation region in C-terminals. Extensive studies have revealed that NAC transcription factors not only play important roles in plant growth and development, but also have functions in regulation of responses to biotic and abiotic stresses. In this minireview, we summarized the functions and mechanisms of the NAC transcriptional factors in plant abiotic and biotic stress responses. We also discussed future directions towards understanding the biological functions of the members of the NAC transcriptional factors in plants. PMID- 22917905 TI - [Progress on XerCD/dif site-specific recombination]. AB - In Escherichia coli, 10% to 15% of growing bacteria produce chromosome dimers during DNA replication. These dimers are resolved by XerC and XerD, two chromosome recombinases that target the dif sequence in the replication terminus of chromosome. Phage CTXPhi integrates into vibrio cholerae chromosome in a site specific manner. However, CTXPhi genome does not encode any recombinase, while recombinase XerC and XerD, which is coded by vibrio cholerae chromosome are required for the integration of CTXPhi into the vibrio cholerae chromosome. The CTXPhi integration site overlaps with the dif site. The wide distribution of XerCD recombinase and dif site among bacteria genome suggests that it may be universal in resolve of chromosome dimers and phage integration. In this article, we reviewed the research progresses on chromosome dimer resolve and phage integration through XerCD/dif site-specific recombination. PMID- 22917906 TI - [Computational approaches for identification and classification of transposable elements in eukaryotic genomes]. AB - Repetitive sequences (repeats) represent a significant fraction of the eukaryotic genomes and can be divided into tandem repeats, segmental duplications, and interspersed repeats on the basis of their sequence characteristics and how they are formed. Most interspersed repeats are derived from transposable elements (TEs). Eukaryotic TEs have been subdivided into two major classes according to the intermediate they use to move. The transposition and amplification of TEs have a great impact on the evolution of genes and the stability of genomes. However, identification and classification of TEs are complex and difficult due to the fact that their structure and classification are complex and diverse compared with those of other types of repeats. Here, we briefly introduced the function and classification of TEs, and summarized three different steps for identification, classification and annotation of TEs in eukaryotic genomes: (1) assembly of a repeat library, (2) repeat correction and classification, and (3) genome annotation. The existing computational approaches for each step were summarized and the advantages and disadvantages of the approaches were also highlighted in this review. To accurately identify, classify, and annotate the TEs in eukaryotic genomes requires combined methods. This review provides useful information for biologists who are not familiar with these approaches to find their way through the forest of programs. PMID- 22917907 TI - [Polymorphism of 17 Y-STR loci in She ethnic population in Fujian and genetic relationship with 11 populations]. AB - To investigate the genetic polymorphisms of 17 Y-chromosomal short tandem repeats(Y-STR) loci in She ethnic population from Fujian province, and to evaluate their forensic application values and genetic relationship with other 11 populations, 152 unrelated male individuals of She ethnic population in Fujian were used to determine the distribution of allele frequencies and haplotypes by using Y-filerTM System. Cluster analysis and phylogenic trees were applied to show the genetic distance among the populations. As a result, 50 haplotypes were found in DYS385a/b loci, and 3~11 alleles were found in the rest 15 Y-STR loci. The GD value was from 0.4037(DYS391) to 0. 9725(DYS385a/b). This study has also revealed "off-ladder" alleles at several Y-loci, namely DYS448, DYS393, DYS458 and DYS635, and several occurrences of duplications at the DYS385a/b, DYS19 and DYS390 loci. One hundred and forty-four haplotypes were found in 17 Y-STR loci, of which 138 were unique, 5 were found in 2 individuals, 1 was found in 4 individuals, and the observed haplotypes diversity value was 0.9990. Comparing with 11 populations, the genetic distance between She ethnic and Han population in Zhejiang was the smallest (0.0042), while it was the largest between She ethnic and Tibet ethnic population (0.2380). Cluster analysis and phylogenetic tree both demonstrated that genetic distance between She ethnic and several south Han populations is closer than between She ethnic and non-Han populations. Multiplex detection of the 17 Y-STR loci revealed a highly polymorphic genetic distribution, which would be very powerful for establishing a Y-STR database, for population genetics and forensic practice. PMID- 22917908 TI - [The analysis of Leber's hereditary optic neuropathy associated with mitochondrial tRNAAla C5601T mutation in seven Han Chinese families]. AB - We reported here the clinical, genetic, and molecular characterization of Leber's hereditary optic neuropathy (LHON) with C5601T mutation in seven Chinese families. The ophthalmologic examinations of seven Chinese families who were clinically diagnosed LHON were conducted. Strikingly, these families exhibited very low penetrance of visual impairment, and the penetrance was 9.5%, 14.3%, 4.5%, 8.3%, 10.0%, 22.2% and 25.0%. Meanwhile, entire mitochondrial genome of seven probands was amplified by PCR using 24 pairs of oligonucleotide primers with overlapping fragments. Molecular analysis of mitochondrial DNA (mtDNA) in these pedigrees revealed the absence of three common LHON associated G11778A, G3460A and T14484C mutations but the presence of homoplastic LHON associated tRNAAla C5601T mutation in probands and other matrilineal relatives. These mtDNA polymorphism sites belongs to the Asian haplogroups G2, G2a1, G2a1, G2, G2b, G2a1 and G2. By analyzing mitochondrial genome, seven LHON families all carry the C5601T mutation. The C5601T mutation occurs at the highly conserved nucleotide (conventional position 59) of tRNAAla, thereby contributing to the structural formation and stabilization of functional tRNAs and leading to mitochondrial dysfunction involved in visual impairment. The incomplete penetrance of visual loss in these seven Chinese pedigrees strongly indicates that the tRNAAla C5601T mutation was itself insufficient to produce a clinical phenotype. The lack of functional mtDNA variants in these pedigrees ruled out the role of mitochondrial background in the phenotypic expression of visual loss. Therefore, nuclear backgrounds and environmental factors seem to be modifying factors for the phenotypic manifestation of the tRNAAla C5601T mutation in the seven Chinese families. PMID- 22917909 TI - [Genetic scanning on chromosome 8 loci for coronary heart disease]. AB - At present, genome-wide association study on coronary heart disease (CHD) has been carried out in several major medical research centers worldwide. Most studies of CHD susceptibility loci or regions focused on chromosome 1, 3, 9, 11 and 16, while studies on chromosome 8 are rare. To the best of our knowledge, the genome study on chromosome 8 about CHD in Chinese Han population has never been reported before. We aimed to identify CHD susceptibility loci or regions in the Chinese Han population. First, two separated DNA pooling samples were prepared from 156 CHD cases and 1000 normal controls. Then, a total of 13 microsatellite markers at an interval of 10 cM on chromosome 8 were selected for genetic scanning. Finally, the difference of allele frequency at each locus between two pooled samples was analyzed by Chi-square test. Significant differences were found between cases and controls at D8S264(8p23.3-p23.2) and D8S285(8q12.1) (both P<0.05). Therefore, 8p23.3-p23.2 and 8q12.1 are possible to be associated with CHD and further study is needed to screen susceptible genes around these regions. PMID- 22917910 TI - [Functional analysis of SNPs in porcine TLR4 gene]. AB - Toll-like receptor 4 (TLR4) plays an important role in immune response and the polymorphism in it might affect protein signaling and host resistance/susceptibility to disease. This study was designed to characterize the functional relevance of 3 nonsynonymous single nucleotide polymorphisms (SNPs), c.611 T>A (p.Leu204His), c.1027 C>A (p.Gln343Lys), and c.1605 G>T (p.Leu535Phe), which were selected based on our previous studies. RT-PCR method was used to clone the complete coding sequence of porcine TLR4 gene and the PCR-based method was used to introduce the point mutation. The effects of 3 SNPs on the ligand recognition and signaling of porcine TLR4 were investigated in transiently transfected PK-15 cells using dual-luciferase reporter system and Western blotting method. At the same time, the distribution of c.1605 G>T among pig populations composed of Min pig, Yorkshire, Landrace, and Wild boar from northeastern China was studied by created restriction site PCR-RFLP method. The complete coding sequence of TLR4 gene in Min pig and 3 variants with single point mutations were obtained. Eukaryotic expression vectors containing different alleles of porcine TLR4 were constructed. SNP c.1605 G>T significantly decreased the TLR4 signaling (P<0.01) and the polymorphism only existed in Min pig and Wild boar from northeastern China with high frequencies. SNP c.1605 G>T in porcine TLR4 might affect the receptor function and host resistance/susceptibility to diseases. PMID- 22917911 TI - [Phylogenetic relationships of honey bees (Hymenoptera: Apinae) inferred from mitochondrial and nuclear DNA sequences]. AB - The sequences of mitochondrial ND2, CO2, and 16S rRNA genes and nuclear ITPR gene were obtained from 22 samples of 5 Apis species from China. The characteristics of the sequences and the pairwise distances among species were analyzed. Phylogenetic trees were reconstructed for Apis species using maximum parsimony, neighbor-joining and maximum likelihood methods together with the sequences of the other 4 Apis species downloaded from GenBank. Results supported that Apis species were divided into three major clusters: dwarf bees (A. florea and A. andreniformis), giant bees (A. dorsata and A. laboriosa), and cavity-nesting bees (A. mellifera, A. cerana, A. koschevnikovi, A. nigrocinta, and A. nuluensis). The dwarf honey bees were confirmed as basal lineage. Our study also revealed a high level of genetic divergence between A. dorsata from Hainan Island and China mainland. PMID- 22917912 TI - [Morphological characteristics and gene mapping of a palea degradation(pd2) mutant in rice]. AB - The yield and quality of rice are directly impacted by floral organ development in rice. Understanding of the floral development mechanism will be useful in genetic improvement of yield and quality. In this study, a rice mutant palea degradation 2 (pd2) in an indica cultivar '8PW33' was obtained after 60Co gamma ray treatment. Analysis of the mutant showed that, compared to the wild type, plant height, total grain number per panicle, and sword leaf width were significantly increased, but the seed setting rate were significantly decreased. The florets of the mutant exhibited degraded palea and sickle-shaped tortuous lemma. Detail examination using scanning electron microscopy revealed that when epidermis of the vane and lemma were normal, epidermis of the palea were arranged tightly, which might result from degraded palea. Genetic analysis supported that this mutation phenotype was controlled by a single recessive gene. Polymorphic analysis of simple sequence repeat markers demonstrated that PD2 gene is located on chromosome 9. With a larger mapping population and more indel markers, we further mapped PD2 gene between 2 indel markers with a physical region of about 82 kb. Within this region, there is a cloned gene REP1 known to control rice palea development. By comparing the DNA sequences of REP1 from pd2 and 8PW33, in combination with the results of phenotypic analysis, we concluded that PD2 is an allele of REP1. PMID- 22917913 TI - [Genetic analysis of fuzzless in cotton germplasm]. AB - The present study was conducted to evaluate genetic analysis of fuzzless seed trait in cotton. One hundred and two upland cotton (G. hirsutum) and eighty-five island cotton (G. barbadense) were used to cross with the same lines, TM-1 (G. hirsutum) and Xinhai 13 (G. barbadense), respectively. Two different F1 populations obtained were assessed to specify the dominant and recessive inheritance of fiber fuzziness in these lines. Three F1 populations (Kuguangzi * TM-1, Luwuxu * TM-1, and SA65 * TM-1) displaying recessive fiber fuzziness inheritance were selected to construct the F2 population for a further genetic study of fuzzless seed trait. The results of this study indicated that (1) the same materials showed different quantities of fuzzy fiber in different environments. Less fuzzy fiber was found in Xinjian and Hainan compared to Anyang. Thus, the quantity of fuzzy cotton seed depends on ecological environment. (2) In upland cotton, the inheritance of fiber fuzziness was dominant for 26 accessions (25.49%), incompletely dominant for 8 accessions (7.84%), and recessive for 22 accessions (21.57%). The inheritance of fiber fuzziness in island cotton was dominant for 5 accessions (5.88%), incompletely dominant for 16 accessions (18.82%), and recessive for 9 accessions (10.59%). Analysis of F2 population indicated that the fiber fuzziness of Kuguangzi was controlled by two recessive complementary effect alleles. The fiber fuzziness of Luwuxu was controlled by two recessive additive effect alleles, and a single recessive gene controlled the same trait for SA65. Fiber fuzziness evaluation in cotton germplasm provides the genetic and basic information for cotton fiber development study and breeding. PMID- 22917914 TI - Adrenal activity in maned wolves is higher on farmlands and park boundaries than within protected areas. AB - In this study we measured excreted fecal corticoid metabolites (FCM) in maned wolves (Chrysocyon brachyurus) living within a protected reserve, on farmlands or in a boundary zone between the two habitats, and determined the impacts of season and reproductive status on adrenal activity. Feces were collected within a national park (n=191 samples), a park boundary zone (n=39) and on nearby farmlands (n=27), processed and analyzed by enzyme immunoassay. FCM amounts from samples collected on farmlands were higher (P<0.05) than in those collected inside the reserve and from the boundary zone. In relation to seasonality, FCM were elevated (P<0.05) in spring (September-November) when wolf pairs were raising young. We then divided the samples collected during breeding season (March-August) into cycling females and male/non-cycling females based on fecal progesterone: fecal testosterone ratio. FCM concentrations of the former collected inside the park were higher than (P<0.05) than the latter group. However, there were no differences in FCM levels between the two groups for samples collected in the boundary zone and on farmlands. Furthermore, FCM concentrations of male/non-cycling females samples collected on farmlands were 2- to 5-fold higher (P<0.05) than in counterparts collected inside the park. The consistently high FCM concentrations in samples collected on farmlands indicate that, in addition to seasonality, gender and reproductive status, anthropogenic pressures also contribute to elevating adrenal steroid for individuals living in altered habitat. PMID- 22917916 TI - Major white matter fiber changes in medically intractable neocortical epilepsy in children: a diffusion tensor imaging study. AB - This study aimed to investigate the extent of microstructural changes in the major white matter fibers and to evaluate whether diffusion tensor imaging (DTI) adds any lateralizing information in children with medically intractable neocortical epilepsy secondary to focal cortical dysplasia. Patient group included twenty-three consecutively enrolled patients with medically intractable focal neocortical epilepsy and focal cortical dysplasia histopathologically confirmed. Thirteen patients (56.5%) had no visible lesion on the conventional magnetic resonance imaging (MRI). Fractional anisotropy (FA) was measured for regions of interest (ROIs) in each major white matter fiber. FA in patients was compared with eighteen age-matched healthy controls. Patient group had lower FA values at corpus callosum, bilateral inferior frontooccipital fasciculus (IFO), bilateral inferior longitudinal fasciculus (ILF) and left superior longitudinal fasciculus (SLF) compared to controls (p<0.05). In the left-side surgery group, the left SLF FA value was lower than controls, while in the right-side surgery group, the right SLF FA values were lower than controls (p<0.05). In the patient group as a whole, ipsilateral SLF FA was significantly lower than the contralateral SLF (p<0.05). Widespread decrease in FA values in the patients compared with the controls suggests that the pathologic changes extend diffusely to most major white matter tracts. In the patient group, the ipsilateral SLF to the seizure focus had greater change compared to the contralateral SLF. These data suggest that the detection of DTI abnormality has an added value to lateralization. PMID- 22917917 TI - Electrochemical impedance spectroscopy biosensor with interdigitated electrode for detection of human immunoglobulin A. AB - Interdigitated electrodes (IDEs) that have a series of parallel microband electrodes with alternating microbands connected together were utilized in electrochemical impedance spectroscopy (EIS) to build a label-free human immunoglobulin A (IgA) immunosensor. Anti-human IgA (anti-IgA) was employed as an IgA receptor and was covalently immobilized on the IDE surface through a self assembled monolayer, as confirmed by atomic force microscopy. EIS measurements revealed that the specific adsorption of IgA onto the immobilized anti-IgA gave rise to a clear increase in the value of interfacial charge transfer resistance (R(ct)). A linear relationship between DeltaR(ct) and the logarithm of IgA concentration was found for the concentration range of 0.01-100 ng/mL. No modulation of R(ct) was detected by immersing the sensor in solutions of other proteins such as human immunoglobulin G or bovine serum albumin, which confirmed a high selectivity of this immunosensor for IgA. These results demonstrated that the anti-IgA receptor simply immobilized on the IDE surface can provide a sensitive biosensor. PMID- 22917915 TI - Social neuroscience and hyperscanning techniques: past, present and future. AB - This paper reviews the published literature on the hyperscanning methodologies using hemodynamic or neuro-electric modalities. In particular, we describe how different brain recording devices have been employed in different experimental paradigms to gain information about the subtle nature of human interactions. This review also included papers based on single-subject recordings in which a correlation was found between the activities of different (non-simultaneously recorded) participants in the experiment. The descriptions begin with the methodological issues related to the simultaneous measurements and the descriptions of the results generated by such approaches will follow. Finally, a discussion of the possible future uses of such new approaches to explore human social interactions will be presented. PMID- 22917918 TI - A label-free electrochemiluminescence aptasensor for thrombin based on novel assembly strategy of oligonucleotide and luminol functionalized gold nanoparticles. AB - In the work, a label-free electrochemiluminescence (ECL) aptasensor for the sensitive and selective detection of thrombin was constructed based on target induced direct ECL signal change by virtue of a novel assembly strategy of oligonucleotide and luminol functionalized gold nanoparticles (luminol-AuNPs). It is the first label-free ECL biosensor based on luminol and its analogs functionalized AuNPs. Streptavidin AuNPs coated with biotinylated DNA capture probe 1 (AuNPs-probe 1) were firstly assembled onto an gold electrode through 1,3 propanedithiol. Then luminol-AuNPs co-loaded with thiolated DNA capture probe 2 and thiolated thrombin binding aptamer (TBA) (luminol-AuNPs-probe 2/TBA) were assembled onto AuNPs-probe 1 modified electrode through the hybridization between capture probes 1 and 2. The luminol-AuNPs-probe 2/TBA acted as both molecule recognition probe and sensing interface. An Au/AuNPs/ds-DNA/luminol-AuNPs/TBA multilayer architecture was obtained. In the presence of target thrombin, TBA on the luminol-AuNPs could capture the thrombin onto the electrode surface, which produced a barrier for electro-transfer and influenced the electro-oxidation reaction of luminol, leading to a decrease in ECL intensity. The change of ECL intensity indirectly reflected the concentration of thrombin. Thus, the approach showed a high sensitivity and a wider linearity for the detection of thrombin in the range of 0.005-50nM with a detection limit of 1.7pM. This work reveals that luminol-AuNPs are ideal platform for label-free ECL bioassays. PMID- 22917919 TI - Impedimetric biosensor based on cell-mediated bioimprinted films for bacterial detection. AB - This work presents the synthesis of bacteria-mediated bioimprinted films for selective bacterial detection. Marine pathogen sulfate-reducing bacteria (SRB) were chosen as the template bacteria. Chitosan (CS) doped with reduced graphene sheets (RGSs) was electrodeposited on an indium tin oxide electrode, and the resulting RGSs-CS hybrid film served as a platform for bacterial attachment. The electrodeposition conditions were optimized to obtain RGSs-CS hybrid films with excellent electrochemical performance. A layer of nonconductive CS film was deposited to embed the pathogen, and acetone was used to wash away the bacterial templates. Electrochemical impedance spectroscopy was performed to characterize the stepwise modification process and monitor the SRB population. Faradic impedance measurements revealed that the charge transfer resistance (R(ct)) increased with increased SRB concentration. A linear relationship between DeltaR(ct) and the logarithm of SRB concentration was obtained within the concentration range of 1.0*10(4)cfum L(-1) to 1.0*10(8)cfum L(-1). The impedimetric sensor showed good selectivity towards SRB based on size and shape. Hence, selectivity for bacterial detection can be improved if the bioimprinting technique is combined with other bio-recognition elements. PMID- 22917920 TI - A whole-cell biosensor as in vitro alternative to skin irritation tests. AB - This study presents the time-resolved detection of chemically induced stress upon intracellular signaling cascades by using genetically modified sensor cells based on the human keratinocyte cell line HaCaT. The cells were stably transfected with a HSP72-GFP reporter gene construct to create an optical sensor cell line expressing a stress-inducible reporter protein. The time- and dose-dependent performance of the sensor cells is demonstrated and discussed in comparison to a label-free impedimetric monitoring approach (electric cell-substrate impedance sensing, ECIS). Moreover, a microfluidic platform was established based on MUSlidesI(0,4)Luer to allow for a convenient, sterile and incubator-independent time-lapse microscopic observation of the sensor cells. Cell growth was successfully achieved in this microfluidic setup and the cellular response to a cytotoxic substance could be followed in real-time and in a non-invasive, sensitive manner. This study paves the way for the development of micro-total analysis systems that combine optical and impedimetric readouts to enable an overall quantitative characterization of changes in cell metabolism and morphology as a response to toxin exposure. By recording multiple parameters, a detailed discrimination between competing stress- or growth-related mechanisms is possible, thereby presenting an entirely new in vitro alternative to skin irritation tests. PMID- 22917921 TI - Evaluation of a vancomycin dosing nomogram in achieving high target trough concentrations in Taiwanese patients. AB - BACKGROUND: The use of a vancomycin dosing nomogram is an alternative and more cost-effective method to conventional dosing; it reliably allows the achievement of trough vancomycin serum concentrations of 5-15 mg/l, with a successful clinical response. Recent guidelines have further recommended that the trough concentration be maintained at 15-20mg/l for complicated infections. However, to date no published nomogram has been constructed to achieve the optimal trough of 15-20mg/l in an Asian population. This study aimed to develop two vancomycin nomograms for the achievement of trough concentrations of 5-15 mg/l and 15-20mg/l in the Taiwanese population, and to ensure the clinical efficacy and safety of such nomograms. METHODS: The estimated concentrations and the real concentrations in our patient population were compared between six pharmacokinetic models to see which was the most precise. As the Ambrose method was the best at predicting the trough, this was used to create two nomograms, one for a target trough at 5-15 mg/l and the other for a target trough at 15-20mg/l. We then evaluated the nomograms by analyzing the number of patients with the target vancomycin trough concentration, clinical and microbiological outcomes, and safety. RESULTS: More patients who had dosing according to the nomogram had a vancomycin trough concentration within the desired target range than patients who had conventional dosing (65.1% vs. 32.1%, p = 0.001). These patients also had a higher rate of 'cure' as the clinical response (35.7% vs. 27.1%) and 'eradication' as the microbiological response (46.4% vs. 29.2%), and a lower rate of nephrotoxicity (14.3% vs. 22.9%). For the patients with a complicated infection, more had a trough between 15 and 20mg/l when vancomycin was dosed with the nomogram than when dosed conventionally (41.2% vs. 12.1%, p = 0.019). CONCLUSIONS: We found that when dosing vancomycin with these nomograms, patients tended to have vancomycin trough concentrations within the target range and also to have a better outcome with regard to clinical efficacy and the safety profile. PMID- 22917922 TI - CCL28 in the mouse hippocampal CA1 area and the dentate gyrus during and after pilocarpine-induced status epilepticus. AB - The present study showed a wide presence of CCL28 in mouse CNS, including cerebral, cerebellum, brain stem and spinal cord. In hippocampus, the expression of CCL28 at both mRNA and protein level was clarified. The CCL28 expression was mainly localized in pyramidal cells of CA area, granular cells of dentate gyrus and some interneurons in CA area and hilus. Double-labelling immunocytochemistry revealed that most of calbindin, calretinin and parvalbumin immunopositive neurons expressed CCL28. During and after pilocarpine induced status epilepticus (SE), a down-regulated expression of CCL28 in hippocampal interneurons in the CA1 area and in the hilus of the dentate gyrus was demonstrated. The present study may, therefore provide evidence that CCL28 may have a novel role in CNS and may be involved in the loss of hippocampal interneurons, and subsequent disinhibition of pyramidal neurons. PMID- 22917923 TI - Glafenine-induced intestinal injury in zebrafish is ameliorated by MU-opioid signaling via enhancement of Atf6-dependent cellular stress responses. AB - Beside their analgesic properties, opiates exert beneficial effects on the intestinal wound healing response. In this study, we investigated the role of MU opioid receptor (MOR) signaling on the unfolded protein response (UPR) using a novel zebrafish model of NSAID-induced intestinal injury. The NSAID glafenine was administered to zebrafish larvae at 5 days post-fertilization (dpf) for up to 24 hours in the presence or absence of the MOR-specific agonist DALDA. By analysis with histology, transmission electron microscopy and vital dye staining, glafenine-treated zebrafish showed evidence of endoplasmic reticulum and mitochondrial stress, with disrupted intestinal architecture and halted cell stress responses, alongside accumulation of apoptotic intestinal epithelial cells in the lumen. Although the early UPR marker BiP was induced with glafenine induced injury, downstream atf6 and s-xbp1 expression were paradoxically not increased, explaining the halted cell stress responses. The MU-opioid agonist DALDA protected against glafenine-induced injury through induction of atf6 dependent UPR. Our findings show that DALDA prevents glafenine-induced epithelial damage through induction of effective UPR. PMID- 22917924 TI - Timing and expression of the angiopoietin-1-Tie-2 pathway in murine lung development and congenital diaphragmatic hernia. AB - Congenital diaphragmatic hernia (CDH) is one of the most common congenital abnormalities. Children born with CDH suffer a number of co-morbidities, the most serious of which is respiratory insufficiency from a combination of alveolar hypoplasia and pulmonary vascular hypertension. All children born with CDH display some degree of pulmonary hypertension, the severity of which has been correlated with mortality. The molecular mechanisms responsible for the development of pulmonary hypertension in CDH remain poorly understood. Angiopoitein-1 (Ang-1), a central mediator in angiogenesis, participates in the vascular development of many tissues, including the lung. Although previous studies have demonstrated that Ang-1 might play an important role in the development of familial pulmonary hypertension, the role of Ang-1 in the development of the pulmonary hypertension associated with CDH is poorly understood. The aim of this study was to examine the role of the Ang-1 pathway in a murine model of CDH. Here, we report that Ang-1 appears important in normal murine lung development, and have established its tissue-level expression and localization patterns at key time-points. Additionally, our data from a nitrofen and bisdiamine-induced murine model of CDH suggests that altered expression patterns of Ang-1, its receptor Tie-2 and one of its transcription factors (epithelium-specific Ets transcription factor 1) might be responsible for development of the pulmonary vasculopathy seen in the setting of CDH. PMID- 22917925 TI - Osteopontin deficiency delays inflammatory infiltration and the onset of muscle regeneration in a mouse model of muscle injury. AB - Osteopontin is secreted by skeletal muscle myoblasts and stimulates their proliferation. Expression of osteopontin in skeletal muscle is upregulated in pathological conditions including Duchenne muscular dystrophy, and recent evidence suggests that osteopontin might influence the course of this disease. The current study was undertaken to determine whether osteopontin regulates skeletal muscle regeneration. A whole muscle autografting model of regeneration in osteopontin-null and wild-type mice was used. Osteopontin expression was found to be strongly upregulated in wild-type grafts during the initial degeneration and subsequent early regeneration phases that are observed in this model. Grafted muscle from osteopontin-null mice degenerated more slowly than that of wild-type mice, as determined by histological assessment, fibre diameter and fibre number. The delayed degeneration in osteopontin-null grafts was associated with a delay in neutrophil and macrophage infiltration. Centrally nucleated (regenerating) muscle fibres also appeared more slowly in osteopontin-null grafts than in wild type grafts. These results demonstrate that osteopontin plays a non-redundant role in muscle remodelling following injury. PMID- 22917926 TI - Creation and preliminary characterization of a Tp53 knockout rat. AB - The tumor suppressor TP53 plays a crucial role in cancer biology, and the TP53 gene is the most mutated gene in human cancer. Trp53 knockout mouse models have been widely used in cancer etiology studies and in search for a cure of cancer with some limitations that other model organisms might help overcome. Via pronuclear microinjection of zinc finger nucleases (ZFNs), we created a Tp53 knockout rat that contains an 11-bp deletion in exon 3, resulting in a frameshift and premature terminations in the open reading frame. In cohorts of 25 homozygous (Tp53(Delta11/Delta11)), 37 heterozygous (Tp53(Delta11/+)) and 30 wild-type rats, the Tp53(Delta11/Delta11) rats lived an average of 126 days before death or removal from study because of clinical signs of abnormality or formation of tumors. Half of Tp53(Delta11/+) were removed from study by 1 year of age because of tumor formation. Both Tp53(Delta11/+) and Tp53(Delta11/Delta11) rats developed a wide spectrum of tumors, most commonly sarcomas. Interestingly, there was a strikingly high incidence of brain lesions, especially in Tp53(Delta11/Delta11) animals. We believe that this mutant rat line will be useful in studying cancer types rarely observed in mice and in carcinogenicity assays for drug development. PMID- 22917927 TI - Loss of MMP-2 in murine osteoblasts upregulates osteopontin and bone sialoprotein expression in a circuit regulating bone homeostasis. AB - Multicentric osteolysis with arthropathy (MOA; MIM 605156) is an inherited osteolyses and arthritis syndrome resulting from loss of matrix metalloproteinase 2 (MMP-2). We recently demonstrated that Mmp2(-/-) mice represent a unique model for the study of the human disease, sharing many features of the human syndrome including skeletal dysplasia and defects in osteoblast behavior. We therefore sought to explore the secondary molecular effects of MMP-2 loss, which coexist with the underlying skeletal and osteoblast phenotypes. We used quantitative real time RT-PCR (qRT-PCR) to measure osteoblast-related gene expression through ex vivo osteoblast differentiation of bone marrow stromal cells (BMSC) from Mmp2(-/ ) and Mmp2(+/+) mice. We used western blot to measure osteopontin (OPN) serum levels and immunohistochemical staining to examine bone expression. MMP-2 expression was inhibited in SaOS2 cells using siRNA, and decreased MMP-2 expression at both RNA and protein levels was confirmed by qRT-PCR and western blot, respectively. Mmp2(-/-) BMSC induced to differentiate into osteoblasts were shown to significantly upregulate OPN and bone sialoprotein (BSP) expression levels compared with controls. Transcriptional upregulation was maintained in vivo, as demonstrated by increased levels of OPN in serum and bone in Mmp2(-/-) mice. These effects are generalizable because siRNA-mediated inhibition in cultured cells also upregulated OPN and BSP. OPN and BSP are known to affect MMP 2 expression and activity but have not previously been shown to be regulated by MMP-2. Identification of this newly defined circuitry provides insight into the potential molecular landscape underlying the MOA phenotype and highlights a pathway that might play a role in normal bone homeostasis. PMID- 22917929 TI - A strategy to implement and support pre-hospital emergency medical systems in developing, resource-constrained areas of South Africa. AB - Resource-constrained countries are in extreme need of pre-hospital emergency care systems. However, current popular strategies to provide pre-hospital emergency care are inappropriate for and beyond the means of a resource-constrained country, and so new ones are needed-ones that can both function in an under developed area's particular context and be done with the area's limited resources. In this study, we used a two-location pilot and consensus approach to develop a strategy to implement and support pre-hospital emergency care in one such developing, resource-constrained area: the Western Cape province of South Africa. Local community members are trained to be emergency first aid responders who can provide immediate, on-scene care until a Transporter can take the patient to the hospital. Management of the system is done through local Community Based Organizations, which can adapt the model to their communities as needed to ensure local appropriateness and feasibility. Within a community, the system is implemented in a graduated manner based on available resources, and is designed to not rely on the whole system being implemented first to provide partial function. The University of Cape Town's Division of Emergency Medicine and the Western Cape's provincial METRO EMS intend to follow this model, along with sharing it with other South African provinces. PMID- 22917930 TI - Humanised mice have functional human neutrophils. AB - The differences between murine and human neutrophils mean that findings in mice may not translate to humans, and therefore an in vivo model with human neutrophils would be an important methodological advance. We generated humanised mice by injecting human cord blood derived CD34+ stem cells into irradiated NOD scid-gammac(-/-) mice. At least 3 months after engraftment, treatment of mice with GCSF mobilised circulating human neutrophils, which comprised 2.6% of human leukocytes, and led to L-selectin shedding and upregulation of CD66b, CD11b and CD63. Subsequent in vivo LPS treatment led to further downregulation of L selectin with upregulation of CD66b and CD63, and also resulted in human neutrophil sequestration in the lungs. Furthermore, human neutrophils from these mice were capable of robust functional responses. They were shown to undergo a respiratory burst, and to degranulate with upregulation of CD63 and CD66b, in response to fMLP and Escherichia coli. These data show that functional human neutrophils develop from CD34+ cord blood stem cells in NOD-scid-gammac(-/-) mice. They suggest that this approach may facilitate the in vivo study of human neutrophils in clinically relevant models of infection and autoimmunity. PMID- 22917928 TI - A cell-based fascin bioassay identifies compounds with potential anti-metastasis or cognition-enhancing functions. AB - The actin-bundling protein fascin is a key mediator of tumor invasion and metastasis and its activity drives filopodia formation, cell-shape changes and cell migration. Small-molecule inhibitors of fascin block tumor metastasis in animal models. Conversely, fascin deficiency might underlie the pathogenesis of some developmental brain disorders. To identify fascin-pathway modulators we devised a cell-based assay for fascin function and used it in a bidirectional drug screen. The screen utilized cultured fascin-deficient mutant Drosophila neurons, whose neurite arbors manifest the 'filagree' phenotype. Taking a repurposing approach, we screened a library of 1040 known compounds, many of them FDA-approved drugs, for filagree modifiers. Based on scaffold distribution, molecular-fingerprint similarities, and chemical-space distribution, this library has high structural diversity, supporting its utility as a screening tool. We identified 34 fascin-pathway blockers (with potential anti-metastasis activity) and 48 fascin-pathway enhancers (with potential cognitive-enhancer activity). The structural diversity of the active compounds suggests multiple molecular targets. Comparisons of active and inactive compounds provided preliminary structure activity relationship information. The screen also revealed diverse neurotoxic effects of other drugs, notably the 'beads-on-a-string' defect, which is induced solely by statins. Statin-induced neurotoxicity is enhanced by fascin deficiency. In summary, we provide evidence that primary neuron culture using a genetic model organism can be valuable for early-stage drug discovery and developmental neurotoxicity testing. Furthermore, we propose that, given an appropriate assay for target-pathway function, bidirectional screening for brain-development disorders and invasive cancers represents an efficient, multipurpose strategy for drug discovery. PMID- 22917933 TI - Risk of osteomyelitis of the jaw induced by oral bisphosphonates in patients taking medications for osteoporosis: a hospital-based cohort study in Japan. AB - Oral bisphosphonates (BPs) represent the first line of prevention and treatment for osteoporosis. However, several studies have reported osteonecrosis of the jaw (ONJ), also known as osteomyelitis of the jaw (OMJ), as a side effect of these drugs. Although absolute risk is suggested to be low, information to date on the relative risk or attributable risk has in fact been limited. Here, we estimated risk of oral BPs for OMJ in osteoporosis patients taking oral BPs compared with other osteoporosis drugs. Using an electronic medical records retrieval system and manual confirmation of OMJ, we conducted a retrospective cohort study of patients taking medications for osteoporosis at Kyoto University Hospital between November 2000 and October 2010. To evaluate relative risks of oral BPs for OMJ, logistic regression analysis was performed and odds ratios (ORs) and 95% confidence interval (CIs) were estimated. In addition, sensitivity analyses were performed according to hierarchical diagnosis. A total of 4129 patients (59.6%) were prescribed BPs while 2794 (40.3%) received other osteoporosis drugs. Absolute risk for OMJ was estimated to range from 0.46% to 0.99% (95% CIs: 0.25 0.66 to 0.69-1.2) among patients receiving oral BPs and 0.071% to 0.17% (95% CIs: 0-0.17 to 0.022-0.33) among patients receiving other osteoporosis drugs. The attributable risks of oral BPs for OMJ were estimated to range from 0.38% to 0.81% (95% CIs: 0.38-0.39 to 0.80-0.81). ORs (95% CIs) adjusted for confounding factors were 5.0 (1.9-12.9) to 6.0 (1.3-26.1) for confirmed cases only. In terms of absolute and attributable risks, the risk of oral BPs for OMJ is considered to be less than 1% in patients with osteoporosis. However, oral BPs may increase the risk of OMJ compared with patients treated with other osteoporosis medications and the risk of side effects should be kept in mind. PMID- 22917932 TI - Local overexpression of GH and GH/IGF1 effects in the adult mouse hippocampus. AB - GH therapy improves hippocampal functions mainly via circulating IGF1. However, the roles of local GH and IGF1 expression are not well understood. We investigated whether transgenic (TG) overexpression in the adult brain of bovine GH (bGH) under the control of the glial fibrillary acidic protein (GFAP) promoter affected cellular proliferation and the expression of transcripts known to be induced by systemic GH in the hippocampus. Cellular proliferation was examined by 5-bromo-2'-deoxyuridine immunohistochemistry. Quantitative PCR and western blots were performed. Although robustly expressed, bGH-Tg did not increase either cell proliferation or survival. However, bGH-Tg modestly increased Igf1 and Gfap mRNAs, whereas other GH-associated transcripts were unaffected, i.e. the GH receptor (Ghr), IGF1 receptor (Igf1r), 2',3'-cyclic nucleotide 3' phosphodiesterase (Cnp), ionotropic glutamate receptor 2a (Nr2a (Grin2a)), opioid receptor delta (Dor), synapse-associated protein 90/postsynaptic density-95 associated protein (Sapap2 (Dlgap2)), haemoglobin beta (Hbb) and glutamine synthetase (Gs (Glul)). However, IGF1R was correlated with the expression of Dor, Nr2a, Sapap2, Gs and Gfap. In summary, although local bGH expression was robust, it activated local IGF1 very modestly, which is probably the reason for the low response of previous GH-associated response parameters. This would, in turn, indicate that hippocampal GH is less important than endocrine GH. However, as most transcripts were correlated with the expression of IGF1R, there is still a possibility for endogenous circulating or local GH to act via IGF1R signalling. Possible reasons for the relative bio-inactivity of bGH include the bell-shaped dose-response curve and cell-specific expression of bGH. PMID- 22917931 TI - A condensed performance-validation strategy for multiplex detection kits used in studies of human clinical samples. AB - Quantification of soluble phase analytes represents one of the most commonly used techniques applied to a broad range of samples in both basic and clinical immunology laboratories, as well as in context of drug development and diagnostic programs. The recent increase in the application of multiplex immunoassays, such as Luminex, has resulted in a growing array of commercially available multiplex kits. Validated, highly sensitive, and precise methods for such quantification is critical, especially when applied to precious sample collections. While vendors are expected to carry out kit performance validation, discrepancies between technical specifications provided with multiplex kits and their actual performance can be relatively common. Here we present a validation strategy that will aid users to select the optimal kits for their purpose and most validly interpret results from the multiplex assays. To illustrate key considerations when validating and comparing kits, we assess the performance of three conventional multiplex cytokine kits. Our findings confirm the importance of validating the performance of commercial multiplex kits and provide a practical and cost-effective approach that can be readily implemented in both academic and translational laboratory settings. PMID- 22917934 TI - The effect of procyanidine crosslinking on the properties of the electrospun gelatin membranes. AB - In this study, the effect of different crosslinkers including glutaraldehyde (GTA), genipin (GIP) and procyanidine (PA) on the properties of the electrospun gelatin membranes was compared. The water-resistant ability of the membranes could be significantly improved after being crosslinked with PA at T > 40 degrees C. In contrast with GTA and GIP, the PA-crosslinking process did not apparently affect the fibrous structure, and induced the lowest shrinkage of the membranes. At the concentration of 5% of PA, the ultimate tensile strength and elongation of the hydrated membrane were 0.87 MPa and 148%, respectively, which were higher than those of the GIP-crosslinked counterparts. In addition, the PA crosslinked membranes displayed the highest resistance to pepsin degradation, and fibroblast cells could migrate deeper into the interior of the membranes due to the good preservation of the fibrous structure during the cell culture process. PMID- 22917935 TI - Posterior reversible encephalopathy syndrome (PRES) after treatment with oxaliplatin and 5-fluorouracil. PMID- 22917936 TI - A multicentre prospective randomised study of single-incision mini-sling (Ajust(r)) versus tension-free vaginal tape-obturator (TVT-OTM) in the management of female stress urinary incontinence: pain profile and short-term outcomes. AB - OBJECTIVES: To compare the postoperative pain profile, peri-operative details, and short-term patient-reported and objective success rates of single-incision mini-slings (SIMS) versus standard mid-urethral slings (SMUS). STUDY DESIGN: In a multicentre prospective randomised trial in six UK centres in the period between October 2009 and October 2010, 137 women were randomised to either adjustable SIMS (Ajust(r), C. R. Bard Inc., NJ, USA), performed under local anaesthesia as an opt-out policy (n=69), or SMUS (TVT-OTM, Ethicon Inc., Somerville, USA) performed under general anaesthesia (n=68). Randomisation was done through number allocation software and using telephone randomisation. Postoperative pain profile (primary outcome) was assessed on a ten-point visual analogue scale at fixed time points. Pre- and post operatively (4-6 months) women completed symptom severity, urgency perception scale (UPS), quality of life and sexual function questionnaires. In addition, women completed a Patient Global Impression of Improvement Questionnaire and underwent a cough stress test at 4-6 months follow up. Sample size calculation was performed and data were analysed using SPSS 18. Descriptive analyses are given and between-group comparisons were performed using chi-square, Fischer exact test and Mann-Whitney test as appropriate. Significance level was set at 5%. RESULTS: Women in the SIMS Ajust(r) group had a significantly lower postoperative pain profile up to 4 weeks (p=<0.001, 95% CI 1.151, 2.480). There was no significant difference in peri-operative complications between groups. All 137 women completed the 4-6 months follow-up. Patient-reported and objective cure rates were not significantly different: 85.5% versus 91.2% (p=0.443) and 90% versus 97% (p=0.165) between the SIMS Ajust(r) and TVT-OTM groups respectively. There was a trend towards higher rates of de novo urgency or worsening of pre-existing urgency in the SIMS Ajust(r) group (21.7% versus 8.8%) but this did not reach statistical significance (p=0.063). Women in the SIMS Ajust(r) group had shorter hospital stay (median (IQR) 3.65 (2.49, 4.96)) compared to (4.42 (3.16, 5.56)) the TVT-OTM group 95% CI (-0.026, 1.326), with significantly earlier return to normal activities (p=0.025) and to work (p=0.006). CONCLUSION: The adjustable single-incision mini-sling (Ajust(r)) is associated with a significantly improved postoperative pain profile and earlier return to work when compared to standard mid-urethral slings (TVT-OTM), with encouraging results in patient-reported and objective success rates at short-term follow-up. PMID- 22917937 TI - Inadequate prenatal care and maternal country of birth: a retrospective study of southeast Spain. AB - OBJECTIVE: To quantify the association between the maternal country of birth and inadequacy in the use of prenatal care, and to identify factors that might explain this association. STUDY DESIGN: A retrospective case series was carried out in a public hospital in southern Spain, including 6873 women who delivered between 2005 and 2007. The maternal country of birth was categorised into four regional groups: Spain, Maghreb (north-west Africa), Eastern Europe and Others (non-Spain), while the use of prenatal care was quantified according to a modified Kotelchuck index: APNCU-1M and APNCU 2M. The effect of country of birth on inadequate prenatal care was analysed using a multiple logistic regression model designed to accommodate factors such as age, parity, previous miscarriages, and pre-gestational and gestational risks. Likelihood ratio tests were performed to assess any interactions. RESULTS: A significant association was found between maternal country of birth and inadequate prenatal care regardless of the index used. Under APNCU 1-M the strength of association was strongest for Eastern European origin (odds ratio (OR) 6.17, 95% confidence interval (CI) 5.2-7.32), followed by the Maghreb (OR: 5.58, 95% CI: 4.69-6.64). These associations remained virtually unchanged after adjusting for potential confounders. Interactions were observed between age and parity, with the highest risk of inadequacy seen among the Eastern European childbearing women over 34 years of age having 1-2 previous children (OR: 7.63, 95% CI: 3.65-15.92). CONCLUSION: Prenatal health care initiatives would benefit from the study of a larger number of variables to address the differences between different groups of women. We recommend the widespread use of standardised indices for the study of prenatal care utilisation. PMID- 22917938 TI - Oral immunogenicity of potato-derived antigens to Mycobacterium tuberculosis in mice. AB - The novel use of transgenic plants as vectors for the expression of viral and bacterial antigens has been increasingly tested as an alternative methodology for the production and delivery of experimental oral vaccines. Here, we examined the immunogenicity of combined plant-made vaccines that include four genes encoding immune-dominant antigens from Mycobacterium tuberculosis. Compared with the wild type and other control groups, mice treated with the combined plant-made vaccines showed significantly higher levels of interferon-gamma and interleukin-2 production in response to all four proteins, and higher levels of antigen specific CD4(+) and CD8(+) T-cell responses and immunoglobulin (Ig) G and IgA titers. These results suggest that combined plant-made vaccines can induce immunogenicity against M. tuberculosis through the induction of stronger Th1 associated immune responses. This is the first report of an orally delivered combined plant-made vaccine against tuberculosis priming an antigen-specific Th1 response, a comprehensive effect including both mucosal and systemic immune responses. PMID- 22917939 TI - Discriminant and convergent validity of TEMPS-A[P]. Correlation with Occupational Personality Questionnaire (OPQ32) during a stressful situation. AB - BACKGROUND: The Temperament Evaluation of the Memphis, Pisa, Paris and San Diego Questionnaire (TEMPS) has, in its self and rater-wise evaluation form, been designed to evaluate temperamental characteristics in clinical and non-clinical populations. METHODS: In this study we aim to extend the field of correlations of TEMPS to include the Occupational Personality Questionnaire, ipsative version (OPQ32i). These correlations, if present, could provide a partial contribute to the validation process of TEMPS, currently in progress in various countries. OPQ32 is a self-report personality questionnaire designed to give information on an individual's preferred behavior, as assessed in terms of a number of work related characteristics. In 921 applicants, who were competing to become cadets in the Italian Navy, we assessed, during the entrance examination, the correlations between TEMPS-A[P] and OPQ32i. RESULTS: Depressive temperament implies a low level of ability to relate to others; hyperthymic temperament implies high levels of feelings and emotions, and the capability to relate to people; cyclothymic temperament appears to be distinguished by creativity and a low level of relationships with others; irritable temperament partly overlaps with cyclothymic temperament, the main difference being the higher level of energy and the lower level of empathy of irritable subjects. CONCLUSIONS: The four affective temperaments, in our sample, proved to significantly differ in the work capacity features measured by OPQ32 factors. These observed correlations between the two tests partially contributes to the ongoing validation process of TEMPS-A[P]. From a personality standpoint this study further supports the hypothesis that temperaments belong to the realm of normality rather than that of pathology, in line with their putative adaptive role. PMID- 22917940 TI - Natural disasters and suicidal behaviours: a systematic literature review. AB - BACKGROUND: Various consequences including suicidal behaviours can arise in the aftermath of natural disasters. The aim of the present review was to systematically analyse the existing literature on the potential impact of natural disasters on suicidal behaviours. METHODS: A systematic search of English language articles indexed in electronic databases was conducted. The current review covers 42 papers containing empirical analyses of the relationship between natural disasters and suicidal behaviours. RESULTS: In total, 19 papers analysed suicide mortality and 23 non-fatal suicidal behaviours. The effects of earthquakes on suicidal behaviours are the most frequently studied among natural disasters (n=20), followed by hurricanes (n=11). Further, there were four papers about tsunamis, three about floods, three about heat waves and drought, and one investigating the effects of multiple natural disasters. The studies show different directions in suicide mortality following natural disasters. Nevertheless, there seems to be a drop in non-fatal suicidal behaviours in the initial post-disaster period, which has been referred to as the 'honeymoon' phase. A delayed increase in suicidal behaviours has been reported in some studies. However, other factors increasing the risk of suicidal behaviours after natural disasters have been reported, such as previous and current mental health problems. Furthermore, contributing factors, such as economic conditions, should also be considered. LIMITATIONS: The exclusion of non-English articles. CONCLUSIONS: In light of the various methodological limitations observed, there is a need for further studies using proper designs. Mental health and suicidal behaviours should continue to be monitored for several years after the disaster. PMID- 22917941 TI - Thermoluminescent dosimetry in veterinary diagnostic radiology. AB - This paper presents the results of Environmental and Personnel Dosimetry made in a radiology area of a veterinary hospital. Dosimetry was realized using thermoluminescent (TL) materials. Environmental Dosimetry results show that areas closer to the X-ray equipment are safe. Personnel Dosimetry shows important measurements of daily workday in some persons near to the limit established by ICRP. TL results of radiation measurement suggest TLDs are good candidates as a dosimeter to radiation dosimetry in veterinary radiology. PMID- 22917942 TI - Feasibility of EBT Gafchromic films for comparison exercises among standard beta radiation fields. AB - The feasibility of using radiochromic films to verify the metrological coherence among standard beta radiation fields was evaluated. Exercises were done between two Brazilian metrology laboratories in beta fields from (90)Sr/(90)Y, (85)Kr and (147)Pm radiation sources. Results showed that the radiochromic film was useful for field mapping aiming uniformity and alignment verification and it was not reliable for absorbed dose measurements only for (147)Pm beta field. PMID- 22917943 TI - A hydrophilic interaction liquid chromatography electrospray tandem mass spectrometry method for the simultaneous determination of gamma-hydroxybutyrate and its precursors in forensic whole blood. AB - A liquid-chromatography-tandem-mass-spectrometry method using pneumatically assisted electrospray ionisation (LC-ESI-MS/MS) was developed for the simultaneous determination of gamma-hydroxybutyric acid (GHB), gamma butyrolactone (GBL) and 1,4-butanediol (1,4-BD) in human ante-mortem and post mortem whole blood. The blood proteins were precipitated using a mixture of methanol and acetonitrile, and the extract was cleaned-up by passage through a polymeric strong cation exchange sorbent. Separation of the analytes and their structural isomers was obtained using a column with a zwitterionic stationary phase. Matrix-matched calibrants, combined with isotope dilution, were used for quantitative analysis. GHB was determined in both positive and negative ion modes. The relative intra-laboratory reproducibility standard deviations were better than 10% and 6% for blood samples at concentrations of 2 mg/L and 20-150 mg/L, respectively. The mean true extraction recoveries were 80% for GHB and greater than 90% for GBL and 1,4-BD at concentration levels of 20-50 mg/L. The limits of detection were approximately 0.5 mg/L for GHB and GBL, and 0.02 mg/L for 1,4-BD in ante-mortem blood. The corresponding lower limits of quantification were less than 1 mg/L for GHB and GBL, and less than 0.1 mg/L for 1,4-BD. GBL was unstable in whole blood freshly preserved with a sodium fluoride oxalate mixture, but the stability could be improved significantly by preservation with a sodium fluoride citrate EDTA mixture. PMID- 22917944 TI - Objective paper structure comparison: assessing comparison algorithms. AB - More than just being a substrate, paper can also provide evidence for the provenance of documents. An earlier paper described a method to compare paper structure, based on the Fourier power spectra of light transmission images. Good results were obtained by using the 2D correlation of images derived from the power spectra as a similarity score, but the method was very computationally intensive. Different comparison algorithms are evaluated in this paper, using information theoretical criteria. An angular invariant algorithm turned out to be as effective as the original one but 4 orders of magnitude faster, making the use of much larger databases possible. PMID- 22917945 TI - Potential explanations for control group benefit. AB - BACKGROUND: Estimating effectiveness of clinical interventions depends on detecting differences between the responses of intervention and control groups. The outcome, intervention, and moderating factors all may influence the between group change. The absence of a clinically or statistically meaningful difference may also result from control group improvement due to nonspecific factors such as participants' perception of attention, positive regard, expectations, desire to please, and therapeutic alliance with the care provider. PURPOSE: We examined perceived benefit and sources of benefit for control caregivers who participated in the CONNECT randomized controlled trial of a dementia caregiving intervention. METHODS: After the final scheduled data collection in CONNECT, control group participants were asked whether they believed they benefited from study participation. Those who reported benefit were asked to describe the benefit received. Data were analyzed qualitatively. RESULTS: Of 60 available control caregivers, 82% reported a perceived benefit from study participation in five areas: getting information about dementia and caregiving; having someone to talk to and feeling supported; receiving understanding and validation of feelings; knowledge that others were in similar situations; and perceived appreciation of own abilities. Control caregivers who reported benefit were less burdened and depressed and spent less time on duty at baseline than those who did not report benefit. From caregivers' responses, we have identified the assessment battery, both content and time spent in data collection, as a possible mechanism of action for benefit. LIMITATIONS: Study limitations include the better baseline characteristics of the control caregivers who reported benefit, the sample size of benefit control caregivers, the possibility of perceptions of benefit being a function of social desirability, and the lack of a similar question about benefit being asked of intervention caregivers. CONCLUSIONS: These findings suggest that the outcome assessment questionnaires used in this and similar trials may be an intervention of sorts for caregiver participants in the control group. Caregivers who are less distressed may benefit more from the attention provided during assessment. These findings underscore the importance of asking caregivers how they are doing. For researchers, there is a need to develop innovative ways to assess outcomes to avoid unintended benefit of assessments. PMID- 22917946 TI - Avoiding transport bottlenecks in an expanding root system: xylem vessel development in fibrous and pioneer roots under field conditions. AB - PREMISE OF THE STUDY: Root systems develop to effectively absorb water and nutrients and to rapidly transport these materials to the transpiring shoot. In woody plants, roots can be born with different functions: fibrous roots are primarily used for water and nutrient absorption, whereas pioneer roots have a greater role in transport. Because pioneer roots extend rapidly in the soil and typically quickly produce fibrous roots, they need to develop transport capacity rapidly so as to avoid becoming a bottleneck to the absorbed water of the developing fibrous roots and, as we hypothesized, immediately activate a specific type of autophagy at a precise time of their development. METHODS: Using microscopy techniques, we monitored xylem development in Populus trichocarpa roots in the first 7 d after emergence under field conditions. KEY RESULTS: Newly formed pioneer roots contained more primary xylem poles and had larger diameter tracheary elements than fibrous roots. While xylogenesis started later in pioneer roots than in fibrous, it was completed at the same time, resulting in functional vessels on the third to fourth day following root emergence. Programmed cell death was responsible for creating the water conducting capacity of xylem. Although the early xylogenesis processes were similar in fibrous and pioneer roots, secondary vascular development proceeded much more rapidly in pioneer roots. CONCLUSIONS: Compared to fibrous roots, rapid development of transport capacity in pioneer roots is not primarily caused by accelerated xylogenesis but by larger and more numerous tracheary elements and by rapid initiation of secondary growth. PMID- 22917947 TI - Effects of flood frequency and duration on the allometry of community-level stem size-density distributions in a floodplain forest. AB - PREMISE OF THE STUDY: Consistent with the self-thinning law of plant population ecology, Niklas et al. in 2003 proposed that stem size-density distributions (SDDs) of multispecies forest communities should change in very predictable ways as a function of the effects of past disturbances on average tree size. To date, empirical tests of this hypothesis have not been pursued in floodplain settings. METHODS: SDDs were constructed using tree stem-size and density data from forest plots positioned along a flood frequency and duration gradient in the Upper Mississippi River floodplain. KEY RESULTS: As flooding (both frequency and duration) increased, several small tree species were eliminated from forest plots and the persistent species increased in their size. Consistent with the predictions of Niklas et al., these changes corresponded with overall decreases in stem density, increases in average stem size, and reductions in both the Y intercept and slope terms of the community-level SDDs. CONCLUSIONS: This study adds to a growing list of examples suggesting that theories related to forest community composition and biomass must account for both the broader effects of disturbances as well as the underlying biochemical processes that regulate plant growth. Further study is needed to fully address the role different disturbance frequencies play in determining plant density, diversity, average size, and associated size?frequency distributions. PMID- 22917948 TI - Allocation tradeoffs among chaparral shrub seedlings with different life history types (Rhamnaceae). AB - PREMISE OF THE STUDY: California chaparral shrub species have different life history types: Nonsprouters (NS) are killed by fire and persist through a fire stimulated seed bank; facultative sprouters (FS) reestablish by a combination of vegetative sprouting and seeding; and obligate sprouters (OS) reestablish exclusively by sprouting. Nonsprouters and FS establish seedlings in open-canopy postfire environments, whereas OS establish seedlings between fires in the shady understory. We hypothesized that allocation differences among seedlings of postfire sprouters and nonsprouters and regeneration niche differences would lead to contrasting patterns in biomass accumulation (NS > FS > OS, in sun; OS > FS > NS, in shade). METHODS: Seedlings of three species from each life history type were grown in sun and 75% shade. We measured net carbon assimilation and biomass accumulation after one year. KEY RESULTS: Biomass accumulation was similar in the sun except FS>OS. In the shade, NS had lower biomass than FS and OS. Assimilation rates, nitrogen relations, and allocation differences could not fully explain biomass accumulation differences. Instead, biomass accumulation was inversely related to water-stress tolerance and shade tolerance. Additionally, OS and FS differed in root/shoot allocation even though both are sprouters. CONCLUSIONS: Seedling growth and carbon assimilation rates were divergent among three life history types and were consistent with differences in tolerance to water stress and shade or sun regeneration niches, but not tradeoffs in sprouting-related allocation differences per se. PMID- 22917949 TI - The function of intercellular spaces along the ray parenchyma in sapwood, intermediate wood, and heartwood of Cryptomeria japonica (Cupressaceae). AB - PREMISE OF THE STUDY: Intercellular spaces along ray parenchyma (ISRP) are common in many conifer xylems, but their function is uncertain because the in-situ structural network among ISRP, ray parenchyma, and tracheids has not been evaluated. Analysis of water distribution in ISRP from sapwood to heartwood is needed to elucidate the function of ISRP in sapwood, intermediate wood, and heartwood. METHODS: We used cryo-scanning electron microscopy, x-ray photography, and water content measurement in xylem to analyze the presence of liquids in ISRP, ray parenchyma, and tracheids from sapwood to heartwood in Cryptomeria japonica (Cupressaceae). KEY RESULTS: In sapwood, almost all ISRP were empty. "Cingulate-cavitated regions", which lose water along the tangential direction within one annual ring, formed in the earlywood tracheids, and their frequency increased toward the inner annual rings, whereas ray parenchyma cells were alive and not involved in the partial cavitation. In intermediate wood, almost all ISRP and earlywood tracheids and many of the ray cells were empty, and only some latewood tracheids retained liquid in their lumina. The ISRP were connected with tracheids via gas-filled ray parenchyma cells. CONCLUSIONS: The ISRP work as a pathway of gas for aspiration of ray parenchyma cells in sapwood. On the other hand, the occurrence of a gas network between ISRP, ray parenchyma, and tracheids facilitates cavitation of tracheids, resulting in the generation of low-moisture, intermediate wood. PMID- 22917950 TI - Empathy, schizophrenia and violence: a systematic review. AB - BACKGROUND: A small but significant association between schizophrenia and violence is open to a number of explanations. Impaired empathy has been associated with schizophrenia, and with violence in the general population. Our aim was to conduct a systematic review of any research into relationships between schizophrenia, empathy and violence. METHODS: The electronic databases Medline, Psychinfo, Embase, Cochrane and DARE were searched using combinations of terms for schizophrenia, empathy and violence, as were selected journals and reference lists of relevant articles. Selection of studies and data extraction was done by each of us, blind to the other. RESULTS: Six studies were identified, but sample selection, research procedures and empathy, illness and violence measures differed sufficiently between them that only descriptive analysis was possible. Apart from one single case study, sample sizes were between 24 (12 violent) and 116 (35 violent). A component of emotional empathy (emotion recognition) was measured in three of the studies, all of which showed some specific dysfunctional recognition related to violence. Cognitive empathy was measured in three studies, two linking impairments to violence and one not. Emotional responsiveness was measured in one study and no association with violence was found. CONCLUSION: Although evidence is inconclusive on empathy impairment as a mediator of violence by people with chronic psychosis, it's likely relevance is most apparent in the better controlled studies. Larger scale studies are indicated with rigorous control for comorbidities. PMID- 22917952 TI - Backyard hazard: a case series of ingested grill brush bristles and a novel approach to extraction. AB - OBJECTIVES: To report a small case series of an unusual ingested foreign body and a new method for removal of tongue base foreign bodies. METHODS: Three patients were identified with wire bristle foreign bodies between 2009 and 2011 at our academic tertiary medical center. Their medical records were reviewed and are described in this report. RESULTS: Each patient presented to our medical center with progressive pain after ingestion of barbecued food. For 2 patients, the metallic bristle foreign body was imbedded within the lingual tonsil. In these 2 cases, radiofrequency plasma ablation (coblation) assisted partial lingual tonsillectomy was performed to identify the foreign body. In a third case, the foreign body presented as a complex deep space neck abscess and an open trans cervical approach was required. CONCLUSION: While oropharyngeal and esophageal foreign bodies are common, there are only a few case reports describing this particular foreign body. The presentation of an imbedded wire grill brush bristle can be insidious. Persistent pain and foreign body sensation should be taken seriously in patients with a history of barbecue food ingestion. Intraoperatively, wire bristles can be difficult to localize and extract. Radiofrequency plasma assisted lingual tonsillectomy may be helpful for identifying and removing foreign bodies that are imbedded in the tongue base. Grill brushes should undergo stringent safety regulation, as ingested wire bristles are difficult to localize and remove and may cause significant morbidity. PMID- 22917951 TI - Unique topology of language processing brain network: a systems-level biomarker of schizophrenia. AB - OBJECTIVE: Schizophrenia is a severe and heritable brain disorder. Language impairment has been hypothesized to spur its onset and underlie the characteristic symptoms. In this study, we investigate whether altered topological pattern of the language processing brain network exists and could be a potential biomarker of schizophrenia. We hypothesized that both patients with schizophrenia and the genetic high risk population would show significantly weakened efficiencies of the network hubs for normal language processing, especially at left inferior frontal and bilateral temporal lobes. METHOD: Language task-based fMRI data from 21 patients with schizophrenia, 22 genetic high risk subjects and 36 controls were analyzed. Graph theoretic and post hoc analyses of the fMRI data, and correlations between the functional network features and scores of language tests were carried out. RESULTS: Compared to controls, patients with schizophrenia and the high risk subjects showed significantly weakened network hubs in left inferior frontal and right fusiform gyri. A unique topology of super active and intercommunicating network hubs at left fusiform gyrus and right inferior/middle frontal gyri, which were associated with the behavioral language impairment was found in the patient group, compared to the high risk and control groups. CONCLUSIONS: Aberrant systems-level topology of language processing network, especially significantly weakened network hubs in left inferior frontal and right fusiform gyri, may serve as a candidate biomarker of schizophrenia. Supported by existing findings, the hyperactive left fusiform gyrus communicating with right frontal lobe might be the key neurophysiological component causing hallucinations in schizophrenia. These findings provided a new systems-level diagnostic target for the disorder. PMID- 22917953 TI - Metastasis of untreated head and neck cancer to percutaneous gastrostomy tube exit sites. AB - BACKGROUND: Percutaneous endoscopic gastrostomy (PEG) has become a mainstay in providing enteral access for patients with obstructive head and neck tumors. PEG tube placement is considered safe and complications are infrequent. METHODS: A comprehensive review of the literature in MEDLINE (1962-2011) was performed. We report herein 3 new cases. RESULTS: The literature search revealed 43 previous cases. The interval between PEG placement and diagnosis of metastasis ranged from 1 to 24 months. CONCLUSIONS: Metastatic cancer should be considered in patients with head and neck cancer that have persistent, unexplained skin changes at PEG site, anemia, or guaiac positive stools without a clear etiology. The direct implantation of tumor cells through instrumentation is the most likely explanation, although hematogenous and/or lymphatic seeding is also a possibility. Our review of the literature and clinical experience indicate that the "pull" technique of PEG placement may directly implant tumor cells at the gastrostomy site. PMID- 22917954 TI - Very-long-chain 1,2- and 1,3-bifunctional compounds from the cuticular wax of Cosmos bipinnatus petals. AB - Four uncommon classes of very-long-chain compounds were identified and quantified in the petal wax of Cosmos bipinnatus (Asteraceae). The first two were homologous series of alkane 1,2-diols and 1,3-diols, both ranging from C20 to C26. The upper and lower petal surfaces contained 0.11 and 0.09 MUg/cm(2) of 1,2-diols, respectively. 1,3-Diols were present at quantities one order of magnitude less than the 1,2-diols. Both series had similar chain length distributions, with 6 20%, 59-73% and 20-31% of the C20, C22 and C24 diols, respectively. The other two compound classes were primary and secondary monoacetates of C20-C24 1,2-diols. The monoacetates had chain length profiles similar to the free 1,2-diols, and amounted to 0.04 and 0.09 MUg/cm(2) on the adaxial and abaxial sides, respectively. Methods were developed to minimize acyl migration during monoacetate isomer analyses. The ratios of diol 1-acetates to diol 2-acetates averaged close to 3:5, and thus opposite to the chemical equilibrium ratio of 7:3. PMID- 22917955 TI - Analysis of commercial proanthocyanidins. Part 3: the chemical composition of wattle (Acacia mearnsii) bark extract. AB - Wattle (Acacia mearnsii) bark extract is an important renewable industrial source of natural polymers for leather tanning and adhesive manufacturing. The wattle bark proanthocyanidin oligomers have 5-deoxy extender units that render the interflavanyl bonds resistant to acid catalysed hydrolysis and their composition cannot be determined via conventional thiolysis. We combined established phyto- and synthetic chemistry perspectives with an electrospray mass spectrometry investigation to establish that the flavan-3-ol based oligomers consist of a starter unit which is either catechin or gallocatechin, angularly bonded to fisetinidol or predominantly robinetinidol extender units. PMID- 22917956 TI - A case of the large retroperitoneal solitary fibrous tumor. AB - A rare autopsy case of the extremely large retroperitoneal solitary fibrous tumor is reported. A 52-year-old female with a huge abdominal distention was found dead at home. She showed remarkable emaciation. The autopsy revealed a huge retroperitoneal tumor weighing 11.9kg (36*30*20cm in size), which occupied the entire intraperitoneal cavity. Histologically, the tumor consisted of spindle parenchymal cells with fibrous tissues. Immunohistochemically, CD34 was positively stained, whereas S-100, smooth muscle actin, and factor VIII were negative. Her cause of death was diagnosed as emaciation due to the compression of the entire intestine by the tumor. This is a rare case of the extremely large retroperitoneal solitary fibrous tumor, which caused the occasional intestinal obstruction. This disease should be considered in the differential diagnosis of retroperitoneal large tumors that cause accidental deaths in forensic autopsies. PMID- 22917957 TI - WHO recommendations for the viruses to be used in the 2012 Southern Hemisphere Influenza Vaccine: epidemiology, antigenic and genetic characteristics of influenza A(H1N1)pdm09, A(H3N2) and B influenza viruses collected from February to September 2011. AB - In February and September each year the World Health Organisation (WHO) recommends influenza viruses to be included in influenza vaccines for the forthcoming winters in the Northern and Southern Hemispheres respectively. These recommendations are based on data collected by National Influenza Centres (NIC) through the Global Influenza Surveillance and Response System (GISRS) and a more detailed analysis of representative and potential antigenically variant influenza viruses from the WHO Collaborating Centres for Influenza (WHO CCs) and Essential Regulatory Laboratories (ERLs). This article provides a detailed summary of the antigenic and genetic properties of viruses and additional background data used by WHO experts during development of the recommendations for the 2012 Southern Hemisphere influenza vaccine composition. PMID- 22917958 TI - A new behavioural apparatus to reduce animal numbers in multiple types of spontaneous object recognition paradigms in rats. AB - Standard object recognition procedures assess animals' memory through their spontaneous exploration of novel objects or novel configurations of objects with other aspects of their environment. Such tasks are widely used in memory research, but also in pharmaceutical companies screening new drug treatments. However, behaviour in these tasks may be driven by influences other than novelty such as stress from handling which can subsequently influence performance. This extra-experimental variance means that large numbers of animals are required to maintain power. In addition, accumulation of data is time consuming as animals typically perform only one trial per day. The present study aimed to explore how effectively recognition memory could be tested with a new continual trials apparatus which allows for multiple trials within a session and reduced handling stress through combining features of delayed nonmatching-to-sample and spontaneous object recognition tasks. In this apparatus Lister hooded rats displayed performance significantly above chance levels in object recognition tasks (Experiments 1 and 2) and in tasks of object-location (Experiment 3) and object-in-context memory (Experiment 4) with data from only five animals or fewer per experimental group. The findings indicated that the results were comparable to those of previous reports in the literature and maintained statistical power whilst using less than a third of the number of animals typically used in spontaneous recognition paradigms. Overall, the results highlight the potential benefit of the continual trials apparatus to reduce the number of animals used in recognition memory tasks. PMID- 22917959 TI - Different distribution patterns of lymphocytes and microglia in the hippocampus of patients with residual versus paranoid schizophrenia: further evidence for disease course-related immune alterations? AB - Certain cytokines have been identified in the peripheral blood as trait markers of schizophrenia, while others are considered relapse-related state markers. Furthermore, data from peripheral blood, cerebrospinal fluid (CSF) and nuclear imaging studies suggest that (1) blood-brain barrier (BBB) dysfunction (e.g., immigration of lymphocytes into brain tissue and intrathecal antibody production) correlates with the development of negative symptoms, while (2) the brain's mononuclear phagocyte system (microglial cells) is activated during acute psychosis. Based on these neuroinflammatory hypotheses, we have quantified the numerical density of immunostained CD3+ T-lymphocytes, CD20+ B-lymphocytes, and HLA-DR+ microglial cells in the posterior hippocampus of 17 schizophrenia patients and 11 matched controls. Disease course-related immune alterations were considered by a separate analysis of residual (prevailing negative symptoms, n=7) and paranoid (prominent positive symptoms, n=10) schizophrenia cases. Higher densities of CD3+ and CD20+ lymphocytes were observed in residual versus paranoid schizophrenia (CD 3: left: P=0.047, right: P=0.038; CD20: left: P=0.020, right: P=0.010) and controls (CD3: left: P=0.057, right: P=0.069; CD20: left: P=0.008, right: P=0.006). In contrast, HLA-DR+ microglia were increased in paranoid schizophrenia versus residual schizophrenia (left: P=0.030, right: P=0.012). A similar trend emerged when this group was compared to controls (left: P=0.090, right: P=0.090). BBB impairment and infiltration of T cells and B cells may contribute to the pathophysiology of residual schizophrenia, while microglial activation seems to play a role in paranoid schizophrenia. The identification of diverse immune endophenotypes may facilitate the development of distinct anti inflammatory schizophrenia therapies to normalize BBB function, (auto)antibody production or microglial activity. PMID- 22917961 TI - Genetic polymorphism of methylenetetrahydrofolate reductase and risk of aggressive behaviour in schizophrenia. PMID- 22917960 TI - Relationship of defense styles with history of childhood trauma and personality in heroin dependent inpatients. AB - In the present study the defense styles were assessed in heroin dependent inpatients to verify whether they used less adaptive defense mechanisms compared to healthy controls and to evaluate if immature defense styles are related with childhood traumas, while controlling the effect of age, temperament and character on this relationship in male heroin dependent inpatients. Participants were consecutively admitted 109 male heroin dependent inpatients and 60 healthy controls. Patients were investigated with the Defense Style Questionnaire, the Childhood Trauma Questionnaire, and Temperament and Character Inventory. Heroin dependent patients were using immature defense style more, particularly acting out and splitting, than the control group. Together with lower age, immature defense style discriminated heroin dependents from control group (lower age, and higher devaluation and splitting in second regression model). Lower physical neglect score was related with a mature defense style, whereas higher cooperativeness (C) and self-transcendence (ST) were related with a neurotic defense style and lower reward dependence (RD), self-directedness (SD) and higher ST and emotional abuse were related with immature defense style. These suggest that heroin dependents are using maladaptive immature defense styles more, which can be taken into account in the development of therapeutic programs for these patients. Also, immature defense style may mediate the relationship between childhood emotional abuse and some personality dimensions (lower RD, SD and higher ST) in heroin dependent inpatients. PMID- 22917962 TI - Multiscale characterization of a chimeric biomimetic polypeptide for stem cell culture. AB - Mesenchymal stem cells have attracted great interest in the field of tissue engineering and regenerative medicine because of their multipotentiality and relative ease of isolation from adult tissues. The medical application of this cellular system requires the inclusion in a growth and delivery scaffold that is crucial for the clinical effectiveness of the therapy. In particular, the ideal scaffolding material should have the needed porosity and mechanical strength to allow a good integration with the surrounding tissues, but it should also assure high biocompatibility and full resorbability. For such a purpose, protein inspired biomaterials and, in particular, elastomeric-derived polypeptides are playing a major role, in which they are expected to fulfil many of the biological and mechanical requirements. A specific chimeric protein, designed starting from elastin, resilin and collagen sequences, was characterized over different length scales. Single-molecule mechanics, aggregation properties and compatibility with human mesenchymal stem cells were tested, showing that the engineered compound is a good candidate as a stem cell scaffold to be used in tissue engineering applications. PMID- 22917963 TI - Larynx-sparing techniques using intensity-modulated radiation therapy for oropharyngeal cancer. AB - The purpose of the current study was to explore whether the laryngeal dose can be reduced by using 2 intensity-modulated radiation therapy (IMRT) techniques: whole neck field IMRT technique (WF-IMRT) vs. junctioned IMRT (J-IMRT). The effect on planning target volumes (PTVs) coverage and laryngeal sparing was evaluated. WF IMRT technique consisted of a single IMRT plan, including the primary tumor and the superior and inferior neck to the level of the clavicular heads. The larynx was defined as an organ at risk extending superiorly to cover the arytenoid cartilages and inferiorly to include the cricoid cartilage. The J-IMRT technique consisted of an IMRT plan for the primary tumor and the superior neck, matched to conventional antero-posterior opposing lower neck fields at the level of the thyroid notch. A central block was used for the anterior lower neck field at the level of the larynx to restrict the dose to the larynx. Ten oropharyngeal cancer cases were analyzed. Both the primary site and bilateral regional lymphatics were included in the radiotherapy targets. The averaged V95 for the PTV57.6 was 99.2% for the WF-IMRT technique compared with 97.4% (p = 0.02) for J-IMRT. The averaged V95 for the PTV64 was 99.9% for the WF-IMRT technique compared with 98.9% (p = 0.02) for J-IMRT and the averaged V95 for the PT70 was 100.0% for WF-IMRT technique compared with 99.5% (p = 0.04) for J-IMRT. The averaged mean laryngeal dose was 18 Gy with both techniques. The averaged mean doses within the matchline volumes were 69.3 Gy for WF-MRT and 66.2 Gy for J-IMRT (p = 0.03). The WF-IMRT technique appears to offer an optimal coverage of the target volumes and a mean dose to the larynx similar with J-IMRT and should be further evaluated in clinical trials. PMID- 22917964 TI - Delivery quality assurance with ArcCHECK. AB - Radiation therapy requires delivery quality assurance (DQA) to ensure that treatment is accurate and closely follows the plan. We report our experience with the ArcCHECK phantom and investigate its potential optimization for the DQA process. One-hundred seventy DQA plans from 84 patients were studied. Plans were classified into 2 groups: those with the target situated on the diodes of the ArcCHECK (D plans) and those with the target situated at the center (C plans). Gamma pass rates for 8 target sites were examined. The parameters used to analyze the data included 3%/3 mm with the Van Dyk percent difference criteria (VD) on, 3%/3 mm with the VD off, 2%/2 mm with the VD on, and x/3 mm with the VD on and the percentage dosimetric agreement "x" for diode plans adjusted. D plans typically displayed maximum planned dose (MPD) on the cylindrical surface containing ArcCHECK diodes than center plans, resulting in inflated gamma pass rates. When this was taken into account by adjusting the percentage dosimetric agreement, C plans outperformed D plans by an average of 3.5%. ArcCHECK can streamline the DQA process, consuming less time and resources than radiographic films. It is unnecessary to generate 2 DQA plans for each patient; a single center plan will suffice. Six of 8 target sites consistently displayed pass rates well within our acceptance criteria; the lesser performance of head and neck and spinal sites can be attributed to marginally lower doses and increased high gradient of plans. PMID- 22917965 TI - Micro-cubic monolithic carbon cryogel electrode for direct electron transfer reaction of fructose dehydrogenase. AB - Micro-cubic monolithic carbon cryogel (CCG) electrode was fabricated for the electrochemical fructose dehydrogenase (FDH) reaction. The CCG can adsorb a sufficient amount of FDH even inside the CCG structure. FDH inside the CCG worked well as an electrocatalyst for d-fructose oxidation. An extremely high catalytic current density as large as 0.6A/cm(3) was achieved under stirring condition. PMID- 22917966 TI - Preventing belt restraint use in newly admitted residents in nursing homes: a quasi-experimental study. AB - BACKGROUND: Physical restraints are commonly used in psychogeriatric nursing home residents despite reports of negative consequences. Most research has focused on restraint reduction without addressing methods to prevent initiation of restraints in nursing homes. EXBELT has been found to decrease belt restraint use but should also be evaluated for its use in preventing restraints. OBJECTIVE: To investigate the effectiveness of the EXBELT intervention to prevent the use of belt restraints on psychogeriatric residents newly admitted to nursing homes. DESIGN: Quasi-experimental study design. SETTING: Twenty-six nursing home wards from thirteen Dutch nursing homes. PARTICIPANTS: Newly admitted residents (n=104) during a four month period. INTERVENTIONS: Fifteen wards (intervention group) implemented the EXBELT intervention, which consisted of four components: a policy change, education, consultation and the availability of alternative interventions. METHODS: Data on the use of belt restraints, other types of physical restraints, falls and fall-related injuries and psychoactive drug use were collected at T2 (4 months) and T3 (8 months) after baseline (T1) for those resident who were newly admitted after baseline and before T2 (4 months). Physical restraint use data were collected by a trained, blinded observer four times during a 24-h period. RESULTS: A total of 104 residents were newly admitted after baseline (T1) and before T2. Of those, 82 were present on T2 and T3. Informed consent was obtained from legal representatives of 49 out of the 82 residents. In the control group (n=20), 15% and 20% used belts at T2 (4 months) and T3 (8 months), respectively. In the intervention group (n=29), these proportions were 3% and 0%, respectively (OR=0.08; 95% CI (0.01-0.76); p=0.03). There was no increase in the intervention group in the use of other physical restraints, falls and fall-related injuries or psychoactive drug use. CONCLUSION: The EXBELT intervention effectively seems to prevent the use of belt restraints in newly admitted residents in psychogeriatric nursing homes. PMID- 22917967 TI - Moderate exercise training modulates cytokine profile and sleep in elderly people. AB - Aging causes several physiological alterations, including alterations in sleep. It is possible that difficulty sleeping can be exacerbated by increased inflammation in older individuals. Moderate exercise training may be a modality of non-pharmacological treatment for sleep disorders and inflammation. We aimed to assess the effects of moderate exercise training on sleep in elderly people as well as their cytokine profiles. Additionally, we examined the effect of exercise training on quality of life parameters using a SF-36 questionnaire. Twenty-two male, sedentary, healthy, elderly volunteers performed moderate training for 60 min/day, 3 days/week for 24 week at a work rate equivalent to their ventilatory aerobic threshold. The environment was kept at a temperature of 23 +/- 2 degrees C, with a humidity of 60 +/- 5%. Blood and polysomnograph were collected twice: at baseline (1 week before training began) and after 6 months of training. Training increased aerobic capacity parameters (p<0.0001), decreased REM latency (p<0.02), and decreased time awake (p<0.05). After training, the levels of IL-6 (p<0.0001) and TNF-alpha (p<0.0001) and the ratio of TNF-alpha/IL-10 (p<0.0001) were decreased, whereas IL-10 levels were increased after training (p<0.001). Furthermore, exercise training was shown to improve quality of life parameters. Our results suggest that 6 months of training can improve sleep in the elderly and is related to the anti-inflammatory effect of moderate training, which modifies cytokine profiles. PMID- 22917968 TI - Regulation of pro-inflammatory cytokines TNFalpha and IL24 by microRNA-203 in primary keratinocytes. AB - Cutaneous homeostasis and innate immunity is procured by a complex circuitry of intercellular cytokine signaling. MicroRNAs are important posttranscriptional regulators of keratinocyte gene expression and assist in modulating the fine balance between cell proliferation and differentiation in skin. A characteristic microRNA profile in inflammatory skin suggests putative functions of microRNAs in perturbed cytokine production and signaling during chronic inflammatory skin conditions such as psoriasis. It remains unclear, however, why certain microRNAs are aberrantly expressed during skin inflammation and if they serve pro- and/or anti-inflammatory functions. In this report, we focus on cytokine regulation by microRNA-203 (miR-203), which is highly abundant in keratinocytes and upregulated in psoriatic lesions. By screening a panel of cytokines that are upregulated in psoriatic skin for regulation by miR-203, we identify the genes encoding the pro inflammatory cytokines TNFalpha and IL24 as direct targets of miR-203. Studies of miR-203 overexpression, inhibition, and mutagenesis validate posttranscriptional regulation of TNFalpha and IL24 by miR-203 in cell lines and primary keratinocytes. Our findings suggest that miR-203 serves to fine-tune cytokine signaling and may dampen skin immune responses by repressing key pro-inflammatory cytokines. PMID- 22917969 TI - Author's reply: pulmonary hypertension in mitochondrial disorders. PMID- 22917970 TI - Structural basis for ASPP2 recognition by the tumor suppressor p73. AB - Tumor suppressors p53, p63 and p73 comprise a family of stress-responsive transcription factors with distinct functions in development and tumor suppression. Most human cancers lose p53 function, yet all three proteins are capable of inducing apoptosis or cellular senescence. Mechanisms are therefore under investigation to activate p73-dependent apoptosis in p53-deficient cancer cells. Significantly, the DNA-binding domain (DBD) of p73 escapes viral oncoproteins and displays an enhanced thermal stability. To further understand the variant features of p73, we solved the high-resolution crystal structure of the p73 DBD as well as its complex with the ankyrin repeat and SH3 domains of the pro-apoptotic factor ASPP2. The p73 structure exhibits the same conserved architecture as p53 but displays a divergent L2 loop, a known site of protein protein interaction. The loop in p73 is changed by a two-residue insertion that also induces repacking around the site of the p53 mutational hotspot R175. Importantly, the binding of ASPP2 is preserved by conformational changes in both the ankyrin repeat and SH3 domains. These results further highlight the structural variation that impacts p53 family interactions within the p53 interactome. PMID- 22917971 TI - Protein folding: adding a nucleus to guide helix docking reduces landscape roughness. AB - The elongated three-helix-bundle spectrin domains R16 and R17 fold and unfold unusually slowly over a rough energy landscape, in contrast to the homologue R15, which folds fast over a much smoother, more typical landscape. R15 folds via a nucleation-condensation mechanism that guides the docking of the A and C-helices. However, in R16 and R17, the secondary structure forms first and the two helices must then dock in the correct register. Here, we use variants of R16 and R17 to demonstrate that substitution of just five key residues is sufficient to alter the folding mechanism and reduce the landscape roughness. We suggest that, by providing access to an alternative, faster, folding route over their landscape, R16 and R17 can circumvent their slow, frustrated wild-type folding mechanism. PMID- 22917972 TI - Paternal uniparental disomy 14 and related disorders: placental gene expression analyses and histological examinations. AB - Although recent studies in patients with paternal uniparental disomy 14 [upd(14)pat] and other conditions affecting the chromosome 14q32.2 imprinted region have successfully identified underlying epigenetic factors involved in the development of upd(14)pat phenotype, several matters, including regulatory mechanism(s) for RTL1 expression, imprinting status of DIO3 and placental histological characteristics, remain to be elucidated. We therefore performed molecular studies using fresh placental samples from two patients with upd(14)pat. We observed that RTL1 expression level was about five times higher in the placental samples of the two patients than in control placental samples, whereas DIO3 expression level was similar between the placental samples of the two patients and the control placental samples. We next performed histological studies using the above fresh placental samples and formalin-fixed and paraffin embedded placental samples obtained from a patient with a maternally derived microdeletion involving DLK1, the-IG-DMR, the MEG3-DMR and MEG3. Terminal villi were associated with swollen vascular endothelial cells and hypertrophic pericytes, together with narrowed capillary lumens. DLK1, RTL1 and DIO3 proteins were specifically identified in vascular endothelial cells and pericytes, and the degree of protein staining was well correlated with the expression dosage of corresponding genes. These results suggest that RTL1as-encoded microRNA functions as a repressor of RTL1 expression, and argue against DIO3 being a paternally expressed gene. Furthermore, it is inferred that DLK1, DIO3 and, specially, RTL1 proteins, play a pivotal role in the development of vascular endothelial cells and pericytes. PMID- 22917973 TI - Comparison of bioequivalence study regulatory requirements for human and veterinary drugs. AB - Guidelines published by the European Union Regulatory Authority, regarding the planning of bioequivalence studies, are the primary source of knowledge about the study design optimization. The goal of this paper is to compare the key elements (27 points) of bioequivalence study optimization based on a comparison of the two European Medicines Agency guidelines relating to medicines used for humans (HB) and to veterinary drugs (AB). In case of the latter, one can get the impression that the issues of species differences in relation to the physiology and anatomy have been completely ignored. Many details that the AB guideline omits are included in the new HB guideline and were present in many other guidelines from the last 20 years. Most have not been adopted by the AB document, even though they are the product of many years of work of many teams and specialists from various agencies in the regulatory affairs field. PMID- 22917974 TI - Acute care observations: can we turn a lemon into lemonade? PMID- 22917975 TI - Reactive oxygen species contribute to the promotion of the ATP-mediated proliferation of mouse skeletal myoblasts. AB - Reactive oxygen species (ROS) and extracellular adenosine 5'-triphosphate (ATP) participate in autocrine and paracrine regulation in skeletal muscle. However, the link between these two signaling systems is not well established. Here, we studied cell proliferation as a possible consequence of the trophic effect of ATP in cultured skeletal mouse myoblasts and we tested the possibility that low concentrations of ROS represent the intermediate signaling molecule mediating this effect. Exposure to 10 MUM ATP increased proliferation of mouse myoblasts by ~20%. ATP also induced intracellular Ca(2+) oscillations, which were independent of extracellular Ca(2+). Both effects of ATP were prevented by suramin, a broad spectrum purinergic P2 receptor antagonist. In contrast, the adenosine receptor blocker CGS-15943 did not modify the ATP-mediated effects. Consistent with this, adenosine per se did not change myoblast growth, indicating the direct action of ATP via P2 receptor activation. The proliferative effect of ATP was prevented after depletion of hydrogen peroxide (H(2)O(2)) by the peroxidase enzyme catalase. Low-micromolar concentrations of exogenous H(2)O(2) mimicked the stimulatory effect of ATP on myoblast growth. DCF imaging revealed ATP-induced catalase and DPI-sensitive ROS production in myoblasts. In conclusion, our results indicate that extracellular ATP controls mouse myoblast proliferation via induction of ROS generation. PMID- 22917976 TI - Photobiomodulation by low-power laser irradiation attenuates Abeta-induced cell apoptosis through the Akt/GSK3beta/beta-catenin pathway. AB - Apoptosis induced by amyloid beta peptide (Abeta) is thought to associate with the pathogenesis of Alzheimer disease (AD). Accumulating evidence shows that low power laser irradiation (LPLI) is capable of reducing Abeta-induced apoptosis. However, the underlying mechanisms remain unclear. In this study, we report a novel molecular mechanism by which LPLI attenuates Abeta(25-35)-induced apoptosis through the Akt/GSK3beta/beta-catenin pathway. We found that Akt activated by LPLI interacted with GSK3beta and phosphorylated it on Ser9 in the presence of Abeta(25-35), which resulted in the inhibition of GSK3beta. Furthermore, LPLI increased the nuclear translocation of beta-catenin and enhanced its T cell factor/lymphocyte enhancer factor-dependent transcriptional activity via the Akt/GSK3beta pathway to promote cell survival upon treatment with Abeta(25-35.) Our data demonstrate that LPLI has a prosurvival effect on Abeta-induced apoptosis and may be an effective therapeutic strategy in treating AD by targeting GSK3beta. PMID- 22917977 TI - Administration of nitrite after chlorine gas exposure prevents lung injury: effect of administration modality. AB - Cl(2) gas toxicity is complex and occurs during and after exposure, leading to acute lung injury (ALI) and reactive airway syndrome (RAS). Moreover, Cl(2) exposure can occur in diverse situations encompassing mass casualty scenarios, highlighting the need for postexposure therapies that are efficacious and amenable to rapid and easy administration. In this study, we assessed the efficacy of a single dose of nitrite (1 mg/kg) to decrease ALI when administered to rats via intraperitoneal (ip) or intramuscular (im) injection 30 min after Cl(2) exposure. Exposure of rats to Cl(2) gas (400 ppm, 30 min) significantly increased ALI and caused RAS 6-24h postexposure as indexed by BAL sampling of lung surface protein and polymorphonucleocytes (PMNs) and increased airway resistance and elastance before and after methacholine challenge. Intraperitoneal nitrite decreased Cl(2)-dependent increases in BAL protein but not PMNs. In contrast im nitrite decreased BAL PMN levels without decreasing BAL protein in a xanthine oxidoreductase-dependent manner. Histological evaluation of airways 6h postexposure showed significant bronchial epithelium exfoliation and inflammatory injury in Cl(2)-exposed rats. Both ip and im nitrite improved airway histology compared to Cl(2) gas alone, but more coverage of the airway by cuboidal or columnar epithelium was observed with im compared to ip nitrite. Airways were rendered more sensitive to methacholine-induced resistance and elastance after Cl(2) gas exposure. Interestingly, im nitrite, but not ip nitrite, significantly decreased airway sensitivity to methacholine challenge. Further evaluation and comparison of im and ip therapy showed a twofold increase in circulating nitrite levels with the former, which was associated with reversal of post-Cl(2) exposure dependent increases in circulating leukocytes. Halving the im nitrite dose resulted in no effect in PMN accumulation but significant reduction of BAL protein levels, indicating a distinct nitrite dose dependence for inhibition of Cl(2)-dependent lung permeability and inflammation. These data highlight the potential for nitrite as a postexposure therapeutic for Cl(2) gas-induced lung injury and also suggest that administration modality is a key consideration in nitrite therapeutics. PMID- 22917978 TI - Schisandrin B exhibits anti-inflammatory activity through modulation of the redox sensitive transcription factors Nrf2 and NF-kappaB. AB - Schisandrin B (SB), a dibenzocyclooctadiene derivative isolated from Schisandra chinensis and used commonly in traditional Chinese medicine for the treatment of hepatitis and myocardial disorders, has been recently shown to modulate cellular redox balance. Since we have shown that cellular redox plays an important role in the modulation of immune responses, the present studies were undertaken to study the effects of SB on activation and effector functions of lymphocytes. SB altered the redox status of lymphocytes by enhancing the basal reactive oxygen species levels and altering the GSH/GSSG ratio in lymphocytes. It also induced nuclear translocation of redox sensitive transcription factor Nrf2 and increased the transcription of its dependent genes. SB inhibited mitogen-induced proliferation and cytokine secretion by lymphocytes. SB also significantly inhibited mitogen induced upregulation of T cell costimulatory molecules and activation markers. It was observed that SB inhibited mitogen-induced phosphorylation of c-Raf, MEK, ERK, JNK, and p38. It suppressed IkappaBalpha degradation and nuclear translocation of NF-kappaB in activated lymphocytes. Anti-inflammatory effects of SB were significantly abrogated by the inhibitors of Nrf2 and HO-1, suggesting the involvement of this pathway. Similar anti-inflammatory effects of SB on lymphocyte proliferation and cytokine secretion were also observed in vivo. To our knowledge, this is the first report showing that the anti-inflammatory effects of SB are mediated via modulation of Nrf2 and NF-kappaB in lymphocytes. PMID- 22917979 TI - A molecular model of the enantioselective liquid chromatographic separation of (R,S)-ifosfamide and its N-dechloroethylated metabolites on a teicoplanin aglycon chiral stationary phase. AB - The enantioselective separations of the chiral oxazaphosphorines (R,S)-ifosfamide (IF), (R,S)-2-N-dechloroethyl-IF (2-DCE-IF) and (R,S)-3-N-dechloroethyl-IF (3-DCE IF) were achieved on teicoplanin-based chiral stationary phase using isopropanol:methanol (60:40, v/v) as the mobile phase. Computational models of the teicoplanin and teicoplanin aglycon (TAG) chiral selectors were constructed and used in docking experiments to examine the chiral recognition mechanism associated with the observed resolutions. Initial data showed no significant differences between the simulated selector-selectand complexes using teicoplanin and TAG, and the full study was conducted using TAG. The data from the study indicate that hydrophobic interactions arise between the chlorine atom present in the cholorethyl moieties of the oxazaphosphorine molecules and hydrophobic pockets within the TAG basket and that these interactions anchored and positioned the selectands within the selector-selectand complexes. The complexes were stabilized through the formation of a network of hydrogen bond and cation-pi interactions, in which the latter involved the phosphorous atom of the phosphoramide moiety and aromatic components of the TAG aglycon basket. The chirality of the oxazaphosphorine molecule determined the number and strength of the stabilizing interactions which resulted in significant differences in the relative mean binding energies between the complexes formed by the (R) and (S) enantiomers of the selectands. These differences were consistent with the observed chromatographic enantioselectivity and suggest a multi-step chrial recognition mechanism involving the tethering of the selectand to the selector followed by conformational adjustments and stabilization of the selectand selector complex. PMID- 22917980 TI - Mechanistic investigations of cinchona alkaloid-based zwitterionic chiral stationary phases. AB - Novel zwitterionic cinchona alkaloid-based chiral selectors (SOs) were synthesized and immobilized on silica gel. The corresponding brush-type chiral stationary phases (CSPs) were characterized as zwitterionic ion-exchange-type materials and exhibited remarkable enantioselectivity for their zwitterionic target analytes, viz. underivatized amino acids and aminosulfonic acids. We rationally designed structural modifications on the strong cation exchange (SCX) subunit of the zwitterionic SO and investigated the influence on chiral recognition power for amphoteric solutes. SOs with chiral isopropyl- or cyclohexyl-moieties in vicinity to the SCX site showed broadest application range by baseline resolving 39 out of 53 test compounds, including alpha-, beta-, and gamma-amino acids with different substitution patterns. Furthermore, we introduced two pseudoenantiomeric zwitterionic CSPs which combined the unique features of providing comparable enantioselectivities but reversed enantiomer elution orders. By application of slightly acidic polar organic mobile phases as preferred elution mode, we found that certain amounts of aprotic acetonitrile in protic methanol substantially increased enantioselectivity and resolution of amino acids in a structure-dependent manner. PMID- 22917981 TI - Quantitative determination of several toxicological important mycotoxins in pig plasma using multi-mycotoxin and analyte-specific high performance liquid chromatography-tandem mass spectrometric methods. AB - A sensitive and reliable multi-mycotoxin method was developed for the identification and quantification of several toxicological important mycotoxins such as deoxynivalenol (DON), deepoxy-deoxynivalenol (DOM-1), T-2 toxin (T-2), HT 2 toxin (HT-2), zearalenone (ZON), zearalanone (ZAN), alpha-zearalenol (alpha ZOL), beta-zearalenol (beta-ZOL), alpha-zearalanol (alpha-ZAL), beta-zearalanol (beta-ZAL), ochratoxin A (OTA), fumonisin B1 (FB1) and aflatoxin B1 (AFB1) in pig plasma using liquid chromatography combined with heated electrospray ionization triple quadrupole tandem mass spectrometry (LC-h-ESI-MS/MS). Sample clean-up consisted of a deproteinization step using acetonitrile, followed by evaporation of the supernatant and resuspension of the dry residue in water/methanol (85/15, v/v). Each plasma sample was analyzed twice, i.e. once in the ESI+ and ESI- mode, respectively. This method can be used for the assessment of animal exposure to mycotoxins and in the diagnosis of mycotoxicoses. For the performance of toxicokinetic studies with individual mycotoxins, highly sensitive analyte specific LC-MS/MS methods were developed. The multi-mycotoxin and analyte specific methods were in-house validated: matrix-matched calibration graphs were prepared for all compounds and correlation and goodness-of-fit coefficients ranged between 0.9974-0.9999 and 2.4-15.5%, respectively. The within- and between run precision and accuracy were evaluated and the results fell within the ranges specified. The limits of quantification for the multi-mycotoxin and analyte specific methods ranged from 2 to 10 ng/mL and 0.5 to 5 ng/mL, respectively, whereas limits of detection fell between 0.01-0.52 ng/mL and <0.01-0.15 ng/mL, respectively. PMID- 22917982 TI - Self-similarity and scaling in two models of phyllotaxis and the selection of asymptotic divergence angles. AB - The arrangement of plant organs - called phyllotaxis - is often highly regular. Surprisingly, these arrangements are not only qualitatively, but also quantitatively similar for different plants. Several abstract mathematical models invoking general principles like circular symmetry and mutual repulsion of plant organs reproduce these characteristic features of phyllotaxis. Two such models, belonging to the class of field models, are analyzed in the present study, they were introduced by Thornley (1975), and by Douady and Couder (1992). It is numerically demonstrated that in the limit of high organ density their bifurcation diagrams ("divergence spectrum") are self-similar under rescaling of two model parameters. Field models are known to give the classically expected behaviour only if the positioning of primordia is controlled exclusively by next neighbor interactions (Kunz, 1995). In the general case, the bifurcation diagram of such models is topologically different and phyllotactic sequences converging to non-noble irrational divergences are possible. It is discussed how in these systems self-similarity and scaling together with the Farey tree structure of the divergence spectrum lead to a universal selection of asymptotic divergences with periodic continued fraction expansion [a(1),a(2),...,a(N),kappa(1),kappa(2),...,kappa(P)], where the overlining denotes infinite repetition. Moreover, it is argued that for solutions easily accessible during growth, divergences are favored where all numbers N, P, a(1),a(2),..., and kappa(1),kappa(2),... are small, thereby selecting in particular the noble limit divergences of the classically observed unijugate phyllotactic sequences. PMID- 22917983 TI - Long-term efficacy and safety of treatment with stimulants and atomoxetine in adult ADHD: a review of controlled and naturalistic studies. AB - Attention-deficit/hyperactivity disorder (ADHD) is a common disorder of childhood that often persists into adulthood. Although stimulant medications are recommended as the first-line treatment for ADHD because of their documented short-term effects in children and adults, less is known about their effects on long-term outcome in adults. Here we review the long-term efficacy and safety of the stimulant drugs methylphenidate and amphetamine, as well as the related compound atomoxetine. We performed a systematic review to identify direct and indirect effects of stimulant therapy on long-term outcome in adults. Five randomized controlled trials (RCTs), and 10 open-label extension studies of initial short-term RCTs, with total follow-up of at least 24weeks, were identified. All these RCTs found that medication was significantly more efficacious than placebo in treating ADHD in adults, and the extension studies showed that this favorable effect of medication was maintained during the open label follow-up period. However, since the maximum duration of these pharmacological trials was 4years, we also reviewed 18 defined naturalistic longitudinal and cross-sectional studies, to provide more information about longer term functional outcomes, side effects and complications. These observational studies also showed positive correlations between early recognition of the disorder, stimulant treatment during childhood and favorable long-term outcome in adult ADHD patients. In conclusion, stimulant therapy of ADHD has long term beneficial effects and is well tolerated. However, more longitudinal studies of long duration should be performed. In addition, the ethical issues involved in performing double blind RCTs of many years duration should be further explored. PMID- 22917984 TI - ICUD-EAU International Consultation on Bladder Cancer 2012: Chemotherapy for urothelial carcinoma-neoadjuvant and adjuvant settings. AB - CONTEXT: We present a summary of the Second International Consultation on Bladder Cancer recommendations on chemotherapy for the treatment of bladder cancer using an evidence-based strategy. OBJECTIVE: To review the data regarding chemotherapy in patients with clinically localized and metastatic bladder cancer with a focus on its use for patients in the neoadjuvant and adjuvant settings. EVIDENCE ACQUISITION: Medline databases were searched for original articles published prior to April 1, 2012, using the following search terms: bladder cancer, urothelial cancer, metastatic, advanced, neoadjuvant, and adjuvant therapy. Proceedings of major conferences from the last 5 yr also were searched. Novel and promising drugs currently in clinical trials were included. EVIDENCE SYNTHESIS: The major findings are addressed in an evidence-based manner. Prospective trials and important cohort data were analyzed. CONCLUSIONS: Cisplatin-based combination chemotherapy for advanced and metastatic bladder cancer is an established standard, improving overall survival. In the advanced setting, cisplatin ineligible patients may benefit from gemcitabine and carboplatin. Meta-analyses undertaken for neoadjuvant cisplatin-based combination chemotherapy show a 5% benefit in overall survival. Pathologic complete remission may be an intermediate surrogate for survival, but requires further validation. Use of neoadjuvant chemotherapy is low, and is attributable to patient and physician choice because of limited benefit, advanced age, and comorbidities including renal and/or cardiac dysfunction. Sufficient data to support adjuvant chemotherapy are lacking. PMID- 22917985 TI - ICUD-EAU International Consultation on Bladder Cancer 2012: Radical cystectomy and bladder preservation for muscle-invasive urothelial carcinoma of the bladder. AB - CONTEXT: New guidelines of the International Consultation on Urological Diseases for the treatment of muscle-invasive bladder cancer (MIBC) have recently been published. OBJECTIVE: To provide a comprehensive overview of the current role of radical cystectomy (RC) in MIBC. EVIDENCE ACQUISITION: A detailed Medline analysis was performed for original articles addressing the role of RC with regard to indication, timing, surgical extent, perioperative morbidity, oncologic outcome, and follow-up. The analysis also included radiation-based bladder preserving strategies. EVIDENCE SYNTHESIS: The major findings are presented in an evidence-based fashion and are based on large retrospective unicenter and multicenter series with some prospective data. CONCLUSIONS: Open RC is the standard treatment for locoregional control of MIBC. Delay of RC is associated with reduced cancer-specific survival. In males, standard RC includes the removal of the bladder, prostate, seminal vesicles, and distal ureters; in females, RC includes an anterior pelvic exenteration including the bladder, entire urethra and adjacent vagina, uterus, and distal ureters. A procedure sparing the urethra and the urethra-supplying autonomous nerves can be performed in case of a planned orthotopic neobladder. Further technical variations (ie, seminal-sparing or vaginal-sparing techniques) aimed at improving functional outcomes must be weighed against the risk of a positive margin. Laparoscopic surgery is promising, but long-term data are required prior to accepting it as an option equivalent to the open procedure. Lymphadenectomy should remove all lymphatic tissue around the common iliac, external iliac, internal iliac, and obturator region bilaterally. Complications after RC should be reported according to the modified Clavien grading system. In selected patients with MIBC, bladder-preserving therapy with cystectomy reserved for tumor recurrence represents a safe and effective alternative to immediate RC. PMID- 22917986 TI - Intermodal attention modulates visual processing in dorsal and ventral streams. AB - Attending to visual objects while ignoring information from other modalities is necessary for performing difficult visual discriminations, but it is unclear how selecting between sensory modalities alters processing within the visual system. We used an audio-visual intermodal selective attention paradigm with fMRI to study the effects of visual attention on cortical activity in the absence of competitive interactions between multiple visual stimuli. Complex stimuli (faces and words) activated higher visual areas even in the absence of visual attention. These stimulus-dependent activations (SDAs) covered foveal retinotopic cortex, extended ventrally to the anterior fusiform gyrus and dorsally to include multiple distinct foci in the intraparietal sulcus (IPS). Attention amplified the baseline response in posterior retinotopic regions and altered activity in different ways in the extrastriate dorsal and ventral pathways. The majority of the IPS was strongly and exclusively activated by visual attention: attention related modulations (ARMs) encompassed and spread well beyond the focal SDAs. In contrast, in the fusiform gyrus only a small subset of the regions activated by unattended stimuli showed ARMs. Ventral cortex was also heterogeneous: we found a distinct ventrolateral region in the occipitotemporal sulcus (OTS) that was activated exclusively by attention, showing neither SDAs nor any significant stimulus preferences. Attention-dependent activations in the IPS and the OTS suggest that these regions play critical roles in intermodal visual attention. PMID- 22917988 TI - A steady-state visual evoked potential approach to individual face perception: effect of inversion, contrast-reversal and temporal dynamics. AB - Presentation of a face stimulus for several seconds at a periodic frequency rate leads to a right occipito-temporal evoked steady-state visual potential (SSVEP) confined to the stimulation frequency band. According to recent evidence (Rossion and Boremanse, 2011), this face-related SSVEP is largely reduced in amplitude when the exact same face is repeated at every stimulation cycle as compared to the presentation of different individual faces. Here this SSVEP individual face repetition effect was tested in 20 participants stimulated with faces at a 4 Hz rate for 84 s, in 4 conditions: faces upright or inverted, normal or contrast reversed (2*2 design). To study the temporal dynamics of this effect, all stimulation sequences started with 15s of identical faces, after which, in half of the sequences, different faces were introduced. A larger response to different than identical faces at the fundamental (4 Hz) and second harmonic (8 Hz) components was observed for upright faces over the right occipito-temporal cortex. Weaker effects were found for inverted and contrast-reversed faces, two stimulus manipulations that are known to greatly affect the perception of facial identity. Addition of the two manipulations further decreased the effect. The phase of the fundamental frequency SSVEP response was delayed for inverted and contrast-reversed faces, to the same extent as the latency delay observed at the peak of the face-sensitive N170 component observed at stimulation sequence onset. Time-course analysis of the entire sequence of stimulation showed an immediate increase of 4Hz amplitude at the onset (16th second) of different face presentation, indicating a fast, large and frequency-specific release to individual face adaptation in the human brain. Altogether, these observations increase our understanding of the characteristics of the human steady-state face potential response and provide further support for the interest of this approach in the study of the neurofunctional mechanisms of face perception. PMID- 22917987 TI - Expected reward modulates encoding-related theta activity before an event. AB - Oscillatory brain activity in the theta frequency range (4-8 Hz) before the onset of an event has been shown to affect the likelihood of successfully encoding the event into memory. Recent work has also indicated that frontal theta activity might be modulated by reward, but it is not clear how reward expectancy, anticipatory theta activity, and memory formation might be related. Here, we used scalp electroencephalography (EEG) to assess the relationship between these factors. EEG was recorded from healthy adults while they memorized a series of words. Each word was preceded by a cue that indicated whether a high or low monetary reward would be earned if the word was successfully remembered in a later recognition test. Frontal theta power between the presentation of the reward cue and the onset of a word was predictive of later memory for the word, but only in the high reward condition. No theta differences were observed before word onset following low reward cues. The magnitude of prestimulus encoding related theta activity in the high reward condition was correlated with the number of high reward words that were later confidently recognized. These findings provide strong evidence for a link between reward expectancy, theta activity, and memory encoding. Theta activity before event onset seems to be especially important for the encoding of motivationally significant stimuli. One possibility is that dopaminergic activity during reward anticipation mediates frontal theta activity related to memory. PMID- 22917989 TI - Relationship between BOLD amplitude and pattern classification of orientation selective activity in the human visual cortex. AB - Orientation-selective responses can be decoded from fMRI activity patterns in the human visual cortex, using multivariate pattern analysis (MVPA). To what extent do these feature-selective activity patterns depend on the strength and quality of the sensory input, and might the reliability of these activity patterns be predicted by the gross amplitude of the stimulus-driven BOLD response? Observers viewed oriented gratings that varied in luminance contrast (4, 20 or 100%) or spatial frequency (0.25, 1.0 or 4.0 cpd). As predicted, activity patterns in early visual areas led to better discrimination of orientations presented at high than low contrast, with greater effects of contrast found in area V1 than in V3. A second experiment revealed generally better decoding of orientations at low or moderate as compared to high spatial frequencies. Interestingly however, V1 exhibited a relative advantage at discriminating high spatial frequency orientations, consistent with the finer scale of representation in the primary visual cortex. In both experiments, the reliability of these orientation selective activity patterns was well predicted by the average BOLD amplitude in each region of interest, as indicated by correlation analyses, as well as decoding applied to a simple model of voxel responses to simulated orientation columns. Moreover, individual differences in decoding accuracy could be predicted by the signal-to-noise ratio of an individual's BOLD response. Our results indicate that decoding accuracy can be well predicted by incorporating the amplitude of the BOLD response into simple simulation models of cortical selectivity; such models could prove useful in future applications of fMRI pattern classification. PMID- 22917991 TI - The short-term clinical performance of a silorane-based resin composite in the proximal contacts of class II restorations. AB - AIM: The aim of this randomized clinical trial was to compare the proximal contact of a silorane-based resin composite with a conventional methacrylate based resin composite in class II restorations after a 6 months follow-up period. MATERIALS AND METHODS: After obtaining informed consent, 33 patients were randomly allocated into a test group (Filtek P90/Adhesive System-3M ESPE) or control group (Filtek P60/ Adper SE Plus-3M ESPE), and 100 direct resin composite restorations (n = 50) were placed. A single operator performed the cavities and restorations. After rubber dam placement, a metal matrix and wooden wedge were placed. The restorative systems were applied according to the manufacturer's instructions. After 1 week, the restorations were finished and polished. The proximal contacts were assessed blindly and independently by two calibrated examiners (kW = 0.8) at the baseline and after 6 months according to a three-step grading criteria. Data were analyzed with the Mann-Whitney U-test and Wilcoxon signed Rank tests (a = 0.05). RESULTS: After 6 months, 96% of the restoration contacts were present for evaluation. The frequencies of restorations classified as Bravo in control and test groups were 6 and 8% at the baseline, and 6.25 and 12.75% after 6 months. No significant difference was found between the restorative materials (p > 0.05; Mann-Whitney U-test) neither between baseline and 6 months period (p > 0.05; Wilcoxon signed Rank tests). CONCLUSION: Both materials performed satisfactorily over 6 months follow-up period. CLINICAL SIGNIFICANCE: The short-term clinical performance of a silorane-based resin composite in the proximal contacts of class II restorations was similar to the well-known methacrylate-based resin composite. PMID- 22917992 TI - Assessment of dental anxiety and its correlation with denture satisfaction in edentulous patients. AB - OBJECTIVE: The objectives of this study were to measure the level of dental anxiety and its correlation with dental history, denture satisfaction and other variables. MATERIALS AND METHODS: A cross-sectional study was conducted on 150 completely edentulous patients reporting to the Department of Prosthodontics, KLES's Institute of Dental Sciences, Belgaum, over a period of 17 months (August 2005 to March 2007). The anxiety level of the patients was assessed with the help of a questionnaire, after obtaining an informed consent. Reliability of the dental anxiety scale was assessed by means of coefficient alpha. RESULTS: The results of this study concluded that dental anxiety scale for edentulous patients was a reliable scale for measuring dental anxiety. The anxiety score was higher for female than male patients. A significant correlation was found between denture satisfaction score and anxiety. DISCUSSION: Anxiety plays a major role in denture satisfaction. The variables included: Previous denture experience, occupation, medical history, age, gender, dental anxiety scale, period of edentulousness, age of previous dentures, number of complete dentures, denture satisfaction score, and the score on the Hamilton anxiety scale. CONCLUSION: The study indicated that gender correlates significantly with dental anxiety. Patients with medical history were found to be more anxious than normal patients. Patients with higher anxiety values were less satisfied with the treatment. Lastly, subjects with higher general anxiety showed greater values on the dental anxiety scale. CLINICAL SIGNIFICANCE: The assessment of dental anxiety will help the prosthodontist in the management of anxious patients and secondly to provide evidence-based research into this psychological construct which has been shown to predict dental avoidance. PMID- 22917990 TI - Including aortic valve morphology in computational fluid dynamics simulations: initial findings and application to aortic coarctation. AB - Computational fluid dynamics (CFD) simulations quantifying thoracic aortic flow patterns have not included disturbances from the aortic valve (AoV). 80% of patients with aortic coarctation (CoA) have a bicuspid aortic valve (BAV) which may cause adverse flow patterns contributing to morbidity. Our objectives were to develop a method to account for the AoV in CFD simulations, and quantify its impact on local hemodynamics. The method developed facilitates segmentation of the AoV, spatiotemporal interpolation of segments, and anatomic positioning of segments at the CFD model inlet. The AoV was included in CFD model examples of a normal (tricuspid AoV) and a post-surgical CoA patient (BAV). Velocity, turbulent kinetic energy (TKE), time-averaged wall shear stress (TAWSS), and oscillatory shear index (OSI) results were compared to equivalent simulations using a plug inlet profile. The plug inlet greatly underestimated TKE for both examples. TAWSS differences extended throughout the thoracic aorta for the CoA BAV, but were limited to the arch for the normal example. OSI differences existed mainly in the ascending aorta for both cases. The impact of AoV can now be included with CFD simulations to identify regions of deleterious hemodynamics thereby advancing simulations of the thoracic aorta one step closer to reality. PMID- 22917993 TI - Dentists' opinion and knowledge about preventive dental care in Saudi Arabia: a nationwide cross-sectional study. AB - AIM: The aim of this study was to determine the dentists' opinions on causes for high prevalence of dental caries in the country and to assess their level of knowledge about preventive dental care. MATERIALS AND METHODS: A questionnaire based national crosssectional survey among 500 dentists was conducted under the auspices of Directorate of Dentistry, Ministry of Health. The data was analyzed using SPSS software version 11.0 and descriptive statistics were obtained. RESULTS: The response rate was 87.8% (n = 439). 83% of dentists identified poor oral hygiene as the major reason for high prevalence of caries, only 39% of patients reportedly brushed teeth at least once a day, oral prophylaxis (83%) is the most common preventive practice followed, social factors (62.5%) are the most challenging barriers in preventive dental programs, 71.3% always give chair side dental health education, school based programs (66.6%) are most effective tools for dental health education. CONCLUSION: Majority of dentists in Saudi Arabia are adequately informed and motivated toward preventive dental care but they are in need of further support from policy makers to enhance preventive dental programs in the Kingdom. CLINICAL SIGNIFICANCE: Oral hygiene should be improved in the country by reaching out to the entire community through extensive and continued education programs. PMID- 22917994 TI - Dermatoglyphics in patients with dental caries: a study on 1250 individuals. AB - AIM: This study was undertaken to investigate and analyze the significance of dermatoglyphics in predicting the susceptibility of individuals to develop dental caries. MATERIALS AND METHODS: This case-control study was conducted on 1250 children in the age group of 5 to 12 years from Chennai Corporation School, Vadapalani, Chennai. Out of 1250 subjects, 625 subjects were in the study group and the remaining 625 subjects were the control group. The study group included children with dental caries in 5 or more teeth based on the DMFT index performed and control group consisted of normal, healthy children without any dental caries. The finger and palmar prints of both hands were taken using a stamp pad. The fingertip patterns were analyzed according to the classical method and configurational types were classified according to the topological method. Statistical analysis was performed using nonparametric tests and t-test to compare the dermatoglyphic pattern changes between the study group and the control group and was applied for each variable, to compare the proportions, and p-value. RESULTS: (1) Dental caries susceptibility of an individual increases with an increase in the incidence of whorl pattern (83% correlation). (2) All the variables show statistically significant value, with a degree of divergence of specific dermatoglyphic patterns among study and control group. (3) The dermatoglyphic patterns are efficient and can predict in assessing the risk of susceptibility to dental caries in study group. CONCLUSION: The dental caries susceptibility of an individual increased with incidence of whorl pattern and it decreased with incidence of loop pattern. CLINICAL SIGNIFICANCE: The dermatoglyphic patterns may be utilized effectively to study the genetic basis of dental caries. In a developing country like India, it might prove to be a noninvasive, inexpensive and effective tool for screening. PMID- 22917995 TI - The interference of the cleaning procedure of root walls with two different solvents on the adhesion of fiberglass intraradicular posts. AB - AIM: This study was undertaken to examine the effect of root canal (RT) sealers content and the cleaning procedure of RT walls on bond strength (BS) of a fiber reinforced composite (FRC) post cemented with resin-based or zinc phosphate cement. MATERIALS AND METHODS: Forty bovine roots were divided into 2 groups (n = 20) and obturated with gutta-percha points plus Sealer 26 sealer or gutta-percha points plus N-Rickert sealer. In each group, half (n = 10) of intracanal walls was cleaned with ethanol and the other half with sulfuric ether. In each of these subgroups, half of intracanal posts (n = 5) were cemented with Bistite resin based cement and half with zinc phosphate cement. Specimens were submitted to pull-out test and tensile force until post dislodgement. The maximum forces required for post removal was expressed in MPa, means were submitted to statistical analysis (Analysis of Variance Test, a = 0.05). RESULTS: Fiber reinforced composite cemented with zinc phosphate were significantly more retentive than those cemented with Bistite (p < 0.05). Regarding the influence of eugenol-based sealer on post retention, there was a statistically significant difference (p < 0.05) only between groups cemented with Bistite, in which canals filled with N-Rickert + gutta-percha showed lower BS than canals filled with Sealer 26 + gutta-percha. CONCLUSION: Despite endodontic cement used, higher pull out bond strength were obtained when posts were cemented with zinc phosphate. CLINICAL SIGNIFICANCE: The importance of ethanol or sulphuric ether application to properly replace water from intraradicular dentine still requires further investigations, especially to clarify if this technique may reduce the effect of aging and improve the stability of the bond, when used to cement fiber posts into the root canal. PMID- 22917996 TI - Effects of a self-etching primer and 37% phosphoric acid etching on enamel: a scanning electron microscopic study. AB - OBJECTIVE: The purpose of this study was to compare the etching effects of a self etching primer with 37% phosphoric acid on enamel by using a scanning electron microscope. Bond strength and the site of bond failure were also determined for brackets bonded using SEP and 37% phosphoric acid. MATERIALS AND METHODS: A total of 60 maxillary premolar teeth were used for this study and they were divided into four groups. First two groups were used for studying the different types of etch patterns obtained and the next two groups were used to test the bond strength with the help of Universal testing machine. After debonding, the amount of residual adhesive was assessed according to adhesive remnant index using a stereomicroscope. RESULTS: The majority of etch patterns obtained in the 37% phosphoric acid group were type II, whereas in the SEP group, type IV pattern was more common. There was no statistically significant difference between mean bond strengths obtained with the SEP group and the phosphoric acid group. Use of SEP results in less amount of residual adhesive on tooth surface after debonding. CONCLUSION: SEP produces more conservative etch pattern compared to 37% phosphoric acid. Use of SEP for bonding provides similar and clinically acceptable bond strength compared to use of 37% phosphoric acid etching technique and requires less clean-up procedures hence, reduces enamel loss. CLINICAL SIGNIFICANCE: Use of 37% phosphoric acid for orthodontic bonding yields high bond strength but, causes enamel loss during both etching and debonding. SEPs not only provide adequate bond strength with a more conservative etch pattern but also enable easy debonding, thereby reducing the enamel damage. PMID- 22917997 TI - Effect of fluoride prophylactic agents on the surface topography of NiTi and CuNiTi wires. AB - AIM: The aim of this study was to see the effect of topical fluoride on surface texture on nickel-titanium and copper-nickel-titanium orthodontic archwires. MATERIALS AND METHODS: Preformed rectangular NiTi and CuNiTi wires were immersed in in fluoride solution and artificial saliva (control) for 90 minutes at 37 degrees C. after immersion optical microscope was used to see the fluoride effect on the wire topography. RESULTS: The acidulated fluoride agents appeared to cause greater corrosive effects as compared to the neutral fluoride agents. CONCLUSION: The result suggest that using topical fluoride agents leads to corrosion of surface topography indirectly affecting the mechanical properties of the wire that will lead to prolonged orthodontic treatment. CLINICAL SIGNIFICANCE: The use of topical fluoride agents has to be limited in patients with prolonged orthodontic treatment as it causes the corrosion of the NiTi and CuNiTi wires. PMID- 22917998 TI - Perception of patients with amalgam fillings about toxicity of mercury in dental amalgam. AB - OBJECTIVE: The objective of this study is to evaluate the awareness of patients with dental fillings about the toxicity of mercury in dental amalgam. MATERIALS AND METHODS: Adult patients having at least one amalgam filling in their mouth were recruited in the Oral Diagnosis Department of OAUTHC, Ile-Ife Dental Hospital. Participants were recruited consecutively as they report in the clinic. Data were collected using a structured questionnaire developed based on standard questions from relevant publications. They were asked to indicate the type of filling material in their mouth, ingredients of the material, previous knowledge of mercury in dental amalgam and ailments due to mercury. They were to indicate their level of agreement with filling their cavities with dental amalgam despite prior information about its mercury content. RESULTS: There were about 446 respondents analyzed; male, 194 (43.5%); female 252 (56.5%). Six (1.4%) and 21 (4.7%) respondents were primary and secondary schools students respectively; 15(3.4%) had no formal education while about 410 (91.9%) were either undergraduate or graduate. All of them had at least one amalgam filling. 249 (55%) participants know the type of filling on their teeth; 156 (34.5%) had the knowledge of the presence of mercury in dental amalgam while 26.1% believed mercury can cause problems in human beings. About 90 (19.9%) participants claimed to have heard about adverse reactions to dental amalgams and 34 (7.5%) of them have heard about people recovering from an illness after removal of their filling. The level of agreement with filling their cavities with amalgam despite prior knowledge of its mercury content was 74% while 60% was observed for allowing just any material to be placed on their teeth. CONCLUSION: Awareness of toxicity of mercury in dental amalgam was slightly low among the respondents studied. This may be suggested to be a reflection of nonexistent of global amalgam controversy in Nigeria. PMID- 22917999 TI - Oral Health-Related Quality of Life (OHQoL) among adolescents seeking orthodontic treatment. AB - AIM: The aim of this study was to assess the effect of different orthodontic treatment needs on the OHQoL of adolescents. MATERIALS AND METHODS: 200 subjects (100 males and 100 females), 11 to 15 years of age were recruited for the study. OHQoL was assessed with the short form of the oral health impact profile (OHIP 14), and malocclusion severity was assessed with the index of orthodontic treatment need (IOTN). The Chi-square test was used to analyse the qualitative data. The level of significance was 0.05. RESULTS: The more severe the malocclusion the worse was the impact on the OHQoL. Orthodontic treatment need had almost similar impact on the daily activities of both males and females. Pronunciation and taste was not significantly affected by the need for orthodontic treatment in either males or females. The proportions of orthodontic patients who found it uncomfortable to eat any food and had to interrupt their meals were significantly correlated with orthodontic treatment needs in both males and females. CONCLUSION: Orthodontic treatment need had an impact on OHQoL of adolescents with no significant difference between males and females. CLINICAL SIGNIFICANCE: Orthodontists should be aware of the impact caused by malocclusion and orthodontic treatment on the quality of life of the patients and should provide regular positive reinforcements to them. PMID- 22918000 TI - Correlation between surface roughness and microhardness of experimental composites with varying filler concentration. AB - AIM: The purpose of this study was to investigate the influence of the surface roughness on the surface microhardness of experimental composites with varying filler concentration. MATERIALS AND METHODS: Experimental resin composites were formulated by mixing Bis-GMA and TEGDMA in a 50/50% weight ratio and CQ/EDAB were added to make the material photosensitive. Silanized glass particles were incorporated in the resin blend in two concentrations: C50 with 50% and C75 with 75% in weight ratio. The surface roughness and the surface microhardness measurements were determined after every three finishing procedures with #280-, #600- and #1200-grit wet sandpapers, respectively. The data were analyzed statistically by Two Way ANOVA and Tukey's test, and comparisons were conducted using the Spearman's correlation test (p > 0.05). RESULTS: The surface roughness and surface microhardness were negatively associated (r = - 0.68) and the finishing procedures of both composites resulted in harder and smoother surfaces than the initial ones. Additionally, in a smooth circumstance, the higher content of fillers has not resulted in a composite with better microhardness and smoothness. CONCLUSION: Finishing procedures decreased the surface roughness and consequently improved the surface microhardness of the composites evaluated. CLINICAL SIGNIFICANCE: Finishing and polishing procedures are effectives in reducing the surface roughness amplitude of composite materials and in improving their surface microhardness. Thus a microhardness test and any hardness evaluation must be conducted only after a properly finished and polished surface is achieved. PMID- 22918001 TI - Antimicrobial effect of conventional root canal medicaments vs propolis against Enterococcus faecalis, Staphylococcus aureus and Candida albicans. AB - AIM: To evaluate and compare antimicrobial effect of various root canal medicaments against Enterococcus faecalis, Staphylococcus aureus and Candida albicans. MATERIALS AND METHODS: Six root canal medicaments: 2% sodium hypochlorite (NaOCl), 2% chlorhexidine (CHX) Calcium hydroxide (Ca(OH)2), EDTA, MTAD and propolis and three microorganisms: Staphylococcus aureus, Enterococcus faecalis and Candida albicans were used. These strains were inoculated in brain heart infusion (BHI) and incubated at 37 degrees C for 24 hours. For the agar diffusion test (ADT), petri plates with 20 ml of BHI agar were inoculated with 0.1 ml of the microbial suspensions, using sterile swabs that were spread on the medium, obtaining growth injunction. Paper disks were immersed in the experimental solutions for 1 minute. Subsequently, four papers disks containing one of the substances were placed on the BHI agar surface in each agar plate. The plates were incubated at 37 degrees C for 48 hours. The diameter of microbial inhibition was measured around the papers disks containing the substances. One way ANOVA followed by Tukey's post-hoc test were used. p-value >0.05 was considered statistically significant. RESULTS: Propolis and other irrigants were found to be effective on C. albicans, S. aureus and E. faecalis. CHX and MTAD were found to be most effective amongst all the materials tested followed by propolis. CONCLUSION: Propolis showed antimicrobial activity against E. faecalis, S. aureus, C. albicans. It appears that propolis is an effective intracanal irrigant in eradicating E. faecalis and C. albicans. CLINICAL SIGNIFICANCE: Propolis is an effective intracanal irrigant in eradicating E. faecalis and C. albicans. It could be used as an alternative intracanal medicament. PMID- 22918002 TI - Assessment of skeletal and dental maturity levels for a given chronological age among Indian children. AB - AIM: The aim of this study was to evaluate the maturity levels of the individual by comparing the correlation between dental, skeletal and the chronological ages. MATERIALS AND METHODS: Intraoral periapical radiographs of the complete right side of the dentition and posteroanterior radiographs of the hand and wrist were obtained from 260 subjects, ranged from 3 to 15 years of age. Evaluation of handwrist roentgenograms for skeletal age and intraoral roentgenograms for dental age was done. RESULTS: The findings of present study indicated that participated children were skeletally and dentally, retarded in maturation as compared with the standards except at 3 and 6 years of age. The girls were found to be skeletally more advanced than boys at all ages except 7 and 10 years of age. The dental maturity is more for girls than that of boys. CONCLUSION: No significant correlation was found among skeletal age, dental age and chronological age. Dental age and skeletal age was found to be correlated at 6, 10 and 11 years in boys and 6 and 9 years of age in girls. CLINICAL SIGNIFICANCE: The results of this study could enhance the diagnosis and treatment planning in orthodontics and other dental disciplines. PMID- 22918003 TI - To determine the prevalence rate of malocclusion among 12 to 14-year-old schoolchildren of urban Indian population (Bagalkot). AB - AIM: To determine the prevalence rates of different occlusal characteristics of permanent dentition in 12 to 14 years old children in Bagalkot city and to determine the differences in occlusal characteristics in the same children by age and sex. MATERIALS AND METHODS: A total of 1000 school going children between the age group of 12 to 14 years were selected in the study from Bagalkot city of India. All the occlusal parameters, such as molar relation, canine relation, overjet, overbite and crowding and spacing were recorded in a record sheet. The gender and sex difference was evaluated using Chi-square test. RESULTS: According to the classification of Angle, the prevalence of class I, II and III malocclusions was 17.8, 30.1 and 1.6%, respectively. Ideal occlusion was 3.2% where as normal occlusion was 46.8%. An overjet of at least 4 mm or more was present in 15.2 and 7.2% had a reverse overjet. A total of 9.2 had an increased overbite and 10.6% had open bite. CONCLUSION: Highly significant (p < 0.001) age differences were found for overjet, overbite and highly significant (p < 0.001) gender differences were found for crowding and spacing. CLINICAL SIGNIFICANCE: The study gives the prevalence of malocclusion amongst 12 to 14 years old in urban Indian population. The data can be used for may research projects and gives us a better understanding of malocclusion in urban Indian population. PMID- 22918004 TI - The quality of Thermafil obturations with different final apical tapers: a three dimensional microcomputed tomographic comparative study. AB - AIM: The aim of this study is to evaluate the influence of final canal taper on the sealing ability of Thermafil by using microcomputed tomography (micro-CT). MATERIALS AND METHODS: Fifty-four single-rooted teeth were instrumented to apical size 40 taper 4, 6 and 8%. Teeth were divided into three groups. All teeth were filled with Thermafil (Dentsply,Tulsa Dental Products). Using micro-CT, roots were scanned and volume measurements of voids at 1, 3 and 5 mm from the apex were calculated using specialized CT software. Measurements were analyzed statistically with ANOVA followed by Bonferroni multiple comparison correction. RESULTS: Data analysis showed that 0.08 preparations provided better results than 0.06 and 0.04% tapered samples especially at 1 mm from the apex. Mean percentage of voids were significantly higher with Thermafil taper 0.06% (p = 0.05). None of the root canals filled teeth were gap free. Root canal preparations with bigger taper exhibited less voids than smaller tapered preparations. CLINICAL SIGNIFICANCE: In our daily practice, enlarging the apical third (last 3 mm) of root canals to an 8% taper gives a better sealing ability and thus long-term success for our root canal obturations. PMID- 22918005 TI - Comparative analysis of postcementation hypersensitivity with glass ionomer cement and a resin cement: an in vivo study. AB - AIM: The aim of this clinical study was to compare the postoperative sensitivity of abutment teeth restored with full coverage restorations retained with either conventional glassionomer cement (GIC) or resin cement. MATERIALS AND METHODS: Fifty patients received full-coverage restorations on vital abutment teeth. Of these, 25 were cemented with GIC (GC Luting and Lining cement) and the other 25 using an adhesive resin cement (Smartcem 2). A randomized single blind study was undertaken for acquiring and evaluating the data. The teeth were examined before cementation, after cementation, 24 hours postcementation and 7 days postcementation. A visual analog scale was used to help the patient rate hypersensitivity. RESULTS: The statistical analysis of the result was done using students paired t-test. No statistically significant difference between Smartcem 2 and GIC was observed, when tested immediately and 24 hours after cementation. Statistically significant difference was seen between Smartcem 2 and GIC when tested 7 days postcementation with a significance level of 0.05. Higher postoperative sensitivity was seen with GIC when compared to resin cement. CONCLUSION: In this study, the incidence of postoperative hypersensitivity after cementation of full-crown restorations with GIC and resin cement was similar when tested immediately. However, 7 days postcementation, abutments with GIC showed higher response compared to resin cement. CLINICAL SIGNIFICANCE: A self-adhesive resin cement can be the material of choice for luting if presence of postoperative sensitivity is of prime consideration. In case GIC is being used, patient should be informed about the presence of sensitivity for a more prolonged period than with resin cement. PMID- 22918006 TI - Blood cells attachment after root conditioning and PRP application: an in vitro study. AB - AIM: Root conditioning is aimed at smear layer removal and at dental matrix collagen exposure, which may promote periodontal regeneration. This in vitro study assessed smear layer removal, collagen fiber exposure and the influence of PRP (platelet-rich plasma) application on adhesion of blood cells to the root surface using scanning electron microscopy (SEM). MATERIALS AND METHODS: Scaled root samples (n = 160) were set in five groups and conditioned with: group I - control group (saline solution); group II (EDTA 24%); group III (citric acid 25%); group IV (tetracycline hydrochloride 50 mg/ml); group V (sodium citrate 30%). Eighty samples were assessed using the root surface modification index (RSMI). The other eighty samples were set in two groups. The first group (n = 40) received PRP gel application with a soft brush and the second group (n = 40) received PRP application and then a blood drop. The fibrin clot formation was assessed in the first group and the blood cells adhesion was assessed in the second group using the BEAI (blood elements adhesion index). A previously trained, calibrated, and blind examiner evaluated photomicrographs. Statistical analysis was performed using the Kruskal-Wallis's and Dunn's tests. RESULTS: Group III attained the best results for RSMI and BEAI. Moreover, it was the only group showing fibrin clot formation. CONCLUSION: Citric acid was the most efficient conditioner for smear layer removal, collagen fiber exposure and blood cell adhesion. Moreover, it was the only group showing fibrin clot formation after PRP application. CLINICAL SIGNIFICANCE: This study demonstrated that root conditioning followed by PRP application may favor blood cell adhesion on root surface which may optimize periodontal healing. PMID- 22918007 TI - Assessment of interobserver variability in mitotic figure counting in different histological grades of oral squamous cell carcinoma. AB - Mitotic counting is often used for classification, grading and prognosis of tumors. The count usually stands as a decision point for treatment as well. The easiest way of counting the number of mitoses is done by screening routine H&E stained slides. However, for proper mitotic counting, certain strict protocols should be taken into consideration. This study on 30 cases of different grades of oral squamous cell carcinoma was undertaken to determine the interobserver variations in two different groups: Group1 (A1, A2), who were given certain criteria to be followed during the counting of the mitotic figures and group 2 investigators (B1, B2) who were unaware of such criteria. The paired t-test gives a correlation of 0.988 and a significant difference of 0.000 between the two investigators in group 1. The correlation was 0.650 with a significant difference of 0.058 between two investigators in-group 2, indicating that group 1 observers exhibit good interobserver agreement. The results emphasize that following of strict protocols are of great help in determining the accuracy of mitotic counting. PMID- 22918008 TI - The effects of 5-fluorouracil alone and in combination with 13-cis retinoic acid and vitamin D3 on human oral squamous cell carcinoma lines. AB - AIM: Oral squamous cell carcinoma (OSCC) is responsible for about 90% of oral malignancies and its incidence is increasing. Despite various treatment protocols, survival rate of OSCC is low. Chemotherapy that is used for treating this carcinoma in advanced stages is systemic therapy that destroys carcinogenic cells, and controls tumor metastasis. Chemotherapy is very toxic and has limitations, especially for patients in advanced stages. Considering positive effects of retinoid and vitamin D3 derivatives in treating some carcinomas, we decided to evaluate the effect of combination of these drugs on OSCC. In this study the effects of combination of 5-fluorouracil, 13-cis retinoic acid and vitamin D3 on cultured cell of OSCC have been evaluated. MATERIALS AND METHODS: OSCC cells were cultured in culture media and different concentration of 5 fluorouracil, 13-cis retinoic acid and vitamin D3 were added to cultured cell as separately and in combinations. The effect of treatment on cell proliferation and induction of apoptosis were evaluated by MTT and TUNEL assays respectively. RESULTS: Combination of 5-fluorouracil and 13- cis retinoic acid had the highest inhibitory effect on SCC cell proliferation. Combination of two drugs had more apoptotic effect than each of them separately, and combination of three drugs had more effect than combination of two drugs. CONCLUSION: Because combination of drugs had more inhibitory effect on cell proliferation than one of them and combination of three drugs had the most apoptotic effect than one of these drugs separately, these drugs may have synergic effect on OSCC. CLINICAL SIGNIFICANCE: Combination of three drugs has more inhibitory effect on cell proliferation and apoptotic effect than one of these drugs. PMID- 22918009 TI - A comparative evaluation of the vertical root fracture resistance of endodontically treated teeth using different root canal sealers: an in vitro study. AB - OBJECTIVE: The objective of this study is to evaluate the vertical root fracture resistance of endodontically treated teeth obturated with - Tubli-Seal EWT/Gutta percha, AH Plus/Gutta-percha, Epiphany SE sealer/Epiphany point. STUDY DESIGN: Sixty-five single rooted premolars were decoronated and root length was 14 mm for each specimen. Fifty five teeth were enlarged up to ISO size 40 master apical file with stainless steel K-files using standardized preparation and remaining ten teeth were served as negative control. Then teeth were randomly assigned into different groups depending on sealer used for obturation as follows: Group 1: Negative control-no instrumentation was performed. Group 2: Positive control gutta-percha with out the use of any sealer. Group 3: Experimental group-gutta percha and Tubli-Seal EWT root canal sealer. Group 4: Experimental group-gutta percha and AH Plus. Group 5: Experimental group-epiphany SE sealer and epiphany points. After 72 hours, the specimens were embedded in autopolymerizing resin leaving 7 mm of each root exposed and were subjected to fracture testing under universal testing machine at a crosshead speed of 1.0 mm per minute until the root fractured. Results were statistically analyzed using one-way ANOVA and independent t-test. RESULTS: Showed that Epiphany SE sealer/Epiphany points showed highest mean fracture resistance and Tubli-Seal EWT group showed the least fracture resistance of all the materials tested. There was no statistically significant difference among experimental groups. CONCLUSION: Epiphany SE sealer/Epiphany points demonstrated highest fracture resistance values than the other materials tested and intact tooth had highest resistance against vertical root fracture. CLINICAL SIGNIFICANCE: Epiphany SE sealer/Epiphany points may be one of the materials of choice in the endodontic treatment of teeth. PMID- 22918010 TI - A comparative study to determine the wettability and castability of different elastomeric impression materials. AB - AIM: The aim of this study was to determine the wettability of different hydrophilic and hydrophobic elastomeric impression materials and the gypsum castability. MATERIALS AND METHODS: The wettability was evaluated by determining the contact angles of different elastomeric impression materials. The contact angle was determined by placing a drop of aqueous solution of calcium sulfate dihydrate on the flat surface of impression material and specimens were measured using a profile projector. Gypsum castability was determined by counting the number of voids formed in the die stone cast made from the impressions of a aluminum die. The voids were counted using an diopter magnifying lens. RESULTS: Polyether, different viscosities of polyvinyl siloxane, and condensation silicone impression materials exhibited low contact angle values and least number of voids in the die stone cast when compared with polysulfide impression material. CONCLUSION: There was significant correlation between the contact angle and voids formed in the die stone casts when fabricating die stone casts from various elastomeric impression material impressions. CLINICAL SIGNIFICANCE: Accurate reproduction of prepared tooth or edentulous arch is of clinical importance in the fabrication of a fixed or removable prosthesis. Inaccuracies in the replication processes will ultimately have an adverse effect on the fit and adaptation of final restoration. The interaction is determined in part by hydrophilic and hydrophobic nature of the elastomeric impression material. Inadequate wetting of an impression results in voids in the stone casts. PMID- 22918011 TI - Analgesic efficacy of tramadol and butorphanol in mandibular third molar surgery: a comparative study. AB - BACKGROUND: Butorphanol tartrate, a mixed synthetic agonistantagonist opioid analgesic has been used for management of postoperative pain in minor and major surgical procedures.(14,20) Tramadol hydrochloride is a centrally acting opioid which is effectively used in postoperative pain in various minor and major surgeries. MATERIALS AND METHODS: Twenty subjects selected randomly received butorphanol tartrate 1 mg intramuscular and 20 subjects received tramadol hydrochloride 50 mg intramuscular after the removal of mandibular third molars. Time of injection, amount of anesthetic injected, duration of surgery, adverse effects were recorded.(21) RESULTS: The mean amount of LA administered in butorphanol group was 2.6450 ml and in tramadol group was 2.640 ml respectively, the mean duration for surgery was 56.75 and 53.5 minutes for butorphanol and tramadol groups respectively which was statistically not significant. Pain assessment was done with VAS which showed mean of 19.2 and 15.5 mm (p = 0.001) which was significant for butorphanol and tramadol respectively after 12 hours. The mean time for rescue medication requirement was 5.9 hours (for tramadol) and 8.4 hours (for butorphanol). Effective analgesic activity was seen by butorphanol 1 mg intramuscular then tramadol 50 mg. CONCLUSION: Butorphanol 1 mg was more effective than tramadol 50 mg in respect to postoperative analgesia. PMID- 22918012 TI - Knowledge, attitude and use of fluorides among dentists in Texas. AB - AIM: The centers for disease control and prevention (CDC) recommendations on fluoride use were published in 2001. This study examines how this information has diffused to practicing dentists and the level of fluoride knowledge and use among Texas dentists. MATERIALS AND METHODS: A questionnaire was sent to dentists who self-identified as being in pediatric (343), dental public health (72), and general practices (980); a 12% sample of registered dentists in Texas. RESULTS: Response rate was 42.9%. About 90% of surveyed dentists reported using fluorides routinely. Only 18.8% reported fluoride varnish as the topical fluoride most often used. About 57% incorrectly identified primary effect of fluoride. 'Makes enamel stronger while tooth is developing prior to eruption' was the most commonly cited wrong answer (44%). Only 5% identified that posteruptive effect exceeds any preeruptive effect. CONCLUSION: Despite the evidence for fluoride varnish preventing and controlling dental caries being Grade I, its use is still uncommon. Dentists are expected to be knowledgeable about products they use, but this study reflects lack of understanding about fluoride's predominant mode of action. More accurate understanding enables dentists to make informed and appropriate judgment on treatment options and effective use of fluoride based on risk assessment of dental caries. CLINICAL SIGNIFICANCE: Lack of knowledge of, or failure of adherence to evidence based guidelines in caries prevention by use of appropriate fluoride regimens may adversely affect caries incidence in the population. PMID- 22918013 TI - Comparison of metal ion release from different bracket archwire combinations: an in vitro study. AB - AIM: The metal ion released from the orthodontic appliance may cause allergic reactions particularly nickel and chromium ions. Hence, this study was undertaken to determine the amount of nickel, chromium, copper, cobalt and iron ions released from simulated orthodontic appliance made of new archwires and brackets. MATERIALS AND METHODS: Sixty sets of new archwire, band material, brackets and ligature wires were prepared simulating fixed orthodontic appliance. These sets were divided into four groups of fifteen samples each. Group 1: Stainless steel rectangular archwires. Group 2: Rectangular NiTi archwires. Group 3: Rectangular copper NiTi archwires. Group 4: Rectangular elgiloy archwires. These appliances were immersed in 50 ml of artificial saliva solution and stored in polypropylene bottles in the incubator to simulate oral conditions. After 90 days the solution were tested for nickel, chromium, copper, cobalt and iron ions using atomic absorption spectrophotometer. RESULTS: Results showed that high levels of nickel ions were released from all four groups, compared to all other ions, followed by release of iron ion levels. There is no significant difference in the levels of all metal ions released in the different groups. CONCLUSION: The study confirms that the use of newer brackets and newer archwires confirms the negligible release of metal ions from the orthodontic appliance. CLINICAL SIGNIFICANCE: The measurable amount of metals, released from orthodontic appliances in artificial saliva, was significantly below the average dietary intake and did not reach toxic concentrations. PMID- 22918014 TI - Epidemiology of dental caries among adults in a rural area in India. AB - BACKGROUND: Data on epidemiology of dental caries of adults in rural India appear to be sparse. OBJECTIVE: The purpose of the study was to assess the oral health status and dental treatment needs of a rural Indian population. MATERIALS AND METHODS: The study population consisted of 189 volunteer subjects with a mean age of 34.9 +/- 14.2 years and 54% males. Decayed, missing due to caries and filled teeth (DMFT) and tooth surfaces (DMFS) assessed the dental caries experience. Structured interviews collected data on perception of health including oral health, oral hygiene practices and snacking habits. RESULTS: While only 38.1% perceived themselves to be in good or very good dental health, nearly 85% felt the same about general health. The most common sugar exposure was sweetened tea; 75% consumed the beverage at least once a day. More than 80% of the subjects had untreated caries with mean DMFT and DMFS scores of 5.1 +/- 3.9 and 13.8 +/- 17.8, which lacked any gender differences. Dental treatment needs ranged from 16.9% two surface fillings to 60.8% one-surface fillings; 23.8% crowns or bridges and 37.6% extractions. Those who perceived themselves to be in better oral health had significantly lower DMFT (4.0 +/- 3.2 vs 5.9 +/- 4.1) and DMFS (8.4 +/- 11.7 vs 17.1 +/- 20.0) scores (p < 0.05). A similar trend was observed between perception of general health and DMFT (4.8 +/- 3.4 vs 7.0 +/- 5.6) and DMFS (11.9 +/- 13.7 vs 24.1 +/- 30.7) scores. CONCLUSION: Results indicate high levels of dental caries as well as dental treatment needs among the study participants. PMID- 22918015 TI - Effect of chemical disinfectant on the transverse strength of heat-polymerized acrylic resins subjected to mechanical and chemical polishing: an in vitro study. AB - AIMS: To evaluate the effect of chemical disinfectant on the transverse strength of heat-polymerized acrylic resins subjected to mechanical and chemical polishing. MATERIALS AND METHODS: A total of 256 rectangular specimens (65 * 10 * 3 mm) 128 per resin (Lucitone-199 and Acralyn-H) were fabricated. One side of each specimen was not polished and the other was either mechanically (n = 96) or chemically (n = 96) polished and immersed for 10, 30 and 60 minutes in 2% alkaline glutaraldehyde. Mechanically polished (n = 32) and chemically polished (n = 32) control specimens were immersed only in distilled water. The transverse strength (N/mm(2)) was tested for failure in a universal testing machine, at a crosshead speed of 5 mm/min. Data were statistically analyzed using 2-way ANOVA and Student t-test. RESULTS: chemical polishing resulted in significantly lower transverse strength values than mechanical polishing. Lucitone- 199 resin demonstrated the highest overall transverse strength for the materials tested. Heat-polymerized acrylic resins either mechanically or chemically polished, did not demonstrate significant changes in transverse strength during immersion in the disinfecting solution tested, regardless of time of immersion. CONCLUSION: Lucitone-199 resin demonstrated the highest overall transverse strength for the materials tested and significantly stronger than Acralyn-H with either type of polishing following immersion in 2% alkaline glutaraldehyde. CLINICAL SIGNIFICANCE: There is a concern that immersion in chemical solutions often used for cleansing and disinfection of prostheses may undermine the strength and structure of denture base resins. In this study it was observed that, the transverse strength of samples of Lucitone-199 was higher than that of the samples of Acralyn-H. The chances of fracture of the denture made of Lucitone-199 are less than that of dentures made of Acralyn-H. The chemically polished dentures may be more prone to fracture than mechanically polished dentures. PMID- 22918016 TI - A study to evaluate and compare the shear bond strength of resilient liners with heat cure denture base resins, with and without the effect of saliva: an in vitro study. AB - AIM: To evaluate and compare the shear bond strength of resilient liners with heat cure denture base resins in the presence or absence of saliva. MATERIALS AND METHODS: Two commercially available heat polymerized acrylics and three commercially available denture liners were immersed in artificial saliva for 7 days and 14 days, respectively. A total of 180 (Acralyn-H, No.90 and Lucitone - 199, No.90) specimens were prepared. Total of 90 overlapping joint specimens were prepared, 45 of them using Acralyn H (AGroup) and rest 45 using Lucitone-199 (L Group). The specimens were tested for flexural strength with a 3-point bending test on an Instron universal testing machine. The results were analyzed with a one-way analysis of variance (ANOVA). RESULTS: The mean difference in shear bond strength (SBS) at different time intervals was found to be statistically significant (p < 0.001). Lucitone-199 recorded a significantly higher mean SBS compared to Acralyn H (p < 0.001). Further, significant differences between GC and Densply, GC and Aswin liners, and between Dentsply and Aswin were noted (p < 0.001). Difference between baseline and 7 days time interval, as well as, between baseline and 14 days time interval with respect to the mean SBS of these materials were significant (p < 0.001). Also, the mean difference in SBS between 7 days time interval and 14 days time interval was statistically significant (p < 0.001). Among the three different liners, GC yielded a higher mean SBS compared to Aswin and Dentsply at all the three time intervals. The mean SBS recorded in Dentsply and Aswin was almost same at 14 days time interval, but at baseline and 7 days, it was higher in Aswin compared to Dentsply. CONCLUSION: Lucitone-199 recorded a higher mean SBS compared to Acralyn H. As the time interval increases, the mean SBS recorded in both the denture base materials decrease. Among the three different liners, GC yields a higher mean SBS compared to Aswin and Dentsply at all the three time intervals. CLINICAL SIGNIFICANCE: The most common reason for failures of resilient linings in removable dentures is the separation of these linings from the denture base. Therefore, poor adhesive bond properties are one of the serious defects of the material in clinical practice. PMID- 22918017 TI - Palatal rugoscopy among Puducherry population. AB - BACKGROUND: Human identification is one of the most challenging subjects that man has been confronted with. The fingerprints and DNA comparison are the most commonly used techniques in human identification. Palatoscopy is one of the recently developing methods to identify a victim-based on the palatal rugae pattern. AIMS AND OBJECTIVES: The aim of the study was to analyze the different rugae pattern in Puducherry population and to find whether palatoscopy is a useful tool in human identification and sex determination. MATERIALS AND METHODS: The studies consist of 100 male and female patients between the age group of 20 to 35 years. The rugae pattern was divided assessed based on Kotze classification. Chi-square test and one-way analysis was used to study the statistical significance. RESULTS: Wavy pattern appeared to be the most predominant pattern followed by curved, straight, branched and circular pattern in both male and female patients. The shape and number of rugae pattern is similar in male and females. CONCLUSION: The present study concludes that wavy pattern appear to be most common rugae pattern among Puducherry population. No significant difference in rugae pattern was noted among the male and female group. Rugae pattern is unique to each individual and can be an effective tool in human identification. PMID- 22918018 TI - Surface morphological changes in human enamel following bleaching: an in vitro scanning electron microscopic study. AB - OBJECTIVE: The purpose of this study was to evaluate, using scanning electron microscopy (SEM), the morphological and structural changes of the enamel induced by three bleaching agents namely old McInnes solution, modified McInnes solution and 10% carbamide peroxide gel at different time intervals. MATERIALS AND METHODS: Fifteen freshly extracted noncarious human central incisors with intact enamel surface were selected. The teeth were sectioned at the cementoenamel junction separating the crown portion from the root using a diamond separating disk. Following this, the samples were subjected to three different bleaching agents: Group 1: Old McInnes solution, group 2: modified McInnes solution and group 3: 10% carbamide peroxide for a period of 15, 30 and 60 minutes, 24 and 30 hours time interval. The sample stubs were subjected to scanning electron microscope and were photographed at 2000 and 10,000 magnifications. CONCLUSION: The present study revealed no indication of either etching or significant change in surface morphology of enamel when evaluated under scanning electron microscope after 6 weeks treatment with various bleaching agents. CLINICAL SIGNIFICANCE: Morphological alterations in bleached enamel are both concentration and time dependent. PMID- 22918019 TI - The use of fragments of thin veneers as a restorative therapy for anterior teeth disharmony: a case report with 3 years of follow-up. AB - AIM: The present case report described the use of contact lens of thin porcelain veneers as a restorative therapy to solve anterior teeth disharmony. BACKGROUND: Fragments of thin veneers are minimally invasive restorations with little or no dental preparation and present thickness ranging from 0.2 to 0.5 mm. They are used in case of diastema closure, small changes of teeth, color and restoration of teeth with small fractures. CASE REPORT: A 25-year-old man was admitted at a dental clinic complaining about the diastema presence on the upper anterior teeth. Patient was referred to an orthodontic treatment in order to provide better distribution of the diastemas and harmonious proportion of the teeth. Afterwards, contact lens of thin porcelain veneers were fabricated on the six upper anterior teeth. CONCLUSION: Based on the outcomes of this clinical report, we considered the use of fragments of thin veneers as a successful treatment option after 3 years of follow-up. CLINICAL SIGNIFICANCE: The fragments of thin veneers have been established to be an interesting alternative to esthetically restore the anterior teeth with minimal invasiveness. However, since it is a new treatment modality, longitudinal studies are necessary to understand the material's behavior. PMID- 22918020 TI - Using the self-etch adhesives in anterior restoration. AB - With the arrival of self-etch adhesives systems, there has been a rise in interest among clinicians, making it imperative for health professionals to have knowledge of the properties, characteristics, the association as well as the dental structures of these materials, in order to select them and use them correctly. The self-etch adhesive systems show good values of bond strength, microleakage and performance, and have therefore become an option in direct adhesive restorations. In the regard, this case study aims to describe the technique involving the use of selfetch adhesives system for direct restoration of anterior teeth. PMID- 22918021 TI - A new alternative jaw motion rehabilitation device: The Okbite. PMID- 22918022 TI - Is there a role for acupuncture in the treatment of tendinopathy? AB - Tendinopathy is a debilitating condition in athletic and sedentary populations for which a gold standard treatment strategy does not yet exist. While the pathophysiology of tendinopathy is well understood, a debate remains as to the nature of the pain mechanism in tendinopathy which makes treatment selection challenging. This clinical discussion presents evidence to suggest that acupuncture may have a role in the treatment of tendinopathy, through the facilitation of tendon blood flow and fibroblastic activity, making recommendations for further research. PMID- 22918023 TI - Local reflexive mechanisms essential for snakes' scaffold-based locomotion. AB - Most robots are designed to work in predefined environments, and irregularities that exist in the environment interfere with their operation. For snakes, irregularities play the opposite role: snakes actively utilize terrain irregularities and move by effectively pushing their body against the scaffolds that they encounter. Autonomous decentralized control mechanisms could be the key to understanding this locomotion. We demonstrate through modelling and simulations that only two local reflexive mechanisms, which exploit sensory information about the stretching of muscles and the pressure on the body wall, are crucial for realizing locomotion. This finding will help develop robots that work in undefined environments and shed light on the understanding of the fundamental principles underlying adaptive locomotion in animals. PMID- 22918024 TI - Hydrogenotrophic methanogens dominate in biogas reactors fed with defined substrates. AB - Methanogenic communities in 200L biogas reactors containing liquid manure were investigated for 33 d. The reactors were consecutively fed with casein, starch and cream. Real-time PCR with primers targeting the gene for methyl coenzyme-M reductase (mcrA) resulted in copy numbers of up to 2.1*10(9) g dry mass(-1). Single strand conformation polymorphism (SSCP) analysis revealed a stable community consisting of few hydrogenotrophic methanogens. One of the two most abundant species was closely related to Methanospirillum hungatei, whereas the other one was only distantly related to other methanogens, with Methanopyrus kandleri being the closest cultivated relative. Most probable number (MPN) cultivations were accomplished with a sample from a 600 m(3) reactor from which all manures used in the experiments originated, and equal cell counts of ca. 10(9) g dry mass(-1) were found for cultivations with acetate, H(2) and methanol. SSCP analysis of these samples and sequencing of the DNA bands identified different hydrogenotrophic methanogens in all samples, and acetoclastic methanogens closely related to Methanosarcina mazei in the samples cultivated with acetate and methanol. As the acetoclastic species were not found in any other SSCP sample, it was supposed that the ammonia values in the manure of the laboratory biogas reactor, which ranged from 2.48 to 3.61 g NH(4)-NL(-1), inhibited the growth of the acetoclastic methanogens. PMID- 22918026 TI - Pre-filled thiopental syringes reduce cost and wastage whilst improving safety. PMID- 22918025 TI - Maternal characteristics and satisfaction associated with intrapartum epidural analgesia use in Canadian women. AB - BACKGROUND: The use of epidural analgesia for intrapartum pain relief has increased over recent decades, with rates varying among developed countries. The objective of this study was to determine the socio-demographic and obstetric characteristics and satisfaction associated with epidural analgesia use for intrapartum analgesia in Canadian women. METHODS: Using the Maternity Experiences Survey of the Canadian Perinatal Surveillance System, a randomly-selected sample of 5350 women who had attempted a vaginal birth was examined, representing 63900 Canadian women. Univariate and multivariate logistic regression models were used to determine the association between socio-demographic and obstetric characteristics and use of epidural analgesia. RESULTS: The rate of epidural analgesia use was 57.3% among women with a trial of vaginal birth. Women with higher education levels (OR 1.12, 95%CI 1.07-1.18) and higher income (OR 1.10, 95%CI 1.05-1.14) were more likely to use epidural analgesia. Women were less likely to use epidural analgesia if they were First Nations (OR 0.77, 95%CI 0.69 0.84), unemployed (OR 0.89, 95%CI 0.81-0.97) or a homemaker (OR 0.86, 95%CI 0.82 0.9), living in a rural area (OR 0.60, 95%CI 0.57-0.63), multiparous (OR 0.32, 95%CI 0.31-0.33) and seeing a midwife, family physician or nurse for prenatal (OR 0.6, 95%CI 0.53-0.67, OR 0.71, 95%CI 0.67-0.74, OR 0.75, 95%CI 0.56-0.99, respectively) and intrapartum care (OR 0.12, 95%CI 0.10-0.14, OR 0.58, 95%CI 0.55 0.61, OR 0.58, 95%CI 0.54-0.63, respectively). Maternal prenatal stressors were associated with epidural analgesia use in a non-linear fashion: compared with women with zero stressful events, women with one stressful event were more likely to use epidural analgesia (OR 1.07, 95%CI 1.02-1.12), but women with two or more events were less likely to use epidural analgesia (OR 0.88, 95%CI 0.84-0.92). Satisfaction with labor was high, regardless of type of analgesia used. CONCLUSIONS: Socio-demographic and obstetric characteristics, combined with a high satisfaction with labor regardless of the method of pain relief, support the existence of smaller rural obstetric centers unable to provide availability of continuous epidural labor analgesia. PMID- 22918027 TI - Novel use of a continuous intrathecal catheter for appendectomy following cesarean section. PMID- 22918028 TI - Vaginal delivery in a parturient excessively anticoagulated with fondaparinux. PMID- 22918029 TI - Epidural lipomatosis causing new debilitating back pain in a patient with human immunodeficiency virus on highly active antiretroviral therapy. AB - Spinal epidural lipomatosis is a rare condition of adipose tissue hypertrophy in the epidural space. Through nerve root and spinal canal compression, it may lead to both sensory and motor compromise. Chronic steroid use, obesity and other metabolic derangements are known causes of spinal epidural lipomatosis. Recently, several cases have been attributed to antiretrovirals taken to treat human immunodeficiency virus, given their side effects of lipodystrophy and altered fat metabolism. We report a patient on highly active antiretroviral therapy (HAART) who developed debilitating back, hip and thigh pain during the third trimester of pregnancy that prevented ambulation. Epidural lipomatosis was diagnosed by magnetic resonance imaging. Given her evolving symptoms, neuraxial anesthesia was considered to be contraindicated. We present her management and labor course. PMID- 22918030 TI - Risk factors for failed conversion of labor epidural analgesia to cesarean delivery anesthesia: a systematic review and meta-analysis of observational trials. AB - BACKGROUND: This systematic review and meta-analysis evaluates evidence for seven risk factors associated with failed conversion of labor epidural analgesia to cesarean delivery anesthesia. METHODS: Online scientific literature databases were searched using a strategy which identified observational trials, published between January 1979 and May 2011, which evaluated risk factors for failed conversion of epidural analgesia to anesthesia or documented a failure rate resulting in general anesthesia. RESULTS: 1450 trials were screened, and 13 trials were included for review (n=8628). Three factors increase the risk for failed conversion: an increasing number of clinician-administered boluses during labor (OR=3.2, 95% CI 1.8-5.5), greater urgency for cesarean delivery (OR=40.4, 95% CI 8.8-186), and a non-obstetric anesthesiologist providing care (OR=4.6, 95% CI 1.8-11.5). Insufficient evidence is available to support combined spinal epidural versus standard epidural techniques, duration of epidural analgesia, cervical dilation at the time of epidural placement, and body mass index or weight as risk factors for failed epidural conversion. CONCLUSION: The risk of failed conversion of labor epidural analgesia to anesthesia is increased with an increasing number of boluses administered during labor, an enhanced urgency for cesarean delivery, and care being provided by a non-obstetric anesthesiologist. Further high-quality studies are needed to evaluate the many potential risk factors associated with failed conversion of labor epidural analgesia to anesthesia for cesarean delivery. PMID- 22918032 TI - The mu-opioid receptor-selective peptide antagonists, antanal-1 and antanal-2, produce anticonvulsant effects in mice. AB - The activation of the mu-opioid receptors (MOR) in the central nervous system has a proconvulsant effect and seizures are a common side effect of high doses of short acting opioids, like morphine or fentanyl. However, the correct assessment of the role of MOR blockade in the initiation and propagation of epilepsy was hampered by the lack of potent and selective MOR antagonists. In this study we aimed at characterizing the effect of MOR blockade on the seizure threshold in mice using recently developed selective antagonists antanal-1 and antanal-2 and a classical MOR antagonist, beta-funaltrexamine (beta-FNA). The effect of the centrally administered MOR antagonists was characterized in the maximal electroshock seizure threshold (MEST), the 6 Hz psychomotor seizure threshold and the intravenous pentylenetetrazole (PTZ) seizure threshold test in mice. The acute effect of the studied compounds on skeletal muscular strength in mice was quantified in the grip-strength test. Antanal-1 and antanal-2 (30 and 50 nmol/mouse, i.c.v.), but not beta-FNA significantly increased the seizure threshold in the MEST test in mice. In the 6-Hz test, all tested MOR antagonists significantly increased the psychomotor seizure threshold and the most potent anticonvulsant effect was observed for antanal-2 (2, 10 and 30 nmol/mouse, i.c.v.). The i.c.v. administration of beta-FNA (10 and 30 nmol/mouse, i.c.v.), antanal-1 and antanal-2 (both 30, 50 and 100 nmol/mouse, i.c.v.) did not produce any significant effect on PTZ seizure threshold, the generalized clonus or the forelimbs tonus. All tested compounds did not affect muscle strength, as determined in the grip strength test. Our study demonstrated that the novel MOR selective antagonists antanal-1 and antanal-2 displayed a potent and dose dependent anticonvulsant action involving non-GABA-ergic, but some other pathways and mechanisms in animal models of epileptic seizures. We suggest that antanals are promising drug templates for future therapeutics, which may be used in the treatment of epilepsy in humans. PMID- 22918034 TI - OCT-guided stenting of a spontaneous coronary artery dissection. AB - We present the case of a 67 year-old patient that presented to our institution with acute and severe chest pain. Optical coherence tomography high-resolution images of the coronary lumen, allowed us to confirm diagnosis of spontaneous coronary artery dissection, guide treatment, and verify the results of our intervention. PMID- 22918035 TI - Urinary, sexual, and cosmetic results after puberty in hypospadias repair: current results and trends. AB - PURPOSE OF REVIEW: To give an overview of the recently published long-term outcomes of hypospadias surgery performed at childhood, of patients who have had multiple previous repairs, and results of surgery done to treat late complications following hypospadias repair. RECENT FINDINGS: Urethral function after hypospadias repair is good, but cosmesis based on the patients' opinion, on the long term, was disappointing. Also erectile function was reported to be good, although persisting curvature and ejaculation disorders were mentioned, more evidently in patients with proximal hypospadias. Long-term results using buccal mucosa repairs in hypospadias cripples are good, but the use of tissue expanders may be a good alternative. Late complications of hypospadias repair, such as urethral strictures, are difficult to treat, and have a high failure rate compared to urethroplasty for other reasons. SUMMARY: Functional results of hypospadias repair are generally satisfactory in the long term, although improvement must be pursued. Most adult men with a history of hypospadias present themselves with urinary tract symptoms. Cosmesis judged by patients remains rather poor in the long run and better techniques should be found. Preferably, assessment of long-term results should be done by validated test methods for better comparison. PMID- 22918033 TI - General anesthetics and beta-amyloid protein. AB - With roughly 234 million people undergoing surgery with anesthesia each year worldwide, it is important to determine whether commonly used anesthetics can induce any neurotoxicity. Alzheimer's disease (AD) is the most common form of age related dementia, and a rapidly growing health problem. Several studies suggest that anesthesia could be associated with the development of AD. Moreover, studies in cultured cells and animals show that commonly used inhalation anesthetics may induce changes consistent with AD neuropathogenesis, e.g., beta-amyloid protein accumulation. Therefore, in this mini review, we focus on the recent research investigating the effects of commonly used anesthetics including isoflurane, sevoflurane, desflurane, nitrous oxide, and propofol, on Abeta accumulation in vitro and in vivo. We further discuss the future direction of the research determining the effects of anesthetics on beta-amyloid protein accumulation. PMID- 22918036 TI - Varicocele repair for nonobstructive azoospermia. AB - PURPOSE OF REVIEW: To evaluate the role of varicocelectomy in the management of patients with varicoceles and nonobstructive azoospermia and to review predictors of successful outcomes. RECENT FINDINGS: Several small, retrospective, noncontrolled studies have documented return of sperm to the ejaculate in up to 56% of men with nonobstructive azoospermia (NOA) following varicocele repair. Additionally, a recent meta-analysis has reported a 6% spontaneous pregnancy rate in amongst NOA patients who underwent varicocele repair, regardless of surgical technique. Although these observations are promising, evidence for whether or not varicocele repair significantly improves spermatogenesis within an impaired testicle is conflicting. No clear predictors of success following varicocele repair have been identified, but a certain level of spermatogenesis on testicular biopsy appears to be necessary for a desirable outcome after varicocele repair. SUMMARY: The role of varicocelectomy for the treatment on NOA is controversial. Prospective, controlled studies are needed in order to define the true benefit of varicocele repair in men with NOA, in terms of improvement in semen parameters, testicular sperm retrieval rates, and pregnancy outcomes. PMID- 22918037 TI - Urethral strictures in children. AB - PURPOSE OF THE REVIEW: The review is an attempt to present the current literature regarding strictures in children to provide an evidence-based recommendation regarding diagnosis and treatment. RECENT FINDINGS: The level of evidence upon which to base therapy of strictures in children is low and consists mostly of case series from single institutions. Hence most of the information is extrapolated from the adult literature. A consensus committee of the Societe Internationale d'Urologie reviewed the literature, and the committee report (which is as yet unpublished) provides the basis for most of the information herein. SUMMARY: Because there is relatively little information published on this subject, there is a need for prospective studies and multi-institutional series. Additionally, there is a need for basic studies of urethral wound healing to provide a better understanding of the problem. PMID- 22918038 TI - Epispadias repair: functional outcome of complete disassembly. AB - PURPOSE OF REVIEW: Complete penile disassembly (CPD) is a widely utilized procedure for epispadias repair. The rarity of the anomaly and limited number of patients in published series limit our ability to fully evaluate the outcome of such a technique. RECENT FINDINGS: We reviewed the literature for published data on CPD. We looked at different complications of the procedure and the main modifications to alleviate such complications. We looked at functional data on the effect of such a technique on erectile function. This review should be helpful in parents/patient counseling. Future areas for research are suggested. SUMMARY: CPD is a safe and highly successful technique for epispadias repair in infants, boys and adults. There is an ongoing concern with the procedure in neonates. The procedure has a satisfactory outcome when performed for isolated epispadias. In the exstrophy population, long-term data are required to evaluate the outcome of the technique on urinary continence and sexual functions. PMID- 22918039 TI - Silent cerebral infarct in child patients with beta thalassaemia intermedia. AB - There are numerous reports that patients with thalassemia are faced with hypercoagulability leading to vascular disorders. One of these complications is known as a silent infarct, defined as a small infarct detected by cerebral imaging but without any neurological symptoms. Since it has a progressive nature, it is of vital importance because it may lead to symptomatic cerebrovascular accidents in the future. Twenty-two children with thalassemia intermedia were enrolled into the study and MRI scans were performed. All demographic data and clinical features of the patients were obtained during the follow-up period. In addition to the patients, 13 healthy controls were included to compare serum anticoagulant levels with those of the thalassemia intermedia patients. Four of the patients were found to have silent cerebral infarcts (SCIs). The lesions involved varying amounts of the deep cerebral white matter and sub-cortical areas. One patient showed 'net line' filling defects within the ambient cistern on MRI images corresponding to moyamoya vessels. Three patients had undergone splenectomy, and three were transfused irregularly and had less than six transfusions per year. More importantly, protein C levels were lower and platelet levels were significantly higher in the patient group compared with controls. We were not able to find any association between SCI and transfusion number or splenectomy. However, of the total patients four thalassemia intermedia patients had SCI in early childhood and this is an unusual finding. In order to verify the findings, further studies must be conducted involving larger numbers of patients. PMID- 22918040 TI - Double-edged sword in the heart: trapped deep venous thrombus in a patent foramen ovale. AB - Trapped thrombus in a patent foramen ovale is a rare condition. Echocardiography is the main tool for diagnosis and for determination of the treatment to choose. There are a number of treatment options for trapped deep venous thrombus in a patent foramen ovale, including surgical thrombectomy, thrombolytics, and anticoagulant therapy. All patients should be evaluated individually, because the systemic and pulmonary thromboembolism risk of all treatment options is like a 'double-edged sword'. Here, we report a case of a patient with trapped thrombus in the patent foramen ovale detected by echocardiography, and successfully treated with surgical thrombectomy under extracorporeal circulation. PMID- 22918031 TI - Cytokine dysregulation in autism spectrum disorders (ASD): possible role of the environment. AB - Autism spectrum disorders (ASD) are neurodevelopmental diseases that affect an alarming number of individuals. The etiological basis of ASD is unclear, and evidence suggests it involves both genetic and environmental factors. There are many reports of cytokine imbalances in ASD. These imbalances could have a pathogenic role, or they may be markers of underlying genetic and environmental influences. Cytokines act primarily as mediators of immunological activity but they also have significant interactions with the nervous system. They participate in normal neural development and function, and inappropriate activity can have a variety of neurological implications. It is therefore possible that cytokine dysregulation contributes directly to neural dysfunction in ASD. Further, cytokine profiles change dramatically in the face of infection, disease, and toxic exposures. Imbalances in cytokines may represent an immune response to environmental contributors to ASD. The following review is presented in two main parts. First, we discuss select cytokines implicated in ASD, including IL-1Beta, IL-6, IL-4, IFN-gamma, and TGF-Beta, and focus on their role in the nervous system. Second, we explore several neurotoxic environmental factors that may be involved in the disorders, and focus on their immunological impacts. This review represents an emerging model that recognizes the importance of both genetic and environmental factors in ASD etiology. We propose that the immune system provides critical clues regarding the nature of the gene by environment interactions that underlie ASD pathophysiology. PMID- 22918041 TI - Plasma tissue-type plasminogen activator increases fibrinolytic activity of exogenous urokinase-type plasminogen activator. AB - The relationship between tissue-type plasminogen activator (tPA) and urokinase type plasminogen activator (uPA) function is not fully understood. The aim of this study was to compare in vitro the fibrinolytic activity of tPA and uPA and evaluate their possible interaction. Blood coagulation and fibrinolysis were conducted by rotation thromboelastometry, whereas blood clotting was induced by CaCl2 and tissue factor and fibrinolysis additively by tPA and uPA. Effective concentration 50% of tPA and uPA fibrinolytic activity in blood was found to be 90 and 33 IU/ml relating to the units of activity established by manufacturers in the absence of blood. uPA-induced fibrinolysis in blood was faster compared with tPA used at the same units of activity. In contrast, in a blood-free system containing fibrinogen, plasminogen, and thrombin, fibrinolysis induced by uPA was weaker than by tPA. Treating of blood with tranexamic acid (60 mmol/l) was followed by decreased fibrinolytic potential of both exogenous tPA and uPA, despite uPA by itself is known to be not sensitive to aminocaproic acids. Thus, uPA exerted stronger activity in blood but weaker activity in blood-free system, compared with tPA. Taking into account the intermolecular binding of uPA to tPA, it could be suggested that interaction of exogenous uPA with plasma-containing tPA provided amplification of fibrinolysis due to formation of uPA/tPA complex possessing high affinity to fibrin. PMID- 22918042 TI - Synthetic farnesoid X receptor agonists induce high-density lipoprotein-mediated transhepatic cholesterol efflux in mice and monkeys and prevent atherosclerosis in cholesteryl ester transfer protein transgenic low-density lipoprotein receptor (-/-) mice. AB - Farnesoid X receptor (FXR), a bile acid-activated nuclear hormone receptor, plays an important role in the regulation of cholesterol and more specifically high density lipoprotein (HDL) homeostasis. Activation of FXR is reported to lead to both pro- and anti-atherosclerotic effects. In the present study we analyzed the impact of different FXR agonists on cholesterol homeostasis, plasma lipoprotein profiles, and transhepatic cholesterol efflux in C57BL/6J mice and cynomolgus monkeys and atherosclerosis development in cholesteryl ester transfer protein transgenic (CETPtg) low-density lipoprotein receptor (LDLR) (-/-) mice. In C57BL/6J mice on a high-fat diet the synthetic FXR agonists isopropyl 3-(3,4 difluorobenzoyl)-1,1-dimethyl-1,2,3,6-tetrahydroazepino[4,5-b]indole-5 carboxylate (FXR-450) and 4-[2-[2-chloro-4-[[5-cyclopropyl-3-(2,6-dichlorophenyl) 4-isoxazolyl]methoxy]phenyl]cyclopropyl]benzoic acid (PX20606) demonstrated potent plasma cholesterol-lowering activity that affected all lipoprotein species, whereas 3-[2-[2-chloro-4-[[3-(2,6-dichlorophenyl)-5-(1-methylethyl)-4 isoxazolyl]methoxy]phenyl]ethenyl]benzoic acid (GW4064) and 6-ethyl chenodeoxycholic acid (6-ECDCA) showed only limited effects. In FXR wild-type mice, but not FXR(-/-) mice, the more efficacious FXR agonists increased fecal cholesterol excretion and reduced intestinal cholesterol (re)uptake. In CETPtg LDLR(-/-) mice PX20606 potently lowered total cholesterol and, despite the observed HDL cholesterol (HDLc) reduction, caused a highly significant decrease in atherosclerotic plaque size. In normolipidemic cynomolgus monkeys PX20606 and 6-ECDCA both reduced total cholesterol, and PX20606 specifically lowered HDL(2c) but not HDL(3c) or apolipoprotein A1. That pharmacological FXR activation specifically affects this cholesterol-rich HDL(2) subclass is a new and highly interesting finding and sheds new light on FXR-dependent HDLc lowering, which has been perceived as a major limitation for the clinical development of FXR agonists. PMID- 22918044 TI - The role of peritoneal cytology at risk-reducing salpingo-oophorectomy (RRSO) in women at increased risk of familial ovarian/tubal cancer: Is the evidence strong enough? PMID- 22918043 TI - Differential effects of Selexipag [corrected] and prostacyclin analogs in rat pulmonary artery. AB - {4-[(5,6-Diphenylpyrazin-2-yl)(isopropyl)amino]butoxy}acetic acid (ACT-333679) is the main metabolite of the selective prostacyclin (PGI(2)) receptor (IP receptor) agonist selexipag. The goal of this study was to determine the influence of IP receptor selectivity on the vasorelaxant efficacy of ACT-333679 and the PGI(2) analog treprostinil in pulmonary artery under conditions associated with pulmonary arterial hypertension (PAH). Selexipag and ACT-333679 evoked full relaxation of pulmonary artery from control and monocrotaline (MCT)-PAH rats, and ACT-333679 relaxed normal pulmonary artery contracted with either endothelin-1 (ET-1) or phenylephrine. In contrast, treprostinil evoked weaker relaxation than ACT-333679 of control pulmonary artery and failed to induce relaxation of pulmonary artery from MCT-PAH rats. Treprostinil did not evoke relaxation of normal pulmonary artery contracted with either ET-1 or phenylephrine. Expression of prostaglandin E(3) (EP(3)) receptor mRNA was increased in pulmonary artery from MCT-PAH rats. In contraction experiments, the selective EP(3) receptor agonist sulprostone evoked significantly greater contraction of pulmonary artery from MCT-PAH rats compared with control rats. The presence of a threshold concentration of ET-1 significantly augmented the contractile response to sulprostone in normal pulmonary artery. ACT-333679 did not evoke direct contraction of rat pulmonary artery, whereas treprostinil evoked concentration dependent contraction that was inhibited by the EP(3) receptor antagonist (2E)-3 (3',4'-dichlorobiphenyl-2-yl)-N-(2-thienylsulfonyl)acrylamide. Antagonism of EP(3) receptors also revealed a relaxant response to treprostinil in normal pulmonary artery contracted with ET-1. These data demonstrate that the relaxant efficacy of the selective IP receptor agonist selexipag and its metabolite ACT 333679 is not modified under conditions associated with PAH, whereas relaxation to treprostinil may be limited in the presence of mediators of disease. PMID- 22918045 TI - Preparation and adsorption performance of 5-azacytosine-functionalized hydrothermal carbon for selective solid-phase extraction of uranium. AB - A new solid-phase extraction adsorbent was prepared by employing a two-step "grafting from" approach to anchor a multidentate N-donor ligand, 5-azacytosine onto hydrothermal carbon (HTC) microspheres for highly selective separation of U(VI) from multi-ion system. Fourier-transform infrared and X-ray photoelectron spectroscopies were used to analyze the chemical structure and properties of resultant HTC-based materials. The adsorption behavior of U(VI) onto the adsorbent was investigated as functions of pH, contact time, ionic strength, temperature, and initial U(VI) concentration using batch adsorption experiments. The U(VI) adsorption was of pH dependent. The adsorption achieved equilibrium within 30 min and followed a pseudo-second-order equation. The adsorption amount of U(VI) increased with raising the temperature from 283.15 to 333.15K. Remarkably, high ionic strength up to 5.0 mol L(-1) NaNO(3) had only slight effect on the adsorption. The maximum U(VI) adsorption capacity reached 408.36 mg g(-1) at 333.15K and pH 4.5. Results from batch experiments in a simulated nuclear industrial effluent, containing 13 co-existing cations including uranyl ion, showed a high adsorption capacity and selectivity of the adsorbent for uranium (0.63 mmol U g(-1), accounting for about 67% of the total adsorption amount). PMID- 22918046 TI - Co-grafting of porphyrins and fullerenes on ZnO nanorods: towards supramolecular donor-acceptor assembly. AB - This work presents the synthesis and physico-chemical characterization of a novel artificial photosynthetic design, using anisotropic semiconducting nanorods as scaffolds to assemble organic donor-acceptor complexes on their surface. These hierarchical hybrid D-A assemblies were obtained by the co-grafting of porphyrins and fullerenes on the ZnO nanorods. Polarity of the solvent and porphyrin to fullerene ratios were investigated to be markedly influencing the donor-acceptor interaction under the co-grafted conditions on ZnO nanorods. Fourier transform infrared spectroscopy, cyclic voltammetry, electronic absorption and fluorescence spectroscopic techniques were used to characterize the formation and investigate the optoelectronic properties of porphyrin-fullerene complexes on the surface of ZnO. To the best of our knowledge, this is the first example of highly interacting porphyrin-fullerene complexes on ZnO nanorods, which may allow generating efficient nanosystems for artificial photosynthesis and harvesting of solar energy. PMID- 22918047 TI - Apparent voluminosity of casein micelles determined by rheometry. AB - The voluminosity of casein micelles was studied by means of static rheometry. In concentrated casein micelle suspensions with fluid-like flow properties to random close packing, the reduced viscosity was obtained and linked via the Krieger Dougherty model of volume fraction effect. The temperature dependency of hydration was fitted in a wide temperature (5 degrees C<=theta<=35 degrees C) and mass fraction range (0.01<=w<=0.16). The results of our study suggested that the voluminosity of casein micelles decreased with increasing temperature and asymptotically reached a plateau (theta>30 degrees C) as a consequence of the protein swelling and decreasing water immobilization. The obtained apparent voluminosity of native casein micelles dispersed in UF permeate was 5.0 ml g(-1) at 5 degrees C, 4.1 ml g(-1) at 20 degrees C, and 3.7 ml g(-1) at 35 degrees C. PMID- 22918048 TI - Generation of diversiform gold nanostructures inspired by honey's components: growth mechanism, characterization, and shape separation by the centrifugation assisted sedimentation. AB - The green synthesis of irregular-shaped nanomaterials used for various applications in nanoplasmonics, medicine, and biotechnology creates an economical and environmental challenge. We describe the rapid wet-chemical approach to synthesis of stable and water-soluble gold nanostructues at room temperature. In addition to spherical and road-like nanoparticles, gold decahedra and triangular plates were grown using the one-step synthesis process of HAuCl(4) in the presence of honey, in which main components act as reducing (glucose) and stabilizing (fructose) agents; the mechanism of the process is discussed in details. The requirements for anisotropic phase boundaries for generation of polyhedral gold nanocrystals in solutions are highlighted. The synthesis, morphology, and separation procedure of gold nanoparticles are examined using the techniques of optical spectroscopy, transmission electron microscopy, and atomic force microscopy. We demonstrate that centrifugation can be used for efficient separation of nanoparticles with different shapes from a mixture. It was found that while centrifuging, the spheres sediment at the bottom of the tube, segregating from rods that form a deposit on the side wall, whereas polygons remain in the solution. PMID- 22918049 TI - High permeate flux of PVA/PSf thin film composite nanofiltration membrane with aluminosilicate single-walled nanotubes. AB - A new type of thin film nanocomposite (TFN) membranes for nanofiltration was successfully prepared by incorporating aluminosilicate single-walled nanotubes (SWNTs) within the poly(vinyl alcohol) (PVA) matrix. The nanocomposite PVA film was composed of well dispersed synthesized aluminosilicate SWNT with up to 20% volume fraction cast on a polysulfone support. Attenuated total reflectance Fourier transform infrared (ATR-FTIR) revealed that the TFN membranes have characteristic bands at 920-1010 cm(-1) corresponding to Si-OH and Si-O-Al stretching vibration of the aluminosilicate SWNT. This insinuated the successful incorporation of aluminosilicate SWNT into the polymer matrix, which was further confirmed and quantified by X-ray photoelectron spectroscopy (XPS). The PVA layers, in the range of 0.99-1.36 MUm, are free from large defects or cracks as observed in the scanning electron microscopy (SEM) images. The membrane surface hydrophilicity increased as the membrane roughness decreased and as the contact angles decreased from 64.2 degrees to 59.4-50.5 degrees . The increase in water flux is due to the presence of hydrophilic nanotubes. With the incorporation of the aluminosilicate single-walled nanotubes, higher permeate water flux was achieved, while sustaining high rejection of divalent ions (97%) and monovalent ions (59%). PMID- 22918050 TI - Surface control and cryogenic durability of transparent CNT coatings on dip coated glass substrates. AB - Transparent carbon nanotube (CNT) coatings were deposited on boro-silicate glass substrates by dip-coating. Ultraviolet-visible (UV) spectra, surface resistance measurement, and the wettability tests were used to investigate the optical transmittance and electrical properties of these CNT coatings. The changes in electrical and optical properties of these coatings were observed to be functions of the number of dip-coating cycles. The surface resistance of the CNT coated substrates decreased dramatically as the number of dip-coatings was increased, whereas the increases in the CNT layer thickness beyond that for the first dipping cycle had little effect on the transparent-properties. Static contact angle measurements proved to be an effective means for evaluating the surface morphology of CNT coatings. The interfacial durability of the CNT coatings on a glass substrate was much better than that of ITO coatings over the temperature range from -150 degrees C to +150 degrees C. PMID- 22918051 TI - Environmentally dependent stability of low-index hematite surfaces. AB - Nanoparticulate hematite is a promising material for catalytic and photoelectrochemical applications, where the surfaces are engineered to improve efficiency in different chemical environments. In the presence of water, the surfaces are typically passivated by hydroxyl groups, which modify the surface stability and reactivity. We use density functional theory and first principles thermodynamics to investigate the low-index surfaces (001), (101), and (104) in hydrous environments. For each of the surfaces, we build various hydroxylation configurations and compare their thermodynamic stability under different environmental conditions (temperature, humidity, and supersaturation of oxygen). The results enable us to construct surface phase diagrams, which provide guidance to the selection of surface structures, and the control of environmental conditions for specific applications. PMID- 22918052 TI - Synthesis and physicochemical characterization of alkanedyil-alpha-omega bis(dimethyldodecylammonium) bromide, 12-s-12,2Br-, surfactants with s=7, 9, 11 in aqueous medium. AB - In this work, three didodecyl dicationic dibromide dimeric surfactants 12-s 12,2Br(-), with different methylene spacer lengths (s=7, 9, and 11) were prepared and characterized and their properties compared to those of 12-s-12,2Br(-) surfactants with s=2, 3, 4, 5, 6, 8, 10, and 12. Information about the critical micelle concentration, the micellar ionization degree, the average aggregation number and the polarity of the interfacial region, and microviscosity of the micellar interior was obtained by using different techniques. Their surface activity was investigated by means of surface tension measurements. Micellization was also studied by using (1)H NMR and diffusion NMR (DOSY) spectroscopy as well as isothermal titration calorimetry. The values of the thermodynamic parameters show that the dimeric surfactants micellization is exothermic and driven by entropy. The occurrence of morphological transitions upon increasing surfactant concentration was studied, and the results indicate that the spacer length, s, plays a key role in the micellar growth of 12-s-12,2Br(-) aggregates. The value of s not only control the magnitude of C(*), the surfactant concentration above which the morphological transition from spherical micelles into elongated ones occurs, but also the sign of the enthalpy change accompanying the sphere-to-rod transition. PMID- 22918053 TI - Preparation and characterization of poly(L-histidine)/poly(L-glutamic acid) multilayer on silicon with nanometer-sized surface structures. AB - The specific design and modification of surfaces is of great interest, especially for functional surfaces and medical applications. In order to obtain films on a surface, the layer-by-layer deposition of polyelectrolytes represents a well established methodology. The alternating deposition of poly(L-histidine) and poly(L-glutamic acid) results in a defined, continuous surface coating that was thoroughly characterized using X-ray photoelectron spectroscopy, Fourier transform infrared spectroscopy, ellipsometry, X-ray reflectometry, atomic force microscopy, scanning electron microscopy, contact angle, and electrokinetic measurements. Surface charge, film growth, and final thickness were measured and cross-validated. Additionally, the chemical composition and distribution of polyelectrolytes in the layerstack were determined. Finally, the optical parameters were specified and the surface topography was visualized by several methods. These characterizations revealed a coating with embedded spheroids forming from the bottom layers. This rough surface formed by (PLH/PGA)(8) was highly reproducible and might provide unique features for the design of tailored surfaces. PMID- 22918054 TI - Synthesis of gold nanoparticles in niosomes. AB - This work outlines a novel method for the synthesis of stable gold nanoparticles within the spatially confined region of vesicles. For the first time, Span/cholesterol based niosomes have been used for nanoparticle synthesis. The restricted geometry within niosomes prevents nanoparticle aggregation. The results have important implications for controlled delivery of nanoparticles for therapeutic applications. PMID- 22918055 TI - Ethical issues in the introduction of case management for elderly people. AB - As case management is under development in France for elderly people, this study sets out to identify and analyse key situations responsible for ethical dilemmas for French case managers. We based our study on the analyses of individual interviews made with case managers and focus-group discussions, bringing together all case managers working in local organisations running for at least a year. We identified three situations giving rise to ethical dilemmas: in the order of importance, the refusals of care, the practicalities of collecting and sharing personal data and the allocation of resources. These three situations can lead to conflict between the principle of beneficence and those of respect for autonomy, non-maleficence and justice. We describe here how French case managers practically deal with these situations. PMID- 22918056 TI - Decisions of psychiatric nurses about duty to warn, compulsory hospitalization, and competence of patients. AB - Nurses who attend patients with psychiatric disorders often encounter ethical dilemmas and experience difficulties in making the right decision. The present study aimed to evaluate the decisions of psychiatric nurses regarding their duty to warn third parties about the dangerousness of the patient, the need for compulsory hospitalization, and the competence of patients. In total, 111 nurses working in the field of psychiatry in Turkey completed a questionnaire form consisting of 33 questions. The nurses generally assessed the decision-making competency of the patient correctly. However, their decisions regarding whether the patient should be compulsorily hospitalized and their understanding of their duty to warn/protect were less consistent. A significant relationship was found between the decisions of the psychiatric nurses and their work experience, them having children, and them having postgraduate education in psychiatric nursing. The nurses stated their desire to be part of the team that decided on ethical problems in psychiatry. PMID- 22918057 TI - Ethical aspects of undergoing a predictive genetic testing for Huntington's disease. AB - The aim of this study was to describe the experiences of undergoing a presymptomatic genetic test for the hereditary and fatal Huntington's disease, using a case study approach. The study was based on 18 interviews with a young woman and her husband from the decision to undergo the test, to receiving the results and trying to adapt to them, which were analysed using a life history approach. The findings show that the process of undergoing a presymptomatic test involves several closely connected ethical and medical questions, such as the reason for the test, the consequences of the test results and how health-care services can be developed to support people in this situation. PMID- 22918059 TI - Ethical issues experienced by intensive care unit nurses in everyday practice. AB - This research aims to identify the ethical issues perceived by intensive care nurses in their everyday practice. It also aims to understand why these situations were considered an ethical issue and what interventions/strategies have been or are expected to be developed so as to minimize them. Data were collected using a semi-structured interview with 15 nurses working at polyvalent intensive care units in 4 Portuguese hospitals, who were selected by the homogenization of multiple samples. The qualitative content analysis identified end-of-life decisions, privacy, interaction, team work, and health-care access as emerging ethical issues. Personal, team, and institutional aspects emerge as reasons behind the experience of these issues. Personal and team resources are used in and for solving these issues. Moral development and training are the most significant strategies. PMID- 22918058 TI - Exploring ethical aspects of elective surgery patients' decision-making experiences. AB - The practice of respecting patients' autonomy is rooted in the healthcare professionals' empathy for patients' situations, without which appropriate supports to the patients during the informed consent process may be remarkably moderated. The purpose of this study was to explore elective surgery patients' experiences during their decision-making process. This research was conducted using a phenomenological approach, and the data analysis was guided by Colaizzi's method. A total of 17 participants were recruited from a hospital in southern Taiwan. Two major themes emerged from the analyses: (a) a voluntary yet necessary alternative--to undergo a surgery and (b) alternatives compelled by the unalterable decision--the surgery. It was concluded that unless healthcare professionals can empathize with the distressed situation of their patients who are facing elective surgery, the practice of informed consent may become merely a routine. Nurses can be the best advocates for patients and facilitators to enhance communication between patients and healthcare personnel. PMID- 22918060 TI - Family involvement in the end-of-life decisions of competent intensive care patients. AB - In this article, we report the findings from a qualitative study that explored how relatives of terminally ill, alert and competent intensive care patients perceived their involvement in the end-of-life decision-making process. Eleven family members of six deceased patients were interviewed. Our findings reveal that relatives narrate about a strong intertwinement with the patient. They experienced the patients' personal individuality as a fragile achievement. Therefore, they viewed their presence as crucial with their primary role to support and protect the patient, thereby safeguarding his values and interests. However, their inclusion in decision making varied from active participation in the decision-making process to acceptance of the physicians' decision or just receiving information. We conclude that models of informed shared decision making should be utilised and optimised in intensive care, where nurses and physicians work with both the patient and his or her family and regard the family as partners in the process. PMID- 22918061 TI - Ethical challenges and how to develop ethics support in primary health care. AB - Ethics support in primary health care has been sparser than in hospitals, the need for ethics support is probably no less. We have, however, limited knowledge about how to develop ethics support that responds to primary health-care workers' needs. In this article, we present a survey with a mixture of closed- and open ended questions concerning: How frequent and how distressed various types of ethical challenges make the primary health-care workers feel, how important they think it is to deal with these challenges better and what kind of ethics support they want. Five primary health-care institutions participated. Ethical challenges seem to be prominent and common. Most frequently, the participants experienced ethical challenges related to scarce resources and lack of knowledge and skills. Furthermore, ethical challenges related to communication and decision making were common. The participants welcomed ethics support responding to their challenges and being integrated in their daily practices. PMID- 22918062 TI - Human rights of drug users according to public health professionals in Brazil. AB - Health is a basic human right, and drug use represents a severe influence on people's health. This qualitative study aimed to understand how health professionals in a public health-care team working with drug users in a city of the state of Sao Paulo, Brazil, perceive the human rights of these users and how these rights are being respected in health care. Data were collected through semistructured interviews with 10 health professionals at the service under analysis. A thematic analysis of the interviews reveals the professionals' difficulty to define the concept of human right and contextualize these rights in their work environment. A deeper understanding of the right to health, however, represents an important premise for a more humanized care practice in health services to drug users. PMID- 22918063 TI - Time ethics for persons with dementia in care homes. AB - The purpose of this study was to explore situations experienced by 12 health-care providers working in two nursing homes. Individual interviews, using a narrative approach, were conducted. A phenomenological-hermeneutical method, developed for researching life experiences, was applied in the analysis. The findings showed that good care situations are experienced when the time culture is flexible, the carers act in a sovereign time rhythm, not mentioning clock time or time as a stress factor. The results are discussed in terms of anthropological and sociological theory: time as event and action and flexible time cultures. Care settings for persons with dementia represent many challenges, such as a heavy workload and time strain. Time ethics is a construction, understanding time used in caring for persons suffering from dementia, which involves a mature, responsible and flexible nursing approach to these patients. PMID- 22918064 TI - Encountering place: a psychoanalytic approach for understanding how therapeutic landscapes benefit health and wellbeing. AB - This paper applies new thinking in psychoanalytic theory to demonstrate how certain therapeutic landscapes work to enhance health and wellbeing. Over the past two decades health geographers have extended the concept of therapeutic landscapes to analyse place and health as it applies to diverse locations embodying therapeutic qualities for different groups of people. Various approaches to how the process works have been psychoanalytic and psychotherapeutic theories. The concept of 'mentalising' as applied to therapeutic landscapes is offered by this paper as a further, hopefully enriching contribution to this line of enquiry. It examines the significance of prior familiarity with representations of specific landscapes, what the actual landscape offers to imaginative or projective reconstructions, the importance of cultural resources enabling landscape to be apprehended metaphorically, and the contribution of landscapes seen in this way to therapeutic effects. Therapeutic landscapes are shown to improve individual self-understanding and to enhance the capacity to empathise with others. PMID- 22918065 TI - Thoracic spinal epidural cavernous haemangioma with an acute onset: case report and the review of the literature. PMID- 22918066 TI - An unusual cause of factitious arthritis. AB - Septic arthritis and toxic synovitis are clinical conditions that can develop in association with various causes and involve symptoms such as pain, swelling, redness, sensitivity and restricted movement in the joint. A 42-year-old male presented to the emergency department with severe joint pain and nausea after injecting a 1-cc mixture of turpentine oil, eucalyptus oil, mint oil and thyme oil, which he purchased from an alternative medicine store, into his right knee with a syringe because of chronic knee pain. Ballottement and sensitivity were present at physical examination. Knee puncture yielded 60 cc of cloudy fluid. There was no growth in the material obtained. Improvement was observed following subsequent arthroscopic washing of the joint space and IV antibiotherapy, and the patient was discharged on day 21 of hospitalization with oral antibiotic and analgesic therapy. Intra-articular injection of foreign bodies into the knee joint space for therapeutic purposes, as in this case report, is a very rare occurrence, but may lead to potentially complicated arthritis. PMID- 22918067 TI - Synthetic pyrethroid increases lipid and protein oxidation and induces glutathione depletion in the cerebellum of adult rats: ameliorative effect of vitamin C. AB - The wide use and wide-spectrum toxicity of synthetic pyrethroid (SP) insecticides make them an emerging ecotoxicological concern. The objective of the current study was aimed to investigate the involvement of oxidative stress in lambda cyhalothrin (LTC)-induced cerebellum damages in adult rats and to evaluate the possible protective effect of vitamin C (vit C) as antioxidant. Exposure of rats to LTC during 3 weeks caused a significant (p < 0.05) increase in the levels of lipid peroxidation (LPO), nitric oxide (NO) and protein carbonyls (PCO) along with a significant (p < 0.05) decrease in the levels of reduced glutathione (GSH) and the activities of acetylcholinesterase, superoxide dismutase, catalase, glutathione peroxidase and gluthione-S-transferase (p < 0.05) when compared with the control group. The oral administration of vit C (200 mg/kg per d) to LTC treated rats significantly (p < 0.05) diminished the levels of LPO, NO and PCO and significantly (p < 0.05) increased the activities of GSH and antioxidant enzymes. Our results showed that the administration of vit C could ameliorate some of the oxidative damage in the cerebellum induced by SPs exposure, suggesting that the ascorbic acid could exhibit a potential antioxidant activity against neurotoxicity induced by pesticides exposure. PMID- 22918068 TI - Thromboprophylaxis in heart failure patients with sinus rhythm: aspirin and warfarin lead to similar cardiovascular outcomes. PMID- 22918069 TI - Atrial fibrillation is associated with an increased risk of cognitive and functional decline. PMID- 22918070 TI - Saliva as a potential diagnostic tool. AB - Saliva is a complex fluid consisting of secretions from the major and minor salivary glands. Gland-specific saliva can be used to diagnose any pathology from the specific major salivary gland. Whole saliva has serum constituents that are derived from the local vasculature of the salivary glands and gingival crevicular fluid. Saliva, as a diagnostic fluid, has distinctive advantages over serum as whole saliva can be collected non-invasively by individuals with limited training using simple equipments. This review aimed to explore the diagnostic applications of saliva in systemic and oral diseases. Analysis of saliva can offer a cost effective approach to screen for a larger population. Salivary analysis may be useful for diagnosing systemic oral disorders, as well as for monitoring hormone and therapeutic levels of drug. PMID- 22918071 TI - Characteristics of depression in obese people living in an insecure environment. AB - BACKGROUND: Obesity and depression are significant characteristics of people living in a state of chronic stress. PURPOSE: Our aim was to determine the characteristics of depression in obese people living in an insecure unstable environment. MATERIALS AND METHODS: The case-control study was organized in two rural environments in Kosovo and Metochia, Serbia. The main criterion for selection of participants was that respondents were more than 18 years old and had a body mass index of 25 kg/m 2 or more. Other anthropometric parameters determined were body weight, height, body fat mass, hip and waist circumference and the waist/hip ratio. The sex, demographic characteristics, profession, marital status, social status, existence of comorbidity, and cigarette smoking habits were recorded, and the arterial blood pressure measured for all participants. In the form of an interview, all respondents answered 17 questions, based on the Hamilton scale for depression. RESULTS: The group of depressed patients was dominated by women (P = 0.009). A significant difference (P = 0.007) was found in relation to profession. Depression was significantly more frequent in those without a regular income (P < 0.001). Depressed patients were significantly older (P = 0.017), more obese (P = 0.04), shorter (P = 0.0001), had a larger hip circumference (P = 0.039) and WHR index (P = 0.049) compared to patients in whom depression was not established. CONCLUSIONS: Depression is a significant characteristic in people living in an insecure environment, more common in women, without a permanent financial income. PMID- 22918072 TI - A study to evaluate asbestos fiber burden in lung and pleural malignancies. AB - BACKGROUND: There is scarcity of data on asbestos fiber burden in lung and pleural malignancies. AIM: To evaluate asbestos fiber burden in biopsy samples of suspected lung and pleural malignancies. STUDY DESIGN: This was a single-centre, observational study. STUDY PERIOD: From August 2010 to July 2010. SETTING: Department of Pulmonary Medicine, CSMMU, UP, Lucknow, a tertiary care hospital in India. STUDY POPULATION: Suspected cases of lung and pleural malignancy. MATERIALS AND METHODS: Biopsy tissues taken by computed tomography (CT)-guided biopsy, bronchoscopic biopsy, and pleural biopsy by Cope's needle were analyzed for histopathology and asbestos burden by Haq et al.'s method. RESULTS: 20 patients were studied. Mean fiber burden was 9.25 * 10 4 fibers/g. Average burden in lung malignancies (11 patients) was 9.178 * 10 4 fibers/g and in pleural tissue (9 patients) was 9.332 * 10 4fibers/g. Among the different cell types, mean fiber burden in squamous cell carcinoma was 8.99 * 10 4 fibers/g, in adenocarcinoma was 9.71 * 10 4 fibers/g, and in small cell carcinoma was 7.54 * 10 4 fibers/g. Mean fiber burden in bronchoscopic endobronchial biopsy tissue was 10.69 * 10 4 fibers/g, while in CT-guided biopsy was 8.60* 10 4fibers/g. CONCLUSION: Maximum number of fibers was found in adenocarcinoma. PMID- 22918073 TI - Isaac's syndrome associated with myasthenia gravis and thymoma. AB - A 65-year-old male developed fatigable weakness of ocular and bulbar muscle and positive anti-acetyl cholinesterase antibodies suggesting the diagnosis of myasthenia gravis. His condition responded to anticholinesterase and immunotherapy. However, 18 months later, he developed painful paresthesiae, muscle cramps with hyperhiderosis, and was diagnosed as having Isaac's syndrome (neuromyotonia, continuous muscle fibre activity). Computed tomography of the chest revealed a thymic mass, which was confirmed after surgery and histopathology as thymic cell carcinoma. The co-occurrence of myasthenia gravis and continuous muscle fiber activity should prompt the consideration of the occurrence of these disorders as one of the paraneoplastic manifestations, most often due to a thymic neoplasm. Both these conditions respond to treatment of underlying thymoma. This case is a very rare presentation worth reporting. PMID- 22918074 TI - Guillain-Barre syndrome in child with prolong intubation. AB - Guillain-Barre syndrome (GBS) is an acute demyelinating disorder of the peripheral nervous system that results from an aberrant immune response directed at peripheral nerves. A typical GBS patient presents with rapidly ascending symmetrical weakness, which may progress to respiratory failure in 30% of patients. There are no definite criteria exists in GBS in children regarding prolonged ventilation. Here we report a child of GBS requiring prolonged intubation and ventilation for 60 days who afterward had a complete recovery. We present this case to highlight the importance that even in children prolonged intubation and ventilation of GBS case prognosis can be good. PMID- 22918075 TI - Tubo-ovarian Actinomycosis: a case report with brief review of literature. AB - Pelvic actinomycosis is an uncommon condition, often associated with the use of intrauterine contraceptive device (IUCD). Pelvic actinomycosis is rare accounting for 3% of all human actinomycotic infections. Ovarian actinomycosis is even rarer. Here, we present a 24-year-old woman using an IUCD for 3 1 / 2 years with right-sided adnexal mass, which was diagnosed postoperatively as tubo-ovarian actinomycosis. Many times, an appropriate management is overlooked or delayed due to its non-specific and variable clinical and radiological features. Sometimes, it can even mimic an advanced pelvic malignancy. Therefore, the gynecologist should consider the possibility of this infection to spare the patient from morbidity of radical surgical procedure. PMID- 22918076 TI - Fever of unknown origin in a patient of systemic onset juvenile idiopathic arthritis. AB - Hemophagocytic lymphohistiocytosis is a potentially fatal condition characterized by pathologic immune activation, which can complicate infections, childhood systemic rheumatologic diseases and malignancies. Here we report a case of reactive hemophagocytic lymphohistiocytosis [macrophage activation syndrome] complicating systemic onset juvenile idiopathic arthritis, which was treated successfully with dexamethasone and cyclosporine. Reactive hemophagocytic lymphohistiocytosis or macrophage activation syndrome should be considered in patients of juvenile idiopathic arthritis with prolonged fever of unknown origin and cytopenias. Early diagnosis with high index of suspicion and prompt, aggressive treatment are needed for successful outcomes. PMID- 22918077 TI - Multiple sclerosis takes venous route: CCSVI and liberation therapy. PMID- 22918078 TI - A phase I dose-escalation study of the immunocytokine EMD 521873 (Selectikine) in patients with advanced solid tumours. AB - BACKGROUND: EMD 521873 (Selectikine), an immunocytokine comprising a DNA targeting antibody, aimed at tumour necrosis, fused with a genetically modified interleukin-2 (IL-2) moiety, was investigated in this first-in-human phase I study. METHODS: Patients had metastatic or locally advanced solid tumours failing previous standard therapy. Selectikine was administered as a 1-hour intravenous infusion on 3 consecutive days, every 3 weeks. A subgroup of patients also received 300 mg/m(2) cyclophosphamide on day 1 of each cycle. Escalating doses of Selectikine were investigated with the primary objective of determining the maximum tolerated dose (MTD). RESULTS: Thirty-nine patients were treated with Selectikine alone at dose levels from 0.075 to 0.9 mg/kg, and nine were treated at doses of 0.45 and 0.6 mg/kg in combination with cyclophosphamide. A dose dependent linear increase of peak serum concentrations and area under curve was found. The dose-limiting toxicity was grade 3 skin rash at the 0.9 mg/kg dose level; the MTD was 0.6 mg/kg. Rash and flu-like symptoms were the most frequent side-effects. No severe cardiovascular side-effects (hypotension or vascular leak) were observed. At all dose-levels, transient increases in total lymphocyte, eosinophil and monocyte counts were recorded. No objective tumour responses, but long periods of disease stabilisation were observed. Transient and non neutralising Selectikine antibodies were detected in 69% of patients. CONCLUSIONS: The MTD of Selectikine with or without cyclophosphamide administered under this schedule was 0.6 mg/kg. The recommended phase II dose was 0.45-0.6 mg/kg. Selectikine had a favourable safety profile and induced biological effects typical for IL-2. PMID- 22918079 TI - Single domain antibody against carcinoembryonic antigen-related cell adhesion molecule 6 (CEACAM6) inhibits proliferation, migration, invasion and angiogenesis of pancreatic cancer cells. AB - Carcinoembryonic antigen-related cell adhesion molecule 6 (CEACAM6) is over expressed in pancreatic cancer cells, and it is associated with the progression of pancreatic cancer. We tested a single domain antibody (sdAb) targeting CEACAM6, 2A3, which was isolated previously from a llama immune library, and an Fc conjugated version of this sdAb, to determine how they affect the pancreatic cancer cell line BxPC3. We also compared the effects of the antibodies to gemcitabine. Gemcitabine and 2A3 slowed down cancer cell proliferation. However, only 2A3 retarded cancer cell invasion, angiogenesis within the cancer mass and BxPC3 cell MMP-9 activity, three features important for tumour growth and metastasis. The IC50s for 2A3, 2A3-Fc and gemcitabine were determined as 6.5MUM, 8MUM and 12nM, respectively. While the 2A3 antibody inhibited MMP-9 activity by 33% compared to non-treated control cells, gemcitabine failed to inhibit MMP-9 activity. Moreover, 2A3 and 2A3-Fc inhibited invasion of BxPC3 by 73% compared to non-treated cells. When conditioned media that were produced using 2A3- or 2A3-Fc treated BxPC3 cells were used in a capillary formation assay, the capillary length was reduced by 21% and 49%, respectively. Therefore 2A3 is an ideal candidate for treating tumours that over-express CEACAM6. PMID- 22918080 TI - pH-induced morphology-shifting of DNA-b-poly(propylene oxide) assemblies. AB - The designed DNA sequences can make DNA-b-PPO undergo in situ transition between diblock and triblock upon pH changes, consequently, induce a morphology-shifting from spherical micelles to nanofibers. This process is reversible and the assembled structures have been characterized by CD, TEM and fluorescent experiments. PMID- 22918081 TI - Prognostic features in acute megakaryoblastic leukemia in children without Down syndrome: a report from the AML02 multicenter trial and the Children's Oncology Group Study POG 9421. PMID- 22918082 TI - Delayed recognition of diaphragmatic injury caused by penetrating thoraco abdominal trauma. AB - INTRODUCTION: Penetrating trauma to the thoraco-abdomen may cause diaphragmatic injury (DI). We present a case which highlights the difficulties of recognizing DI and the limited role of multimodal diagnostic imaging. PRESENTATION OF CASE: A 19 year old male presented with stab wounds to his left lateral chest wall. CT was suspicious for diaphragmatic injury but this could not be confirmed despite ultrasound and serial plain radiographs. He was discharged but re-presented with respiratory compromise and diaphragmatic herniation. DISCUSSION: We review the clinical features of diaphragmatic injury after penetrating thoraco-abdominal trauma and the various imaging modalities available to clinicians. CONCLUSION: A high index of suspicion must be employed for DI in the context of penetrating thoraco-abdominal trauma. Inpatient observation and laparoscopy/thoracoscopy should be considered when radiological findings are ambiguous. Front line physicians should also consider diaphragmatic herniation in stab victims who re present with respiratory, circulatory, or gastrointestinal symptomology. PMID- 22918083 TI - Breast tuberculosis: Diagnosis, management and treatment. AB - INTRODUCTION: Mammary (breast) tuberculosis is a rare manifestation of extra pulmonary localization of the disease which accounts for less than 0.1% of breast conditions in developed countries, but reaches 3-4% in regions where the disease presents with high incidence (India, Africa). It appears mostly in women of reproductive age, multiparous, lactating. It has been scarcely reported to infect male patients, mainly before puberty, as well as women of older age. The most common presentation is that of a tumor in the middle or upper-outer quadrant of the breast, with multifocal involvement being rarely documented. The differential diagnosis includes breast cancer and abscess formation. PRESENTATION OF CASE: We report a case of breast tuberculosis that was treated in the Breast Unit of our hospital. Differential diagnosis, imaging methods, operative diagnostic approach and surgical treatment, histological verification of the disease and further therapeutic management are described. DISCUSSION: High risk population is identified, primary and secondary disease is described and clinical presentations are analyzed. Evaluation of diagnostic workup and limitations are reported. CONCLUSION: In accordance with the present worldwide revival of the disease, mainly because of massive numbers of migrating population, this subject is reviewed, reminding us of a rather uncommon clinical entity. PMID- 22918084 TI - Association of telomerase expression with recurrence of sacral chordoma. PMID- 22918085 TI - Carotenoid-based phenotypic screen of the yeast deletion collection reveals new genes with roles in isoprenoid production. AB - Beside their essential cellular functions, isoprenoids have value as pharmaceuticals, nutriceuticals, pesticides, and fuel alternatives. Engineering microorganisms for production of isoprenoids is relatively easy, sustainable, and cost effective in comparison to chemical synthesis or extraction from natural producers. We introduced genes encoding carotenoid biosynthetic enzymes into the haploid yeast deletion collection to identify gene deletions that improved isoprenoid production. Deletions that showed significant improvement in carotenoid production were further screened for production of bisabolene, an isoprenoid alternative to petroleum-derived diesel. Combining those deletions with other mevalonate pathway modifications increased production of bisabolene from 40mg/L to 800mg/L in shake-flask cultures. In a fermentation process, this engineered strain produced 5.2g/L of bisabolene. PMID- 22918086 TI - Cardiovascular indices of challenge and threat states predict competitive performance. AB - Cardiovascular (CV) reactivity is proposed by both the Biopsychosocial Model and the Theory of Challenge and Threat States in Athletes to predict competitive performance. The association between CV reactivity and competitive performance was examined in cognitive (Study 1) and motor (Study 2) tasks. In Study 1, 25 participants (9 female) completed a modified Stroop Test, and in Study 2, 21 female netballers completed a netball shooting task, under competition. Measures of CV reactivity, self-report measures of self-efficacy, control, achievement goals and emotions along with baseline and competitive task performance were taken. CV reactivity indicative of a challenge state predicted superior performance in both tasks compared to CV reactivity indicative of a threat state. In both studies the purported relationships between CV reactivity and the psychological and emotional responses were weak or absent. The mechanisms for the observed association between CV reactivity and task performance are discussed alongside implications of the findings for future research and practice. PMID- 22918087 TI - Ligand substitution effect on single-molecule magnet behavior in dinuclear dysprosium complexes with radical functionalized phenol as bridging ligands. AB - Reaction of Dy(hfac)(3).2H(2)O (hfac = hexafluoroacetyl acetonate) with 2-(2 hydroxyphenyl)nitronyl nitroxide (NITPhOH) and 2-(5-bromo-2 hydroxyphenyl)nitronyl nitroxide (NIT5BrPhOH) yielded [Dy(2)(hfac)(4)(NITPhO)(2)] 1 and [Dy(2)(hfac)(4)(NIT5BrPhO)(2)] 2, respectively. These compounds are phenoxo O bridged binuclear complexes with the radical unit of a ligand coordinated to a single Dy. The Ln centers exhibit a heptacoordinated environment. Despite having very similar structures, these compounds exhibit distinct magnetic behaviors. Compound 1 shows slow relaxation of its magnetization indicating single-molecule magnet behavior, while no frequency-dependent out-of-phase signals were found for complex 2. This difference is likely to result from electronic effects induced by halogen substitution. PMID- 22918088 TI - Acquired hemophilia successfully treated with activated prothrombin complex concentrate and immunosuppressant combination: a case report. AB - Acquired hemophilia A is a very rare but life-threatening disorder caused by autoantibody against coagulation factor VIII. The incidence was much rarer in young people. In this case report, a young woman presented with spontaneous muscle hematoma. Because of pain and limited range of motion, she underwent surgery for resolution at first. However, her symptoms and hemorrhage worsened. She was diagnosed with acquired hemophilia A. We started combination treatment with bypassing agent, activated prothrombin complex and immunosuppressants immediately and the results were successful. The acute bleeding was controlled and autoantibody was completely resolved. PMID- 22918089 TI - The Assessment of Services Promoting Independence and Recovery in Elders Trial (ASPIRE): a pre-planned meta-analysis of three independent randomised controlled trial evaluations of ageing in place initiatives in New Zealand. AB - INTRODUCTION: intermediate care has been developed to support older people to remain living in their own homes, combining a higher level of support with a rehabilitation focus. Evidence around their effectiveness remains mixed and there is ambiguity around the components. AIMS: to establish the impact of intermediate care on institutional free survival in frail older people referred for needs assessment in New Zealand (NZ). METHODS: pre-planned meta-analysis of three randomised controlled trials with follow-up at 3, 6, 12, 18 and 24 months. A total of 567 older people at risk of permanent institutionalisation as well as their primary informal carer (n = 234) were randomised to either intermediate or usual care. Interventions had common key features of care management, though varied in the use of ongoing care provision. RESULTS: the adjusted hazard ratio for the combined primary outcome of death or residential entry was 31% lower with a 95% confidence interval of (9%, 47%) for the intermediate care initiatives compared with usual care. CONCLUSION: intermediate care utilising a care management approach reduces a frail older person's risk of mortality and permanent institutionalisation. PMID- 22918090 TI - Association of age at diagnosis and Crohn's disease phenotype. AB - BACKGROUND: fifteen percent of patients with Crohn's disease (CD) are elderly; they are less likely to have complications and more likely to have colonic disease. OBJECTIVE: to compare disease behaviour in patients with CD based on age at diagnosis. DESIGN: cross-sectional study. SETTING: tertiary referral centre. SUBJECTS: patients with confirmed CD. METHODS: behaviour was characterised according to the Montreal classification. Patients with either stricturing or penetrating disease were classified as having complicated disease. Age at diagnosis was categorised as <17, 17-40, 41-59 and >= 60 years. Logistic regression analysis was performed to examine the association between advanced age >= 60 and complicated disease. RESULTS: a total of 467 patients were evaluated between 2004 and 2010. Increasing age of diagnosis was negatively associated with complicated disease and positively associated with colonic disease. As age of diagnosis increased, disease duration (P < 0.001), family history of Inflammatory bowel disease (IBD) (P = 0.015) and perianal disease decreased (P < 0.0015). After adjustment for confounding variables, the association between age at diagnosis and complicated disease was no longer significant (OR: 0.60, 95% CI: 0.21-1.65). CONCLUSIONS: patients diagnosed with CD >= 60 were more likely to have colonic disease and non-complicated disease. However, the association between age at diagnosis and complicated disease did not persist after adjustment for confounding variables. PMID- 22918091 TI - Greetings from Davangere, Karnataka, India. PMID- 22918092 TI - Radix entomolaris and paramolaris in children: a review of the literature. AB - Pediatric dentistry in the current scenario is not just about teeth and gums that are easily visible in children's mouth anymore. It is all about those structures that are hidden, difficult to identify, and often remain undiagnosed. Dentist can come across various anomalies pertaining to the crown structure during the clinical practice. Although supernumerary tooth is the most commonly seen anomaly, the presence of extra roots in molars is an interesting example of anatomic root variation. It is well known that both primary and permanent mandibular first molars usually have roots, one mesial, and the other distal root. Very rarely an additional third root (supernumerary root) is seen and when it is located distolingually to the main distal root is called "radix entomolaris (RE)" and when it is placed mesiobuccaly to the mesial root is called "radix paramolaris (RP)." The purpose of this article is to discuss the prevalence, morphology, classification, clinical diagnosis, and significance of supernumerary roots in contemporary clinical pediatric dentistry. PMID- 22918093 TI - Speech and language delay in children: a review and the role of a pediatric dentist. AB - Speech and language development is a useful indicator of a child's overall development and cognitive ability. Identification of children at a risk for developmental delay or related problems may lead to intervention and assistance at a young age, when the chances for improvement are the best. This rationale supports screening of preschool children for speech and language delay or primary language impairment or disorder, which needs to be integrated into routine developmental surveillance practices of clinicians caring for children. PMID- 22918094 TI - Comparison of oral midazolam with oral tramadol, triclofos and zolpidem in the sedation of pediatric dental patients: an in vivo study. AB - OBJECTIVE: oral sedation is the simplest and most convenient sedation method for managing uncooperative child patients because it is easy to administer and there is no need for nasal hood or injection. Oral midazolam is the most commonly used preanesthetic medication for children. When given in amounts between 0.5 and 0.75 mg/kg of body weight, oral midazolam has been found to be an effective sedative agent for pediatric outpatients. Tramadol is a synthetic, centrally acting analgesic indicated for moderate to severe pain. Chloral hydrate is one of the sedatives most commonly used, has excellent absorption, fast induction, and exert minimal effects on respiration. zolpidem is the most commonly prescribed hypnotic due to its clinical efficacy, safety, and ability to be well tolerated with patients. MATERIALS AND METHODS: 60 anxious and fearful children who reported to the department were treated under conscious sedation for the accomplishment of dental treatment. Patients were randomly assigned to four groups. Statistical analysis was done using Kruskal Wallis Test and decision criterion was to reject the null hypothesis if the P-value is less than 0.05. RESULTS: it was observed that there is a statistically significant difference in median scores recorded for the level of sedation between the different groups (P < 0.001). CONCLUSION: this study concluded that midazolam is the best drug for producing conscious sedation followed by tramadol and triclofos. Zolpidem was not able to produce a sufficient level of sedation and it cannot be supported as a sedative agent at the present dosage. PMID- 22918095 TI - Comparison of mechanical and chemomechanical methods of caries removal in deciduous and permanent teeth: a SEM study. AB - BACKGROUND: Mechanical method of caries removal is associated with the removal of sound tooth structure, production of pain, heat, annoying sounds, and vibrations. Chemomechanical caries removal method is based on removal of only carious dentin leaving sound dentin intact. AIM: The aim of this study was to compare the efficacy of mechanical and chemomechanical methods of caries removal in deciduous and permanent teeth. STUDY DESIGN: A total of 30 carious teeth including 15 deciduous and 15 permanent teeth having dentinal caries selected randomly and cut into two halves through center of the lesion, were subjected to caries removal by mechanical (Group A), and chemomechanical methods (Group B). Time taken for removal of caries was noted with stopwatch. Samples were prepared and seen under the scanning electron microscope for the presence of bacterial colonies. Data were analyzed using statistical package for social sciences (SPSS) Software. RESULTS: No significant difference was found for the presence of bacterial colonies in both groups of deciduous and permanent teeth; however, time taken for caries removal by the chemomechanical method was twice than the mechanical method. CONCLUSION: despite the insignificant presence of bacterial colonies and twice time taken as compared to mechanical method, chemomechanical method was easy to introduce, was painless, did not form smear layer and conserved the sound tooth structure. PMID- 22918096 TI - An estimation of fluoride release from various dental restorative materials at different pH: In vitro study. AB - BACKGROUND: In the mid of 1980s, the cariostatic effect of fluoride ions on enamel caries had been demonstrated in many studies. The use of fluoride releasing dental restorative materials has seen increasing from many years for the specific purpose of leaching of fluoride into the surrounding tissues to inhibit secondary dental caries as well as prevention of caries in the newly erupted tooth. In the dental caries, acidic environment causes the demineralization of tooth structure and also affect the restorative margins of dental restoration. AIM: various restorative materials show different behavior in different pH conditions of oral cavity. Thus, the aim of this study was to evaluate the fluoride release of the various restorative materials at different pH. DESIGN: In this in vitro study, 30 samples of each dental restorative material were prepared and grouped into five with six samples in each group as per the pH of the solution 4.3, 4.6, 5.0, 5.5, and 6.2. All the samples were subjected to alternate cycling of the demineralizing solution (6 h) and remineralizing solution (18 h) for 15 days. RESULTS: the fluoride release was measured by using fluoride ion specific electrode and digital ion analyzer. The result showed that the fluoride release rate was significantly higher in first day and reduced after third day to nearly constant level. At pH 4.3, the fluoride release was highest and lowest at pH 6.2. CONCLUSION: the Amalgomer CR showed the highest fluoride release among all the experimental dental restorative materials. PMID- 22918097 TI - Inter-relationship of intelligence-quotient and self-concept with dental caries amongst socially handicapped orphan children. AB - CONTEXT: India has been the focus of many health surveys among normal, physically, and mentally handicapped children. However, the data, concerning oral health conditions of socially handicapped children living in orphanages, are scanty. AIMS: To study the effect of parental inadequacy, environmental deprivation, and emotional disturbances on dental caries through intelligence quotient (IQ) and self-concept in orphan children and also to co-relate dental caries with different levels of IQ and self-concept. SETTINGS AND DESIGN: The study was carried out amongst socially handicapped children living in orphanages. PATIENTS AND METHODS: 100 children in the age group of 10-14 years from orphanages were selected. Malin's Intelligence Scale for Indian Children (MISIC) was used to assess the intelligence quotient; self-concept questionnaire to assess self-concept of the child and recording of dental caries status of children was done as per WHO Index (1997). STATISTICAL ANALYSIS USED: To assess the relationship of dental caries with IQ, student's unpaired t-test was used and; to find the relationship between self-concept and dental caries, Karl Pearson's coefficient of co-relation was applied. RESULTS: the children in orphanages had a lower IQ and high caries experience but had an above average self-concept. There was also no co-relation between dental caries and self concept. CONCLUSIONS: Orphan children, being socially handicapped, are at an increased risk for dental caries due to a lower IQ level, parental deprivation, and institutionalization. Moreover, lack of co-relation between dental caries and self-concept could be explained by the fact that dental caries is a lifelong process whereas different dimensions of self-concept are in a state of constant flux. PMID- 22918098 TI - Self etching adhesive on intact enamel. AB - BACKGROUND AND OBJECTIVE: to analyze the poor performance of self-etch adhesives on intact enamel. MATERIALS AND METHODS: labial surfaces of 20 caries free permanent upper central and lateral incisors were cleaned, sectioned of their roots. All specimens were mounted on acrylic block and divided randomly into two groups. In one group the application of self-etch adhesive was carried as per manufacturer's instructions, composite cylinders were built, whereas in the other group, 37% phosphoric acid was applied before the application of self-etching adhesives. Then the resin tags were analyzed using the scanning electron microscope. RESULTS: showed that when phosphoric acid was used, there was significant increase in the depth of penetration of resin tags. CONCLUSION: the results indicate that out of both treatment groups, pre-etching the intact enamel with 37% phosphoric acid resulted in the formation of longer resin tags and higher depth of penetration of resin tags of the Clearfil SE bond, which might have resulted in attaining higher bond strength of the Clearfil SE bond to intact enamel. PMID- 22918099 TI - The effectiveness of a musical toothbrush for dental plaque removal: a comparative study. AB - BACKGROUND AND OBJECTIVES: the purpose of this study was to clinically evaluate and compare the efficacy of "Brush Buddies" musical tooth brush and Colgate Smile tooth brush in the reduction of established plaque and gingivitis. MATERIALS AND METHODS: for this study, 120 healthy kids (73 boys and 47 Girls) were selected. The subjects were randomly assigned into two groups by a second examiner; one group used Colgate Smile brush and the other group used "Brush Buddies" musical tooth brush. Plaque index (Quigley and Hein), Modified Gingival Index (Lobene and Associates) and Gingival Bleeding Index (Ainamo and Bay) were assessed at baseline, 30th day, 60th day, and 90th day. RESULTS: all the baseline indices appeared to be well balanced. At the end of the study, reduction in plaque index, modified gingival index and gingival bleeding index were statistically highly significant during each interval for both the toothbrushes. For "Brush Buddies" musical tooth brush, the reduction in all clinical parameters were statistically significant for 30 days and 60 days interval, while nonsignificant at 90 days interval. INTERPRETATION AND CONCLUSION: both the tooth brushes used in this study were clinically effective in removing plaque, improving gingival health. Musical tooth brush is more effective initially but as the time period increases both tooth brushes give almost similar results. PMID- 22918100 TI - Effect of casein phosphopeptide-amorphous calcium phosphate containing chewing gum on salivary concentration of calcium and phosphorus: an in-vivo study. AB - AIM: Caries clinical trials of sugar-free chewing gum have shown that the gum is noncariogenic and in fact has anticariogenic effect through the stimulation of saliva. Sugar-free gums, therefore, may be an excellent delivery vehicle for safe and effective additive, capable of promoting enamel remineralization. Casein phosphopeptide-amorphous calcium phosphate (CPP-ACP) nanocomplexes incorporated into sugar-free chewing gum have shown to remineralize enamel subsurface lesions in situ. So this study was conducted to evaluate the effect of CPP-ACP containing sugar-free chewing gum on salivary concentration of calcium and phosphorous. MATERIALS AND METHODS: Unstimulated saliva from each 24 selected subjects was collected. Then each subject was given two pellets of chewing gum containing CPP ACP and asked to chew for a period of 20 min, after which saliva samples were collected from each individual. Once all the samples were collected they were assessed for calcium and phosphorous concentration using affiliated reagent kits and photometer. STATISTICAL ANALYSIS USED: Data obtained were analyzed using student's paired t test. RESULTS: Significant difference was found in the calcium and phosphorus concentration of saliva before and after chewing CPP-ACP containing chewing gum. CONCLUSIONS: Chewing of CPP-ACP containing chewing gum showed a significant increase in the salivary concentration of calcium for a prolonged period of time hence it may help in the remineralization of tooth surfaces. PMID- 22918101 TI - The prevalence of traumatic dental injuries to permanent anterior teeth and its relation with predisposing risk factors among 8-13 years school children of Vadodara city: an epidemiological study. AB - BACKGROUND AND OBJECTIVE: dental trauma is an irreversible pathology that after occurrence is characterized by life-long debilitating effects. The objectives of this study were to measure the prevalence of anterior teeth fracture and their association with predisposing factors such as lip coverage, molar relationship, overjet, and variables such as age, sex, cause, and place of trauma. MATERIALS AND METHODS: an epidemiological cross-sectional study was carried out among 3708 school children aged 8-13 years in the Vadodara city. All children completed a questionnaire related to history of trauma to their anterior teeth after which they were examined for lip competence, Angle's molar relationship amount of overjet and nature of trauma sustained. The results were statistically analyzed using the prevalence test, Chi-square test, and Mantel-Haenszel Common Odds Ratio. RESULTS: the prevalence of traumatic injuries was 8.79% and the ratio of boys: girl's was 1.28:1. Inadequate lip coverage group sustained about five times more injuries than the adequate lip coverage group (P = 0.000, OR= 5.407). The maximum traumatic injuries were seen in children having Angle Class II Div 1 molar relationship and/or overjet greater than 5.5 mm and was statistically significant (P<0.05). Maximum number of injuries occurred at 9 years of age. The most predominant injuries were enamel fractures, the most common place for occurrence was home and fall against object, the most frequent cause. CONCLUSION: the prevalence of dental injuries in the Vadodara city is high and it has a great potential to be considered as an emerging public health problem. PMID- 22918102 TI - Dynamic 3 T MRI of temporomandibular joint in diagnosing a stuck disk. AB - Magnetic resonance imaging (MRI) is the imaging modality of choice in the evaluation of internal derangement of the temporomandibular joint (TMJ). Dynamic MRI including the open and close mouth views in sagittal plane determine the exact position of articular disk and thus help to evaluate the joint for internal derangement. We also highlight the role of dynamic MRI of TMJ in diagnosis of stuck disk in a 17-year-old male who presented with symptoms of pain and difficulty in opening the mouth. PMID- 22918104 TI - Oral manifestations leading to the diagnosis of acute lymphoblastic leukemia in a young girl. AB - BACKGROUND: oral complications may be leukemia's first presentation. AIM: to present a case of a young girl with a swelling on the face that led to the diagnosis of acute lymphoblastic leukemia is reported. RESULTS: a 10-year old anemic girl was referred for evaluation and treatment of a swelling at the left nasolabial region. Symptoms reported (tiredness, poor appetite, fever, lethargy, and musculoskeletal pain) and clinical findings (enlargement at the presternal region and brownish stain in the lumbar region) led to the suspicion of a hematopoietic malignancy. The diagnosis of lymphoblastic leukemia was attained after specific examination conducted by the pediatric oncologist and hematologist. CONCLUSION: dentists must be able to clearly recognize oral physiological characteristics, and, when identifying changes of normalcy, to fully investigate it requesting additional tests or referring the patient to specialized professionals. PMID- 22918103 TI - New design space regainers: 'lingual arch crossbow' and 'double banded space regainer'. AB - This article highlights the use of two new design space regainers--the "lingual arch crossbow" and the "double-banded space regainer." The former may be used for distalizing a mesially migrated mandibular first premolar, if it erupts prior to the canine. The latter may be used in conventional cases of interdental space loss. They both contain assemblies that function through the action of NiTi open coil springs. PMID- 22918105 TI - Enamel renal syndrome: a rare case report. AB - Enamel renal syndrome is a very rare disorder associating amelogenesis imperfecta with nephrocalcinosis. It is known by various synonyms such as amelogenesis imperfecta nephrocalcinosis syndrome, MacGibbon syndrome, Lubinsky syndrome, and Lubinsky-MacGibbon syndrome. It is characterized by enamel agenesis and medullary nephrocalcinosis. This paper describes enamel renal syndrome in a female patient born in a consanguineous family. PMID- 22918106 TI - Benign migratory glossitis with fissured tongue. AB - Symptomatic benign migratory glossitis (BMG) or "geographic tongue" is a rare occurrence in pediatric dentistry though asymptomatic BMG is comparatively common. BMG presents itself as an ulcer-like region on the dorsum of the tongue, which may recur at different sites on the tongue, creating a migratory appearance. Asymptomatic cases usually resolve on their own but symptomatic cases need treatment. Fissured tongue is a benign condition characterized by deep grooves on the dorsum of the tongue and, in many cases, is associated with geographic tongue. This article presents a case of symptomatic geographic tongue with fissured tongue with a history of asthma. PMID- 22918107 TI - Regional odontodysplasia: a case of progressive tooth development. AB - Regional odontodysplasia (RO) is considered a relatively rare dental anomaly despite increasing numbers of case reports in recent years. It usually presents as a localized anomaly in tooth development affecting a few adjacent teeth in a single maxillary or mandibular quadrant. The purpose of this paper is to describe an uncommon case of regional odotodysplasia involving noncontiguous mandibular teeth, crossing the midline in a male patient, and showing progressive normalization of tooth anatomy over a period of 6 years. Typically, teeth affected with RO become pulpally involved early on and are either extracted or endodontically treated. Such reports of automatic normalization over time in RO is supportive of a more conservative treatment approach. PMID- 22918108 TI - Mandibular mass in pediatric patient: a diagnostic dilemma. AB - A case of aggressive juvenile ossifying fibroma in a child has been discussed. The unique appearance of this particular lesion demonstrates a close relationship between aggressive ossifying fibroma and well-differentiated osteogenic sarcoma. The age of the patient and the location of the tumor in the case presented made it mandatory to utilize multiple diagnostic parameters and adjunctive diagnostic help to resolve the dilemma posed by this tumor. Differentiation of ossifying fibroma from other benign and malignant neoplasms as well as fibrous dysplasia is important in correct management of the lesion. PMID- 22918109 TI - Presurgical management of a child with missing lower lip using a new design of fixed lower tongue crib. AB - Missing of any perioral structure can result in imbalance of muscular forces leading to loss of structure and function along with esthetics especially in a growing individual and can result in permanent damage. Rehabilitation of such children is a challenge and requires an integrated multidisciplinary approach not only to correct the defect, but also to ensure normal development with minimal handicap. Here is a case report of a 10-year-old child with missing lower lip due to childhood infection and its presurgical management using a new design of fixed lower tongue crib used to limit tongue pressure, improve tongue position, and facilitate lower incisor retraction. A new clinical experience for lower lip missing cases in children are added, as these cases are rare. PMID- 22918110 TI - Histologic evaluation of soft tissue integration of experimental abutments for bone anchored hearing implants using surgery without soft tissue reduction. AB - OBJECTIVE: The protocol for bone-anchored hearing implants (e.g., Baha) surgery involves reduction of soft tissues around the abutment to minimize the risk of skin-related complications. It is hypothesized that good soft tissue outcomes may be achieved without performing skin reduction if improved abutment designs and/or materials are used that provide enhanced integration with surrounding soft tissues. The aim of the study was to investigate soft tissue response to different abutment designs/materials. METHODS: Thirty-six Baha implants and abutments were inserted in the skull of six sheep without performing soft tissue reduction. Four different abutments were used: 1) standard Baha abutments, 2) hydroxyapatite-coated standard Baha abutments, 3) concave titanium abutments, and 4) hydroxyapatite-coated concave abutments. Healing times of 1, 2, and 4 weeks were used (2 animals per time point). Samples were analyzed using descriptive histology and morphometric measurements, and results were compared using Wilcoxon's signed-ranked test. RESULTS: Histologic assessment showed healthy soft tissues around the abutments with limited or no signs of inflammation. Hydroxyapatite-coated abutments showed tight adherence with dermis and limited epidermal downgrowth and pocket formation. Weaker adherence, often associated with significant epidermal downgrowth and pocket formation, was noted for noncoated titanium abutments. The mean pocket depth for abutment types A, B, C, and D was 1.38, 0.42, 1.51, and 0.24 mm, respectively. The difference between C and D was statistically significant (p = 0.031). CONCLUSION: The results showed enhanced dermal adherence and reduced epidermal downgrowth and pocket formation for hydroxyapatite-coated abutments, with the most significant effect recorded for the hydroxyapatite-coated abutments with a concave shape. PMID- 22918111 TI - Use of a microendoscope for transtympanic drug delivery to the round window membrane in chinchillas. AB - INTRODUCTION: Systemic drug application for the treatment of inner ear diseases is restricted because of the blood-labyrinthine barrier and the limited blood supply to the inner ear. Local drug delivery to the inner ear can be an alternative method to overcome the problems with systemic application. The purpose of the present study was to describe the anatomic orientation of the round window membrane (RWM) and to examine the use of a microendoscope for transtympanic drug delivery to the RWM in the chinchilla animal model. MATERIALS AND METHODS: Fourteen female chinchillas were used for anatomic dissections (n = 4, 8 ears) and comparison of otomicroscopy (n = 5, 10 ears) with otoendoscopy (n = 5, 10 ears) for visualization and transtympanic application of methylene blue to the RWM of the animals. RESULTS: The external auditory meatus in chinchillas is S-shaped, and the RWM is not accessible through the tympanic membrane in otomicroscopy. The use of a special microendoscope makes it relatively easy to have an accurate transtympanic access to the RWM. The working channel of the microendoscope permitted successful delivery of methylene blue to the RWM in all tested chinchillas. CONCLUSION: The present study is the first published study that shows the feasibility of a microendoscope for transtympanic drug delivery to the RWM in animal models. Minor technical modifications are recommended, which will make the microendoscope an easy tool for future studies on local drug delivery to the RWM in the chinchilla animal model. PMID- 22918112 TI - The Lubeck flowchart for functional and aesthetic rehabilitation of aural atresia and microtia. AB - OBJECTIVE: Current strategies for functional rehabilitation of microtia-atresia patients with bone-anchored implants or surgical atresia repair have been extended by the feasibility of active middle ear implants. The aim of the present research is to evaluate a new flowchart of the treatment of these patients that considers active middle ear implants. PATIENTS: Congenital aural atresia and microtia. INTERVENTION(S): Bilateral cases are provided with a conductive hearing aid after birth and implanted with an active middle ear implant within the second year. Unilateral cases are provided with a conductive hearing aid and implanted with a middle ear or bone-conduction device in early childhood. Unilateral cases without amplification in the vulnerable time after birth are carefully selected for late implantation. At age 8 to 10, the auricular reconstruction is completed. MAIN OUTCOME MEASURE(S): Feasibility of implantation irrespective of age, functional gain in audiometry. RESULTS: The results of early implantation are as good as those previously published for adolescents. Mean reaction threshold with the Vibrant Soundbridge was 21 dB. Mean functional gain was 48 dB. The local tissues are unaltered and ready for auricular reconstruction. CONCLUSION: Active middle ear implants allow early and selective stimulation of the auditory pathway in children with congenital conductive hearing loss and are expected to lead to the normal development of the binaural hearing functions. To date, it is the only option if the stimulation is to be started at the age of 12 to 18 months. This was implemented into a new flowchart for aural atresia-microtia. PMID- 22918113 TI - Inner ear changes in mucopolysaccharidosis type I/Hurler syndrome. AB - OBJECTIVE: Mucopolysaccharidosis type I/Hurler syndrome is an autosomal recessive disease caused by a deficiency of alpha-L-iduronidase activity. Recurrent middle ear infections and hearing loss are common complications in Hurler syndrome. Although sensorineural and conductive components occur, the mechanism of sensorineural hearing loss has not been determined. The purpose of this study is to evaluate the quantitative inner ear histopathology of the temporal bones of patients with Hurler syndrome. PATIENTS: Eleven temporal bones from 6 patients with Hurler syndrome were examined. Age-matched healthy control samples consisted of 14 temporal bones from 7 cases. MAIN OUTCOME MEASURES: Temporal bones were serially sectioned in the horizontal plane and stained with hematoxylin and eosin. The number of spiral ganglion cells, loss of cochlear hair cells, area of stria vascularis, and cell density of spiral ligament were evaluated using light microscopy. RESULTS: There was no significant difference between Hurler syndrome and healthy controls in the number of spiral ganglion cells, area of stria vascularis, or cell density of spiral ligament. The number of cochlear hair cells in Hurler syndrome was significantly decreased compared with healthy controls. CONCLUSION: Auditory pathophysiology in the central nerve system in Hurler syndrome remains unknown; however, decreased cochlear hair cells may be one of the important factors for the sensorineural component of hearing loss. PMID- 22918114 TI - Re: "Postoperative validation of bone-anchored implants in the single-sided deafness population." Snapp et al. Otol Neurotol 2012: 33;291-6. PMID- 22918115 TI - Herniation of the membranous labyrinth into the horizontal semicircular canal is correlated with impaired caloric response in Meniere's disease. AB - INTRODUCTION: Canal paresis of the horizontal semicircular canal in Meniere's disease is a frequent finding. Endolymphatic hydrops is the single most characteristic morphologic finding in Meniere's disease. However, the relationship between endolymphatic hydrops and canal paresis is still not elucidated. METHODS: We used magnetic resonance imaging to visualize herniation of parts of the vestibular membranous labyrinth into the horizontal semicircular canal and correlated this morphologic feature with the caloric function of the horizontal semicircular canal. RESULTS: Patients who showed herniation into the horizontal canal had a significantly impaired caloric function when compared with patients without this morphologic feature. CONCLUSION: Herniation into the semicircular canal may be the morphologic correlate for impaired caloric response in patients with Meniere's disease. PMID- 22918116 TI - The role of obesity in spontaneous temporal bone encephaloceles and CSF leak. AB - OBJECTIVE: Temporal bone encephaloceles and cerebrospinal fluid (CSF) otorrhea can lead to life-threatening sequelae such as meningitis and cerebritis. Obesity has been associated with spontaneous CSF leaks. We wished to determine if there were differences in the body mass index (BMI) of patients with spontaneous temporal bone encephaloceles/CSF leaks and nonspontaneous temporal bone encephaloceles/CSF leaks to help determine if obesity may be associated with their development. STUDY DESIGN: Single institution retrospective comparison. METHODS: Demographic and clinical information was obtained from 20 patients treated for surgically confirmed temporal bone dehiscence leading to encephalocele and/or CSF otorrhea. Statistical analysis was performed on patients with spontaneous and nonspontaneous encephaloceles/CSF leaks to determine if there were differences in the degree of obesity between these groups. RESULTS: Temporal bone dehiscence was spontaneous in 11 patients, related to chronic infection in 4 patients, posttraumatic in 3 patients, postsurgical in 1 patient, and because of massive hydrocephalus in a final patient. The average BMI for patients with spontaneous encephalocele was 33.4 kg/m. The average BMI for patients with nonspontaneous encephaloceles was 27.0 kg/m. This difference was statistically significant (p = 0.02). CONCLUSION: Although several previous studies have demonstrated an association of obesity with spontaneous encephaloceles or CSF leaks, this study is one of the first to demonstrate a statistically significant increase in BMI for patients with spontaneous encephaloceles and CSF leaks as compared with patients developing them for other reasons. This suggests a potential etiologic role of obesity in the development of spontaneous encephaloceles and CSF leaks. LEVEL OF EVIDENCE: 4. PMID- 22918118 TI - DNA damage in leukocytes of sickle cell anemia patients is associated with hydroxyurea therapy and with HBB*S haplotype. AB - Hydroxyurea (HU) is the primary pharmacologic agent for preventing the complications and improving the quality of life of sickle cell anemia (SCA) patients. Although HU has been associated with an increased risk of leukemia in some patients with myeloproliferative disorders, the mutagenic and carcinogenic potential of HU has not been established. This study used the alkaline comet assay to investigate DNA damage in peripheral blood leukocytes from 41 individuals with SCA treated with HU (SCAHU) and from 26 normal individuals. The presence of HbS and the analysis of the haplotypes of the beta S gene cluster were done by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). The damage index (DI) in the SCAHU group was significantly higher than in controls (p<0.001). Neither gender nor age was associated with DNA damage in controls or SCAHU individuals. Among the SCAHU individuals, DI was significantly influenced by length of HU treatment (p=0.0039) and BMI (p=0.001). Individuals with length of HU treatment>=20 months and BMI<=20kg/m(2) had a significantly greater DI than those with length of HU treatment<20 months and BMI>20kg/m(2). No significant influence of mean HU dose was observed on DI (p=0.950). However, individuals who received a mean HU dose>=20mg/kg showed a higher DI than those who received less. Furthermore, an association was observed between DI damage and HBB*S gene haplotypes. DI values for the Bantu/Bantu haplotype was greater when compared to the Benin/Benin haplotype; and the Bantu/Benin haplotype had a DI lower than the Bantu/Bantu haplotype and greater than the Benin/Benin haplotype. Our results show that DNA damage in sickle cell anemia is associated not only with treatment with HU but also with genotype. PMID- 22918119 TI - On the thermal stability of vacancy-carbon complexes in alpha iron. AB - In this work we have summarized the available ab initio data addressing the interaction of carbon with vacancy defects in bcc Fe and performed additional calculations to extend the available dataset. Using an ab initio based parameterization, we apply object kinetic Monte Carlo (OKMC) simulations to model the process of isochronal annealing in bcc Fe doped with carbon to compare with experimental data. As a result of this work, we clarify that a binding energy of ~0.65 eV for a vacancy-carbon (V-C) pair fits the available experimental data best. It is found that the V (2)-C complex is less stable than the V-C pair and its dissociation with activation energy of 0.55 + 0.49 eV also rationalizes a number of experimental data where the breakup of V-C complexes was assumed instead. From the summarized ab initio data, the subsequently obtained OKMC results and critical discussion, provided here, we suggest that the twofold interpretation of the V-C binding energy, which is believed to vary between 0.47 and 0.65 eV, depending on the ab initio approximation, should be removed. The stability and mobility of small and presumably immobile SIA clusters formed at stage II is also discussed in the view of experimental data. PMID- 22918120 TI - Dkk3 is a component of the genetic circuitry regulating aldosterone biosynthesis in the adrenal cortex. AB - Primary aldosteronism (PA, autonomous aldosterone production from the adrenal cortex) causes the most common form of secondary arterial hypertension (HT), which is also the most common curable form of HT. Recent studies have highlighted an important role of mutations in genes encoding potassium channels in the pathogenesis of PA, both in human disease and in animal models. Here, we have exploited the unique features of the hyperaldosteronemic phenotype of Kcnk3 null mice, which is dependent on sexual hormones, to identify genes whose expression is modulated in the adrenal gland according to the dynamic hyperaldosteronemic phenotype of those animals. Genetic inactivation of one of the genes identified by our strategy, dickkopf-3 (Dkk3), whose expression is increased by calcium influx into adrenocortical cells, in the Kcnk3 null background results in the extension of the low-renin, potassium-rich diet insensitive hyperaldosteronemic phenotype to the male sex. Compound Kcnk3/Dkk3 animals display an increased expression of Cyp11b2, the rate-limiting enzyme for aldosterone biosynthesis in the adrenal zona glomerulosa (ZG). Our data show that Dkk3 can act as a modifier gene in a mouse model for altered potassium channel function and suggest its potential involvement in human PA syndromes. PMID- 22918121 TI - Suppression of the let-7b microRNA pathway by DNA hypermethylation in infant acute lymphoblastic leukemia with MLL gene rearrangements. AB - MicroRNAs (miRNAs) regulate cell proliferation and differentiation by controlling the expression of proteins involved in many signaling pathways. Recent studies have shown that dysregulation of miRNA expression is associated with increased tumorigenicity and a poor prognosis in several types of cancers. The miRNA let-7b is one of the severely downregulated miRNAs in mixed-lineage leukemia (MLL) rearranged acute lymphoblastic leukemia (ALL) patients. In vitro transfection of leukemogenic MLL fusion genes into human embryonic kidney-293 cells suppressed let-7b expression. In leukemic cells with an MLL fusion gene, the regulatory region for let-7b expression was hypermethylated, and its expression was partially recovered after culturing the cells with the demethylating agent 5 azacitidine. These results suggest that loss of let-7b expression may be one of the consequences of oncogenic MLL fusion proteins, and contributes to leukemogenesis possibly through the upregulation of let-7b-regulated target genes with leukemogenic potential in hematopoietic cells. The enforced expression of let-7b in ALL cell lines with an MLL fusion gene inhibited their growth, indicating the possible use of let-7b as a new therapeutic tool for refractory infant ALL with an MLL fusion gene. PMID- 22918124 TI - Obscure clinical implication of occult hepatitis B virus infection by perinatal transmission despite prophylaxis with hepatitis B vaccination and HBIG. PMID- 22918122 TI - EuroClonality/BIOMED-2 guidelines for interpretation and reporting of Ig/TCR clonality testing in suspected lymphoproliferations. AB - PCR-based immunoglobulin (Ig)/T-cell receptor (TCR) clonality testing in suspected lymphoproliferations has largely been standardized and has consequently become technically feasible in a routine diagnostic setting. Standardization of the pre-analytical and post-analytical phases is now essential to prevent misinterpretation and incorrect conclusions derived from clonality data. As clonality testing is not a quantitative assay, but rather concerns recognition of molecular patterns, guidelines for reliable interpretation and reporting are mandatory. Here, the EuroClonality (BIOMED-2) consortium summarizes important pre and post-analytical aspects of clonality testing, provides guidelines for interpretation of clonality testing results, and presents a uniform way to report the results of the Ig/TCR assays. Starting from an immunobiological concept, two levels to report Ig/TCR profiles are discerned: the technical description of individual (multiplex) PCR reactions and the overall molecular conclusion for B and T cells. Collectively, the EuroClonality (BIOMED-2) guidelines and consensus reporting system should help to improve the general performance level of clonality assessment and interpretation, which will directly impact on routine clinical management (standardized best-practice) in patients with suspected lymphoproliferations. PMID- 22918125 TI - Raltegravir-based regimens are effective in HIV-1 group O-infected patients. PMID- 22918127 TI - The relationship between daily organization and adherence to antiretroviral therapy: a qualitative perspective. PMID- 22918128 TI - Test and treat: a new standard for smear-positive tuberculosis. PMID- 22918129 TI - Were the interests of the vulnerable truly served? The predictable failure of HIVIG. PMID- 22918130 TI - Spectral shifts of the n -> pi* and pi -> pi* transitions of uracil based on a modified form of solvent reorganization energy. AB - According to our recent studies on the nonequilibrium solvation, the solvent reorganization energy is found to be the cost of maintaining the residual polarization P', which equilibrates with the extra electric field E(ex). On the basis of this solvent reorganization energy and the well-established equilibrium solvation energy, a novel and reasonable expression for the spectral shift of the electronic absorption spectra is proposed in this work. Furthermore, the two lowest transitions of uracil in aqueous solution are investigated as test cases with the TDDFT/6-311++G** method. The obtained spectral shift is 0.48 eV for n -> pi* transition and -0.14 eV for pi -> pi* transition, agreeing well with available experimental results. The contributions to the shift are discussed and the electrostatic plus polarization components are found to be crucial for the electronic absorption spectra of uracil in aqueous solution. PMID- 22918131 TI - Physicians' discussions about body weight, healthy diet, and physical activity with overweight or obese elderly patients. AB - OBJECTIVE: To investigate the correlates of physician-patient discussions about body weight, healthy diet, and physical activity. METHOD: Subjects were 635 adults (>=65 years; mean 72.8 years) who had an increased body mass index (BMI>=25 kg/m2) and participated in a self-administered community survey. Logistic regression analyses were performed. RESULTS: While approximately half of study participants reported having discussed healthy diets (51%) and physical activity (52%) with their physician, only 42% of those who were overweight or obese reported being recognized as such by their physician. Being moderately or severely obese, more chronic conditions, and more frequent physician visits increased the likelihood of being recognized as overweight or obese and reporting lifestyle discussions. DISCUSSION: The health care provider is important in recognizing older patient's weight problems and discussing practical lifestyle changes. Tools for more proactive screening and implementation of follow-up behavioral counseling can help the health care providers better address obesity prevention in clinical practice. PMID- 22918132 TI - A chemical precursor for depositing Sb2S3 onto mesoporous TiO2 layers in nonaqueous media and its application to solar cells. AB - Deposition of nanocrystalline Sb(2)S(3) onto a mesoporous TiO(2) photoanode is an important process in the fabrication of Sb(2)S(3)-sensitized solar cells. In order to generate oxide-free nanosized Sb(2)S(3), a single-source precursor for the chemical bath deposition of Sb(2)S(3) in nonaqueous media, Sb(III)(thioacetamide)(2)Cl(3), was synthesized and used to produce high-quality Sb(2)S(3) for solar cells. PMID- 22918133 TI - Simulating nursing unit performance with OrgAhead: strengths and challenges. AB - In this article, we briefly describe our use of a computational modeling tool, OrgAhead, details of which have been reported previously, then discuss several of the challenges computational modeling presented and our solutions. We used OrgAhead to simulate 39 nursing units in 13 Arizona hospitals and then predict changes to improve overall patient quality and safety outcomes. Creating the virtual units required (1) collecting data from managers, staff, patients, and quality and information services on each of the units; (2) mapping specific data elements (eg, control over nursing practice, nursingworkload, patient complexity, turbulence, orientation/tenure, education) to OrgAhead's parameters and variables; and then (3) validating that the newly created virtual units performed functionally like the actual units (eg, actual patient medication errors and fall rates correlated with the accuracy outcome variable in OrgAhead). Validation studies demonstrated acceptable correspondence between actual and virtual units. For all but the highest performing unit, we generated strategies that improved virtual performance and could reasonably be implemented on actual units to improve outcomes. Nurse managers, to whom we reported the results, responded positively to the unit-specific recommendations, which other methods cannot provide. In the end, resolving the modeling challenges we encountered has improved OrgAhead's functionality and usability. PMID- 22918134 TI - Promoting pedagogical experimentation: using a wiki in graduate level education. AB - Learning to write in a scholarly manner is often a challenge for graduate students. This study describes nursing students' use of a wiki to encourage writing collaboration among students by allowing them to cocreate, review, and edit each other's material as it is created. Students are introduced to the online wiki site the first week of the course. A technology representative assists students with a short introduction and class visits. All students participate in making decisions related to the overall character of the site. They create pages on topics related to their clinical placements. Student pages are peer and content expert reviewed for accuracy and comprehensiveness. Students include pictures, YouTube links, attachments, videos, and Web site links into their pages. Evidence-based content includes pharmacology, diagnostic criteria, pathophysiology, history, genetics, and references. Students present their pages, and feedback questionnaires are collected at the end of the semester. The wiki writing assignment introduces students, faculty, and the community to graduate student projects while exposing students to new technology. Areas explored include issues and best practices regarding classroom pedagogy, as well as student support and technical challenges in the use of a wiki. Suggestions for improvement are discussed. PMID- 22918135 TI - Practical guidelines for qualitative research using online forums. AB - With an increasing number of Internet research in general, the number of qualitative Internet studies has recently increased. Online forums are one of the most frequently used qualitative Internet research methods. Despite an increasing number of online forum studies, very few articles have been written to provide practical guidelines to conduct an online forum as a qualitative research method. In this article, practical guidelines in using an online forum as a qualitative research method are proposed based on three previous online forum studies. First, the three studies are concisely described. Practical guidelines are proposed based on nine idea categories related to issues in the three studies: (a) a fit with research purpose and questions, (b) logistics, (c) electronic versus conventional informed consent process, (d) structure and functionality of online forums, (e) interdisciplinary team, (f) screening methods, (g) languages, (h) data analysis methods, and (i) getting participants' feedback. PMID- 22918136 TI - Usability and navigability of an HIV/AIDS internet intervention for adolescents in a resource-limited setting. AB - Use of the Internet is growing in Sub-Saharan Africa. Evidence of computer and Internet effectiveness for reduction in risk behaviors associated with HIV shown in US settings has yet to be replicated in Africa. We describe the development, usability, and navigability testing of an Internet-based HIV prevention program for secondary school students in Uganda, called CyberSenga. For this work, we used four data collection activities, including observation of (a) computer skills and (b) navigation, (c) focus group discussions, and (d) field assessments to document comprehension and usability of program content. We document limited skills among students, but youth with basic computer skills were able to navigate the program after instruction. Youth were most interested in activities with more interaction. Field testing illustrated the importance of using a stand-alone electrical source during program delivery. This work suggests that delivery of Internet-based health promotion content in Africa requires attention to user preparedness and literacy, bandwidth, Internet connection, and electricity. PMID- 22918137 TI - A transition to e-mentoring: factors that influence nurse engagement. AB - E-mentoring is a form of mentoring that uses the Internet to remove the boundaries of traditional mentoring. Instead of face-to-face and synchronous communication, interactions between mentor(s) and protege(s) of e-mentoring relationships are primarily asynchronous. Since there was limited information about nurses and e-mentoring in the literature, this quantitative study was undertaken to explore nurses' attitudes and the identification of facilitators and constraints that could influence the adoption of e-mentoring. Overall, participants (n = 139) had positive attitudes; there were differences in attitudes between participants who had previously experienced mentoring and those who never had (P < .05). The likely-to-engage group had more positive attitudes and identified more facilitators and fewer constraints than did the indecisive and not-likely groups (P < .001). Age and attitudes had a positive relationship with e-mentoring (P = .01). These findings suggest that e-mentoring can be adopted by nurses of all ages, and despite the constraints identified, the benefits of e-mentoring may outweigh the constraints. Organizations considering the adoption of e-mentoring should encourage nurses with positive attitudes and previous mentoring experience to participate in their endeavors. E-mentoring can address today's multigenerational nursing workforce and positively influence the mentoring process. PMID- 22918138 TI - Opportunities and challenges associated with clinical diagnostic genome sequencing: a report of the Association for Molecular Pathology. AB - This report of the Whole Genome Analysis group of the Association for Molecular Pathology illuminates the opportunities and challenges associated with clinical diagnostic genome sequencing. With the reality of clinical application of next generation sequencing, technical aspects of molecular testing can be accomplished at greater speed and with higher volume, while much information is obtained. Although this testing is a next logical step for molecular pathology laboratories, the potential impact on the diagnostic process and clinical correlations is extraordinary and clinical interpretation will be challenging. We review the rapidly evolving technologies; provide application examples; discuss aspects of clinical utility, ethics, and consent; and address the analytic, postanalytic, and professional implications. PMID- 22918139 TI - Enantioselective aza-Henry reactions of cyclic alpha-carbonyl ketimines under bifunctional catalysis. AB - The aza-Henry reaction of nitroalkanes with the C=N group of 2-aryl-3H-indol-3 ones catalyzed by thiourea-chincona derivatives takes place with good yield and high ee's. PMID- 22918140 TI - Near-infrared quantum cutting through a three-step energy transfer process in Nd3+-Yb3+ co-doped fluoroindogallate glasses. AB - The Nd(3+)-Yb(3+) couple was investigated in fluoroindogallate glasses using optical spectroscopy to elucidate the energy transfer mechanisms involved in the downconversion (DC) process. Upon excitation of a Nd(3+) ion by an ultraviolet photon, DC through a three-step energy transfer process occurs, in which the energy of the ultraviolet photon absorbed by the Nd(3+) ion is converted into three infrared photons emitted by Yb(3+) ions, i.e. quantum cutting (QC). In addition, with excitation in the visible, our results confirm that the DC process occurs through a one-step energy transfer process, in which the energy of a visible photon absorbed by the Nd(3+) ion is converted into only one infrared photon emitted by an Yb(3+) ion. Time-resolved measurements enabled the estimation of the efficiencies of the cross-relaxation processes between Nd(3+) and Yb(3+) ions. PMID- 22918142 TI - Estimating occupant satisfaction of HVAC system noise using quality assessment index. AB - Noise may be defined as any unwanted sound. Sound becomes noise when it is too loud, unexpected, uncontrolled, happens at the wrong time, contains unwanted pure tones or unpleasant. In addition to being annoying, loud noise can cause hearing loss, and, depending on other factors, can affect stress level, sleep patterns and heart rate. The primary object for determining subjective estimations of loudness is to present sounds to a sample of listeners under controlled conditions. In heating, ventilation and air conditioning (HVAC) systems only the ventilation fan industry (e.g., bathroom exhaust and sidewall propeller fans) uses loudness ratings. In order to find satisfaction, percent of exposure to noise is the valuable issue for the personnel who are working in these areas. The room criterion (RC) method has been defined by ANSI standard S12.2, which is based on measured levels of in HVAC systems noise in spaces and is used primarily as a diagnostic tool. The RC method consists of a family of criteria curves and a rating procedure. RC measures background noise in the building over the frequency range of 16-4000 Hz. This rating system requires determination of the mid frequency average level and determining the perceived balance between high frequency (HF) sound and low-frequency (LF) sound. The arithmetic average of the sound levels in the 500, 1000 and 2000 Hz octave bands is 44.6 dB; therefore, the RC 45 curve is selected as the reference for spectrum quality evaluation. The spectral deviation factors in the LF, medium-frequency sound and HF regions are 2.9, 7.5 and -2.3, respectively, giving a Quality Assessment Index (QAI) of 9.8. This concludes the QAI is useful in estimating an occupant's probable reaction when the system design does not produce optimum sound quality. Thus, a QAI between 5 and 10 dB represents a marginal situation in which acceptance by an occupant is questionable. However, when sound pressure levels in the 16 or 31.5 Hz octave bands exceed 65 dB, vibration in lightweight office construction is possible. PMID- 22918143 TI - Traffic noise and cardiovascular health in Sweden: the roadside study. AB - Long-term exposure to traffic noise has been suggested to increase the risk of cardiovascular diseases (CVD). However, few studies have been performed in the general population and on railway noise. This study aimed to investigate the cardiovascular effects of living near noisy roads and railways. This cross sectional study comprised 25,851 men and women, aged 18-80 years, who had resided in Sweden for at least 5 years. All subjects participated in a National Environmental Health Survey, performed in 2007, in which they reported on health, annoyance reactions and environmental factors. Questionnaire data on self reported doctor's diagnosis of hypertension and/or CVD were used as outcomes. Exposure was assessed as Traffic Load (millions of vehicle kilometres per year) within 500 m around each participant's residential address. For a sub-population (n = 2498), we also assessed road traffic and railway noise in L(den) at the dwelling facade. Multiple logistic regression models were used to assess Prevalence Odds Ratios (POR) and 95% Confidence Intervals (CI). No statistically significant associations were found between Traffic Load and self-reported hypertension or CVD. In the sub-population, there was no association between road traffic noise and the outcomes; however, an increased risk of CVD was suggested among subjects exposed to railway noise >=50 dB(A); POR 1.55 (95% CI 1.00-2.40). Neither Traffic Load nor road traffic noise was, in this study, associated with self-reported cardiovascular outcomes. However, there was a borderline significant association between railway noise and CVD. The lack of association for road traffic may be due to methodological limitations. PMID- 22918144 TI - Occupational noise exposure of nightclub bar employees in Ireland. AB - Due to the transposition of the EU Directive 2003/10/EC into Irish Law, the entertainment sector was obligated to comply with the requirements of the Safety, Health and Welfare at Work (General Application) Regulations 2007, Chapter 1 Part 5: Control of Noise at Work since February 2008. Compliance with the Noise Regulations was examined in 9 nightclubs in Ireland. The typical daily noise exposure of 19 bar employees was measured using 2 logging dosimeters and a Type 1 fixed position sound level meter. Physical site inspections identified nightclub noise control measures. Interviews and questionnaires were used to assess the managers and employees awareness of the noise legislation. The average bar employee daily noise exposure (L(EX, 8h)) was 92 dBA, almost 4 times more than the accepted legal limit. None of the venues examined were fully compliant with the requirements of the 2007 Noise Regulations, and awareness of this legislation was limited. PMID- 22918145 TI - Effect of low frequency noise on the echocardiographic parameter E/A ratio. AB - The hearing condition of the Taiwanese aerospace maintenance workers affected by the low frequency noise had not been reported. The purpose of this research is to clarify the maintenance workers' health effect when exposed to low frequency and/or general noises and to understand the relationship between the variations of the worker's echocardiographic E/A ratio and the low frequency noise. The low frequency noise monitoring and echocardiographic E/A ratio results obtained for 213 aerospace maintenance workers indicated that the workers' hearing loss was more serious at high frequency 4k and 6k when exposed to the low frequency noise and could be more than 40 dB. The abnormality of echocardiographic E/A ratio was also higher than that of control group. PMID- 22918146 TI - Noise and hand-arm vibration exposure in relation to the risk of hearing loss. AB - The aim of this study was to examine the possible association of combined exposure of noise and hand-arm vibration (HAV) and the risk of noise-induced hearing loss. Workers in a heavy engineering industry were part of a dynamic cohort. Of these workers, 189 had HAV exposure, and their age and hearing status were recorded in the same year and were, therefore, included in the analysis. Data on HAV duration and acceleration was gathered through questionnaires, observations, and measurements. All available audiograms were categorized into normal and hearing loss. The first exposure variable included the lifetime HAV exposure. The lifetime HAV exposure was multiplied by the acceleration of HAV for the second and third exposure variable. Logistic regression using the Generalized Estimation Equations method was chosen to analyze the data to account for the repeated measurements. The analysis was performed with both continuous exposure variables and with exposure variables grouped into exposure quartiles with hearing loss as an outcome and age as a covariate. With continuous exposure variables, the odds ratio (OR) with a 95% confidence interval (CI) for hearing loss was equal to or greater than one for all exposure variables. When the exposure variables were grouped into quartiles, the OR with a 95% CI was greater than one at the third and fourth quartile. The results show that working with vibrating machines in an environment with noise exposure increases the risk of hearing loss, supporting an association between exposure to noise and HAV, and the noise-induced hearing loss. PMID- 22918147 TI - Noise and stress effects on preschool personnel. AB - The aim of the study was to analyze the presence of stress-related health problems among preschool employees and the way in which these reactions are related to noise and other work parameters. The investigation included 101 employees at 17 preschools in Umea County, located in northern Sweden. Individual noise recordings and recordings in dining rooms and play halls were made at two departments from each preschool. The adverse effects on the employees were analyzed by use of different validated questionnaires and by saliva cortisol samples. Stress and energy output were pronounced among the employees, and about 30% of the staff experienced strong burnout syndromes. Mental recovery after work was low, indicated by remaining high levels of stress after work. The burnout symptoms were associated with reduced sleep quality and morning sleepiness. Cortisol levels supported the conclusion about pronounced daily stress levels of the preschool employees. PMID- 22918148 TI - Early detection of non-organic hearing loss using a simple tone-in-noise test. AB - Early detection of non-organic hearing loss (NOHL) is important in order to ensure appropriate management decisions. One possible audiometric test for achieving this is the tone-in-noise (TIN) test although its current format is not widely applicable and may not optimize accuracy. We sought to investigate a modified TIN test, using narrowband noise, and the influence of different noise levels and alternative approaches to determining the outcome. Seventy-five normal hearing and 8 hearing-impaired subjects were asked to feign or exaggerate a hearing loss. The shift in genuine or exaggerated/feigned thresholds with the introduction of ipsilateral noise was determined. The TIN test was able to accurately separate between genuine and feigned thresholds when using narrowband noise presented at the effective masking level corresponding to the apparent tone threshold and using a 'fail' criterion of a repeatable threshold shift of >= 10 dB at one or more frequencies. It also produced similar shifts in exaggerated thresholds. In conclusion, this modified TIN test is a potentially accurate method to rapidly identify unilateral and bilateral NOHL in a wide range on contexts and could be applied to automated audiometry. PMID- 22918149 TI - Industrial noise exposure and salivary cortisol in blue collar industrial workers. AB - Measuring non-auditory effects of noise such as stress-inducing ones have become of interest recently. Salivary cortisol has become a popular measure in stress research. So, assessing noise-induced stress via saliva cortisol evaluation can present a bright future in non-invasive exposure assessment methods. This study had 3 goals: (1) Assess and compare saliva cortisol concentrations in the morning and evening in normal work day and leisure day in industrial workers, (2) assess the relationship between industrial noise exposure and salivary cortisol concentrations, and (3) assess the possibility of using salivary cortisol as a possible marker of noise-induced stress. This study included 80 male participants working in 4 different parts (painting, assembling lines, casting, and packaging) of a household manufacturing company. Morning and evening saliva samples were collected at 7.00 am and 4.00 pm, respectively. Noise exposure levels were assessed by sound level meter and noise dosimeter. All measurements occurred in two days: One in leisure day and other in working day. Descriptive statistics, paired sample t-test, and regression analysis were used as statistical tools of this study with P < 0.05. On the leisure day, morning salivary cortisol (geometric mean [GM], 15.0; 95% CI, 12.0 to 19.0 nmol/L) was significantly higher than evening cortisol (GM, 5.2; 95% CI, 4.2 to 6.3 nmol/L) (P < 0.05). Also, on the working day, morning salivary cortisol (GM, 14.0; 95% CI, 11.25 to 18.0 nmol/L) was significantly higher than evening cortisol (GM, 8.0; 95% CI, 6.5 to 10.0 nmol/L) (P < 0.05). No significant difference was obtained for morning cortisol levels between leisure day and working day samples (P = 0.117). But, for evening cortisol concentrations, a strong significant difference was noted leisure day and working day (P < 0.001). The evening cortisol in the working day correlated significantly with noise exposure > 80 dBA. Our study revealed that industrial noise, with levels > 80 dBA, has a significant effect on salivary cortisol elevation. PMID- 22918150 TI - Railway noise annoyance and the importance of number of trains, ground vibration, and building situational factors. AB - Internationally accepted exposure-response relationships show that railway noise causes less annoyance than road traffic and aircraft noise. Railway transport, both passenger and freight transport, is increasing, and new railway lines are planned for environmental reasons. The combination of more frequent railway traffic and faster and heavier trains will, most probably, lead to more disturbances from railway traffic in the near future. To effectively plan for mitigations against noise and vibration from railway traffic, new studies are needed to obtain a better basis of knowledge. The main objectives of the present study was to investigate how the relationship between noise levels from railway traffic and general annoyance is influenced by (i) number of trains, (ii) the presence of ground borne vibrations, and (iii) building situational factors, such as orientation of balcony/patio and bedroom window. Socio-acoustic field studies were executed in residential areas; (1) with relatively intense railway traffic; (2) with strong vibrations, and; (3) with the most intense railway traffic in the country. Data was obtained for 1695 respondents exposed to sound levels ranging from L(Aeq,24h) 45 to 65 dB. Both number of trains and presence of ground-borne vibrations, and not just the noise level per se, are of relevance for how annoying railway noise is perceived. The results imply that, for the proportion annoyed to be equal, a 5 - 7 dB lower noise level is needed in areas where the railway traffic causes strong ground-borne vibrations and in areas with a very large number of trains. General noise annoyance was twice as high among residents in dwellings with balcony / patio oriented towards the railway and about 1.5 times higher among residents with bedroom windows facing the railway. PMID- 22918151 TI - Hearing protection use in manufacturing workers: a qualitative study. AB - Occupational noise is a significant contributor to disabling hearing loss worldwide. Noise-induced hearing loss (NIHL) has resulted in huge human and economic consequences costing New Zealand approximately $53M annually and rising. A high proportion of hearing loss claims are made by workers in the manufacturing sector. Hearing protection devices (HPDs) are used together with engineering and administrative controls to minimize noise exposure and to prevent hearing loss. Unfortunately, inconsistent and improper use of HPDs has hindered efforts to prevent NIHL. The purpose of this study was to understand the factors that influence the use of HPDs amongst a group of manufacturing workers in New Zealand. A purposive sample of twenty-five workers was recruited to take part in semi-structured interviews. The open-ended questions were aimed at exploring the participants' knowledge, attitude, beliefs, and behavior towards noise and HPDs. The data were analyzed using conventional content analysis and key themes emerged in relation to HPD use. Themes that emerged from the interviews either supported good hearing protection behavior or acted as barriers against it. Five major themes, (perception of noise, hearing preservation, reluctance to use HPDs, workplace interaction, and value of hearing) and sub-themes described various factors that influence hearing protection use. Both personal and environmental factors influence the use of HPDs. Based on this study, personal and environmental factors need to be targeted for further research using ecological models to develop interventions that promote HPD use amongst workers. PMID- 22918152 TI - A proposal for a more refined single number rating system for hearing protector attenuation specification. AB - From a study of recent hearing protector attenuation test data, this work presents a proposal to reconsider how data, gathered by recognized standard subjective test procedures, is used to calculate the single number performance rating of hearing protectors. Current practice is to embed the expected performance (mean) and the variation in performance (standard deviation) in a single rating figure. A proposal is made for clearly separating expected performance from the variation while retaining the use of the current subjective test procedures. This proposal is applicable to all current single number rating systems including SNR, NRR, SLC(80), and the newer ANSI NRS(Ax). PMID- 22918154 TI - Prevalence of proteinuria and elevated serum cystatin C among HIV-Infected Adolescents in the Reaching for Excellence in Adolescent Care and Health (REACH) study. AB - OBJECTIVE: In the United States, kidney dysfunction is prevalent in almost 30% of HIV-infected patients and is an independent predictor of mortality. Proteinuria and elevated serum cystatin C (eCysC) are used as markers of kidney disease in the general population; however, the prevalence of these markers in HIV-infected adolescents is largely unknown. METHODS: This study includes 304 HIV-infected adolescents from the Reaching for Excellence in Adolescent Care and Health (REACH) cohort, an observational study of adolescents recruited from 13 US cities. Clinical and demographic characteristics of participants were evaluated as correlates of proteinuria, a urine protein to creatinine ratio of >=200 mg/g. Select univariate predictors were assessed to determine the association with urinary protein excretion and serum cystatin C in multivariable linear regression models and proteinuria and eCysC (eCysC >= 75th percentile) in multivariable logistic regression models. RESULTS: Overall, 19.1% of the participants had proteinuria, whereas 23.7% had an eCysC. Low CD4 T-lymphocyte counts (<200 cells/mm) were significantly associated with a greater urine protein to creatinine ratio in linear models and with proteinuria in logistic regression models. CD4 T-lymphocyte counts <500 cells/mm were significantly associated with a greater serum cystatin C concentration in linear models and with eCysC in logistic regression models. CONCLUSIONS: Proteinuria among HIV-infected adolescents in the REACH cohort was approximately 2-fold greater than healthy US adolescents. Both proteinuria and eCysC are associated with CD4 T-lymphocyte counts. Further studies investigating early markers of kidney disease and the association with immune status and inflammation in HIV-infected adolescents are needed. PMID- 22918155 TI - Sexual risk behaviors and HIV among female sex workers in Nigeria. AB - BACKGROUND: Female sex workers (FSWs) account for about 20% of new HIV infections in Nigeria. We estimated the change in HIV prevalence and sexual risk behaviors between 2 consecutive rounds of integrated biological and behavioral surveillance surveys (IBBSSs) and determined correlates of HIV transmission among FSWs. METHODS: In 2007 and 2010, HIV prevalence and risk behavior data on brothel-based (BB) and non-brothel-based (NBB) FSWs from the integrated biological and behavioral surveillance survey were evaluated in 6 Nigerian states. Logistic regression was used to identify correlates of HIV infection. RESULTS: A total of 2897 and 2963 FSWs were surveyed in 2007 and 2010, respectively. Overall HIV prevalence decreased in 2010 compared to 2007 (20% vs. 33%; P < 0.001), with similar magnitude of declines among BB-FSW (23% vs. 37%; P < 0.0001) and NBB-FSW (16% vs. 28%; P < 0.0001). Consistent condom use with boyfriends in the last 12 months was lower in 2010 compared to 2007 overall (23% vs. 25%; P = 0.02) and among BB-FSWs (17% vs. 23%; P < 0.01] while NBB-FSWs showed a marginal increase (30% vs. 27%; P = 0.08). FSWs residing in the Federal Capital Territory [adjusted odds ratio (AOR): 1.74 (1.34 - 2.27)] and Kano state [AOR: 2.07 (1.59 - 2.70)] were more likely to be HIV-positive while FSWs recruited in 2010 [AOR: 0.81 (0.77 0.85)] and those who had completed secondary education [AOR: 0.70 (0.60-0.80)] were less likely to be HIV-positive. CONCLUSIONS: Results suggest significant progress in reducing the burden of HIV among FSWs in Nigeria, although low condom use with boyfriends continued to be a potential bridge between FSWs and the general population. Venue-based prevention programs are needed to improve safer sex practices among BB-FSWs. PMID- 22918156 TI - A randomized controlled trial assessing the effects of raltegravir intensification on endothelial function in treated HIV infection. AB - OBJECTIVES: To determine whether intensification with raltegravir improves endothelial function in antiretroviral-treated HIV-infected individuals. DESIGN: : Randomized, double-blinded, placebo-controlled study. METHODS: Fifty-six subjects with treatment-mediated viral suppression for at least 1 year were randomized to add 400 mg of raltegravir twice daily or matching placebo for 24 weeks. The primary endpoint was the difference in rate of change in endothelial function [as assessed by flow-mediated vasodilation (FMD) of the brachial artery] from baseline to week 24 between the raltegravir and placebo groups. Linear mixed models were used to evaluate the association of treatment group with changes in FMD, immune activation, and measures of viral persistence. RESULTS: At baseline, the median CD4 T-cell count was 498 cells/mm, nadir CD4 T-cell count was 191 cells/mm, duration of HIV infection was 18 years, FMD was 3.3%, and hyperemic velocity (a marker of microvascular function) was 68.3 cm. There were no significant differences between treatment groups in rate of change in FMD (raltegravir group: +0.032% per week, placebo group: +0.023% per week; P = 0.60). There were also no differences between treatment groups in rate of change in hyperemic velocity, immune activation, or viral persistence. In multivariable analysis, older age, longer duration of HIV infection, and current abacavir use were associated with lower FMD. Lower CD4 T-cell count and current abacavir use were associated with lower hyperemic velocity. CONCLUSIONS: The addition of raltegravir to suppressive antiretroviral therapy did not have a significant impact on cardiovascular risk, as assessed by endothelial function (ClinicalTrials.gov NCT00843713). PMID- 22918157 TI - Prevalence and risk factors of low bone mineral density among perinatally HIV infected Thai adolescents receiving antiretroviral therapy. AB - BACKGROUND: Low bone mineral density (BMD) has been reported among 10%-54% of HIV infected adolescents in developed countries. We studied the prevalence and predictors of low BMD among HIV-infected Thai adolescents receiving antiretroviral therapy. METHODS: A cross-sectional study of lumbar spine (L2-L4) BMD as measured by dual-energy X-ray absorptiometry in Thai HIV-infected adolescents aged 12-20 years was performed. The BMD Z score was analyzed using age-matched healthy Thai children as a reference. Serum 25-hydroxyvitamin D was performed. Osteopenia was defined as BMD Z score <= -2. RESULTS: From October 2010 to February 2011, 101 adolescents, 50% male, with a median age of 14.3 (range: 13.0-15.7) years were enrolled. The median [interquartile range (IQR)] current CD4 T-cell count was 646 (506-796) cells per cubic millimeter and 90% had plasma HIV-1 RNA <50 copies per milliliter. The mean BMD among HIV-infected adolescents and controls were 0.855 and 0.980 g/cm (P < 0.001). The median (IQR) L2-L4 spine BMD Z score was -1.0 (-1.9 to -0.1), of which 24% had BMD Z score <= 2.0. The median (IQR) of 25-hydroxyvitamin D level was 24.8 (20.0-31.4) ng/mL, of which 25% had vitamin D level < 20 ng/mL. In multivariate analysis, the height for age Z score < -1.5 (adjusted odds ratio: 6.2; 95% confidence interval: 2.2 to 17.7) and history of World Health Organization clinical stage 4 before antiretroviral therapy (adjusted odds ratio: 3.7; 95% confidence interval: 1.3 to 10.7) were significantly associated with osteopenia. CONCLUSION: One fourth of HIV-infected Thai adolescents have osteopenia. Children with history of advanced staging or having low height for age are at risk of osteopenia. Preventive measures to prevent osteopenia should be incorporated in routine care for these adolescents. PMID- 22918160 TI - Standardized care management ensures similar survival rates in HIV-positive and HIV-negative patients with hepatocellular carcinoma. AB - OBJECTIVE: It has been suggested that HIV infection has a detrimental impact on patients with hepatocellular carcinoma (HCC). The present study sought to test this hypothesis, while controlling for tumor extension and liver disease. DESIGN AND SETTING: A case control and a cohort approach were performed in patients with HCC managed prospectively via dedicated multidisciplinary team meeting in a single tertiary institution between 2004 and 2009. SUBJECTS: Of 473 consecutive treatment-naive patients with HCC, 23 were HIV-positive (HIV) and 450 were HIV negative (HIV). HIV patients were matched 1:2 with a control group of HIV patients in terms of the etiology of HCC, the severity of liver disease, tumor extension, and year of diagnosis. INTERVENTION: Curative or palliative treatment of HCC. MAIN OUTCOME MEASURES: Eligibility for HCC treatment, the treatment actually administered, and the survival rate. RESULTS: The HIV population was younger than the HIV population (mean age: 49 vs. 61 years, respectively; P < 0.0001). Curative treatment was recommended by the multidisciplinary team meeting and then actually performed to a similar extent in HIV patients (74% and 43%, respectively) and their matched HIV controls (74% and 56%, respectively). The HIV and their matched HIV patients did not differ significantly in terms of the 3 year survival rate [44% vs. 48%, respectively; mean (95% confidence interval) hazard ratio = 0.64 (0.3-1.3); P = 0.2]. In a cohort analysis, HIV status was not an independent predictor of survival among curatively treated patients. CONCLUSION: In an equal-access unbiased environment, HIV status does not significantly influence treatment access, delivery, and outcome. PMID- 22918158 TI - Concomitant efavirenz reduces pharmacokinetic exposure to the antimalarial drug artemether-lumefantrine in healthy volunteers. AB - BACKGROUND: The antiretroviral drug efavirenz (EFV) and the antimalarial artemisinin-based combination therapy artemether-lumefantrine (AL) are commonly co-administered to treat HIV and malaria. EFV is a known inducer of cytochrome P450 3A4, which converts artemether to dihydroartemisinin (DHA) that is also active and metabolizes longer acting lumefantrine (LR). A study in healthy volunteers was completed to address the concern that EFV impacts AL pharmacokinetics (PKs). METHODS: Adults received AL (80/480 mg twice daily) for 3 days before and during EFV co-administration (600 mg daily for 26 days) with intensive PK for artemether, DHA, and LR conducted after the last AL dose for each period. EFV PK was evaluated with and without AL. PK parameters were estimated using noncompartmental methods. RESULTS: Twelve subjects completed the 2-period study. PK exposure for artemether, DHA, and LR [as estimated by the area under the concentration time curve (AUClast)] decreased or trended toward decrease with EFV, compared with when administered alone [-51% (P = 0.084), -46% (P = 0.005), and -21% (P = 0.102), respectively]. Day-7 LR levels, previously deemed predictive of treatment success, were 46% lower (P = 0.002) with EFV, but the LR half-life was unchanged. EFV PK exposure was minimally altered after AL co administration [AUC0-24 hrs decreased by 17% (P = 0.034)]. CONCLUSIONS: Exposure to DHA, but not LR, was significantly lower during EFV-AL co-administration compared with that during administration of AL alone. These findings may have implications for the treatment efficacy of AL, particularly in children. However, the observed modest changes probably do not warrant dosage adjustment during co administration of AL with EFV. PMID- 22918161 TI - Endometrial sarcomas: an immunohistochemical and JAZF1 re-arrangement study in low-grade and undifferentiated tumors. AB - The current World Health Organization classification divides endometrial sarcomas into low-grade endometrial stromal sarcoma and undifferentiated endometrial sarcoma. Recent studies suggest undifferentiated endometrial sarcoma is a heterogeneous group and a subgroup with uniform nuclei is more akin to low-grade endometrial stromal sarcoma in terms of morphologic, immunohistochemical and genetic features. We classified endometrial sarcomas treated at our institution from 1998 to 2011 into low-grade endometrial stromal sarcoma and undifferentiated endometrial sarcoma, the latter being further categorized into a group with either uniform or pleomorphic nuclei. Morphological features, immunoprofile and fluorescence in situ hybridization rearrangements of JAZF1 and PHF1 genes were correlated with tumor category and outcome. A total of 40 cases were evaluated comprising 23 low-grade endometrial stromal sarcomas, 10 undifferentiated endometrial sarcomas with nuclear uniformity and 7 undifferentiated endometrial sarcomas with nuclear pleomorphism. Low-grade endometrial stromal sarcomas were more often estrogen and progesterone receptor positive (83%) compared with undifferentiated endometrial sarcoma with nuclear uniformity (10%) or with nuclear pleomorphism (0%) (P<0.001). Positivity for p53 was restricted to undifferentiated endometrial sarcomas with more frequent expression in the group with nuclear pleomorphism (57%) than with nuclear uniformity (10%) (P=0.06). Ki 67 proliferation index in >10% of tumor cells more frequent in undifferentiated endometrial sarcoma than low-grade endometrial stromal sarcoma (P=<0.001). JAZF1 rearrangement was detected in 32% of low-grade endometrial stromal sarcomas and in none of the undifferentiated sarcomas. Rearrangement of PHF1 was found in two patients, one with JAZF1-PHF1 fusion. There were no significant differences in clinical behavior between undifferentiated endometrial sarcoma with nuclear uniformity versus nuclear pleomorphism. In conclusion, we found undifferentiated endometrial sarcoma subtypes and low-grade endometrial stromal sarcoma have distinct immunohistochemical and cytogentic profiles. Our data do not show any difference in clinical behavior between subgroups in undifferentiated sarcomas. PMID- 22918162 TI - Secondary mutation in a coding mononucleotide tract in MSH6 causes loss of immunoexpression of MSH6 in colorectal carcinomas with MLH1/PMS2 deficiency. AB - Immunohistochemical staining for DNA mismatch repair proteins may be affected by various biological and technical factors. Staining variations that could potentially lead to erroneous interpretations have been recognized. A recently recognized staining variation is the significant reduction of staining for MSH6 in some colorectal carcinomas. The frequency and specific characteristics of this aberrant MSH6 staining pattern, however, have not been well analyzed. In this study of 420 colorectal carcinoma samples obtained from patients fulfilling the Revised Bethesda Guidelines, we detected 9 tumors (2%) showing extremely limited staining for MSH6 with positive staining present in <5% of the tumor cells. Our analyses showed that these tumors belonged to two distinct categories: (1) MLH1 and/or PMS2 protein-deficient carcinomas (n=5, including 1 with a pathogenic mutation in PMS2); and (2) MLH1, PMS2 and MSH2 normal but with chemotherapy or chemoradiation therapy before surgery (n=4). To test our hypothesis that somatic mutation in the coding region microsatellite of the MSH6 gene might be a potential underlying mechanism for such limited MSH6 staining, we evaluated frameshift mutation in a (C)(8) tract in exon 5 of the MSH6 gene in seven tumors that had sufficient DNA for analysis, and detected mutation in four; all four tumors belonged to the MLH1/PMS2-deficient group. In conclusion, our data outline the main scenarios where significant reduction of MSH6 staining is more likely to occur in colorectal carcinoma, and suggest that somatic mutations of the coding region microsatellites of the MSH6 gene is an underlying mechanism for this staining phenomenon in MLH1/PMS2-deficient carcinomas. PMID- 22918163 TI - Evaluation of microvascular density in Barrett's associated neoplasia. AB - Angiogenesis has an important role in the carcinogenesis of esophageal adenocarcinoma, however, the diagnostic and prognostic utility of microvascular density counts have not been clinically established. The aim of this study is to assess the correlation between microvascular density and disease progression of non-dysplastic Barrett's esophagus, low-grade dysplasia, high-grade dysplasia and invasive carcinoma in the superficial aspects of the tissue. Archival histological specimens from two referral centers for Barrett's esophagus and esophageal cancer were selected for review. A total of 160 regions marked according to histological grade were assessed with digitally interactive software to measure microvascular density. This was quantified in three levels: 0-50, 50 100 and 100-150 MUm. In the areas of gastric cardia, Barrett's esophagus, low grade dysplasia, high-grade dysplasia and cancer, microvascular density was significantly different (P<0.0001) among the five groups in the most superficial 150 MUm of the mucosa. Furthermore, when examining the pairwise difference between the groups, there was a significant difference between cancer and each of the lower grades of histology (P<0.05) and between high-grade dysplasia and each of the lower grades of histology (P<0.05). These statistically significant differences were preserved in examining the depth at the most superficial 50 MUm. We have used digital pathology to demonstrate a significant and stepwise increase in microvascular density, which supports the hypothesis that angiogenesis has a key role in Barrett's carcinogenesis. Furthermore, the differences in the most superficial mucosal layers are consistent with findings of increased vascularity by depth-restricted imaging modalities. PMID- 22918164 TI - Follicular center helper T-cell (TFH) marker positive mycosis fungoides/Sezary syndrome. AB - We identified 11 patients with CD10(+) cutaneous T-cell lymphoma by flow cytometry. All cases were CD4(+) and CD8(-). Three patients had extensive lymphadenopathy, systemic symptoms and an aggressive clinical course consistent with angioimmunoblastic T-cell lymphoma or peripheral T-cell lymphoma. However, 8 of the 11 patients had a prolonged disease course with gross morphology, histology and tumor cell phenotype indistinguishable from mycosis fungoides or Sezary syndrome. Immunohistochemical studies confirmed CD10 expression in seven of the eight cases and revealed the lymphoma cells were Bcl-6(+), PD-1(+), and EBV(-). Two had significant expression of CXCL-13(+). The findings indicate that lymphoma cells from mycosis fungoides or Sezary syndrome may express follicular center helper T-cell markers CD10, Bcl-6, and PD-1 and occasionally CXCL-13. The expression of these markers in some cases of mycosis fungoides/Sezary syndrome suggests follicular center helper T-cell differentiation and may lead to confusion in distinguishing mycosis fungoides/Sezary syndrome from other follicular center helper T-cell marker positive T-cell lymphomas with cutaneous manifestations. PMID- 22918165 TI - BRAFV600E mutation in papillary thyroid microcarcinoma: a genotype-phenotype correlation. AB - BRAF(V600E) mutation has emerged as a marker of aggressive behavior in papillary thyroid carcinoma but its significance in microcarcinoma is not entirely clear. One-hundred and twenty-nine papillary thyroid microcarcinomas were tested for BRAF(V600E) mutation by single-strand conformation polymorphism, and their clinicopathologic features (age, sex, tumor size, multifocality, nodal metastases, histologic subtype, tumor cell morphology, architecture, tumor associated stromal reaction, tumor interface to non-neoplastic thyroid (well circumscribed vs infiltrative), extrathyroidal extension, lymphovascular invasion, intratumoral multinucleated giant cells, and adjacent non-neoplastic thyroid pathology) were examined. Compared with tumors without the mutation (39/129, 30%), the mutated microcarcinomas (90/129, 70%) showed significantly higher prevalence of infiltrative tumor borders (78/90 vs 23/39, P=0.001), tumor associated stromal desmoplasia/fibrosis and/or sclerosis (80/90 vs 25/39, P=0.002), classic nuclear features of papillary thyroid carcinoma (90/90 vs 35/39, P=0.008) and cystic change (43/90 vs 11/39, P=0.05). BRAF(V600E) mutation was more frequent in classic (75%), tall cell (91%), and other variants (>70%) than in follicular variant (21%) of papillary thyroid microcarcinoma. Tumors without the mutation were significantly more likely to be solid, well circumscribed, and lacked desmoplasia/fibrosis or sclerosis. However, on multivariate analysis, only the follicular variant of papillary microcarcinoma was significantly associated with the absence of mutation (odds ratio (95% confidence interval): 0.09 (0.01-0.54)). Lymph node metastases (n=24) were more frequent in microcarcinomas with mutation than without (21/24 vs 3/24, P=0.02). All patients with lateral cervical node metastasis (n=9), and all but one tumor with extrathyroidal extension (n=17/18) showed BRAF(V600E) mutation. No significant differences were noted in age, sex, tumor size, multifocality, lymphovascular invasion, psammoma bodies, stromal calcification, intratumoral multinucleated osteoclastic-type giant cells, and lymphocytic infiltration between the two groups of tumors. BRAF(V600E) mutation is an early event in thyroid carcinogenesis, and is associated with distinctive morphology and aggressive features even in papillary thyroid microcarcinomas. PMID- 22918166 TI - Heterogeneity in signaling pathways of gastroenteropancreatic neuroendocrine tumors: a critical look at notch signaling pathway. AB - The molecular pathogenesis of gastroenteropancreatic neuroendocrine tumors is largely unknown. We hypothesize that gastroenteropancreatic neuroendocrine tumors are heterogeneous with regard to these signaling pathways and these differences could have a significant impact on the outcome of clinical trials. We selected 120 well-differentiated neuroendocrine tumors including tumors originating in pancreas (n=74), ileum (n=31), and rectum (n=15). Immunohistochemistry was performed on tissue microarrays using the following antibodies: NOTCH1, HES1, HEY1, pIGF1R, and FGF2. Gene profiling study was performed by using human genome U133A 2.0 array and data were analyzed. The gene profiling results were selectively confirmed by using quantitative reverse-transcription PCR. Initial immunohistochemical analysis showed NOTCH1 was uniformly expressed in rectal neuroendocrine tumors (100%), a subset of pancreatic neuroendocrine tumors (34%), and negative in ileal neuroendocrine tumors. Similarly, a downstream target of NOTCH1, HES1 was preferentially expressed in rectal neuroendocrine tumors (64%), a subset of pancreatic neuroendocrine tumors (10%), and uniformly negative in ileal neuroendocrine tumors. Messenger RNAs for NOTCH1, HES1, and HEY1 were 2.32 , 2.44-, and 2.39-folds, respectively, higher in rectal neuroendocrine tumors as compared with ileal neuroendocrine tumors. Global gene expression profiling showed 95 genes were differentially expressed in small intestinal vs rectal neuroendocrine tumors, with changes as high as 50-fold. These genes were concentrated in several signal transduction pathways including cancer endocrine pathway and cell growth/proliferation pathway. The differential expression of selected genes including ISL LIM homeobox 1, cathepsin B, glucagon, and tryptophan hydroxylase 1 were confirmed by qPCR and immunohistochemistry. Our results confirm the heterogeneity in signaling pathways of gastroenteropancreatic neuroendocrine tumors. NOTCH1 inhibitors are unlikely to provide benefit in ileal neuroendocrine tumors; conversely, their efficacy in rectal neuroendocrine tumors needs further study. Further analysis of signaling pathways is critical for designing clinical trials in gastroenteropancreatic neuroendocrine tumors. PMID- 22918167 TI - High proliferation is associated with inferior outcome in male breast cancer patients. AB - Assessment of proliferation is important in female breast cancer and individual treatment decisions are based upon its results, especially in the luminal subgroups. Gene expression analyses fail to group male breast cancer into the intrinsic subgroups previously established in female breast cancer. Even though proliferation has been shown to divide male breast cancer into molecular subgroups with different prognoses, the clinical importance of proliferation markers has not yet been elucidated. Previous studies in male breast cancer have demonstrated contradictory results regarding the prognostic impact of histological grade and Ki-67, parameters strongly associated with proliferation. The aim of the present project was to study proliferation in male breast cancer by assessing other proliferation-related markers viz. cyclins A, B, D1 and mitotic count. A total of 197 male breast cancer cases with accessible paraffin embedded material and outcome data were investigated. Immunohistochemical stainings were performed on tissue microarrays. Kaplan-Meier estimates and the Cox proportional regression models were used for survival analyses with breast cancer death as the event. The subset of patients with high expression of cyclin A (hazard ratio (HR) 3.7; P=0.001) and B (HR 2.7; P=0.02) demonstrated a poorer survival. Furthermore, high mitotic count was associated with an increased risk of breast cancer death (HR 2.5; P=0.01). In contrast, cyclin D1 overexpression was predictive of better breast cancer survival (HR 0.3; P=0.001). In conclusion, high levels of cyclin A and B expression and an elevated mitotic count result in a two to threefold higher risk for breast cancer death, whereas cyclin D1 overexpression halves the risk. The clinical utility of these proliferation markers needs further elucidation. PMID- 22918168 TI - Comparison of prognostic values between combined immunohistochemical score of estrogen receptor, progesterone receptor, human epidermal growth factor receptor 2, Ki-67 and the corresponding gene expression score in breast cancer. AB - In the clinical diagnosis of breast cancer, immunohistochemistry panels with estrogen receptor (ER), progesterone receptor (PgR), human epidermal growth factor receptor 2 (HER2) and Ki-67 are routinely used, and they have been proposed for the classification of breast tumors into distinct subtypes. Gene expression analysis with formalin-fixed paraffin-embedded material have also become widely available recently, but the prognostic values of corresponding gene panels compared with these four immunohistochemical panels had never tested. We independently evaluated the 5-year relapse risk-estimation scores using semiquantitative data of four immunohistochemical panels (Ku-IHC4 score) and compared these with the results of four-gene expression profiling of formalin fixed paraffin-embedded specimens (Ku-FFPE4 score) in a consecutive series of 235 primary invasive breast cancer patients. Ku-IHC4 score was revealed to be an independent predictor of recurrence other than Ku-FFPE4 score in a multivariate model analyzed by classical clinical parameters (Ku-IHC4 score vs Ku-FFPE4 score; chi(2): 14.2 vs 2.5, P: 0.0002 vs 0.11). When patients were trichotomized into high-, intermediate- and low-risk groups using the thresholds determined from the approximately calculated 5-year relapse rate, Kaplan-Meier analyses showed a significant difference among the three groups in Ku-IHC4 score (log-rank, P<0.0001), but not in Ku-FFPE4 score. The high-risk group according to Ku-FFPE4 score showed contradictory low recurrence rates (Ku-IHC4 score vs Ku-FFPE4 score, 53.1 vs 24.8%), which might be caused by risk-dependently extended error ranges. We show that the Ku-IHC4 score, consisted with semiquantitative measures of immunohistochemistry, provides better prognostic information than the corresponding quantitative RNA measurements. Prognostication tools such as the Ku IHC4 score may be potentially useful in screening which patients had better be assessed by further testing using other genes rather than ER, PgR, HER2 and Ki-67 to determine critical aspects of therapeutic decision making. PMID- 22918169 TI - Primary and oncology care: can we coordinate the care? PMID- 22918170 TI - Patient satisfaction is a customer relations issue but an even greater health issue. PMID- 22918171 TI - Synthesis, crystal structure and optical properties of Na2RE(PO4)(WO4) (RE = Y, Tb-Lu). AB - Phase-pure samples of sodium rare-earth phosphate tungstates Na(2)RE(PO(4))(WO(4)) (RE = Y, Dy-Lu) and Na(2)Y(PO(4))(WO(4)):Ln(3+) (Ln = Eu, Tb) were obtained by reaction of the respective rare-earth oxide with ammonium hydrogen phosphate with sodium tungstate Na(2)WO(4).2H(2)O as a flux at 1220 K. According to X-ray single-crystal investigations Na(2)RE(PO(4))(WO(4)) (RE = Y, Tb-Lu) crystallise orthorhombically in space group Ibca (no. 73) (RE = Y, Z = 8, a = 1799.7(4), b = 1210.2(2), c = 683.82(14) pm, wR(2) = 0.040, R(1) = 0.037, 661 reflections, 62 parameters). The crystal structure contains non-condensed phosphate and tungstate tetrahedra with the (3 + 3)-coordinate sodium and eight coordinate rare-earth ions in the voids. Relevant absorption and infrared spectra as well as the fluorescence spectra of Na(2)Y(PO(4))(WO(4)):Ln(3+) (Ln = Eu, Tb) are presented. An FP-LAPW band-structure calculation confirms the assignment of the main absorption as well as the optical band-gap (epsilon(calc) = 5.1 eV; epsilon(meas) = 5.2(1) eV) of Na(2)Y(PO(4))(WO(4)). PMID- 22918172 TI - WITHDRAWN: The Dutch Eating Behaviour Questionnaire (DEBQ): Assessment of eating behaviour in an aging French population. AB - This article has been withdrawn at the request of the author(s) and/or editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy. PMID- 22918173 TI - Stress, emotional eating behaviour and dietary patterns in children. AB - Psychological stress has been suggested to change dietary pattern towards more unhealthy choices and as such to contribute to overweight. Emotional eating behaviour could be an underlying mediating mechanism. The interrelationship between stress, emotional eating behaviour and dietary patterns has only rarely been examined in young children. Nevertheless, research in children is pivotal as the foundations of dietary habits are established starting from childhood and may track into adulthood. In 437 children (5-12years) of the ChiBS study, stress was measured by questionnaires on stressful events, emotions (happy, angry, sad, anxious) and problems (emotional, peer, conduct and hyperactivity). Data were collected on children's emotional eating behaviour and also on dietary patterns: frequency of fatty foods, sweet foods, snacks (fat and sweet), fruit and vegetables. Stressful events, negative emotions and problems were positively associated with emotional eating. Positive associations were observed between problems and both sweet and fatty foods consumption. Negative associations were observed between events and fruit and vegetables consumption. Overall, stress was associated with emotional eating and a more unhealthy dietary pattern and could thus contribute to the development of overweight, also in children. Nevertheless, emotional eating behaviour was not observed to mediate the stress-diet relation. PMID- 22918174 TI - Understanding how consumers categorise nutritional labels: a consumer derived typology for front-of-pack nutrition labelling. AB - Significant ongoing debate exists amongst stakeholders as to the best front-of pack labelling approach and emerging evidence suggests that the plethora of schemes may cause confusion for the consumer. To gain a better understanding of the relevant psychological phenomena and consumer perspectives surrounding FoP labelling schemes and their optimal development a Multiple Sort Procedure study involving free sorting of a range of nutritional labels presented on cards was performed in four countries (n=60). The underlying structure of the qualitative data generated was explored using Multiple Scalogram Analysis. Elicitation of categorisations from consumers has the potential to provide a very important perspective in this arena and results demonstrated that the amount of information contained within a nutrition label has high salience for consumers, as does the health utility of the label although a dichotomy exists in the affective evaluation of the labels containing varying degrees of information aggregation. Classification of exiting front-of-pack labelling systems on a proposed dimension of 'directiveness' leads to a better understanding of why some schemes may be more effective than others in particular situations or for particular consumers. Based on this research an enhanced hypothetical front-of-pack labelling scheme which combines both directive and non-directive elements is proposed. PMID- 22918175 TI - Eating style, overeating and weight gain. A prospective 2-year follow-up study in a representative Dutch sample. AB - This study examined which individuals are particularly at risk for developing overweight and whether there are behavioral lifestyle factors that may attenuate this susceptibility. A prospective study with a 2-year follow-up was conducted in a sample representative of the general population of The Netherlands (n=590). Body mass change (self-reported) was assessed in relation to overeating and change in physical activity (both self-reported), dietary restraint, emotional eating, and external eating, as assessed by the Dutch Eating Behavior Questionnaire. There was a consistent main (suppressive) effect of increased physical activity on BMI change. Only emotional eating and external eating moderated the relation between overeating and body mass change. However, the interaction effect of external eating became borderline significant with Yes or No meaningful weight gain (weight gain >3%) as dependent variable. It was concluded that whilst increasing physical activity may attenuate weight gain, particularly high emotional eaters seem at risk for developing overweight, because overconsumption seems to be more strongly related to weight gain in people with high degrees of emotional eating. PMID- 22918176 TI - A test of different menu labeling presentations. AB - Chain restaurants will soon need to disclose calorie information on menus, but research on the impact of calorie labels on food choices is mixed. This study tested whether calorie information presented in different formats influenced calories ordered and perceived restaurant healthfulness. Participants in an online survey were randomly assigned to a menu with either (1) no calorie labels (No Calories); (2) calorie labels (Calories); (3) calorie labels ordered from low to high calories (Rank-Ordered Calories); or (4) calorie labels ordered from low to high calories that also had red/green circles indicating higher and lower calorie choices (Colored Calories). Participants ordered items for dinner, estimated calories ordered, and rated restaurant healthfulness. Participants in the Rank-Ordered Calories condition and those in the Colored Calories condition ordered fewer calories than the No Calories group. There was no significant difference in calories ordered between the Calories and No Calories groups. Participants in each calorie label condition were significantly more accurate in estimating calories ordered compared to the No Calories group. Those in the Colored Calories group perceived the restaurant as healthier. The results suggest that presenting calorie information in the modified Rank-Ordered or Colored Calories formats may increase menu labeling effectiveness. PMID- 22918177 TI - Ingestion of nutrition bars high in protein or carbohydrate does not impact 24-h energy intakes in healthy young adults. AB - Sales of nutrition bars increased almost 10-fold to $1.7billion over the past decade yet few studies have examined the impact of bar ingestion on dietary parameters. In this crossover trial, 24-h energy intakes were assessed in free living college students ingesting a high-protein (HP, 280kcal) or a high carbohydrate (HC, 260kcal) nutrition bar upon waking. Fifty-four students entered the trial, and 37 participants completed the three test days. Daily energy intakes ranged from 1752+/-99kcal for the non-intervention day to 1846+/-75 and 1891+/-110kcal for the days the HP and HC bars were consumed respectively (p=0.591). However, for individuals who reported high levels of physically activity (n=11), daily energy intakes increased significantly compared to the control day for the HC bar day (+45%; p=0.030) and HP bar day (+22%; p=0.038). Macro- and micro-nutrient intakes differed significantly across test days in the total sample mirroring the nutrient profile of the specific bars. These data suggest that young adults adjust caloric intakes appropriately following the ingestion of energy-dense nutrition bars over a 24-h period. Moreover, nutrition bars may represent a unique opportunity to favorably influence nutrient status of young adults. PMID- 22918178 TI - Meta-analysis of clinical data using human meiotic genes identifies a novel cohort of highly restricted cancer-specific marker genes. AB - Identifying cancer-specific biomarkers represents an ongoing challenge to the development of novel cancer diagnostic, prognostic and therapeutic strategies. Cancer/testis (CT) genes are an important gene family with expression tightly restricted to the testis in normal individuals but which can also be activated in cancers. Here we develop a pipeline to identify new CT genes. We analysed and validated expression profiles of human meiotic genes in normal and cancerous tissue followed by meta-analyses of clinical data sets from a range of tumour types resulting in the identification of a large cohort of highly specific cancer biomarker genes, including the recombination hot spot activator PRDM9 and the meiotic cohesin genes SMC1beta and RAD21L. These genes not only provide excellent cancer biomarkers for diagnostics and prognostics, but may serve as oncogenes and have excellent drug targeting potential. PMID- 22918179 TI - Cortisol response to waterborne 4-nonylphenol exposure leads to increased brain POMC and HSP70 mRNA expressions and reduced total antioxidant capacity in juvenile sole (Solea solea). AB - 4-Nonylphenol (4-NP) is a breakdown product of alkylphenolpolyethoxylates and can be found in almost all environmental water matrices. 4-NP can act as environmental stressor on fish, typically causing modulation of hypothalamic pituitary-interrenal axis (HPI). To examine the effects of the xenoestrogen 4-NP or 17beta-estradiol (E2) on induction of stress response mechanisms by evaluating the levels of proopiomelanocortin (POMC) mRNA, heat shock protein 70 (HSP70) mRNA and plasma cortisol, we exposed juvenile sole (Solea solea), under static condition for 7 day, to either 10(-6) or 10(-8) M 4-NP, or 10(-8) M E2. In addition, plasma cortisol titers were correlated to the total antioxidant capacity (TAC), one of the oxidative stress parameters. 4-NP treatments resulted in high levels of POMC mRNA, HSP70 mRNA and plasma cortisol. On the contrary, E2 basically down-regulated POMC expression. Moreover, elevated cortisol levels in fish exposed to the highest dose of 4-NP were accompanied by low TAC. These results suggest that 4-NP modulates the sole HPI axis inducing a cortisol mediated stress response. Specifically, we suggest that 4-NP affects brain POMC mRNA levels via non-estrogen receptor (ER)-mediated mechanism further supporting the ability of 4-NP to target multiple receptor systems. PMID- 22918180 TI - What does the patient know about quality? PMID- 22918181 TI - Simultaneous mitral valve and pectus excavatum repair with a Nuss bar. AB - We present the successful management of an interesting case of a single-stage combined mitral valve repair plus repair of the pectus excavatum with a Nuss bar. PMID- 22918182 TI - Atrial septal defect closure in the adult remains controversial. PMID- 22918183 TI - Prediction of in-hospital death following aortic valve replacement: a new accurate model. AB - OBJECTIVES: Aortic valve replacement (AVR) is accepted as the standard treatment for severe symptomatic aortic valve stenosis and regurgitation. As novel treatments are introduced for patients at high risk for conventional surgery, it is important to have models that accurately predict procedural risk. The aim of this study was to develop and validate a risk-stratification model to predict in hospital risk of death for patients undergoing AVR and to compare the model with existing algorithms. METHODS: We reviewed data from the Central Cardiac Adult Database, which holds prospectively collected clinical information on all adult patients undergoing cardiac surgery in National Health Service (NHS) hospitals and some private providers in the UK and Ireland. We included all the patients undergoing AVR with or without coronary artery bypass grafting. The study population consists of 55 157 patients undergoing surgery between 1 April 2001 and 31 March 2009. The model was built using data from April 2001 to March 2008 and validated using data from patients undergoing surgery from April 2008 to March 2009. The model was compared against the additive and logistic EuroSCORE models and a valve-specific risk-prediction model. RESULTS: The final multivariable model includes items describing cardiovascular risk status and procedural factors. Applying the model to the independent validation dataset provided a c-statistic (index of rank correlation) of 0.791, which was substantially better than that achieved by previously developed risk models in Europe, and significantly improved risk prediction in higher-risk patients. CONCLUSIONS: We have produced an accurate risk model to predict outcome following AVR surgery. It will be of use for patient selection and informed consent, and of particular interest in defining those patients at high risk who may benefit from novel approaches to AVR. PMID- 22918184 TI - Properties and osteoblast cytocompatibility of self-curing acrylic cements modified by glass fillers. AB - Materials filled with a silicate glass (MSi) and a borate glass (MB) were developed and compared in terms of their in vitro behavior. The effect of filler composition and concentration (0, 30, 40 and 50 wt%) on the curing parameters, residual monomer, water uptake, weight loss, bioactivity, mechanical properties (bending and compression) and osteoblast cytocompatibility was evaluated. The addition of bioactive glass filler significantly improved the cements curing parameters and the mechanical properties. The most relevant results were obtained for the lower filler concentration (30 t%) a maximum flexural strength of 40.4 Pa for MB3 and a maximum compressive strength of 95.7 MPa for MSi3. In vitro bioactivity in acellular media was enhanced by the higher glass contents in the cements. Regarding the biological assessment, the incorporation of the silicate glass significantly improved osteoblast cytocompatibility, whereas the presence of the borate glass resulted in a poor cell response. Nevertheless it was shown that the surviving cells on the MB surface were in a more differentiated stage compared to those growing over non-filled poly(methyl methacrylate). Results suggest that the developed formulations offer a high range of properties that might be interesting for their use as self-curing cements. PMID- 22918185 TI - Tuning the phase transition dynamics by variation of cooling field and metastable phase fraction in Al doped Pr0.5Ca0.5MnO3. AB - We report the effect of field, temperature and thermal history on the time dependence in resistivity and magnetization in the phase separated state of Al doped Pr(0.5)Ca(0.5)MnO(3). The rate of time dependence in resistivity is much higher than that of magnetization and it exhibits a different cooling field dependence due to percolation effects. Our analysis shows that the time dependence in physical properties depends on the phase transition dynamics, which can be effectively tuned by variation of temperature, cooling field and metastable phase fraction. The phase transition dynamics can be broadly divided into the arrested and unarrested regimes, and in the arrested regime this dynamics is mainly determined by time taken in the growth of critical nuclei. An increase in cooling field and/or temperature shifts this dynamics from the arrested to unarrested regime, and in this regime, this dynamics is determined by the thermodynamically allowed rate of formation of critical nuclei, which in turn depends on the cooling field and available metastable phase fraction. At a given temperature, a decrease in metastable phase fraction shifts the crossover from arrested to unarrested regimes towards lower cooling field. It is rather significant that in spite of the metastable phase fraction calculated from resistivity being somewhat off that of magnetization, their cooling field dependence exhibits a striking similarity, which indicates that the dynamics in arrested and unarrested regimes are so different that it comes out vividly provided that the measurements are performed around the percolation threshold. PMID- 22918186 TI - Anion coordination by metallamacrocycles: a cryptand-like cavity. AB - A {Ni(9)(N(3))(9)} metallamacrocycle is able to coordinate azide and halide anions in trigonal prismatic cavities by means of H-bond interactions. It provides an unprecedented example of a self-assembled cryptand-like cavity. PMID- 22918190 TI - Enhanced light emission of GaN-based diodes with a NiO(x)/graphene hybrid electrode. AB - A NiO(x) buffer layer is introduced in GaN-based light-emitting diodes to form low resistance ohmic contacts between p-type GaN and graphene conductive electrodes, leading to improved performance with lower operating voltage and higher light output power. PMID- 22918191 TI - Ophthalmic antihistamines and H1-H4 receptors. AB - PURPOSE OF REVIEW: Antihistamines exert pharmacologic effects by binding to four histamine receptors (H1-H4) at different affinities, producing variable effects depending on the receptor they predominantly bind to. This review's purpose is to determine the relative potency of antihistamines by comparing their binding affinities to these receptors. Studies on binding affinities of antihistamines to histamine receptors were reviewed and the dissociation constant for inhibitor binding (Ki) analyzed to determine the most and least potent antihistamine for each receptor. RECENT FINDINGS: We retrieved the binding affinities for nineteen antihistamines. For H1 receptors, pyrilamine exhibited the highest affinity (Ki = 0.8 nM), and thioperamide the lowest (Ki = 280, 000 nM). For H2 receptors, ranitidine exhibited the highest affinity (Ki = 187 nM), and olopatadine the lowest (Ki = 100 ,000 nM). For the recently discovered H3 and H4 receptors, thioperamide exhibited the highest affinity (Ki = 1.1 nM), and olopatadine exhibited the lowest (Ki = 79 ,400 nM), to H3. Data on binding affinities to the H4 receptor exist for: ketotifen, pheniramine, ranitidine, cimetidine and thioperamide. Of these, thioperamide exhibited the highest affinity (Ki = 27 nM), whereas cimetidine and ranitidine exhibited the lowest affinity (Ki = >10, 000 nM) for H4 receptors. SUMMARY: This review summarizes the relative potency of antihistamines based on their binding affinities to the four histamine receptors. Although data on binding affinities of antihistamines to the H4 receptor are sparse, it is apparent that further research on these histamine subtypes may open new venues for more direct treatment with a higher therapeutic efficacy on allergic disorders including those affecting the ocular surface. PMID- 22918193 TI - Monocyte function and trafficking in cardiovascular disease. AB - Monocytes are key effectors of the immune homeostasis and play a crucial role in (vascular) injury repair. Despite their role in immune defense and tissue repair mechanisms, monocytes are also involved in several pathological conditions such as autoimmune and cardiovascular diseases as well as cancer. This suggests that monocytes can be used as diagnostic and as therapeutic targets. A better understanding and characterisation of monocytes and their function in both physiological and pathological situations is thus of great interest. This review focuses on recent advances on the role of monocytes in cardiovascular diseases and describes the value of monocytes as either disease marker or therapeutic target for (cardio)vascular diseases. PMID- 22918192 TI - Long-term exposure to traffic-related air pollution and diabetes-associated mortality: a cohort study. AB - AIMS/HYPOTHESIS: The aim of this study was to investigate whether air pollution from traffic at a residence is associated with mortality related to type 1 or type 2 diabetes. METHODS: We followed up 52,061 participants in the Danish Diet, Cancer and Health cohort for diabetes-related mortality in the nationwide Register of Causes of Death, from baseline in 1993-1997 up to the end of 2009, and traced their residential addresses since 1971 in the Central Population Registry. We used dispersion-modelled concentration of nitrogen dioxide (NO2) since 1971 and amount of traffic at the baseline residence as indicators of traffic-related air pollution and used Cox regression models to estimate mortality-rate ratios (MRRs) with adjustment for potential confounders. RESULTS: Mean levels of NO2 at the residence since 1971 were significantly associated with mortality from diabetes. Exposure above 19.4 MUg/m3 (upper quartile) was associated with a MRR of 2.15 (95% CI 1.21, 3.83) when compared with below 13.6 MUg/m3 (lower quartile), corresponding to an MRR of 1.31 (95% CI 0.98, 1.76) per 10 MUg/m3 NO2 after adjustment for potential confounders. CONCLUSIONS/INTERPRETATION: This study suggests that traffic-related air pollution is associated with mortality from diabetes. If confirmed, reduction in population exposure to traffic-related air pollution could be an additional strategy against the global public health burden of diabetes. PMID- 22918194 TI - The ADHD-linked gene Lphn3.1 controls locomotor activity and impulsivity in zebrafish. PMID- 22918195 TI - Determination of the magnetic structure of SmFe3(BO3)4 by neutron diffraction: comparison with other RFe3(BO3)4 iron borates. AB - Temperature dependent neutron diffraction studies were performed on SmFe(3)(BO(3))(4). The crystallographic structure was determined to stay as R32 over the whole studied temperature range of 2 K < T < 300 K. A magnetic phase transition characterized by the magnetic propagation vector kappa = [0 0 3/2] takes place at T(N) = 34 K. The magnetic structure sees an easy-plane arrangement within the trigonal basal a-b-plane of ferromagnetic layers of iron and samarium having a canting angle of about 70 degrees relative to each other. Neighbouring layers in the c-direction are antiferromagnetically coupled; at 2 K the magnetic moment values amount to MU(Fe ) = 4.2(1) MU(B ) and MU(Sm) = 0.8(2) MU(B). The non-Brillouin type increase of the iron magnetic moment below T(N) points to a strong Fe-Sm exchange and to the simultaneous appearance of long range magnetic order on both sublattices. PMID- 22918197 TI - Reversible thermal transition of polydiacetylene based on KTTKS collagen sequence. AB - Here we explore the physico-chemical properties of a peptide amphiphile obtained by chemical conjugation of the collagen-stimulating peptide KTTKS with 10,12 pentacosadiynoic acid which photopolymerizes as a stable and extended polydiacetylene. We investigate the self-assembly of this new polymer and rationalize its peculiar behavior in terms of a thermal conformational transition. Surprisingly, this polymer shows a thermal transition associated with a non-cooperative increase in beta-sheet content at high temperature. PMID- 22918198 TI - Serum levels of adipocyte fatty acid-binding protein are independently associated with left ventricular mass and myocardial performance index in obstructive sleep apnea syndrome. AB - OBJECTIVE: To investigate the cross-sectional association between serum adipocyte fatty acid-binding protein (A-FABP) level and diagnosis or severity of obstructive sleep apnea syndrome (OSAS) and some echocardiographic indices related with cardiac dysfunction. METHODS: In this study, plasma A-FABP and high sensitivity C-reactive protein concentrations were measured, and echocardiography was performed in subjects without any cardiac or pulmonary disease who were referred for evaluation of OSAS. According to the apnea-hypopnea index (AHI), subjects were classified into 3 groups: control group (AHI <5; n = 33), mild to moderate OSAS (30 > AHI >= 5; n = 30), and severe OSAS (AHI >= 30; n = 31). RESULTS: Levels of A-FABP were significantly different between the groups (P < 0.001). After post hoc analyses, all 3 groups were also significantly different from each other. The levels of A-FABP were significantly higher in the patients with severe OSAS (36.4 +/- 13.0 ng/mL) than in the control subjects (9.3 +/- 4.6 ng/mL; P < 0.0001) or in patients with mild-moderate OSAS (24.5 +/- 10.5 ng/mL; P < 0.001). Patients with myocardial performance index (MPI) greater than 0.47 had higher serum A-FABP levels than those with MPI of less than 0.47 (31.8 +/- 13.2 ng/mL vs 10.9 +/- 6.3 ng/mL; P = 0.001). Multivariable regression analyses revealed that increased serum A-FABP concentrations were independently associated with increased left ventricular mass index (beta = 0.195; P = 0.033) and increased MPI (beta = 0.165; P = 0.015). CONCLUSIONS: Increased A-FABP levels were found in the patients with OSAS, which were correlated significantly with left ventricular mass index and MPI. Further prospective studies are needed to clarify whether increased serum A-FABP level is a marker or a potential mechanism for left ventricular involvement in patients with OSAS. PMID- 22918200 TI - Translational research and the evolving landscape for biomedical innovation. AB - This article addresses current challenges facing pharmaceutical and biopharmaceutical developers, including the expiration of patents on many high revenue-generating products, increasing competition in the marketplace, low public support, high regulatory hurdles, and the increasing time, cost, and risk of new product development. To meet these challenges, drug developers are looking to new models of innovation to improve efficiency, lower risk, and increase output. These new models include codevelopment agreements with small companies, multicompany consortia, and strategic partnerships with academic research centers. In the United States and the European Union, the government is supporting these efforts by creating incentives for academic centers to foster translational research and become more "commercially minded". The goal for all stakeholders is to reduce the barriers to product development and bring new medicines to market in a timely and cost-efficient manner. PMID- 22918201 TI - Intraprostatic botulinum neurotoxin type a injection for benign prostatic hyperplasia: preliminary results with a newly purified neurotoxin. AB - Several studies have demonstrated the efficacy of intraprostatic injection of botulinum neurotoxin type A (BoNT/A) against symptomatic benign prostatic hyperplasia (BPH). The most commonly used BoNT/A product, Botox((r)), forms large complexes and composed of neurotoxin (NTX) as well as non-toxic components. We purified NTX lacking non-toxic components. We investigated the efficacy of this newly purified NTX for men with BPH. Ten male patients (mean age, 70.0 years) with BPH received 100 units (prostate volume [PV] <30 ml) or 200 units (PV >30 ml) of NTX injected into the prostate via a minimally invasive outpatient technique. Evaluation included uroflowmetry, postvoid residual urine volume (PVR), PV, and International Prostate Symptom Score (IPSS) measured at baseline and 1, 3, 6, and 12 months post-treatment. The status of 7 of the 10 patients examined was found to have improved within 1 month of treatment. The mean IPSS decreased from 23.8 +/- 7.0 to 16.3 +/- 10.3 (p=0.0093) at 1 month, to 14.9 +/- 8.2 (p=0.0074) at 3 months, and to 16.9 +/- 7.3 (p=0.018) at 12 months. The mean PV decreased from 47.8 +/- 21.2 to 39.2 +/- 19.5 ml (p=0.0076) at 3 months. The PVR improved at 3 and 6 months post-treatment. Intraprostatic NTX injection induces prostate shrinkage and is effective in men with BPH. PMID- 22918199 TI - Early elevation of serum tumor necrosis factor-alpha is associated with poor outcome in subarachnoid hemorrhage. AB - OBJECTIVE: Subarachnoid hemorrhage (SAH) is associated with inflammation that may mediate poor outcome in SAH. We hypothesize that elevated serum tumor necrosis factor alpha (TNF-alpha) and interleukin 6 (IL-6) are associated with vasospasm and poor outcome in SAH. METHODS: In 52 consecutive SAH subjects, we compared TNF alpha and IL-6 levels on post-SAH days 0 to 1, 2 to 3, 4 to 5, 6 to 8, and 10 to 14 with respect to vasospasm and to poor outcome at 3 and 6 months. Vasospasm was defined as more than 50% reduction in vessel caliber on angiography. Poor outcome was defined as modified Rankin score greater than 2. RESULTS: Elevated TNF-alpha on post-SAH days 2 to 3 was associated with poor 3-month outcome (P = 0.0004). Global elevation of TNF-alpha over time (post-SAH days 0-14) was independently associated with poor 3-month outcome after adjusting for Hunt-and-Hess grade and age (P = 0.02). Neither cross-sectional nor IL-6 levels over time were associated with outcome. Neither TNF-alpha nor IL-6 levels were associated with vasospasm. CONCLUSIONS: Elevation in serum TNF-alpha on post-SAH days 2 to 3 and global elevation of TNF-alpha over time are associated with poor outcome but not with angiographic vasospasm in this small cohort. Future studies are needed to define the role of TNF-alpha in SAH-related brain injury and its potential as a SAH outcome biomarker. PMID- 22918202 TI - Analysis of surgical outcomes of diverticular disease of the colon. AB - We analyzed retrospectively the surgical outcomes of diverticular diseases of the colon at the surgical division of Fukuyama Medical Center. Data were collected from 39 patients who underwent surgery for diverticular disease at Fukuyama Medical Center. Thirty-nine patients were admitted between 2005 and 2010. The mean age of the 39 patients was 63.6 years. The collected data included patient demographics, patient history, type of surgery and complications. Patients were divided into 2 groups, Elective vs. Emergent group, right vs. left colon group and laparotomy vs. laparoscopic approach. Multivariate analysis of the logistic model of morbidity revealed a significantly higher rate in the left colon and the Cox proportional hazards model clearly showed fewer postoperative hospital days with the laparoscopic approach. Surgical procedures should be decided in reference to the particular clinical and pathological features of diverticular disease to gain an acceptable morbidity and mortality rates. PMID- 22918203 TI - Factors predicting bone mineral density (BMD) changes in young women over a one year study:changes in body weight and bone metabolic markers during the menstrual cycle and their effects on BMD. AB - Currently, 26% of Japanese women in their twenties are under weight, and therefore at risk of developing various metabolic abnormalities due to an inadequate nutrient intake, which in turn affects the acquisition of a peak bone mineral density (BMD). In this study, we aimed to clarify the effects of menstrual cycle-related changes in body weight and bone metabolic marker levels on the BMD changes. The subjects were 42 women (19.6 +/- 0.8 years). The levels of osteocalcin (OC), BAP, s-NTx, u-DPD, and E2 in the menstrual and ovulatory phases were measured. The associations between dependent variables (BMD changes/year in the lumbar spine, femur, femoral neck) and explanatory variables (body weight changes/year, the levels of OC, BAP, s-NTx, u-DPD) were evaluated using multiple regression analysis. Analysis of the correlations between the changes in bone metabolic markers and changes in BMD showed a correlation between the OC level in the menstrual phase and changes in the BMD of the entire femur, suggesting that a high OC level protects against BMD reduction, probably by promoting osteoblast activity, and that bone formation activity suppresses the decrease in BMD. These results suggest that, to predict BMD changes from bone metabolic markers in young women, it is necessary to measure OC levels in the menstrual phase. PMID- 22918204 TI - Water extract of Vitis coignetiae Pulliat leaves attenuates oxidative stress and inflammation in progressive NASH rats. AB - This study aimed to investigate the therapeutic effects of the water extract of leaves of Vitis coignetiae Pulliat (VCPL) on nonalcoholic steatohepatitis (NASH) with advanced fibrosis, as our previous study exhibited its preventive effect on NASH. The NASH animal model [PCT/JP2007/52477] was prepared by loading recurrent and intermittent hypoxemia stress to a rat with fatty liver, which resembled the condition occurring in patients with obstructive sleep apnea (OSA) and fatty liver, who have a high incidence of NASH. Intermittent hypoxemia stress is regarded as a condition similar to warm ischemia followed by re-oxygenation, which induces oxidative stress (OS). The daily 100 or 300 mg/kg VCPL administrations were performed for 3 weeks perorally beginning at the time of detection of advanced liver fibrosis. The therapeutic efficacy of VCPL on NASH was demonstrated by the reduction of the leakage of hepato-biliary enzymes and the amelioration of liver fibrosis. The OS elevation in NASH rats was measured based on the derivation of reactive oxygen species from liver mitochondrial energy metabolism and on the decrease in plasma SOD-like activity. The aggravation of inflammatory responses was demonstrated by the neutrophil infiltration (elevated myeloperoxidase activity) and the progression of fibrosis in the livers of NASH rats. In addition, the NASH rats without VCPL treatment also exhibited activation of nuclear factor-kappaB, a key factor in the link between oxidative stress and inflammation. All of these changes were reduced dose dependently by the VCPL administration. These findings indicate that VCPL may improve hepatic fibrosis or at least suppress the progression of NASH, by breaking the crosstalk between OS and inflammation. PMID- 22918205 TI - Effect of taurine on acinar cell apoptosis and pancreatic fibrosis in dibutyltin dichloride-induced chronic pancreatitis. AB - The relationship between pancreatic fibrosis and apoptosis of pancreatic acinar cells has not been fully elucidated. We reported that taurine had an anti fibrotic effect in a dibutyltin dichloride (DBTC)-chronic pancreatitis model. However, the effect of taurine on apoptosis of pancreatic acinar cells is still unclear. Therefore, we examined apoptosis in DBTC-chronic pancreatitis and in the AR42J pancreatic acinar cell line with/without taurine. Pancreatic fibrosis was induced by a single administration of DBTC. Rats were fed a taurine-containing diet or a normal diet and were sacrificed at day 5. The AR42J pancreatic acinar cell line was incubated with/without DBTC with taurine chloramines. Apoptosis was determined by using terminal deoxynucleotidyl transferase-mediated dUTP digoxigenin nick end labeling (TUNEL) assay. The expression of Bad and Bcl-2 proteins in the AR42J cells lysates was detected by Western blot analysis. The apoptotic index of pancreatic acinar cells in DBTC-administered rats was significantly increased. Taurine treatment inhibited pancreatic fibrosis and apoptosis of acinar cells induced by DBTC. The number of TUNEL-positive cells in the AR42J pancreatic acinar cell lines was significantly increased by the addition of DBTC. Incubation with taurine chloramines ameliorated these changes. In conclusion, taurine inhibits apoptosis of pancreatic acinar cells and pancreatitis in experimental chronic pancreatitis. PMID- 22918206 TI - Humidification of base flow gas during adult high-frequency oscillatory ventilation: an experimental study using a lung model. AB - In adult high-frequency oscillatory ventilation (HFOV) with an R100 artificial ventilator, exhaled gas from patient's lung may warm the temperature probe and thereby disturb the humidification of base flow (BF) gas. We measured the humidity of BF gas during HFOV with frequencies of 6, 8 and 10 Hz, maximum stroke volumes (SV) of 285, 205, and 160 ml at the respective frequencies, and, BFs of 20, 30, 40 l/min using an original lung model. The R100 device was equipped with a heated humidifier, Hummax II, consisting of a porous hollow fiber in circuit. A 50-cm length of circuit was added between temperature probe (located at 50 cm proximal from Y-piece) and the hollow fiber. The lung model was made of a plastic container and a circuit equipped with another Hummax II. The lung model temperature was controlled at 37C. The Hummax II of the R100 was inactivated in study-1 and was set at 35C or 37C in study-2. The humidity was measured at the distal end of the added circuit in study-1 and at the proximal end in study-2. In study-1, humidity was detected at 6 Hz (SV 285 ml) and BF 20 l/min, indicating the direct reach of the exhaled gas from the lung model to the temperature probe. In study-2 the absolute humidity of the BF gas decreased by increasing SV and by increasing BF and it was low with setting of 35C. In this study setting, increasing the SV induced significant reduction of humidification of the BF gas during HFOV with R100. PMID- 22918207 TI - Does caregiver's social bonding enhance the health of their children?: the association between social capital and child behaviors. AB - Little is known about the association between social capital and child behaviors. This study aims to investigate that association. A complete population-based, cross-sectional survey was conducted for all the caregivers with preschool children in a rural town in Okayama prefecture in Japan. Two dimensions of individual-level social capital and unhealthy child behaviors were reported by parent-administered questionnaire. We analyzed 354 preschool children (57.6% of all children for whom questionnaires were completed). Children whose main caregiver had high cognitive social capital were 89% less likely to miss breakfast (odds ratio [OR]=0.11;95% confidence interval [CI]:0.01-1.03). Children whose caregiver had high structural social capital were 71% less likely to wake up late (OR=0.29;95% CI:0.12-0.71) and 78% less likely to skip tooth brushing more than once per day (OR=0.22;95% CI:0.05-0.93). Both cognitive and structural social capital were negatively associated with unhealthy child behaviors. A further intervention study is needed to confirm the impact of social capital on child behavior. PMID- 22918208 TI - Serotonin- and somatostatin-positive goblet cell carcinoid of the duodenum. AB - In the duodenum, mixed exocrine-endocrine tumors exhibiting both neuroendocrine and glandular differentiations [cf. appendiceal goblet cell carcinoids (GCCs)] are rare. We present a Japanese case with a duodenal GCC that was found during pathologic examination of a gastrectomy specimen removed for gastric mucosal cancer. The tumor was widely distributed within both the first portion of the duodenum and the gastric antrum, although mucosal involvement was observed only in the duodenum. The tumor cells formed solid nests, trabeculae, or tubules, and some displayed a goblet cell appearance. They were immunoreactive against antibodies for both serotonin and somatostatin, and showed an argentaffin reaction (similar to a "midgut" enterochromaffin cell carcinoid). Ultra structurally, the tumor cells had an amphicrine nature. Physicians encounter GCC in the duodenum only rarely, and its discovery may be incidental. Its diagnosis will be challenging and will require careful clinical and pathologic examinations. PMID- 22918209 TI - Ectopic cervical thymoma: a case report with 18F-fluorodeoxyglucose positron emission tomography findings. AB - Ectopic thymoma is considered to arise from ectopic thymus tissue deposited as a result of the abnormal mislocalization of thymus tissue during the embryonic stage. An 86-year-old man visited our hospital with chief complaints of hoarseness and a mass in his anterior neck. A preoperative needle biopsy of the mass did not yield a definitive diagnosis. A positron emission tomography (PET) study revealed heterogeneous accumulation of (18)F-fluorodeoxyglucose (FDG) in the tumor. The tumor, affecting the left sternocleidomastoid muscle, the recurrent laryngeal nerve, the internal carotid vein, and the brachiocephalic vein, was resected using a combination of a collar incision in the neck and a median incision in the sternum. Immunohistochemically, the tumor was diagnosed as an ectopic thymoma of the neck. To date, only a few cases of ectopic thymoma presenting with FDG accumulation have been reported. Our experience indicates that ectopic thymoma should be kept in mind during the differential diagnosis of neck tumors with FDG accumulation appearing on PET images. PMID- 22918210 TI - Segmental pedicle screw fixation for a scoliosis patient with post-laminectomy and post-irradiation thoracic kyphoscoliosis of spinal astrocytoma. AB - Spinal deformity is an important clinical manifestation after surgery for spinal cord tumors. One-third of patients who receive laminectomies and irradiation of the spinal column develop scoliosis, kyphosis, or kyphoscoliosis. Recent reports indicate good results after scoliosis surgery using segmental pedicle screws and a navigation system, but these reported studies have not included surgery for post-laminectomy kyphosis. Hooks and wires are ineffective in such patients who undergo laminectomy, and there are also high perioperative risks with insertion of pedicle screws because landmarks have been lost. Here, we report on the 5-year follow-up of a 13-year-old male patient with post-laminectomy and post irradiation thoracic kyphoscoliosis after surgical treatment of spinal astrocytoma. Posterior segmental pedicle screw fixation was performed safely using a computer-assisted technique. The authors present the first case report for treatment of this condition using a navigation system. PMID- 22918211 TI - Periostin contributes to the pathogenesis of atopic dermatitis by inducing TSLP production from keratinocytes. AB - BACKGROUND: Atopic dermatitis (AD) is a chronic inflammatory skin disease where Th2-type immune responses are dominant. Keratinocytes persistently secrete proinflammatory cytokines and chemokines, amplifying Th2-type responses in AD. We have recently reported that periostin, an extracellular matrix protein induced by Th2 cytokines, plays a critical role in AD. In the present study, we have further investigated the characteristics of our allergen-induced AD model mice and the role of periostin in the pathogenesis of AD. METHODS: The ears of C57BL/6 mice, BALB/c mice, and Rag-2-/- gamma(c)-/- mice (BALB/c background) were epicutaneously sensitized repeatedly with HDM. Mice were analyzed after the final sensitization. To examine the direct role of periostin, we reconstituted skin in vitro by coculture of keratinocytes with wild-type or periostin-deficient fibroblasts. RESULTS: Epicutaneous sensitization with HDM induced AD-like phenotypes and accumulation of periostin in dermis in C57BL/6 mice but not in Rag 2-/- gamma(c)-/- mice. In vitro organotypic coculture systems revealed that periostin promoted survival and proliferation of keratinocytes and directly induced production of thymic stromal lymphopoietin (TSLP). CONCLUSIONS: Our results suggest that periostin exacerbates the pathogenesis of AD through TSLP production from keratinocytes. PMID- 22918212 TI - Frequency of persistent cough and trends in seeking medical care and treatment results of an internet survey. AB - BACKGROUND: Cough is a frequently encountered symptom and can be indicative of a serious underlying disease. However, no studies have investigated the incidence of cough in the general population in Japan, the diseases causing cough or the treatments administered. METHODS: We sent a screening survey to 29,085 randomly selected individuals and a more detailed survey to the first 1,000 individuals with cough who agreed to participate and provided consent. The survey included questions to determine the duration of cough, disturbances of daily living and whether the individual had consulted a physician. RESULTS: The prevalence of cough among the general population was 10.2%. There was no difference in cough frequency between males and females or across age groups. The prevalence of prolonged or chronic cough (cough lasting >=3 weeks) was 35.8% and the duration of cough increased with age. Women were more troubled by cough than men were. "Feeling ashamed to cough in front of other people" (49.0%) and "causing trouble to other people" (42.8%) were the main reasons for feeling troubled by cough. More than 60% of surveyed individuals were not receiving care and 44.0% had no plans to visit a medical facility. Although cold was the most common cause of cough overall, asthma was the main cause among individuals with cough lasting >=8 weeks. CONCLUSIONS: In this large-scale cohort study, many respondents were unwilling to visit their doctor, despite having chronic cough. Improvements in educational campaigns are needed to encourage people with chronic cough to visit a doctor. PMID- 22918213 TI - Expression of pendrin and periostin in allergic rhinitis and chronic rhinosinusitis. AB - BACKGROUND: Pendrin and periostin are newly identified mediators of the inflammatory process. The expression of these proteins in human sinonasal tissue and their roles in allergic rhinitis and chronic rhinosinusitis remain to be elucidated. This study investigated the expression of pendrin and periostin in sinonasal tissue of patients with allergic rhinitis, chronic rhinosinusitis, and aspirin-induced asthma. Prospective control study conducted at Yamagata University, Japan. METHODS: Surgical samples were investigated by means of real time reverse transcription-polymerase chain reaction to evaluate the expression of pendrin and periostin mRNA. The presence and location of pendrin and periostin were determined by immunohistochemistry and Western blotting. RESULTS: Pendrin and periostin production was significantly higher in patients with nasal disorders than in controls. Further significant increases in periostin expression were noted in patients with chronic rhinosinusitis with nasal polyps and in those with aspirin-induced asthma. Immunohistochemistry revealed positive staining for pendrin in epithelial cells and submucosal glands and for periostin in the basement membrane in all three disorders, and additionally for periostin in nasal polyp tissue in chronic rhinosinusitis and aspirin-induced asthma. CONCLUSIONS: Production of pendrin and periostin is upregulated in allergic rhinitis, chronic rhinosinusitis with nasal polyps, and aspirin-induced asthma. These findings suggest that pendrin can induce mucus production and that periostin can induce tissue fibrosis and remodeling in the nasal mucosa. Therefore, these mediators may be therapeutic target candidates for allergic rhinitis, chronic rhinosinusitis with nasal polyps, and aspirin-induced asthma. PMID- 22918214 TI - Anti-allergic effects of Vernonia amygdalina leaf extracts in hapten-induced atopic dermatitis-like disease in mice. AB - BACKGROUND: Atopic dermatitis (AD) is a chronic inflammatory skin disease characterized by pruritic and eczematous skin lesions. In this study, AD-like disease was induced in NC/Nga mice so as to evaluate the anti-allergic effects of Vernonia amygdalina leaf extracts (VAM). METHODS: Forty NC/Nga mice were purchased for each of the two protocols (prophylactic and curative) of the study. Mice were randomly divided in groups of five or six after sensitization with 5% trinitrochlorobenzene (TNCB): aqueous extracts (VAM1), methanolic extracts (VAM2), hydrocortisone (HCT), buffer for the control (TNCB) and the normal mice (NORM) groups. RESULTS: As for HCT, VAM1 and VAM2-pretreated mice showed significantly lower number of scratching behavior episodes (p < 0.01; vs. TNCB) following TNCB challenge. In addition, VAM1, VAM2 exerted a significant inhibitory effect on the development of AD skin symptoms (vs. TNCB group; p < 0.001), the production of IgE, TNF-alpha (p < 0.05), IL-5 and IFN-gamma (p < 0.01) (vs. TNCB group) and on the increase in ear thickness (p < 0.05) in prophylactic protocol. In the AD curative protocol, topical VAM1, VAM2 markedly improved skin lesions such as erythema/hemorrhage (p < 0.05), scaling/dryness, erosion/excoriation (p < 0.01) (vs. TNCB mice). Furthermore, a significant decrease in ear thickness was noted in VAM1, VAM2, HCT groups (vs. TNCB group; p < 0.05) as well as the serum total IgE, MCP-1 (p < 0.01) and eotaxin (p < 0.05). VAM2 also improved chronic eczema dermatitis skin symptoms in a patient. CONCLUSIONS: Results from this report suggest that VAM extracts, known as ERK pathway inhibitor, prevent and improve atopic/eczema dermatitis syndrome. PMID- 22918215 TI - Risk factors of local oropharyngeal and laryngeal adverse effects from use of single inhaled corticosteroids and long-acting beta-agonists. AB - BACKGROUND: Single inhaled corticosteroids and long-acting beta-agonists (ICS/LABA) are clinically effective and safe. However, if local oropharyngeal and laryngeal adverse effects (LOLAE) appear, adherence to the use of ICS is impaired. To minimize the development of adverse effects, it is essential to identify the underlying risk factors. METHODS: The study included 481 asthmatic patients who were prescribed ICS/LABA for the first time in their life between January and September of 2010. Patients ranged in age from 14 to 86 years old and consisted of 281 never smokers and 200 smokers. All data were collected retrospectively by respirologists. RESULTS: Seventy-three out of 481 patients suffered from one or more adverse effects, with 54 of these exhibiting LOLAE. Patients with LOLAE (51.4 +/- 16.2 yrs) were significantly older than those without LOLAE (43.7 +/- 15.9 yrs) (p = 0.0011) and were also prescribed a significantly higher dose of ICS. The pack-years of patients with LOLAE (2.1 +/- 4.9) were significantly lower than those without LOLAE (6.0 +/- 13.0) (p = 0.0087). The type of administered ICS was also significantly associated with a risk of developing LOLAE. CONCLUSIONS: Our survey indicated that a greater age, a higher dose of ICS, and the type of ICS were potential risk factors of LOLAE. The identified factors should be considered in a clinical setting in order to prevent the development of LOLAE and provide optimal treatment to patients. PMID- 22918216 TI - Diastolic dysfunction in patients with end-stage liver disease is associated with development of heart failure early after liver transplantation. AB - BACKGROUND: Liver transplantation (LTx) is a life-saving treatment of end-stage liver disease. Cardiac complications including heart failure (HF) are among the leading causes of death after LTx. THE AIM: The aim is to identify clinical and echocardiographic predictors of developing HF after LTx. METHODS: Patients who underwent LTx at the University of Nebraska Medical Center (UNMC) between January 2001 and January 2009 and had echocardiographic study before and within 6 months after transplantation were identified. Patients with coronary artery disease (>70% lesion) were excluded. HF after LTx was defined by clinical signs, symptoms, radiographic evidence of pulmonary congestion, and echocardiographic evidence of left ventricular dysfunction (left ventricle ejection fraction <50%). RESULTS: Among 107 patients (presented as mean age [SD], 55 [10] years; male, 70%) who met the inclusion criteria, 26 (24%) patients developed HF after LTx. The pre-LTx left ventricle ejection fraction did not differ between the HF (69 [7]) and the control groups (69 [7] vs. 67 [6], P=0.30). However, pre-LTx elevation of early mitral inflow velocity/mitral annular velocity (P=0.02), increased left atrial volume index (P=0.05), and lower mean arterial pressure (P=0.03) were predictors of HF after LTx in multivariate analysis. Early mitral inflow velocity/mitral annular velocity greater than 10 and left atrial volume index 40 mL/m2 or more were associated with a 3.4-fold (confidence interval, 1.2 9.4; P=0.017) and 2.9-fold (confidence interval, 1.1-7.5; P=0.03) increase in risk of development of HF after LTx, respectively. CONCLUSIONS: This study suggests that elevated markers of diastolic dysfunction during pre-LTx echocardiographic evaluation are associated with an excess risk of HF and may predict post-LTx survival. PMID- 22918217 TI - CKD-EPI instead of MDRD for candidates to kidney donation. AB - BACKGROUND: The determination of the glomerular filtration rate (GFR) is critical for the selection of a potential kidney donor. The complex and impractical techniques for the measurement of GFR have led to the development of equations to estimate GFR. Modification of diet in renal disease (MDRD) formula is the most widely used but its performance is poor because it systematically underestimates GFR above 60 mL/min. A new formula called the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) seems to overcome this limitation but needs to be tested in healthy potential kidney donors. METHODS: From 2007 to 2011, a cross-sectional study was performed on 85 adults who were candidates for living-related kidney donation. GFR was measured by nonradiolabeled iothalamate clearance determined by high-performance liquid chromatography, and renal function was estimated by using CKD-EPI and MDRD equations. The overall performance of the equations was analyzed, and the estimation for GFR above 90 mL/min was studied by means of receiver operating characteristic curves. RESULTS: The mean (SD) (range) of the measured GFR was 116 (24) (64-160) mL/min per 1.73 m(2), estimated GFR with CKD EPI was 108 (22) (64-153) mL/min per 1.73 m(2), and MDRD was 99 (28) (46-157) mL/min per 1.73 m(2). CKD-EPI presented lower bias (3.3 vs. 10.2 mL/min/1.73 m(2)), higher precision [interquartile range (minimum value-maximum value), 25 (53-140) vs. 32 (43-161) ml/min] and higher accuracy (100% vs. 89%) compared with MDRD. CONCLUSION: The CKD-EPI equation showed a higher performance than the MDRD equation in the GFR estimation of healthy population. CKD-EPI is applicable instead of MDRD, to subjects or candidates for kidney donation to avoid wrong GFR underestimates, which may lead to an inappropriate exclusion of candidates. PMID- 22918218 TI - Transcranial Doppler shortens the time between clinical brain death and angiographic confirmation: a randomized trial. AB - BACKGROUND: Brain death diagnosis relies on clinical signs, but confirmatory tests are legally mandatory in some countries. In France, transcranial Doppler (TCD) is not recognized as a legal test to confirm brain death. Nevertheless, experts recommend its use to determine the need for a legal confirmatory test. The aim of this study was to test the hypothesis that TCD shortens the time between clinical brain death and computed tomography angiography (CTA) confirmation. METHODS: We conducted a prospective randomized controlled study to evaluate the benefit of a TCD-directed strategy before performing the CTA to confirm brain death. Once the clinical diagnosis of brain death was established, subjects were randomized in a conventional group (CTA 6 hr later as recommended in France) or a TCD group (TCD examination every 2 hr until intracranial brain death flow patterns were found). Forty-four subjects were needed to show a difference of 2 hr between the two strategies. RESULTS: TCD strategy resulted in a shorter time between clinical diagnosis of brain death and CTA confirmation compared with conventional strategy (2.0 [1.3-2.6] vs. 7.2 [6.3-9.5] hr, P<0.0001). The number of brain CTA performed to confirm the diagnosis of brain death was not different between groups. CONCLUSIONS: Our results suggest that TCD directed strategy allows reducing the time between clinical diagnosis of brain death and CTA confirmation. PMID- 22918221 TI - Allergen-specific immunotherapy for atopic eczema: updated. AB - PURPOSE OF REVIEW: Aeroallergens are relevant eliciting factors of not only respiratory allergy but also atopic eczema in subgroups of patients. Due to a low number of controlled studies, the use of allergen-specific immunotherapy (ASIT) as potentially curative therapy as in respiratory atopic diseases is controversial in treating atopic eczema. This article summarizes theoretical aspects and recent results of clinical trials associated with ASIT in atopic eczema. RECENT FINDINGS: Literature demonstrates variability in study design and results, but ASIT has potential to improve the course of atopic eczema if type I sensitizations are present. Studies suggest the efficacy of ASIT on eczema not only in house dust mite allergy but also in patients with birch or grass pollen sensitization. In several studies, only defined subgroups of patients with atopic eczema showed positive results of ASIT. A generally good tolerability of ASIT was seen. SUMMARY: Atopic eczema patients with relevant allergies might benefit from ASIT as an additional therapeutic option. Side effects have been overestimated in the past. Hypothetically, the atopy patch test helps to identify an atopic eczema patient subgroup for successful ASIT. PMID- 22918222 TI - Monogenic defects in lymphocyte apoptosis. AB - PURPOSE OF REVIEW: The recognition that apoptosis - programmed cell death - is an important mechanism in immune homeostasis has led to the identification of human disorders associated with defects in the critical control mechanism. RECENT FINDINGS: Patients have been identified with defects affecting the extrinsic apoptotic pathway mediated by the protein receptor FAS which results in the autoimmune lymphoproliferative syndrome and more recently in defects affecting the intrinsic apoptotic pathway mediated by RAS proteins resulting in the RAS associated autoimmune leukoproliferative disorder. This review summarizes the immunopathogenesis, clinical features and diagnostic approaches to these human disorders. SUMMARY: Apoptotic pathways are critical in the maintenance of leukocyte homeostasis, and genetic defects impacting these can result in clinical disease manifested as expansion of selected leukocyte populations, autoimmunity, increased risk for malignancy and in some situations defects in host defense. PMID- 22918223 TI - Contra: "Antidotes for novel anticoagulants?"--Do we really need them. PMID- 22918224 TI - A case of isolated transverse sigmoid sinus dural arteriovenous fistula in which ipsilateral sensory neural hearing loss developed after transvenous embolization- letter to the editor. PMID- 22918225 TI - Total ApoE and ApoE4 isoform assays in an Alzheimer's disease case-control study by targeted mass spectrometry (n=669): a pilot assay for methionine-containing proteotypic peptides. AB - Allelic polymorphism of the apolipoprotein E (ApoE) gene (ApoE epsilon2, ApoE epsilon3 and ApoE epsilon4 alleles) gives rise to three protein isoforms (ApoE2, ApoE3 and ApoE4) that differ by 1 or 2 amino acids. Inheritance of the ApoE epsilon4 allele is a risk factor for developing Alzheimer's disease (AD). The potential diagnostic value of ApoE protein levels in biological fluids (i.e. cerebrospinal fluid, plasma and serum) for distinguishing between AD patients and healthy elderly subjects is subject to great controversy. Although a recent study reported subnormal total ApoE and ApoE4 levels in the plasma of AD patients, other studies have found normal or even elevated protein levels (versus controls). Because all previously reported assays were based on immunoenzymatic techniques, we decided to develop an orthogonal assay based on targeted mass spectrometry by tracking (i) a proteotypic peptide common to all ApoE isoforms and (ii) a peptide that is specific for the epsilon4 allele. After trypsin digestion, the ApoE4-specific peptide contains an oxidation-prone methionine residue. The endogenous methionine oxidation level was evaluated in a small cohort (n=68) of heterozygous epsilon3epsilon4 carriers containing both healthy controls and AD patients. As expected, the proportion of oxidized residues varied from 0 to 10%, with an average of 5%. We therefore developed a standardized strategy for the unbiased, absolute quantification of ApoE4, based on performic acid oxidization of methionine. Once the sample workflow had been thoroughly validated, it was applied to the concomitant quantification of total ApoE and ApoE4 isoform in a large case-control study (n=669). The final measurements were consistent with most previously reported ApoE concentration values and confirm the influence of the different alleles on the protein expression level. Our results illustrate (i) the reliability of selected reaction monitoring-based assays and (ii) the value of the oxidization step for unbiased monitoring of methionine-containing proteotypic peptides. Furthermore, a statistical analysis indicated that neither total ApoE and ApoE4 levels nor the ApoE/ApoE4 ratio correlated with the diagnosis of AD. These findings reinforce the conclusions of previous studies in which plasma ApoE levels had no obvious clinical significance. PMID- 22918226 TI - Potentially novel candidate biomarkers for head and neck squamous cell carcinoma identified using an integrated cell line-based discovery strategy. AB - Head and neck squamous cell carcinomas (HNSCC) can arise from the oral cavity, oropharynx, larynx or hypopharynx, and is the sixth leading cancer by incidence worldwide. The 5-year survival rate of HNSCC patients remains static at 40-60%. Hence, biomarkers which can improve detection of HNSCC or early recurrences should improve clinical outcome. Mass spectrometry-based proteomics methods have emerged as promising approaches for biomarker discovery. As one approach, mass spectrometric identification of proteins shed or secreted from cancer cells can contribute to the identification of potential biomarkers for HNSCC and our understanding of tumor behavior. In the current study, mass spectrometry-based proteomic profiling was performed on the conditioned media (i.e. secretome) of head and neck cancer (HNC) cell lines (FaDu, UTSCC8 and UTSCC42a) in addition to gene expression microarrays to identify over-expressed transcripts in the HNSCC cells in comparison to a normal control cell line. This integrated data set was systematically mined using publicly available resources (Human Protein Atlas and published proteomic/transcriptomic data) to prioritize putative candidates for validation. Subsequently, quantitative real-time PCR (qRT-PCR), Western blotting, immunohistochemistry (IHC), and ELISAs were performed to verify selected markers. Our integrated analyses identified 90 putative protein biomarkers that were secreted or shed to the extracellular space and over-expressed in HNSCC cell lines, relative to controls. Subsequently, the over-expression of five markers was verified in vitro at the transcriptional and translational levels using qRT PCR and Western blotting, respectively. IHC-based validation conducted in two independent cohorts comprising of 40 and 39 HNSCC biopsies revealed that high tumor expression of PLAU, IGFBP7, MMP14 and THBS1 were associated with inferior disease-free survival, and increased risk of disease progression or relapse. Furthermore, as demonstrated using ELISAs, circulating levels of PLAU and IGFBP7 were significantly higher in the plasma of HNSCC patients compared with healthy individuals. PMID- 22918227 TI - Functional interaction of the ankylosing spondylitis-associated endoplasmic reticulum aminopeptidase 1 polymorphism and HLA-B27 in vivo. AB - The association of ERAP1 with ankylosing spondylitis (AS)1 among HLA-B27-positive individuals suggests that ERAP1 polymorphism may affect pathogenesis by altering peptide-dependent features of the HLA-B27 molecule. Comparisons of HLA-B*27:04 bound peptidomes from cells expressing different natural variants of ERAP1 revealed significant differences in the size, length, and amount of many ligands, as well as in HLA-B27 stability. Peptide analyses suggested that the mechanism of ERAP1/HLA-B27 interaction is a variant-dependent alteration in the balance between epitope generation and destruction determined by the susceptibility of N terminal flanking and P1 residues to trimming. ERAP1 polymorphism associated with AS susceptibility ensured efficient peptide trimming and high HLA-B27 stability. Protective polymorphism resulted in diminished ERAP1 activity, less efficient trimming, suboptimal HLA-B27 peptidomes, and decreased molecular stability. This study demonstrates that natural ERAP1 polymorphism affects HLA-B27 antigen presentation and stability in vivo and proposes a mechanism for the interaction between these molecules in AS. PMID- 22918228 TI - Native tandem and ion mobility mass spectrometry highlight structural and modular similarities in clustered-regularly-interspaced shot-palindromic-repeats (CRISPR) associated protein complexes from Escherichia coli and Pseudomonas aeruginosa. AB - The CRISPR/Cas (clustered regularly interspaced short palindromic repeats/CRISPR associated genes) immune system of bacteria and archaea provides acquired resistance against viruses and plasmids, by a strategy analogous to RNA interference. Key components of the defense system are ribonucleoprotein complexes, the composition of which appears highly variable in different CRISPR/Cas subtypes. Previous studies combined mass spectrometry, electron microscopy, and small angle x-ray scattering to demonstrate that the E. coli Cascade complex (405 kDa) and the P. aeruginosa Csy-complex (350 kDa) are similar in that they share a central spiral-shaped hexameric structure, flanked by associating proteins and one CRISPR RNA. Recently, a cryo-electron microscopy structure of Cascade revealed that the CRISPR RNA molecule resides in a groove of the hexameric backbone. For both complexes we here describe the use of native mass spectrometry in combination with ion mobility mass spectrometry to assign a stable core surrounded by more loosely associated modules. Via computational modeling subcomplex structures were proposed that relate to the experimental IMMS data. Despite the absence of obvious sequence homology between several subunits, detailed analysis of sub-complexes strongly suggests analogy between subunits of the two complexes. Probing the specific association of E. coli Cascade/crRNA to its complementary DNA target reveals a conformational change. All together these findings provide relevant new information about the potential assembly process of the two CRISPR-associated complexes. PMID- 22918232 TI - Regioselective placement of alkanethiolate domains on tetrahedral and octahedral gold nanocrystals. AB - Electrostatically stabilized monolayer shells of metal-oxide cluster anions (polyoxometalates, or POMs) on the surfaces of ca. 8 nm tetrahedral and octahedral gold nanocrystals regioselectively direct water-soluble alkanethiolate ligands to the corners and edges of the gold polyhedra. PMID- 22918233 TI - How not to get cross(ed): a novel role for FANCM orthologs in meiotic recombination. AB - Comment on: Lorenz A, et al. Science 2012; 336:1585-8. PMID- 22918229 TI - Dicer-dependent and -independent Argonaute2 protein interaction networks in mammalian cells. AB - Argonaute (Ago) proteins interact with small regulatory RNAs such as microRNAs (miRNAs) and facilitate gene-silencing processes. miRNAs guide Ago proteins to specific mRNAs leading to translational silencing or mRNA decay. In order to understand the mechanistic details of miRNA function, it is important to characterize Ago protein interactors. Although several proteomic studies have been performed, it is not clear how the Ago interactome changes on miRNA or mRNA binding. Here, we report the analysis of Ago protein interactions in miRNA containing and miRNA-depleted cells. Using stable isotope labeling in cell culture in conjunction with Dicer knock out mouse embryonic fibroblasts, we identify proteins that interact with Ago2 in the presence or the absence of Dicer. In contrast to our current view, we find that Ago-mRNA interactions can also take place in the absence of miRNAs. Our proteomics approach provides a rich resource for further functional studies on the cellular roles of Ago proteins. PMID- 22918235 TI - Doubling the deck: Tetraploidy induces chromosome shuffling and cancer. AB - Comment on: Lv L, et al. Cell Cycle 2012; 11:2864-75. PMID- 22918236 TI - TLS/FUS: a protein in cancer and ALS. AB - Comment on: Tan AY, et al. Proc Natl Acad Sci USA 2012; 109:6030-5. PMID- 22918234 TI - The Mck1 GSK-3 kinase inhibits the activity of Clb2-Cdk1 post-nuclear division. AB - The glycogen synthase kinase-3 homolog, Mck1, has been implicated in many cellular functions, from sporulation to calcium stress response in budding yeast. Here, we report a novel function for Mck1 in the inhibition of Clb2-Cdk1 activity post nuclear division. Clb2-Cdk1, the major mitotic cyclin-Cdk complex in yeast, accumulates before anaphase and must be inhibited in telophase for cells to exit mitosis and enter into the next cell cycle. We show that the mck1Delta mutant is highly sensitive to increased Clb2-Cdk1 activity caused either by overexpression of Clb2 or the Cdk1-activating phosphatase Mih1. Deletion of the Cdk1 inhibitory kinase, SWE1, in combination with a mck1Delta mutant results in a synthetic growth defect, suggesting that Mck1 and Swe1 function in parallel pathways to inhibit Clb2-Cdk1. We find that mck1Delta strains have a delay in mitotic exit as well as elevated levels of Clb2-Cdk1 activity post-nuclear division. Using a co immunoprecipitation assay, we identify a physical interaction between Mck1 and both Clb2 and Mih1. Finally, we demonstrate that phosphorylation of purified Clb2 by Cdk1 is inhibited by catalytically active Mck1 but not catalytically inactive Mck1 in vitro. We propose that Mck1 inhibits the activity of Clb2-Cdk1 via interaction with Clb2. The mammalian glycogen synthase kinase-3 homolog has been implicated in cyclin inhibition, suggesting a conserved cell cycle function for both yeast and mammalian glycogen synthase kinases. PMID- 22918237 TI - 4E-BP1 participates in maintaining spindle integrity and genomic stability via interacting with PLK1. AB - The essential function of eIF4E-binding protein 1 (4E-BP1) in translation initiation has been well established; however, the role of 4E-BP1 in normal cell cycle progression is coming to attention. Here, we revealed the role of 4E-BP1 on mitotic regulation and chromosomal DNA dynamics during mitosis. First, we have observed the co-localization of the phosphorylated 4E-BP1 at T37/46 with Polo like kinase 1 (PLK1) at the centrosomes during. Depression of 4E-BP1 by small interfering RNA in HepG2 or HeLa cells resulted in an increased outcome of polyploidy and aberrant mitosis, including chromosomal DNA misaligned and multi polar spindles or multiple centrosomes. We observed that 4E-BP1 interacted with PLK1 directly in vitro and in vivo in mitotic cells, and the C-terminal aa 77-118 of 4E-BP1 mediates its interaction with PLK1. PLK1 can phosphorylate 4E-BP1 in vitro. Furthermore, the depletion of 4E-BP1 sensitized HepG2 and HeLa cells to the microtubule disruption agent paclitaxel. These results demonstrate that 4E BP1, beyond its role in translation regulation, can function as a regulator of mitosis via interacting with PLK1, and possibly plays a role in genomic stability maintaining. PMID- 22918239 TI - A novel G1 checkpoint mediated by the p57 CDK inhibitor and p38 SAPK promotes cell survival upon stress. AB - Comment on: Joaquin M, et al. EMBO J 2012; 31:2952-64. PMID- 22918238 TI - Convergent signaling in the regulation of connective tissue growth factor in malignant mesothelioma: TGFbeta signaling and defects in the Hippo signaling cascade. AB - Malignant mesothelioma (MM) is a neoplasm that arises from serosal surfaces of the pleural, peritoneal and pericardial cavities with worldwide incidence, much of which is caused by asbestos exposure. Patients suffer from pain and dyspnea due to direct invasion of the chest wall, lungs and vertebral or intercostal nerves by masses of thick fibrotic tumors. Although there has been recent progress in the clinical treatment, current therapeutic approaches do not provide satisfactory results. Therefore, development of a molecularly targeted therapy for MM is urgently required. Our recent studies suggest that normal mesothelial and MM cell growth is promoted by TGFbeta, and that TGFbeta signaling together with intrinsic disturbances in neurofibromatosis type 2 (NF2) and Hippo signaling cascades in MM cells converges upon further expression of connective tissue growth factor (CTGF). The formation of a YAP-TEAD4-Smad3-p300 complex on the specific CTGF promoter site with an adjacent TEAD and Smad binding motif is a critical and synergistic event caused by the dysregulation of these two distinct cascades. Furthermore, we demonstrated the functional importance of CTGF through the mouse studies and human histological analyses, which may elucidate the clinical features of MM with severe fibrosis in the thoracic cavity. PMID- 22918240 TI - TOR under stress: targeting TORC1 by Rho1 GTPase. AB - In the yeast Saccharomyces cerevisiae, small GTPase Rho1 controls polarized actin distribution and cell wall expansion in response to many different environmental and intracellular stimuli. Its activity is essential for cell survival and adaptation under various stress conditions. A recent study identified the TOR complex 1 (TORC1), a central regulator in cell growth and metabolism, as a direct target of the small GTPase. This novel crosstalk extends the signaling network of Rho1 into many TORC1-dependent processes and sheds light on how yeast cells coordinate polarized spatial expansion with mass increase. PMID- 22918241 TI - How a mismatch repair enzyme balances the needs for efficient lesion processing and minimal action on undamaged DNA. AB - Comment on: Maiti A, et al. Proc Natl Acad Sci USA 2012; 109:8091-6. PMID- 22918242 TI - Directing p53 to induce autophagy. AB - Comment on: Naidu SR, et al. Cell Cycle 2012; 11:2717-28. PMID- 22918243 TI - Switch of FANCL, a key FA-BRCA component, between tumor suppressor and promoter by alternative splicing. AB - Comment on: Panneerselvam J, et al. Cell Cycle 2012; 11:2947-55. PMID- 22918244 TI - Independent transcriptional reprogramming and apoptosis induction by cisplatin. AB - Neither the molecular mechanisms whereby cancer cells intrinsically are or become resistant to the DNA-damaging agent cisplatin nor the signaling pathways that account for cisplatin cytotoxicity have thus far been characterized in detail. In an attempt to gain further insights into the molecular cascades elicited by cisplatin (leading to resistance or underpinning its antineoplastic properties), we comparatively investigated the ability of cisplatin, C2-ceramide and cadmium dichloride, alone or in the presence of an array of mitochondrion-protective agents, to trigger the permeabilization of purified mitochondria. In addition, we compared the transcriptional response triggered by cisplatin, C2-ceramide and cadmium dichloride in non-small cell lung carcinoma A549 cells. Finally, we assessed the capacity of cisplatin, C2-ceramide and cadmium dichloride to reduce the clonogenic potential of a battery of yeast strains lacking proteins involved in the regulation of cell death, DNA damage signaling and stress management. This multipronged experimental approach revealed that cisplatin elicits signaling pathways that are for the most part "private," i.e., that manifest limited overlap with the molecular cascades ignited by other inducers of mitochondrial apoptosis, and triggers apoptosis mainly in a transcription-independent fashion. Indeed, bona fide cisplatin-response modifiers that we have recently identified by a functional genome-wide siRNA screen are either not transcriptionally regulated during cisplatin-induced cell death or their transcriptional modulation reflects the activation of an adaptive response promoting cisplatin resistance. PMID- 22918245 TI - Multipotent nestin-expressing stem cells capable of forming neurons are located in the upper, middle and lower part of the vibrissa hair follicle. AB - We have previously demonstrated that the neural stem-cell marker nestin is expressed in hair follicle stem cells. Nestin-expressing cells were initially identified in the hair follicle bulge area (BA) using a transgenic mouse model in which the nestin promoter drives the green fluorescent protein (ND-GFP). The hair follicle ND-GFP-expressing cells are keratin 15-negative and CD34-positive and could differentiate to neurons, glia, keratinocytes, smooth muscle cells and melanocytes in vitro. Subsequently, we showed that the nestin-expressing stem cells could affect nerve and spinal cord regeneration after injection in mouse models. In the present study, we separated the mouse vibrissa hair follicle into three parts (upper, middle and lower). Each part of the follicle was cultured separately in DMEM-F12 containing B-27 and 1% methylcellulose supplemented with basic FGF. After 2 mo, the nestin-expressing cells from each of the separated parts of the hair follicle proliferated and formed spheres. Upon transfer of the spheres to RPMI 1640 medium containing 10% FBS, the nestin-expressing cells in the spheres differentiated to neurons, as well as glia, keratinocytes, smooth muscle cells and melanocytes. The differentiated cells were produced by spheres which formed from nestin-expressing cells from all segments of the hair follicle. However, the differentiation potential is greatest in the upper part of the follicle. This result is consistent with trafficking of nestin-expressing cells throughout the hair follicle from the bulge area to the dermal papilla that we previously observed. The nestin-expressing cells from the upper part of the follicle produced spheres in very large amounts, which in turn differentiated to neurons and other cell types. The results of the present study demonstrate that multipotent, nestin-expressing stem cells are present throughout the hair follicle and that the upper part of the follicle can produce the stem cells in large amounts that could be used for nerve and spinal cord repair. PMID- 22918246 TI - Emerging role of DYRK family protein kinases as regulators of protein stability in cell cycle control. AB - Dual-specificity tyrosine phosphorylation-regulated kinases (DYRKs) constitute an evolutionarily conserved family of protein kinases with key roles in the control of cell proliferation and differentiation. Members of the DYRK family phosphorylate many substrates, including critical regulators of the cell cycle. A recent report revealed that human DYRK2 acts as a negative regulator of G1/S transition by phosphorylating c-Jun and c-Myc, thereby inducing ubiquitination mediated degradation. Other DYRKs also function as cell cycle regulators by modulating the turnover of their target proteins. DYRK1B can induce reversible cell arrest in a quiescent G0 state by targeting cyclin D1 for proteasomal degradation and stabilizing p27 (Kip1). The DYRK2 ortholog of C. elegans, MBK-2, triggers the proteasomal destruction of oocyte proteins after meiosis to allow the mitotic divisions in embryo development. This review summarizes the accumulating results that provide evidence for a general role of DYRKs in the regulation of protein stability. PMID- 22918247 TI - A general requirement for FcgammaRIIB co-engagement of agonistic anti-TNFR antibodies. AB - Comment on: Li F, et al. Proc Natl Acad Sci USA 2012; 109:10966-71. PMID- 22918249 TI - The fox and the fat: an unexpected new treatment for brain tumors. AB - Comment on: Wilk A, et al. Cell Cycle 2012; 11:2660-71. PMID- 22918250 TI - New evidence that SAC can tolerate misaligned chromosomes in mouse oocytes. AB - Comment on: Sebestova J, et al. Cell Cycle 2012; 11:3011-8. PMID- 22918248 TI - Metabolic remodeling of the tumor microenvironment: migration stimulating factor (MSF) reprograms myofibroblasts toward lactate production, fueling anabolic tumor growth. AB - Migration stimulating factor (MSF) is a genetically truncated N-terminal isoform of fibronectin that is highly expressed during mammalian development in fetal fibroblasts, and during tumor formation in human cancer-associated myofibroblasts. However, its potential functional role in regulating tumor metabolism remains unexplored. Here, we generated an immortalized fibroblast cell line that recombinantly overexpresses MSF and studied their properties relative to vector-alone control fibroblasts. Our results indicate that overexpression of MSF is sufficient to confer myofibroblastic differentiation, likely via increased TGF-b signaling. In addition, MSF activates the inflammation-associated transcription factor NFkappaB, resulting in the onset of autophagy/mitophagy, thereby driving glycolytic metabolism (L-lactate production) in the tumor microenvironment. Consistent with the idea that glycolytic fibroblasts fuel tumor growth (via L-lactate, a high-energy mitochondrial fuel), MSF fibroblasts significantly increased tumor growth, by up to 4-fold. Mechanistic dissection of the MSF signaling pathway indicated that Cdc42 lies downstream of MSF and fibroblast activation. In accordance with this notion, Cdc42 overexpression in immortalized fibroblasts was sufficient to drive myofibroblast differentiation, to provoke a shift towards glycolytic metabolism and to promote tumor growth by up to 2-fold. In conclusion, the MSF/Cdc42/NFkappaB signaling cascade may be a critical druggable target in preventing "Warburg-like" cancer metabolism in tumor associated fibroblasts. Thus, MSF functions in the metabolic remodeling of the tumor microenvironment by metabolically reprogramming cancer-associated fibroblasts toward glycolytic metabolism. PMID- 22918251 TI - Combination of isoform-selective histone/protein deacetylase inhibitors improves Foxp3+ T-regulatory cell function. AB - Comment on: Beier UH, et al. Sci Signal 2012; 5:ra45. PMID- 22918252 TI - Effect of circadian clock mutations on DNA damage response in mammalian cells. AB - The circadian clock is a global regulatory mechanism that confers daily rhythmicity on many biochemical and physiological functions, including DNA excision repair in mammalian organisms. Here, we investigated the effect of the circadian clock on the major DNA damage response pathways by using mouse cell lines mutated in genes encoding proteins in the positive (Bmal1, CLOCK) or negative (Cry 1/2, Per 1/2) arms of the transcription-translation feedback loop that generates the circadian clock. We find that cells mutated in these genes are indistinguishable from wild-type in their response to UV, ionizing radiation and mitomycin C. We conclude that either the majority of DNA damage response reactions are not controlled by the circadian clock or that, even if such a control exists at the organism level, it is supplanted by homeostatic control mechanisms at the cellular level in tissue culture. We suggest that caution must be exercised in extrapolating from experiments in tissue culture to whole animals with respect to the effect of the circadian clock on cellular response to DNA damaging agents. PMID- 22918253 TI - Oncogenic transcription factors as master regulators of chromatin topology: a new role for ERG in prostate cancer. AB - The three-dimensional (3D) conformation of the genome is known to be structured and to affect gene transcription, but how chromatin conformation changes in diseases such as cancer is poorly understood. Similarly, oncogenic transcription factors bind to thousands of sites in the genome without a clear transcriptional role on nearby genes. Could these factors play a non-transcriptional role in promoting tumor progression by restructuring the shape of the genome? To address this question, we recently performed unbiased high-resolution mapping of intra- and inter-chromosome interactions upon overexpression of ERG, an oncogenic transcription factor frequently overexpressed in prostate cancer as a result of a gene fusion. By integrating data from genome-wide chromosome conformation capture (Hi-C), ERG binding and gene expression, we have demonstrated that oncogenic transcription factor overexpression is associated with global, reproducible and functionally coherent changes in chromatin organization. Perhaps more importantly, we have identified novel genomic alterations associated with ERG overexpression. These results suggest a yet unappreciated role for transcription factors in promoting genomic alterations through their effect on chromatin architecture. PMID- 22918254 TI - Impaired adult myeloid progenitor CMP and GMP cell function in conditional c-myb knockout mice. AB - The differentiation of myeloid progenitors to mature, terminally differentiated cells is a highly regulated process. Here, we showed that conditional disruption of the c-myb proto-oncogene in adult mice resulted in dramatic reductions in CMP, GMP and MEP myeloid progenitors, leading to a reduction of neutrophils, basophils, monocytes and platelets in peripheral blood. In addition, c-myb plays a critical role at multiple stages of myeloid development, from multipotent CMP and bipotent GMP to unipotent CFU-G and CFU-M progenitor cells. c-myb controls the differentiation of these cells and is required for the proper commitment, maturation and normal differentiation of CMPs and GMPs. Specifically, c-myb regulates the precise commitment to the megakaryocytic and granulo-monocytic pathways and governs the granulocytic-monocytic lineage choice. c-myb is also required for the commitment along the granulocytic pathway for early myeloid progenitor cells and for the maturation of committed precursor cells along this pathway. On the other hand, disruption of the c-myb gene favors the commitment to the monocytic lineage, although monocytic development was abnormal with cells appearing more mature with atypical CD41 surface markers. These results demonstrate that c-myb plays a pivotal role in the regulation of multiple stages in adult myelogenesis. PMID- 22918257 TI - Abstracts of the 48th EASD (European Association for the Study of Diabetes) Annual Meeting of the European Association for the Study of Diabetes. October 1 5, 2012. Berlin, Germany. PMID- 22918255 TI - The oncogenic transcription factor FOXM1 and anticancer therapy. AB - Comment on: Halasi M,et al. PLoS ONE 2012; 7:e31761. PMID- 22918258 TI - ICU-acquired weakness: mechanisms of disability. AB - PURPOSE OF REVIEW: ICU-acquired weakness (ICUAW) is now recognized as a major complication of critical illness. There is no doubt that ICUAW is prevalent - some might argue ubiquitous - after critical illness, but its true role, the interaction with preexisting nerve and muscle lesions as well as its contribution to long-term functional disability, remains to be elucidated. RECENT FINDINGS: In this article, we review the current state-of-the-art of the basic pathophysiology of nerve and muscle weakness after critical illness and explore the current literature on ICUAW with a special emphasis on the most important mechanisms of weakness. SUMMARY: Variable contributions of structural and functional changes likely contribute to both early and late myopathy and neuropathy, although the specifics of the temporality of both processes, and the influence patient comorbidities, age, and nature of the ICU insult have on them, remain to be determined. PMID- 22918259 TI - Trauma scoring systems. AB - PURPOSE OF REVIEW: Trauma scoring systems are used by researchers, registries, or individuals to describe injury severity or to estimate the prognosis of trauma patients. Triage scores also may influence the treatment of a trauma case. RECENT FINDINGS: The first trauma scores appeared about 40 years ago. Since then, multiple attempts to improve their performance have been published, or new scores were introduced. However, only few scoring systems manage to survive. Actual research focuses on further optimization of the available scores as well as the consequences of coding the injuries. SUMMARY: Cross-national comparisons evaluating different scores will further help to identify the optimal scoring system, based on the available information. The inclusion of patients with partially missing data is also an important task for the future. PMID- 22918261 TI - Freedom of choice and adherence to the health regimen for African Americans with hypertension. AB - The prevalence of hypertension in African Americans exceeds that of all other racial/ethnic groups in the world. Hypertension in African Americans is less likely to be controlled and this problem is further complicated by failure to adhere to prescribed hypertension management regimens. Oftentimes, health care providers give African American patients with hypertension multiple health "rules" to follow that may arouse reactance behaviors: that is, patients may choose to do the opposite of what they are told to do. The theory of psychological reactance offers a framework for understanding the relationship between freedom of choice and adherence to hypertension regimens in African Americans. PMID- 22918262 TI - Multicomponent and sequential organocatalytic reactions: diversity with atom economy and enantiocontrol. AB - Reactions in which several components are combined in sequence, and without isolation of intermediates, are greatly sought because of the inherent molecular diversity, efficiency, and atom-economy. However, organocatalytic reactions, employing an organic catalyst to assemble products of high enantiomeric excess (a single optical isomer), are also cutting-edge methodology. This tutorial review covers the overlap of these two areas, outling the structural diversity and stereocontrol arising from one-pot combinations of at least three components, powerful approaches with great potential that minimise formation of by-products and operating costs. PMID- 22918263 TI - Optic disc doubling. AB - Many developmental defects can simulate the optic disc (optic disc pseudodoubling). True optic disc duplication with 2 independent retinal vasculatures is rare. Associated optic nerve duplication is rarer still and seen in lower vertebrates. We report a rare case of unilateral double optic discs with a single optic nerve in the left eye of a 41-year-old man, otherwise asymptomatic in the affected eye. PMID- 22918265 TI - Haemorrhage due to proteolysis of FXIII and hyperfibrinolysis under vemurafenib treatment of metastatic melanoma. PMID- 22918266 TI - High performance metal-organic-framework coatings obtained via thermal gradient synthesis. AB - For many possible applications of metal-organic frameworks, a coating onto a metallic support capable of both superior heat and mass transfer is required. A heated substrate in contact with a chilled solution of metal salt and linker reproducibly yields polycrystalline, highly stable, thermally conductive MOF coatings at a growth rate of 50 MUm h(-1), illustrated by the formation of Cu(3)(btc)(2) as an example. PMID- 22918269 TI - An Au clusters related spill-over sensitization mechanism in SnO2-based gas sensors identified by operando HERFD-XAS, work function changes, DC resistance and catalytic conversion studies. AB - The role of Au additives in SnO(2)-based thick film gas sensors was investigated by a combination of operando investigation techniques, namely spectroscopic high energy resolved fluorescence detected X-ray absorption spectroscopy (HERFD-XAS) and simultaneous DC resistance and work function change measurements. The results have shown that the Au is present in the form of small metallic particles at the surface of the host metal oxide without changing its bulk or surface electronic properties. The sensitization effect of Au can therefore be attributed to the "spill-over effect", meaning that the Au particles enrich the surface of the active metal oxide with oxygen species which consequently react with reducing gases such as CO and H(2). This is in contrast to the effect of Pd and Pt promoters which were found to be distributed at an atomic level on the surface and in the bulk of the supporting sensing material and therefore have a tremendous effect on its bulk and surface electronic properties. PMID- 22918290 TI - Gastric conditions control both the evolution of the organization of protein stabilized emulsions and the kinetic of lipolysis during in vitro digestion. AB - During digestion, lipids undergo modifications of their colloidal and molecular structures, which depend on the digestive conditions and the composition of the digestive juices. The aim of this work was to evaluate whether gastric pH and pepsin modulate the colloidal evolution and the bioacessibility of fatty acids of an oil-in-water emulsion stabilized by a protein during in vitro digestion. The fate of BSA-stabilized rapeseed oil-in-water emulsion during gastric phase at pH 2.5 or 4.0 with or without pepsin and its consequences on intestinal lipolysis was measured in the simulated gastric and duodenal conditions. The pH had limited impact but pepsin favoured flocculation and coalescence of the droplets, modulating the early stage of lipolysis but not its final extent. PMID- 22918268 TI - Effectiveness and safety of ultrasound-guided percutaneous liver biopsy in children. AB - BACKGROUND: Percutaneous liver biopsy (PLB) is an important procedure in the diagnosis and follow-up of paediatric liver disease. Its purpose is to obtain tissue for histopathological observation, in our case, with ultrasound (US) guidance. OBJECTIVE: To evaluate the effectiveness and safety of US-guided PLB in children. MATERIAL AND METHODS: A retrospective study over a period of 12 years, from January 1999 until December 2010, with a selection of US-guided PLB performed in children with focal liver lesions or diffuse hepatic disease and liver transplant (LT). A 16-gauge automatic needle was used and a maximum of three fragments of liver were collected. Contraindications were: bile duct dilatation (>3 mm) INR > 1.5 (reference range, 0.9 -- 1.2) and platelet count <50,000 (reference range, 150,000 -- 450,000). Analysis focused on complications and final diagnosis. RESULTS: A total of 513 biopsies were performed, 379 (73.9%) in children who had undergone orthotopic LT, 117 (22.8%) in children with liver disease of unknown cause and 17 (3.3%) in children with focal hepatic lesions. Histological diagnosis was obtained in 509 of 513 (99.3%) biopsies performed. Minor complications were registered in 38 patients (7.4%) and major complications occurred in 5 patients (1%). None needed a surgical intervention. CONCLUSION: US guided PLB in children is a safe and efficient method to achieve a specific diagnosis in liver disease. PMID- 22918267 TI - The identification of candidate genes and SNP markers for classical bovine spongiform encephalopathy susceptibility. AB - Classical bovine spongiform encephalopathy is a transmissible prion disease that is fatal to cattle and is a human health risk due to its association with a strain of Creutzfeldt-Jakob disease (vCJD). Mutations to the coding region of the prion gene (PRNP) have been associated with susceptibility to transmissible spongiform encephalopathies in mammals including bovines and humans. Additional loci such as the retinoic acid receptor beta (RARB) and stathmin like 2 (STMN2) have also been associated with disease risk. The objective of this study was to refine previously identified regions associated with BSE susceptibility and to identify positional candidate genes and genetic variation that may be involved with the progression of classical BSE. The samples included 739 samples of either BSE infected animals (522 animals) or non-infected controls (207 animals). These were tested using a custom SNP array designed to narrow previously identified regions of importance in bovine genome. Thirty one single nucleotide polymorphisms were identified at p < 0.05 and a minor allele frequency greater than 5%. The chromosomal regions identified and the positional and functional candidate genes and regulatory elements identified within these regions warrant further research. PMID- 22918292 TI - Recent criminal offending and suicide attempts: a national sample. AB - PURPOSE: Few studies have assessed the risk of suicide and suicidal behavior among the community-residing population with recent criminal justice involvement despite evidence of high rates of suicide in jails and prisons. This study assessed the association between recent arrest history and a suicide attempt in the previous year including multiple arrests and specific offense categories using a national representative sample of adults. METHODS: Data were derived from 2 years of the National Survey on Drug Use and Health (2008 and 2010), a nationally representative cross-sectional survey of non-institutionalized US adults. Suicide attempts in the previous year based on self-report were assessed in relation to recent arrest history while accounting for socio-demographic factors, mental and physical health status and substance use. RESULTS: Suicide attempts in the previous year are relatively common among those with recent arrests (2.3 %) compared to the general US population (0.4 %), with much higher prevalence among those with multiple recent arrests or charges (4.5 %). The prevalence of recent suicide attempts among those with multiple recent arrests was highest among adults aged 25-34 (5.7 %), with similar risks between men and women, and across racial and ethnic subgroups. There was no association between arrests prior to the most recent year and recent suicide attempts. CONCLUSIONS: Suicide attempts are common among the non-institutionalized population of US adults with recent criminal justice involvement. Suicide prevention efforts in the criminal justice system should extend to clients who remain in the community both during and immediately following periods of court-processing. Future research is needed to better identify case and client characteristics indicating the highest suicide risk. PMID- 22918293 TI - Could it be permissible to prevent the existence of morally enhanced people? AB - This paper discusses Nicholas Agar's argument in Humanity's End, that it can be morally permissible for human beings to prevent the coming into existence of morally enhanced people because this can harm the interests of the unenhanced humans. It contends that Agar's argument fails because it overlooks the distinction between morally permissible and morally impermissible harm. It is only if the harm to them would be of the morally impermissible kind that humans are provided with a reason to prevent the coming into existence of enhanced people. But if their enhancement includes moral enhancement, it is unlikely that the enhanced people will cause morally impermissible harm. PMID- 22918294 TI - Pro: "Antidote for new anticoagulants"--specific target of inhibition requires a specific target for neutralisation. PMID- 22918295 TI - Facile assembly of an efficient CoO(x) water oxidation electrocatalyst from Co containing polyoxotitanate nanocages. AB - Cobalt-containing polyoxotitanates (TiCo) are excellent precursors for the simple and scalable preparation of Nocera-type CoOx water-oxidation electrocatalysts. The TiCo cages serve as a reservoir for cobalt ions in a titania matrix on fluoride-doped tin oxide electrodes, and form, in situ, the active CoOx catalyst for O2 evolution with high stability in phosphate buffer in pH neutral water. PMID- 22918296 TI - Retinal nerve fiber layer thickness in patients with Alzheimer disease. AB - The aim of this study was to investigate retinal nerve fiber layer (RNFL) thickness in patients with Alzheimer disease (AD) without visual impairment using spectral domain optical coherence tomography (SD-OCT) and to compare the results with healthy controls. A total of 80 subjects, including 40 patients with early untreated AD (mean age, 69.3 +/- 4.9 years) and 40 healthy controls (mean age, 68.9 +/- 5.1 years) were enrolled. Both eyes of patients with AD and controls were imaged using SD-OCT. The average RNFL thickness was significantly less in the AD patients than in controls (65 +/- 6.2 MUm vs 75 +/- 3.8MUm; P = 0.001). There was selective thinning of the RNFL in the superior quadrant, the mean superior quadrant RNFL thickness being 76 +/- 6.7 MUm in AD patients and 105 +/- 4.8 MUm in controls (P = 0.001). In our study, the thickness of RNFL in patient with AD was lower than that of controls. This suggests that SD- OCT has the potential to be used in the early diagnosis of AD as well as in the study of therapeutic agents. Further studies are needed to validate this technology as a viable ocular biomarker over time in AD. PMID- 22918297 TI - Low band gap polycyclic hydrocarbons: from closed-shell near infrared dyes and semiconductors to open-shell radicals. AB - Low band gap (E(g) < 1.5 eV) polycyclic hydrocarbons have become one of the most important types of materials for many applications, for example, as semiconductors in organic field effect transistors (OFETs), as light-harvesting dyes in organic solar cells and photodetectors, as near infrared (NIR) fluorescent probes in high resolution bio-imaging and bio-sensing, and as chromophores in non-linear optics. The benzenoid polycyclic hydrocarbons as nano sized graphene fragments also serve as perfect model compounds to understand the fundamental structure-property relationship of graphene. The ground state of these molecules can be described as either a closed-shell or an open-shell structure on the basis of their molecular size and edge structure. In this review, a summary will be given on a series of low band gap polycyclic hydrocarbons about their synthesis, physical properties and material applications. PMID- 22918299 TI - Zinc oxide-doped poly(urethane) spider web nanofibrous scaffold via one-step electrospinning: a novel matrix for tissue engineering. AB - Zinc oxide (ZnO) nanostructures have been commonly studied for electronic purposes due to their unique piezoelectric and catalytic properties; however, recently, they have been also exploited for biomedical applications. The purpose of this study was to fabricate ZnO-doped poly(urethane) (PU) nanocomposite via one-step electrospinning technique. The utilized nanocomposite was prepared by using colloidal gel composed of ZnO and PU, and the obtained mats were vacuum dried at 60 degrees C overnight. The physicochemical characterization of as-spun composite nanofibers was carried out by X-ray diffraction pattern, field emission scanning electron microscopy, energy-dispersive X-ray spectroscopy, electron probe microanalysis, and transmission electron microscopy, whereas the thermal behavior was analyzed by thermogravimetric analysis. The viability, attachment, and proliferation of NIH 3T3 mouse fibroblast cells on the ZnO/PU composite nanofibers were analyzed by in vitro cell compatibility test. The morphological features of the cells attached on nanofibers were examined by Bio-SEM. We conclude that the electrospun nanofibrous scaffolds with unique spider nets had good biocompatibility. Cytotoxicity experiments indicated that the mouse fibroblasts could attach to the nanocomposite after being cultured. Thus, the current work demonstrates that the as-synthesized ZnO/PU hybrid nanofibers represent a promising biomaterial to be exploited for various tissue engineering applications. PMID- 22918300 TI - Long-term analysis of the efficacy and tolerability of sorafenib in advanced radio-iodine refractory differentiated thyroid carcinoma: final results of a phase II trial. AB - OBJECTIVE: We conducted a prospective phase II clinical trial to determine the efficacy of sorafenib in patients with advanced radio-iodine refractory differentiated thyroid cancer. In this article, the long-term results are presented. PATIENTS AND METHODS: Thirty-one patients with progressive metastatic or locally advanced radioactive iodine refractory differentiated thyroid cancer received sorafenib 400 mg orally twice daily. The study end points included response rate, progression-free survival (PFS), overall survival (OS), best response by Response Evaluation Criteria in Solid Tumors criteria 1.0, and toxicity. RESULTS: Median PFS was 18 months (95% confidence interval (95% CI): 7 29 months) and median OS was 34.5 months (95% CI: 19-50 months). Eight patients (31%) achieved a partial response and 11 patients (42%) showed stable disease after a median follow-up of 25 months (range 3.5-39 months). Toxicity mostly included hand foot syndrome, weight loss, diarrhea, and rash. CONCLUSION: Sorafenib has clinically relevant antitumor activity in patients with progressive metastatic or locally advanced radio-iodine refractory differentiated thyroid cancer. Sorafenib can nowadays be considered as the standard option in these patients. PMID- 22918301 TI - Prolactinomas resistant to standard doses of cabergoline: a multicenter study of 92 patients. AB - BACKGROUND: Dopamine agonist resistance in prolactinoma is an infrequent phenomenon. Doses of cabergoline (CAB) of up to 2.0 mg/week are usually effective in controlling prolactin (PRL) secretion and reducing tumor size in prolactinomas. The clinical presentation, management, and outcome of patients that are not well controlled by such commonly used doses of CAB-resistant patients are poorly understood. DESIGN AND METHODS: A multicenter retrospective study was designed to collect a large series of resistant prolactinoma patients, defined by uncontrolled hyperprolactinemia on CAB >=2.0 mg weekly. RESULTS: Ninety-two patients (50 F, 42 M) were analyzed. At diagnosis, most had macroprolactinomas (82.6%); males were significantly older than females (P=0.0003) and presented with a more aggressive disease. A genetic basis was identified in 12 patients. Thirty-six patients (39.1%) received only medical therapy, most underwent surgery (60.9%, including multiple interventions in 10.9%), and 14.1% received postoperative radiotherapy. Eight patients developed late CAB resistance (8.7%). The median maximal weekly dose of CAB (CAB(max/w)) was 3.5 mg (2.0-10.5). Despite a higher CAB(max/w) in patients treated with multimodal therapy (P=0.003 vs exclusive pharmacological treatment), a debulking effect of surgery was shown in 14 patients, with a higher rate of PRL control (P=0.006) and a significant reduction in CAB(max/w) (P=0.001) postoperatively. At last follow-up (median 88 months), PRL normalization and tumor disappearance were achieved in 28 and 19.9% of the patients respectively, with no significant sex related difference observed in CAB(max/w) or disease control. Mortality was 4.8%, with four patients developing aggressive tumors (4.3%) and three a pituitary carcinoma (3.3%). CONCLUSION: CAB-resistant prolactinomas remain a serious concern. Surgical debulking, newer therapeutic strategies, and early diagnosis of genetic forms could help to improve their outcome. PMID- 22918302 TI - Mortality and socioeconomic status in adults with childhood onset GH deficiency (GHD) is highly dependent on the primary cause of GHD. AB - OBJECTIVE: Childhood onset GH deficiency (CO-GHD) is associated with increased morbidity and mortality; however, the patients' socioeconomic profile as adults is not fully known. DESIGN: Register study using Danish nationwide registries. Two hundred and sixty GHD males and 156 GHD females and 25,358 male and 15,110 female controls were included. METHODS: Information was obtained concerning cohabitation, parenthood, education, income, retirement, convictions, and death. Income was analyzed using conditional logistic regression, and other outcomes were analyzed using Cox regression. Subgroups of GHD patients with malignant tumors, craniopharyngioma, idiopathic GHD, and others were investigated separately. RESULTS: Both male and female GHD patients had a significantly worse outcome on all studied socioeconomic parameters. Fewer GHD patients lived in partnerships and entered them later (male hazard ratio (HR): 0.31; female HR: 0.33), had fewer parenthoods (male HR: 0.26; female HR: 0.26), lower educational level (male HR: 0.58; female HR: 0.48), lower income, higher risk of retirement (male HR: 13.4; female HR: 24.2), and fewer convictions (male HR: 0.67; female HR: 0.49). Mortality was increased (male HR: 10.7; female HR: 21.4). Adjusted for marital and educational status, male HR of death was 5.2 and female HR 10.5. Patients with idiopathic GHD had a socioeconomic profile similar to controls. CONCLUSION: The primary causes of CO-GHD and concomitant diseases severely impair socioeconomic conditions and impact mortality; only the subgroup of patients with idiopathic GHD conditions was similar to the background population. PMID- 22918303 TI - Growth differentiation factor 15 predicts future insulin resistance and impaired glucose control in obese nondiabetic individuals: results from the XENDOS trial. AB - OBJECTIVE: Growth differentiation factor-15 (GDF-15) is a stress-responsive cytokine that is increased in obesity and established type 2 diabetes. We assessed whether GDF-15 can predict future insulin resistance and impaired glucose control in obese nondiabetic individuals. DESIGN AND METHODS: Plasma GDF 15 concentrations were measured with an automated electrochemiluminescent immunoassay at baseline and after 4 years in 496 obese nondiabetic individuals (52% men, median age 48 years, median body mass index (BMI) 37.6 kg/m(2)) enrolled in the XENical in the prevention of Diabetes in Obese subjects (XENDOS) trial. RESULTS: The median GDF-15 concentration at baseline was 869 ng/l (interquartile range 723-1064 ng/l). GDF-15 was related to body weight, BMI, waist-to-hip ratio, and insulin resistance (homeostasis model assessment of insulin resistance (HOMA-IR)) (all P < 0.01). Changes in GDF-15 from baseline to 4 years were related to changes in body weight, BMI, waist-to-hip ratio, and HOMA IR (all P < 0.05). Baseline GDF-15 was associated with the risk to have prediabetes or diabetes at 4 years by univariate analysis (odds ratio (OR) FOR 1 unit increase in ln GDF-15, 3.2; 95% confidence interval (CI): 1.7-6.1; P<0.001), and after multivariate adjustment for age, gender, treatment allocation (orlistat vs placebo), BMI, waist-to-hip ratio, and glucose control at baseline (OR 2.2; 95% CI: 1.1-4.7; P=0.026). Similarly, baseline GDF-15 was independently associated with HOMA-IR at 4 years (P=0.024). CONCLUSIONS: This first longitudinal study of GDF-15 in a large cohort of obese individuals indicates that GDF-15 is related to abdominal obesity and insulin resistance and independently associated with future insulin resistance and abnormal glucose control. PMID- 22918312 TI - Tissue engineering: Perfusable vascular networks. PMID- 22918313 TI - Material witness: Shock relief. PMID- 22918304 TI - Rodent models to study the relationships between mammals and their bacterial inhabitants. AB - Laboratory rodents have been instrumental in helping researchers to unravel the complex interactions that mammals have with their microbial commensals. Progress in defining these interactions has also been possible thanks to the development of culture-independent methods for describing the microbiota associated to body surfaces. Understanding the mechanisms that govern this relationship at the molecular, cellular, and ecological levels is central to both health and disease. The present review of rodent models commonly used to investigate microbial-host "conversations" is focused on those complex bacterial communities residing in the lower gut. Although many types of pathology have been studied using gnotobiotic animals, only the models relevant to commensal bacteria will be described. PMID- 22918315 TI - Mesoporous silica: Holey quasicrystals. PMID- 22918314 TI - Dielectric nanoparticles: Polarizability reveals identity. PMID- 22918316 TI - Electronics: Electronic materials through time. PMID- 22918317 TI - Polymer chemistry: Still in control. PMID- 22918318 TI - Mercury in different feather types from Great Cormorants (Phalacrocorax carbo L.) inhabiting the Vistula Lagoon ecosystem in Poland. AB - Total mercury levels in different feather types (down, contour, tail and flight) in Great Cormorants (Phalacrocorax carbo L.) were determined using CV-AAS. Feathers from Great Cormorants inhabiting the Vistula Lagoon ecosystem have an average Hg level of 7.14 +/- 3.99 (MUg/g w.w.). Age-dependent concentrations of Hg were statistically significant (ANOVA Kruskal-Wallis, p < 0.0001). There were also significant differences in Hg levels in different parts of feathers from adults and immature birds (ANOVA Kruskal-Wallis, p < 0.0001). Cormorant chick feathers appear to be a potential biomonitor of Hg pollution in the Vistula Lagoon ecosystem, but this subject requires further research. PMID- 22918319 TI - Winter mass concentrations of carbon species in PM10, PM 2.5 and PM1 in Zagreb air, Croatia. AB - The purpose of our investigation was to examine the mass concentrations of EC, OC and TC (EC + OC) in PM(10), PM(2.5) and PM(1) particle fractions. Daily PM(10), PM(2.5) and PM(1) samples were collected at an urban background monitoring site in Zagreb during winter 2009. Average OC and EC mass concentrations were 11.9 and 1.8 MUg m(-3) in PM(10), 9.0 and 1.4 MUg m(-3) in PM(2.5), and 5.5 and 1.1 MUg m( 3) in PM(1). Average OC/EC ratios in PM(10), PM(2.5), and PM(1) were 7.4, 6.9 and 5.4, respectively. PMID- 22918320 TI - Contamination of metals in tissues of Ctenopharyngodon idella and Perca fluviatilis, from Anzali Wetland, Iran. AB - The objective of the present study was to investigate the levels of metals (Cd, Cu, Zn, Pb and Cr) in muscle, gill, liver, kidney and intestine of two freshwater fish, Ctenopharyngodon idella and Perca fluviatilis, in Anzali Wetland, Iran. The concentrations were different between the fish species as well as among the tissues of fish. Results showed that the metal concentrations in both fish species were in descending order of Zn > Cu > Pb > Cr > Cd. Results also showed that the Cd, Cu, Zn, and Pb concentrations in the muscle of both fish from Anzali Wetland are below levels of concern for human consumption. PMID- 22918321 TI - Distribution of metals in surface sediments from a small river flowing through urban and agricultural areas. AB - The characteristic distributions of 12 metals (Al, Ti, Cr, Mn, Fe, Co, Ni, Cu, Zn, Sr, Cd and Pb) were investigated in surface sediments from a small river (Niitsu River) flowing through both urban and agricultural areas by comparison with those from the upper main stream (Nodai River). Among the investigated metals, the mean concentrations of Al, Cr, Fe, Zn, Cd and Pb in the Niitsu River were significantly higher than those in the Nodai River. The investigated sites can be characterized by the principal components 1-3. PMID- 22918322 TI - Dental Team GB. PMID- 22918323 TI - Trauma by iPad. PMID- 22918324 TI - TMJ dysfunction. PMID- 22918325 TI - Systemic health screening. PMID- 22918326 TI - Doubly impossible. PMID- 22918327 TI - Unjustified vindictiveness. PMID- 22918328 TI - Flawed pension schemes. PMID- 22918329 TI - Gun pellet radiopacity. PMID- 22918330 TI - For the record. PMID- 22918331 TI - Time best served. PMID- 22918342 TI - Peer review: a view based on recent experience as an author and reviewer. AB - Peer review is an important stage in academic publishing, as a form of quality control to maintain the integrity of both the articles and the journals they appear in. However, the confidential nature of the relationship between reviewer and author does not necessarily benefit the system; with some reviewers using their anonymity to give unnecessary, injudicious comment. This paper explores the motives behind the reviewer's comments and how peer review could be improved by openness and honesty. PMID- 22918343 TI - Oral diagnosis and treatment planning: part 4. Non-carious tooth surface loss and assessment of risk. AB - Non-carious tooth surface loss or tooth wear is becoming an increasingly significant factor affecting the long-term health of the dentition. The adverse effects of tooth wear are becoming increasingly apparent both in young persons and, as more people retain their teeth, into old age. This situation challenges the preventive and restorative skills of dental practitioners. PMID- 22918344 TI - Contemporary issues in the provision of restorative dentistry. AB - This review highlights current issues in the provision of restorative dentistry both in primary and secondary care settings. Current challenges in the provision of restorative procedures are reviewed and methods in improving care and efficiency are proposed. Possible changes to the infrastructure and delivery of care are suggested in order to improve effectiveness and the patient pathway. PMID- 22918345 TI - National clinical guidelines for management of the palatally ectopic maxillary canine. AB - This review summarises updated clinical guidelines produced by the Clinical Standards Committee of the Faculty of Dental Surgery, Royal College of Surgeons of England (FDSRCS). This guideline on the management of the palatally ectopic maxillary canine illustrates the information contained in the recently updated online version. The timely recognition of ectopic canines is important for the overall management of the dentition. This review illustrates five management strategies for ectopic permanent canines: interceptive treatment by extraction of the deciduous canine, surgical exposure and orthodontic alignment, surgical removal of the palatally ectopic permanent canine, auto-transplantation and no active treatment/leave and observe. The current available evidence for each of these management options has been evaluated and awarded a grade used by the Scottish Intercollegiate Guidelines Network. PMID- 22918350 TI - Summary of: Socioeconomic deprivation and NHS orthodontic treatment delivery in Scotland. PMID- 22918351 TI - Summary of: NICE guideline and current practice of antibiotic prophylaxis for high risk cardiac patients (HRCP) among dental trainers and trainees in the United Kingdom (UK). PMID- 22918368 TI - Pascal Magne: 'It should not be about aesthetics but tooth-conserving dentistry'. Interview by Ruth Doherty. AB - Pascal Magne, lecturer in adhesive and aesthetic dentistry at the University of Southern California in the USA, on biomimetics, mentorship and the future for the profession. PMID- 22918373 TI - NICE guideline and current practice of antibiotic prophylaxis for high risk cardiac patients (HRCP) among dental trainers and trainees in the United Kingdom (UK). AB - OBJECTIVE: The National Institute for Health and Clinical Excellence (NICE) introduced the antibiotic prophylaxis guideline in 2008 for cardiac patients in the UK, which has led to a decrease in national prescription levels for antibiotic prophylaxis. Despite the introduction of the guideline there is still a discrepancy in levels of compliance among the dental community. The aims of this study were to determine the understanding of the NICE clinical guideline on antimicrobial prophylaxis against infective endocarditis (IE) and the difference in antibiotic prescription for high risk cardiac patients (HRCP) between dental trainers and trainees. METHODS: A proforma was designed and distributed among dental trainers and trainees attending a conference at the London deanery. The trainers were GDPs responsible for training dental trainees allocated to them over a 12 month period based in a general dental practice. Dental trainees were recent graduates about to commence their vocational dental training. Eighty-five vocational dental trainees and 70 trainers completed the proforma on a voluntary basis. RESULTS: The results of the study confirm that most trainers (95.7%) and trainees (94.1%) are aware of this guideline but only 62% of trainers and 69.7% of trainees have read the guideline. Compliancy with the guideline was low among trainers (55.7%) and trainees (77.6%). Compliance was high among those who had read the guideline. Trainers were more likely to prescribe prophylaxis antibiotics for HRCP. The majority (74-76%) would prescribe antibiotics on a specialist's request. Some trainers (54.9%) and trainees (48.2%) would want antibiotics themselves if they were HRCP. CONCLUSION: This study concludes that much needs to be done to improve the understanding and practice of NICE guideline among the dental trainers and trainees. PMID- 22918374 TI - Socioeconomic deprivation and NHS orthodontic treatment delivery in Scotland. AB - OBJECTIVE: The purpose of this observational study was to investigate the relationship between deprivation and the delivery of primary care NHS orthodontic services across Scotland. METHOD: Deprivation was measured using the Scottish Index of Multiple Deprivation (SIMD). The Information Services Division, NHS National Services Scotland, supplied data on all claims for orthodontic treatments in Scotland for the years 2008 and 2009. Each claim was assigned to a SIMD quintile (SIMD 1 being the most deprived, and SIMD 5 the least deprived), and odds ratios were calculated. RESULTS: Uptake of orthodontic services is highest in the least deprived areas. Patients from the least deprived areas are nearly twice as likely to receive orthodontic treatment as those from the most deprived areas (odds ratio of 1.90 with a 95% confidence interval (CI) 1.86 to 1.94). CONCLUSION: Patients from more the most deprived backgrounds are less likely to receive orthodontic treatment than those from more affluent backgrounds, which does not necessarily reflect need. PMID- 22918375 TI - Cu(1.94)S nanocrystal seed mediated solution-phase growth of unique Cu2S-PbS heteronanostructures. AB - Unique Cu(2)S-PbS heteronanostructures with good photothermal conversion effect have been synthesized for the first time by a Cu(1.94)S nanocrystal seed mediated colloidal solution-phase growth method. The present nanocrystal seed mediated growth method may be extended for the growth of other unique semiconductor heteronanostructures. PMID- 22918377 TI - Chalcogenide clusters of copper and silver from silylated chalcogenide sources. AB - This review summarizes the rich structural variety of copper and silver chalcogenide clusters with protecting ligand shells of phosphane and/or organic ligands that were generated starting out from silylated chalcogenide sources. This route turned out to be fairly selective and thus allows for the isolation of uniform, polynuclear to nanosized cluster molecules that can consist of only a few or up to hundreds of metal atoms, being bridged by the chalcogen atoms. However, all of these clusters are only kinetically stable with respect to the formation of the binary coinage metal chalcogen phases, but do not collapse into the solid M(2)E materials owing to the protection by bulky ligands on the surface. Upon a more detailed analysis of the development of the structural properties with the cluster size, one recognizes differences for the particular M/E combinations: whereas copper chalcogenide and silver selenide clusters show a clear tendency to approach structural patterns of the Cu(2)E bulk, most obvious for the Cu/Se combination, this is not visible for silver sulfide clusters, even not at the largest species with 490 silver and 302 sulfur atoms. Besides the discussion on the structures of title compounds, the review presents insight into the bonding properties, reactivity, thermal and photophysical properties. The latter can be interpreted in terms of the quantum confinement effect, thus demonstrating the clusters to be understood as intermediates between mononuclear complexes and binary bulk phases. PMID- 22918376 TI - Myosinopathies: pathology and mechanisms. AB - The myosin heavy chain (MyHC) is the molecular motor of muscle and forms the backbone of the sarcomere thick filaments. Different MyHC isoforms are of importance for the physiological properties of different muscle fiber types. Hereditary myosin myopathies have emerged as an important group of diseases with variable clinical and morphological expression depending on the mutated isoform and type and location of the mutation. Dominant mutations in developmental MyHC isoform genes (MYH3 and MYH8) are associated with distal arthrogryposis syndromes. Dominant or recessive mutations affecting the type IIa MyHC (MYH2) are associated with early-onset myopathies with variable muscle weakness and ophthalmoplegia as a consistent finding. Myopathies with scapuloperoneal, distal or limb-girdle muscle weakness including entities, such as myosin storage myopathy and Laing distal myopathy are the result of usually dominant mutations in the gene for slow/beta cardiac MyHC (MYH7). Protein aggregation is part of the features in some of these myopathies. In myosin storage myopathy protein aggregates are formed by accumulation of myosin beneath the sarcolemma and between myofibrils. In vitro studies on the effects of different mutations associated with myosin storage myopathy and Laing distal myopathy indicate altered biochemical and biophysical properties of the light meromyosin, which is essential for thick filament assembly. Protein aggregates in the form of tubulofilamentous inclusions in association with vacuolated muscle fibers are present at late stage of dominant myosin IIa myopathy and sometimes in Laing distal myopathy. These protein aggregates exhibit features indicating defective degradation of misfolded proteins. In addition to protein aggregation and muscle fiber degeneration some of the myosin mutations cause functional impairment of the molecular motor adding to the pathogenesis of myosinopathies. PMID- 22918378 TI - Crowd-sourced BioGames: managing the big data problem for next-generation lab-on a-chip platforms. AB - We describe a crowd-sourcing based solution for handling large quantities of data that are created by e.g., emerging digital imaging and sensing devices, including next generation lab-on-a-chip platforms. We show that in cases where the diagnosis is a binary decision (e.g., positive vs. negative, or infected vs. uninfected), it is possible to make accurate diagnosis by crowd-sourcing the raw data (e.g., microscopic images of specimens/cells) using entertaining digital games (i.e., ) that are played on PCs, tablets or mobile phones. We report the results and the analysis of a large-scale public experiment toward diagnosis of malaria infected human red blood cells (RBCs), where binary responses from approximately 1000 untrained individuals from more than 60 different countries are combined together (corresponding to more than 1 million cell diagnoses), resulting in an accuracy level that is comparable to those of expert medical professionals. This platform holds promise toward cost-effective and accurate tele-pathology, improved training of medical personnel, and can also be used to manage the "Big Data" problem that is emerging through next generation digital lab-on-a-chip devices. PMID- 22918379 TI - Natural elicitors, effectors and modulators of plant responses. AB - In plants, successful defense relies on fast and specific response to biotic attack. In plant-microbial and plant-plant interactions several elicitors, effectors and modulators are recognized by specific and unspecific receptors that trigger signal cascades eventually leading to gene expression and plant responses. Here we review the chemical nature and signaling pathways of natural products released by microorganisms, herbivores, and plants during pathogenic infections, herbivory, symbioses and allelopathic interactions. PMID- 22918380 TI - Work-related health effects in swine building workers after respiratory protection use. AB - OBJECTIVE: To compare inflammation and lung function in swine workers after periods with and without respiratory protection during work. METHODS: Twenty three workers were examined before and after two nonprotected work shifts. One shift was preceded by a period with diminished exposure by use of respirators. The other shift was preceded by an unprotected period of work. RESULTS: Endotoxin concentrations were similarly high (24,636 and 28,775 endotoxin units/m(3)). A 3.1% cross-shift decline in forced vital capacity occurred after the period with respiratory protection (P = 0.01). Blood leukocytes increased more (P = 0.01) and bactericidal/permeability-increasing protein was reduced (P = 0.015) only after the period with respiratory protection. Plasma interleukin-6 increased (P < 0.0001) during both visits. CONCLUSION: Respiratory protection resulted in cross shift inflammatory and respiratory reactions at return to unprotected work. PMID- 22918381 TI - Cancer incidence among workers at a satellite manufacturing facility. AB - OBJECTIVE: To evaluate cancer incidence overall and renal cancer in particular among workers at the Valley Forge satellite manufacturing complex in Pennsylvania. A previous mortality study observed a slightly elevated risk estimate for brain cancer. METHODS: A cohort of 27,586 workers, employed between 1962 and 2008 and alive in 1990 when cancer follow-up began, was investigated. Standardized incidence ratios (SIRs) were calculated. RESULTS: A total of 4303 incident cancers were diagnosed. The SIRs were significantly reduced for all cancers (0.88; 95% confidence interval [CI], 0.85 to 0.90) and several site specific cancers. The renal cancer SIR was 1.00 (95% CI, 0.84 to 1.19) and the brain cancer SIR was 1.17 (95% CI, 0.90 to 1.49). CONCLUSIONS: This cancer incidence study of satellite manufacturing workers found no convincing evidence of increased cancer risk overall, or for renal or brain cancer in particular. PMID- 22918382 TI - Temperature dependent solid-state proton migration in dimethylurea-oxalic acid complexes. AB - The phenomenon of solid-state proton migration within molecular complexes containing short hydrogen bonds is investigated in two dimethylurea-oxalic acid complexes. Extensive characterisation by both X-ray and neutron diffraction shows that proton migration along the hydrogen bond can be induced in these complexes as a function of temperature. This emphasises the subtle features of the hydrogen bond potential well in such short hydrogen bonded complexes, both intrinsically and in the effect of the local crystalline environment. Based on these findings, the synthesis and analysis of a series of solid-state molecular complexes is shown to be a potential route to designing materials with tuneable proton migration effects. PMID- 22918383 TI - Introduction to the feature section on functional imaging of the pelvic floor. AB - This is the introduction to the feature section of functional imaging of the pelvic floor, which includes 6 articles, two focused on clinical issues, while four on radiological aspects, mostly on dynamic pelvic floor MRI. PMID- 22918384 TI - Dyspepsia. AB - PURPOSE OF REVIEW: A variety of organic diseases can cause dyspepsia, but most patients with epigastric pain have functional dyspepsia. As dyspepsia is common and usually has a benign cause, it is not possible to fully investigate everyone with epigastric pain. Current recommendations suggest that young patients without alarm symptoms can be treated empirically with Helicobacter pylori test and treat and proton pump inhibitor therapy can be offered to those who are negative or remain symptomatic despite treatment for their H. pylori. Patients who remain symptomatic with this strategy may be investigated with endoscopy, but most will have functional dyspepsia. RECENT FINDINGS: There are a large number of trials for prokinetic therapy in functional dyspepsia, but treatment efficacy is uncertain, as there is evidence of publication bias. There are very limited data for the effectiveness of tricyclic antidepressants in functional dyspepsia. There has been recent interest in the observation that patients with functional dyspepsia have increased eosinophils in the duodenum and this may be accompanied by other subtle manifestations of upregulated mucosal immunity. It is possible that this is being driven by a dietary substance or by a change in the upper gut microbiome. SUMMARY: The initial management of dyspepsia is well established, but how to manage those who do not respond is a challenge. Future studies evaluating diet and altering the gut microbiome may give clinicians more therapeutic options. PMID- 22918385 TI - Micronutrient status and global DNA methylation in school-age children. AB - Aberrations in global LINE-1 DNA methylation have been related to risk of cancer and cardiovascular disease. Micronutrients including methyl-donors and retinoids are involved in DNA methylation pathways. We investigated associations of micronutrient status and LINE-1 methylation in a cross-sectional study of school age children from Bogota, Colombia. Methylation of LINE-1 repetitive elements was quantified in 568 children 5-12 years of age using pyrosequencing technology. We examined the association of LINE-1 methylation with erythrocyte folate, plasma vitamin B12, vitamin A ferritin (an indicator of iron status) and serum zinc concentrations using multivariable linear regression. We also considered associations of LINE-1 methylation with socio-demographic and anthropometric characteristics. Mean (+/- SD) LINE-1 methylation was 80.25 (+/- 0.65) percentage of 5-mC (%5-mC). LINE-1 methylation was inversely related to plasma vitamin A. After adjustment for potential confounders, children with retinol levels higher than or equal to 1.05 umol/L showed 0.19% 5-mC lower LINE-1 methylation than children with retinol levels lower than 0.70 umol/L. LINE-1 methylation was also inversely associated with C-reactive protein, a marker of chronic inflammation, and female sex. We identified positive associations of maternal body mass index and socioeconomic status with LINE-1 methylation. These associations were not significantly different by sex. Whether modification of these exposures during school-age years leads to changes in global DNA methylation warrants further investigation. PMID- 22918386 TI - Quick regulation of mRNA functions by a few seconds of photoirradiation. AB - 3-Cyanovinylcarbazole nucleoside, which effectively photocrosslinks to the pyrimidine base in complementary RNA strands, was incorporated into antisense oligonucleotides, and we evaluated the photoreactivity and the sequence selectivity to mutated K-ras oligoRNAs, as well as the regulation of the function of K-ras mRNA. We demonstrated that the reverse transcription and the translation activity of K-ras mRNA were quickly suppressed by a few seconds of photoirradiation with the addition of the photoresponsive antisense ODN. PMID- 22918387 TI - Imaging of plant cell walls by confocal Raman microscopy. AB - Raman imaging of plant cell walls represents a nondestructive technique that can provide insights into chemical composition in context with structure at the micrometer level (<0.5 MUm). The major steps of the experimental procedure are described: sample preparation (embedding and microcutting), setting the mapping parameters, and finally the calculation of chemical images on the basis of the acquired Raman spectra. Every Raman image is based on thousands of spectra, each being a spatially resolved molecular 'fingerprint' of the cell wall. Multiple components are analyzed within the native cell walls, and insights into polymer composition as well as the orientation of the cellulose microfibrils can be gained. The most labor-intensive step of this process is often the sample preparation, as the imaging approach requires a flat surface of the plant tissue with intact cell walls. After finishing the map (acquisition time is ~10 min to 10 h, depending on the size of the region of interest and scanning parameters), many possibilities exist for the analysis of spectral data and image generation. PMID- 22918388 TI - Establishment of outgrowth endothelial cells from peripheral blood. AB - Blood outgrowth endothelial cells (BOECs) are important tools when investigating diagnostic and therapeutic approaches for vascular disease. In this protocol, mononuclear cells are isolated from peripheral blood and plated on type I collagen at ~135,000 cells per cm(2) in endothelial cell differentiation medium. On average, 0.34 colonies of endothelial cells per milliliter of blood can be obtained. Colonies of endothelial cells become visible after 14-28 d. Upon confluence, these rapidly expanding colonies can be passaged and have been shown to propagate up to 10(18)-fold. Isolated BOECs are phenotypically similar to vascular endothelial cells, as revealed by their cobblestone morphology, the presence of endothelial cell-specific Weibel-Palade bodies and the expression of endothelial cell markers such as VE-cadherin. The protocol presented here also provides a particularly useful tool for the ex vivo assessment of endothelial cell function from patients with different vascular abnormalities. PMID- 22918389 TI - Preparation of plant cells for transmission electron microscopy to optimize immunogold labeling of carbohydrate and protein epitopes. AB - Despite the remarkable advances in electron microscopy, the difficulty in preserving the ultrastructural details of many plant cells is the major limitation to exploiting the full potential of this technology. The very nature of plant cells, including their hydrophobic surfaces, rigid cell walls and large vacuoles, make them recalcitrant to the efficient exchange of reagents that are crucial to preserving their fine structure. Achieving ultrastructural preservation while protecting the antigenicity of molecular epitopes has proven difficult. Here we describe two methods that provide good ultrastructural detail in plant cells while preserving the binding capacity of carbohydrate and protein epitopes. The first is a traditional, chemical-based protocol used to prepare developing grass (cereal) grain for electron microscopy and to locate carbohydrates as they are deposited using immunogold labeling. The second uses cryofixation techniques, including high-pressure freezing and freeze substitution, to prepare delicate, tip-growing pollen tubes and to locate the intracellular site of a polysaccharide synthase. Both procedures can take as long as 2 weeks to achieve results, but there is scope to fast-track some steps depending on the physical characteristics of the material being processed. PMID- 22918390 TI - A fermentation-powered thermopneumatic pump for biomedical applications. AB - We present a microorganism-powered thermopneumatic pump that utilizes temperature dependent slow-kinetics gas (carbon dioxide) generating fermentation of yeast as a pressure source. The pump consists of stacked layers of polydimethylsiloxane (PDMS) and a silicon substrate that form a drug reservoir, and a yeast-solution filled working chamber. The pump operates by the displacement of a drug due to the generation of gas produced via yeast fermentation carried out at skin temperatures. The robustness of yeast allows for long shelf life under extreme environmental conditions (50 degrees C, >250 MPa, 5-8% humidity). The generation of carbon dioxide is a linear function of time for a given temperature, thus allowing for a controlled volume displacement. A polymeric prototype (dimensions 15 mm * 15 mm * 10 mm) with a slow flow rate of <0.23 MUL min(-1) and maximum backpressure of 5.86 kPa capable of continuously pumping for over two hours is presented and characterized. PMID- 22918391 TI - Cyclic metalloporphyrin dimers and tetramers: tunable shape-selective hosts for fullerenes. AB - Covalently linked cyclic metalloporphyrin dimers and tetramers have been demonstrated to be good shape-selective hosts for fullerene guests. The fullerene affinities of these hosts can readily be tuned by modulating the covalent linkage and the metal ions in the porphyrin subunits. A rigid Zn(porphyrin) dimer with conjugated bis(alkynyl) linkers exhibits a high selectivity towards C(70) over C(60) in toluene (K(a,C70)/K(a,C60) = ~28). For the host structures examined, a synergistic combination of rigidity in the linker and electropositive Al ions gives rise to the strongest binding of C(70). In the case of a bisected Zn(porphyrin) tetramer, two well-defined cavities exist; however, due to their comparatively small size, only one C(60) can be accommodated. Studies of fullerene binding as a function of metal ion in a porphyrin divider suggest that the right combination of shape and steric match is essential to exploit both van der Waals and local-charge/induced-dipole interactions. PMID- 22918392 TI - Face-to-face vs telephone pre-colonoscopy consultation in colorectal cancer screening; a randomised trial. AB - BACKGROUND: A pre-colonoscopy consultation in colorectal cancer (CRC) screening is necessary to assess a screenee's general health status and to explain benefits and risks of screening. The first option allows for personal attention, whereas a telephone consultation does not require travelling. We hypothesised that a telephone consultation would lead to higher response and participation in CRC screening compared with a face-to-face consultation. METHODS: A total of 6600 persons (50-75 years) were 1:1 randomised for primary colonoscopy screening with a pre-colonoscopy consultation either face-to-face or by telephone. In both arms, we counted the number of invitees who attended a pre-colonoscopy consultation (response) and the number of those who subsequently attended colonoscopy (participation), relative to the number invited for screening. A questionnaire regarding satisfaction with the consultation and expected burden of the colonoscopy (scored on five-point rating scales) was sent to invitees. Besides, a questionnaire to assess the perceived burden of colonoscopy was sent to participants, 14 days after the procedure. RESULTS: In all, 3302 invitees were allocated to the telephone group and 3298 to the face-to-face group, of which 794 (24%) attended a telephone consultation and 822 (25%) a face-to-face consultation (P=0.41). Subsequently, 674 (20%) participants in the telephone group and 752 (23%) in the face-to-face group attended colonoscopy (P=0.018). Invitees and responders in the telephone group expected the bowel preparation to be more painful than those in the face-to-face group while perceived burden scores for the full screening procedure were comparable. More subjects in the face-to-face group than in the telephone group were satisfied by the consultation in general: (99.8% vs 98.5%, P=0.014). CONCLUSION: Using a telephone rather than a face-to face consultation in a population-based CRC colonoscopy screening programme leads to similar response rates but significantly lower colonoscopy participation. PMID- 22918393 TI - Prognostic utility of pre-operative circulating osteopontin, carbonic anhydrase IX and CRP in renal cell carcinoma. AB - BACKGROUND: Objectively measured circulating biomarkers of prognosis complementing existing clinicopathological models are needed in renal cell carcinoma (RCC). METHODS: Blood samples collected from 216 RCC patients in Leeds before nephrectomy (median follow-up 7 years) were analysed for C-reactive protein (CRP), osteopontin (OPN) and carbonic anhydrase IX (CA9) and prognostic significance determined. RESULTS: CA9, OPN and CRP were univariately prognostic for overall survival (OS), cancer-specific survival (CSS) and disease-free survival (DFS) with CRP and CA9 being independently prognostic for OS/CSS and OS, respectively. Including CA9, OPN and CRP with other conventional prognostic factors gave a superior predictive capacity when compared with a previously published pre-operative clinical nomogram (Karakiewicz et al, 2009). Osteopontin outperformed this nomogram and the post-operative SSIGN score for OS but not for CSS, being significantly predictive for non-cancer deaths. Osteopontin, CRP and CA9 outperformed stage (c-index 76% compared with 70% for stage) and OPN or CA9 identified several subsets of poor prognosis patients including in T1 patients, who may benefit from adjuvant therapy and increased surveillance. CONCLUSION: Circulating CA9, OPN and CRP add value to existing clinicopathological prognostic factors/models and support further studies to investigate their potential use in improving the clinical management of RCC. PMID- 22918395 TI - The utility of molecular diagnostics to predict recurrence of head and neck carcinoma. AB - BACKGROUND: Locoregional recurrence is the major cause of treatment failure after surgery for oral squamous cell carcinoma. Molecular diagnostics have the potential to improve on clinicopathological parameters to predict this recurrence and plan adjuvant treatment. The test most frequently applied is based on detecting TP53 mutations, but alternative methodology is required for cases that harbour the wild-type gene. METHODS: One hundred and two cases with tumour adjacent margins, considered to be clear margins by microscopy, were examined using carefully optimised molecular diagnostics based on detection of the TP53 and Ly-6D markers. The markers were also combined to provide a dual approach. RESULTS: The dual molecular diagnostic identified cases with a significant increase in the probablility of developing locoregional recurrence when tumour adjacent positive and clear margins were compared (P=0.0001). These tests were most useful when the clearance at the resection margins was 5 mm or less. The TP53-based diagnostic was a better predictor of locoregional recurrence than established clinicopathological parameters. CONCLUSION: The optimised TP53-based diagnostic rapidly identifies an important subgroup of cases with close margins that will benefit from new treatment modalities to reduce the risk of recurrence. PMID- 22918394 TI - Brain metastases in Asian HER2-positive breast cancer patients: anti-HER2 treatments and their impact on survival. AB - BACKGROUND: In Asia, large-scale studies on anti-HER2 treatment in HER2-positive breast cancer patients with brain metastases are limited. We studied the treatment patterns of these patients in Asia to evaluate the impact of anti-HER2 treatment on the time to occurrence of brain metastases (TTBM) and survival after brain metastasis (BM). METHODS: A retrospective study of HER2-positive breast cancer patients diagnosed with BM between January 2006 and December 2008 in six Asian countries was conducted. Demographics, tumour characteristics, treatment details, and events dates were collected from medical records. RESULTS: Data from 280 patients were analysed. Before BM, 63% received anti-HER2 treatment. These patients had significantly longer TTBM than those without anti-HER2 treatment (median 33 vs 19 months; P<0.002). After BM, 93% received radiotherapy, 57% received chemotherapy, and 41% received anti-HER2 treatment (trastuzumab and/or lapatinib). Use of both anti-HER2 agents, primarily sequentially, after BM demonstrated the longest survival after BM and was associated with a significant survival benefit over no anti-HER2 treatment (median 26 vs 6 months; hazard ratio 0.37; 95% CI 0.19-0.72). CONCLUSION: Anti-HER2 treatment before BM was associated with longer TTBM. Anti-HER2 treatment after BM was associated with a survival benefit, especially when both trastuzumab and lapatinib were utilised. PMID- 22918396 TI - Development of a nomogram incorporating serum C-reactive protein level to predict overall survival of patients with advanced urothelial carcinoma and its evaluation by decision curve analysis. AB - BACKGROUND: The purpose of this study is to investigate the prognostic impact of C-reactive protein (CRP) on patients with advanced urothelial carcinoma and to develop a novel nomogram predicting survival. METHODS: A total of 223 consecutive patients were treated at Tokyo Medical and Dental Hospital. A nomogram incorporating V was developed based on the result of a Cox proportional hazards model. Its efficacy and clinical usefulness was evaluated by concordance index (c index) and decision curve analysis. RESULTS: Of the 223 patients, 184 (83%) died of cancer. Median follow-up periods of patients who died and those who remained alive were 5 and 11 months, respectively. We developed a novel nomogram incorporating Eastern Cooperative Oncology Group Performance Status, presence of visceral metastasis, haemoglobin and age. The c-index of the nomogram predicting survival probability 6 and 12 months after diagnosis was 0.788 and 0.765, respectively. Decision curve analyses revealed that the novel nomogram incorporating CRP had a superior net benefit than that without CRP for most of the examined probabilities. CONCLUSION: We demonstrated the prognostic impact of CRP that improved the predictive accuracy of a nomogram for survival probability in patients with advanced urothelial carcinoma. PMID- 22918397 TI - Natural sesquiterpenoids. AB - This review covers the isolation, structural determination, synthesis and chemical and microbiological transformations of natural sesquiterpenoids. The literature is reviewed, and 435 references are cited. PMID- 22918399 TI - A rhodium complex-linked beta-barrel protein as a hybrid biocatalyst for phenylacetylene polymerization. AB - Our group recently prepared a hybrid catalyst containing a rhodium complex, Rh(Cp)(cod), with a maleimide moiety at the peripheral position of the Cp ligand. This compound was then inserted into a beta-barrel protein scaffold of a mutant of aponitrobindin (Q96C) via a covalent linkage. The hybrid protein is found to act as a polymerization catalyst and preferentially yields trans poly(phenylacetylene) (PPA), although the rhodium complex without the protein scaffold normally produces cis PPA. PMID- 22918398 TI - Effect of autologous platelet-rich plasma on the repair of full-thickness articular defects in rabbits. AB - PURPOSE: To assess the effect of autologous platelet-rich plasma on the repair of full-thickness articular cartilage lesions in immature rabbits. To that end, the samples were studied using macroscopic, microscopic and biomechanical techniques. METHODS: Twenty-four 11-week-old New Zealand rabbits were divided into two groups based on the treatment (physiological saline serum PCB, autologous platelet-rich plasma PRP). Cartilage lesions were drilled in medial femoral condyle of these rabbits. Other 12 rabbits were under the same conditions, but they did not suffer any lesion and treatment (control group CTR). The three groups were divided into two subgroups, depending on the age at the time of killing (16 and 19 weeks old). RESULTS: The CTR group showed the best possible value in the macroscopic and microscopic evaluation. Meanwhile, the PCB and PRP group values were lower than the CTR group values, at two times of the study, but similar to each other at 19 weeks. In the biomechanical study, at 16 weeks, the CTR and PCB groups behaved similarly, with values above PRP group values, while at 19 weeks, CTR group showed higher values than PCB and PRP groups, and there were no differences between these values. CONCLUSIONS: The evolution of the tissue treated with autologous PRP showed a positive tendency over time, while the PCB group was negative. Nevertheless, at 19 weeks of age, the PRP treatment did not show better results than the PCB, both showing the characteristics of fibrocartilaginous tissue. Likewise, none of the two treatments produced a repair tissue as the healthy cartilage. PMID- 22918400 TI - Charge transport improvement employing TiO2 nanotube arrays as front-side illuminated dye-sensitized solar cell photoanodes. AB - TiO(2) nanotube (NT) arrays with different lengths were fabricated by anodic oxidation of Ti foil and free-standing NT membranes were detached by the metal substrate and bonded on the fluorine-doped tin oxide surface implementing an easy procedure. Morphology of the as-grown material and of the prepared photoanode was investigated by means of electron microscopy, deepening the investigation on the thermal treatment effect. Crystalline orientation and exposed surface area were studied by X-ray diffraction and Brunauer-Emmett-Teller measurements, showing suitable characteristics for the application in dye-sensitized solar cells (DSCs). DSCs were assembled employing a microfluidic housing system. The cell performances and the electron transport properties as a function of the tube length, before and after a TiCl(4) treatment, were characterized by I-V electrical measurements, incident photon-to-electron conversion efficiency, electrochemical impedance spectroscopy and open circuit voltage decay. Fitting the impedance spectra with an equivalent circuit, it was possible to obtain information on the electron diffusion properties into the TiO(2) nanotubes. A comparison with the charge transport properties evaluated in nanoparticle-based photoanodes witnesses a noteworthy increase of electron lifetime and diffusion length, yielding an overall power conversion efficiency up to 7.56%. PMID- 22918401 TI - Cranialization in a cohort of 154 consecutive patients with frontal sinus fractures (1987-2007): review and update of a compelling procedure in the selected patient. AB - Retrospective review of charts of 180 consecutive patients with frontal sinus fractures managed by plastic surgeons at the University of Kentucky between 1987 and 2007 was performed with institutional review board approval. Twenty-six charts did not meet the criteria. The remaining 154 records provided 1-to-20-year follow-up. The study included 34 patients who underwent cranialization and 120 patients who did not. A low-complication rate of 6% after cranialization is ascribed by the authors to meticulous sinus mucosal debridement; thorough obliteration of the frontal sinus outflow tract (with sterile gelatin sponge pledgets and bone chips from the outer cortex of the temporoparietal skull); and avoidance of avascular barriers, such as abdominal fat. As high-resolution computerized tomography with parasaggital views was introduced, an increasing ability to preoperatively define the extent of injury of the medial and lateral sinus floor was observed. The authors conclude selective use of cranialization is indicated. PMID- 22918402 TI - Use of TK-cells in haploidentical hematopoietic stem cell transplantation. AB - PURPOSE OF REVIEW: Preserving the beneficial effects of donor T cells against tumor and pathogens while avoiding noxious graft-versus-host disease (GvHD) is the 'holy grail' of allogeneic hematopoietic stem cell transplantation (HSCT). The suicide gene strategy allows the selective elimination of genetically modified donor T cells during GvHD. This review summarizes the results obtained in recent years in the clinical trials of suicide gene therapy using the paradigmatic herpes simplex virus thymidine kinase (TK) suicide gene. RECENT FINDINGS: T cells genetically modified to express the TK suicide gene, TK-cells, are safe and preserve most of their functional features; when infused into patients they are capable of conferring substantial protection against infections and tumor recurrence, and are promptly eliminated in the case of GvHD, with complete resolution of the adverse reaction in all treated cases. Unexpectedly, TK-cells also have the indirect effect of promoting patient thymopoiesis, contributing to the renewal of a host-tolerant immune repertoire. SUMMARY: Suicide gene therapy with TK-cells is a promising approach to overcome the risk of GvHD in allogeneic HSCT, especially from partially incompatible donors, and is currently under evaluation in a multicentric phase III clinical trial. PMID- 22918403 TI - Haploidentical hematopoietic stem cell transplantation with unmanipulated granulocyte colony stimulating factor mobilized marrow and blood grafts. AB - PURPOSE OF REVIEW: This article summarizes recent improvements and progress with unmanipulated haploidentical blood and marrow transplantation (HBMT) and discusses the difference in outcomes between patients receiving HBMT and those receiving unmanipulated granulocyte colony stimulating factor (G-CSF) mobilized haploidentical peripheral blood (G-PB) grafts as allografts. RECENT FINDINGS: Long-term follow-up confirmed that unmanipulated HBMT is a promising protocol that can be successfully extended to treat severe aplastic anemia. Recent observations regarding immune recovery, infections, and strategy for modified donor lymphocyte infusions have provided insight into the prevention of infections and the decrease in relapse after HBMT. Extensive chronic graft-versus host disease (GVHD) strongly and negatively impacts patient health-related quality of life, suggesting that it should be successfully controlled. A prospective study suggested the inclusion of HBMT in treatment algorithms as a viable option for adults with acute myeloid leukemia with unfavorable cytogenetics who lack a matched donor. Randomized clinical trials are warranted to investigate whether mixture grafts of G-CSF-mobilized blood and marrow or G-PB alone should be chosen as allografts in haploidentical settings. SUMMARY: Unmanipulated HBMT is a reliable protocol. New strategies should be investigated to decrease the incidences of GVHD and relapse. Novel mobilization regimens such as AMD3100 alone or G-CSF+AMD3100 for allograft engineering may improve transplant outcomes following HBMT. PMID- 22918404 TI - Will mechanical dyssynchrony one day impact our management of chronic heart failure patients? PMID- 22918405 TI - Should we use myocardial perfusion imaging for prognostic stratification in low risk patients after exercise ECG? PMID- 22918406 TI - Time to twist: marker of systolic dysfunction in Africans with hypertension. AB - AIMS: Speckle-tracking echocardiography (STE) has emerged as a quantitative technique to assess left ventricular (LV) function via twist mechanics. Hypertension-associated changes in LV twist have not been previously evaluated in African patients with LV systolic dysfunction. This study evaluates LV twist dynamics in hypertensive patients with a low ejection fraction (EF). METHODS AND RESULTS: Forty-one hypertensive patients with EF <45% and normal coronary angiography (HTLEF group) were compared with 41 control subjects using STE. Peak apical rotation (AR) and isochronous basal rotation (BR) were measured, as was net twist (maximal value of simultaneous AR-BR). Rigid body rotation (RBR) was defined as AR and BR occurring in the same direction. Of 41 HTLEF patients, 28 (68%) had normal twist pattern, whereas 13 (32%) exhibited RBR; 11 of those 13 exhibited clockwise rotation. AR (1.89 degrees +/- 0.99 vs. 7.15 degrees +/- 2.26; P < 0.0001), BR (1.44 degrees +/- 0.78 vs. -3.75 degrees +/- 1.61; P < 0.0001), and net twist (3.3 degrees +/- 1.17 vs. 10.9 degrees +/- 2.7; P < 0.0001) were lower in HTLEF patients. The subgroup with clockwise RBR showed greater LV dysfunction (EF: 27.9 +/- 5.8 vs. 35 +/- 7.5%; P = 0.005) and more spherical LV geometry in both diastole and systole (P = 0.0009 and P = 0.0002, respectively) compared with those who had a normal pattern of twist. In the HTLEF subgroup with normal twist pattern, AR (r = 0.57; P = 0.002) and net twist (r = 0.57; P = 0.002) correlated with EF. CONCLUSIONS: LV twist in patients with hypertension and EF <45% is diminished. Apical rotation and net twist are good correlates for EF in hypertensive patients with EF <45%. PMID- 22918407 TI - Controlling health care costs in Massachusetts with a global spending target. PMID- 22918408 TI - Regioselective phosphorylation and thiophosphorylation of N-confused porphyrin: a route to hybrid carbaporphyrinoids. AB - N-confused porphyrin (NCP) undergoes controlled regioselective phosphorylations at the inner, outer or both carbon atoms of the inverted pyrrole ring. Reactivity centered at the internal carbon atom is enhanced in the Ag(III) NCP's whereas the preference for perimeter substitution is characteristic of free base NCP. The addition of S(8) resulted in the formation of thio-derivatives containing 21 diphenylthiophosphoryl or 21-phosphinodithioic substituents. PMID- 22918409 TI - Balloon osteoplasty--a new technique for minimally invasive reduction and stabilisation of Hill-Sachs lesions of the humeral head: a cadaver study. AB - PURPOSE: Traumatic shoulder dislocation may be complicated by concomitant bony injury of the glenoid rim or the humeral head. In Hill-Sachs lesions, reconstruction techniques vary widely and range from open reduction to tendon transposition or humeral head derotation. These operations are extensive and have questionable outcomes. With the expertise from vertebral compression fracture reduction by kyphoplasty, we examined in a cadaver feasibility study whether reduction of the Hill-Sachs lesion via hydraulic lift might be an anatomical and minimally invasive treatment option. We postulated that the use a of a balloon- assisted kyphoplasty reduction could achieve almost anatomical correction of the defect. METHODS: We created Hill-Sachs lesions in six humeral specimens and performed a computed tomography (CT) scan before and after reduction with the kyphoplasty system. The entry point at the greater tuberosity and balloon positioning was visualised by fluoroscopy. The size of the Hill-Sachs lesion before and after reduction was measured using CT scans in the axial orientation. RESULTS: Using the balloon kyphoplasty system, we achieved a statistically significant reduction (80 % ) of the Hill-Sachs lesion. CONCLUSION: In a preliminary cadaver study we show that using a balloon kyphoplasty system might be an alternative treatment option for Hill-Sachs lesions, with reduced collateral damage that can occur with other minimally invasive techniques. Future work is needed to evaluate the technique under arthroscopic conditions. PMID- 22918410 TI - Postoperative changes of early-phase inflammatory indices after uncomplicated anterior cervical discectomy and fusion using allograft and demineralised bone matrix. AB - PURPOSES: We investigated sequential levels of C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) in uncomplicated ACDF (anterior cervical discectomy and fusion) using allograft and DBM (demineralised bone matrix) for primary cervical spondylosis and/or disc herniation. To our knowledge, there has been no study to investigate the diagnostic value of CRP and ESR for postoperative infection in ACDF using allograft and DBM. METHODS: Blood samples of 85 patients, who underwent one- (n = 51) or two-level (n = 34) ACDF, were obtained and evaluated before surgery and on the first, third, fifth, seventh, 14th, 30th, and 90th postoperative days. No infection was found in any patient for at least one year follow-up period. RESULTS: Mean CRP value increased significantly on the first postoperative day and reached a peak on the third postoperative day. The peak level rapidly decreased but remained elevated on the fifth, seventh, and 14th postoperative days. Mean ESR value increased significantly and reached a peak on the third postoperative day. The peak level gradually decreased but remained elevated on the fifth and seventh postoperative days. One- and two-level ACDF exhibited similar postoperative changes in CRP and ESR values and no significant difference in mean levels of CRP and ESR throughout the follow-up periods. CONCLUSIONS: This study demonstrates that uncomplicated ACDF using allograft and DBM showed significant abnormal values of CRP and ESR during the early postoperative period. This result suggests that abnormal values of CRP and ESR in the early postoperative period do not indicate acute postoperative infection after ACDF using allograft and DBM. Straying from the normal course, such as a second rise or a failure to decrease, of CRP and ESR is more important to signpost acute postoperative infection in ACDF using allograft and DBM. PMID- 22918412 TI - Therapeutics: Holding JAK back. PMID- 22918413 TI - Immunology: TIM3 suppresses antitumour DCs. PMID- 22918416 TI - Two-hundredfold volume concentration of dilute cell and particle suspensions using chip integrated multistage acoustophoresis. AB - Concentrating cells is a frequently performed step in cell biological assays and medical diagnostics. The commonly used centrifuge exhibits limitations when dealing with rare cell events and small sample volumes. Here, we present an acoustophoresis microfluidic chip utilising ultrasound to concentrate particles and cells into a smaller volume. The method is label-free, continuous and independent of suspending fluid, allowing for low cost and minimal preparation of the samples. Sequential concentration regions and two-dimensional acoustic standing wave focusing of cells and particles were found critical to accomplish concentration factors beyond one hundred times. Microparticles (5 MUm in diameter) used to characterize the system were concentrated up to 194.2 +/- 9.6 times with a recovery of 97.1 +/- 4.8%. Red blood cells and prostate cancer cells were concentrated 145.0 +/- 5.0 times and 195.7 +/- 36.2 times, respectively, with recoveries of 97.2 +/- 3.3% and 97.9 +/- 18.1%. The data demonstrate that acoustophoresis is an effective technique for continuous flow-based concentration of cells and particles, offering a much needed intermediate step between sorting and detection of rare cell samples in lab-on-a-chip systems. PMID- 22918414 TI - The effects of deregulated DNA damage signalling on cancer chemotherapy response and resistance. AB - Tumours with specific DNA repair defects can be completely dependent on back-up DNA repair pathways for their survival. This dependence can be exploited therapeutically to induce synthetic lethality in tumour cells. For instance, homologous recombination (HR)-deficient tumours can be effectively targeted by DNA double-strand break-inducing agents. However, not all HR-defective tumours respond equally well to this type of therapy. Tumour cells may acquire resistance by invoking biochemical mechanisms that reduce drug action or by acquiring additional alterations in DNA damage response pathways. A thorough understanding of these processes is important for predicting treatment response and for the development of novel treatment strategies that prevent the emergence of therapy resistant tumours. PMID- 22918417 TI - Exchange coupling in TbCu and DyCu single-molecule magnets and related lanthanide and vanadium analogs. AB - Heterometallic coordination compounds [Cu(II)(L)(C(3)H(6)O)Ln(III)(NO(3))(3)] and [V(IV)O(L)(C(3)H(6)O)Ln(III)(NO(3))(3)] (abbreviated as LnCu and LnV, respectively; H(2)L = N,N'-bis(3-methoxysalicylidene)-1,3-diamino-2,2 dimethylpropane; Ln = Gd, Tb, Dy, Ho, and Er) were synthesized, and the X-ray crystallographic analysis shows that their structures are isomorphous for each series. The single-molecule magnet behavior was observed for TbCu and DyCu, and the activation energies of magnetization reversal were 42.3(4) and 11.5(10) K, respectively. The magnetic exchange couplings in LnCu and LnV were precisely evaluated by means of combined high-frequency EPR and pulsed-field magnetization studies, to give J(Tb-Cu)/k(B)>= 3.3 K, J(Dy-Cu)/k(B) = 1.63(1) K, J(Ho-Cu)/k(B) = 1.09(2) K, and J(Er-Cu)/k(B) = 0.24(1) K. A monotonic decrease of ferromagnetic J(Ln-Cu) was found in the order of the atomic number, (64)Gd to (68)Er. The corresponding exchange parameters in LnV are smaller than those of the Cu derivatives, and J(Gd-V) was antiferromagnetic (-3.0 K determined from the magnetization jump). A possible mechanism for the exchange coupling and chemical trend is discussed. PMID- 22918418 TI - ATRA plus arsenic gets another "A" in APL. AB - In this issue of Blood, Iland et al report that the addition of arsenic trioxide during induction and consolidation can substantially reduce the amount of chemotherapy and the duration of consolidation to achieve excellent outcomes in patients with newly diagnosed acute promyelocytic leukemia (APL; see figure). PMID- 22918415 TI - Aiding and abetting roles of NOX oxidases in cellular transformation. AB - NADPH oxidases of the NADPH oxidase (NOX) family are dedicated reactive oxygen species-generating enzymes that broadly and specifically regulate redox-sensitive signalling pathways that are involved in cancer development and progression. They act at specific cellular membranes and microdomains through the activation of oncogenes and the inactivation of tumour suppressor proteins. In this Review, we discuss primary targets and redox-linked signalling systems that are influenced by NOX-derived ROS, and the biological role of NOX oxidases in the aetiology of cancer. PMID- 22918419 TI - When it comes to MRD, AML ? ALL. AB - Only the most specific main institutional affiliation is listed for Inside Blood authors, without indications of subdivisions, departments, parent institutions, or postal/geographic information. Please confirm or correct affiliation. Minimal residual disease (MRD) detection is standard of care in acute lymphoblastic leukemia (ALL),(1) but not acute myeloid leukemia (AML). In this issue of Blood, an AML trial by Loken and colleagues from the Children's Oncology Group (COG) retrospectively demonstrates clinical significance of MRD.(2) These data reaffirm that AML-MRD is unlike ALL-MRD. PMID- 22918420 TI - Second to none. AB - In this issue of Blood, Usmani et al provide important information on second primary malignancies in patients treated with thalidomide and lenalidomide in the Arkansas total therapy trials. PMID- 22918421 TI - Toward an off-the-shelf vaccine for B-cell malignancies. AB - While idiotype vaccines have shown promise for B-cell malignancies, production is cumbersome; thus, targeting a common antigen on malignant B cells using an off the-shelf approach would provide significant logistical advantages. PMID- 22918422 TI - What T cells see in WT-1. AB - The Wilms tumor protein, WT-1, is a widely recognized tumor antigen that is aberrantly expressed in myeloid and lymphoid leukemia and in this issue of Blood, Doubrovina et al report the most extensive catalog heretofore of HLA-restricted immunogenic peptides derived from WT-1, which are recognized by CD8 and CD4T cells. PMID- 22918423 TI - Allogeneic HSCT for ATL: a good start. AB - In this issue of Blood, Ishida and colleagues report the latest update on their nationwide retrospective study of allogeneic hematopoietic stem cell transplantation for adult T-cell leukemia in Japan. PMID- 22918425 TI - Flow diverters for unruptured internal carotid artery aneurysms: dangerous and not yet an alternative for conventional endovascular techniques. PMID- 22918426 TI - Cerebral hemodynamic benefits after contralateral carotid artery stenting in patients with internal carotid artery occlusion. AB - CEA contralateral to an ICA occlusion is considered a surgical risk, and CAS may be an alternative for these patients. Our goal was to examine whether CAS improves cerebral hemodynamics on the treated side and on the side of the ICA occlusion, on the basis of measurement of CBF and CVR by using SPECT. The subjects were 8 patients who underwent contralateral CAS. Resting CBF and CVR to acetazolamide were measured by using (123)I-IMP SPECT before and chronically (3-6 months) after CAS. Resting CBF was also measured immediately (<2 hours) after CAS by using (123)I-IMP SPECT. There were no significant differences in resting CBF in both hemispheres immediately after CAS. However, resting CBF and CVR both significantly increased in the chronic period in both hemispheres. Contralateral CAS in patients with ICA occlusion resulted in cerebral hemodynamic improvement on the treated side and on the side of ICA occlusion. PMID- 22918427 TI - Overwhelmed by choices. PMID- 22918428 TI - Do not brainstorm! PMID- 22918430 TI - Magnetization transfer imaging in premanifest and manifest huntington disease: a 2-year follow-up. AB - BACKGROUND AND PURPOSE: MTI is a quantitative MR imaging technique that has recently demonstrated structural integrity differences between controls and patients with HD. Potentially, MTI can be used as a biomarker for monitoring disease progression. To establish the value of MTI as a biomarker, we aimed to examine the change in these measures during the course of HD. MATERIALS AND METHODS: From the Leiden TRACK-HD study, 25 controls, 21 premanifest gene carriers, and 21 patients with manifest HD participated at baseline and during a 2-year follow-up visit. Brain segmentation of the cortical gray matter, white matter, caudate nucleus, putamen, pallidum, thalamus, amygdala, and hippocampus was performed by using the automated tools FAST and FIRST in FSL. Individual MTR values were calculated from these regions, and MTR histograms were constructed. RESULTS: In the premanifest HD group stage "far from disease onset," a significant increase in MTR peak height of the putamen was observed with time. During the manifest HD stage, neither the mean MTR nor the MTR peak height showed a significant change during a 2-year follow-up. CONCLUSIONS: MTI-derived measures are not suitable for monitoring in Huntington disease during a 2-year period because there was no decrease in structural integrity detected in any of the manifest HD groups longitudinally. The finding of increased putaminal MTR peak height in the premanifest far from disease onset group could relate to a predegenerative process, compensatory mechanisms, or aberrant development but should be interpreted with caution until future studies confirm this finding. PMID- 22918429 TI - Blood-brain barrier disruption after cardiac surgery. AB - BACKGROUND AND PURPOSE: CNS complications are often seen after heart surgery, and postsurgical disruption of the BBB may play an etiologic role. The objective of this study was to determine the prevalence of MR imaging-detected BBB disruption (HARM) and DWI lesions after cardiac surgery. MATERIALS AND METHODS: All patients had an MRI after cardiac surgery. For half the patients (group 1), we administered gadolinium 24 hours after surgery and obtained high-resolution DWI and FLAIR images 24-48 hours later. We administered gadolinium to the other half (group 2) at the time of the postoperative scan, 2-4 days after surgery. Two stroke neurologists evaluated the images. RESULTS: Of the 19 patients we studied, none had clinical evidence of a stroke or delirium at the time of the gadolinium administration or the scan, but 9 patients (47%) had HARM (67% in group 1; 30% in group 2; P = .18) and 14 patients (74%) had DWI lesions (70% in group 1; 78% in group 2; P = 1.0). Not all patients with DWI lesions had HARM, and not all patients with HARM had DWI lesions (P = .56). CONCLUSIONS: Almost half the patients undergoing cardiac surgery have evidence of HARM, and three-quarters have acute lesions on DWI after surgery. BBB disruption is more prevalent in the first 24 hours after surgery. These findings suggest that MR imaging can be used as an imaging biomarker to assess therapies that may protect the BBB in patients undergoing heart surgery. PMID- 22918431 TI - Reconstructive endovascular treatment of fusiform and dissecting basilar trunk aneurysms with flow diverters, stents, and coils. AB - BACKGROUND AND PURPOSE: Patients with fusiform basilar trunk aneurysms have a poor prognosis. Reconstructive endovascular therapy is possible with modern devices. We describe the clinical presentation, radiologic features, and clinical outcome of 13 patients with fusiform basilar trunk aneurysms treated with flow diverters, stents, and coils. MATERIALS AND METHODS: Of the 13 patients, 7 were men and 6 were women with a mean age of 59.7 years. Clinical presentation was SAH in 3 patients, mass effect on the brain stem in 4 patients, vertebral artery dissection in 1 patient, and the aneurysm was an incidental finding in 5 patients. Mean aneurysm size was 21 mm. All except 1 were large or giant aneurysms. Nine aneurysms were partially thrombosed. RESULTS: Stents were used in all 13 patients, in 2 patients with additional flow diverters and in 11 patients with additional coils. In 4 patients, 1 vertebral artery was subsequently occluded with coils to decrease flow into the aneurysm. Of 13 patients, 9 had a good outcome with adequate aneurysm occlusion and stable size on follow-up of 6 72 months. One of 3 patients who presented with SAH died of a rebleed 1 month later. One other patient died soon after treatment of in-stent thrombosis, and another patient became mute after treatment. In 2 of 3 patients who presented with symptoms of mass effect, there was improvement at a follow-up of 6-24 months. CONCLUSIONS: Reconstructive endovascular therapy of fusiform and dissecting basilar trunk aneurysms is feasible but carries substantial risks. The safety and effectiveness in relation to natural history has not yet been elucidated. PMID- 22918432 TI - The role of amyloid-beta, tau, and apolipoprotein E epsilon4 in Alzheimer disease: how is the team playing? PMID- 22918433 TI - Pulse-triggered DTI sequence with reduced FOV and coronal acquisition at 3T for the assessment of the cervical spinal cord in patients with myelitis. AB - BACKGROUND AND PURPOSE: DTI is a promising technique for imaging of the spinal cord, but the technique has susceptibility-induced artifacts. We evaluated a pulse-triggered DTI sequence with an rFOV technique and coronal acquisition for the assessment of the cervical spinal cord in patients with myelitis at 3T. MATERIALS AND METHODS: A rFOV acquisition was established by a noncoplanar application of the excitation and the refocusing pulse in conjunction with outer volume suppression. The DTI sequence was performed in the coronal plane in 12 healthy volunteers and 40 consecutive patients with myelitis. Probabilistic tractography of the posterior and lateral funiculi was performed from the C1 to C7 levels. FA, MD, aD, rD, and ratios of aD and rD were measured. RESULTS: In healthy volunteers, mean DTI indices within the whole-fiber pathways were the following: FA = 0.61, MD = 1.17 * 10(-3) mm(2)/s, aD = 1.96 * 10(-3) mm(2)/s, rD = 0.77 * 10(-3) mm(2)/s, and ratios of aD and rD = 2.5. Comparison of healthy controls and patients with myelitis identified statistically significant differences for all DTI parameters. Different patterns of myelitis, including spinal cord atrophy and active inflammatory lesions, were recognized. There was a significant correlation between clinical severity and DTI parameters. CONCLUSIONS: The present work introduces a new approach for DTI of the cervical spinal cord at 3T, enabling a quantitative follow-up of patients with myelitis. PMID- 22918434 TI - Inhibition of PrP(Sc) formation in scrapie infected N2a cells by 5,7,8-trimethyl 3,4-dihydro-2H-1,4-benzoxazine derivatives. AB - Prion diseases are fatal, neurodegenerative diseases characterized by the structural conversion of the normal, cellular prion protein, PrP (C) into an abnormally structured, aggregated and partially protease-resistant isoform, termed PrP (Sc) . Although substantial research has been directed toward development of therapeutics targeting prions, there is still no curative treatment for the disease. Benzoxazines are bicyclic heterocyclic compounds possessing several pharmaceutically important properties, including neuroprotection and reactive oxygen species scavenging. In an effort to identify novel inhibitors of prion formation, several 5,7,8-trimethyl-1,4-benzoxazine derivatives were evaluated in vitro for their effectiveness on the expression levels of normal PrP (C) and its conversion to the abnormal isoforms of PrP (Sc) in a scrapie-infected cell culture model. The most potent compound was 2-(4 methoxyphenyl)-5,7,8-trimethyl-3,4-dihydro-2H-1,4-benzoxazine, with a diminishing effect on the formation of PrP (Sc) , thus establishing a class of compounds with a promising therapeutic use against prion diseases. PMID- 22918435 TI - Prediction of people's origin from degraded DNA--presentation of SNP assays and calculation of probability. AB - The characterization of externally visible traits by DNA analysis is already an important tool when investigating ancient skeletal remains and may gain similar importance in future forensic DNA analysis. This, however, depends on the different legal regulations in the different countries. Besides eye or hair color, the population origin can provide crucial information in criminal prosecution. In this study, we present the analysis of 16 single-nucleotide polymorphisms (SNPs) combined to two robust SNaPshot assays with a detection threshold of 25-pg DNA. This assay was applied to 891 people from seven different populations (West Africa, North Africa, Turkey, Near East, Balkan states, North Europe, and Japan) with a thorough statistical evaluation. The prediction model was validated by an additional 125 individuals predominantly with an ancestry from those same regions. The specificity of these SNPs for the prediction of all population origins is very high (>90 %), but the sensitivity varied greatly (more than 90 % for West Africa, but only 25 % for the Near East). We could identify West Africans with a certainty of 100 %, and people from North Africa, the Balkan states, or North Europe nearly with the same reliability while determination of Turks or people from the Near East was rather difficult. In conclusion, the two SNaPshot assays are a powerful and reliable tool for the identification of people with an ancestry in one of the above listed populations, even from degraded DNA. PMID- 22918436 TI - The Fellows' Pelvic Research Network (FPRN) 5 years later: an update. PMID- 22918437 TI - Noble metal nanostructure both as a SERS nanotag and an analyte probe. AB - We report nanotags encapsulated in Au-Ag nanostructure that are active in surface enhanced Raman scattering. The Au-Ag nanoshells are filled with Ag via citrate reduction, entrapping label molecules in the process. The nanotags can be used for quantitative SERS measurements with the label molecules as internal reference. PMID- 22918438 TI - The critical role of catalase in prooxidant and antioxidant function of p53. AB - The tumor suppressor p53 is an important regulator of intracellular reactive oxygen species (ROS) levels, although downstream mediators of p53 remain to be elucidated. Here, we show that p53 and its downstream targets, p53-inducible ribonucleotide reductase (p53R2) and p53-inducible gene 3 (PIG3), physically and functionally interact with catalase for efficient regulation of intracellular ROS, depending on stress intensity. Under physiological conditions, the antioxidant functions of p53 are mediated by p53R2, which maintains increased catalase activity and thereby protects against endogenous ROS. After genotoxic stress, high levels of p53 and PIG3 cooperate to inhibit catalase activity, leading to a shift in the oxidant/antioxidant balance toward an oxidative status, which could augment apoptotic cell death. These results highlight the essential role of catalase in p53-mediated ROS regulation and suggest that the p53/p53R2 catalase and p53/PIG3-catalase pathways are critically involved in intracellular ROS regulation under physiological conditions and during the response to DNA damage, respectively. PMID- 22918440 TI - Activated macrophages utilize glycolytic ATP to maintain mitochondrial membrane potential and prevent apoptotic cell death. AB - This corrects the article DOI: 10.1038/cdd.2010.27. PMID- 22918439 TI - Conservation of caspase substrates across metazoans suggests hierarchical importance of signaling pathways over specific targets and cleavage site motifs in apoptosis. AB - Caspases, cysteine proteases with aspartate specificity, are key players in programmed cell death across the metazoan lineage. Hundreds of apoptotic caspase substrates have been identified in human cells. Some have been extensively characterized, revealing key functional nodes for apoptosis signaling and important drug targets in cancer. But the functional significance of most cuts remains mysterious. We set out to better understand the importance of caspase cleavage specificity in apoptosis by asking which cleavage events are conserved across metazoan model species. Using N-terminal labeling followed by mass spectrometry, we identified 257 caspase cleavage sites in mouse, 130 in Drosophila, and 50 in Caenorhabditis elegans. The large majority of the caspase cut sites identified in mouse proteins were found conserved in human orthologs. However, while many of the same proteins targeted in the more distantly related species were cleaved in human orthologs, the exact sites were often different. Furthermore, similar functional pathways are targeted by caspases in all four species. Our data suggest a model for the evolution of apoptotic caspase specificity that highlights the hierarchical importance of functional pathways over specific proteins, and proteins over their specific cleavage site motifs. PMID- 22918441 TI - Organocatalytic asymmetric epoxidation and tandem epoxidation/Passerini reaction under eco-friendly reaction conditions. AB - An eco-friendly synthesis of highly functionalized epoxides and their incorporation into an organocatalytic multicomponent approach are reported. For this, a modified class of diarylprolinol silyl ethers was designed to enable high catalytic activity in an environmentally benign solvent system. The one-pot procedure showed great efficiency in promoting stereoselective multicomponent transformations in a tandem, 'green' fashion. Because of its non-residual, efficient and selective character, this synthetic design shows promise for large scale applications in both diversity and target-oriented syntheses. PMID- 22918442 TI - A rare cause of nephrotic syndrome in a 14-year-old boy: questions. PMID- 22918445 TI - DFT studies on the structure and properties of the carbon aluminium Al3C cluster, a pseudohalogen superatom. AB - The neutral carbon aluminium cluster Al(3)C and its anion Al(3)C(-) have been investigated at the B3LYP/6-311+G(d) and BP86/6-311+G(d) levels of theory. It is suggested that the C(2v) neutral cluster Al(3)C could be considered as a pseudohalogen superatom with a smaller electron affinity than the iodine atom. The DFT calculation results confirm that, similar to the halogen atoms, the pseudohalogen superatom Al(3)C cluster could form the compounds corresponding to the dimer, salts, interhalogen compounds, oxides, acid radicals, and coordination complexes as well as superatom compounds of halogen, showing that Al(3)C has similar chemical properties to halogens and maintains its integrity in the related reactions. Based on the maintenance of integrity in the chemical assemblies [(Al(3)C)(KCAl(3))(n)](-) (n = 1-5), it could be anticipated that the neutral cluster Al(3)C holds great potential as a building block for the development of future nanostructured materials. Further, corresponding experimental verifications are invited. PMID- 22918444 TI - Impact of sepsis on the urinary level of interleukin-18 and cystatin C in critically ill neonates. AB - BACKGROUND: Urinary interleukin-18 (uIL-18) and cystatin C (uCysC) are biomarkers of acute kidney injury (AKI). We hypothesized that in non-AKI neonates, the level of uIL-18 and uCysC would be higher in those with sepsis compared to those without sepsis. The aims of this study were to determine the association between urinary biomarkers and sepsis in non-AKI critically ill neonates, and to evaluate whether uIL-18 and uCysC could serve as predictors of sepsis in this population. METHODS: The study included 111 non-AKI critically ill neonates with acute clinical deterioration suggestive of sepsis: 26 with infection, 57 without infection, and 28 were assigned to the unclassified group. Urinary samples were collected and a full sepsis screen was performed at the time of enrollment. RESULTS: The level of uIL-18, but not uCysC, was significantly elevated in non AKI septic neonates. Urinary IL-18 was an independent factor associated with sepsis assessed by multivariate analysis, had odds ratio of 1.73 (95 % CI 1.15 to 2.58, p = 0.008), and achieved the area under the receiver operating characteristic curve of 0.74 for predicting the presence of sepsis in non-AKI critically ill neonates. CONCLUSIONS: Sepsis has an impact on the level of uIL 18, but not on the uCysC in non-AKI neonates, suggesting systemic infection might influence the diagnostic value of uIL-18 to detect AKI in the general population. PMID- 22918446 TI - MINI PCNL in a pediatric population. AB - PURPOSE: We report our initial experience of MINI percutaneous nephrolithotomy (PCNL) in a pediatric population using a miniature nephroscope through a 16F metal access sheath. METHODS: All pediatric patients who underwent PCNL from August 2007 to September 2010 using a 14F miniature nephroscope through a 16F metal access sheath for renal stone extraction were evaluated. Patients' demographic details, procedural information, and posttreatment outcomes were prospectively documented. RESULTS: A total of 23 MINI PCNLs were performed on 23 kidneys of 12 patients whose ages ranged from 1.6 to 14.6 years. The median stone burden was 3.44 cm(2), and there were 11 "Staghorn" stones. The procedure was primary via a single puncture in 19 kidneys and secondary using a preexisting nephrostomy tract in 4 kidneys. Access was successful in all primary and two secondary cases, for a total of success rate of 91.3 %. Stones were fragmented using a Holmium laser and/or lithoclast, and fragments were irrigated or sequentially removed by various stone grasping devices. The mean procedural X-ray screening time and total stone extraction period were 4.5 and 109.4 min, respectively. The primary stone free rate was 83.6 %, which increased to 90.5 % after treating the residual fragments. Postoperative hydrothorax developed in one patient, which required a chest drain. Symptoms of chest infection and positive urine culture were detected in one and two patients, respectively. CONCLUSIONS: Our initial experience supports previous reports that MINI PCNL is safe and effective for the management of renal stones in children. PMID- 22918448 TI - Considerations regarding antiretroviral chemoprophylaxis in MSM. AB - PURPOSE OF REVIEW: HIV infection among MSM remains a significant issue. Data relevant to MSM populations from animal models, pharmacokinetic studies and clinical trials are summarized and challenges and potential consequences of use of preexposure prophylaxis (PrEP) by MSM are discussed. RECENT FINDINGS: Rectal simian-human immunodeficiency virus transmission in macaque models can be prevented by intermittent PrEP dosing. The Preexposure Prophylaxis Initiative (iPrEx) study found that daily oral emtricitabine-tenofovir disoproxyl fumarate (TDF/FTC) decreased HIV infection by 44% among 2499 high-risk MSM. Men with detectable levels of TDF or FTC in plasma and peripheral blood mononuclear cells experienced more than 90% protective effect, emphasizing the importance of adherence. In iPrEX and other studies, PrEP was generally safe and well tolerated. However, it appears that TDF use is associated with a small but significant decrease in mean bone mineral density. No risk compensation has been demonstrated, but this remains an area of potential concern when PrEP is used outside the setting of a placebo-controlled trial. Numerous PrEP trials in MSM are currently underway. SUMMARY: Oral FTC/TDF is effective in preventing HIV infection among MSM. Optimal PrEP agents and dosing regimens now need to be identified. Understanding the patterns of and impediments to PrEP use among MSM is vital and these should be monitored in ongoing demonstration projects and open label studies. PMID- 22918447 TI - Induction of ligand-specific PrP (C) signaling in human neuronal cells. AB - Cellular prion protein (PrP (C) ) has attracted considerable attention for its role in transmissible spongiform encephalopathies (TSEs). In spite of being a point of intense research effort critical questions still remain regarding the physiological function of PrP (C) and how these functions may change with the conversion of the protein into the infectious and pathological conformation (PrP (Sc) ). While emerging evidence suggests PrP (C/Sc) are involved in signal transduction there is little consensus on the signaling pathways associated with the normal and diseased states. The purported involvement of PrP (C) in signal transduction, and the association of TSEs with neural pathology, makes kinome analysis of human neurons an interesting and appropriate model to characterize patterns of signal transduction following activation of PrP (C) by two commonly employed experimental ligands; antibody-induced dimerization by 6H4 and the amino acids 106-126 PrP peptide fragment (PrP 106-126). Analysis of the induced kinome responses reveals distinct patterns of signaling activity following each treatment. Specifically, stimulation of human neurons with the 6H4 antibody results in alterations in mitogen activated protein kinase (MAPK) signaling pathways while the 106-126 peptide activates growth factor related signaling pathways including vascular endothelial growth factor (VEGF) signaling and the phosphoinositide-3 kinase (PI3K) pathway. These pathways were validated through independent functional assays. Collectively these results indicate that stimulation of PrP (C) with distinct ligands, even within the same cell type, results in unique patterns of signaling. While this investigation highlights the apparent functional versatility of PrP (C) as a signaling molecule and may offer insight into cellular mechanisms of TSE pathology it also emphasizes the potential dangers associated with attributing activation of specific intracellular events to particular receptors through artificial models of receptor activation. PMID- 22918449 TI - Current status of topical antiretroviral chemoprophylaxis. AB - PURPOSE OF REVIEW: Recent studies suggest that the vaginal delivery of antiretroviral (ARV) agents - such as tenofovir, dapivirine and UC781 - may be a promising way to reduce the high rates of HIV infection among women in developing countries. This review examines these developments. RECENT FINDINGS: The Microbicide Trials Network 003 study, a large phase IIb trial, was unable to show that daily dosing with 1% tenofovir vaginal gel was effective for HIV prevention. Nevertheless, preclinical and early-phase clinical trials suggest that ARV drugs formulated in vaginal gels, rings, films, tablets and diaphragms - could be effective for HIV chemoprophylaxis. SUMMARY: Investigations of topical chemoprophylaxis methods have seen mixed results in the past 12-18 months. Product adherence may prove to be one of the field's greatest challenges. Phase II and III trials continue to explore different dosing strategies for topical products that contain one or more ARV agents. PMID- 22918450 TI - Diorganotin(IV) 2-pyridyl selenolates: synthesis, structures and their utility as molecular precursors for the preparation of tin selenide nanocrystals and thin films. AB - Reactions of R(2)SnCl(2) (R = Me, Et, (t)Bu) with NaSeC(5)H(3)(R'-3)N (R' = H or Me) gave complexes of the composition [R(2)Sn{2-SeC(5)H(3)(R'-3)N)}(2)], which on treatment with R(2)SnCl(2) afforded chloro complexes, [R(2)Sn{2-SeC(5)H(3)(R' 3)N}Cl]. These complexes were characterized by elemental analyses and UV-vis and NMR ((1)H, (13)C, (77)Se and (119)Sn) spectroscopy. The crystal structures of [R(2)Sn(SeC(5)H(4)N)(2)] (R = Me or (t)Bu) and [Me(2)Sn{2-SeC(5)H(3)(Me-3)N}Cl] were determined by single crystal X-ray diffraction. The tin atom in the former two structures acquires a skew trapezoidal configuration, whereas in the latter it adopts a distorted trigonal bipyramidal geometry. Thermolysis of [R(2)Sn(2 SeC(5)H(4)N)(2)] (R = Me, Et or (t)Bu) and [Et(2)Sn{2-SeC(5)H(3)(Me-3)N}(2)] in oleylamine (OA) afforded tin selenide nanostructures. Thin films of SnSe were deposited on glass and silicon substrates by the AACVD of [(t)Bu(2)Sn(2 SeC(5)H(4)N)(2)]. The nanostructures and thin films were characterized by XRD, EDX, AFM, SEM, TEM and SAED techniques. The photovoltaic properties of the thin films have been evaluated. PMID- 22918451 TI - Protein kinase cdelta in apoptosis: a brief overview. AB - Protein kinase C-delta (PKCdelta), a member of the lipid-regulated serine/threonine PKC family, has been implicated in a wide range of important cellular processes. In the past decade, the critical role of PKCdelta in the regulation of both intrinsic and extrinsic apoptosis pathways has been widely explored. In most cases, over-expression or activation of PKCdelta results in the induction of apoptosis. The phosphorylations and multiple cell organelle translocations of PKCdelta initiate apoptosis by targeting multiple downstream effectors. During apoptosis, PKCdelta is proteolytically cleaved by caspase-3 to generate a constitutively activated catalytic fragment, which amplifies apoptosis cascades in nucleus and mitochondria. However, PKCdelta also exerts its anti apoptotic and pro-survival roles in some cases. Therefore, the complicated role of PKCdelta in apoptosis appears to be stimulus and cell type dependent. This review is mainly focused on how PKCdelta gets activated in diverse ways in response to apoptotic signals and how PKCdelta targets different downstream regulators to sponsor or restrain apoptosis induction. PMID- 22918452 TI - Monitoring of volatile organic compounds using a single tin dioxide sensor. AB - The paper describes a new and simple method for monitoring volatile organic compounds resulting from a specific industrial indoor process. The method is based on the characteristics of tin dioxide sensors to be sensitive and non selective to a large variety of gases. We use these characteristics to determine an equivalent concentration of the volatile organic compound mixture, a method which has not been used in other studies or experiments. The value of the equivalent concentration shows the accuracy of the process and the air purity of an industrial environment. A system including a tin dioxide sensor with its conditioning circuits and a temperature compensation circuit, a microcontroller and a graphical interface, was built in order to obtain a versatile, online and user friendly monitoring tool. The system was used for monitoring the volatile organic compound concentrations resulting from leather finishing processes in the Romanian industry. PMID- 22918453 TI - Amyotrophic lateral sclerosis/frontotemporal dementia with predominant manifestations of obsessive-compulsive disorder associated to GGGGCC expansion of the c9orf72 gene. PMID- 22918454 TI - Devastating aquaporin-4 and HTLV-1-associated necrotizing encephalopathy. PMID- 22918455 TI - Neuroimaging. PMID- 22918456 TI - Knockout of fatty acid desaturase genes in Pichia pastoris GS115 and its effect on the fatty acid biosynthesis and physiological consequences. AB - Unsaturated fatty acids (UFAs), including oleic acid (OA, C18:1n-9), linoleic acid (LA, C18:2n-6) and alpha-linolenic acid (ALA, C18:3n-3), are major components of membrane lipids in Pichia pastoris GS115. In order to clarify the biosynthesis pathway of UFAs on the molecular level and investigate their possible roles in growth and development of this strain, we here report modified strains with disrupted desaturase gene by homologous recombination. Gas chromatography analysis of fatty acid composition in the corresponding mutants confirmed that ?(12)-desaturase encoded by Fad12 was responsible for the formation of LA, and ALA was synthesized by ?(15)-desaturase encoded by Fad15. Simultaneous deletion of Fad9A and Fad9B was lethal and supplementation of OA could restore growth, indicating that possibly both Fad9A and Fad9B encoded ?(9) desaturase that converted SA into OA. Phenotypic analysis demonstrated that wild type and Fad15 mutant grew at almost the same rate, Fad12 mutant grew much slower than these two strains. Moreover, OA was positively correlated to cold tolerance and ethanol tolerance of GS115, whereas LA and ALA did not affect cold tolerance and ethanol tolerance of it. In addition, we showed that tolerance of GS115 to high concentration of methanol was independent of these three UFAs. PMID- 22918458 TI - Immune regulation: Local government. PMID- 22918457 TI - Pseudomonas nitritireducens sp. nov., a nitrite reduction bacterium isolated from wheat soil. AB - A Gram-negative, non-mobile, polar single flagellum, rod-shaped bacterium WZBFD3 5A2(T) was isolated from a wheat soil subjected to herbicides for several years. Cells of strain WZBFD3-5A2(T) grow optimally on Luria-Bertani agar medium at 30 degrees C in the presence of 0-4.0 % (w/v) NaCl and pH 8.0. 16S rRNA gene sequence analysis revealed that strain WZBFD3-5A2(T) belongs to the genus Pseudomonas. Physiological and biochemical tests supported the phylogenetic affiliation. Strain WZBFD3-5A2(T) is closely related to Pseudomonas nitroreducens IAM1439(T), sharing 99.7 % sequence similarity. DNA-DNA hybridization experiments between the two strains showed only moderate reassociation similarity (33.92 +/- 1.0 %). The DNA G+C content is 62.0 mol%. The predominant respiratory quinine is Q-9. The major cellular fatty acids present are C(16:0) (28.55 %), C(16:1omega6c) or C(16:1omega7c) (20.94 %), C(18:1omega7c) (17.21 %) and C(18:0) (13.73 %). The isolate is distinguishable from other related members of the genus Pseudomonas on the basis of phenotypic and biochemical characteristics. From the genotypic, chemotaxonomic and phenotypic data, it is evident that strain WZBFD3-5A2(T) represents a novel species of the genus Pseudomonas, for which the name Pseudomonas nitritereducens sp. nov. is proposed. The type strain is WZBFD3 5A2(T) (=CGMCC 1.10702(T) = LMG 25966(T)). PMID- 22918459 TI - Antiviral immunity: LGP2 rigs CD8+ T cells for survival. PMID- 22918460 TI - Antiviral immunity: Deconstructing CD4+ T cell memory. PMID- 22918461 TI - Tumour immunology: TIM3 suppresses antitumour DCs. PMID- 22918462 TI - Viral pathogenesis: HIV hitchhikes on migratory T cells. PMID- 22918466 TI - The impact of differential antiviral immunity in children and adults. AB - The course of immune maturation has evolved to favour survival at each stage of development in early life. Fetal and neonatal immune adaptations facilitate intrauterine survival and provide early postnatal protection against extracellular pathogens, but they leave infants susceptible to intracellular pathogens such as viruses that are acquired perinatally. This Review focuses on three such pathogens--HIV, hepatitis B virus and cytomegalovirus--and relates the differential impact of these infections in infants and adults to the antiviral immunity that is generated at different ages. A better understanding of age specific antiviral immunity may inform the development of integrated prevention, treatment and vaccine strategies to minimize the global disease burden resulting from these infections. PMID- 22918469 TI - Microspheres as resistive elements in a check valve for low pressure and low flow rate conditions. AB - In this paper we describe a microsphere-based check valve integrated with a micropump. The check valve uses O20 MUm polystyrene microspheres to rectify flow in low pressure and low flow rate applications (Re < 1). The microspheres form a porous medium in the check valve increasing fluidic resistance based on the direction of flow. Three check valve designs were fabricated and characterized to study the microspheres' effectiveness as resistive elements. A maximum diodicity (ratio of flow in the forward and reverse direction) of 18 was achieved. The pumping system can deliver a minimum flow volume of 0.25 MUL and a maximum flow volume of 1.26 MUL under an applied pressure of 0.2 kPa and 1 kPa, respectively. A proof-of-concept study was conducted using a pharmaceutical agent, docetaxel (DTX), as a sample drug showing the microsphere check valve's ability to limit diffusion from the micropump. The proposed check valve and pumping concept shows strong potential for implantable drug delivery applications with low flow rate requirements. PMID- 22918468 TI - Why must T cells be cross-reactive? AB - Clonal selection theory proposed that individual T cells are specific for a single peptide-MHC antigen. However, the repertoire of alphabeta T cell receptors (TCRs) is dwarfed by the vast array of potential foreign peptide-MHC complexes, and a comprehensive system requires each T cell to recognize numerous peptides and thus be cross-reactive. This compromise on specificity has profound implications because the chance of any natural peptide-MHC ligand being an optimal fit for its cognate TCR is small, as there will almost always be more potent agonists. Furthermore, any TCR raised against a specific peptide-MHC complex in vivo can only be the best available solution from the naive T cell pool and is unlikely to be the best possible solution from the substantially greater number of TCRs that could theoretically be produced. This 'systems view' of TCR recognition provides a plausible cause for autoimmune disease and substantial scope for multiple therapeutic interventions. PMID- 22918470 TI - Organocatalytic deprotonative functionalization of C(sp2)-H and C(sp3)-H bonds using in situ generated onium amide bases. AB - Onium amides, generated in situ from the combination of aminosilanes and onium fluorides (R(4)PF, R(4)NF), are employed for the first time as bases for catalytic deprotonative functionalization of C(sp(2))-H and activated C(sp(3))-H bonds under mild conditions. PMID- 22918467 TI - FOXO transcription factors throughout T cell biology. AB - The outcome of an infection with any given pathogen varies according to the dosage and route of infection, but, in addition, the physiological state of the host can determine the efficacy of clearance, the severity of infection and the extent of immunopathology. Here we propose that the forkhead box O (FOXO) transcription factor family--which is central to the integration of growth factor signalling, oxidative stress and inflammation--provides connections between physical well-being and the form and magnitude of an immune response. We present a case that FOXO transcription factors guide T cell differentiation and function in a context-driven manner, and might provide a link between metabolism and immunity. PMID- 22918472 TI - Human positive coactivator 4 is a potential novel therapeutic target in non-small cell lung cancer. AB - Transcriptional positive coactivator 4 (PC4) is a multifunctional nuclear protein that has important roles in DNA transcription, replication, repair and heterochromatinization. However, the role of PC4 in cancer remains to be clarified. Several studies propose that PC4 may act as a putative tumor suppressor. Here, we demonstrate for the first time that PC4 may represent a potential therapeutic target in non-small cell lung cancer (NSCLC). PC4 protein expression is significantly upregulated in NSCLC carcinoma tissues compared with their adjacent noncancerous counterparts as shown by immunohistochemical staining and western blotting in 104 pairs of formalin-fixed human NSCLC specimens and 6 fresh NSCLC samples. Knockdown of PC4 expression by sequence-specific small interfering RNA (siRNA) in human NSCLC cells (A549, H460 and H358) significantly inhibits the growth of cancer cells by the induction of cell cycle arrest and the increase of cell apoptosis in vitro. Interrupting the PC4 signaling pathway by injection of the PC4 siRNA liposome complex produced an effective regression of pre-established A549 cell xenografts in mice through growth inhibition and increased apoptosis. These results indicated that PC4 could be an attractive new therapeutic target for the treatment of NSCLC. PMID- 22918471 TI - A non-oncogenic HPV 16 E6/E7 vaccine enhances treatment of HPV expressing tumors. AB - Human papillomaviruses (HPVs) are the causative factor for >90% of cervical cancers and 25% of head and neck cancers. The incidence of HPV positive (+) head and neck squamous cell carcinomas has greatly increased in the last 30 years. E6 and E7 are the two key viral oncoproteins that induce and propagate cellular transformation. An immune response generated during cisplatin/radiation therapy improves tumor clearance of HPV(+) cancers. Augmenting this induced response during therapy with an adenoviral HPV16 E6/E7 vaccine improves long-term survival in pre-clinical models. Here, we describe the generation of an HPV16 E6/E7 construct, which contains mutations that render E6/E7 non-oncogenic, while preserving antigenicity. These mutations do not allow E6/E7 to degrade p53, pRb, PTPN13, or activate telomerase. Non-oncogenic E6/E7 (E6(Delta)/E7(Delta)) expressed as a stable integrant, or in the [E1-, E2b-] adenovirus, lacks the ability to transform human cells while retaining the ability to induce an HPV specific immune response. Moreover, E6(Delta)/E7(Delta) plus chemotherapy/radiation statistically enhances clearance of established HPV(+) cancer in vivo. PMID- 22918473 TI - Effect of silencing PARG in human colon carcinoma LoVo cells on the ability of HUVEC migration and proliferation. AB - Our aim was to investigate the influence of silencing poly-(ADP ribose)glycohydrolase (PARG) in human colon carcinoma LoVo cells on the ability of human umbilical vein endothelial cell (HUVEC) migration, proliferation and its possible mechanisms. PARG mRNA expression was detected by reverse transcriptase (RT) and real-time-PCR. PARG, poly-(ADP-ribose)polymerase (PARP), p38, p-p38, extracellular signal-regulated kinase (ERK), p-ERK, nuclear factor (NF)-kappaB, phosphorylated IkappaBalpha (p-IkappaBalpha), vascular endothelial growth factor (VEGF), basic fibroblast growth factor (b-FGF), intercellular cell adhesion molecule (ICAM)-1 and matrix metalloproteinases (MMP)-9 expressions were detected by western blot. The influence of PARG-short hairpin (sh)RNA on the ability of HUVEC migration and proliferation were observed by transwell migration and Counting Kit-8 (CCK-8) assay. Both RT-PCR and western blot results showed that the expression of PARG in PARG-shRNA cells was decreased and expressions of PARP, p38, p-p38, ERK, p-ERK, NF-kappaB, p-IkappaBalpha, VEGF, b-FGF, ICAM-1 and MMP-9 in those cells were lower than that in the untransfected and control-shRNA groups (P<0.05). Migration assay showed that migratory inhibition rate for HUVEC was decreased (55.23%) in cocultured PARG-shRNA cells; moreover, CCK-8 assay showed that the proliferation of HUVECs cultured with the supernatant of PARG-shRNA cells was also comparatively lower. Hence, concluding that PARG silencing could inhibit the ability of HUVEC migration and proliferation by downregulating the activity of NF-kappaB in LoVo cells that in turn decreases angiogenic factors such as VEGF, b-FGF, ICAM-1, MMP-9, as well as phosphorylation of p38 and ERK. PMID- 22918474 TI - Morphometry and localization of the temporal transverse Heschl's gyrus in magnetic resonance imaging: a guide for cortical stimulation of chronic tinnitus. AB - PURPOSE: Subjective tinnitus is considered a phantom auditory phenomenon. Recent studies show that electrical or magnetic stimulation of the cortex can alleviate some tinnitus. The usual target of the stimulation is the primary auditory cortex (PAC) on Heschl's gyrus (HG). The objective of this study was to specify the anatomy of HG by magnetic resonance imaging (MRI). METHODS: Cerebral MRI of 60 patients with chronic tinnitus, carried out before neuronavigated repetitive transcranial magnetic stimulation targeting the auditory cortex, were included. 3D-T1 MRI was reformatted in Talairach-Tournoux's stereotactic space, then the following steps were performed: morphometry of HG, localization of the probabilistic center of the PAC (pcPAC) chosen at the junction between the medial third and the lateral two-thirds of HG, relative to external and cortical landmarks, and identification of its coordinates relative to the bicommissural line (AC-PC). RESULTS: In relation to external landmarks, the pcPAC was identified around 5 cm above the root of the helix of the ear in the direction of a point on the vertex located 4 cm behind the coronal suture, for both sides. In Talairach-Tournoux's stereotactic space with the anterior commissure as the origin, the pcPAC coordinates were x = 43, y = -20, z = 6.8 on the right side, and x = -42.5, y = -21.5, and z = 6.5 on the left. Probabilistic maps of the presence of HG pointed to a relative contraction of data in space, despite inter- and intraindividual differences. CONCLUSION: The choice of our stimulation target was established in the middle of the theoretical position of the PAC. MRI allows a reliable identification of the target structure. PMID- 22918477 TI - Learning from paediatric palliative care: lessons for adult practice. PMID- 22918475 TI - 3D CBCT anatomy of the pterygopalatine fossa. AB - The anatomy of the pterygopalatine fossa keeps a traditional level and is viewed as constant, even though a series of structures neighboring the fossa are known to present individual variations. We aimed to evaluate on 3D volume renderizations the anatomical variables of the pterygopalatine fossa, as related to the variable pneumatization patterns of the bones surrounding the fossa. The study was performed retrospectively on cone beam computed tomography (CBCT) scans of 100 patients. The pterygopalatine fossa was divided into an upper (orbital) and a lower (pterygomaxillary) floor; the medial compartment of the orbital floor lodges the pterygopalatine ganglion. The pneumatization patterns of the pterygopalatine fossa orbital floor walls were variable: (a) the posterior wall pneumatization pattern was determined in 89.5 % by recesses of the sphenoidal sinus related to the maxillary nerve and pterygoid canals; (b) the upper continuation of the pterygopalatine fossa with the orbital apex was narrowed in 79.5 % by ethmoid air cells and/or a maxillary recess of the sphenoidal sinus; (c) according to its pneumatization pattern, the anterior wall of the pterygopalatine fossa was a maxillary (40.5 %), maxillo-ethmoidal (46.5 %), or maxillo-sphenoidal (13 %) wall. The logistic regression models showed that the maxillo-ethmoidal type of pterygopalatine fossa anterior wall was significantly associated with a sphenoidal sinus only expanded above the pterygoid canal and a spheno-ethmoidal upper wall. The pterygopalatine fossa viewed as an intersinus space is related to variable pneumatization patterns which can be accurately identified by CBCT and 3DVR studies, for anatomic and preoperatory purposes. PMID- 22918478 TI - A case of possible glossitis in a patient with non small cell carcinoma of the lung secondary to levomepromazine. PMID- 22918479 TI - Blood transfusions in a day hospice setting. PMID- 22918480 TI - Sector-wide approach to phase III studies. PMID- 22918481 TI - Home-monitoring of oral anticoagulation vs. dabigatran. An indirect comparison. AB - Oral anticoagulation with vitamin k antagonists (VKAs) requires regular testing and dose adjustment. Home-monitoring (self-testing or self-management) is more effective than usual management. Dabigatran, does not require dose-adjustment and appears to be more effective at reducing the risk of stroke with similar risks of bleeding in patients with atrial fibrillation (AF). Dabigatran, however, has not been compared to the home-monitoring. It was the objective to evaluate the efficacy of dabigatran compared with home-monitoring of oral anticoagulation with VKAs. Randomised controlled trials (RCTs) comparing usual management of oral anticoagulation with home-monitoring, dabigatran with usual management, and RCTs comparing dabigatran with home-monitoring and including patient-important outcomes (thromboembolic events, death and major bleeding) were eligible. For our direct comparison we calculated pooled relative risks (RRs) using the Mantzel Haenzel random effect model. For the indirect comparison we estimated lnRRs and back transformed to RR. We evaluated the quality of the evidence with the GRADE system. Dabigatran, compared with warfarin, was associated with lower rates of stroke or thromboembolism and systemic embolism but similar rates of major haemorrhage and death. Dabigatran 150 mg also increased non-significantly the rate of myocardial infarction. The quality of the evidence was high. Our indirect comparison of home-monitoring of oral anticoagulation versus dabigatran showed no convincing differences in the risk of thromboembolism, death or major bleeding. The estimates for self-management vs. dabigatran showed stronger but still non significant trends. The quality of the evidence was low. In conclusion, the indirect comparison of home monitoring of oral anticoagulation with dabigatran suggests that the treatments have similar impact on thrombosis, bleeding and death. However, the confidence in the estimate of effect is low to very low. Our analyses contrast with the available comparison of dabigatran with conventional warfarin monitoring. PMID- 22918482 TI - Organic-inorganic hybrid materials based on iron(III)-polyoxotungstates and 1 butyl-3-methylimidazolium cations. AB - The iron(III) MU-oxo bridged dimeric polyoxometalate [(PW(11)O(39)Fe)(2)O](10-) was isolated by reacting the transition metal monosubstituted Keggin anion [PW(11)O(39)Fe(H(2)O)](4-) and the ionic liquid 1-butyl-3-methylimidazolium bromide, (Bmim)Br, at pH 5.5. The crystal structure of (Bmim)(10)[(PW(11)O(39)Fe)(2)O].0.5H(2)O (1) (monoclinic, space group P2(1)/n, Z = 4) was determined by single crystal X-ray diffraction. By changing the reaction conditions, (Bmim)(4)[PW(11)O(39)Fe(H(2)O)].H(2)O (2) was obtained, whilst the reaction between the Bmim(+) cation and the heteropolyanion [SiW(11)O(39)Fe(H(2)O](5-), in the pH conditions used for 1, afforded (Bmim)(5)[SiW(11)O(39)Fe(H(2)O)].4H(2)O (3). The compounds were characterized by spectroscopic techniques, thermal analysis, cyclic voltammetry, magnetic measurements and mass spectrometry. This study contributes to the understanding of iron MU-oxo dimer formation in polyoxometalate chemistry and calls attention to the influence of the counter-cations on the stability and formation of compound 1. The combination of the cationic part of ionic liquids and iron substituted polyoxotungstates is predicted to lead to new materials with interest to catalysis, electrocatalysis and ionic liquid based nanocomposites. PMID- 22918485 TI - QM/MM non-adiabatic decay dynamics of formamide in polar and non-polar solvents. AB - Non-adiabatic on-the-fly dynamics simulations of the photodynamics of formamide in water and n-hexane were performed using a QM/MM approach. It was shown that steric restrictions imposed by the solvent cage do not have an influence on the initial motion which leads to the lowest energy conical intersection seam. The initial deactivation in water is faster than in n-hexane and in the gas phase. However, most of the formamide molecules in water do not reach the ground state. The reason for the deactivation inefficiency in water is traced back to a decrease of close CO...HOH and NH...OH(2) contacts which fall in the range of hydrogen bonds. The energy deposition into H-bond breaking events leaves molecules with less energy for surmounting the CN dissociation barrier. In both solvents, after hopping to the ground state, the solvent cage keeps the HCO and NH(2) fragments or CO and NH(3) products in close proximity. Consequently, the number of trajectories where fast recombination happens is augmented with delayed recombinations that start when the dissociation fragments hit the cage wall and return back. The hot ground state formamide is formed in an internal conversion process identical to the path leading to CN photodissociation. In the case of aqueous formamide, good agreement with experimental results is achieved by combining dynamics simulations starting from the S(1) and the S(2) excited states collecting high and low energy trajectories, respectively. PMID- 22918483 TI - RNA recognition by double-stranded RNA binding domains: a matter of shape and sequence. AB - The double-stranded RNA binding domain (dsRBD) is a small protein domain of 65-70 amino acids adopting an alphabetabetabetaalpha fold, whose central property is to bind to double-stranded RNA (dsRNA). This domain is present in proteins implicated in many aspects of cellular life, including antiviral response, RNA editing, RNA processing, RNA transport and, last but not least, RNA silencing. Even though proteins containing dsRBDs can bind to very specific dsRNA targets in vivo, the binding of dsRBDs to dsRNA is commonly believed to be shape-dependent rather than sequence-specific. Interestingly, recent structural information on dsRNA recognition by dsRBDs opens the possibility that this domain performs a direct readout of RNA sequence in the minor groove, allowing a global reconsideration of the principles describing dsRNA recognition by dsRBDs. We review in this article the current structural and molecular knowledge on dsRBDs, emphasizing the intricate relationship between the amino acid sequence, the structure of the domain and its RNA recognition capacity. We especially focus on the molecular determinants of dsRNA recognition and describe how sequence discrimination can be achieved by this type of domain. PMID- 22918486 TI - Amyotrophic lateral sclerosis. AB - PURPOSE OF REVIEW: The field of amyotrophic lateral sclerosis (ALS) has seen a number of remarkable advances during recent years that will be summarized in this review. RECENT FINDINGS: In particular, the progress in the molecular neuropathology with the discovery of pathogenic mutations in TAR DNA binding protein (TARDBP), fused in sarcoma (FUS), ubiquilin2 (UBQLN2) and most recently C9ORF72 (abbreviation for the open reading frame 72 on chromosome 9) has further substantiated the - clinically temporarily forgotten - relation of classic ALS to frontotemporal degeneration (FTD). Also, major progress has been made by the discovery of genes relevant for the disease, and pathogenetic concepts have been suggested which imply that not one, but multiple genetic and cell biological hits are involved in the causation of the disease. Progress in interventional therapies has remained poor; important recent examples are the failure of the interventional lithium and pioglitazone trials. However, a study of a third interventional compound - dexpramipexol - raises substantial hopes that the class of chemicals originally represented by riluzole - benzothiazoles - may provide additional therapeutic progress for ALS patients. SUMMARY: Tremendous progress has been made in the field of ALS based on recent neuropathological and genetic discoveries. Moreover, the role of metabolism and nutrition in the pathogenesis of the disease is debated and may potentially serve as a future therapeutic target. For the facilitation and cost reduction of clinical trials, the development and international standardization of disease-specific 'wet' and 'dry' biomarkers is essential. PMID- 22918484 TI - Connexin 43 a check-point component of cell proliferation implicated in a wide range of human testis diseases. AB - Gap junction channels link cytoplasms of adjacent cells. Connexins, their constitutive proteins, are essential in cell homeostasis and are implicated in numerous physiological processes. Spermatogenesis is a sophisticated model of germ cell proliferation, differentiation, survival, and apoptosis, in which a connexin isotype, connexin 43, plays a crucial role as evidenced by genomic approaches based on gene deletion. The balance between cell proliferation/differentiation/apoptosis is a prerequisite for maintaining levels of spermatozoa essential for fertility and for limiting anarchic cell proliferation, a major risk of testis tumor. The present review highlights the emerging role of connexins in testis pathogenesis, focusing specifically on two intimately interconnected human testicular diseases (azoospermia with impaired spermatogenesis and testicular germ cell tumors), whose incidence increased during the last decades. This work proposes connexin 43 as a potential cancer diagnostic and prognostic marker, as well as a promising therapeutic target for testicular diseases. PMID- 22918487 TI - The vasculitic neuropathies: an update. AB - PURPOSE OF REVIEW: Vasculitic neuropathy is a heterogeneous disorder that usually occurs in systemic diseases, but less commonly appears as nonsystemic vasculitic neuropathy (NSVN). This review is intended to highlight recent developments in the field of vasculitic neuropathies. RECENT FINDINGS: A Peripheral Nerve Society guideline provides data-driven consensus recommendation on classification of vasculitic neuropathies and diagnosis/treatment of NSVN. NSVN is sometimes accompanied by subclinical inflammation of adjacent skin. Amyotrophic lateral sclerosis with sensory involvement can mimic NSVN. Systemic vasculitides with neuropathy include polyarteritis nodosa, microscopic polyangiitis (MPA), rheumatoid vasculitis, Churg-Strauss syndrome (CSS), and hepatitis C-related mixed cryoglobulinemic vasculitis (MCV). At autopsy, MPA affects limb nerves diffusely, with maximal damage in proximal/middle segments. CSS can be accompanied by antineutrophil cytoplasmic antibodies (ANCAs), but most patients with neuropathy lack ANCAs. Cryoglobulinemic neuropathies are usually caused by vasculitis, irrespective of phenotype. Two randomized trials revealed rituximab to be noninferior to cyclophosphamide for inducing remission in ANCA-associated vasculitis. Many reports also document efficacy of rituximab in MCV. SUMMARY: Consensus guidelines on NSVN should be evaluated prospectively. MPA-associated vasculitic neuropathy results from vasculitic lesions distributed diffusely throughout peripheral extremity nerves. Rituximab is effective for ANCA associated and cryoglobulinemic vasculitis with neuropathy. PMID- 22918488 TI - Stem cell therapies for muscle disorders. AB - PURPOSE OF REVIEW: This review focuses on stem cell-based therapies to treat skeletal muscle disorders, with a special emphasis on muscular dystrophies. RECENT FINDINGS: We briefly review previous attempts at cell therapy by the use of donor myoblasts, explaining the likely reasons for the poor clinical results; we then describe the use of the same cells in current promising trials for localized treatments of different diseases of skeletal muscle. Moreover, we discuss important novel findings on muscle stem/progenitor cell biology and their promise for future clinical translation. Preclinical and clinical applications of novel myogenic stem/progenitor cells are also described. SUMMARY: We summarize several ongoing clinical trials for different muscle disorders and the advances in the understanding of the biology of the myogenic progenitors used in such trials. On the basis of the currently available information, a prediction of developments in the field is proposed. PMID- 22918489 TI - Isolation and characterization of two new non-hemorrhagic metalloproteinases with fibrinogenolytic activity from the mapanare (Bothrops colombiensis) venom. AB - Colombienases are acidic, low molecular weight metalloproteinases (Mr of 23,074.31 Da colombienase-1 and 23,078.80 Da colombienase-2; pI of 6.0 and 6.2, respectively) isolated from Bothrops colombiensis snake venom. The chromatographic profile in RP-HPLC and its partial sequence confirmed its high homogeneity. Both colombienases present fibrino(geno)lytic activity, but did not show any hemorrhagic, amidolytic, plasminogen activator or coagulant activities, and no effect on platelet aggregation induced by collagen or ADP. Both enzymes were strongly active on fibrinogen Aalpha chains followed by the Bbeta chains, and colombienases-2, at high doses, also degraded the gamma chains. This activity was stable at temperatures ranging between 4 and 37 degrees C, with a maximum activity at 25 degrees C, and at pHs between 7 and 9. The homology demonstrated by the comparison of sequences, with zinc-dependent metalloproteinases, as well as the metal chelant effects on, confirmed that the colombienases were metalloproteinases, particularly to alpha-fibrinogenases belonging to the P-I class of SVPMs (20-30 kDa), which contain only the single-domain proteins. The biological characteristics of the colombienases confer a therapeutic potential, since they contain a high fibrino(geno)lytic activity, devoid of hemorrhagic activity. These metalloproteinases might be explored as thrombolytic agents given that they dissolve fibrin clots or prevent their formation. PMID- 22918490 TI - Microfluidic evaporator for on-chip sample concentration. AB - We present a simple technique for the concentration of liquid samples in microfluidic devices applicable for single or multiple-phase configurations. The strategy consists of capturing the sample of interest within microfluidic traps and breaking its continuity by the introduction of a gas phase, which is also used to evaporate it. PMID- 22918491 TI - Response to Schwerla. PMID- 22918492 TI - Biosimilars in rheumatology: a view from Latin America. PMID- 22918493 TI - Localized, single-organ vasculitis: clinical presentation and management. AB - The term vasculitis usually evokes a systemic disease with catastrophic outcomes; however, vasculitides may also present in a localized form, with a better prognosis when compared with their systemic counterpart. In order to avoid confusion and facilitate classification, the term single-organ vasculitis (SOV) has been proposed. Remarkably, current criteria for the classification of the vasculitis do not include the SOV term, due in part to the lack of appropriate definitions, since most data come from case series; moreover, the scarce information available is also extremely heterogeneous. This review focuses on the epidemiology, clinical course, prognosis, and suggested treatment of the SOV, with emphasis in the most recent information available. PMID- 22918494 TI - Response to 'An economic comparison of hospital-based and community-based glaucoma clinics'. PMID- 22918496 TI - Sample size calculations: should the emperor's clothes be off the peg or made to measure? PMID- 22918497 TI - Fight to tackle unhealthy lifestyles has widened gap in health inequalities. PMID- 22918498 TI - On the ligand binding profile and desensitization of plant ionotropic glutamate receptor (iGluR)-like channels functioning in MAMP-triggered Ca2+ influx. AB - The generation of intracellular microbe-associated molecular pattern (MAMP) triggered Ca2+ transients was recently demonstrated to involve ionotropic Glutamate Receptor (iGluR)-like channels in Arabidopsis and tobacco. Here we elaborate on our previous findings and refine our insights in the putative agonist binding profile and potential mode of desensitization of MAMP-activated plant iGluRs. Based on results from pharmacological inhibition and desensitization experiments, we propose that plant iGluR complexes responsible for the MAMP-triggered Ca2+ signature have a binding profile that combines the specificities of mammalian NMDA-and non-NMDA types of iGluRs, possibly reflecting the evolutionary history of plant and animal iGluRs. We further hypothesize that, analogous to the mammalian NMDA-NR1 receptor, desensitization of plant iGluR-like channels might involve binding of the ubiquitous Ca2+ sensor calmodulin to a cytoplasmic C-terminal domain. PMID- 22918499 TI - Methyl jasmonate is transported to distal leaves via vascular process metabolizing itself into JA-Ile and triggering VOCs emission as defensive metabolites. AB - Plants have developed multifaceted defensive systems against adverse environmental factors. One such recognized system is the production of metabolites in plants. Jasmonic acid (JA) and its metabolite methyl jasmonate (MeJA) are known to play key roles in metabolites production. The role of MeJA as a mobile signal has been established in Arabidopsis and Solanaceae plants. However, it remains largely unclear how MeJA-based signaling is organized via its elicited metabolites. Here, we investigated the signaling ability of MeJA by means of vascular transport using Achyranthes bidentata as an experimental plant. Results showed that MeJA was transported and essentially metabolized into its active form JA-Ile in the distal undamaged leaves accompanied by emission of volatile organic compounds. Results presented and discussed therein provide convincing evidence that MeJA acts as a transportable inter-cellular mobile compound in plants self-defense scheme. PMID- 22918500 TI - Pectate chemistry links cell expansion to wall deposition in Chara corallina. AB - Pectate (polygalacturonic acid) acts as a chelator to bind calcium and form cross links that hold adjacent pectate polymers and thus plant cell walls together. When under tension from turgor pressure in the cell, the cross-links appear to distort and weaken. New pectate supplied by the cytoplasm is undistorted and removes wall calcium preferentially from the weakened bonds, loosening the wall and accelerating cell expansion. The new pectate now containing the removed calcium can bind to the wall, strengthening it and linking expansion to wall deposition. But new calcium needs to be added as well to replenish the calcium lost from the vacated wall pectate. A recent report demonstrated that growth was disrupted if new calcium was unavailable. The present addendum highlights this conclusion by reviewing an experiment from before the chelation chemistry was understood. Using cell wall labeling, a direct link appeared between wall expansion and wall deposition. Together, these experiments support the concept that newly supplied pectate has growth activity on its way to deposition in the wall. Growth rate is thus controlled by signals affecting the rate of pectate release. After release, the coordination of expansion and deposition arises naturally from chelation chemistry when polymers are under tension from turgor pressure. PMID- 22918501 TI - Signaling role of oligogalacturonides derived during cell wall degradation. AB - In addition to the role of the cell wall as a physical barrier against pathogens, some of its constituents, such as pectin-derived oligogalacturonides (OGAs) are essential components to trigger signaling pathways that induce rapid defense responses. Many pathogens directly penetrate the cell wall to access water and nutrients of the plant protoplast, and a rigid cell wall can fend off pathogen attack by forming an impenetrable physical barrier. Thus, cell wall integrity sensing is one mechanism by which plants may detect pathogen attack. Moreover, when the plant-pathogen interaction occurred, OGAs released during cell wall modification can trigger plant defense (e.g., production of reactive oxygen species, production of anti-microbial metabolites and synthesis of pathogenesis related proteins). This review documents and discusses studies suggesting that OGAs play a dual signaling role during pathogen attack by inducing defense responses and plant architecture adjustment. PMID- 22918502 TI - ATHB4 and HAT3, two class II HD-ZIP transcription factors, control leaf development in Arabidopsis. AB - In response to plant proximity or canopy shade, plants can react by altering elongation growth and development. Several members of the class II homeodomain leucine zipper (HD-ZIPII) transcription factor family have been shown to play an instrumental role in the responses to shade. HD-ZIP members of the class III (HD ZIPIII), by contrast, are involved in basic patterning processes. We recently showed that REVOLUTA (REV), a member of the HD-ZIPIII family, directly and positively regulates the expression of several genes involved in shade-induced growth, such as those encoding HD-ZIPII factors HAT2, HAT3, ATHB2/HAT4 and ATHB4, and of the components of the auxin biosynthesis pathway YUCCA5 and TAA1. Furthermore, we could demonstrate a novel role for HD-ZIPIII in shade-induced promotion of growth. Here we show that besides responding to shade, ATHB4 and HAT3 have a critical role in establishing the dorso-ventral axis in cotyledons and developing leaves. Loss-of-function mutations in these two HD-ZIPII genes (athb4 hat3) results in severely abaxialized, entirely radialized leaves. Conversely, overexpression of HAT3 results in adaxialized leaf development. Taken together, our findings unravel a so far unappreciated role for an HD-ZIPII/HD ZIPIII module required for dorso-ventral patterning of leaves. The finding that HD-ZIPII/HD-ZIPIII also function in shade avoidance suggests that this module is at the nexus of patterning and growth promotion. PMID- 22918503 TI - Plant sphingolipid fatty acid 2-hydroxylases have unique characters unlike their animal and fungus counterparts. AB - 2-Hydroxy fatty acids mainly contained in sphingolipids are synthesized by a sphingolipid fatty acid 2-hydroxylase (FAH). Recently, two FAH homologs in Arabidopsis thaliana (AtFAH1 and AtFAH2), without any cytochrome b5(Cb5)-like domains, which are essential for the function of Saccharomyces cerevisiae and mammalian FAH, were identified and both AtFAHs were shown to be activated by the interaction with Cb5. In this study, we compared FAHs of various plants, animals and fungi. Interestingly, only plants had two FAH homologs and none of plant FAHs had any Cb5-like domains. In addition, we showed from the interaction and expression analyses that AtFAHs interacted with multiple Cb5s probably in various tissues. Thus, plant FAHs may have evolved unlike animal and fungus FAHs. PMID- 22918504 TI - Abiotic stress-responsive expression of wali1 and wali5 genes from wheat. AB - Two cDNA clones, encoding Aluminum-responsive wali1 and wali5, were identified in dehydration stress-specific cDNA library from wheat. Their sequence variations and structural dissimilarities indicated them to be non-homologous genes. Expression of both genes was induced by various abiotic stresses as well as in response to plant hormones and oxidative molecules. Further, they were expressed differentially in shoot and root tissues of wheat seedlings, their transcripts being specifically abundant in roots. Previously characterized as being only Aluminum treatment induced, this report proposes them as novel candidates for stress-responsive studies. PMID- 22918505 TI - Sorting out the role of nitric oxide in cadmium-induced Arabidopsis thaliana programmed cell death. AB - As a vital cell-signaling molecule, nitric oxide (NO) has been reported to regulate toxic metal responses in plants. Our recent report has suggested that caspase-3-like protease activation was detected in Arabidopsis (Arabidopsis thaliana) after Cd2+ treatment. NO contributed caspase-3-like protease activation in Cd2+ induced Arabidopsis thaliana programmed cell death (PCD), which was mediated by MPK6. It was first shown that NO promotes Cd2+-induced Arabidopsis PCD by promoting MPK6-mediated caspase-3-like activation. Our study contributed to the understanding of NO signaling pathway in Cd2+-induced Arabidopsis thaliana PCD. Although several studies have revealed that NO regulates plant PCD, compared with the study of signaling pathways involved in animal cell apoptosis, the mechanism of NO function still remains elusive and the molecular mechanisms of MAPK are far from clear in Cd2+-induced PCD. By using the fluorescence techniques and the Arabidopsis seedlings as the reference model, the subsequent researches have been performed to obtain comprehensive understanding of Cd2+-induced plant PCD. PMID- 22918506 TI - Polymorphisms in antithrombin and in tissue factor pathway inhibitor genes are associated with recurrent pregnancy loss. AB - Recurrent pregnancy loss (RPL) is a multifactorial condition. The effect of antithrombin (SERPINC1), protein C (PROC), thrombomodulin (THBD) and tissue factor pathway inhibitor (TFPI) single nucleotide polymorphisms (SNPs) on the risk of RPL is thus far unknown. Our objective was to determine the association of SNPs in the above mentioned genes with RPL. We included 117 non-pregnant women with three or more consecutive losses prior to 20 weeks of pregnancy without a previous history of carrying a fetus to viability, and 264 healthy fertile non pregnant women who had at least two term deliveries and no known pregnancy losses. The PROC (rs1799809 and rs1799808), SERPINC1 (rs2227589), THBD (rs1042579) and TFPI (rs10931292, rs8176592 and rs10153820) SNPs were analysed by Real Time PCR. Genotype frequencies for PROC 2418A>G, PROC 2405C>T, THBD 1418C>T, TFPI (T-33C and TFPI C-399T) SNPs were similar in cases and controls. The carriers of SERPINC1 786A allele (GA + AA genotypes) had an increased risk for RPL (odds ratio [OR]: 1.77, 95% confidence interval [CI]: 1.05-3.00, p= 0.034) while women carrying the TFPI -287C allele (TC + CC genotypes) had a protection effect on having RPL (OR: 0.46, 95% CI: 0.26-0.83, p= 0.009). The TCC haplotype for TFPI T-33C/ TFPI T-287C/ TFPI C-399T SNPs was less frequent in cases (5.7%) than in controls (11.6%) (OR: 0.45, 95% CI: 0.23-0.90, p= 0.025). In conclusion, our data indicate that SERPINC1 786G>A variant increases the risk for RPL, while TFPI T-287C variant is protective; however, further studies are required to confirm our findings. PMID- 22918507 TI - Methane-selective nanoporous graphene membranes for gas purification. AB - The capability of functionalized graphene nanopores to efficiently separate methane from air is analyzed using density functional theory. We study the interaction between selected gas molecules and two finite model pores. Saddle point energies of the activated complexes are used to estimate transmission probabilities and selectivities as a function of temperature. We account for geometry distortions caused by the transient gas molecules and discuss the applicability and limitations of descriptions based on "molecular size" for the judgement of quasi-two-dimensional membranes. PMID- 22918508 TI - A N-aryloxy-beta-diketiminate ligand in 4d, 4f and 5f-metals complexes. AB - A new class of functionalized beta-diketiminate ligands has been prepared from commercially available reagents. The novel N-aryloxy-beta-diketiminate ligand proves to be an excellent ligand to support 4d, 4f and 5f metal ions. PMID- 22918509 TI - Cytoplasmic localization of PML particles in laminopathies. AB - There is growing evidence that laminopathies, diseases associated with mutations in the LMNA gene, are caused by a combination of mechanical and gene regulatory distortions. Strikingly, there is a large variability in disease symptoms between individual patients carrying an identical LMNA mutation. This is why classical genetic screens for mutations appear to have limited predictive value for disease development. Recently, the widespread occurrence of repetitive nuclear ruptures has been described in fibroblast cultures from various laminopathy patients. Since this phenomenon was strongly correlated with disease severity, the identification of biomarkers that report on these rupture events could have diagnostic relevance. One such candidate marker is the PML nuclear body, a structure that is normally confined to the nuclear interior, but leaks out of the nucleus upon nuclear rupture. Here, we show that a variety of laminopathies shows the presence of these cytoplasmic PML particles (PML CPs), and that the amount of these protein aggregates increases with severity of the disease. In addition, between clinically healthy individuals, carrying LMNA mutations, significant differences can be found. Therefore, we postulate that detection of PML CPs in patient fibroblasts could become a valuable marker for diagnosis of disease development. PMID- 22918510 TI - FIB/SEM tomography with TEM-like resolution for 3D imaging of high-pressure frozen cells. AB - Focused ion beam/scanning electron microscopy (FIB/SEM) tomography is a novel powerful approach for three-dimensional (3D) imaging of biological samples. Thereby, a sample is repeatedly milled with the focused ion beam (FIB) and each newly produced block face is imaged with the scanning electron microscope (SEM). This process can be repeated ad libitum in arbitrarily small increments allowing 3D analysis of relatively large volumes such as eukaryotic cells. High-pressure freezing and freeze substitution, on the other hand, are the gold standards for electron microscopic preparation of whole cells. In this work, we combined these methods and substantially improved resolution by using the secondary electron signal for image formation. With this imaging mode, contrast is formed in a very small, well-defined area close to the newly produced surface. By using this approach, small features, so far only visible in transmission electron microscope (TEM) (e.g., the two leaflets of the membrane bi-layer, clathrin coats and cytoskeletal elements), can be resolved directly in the FIB/SEM in the 3D context of whole cells. PMID- 22918511 TI - Pedicle subtraction osteotomy for sagittal imbalance. PMID- 22918512 TI - Cervical spinal epidural abscess after oesophagoscopy. AB - INTRODUCTION: Spinal epidural abscess is an uncommon entity, especially in the cervical region. CASE REPORT: We report a patient with epidural abscess, vertebral osteomyelitis and discitis in the cervical spine that was caused by iatrogenic perforation of the pharynx during diagnostic oesophagoscopy, which has not been recorded previously in the literature. CONCLUSION: Cervical spinal epidural abscess may be caused by iatrogenic perforation of pharyngeal wall during diagnostic oesophagoscopy. Early diagnosis with an MRI and surgical treatment with antimicrobial chemotherapy are keys to successful management of this rare and life-threatening complication. PMID- 22918513 TI - Clinical and radiological features in young individuals with nevoid basal cell carcinoma syndrome. AB - PURPOSE: Nevoid basal cell carcinoma syndrome is an autosomal dominant disorder characterized by multiple basal cell carcinomas, jaw cysts, palmar/plantar pits, spine and rib anomalies, and falx cerebri calcification. Current diagnostic criteria are suboptimal when applied to pediatric populations, as most common symptoms often do not begin to appear until teenage years. METHODS: We studied minor and major clinical features in 30 children/teenagers and compared the findings with 75 adults from 26 families with nevoid basal cell carcinoma syndrome. RESULTS: Fifty percent of children/teenagers and 82% of adults had at least one basal cell carcinoma. Jaw cysts occurred in 60% of children/teenagers and 81% of adults. Palmar/plantar pits were the most frequent feature seen in affected individuals at all ages. Macrocephaly was seen in 50% of affected and 8% of unaffected children/teenagers. Frontal bossing, hypertelorism, Sprengel deformity, pectus deformity, and cleft lip/palate were seen among affected children/teenagers but not among their unaffected siblings. Falx calcification, the most frequent radiological feature, was present in 37% of individuals <20 and 79% of those >20 years. CONCLUSION: We report clinical and radiological manifestations of nevoid basal cell carcinoma syndrome in children/teenagers, many of whom lacked major features such as basal cell carcinomas, jaw cysts, and falx calcification. Evaluations for palmar/plantar pits, craniofacial features, and radiological manifestations permit early diagnosis and optimum surveillance. PMID- 22918514 TI - Consequences of treated versus untreated asymptomatic bacteriuria in the first year following kidney transplantation: retrospective observational study. AB - Asymptomatic bacteriuria (AB) is frequent among kidney transplant patients during the first year post transplantation. Currently, there are no clear guidelines for the antibiotic treatment of AB among these patients. We examined the outcomes of treatment versus no treatment of AB in kidney transplant patients during the first year post transplantation. A retrospective cohort study including adults >16 years of age transplanted in one center between 1/2004 and 12/2010 was undertaken. The primary outcome was a composite of hospitalization for symptomatic urinary tract infection (UTI) or more than 25 % reduction in the estimated glomerular filtration rate (eGFR) 30 days after the documentation of AB. Secondary outcomes included symptomatic UTIs following the episode of AB, persistent recurrent AB, total days in hospital, mortality, adverse events, and resistance development. A total of 112 patients with AB fulfilled the inclusion criteria. Twenty-two patients received antibiotic treatment (19.6 %), while 90 patients did not. The primary outcome occurred in 4/22 (18.2 %) of the treated patients versus 5/90 (5.6 %) of the untreated patients [odds ratio (OR) = 3.78, 95 % confidence interval (CI) 0.9-15]. The risk of developing symptomatic UTI after AB was almost three times higher (p < 0.05) and the total number of hospitalization days at 6 months post AB was also significantly higher (p < 0.026) in the treated group. No patient died during the study period. UTI caused by bacteria resistant to the antibiotic used for the treatment of AB occurred in 36 % of the treated patients. We observed no benefit for the antibiotic treatment of AB in the short- and long-term follow-up. A prospective observational study is needed. PMID- 22918515 TI - Unsolicited post-prescription antibiotic review in surgical and medical wards: factors associated with counselling and physicians' compliance. AB - The purpose of this investigation was to describe the impact of an early review of antibiotic prescriptions in a hospital using unsolicited infectious disease physician (IDP) counselling, identify areas for improvement and examine factors associated with physicians' non-compliance. The prescriptions of 15 selected antibiotics from surgical or medical wards were screened daily and reviewed between days 3 and 5 by a single IDP during an 8-month period to identify those likely needing counselling. Improved antibiotic use was sought by encouraging ward physicians to withdraw or de-escalate therapy, promoting oral switch or reducing the duration of therapy whenever appropriate. Variables potentially associated with IDP counselling and physicians' non-compliance were tested using bivariate analysis and then entered in a logistic regression model. Among 857 prescriptions analysed, 54.6 % prompted unsolicited counselling, mostly for stopping therapy (18.8 %), reducing its duration (18.0 %) or de-escalation (13.0 %). Variables independently associated with IDP counselling included antibiotic combination (adjusted odds ratio [aOR], 5.27 [95 % confidence interval (CI), 1.80 15.45]; p = 0.002), non-clinically documented infection (aOR, 4.98 [95 % CI, 2.81 8.82]; p < 0.001) and microbiologically documented infection (aOR, 2.04 [95 % CI, 1.51-2.75]; p < 0.001). The physicians' compliance rate was 77.3 %. Variables independently associated with physicians' non-compliance to the IDP recommendation were the surgical speciality of the ward physician (aOR, 1.91 [95 % CI, 1.17-3.12]; p = 0.009) and advice to reduce the duration of therapy (aOR, 1.88 [95 % CI, 1.12-3.15]; p = 0.017). An unsolicited post-prescription antibiotic review can be successfully implemented with a high rate of physicians' compliance. Areas for targeting improvement measures include prescriptions in surgical wards and shortening the duration of therapy. PMID- 22918516 TI - Biliary tract infections caused by Aeromonas species. AB - This study investigated the clinical and microbiological characteristics of patients with Aeromonas infections of the biliary tract. Patients with bile cultures positive for Aeromonas species during the period July 2004 to December 2011 were identified from a computerized database of a hospital in Taiwan. Patients with Aeromonas infections of the biliary tract were further identified. During the study period, a total of 1,142 isolates of Aeromonas species were obtained from 750 patients. Of those patients, 91 (12.1 %) had Aeromonas infections of the biliary tract. The annual incidence (episodes per 10,000 patient-days) of biliary tract infections caused by all Aeromonas species was 0.31 in 2007, 0.12 in 2010, and 0.27 in 2011. A. hydrophila was the most common species isolated (n = 41, 45.1 %), followed by A. caviae (n = 30, 33.0 %), A. veronii biovar sobria (n = 15, 16.5 %), and A. veronii biovar veronii (n = 5, 5.5 %). The majority of patients (n = 77, 84.6 %) had polymicrobial infections. Hepatobiliary stones (n = 50, 54.9 %) and hepatobiliary cancer (n = 38, 41.8 %) were the most common underlying diseases, followed by diabetes mellitus (n = 29, 31.9 %) and liver cirrhosis (n = 7, 7.7 %). The in-hospital mortality rate was 8.8 %. Infection-related mortality was associated with underlying immunocompromised condition (p = 0.044) and use of mechanical ventilation (p = 0.004), but was not associated with inappropriate antibiotic usage or concomitant bacteremia (n = 8, 8.8 %). In conclusion, biliary tract infections caused by Aeromonas species are not uncommon and can develop in both immunocompromised and immunocompetent patients; however, patients with underlying hepatobiliary diseases are particularly susceptible to these infections. PMID- 22918517 TI - Education and physical health trajectories in old age. Evidence from the Survey of Health, Ageing and Retirement in Europe (SHARE). AB - OBJECTIVES: The model of cumulative inequality predicts that health differences between educational levels increase with age. Using a variety of analytical approaches and measures of health, studies have, however, reported increasing as well as decreasing and constant patterns of educational health inequality. The aim of this study is use a standardized research design to compare different dimensions of health inequality trajectories across educational levels. METHODS: We used data from two waves (2004/2005 and 2006/2007) of SHARE. The sample consisted of respondents aged 50-80 (n = 14,818). Using OLS regression models, we analyzed trajectories of health inequality in self-reported measures (ADL, IADL, mobility, chronic diseases, and self-rated health) as well as non-invasive objective measures (grip strength) of physical health. RESULTS: Inequality between higher and lower educated individuals increased significantly in limitations of physical functioning and grip strength. In chronic diseases and self-rated health, the gap between these two groups remained constant. CONCLUSION: Although our results mainly supported the model of cumulative inequality, they also showed that the trajectory of the education-health gradient is not uniform but varies across different dimensions of physical health. PMID- 22918518 TI - Projected impact of urbanization on cardiovascular disease in China. AB - OBJECTIVES: The Coronary Heart Disease (CHD) Policy Model-China, a national scale cardiovascular disease computer simulation model, was used to project future impact of urbanization. METHODS: Populations and cardiovascular disease incidence rates were stratified into four submodels: North-Urban, South-Urban, North-Rural, and South-Rural. 2010 was the base year, and high and low urbanization rate scenarios were used to project 2030 populations. RESULTS: Rural-to-urban migration, population growth, and aging were projected to more than double cardiovascular disease events in urban areas and increase events by 27.0-45.6% in rural areas. Urbanization is estimated to raise age-standardized coronary heart disease incidence by 73-81 per 100,000 and stroke incidence only slightly. CONCLUSIONS: Rural-to-urban migration will likely be a major demographic driver of the cardiovascular disease epidemic in China. PMID- 22918519 TI - Working memory in the odor span task: effects of chlordiazepoxide, dizocilpine (MK801), morphine, and scopolamine. AB - RATIONALE: A number of tasks are used to assess working memory in rodents, but the odor span task (OST) is unique in studying performance as a function of the number of stimuli to remember. OBJECTIVES: The purpose of the present study was to better characterize the behavioral pharmacology of the OST by exploring the effects of several amnestic agents including an NMDA antagonist (dizocilpine), a positive GABA-A modulator (chlordiazepoxide), an anticholinergic compound (scopolamine), and as a negative control, an opiate receptor agonist (morphine). METHODS: Rats were trained to perform on the OST which is a non-match-to-sample procedure with an incrementing number of sample odors to remember as the session progresses. Trials with a simple odor discrimination task (SD) were interspersed to provide a control for effects unrelated to memory load. RESULTS: All four drugs disrupted performances on the OST task in a dose-dependent fashion, but only the NMDA antagonist dizocilpine produced impairments that were clearly dependent on the number of stimuli to remember. Dizocilpine impaired OST performance at a dose (0.1 mg/kg) that did not affect SD, and that impairment depended on memory load. Chlordiazepoxide (3.0 mg/kg) also produced amnestic effects that were manifest by shorter memory spans and runs of correct responding. In contrast, morphine and scopolamine impaired OST accuracy only at doses that also disrupted SD (18.0 and 0.3 mg/kg, respectively). CONCLUSIONS: These results provide evidence of NMDA and benzodiazepine modulation of working memory as assessed by the OST. PMID- 22918520 TI - Computational prediction and analysis of protein gamma-carboxylation sites based on a random forest method. AB - The glutamate gamma-carboxylation plays a pivotal part in a number of important human diseases. However, traditional protein gamma-carboxylation site detection by experimental approaches are often laborious and time-consuming. In this study, we initiated an attempt for the computational prediction of protein gamma carboxylation sites. We developed a new method for predicting the gamma carboxylation sites based on a Random Forest method. As a result, 90.44% accuracy and 0.7739 MCC value were obtained for the training dataset, and 89.83% accuracy and 0.7448 MCC value for the testing dataset. Our method considered several features including sequence conservation, residual disorder, secondary structures, solvent accessibility, physicochemical/biochemical properties and amino acid occurrence frequencies. By means of the feature selection algorithm, an optimal set of 327 features were selected; these features were considered as the ones that contributed significantly to the prediction of protein gamma carboxylation sites. Analysis of the optimal feature set indicated several important factors in determining the gamma-carboxylation and a possible consensus sequence of the gamma-carboxylation recognition site (gamma-CRS) was suggested. These may shed some light on the in-depth understanding of the mechanisms of gamma-carboxylation, providing guidelines for experimental validation. PMID- 22918521 TI - The effect of custom-made splints in patients with the first carpometacarpal joint osteoarthritis. AB - BACKGROUND: Pain, reduced grip strength, loss of range of motion, and joint stiffness, leading to impaired hand function, and difficulty with daily activities are documented symptoms of first carpometacarpal joint osteoarthritis. Splinting is a common type of conservative treatment for this injury. OBJECTIVES: The aim of this study was to evaluate the effect of custom-made thumb splints on pain, function, grip strength, and key pinch in patients with first carpometacarpal joint osteoarthritis. STUDY DESIGN: Quasi experimental. METHODS: Patients with first carpometacarpal grade I and II osteoarthritis (n = 18) participated in a repeated measure study. The patients all wore custom-made thumb splints. All parameters were measured at baseline, and also after 30, 60, and 90 days from initial supply. A visual analogue scale, along with a disability of the arm, shoulder, and hand questionnaire, a dynamometer and pinch gauge were used to assess pain, function, grip strength, and pinch, respectively. RESULTS: After 60 days of splint usage, grip strength was improved. However, a reduction in pain was demonstrated after only 30 days and this continued to improve with time. Function and pinch strength also increased significantly and continued to do so during the study period when compared to baseline. CONCLUSIONS: The use of a custom-made splint for patients with osteoarthritis of the first carpometacarpal joint produced decreased pain and increased grip strength, pinch strength, and hand function. Clinical relevance Custom-made splints may be recommended for the treatment of first carpometacarpal joint osteoarthritis. PMID- 22918522 TI - Studies of cavitation and ice nucleation in 'doubly-metastable' water: time-lapse photography and neutron diffraction. AB - High-speed photographic studies and neutron diffraction measurements have been made of water under tension in a Berthelot tube. Liquid water was cooled below the normal ice-nucleation temperature and was in a doubly-metastable state prior to a collapse of the liquid state. This transition was accompanied by an exothermic heat release corresponding with the rapid production of a solid phase nucleated by cavitation. Photographic techniques have been used to observe the phase transition over short time scales in which a solidification front is observed to propagate through the sample. Significantly, other images at a shorter time interval reveal the prior formation of cavitation bubbles at the beginning of the process. The ice-nucleation process is explained in terms of a mechanism involving hydrodynamically-induced changes in tension in supercooled water in the near vicinity of an expanding cavitation bubble. Previous explanations have attributed the nucleation of the solid phase to the production of high positive pressures. Corresponding results are presented which show the initial neutron diffraction pattern after ice-nucleation. The observed pattern does not exhibit the usual crystalline pattern of hexagonal ice [I(h)] that is formed under ambient conditions, but indicates the presence of other ice forms. The composite features can be attributed to a mixture of amorphous ice, ice I(h)/I(c) and the high-pressure form, ice-III, and the diffraction pattern continues to evolve over a time period of about an hour. PMID- 22918523 TI - Childhood IQ, hearing loss, and maternal thyroid autoimmunity in the Baltimore Collaborative Perinatal Project. AB - BACKGROUND: Maternal thyroid autoantibodies during pregnancy have been implicated in neurodevelopmental delays, including early childhood cognitive deficits. We evaluated whether maternal autoantibodies to thyroid peroxidase (TPOaAbs) during late pregnancy were associated with childhood intelligence quotient (IQ) scores in their offspring and how the children's TPOaAb-associated sensorineural hearing loss (HL) might affect the result. METHODS: We evaluated banked third-trimester sera corresponding to 1,733 children for whom childhood cognitive test scores and audiology data were available. The mothers and their children participated in the National Institutes of Health (NIH)-sponsored Collaborative Perinatal Project (CPP) that ran from 1959 to 1974. RESULTS: A modest, statistically significant, effect of TPOaAbs on cognitive performance observed at 4 y of age lessened in both magnitude and P value by the age of 7 y. Children with sensorineural HL (SNHL) had lower IQ scores at both ages. CONCLUSION: Our data suggest that the reported effect of maternal TPOaAbs on IQ may involve early developmental delays or transient effects rather than permanent deficits. Reports associating TPOaAbs directly with IQ may reflect a portion with unexamined TPOaAb-associated SNHL. Whether the TPOaAb-associated SNHL is in the neurodevelopmental pathway of later cognitive delays or is independently associated with IQ requires investigation in other studies. PMID- 22918525 TI - Effect of obesity on toxicity in women treated with adjuvant chemotherapy for early-stage breast cancer: a systematic review. AB - The purpose of this study is to provide more definite evidence regarding the role of dose modification of chemotherapy in obese women with breast cancer by systematically reviewing current literature regarding chemotherapy-induced toxicity rates in obese and non-obese women with early-stage breast cancer. A systematic search of Pubmed and EMBASE was conducted to identify original studies investigating chemotherapy-induced toxicity in obese women receiving adjuvant chemotherapy treatment for breast cancer. Ten studies were identified. We noted low rates of adjustment for confounders such as prophylactic hematopoietic growth factor use and empirical dose reductions. Seven studies found reduced toxicity in obese compared to non-obese women. Of four studies, where dose capping was precluded or statistically adjusted for, three found reduced toxicity in obese women. These outcomes include less febrile neutropenia (body mass index (BMI) >23.6; odds ratio (OR) 4.4; 95 % confidence interval (CI) 1.65-12.01), fewer hospital admissions (BMI >35; OR 0.61, 95 % CI 0.38-0.97), and fewer neutropenic events (BMI >25; OR 0.49; 95 % CI 0.37-0.66). Only a single study reported higher rates of toxicity in obese women, but this study had significant methodological issues. As a conclusion, we observed that obese patients tolerate chemotherapy better than lean patients. However, this may be confounded by poorly specified dose capping practices and the use of hematopoietic growth factors. Further research should focus on improved documentation of body size, of dose, and of use of growth factors, and analysis of how these affect recurrence rates, toxicity, and survival. PMID- 22918524 TI - Advanced cognitive training for breast cancer survivors: a randomized controlled trial. AB - The purpose of this study was to evaluate the preliminary efficacy and satisfaction/acceptability of training in memory or speed of processing versus wait-list control for improving cognitive function in breast cancer survivors. 82 breast cancer survivors completed a three-group randomized, controlled trial. Primary outcomes were objective neuropsychological tests of memory and speed of processing. Secondary outcomes were perceived cognitive functioning, symptom distress (mood disturbance, anxiety, and fatigue), quality of life, and intervention satisfaction/acceptability. Data were collected at baseline, post intervention, and 2-month follow-up. Using repeated-measures mixed-linear ANCOVA models, each intervention was compared to wait-list control while adjusting for age, education, and baseline measures. The effect sizes for differences in means and the reliable improvement percentage were reported. The results show that domain-specific effects were seen for both interventions: memory training improved memory performance at 2-month follow-up (p = 0.036, d = 0.59); speed of processing training improved processing speed post-intervention (p = 0.040, d = 0.55) and 2-month follow-up (p = 0.016; d = 0.67). Transfer effects to non trained domains were seen for speed of processing training with improved memory post-intervention (p = 0.007, d = 0.75) and 2-month follow-up (p = 0.004, d = 0.82). Both interventions were associated with improvements in perceived cognitive functioning, symptom distress, and quality of life. Ratings of satisfaction/acceptability were high for both interventions. It was concluded that while both interventions appeared promising, speed of processing training resulted in immediate and durable improvements in objective measures of processing speed and verbal memory. Speed of processing training may have broader benefits in this clinical population. PMID- 22918526 TI - Diurnal changes and levels of fibrin generation are not altered by continuous positive airway pressure (CPAP) in obstructive sleep apnoea (OSA). A randomised, placebo-controlled crossover study. AB - Obstructive sleep apnoea (OSA) is associated with increased cardiovascular disease (CVD) risk. In the general population, CVD events peak at 9:00-10:00 AM, associated with diurnal changes in thrombotic potential. However in OSA, these CVD events occur frequently at night. Measuring thrombotic potential across the sleep-wake cycle may provide insight into the temporal association of OSA with CVD. This study aimed to determine diurnal changes in fibrin generation in OSA and whether treatment of OSA with continuous positive airway pressure (CPAP) alters fibrin generation across the sleep-wake cycle. In a randomised placebo controlled crossover trial, patients with OSA were assigned to two months each of therapeutic CPAP and placebo. After each treatment period, fibrin generation was determined by overall haemostatic potential assay at seven time points over 24 hours (h). Twenty-eight patients (25 men, 3 women) with severe OSA (Apnoea Hypopnoea Index = 37.9 +/- 23.9/h, Oxygen Desaturation Index 31.3 +/- 22.4/h) completed the study. All parameters, except lag time to fibrin generation, showed significant diurnal changes, both on CPAP and placebo. Compared to 9:00 AM, fibrin generation parameters were significantly lower at midnight and 3:00 AM for overall coagulation potential (OCP), overall haemostasis potential (OHP), maximum optical density, and maximum slope (all p<=0.001). CPAP produced no change in fibrin generation parameters compared to placebo. In severe OSA patients, fibrin generation peaked at 6:00 AM and 9:00 AM rather than during the sleep period (midnight and 3:00 AM). These findings suggest a prothrombotic shift in the morning similar to individuals without OSA. There was no difference between CPAP and placebo on fibrin generation. PMID- 22918527 TI - Normative data for the chemical sensitivity scale for sensory hyperreactivity: the Vasterbotten environmental health study. AB - OBJECTIVES: The chemical sensitivity scale for sensory hyperreactivity (CSS-SHR) is used to quantify affective reactions to and behavioral disruptions by odorous/pungent substances in the environment and has documented good metric properties. However, normative data have not been available. The main objective of the present study was therefore to establish normative data for reference by means of a large-scale population-based study. MATERIALS AND METHODS: From a random sample of 8,520 reachable inhabitants in the county of Vasterbotten in Sweden, aged 18-79 years, stratified for age and gender, 3,406 individuals agreed to participate. RESULTS: The results show fairly high internal consistency (Cronbach's alpha = 0.78-0.83) of the CSS-SHR and that it generates scores with approximately normal distributions (skewness: 0.045-0.454; kurtosis: -0.314 to 0.230), irrespective of age group and gender. Mean scores, standard deviations, confidence intervals, and proportions of individuals who met the diagnostic cutoff score for the CSS-SHR were obtained for reference of normality. CONCLUSIONS: CSS-SHR can be recommended for quantification of affective reactions to and behavioral disruptions by odorous/pungent environmental substances, and with the advantage of comparing scores with normality. PMID- 22918528 TI - [Intraoperative pathological rapid investigations in breast surgery]. AB - In breast surgery intraoperative frozen sections for the diagnosis of malignancy has lost impact and has largely been replaced by preoperative core needle biopsies. Nevertheless, there is still need for immediate pathological investigation of native breast tissue during surgery due to three reasons: (1) macroscopic and microscopic evaluation of resection margins, (2) the histological analysis of sentinel lymph nodes in order to circumvent secondary axillary surgery and (3) the preparation of native tissue for tumor banking or measurement of biomarkers. Because histology provides only a facultative component of immediate pathological examination of breast specimens during surgery, the term frozen section does not seem to be appropriate anymore. Intraoperative evaluation of resection specimens by pathologists provides surgically relevant information immediately, guarantees standardized preparation and fixation of specimens and enables tissue banking of native tissue for assessment of biological markers. PMID- 22918529 TI - Critical illness myopathy. AB - PURPOSE OF REVIEW: To describe the incidence, major risk factors, and the clinical, electrophysiological, and histological features of critical illness myopathy (CIM). Major pathogenetic mechanisms and long-term consequences of CIM are also reviewed. RECENT FINDINGS: CIM is frequently associated with critical illness polyneuropathy (CIP), and may have a relevant impact on patients' outcome. CIM has an earlier onset than CIP, and recovery is faster. Loss of myosin filaments on muscle biopsy is important to diagnose CIM, and has a good prognosis. Critical illness, use of steroids, and immobility concur in causing CIM. SUMMARY: A rationale diagnostic approach to CIM using clinical, electrophysiological, and muscle biopsy investigations is important to plan adequate therapy and to predict recovery. PMID- 22918530 TI - The role of endoplasmic reticulum stress and the unfolded protein response in fibrosis. AB - PURPOSE OF REVIEW: To review the present knowledge of the role of endoplasmic reticulum (ER) stress and unfolded protein response (UPR) in the pathogenesis of fibrotic diseases. RECENT FINDINGS: ER stress and UPR occur in a number of diseases associated with organ fibrosis; however, the contribution of these pathways to the fibrotic process has not been systematically investigated. Current studies suggest that prolonged ER stress may lead to fibrosis through activation of CCAAT/enhancer-binding homologous protein-mediated apoptosis, followed by an inflammatory response and release of profibrotic cytokines. A direct profibrotic role of UPR mediators in activation of TGF-beta signaling has been shown in lung fibroblasts. In addition, activation of ER stress and UPR pathways in immune cells contributes to increased production of proinflammatory cytokines. SUMMARY: Although limited in scope, current studies strongly suggest that ER stress and UPR may play an important role during development of fibrosis. Further studies are warranted to gain additional insights into the relationship between these processes. PMID- 22918533 TI - Emerging contaminants in biota. PMID- 22918531 TI - TGFbeta signaling: its role in fibrosis formation and myopathies. AB - PURPOSE OF REVIEW: Modifiers of TGFbeta signaling have been investigated as treatment options for several types of muscle diseases. The purpose of this review is to focus on the most recent studies that have used this treatment strategy for pathological muscle disorders. We also review the recent insight into the mechanistic processes by which TGFbeta signaling contributes to these pathologies by promoting fibrosis formation. RECENT FINDINGS: Recent research has shed light on the role of TGFbeta signaling in the regulation of microRNAs associated with fibrosis formation. Inhibition of TGFbeta signaling by Losartan treatment greatly improved the phenotype of myopathies associated with laminin alpha2-deficient congenital muscular dystrophy. Caveolin 3 deficiency was also ameliorated by the use of several different types of TGFbeta signaling inhibitors. Use of Losartan had dramatically beneficial effects on sarcopenic muscle by improving the regeneration after injury. Pharmacological manipulation to increase muscle mass is an emerging trend in obesity treatment research. New advances in the use of potent myostatin inhibitors have made this an attractive approach for future studies. SUMMARY: An increasing number of skeletal myopathies are demonstrating favorable responses to alterations of the TGFbeta signaling pathway. However, future research is needed to fully understand the downstream molecular signature associated with this pathway in order to develop more specific targeted therapies. PMID- 22918534 TI - Direct surface plasmon resonance immunosensing of pyraclostrobin residues in untreated fruit juices. AB - A surface plasmon resonance (SPR) immunoassay for on-line detection of the strobilurin fungicide pyraclostrobin in untreated fruit juices is presented. The analysis of pyraclostrobin residues is accomplished in apple, grape, and cranberry samples by monitoring the recognition events occurring separately in a two-channel home-made SPR biosensor. Covalent coupling of the analyte derivative results in a reversible method, enabling more than 80 measurements on the same sensor surface. Optimization of the immunoassay conditions provides limits of detection as low as 0.16 MUg L(-1). The selectivity and reproducibility of the analysis is ensured by studying both non-specific interactions with unrelated compounds and inter-assay coefficients of variation. Excellent recovery ranging from 98 to 103% was achieved by a simple 1:5 dilution of fruit juice with assay buffer before the analysis. The lack of previous cleaning and homogenization procedures reduces the analysis time of a single food sample to only 25 min, including the regeneration cycle. PMID- 22918535 TI - Intercomparison of inductively coupled plasma mass spectrometry, quantitative neutron capture radiography, and prompt gamma activation analysis for the determination of boron in biological samples. AB - Boron determination in blood and tissue samples is a crucial task especially for treatment planning, preclinical research, and clinical application of boron neutron capture therapy (BNCT). Comparison of clinical findings remains difficult due to a variety of analytical methods, protocols, and standard reference materials in use. This paper addresses the comparability of inductively coupled plasma mass spectrometry, quantitative neutron capture radiography, and prompt gamma activation analysis for the determination of boron in biological samples. It was possible to demonstrate that three different methods relying on three different principles of sample preparation and boron detection can be validated against each other and yield consistent results for both blood and tissue samples. The samples were obtained during a clinical study for the application of BNCT for liver malignancies and therefore represent a realistic situation for boron analysis. PMID- 22918536 TI - A novel method for quantification of sulfolane (a metabolite of busulfan) in plasma by gas chromatography-tandem mass spectrometry. AB - The role of busulfan (Bu) metabolites in the adverse events seen during hematopoietic stem cell transplantation and in drug interactions is not explored. Lack of availability of established analytical methods limits our understanding in this area. The present work describes a novel gas chromatography-tandem mass spectrometric assay for the analysis of sulfolane (Su) in plasma of patients receiving high-dose Bu. Su and Bu were extracted from a single 100 MUL plasma sample by liquid-liquid extraction. Bu was separately derivatized with 2,3,5,6 tetrafluorothiophenolfluorinated agent. Mass spectrometric detection of the analytes was performed in the selected reaction monitoring mode on a triple quadrupole instrument after electronic impact ionization. Bu and Su were analyzed with separate chromatographic programs, lasting 5 min each. The assay for Su was found to be linear in the concentration range of 20-400 ng/mL. The method has satisfactory sensitivity (lower limit of quantification, 20 ng/mL) and precision (relative standard deviation less than 15 %) for all the concentrations tested with a good trueness (100 +/- 5 %). This method was applied to measure Su from pediatric patients with samples collected 4 h after dose 1 (n = 46), before dose 7 (n = 56), and after dose 9 (n = 54) infusions of Bu. Su (mean +/- SD) was detectable in plasma of patients 4 h after dose 1, and higher levels were observed after dose 9 (249.9 +/- 123.4 ng/mL). This method may be used in clinical studies investigating the role of Su on adverse events and drug interactions associated with Bu therapy. PMID- 22918537 TI - Determination of currently used pesticides in biota. AB - Although pesticides enable control of the quantity and quality of farm products and food, and help to limit diseases in humans transmitted by insects and rodents, they are regarded as among the most dangerous environmental contaminants because of their tendency to bioaccumulate, and their mobility and long-term effects on living organisms. In the past decade, more analytical methods for accurate identification and quantitative determination of traces of pesticides in biota have been developed to improve our understanding of their risk to ecosystems and humans. Because sample preparation is often the rate-determining step in analysis of pesticides in biological samples, this review first discusses extraction and clean-up procedures, after a brief introduction to the classes, and the methods used in the analysis of pesticides in biota. The analytical methods, especially chromatographic techniques and immunoassay-based methods, are reviewed in detail, and their corresponding advantages, limitations, applications, and prospects are also discussed. This review mainly covers reports published since 2008 on methods for analysis of currently used pesticides in biota. PMID- 22918538 TI - Fragment screening of cyclin G-associated kinase by weak affinity chromatography. AB - Fragment-based drug discovery (FBDD) has become a new strategy for drug discovery where lead compounds are evolved from small molecules. These fragments form low affinity interactions (dissociation constant (K(D)) = mM - MUM) with protein targets, which require fragment screening methods of sufficient sensitivity. Weak affinity chromatography (WAC) is a promising new technology for fragment screening based on selective retention of fragments by a drug target. Kinases are a major pharmaceutical target, and FBDD has been successfully applied to several of these targets. In this work, we have demonstrated the potential to use WAC in combination with mass spectrometry (MS) detection for fragment screening of a kinase target-cyclin G-associated kinase (GAK). One hundred seventy fragments were selected for WAC screening by virtual screening of a commercial fragment library against the ATP-binding site of five different proteins. GAK protein was immobilized on a capillary HPLC column, and compound binding was characterized by frontal affinity chromatography. Compounds were screened in sets of 13 or 14, in combination with MS detection for enhanced throughput. Seventy-eight fragments (46 %) with K(D) < 200 MUM were detected, including a few highly efficient GAK binders (K(D) of 2 MUM; ligand efficiency = 0.51). Of special interest is that chiral screening by WAC may be possible, as two stereoisomeric fragments, which both contained one chiral center, demonstrated twin peaks. This ability, in combination with the robustness, sensitivity, and simplicity of WAC makes it a new method for fragment screening of considerable potential. PMID- 22918540 TI - Spinal cord herniation: management and outcome. PMID- 22918539 TI - A DNA-conjugated magnetic nanoparticle assay for assessing genotoxicity. AB - The genotoxicity of a molecule refers to its ability to interact with DNA in a way that inhibits normal DNA replication and transcription possibly leading to mutagenesis or carcinogenesis. Assessing the genotoxicity of a compound is critical in the development of pharmaceuticals and other products designed for human consumption or use. Typically genotoxicity is established using expensive and time consuming methods using animals or bacteria like the Ames test, mouse lymphoma assay, or mouse and rat carcinogenicity tests. We have developed a magnetic nanoparticle-based assay that uses conjugated double-stranded DNA to serve as a substrate for interaction with genotoxic molecules. After application of a magnetic field, the genotoxic molecules are extracted with the DNA conjugated magnetic nanoparticles. The genotoxic molecules can then be released and detected. To evaluate the potential of this assay, we have screened several genotoxic and non-genotoxic compounds and have demonstrated the ability to extract a genotoxic compound in the presence of a non-genotoxic molecule. The assay demonstrates suitable analytical performance and the ability to differentiate between genotoxic and non-genotoxic molecules providing a rapid and inexpensive alternative to more traditional methods of evaluating genotoxicity. PMID- 22918541 TI - [Not Available]. PMID- 22918542 TI - Severe growth hormone deficiency is rare in surgically-cured acromegalics. AB - Growth hormone deficiency (GHD) in surgically-cured acromegalics has been reported to negatively affect their metabolic condition and quality of life (QOL). The incidence of GHD, its causes, and its effects on their physio psychological condition remain to be examined in detail. We performed a retrospective study to investigate GH secretory function in surgically-cured acromegalics, prognostic factors of GHD, and its impact on QOL. The study population consisted of 72 acromegalics who were determined to be surgically cured according to the Cortina consensus criteria. We recorded the incidence of impaired GH secretory function based on the peak GH level during postoperative insulin tolerance test (ITT) which lowered their nadir blood sugar to under 50 mg/dL. Their QOL was evaluated by SF-36. In surgically-cured acromegalics, the incidence of severe GHD (peak GH during ITT ? 3.0 MUg/L) was 12.5 % (9/72). The preoperative tumor size was significantly larger in patients with severe GHD than without severe GHD (21.9 +/- 9.0 vs. 15.5 +/- 7.1 mm, p = 0.017). The peak GH levels during postoperative ITT were statistically correlated with the physical but not the mental component summary of the SF-36 score. The incidence of GHD was 12.5 % in our surgically-cured acromegalics. As some QOL aspects are positively related with peak GH levels during postoperative ITT, efforts should be made to preserve pituitary function in acromegalic patients undergoing adenomectomy. PMID- 22918543 TI - Pituitary-directed medical therapy with pasireotide for a corticotroph macroadenoma: pituitary volume reduction and literature review. AB - Hypercortisolism due to an ACTH-secreting pituitary adenoma (Cushing's disease) is a chronic condition associated with high morbidity and mortality if inadequately managed. Pasireotide is a multireceptor-targeted somatostatin analogue and is the only approved medical therapy for Cushing's disease that treats the underlying cause of the disorder. This paper reviews the available literature for medical-therapy-induced adenoma volume reduction in patients with Cushing's disease and reports the experience of a 53-year-old surgically, radiologically and medically naive (de novo) female with a pituitary macroadenoma who declined surgery. This patient was treated with pasireotide as first-line therapy as part of the largest randomized Phase III study evaluating a medical therapy in patients with Cushing's disease (SOM230B2305 trial). Subcutaneous pasireotide significantly decreased tumor volume, suppressed cortisol secretion, and improved clinical signs and symptoms of Cushing's disease in this patient. Based on this experience, first-line pasireotide has the potential to achieve substantial tumor volume reduction in addition to significant improvements in cortisol levels and signs and symptoms in patients with Cushing's disease for whom surgery is not an option. PMID- 22918544 TI - The coordination abilities of the multiHis-cyclopeptide with two metal-binding centers--potentiometric and spectroscopic investigation. AB - In this paper we present the formation of mono- and binuclear complexes by the octapeptide (c(HKHPHKHP)) with copper(II) ions. The ligand was synthesized manually by the solid-phase method. Its characteristic cyclic structure significantly influences the coordination abilities. The studied peptide has two Pro amino acid residues in the sequence. This causes the formation of two independent centres able to undertake metal ion binding. The potentiometric and spectroscopic (UV-vis, CD and EPR) studies were carried out in aqueous solutions in the pH range 2.5-11.0 at 298 K, HNO(3) was used as the solvent with KNO(3), where the ionic strength was 0.1 M. The analysis of the potentiometric together with spectroscopic studies have shown that the investigated peptide forms only mono-nuclear complexes when the metal-to-ligand molar ratio is 1 : 1. When the concentration of Cu(ii) ions increases and the ligand-to-metal molar ratio is 1 : 2 the formation of binuclear complexes is preferred in the system. PMID- 22918545 TI - Endoscope-integrated ICG technology: first application during intracranial aneurysm surgery. AB - Microscopic indocyanine green videoangiography (mICG-VA) has gained wide acceptance during intracranial aneurysm surgery by lowering rates of incomplete clipping and occlusion of surrounding vessels. However, mICG-VA images are limited to the microscopic view and some deeper areas, including the aneurysm sac/neck posterior side, cannot be efficiently assessed as they are hidden by the aneurysm, clips, or surrounding structures. Contrarily, endoscopes allow a wider area of visualization, but neurosurgical endoscopes to date only provided visual data. We describe the first application of endoscope ICG-integrated technology (eICG) applied in an initial case of anterior communicating artery aneurysm clipping. This new technique provided also relevant information regarding aneurysm occlusion and patency of parent and branching vessels and small perforating arteries. eICG-VA provided additional information compared to mICG-VA by magnifying areas of interest and improving the ability to view less accessible regions, especially posterior to the aneurysm clip. Obtaining eICG sequences required currently the microscope to be moved away from the operating field. eICG VA was only recorded under infrared illumination which prevented tissue handling, but white-infrared light views could be interchanged instantaneously. Further development of angled endoscopes integrating the ICG technology and dedicated filters blocking the microscopic light could improve visualization capacities even further. In conclusion, as a result of its ability to reveal structures around corners, the eICG-VA technology could be beneficial when used in combination with mICG-VA to visualize and confirm vessel patency in areas that were previously hidden from the microscope. PMID- 22918546 TI - Impact and feasibility of breast crawl in a tertiary care hospital. AB - OBJECTIVE: To determine the impact of breast crawl on breast feeding and its feasibility and acceptability in a busy labor room. STUDY DESIGN: A prospective, single blinded, randomized controlled clinical trial. Impact of breast crawl was studied in one group and the outcome was compared with the other group where breast crawl was not performed. Feasibility and acceptability was determined by analysis of questionnaire given to obstetricians and nurses. Descriptive statistics and chi(2)-analysis was applied to evaluate the questionnaire and to compare the outcome in the two groups. RESULT: Breast crawl had a significant positive impact on the onset of lactation (P=0.0005) as well as extent of neonatal weight loss on day 3 (0.032). CONCLUSION: Our study adds to the body of evidence that breast crawl results in positive short-term breast feeding outcome but acceptability of breast crawl as a routine in a busy labor room remains a major issue. PMID- 22918547 TI - Comprehensive strategy including prophylactic mupirocin to reduce Staphylococcus aureus colonization and infection in high-risk neonates. AB - OBJECTIVE: To examine the use of long-term prophylactic mupirocin as part of a comprehensive strategy in reducing Staphylococcus aureus colonization and infection in a neonatal intensive care unit (NICU). STUDY DESIGN: Twice daily mupirocin was applied to all infants admitted to the NICU throughout hospitalization starting in 2004. S. aureus surveillance was implemented in 2008. The efficacy of these practices was evaluated with a retrospective review of infants admitted from 2004 to 2010 found to be colonized or infected with S. aureus. RESULT: During the study period, 66 of 6283 NICU infants had a S. aureus infection with 67% methicillin resistance. There were three distinctive S. aureus outbreaks, the first being a methicillin-resistant strain July 2004. After implementation of daily mupirocin, the outbreak was eradicated and the rate of S. aureus infection significantly decreased (1.82 to 0.40/1000 patient-days-at-risk, P=0.0049). Mupirocin was discontinued March 2005 followed by a methicillin sensitive S. aureus outbreak November 2005. In December 2005, mupirocin was reinstituted and has continued to present day, again significantly reducing S. aureus infections (1.42 to 0.33/1000 patient-days-at-risk, P<0.0001) with zero isolates resistant to mupirocin. In the pre-mupirocin period, S. aureus colonization was upwards of 60% now with rates typically <5%. S. aureus colonization strongly predicted later invasive infection (P<0.0001). CONCLUSION: Although controversial, prophylactic mupirocin in all NICU infants has acted as a barrier to colonization and markedly decreased S. aureus infection rates over a 5 year period. PMID- 22918548 TI - Integrated in silico approaches for the prediction of Ames test mutagenicity. AB - The bacterial reverse mutation assay (Ames test) is a biological assay used to assess the mutagenic potential of chemical compounds. In this paper approaches for the development of an in silico mutagenicity screening tool are described. Three individual in silico models, which cover both structure activity relationship methods (SARs) and quantitative structure activity relationship methods (QSARs), were built using three different modelling techniques: (1) an in house alert model: which uses SAR approach where alerts are generated based on experts judgements; (2) a kNN approach (k-Nearest Neighbours), which is a QSAR model where a prediction is given based on outcomes of its k chemical neighbours; (3) a naive Bayesian model (NB), which is another QSAR model, where a prediction is derived using a Bayesian formula through preselected identified informative chemical features (e.g., physico-chemical, structural descriptors). These in silico models, were compared against two well-known alert models (DEREK and ToxTree) and also against three different consensus approaches (Categorical Bayesian Integration Approach (CBI), Partial Least Squares Discriminate Analysis (PLS-DA) and simple majority vote approach). By applying these integration methods on the validation sets it was shown that both integration models (PLS-DA and CBI) achieved better performance than any of the individual models or consensus obtained by simple majority rule. In conclusion, the recommendation of this paper is that when obtaining consensus predictions for Ames mutagenicity, approaches like PLS-DA or CBI should be the first choice for the integration as compared to a simple majority vote approach. PMID- 22918549 TI - The risk of a second primary lung cancer after a first invasive breast cancer according to estrogen receptor status. AB - PURPOSE: Lung cancers account for 5 % of second primary cancers after breast cancer. The low overall 5-year relative survival rate of lung cancer makes it a particularly concerning new malignancy for breast cancer survivors. It is unknown whether second lung cancer risk varies by estrogen receptor (ER) expression of the first breast cancer. METHODS: We evaluated second primary lung cancer risks using standardized incidence ratios (SIRs) (95 % confidence intervals (CIs)) among 222,148 one-year breast cancer survivors in the NCI-SEER Program registry database (1992-2008). Relative risks (RRs) and 95 % CIs for lung cancer following ER(-) compared with ER(+) breast cancer were estimated using Poisson regression, adjusted for age, year, and stage of breast cancer diagnosis, attained age, latency, and radiotherapy. We also examined the reciprocal association of second ER(-) and ER(+) breast cancers among 28,107 1-year lung cancer survivors. RESULTS: There were 418 and 1,444 second lung cancers diagnosed following 50,781 ER(-) and 171,367 ER(+) breast cancers. Second lung cancer rates were significantly elevated after ER(-) (SIR = 1.20 (1.09-1.33)), but not ER(+) (SIR = 0.96 (0.91-1.01)) breast cancer. The adjusted RR for a second lung cancer following ER(-) compared with ER(+) breast cancer was 1.22 (1.10-1.37). The reciprocal adjusted RR for a second ER(-) compared with ER(+) breast cancer following lung cancer was 1.29 (0.98-1.70). CONCLUSION: The parallel increase for a second lung cancer following an ER(-) first breast cancer and for a second ER( ) breast cancer after a first lung cancer suggests that there may be shared etiologic factors for these cancers. Further evaluation of lung cancer risk after ER(-) breast cancer may identify women at high risk for this fatal malignancy. PMID- 22918550 TI - Surface characterization and biocompatibility of titanium alloys implanted with nitrogen by Hardion+ technology. AB - In this study, the new Hardion+ micro-implanter technology was used to modify surface properties of biomedical pure titanium (CP-Ti) and Ti-6Al-4V ELI alloy by implantation of nitrogen ions. This process is based on the use of an electron cyclotron resonance ion source to produce a multienergetic ion beam from multicharged ions. After implantation, surface analysis methods revealed the formation of titanium nitride (TiN) on the substrate surfaces. An increase in superficial hardness and a significant reduction of friction coefficient were observed for both materials when compared to non-implanted samples. Better corrosion resistance and a significant decrease in ion release rates were observed for N-implanted biomaterials due to the formation of the protective TiN layer on their surfaces. In vitro tests performed on human fetal osteoblasts indicated that the cytocompatibility of N-implanted CP-Ti and Ti-6Al-4V alloy was enhanced in comparison to that of the corresponding non treated samples. Consequently, Hardion+ implantation technique can provide titanium alloys with better qualities in terms of corrosion resistance, cell proliferation, adhesion and viability. PMID- 22918551 TI - Body weight loss by very-low-calorie diet program improves small artery reactive hyperemia in severely obese patients. AB - BACKGROUND: Endothelial dysfunction is a major underlying mechanism for the elevated cardiovascular risk associated with increased body weight. We aimed to assess the impact of weight loss induced by an intensive very-low-calorie diet (VLCD) on arterial wall function in severely obese patients (SOP). METHODS: Thirty-four SOP were admitted to the metabolic ward of the hospital for a 3-week period. A VLCD characterized by a liquid diet providing 800 kcal/day was administered. The small artery reactivity to postischemic hyperemia index (saRHI), a surrogate marker of endothelial function, was assessed before and 1 week after hospital discharge. Anthropometry and biochemical parameters were also measured. Obese and non-obese age- and gender-matched groups were recruited for baseline comparisons. RESULTS: SOP had significantly lower saRHI compared with obese and non-obese individuals. SaRHI significantly increased after the intervention in SOP (1.595 +/- 0.236 vs. 1.737 +/- 0.417, p = 0.015). A significant improvement in glucose (p = 0.026), systolic blood pressure (p = 0.049), LDLc (p < 0.001), and inflammatory parameters was observed. Body weight loss was associated with a higher saRHI (r = -0.385, p = 0.033), and it was the main determinant of saRHI variation independently of confounders (beta -0.049, IC 95 % -0.091-0.008, p = 0.021). CONCLUSIONS: Weight loss induced by a VLCD in SOP improved small artery reactivity, and it was associated with the amelioration of metabolic and inflammation markers. Endothelial dysfunction may be softened by body weight loss interventions and useful in the management of cardiovascular risk factors in SOP. PMID- 22918552 TI - Effectiveness of bariatric surgery in reducing weight and body mass index among Hispanic adolescents. AB - BACKGROUND: Ethnic minority adolescents, Hispanics in particular, are disproportionately affected by extreme obesity and its associated co-morbidities. Bariatric surgery is one of the few effective treatments for morbid obesity, yet little information about weight outcomes after surgery in this demographic are available. We determined the effectiveness of bariatric surgery in reducing weight and body mass index (BMI) in adolescents, a majority of whom were non Mexican American Hispanic and originated from Central and/or South America and the Caribbean Basin region. METHODS: Adolescents (16-to-19 years old) who had undergone gastric bypass or adjustable gastric band surgery between 2001 and 2010 and who had complete follow-up data available (91 %) were included in the analysis. Mean weight and BMI before and 1-year after surgery were compared. RESULTS: Among 71 adolescents (80 % Hispanic, 77 % female), mean BMI and weight, and z-scores and percentile transformations were all significantly lower after surgery for the entire sample (P < 0.001). Gastric bypass surgery showed significantly better weight loss outcomes for all anthropometric measures versus adjustable gastric band surgery (P < 0.05). Weight loss was similar among Hispanics and non-Hispanics. No peri-operative complications were reported. Three patients who stopped taking supplements as prescribed experienced iron deficiency anemia within the year following surgery. CONCLUSIONS: Our results show that bariatric surgery, gastric bypass procedure in particular, can markedly reduce weight among a predominantly Hispanic adolescent patient sample. These findings indicate that bariatric surgery has the potential to be safe and effective in substantially reducing weight in a group of adolescents who are at a particularly high risk for obesity-related health consequences. PMID- 22918553 TI - Determinants of bleeding phenotype in adult patients with moderate or severe von Willebrand disease. AB - We performed a nation-wide cross-sectional study to evaluate determinants of bleeding symptoms in a large unselected cohort of adults with von Willebrand disease (VWD). VWD patients were included (n=664), based on lowest historically measured VWF:Ag and VWF:Act levels <=30 U/dl. Menorrhagia (85%), cutaneous bleeding (77%), bleeding from minor wounds (77%) and oral-cavity bleeding (62%) occurred most frequently. Higher age was associated with a higher bleeding score (BS), determined according to Tosetto, in females. A 10 year increase in age was associated with 0.8 point (95% confidence interval [CI] 0.4-1.1) higher BS. Females had higher BS than males (median 12 vs. 10, p=0.012). BS differed significantly between VWD type 1, 2 and 3: median 9 (-2-31), 13 (-1-33) and 19.5 (1-35), respectively (p<0.001). BS was strongly associated with VWF and FVIII levels: individuals with VWF:Ag levels <=10 IU/dl, VWF:Act <=10 IU/dl and FVIII:C <=10 IU/dl had, respectively, 5.3 point (95%CI 3.2-7.3), 4.3 point (95%CI 2.9 5.8) and 9.6 point (95%CI 6.5-12.7) higher BS, than those with levels >30 IU/dl. In type 3 patients 1 IU/dl FVIII:C decrease was associated with 0.6 point (95% CI 0.1-1.1) BS increase (p=0.021). In conclusion, in VWD patients the bleeding phenotype is strongly associated with type of VWD and VWF and FVIII levels. PMID- 22918554 TI - Identification of human immunodeficiency virus-1 (HIV-1) transmission from a 29 year-old daughter to her mother in Shanghai, China. AB - BACKGROUND AND METHODS: Routes of intrafamilial transmission of HIV-1 are not always clear. Here, we describe transmission to a mother from her 29-year-old daughter within a family setting through clinical, epidemiological and molecular evidence. We evaluated the risk factors for intrafamilial transmission of HIV-1 infection through qualitative epidemiology following pol and env gene sequencing and phylogenetic analysis. RESULT: The nucleotide sequences of the pol and env genes of the two strains from the two patients in the family were 99 % and 100 % identical, respectively, and they clustered with CRF07_BC, which includes the main recombinant strains in Shanghai, China. The diversity of genetic clones between the env and pol genes was insignificant (p > 0.05). The drug-resistance associated mutation positions of the two viral strains were basically similar and indicated that both were susceptible to the first-line anti-retroviral drugs including zidovudine (AZT), lamivudine (3TC), efavirenz (EFV) and nevirapine (NVP) prior to the initiation of highly active antiretroviral treatment (HAART), providing additional evidence of a close similarity between the quasispecies of the two family members. CONCLUSION: In this family, the two strains of the virus, isolated from the mother and her adult daughter, had very high homology. In the context of their clinical histories, we can make a conclusion that the mother was infected by the virus in her daughter's blood or other body fluids, but no overt transmission route has been clarified. This investigation also suggested that intimate personal exposure in the same household can contribute to HIV-1 transmission and underscores the need to educate persons who care for or are in contact with HIV-infected persons in household settings where such exposures may occur. PMID- 22918555 TI - Tomato leaf curl Joydebpur virus: a monopartite begomovirus causing severe leaf curl in tomato in West Bengal. AB - A begomovirus was isolated from tomato plants showing leaf curl and stunting symptoms in farmers' fields near the district of Kalyani, West Bengal, India. Viral genomic components amplified by rolling-circle amplification were cloned and sequenced. The genome organization of this virus was found to be similar to those of Old World monopartite begomovirus, with DNA A and a betasatellite component. Neither alphasatellite nor DNA B component was detected. The begomovirus showed highest sequence identity of 93.6% to tomato leaf curl Joydebpur virus (ToLCJoV-[IN:Kal:Chi:06]) and was thus identified to be an isolate of ToLCJoV. The betasatellite isolated from these samples was identified as tomato leaf curl Joydebpur betasatellite. ToLCJoV-[IN:Kal:Tom:08] alone induced severe symptoms in Solanum lycopersicum, N. benthamiana and N. glutinosa plants, and its severity was enhanced when co-inoculated with the cognate betasatellite. ToLCJoV-[IN:Kal:Tom:08] trans-replicated four more non-cognate betasatellites and induced severe symptoms in N. benthamiana and tomato. Since DNA A replicated efficiently and caused systemic symptom expression, it is hypothesized that ToLCJoV is essentially a monopartite virus, which could have acquired a betasatellite from an unknown source. PMID- 22918556 TI - Electron and nuclear spin dynamics in the thermal mixing model of dynamic nuclear polarization. AB - A novel mathematical treatment is proposed for computing the time evolution of dynamic nuclear polarization processes in the low temperature thermal mixing regime. Without assuming any a priori analytical form for the electron polarization, our approach provides a quantitative picture of the steady state that agrees with the well known Borghini prediction based on thermodynamic arguments, as long as the electrons-nuclei transition rates are fast compared to the other relevant time scales. Substantially different final polarization levels are achieved instead when the latter assumption is relaxed in the presence of a nuclear leakage term, even though very weak, suggesting a possible explanation for the deviation between the measured steady state polarizations and the Borghini prediction. The proposed methodology also allows us to calculate nuclear polarization and relaxation times, once the electrons/nuclei concentration ratio and the typical rates of the microscopic processes involving the two spin species are specified. Numerical results are shown to account for the manifold dynamic behaviours of typical DNP samples. PMID- 22918557 TI - Effects of a high-carbohydrate versus high-protein meal on acute responses to hypoxia at rest and exercise. AB - A carbohydrate (CHO) solution consumed before exposure to hypoxia has been reported to reduce arterial oxygen desaturation at rest. The purpose of this study was to determine whether this effect occurred during exercise and when the CHO load is part of a meal. Eleven male subjects (mean age 20.1 +/- 1.8 years, BMI 24.3 +/- 2.4 kg m(2)) consumed either a high-CHO (2,340 kJ, 70 % CHO, 12 % protein) or an isoenergetic high-protein (35 % CHO, 48 % protein) breakfast meal 60 min before being exposed to 15 min of hypoxia (F(I)O(2) = 13.5 %) followed by 30 min of exercise in hypoxia (60 % of VO2max). Saturation of oxygen via a pulse oxymeter (SpO(2)), ventilatory parameters, substrate oxidation, interstitial glucose concentrations, and heart rate variability (HRV) were monitored continuously during the whole session. Results showed no effect from the type of meal on SpO(2) at rest but a 3.1 +/- 0.4 % reduction of desaturation during exercise (P < 0.005) compared to the high-protein version. This was associated with higher levels of ventilation (P < 0.05) and CO(2) production (P < 0.01). Glucose oxidation was higher after the high-CHO than the high-protein breakfast over the whole session (+19.4 + 4.0 %, P < 0.0001), whereas the interstitial glucose levels were increased only at rest (P < 0.001). HRV indices were not different between conditions. In conclusion, a high-CHO meal consumed prior to moderate exercise in hypoxia condition reduced oxygen desaturation compared to a high-protein meal. PMID- 22918558 TI - Acute anxiety increases the magnitude of the cold shock response before and after habituation. AB - Cold immersion evokes the life-threatening cold shock response (CSR). We hypothesised that anxiety may increase the magnitude of (Study 1), and diminish habituation to (Study 2), the CSR. Study 1: eleven participants completed two 7 min immersions in cold water (15 degrees C). On one occasion, to induce anxiety, participants were instructed that the water would be 5 degrees C colder (ANX); it was unchanged. The other immersion was a control (CON). Study 2: ten different participants completed seven, 7-min immersions. Immersions 1-5 induced habituation. Immersions 6 and 7 were counter-balanced to produce anxiety (ANX) or acted as a control (CON). Anxiety (20 cm scale) and cardiorespiratory responses (cardiac frequency [f(c)]), respiratory frequency [f(R)], tidal volume [V(T)], minute ventilation [V(E)]) were measured in both studies. Results of study 1: participants were more anxious in the ANX immersion (mean [SD]; CON 5.3 [3.6] and ANX 8.4 [5.0] cm). f(c) peaked at higher levels in ANX (136.4 [15.0]; CON: 124.0 [17.6] b min(-1)) and was higher pre-immersion and in minutes 3 and 5-7 by 7.2 [2.1] b min(-1). ANX [Formula: see text] was higher pre immersion and in minutes 5-6. Results of study 2: repeated immersion habituated the CSR. Anxiety was greater prior to ANX (CON 1.9 [2.3], ANX 6.6 [4.8] cm). f (c) in ANX was higher prior to immersion and in minutes 1-2, 4-6 cf CON; ANX f (c) was not different to the CSR seen in pre-habituation. f (R) was higher in minute 1 of immersion 1 (cf min 1 CON and ANX) following which it exceeded the CSR in CON. The magnitude and duration of CSR (f(c), V(E)) increased with anxiety. Anxiety diminishes CSR habituation. PMID- 22918559 TI - Distinctive bronchial inflammation status in athletes: basophils, a new player. AB - The aim of the study was to establish bronchial inflammation status and to measure eicosanoids in sputum obtained from active elite athletes. A total of 68 subjects were enrolled. Twelve were non-athletes and non-asthmatic (NAtNAs), 21 non-athlete asthmatics (NAtAs), 11 athlete non-asthmatics (AtNAs), and 24 athletes with asthma (AtAs) with positive indirect or direct bronchial challenges. Induced sputum was used to measure cells and eicosanoids. Sputum differential cell counts in all the subject groups revealed eosinophilia with the exception of NAtNAs control subjects. Athletes with and without diagnosed asthma showed a significant increase in bronchial epithelial cells and lymphocytes present in their sputum. Also, flow cytometry revealed that a significantly higher number of basophils were present in sputum from athletes (without and with asthma) when compared with non-athletes (without and with asthma). Asthmatic athletes and non-athletes showed a higher increase in LTC(4) levels and PGE(2) metabolites in sputum when compared with healthy controls. The present study identifies basophils as a new player present in athletes bronchial inflammation defining athlete status and not necessarily associated with exercise-induced bronchoconstriction. PMID- 22918560 TI - Symptoms of anxiety and mood disturbance alter cardiac and peripheral autonomic control in patients with metabolic syndrome. AB - Previous investigations show that metabolic syndrome (MetSyn) causes sympathetic hyperactivation. Symptoms of anxiety and mood disturbance (AMd) provoke sympatho vagal imbalance. We hypothesized that AMd would alter even further the autonomic function in patients with MetSyn. Twenty-six never-treated patients with MetSyn (ATP-III) were allocated to two groups, according to the levels of anxiety and mood disturbance: (1) with AMd (MetSyn + AMd, n = 15), and (2) without AMd (MetSyn, n = 11). Ten healthy control subjects were also studied (C, n = 10). AMd was determined using quantitative questionnaires. Muscle sympathetic nerve activity (MSNA, microneurography), blood pressure (oscillometric beat-to-beat basis), and heart rate (ECG) were measured during a baseline 10-min period. Spectral analysis of RR interval and systolic arterial pressure were analyzed, and the power of low (LF) and high (HF) frequency bands were determined. Sympatho vagal balance was obtained by LF/HF ratio. Spontaneous baroreflex sensitivity (BRS) was evaluated by calculation of alpha-index. MSNA was greater in patients with MetSyn + AMd compared with MetSyn and C. Patients with MetSyn + AMd showed higher LF and lower HF power compared with MetSyn and C. In addition, LF/HF balance was higher in MetSyn + AMd than in MetSyn and C groups. BRS was decreased in MetSyn + AMd compared with MetSyn and C groups. Anxiety and mood disturbance alter autonomic function in patients with MetSyn. This autonomic dysfunction may contribute to the increased cardiovascular risk observed in patients with mood alterations. PMID- 22918561 TI - Inhibition, interference, and conflict in task switching. AB - The role of inhibition in the task-switching process has received increased empirical and theoretical attention in the literature on cognitive control. Many accounts have suggested that inhibition occurs when a conflict must be resolved for example, when a target stimulus contains features of more than one task. In the two experiments reported here, we used variants of backward inhibition, or N 2 repetition, designs to examine (1) whether inhibition occurs in the absence of conflict at the stimulus or response level, (2) when in the task-switching process such inhibition may occur, and (3) the potential consequences of inhibition. In Experiment 1, we demonstrate that neither stimulus- nor response level conflict is necessary for inhibition to occur, while the results of Experiment 2 suggest that inhibition may be associated with a reduction of proactive interference (PI) from a previously performed task. Evidence of inhibition and the reduction of PI both occurred at the task-set level. However, inhibition of specific stimulus values can also occur, but this is clearly separable from task-set inhibition. Both experiments also provided evidence that task-set inhibition can be applied at the time of the new task cue, as opposed to at the onset of the target or at the response stage of the trial. Taken together, the results from these experiments provide insight into when and where in the task-switching process inhibition may occur, as well as into the potential functional benefits that inhibition of task sets may provide. PMID- 22918562 TI - Initial experience with single-source dual-energy CT abdominal angiography and comparison with single-energy CT angiography: image quality, enhancement, diagnosis and radiation dose. AB - OBJECTIVES: To assess image quality of virtual monochromatic spectral (VMS) images, compared to single-energy (SE) CT, and to evaluate the feasibility of material density imaging in abdominal aortic disease. METHODS: In this retrospective study, single-source (ss) dual-energy (DE) CT of the aorto-iliac system in 35 patients (32 male, mean age 76.5 years) was compared to SE-CT. By post-processing the data from ssDECT, VMS images at different energies and material density water (WD) images were generated. The image quality parameters were rated on 5-point scales. The aorto-iliac attenuation and contrast-to-noise ratio (CNR) were recorded. Quality of WD images was compared to true unenhanced (TNE) images. Radiation dose was recorded and statistical analysis was performed. RESULTS: Image quality and noise were better at 70 keV (P < 0.01). Renal artery branch visualisation was better at 50 keV (P < 0.005). Attenuation and CNR were higher at 50 and 70 keV (P < 0.0001). The WD images had diagnostic quality but higher noise than TNE images (P < 0.0001). Radiation dose was lower using single phase ssDECT compared to dual-phase SE-CT (P < 0.0001). CONCLUSION: 70-keV images from ssDECT provide higher contrast enhancement and improved image quality for aorto-iliac CT when compared to SE-CT at 120 kVp. WD images are an effective substitute for TNE images with a potential for dose reduction. PMID- 22918563 TI - Quantitative assessment of change in regional disease patterns on serial HRCT of fibrotic interstitial pneumonia with texture-based automated quantification system. AB - OBJECTIVES: To evaluate the usefulness of a texture-based automated quantification system (AQS) for evaluating the extent and interval change of regional disease patterns on initial and follow-up high-resolution computed tomographies (HRCTs) of fibrotic interstitial pneumonia (FIP). METHODS: Eighty nine patients with clinically and/or biopsy confirmed usual interstitial pneumonia (UIP) (n = 71) and non-specific interstitial pneumonia (NSIP) (n = 18) were included. An AQS to quantify five disease patterns (ground-glass opacity [GGO], reticular opacity [RO], honeycombing [HC], emphysema [EMPH], consolidation [CONS]) and normal lung was developed. The extent and interval changes of each disease pattern, FS (fibrosis score), TA (total abnormal lung fraction) of entire lung on initial and 1-year follow-up HRCTs were quantified. The agreement between the results of AQS and two readers was assessed. Results of AQS were correlated with forced vital capacity (FVC) and carbon monoxide diffusing capacity (DLco). RESULTS: The Intraclass correlation coefficient (ICC) study revealed acceptable agreement between visual assessment and AQS (r = 0.78, 0.66 for HC; 0.76, 0.61 for FS; 0.64, 0.68 for TA, initial and follow-up HRCTs, respectively). Linear regression analysis revealed the extent of HC, TA on initial CT, interval changes of FS contributed negatively to DLco, and interval changes of FS, TA contributed negatively to FVC. CONCLUSIONS: Our AQS is comparable with visual assessment for evaluating the disease extent and the interval changes of FIP on HRCT. PMID- 22918564 TI - Choi response criteria for prediction of survival in patients with metastatic renal cell carcinoma treated with anti-angiogenic therapies. AB - OBJECTIVE: Anti-angiogenic drugs cause a reduction in tumour density (Choi criteria) first and then in size [Response Evaluation Criteria In Solid Tumours (RECIST)]. The prognostic significance of changes in tumour density in metastatic renal cell carcinoma (mRCC) is unknown and was assessed in this study. METHODS: The prognostic significance of partial response (PR) as opposed to non-response [stable disease (SD) + progressive (PD)] to anti-angiogenic therapy was assessed in patients with mRCC separately for both criteria using the log-rank test and Cox regression models. RESULTS: Both criteria were applied to 35 patients. The response was identical for all eight patients with PR and most patients with PD (10/12) when using the RECIST and Choi criteria. Adding tumour density information, 14 patients with SD were re-categorised as having PR (7), SD (4), and PD (3). Patients with PR (Choi) were progression free significantly longer [hazard ratio (HR) 0.24; 95 % CI 0.10-0.57; P = 0.001] and had better overall survival (HR 0.36; 95 % CI 0.15-0.89; P = 0.026) compared to patients with SD or PD. The predictive value of PR according to RECIST was not statistically significant. CONCLUSIONS: In mRCC, the Choi criteria separate prognostic groups better when compared with RECIST. This may allow early discrimination of patients benefiting from continued treatment. PMID- 22918565 TI - Prediction of lethal and synthetically lethal knock-outs in regulatory networks. AB - The complex interactions involved in regulation of a cell's function are captured by its interaction graph. More often than not, detailed knowledge about enhancing or suppressive regulatory influences and cooperative effects is lacking and merely the presence or absence of directed interactions is known. Here, we investigate to which extent such reduced information allows to forecast the effect of a knock-out or a combination of knock-outs. Specifically, we ask in how far the lethality of eliminating nodes may be predicted by their network centrality, such as degree and betweenness, without knowing the function of the system. The function is taken as the ability to reproduce a fixed point under a discrete Boolean dynamics. We investigate two types of stochastically generated networks: fully random networks and structures grown with a mechanism of node duplication and subsequent divergence of interactions. On all networks we find that the out-degree is a good predictor of the lethality of a single node knock out. For knock-outs of node pairs, the fraction of successors shared between the two knocked-out nodes (out-overlap) is a good predictor of synthetic lethality. Out-degree and out-overlap are locally defined and computationally simple centrality measures that provide a predictive power close to the optimal predictor. PMID- 22918567 TI - ALCAPA syndrome in an adult. PMID- 22918566 TI - Molecular signatures and the study of gene expression profiles in inflammatory heart diseases. AB - Myocarditis, a common heart disease pathologically defined as an inflammatory reaction of the myocardium, is most frequently caused by infectious agents, including viruses and bacteria, and may develop in later stages into dilated cardiomyopathy (DCM). Several studies have identified inflammatory components engaged in the transition from acute myocarditis to chronic DCM, and there is growing evidence that myocarditis and DCM are closely related. Novel technological advances in genomic screening have gained insight into molecular and cellular mechanisms involved the pathogenesis of inflammatory heart disease and, in particular, in the development of systolic dysfunction resulting from DCM. Detection of differential gene expression profiles have become valid tools in the study of inflammatory heart disease. Molecular signatures are defined as individual sets of genes, mRNA transcripts, proteins, genetic variations or other variables, which can be used as markers for a particular phenotype. These signatures may be useful for clinical diagnosis or risk assessment and, in addition, may help to identify molecules not previously known to be involved in the pathogenesis of these disease conditions. Microarray analyses have dramatically refined our knowledge about tissue-specific gene expression patterns, simply by being able to study thousands of genes simultaneously in a single experiment. In the field of cardiovascular research, microarrays are increasingly used in the study of end-stage cardiomyopathies, such as DCM, that ultimately lead to symptoms of heart failure. By means of microarray analysis, a set of differentially expressed genes can be detected, among them are transcripts coding for sarcomeric and extracellular matrix proteins, stress response and inflammatory proteins as well as transcription factors and translational regulators. Expression profiling may be particularly helpful to improve the differential diagnosis of heart failure and enable novel insight into selected molecular pathways. PMID- 22918568 TI - X-ray microscopy and tomography detect the accumulation of bare and PEG-coated gold nanoparticles in normal and tumor mouse tissues. AB - We demonstrate that, with appropriate staining, high-resolution X-ray microscopy can image complicated tissue structures--cerebellum and liver--and resolve large or small amounts of Au nanoparticles in these tissues. Specifically, images of tumor tissue reveal high concentrations of accumulated Au nanoparticles. PEG (poly(ethylene glycol)) coating is quite effective in enhancing this accumulation and significantly modifies the mechanism of uptake by reticuloendothelial system (RES) organs. PMID- 22918569 TI - Use of synchrotron-radiation-based FTIR imaging for characterizing changes in cell contents. AB - FTIR imaging of individual cells is still limited by the low signal-to-noise ratio obtained from analysis of such weakly absorbing organic matter when using a Globar IR source. In this study, we used FTIR imaging with a synchrotron radiation source and a focal plane array detector to determine changes in the cellular contents of cryofixed cells after culture for 48 h on Si(3)N(4) substrate. Several spectral differences were observed for cells deprived of glucose compared with control cells: a lower amide I-to-amide II ratio (P < 0.01); a different secondary structure profile of proteins (obtained from amide I spectral region curve fitting), with a significant increase in non-ordered structure components (P < 0.01); and a higher nu(C = C-H)/nu(as)(CH(3)) absorption ratio (P < 0.01), suggesting increased unsaturation of fatty acyl chains. Therefore, our study has shown that FTIR imaging with a synchrotron radiation source enables determination of several spectral changes of individual cells between two experimental conditions, which thus opens the way to cell biology studies with this vibrational spectroscopy technique. PMID- 22918571 TI - Low-dose coronary-CT angiography using step and shoot at any heart rate: comparison of image quality at systole for high heart rate and diastole for low heart rate with a 128-slice dual-source machine. AB - To compare image quality of coronary CT angiography in step-and-shoot mode at the diastolic phase at low heart rates (<70 bpm) and systolic phase at high heart rates (>=70 bpm). We prospectively included 96 consecutive patients then excluded 5 patients with arrhythmia. Coronary CT-angiography was performed using a dual source 128-slice CT machine, at the diastolic phase in the 55 patients with heart rates <70 bpm (group D) and at the systolic phase in the 36 patients with heart rates >=70 (group S). Image quality was scored on a 5 point-scale (1, not interpretable; 2, insufficient for diagnosis; 3, fair, sufficient for diagnosis; 4, good; 5, excellent). In addition, we compared the number of stair-step artifacts in the two groups. Mean image quality score was 4 (0.78) in group D and 4.1 (0.34) in group S (NS), with an unequal distribution (p = 0.01). Step artifacts were seen in 44 % of group D and 18 % of group S patients (p = 0.02). In 3 group D patients and no group S patients, the image score was <3 due to artifacts, requiring repeat CT-angiography. When performing dual-source 128-slice CT-angiography, step-and-shoot acquisition provides comparable mean image quality in systole, with less variability and fewer stair-step artifacts, compared to diastole. This method may be feasible at any heart rate in most patients in sinus rhythm, allowing low-dose prospective acquisition without beta-blocker premedication. PMID- 22918570 TI - Serotonin circuits and anxiety: what can invertebrates teach us? AB - Fear, a reaction to a threatening situation, is a broadly adaptive feature crucial to the survival and reproductive fitness of individual organisms. By contrast, anxiety is an inappropriate behavioral response often to a perceived, not real, threat. Functional imaging, biochemical analysis, and lesion studies with humans have identified the HPA axis and the amygdala as key neuroanatomical regions driving both fear and anxiety. Abnormalities in these biological systems lead to misregulated fear and anxiety behaviors such as panic attacks and post traumatic stress disorders. These behaviors are often treated by increasing serotonin levels at synapses, suggesting a role for serotonin signaling in ameliorating both fear and anxiety. Interestingly, serotonin signaling is highly conserved between mammals and invertebrates. We propose that genetically tractable invertebrate models organisms, such as Drosophila melanogaster and Caenorhabditis elegans, are ideally suited to unravel the complexity of the serotonin signaling pathways. These model systems possess well-defined neuroanatomies and robust serotonin-mediated behavior and should reveal insights into how serotonin can modulate human cognitive functions. PMID- 22918572 TI - Salmonella mycotic aneurysm: a rare cause of fever and back pain in elderly. AB - An 85-year-old man with history of hypertension presented with fever, cough and abdominal pain. Unfortunately fever and leukocytosis persisted despite treatment. Blood cultures obtained on admission grew Salmonella enteritidis. Subsequently he developed increasing back pain and transoesophageal echocardiography (TOE) was performed, demonstrating a complex ulcer at the aortic arch with multiple small mobile strandlike densities suggestive of vegetation. Contrast thoracic CT scan confirmed an ulcerated atherosclerotic plaque which progressively increasing in size over 3 months despite antibiotics. Therefore, a stent was deployed in view of high risk of perforation and he was placed on prolonged antibiotics. Post stenting CT scan a few months later showed a patent stent with the aneurysm remained stable in size. Cardiovascular infections develop in approximately 25 % of patients with Salmonella bacteremia. Most patients with Salmonella aortitis have preexisting atherosclerosis at the site of the subsequently infected aneurysm. The diagnosis of S. aortitis can be challenging, because the clinical course may be indolent and the symptoms are nonspecific. A high index of suspicion is required to make the diagnosis of S. aortitis, especially in patients with Salmonella bacteraemia, fever, back pain and/or abdominal pain. This case highlights the usefulness of TOE in the evaluation of diseases involving the thoracic aorta, leading to a successful intervention. PMID- 22918574 TI - Abstracts of the 15th Biennial Meeting of the European Society for Immunodeficiency. October 3-6, 2012. Florence, Italy. PMID- 22918573 TI - Impact of acute normobaric hypoxia on regional and global myocardial function: a speckle tracking echocardiography study. AB - Aim of this study was to evaluate the influence of normobaric hypoxia on myocardial function in healthy humans. Fourteen subjects underwent two dimensional speckle tracking echocardiography (2D-STE) examination during normoxia and in a normobaric hypoxia chamber. Examinations were performed at rest and during bicycle exercise test. The following parameters were quantified in both atria and ventricles by 2D-STE: Global Strain (S), systolic strain rate (SRS), early (SRE) and late (SRA) diastolic strain rate. During hypoxia SRS and SRE increased significantly in both ventricles compared to baseline. The increase of LV SRS and SRE during normoxic exercise was significantly higher when compared with exercise under hypoxia (for SRS -0.55 +/- 0.22 vs. -0.34 +/- 0.24 1/s, p = 0.024; for SRE 0.56 +/- 0.29 vs. 0.23 +/- 0.29 1/s, p = 0.005). For the right ventricle (RV) no significant difference of exercise induced increase of systolic contractility was found (SRS -1.07 +/- 0.53 under normoxia vs. -1.28 +/- 0.24 1/s under hypoxic conditions, p = 0.47). A shift from passive conduit (SRE) to active contraction (SRA) phase during hypoxia was noted for the right atrium (RA) (SRE/SRA 0.72 +/- 0.13 under hypoxia vs. 1.17 +/- 0.17 under normoxia). The ratio SRE/SRA of RA was closely related to pulmonary systolic pressure (r = -0.78, p < 0.001). Exposure to normobaric hypoxia leads to an increase of regional myocardial deformation in both ventricles. The contractile reserve during hypoxic exercise is reduced in LV, whereas RV systolic deformation rate is maintained. In addition, hypoxia had an impact on the ratio of passive conduit to active contraction phase in right atrium. PMID- 22918575 TI - Payor issues: barriers to optimal management of patients with primary immunodeficiency. AB - Since 2005, when changes in Medicare reimbursement for IgG replacement therapy went into effect, physicians and patients with primary immunodeficiency disease (PIDD) have encountered a number of challenges to administering and receiving appropriate immunoglobulin therapy. A 2006 membership survey conducted by the American Academy of Allergy, Asthma & Immunology found that 95 % of responders thought that the health of their patients was at risk due to Medicare changes; many patient surveys also found a significant number adversely affected by these changes. Decisions critical for optimal care being made by third-party payors are often in conflict with guidelines on recommended standard of care. Many payors, for example, are dictating where infusions can occur despite evidence clearly demonstrating that choice of the site of care needs to be determined by the particular patient's circumstance and experience. Another critical issue is the lack of product availability due to the determination by payors of which IgG products appear on formularies. Patients, physicians, and payors all bring their own perspective to these issues, and finding a solution to these challenges requires balancing the needs of all three groups. PMID- 22918577 TI - Composition and dynamics of the eukaryotic replisome: a brief overview. AB - High-fidelity chromosomal DNA replication is vital for maintaining the integrity of the genetic material in all forms of cellular life. In eukaryotic cells, around 40-50 distinct conserved polypeptides are essential for chromosome replication, the majority of which are themselves component parts of a series of elaborate molecular machines that comprise the replication apparatus or replisome. How these complexes are assembled, what structures they adopt, how they perform their functions, and how those functions are regulated, are key questions for understanding how genome duplication occurs. Here I present a brief overview of current knowledge of the composition of the replisome and the dynamic molecular events that underlie chromosomal DNA replication in eukaryotic cells. PMID- 22918576 TI - Reduction of rat cardiac hypertrophy by osthol is related to regulation of cardiac oxidative stress and lipid metabolism. AB - The objective of this study was to examine the therapeutic effect of osthol, a coumarin compound isolated from the fruit of Cnidium monnieri (L.) Cusson, on cardiac hypertrophy in rats and investigate its potential mechanisms. The rats with cardiac hypertrophy induced by renovascular hypertension were given osthol orally by gavage for 4 weeks. The results showed that in the osthol 20 mg/kg group, the blood pressure, heart weight index and myocardial malondialdehyde content were lowered (p < 0.001, p = 0.002 and p = 0.025, respectively), the myocardial superoxide dismutase and glutathione peroxidase contents were increased (p < 0.001), and the elevated unesterified fatty acids and triacylglycerols in myocardial tissues were decreased (p = 0.017 and p = 0.004, respectively). At the same time, the myocardial peroxisome proliferator-activated receptor (PPAR)-alpha and carnitine palmitoyltransferase (CPT)-1a mRNA expressions were increased and the myocardial diacylglycerol acyltransferase (DGAT) mRNA expression was decreased in the osthol 20 mg/kg group (p < 0.001). Osthol treatment was associated with a decreased cross-sectional area of cardiomyocytes (p < 0.001). These findings suggest that osthol may exert a therapeutic effect on cardiac hypertrophy in rats, and its mechanisms may be related to the improvement of myocardial oxidative stress and lipid metabolism via regulation of PPARalpha-mediated target gene expressions including an increase in CPT-1a mRNA expression and a decrease in DGAT mRNA expression. PMID- 22918578 TI - Evolutionary diversification of eukaryotic DNA replication machinery. AB - DNA replication research to date has focused on model organisms such as the vertebrate Xenopus laevis and the yeast species Saccharomyces cerevisiae and Schizosaccharomyces pombe. However, animals and fungi both belong to the Opisthokonta, one of about six eukaryotic phylogenetic 'supergroups', and therefore represent only a fraction of eukaryotic diversity. To explore evolutionary diversification of the eukaryotic DNA replication machinery a bioinformatic approach was used to investigate the presence or absence of yeast/animal replisome components in other eukaryotic taxa. A comparative genomic survey was undertaken of 59 DNA replication proteins in a diverse range of 36 eukaryotes from all six supergroups. Twenty-three proteins including Mcm2-7, Cdc45, RPA1, primase, some DNA polymerase subunits, RFC1-5, PCNA and Fen1 are present in all species examined. A further 20 proteins are present in all six eukaryotic supergroups, although not necessarily in every species: with the exception of RNase H2B and the fork protection complex component Timeless/Tof1, all of these are members of anciently derived paralogous families such as ORC, MCM, GINS or RPA. Together these form a set of 43 proteins that must have been present in the last common eukaryotic ancestor (LCEA). This minimal LCEA replisome is significantly more complex than the related replisome in Archaea, indicating evolutionary events including duplications of DNA replication genes in the LCEA lineage which parallel the early evolution of other complex eukaryotic cellular features. PMID- 22918580 TI - Archaeal orc1/cdc6 proteins. AB - The initiation of DNA replication in most archaeal genomes is mediated by proteins related to eukaryotic Orc1 and Cdc6. Archaeal replication origins have been mapped and their interactions with Orc1/Cdc6 proteins have been characterized at the biochemical level. Structural and biophysical studies have revealed the basic rules of sequence recognition by archaeal initiators. PMID- 22918581 TI - Cdt1 and geminin in DNA replication initiation. AB - One of the mechanisms controlling the initiation of DNA replication is the dynamic interaction between Cdt1, which promotes assembly of the pre-replication license complex, and Geminin, which inhibits it. Specifically, Cdt1 cooperates with the cell cycle protein Cdc6 to promote loading of the minichromosome maintenance helicases (MCM) onto the chromatin-bound origin recognition complex (ORC), by directly interacting with the MCM complex, and by modulating histone acetylation and inducing chromatin unfolding. Geminin, on the other hand, prevents the loading of the MCM onto the ORC both by directly binding to Cdt1, and by modulating Cdt1 stability and activity. Protein levels of Geminin and Cdt1 are tightly regulated through the cell cycle, and the Cdt1-Geminin complex likely acts as a molecular switch that can enable or disable the firing of each origin of replication. In this review we summarize structural studies of Cdt1 and Geminin and subsequent insights into how this molecular switch may function to ensure DNA is faithfully replicated only once during S phase of each cell cycle. PMID- 22918582 TI - MCM structure and mechanics: what we have learned from archaeal MCM. AB - Minichromosome maintenance (MCM) complexes have been identified as the primary replicative helicases responsible for unwinding DNA for genome replication. The focus of this chapter is to discuss the current structural and functional understanding of MCMs and their role at origins of replication, which are based mostly on the studies of MCM proteins and MCM complexes from archaeal genomes. PMID- 22918579 TI - The origin recognition complex: a biochemical and structural view. AB - The origin recognition complex (ORC) was first discovered in the baker's yeast in 1992. Identification of ORC opened up a path for subsequent molecular level investigations on how eukaryotic cells initiate and control genome duplication each cell cycle. Twenty years after the first biochemical isolation, ORC is now taking on a three-dimensional shape, although a very blurry shape at the moment, thanks to the recent electron microscopy and image reconstruction efforts. In this chapter, we outline the current biochemical knowledge about ORC from several eukaryotic systems, with emphasis on the most recent structural and biochemical studies. Despite many species-specific properties, an emerging consensus is that ORC is an ATP-dependent machine that recruits other key proteins to form pre replicative complexes (pre-RCs) at many origins of DNA replication, enabling the subsequent initiation of DNA replication in S phase. PMID- 22918583 TI - The eukaryotic Mcm2-7 replicative helicase. AB - In eukaryotes, the Mcm2-7 complex forms the core of the replicative helicase - the molecular motor that uses ATP binding and hydrolysis to fuel the unwinding of double-stranded DNA at the replication fork. Although it is a toroidal hexameric helicase superficially resembling better-studied homohexameric helicases from prokaryotes and viruses, Mcm2-7 is the only known helicase formed from six unique and essential subunits. Recent biochemical and structural analyses of both Mcm2-7 and a higher-order complex containing additional activator proteins (the CMG complex) shed light on the reason behind this unique subunit assembly: whereas only a limited number of specific ATPase active sites are needed for DNA unwinding, one particular ATPase active site has evolved to form a reversible discontinuity (gate) in the toroidal complex. The activation of Mcm2-7 helicase during S-phase requires physical association of the accessory proteins Cdc45 and GINS; structural data suggest that these accessory factors activate DNA unwinding through closure of the Mcm2-7 gate. Moreover, studies capitalizing on advances in the biochemical reconstitution of eukaryotic DNA replication demonstrate that Mcm2-7 loads onto origins during initiation as a double hexamer, yet does not act as a double-stranded DNA pump during elongation. PMID- 22918584 TI - The GINS complex: structure and function. AB - Eukaryotic chromosomal DNA replication is controlled by a highly ordered series of steps involving multiple proteins at replication origins. The eukaryotic GINS complex is essential for the establishment of DNA replication forks and replisome progression. GINS is one of the core components of the eukaryotic replicative helicase, the CMG (Cdc45-MCM-GINS) complex, which unwinds duplex DNA ahead of the moving replication fork. Eukaryotic GINS also links with other key proteins at the fork to maintain an active replisome progression complex. Archaeal GINS homologues play a central role in chromosome replication by associating with other replisome components. This chapter focuses on the molecular events related with DNA replication initiation, and summarizes our current understanding of the function, structure and evolution of the GINS complex in eukaryotes and archaea. PMID- 22918585 TI - The Pol alpha-primase complex. AB - Initiation of DNA synthesis in eukaryotic replication depends on the Pol alpha primase complex, a multi-protein complex endowed with polymerase and primase activity. The Pol alpha-primase complex assembles the RNA-DNA primers required by the processive Pol delta and Pol epsilon for bulk DNA synthesis on the lagging and leading strand, respectively. During primer synthesis, the primase subunits synthesise de novo an oligomer of 7-12 ribonucleotides in length, which undergoes limited extension with deoxyribonucleotides by Pol alpha. Despite its central importance to DNA replication, little is known about the mechanism of primer synthesis by the Pol alpha-primase complex, which comprises the steps of initiation, 'counting' and hand-off of the RNA primer by the primase to Pol alpha, followed by primer extension with dNTPs and completion of the RNA-DNA hybrid primer. Recent biochemical and structural work has started to provide some insight into the molecular basis of initiation of DNA synthesis. Important advances include the structural characterisation of the evolutionarily related archaeal primase, the elucidation of the mechanism of interaction between Pol alpha and its B subunit and the observation that the regulatory subunit of the primase contains an iron-sulfur cluster domain that is essential for primer synthesis. PMID- 22918586 TI - The structure and function of replication protein A in DNA replication. AB - In all organisms from bacteria and archaea to eukarya, single-stranded DNA binding proteins play an essential role in most, if not all, nuclear metabolism involving single-stranded DNA (ssDNA). Replication protein A (RPA), the major eukaryotic ssDNA binding protein, has two important roles in DNA metabolism: (1) in binding ssDNA to protect it and to keep it unfolded, and (2) in coordinating the assembly and disassembly of numerous proteins and protein complexes during processes such as DNA replication. Since its discovery as a vital player in the process of replication, RPAs roles in recombination and DNA repair quickly became evident. This chapter summarizes the current understanding of RPA's roles in replication by reviewing the available structural data, DNA-binding properties, interactions with various replication proteins, and interactions with DNA repair proteins when DNA replication is stalled. PMID- 22918588 TI - Structure and function of eukaryotic DNA polymerase delta. AB - DNA polymerase delta (Pol delta) is a member of the B-family DNA polymerases and is one of the major replicative DNA polymerases in eukaryotes. In addition to chromosomal DNA replication it is also involved in DNA repair and recombination. Pol delta is a multi-subunit complex comprised of a catalytic subunit and accessory subunits. The latter subunits play a critical role in the regulation of Pol delta functions. Recent progress in the structural characterization of Pol delta, together with a vast number of biochemical and functional studies, provides the basis for understanding the intriguing mechanisms of its regulation during DNA replication, repair and recombination. In this chapter we review the current state of the Pol delta structure-function relationship with an emphasis on the role of its accessory subunits. PMID- 22918587 TI - Structural biology of replication initiation factor Mcm10. AB - Minichromosome maintenance protein 10 (Mcm10) is a non-enzymatic replication factor required for proper assembly of the eukaryotic replication fork. Mcm10 interacts with single-stranded and double-stranded DNA, DNA polymerase alpha and Mcm2-7, and is important for activation of the pre-replicative complex and recruitment of subsequent proteins to the origin at the onset of S-phase. In addition, Mcm10 has recently been implicated in coordination of helicase and polymerase activities during replication fork progression. The nature of Mcm10's involvement in these activities, whether direct or indirect, remains unknown. However, recent biochemical and structural characterization of Mcm10 from multiple organisms has provided insights into how Mcm10 utilizes a modular architecture to act as a replisome scaffold, which helps to define possible roles in origin DNA melting, Pol alpha recruitment and coordination of enzymatic activities during elongation. PMID- 22918589 TI - DNA polymerase epsilon. AB - DNA polymerase epsilon (Pol epsilon) is one of three replicative DNA polymerases in eukaryotic cells. Pol epsilon is a multi-subunit DNA polymerase with many functions. For example, recent studies in yeast have suggested that Pol epsilon is essential during the initiation of DNA replication and also participates during leading strand synthesis. In this chapter, we will discuss the structure of Pol epsilon, the individual subunits and their function. PMID- 22918590 TI - The RFC clamp loader: structure and function. AB - The eukaryotic RFC clamp loader couples the energy of ATP hydrolysis to open and close the circular PCNA sliding clamp onto primed sites for use by DNA polymerases and repair factors. Structural studies reveal clamp loaders to be heteropentamers. Each subunit contains a region of homology to AAA+ proteins that defines two domains. The AAA+ domains form a right-handed spiral upon binding ATP. This spiral arrangement generates a DNA binding site within the center of RFC. DNA enters the central chamber through a gap between the AAA+ domains of two subunits. Specificity for a primed template junction is achieved by a third domain that blocks DNA, forcing it to bend sharply. Thus only DNA with a flexible joint can bind the central chamber. DNA entry also requires a slot in the PCNA clamp, which is opened upon binding the AAA+ domains of the clamp loader. ATP hydrolysis enables clamp closing and ejection of RFC, completing the clamp loading reaction. PMID- 22918591 TI - PCNA structure and function: insights from structures of PCNA complexes and post translationally modified PCNA. AB - Proliferating cell nuclear antigen (PCNA), the eukaryotic DNA sliding clamp, forms a ring-shaped homo-trimer that encircles double-stranded DNA. This protein is best known for its ability to confer high processivity to replicative DNA polymerases. However, it does far more than this, because it forms a mobile platform on the DNA that recruits many of the proteins involved in DNA replication, repair, and recombination to replication forks. X-ray crystal structures of PCNA bound to PCNA-binding proteins have provided insights into how PCNA recognizes its binding partners and recruits them to replication forks. More recently, X-ray crystal structures of ubiquitin-modified and SUMO-modified PCNA have provided insights into how these post-translational modifications alter the specificity of PCNA for some of its binding partners. This article focuses on the insights gained from structural studies of PCNA complexes and post translationally modified PCNA. PMID- 22918594 TI - Tumor necrosis factor receptor-associated periodic syndrome (TRAPS) in Japan: a review of the literature. AB - Tumor necrosis factor receptor-associated periodic syndrome (TRAPS) is a dominantly inherited autoinflammatory syndrome that is characterized by recurrent episodes of fever attacks associated with rashes, abdominal pain, myalgia, conjunctivitis, chest pain, and arthralgia. Some patients have severe abdominal pain leading to abdominal surgery. Most reported cases of TRAPS involve patients of European ancestry, but there have been nine reports of patients with TRAPS in Japan. Here, we review these nine case reports. Reported TNFRSF1A gene mutations in these nine index patients were C70S, T61I, C70G, C30Y, C30R, N101K, and N25D. Fever (100 %) was seen in all 23 cases. Most patients developed rash (erythema) (84.6 %) and arthralgia (73.3 %), and half suffered from myalgia (54.5 %) and abdominal pain (50.0 %). Although one-half of the patients suffered from abdominal pain, none underwent surgery. In contrast, only a small percentage of patients suffered from chest pain (20.0 %), conjunctivitis (20.0 %), and headache (10.0 %). Almost all cases (95.7 %) concerned patients whose relatives suffered from periodic fever. These findings suggest that the clinical features of Japanese TRAPS patients may be milder than those of patients in Western countries. PMID- 22918593 TI - DNA ligase I, the replicative DNA ligase. AB - Multiple DNA ligation events are required to join the Okazaki fragments generated during lagging strand DNA synthesis. In eukaryotes, this is primarily carried out by members of the DNA ligase I family. The C-terminal catalytic region of these enzymes is composed of three domains: a DNA binding domain, an adenylation domain and an OB-fold domain. In the absence of DNA, these domains adopt an extended structure but transition into a compact ring structure when they engage a DNA nick, with each of the domains contacting the DNA. The non-catalytic N-terminal region of eukaryotic DNA ligase I is responsible for the specific participation of these enzymes in DNA replication. This proline-rich unstructured region contains the nuclear localization signal and a PCNA interaction motif that is critical for localization to replication foci and efficient joining of Okazaki fragments. DNA ligase I initially engages the PCNA trimer via this interaction motif which is located at the extreme N-terminus of this flexible region. It is likely that this facilitates an additional interaction between the DNA binding domain and the PCNA ring. The similar size and shape of the rings formed by the PCNA trimer and the DNA ligase I catalytic region when it engages a DNA nick suggest that these proteins interact to form a double-ring structure during the joining of Okazaki fragments. DNA ligase I also interacts with replication factor C, the factor that loads the PCNA trimeric ring onto DNA. This interaction, which is regulated by phosphorylation of the non-catalytic N-terminus of DNA ligase I, also appears to be critical for DNA replication. PMID- 22918592 TI - The wonders of flap endonucleases: structure, function, mechanism and regulation. AB - Processing of Okazaki fragments to complete lagging strand DNA synthesis requires coordination among several proteins. RNA primers and DNA synthesised by DNA polymerase alpha are displaced by DNA polymerase delta to create bifurcated nucleic acid structures known as 5'-flaps. These 5'-flaps are removed by Flap Endonuclease 1 (FEN), a structure-specific nuclease whose divalent metal ion dependent phosphodiesterase activity cleaves 5'-flaps with exquisite specificity. FENs are paradigms for the 5' nuclease superfamily, whose members perform a wide variety of roles in nucleic acid metabolism using a similar nuclease core domain that displays common biochemical properties and structural features. A detailed review of FEN structure is undertaken to show how DNA substrate recognition occurs and how FEN achieves cleavage at a single phosphate diester. A proposed double nucleotide unpairing trap (DoNUT) is discussed with regards to FEN and has relevance to the wider 5' nuclease superfamily. The homotrimeric proliferating cell nuclear antigen protein (PCNA) coordinates the actions of DNA polymerase, FEN and DNA ligase by facilitating the hand-off intermediates between each protein during Okazaki fragment maturation to maximise through-put and minimise consequences of intermediates being released into the wider cellular environment. FEN has numerous partner proteins that modulate and control its action during DNA replication and is also controlled by several post-translational modification events, all acting in concert to maintain precise and appropriate cleavage of Okazaki fragment intermediates during DNA replication. PMID- 22918595 TI - 1H, 13C, and 15N backbone resonance assignments of the L124D mutant of StAR related lipid transfer domain protein 4 (StARD4). AB - Protein-mediated cholesterol trafficking is central to maintaining cholesterol homeostasis in cells. START (Steroidogenic acute regulatory protein-related lipid transfer) domains constitute a sterol and lipid binding motif and the START domain protein StARD4 typifies a small family of mammalian sterol transport proteins. StARD4 consists of a single START domain and has been reported to act as a general cholesterol transporter in cells. However, the structural basis of cholesterol uptake and transport is not well understood and no cholesterol-bound START domain structures have been reported. We have undertaken the study of cholesterol binding and transport by StARD4 using solution state NMR spectroscopy. To this end, we report nearly complete (1)H, (15)N, and (13)C backbone resonance assignments of an inactive but well behaved mutant (L124D) of StARD4. PMID- 22918596 TI - Haemostatic effects of levothyroxine and selenomethionine in euthyroid patients with Hashimoto's thyroiditis. AB - The aim of this prospective study was to investigate for the first time whether levothyroxine and selenomethionine, administered alone or in combination, affect coagulation and fibrinolysis in Hashimoto's thyroiditis patients with normal thyroid function tests. A group of 155 ambulatory women with recently diagnosed and previously untreated Hashimoto's thyroiditis, of whom 149 completed the study, were randomly assigned in a double-blind fashion to six months of treatment with levothyroxine, selenomethionine, levothyroxine plus selenomethionine, or placebo. The control group included 39 matched healthy women. The prothrombin time ratio, the activated partial thromboplastin time, and plasma levels/activities of fibrinogen, factor VII, von Willebrand factor, factor X and plasminogen activator inhibitor-1 (PAI-1) were assessed at baseline and after three and six months of treatment. Compared with the healthy subjects, Hashimoto's thyroiditis patients exhibited higher plasma levels/activities of all of the parameters studied, as well as were characterised by the abnormal prothrombin time ratio and activated partial thromboplastin time. All these haemostatic disturbances were reduced or normalised by levothyroxine + selenomethionine treatment, while the effect of levothyroxine or selenomethionine was limited to fibrinogen and PAI-1, respectively. Our results demonstrate that euthyroid women with Hashimoto's thyroiditis are characterised by abnormal coagulation and fibrinolysis. Levothyroxine and selenomethionine, especially if administered together, produce a beneficial effect on haemostasis in euthyroid patients with this disorder. PMID- 22918597 TI - Spanish doctors protest against law that excludes immigrants from public healthcare. PMID- 22918598 TI - The "exclamation mark" school of patient safety. PMID- 22918599 TI - Many foundation trusts face tough financial future, warns Monitor. PMID- 22918600 TI - Dofetilide promotes repolarization abnormalities in perfused Guinea-pig heart. AB - PURPOSE: Dofetilide is class III antiarrhythmic agent which prolongs cardiac action potential duration because of selective inhibition of I (Kr), the rapid component of the delayed rectifier K(+) current. Although clinical studies reported on proarrhythmic risk associated with dofetilide treatment, the contributing electrophysiological mechanisms remain poorly understood. This study was designed to determine if dofetilide-induced proarrhythmia may be attributed to abnormalities in ventricular repolarization and refractoriness. METHODS: The monophasic action potential duration and effective refractory periods (ERP) were assessed at distinct epicardial and endocardial sites along with volume-conducted ECG recordings in isolated, perfused guinea-pig heart preparations. RESULTS: Dofetilide was found to produce the reverse rate-dependent prolongation of ventricular repolarization, increased the steepness of action potential duration rate adaptation, and amplified transepicardial variability in electrical restitution kinetics. Dofetilide also prolonged the T peak-to-end interval on ECG, and elicited a greater prolongation of endocardial than epicardial ERP, thereby increasing transmural dispersion of refractoriness. At epicardium, dofetilide prolonged action potential duration to a greater extent than ERP, thus extending the critical interval for ventricular re-excitation. This change was associated with triangulation of epicardial action potential because of greater dofetilide-induced prolonging effect at 90 % than 30 % repolarization. Premature ectopic beats and spontaneous short-lasting episodes of monomorphic ventricular tachycardia were observed in 44 % of dofetilide-treated heart preparations. CONCLUSIONS: Proarrhythmic potential of dofetilide in guinea-pig heart is attributed to steepened electrical restitution, increased transepicardial variability in electrical restitution kinetics, amplified transmural dispersion of refractoriness, increased critical interval for ventricular re-excitation, and triangulation of epicardial action potential. PMID- 22918601 TI - Rosuvastatin may modulate insulin signaling and inhibit atherogenesis beyond its plasma cholesterol-lowering effect in insulin-resistant mice. AB - OBJECTIVES: To provide evidence that rosuvastatin may improve insulin-resistance and inhibit atherogenesis by modulating insulin signaling, and whether this effect occurs beyond its plasma cholesterol-lowering effect. METHODS: Thirty-two 6-week-old low-density lipoprotein receptor deficient mice were randomized into 4 groups (n = 8 in each group): Normal control group (NC); High fat and high fructose diet group (HFF); HFF plus rosuvastatin group (HFFR); HFFR plus mevalonic acid group (HFFRMA). After 12 weeks, we measured fasting blood sugar, fasting insulin and cholesterol levels; the morphological concentrations of the aorta and aortic sinus; the expression of insulin receptor substrate 2, phosphorylated insulin receptor substrate 2, protein kinase B, phosphorylated protein kinase B and the glucose transporter 4 in the liver. RESULTS: Compared with other groups, fasting blood sugar and fasting insulin increased significantly in HFF group. Furthermore, HFF group had an increase in the morphological concentrations of the aorta and aortic sinus, but there was a significant decrease in the HFFRMA group and the HFFR group. Moreover, there was a high expression of insulin receptor substrate 2, phosphorylated insulin receptor substrate 2, protein kinase B, phosphorylated protein kinase B and the glucose transporter 4 in the HFFRMA and HFFR groups, but a low expression in the HFF group. No significant differences regarding each afore-mentioned index was observed in the HFFR and HFFRMA groups. CONCLUSIONS: Our data show that rosuvastatin may improve insulin-resistance and inhibit atherogenesis in HFF-fed mice by partially reversing the decrease in the insulin stimulated insulin receptor substrate 2/Phosphatidylinositol 3-kinase/protein kinase B/glucose transporter 4 pathway in the liver, and that this effect is independent of its cholesterol-lowering effect. PMID- 22918602 TI - Beneficial effects of sustained activity on the use of dietary protein and carbohydrate traced with stable isotopes 15N and 13C in gilthead sea bream (Sparus aurata). AB - To determine the effects of sustained swimming on the use and fate of dietary nutrients in gilthead sea bream, a group of fish were forced to undertake moderate and sustained swimming (1.5 BL s(-1)) for 3 weeks and compared with a control group undertaking voluntary activity. The exercise group showed a significant increase in specific growth rate (C: 1.13 +/- 0.05; E: 1.32 +/- 0.06 % day(-1), P < 0.05) with no significant change in food intake (C: 3.56 +/- 0.20; E: 3.84 +/- 0.03 % of body weight). The addition of (13)C-starch and (15)N protein to a single meal of 1 % ration allowed analysis of the fate of both nutrients in several tissues and in their components, 6 and 24 h after force feeding. In exercised fish improved redistribution of dietary components increased the use of carbohydrates and lipid as fuels. Gilthead sea bream have a considerable capacity for carbohydrate absorption irrespective of swimming conditions, but in trained fish (13)C rose in all liver fractions with no changes in store contents. This implies higher nutrient turnover with exercise. Higher retention of dietary protein (higher (15)N uptake into white muscle during the entire post-prandial period) was found under sustained exercise, highlighting the protein-sparing effect. The combined effects of a carbohydrate-rich, low-protein diet plus sustained swimming enhanced amino acid retention and also prevented excessive lipid deposition in gilthead sea bream. PMID- 22918603 TI - Effect of a smoking ban and school-based prevention and control policies on adolescent smoking in Spain: a multilevel analysis. AB - We evaluated the impact of a smoking ban in schools and of school-based smoking prevention and control policies on adolescent smoking. Annual surveys carried out between 2001 and 2005 that were representative of students in the 4th year of secondary education in the Madrid region, with 203 schools and 9127 students participating. The student questionnaire gathered information about personal and family variables. The contextual factors were: the periods before (years 2001 2002) and after the law; and through a survey of school management boards: compliance with the law, policy reflected in the school regulations, existence of complaints against smoking, and undertaking of educational activities regarding smoking. Multilevel logistic regression models were constructed with two dependent variables: current smoking and the proportion giving up smoking. Smoking declined in 2003, the first year after the law came into force (Odds ratio: 0.80; CI 95%: 0.66-0.96), and this decline was maintained in 2005. By contrast, smoking increased in those schools that did not undertake educational programmes regarding smoking (Odds ratio: 1.34; CI 95%: 1.13-1.59), and in those that received complaints about smoking (Odds ratio: 1.12; CI 95%: 0.96-1.29). This association is partly due to the effect of the increase in giving up smoking. The inclusion of contextual variables into the model with the individual factors reduces the variability of smoking between schools by 32.6%. In summary, the coming into force of a law banning smoking in schools, and the implementing of educational policies for the prevention and control of smoking are related to a lower risk of adolescent smoking. PMID- 22918604 TI - Taurine and liver diseases: a focus on the heterogeneous protective properties of taurine. AB - Taurine (2-aminoethylsulfonic acid) has many physiological and pharmacological functions in most tissues. It is abundantly maintained in the liver by both endogenous biosynthesis and exogenous transport, but is decreased in liver diseases. In the hepatic lobule, there are heterogeneous differences in metabolism between the pericentral (PC) and periportal regions, and the distributions of the biosynthesis capacity and specific taurine transporter expression are predominantly in the PC region. In cases of depletion of hepatic taurine level, serious liver damages were observed in the PC region. Taurine has protective effects against xenobiotics-induced liver damages in the PC region, but not xenobiotics-induced PP region damages. The xenobiotics that injure the PC region are mainly catabolized by NADPH-dependent cytochrome P450 2E1 that is also predominantly expressed in the PC region. Taurine treatment seems to be a useful agent for CYP2E1-related liver diseases with predominant damages in the PC region. PMID- 22918605 TI - Laparoscopic versus open liver surgery: a single center analysis of post operative in-hospital and post-discharge results. AB - PURPOSE: Laparoscopic hepatectomy (LH) is established as a safe and feasible surgical procedure for benign and malignant liver lesions showing many benefits in terms of short-term post-operative outcomes. Nevertheless, it remains unclear if these benefits extend beyond the hospital stay. The aim of this study was to compare in-hospital and post-discharge outcomes between two groups of patients who have undergone either laparoscopic or open hepatectomy (OH). METHODS: Forty six patients who have undergone LH from September 2008 to September 2011 were compared to 46 matched-pair control patients who have undergone OH. The two groups were compared in terms of in-hospital and 6-month outcomes. Post-discharge outcomes were analyzed in terms of the number of outpatient clinic appointments (OCAs) and readmissions (RAs). Analyses were performed excluding and including conversion cases. RESULTS: The two groups resulted in homogeneous patients' and lesions' characteristics. Patients who underwent LH showed statistically lower intra-operative blood loss, less total and major morbidity and shorter hospital stay. Regarding post-discharge outcomes, significantly less patients of LH group compared to patients of OH group required more than two post-discharge OCAs (in the intention to treat analysis, 28.3 versus 63%, respectively; P = 0.006) or RA (4.3 versus 15.2%, respectively; P = 0.008). The benefits of LH appeared to be maximized in cirrhotic patients; those represented the large part of patients readmitted after hepatectomy regardless of the type of surgical approach (77.8%). CONCLUSIONS: Advantages related to LH extend over the post-discharge period suggesting potential better patient's satisfaction and lower hospital cost. PMID- 22918606 TI - How visual information links to multijoint coordination during quiet standing. AB - The link between visual information and postural control was investigated based on a multi-degree-of-freedom model using the framework of the uncontrolled manifold (UCM) hypothesis. The hypothesis was that because visual information specifies the position of the body in space, it would couple preferentially into those combinations of degrees of freedom (DOFs) that move the body in space and not into combinations of DOFs that do not move the body in space. Subjects stood quietly in a virtual reality cave for 4-min trials with or without a 0.2, 2.0 Hz, or combined 0.2 and 2.0 Hz visual field perturbation that was below perceptual threshold. Motion analysis was used to compute six sagittal plane joint angles. Variance across time of the angular motion was partitioned into (1) variance associated with motion of the body and (2) variance reflecting the use of flexible joint combinations that keep the anterior-posterior positions of the head (HD(POS)) and center of mass (CM(POS)) invariant. UCM analysis was performed in the frequency domain in order to link the sensory perturbation to each variance component at different frequencies. As predicted, variance related to motion of the body was selectively increased at the 0.2-Hz drive frequency but not at other frequencies of sway for both CM(POS) and HD(POS). The dominant effect with the 2.0-Hz visual drive also was limited largely to variance related to motion of the body. PMID- 22918607 TI - Solid shape discrimination from vision and haptics: natural objects (Capsicum annuum) and Gibson's "feelies". AB - A set of three experiments evaluated 96 participants' ability to visually and haptically discriminate solid object shape. In the past, some researchers have found haptic shape discrimination to be substantially inferior to visual shape discrimination, while other researchers have found haptics and vision to be essentially equivalent. A primary goal of the present study was to understand these discrepant past findings and to determine the true capabilities of the haptic system. All experiments used the same task (same vs. different shape discrimination) and stimulus objects (James Gibson's "feelies" and a set of naturally shaped objects--bell peppers). However, the methodology varied across experiments. Experiment 1 used random 3-dimensional (3-D) orientations of the stimulus objects, and the conditions were full-cue (active manipulation of objects and rotation of the visual objects in depth). Experiment 2 restricted the 3-D orientations of the stimulus objects and limited the haptic and visual information available to the participants. Experiment 3 compared restricted and full-cue conditions using random 3-D orientations. We replicated both previous findings in the current study. When we restricted visual and haptic information (and placed the stimulus objects in the same orientation on every trial), the participants' visual performance was superior to that obtained for haptics (replicating the earlier findings of Davidson et al. in Percept Psychophys 15(3):539-543, 1974). When the circumstances resembled those of ordinary life (e.g., participants able to actively manipulate objects and see them from a variety of perspectives), we found no significant difference between visual and haptic solid shape discrimination. PMID- 22918608 TI - Detecting delay in visual feedback of an action as a monitor of self recognition. AB - How do we distinguish "self" from "other"? The correlation between willing an action and seeing it occur is an important cue. We exploited the fact that this correlation needs to occur within a restricted temporal window in order to obtain a quantitative assessment of when a body part is identified as "self". We measured the threshold and sensitivity (d') for detecting a delay between movements of the finger (of both the dominant and non-dominant hands) and visual feedback as seen from four visual perspectives (the natural view, and mirror reversed and/or inverted views). Each trial consisted of one presentation with minimum delay and another with a delay of between 33 and 150 ms. Participants indicated which presentation contained the delayed view. We varied the amount of efference copy available for this task by comparing performances for discrete movements and continuous movements. Discrete movements are associated with a stronger efference copy. Sensitivity to detect asynchrony between visual and proprioceptive information was significantly higher when movements were viewed from a "plausible" self perspective compared with when the view was reversed or inverted. Further, we found differences in performance between dominant and non dominant hand finger movements across the continuous and single movements. Performance varied with the viewpoint from which the visual feedback was presented and on the efferent component such that optimal performance was obtained when the presentation was in the normal natural orientation and clear efferent information was available. Variations in sensitivity to visual/non visual temporal incongruence with the viewpoint in which a movement is seen may help determine the arrangement of the underlying visual representation of the body. PMID- 22918609 TI - The key role of 4-methyl-5-vinylthiazole in the attraction of scarab beetle pollinators: a unique olfactory floral signal shared by Annonaceae and Araceae. AB - Cyclocephaline scarabs are specialised scent-driven pollinators, implicated with the reproductive success of several Neotropical plant taxa. Night-blooming flowers pollinated by these beetles are thermogenic and release intense fragrances synchronized to pollinator activity. However, data on floral scent composition within such mutualistic interactions are scarce, and the identity of behaviorally active compounds involved is largely unknown. We performed GC-MS analyses of floral scents of four species of Annona (magnoliids, Annonaceae) and Caladium bicolor (monocots, Araceae), and demonstrated the chemical basis for the attraction of their effective pollinators. 4-Methyl-5-vinylthiazole, a nitrogen and sulphur-containing heterocyclic compound previously unreported in flowers, was found as a prominent constituent in all studied species. Field biotests confirmed that it is highly attractive to both male and female beetles of three species of the genus Cyclocephala, pollinators of the studied plant taxa. The origin of 4-methyl-5-vinylthiazole in plants might be associated with the metabolism of thiamine (vitamin B1), and we hypothesize that the presence of this compound in unrelated lineages of angiosperms is either linked to selective expression of a plesiomorphic biosynthetic pathway or to parallel evolution. PMID- 22918611 TI - The genetic basis of depression. AB - Since the publication of the working draft of the human genome just over a decade ago, there have been dramatic advances in our understanding of the role genetics play in both normal human functioning as well as in disease. The identification of genes, which influence an individual's susceptibility to depression, is not only an intriguing scientific endeavour in its own right, but further, if a gene can be confidently implicated in depression, then this could shed light on the aetiological processes involved in the disease. Moreover, a genetic association with depression may identify targets for consideration in the development of novel treatments for the illness. This chapter will summarise the current research into the genetic basis of depression. A number of genes of interest have been highlighted, although a genetic variant, that is unequivocally associated with increased risk for the disease, is yet to be identified. However, technologies and methodologies are evolving rapidly, and genetic approaches have helped shape how we conceptualise depression as an illness. PMID- 22918610 TI - Benign painful elbow syndrome. First results of a single center prospective randomized radiotherapy dose optimization trial. AB - BACKGROUND AND PURPOSE: The goal of the present study was to evaluate the efficacy of two different dose-fractionation schedules for radiotherapy (RT) of patients with painful elbow syndrome. PATIENTS AND METHODS: Between February 2006 and February 2010, 199 consecutive evaluable patients were recruited for this prospective randomized trial. All patients received RT in orthovoltage technique. One RT course consisted of 6 single fractions/3 weeks. In case of insufficient remission of pain after 6 weeks a second radiation series was performed. Patients were randomly assigned to receive either single doses of 0.5 or 1.0 Gy. Endpoint was pain reduction. Pain was measured before, right after, and 6 weeks after RT by a visual analogue scale (VAS) and a comprehensive pain score (CPS). RESULTS: The overall response rate for all patients was 80% direct after and 91% 6 weeks after RT. The mean VAS values before, after and 6 weeks after treatment for the 0.5 and 1.0 Gy groups were 59.6 +/- 20.2 and 55.7 +/- 18.0 (p = 0.463), 32.1 +/- 24.5 and 34.4 +/- 22.5 (p = 0.256), and 27.0 +/- 27.7 and 23.5 +/- 21.6 (p = 0.818). The mean CPS before, after, and 6 weeks after treatment was 8.7 +/- 2.9 and 8.1 +/- 3.1 (p = 0.207), 4.5 +/- 3.2 and 5.0 +/- 3.4 (p = 0.507), 3.9 +/- 3.6 and 2.8 +/- 2.8 (p = 0.186), respectively. No statistically significant differences between the two single dose trial arms for early (p = 0.103) and delayed response (p = 0.246) were found. CONCLUSION: RT is an effective treatment option for the management of benign painful elbow syndrome. For radiation protection reasons the dose for a RT series is recommended not to exceed 3.0 Gy. PMID- 22918612 TI - Role of metal ions in growth and stability of Langmuir-Blodgett films on homogeneous and heterogeneous surfaces. AB - Structure and stability of cadmium arachidate (CdA) Langmuir-Blodgett (LB) films on homogeneous (i.e., OH-, H-passivated Si(001) substrates) and heterogeneous (i.e., Br-passivated Si(001) substrates) surfaces were studied using X-ray reflectivity and atomic force microscopy techniques and compared with those of nickel arachidate (NiA) LB films. While on OH-passivated Si, an asymmetric monolayer (AML) structure starts to grow, on H-passivated Si, a symmetric monolayer (SML) of CdA forms, although for both the films, pinhole-type defects are present as usual. However, on heterogeneous Br-passivated Si substrates, a combination of AML, SML, shifted SML and SML on top of AML (i.e., AML/SML), all types of structures are found to grow in such a way that, due to the variation of heights in the out-of-plane direction, ring-shaped in-plane nanopatterns of CdA molecules are generated. Probably due to stronger head-head interactions and higher metal ion-carboxylic ligand bond strength for CdA molecules compared to NiA, easy flipping of SML on top of another preformed SML, i.e. a SML/SML structure formation was not possible and as a result a wave-like modulation is observed for the CdA film on such heterogeneous substrate. The presence of hydrophilic/hydrophobic interfacial stress on the heterogeneous substrate thus modifies the deposited molecular structure so that the top surface morphology for a CdA film is similar to monolayer buckling while that for NiA film is similar to monolayer collapse. PMID- 22918613 TI - Discerning whether and how long-chain, n-3 fatty acids lower blood pressure: a comment on Skulas-Ray et al. PMID- 22918614 TI - Population pharmacokinetics of phenytoin after intravenous administration of fosphenytoin sodium in pediatric patients, adult patients, and healthy volunteers. AB - PURPOSE: We performed a population pharmacokinetic analysis of phenytoin after intravenous administration of fosphenytoin sodium in healthy, neurosurgical, and epileptic subjects, including pediatric patients, and determined the optimal dose and infusion rate for achieving the therapeutic range. METHODS: We used pooled data obtained from two phase I studies and one phase III study performed in Japan. The population pharmacokinetic analysis was performed using NONMEM software. The optimal dose and infusion rate were determined using simulation results obtained using the final model. The therapeutic range for total plasma phenytoin concentration is 10-20 MUg/mL. RESULTS: We used a linear two compartment model with conversion of fosphenytoin to phenytoin. Pharmacokinetic parameters of phenytoin, such as total clearance and central and peripheral volume of distribution were influenced by body weight. The dose simulations are as follows. In adult patients, the optimal dose and infusion rate of phenytoin for achieving the therapeutic range was 22.5 mg/kg and 3 mg/kg/min respectively. In pediatric patients, the total plasma concentration of phenytoin was within the therapeutic range for a shorter duration than that in adult patients at 22.5 mg/kg (3 mg/kg/min). However, many pediatric patients showed phenytoin concentration within the toxic range after administration of a dose of 30 mg/kg. CONCLUSIONS: The pharmacokinetics of phenytoin after intravenous administration of fosphenytoin sodium could be described using a linear two-compartment model. The administration of fosphenytoin sodium 22.5 mg/kg at an infusion rate of 3 mg/kg/min was optimal for achieving the desired plasma phenytoin concentration. PMID- 22918615 TI - Diabetes care among older adults in primary care in Austria--a cross-sectional study. AB - QUESTIONS UNDER STUDY: The prevalence of diabetes mellitus in the older population is high, but hardly any data are available on current diabetes care in the primary care setting. We aimed at investigating the diabetes management of older patients with type 2 diabetes (T2DM) in the primary care setting, including adherence to current guidelines, comparing patients aged 70-79 years to those aged 80 years and above. METHODS: From November 2008 through March 2009 a total of 23 primary care physicians and one consultant in internal medicine consecutively enrolled 203 unselected patients with T2DM aged >=70 years. RESULTS: From the 203 study participants 66% were 70-79 years of age, and 34% were 80 years or older. Mean HbA1c and LDL-cholesterol were not significantly different between the older and the younger age group (7.6 +/- 1.6 vs. 7.1 +/- 0.9%; p = 0.080; and 122 +/- 40 vs. 114 +/- 34 mg/dl; p = 0.273), whereas BMI was lower (27.5 +/- 5.0 vs. 29.6 +/- 5.0 kg/m2, p = 0.010), and the prevalent rates of coronary heart disease (55.1 vs. 37.1%, p = 0.011) and of dementia (29% vs. 6.1%, p = 0.001) were higher in the older age group. LDL-cholesterol (77.6% vs. 66.7%, p = 0.012), creatinine clearance (34.6% vs. 30.9%, p = 0.049) but not HbA1c (74.6% vs.73.9; p = 0.520) were monitored significantly less often in the older than in the younger age group. CONCLUSIONS: While glycaemic control on average appears strict, there may be ample room for improvement in reaching lipid targets and in the monitoring of lipid and renal function among older adults in primary care, in particular among individuals aged >=80 years. PMID- 22918616 TI - The failure mode of two reabsorbable fixation systems: Swivelock with Fibertape versus Bio-Corkscrew with Fiberwire in bovine rotator cuff. AB - BACKGROUND: Despite technical advances in rotator cuff surgery, recurrent or persistent defects in the repaired tendon continue to occur. The improved strength of sutures and suture anchors has shown that the most common site of failure is the suture-tendon interface. The purpose of this study was to compare two different types of repair under both cyclic and load-to-failure conditions. The hypothesis is that the use of a fixation system with knotless anchor and taped suture results in better biomechanical performance, under both cyclic and load-to-failure conditions. METHODS: Thirty bovine shoulder specimens were randomly assigned to two group tests: the Swivelock 5-mm anchor with Fibertape (Group A) and the Bio-Corkscrew 5 mm with Fiberwire (Group B). We simulated the reconstruction of a rotator cuff tear with a single-row technique, performing a tenodesis with types A and B fixation. Each specimen underwent cyclic testing from 5 to 30 N for 30 cycles, followed by load-to-failure testing, in order to calculate the ultimate failure load (UFL). RESULTS: Load-to-failure tests revealed a significantly higher UFL in Group A than in Group B. Wire fixing failed at the anchor loop whereas tape fixing failed at the sutures, suture tendon interface, and anchors. Cyclic testing revealed no significantly greater slippage between the two groups. Stiffness values were not statistically significantly different. In all cases, tendons remained intact until the end of the cyclic testing. CONCLUSIONS: The tape structure is biomechanically stronger than the wire structure. PMID- 22918617 TI - Complete avulsion of the patellar tendon from the tibial tubercle in an adult without predisposing factors. PMID- 22918618 TI - Effects of weekly and fortnightly therapeutic exercise on physical function and health-related quality of life in individuals with hip osteoarthritis. AB - BACKGROUND: Most previous studies on the effects of therapeutic exercise on osteoarthritis (OA) of the hip joint included participants with knee OA or postoperative participants. Moreover, although some systematic reviews recommend therapeutic exercise for hip OA, a consensus on the effective interventional frequency has not been reached. This study aimed to investigate the effects of therapeutic exercise performed at different frequencies on physical function and health-related quality of life in participants with hip OA. METHODS: Individuals diagnosed with hip OA (36 women, age 42-79 years; 19 in 2009 and 17 in 2010) were recruited from the cooperating medical institutions. They were divided into two groups depending on the frequency of therapeutic exercise: fortnightly in 2009 (fortnightly group) and weekly in 2010 (weekly group). Participants in each group performed the same land-based and aquatic exercises on the same day for a total of ten sessions. Muscle strength of the lower extremity, "timed up and go" (TUG), time of one-leg standing with open eyes (TOLS), Harris Hip Score, and scores of the Medical Outcomes Survey Short Form-36 questionnaire, were measured before and after interventions. RESULTS: The fortnightly group had no significant changes in lower-extremity muscle strength following intervention, but the strength of all muscles in the weekly group improved significantly after intervention. Further, in both groups, TUG and TOLS of the worse side of the hip joint significantly improved after interventions. CONCLUSIONS: Weekly exercise improves muscle strength of the lower extremity and may therefore be an effective interventional technique for managing hip OA. In addition, in persons with hip OA, therapeutic exercise consisting of both land- and water-based exercises markedly improved physical function. PMID- 22918619 TI - CSF diversion in refractory idiopathic intracranial hypertension: single-centre experience and review of efficacy. AB - PURPOSE: The current surgical management strategies for refractory cases of idiopathic intracranial hypertension (IIH) remain unresolved. We evaluated the outcome of our paediatric patients who were offered a CSF diversion procedure in order to control their symptoms. METHODS: We retrospectively reviewed the medical notes of the patients under 16 years of age, who presented in our centre from 2005 to 2010, with a confirmed diagnosis of IIH, and ultimately had a lumboperitoneal shunt (LPS). We describe their immediate postoperative course, shunt-related complications and recent outcome. RESULTS: Seven patients presented at a mean age of 8.7 years. Two presented with significant visual loss and had a shunt acutely; the remaining five presented with headaches and were shunted within 2 years. In the immediate postoperative period two patients experienced low-pressure symptoms. All patients required shunt revisions; in total 15 revisions took place, mainly secondary to symptomatic overdrainage or obstruction. After a mean follow-up of 26 months, two patients have diminished visual acuity at least on one side; only one patient became headache-free, despite resolution of the CSF pressure post diversion in four out of the six remaining patients. CONCLUSIONS: All patients required shunt revisions and 6/7 (85.7%) had persisting headaches at their last follow-up. It is apparent that once functional, the LPS seems adequate to lower the CSF pressure but not effective in eliminating symptoms. PMID- 22918621 TI - Eddy current compensation for delta relaxation enhanced MR by dynamic reference phase modulation. AB - OBJECT: Eddy current compensation by dynamic reference phase modulation (eDREAM) is a compensation method for eddy current fields induced by B 0 field-cycling which occur in delta relaxation enhanced MR (dreMR) imaging. The presented method is based on a dynamic frequency adjustment and prevents eddy current related artifacts. It is easy to implement and can be completely realized in software for any imaging sequence. MATERIALS AND METHODS: In this paper, the theory of eDREAM is derived and two applications are demonstrated. The theory describes how to model the behavior of the eddy currents and how to implement the compensation. Phantom and in vivo measurements are carried out and demonstrate the benefits of eDREAM. RESULTS: A comparison of images acquired with and without eDREAM shows a significant improvement in dreMR image quality. Images without eDREAM suffer from severe artifacts and do not allow proper interpretation while images with eDREAM are artifact free. In vivo experiments demonstrate that dreMR imaging without eDREAM is not feasible as artifacts completely change the image contrast. CONCLUSION: eDREAM is a flexible eddy current compensation for dreMR. It is capable of completely removing the influence of eddy currents such that the dreMR images do not suffer from artifacts. PMID- 22918622 TI - Sterilization of tendon allografts: a method to improve strength and stability after exposure to 50 kGy gamma radiation. AB - Terminal sterilization of tendon allografts with high dose gamma irradiation has deleterious effects on tendon mechanical properties and stability after implantation. Our goal is to minimize these effects with radio protective methods. We previously showed that radio protection via combined crosslinking and free radical scavenging maintained initial mechanical properties of tendon allografts after irradiation at 50 kGy. This study further evaluates the tissue response and simulated mechanical degradation of tendons processed with radio protective treatment, which involves crosslinking in 1-ethyl-3-(3 dimethylaminopropyl) carbodiimide followed by soaking in an ascorbate/riboflavin 5-phosphate solution. Control untreated and treated tendons were irradiated at 50 kGy and implanted in New Zealand White rabbit knees within the joint capsule for four and 8 weeks. Tendons were also exposed to cyclic loading to 20 N at one cycle per 12 s in a collagenase solution for 150 cycles, followed by tension to failure. Control irradiated tendons displayed increased degradation in vivo, and failed prematurely during cyclic processing at an average of 25 cycles. In contrast, radio protected irradiated tendons displayed greater stability following implantation over 8 weeks, and possessed strength at 59 % of native tendons and modulus equivalent to that of native tendons after cyclic loading in collagenase. These results suggest that radio protective treatment improves the strength and the stability of tendon allografts. PMID- 22918623 TI - Which diuretic is the preferred agent for treating essential hypertension: hydrochlorothiazide or chlorthalidone? AB - Since their introduction over 50 years ago thiazide and thiazide-like diuretics have been a mainstay in the treatment of hypertension. Yet despite outcome evidence with chlorthalidone, the preponderance of usage has been with hydrochlorothiazide-either as monotherapy or in combination with other drugs. There is an increasing debate as to whether or not there are significant differences between hydrochlorothiazide and chlorthalidone. Early outcome studies, upon which the recommendations were made, utilized higher doses than those not only commonly employed in clinical practice, but also studied in more recent outcome trials. In addition, data suggests that chlorthalidone may be more potent, in equal doses, in its BP response than hydrochlorothiazide. A fundamental question asked in the debate is whether or not the benefits attributed to chlorthalidone as a thiazide-like diuretic may be reasonably ascribed to thiazides given differences in their pharmacokinetic properties and perhaps some other more recently noted differences. PMID- 22918626 TI - Sensitive fluorescence detection of etimicin based on derivatives of formaldehyde and acetylacetone. AB - A novel fluorescence method for the determination of etimicin is described. Etimicin reacts with acetylacetone and formaldehyde in pH 4.0 Britton-Robinson (B.R.) buffer solution to from a fluorescent substance [I]. Emission spectra of [I] and the reagent blank were overlapped, so the arithmetic emission spectra of the fluorescent substance were obtained by subtracted form the spectra of [I] to the spectra of the reagent blank using the Fluorescence Data Software. There is a linear relationship between the intensity of the arithmetic emission spectra and the concentration of etimicin. Effects of pH, amount of acetylacetone formaldehyde, and heating time on the determination of etimicin have been examined. Etimicin can be determined over the concentration range of 1.0 to 10.0 MUg mL(-1) with a correlation coefficient of 0.9991. The relative standard deviation (RSD) for 11 repetitive determinations of 5.0 MUg mL(-1) etimicin is 0.22%. The utility of this method was demonstrated by determining etimicin in commercial samples. PMID- 22918624 TI - Augmented intrarenal and urinary angiotensinogen in hypertension and chronic kidney disease. AB - Activated intrarenal renin-angiotensin system plays a cardinal role in the pathogenesis of hypertension and chronic kidney disease. Angiotensinogen is the only known substrate for renin, which is the rate-limiting enzyme of the renin angiotensin system. Because the levels of angiotensinogen are close to the Michaelis-Menten constant values for renin, angiotensinogen levels as well as renin levels can control the renin-angiotensin system activity, and thus, upregulation of angiotensinogen leads to an increase in the angiotensin II levels and ultimately increases blood pressure. Recent studies using experimental animal models have documented the involvement of angiotensinogen in the intrarenal renin angiotensin system activation and development of hypertension. Enhanced intrarenal angiotensinogen mRNA and/or protein levels were observed in experimental models of hypertension and chronic kidney disease, supporting the important roles of angiotensinogen in the development and the progression of hypertension and chronic kidney disease. Urinary excretion rates of angiotensinogen provide a specific index of the intrarenal renin-angiotensin system status in angiotensin II-infused rats. Also, a direct quantitative method has been developed recently to measure urinary angiotensinogen using human angiotensinogen enzyme-linked immunosorbent assay. These data prompted us to measure urinary angiotensinogen in patients with hypertension and chronic kidney disease, and investigate correlations with clinical parameters. This short article will focus on the role of the augmented intrarenal angiotensinogen in the pathophysiology of hypertension and chronic kidney disease. In addition, the potential of urinary angiotensinogen as a novel biomarker of the intrarenal renin angiotensin system status in hypertension and chronic kidney disease will be also discussed. PMID- 22918625 TI - Monoamine transporter structure, function, dynamics, and drug discovery: a computational perspective. AB - With the breakthrough crystallization of the bacterial leucine transporter protein LeuT, the first available X-ray structure for the neurotransmitter/sodium symporter family, development of 3-D computational models is suddenly essential for structure-function studies on the plasmalemmal monoamine transporters (MATs). LeuT-based MAT models have been used to guide elucidation of substrate and inhibitor binding pockets, and molecular dynamics simulations using these models are providing insight into conformations involved in the substrate translocation cycle. With credible MAT models finally in hand, structure-based virtual screening for novel ligands is yielding lead compounds toward the development of new medications for psychostimulant dependence, attention deficit hyperactivity, depression, anxiety, schizophrenia, and other disorders associated with dopamine, norepinephrine, or serotonin dysregulation. PMID- 22918627 TI - Functional consequences of sulfhydryl modification of the gamma-aminobutyric acid transporter 1 at a single solvent-exposed cysteine residue. AB - The aims of this study were to optimize the experimental conditions for labeling extracellularly oriented, solvent-exposed cysteine residues of gamma-aminobutyric acid transporter 1 (GAT1) with the membrane-impermeant sulfhydryl reagent [2 (trimethylammonium)ethyl]methanethiosulfonate (MTSET) and to characterize the functional and pharmacological consequences of labeling on transporter steady state and presteady-state kinetic properties. We expressed human GAT1 in Xenopus laevis oocytes and used radiotracer and electrophysiological methods to assay transporter function before and after sulfhydryl modification with MTSET. In the presence of NaCl, transporter exposure to MTSET (1-2.5 mM for 5-20 min) led to partial inhibition of GAT1-mediated transport, and this loss of function was completely reversed by the reducing reagent dithiothreitol. MTSET treatment had no functional effect on the mutant GAT1 C74A, whereas the membrane-permeant reagents N-ethylmaleimide and tetramethylrhodamine-6-maleimide inhibited GABA transport mediated by GAT1 C74A. Ion replacement experiments indicated that MTSET labeling of GAT1 could be driven to completion when valproate replaced chloride in the labeling buffer, suggesting that valproate induces a GAT1 conformation that significantly increases C74 accessibility to the extracellular fluid. Following partial inhibition by MTSET, there was a proportional reduction in both the presteady-state and steady-state macroscopic signals, and the functional and pharmacological properties of the remaining signals were indistinguishable from those of unlabeled GAT1. Therefore, covalent modification of GAT1 at C74 results in completely nonfunctional as well as electrically silent transporters. PMID- 22918628 TI - The Relationship between caffeine and coffee consumption and exfoliation glaucoma or glaucoma suspect: a prospective study in two cohorts. AB - PURPOSE: We examined the association between caffeine and caffeinated beverage consumption in relation to the risk of exfoliation glaucoma or exfoliation glaucoma suspect (EG/EGS). METHODS: We followed 78,977 women from the Nurses' Health Study (NHS) and 41,202 men from the Health Professionals Follow-up Study (HPFS) who were at least 40 years of age, did not have glaucoma, and reported undergoing eye examinations from 1980 (NHS) or 1986 (HPFS) to 2008. Information on consumption of caffeine-containing beverages and potential confounders were repeatedly ascertained in validated follow-up questionnaires. Confirmation with medical record review revealed 360 incident EG/EGS cases. Multivariate rate ratios (RRs) for EG/EGS were calculated in each cohort and then pooled using meta analytic techniques. RESULTS: Compared with participants whose cumulatively updated total caffeine consumption was <125 mg/day, participants who consumed >= 500 mg/day had a trend toward increased risk of EG/EGS that was not statistically significant (RR = 1.43; 95% confidence interval [CI], 0.98-2.08); P trend = 0.06). Compared to abstainers, those who drank >= 3 cups of caffeinated coffee daily were at increased risk of EG/EGS (RR = 1.66; 95% CI, 1.09-2.54; P trend = 0.02). These results were not materially altered after adjustment for total fluid intake. Associations were stronger among women with a family history of glaucoma (P interaction = 0.06 for coffee; P interaction = 0.03 for caffeine). We did not find associations with consumption of other caffeinated products (caffeinated soda, caffeinated tea, decaffeinated coffee or chocolate) and risk of EG/EGS (P trend >= 0.31). CONCLUSIONS: We observed a positive association between heavier coffee consumption with risk of EG/EGS in this large prospective study. PMID- 22918630 TI - The role of type III secretion system and lens material on adhesion of Pseudomonas aeruginosa to contact lenses. AB - PURPOSE: To determine the distribution of invasive and cytotoxic genotypes among ocular isolates of P. aeruginosa and investigate the influence of the type III secretion system (T3SS) on adhesion to conventional, cosmetic, and silicone hydrogel contact lenses (CL). METHODS: Clinical isolates from 2001 to 2010 were analyzed by multiplex PCR for exoS, exoU, and exoT genes. Bacterial adhesion to etafilcon, nelfilcon (gray colored), balafilcon, and galyfilcon CL with or without artificial tear fluid (ATF) incubation were compared. Surface characteristics were determined with scanning electron microscopy (SEM). RESULTS: Among 87 total isolates, 64 strains were from microbial keratitis cases. CL related microbial keratitis (CLMK) isolates were mostly of the cytotoxic genotype (expressing exoU) (P = 0.002). No significant differences were found in bacterial adhesion to all types of CL between the genotypes under T3SS-inducing conditions. A trend for least bacterial adhesion of galyfilcon compared to the other CL was noted for both genotypes. Needle complex pscC mutants adhered less to all materials than the wild type (P < 0.05), indicating a role of the T3SS in contact lens adhesion. ATF-incubated CL had significantly more bacterial adhesion (P < 0.05). SEM showed most of the bacteria adhering on CL surfaces. CONCLUSIONS: CLMK isolates were mostly of cytotoxic genotype. Different genotypes did not significantly differ in its adhesion to various CL. T3SS and other adhesins are involved in bacteria-contact lens adhesion through complex interactions. Contact lens materials may also play an important role in the adherence of both genotypes of P. aeruginosa. PMID- 22918629 TI - Toward an animal model of the human tear film: biochemical comparison of the mouse, canine, rabbit, and human meibomian lipidomes. AB - PURPOSE: Secretions that are produced by meibomian glands (also known as meibum) are a major source of lipids for the ocular surface of humans and animals alike. Many animal species have been evaluated for their meibomian lipidomes. However, there have been a very small number of studies in which the animals were compared with humans side by side. Therefore, the purpose of this study was to compare meibum collected from humans and three typical laboratory animals, canines, mice, and rabbits, for their meibomian lipid composition in order to determine which animal species most resembles humans. METHODS: High pressure liquid chromatography (HPLC) and gas-liquid chromatography (GLC) in combination with mass spectrometry were used to evaluate lipidomes of all tested species. RESULTS: Among three tested animal species, mice were found to be the closest match to humans in terms of their meibomian lipidomes, while canines were the second closest species. The lipids of these three species were close to each other structurally and, for most lipid classes, quantitatively. The rabbit meibomian lipidome, on the other hand, was vastly different from lipidomes of all other tested species. Interestingly, a previously described class of lipids, acylated omega-hydroxy fatty acids (OAHFA), was found to be present in every tested species as the major amphiphilic component of meibum. CONCLUSIONS: Our side by side comparison of the rabbit and the human meibum demonstrated their vast differences. Thus, the rabbit seems to be a poor animal model of the human tear film, at least when studying its biochemistry and biophysics. PMID- 22918631 TI - Correlation of SD-OCT features and retinal sensitivity in neovascular age-related macular degeneration. AB - PURPOSE: To correlate retinal sensitivity in patients with neovascular age related macular degeneration (AMD) with specific characteristics of retinal morphology. METHODS: Thirty eyes of 30 patients presenting with active choroidal neovascularization were examined by spectral domain optical coherence tomography (SD-OCT) and microperimetry (MP-1). Image-processing software was used to match a fundus photographic (FP) MP-1 image with an infrared+OCT SD-OCT image. Each MP test point for retinal sensitivity was positioned at the corresponding SD-OCT location, and the microperimetric results were evaluated. RESULTS: An intact retinal configuration was associated with a median retinal sensitivity of 15.5 dB (quartiles: 12 dB, 18 dB). The median retinal sensitivities were 0 dB (quartiles: 0 dB, 1 dB) for the neovascular complex, 4 dB (0 dB, 9 dB) for the subretinal fluid, 1 dB (0 dB, 6 dB) for the intraretinal fluid, and 0 dB (0 dB, 3 dB) for intraretinal cysts. Pigment epithelium detachment was associated with a median retinal sensitivity of 3 dB (0 dB, 8 dB), and subretinal drusen had a median value of 8 dB (5 dB, 12 dB). Deep retinal layer analyses gave low median retinal sensitivities of 0 dB (0 dB, 3 dB) for an absent retinal pigment epithelium layer and 1 dB (0 dB, 5 dB) for an absent photoreceptor layer. CONCLUSIONS: Superimposition of morphological SD-OCT features and microperimetric retinal sensitivity allowed exact determination of the differential impact of retinal alteration on the corresponding sensitivity. Individual OCT-related indicators of neurosensory integrity were distinctly correlated with visual function. "Morphofunctional" findings could be relevant as prognostic factors and for (re)treatment decisions. (https://www.clinicaltrialsregister.eu/ number, 2006 005684-26.). PMID- 22918632 TI - Lack of immunoglobulins does not prevent C1q binding to RGC and does not alter the progression of experimental glaucoma. AB - PURPOSE: The degeneration of retinal ganglion cells (RGC) in the glaucomatous retina is accompanied by activation of the classical complement cascade. The purpose of this study was to evaluate whether complement component C1q binding and activation of the complement cascade in the glaucomatous retina requires the presence of immunoglobulins. METHODS: Experimental glaucoma was induced in normal mice and those carrying a targeted deletion of the RAG1 gene. Binding of C1q to RGC and accumulation of C3 and C5b-9 was investigated using immunohistochemical and proteomic approaches. Damage to the optic nerve and RGC was determined and compared between the two strains. Complement activation and accumulation were also evaluated in vitro using dissociated retinal cell cultures. RESULTS: C1q was detected in the RGC layer in both RAG1(-/-) and control mice with elevated IOP, but not in mice with normal IOP. Proteomic analysis of retinal membrane fractions indicated that C1q and C3 are membrane bound to a similar degree in RAG1(-/-) and control mice with elevated IOP. The absence of Ig does not affect the rate of axonal damage or RGC loss. Furthermore, cultured RGC maintained in serum-free media are also C1q and C3 immunoreactive, demonstrating that Ig is not required for C1q binding to damaged RGC. CONCLUSIONS: Our data demonstrate that lack of immunoglobulins and mature T/B cells does not influence the progression of glaucoma. Furthermore, immunoglobulins do not appear to be required for C1q binding and complement cascade activation on damaged RGC. These findings suggest that C1q recognizes an alternative binding partner expressed by stressed RGC. PMID- 22918633 TI - The effect of simultaneous negative and positive defocus on eye growth and development of refractive state in marmosets. AB - PURPOSE: We evaluated the effect of imposing negative and positive defocus simultaneously on the eye growth and refractive state of the common marmoset, a New World primate that compensates for either negative and positive defocus when they are imposed individually. METHODS: Ten marmosets were reared with multizone contact lenses of alternating powers (-5 diopters [D]/+5 D), 50:50 ratio for average pupil of 2.80 mm over the right eye (experimental) and plano over the fellow eye (control) from 10 to 12 weeks. The effects on refraction (mean spherical equivalent [MSE]) and vitreous chamber depth (VC) were measured and compared to untreated, and -5 D and +5 D single vision contact lens-reared marmosets. RESULTS: Over the course of the treatment, pupil diameters ranged from 2.26 to 2.76 mm, leading to 1.5 times greater exposure to negative than positive power zones. Despite this, at different intervals during treatment, treated eyes were on average relatively more hyperopic and smaller than controls (experimental control [exp-con] mean MSE +/- SE +1.44 +/- 0.45 D, mean VC +/- SE -0.05 +/- 0.02 mm) and the effects were similar to those in marmosets raised on +5 D single vision contact lenses (exp-con mean MSE +/- SE +1.62 +/- 0.44 D. mean VC +/- SE 0.06 +/- 0.03 mm). Six weeks into treatment, the interocular growth rates in multizone animals were already lower than in -5 D-treated animals (multizone -1.0 +/- 0.1 MUm/day, -5 D +2.1 +/- 0.9 MUm/day) and did not change significantly throughout treatment. CONCLUSIONS: Imposing hyperopic and myopic defocus simultaneously using concentric contact lenses resulted in relatively smaller and less myopic eyes, despite treated eyes being exposed to a greater percentage of negative defocus. Exposing the retina to combined dioptric powers with multifocal lenses that include positive defocus might be an effective treatment to control myopia development or progression. PMID- 22918634 TI - Introducing a new parameter for the assessment of the tear film lipid layer. AB - PURPOSE: The differential diagnosis of dry eye syndrome is still a challenging task. The purpose of this study was to understand the relationship between a novel, objective clinical parameter, the "corrected lipid layer stabilization time," and commonly performed clinical tests for dry eye patients. METHODS: Data were obtained from a prospective clinical study with 59 patients of different subjective severity, as determined with the Ocular Surface Disease Index (OSDI). The dynamics of the tear film lipid layer were made visible through a white light source and were stored digitally. Because the distance between the upper and lower eyelid affects the lipid layer dynamics and varies significantly between subjects, the distance of the eyelids was determined and used to correct the lipid layer stabilization time. The resulting parameter was compared with common clinical procedures. RESULTS: The corrected lipid layer stabilization time has a highly significant correlation with tear film breakup time (Spearman r = -0.485, P < 0.01), Schirmer test without anesthesia (r = -0.431, P < 0.01) and with the Ocular Surface Disease Index (r = 0.498, P < 0.01). It also correlates with the lissamine green staining score (r = 0.379, P < 0.05), but shows no correlation with the osmolarity of the tear film. Without the correction for the eyelid opening, the correlations decrease considerably. CONCLUSIONS: These data suggest that the diagnostic value of the lipid layer stabilization time for the assessment of the severity of dry eye syndrome increases considerably when it is corrected by the distance of the eyelids. PMID- 22918635 TI - Age-related changes in the pattern electroretinogram of normal and glatiramer acetate-immunized rats. AB - PURPOSE: Age-related changes in retinal ganglion cell (RGC) activity may impact results of long-term functional studies of disease progression and drug efficacy in humans and animal models. Though these changes can be evaluated using the pattern electroretinogram (PERG), longitudinal studies suffer from failure of follow-up from birth to senescence. Our aim was to perform a long-term, longitudinal study evaluating age-related changes in the rat PERG, by conducting repeated, serial recordings in the same animals. Additionally, we tested the hypothesis that neuroprotective treatment using glatiramer acetate (COP-1) immunization may delay age-related decline in function. METHODS: PERG was recorded from six untreated and seven Cop-1-immunized Lewis rats. Recordings were conducted at 2- to 4-week intervals from age 5 to 59 weeks. RESULTS: PERG amplitudes significantly increased between 5 to 7 weeks of age, and decreased from age 30 weeks onward (P = 0.016 and 0.0002, respectively). Amplitudes fluctuated insignificantly in weeks 7 to 30, with peak amplitudes reached at age 18 weeks in most spatial frequencies tested. N2 implicit times were shortened, mainly during weeks 5 to 18 and 40 to 59 (P < 0.001). PERG amplitudes of Cop-1 treated rats were similar to controls (P = 0.137) but peaked later (22-26 weeks). CONCLUSIONS: This 14-month-long study provided accurate measurement of developmental and aging changes of rat RGC function using repeated testing of individual animals. We found functional development to extend beyond the reported period of structural changes. Cop-1-immunized rats were not protected against age related decline in inner retinal function, although their PERG maturation dynamics were altered. PMID- 22918636 TI - Effect of photodynamic therapy with methylene blue on Acanthamoeba in vitro. AB - PURPOSE: To evaluate the disinfectant effect of methylene blue (MB)-mediated photodynamic therapy (PDT) on a pathogenic strain of Acanthamoeba. METHODS: Acanthamoeba castellanii (ATCC 50370) used in this study were treated under one of four experimental conditions: light irradiation and incubation in MB (L+M+), light irradiation and incubation in physiologic solution (L+M-), incubation in MB only (L-M+), and incubation in physiologic solution (L-M-). M+ trophozoites were incubated in either 0.25 or 0.5 mM MB for 10 minutes. L+ organisms were irradiated for 30 minutes following incubation in solution. A halogen lamp (660 +/- 10 nm) with a maximum output of 6 mW/cm(2) was used as the PDT light source. After treatment, antiacanthamoeba activity was evaluated by checking the respiratory activity of the amoeba with 5-cyano-2,3-tetrazolium chloride (CTC) staining. We also determined whether the effect of PDT with MB had been retained or augmented when it was performed in combination with conventional antiamoebic agents. RESULTS: MB-PDT suppressed the respiratory activity of trophozoites in an MB-concentration-dependent manner at total light doses of 10.8 J/cm(2). The respiratory activity of each group as a percentage of that of L-M- is as follows: L+M+ 11.6% (0.5 mM), 60.9% (0.25 mM); L-M+ 116.5% (0.5 mM), 105.5% (0.25 mM); L+M 107.6%; and L-M- 106.3%. (L+M+ versus L-M- P < 0.05). MB-PDT had a synergistic effect when used in combination with polyhexamethylene biguanide (PHMB) or amphotericin B, but not with voriconazole. CONCLUSIONS: MB-PDT is effective against Acanthamoeba in vitro and has synergistic effects with PHMB and amphotericin B. PMID- 22918637 TI - Axial length changes with shifts of gaze direction in myopes and emmetropes. AB - PURPOSE: The purpose of the study was to investigate the changes in axial length occurring with shifts in gaze direction. METHODS: Axial length measurements were obtained from the left eye of 30 young adults (10 emmetropes, 10 low myopes, and 10 moderate myopes) through a rotating prism with 15 degrees deviation, along the foveal axis, using a noncontact optical biometer in each of the nine different cardinal directions of gaze over 5 minutes. The subject's fellow eye fixated on an external distance (6 m) target to control accommodation, also with 15 degrees deviation. Axial length measurements were also performed in 15 degrees and 25 degrees downward gaze with the biometer inclined on a tilting table, allowing gaze shifts to be achieved with either full head turn but no eye turn, or full eye turn with no head turn. RESULTS: There was a significant influence of gaze angle and time on axial length (both P < 0.001), with the greatest axial elongation (+18 +/- 8 MUm) occurring with inferonasal gaze (P < 0.001) and a slight decrease in axial length in superior gaze (-12 +/- 17 MUm) compared with primary gaze (P < 0.001). In downward gaze, a significant axial elongation occurred when eye turn was used (P < 0.001), but not when head turn was used to shift gaze (P > 0.05). CONCLUSIONS: The angle of gaze has a small but significant short-term effect on axial length, with greatest elongation occurring in inferonasal gaze. The elongation of the eye appears to be due to the influence of the extraocular muscles, in particular the oblique muscles. PMID- 22918638 TI - Multifocal electroretinography in eyes with reticular pseudodrusen. AB - PURPOSE: The aim of our study was to evaluate the impact of reticular pseudodrusen (RPD) on retinal function by multifocal electroretinography (mfERG), and combined simultaneous confocal scanning laser ophthalmoscopy (cSLO) and spectral-domain optical coherence tomography (SD-OCT). METHODS: We included 19 eyes of 15 patients with RPD in the posterior pole and no other phenotypic retinal alteration were included (7 females and 8 males, age 77.2 +/- 5.1 years) as well as 24 eyes of 17 healthy control subjects (7 females and 10 males, age 73.2 +/- 5.9 years). All patients underwent fundus photography, SD-OCT, fluorescence angiography (FA), fundus autofluorescence, and near-infrared reflectance cSLO. mfERG measurements were performed by stimulating the retina by a field of 103 hexagons covering an area of approximately 30 degrees . Amplitudes and latencies of focal retinal responses obtained at affected and nonaffected sites of RPD eyes and retinal responses of healthy control subjects were compared. RESULTS: In all included study eyes, RPD stages 1-3 could be demonstrated clearly in SD-OCT, FA, and cSLO. The mean amplitudes measured in the areas affected by RPD were 12.5 to 53.1 nV/deg2 (control group 19.4-50.1 nV/deg2). The mean latencies were 33.2 to 41.3 ms (control group 33.6-39.7 ms). mfERG amplitudes and latencies of retinal areas affected by RPD were not altered significantly when compared to corresponding nonaffected areas. CONCLUSIONS: mfERG measurements did not show a definite influence on electrophysiologic activity in retinal areas affected exclusively with RPD. PMID- 22918639 TI - How do flanking objects affect reaching and grasping behavior in participants with macular disorders? AB - PURPOSE: To investigate how objects (flankers) placed on either side of a target affect reaching and grasping behavior in visually impaired (VI) subjects due to macular disorders compared with age-matched normals. METHODS: Subjects reached out to grasp a cylindrical target placed on its own and when it had two identical objects (flankers) placed either half or one target diameter away on each side of the target. A motion analysis system (Vicon 460) recorded and reconstructed the 3 dimemsional (3D) hand and finger movements. Kinematic data for transport and grasping mechanisms were measured. RESULTS: In subjects with VI, crowding effected the overall movement duration, time after maximum velocity, and maximum grip aperture. Maximum effect was shown when the flankers were placed close to the target (high-level crowding) with a decreased effect shown for flankers placed farther away (medium-level crowding). Compared with normals, subjects with VI generally took longer to initiate the hand movement and to complete the movement. Time after maximum velocity and time after maximum grip aperture were also longer in subjects with VI. No interaction effects were found for any of the indices for the different levels of crowding in the two visual groups. CONCLUSIONS: Reaching and grasping behavior is compromised in subjects with VI due to macular disorders compared with normals, and crowding affected performance for both normal subjects and those with VI. Flankers placed half an object diameter away showed greater deterioration than those placed further away. PMID- 22918640 TI - Effect of 1,25-dihydroxyvitamin D3 on Th17 and Th1 response in patients with Behcet's disease. AB - PURPOSE: 1,25-Dihydroxyvitamin D3 (VitD3) has been shown to have immunoregulatory properties in animal models. In this study, we investigated its inhibitory effect on the immune response in Behcet's disease (BD) patients and the possible mechanisms involved. METHODS: Naive CD4(+) T cells from active BD patients and normal controls were cultured under Th17 polarizing conditions in the presence or absence of VitD3, and cytokine production was determined by ELISA and flow cytometry. mRNA expression of several factors related to Th17 cell function was determined by real-time PCR. RNA interference for IFN regulatory factor 8 (IRF-8) was performed to study whether it was involved in the inhibitory effect of VitD3 on Th17 cell differentiation. The effect of VitD3-treated dendritic cells (DCs) on CD4(+) T cell response was determined by ELISA and flow cytometry. RESULTS: Stimulation of naive CD4(+) T cells under Th17 polarizing conditions showed a higher Th17 cell differentiation in active BD patients. The addition of VitD3 significantly inhibited Th17 cell differentiation both in BD patients and in normal controls. The knockdown of IRF-8 by RNA interference significantly decreased the suppressive effect of VitD3 on Th17 differentiation. VitD3 was able to inhibit the gene expression of RORC, IL-17, IL-23R, CCR6, and Th1 cell differentiation, but upregulated IL-10 expression. VitD3-treated DCs significantly inhibited the Th17 and Th1 response. CONCLUSIONS: The findings suggest that the inhibitory effect of VitD3 on the Th17 and Th1 response was mediated via both T cells and DCs and that the IRF-8 pathway is involved in the direct inhibition of VitD3 on Th17 cell differentiation. PMID- 22918641 TI - Tear lacritin levels by age, sex, and time of day in healthy adults. AB - PURPOSE: Several small proteomic studies suggest that the prosecretory tear protein lacritin may be selectively downregulated in dry eye syndrome and in blepharitis, yet little information is available about normal baseline levels. This study assessed lacritin levels in tears from healthy individuals and addressed whether they differ according to sex, age, or time of day. METHODS: Rabbit antibodies against lacritin N-terminal peptide EDASSDSTGADPAQEAGTS (Pep Lac N-Term) were generated and characterized against human recombinant lacritin and N-65 truncation mutant. Basal tears were collected from 66 healthy individuals ranging in age from 18 to 52 years, and at four times during one 24 hour period from 34 other individuals. Lacritin levels were then analyzed by ELISA and Western blotting. RESULTS: Anti-Pep Lac N-Term bound lacritin, but not truncation mutant N-65 that lacks the N-terminal antigenic site. Tear lacritin levels followed a normal distribution with a mean of 4.2 +/- 1.17 ng/100 ng total tear protein. Levels differed little by age or sex, and decreased slightly between 4 and 8 hours in a 24-hour cycle. Tear-blocking effects were minimal, as suggested by spiking of tears with recombinant lacritin. CONCLUSIONS: Anti-Pep Lac N-Term-detectable lacritin comprises ~4.2 ng/100 ng total tear protein in healthy individuals, with no significant differences between males and females or among individuals between 18 and 52 years old. Levels decrease slightly in the late afternoon. These findings provide a baseline for future immunodiagnostic studies of lacritin in dry eye and other ocular diseases. PMID- 22918642 TI - Ethyl pyruvate ameliorates endotoxin-induced corneal inflammation. AB - PURPOSE: The purpose of this study was to evaluate the anti-inflammatory effect of ethyl pyruvate (EP) in a mouse model of lipopolysaccharide (LPS)-induced corneal inflammation. METHODS: LPS was injected intrastromally into the corneas of C57BL/6 mice followed by treatment with a solution of 2.5% EP in 0.2% hydroxypropyl methylcellulose (HPMC) every 90 minutes during the course of 12 hours. Prednisolone acetate 1% solution (PRED FORTE) was used as a positive control. Mice were sacrificed after 3 days, and corneas were examined by in vivo confocal microscopy and analyzed for infiltrated cells by flow cytometry. Gr-1, TNF-alpha, and pNF-kappaB-p65 were detected immunohistochemically, and TNF-alpha, IL-6, and IL-1beta levels were quantified by ELISA. RESULTS: LPS-induced haze in mice corneas was decreased by 2-fold upon EP treatment; however, it was not changed upon PRED FORTE treatment. Flow cytometry and immunohistochemistry showed infiltration of leukocytes in the LPS-treated corneas; among the infiltrated cells, neutrophils (Gr-1+ and CD11b+) and macrophages (F4/80+ and CD11b+) were 3403.4- and 4.5-fold higher in number, respectively, than in vehicle-treated control corneas. EP or PRED FORTE treatment of LPS-injected corneas decreased the number of neutrophils 7.5- and 7.2-fold and macrophages by 5.6- and 3.5-fold, respectively. Both EP and PRED FORTE decreased TNF-alpha and IL-6 expression considerably, and to a lesser extent IL-1beta expression, in the LPS-treated corneas. CONCLUSIONS: The present study demonstrated that EP reduces LPS-induced inflammation in the cornea and thus may have a potential therapeutic application in the inhibition of corneal inflammation. PMID- 22918643 TI - Effects of simvastatin on the expression of heme oxygenase-1 in human RPE cells. AB - PURPOSE: Chronic oxidative stress can lead to the impairment of RPE cells, indicating it to be a risk factor for AMD. The cholesterol-independent, pleiotropic effects of statins have protective effects on several cell types via unknown mechanisms. This study examined the role of heme oxygenase-1 (HO-1) as a target and potential mediator of statins in cultured human RPE cells. METHODS: The RPE cell viability was measured using a 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyl tetrazolium bromide assay. After 24 hours incubation, RT-PCR and Western blot was performed to measure the levels of HO-1 mRNA and protein expression, respectively, in RPE cells. Intracellular reactive oxygen species (ROS) production was measured using a fluorescence-activated cell sorter. RESULTS: In cultured human RPE cells, simvastatin showed no toxicity up to 10 MUM. Simvastatin increased the HO-1 mRNA and protein levels in a concentration dependent manner up to 10 MUM. HO-1 protein induction by simvastatin was unaffected by mevalonate or N-nitro-L-arginine methyl ester, showing that the isoprenoid- and NO-dependent pathways are not involved. Simvastatin-dependent HO 1 protein induction was reduced significantly by pharmacological inhibition of the phosphotidylinositol-3-kinase (PI3K)/Akt pathways. The simvastatin-induced inhibition of free radical formation was recovered by the presence of an HO inhibitor, zinc protoporphyrin. CONCLUSIONS: These results demonstrate that HO-1 is a target site and an antioxidant mediator of simvastatin in human RPE cells. Simvastatin-dependent upregulation of HO-1 is mainly via PI3K/Akt-dependent signaling pathways. Simvastatin may have some clinical benefits in preventing retinal diseases associated with oxidative stress, such as AMD. PMID- 22918644 TI - Choroidal thickness change after water drinking is greater in angle closure than in open angle eyes. AB - PURPOSE: To study change in choroidal thickness (CT) after water drinking test (WDT), comparing angle closure (AC) to open angle (OA) eyes. METHODS: Before and 30 minutes after drinking 1 L of water, 88 glaucoma subjects underwent measurements of CT by spectral domain-optical coherence tomography, IOP, blood pressure (BP), axial length (AL), and anterior chamber depth (ACD). RESULTS: Baseline CT was significantly greater in AC than in OA eyes (P = 0.002). After WDT, BP, IOP, and AL increased significantly (all P <= 0.0001). Mean CT increased significantly in the AC group (5.6 MUm, P = 0.04, n = 40) and among 80 subjects whose IOP rose > 2 mm Hg (responders; 3.2 MUm, P = 0.048), but not in the OA group or among all subjects (2.5 MUm increase overall, <1% of baseline CT, P = 0.10). ACD decreased in AC (-18 MUm, P = 0.07), but not in OA eyes (+3 MUm, P = 0.74). AC eyes had a significantly greater IOP increase after WDT than OA eyes (P = 0.002, multivariate regression). Among responders, CT increased more in those with larger diastolic perfusion pressure increase and in AC compared to OA eyes (P = 0.04 and P = 0.053, respectively, multivariate regression). CONCLUSIONS: A significant increase in CT and a decrease in ACD after WDT were observed in AC but not in OA eyes, and IOP increased significantly more in AC than in OA eyes, suggesting that the dynamic behavior of the choroid may play a role in the AC process. IOP increase after the WDT was not fully explained by CT increase. PMID- 22918647 TI - [The Patients' Rights Act - a medical examination]. PMID- 22918646 TI - Complement factor H deficiency results in decreased neuroretinal expression of Cd59a in aged mice. AB - PURPOSE: The complement system is closely linked to the pathogenesis of AMD. Several complement genes are expressed in RPE, and complement proteins accumulate in drusen. Further, a common variant of complement factor H (CFH) confers increased risk of developing AMD. Because the mechanisms by which changes in the function of CFH influence development of AMD are unclear, we examined ocular complement expression as a consequence of age in control and CFH null mutant mice. METHODS: Gene expression in neuroretinas and RPE/choroid from young and aged WT and Cfh(-/-) C57BL/6J mice was analyzed by microarrays. Expression of a wide range of complement genes was compared with expression in liver. RESULTS: An age-associated increased expression of complement, particularly C1q, C3, and factor B, in the RPE/choroid coincided with increased expression of the negative regulators Cfh and Cd59a in the neuroretina. Young mice deficient in CFH expressed Cd59a similar to WT, but failed to upregulate Cd59a expression with age. Hepatic expression of Cd59a increased with age regardless of Cfh genotype. CONCLUSIONS: While the connection between CFH deficiency and failure to upregulate CD59a remains unknown, these results suggest that expression of CD59 is tissue-specific and that neuroretinal regulation depends on CFH. This could contribute to the visual functional deficits and morphological changes in the Cfh(-/-) mouse retina that occur with age. PMID- 22918645 TI - A microparticle/hydrogel combination drug-delivery system for sustained release of retinoids. AB - PURPOSE: To design and develop a drug-delivery system containing a combination of poly(D,L-lactide-co-glycolide) (PLGA) microparticles and alginate hydrogel for sustained release of retinoids to treat retinal blinding diseases that result from an inadequate supply of retinol and generation of 11-cis-retinal. METHODS: To study drug release in vivo, either the drug-loaded microparticle-hydrogel combination was injected subcutaneously or drug-loaded microparticles were injected intravitreally into Lrat(-/-) mice. Orally administered 9-cis-retinoids were used for comparison and drug concentrations in plasma were determined by HPLC. Electroretinography (ERG) and both chemical and histologic analyses were used to evaluate drug effects on visual function and morphology. RESULTS: Lrat(-/ ) mice demonstrated sustained drug release from the microparticle/hydrogel combination that lasted 4 weeks after subcutaneous injection. Drug concentrations in plasma of the control group treated with the same oral dose rose to higher levels for 6-7 hours but then dropped markedly by 24 hours. Significantly increased ERG responses and a markedly improved retinal pigmented epithelium (RPE)-rod outer segment (ROS) interface were observed after subcutaneous injection of the drug-loaded delivery combination. Intravitreal injection of just 2% of the systemic dose of drug-loaded microparticles provided comparable therapeutic efficacy. CONCLUSIONS: Sustained release of therapeutic levels of 9 cis-retinoids was achieved in Lrat(-/-) mice by subcutaneous injection in a microparticle/hydrogel drug-delivery system. Both subcutaneous and intravitreal injections of drug-loaded microparticles into Lrat(-/-) mice improved visual function and retinal structure. PMID- 22918648 TI - [Anesthesia in endoscopic and percutaneous procedures in cardio-thoracic and cardiovascular interventions, Part 1-- percutaneous aortic valve replacement and mitral valve repair]. AB - Further development of surgical techniques and instruments provide complex endoscopic or transcatheter guided interventions in thoracic organs. However, minimalinvasive surgery does not mean minimalinvasive anaesthesia. Particularly concerning cardiothoracic surgery, complex endoscopic procedures represent a challenge to the anaesthesiological management. These interventions require a close interdisciplinary cooperation. Considering the surgical procedures, this review describes the anaesthesiological management for transcatheter aortic valve implantation (TAVI) and percutaneous mitral valve repair. Furthermore it focuses on the anaesthesiological management of pitfalls and complications related to the surgical procedure. PMID- 22918649 TI - [Retrograde intubation in an emergency situation - indication, technical performance, risks and pitfalls]. AB - Retrograde intubation is an alternative technique to endotracheal intubation. It is used for the management of expected or unexpected difficult intubation. The indication for use of this technique is, above all, a situation in which a flexible bronchoscope, a video laryngoscope or other alternative devices are not available or, respectively, when their use is - or appears to be - not possible due to bleeding and secretions or other particular anatomic pathological conditions. Although the necessary equipment for a retrograde intubation is frequently available, the technique is rarely used, especially in the German speaking regions.The present article describes the technical steps of retrograde intubation and discusses its possible risks and pitfalls. Furthermore, modifications that facilitate the technical procedure are presented. This contribution is intended to promote the acceptance and use of this less invasive technique in order to avoid possible injury to the patient due to hypoxia, trauma of the airways, and surgical emergency procedures or tracheotomies during the management of difficult airway conditions. PMID- 22918650 TI - [Perioperative fluid management--A never ending story?]. PMID- 22918651 TI - [Fluid management: estimation of fluid status]. AB - Cardiac filling pressures alone are not appropriate to estimate the effect of a volume challenge on the corresponding change in stroke volume. Dynamic variables of fluid responsiveness have been shown to discriminate with acceptable sensitivity and specificity between responders and non-responders to a volume challenge. However, several clinical confounders have been indentified which potentially influence the predictive power of these variables. Sound knowledge of these confounders and the acknowledgement that there is no unique threshold value for volume optimisation but a considerable "gray zone" is necessary to fully exploit the advantages of functional haemodynamic monitoring. PMID- 22918652 TI - [Fluid management - which fluid for what type of patients?]. AB - There is a renewed discussion about the role of crystalloids and natural as well as synthetic colloids in fluid resuscitation. Based on the currently available evidence the choice of fluid replacement does not influence mortality. However, there is increasing evidence that due to unwarranted organ effects of the specific replacement fluids, individual subgroups of patients may be preferentially treated either with cristalloids or colloids. PMID- 22918653 TI - [Fluid management: goal-directed therapy]. AB - Goal-directed fluid therapy (GDT) is one important step in perioperative therapy as it improves complication rate and mortality by optimisation of oxygen delivery. There is a convincing evidence for GDT when used early, before organ failure occurs, and in high-risk patients. Moderne algorithms use goals derived from advanced haemodynamic monitoring and are based on the concept of fluid responsiveness and optimisation of global perfusion. Future investigations will have to prove the advantage of using the new less or non-invasive haemodynamic monitoring devices or automatic closed-loop fluid administration systems for GDT. PMID- 22918654 TI - [German Anaesthesia Congress 2012 - Review of the Congress President]. PMID- 22918655 TI - [Thieme Teaching Award - How useful is a "leap of faith"?]. PMID- 22918656 TI - [Multimodal pain therapy - implementation of process management - an attempt to consider management approaches]. AB - The combination of medical and economical proceedings allows new perspectives in the illustration of medical workflows. Considering structural and developmental aspects multimodal therapy programs show similarities with typical subjects of economic process systems. By pointing out the strategic appearance of the multimodal pain therapy concept multimodal approaches can be described to some extent by using management approaches. E. g., an economic process landscape can be used to represent procedures of a multimodal pain therapy program. PMID- 22918657 TI - [Puzzle and win - Crossword]. PMID- 22918658 TI - [In Memoriam - Dr. Otto Heinrich Just (1922-2012)]. PMID- 22918659 TI - Insurance status of urban detained adolescents. AB - The primary goal was to describe the health care coverage of detained youth. An exploratory second goal was to describe the possible relationship between redetention and coverage. Health care coverage status was abstracted from electronic detention center records for 1,614 adolescents in an urban detention center (October 2006 to December 2007). The majority of detained youth reported having Medicaid coverage (66%); 18% had private insurance and 17% had no insurance. Lack of insurance was more prevalent among older, male, and Hispanic youth. A substantial minority of detained youth were uninsured or had inconsistent coverage over time. While having insurance does not guarantee appropriate health care, lack of insurance is a barrier that should be addressed to facilitate coordination of medical and mental health care once the youth is released into the community. PMID- 22918660 TI - Close distal margins do not increase rectal cancer recurrence after sphincter saving surgery without neoadjuvant therapy. AB - PURPOSE: The oncological results of close distal resection margins (DM) have been mixed due to variations in perioperative treatment protocols and surgical expertise. With the increased application of sphincter-saving surgery in the management of rectal cancer, "close shave" DM is an increasingly encountered phenomenon. Our center aims to examine the oncological outcomes of "close shave" DM in the absence of neoadjuvant therapy in the surgical treatment of rectal cancer. METHODS: A prospective database of 320 patients who underwent curative surgical resection for primary rectal cancer between 1999 and 2007 was reviewed. One hundred forty-eight patients had "close shave" DM (DM <1 cm) and 70 (22 %) patients had stage 1, 102 (32 %) patients had stage 2, and 148 (46 %) patients presented with stage 3 disease. Median follow-up was 45 months. RESULTS: The overall recurrence rate for the entire study cohort was 29 % (n = 94), with 6.6 % of patients developing locoregional recurrence. Recurrence was noted to be significantly associated with decreasing circumferential resection margin (p = 0.008) and increasing American Joint Committee on Cancer stage (p < 0.001). Five year cancer-specific survival (CSS) for patients with DM <1 cm was 75.6 % and is higher compared to patients with longer DM (p = 0.041). Multivariate analysis showed that CSS was worsened with T stage, N stage, and perineural invasion status. Decreasing DM, however, was not significantly associated with poorer CSS or recurrence rates. CONCLUSION: Close distal resection margins do not negatively impact long-term disease control, even without the use of neoadjuvant therapy, provided that safe, optimal surgical resection is performed. Circumferential radial margin may be a more important indicator for outcomes. PMID- 22918661 TI - The gentamicin-collagen sponge for surgical site infection prophylaxis in colorectal surgery: a prospective case-matched study of 606 cases. AB - PURPOSE: Surgical site infection (SSI) is a major concern in colorectal surgery (CRS). It accounts for 60 % of all postoperative complications and has an incidence of between 10 and 30 %. The gentamicin-collagen sponge (GCS) was developed to help avoid SSI. The aim of this study was the evaluation of the efficacy of a GCS in preventing SSI after CRS. METHOD: This study was a retrospective analysis of data collected in a prospective database. Six hundred six CRS patients were enrolled in the study and prospectively assigned to one of two groups. From January 2007 to December 2008, all procedures were performed without the use of GCS (forming the non-GCS group). From January 2009 to July 2011, all procedures included a GCS (forming the GCS group). The primary endpoint was the presence or absence of SSI at postoperative day 30. RESULTS: The incidence of SSI was 29.7 and 20.8 % in the non-GCS and GCS groups, respectively (p = 0.019). By using a stepwise logistic regression, the predictors of SSI were found to be ASA grade (p < 0.001), operating time (log-transformed value, p < 0.001), gender (p = 0.021), and GCS use (p < 0.001). By adjusting on these variables, a mean reduction in postoperative hospitalization of 8.3 days was found in the GCS group. The proportions of Clavien IIIB-V were 16.6 and 8.9 % for the non-GCS and GCS groups, respectively (p = 0.041). CONCLUSIONS: This study provides additional evidence of the efficacy of the GCS in reducing SSI rates and shortening hospitalization after CRS. PMID- 22918662 TI - Hybrid breeding in autogamous cereals. AB - Hybrid breeding in autogamous cereals has a long history of attempts with moderate success. There is a vast amount of literature investigating the potential problems and solutions, but until now, market share of hybrids is still a niche compared to line varieties. Our aim was to summarize the status quo of hybrid breeding efforts for the autogamous cereals wheat, rice, barley, and triticale. Furthermore, the research needs for a successful hybrid breeding in autogamous cereals are intensively discussed. To our opinion, the basic requirements for a successful hybrid breeding in autogamous cereals are fulfilled. Nevertheless, optimization of the existing hybridization systems is urgently required and should be coupled with the development of clear male and female pool concepts. We present a quantitative genetic framework as a first step to compare selection gain of hybrid versus line breeding. The lack of precise empirical estimates of relevant quantitative genetic parameters, however, is currently the major bottleneck for a robust evaluation of the potential of hybrid breeding in autogamous cereals. PMID- 22918663 TI - Influence of IL-6 haplotypes on clinical and inflammatory response in aggressive periodontitis. AB - OBJECTIVES: The aim of this study was to investigate the inflammatory response in aggressive periodontitis (AgP) patients after periodontal therapy and associate these changes to subjects' interleukin-6 (IL-6) genetic variants. MATERIALS AND METHODS: Twelve non-smoking UK Caucasian patients with AgP were selected based on their IL6 haplotypes (six haplotype positive and six haplotype negative based on polymorphisms rs 2069827 and rs 2069825) and underwent full mouth non-surgical periodontal therapy, followed by open flap surgery. Gingival crevicular fluid (GCF) and peripheral blood samples were taken at baseline and at six different time points after treatment. Gingival biopsy samples were harvested during surgery and underwent immunohistochemical analysis for identification of IL-6. RESULTS: An overall improvement in clinical periodontal parameters was observed following periodontal therapy. Haplotype status was associated with clinical presentation, Aggregatibacter actinomycetemcomitans counts in subgingival plaque samples, white cell count, neutrophils, red cell count and haemoglobin. GCF IL-6 concentrations increased dramatically 1 day after surgery and IL-6 haplotype positive subjects exhibited a higher magnitude in this increase. CONCLUSIONS: IL6 haplotypes may have an effect on clinical presentation and magnitude and kinetics of local and systemic inflammatory responses following non-surgical and surgical periodontal therapy in aggressive periodontitis. CLINICAL RELEVANCE: Detecting IL 6 haplotype-positive periodontitis patients might become helpful in identifying subjects prone to excessive inflammatory response and increased periodontal breakdown. PMID- 22918664 TI - Genetic thromobophilia in pregnancy: a case-control study among North Indian women. AB - In the present study, an attempt is made to understand the role of genetic thrombophilias i.e. MTHFR C677T and FVL in the causation of various pregnancy complications like pregnancy induced hypertension (PIH), recurrent abortions, intra-uterine growth retardation (IUGR) and intra-uterine death on the whole and also individually along with the comparative assessment of pathophysiological basis of various pregnancy complications via the genetic proximities. One thousand and eleven (1,011) women of reproductive age group were recruited in the present study comprising various complications and controls. Recruitment criteria for all the pregnancy complications and controls was made and followed strictly. MTHFR C677T and FVL mutation detection was done in all the subjects. Vegetarianism was found to be significant risk factors for all the pregnancy complications and also when assessed individually. With respect to MTHFR C677T polymorphism, higher frequency of 677T allele was found among controls as compared to cases. 677T allele was found to pose decreased risk for various pregnancy complications on the whole and also individually. On adjusting the diet, regression analysis revealed no risk of mutant allele (T) for various pregnancy complications. FVL homozygous mutants were found to be absent among controls. In conclusion, the present study depicts dietary pattern as one of the most important factors in demonstrating the role of MTHFR C677T in various pregnancy complications and is indicative of a relatively deleterious effect of double dose of FVL in the presently studied population. Additionally, these polymorphisms play an important role in the orchestration of PIH to IUGR and vice versa. PMID- 22918665 TI - An inverse problem approach to recovery of in vivo nanoparticle concentrations from thermal image monitoring of MR-guided laser induced thermal therapy. AB - Quantification of local variations in the optical properties of tumor tissue introduced by the presence of gold-silica nanoparticles (NP) presents significant opportunities in monitoring and control of NP-mediated laser induced thermal therapy (LITT) procedures. Finite element methods of inverse parameter recovery constrained by a Pennes bioheat transfer model were applied to estimate the optical parameters. Magnetic resonance temperature imaging (MRTI) acquired during a NP-mediated LITT of a canine transmissible venereal tumor in brain was used in the presented statistical inverse problem formulation. The maximum likelihood (ML) value of the optical parameters illustrated a marked change in the periphery of the tumor corresponding with the expected location of NP and area of selective heating observed on MRTI. Parameter recovery information became increasingly difficult to infer in distal regions of tissue where photon fluence had been significantly attenuated. Finite element temperature predictions using the ML parameter values obtained from the solution of the inverse problem are able to reproduce the NP selective heating within 5 degrees C of measured MRTI estimations along selected temperature profiles. Results indicate the ML solution found is able to sufficiently reproduce the selectivity of the NP mediated laser induced heating and therefore the ML solution is likely to return useful optical parameters within the region of significant laser fluence. PMID- 22918667 TI - Genetic disorders of intellectual disability: expanding our concepts of phenotypes and of family outcomes. AB - Over the past two decades, great strides have been made in our understandings of how genetic conditions influence behavior and how such so-called "behavioral phenotypes" influence parent and family stress and coping. In this paper, we call for expansions in two directions. First, as a field we need to go beyond behavior in our concepts of phenotypes, to also include the many medical, physical, and other "non-behavioral" phenotypes that influence children's everyday lives. Second, in examining how etiology-related phenotypes affect others, we need to go beyond the outcome of parental stress. In this regard, we focus on parental health, well-being, and various life choices, as well as how parenting children with specific genetic disorders can often lead to positive perceptions and outcomes. We end by discussing remaining research issues and how these two expansions relate to clinical practice. PMID- 22918666 TI - Prevalence and importance of comorbidities in patients with heart failure. AB - Heart failure (HF), being a disease of the elderly, is associated with several noncardiac comorbidities, defined as chronic conditions coexisting with HF that play an integral role in its development, progression, and response to treatment. These include pulmonary dysfunction, sleep-disordered breathing, renal dysfunction, liver dysfunction, anaemia, thyroid disorders, diabetes mellitus, skeletal myopathy, depression, and cognitive impairment. The noncardiac comorbidity burden is higher and associated with higher non-HF hospitalizations in patients with HF and preserved, as compared with those with HF and reduced, left-ventricular ejection fraction. Since chronic inflammation is a characteristic feature of both HF and the coexisting morbidities, it may play a pivotal role in their development, progression, and interactions. PMID- 22918668 TI - Expression patterns of carcinogen detoxifying genes (CYP1A1, GSTP1 & GSTT1) in HNC patients. AB - Carcinogen detoxifying genes may be involved in pathogenesis of head and neck cancer (HNC). CYP1A1 is phase I enzyme that converts carcinogens into water soluble compounds which are easily excreted from body. GSTs constitute phase II detoxification enzymes that recognize these highly electrophilic compounds and detoxify them. Abnormal expression of these genes can potentially lead to cancer initiation. In present study, we analyzed protein expression of these genes in a total of 192 HNC patients and noncancerous healthy control serum samples screened for GSTs specific activity by ELISA. Furthermore, expression of these molecules was also determined in 49 HNC tissues/ adjacent control tissue by immunohistochemistry with specific antibodies. Mean serum GSTs specific activity was found to be 7.7 (+11.5)U/L in HNC patients and 11.4 (+7.5)U/L in controls. Significant decrease (P < 0.05) in GSTs specific activity was observed in HNC patients compared with controls (P < 0.001). Data for immunohistochemistry showed that CYP1A1 and GSTT1 was down expressed whereas GSTP1 was over expressed in HNC tissues compared with adjacent normal control tissues. Results of immunohistochemistry revealed 63 % HNC tissues had weak, 27 % moderate and 10 % strong staining for CYP1A1. For GSTT1, 27 % HNC tissues had no staining, 49 % weak staining, 16 % moderate and 8 % strong staining. Similarly for GSTP1, percentages for weak, moderate and strong staining were 6 %, 12 % and 82 % respectively. These reduced proteins observed in cancer patients highlight a potential breach on DNA repair mechanism when compared with control. Thus altered expression of these detoxifying molecules may collectively contribute to HNC development in Pakistani population. PMID- 22918669 TI - The effect of praise, positive nonverbal response, reprimand, and negative nonverbal response on child compliance: a systematic review. AB - Lack of compliance has both short- and long-term costs and is a leading reason why parents seek mental health services for children. What parents do to help children comply with directives or rules is an important part of child socialization. The current review examines the relationship between a variety of parenting discipline behaviors (i.e., praise, positive nonverbal response, reprimand, negative nonverbal response) and child compliance. Forty-one studies of children ranging in age from 11/2 to 11 years were reviewed. Reprimand and negative nonverbal responses consistently resulted in greater compliance. Praise and positive nonverbal responses resulted in mixed child outcomes. The findings are discussed based on theory and populations studied. The authors propose a mechanism that may increase children's sensitivity to both positive and negative behavioral contingencies. PMID- 22918670 TI - Understanding variation in primary medical care: a nine-country qualitative study of clinicians' accounts of the non-clinical factors that shape antibiotic prescribing decisions for lower respiratory tract infection. AB - OBJECTIVES: There is a wide variation between European countries in antibiotic prescribing for patients in primary care with lower respiratory tract infection (LRTI) that is not explained by case mix and clinical factors alone. Variation in antibiotic prescribing that is not warranted by differences in illness and clinical presentation may increase selection of resistant organisms, contributing to the problem of antibiotic resistance. This study aimed to investigate clinicians' accounts of non-clinical factors that influence their antibiotic prescribing decision for patients with LRTI, to understand variation and identify opportunities for addressing possible unhelpful variation. DESIGN: Multicountry qualitative semistructured interview study, with data subjected to a five-stage analytic framework approach (familiarisation, developing a thematic framework from interview questions and emerging themes, indexing, charting and interpretation), and with interviewers commenting on preliminary analytic themes. SETTING: Primary care. PARTICIPANTS: Eighty primary care clinicians randomly selected from primary care research networks based in nine European cities. RESULTS: Clinicians' accounts identified non-clinical factors imposed by the healthcare system operating within specific regional primary care research networks, including patient access to antibiotics before consulting a doctor (Barcelona and Milan), systems to reduce patient expectations for antibiotics (Southampton and Antwerp) and lack of consistent treatment guidelines (Balatonfured and Lodz). Secondly, accounts revealed factors related to specific characteristics of clinicians regardless of network (professional ethos, self belief in decision-making and commitment to shared decision-making). CONCLUSIONS: Addressing healthcare system factors (eg, limiting patients' self-management with antibiotics before consulting in primary care, increased public awareness and provision of more consistent guidelines) may assist in reducing unhelpful variation in antibiotic prescribing. Promoting clinicians' receptivity to change, confidence in decision-making and readiness to invest in explaining prescribing decisions may also be beneficial. As factors were emphasised differently between networks, local flexibility in interventions is likely to maximise effectiveness. PMID- 22918671 TI - Twenty-four-hour effects of bimatoprost 0.01% monotherapy on intraocular pressure and ocular perfusion pressure. AB - OBJECTIVES: To investigate the 24 h effects of bimatoprost 0.01% monotherapy on intraocular pressure (IOP) and ocular perfusion pressure (OPP). DESIGN: Prospective, open-label experimental study. SETTING: Single tertiary ophthalmic clinic. PARTICIPANTS: Sixteen patients with diagnosed primary open-angle glaucoma (POAG) or ocular hypertension (ages, 49-77 years). INTERVENTIONS: Baseline data of 24 h IOP in untreated patients were collected in a sleep laboratory. Measurements of IOP were taken using a pneumatonometer every 2 h in the sitting and supine body positions during the 16 h diurnal/wake period and in the supine position during the 8 h nocturnal/sleep period. After baseline measurements were taken, patients were treated with bimatoprost 0.01% one time per day at bedtime for 4 weeks, and then 24 h IOP data were collected under the same laboratory conditions. PRIMARY AND SECONDARY OUTCOME MEASURES: Diurnal and nocturnal IOP and OPP means under bimatoprost 0.01% treatment were compared with baseline. RESULTS: The diurnal and nocturnal IOP means were significantly lower under the bimatoprost 0.01% treatment than baseline in both the sitting and supine positions. The diurnal and nocturnal OPP means were significantly higher under treatment than baseline in both the sitting and supine positions. CONCLUSION: Bimatoprost 0.01% monotherapy significantly lowered IOP and increased OPP during the 24 h period. PMID- 22918672 TI - Can patients really make an informed choice? An evaluation of the availability of online information about consultant surgeons in the United Kingdom. AB - OBJECTIVES: The National Health Service (NHS) 'Choose and Book' online scheme, which allows patients to select the location and time of hospital appointments, has now been extended to include the option for patients to select a specific consultant to carry out any necessary treatment. The aim of this study was to determine whether there is sufficient online information about consultants or consultant-led teams for patients to make an informed choice regarding a specific consultant. DESIGN: A web-based analysis of the availability of information. SETTING: North of England. PARTICIPANTS: Two hundred websites of orthopaedic surgeons. MAIN OUTCOME MEASURES: The websites were analysed using a bespoke template that took into account recommendations of the 2010 UK Government white paper. Each website was scored in relation to the availability of specific content relating to each surgeon. RESULTS: The majority of websites detailed authorship information (73.2%), level of professional qualification (98.5%) and area of general (73.7%) and specialist (93.3%) interest. However, approximately 50% of websites provided no information in relation to update cycle, involvement in teaching or research and patient satisfaction. Only five (2.6%) of the websites presented death rates, and none indicated morbidity rates. CONCLUSIONS: For patients to be able to make informed choices about their healthcare, surgeons need to ensure that sufficient information is available online, according to the identified limitations of the websites investigated in this study. PMID- 22918673 TI - Efficient production of transgenic chickens based on piggyBac. AB - Transgenic techniques in chickens have been developed much more slowly than in mammals due to chickens' unique reproduction mechanism. Retroviral methods have been the most successful. piggyBac (PB) is a transposon that has a 13 bp perfect terminal invert repeat sequence. PB can be inserted into TTAA sites and can also be precisely excised in mammals. Therefore, we have selected PB as a candidate to establish a new method to produce transgenic chickens. We constructed three donor vectors (ZGl-neo, ZGm-neo and ZGs-neo) expressing a GFP marker-gene and a neomycin resistant gene based on PB. We co-transfected each donor vector with a helper vector (CAG-PBase). We found that ZGl-neo was the most efficient PB vector. This vector could insert into TTAA sites in DF-1 cells. PB vectors were microinjected into sub-germinal cavity of newly laid eggs, and electroporation was then performed with a 20-V pulse for 5 cycles of 50 ms on and 100 ms off. GFP was expressed in different tissues of the embryos, including the gonads. Twenty two chickens hatched after microinjection with compounds ZGl-neo and CAG-PBase (3:1). When we screened the blood DNA, 73 % (16/22) of the individuals were positive. Thirteen of the chickens grew to adulthood, 11 of which were males. 40 % (4/10) of the individuals were semen positive, and their copy numbers ranged from 0.05 to 0.21 (0.11, 0.21, 0.05, 0.06). No G1 offspring containing the integrated transposon were produced. We conclude that the PB transposon system is a novel useful tool for the efficient production of transgenic chickens. PMID- 22918674 TI - Pathogenic Escherichia coli and One Health implications. AB - Escherichia coli are common inhabitants in the intestinal tracts of warm blooded animals where they generally cause no harm to the host, although there are some types of E. coli which are able to cause disease. The most significant of these are enterohaemorrhagic E. coli (EHEC) which can cause severe human disease that can result in death. EHEC have an animal reservoir, particularly cattle, and are considered to be an important zoonotic pathogen having significant impact for One Health. EHEC can be transmitted from animals into humans, either from consumption of foods made from these animals, or from contact with foods which may have become contaminated directly or indirectly from animal wastes. Increasingly, EHEC have also been associated with uncooked leafy green vegetables and sprouts. Several large outbreaks of E. coli have highlighted the importance for addressing these organisms in a One Health perspective. PMID- 22918675 TI - Variations in transport outcomes of outborn infants among Canadian neonatal intensive care units. AB - BACKGROUND: Outborn infants born at community hospitals and transported to tertiary neonatal intensive care units (NICUs) for treatment account for 20% of all tertiary NICU admissions in Canada. Little is known about variations in their outcomes. The Transport Risk Index of Physiologic Stability (TRIPS) is a validated score of neonatal physiological status that can identify differences between transport teams' outcomes. OBJECTIVE: To examine regional variations in outcomes among outborn infants transported to Canadian tertiary NICUs using TRIPS. DESIGN AND METHODS: Transport teams prospectively collected data for all outborn infants admitted to 25 Canadian NICUs during 2006 to 2007. Singleton outborn infants >= 32 weeks' gestation admitted to NICUs for at least 24 hours who died or who were transferred to another NICU within 24 hours were examined for overall incidence of mortality, major morbidity, and change in TRIPS score. RESULTS: Complete transport data were available for 2313 (72.9%) of 3193 eligible infants. There were significant variations in interhospital and interprovincial outcomes. Factors significantly affecting change in TRIPS score were gender, pretransport TRIPS score, composition of transport team and distance traveled. CONCLUSION: Significant variation exists in transport outcomes in Canada. Further investigation is required to optimize infant transport systems, processes, and clinical care. PMID- 22918676 TI - Relationship between platelet count and volume and spontaneous and pharmacological closure of ductus arteriosus in preterm infants. AB - It has been reported that low platelet count may increase the risk of patent ductus arteriosus (PDA) in preterm infants. Moreover, high mean platelet volume (MPV) has been found to be associated with the development of prematurity complications due to enhanced platelet reactivity. Our aim was to assess the relationship between platelet count and MPV and the occurrence of PDA and its resistance to ibuprofen closure in a cohort of extremely preterm infants. Platelet count <100 (*10(3)/mm(3); odds ratio 4.50; 95% confidence limits 1.39 to 14.61) at birth is an independent risk factor for PDA but does not affect its response to ibuprofen. MPV values did not influence PDA fate. Low platelet count increases the risk of developing a hemodynamically significant PDA but does not affect the ibuprofen closure rate. MPV is unrelated to the DA outcome. PMID- 22918677 TI - Early versus conventional treatment for patent ductus arteriosus in preterm infants. AB - OBJECTIVE: After the introduction of a new protocol based on the early treatment with indomethacin for patent ductus arteriosus, the objective of this study was to assess the safety and efficacy of this new practice in comparison with the safety and efficacy of the conventional treatment in a high-risk population. STUDY DESIGN: We conducted a retrospective cohort study including 154 newborns with an average gestational age of 26.4 weeks (1.37 standard deviation) and an average birth weight of 855 g (201.5 standard deviation). A statistically descriptive analysis was performed with SPSS Statistics Pack version 17.0. RESULTS AND CONCLUSIONS: We did not find any statistically significant differences in the clinical features of the two treatment groups, nor in the main efficacy, morbidity, and mortality results. PMID- 22918678 TI - Bacillus bloodstream infections in a tertiary perinatal centre: an 8-year study. AB - BACKGROUND: Isolates of nonanthrax Bacillus species in clinical samples are frequently considered as contaminants. However, there were case reports describing Bacillus sepsis among infants, associated with high mortality and morbidity. METHODS: We performed a retrospective review of the clinical and epidemiological features of Bacillus bacteremia at our neonatal intensive care unit from January 2002 to December 2009. RESULTS: Bacillus bacteremia was considered to be clinically significant in 11 infants. The median gestational age was 30 weeks. All had either central catheters or peripherally inserted arterial lines in situ. The mean neutrophil and lymphocyte counts were 6.73 * 10(9)/L (0.78 to 12.56 * 10(9)/L) and 2.75 * 10(9)/L (0.82 to 6.15 * 10(9)/L), respectively. All 11 infants received intravenous vancomycin, with an average duration of 12.4 days. In general, the earlier the catheter was removed, the quicker the clearance of bacteremia was achieved. All infants survived and were discharged from the hospital. CONCLUSIONS: The growth of Bacillus species in blood cultures cannot simply be regarded as a contaminant. Hematologic parameters are frequently unremarkable at the disease onset. Increased vigilance, early diagnosis, and effective therapy in conjunction with prompt catheter removal are the keys to successful management of Bacillus bacteremia. PMID- 22918679 TI - Trends in emergency peripartum hysterectomy at a single institution: 1988-2009. AB - OBJECTIVE: To evaluate trends of emergency peripartum hysterectomy over two decades. STUDY DESIGN: This was a retrospective cohort study of peripartum hysterectomies at one institution from 1988 to 2009. Medical records were reviewed and data from the first 11 years were compared with data from the second 11 years. RESULTS: During the study period, 558 emergent peripartum hysterectomies were performed with full records available for 553 to review: 280 in the first period, 273 in the second (p = 0.19). In the second period, prior cesarean deliveries, length of surgery, estimated blood loss, blood transfusions, and the number of units transfused were all increased (p < 0.001). Also in the second period, there were twice as many hysterectomies for suspected placental invasion, and an almost threefold increase in pathologically confirmed placental invasion (both p < 0.001). CONCLUSION: Although emergent peripartum hysterectomies are not increasing in frequency, the risk factors and morbidities have changed. PMID- 22918680 TI - The methodological quality of economic evaluation studies in obstetrics and gynecology: a systematic review. AB - We evaluated the methodological quality of economic evaluation studies in the field of obstetrics and gynecology published in the last decade. A MEDLINE search was performed to find economic evaluation studies in obstetrics and gynecology from the years 1997 through 2009. We included full economic evaluation studies concerning tests or interventions in the field of obstetrics or gynecology. Each included study was evaluated by two reviewers using a quality checklist that was based on international guidelines for medical economic evaluation studies and a checklist used in a previous review. The mean number of quality criteria adhered to was 23 of 30 items, whereas five articles (3%) met all 30 criteria. Compliance was low for the description of the perspective (40%), the completeness of costs looking at the perspective (48%) or time horizon (48%), and reporting of quantities of resources (47%). Furthermore, if no discounting was applied, an explanation was infrequently given (14%). A comparison of study quality to that reported by Smith and Blackmore showed a considerable improvement in the following criteria: presentation perspective (from 19 to 40%), statement of primary outcome measure (from 72 to 81%), completeness costs looking at the time horizon (from 14 to 48%), the presentation of discount rates (from 10 to 54%), details of sensitivity analyses (from 21 to 61%), reporting incremental results (from 17 to 70%), and reporting a summary measure (from 57 to 74%). The quality of economic studies in obstetrics and gynecology has considerably improved in the last decade, but room for further improvement is present. PMID- 22918681 TI - Antifibrotic activity of sorafenib in experimental hepatic fibrosis: refinement of inhibitory targets, dosing, and window of efficacy in vivo. AB - BACKGROUND: Sorafenib, which is approved for treatment of HCC, has also shown promising antifibrotic activity, and therefore refinement of its dosing requirements and window of efficacy are important goals prior to antifibrotic clinical trials. AIM: The purpose of this study was to determine the minimal effective dose and optimal timing of sorafenib therapy in cultured human stellate cells and in rats with experimental hepatic fibrosis. METHODS: Effects of sorafenib were assessed in a human stellate cell line (LX-2). In vivo, rats were treated for 8 weeks with TAA three times per week (150 mg/kg IP), and with either PBS or sorafenib administered daily at doses of 1.25, 5 or 7 mg/kg/day gavage either at the beginning of TAA administration for 8 weeks, during weeks 4-8, or from weeks 8-12. RESULTS: Sorafenib treatment significantly inhibited LX-2 proliferation by >75% (7.5 or 15 MUM). Treatment with 7.5-MUM sorafenib for 12 h markedly inhibited expression of TGFbeta1, TIMP-1, collagen I, and MMP2 mRNAs, but not of beta-PDGFR or type I TGFbetaR. In vivo, sorafenib significantly inhibited liver fibrosis when started concurrently with TAA and during weeks 4-8 with TAA. In contrast, there was no significant effect of sorafenib on fibrogenic gene expression or fibrosis when begun after cirrhosis was already established. CONCLUSION: Sorafenib is anti-proliferative and antifibrotic towards human HSCs in culture, and is a potent antifibrotic agent in TAA-induced hepatic fibrosis in rats. The drug is effective at relatively low doses at the early stage of liver fibrosis, but is not effective when cirrhosis is already established. PMID- 22918682 TI - Readressing the role of Toll-like receptor-4 alleles in inflammatory bowel disease: colitis, smoking, and seroreactivity. AB - BACKGROUND: Toll-like receptor (TLR) polymorphisms, and especially TLR-4 Asp299Gly and TLR-4 Thr399Ile, have been linked with Crohn's disease (CD) and to a lesser extent with ulcerative colitis (UC), CD behavior, and compromised seroreactivity to microbial antigens. Available data, however, are conflicting. AIMS: To address these issues, the distribution of TLR-4 polymorphic alleles was assessed in patients with UC, CD, and healthy controls (HC), considering patient and disease characteristics as well as related serological markers. METHODS: TLR 4 Asp299Gly and TLR-4 Thr399Ile polymorphisms were determined in 187 UC and 163 CD patients and 274 randomly selected HC. C reactive protein, anti-Saccharomyces cerevisiae mannan antibodies, anti-mannobioside carbohydrate antibodies, anti laminariobioside carbohydrate antibodies IgG, and anti-chitobioside carbohydrate antibodies (ACCA) IgA levels were also assessed. RESULTS: UC and especially pancolitis patients carried the mutant alleles more frequently compared to CD patients and HC or UC patients with different disease extents (P = 0.002 and P < 0.0001, respectively). Involvement of the colon was more frequent in CD patients with mutant TLR-4 compared to those with wild-type alleles (P = 0.004). Levels and positivity rates of ACCA IgA were lower in inflammatory bowel disease (IBD) patients carrying the mutant compared to those with wild-type alleles (0.075 < P < 0.05). Despite the mutant TLR-4 predisposition for UC pancolitis, smoking was associated with more limited disease (P < 0.001). CONCLUSIONS: The presence of TLR-4 Asp299Gly and TLR-4 Thr399Ile polymorphisms is related to UC pancolitis, involvement of the colon in CD, and lower ACCA IgA levels. Smoking reduces the extent of UC, even in the presence of mutant alleles. PMID- 22918683 TI - Attenuation of acetic acid-induced gastric ulcer formation in rats by glucosylceramide synthase inhibitors. AB - INTRODUCTION: Ceramide has been suggested to play a role in apoptosis during gastric ulcerogenesis. The present study is designed to investigate whether accumulated ceramide could serve as the effector molecules of ulcer formation in a rat model of acetic acid-induced gastric ulcer. METHODS: The effect of fumonisin B1, an inhibitor of ceramide synthase, and of d,l,-threo-1-phenyl-2 hexadecanoylamino-3-morpholino-1-propanol (PPMP) and N-butyldeoxynojirimycin (NB DNJ), both inhibitors of glucosylceramide synthase, on the accumulation of ceramide and formation of gastric ulcer were examined in the rat model of acetic acid-induced gastric ulcer. RESULTS: Fumonisin B1 attenuated acetic acid-induced gastric ulcer formation, associated with a decrease in the number of apoptotic cells. Our results showed that it is neither the C18- nor the C24-ceramide itself, but the respective metabolites that were ulcerogenic, because PPMP and NB DNJ attenuated gastric mucosal apoptosis and the consequent mucosal damage in spite of their reducing the degradation of ceramide. CONCLUSION: The ceramide pathway, in particular, the metabolites of ceramide, significantly contributes to acetic acid-induced gastric damage, possibly via enhancing apoptosis. On the other hand, PPMP and NB-DNJ treatment attenuated gastric mucosal apoptosis and ulcer formation despite increasing the ceramide accumulation, suggesting that it was not the ceramides themselves, but their metabolites that contributed to the ulcer formation in the acetic acid-induced gastric ulcer model. PMID- 22918684 TI - Dipeptidyl peptidase 4-deficient rats have improved bile secretory function in high fat diet-induced steatosis. AB - BACKGROUND/AIMS: Rodent obesity models have been shown to display impaired bile secretory functions. We have shown that glucagon-like peptide 1 (GLP-1) attenuates hepatic lipogenesis, and in the present study we investigated whether GLP-1 also improves high fat diet-associated cholestatic injury. METHODS: Wild type (WT) and dipeptidyl peptidase 4-deficient rats (DPP4-) with chronic elevated serum levels of active GLP-1 were fed regular chow and a Western diet for 2 months. Primary hepatocytes were used to assess GLP-1 effects on mRNA expression and transcription of genes encoding bile acid synthesis enzymes and transporters. RESULTS: DPP4- exhibited attenuated liver injury as expressed by lower serum AST and ALT after 2 months of a Western diet. In addition, DPP4- had better insulin sensitivity, lower serum triglycerides, cholesterol and bile acids. Hepatic expression of cyp7A1, the rate limiting enzyme in conversion of cholesterol into bile acids, was strongly attenuated in DPP4- fed with a Western diet. Moreover, hepatic expression of bile transporter, ABCB11, was increased, facilitating a higher rate of bile secretion. Mechanistically, we showed that GLP-1 directly reduced basal and LXR-induced cyp7A1 mRNA expression and suppressed cyp7A1 transcription in transient transfection assays in primary hepatocytes. However, GLP-1 and its analog exendin 4 also induced mRNA expression of bile acid transporter ABCC3 in primary rat hepatocyte cultures. CONCLUSIONS: Our data suggest that GLP-1 analogs may serve as a novel therapeutic drug to alleviate obesity-induced liver injury by reducing bile acid synthesis and improving liver bile secretory function. PMID- 22918685 TI - Severity of dyspeptic symptoms correlates with delayed and early variables of gastric emptying. AB - BACKGROUND: A simplified report of gastric retention values at select times is now recommended for scintigraphic gastric emptying test (GET). AIMS: The purpose of this study was to assess correlation between severity of gastroparetic symptoms and all variables of GET, compared to select variables in clinical use. METHODS: This was a prospective study of patients referred for scintigraphic GET. The Gastroparesis Cardinal Symptom Index questionnaire was obtained prior to the scintigraphy. Variables determined were lag time, half emptying time (T1/2), retention at 30 min, 1, 2 and 4 h. Statistical analysis was by Spearman rank correlation and Wilcoxon rank test with a significance set at p <= 0.05. RESULTS: Seven hundred seventeen patients had GET from 03/09 to 03/11. Results are from 325 patients who did not take medications known to affect GET were analyzed (64.9 % females, mean age 47 +/- 18.9 years, 21.8 % diabetics, 78.2 % non-diabetic, of which 7.6 % were post-surgical, primarily post-fundoplication). Combined gastric retention at 2 and 4 h detected delayed GET in 83.5 % non-diabetics and 76.6 % of diabetics. Rapid GET was present in 11 % of patients at 30 min and 4 % at 1 h. Significant positive correlation was observed between nausea, vomiting, loss of appetite and variables of GET, but not with the half-time of emptying (T1/2). Bloating negatively correlated with retention at 2 h. There was no association between duration of symptoms and GET variables. CONCLUSIONS: Gastroparetic symptoms correlate with different retention times of GET, but not with T1/2. However, symptoms poorly distinguish between categories of gastroparesis or status of gastric emptying. Delayed GE is best detected by 2 and 4 h retention times, while 30 min and 1 h retention times detect rapid GE. PMID- 22918686 TI - Egr-1 promotes cell proliferation and invasion by increasing beta-catenin expression in gastric cancer. AB - BACKGROUND: Abnormal expression of early growth response gene 1 (Egr-1) and beta catenin may play a crucial role in the development and progression of human cancer. However, little is known about the expression and underlying molecular mechanisms in which Egr-1 and beta-catenin are involved in the development and progression of gastric cancer. AIMS: The purpose of this study was to elucidate the potential relationship between Egr-1 and beta-catenin expression in gastric cancer, which contributes to finding new molecular carcinogenesis as a potential therapeutic target for gastric cancer. METHODS: In a sample of 102 cases of human gastric cancer, the expression of Egr-1 and beta-catenin was detected using immunohistochemistry. Egr-1 gene was transfected into gastric cancer SGC7901 cells and its role in proliferation and cell invasion was detected by MTT assay, flow cytometry, wound-healing and transwell invasion assay. Western blot analysis was used to study the expression of beta-catenin and cyclin D1 proteins. RESULTS: Upregulated Egr-1 and beta-catenin protein expression were strongly correlated with cancer progression and depth of invasion in gastric cancer. beta-catenin, present mainly in cytoplasmic and nucleus of gastric cancer cells, was also positively correlated with Egr-1 expression in gastric cancer. Furthermore, the overexpression of Egr-1 upregulated beta-catenin expression level, promoted cell proliferation, increased cell population in S-phase and enhanced gastric cancer cell migration and invasion in vitro. CONCLUSIONS: Egr-1 might contribute to gastric cancer proliferation and invasion through activation of the beta-catenin signaling pathway. PMID- 22918687 TI - Are biopsy specimens predictive of HER2 status in gastric cancer patients? AB - BACKGROUND: Trastuzumab has been recently proposed as a treatment for patients with HER2-positive advanced/metastatic gastric cancer (GC). Since most patients have inoperable disease at diagnosis, accurate assessment of HER2 status on biopsy specimens is essential to select the patients who may benefit from therapy. AIM: The aim of this study is to establish whether HER2 status assessed on biopsy material could be reliable for treatment decisions using anti-HER2 agents. METHODS: The HER2 status was evaluated in 61 consecutive pairs of biopsy and surgical GCs samples by immunohistochemistry and chromogenic in situ hybridization. RESULTS: The overall concordance of HER2 status between biopsy and surgical specimens was 91.8 % with a predictive positive value of 71.4 % and a negative predictive value of 94.4 %. Of five discordant cases, there were three negative and two positive false biopsy results. All the false negative cases showed heterogeneous expression of HER2 protein in surgical samples. Two cases displayed overexpression of the receptors without corresponding gene amplification. CONCLUSIONS: HER2 status as evaluated on biopsy samples is a fairly good predictor of HER2 status of surgically-excised GCs. The most important influence for discordant results is tumor heterogeneity. However, HER2 overexpression, especially without coexisting gene amplification, may only be a temporary change in a tumor population. This may explain those cases with positive HER2 evaluation on biopsy material and a negative result on corresponding surgical specimen. PMID- 22918688 TI - Use of serum vitamin B12 level as a marker to differentiate idiopathic noncirrhotic intrahepatic portal hypertension from cryptogenic cirrhosis. AB - BACKGROUND AND AIMS: Idiopathic non-cirrhotic intrahepatic portal hypertension (NCIPH) is often mis-diagnosed as cryptogenic cirrhosis. Serum vitamin B12 levels can be raised in cirrhosis, probably because of excess release or reduced clearance. Because NCIPH is characterised by long periods of preserved liver function, we examined whether serum B12 level could be used as a marker to differentiate NCIPH from cryptogenic cirrhosis. METHODS: We analysed serum B12 levels in 45 NCIPH and 43 cryptogenic cirrhosis patients from January 2009 to September 2011. RESULTS: Serum B12 levels were significantly lower in NCIPH patients than in cryptogenic cirrhosis patients (p < 0.001) and were useful in differentiating the two disorders (area under ROC: 0.84; 95% C.I: 0.76-0.93). Low serum B12 level (<=250 pg/ml) was noted in 25/72 (35%) healthy controls, 14/42 (33%) NCIPH patients, and 1/38 (3 %) cryptogenic cirrhosis patients. In patients with intrahepatic portal hypertension of unknown cause, serum B12 level <= 250 pg/ml was useful for diagnosing NCIPH (positive predictive value: 93 %, positive likelihood ratio 12.7), and serum B12 level >1,000 pg/ml was useful in ruling out NCIPH (negative predictive value: 86 %, negative likelihood ratio: 6.67). Low serum B12 levels (<=250 pg/ml) correlated with diagnosis of NCIPH after adjusting for possible confounders (O.R: 13.6; 95% C.I:1.5-126.2). Among patients in Child's class A, serum B12 level was <=250 pg/ml in 14/35 NCIPH patients compared with 1/21 cryptogenic cirrhosis patients (O.R: 13.3; 95% C.I: 1.6-111). CONCLUSION: Serum vitamin B12 level seems to be a useful non-invasive marker for differentiation of NCIPH from cryptogenic cirrhosis. PMID- 22918689 TI - Stimulation of calcitonin gene-related peptide release through targeting capsaicin receptor: a potential strategy for gastric mucosal protection. AB - Calcitonin gene-related peptide (CGRP) is a predominant neurotransmitter from capsaicin-sensitive sensory nerves, which are widely distributed in the gastrointestinal system. These sensory nerves are reported to be involved in the protection of gastric mucosa against damage by various stimuli, and CGRP is a potential mediator in this process. In addition to increase in gastric mucosal blood flow, the beneficial effects of CGRP on gastric mucosa include inhibition of gastric acid secretion, prevention of cellular apoptosis and oxidative injury. The synthesis and release of CGRP is regulated by the capsaicin receptor which is known as transient receptor potential vanilloid subfamily member 1 (TRPV1) and the agonists of TRPV1 have the potential for gastric mucosal protection. So far, multiple TRPV1 agonists, including capsaicin, capsiate, anandamide and rutaecarpine are reported to exert beneficial effects on gastric mucosal injury induced by various stimuli. Therefore, the TRPV1/CGRP pathway represents a novel target for therapeutic intervention in human gastric mucosal injury. PMID- 22918691 TI - Pharmacodynamic and clinical endpoints for functional colonic disorders: statistical considerations. AB - BACKGROUND: Intra- and inter-subject coefficients of variation (COV) of scintigraphic colonic transit (SCT) are well characterized. SCT response to therapy predicts clinical efficacy of experimental medications in lower functional gastrointestinal disorders (FGID). AIM: To compare COVs for bowel function with pharmacodynamic (PD) colonic transit geometric center (GC) as endpoints in lower FGID studies. METHODS: We evaluated data from placebo arm of 9 phase IIA, parallel-group, clinical trials of PD effects of linaclotide, dexloxiglumide, renzapride, elobixibat, ROSE 010, and chenodeoxycholate in lower FGID with constipation, and pexacerafont, VSL#3, and colesevelam in lower FGID with diarrhea. Patients completed daily diaries for at least 7 days of stool frequency, consistency (7-point Bristol Stool Form Scale), and ease of passage (7 point scale from manual disimpaction to incontinence). Seventeen patients received placebo in 2 separate studies allowing assessment of intra-patient COVs. We calculated sample sizes required to demonstrate a 30 % effect size for colonic transit, stool frequency, consistency and ease of passage for patients with lower FGID with constipation and, separately, diarrhea. RESULTS: COV(inter) from 87 patients and COV(intra) from 17 patients are reported. Generally, COV(intra) is somewhat greater than COV(inter). The COVs for PD endpoints are lower than for clinical endpoints; however, clinically relevant effects can be identified with modest (~50 %) increases in the sample size using parallel-group design studies. CONCLUSION: Phase IIA studies that incorporate clinical and PD endpoints are feasible in lower FGID associated with constipation or diarrhea. Crossover design would require lower sample size for most endpoints compared to parallel-group studies. PMID- 22918692 TI - A bi-national comparative study of health behaviors of Koreans in South Korea and Korean Americans in California. AB - Few studies have compared health behaviors of Koreans in their home country and Korean Americans. Using 2009 data from the Community Health Survey (South Korea) and the California Health Interview Survey (USA), we compared native Koreans and Korean Americans, grouped by level of acculturation, on prevalence of specific health behaviors and self-rated health, and conducted multiple logistic regression comparing the odds of these behaviors among the groups adjusted for demographic variables. While Korean Americans exhibit healthier behaviors than Koreans in some areas (e.g., reduced smoking and binge drinking in men, increased utilization of flu vaccinations), we also identified problem behaviors (e.g., increased body weight in Korean American men, uptake of alcohol drinking and smoking among Korean American women). Findings support the critical need for health promotion programs addressing these health behaviors to prevent future health problems among Korean Americans. PMID- 22918693 TI - Medical assistance is scarcely sought by immigrants and immigrant-travelers in Spain. PMID- 22918690 TI - The overlap syndromes of autoimmune hepatitis. AB - Autoimmune hepatitis has two major variant phenotypes in which the features of classical disease are co-mingled with those of primary biliary cirrhosis or primary sclerosing cholangitis. These overlap syndromes lack codified diagnostic criteria, established pathogenic mechanisms, and confident management strategies. Their clinical importance relates mainly to the identification of patients who respond poorly to conventional corticosteroid treatment. Scoring systems that lack discriminative power have been used in their definition, and a clinical phenotype based on pre-defined laboratory and histological findings has not been promulgated. The frequency of overlap with primary biliary cirrhosis is 7-13 %, and the frequency of overlap with primary sclerosing cholangitis is 8-17 %. Patients with autoimmune hepatitis and features of cholestatic disease must be distinguished from patients with cholestatic disease and features of autoimmune hepatitis. Variants of the overlap syndromes include patients with small duct primary sclerosing cholangitis, antimitochondrial antibody-negative primary biliary cirrhosis, autoimmune sclerosing cholangitis, and immunoglobulin G4 associated disease. Conventional corticosteroid therapy alone or in conjunction with ursodeoxycholic acid (13-15 mg/kg daily) has been variably effective, and cyclosporine, mycophenolate mofetil, and budesonide have been beneficial in selected patients. The key cholestatic features that influence the prognosis of autoimmune hepatitis must be defined and incorporated into the definition of the syndrome rather than rely on designations that imply the co-mingling of different diseases with manifestations of variable clinical relevance. The overlap syndromes in autoimmune hepatitis are imprecise, heterogeneous, and unfounded, but they constitute a clinical reality that must be accepted, diagnosed, refined, treated, and studied. PMID- 22918694 TI - Rate of cervical cancer screening associated with immigration status and number of years since immigration in Ontario, Canada. AB - Cervical cancer screening is a vital public health measure intended to reduce the morbidity and mortality from what is a largely preventable cancer. Previous Canadian studies have documented that immigrants have significantly lower Papanicolaou (Pap) testing rates than women born in Canada. However, the impact of number of years since immigration is less clear. Data were taken from the 2007 2008 Canadian Community Health Survey. Responses from 16, 706 women living in Ontario, Canada were included. The focus was on self-reported Pap testing rates within the last 3 years, immigrant status and number of years since immigration. A robust Poisson regression model was used to determine prevalence ratios (PR) with 95 % confidence intervals (CIs) after adjustment for covariates. The results demonstrated that recent immigrant women (less than 10 years in Canada) were less likely to have had a Pap test in the past 3 years than those who were Canadian born (PR = 0.77; 95 % CI: 0.71, 0.84). In contrast, immigrants who had lived in Canada for 10 years or longer showed similar compliance with recommended Pap testing intervals as non-immigrants. Higher income, higher level of education, younger age and being married were independently associated with better Pap testing rates. A strategy targeting recent immigrants to Canada is needed to promote Pap testing in this population and reduce their risk of invasive cervical cancer. PMID- 22918695 TI - The maternal folate hydrolase gene polymorphism is associated with neural tube defects in a high-risk Chinese population. AB - Folate hydrolase 1 (FOLH1) gene encodes intestinal folate hydrolase, which regulates intestinal absorption of dietary folate. Previous studies on the association between polymorphisms rs202676 and rs61886492 and the risk of neural tube defects (NTDs) were inconclusive. A case-control study of women with NTD affected pregnancies (n = 160) and controls (n = 320) was conducted in the Chinese population of Lvliang, a high-risk area for NTDs. We genotyped the polymorphic sites rs202676 and rs61886492 and assessed maternal plasma folate and total homocysteine (tHcy). Our results showed that in case group, plasma folate concentrations were 18 % lower compared with those of control group (8.32 vs. 6.79 nmol/L, p = 0.033) and tHcy concentrations were 17 % higher (10.47 vs. 12.65 MUmol/L, p = 0.047). Almost all samples had the rs61886492 GG genotype (99.78 %). The result showed that the frequency of GG genotype in rs202676 was significantly higher in group with multiple NTDs than in controls (p = 0.030, OR = 2.157, 95 % CI, 1.06-4.38). The multiple-NTD group showed higher maternal plasma concentrations of tHcy (10.47 vs. 13.96 MUmol/L, p = 0.024). The GG genotype of rs202676 had a lower maternal folate and higher tHcy concentrations than other genotypes with no significant differences. The result of structural prediction indicated that this variation might change the spatial structure of the protein. These results suggested that the maternal polymorphism rs202676 was a potential risk factor for multiple NTDs in this Chinese population. The allele G might affect maternal plasma folate and tHcy concentration. PMID- 22918696 TI - Surgery for relapsed ovarian cancer: when should it be offered? AB - Whilst cytoreductive surgery is the mainstay treatment for primary ovarian cancer, its role in relapse is still unclear. Surgery in platinum-sensitive recurrent ovarian cancer might be beneficial if it results in complete resection of the disease. Clinical scores could help to identify suitable patients. Level I evidence is still missing; however, two randomized trials (DESKTOP III and GOG 213) are ongoing. PMID- 22918697 TI - An in vivo neovascularization assay for screening regulators of angiogenesis and assessing their effects on pre-existing vessels. AB - Therapeutic regulation of tissue vascularization has appeared as an attractive approach to treat a number of human diseases. In vivo neovascularization assays that reflect physiological and pathological formation of neovessels are important in this effort. In this report we present an assay where the effects of activators and inhibitors of angiogenesis can be quantitatively and qualitatively measured. A provisional matrix composed of collagen I and fibrin was formed in a plastic cylinder and implanted onto the chick chorioallantoic membrane. A nylon mesh separated the implanted matrix from the underlying tissue to distinguish new from pre-existing vessels. Vascularization of the matrix in response to fibroblast growth factor-2 or platelet-derived growth factor-BB was scored in a double-blinded manner, or vessel density was measured using a semi-automated image analysis procedure. Thalidomide, fumagillin, U0126 and TGFbeta inhibited neovessel growth while hydrocortisone exerted a negative and wortmannin a toxic effect on the pre-existing vasculature. This quantitative, inexpensive and rapid in vivo angiogenesis assay might be a valuable tool in screening and characterizing factors that influence wound or tumor induced vascularization and in assessing their effects on the normal vasculature. PMID- 22918698 TI - Chemical coding of zinc-enriched neurons in the intramural ganglia of the porcine jejunum. AB - Zinc ions in the synaptic vesicles of zinc-enriched neurons (ZEN) seem to have an important role in normal physiological and pathophysiological processes in target organ innervation. The factor directly responsible for the transport of zinc ions into synaptic vesicles is zinc transporter 3 (ZnT3), a member of the divalent cation zinc transporters and an excellent marker of ZEN neurons. As data concerning the existence of ZEN neurons in the small intestine is lacking, this study was designed to disclose the presence and neurochemical coding of such neurons in the porcine jejunum. Cryostat sections (10 mMU thick) of porcine jejunum were processed for routine double- and triple-immunofluorescence labeling for ZnT3 in various combinations with immunolabeling for other neurochemicals including pan-neuronal marker (PGP9.5), substance P (SP), somatostatin (SOM), vasoactive intestinal peptide (VIP), nitric oxide synthase (NOS), leu-enkephalin (LENK), vesicular acetylcholine transporter (VAChT), neuropeptide Y (NPY), galanin (GAL), and calcitonin-gene related peptide (CGRP). Immunohistochemistry revealed that approximately 39%, 49%, and 45% of all PGP9.5- positive neurons in the jejunal myenteric (MP), outer submucous (OSP), and inner submucous (ISP) plexuses, respectively, were simultaneously ZnT3(+). The majority of ZnT3(+) neurons in all plexuses were also VAChT-positive. Both VAChT-positive and VAChT negative ZnT3(+) neurons co-expressed a variety of active substances with diverse patterns of co-localization depending on the plexus studied. In the MP, the largest populations among both VAChT-positive and VAChT-negative ZnT3(+) neurons were NOS-positive cells. In the OSP and ISP, substantial subpopulations of ZnT3(+) neurons were VAChT-positive cells co-expressing SOM and GAL, respectively. The broad-spectrum of active substances that co-localize with the ZnT3(+) neurons in the porcine jejunum suggests that ZnT3 takes part in the regulation of various processes in the gut, both in normal physiological and during pathophysiological processes. PMID- 22918699 TI - Differential expression of TAR DNA-binding protein (TDP-43) in the central nervous system of horses afflicted with equine motor neuron disease (EMND): a preliminary study of a potential pathologic marker. AB - Equine motor neuron disease (EMND) is a neurodegenerative disorder of unknown etiology affecting horses worldwide. Trans-Active Response DNA Binding Protein of 43 kDa (TDP-43) has been reported in the central nervous system (CNS) of several neurodegenerative conditions in humans including Amyotrophic Lateral Sclerosis (ALS) and assumed to play role in the disease. We examined whether horses afflicted with EMND express the TDP-43 in CNS. Ten horses with EMND and 6 controls of different ages and breed we enrolled. Detection of presence of TDP-43 protein in the CNS was analyzed by immunohistochemical staining using rabbit anti human TARDBP (TDP-43) polyclonal antibody. Formalin fixed neuronal tissues from medulla, cervical, and lumbar spinal cord were harvested from EMND and from control horses. Sections were assigned randomly to TDP-43 treated or rabbit anti IgG as control. Nuclear staining of TDP-43 was detected in one of the neural tissues of 75 % of EMND-positive and 0 of 0 % of control horses in the central nervous system (medulla, and/or cervical spinal cord and/or lumbar spinal cord). TDP-43 antibody was detected in the nucleus of EMND horses and no cytoplasmic staining was noted. As in ALS, there was no pattern of age clustering associated with the detection of TDP-43. This is the first report on the staining of TDP-43 in neuronal tissues of horses and suggests that TDP-43 may play a role in the pathogenesis of EMND. Further studies are needed to elucidate the etiologic role of this protein in the diseases. PMID- 22918700 TI - Ability of stroke volume variation measured by oesophageal Doppler monitoring to predict fluid responsiveness during surgery. AB - BACKGROUND: The objective of this study was to test whether non-invasive assessment of respiratory stroke volume variation (DeltarespSV) by oesophageal Doppler monitoring (ODM) can predict fluid responsiveness during surgery in a mixed population. The predictive value of DeltarespSV was evaluated using a grey zone approach. METHODS: Ninety patients monitored using ODM who required i.v. fluids to expand their circulating volume during surgery under general anaesthesia were studied. Patients with a preoperative arrhythmia, right ventricular failure, frequent ectopic beats, or breathing spontaneously were excluded. Haemodynamic variables and oesophageal Doppler indices [peak velocity (PV), stroke volume (SV), corrected flow time (FTc), cardiac output (CO), DeltarespSV, and respiratory variation of PV (DeltarespPV)] were measured before and after fluid expansion. Responders were defined by a >15% increase in SV after infusion of 500 ml crystalloid solution. RESULTS: SV was increased by >=15% after 500 ml crystalloid infusion in 53 (59%) of the 90 patients. DeltarespSV predicted fluid responsiveness with an area under the receiver-operating characteristic (AUC) curve of 0.91 [95% confidence interval (95% CI): 0.85-0.97, P<0.0001]. The optimal DeltarespSV cut-off was 14.4% (95% CI: 14.3-14.5%). The grey zone approach identified 12 patients (14%) with a range of DeltarespSV values between 14% and 15%. FTc was not predictive of fluid responsiveness (AUC 0.49, 95% CI: 0.37-0.62, P=0.84). CONCLUSIONS: DeltarespSV predicted fluid responsiveness accurately during surgery over a DeltarespSV range between 14% and 15%. In contrast, FTc did not predict fluid responsiveness. PMID- 22918701 TI - Conformational entropy of a polymer chain grafted to rough surfaces. AB - A polymer molecule (represented by a statistical chain) end-grafted to a topologically rough surface was studied by static MC simulations. A modified self avoiding walk on a cubic lattice was used to model the polymer in an athermal solution. Different statistical models of surface roughness were applied. Conformational entropies of chains attached to uncorrelated Gaussian, Brownian, and fractional Brownian surfaces were calculated. Results were compared with the predictions of a simple analytical model of a macromolecule end-grafted to a fractal surface. PMID- 22918702 TI - Evidence synthesis through a degradation model applied to myocardial infarction. AB - We propose an evidence synthesis approach through a degradation model to estimate causal influences of physiological factors on myocardial infarction (MI) and coronary heart disease (CHD). For instance several studies give incidences of MI and CHD for different age strata, other studies give relative or absolute risks for strata of main risk factors of MI or CHD. Evidence synthesis of several studies allows incorporating these disparate pieces of information into a single model. For doing this we need to develop a sufficiently general dynamical model; we also need to estimate the distribution of explanatory factors in the population. We develop a degradation model for both MI and CHD using a Brownian motion with drift, and the drift is modeled as a function of indicators of obesity, lipid profile, inflammation and blood pressure. Conditionally on these factors the times to MI or CHD have inverse Gaussian ([Formula: see text]) distributions. The results we want to fit are generally not conditional on all the factors and thus we need marginal distributions of the time of occurrence of MI and CHD; this leads us to manipulate the inverse Gaussian normal distribution ([Formula: see text]) (an [Formula: see text] whose drift parameter has a normal distribution). Another possible model arises if a factor modifies the threshold. This led us to define an extension of [Formula: see text] obtained when both drift and threshold parameters have normal distributions. We applied the model to results published in five important studies of MI and CHD and their risk factors. The fit of the model using the evidence synthesis approach was satisfactory and the effects of the four risk factors were highly significant. PMID- 22918703 TI - CCAAT/Enhancer-binding protein-homologous protein sensitizes to SU5416 by modulating p21 and PI3K/Akt signal pathway in FRO anaplastic thyroid carcinoma cells. AB - SU5416, vascular endothelial cell growth factor receptor inhibitor, suppresses hypoxia-induced angiogenesis, growth, proliferation, and metastasis in cancer cells. CCAAT/enhancer-binding protein-homologous protein (CHOP) has pivotal roles in regulation of growth and survival. In the present study, we evaluated the effects of SU5416 on cell survival, p21, and PI3K/Akt signal pathway in FRO anaplastic thyroid carcinoma (ATC) cells. Moreover, we investigated the roles of CHOP in cell survival under condition of SU5416 treatment in FRO ATC cells. After SU5416 treatment, cell viability, PARP-1, and caspase-3 protein levels were not changed. p53 and p27 protein levels decreased while p21 protein levels increased. Phospho-Akt protein levels were not altered. In SU5416-treated situation, cell viability was not different before and after administration of either p21 siRNA or LY294002 whereas it was lessened after co-administration of p21 siRNA and LY294002. Compared to SU5416 treatment alone, cell viability was reduced with CHOP plasmid but it was unchanged with CHOP siRNA. PARP-1 and caspase-3 protein levels with CHOP plasmid were elevated whereas the protein levels with CHOP siRNA were similar. While CHOP plasmid transfection diminished p21 and phospho-Akt protein levels, CHOP siRNA transfection did not alter the protein levels. In conclusion, these results suggest that CHOP may sensitize FRO ATC cells to SU5416 thereby inhibiting cell survival by modulating p21 and PI3K/Akt signal pathway. Furthermore, these findings imply that CHOP may be a possible candidate as the chemosensitizing factor for induction of cytotoxicity in ATC cells exposed to SU5416. PMID- 22918704 TI - Osteoprotegerin levels decrease during testosterone therapy in aging men and are associated with changed distribution of regional fat. AB - The cardiovascular effects of testosterone treatment are debated. Osteoprotegerin (OPG) is an independent marker of cardiovascular risk. We investigated the effect of testosterone therapy on OPG levels in aging men with low normal bioavailable testosterone levels. A randomized, double-blinded, placebo-controlled study of 6 months testosterone therapy (gel) in 38 men aged 60-78 years with bioavailable testosterone <7.3 nmol/l and waist circumference >94 cm was performed. Clinical evaluation, OPG, and C-reactive protein (CRP) measurements were carried out. Lean body mass (LBM), total fat mass, and bone mineral density (BMD) were established by dual X-ray absorptiometry. Visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) were measured by magnetic resonance imaging. Power calculation was based on an increase in LBM during testosterone therapy and responders were defined as testosterone treated patients with increased LBM (Delta LBM positive), n=14. Data are presented as median (interquartile range). Testosterone therapy decreased total fat mass and SAT, whereas VAT was unchanged (n=38). OPG levels decreased during testosterone therapy (from 2.0 (1.9-2.5) to 1.9 (1.6-2.2) ng/ml, p<0.05 vs. placebo), whereas CRP levels were unchanged (n=38). In responders to testosterone therapy (n=14), DeltaOPG levels were inversely associated with DeltaSAT (r= - 0.60, p=0.03) and positively associated with DeltaVAT (r=0.56, p=0.04). OPG levels decreased during testosterone therapy suggesting decreased cardiovascular risk. Decreased OPG levels were associated with changes in regional fat distribution and future studies are needed to further evaluate the association between OPG and regional fat mass distribution. PMID- 22918707 TI - A key role for nuclear cardiac imaging in evaluating and managing patients with heart failure. PMID- 22918708 TI - Agreement between chart diagnoses and standardized instrument ratings of youth psychopathology. AB - Rating scales are useful for evidence-based assessment of youth psychopathology. However, it is not known whether these scales contribute information beyond that which clinicians gather without them. This study examined agreement between chart diagnoses and the Child Behavior Checklist (CBCL) for 82 community mental health clinic clients. Agreement was low, suggesting that the CBCL was not redundant with clinicians' clinical impressions. These findings suggest that use of an instrument like the CBCL could potentially improve clinician diagnostic accuracy; future research should examine how best to utilize these scales in the diagnostic process and how to train clinicians in their use. PMID- 22918710 TI - Osteoporosis treatment by a new active vitamin D3 compound, eldecalcitol, in Japan. AB - Although vitamin D is used mainly as a nutritional supplement in osteoporosis treatment, its active form, 1,25-dihydroxyvitamin D [1,25(OH)(2)D], has an effect to maintain bone remodeling balance as well. Eldecalcitol is an analog of 1,25(OH) (2)D(3) with stronger effects than its native form in improving bone remodeling balance and increasing bone mineral density in osteoporotic patients. Daily 0.75 MUg eldecalcitol is superior to 1.0 MUg alfacalcidol in preventing new vertebral fractures under vitamin D supplementation, and is approved for osteoporosis treatment in Japan. Eldecalcitol also decreases wrist fractures. Further studies are warranted to examine the effect of eldecalcitol on other nonvertebral fractures, extraskeletal systems including falls, and combined treatment with other drugs in osteoporotic patients, as well as the mechanism of action of eldecalcitol. PMID- 22918709 TI - Motion and pattern cortical potentials in adults with high-functioning autism spectrum disorder. AB - PURPOSE: Autism spectrum disorder (ASD) is a condition in which visual perception to both static and moving stimuli is altered. The aim of this study was to investigate the early cortical responses of subjects with ASD to simple patterns and moving radial rings using visual evoked potentials (VEPs). METHODS: Male ASD participants (n = 9) and typically developing (TD) individuals (n = 7) were matched for full, performance and verbal IQ (p > 0.263). VEPs were recorded to the pattern reversing checks of 50' side length presented with Michelson contrasts of 98 and 10 % and to the onset of motion-either expansion or contraction of low-contrast concentric rings (33.3 % duty cycle at 10 % contrast). RESULTS: There were no significant differences between groups in the VEPs elicited by pattern reversal checkerboards of high (98 %) or low (10 %) contrast. The ASD group had a significantly larger N160 peak (1.85 x) amplitude to motion onset VEPs elicited by the expansion of radial rings (p = 0.001). No differences were evident in contraction VEP peak amplitudes nor in the latencies of the motion onset N160 peaks. There was no evidence of a response that could be associated with adaptation to the motion stimulus in the interstimulus interval following an expansion or contraction phase of the rings. CONCLUSION: These data support a difference in processing of motion onset stimuli in this adult high functioning ASD group compared to the TD group. PMID- 22918711 TI - The role of C2-C7 and O-C2 angle in the development of dysphagia after cervical spine surgery. AB - Dysphagia is a known complication of cervical surgery and may be prolonged or occasionally serious. A previous study showed that dysphagia after occipitocervical fusion was caused by oropharyngeal stenosis resulting from O-C2 (upper cervical lordosis) fixation in a flexed position. However, there have been few reports analyzing the association between the C2-C7 angle (middle-lower cervical lordosis) and postoperative dysphagia. The aim of this study was to analyze the relationship between cervical lordosis and the development of dysphagia after anterior and posterior cervical spine surgery (AC and PC). Three hundred fifty-four patients were reviewed in this retrospective clinical study, including 172 patients who underwent the AC procedure and 182 patients who had the PC procedure between June 2007 and May 2010. The presence and duration of postoperative dysphagia were recorded via face-to-face questioning or telephone interview performed at least 1 year after the procedure. Plain cervical radiographs before and after surgery were collected. The O-C2 angle and the C2-C7 angle were measured. Changes in the O-C2 angle and the C2-C7 angle were defined as dO-C2 angle = postoperative O-C2 angle - preoperative O-C2 angle and dC2-C7 angle = postoperative C2-C7 angle - preoperative C2-C7 angle. The association between postoperative dysphagia with dO-C2 angle and dC2-C7 angle was studied. Results showed that 12.8 % of AC and 9.4 % of PC patients reported dysphagia after cervical surgery. The dC2-C7 angle has considerable impact on postoperative dysphagia. When the dC2-C7 angle is greater than 5 degrees , the chance of developing postoperative dysphagia is significantly greater. The dO-C2 angle, age, gender, BMI, operative time, blood loss, procedure type, revision surgery, most cephalic operative level, and number of operative levels did not significantly influence the incidence of postoperative dysphagia. No relationship was found between the dC2-C7 angle and the degree of dysphagia. We conclude that postoperative dysphagia is common after cervical surgery. The dC2-C7 angle may play an important role in the development of dysphagia in both anterior and posterior cervical spine surgery. Intraoperative measurement of the dC2-C7 angle is practical and essential in avoiding inadvertent postoperative dysphagia. PMID- 22918712 TI - Health disparities among childrearing women with disabilities. AB - This study examines leading health indicators for childrearing women with disabilities, including health-related quality of life, chronic health conditions, adverse and preventive health behaviors, health care access, and social and emotional support. The study analyzes aggregated data from the Washington State Behavioral Risk Factor Surveillance System (n = 28,629). The weighted prevalence of key health indicators of childrearing women with disabilities (aged 18-59) are compared with childrearing women without disabilities. A series of adjusted logistic regression analyses are applied, controlling for confounding variables. When compared to childrearing women without disabilities, childrearing women with disabilities are less likely to have a partner or spouse, report lower income and education levels and are older. Childrearing women with disabilities, compared to childrearing women without disabilities, report significantly lower health-related quality of life including poor general health (adjusted odds ratio[AOR] = 6.85; p < .001), frequent mental distress (AOR = 4.02; p < .001), and frequent poor physical health (AOR = 9.34; p < .001); higher prevalence of chronic health conditions, including arthritis, cardiovascular diseases, diabetes, asthma, high blood pressure and cholesterol, and obesity (the range of AORs = 1.59 to 5.65; p < .001); higher prevalence of adverse health behaviors including smoking (AOR = 2.14; p < .001) and lack of exercise (AOR = 1.61; p < .001); more financial barriers to health care (AOR = 2.11; p < .001) and lack of social and emotional support (AOR = 2.05; p < .001) while controlling for age, education, income, and relationship status. Based on population level data, the study reveals that childrearing women with disabilities experience elevated risks of health disparities across many key health indicators, many of which are preventable and modifiable. These findings underscore the importance of identifying contributing factors and developing interventions to improve the health and quality of life of childrearing women with disabilities. PMID- 22918713 TI - Regional variations in early intervention utilization for children with developmental delay. AB - We tested whether state-level variations in early intervention program (EI) participation were consistent with rates of key risk factors for early developmental delay. Based on the results of prior studies, we focused on child poverty and low birth weight as risk factors, included state threshold for EI eligibility by category (classified as broad/moderate or narrow), and aggregated the states into regions. Bivariate analyses were done in SPSS 15.0. All data were for 2009. Results were tested against data for prior years to ascertain whether findings for 2009 were anomalous. Nationally, 2.67 % of the age-eligible population was served in EI (range among states, 1.24-6.51 %). Variation in EI participation was significant at the regional level. Early intervention participation was lowest in the south and highest in the northeast (p < 0.01). Regional variations in low birth weight (p < 0.01) and child poverty (p < 0.01) were also significant. Both were highest in the south. While EI participation varied significantly by state eligibility standards, this factor did not entirely explain variance in utilization. Results for 2009 were representative of multi year trend data. National EI utilization rates consistently lagged behind need as identified in epidemiologic studies from multiple sources. The results strongly suggest that there is a significant population of infants and toddlers who need but do not receive EI services, especially in the south. PMID- 22918714 TI - Full genomic sequence of an African avian paramyxovirus type 4 strain isolated from a wild duck. AB - A random amplification/deep sequencing approach was applied to determine the complete genomic sequence of an Avian Paramyxovirus Type 4 (APMV-4) strain isolated from a wild duck in South Africa in 2010. This sequence represents the fourth full genome of APMV-4 in public sequence databases and the first for the African continent. A total of 87,402,081 Illumina paired-end reads were obtained of which 47,338,867 (54.16 %) mapped to the reference genome EU877976. The entire genomic sequence of 15,054 nt, including the intact termini, was recovered at a high redundancy (coverage per base: average = 198,861.06, minimum = 52 and maximum = 1,790,889). Pairwise comparison of full genomic nucleotide sequences indicated that APMV-4/Egyptian goose/South Africa/N1468/10 shared 97.3 % sequence identity with APMV-4/KR/YJ/06, 96.4 % sequence identity with APMV 4/mallard/Belgium/15129/07 and 90.8 % nucleotide sequence identity with APMV 4/duck/HK/D3/75. Genomic features were consistent with previously sequenced viruses including predicted open reading frames for the NP, P, F and L genes, but variations in coding regions for the M and HN genes were identified. The sequencing approach adopted in this study could successfully indicate quasispecies in the viral stock. PMID- 22918715 TI - Clinical applications of the latest molecular diagnostics in noninvasive prenatal diagnosis. AB - The presence of cell-free fetal DNA in the plasma of pregnant women has opened up the possibility of noninvasive prenatal diagnosis. With the advances in molecular techniques of microfluidics and massive parallel sequencing, an increasing number of fetal genetic diseases/conditions can be noninvasively detected using maternal plasma DNA analysis. Remarkably, it has recently been shown that the genome-wide genetic map of an unborn fetus can be constructed through extensive sequencing of maternal plasma DNA. In this chapter the different qualitative and quantitative approaches and related methodology for the analysis of fetal DNA in maternal plasma are discussed. PMID- 22918716 TI - Responses of angiogenic growth factors to exercise, to hypoxia and to exercise under hypoxic conditions. AB - The purpose of the present study was to compare the acute hormonal response of angiogenic regulators to a short-term hypoxic exposure at different altitudes with and without exercise. 7 subjects participated in 5 experimental trials. 2 times subjects stayed in a sedentary position for 90 min at 2000 m or 4000 m, respectively. The same was carried out again in combination with exercise at the same relative intensity (2 mmol?L(-1) of lactate). The fifth trial consisted of 90 min exercise at sea level. Venous blood samples were taken under resting conditions, 0 and 180 min after each condition to determine VEGF, EPO, IL-6, IL-8 and IGF-1 serum concentrations. EPO, VEGF, and IL-8 showed increases only, when hypoxia was combined with exercise. IL-6 was increased after exercise, independent of altitude. IGF-1 showed no changes in any intervention. The present study suggests that short term hypoxic exposure combined with low intensity exercise is able to up-regulate angiogenic regulators, which might be beneficial to induce angiogenesis and to improve endurance performance. However, in some cases high altitudes are needed, or it can be speculated that exercise intensity needs to be increased. PMID- 22918717 TI - Hand-rim forces and gross mechanical efficiency at various frequencies of wheelchair propulsion. AB - To determine the effects of push frequency changes on force application, fraction of effective force (FEF) and gross efficiency (GE) during hand-rim propulsion. 8 male able-bodied participants performed five 4-min sub-maximal exercise bouts at 1.8 ms(-1); the freely chosen frequency (FCF), followed by 4 counter-balanced trials at 60, 80, 120 and 140% FCF. Kinetic data was obtained using a SMART(Wheel), measuring forces and moments. The GE was determined as the ratio of external work done and the total energy expended. Increased push frequency led to reductions in peak resultant force (P<0.05), ranging from 167 to 117 N and peak tangential force (P<0.05), ranging from 117 to 77 N. However, FEF only demonstrated a significant difference between 60% and 140% FCF (69 +/- 9% and 63 +/- 7, respectively; P<0.05). Work per cycle decreased significantly (P<0.05) and rate of force development increased significantly (P<0.05) with increased push frequency. GE values were significantly lower at 60%, 120% and 140% FCF than 80% and 100% FCF (P<0.05). No meaningful associations were present between FEF and GE. Under the current testing conditions, changes in push frequency are accompanied with changes in the absolute force values, albeit without changes in either the gross pattern/trend of force application or FEF. Changes in GE are not explained by different levels of force effectiveness. PMID- 22918718 TI - Prosthetic valves in adult patients with congenital heart disease: Rationale and design of the Dutch PROSTAVA study. AB - BACKGROUND: Data on long-term complications in adult patients with congenital heart disease (ACHD) and a prosthetic valve are scarce. Moreover, the influence of prosthetic valves on quality of life (QoL) and functional outcome in ACHD patients with prosthetic valves has not been studied. OBJECTIVES: The primary objective of the PROSTAVA study is to investigate the relation between prosthetic valve characteristics (type, size and location) and functional outcome as well as QoL in ACHD patients. The secondary objectives are to investigate the prevalence and predictors of prosthesis-related complications including prosthesis-patient mismatch. METHODS: The PROSTAVA study, a multicentre cross-sectional observational study, will include approximately 550 ACHD patients with prosthetic valves. Primary outcome measures are maximum oxygen uptake during cardiopulmonary exercise testing and QoL. Secondary outcomes are the prevalence and incidence of valve-related complications including prosthesis-patient mismatch. Other evaluations are medical history, physical examination, echocardiography, MRI, rhythm monitoring and laboratory evaluation (including NT-proBNP). IMPLICATIONS: Identification of the relation between prosthetic valve characteristics in ACHD patients on one hand and functional outcome, QoL, the prevalence and predictors of prosthesis-related complications on the other hand may influence the choice of valve prosthesis, the indication for more extensive surgery and the indication for re-operation. PMID- 22918719 TI - Metabolism of patupilone in patients with advanced solid tumor malignancies. AB - A phase 1, open-label, non-randomized, single center study was conducted to determine the pharmacokinetics, distribution, metabolism, elimination, and mass balance of patupilone in patients with advanced solid tumors. Five patients with advanced solid tumors received 10 mg/m(2) (1.1 MBq) of (14) C-radiolabeled patupilone at cycle 1 as a 20-minute intravenous infusion every 3 weeks until disease progression. Sequential samples of blood/plasma were taken for 3 weeks and urine and fecal samples were collected for seven days after the first dose of patupilone. Patupilone blood levels decreased rapidly after the infusion. The compound showed a large volume of distribution (Vss: 2242 L). The main radiolabeled component in blood was patupilone itself, accompanied by the lactone hydrolysis products that are unlikely to contribute to the pharmacological effect of patupilone. The blood clearance of patupilone was relatively low at 14 L/h. The administered radioactivity dose was excreted slowly (46 % of dose up to 168 h) but ultimately accounted for 91 % of the dose by extrapolation. The fecal excretion of radioactivity was 2-3 times higher than the urinary excretion consistent with hepato-biliary elimination. Three patients had progressive disease and two patients had stable disease as their best response. Patupilone was generally well tolerated in patients with advanced solid tumors with no newly occurring safety events compared to previous clinical studies. In adult solid tumor patients, intravenous radiolabeled patupilone undergoes extensive metabolism with fecal excretion of radioactive metabolites predominating over renal excretion. PMID- 22918720 TI - Phase II trial of single-agent foretinib (GSK1363089) in patients with recurrent or metastatic squamous cell carcinoma of the head and neck. AB - BACKGROUND: Foretinib is a small-molecule, oral multikinase inhibitor primarily targeting the mesenchymal epithelial transition (MET) factor receptor, and the vascular endothelial growth factor receptor 2. We conducted a phase II study to evaluate the single-agent activity and tolerability of foretinib in patients with recurrent/metastatic squamous cell carcinoma of the head and neck (SCCHN). METHODS: An open-label, single-arm, multicenter trial employing a Simon 2-stage design was conducted with a total of 41 patients planned for the study. One or more responses in the first 14 patients were required in order to progress to the second stage. Foretinib was administered as 240 mg orally for 5 consecutive days of a 14-day treatment cycle (5/9 schedule) to patients with recurrent and/or metastatic SCCHN. RESULTS: Fourteen patients were enrolled. The study did not meet criteria for continuing to the second stage. A maximum of 30 cycles were administered (median = 4.0). Fifty percent of patients (7/14) showed stable disease (SD), 43% of patients (6/14) experienced tumor shrinkage and two patients had prolonged disease stabilization for >=13 months. The most common adverse events were fatigue, constipation and hypertension, which were manageable with additional medication or adjustments to the dosing schedule. CONCLUSION: Foretinib 240 mg on a 5/9 schedule was generally well tolerated. SD was the best observed outcome, with minor tumor shrinkage detected in nearly half of all patients. The efficacy results, prolonged disease stabilization and tolerable side-effect profile, support further investigation, possibly in combination with other targeted agents or cytotoxic chemotherapy for SCCHN. PMID- 22918721 TI - Distinctive microRNA profiles in the salivary glands of Haemaphysalis longicornis related to tick blood-feeding. AB - The salivary glands are vital to the biological success of ticks and they are a major route of pathogen transmission. Tick salivary glands undergo remarkable growth and differentiation during the blood-feeding period. MicroRNAs (miRNAs) are noncoding small RNA molecules found in diverse organisms that regulate gene expression at the post-transcriptional level. To explore transcriptional differences in the miRNAs of fed and unfed tick (Haemaphysalis longicornis) salivary glands, we investigated small RNA (sRNA) transcriptomes derived from the salivary glands and made a comparative analysis of miRNA profiles related to tick blood-feeding in the salivary glands. We generated two small RNA libraries from the salivary glands of unfed and fed H. longicornis, and obtained 14.8 and 10.3 million reads of 18-30 nt, respectively. The unfed-specific sRNAs were clearly richer than the fed-specific sRNAs in terms of the unique and total sRNAs. Overall, 769 conserved miRNA families were found in unfed samples, whereas 440 conserved miRNA families were found in fed samples. Six of the ten most abundant miRNA were found in both the unfed and fed tick salivary glands, i.e., miR-1, miR 375, bantam, miR-184, miR-739, and miR-263a. We found that known miRNA homologs displayed a wide variety of expression profiles in unfed and fed tick salivary glands. After blood-feeding, 162 known miRNAs were upregulated. The six main upregulated miRNAs were mir-1810, mir-2138, mir-2140, mir-425*, mir-429, and mir 516*. Likewise, 231 known miRNAs were downregulated after blood-feeding. The six main downregulated miRNAs were miR-2941-1*, miR-10-5p, miR-2973, miR-1183, miR 4006b-5p, and miR-881. We found that distinct microRNA profiles in the salivary glands of H. longicornis were relating to tick blood feeding. The differential expression of miRNAs in unfed and fed tick salivary glands supported their involvement at new levels in the regulation of tick blood-feeding. Our data provide an important resource for a more detailed functional analysis of miRNAs in this species. PMID- 22918722 TI - Comparative study on the antibiotic susceptibility and plasmid profiles of Vibrio alginolyticus strains isolated from four Tunisian marine biotopes. AB - The antibiotic resistance patterns and the plasmids profiles of the predominant etiological agent responsible for vibriosis in Tunisia, V. alginolyticus were studied to contribute to control their spread in some Mediterranean aquaculture farms and seawater. The sixty-nine V. alginolyticus strains isolated from different marine Tunisian biotopes (bathing waters, aquaculture and conchylicole farms and a river connected to the seawater during the cold seasons) were multi drug resistant with high resistance rate to ampicillin, kanamycin, doxycyclin, erythromycin, imipinem, and nalidixic acid. The multiple resistance index ranged from 0.3 to 0.7 for the isolates of Khenis, from 0.5 to 0.8 for those of Menzel Jmil, from 0.5 to 0.75 (Hergla) and from 0.3 to 0.7 for the isolates of Oued Soltane. The high value of antibiotic resistance index was recorded for the V. alginolyticus population isolated from the fish farm in Hergla (ARI = 0.672) followed by the population isolated from the conchylicole station of Menzel Jmil (ARI = 0.645). The results obtained by the MIC tests confirmed the resistance of the V. alginolyticus to ampicillin, erythromycin, kanamycin, cefotaxime, streptomycin and trimethoprim. Plasmids were found in 79.48 % of the strains analyzed and 30 different plasmid profiles were observed. The strains had a high difference in the size of plasmids varying between 0.5 and 45 kb. Our study reveals that the antibiotic-resistant bacteria are widespread in the aquaculture and conchylicole farm relatively to others strains isolated from seawater. PMID- 22918723 TI - Molecular modeling of metabolism for allergen-free low linoleic acid peanuts. AB - It is necessary to eliminate linoleic acid and allergenic arachins from peanuts for good health reasons. Virginia-type peanuts, harvested from plots treated with mineral salts combinations that mimic the subunit compositions of glutamate dehydrogenase (GDH) were analyzed for fatty acid and arachin compositions by HPLC and polyacrylamide gel electrophoresis, respectively. Fatty acid desaturase and arachin encoding mRNAs were analyzed by Northern hybridization using the homologous RNAs synthesized by peanut GDH as probes. There were 70-80 % sequence similarities between the GDH-synthesized RNAs and the mRNAs encoding arachins, fatty acid desaturases, glutamate synthase, and nitrate reductase, which similarities induced permutation of the metabolic pathways at the mRNA level. Modeling of mRNAs showed there were 210, 3,150, 1,260, 2,520, and 4,200 metabolic permutations in the control, NPKS-, NS-, Pi-, NH(4)Cl-, and PK-treated peanuts, respectively. The mRNA cross-talks decreased the arachin to almost zero percent in the NPKS- and PK-treated peanuts, and linoleate to ~18 % in the PK-treated peanut. The mRNA cross-talks may account for the vastly reported environmentally induced variability in the linoleate contents of peanut genotypes. These results have quantitatively unified molecular biology and metabolic pathways into one simple biotechnology for optimizing peanut quality and may encourage small-scale industry to produce arachin-free low linoleate peanuts. PMID- 22918725 TI - Platelets: production, morphology and ultrastructure. AB - Platelets are anucleate, discoid cells, roughly 2-3 MUm in diameter that function primarily as regulators of hemostasis, but also play secondary roles in angiogensis and innate immunity. Although human adults contain nearly one trillion platelets in circulation that are turned over every 8-10 days, our understanding of the mechanisms involved in platelet production is still incomplete. Platelets stem from large (30-100 MUm) nucleated cells called megakaryocytes that reside primarily in the bone marrow. During maturation megakaryocytes extend long proplatelet elongations into sinusoidal blood vessels from which platelets ultimately release. During this process, platelets develop a number of distinguishable structural elements including: a delimited plasma membrane; invaginations of the surface membrane that form the open canalicular system (OCS); a closed-channel network of residual endoplasmic reticulum that form the dense tubular system (DTS); a spectrin-based membrane skeleton; an actin based cytoskeletal network; a peripheral band of microtubules; and numerous organelles including alpha-granules, dense-granules, peroxisomes, lysosomes, and mitochondria. Proplatelet elongation and platelet production is an elaborate and complex process that defines the morphology and ultrastructure of circulating platelets, and is critical in understanding their increasingly numerous and varied biological functions. PMID- 22918724 TI - A rational approach to selective pharmacophore designing: an innovative strategy for specific recognition of Gsk3beta. AB - We propose a novel cheminformatics approach that combines structure and ligand based design to identify target-specific pharmacophores with well-defined exclusion ability. Our strategy includes the prediction of selective interactions, developing structure, and knowledge-based selective pharmacophore models, followed by database screening and molecular docking. This unique strategy was employed in addressing the off-target toxicity of Gsk3beta and CDKs. The connections of Gsk3beta in eukaryotic cell apoptosis and the extensive potency of Gsk3beta inhibitors to block cell death have made it a potential drug discovery target for many grievous human disorders. Gsk3beta is phylogenetically very closely related to the CDKs, such as CDK1 and CDK2, which are suggested to be the off-target proteins of Gsk3beta inhibitors. Here, we have employed novel computational approaches in designing the ligand candidates that are potentially inhibitory against Gsk3beta, with well-defined the exclusion ability to CDKs. A structure-ligand -based selective pharmacophore was modeled. This model was used to retrieve molecules from the zinc database. The hits retrieved were further screened by molecular docking and protein-ligand interaction fingerprints. Based on these results, four molecules were predicted as selective Gsk3beta antagonists. It is anticipated that this unique approach can be extended to investigate any protein-ligand specificity. PMID- 22918726 TI - Platelet receptors. AB - Well-understood functions for "traditional" platelet receptors are described, but "newer" receptors are equally discussed. Receptors are described biochemically (structure, ligand(s), protein partners, and function) and whenever possible, their clinical importance (mutations, polymorphisms, syndrome) are highlighted. PMID- 22918728 TI - Platelet interaction with the vessel wall. AB - Platelets have attracted a growing interest among basic scientists and clinicians, as they have been shown to play an important role in many physiological and pathophysiological conditions. Beyond hemostasis, platelets participate in wound healing, inflammation, infectious diseases, maintenance of the endothelial barrier function, angiogenesis, and tumor metastasis. Over the last 50 years enormous progress has been made in our understanding of the role of platelets in hemostasis. Platelets circulate in blood in a resting state, but they are able to react immediately upon a vessel wall injury by adhering to the exposed collagen, followed by platelet-platelet interaction to form a plug that effectively seals the injured vessel wall to prevent excessive blood loss. Comparable events will take place on a rupturing atherosclerotic plaque, which may result in a platelet-rich thrombus. This chapter will address the molecular basis of platelet adhesion and aggregation, the regulation of platelet function and the interaction of primary and secondary hemostasis. PMID- 22918727 TI - Platelet signaling. AB - This chapter summarizes current ideas about the intracellular signaling that drives platelet responses to vascular injury. After a brief overview of platelet activation intended to place the signaling pathways into context, the first section considers the early events of platelet activation leading up to integrin activation and platelet aggregation. The focus is on the G protein-mediated events utilized by agonists such as thrombin and ADP, and the tyrosine kinase based signaling triggered by collagen. The second section considers the events that occur after integrin engagement, some of which are dependent on close physical contact between platelets. A third section addresses the regulatory events that help to avoid unprovoked or excessive platelet activation, after which the final section briefly considers individual variations in platelet reactivity and the role of platelet signaling in the innate immune response and embryonic development. PMID- 22918729 TI - Platelets in atherosclerosis and thrombosis. AB - Rupture of an atherosclerotic plaque exposes a thrombogenic matrix, which instantly triggers platelet tethering and activation. We here delineate the sequence of events during arterial thrombus formation and dissect the specific role of the various platelet receptors in this process. We also discuss the interplay of platelets with circulating immune cells, which support arterial thrombosis by fibrin formation in a process that involves extracellular nucleosomes. In the second part of this chapter we describe the role of platelets in atherosclerotic lesion formation. Platelets adhere to the dysfunctional endothelium early during atherogenesis. They contain a large machinery of proinflammatory molecules, which can be released upon their activation. This prepares the ground for subsequent leukocyte recruitment and infiltration, and boosts the inflammatory process of the arterial wall. Together, platelets play a critical role in both acute and chronic processes of the vascular wall, which makes them an attractive target for pharmacological strategies to treat arterial thrombosis and, potentially, also atheroprogression. PMID- 22918730 TI - Aspirin and Other COX-1 inhibitors. AB - Currently available antiplatelet drugs interfere with the process of platelet activation and aggregation by selectively blocking key enzymes involved in the synthesis of platelet agonists, or membrane receptors mediating activation signals. Pharmacological interference with critical molecular pathways of platelet activation and aggregation may reduce the risk of atherothrombotic complications through mechanisms that are also responsible for an increased risk of bleeding. Acetylsalicylic acid (aspirin) represents a prototypic antiplatelet agent. The aim of this chapter is to integrate our current understanding of the molecular mechanism of action of aspirin with the results of clinical trials and epidemiological studies assessing its efficacy and safety. Moreover, the antiplatelet properties of reversible inhibitors of the same drug target will also be reviewed. PMID- 22918731 TI - Thienopyridines and other ADP-receptor antagonists. AB - Platelet P2Y12 receptor inhibition plays a pivotal role in preventing thrombotic vascular events in patients with ACS and in patients undergoing percutaneous coronary intervention (PCI). Among the P2Y12 receptor inhibitors, the group of thienopyridines include ticlopidine, clopidogrel and prasugrel, all of which are orally administered prodrugs leading to irreversible P2Y12 receptor inhibition. Non-thienopyridine derivatives including ticagrelor, cangrelor and elinogrel do not require metabolic activation and lead to a reversible P2Y12 receptor inhibition in contrast to thienopyridines. The extend of platelet inhibition is subject to the administered antiplatelet agent and influenced by individual genetic and clinical factors. Insufficient platelet inhibition, termed high platelet reactivity (HPR) is associated with an increased risk for ischemic events after PCI whereas exceeding platelet inhibition results in an increased bleeding risk. Pharmacologic properties and clinical outcome data differ substantially between the existing P2Y12 receptor inhibitors. Whether individualized antiplatelet treatment incorporating different P2Y12 receptor inhibitors improves patients' clinical outcomes warrants further investigation. PMID- 22918732 TI - Glycoprotein IIb/IIIa antagonists. AB - Mortality from ischemic cardiac disease in adults has been dramatically reduced by the development of novel therapies for inhibiting platelet function. Circulating platelets are maintained in a resting state and are activated at sites of vascular injury by exquisitely controlled mechanisms, thereby maintaining vascular integrity without causing intravascular thrombosis. As it became clear that platelets play a central role in arterial thrombosis, the processes of platelet activation, adhesion, and aggregation became logical targets for the development of antithrombotic agents. PMID- 22918734 TI - PAR-1 inhibitors: a novel class of antiplatelet agents for the treatment of patients with atherothrombosis. AB - Stroke and myocardial infarction are leading causes of death and disability worldwide. Typically, these events are triggered by the rupture or erosion of "vulnerable" atherosclerotic plaque, a phenomenon termed atherothrombosis.Three platelet activation pathways are presumed to be particularly important in the genesis of atherothrombosis and are triggered by 1) cyclo-oxygenase (COX)-1 mediated thromboxane A2 (TXA2) synthesis and activation via the TXA2 receptor, 2) adenosine diphosphate (ADP) via the P2Y12 receptor, and 3) thrombin via the protease activated receptor (PAR)-1.Despite the efficacy of aspirin and of a growing family of P2Y12 receptor antagonists on the first 2 pathways, major cardiovascular events continue to occur in patients with coronary and cerebrovascular disease, suggesting that thrombin-mediated platelet activation may contribute to these adverse events.Recently, a novel class of antiplatelet agents able to inhibit thrombin-mediated platelet activation has been developed, PAR-1 inhibitors. In this chapter, we will discuss the rationale underlying the development of this novel class of agents focus on the two drugs in the most advanced stages of development: vorapaxar (SCH530348) and atopaxar (E5555). PMID- 22918733 TI - Targeting phosphodiesterases in anti-platelet therapy. AB - There are two primary modes of platelet inhibition: blockade of membrane receptors or neutralization of intracellular pathways. Both means of inhibition have proven benefits in the prevention and resolution of atherothrombotic events. With regard to intracellular inhibition, phosphodiesterases (PDEs) are fundamental for platelet function. Platelets possess several PDEs (PDE2, PDE3 and PDE5) that catalyze the hydrolysis of cyclic adenosine 3'-5'-monophosphate (cAMP) and cyclic guanosine 3'-5'-monophosphate (cGMP), thereby limiting the levels of intracellular nucleotides. PDE inhibitors, such as cilostazol and dipyridamole, dampen platelet function by increasing cAMP and cGMP levels. This review focuses on the roles of PDE inhibitors in modulating platelet function, with particular attention paid to drugs that have anti-platelet clinical indications. PMID- 22918735 TI - Thromboxane receptors antagonists and/or synthase inhibitors. AB - Atherothrombosis is the major cause of mortality and morbidity in Western countries. Several clinical conditions are characterized by increased incidence of cardiovascular events and enhanced thromboxane (TX)-dependent platelet activation. Enhanced TX generation may be explained by mechanisms relatively insensitive to aspirin. More potent drugs possibly overcoming aspirin efficacy may be desirable. Thromboxane synthase inhibitors (TXSI) and thromboxane receptor antagonists (TXRA) have the potential to prove more effective than aspirin due to their different mechanism of action along the pathway of TXA(2). TXSI prevent the conversion of PGH(2) to TXA(2), reducing TXA(2) synthesis mainly in platelets, whereas TXRA block the downstream consequences of TXA(2) receptors (TP) activation.TXA(2) is a potent inducer of platelet activation through its interaction with TP on platelets. TP are activated not only by TXA(2), but also by prostaglandin (PG) D(2), PGE(2), PGF(2alpha), PGH(2), PG endoperoxides (i.e., 20-HETE), and isoprostanes, all representing aspirin-insensitive mechanisms of TP activation. Moreover, TP are also expressed on several cell types such as macrophages or monocytes, and vascular endothelial cells, and exert antiatherosclerotic, antivasoconstrictive, and antithrombotic effects, depending on the cellular target.Thus, targeting TP receptor, a common downstream pathway for both platelet and extraplatelet TXA(2) as well as for endoperoxides and isoprostanes, may be a useful antiatherosclerotic and a more powerful antithrombotic intervention in clinical settings, such as diabetes mellitus, characterized by persistently enhanced thromboxane (TX)-dependent platelet activation through isoprostane formation and low-grade inflammation, leading to extraplatelet sources of TXA(2). Among TXRA, terutroban is an orally active drug in clinical development for use in secondary prevention of thrombotic events in cardiovascular disease. Despite great expectations on this drug supported by a large body of preclinical and clinical evidence and pathophysiological rationale, the PERFORM trial failed to demonstrate the superiority of terutroban over aspirin in secondary prevention of cerebrovascular and cardiovascular events among ~20,000 patients with stroke. However, the clinical setting and the design of the study in which the drug has been challenged may explain, at least in part, this unexpected finding.Drugs with dual action, such as dual TXS inhibitors/TP antagonist and dual COXIB/TP antagonists are currently in clinical development. The theoretical rationale for their benefit and the ongoing clinical studies are herein discussed. PMID- 22918736 TI - Inhibitors of the interaction between von Willebrand factor and platelet GPIb/IX/V. AB - The formation of platelet-rich thrombi, a critical step in the pathogenesis of atherothrombotic events, is a multistep process involving several components, among which von Willebrand Factor (VWF) plays a central role. Ruptured atherosclerotic plaques expose subendothelial matrix proteins which bind VWF that represents a bridge between the injured blood vessel and activated platelets, playing a crucial role in platelet adhesion and aggregation, especially in conditions of high-shear rate. Due to these peculiarities, the binding of VWF to GPIbalpha is an attractive drug target. Here we summarize the present knowledge on the different classes of drugs targeting the VWF-GPIb interaction and we give an account of their level of clinical development. In particular, the following compounds are discussed: AJW200, an IgG4 humanized monoclonal antibody against VWF-A1; 82D6A3, a monoclonal antibody against VWF-A3; ALX-0081 and ALX-0681, bivalent humanized nanobodies targeting the VWF-A1 domain; ARC1779 and its advanced formulation ARC15105, second-generation aptamers that bind the VWF-A1 domain; h6B4-Fab, a murine monoclonal antibody, and GPG-290, a recombinant chimeric protein, both directed against GPIbalpha. PMID- 22918737 TI - Inhibitors of the interactions between collagen and its receptors on platelets. AB - At sites of vascular injury, collagen-mediated platelet adhesion and activation have long been known as one of the first events in platelet-dependent thrombus formation. Studying patients with bleeding disorders that are caused by defective platelet adhesion to collagen resulted in the identification of several platelet collagen receptors, with glycoprotein VI and integrin alpha2beta1 being the most important ones. Subsequent development of specific collagen receptor knockout mice and various inhibitors of platelet binding to collagen have further proven the role of these receptors in haemostasis and thrombosis. The search for clinically applicable inhibitors for use as antithrombotic drug has led to the identification of inhibitory antibodies, soluble receptor fragments, peptides, collagen-mimetics and proteins from snake venoms or haematophagous animals. In experimental settings, these inhibitors have a good antithrombotic effect, with little prolongation of bleeding times, suggesting a larger therapeutic window than currently available antiplatelet drugs. However, at present, none of the collagen receptor blockers are in clinical development yet. PMID- 22918738 TI - Intracellular signaling as a potential target for antiplatelet therapy. AB - Three classes of inhibitors of platelet aggregation have demonstrated substantial clinical benfits. Aspirin acts by irreversibly inhibiting COX-1 and therefore blocking the synthesis of proaggregatory thromboxane A (2) (TxA(2)). The indirect acting (ticlopidine, clopidogrel, prasugrel) and the direct acting (ticagrelor) antagonists of P2Y(12) block the thrombus stabilizing activity of ADP. Parenteral GP IIb-IIIa inhibitors directly block platelet-platelet interactions. Despite well-established benefits, all antiplatelet agents have important limitations: increased bleeding and gastrointestinal toxicities (aspirin), high incidence of thrombotic thrombocytopenic purpura (ticlopidine), potentially nonresponders (clopidogrel), severe bleeding (prasugrel, GP IIb-IIIa antagonists) and "complicated" relationships with aspirin ticagrelor). In this chapter, we present the genetic and pharmacological evidence that supports the development and expectations associated with novel antiplatelet strategies directed at intrasignaling pathways. PMID- 22918739 TI - Novel targets for platelet inhibition. AB - Atherothrombosis often underlies coronary artery disease, stroke, and peripheral arterial disease. Antiplatelet drugs have come to the forefront of prophylactic treatment of atherothrombotic disease. Dual antiplatelet therapy of aspirin plus clopidogrel-the current standard-has benefits, but it also has limitations with regard to pharmacologic properties and adverse effects with often severe bleeding complications. For these reasons, within the last decade or so, the investigation of novel antiplatelet targets has prospered. Target identification can be the result of large-scale genomic or proteomic studies, functional genomics in animal models, the genetic analysis of patients with inherited bleeding disorders, or a combination of these techniques. PMID- 22918740 TI - Variability of platelet indices and function: acquired and genetic factors. AB - Each individual has an inherent variable risk of bleeding linked to genetic or acquired abnormal platelet number or platelet dysfunction. In contrast, it is less obvious that the variability of platelet phenotypes (number, mean platelet volume, function) may contribute to the variable individual risk of thrombosis. Interindividual variability of platelet indices or function may be either due to acquired factors, such as age, sex, metabolic variables, smoke, dietary habits, and ongoing inflammation, or due to genetic factors. Acquired variables explain a small portion of the heterogeneity of platelet parameters. Genetic factors, instead, appear to play a major role, although a consistent portion of such a genetic variance has not yet been attributed to any specific genetic factor, possibly due to the high number of DNA loci potentially involved and to the limited effect size of each individual SNP. A portion of variance remains thus unexplained, also due to variability of test performance. A major contradiction in present platelet knowledge is, indeed, the difficulty to reconcile the universally accepted importance of platelet indices or function and the lack of reliable platelet parameters in cardiovascular risk prediction models. Trials on antiplatelet drugs were generally designed to select a homogeneous sample, whose results could be applied to an "average subject," tending to exclude the deviation/extreme values. As the current indications for antiplatelet treatment in primary or secondary prevention of ischemic vascular disease still derive from the results of such clinical trials where platelet function and its variability was not investigated, we cannot at present rely upon any current platelet test to either initiate, or monitor, or modify or stop treatment with any antiplatelet drug. Evidence is, however, increasing that traditional platelet aggregometry and other more recently developed platelet function assays could be useful to optimize antiplatelet therapy and to predict major adverse cardiac events.The observation of interindividual differences in platelet response to antiplatelet drugs has enlarged the spectrum and the possible clinical relevance of the variability of platelet indices or function. The development of "personalized medicine" will benefit from the concepts discussed in this chapter. PMID- 22918741 TI - Small RNAs as potential platelet therapeutics. AB - MicroRNAs (miRNAs) are 21-23 nucleotide RNAs that regulate more than 60% of mammalian protein coding genes. miRNAs play critical roles in hematopoiesis and megakaryocyte function and development. Platelets, in addition to possessing functional miRNA processing machinery, have miRNA levels that have been correlated with platelet reactivity, and these miRNAs have been shown to target mRNAs that encode proteins that alter platelet function. There are potential uses of platelet miRNA as biomarkers and therapeutic agents. Due to the ability of platelets to release miRNA-containing microparticles at sites of activation, including angiogenic regions, tumors, and atherosclerotic plaques, there is the possibility of engineering platelets to deliver miRNA-based therapies to these sites. Cellpreferential expression of miRNAs could be exploited to restrict transgene expression in hematopoietic stem cell gene therapy to the desired lineage, including megakaryocytes and platelets. Finally, manipulation of gene expression in stored platelets may allow more effective platelet storage. Although much work remains to be done, there is great potential in miRNA-based platelet therapies. PMID- 22918742 TI - Pharmacological modulation of the inflammatory actions of platelets. AB - Patients with inflammatory diseases often exhibit a change in platelet function, with these alterations being clearly distinct from the well-characterized role of platelets in haemostasis and thrombosis. It has recently been revealed that platelets can behave as innate inflammatory cells in immune responses with roles in leukocyte recruitment, migration into tissues, release of cytotoxic mediators, and in tissue remodelling following injury.Platelets exhibit a wide range of receptors for mediators involved in the inflammatory pathway and the immune response (Fig. 1). These include purinergic receptors, selectins, integrins, toll like receptors, immunoglobulins, and chemokine receptors, but the precise role platelets play in the inflammatory process is still under investigation. Nevertheless, given that many of these receptors are distinct from those involved in thrombosis and haemostasis, this raises the real possibility of targeting these receptors to regulate inflammatory diseases without compromising haemostasis. PMID- 22918743 TI - The role of laboratory monitoring in antiplatelet therapy. AB - In the last decade, several studies reported a high inter-individual variability in the pharmacological response to antiplatelet drugs. Suboptimal response to aspirin, as determined by specific tests (serum thromboxane B(2)), is rare and, when present, it appears to be caused by poor compliance in most instances. In contrast, studies that used specific tests to measure the pharmacological effect of clopidogrel showed a wide variability of response, with about 1/3 of treated subjects who are very poor responders. Inter-individual difference in the extent of metabolism of clopidogrel to its active metabolite by cytochrome P450 isoforms is the most relevant cause of the observed inter-individual variability in platelet inhibition. Tailored treatment based on laboratory monitoring of platelet function has been proposed as a solution to poor responsiveness to clopidogrel. However, we still need to identify the ideal laboratory test and to answer basic questions on its clinical utility and cost-effectiveness, before monitoring clopidogrel therapy can be recommended in clinical practice. PMID- 22918744 TI - Antiplatelet agents in ischemic heart disease. PMID- 22918745 TI - Antiplatelet therapy in cerebrovascular disorders. AB - Antiplatelet treatment is a mainstay in acute and long-term secondary stroke prevention. Aspirin is still most widely used worldwide, however, there is increasing evidence from small randomised trials that dual antiplatelet therapy combining aspirin with dipyridamole or clopidogrel might be more effective in the acute and early chronic post-ischemic phase (i.e. first 90 days). Both clopidogrel and the combination of aspirin and extended-release dipyridamole are recommended by current guidelines in long-term secondary stroke prevention in patients who are at high risk for a recurrent ischemic stroke, since they are more effective compared with aspirin monotherapy. Antiplatelet agents are the therapy of choice in patients with ischemic stroke due to intracranial stenosis and patent foramen ovale. In contrast, oral anticoagulation is clearly superior to single or double antiplatelet therapy in patients with cardioembolic stroke, mainly caused by atrial fibrillation.Concerning newer antiplatelet agents, only cilostazol appears to be a promising therapeutic option in patients with ischemic stroke in the near future, but so far, only studies in Asian stroke patients have been performed. PMID- 22918746 TI - Antiplatelet therapy in peripheral artery disease. AB - Peripheral artery disease (PAD) is a term that relates to atherosclerosis and narrowing of the arteries in the lower extremities. The prevalence of PAD is approximately 12% of the adult population. Despite the low rate of peripheral complications and amputation, PAD is complicated by a high rate of cardiovascular events including myocardial infarction, stroke, and vascular death with an annual incidence of about 5%.The detection of PAD is initially based on the appearance of typical symptoms (claudication and critical limb ischemia) related to peripheral arterial insufficiency. However, PAD may also be present in the absence of clinical symptoms (asymptomatic PAD). Accordingly, asymptomatic disease may occur in up to 50% of all patients with PAD. Ankle brachial index (ABI) is a diagnostic test used to evaluate the presence of PAD, defined by an ABI <=0.90. The ABI is also demonstrated to be useful in the assessment of vascular risk in asymptomatic and symptomatic patients. Antiplatelet therapy remains a key intervention to reduce cardiovascular risk in PAD. Data from Antithrombotic Trialists' Collaboration showed that antiplatelet treatment was associated with a 23% risk reduction of vascular events in overall population with PAD. However, closer scrutiny of these data reveals that nonaspirin antiplatelet drugs, including ticlopidine, clopidogrel, picotamide, and dipyridamole largely drove the benefits in the PAD subgroup. It remains an open issue if PAD represents an atherosclerotic clinical model where aspirin, differently from coronary heart disease, is less effective in reducing atherosclerotic progression. Based on the reported results further trials with aspirin should be done in asymptomatic (ABI <=0.90) and symptomatic PAD patients. Finally, the role of new antiplatelet drugs such as prasugrel and ticagrelor has not yet been studied in PAD. PMID- 22918747 TI - Primary prevention of ischaemic cardiovascular disorders with antiplatelet agents. AB - In those who have already survived myocardial infarction (MI) or stroke, or have had a transient ischaemic episode (TIA), daily low dose aspirin (ASA) reduces the risk of recurrences by an amount that greatly exceeds the risk of serious bleeding (secondary prevention). ASA is therefore recommended for these people. However, in primary prevention-reducing risk in those so far free of clinically manifest episodes-the benefit is of the same order as the bleeding hazard, (which is much the same in both primary and secondary prevention contexts). The use of other effective agents such as statins further emphasises the even balance between benefit and hazard in primary prevention. Six primary prevention trials are reviewed, first singly and then in a meta-analysis based on individual patient data. ASA reduced non-fatal myocardial infarction by about 25%. However, death from coronary heart disease (CHD) was not significantly reduced (by 5%), nor was any vascular death (3%). There was a non- significant reduction in strokes of 5%, this being the net result of an 8% reduction in non-fatal stroke and a 21% increase in stroke death (mainly from haemorrhagic events), both effects being non-significant. Serious vascular events (MI, stroke or vascular death) were significantly reduced by 12%, mainly due to the large effect on non fatal MI. About 1650 people would need to be treated with ASA for a year to avoid one serious vascular event, which contrasts with the 10-20 events avoided in secondary prevention by treating 1,000 patients for a year. Other primary prevention trials not included in the meta-analysis have also reported no benefits in MI or stroke, but the findings of still unpublished trials are awaited. Recently, however, encouraging results have come from meta-analyses of the effects of ASA on cancer incidence and mortality and on its effects on cancer metastasis, particularly for adenocarcinomas. Typically, reductions in these measures have been around 30% following treatment for four or five years, but more in several instances. These results alter the balance in primary prevention between benefit and hazard as it appears for arterial events alone, tipping it towards the use of ASA. Consequently, new guidelines on advice and decisions on ASA in primary prevention are now needed. Low dose ASA, eg. 75 mg daily is as effective as higher doses for all the vascular and cancer benefits established in the meta-analyses, and it causes less serious bleeding than higher doses. PMID- 22918748 TI - Influence of existing site contamination on sensitivity of Rhinella fernandezae (Anura, Bufonidae) tadpoles to Lorsban(r)48E formulation of chlorpyrifos. AB - Effects of the widely employed insecticide Lorsban((r))48E formulation of chlorpyrifos (CPF) was studied on Rhinella fernandezae tadpoles, a native species of Argentina, Brazil, Paraguay and Uruguay, under the hypothesis of a differential response of organisms from ponds of two sites with different degree of anthropogenic disturbance: S1 an unpolluted area, and S2 area with high degree of antropogenic disturbance. To collect a representative sample of the genotypic variability of each population, small portions from six clutches were taken randomly from each site when the period of clutching was finished. Embryos and tadpoles were maintained under controlled laboratory conditions. Toxicity tests were conducted under standardized conditions to study acute and chronic lethal (mortality) and sublethal effects (behavior, growth, and abnormalities), within the range of concentrations of 0.010 to 5 mg/L. Chronic effects were assessed with organisms from one of the demes (S1). CPF showed high toxicity on the tadpoles, inducing lethal and sublethal effects at 96 h exposure within a narrow range of concentrations from 0.066 to 0.887 mg/L. Results indicate that R. fernandezae tadpoles are below the 30th percentile in the species sensitivity distribution of existing data. The acute LC50, NOEC, and LOEC values were 0.151, 0.066, and 0.133 mg/L for S1, and 0.293, 0.177, and 0.266 mg/L for S2, respectively. Considering all acute end-points evaluated, the effects of CPF showed no significant differences (p = 0.3484) between the studied populations. CPF has more severe effects at higher concentrations than at higher times of exposure. Contaminants in S2 do not seem to induce local adaptation. Sublethal effects data and measured environmental concentrations indicate potential risk for populations inhabiting agroecosystems. PMID- 22918750 TI - Reliability and variability of sleep and activity as biomarkers of ageing in Drosophila. AB - There are currently no reliable biomarkers of ageing. A biomarker should indicate biological age, that is, the amount of an animal's total lifespan it has lived and, therefore, the amount of time it has remaining. Some potential biomarkers cannot be validated as their measurement involves harm or death of the animal, such that its ultimate lifespan cannot be determined. A non-destructive biomarker would allow us to test molecular markers potentially involved directly in the ageing process, to monitor the effectiveness of therapeutic interventions to delay ageing, and provide a useful measure of general health of the organism. In the model organism Drosophila, various behavioural phenotypes change directionally with age, but we do not know whether they predict lifespan. Here we measure activity and sleep parameters in 64 wild type male flies from two recently wild-caught populations over the course of their natural lives, and determine whether such measures may predict biological age and ultimate lifespan. Indices of sleep fragmentation and circadian rhythm were the best predictors of lifespan, though population differences were evident. However, when used to predict a biological age of 50 % lifespan elapsed our best behavioural measure was slightly less accurate and less precise compared with using chronological age as predictor. PMID- 22918749 TI - Citrulline diet supplementation improves specific age-related raft changes in wild-type rodent hippocampus. AB - The levels of molecules crucial for signal transduction processing change in the brain with aging. Lipid rafts are membrane microdomains involved in cell signaling. We describe here substantial biophysical and biochemical changes occurring within the rafts in hippocampus neurons from aging wild-type rats and mice. Using continuous sucrose density gradients, we observed light-, medium-, and heavy raft subpopulations in young adult rodent hippocampus neurons containing very low levels of amyloid precursor protein (APP) and almost no caveolin-1 (CAV-1). By contrast, old rodents had a homogeneous age-specific high density caveolar raft subpopulation containing significantly more cholesterol (CHOL), CAV-1, and APP. C99-APP-Cter fragment detection demonstrates that the first step of amyloidogenic APP processing takes place in this caveolar structure during physiological aging of the rat brain. In this age-specific caveolar raft subpopulation, levels of the C99-APP-Cter fragment are exponentially correlated with those of APP, suggesting that high APP concentrations may be associated with a risk of large increases in beta-amyloid peptide levels. Citrulline (an intermediate amino acid of the urea cycle) supplementation in the diet of aged rats for 3 months reduced these age-related hippocampus raft changes, resulting in raft patterns tightly close to those in young animals: CHOL, CAV-1, and APP concentrations were significantly lower and the C99-APP-Cter fragment was less abundant in the heavy raft subpopulation than in controls. Thus, we report substantial changes in raft structures during the aging of rodent hippocampus and describe new and promising areas of investigation concerning the possible protective effect of citrulline on brain function during aging. PMID- 22918751 TI - (68)Ge/ (68)Ga generators: past, present, and future. AB - In 1964, first (68)Ge/(68)Ga radionuclide generators were described. Although the generator design was by far not adequate to our today's level of chemical, radiopharmaceutical and medical expectations, it perfectly met the needs of molecular imaging of this period. (68)Ga-EDTA as directly eluted from the generators entered the field of functional diagnosis, in particular for brain imaging. A new type of generators became commercially available in the first years of the 21st century. Generator eluates based on hydrochloric acid provided "cationic" (68)Ga instead of "inert" (68)Ga-complexes and opened new pathways of Me(III) based radiopharmaceutical chemistry. The impressive success of utilizing (68)Ga- DOTA-octreotides and PET/CT instead of e.g., (111)In-DTPA-octreoscan and SPECT paved the way not only towards clinical acceptance of this particular tracer for imaging neuroendocrine tracers, but to the realisation of the great potential of the (68)Ge/(68)Ga generator for modern nuclear medicine in general. The last decade has seen a (68)Ga rush. Increasing applications of generator based (68)Ga radiopharmaceuticals (for diagnosis alone, but increasingly for treatment planning thanks to the inherent option as expressed by THERANOSTICS), now ask for further developments - towards the optimization of (68)Ge/(68)Ga generators both from chemical and regulatory points of view. Dedicated chelators may be required to broaden the feasibility of (68)Ga labeling of more sensitive targeting vectors and generator chemistry may be adopted to those chelators - or vice versa. This review describes the development and the current status of (68)Ge/(68)Ga radionuclide generators. PMID- 22918752 TI - Overview and perspectives on automation strategies in (68)Ga radiopharmaceutical preparations. AB - The renaissance of (68)Ga radiopharmacy has led to great advances in automation technology. The availability of a highly efficient, reliable, long-lived (68)Ge/(68)Ga generator system along with a well-established coordination chemistry based on bifunctional chelating agents have been the bases of this development in (68)Ga radiopharmacy. Syntheses of (68)Ga peptides were originally performed by manual or semiautomated systems, but increasing clinical demand, radioprotection, and regulatory issues have driven extensive automation of their production process. Several automated systems, based on different post-processing of the (68)Ga generator eluate, on different engineering, and on fixed tubing or disposable cassette approaches, have been developed and are discussed in this chapter. Since automatic systems for preparation of radiopharmaceuticals should comply with qualification and validation protocols established by regulations such as current Good Manufacturing Practices (cGMP) and local regulations, some regulatory issues and the more relevant qualification protocols are also discussed. PMID- 22918753 TI - Post-processing via cation exchange cartridges: versatile options. AB - New (68)Ge/(68)Ga radionuclide generators provide the positron emitter (68)Ga (T1/2 = 67.7 min) as an easily available and relatively inexpensive source of a PET nuclide for labeling of interesting targeting vectors. However, currently available "ionic" (68)Ge/(68)Ga radionuclide generators are not necessarily optimized for the routine synthesis of (68)Ga-labeled radiopharmaceuticals in a clinical environment. Post-processing of (68)Ge/(68)Ga generators using cation exchange resins provides chemically and radiochemically pure (68)Ga with 97+/-2% within less than 4 min, with (68)Ge almost completely removed, and ready for online labeling. This simple, fast, and efficient technology can be extended for new applications. The options are (a) to transfer (68)Ga from the cation exchange resin onto an anion exchange resin, to remove acetone, and to further purify the (68)Ga, (b) to obtain (68)Ga in pure non-aqueous solution via (68)Ga(acac)(3) as a synthon for syntheses in organic solvents, and (c) to create an option toward instantaneous determination of (68)Ge breakthrough, what may be required prior to the release of (68)Ga radiopharmaceutical preparations. PMID- 22918754 TI - (68)Ga generator integrated system: elution-purification-concentration integration. AB - A (68)Ge/(68)Ga generator combined with an automated (68)Ga eluate purification concentration unit [radioisotope generator integrated system (RADIGIS)], specially designed for (68)Ga processing (RADIGIS-(68)Ga), was developed. The high-stability sorbents of a nanocrystalline structure Zr-Ti ceramic matrix were used for immobilizing the (68)Ge, and the (68)Ga was eluted from the sorbent column with 3.5 mL 0.05-0.1 M HCl solution following an optimized (68)Ga-elution schedule. The (68)Ge breakthrough <10(-3)% and no (68)Ge zone spreading/drift found in PET imaging of the (68)Ga generator column prove the excellent performance of the sorbents. (68)Ga eluate was purified on a small column of salt form ion exchange resin using an aqueous alcohol solution mixture of hydrochloric and ascorbic acids, and halide salts. An alkali solution was used for stripping (68)Ga from the ion exchange resin column to obtain a purified (68)Ga solution, which is conditioned with acidic solution to obtain a final (68)Ga product in either 0.75 mL 0.5 M NaCl solution of pH 3-4 or 0.5 M sodium acetate or citrate solution of pH 5. The (68)Ge content in purified (68)Ga solution was <10(-6)%. An insignificant metallic contamination including (68)Zn found in the (68)Ga solution and its alkalinity-acidity were evaluated with respect to (68)Ga radiolabeling efficacy for DOTATATE and DOTATOC ligands. Quality control protocols were also developed to evaluate the quality of (68)Ga solution. PMID- 22918755 TI - Purification and labeling strategies for (68)Ga from (68)Ge/ (68)Ga generator eluate. AB - For successful labeling, (68)Ge/(68)Ga generator eluate has to be concentrated (from 10 mL or more to less than 1 mL) and to be purified of metallic impurities, especially Fe(III), and (68)Ge breakthrough. Anionic, cationic and fractional elution methods are well known. We describe two new methods: (1) a combined cationic-anionic purification and (2) an easy-to-use and reliable cationic purification with NaCl solution. Using the first method, (68)Ga from 10 mL generator eluate was collected on a SCX cartridge, then eluted with 1.0 mL 5.5 M HCl directly on an anion exchanger (30 mg AG1X8). After drying with a stream of helium, (68)Ga was eluted with 0.4 mL water into the reaction vial. We provide as an example labeling of BPAMD. Using the second method, (68)Ga from 10 mL generator eluate was collected on a SCX cartridge, then eluted with a hydrochloric solution of sodium chloride (0.5 mL 5 M NaCl, 12.5 MUL 5.5 M HCl) into the reaction vial, containing 40 MUg DOTATOC and 0.5 mL 1 M ammonium acetate buffer pH 4.5. After heating for 7 min at 90 degrees C, the reaction was finished. Radiochemical purity was higher than 95% without further purification. No (68)Ge breakthrough was found in the final product. PMID- 22918756 TI - (67)Ga and (68)Ga purification studies: preliminary results. AB - The positron emission tomography technique is very useful for diagnosis of several diseases. (68)Ga is a positron emitter with half-life of 67.7 min. As it is available from (68)Ge/(68)Ga generator systems, it is not necessary to have a nearby cyclotron. However, the eluate from commercial generators contains high levels of metallic impurities, which compete with (68)Ga in biomolecular labeling. Thus, a subsequent purification step is needed after generator elution. Here we present the results of two different methods developed for handmade purification of (68)Ga and (67)Ga for subsequent radiolabeling of biomolecules. Two purification methods were employed. The first one uses a cation exchange resin, and (68)Ga is eluted with a solution of acetone/acid. The second method of purification is performed by column chromatography solvent extraction, with (68)Ga recovery in deionized water. The best result was achieved with cationic resin AG50W-X8 (>400 mesh). However, the resin is not commercially available. The extraction chromatography column based on absorption of diisopropyl ether in XAD 16 is the most promising purification method. Although the levels of (68)Ga recovery and purification were smaller with the cationic resin method, its advantage is the (68)Ga recovery in deionized water. PMID- 22918757 TI - The diversity of (68)Ga-based imaging agents. AB - Development of new radiopharmaceuticals and their availability are crucial factors influencing the expansion of clinical nuclear medicine. The number of new (68)Ga-based imaging agents for positron emission tomography (PET) is increasing greatly. (68)Ga has been used for labeling of a broad range of molecules (small organic molecules, peptides, proteins, and oligonucleotides) as well as particles, thus demonstrating its potential to become a PET analog of the legendary generator-produced gamma-emitting (99m)Tc but with added value of higher sensitivity and resolution as well as quantitation and dynamic scanning. Further, the availability of technology for GMP-compliant automated tracer production can facilitate the introduction of new radiopharmaceuticals and enable standardized, harmonized multicenter studies to be conducted for regulatory approval. This chapter presents some examples of tracers for targeted, pretargeted, and nontargeted imaging with emphasis on the potential of (68)Ga to facilitate clinically practical PET development and to promote the PET technique worldwide for earlier and better diagnostics, and personalized medicine with the ultimate objective of improved therapeutic outcome. PMID- 22918758 TI - Nanoparticles and phage display selected peptides for imaging and therapy of cancer. AB - Molecular imaging probes are a special class of pharmaceuticals that target specific biochemical signatures associated with disease and allow for noninvasive imaging on the molecular level. Because changes in biochemistry occur before diseases reach an advanced stage, molecular imaging probes make it possible to locate and stage disease, track the effectiveness of drugs, treat disease, monitor response, and select patients to allow for more personalized diagnosis and treatment of disease. Targeting agents radiolabeled with positron emitters are of interest due to their ability to quantitatively measure biodistribution and receptor expression to allow for optimal dose determinations. (68)Ga is a positron emitter, which allows for quantitative imaging through positron emission chromatography (PET). The availability of (68)Ga from a generator and its ability to form stable complexes with a variety of chelates hold promise for expanding PET utilization to facilities unable to afford their own cyclotron. Nanoparticles conjugated with various proteins and peptides derived from phage display that can be selectively targeted are being developed and evaluated for guided imaging and therapy. Herein we highlight some initial efforts in combining the enhanced selectivity of nanoparticles and peptides with (68)Ga for use as molecular imaging probes. PMID- 22918760 TI - Early experience with (68)Ga-DOTATATE preparation. AB - Neuroendocrine tumors (NETs) are a rare form of cancer. NETs frequently express cell membrane-specific peptide receptors, such as somatostatin receptors (SSTRs). Radiolabeled peptides bind to SSTR and provide in vivo histopathological information for diagnostic purposes. (68)Ga-DOTATATE has higher sensitivity for low-grade tumors and greater avidity to well-differentiated NETs than (18)F-FDG, being superior to (111)In-DTPA-octreotide and (18)F-DOPA in evaluation of well differentiated metastatic NETs. The feasibility of (68)Ga-DOTATATE application in routine clinical practice for PET imaging of NETs was determined in a limited number of known cases (n = 6). (68)Ga-DOTATATE scan could detect all known sites of NETs and in one case previously unknown peritoneal metastasis. Early regulatory consideration is important for routine clinical use. PMID- 22918759 TI - "Click"-cyclized (68)Ga-labeled peptides for molecular imaging and therapy: synthesis and preliminary in vitro and in vivo evaluation in a melanoma model system. AB - Cyclization techniques are used often to impart higher in vivo stability and binding affinity to peptide targeting vectors for molecular imaging and therapy. The two most often used techniques to impart these qualities are lactam bridge construction and disulfide bond formation. While these techniques have been demonstrated to be effective, orthogonal protection/deprotection steps can limit achievable product yields. In the work described in this chapter, new alpha melanocyte stimulating hormone (alpha-MSH) peptide analogs were synthesized and cyclized by copper-catalyzed terminal azide-alkyne cycloaddition "click" chemistry techniques. The alpha-MSH peptide and its cognate receptor (melanocortin receptor subtype 1, MC1R) represent a well-characterized model system to examine the effect of the triazole linkage for peptide cyclization on receptor binding in vitro and in vivo. Four new DOTA-conjugated alpha-MSH analogs were cyclized and evaluated by in vitro competitive binding assays, serum stability testing, and in vivo imaging by positron emission tomography (PET) of tumor-bearing mice. These new DOTA-conjugated click-cyclized analogs exhibited selective high binding affinity (<2 nM) for MC1R on melanoma cells in vitro, high stability in human serum, and produced high-contrast PET/CT images of tumor xenografts. (68)Ga-labeled DOTA bioconjugates displayed rapid pharmacokinetics with receptor-mediated tumor accumulation of up to 16 +/- 5% ID/g. The results indicate that the triazole ring is an effective bioisosteric replacement for the standard lactam bridge assemblage for peptide cyclization. Radiolabeling results confirm that Cu catalyst is sufficiently removed prior to DOTA chelator addition to enable insertion of radio metals or stable metals for molecular imaging and therapy. Thus, these click-chemistry-cyclized variants show promise as agents for melanocortin receptor-targeted imaging and radionuclide therapy. PMID- 22918761 TI - (68)Ga-radiopharmaceuticals for PET imaging of infection and inflammation. AB - Infection imaging has been challenging over the past four decades, which provided an excellent playing field for researchers working in this area, and till date the quest continues to find an ideal imaging agent. Labelled leukocytes were first developed in the 1970s for imaging infection lesions such as osteomyelitis, cellulitis, diabetic foot, Crohn's disease, inflammatory bowel disease, fever of unknown origin, etc. Subsequently labelled antibiotics such as (99m)Tc-labelled ciprofloxacin have emerged for directly identifying live bacterial infections. From the early 1970s through the mid-1980s,( 67)Ga-Citrate was the prime radionuclide for imaging of inflammation and infection of musculoskeletal origin. Although (68)Ga-PET was described in 1960s for tumour imaging, recent reports described (68)Ga-Citrate and (68)Ga-transferrin as possible agents for PET imaging of infection due to successful application of (67)Ga-Citrate SPECT in the past, despite its limitations. It is important to establish a faster imaging method for (68)Ga, as its half-life is 68 min compared to 78.3 hrs for (67)Ga. Preparation of (68)Ga-Citrate and (68)Ga-transferrin is described, with very high yield and high radiochemical purity (RCP), which is ideally suited for routine clinical studies. Biodistribution of (68)Ga-Citrate-PET images were characterised with high blood pool, high liver and bone (growth plate) uptake with low soft tissue activity. (68)Ga-Citrate or (68)Ga-transferrin was able to detect infected lesions in rats within 5-10 min post injection but a focal intense uptake at the lesion (SUV(max)) was visualized only at 30 min, which increased for up to 6 hrs post injection with concomitant decrease in the cardiac blood pool activity. The liver and bowel activity decreased after 90 min then stabilised. In the patient studies, infection lesions were detected within 30 min post injection of (68)Ga Citrate. Cardiac blood pool and liver activities decreased during the period of study. Interestingly, there was persistent high vascular activity in the thigh region. One of the major limitations of (67)Ga-Citrate SPECT is the delayed post injection waiting time of 48 hrs, in contrast to 60 min post injection waiting with (68)Ga-Citrate. The distinct difference in imaging time is intriguing, although there is no chemical difference between (67)Ga-Citrate and (68)Ga Citrate, except for the radiolabel. No literature is available on early imaging times using (67)Ga-SPECT. When compared (68)Ga/(67)Ga-Citrate images at 60 min post injection in normal rats, (68)Ga-PET showed better images with low background activity than (67)Ga-SPECT agent. This may be due to short half-life of (68)Ga (68 min), as it would have decayed one half-life at 60 min post-imaging time, compared to the SPECT agent ((67)Ga), which would require 76 hrs to undergo one half-life. Therefore, the visual difference in background can be attributed to the difference in the half-lives of these two agents. Similarly, uptake of (68)Ga by liver, cardiac blood pool activity is much lower than (67)Ga at 60 min post injection period, may be attributed to the faster decay of (68)Ga than (67)Ga. High background activity of (68)Ga-Citrate in the thorax and upper abdomen at 60 min post-injection may interfere with detecting lesions in these regions; therefore, (68)Ga-PET is more suitable for imaging lesions in the lower abdomen and the extremities. The short half-life of (68)Ga (68 min) may be advantageous from low dosimetry to the patients, but disadvantageous for longer periods of study. Since (68)Ga-Citrate was capable of detecting infection within 60 min, the need for imaging for longer periods may not be warranted. The functional imaging was not limited to diagnosing infection but it could be extended to surgical planning and antibiotic therapy monitoring of osteomyelitis and in distinguishing prosthetic infection from loosening of prosthesis. (18)F FDG is sensitive but has the limitation of giving false positive results in patients with bone prosthesis, even if there is no infection or mobilisation. But the available literature clearly indicated (68)Ga-Citrate was positive only in cases of infection. In summary, preliminary reports suggest (68)Ga-Citrate PET/CT is useful in the diagnosis of suspected bone infections with reliable sensitivity, specificity, positive predictive value, negative predictive value and overall accuracy. Preliminary reports with (68)Ga-Transferrin showed it is capable of detecting both Gram-positive Staphylococcus aureus (Staph A) and Gram negative Proteus mirobilis. This is an incidental finding but gives an insight into the potential of this agent to detect more than one bacterial infection. PMID- 22918762 TI - (68)Ga-labeled bombesin analogs for receptor-mediated imaging. AB - Targeted receptor-mediated imaging techniques have become crucial tools in present targeted diagnosis and radiotherapy as they provide accurate and specific diagnosis of disease information. Peptide-based pharmaceuticals are gaining popularity, and there has been vast interest in developing (68)Ga-labeled bombesin (Bn) analogs. The gastrin-releasing peptide (GRP) family and its Bn analog have been implicated in the biology of several human cancers. The three bombesin receptors GRP, NMB, and BRS-3 receptor are most frequently ectopically expressed by common, important malignancies. The low expression of Bn/GRP receptors in normal tissue and relatively high expression in a variety of human tumors can be of biological importance and form a molecular basis for Bn/GRP receptor-mediated imaging. To develop a Bn-like peptide with favorable tumor targeting and pharmacokinetic characteristics for possible clinical use, several modifications in the Bn-like peptides, such as the use of a variety of chelating agents, i.e., acyclic and macrocyclic agents with different spacer groups and with different metal ions (gallium), have been performed in recent years without significant disturbance of the vital binding scaffold. The favorable physical properties of (68)Ga, i.e., short half-life, and the fast localization of small peptides make this an ideal combination to study receptor-mediated imaging in patients. PMID- 22918763 TI - A novel (68)Ga-labeled pteroic acid-based pet tracer for tumor imaging via the folate receptor. AB - The folate receptor (FR) is a very attractive target in oncological imaging as it is overexpressed by a variety of cancer types, whereas the expression in healthy tissue is very limited. The synthesis of regioisomeric pure folic acid derivatives normally requires a regioselective approach and does not allow the use of native folic acid (FA). As the pharmacophore of FA is assumed to be pteroic acid, its use without the glutamic acid moiety may enable the possibility to considerably simplify the synthesis of a positron emission tomography (PET) tracer for FR imaging. In this work, DO3A-EA-Pte was successfully synthesized and labeled with (68)Ga. It is stable for up to 3 h in PBS and against transchelation by transferrin. It also displays a lipophilicity that allows the assumption that it will show favorable in vivo characteristics for FR imaging via PET. PMID- 22918764 TI - Measurement of protein synthesis: in vitro comparison of (68)Ga-DOTA-puromycin, [ (3)H]tyrosine, and 2-fluoro-[ (3)H]tyrosine. AB - AIM: Puromycin has played an important role in our understanding of the eukaryotic ribosome and protein synthesis. It has been known for more than 40 years that this antibiotic is a universal protein synthesis inhibitor that acts as a structural analog of an aminoacyl-transfer RNA (aa-tRNA) in eukaryotic ribosomes. Due to the role of enzymes and their synthesis in situations of need (DNA damage, e.g., after chemo- or radiation therapy), determination of protein synthesis is important for control of antitumor therapy, to enhance long-term survival of tumor patients, and to minimize side-effects of therapy. Multiple attempts to reach this goal have been made through the last decades, mostly using radiolabeled amino acids, with limited or unsatisfactory success. The aim of this study is to estimate the possibility of determining protein synthesis ratios by using (68)Ga-DOTA-puromycin ((68)Ga-DOTA-Pur), [(3)H]tyrosine, and 2-fluoro [(3)H]tyrosine and to estimate the possibility of different pathways due to the fluorination of tyrosine. METHODS: DOTA-puromycin was synthesized using a puromycin-tethered controlled-pore glass (CPG) support by the usual protocol for automated DNA and RNA synthesis following our design. (68)Ga was obtained from a (68)Ge/(68)Ga generator as described previously by Zhernosekov et al. (J Nucl Med 48:1741-1748, 2007). The purified eluate was used for labeling of DOTA-puromycin at 95 degrees C for 20 min. [(3)H]Tyrosine and 2-fluoro-[(3)H]tyrosine of the highest purity available were purchased from Moravek (Bera, USA) or Amersham Biosciences (Hammersmith, UK). In vitro uptake and protein incorporation as well as in vitro inhibition experiments using cycloheximide to inhibit protein synthesis were carried out for all three substances in DU145 prostate carcinoma cells (ATCC, USA). (68)Ga-DOTA-Pur was additionally used for MUPET imaging of Walker carcinomas and AT1 tumors in rats. Dynamic scans were performed for 45 min after IV application (tail vein) of 20-25 MBq (68)Ga-DOTA-Pur. RESULTS: No significant differences in the behavior of [(3)H]tyrosine and 2-fluoro [(3)H]tyrosine were observed. Uptake of both tyrosine derivatives was decreased by inhibition of protein synthesis, but only to a level of 45-55% of initial uptake, indicating no direct link between tyrosine uptake and protein synthesis. In contrast, (68)Ga-DOTA-Pur uptake was directly linked to ribosomal activity and, therefore, to protein synthesis. (68)Ga-DOTA-Pur MUPET imaging in rats revealed high tumor-to-background ratios and clearly defined regions of interest in the investigated tumors. SUMMARY: Whereas the metabolic pathway of (68)Ga-DOTA Pur is directly connected with the process of protein synthesis and shows high tumor uptake during MUPET imaging, neither [(3)H]tyrosine nor 2-fluoro [(3)H]tyrosine can be considered useful for determination of protein synthesis. PMID- 22918765 TI - Hypoxia imaging agents labeled with positron emitters. AB - Imaging hypoxia using positron emission tomography (PET) is of great importance for therapy of cancer. [(18)F]Fluoromisonidazole (FMISO) was the first PET agent for hypoxia imaging, and various radiolabeled nitroimidazole derivatives such as [(18)F]fluoroerythronitroimidazole (FETNIM), [(18)F]1-alpha-D: -(2-deoxy-2 fluoroarabinofuranosyl)-2-nitroimidazole (FAZA), [(18)F]2-(2-nitro-1H-imidazol-1 yl)-N-(2,2,3,3,3-pentafluoropropyl) acetamide (EF-5), and [(18)F]fluoroetanidazole (FETA) have been developed successively. To overcome the high cost of cyclotron installation, (68)Ga-labeled nitroimidazole derivatives also have been developed. Another important hypoxia imaging agent is (64)Cu diacetyl-bis(N (4)-methylthiosemicarbazone) ((64)Cu-ATSM), which can distribute in cancer tissue rapidly due to high lipophilicity. However, its application is limited due to high cost of radionuclide production. Although various hypoxia imaging agents have been reported and tested, hypoxia PET images still have to be improved, because of the low blood flow in hypoxic tissues and resulting low uptake of the agents. PMID- 22918766 TI - (177)Lu/ (90)Y intermediate-affinity monoclonal antibodies targeting EGFR and HER2/c-neu: preparation and preclinical evaluation. AB - The epidermal growth factor receptor (EGFR) is a rational target of anticancer therapies due to its overexpression in a variety of malignant epithelial tumors. Nevertheless, this antigen is also present in normal tissues. Consequently, monoclonal antibodies which selectively bind to EGFR-overexpressing tumors will be choice drug candidates for development of radioimmunoconjugates (RIC). Nimotuzumab (h-R3) and trastuzumab are monoclonal antibodies (mAbs) which would preferentially target tissues with EGFR and HER2 overexpression, respectively. In this chapter, we describe preparation and evaluation of the targeting properties of RIC formed by (177)Lu/(90)Y and monoclonal antibodies which selectively target EGFR- and HER2/c-neu-overexpressing tissues. mAbs were labeled with n.c.a. (177)Lu/(90)Y using bifunctional chelating agents. RIC binding properties and toxicity were evaluated in vitro using cell lines with varying antigen expression. In vivo tumor targeting properties of RIC were evaluated in mice bearing colorectal (SNU-C2B) and A431 tumor xenografts. RICs were prepared with specific activities up to 2 GBq/mg without significant loss in biological activity. (90)Y-h-R3/trastuzumab increased cell growth inhibition compared with unmodified mAbs or (90)YCl(3) alone in cell lines with overexpression of the target antigen. (177)Lu-h-R3 showed significantly higher uptake in A431 (22.8 +/- 3.1% ID/g) than in SNU-C2B (8.8 +/- 4.1% ID/g) xenografts at 72 h post injection, indicating strong association between tumor uptake and EGFR expression levels. PMID- 22918767 TI - Divergent role of (68)Ga-labeled somatostatin analogs in the workup of patients with NETs: AIIMS experience. AB - Neuroendocrine tumors (NETs) encompass a wide range of rare and heterogeneous neoplasms arising from the neural crest. Diagnosis of NETs is conventionally done by a combination of common clinical symptoms and biochemical evidence of hormonal excess, which these tumors are known to secrete. After a diagnosis of NET is established, a search for its localization is carried out using common morphologic imaging methods such as ultrasonography, computed tomography (CT), and magnetic resonance imaging (MRI). The main problem with structural imaging is, however, its inability to distinguish between endocrine and exocrine lesions. Functional imaging of NETs started with use of iodine-131-meta iodobenzylguanidine ((131)I-MIBG) and has come a long way since. From accurate demonstration of functioning tumors to detection of small and occult lesions, functional imaging has penetrated almost every aspect of NET management. Procedures such as (131/123)I-MIBG, (111)In-Octreoscan and others are rapidly giving way to use of PET/CT based on the superior resolution of the system and the availability of target-specific positron-emitting radiotracers. The availability of (68)Ga from generator-based radionuclide systems, namely (68)Ge/(68)Ga generators, opened up a new era of molecular imaging for NETs. A multitude of somatostatin analogs can be easily radioliganded with (68)Ga using heterocyclic macromolecular bifunctional chelating systems for targeted diagnosis of somatostatin receptor-expressing tumors, used most effectively to date for detection of NETs. This chapter focuses on our experience at the All India Institute of Medical Sciences, New Delhi regarding the divergent roles of (68)Ga labeled somatostatin analogs in the workup of patients with NETs. PMID- 22918768 TI - Differential uptake of (68)Ga-DOTATOC and (68)Ga-DOTATATE in PET/CT of gastroenteropancreatic neuroendocrine tumors. AB - PURPOSE: Abundant expression of somatostatin receptors (sst) is a characteristic of neuroendocrine tumors (NET). Thus, radiolabeled somatostatin analogs have emerged as important tools for both in vivo diagnosis and therapy of NET. The two compounds most often used in functional imaging with positron emission tomography (PET) are (68)Ga-DOTATATE and (68)Ga-DOTATOC. Both analogs share a quite similar sst binding profile. However, the in vitro affinity of (68)Ga-DOTATATE in binding the sst subtype 2 (sst2) is approximately tenfold higher than that of (68)Ga DOTATOC. This difference may affect their efficiency in detection of NET lesions, as sst2 is the predominant receptor subtype on gastroenteropancreatic NET. We thus compared the diagnostic value of PET/CT with both radiolabeled somatostatin analogs ((68)Ga-DOTATATE and (68)Ga-DOTATOC) in the same patients with gastroenteropancreatic NET. PATIENTS AND METHODS: Twenty-seven patients with metastatic gastroenteropancreatic NET underwent (68)Ga-DOTATOC and (68)Ga DOTATATE PET/CT as part of the workup before prospective peptide receptor radionuclide therapy (PRRT). The performance of both imaging methods was analyzed and compared for detection of individual lesions per patient and for eight defined body regions. A region was regarded as positive if at least one lesion was detected in that region. In addition, radiopeptide uptake in terms of the maximal standardized uptake value (SUV(max)) was compared for concordant lesions and renal parenchyma. RESULTS: Fifty-one regions were found positive with both (68)Ga-DOTATATE and (68)Ga-DOTATOC. Overall, however, significantly fewer lesions were detected with (68)Ga-DOTATATE in comparison with (68)Ga-DOTATOC (174 versus 179, p < 0.05). Mean (68)Ga-DOTATATE SUV(max) across all lesions was significantly lower compared with (68)Ga-DOTATOC (16.9 +/- 6.8 versus 22.1 +/- 12.0, p < 0.01). Mean SUV(max) for renal parenchyma was not significantly different between (68)Ga-DOTATATE and (68)Ga-DOTATOC (12.6 +/- 2.6 versus 12.6 +/ 2.7). CONCLUSIONS: (68)Ga-DOTATOC and (68)Ga-DOTATATE possess similar diagnostic accuracy for detection of gastroenteropancreatic NET lesions (with a potential advantage of (68)Ga-DOTATOC) despite their evident difference in affinity for sst2. Quite unexpectedly, maximal uptake of (68)Ga-DOTATOC tended to be higher than its (68)Ga-DOTATATE counterpart. However, tumor uptake shows high inter- and intraindividual variance with unpredictable preference of one radiopeptide. Thus, our data encourage the application of different sst ligands to enable personalized imaging and therapy of gastroenteropancreatic NET with optimal targeting of tumor receptors. PMID- 22918769 TI - High uptake of (68)Ga-DOTATOC in spleen as compared to splenosis: measurement by PET/CT. AB - AIM: The aim of this study is to ascertain the high somatostatin receptor (SSTR) uptake in spleen and to compare the uptake in spleen and splenosis using SSTR PET/CT using( 68)Ga-DOTATOC. MATERIALS AND METHODS: SUV(max) of spleen on (68)Ga DOTATOC SSTR PET/CT (acquired for initial staging) in 10 patients with known neuroendocrine neoplasm of pancreatic tail was analyzed. All patients underwent left pancreatectomy and splenectomy. Diagnosis of splenosis was confirmed on CT, and SUV(max) was noted on follow-up SSTR PET/CT. RESULTS: SUV(max)was 28.8 +/- 12.5 in normal spleen and 10.5 +/- 4.3 in splenosis. CONCLUSION: The high uptake of( 68)Ga-DOTATOC (which has a high affinity to SSTR 2) in the spleen as compared to splenosis, which has a different histology, suggests white pulp as the probable site of high SSTR 2 expression. PMID- 22918770 TI - Rare metastases detected by (68)Ga-somatostatin receptor PET/CT in patients with neuroendocrine tumors. AB - AIM: The most common sites of metastasis in neuroendocrine tumors are liver, lymph nodes, and bone. The aim of this study is to determine the prevalence and location of other sites of metastasis. METHODS: 4,210 Ga-68 somatostatin-receptor PET/CT studies were performed at our center between July 2004 and December 2009. We retrospectively reviewed the reports of patients to check rare sites of metastasis other than liver, bone, and lymph nodes. Lesions were confirmed on follow-up and/or other imaging methods (MRI, echocardiography, and ultrasound). RESULTS: The different sites of metastasis according to frequency of occurrence were: cardiac (n = 29), breast (n = 21), retro-orbital (n = 9), uterus (n = 7), skin (n = 8), brain (n = 6), spleen (n = 3), testes (n = 1), seminal vesicle (n = 1), and intramuscular in psoas muscle (n = 4). CONCLUSIONS: Cardiac and breast metastases appear to be not infrequent in neuroendocrine tumor patients. Ga-68 somatostatin-receptor PET/CT enables detection of these and other rare sites of metastasis. PMID- 22918771 TI - Comparison of different positron emission tomography tracers in patients with recurrent medullary thyroid carcinoma: our experience and a review of the literature. AB - Several morphological and functional imaging techniques are usually used to detect residual/recurrent medullary thyroid carcinoma (MTC) with variable results; currently, there is growing interest in positron emission tomography (PET) methodology. Herein, we report our experience of and a literature review about the comparison of different positron emission tomography (PET) tracers in patients with residual/recurrent MTC. (18)F-DOPA PET/CT seems to be the most useful imaging method to detect recurrent MTC lesions, performing better than (18)F-FDG and (68)Ga-somatostatin analogs PET/CT. (18)F-FDG may complement (18)F DOPA in patients with aggressive tumors. (68)Ga-somatostatin analogs PET/CT may be useful to select patients who could benefit from radioreceptor therapy. The information provided by the various PET tracers reflects different metabolic pathways, and may help to select the most appropriate treatment. PMID- 22918772 TI - PET lung ventilation/perfusion imaging using (68)Ga aerosol (Galligas) and (68)Ga labeled macroaggregated albumin. AB - Pulmonary imaging using ventilation/perfusion (V/P) single-photon emission tomography (V/P scan) with Tc-99m-labeled radiotracers is a well-established diagnostic tool for clinically suspected pulmonary embolism (PE). Ga-68 aerosol (Galligas) and Ga-68-labeled macroaggregated albumin (MAA) are potential tracers for positron emission tomography (PET) lung V/P imaging and could display an advantage over conventional V/P scans in terms of sensitivity and specificity. After radiochemical and animal studies, the clinical applicability of Ga-68 aerosol (Galligas) and Ga-68-labeled MAA was investigated in an exploratory study in patients with clinical suspicion of PE. PET scans were acquired using a 16 slice Gemini TF positron emission tomography/computed tomography (PET/CT) scanner. The acquisition protocol included low-dose computed tomography (CT) for attenuation correction (AC). Dosimetry calculations and continuative phantom measurements were performed. Structural analyses showed no modification of the particles due to the labeling process. In addition, in vitro experiments showed stability of Ga-68 MAA in various media. As expected, Ga-68-labeled human serum albumin microspheres (HSAM) were completely retained in the lung of the animals. In clinical use, PET lung ventilation and perfusion imaging using Ga-68 aerosol (Galligas) and Ga-68-labeled MAA was successful in all cases. In one case a clinically suspected PE could be detected and verified. The administered activity of Ga-68 aerosol (Galligas) and Ga-68-labeled MAA may be reduced by more than 50%, resulting in comparable radiation exposure to conventional V/P scans. In conclusion, Ga-68 aerosol (Galligas) and Ga-68-labeled MAA are efficient substitutes for clinical use and could be an interesting alternative with high accuracy for lung V/P imaging with Tc-99m-labeled radiotracers, especially in times of Mo-99 shortages and increasing use and spread of PET/CT scanners and Ga 68 generators, respectively. PMID- 22918773 TI - Combined PET/MR imaging using (68)Ga-DOTATOC for radiotherapy treatment planning in meningioma patients. AB - Hybrid imaging is beneficial for improved medical diagnosis and therapy planning today. Hybrid imaging describes the prospective correlation of two or more complementary sets of imaging information, such as functional and anatomical image volumes. Correlation can be performed through physically combined imaging modalities, such as PET/CT, SPECT/CT, or PET/MR. Here we present first results from employing fully integrated PET/MR tomography for intensity-modulated radiotherapy (IMRT) treatment planning in patients with meningioma using [(68)Ga] DOTATOC as the biomarker of choice. Combined PET/MR offers higher soft tissue contrast and the ability to add functional information to the plain combination of MR-based anatomy and PET-based metabolic and molecular information. Furthermore, fully integrated PET/MR employs novel PET technology that is neither available in PET-only nor PET/CT systems. Despite the current lack of broad clinical evidence, integrated PET/MR may become particularly important and clinically useful for improved, individualized RT therapy planning for brain lesions. In particular, logistical and diagnostic benefits of integrated PET/MR based treatment planning over treatment planning based on PET/CT data may be expected in meningioma patients. PMID- 22918774 TI - A rare case of a large spinal meningioma with mediastinal extension and malignant behavior classified histologically as benign. AB - AIM: To report a rare case of a spinal WHO grade I meningioma extending through intervertebral foramina C7 to D4 with an extensive mediastinal mass and infiltration of the vertebrae, and to discuss the malignant behavior of a tumor classified as benign. METHODS: (Clinical Presentation, Histology, and Imaging): A 54-year-old man suffered from increasing lower back pain with gait difficulties, weakness and numbness of the lower extremities, as well as urge incontinence. CT scan of the thorax and MRI scan of the spine revealed a large prevertebral tumor, which extended to the spinal canal and caused compression of the spinal cord at the levels of C7 to D4 leading to myelopathy with hyperintense signal alteration on T2-weighted MRI images. The signal constellation (T1 with and without contrast, T2, TIR) was highly suspicious for infiltration of vertebrae C7 to D5. Somatostatin receptor SPECT/CT with (111)In-DTPA-D: -Phe-1-octreotide detected a somatostatin receptor-positive mediastinal tumor with infiltration of multiple vertebrae, dura, and intervertebral foramina C7-D4, partially with Krenning score >2. Percutaneous biopsies of the mediastinal mass led to histopathological findings of WHO grade I meningioma of meningothelial subtype. RESULTS: (Therapy): C7 to D4 laminoplasty was performed, and the intraspinal, extradural part of the tumor was microsurgically removed. Postoperative stereotactic radiation therapy was done using the volumetric modulated arc therapy (VMAT) technique (RapidArc). No PRRNT with (90)Y-DOTA-TOC was done. CONCLUSIONS: Due to the rare incidence and complex presentation of this disease not amenable to complete surgical resection, an individualized treatment approach should be worked out interdisciplinarily. The treatment approach should be based not only on histology but also on clinical and imaging findings. Close clinical and radiological follow-up may be mandatory even for benign tumors. PMID- 22918775 TI - Peptide receptor radionuclide therapy for neuroendocrine tumors in Germany: first results of a multi-institutional cancer registry. AB - Peptide receptor radionuclide therapy is an effective treatment option for patients with well-differentiated somatostatin receptor-expressing neuroendocrine tumors. However, published data result mainly from retrospective monocentric studies. We initiated a multi-institutional, prospective, board-reviewed registry for patients treated with peptide receptor radionuclide therapy in Germany in 2009. In five centers, 297 patients were registered. Primary tumors were mainly derived from pancreas (117/297) and small intestine (80/297), whereas 56 were of unknown primary. Most tumors were well differentiated with median Ki67 proliferation rate of 5% (range 0.9-70%). Peptide receptor radionuclide therapy was performed using mainly yttrium-90 and/or lutetium-177 as radionuclides in 1-8 cycles. Mean overall survival was estimated at 213 months with follow-up between 1 and 230 months after initial diagnosis, and 87 months with follow-up between 1 and 92 months after start of peptide receptor radionuclide therapy. Median overall survival was not yet reached. Subgroup analysis demonstrated that best results were obtained in neuroendocrine tumors with proliferation rate below 20%. Our results indicate that peptide receptor radionuclide therapy is an effective treatment for well- and moderately differentiated neuroendocrine tumors irrespective of previous therapies and should be regarded as one of the primary treatment options for patients with somatostatin receptor-expressing neuroendocrine tumors. PMID- 22918776 TI - Polish experience in Peptide receptor radionuclide therapy. AB - PATIENTS AND METHODS: During the period from April 2004 to December 2010, 358 patients underwent peptide receptor radionuclide therapy (PRRT) ((90)Y-DOTATATE, (177)Lu-DOTATATE, and (90)Y/(177)Lu-DOTATATE) in Poland. RESULTS: The majority of patients underwent (90)Y-DOTATATE therapy (n = 177) with progression-free survival (PFS)/time to progression (TTP) of 17-44 months and overall survival (OS) of 22-34.2 months. Twelve-month follow-up revealed stable disease (SD) in 46 60%, disease regression (RD) in 16-35%, disease progression (PD) in 7-17%, and complete remission (CR) in 3% of patients. In patients treated with (90)Y/(177)Lu DOTATATE (n = 44), PFS/TTP was 24.2-28.3 months and OS was 49.8-52.8 months. Twelve-month follow-up showed SD in 62-70%, RD in 15-20%, and PD in 10-12% of patients. The treatment was well tolerated. No severe adverse events occurred. Grade 3 toxicity [in leucocytes (WBC) and thrombocytes (PLT)] was seen in 6-20% of patients treated with (90)Y-DOTATATE. In that group, renal toxicity grade 3 was seen in 5-12% and grade 4 in 3-8%. In patients treated with tandem therapy with (90)Y/(177)Lu-DOTATATE or (177)Lu-DOTATATE alone, hematological and renal toxicity grade 3 or 4 was not observed. CONCLUSIONS: The results indicate that PRRT with the procedures and isotopes used is an effective and safe therapy option for patients with metastatic or inoperable neuroendocrine tumors (NETs). Our results suggest that tandem therapy with (90)Y/(177)Lu-DOTATATE provides longer overall survival than single-isotope treatment. Hematological toxicity was rare in all treated patients. Renal toxicity grade 3 and 4 was observed only in the group treated with (90)Y-DOTATATE. PMID- 22918777 TI - PRRT as neoadjuvant treatment in NET. AB - This chapter describes the possibility of using peptide receptor radionuclide therapy (PRRT) as neoadjuvant treatment. PRRT is acknowledged to be a palliative treatment. Recently it has been reported that tumor size decrease followed by surgical intervention might be achieved in patients with neuroendocrine tumors (NETs) treated with somatostatin analogs labeled with beta emitters. Such outcome of therapy has been described in a relatively small group of patients. In those patients, the treatment enabled total or partial excision of the tumor, also with liver metastases. Reduction of tumor dimensions or total excision of the tumor corresponded with prolongation of overall survival. The discussed papers on this subject differ in details of treatment (utilization of various isotopes, total activity of the isotope, or combination with radiosensitizing chemotherapy). The chapter presents a brief review of recently published manuscripts. PMID- 22918778 TI - Intraoperative somatostatin receptor detection after peptide receptor radionuclide therapy with (177)Lu- and (90)Y-DOTATOC (tandem PRRNT) in a patient with a metastatic neuroendocrine tumor. AB - AIM: The aim of this chapter is to present the results of the first intraoperative somatostatin receptor detection after peptide receptor radionuclide therapy (PRRNT) with (90)Y- and (177)Lu-DOTATOC using a handheld gamma probe and comparison with the findings of preoperative (68)Ga-DOTATOC PET/CT in a patient with a metastatic neuroendocrine tumor (NET) of the ileum. MATERIALS AND METHODS: A 56-year-old female patient, treated twice by PRRNT, was admitted for the third cycle and subsequent surgery. Before operation, the following studies were performed for restaging after the second cycle of PRRNT: (99m)Tc-MAG3 + TER, (99m)Tc-DTPA + GFR, abdominal ultrasonography, MRI of the abdomen, (68)Ga-DOTATOC PET/CT as well as (18)F-fluoride PET/CT. Serum tumor markers were measured before and after PRRNT. Tandem PRRNT was performed using 3000 MBq (90)Y-DOTATOC and 6000 MBq (177)Lu-DOTATOC. Whole-body scintigrams were obtained at 23 and 43 h. Five days after PRRNT, the patient was operated using a handheld gamma probe. Immunohistochemistry and histopathology of the resected tissue were performed. RESULTS: Tandem PRRNT was very well tolerated by the patient. Before PRRNT, (68)Ga-DOTATOC PET/CT revealed the primary tumor in the ileocoecal region as well as bilobular liver metastases and a right iliac bone lesion (osteoblastic on (18)F-fluoride PET/CT). Compared with the previous findings, there was good therapy response (partial remission of the tumor lesions). No nephrotoxicity was observed. Serum chromogranin A (836 MUg/l, n < 100) and serotonin (852 MUg/l, n < 200) were strongly elevated. Posttherapy scans showed intense uptake in metastases and the primary tumor. Intraoperative gamma probe detected-in addition to the known lesions-bilateral ovarian metastases not visualized by (68)Ga-DOTATOC PET/CT. Bilateral adnexectomy, right hemicolectomy, excision of hepatic metastases in S3, and partial resection of peritoneum were performed. Histopathology confirmed metastases in both ovaries. CONCLUSIONS: Gamma probe-guided surgery after (177)Lu PRRNT is feasible and appears to be more sensitive than (68)Ga-DOTATOC PET/CT. This technique might aid the surgeon in achieving more complete tumor resection through intraoperative detection of very small lesions (<5 mm) directly after PRRNT. PMID- 22918779 TI - Personalized image-based radiation dosimetry for routine clinical use in peptide receptor radionuclide therapy: pretherapy experience. AB - Patient-specific dose calculations are not routinely performed for targeted radionuclide therapy procedures, partly because they are time consuming and challenging to perform. However, it is becoming widely recognized that a personalized dosimetry approach can help plan treatment and improve understanding of the dose-response relationship. In this chapter, we review the procedures and essential elements of an accurate internal dose calculation and propose a simplified approach that is aimed to be practical for use in a busy nuclear medicine department. PMID- 22918780 TI - The Bad Berka dose protocol: comparative results of dosimetry in peptide receptor radionuclide therapy using (177)Lu-DOTATATE, (177)Lu-DOTANOC, and (177)Lu DOTATOC. AB - PURPOSE: The objective of this study is to analyze the in vivo behavior of the (177)Lu-labeled peptides DOTATATE, DOTANOC, and DOTATOC used for peptide receptor radionuclide therapy (PRRNT) of neuroendocrine tumors (NETs), by measuring organ and tumor kinetics and by performing dosimetric calculations. METHODS: Two hundred fifty-three patients (group 1) with metastasized NET who underwent PRRNT were examined. Out of these, 185 patients received (177)Lu-DOTATATE, 9 were treated with (177)Lu-DOTANOC, and 59 with (177)Lu-DOTATOC. Additionally, 25 patients receiving, in consecutive PRRNT cycles, DOTATATE followed by DOTATOC (group 2) and 3 patients receiving DOTATATE and DOTANOC (group 3) were analyzed. Dosimetric calculations (according to MIRD scheme) were performed using OLINDA software. RESULTS: In group 1, DOTATOC exhibited the lowest and DOTANOC the highest uptake and therefore mean absorbed dose in normal organs (whole body, kidney, and spleen). In group 2, there was a significant difference between DOTATATE and DOTATOC concerning kinetics and normal organ doses. (177)Lu-DOTATOC had the lowest uptake/dose delivered to normal organs and highest tumor-to-kidney ratio. There were no significant differences between the three peptides concerning tumor kinetics and mean absorbed tumor dose. CONCLUSIONS: The study demonstrates a correlation between high affinity of DOTANOC in vitro and high uptake in normal organs/whole body in vivo, resulting in a higher whole-body dose. DOTATOC exhibited the lowest uptake and dose delivered to normal tissues and the best tumor-to-kidney ratio. Due to large interpatient variability, individual dosimetry should be performed for each therapy cycle. PMID- 22918781 TI - 4D SPECT/CT acquisition for 3D dose calculation and dose planning in (177)Lu peptide receptor radionuclide therapy: applications for clinical routine. AB - Molecular radiotherapy combines the potential of a specific tracer (vector) targeting tumor cells with local radiotoxicity. Designing a specific tumor targeting/killing combination is a tailoring process. Radionuclides with imaging capacity serve best in the selection of the targeting molecule. The potential of targeted therapy with radiolabeled peptides has been reported in many conditions; peptide receptor radionuclide therapy (PRRT) is already part of Scandinavian guidelines for treating neuroendocrine tumors. Lu-177- and Y-90-labeled somatostatin analogs, including DOTATOC, DOTANOC, and DOTATATE, are most the commonly used and have turned out to be effective. For routine use, an efficient, rapid, and reliable dose calculation tool is needed. In this chapter we describe how serial pre- and posttherapeutic scans can be used for dose calculation and for predicting therapy doses. Our software for radionuclide dose calculation is a three-dimensional, voxel-based system. The 3D dose calculation requires coregistered SPECT image sets from several time points after infusion to reconstruct time-activity curves for each voxel. Image registration is done directly by SPECT image registration using the first time point as a target. From the time-activity curves, initial activity and total half-life maps are calculated to produce a cumulated activity map. The cumulated activity map is then convoluted with a voxel-dose kernel to obtain a 3D dose map. We performed dose calculations similarly for both therapeutic and preplanning images. Preplanning dose was extrapolated to predict therapy dose using the ratio of administered activities. Our 3D dose calculation results are also compared with those of OLINDA. Our preliminary results indicate that dose planning using pretherapeutic scanning can predict critical organ and tumor doses. In some cases, the dose planning prediction resulted in slight, and slightly dose dependent, overestimation of final therapy dose. Real tumor dose was similar in both pretherapeutic and posttherapeutic scans using our software. The OLINDA software and our program gave similar normal organ doses, whereas tumor doses could be calculated in a more detailed manner using the 3D program. PMID- 22918782 TI - Peptide receptor radionuclide therapy with (177)Lu labeled somatostatin analogs DOTATATE and DOTATOC: contrasting renal dosimetry in the same patient. AB - AIM: The aim of this study is to correlate the uptake, residence time, and resulting mean absorbed dose in the kidneys with the posttherapy effect on renal function using the two most commonly used somatostatin analogs, (177)Lu-DOTATATE and (177)Lu-DOTATOC, during consecutive cycles of peptide receptor radionuclide therapy (PRRNT) in the same patient. METHODS: 22 patients with metastatic neuroendocrine tumors underwent PRRNT with (177)Lu-DOTATATE and (177)Lu-DOTATOC. Dosimetry (MIRD scheme) was performed using OLINDA software. The patients were followed up for 6-12 months with serum creatinine, BUN, tubular extraction rate (TER) using (99m)Tc-MAG3, and glomerular filtration rate (GFR) using (99m)Tc-DTPA before and after therapy. Age, hypertension, and diabetes mellitus were the associated risk factors for renal toxicity, which were taken into account. RESULTS: Uptake, residence time, and mean absorbed dose to the kidney were slightly, but significantly, higher for DOTATATE (actual absorbed dose 1.9-9.2 Gy) as compared with DOTATOC (dose 2.3-7.8 Gy) in 19 out of the 22 (86%) patients (p < 0.05). The tumor-to-kidney ratio was higher for DOTATOC in 23 out of 43 (53%) of the lesions analyzed; however, this difference was not statistically significant. There were no statistically significant changes in serum creatinine, BUN, TER or GFR pre and post-therapy with either DOTATATE or DOTATOC. Five of the 22 patients had mildly elevated serum creatinine after PRRNT, of whom 3 had history of hypertension, 1 had diabetes, and 1 was more than 65 years of age. CONCLUSIONS: (177)Lu-DOTATATE and (177)Lu-DOTATOC are safe radiopharmaceuticals concerning renal toxicity. (177)Lu-DOTATOC delivers a slightly, but significantly, lower renal dose. PMID- 22918783 TI - Is there a correlation between peptide receptor radionuclide therapy-associated hematological toxicity and spleen dose? AB - AIM: The spleen receives a high mean absorbed radiation dose during peptide receptor radionuclide therapy (PRRNT). The aim of this study is to correlate the radiation dose to spleen with the effect on blood cell count after PRRNT. METHODS: Fifty-three neuroendocrine tumor (NET) patients were treated with 3.8 8.5 GBq (177)Lu-DOTATATE or (177)Lu-DOTATOC. Dosimetry was performed according to MIRD scheme. Eleven NET patients who had undergone splenectomy before PRRNT and who received 4.7-7.6 GBq (177)Lu-DOTATATE or (177)Lu-DOTATOC were selected as controls. RBC, WBC (total and differential), and platelet counts before and after each cycle of PRRNT were documented. RESULTS: The median dose to the spleen in the study group was 6.34 Gy (2.32-20.06 Gy). There was no significant difference in the posttherapy changes in the blood cell counts (RBC, WBC, or platelets) between the study group and the control group. Mild hematological toxicity was found in 7 of the 53 (13.2%) patients in the study group and in 1 out of the 11 patients (9.1%) in the control group. However, there was no correlation between the incidence or grade of hematological toxicity and the dose to the spleen. CONCLUSION: This study demonstrates for the first time that hematological toxicity after PRRNT is not related to the radiation dose to the spleen. PMID- 22918784 TI - Old and new peptide receptor targets in cancer: future directions. AB - A precise definition of the tumor tissue targets to be selected for in vivo peptide receptor targeting, namely to know which peptide receptor is expressed in which type of cancer, is an important prerequisite for successful clinical application of this technology. In this short review, I give three selected examples of new and promising peptide receptor targets. In the somatostatin receptor field, based on in vitro receptor autoradiography experiments showing that much more sst(2) binding sites are detected in tumors using a (177)Lu labeled sst(2) antagonist than a (177)Lu-labeled agonist, it can be proposed that, in addition to neuroendocrine tumors, nonneuroendocrine tumors with lower sst(2) levels such as breast carcinomas, renal cell carcinomas, and non-Hodgkin lymphomas may become potential candidates for sst(2) antagonist targeting. In the gastrin-releasing peptide receptor field, recent in vitro data show that not only tumor cells may overexpress gastrin-releasing peptide receptors but also neoangiogenic tumoral vessels, making tumors expressing high levels of gastrin releasing peptide receptors in tumor vessels, such as ovarian or urinary tract cancers, attractive new candidates for gastrin-releasing peptide receptor targeting. In the incretin receptor field, it was found in vitro that, apart from glucagon-like peptide 1 receptors overexpressed in benign insulinomas, incretin receptors, especially the glucose-dependent insulinotropic polypeptide receptors, can be overexpressed in medullary thyroid cancers, an unexpected finding making also these tumors potential novel candidates for incretin receptor targeting. Due to the abundance of peptide receptors in various cancers, it may be possible in the future to define for each tumor type a corresponding overexpressed peptide receptor suitable for targeting. PMID- 22918786 TI - Combined impact of exercise and temperature in learning and memory performance of fluoride toxicated rats. AB - In previous studies, we investigated a link between high fluoride exposure and functional IQ deficits in rats. This study is an extension conducted to explore the combined influence of physical exercise and temperature stress on the learning ability and memory in rats and to assess whether any positive modulation could be attenuated due to exercise regimen subjected to F-toxicated animals at different temperatures. Accumulation of ingested fluoride resulted significant inhibition in acetylcholinesterase activity (P < 0.05), plasma cortisol levels (P < 0.05), and impaired the acquisition, performance, latency time, and retention in fluoride-exposed animals. Fluoride-toxicated rats took more number of sessions during the learning phase [F (5, 35) = 19.065; P < 0.05] and post hoc analysis on the number of correct choices revealed that there was a significant effect of treatments [F (5, 30) = 15.763; P < 0.05]; sessions [F (8, 240) = 58.698; P < 0.05]; and also significant difference in the interactions [F (40, 240) = 1.583; P < 0.05]. The latency data also revealed a significant difference between groups [F (5, 30) = 28.085; P < 0.05]; time = [F (8, 240) = 136.314; P < 0.05]; and there was a significant difference in the interactions [F (40, 240) = 2.090; P < 0.05]. In order to ascertain if interdependence between fluoride concentrations and the foregoing free radical parameters, respective correlation coefficients were calculated and results clearly emphasize the positive role of exercise in the promotion of cognitive functions by decreasing fluoride levels in rat hippocampus. A significant recovery in cognitive function was noticed in all the exercised animals due to reduced burden of brain oxidative stress. In comparison to exercise regimens performed at different temperatures, high (35 degrees C) and low temperatures (20 degrees C) led to a slower acquisition and poor retention of the task when compared to thermo neutral temperatures (25 and 30 degrees C). Thus exercise up-regulate antioxidant defenses and promote learning abilities in fluorotic population. PMID- 22918787 TI - Does fluoride toxicity cause hypertension in patients with endemic fluorosis? PMID- 22918785 TI - Quercetin protects against chronic aluminum-induced oxidative stress and ensuing biochemical, cholinergic, and neurobehavioral impairments in rats. AB - In this study, we investigated the protective effect of chronic quercetin (a natural flavanoid) administration against Al-induced cognitive impairments, oxidative damage, and cholinergic dysfunction in male Wistar rats. Al lactate (10 mg/kg b.wt./day) was administered intragastrically to rats which were pre-treated with quercetin (10 mg/kg b.wt./day, intragastrically) for 12 weeks. At the end of 6 or 12 weeks of the study, several behavioral parameters were carried out to evaluate cognitive functions. Further after 12 weeks of exposure, various biochemical tests and H&E staining were performed to assess the extent of oxidative damage and neurodegeneration, respectively. Al levels were also estimated in HC and CS regions of rat brain. Chronic administration of quercetin caused significant improvement in the muscle coordination, cognition, anxiety, locomotion, and initial exploratory patterns in Al-treated rats. Quercetin supplementation to Al-treated animals also reduced oxidative stress, decreased ROS production, increased MnSOD activity and glutathione levels with decreased lipid peroxidation and protein oxidation. It increased AChE activity and ATP levels in HC and CS regions of rat brain compared to Al-treated rats. Quercetin administration ameliorates Al-induced neurodegenerative changes in Al-treated rats as seen by H&E staining. Further with the help of atomic absorption spectrophotometer, we found that quercetin supplementation to Al-treated rats also decreases the accumulation of Al in the HC and CS regions of rat brain. Taken together the results of this study show that quercetin offers neuroprotection against Al-induced cognitive impairments, cholinergic dysfunction, and associated oxidative damage in rats. PMID- 22918788 TI - The role of air pollution in adult-onset asthma: a review of the current evidence. AB - The causes of adult-onset asthma are poorly established, and the asthmogenic role of air pollution has been investigated primarily in children. This review assesses the current evidence of the association between air pollution and asthma incidence among subjects free of asthma at least until late childhood. Seven publications from five study populations fulfilled the inclusion criteria (one case-control and six cohort studies). All but one used markers of local traffic related air pollution to characterize long-term exposure. Those studies reported similar associations with traffic-related air pollution. However, protocols, definitions of asthma, and exposure assignment were rather heterogeneous, and three publications relied on the same study; thus we abstain from meta-analytic summaries. Reported patterns of effect modification (e.g., by sex, atopy, or smoking) were inconsistent. Overall, the role of traffic-related air pollution in adult-onset asthma is less conclusive than in childhood asthma. Larger studies with more consistent definitions of phenotypes and exposure assessment for local traffic-related pollutants (e.g., ultrafine particles) are needed. Pooling existing cohorts such as in the ongoing European ESCAPE and TRANSPHORM consortia are promising steps. There is, however, a need for large-scale megacohorts to investigate these effects in standardized ways and to identify the most susceptible populations. PMID- 22918789 TI - A dose escalation trial for the combination of erlotinib and sirolimus for recurrent malignant gliomas. AB - In order to achieve higher dosages than previously used in clinical trials, we conducted a phase I trial to determine the maximum tolerated dose (MTD) for the combination of erlotinib and sirolimus for the treatments of recurrent malignant gliomas. Patients with pathologically proven World Health Organization (WHO) grade III glioma and grade IV glioblastoma and radiographically proven tumor recurrence were eligible for this study. Treatments included once daily erlotinib, which was given alone for the first 7 days of treatments, then in combination with once daily sirolimus. Sirolimus was given with a loading dose on day 8 followed by a maintenance dose starting on day 9. Dose-limiting toxicity (DLT) was determined over the first 28 days of treatments, and the MTD was determined in a 3 + 3 classic study design. 19 patients were enrolled, and 13 patients were eligible for MTD determination. The MTD was determined to be 150 mg daily for erlotinib and 5 mg daily (after a 15 mg loading dose) for sirolimus. The DLTs included rash and mucositis (despite maximal medical managements), hypophosphatemia, altered mental status, and neutropenia. The combination of erlotinib and sirolimus is difficult to tolerate at dosages higher than previously reported in phase II trials. PMID- 22918790 TI - CDA-2 induces cell differentiation through suppressing Twist/SLUG signaling via miR-124 in glioma. AB - Cell differentiation agent-2 (CDA-2) is an extraction from healthy human urine consisting of primary organic acids and peptides, and it has been demonstrated to inhibit growth and induce differentiation in glioma and other cell lines. But the mechanism of CDA-2 remains unclear. In this study, we demonstrated that CDA-2 inhibited cell growth and induced differentiation of glioma cells, accompanied with decreased expression of SLUG, Twist and Vimentin in both SWO-38 and U251 cell lines. Overexpression of SLUG or Twist greatly eliminated the efficiency of CDA-2 in inducing differentiation. Further study showed that CDA-2 treatment resulted in great changed microRNAs (miRNAs) detected by quantitative PCR, in which miR-124 was one of the most changed miRNAs and its level was increased by fourfold. The result of miRNA target prediction showed that miR-124 could regulate hundreds of genes which were relative to cell differentiation, such as SLUG, Vimentin, actin cytoskeleton, focal adhesion, tight junction. Inhibition of miR-124 up-regulated SLUG, Twist and Vimentin proteins, and partly eliminated the function of CDA-2 on these mesenchymal markers. Our findings demonstrated for the first time that CDA-2 induced cell differentiation through suppressing Twist and SLUG via miR-124 in glioma cells. PMID- 22918791 TI - Characterization of vitellogenin and its derived yolk proteins in cloudy catshark (Scyliorhinus torazame). AB - Elasmobranchs (sharks and rays) exhibit unique reproductive characteristics and, in contrast to the situation in teleosts, very little is known about the identity, structure and physical characteristics of their egg yolk proteins. The aims of this study were to (1) detect and purify the vitellogenin (Vtg; egg yolk precursor) and yolk proteins (YPs) of the cloudy catshark (Scyliorhinus torazame), (2) examine the relationships between Vtg and YPs and (3) characterize and classify the deduced primary structure of the Vtg transcript (vtg). The apparent molecular weights of purified Vtg and putative Vtg-related YPs (lipovitellin: Lv, phosvitin: Pv) were determined by gel filtration and were ~560, >669 and ~58 kDa, respectively. Following SDS-PAGE, these purified products (i.e., Vtg, Lv and Pv) appeared as bands of ~210, ~110 and ~22 kDa, respectively. On Western blots, antisera against purified Vtg, Lv and Pv recognized the ~210 kDa Vtg band. Catshark Pv, in contrast to teleost Pvs, had a very low serine content. The catshark Vtg cDNA sequence (vtg) appeared to contain an open-reading frame consisting of domains encoding Lv, Pv and beta'-component (beta'-c). A phylogenetic analysis, with a consideration of genome duplication events, placed catshark vtg into the 'vtgAB type.' It is concluded that at least a single major type of Vtg protein, which is transcribed and translated from catshark vtgAB gene, is the precursor of three egg yolk proteins (Lv, Pv and beta'-c) in catshark. PMID- 22918792 TI - Development of a substrate-coupled biocatalytic process driven by an NADPH dependent sorbose reductase from Candida albicans for the asymmetric reduction of ethyl 4-chloro-3-oxobutanoate. AB - A substrate-coupled biocatalytic process was developed based on the reactions catalyzed by an NADPH-dependent sorbose reductase (SOU1) from Candida albicans in which ethyl 4-chloro-3-oxobutanoate (COBE) was reduced to (S)-4-chloro-3 hydroxybutanoate [(S)-CHBE], while NADPH was regenerated by the same enzyme via oxidation of sugar alcohols. (S)-CHBE yields of 1,140, 1,150, and 780 mM were obtained from 1,220 mM COBE when sorbitol, mannitol, and xylitol were used as co substrates, respectively. Optimization of COBE and sorbitol proportions resulted in a maximum yield of (S)-CHBE (2,340 mM) from 2,500 mM COBE, and the enantiomeric excess was 99.6 %. The substrate-coupled system driven by SOU1 maintained a stable pH and a robust intracellular NADPH circulation; thus, pH adjustment and addition of extra coenzymes were unnecessary. PMID- 22918793 TI - Biodegradation of mono-hydroxylated PCBs by Burkholderia xenovorans. AB - Three hydroxylated derivatives of PCBs, 2'-hydroxy-4-chlorobiphenyl (2'-OH-4-CB), 3'-hydroxy-4-chlorobiphenyl (3'-OH-4-CB), and 4'-hydroxy-4-chlorobiphenyl (4'-OH 4-CB), were transformed by the PCB degrader, Burkholderia xenovorans. When the bacterium was growing on biphenyl (biphenyl pathway-inducing conditions), all three hydroxylated isomers were transformed. However, only 2'-OH-4-CB was transformed by the bacterium growing on succinate (conditions non-inductive of the biphenyl pathway). Gene expression analyses showed a strong induction of key genes of the biphenyl pathway (bph) when cells were grown on biphenyl, which is consistent with the transformation of the three isomers by biphenyl-grown cells. When cells were grown on succinate, only exposure to 2'-OH-4-CB resulted in expression of biphenyl pathway genes, which suggests that this isomer was capable of inducing the biphenyl pathway. These results provide the first evidence that bacteria are able to metabolize PCB derivatives hydroxylated on the non chlorinated ring. PMID- 22918794 TI - Targeting neuroendocrine tumor: mixing standard options with novel therapies. PMID- 22918795 TI - Quality and readability of information materials for people with brain tumours and their families. AB - Written information is commonly used to inform patients about their disease and treatment but must be evidence-based and understandable to be useful. This study assessed the quality of the content and the readability of information brochures for people affected by brain tumours. We randomly selected 18 publicly available brochures. Brochures were assessed by criteria to assess the quality of content using the DISCERN instrument. Readability was tested using three commonly used formulas, which yield the reading grade level required to comprehend the brochure (sixth grade level recommended). The mean overall DISCERN score was 3.17 out of a maximum of 5 (moderate quality); only one achieved a rating greater than 4 (high quality). Only one brochure met the sixth grade readability criteria. Although brochures may have accurate content, few satisfied all of the recommended criteria to evaluate their content. Existing brochures need to be critically reviewed and simplified and consumer-focused brochures, produced. PMID- 22918796 TI - Relative quality of internet-derived gastrointestinal cancer information. AB - Internet-derived health care information is increasingly accessed by patients, yet its quality and accuracy is variable and unregulated. The aim of this study was to assess the information available regarding common gastrointestinal cancers via three internet search engines (Google, Yahoo and Bing). The top 30 websites for each of the terms: oesophageal, gastric, pancreatic, colon and rectal cancer were evaluated (University of Michigan Consumer Health Website Checklist) and scored [-80 (poor) to 90 (excellent)]. The median score was 53 (-7 to 81) and was significantly higher for oesophageal (61) and pancreatic (65) cancer websites, compared with gastric (49), colon (48) and rectal cancer (50) (p = 0.014). Median scores related to charitable organisations were significantly better than academic, commercial, news agency, care provider, layperson and medical information websites collectively (79 vs. 42, p < 0.0001). Overall quality of internet-derived gastrointestinal cancer information remains poor and patients and clinicians should be aware. PMID- 22918797 TI - Knowledge about cervical cancer, pap test and barriers towards cervical screening of women in Turkey. AB - We aimed to identify knowledge about cervical cancer (CC) and Pap test (PT) and the barriers why women do not have Pap test done. The study was conducted with a sample of 1,036 women. Overall, 64.4 % had heard of CC, 43.1 % had heard about PT and 24.7 % had had a test at least once. It was determined that women had moderate knowledge of cervical cancer but poor knowledge of Pap test. Knowledge of CC and PT was significantly better among employed and single women, who had higher education, no prior delivery, a higher income level and regular gynaecological examination. Common barriers to PT were lack of awareness, being uncomfortable with the procedure and not knowing where to go for a PT. Utilization of the PT will not increase unless knowledge is improved and barriers are eliminated. Healthcare professionals are the key persons to provide both knowledge and facilities towards the goal of CC prevention. PMID- 22918798 TI - Post-transcriptional control of gene expression during mouse oogenesis. AB - Post-transcriptional mechanisms play a central role in regulating gene expression during oogenesis and early embryogenesis. Growing oocytes accumulate an enormous quantity of messenger RNAs (mRNAs), but transcription decreases dramatically near the end of growth and is undetectable during meiotic maturation. Following fertilization, the embryo is initially transcriptionally inactive and then becomes active at a species-specific stage of early cleavage. Meanwhile, beginning during maturation and continuing after fertilization, the oocyte mRNAs are eliminated, allowing the embryonic genome to assume control of development. How the mammalian oocyte manages the storage, translation, and degradation of the huge quantity and diversity of mRNAs that it harbours has been the focus of enormous research effort and is the subject of this review. We discuss the roles of sequences within the 3'-untranslated region of certain mRNAs and the proteins that bind to them, sequence-non-specific RNA-binding proteins, and recent studies implicating ribonucleoprotein processing (P-) bodies and cytoplasmic lattices. We also discuss mechanisms that may control the temporally regulated translational activation of different mRNAs during meiotic maturation, as well as the signals that trigger silencing and degradation of the oocyte mRNAs. We close by highlighting areas for future research including the potential key role of small RNAs in regulating gene expression in oocytes. PMID- 22918799 TI - Polarity and asymmetry during mouse oogenesis and oocyte maturation. AB - Cell polarity and asymmetry play a fundamental role in embryo development. The unequal segregation of determinants, cues, and activities is the major event in the differentiation of cell fate and function in all multicellular organisms. In oocytes, polarity and asymmetry in the distribution of different molecules are prerequisites for the progression and proper outcome of embryonic development. The mouse oocyte, like the oocytes of other mammals, seems to apply a less stringent strategy of polarization than other vertebrates. The mouse embryo undergoes a regulative type of development, which permits the full rectification of development even if the embryo loses up to half of its cells or its size is experimentally doubled during the early stages of embryogenesis. Such pliability is strongly related to the proper oocyte polarization before fertilization. Thus, the molecular mechanisms leading to the development and maintenance of oocyte polarity must be included in any fundamental understanding of the principles of embryo development. In this chapter, we provide an overview of current knowledge regarding the development and maintenance of polarity and asymmetry in the distribution of organelles and molecules in the mouse oocyte. Curiously, the mouse oocyte becomes polarized at least twice during ontogenesis; the question of how this phenomenon is achieved and what role it might play is addressed in this chapter. PMID- 22918800 TI - Chromatin structure and ATRX function in mouse oocytes. AB - Differentiation of chromatin structure and function during oogenesis is essential to confer the mammalian oocyte with meiotic and developmental potential. Errors in chromosome segregation during female meiosis and subsequent transmission of an abnormal chromosome complement (aneuploidy) to the early conceptus are one of the leading causes of pregnancy loss in women. The chromatin remodeling protein ATRX (alpha-thalassemia mental retardation X-linked) has recently emerged as a critical factor involved in heterochromatin formation at mammalian centromeres during meiosis. In mammalian oocytes, ATRX binds to centromeric heterochromatin domains where it is required for accurate chromosome segregation. Loss of ATRX function induces abnormal meiotic chromosome morphology, reduces histone H3 phosphorylation, and promotes a high incidence of aneuploidy associated with severely reduced fertility. The presence of centromeric breaks during the transition to the first mitosis in the early embryo indicates that the role of ATRX in chromosome segregation is mediated through an epigenetic mechanism involving the maintenance of chromatin modifications associated with pericentric heterochromatin (PCH) formation and chromosome condensation. This is consistent with the existence of a potential molecular link between centromeric and PCH in the epigenetic control of centromere function and maintenance of chromosome stability in mammalian oocytes. Dissecting the molecular mechanisms of ATRX function during meiosis will have important clinical implications towards uncovering the epigenetic factors contributing to the onset of aneuploidy in the human oocyte. PMID- 22918801 TI - Cyclin B in mouse oocytes and embryos: importance for human reproduction and aneuploidy. AB - Oocyte maturation and early embryo development require precise coordination between cell cycle progression and the developmental programme. Cyclin B plays a major role in this process: its accumulation and degradation is critical for driving the cell cycle through activation and inactivation of the major cell cycle kinase, CDK1. CDK1 activation is required for M-phase entry whereas its inactivation leads to exit from M-phase. The tempo of oocyte meiotic and embryonic mitotic divisions is set by the rate of cyclin B accumulation and the timing of its destruction. By controlling when cyclin B destruction is triggered and by co-ordinating this with the completion of chromosome alignment, the spindle assembly checkpoint (SAC) is a critical quality control system important for averting aneuploidy and for building in the flexibility required to better integrate cell cycle progression with development. In this review we focus on cyclin B metabolism in mouse oocytes and embryos and illustrate how the cell cycle-powered clock (in fact cyclin B-powered clock) controls oocyte maturation and early embryo development, thereby providing important insight into human reproduction and potential causes of Down syndrome. PMID- 22918802 TI - Src protein kinases in mouse and rat oocytes and embryos. AB - Meiosis of the mammalian oocytes is a specialized cell division, initiated during the female's embryonic life. It arrests at the germinal vesicle (GV) stage and resumes with GV breakdown, followed by segregation of the chromosomes and extrusion of the first polar body in an asymmetric cell division that concludes the first meiotic division, before arresting at metaphase of the second meiotic division (MII). Once fertilized, the oocyte exits from MII, extrudes the second polar body, and the developing zygote will continue dividing to create a blastocyst. Although the two processes of meiosis and mitosis have different developmental functions, it is believed that they share similar mechanisms. Src family kinases (SFKs) are nine non-receptor protein tyrosine kinases that regulate many key cellular functions including meiotic and mitotic cell cycles. In this review we discuss the involvement of SFKs in meiotic and mitotic cell cycle key processes as nuclear envelope breakdown, spindle stabilization, karyokinetic exit from metaphase, regulation of cortical actin, and cytokinetic cleavage furrow ingression. PMID- 22918803 TI - Gradual meiosis-to-mitosis transition in the early mouse embryo. AB - The transition from meiosis to mitosis is a fundamental process to guarantee the successful development of the embryo. In the mouse, the transition includes extensive reorganisation of the division machinery, centrosome establishment and changes in spindle proprieties and characteristic. Recent findings indicate that this transition is gradual and lasts until the late blastocyst stage. In-depth knowledge of the mechanisms underlying the transition would provide new insight into de novo centrosome formation and regulation of spindle size and proprieties. Here, we review recent advances in the understanding of acentrosomal spindle formation, centriole establishment and the meiosis-to-mitosis transition in the mouse pre-implantation embryo. PMID- 22918804 TI - Maternal control of mouse preimplantation development. AB - Mammalian preimplantation development is a process of dedifferentiation from the terminally differentiated eggs to the totipotent blastomeres at the cleavage stage, and then to the pluripotent cells at the blastocyst stage. Maternal factors that accumulate during oogenesis dominate early preimplantation development until the embryonic factors gain control after the activation of the embryonic genome. Recently, a handful of maternal factors that are encoded by the maternal-effect genes have been characterized in genetically modified mouse models. These factors are shown to participate in many aspects of preimplantation development, such as the degradation of maternal macromolecues, epigenetic modification, protein translation, cellular signaling transduction, and cell compaction. Even so, little is known about the interactions between different maternal factors. In this chapter, we have summarized the functions of known maternal factors and hopefully this will lead to a better understanding of the regulation of preimplantation embryogenesis by the maternal regulatory network. PMID- 22918805 TI - Preimplantation mouse embryo: developmental fate and potency of blastomeres. AB - During the past decade we have witnessed great progress in the understanding of cellular, molecular, and epigenetic aspects of preimplantation mouse development. However, some of the issues, especially those regarding the nature and regulation of mouse development, are still unresolved and controversial and raise heated discussion among mammalian embryologists. This chapter presents different standpoints and various research approaches aimed at examining the fate and potency of cells (blastomeres) of mouse preimplantation embryo. In dealing with this subject, it is important to recognize the difference between the fate of blastomere and the prospective potency of blastomere, with the first being its contribution to distinct tissues during normal development, and the second being a full range of its developmental capabilities, which can be unveiled only by experimental perturbation of the embryo. Studies of the developmental potential and the fate of blastomeres are of the utmost importance as they may lead to future clinical application in reproductive and regenerative medicine. PMID- 22918808 TI - Formation of distinct cell types in the mouse blastocyst. AB - Early development of the mouse comprises a sequence of cell fate decisions in which cells are guided along a pathway of restricted potential and increasing specialisation. The first choice faced by cells of the embryo is whether to become trophectoderm (TE) or inner cell mass (ICM); TE is an extra-embryonic tissue which will form the embryonic portion of the placenta, whilst ICM gives rise to cells responsible for generating the foetus. In the second cell fate decision, the ICM is further refined into pluripotent cells forming the future body of the embryo, epiblast (EPI) and extra-embryonic primitive endoderm (PE), a tissue essential for patterning the embryo and establishing the developmental circulation. Understanding this early lineage segregation is critical for informing attempts to capture pluripotency and direct cell fate in vitro. Unlike the predictability of nonmammalian cell fate, development of the mouse embryo retains the flexibility to adapt to changing circumstances during development. Here we describe these first cell fate decisions, how they can be biased whilst maintaining flexibility and, finally, some of the molecular circuitry underlying early fate choice. PMID- 22918806 TI - Creation of trophectoderm, the first epithelium, in mouse preimplantation development. AB - Trophectoderm (TE) is the first cell type that emerges during development and plays pivotal roles in the viviparous mode of reproduction in placental mammals. TE adopts typical epithelium morphology to surround a fluid-filled cavity, whose expansion is critical for hatching and efficient interaction with the uterine endometrium for implantation. TE also differentiates into trophoblast cells to construct the placenta. This chapter is an overview of the cellular and molecular mechanisms that control the critical aspects of TE formation, namely, the formation of the blastocyst cavity, the expression of key transcription factors, and the roles of cell polarity in the specification of the TE lineage. Current gaps in our knowledge and challenging issues are also discussed that should be addressed in future investigations in order to further advance our understanding of the mechanisms of TE formation. PMID- 22918809 TI - Cell movements in the egg cylinder stage mouse embryo. PMID- 22918807 TI - Cell lineage allocation within the inner cell mass of the mouse blastocyst. AB - At the time of implantation, the early mouse embryo consists of three distinct cell lineages: the epiblast (EPI), primitive endoderm (PrE), and trophectoderm (TE). Here we will focus on the EPI and PrE cell lineages, which arise within the inner cell mass (ICM) of the blastocyst. Though still poorly understood, our current understanding of the mechanisms underlying this lineage allocation will be discussed. It was originally thought that lineage choice was strictly controlled by the position of a cell within the ICM. However, it is now believed that the EPI and PrE lineages are defined both by their position and by the expression of lineage-specific transcription factors. Interestingly, these lineage-specific transcription factors are initially co-expressed in early ICM cells, suggesting an initial multi-lineage priming state. Thereafter, lineage specific transcription factors display a mutually exclusive salt-and-pepper distribution that reflects cell specification of the EPI or PrE fates. Later on, lineage segregation and likely commitment are completed with the sequestration of PrE cells to the surface of the ICM, which lies at the blastocyst cavity roof. We discuss recent advances that have focused on elucidating how the salt-and-pepper pattern is established and then resolved within the ICM, leading to the correct apposition of cell lineages in preparation for implantation. PMID- 22918810 TI - Balancing the dose in the mouse. AB - Organisms that use a chromosomal basis of sex determination have a problem of gene inequality. In the mouse, this dimorphism is evident by the presence of two X-chromosomes in females, while males have a single X- and a single Y-chromosome. To balance this disparity, one of the two female X-chromosomes is transcriptionally silenced to neutralize the gene dose with the XY male. Dosage compensation in mammals is known as X-chromosome inactivation (XCI) and is a crucial early developmental process. XCI is an example of epigenetics: a phenotype resulting in changes on a chromosome without a change in nucleic acid sequence. Studies in mouse embryology and genetics have answered many questions about the process of balancing the dose. In this chapter, I highlight how the mouse dosage compensates the gene disparity between XX females and XY males in a crucial epigenetic process called X-chromosome inactivation (XCI). PMID- 22918811 TI - Mouse oviduct development. AB - The oviduct, or Fallopian tube in humans, transports oocytes and sperm, serves as the site of fertilization, and supports early embryonic development. The oviduct is essential for fertility. In the mouse, the oviduct is a coiled, complex structure that develops from the simple embryonic Mullerian duct. The oviduct consists of four segments, including the infundibulum, ampulla, isthmus, and uterotubal junction. Additionally, the mouse oviduct forms coils, develops longitudinal folds, and undergoes both mesenchymal and epithelial differentiation. Oviduct development and differentiation occurs perinatally. Several signaling pathways have been found to be involved in oviduct formation, such as Wnt, Tgfbeta, microRNA processing, as well as others. Overall, the process of oviduct development is poorly understood and can be utilized to further knowledge of epithelial-mesenchymal interactions, regulation of coiling, characteristics of pseudostratified epithelia, and smooth muscle differentiation. PMID- 22918812 TI - Cell lineages, growth and repair of the mouse heart. AB - The formation of the heart involves diversification of lineages which differentiate into distinct cardiac cell types or contribute to different regions such as the four cardiac chambers. The heart is the first organ to form in the embryo. However, in parallel with the growth of the organism, before or after birth, the heart has to adapt its size to maintain pumping efficiency. The adult heart has only a mild regeneration potential; thus, strategies to repair the heart after injury are based on the mobilisation of resident cardiac stem cells or the transplantation of external sources of stem cells. We discuss current knowledge on these aspects and raise questions for future research. PMID- 22918813 TI - Cellular reprogramming during mouse development. AB - States of terminal cell differentiation are often considered to be fixed. There are examples, however, in which cells of one type can be converted to a completely different cell type. The process whereby one cell type can be converted to another is referred to as cellular reprogramming. Cellular reprogramming is also referred to in the literature as transdifferentiation (or the direct conversion of one cell type to another without dedifferentiation to an intermediate cell type). Where the conversion between cell types occurs in the developing embryo, the process is referred to as transdetermination. Herein we examine some well-defined examples of transdetermination. Defining the molecular and cellular basis of transdetermination will help us to understand the normal developmental biology of the cells that interconvert, as well as identifying key regulatory transcription factors (master switch genes) that may be important for the reprogramming of stem cells. Harnessing the therapeutic potential of reprogramming and master genes is an important goal in regenerative medicine. PMID- 22918814 TI - Differentiation of definitive endoderm from mouse embryonic stem cells. AB - Efficient production of definitive endoderm from embryonic stem (ES) cells opens doors to the possibilities of differentiation of endoderm-derived tissues such as the intestines, pancreas, and liver that could address the needs of people with chronic diseases involving these organs. The lessons learned from developmental biology have contributed significantly to in vitro differentiation of definitive endoderm. Gastrulation, a process that results in the production of all three embryonic germ cell layers, definitive endoderm, mesoderm, and ectoderm, is an important step in embryonic development. Gastrulation occurs as a result of the events that are orchestrated by the signaling pathways involving Nodal, FGF, Wnt, and BMP. Understanding these signaling pathways has led to the introduction of key ingredients such as Activin A, FGF, Wnt, and BMP to the differentiation protocols that have been able to produce definitive endoderm from ES cells. Efficient production of definitive endoderm needs to meet the specific criteria that include (a) increase in the production of markers of definitive endoderm such as Sox 17, FOXA2, GSC, and Mixl1; (b) decrease in the production of markers of primitive/visceral/parietal endoderm, Sox 7 and OCT4; and (c) decrease in the mesoderm markers (Brachyury, MEOX) and ectoderm markers (Sox1 and ZIC1). PMID- 22918815 TI - Mouse and human pluripotent stem cells and the means of their myogenic differentiation. AB - Pluripotent stem cells, such as embryonic stem cells and induced pluripotent stem cells, are an important tool in the studies focusing at the differentiation of various cell types, including skeletal myoblasts. They are also considered as a source of the cells that due to their pluripotent character and availability could be turned into any required tissue and then used in future in regenerative medicine. However, the methods of the derivation of some of cell types from pluripotent cells still need to be perfected. This chapter summarizes the history and current advancements in the derivation and testing of pluripotent stem cells derived skeletal myoblasts. It focuses at the in vitro methods allowing the differentiation of stem cells grown in monolayer or propagated as embryoid bodies, and also at in vivo tests allowing the verification of the functionality of obtained skeletal myoblasts. PMID- 22918817 TI - Mouse-induced pluripotent stem cells. PMID- 22918818 TI - Aging in the mouse and perspectives of rejuvenation through induced pluripotent stem cells (iPSCs). AB - The mouse is a perfect model to study aging in mammals. It has a relatively short life span and genetic manipulations in this species are well established. Most interestingly, the mouse is a fantastic tool to produce stem cells. Forced expression of only four transcription factors (Oct3/4, Sox2, Klf4, and c-Myc) in murine and human somatic cells resets the expression of genes that are characteristic of differentiated cells and consequently induces the formation of pluripotent stem cells (iPSCs). This technology opens new and exciting possibilities in medical research, especially personalized cell therapies for treating human disease. To treat damaged tissues or repair organs in elderly patients, it will be necessary to establish iPSCs from their tissues. To determine the feasibility of using this technology with elderly patients, we asked whether it was indeed possible to establish iPSCs from the tissues of aged mice and to differentiate them to tissue cells. We succeeded in establishing iPSC clones using bone marrow (BM) from 21-month-old EGFP-C57BL/6 mice, which had been cultured for 4 days in the presence of granulocyte macrophage-colony stimulating factor (GM-CSF). Our iPSCs from aged mice (aged iPSCs) and those from mouse embryonic fibroblasts (MEFs) strongly expressed SSEA-1 and Pou5f1, and showed strong alkaline phosphatase (AP) activity. Our aged iPSCs made teratomas when injected into the back skin of syngeneic mice, and differentiated to tissue cells of three germ lines in vitro. Further experiments to make chimeric mice and germ line cells will determine whether the aged iPSCs possess the properties of much younger cells and are capable of regenerating aged mice. PMID- 22918816 TI - Stem cells and corneal epithelial maintenance: insights from the mouse and other animal models. AB - Maintenance of the corneal epithelium is essential for vision and is a dynamic process incorporating constant cell production, movement and loss. Although cell based therapies involving the transplantation of putative stem cells are well advanced for the treatment of human corneal defects, the scientific understanding of these interventions is poor. No definitive marker that discriminates stem cells that maintain the corneal epithelium from the surrounding tissue has been discovered and the identity of these elusive cells is, therefore, hotly debated. The key elements of corneal epithelial maintenance have long been recognised but it is still not known how this dynamic balance is co-ordinated during normal homeostasis to ensure the corneal epithelium is maintained at a uniform thickness. Most indirect experimental evidence supports the limbal epithelial stem cell (LESC) hypothesis, which proposes that the adult corneal epithelium is maintained by stem cells located in the limbus at the corneal periphery. However, this has been challenged recently by the corneal epithelial stem cell (CESC) hypothesis, which proposes that during normal homeostasis the mouse corneal epithelium is maintained by stem cells located throughout the basal corneal epithelium with LESCs only contributing during wound healing. In this chapter we review experimental studies, mostly based on animal work, that provide insights into how stem cells maintain the normal corneal epithelium and consider the merits of the alternative LESC and CESC hypotheses. Finally, we highlight some recent research on other stem cell systems and consider how this could influence future research directions for identifying the stem cells that maintain the corneal epithelium. PMID- 22918819 TI - Implementing quality by design in pharmaceutical salt selection: a modeling approach to understanding disproportionation. AB - PURPOSE: Salts of active pharmaceutical ingredients are often used to enhance solubility, dissolution rate, or take advantage of other improved solid-state properties. The selected form must be maintained during processing and shelf-life to ensure quality. We aimed to develop a model to quantify risk of disproportionation, where the salt dissociates back to the freebase form. METHODS: A mechanistic model based on thermodynamics was built to predict disproportionation. Stress testing of molecules in combination with excipients was used to benchmark model predictions. X-ray powder diffraction and solid-state NMR were used to quantify the formation of freebase experimentally. RESULTS: 13 pharmaceutical compounds were screened in 4 formulations containing different combinations of excipients. The test set spanned molecules which did and did not disproportionate and also formulations which did and did not induce disproportionation. Model predictions were in qualitative agreement with the experimental data, recovering trends of how disproportionation varies with humidity, formulation excipients, base pK(a) and solubility of the API. CONCLUSIONS: The model can predict the balance between different driving forces for disproportionation with limited experimental data resulting in a tool to aid in early-phase risk assessment and formulation design with respect to disproportionation. PMID- 22918822 TI - [Editorial]. PMID- 22918821 TI - Methadone but not morphine inhibits lubiprostone-stimulated Cl- currents in T84 intestinal cells and recombinant human ClC-2, but not CFTR Cl- currents. AB - In clinical trials, methadone, but not morphine, appeared to prevent beneficial effects of lubiprostone, a ClC-2 Cl(-) channel activator, on opioid-induced constipation. Effects of methadone and morphine on lubiprostone-stimulated Cl(-) currents were measured by short circuit current (Isc) across T84 cells. Whole cell patch clamp of human ClC-2 (hClC-2) stably expressed in HEK293 cells and in a high expression cell line (HEK293EBNA) as well as human CFTR (hCFTR) stably expressed in HEK293 cells was used to study methadone and morphine effects on recombinant hClC-2 and hCFTR Cl(-) currents. Methadone but not morphine inhibited lubiprostone-stimulated Isc in T84 cells with half-maximal inhibition at 100 nM. Naloxone did not affect lubiprostone stimulation or methadone inhibition of Isc. Lubiprostone-stimulated Cl(-) currents in hClC-2/HEK293 cells, but not forskolin/IBMX-stimulated Cl(-) currents in hCFTR/HEK293 cells, were inhibited by methadone, but not morphine. HEK293EBNA cells expressing hClC-2 showed time dependent, voltage-activated, CdCl2-inhibited Cl(-) currents in the absence (control) and the presence of lubiprostone. Methadone, but not morphine, inhibited control and lubiprostone-stimulated hClC-2 Cl(-) currents with half maximal inhibition at 100 and 200-230 nM, respectively. Forskolin/IBMX-stimulated hClC-2 Cl(-) currents were also inhibited by methadone. Myristoylated protein kinase inhibitor (a specific PKA inhibitor) inhibited forskolin/IBMX- but not lubiprostone-stimulated hClC-2 Cl(-) currents. Methadone caused greater inhibition of lubiprostone-stimulated currents added before patching (66.1 %) compared with after patching (28.7 %). Methadone caused inhibition of lubiprostone-stimulated Cl(-) currents in T84 cells and control; lubiprostone- and forskolin/IBMX-stimulated recombinant hClC-2 Cl(-) currents may be the basis for reduced efficacy of lubiprostone in methadone-treated patients. PMID- 22918823 TI - [Clinical and radiological mid-term results after autologous osteochondral transplantation under consideration of quality of life]. AB - BACKGROUND: Treatment of full-thickness cartilage defects remains a challenge in musculoskeletal surgery. Autologous osteochondral transplantation represents a possible solution for the repair of affected areas. However, some problems like degenerative changes of the transplanted cylinders and the surrounding cartilage or lack of cylinder integration to the surrounding cartilage arise with this method. Thus mid-term results respecting the quality of life are useful for assessment of the method. PATIENTS/MATERIAL AND METHODS: We investigated 22 patients with a mean follow-up of 88 +/- 14.5 months after autologous osteochondral transplantation due to a full-thickness cartilage defect of the medial femoral condyle. Beside clinical scores we assessed at follow-up the quality of life using the SF-36 health survey and the EQ-5D. Furthermore, radiological changes were detected and MRI was performed in 21 patients. A control group of 19 patients, treated with microfracture, was matched in terms of BMI, gender and age. Exclusion criteria for this group were tibial kissing lesion, ligament instability, arthrosis and malalignment. RESULTS: In a longitudinal comparison with results 13.5 months after operation, no difference in Lysholm score was found. In plain radiographs higher degrees of arthritic changes in the medial compartment compared to the unaffected knee were observed. MRI revealed a mean modified MOCART score of 41.2 +/- 7.7 for the OAT group and of 39.4 +/- 16.1 for the microfracture group, without being significant. For OAT patients all cylinders showed an osseous integration. However, cylinder oedema was found in 9 patients. Those patients had a higher intensity of pain on a visual analogue scale. Quality of life was better for OAT patients in the physical scale of SF-36, but not in the mental scale. CONCLUSION: Autologous osteochondral transplantation has an unaltered significance in treating full thickness cartilage defects and leads to satisfying mid-term results. The development of early arthritic changes might not be preventable by this method. Oedema of the transplanted cylinders is attended by higher pain intensity and might be an indirect sign of cartilage degeneration. PMID- 22918824 TI - [Total knee arthroplasty in post-traumatic osteoarthritis]. AB - BACKGROUND: This study aims to analyse the outcome and the complications after total knee arthroplasty in post-traumatic osteoarthritis in comparison to TKA in patients with degenerative osteoarthritis. PATIENTS AND METHODS: In a period of six years 43 patients with a post-traumatic osteoarthritis were treated with a total knee arthroplasty (group PT). 38 (88 %) patients (age median 55 years, 22 female, 16 male) were investigated clinically and radiologically after an average follow-up time of 2.7 years. The OKS (Oxford Knee Score, max. 48 points), the Knee Society Scores "function" (max. 100 points) and "knee" (max. 100 points) as well as the visual analogue scale (VAS, 0 to 10 points) were recorded preoperatively and at follow-up. For comparison we chose a matched-pair selection of patients with degenerative osteoarthritis and TKA (group DO, age median 63 years, 22 female, 16 male). For statistical analysis we used common parametric tests (Wilcoxon and U test) and a level of significance of 0.05. RESULTS: In 19 patients (50 %) of the group PT the osteoarthritis was caused by a bone injury. Furthermore in 19 patients a meniscal and/or ligamentous injury led to osteoarthritis. Out of all patients of group PT, 10 patients showed a preoperative valgus malalignment higher than 10 degrees . KSS knee and KSS function added up to 76.9 and 84.9 points. So they are significantly less than in the matched group (DO, knee: 86.1; function: 94.4). Similarly, the OKS is significantly less in group PT after follow-up (PT: 32.3; DO: 38.4, p <= 0.05) although the preoperative values are equal in both groups. The VAS value decreased significantly in both groups. Initial level of pain was significantly higher in the group DO compared to the group PT. Patients with osteoarthritis after trauma showed complications in 17 cases (^ = 44.7 %) that led to 28 revision operations (^ = 0.7 operations per knee). The group with valgus malalignment had a revision rate of 1.4 operations per knee. In the group DO 8 complications occurred (^ = 21,1 %) that led to 11 revision operations (^=0.3 per knee). The deviation from the "ideal" leg axis could be reduced from 3.8 degrees varus to 1.7 degrees varus in the group DO and from 1.3 degrees valgus auf 1.2 degrees valgus in the group PT. Patients with a preoperative valgus deviation > 10 degrees were reduced from 13.6 degrees (+/- 3.9 degrees ) valgus to 0.5 degrees (+/- 9.2 degrees ) varus. CONCLUSION: Patients after TKA because of post traumatic osteoarthritis show worse results concerning function and condition compared to patients with degenerative osteoarthritis. Heterogeneous pathogenesis and high rates of revision operations underline the complexity of this group of patients. The treatment has to be adjusted to the patient's requirements as well to the pathoanatomy. PMID- 22918825 TI - [Radiofrequency kyphoplasty - an innovative method for the treatment of vertebral compression fractures - comparison with conservative treatment]. AB - OBJECTIVE: An evaluation of treatment protocols was used to expand the documentation of efficacy and safety of radiofrequency kyphoplasty (RFK). Additionally, a comparison of this new and innovative procedure with conservative treatment was carried out. PATIENTS, MATERIALS AND METHODS: Patients with painful osteoporotic vertebral fractures according to the common findings in an orthopaedic university hospital were included in the comparison study in which the indication for surgical intervention action according to the DVO guidelines was interdisciplinary confirmed. For the comparison group, patients with the same clinical and radiological findings were recruited who rejected a surgical intervention. For surgery, the StabiliT(r) Vertebral Augmentation System for a radiofrequency kyphoplasty by the company DFine was used. The cement was injected with a "multiplex controller". Thus, the results of the new method were compared to those of a group that was treated conservatively. RESULTS: The radiofrequency kyphoplasty (n = 114) resulted in an average decrease of VAS scores by almost 60 mm, which increased during the follow-up. Similarly, the Oswestry scores showed a marked improvement by 46 % points after 6 weeks. The mean increase in vertebral body height was 2.8 mm after radiofrequency kyphoplasty. In the conservatively treated group only very small changes compared to the initial findings were registered during the 6-week observation period. Accordingly, 33 of 67 patients decided after 6 weeks for surgery, which led to corresponding improvements (VAS, Oswestry, vertebral body height). Noteworthy is the low rate of cement leakage in the radiofrequency kyphoplasty group of 6 % (n = 7). CONCLUSIONS: Radiofrequency kyphoplasty offers a secure superiority over conservative treatment regarding clinical efficacy. In addition, the fractured vertebrae can be better targeted and erected, a longer processing time of the cement is ensured, a high interdigitation of the cement with the bone is guaranteed, the rate of cement leakage is low, the risk of radiation for the surgeon is minimised, and the operation time is shortened. PMID- 22918826 TI - [Ultrasound as a viable alternative to standard X-rays for the diagnosis of distal forearm fractures in children]. AB - AIM: Distal forearm fractures are very common in childhood. Radiography of the wrist is the standard diagnostic procedure. But because of higher sensitivity of growing bones to ionising radiation the diagnostic use of X-rays should be minimised as much as possible. Recent studies have shown that distal forearm fractures in children can be safely and reliably diagnosed using only ultrasound. The aim of our study was to evaluate and confirm the safety and applicability of the ultrasound diagnostic procedure in comparison to X-ray diagnosis under routine conditions of our paediatric emergency department. PATIENTS AND METHODS: We investigated 115 patients aged 2-14 years. After clinical assessment patients with suspected forearm fractures first underwent ultrasound examination of the metaphyseal forearm followed by standard two view radiographs of the wrist. Ultrasound and radiographic findings were then compared and sensitivity and specificity for ultrasound were calculated. In 9 patients with suspected displacements, sonographic and radiographic axis measurement were done and also compared. RESULTS: Radiologically we found 62 patients with 78 distal forearm fractures. By ultrasound we also diagnosed 52 fractures. All patients with no fractures were correctly diagnosed as well. Referring to X-rays we calculated for ultrasound a sensitivity of 94.9 %, a specificity of 98 %, a negative predictive value of 97.4 % and a positive predictive value of 96.1 %. The mean difference of the deformities of the radius in the sagittal section measured sonographically and radiologically were 1.7 degrees (SD 1.6 degrees ). CONCLUSION: We confirm ultrasound is an applicable, rapid and safe alternative to X-rays in diagnosing metaphyseal forearm fractures in children. Even sonographic axis measurement seems to be a viable method. Thereby ultrasound potentially reduces the X-ray burden in children and additionally accelerates the diagnostic procedure. PMID- 22918827 TI - [Diagnostics and therapy for periprosthetic joint infection in Germany - A survey of 450 hospitals and a comparison with the literature]. AB - The diagnosis and treatment of periprosthetic joint infections is a difficult situation for the attending physician. From the extensive literature, algorithms for diagnosis and therapy can be created. The aim of this study was to collect a representative survey of current concepts in the Federal States of the former West Germany and to compare them with those in the current literature. In 2011 orthopaedic and trauma clinics were surveyed anonymously in western Germany about diagnosis and treatment of periprosthetic infections. 450 questionnaires could be evaluated. Septic hip arthroplasty revisions were performed on average 12 (+/- 20)/year, septic knee arthroplasty revisions were performed on average 9 (+/- 17)/year. On average 205 (+/- 178) primary hip and 167 (+/- 155) primary knee arthroplasties were implanted/year. The analysis of the collected parameters is summarised in three tables. In the field of diagnostics, parameters such as CRP are determined. The interpretation, however, differs in more than 50 % of the hospitals on the relevant literature. Some important diagnostic parameters are not used. Therapy concepts are largely consistent with the literature. To a non negligible extent, the vacuum-assisted therapy (approximately 30 % of hospitals) is used. In the literature it is described only for early infection. But even for use in early infection, there are very few data available. A unified diagnostic algorithm would be desirable. PMID- 22918828 TI - [Efficacy of a manual treatment method according to the fascial distortion model in the management of contracted ("frozen") shoulder]. AB - BACKGROUND: Frozen shoulder is a common problem and difficult to treat. The present prospective randomised single-blind controlled trial evaluates the efficacy of the 'fascial distortion model' according to Typaldos as a remedy for the 'frozen shoulder'. MATERIALS AND METHODS: A total of 60 patients were randomised to receive either the FDM-guided treatment (FDM, n = 30) or a 'conventional' manual therapy (MT, n = 30). The primary endpoint for the treatment effect was the shoulder mobility, and secondary endpoints were pain (measured on a VAS), raw force and function as expressed by the Constant-Murley and DASH scores. RESULTS: Before therapy, groups were well comparable in terms of all outcome parameters. All endpoints showed a substantial and significant improvement in both treatment groups. Improvement was significantly more marked in the FDM group as compared to the MT group, and the effect occurred significantly faster. During post-treatment observation, there was no further improvement and the achieved benefit in mobility in the FDM group decreased. However, the abduction ability of 150.2 +/- 37.2 degrees continued to be substantially better than in control patients (124.1 +/- 38.6 degrees , p < 0.01), and the ultimate improvement in abduction was 59.4 degrees (64 % more than baseline) as opposed to 25.9 degrees (27 %) in controls. Secondary outcome parameters (raw force, functional handicap, and pain) showed a significant improvement in both groups but a significantly better result in patients treated according to FDM guidelines. However, patients in this group experienced pain during the treatment more frequently (21/27 vs. 10/27, p < 0.01). CONCLUSION: Frozen shoulder treatment according to the FDM is an effective modality with swift onset of action and acceptable side effects that is superior to conventional manual therapy. Long-term effects and modes of action need to be investigated. PMID- 22918829 TI - Identification of an N-methyl-D-aspartate receptor in isolated nervous system mitochondria. AB - NMDA ionotropic glutamate receptors gate the cytoplasmic influx of calcium, which may, depending on the intensity of the stimulus, subserve either normal synaptic communication or cell death. We demonstrate that when isolated mitochondria are exposed to calcium and NMDA agonists, there is a significant increase in mitochondrial calcium levels. The agonist/antagonist response studies on purified mitochondria suggest the presence of a receptor on mitochondria with features similar to plasma membrane NMDA receptors. Immunogold electron microscopy of hippocampal tissue sections revealed extensive localization of NR2a subunit immunoreactivity on mitochondria. Transient transfection of neuronal GT1-7 cells with an NR1-NR2a NMDA receptor subunit cassette specifically targeting mitochondria resulted in a significant increase in mitochondrial calcium and neuroprotection against glutamate-induced cell death. Mitochondria prepared from GT1-7 cells in which the NR1 subunit of NMDA receptors was silenced demonstrated a decrease in calcium uptake. Our findings are the first to demonstrate that mitochondria express a calcium transport protein that shares characteristics with the NMDA receptor and may play a neuroprotective role. PMID- 22918831 TI - Autoacetylation of the MYST lysine acetyltransferase MOF protein. AB - The MYST family of histone acetyltransferases (HATs) plays critical roles in diverse cellular processes, such as the epigenetic regulation of gene expression. Lysine autoacetylation of the MYST HATs has recently received considerable attention. Nonetheless, the mechanism and function of the autoacetylation process are not well defined. To better understand the biochemical mechanism of MYST autoacetylation and the impact of autoacetylation on the cognate histone acetylation, we carried out detailed analyses of males-absent-on-the-first (MOF), a key member of the MYST family. A number of mutant MOF proteins were produced with point mutations at several key residues near the active site of the enzyme. Autoradiography and immunoblotting data showed that mutation of these residues affects the autoacetylation activity and HAT activity of MOF by various degrees demonstrating that MOF activity is highly sensitive to the chemical changes in those residues. We produced MOF protein in the deacetylated form by using a nonspecific lysine deacetylase. Interestingly, both the autoacetylation activity and the histone acetylation activity of the deacetylated MOF were found to be very close to that of wild-type MOF, suggesting that autoacetylation of MOF only marginally modulates the enzymatic activity. Also, we found that the autoacetylation rates of MOF and deacetylated MOF were much slower than the cognate substrate acetylation. Thus, autoacetylation does not seem to contribute to the intrinsic enzymatic activity in a significant manner. These data provide new insights into the mechanism and function of MYST HAT autoacetylation. PMID- 22918830 TI - Histone deacetylase-1 (HDAC1) is a molecular switch between neuronal survival and death. AB - Both neuroprotective and neurotoxic roles have previously been described for histone deacetylase-1 (HDAC1). Here we report that HDAC1 expression is elevated in vulnerable brain regions of two mouse models of neurodegeneration, the R6/2 model of Huntington disease and the Ca(2+)/calmodulin-dependent protein kinase (CaMK)/p25 double-transgenic model of tauopathic degeneration, suggesting a role in promoting neuronal death. Indeed, elevating HDAC1 expression by ectopic expression promotes the death of otherwise healthy cerebellar granule neurons and cortical neurons in culture. The neurotoxic effect of HDAC1 requires interaction and cooperation with HDAC3, which has previously been shown to selectively induce the death of neurons. HDAC1-HDAC3 interaction is greatly elevated under conditions of neurodegeneration both in vitro and in vivo. Furthermore, the knockdown of HDAC3 suppresses HDAC1-induced neurotoxicity, and the knockdown of HDAC1 suppresses HDAC3 neurotoxicity. As described previously for HDAC3, the neurotoxic effect of HDAC1 is inhibited by treatment with IGF-1, the expression of Akt, or the inhibition of glycogen synthase kinase 3beta (GSK3beta). In addition to HDAC3, HDAC1 has been shown to interact with histone deacetylase related protein (HDRP), a truncated form of HDAC9, whose expression is down regulated during neuronal death. In contrast to HDAC3, the interaction between HDRP and HDAC1 protects neurons from death, an effect involving acquisition of the deacetylase activity of HDAC1 by HDRP. We find that elevated HDRP inhibits HDAC1-HDAC3 interaction and prevents the neurotoxic effect of either of these two proteins. Together, our results suggest that HDAC1 is a molecular switch between neuronal survival and death. Its interaction with HDRP promotes neuronal survival, whereas interaction with HDAC3 results in neuronal death. PMID- 22918832 TI - Biochemical and structural insights into xylan utilization by the thermophilic bacterium Caldanaerobius polysaccharolyticus. AB - Hemicellulose is the next most abundant plant cell wall component after cellulose. The abundance of hemicellulose such as xylan suggests that their hydrolysis and conversion to biofuels can improve the economics of bioenergy production. In an effort to understand xylan hydrolysis at high temperatures, we sequenced the genome of the thermophilic bacterium Caldanaerobius polysaccharolyticus. Analysis of the partial genome sequence revealed a gene cluster that contained both hydrolytic enzymes and also enzymes key to the pentose-phosphate pathway. The hydrolytic enzymes in the gene cluster were demonstrated to convert products from a large endoxylanase (Xyn10A) predicted to anchor to the surface of the bacterium. We further use structural and calorimetric studies to demonstrate that the end products of Xyn10A hydrolysis of xylan are recognized and bound by XBP1, a putative solute-binding protein, likely for transport into the cell. The XBP1 protein showed preference for xylo oligosaccharides as follows: xylotriose > xylobiose > xylotetraose. To elucidate the structural basis for the oligosaccharide preference, we solved the co-crystal structure of XBP1 complexed with xylotriose to a 1.8-A resolution. Analysis of the biochemical data in the context of the co-crystal structure reveals the molecular underpinnings of oligosaccharide length specificity. PMID- 22918833 TI - Specific function of the Met-Tyr-Trp adduct radical and residues Arg-418 and Asp 137 in the atypical catalase reaction of catalase-peroxidase KatG. AB - Catalase activity of the dual-function heme enzyme catalase-peroxidase (KatG) depends on several structural elements, including a unique adduct formed from covalently linked side chains of three conserved amino acids (Met-255, Tyr-229, and Trp-107, Mycobacterium tuberculosis KatG numbering) (MYW). Mutagenesis, electron paramagnetic resonance, and optical stopped-flow experiments, along with calculations using density functional theory (DFT) methods revealed the basis of the requirement for a radical on the MYW-adduct, for oxyferrous heme, and for conserved residues Arg-418 and Asp-137 in the rapid catalase reaction. The participation of an oxyferrous heme intermediate (dioxyheme) throughout the pH range of catalase activity is suggested from our finding that carbon monoxide inhibits the activity at both acidic and alkaline pH. In the presence of H(2)O(2), the MYW-adduct radical is formed normally in KatG[D137S] but this mutant is defective in forming dioxyheme and lacks catalase activity. KatG[R418L] is also catalase deficient but exhibits normal formation of the adduct radical and dioxyheme. Both mutants exhibit a coincidence between MYW-adduct radical persistence and H(2)O(2) consumption as a function of time, and enhanced subunit oligomerization during turnover, suggesting that the two mutations disrupting catalase turnover allow increased migration of the MYW-adduct radical to protein surface residues. DFT calculations showed that an interaction between the side chain of residue Arg-418 and Tyr-229 in the MYW-adduct radical favors reaction of the radical with the adjacent dioxyheme intermediate present throughout turnover in WT KatG. Release of molecular oxygen and regeneration of resting enzyme are thereby catalyzed in the last step of a proposed catalase reaction. PMID- 22918835 TI - Involvement of apoptosis and proliferation of acinar cells in atrophy of rat parotid glands induced by liquid diet. AB - Parotid glands of experimental animals fed a liquid diet are reported to show atrophy (Hall and Schneyer 1964; Wilborn and Schneyer 1970; Hand and Ho 1981; Scott et al. 1990; Scott and Gunn 1991). To clarify whether apoptosis and proliferation of acinar cells participate in atrophy of rat parotid glands induced by liquid diet, rats were fed a liquid diet and compared to pellet-fed controls. Parotid glands were removed at 3, 7, 14 or 21 days, weighed, and examined using transmission electron microscopy (TEM), and studied immunohistochemically for cleaved-caspase-3 (Casp-3), a marker of apoptotic cells, and 5-bromo-2'-deoxyuridine (BrdU), a marker for proliferating cells. Body weights of experimental rats fed liquid diets were not significantly different from controls fed pellet diets; however weights of experimental parotid glands were smaller than those of controls. In the experimental parotid glands, structures like apoptotic bodies were histologically observed in acini at each time point; more Casp-3-positive acinar cells were identified in experimental parotid glands than in the controls on days 3, 7, and 14. Experimental glands showed fewer BrdU-positive acinar cells at each time point. TEM confirmed typical apoptotic acinar cells in the atrophic glands. These findings suggest that increased acinar cell apoptosis and reduced acinar cell proliferation occur in atrophic parotid glands of rats fed a liquid diet. PMID- 22918834 TI - Amyloid fibrils trigger the release of neutrophil extracellular traps (NETs), causing fibril fragmentation by NET-associated elastase. AB - The accumulation of amyloid fibrils is a feature of amyloid diseases, where cell toxicity is due to soluble oligomeric species that precede fibril formation or are formed by fibril fragmentation, but the mechanism(s) of fragmentation is still unclear. Neutrophil-derived elastase and histones were found in amyloid deposits from patients with different systemic amyloidoses. Neutrophil extracellular traps (NETs) are key players in a death mechanism in which neutrophils release DNA traps decorated with proteins such as elastase and histones to entangle pathogens. Here, we asked whether NETs are triggered by amyloid fibrils, reasoning that because proteases are present in NETs, protease digestion of amyloid may generate soluble, cytotoxic species. We show that amyloid fibrils from three different sources (alpha-synuclein, Sup35, and transthyretin) induced NADPH oxidase-dependent NETs in vitro from human neutrophils. Surprisingly, NET-associated elastase digested amyloid fibrils into short species that were cytotoxic for BHK-21 and HepG2 cells. In tissue sections from patients with primary amyloidosis, we also observed the co-localization of NETs with amyloid deposits as well as with oligomers, which are probably derived from elastase-induced fibril degradation (amyloidolysis). These data reveal that release of NETs, so far described to be elicited by pathogens, can also be triggered by amyloid fibrils. Moreover, the involvement of NETs in amyloidoses might be crucial for the production of toxic species derived from fibril fragmentation. PMID- 22918836 TI - Time-dependent expression and distribution of Egr-1 during skeletal muscle wound healing in rats. AB - Recent studies have shown that early growth response factor-1 (Egr-1) plays an important role in regulation of inflammation and tissue repair, but little is known about its expression after trauma to skeletal muscles. A preliminary study on time-dependent expression and distribution of Egr-1 was performed by immunohistochemistry, immunofluorescence and Western blotting during skeletal muscle wound healing in rats. An animal model of skeletal muscle contusion was established in 45 Sprague-Dawley male rats. Samples were taken at 6 h, 12 h, 1 day, 3 days, 5 days, 7 days, 10 days, 14 days and 21 days post-injury, respectively (5 rats in each posttraumatic interval). 5 rats were employed as control. In the uninjured controls, Egr-1 positive staining was observed in the sarcoplasm and nuclei of normal myofibers. In wounded specimens, a small number of polymorphonuclear cells (PMNs), a number of mononuclear cells (MNCs), fibroblastic cells (FBCs) and regenerated multinucleated myotubes showed positive reaction for Egr-1 in contused zones. By morphometric analysis, an increase in Egr-1 expression was verified at inflammatory phase after contusion, which reached a peak in the regenerated phase overlapping with the fibrotic phase during skeletal muscle wound healing. The expression tendency was further confirmed by Western blotting assay. By immunofluorescent staining for co localization, the Egr-1-positive MNCs and FBCs in wounds were identified as macrophages and myofibroblasts. The results demonstrate that the expression of Egr-1 is up-regulated and temporally distributed in certain cell types after trauma to skeletal muscles, which may be closely involved in inflammatory response, fibrotic repair and muscle regeneration during skeletal muscle wound healing. PMID- 22918837 TI - Facilitating neuronal connectivity analysis of evoked responses by exposing local activity with principal component analysis preprocessing: simulation of evoked MEG. AB - When connectivity analysis is carried out for event related EEG and MEG, the presence of strong spatial correlations from spontaneous activity in background may mask the local neuronal evoked activity and lead to spurious connections. In this paper, we hypothesized PCA decomposition could be used to diminish the background activity and further improve the performance of connectivity analysis in event related experiments. The idea was tested using simulation, where we found that for the 306-channel Elekta Neuromag system, the first 4 PCs represent the dominant background activity, and the source connectivity pattern after preprocessing is consistent with the true connectivity pattern designed in the simulation. Improving signal to noise of the evoked responses by discarding the first few PCs demonstrates increased coherences at major physiological frequency bands when removing the first few PCs. Furthermore, the evoked information was maintained after PCA preprocessing. In conclusion, it is demonstrated that the first few PCs represent background activity, and PCA decomposition can be employed to remove it to expose the evoked activity for the channels under investigation. Therefore, PCA can be applied as a preprocessing approach to improve neuronal connectivity analysis for event related data. PMID- 22918839 TI - The relationship between drug user stigma and depression among inner-city drug users in Baltimore, MD. AB - There is growing awareness of the role of stigma and discrimination in HIV prevention, testing, and medical care. Yet, few studies have examined the stigma associated with using illicit drugs. In the present study, we examined the relationship between social network characteristics, drug user stigma, and depression. Study participants were comprised of 340 individuals who reported cocaine, crack, and/or heroin use in the prior 6 months and were involved in an HIV prevention study. They were recruited through street outreach, referrals, and word of mouth in inner-city Baltimore, MD, USA. The stigma scale was comprised of eight items, such as "how much do you feel ashamed of using drugs?" Depression was assessed with the Center for Epidemiological Studies Depression Scale, using cutoffs of 16 and 20 or greater. In the bivariate analyses, gender, homelessness in the past 6 months, drug user stigma, larger size of drug network, and current use of heroin, cocaine, and crack were all significantly associated with high levels of depression, whereas in the multivariate analyses, only drug user stigma remained significantly associated with depression. The results of this study suggest that drug treatment providers and other professionals who provide services to drug users should consider developing trainings to address drug user stigma. These programs should focus on the attitudes and behaviors of health and service providers toward drug users, among drug users themselves, and among family members and others who provide social support to drug users. PMID- 22918840 TI - Bilateral intrathyroidal hemorrhage after fine needle aspiration completely resolved by compression without thyroidectomy. PMID- 22918842 TI - Feline bartonellosis: we're just scratching the surface. PMID- 22918843 TI - Welcome chinks of light. PMID- 22918841 TI - Thyrotoxic periodic paralysis: clinical and molecular aspects. AB - Thyrotoxic periodic paralysis (TPP) is a rare complication of hyperthyroidism that most often affects young East Asian males but increasingly also in other ethnic groups. The typical presentation is acute attacks varying from mild weakness to total paralysis starting at night or in the early morning a few hours after a heavy meal, alcohol abuse or strenuous exercise with complete recovery within 72 h. Signs and symptoms of hyperthyroidism may not be obvious. The hallmark is hypokalemia from increased cellular sodium/potassium-ATPase pump activity with transport of potassium from the extracellular to the intracellular space in combination with reduced potassium output. Recently, KCNJ18 gene mutations which alter the function of an inwardly rectifying potassium channel named Kir2.6 have been detected in 0-33 % of cases. Hence, the pathophysiology in TPP includes a genetic predisposition, thyrotoxicosis and environmental influences and the relative impact from each of these factors may vary. The initial treatment, which is potassium supplementation, should be given with caution due to a high risk of hyperkalemia. Propranolol is an alternative first line therapeutic option based on the assumption that hyperadrenergic activity is involved in the pathogenesis. If thyroid function tests are unobtainable in the acute situation the diagnosis is supported by the findings of hypokalemia, low spot urine potassium excretion, hypophosphatemia with hypophosphaturia, high spot urine calcium/phosphate ratio, and electrocardiographic abnormalities as tachycardia, atrial fibrillation, high QRS voltage, and atrioventricular block. Definitive treatment is cure of the hyperthyroidism. The underlying mechanisms of TPP remain, however, incompletely understood awaiting further studies. PMID- 22918844 TI - Chronic Bartonellosis in cats: what are the potential implications? AB - PRACTICAL RELEVANCE: Bartonellae are small, vector-transmitted Gram-negative intracellular bacteria that are well adapted to one or more mammalian reservoir hosts. Cats are the natural reservoir for Bartonella henselae, which is a (re )emerging bacterial pathogen. It can cause cat scratch disease in humans and, in immunocompromised people, may lead to severe systemic diseases, such as bacillary angiomatosis. Cats bacteraemic with B henselae constitute the main reservoir from which humans become infected. Most cats naturally infected with B henselae show no clinical signs themselves, but other Bartonella species for which cats are accidental hosts appear to have more pathogenicity. GLOBAL IMPORTANCE: Several studies have reported a prevalence of previous or current Bartonella species infection in cats of up to 36%. B henselae is common in cats worldwide, and bacteraemia can be documented by blood culture in about a quarter of healthy cats. The distribution of B henselae to various parts of the world has largely occurred through humans migrating with their pet cats. The pathogen is mainly transmitted from cat to cat by fleas, and the majority of infected cats derive from areas with high flea exposure. No significant difference in B henselae prevalence has been determined between male and female cats. In studies on both naturally and experimentally infected cats, chronic bacteraemia has mainly been found in cats under the age of 2 years, while those over 2 years of age are rarely chronically bacteraemic. EVIDENCE BASE: This article reviews published studies and case reports on bartonellosis to explore the clinical significance of the infection in cats and its impact on humans. The article also discusses possible treatment options for cats and means of minimising the zoonotic potential. PMID- 22918845 TI - Feline physiotherapy and rehabilitation: 1. principles and potential. AB - PRACTICAL RELEVANCE: Physiotherapy is highly valued within human medicine and relatively well established for canine patients. Despite a popular misconception that feline patients will not cooperate with such treatment, physiotherapy is now increasingly being performed with cats. With cat ownership increasing in many countries, and an emergence of specialist physiotherapy practitioners, there is demand for effective postoperative and post-injury rehabilitation for any cat with compromised physical function due to injury, surgery or disease. CLINICAL CHALLENGES: While physiotherapy and rehabilitation are potentially beneficial for cats, due to their independent nature feline patients certainly present a greater challenge in the pursuit of effective therapy than their canine counterparts. AUDIENCE: This two-part review article is directed at the primary care veterinary team. The benefits of physiotherapy and the various treatment modalities available to the qualified veterinary physiotherapist, as well as the non specialist veterinarian and veterinary nurse or technician, are examined in this first part. EVIDENCE BASE: The benefits of human physiotherapeutic intervention are well documented, and there is good evidence for the effectiveness of most treatment modalities. Animal studies are still in their infancy, although some preliminary studies in dogs have shown good results. PMID- 22918846 TI - Feline physiotherapy and rehabilitation: 2. clinical application. AB - PRACTICAL RELEVANCE: There is an increasing demand for effective postoperative and post-injury rehabilitation for any cat with compromised physical function due to injury, surgery or disease. CLINICAL CHALLENGES: The design of a suitable rehabilitation programme that will assist the recovery process, as well as ensure the return of neuromusculoskeletal control to the highest levels of function possible, requires a good understanding of feline behaviour, accurate assessment of the cat's condition and the correct implementation of a range of physiotherapeutic modalities. AUDIENCE: This two-part review article is directed at the primary care veterinary team. The clinical application of a variety of physiotherapeutic modalities in the rehabilitation of cats is examined in this second part. EVIDENCE BASE: Although evidence supporting the benefits of physiotherapy and rehabilitation with cats is sparse, many techniques, treatments and rehabilitation regimens successfully used on human patients are being readily adapted for animal use. Treatment recommendations described in this review are primarily based on the author's experience, and that of colleagues, except where specific reference is made to published evidence. PMID- 22918847 TI - Cerebral coenurosis in a cat caused by Taenia serialis: neurological, magnetic resonance imaging and pathological features. AB - CLINICAL SUMMARY: A 4-year-old Birman cat was presented with marked obtundation and non-ambulatory tetraparesis. Two well-demarcated, intra-axial T2 hyperintense, T1-hypointense structures, which did not contrast enhance, were evident on magnetic resonance imaging (MRI). Histopathology of the structures revealed metacestodes that were morphologically indicative of larval stages of Taenia species. Polymerase chain reaction amplification of a fragment within the 12S rRNA gene confirmed the subspecies as Taenia serialis. PRACTICAL SIGNIFICANCE: This is the first report of MRI findings of cerebral coenurosis caused by T serialis in a cat. Early MRI should be considered an important part of the diagnostic work-up for this rare clinical disease, as it will help guide subsequent treatment and may improve the prognosis. PMID- 22918850 TI - Downregulation of CCR5 expression on the peripheral blood CD8+ T cells of southeastern Iranian patients with chronic hepatitis B infection. AB - Studies indicated that CC receptor 5 (CCR5), as a receptor for CC ligand 3, CCL4, and CCL5, plays important roles in the recruitment of T cytotoxic lymphocytes to the liver of chronic HBV (CHB)-infected patients. The main purpose of this study was to investigate the expression levels of CCR5 on the CD8(+) T lymphocytes of CHB patients. This clinical study was performed on 63 CHB patients and 96 healthy controls. Flow cytometric analysis was performed to examine the expression of CCR5 on CD8(+) T cells of CHB patients. Real-time PCR was also used for HBV-DNA quantification. The results of our study demonstrated that CCR5 expressing T cytotoxic cells were decreased significantly in CHB patients in comparison to healthy control. Based on our results, it can be concluded that the percent of CCR5(+)/CD8(+) T cells in Iranian CHB patients is significantly decreased, hence their migration to the infected liver, and HBV eradication from the hepatocytes is disrupted. PMID- 22918851 TI - Contrast-enhanced ultrasound should be used more frequently for aortic endograft surveillance. PMID- 22918852 TI - Retrograde axonal transport of VZV: kinetic studies in hESC-derived neurons. AB - Retrograde axonal transport of the neurotropic alphaherpesvirus Varicella zoster virus (VZV) from vesicles at the skin results in sensory neuron infection and establishment of latency. Reactivation from latency leads to painful herpes zoster. The lack of a suitable animal model of these processes for the highly human-restricted VZV has resulted in a dearth of knowledge regarding the axonal transport of VZV. We recently demonstrated VZV infection of distal axons, leading to subsequent capsid transport to the neuronal somata, and replication and release of infectious virus using a new model based on neurons derived from human embryonic stem cells (hESC). In the present study, we perform a kinetic analysis of the retrograde transport of green fluorescent protein-tagged ORF23 in VZV capsids using hESC-derived neurons compartmentalized microfluidic chambers and time-lapse video microscopy. The motion of the VZV was discontinuous, showing net retrograde movement with numerous short pauses and reversals in direction. Velocities measured were higher 1 h after infection than 6 h after infection, while run lengths were similar at both time points. The hESC-derived neuron model was also used to show that reduced neuronal spread by a VZV loss-of-function mutant for ORF7 is not due to the prevention of axonal infection and transport of the virus to the neuronal somata. hESC-derived neurons are, therefore, a powerful model for studying axonal transport of VZV and molecular characteristics of neuronal infection. PMID- 22918853 TI - "Bochdalek's" skull: morphology report and reconstruction of face. AB - The objective of this study was to create a real model of a face using the well preserved "Bochdalek's skull" (from an eighteenth Century female aged 18 years) kept in the museum of anatomy (Institute of Anatomy, 1st Medical Faculty, Charles University in Prague). The skull had previously been appraised as a deformed skull with an adhesion present on both sides of the jaw, most likely of post traumatic origin (bilateral syngnathia). In an attempt to find the best description for it, and to identify the spatial relationships between the surface of the facial bones which had changed in shape, as well as the formation of soft tissue on the face, we decided to perform a 3D reconstruction of the face. Due to the necessity of preserving the unique original undamaged skull, we created an exact digital "casting" of the facial bone structure on a computer first, which we then converted into a three-dimensional model using a 3D RepRap printer. We needed to take into consideration the fact that we had no portrait of the girl, just the skull. For this reason, we opted for a selected combination of anthropologic steps (the modified Manchester technique), which in our view, allows for optimum creation of the topography of the face in keeping with the deformed skull. The resulting reconstructed face was old in appearance with an overhanging lower lip and flattened surfaces in the areas of the temporalis and masseter muscles. PMID- 22918854 TI - Pharmacokinetic study of a new derivative of sulfamethoxazole. AB - The study was aimed at determination of pharmacokinetic parameters of a previously synthesized salicylidine-sulfamethoxazole-Zn(II) monohydrate in normal humans. This new derivative of sulfamethoxazole was reported to be more active and less toxic than the parent drug by our group. 10 volunteers received a 200 mg dose of the drug orally. Blood samples were collected just before and after 0.16, 0.33, 0.5, 1.0, 2.0, 3.0, 4.0, 5.0, 6.0, 7.0 and 8.0 h of administration of the drug. The plasma samples were analyzed for sulfamethoxazole by a new validated high performance liquid chromatography method having a suitable limit of quantification. The dose of each drug was well tolerated without any adverse effect. The maximum plasma sulfamethoxazole concentration was 280 MUg L - 1 at a tmax 1.30 h. This suggests a rapid onset effect of the complex as compared with the parent drug. The plasma half-life, clearance, and volume of distribution of sulfamethoxazole from salicylidine-sulfamethoxazole-Zn(II) monohydrate were 1.64 h, 0.24 L h - 1 and 0.57 L kg - 1 respectively. The elimination of sulfamethoxazole followed the first order kinetics with R2>0.984. The larger value of volume of distribution and clearance for the new derivative, as compared to that of the parent drug, show that the new derivative may exhibit prolonged antimicrobial effect with rapid clearance. PMID- 22918855 TI - Bioequivalence study of 2 orodispersible formulations of zolmitriptan 5 mg in healthy volunteers. AB - A bioequivalence study of 2 zolmitriptan (CAS 139264-17-8) orodispersible tablet formulations was carried out in 26 healthy volunteers according to an open label, randomized, 2-period, 2-sequence, crossover, single dose and fasting conditions design. The test and reference formulations were administered in 2 treatment days, separated by a washout period of 7 days. Plasma concentrations of zolmitriptan and its active metabolite (N-desmethyl-zolmitriptan) were obtained by LC/MS/MS method. Log-transformed AUCs and Cmax values were tested for bioequivalence based on the ratios of the geometric means (test/reference). Tmax was analysed nonparametrically. The 90% confidence intervals of the geometric mean values for the test/reference ratios for AUC0-t and Cmax were within the bioequivalence acceptance range of 80-125%. According to the European Guideline 1 it may be therefore concluded that test formulation of zolmitriptan 5 mg orodispersible tablet is bioequivalent to the reference formulation. PMID- 22918856 TI - Metronidazole immediate release formulations: a fasting randomized open-label crossover bioequivalence study in healthy volunteers. AB - Metronidazole is a BCS (Biopharmaceutics Classification System) class 1 drug, traditionally considered the choice drug in the infections treatment caused by protozoa and anaerobic microorganisms. This study aimed to evaluate bioequivalence between 2 different marketed 250 mg metronidazole immediate release tablets. A randomized, open-label, 2*2 crossover study was performed in healthy Brazilian volunteers under fasting conditions with a 7-day washout period. The formulations were administered as single oral dose and blood was sampled over 48 h. Metronidazole plasma concentrations were determined by a liquid chromatography mass spectrometry (LC-MS/MS) method. The plasma concentration vs. time profile was generated for each volunteer and the pharmacokinetic parameters Cmax, Tmax, AUC0-t, AUC0-infinity, ke, and t1/2 were calculated using a noncompartmental model. Bioequivalence between pharmaceutical formulations was determined by calculating 90% CIs (Confidence Intervall) for the ratios of Cmax, AUC0-t, and AUC0-infinity values for test and reference using log transformed data. 22 healthy volunteers (11 men, 11 women; mean (SD) age, 28 (6.5) years [range, 21-45 years]; mean (SD) weight, 66 (9.3) kg [range, 51-81 kg]; mean (SD) height, 169 (6.5) cm [range, 156-186 cm]) were enrolled in and completed the study. The 90% CIs for Cmax (0.92-1.06), AUC0-t (0.97-1.02), and AUC0-infinity (0.97-1.03) values for the test and reference products fitted in the interval of 0.80-1.25 proposed by most regulatory agencies, including the Brazilian agency ANVISA. No clinically significant adverse effects were reported. After pharmacokinetics analysis, it concluded that test 250 mg metronidazole formulation is bioequivalent to the reference product according to the Brazilian agency requirements. PMID- 22918857 TI - Development of a subcutaneous formulation for trastuzumab - nonclinical and clinical bridging approach to the approved intravenous dosing regimen. AB - A subcutaneous (SC) formulation has been developed for the humanized monoclonal antibody (mAb) trastuzumab as an alternative to established intravenous (IV) infusion. The ready-to-use liquid SC formulation is injected as a fixed dose in approximately 5 min, which is expected to increase patient's convenience, reduce pharmacy preparation time, and administration costs overall.The trastuzumab dose as well as the dose of recombinant human hyaluronidase (rHuPH20), an enzyme that enables SC administration of volumes larger than 2 mL, was selected based on nonclinical xenograft, pharmacology, and pharmacokinetics mouse and minipig studies.The basic assumption for bridging from the IV to the SC regimen was that comparable trastuzumab serum trough concentrations would result in comparable efficacy. This hypothesis is confirmed by the results from the Phase 3 study in the neo-adjuvant/adjuvant setting. The safety profiles of the trastuzumab SC and IV formulations are comparable and consistent with the known safety profile of trastuzumab. PMID- 22918858 TI - Effects of milk casein derived tripeptides on endothelial enzymes in vitro; a study with synthetic tripeptides. AB - In the fermentation of milk by certain lactic acid bacteria, casein is degraded into bioactive tripeptides shown to lower blood pressure in experimental animal models and in mildly hypertensive humans. This effect is suggested to result mainly in inhibition of angiotensin converting enzyme 1 (ACE-1).Due to the complexity of renin-angiotensin system (RAS), several other enzymes than ACE-1 can participate in the production of vasoactive components. Therefore, in the present study we investigated effects of tripeptides isoleucine-proline-proline (IPP), valine-proline-proline (VPP) and leucine-proline-proline (LPP) on some endothelial enzymes that are important in RAS or otherwise have a role in the endothelial function. The enzymes investigated were renin, chymase, neutral endopeptidase (NEP), prolyl oligopeptidase (POP), cathepsin G, endothelin converting enzyme 1 (ECE-1), and cyclooxygenase 1 and 2 (COX -1 and COX-2).The tripeptides inhibited prolyl oligopeptidase (POP) dose-dependently. IPP was the most potent inhibitor (IC50 486+/-95 uM). Contrary, cathepsin G was activated by IPP, VPP and LPP as well as the amino acids proline and isoleucine. The other investigated enzymes were not affected. Inhibition of POP and activation of cathepsin G do not explain the blood pressure lowering effects of the tripeptides. Thus the inhibition of ACE-1 remains the most plausible mechanism of the antihypertensive effects of the tripeptides. PMID- 22918860 TI - Emotional responses to odors in children with high-functioning autism: autonomic arousal, facial behavior and self-report. AB - Although emotional functioning is impaired in children with autism, it is unclear if this impairment is due to difficulties with facial expression, autonomic responsiveness, or the verbal description of emotional states. To shed light on this issue, we examined responses to pleasant and unpleasant odors in eight children (8-14 years) with high-functioning autism and 8 age-matched typically developing controls. Despite subtle differences in the facial actions of the children with autism, children in both groups had similar facial and autonomic emotional responses to the odors. However, children with autism were less likely than controls to report an emotional reaction to the odors that matched their facial expression, suggesting difficulties in the self report of emotional states. PMID- 22918859 TI - Temperament in the first 2 years of life in infants at high-risk for autism spectrum disorders. AB - The current study investigated early temperament in 54 infants at familial high risk of ASD and 50 controls. Parental report of temperament was assessed around 7, 14 and 24 months of age and diagnostic assessment was conducted at 3 years. The high-risk group showed reduced Surgency at 7 and 14 months and reduced Effortful Control at 14 and 24 months, compared to controls. High-risk infants later diagnosed with ASD were distinguished from controls by a temperament profile marked by increased Perceptual Sensitivity from the first year of life, and increased Negative Affect and reduced Cuddliness in the second year of life. Temperament may be an important construct for understanding the early infant development of ASD. PMID- 22918862 TI - Appendicitis following virtual colonoscopy: a case report. PMID- 22918864 TI - Direct molecular typing of Bordetella pertussis from clinical specimens submitted for diagnostic quantitative (real-time) PCR. AB - Molecular typing of Bordetella pertussis is routinely performed on bacterial isolates, but not on DNA extracted from nasopharyngeal aspirates or pernasal swabs submitted for diagnostic real-time PCR (qPCR). We investigated whether these DNA extracts were suitable for multilocus variable-number tandem repeat analysis (MLVA) and DNA sequence-based typing. We analysed all the available qPCR positive samples received by our laboratory from patients <1 year of age between January 2008 and August 2010. Eighty-one per cent (106/131) of these generated a complete MLVA profile. This rose to 92 % (105/114) if only samples positive for both of the two targets used for the B. pertussis PCR (insertion element IS481 and pertussis toxin promoter ptxP) were analysed. Sequence-based typing of the pertactin, pertussis toxin S1 subunit and pertussis promoter regions (prn, ptxA and ptxP) was attempted on 89 of the DNA extracts that had generated a full MLVA profile. Eighty-three (93 %) of these produced complete sequences for all three targets. Comparison of molecular typing data from the 89 extracts with those from 111 contemporary bacterial isolates showed that the two sources yielded the same picture of the B. pertussis population [dominated by the MLVA-27 prn(2) ptxA(1) ptxP(3) clonal type]. There was no significant difference in MLVA type distribution or diversity between the two sample sets. This suggests that clinical extracts can be used in place of, or to complement, bacterial cultures for typing purposes (at least, in this age group). With small modifications to methodology, generating MLVA and sequence-based typing data from qPCR-positive clinical DNA extracts is likely to generate a complete dataset in the majority of samples from the <1 year age group. Its success with samples from older subjects remains to be seen. However, our data suggest that it is suitable for inclusion in molecular epidemiological studies of the B. pertussis population or as a tool in outbreak investigations. PMID- 22918865 TI - The fungicide fludioxonil antagonizes fluconazole activity in the human fungal pathogen Candida albicans. AB - The fungicide fludioxonil is widely used in agriculture. Residua of this fungicide are occasionally detected in fruits and can therefore be ingested by humans. The human fungal pathogen Candida albicans expresses the target of fludioxonil, Nik1p, a type III histidine kinase involved in stress response. Inhibition of yeast and hyphae growth was hardly observable after treatment of C. albicans SC5314 with fludioxonil. As a side effect, however, we observed a concentration-dependent induction of the expression of the genes CDR1 and CDR2, encoding ATP-binding cassette (ABC) transporters. This was independent of the presence of the target of fludioxonil as induction was also observed in a Deltanik1 deletion mutant. Deletion of the CDR1 gene aggravated the inhibition of germ tube formation by fludioxonil, indicating that, in the wild-type, the fungicide was discharged from the cell by Cdr1p. Cdr1p is also known as a resistance factor of C. albicans against the commonly used antimycotic fluconazole. Thus, the effect of concurrent exposure to fludioxonil and known cargoes of ABC transporters on their extrusion and the growth of C. albicans was examined. Pre-incubation with fludioxonil decreased the export rate of rhodamine 6G. The resistance to fluconazole was increased by fludioxonil, independently of Nik1p. Therefore, exposure of C. albicans to fludioxonil may lead to increased resistance to fluconazole treatment. PMID- 22918866 TI - Desulfurization of mucin by Pseudomonas aeruginosa: influence of sulfate in the lungs of cystic fibrosis patients. AB - Pseudomonas aeruginosa is a common cause of chronic respiratory infection in cystic fibrosis (CF) patients. Infection is established within the lung epithelial mucus layer through adhesion to mucins. Terminal residues on mucin oligosaccharide chains are highly sulfated and sialylated, which increases their resistance to degradation by bacterial enzymes. However, a number of microbes, including P. aeruginosa, display mucin sulfatase activity. Using ion chromatography, the levels of sulfation on different respiratory mucins and the availability of inorganic sulfate to pathogens in sputum from CF patients were quantified. The ability of clinical isolates of P. aeruginosa to desulfate mucin was tested by providing mucin as a sole sulfur source for growth. All tested P. aeruginosa strains isolated from the lungs of CF patients were able to use human respiratory mucin as a source of sulfur for growth, whereas other non-clinical species of the genus Pseudomonas were not. However, measured levels of inorganic sulfate in sputum from CF patients suggested that bacteria resident in the lung have sufficient inorganic sulfate for growth and are unlikely to require access to mucin sulfur as a sulfur source during chronic infection. This was confirmed when expression of sulfate-repressed P. aeruginosa genes atsK and msuE was found to be repressed in the sputum of CF patients, which was detected by using quantitative RT-PCR. These results indicate that sulfate starvation is unlikely to occur in pathogens residing in the sputum of CF patients and, therefore, mucin desulfation may have an alternative purpose in the association between P. aeruginosa and the airways of CF patients. PMID- 22918867 TI - Combined Bacillus licheniformis and Bacillus subtilis infection in a patient with oesophageal perforation. AB - Species of the genus Bacillus are a common laboratory contaminant, therefore, isolation of these organisms from blood cultures does not always indicate infection. In fact, except for Bacillus anthracis and Bacillus cereus, most species of the genus Bacillus are not considered human pathogens, especially in immunocompetent individuals. Here, we report an unusual presentation of bacteraemia and mediastinitis due to co-infection with Bacillus subtilis and Bacillus licheniformis, which were identified by 16S RNA gene sequencing, in a patient with an oesophageal perforation. PMID- 22918868 TI - In vitro antifungal activity of the flavonoid baicalein against Candida species. AB - The aim of the present study was to evaluate the in vitro activity of baicalein, the flavone constituent of Scutellaria baicalensis, and synergism of the combination of baicalein and fluconazole against Candida albicans, Candida tropicalis and Candida parapsilosis. The MIC(50) (lowest concentration at which there was 50 % inhibition of growth) of baicalein alone against six Candida strains ranged from 13 to 104 ug ml(-1). For the three species tested, exposure to baicalein at the MIC(50) concentrations obtained for each strain resulted in a high loss of viability. The fluconazole plus baicalein combination markedly reduced the MICs of both drugs for all three strains analysed. In addition, a synergistic effect between baicalein and fluconazole was observed for C. parapsilosis in terms of MIC(50) (fractional inhibitory concentration index = 0.207). Scanning electron microscopy analysis revealed that yeast cells exposed to baicalein at MIC(50) produced a profusely flocculent extracellular material, resembling a biofilm-like structure. In conclusion, these results showed the antifungal capability of baicalein against Candida species and highlight a promising role of baicalein when used in combination with fluconazole against Candida infections. PMID- 22918869 TI - Emergence of carbapenem-resistant OXA-48 carbapenemase-producing Enterobacteriaceae in Tunisia. AB - We screened 21 extended spectrum beta-lactamase-producing Enterobacteriaceae with reduced susceptibility to carbapenems for carbapenemase production. Five strains (four Klebsiella pneumoniae and one Citrobacter freundii) showed carbapenemase production, which was identified as OXA-48. The bla(OXA-48) gene was detected on ~54 kb plasmids belonging to IncA/C in one case. Two isolates harboured IS1999, which is involved in bla(OXA-48) mobilization. Carbapenem resistance in enterobacteria should be regarded as an emerging clinical problem in our hospital and necessitates rigorous surveillance in order to limit its spread. PMID- 22918870 TI - Fifteen Streptococcus suis serotypes identified by multiplex PCR. AB - A multiplex PCR was developed to detect 15 serotypes of Streptococcus suis. This multiplex PCR was separated into two reaction sets. The first set identified nine serotypes (serotypes 1/2, 1, 2, 3, 4, 7, 9, 14 and 16) and the second set identified six serotypes (serotypes 5, 8, 10, 19, 23 and 25). This assay correctly detected serotypes 2, 5 and 14 in human isolates, and serotypes 1, 2, 1/2, 3, 4, 5, 7, 9, 14, 16 and 19 in pig isolates from Thailand. No cross reaction was observed with other streptococcal species. This assay may be useful for the serotype surveillance of human and pig isolates of S. suis. PMID- 22918871 TI - Gastrointestinal basidiobolomycosis, an emerging infection in the immunocompetent host: a report of 14 patients. AB - Zygomycosis is characterized by tissue invasion with broad, non-septate hyphae of species such as Rhizopus, Rhizomucor, Lichtheimia (Absidia) and Basidiobolus. Basidiobolus ranarum usually causes subcutaneous infection, and gastrointestinal manifestations in immunocompetent patients have rarely been reported. It is difficult to diagnose gastrointestinal basidiobolomycosis because of the non specific clinical presentation and the absence of a definite risk factor. This study identified 14 cases of gastrointestinal basidiobolomycosis, all of which were diagnosed after surgery by characteristic histopathological findings. Diagnosis of this disease requires a high index of suspicion in patients presenting with abdominal symptoms, fever, gastrointestinal mass and eosinophilia accompanied by a high erythrocyte sedimentation rate. PMID- 22918872 TI - A clinical prediction score to diagnose unilateral primary aldosteronism. AB - CONTEXT: Adrenal venous sampling is recommended to assess whether aldosterone hypersecretion is lateralized in patients with primary aldosteronism. However, this procedure is invasive, poorly standardized, and not widely available. OBJECTIVE: Our goal was to identify patients' characteristics that can predict unilateral aldosterone hypersecretion in some patients who could hence bypass adrenal venous sampling before surgery. DESIGN AND SETTING: A cross-sectional diagnostic study was performed from February 2009 to July 2010 at a single center specialized in hypertension care. PATIENTS: A total of 101 consecutive patients with primary aldosteronism who underwent adrenal venous sampling participated in the study. The autonomy of aldosterone hypersecretion was assessed with the saline infusion test. INTERVENTION: Adrenal venous sampling was performed without ACTH infusion but with simultaneous bilateral sampling. MAIN OUTCOME MEASURES: Variables independently associated with a lateralized adrenal venous sampling in multivariate logistic regression were used to derive a clinical prediction rule. RESULTS: Adrenal venous sampling was successful in 87 patients and lateralized in 49. All 26 patients with a typical Conn's adenoma plus serum potassium of less than 3.5 mmol/liter or estimated glomerular filtration rate of at least 100 ml/min/1.73 m2 (or both) had unilateral primary aldosteronism; this rule had 100% specificity (95% confidence interval, 91-100) and 53% sensitivity (95% confidence interval, 38-68). CONCLUSIONS: If our results are validated on an independent sample, adrenal venous sampling could be omitted before surgery in patients with a typical Conn's adenoma if they meet at least one of two supplementary biochemical characteristics (serum potassium<3.5 mmol/liter or estimated glomerular filtration rate >=100 ml/min/1.73 m2). PMID- 22918873 TI - Giant adrenal angiomyolipoma. AB - CONTEXT: We report on a case of adrenal angiomyolipoma. OBJECTIVE: The aim was to present a case report and review of the literature about adrenal angiomyolipoma. DESIGN: The case report includes a history of patient data and literature review. SETTING: The patient was offered adrenalectomy with adrenal gland neoplasms and gave consent. The tumor was completely removed. PATIENT: We present the case of a 55-yr-old patient with a 15 * 16-cm adrenal angiomyolipoma. INTERVENTION: We performed adrenalectomy with adrenal gland neoplasms. RESULTS: The histopathological features confirmed the diagnosis of adrenal angiomyolipoma. The patient made an uneventful recovery and was normal at the 6-month follow-up. CONCLUSIONS: Angiomyolipomas are rare mesenchymal tumors derived from perivascular epithelioid cells. These are commonly found in the kidney. Angiomyolipoma arising in the adrenal is a very rare entity. We present a case of adrenal angiomyolipoma. In our case, the tumor size was (15 * 16 cm), the largest being reported. PMID- 22918874 TI - Remembering change: the critical role of recursive remindings in proactive effects of memory. AB - In three experiments, we examined the role of the detection and recollection of change in proactive effects of memory in a classic A-B, A-D paradigm. Participants studied two lists of word pairs that included pairs repeated across lists (A-B, A-B), pairs with the same cue but a changed response (A-B, A-D) in the second list, and control pairs (A-B, C-D). The results revealed that performance on A-B, A-D pairs reflected a mixture of facilitation and interference effects. Proactive facilitation occurred when changes in responses were detected and recollected, whereas proactive interference occurred when change was not detected or when it was not recollected. We describe detecting change as involving recursive remindings that result in memory for the List 1 response being embedded in the representation of memory for the List 2 response. These embedded representations preserve the temporal order of the responses. Our findings highlight the importance of detection and recollection of change for proactive effects of memory. PMID- 22918875 TI - Chloroplast genome diversity in Portuguese grapevine (Vitis vinifera L.) cultivars. AB - Grapevine chloroplast (cp) DNA diversity was analysed for the first time through amplification and digestion of fragments of the large single copy (LSC) region by polymerase chain reaction-restriction fragment length polymorphism methodology and also by amplification of three microsatellite loci, previously described as polymorphic in grapevine. Thirty-eight grapevine cultivars collected mainly in the North of Portugal, including some neglected cultivars, four international cultivars (Chasselas, Muscat of Alexandria, Muscat of Hamburg and Pinot) and Vitis riparia and Vitis rupestris, were used in this study with the main goal of finding out their cpDNA diversity and compare the obtained results with previously published data on cultivars from other regions to ascertain their possible origin. Two different alleles were found in each of the three cpSSR loci. Allele variants of the three loci combined in a total of three different haplotypes (A, B and D). The most frequent haplotype, A, was previously reported as the most frequent in Iberian Peninsula and Occidental Europe. Haplotype B was unique to Rabigato, Muscat of Alexandria, V. riparia and V. rupestris. This haplotype was previously proposed to be an ancestral haplotype. Twenty-seven fragments of the LSC region of Vitis vinifera cpDNA were amplified and then digested with HinfI and TaqI restriction enzymes. Polymorphisms were found in the trnT-psbC (TC) and orf184-petA (OA) fragments. In the TC fragment, the polymorphism corresponds to a point mutation in a restriction site of TaqI and is only present in all cultivars with cpSSR haplotype D. In the OA fragment, a short deletion exclusive to the Rabigato cultivar was found. In this case, one sequence tagged site-based marker was developed and will be very useful in future phylogenetic and fingerprinting studies in a broader number of cultivars and in wild grapevine populations. Inference about the progenitors of the Touriga Franca cultivar is done. The present work supports and completes its origin as a descendent of the female and male parents, Marufo and Touriga Nacional. PMID- 22918876 TI - 20-HETE induces hyperglycemia through the cAMP/PKA-PhK-GP pathway. AB - We previously generated cytochrome P450 4F2 (CYP4F2) transgenic mice and showed high 20-hydroxyeicosatetraenoic acid (20-HETE) production, which resulted in an elevation of blood pressure. However, it was unclear whether 20-HETE affected glucose metabolism. We measured fasting plasma glucose, insulin, hepatic CYP4F2 expression, and 20-HETE production by hepatic microsomes, and hepatic 20-HETE levels in transgenic mice. We also assessed glycogen phosphorylase (GP) activity and the cAMP/protein kinase A (PKA)-phosphorylase kinase (PhK)-GP pathway, as well as expressions of insulin receptor substrate 1 and glucose transporters in vivo and in vitro. The transgenic mice had overexpressed hepatic CYP4F2, high hepatic 20-HETE and fasting plasma glucose levels but normal insulin level. The GP activity was increased and the cAMP/PKA-PhK-GP pathway was activated in the transgenic mice compared with wild-type mice. Moreover, these alterations were eliminated with the addition of N-hydroxy-N'-(4-butyl-2 methylphenyl) formamidine, which is a selective 20-HETE inhibitor. The results were further validated in Bel7402 cells. In addition, the transgenic mice had functional insulin signaling, and 20-HETE had no effect on insulin signaling in Bel7402 cells, excluding that the observed hyperglycemia in CYP4F2 transgenic mice resulted from insulin dysfunction, because the target tissues were sensitive to insulin. Our study suggested that 20-HETE can induce hyperglycemia, at least in part, through the cAMP/PKA-PhK-GP pathway but not through the insulin-signaling pathway. PMID- 22918877 TI - Dopamine synthesis and D3 receptor activation in pancreatic beta-cells regulates insulin secretion and intracellular [Ca(2+)] oscillations. AB - Pancreatic islets are critical for glucose homeostasis via the regulated secretion of insulin and other hormones. We propose a novel mechanism that regulates insulin secretion from beta-cells within mouse pancreatic islets: a dopaminergic negative feedback acting on insulin secretion. We show that islets are a site of dopamine synthesis and accumulation outside the central nervous system. We show that both dopamine and its precursor l-dopa inhibit glucose stimulated insulin secretion, and this inhibition correlates with a reduction in frequency of the intracellular [Ca(2+)] oscillations. We further show that the effects of dopamine are abolished by a specific antagonist of the dopamine receptor D3. Because the dopamine transporter and dopamine receptors are expressed in the islets, we propose that cosecretion of dopamine with insulin activates receptors on the beta-cell surface. D3 receptor activation results in changes in intracellular [Ca(2+)] dynamics, which, in turn, lead to lowered insulin secretion. Because blocking dopaminergic negative feedback increases insulin secretion, expanding the knowledge of this pathway in beta-cells might offer a potential new target for the treatment of type 2 diabetes. PMID- 22918880 TI - Free vascularized cortico-periosteal grafting for a traumatic defect of the DIP joint. PMID- 22918878 TI - Mice harboring Gnrhr E90K, a mutation that causes protein misfolding and hypogonadotropic hypogonadism in humans, exhibit testis size reduction and ovulation failure. AB - GnRH, produced in the hypothalamus, acts on pituitary gonadotropes to stimulate release of the gonadotropins LH and FSH. Reduced responsiveness of gonadotropes to GnRH is a primary cause of hypogonadotropic hypogonadism (HH), a disease characterized by gonadal dysfunction and low blood levels of gonadotropins. Loss of-function mutations in the gene encoding the receptor for GnRH (GNRHR) are a common cause of HH. Sequencing of the GNRHR gene in patients with HH revealed mainly point mutations producing single amino acid substitutions that cause misfolding and misrouting of this G protein-coupled receptor. To generate a mouse model that mimics the human disease, we introduced a single amino acid substitution (E90K) into the mouse Gnrhr gene, which is identical to a known human recessive mutation. In humans, E90K causes severe HH by preventing formation of the E90-K121 salt bridge, which is essential for correct folding. In cell cultures, E90K causes misfolding that leads to almost complete retention by the protein quality control system and subsequent degradation. Here we report that the primary phenotype of mice homozygous for E90K is female infertility due to ovulation failure. Mutant males are fertile despite reduced gonadotropin levels and smaller testes. These results suggest decreased GnRH receptor signaling in the mutant animal, compared with wild type. Our findings suggest that a threshold level of GnRH receptor activity is required for ovulation. PMID- 22918879 TI - Concomitant use of pazopanib and simvastatin increases the risk of transaminase elevations in patients with cancer. PMID- 22918881 TI - Limb salvage after clostridial myonecrosis of upper limb caused by intramuscular injection. PMID- 22918882 TI - Biomechanical effect of isolated capitate shortening in Kienbock's disease: an anatomical study. AB - Multiple operations have been proposed to slow the progression of osteonecrosis and secondary carpal damage in Kienbock's disease. To assess the biomechanical changes after capitate shorting, we inserted pressure-testing devices into the carpal and radiocarpal joints in an anatomical study. Pressure sensors were placed into eight thawed non-fixated human cadaver arms to measure the forces transmitted in physiological loading. Longitudinal 9.8 N and 19.6 N forces were applied before and after capitate shortening. After capitate shortening, significant load reduction on the lunate was evident in all specimens. An average decrease of 49% was seen under a 9.8 N load and 56% under a 19.6 N load. The load was transferred to the radial and ulnar intercarpal joints. More relief of pressure on the lunate after isolated capitate shortening is achieved with a shallow angle between the scaphoid and capitate in the posteroanterior radiograph. PMID- 22918883 TI - The effects of 5-fluorouracil on flexor tendon healing by using a biodegradable gelatin, slow releasing system: experimental study in a hen model. AB - This study investigated the effects of 5-fluorouracil in a slow-release biodegradable gelatin system on tendon healing. Gelatin blocks prepared in a size of 10 * 20 * 1 mm were loaded with 10, 20, and 30 mg of 5-fluorouracil, and 30 adult white Leghorn chickens were used. The tendons to the third and fourth toes were severed and repaired. The extremities were casted for three weeks. After sacrifice, the tendons were examined histologically and biomechanically for adhesion formation. The 10 mg-loaded gelatin group showed a decrease in adhesion formation when compared with the operative control group; the 20 and 30 mg groups showed signs of severe inflammation. Low doses of 5-fluorouracil applied via a slow-release gelatin system reduced adhesion formation in flexor tendon healing. PMID- 22918884 TI - The functional range of movement of the human wrist. PMID- 22918886 TI - Gastrointestinal cancers accompanied by a dense lymphoid component: an overview with special reference to gastric and colonic medullary and lymphoepithelioma like carcinomas. AB - This review highlights the difference between so-called medullary carcinoma and lymphoepithelioma-like carcinoma with reference to the gastrointestinal tract. The two terms have been applied synonymously in the gastrointestinal tract, with the majority of carcinomas associated with lymphocytes being termed medullary carcinomas. True medullary carcinomas are disposed in syncytial sheets and have well defined peripheral margins; the preponderance of inflammation is peri tumoural. These tumours are also associated with microsatellite instability (MSI). Lymphoepithelioma-like carcinomas tend not to have continuous sheets of tumour but are instead made up of small clusters and aggregates of tumour that are broken up by large numbers of intra-tumoural lymphocytes. These tumours may be associated with Epstein-Barr virus (EBV). Occasional cases may be associated with epigenetic silencing of MLH-1. In conclusion, carcinomas associated with dense lymphoid stroma maybe associated with either MSI or EBV. There are some morphological features that favour either type and in the stomach MSI and EBV are mutually exclusive. PMID- 22918885 TI - In vivo regulation of TGF-beta by R-Ras2 revealed through loss of the RasGAP protein NF1. AB - Ras superfamily proteins participate in TGF-beta-mediated developmental pathways that promote either tumor suppression or progression. However, the specific Ras proteins, which integrate in vivo with TGF-beta signaling pathways, are unknown. As a general approach to this question, we activated all Ras proteins in vivo by genetic deletion of the RasGAP protein Nf1 and examined mice doubly deficient in a Ras protein to determine its requirement in formation of TGF-beta-dependent neurofibromas that arise in Nf1-deficient mice. Animals lacking Nf1 and the Ras related protein R-Ras2/TC21 displayed a delay in formation of neurofibromas but an acceleration in formation of brain tumors and sarcomas. Loss of R-Ras2 was associated with elevated expression of TGF-beta in Nf1-deficient Schwann cell precursors, blockade of a Nf1/TGFbetaRII/AKT-dependent autocrine survival loop in tumor precursor cells, and decreased precursor cell numbers. Furthermore, the increase in size of sarcomas from xenografts doubly deficient in these genes was also found to be TGF-beta-dependent, in this case resulting from cell nonautonomous effects on endothelial cells and myofibroblasts. Extending these findings in clinical specimens, we documented an increase in TGF-beta ligands and an absence of TGF-beta receptor II in malignant peripheral nerve sheath tumors, which correspond to tumors in the Nf1-deficient mouse model. Together, our findings reveal R-Ras2 as a critical regulator of TGF-beta signaling in vivo. PMID- 22918887 TI - Validation of tissue microarrays in oral epithelial dysplasia using a novel virtual-array technique. AB - BACKGROUND: Malignant transformation risk in oral epithelial dysplasia (OED) is currently determined by histological assessment. The subjectivity of this approach has led to interest in identifying prognostic biomarkers. Tissue microarrays (TMA) can reduce the utilization of the finite resources of a pathological archive. However, the selectivity involved in TMA construction necessitates the need to ensure that individual cores are representative of the overall features of the donor specimen. We aimed to validate, for the first time, the use of the TMA technique in OED by using a novel virtual array technique. METHODS: Sections from 38 cases of OED were stained with H&E and 6 immunohistochemical (IHC) biomarkers. All were then digitally scanned. Virtual cores were generated by image capturing a 0.6mm(2) area of the IHC slide that corresponded to the same dysplastic area marked on the H&E slide. Two trained blinded observers scored both whole slides and virtual cores independently. The degree of reliability in scores between the individual raters and between virtual TMA cores and slides was assessed using both interclass correlation coefficient (ICCC) and weighted kappa statistics. RESULTS: Excellent inter-observer reliability was demonstrated with all the immunohistochemical markers. ICCC ranged from 0.67-1.0 and kappa scores >0.8. There was also a high reliability in the scores between whole slides and virtual TMAs, with ICCC of between 0.66 and 0.89 for the 6 markers. CONCLUSIONS: This study validates the use of TMAs in OED using a variety of biomarkers. We also report a novel method for achieving this using a novel virtual-array technique. PMID- 22918888 TI - Low predictive value of positive transplant perfusion fluid cultures for diagnosing postoperative infections in kidney and kidney-pancreas transplantation. AB - AIMS: Infection following transplantation is a cause of morbidity and mortality. Perfusion fluid (PF) used to preserve organs between recovery and transplantation represents a medium suitable for the growth of microbes. We evaluated the relevance of positive growth from PF sampled before the implantation of kidney or kidney-pancreas (KP) allografts. METHODS: Between January 2007 and January 2011, 548 kidney/KP transplants were performed in our centre. A retrospective review of patient records with culture-positive PF was performed. RESULTS: PF was received from 483 (88%) patients, of which 35 (7%, 95% CI 5.3% to 9.9%) were positive for bacteria (31/483, 6.4%, 95% CI 4.6% to 9.8%) and fungi (4/483, 0.8%, 95% CI 0.3% to 2.1%). Thirty-two of the 35 culture-positive PF (91.4%, 95% CI 77.6% to 97%) were considered insignificant. The remaining three patients developed sepsis postoperatively, which was considered to be possibly related to growth in PF; Escherichia coli in one and Klebsiella pneumoniae in two. Of the non-skin flora bacteria cultured from PF, six were resistant to the prophylactic antibiotic given intraoperatively, but only one developed infection postoperatively (E coli, resistant to the co-amoxiclav). CONCLUSIONS: Significant attributable morbidity associated with PF-positive culture results was relatively rare. Culture of organisms other than Enterobacteriaceae or fungi are likely to represent contamination. PMID- 22918889 TI - The value of examination of multiple levels of mammary needle core biopsy specimens taken for investigation of lesions other than calcification. AB - AIMS: It is a standard practice to examine multiple levels of needle core biopsies taken for mammographic calcification, but there is almost no evidence on the value of levels in core biopsies taken for other reasons. This study aimed to assess the value of levels for needle core biopsies taken for investigation of lesions other than calcification. A secondary aim was to assess interobserver agreement of diagnosis. METHODS: For each of the 375 breast core biopsies with three levels the first level was reviewed and a diagnosis made. Then levels 2 and 3 were reviewed and a final diagnosis was made. RESULTS: The diagnosis after examining three levels was different from that in the initial level in 4 of 272 (1.5%, 95% CI 0.04% to 3%) core biopsies taken for reasons other than calcification and in 13 of 103 (13%, 95% CI 6% to 19%) biopsies taken for investigation of calcification. Interobserver agreement of the original diagnosis at the time of reporting and the final diagnosis at the review for this study was 96% (kappa 0.947). CONCLUSIONS: This study confirms the value of levels of biopsies taken to investigate mammographic calcification, but suggests that routine levels are of limited value for breast core biopsies taken for other reasons. PMID- 22918890 TI - RSK2 as a key regulator in human skin cancer. AB - Our previous report demonstrated that RSK2 plays an important role in cell proliferation and transformation induced by tumor promoters such as epidermal growth factor mediated through the N-terminal kinase domain of RSK2 in JB6 Cl41 mouse skin epidermal cells in vitro. However, no direct evidence has been reported regarding the relationship of RSK2 activity and human skin cancer. To elucidate the relationship of RSK2 activity and human skin cancer, we examined the effect of knocking down RSK2 expression on epidermal growth factor-induced anchorage-independent transformation in the premalignant HaCaT human skin keratinocyte cell line and on soft agar colony growth of SK-MEL-28 malignant melanoma cells. We found that the phosphorylated protein levels of RSK2 were enhanced in cancer tissues compared with normal tissues in a human skin cancer tissue array. We found that UVB stimulation induced increased in not only the total and phosphorylated protein levels of ERKs and RSK2 but also the nuclear localization and gene expression of RSK2. RSK2 knockdown inhibited proliferation and anchorage-independent transformation of HaCaT cells and soft agar colony growth of malignant melanoma cells. Moreover, RSK2(-/-) mouse embryonic fibroblast (MEF) showed enhanced sub-G(1) accumulation induced by UVB stimulation compared with RSK2(+/+) MEFs, indicating that RSK2 might play an important role in tolerance against stress associated with ultraviolet. Importantly, activated RSK2 protein levels were highly abundant in human skin cancer tissues compared with matched skin normal tissues. Taken together, our results demonstrated that RSK2 plays a key role in neoplastic transformation of human skin cells and in skin cancer growth. PMID- 22918891 TI - Emergency pharmacist impact on health care-associated pneumonia empiric therapy. AB - PURPOSE: Health care-associated pneumonia (HCAP) is a serious infection dependent on proper treatment that often presents in the emergency department (ED) and deviation from treatment guidelines appears to be high. This study was conducted to evaluate the impact of emergency medicine pharmacists (EPhs) on adherence of empiric antibiotic therapy to guideline recommendations. METHODS: A retrospective chart review of adult patients with HCAP who presented to an academic medical center ED from September 1, 2008 to June 30, 2010 was conducted. The control group included those patients with HCAP who presented to the ED outside of the EPhs' hours (23:00-13:00), and the treatment group consisted of those patients who presented during the EPhs' hours (13:00-23:00). RESULTS: The 81 patients presenting inside the EPhs' hours were significantly more likely to receive guideline adherent empiric antibiotics than the 70 patients presenting outside the EPhs' hours (49.38% vs 25.7%, P = .005). Also, patients in the treatment group received antibiotics in a shorter amount of time (11.37 vs 15.56 hours, P = .272) and at more appropriate doses (85.2% vs 77.1%, P = .29) although these outcomes were not statistically significant. CONCLUSION: The presence of the EPh significantly increased the likelihood of at-risk patients receiving empiric antimicrobial therapy consistent with guideline recommendations. PMID- 22918892 TI - Copper-responsive gene regulation in bacteria. AB - Copper is an essential cofactor of various enzymes, but free copper is highly toxic to living cells. To maintain cellular metabolism at different ambient copper concentrations, bacteria have evolved specific copper homeostasis systems that mostly act as defence mechanisms. As well as under free-living conditions, copper defence is critical for virulence in pathogenic bacteria. Most bacteria synthesize P-type copper export ATPases as principal defence determinants when copper concentrations exceed favourable levels. In addition, many bacteria utilize resistance-nodulation-cell division (RND)-type efflux systems and multicopper oxidases to cope with excess copper. This review summarizes our current knowledge on copper-sensing transcriptional regulators, which we assign to nine different classes. Widespread one-component regulators are CueR, CopY and CsoR, which were initially identified in Escherichia coli, Enterococcus hirae and Mycobacterium tuberculosis, respectively. CueR activates homeostasis gene expression at elevated copper concentrations, while CopY and CsoR repress their target genes under copper-limiting conditions. Besides these one-component systems, which sense the cytoplasmic copper status, many Gram-negative bacteria utilize two-component systems, which sense periplasmic copper concentrations. In addition to these well-studied transcriptional factors, copper control mechanisms acting at the post-transcriptional and the post-translational levels will be discussed. PMID- 22918894 TI - Determination of strain-specific wall teichoic acid structures in Lactobacillus plantarum reveals diverse alpha-D-glucosyl substitutions and high structural uniformity of the repeating units. AB - The structural diversity of wall teichoic acid (WTA) was investigated using biochemical and NMR analyses among 19 strains of Lactobacillus plantarum, of which seven were previously established to contain a glycerol-type backbone, whereas the remaining 12 strains possess ribitol-containing WTA. Despite the fact that the WTAs consisted of identical components, namely phosphoric acid, alditol (glycerol or ribitol) and glucose, comparative analysis of the (1)H and (13)C NMR spectra indicated the presence of six different structures, based on the observed differences in the anomeric signals of glucose residues. To determine the six WTA structures, their repeating units were prepared by alkaline hydrolysis, followed by fractionation on HPLC, and analysis by NMR spectroscopy using synthetic molecules as a reference. The structures of the six isolates were established as 1-alpha-D-glucosyl-sn-glycerol 3-phosphate, 1-alpha-D-kojibiosyl-sn-glycerol 3 phosphate, 1-alpha-D-nigerosyl-sn-glycerol 3-phosphate, 4-alpha-D kojibiosylribitol 1-phosphate and 1,5-linked di-(2,4-di-alpha-D-glucosylribitol) phosphate. The backbone structures appeared to be 3,6'-linked poly(1-alpha-D glucosyl-sn-glycerol phosphate) for the glycerol-type WTA and 1,5-linked poly(ribitol phosphate) for the ribitol-containing WTA. Moreover, in the analysis of the alkaline hydrolysates on HPLC, only single structures of repeating units were released from each WTA, indicating the high structural uniformity of the WTA in each strain. Notably, analyses of lipoteichoic acid isolated from representative strains harbouring the six different WTAs revealed the universal presence of a 1,3-linked poly(glycerol phosphate) chain, substituted at C-2 of the glycerol residues with glucose residues. These findings provide fundamental information on WTA structural variability in Lb. plantarum, which seems likely to play a pivotal role in the physiology of this bacterial species. PMID- 22918893 TI - Staphylococcus aureus adherence to Candida albicans hyphae is mediated by the hyphal adhesin Als3p. AB - The bacterium Staphylococcus (St.) aureus and the opportunistic fungus Candida albicans are currently among the leading nosocomial pathogens, often co-infecting critically ill patients, with high morbidity and mortality. Previous investigations have demonstrated preferential adherence of St. aureus to C. albicans hyphae during mixed biofilm growth. In this study, we aimed to characterize the mechanism behind this observed interaction. C. albicans adhesin deficient mutant strains were screened by microscopy to identify the specific receptor on C. albicans hyphae recognized by St. aureus. Furthermore, an immunoassay was developed to validate and quantify staphylococcal binding to fungal biofilms. The findings from these experiments implicated the C. albicans adhesin agglutinin-like sequence 3 (Als3p) in playing a major role in the adherence process. This association was quantitatively established using atomic force microscopy, in which the adhesion force between single cells of the two species was significantly reduced for a C. albicans mutant strain lacking als3. Confocal microscopy further confirmed these observations, as St. aureus overlaid with a purified recombinant Als3 N-terminal domain fragment (rAls3p) exhibited robust binding. Importantly, a strain of Saccharomyces cerevisiae heterologously expressing Als3p was utilized to further confirm this adhesin as a receptor for St. aureus. Although the parental strain does not bind bacteria, expression of Als3p on the cell surface conferred upon the yeast the ability to strongly bind St. aureus. To elucidate the implications of these in vitro findings in a clinically relevant setting, an ex vivo murine model of co-infection was designed using murine tongue explants. Fluorescent microscopic images revealed extensive hyphal penetration of the epithelium typical of C. albicans mucosal infection. Interestingly, St. aureus bacterial cells were only seen within the epithelial tissue when associated with the invasive hyphae. This differed from tongues infected with St. aureus alone or in conjunction with the als3 mutant strain of C. albicans, where bacterial presence was limited to the outer layers of the oral tissue. Collectively, the findings generated from this study identified a key role for C. albicans Als3p in mediating this clinically relevant fungal-bacterial interaction. PMID- 22918895 TI - Navigating non-positivity in neighbourhood studies: an analysis of collective efficacy and violence. AB - BACKGROUND: In multilevel studies, strong correlations of neighbourhood exposures with individual and neighbourhood confounders may generate problems with non positivity (ie, inferences that are 'off-support'). The authors used propensity restriction and matching to (1) assess the utility of propensity restriction to ensure analyses are 'on-support' and (2) examine the relation between collective efficacy and violence in a previously unstudied city. METHODS: Associations between neighbourhood collective efficacy and violent victimisation were estimated in data from New York City in 2005 (n=4000) using marginal models and propensity matching. RESULTS: In marginal models adjusted for individual confounders and limited to observations 'on-support', under conditions of high collective efficacy, the estimated prevalence of violent victimisation was 3.5/100, while under conditions of low collective efficacy, it was 7.5/100, resulting in a difference of 4.0/100 (95% CI 2.6 to 5.8). In propensity-matched analysis, the comparable difference was 4.0/100 (95% CI 2.1 to 5.9). In analyses adjusted for individual and neighbourhood confounders and limited to observations 'on-support', the difference in violent victimisation associated with collective efficacy was 3.1/100 (95% CI 1.2 to 5.2) in marginal models and 2.4/100 (95% CI 0.2 to 4.5) in propensity-matched analysis. Analyses without support restrictions produced surprisingly similar results. CONCLUSIONS: Under conditions of high collective efficacy, there was about half the prevalence of violence compared with low collective efficacy. The results contribute to a growing body of evidence that suggests collective efficacy may shape violence, and illustrate how careful techniques can be used to disentangle exposures from highly correlated confounders without relying on model extrapolation. PMID- 22918896 TI - Urban neighbourhood unemployment history and depressive symptoms over time among late middle age and older adults. AB - BACKGROUND: Little is known about how a neighbourhood's unemployment history may set the stage for depressive symptomatology. This study examines the effects of urban neighbourhood unemployment history on current depressive symptoms and subsequent symptom trajectories among residentially stable late middle age and older adults. Contingent effects between neighbourhood unemployment and individual-level employment status (ie, cross-level interactions) are also assessed. METHODS: Individual-level survey data are from four waves (2000, 2002, 2004 and 2006) of the original cohort of the nationally representative US Health and Retirement Study. Neighbourhoods are operationalised with US Census tracts for which historical average proportion unemployed between 1990 and 2000 and change in proportion unemployed between 1990 and 2000 are used to characterise the neighbourhood's unemployment history. Hierarchical linear regressions estimate three-level (time, individual and neighbourhood) growth models. RESULTS: Symptoms in 2000 are highest among those residing in neighbourhoods characterised by high historical average unemployment beginning in 1990 and increasing unemployment between 1990 and 2000, net of a wide range of socio-demographic controls including individual-level employment status. These neighbourhood unemployment effects are not contingent upon individual-level employment status in 2000. 6-year trajectories of depressive symptoms decrease over time on average but are not significantly influenced by the neighbourhood's unemployment history. CONCLUSIONS: Given the current US recession, future studies that do not consider historical employment conditions may underestimate the mental health impact of urban neighbourhood context. The findings suggest that exposure to neighbourhood unemployment earlier in life may be consequential to mental health later in life. PMID- 22918897 TI - Friends are equally important to men and women, but family matters more for men's well-being. AB - BACKGROUND: People with larger social networks are known to have better well being; however, little is known about (1) the association with socio-demographic factors that may predict the size and composition of social networks and (2) whether the association with well-being is independent of pre-existing psychological health or socio-demographic factors. METHODS: The authors used information collected from 3169 men and 3512 women who were born in Great Britain in 1958. First, age on leaving full-time education, partnership and employment status at age 42 were used to predict the size and composition of cohort members' social networks at age 45 using ordered logistic regression. Second, using multiple linear regression, the associations between social network size by composition (relatives and friends) and psychological well-being at age 50 were assessed, adjusting for socio-demographic factors and psychological health at age 42. RESULTS: Not having a partner and staying in full-time education after age 16 was associated with a smaller kinship network in adults. Having a smaller friendship network at age 45 was associated with poorer psychological well-being among adults at age 50, over and above socio-demographic factors and previous psychological health. Additionally, having a smaller kinship network was associated with poorer psychological well-being among men. CONCLUSIONS: Having a well-integrated friendship network is a source of psychological well-being among middle-aged adults, while kinship networks appear to be more important for men's well-being than for women's. These relationships are independent of education, material status and prior psychological health. PMID- 22918898 TI - A randomised controlled study to evaluate the effectiveness of targeted occupational health and safety consultation or inspection in Ontario manufacturing workplaces. AB - OBJECTIVE: From 2004 to 2008, the prevention system in Ontario, Canada ran the High Risk Firm Initiative, an injury-experience based targeted consultation or inspection programme. Our objective was to establish whether prevention system targeting of firms was effective in improving injury outcomes. METHODS: Randomised controlled parallel groups. Population included all manufacturing firms registered with the Ontario Workplace Safety & Insurance Board in 2005. Firms ranked between the 2nd and 10th percentile on a composite measure of occupational health and safety performance were randomised to three study arms in 2006: targeted for Health & Safety Association (HSA) consultation, targeted for Ministry of Labour (MOL) inspection, or services as usual. Data included firm characteristics (sector, size, years in business, region, branches), work injury claims 2002-2008 and measures of consulting and inspecting activity. Negative binomial generalised estimating equations modelled claim and disability day rates by study arm and year, controlling for firm characteristics. RESULTS: Among 2153 firms, firm characteristics and 2002-2005 rates of work injury claims and disability days were similar across arms. Firm outcomes were significantly different from year to year, but study arm by year interactions were insignificant indicating similar trends for all three study arms. 83% of HSA targeted firms were contacted and 63% engaged while 75% of MOL targeted firms were inspected with orders written in 56%. CONCLUSIONS: Consultation and enforcement programmes as implemented were not sufficient to reduce work injury outcomes over 21 month follow-up. Lack of benefit could be due to non-specific firm selection methods, limited firm participation in interventions, low intervention intensity or insensitivity of available outcomes. PMID- 22918899 TI - Vaccinating welders against pneumonia. PMID- 22918900 TI - Yellowstone bison--should we preserve artificial population substructure or rely on ecological processes? PMID- 22918901 TI - Paralympics 2012: creating a foundation and determining success. PMID- 22918902 TI - Motivations and barriers to prosthesis users participation in physical activity, exercise and sport: a review of the literature. AB - BACKGROUND: The UK will host the Paralympics in 2012 and the Commonwealth Games in 2014 showcasing the talents of elite athletes and aiming to inspire the population to become involved. However, low levels of physical activity are prevalent: only 40% of men and 28% of women meet the minimum UK physical activity recommendations. The population of people with limb absence is no exception. OBJECTIVES: To determine if people with amputation are participating in physical activity and sport; whether post-amputation activity levels match pre-amputation levels; and if there are motivations and barriers to participation. STUDY DESIGN: Literature review. METHODS: Five reviewers systematically searched all peer reviewed and gray literature in seven bibliographic databases and the Cochrane Library. RESULTS: Following rigorous elimination, 12 articles were finally included in the review and critically appraised. Four themes were identified: components; rehabilitation outcomes; body image; and motivations and barriers to participation. CONCLUSION: People with limb absence are not participating in physical activity conducive to health benefits, and only a minority participate in exercise and sports. Participation following amputation does not mirror that of pre-amputation levels, and more barriers than motivations exist to adopting or maintaining a physically active lifestyle. PMID- 22918903 TI - Should preparation for elite sporting participation be included in the rehabilitation process of war-injured veterans? AB - BACKGROUND: Participation in sport and exercise training, while aiding in the reintegration and confidence building of wounded service personnel, also has potential to prepare them for elite sport competition. It is this encouragement of the war injured to use sport and recreational physical activity as a means of rehabilitation back into civilian life, which has become the worldwide phenomenon of Paralympic sport. OBJECTIVES: This paper evaluates existing research relating to the incidence of types of war injuries and the use of sport within the rehabilitation process. STUDY DESIGN: Literature review. METHODS: Initial searches were conducted in the electronic databases EBSCOHost, ScienceDirect and Pubmed using the keywords 'veterans' and 'sport' or 'physical activity'. These searches were then supplemented by tracking all key references from the appropriate articles identified. A narrative literature review methodology was employed. RESULTS: Although it is clear from the reported literature that further development of available rehabilitation services is necessary to provide the required level of care for the types of mental and physical injuries and the concept of 'therapeutic recreation' is becoming popular, there is still a need for the development of specific protocols to identify individuals who can participate and excel in a specific sport at an elite level. CONCLUSIONS: Drawing on the US military experience it can be argued that sport in the UK and other parts of the world should be more widely recognized as a component of rehabilitation. This is not just for the role that sport can play as a tool for rehabilitation but also for the intrinsic and extrinsic benefits that participation in elite sport can offer. PMID- 22918904 TI - The Paralympic athlete: a systematic review of the psychosocial literature. AB - BACKGROUND: There is a lack of knowledge of the psychosocial wellbeing and attributes of Paralympic athletes. Such knowledge may reveal what contributes to exceptional performance. OBJECTIVES: To systematically review the literature on psychosocial wellbeing and attributes of the Paralympic athlete. STUDY DESIGN: Systematic literature review. METHODS: Five key databases that index psychosocial literature were searched: CINAHL, ISI Web of Science, MEDLINE, PsycINFO and SportsDiscus. RESULTS: Sixteen papers were found that met the inclusion criteria. The studies were characterised by heterogeneity of design, sample characteristics, outcome assessment and outcomes examined. The emerging thematic areas are 1) participation, motivations and goals; 2) mental imagery; 3) stress and coping; 4) personality; 5) attitudes towards other disabled-bodied athlete groups; 6) knowledge and attitudes towards doping; and 7) transitions to retirement. CONCLUSIONS: Relative to the biomechanical aspects of the Paralympian, the psychosocial literature remains limited and diffuse. Nonetheless an understanding of the psychosocial profile of these athletes complements the extant physiological and technological knowledge in enabling a holistic view of what contributes to the successful Paralympic athlete and may facilitate the team working to optimize performance and wellbeing in these high-performing individuals. PMID- 22918905 TI - Sport prostheses and prosthetic adaptations for the upper and lower limb amputees: an overview of peer reviewed literature. AB - BACKGROUND: Sport prostheses are used by both upper- and lower-limb amputees while participating in sports and other physical activities. Although the number of these devices has increased over the past decade, no overview of the peer reviewed literature describing them has been published previously. Such an overview will allow specialists to choose appropriate prostheses based on available scientific evidence rather than on personal experience or preference. OBJECTIVE: To provide an overview of the sport prostheses as they are described by the papers published in peer reviewed literature. STUDY DESIGN: Literature review. METHODS: Four electronic databases were searched using free text and Medical Subject Headings (MESH) terms. Papers were included if they concerned a prosthesis or a prosthetic adaptation used in sports. Papers were excluded if they did not originate from peer reviewed sources, if they concerned prostheses for body parts other than the upper or lower limbs, if they concerned amputations distal to the wrist or ankle, or if they were written in a language other than English. RESULTS: Twenty-four papers were included in this study. The vast majority contained descriptive data and consisted of expert opinions and technical notes. CONCLUSION: Data concerning the energy efficiency, technical characteristics and special mechanical properties of prostheses or prosthetic adaptations for sports, other than running, are scarce. PMID- 22918906 TI - Effect of take-off from prosthetic versus intact limb on transtibial amputee long jump technique. AB - BACKGROUND: Increasing numbers of long jumpers with lower limb amputations choose to take off from their prosthetic limb. It is not yet known what difference in technique, if any, this requires, or which is more advantageous. OBJECTIVES: To investigate kinematic differences in long jump technique in athletes with a unilateral transtibial ampution (TT) who take off from their prosthetic limb versus those who take off from their intact limb. STUDY DESIGN: Naturalistic, field-based, observational; independent group, nonparametric comparison. METHODS: Two-dimensional sagittal plane kinematic analysis was performed on all athletes competing in the men's Paralympic TT long jump finals. Five athletes took off from their prosthetic limb (TO(prosth)) and five from their intact limb (TO(intact)). RESULTS: No differences were seen between the two groups in terms of jump distance, approach speed or vertical velocity at touch down. While in contact with the take-off board, the two groups gained a similar amount of vertical velocity. However, the TO(prosth) group appeared to conserve horizontal velocity by using the prosthesis as a 'springboard', minimizing the large hip and knee range of motion displayed by the TO(intact) group and athletes in previous studies. CONCLUSIONS: While differences in technique were observed, no difference was found for jump distance. PMID- 22918907 TI - Sprint prostheses used at the Paralympics: a proposal for an assessment method to maintain fairness. AB - BACKGROUND: Unique to sport with a disability such as those performed at the Paralympics, the need to improve the performance of lower limb prostheses can conflict with the need to provide an equal opportunity to win whilst still needing to encourage and maximise participation. OBJECTIVES: This paper extends previous research by attempting to propose a method suitable for sports governing bodies to help any functional assessment of sprinting lower limb prosthesis technology in the future. STUDY DESIGN: The study comprises two elements: 1) A historical review and evaluation of drop jump assessment techniques. 2) A pilot test of a candidate using two mechanically different lower limb regions. METHODS: A unilateral drop jump technique is assessed historically as an evaluation technique for sprinters with a lower-limb amputation. Further, a unilateral drop jump using mechanically altered lower limbs is piloted. RESULTS: The historical review provides no evidence to suggest that this technique is not suitable for athlete participants. The pilot trials show a statistically stable and repeatable method of demonstrating a mechanical deficiency of one limb to another. Six jumps are suitable to obtain stable results but the mechanical behaviour of one limb may eventually change based on accumulated fatigue. CONCLUSIONS: The unilateral drop jump is shown to be viable for application to an athlete population with a lower limb unilateral amputation. PMID- 22918908 TI - Leg stiffness and sprint ability in amputee sprinters. AB - BACKGROUND: Understanding leg stiffness (K (leg)) in amputee sprinters is important for the evaluation of their sprint ability and development of running specific prostheses (RSP). OBJECTIVES: To investigate K (leg) during hopping in amputee sprinters. STUDY DESIGN: Cross-sectional study. METHODS: Seven transtibial (TT) and seven transfemoral (TF) amputee sprinters, as well as seven non-active able-bodied subjects, performed one-legged hopping matching metronome beats at 2.2 Hz. Amputees hopped on their sound limb whereas able-bodied (AB) subjects hopped on their dominant limb. Using a spring-mass model, K (leg) was calculated from the subjects' body mass, ground contact and flight times. RESULTS: Both TT and TF sprinters demonstrated significantly higher K (leg) than AB subjects. K (leg) during hopping on the sound leg significantly correlated with personal records attained in a 100-m sprint in both TT (r = -0.757) and TF sprinters (r = -0.855). CONCLUSION: The results of the present study suggest that amputee sprinters have a greater K (leg) during hopping than inactive non amputees, and that their sprint ability can be predicted from the K (leg) during hopping at 2.2 Hz on the sound limb. PMID- 22918909 TI - Mechanisms to absorb load in amputee running. AB - BACKGROUND: We aimed to determine if a shock absorbing pylon (SAP) influenced the ground reaction force characteristics and the shock absorbing mechanisms compared to a rigid pylon (Rigid) during the loading phase in running. OBJECTIVES: To determine if the SAP influences the mechanisms of loading compared to the Rigid condition. STUDY DESIGN: A convenience sample of transtibial amputees participated in a laboratory-based study. The prosthetic set-up was randomly altered fd?sdsd. METHODS: Five recreationally active male transtibial amputees age: 18-50 years; mean mass: 86.7 +/- 17.5 kg; height: 1.77 +/- 0.07 m) volunteered from a population-based sample. They completed a within-participant designed study assessing a SAP and a Rigid condition during running. Kinematic and kinetic data were collected during two sessions following a one-week customization period. RESULTS: Loading rate, peak vertical and horizontal ground reaction forces and the time to each measure along with knee and hip angular displacement, absorbing powers and work done between the SAP and Rigid conditions were not systematically affected by the prosthetic condition. CONCLUSIONS: The effect of the SAP was minimal and inconsistent in the loading phase, with only some amputees presenting higher and others with lower values for the tested variables. PMID- 22918910 TI - Biomechanical differences between experienced and inexperienced wheelchair users during sport. AB - BACKGROUND: During functional wheelchair movement there are several types of stroke pattern that a manual wheelchair user (MWCU) can utilize in order to propel. OBJECTIVES: To examine the biomechanical differences between disabled (WCU) and able-bodied (NWCU) children whilst taking part in functional activities at the Cheetahs Wheelchair Sports Club. STUDY DESIGN: A multiple measures cohort study. METHODS: Eleven participants were divided into two groups; WCU (n = 7) and NWCU (n = 4). All subjects were asked to perform three functional tasks; 30 second agility test, 1-minute distance test and a 10-metre sprint test. Upper body kinematics were recoded using a XSens MVN BIOMECH motion capture suit. RESULTS: NWCU outperformed the WCU in all of the tasks, however, no significant differences between the group's results were found. Nevertheless, significant differences were found in the maximum shoulder flexion angle for both right and left with NWCU utilizing more flexion and near significant differences in the NWCU overall shoulder range for right and left. CONCLUSIONS: In order to increase function in young MWCU then more specific-based sessions should be implemented targeting the exploitation of large shoulder ranges during propulsion, consequently resulting in more efficient movement. PMID- 22918911 TI - Is there a relationship between core stability, balance and strength in amputee soccer players? A pilot study. AB - BACKGROUND: The body is a kinetic chain and all the systems and muscle groups play important roles in this chain. Core stability, strength and balance are important components of performance within many sports, and in particular soccer. However, the relationship between these components is not fully understood. OBJECTIVES: To investigate the relationship between core stability, balance and strength in amputee soccer players. STUDY DESIGN: Clinical pilot trial. METHODS: Eleven amputee soccer players (mean age = 24.63 +/- 6.48 years) participated in our study. A Kinesthetic Ability Trainer device was used to assess balance. Trunk strength was evaluated by isokinetic dynamometer. Gillet test was used to evaluate the sacroiliac joint movement. Modified plank test was used to determined dynamic core stability. Disability was evaluated using the Oswestry Disability Index. RESULTS: The results showed that there was a correlation between flexor isokinetic trunk muscle strength at the velocity of 60 degrees /sec and modified plank test (r = 0.630, p = 0.038). There was a negative correlation between flexor isokinetic trunk muscle strength at the velocity of 180 degrees /sec and Oswestry Disability Index score (r = -0.649, p = 0.031). CONCLUSIONS: Amputee soccer is a sport which is generally performed with one limb balance with crutches. It is therefore perceived that a relationship between balance and sacroiliac mobility, and should be considered for evaluation process and performance analysis in amputee soccer. However, in future studies, we recommend that such evaluations on amputee soccer players should be carried out with increased numbers. PMID- 22918912 TI - Functional improvement and social participation through sports activity for children with mental retardation: a field study from a developing nation. AB - BACKGROUND: While the positive effect of sports and exercise on physical and psychological well being is well documented within the general population, the effects of sports on the functional ability of a child with mental retardation are limited. OBJECTIVES: To determine if sports activities have been detrimental in improving functional ability in sample of children with mental retardation based in Kolkata, a metropolis in India. STUDY DESIGN: Field level study. METHODS: Six sports associations registered under the Sports Authority of India for training children with mental retardation were shortlisted on the basis of four criteria. From the register, every third name (gender irrespective) belonging to the second (12-15 years) and third (15-21 years) subclasses (out of the four categories laid down in the Special Olympics participation rules) against a constraint of at least two years active attendance in the sports facility for the child was selected. A sample of 31 children was drawn and the WHO Disability Assessment Schedule 2.0 (WHODAS 2.0) 12-item version was administered to the caregiver-teacher-coach team of the sample. Relative changes in scores between the point when the survey was conducted and the point when the child joined the sports facility was used as the dependent variable for regression analysis. The number of years in active sports, in school age of the respondent and base score of the children when they joined school were the independent variables. RESULTS: For seven of the WHODAS 2.0 12-item attributes, the number of years in sports activities was found to have a statistically significant effect (p < 0.01) on the functional well being of children with mild to moderate mental retardation. The number of years in school was also another statistically significant factor (p < 0.01) responsible for this improvement. The children, however, perceived of being not welcome in community activities, but participated in activities meant exclusively for them. CONCLUSIONS: This small study showed that the proposition that number of years in sports activities was a significant factor responsible for improving the functioning of children with mild to moderate mental retardation. PMID- 22918913 TI - Performance dispersion for evidence-based classification of stationary throwers. AB - BACKGROUND: There is a need for better understanding of the dispersion of classification-related variable to develop an evidence-based classification of athletes with a disability participating in stationary throwing events. OBJECTIVES: The purposes of this study were as follows: (1) to describe tools designed to comprehend and represent the dispersion of the performance between successive classes and (2) to present this dispersion for the elite male and female stationary shot-putters who participated in Beijing 2008 Paralympic Games. STUDY DESIGN: Retrospective study. METHODS: This study analysed a total of 479 attempts performed by 114 male and female stationary shot-putters in three F30s (F32-F34) and seven F50s (F52-F58) classes during the course of eight events during Beijing 2008 Paralympic Games. RESULTS: The average differences of best performance were 1.46 +/- 0.46 m for males between F54 and F58 classes as well as 1.06 +/- 1.18 m for females between F55 and F58 classes. The results demonstrated a linear relationship between best performance and classification while revealing two male gold medallists in F33 and F52 classes as outliers. CONCLUSIONS: This study confirms the benefits of the comparative matrices, performance continuum and dispersion plots to comprehend classification-related variables. The study presented here represents a stepping stone into biomechanical analyses of stationary throwers, particularly on the eve of the London 2012 Paralympic Games where new evidences could be gathered. PMID- 22918914 TI - The effects of altering initial ground contact in the running gait of an individual with transtibial amputation. AB - BACKGROUND: High rates of osteoarthritis of the knee joint of the intact limb in persons with amputation have raised concern about the long-term consequence of running. The purpose of this intervention was to determine if loading of the knee on the intact limb of a person with transtibial amputation during running could be decreased by changing the intact limb initial ground contact from rear foot to forefoot strike. CASE DESCRIPTION AND METHODS: This study compared kinematic, kinetic and temporal-spatial data collected while a 27-year-old male, who sustained a traumatic unilateral transtibial amputation of the left lower extremity, ran using a forefoot ground contact and again while using a heel first ground contact. FINDINGS AND OUTCOMES: Changing initial ground contact from rear foot strike to forefoot strike resulted in decreases in vertical ground reaction forces at impact, peak knee moments in stance, peak knee powers, and improved symmetry in step length. CONCLUSION: This case suggests forefoot initial contact of the intact limb may minimize loading of the knee on the intact limb in individuals with transtibial amputation. PMID- 22918915 TI - A novelty universal adaptive seating system for dragon boating. AB - BACKGROUND AND AIM: Dragon boating is a non-weight-bearing sport that requires strenuous and repetitive upper body movements. Athletes with lower limb and trunk weakness are unable to participate due to insufficient seating balance and are at an increased risk of injury. This technical note presents an innovative and successful design of an adaptive seating system for dragon boating. TECHNIQUE: The adaptive seating system provided an optimal trunk support and required stability through an adjustable upholder and angled seat. It also facilitated the athletes to maximize their upper limb function. Specific design for safety measures and quick installation were also highlighted. DISCUSSION: The adaptive seating system is functional, safe, and a universal design for physically disabled athletes with lower limb and trunk weakness in dragon boating. PMID- 22918916 TI - Preparing our Paralympians: research and development at Ossur, UK. Interview by Sarah A. Curran. AB - In the last 25 years, the continuous evolution in the design of prostheses for individuals with transfemoral and transtibial amputations has been remarkable. Mirroring this development is the dependency and expectancy of the prosthesis technology by the athletes, coaches and other personnel involved in creating Paralympians of today and the future. Ossur is recognised as a leader in designing innovative prosthetic products that have contributed worldwide to developing leading Paralympians. The opening section of this article presents an overview of the new Ossur products for 2012. Discussion is also focussed on how Ossur's high-function prosthetic products are integrated into an athlete's training regime. With involvement of the clinical team discussion is also expanded to recognise the important contribution coaching staff has on optimising performance of a Paralympian's training regime. The dialogue continues with a viewpoint on whether Oscar Pistorius, the face of Ossur who wears Flex-Foot Cheetah blades, should participate in the Olympics and Paralympics. While the conclusion of this article may leave more questions than answers, the technology and products offered by Ossur provide for a credible foundation and preparation for future challenges beyond the London 2012 Paralympic Games. PMID- 22918917 TI - Adaptive sports ankle prosthetics. Interview by Sarah A. Curran. AB - Participating in sport at all levels is gaining a dedicated following and this is also apparent in individuals with an amputation. Currently, there is a wide variety of ankle prostheses available which attempt to provide function, control, and comfort, as well as good aesthetic appeal. Participation in sport, however, increases the demands placed upon ankle prostheses. This can compromise function and performance, and constrain the opportunities of participation in various outdoor and water sports. In acknowledging this limitation and the need to develop more versatile ankle prostheses, this article introduces the evolution of a prototype ankle prosthesis referred to as "Adaptive Sports Ankle." The ankle prosthesis, which is compatible with any foot pyramid adapter, offers the same range of motion as the normal human ankle joint and is made up of components that are chemical and corrosion resistant. These design features that are specifically created to accommodate below-the-knee amputees provide an ideal prosthesis for those wishing to lead an active lifestyle and participate in aquatic (i.e. swimming, surfing, and scuba diving), snowboarding, and equestrian activities. Although it is acknowledged that there is a need to establish research on the Adaptive Sports Ankle, its introduction to the market will enhance and expand opportunities of those individuals with a lower limb amputation to lead an active and healthy lifestyle. PMID- 22918918 TI - Research and development at novel GmbH, Germany for prosthetics and paraplegics. Interview by Sarah A. Curran. AB - Pressure distribution measurement offers an objective and quantifiable method of determining the loads applied to the human body during static and dynamic situations such as walking and the more demanding tasks associated with sporting activities. While there are various systems available on the market, the technology and developments offered by novel (novel.de) a company based in Munich, Germany are regarded as innovative. The intent of this article is to outline the development of novel's pressure measurement technology and explore how the pliance(r) system can assist in determining an optimal fit of a prosthesis in an athlete. The discussion also focuses on the introduction of a new Elastisens(r) technology of the novel sensor pads to enable analysis of very contoured surfaces. Key pressure parameters for determining optimal performance are also explored; however, clinicians and researchers are guided to acknowledging the need to direct and perform their analysis within context - in other words, the analysis must be hypothesis driven. PMID- 22918919 TI - Biomechanical analyses of the performance of Paralympians: from foundation to elite level. Interview by Sarah A. Curran. AB - A biomechanical analysis of sports performance provides an objective method of determining performance of a particular sporting technique. In particular, it aims to add to the understanding of the mechanisms influencing performance, characterization of athletes and provide insights into injury predisposition. While the performance in sport of able-bodied athletes is well recognized in the literature, less information and understanding are known on the complexity, constraints and demands placed on the body of an individual with a disability. This article provides a dialogue that outlines scientific issues of the performance analysis of multi-level athletes with a disability, including Paralympians. Four integrated themes are explored, the first of which focuses on how biomechanics can contribute to the understanding of sports performance in athletes with a disability and how it may be used as an evidence-based tool. This latter point questions the potential for a possible cultural shift led by the emergence of user-friendly instruments. The second theme briefly discusses the role of reliability of sports performance and addresses the debate of two dimensional and three-dimensional analyses. The third theme addresses key biomechanical parameters and provides guidance to clinicians and coaches on the approaches adopted using the biomechanical/sports performance analysis for an athlete with a disability starting out, to the emerging and elite Paralympian. For completeness of this discourse, the final theme is based on the controversial issues on the role of assisted devices, and the inclusion of Paralympians into able-bodied sport. All combined, this dialogue highlights the intricate relationship between biomechanics and training of individuals with a disability. Furthermore, it illustrates the complexity of modern training of athletes, which can only lead to a better appreciation of the performances to be delivered in the London 2012 Paralympic Games. PMID- 22918920 TI - Musculoskeletal simulations: a complementary tool for classification of athletes with physical impairments. PMID- 22918922 TI - Melanoma as a model tumour for immuno-oncology. AB - Melanoma is one of the most aggressive forms of skin cancer. Furthermore, incidence rates are increasing. Until recently, no agent had been shown to improve survival over supportive care and treatment guidelines recommended that patients with metastatic disease were entered into clinical trials. With so few treatment options available, there was a clear need for new, more effective treatments in this setting. Melanoma serves as a 'model' tumour for understanding immunity to cancer. Melanoma tumour-associated antigens were among the first cancer antigens to be identified and classified, with further studies showing that many of these are also expressed by other tumour types. In addition, melanoma regression has been associated with vitiligo, visibly confirming an active role of the immune system in this type of cancer, and spontaneous regression of primary melanomas has also been observed in some cases. These observations, relating to the activity of the immune system in melanoma, provided strong evidence that this tumour would be amenable to immunotherapy, with immunotherapies such as cytokines, adoptive cell transfer and T-cell modulators shown to be an effective therapeutic approach. Against this background, melanoma has long been at the cutting edge of immuno-oncology research and will likely continue to be used as a model tumour to increase our understanding of immuno oncology and to inform development in other types of cancer. PMID- 22918923 TI - How recent advances in immunotherapy are changing the standard of care for patients with metastatic melanoma. AB - In 2011, two therapies were approved for the treatment of metastatic melanoma: ipilimumab, an immunotherapeutic agent, and vemurafenib, a BRAF kinase inhibitor. These approvals were based on data from phase III trials, which showed that treatment with these agents produced substantial improvements in overall survival (OS). Ipilimumab has been investigated in two phase III trials: one as monotherapy in patients with pretreated metastatic melanoma at a dose of 3 mg/kg and the second in combination with dacarbazine (DTIC) chemotherapy in patients with previously untreated metastatic melanoma at a dose of 10 mg/kg. Among the pretreated patients, ipilimumab monotherapy significantly improved median OS (Hazard ratio (HR): 0.66, P = 0.003) from 6.4 months in gp100 vaccine controls to 10.1 months. The rates of OS in the ipilimumab-alone group and the gp100 group, respectively, were 45.6% and 25.3% at 12 months and 23.5% and 13.7% at 24 months. In the second trial, OS was significantly longer in previously untreated patients receiving ipilimumab plus DTIC than those receiving DTIC plus placebo (11.2 months versus 9.1 months; HR: 0.72, P < 0.001), with higher survival rates in the ipilimumab plus DTIC group at 1 year (47.3% versus 36.3%), 2 years (28.5% versus 17.9%) and 3 years (20.8% versus 12.2%). When using ipilimumab in the clinic, special consideration should be given to immune-related adverse events (irAEs) and assessment of response. Established guidelines can be used to manage the majority of irAEs effectively. Proposed modifications made to the existing response criteria mean that the clinician can accurately detect immune-related responses that would have been considered representative of progressive disease using conventional criteria. Further research is warranted to establish how immunotherapeutic agents can be combined with conventional agents, with each other or with molecularly targeted agents such as vemurafenib, to further optimise clinical outcomes. PMID- 22918924 TI - The evolving role of immunotherapy in prostate cancer. AB - The prognosis for men with metastatic, castration-resistant prostate cancer (CRPC) is limited, and patients have very few treatment options, particularly if the treatment failed with docetaxel (Taxotere). As a result, there is a requirement for novel approaches to therapy. Using immunotherapy to induce immune responses to prostate cancer in preclinical and clinical studies appears to be a valid therapeutic approach. In a pivotal phase III trial, treatment with sipuleucel-T, an autologous cellular vaccine consisting of activated antigen presenting cells loaded with prostatic acid phosphatase (PAP), gave a median overall survival of 25.8 months compared with 21.7 months for placebo-treated patients, resulting in a 22% relative reduction in the risk of death. Based on these results, sipuleucel-T became the first therapeutic vaccine approved for any type of cancer in the USA. PROSTVAC((r))-VF, a poxvirus-based vaccine engineered to present prostate-specific antigen (PSA) and three immune costimulatory molecules, and GVAX, a vaccine consisting of two prostate cancer cell lines (LnCAP and PC3) and genetically modified to secrete granulocyte-macrophage colony stimulating factor (GM-CSF), both showed promising results in phase II studies, although GVAX failed to meet its primary end point of overall survival when compared with docetaxel in a phase III study. T-cell modulation is another potential immunotherapeutic strategy for CRPC. Ipilimumab, an antibody against the cytotoxic T-lymphocyte-associated antigen-4, is being evaluated in phase I/II studies, both alone and in combination with chemotherapy, radiotherapy or GVAX, with activity in prostate cancer. CRPC is one of the few tumour types where immunotherapy is the current standard of care. Further research, however, will be necessary to improve antitumour responses and clinical benefits, including the use of novel combinatorial approaches. PMID- 22918925 TI - What future opportunities may immuno-oncology provide for improving the treatment of patients with lung cancer? AB - Lung cancer is the leading cause of cancer-related mortality worldwide, with non small-cell lung cancer (NSCLC) accounting for approximately 85% of all cases. Most patients with NSCLC are diagnosed at an advanced stage and have a poor prognosis, with a 5-year survival rate of <5%. Despite the introduction of new chemotherapeutic agents and molecularly targeted drugs, outcomes remain poor, emphasising the need for new treatment approaches. Inducing or potentiating immune responses via immunotherapeutic manipulation is a viable treatment approach for lung cancer. Antigen-specific, tumour-cell, and dendritic cell-based vaccines have all been evaluated in lung cancer, and some have shown promising clinical activity in phase II trials. These include liposomal BLP25 vaccine (L BLP25), which targets mucin 1, and melanoma-associated antigen 3 (MAGE-A3) antigen-specific cancer immunotherapeutic (ASCI), which targets MAGE-A3, a peptide expressed almost exclusively on tumour cells. MAGE-A3 ASCI is being evaluated in the adjuvant setting in a phase III trial of patients with early stage NSCLC, while a phase III trial of L-BLP25 is enrolling patients with unresectable stage III NSCLC. T-cell modulating agents (e.g. antibodies against programmed death 1 and cytotoxic T-lymphocyte-associated antigen-4 [CTLA-4]) are also being investigated. For example, in patients with NSCLC treated with paclitaxel and carboplatin, the phased administration of ipilimumab (an antibody against CTLA-4) resulted in substantial improvements in immune-related progression-free survival compared with chemotherapy alone (5.7 versus 4.6 months; P = 0.05). Immunotherapy in lung cancer is starting to deliver promising results in clinical trials. However, further research will be required to establish the optimal timing of therapy (i.e. in the adjuvant or metastatic settings). In addition, it will be important to determine if immunotherapies are most effective when used alone or in combination with other agents. PMID- 22918926 TI - Emerging immunotherapies for renal cell carcinoma. AB - In recent years, an improved understanding of renal cell carcinoma (RCC) tumour biology has resulted in major advances in the treatment of patients with metastatic RCC (mRCC). Although immunotherapy with interleukin-2 and interferon alpha was once the standard of care for mRCC, the introduction of novel agents targeting angiogenesis and signal transduction pathways has markedly improved patient outcomes. However, targeted agents rarely induce complete responses, and patients eventually develop resistance to therapy, prompting consideration of novel therapeutic approaches and a resurgence of interest in immunotherapy for RCC. Phase I/II trials of vaccination with allogeneic dendritic cell/tumour fusions in patients with mRCC have demonstrated immunological and clinical responses in some patients, and T-cell modulating agents (e.g. antibodies against programmed death 1 and cytotoxic T lymphocyte-associated antigen-4, or soluble lymphocyte activation gene-3) and dendritic cell-activating toll-like receptor agonists have also shown encouraging evidence of efficacy in early-phase clinical trials. These early studies suggest that immunotherapy may continue to be an effective approach for patients with mRCC. As such, a number of other strategies are currently under investigation, including adoptive cell transfer (ACT) with T cells modified to target proteins expressed by renal tumours such as MAGE-A3/12, DR4 and TRAIL, and ACT with autologous natural killer cells. Results from trials of novel immunotherapies are encouraging, with data from other indications helping to facilitate development. To realise the full benefit for patients, it is likely that immunotherapy will need to be combined with targeted agents or other agents. Novel therapies used in combination or sequentially have the potential to improve outcomes in mRCC, and results from ongoing/planned trials will shape future therapy. PMID- 22918928 TI - Evolution of end points for cancer immunotherapy trials. AB - The effect of cancer immunotherapies is on the immune system and not directly on the tumour. The kinetics of immunotherapy are characterised by a cellular immune response followed by potential changes in tumour burden or patient survival. To adequately investigate immunotherapies in clinical trials, a new development paradigm including reconsideration of established end points addressing this biology is needed. Over the last 7 years, several initiatives across the cancer immunotherapy community were facilitated by the Cancer Research Institute Cancer Immunotherapy Consortium. They systematically evolved an immunotherapy-focused clinical development paradigm and proposed to redefine trial end points. On that basis, analysis of several large datasets generated throughout the immunotherapy community supports three novel end point proposals. First, results from T-cell immune response assays are highly variable and often nonreproducible. Harmonisation of assays can minimise this variability and support the investigation of the cellular immune response as a biomarker and testing it for clinical surrogacy. Secondly, immunotherapy induces novel patterns of the antitumour response not captured by World Health Organisation criteria or Response Evaluation Criteria in Solid Tumours. New immune-related response criteria were defined which more comprehensively capture all response patterns. Thirdly, survival curves in randomised immunotherapy trials can show a delayed separation, which can impact study results. Altered statistical models are needed to describe the hazard ratios as a function of time, and differentiate them before and after separation of curves to improve planning of phase III trials. Taken together, these recommendations may improve our tools for cancer immunotherapy investigations. PMID- 22918927 TI - Combination immunotherapy approaches. AB - Combination immunotherapy approaches involving radiation, chemotherapy, androgen manipulation and T-cell modulation have been studied extensively in animal models, setting the stage for clinical trials. Radiation therapy, in particular, is an interesting modality in this regard, leading to synergistic efficacy when used in combination with immunotherapies in several models. Chemotherapy, the foundation of treatment of metastatic disease, may also augment the immune response to cancer; however, the potential immunosuppressive effects of chemotherapy render issues of dosing and timing critical. Perhaps, the most exciting combinatorial approach may be the co-administration of multiple immunological treatments. For example, in preclinical investigations, combined blockade of programmed death-1 (PD1) and cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4), which have key roles in the negative regulation of T-cell activation, has been shown to enhance antitumour immune responses compared with either agent alone. Taken together, the available data provide a strong rationale for initiating combination clinical trials, but lend a note of caution in that issues of dosing and timing likely require careful exploration in a phase II setting. PMID- 22918929 TI - Advances in immuno-oncology. Foreword. PMID- 22918930 TI - Can immuno-oncology offer a truly pan-tumour approach to therapy? AB - Increased understanding of cellular and molecular tumour immunology over the past two decades has enabled the identification of new and innovative ways to manipulate the immune response to cancer, with recent phase III trials in patients with metastatic melanoma and hormone-resistant prostate cancer providing proof-of-principle that immunotherapies can improve survival. Based on these successes, many new immunotherapies are being developed, including vaccines and other agents that prime or boost the immune system, T-cell modulatory agents, agents that enhance innate immunity and agents designed to inhibit immunosuppression within the tumour microenvironment. Current experience suggests that immunotherapies are a promising foundation to build treatment regimens for a variety of tumour types. Because many approaches target the immune system and not the cancer, immunotherapies are being evaluated in almost every tumour type, including those that were not previously considered likely to respond to immune manipulation. Immunotherapies also have potential for durable and adaptable cancer control at different stages of disease, including those with early-stage disease and low tumour burdens. To maximise benefits, however, it is likely that combination regimens with conventional cancer treatments or other immunotherapies will be necessary. In addition, the identification of biomarkers will allow further optimisation from a mechanistic and a patient selection perspective. Further advances in research will necessitate multidisciplinary collaboration among physicians, basic and translational researchers and the pharmaceutical industry to ensure that immuno-oncology becomes a cornerstone element in the development of cancer therapy. PMID- 22918931 TI - Immuno-oncology: understanding the function and dysfunction of the immune system in cancer. AB - The immune system has the greatest potential for the specific destruction of tumours with no toxicity to normal tissue and for long-term memory that can prevent cancer recurrence. The last 30 years of immuno-oncology research have provided solid evidence that tumours are recognised by the immune system and their development can be stopped or controlled long term through a process known as immunosurveillance. Tumour specificity of the immune response resides in the recognition of tumour antigens. Viral proteins in tumours caused by viruses and mutated proteins from oncogenes or other genes, as well as nonmutated but abnormally expressed self proteins found on all tumours, have been shown to be good antigens and good targets for immunosurveillance. In many cancers, however, malignant progression is accompanied by profound immune suppression that interferes with an effective antitumour response and tumour elimination. Initially, most of the escape from immunosurveillance was ascribed to changes in the tumour cells themselves (loss of tumour antigens, loss of human leukocyte antigen molecules, loss of sensitivity to complement, or T cell or natural killer (NK) cell lysis), making them a poor target of an immune attack. However, it has become clear that the suppression comes from the ability of tumours to subvert normal immune regulation to their advantage. The tumour microenvironment can prevent the expansion of tumour antigen-specific helper and cytotoxic T cells and instead promote the production of proinflammatory cytokines and other factors, leading to the accumulation of suppressive cell populations that inhibit instead of promote immunity. The best described are regulatory T cells and myeloid derived suppressor cells. Great conceptual and technical advances in the field of immuno-oncology over the past 30 years have provided us with the knowledge and techniques to develop novel immunotherapeutic approaches for the treatment of cancer. These include methods that enhance tumour immunity by blocking inhibitory pathways and inhibitory cells in the tumour microenvironment (e.g. antibodies against cytotoxic T-lymphocyte-associated antigen-4, programmed death 1 or its ligand programmed death ligand 1, or low-dose chemotherapy). Of equal importance, they include methods that can enhance the specificity of antitumour immunity by inducing the expansion of T cells and antibodies directed to well-defined tumour antigens (e.g. cancer vaccines, potent adjuvants, immunostimulatory cytokines). Even as monotherapies, these approaches are having a substantial impact on the treatment of some patients with advanced, previously untreatable, malignancies. Most exciting of all, these successes provide a rationale to expect that used in various combinations or earlier in disease, current and future immunotherapies may transform cancer treatment, improving a prognosis for many patients. PMID- 22918932 TI - Immune complex-induced inhibition of osteoclastogenesis is mediated via activating but not inhibitory Fcgamma receptors on myeloid precursor cells. AB - OBJECTIVE: To investigate the role of Fcgamma receptors (FcgammaRs) in osteoclastogenesis and osteoclast function. METHODS: Bone destruction was analysed in arthritic knee joints of several FcgammaR-knockout mouse strains. Unfractionated bone marrow cells were differentiated in vitro towards osteoclasts in the absence or presence of immune complexes (ICs) and stimulated thereafter for 24 h with tumour necrosis factor alpha (TNFalpha) or lipopolysaccharide (LPS). In addition, mature osteoclasts were stimulated with ICs. Experiments were analysed for osteoclast formation, bone resorption and the expression of FcgammaRs and osteoclast markers. RESULTS: Bone destruction was significantly increased in arthritic knee joints of FcgammaRIIB-deficient mice. All FcgammaR classes were highly expressed on osteoclast precursors. Expression of the inhibitory FcgammaRIIB was similar on mature osteoclasts compared to macrophages, whereas activating FcgammaR levels were significantly lower. IC stimulation of mature osteoclasts did not affect their number or their bone resorptive capacity. ICs significantly inhibited differentiation of unfractionated bone marrow cells towards osteoclasts, bone resorption and expression of osteoclast markers. In the presence of ICs, osteoclastogenesis of FcgammaRIIB(-/-) precursors and bone resorption remained inhibited. In contrast, ICs could not inhibit osteoclast formation or bone resorption of FcRgamma-chain(-/-) precursors. When IC-inhibited osteoclastogenesis was followed by stimulation with TNFalpha or LPS, the inhibitory effects of ICs were overruled. CONCLUSION: Activating FcgammaRs mediate IC-induced inhibition of osteoclastogenesis, which might be overruled in the presence of proinflammatory mediators. This suggests that the balance of FcgammaR-mediated inflammation, through proinflammatory cytokine production, as well as the direct inhibitory effect of ICs on osteoclastogenesis determines the net effect on bone loss. PMID- 22918933 TI - Evaluation of the new generation dual-lumen catheter for neonatal ECMO. AB - OBJECTIVES: The purpose of this study was to compare the newly designed dual lumen venovenous catheter (VR13, OriGen Biomedical, Austin, TX) with the current dual-lumen catheter (VV12, OriGen Biomedical). METHODS: Five newborn lambs, 1 to 5 days old and weighing 4.2 +/- 0.5 kg, were cannulated with the VV13 OriGen catheter and placed on extracorporeal membrane oxygenation (ECMO). ECMO flows were increased from 200 to 600 ml/min, with measurements taken after the changes. The experiment was then repeated using the VV12 catheter. RESULTS: Recirculation values were equal for both catheters. The pressure drop at the reinfusion port was equal for both catheters at 200 ml/min, increasing to 275 mmHg at 500 ml/min for the VR13 vs. 240 mmHg for the VV12 catheter. CONCLUSION: These findings indicate that the VR13 catheter resulted in levels of recirculation equal to the VV12. Based on resistance measurements, we do not recommend the use of this new catheter beyond 400 ml/min until minor design changes are made. PMID- 22918934 TI - A pilot study comparing two polymethylpentene extracorporeal membrane oxygenators. AB - OBJECTIVE: We compared two polymethylpentene oxygenators being used in our unit: the Maquet Quadrox-iD paediatric and the Medos Hilite 800LT. STUDY DESIGN: A mono centric, prospective pilot study was conducted on ten consecutive newborn patients who had been admitted to our hospital service for extracorporeal circulation (EC) treatment. We examined the rate of oxygen transfer, the CO2 removal capacity and the average sweep gas flow required to produce this result. We also assessed the disturbances of haemostasis, the need for labile blood products and the membrane oxygenator lifetime and cost of use. CONCLUSIONS: According to our study, it seems to us that Medos Hilite 800LT membrane oxygenators demonstrate greater oxygen transfer and CO2 removal capacity than Maquet Quadrox-iD paediatric membrane oxygenators, at a similar cost. These results lead us to conclude that it is reasonable to continue using Medos Hilite 800LT membrane oxygenators. A broader comparison study would be necessary in order to support these initial results. PMID- 22918935 TI - A 6-year experience treating vascular malformations with foam sclerotherapy. AB - In this study, the authors present an analysis of the outcomes of 105 low-flow vascular malformation patients treated over a 6-year period and report specific lesion characteristics that correlate with those vascular malformations that will benefit from sodium tetradecyl sulfate foam sclerotherapy (STS FS) versus surgical resection as well as morphological characteristics of vascular malformations that are associated with a poor response to FS treatment. Improvement in symptoms was documented in 92.9% of patients treated with STS FS. There were no complications. Low-flow vascular malformations that were morphologically characterized by microcystic, septated vessels did not respond to FS, and these vascular malformations are best treated with surgical resection. Primary surgical resection is also the treatment of choice for localized, microcystic, and superficial low-flow vascular malformations. Symptomatic, diffuse, extensive, macrocystic malformations that involve multiple tissue planes and vital structures are best treated with FS. PMID- 22918936 TI - Does training of the nondominant upper extremity reduce the surgeon's muscular strain during laparoscopy?: Results from a randomized controlled trial. AB - INTRODUCTION: In laparoscopy, suboptimal ergonomics frequently lead to morbidity for surgeons. Physical complaints are more commonly reported on the dominant upper extremity. This may be the consequence of challenging laparoscopic tasks being easier to perform with the dominant side. The authors hypothesized that specific training of the nondominant upper extremity may equip this side better and lead to a more equal distribution of physical load. MATERIALS AND METHODS: Participants (medical doctors) were randomized to a 3-week training schedule or no training. The training program consisted of training the nondominant upper extremity. Participants were not allowed to train on a laparoscopic box or virtual reality trainer during the study period. Baseline and outcome measurements after 3 weeks were examined with the use of EMG measurements during a validated task on a laparoscopic box trainer. Muscle strain of the trapezius and deltoid muscles and effective alternation of brachioradial and abductor pollicis brevis muscles were used as outcome variables. RESULTS: In all, 26 participants were included. EMG analysis revealed that participants in both intervention and control groups showed a decrease in muscle strain of trapezius and deltoid muscles. However, there were no significant differences between groups. Those in the intervention group showed significantly better alternation in the brachioradial muscle. CONCLUSION: Training the nondominant upper extremity leads to better alternated use of lower-arm muscles during a validated box trainer task. Repeating the task after 3 weeks led to less muscle tension in the trapezius and deltoid muscles. PMID- 22918937 TI - Caveolae-mediated endocytosis of intratracheally instilled gold colloid nanoparticles at the air-blood barrier in mice. AB - Endocytosis is the primary mechanism by which nanoparticles are translocated over the alveolar epithelium. The purpose of this study was to elucidate the association between endocytosis and the translocation of nanoparticles at the air blood barrier (ABB). Gold colloid particles (diameter, 20 nm) were intratracheally instilled into male ICR mice. Fifteen minutes after instillation, localized accumulation of agglomerated gold particles was observed in the cytoplasm of macrophages, on the surface of alveolar epithelial cells (AECs), and in alveoli. Electron microscopy revealed particles in the vesicles of macrophages, on the surface of AECs, and in caveolae-like vesicles in type 1 AECs. Immunohistochemistry demonstrated positive immunolabeling for caveolin-1 in the ABB of untreated lungs as well as lungs treated with gold particles. Double immunofluorescence and immunoelectron microscopy revealed the presence of caveolin-1 in AECs in the untreated lungs. These results suggest that instilled gold colloid particles are internalized into the alveolar epithelium at the ABB by caveolae-mediated endocytosis, which is regarded as a physiological function of AECs. PMID- 22918938 TI - Complicated cerebral venous sinus thrombosis with intracranial hemorrhage and mastoiditis. AB - Cerebral venous sinus thrombosis (CVST) is a rare cause of stroke, occurring when a blood clot forms in any of the brain venous sinuses. Symptoms include neurological deficits, headache, seizures, and coma. There are many predisposing factors for CVST including prothrombotic conditions, oral contraceptives, pregnancy/puerperium, malignancy, infection, and head injury. Cerebral venous sinus thrombosis has no identifiable underlying etiology in about 12.5% to 33% of the cases. Diagnosis has become easier with newer imaging techniques, such as magnetic resonance venography. The treatment options for CVST include symptomatic treatment, anticoagulation (AC), thrombolysis, and thrombectomy. Controversy exists over the efficacy and safety of AC in patients with CVST with concurrent intracranial hemorrhage (ICH). We present a complex case of CVST with ICH and mastoiditis as well as provide a literature review about CVST. PMID- 22918939 TI - Should anti-tobacco media messages be culturally targeted for Indigenous populations? A systematic review and narrative synthesis. AB - OBJECTIVE: To summarise published empirical research on culturally targeted anti tobacco media messages for Indigenous or First Nations people and examine the evidence for the effectiveness of targeted and non-targeted campaigns. METHODS: Studies were sought describing mass media and new media interventions for tobacco control or smoking cessation in Indigenous or First Nations populations. Studies of any design were included reporting outcomes of media-based interventions including: cognitions, awareness, recall, intention to quit and quit rates. Then, 2 reviewers independently applied inclusion criteria, which were met by 21 (5.8%) of the studies found. One author extracted data with crosschecking by a second. Both independently assessed papers using Scottish Intercollegiate Guidelines Network (SIGN; quantitative studies) and Daly et al (qualitative studies). RESULTS: A total of 21 studies were found (4 level 1 randomised controlled trials (RCTs), 11 level 2 studies and 6 qualitative studies) and combined with narrative synthesis. Eight evaluated anti-tobacco TV or radio campaigns; two assessed US websites; three New Zealand studies examined mobile phone interventions; five evaluated print media; three evaluated a CD-ROM, a video and an edutainment intervention. CONCLUSIONS: Although Indigenous people had good recall of generic anti-tobacco messages, culturally targeted messages were preferred. New Zealand Maori may be less responsive to holistic targeted campaigns, despite their additional benefits, compared to generic fear campaigns. Culturally targeted internet or mobile phone messages appear to be as effective in American Indians and Maori as generic messages in the general population. There is little research comparing the effect of culturally targeted versus generic messages with similar message content in Indigenous people. PMID- 22918940 TI - Diacylglycerol kinase zeta regulates RhoA activation via a kinase-independent scaffolding mechanism. AB - Rho GTPases share a common inhibitor, Rho guanine nucleotide dissociation inhibitor (RhoGDI), which regulates their expression levels, membrane localization, and activation state. The selective dissociation of individual Rho GTPases from RhoGDI ensures appropriate responses to cellular signals, but the underlying mechanisms are unclear. Diacylglycerol kinase zeta (DGKzeta), which phosphorylates diacylglycerol to yield phosphatidic acid, selectively dissociates Rac1 by stimulating PAK1-mediated phosphorylation of RhoGDI on Ser-101/174. Similarly, phosphorylation of RhoGDI on Ser-34 by protein kinase Calpha (PKCalpha) selectively releases RhoA. Here we show DGKzeta is required for RhoA activation and Ser-34 phosphorylation, which were decreased in DGKzeta-deficient fibroblasts and rescued by wild-type DGKzeta or a catalytically inactive mutant. DGKzeta bound directly to the C-terminus of RhoA and the regulatory arm of RhoGDI and was required for efficient interaction of PKCalpha and RhoA. DGKzeta-null fibroblasts had condensed F-actin bundles and altered focal adhesion distribution, indicative of aberrant RhoA signaling. Two targets of the RhoA effector ROCK showed reduced phosphorylation in DGKzeta-null cells. Collectively our findings suggest DGKzeta functions as a scaffold to assemble a signaling complex that functions as a RhoA-selective, GDI dissociation factor. As a regulator of Rac1 and RhoA activity, DGKzeta is a critical factor linking changes in lipid signaling to actin reorganization. PMID- 22918941 TI - Actin-capping protein promotes microtubule stability by antagonizing the actin activity of mDia1. AB - In migrating fibroblasts, RhoA and its effector mDia1 regulate the selective stabilization of microtubules (MTs) polarized in the direction of migration. The conserved formin homology 2 domain of mDia1 is involved both in actin polymerization and MT stabilization, and the relationship between these two activities is unknown. We found that latrunculin A (LatA) and jasplakinolide, actin drugs that release mDia1 from actin filament barbed ends, stimulated stable MT formation in serum-starved fibroblasts and caused a redistribution of mDia1 onto MTs. Knockdown of mDia1 by small interfering RNA (siRNA) prevented stable MT induction by LatA, whereas blocking upstream Rho or integrin signaling had no effect. In search of physiological regulators of mDia1, we found that actin capping protein induced stable MTs in an mDia1-dependent manner and inhibited the translocation of mDia on the ends of growing actin filaments. Knockdown of capping protein by siRNA reduced stable MT levels in proliferating cells and in starved cells stimulated with lysophosphatidic acid. These results show that actin-capping protein is a novel regulator of MT stability that functions by antagonizing mDia1 activity toward actin filaments and suggest a novel form of actin-MT cross-talk in which a single factor acts sequentially on actin and MTs. PMID- 22918942 TI - APC(FZR1) prevents nondisjunction in mouse oocytes by controlling meiotic spindle assembly timing. AB - FZR1 is an anaphase-promoting complex (APC) activator best known for its role in the mitotic cell cycle at M-phase exit, in G1, and in maintaining genome integrity. Previous studies also established that it prevents meiotic resumption, equivalent to the G2/M transition. Here we report that mouse oocytes lacking FZR1 undergo passage through meiosis I that is accelerated by ~1 h, and this is due to an earlier onset of spindle assembly checkpoint (SAC) satisfaction and APC(CDC20) activity. However, loss of FZR1 did not compromise SAC functionality; instead, earlier SAC satisfaction was achieved because the bipolar meiotic spindle was assembled more quickly in the absence of FZR1. This novel regulation of spindle assembly by FZR1 led to premature bivalent attachment to microtubules and loss of kinetochore-bound MAD2. Bivalents, however, were observed to congress poorly, leading to nondisjunction rates of 25%. We conclude that in mouse oocytes FZR1 controls the timing of assembly of the bipolar spindle and in so doing the timing of SAC satisfaction and APC(CDC20) activity. This study implicates FZR1 as a major regulator of prometaphase whose activity helps to prevent chromosome nondisjunction. PMID- 22918943 TI - Anillin-related protein Mid1p coordinates the assembly of the cytokinetic contractile ring in fission yeast. AB - In fission yeast cells cortical nodes containing the protein Blt1p and several kinases appear early in G2, mature into cytokinetic nodes by adding anillin Mid1p, myosin-II, formin Cdc12p, and other proteins, and condense into a contractile ring by movements that depend on actin and myosin-II. Previous studies concluded that cells without Mid1p lack cytokinetic nodes and assemble rings unreliably from myosin-II strands but left open questions. Why do strands form outside the equatorial region? Why is ring assembly unreliable without Mid1p? We found in Deltamid1 cells that Cdc12p accumulates in cytokinetic nodes scattered in the cortex and produces actin filaments that associate with myosin II, Rng2p, and Cdc15p to form strands located between the nodes. Strands incorporate nodes, and in ~67% of cells, strands slowly close into rings that constrict without the normal ~25-min maturation period. Ring assembly is unreliable and slow without Mid1p because the scattered Cdc12p nodes generate strands spread widely beyond the equator, and growing strands depend on random encounters to merge with other strands into a ring. We conclude that orderly assembly of the contractile ring in wild-type cells depends on Mid1p to recruit myosin-II, Rng2p, and Cdc15p to nodes and to place cytokinetic nodes around the cell equator. PMID- 22918944 TI - RhoA activation during polarization and cytokinesis of the early Caenorhabditis elegans embryo is differentially dependent on NOP-1 and CYK-4. AB - The GTPase RhoA is a central regulator of cellular contractility in a wide variety of biological processes. During these events, RhoA is activated by guanine nucleotide exchange factors (GEFs). These molecules are highly regulated to ensure that RhoA activation occurs at the proper time and place. During cytokinesis, RhoA is activated by the RhoGEF ECT-2. In human cells, ECT-2 activity requires its association with CYK-4, which is a component of the centralspindlin complex. In contrast, in early Caenorhabditis elegans embryos, not all ECT-2-dependent functions require CYK-4. In this study, we identify a novel protein, NOP-1, that functions in parallel with CYK-4 to promote RhoA activation. We use mutations in nop-1 and cyk-4 to dissect cytokinesis and cell polarization. NOP-1 makes a significant, albeit largely redundant, contribution to cytokinesis. In contrast, NOP-1 is required for the preponderance of RhoA activation during the establishment phase of polarization. PMID- 22918945 TI - Role of mitochondrial inner membrane organizing system in protein biogenesis of the mitochondrial outer membrane. AB - Mitochondria contain two membranes, the outer membrane and the inner membrane with folded cristae. The mitochondrial inner membrane organizing system (MINOS) is a large protein complex required for maintaining inner membrane architecture. MINOS interacts with both preprotein transport machineries of the outer membrane, the translocase of the outer membrane (TOM) and the sorting and assembly machinery (SAM). It is unknown, however, whether MINOS plays a role in the biogenesis of outer membrane proteins. We have dissected the interaction of MINOS with TOM and SAM and report that MINOS binds to both translocases independently. MINOS binds to the SAM complex via the conserved polypeptide transport-associated domain of Sam50. Mitochondria lacking mitofilin, the large core subunit of MINOS, are impaired in the biogenesis of beta-barrel proteins of the outer membrane, whereas mutant mitochondria lacking any of the other five MINOS subunits import beta-barrel proteins in a manner similar to wild-type mitochondria. We show that mitofilin is required at an early stage of beta-barrel biogenesis that includes the initial translocation through the TOM complex. We conclude that MINOS interacts with TOM and SAM independently and that the core subunit mitofilin is involved in biogenesis of outer membrane beta-barrel proteins. PMID- 22918946 TI - Cdc42p regulation of the yeast formin Bni1p mediated by the effector Gic2p. AB - Actin filaments are dynamically reorganized to accommodate ever-changing cellular needs for intracellular transport, morphogenesis, and migration. Formins, a major family of actin nucleators, are believed to function as direct effectors of Rho GTPases, such as the polarity regulator Cdc42p. However, the presence of extensive redundancy has made it difficult to assess the in vivo significance of the low-affinity Rho GTPase-formin interaction and specifically whether Cdc42p polarizes the actin cytoskeleton via direct formin binding. Here we exploit a synthetically rewired budding yeast strain to eliminate the redundancy, making regulation of the formin Bni1p by Cdc42p essential for viability. Surprisingly, we find that direct Cdc42p-Bni1p interaction is dispensable for Bni1p regulation. Alternative paths linking Cdc42p and Bni1p via "polarisome" components Spa2p and Bud6p are also collectively dispensable. We identify a novel regulatory input to Bni1p acting through the Cdc42p effector, Gic2p. This pathway is sufficient to localize Bni1p to the sites of Cdc42p action and promotes a polarized actin organization in both rewired and wild-type contexts. We suggest that an indirect mechanism linking Rho GTPases and formins via Rho effectors may provide finer spatiotemporal control for the formin-nucleated actin cytoskeleton. PMID- 22918947 TI - Nucleolar accumulation of APE1 depends on charged lysine residues that undergo acetylation upon genotoxic stress and modulate its BER activity in cells. AB - Apurinic/apyrimidinic endonuclease 1 (APE1) is the main abasic endonuclease in the base excision repair (BER) pathway of DNA lesions caused by oxidation/alkylation in mammalian cells; within nucleoli it interacts with nucleophosmin and rRNA through N-terminal Lys residues, some of which (K(27)/K(31)/K(32)/K(35)) may undergo acetylation in vivo. Here we study the functional role of these modifications during genotoxic damage and their in vivo relevance. We demonstrate that cells expressing a specific K-to-A multiple mutant are APE1 nucleolar deficient and are more resistant to genotoxic treatment than those expressing the wild type, although they show impaired proliferation. Of interest, we find that genotoxic treatment induces acetylation at these K residues. We also find that the charged status of K(27)/K(31)/K(32)/K(35) modulates acetylation at K(6)/K(7) residues that are known to be involved in the coordination of BER activity through a mechanism regulated by the sirtuin 1 deacetylase. Of note, structural studies show that acetylation at K(27)/K(31)/K(32)/K(35) may account for local conformational changes on APE1 protein structure. These results highlight the emerging role of acetylation of critical Lys residues in regulating APE1 functions. They also suggest the existence of cross-talk between different Lys residues of APE1 occurring upon genotoxic damage, which may modulate APE1 subnuclear distribution and enzymatic activity in vivo. PMID- 22918948 TI - Dynactin's pointed-end complex is a cargo-targeting module. AB - Dynactin is an essential part of the cytoplasmic dynein motor that enhances motor processivity and serves as an adaptor that allows dynein to bind cargoes. Much is known about dynactin's interaction with dynein and microtubules, but how it associates with its diverse complement of subcellular binding partners remains mysterious. It has been suggested that cargo specification involves a group of subunits referred to as the "pointed-end complex." We used chemical cross linking, RNA interference, and protein overexpression to characterize interactions within the pointed-end complex and explore how it contributes to dynactin's interactions with endomembranes. The Arp11 subunit, which caps one end of dynactin's Arp1 filament, and p62, which binds Arp11 and Arp1, are necessary for dynactin stability. These subunits also allow dynactin to bind the nuclear envelope prior to mitosis. p27 and p25, by contrast, are peripheral components that can be removed without any obvious impact on dynactin integrity. Dynactin lacking these subunits shows reduced membrane binding. Depletion of p27 and p25 results in impaired early and recycling endosome movement, but late endosome movement is unaffected, and mitotic spindles appear normal. We conclude that the pointed-end complex is a bipartite structural domain that stabilizes dynactin and supports its binding to different subcellular structures. PMID- 22918949 TI - Regulation of axonal growth and neuromuscular junction formation by neuronal phosphatase and tensin homologue signaling. AB - During the development of the vertebrate neuromuscular junction (NMJ), motor axon tips stop growing after contacting muscle and transform into presynaptic terminals that secrete the neurotransmitter acetylcholine and activate postsynaptic ACh receptors (AChRs) to trigger muscle contraction. The neuron intrinsic signaling that retards axonal growth to facilitate stable nerve-muscle interaction and synaptogenesis is poorly understood. In this paper, we report a novel function of presynaptic signaling by phosphatase and tensin homologue (PTEN) in mediating a growth-to-synaptogenesis transition in neurons. In Xenopus nerve-muscle cocultures, axonal growth speed was halved after contact with muscle, when compared with before contact, but when cultures were exposed to the PTEN blocker bisperoxo (1,10-phenanthroline) oxovanadate, axons touching muscle grew ~50% faster than their counterparts in control cultures. Suppression of neuronal PTEN expression using morpholinos or the forced expression of catalytically inactive PTEN in neurons also resulted in faster than normal axonal advance after contact with muscle cells. Significantly, interference with PTEN by each of these methods also led to reduced AChR clustering at innervation sites in muscle, indicating that disruption of neuronal PTEN signaling inhibited NMJ assembly. We thus propose that PTEN-dependent slowing of axonal growth enables the establishment of stable nerve-muscle contacts that develop into NMJs. PMID- 22918950 TI - In vivo evidence for cooperation of Mia40 and Erv1 in the oxidation of mitochondrial proteins. AB - The intermembrane space of mitochondria accommodates the essential mitochondrial intermembrane space assembly (MIA) machinery that catalyzes oxidative folding of proteins. The disulfide bond formation pathway is based on a relay of reactions involving disulfide transfer from the sulfhydryl oxidase Erv1 to Mia40 and from Mia40 to substrate proteins. However, the substrates of the MIA typically contain two disulfide bonds. It was unclear what the mechanisms are that ensure that proteins are released from Mia40 in a fully oxidized form. In this work, we dissect the stage of the oxidative folding relay, in which Mia40 binds to its substrate. We identify dynamics of the Mia40-substrate intermediate complex. Our experiments performed in a native environment, both in organello and in vivo, show that Erv1 directly participates in Mia40-substrate complex dynamics by forming a ternary complex. Thus Mia40 in cooperation with Erv1 promotes the formation of two disulfide bonds in the substrate protein, ensuring the efficiency of oxidative folding in the intermembrane space of mitochondria. PMID- 22918951 TI - Multilevel regulation of HIF-1 signaling by TTP. AB - Hypoxia-inducible factor-1 (HIF-1) is a well-studied transcription factor mediating cellular adaptation to hypoxia. It also plays a crucial role under normoxic conditions, such as in inflammation, where its regulation is less well understood. The 3'-untranslated region (UTR) of HIF-1alpha mRNA is among the most conserved UTRs in the genome, hinting toward posttranscriptional regulation. To identify potential trans factors, we analyzed a large compilation of expression data. In contrast to its known function of being a negative regulator, we found that tristetraprolin (TTP) positively correlates with HIF-1 target genes. Mathematical modeling predicts that an additional level of posttranslational regulation of TTP can explain the observed positive correlation between TTP and HIF-1 signaling. Mechanistic studies revealed that TTP indeed changes its mode of regulation from destabilizing to stabilizing HIF-1alpha mRNA upon phosphorylation by p38 mitogen-activated protein kinase (MAPK)/MAPK-activated protein kinase 2. Using a model of monocyte-to-macrophage differentiation, we show that TTP-driven HIF-1alpha mRNA stabilization is crucial for cell migration. This demonstrates the physiological importance of a hitherto-unknown mechanism for multilevel regulation of HIF-1alpha in normoxia. PMID- 22918952 TI - Multiple protein kinases influence the redistribution of fission yeast Clp1/Cdc14 phosphatase upon genotoxic stress. AB - The Cdc14 phosphatase family antagonizes Cdk1 phosphorylation and is important for mitotic exit. To access their substrates, Cdc14 phosphatases are released from nucleolar sequestration during mitosis. Clp1/Flp1, the Schizosaccharomyces pombe Cdc14 orthologue, and Cdc14B, a mammalian orthologue, also exit the nucleolus during interphase upon DNA replication stress or damage, respectively, implicating Cdc14 phosphatases in the response to genotoxic insults. However, a mechanistic understanding of Cdc14 phosphatase nucleolar release under these conditions is incomplete. We show here that relocalization of Clp1 during genotoxic stress is governed by complex phosphoregulation. Specifically, the Rad3 checkpoint effector kinases Cds1 and/or Chk1, the cell wall integrity mitogen activated protein kinase Pmk1, and the cell cycle kinase Cdk1 directly phosphorylate Clp1 to promote genotoxic stress-induced nucleoplasmic accumulation. However, Cds1 and/or Chk1 phosphorylate RxxS sites preferentially upon hydroxyurea treatment, whereas Pmk1 and Cdk1 preferentially phosphorylate Clp1 TP sites upon H(2)O(2) treatment. Abolishing both Clp1 RxxS and TP phosphosites eliminates any genotoxic stress-induced redistribution. Reciprocally, preventing dephosphorylation of Clp1 TP sites shifts the distribution of the enzyme to the nucleoplasm constitutively. This work advances our understanding of pathways influencing Clp1 localization and may provide insight into mechanisms controlling Cdc14B phosphatases in higher eukaryotes. PMID- 22918953 TI - Regulation of the formin Bnr1 by septins anda MARK/Par1-family septin-associated kinase. AB - Formin-family proteins promote the assembly of linear actin filaments and are required to generate cellular actin structures, such as actin stress fibers and the cytokinetic actomyosin contractile ring. Many formin proteins are regulated by an autoinhibition mechanism involving intramolecular binding of a Diaphanous inhibitory domain and a Diaphanous autoregulatory domain. However, the activation mechanism for these Diaphanous-related formins (DRFs) is not completely understood. Although small GTPases play an important role in relieving autoinhibition, other factors likely contribute. Here we describe a requirement for the septin Shs1 and the septin-associated kinase Gin4 for the localization and in vivo activity of the budding yeast DRF Bnr1. In budding yeast strains in which the other formin, Bni1, is conditionally inactivated, the loss of Gin4 or Shs1 results in the loss of actin cables and cell death, similar to the loss of Bnr1. The defects in these strains can be suppressed by constitutive activation of Bnr1. Gin4 is involved in both the localization and activation of Bnr1, whereas the septin Shs1 is required for Bnr1 activation but not its localization. Gin4 promotes the activity of Bnr1 independently of the Gin4 kinase activity, and Gin4 lacking its kinase domain binds to the critical localization region of Bnr1. These data reveal novel regulatory links between the actin and septin cytoskeletons. PMID- 22918954 TI - Characterization of structural and functional domains of the anillin-related protein Mid1p that contribute to cytokinesis in fission yeast. AB - Fission yeast cells depend on the anillin-related protein Mid1p for reliable cytokinesis. Insolubility limits the purification of full-length Mid1p for biophysical analysis, and lack of knowledge about the structural domains of Mid1p limits functional analysis. We addressed these limitations by identifying in a bacterial expression screen of random Mid1p fragments five soluble segments that can be purified and one insoluble segment. Using complementation experiments in Deltamid1 cells, we tested the biological functions of these six putative domains that account for full-length Mid1p. The N-terminal domain (residues 1-149) is essential for correct positioning and orientation of septa. The third domain (residues 309-452) allows the construct composed of the first three domains (residues 1-452) to form hydrodynamically well-behaved octamers. Constructs consisting of residues 1-452 or 1-578 carry out most functions of full-length Mid1p, including concentration at the equatorial cortex in nodes that accumulate myosin-II and other contractile ring proteins during mitosis. However, cells depending on these constructs without the insoluble domain (residues 579-797) form equatorially located rings slowly from strands rather than by direct condensation of nodes. We conclude that residues 1-578 assemble node components myosin-II, Rng2p, and Cdc15p, and the insoluble domain facilitates the normal, efficient condensation of nodes into rings. PMID- 22918955 TI - Matrix compliance regulates Rac1b localization, NADPH oxidase assembly, and epithelial-mesenchymal transition. AB - Epithelial-mesenchymal transition (EMT) is a form of epithelial plasticity implicated in fibrosis and tumor metastasis. Here we show that the mechanical rigidity of the microenvironment plays a pivotal role in the promotion of EMT by controlling the subcellular localization and downstream signaling of Rac GTPases. Soft substrata, with compliances comparable to that of normal mammary tissue, are protective against EMT, whereas stiffer substrata, with compliances characteristic of breast tumors, promote EMT. Rac1b, a highly activated splice variant of Rac1 found in tumors, localizes to the plasma membrane in cells cultured on stiff substrata or in collagen-rich regions of human breast tumors. At the membrane, Rac1b forms a complex with NADPH oxidase and promotes the production of reactive oxygen species, expression of Snail, and activation of the EMT program. In contrast, soft microenvironments inhibit the membrane localization of Rac1b and subsequent redox changes. These results reveal a novel mechanotransduction pathway in the regulation of epithelial plasticity via EMT. PMID- 22918956 TI - Ergosterol content specifies targeting of tail-anchored proteins to mitochondrial outer membranes. AB - Tail-anchored (TA) proteins have a single C-terminal transmembrane domain, making their biogenesis dependent on posttranslational translocation. Despite their importance, no dedicated insertion machinery has been uncovered for mitochondrial outer membrane (MOM) TA proteins. To decipher the molecular mechanisms guiding MOM TA protein insertion, we performed two independent systematic microscopic screens in which we visualized the localization of model MOM TA proteins on the background of mutants in all yeast genes. We could find no mutant in which insertion was completely blocked. However, both screens demonstrated that MOM TA proteins were partially localized to the endoplasmic reticulum (ER) in spf1 cells. Spf1, an ER ATPase with unknown function, is the first protein shown to affect MOM TA protein insertion. We found that ER membranes in spf1 cells become similar in their ergosterol content to mitochondrial membranes. Indeed, when we visualized MOM TA protein distribution in yeast strains with reduced ergosterol content, they phenocopied the loss of Spf1. We therefore suggest that the inherent differences in membrane composition between organelle membranes are sufficient to determine membrane integration specificity in a eukaryotic cell. PMID- 22918957 TI - Myo1c binding to submembrane actin mediates insulin-induced tethering of GLUT4 vesicles. AB - GLUT4-containing vesicles cycle between the plasma membrane and intracellular compartments. Insulin promotes GLUT4 exocytosis by regulating GLUT4 vesicle arrival at the cell periphery and its subsequent tethering, docking, and fusion with the plasma membrane. The molecular machinery involved in GLUT4 vesicle tethering is unknown. We show here that Myo1c, an actin-based motor protein that associates with membranes and actin filaments, is required for insulin-induced vesicle tethering in muscle cells. Myo1c was found to associate with both mobile and tethered GLUT4 vesicles and to be required for vesicle capture in the total internal reflection fluorescence (TIRF) zone beneath the plasma membrane. Myo1c knockdown or overexpression of an actin binding-deficient Myo1c mutant abolished insulin-induced vesicle immobilization, increased GLUT4 vesicle velocity in the TIRF zone, and prevented their externalization. Conversely, Myo1c overexpression immobilized GLUT4 vesicles in the TIRF zone and promoted insulin-induced GLUT4 exposure to the extracellular milieu. Myo1c also contributed to insulin-dependent actin filament remodeling. Thus we propose that interaction of vesicular Myo1c with cortical actin filaments is required for insulin-mediated tethering of GLUT4 vesicles and for efficient GLUT4 surface delivery in muscle cells. PMID- 22918958 TI - Pkh1/2-dependent phosphorylation of Vps27 regulates ESCRT-I recruitment to endosomes. AB - Multivesicular endosomes (MVBs) are major sorting platforms for membrane proteins and participate in plasma membrane protein turnover, vacuolar/lysosomal hydrolase delivery, and surface receptor signal attenuation. MVBs undergo unconventional inward budding, which results in the formation of intraluminal vesicles (ILVs). MVB cargo sorting and ILV formation are achieved by the concerted function of endosomal sorting complex required for transport (ESCRT)-0 to ESCRT-III. The ESCRT-0 subunit Vps27 is a key player in this pathway since it recruits the other complexes to endosomes. Here we show that the Pkh1/Phk2 kinases, two yeast orthologues of the 3-phosphoinositide-dependent kinase, phosphorylate directly Vps27 in vivo and in vitro. We identify the phosphorylation site as the serine 613 and demonstrate that this phosphorylation is required for proper Vps27 function. Indeed, in pkh-ts temperature-sensitive mutant cells and in cells expressing vps27(S613A), MVB sorting of the carboxypeptidase Cps1 and of the alpha-factor receptor Ste2 is affected and the Vps28-green fluorescent protein ESCRT-I subunit is mainly cytoplasmic. We propose that Vps27 phosphorylation by Pkh1/2 kinases regulates the coordinated cascade of ESCRT complex recruitment at the endosomal membrane. PMID- 22918959 TI - Inherited effects of low-dose exposure to methylmercury in neural stem cells. AB - Methylmercury (MeHg) is an environmental contaminant with recognized neurotoxic effects, particularly to the developing nervous system. In the present study, we show that nanomolar concentrations of MeHg can induce long-lasting effects in neural stem cells (NSCs). We investigated short-term direct and long-term inherited effects of exposure to MeHg (2.5 or 5.0 nM) using primary cultures of rat embryonic cortical NSCs. We found that MeHg had no adverse effect on cell viability but reduced NSC proliferation and altered the expression of cell cycle regulators (p16 and p21) and senescence-associated markers. In addition, we demonstrated a decrease in global DNA methylation in the exposed cells, indicating that epigenetic changes may be involved in the mechanisms underlying the MeHg-induced effects. These changes were observed in cells directly exposed to MeHg (parent cells) and in their daughter cells cultured under MeHg-free conditions. In agreement with our in vitro data, a trend was found for decreased cell proliferation in the subgranular zone in the hippocampi of adult mice exposed to low doses of MeHg during the perinatal period. Interestingly, this impaired proliferation had a measurable impact on the total number of neurons in the hippocampal dentate gyrus. Importantly, this effect could be reversed by chronic antidepressant treatment. Our study provides novel evidence for programming effects induced by MeHg in NSCs and supports the idea that developmental exposure to low levels of MeHg may result in long-term consequences predisposing to neurodevelopmental disorders and/or neurodegeneration. PMID- 22918961 TI - Sex-related and stage-dependent source-to-sink transition in Populus cathayana grown at elevated CO(2) and elevated temperature. AB - Dioecious plants, which comprise more than 14,620 species, account for an important component of terrestrial ecosystems. Hence, understanding the sexually dimorphic responses in balancing carbon (C) supply and demand under elevated CO(2) is important for understanding leaf sink-to-source transitions. Here we investigate sex-related responses of the dioecious Populus cathayana Rehd. to elevated CO(2) and elevated temperature. The plants were grown in environmentally controlled growth chambers at two CO(2) enrichment regimes (350 +/- 20 and 700 +/ 20 MUmol mol(-1)) with two temperature levels, elevated by 0 and 2 +/- 0.2 degrees C (compared with the out-of-chamber environment). Plant growth characteristics, carbohydrate accumulation, C and nitrogen (N) allocation, photosynthetic capacity, N use efficiency and the morphology of mesophyll cells were investigated in the developing leaves (DLs) and expanded leaves (ELs) of both males and females. Elevated CO(2) enhanced plant growth and photosynthetic capacity in DLs of both males and females, and induced the male ELs to have a greater leaf mass production, net photosynthesis rate (P(n)), chlorophyll a/b ratio (Chl a/b), soluble protein level (SP), photosynthetic N use efficiency and soluble sugar level compared with females at the same leaf stage. Elevated temperature enhanced source activities and N uptake status during CO(2) enrichment, and the combined treatment induced males to be more responsive than females in sink capacities, especially in ELs, probably due to greater N acquisition from other plant parts. Our findings showed that elevated CO(2) increases the sink capacities of P. cathayana seedlings, and elevated temperature enhances the stimulation effect of elevated CO(2) on plant growth. Male ELs were found to play an important role in N acquisition from roots and stems under decreasing N in total leaves under elevated CO(2). Knowledge of the sex-specific leaf adaptability to warming climate can help us to understand sex-related source to-sink transitions in dioecious plant species. PMID- 22918962 TI - A case of multidisciplinary treatment for a massive locoregional recurrence of breast cancer. PMID- 22918960 TI - Molecular reconstruction of extinct LINE-1 elements and their interaction with nonautonomous elements. AB - Non-long terminal repeat retroelements continue to impact the human genome through cis-activity of long interspersed element-1 (LINE-1 or L1) and trans mobilization of Alu. Current activity is dominated by modern subfamilies of these elements, leaving behind an evolutionary graveyard of extinct Alu and L1 subfamilies. Because Alu is a nonautonomous element that relies on L1 to retrotranspose, there is the possibility that competition between these elements has driven selection and antagonistic coevolution between Alu and L1. Through analysis of synonymous versus nonsynonymous codon evolution across L1 subfamilies, we find that the C-terminal ORF2 cys domain experienced a dramatic increase in amino acid substitution rate in the transition from L1PA5 to L1PA4 subfamilies. This observation coincides with the previously reported rapid evolution of ORF1 during the same transition period. Ancestral Alu sequences have been previously reconstructed, as their short size and ubiquity have made it relatively easy to retrieve consensus sequences from the human genome. In contrast, creating constructs of extinct L1 copies is a more laborious task. Here, we report our efforts to recreate and evaluate the retrotransposition capabilities of two ancestral L1 elements, L1PA4 and L1PA8 that were active ~18 and ~40 Ma, respectively. Relative to the modern L1PA1 subfamily, we find that both elements are similarly active in a cell culture retrotransposition assay in HeLa, and both are able to efficiently trans-mobilize Alu elements from several subfamilies. Although we observe some variation in Alu subfamily retrotransposition efficiency, any coevolution that may have occurred between LINEs and SINEs is not evident from these data. Population dynamics and stochastic variation in the number of active source elements likely play an important role in individual LINE or SINE subfamily amplification. If coevolution also contributes to changing retrotransposition rates and the progression of subfamilies, cell factors are likely to play an important mediating role in changing LINE-SINE interactions over evolutionary time. PMID- 22918963 TI - Cancer mortality attributable to tobacco by selected countries based on the WHO Global Report. PMID- 22918964 TI - Association between maladaptive parenting and child self-control over time: cross lagged study using a monozygotic twin difference design. AB - BACKGROUND: Harsh parenting practices and negative parental feelings may be environmental risk factors for low self-control in children. Children may also evoke certain parenting reactions. AIMS: To investigate the longitudinal relationship between parenting and self-control, as well as associated outcomes within the monozygotic (MZ) twin differences framework. METHOD: Longitudinal MZ twin differences analysis was conducted on a community sample of 5184 twins using data from ages 3, 4, 7 and 9 years. Outcomes related to self-control and parenting were analysed at age 12 years. RESULTS: Non-shared environmental effects of parenting on the development of self-control and an evocative effect of child self-control on parenting were found. Harsh parenting predicted conduct problems for both boys and girls. Self-control at age 9 predicted conduct problems and emotional difficulties at age 12. CONCLUSIONS: Parenting and child self-control affect one another, highlighting the potential of early interventions that target parents and children simultaneously. PMID- 22918965 TI - Frontal information flow and connectivity in psychopathy. AB - Despite accumulating evidence of structural deficits in individuals with psychopathy, especially in frontal regions, our understanding of systems-level disturbances in cortical networks remains limited. We applied novel graph theory based methods to assess information flow and connectivity based on cortical thickness measures in 55 individuals with psychopathy and 47 normal controls. Compared with controls, the psychopathy group showed significantly altered interregional connectivity patterns. Furthermore, bilateral superior frontal cortices in the frontal network were identified as information flow control hubs in the psychopathy group in contrast to bilateral inferior frontal and medial orbitofrontal cortices as network hubs of the controls. Frontal information flow and connectivity may have a significant role in the neuropathology of psychopathy. PMID- 22918966 TI - Randomised, double-blind, placebo-controlled study of olanzapine in patients with bipolar I depression. AB - BACKGROUND: Atypical antipsychotics are widely used in bipolar mania. However, the efficacy of atypical antipsychotics in bipolar depression has not been comprehensively explored. AIMS: To evaluate olanzapine monotherapy in patients with bipolar depression. METHOD: Patients with bipolar depression received olanzapine (5-20 mg/day, n = 343) or placebo (n = 171) for 6 weeks. The primary outcome was change from baseline to end-point in Montgomery-Asberg Depression Rating Scale (MADRS) total score. Secondary outcomes included: Clinical Global Impression - Bipolar Version (CGI-BP) scale, 17-item Hamilton Rating Scale for Depression (HRSD-17) and Young Mania Rating Scale (YMRS) scores, and the rate of response (>=50% reduction in MADRS at end-point), recovery (MADRS <=12 for >=4 weeks plus treatment completion) and remission (MADRS <=8). The trial was registered with ClinicalTrials.gov (NCT00510146). RESULTS: Olanzapine demonstrated: significantly greater (P<0.04) improvements on MADRS (least-squares mean change -13.82 v. -11.67), HRSD-17 and YMRS total scores and all CGI-BP subscale scores v. placebo; significantly (P<=0.05) more response and remission, but not recovery; significantly (P<0.01) greater mean increases in weight, fasting cholesterol and triglycerides; and significantly more (P<0.001) patients gained >=7% body weight. CONCLUSIONS: Olanzapine monotherapy appears to be efficacious in bipolar depression. Additional long-term studies are warranted to confirm these results. Safety findings were consistent with the known safety profile of olanzapine. PMID- 22918967 TI - Coordinated regulation of murine cardiomyocyte contractility by nanomolar (-) epigallocatechin-3-gallate, the major green tea catechin. AB - Green tea polyphenolic catechins exhibit biological activity in a wide variety of cell types. Although reports in the lay and scientific literature suggest therapeutic potential for improving cardiovascular health, the underlying molecular mechanisms of action remain unclear. Previous studies have implicated a wide range of molecular targets in cardiac muscle for the major green tea catechin, (-)-epigallocatechin-3-gallate (EGCG), but effects were observed only at micromolar concentrations of unclear clinical relevance. Here, we report that nanomolar concentrations of EGCG significantly enhance contractility of intact murine myocytes by increasing electrically evoked Ca(2+) transients, sarcoplasmic reticulum (SR) Ca(2+) content, and ryanodine receptor type 2 (RyR2) channel open probability. Voltage-clamp experiments demonstrate that 10 nM EGCG significantly inhibits the Na(+)-Ca(2+) exchanger. Of importance, other Na(+) and Ca(2+) handling proteins such as Ca(2+)-ATPase, Na(+)-H(+) exchanger, and Na(+)-K(+) ATPase were not affected by EGCG <= 1 MUM. Thus, nanomolar EGCG increases contractility in intact myocytes by coordinately modulating SR Ca(2+) loading, RyR2-mediated Ca(2+) release, and Na(+)-Ca(2+) exchange. Inhibition of Na(+)-K(+) ATPase activity probably contributes to the positive inotropic effects observed at EGCG concentrations >1 MUM. These newly recognized actions of nanomolar and micromolar EGCG should be considered when the therapeutic and toxicological potential of green tea supplementation is evaluated and may provide a novel therapeutic strategy for improving contractile function in heart failure. PMID- 22918968 TI - Critical role for mixed-lineage kinase 3 in acetaminophen-induced hepatotoxicity. AB - c-Jun NH(2)-terminal kinase (JNK) activation plays a major role in acetaminophen (APAP)-induced hepatotoxicity. However, the exact mechanism of APAP-induced JNK activation is incompletely understood. It has been established that apoptosis signal-regulating kinase 1 (ASK1) regulates the late phase of APAP-induced JNK activation, but the mitogen-activated protein kinase kinase kinase that mediates the initial phase of APAP-induced JNK activation has not been identified. Oxidative stress produced during APAP metabolism causes JNK activation, which promotes mitochondrial dysfunction and results in the amplification of oxidative stress. Therefore, inhibition of the initial phase of JNK activation may be key to protection against APAP-induced liver injury. The goal of this study was to determine whether mixed-lineage kinase 3 (MLK3) mediates the initial, ASK1 independent phase of APAP-induced JNK activation and thus promotes drug-induced hepatotoxicity. We found that MLK3 was activated by oxidative stress and was required for JNK activation in response to oxidative stress. Loss of MLK3 attenuated APAP-induced JNK activation and hepatocyte death in vitro, independent of receptor-interacting protein 1. Moreover, JNK and glycogen synthase kinase 3beta activation was significantly attenuated, and Mcl-1 degradation was inhibited in APAP-treated MLK3-knockout mice. Furthermore, we showed that loss of MLK3 increased expression of glutamate cysteine ligase, accelerated hepatic GSH recovery, and decreased production of reactive oxygen species after APAP treatment. MLK3-deficient mice were significantly protected from APAP-induced liver injury, compared with wild-type mice. Together, these studies establish a novel role for MLK3 in APAP-induced JNK activation and hepatotoxicity, and they suggest MLK3 as a possible target in the treatment of APAP-induced liver injury. PMID- 22918969 TI - Generation and characterization of novel cytochrome P450 Cyp2c gene cluster knockout and CYP2C9 humanized mouse lines. AB - Compared with rodents and many other animal species, the human cytochrome P450 (P450) Cyp2c gene cluster varies significantly in the multiplicity of functional genes and in the substrate specificity of its enzymes. As a consequence, the use of wild-type animal models to predict the role of human CYP2C enzymes in drug metabolism and drug-drug interactions is limited. Within the human CYP2C cluster CYP2C9 is of particular importance, because it is one of the most abundant P450 enzymes in human liver, and it is involved in the metabolism of a wide variety of important drugs and environmental chemicals. To investigate the in vivo functions of cytochrome P450 Cyp2c genes and to establish a model for studying the functions of CYP2C9 in vivo, we have generated a mouse model with a deletion of the murine Cyp2c gene cluster and a corresponding humanized model expressing CYP2C9 specifically in the liver. Despite the high number of functional genes in the mouse Cyp2c cluster and the reported roles of some of these proteins in different biological processes, mice deleted for Cyp2c genes were viable and fertile but showed certain phenotypic alterations in the liver. The expression of CYP2C9 in the liver also resulted in viable animals active in the metabolism and disposition of a number of CYP2C9 substrates. These mouse lines provide a powerful tool for studying the role of Cyp2c genes and of CYP2C9 in particular in drug disposition and as a factor in drug-drug interaction. PMID- 22918976 TI - Mechanisms of post-intervention arterial remodelling. AB - It has been appreciated over the past two decades that arterial remodelling, in addition to intimal hyperplasia, contributes significantly to the degree of restenosis that develops following revascularization procedures. Remodelling appears to be an adventitia-based process that is contributed to by multiple factors including cytokines and growth factors that regulate extracellular matrix or phenotypic transformation of vascular cells including myofibroblasts. In this review, we summarize the currently available information from animal models as well as clinical investigations regarding arterial remodelling. The factors that contribute to this process are presented with an emphasis on potential therapeutic methods to enhance favourable remodelling and prevent restenosis. PMID- 22918979 TI - Changes in sensory hand representation and pain thresholds induced by motor cortex stimulation in humans. AB - Shrinking of deafferented somatosensory regions after neural damage is thought to participate to the emergence of neuropathic pain, and pain-relieving procedures have been reported to induce the normalization of altered cortical maps. While repetitive magnetic stimulation (rTMS) of the motor cortex can lessen neuropathic pain, no evidence has been provided that this is concomitant to changes in sensory maps. Here, we assessed in healthy volunteers the ability of 2 modes of motor cortex rTMS commonly used in pain patients to induce changes in pain thresholds and plastic phenomena in the S1 cortex. Twenty minutes of high frequency (20 Hz) rTMS significantly increased pain thresholds in the contralateral hand, and this was associated with the expansion of the cortical representation of the hand on high-density electroencephalogram source analysis. Neither of these effects were observed after sham rTMS, nor following intermittent theta-burst stimulation (iTBS). The superiority of 20-Hz rTMS over iTBS to induce sensory plasticity may reflect its better match with intrinsic cortical motor frequencies, which oscillate at around 20 Hz. rTMS-induced changes might partly counterbalance the plasticity induced by a nerve lesion, and thus substantiate the use of rTMS to treat human pain. However, a mechanistic relation between S1 plasticity and pain-relieving effects is far from being established. PMID- 22918978 TI - Matrix metalloproteinase-9 deletion attenuates myocardial fibrosis and diastolic dysfunction in ageing mice. AB - AIMS: Age-related diastolic dysfunction has been attributed to an increased passive stiffness, which is regulated by extracellular matrix (ECM). We recently showed that matrix metalloproteinase (MMP)-9, an ECM mediator, increases in the left ventricle (LV) with age. The aim of this study, accordingly, was to determine the role of MMP-9 in cardiac ageing. METHODS AND RESULTS: We compared LV function in young (6-9 months), middle-aged (12-15 months), old (18-24 months) and senescent (26-34 months) wild-type (WT) and MMP-9 null mice (n >= 12/group). All groups had similar fractional shortenings and aortic peak velocities, indicating that systolic function was not altered by ageing or MMP-9 deletion. The mitral ratios of early to late diastolic filling velocities were reduced in old and senescent WT compared with young controls, and this reduction was attenuated in MMP-9 null mice. Concomitantly, the increase in LV collagen content was reduced in MMP-9 null mice (n = 5-6/group). To dissect the mechanisms of these changes, we evaluated the mRNA expression levels of 84 ECM and adhesion molecules by real-time qPCR (n = 6/group). The expression of pro-fibrotic periostin and connective tissue growth factor (CTGF) increased with senescence, as did transforming growth factor-beta (TGF-beta)-induced protein levels and Smad signalling, and these increases were blunted by MMP-9 deletion. In senescence, MMP-9 deletion also resulted in a compensatory increase in MMP-8. CONCLUSION: MMP 9 deletion attenuates the age-related decline in diastolic function, in part by reducing TGF-beta signalling-induced periostin and CTGF expression and increasing MMP-8 expression to regulate myocardial collagen turnover and deposition. PMID- 22918977 TI - Upregulation of junctional adhesion molecule-A is a putative prognostic marker of hypertension. AB - AIMS: Establishing biochemical markers of pre-hypertension and early hypertension could help earlier diagnostics and therapeutic intervention. We assess dynamics of junctional adhesion molecule-A (JAM-A) expression in rat models of hypertension and test whether JAM-A expression could be driven by angiotensin (ANG) II and whether JAM-A contributes to the progression of hypertension. We also compare JAM-A expression in normo- and hypertensive humans. METHODS AND RESULTS: In pre-hypertensive and spontaneously hypertensive rats (SHRs), JAM-A protein was overexpressed in the brainstem microvasculature, lung, liver, kidney, spleen, and heart. JAM-A upregulation at early and late stages was even greater in the stroke-prone SHR. However, JAM-A was not upregulated in leucocytes and platelets of SHRs. In Goldblatt 2K-1C hypertensive rats, JAM-A expression was augmented before any increase in blood pressure, and similarly JAM-A upregulation preceded hypertension caused by peripheral and central ANG II infusions. In SHRs, ANG II type 1 (AT(1)) receptor antagonism reduced JAM-A expression, but the vasodilator hydralazine did not. Body-wide downregulation of JAM-A with Vivo morpholinos in juvenile SHRs delayed the progression of hypertension. In the human saphenous vein, JAM-A mRNA was elevated in hypertensive patients with untreated hypertension compared with normotensive patients but reduced in patients treated with renin-angiotensin system antagonists. CONCLUSION: Body-wide upregulation of JAM-A in genetic and induced models of hypertension in the rat precedes the stable elevation of arterial pressure. JAM-A upregulation may be triggered by AT(1) receptor-mediated signalling. An association of JAM-A with hypertension and sensitivity to blockers of ANG II signalling were also evident in humans. We suggest a prognostic and possibly a pathogenic role of JAM-A in arterial hypertension. PMID- 22918981 TI - Common and segregated processing of observed actions in human SPL. AB - To clarify the functional organization of parietal cortex involved in action observation, we scanned subjects observing 3 widely different classes of actions: Manipulation with the hands, locomotion, and climbing. An effector-based organization predicts that parietal regions involved in the observation of climbing should not differ from those involved in observing manipulation and locomotion, opposite to the prediction of an organization based upon the action performed. Compared with individual controls, the observation of climbing evoked activity in dorsal superior parietal lobule (SPL), extending into precuneus and posterior cingulate sulcus. Observation of locomotion differentially activated similar regions less strongly. Observation of manipulation activated ventro rostral SPL, including putative human AIP (phAIP). Using interaction testing and exclusive masking to directly compare the parietal regions involved in observing the 3 action classes, relative to the controls, revealed that the rostral part of dorsal SPL was specifically involved in observing climbing and phAIP in observing manipulation. Parietal regions common to observing all 3 action classes were restricted and likely reflected higher order visual processing of body posture and 3D structure from motion. These results support a functional organization of some parietal regions involved in action observation according to the type of action in the case of climbing and manipulation. PMID- 22918980 TI - Evidence for pitch chroma mapping in human auditory cortex. AB - Some areas in auditory cortex respond preferentially to sounds that elicit pitch, such as musical sounds or voiced speech. This study used human electroencephalography (EEG) with an adaptation paradigm to investigate how pitch is represented within these areas and, in particular, whether the representation reflects the physical or perceptual dimensions of pitch. Physically, pitch corresponds to a single monotonic dimension: the repetition rate of the stimulus waveform. Perceptually, however, pitch has to be described with 2 dimensions, a monotonic, "pitch height," and a cyclical, "pitch chroma," dimension, to account for the similarity of the cycle of notes (c, d, e, etc.) across different octaves. The EEG adaptation effect mirrored the cyclicality of the pitch chroma dimension, suggesting that auditory cortex contains a representation of pitch chroma. Source analysis indicated that the centroid of this pitch chroma representation lies somewhat anterior and lateral to primary auditory cortex. PMID- 22918983 TI - Impairment of online control of hand and eye movements in a monkey model of optic ataxia. AB - The parietal mechanisms for online control of hand trajectory were studied by combining single-cell recording and reversible inactivation of superior parietal area 5 (PE/PEc; SPL) of monkeys while these made reaches and saccades to visual targets, when the target position changed unexpectedly. Neural activity was modulated by hand position, speed, and movement direction, and by pre- and/or postsaccadic signals. After bilateral muscimol injection, an increase in the hand reaction- and movement-time toward both the first and second targets was observed. This caused an increase in the time necessary for the trajectory correction, and therefore an elongation of the hand-path toward the first target location. Furthermore, hand trajectories were different in shape than control ones. An elongation of the eye reaction time to both first and second targets was also observed, which could partially explain the deficit of planning and correction of hand movement. These results identify the superior parietal lobule as a crucial node in the online control of hand and eye movement and highlight the role of the eye impairment in the emergence of the reaching disorder so far regarded as the hallmark of optic ataxia. PMID- 22918982 TI - Differential wiring of layer 2/3 neurons drives sparse and reliable firing during neocortical development. AB - Sensory information is transmitted with high fidelity across multiple synapses until it reaches the neocortex. There, individual neurons exhibit enormous variability in responses. The source of this diversity in output has been debated. Using transgenic mice expressing the green fluorescent protein coupled to the activity-dependent gene c-fos, we identified neurons with a history of elevated activity in vivo. Focusing on layer 4 to layer 2/3 connections, a site of strong excitatory drive at an initial stage of cortical processing, we find that fluorescently tagged neurons receive significantly greater excitatory and reduced inhibitory input compared with neighboring, unlabeled cells. Differential wiring of layer 2/3 neurons arises early in development and requires sensory input to be established. Stronger connection strength is not associated with evidence for recent synaptic plasticity, suggesting that these more active ensembles may not be generated over short time scales. Paired recordings show fosGFP+ neurons spike at lower stimulus thresholds than neighboring, fosGFP- neurons. These data indicate that differences in circuit construction can underlie response heterogeneity amongst neocortical neurons. PMID- 22918984 TI - Homeostatic regulation of gephyrin scaffolds and synaptic strength at mature hippocampal GABAergic postsynapses. AB - Gephyrin is a scaffolding protein important for the postsynaptic clustering of inhibitory neurotransmitter receptors. Here, we investigated the properties of gephyrin scaffolds at gamma-aminobutyric acid- (GABA-)ergic synapses in organotypic entorhino-hippocampal cultures prepared from a transgenic mouse line, which expresses green fluorescent protein-tagged gephyrin under the control of the Thy1.2 promoter. Fluorescence recovery after photobleaching revealed a developmental stabilization of postsynaptic gephyrin clusters concomitant with an increase in cluster size and synaptic strength between 1 and 4 weeks in vitro. Prolonged treatment of the slice cultures with diazepam or a GABAA receptor antagonist disclosed a homeostatic regulation of both inhibitory synaptic strength and gephyrin cluster size and stability in 4-weeks-old cultures, whereas at 1 week in vitro, the same drug treatments modulated GABAergic postsynapse and gephyrin cluster properties following a Hebbian mode of synaptic plasticity. Our data are consistent with a model in which the postnatal maturation of the hippocampal network endows CA1 pyramidal neurons with the ability to homeostatically adjust the strength of their inhibitory postsynapses to afferent GABAergic drive by regulating gephyrin scaffold properties. PMID- 22918985 TI - Acute stress, but not corticosterone, disrupts short- and long-term synaptic plasticity in rat dorsal subiculum via glucocorticoid receptor activation. AB - The subiculum (SUB) serves as the major output structure of the hippocampus; therefore, exploring synaptic plasticity within this region is of great importance for understanding the dynamics of hippocampal circuitry and hippocampal-cortical interactions. Previous research has shown exposure to acute stress dramatically alters synaptic plasticity within the hippocampus proper. Using in vivo electrophysiological recordings in urethane-anesthetized adult male Sprague-Dawley rats, we tested the effects of either acute restraint stress (30 min) or corticosterone (CORT) injections (3 mg/kg; s.c.) on short- and long-term forms of synaptic plasticity in the Cornu Ammonis 1-SUB pathway. Paired-pulse facilitation and two forms of long-term plasticity (long-term potentiation and late-developing potentiation) were significantly reduced after exposure to acute stress but not CORT treatment. Measurements of plasma CORT confirmed similar levels of circulating hormone in animals exposed to either acute stress or CORT treatment. The disruptive effects of acute stress on both short- and long-term forms of synaptic plasticity are mediated by glucocorticoid receptor (GR) activation as these disruptions were blocked by pre-treatment with the selective GR antagonist RU38486 (10 mg/kg; s.c.). The present results highlight the susceptibility of subicular plasticity to acute stress and provide evidence that GR activation is necessary but not sufficient for mediating these alterations. PMID- 22918986 TI - Neural substrates of executive dysfunction in fragile X-associated tremor/ataxia syndrome (FXTAS): a brain potential study. AB - Executive dysfunction in fragile X-associated tremor/ataxia syndrome (FXTAS) has been suggested to mediate other cognitive impairments. In the present study, event-related potentials and neuropsychological testing were combined to investigate the brain mechanisms underlying the executive dysfunction in FXTAS. Thirty-two-channel electroencephalography was recorded during an auditory "oddball" task requiring dual responses. FXTAS patients (N= 41, mean age= 62) displayed prolonged latencies of N1 and P3 and reduced amplitudes of P2 and P3, whereas their N2 measures remained within the normal range, indicating relatively preserved early-stage auditory attention but markedly impaired late-stage attention and working memory updating processes (as indexed by P3). Topographical mapping revealed a typical parietal P3 peak preceded by a prominent fronto central P3 in normal control subjects (N= 32), whereas FXTAS patients had decreased parietal P3 amplitude and diminished fronto-central positivities with a delayed onset (~50 ms later than controls, P < 0.002). The P3 abnormalities were associated with lower executive function test (e.g., BDS-2) scores. Smaller P3 amplitudes also correlated with increased CGG repeat length of fragile X mental retardation 1 (FMR1) gene and higher FMR1 mRNA levels. These results indicate that abnormal fronto-parietal attentional network dynamics underlie executive dysfunction, the cardinal feature of cognitive impairment in FXTAS. PMID- 22918988 TI - Recorded quality of primary care for patients with diabetes in England before and after the introduction of a financial incentive scheme: a longitudinal observational study. AB - BACKGROUND: The UK's Quality and Outcomes Framework (QOF) was introduced in 2004/5, linking remuneration for general practices to recorded quality of care for chronic conditions, including diabetes mellitus. We assessed the effect of the incentives on recorded quality of care for diabetes patients and its variation by patient and practice characteristics. METHODS: Using the General Practice Research Database we selected a stratified sample of 148 English general practices in England, contributing data from 2000/1 to 2006/7, and obtained a random sample of 653,500 patients in which 23,920 diabetes patients identified. We quantified annually recorded quality of care at the patient-level, as measured by the 17 QOF diabetes indicators, in a composite score and analysed it longitudinally using an Interrupted Time Series design. RESULTS: Recorded quality of care improved for all subgroups in the pre-incentive period. In the first year of the incentives, composite quality improved over-and-above this pre-incentive trend by 14.2% (13.7-14.6%). By the third year the improvement above trend was smaller, but still statistically significant, at 7.3% (6.7-8.0%). After 3 years of the incentives, recorded levels of care varied significantly for patient gender, age, years of previous care, number of co-morbid conditions and practice diabetes prevalence. CONCLUSIONS: The introduction of financial incentives was associated with improvements in the recorded quality of diabetes care in the first year. These improvements included some measures of disease control, but most captured only documentation of recommended aspects of clinical assessment, not patient management or outcomes of care. Improvements in subsequent years were more modest. Variation in care between population groups diminished under the incentives, but remained substantial in some cases. PMID- 22918987 TI - Is there "one" DLPFC in cognitive action control? Evidence for heterogeneity from co-activation-based parcellation. AB - The dorsolateral prefrontal cortex (DLPFC) has consistently been implicated in cognitive control of motor behavior. There is, however, considerable variability in the exact location and extension of these activations across functional magnetic resonance imaging (fMRI) experiments. This poses the question of whether this variability reflects sampling error and spatial uncertainty in fMRI experiments or structural and functional heterogeneity of this region. This study shows that the right DLPFC as observed in 4 different experiments tapping executive action control may be subdivided into 2 distinct subregions-an anterior ventral and a posterior-dorsal one -based on their whole-brain co-activation patterns across neuroimaging studies. Investigation of task-dependent and task independent connectivity revealed both clusters to be involved in distinct neural networks. The posterior subregion showed increased connectivity with bilateral intraparietal sulci, whereas the anterior subregion showed increased connectivity with the anterior cingulate cortex. Functional characterization with quantitative forward and reverse inferences revealed the anterior network to be more strongly associated with attention and action inhibition processes, whereas the posterior network was more strongly related to action execution and working memory. The present data provide evidence that cognitive action control in the right DLPFC may rely on differentiable neural networks and cognitive functions. PMID- 22918990 TI - The ethics of testing a test: randomized trials of the health impact of diagnostic tests for infectious diseases. AB - In the last decade, many new rapid diagnostic tests for infectious diseases have been developed. In general, these new tests are developed with the intent to optimize feasibility and population health, not accuracy alone. However, unlike drugs or vaccines, diagnostic tests are evaluated and licensed on the basis of accuracy, not health impact (eg, reduced morbidity or mortality). Thus, these tests are sometimes recommended or scaled up for purposes of improving population health without randomized evidence that they do so. We highlight the importance of randomized trials to evaluate the health impact of novel diagnostics and note that such trials raise distinctive ethical challenges of equipoise, equity, and informed consent. We discuss the distinction between equipoise for patient important outcomes versus diagnostic accuracy, the equity implications of evaluating health impact of diagnostics under routine conditions, and the importance of offering reasonable choices for informed consent in diagnostic trials. PMID- 22918991 TI - Population-based study of statins, angiotensin II receptor blockers, and angiotensin-converting enzyme inhibitors on pneumonia-related outcomes. AB - BACKGROUND: Studies suggest that statins and angiotensin-converting enzyme (ACE) inhibitors might be beneficial for the treatment of infections. Our purpose was to examine the association of statin, ACE inhibitor, and angiotensin II receptor blocker (ARB) use with pneumonia-related outcomes. METHODS: We conducted a retrospective cohort study using Department of Veterans Affairs data of patients aged >= 65 years hospitalized with pneumonia. We performed propensity-score matching for 3 medication classes simultaneously. RESULTS: Of 50119 potentially eligible patients, we matched 11498 cases with 11498 controls. Mortality at 30 days was 13%; 34% used statins, 30% ACE inhibitors, and 4% ARBs. In adjusted models, prior statin use was associated with decreased mortality (odds ratio [OR], 0.74; 95% confidence interval [CI], .68-.82) and mechanical ventilation (OR, 0.81; 95% CI, .70-.94), and inpatient use with decreased mortality (OR, 0.68; 95% CI, .59-.78) and mechanical ventilation (OR, 0.68; 95% CI, .60-.90). Prior (OR, 0.88; 95% CI, .80-.97) and inpatient (OR, 0.58; 95% CI, .48-.69) ACE inhibitor use was associated with decreased mortality. Prior (OR, 0.73; 95% CI, .58-.92) and inpatient ARB use (OR, 0.47; 95% CI, .30-.72) was only associated with decreased mortality. Use of all 3 medications was associated with reduced length of stay. CONCLUSIONS: Statins, and to a lesser extent ACE inhibitors and ARBs, are associated with improved pneumonia-related outcomes. Prospective cohort and randomized controlled trials are needed to examine potential mechanisms of action and whether acute initiation at the time of presentation with these infections is beneficial. PMID- 22918992 TI - Q fever: single-point source outbreak with high attack rates and massive numbers of undetected infections across an entire region. AB - BACKGROUND: In early 2009, a dairy-goat annex care farm in South Limburg, the Netherlands, reported 220 Coxiella burnetii-related abortions in 450 pregnant goats. These preceded human cases and occurred in a region that was Q-fever free before 2009, providing a unique quasi-experimental setting for investigating regional transmission patterns associated with a Q-fever point source. METHODS: Index-farm residents/employees, visitors, and their household contacts were traced and screened for C. burnetii. Distribution of community cases was analysed using a geographic information system. True incidence, including undetected infections, was estimated regionwide by seroprevalence in a pre- versus postoutbreak sample, and near-farm by immunoglobulin M seroprevalence in a municipal population sample. Environmental bacterial load was repeatedly measured in surface and aerosol samples. RESULTS: Serological attack rate was 92% (24/26) in index-farm residents/employees, 56% (28/50) in visitors, and 50% (7/14) in household contacts, and the clinical attack rate (ie, the proportion of persons seropositive for acute infection who also had clinical illness) was >= 80%. Notified symptomatic community cases (n = 253) were scattered downwind from the index farm, following a significant exposure-response gradient. Observed incidence ranged from 6.3% (0-1 km) to 0.1% (4-5 km), and remained high beyond. True incidence of infections was estimated at 2.9% regionwide, extrapolating to 8941 infections; estimated near-farm incidence was 12%. Coxiella burnetii load was high on-farm (2009), and lower off-farm (2009-2010). CONCLUSIONS: Linking a single dairy-goat farm to a human Q-fever cluster, we show widespread transmission, massive numbers of undetected infections, and high attack rates on- and off-farm, even beyond a 5-km high-risk zone. Our investigation may serve as an essential case study for risk assessment in public health and related fields such as bioterrorism response and preparedness. PMID- 22918993 TI - Choice and doses of antibacterial agents for cement spacers in treatment of prosthetic joint infections: review of published studies. AB - BACKGROUND: Addition of antibacterial drugs to interim antibacterial cement spacers (ACSs) is considered to be standard of care for surgical revision in prosthetic joint infections (PJIs). We reviewed published studies evaluating the choice and doses of antibacterials in spacers. METHODS: We conducted a PubMed search of all clinical study reports evaluating the use of ACSS in a 2-stage hip or knee arthroplasty for treatment of PJI (1988 through August 2011). The trial design, antibacterials used, and end points studied were analyzed. RESULTS: No randomized trials were found comparing either ACSs with different concentrations of antibacterials or ACSs with or without antibacterials. Most of the studies were uncontrolled and used various time points to evaluate the outcome. Twenty publications that reported doses of antibacterials in spacers and had a follow-up of >= 24 months after the second stage were selected for review. Most ACSs included vancomycin and aminoglycosides. The doses of aminoglycosides and vancomycin ranged from 0.25 to 4.8 g and from 1 to 4 g, respectively, per 4 g of cement. No association between reported eradication of the infection and antibacterial load was found. CONCLUSIONS: Published data do not allow evaluation of whether antibacterials in temporary cement spacers provide additional benefits in the treatment of PJI, compared with systemic antibacterials, and are not sufficient to support recommendations on dosages. Complications of ACSs have not been consistently analyzed. Prospective randomized trials comparing spacers with and without antibacterials or spacers with different loads of antibacterials are needed to evaluate the safety and efficacy of ACSs. PMID- 22918995 TI - Termination of an Extreme-Drug Resistant-Acinetobacter baumannii Outbreak in a Hospital After Flooding: Lessons Learned. PMID- 22918996 TI - Digitizing historical plague. PMID- 22918997 TI - Reconsidering cryptococcal antigen screening in the U.S. among persons with CD4 <100 cells/mcL. PMID- 22918998 TI - Antiretroviral Medication Errors among Hospitalized HIV-Infected Adults. PMID- 22918999 TI - "Community-acquired Clostridium difficile infection: an emerging entity". PMID- 22919000 TI - Primary amebic meningoencephalitis deaths associated with sinus irrigation using contaminated tap water. AB - BACKGROUND: Naegleria fowleri is a climate-sensitive, thermophilic ameba found in the environment, including warm, freshwater lakes and rivers. Primary amebic meningoencephalitis (PAM), which is almost universally fatal, occurs when N. fowleri-containing water enters the nose, typically during swimming, and N. fowleri migrates to the brain via the olfactory nerve. In 2011, 2 adults died in Louisiana hospitals of infectious meningoencephalitis after brief illnesses. METHODS: Clinical and environmental testing and case investigations were initiated to determine the cause of death and to identify the exposures. RESULTS: Both patients had diagnoses of PAM. Their only reported water exposures were tap water used for household activities, including regular sinus irrigation with neti pots. Water samples, tap swab samples, and neti pots were collected from both households and tested; N. fowleri were identified in water samples from both homes. CONCLUSIONS: These are the first reported PAM cases in the United States associated with the presence of N. fowleri in household plumbing served by treated municipal water supplies and the first reports of PAM potentially associated with the use of a nasal irrigation device. These cases occurred in the context of an expanding geographic range for PAM beyond southern tier states with recent case reports from Minnesota, Kansas, and Virginia. These infections introduce an additional consideration for physicians recommending nasal irrigation and demonstrate the importance of using appropriate water (distilled, boiled, filtered) for nasal irrigation. Furthermore, the changing epidemiology of PAM highlights the importance of raising awareness about this disease among physicians treating persons showing meningitislike symptoms. PMID- 22919001 TI - Association between coronary vascular dysfunction and cardiac mortality in patients with and without diabetes mellitus. AB - BACKGROUND: Diabetes mellitus increases the risk of adverse cardiac outcomes and is considered a coronary artery disease (CAD) equivalent. We examined whether coronary vascular dysfunction, an early manifestation of CAD, accounts for increased risk among diabetics compared with nondiabetics. METHODS AND RESULTS: A total of 2783 consecutive patients (1172 diabetics and 1611 nondiabetics) underwent quantification of coronary flow reserve (CFR; CFR=stress divided by rest myocardial blood flow) by positron emission tomography and were followed up for a median of 1.4 years (quartile 1-3, 0.7-3.2 years). The primary end point was cardiac death. Impaired CFR (below the median) was associated with an adjusted 3.2- and 4.9-fold increase in the rate of cardiac death for diabetics and nondiabetics, respectively (P=0.0004). Addition of CFR to clinical and imaging risk models improved risk discrimination for both diabetics and nondiabetics (c index, 0.77-0.79, P=0.04; 0.82-0.85, P=0.03, respectively). Diabetic patients without known CAD with impaired CFR experienced a rate of cardiac death comparable to that for nondiabetic patients with known CAD (2.8%/y versus 2.0%/y; P=0.33). Conversely, diabetics without known CAD and preserved CFR had very low annualized cardiac mortality, which was similar to patients without known CAD or diabetes mellitus and normal stress perfusion and systolic function (0.3%/y versus 0.5%/y; P=0.65). CONCLUSIONS: Coronary vasodilator dysfunction is a powerful, independent correlate of cardiac mortality among both diabetics and nondiabetics and provides meaningful incremental risk stratification. Among diabetic patients without CAD, those with impaired CFR have event rates comparable to those of patients with prior CAD, whereas those with preserved CFR have event rates comparable to those of nondiabetics. PMID- 22919002 TI - MicroRNA dissects out dangerous pancreatic cysts from all the rest. AB - Malignant transformation of pancreatic cysts occurs in only a fraction of patients. The diagnostic dilemma is identifying which cysts pose a cancerous threat. Cyst fluid has been analyzed in a variety of ways to answer this question but the microRNA (miRNA) profile of the fluid may finally hold the answer. PMID- 22919003 TI - Identifying and targeting ROS1 gene fusions in non-small cell lung cancer. AB - PURPOSE: Oncogenic gene fusions involving the 3' region of ROS1 kinase have been identified in various human cancers. In this study, we sought to characterize ROS1 fusion genes in non-small cell lung cancer (NSCLC) and establish the fusion proteins as drug targets. EXPERIMENTAL DESIGN: An NSCLC tissue microarray (TMA) panel containing 447 samples was screened for ROS1 rearrangement by FISH. This assay was also used to screen patients with NSCLC. In positive samples, the identity of the fusion partner was determined through inverse PCR and reverse transcriptase PCR. In addition, the clinical efficacy of ROS1 inhibition was assessed by treating a ROS1-positive patient with crizotinib. The HCC78 cell line, which expresses the SLC34A2-ROS1 fusion, was treated with kinase inhibitors that have activity against ROS1. The effects of ROS1 inhibition on proliferation, cell-cycle progression, and cell signaling pathways were analyzed by MTS assay, flow cytometry, and Western blotting. RESULTS: In the TMA panel, 5 of 428 (1.2%) evaluable samples were found to be positive for ROS1 rearrangement. In addition, 1 of 48 patients tested positive for rearrangement, and this patient showed tumor shrinkage upon treatment with crizotinib. The patient and one TMA sample displayed expression of the recently identified SDC4-ROS1 fusion, whereas two TMA samples expressed the CD74-ROS1 fusion and two others expressed the SLC34A2-ROS1 fusion. In HCC78 cells, treatment with ROS1 inhibitors was antiproliferative and downregulated signaling pathways that are critical for growth and survival. CONCLUSIONS: ROS1 inhibition may be an effective treatment strategy for the subset of patients with NSCLC whose tumors express ROS1 fusion genes. PMID- 22919005 TI - An update on radioactive release and exposures after the Fukushima Dai-ichi nuclear disaster. AB - On 11 March 2011, the Richter scale 0.9-magnitude Tokohu earthquake and tsunami struck the northeast coast of Japan, resulting in widespread injury and loss of life. Compounding this tragic loss of life, a series of equipment and structural failures at the Fukushima Dai-ichi nuclear power plant (FDNP) resulted in the release of many volatile radioisotopes into the atmosphere. In this update, we detail currently available evidence about the nature of immediate radioactive exposure to FDNP workers and the general population. We contrast the nature of the radioactive exposure at FDNP with that which occurred at the Chernobyl power plant 25 years previously. Prediction of the exact health effects related to the FDNP release is difficult at present and this disaster provides the scientific community with a challenge to help those involved and to continue research that will improve our understanding of the potential complications of radionuclide fallout. PMID- 22919004 TI - Utility of positron emission tomography/CT in the evaluation of small bowel pathology. AB - We describe the management principles and different roles of positron emission tomography (PET)/CT in the evaluation of patients with small bowel tumours (adenocarcinoma, gastrointestinal stromal tumour, lymphoma, metastases) from initial staging, monitoring response to treatment, to detection of recurrent disease. We also discuss the various non-malignant aetiologies of small bowel fludeoxyglucose (FDG) PET uptake, and other pitfalls in FDG PET/CT interpretation. Awareness of the imaging appearances of small bowel tumours, patterns of disease spread and potential PET/CT interpretation pitfalls are of paramount importance to optimise diagnostic accuracy. PMID- 22919006 TI - Reproducibility and clinical correlations of post-treatment changes on CT of prostate cancer bone metastases treated with chemotherapy. AB - OBJECTIVES: The objective of this study was to determine whether, in patients with prostate cancer (PCa) bone metastases receiving chemotherapy, early post treatment changes on CT are reproducible and associated with clinical outcomes. METHODS: Blinded to outcomes, two radiologists with 1 year and 5 years of experience independently reviewed CTs obtained before and 3 months after chemotherapy initiation in 38 patients with bone metastases from castration resistant PCa, recording the size, matrix and attenuation of <=5 lesions; presence of new lesions, extraosseous components, periosteal reactions and cortical thickening; and overall CT assessment (improved, no change or worse). Kappa statistics were used to assess inter-reader agreement; the Kruskal-Wallis test and Cox regression model were used to evaluate associations. RESULTS: Inter reader agreement was low/fair for size change (concordance correlation coefficient=0.013), overall assessment and extraosseous involvement (kappa=0.3), moderate for periosteal reaction and cortical thickening (kappa=0.4-0.5), and substantial for CT attenuation (kappa=0.7). Most metastases were blastic (Reader 1, 58%; Reader 2, 67%) or mixed lytic-blastic (Reader 1, 42%; Reader 2, 34%). No individual CT features correlated with survival. Readers 1 and 2 called the disease improved in 26% and 5% of patients, unchanged in 11% and 21%, and worse in 63% and 74%, respectively, with 64% interreader agreement. Overall CT assessment did not correlate with percentage change in prostate-specific antigen level. For the more experienced reader (Reader 2), patients with improved or unchanged disease had significantly longer median survival (p=0.036). CONCLUSIONS: In PCa bone metastases, interreader agreement is low in overall CT post-treatment assessment and varies widely for individual CT features. Improved or stable disease identified by an experienced reader is statistically associated with longer survival. PMID- 22919007 TI - Radiological staging in patients with hilar cholangiocarcinoma: a systematic review and meta-analysis. AB - OBJECTIVE: To obtain diagnostic performance values of CT, MRI, ultrasound and 18 fludeoxyglucose positron emission tomography (PET)/CT for staging of hilar cholangiocarcinoma. METHODS: A comprehensive systematic search was performed for articles published up to March 2011 that fulfilled the inclusion criteria. Study quality was assessed with the quality assessment of diagnostic accuracy studies tool. RESULTS: 16 articles (448 patients) were included that evaluated CT (n=11), MRI (n=3), ultrasound (n=3), or PET/CT (n=1). Overall, their quality was moderate. The accuracy estimates for evaluation of CT for ductal extent of the tumour was 86%. The sensitivity and specificity estimates of CT were 89% and 92% for evaluation of portal vein involvement, 83% and 93% for hepatic artery involvement, and 61% and 88% for lymph node involvement, respectively. Data were too limited for adequate comparisons of the different techniques. CONCLUSION: Diagnostic accuracy studies of CT, MRI, ultrasound or PET/CT for staging of hilar cholangiocarcinoma are sparse and have moderate methodological quality. Data primarily concern CT, which has an acceptable accuracy for assessment of ductal extent, portal vein and hepatic artery involvement, but low sensitivity for nodal status. PMID- 22919008 TI - A computer-aided algorithm to quantitatively predict lymph node status on MRI in rectal cancer. AB - OBJECTIVE: The aim of this study was to demonstrate the principle of supporting radiologists by using a computer algorithm to quantitatively analyse MRI morphological features used by radiologists to predict the presence or absence of metastatic disease in local lymph nodes in rectal cancer. METHODS: A computer algorithm was developed to extract and quantify the following morphological features from MR images: chemical shift artefact; relative mean signal intensity; signal heterogeneity; and nodal size (volume or maximum diameter). Computed predictions on nodal involvement were generated using quantified features in isolation or in combinations. Accuracies of the predictions were assessed against a set of 43 lymph nodes, determined by radiologists as benign (20 nodes) or malignant (23 nodes). RESULTS: Predictions using combinations of quantified features were more accurate than predictions using individual features (0.67-0.86 vs 0.58-0.77, respectively). The algorithm was more accurate when three dimensional images were used (0.58-0.86) than when only middle image slices (two dimensional) were used (0.47-0.72). Maximum node diameter was more accurate than node volume in representing the nodal size feature; combinations including maximum node diameter gave accuracies up to 0.91. CONCLUSION: We have developed a computer algorithm that can support radiologists by quantitatively analysing morphological features of lymph nodes on MRI in the context of rectal cancer nodal staging. We have shown that this algorithm can combine these quantitative indices to generate computed predictions of nodal status which closely match radiological assessment. This study provides support for the feasibility of computer-assisted reading in nodal staging, but requires further refinement and validation with larger data sets. PMID- 22919009 TI - Quantitative MRI of colonic mural enhancement: segmental differences exist in endoscopically proven normal colon. AB - OBJECTIVES: Abnormal contrast enhancement on MRI is advocated as a biomarker for inflammation in colitis, although the enhancement kinetics of normal colon are poorly described. Our purpose was to quantitatively assess mural enhancement in normal colon and test for intersegmental differences. METHODS: Eight patients without prior history of inflammatory bowel disease underwent standard MRI colonography followed by normal same-day colonoscopy. Acquired sequences included a volumetric interpolated breath-hold examination (VIBE) to encompass the whole colonic volume, performed at 5 degrees , 10 degrees and 35 degrees flip angles for T(1) quantitation and then at a fixed 35 degrees flip angle three times prior to and every 30 s following intravenous gadoterate meglumine for 220 s. Ascending colon, descending colon and rectal R(1) (1/T(1)) was plotted against time. Mean pre-contrast R(1), initial change of R(1) (DeltaR(1)), early and late "plateau phase" enhancement and the area under the R(1)-time (AUC-R(1)) curve were compared between segments using the Student's paired t-test. RESULTS: There was no significant difference of pre-contrast R(1) between segments (p=0.49 to 0.62). DeltaR(1) was higher for ascending colon compared with descending colon (0.0023+/-0.0012 ms(-1) vs 0.0010+/-0.0011 ms(-1), p=0.03). There was no significant difference for early or late plateau phase R(1) between colonic segments (p=0.08 to 1.00). AUC-R(1) was greater for ascending than descending colon (0.54+/-0.19 vs 0.30+/-0.14, p=0.03). CONCLUSIONS: Intersegmental differences in colonic enhancement are present and should be considered when interpreting differential segmental enhancement. PMID- 22919010 TI - Can you diagnose this condition on plain radiography? PMID- 22919011 TI - Enhancement patterns of hepatocellular carcinomas on multiphasicmultidetector row CT: comparison with pathological differentiation. AB - OBJECTIVE: The objective of this study was to determine the incidence of typical and atypical enhancement patterns of hepatocellular carcinomas (HCCs) on multiphasic multidetector row CT (MDCT) and to correlate the enhancement patterns and morphological image findings of HCC with the degree of tumour differentiation. METHODS: MDCT images of 217 patients with 243 surgically proven HCCs were evaluated through consensus reading by two radiologists. Our MDCT protocol was composed of precontrast, arterial, portal and delayed phases. The reviewers analysed the CT images for degree of attenuation; relative timing of washout; presence of dysmorphic intratumoral vessels, aneurysms and necrosis; tumour size; tumour margin; presence of pseudocapsule; intratumoral heterogeneity; and determined enhancement pattern. The imaging features were correlated with tumour differentiation using Fisher's exact test or the chi(2) test. RESULTS: Among 243 HCCs, 137 (56.4%) showed the typical enhancement pattern of HCC, which is arterial enhancement and washout on portal or equilibrium phase images. In the arterial phase, 190 of 243 (78.2%) HCCs showed hypervascularity, with approximately three quarters of poorly differentiated (PD) (34 of 45, 75.6%) and moderately differentiated (MD) HCCs (92 of 123, 74.8%) showing washout during the portal or delayed phases, vs only 50% of well-differentiated (WD) HCCs (11 of 22; p<0.048). The presence of intratumoral vessels and aneurysms, tumour necrosis, attenuation of precontrast, the relative timing of washout, intratumoral attenuation heterogeneity, tumour margin and tumour size were correlated with the pathological differentiation of HCCs (p<0.05). CONCLUSION: A typical enhancement of HCCs on MDCT was not unusual (43.6%) and WD and PD HCCs account for most of the atypical enhancement patterns. Early washout favoured MD and PD HCCs rather than WD HCCs, whereas in our study the presence of intratumoral aneurysm was a highly specific finding for PD HCC. PMID- 22919012 TI - Evaluation of the utility of abdominal CT scans in the diagnosis, management, outcome and information given at discharge of patients with non-traumatic acute abdominal pain. AB - OBJECTIVES: The role of CT imaging in the diagnosis and management of acute abdominal pain is well established, but its utility is limited in a minority of cases. The aim of this study was to quantify the degree to which radiological and clinical findings differ. Interobserver variability in CT reporting was also assessed. METHODS: Clinical data and CT reports were analysed retrospectively for any discrepancies by comparing CT diagnosis, clinical diagnosis as stated on the discharge summary and final diagnosis (based on consensus review of all information). Blinded review of all CT imaging was performed to determine interobserver variability. RESULTS: 120 consecutive scans fulfilled the inclusion criteria (114 patients; 79 women; mean age 55 years). The correct clinical diagnosis was made in 87.5% of cases based on CT findings. The lack of intravenous contrast limited diagnostic interpretation in 6 of the 15 discrepant cases. CT was unable to define early inflammatory changes in three patients and early caecal carcinoma in one. A right paraduodenal internal hernia was difficult to detect in another patient. Interobserver agreement was 93%, but with a low kappa value of 0.27. A paradox exists due to an imbalance in the positive and negative agreement of 96% and 31%, respectively. CONCLUSIONS: The utility of CT imaging in the diagnosis and management of patients presenting with acute abdominal pain is confirmed, but is limited in a minority of cases where poor negative interobserver agreement exists. Good communication to the reporting radiologist of the relevant patient history and clinical question becomes important. PMID- 22919013 TI - Comparison of sensitivity of lung nodule detection between radiologists and technologists on low-dose CT lung cancer screening images. AB - OBJECTIVES: The objective of this study was to compare the sensitivity of detection of lung nodules on low-dose screening CT images between radiologists and technologists. METHODS: 11 radiologists and 10 technologists read the low dose screening CT images of 78 subjects. On images with a slice thickness of 5 mm, there were 60 lung nodules that were >=5 mm in diameter: 26 nodules with pure ground-glass opacity (GGO), 7 nodules with mixed ground-glass opacity (GGO with a solid component) and 27 solid nodules. On images with a slice thickness of 2 mm, 69 lung nodules were >=5 mm in diameter: 35 pure GGOs, 7 mixed GGOs and 27 solid nodules. The 21 observers read screening CT images of 5-mm slice thickness at first; then, 6 months later, they read screening CT images of 2-mm slice thickness from the 78 subjects. RESULTS: The differences in the mean sensitivities of detection of the pure GGOs, mixed GGOs and solid nodules between radiologists and technologists were not statistically significant, except for the case of solid nodules; the p-values of the differences for pure GGOs, mixed GGOs and solid nodules on the CT images with 5-mm slice thickness were 0.095, 0.461 and 0.005, respectively, and the corresponding p-values on CT images of 2-mm slice thickness were 0.971, 0.722 and 0.0037, respectively. CONCLUSION: Well trained technologists may contribute to the detection of pure and mixed GGOs >=5 mm in diameter on low-dose screening CT images. PMID- 22919014 TI - CT attenuation measurements are valuable to discriminate pledgets used in prosthetic heart valve implantation from paravalvular leakage. AB - OBJECTIVES: Sutures with polytetrafluorethylene (PTFE) felt pledgets are commonly used in prosthetic heart valve (PHV) implantation. Paravalvular leakage can be difficult to distinguish from PTFE felt pledgets on multislice CT because both present as hyperdense structures. We assessed whether pledgets can be discriminated from contrast-enhanced solutions (blood/saline) on CT images based on attenuation difference in an ex vivo experiment and under in vivo conditions. METHODS: PTFE felt pledgets were sutured to the suture ring of a mechanical PHV and porcine aortic annulus, and immersed and scanned in four different contrast enhanced (Ultravist(r); 300 mg jopromide ml(-1)) saline concentrations (10.0, 12.0, 13.6 and 15.0 mg ml(-1)). Scanning was performed on a 256-slice scanner with eight different scan protocols with various tube voltage (100 kV, 120 kV) and tube current (400 mAs, 600 mAs, 800 mAs, 1000 mAs) settings. Attenuation of the pledgets and surrounding contrast-enhanced saline were measured. Additionally, the attenuation of pledgets and contrast-enhanced blood was measured on electrocardiography (ECG)-gated CTA scans of 19 patients with 22 PHVs. RESULTS: Ex vivo CT attenuation differences between the pledgets and contrast-enhanced solutions were larger by using higher tube voltages. CT attenuation values of the pledgets were higher than contrast-enhanced blood in patients: 420+/-26 Hounsfield units (mean+/-SD, range 383-494) and 288+/-41 Hounsfield units (range 202-367), respectively. CONCLUSIONS: PTFE felt pledgets have consistently higher attenuation than surrounding contrast-enhanced blood. CT attenuation measurements therefore may help to differentiate pledgets from paravalvular leakage, and detect paravalvular leakage in patients with suspected PHV dysfunction. PMID- 22919015 TI - Interobserver delineation variation in lung tumour stereotactic body radiotherapy. AB - OBJECTIVES: In radiotherapy, delineation uncertainties are important as they contribute to systematic errors and can lead to geographical miss of the target. For margin computation, standard deviations (SDs) of all uncertainties must be included as SDs. The aim of this study was to quantify the interobserver delineation variation for stereotactic body radiotherapy (SBRT) of peripheral lung tumours using a cross-sectional study design. METHODS: 22 consecutive patients with 26 tumours were included. Positron emission tomography/CT scans were acquired for planning of SBRT. Three oncologists and three radiologists independently delineated the gross tumour volume. The interobserver variation was calculated as a mean of multiple SDs of distances to a reference contour, and calculated for the transversal plane (SD(trans)) and craniocaudal (CC) direction (SD(cc)) separately. Concordance indexes and volume deviations were also calculated. RESULTS: Median tumour volume was 13.0 cm(3), ranging from 0.3 to 60.4 cm(3). The mean SD(trans) was 0.15 cm (SD 0.08 cm) and the overall mean SD(cc) was 0.26 cm (SD 0.15 cm). Tumours with pleural contact had a significantly larger SD(trans) than tumours surrounded by lung tissue. CONCLUSIONS: The interobserver delineation variation was very small in this systematic cross sectional analysis, although significantly larger in the CC direction than in the transversal plane, stressing that anisotropic margins should be applied. This study is the first to make a systematic cross-sectional analysis of delineation variation for peripheral lung tumours referred for SBRT, establishing the evidence that interobserver variation is very small for these tumours. PMID- 22919016 TI - Assessment of thermal sensitivity of CT during heating of liver: an ex vivo study. AB - OBJECTIVES: The purpose of this study was to assess the thermal sensitivity of CT during heating of ex-vivo animal liver. METHODS: Pig liver was indirectly heated from 20 to 90 degrees C by passage of hot air through a plastic tube. The temperature in the heated liver was measured using calibrated thermocouples. In addition, image acquisition was performed with a multislice CT scanner before and during heating of the liver sample. The reconstructed CT images were then analysed to assess the change of CT number as a function of temperature. RESULTS: During heating, a decrease in CT numbers was observed as a hypodense area on the CT images. In addition, the hypodense area extended outward from the heat source during heating. The analysis showed a linear decrease of CT number as a function of temperature. From this relationship, we derived a thermal sensitivity of CT for pig liver tissue of -0.54+/-0.03 HU degrees C(-1) with an r(2) value of 0.91. CONCLUSIONS: The assessment of the thermal sensitivity of CT in ex-vivo pig liver tissue showed a linear dependency on temperature <=90 degrees C. This result may be beneficial for the application of isotherms or thermal maps in CT images of liver tissue. PMID- 22919017 TI - Inversion-recovery single-shot cardiac MRI for the assessment of myocardial infarction at 1.5 T with a dedicated cardiac coil. AB - OBJECTIVE: The aim of this study was to assess the diagnostic accuracy of imaging myocardial infarction with a two-dimensional (2D) single-shot inversion-recovery (IR)-gradient-echo (GE) sequence compared with a standard 2D segmented IR-GE sequence at 1.5 T using a dedicated cardiac coil. METHODS: 22 patients with myocardial infarction documented in the past 3-12 months were examined at 1.5 T using a 5 channel cardiac coil. Imaging of delayed enhancement was performed 15 min after administration of 0.2 mmol of gadopentetate dimeglumine per kilogram of body weight. Immediately after completion of the single-shot sequence, which allows for coverage of the entire ventricle during a single breath-hold with nine slices, the segmented IR sequence was started. Infarct volumes, infarct transmurality and contrast-to-noise ratios (CNRs) of infarcted and healthy myocardium were compared between both techniques. RESULTS: Despite a moderate, non-significant loss of CNR (CNR(single-shot IR)=31.2+/-4.1; CNR(segmented IR)=37.9+/-4.1; p=0.405), the 2D single-shot technique correctly determined infarct size when compared with the standard 2D segmented IR-GE sequence. Assessment of both infarct volume (r=0.95; p<0.0001) and transmurality (r=0.97; p<0.0001) is possible, with excellent correlation of both techniques. CONCLUSION: Single-shot delayed enhancement imaging during a single breath-hold is feasible at 1.5 T with the use of a dedicated cardiac coil. Despite a moderately lower CNR, the single-shot technique allows for fast and accurate determination of infarct size with high spatial resolution and has the potential to reduce electrocardiogram and breathing artefacts. PMID- 22919018 TI - Tricuspid annular plane systolic excursion assessed using MRI for semi quantification of right ventricular ejection fraction. AB - OBJECTIVE: Accurate determination of right ventricular volume and ejection fraction (RVEF) is established using MRI. Automatic contour detection of the right ventricular endocardial border is not established in clinical practice, resulting in considerable manual efforts to quantify RVEF. Using transthoracic echocardiography (TTE), the tricuspid annular plane systolic excursion (TAPSE) has proved its worth for quantification of RVEF and risk prediction. Therefore, the aim of this study was to clarify whether TAPSE assessed with MRI as a fast and easily obtainable parameter correlated with volumetric quantification of RVEF. METHODS: Right ventricular volumes and RVEF were measured with the standardised slice-summation method at MRI. MRI-TAPSE was defined as maximum apical excursion of lateral tricuspid annular plane and measured in a four chamber view using steady-state free precession sequences. Additionally, MRI TAPSE was compared with TAPSE assessed using TTE. RESULTS: 76 consecutive patients (aged 58+/-17 years) were examined. At MRI, right end-diastolic volumes were 97+/-36 ml, right end-systolic volumes were 57+/-27 ml and the mean RVEF was 42+/-14%. MRI-TAPSE was determined with 19+/-6 mm and correlated well at linear regression analysis with volumetric RVEF (r=0.72, p<0.001). Furthermore, MRI TAPSE discriminated sufficiently between patients with impaired and normal RVEF. Multiplying MRI-TAPSE by 2.5 led to values close to the RVEF by volumetry. Additionally, MRI-TAPSE correlated well with TAPSE determined using TTE. The inter- and intra-observer variabilities of MRI-TAPSE determination were low (3.1% and 1.8%). CONCLUSION: TAPSE assessed with MRI is a fast and easily obtainable parameter which correlates well with volumetric quantification of RVEF. PMID- 22919019 TI - Respiratory-aspirated 35-mm hairpin successfully retrieved with a Teflon(r) snare system under fluoroscopic guidance via a split endotracheal tube: a useful technique in cases of failed extraction by bronchoscopy and avoiding the need for a thoracotomy. AB - Respiratory foreign body aspiration (FBA) is a common global health problem requiring prompt recognition and early treatment to prevent potentially fatal complications. The majority of FBAs are due to organic objects and treatment is usually via either endoscopic or surgical extraction. FBA of a straight hairpin has been described as a unique entity in the literature, occurring most commonly in females, particularly during adolescence. In the process of inserting hairpins, the pins will typically be between the teeth with the head tilted backwards, while tying their hair with both hands. This position increases the risk of aspiration, particularly if there is any sudden coughing or laughing. To our knowledge, this is the first case report of a 35-mm straight metallic hairpin foreign body that has been successfully retrieved by a radiological snare system under fluoroscopic guidance. This was achieved with the use of a split endotracheal tube, and therefore avoided the need for a thoracotomy in an adolescent female patient. PMID- 22919020 TI - Hypofractionated radiotherapy for glioblastoma: strategy for poor-risk patients or hope for the future? AB - The prognosis of patients with glioblastoma (GBM) remains poor, and the use of hyperfractionation or dose escalation beyond 60 Gy has not conferred any survival benefit. More recently, hypofractionated radiotherapy (HFRT) has been employed as a novel approach for achieving dose escalation, with interesting results. We present here a systematic overview of the role and development of HFRT as a possible therapeutic strategy in patients with GBM. We searched the PubMed database for studies published since 1990 that reported on the tolerance, safety and survival outcomes after HFRT. These studies reported on the paradox of improved survival in patients developing central radionecrosis within the high-dose volume. Most series reported no significant increase in early or late toxicity, except for one study that reported visual loss in one patient at 7 months after treatment. More recently, studies of HFRT combined with concurrent temozolomide (TMZ) reported a trend towards improved survival compared with historical controls, with a few studies reporting a median survival of approximately 20 months. The interpretation of data from the above studies is limited by the heterogeneities of patient population and the significant variation in the range of employed dose schedules. However, high-dose HFRT using intensity-modulated radiotherapy appears to be a safe and feasible therapeutic option. There is a suggestion of improved outcomes on combining HFRT with TMZ, which warrants further investigation in a randomised trial. PMID- 22919021 TI - Coding OSICS sports injury diagnoses in epidemiological studies: does the background of the coder matter? AB - OBJECTIVE: To compare Orchard Sports Injury Classification System (OSICS-10) sports medicine diagnoses assigned by a clinical and non-clinical coder. DESIGN: Assessment of intercoder agreement. SETTING: Community Australian football. PARTICIPANTS: 1082 standardised injury surveillance records. MAIN OUTCOME MEASUREMENTS: Direct comparison of the four-character hierarchical OSICS-10 codes assigned by two independent coders (a sports physician and an epidemiologist). Adjudication by a third coder (biomechanist). RESULTS: The coders agreed on the first character 95% of the time and on the first two characters 86% of the time. They assigned the same four-digit OSICS-10 code for only 46% of the 1082 injuries. The majority of disagreements occurred for the third character; 85% were because one coder assigned a non-specific 'X' code. The sports physician code was deemed correct in 53% of cases and the epidemiologist in 44%. Reasons for disagreement included the physician not using all of the collected information and the epidemiologist lacking specific anatomical knowledge. CONCLUSIONS: Sports injury research requires accurate identification and classification of specific injuries and this study found an overall high level of agreement in coding according to OSICS-10. The fact that the majority of the disagreements occurred for the third OSICS character highlights the fact that increasing complexity and diagnostic specificity in injury coding can result in a loss of reliability and demands a high level of anatomical knowledge. Injury report form details need to reflect this level of complexity and data management teams need to include a broad range of expertise. PMID- 22919022 TI - Increasing physical activity in healthy adults: a meta-analysis. PMID- 22919024 TI - Tropical distal renal tubular acidosis: clinical and epidemiological studies in 78 patients. AB - BACKGROUND: Distal renal tubular acidosis (dRTA) caused by mutations of the SLC4A1 gene encoding the erythroid and kidney isoforms of anion exchanger 1 (AE1 or band 3) has a high prevalence in some tropical countries, particularly Thailand, Malaysia, the Philippines and Papua New Guinea (PNG). Here the disease is almost invariably recessive and can result from either homozygous or compound heterozygous SLC4A1 mutations. METHODS: We have collected and reviewed our own and published data on tropical dRTA to provide a comprehensive series of clinical and epidemiological studies in 78 patients. RESULTS: Eight responsible SLC4A1 mutations have been described so far, four of them affecting multiple unrelated families. With the exception of the mutation causing South-East Asian ovalocytosis (SAO), none of these mutations has been reported outside the tropics, where dRTA caused by SLC4A1 mutations is much rarer and almost always dominant, resulting from mutations that are quite different from those found in the tropics. SLC4A1 mutations, including those causing dRTA, may cause morphological red cell changes, often with excess haemolysis. In dRTA, these red cell changes are usually clinically recessive and not present in heterozygotes. The high tropical prevalence of dRTA caused by SLC4A1 mutations is currently unexplained. CONCLUSION: A hypothesis suggesting that changes in red cell metabolism caused by these mutations might protect against malaria is put forward to explain the phenomenon, and a possible mechanism for this effect is proposed. PMID- 22919025 TI - SRSF2 mutations in 275 cases with chronic myelomonocytic leukemia (CMML). AB - We analyzed the mutational hotspot region of SRSF2 (Pro95) in 275 cases with chronic myelomonocytic leukemia (CMML). In addition, ASXL1, CBL, EZH2, JAK2V617F, KRAS, NRAS, RUNX1, and TET2 mutations were investigated in subcohorts. Mutations in SRSF2 (SRSF2mut) were detected in 47% (129 of 275) of all cases. In detail, 120 cases had a missense mutation at Pro95, leading to a change to Pro95His, Pro95Leu, Pro95Arg, Pro95Ala, or Pro95Thr. In 9 cases, 3 new in/del mutations were observed: 7 cases with a 24-bp deletion, 1 case with a 3-bp duplication, and 1 case with a 24-bp duplication. In silico analyses predicted a damaging character for the protein structure of SRSF2 for all mutations. SRSF2mut was correlated with higher age, less pronounced anemia, and normal karyotype. SRSF2mut and EZH2mut were mutually exclusive, but SRSF2mut was associated with TET2mut. In the total cohort, no effect of SRSF2mut on survival was observed. However, in the RUNX1mut subcohort, SRSF2 Pro95His had a favorable effect on overall survival. This comprehensive mutation analysis found that 93% of all patients with CMML carried at least 1 somatic mutation in 9 recurrently mutated genes. In conclusion, these data show the importance of SRSF2mut as new diagnostic marker in CMML. PMID- 22919026 TI - SMILE for natural killer/T-cell lymphoma: analysis of safety and efficacy from the Asia Lymphoma Study Group. AB - Natural killer/T-cell lymphoma is rare and aggressive, with poor outcome. Optimal treatment remains unclear. A novel regimen dexamethasone, methotrexate, ifosfamide, l-asparaginase, and etoposide (SMILE) showed promise in phase 1/2 studies with restrictive recruitment criteria. To define the general applicability of SMILE, 43 newly diagnosed and 44 relapsed/refractory patients (nasal, N = 60, nonnasal, N = 21; disseminated, N = 6; male, N = 59; female, N = 28) at a median age of 51 years (23-83 years) were treated. Poor-risk factors included stage III/IV disease (56%), international prognostic index of 3 to 5 (43%), and Korean prognostic scores of 3 to 4 (41%). A median of 3 (0-6; total = 315) courses of SMILE were administered. Significant toxicities included grade 3/4 neutropenia (N = 57; 5 sepsis-related deaths); grade 3/4 thrombocytopenia (N = 36); and nephrotoxicity (N = 15; 1 acute renal failure and death). Interim analysis after 2 to 3 cycles showed complete remission rate of 56%, partial remission rate of 22%, giving an overall response rate of 78%. On treatment completion, the overall-response rate became 81% (complete remission = 66%, partial remission = 15%). Response rates were similar for newly diagnosed or relapsed/refractory patients. At a median follow-up of 31 months (1-84 months), the 5-year overall survival was 50% and 4-year disease-free-survival was 64%. Multivariate analysis showed that international prognostic index was the most significant factor impacting on outcome and survivals. PMID- 22919027 TI - The efficacy and the risk of immunogenicity of FIX Padua (R338L) in hemophilia B dogs treated by AAV muscle gene therapy. AB - Studies on gene therapy for hemophilia B (HB) using adeno-associated viral (AAV) vectors showed that the safety of a given strategy is directly related to the vector dose. To overcome this limitation, we sought to test the efficacy and the risk of immunogenicity of a novel factor IX (FIX) R338L associated with ~ 8-fold increased specific activity. Muscle-directed expression of canine FIX-R338L by AAV vectors was carried out in HB dogs. Therapeutic levels of circulating canine FIX activity (3.5%-8%) showed 8- to 9-fold increased specific activity, similar to humans with FIX-R338L. Phenotypic improvement was documented by the lack of bleeding episodes for a cumulative 5-year observation. No antibody formation and T-cell responses to FIX-R338L were observed, even on challenges with FIX wild type protein. Moreover, no adverse vascular thrombotic complications were noted. Thus, FIX-R338L provides an attractive strategy to safely enhance the efficacy of gene therapy for HB. PMID- 22919029 TI - How I treat transfusional iron overload. AB - Patients with beta-thalassemia major (TM) and other refractory anemias requiring regular blood transfusions accumulate iron that damages the liver, endocrine system, and most importantly the heart. The prognosis in TM has improved remarkably over the past 10 years. This improvement has resulted from the development of magnetic resonance imaging (MRI) techniques, especially T2*, to accurately measure cardiac and liver iron, and from the availability of 3 iron chelating drugs. In this article we describe the use of MRI to determine which adult and pediatric patients need to begin iron chelation therapy and to monitor their progress. We summarize the properties of each of the 3 drugs, deferoxamine (DFO), deferiprone (DFP), and deferasirox (DFX), including their efficacy, patient acceptability, and side effects. We describe when to initiate or intensify therapy, switch to another drug, or use combined therapy. We also discuss the management of refractory anemias other than TM that may require multiple blood transfusions, including sickle cell anemia and myelodysplasia. The development of a potential fourth chelator FBS 0701 and the combined use of oral chelators may further improve the quality of life and survival in patients with TM and other transfusion-dependent patients. PMID- 22919028 TI - Expression of the runt homology domain of RUNX1 disrupts homeostasis of hematopoietic stem cells and induces progression to myelodysplastic syndrome. AB - Mutations of RUNX1 are detected in patients with myelodysplastic syndrome (MDS). In particular, C-terminal truncation mutations lack a transcription regulatory domain and have increased DNA binding through the runt homology domain. The expression of the runt homology domain, RUNX1(41-214), in mouse hematopoietic cells induced progression to MDS and acute myeloid leukemia. Analysis of premyelodysplastic animals found expansion of c-Kit(+)Sca-1(+)Lin(-) cells and skewed differentiation to myeloid at the expense of the lymphoid lineage. These abnormalities correlate with the phenotype of Runx1-deficient animals, as expected given the reported dominant-negative role of C-terminal mutations over the full-length RUNX1. However, MDS is not observed in Runx1-deficient animals. Gene expression profiling found that RUNX1(41-214) c-Kit(+)Sca-1(+)Lin(-) cells have an overlapping yet distinct gene expression profile from Runx1-deficient animals. Moreover, an unexpected parallel was observed between the hematopoietic phenotype of RUNX1(41-214) and aged animals. Genes deregulated in RUNX1(41-214), but not in Runx1-deficient animals, were inversely correlated with the aging gene signature of HSCs, suggesting that disruption of the expression of genes related to normal aging by RUNX1 mutations contributes to development of MDS. The data presented here provide insights into the mechanisms of development of MDS in HSCs by C-terminal mutations of RUNX1. PMID- 22919030 TI - Erythrocyte density in sickle cell syndromes is associated with specific clinical manifestations and hemolysis. AB - Dense, dehydrated red blood cells (DRBCs) are a characteristic feature of sickle cell disease (SCD). DRBCs play a role in the pathophysiology of SCD acute and chronic organ damage because of heightened tendency to undergo polymerization and sickling because of their higher hemoglobin S concentration. Relations between red cell density (assessed with phthalate density-distribution profile method) and several hematologic, biochemical, genetic parameters, and clinical manifestations were studied in a large cohort of homozygous patients. The percentage of DRBCs was significantly higher in patients who experienced skin ulcers, priapism, or renal dysfunction. Presence of alpha-thalassemia deletions was associated with fewer DRBCs. A multivariable analysis model showed DRBCs to be positively associated with hemolytic parameters such as lactate dehydrogenase and bilirubin and negatively with fetal hemoglobin. The percentage of DRBCs decreased by 34% at 6 months of hydroxycarbamide (xydroxyurea) therapy. Thus, DRBCs are associated with specific clinical manifestations and biologic markers and may be a useful addition to the biologic and clinical evaluation of patients with SCD, because they can easily be measured in a hematocrit tube. PMID- 22919031 TI - Endothelial cells provide an instructive niche for the differentiation and functional polarization of M2-like macrophages. AB - Endothelial cells and macrophages are known to engage in tight and specific interactions that contribute to the modulation of vascular function. Here we show that adult endothelial cells provide critical signals for the selective growth and differentiation of macrophages from several hematopoietic progenitors. The process features the formation of well-organized colonies that exhibit progressive differentiation from the center to the periphery and toward an M2 like phenotype, characterized by enhanced expression of Tie2 and CD206/Mrc1. These colonies are long-lived depending on the contact with the endothelium; removal of the endothelial monolayer results in rapid colony dissolution. We further found that Csf1 produced by the endothelium is critical for the expansion of the macrophage colonies and that blockade of Csf1 receptor impairs colony growth. Functional analyses indicate that these macrophages are capable of accelerating angiogenesis, promoting tumor growth, and effectively engaging in tight associations with endothelial cells in vivo. These findings uncover a critical role of endothelial cells in the induction of macrophage differentiation and their ability to promote further polarization toward a proangiogenic phenotype. This work also highlights some of the molecules underlying the M2-like differentiation, a process that is relevant to the progression of both developmental and pathologic angiogenesis. PMID- 22919033 TI - Science to practice: can macrophage infiltration serve as a surrogate marker for stem cell viability? AB - Following in vivo prelabeling of host macrophages with ultrasmall superparamagnetic iron oxide (USPIO) nanoparticles, it was shown that their magnetic resonance (MR) imaging-visible migration into knee implants of scaffolded adipose-derived stem cells (ADSCs) undergoing apoptosis can serve as a surrogate marker of stem cell death. PMID- 22919032 TI - Mammalian target of rapamycin regulates neutrophil extracellular trap formation via induction of hypoxia-inducible factor 1 alpha. AB - Neutrophils are highly specialized innate immune effector cells that evolved for antimicrobial host defense. In response to inflammatory stimuli and pathogens, they form neutrophil extracellular traps (NETs), which capture and kill extracellular microbes. Deficient NET formation predisposes humans to severe infection, but, paradoxically, dysregulated NET formation contributes to inflammatory vascular injury and tissue damage. The molecular pathways and signaling mechanisms that control NET formation remain largely uncharacterized. Using primary human neutrophils and genetically manipulated myeloid leukocytes differentiated to surrogate neutrophils, we found that mammalian target of rapamycin (mTOR) regulates NET formation by posttranscriptional control of expression of hypoxia-inducible factor 1 alpha (HIF-1alpha), a critical modulator of antimicrobial defenses. Next-generation RNA sequencing, assays of mRNA and protein expression, and analysis of NET deployment by live cell imaging and quantitative histone release showed that mTOR controls NET formation and translation of HIF-1alpha mRNA in response to lipopolysaccharide. Pharmacologic and genetic knockdown of HIF-1alpha expression and activity inhibited NET deployment, and inhibition of mTOR and HIF-1alpha inhibited NET-mediated extracellular bacterial killing. Our studies define a pathway to NET formation involving 2 master regulators of immune cell function and identify potential points of molecular intervention in strategies to modify NETs in disease. PMID- 22919034 TI - The double-edged sword of functional liver imaging. PMID- 22919035 TI - Interpretation of CT colonographic images: should we rely on nonradiologists? PMID- 22919036 TI - 100 years of individual radiosensitivity: how we have forgotten the evidence. PMID- 22919037 TI - Breast density legislation and opportunities for patient-centered outcomes research. PMID- 22919038 TI - Role of nonenhanced multidetector CT coronary artery calcium testing in asymptomatic and symptomatic individuals. AB - Arteriosclerotic cardiovascular disease is the leading cause of death in the United States, with coronary artery disease (CAD) accounting for half of all cardiovascular disease deaths. Current risk assessment approaches for coronary heart disease, such as the Framingham risk score, substantially misclassify intermediate- to long-term risk for the occurrence of CAD in asymptomatic individuals. A screening modality such as a simple non-contrast-enhanced, or noncontrast, computed tomographic (CT) detection of coronary artery calcium (CAC) improves the ability to accurately predict risk in vulnerable groups and adds information above and beyond global risk assessment as shown by the recent Multi Ethnic Study of Atherosclerosis. In addition, absence of CAC is associated with a very low risk of future CAD and as a result can be used to identify a group among which further testing and pharmacotherapies can be avoided. The Expert Consensus Document by the American College of Cardiology Foundation and the American Heart Association now recommends screening individuals at intermediate risk but did not find enough evidence to recommend CAC testing and further stratification of those in the low- or high-risk categories for CAD. In addition, emerging guidelines have suggested that absence of CAC can act as a "gatekeeper" for further testing among low- and intermediate-risk patients presenting with chest pain. This review of the current literature outlines the role of CAC testing in both asymptomatic and symptomatic individuals. PMID- 22919039 TI - New developments in hip imaging. AB - The way the hip joint is imaged has changed in the past few years as a result of new discoveries in the biomechanics of the hip joint and the rapid developments in hip-preserving surgery. This review discusses technical advances made in the field of hip imaging, covering the roles of radiography, computed tomography, sonography and magnetic resonance (MR) imaging, as well as their limitations. New insight into anatomy and pathogenesis can be useful for the diagnosis of hip abnormalities and in treatment planning. While radiographs are the basis of any imaging of the hip, MR imaging is paramount in the evaluation and preoperative planning of patients suspected of having femoroacetabular impingement, especially when assessing geometrical deformities of the proximal femur. Damage patterns of labrum and cartilage in patients with femoroacetabular impingement are described, as well as new techniques of cartilage MR imaging that might allow the detection of cartilage degeneration before macroscopic defects are formed. Finally, new data on structural variants of the hip joint and pitfalls in imaging of the hip joint are reviewed. PMID- 22919040 TI - Characteristics and trends of radiology research: a survey of original articles published in AJR and Radiology between 2001 and 2010. AB - PURPOSE: To determine the characteristics and trends of the original articles published in two major American radiology journals, AJR American Journal of Roentgenology (AJR) and Radiology, between 2001 and 2010. MATERIALS AND METHODS: This was a retrospective bibliometric analysis that did not involve human subjects and was exempt from institutional review board approval. All 6542 original articles published in AJR and Radiology between 2001 and 2010 were evaluated. The following information was abstracted from each article: radiologic subspecialty, radiologic technique used, type of research, sample size, study design, statistical analysis, study outcome, declared funding, number of authors, affiliation of the first author, and country of the first author. In addition, all the variables examined were presented along with the trend over time. RESULTS: The most common subspecialty of study was abdominal (1219 of 6542, 18.6%), followed by vascular/interventional (804 of 6542, 12.3%). A total of 3744 (57.2%) original articles used magnetic resonance (MR) imaging or computed tomography (CT), 5495 (84.1%) were clinical research articles, 3060 (46.8%) had sample size of more than 50, 4087 (62.5%) were retrospective, 4714 (72.1%) performed statistical analysis, 6225 (95.2%) showed positive study outcome, 4784 (73.1%) were not funded, 3942 (60.3%) had four to seven authors, and 5731 (87.6%) were written by the primary author who was from a department of radiology or radiology-related specialties. The United States published 45.5% (2975 of 6542) of the articles, followed by Japan (n = 525, 8.0%), Germany (n = 485, 7.4%), and South Korea (n = 455, 7.0%). In the time trend analysis, the following variables showed a significantly positive trend: cardiac subspecialty, CT and MR imaging as the radiologic techniques, type of research as other (nonbasic, nonclinical), sample size of more than 50, four to seven as the number of authors, medicine related department of the first author, and South Korea and Italy as countries of the first author. On the other hand, pediatric subspecialty, combined (basic and clinical) type of research, and number of authors fewer than four showed a significantly negative trend. CONCLUSION: The bibliometric analysis of the AJR and Radiology journals with articles published between 2001 and 2010 revealed characteristics and trends of the current radiology research that may provide useful information to researchers and editorial staff in radiology. PMID- 22919041 TI - Evaluation of rotator cuff tendon tears: comparison of multidetector CT arthrography and 1.5-T MR arthrography. AB - PURPOSE: To compare the diagnostic performance of multidetector computed tomographic (CT) arthrography and 1.5-T magnetic resonance (MR) arthrography in the evaluation of rotator cuff lesions, with arthroscopic correlation. MATERIALS AND METHODS: This study was approved by the institutional ethical committee, and informed consent was obtained from all patients. CT and MR arthrographic images prospectively obtained in 56 consecutive patients, following the same arthrographic procedure, were independently evaluated by two radiologists. Arthroscopy, performed within 1 month of the imaging, was used as the reference standard. Sensitivity and specificity of CT and MR arthrography were compared by using the McNemar test. Interobserver and intertechnique agreement for detecting rotator cuff lesions were measured and compared with kappa and Z statistics. The Bland-Altman method was used to determine interobserver and intertechnique agreement for measuring tendon tears. For grading fatty infiltration of rotator cuff muscles, kappa and Z statistics were used. RESULTS: There was no statistically significant difference in sensitivity and specificity between CT arthrography and MR arthrography in depiction of rotator cuff lesions. The respective sensitivity and specificity of CT arthrography were 92% and 93%-97% for the supraspinatus, 100% and 77%-79% for the infraspinatus, 75%-88% and 85% 90% for the subscapularis, and 55%-65% and 100% for the biceps tendon. The respective sensitivity and specificity of MR arthrography were 96% and 83%-93% for the supraspinatus, 88%-100% and 81%-83% for the infraspinatus, 75%-88% and 90%-100% for the subscapularis, and 65%-85% and 100% for the biceps tendon. Interobserver agreement was substantial to almost perfect (kappa = 0.744-0.964 for CT arthrography; kappa = 0.641-0.893 for MR arthrography), and intertechnique agreement was almost perfect (kappa > 0.819). CT and MR arthrography both yielded moderate interobserver and intertechnique agreement for measuring rotator cuff tears and grading muscle fatty infiltration. CONCLUSION: Data suggest that CT and MR arthrography have similar diagnostic performance for the evaluation of rotator cuff tendon tears. PMID- 22919043 TI - Case 185: inflammatory myofibroblastic tumor. PMID- 22919044 TI - MR imaging of pulmonary embolism. PMID- 22919045 TI - FDG PET/CT for the evaluation of normal thymus, lymphoma recurrence, and mediastinal lymphoma in pediatric patients. PMID- 22919047 TI - Puerarin, a selective oestrogen receptor modulator, disrupts pregnancy in rats at pre-implantation stage. AB - The tubers of Pueraria tuberosa have folkloric repute as emmenagogue. The n-BuOH fraction of the ethanolic extract of tubers exhibits significant antifertility activity in laboratory animals. The present investigation explored the active principle(s) of the tuber extract with reference to contragestive effects in rats and probed the possible mechanism of action. Bioactivity-guided fractionation identified puerarin as the major constituent that exerted pregnancy-terminating effects. Oral administration of puerarin at >=300 mg/kg per day for days (D) 1-2 post-coitus resulted in complete implantation failure. Serum oestradiol levels during D2-D5 and progesterone (P(4)) level on D5 remained unaffected, but the endometrial expression of oestrogen receptor alpha (ERalpha) and ERbeta was adversely modulated that disrupted the implantation-specific characteristic endometrial oestrogenic milieu. The eventual consequence was loss of endometrial receptivity characterised by down-regulation of the uterine expression of P(4) receptor (PR) and attenuation of endometrial expression of leukaemia inhibitory factor, vascular endothelial growth factor and cyclo-oxygenase-2, the three important signalling molecules involved in the process of implantation. Light microscopic examination of the embryos demonstrated no untoward effect of puerarin on the development of embryos until D4, but D5 blastocysts underwent gross morphological distortion. The findings taken together are interpreted to suggest that puerarin adversely impacts the uterine expression of ER and PR that disrupts the implantation-conducive uterine milieu and prevents implantation. In conclusion, puerarin may be envisaged as a prospective molecule that merits further exploration for the development of non-steroidal post-coital contraceptive for women. PMID- 22919046 TI - Embryos generated from oocytes lacking complex N- and O-glycans have compromised development and implantation. AB - Female mice generating oocytes lacking complex N- and O-glycans (double mutants (DM)) produce only one small litter before undergoing premature ovarian failure (POF) by 3 months. Here we investigate the basis of the small litter by evaluating ovulation rate and embryo development in DM (Mgat1(F/F)C1galt1(F/F):ZP3Cre) and Control (Mgat1(F/F)C1galt1(F/F)) females. Surprisingly, DM ovulation rate was normal at 6 weeks, but declined dramatically by 9 weeks. In vitro development of zygotes to blastocysts was equivalent to Controls although all embryos from DM females lacked a normal zona pellucida (ZP) and ~30% lacked a ZP entirely. In contrast, in vivo preimplantation development resulted in less embryos recovered from DM females compared with Controls at 3.5 days post coitum (dpc) (3.2+/-1.3 vs 7.0+/-0.6). Furthermore, only 45% of mated DM females contained embryos at 3.5 dpc. Of the preimplantation embryos collected from DM females, approximately half were morulae unlike Controls where the majority were blastocysts, indicating delayed embryo development in DM females. Post-implantation development in DM females was analysed to determine whether delayed preimplantation development affected subsequent development. In DM females at 5.5 dpc, only ~40% of embryos found at 3.5 dpc had implanted. However, at 6.5 dpc, implantation sites in DM females corresponded to embryo numbers at 3.5 dpc indicating delayed implantation. At 9.5 dpc, the number of decidua corresponded to embryo numbers 6 days earlier indicating that all implanted embryos progress to midgestation. Therefore, a lack of complex N- and O-glycans in oocytes during development impairs early embryo development and viability in vivo leading to delayed implantation and a small litter. PMID- 22919048 TI - International Classification of Functioning, Disability and Health Core Set construction in systemic sclerosis and other rheumatic diseases: a EUSTAR initiative. AB - OBJECTIVES: To outline rationale and potential strategies for rheumatology experts to be able to develop disease-specific Core Sets under the framework of the International Classification of Functioning, Disability and Health (ICF). ICF is a universal framework introduced by the World Health Organization (WHO) to describe and quantify the impact and burden on functioning of health conditions associated with impairment/disability. METHODS: A combined effort of the EULAR Scleroderma Clinical Trial and Research and the ICF Research Branch was initiated to develop an ICF language for scleroderma. From our Medline literature review, using the abbreviation and spelled out version of ICF, we assembled approaches and methodological reasoning for steps of core set development. RESULTS: The ICF can be used for patient care and policy-making, as well as the provision of resources, services and funding. The ICF is used on institutional, regional, national and global levels. Several diseases now have ICF Core Sets. Patients with complex rheumatologic diseases will benefit from a disease-specific ICF Core Set and should be included in all stages of development. ICF Core Set development for rheumatic diseases can be conducted from a number of feasible strategies. CONCLUSION: This overview should help to clarify useful processes leading to development of an ICF Core Set, and also provide a platform for expert groups considering such an endeavour. PMID- 22919049 TI - Maf1-mediated repression of RNA polymerase III transcription inhibits tRNA degradation via RTD pathway. AB - tRNA precursors, which are transcribed by RNA polymerase III, undergo end maturation, splicing, and base modifications. Hypomodified tRNAs, such as tRNA(Val(AAC)), lacking 7-methylguanosine and 5-methylcytidine modifications, are subject to degradation by a rapid tRNA decay pathway. Here we searched for genes which, when overexpressed, restored stability of tRNA(Val(AAC)) molecules in a modification-deficient trm4Deltatrm8Delta mutant. We identified TEF1 and VAS1, encoding elongation factor eEF1A and valyl-tRNA synthetase respectively, which likely protect hypomodified tRNA(Val(AAC)) by direct interactions. We also identified MAF1 whose product is a general negative regulator of RNA polymerase III. Expression of a Maf1-7A mutant that constitutively repressed RNA polymerase III transcription resulted in increased stability of hypomodified tRNA(Val(AAC)). Strikingly, inhibition of tRNA transcription in a Maf1-independent manner, either by point mutation in RNA polymerase III subunit Rpc128 or decreased expression of Rpc17 subunit, also suppressed the turnover of the hypomodified tRNA(Val(AAC)). These results support a model where inhibition of tRNA transcription leads to stabilization of hypomodified tRNA(Val(AAC)) due to more efficient protection by tRNA-interacting proteins. PMID- 22919051 TI - Gadolinium-chitosan nanoparticles as a novel contrast agent for potential use in clinical bowel-targeted MRI: a feasibility study in healthy rats. AB - BACKGROUND: MRI is of increasing importance in the diagnostic evaluation of gastrointestinal diseases, with depiction of mucosal enhancement obtained with conventional intravenous contrast. Routine clinical use of contrast agents has been carried out using intravenous injection for mucosal imaging. Contrast agents that specifically target the intestinal mucosa are therefore needed to improve clinical imaging of the mucosal surface. PURPOSE: To synthesize a novel contrast agent for gadopentetic acid (Gd-DTPA)-loaded chitosan nanoparticles and observe the absorption of the nanoparticles in the colon wall of healthy rats by MR imaging in vivo. MATERIAL AND METHODS: A contrast agent was successfully synthesized by a modified emulsion coalescence method, and the resulting agents were characterized in detail by dynamic light-scattering spectroscopy and inductively coupled plasma emission spectroscopy. The cytotoxicity of Gd-chitosan nanoparticles was evaluated by an MTT assay. Gadolinium-chitosan (Gd@chitosan) nanoparticles were administered to the colon mucosa of healthy rats by rectal administration, and MRI scans in vivo were carried out with a 3.0 T imaging scanner at various time points. RESULTS: The prepared Gd@chitosan nanoparticles were ~420 nm in diameter with a 74.4% Gd-DTPA content. The MTT assay indicated little cytotoxicity. MRI results showed that nanoparticles can be retained in both the stratum submucosum and epithelial cells of the colon for almost 80 min. Transmission electron microscopy images further revealed that Gd@chitosan nanoparticles were localized inside the mucosal cells or intercellular space, while tissue from Gd-DTPA aqueous solution administration showed nothing. Due to the infusion of Gd@chitosan nanoparticles, the MR signal intensity of colon mucosa increased from about 6% to 35%, and the contrast enhancement was highest at 20 min after administration. CONCLUSION: Gd@chitosan nanoparticles with high Gd-DTPA content were successfully prepared for use as a novel MRI contrast agent. All results indicated that rectally administered Gd@chitosan nanoparticles have the potential for MRI diagnosis of colon mucosal disease. PMID- 22919050 TI - Mutational analysis of Trypanosoma brucei editosome proteins KREPB4 and KREPB5 reveals domains critical for function. AB - The transcriptome of kinetoplastid mitochondria undergoes extensive RNA editing that inserts and deletes uridine residues (U's) to produce mature mRNAs. The editosome is a multiprotein complex that provides endonuclease, TUTase, exonuclease, and ligase activities required for RNA editing. The editosome's KREPB4 and KREPB5 proteins are essential for editosome integrity and parasite viability and contain semi-conserved motifs corresponding to zinc finger, RNase III, and PUF domains, but to date no functional analysis of these domains has been reported. We show here that various point mutations to KREPB4 and KREPB5 identify essential domains, and suggest that these proteins do not themselves perform RNase III catalysis. The zinc finger of KREPB4 but not KREPB5 is essential for editosome integrity and parasite viability, and mutation of the RNase III signature motif in KREPB5 prevents integration into editosomes, which is lethal. Isolated TAP-tagged KREPB4 and KREPB5 complexes preferentially associate with components of the deletion subcomplex, providing additional insights into editosome architecture. A new alignment of editosome RNase III sequences from several kinetoplastid species implies that KREPB4 and KREPB5 lack catalytic activity and reveals that the PUF motif is present in the editing endonucleases KREN1, KREN2, and KREN3. The data presented here are consistent with the hypothesis that KREPB4 and KREPB5 form intermolecular heterodimers with the catalytically active editing endonucleases, which is unprecedented among known RNase III proteins. PMID- 22919052 TI - Assessment of ultrasound acoustic artifacts in patients with acute dyspnea: a multicenter study. AB - BACKGROUND: Recent reports indicate that numerical assessment of B-lines during transthoracic ultrasound may aid the differential diagnosis of acute diffuse pleuropulmonary disorders. PURPOSE: To determine whether B-lines are different in normal and diseased lungs and whether they can be used to discriminate between different types of pulmonary disorders in acutely ill patients. MATERIAL AND METHODS: In this multicenter study, transthoracic ultrasonography was performed on 193 patients with acute dyspnea, 193 healthy non-smokers, and 58 patients who had undergone pneumonectomy for lung cancer. Examinations were done with a low medium frequency (3.5-5.0 MHz) convex probe and a high-frequency (8-12.5 MHz) linear probe. Video recordings were re-examined by a second set of examiners. In each participant, we measured the number of B-lines observed per scan. RESULTS: B lines counts were higher in dyspnoic patients (means: 3.11 per scan per linear probe scan vs. 1.93 in healthy controls and 1.86 in pneumonectomized patients; P < 0.001 for all); all counts were higher when convex probes were used (5.4 in dyspnoic patients and 2 in healthy controls; P < 0.001 vs. the linear probe). Subgroups of dyspnoic patients defined by cause of dyspnea displayed no significant differences in the number of B-lines. CONCLUSION: Our results demonstrate that there are a significant higher number of B-lines in the lungs of patients with dyspnea compared to healthy subjects and to pneumonectomized patients. Nevertheless, the quantification of B-lines does not make any significant contribution to the differential diagnosis of dyspnea. PMID- 22919053 TI - Organ dose calculation in CT based on scout image data and automatic image registration. AB - BACKGROUND: Computed tomography (CT) has become the main contributor of the cumulative radiation exposure in radiology. Information on cumulative exposure history of the patient should be available for efficient management of radiation exposures and for radiological justification. PURPOSE: To develop and evaluate automatic image registration for organ dose calculation in CT. MATERIAL AND METHODS: Planning radiograph (scout) image data describing CT scan ranges from 15 thoracic CT examinations (9 men and 6 women) and 10 abdominal CT examinations (6 men and 4 women) were co-registered with the reference trunk CT scout image. 2-D affine transformation and normalized correlation metric was used for image registration. Longitudinal (z-axis) scan range coordinates on the reference scout image were converted into slice locations on the CT-Expo anthropomorphic male and female models, following organ and effective dose calculations. RESULTS: The average deviation of z-location of studied patient images from the corresponding location in the reference scout image was 6.2 mm. The ranges of organ and effective doses with constant exposure parameters were from 0 to 28.0 mGy and from 7.3 to 14.5 mSv, respectively. The mean deviation of the doses for fully irradiated organs (inside the scan range), partially irradiated organs and non irradiated organs (outside the scan range) was 1%, 5%, and 22%, respectively, due to image registration. CONCLUSION: The automated image processing method to registrate individual chest and abdominal CT scout radiograph with the reference scout radiograph is feasible. It can be used to determine the individual scan range coordinates in z-direction to calculate the organ dose values. The presented method could be utilized in automatic organ dose calculation in CT for radiation exposure tracking of the patients. PMID- 22919054 TI - Bilateral approach of redistributed subclavian arterial infusion chemotherapy for locally advanced breast cancer spreading to the contralateral chest wall. AB - A catheter port system technique called redistributed subclavian arterial infusion chemotherapy (RESAIC) for locally advanced breast cancer was reported and seemed to be effective for local control and as a palliative treatment. However, when the cancer spreads beyond the medial line to the contralateral chest wall, ipsilateral RESAIC would not achieve a favorable drug distribution. We report on two patients with advanced breast cancer spreading to the contralateral chest wall in whom bilateral RESAIC was attempted. In summary, when advanced breast cancer spreads to the contralateral chest wall, bilateral RESAIC may be useful for local control or palliation. PMID- 22919055 TI - Analysis of intimal extent and predictors of renal atrophy in patients with aortic dissection. AB - BACKGROUND: The intimal flap of aortic dissection may extend to the abdominal branches and probably lead to malperfusion syndrome. Renal malperfusion and renal atrophy are significantly related to patient outcomes. PURPOSE: To study the extent of the intimal flap and predisposing factors for renal atrophy in patients with aortic dissection. MATERIAL AND METHODS: From January 2001 to June 2008, 176 (137 men, aged 21-86 years, mean 51.9 years) of 225 subjects with aortic dissection and computed tomography (CT) met the inclusion criteria for this study. Of these 176 patients, 35 (19.9%) developed unilateral renal atrophy. A review of the CT was conducted to classify aortic branch vessel perfusion into three types: type 1, in which the branch vessels are perfused exclusively from the true lumen; type 2, in which the branches are perfused from both the true and false lumens; and type 3, in which the branches are perfused exclusively from the false lumen. Variables including age, gender, type of aortic dissection, type of perfusion of the abdominal branches, and the presence of thrombi in the false lumen were analyzed to determine whether these factors were related to the left or right side and global or focal renal atrophy. RESULTS: Of 880 abdominal branches in 176 patients, 622 (70.7%) were classed as perfusion type 1, 50 (5.7%) as type 2, and 208 (23.6%) as type 3. Type 3 perfusion was most commonly observed in the left renal artery, at a frequency of 31.7% (66/208). Partial thrombosis in the false lumen above the level of the renal arteries was seen in 68.8% of patients; such thrombi and type 3 perfusion of the renal artery were significantly related to renal atrophy. The laterality (left or right) and extent (global or focal) of renal atrophy were not related to age, gender, type of aortic dissection, or perfusion type. CONCLUSION: Type 3 perfusion is most frequent in the left renal artery, and such perfusion and partial thrombi in the false lumen above the renal arteries are significantly related to the development of renal atrophy. PMID- 22919056 TI - Identification of an MRAP-independent melanocortin-2 receptor: functional expression of the cartilaginous fish, Callorhinchus milii, melanocortin-2 receptor in CHO cells. AB - Phylogenetic analyses indicate that the genome of the cartilaginous fish, Callorhynchus milii (elephant shark), encodes a melanocortin-2 receptor (MC2R) ortholog. Expression of the elephant shark mc2r cDNA in Chinese hamster ovary (CHO) cells revealed that trafficking to the plasma membrane and functional activation of the receptor do not require coexpression with an exogenous melanocortin receptor-2 accessory protein (mrap) cDNA. Ligand selectivity studies indicated that elephant shark MC2R-transfected CHO cells produced cAMP in a dose dependent manner when stimulated with either human ACTH (1-24) or [Nle(4), d Phe(7)]-MSH. Furthermore, the order of ligand selectivity when elephant shark MC2R-transfected CHO cells were stimulated with cartilaginous fish melanocortins was as follows: ACTH (1-25) = gamma-MSH = delta-MSH > alphaMSH = beta-MSH. Elephant shark MC2R is the first vertebrate MC2R ortholog to be analyzed that does not require melanocortin receptor-2 accessory protein 1 for functional activation. In addition, elephant MC2R is currently the only MC2R ortholog that can be activated by either ACTH- or MSH-sized ligands. Hence, it would appear that MC2R dependence on melanocortin receptor-2 accessory protein 1 for functional activation and the exclusive selectivity of this melanocortin receptor for ACTH are features that emerged after the divergence of the ancestral cartilaginous fishes and the ancestral bony fishes more than 400 million years ago. PMID- 22919057 TI - Role of TSH in the spontaneous development of asymmetrical thyroid carcinoma in mice with a targeted mutation in a single allele of the thyroid hormone-beta receptor. AB - Mutations of the thyroid hormone receptor-beta gene (THRB) cause resistance to thyroid hormone (RTH). A mouse model of RTH harboring a homozygous thyroid hormone receptor (TR)-beta mutation known as PV (Thrb(PV/PV) mouse) spontaneously develops follicular thyroid cancer (FTC). Similar to RTH patients with mutations of two alleles of the THRB gene, the Thrb(PV/PV) mouse exhibits elevated thyroid hormones accompanied by highly nonsuppressible TSH. However, the heterozygous Thrb(PV/+) mouse with mildly elevated TSH (~2-fold) does not develop FTC. The present study examined whether the mutation of a single allele of the Thrb gene is sufficient to induce FTC in Thrb(PV/+) mice under stimulation by high TSH. Thrb(PV/+) mice and wild-type siblings were treated with propylthiouracil (PTU) to elevate serum TSH. Thrb(PV/+)mice treated with PTU (Thrb(PV/+)-PTU) spontaneously developed FTC similar to human thyroid cancer, but wild-type siblings treated with PTU did not. Interestingly, approximately 33% of Thrb(PV/+) PTU mice developed asymmetrical thyroid tumors, as is frequently observed in human thyroid cancer. Molecular analyses showed activation of the cyclin 1-cyclin dependent kinase-4-transcription factor E2F1 pathway to increase thyroid tumor cell proliferation of Thrb(PV/+)-PTU mice. Moreover, via extranuclear signaling, the PV also activated the integrin-Src-focal adhesion kinase-AKT metalloproteinase pathway to increase migration and invasion of tumor cells. Therefore, mutation of a single allele of the Thrb gene is sufficient to drive the TSH-simulated hyperplastic thyroid follicular cells to undergo carcinogenesis. The present study suggests that the Thrb(PV/+)-PTU mouse model potentially could be used to gain insights into the molecular basis underlying the association between thyroid cancer and RTH seen in some affected patients. PMID- 22919058 TI - Deficiency of angiotensin type 1a receptors in adipocytes reduces differentiation and promotes hypertrophy of adipocytes in lean mice. AB - Adipocytes express angiotensin receptors, but the direct effects of angiotensin II (AngII) stimulating this cell type are undefined. Adipocytes express angiotensin type 1a receptor (AT1aR) and AT2R, both of which have been implicated in obesity. In this study, we determined the effects of adipocyte AT1aR deficiency on adipocyte differentiation and the development of obesity in mice fed low-fat (LF) or high-fat (HF) diets. Mice expressing Cre recombinase under the control of the aP2 promoter were bred with AT1aR-floxed mice to generate mice with adipocyte AT1aR deficiency (AT1aR(aP2)). AT1aR mRNA abundance was reduced significantly in both white and brown adipose tissue from AT1aR(aP2) mice compared with nontransgenic littermates (AT1aR(fl/fl)). Adipocyte AT1aR deficiency did not influence body weight, glucose tolerance, or blood pressure in mice fed either LF or high-fat diets. However, LF-fed AT1aR(aP2) mice exhibited striking adipocyte hypertrophy even though total fat mass was not different between genotypes. Stromal vascular cells from AT1aR(aP2) mice differentiated to a lesser extent to adipocytes compared with controls. Conversely, incubation of 3T3-L1 adipocytes with AngII increased Oil Red O staining and increased mRNA abundance of peroxisome proliferator-activated receptor gamma (PPARgamma) via AT1R stimulation. These results suggest that reductions in adipocyte differentiation in LF-fed AT1aR(aP2) mice resulted in increased lipid storage and hypertrophy of remaining adipocytes. These results demonstrate that AngII regulates adipocyte differentiation and morphology through the adipocyte AT1aR in lean mice. PMID- 22919059 TI - Estrogen receptors are found in glia and at extranuclear neuronal sites in the dorsal striatum of female rats: evidence for cholinergic but not dopaminergic colocalization. AB - Estrogens rapidly affect dopamine (DA) neurotransmission in the dorsal striatum (dSTR) and DA-related diseases, such as Parkinson's disease and schizophrenia. How estrogens influence DA function remains unclear, in part, because the ultrastructural localization of estrogen receptors (ER) in the dSTR is not known. Light microscopic studies of the dSTR have suggested the presence of ER. This experiment used electron microscopy to determine whether these ER are at extranuclear sites in the dSTR, providing evidence for a mechanism through which estrogen could rapidly affect DA transmission. The dSTR was labeled with antibodies for ERalpha, ERbeta, and G protein-coupled ER 1 (GPER-1) to confirm whether these ER were present in this brain area. After this, the dSTR was dual labeled with antibodies for ERalpha or GPER-1 and tyrosine hydroxylase or vesicular acetylcholine transporter to determine whether ER are localized to dopaminergic and/or cholinergic processes, respectively. Ultrastructural analysis revealed immunoreactivity (IR) for ERalpha, ERbeta, and GPER-1 exclusively at extranuclear sites throughout the dSTR. ERalpha-, ERbeta-, and GPER-1-IR are mostly frequently observed in axons and glial profiles but are also localized to other neuronal profiles. Dual labeling revealed that ERalpha- and GPER-1-IR is not associated with DA axons and terminals but is sometimes associated with cholinergic neurons. Because these receptors are exclusively extranuclear in the dSTR, binding at these receptors likely affects neurotransmission via nongenomic mechanisms. PMID- 22919060 TI - Cross talk between PKC and CREB in the induction of COX-2 by PGF2alpha in human amnion fibroblasts. AB - Compelling evidence indicates a crucial role of prostaglandin F2alpha (PGF2alpha) in parturition. Both the maternal and fetal sides of the fetal membranes synthesize PGF2alpha, which exerts effects via the prostaglandin F2alpha receptor (FP) that is coupled to the activation of protein kinase C (PKC). Cyclooxygenase 2 (COX-2) catalyzes the rate-limiting step of the inducible synthesis of prostaglandin. Although activation of PKC is known to induce COX-2 expression, it is not clear whether PGF2alpha can induce COX-2 via FP receptor-coupled PKC activation. COX-2 promoter carries a cAMP-response element (CRE) and phosphorylation of CRE binding protein 1 (CREB1) is associated with COX-2 expression in human amnion fibroblasts. We demonstrated that human amnion fibroblasts produced PGF2alpha and expressed FP receptor. PGF2alpha increased COX 2 expression and CREB1 phosphorylation, which could be blocked by either the FP receptor antagonist AL8810 or PKC inhibitor Ro31-7549. The PKC activator, phorbol 12-myristate-13-acetate (PMA), could mimic the induction of COX-2 and CREB1 phosphorylation. The induction of COX-2 by PGF2alpha and PMA could be attenuated by the small interfering RNA-mediated knockdown of CREB1 expression or overexpressing dominant-negative CREB1. A chromatin immunoprecipitation assay showed that the binding of CREB1 to the COX-2 promoter was increased by PGF2alpha and PMA in amnion fibroblasts. In conclusion, we provide evidence that PGF2alpha induces COX-2 expression via the FP receptor and phosphorylates CREB1 by PKC, thus increasing CREB1 binding to the COX-2 promoter and the expression of COX-2 in human amnion fibroblasts. This feed-forward loop may be crucial for the production of prostaglandins in the fetal membranes prior to the onset of labor. PMID- 22919061 TI - Subpopulations of GFP-marked mouse pancreatic beta-cells differ in size, granularity, and insulin secretion. AB - There is growing information about the heterogeneity of pancreatic beta-cells and how it relates to insulin secretion. This study used the approach of flow cytometry to sort and analyze beta-cells from transgenic mice expressing green fluorescent protein (GFP) under the control of the mouse insulin I gene promoter. Three populations of beta-cells with differing GFP brightness could be identified, which were classified as GFP-low, GFP-medium, and GFP-bright. The GFP medium population comprised about 70% of the total. The GFP-low population had less insulin secretion as determined by the reverse hemolytic plaque assay and reduced insulin gene expression. Additionally, all three subpopulations of beta cells were found in mice of varying ages (embryonic d 15.5 and postnatal wk 1-9). The three populations from the youngest had larger cells (forward scatter) and less granularity (side scatter) than those from the adults. This approach opens up new ways to advance knowledge about beta-cell heterogeneity. PMID- 22919062 TI - Serotonin (5-HT) activation of immortalized hypothalamic neuronal cells through the 5-HT1B serotonin receptor. AB - Serotonin [or 5-hydroxytryptamine or (5-HT)] has been implicated as a key modulator in energy homeostasis and a primary focus in the treatment of obesity. There is growing evidence that 5-HT, acting through the 5-HT 1B receptor (5 HT(1B)R) in the paraventricular nucleus of the hypothalamus (PVN), is important to this regulation. However, there is some contention as to whether 5-HT(1B)R action occurs directly on PVN neurons or indirectly via inhibitory inputs into the PVN. To address these questions, we used a novel clonal, hypothalamic neuronal cell model, adult mouse hypothalamic-2/30 (mHypoA-2/30), expressing a PVN-specific marker, single-minded homolog 1, as well as a complement of PVN neuropeptides, including TRH, vasopressin, ghrelin, nucleobindin-2, and galanin. Adult mouse hypothalamic-2/30 neurons were also found to express the 5-HT(1B)R and 5-HT 6 receptor, but not 2C, all previously linked to feeding regulation. Direct serotonergic stimulation (100 nm to 10 MUm) of these neurons resulted in dose-dependent cFos activation. 5-HT (10 MUm) suppressed forskolin-induced cAMP levels and induced a rise in intracellular Ca(2+) through ER Ca(2+) release, effects that were mimicked by the 5-HT(1B)R agonists, CGS12066B and CP93129, and that were attenuated in the presence of the 5-HT(1B)R-specific inhibitors, GR55562 and isamoltane hemifumarate. Modest transcriptional changes in ghrelin and nucleobindin-2 were also observed in response to 100 nm and 10 MUm 5-HT, respectively. These findings support the model wherein 5-HT action through the 1B receptor subtype occurs directly on PVN neurons, leading to potential modification of neuronal transcriptional and secretory machinery. PMID- 22919063 TI - The mitochondrial Atp8 mutation induces mitochondrial ROS generation, secretory dysfunction, and beta-cell mass adaptation in conplastic B6-mtFVB mice. AB - Mutations in mitochondrial DNA (mtDNA) cause a variety of pathologic phenotypes. In this study, we used conplastic mouse strains to characterize the impact of a mtDNA mutation in the Atp8 gene on beta-cell function, reactive oxygen species (ROS) generation, beta-cell mass, and glucose metabolism in response to high-fat diet (HFD). In comparison with B6-mt(AKR) controls, the B6-mt(FVB) strain carries a point mutation of the mtDNA-coded Atp8 gene (ATP synthase), leading to a fragmentated mitochondrial phenotype. Isolated pancreatic islets from 3-month-old B6-mt(FVB) mice showed increased mitochondrial generation of ROS, reduced cellular ATP levels, reduced glucose-induced insulin secretion, higher susceptibility to palmitate stress, and pathological morphology of mitochondria. ROS generation in beta-cells was not affected by changes of the ambient glucose concentrations. Feeding a HFD for 3 months resulted in impaired glucose tolerance in B6-mt(FVB) mice but not in B6-mt(AKR) controls. In B6-mt(FVB) animals, glucose intolerance positively correlated with gain of body weight. Serum insulin levels and beta-cell mass significantly increased in B6-mt(FVB) mice after a 3-month HFD. The data indicate that the mutation in the Atp8 gene induces mitochondrial dysfunction in beta-cells with concomitant impairment of secretory responsiveness. This mitochondrial dysfunction induced a higher susceptibility to metabolic stressors, although this effect appeared not strictly linked to nutrient-induced ROS generation. The Atp8 gene mutation caused mitochondrial dysfunction, apparently stimulating an adaptive increase of beta-cell mass in response to HFD, whereas mitochondrial ROS might have had an supportive role. PMID- 22919064 TI - Maternal corticosterone exposure in the mouse has sex-specific effects on placental growth and mRNA expression. AB - Maternal exposure to increased synthetic glucocorticoids (GC) during pregnancy is known to disturb fetal development and increase the risk of long-term disease. Maternal exposure to elevated levels of natural GC is likely to be common yet is relatively understudied. The placenta plays an important role in regulating fetal exposure to maternal GC but is itself vulnerable to maternal insults. This study uses a mouse model of maternal corticosterone (Cort) exposure to investigate its effects on the developing placenta. Mice were treated with Cort (33 MUg/kg.h) for 60 h starting at embryonic d 12.5 (E12.5) before collection of placentas at E14.5 and E17.5. Although Cort exposure did not affect fetal size, placentas of male fetuses were larger at E17.5 in association with changes in placental Igf2. This increase in size was associated with an increase in placental thickness and an increase in placental junctional zone volume. Placentas from female fetuses were of normal size and had no changes in growth factor mRNA levels. The expression of the protective enzyme 11beta-hydroxysteroid dehydrogenase type 2 was increased at E14.5 but was decreased in males at E17.5. In contrast, the expression of Nr3c1 (which encodes the GC receptor) was increased during the Cort exposure and remained elevated at E17.5 in the placentas of male fetuses. Our study has shown that maternal Cort exposure infers a sex-specific alteration to normal placental growth and growth factor expression, thus further adding to our understanding of the mechanisms of male dominance of programmed disease. PMID- 22919065 TI - Adverse cardiovascular outcomes of corticosteroid excess. AB - Corticosteroid excess is associated with adverse cardiovascular outcomes. Patients with Cushings's syndrome, either caused by endogenous or exogenous glucocorticoid excess, and patients with primary aldosteronism have increased cardiovascular risk. The increase in risk is mediated partly by traditional cardiovascular risk factors including hypertension and metabolic syndrome but also by other, less well-characterized mechanisms. Experimental and human studies have shown that target organ deterioration induced by aldosterone depends on concomitant high dietary salt intake. Key ongoing research questions that warrant further study by both clinical and experimental approaches include the following: 1) beyond inducing the metabolic syndrome, what are the mechanisms by which glucocorticoids are associated with excess cardiovascular risk, 2) what are the cellular pathways by which excessive mineralocorticoid receptor activation brings about cardiovascular and renal damage, and 3) why is salt critical in this process? PMID- 22919067 TI - Arsenic trioxide synergizes with everolimus (Rad001) to induce cytotoxicity of ovarian cancer cells through increased autophagy and apoptosis. AB - Phosphatidylinositol 3-kinase/AKT/mammalian target of rapamycin pathway plays a key role in the tumorigenesis of a variety of human cancers including ovarian cancer. However, inhibitors of this pathway such as Rad001 have not shown therapeutic efficacy as a single agent for this cancer. Arsenic trioxide (ATO) induces an autophagic pathway in ovarian carcinoma cells. We found that ATO can synergize with Rad001 to induce cytotoxicity of ovarian cancer cells. Moreover, we identified synergistic induction of autophagy and apoptosis as the likely underlying mechanism that is responsible for the enhanced cytotoxicity. The enhanced cytotoxicity is accompanied by decreased p-AKT levels as well as upregulation of ATG5-ATG12 conjugate and LC3-2, hallmarks of autophagy. Rad001 and ATO can also synergistically inhibit tumors in a xenograft animal model of ovarian cancer. These results thus identify and validate a novel mechanism to enhance and expand the existing targeted therapeutic agent to treat human ovarian cancer. PMID- 22919068 TI - FOXM1 is a molecular determinant of the mitogenic and invasive phenotype of anaplastic thyroid carcinoma. AB - Anaplastic thyroid carcinoma (ATC) is a very aggressive thyroid cancer. forkhead box protein M1 (FOXM1) is a member of the forkhead box family of transcription factors involved in control of cell proliferation, chromosomal stability, angiogenesis, and invasion. Here, we show that FOXM1 is significantly increased in ATCs compared with normal thyroid, well-differentiated thyroid carcinomas (papillary and/or follicular), and poorly differentiated thyroid carcinomas (P=0.000002). Upregulation of FOXM1 levels in ATC cells was mechanistically linked to loss-of-function of p53 and to the hyperactivation of the phosphatidylinositol-3-kinase/AKT/FOXO3a pathway. Knockdown of FOXM1 by RNA interference inhibited cell proliferation by arresting cells in G2/M and reduced cell invasion and motility. This phenotype was associated with decreased expression of FOXM1 target genes, like cyclin B1 (CCNB1), polo-like kinase 1 (PLK1), Aurora B (AURKB), S-phase kinase-associated protein 2 (SKP2), and plasminogen activator, urokinase: uPA (PLAU). Pharmacological inhibition of FOXM1 in an orthotopic mouse model of ATC reduced tumor burden and metastasization. All together, these findings suggest that FOXM1 represents an important player in thyroid cancer progression to the anaplastic phenotype and a potential therapeutic target for this fatal cancer. PMID- 22919069 TI - The extracellular matrix is a novel attribute of endothelial progenitors and of hypoxic mature endothelial cells. AB - Extracellular matrix (ECM) production is critical to preserve the function and integrity of mature blood vessels. Toward the engineering of blood vessels, studies have centered on ECM production by supporting cells, whereas few studies implicate endothelial cells (ECs) with ECM synthesis. Here, we elucidate variations between cultured human arterial, venous, and progenitor ECs with respect to ECM deposition assembly, composition, and response to biomolecular and physiological factors. Our studies reveal that progenitor ECs, endothelial colony forming cells (ECFCs), deposit collagen IV, fibronectin, and laminin that assemble to an organized weblike structure, as confirmed by decellularized cultures. Mature ECs only express these ECM proteins intracellularly. ECFC derived ECM is abrogated in response to TGFbeta signaling inhibition and actin cytoskeleton disruption. Hypoxic (1%) and physiological (5%) O(2) tension stimulate ECM deposition from mature ECs. Interestingly, deposition of collagen I is observed only under 5% O(2) tension. ECM production from all ECs is found to be regulated by hypoxia-inducible factors 1alpha and 2alpha but differentially in the different cell lines. Collectively, we suggest that ECM deposition and assembly by ECs is dependent on maturation stage and oxygen supply and that these findings can be harnessed to advance engineered vascular therapeutics. PMID- 22919070 TI - Chemically engineering ligand selectivity at the free fatty acid receptor 2 based on pharmacological variation between species orthologs. AB - When it is difficult to develop selective ligands within a family of related G protein-coupled receptors (GPCRs), chemically engineered receptors activated solely by synthetic ligands (RASSLs) are useful alternatives for probing receptor function. In the present work, we explored whether a RASSL of the free fatty acid receptor 2 (FFA2) could be developed on the basis of pharmacological variation between species orthologs. For this, bovine FFA2 was characterized, revealing distinct ligand selectivity compared with human FFA2. Homology modeling and mutational analysis demonstrated a single mutation in human FFA2 of C4.57G resulted in a human FFA2 receptor with ligand selectivity similar to the bovine receptor. This was exploited to generate human FFA2-RASSL by the addition of a second mutation at a known orthosteric ligand interaction site, H6.55Q. The resulting FFA2-RASSL displayed a >100-fold loss of activity to endogenous ligands, while responding to the distinct ligand sorbic acid with pEC(50) values for inhibition of cAMP, 5.83 +/- 0.11; Ca(2+) mobilization, 4.63 +/- 0.05; ERK phosphorylation, 5.61 +/- 0.06; and dynamic mass redistribution, 5.35 +/- 0.06. This FFA2-RASSL will be useful in future studies on this receptor and demonstrates that exploitation of pharmacological variation between species orthologs is a powerful method to generate novel chemically engineered GPCRs. PMID- 22919071 TI - Telomerase expression in the mammalian heart. AB - While the mammalian heart has low, but functionally significant, levels of telomerase expression, the cellular population responsible remains incompletely characterized. This study aimed to identify the cell types responsible for cardiac telomerase activity in neonatal, adult, and cryoinjured adult hearts using transgenic mice expressing green fluorescent protein (GFP), driven by the promoter for murine telomerase reverse transcriptase (mTert), which is a necessary and rate-limiting component of telomerase. A rare population of mTert GFP-expressing cells was identified that possessed all detectable cardiac telomerase RNA and telomerase activity. It was heterogeneous and included cells coexpressing markers of cardiomyocytic, endothelial, and mesenchymal lineages, putative cardiac stem cell markers, and, interestingly, cardiomyocytes with a differentiated phenotype. Quantification using both flow cytometry and immunofluorescence identified a significant decline in mTert-GFP cells in adult animals compared to neonates (~9- and ~20-fold, respectively). Cardiac injury resulted in a ~6.45-fold expansion of this population (P<0.005) compared with sham-operated controls. This study identifies the cells responsible for cardiac telomerase activity, demonstrates a significant diminution with age but a marked response to injury, and, given the relationship between telomerase activity and stem cell populations, suggests that they represent a potential target for further investigation of cardiac regenerative potential. PMID- 22919072 TI - Uterine natural killer cells initiate spiral artery remodeling in human pregnancy. AB - Uterine spiral artery remodeling is required for successful human pregnancy; impaired remodeling is associated with pregnancy complications, including late miscarriage, preeclampsia, and fetal growth restriction. The molecular triggers of remodeling are not known, but it is now clear that there are "trophoblast independent" and "trophoblast-dependent" stages. Uterine natural killer (uNK) cells are abundant in decidualized endometrium in early pregnancy; they surround spiral arteries and secrete a range of angiogenic growth factors. We hypothesized that uNK cells mediate the initial stages of spiral artery remodeling. uNK cells and extravillous trophoblast (EVT) cells were isolated from early pregnancy decidua and placenta. Chorionic plate arteries from full-term placentas and spiral arteries from nonpregnant myometrium were cultured with angiogenic growth factors or conditioned medium (CM) from uNK cells or EVT or uNK cell/EVT cocultures. In both vessel models, uNK cell CM induced disruption of vascular smooth muscle cells (VSMCs) and breakdown of extracellular matrix components. Angiopoietin (Ang)-1, Ang-2, interferon-gamma, and VEGF-C also disrupted VSMC integrity with an Ang-2 inhibitor abrogating the effect of uNK cell CM. These results provide compelling evidence that uNK cells contribute to the early stages of spiral artery remodeling; failure of this process could contribute to pregnancy pathology. PMID- 22919074 TI - Guthrie card methylomics identifies temporally stable epialleles that are present at birth in humans. AB - A major concern in common disease epigenomics is distinguishing causal from consequential epigenetic variation. One means of addressing this issue is to identify the temporal origins of epigenetic variants via longitudinal analyses. However, prospective birth-cohort studies are expensive and time consuming. Here, we report DNA methylomics of archived Guthrie cards for the retrospective longitudinal analyses of in-utero-derived DNA methylation variation. We first validate two methodologies for generating comprehensive DNA methylomes from Guthrie cards. Then, using an integrated epigenomic/genomic analysis of Guthrie cards and follow-up samplings, we identify interindividual DNA methylation variation that is present both at birth and 3 yr later. These findings suggest that disease-relevant epigenetic variation could be detected at birth, i.e., before overt clinical disease. Guthrie card methylomics offers a potentially powerful and cost-effective strategy for studying the dynamics of interindividual epigenomic variation in a range of common human diseases. PMID- 22919073 TI - Analysis of gene expression from the Wolbachia genome of a filarial nematode supports both metabolic and defensive roles within the symbiosis. AB - The alpha-proteobacterium Wolbachia is probably the most prevalent, vertically transmitted symbiont on Earth. In contrast with its wide distribution in arthropods, Wolbachia is restricted to one family of animal-parasitic nematodes, the Onchocercidae. This includes filarial pathogens such as Onchocerca volvulus, the cause of human onchocerciasis, or river blindness. The symbiosis between filariae and Wolbachia is obligate, although the basis of this dependency is not fully understood. Previous studies suggested that Wolbachia may provision metabolites (e.g., haem, riboflavin, and nucleotides) and/or contribute to immune defense. Importantly, Wolbachia is restricted to somatic tissues in adult male worms, whereas females also harbor bacteria in the germline. We sought to characterize the nature of the symbiosis between Wolbachia and O. ochengi, a bovine parasite representing the closest relative of O. volvulus. First, we sequenced the complete genome of Wolbachia strain wOo, which revealed an inability to synthesize riboflavin de novo. Using RNA-seq, we also generated endobacterial transcriptomes from male soma and female germline. In the soma, transcripts for membrane transport and respiration were up-regulated, while the gonad exhibited enrichment for DNA replication and translation. The most abundant Wolbachia proteins, as determined by geLC-MS, included ligands for mammalian Toll like receptors. Enzymes involved in nucleotide synthesis were dominant among metabolism-related proteins, whereas the haem biosynthetic pathway was poorly represented. We conclude that Wolbachia may have a mitochondrion-like function in the soma, generating ATP for its host. Moreover, the abundance of immunogenic proteins in wOo suggests a role in diverting the immune system toward an ineffective antibacterial response. PMID- 22919077 TI - Rethinking faculty career development strategies. PMID- 22919075 TI - Extensive compensatory cis-trans regulation in the evolution of mouse gene expression. AB - Gene expression levels are thought to diverge primarily via regulatory mutations in trans within species, and in cis between species. To test this hypothesis in mammals we used RNA-sequencing to measure gene expression divergence between C57BL/6J and CAST/EiJ mouse strains and allele-specific expression in their F1 progeny. We identified 535 genes with parent-of-origin specific expression patterns, although few of these showed full allelic silencing. This suggests that the number of imprinted genes in a typical mouse somatic tissue is relatively small. In the set of nonimprinted genes, 32% showed evidence of divergent expression between the two strains. Of these, 2% could be attributed purely to variants acting in trans, while 43% were attributable only to variants acting in cis. The genes with expression divergence driven by changes in trans showed significantly higher sequence constraint than genes where the divergence was explained by variants acting in cis. The remaining genes with divergent patterns of expression (55%) were regulated by a combination of variants acting in cis and variants acting in trans. Intriguingly, the changes in expression induced by the cis and trans variants were in opposite directions more frequently than expected by chance, implying that compensatory regulation to stabilize gene expression levels is widespread. We propose that expression levels of genes regulated by this mechanism are fine-tuned by cis variants that arise following regulatory changes in trans, suggesting that many cis variants are not the primary targets of natural selection. PMID- 22919078 TI - Treating mentoring programs as a scholarly endeavor. PMID- 22919079 TI - In pursuit of prestige: the folly of the US News and World Report survey. PMID- 22919080 TI - A graduate student mentoring program to develop interest in research. AB - OBJECTIVE: To assess the impact of a graduate student mentoring program on student interest in research and postgraduate education and on graduate student confidence in mentoring. METHODS: Undergraduate and pharmacy students (mentees) and graduate students (mentors) were matched and participated in the study, which required them to engage in at least 2 discussions regarding research and careers. Mentees completed a pre- and post-assessment of their perceptions of research, postgraduate training plans, and perceptions about mentors. Mentors completed a pre- and post-assessment of their perceptions about themselves as mentors and their confidence in mentoring. RESULTS: Although there were no significant differences among the mentees' perceptions of research or the mentors' confidence in mentoring, qualitative analysis indicated that the mentees' perceptions of research improved and that the mentors believed their mentoring skills improved. CONCLUSIONS: Based on the results of the qualitative analysis, implementing a graduate student mentoring program may help improve students' perceptions of research and graduate students' confidence in mentoring, which could increase student interest in postgraduate education and prepare mentors for future leadership roles. PMID- 22919081 TI - Prospective student pharmacist interest in a rural pharmacy curriculum. AB - OBJECTIVE: To determine prospective student pharmacists' interest in a rural pharmacy health curriculum. METHODS: All applicants who were selected to interview for fall 2011 enrollment at the UNC Eshelman School of Pharmacy were invited to participate in a Web-based survey. Questions addressed participants' willingness to participate in a rural health pharmacy curriculum, interest in practicing in a rural area, and beliefs regarding patient access to healthcare in rural areas. RESULTS: Of the 250 prospective student pharmacists invited to participate, 91% completed the survey instrument. Respondents agreed that populations living in rural areas may have different health needs, and students were generally interested in a rural pharmacy health curriculum. CONCLUSIONS: An online survey of prospective student pharmacists was an effective way to assess their interest in a rural pharmacy program being considered by the study institution. Location of the rural program at a satellite campus and availability of housing were identified as factors that could limit enrollment. PMID- 22919082 TI - European pharmacy students' experience with virtual patient technology. AB - OBJECTIVE: To describe how virtual patients are being used to simulate real-life clinical scenarios in undergraduate pharmacy education in Europe. METHODS: One hundred ninety-four participants at the 2011 Congress of the European Pharmaceutical Students Association (EPSA) completed an exploratory cross sectional survey instrument. RESULTS: Of the 46 universities and 23 countries represented at the EPSA Congress, only 12 students from 6 universities in 6 different countries reported having experience with virtual patient technology. The students were satisfied with the virtual patient technology and considered it more useful as a teaching and learning tool than an assessment tool. Respondents who had not used virtual patient technology expressed support regarding its potential benefits in pharmacy education. French and Dutch students were significantly less interested in virtual patient technology than were their counterparts from other European countries. CONCLUSION: The limited use of virtual patients in pharmacy education in Europe suggests the need for initiatives to increase the use of virtual patient technology and the benefits of computer-assisted learning in pharmacy education. PMID- 22919083 TI - Use of a general level framework to facilitate performance improvement in hospital pharmacists in Singapore. AB - OBJECTIVE: To evaluate the acceptability and validity of an adapted version of the General Level Framework (GLF) as a tool to facilitate and evaluate performance development in general pharmacist practitioners (those with less than 3 years of experience) in a Singapore hospital. METHOD: Observational evaluations during daily clinical activities were prospectively recorded for 35 pharmacists using the GLF at 2 time points over an average of 9 months. Feedback was provided to the pharmacists and then individualized learning plans were formulated. RESULTS: Pharmacists' mean competency cluster scores improved in all 3 clusters, and significant improvement was seen in all but 8 of the 63 behavioral descriptors (p <= 0.05). Nonsignificant improvements were attributed to the highest level of performance having been attained upon initial evaluation. Feedback indicated that the GLF process was a positive experience, prompting reflection on practice and culminating in needs-based learning and ultimately improved patient care. CONCLUSIONS: The General Level Framework was an acceptable tool for the facilitation and evaluation of performance development in general pharmacist practitioners in a Singapore hospital. PMID- 22919084 TI - Identifying psychological contract breaches to guide improvements in faculty recruitment, retention, and development. AB - OBJECTIVE: To identify pharmacy faculty members' perceptions of psychological contract breaches that can be used to guide improvements in faculty recruitment, retention, and development. METHODS: A list of psychological contract breaches was developed using a Delphi procedure involving a panel of experts assembled through purposive sampling. The Delphi consisted of 4 rounds, the first of which elicited examples of psychological contract breaches in an open-ended format. The ensuing 3 rounds consisting of a survey and anonymous feedback on aggregated group responses. RESULTS: Usable responses were obtained from 11 of 12 faculty members who completed the Delphi procedure. The final list of psychological contract breaches included 27 items, after modifications based on participant feedback in subsequent rounds. CONCLUSION: The psychological contract breach items generated in this study provide guidance for colleges and schools of pharmacy regarding important aspects of faculty recruitment, retention, and development. PMID- 22919085 TI - Educating Pharmacy Students to Improve Quality (EPIQ) in colleges and schools of pharmacy. AB - OBJECTIVE: To assess course instructors' and students' perceptions of the Educating Pharmacy Students and Pharmacists to Improve Quality (EPIQ) curriculum. METHODS: Seven colleges and schools of pharmacy that were using the EPIQ program in their curricula agreed to participate in the study. Five of the 7 collected student retrospective pre- and post-intervention questionnaires. Changes in students' perceptions were evaluated to assess their relationships with demographics and course variables. Instructors who implemented the EPIQ program at each of the 7 colleges and schools were also asked to complete a questionnaire. RESULTS: Scores on all questionnaire items indicated improvement in students' perceived knowledge of quality improvement. The university the students attended, completion of a class project, and length of coverage of material were significantly related to improvement in the students' scores. Instructors at all colleges and schools felt the EPIQ curriculum was a strong program that fulfilled the criteria for quality improvement and medication error reduction education. CONCLUSION: The EPIQ program is a viable, turnkey option for colleges and schools of pharmacy to use in teaching students about quality improvement. PMID- 22919086 TI - An advanced pharmacy practice experience in a student-staffed medication therapy management call center. AB - OBJECTIVE: To describe the implementation of an advanced pharmacy practice experience (APPE) in medication therapy management (MTM) designed to contribute to student pharmacists' confidence and abilities in providing MTM. DESIGN: Sixty four student pharmacists provided MTM services during an APPE in a communication and care center. ASSESSMENT: Students conducted 1,495 comprehensive medication reviews (CMRs) identifying 6,056 medication-related problems. Ninety-eight percent of the students who completed a survey instrument (52 of 53) following the APPE expressed that they had the necessary knowledge and skills to provide MTM services. Most respondents felt that pharmacist participation in providing Medicare MTM could move the profession of pharmacy forward and that pharmacists will have some role in deciding the specific provisions of the Medicare MTM program (92% and 91%, respectively). CONCLUSION: Students completing the MTM APPE received patient-centered experiences that supplemented their confidence, knowledge, and skill in providing MTM services in the future. PMID- 22919088 TI - An active-learning assignment requiring pharmacy students to write medicinal chemistry examination questions. AB - OBJECTIVES: To implement and assess the effectiveness of an assignment requiring doctor of pharmacy (PharmD) students to write examination questions for the medicinal chemistry sections of a pharmacotherapeutics course. DESIGN: Students were divided into groups of 5-6 and given detailed instructions and grading rubrics for writing multiple-choice examination questions on medicinal chemistry topics. The compiled student-written questions for each examination were provided to the entire class as a study aid. Approximately 5% of the student-written questions were used in course examinations. ASSESSMENT: Student appreciation of and performance in the medicinal chemistry portion of the course was significantly better than that of the previous year's class. Also, students' responses on a qualitative survey instrument indicated that the assignment provided students' guidance on which concepts to focus on, helped them retain knowledge better, and fostered personal exploration of the content, which led to better performance on examinations. CONCLUSION: Adding an active-learning assignment in which students write examination questions for the medicinal chemistry portion of a pharmacotherapeutics course was an effective means of increasing students engagement in the class and knowledge of the course material. PMID- 22919087 TI - An interprofessional pediatric prescribing workshop. AB - OBJECTIVE: To design, implement, and evaluate an interprofessional learning workshop on pediatric prescribing. DESIGN: An interactive workshop on pediatric prescribing was designed and delivered by pediatricians and pharmacists to fourth year medical and pharmacy students on 3 university campus settings. Students were assigned to either interprofessional workshop groups (pharmacy and medical students) or non-interprofessional workshop groups (medical students only). ASSESSMENT: Two hundred thirty students completed the workshops and 92% returned both the pre- and post-workshop questionnaires. Attitudes toward interprofessional learning significantly improved among students in the interprofessional workshop groups (p< 0.001) and confidence in prescribing for pediatric patients significantly improved among all students (p< 0.001). CONCLUSIONS: The workshop improved medical and pharmacy students' knowledge and confidence in pediatric prescribing and significantly improved their attitudes toward working and learning with other professionals. PMID- 22919089 TI - An active-learning assignment involving peer-to-peer presentations to improve pharmacy students' attitudes and knowledge of dietary supplements. AB - OBJECTIVE: To design and implement a small-group self-guided active-learning format for a complementary and alternative medicine (CAM) curriculum, and assess changes in first-year doctor of pharmacy (PharmD) students' attitudes and knowledge of CAM. DESIGN: Students received an overview CAM lecture from a faculty member, and brief presentations with defined parameters on natural products from their peers. ASSESSMENT: Based on pre- and post-intervention survey responses, the percentage of students who strongly agreed about the importance of CAM in pharmacy practice increased from 28% to 55% and the percentage of students who agreed or strongly agreed about the harmful effects of dietary supplements increased from 60% to 96%. Overall, students' attitude toward and self-assessed knowledge of dietary supplements improved significantly from pre- to post intervention survey. CONCLUSION: Small-group self-guided learning of CAM, followed by peer presentations on dietary supplements, was successful in significantly improving pharmacy students' attitude toward and knowledge of CAM. PMID- 22919090 TI - Incorporation of Bloom's taxonomy into multiple-choice examination questions for a pharmacotherapeutics course. AB - OBJECTIVE: To incorporate Bloom's taxonomy into multiple-choice examination questions in a pharmacotherapeutics course and assess its effectiveness in detecting areas of improvement in learning. DESIGN: Bloom's taxonomy was incorporated into examination questions through a multi-step process: Sample questions representing each learning domain within Bloom's taxonomy (knowledge, comprehension, application, analysis, synthesis, and evaluation) were introduced to students during lecture presentations and discussions. Quiz and examination containing questions categorized according to Bloom's taxonomy were administered to students. During review sessions following each quiz or examination, the categorization of each question was provided to students and feedback from students was gathered. ASSESSMENT: The effect of the 5 types of test questions on the correct response fraction and discrimination index was determined after combining synthesis and evaluation. Correct response fractions for knowledge, comprehension, and application questions were significantly higher than those for analysis and synthesis/evaluation questions (p<0.05). However, discrimination index for application and synthesis/evaluation questions were significantly higher than those for knowledge and comprehension questions (p<0.05). In interviews with students who had requested learning assistance, the majority realized the importance of critical-thinking skills in the learning process. CONCLUSION: Well-designed multiple-choice questions incorporating different learning domains of Bloom's taxonomy may be a potential method of assessing critical-thinking skills in large classes of students. PMID- 22919091 TI - A pharmacoeconomics and formulary management collaborative project to teach decision analysis principles. AB - OBJECTIVE: To implement and assess the effectiveness of a 2-course collaborative decision analysis project intended to help students understand the relevance of pharmacoeconomics to clinical pharmacy practice and provide them an opportunity to apply skills taught in pharmacoeconomics to a "real world" problem. DESIGN: Students were assigned a pair of drugs, 1 commonly used as standard therapy and 1 newly approved, and conducted a decision analysis. The results were then used in a mock pharmacy and therapeutics (P&T) committee meeting. ASSESSMENT: Ninety eight of 106 (92%) students completed a 4-question survey instrument. Ninety-six percent of students agreed or somewhat agreed that the decision analysis project met the learning objectives. Students felt the shared assignment influenced their choice of formulary drug, augmented understanding of factors influencing decisions, broadened their thinking about drug costs, and was a good approximation of a "real world" application. CONCLUSION: An innovative joint course assignment proved to be a successful technique for teaching decision analysis. PMID- 22919092 TI - A root cause analysis project in a medication safety course. AB - OBJECTIVE: To develop, implement, and evaluate team-based root cause analysis projects as part of a required medication safety course for second-year pharmacy students. DESIGN: Lectures, in-class activities, and out-of-class reading assignments were used to develop students' medication safety skills and introduce them to the culture of medication safety. Students applied these skills within teams by evaluating cases of medication errors using root cause analyses. Teams also developed error prevention strategies and formally presented their findings. ASSESSMENT: Student performance was assessed using a medication errors evaluation rubric. Of the 211 students who completed the course, the majority performed well on root cause analysis assignments and rated them favorably on course evaluations. CONCLUSION: Medication error evaluation and prevention was successfully introduced in a medication safety course using team-based root cause analysis projects. PMID- 22919093 TI - A model for small-group problem-based learning in a large class facilitated by one instructor. AB - OBJECTIVE: To implement and evaluate a model for small-group problem-based learning (PBL) in a large class facilitated by 1 instructor. DESIGN: A PBL model that included weekly assignments, quizzes, peer feedback, and case wrap-up sessions was developed and implemented in the final year of the pharmacy program to allow 1 instructor to facilitate PBL for up to 16 student teams in a large classroom. ASSESSMENT: Student and team scores on multiple-choice examinations confirmed achievement of learning objectives. Students reported on course evaluation surveys that they were able to engage in the learning process and were satisfied with the new PBL model. This model achieved a cost savings of $42,000 per term. CONCLUSIONS: A revised PBL model without individual group tutors allowed students to achieve the required learning outcomes in an interactive and engaging atmosphere, avoided classroom-scheduling conflicts, and produced a large cost savings for the university. PMID- 22919094 TI - The pharmacy student population: applications received 2010-11, degrees conferred 2010-11, fall 2011 enrollments. PMID- 22919095 TI - Cultivating 'habits of mind' in the scholarly pharmacy clinician: report of the 2011-12 Argus Commission. PMID- 22919096 TI - Report of the 2011-2012 AACP Professional Affairs Committee: addressing the teaching excellence of volunteer pharmacy preceptors. PMID- 22919097 TI - Report of the 2011-2012 Academic Affairs Standing Committee: the evolving role of scholarly teaching in teaching excellence for current and future faculty. PMID- 22919098 TI - Report of the 2011-2012 Standing Committee On Advocacy: the relevance of excellent research: strategies for impacting public policy. PMID- 22919099 TI - AACP strategy for addressing the professional development needs of department chairs. AB - OBJECTIVES: Characterize the skills and abilities required for department chairs, identify development needs, and then create AACP professional development programs for chairs. METHODS: A 30-question electronic survey was sent to AACP member department chairs related to aspects of chairing an academic department. RESULTS: The survey identified development needs in the leadership, management, and personal abilities required for effective performance as department chair. The information was used to prioritize topics for subsequent AACP development programs. Subsequent programs conducted at AACP Interim and Annual Meetings were well attended and generally received favorable reviews from participants. A list of development resources was placed on the AACP website. CONCLUSIONS: This ongoing initiative is part of an AACP strategy to identify and address the professional development needs of department chairs. Survey results may also inform faculty members and other academic leaders about the roles and responsibilities of department chairs. PMID- 22919101 TI - Evolution in pharmacy education: developing effective patient care practitioners. PMID- 22919102 TI - Diagnostic reasoning by hospital pharmacists: assessment of attitudes, knowledge, and skills. AB - BACKGROUND: Hospital pharmacists participate in activities that may be considered diagnostic. Two reasoning approaches to diagnosis have been described: non analytic and analytic. Of the 6 analytic traditions, the probabilistic tradition has been shown to improve diagnostic accuracy and reduce unnecessary testing. To the authors' knowledge, pharmacists' attitudes toward having a diagnostic role and their diagnostic knowledge and skills have never been studied. OBJECTIVES: To describe pharmacists' attitudes toward the role of diagnosis in pharmacotherapeutic problem-solving and to characterize the extent of pharmacists' knowledge and skills related to diagnostic literacy. METHODS: Pharmacists working within Lower Mainland Pharmacy Services (British Columbia) who spent at least 33% of their time in direct patient care were invited to participate in a prospective observational survey. The survey sought information about demographic characteristics and attitudes toward diagnosis. Diagnostic knowledge and skills were tested by means of 3 case scenarios. The analysis included simple descriptive statistics and inferential statistics to evaluate relationships between responses and experience and training. RESULTS: Of 266 pharmacists invited to participate, 94 responded. The attitudes section of the survey was completed by 90 pharmacists; of these, 80 (89%) agreed with the definition of "diagnosis" proposed in the survey, and 83 (92%) agreed that it is important for pharmacists to have diagnosis-related skills. Respondents preferred an analytic to a non-analytic approach to diagnostic decision-making. The probabilistic tradition was not the preferred method in any of the 3 cases. In evaluating 5 clinical scenarios that might require diagnostic skills, on average 84% of respondents agreed that they should be involved in assessing such problems. Respondents' knowledge of and ability to apply probabilistic diagnostic tools were highest for test sensitivity (average of 61% of respondents with the correct answers) and lower for test specificity (average of 48% with correct answers) and likelihood ratios (average of 39% with correct answers). CONCLUSIONS: Respondents to this survey strongly believed that diagnostic skills were important for solving drug-related problems, but they demonstrated low levels of knowledge and ability to apply concepts of probabilistic diagnostic reasoning. Opportunities to expand pharmacists' knowledge of diagnostic reasoning exist, and the findings reported here indicate that pharmacists would consider such professional development valuable. PMID- 22919103 TI - Medication records in the emergency department: agreement between paper-based charts and automated dispensing device. AB - BACKGROUND: Research exploring the agreement between traditional medication records and electronic records generated by an automated dispensing device has been limited. OBJECTIVE: To evaluate the extent of agreement between medication administration records written in paper-based emergency department charts and records generated by an automated dispensing device with regard to the presence or absence of a single, prespecified medication. METHODS: Medication administration records in paper-based emergency department charts and medication dispensation records generated by an automated dispensing device were evaluated for concordance. The primary outcome measure was agreement between the 2 sources with regard to the presence or absence of a record for salbutamol by metered-dose inhaler (MDI) for randomly selected patients who presented to a pediatric emergency department with wheeze-related illness from January 1, 2008, to December 31, 2009. RESULTS: In total, 1172 patient visits met the inclusion criteria. Of these, records for 1013 visits showed agreement between the paper based emergency department chart and the dispensation record of the automated dispensing device (kappa = 0.71, 95% confidence interval 0.67-0.75). This value did not meet the target kappa of 0.80. Stratification by time of day, day of week, month, season, or year of presentation at triage or by triage level or disposition (whether or not the patient was admitted to the hospital ward) did not significantly affect the level of agreement between the 2 sources. CONCLUSIONS: Agreement between records of salbutamol MDI administration in paper based charts and dispensation records from an automated dispensing device was substantial, but discrepancies were present. There are significant quality management, legal, clinical, and research reasons to strive for concordance between multiple records with respect to medication use in the emergency department. Data generated by automated dispensing devices have potential value for research, but their strengths and limitations need to be understood. PMID- 22919104 TI - Does etomidate increase vasopressor requirements in patients needing mechanical ventilation? AB - BACKGROUND: Single-dose etomidate is used as an induction agent for rapid sequence intubation and is associated with transient adrenal insufficiency. There is ongoing debate as to the clinical consequences of this transient adrenal insufficiency for critically ill patients. OBJECTIVE: To determine if the use of etomidate is associated with higher requirements for a vasopressor, relative to other induction agents, at a single time point (24 h after administration of the induction agent) in patients needing mechanical ventilation. METHODS: In this retrospective observational study utilizing electronic health records, a convenience sample of 50 patients who had undergone intubation in the emergency department with etomidate were matched (1:1) with patients who had received other induction agents. Matching was based on primary admitting diagnosis relating to the cause of shock, APACHE II (Acute Physiology and Chronic Health Evaluation II) score, age, and sex. All patients were subsequently admitted to critical care areas for management. As a surrogate marker of hemodynamic instability, the vasopressor dose was recorded 24 h after intubation. Vasopressor doses were converted to norepinephrine equivalents for comparison. RESULTS: The mean dose of vasopressors, in norepinephrine equivalents, was 4 MUg/min(-1) for patients receiving etomidate and 3 MUg/min(-1) for the control group (mean difference 0.7 MUg min(-1), 95% confidence interval [CI] -1.9 to 3.2 MUg min(-1), p = 0.61). Twelve of the patients in the etomidate group and 16 of those in the control group required the use of vasopressors at 24 h following intubation (odds ratio 2.3, 95% CI 0.53 to 13.99, p = 0.34). CONCLUSIONS: Single-dose etomidate does not adversely affect hemodynamic stability, as measured by the dose of vasopressors required at 24 h after administration. PMID- 22919105 TI - Audit of renal drug dosing: comparison of 2 methods and evaluation of pharmacists' knowledge, attitudes, and behaviour. AB - BACKGROUND: The renal dosing directive of the Winnipeg Regional Health Authority Pharmacy Program outlines an auditable pharmacy service whereby pharmacists are required to perform documentation (i.e., document their rationale) only if they do not adjust the dose of any medications listed in the directive. OBJECTIVE: To compare the suitability of manual orders (hard copy) and reports from the pharmacy information system (computer-generated) for determining pharmacists' compliance with the renal dosing directive; to measure compliance with the renal dosing directive; and to determine pharmacists' opinions about audit programs. METHODS: A retrospective audit was used to compare 400 manual orders with the corresponding orders in reports from the pharmacy information system, to determine compliance with the renal dosing directive. An e-mail survey was performed to gather pharmacists' opinions about audit programs. RESULTS: Of the 400 orders evaluated, 86 (22%) required consideration of a dose adjustment. Of these, 78 (91%) showed that dosing followed the guidelines for renal dysfunction in standard pharmacy references. Six (7%) of 86 manual orders and 8 (9%) of 86 pharmacy information system orders were not compliant with the renal dosing directive (i.e., no dosage adjustment and no documentation of rationale). Of 77 pharmacists approached, 34 (44%) completed the survey. Most respondents (31/34 [91%]) agreed that auditing is beneficial to patients, and the same number (31/34 [91%]) agreed that auditing provides important information to the pharmacy program. Only 17 (50%) were aware of medications listed in the renal dosing directive, and 14 (41%) felt that they had received sufficient education about pharmacy directives. Most respondents (29/34 [85%]) agreed that audits would reveal areas for improvement, and all (34/34 [100%]) would comply with any changes required to facilitate performance of an audit if such changes did not increase workload. CONCLUSIONS: Similar results were obtained with the 2 auditing methods used for this study (manual orders and reports from the pharmacy information system). However, pharmacists' current use of electronic documentation limits the feasibility of pharmacy information system audits. Survey respondents claimed that they were not familiar with the renal dosing directive, but they did agree that auditing clinical services is beneficial. PMID- 22919106 TI - Experiential training for pharmacy students: time for a new approach. PMID- 22919107 TI - Prohibited abbreviations: seeking to educate, not enforce. PMID- 22919108 TI - Potential risks associated with medication administration, as identified by simple tools and observations. PMID- 22919109 TI - [Not Available]. PMID- 22919110 TI - Practice spotlight: pharmacists in a centre for ambulatory care education. PMID- 22919111 TI - Should there be a cap on the number of patients under the care of a clinical pharmacist? PMID- 22919112 TI - Completing a residency project involving 2 residents. PMID- 22919113 TI - "Just explore things". PMID- 22919114 TI - DeMO: An Ontology for Discrete-event Modeling and Simulation. AB - Several fields have created ontologies for their subdomains. For example, the biological sciences have developed extensive ontologies such as the Gene Ontology, which is considered a great success. Ontologies could provide similar advantages to the Modeling and Simulation community. They provide a way to establish common vocabularies and capture knowledge about a particular domain with community-wide agreement. Ontologies can support significantly improved (semantic) search and browsing, integration of heterogeneous information sources, and improved knowledge discovery capabilities. This paper discusses the design and development of an ontology for Modeling and Simulation called the Discrete event Modeling Ontology (DeMO), and it presents prototype applications that demonstrate various uses and benefits that such an ontology may provide to the Modeling and Simulation community. PMID- 22919115 TI - PRACTICAL PREPARATION OF RESVERATROL 3-O-beta-D-GLUCURONIDE. AB - A practical synthesis of resveratrol 3-O-beta-D-glucuronide, suitable for preparation of large quantities, was developed using selective deacetylation of resveratrol triacetate with ammonium acetate. A simplified procedure for large scale preparation of resveratrol is also reported. PMID- 22919116 TI - Enantioselective synthesis of C2-functionalized, N-protected morpholines and orthogonally N,N'-protected piperazines via organocatalysis. AB - In this Letter, we describe a novel three-step, one-pot procedure for the enantioselective synthesis of N-benzyl protected morpholines and orthogonally N,N'-protected piperazines with chiral alkyl groups installed at the C2 position of each heterocyclic core via organocatalysis. This methodology allows for the rapid preparation of functionalized morpholines and piperazines that are not readily accessible through any other chemistry in good to excellent % ee (55-98% ee). PMID- 22919117 TI - Quantitative Genetics, Pleiotropy, and Morphological Integration in the Dentition of Papio hamadryas. AB - Variation in the mammalian dentition is highly informative of adaptations and evolutionary relationships, and consequently has been the focus of considerable research. Much of the current research exploring the genetic underpinnings of dental variation can trace its roots to Olson and Miller's 1958 book Morphological Integration. These authors explored patterns of correlation in the post-canine dentitions of the owl monkey and Hyopsodus, an extinct condylarth from the Eocene. Their results were difficult to interpret, as was even noted by the authors, due to a lack of genetic information through which to view the patterns of correlation. Following in the spirit of Olson and Miller's research, we present a quantitative genetic analysis of dental variation in a pedigreed population of baboons. We identify patterns of genetic correlations that provide insight to the genetic architecture of the baboon dentition. This genetic architecture indicates the presence of at least three modules: an incisor module that is genetically independent of the post-canine dentition, and a premolar module that demonstrates incomplete pleiotropy with the molar module. We then compare this matrix of genetic correlations to matrices of phenotypic correlations between the same measurements made on museum specimens of another baboon subspecies and the Southeast Asian colobine Presbytis. We observe moderate significant correlations between the matrices from these three primate taxa. From these observations we infer similarity in modularity and hypothesize a common pattern of genetic integration across the dental arcade in the Cercopithecoidea. PMID- 22919118 TI - Frontiers in growth and remodeling. AB - Unlike common engineering materials, living matter can autonomously respond to environmental changes. Living structures can grow stronger, weaker, larger, or smaller within months, weeks, or days as a result of a continuous microstructural turnover and renewal. Hard tissues can adapt by increasing their density and grow strong. Soft tissues can adapt by increasing their volume and grow large. For more than three decades, the mechanics community has actively contributed to understand the phenomena of growth and remodeling from a mechanistic point of view. However, to date, there is no single, unified characterization of growth, which is equally accepted by all scientists in the field. Here we shed light on the continuum modeling of growth and remodeling of living matter, and give a comprehensive overview of historical developments and trends. We provide a state of-the-art review of current research highlights, and discuss challenges and potential future directions. Using the example of volumetric growth, we illustrate how we can establish and utilize growth theories to characterize the functional adaptation of soft living matter. We anticipate this review to be the starting point for critical discussions and future research in growth and remodeling, with a potential impact on life science and medicine. PMID- 22919119 TI - Preparation and Properties of Novel Dentin Adhesives with Esterase Resistance. AB - A new methacrylate monomer, trimethylolpropane mono allyl ether dimethacrylate (TMPEDMA), was synthesized and evaluated. This branched methacrylate was designed to increase esterase-resistance when incorporated into conventional HEMA (2 hydroxyethyl methacrylate)/BisGMA (2,2-bis[4(2-hydroxy-3-methacryloyloxy propyloxy)-phenyl] propane) dental adhesives. The new adhesives, HEMA/BisGMA/TMPEDMA in a 45/30/25 (w/w) ratio were formulated with H(2)O at 0 (A0T) and 8 wt % water (A8T) and compared with control adhesives (HEMA/BisGMA, 45/55 (w/w), at 0 (A0) and 8 wt % (A8) water). Camphoroquinone (CQ), 2 (dimethylamino) ethyl methacrylate and diphenyliodonium hexafluorophosphate were used as photoinitiators. The new adhesives showed a degree of conversion comparable with the control and improved modulus and glass transition temperature (T(g)). Exposure of photopolymerized discs to porcine liver esterase for up to eight days showed that the net cumulative methacrylic acid (MAA) release in adhesives formulated with the new monomer and 8% water (A8T: 182 MUg/mL) was dramatically (P < 0.05) decreased in comparison to the control (A8: 361.6 MUg/mL). The results demonstrate that adhesives made with the new monomer and cured in water to simulate wet bonding are more resistant to esterase than conventional HEMA/BisGMA adhesive. PMID- 22919120 TI - Specifying the Links Between Household Chaos and Preschool Children's Development. AB - Household chaos has been linked to poorer cognitive, behavioral, and self regulatory outcomes in young children, but the mechanisms responsible remain largely unknown. Using a diverse sample of families in Chicago, the present study tests for the independent contributions made by five indicators of household chaos: noise, crowding, family instability, lack of routine, and television usually on. Chaos was measured at age 2; outcomes measured at age 5 tap receptive vocabulary, attention and behavior problems, and effortful control. Results show that controlling for all other measures of chaos, children with a lack of routine scored lower on receptive vocabulary and delayed gratification, while children whose television was generally on scored higher on aggression and attention problems. The provision of learning materials mediated a small part of the association between television and receptive vocabulary. Family instability, crowding, and noise did not predict any outcomes once other measures of chaos were controlled. PMID- 22919123 TI - A Hierarchy of 21st Birthday Drinking Norms. PMID- 22919121 TI - Laparoscopy in Liver Transplantation: The Future has Arrived. AB - In the last two decades, laparoscopy has revolutionized the field of surgery. Many procedures previously performed with an open access are now routinely carried out with the laparoscopic approach. Several advantages are associated with laparoscopic surgery compared to open procedures: reduced pain due to smaller incisions and hemorrhaging, shorter hospital length of stay, and a lower incidence of wound infections. Liver transplantation (LT) brought a radical change in life expectancy of patients with hepatic end-stage disease. Today, LT represents the standard of care for more than fifty hepatic pathologies, with excellent results in terms of survival. Surely, with laparoscopy and LT being one of the most continuously evolving challenges in medicine, their recent combination has represented an astonishing scientific progress. The intent of the present paper is to underline the current role of diagnostic and therapeutic laparoscopy in patients waiting for LT, in the living donor LT and in LT recipients. PMID- 22919122 TI - Review of Long-Wavelength Optical and NIR Imaging Materials: Contrast Agents, Fluorophores and Multifunctional Nano Carriers. AB - The importance of long wavelength and near infra-red (NIR) imaging has dramatically increased due to the desire to perform whole animal and deep tissue imaging. The adoption of NIR imaging is also growing rapidly due to the availability of targeted biological agents for diagnosis and basic medical research that can be imaged in vivo. The wavelength range of 650-1450 nm falls in the region of the spectrum with the lowest absorption in tissue and therefore enables the deepest tissue penetration. This is the wavelength range we focus on with this review. To operate effectively the imaging agents must both be excited and must emit in this long-wavelength window. We review the agents used both for imaging by absorption, scattering, and excitation (such as fluorescence). Imaging agents comprise both aqueous soluble and insoluble species, both organic and inorganic, and unimolecular and supramolecular constructs. The interest in multi modal imaging, which involves delivery of actives, targeting, and imaging, requires nanocarriers or supramolecular assemblies. Nanoparticles for diagnostics also have advantages in increasing circulation time and increased imaging brightness relative to single molecule imaging agents. This has led to rapid advances in nanocarriers for long-wavelength, NIR imaging. PMID- 22919125 TI - Should Mr. Aamir Khan apologize - Medical professionalism in crisis. PMID- 22919124 TI - Cathepsin G induces cell aggregation of human breast cancer MCF-7 cells via a 2 step mechanism: catalytic site-independent binding to the cell surface and enzymatic activity-dependent induction of the cell aggregation. AB - Neutrophils often invade various tumor tissues and affect tumor progression and metastasis. Cathepsin G (CG) is a serine protease secreted from activated neutrophils. Previously, we have shown that CG induces the formation of E cadherin-mediated multicellular spheroids of human breast cancer MCF-7 cells; however, the molecular mechanisms involved in this process are unknown. In this study, we investigated whether CG required its enzymatic activity to induce MCF-7 cell aggregation. The cell aggregation-inducing activity of CG was inhibited by pretreatment of CG with the serine protease inhibitors chymostatin and phenylmethylsulfonyl fluoride. In addition, an enzymatically inactive S195G (chymotrypsinogen numbering) CG did not induce cell aggregation. Furthermore, CG specifically bound to the cell surface of MCF-7 cells via a catalytic site independent mechanism because the binding was not affected by pretreatment of CG with serine protease inhibitors, and cell surface binding was also detected with S195G CG. Therefore, we propose that the CG-induced aggregation of MCF-7 cells occurs via a 2-step process, in which CG binds to the cell surface, independently of its catalytic site, and then induces cell aggregation, which is dependent on its enzymatic activity. PMID- 22919126 TI - Testosterone replacement and prostate cancer. AB - This article is intended as a review of the available clinical data outlining the risks and benefits of testosterone (androgen) replacement therapy, specifically addressing the issue of the relationship between exogenous androgen administration and prostate cancer risk. There is controversy over whether androgen replacement is a risk factor for incident prostate cancer. Our review of current clinical information revealed that to date, no study or review has definitively shown that androgen replacement therapy is an independent risk factor for development of prostate cancer. Androgen administration seems to be beneficial in decreasing fatal cardiovascular events, body fat mass, and insulin resistance. Overall, the current clinical data seems to suggest that androgen replacement is an appropriate therapeutic option for men with symptomatic hypogonadism provided that patients continue to receive regular prostate screenings. PMID- 22919129 TI - New paradigms of urinary tract infection. PMID- 22919128 TI - New paradigms of urinary tract infections: Implications for patient management. AB - Urinary tract infections (UTIs) represent one of the most commonly acquired diseases among the general population as well as hospital in-patients, yet remain difficult to effectively and consistently treat. High rates of recurrence, anatomic abnormalities, and functional disturbances of the urinary tract all contribute to the difficulty in management of these infections. However, recent advances reveal important molecular and genetic factors that contribute to bacterial invasion and persistence in the urinary tract, particularly for the most common causative agent, uropathogenic Escherichia coli. Recent studies using animal models of experimental UTIs have recently provided mechanistic insight into the clinical observations that question the effectiveness of antibiotic therapy in treatment. Ultimately, continuing research will be necessary to identify the best targets for effective treatment of this costly and widespread infectious disease. PMID- 22919127 TI - Mesh complications in female pelvic floor reconstructive surgery and their management: A systematic review. AB - We reviewed the incidence, predisposing factors, presentation and management of complications related to the use of synthetic mesh in the management of stress urinary incontinence and pelvic organ prolapse repair. Immediate complications, such as bleeding, hematoma, injury to adjacent organs during placement of mesh and complication of voiding dysfunction are not discussed in this review, since they are primarily related to technique. A PubMed search of related articles published in English was done from April 2008 to March 2011. Key words used were urinary incontinence, mesh, complications, midurethral sling, anterior prolapse, anterior vaginal repair, pelvic organ prolapse, transvaginal mesh, vault prolapse, midurethral slings, female stress urinary incontinence, mesh erosion, vaginal mesh complications, and posterior vaginal wall prolapse. Since there were very few articles dealing with the management of mesh-related complications in the period covered in the search we extended the search from January 2005 onwards. Articles were selected to fit the scope of the topic. In addition, landmark publications and Manufacturer and User Facility Device Experience (MAUDE) data (FDA website) were included on the present topic. A total of 170 articles were identified. The use of synthetic mesh in sub-urethral sling procedures is now considered the standard for the surgical management of stress urinary incontinence. Synthetic mesh is being increasingly used in the management of pelvic organ prolapse. While the incidence of extrusion and erosion with mid urethral sling is low, the extrusion rate in prolapse repair is somewhat higher and the use in posterior compartment remains controversial. When used through the abdominal approach the extrusion and erosion rates are lower. The management of mesh complication is an individualized approach. The choice of the technique should be based on the type of mesh complication, location of the extrusion and/or erosion, its magnitude, severity and potential recurrence of pelvic floor defect. PMID- 22919130 TI - Perioperative outcome of initial 190 cases of robot-assisted laparoscopic radical prostatectomy - A single-center experience. AB - OBJECTIVE: To analyze the perioperative outcome of the first 190 cases of robot assisted laparoscopic radical prostatectomy performed at our center from July 2006 to December 2010. MATERIALS AND METHODS: Operative and recovery data for men with localized prostate cancer undergoing robot-assisted radical prostatectomy at our center were reviewed. All surgeries were performed using the 4-arm da Vinci-S surgical robot. Preoperative data included age, body mass index (BMI), prostate specific antigen (PSA) level, prostate weight, biopsy Gleason score and TNM staging, while operative and recovery data included total operative time, estimated blood loss, complications, hospital stay and catheter time. These parameters were evaluated for the safety and efficacy of this procedure in our center. RESULTS: The mean age of our patients was 65 +/- 1.2 years. The mean BMI was 25.20 +/- 2.88 and the median PSA was 14.8 ng/ml. Majority of our patients belonged to clinical stage T2 (51.58%). The mean total operative time was 166.44 +/- 11.5 min. Six patients required conversion to open procedure and there was one rectal injury. The median estimated blood loss was 302 +/- 14.45 ml and the median duration of hospital stay was 4 days. The overall margin positivity rate was 12.63%. CONCLUSION: Despite our limited robotic surgery experience, our perioperative outcome and complication rate is comparable to most contemporary series. Robot-assisted laparoscopic prostatectomy (RALP) is easy to learn and provides the patient with the benefits of minimally invasive surgery with minimal perioperative morbidity. PMID- 22919131 TI - Virtual cystoscopy (pneumo-cystoscopy)-Its utility in the prospective evaluation of bladder tumor. AB - AIM: To evaluate the role of virtual cystoscopy (VC) comparing it with cystopanendoscopy (CPE) for detecting bladder tumor(s). MATERIAL AND METHODS: Ethical clearance was obtained from the Institutional ethics committee. After an informed consent 30 patients fulfilling the inclusion criteria were enrolled in the prospective non-randomized clinical study and were evaluated as per protocol with VC performed by a qualified radiologist who was blinded to the findings of CPE performed by a qualified urologist. The results so obtained were analyzed using appropriate statistical tools. RESULTS: The mean age of the patients was 56 years. Sensitivity of VC in detecting bladder lesions was 92%. However, when axial images were also interpreted along with VC, the sensitivity increased to 96% for detecting bladder lesions. The specificity of VC with axial CT was 40% in respect of detecting bladder lesions. VC with axial CT was 85.7% sensitive in identifying multiple bladder tumors. There were no complications on account of performing VC. Minor problems were encountered with VC and CPE in 16.7% and 13.3% patients respectively. CONCLUSIONS: VC with axial CT is 96% sensitive in detecting bladder lesions and 85.7% sensitive in detecting the multiplicity of the tumors. VC may be a useful complementary diagnostic tool for the workup of select patients with suspected bladder lesions. However, larger randomized controlled studies are needed to better define the precise clinical and diagnostic role of VC in routine practice. SETTINGS AND DESIGN: Prospective Clinical Comparative Non Randomized Clinical Study. PMID- 22919132 TI - Is port site metastasis a result of systemic involvement? AB - AIMS: Port site metastasis (PSM) is an unwelcome consequence of laparoscopy for oncological procedures with uncertain etiology. We present the clinical evidence to prove that PSM is likely to be due to the hematogenous spread of tumor cells. MATERIALS AND METHODS: Six cases of port site metastasis, four following laparoscopic radical nephrectomy for localized renal cell carcinoma (RCC), one after laparoscopic radical prostatectomy done in two patients and one after laparoscopic partial cystectomy for tumor at bladder dome done in two were studied. One case of metastatic RCC with bilateral gluteal masses and two cases of open radical nephrectomy, with recurrence at the drain and incision site were also studied. RESULTS: During the median follow up of 59 months (range 24-120), 4/136 patients with RCC (1.47%) developed port site metastasis between 7-36 months after surgery. All six cases of PSM had advanced disease and recurrences at other sites, that is, peritoneum, omentum, bones, and lungs. None of the patients had isolated PSM. One patient of metastatic RCC, who did not have any intervention but repeated intramuscular injections of analgesics-developed bilateral gluteal masses, confirmed to be RCC on fine needle aspiration cytology. Two patients had metastasis at the incision site (one at the drain site) with distance, including cutaneous metastases. CONCLUSIONS: Port site metastasis did not develop in isolation. There could be a likely existence of circulating tumor cells at the time of surgical trauma of penetrating nature, that is, port site or injection site, which manifest in some patients depending upon their immune response. PMID- 22919133 TI - Clinicopathological spectrum and the outcome of treatment of upper tract transitional cell carcinoma. AB - INTRODUCTION: Disease spectrum of upper tract transitional cell carcinoma (TCC) in Indian patients is not known. Herein, we present data on clinical presentation, pathological characteristics, and the outcome of treatment of upper tract TCC. MATERIALS AND METHODS: Clinicopathological data of patients who were diagnosed for upper tract TCC between January 2000 and January 2010 were collected from the hospital information system and case records. Preoperative diagnosis was based on contrast-enhanced computerized tomography of the whole abdomen and urine cytology. Cross tab and logistic regression analysis was done on the effect of various clinicopathological characteristics on the outcome and cancer-specific and recurrence survival were derived. RESULTS: There were total 40 patients, 35 (87.5%) of them were male. The mean age was 62.7 +/- 7.9 years. The most common symptom was gross hematuria present in 30 (75%). Mean tumor size was 2.8 +/- 1.2 cm. Median duration of follow up was 36 (12 to 100) months. Laparoscopic nephroureterectomy was done in 27 patients along with bladder cuff excision and seven patients underwent open surgery. Thirty two (88.8%) patients had invasive T stage and high-grade lesions were seen in 24 (66.6%). Lymphovascular invasion was found only in one case and necrosis in 30 (83.3%). Necrosis was found to be the poor prognostic factor. Five-year recurrence-free and cancer-specific survivals were 36.33% and 26%, respectively. CONCLUSION: Patients with upper tract TCC present very late with a high-stage disease and a very low 5-year cancer-specific and recurrence-free survivals. PMID- 22919134 TI - Clinical outcomes of surgical treatment and longitudinal non-surgical observation of patients with subclinical Cushing's syndrome and nonfunctioning adrenocortical adenoma. AB - AIMS: To investigate the outcomes of the surgical management and longitudinal assessment of patients with subclinical Cushing's syndrome (SCS) and nonfunctioning adrenocortical adenoma (NFA). MATERIALS AND METHODS: Between the years 1995 and 2008, 73 patients with asymptomatic adrenocortical adenoma were enrolled. They were informed of the risks and benefits of adrenalectomy and conservative management, and then chose the treatment. RESULTS: SCS was observed in 13 patients (17.8%) and NFA in 60 patients (82.2%). Tumor size in SCS was significantly larger than that in NFA (34.6 +/- 9.7 mm vs. 24.5 +/- 8.0 mm in diameter, P=0.001). Of the SCS patients, 7 also suffered from hypertension (HT), 2 from diabetes mellitus (DM) and 3 from hyperlipidemia (HL). After adrenalectomy, the insulin dose could be reduced in 2 (100%) patients with DM, in 5 (71.4%) of those with HT and in 2 (66.7%) of those with HL. In the NFA surveillance group, 1 (2.6%) case developed into SCS 3 years after the initial presentation and an increase in size of the tumor was observed in 1 (2.6%), with a mean follow-up of 51.2 months. CONCLUSIONS: Surgical resection may be beneficial for the control of SCS and is likely to provide improvement of concomitant HT, DM and HL. Although NFA can be managed conservatively, its size and hormonal activities may change longitudinally. Thus, long-term follow-up is necessary for NFA. PMID- 22919135 TI - Assessment of bio-safety of low-cost polyurethane urologic stents used in developing countries. AB - BACKGROUND: Ureteral stents, despite their ubiquitous use, have not been evaluated for their safety and strength after removal from the patient. While literature is available from the industry with regards to manufacturing and specifications of stents, what happens to a stent after it is inserted into the body, still needs to be explored. MATERIALS AND METHODS: We conducted a methodical study of 153 consecutive patients with urological problems who were stented with inexpensive polyurethane stents. Once removed from the patients, the stents were analyzed for breakload, tensile strength, elongation, pH, decomposition temperature, residue as well as diameter change. RESULTS: There was no significant change in the physical and mechanical properties of the stent after clinical use and the variance was within the acceptable range of biomaterials. There was minimal leaching of material and color change in all stents. CONCLUSION: The cheap polyurethane stents were found to be safe for use in patients, for the short time periods of in situ stenting. The degradation of physical and chemical properties of the stent was not significant. Thus it can be safely said that the stents currently in widespread use are cost-effective and physically safe for short spans of time. PMID- 22919136 TI - Radical cystectomy in octogenarians. AB - This retrospective study evaluates the morbidity and outcome of cystectomy and urinary diversion in octogenarians with invasive bladder cancer. Records of all patients older than 80 years who underwent cystectomy during the last 10 years were analyzed retrospectively. Among 565 cystectomies, 11(< 2%) patients were identified and evaluated for intraoperative and postoperative complications and mortality post surgery. The median age was 82 years. One female and ten male patients were selected. Eight patients were hypertensive, three were diabetic, one had coronary artery disease, two had chronic lung disease and one had depression. Seven patients presented with hematuria, two had lower urinary tract symptoms and two presented with renal failure who were optimized for renal function. All patients had ileal conduit as the form of urinary diversion. Simultaneous urethrectomy was done in two patients. Median surgical time was 5 h. Median hospital stay after surgery was 10 days. Four patients had pneumonitis and one patient developed hemiplegia, but all patients were eventually discharged. One patient expired due to stent septicemia within one month after discharge. Follow-up ranged from four months to five years. Three patients expired three years after surgery-one due to disease recurrence and the other two due to unrelated cause. One patient was lost to follow-up and six patients are doing well. Our results support the use of cystectomy in octogenarians with invasive bladder cancer, which has acceptable morbidity and mortality, and offers the best chance for sustained disease-free quality survival. PMID- 22919137 TI - Incomplete transverse vesical septum: An unusual congenital anomaly. AB - A rare case of incomplete transverse vesical septum with urinary tract tuberculosis is being reported. A 52-year-old male presented with lower urinary tract and systemic symptoms. On investigation he had anemia, leucocytosis, and high serum creatinine. On cystopanendoscopy, there was a transverse ledge of tissue connecting the two lateral walls of the bladder approximately 4 cm proximal to the bladder neck dividing the caudal vesical cavity into anterior and posterior parts. Also, the left ureteric orifice had double barrel look. To our knowledge this is the first ever reported case of incomplete transverse vesical septum. PMID- 22919139 TI - Hepatorenal bypass using autogenous, free internal iliac artery graft: An attractive alternative to revascularize the right kidney in Takayasu's disease. AB - Nonspecific aortoarteritis or Takayasu's disease (TD) is a chronic pan endarteritis of unknown origin involving the aorta and its major branches affecting young adults especially women. The disease is more common in eastern Asian countries. Hypertension in these patients generally reflects as renal artery stenosis, which is seen in 28-75% of patients. Surgical revascularization is occasionally needed in patients with failed medical management or endovascular interventions. We report two cases of Takayasu's arteritis in young women where renal revascularization was done using free internal iliac artery hepatorenal bypass graft with excellent control of hypertension in the postoperative period. PMID- 22919138 TI - Primary diffuse large B-cell lymphoma of the corpora cavernosa presented as a perineal mass. AB - Primary male genital lymphomas may appear rarely in testis, and exceptionally in the penis and prostate, but there is not previous evidence of a lymphoma arising from the corpora cavernosa. We report the first case in the literature of a primary diffuse cell B lymphoma of the corpora cavernosa presented with low urinary tract symptoms, perineal pain and palpable mass. Diagnosis was based on trucut biopsy, histopathological studies and computed tomographic images. PMID- 22919140 TI - Incidental solid renal mass in a cadaveric donor kidney. AB - The number of patients living with end-stage renal disease (ESRD) is increasing in our country and demand for renal grafts is ever increasing. Cadaver renal transplantation is being established as a viable supplement to live transplantation. We present a case where a mass lesion was encountered in the donor kidney from a cadaver. Enucleation of the lesion was done and we proceeded with the grafting. Histopathological examination showed a 'Renomedullary interstitial cell tumour', a rare benign lesion. Post transplant, the renal function recovered well and the patient is asymptomatic. Such incidental renal masses present an ethical dilemma to the operating surgeon. PMID- 22919141 TI - Xanthogranulomatous prostatitis: Rare presentation of rare disease. AB - Granulomatous inflammation of the prostate is a rare type of inflammation of the prostate. It is of various types, with the non-specific type of granulomatous inflammation being the most common. Xanthogranulomatous prostatitis is a rare type of granulomatous prostatitis of which very few cases have been reported. Histologically it is characterized by the presence of pale-looking foamy macrophages. It can be an incidental finding after transurethral resection of the prostate (TURP), although it may mimic prostatic malignancy clinically, biochemically, and rarely histologically. We report a rare case of xanthogranulomatous prostatitis which presented as a prostatic abscess, a presentation never reported in literature so far. The patient was managed with TURP. PMID- 22919142 TI - Mullerianosis of the urinary bladder. AB - Mullerianosis of the urinary bladder is a rare and morphologically complex tumor like lesion, composed of several types of mullerian lesions like endometriosis, endocervicosis, and endosalpingiosis. This disease occurs in women of reproductive age group. Implantative and metaplastic origins have been suggested in the pathogenesis. PMID- 22919143 TI - Renal dedifferentiated liposarcoma with intra-caval tumor thrombus: A rare case. AB - Combined penoscrotal incarceration is rarely reported in the literature. It is a urological emergency. Depending on the nature of the constricting object, duration of constriction, and with no defined treatment methods, inventiveness is usually required in removing difficult objects. This is a report of a penoscrotal incarceration by four closed steel rings, treated in Northern Ireland with a few minor points reiterated. PMID- 22919144 TI - Testicular microlithiasis in two boys with a chromosomal abnormality. AB - A nine and 13-year-old boy, previously diagnosed with 18q syndrome and an 11q deletion, respectively were diagnosed with testicular microlithiasis (TM). Both cases demonstrate that TM occurs in patients with various chromosomal abnormalities. PMID- 22919145 TI - Penoscrotal incarceration, four rings, and estate department bolt to the rescue. AB - Combined penoscrotal incarceration is rarely reported in the literature. It is a urological emergency. Depending on the nature of the constricting object, duration of constriction, and with no defined treatment methods, inventiveness is usually required in removing difficult objects. This is a report of a penoscrotal incarceration by four closed steel rings, treated in Northern Ireland with a few minor points reiterated. PMID- 22919146 TI - Female urethral diverticulum presenting with acute urinary retention: Reporting the largest diverticulum with review of literature. AB - Female urethral diverticulum is a rare entity with diverse spectrum of clinical manifestations. It is a very rare cause of bladder outlet obstruction and should be considered as a differential diagnosis in females presenting with acute urinary retention associated with a vaginal mass. Strong clinical suspicion combined with thorough physical examination and focused radiological investigations are vital for its diagnosis. Herein we report a case of giant urethral diverticulum presenting with acute urinary retention in a young female. It was managed by excision and urethral closure, and is the largest urethral diverticulum reported till date in the literature. PMID- 22919147 TI - Lower urinary tract symptoms and prostatic calculi: A rare presentation of alkaptonuria. AB - Alkaptonuria is a rare tyrosine metabolic disorder. A deficiency of homogentisic acid oxidase leads to accumulation of homogentisic acid in the body. Dark-colored urine, cutaneous pigmentations and musculoskeletal deformities are characteristic features. Storage and voiding lower urinary tract symptoms due to prostatic calculi is a rare presentation. PMID- 22919148 TI - False urethral anastomosis. AB - We present images of three cases with false urethral anastomosis following urethroplasty. The likely causes are inadequate posterior urethral dissection and blind use of Hey Grove dilator. We recommend use of antegrade flexible cystoscopy to prevent this complication. PMID- 22919149 TI - Primary borderline mucinous neoplasm of the testis: A case report and literature review. AB - Testicular/paratesticular neoplasms morphologically resembling surface epithelial tumors of ovarian type are rare neoplasms. The criteria for the diagnosis and nomenclature of these tumors parallels those used for ovarian homologues. Pathologists and urologists need to be wary of this uncommon entity, excluding metastatic mucinous adenocarcinoma and herniation of mucinous tumors into paratestis/scrotal sac by careful clinicopathological correlation. Herein, we present the first case of borderline mucinous tumor of testis to be reported from India. PMID- 22919150 TI - Imaging studies for non-palpable testis: Are they at all required? AB - Undescended testis is one of the common surgical disorders in childhood and twenty percent of the undescended testes are nonpalpable. Surgical management is required in almost all cases for the repositioning or removal of the undescended testes and early intervention is preferred for optimal outcome. Use of imaging studies for accurate preoperative localisation of the nonpalpable testis is a wide prevalent practice. However, available evidences have questioned the need of such studies. PMID- 22919151 TI - Laparoscopic en bloc kidney transplantation. PMID- 22919152 TI - Robotic-assisted simple prostatectomy with complete urethrovesical reconstruction. PMID- 22919153 TI - Robotic-assisted inguinal lymph node dissection - Initial experience. PMID- 22919154 TI - A positive magnetic resonance spectroscopic imaging with negative initial biopsy may predict future detection of prostate cancer. AB - Current diagnostic modalities for early prostate cancer (PCa) lack sufficient sensitivity and specificity. Magnetic resonance spectroscopic imaging (MRSI) detects biochemical changes in tissues that may predate histological changes that can be diagnosed on a biopsy. Men with MRSI suggestive of malignancy but negative biopsy may thus be harboring cancer that manifests at a later date. We report the first case in our cohort of men with positive MRSI but negative initial biopsy who, 6 years after the initial MRSI, were detected to have PCa despite a "normal" prostate specific antigen (<4.0 ng/ml). PMID- 22919155 TI - Lung India: 30 years of my association. PMID- 22919156 TI - Down the memory lane: Lung India three decades. PMID- 22919157 TI - Price and consumption of tobacco. AB - BACKGROUND: It is thought that price increase in tobacco products leads to reduced consumption. Though many studies have substantiated this concept, it has not been well studied in India. Recently, price of tobacco products was increased due to ban on plastic sachets of chewing tobacco and increased tax in Rajasthan. This study was designed to evaluate the effect of price rise on overall consumption of tobacco in Jaipur city, Rajasthan. MATERIALS AND METHODS: This study was carried out in Jaipur city. Two-staged stratified sampling was used. In the first phase of study, cost and consumption of various tobacco products in the months of February and April were enquired from 25 retail tobacco shops. In the second phase, tobacco consumption was enquired from 20 consecutive consumers purchasing any tobacco product from all the above retail tobacco shops. The data were statistically analyzed using descriptive statistics and paired "t" test. RESULTS: The comparison of prices of tobacco products between February and April revealed that the price of cigarette, bidi, and chewing tobacco has increased by 19%, 21%, and 68%, respectively. Average decrease in sales of cigarettes, bidi, and chewing tobacco at shops included in the study were 14%, 23%, and 38%, respectively. The consumers purchasing tobacco also reported decreased consumption. Chewing tobacco showed the maximum reduction (21%). Consumption of cigarette and bidi has also reduced by 15% and 13%, respectively. CONCLUSION: It may be concluded that reduction in consumption is associated with increased price of tobacco products. Reduced consumption is comparative to the magnitude of price increase. PMID- 22919158 TI - Use of cotinine urinalysis to verify self-reported tobacco use among male psychiatric out-patients. AB - CONTEXT: There is a complex and significant correlation between respiratory disorders and psychiatric conditions. Reliability of self-reported tobacco use has been questioned in recent times. AIMS: The current study aims at assessment of accuracy of self-reported tobacco use (both smoked and smokeless) among psychiatric out-patients. SETTINGS AND DESIGN: We recruited 131 consecutive subjects from the out-patient psychiatry department of a tertiary care hospital. MATERIALS AND METHODS: Male patients meeting the study criteria were approached for participation in the study. They were asked about their recent tobacco use history. Those reporting recent use were assessed for severity of dependence using Fagerstrom Test for Nicotine Dependence (FTND)-smoking and FTND-smokeless scales. Quantitative urine cotinine analysis was performed using the Enzyme Linked Immunesorbant Assay (ELISA) method. Based on this method, a (50 ng/ml) cut off score for urinary cotinine level for tobacco use was set. STATISTICAL ANALYSIS USED: Concordance between the self-report of tobacco use and urinary cotinine level was assessed using the Cohen's kappa. Additionally, Pearson's correlation coefficient was used to examine the correlation between the FTND smoking and FTND-smokeless scales and the urinary cotinine levels. RESULTS: The values of Cohen's kappa suggest no significant concordance between the self reported recent tobacco use and urinary cotinine levels for both smoking and smokeless tobacco forms. The discordance was present irrespective of a higher (550 ng/ml) or a lower (50 ng/ml) cut off score for a urinary cotinine level. Pearson's correlation coefficient failed to reveal any significant direct correlation between the FTND scores and urinary cotinine levels. CONCLUSIONS: It is recommended to use biological markers such as urinary cotinine levels to corroborates the information provided by the patients. PMID- 22919159 TI - Socioeconomic impact of TB on patients registered within RNTCP and their families in the year 2007 in Chennai, India. AB - BACKGROUND: Tuberculosis patients are registered in government clinics under Directly Observed Treatment Short-course (DOTS) program in Chennai city catering to 4.34 million population. With the entire country geographically covered under the DOTS program, research into socioeconomic impact of TB on patients and their households is crucial for providing comprehensive patient-friendly TB services and to document the benefits of DOTS. OBJECTIVE: To assess the social and economic impact of TB on patients registered under DOTS program and their families. MATERIALS AND METHODS: A cross-sectional study of 300 TB patients was done using a pre-coded semi-quantitative questionnaire between March and June 2007 in all the Tuberculosis Units (TUs) of Chennai city. RESULTS: Social and economic impact was perceived by 69.0% and 30.3% patients, respectively. About 24.3% suffered from both social and economic impact, while 75% patients suffered from any one form of impact. Social impact was perceived by more female patients as compared to males (80.7% vs. 62%; P < 0.001). More patients with extra pulmonary disease (44.4%) and patients belonging to joint families (40.7%) perceived economic impact (P < 0.05). CONCLUSION: After 8 years of DOTS implementation, the present study has shown that with the availability of DOTS, percentage of patients who mortgaged assets or took loans has reduced. Social impact of TB is still perceived by two-thirds of the patients (69%). Elimination or reduction of social stressors with specific, focused, and intense social support services, awareness generation, and counseling to patients and families need to be built into the program. PMID- 22919160 TI - Drug resistance profiles of Mycobacterium tuberculosis isolates to first line anti-tuberculous drugs: A five years study. AB - BACKGROUND: Drug resistance is a major problem in the treatment of tuberculosis (TB). An estimate of drug resistance is extremely important in the epidemiology and control of TB. However, an assessment of the magnitude of drug resistance in TB is not very well described globally and data remains scantier for India. In view of this, we reviewed our data over last five years. MATERIALS AND METHODS: Six hundred and seventy-three Mycobacterium tuberculosis isolates were subjected to drug susceptibility against primary anti-tuberculosis drugs by economic variant proportion method. All isolates resistant to isoniazid and rifampicin were taken as multi-drug resistant (MDR). RESULTS: Out of the 673 strains tested, 95 (14.11%) showed monoresistance, 365 (54.23%) strains were found to be resistant to more than one drug. A total of 118 (17.53%) strains were found to be resistant to all the four drugs tested. MDR was seen with 320 (47.54%) isolates. This study observed maximum resistance with rifampicin (74.4%) followed by streptomycin (70.0%), isoniazid (53.2%), and ethambutol (21.7%). CONCLUSION: While this information may not reflect true prevalence of drug resistance in the region, this may help in further planning long term surveillance studies to know the trend of drug resistance in this area. PMID- 22919161 TI - Vaccination rates for pandemic influenza among pregnant women: An early observation from Chennai, South India. AB - CONTEXT: World Health organization considers pregnancy as an important risk factor for severe illness due to pandemic influenza and recommends better vaccination coverage for them. AIMS: This study was initiated to observe the vaccination rates among pregnant women in Chennai during 2 months following the availability of influenza vaccine in the region. SETTINGS AND DESIGN: An urban community-based setting. Questionnaire-based observational study design. MATERIALS AND METHODS: Pregnant women residing in Chennai selected by simple random sampling formed the study population. The study was conducted from 15(th) to 30(th) November 2010. Each pregnant woman was interviewed using a uniform questionnaire. STATISTICAL ANALYSIS USED: Characteristics between vaccinated and unvaccinated participants were compared using the Chi-square test or the Fisher exact test for categorical variables and Student's t-test or Mann-Whitney U test for continuous variables. RESULTS: 140 pregnant women were interviewed during the study period. The mean age of study participants was 25 years (range 21-35 years). 55% were less than 26 years of age and 65% were home makers. 32% had no basic school education. Of the 29 women with co-morbidities, 15 had gestational diabetes, 13 hypertension, 7 pre-eclampsia, and 7 had bronchial asthma. Fifty eight had anemia diagnosed earlier or during current pregnancy. 32 (22.8%) were given advice to get vaccinated for pandemic influenza of which 18 (12.8%) received the vaccine. CONCLUSIONS: Observations on vaccination rates for pandemic influenza among pregnant women in Chennai, 2 months after the initiation of vaccination program is not encouraging. PMID- 22919162 TI - Assessment of pulmonary functions in obese adolescent boys. AB - BACKGROUND: Obesity is rapidly escalating in India in all age groups. School based data indicate a prevalence rate between 5.6% and 24% in children and adolescents. Adolescent obesity is associated with a greater long-term risk of hypertension and type 2 diabetes mellitus in adulthood. However, studies investigating pulmonary functions in obese adolescents are few. The present study assesses pulmonary functions in obese adolescent boys from a school in Baroda city, Gujarat. AIMS: (i) To assess the dynamic lung functions in obese adolescent boys. (ii) To determine the predominant lung function impairment associated with obesity in adolescence. MATERIALS AND METHODS: Dynamic lung functions were measured in 30 obese adolescent boys and an equal number of age-matched controls using MEDI:SPIRO software (Maestros Mediline Systems Ltd., Navi Mumbai, India). RESULTS: Forced expiratory volume in the 1(st) second (FEV(1))/forced vital capacity (FVC) and maximum voluntary ventilation (MVV) were significantly decreased in the obese group (P < 0.001). Pulmonary functions in the study population correlated negatively with various indices of obesity, viz. weight, body mass index (BMI), waist circumference, hip circumference, and waist-to-hip ratio. The strongest negative correlation was between BMI and FEV(1)/FVC (P < 0.001) and between BMI, MVV, and Forced Expiratory Flow (FEF(25-75%)) (P < 0.001). Waist-to-hip ratio in the study population correlated negatively with MVV (P < 0.01), but not with FEV(1)/FVC. CONCLUSIONS: Lung function impairment, particularly decreased MVV and reduced FEV(1)/FVC ratio, is associated with obesity in adolescence. In addition, pulmonary functions deteriorate with increasing obesity in adolescence and correlate negatively with various indices of obesity, viz. weight, BMI, waist circumference, hip circumference, and waist to-hip ratio. This study reveals another health hazard associated with obesity and highlights the need to aggressively reduce weight at a younger age. PMID- 22919163 TI - Prevalence of obstructive airway disease by spirometric indices in non-smoker subjects with IHD and HTN. AB - BACKGROUND: Recent studies have found that there is a strong association between ischemic heart disease (IHD) and hypertension (HTN) with spirometric indices. AIMS: To study the prevalence of obstructive airway disease (OAD) in non-smoker subjects with IHD and HTN and to compare them with healthy population. SETTINGS AND DESIGN: This was a prospective, case-control, and observational study. SUBJECTS AND METHODS: A total of 100 patients (cases) (n = 100) admitted in medicine department were recruited for this study. Controls (n = 100) were apparently healthy age- and sex-matched without HTN and IHD, recruited from March 2007 to July 2008. All eligible subjects were subjected to spirometric examination on a turbine-based spirometer (MIR spirolab-II) according to ATS/ERS guidelines. Forced expiratory volume/forced vital capacity (FEV(1)/FVC) ratio <70% was used to make a diagnosis of OAD. STATISTICAL ANALYSIS USED: All analyses were carried out using Statistical Software Package for Social Sciences trial version (SPSS 10 version). RESULTS: Out of 100 cases, 18 were with FEV(1)/FVC ratio <70% (OAD) and 82 had >70% FEV(1)/FVC ratio. Out of 100 controls, 2 were with FEV(1)/FVC ratio <70% (OAD) and 98 had >70% FEV(1)/FVC ratio. Eleven patients out of 66 from the case population with HTN had FEV(1)/FVC ratio <70% (Odds ratio 8.044). Prevalence of OAD in the hypertensive individuals was 16.66%. Twelve patients out of 62 from the case population with IHD had FEV(1)/FVC ratio <70% (Odds ratio of 9.333). Prevalence of OAD in the IHD individuals was 19.35%. In multiple correlation results for case population, when pulmonary function test variables were correlated with various dependant (age) and independent variables [HTN, IHD, height, weight, body mass index (BMI)], they were significantly reduced (P = 0.00017). In multivariate analysis (MANOVA), spirometric variables like FEV(1), FEV(1)/FVC%, FVC, forced expiratory flow (FEF) 25-75%, and peak expiratory flow rate (PEFR) were compared with factors like IHD, HTN, and covariates like age and BMI. We found that systolic blood pressure (SBP; P = 0.005), diastolic blood pressure (DBP; P = 0.05), height (P = 0.05), weight (P = 0.042), and IHD (P = 0.0001) were strongly associated with reduced pulmonary functions like FEV(1), FEV(1)/FVC%, and FVC. The presence of IHD and HTN were independently associated with the presence of OAD. CONCLUSIONS: This study highlights the increased prevalence of OAD amongst patients with IHD and HTN. Patients with IHD and HTN should routinely undergo inexpensive investigations like spirometry to detect the presence of underlying OAD. PMID- 22919164 TI - Efficacy and safety of oral gemifloxacin for the empirical treatment of pneumonia. AB - CONTEXT: Respiratory tract infections (RTI) are common causes of morbidity and mortality worldwide. Initial antibiotic therapy in upper and lower respiratory tract infections is usually empirical. The increasing evidence of antibacterial resistance in the pathogens commonly associated with pneumonia has raised concerns about the efficacy of currently available therapies and poses a challenge to clinicians. Gemifloxacin is a synthetic fluoroquinolone antimicrobial agent exhibiting potent activity against most Gram negative and Gram positive organisms. Hence, this study was planned to evaluate the efficacy of gemifloxacin as an empirical therapy in pneumonia. MATERIALS AND METHODS: This was an open labelled, single-arm study. Patients with clinical features of community acquired pneumonia (CAP) who fulfilled the inclusion criteria received treatment with oral gemifloxacin 320 mg once daily for 5-7 days. Once enrolled in the study, patients were treated as outpatient or as inpatient depending on clinical need. The primary efficacy was to evaluate the clinical response at the end of therapy, i.e., day 9-11 for CAP. Secondary efficacy parameters included radiological and bacteriological response at the end of therapy. Patients were evaluated three times during the entire course of treatment (Visit 1, Day 0; Visit 2, Day 2-4; Visit 3, Day 9-11) for their clinical, radiological and/or bacteriological response, as well as for safety assessment. RESULTS: A total of 105 patients received the study medication (gemifloxacin 320 mg orally). Two patients were "lost to follow-up" and one patient had to discontinue medication due to insufficient therapeutic effects. Clinical response at the end of therapy was successful in 99 (96.1%) while clinical failure was reported in 4 (3.9%) patient. As per the radiological response, 77.1% of the total cases showed improvement, 8.6% had no change, and 2.9% cases had deterioration in radiological findings. Gemifloxacin is an effective drug in the management of CAP. CONCLUSIONS: Gemifloxacin with coverage against both Gram positive and Gram negative organisms as well as atypical pathogens, with once daily oral dosing and minimum side effect is a very effective and economical choice for treating CAP empirically. PMID- 22919165 TI - Autonomic modulations in patients with bronchial asthma based on short-term heart rate variability. AB - BACKGROUND: Although enhanced cholinergic activity of asthmatics has been established early on, little heart rate variability (HRV) studies were done on asthma patients. Previous HRV studies were based on 24-hour recordings and therefore have not considered the extremely labile activity of bronchial asthma. OBJECTIVE: To evaluate the pattern of autonomic modulations in asthmatic patients based on short-term HRV studies. MATERIALS AND METHODS: The study involved 100 asthmatic patients with an age range of 20-40 years. Asthma activity was evaluated over the last month prior to patients' assessment using asthma control test (ACT). Allflow Spirometer was used for assessing pulmonary function, while Biocom 3000 electrocardiography recorder was used for studying 5-minute HRV. Data was analyzed using the Statistical Package for the Social Sciences Software. Heart rate and asthma medications were introduced as a covariate when studied variables were screened for significant correlation between measurements of asthma severity and heart rate variability indices using partial correlations. RESULTS: The level of asthma control correlate positively with both normalized low frequency (LF Norm) and the ratio of low frequency/high frequency (LF/HF) (CC = 0.302, 0.212 and P = 0.002, 0.036, respectively) and negatively with HF Norm (CC = -0.317, P = 0.001). Duration of asthma correlates positively with normalized high frequency (HF Norm) (CC = 0.235, P = 0.020) and negatively with LF Norm (CC = -0.250, P = 0.013). CONCLUSION: Poor asthma control is associated with lower HRV, depressed sympathetic and enhanced parasympathetic modulations especially in those with longer asthma duration. PMID- 22919166 TI - Tuberculosis diagnostics: Challenges and opportunities. AB - Tuberculosis (TB) has been a disease affecting almost all parts of the world since ages. Lot many efforts came in the past for improving diagnosis and treatment. Also, an effective vaccine has been sought after for long. With the emergence of resistant strains of Mycobacterium tuberculosis, the causal organisms of tuberculosis, and complexities emerging due to other associated infections and disease conditions, there is a desperate need for further research input in the field. Be it the better medication and care or better resistance management, proper diagnostics holds the key to success. It has been observed that a high burden of the disease was accompanied by resource limitations and poor research set-up. The scenario remained like this for several decades. With the refreshed vision of resourceful countries and funding agencies, funding is being provided in many areas of research in tuberculosis diagnosis and treatment. This review has been written with an aim to bring forth the limitations of available methods in the field of diagnostics and making researchers aware about the changing scenario with better funding opportunities and support. The author visualizes an enthusiasm from all over the world for the development of better modalities and urges scientists to join the struggle at this very perfect time to take the challenge and come forward with innovations in this field. PMID- 22919167 TI - The sweet lung: Chewing gummi bear aspiration. AB - Inhalation of foreign bodies, a leading cause of accidental death, is most common in preschool children. In this article we report our experience with a 5-year-old Greek girl who presented with a 24-hour history of sore throat, chest pain, and shortness of breath. Emergency bronchoscopy was performed and multiple small chewing gummi bear (HARIBO) particles impacted in the orifices of the right main bronchus and right lobar and segmentalinic bronchi were successfully removed and aspirated. Aspiration of gummi bears, which is for the first time reported, may cause a silent choking episode leading to life-threatening bronchi obstruction at multiple sites, even in children older than 4 years. PMID- 22919168 TI - Non-invasive ventilation in patients with acute lupus pneumonitis: A case report and review of literature. AB - Acute lupus pneumonitis is an uncommon but life threatening condition associated with systemic lupus erythematosus. We report the case of a young female who presented to us with acute hypoxemic respiratory failure secondary to acute lupus pneumonitis as initial presenting manifestation of lupus. She was managed with non-invasive ventilation and pulse steroids, with which she had dramatic improvement. PMID- 22919169 TI - Combined pulmonary fibrosis and emphysema in a tyre industry worker. AB - We report a case of combined pulmonary fibrosis and emphysema (CPFE) with severe pulmonary hypertension in a 46-year-old man, nonsmoker, tyre industry worker. CPFE is commonly reported to be associated with tobacco smoking. This case highlights the possible role of environmental dust exposure (talc) in the pathogenesis of the disease and confirms the clinical characteristics of CPFE described in previous studies. PMID- 22919170 TI - Pulmonary sequelae in a patient recovered from swine flu. AB - The pandemic of swine flu (H1N1) influenza spread to involve the whole world rapidly. Many patients manifested a mild clinical illness but some developed pneumonia and respiratory failure. High mortality was observed in patients with severe disease. Among survivors, studies are limited. Ground-glass opacities on a high-resolution computerized tomography scan and reduced diffusion capacity were noted after 3 months in a study. But long-term complications in patients with swine flu pneumonia have not been studied well. We are presenting an unusual case of swine flu pneumonia who developed interstitial lung disease after recovery. PMID- 22919171 TI - Bilateral acute lupus pneumonitis in a case of rhupus syndrome. AB - Rhupus syndrome, the overlap of rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE), is an extremely uncommon condition. Organ damages found due to SLE are usually mild in rhupus. Lupus pneumonitis in rhupus syndrome has not been reported worldwide. We are reporting a 23-year-old female with bilateral symmetric erosive arthritis, oral ulcer, alopecia, polyserositis, anemia, leucopenia, positive RA-factor, anti nuclear antibody (ANA) and anti ds-DNA. She presented with acute onset dyspnea, high fever, chest pain, tachycardia, tachypnea, hypoxia and respiratory alkalosis. High resolution computed tomography (HRCT)-thorax showed bilateral, basal consolidation with air bronchogram. Repeated sputum and single broncho alveolar lavage (BAL) fluid examination revealed no organism or Hemosiderin-laden macrophage. The diagnosis of rhupus was confirmed by combined manifestations of RA and SLE, and the diagnosis of acute lupus pneumonitis was established by clinico-radiological picture and by excluding other possibilities. PMID- 22919172 TI - A case of Nocardia transvalensis pneumonia in a 19-year-old cystic fibrosis patient. AB - Nocardia species is rarely encountered in cystic fibrosis (CF) patients. Its isolation usually implies colonization. Of all other Nocardia species, Nocardia transvalensis is very unusual and is clinically distinguishable because of its resistance to aminoglycosides, a standard antinocardial therapy. We report a case of N. transvalensis pulmonary infection in a CF patient. PMID- 22919173 TI - Allergic bronchopulmonary aspergillosis without asthma complicating pulmonary tuberculosis. AB - Allergic bronchopulmonary aspergillosis (ABPA) is typically associated with asthma. Presence of asthma is one of the minimal essential diagnostic criteria for ABPA. Rarely, ABPA has been described in association with other diseases without asthma. It has so far not been known to complicate pulmonary tuberculosis. We report one such case in a young lady where all other diagnostic criteria were fulfilled. The patient responded to corticosteroids and then had acute exacerbations of ABPA twice, each time requiring an increased dosage of corticosteroids as well as itraconazole and responded favorably. PMID- 22919174 TI - Tracheo-esophageal fistula: Successful palliation after failed esophageal stent. AB - The incidence of tracheo-esophageal (TO) fistula is on the rise, especially after palliative management for esophageal malignancies. We report a case of cancer of esophagus who after chemotherapy and radiotherapy developed TO fistula. Placement of an esophageal stent helped him in taking food orally, but his cough and dyspnoea continued to worsen. Fibreoptic bronchoscopy demonstrated a severely compressed trachea secondary to protrusion of esophageal stent which responded very well to an Ultraflex-covered tracheal stent and the patient achieved relief from cough and dyspnoea. PMID- 22919175 TI - Glue therapy in hemoptysis: A new technique. AB - Hemoptysis is defined as the spitting of blood derived from the lungs or bronchial tubes as a result of pulmonary or bronchial hemorrhage. There is a large chunk of patients with hemoptysis who do not respond to conservative treatment including use of cough suppressants, antibiotics, vitamin C, hemostatics, and anxiolytics. The advanced management of such a situation is bronchial artery embolization (BAE) or open thoracic surgery, which is often not possible. We have attempted a cheap, effective, and safe alternative in the form of intrabronchial instillation of glue (n-butyl cyanoacrylate) under vision with the help of a therapeutic video bronchoscope (OLYMPUS T-180). The glue is instilled through a polyethylene catheter placed through the working channel of the video bronchoscope. PMID- 22919176 TI - Spontaneous pneumomediastinum with a classical radiological sign. PMID- 22919177 TI - Isolated absence of right pulmonary artery: Radiographic and multi-detector CT demonstration. PMID- 22919178 TI - Comments on "An unusual cause of bronchial obstruction". PMID- 22919179 TI - Scientific journals: Indexation and impact factor. PMID- 22919180 TI - Comments: Pleuroscopy in undiagnosed exudative pleural effusion. PMID- 22919181 TI - Authors' reply. PMID- 22919182 TI - Comments: Other considerations about surgery in lung cancer. PMID- 22919183 TI - Authors' reply. PMID- 22919184 TI - The lungs and drug delivery. PMID- 22919185 TI - Smokeless tobacco use in pediatric population: What is the role of a Dental Surgeon in India? PMID- 22919186 TI - Publication trends of neurology articles in a biomedical journal from India. AB - BACKGROUND: The details about the research productivity in the neurology specialty from India is lacking. We analyzed the publishing trends and the research productivity of neurology-related articles in the Journal of the Association of Physicians of India (JAPI). MATERIALS AND METHODS: We carried the bibliometric analysis of articles related to neurology specialty from JAPI published between 2000 and 2011. Data were derived from the journal's website and the articles were analyzed for type (original article, case reports, etc.), disease (infection, vascular, etc.), place, and timelines for publication. RESULTS: Out of total 2977 articles published, 256 articles belong to neurology. Neurology contributed to 7--20% of the published articles per year in JAPI. Case reports (52%) constitute the majority type of articles followed by Original Articles (20%), Correspondence and Images (15% each). Infections (27%), structural disorders (19%), cerebrovascular and peripheral nervous system disorders (16% each) contribute the majority of research articles in Neurology. Mumbai (15%), Delhi (13%), and Chennai (9%) are the top three contributors followed by Lucknow and Varanasi. All types of articles took about 9--10 months for acceptance and another 4--5 months for publication. Letters to the Editor were published faster when compared to other articles (P=0.0035). CONCLUSION: Neurology specialty contributes an average 14% of articles per annum in JAPI. Infections, vascular, structural, and peripheral nervous system disorders together account for 80% of published literature with a small representation from other diseases. Mumbai and Delhi are the leading contributors toward research productivity in neurology. PMID- 22919187 TI - The split hand sign. AB - Amyotrophic Lateral sclerosis (ALS) is a disease characterized by pure motor asymmetric wasting of various muscles with associated upper motor neuron signs. The split hand sign, which is because of dissociated muscle weakness in the hands (thenar muscles disproportionately wasted as compared to the hypothenar muscles) is a useful clinical sign for bed side diagnosis of ALS. PMID- 22919188 TI - Role of magnesium sulfate in neuroprotection in acute ischemic stroke. AB - AIMS: To study the effect of intravenous magnesium sulfate infusion on clinical outcome of patients of acute stroke. MATERIALS AND METHODS: Sixty consecutive cases of acute ischemic stroke hospitalised within 24 h of an episode of stroke were taken as subjects. All subjects underwent a computed tomography head, and those found to have evidence of bleed/space-occupying lesions were excluded from the study. The subjects taken up for the study were divided into two groups of 30 subjects each. Both the groups received the standard protocol management for acute ischemic stroke. Subjects of Group 1 additionally received intravenous magnesium sulfate as initial 4 g bolus dose over 15 min followed by 16 g as slow infusion over the next 24 h. In all the subjects of the two study groups, serum magnesium levels were estimated at the time of admission (Day 0), Day 1 and Day 2 of hospitalization using an atomic absorption spectrometer. STATISTICAL ANALYSIS USED: Scandinavian stroke scores were calculated on Day 3, day of discharge and Day 28. Paired t-test was employed for comparison of stroke scores on Day 3, day of discharge and Day 28 within the same group and the unpaired t-test was used for the intergroup comparison, i.e. comparison of stroke scores of control group with corresponding stroke scores of magnesium group. RESULTS: Comparison of stroke scores on Day 3 and day of discharge, on the day of discharge and Day 28 and on Day 3 and Day 28 in the magnesium group produced a t-value of 5.000 and P <0.001, which was highly significant. However, the comparison of the mean stroke scores between the magnesium and the control groups on Day 3, day of discharge and Day 28 yielded a P-value of >0.05, which was not significant. CONCLUSIONS: The study failed to document a statistical significant stroke recovery in spite of achieving a significant rise in serum magnesium level, more than that necessary for neuroprotection, with an intravenous magnesium sulfate regime. PMID- 22919189 TI - Time course of inflammatory cytokines in acute ischemic stroke patients and their relation to inter-alfa trypsin inhibitor heavy chain 4 and outcome. AB - BACKGROUND: Biomarker for prognosis of stroke is urgently needed for the management of acute ischemic stroke (AIS) patients. OBJECTIVE: To evaluate the course of inflammatory cytokines in AIS patients and its comparison with inter alfa trypsin inhibitor heavy chain 4 (ITIH4) and outcome after AIS. MATERIALS AND METHODS: A panel of 12 inflammatory cytokines and ITIH4 were estimated in serial blood samples collected at admission, 24 h, 48 h, 72 h, 144 h and at discharge of AIS patients (n = 5). RESULTS: Out of the 12 cytokines, only interleukin (IL)-2, tumor necrosis factor-alfa (TNF-alpha), IL-10, IL-6, IL-1B and IL-8 were in the measurable range of the kit (10 pg/mL). We found high IL-2 at admission, which decreased (P < 0.05) in the follow-up samples. TNF-alpha initially increases (P < 0.05) at 24 h followed by gradual decrease (P < 0.05) after 72 h. IL-10 decreases initially (P < 0.05) till 72 h as compared with its level at admission and then increases (P < 0.05) after 144 h. Similarly, ITIH4 was down-regulated in the early 72 h followed by further increase with improvement of the patient. ITIH4 correlates with IL-10 and computed tomography scan infarct volume. Serum IL-6, IL 1B and IL-8 increased in the AIS patients, but did not show any pattern. CONCLUSIONS: Serial measurement of IL-10, IL-2 and TNF-alpha and ITIH4 may be useful for the follow-up of clinical outcome after AIS. PMID- 22919190 TI - Comparative study of thyrotoxic periodic paralysis from idiopathic hypokalemic periodic paralysis: An experience from India. AB - OBJECTIVE: There is paucity of reports on thyrotoxic periodic paralysis (TPP) from India. We report the patients with TPP and compare them with idiopathic hypokalemic periodic paralysis (IHPP). MATERIALS AND METHODS: Patients with hypokalemic periodic paralysis (HPP) treated during the past 11 years were evaluated retrospectively. Their demographic parameters, family history, clinical features, precipitating factors, severity of weakness, laboratory parameters and rapidity of recovery were recorded. The demographic, clinical and laboratory parameters of TPP and IHPP were compared. RESULTS: During the study period, we managed 52 patients with HPP; nine (17.3%) of whom had TPP and 27 (52%) had IHPP. The demographic, precipitating factors, number of attacks and severity of limb weakness were similar between the TPP and IHPP groups, except in the IHPP group, bulbar weakness was present in four and respiratory paralysis in six, needing artificial ventilation in two patients. Serum potassium was significantly lower in TPP (2.21 +/- 0.49) compared with IHPP (2.67 +/- 0.59, P = 0.04). Four patients with TPP had subclinical thyrotoxicosis and two had subclinical hyperthyroidism. Rebound hyperkalemia occurred in both TPP and IHPP (three versus eight patients). The recovery was faster in IHPP (26.7 +/- 15.4 h) compared with TPP (34.0 +/- 14.0 h), but was statistically insignificant. CONCLUSION: TPP constitutes 17.3% of HPP, and absence of clinical features of thyrotoxicosis and subclinical hyperthyroidism in TPP is not uncommon. Clinical features, demographic profile and rebound hyperkalemia are similar in both TPP and IHPP. The serum potassium level is significantly low in the TPP compared with the IHPP group. PMID- 22919191 TI - Validation of the use of the ROSIER scale in prehospital assessment of stroke. AB - AIM: To determine the utility of the Recognition of Stroke in the Emergency Room (ROSIER) scale as a stroke recognition tool among Chinese patients in the prehospital setting. MATERIALS AND METHODS: Compared with the Cincinnati Prehospital Stroke Scale (CPSS), emergency physicians prospectively used the ROSIER as a stroke recognition tool on suspected patients in the prehospital setting. And, the final discharge diagnosis of stroke or transient ischemic attack made by neurologists, after assessment and review of clinical symptomatology and brain imaging findings, was used as the reference standard for diagnosis in the study. Then, the ROSIER and the CPSS like sensitivity (Se), specificity (Sp), positive predictive value (PPV), negative predictive value (NPV), related coefficient (r) and Kappa value were calculated. RESULTS: In this study, 540 of 582 suspected stroke patients met the study criteria. The CPSS showed a diagnostic Se of 88.77% (95% confidence intervals [CI] 86.11-91.43%), Sp of 68.79% (95% CI 64.88-72.70%), PPV of 87.40% (95% CI 85.97-88.83%), NPV of 71.52% (95% CI 67.71-75.33%) and r of 0.503. Relatively, the ROSIER showed a diagnostic Se of 89.97% (95% CI 87.44-92.64%), Sp of 83.23% (95% CI 80.08 86.38%), PPV of 92.66% (95% CI 90.46-94.86%), NPV of 77.91% (95% CI 74.41-81.41%) and r of 0.584. According to the final discharge diagnosis, both the ROSIER and the CPSS were associated with the final discharge diagnosis (P < 0.05).The Kappa statistic value of the ROSIER and the CPSS were 0.718 and 0.582, respectively. However, there was no statistical significance of the positive rate between the ROSIER and the CPSS in this study (P > 0.05). CONCLUSIONS: The ROSIER is a sensitive and specific stroke recognition tool for health providers' use among Chinese patients in the prehospital setting. However, it cannot be used to confidently rule out or identify stroke as a diagnosis. Comprehensive clinical assessment and further examination on potential stroke patients are still important and cannot be replaced. When it is difficult to objectively complete the ROSIER for patients, the CPSS could replace it in the prehospital setting. PMID- 22919192 TI - Can Alberta infant motor scale and milani comparetti motor development screening test be rapid alternatives to bayley scales of infant development-II at high-risk infants. AB - PURPOSE: The main object of the present study is to assess neuromotor development of high-risk infants by using three tests, and to determine inter-test concordance and the feasibility of these tests. MATERIALS AND METHODS: One hundred and nine patients aged between 0 and 6 months and identified as "high risk infant" according to the Kliegman's criteria were enrolled to the study. Three different tests were used to assess neuromotor development of the patients: Bayley scales of infant development-II (BSID-II), Alberta infant motor scale (AIMS), and Milani Comparetti Motor Development Screening Test (MCMDST). RESULTS: Correlation analysis was performed between pure scores of BSID-II motor scale and total scores of AIMS. These two tests were highly correlated (r:0.92). Moderate concordance was found between BSID-II and AIMS (k:0.35). Slight concordance was found between BSID-II and MCMDST; and the concordance was slight again for AIMS and MCMDST (k:0.11 and k:0.16, respectively) too. CONCLUSION: AIMS has a high correlation and consistency with BSID-II and can be used with routine neurological examination as it is based on observations, has few items, and requires less time to complete. PMID- 22919193 TI - Ocular signs in Wilson disease. PMID- 22919194 TI - Bilateral Charcot arthropathy of shoulder secondary to syringomyelia: An unusual case report. AB - Neuropathic arthropathy of the shoulder is a relatively rare disorder characterized by destruction of joint secondary to loss of sensory innervation. Bilateral Charcot arthropathy is an even rarer disorder, with very few cases reported in the English literature. We herein present a case of bilateral shoulder arthropathy secondary to syringomyelia with classical clinical and radiological findings. Radiological finding on one side was of resorptive type and resorptive mixed with productive on the other side. PMID- 22919195 TI - Paraneoplastic cerebellar degeneration in Hodgkin's lymphoma. AB - Paraneoplastic cerebellar degeneration (PCD) is a rare disorder presenting typically with acute or subacute severe cerebellar ataxia. PCD is most commonly associated with small cell lung cancer followed by adenocarcinoma of breast and ovary, and Hogdkin's lymphoma. We report a case of a 54-year-old male with acute onset pancerebellar syndrome with underlying Hodgkin's lymphoma. A high index of suspicion of PCD resulted in arriving at an early diagnosis of underlying Hodgkin's disease. The patient was managed with six cycles of chemotherapy, which resulted in clinical stabilization and reversal of magnetic resonance imaging abnormalities. Antitumor therapy appears to have a significant impact on reversing PCD and hence early diagnosis and intervention for the primary remains the corner stone in stabilizing the neurological condition. PMID- 22919196 TI - Recurrent and atypical posterior reversible encephalopathy syndrome in a child with hypertension. AB - Posterior reversible encephalopathy syndrome (PRES) is a clinical and radiologic entity with typical symptoms including headache, seizures, visual disturbance, altered mental status, vomiting, nausea and focal neurologic signs. In this article, we report recurrent and atypical PRES in a child with hypertension due to end-stage renal disease (ESRD) who was on a peritoneal dialysis program for 6 months. After the second hypertension attack, PRES findings did not recover and persisted as encephalomalacia. As far as we know, this case is the first child with ESRD who developed encephalomalacia after recurrent episodes of PRES. When a patient with a history of PRES presented with new clinical and neuroradiological findings, recurrent PRES should be considered. PMID- 22919197 TI - Hip dysplasia associated with a hereditary sensorimotor polyneuropathy mimics a myopathic process. AB - Some orthopedic complications have been reported in the hereditary neuropathies. However, the association of the hip dysplasia with this category of neuropathy is rarely recognized. We present a 13-year-old boy with the progressive weakness of the lower extremities, difficulty in walking, climbing stairs, and rising from floor; a wide-based, hyper-extended and waddling gait similar to a myopathic process. Hip radiography showed dysplastic acetabulae with hip subluxation, broken Shenton's lines, and valgus femoral necks. In electrodiagnosis, there was a significant neuropathic process (absent all evoked sensory potentials, abnormal evoked motor responses, and neurogenic electeromyography) which eventually was found to be a hereditary mixed axonal and demyelinating sensorimotor polyneuropathy with concomitant hip dysplasia confirmed with thorough physical examination and the electrodiagnostic study. In patients with gait difficulties such as waddling gait mimicking a myopathic process, hereditary polyneuropathy complicated with hip dysplasia should be considered as well. PMID- 22919198 TI - Megalencephalic leukoencephalopathy with subcortical cysts in all three siblings of a non-Aggarwal Indian family. AB - Megalencephalic leukoencephalopathy with subcortical cysts (MLC) is a rare neurodegenerative disease seen mainly in the Aggarwal community in India. It is characterized by early-onset macrocephaly with mild motor developmental delay, gradual onset ataxia, spasticity, seizures and usually late onset mild cognitive deterioration. Very few familial cases of MLC have been reported in the world literature, and to the best of our knowledge, there is no published study of all three siblings affected with MLC in a same family. Here, we are reporting three siblings belonging to a non-Aggarwal Hindu family, affected with MLC, who presented with early-onset macrocephaly and gradual onset ataxia. PMID- 22919199 TI - Cryptoccocal menigitis as a primary manifestation in a patient with intestinal lymphangictasia. AB - Opportunistic infections usually occur in patients with an immunocompromised state, and can be severe. Cryptoccocal meningitis is a fatal condition if left untreated, and is usually found in such patients. We report the case of an adult patient with cryptoccocal meningitis secondary to intestinal lymphangiectasia. A 30 year old female was admitted to our hospital for meningitis. Biochemical and radiological investigations were performed. A cerebrospinal fluid latex agglutination test showed positive cryptoccocal antigen. In addition, there were features of humoral and cell mediated immunity deficiency (lymphopenia, hypoalbuminemia, hypogammaglobulinemia), with a negative human immunodeficiency virus (HIV) test by enzyme linked immunosorbent assay and polymerase chain reaction. An upper gastroduodenoscopy was performed, which showed multiple lymphangiectasias, and a biopsy confirmed the diagnosis of primary intestinal lymphangiectasia (PIL). The patient was treated with intravenous amphotericin B and oral flucytosine, and the meningitis resolved. PIL should be suspected in patients with cryptoccocal meningitis, combined with humoral and cell mediated immunity with a negative HIV test. The management issues, in addition to antifungal therapy, include nutritional supplements for the protein losing enteropathy. PMID- 22919200 TI - Rabies viral encephalitis with proable 25 year incubation period! AB - We report a case of rabies viral encephalitis in a 48-year-old male with an unusually long incubation period, historically suspected to be more than 20 years. The case was referred for histological diagnosis following alleged medical negligence to the forensic department. The histology and immunocytochemical demonstration of rabies viral antigen established the diagnosis unequivocally. The case manifested initially with hydrophobia and aggressive behavior, although he suddenly went to the bathroom and drank a small amount of water. History of dog bite 25 years back was elicited retrospectively following clinical suspicion. There was no subsequent history to suggest nonbite exposure to a rabid dog to consider recent event causing the disease, although this cannot be totally excluded. PMID- 22919201 TI - Painless orbital myositis. AB - Idiopathic orbital inflammation is the third most common orbital disease, following Graves orbitopathy and lymphoproliferative diseases. We present a 11 year old girl with 15 days history of painless diplopia. There was no history of fluctuation of symptoms, drooping of eye lids or diminished vision. She had near total restricted extra-ocular movements and mild proptosis of the right eye. There was no conjunctival injection, chemosis, or bulb pain. There was no eyelid retraction or lid lag. Rest of the neurological examination was unremarkable.Erythrocyte sedimentation rate was raised with eosinophilia. Antinuclear antibodies were positive. Liver, renal and thyroid functions were normal. Antithyroid, double stranded deoxyribonucleic acid and acetylcholine receptor antibodies were negative. Repetitive nerve stimulation was negative. Magnetic resonance imaging (MRI) of the orbit was typical of orbital myositis. The patient responded to oral steroids. Orbital myositis can present as painless diplopia. MRI of orbit is diagnostic in orbital myositis. PMID- 22919202 TI - Klinefelter's syndrome associated with progressive muscular atrophy simulating Kennedy's disease. AB - Kennedy's disease, an X-linked spinal and bulbar muscular atrophy, is characterized by loss of lower motor neurons. Mild sensory deficits, gynecomastia and infertility may be observed. Klinefelter's syndrome is a variation of sex chromosome disorder characterized by hypogonadism, gynecomastia and azoospermia, and the most frequent karyotype is XXY. A 55-year-old man who presented with slowly progressive and diffuse neurogenic muscle atrophy without bulbar or sensory symptoms. He also had Klinefelter's syndrome. Genetic study of Kennedy's disease was normal. Our patient differs from those with Kennedy's disease in the absence of bulbar and sensory symptoms. It is suggested that the X chromosome plays an important role in the biology of motor neurons. PMID- 22919203 TI - Low cholesterol as a risk factor for primary intracerebral hemorrhage: A case control study: A comment on the study. PMID- 22919204 TI - Authors' reply. PMID- 22919205 TI - Management of hydrocephalus in tuberculous meningitis. PMID- 22919206 TI - Decompression sickness in an Indian diver. PMID- 22919207 TI - Endoscopic third ventriculostomy in tuberculous meningitis needs more evidence. PMID- 22919208 TI - Brachial plexitis following bee sting. PMID- 22919209 TI - Why need for five anti-tubercular drugs in a child with CNS TB? PMID- 22919210 TI - Stem cells: Promise to cure? PMID- 22919211 TI - Evaluation of interleukin -1B (+3954) gene polymorphism in patients with chronic and aggressive periodontitis: A genetic association study. AB - BACKGROUND: IL-1 cytokines have central roles in the pathogenesis of periodontal disease. Polymorphism in the locus +3954 (C/T) of the human IL-1B gene has been shown to affect the levels of this cytokine. AIM: The aim of the present study was to investigate the association between the IL-1 B (+3954) gene polymorphism and the occurrence of different clinical forms of periodontitis. MATERIALS AND METHODS: Genomic DNA was obtained from 90 individuals and amplified using the PCR with specific primers flanking the locus +3954 of IL-1B. PCR products were submitted to restriction endonuclease digestion and analyzed by gel electrophoresis, allowing for the determination of the genotypes and detection of the polymorphism. STATISTICAL ANALYSIS: Fisher's exact test was used for comparing the frequency of genotype distributions between groups. RESULTS: The chronic periodontitis group displayed a higher percentage of T alleles (38%) when compared to the aggressive periodontitis group (20%) and to the control group (19%). CONCLUSION: Our study data states that polymorphism in the locus +3954 of IL-1B gene could be a risk factor for chronic periodontitis in a sample of Indian population of Karnataka state. PMID- 22919212 TI - Effect of locally delivered tetracycline hydrochloride as an adjunct to scaling and root planing on Hba1c, C-reactive protein, and lipid profile in type 2 diabetes: A clinico-biochemical study. AB - AIM: The aim was to assess the levels of HbA1c, C-reactive protein, and lipid profile in patients with type 2 diabetes mellitus by treating the pockets using collagen impregnated sustained release resorbable tetracycline fiber (periodontal plus AB fiber) following scaling and root planing (SRP). MATERIALS AND METHODS: A total of 40 patients with type 2 diabetes mellitus were randomly distributed into two groups receiving either SRP and tetracycline fiber or SRP alone. Patients were evaluated clinically with gingival index, plaque index, probing depth, and relative attachment level, and bio-chemically with HbA1c, C Reactive Protein, and lipid profile at baseline, 1 month, and 3 months. RESULTS: Significant reduction in all the clinical parameters was seen in the tetracycline group compared to the control group. Bio-chemical analysis also revealed similar results except for cholesterol and High density lipoprotein who did not show any significant reduction. CONCLUSION: Locally delivered tetracycline as a better treatment modality compared to SRP alone. PMID- 22919213 TI - Prevalence of areca nut chewing in the middle school-going children of Indore, India. AB - OBJECTIVES: To assess areca nut chewing habit among middle school-aged children in Indore, India. Areca nut is chewed by itself, and in various scented preparations. It is associated with carcinogenesis, foreign body aspiration in children, and oral submucous fibrosis and may aggravate asthma. MATERIALS AND METHODS: A retrospective collection of data to evaluate the prevalence of areca nut chewing among 3896 children was done. A simple random sampling was done. Children of both sexes were included in this study. RESULTS: 27.06% of the school going children (1054/3896) had areca nut chewing habit. More boys chewed areca nut than girls (2:1). 45.42% of school going children of rural area pander to areca nut chewing habit, whereas in urban area 20.09% children are indulged. Government school children are more involved in areca nut chewing habit. 81.02% of the children used sweetened and flavoured form of areca nut. The majority of the users were not aware of harmful effects that the use of areca nut might be harmful for health CONCLUSION: To diminish the use of areca nut, the Indian Government should consider limiting trade, advertising, and actively communicating its health risks to the public and should deem heavy taxes on it. PMID- 22919214 TI - A comparison of the resin tag penetration of the total etch and the self-etch dentin bonding systems in the primary teeth: An in vitro study. AB - BACKGROUND AND OBJECTIVE: Restoration of carious lesions with a strong permanent bond would be a highly desirable requisite. Ultra morphological characterization shows that observing and understanding the interfacial phenomenon and its quality would be of great importance in the selection of a dental adhesive for its use in pediatric restorative dentistry. STUDY DESIGN: Human primary molars, indicated for extraction, for reasons like caries, normal exfoliation, pathological root resorption, over-retained and serial extraction, were collected. Teeth were then equally distributed into 2 subgroups each namely B1 - Prime and Bond NT & B2 - Xeno III. RESULTS: The resin tags seen in the samples of group B2 were both qualitatively and quantitatively advanced as compared to group B1. This reveals that the quality of the penetration of the resin was better in group B2. CONCLUSION: Reduction in the technique sensitivity of any bonding system would always be a preferred factor in pediatric restorative dentistry. Thus the inclination towards the selection of adhesive system may lean towards the self etching bonding system at this juncture. PMID- 22919215 TI - Prevalence of traumatic dental injuries to the anterior teeth among three to thirteen-year-old school children of Tamilnadu. AB - CONTEXT: Dental trauma has become an important attribute of dental public health. The primary requisite before actively dealing with such problems is to describe the extent, distribution, and associated variables with the specific condition. AIMS: The aim of the present study was to assess the prevalence and distribution of traumatic dental injuries (TDI) to anterior teeth among 3 to 13 years old Chidambaram school children. SETTINGS AND DESIGN: A cross-sectional study was conducted. Data was collected through a survey form and clinical examination. MATERIALS AND METHODS: A total of 3200 school children in the age group of 3-13 years were selected from 10 schools of Chidambaram, Tamilnadu. Information concerning sex, age, cause of trauma, number of injured teeth, type of the teeth, lip competence, terminal plane relationship and the molar relationship were recorded. STATISTICAL ANALYSIS USED: The statistical software EPIINFO (Version 6.0) was used for statistical analysis. In the present study, P<=0.05 was considered as the level of significance. RESULTS: The trauma prevalence in the present study was 10.13%. Children with class I type 2 and mesial step molar relationship exhibited more number of dental injuries. Enamel fracture was the most common injury recorded. Only 3.37% of the children had undergone treatment. CONCLUSION: The high level of dental trauma and low percentage of children with trauma seeking treatment stresses the need for increased awareness in Chidambaram population. PMID- 22919216 TI - Evaluation of efficacy of commercial denture cleansing agents to reduce the fungal biofilm activity from heat polymerized denture acrylic resin: An in vitro study. AB - AIMS: To compare and evaluate Candida removing effects of three most commonly available varieties of commercial denture cleansers from heat polymerized acrylic resins. To compare and evaluate Candida lytic effects of denture cleansers. To assess the effect of time on ability of denture cleansers in reducing Candidal biofilm. MATERIALS AND METHODS: A specially designed metal mold was fabricated to obtain wax plates of uniform dimensions which were used to fabricate heat cure acrylic resin plates. A square-shaped window of dimension 15 mm and thickness of 1.5 mm was provided in metal mould to simulate thickness of denture base. All samples used in this study were prepared using this mould. Candida albicans colonies were then cultured on this acrylic resin plates by colonization assay. Yeast removing test for samples was performed using microscope and yeast lytic test was performed using photo colorimeter. RESULTS: Denture cleanser D2 showed the highest Candida removing activity when compared with cleansers D1, D3, and control solution. Denture cleansers D2 showed increased yeast lytic ability when compared with denture cleansers D1, D3, and control solution. More time span shared a definite influence on yeast lytic ability of denture cleansers. CONCLUSIONS: The effect of cleansing agents on removal of colonized yeasts particularly fungal biofilm from acrylic resins was assessed for clinical implications. The observation indicated superior performance of cleanser D2 when compared with D1 and D3 even though they all belong to same chemical group of alkaline peroxide. The increased effectiveness may be due to presence of sodium lauryl sulphate in formula of D2. PMID- 22919217 TI - Drug induced xerostomia in elderly individuals: An institutional study. AB - INTRODUCTION: With better health care facilities and nutritional levels the average life expectancy of Indian population has been on the rise over the years. Most of the geriatric population is under long-term medication. AIM: The aim of this study was to evaluate the synergistic effect of multiple xerostomia drugs. MATERIALS AND METHODS: Unstimulated saliva was measured in 60 geriatric patients, and xerostomia questionnaire and quality-of-life scale were also administered. RESULTS: There was a very highly significant reduction in the salivary flow rates of patients under multiple xerostomia-inducing drugs. CONCLUSION: The synergistic effect of the xerostomia inducing medication could be the possible factor responsible for reduced salivary flow in elderly individuals using such drugs. PMID- 22919218 TI - A comparative study of linear measurements on facial skeleton with frontal and lateral cephalogram. AB - OBJECTIVE: To compare the accuracy of linear measurements on lateral and frontal cephalograms with gold standard skull measurements. MATERIALS AND METHODS: Based on the specific criteria including reliable occlusion and condyles fitting in glenoid fossa, 15 dry human skulls were selected from a larger collection. Lateral and frontal cephalograms were taken of each skull by standardized methods. Steel ball bearings were used to identify the anatomic landmarks. Linear measurements in midsagittal plane were made on all three records. Intraclass correlation coefficients, Pearson's correlation coefficient and regression constant were calculated to assess the records simultaneously. RESULTS: The frontal cephalometric measurements showed high correlation to the direct skull measurements (Pearson's coefficient 0.943= 30% from the pre-study baseline ALT level was observed in 26 (45%) of the 58 patients, while 25 (43%) patients exhibited similar AST level reductions. The chronic hepatitis C group exhibited significant ALT and AST level reductions from 93.4 +/- 51.1 IU/L to 64.6 +/- 35.1 IU/L (P < 0.05) and from 94.2 +/- 55.5 IU/L to 67.2 +/- 35.6 IU/L (P < 0.05), respectively. A reduction of >= 30% from the pre-study baseline ALT level was observed in 20 (50%) of the 40 patients. ALT levels in both the combined ursodeoxycholic acid (UDCA) treatment and the UDCA uncombined groups were significantly lower after Misatol ME administration. MK615 protected hepatocytes from D-GalN-induced cytotoxicity in rats. Misatol ME decreased elevated ALT and AST levels in patients with liver disorders. CONCLUSION: These results suggest that MK615 and Misatol ME are promising hepatoprotective agents for patients with liver disorders. PMID- 22919244 TI - siRNA-mediated downregulation of TC21 sensitizes esophageal cancer cells to cisplatin. AB - AIM: To determine the functional significance of TC21 in esophageal squamous cell carcinoma (ESCC). METHODS: TC21 siRNA transfection was carried out using Hyperfectamine to knock down TC21, and transcripts were analyzed by reverse transcription-polymerase chain reaction and protein by Western blotting. We demonstrated the effect of TC21 downregulation of cell signaling in esophageal cancer cells by assessing the phosphorylation status of its downstream targets, phosphoinositide 3-kinase (PI3K), phosphatase and tensin homolog (PTEN), protein kinase B (pAkt), nuclear factor-kappaB (NF-kappaB) and cyclinD1 using specific antibodies. Cell survival analysis after cisplatin treatment was carried out by cell viability assay and cell cycle analysis using flow cytometry. RESULTS: TC21 knockdown in human ESCC cell line TE13 cells, showed only a marginal increase (14.2%) in cell death compared with control cells. The expressions of the signaling proteins PI3K and pAkt, transcription factor NF-kappaB, and cell cycle protein cyclin D1 were markedly decreased in response to TC21 downregulation, whereas the level of pPTEN, an antagonist of PI3K, was increased. In addition, we evaluated the potential of TC21 as a putative target for sensitizing ESCC cells to the chemotherapeutic agent cisplatin. Increased cell death (38.4%) was observed in cells treated with cisplatin after TC21 knockdown compared with cells which were treated with cisplatin alone (20% cell death). CONCLUSION: Results suggest that TC21 mediates its effects via the PI3K-Akt pathway, NF-kappaB and cyclin D1, and enhances chemoresistance in esophageal cancer cells. PMID- 22919245 TI - Double contrast-enhanced two-dimensional and three-dimensional ultrasonography for evaluation of gastric lesions. AB - AIM: To investigate the value of two-dimensional (2D) and three-dimensional (3D) double contrast-enhanced ultrasonography (DCUS) imaging for evaluation of gastric lesions. METHODS: 2D and 3D DCUS imaging with both oral and intravenous administrations of contrast agents was used to assess gastroscopiclly-confirmed gastric lesions in 46 patients with benign and malignant diseases. Initially, liquid-based ultrasound contrast agent (Xinzhang(r)) was given orally at dose of 500-600 mL for conventional ultrasound examination of the gastric lesions, and then a microbubble-based contrast agent (SonoVue) was injected intravenously at dose of 1.2-2.4 mL in bolus fashion to assess the perfusion pattern of the lesions using contrast imaging modes. The parameters derived from time-intensity curves including the arrival time (AT), time to peak (TTP), peak intensity (PI) and enhanced intensity (EI) were measured on the 2D DCUS imaging. 3D DCUS of the lesions was acquired to demonstrate the value of this imaging mode. RESULTS: There were 22 cases with benign lesions including chronic gastritis (n = 5), gastric ulcer (n = 9), gastric polyps (n = 3), gastric stromal tumors (n = 5), and 24 cases with malignant lesions including gastric cancer (n = 20), gastric cardia carcinoma (n = 3) and post-operative recurrent gastric cancer (n = 1) in the study. The oral contrast-enhanced ultrasonography (CEUS) imaging of the stomach clearly demonstrated the anatomy of the stomach and morphologic features of gastric lesions. With optimal scanning window and imaging display under oral CEUS, intravenous CEUS clearly showed the perfusion of gastric lesions with various characteristic manifestations. Both 2D and 3D DCUS images clearly demonstrated normal gastric wall as a three-layer structure, from the inside out, hyperechoic mucosa, hypoechoic muscularis and hyperechoic serosa, respectively. There were statistical significant differences of AT (8.68 +/- 2.06 vs 10.43 +/- 2.75, P = 0.017), PI (34.64 +/- 6.63 vs 29.58 +/- 8.22, P = 0.023) and EI (29.72 +/- 6.69 vs 22.66 +/- 7.01, P = 0.001) between malignant lesions and normal gastric wall. However, no differences of AT, PI and EI between benign lesions and normal gastric wall tissue were found. 3D DCUS could intuitively display morphological features and vascularities of the lesions with multiplanar and volume views. 3D DCUS imaging provided comprehensive information complementary to 2D imaging. The crater or wellhead appearances and feeding vessels as well as distorted nourishing vasculature of gastric carcinoma were better seen with 3D imaging than 2D imaging. CONCLUSION: DCUS imaging can simultaneously display the anatomic and perfusion features of gastric lesions. 3D DCUS can provide additional information to 2D DCUS for evaluation of gastric lesions. PMID- 22919246 TI - A comparison of survival and pathologic features of non-alcoholic steatohepatitis and hepatitis C virus patients with hepatocellular carcinoma. AB - AIM: To compare the clinical outcome and pathologic features of non-alcoholic steatohepatitis (NASH) patients with hepatocellular carcinoma (HCC) and hepatitic C virus (HCV) patients with HCC (another group in which HCC is commonly seen) undergoing liver transplantation. METHODS: Patients transplanted for HCV and NASH at our institution from January 2000 to April 2011 were analyzed. All explanted liver histology and pre-transplant liver biopsies were examined by two specialist liver histopathologists. Patient demographics, disease free survival, explant liver characteristics and HCC features (tumour number, cumulative tumour size, vascular invasion and differentiation) were compared between HCV and NASH liver transplant recipients. RESULTS: A total of 102 patients with NASH and 283 patients with HCV were transplanted. The incidence of HCC in NASH transplant recipients was 16.7% (17/102). The incidence of HCC in HCV transplant recipients was 22.6% (64/283). Patients with NASH-HCC were statistically older than HCV-HCC patients (P < 0.001). A significantly higher proportion of HCV-HCC patients had vascular invasion (23.4% vs 6.4%, P = 0.002) and poorly differentiated HCC (4.7% vs 0%, P < 0.001) compared to the NASH-HCC group. A trend of poorer recurrence free survival at 5 years was seen in HCV-HCC patients compared to NASH-HCC who underwent a Liver transplantation (P = 0.11). CONCLUSION: Patients transplanted for NASH-HCC appear to have less aggressive tumour features compared to those with HCV-HCC, which likely in part accounts for their improved recurrence free survival. PMID- 22919247 TI - Adjusting CA19-9 values to predict malignancy in obstructive jaundice: influence of bilirubin and C-reactive protein. AB - AIM: To find a possible relationship between inflammation and CA19-9 tumor marker by analyzing data from patients with benign jaundice (BJ) and malignant jaundice (MJ). METHODS: All patients admitted for obstructive jaundice, in the period 2005 2009, were prospectively enrolled in the study, obtaining a total of 102 patients. On admission, all patients underwent complete standard blood test examinations including C-reactive protein (CRP), bilirubin, CA19-9. Patients were considered eligible for the study when they presented obstructive jaundice confirmed by instrumental examinations and increased serum bilirubin levels (total bilirubin > 2.0 mg/dL). The standard cut-off level for CA19-9 was 32 U/mL, whereas for CRP this was 1.5 mg/L. The CA19-9 level was adjusted by dividing it by the value of serum bilirubin or by the CRP value. The patients were divided into 2 groups, MJ and BJ, and after the adjustment a comparison between the 2 groups of patients was performed. Sensitivity, specificity and positive predictive values were calculated before and after the adjustment. RESULTS: Of the 102 patients, 51 were affected by BJ and 51 by MJ. Pathologic CA19-9 levels were found in 71.7% of the patients. In the group of 51 BJ patients there were 29 (56.9%) males and 22 (43.1%) females with a median age of 66 years (range 24-96 years), whereas in the MJ group there were 24 (47%) males and 27 (53%) females, with a mean age of 70 years (range 30-92 years). Pathologic CA19-9 serum level was found in 82.3% of MJ. CRP levels were pathologic in 66.6% of the patients with BJ and in 49% with MJ. Bilirubin and CA19-9 average levels were significantly higher in MJ compared with BJ (P = 0.000 and P = 0.02), while the CRP level was significantly higher in BJ (P = 0.000). Considering a CA19-9 cut off level of 32 U/mL, 82.3% in the MJ group and 54.9% in the BJ group were positive for CA19-9 (P = 0.002). A CA19-9 cut-off of 100 U/mL increases the difference between the two groups: 35.3% in BJ and 68.6% in MJ (P = 0.0007). Adjusting the CA19-9 value by dividing it by serum bilirubin level meant that 21.5% in the BJ and 49% in the MJ group remained with a positive CA19-9 value (P = 0.003), while adjusting the CA19-9 value by dividing it by serum CRP value meant that 31.4% in the BJ group and 76.5% in the MJ group still had a positive CA19-9 value (P = 0.000004). Sensitivity, specificity, positive predictive values of CA19-9 > 32 U/mL were 82.3%, 45% and 59.1%; when the cut-off was CA19-9 > 100 U/mL they were, respectively, 68.6%, 64.7% and 66%. When the CA19-9 value was adjusted by dividing it by the bilirubin or CRP values, these became 49%, 78.4%, 69.4% and 76.5%, 68.6%, 70.9%, respectively. CONCLUSION: The present study proposes CRP as a new and useful correction factor to improve the diagnostic value of the CA19-9 tumor marker in patients with cholestatic jaundice. PMID- 22919248 TI - Intrahepatic expression of genes related to metabotropic receptors in chronic hepatitis. AB - AIM: To screen for genes related to metabotropic receptors that might be involved in the development of chronic hepatitis. METHODS: Assessment of 20 genes associated with metabotropic receptors was performed in liver specimens obtained by punch biopsy from 12 patients with autoimmune and chronic hepatitis type B and C. For this purpose, a microarray with low integrity grade and with oligonucleotide DNA probes complementary to target transcripts was used. Evaluation of gene expression was performed in relation to transcript level, correlation between samples and grouping of clinical parameters used in chronic hepatitis assessment. Clinical markers of chronic hepatitis included alanine and aspartate aminotransferase, gamma-glutamyltranspeptidase, alkaline phosphatase and cholinesterase activity, levels of iron ions, total cholesterol, triglycerides, albumin, glucose, hemoglobin, platelets, histological analysis of inflammatory and necrotic status, fibrosis according to METAVIR score, steatosis, as well as anthropometric body mass index, waist/hip index, percentage of adipose tissue and liver size in ultrasound examination. Gender, age, concomitant diseases and drugs were also taken into account. Validation of oligonucleotide microarray gene expression results was done with the use of quantitative real time polymerase chain reaction (qRT-PCR). RESULTS: The highest (0.002 < P < 0.046) expression among genes encoding main components of metabotropic receptor pathways, such as the alpha subunit of G-coupled protein, phosphoinositol dependent protein kinase or arrestin was comparable to that of angiotensinogen synthesized in the liver. Carcinogenesis suppressor genes, such as chemokine ligand 4, transcription factor early growth response protein 1 and lysophosphatidic acid receptor, were characterized by the lowest expression (0.002 < P < 0.046), while the factor potentially triggering hepatic cancer, transcription factor JUN-B, had a 20-fold higher expression. The correlation between expression of genes of protein kinases PDPK1, phosphoinositide 3-kinase and protein kinase A (Spearman's coefficient range: 0.762-0.769) confirmed a functional link between these enzymes. Gender (P = 0.0046) and inflammation severity, measured by alanine aminotransferase activity (P = 0.035), were characterized by diverse metabotropic receptor gene expression patterns. The Pearson's coefficient ranging from -0.35 to 0.99 from the results of qRT-PCR and microarray indicated that qRT-PCR had certain limitations as a validation tool for oligonucleotide microarray studies. CONCLUSION: A microarray-based analysis of hepatocyte metabotropic G-protein-related gene expression can reveal the molecular basis of chronic hepatitis. PMID- 22919249 TI - Growth inhibitory effects of Phyllanthus niruri extracts in combination with cisplatin on cancer cell lines. AB - AIM: To investigate the cytotoxic effects of spray-dried extracts of Phyllanthus niruri in combination with cisplatin on two cancer cell lines. METHODS: Colorectal carcinoma (HT29) and human hepatocellular carcinoma (HepG2) cells were treated with spray-dried extracts of Phyllanthus niruri (SDEPN) either alone or in combination with cisplatin at different concentrations (0.5 mg/mL and 1 mg/mL) for 4 h and 24 h. To verify and quantify cancer cells treated with these products as well as identify the cell cycle stage and cell viability, we stained the cells with propidium iodide and assessed them by flow cytometry. The percentage of cells in different cell cycle phases was quantified and data were expressed as histograms. Significant differences between groups were determined using analysis of variance and Bonferroni's test, as indicated. A value of P < 0.05 was considered to be statistically significant. RESULTS: SDEPN had significantly different cytotoxic effects on HT29 (2.81 +/- 0.11 vs 3.51 +/- 1.13, P > 0.05) and HepG2 (5.07 +/- 0.3 vs 15.9 +/- 1.04, P < 0.001) cells when compared to control cells for 4 h. SDEPN also had significantly different cytotoxic effects on HT29 (1.91 +/- 0.57 vs 4.53 +/- 1.22, P > 0.05) and HepG2 (14.56 +/- 1.6 vs 35.67 +/- 3.94, P < 0.001) cells when compared to control cells for 24 h. Both cell lines were killed by cisplatin in a dose-dependent manner compared to control cells (HepG2 cells for 4 h: 10.78 +/- 1.58 vs 53.89 +/- 1.53, P < 0.001; 24 h: 8.9 +/- 1.43 vs 62.78 +/- 1.87, P < 0.001 and HT29 cells for 4 h: 9.52 +/- 0.913 vs 49.86 +/- 2.89, P < 0.001; 24 h: 11.78 +/- 1.05 vs 53.34 +/- 2.65, P < 0.001). In HT29 cells, pretreatment with SDEPN and subsequent treatment with cisplatin resulted in a greater number of cells being killed (12.78 +/- 1.01 vs 93.76 +/- 1.6, P < 0.001). HepG2 cells showed significant cell killing with treatment with SDEPN when combined with cisplatin (12.87 +/- 2.78 vs 78.8 +/- 3.02, P < 0.001). CONCLUSION: SDEPN is selectively toxic against two cancer cell lines. Moreover, SDEPN in combination with cisplatin induces a synergistic increase in the cell death of both HT29 and HepG2 cells. PMID- 22919250 TI - Sensitivity of the suspected blood indicator: an experimental study. AB - AIM: To investigate whether suspected blood indicator (SBI) in capsule endoscopy (CE) is affected by background color and capsule passage velocity. METHODS: Experimental models of the small intestine constructed from paper in a variety of colors were used to simulate the background colors observed in CE images. The background colors studied included very pale yellow, yellow, very pale magenta, light grayish pink, burnt sienna, and deep and dark brown, and red spots were attached inside them. An endoscopic capsule was manually passed through the models. The rate of detection of the red spots by the SBI was evaluated based on the colors of the models and the capsule passage velocities (0.5 cm/s, 1 cm/s, and 2 cm/s). RESULTS: The rate of detection of the red spots by the SBI differed significantly according to the background color of the model (P < 0.001). Detection rates were highest for backgrounds of very pale magenta, burnt sienna, and yellow, in that order. They were lowest for backgrounds of dark brown and very pale yellow. The rate of detection of red spots by the SBI tended to decrease at rapid capsule passage velocities (1-2 cm/s) compared to slow velocities (0.5 cm/s) for backgrounds of very pale yellow (P = 0.042), yellow (P = 0.001), very pale magenta (P = 0.002), and burnt sienna (P = 0.001). No significant differences in the rate of detection were observed according to velocity for light grayish pink (P = 0.643) or dark brown (P = 0.396). CONCLUSION: SBI sensitivity was affected by background color and capsule passage velocity in the models. These findings may facilitate the rapid detection of bleeding lesions by CE. PMID- 22919251 TI - Impact of surgical volume on nationwide hospital mortality after pancreaticoduodenectomy. AB - AIM: To evaluate the impact of surgical volume on nationwide hospital mortality after pancreaticoduodenectomy (PD) for periampullary tumors in South Korea. METHODS: Periampullary cancer patients who underwent PD between 2005 and 2008 were analyzed from the database of the Health Insurance Review and Assessment Service of South Korea. A total of 126 hospitals were divided into 5 categories, each similar in terms of surgical volume for each category. We used hospital mortality as a quality indicator, which was defined as death during the hospital stay for PD, and calculated adjusted mortality through multivariate logistic models using several confounder variables. RESULTS: A total of eligible 4975 patients were enrolled in this study. Average annual surgical volume of hospitals was markedly varied, ranging from 215 PDs in the very-high-volume hospital to < 10 PDs in the very-low-volume hospitals. Admission route, type of medical security, and type of operation were significantly different by surgical volume. The overall hospital mortality was 2.1% and the observed hospital mortality by surgical volume showed statistical difference. Surgical volume, age, and type of operation were independent risk factors for hospital death, and adjusted hospital mortality showed a similar difference between hospitals with observed mortality. The result of the Hosmer-Lemeshow test was 5.76 (P = 0.674), indicating an acceptable appropriateness of our regression model. CONCLUSION: The higher-volume hospitals showed lower hospital mortality than the lower-volume hospitals after PD in South Korea, which were clarified through the nationwide database. PMID- 22919252 TI - Diabetes but not insulin is associated with higher colon cancer mortality. AB - AIM: To evaluate whether diabetic patients had a higher risk of colon cancer mortality and its associated risk factors. METHODS: The sex-specific crude and age-standardized (to the 2000 World Health Organization population) mortality rates of colon cancer in the Taiwanese general population were first calculated from 1995 to 2006. The trends were evaluated by linear regression. A total of 113,347 diabetic men and 131,573 diabetic women aged >= 25 years at recruitment from 1995 to 1998 were followed up until the end of 2006. Age/sex-specific colon cancer mortality rate ratios were calculated comparing the mortality rates of the diabetic patients with the average mortality rates of the general population within 12 years (1995-2006). A sub-cohort of diabetic patients (42,260 men and 49,405 women) was interviewed using a baseline questionnaire and Cox's regression was used to evaluate the risk factors for colon cancer mortality in these diabetic patients. RESULTS: The crude and age-standardized trends of colon cancer mortality from 1995 to 2006 increased significantly for both sexes in the general population. A total of 641 diabetic men and 573 diabetic women died of colon cancer, with a mortality rate of 74.4 and 54.3 per 100,000 person-years, respectively. Mortality rate ratios [95% confidence intervals (CIs)] showed a significantly higher risk of mortality from colon cancer for the diabetic patients compared to the general population, with the magnitude increasing with decreasing age: 1.65 (1.40-1.95), 2.01 (1.78-2.27), 2.75 (2.36-3.21) and 5.69 (4.65-6.96) for >= 75, 65-74, 55-64 and 25-54 years old, respectively, for men; and 1.46 (1.24-1.72), 2.09 (1.84-2.38), 2.67 (2.27-3.14) and 3.05 (2.29-4.06), respectively, for women. Among the sub-cohort of diabetic patients who had been interviewed with the baseline questionnaire, including information on age, sex, diabetes duration, diabetes type, body mass index, smoking, insulin use and area of residence, age and smoking were significantly predictive for colon cancer mortality, with respective adjusted hazard ratios (HRs) (95% CIs) of 1.077 (1.066 1.088) and 1.384 (1.068-1.792). Diabetes duration became a significant factor when those who died of colon cancer within 5 years of diabetes diagnosis were excluded to minimize the possible contamination of diabetes caused by incipient colon cancer, with an adjusted hazard ratio of 1.021 (1.007-1.034). Sex, diabetes type, insulin use, body mass index and area of residence were not significant predictors for colon cancer mortality in the diabetic patients. Although insulin use was categorized into subgroups of duration of use (non-users and users < 5 years, 5-9 years and >= 10 years), none of the HRs for colon cancer mortality was significant with regards to different durations of insulin use. CONCLUSION: Colon cancer mortality is increasing in Taiwan. A higher risk is observed in diabetic patients. Smoking, but not insulin use, is a modifiable risk factor. PMID- 22919253 TI - Role of body mass index in colon cancer patients in Taiwan. AB - AIM: To determine the effect of body mass index (BMI) on the characteristics and overall outcome of colon cancer in Taiwan. METHODS: From January 1995 to July 2003, 2138 patients with colon cancer were enrolled in this study. BMI categories (in kg/m2) were established according to the classification of the Department of Health of Taiwan. Postoperative morbidities and mortality, and survival analysis including overall survival (OS), disease-free survival (DFS), and cancer-specific survival (CSS) were compared across the BMI categories. RESULTS: There were 164 (7.7%) underweight (BMI < 18.5 kg/m2), 1109 (51.9%) normal-weight (BMI = 18.5 23.9 kg/m2), 550 (25.7%) overweight (BMI = 24.0-26.9 kg/m2), and 315 (14.7%) obese (BMI >= 27 kg/m2) patients. Being female, apparently anemic, hypoalbuminemic, and having body weight loss was more likely among underweight patients than among the other patients (P < 0.001). Underweight patients had higher mortality rate (P = 0.007) and lower OS (P < 0.001) and DFS (P = 0.002) than the other patients. OS and DFS did not differ significantly between normal weight, overweight, and obese patients, while CSS did not differ significantly with the BMI category. CONCLUSION: In Taiwan, BMI does not significantly affect colon-CSS. Underweight patients had a higher rate of surgical mortality and a worse OS and DFS than the other patients. Obesity does not predict a worse survival. PMID- 22919254 TI - Oxymatrine liposome attenuates hepatic fibrosis via targeting hepatic stellate cells. AB - AIM: To investigate the potential mechanism of Arg-Gly-Asp (RGD) peptide-labeled liposome loading oxymatrine (OM) therapy in CCl4-induced hepatic fibrosis in rats. METHODS: We constructed a rat model of CCl4-induced hepatic fibrosis and treated the rats with different formulations of OM. To evaluate the antifibrotic effect of OM, we detected levels of alkaline phosphatase, hepatic histopathology (hematoxylin and eosin stain and Masson staining) and fibrosis-related gene expression of matrix metallopeptidase (MMP)-2, tissue inhibitor of metalloproteinase (TIMP)-1 as well as type I procollagen via quantitative real time polymerase chain reaction. To detect cell viability and apoptosis of hepatic stellate cells (HSCs), we performed 3-(4,5)-dimethylthiahiazo(-z-y1)-3,5 diphenytetrazoliumromide assay and flow cytometry. To reinforce the combination of oxymatrine with HSCs, we constructed fluorescein-isothiocyanate-conjugated Arg Gly-Asp peptide-labeled liposomes loading OM, and its targeting of HSCs was examined by fluorescent microscopy. RESULTS: OM attenuated CCl4-induced hepatic fibrosis, as defined by reducing serum alkaline phosphatase (344.47 +/- 27.52 U/L vs 550.69 +/- 43.78 U/L, P < 0.05), attenuating liver injury and improving collagen deposits (2.36% +/- 0.09% vs 7.70% +/- 0.60%, P < 0.05) and downregulating fibrosis-related gene expression, that is, MMP-2, TIMP-1 and type I procollagen (P < 0.05). OM inhibited cell viability and induced apoptosis of HSCs in vitro. RGD promoted OM targeting of HSCs and enhanced the therapeutic effect of OM in terms of serum alkaline phosphatase (272.51 +/- 19.55 U/L vs 344.47 +/- 27.52 U/L, P < 0.05), liver injury, collagen deposits (0.26% +/- 0.09% vs 2.36% +/- 0.09%, P < 0.05) and downregulating fibrosis-related gene expression, that is, MMP-2, TIMP-1 and type I procollagen (P < 0.05). Moreover, in vitro assay demonstrated that RGD enhanced the effect of OM on HSC viability and apoptosis. CONCLUSION: OM attenuated hepatic fibrosis by inhibiting viability and inducing apoptosis of HSCs. The RGD-labeled formulation enhanced the targeting efficiency for HSCs and the therapeutic effect. PMID- 22919255 TI - X-ray repair cross-complementing group 1 polymorphisms and hepatocellular carcinoma: a meta-analysis. AB - AIM: To perform a systematic meta-analysis to investigate the association between X-ray repair cross-complementing group 1 (XRCC1) polymorphisms and hepatocellular carcinoma (HCC) risk. METHODS: Relevant studies extracted from PubMed, Embase, Wanfang, VIP and the Chinese National Knowledge Infrastructure databases up to March 2012 were included in the study. Stata software, version 11.0, was used for the statistical analysis. The odds ratios (ORs) and 95% confidence interval (CI) of the XRCC1 polymorphisms in HCC patients were analyzed and compared with healthy controls. The meta-analysis was performed using fixed-effect or random effect methods, depending on the absence or presence of significant heterogeneity. RESULTS: Eleven studies with 2075 HCC cases and 2604 controls met our eligibility criteria (four studies, 888 cases and 938 controls for Arg194Trp, four studies, 858 cases and 880 controls for Arg280His, and nine studies, 1845 cases and 2401 controls for Arg399Gln). The meta-analysis revealed no associations between the Arg194Trp and Arg399Gln polymorphisms of the XRCC1 gene and HCC risk under all contrast models (codominant, dominant and recessive models) in the overall analysis and sensitivity analysis (the studies with controls not in the Hardy-Weinberg equilibrium were excluded). For XRCC1 Arg280His polymorphism, the overall analysis revealed the significant association between the His/His genotype and the increased risk of HCC (His/His vs Arg/Arg model, OR: 1.96, 95% CI: 1.03-3.75, P = 0.04). However, sensitivity analysis showed an altered pattern of result and non-significant association (OR: 2.06, 95% CI: 0.67-6.25, P = 0.20). The heterogeneity hypothesis test did not reveal any heterogeneity, and Begg's and Egger's tests did not find any obvious publication bias. CONCLUSION: The XRCC1 Arg194Trp and Arg399Gln polymorphisms are not associated with HCC risk. More rigorous association studies are needed to verify the involvement of XRCC1 Arg280His polymorphism in HCC susceptibility. PMID- 22919257 TI - Eosinophilic esophagitis-endoscopic distinguishing findings. AB - Eosinophilic esophagitis (EE) is the most frequent condition found in a group of gastrointestinal disorders called eosinophilic gastrointestinal diseases. The hypothetical pathophysiological mechanism is related to a hypersensitivity reaction. Gastroesophageal reflux disease-like complaints not ameliorated by acid blockade or occasional symptoms of dysphagia or food impaction are likely presentations of EE. Due to its unclear pathogenesis and unspecific symptoms, it is difficult to diagnose EE without a strong suspicion. Although histological criteria are necessary to diagnosis EE, there are some characteristic endoscopic features. We present the case of a healthy 55-year-old woman with dysphagia and several episodes of esophageal food impaction over the last six months. This case report stresses the most distinguishing endoscopic findings-mucosa rings, white exudative plaques and linear furrows-that can help in the prompt recognition of this condition. PMID- 22919256 TI - Metabolic syndrome and gallstone disease. AB - AIM: To investigate the association between metabolic syndrome (MetS) and the development of gallstone disease (GSD). METHODS: A cross-sectional study was conducted in 7570 subjects (4978 men aged 45.0 +/- 8.8 years, and 2592 women aged 45.3 +/- 9.5 years) enrolled from the physical check-up center of the hospital. The subjects included 918 patients with gallstones (653 men and 265 women) and 6652 healthy controls (4325 men and 2327 women) without gallstones. Body mass index (BMI), waist circumference, blood pressure, fasting plasma glucose (FPG) and serum lipids and lipoproteins levels were measured. Colorimetric method was used to measure cholesterol, high-density lipoprotein cholesterol (HDL-C) and low density lipoprotein cholesterol (LDL-C). Dextrose oxidizing enzyme method was used to measure FPG. Subjects were asked to complete a questionnaire that enquired about the information on demographic data, age, gender, histories of diabetes mellitus, hypertension, and chronic liver disease and so on. Metabolic syndrome was diagnosed according to the Adult Treatment Panel III (ATP III) criteria. Gallstones were defined by the presence of strong intraluminal echoes that were gravity-dependent or attenuated ultrasound transmission. RESULTS: Among the 7570 subjects, the prevalence of the gallstone disease was 12.1% (13.1% in men and 10.2% in women). BMI, waist circumference, systolic blood pressure, diastolic blood pressure, fasting blood glucose and serum triglyceride (TG) in cases group were higher than in controls, while serum high-density lipid was lower than in controls. There were significant differences in the waist circumference, blood pressure, FPG and TG between cases and controls. In an age adjusted logistic regression model, metabolic syndrome was associated with gallstone disease. The age-adjusted odds ratio of MetS for GSD in men was 1.29 [95% confidence interval (CI), 1.09-1.52; P = 0.0030], and 1.68 (95% CI, 1.26 2.25; P = 0.0004) in women; the overall age-adjusted odds ratio of MetS for GSD was 1.42 (95% CI, 1.23-1.64; P < 0.0001). The men with more metabolic disorders had a higher prevalence of gallstone disease, the trend had statistical significance (P < 0.0001). The presence of 5 components of the MetS increased the risk of gallstone disease by 3.4 times (P < 0.0001). The prevalence of GSD in women who had 5 components of MetS was 5 times higher than in those without MetS component. The more the components of MetS, the higher the prevalence of GSD (P < 0.0001). The presence of 5 components of the MetS increased the risk of gallstone disease by 4.0 times. CONCLUSION: GSD appears to be strongly associated with MetS, and the more the components of MetS, the higher the prevalence of GSD. PMID- 22919258 TI - Dehiscence following successful endoscopic closure of gastric perforation during endoscopic submucosal dissection. AB - Gastric perforation is one of the most serious complications that can occur during endoscopic submucosal dissection (ESD). In terms of the treatment of such perforations, we previously reported that perforations immediately observed and successfully closed with endoclips during endoscopic resection could be managed conservatively. We now report the first case in our medical facility of a gastric perforation during ESD that was ineffectively treated conservatively even after successful endoscopic closure. In December 2006, we performed ESD on a recurrent early gastric cancer in an 81-year-old man with a medical history of laparotomy for cholelithiasis. A perforation occurred during ESD that was immediately observed and successfully closed with endoclips so that ESD could be continued resulting in an en-bloc resection. Intensive conservative management was conducted following ESD, however, an endoscopic examination five days after ESD revealed dehiscence of the perforation requiring an emergency laparotomy. PMID- 22919259 TI - Autoimmune pancreatitis complicated by gastric varices: a report of 3 cases. AB - We present three cases of autoimmune pancreatitis (AIP) complicated by gastric varices. Case 1: A 57-year-old man was diagnosed with AIP complicated by gastric varices and splenic vein obstruction. Splenomegaly was not detected at the time of the diagnosis. The AIP improved using steroid therapy, the splenic vein was reperfused, and the gastric varices disappeared; case 2: A 55-year-old man was diagnosed with AIP complicated by gastric varices, splenic vein obstruction, and splenomegaly. Although the AIP improved using steroid therapy, the gastric varices and splenic vein obstruction did not resolve; case 3: A 68-year-old man was diagnosed with AIP complicated by gastric varices, splenic vein obstruction, and splenomegaly. The gastric varices, splenic vein obstruction, and AIP did not improve using steroid therapy. These three cases suggest that gastric varices or splenic vein obstruction without splenomegaly may be an indication for steroid therapy in patients with AIP because the complications will likely become irreversible over time. PMID- 22919260 TI - Ischemic colitis during interferon-ribavirin therapy for chronic hepatitis C: a case report. AB - Ischemic colitis is a rare complication of interferon administration. Only 9 cases in 6 reports have been described to-date. This report describes a case of ischemic colitis during pegylated interferon and ribavirin treatment for chronic hepatitis C, and includes a review of the relevant literature. A 48-year-old woman was treated with pegylated interferon alpha-2a and ribavirin for chronic hepatitis C, genotype Ib. After 19 wk of treatment, the patient complained of severe afebrile abdominal pain with hematochezia. Vital signs were stable and serum white blood cell count was within the normal range. Abdominal computed tomography showed diffuse colonic wall thickening from the splenic flexure to the proximal sigmoid colon, which is the most vulnerable area for the development of ischemic colitis. Colonoscopy revealed an acute mucosal hyperemic change, with edema and ulcerations extending from the proximal descending colon to the sigmoid colon. Colonic mucosal biopsy revealed acute exudative colitis. Polymerase chain reaction and culture for Mycobacterium tuberculosis were negative and the cultures for cytomegalovirus, Salmonella and Shigella species were negative. After discontinuation of interferon and ribavirin therapy, abdominal pain and hematochezia subsided and, following colonoscopy showed improvement of the mucosal ulcerations. Ischemic colitis cases during interferon therapy in patients with chronic hepatitis C reported so far have all involved the descending colon. Ischemic colitis is a rarely encountered complication of interferon administration in patients with chronic hepatitis C and should be considered when a patient complains of abdominal pain and hematochezia. PMID- 22919261 TI - Spontaneous hemoperitoneum from hepatic metastatic trophoblastic tumor. AB - Spontaneous hemoperitoneum (SP) is defined as the presence of blood within the peritoneal cavity that is unrelated to trauma. Although there is a vast array of etiologies for SP, primary hepatocellular carcinoma and hepatic adenoma are considered to be the most common causes. Hepatic metastatic tumor associated with spontaneous rupture is rare. SP from hepatic metastatic trophoblastic tumor may initially present with a sudden onset of abdominal pain. Abdominal computed tomography (CT) plays an important role in establishing the diagnosis of SP, indicating its origin and etiology, and determining subsequent management. Herein, we report an uncommon case of hemoperitoneum from spontaneous rupture of a hepatic metastatic trophoblastic tumor in a young female patient. Interestingly, the contrast-enhanced CT findings demonstrated hypervascular hepatic masses with persistent enhancement at all phases, which were completely different from the common appearances of hepatic metastases. For SP resulting from hepatic metastatic tumors, surgical intervention is still the predominant therapeutic method, but the prognosis is very poor. PMID- 22919262 TI - Non-steroidal anti-inflammatory drugs-induced small intestinal injury and probiotic agents. AB - Intestinal bacteria play a role in the development of non-steroidal anti inflammatory drugs (NSAID)-induced small intestinal injury. Agents such as probiotics, able to modify the gut ecology, might theoretically be useful in preventing small intestinal damage induced by NSAIDs. The clinical studies available so far do suggest that some probiotic agents can be effective in this respect. PMID- 22919263 TI - USE OF THE MINIMAL CLINICALLY IMPORTANT DIFFERENCE (MCID) FOR EVALUATING TREATMENT OUTCOMES WITH TMJMD PATIENTS: A PRELIMINARY STUDY(). AB - Temporomandibular joint and muscle disorder (TMJMD) is one of the most prevalent types of musculoskeletal disorders. The major goal of the study was to more objectively quantify clinically meaningful relief for TMJMD treatment outcomes by using the new metric of minimal clinically important difference (MCID). Pre- to post-treatment changes on a number of self-report measures were evaluated in a cohort of 101 acute TMJMD patients. An anchor-based MCID approach was employed, with an objective chewing performance measure serving as the clinical outcome of interest. Using a Receiver Operating Curve analysis, it was found that the Physical Component Scale (PCS) of the SF-36 was the most robust self-report measure to use as the MCID in a TMJMD patient population. PMID- 22919264 TI - No difference in genotype frequencies of polymorphisms of the nitric oxide pathway between Caucasian normal and high tension glaucoma patients. AB - PURPOSE: Substantial evidence suggests that ocular perfusion is regulated by nitric oxide (NO), and polymorphisms in genes encoding for enzymes involved in NO formation and degradation (endothelial nitric oxide synthase [NOS3] and cytochrome b-235 alpha polypeptide gene [CYBA]) might contribute to vascular dysregulation observed in glaucoma. We therefore assessed the association of glaucoma with polymorphisms of NOS3 and CYBA previously associated with cardiovascular disease. We also compared the distribution of these polymorphisms in patients with high tension glaucoma (HTG) and normal tension glaucoma (NTG) and evaluated its association with vascular dysregulation in a subset of glaucoma patients. METHODS: Three hundred Caucasian patients with HTG and 127 with NTG were enrolled in the study and genotyped for G894T (rs1799983) and T-786C (rs2070744) in NOS3 and C242T (rs4673) in CYBA. RESULTS: None of these polymorphisms had a different allele or genotype distribution between HTG and NTG patients nor had the presence of vasospasms any impact. CONCLUSIONS: We studied the frequencies of a set of relevant polymorphisms of the NO system in a large cohort of glaucoma patients and found no association. These results therefore suggest the absence of a relevant relationship with different glaucoma forms in Caucasians. PMID- 22919265 TI - Yeast two-hybrid analysis of a human trabecular meshwork cDNA library identified EFEMP2 as a novel PITX2 interacting protein. AB - PURPOSE: Mutations in the homeobox transcription factor paired-like homeodomain transcription factor 2 (PITX2) cause Axenfeld-Reiger syndrome (ARS), which is associated with anterior segment dysgenesis (ASD) and glaucoma. To understand ARS pathogenesis, it is essential to know the normal functions of PITX2 and the proteins with which PITX2 interacts in the eye. Therefore, we used a unique cDNA library that we created from human trabecular meshwork (TM) primary cells to discover PITX2-interacting proteins (PIPs). METHODS: A human TM cDNA library was created from primary cells in the ProQuest Two-Hybrid prey vector: pEXP-AD502. Human PITX2A and PITX2C isoforms were used independently as "bait" to identify novel PIPs. A total of 1.25*106 clones were screened by yeast two-hybrid (Y2H) analyses. PIPs obtained from each Y2H experiment were confirmed by yeast retransformation and mammalian co-immunoprecipitation assays. RESULTS: EGF containing fibulin-like extracellular matrix protein 2 (EFEMP2) was identified by both PITX2A and PITX2C isoforms as a novel PIP from Y2H analyses. EFEMP2 is 443 amino acids long with six epidermal growth factor (EGF)-like modules and one fibulin-like module. The PITX2-interaction domain in EFEMP2 lies between the second EGF-like module and the COOH-terminal fibulin-like module. Co immunoprecipitation assays in COS-7 cells confirmed the interaction between PITX2 and EFEMP2. CONCLUSIONS: We discovered EFEMP2 as a novel PITX2-interacting protein. Further, our cDNA library made from human TM primary cells is a unique and effective resource to identify novel interacting proteins for glaucoma and ASD candidates. This resource could be used both for discovery and validation of interactomes identified from in silico analysis. PMID- 22919266 TI - PAX6 analysis of two sporadic patients from southern China with classic aniridia. AB - PURPOSE: To investigate the paired box 6 (PAX6) gene in two sporadic patients from southern China presenting with classic aniridia. METHODS: The two sporadic patients underwent complete physical and ophthalmic examinations. Genomic DNA was extracted from the leukocytes of the peripheral blood collected from the families of the two sporadic patients and 100 unrelated control subjects from the same population. Exons 4-13 of PAX6 were amplified by polymerase chain reaction (PCR) and sequenced directly. The ophthalmic examinations included best-corrected visual acuity, slit-lamp examination, fundus examination, optical coherence tomography, and Pentacam and Goldmann perimetry. RESULTS: The two patients were affected with aniridia accompanied by nystagmus. A heterozygous PAX6 frameshift mutation in exon 7, c.375_376delAG (p.Arg125SerfsX7), was identified in sporadic patient 1 and not in any of the unaffected family members and normal controls. One novel mutation in exon 10, c.868_871dupAGTT (p.Phe291X), was detected in sporadic patient 2. The frameshift mutation we identified has not previously been reported either in China or abroad. CONCLUSIONS: Although PAX6 mutations and polymorphisms have been reported in various ethnic groups, we report, for the first time, the identification of one new PAX6 mutation in Chinese aniridia patient. PMID- 22919267 TI - Ocular safety of cationic emulsion of cyclosporine in an in vitro corneal wound healing model and an acute in vivo rabbit model. AB - PURPOSE: Topical preparations of cyclosporine (CsA) are common therapeutics for the treatment of dry eye. However, they are not devoid of side effects, such as allergy and irritation. The present study aimed at evaluating the safety profile of a new CsA formulation in cationic emulsion (CEm) in vitro with a dynamic corneal wound healing assay using human corneal epithelial (HCE) cells, and in vivo in a rabbit acute toxicity model. METHODS: Three different csa formulations were tested: 1) 0.05%CsA-CEm, 2) commercial 0.05%CsA-Anionic emulsion (CsA-AEm, Restasis(r)), and 3) 0.05%CsA-Oil solution. Phosphate buffered saline (PBS) was used as negative control and 0.02% benzalkonium chloride (BAK) as the toxic control. In vitro, a wound was created by scratching through a confluent HCE cell layer and exposed 30 min to 1/10 dilutions of the different formulations. Cytotoxicity, cell migration, and proliferation were performed to analyze the recovery at days 1, 2, and 3. In vivo, the eye drops were applied to rabbit eyes 15 times at 5-min intervals. The ocular surface structures were examined with a slit-lamp and by corneal in vivo confocal microscopy (IVCM) for detailed examination of corneal epithelium, stroma, limbus, and conjunctiva-associated lymphoid tissue (CALT) structures. RESULTS: The in vitro study confirmed that a 0.02% BAK solution delayed the corneal healing process (-57%) by severely damaging the remaining HCE cells. The other formulations maintained a normal healing rate with a similar behavior for CsA-CEm, CsA-AEm, and PBS with no significant differences (at D3, 66%-74% closure). In the rabbit, 0.02%BAK showed the highest toxicity, inducing redness, chemosis with damaged corneal epithelium, and inflammatory cell infiltrations. CsA-AEm and CsA-Oil induced moderate infiltrations of inflammatory cells around the CALT. CsA-CEm presented the lowest toxicity with patterns similar to PBS. CONCLUSIONS: The combination of these in vitro and in vivo models evaluated the tolerance/cytotoxicity and the dynamic wound healing potential of CsA in different formulations. While CsA-AEm, CsA-CEm, and CsA-Oil are generally well tolerated, only CsA-CEm appeared to maintain the HCE cells' normal healing rate in vitro and low levels of inflammation in vivo. PMID- 22919268 TI - A novel splice site mutation in the COL4A5 gene in a Chinese female patient with rare ocular abnormalities. AB - PURPOSE: To describe an unusual ocular phenotype in a Chinese female patient with X-linked Alport syndrome (XLAS), and to characterize the type IV collagen alpha 5 (COL4A5) gene mutation in the patient and her son. METHODS: Detailed ophthalmologic examinations and optical coherence tomography were performed in the patient and her family members. For gene analysis of COL4A5, the entire coding region of COL4A5 mRNA from cultured skin fibroblast was analyzed by using reverse-transcription-polymerase chain reaction (RT-PCR) and direct sequencing, and genomic DNA was analyzed by using PCR and direct sequencing. RESULTS: The patient presented with progressive myopia at age 14 and bilateral giant macular holes (about 2 disc diameter) at age 28. At age 33 when presented to our hospital, slit lamp examination of the anterior segment showed bilateral anterior and posterior lenticonus; fundus photography and optical coherence tomography showed bilateral giant macular holes which were larger than photographed at age 28. Electron microscopy of renal biopsy showed irregular thinned and thickened areas of the glomerular basement membrane with splitting of the lamina densa. Her son was then found to have hematuria (at age 3), and indirect immunofluorescence of the epidermal basement membrane showed negative staining for the collagen alpha5(IV) chain. However, the ophthalmological examinations of her son were unremarkable. A novel COL4A5 mutation g. 4400_4400+1del, leading to an indel in exon 45 (r. 4198delins4198+2_ 4198+72), was detected in the patient and her son. This mutation produces a shift in the reading frame, resulting in a missense sequence of 13 codons followed by a premature stop codon. Her mother was not affected with the mutation. CONCLUSIONS: Our report extends the phenotypic and genotypic spectrum of X-linked Alport syndrome. PMID- 22919269 TI - Congenital polymorphic cataract associated with a G to A splice site mutation in the human beta-crystallin gene CRYbetaA3/A1. AB - PURPOSE: To identify the underlying genetic defect in four generations of a Chinese family affected with bilateral congenital polymorphic cataracts. METHODS: Family history and clinical data were recorded. The phenotype was documented using slit-lamp photography. Genomic DNA samples were extracted from peripheral blood of family members. Candidate genes were amplified using polymerase chain reaction (PCR) and screened for mutations on both strands using bidirectional sequencing. RESULTS: Affected individuals exhibited variable opacities in the embryonic nucleus, sutures, and peripheral cortical opacities. The phenotype for this family was identified as polymorphic. Direct sequencing revealed a splice site mutation (c.215+1G>A) at the first base of intron 3 of the crystallin beta A3/A1 (CRYBA3/A1) gene. This mutation co-segregated with all affected individuals in the family and was not found in unaffected family members or in 100 unrelated controls. CONCLUSIONS: Our results identified a recurrent c.215+1G>A mutation in CRYBA3/A1 in a polymorphic congenital cataract family, summarized the variable phenotypes among the patients, which expanded the phenotypic spectrum of congenital cataract in a different ethnic background, and suggested a mechanism that influences cataractogenesis. PMID- 22919270 TI - Bayesian integration of isotope ratio for geographic sourcing of castor beans. AB - Recent years have seen an increase in the forensic interest associated with the poison ricin, which is extracted from the seeds of the Ricinus communis plant. Both light element (C, N, O, and H) and strontium (Sr) isotope ratios have previously been used to associate organic material with geographic regions of origin. We present a Bayesian integration methodology that can more accurately predict the region of origin for a castor bean than individual models developed independently for light element stable isotopes or Sr isotope ratios. Our results demonstrate a clear improvement in the ability to correctly classify regions based on the integrated model with a class accuracy of 60.9 +/- 2.1% versus 55.9 +/- 2.1% and 40.2 +/- 1.8% for the light element and strontium (Sr) isotope ratios, respectively. In addition, we show graphically the strengths and weaknesses of each dataset in respect to class prediction and how the integration of these datasets strengthens the overall model. PMID- 22919273 TI - A survey and proposed framework on the soft biometrics technique for human identification in intelligent video surveillance system. AB - Biometrics verification can be efficiently used for intrusion detection and intruder identification in video surveillance systems. Biometrics techniques can be largely divided into traditional and the so-called soft biometrics. Whereas traditional biometrics deals with physical characteristics such as face features, eye iris, and fingerprints, soft biometrics is concerned with such information as gender, national origin, and height. Traditional biometrics is versatile and highly accurate. But it is very difficult to get traditional biometric data from a distance and without personal cooperation. Soft biometrics, although featuring less accuracy, can be used much more freely though. Recently, many researchers have been made on human identification using soft biometrics data collected from a distance. In this paper, we use both traditional and soft biometrics for human identification and propose a framework for solving such problems as lighting, occlusion, and shadowing. PMID- 22919271 TI - Artificial chromosomes to explore and to exploit biosynthetic capabilities of actinomycetes. AB - Actinomycetes are an important source of biologically active compounds, like antibiotics, antitumor agents, and immunosuppressors. Genome sequencing is revealing that this class of microorganisms has larger genomes relative to other bacteria and uses a considerable fraction of its coding capacity (5-10%) for the production of mostly cryptic secondary metabolites. To access actinomycetes biosynthetic capabilities or to improve the pharmacokinetic properties and production yields of these chemically complex compounds, genetic manipulation of the producer strains can be performed. Heterologous expression in amenable hosts can be useful to exploit and to explore the genetic potential of actinomycetes and not cultivable but interesting bacteria. Artificial chromosomes that can be stably integrated into the Streptomyces genome were constructed and demonstrated to be effective for transferring entire biosynthetic gene clusters from intractable actinomycetes into more suitable hosts. In this paper, the construction of several shuttle Escherichia coli-Streptomyces artificial chromosomes is discussed together with old and new strategies applied to improve heterologous production of secondary metabolites. PMID- 22919272 TI - Distribution of genes and repetitive elements in the Diabrotica virgifera virgifera genome estimated using BAC sequencing. AB - Feeding damage caused by the western corn rootworm, Diabrotica virgifera virgifera, is destructive to corn plants in North America and Europe where control remains challenging due to evolution of resistance to chemical and transgenic toxins. A BAC library, DvvBAC1, containing 109,486 clones with 104 +/- 34.5 kb inserts was created, which has an ~4.56X genome coverage based upon a 2.58 Gb (2.80 pg) flow cytometry-estimated haploid genome size. Paired end sequencing of 1037 BAC inserts produced 1.17 Mb of data (~0.05% genome coverage) and indicated ~9.4 and 16.0% of reads encode, respectively, endogenous genes and transposable elements (TEs). Sequencing genes within BAC full inserts demonstrated that TE densities are high within intergenic and intron regions and contribute to the increased gene size. Comparison of homologous genome regions cloned within different BAC clones indicated that TE movement may cause haplotype variation within the inbred strain. The data presented here indicate that the D. virgifera virgifera genome is large in size and contains a high proportion of repetitive sequence. These BAC sequencing methods that are applicable for characterization of genomes prior to sequencing may likely be valuable resources for genome annotation as well as scaffolding. PMID- 22919274 TI - Environmental impacts of Jatropha curcas biodiesel in India. AB - In the context of energy security, rural development and climate change, India actively promotes the cultivation of Jatropha curcas, a biodiesel feedstock which has been identified as suitable for achieving the Indian target of 20% biofuel blending by 2017. In this paper, we present results concerning the range of environmental impacts of different Jatropha curcas cultivation systems. Moreover, nine agronomic trials in Andhra Pradesh are analysed, in which the yield was measured as a function of different inputs such as water, fertilizer, pesticides, and arbuscular mycorrhizal fungi. Further, the environmental impact of the whole Jatropha curcas biodiesel value chain is benchmarked with fossil diesel, following the ISO 14040/44 life cycle assessment procedure. Overall, this study shows that the use of Jatropha curcas biodiesel generally reduces the global warming potential and the nonrenewable energy demand as compared to fossil diesel. On the other hand, the environmental impacts on acidification, ecotoxicity, eutrophication, and water depletion all showed increases. Key for reducing the environmental impact of Jatropha curcas biodiesel is the resource efficiency during crop cultivation (especially mineral fertilizer application) and the optimal site selection of the Jatropha curcas plantations. PMID- 22919276 TI - A hybrid technique for medical image segmentation. AB - Medical image segmentation is an essential and challenging aspect in computer aided diagnosis and also in pattern recognition research. This paper proposes a hybrid method for magnetic resonance (MR) image segmentation. We first remove impulsive noise inherent in MR images by utilizing a vector median filter. Subsequently, Otsu thresholding is used as an initial coarse segmentation method that finds the homogeneous regions of the input image. Finally, an enhanced suppressed fuzzy c-means is used to partition brain MR images into multiple segments, which employs an optimal suppression factor for the perfect clustering in the given data set. To evaluate the robustness of the proposed approach in noisy environment, we add different types of noise and different amount of noise to T1-weighted brain MR images. Experimental results show that the proposed algorithm outperforms other FCM based algorithms in terms of segmentation accuracy for both noise-free and noise-inserted MR images. PMID- 22919275 TI - Insulin resistance in patients with chronic kidney disease. AB - Metabolic syndrome and its components are associated with chronic kidney disease (CKD) development. Insulin resistance (IR) plays a central role in the metabolic syndrome and is associated with increased risk for CKD in nondiabetic patients. IR is common in patients with mild-to-moderate stage CKD, even when the glomerular filtration rate is within the normal range. IR, along with oxidative stress and inflammation, also promotes kidney disease. In patients with end stage renal disease, IR is an independent predictor of cardiovascular disease and is linked to protein energy wasting and malnutrition. Systemic inflammation, oxidative stress, elevated serum adipokines and fetuin-A, metabolic acidosis, vitamin D deficiency, depressed serum erythropoietin, endoplasmic reticulum stress, and suppressors of cytokine signaling all cause IR by suppressing insulin receptor-PI3K-Akt pathways in CKD. In addition to adequate renal replacement therapy and correction of uremia-associated factors, thiazolidinedione, ghrelin, protein restriction, and keto-acid supplementation are therapeutic options. Weight control, reduced daily prednisolone dosage, and the use of cyclosporin decrease the risk of developing new-onset diabetes after kidney transplantation. Improved understanding of the pathogenic mechanisms underlying IR in CKD may lead to more effective therapeutic strategies to reduce uremia-associated morbidity and mortality. PMID- 22919277 TI - A classification method of normal and overweight females based on facial features for automated medical applications. AB - Obesity and overweight have become serious public health problems worldwide. Obesity and abdominal obesity are associated with type 2 diabetes, cardiovascular diseases, and metabolic syndrome. In this paper, we first suggest a method of predicting normal and overweight females according to body mass index (BMI) based on facial features. A total of 688 subjects participated in this study. We obtained the area under the ROC curve (AUC) value of 0.861 and kappa value of 0.521 in Female: 21-40 (females aged 21-40 years) group, and AUC value of 0.76 and kappa value of 0.401 in Female: 41-60 (females aged 41-60 years) group. In two groups, we found many features showing statistical differences between normal and overweight subjects by using an independent two-sample t-test. We demonstrated that it is possible to predict BMI status using facial characteristics. Our results provide useful information for studies of obesity and facial characteristics, and may provide useful clues in the development of applications for alternative diagnosis of obesity in remote healthcare. PMID- 22919280 TI - Comparative gene expression profiling of benign and malignant lesions reveals candidate therapeutic compounds for leiomyosarcoma. AB - Leiomyosarcoma (LMS) is a malignant, soft-tissue tumor for which few effective therapies exist. Previously, we showed that there are three molecular subtypes of LMS. Here, we analyzed genes differentially expressed in each of the three LMS subtypes as compared to benign leiomyomas and then used the Connectivity Map (cmap) to calculate enrichment scores for the 1309 cmap drugs in order to identify candidate molecules with the potential to induce a benign, leiomyoma like phenotype in LMS cells. 11 drugs were selected and tested for their ability to inhibit the growth of three human LMS cell lines. We identified two drugs with in vitro efficacy against LMS, one of which had a strongly negative enrichment score (Cantharidin) and the other of which had a strongly positive enrichment score (MG-132). Given MG-132's strong inhibitory effect on LMS cell viability, we hypothesized that LMS cells may be sensitive to treatment with other proteasome inhibitors and demonstrated that bortezomib, a clinically-approved proteasome inhibitor not included in the original cmap screen, potently inhibited the viability of the LMS cell lines. These findings suggest that systematically linking LMS subtype-specific expression signatures with drug-associated expression profiles represents a promising approach for the identification of new drugs for LMS. PMID- 22919278 TI - Alterations of the TP53 gene in gastric and esophageal carcinogenesis. AB - TP53 genes is one of more important tumor suppressor gene, which acts as a potent transcription factor with fundamental role in the maintenance of genetic stability. The development of esophageal and gastric cancers is a multistep process resulting in successive accumulation of genetic alterations that culminates in the malignant transformation. Thus, this study highlights the participation of the main genetic alterations of the TP53 gene in esophageal and gastric carcinogenesis. Among these changes, high frequency of TP53 mutations, loss of heterozygosity (LOH), overexpression of the p53 protein, and consequently loss of p53 function, which would be early events in esophageal and gastric cancers, as well as an important biomarker of the prognosis and treatment response. Furthermore, Single Nucleotide Polymorphisms (SNPs) of TP53 have been implicated in the development and prognosis of several cancers, mainly TP53 codon 72 polymorphism whose role has been extensively studied in relation to susceptibility for esophageal and gastric cancer development. PMID- 22919282 TI - Constitutive over expression of IL-1beta, IL-6, NF-kappaB, and Stat3 is a potential cause of lung tumorgenesis in urethane (ethyl carbamate) induced Balb/c mice. AB - BACKGROUND: Lung cancer is a leading cause of cancer death. There has been found a substantial gap in the understanding of lung cancer genesis at the molecular level. We developed urethane (ethyl carbamate) induced lung tumor mice model to understand the mechanism and molecules involved in the cancer genesis. There might be many molecules involved, but we subsequently emphasized here the study of alternation in the expression of NF-kappaB, Stat3, and inflammatory cytokines interleukin-1beta and interleukin-6 to hypothesize that the microenvironment created by these molecules is promoting tumor formation. MATERIALS AND METHODS: 7 8 week old Balb/c mice of either sex were given intraperitoneal (i.p.) injection of urethane (1g/kgbw) for eight consecutive weeks. Histopathological analysis was done to detect abnormality or invasions occurred in the lung tissues. Automated cell counter was used to count the number of inflammatory cells. The expression of NF-kappaB, Stat3, and IL-1beta was observed at translational level by western blot, while the expression of IL-1beta and IL-6 was observed at transcriptional level by semiquantitative reverse transcriptase polymerase chain reaction (RT PCR) method. Secretion of IL-1beta and IL-6 in the blood was measured by enzyme linked immunosorbent assay (ELISA) method at different time intervals. RESULTS: Histopathological analysis showed various lung cancer stages hyperplasia, atypical adenomatous hyperplasia, and adenocarcinoma. Increased population of inflammatory cells, persistant expression of NF-kappaB, Stat3, pStat3, and IL 1beta at translational level, while at transcriptional level constitutive enhanced expression of IL-1beta and IL-6 followed by increased secretion of IL 1beta and IL-6 in the blood were observed in urethane-injected mice in comparison to phosphate buffer saline (PBS) injected mice at 12, 24, and 36 weeks CONCLUSIONS: Overexpression of key molecules such as NF-kappaB, Stat3, pStat3, IL 1beta, and IL-6 might have caused chronic inflammation, leading to the progression of lung cancer. PMID- 22919283 TI - Caloric restriction reduced 1, 2-dimethylhydrazine-induced aberrant crypt foci and induces the expression of Sirtuins in colonic mucosa of F344 rats. AB - BACKGROUND: Caloric restriction (CR), a lowering of caloric intake without malnutrition, is associated with longevity. CR also decreases incidences of age related diseases including cancer. The sirtuins (SIRTs) have been implicated as a key mediator for the beneficial effects of CR on longevity. However, the underlying mechanisms by which CR decreases cancer risk have not yet been fully elucidated. MATERIALS AND METHODS: The present study was conducted to determine whether CR would modify the growth of preneoplastic colonic aberrant crypt foci (ACF). We also analyzed the expression of SIRTs to elucidate the molecular mechanisms of cancer-preventive effects of CR. F344 rats were fed a CR diet (60% of ad libitum diet) or a basal diet ad libitum. Then, the animals were given subcutaneous injection of either 1, 2-dimethylhydrazine (DMH) that enhances cell proliferation of colonic mucosa or saline. All animals were sacrificed at 5 weeks after the beginning of the experiment. RESULTS: The number of ACF in colonic mucosa was significantly decreased in DMH-treated rats with CR as compared to in those without CR. No ACF was found in DMH-untreated animals with or without CR. Also, we found that CR decreased the cell proliferation of colonic mucosa in DMH treated rats. The expressions of anti-apoptotic gene, Survivin, and cell cycle progression-associated gene, Cyclin D1, were increased by DMH-treatment. Both of the genes expressions were declined by CR in those of DMH-treated rats. The expressions of all SIRT1-7 mRNAs were significantly increased by CR in DMH treated rats. CONCLUSION: As previous studies demonstrated that SIRT1 down regulates Survivin and Cyclin D1, our findings suggest that at least SIRT1 protect colonic mucosa from formation and development of ACF by increasing apoptosis and reducing excessive cell growth in colon epithelial cells. PMID- 22919284 TI - Developing Intuitions about How Personal and Social Properties Are Linked to the Brain and the Body. AB - This study investigated the development of intuitions about which properties are associated with the brain and which are associated with the body. A sample of 60 children aged 6, 8, and 10 years, as well a sample of 20 adults, were told about a brain transplant between two individuals and were asked about where certain properties resided after the transplant. Adults and older children construed the characteristics associated with fine-motor behaviour, culpability, social contract and best friendships as transferring with the brain. Characteristics associated with gross-motor behaviour, physical/biological properties, ownership and familial relationships were more likely to be seen as remaining with the body. Domain-based explanations for this pattern of results are discussed. PMID- 22919281 TI - Prolonged sulforaphane treatment does not enhance tumorigenesis in oncogenic K ras and xenograft mouse models of lung cancer. AB - BACKGROUND: Sulforaphane (SFN), an activator of nuclear factor erythroid-2 related factor 2 (Nrf2), is a promising chemopreventive agent which is undergoing clinical trial for several diseases. Studies have indicated that there is gain of Nrf2 function in lung cancer and other solid tumors because of mutations in the inhibitor Kelch-like ECH-associated protein 1 (Keap1). More recently, several oncogenes have been shown to activate Nrf2 signaling as the main prosurvival pathway mediating ROS detoxification, senescence evasion, and neoplastic transformation. Thus, it is important to determine if there is any risk of enhanced lung tumorigenesis associated with prolonged administration of SFN using mouse models of cancer. MATERIALS AND METHODS: We evaluated the effect of prolonged SFN treatment on oncogenic K-ras (K-ras(LSL-G12D))-driven lung tumorigenesis. One week post mutant-K-ras expression, mice were treated with SFN (0.5 mg, 5 d/wk) for 3 months by means of a nebulizer. Fourteen weeks after mutant K-ras expression (K-ras(LSL-G12D)), mice were sacrificed, and lung sections were screened for neoplastic foci. Expression of Nrf2-dependent genes was measured using real time RT-PCR. We also determined the effect of prolonged SFN treatment on the growth of preclinical xenograft models using human A549 (with mutant K-ras and Keap1 allele) and H1975 [with mutant epidermal growth factor receptor (EGFR) allele] nonsmall cell lung cancer cells. RESULTS: Systemic SFN administration did not promote the growth of K-ras(LSL-G12D)-induced lung tumors and had no significant effect on the growth of A549 and H1975 established tumor xenografts in nude mice. Interestingly, localized delivery of SFN significantly attenuated the growth of A549 tumors in nude mice, suggesting an Nrf2-independent antitumorigenic activity of SFN. CONCLUSIONS: Our results demonstrate that prolonged SFN treatment does not promote lung tumorigenesis in various mouse models of lung cancer. PMID- 22919285 TI - Infant Distress and Regulatory Behaviors Vary as a Function of Attachment Security Regardless of Emotion Context and Maternal Involvement. AB - Differences in infant distress and regulatory behaviors based on the quality of attachment to mother, emotion context (frustration versus fear), and whether or not mothers were actively involved in the emotion-eliciting tasks were examined in a sample of 98 16-month-old infants and their mothers. Dyads participated in the Strange Situation, a limiting task designed to elicit infant frustration, and a novelty task designed to elicit infant fear. Mothers were asked to remain uninvolved during the first minute of each task, and then instructed to engage with their infants as they wished for the remaining three minutes. Independent of concurrent maternal sensitivity, resistant infants were significantly more distressed than secure and avoidant infants. Avoidant infants engaged in fewer active mother-oriented regulation behaviors than secure and resistant infants and engaged in more self-soothing in the mother involved condition than the mother uninvolved condition. Resistant infants engaged in more physical comfort with their mothers and more venting than both secure and avoidant infants, and exhibited a smaller variety of adaptive non-mother-oriented strategies than did secure infants. There were few differences in infant distress and regulatory behaviors as a function of emotion task and maternal involvement. Limitations and implications for future research are discussed. PMID- 22919286 TI - Multidimensional scaling applied to histogram-based DNA analysis. AB - This paper aims to study the relationships between chromosomal DNA sequences of twenty species. We propose a methodology combining DNA-based word frequency histograms, correlation methods, and an MDS technique to visualize structural information underlying chromosomes (CRs) and species. Four statistical measures are tested (Minkowski, Cosine, Pearson product-moment, and Kendall tau rank correlations) to analyze the information content of 421 nuclear CRs from twenty species. The proposed methodology is built on mathematical tools and allows the analysis and visualization of very large amounts of stream data, like DNA sequences, with almost no assumptions other than the predefined DNA "word length." This methodology is able to produce comprehensible three-dimensional visualizations of CR clustering and related spatial and structural patterns. The results of the four test correlation scenarios show that the high-level information clusterings produced by the MDS tool are qualitatively similar, with small variations due to each correlation method characteristics, and that the clusterings are a consequence of the input data and not method's artifacts. PMID- 22919287 TI - Minding the Gap: An approach to determine critical drivers in the development of Point of Care diagnostics. AB - INTRODUCTION: A point of care test (POCT) for Chlamydia trachomatis detection is an urgent public health need. Technology advances in diagnostics have made solutions possible. Yet no reliable POCT exist. Our goal was to address the gap between chlamydia POCT needs and successful POCT development by determining which characteristics of POCT tests are most critical and if any flexibility in the attributes assigned those characteristics exist between technology developer and end user. METHODS: We employed a process known as WALEX (Warfare Analysis Laboratory Exercise) in combination with Design of Experiment (DOE) methodology using discrete choice experiments (DCE), to describe the attributes of the most realistic, rather than the most ideal POCT. The WALEX was conducted as interactive oral and simultaneous electronic discussion among experts with differing expertise, but linked by a common interest in development of a chlamydia POCT. RESULTS: Our studies demonstrated which features of the ideal chlamydia POCT were considered critical to test acceptance by users and which were open to negotiation. In particular, end users were more lenient on the requirement for the fastest ideal test and the lowest one time instrument costs, if the requirement for higher throughput, lowest cost and vaginal sample source collection were preserved. DOE methods used in forced choice question design provided confirmation of opinions derived from oral and electronic WALEX comments CONCLUSIONS: The WALEX in combination with DCE helped us achieve our goal in identifying the gaps in the chlamydia POCT and determining the most realistic solutions to bridge those gaps. PMID- 22919288 TI - Prognostic assessment in patients with indolent B-cell lymphomas. AB - Follicular lymphoma (FL) is an indolent lymphoma with long median survival. Many studies have been performed to build up prognostic scores potentially useful to identify patients with poorer outcome. In 2004, an international consortium coordinated by the International Follicular Lymphoma Prognostic Factor project was established and a new prognostic study was launched (FLIPI2) using progression-free survival (PFS) as main endpoint and integrating all the modern parameters prospectively collected. Low-grade non-Hodgkin lymphomas were once considered as a heterogenous group of lymphomas characterized by an indolent clinical course. Each entity is characterized by unique clinicobiologic features. Some studies have been focused on prognostic factors in single lymphoma subtypes, with the development of specific-entity scores based on retrospective series, for instance splenic marginal zone lymphoma (SMZL). A widely accepted prognostic tool for clinical usage for indolent non-follicular B-cell lymphomas is largely awaited. In this paper we summarized the current evidence regarding prognostic assessment of indolent follicular and non-follicular lymphomas. PMID- 22919289 TI - In vitro evaluation of antiprotozoal and antiviral activities of extracts from Argentinean Mikania species. AB - The aim of this study was to investigate the antiprotozoal and antiviral activities of four Argentinean Mikania species. The organic and aqueous extracts of Mikania micrantha, M. parodii, M. periplocifolia, and M. cordifolia were tested on Trypanosoma cruzi epimastigotes, Leishmania braziliensis promastigotes, and dengue virus type 2. The organic extract of M. micrantha was the most active against T. cruzi and L. braziliensis exhibiting a growth inhibition of 77.6 +/- 4.5% and 84.9 +/- 6.1%, respectively, at a concentration of 10 MUg/ml. The bioguided fractionation of M. micrantha organic extract led to the identification of two active fractions. The chromatographic profile and infrared analysis of these fractions revealed the presence of sesquiterpene lactones. None of the tested extracts were active against dengue virus type 2. PMID- 22919290 TI - Family and personal adjustment of economically disadvantaged chinese adolescents in Hong Kong. AB - This study attempted to examine the relationship between poverty and adolescent developmental outcomes in the family and personal domains in 3,328 Chinese secondary school students in Hong Kong. Developmental outcomes included positive youth development constructs, problem behaviors, perceived family interaction, and parental parenting. Results showed that adolescents experiencing poverty did not differ from nonpoor adolescents in terms of risk behavior and in most indicators of positive youth development. On the other hand, adolescents with economic disadvantage displayed lower levels of positive identity, family interaction, and perceived paternal parenting than did those without economic disadvantage. PMID- 22919291 TI - Smoothed particle hydrodynamics simulation of wave overtopping characteristics for different coastal structures. AB - This research paper presents an incompressible smoothed particle hydrodynamics (ISPH) technique to investigate a regular wave overtopping on the coastal structure of different types. The SPH method is a mesh-free particle modeling approach that can efficiently treat the large deformation of free surface. The incompressible SPH approach employs a true hydrodynamic formulation to solve the fluid pressure that has less pressure fluctuations. The generation of flow turbulence during the wave breaking and overtopping is modeled by a subparticle scale (SPS) turbulence model. Here the ISPH model is used to investigate the wave overtopping over a coastal structure with and without the porous material. The computations disclosed the features of flow velocity, turbulence, and pressure distributions for different structure types and indicated that the existence of a layer of porous material can effectively reduce the wave impact pressure and overtopping rate. The proposed numerical model is expected to provide a promising practical tool to investigate the complicated wave-structure interactions. PMID- 22919292 TI - Collaboration between HPMC and NaCMC in order to reach the polymer critical point in theophylline hydrophilic matrices. AB - Percolation theory has been applied in order to study the existence of critical points as well as the possibility to find a "combined percolation threshold" for ternary hydrophilic matrices prepared with HPMC, NaCMC, and theophylline. For this purpose, different batches of ternary as well as binary hydrophilic matrices have been prepared. Critical points have been found for binary hydrophilic matrices between 21.5 and 31.3% (v/v) of HPMC and between 39 and 54% (v/v) of NaCMC, respectively. In a previous work carried out with the same polymers but a much more soluble drug (KCl), it was demonstrated the existence of a partial collaboration between the polymers in order to establish the gel layer. In this work, it has been observed for the first time the need of a minimum concentration of one of the matrix-forming polymer (between 10 and 20% v/v, approximately) for establishing an effective collaboration. PMID- 22919293 TI - Measurement of prosocial reasoning among Chinese adolescents. AB - This study attempted to develop a standardized instrument for assessment of prosocial reasoning in Chinese populations. The Prosocial Reasoning Objective Measure (PROM) was translated, and a two-stage study was conducted to evaluate the psychometric properties of the translated instrument. The content validity, cultural relevance, and reading level of the translated instrument were evaluated by an expert panel. Upon revisions according to the expert opinions, the Chinese PROM demonstrated good content validity, "good-to-very good test-retest" reliability, and internal consistency. However, only partial support to the convergent validity of the Chinese PROM was found. In the first stage of the study (n = 50), the PROM scores had high positive correlations with empathy and negative correlations with personal distress and fantasy. These results were consistent with theoretical expectations, although this is also a concern that empathy had a close-to-unity correlation with PROM score in the small sample study of stage 1. In the second stage of the study (n = 566), the relationship between PROM scores and prosocial behavior appeared to be weak. Results suggest that there were many personal, family, or social factors that were linked to prosocial behavior, and prosocial reasoning might only contribute to a small proportion of variation in prosocial behavior among adolescents. PMID- 22919294 TI - Isolation and identification of sodium fluoroacetate degrading bacteria from caprine rumen in Brazil. AB - The objective of this paper was to report the isolation of two fluoroacetate degrading bacteria from the rumen of goats. The animals were adult goats, males, crossbred, with rumen fistula, fed with hay, and native pasture. The rumen fluid was obtained through the rumen fistula and immediately was inoculated 100 MUL in mineral medium added with 20 mmol L(-1) sodium fluoroacetate (SF), incubated at 39 degrees C in an orbital shaker. Pseudomonas fluorescens (strain DSM 8341) was used as positive control for fluoroacetate dehalogenase activity. Two isolates were identified by 16S rRNA gene sequencing as Pigmentiphaga kullae (ECPB08) and Ancylobacter dichloromethanicus (ECPB09). These bacteria degraded sodium fluoroacetate, releasing 20 mmol L(-1) of fluoride ion after 32 hours of incubation in Brunner medium containing 20 mmol L(-1) of SF. There are no previous reports of fluoroacetate dehalogenase activity for P. kullae and A. dichloromethanicus. Control measures to prevent plant intoxication, including use of fences, herbicides, or other methods of eliminating poisonous plants, have been unsuccessful to avoid poisoning by fluoroacetate containing plants in Brazil. In this way, P. kullae and A. dichloromethanicus may be used to colonize the rumen of susceptible animals to avoid intoxication by fluoroacetate containing plants. PMID- 22919295 TI - Design space approach in optimization of fluid bed granulation and tablets compression process. AB - The aim of this study was to optimize fluid bed granulation and tablets compression processes using design space approach. Type of diluent, binder concentration, temperature during mixing, granulation and drying, spray rate, and atomization pressure were recognized as critical formulation and process parameters. They were varied in the first set of experiments in order to estimate their influences on critical quality attributes, that is, granules characteristics (size distribution, flowability, bulk density, tapped density, Carr's index, Hausner's ratio, and moisture content) using Plackett-Burman experimental design. Type of diluent and atomization pressure were selected as the most important parameters. In the second set of experiments, design space for process parameters (atomization pressure and compression force) and its influence on tablets characteristics was developed. Percent of paracetamol released and tablets hardness were determined as critical quality attributes. Artificial neural networks (ANNs) were applied in order to determine design space. ANNs models showed that atomization pressure influences mostly on the dissolution profile, whereas compression force affects mainly the tablets hardness. Based on the obtained ANNs models, it is possible to predict tablet hardness and paracetamol release profile for any combination of analyzed factors. PMID- 22919297 TI - Student classroom misbehavior: an exploratory study based on teachers' perceptions. AB - This study aimed to examine the conceptions of junior secondary school student misbehaviors in classroom, and to identify the most common, disruptive, and unacceptable student problem behaviors from teachers' perspective. Twelve individual interviews with teachers were conducted. A list of 17 student problem behaviors was generated. Results showed that the most common and disruptive problem behavior was talking out of turn, followed by nonattentiveness, daydreaming, and idleness. The most unacceptable problem behavior was disrespecting teachers in terms of disobedience and rudeness, followed by talking out of turn and verbal aggression. The findings revealed that teachers perceived student problem behaviors as those behaviors involving rule-breaking, violating the implicit norms or expectations, being inappropriate in the classroom settings and upsetting teaching and learning, which mainly required intervention from teachers. PMID- 22919296 TI - Caatinga revisited: ecology and conservation of an important seasonal dry forest. AB - Besides its extreme climate conditions, the Caatinga (a type of tropical seasonal forest) hosts an impressive faunal and floristic biodiversity. In the last 50 years there has been a considerable increase in the number of studies in the area. Here we aimed to present a review of these studies, focusing on four main fields: vertebrate ecology, plant ecology, human ecology, and ethnobiology. Furthermore, we identify directions for future research. We hope that the present paper will help defining actions and strategies for the conservation of the biological diversity of the Caatinga. PMID- 22919298 TI - Different accumulation of free amino acids during short- and long-term osmotic stress in wheat. AB - The effect of wheat chromosome 5A on free amino acid accumulation induced by osmotic stress was compared in chromosome 5A substitution lines with different freezing tolerance. Treatment with 15% polyethylene glycol (PEG) resulted in greater total free amino acid content even after 3 days compared to the controls. The ratio of amino acids belonging to various amino acid families differed after 3-week treatment in the control and PEG-treated plants only in the case of the freezing-sensitive substitution line. There was a transient increase with a maximum after 3 days in the amounts of several amino acids, after which their concentrations exhibited a more gradual increase. During the first days of osmotic stress the Glu, Gln, Asp, Asn, Thr, Ser, Leu, and His concentrations were greater in the tolerant substitution line than in the sensitive one, while the opposite relationship was observed at the end of the PEG treatment. The coordinated changes in the levels of individual amino acids indicated that they are involved in both the short- and long-term responses to osmotic stress. The alterations differed in the two chromosome 5A substitution lines, depending on the stress tolerance of the chromosome donor genotype. PMID- 22919299 TI - Molecular characterization of Shiga toxin-producing Escherichia coli isolated from ruminant and donkey raw milk samples and traditional dairy products in Iran. AB - The aims of the current study were to detect the virulence factors and antibiotic resistance of Shiga toxin-producing E. coli, in animal milk and dairy products in Iran. After E. coli dentification with culture method, PCR assay were developed for detection of pathogenic genes, serotypes and antibiotic resistance genes of E. coli. Results showed that out of 719 samples, 102 (14.18%) were confirmed to be positive for E. coli and out of 102 positive samples, 17.64% were O26 and 13.72% were O157 and 1.96% were O91 and 1.96% were O145 serotypes. Totally, the prevalence of stx1 and papA genes were the highest while the prevalence of sfaS and fyuA were the lowest in the positive samples. PCR results showed that tetA, tetB were the highest (64.70%) and aac(3)-IV were the lowest (27.45%) antibiotic resistant genes in E. coli positive samples. Our study indicated that the isolated E. coli trains in these regions had a highest antibiotic resistance to tetracycline (58.82%) and the lowest to nitrofurantoin (3.92%). tetA gene and E. coli O157 serotype had highest and aac(3)-IV gene, and E. coli O145 serotype had a lowest frequency rates of antibiotics resistance genes, in the region. PMID- 22919300 TI - Morphology of the myoepithelial cell: immunohistochemical characterization from resting to motile phase. AB - Myoepithelium is present in canine mammary tumors as resting and proliferative suprabasal and spindle and stellate interstitial cells. The aim of this paper was to evaluate a panel of markers for the identification of four different myoepithelial cell morphological types in the normal and neoplastic mammary gland and to investigate immunohistochemical changes from an epithelial to a mesenchymal phenotype. Cytokeratin 19 (CK19), cytokeratin 5/6 (CK5/6), cytokeratin 14 (CK14), estrogen receptor (ER), p63 protein, vimentin (VIM), and alpha-smooth muscle actin (Alpha-SMA) antibodies were used on 29 neoplasms (3 benign and 3 malignant myoepithelial tumors, 7 carcinomas in benign-mixed tumors and 16 complex carcinomas) and on normal tissue of mammary glands. All these antibodies were also tested on 3 mammary tissues from animals with no mammary pathology. The myoepithelial markers were well expressed in the suprabasal cells and gradually lost in the motile types, with the stellate cells maintaining only VIM expression typical of mesenchyma. ER labeled some resting and motile myoepithelial cells. On the basis of our results, we propose a transition from myoepithelial immotile cells into migratory fibroblast-like cells. This transition and the characterization of an immunohistochemical panel for resting and motile myoepithelial cells shed more light on the biological behavior of myoepithelial cells. PMID- 22919301 TI - Effect of long-term paddy-upland yearly rotations on rice (Oryza sativa) yield, soil properties, and bacteria community diversity. AB - A 10-year-long field trial (between 2001 and 2010) was conducted to investigate the effect of paddy-upland rotation on rice yield, soil properties, and bacteria community diversity. Six types of paddy-upland crop rotations were evaluated: rice-fallow (control; CK), rice-rye grass (RR), rice-potato with rice straw mulches (RP), rice-rapeseed with straw incorporated into soil at flowering (ROF), rice-rapeseed incorporated in soil after harvest (ROM), and rice-Chinese milk vetch (RC). Analysis of terminal restriction fragment length polymorphism (T RFLP) was used to determine microbial diversity among rotations. Rice yield increased for upland crops planted during the winter. RC had the highest average yield of 7.74 t/ha, followed by RR, RP, ROM, and ROF. Soil quality differences among rotations were found. RC and RP improved the soil mean weight diameter (MWD), which suggested that rice rotated with milk vetch and potato might improve the paddy soil structure. Improved total nitrogen (TN) and soil organic matter (SOM) were also found in RC and RP. The positive relationship between yield and TN/SOM might provide evidence for the effect of RC rotation on rice yield. A strong time dependency of soil bacterial community diversity was also found. PMID- 22919302 TI - Temporal aspects of surface water quality variation using robust statistical tools. AB - Robust statistical tools were applied on the water quality datasets with the aim of determining the most significance parameters and their contribution towards temporal water quality variation. Surface water samples were collected from four different sampling points during dry and wet seasons and analyzed for their physicochemical constituents. Discriminant analysis (DA) provided better results with great discriminatory ability by using five parameters with (P < 0.05) for dry season affording more than 96% correct assignation and used five and six parameters for forward and backward stepwise in wet season data with P-value (P < 0.05) affording 68.20% and 82%, respectively. Partial correlation results revealed that there are strong (r(p) = 0.829) and moderate (r(p) = 0.614) relationships between five-day biochemical oxygen demand (BOD(5)) and chemical oxygen demand (COD), total solids (TS) and dissolved solids (DS) controlling for the linear effect of nitrogen in the form of ammonia (NH(3)) and conductivity for dry and wet seasons, respectively. Multiple linear regression identified the contribution of each variable with significant values r = 0.988, R(2) = 0.976 and r = 0.970, R(2) = 0.942 (P < 0.05) for dry and wet seasons, respectively. Repeated measure t-test confirmed that the surface water quality varies significantly between the seasons with significant value P < 0.05. PMID- 22919303 TI - Effect and removal mechanisms of 6 different washing agents for building wastes containing chromium. AB - With the building wastes contaminated by chromium in Haibei Chemical Plan in China as objects, we studied the contents of total Cr and Cr (VI) of different sizes, analyzed the effect of 6 different washing agents, discussed the removal mechanisms of 6 different washing agents for Cr in various forms, and finally selected applicable washing agent. As per the results, particle size had little impact on the contents of total Cr and Cr (VI); after one washing with water, the removal rate of total Cr and Cr (VI) was 75% and 78%, respectively, and after the second washing with 6 agents, the removal rate of citric acid was the highest, above 90% for total Cr and above 99% for hexavalent chromium; the pH of building wastes were reduced by citric acid, and under acid condition, hexavalent chromium was reduced to trivalent chromium spontaneously by organic acid, which led to better removal rate of acid soluble Cr and reducible Cr; due to the complexing action, citric acid had best removal rate for oxidizable trivalent chromium. In conclusion, citric acid is the most applicable second washing agent for building wastes. PMID- 22919304 TI - Decreased erythrocyte NA+,K+-ATPase activity and increased plasma TBARS in prehypertensive patients. AB - The essential hypertension has been associated with membrane cell damage. The aim of the present study is investigate the relationship between erythrocyte Na(+),K(+)-ATPase and lipoperoxidation in prehypertensive patients compared to normotensive status. The present study involved the prehypertensive patients (systolic: 136 +/- 7 mmHg; diastolic: 86.8 +/- 6.3 mmHg; n = 8) and healthy men with normal blood pressure (systolic: 110 +/- 6.4 mmHg; diastolic: 76.1 +/- 4.2 mmHg; n = 8) who were matched for age (35 +/- 4 years old). The venous blood samples of antecubital vein (5 mL) were collected into a tube containing sodium heparin as anticoagulant (1000 UI), and erythrocyte ghosts were prepared for quantifying Na(+),K(+)-ATPase activity. The extent of the thiobarbituric acid reactive substances (TBARS) was determined in plasma. The statistical analysis was carried out by Student's t-test and Pearson's correlation coefficient. A P < 0.05 was considered significant. The Na(+),K(+)-ATPase activity was lower in prehypertensive patients compared with normotensive subjects (4.9 versus 8.0 nmol Pi/mg protein/min; P < 0.05). The Na(+),K(+)-ATPase activity correlated negatively with TBARS content (r = -0.6; P < 0.05) and diastolic blood pressure (r = -0.84; P < 0.05). The present study suggests that Na(+),K(+)-ATPase activity reduction and elevation of the TBARS content may underlie the pathophysiological aspects linked to the prehypertensive status. PMID- 22919305 TI - Ipsilateral testicular catch-up growth rate following microsurgical inguinal adolescent varicocelectomy. AB - OBJECTIVE: To evaluate the ipsilateral catch-up growth rates compared to contralateral testicular growth in adolescents with varicocele undergoing microsurgical inguinal varicocelectomy. MATERIALS AND METHODS: Between December 2005 and May 2007, 39 adolescent patients with grade 2-3 varicocele admitted to our clinic with complaints of pain and/or testicular asymmetry were operated. Preoperative mean age was 14.5 +/- 1.96 (9-17). Testicular volumes were assessed with ultrasound every 3 months. The available followup was 39 months. RESULTS: In our series, mean testicular preoperative volumes were 9.07 +/- 3.19 mL for the right and 5.90 +/- 1.74 mL for the left. Mean testicular volumes at the end of follow up were 13.97 +/- 3.42 mL for the right and 12.20 +/- 4.05 mL for the left. The testicular catch-up growth approximately begins after the 9th month and significant catch-up occurred in the 12-24 months (P < 0.05). CONCLUSION: Since testicular volume is the primary method of assessing testicular function in adolescents, testicular size can predict future fertility status significantly 9 months after surgical varicocele correction. PMID- 22919306 TI - Effects of elevated ambient temperature on reproductive outcomes and offspring growth depend on exposure time. AB - Reproductive performance has been shown to be greatly affected by changes in environmental factors, such as temperature. However, it is also crucial to identify the particular stage of pregnancy that is most adversely affected by elevated ambient temperature. The aims of this study were to determine the effect on reproductive outcomes of exposure to elevated ambient temperature during different stages of pregnancy and to determine the effect of prenatal heat stress on offspring growth. Sixty pregnant rats were used in this study. The rats were divided equally into four groups as group 1 (control), group 2 (exposed to elevated temperature following implantation), group 3 (exposed to elevated temperature during pre- and periimplantation), and group 4 (exposed to elevated temperature during pre- and periimplantation and following implantation). Groups 3 and 4 had prolonged gestation periods, reduced litter sizes, and male-biased sex ratios. Moreover, the growth patterns of group 3 and 4 pups were adversely affected by prenatal exposure to elevated temperature. The differences between group 1 and group 3 and between group 1 and group 4 were highly significant. However, no significant differences were observed between groups 1 and 2 in the gestation length, sex ratios, and growth patterns. Thus, it can be concluded that exposure to elevated ambient temperature during pre- and periimplantation has stronger adverse effects on reproductive outcomes and offspring growth than postimplantation exposure. PMID- 22919307 TI - Effects of Chinese liquors on cardiovascular disease risk factors in healthy young humans. AB - OBJECTIVES: To elucidate whether consumption of two Chinese liquors, tea-flavor liquor (TFL) and traditional Chinese liquor (TCL) have protective effects on cardiovascular disease (CVD) risk factors in healthy human subjects. METHODS: Forty-five healthy subjects (23 men, 22 women), aged 23-28, were recruited and randomized into two groups: TFL and TCL, and consumed 30 mL/day (45% (v/v) alcohol) of either liquor for 28 days. RESULTS: Serum high-density lipoprotein cholesterol/low-density lipoprotein cholesterol (HDL-C/LDL-C) and apolipoprotein A1 were significantly increased, and total cholesterol (TC) and TC/HDL-C were significantly decreased after the intervention in both groups (P < 0.05). Serum uric acid (P = 0.004 for TFL, P = 0.001 for TCL), glucose (P < 0.001 for TFL, P < 0.001 for TCL) and endothelial adhesion molecules (P < 0.05) were significantly decreased after the intervention. ADP-induced whole blood platelet aggregation was also significantly decreased after the intervention in both TFL and TCL groups (P < 0.05). CONCLUSIONS: TFL and TCL consumption had protective effects on CVD risk factors in young humans. However, the results were valid only for 28 days, and that the possibility of adverse effect (liver, kidney) of chronic alcohol consumption should be considered. PMID- 22919308 TI - The efficacy of pramipexole, a dopamine receptor agonist, as an adjunctive treatment in treatment-resistant depression: an open-label trial. AB - Dopaminergic dysfunction is implicated in the pathophysiology of treatment resistant depression. Although the efficacy of adjunctive pramipexole treatment has been demonstrated in treatment-resistant bipolar depression, such data are scarce for major depressive disorder (MDD). We recruited 17 patients with DSM-IV major depressive episode who have failed to respond to previous treatment with a selective serotonin reuptake inhibitor. Five patients were diagnosed as having bipolar II disorder and 12 as having unipolar MDD. Patients were monitored at an ambulatory care facility every two weeks until 12 weeks. Pramipexole was added to existing medication. Depression severity was assessed with the Hamilton Depression Rating Scale 21-item version (HDRS-21). The mean maximum dosage of pramipexole was 1.6 mg (SD 0.9). The HDRS-21 total score decreased from 19.4 (SD 3.8) at baseline to 7.2 (SD 5.4) at endpoint (P < 0.000001). Twelve patients (71%) were responders based on the definition of 50% or more reduction in the HDRS-21 score. Ten patients (59%) remitted (HDRS-21 total score at endpoint <8). These results were almost unchanged when the sample was confined to patients with MDD. No serious adverse events were observed. Our findings indicate that pramipexole augmentation therapy may be effective and well tolerated in refractory depressed patients. PMID- 22919309 TI - Internationally adopted children from non-European countries: general development during the first two years in the adoptive family. AB - Internationally adopted children are often delayed in their development and demonstrate more behaviour problems than nonadopted children due to adverse preadoption circumstances. This is especially true for children adopted from Eastern European countries. Few studies have focused on children adopted from non European countries. This paper presents results from an ongoing longitudinal study of 119 internationally adopted children from non-European countries during their first two years in Norway. Several scales measuring different aspects of the children's development are included in the study: communication and gross motor development, temperamental characteristics, and behaviour problems. The results show that internationally adopted children are delayed in their general development when they first arrive in their adoptive families. After two years the children have made significant progress in development. However, they still lag behind in communication and motor skills compared to non-adopted children. The temperamental characteristics seem very stable from time of adoption until two years after adoption. The children demonstrate a low frequency of behaviour problems. However, the behaviour problems have changed during the two years. At time of adoption they show more nonphysically challenging behaviour while after two years their physically challenging behaviour has increased. PMID- 22919310 TI - Olive fertility as affected by cross-pollination and boron. AB - Self-compatibility of local olive (Olea europaea L.) accessions and of the cultivars "Frantoio" and "Leccino" was investigated in Garda Lake area, northern Italy. Intercompatibility was determined for "Casaliva," "Frantoio," and "Leccino," as well as the effects of foliar Boron applications (0, 262, 525, or 1050 mg.L(-1)) applied about one week before anthesis on fruit set, shotberry set, and on in vitro pollen germination. Following self-pollination, fruit set was significantly lower and the occurrence of shot berries significantly higher than those obtained by open pollination. No significant effect of controlled cross-pollination over self-pollination on fruit set and shotberry set was detectable. B treatments increased significantly fruit set in "Frantoio" and "Casaliva" but not in "Leccino." B sprays had no effect on shotberry set, suggesting that these parthenocarpic fruits did not strongly compete for resources allocation and did not take advantage of increased B tissue levels. Foliar B application enhanced in vitro pollen germination, and the optimal level was higher for pollen germination than for fruit set. Our results highlight the importance of olive cross pollination for obtaining satisfactory fruit set and the beneficial effect of B treatments immediately prior to anthesis, possibly by affecting positively the fertilisation process and subsequent plant source-sink relations linked to fruitlet retention. PMID- 22919311 TI - Ureteral reimplantation with psoas bladder hitch in adults: a contemporary series with long-term followup. AB - We retrospectively evaluated our experience with ureteral reimplantation and psoas bladder hitch to restore urinary tract continuity in patients with lower ureteral defects, since long-term data on the outcomes of this procedure have been relatively scarce in the last two decades. The procedure was performed in 24 patients (7 male, 17 female) with a mean age of 54.6 years. The mean ureteral defect length was 4.8 cm (range 3-10), the ureterovesical anastomosis was performed with simplified split-cuff technique in 18 patients, submucosal tunnel in 2, and direct anastomosis without antireflux technique in 2. Mean followup was 53 months (range 12-125), and there were no reinterventions. Postoperative renal imaging was normal in 22 cases (91.6%) and revealed decreased kidney size in 2, 3 patients presented intermittent flank pain, and 5 had sporadic episodes of lower tract UTI but no one pyelonephritis. Psoas hitch ureteral reimplantation can be successfully used for bridging defects of the lower ureter up to 10 cm in length in difficult clinical situations. It is relatively simple to perform, compared to other procedures of ureteral reconstruction, and it provides adequate protection of the upper urinary tract. PMID- 22919312 TI - Neuronal ceroid lipofuscinosis in Border Collie dogs in Japan: clinical and molecular epidemiological study (2000-2011). AB - Neuronal ceroid lipofuscinosis (NCL) is an inherited, neurodegenerative lysosomal disease that causes premature death. The present study describes the clinical and molecular epidemiologic findings of NCL in Border Collies in Japan for 12 years, between 2000 and 2011. The number of affected dogs was surveyed, and their clinical characteristics were analyzed. In 4 kennels with affected dogs, the dogs were genotyped. The genetic relationships of all affected dogs and carriers identified were analyzed. The survey revealed 27 affected dogs, but there was a decreasing trend at the end of the study period. The clinical characteristics of these affected dogs were updated in detail. The genotyping survey demonstrated a high mutant allele frequency in examined kennels (34.8%). The pedigree analysis demonstrated that all affected dogs and carriers in Japan are related to some presumptive carriers imported from Oceania and having a common ancestor. The current high prevalence in Japan might be due to an overuse of these carriers by breeders without any knowledge of the disease. For NCL control and prevention, it is necessary to examine all breeding dogs, especially in kennels with a high prevalence. Such endeavors will reduce NCL prevalence and may already be contributing to the recent decreasing trend in Japan. PMID- 22919313 TI - Different modulating effects of adenosine on neonatal and adult polymorphonuclear leukocytes. AB - Polymorphonuclear leukocytes (PMNs) are the major leukocytes in the circulation and play an important role in host defense. Intact PMN functions include adhesion, migration, phagocytosis, and reactive oxygen species (ROS) release. It has been known for a long time that adenosine can function as a modulator of adult PMN functions. Neonatal plasma has a higher adenosine level than that of adults; however, little is known about the modulating effects of adenosine on neonatal PMNs. The aim of this study was to investigate the effects of adenosine on neonatal PMN functions. We found that neonatal PMNs had impaired adhesion, chemotaxis, and ROS production abilities, but not phagocytosis compared to adult PMNs. As with adult PMNs, adenosine could suppress the CD11b expressions of neonatal PMNs, but had no significant suppressive effect on phagocytosis. In contrast to adult PMNs, adenosine did not significantly suppress chemotaxis and ROS production of neonatal PMNs. This may be due to impaired phagocyte reactions and a poor neonatal PMN response to adenosine. Adenosine may not be a good strategy for the treatment of neonatal sepsis because of impaired phagocyte reactions and poor response. PMID- 22919314 TI - FAD2-DGAT2 genes coexpressed in endophytic Aspergillus fumigatus derived from tung oilseeds. AB - Recent efforts to genetically engineer plants that contain fatty acid desaturases to produce valuable fatty acids have made only modest progress. Diacylglycerol acyltransferase 2 (DGAT2), which catalyzes the final step in triacylglycerol (TAG) assembly, might potentially regulate the biosynthesis of desired fatty acids in TAGs. To study the effects of tung tree (Vernicia fordii) vfDGAT2 in channeling the desired fatty acids into TAG, vfDGAT2 combined with the tung tree fatty acid desaturase-2 (vfFAD2) gene was co-introduced into Aspergillus fumigatus, an endophytic fungus isolated from healthy tung oilseed. Two transformants coexpressing vfFAD2 and vfDGAT2 showed a more than 6-fold increase in linoleic acid production compared to the original A. fumigatus strain, while a nearly 2-fold increase was found in the transformant expressing only vfFAD2. Our data suggest that vfDGAT2 plays a pivotal role in promoting linoleic acid accumulation in TAGs. This holds great promise for further genetic engineering aimed at producing valuable fatty acids. PMID- 22919315 TI - A neutral risk on the development of new-onset diabetes mellitus (NODM) in Taiwanese patients with dyslipidaemia treated with fibrates. AB - There are no data on the incidence of new-onset diabetes mellitus (NODM ) in nondiabetic dyslipidaemia patients treated with fibrates. The aim of our study was to clarify these issues, to investigate the relationship between NODM and fibrate and whether the fibrates lead to increased risk for developing NODM. A retrospective cohort study was conducted by analyzing the Longitudinal Health Insurance Database (LHID 2005) of the National Health Insurance Research Database (NHIRD) from 2005 to 2010 to investigate all fibrate prescriptions for patients with dyslipidaemia. We estimated the hazard ratios (HRs) of NODM associated with fibrate use. We identified 145 NODM patients among 3,815 dyslipidaemic patients in the database for the study period. The risk estimates for NODM for users of fenofibrate (HR 1.30; 95% CI 0.82, 2.05) and gemfibrozil (HR 0.771; 95% CI 0.49, 1.22) were not associated with an increased risk of developing NODM (P > 0.05). Our results revealed that patients with dyslipidaemia who took fenofibrate and gemfibrozil had a neutral risk of NODM. The reasons may be associated with the fibrates have the properties that activate PPARalpha and in some cases also activated PPARgamma, leading to showing a neutral risk of NODM. PMID- 22919316 TI - Classroom misbehavior in the eyes of students: a qualitative study. AB - Using individual interviews, this study investigated perceptions of classroom misbehaviors among secondary school students in Hong Kong (N = 18). Nineteen categories of classroom misbehaviors were identified, with talking out of turn, disrespecting teacher, and doing something in private being most frequently mentioned. Findings revealed that students tended to perceive misbehaviors as those actions inappropriate in the classroom settings and even disrupting teachers' teaching and other students' learning. Among various misbehaviors, talking out of turn and disrespecting teacher were seen as the most disruptive and unacceptable. These misbehaviors were unacceptable because they disturbed teaching and learning, and violated the values of respect, conformity, and obedience in the teacher-student relationship within the classroom. The frequency and intensity of misbehaviors would escalate if students found it fun, no punishment for such misbehaviors, or teachers were not authoritative enough in controlling the situations. Implications for further research and classroom management are discussed. PMID- 22919317 TI - The rs2071559 AA VEGFR-2 genotype frequency is significantly lower in neovascular age-related macular degeneration patients. AB - In this prospective, case-control genetic study, 120 consecutive neovascular age related macular degeneration (AMD) cases and 78 controls were enrolled. Two SNPs (rs2071559 and rs1870377) of VEGF-A receptor-2 (VEGFR-2) gene were analyzed with the technique of Real-Time PCR to investigate a genetic link between AMD and VEGFR-2 gene polymorphisms in Italian patients. The frequency of the VEGFR-2 genotype rs2071559 AA was significantly lower (18.33%) in patients with AMD than in the control subjects (34.62%; P = 0.0095, chi-square test; P(corr) = 0.038; OR = 0.42, 95% CI 0.22 to 0.82). In conclusion, although with the limitations of a small sample size and the few SNPs studied, this study demonstrates a lower frequency of VEGFR-2 rs2071559 AA genotype in an AMD patient population, suggesting future studies on the role VEGFR-2 SNPs. PMID- 22919318 TI - Local treatment of hand-foot syndrome with uridine/thymidine: in vitro appraisal on a human keratinocyte cell line HaCaT. AB - 5-fluorouracil (5-FU) is one of the most commonly used antineoplastic drugs in the anticancer therapy. The hand-foot (HF) syndrome (palmar-plantar erythrodysesthesia) is an adverse effect frequently related to long-term i.v. administration of 5-FU or its orally applicable prodrug capecitabine. Its severity can even lead to interruption of the otherwise effective anticancer therapy. Tentative practice in some clinics has shown that topical application of 10% uridine ointment is beneficial for calming down the HF syndrome. This study is focused on verifying the alleged protective activity of uridine in the in vitro model of cultured human keratinocyte cell line HaCaT. We also tested the protective effects of thymidine alone or uridine-thymidine combination. The cellular viability time progression was measured in order to evaluate the effect of protective agents by three different types of cytopathogenicity tests-NTCA test (non-destructive test of cellular activity), modified MTT test and RTCA (real-time cell analyser, Roche). All three methods proved the ability of uridine and uridine-thymidine combination to protect keratinocytes against 5-FU damage in vitro. While thymidine alone did not show any remarkable effect, the thymidine uridine combination demonstrated enhanced protective activity compared to uridine alone. Our findings provided the supporting rationale for using uridine or uridine-thymidine ointments in the HF syndrome local therapy. PMID- 22919319 TI - Seed yield of mungbean (Vigna radiata (L.) Wilczek) in relation to growth and developmental aspects. AB - Growth parameters such as leaf area (LA), total dry mass (TDM) production, crop growth rate (CGR), relative growth rate (RGR), and net assimilation rate (NAR) were compared in six varieties of mungbean under subtropical condition (24 degrees 8' N 90 degrees 0' E) to identify limiting growth characters for the efficient application of physiology breeding for higher yields. Results revealed that a relatively smaller portion of TDM was produced before flower initiation and the bulk of it after anthesis. The maximum CGR was observed during pod filling stage in all the varieties due to maximum leaf area (LA) development at this stage. Two plant characters such as LA and CGR contributed to the higher TDM production. Results indicated that high yielding mungbean varieties should possess larger LA, higher TDM production ability, superior CGR at all growth stages, and high relative growth rate and net assimilation rate at vegetative stage which would result in superior yield components. PMID- 22919320 TI - Postharvest analysis of lowland transgenic tomato fruits harboring hpRNAi-ACO1 construct. AB - The plant hormone, ethylene, is an important regulator which involved in regulating fruit ripening and flower senescence. In this study, RNA interference (RNAi) technology was employed to silence the genes involved in ethylene biosynthetic pathway. This was achieved by blocking the expression of specific gene encoding the ACC oxidase. Initially, cDNA corresponding to ACO1 of lowland tomato cultivar (MT1), which has high identity with ACO1 of Solanum lycopersicum in GenBank, was cloned through RT-PCR. Using a partial coding region of ACO1, one hpRNAi transformation vector was constructed and expressed ectopically under the 35S promoter. Results showed that transgenic lines harboring the hpRNA-ACO1 construct had lower ethylene production and a longer shelf life of 32 days as compared to 10 days for wild-type fruits. Changes in cell wall degrading enzyme activities were also investigated in cases where the transgenic fruits exhibited reduced rates of firmness loss, which can be associated with a decrease in pectin methylesterase (PME) and polygalacturonase (PG) activities. However, no significant change was detected in both transgenic and wild-type fruits in terms of beta-galactosidase (beta-Gal) activity and levels of total soluble solid, titratable acid and ascorbic acid. PMID- 22919321 TI - A comparison of third-generation semi-invasive arterial waveform analysis with thermodilution in patients undergoing coronary surgery. AB - Uncalibrated semi-invasive continous monitoring of cardiac index (CI) has recently gained increasing interest. The aim of the present study was to compare the accuracy of CI determination based on arterial waveform analysis with transpulmonary thermodilution. Fifty patients scheduled for elective coronary surgery were studied after induction of anaesthesia and before and after cardiopulmonary bypass (CPB), respectively. Each patient was monitored with a central venous line, the PiCCO system, and the FloTrac/Vigileo-system. Measurements included CI derived by transpulmonary thermodilution and uncalibrated semi-invasive pulse contour analysis. Percentage changes of CI were calculated. There was a moderate, but significant correlation between pulse contour CI and thermodilution CI both before (r(2) = 0.72, P < 0.0001) and after (r(2) = 0.62, P < 0.0001) CPB, with a percentage error of 31% and 25%, respectively. Changes in pulse contour CI showed a significant correlation with changes in thermodilution CI both before (r(2) = 0.52, P < 0.0001) and after (r(2) = 0.67, P < 0.0001) CPB. Our findings demonstrated that uncalibrated semi invasive monitoring system was able to reliably measure CI compared with transpulmonary thermodilution in patients undergoing elective coronary surgery. Furthermore, the semi-invasive monitoring device was able to track haemodynamic changes and trends. PMID- 22919322 TI - Effects of 1-methylcyclopropene and modified atmosphere packaging on the antioxidant capacity in pepper "Kulai" during low-temperature storage. AB - The objective of the present study was to simultaneously evaluate the effect of a postharvest treatment on the pepper's antioxidant content and its ability to retain its economical value during the postharvest period. The fruits were pretreated by modified atmosphere packaging (MAP) with or without treatment with 1-methylcyclopropene (1-MCP) before cold storage at 10 degrees C. Changes in the levels of non-enzymatic antioxidants, including the total phenolic, ascorbic acid levels and the total glutathione level, as well as enzymatic antioxidants, including ascorbate peroxidase (APX), glutathione reductase (GR), and catalase (CAT), were determined. Both treatments successfully extended the shelf life of the fruit for up to 25 days, and a high level of antioxidant capacity was maintained throughout the storage period. However, 1-MCP treatment maintained the high antioxidant capacity for a longer period of time. The 1-MCP-treated peppers maintained high levels of phenolic content, a high reduced glutathione (GSH)/oxidised glutathione (GSSG) ratio, decreased levels of ascorbic acid and CAT activity, and increased levels of APX and GR compared with the peppers that were not treated with 1-MCP. The overall results suggested that a combination of 1-MCP and MAP was the most effective treatment for extending shelf life while retaining the nutritional benefits. PMID- 22919323 TI - Metabolic basis for thyroid hormone liver preconditioning: upregulation of AMP activated protein kinase signaling. AB - The liver is a major organ responsible for most functions of cellular metabolism and a mediator between dietary and endogenous sources of energy for extrahepatic tissues. In this context, adenosine-monophosphate- (AMP-) activated protein kinase (AMPK) constitutes an intrahepatic energy sensor regulating physiological energy dynamics by limiting anabolism and stimulating catabolism, thus increasing ATP availability. This is achieved by mechanisms involving direct allosteric activation and reversible phosphorylation of AMPK, in response to signals such as energy status, serum insulin/glucagon ratio, nutritional stresses, pharmacological and natural compounds, and oxidative stress status. Reactive oxygen species (ROS) lead to cellular AMPK activation and downstream signaling under several experimental conditions. Thyroid hormone (L-3,3',5 triiodothyronine, T(3)) administration, a condition that enhances liver ROS generation, triggers the redox upregulation of cytoprotective proteins affording preconditioning against ischemia-reperfusion (IR) liver injury. Data discussed in this work suggest that T(3)-induced liver activation of AMPK may be of importance in the promotion of metabolic processes favouring energy supply for the induction and operation of preconditioning mechanisms. These include antioxidant, antiapoptotic, and anti-inflammatory mechanisms, repair or resynthesis of altered biomolecules, induction of the homeostatic acute-phase response, and stimulation of liver cell proliferation, which are required to cope with the damaging processes set in by IR. PMID- 22919324 TI - Selection of the in vitro culture media influences mRNA expression of Hedgehog genes, Il-6, and important genes regarding reactive oxygen species in single murine preimplantation embryos. AB - BACKGROUND: The aim of this paper was to determine the influence of different in vitro culture media on mRNA expression of Hedgehog genes, il-6, and important genes regarding reactive oxygen species in single mouse embryos. METHODS: Reverse transcription of single embryos either cultured in vitro from day 0.5 until 3.5 (COOK's Cleavage medium or Vitrolife's G-1 PLUS medium) or in vivo until day 3.5 post coitum. PCR was carried out for beta-actin followed by nested-PCR for shh, ihh, il-6, nox, gpx4, gpx1, and prdx2. RESULTS: The number of murine blastocysts cultured in COOK medium which expressed il-6, gpx4, gpx1, and prdx2 mRNA differed significantly compared to the in vivo group. Except for nox, the mRNA profile of the Vitrolife media group embryos varied significantly from the in vivo ones regarding the number of blastocysts expressing the mRNA of shh, ihh, il-6, gpx4, gpx1 and prdx2. CONCLUSIONS: The present study shows that different in vitro culture media lead to different mRNA expression profiles during early development. Even the newly developed in vitro culture media are not able to mimic the female reproductive tract. The question of long-term consequences for children due to assisted reproduction techniques needs to be addressed in larger studies. PMID- 22919325 TI - ZnFe2O4-TiO2 nanoparticles within mesoporous MCM-41. AB - A novel nanocomposite ZnFe(2)O(4)-TiO(2)/MCM-41 (ZTM) was synthesized by a sol gel method and characterized through X-ray diffraction (XRD), high-resolution transmission electron microscopy (HRTEM), N(2) adsorption-desorption, Raman spectroscopy, and ultraviolet visible (UV-vis) spectrophotometry. The results confirmed the incorporation of ZnFe(2)O(4)-TiO(2) nanoparticles inside the pores of the mesoporous MCM-41 host without destroying its integrity. ZnFe(2)O(4) nanoparticles can inhibit the transformation of anatase into rutile phase of TiO(2). Incorporation of ZnFe(2)O(4)-TiO(2) within MCM-41 avoided the agglomeration of nanoparticles and reduced the band gap energy of TiO(2) to enhance its visible light photocatalytic activity. UV-vis absorption edges of ZTM nanocomposites redshifted with the increase of Zn/Ti molar ratio. The nanocomposite approach could be a potential choice for enhancing the photoactivity of TiO(2), indicating an interesting application in the photodegradation and photoelectric fields. PMID- 22919326 TI - Predictors of prosocial behavior among Chinese high school students in Hong Kong. AB - This study examined the correlates and predictors of prosocial behavior among Chinese adolescents in Hong Kong. A sample of 518 high school students responded to a questionnaire containing measures of antisocial and prosocial behavior, prosocial norms, pragmatic values, moral reasoning, and empathy. Preliminary analyses showed that there were gender differences in some of the measures. While correlation analyses showed that parental education, prosocial norms, pragmatic values, moral reasoning, and empathy were related to prosocial behavior, regression analyses showed that prosocial norms, pragmatic values, and empathy dimensions (personal distress and empathy) were key predictors of it. The findings are largely consistent with theoretical predictions and previous research findings, other than the negative relationship between personal distress and prosocial behavior. The study also underscores the importance of values and norms in predicting prosocial behavior, which has been largely neglected in previous studies. PMID- 22919327 TI - Bioremediation of parboiled rice effluent supplemented with biodiesel-derived glycerol using Pichia pastoris X-33. AB - This paper describes the use of Pichia pastoris X-33 as a bioremediator to reduce the chemical oxygen demand (COD), total Kjeldahl nitrogen (TKN), and phosphorus (P-PO(4) (3-)), after culture in parboiled rice effluent supplemented with p.a. glycerol or a glycerol by-product of the biodiesel industry. The greatest reduction in the COD (55%), TKN (45%), and P-PO(4) (3-) (52%) of the effluent was observed in cultures of P. pastoris X-33 supplemented with 15 g.L(-1) of biodiesel-derived glycerol. Furthermore, the overall biomass yield was 2.1 g.L( 1). These data suggest that biodiesel-derived glycerol is an efficient carbon source for the bioremediation of parboiled rice effluent and biomass production. PMID- 22919328 TI - Subjective outcome evaluation of the project P.A.T.H.S. In different cohorts of students. AB - The project P.A.T.H.S. is an indigenously developed positive youth development program in Hong Kong. In the extension phase (2009/2010 school year), subjective outcome evaluation data were collected from 231 schools involving 89,068 participants after completion of the curricula-based Tier 1 Program. With schools as the units of analysis, results showed that participants generally had positive perceptions of the program content and implementers, with over four-fifth of the participants regarded the program as helpful to them. There were some significant grade differences in the subjective outcome evaluation findings, although the related effect size was not strong. Multiple regression analyses revealed that program content and program implementers predicted perceived effectiveness of the program. The present study suggests that irrespective of cohorts, students in the junior secondary years perceived the program to be beneficial to them. PMID- 22919329 TI - Inconsistent condom use among public primary care patients with tuberculosis in South Africa. AB - The high rate of HIV infections among tuberculosis (TB) patients in South Africa calls for urgent HIV reduction interventions in this subpopulation. While correct and consistent condom use is one of the effective means of HIV prevention among sexually active people, there is insufficient research on condom use among TB patients in South Africa. The aim of this paper was to determine the prevalence of inconsistent condom use among public primary care TB patients and its associated factors using a sample of 4900 TB patients from a cross-sectional survey in three health districts in South Africa. Results indicated that when asked about their consistency of condom use in the past 3 months, 63.5% of the participants reported that they did not always use condoms. In the multivariable analysis, being married (OR = 1.66; 95% CI 1.25-2.20) or cohabitating or separated, divorced, or widowed (OR = 3.67; 1.85-7.29), lower educational level (OR = 0.66; 0.46-0.94), greater poverty (OR = 1.60; 1.25-2.20), not having HIV status disclosed (OR = 0.34; 0.25-0.48), sexual partner on antiretroviral treatment (OR = 0.38; 0.23-0.60), and partner alcohol use before sex (OR = 1.56; 1.30-1.90) were significantly associated with inconsistent condom use in the past 3 months. The low proportion of consistent condom use among TB patients needs to be improved. PMID- 22919330 TI - Expanding the use of a fluorogenic method to determine activity and mode of action of Bacillus thuringiensis bacteriocins against Gram-positive and Gram negative bacteria. AB - Previously we described a rapid fluorogenic method to measure the activity of five bacteriocins produced by Mexican strains of Bacillus thuringiensis against B. cereus 183. Here we standardize this method to efficiently determine the activity of bacteriocins against both Gram-positive and Gram-negative bacteria. It was determined that the crucial parameter required to obtain reproducible results was the number of cells used in the assay, that is, ~4 * 10(8) cell/mL and ~7 * 10(8) cell/mL, respectively, for target Gram-positive and Gram-negative bacteria. Comparative analyses of the fluorogenic and traditional well-diffusion assays showed correlation coefficients of 0.88 to 0.99 and 0.83 to 0.99, respectively, for Gram-positive and Gram-negative bacteria. The fluorogenic method demonstrated that the five bacteriocins of B. thuringiensis have bacteriolytic and bacteriostatic activities against all microorganisms tested, including clinically significant bacteria such as Listeria monocytogenes, Proteus vulgaris, and Shigella flexneri reported previously to be resistant to the antimicrobials as determined using the well-diffusion protocol. These results demonstrate that the fluorogenic assay is a more sensitive, reliable, and rapid method when compared with the well-diffusion method and can easily be adapted in screening protocols for bacteriocin production by other microorganisms. PMID- 22919331 TI - Serum bone resorption markers after parathyroidectomy for renal hyperparathyroidism: correlation analyses for the cross-linked N-telopeptide of collagen I and tartrate-resistant acid phosphatase. AB - Patients on long-term dialysis may develop secondary hyperparathyroidism (SHPT) with increased serum concentrations of bone resorption markers such as the cross linked N-telopeptide of type I collagen (NTX) and type-5b tartrate-resistant acid phosphatase (TRAP). When SHPT proves refractory to treatment, parathyroidectomy (PTX) may be needed. Renal patients on maintenance HD who received PTX for refractory SHPT (n = 23) or who did not develop refractory SHPT (control subjects; n = 25) were followed prospectively for 4 weeks. Serum intact parathyroid hormone (iPTH), NTX, TRAP, and bone alkaline phosphatase (BAP) concentrations were measured serially and correlation analyses were performed. iPTH values decreased rapidly and dramatically. BAP values increased progressively with peak increases observed at 2 weeks after surgery. NTX and TRAP values decreased concurrently and progressively through 4 weeks following PTX. A significant correlation between TRAP and NTX values was observed before PTX but not at 4 weeks after PTX. Additionally, the fractional changes in serum TRAP were larger than those in serum NTX at all times examined after PTX. Serum iPTH, TRAP, and NTX values declined rapidly following PTX for SHPT. Serum TRAP values declined to greater degrees than serum NTX values throughout the 4-week period following PTX. PMID- 22919332 TI - The effect of the retroperitoneal transpsoas minimally invasive lateral interbody fusion on segmental and regional lumbar lordosis. AB - BACKGROUND: The minimally invasive lateral interbody fusion (MIS LIF) in the lumbar spine can correct coronal Cobb angles, but the effect on sagittal plane correction is unclear. METHODS: A retrospective review of thirty-five patients with lumbar degenerative disease who underwent MIS LIF without supplemental posterior instrumentation was undertaken to study the radiographic effect on the restoration of segmental and regional lumbar lordosis using the Cobb angles on pre- and postoperative radiographs. Mean disc height changes were also measured. RESULTS: The mean follow-up period was 13.3 months. Fifty total levels were fused with a mean of 1.42 levels fused per patient. Mean segmental Cobb angle increased from 11.10 degrees to 13.61 degrees (P < 0.001) or 22.6%. L2-3 had the greatest proportional increase in segmental lordosis. Mean regional Cobb angle increased from 52.47 degrees to 53.45 degrees (P = 0.392). Mean disc height increased from 6.50 mm to 10.04 mm (P < 0.001) or 54.5%. CONCLUSIONS: The MIS LIF improves segmental lordosis and disc height in the lumbar spine but not regional lumbar lordosis. Anterior longitudinal ligament sectioning and/or the addition of a more lordotic implant may be necessary in cases where significant increases in regional lumbar lordosis are desired. PMID- 22919333 TI - Evaluation of the stress level of children with idiopathic scoliosis in relation to the method of treatment and parameters of the deformity. AB - Stress level due to existing body deformity as well as to the treatment with a corrective brace is one of factors influencing the quality of life of children with idiopathic scoliosis undergoing non-surgical management. The purpose of the study was to evaluate the stress level among children suffering from idiopathic scoliosis in relation to the method of treatment and the parameters of the deformity. Seventy-three patients with idiopathic scoliosis participated in the study. Fifty-two children were treated by means of physiotherapy, while 21 patients were treated with both Cheneau corrective brace and physiotherapy. To assess the stress level related to the deformity itself and to the method of treatment with corrective brace, the two Bad Sobernheim Stress Questionnaires (BSSQs) were applied, the BSSQ Deformity and the BSSQ Brace, respectively. PMID- 22919334 TI - Spectroscopic evaluation of glioma grading at 3T: the combined role of short and long TE. AB - PURPOSE: To evaluate the diagnostic value of 3T (1)H-MRS in grading cerebral gliomas using short and long echo times. METHODS: 1H-MRS was performed on 71 patients with untreated cerebral gliomas. Metabolite ratios of NAA/Cr, Cho/Cr, Cho/NAA, and mI/Cr were calculated for short and long TE and compared between low and high grade gliomas. Lipids were qualitatively evaluated. ROC analysis was performed to obtain the cut-off values for the metabolic ratios presenting statistical difference between the two glioma grades. RESULTS: Intratumoral Cho/Cr at both TEs and long TE Cho/NAA were significantly different between low and high grade gliomas. Peritumoral NAA/Cr of both TEs, as well as long TE Cho/Cr and Cho/NAA ratios, significantly differentiated the two tumor grades. Diagnostic sensitivity of peritumoral short TE NAA/Cr proved to be superior over the other metabolic ratios, whereas intratumoral short TE Cho/Cr reached the highest levels of specificity and accuracy. Overall, short TE 1H-MRS reached higher total sensitivity in predicting glioma grade, over long TE. CONCLUSION: An advantage was found in using short TE over long TE 1H-MRS in the discrimination of low versus high grade gliomas. Moreover, the results suggested that the peritumoral area of gliomas may be more valuable in predicting glioma grade than using only the intratumoral area. PMID- 22919336 TI - Study of physico-chemical characteristics of wastewater in an urban agglomeration in Romania. AB - This study investigates the level of wastewater pollution by analyzing its chemical characteristics at five wastewater collectors. Samples are collected before they discharge into the Danube during a monitoring campaign of two weeks. Organic and inorganic compounds, heavy metals, and biogenic compounds have been analyzed using potentiometric and spectrophotometric methods. Experimental results show that the quality of wastewater varies from site to site and it greatly depends on the origin of the wastewater. Correlation analysis was used in order to identify possible relationships between concentrations of various analyzed parameters, which could be used in selecting the appropriate method for wastewater treatment to be implemented at wastewater plants. PMID- 22919335 TI - Factors predicting ventilator dependence in patients with ventilator-associated pneumonia. AB - OBJECTIVES: To determine risk factors associated with ventilator dependence in patients with ventilator-associated pneumonia (VAP). STUDY DESIGN: A retrospective study was conducted at Chang Gung Memorial Hospital, Kaohsiung, from January 1, 2007 to January 31, 2008. METHODS: This study evaluated 163 adult patients (aged >= 18 years). Eligibility was evaluated according to the criterion for VAP, Sequential Organ Failure Assessment (SOFA) score, Acute Physiological Assessment and Chronic Health Evaluation II (APACHE II) score. Oxygenation index, underlying comorbidities, septic shock status, previous tracheostomy status, and factors related to pneumonia were collected for analysis. RESULTS: Of the 163 VAP patients in the study, 90 patients survived, yielding a mortality rate of 44.8%. Among the 90 surviving patients, only 36 (40%) had been weaned off ventilators at the time of discharge. Multivariate logistic regression analysis was used to identify underlying factors such as congestive cardiac failure (P = 0.009), initial high oxygenation index value (P = 0.04), increased SOFA scores (P = 0.01), and increased APACHE II scores (P = 0.02) as independent predictors of ventilator dependence. Results from the Kaplan-Meier method indicate that initial therapy with antibiotics could increase the ventilator weaning rate (log Rank test, P < 0.001). CONCLUSIONS: Preexisting cardiopulmonary function, high APACHE II and SOFA scores, and high oxygenation index were the strongest predictors of ventilator dependence. Initial empiric antibiotic treatment can improve ventilator weaning rates at the time of discharge. PMID- 22919337 TI - Spatial and temporal distribution of tuberculosis in the State of Mexico, Mexico. AB - Tuberculosis (TB) is one of the oldest human diseases that still affects large population groups. According to the World Health Organization (WHO), there were approximately 9.4 million new cases worldwide in the year 2010. In Mexico, there were 18,848 new cases of TB of all clinical variants in 2010. The identification of clusters in space-time is of great interest in epidemiological studies. The objective of this research was to identify the spatial and temporal distribution of TB during the period 2006-2010 in the State of Mexico, using geographic information system (GIS) and SCAN statistics program. Nine significant clusters (P < 0.05) were identified using spatial and space-time analysis. The conclusion is that TB in the State of Mexico is not randomly distributed but is concentrated in areas close to Mexico City. PMID- 22919338 TI - Germination and plantlet regeneration of encapsulated microshoots of aromatic rice (Oryza sativa L. Cv. MRQ 74). AB - Plant tissues such as somatic embryos, apical shoot tips, axillary shoot buds, embryogenic calli, and protocom-like bodies are potential micropropagules that have been considered for creating synthetic seeds. In the present study, 3-5 mm microshoots of Oryza sativa L. Cv. MRQ 74 were used as explant sources for obtaining synthetic seeds. Microshoots were induced from stem explants on Murashige and Skoog (MS) medium supplemented with 1.5 mg/L benzylaminopurine (BAP). They were encapsulated in 3% (w/v) sodium alginate, 3% sucrose, 0.1 mg/L BAP, and 0.1 mg/L alpha-Naphthalene acetic acid (NAA). Germination and plantlet regeneration of the encapsulated seeds were tested by culturing them on various germination media. The effect of storage period (15-30 days) was also investigated. The maximum germination and plantlet regeneration (100.0%) were recorded on MS media containing 3% sucrose and 0.8% agar with and without 0.1 mg/L BAP. However, a low germination rate (6.67%) was obtained using top soil as a sowing substrate. The germination rate of the encapsulated microshoots decreased from 93.33% to 3.33% after 30 days of storage at 4 degrees C in the dark. Therefore, further research is being done to improve the germination rate of the synthetic seeds. PMID- 22919339 TI - Temporal dynamics of reproduction of the neotropical fish, Crenicichla menezesi (Perciformes: Cichlidae). AB - The reproductive biology and the gonadal development cycle of the Neotropical cichlid fish, Crenicichla menezesi, is described. This species exhibits sexual dimorphism only during the spawning season. First sexual maturity of females is attained earlier than the males. Both macroscopic and histological investigations of ovaries and testes revealed four stages of gonadal maturation. Mean batch fecundity of females was 372 (+/- 10,41) of mature oocytes. This species is a partial spawner, with an extended spawning period. Monthly values of GSI and the condition factor are negatively correlated during the gonadal development cycle of this species. PMID- 22919340 TI - Subjective outcome evaluation of the project P.A.T.H.S. (extension phase) based on the perspective of program implementer. AB - A total of 231 schools participated in the Project P.A.T.H.S. in 2009/2010 school year. After completion of the Tier 1 Program, subjective outcome evaluation data were collected from 3,259 program implementers. Based on the consolidated data with schools as units, results showed that participants had positive perceptions of the program, implementers, and benefits of the program. More than four-fifth of the implementers regarded the program as helpful to the program participants. Multiple regression analyses revealed that perceived qualities of the program and the program implementers predicted perceived effectiveness of the program. Similar to previous studies, compared to implementers' perception about their performance, the perceived program content appeared to be a stronger predictor of program success. The present study provides additional support for the effectiveness of the Tier 1 Program of the Project P.A.T.H.S. in Hong Kong. PMID- 22919341 TI - Evaluation of the effectiveness of a positive youth development program for secondary students in Macau. AB - A well-tested comprehensive Chinese positive youth development program (Project P.A.T.H.S.) developed in Hong Kong has been modified and adapted for use in Macau. This program aims to help adolescent school children develop positively and to be better prepared for their future. The present study investigated the effectiveness of the Tier 1 Program of "P.A.T.H.S." for Secondary 2 students of two pilot schools. Since there were "repeating" and "transferring" students joining the program, the effectiveness of the program on these particular groups of participants was also examined. The subjective outcome evaluations including participants' perceptions of the program, program instructors, benefits from the program, and overall satisfaction were positive. Although the longitudinal data from the objective outcome evaluation did not show any notable improvement, the overall effect of the program was found to be positive to the new comers in the junior secondary years. The existing evaluation findings suggest that the Secondary 2 program is especially effective to those newly joining the program. In view of the paucity of youth studies in Macau, the present study can contribute to evidence-based youth work and provide baseline data for the program to be evaluated in the Secondary 3 periods in the future. PMID- 22919342 TI - Relationship of nitrogen use efficiency with the activities of enzymes involved in nitrogen uptake and assimilation of finger millet genotypes grown under different nitrogen inputs. AB - Nitrogen responsiveness of three-finger millet genotypes (differing in their seed coat colour) PRM-1 (brown), PRM-701 (golden), and PRM-801 (white) grown under different nitrogen doses was determined by analyzing the growth, yield parameters and activities of nitrate reductase (NR), glutamine synthetase (GS), glutamate synthase; GOGAT, and glutamate dehydrogenase (GDH) at different developmental stages. High nitrogen use efficiency and nitrogen utilization efficiency were observed in PRM-1 genotype, whereas high nitrogen uptake efficiency was observed in PRM-801 genotype. At grain filling nitrogen uptake efficiency in PRM-1 negatively correlated with NR, GS, GOGAT activities whereas it was positively correlated in PRM-701 and PRM-801, however, GDH showed a negative correlation. Growth and yield parameters indicated that PRM-1 responds well at high nitrogen conditions while PRM-701 and PRM-801 respond well at normal and low nitrogen conditions respectively. The study indicates that PRM-1 is high nitrogen responsive and has high nitrogen use efficiency, whereas golden PRM-701 and white PRM-801 are low nitrogen responsive genotypes and have low nitrogen use efficiency. However, the crude grain protein content was higher in PRM-801 genotype followed by PRM-701 and PRM-1, indicating negative correlation of nitrogen use efficiency with source to sink relationship in terms of seed protein content. PMID- 22919343 TI - Methylene blue-aided in vivo staining of central airways during flexible bronchoscopy. AB - BACKGROUND: The early diagnosis of malignant and premalignant changes of the bronchial mucosa remains a major challenge during bronchoscopy. Intravital staining techniques are not new. Previous small case series suggested that analysis of the bronchial mucosal surface using chromoendoscopy allows a prediction between neoplastic and nonneoplastic lesions. OBJECTIVES: The aim of the present study was to evaluate chromobronchoscopy as a method to identify malignant and premalignant lesions in the central airways in a prospective manner. METHODS: In 26 patients we performed chromoendoscopy with 0.1% methylene blue during ongoing flexible white light bronchoscopy. Circumscribed lesions in central airways were further analyzed by biopsies and histopathologic examination. RESULTS: In the majority of cases neither flat nor polypoid lesions in the central airways were stained by methylene blue. In particular, exophytic growth of lung cancer did not show any specific pattern in chromobronchoscopy. However, a specific dye staining was detected in one case where exophytic growth of metastatic colorectal cancer was present in the right upper lobe. In two other cases, a circumscribed staining was noted in unsuspicious mucosa. But histology revealed inflammation only. CONCLUSIONS: In contrast to previous studies, the present findings clearly indicate that chromobronchoscopy is not useful for early detection of malignant or premalignant lesions of the central airways. PMID- 22919344 TI - Proteomic analysis of saliva identifies potential biomarkers for orthodontic tooth movement. AB - Orthodontic treatment has been shown to induce inflammation, followed by bone remodelling in the periodontium. These processes trigger the secretion of various proteins and enzymes into the saliva. This study aims to identify salivary proteins that change in expression during orthodontic tooth movement. These differentially expressed proteins can potentially serve as protein biomarkers for the monitoring of orthodontic treatment and tooth movement. Whole saliva from three healthy female subjects were collected before force application using fixed appliance and at 14 days after 0.014'' Niti wire was applied. Salivary proteins were resolved using two-dimensional gel electrophoresis (2DE) over a pH range of 3-10, and the resulting proteome profiles were compared. Differentially expressed protein spots were then identified by MALDI-TOF/TOF tandem mass spectrometry. Nine proteins were found to be differentially expressed; however, only eight were identified by MALDI-TOF/TOF. Four of these proteins-Protein S100-A9, immunoglobulin J chain, Ig alpha-1 chain C region, and CRISP-3-have known roles in inflammation and bone resorption. PMID- 22919345 TI - mRNA expression of EgCHI1, EgCHI2, and EgCHI3 in oil palm leaves (Elaeis guineesis Jacq.) after treatment with Ganoderma boninense pat. and Trichoderma harzianum Rifai. AB - BACKGROUND: Basal stem rot (BSR) disease caused by the fungus Ganoderma boninense is the most serious disease affecting the oil palm; this is because the disease escapes the early disease detection. The biocontrol agent Trichoderma harzianum can protect the disease only at the early stage of the disease. In the present study, the expression levels of three oil palm (Elaeis guineensis Jacq.) chitinases encoding EgCHI1, EgCHI2, and EgCHI3 at 2, 5, and 8 weeks inoculation were measured in oil palm leaves from plants treated with G. boninense or T. harzianum alone or both. METHODS: The five-month-old oil palm seedlings were treated with Gano-wood blocks inoculum and trichomulch. Expression of EgCHI1, EgCHI2, and EgCHI3 in treated leaves tissue was determined by real-time PCR. RESULTS: Oil palm chitinases were not strongly expressed in oil palm leaves of plants treated with G. boninense alone compared to other treatments. Throughout the 8-week experiment, expression of EgCHI1 increased more than 3-fold in leaves of plants treated with T. harzianum and G. boninense when compared to those of control and other treated plants. CONCLUSION: The data illustrated that chitinase cDNA expression varied depending on tissue and the type of treatment. PMID- 22919346 TI - Spatial variability of metals in surface water and sediment in the langat river and geochemical factors that influence their water-sediment interactions. AB - This paper determines the controlling factors that influence the metals' behavior water-sediment interaction facies and distribution of elemental content ((75)As, (111)Cd, (59)Co, (52)Cr, (60)Ni, and (208)Pb) in water and sediment samples in order to assess the metal pollution status in the Langat River. A total of 90 water and sediment samples were collected simultaneously in triplicate at 30 sampling stations. Selected metals were analyzed using ICP-MS, and the metals' concentration varied among stations. Metal concentrations of water ranged between 0.08-24.71 MUg/L for As, <0.01-0.53 MUg/L for Cd, 0.06-6.22 MUg/L for Co, 0.32 4.67 MUg/L for Cr, 0.80-24.72 MUg/L for Ni, and <0.005-6.99 MUg/L for Pb. Meanwhile, for sediment, it ranged between 4.47-30.04 mg/kg for As, 0.02-0.18 mg/kg for Cd, 0.87-4.66 mg/kg for Co, 4.31-29.04 mg/kg for Cr, 2.33-8.25 mg/kg for Ni and 5.57-55.71 mg/kg for Pb. The average concentration of studied metals in the water was lower than the Malaysian National Standard for Drinking Water Quality proposed by the Ministry of Health. The average concentration for As in sediment was exceeding ISQG standards as proposed by the Canadian Sediment Quality Guidelines. Statistical analyses revealed that certain metals (As, Co, Ni, and Pb) were generally influenced by pH and conductivity. These results are important when making crucial decisions in determining potential hazardous levels of these metals toward humans. PMID- 22919347 TI - Virulence genes and antimicrobial resistance profiles of Pasteurella multocida strains isolated from rabbits in Brazil. AB - Pasteurella multocida is responsible for a wide range of diseases in domestic animals. In rabbits, the agent is related to nasal discharge, pneumonia, otitis media, pyometra, orchitis, abscess, and septicemia. One hundred and forty rabbits with respiratory diseases from four rabbitries in Sao Paulo State, Brazil were evaluated for the detection of P. multocida in their nasal cavities. A total of twenty-nine animals were positive to P. multocida isolation, and 46 strains were selected and characterized by means of biochemical tests and PCR. P. multocida strains were tested for capsular type, virulence genes, and resistance profile. A total of 45.6% (21/46) of isolates belonged to capsular type A, and 54.34% (25/46) of the isolates were untypeable. None of the strains harboured toxA or pfhA genes. The frequency of the other twenty genes tested was variable, and the data generated was used to build a dendrogram, showing the relatedness of strains, which were clustered according to origin. Resistance revealed to be more common against sulfonamides and cotrimoxazole, followed by erythromycin, penicillin, and amoxicillin. PMID- 22919348 TI - Effects of repetitive hyperbaric oxygen treatment in patients with acute cerebral infarction: a pilot study. AB - The role of hyperbaric oxygen therapy (HBOT) in the treatment of acute ischemic stroke is controversial. This prospective study assessed the efficacy and safety of HBOT as adjuvant treatment on 46 acute ischemic stroke in patients who did not receive thrombolytic therapy. The HBOT group (n = 16) received conventional medical treatment with 10 sessions of adjunctive HBOT within 3-5 days after stroke onset, while the control group (n = 30) received the same treatment but without HBOT. Early (around two weeks after onset) and late (one month after onset) outcomes (National Institutes of Health Stroke Scale, NIHSS scores) and efficacy (changes of NIHSS scores) of HBOT were evaluated. The baseline clinical characteristics were similar in both groups. Both early and late outcomes of the HBOT group showed significant difference (P <= 0.001). In the control group, there was only significant difference in early outcome (P = 0.004). For early efficacy, there was no difference when comparing changes of NIHSS scores between the two groups (P = 0.140) but there was statistically significant difference when comparing changes of NIHSS scores at one month (P <= 0.001). The HBOT used in this study may be effective for patients with acute ischemic stroke and is a safe and harmless adjunctive treatment. PMID- 22919349 TI - Potential canonical wnt pathway activation in high-grade astrocytomas. AB - Aberrant wnt pathway activation through cytoplasmic stabilization of beta-catenin is crucial for the development of various human malignancies. In gliomagenesis, the role of canonical (i.e., beta-catenin-dependent) signalling is largely unknown. Here, we studied canonical wnt pathway activation in 15 short-term cultures from high-grade gliomas and potential pathomechanisms leading to cytoplasmic beta-catenin accumulation. Furthermore, we assessed the prognostic relevance of beta-catenin expression in a tissue microarray comprising 283 astrocytomas. Expression of beta-catenin, its transcriptional cofactors TCF-1 and TCF-4 as well as GSK-3beta and APC, constituents of the beta-catenin degradation complex was confirmed by RT-PCR in all cultures. A cytoplasmic beta-catenin pool was detectable in 13/15 cultures leading to some transcriptional activity assessed by luciferase reporter gene assay in 8/13. Unlike other malignancies, characteristic mutations of beta-catenin and APC leading to cytoplasmic stabilization of beta-catenin were excluded by direct sequencing or protein truncation test. In patient tissues, beta-catenin expression was directly and its degradation product's (beta-catenin-P654) expression was inversely correlated with WHO grade. Increased beta-catenin expression and low beta-catenin-P654 expression were associated with shorter survival. Altogether, we report on potential canonical wnt pathway activation in high-grade gliomas and demonstrate that beta-catenin expression in astrocytomas is associated with increased malignancy and adverse outcome. PMID- 22919350 TI - Detection of gastroesophageal reflux esophagitis using 2-fluoro-2-deoxy-d-glucose positron emission tomography. AB - BACKGROUND: Gastroesophageal reflux disease (GERD) is a common disease and a major upper gastrointestinal problem. The purpose of the present study is to evaluate the use of noninvasive 2-fluoro-2-deoxy-d-glucose positron emission tomography (FDG-PET) to detect gastroesophageal reflux esophagitis. MATERIALS AND METHODS: This is a retrospective study reviewing 408 healthy check-up subjects (169 females and 239 men), who underwent both FDG-PET and upper gastrointestinal endoscopy during September 2008 to December 2009. Quantitative analysis of FDG uptake in the distal part of the esophagus was performed by calculating the maximum standard uptake value (SUVmax). This indicated the degree of esophagitis. FDG-PET findings were compared with endoscopic (modified version of the Los Angeles classification) diagnoses as the gold standard. RESULTS: The SUVmax ranged from 1.30 to 3.40 in normal subjects and from 1.30 to 4.00 in subjects with gastroesophageal reflux esophagitis. In the esophagitis group, the SUVmax was 2.13 +/- 0.42 in subjects with modified LA grade M, 2.21 +/- 0.45 in subjects with LA grade A, and 2.48 +/- 0.44 in subjects with LA grade B and C gastroesophageal reflux esophagitis. One-way ANOVA and post-hoc comparison with Bonferroni correction (P value = 0.003) identified statistical differences between the three groups. CONCLUSION: Noninvasive FDG-PET may be useful in the detection and evaluation of various degrees of gastroesophageal reflux esophagitis. PMID- 22919351 TI - Identification of xylem occlusions occurring in cut clematis (Clematis L., fam. Ranunculaceae Juss.) stems during their vase life. AB - During the vase life of cut stems obstruction of xylem vessels occurs due to microbial growth, formation of tyloses, deposition of materials in the lumen of xylem vessels and the presence of air emboli in the vascular system. Such obstructions may restrict water uptake and its transport towards upwards thus lowering their ornamental value and longevity of cut flowers. Clematis is a very attractive plant material which may be used as cut flower in floral compositions. Nothing is known about the histochemical or cytological nature of xylem blockages occurring in cut stems of this plant. This study shows that in clematis, tyloses are the main source of occlusions, although bacteria and some amorphic substances may also appear inside the vessels. A preservative composed of 200 mg dm(-3) 8 HQC (8-hydroxyquinolin citrate) and 2% sucrose arrested bacterial development and the growth of tyloses. This information can be helpful in the development of new treatments to improve keeping qualities of cut clematis stems. PMID- 22919352 TI - Effects of experimental conditions on extraction yield of extracellular polymeric substances by cation exchange resin. AB - Effects of experimental conditions on the yield of extracellular polymeric substances (EPSs) extraction by cation exchange resin (CER) were investigated using activated sludge flocs. The experimental variables included resin dose, extraction time, sample dilution, and storage time. An empirical model was proposed to describe the kinetics of extraction process. The extraction yield increases with the extraction time and CER dose until it reached the maximum amount of EPS extraction. The maximum yield of EPS was affected as well by the sample dilution, exhibiting a decreasing trend with increasing dilution factor. It was also found that the amount of EPS extracted from a raw sample depends on the storage time. Once EPS was extracted from the sample, however, the EPS keeps its original quantity under storage at 4 degrees C. Based on the model, the maximum amount of EPS extraction and yield rate could be estimated for different conditions. Comparing the model parameters allows one to quantitatively compare the extraction efficiencies under various extracting conditions. Based on the results, we recommend the original sample should be diluted with the volume ratio of above 1:2 and a raw sample should be treated quickly to prevent the reduction of sample homogeneity and original integrity. PMID- 22919353 TI - Carrizo citrange plants do not require the presence of roots to modulate the response to osmotic stress. AB - The study of the effects of a specific stress condition on the performance of plants grown under field conditions is difficult due to interactions among multiple abiotic and biotic factors affecting the system. In vitro tissue-culture based techniques allow the study of each adverse condition independently and also make possible to investigate the performance of genotypes of interest under stress conditions avoiding the effect of the root. In this paper, the response of Carrizo citrange, a commercial citrus rootstock, to osmotic stress was evaluated by culturing in vitro intact plants and micropropagated shoots. The osmotic stress was generated by adding two different concentrations of polyethyleneglycol to the culture media. Different parameters such as plant performance, organ length, antioxidant activities, and endogenous contents of proline, malondialdehyde, and hormones were determined. Differently to that observed under high salinity, when subjected to osmotic stress conditions, Carrizo citrange showed increased endogenous levels of MDA, proline, and ABA. These results evidence that the mechanisms of response of Carrizo citrange to saline or osmotic stress are different. The presence of roots was not necessary to activate any of the plant responses which indicates that the organs involved in the stress perception and signaling depends on the type of adverse condition to which plants are subjected. PMID- 22919354 TI - In vitro chondrogenesis transformation study of mouse dental pulp stem cells. AB - A major challenge in the application of mesenchymal stem cells in cartilage reconstruction is that whether the cells are able to differentiate into fully mature chondrocytes before grafting. The aim of this study was to isolate mouse dental pulp stem cells (DPSC) and differentiate them into chondrocytes. For this investigation, morphological, molecular, and biochemical analyses for differentiated cells were used. To induce the chondrocyte differentiation, DPSC were cultured in chondrogenic medium (Zen-Bio, Inc.). Based on morphological analyses using toluidine blue staining, proteoglycan products appear in DPSC after 21 days of chondrocyte induction. Biochemical analyses in differentiated group showed that alkaline phosphatase activity was significantly increased at day 14 as compared to control (P < 0.05). Cell viability analyses during the differentiation to chondrocytes also showed that these cells were viable during differentiation. However, after the 14th day of differentiation, there was a significant decrease (P < 0.05) in the viability proportion among differentiated cells as compared to the control cells. In RT-PCR molecular analyses, mouse DPSC expressed Cd146 and Cd166 which indicated that these cells belong to mesenchymal stem cells. Coll I and Coll II markers showed high expression after 14 and 21 days, respectively. In conclusion, this study showed that DPSC successfully differentiated into chondrocytes. PMID- 22919355 TI - Quantitative portal vein velocity of liver cancer patients with transcatheter arterial chemoembolization on angiography. AB - OBJECTIVE: We applied optical flow method (OFM) to quantify relative velocities of blood flow using digital subtraction angiography (DSA) in the vascular analysis of hepatocellular carcinoma (HCC) patients who underwent transarterial chemoembolization (TACE) treatment. METHODS: A total of 40 HCC patients treated by TACE were analyzed in this study. DSA imaging with a 12-inch field of view, 1024 * 1024 pixels and 4 frames/second was acquired. OFM developed for motion estimation is applied for blood flow estimation. Two acrylic phantoms were built to validate the method. RESULTS: The relationship between the OFM and Doppler measurements was found linear with R(2) = 0.99 for both straight and curved tube phantoms. Quantitative blood flow distribution images of the portal vein region were presented. After TACE, the minimum, maximum and mean velocities in the portal vein all decreased (P < 0.05). Additionally, the velocity in the portal vein is significantly lower with a higher Child-Pugh score (P < 0.01). CONCLUSIONS: The present technique provides add-on quantitative information of flows to DSA and the hemodynamic analysis in relative quantifications of blood flow in portal vein of hepatocellular carcinoma patients using DSA. PMID- 22919356 TI - Reliability and validity of the Greek QLQ-C30 and QLQ-MY20 for measuring quality of life in patients with multiple myeloma. AB - OBJECTIVES: The aim of this study was to assess the psychometric properties of the Greek EORTC QLQ-C30 and QLQ-MY20 instruments. METHOD: A sample of myeloma patients (N = 89) from two tertiary hospitals were surveyed with the QLQ-C30, QLQ MY20 and various demographic and disease related questions. The previously validated Greek SF-36 instrument was used as a "gold standard" for health-related quality of life (HRQoL) comparisons. Hypothesized scale structure, internal consistency reliability (Cronbach's alpha) and various forms of construct validity (convergent, discriminative, concurrent and known-groups) were assessed. RESULTS: Multitrait scaling confirmed scale structure of the QLQ-C30 and QLQ MY20, with good item convergence (96% and 72%) and discrimination (78% and 58%) rates. Cronbach's alpha was >0.70 for all but one scale (cognitive functioning). Spearman's correlations between similar QLQ-C30 and SF-36 scales ranged between 0.35-0.80 (P < 0.001). Expected interscale correlations and known-groups comparisons supported construct validity. QLQ-MY20 scales showed comparatively lower correlations with QLQ-C30 functional scales, and higher correlations with conceptually related symptom scales. CONCLUSIONS: The observed psychometric properties of the two instruments imply suitability for assessing myeloma HRQoL in Greece. Future studies should focus on generalizability of the results, as well as on specific issues such as longitudinal validity and responsiveness. PMID- 22919357 TI - Radioprotective effect of alk(en)yl thiosulfates derived from allium vegetables against DNA damage caused by X-ray irradiation in cultured cells: antiradiation potential of onions and garlic. AB - To evaluate a radioprotective effect of sodium n-propyl thiosulfate (NPTS) and sodium 2-propenyl thiosulfate (2PTS) derived from onions and garlic, respectively, rat hepatoma H4IIE cells and mouse lymphoma L5178Y cells were preincubated with each of these compounds for 48 hours at 37 degrees C before receiving 10 Gy of X-ray irradiation. Cell damage caused by the irradiation was quantified as comet tail moment, which represents the degree of DNA damage. X-ray induced DNA damage was significantly decreased in both H4IIE and L5178Y cells by micromolar concentrations of NPTS and 2PTS compared with the control without the compounds. The protective effect was more potent with 2PTS than NPTS. Onions and garlic have antiradiation potential. PMID- 22919358 TI - Deriving freshwater quality criteria for iron, lead, nickel, and zinc for protection of aquatic life in Malaysia. AB - Freshwater quality criteria for iron (Fe), lead (Pb), nickel (Ni), and zinc (Zn) were developed with particular reference to aquatic biota in Malaysia, and based on USEPA's guidelines. Acute toxicity tests were performed on eight different freshwater domestic species in Malaysia which were Macrobrachium lanchesteri (prawn), two fish: Poecilia reticulata and Rasbora sumatrana, Melanoides tuberculata (snail), Stenocypris major (ostracod), Chironomus javanus (midge larvae), Nais elinguis (annelid), and Duttaphrynus melanostictus (tadpole) to determine 96 h LC(50) values for Fe, Pb, Ni, and Zn. The final acute value (FAV) for Fe, Pb, Ni, and Zn were 74.5, 17.0, 165, and 304.9 MUg L(-1), respectively. Using an estimated acute-to-chronic ratio (ACR) of 8.3, the value for final chronic value (FCV) was derived. Based on FAV and FCV, a criterion maximum concentration (CMC) and a criterion continuous concentration (CCC) for Fe, Pb, Ni, and Zn that are 37.2, 8.5, 82.5, and 152.4 MUg L(-1) and 9.0, 2.0, 19.9, and 36.7 MUg L(-1), respectively, were derived. The results of this study provide useful data for deriving national or local water quality criteria for Fe, Pb, Ni, and Zn based on aquatic biota in Malaysia. Based on LC(50) values, this study indicated that N. elinguis, M. lanchesteri, N. elinguis, and R. sumatrana were the most sensitive to Fe, Pb, Ni, and Zn, respectively. PMID- 22919359 TI - Muscle-derived cells for treatment of iatrogenic sphincter damage and urinary incontinence in men. AB - INTRODUCTION: Aim of this study was to assess the safety and efficacy of injection of autologous muscle-derived cells into the urinary sphincter for treatment of postprostatectomy urinary incontinence in men and to characterize the injected cells prior to transplantation. METHODS: 222 male patients with stress urinary incontinence and sphincter damage after uroloical procedures were treated with transurethral injection of autologous muscle-derived cells. The transplanted cells were investigated after cultivation and prior to application by immunocytochemistry using different markers of myogenic differentiation. Feasibility and functionality assessment was achieved with a follow-up of at least 12 months. RESULTS: Follow-up was at least 12 months. Of the 222 treated patients, 120 responded to therapy of whom 26 patients (12%) were continent, and 94 patients (42%) showed improvement. In 102 (46%) patients, the therapy was ineffective. Clinical improvement was observed on average 4.7 months after transplantation and continued in all improved patients. The cells injected into the sphincter were at least ~50% of myogenic origin and representative for early stages of muscle cell differentiation. CONCLUSIONS: Transurethral injection of muscle-derived cells into the damaged urethral sphincter of male patients is a safe procedure. Transplanted cells represent different phases of myogenic differentiation. PMID- 22919360 TI - Postlecture evaluation of a positive youth development subject for university students in Hong Kong. AB - The purpose of this study was to examine the postlecture evaluation by the students taking a course (Tomorrow's Leaders) that attempted to promote their leadership qualities and intrapersonal competencies at The Hong Kong Polytechnic University in Hong Kong. Except for the last lecture, students were invited to respond to a 12-item postlecture questionnaire after each lecture. Results showed that the students had positive perceptions of the subject, class, and teacher attributes, and they had positive global evaluation of the teacher and the subject. The postlecture evaluation questionnaire was found to possess good psychometric properties. Multiple regression analyses showed that subject, class, and teacher attributes were predictive of global evaluation of the lecture and the teacher. In conjunction with other evaluation findings, the present findings strongly suggest that students had positive perceptions of the attributes and benefits of "Tomorrow's Leaders." PMID- 22919362 TI - 18FDG uptake in sinonasal inverted papilloma detected by positron emission tomography/computed tomography. AB - Inverted papilloma (IP) is a benign but locally aggressive sinonasal tumour. Aggressive surgical treatment has thus been traditionally recommended because of the risk of transformation in squamous carcinoma. CT and MRI are used to evaluate bone destruction and soft-tissue extension before surgery but may be ineffective to differentiate an inverted papilloma from squamous cell carcinoma. In recent years, F-18 Fluorodeoxyglucose positron emission tomography ((18)FDG-PET) is widely used as diffuse imaging procedure for diagnosis and followup of malignancy affecting the head and neck district. To evaluate the utility of (18)FDG-PET/CT in the diagnosis of patients with suspicious lesions for IP, twelve patients with suspicious sinonasal inverted papilloma were selected for this study. (18)FDG PET/CT imaging was performed, and standard uptake value (SUV) was calculated for each patient. SUV(max) was considered as the maximum value measured in the visualized lesions. Seven of the twelve cases exhibited uptake of (18)FFDG with an SUV(max) ranging from 1 to 8.1. Histopathologic diagnosis after surgery confirmed the diagnosis of IP in five cases; all these cases had an SUV(max) > 3. The five cases, which exhibited absence of (18)FDG uptake, had a histological diagnosis of absence of IP. PMID- 22919363 TI - Regularization in retrieval-driven classification of clustered microcalcifications for breast cancer. AB - We propose a regularization based approach for case-adaptive classification in computer-aided diagnosis (CAD) of breast cancer. The goal is to improve the classification accuracy on a query case by making use of a set of similar cases retrieved from an existing library of known cases. In the proposed approach, a prior is first derived from a traditional CAD classifier (which is typically pre trained offline on a set of training cases). It is then used together with the retrieved similar cases to obtain an adaptive classifier on the query case. We consider two different forms for the regularization prior: one is fixed for all query cases and the other is allowed to vary with different query cases. In the experiments the proposed approach is demonstrated on a dataset of 1,006 clinical cases. The results show that it could achieve significant improvement in numerical efficiency compared with a previously proposed case adaptive approach (by about an order of magnitude) while maintaining similar (or better) improvement in classification accuracy; it could also adapt faster in performance with a small number of retrieved cases. Measured by the area of under the ROC curve (AUC), the regularization based approach achieved AUC = 0.8215, compared with AUC = 0.7329 for the baseline classifier (P-value = 0.001). PMID- 22919361 TI - An emerging new paradigm in opioid withdrawal: a critical role for glia-neuron signaling in the periaqueductal gray. AB - The chronic use of opiates (i.e., narcotics such as the natural derivatives of opium including morphine or codeine) or opioids (i.e., semisynthetic derivatives of opium and other molecules that activate opioid receptors) induces dependence, which is associated with various specific behavioral and somatic signs after their withdrawal or after the administration of an opioid antagonist. Among the brain regions implicated in opiate dependence and withdrawal, the periaqueductal gray area (PAG) appears to be critical in regulating the complex signs and symptoms of opioid withdrawal. Numerous neurochemical mechanisms in the PAG have been identified that may contribute to the opioid withdrawal syndrome. Accumulating evidence suggests that glial activation leading to the release of proinflammatory molecules acting on neurons is important in the complex syndrome of opioid dependence and withdrawal. This paper focuses on the recent advances in our understanding of the vital role that glia-neuron interactions play in opioid dependence and withdrawal within the PAG. We summarize those neurochemical mechanisms associated with opioid withdrawal including the recently defined importance of TNFalpha release from activated glial cells that communicate with TNF receptors on PAG neurons. PMID- 22919364 TI - Correlations among PPARgamma, DNMT1, and DNMT3B Expression Levels and Pancreatic Cancer. AB - Emerging evidence indicates that peroxisome proliferator-activated receptor gamma (PPARgamma) and DNA methyltransferases (DNMTs) play a role in carcinogenesis. In this study we aimed to evaluate the expression of PPARgamma, DNMT1, and DNMT3B and their correlation with clinical-pathological features in patients with pancreatic cancer (PC), and to define the effect of PPARgamma activation on DNMTs expression in PC cell lines. qRT-PCR analysis showed that DNMT3B expression was downregulated in tumors compared to normal tissues (P = 0.03), whereas PPARgamma and DNMT1 levels did not show significant alterations in PC patients. Expression levels between PPARgamma and DNMT1 and between DNMT1 and DNMT3B were highly correlated (P = 0.008 and P = 0.05 resp.). DNMT3B overexpression in tumor tissue was positively correlated with both lymph nodes spreading (P = 0.046) and resection margin status (P = 0.04), and a borderline association with perineural invasion (P = 0.06) was found. Furthermore, high levels of DNMT3B expression were significantly associated with a lower mortality in the whole population (HR = 0.485; 95%CI = 0.262-0.895, P = 0.02) and in the subgroup of patients without perineural invasion (HR = 0.314; 95%CI = 0.130-0.758; P = 0.01), while such association was not observed in patients with tumor invasion into perineural structures (P = 0.70). In conclusion, in vitro and in vivo PPARgamma and DNMTs appear interrelated in PC, and this interaction might influence cell phenotype and disease behavior. PMID- 22919366 TI - The Nitrated Fatty Acid 10-Nitro-oleate Diminishes Severity of LPS-Induced Acute Lung Injury in Mice. AB - Acute lung injury (ALI) is an inflammatory condition culminating in respiratory failure. There is currently no effective pharmacological treatment. Nitrated fatty acids (NFAs) have been shown to exert anti-inflammatory effects. We therefore hypothesized that delivery of NFAs directly to the site of inflammation would reduce the severity of ALI. Pulmonary delivery of 10-nitro-oleate following endotoxin-induced ALI in mice reduced markers of lung inflammation and injury, including capillary leakage, lung edema, infiltration of neutrophils into the lung, and oxidant stress, as well as plasma levels of proinflammatory cytokines. Nitro-oleate delivery likewise downregulated expression of proinflammatory genes by alveolar macrophages, key cells in regulation of lung inflammation. These effects may be accounted for by the observed increases in the activity of PPAR gamma and the PPAR-gamma-induced antioxidant transcription factor Nrf2, together with the decreased activity of NF-kappaB. Our results demonstrate that pulmonary delivery of NFAs reduces severity of acute lung injury and suggest potential utility of these molecules in other inflammatory lung diseases. PMID- 22919365 TI - PPAR Medicines and Human Disease: The ABCs of It All. AB - ATP-dependent binding cassette (ABC) transporters are a family of transmembrane proteins that pump a variety of hydrophobic compounds across cellular and subcellular barriers and are implicated in human diseases such as cancer and atherosclerosis. Inhibition of ABC transporter activity showed promise in early preclinical studies; however, the outcomes in clinical trials with these agents have not been as encouraging. Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors that regulate genes involved in fat and glucose metabolism, and inflammation. Activation of PPAR signaling is also reported to regulate ABC gene expression. This suggests the potential of PPAR medicines as a novel means of controlling ABC transporter activity at the transcriptional level. This paper summarizes the advances made in understanding how PPAR medicines affect ABC transporters, and the potential implications for impacting on human diseases, in particular with respect to cancer and atherosclerosis. PMID- 22919367 TI - Efficient differentiation of mouse embryonic stem cells into insulin-producing cells. AB - Embryonic stem (ES) cells are a potential source of a variety of differentiated cells for cell therapy, drug discovery, and toxicology screening. Here, we present an efficacy strategy for the differentiation of mouse ES cells into insulin-producing cells (IPCs) by a two-step differentiation protocol comprising of (i) the formation of definitive endoderm in monolayer culture by activin A, and (ii) this monolayer endoderm being induced to differentiate into IPCs by nicotinamide, insulin, and laminin. Differentiated cells can be obtained within approximately 7 days. The differentiation IPCs combined application of RT-PCR, ELISA, and immunofluorescence to characterize phenotypic and functional properties. In our study, we demonstrated that IPCs produced pancreatic transcription factors, endocrine progenitor marker, definitive endoderm, pancreatic beta-cell markers, and Langerhans alpha and delta cells. The IPCs released insulin in a manner that was dose dependent upon the amount of glucose added. These techniques may be able to be applied to human ES cells, which would have very important ramifications for treating human disease. PMID- 22919368 TI - Antioxidant sol-gel improves cutaneous wound healing in streptozotocin-induced diabetic rats. AB - We examined the effects of vitamin C in Pluronic F127 on diabetic wound healing. Full-thickness excision skin wounds were made in normal and diabetic Wistar rats to evaluate the effect of saline, saline plus vitamin C (antioxidant sol), Pluronic F127, or Pluronic F127 plus vitamin C (antioxidant sol-gel). The rate of wound contraction, the levels of epidermal and dermal maturation, collagen synthesis, and apoptosis production in the wound tissue were determined. In vitro data showed that after 6 hours of air exposure, the order of the scavenging abilities for HOCl, H(2)O(2), and O(2) (-) was antioxidant sol-gel > antioxidant saline > Pluronic F127 = saline. After 7 and 14 days of wound injury, the antioxidant sol-gel improved wound healing significantly by accelerated epidermal and dermal maturation, an increase in collagen content, and a decrease in apoptosis formation. However, the wounds of all treatments healed mostly at 3 weeks. Vitamin C in Pluronic F127 hastened cutaneous wound healing by its antioxidant and antiapoptotic mechanisms through a good drug delivery system. This study showed that Pluronic F127 plus vitamin C could potentially be employed as a novel wound-healing enhancer. PMID- 22919369 TI - Impact of diabetes and hyperglycemia on survival in advanced breast cancer patients. AB - PURPOSE: We examined the impact of diabetes and hyperglycemia on cancer-specific survival of patients with metastatic or recurrent breast cancer (BC). METHODS: We performed a retrospective analysis of 265 patients with advanced BC receiving palliative chemotherapy. BC-specific mortality was compared for diabetic and nondiabetic patients as well as for patients that presented hyperglycemia during treatment. RESULTS: No difference was observed between the diabetic and nondiabetic patients in terms of overall survival (OS). A difference in OS was observed between nondiabetic patients and diabetic patients who had hyperglycemia. The OS was greater in diabetic patients with proper metabolic control than diabetic patients with hyperglycemia. The risk of death was higher in patients with mean glucose levels >130 mg/dL during treatment. Several factors were associated with poor OS: tumor stage, hormone-receptor-negative tumors, HER2 negative disease, multiple metastatic sites, presence of visceral metastases, and mean glucose >130 mg/dL. CONCLUSION: Elevated glucose levels are associated with a poor outcome in diabetic and nondiabetic patients in contrast to patients with normoglycemic levels, conferring an elevated risk of death. According to these results, clinicians should monitor glucose levels during treatment for advanced breast cancer disease and take action to maintain normal glucose levels. PMID- 22919370 TI - Random bin for analyzing neuron spike trains. AB - When analyzing neuron spike trains, it is always the problem of how to set the time bin. Bin width affects much to analyzed results of such as periodicity of the spike trains. Many approaches have been proposed to determine the bin setting. However, these bins are fixed through the analysis. In this paper, we propose a randomizing method of bin width and location instead of conventional fixed bin setting. This technique is applied to analyzing periodicity of interspike interval train. Also the sensitivity of the method is presented. PMID- 22919371 TI - A new stochastic technique for Painleve equation-I using neural network optimized with swarm intelligence. AB - A methodology for solution of Painleve equation-I is presented using computational intelligence technique based on neural networks and particle swarm optimization hybridized with active set algorithm. The mathematical model of the equation is developed with the help of linear combination of feed-forward artificial neural networks that define the unsupervised error of the model. This error is minimized subject to the availability of appropriate weights of the networks. The learning of the weights is carried out using particle swarm optimization algorithm used as a tool for viable global search method, hybridized with active set algorithm for rapid local convergence. The accuracy, convergence rate, and computational complexity of the scheme are analyzed based on large number of independents runs and their comprehensive statistical analysis. The comparative studies of the results obtained are made with MATHEMATICA solutions, as well as, with variational iteration method and homotopy perturbation method. PMID- 22919372 TI - Prediction of the setting properties of calcium phosphate bone cement. AB - Setting properties of bone substitutes are improved using an injectable system. The injectable bone graft substitutes can be molded to the shape of the bone cavity and set in situ when injected. Such system is useful for surgical operation. The powder part of the injectable bone cement is included of beta tricalcium phosphate, calcium carbonate, and dicalcium phosphate and the liquid part contains poly ethylene glycol solution with different concentrations. In this way, prediction of the mechanical properties, setting times, and injectability helps to optimize the calcium phosphate bone cement properties. The objective of this study is development of three different adaptive neurofuzzy inference systems (ANFISs) for estimation of compression strength, setting time, and injectability using the data generated based on experimental observations. The input parameters of models are polyethylene glycol percent and liquid/powder ratio. Comparison of the predicted values and measured data indicates that the ANFIS model has an acceptable performance to the estimation of calcium phosphate bone cement properties. PMID- 22919373 TI - Interspike interval based filtering of directional selective retinal ganglion cells spike trains. AB - The information regarding visual stimulus is encoded in spike trains at the output of retina by retinal ganglion cells (RGCs). Among these, the directional selective cells (DSRGC) are signaling the direction of stimulus motion. DSRGCs' spike trains show accentuated periods of short interspike intervals (ISIs) framed by periods of isolated spikes. Here we use two types of visual stimulus, white noise and drifting bars, and show that short ISI spikes of DSRGCs spike trains are more often correlated to their preferred stimulus feature (that is, the direction of stimulus motion) and carry more information than longer ISI spikes. Firstly, our results show that correlation between stimulus and recorded neuronal response is best at short ISI spiking activity and decrease as ISI becomes larger. We then used grating bars stimulus and found that as ISI becomes shorter the directional selectivity is better and information rates are higher. Interestingly, for the less encountered type of DSRGC, known as ON-DSRGC, short ISI distribution and information rates revealed consistent differences when compared with the other directional selective cell type, the ON-OFF DSRGC. However, these findings suggest that ISI-based temporal filtering integrates a mechanism for visual information processing at the output of retina toward higher stages within early visual system. PMID- 22919374 TI - Review of minimally invasive esophagectomy and current controversies. AB - Esophagectomy is a complex operation with significant morbidity and mortality. Minimally invasive esophagectomy (MIE) was described in the 1990s in an effort to reduce operative morbidity. Since then many institutions have adopted and described their series with this technique. This paper reviews the literature on the variety of MIE techniques, clinical and quality of life outcomes with open versus MIE, and controversies surrounding MIE-such as prone positioning, stapling techniques, size of the gastric conduit, and robotic techniques. PMID- 22919376 TI - Anesthesia for pars plana vitrectomy with insulin needle, is it possible? AB - Peribulbar block is commonly used for ocular posterior segment surgery. This work aimed to compare the efficacy of using 12.5 mm to 25 mm standard needle length in performing single injection peribulbar block for retinal surgery. Peribulbar block was performed in 120 patients using either standard 25 mm or 12.5 mm 30 G needle (insulin needle). While applying digital pressure around the needle hub, 8 10 mL of local anesthetic are injected. Ocular movement was assessed at 5 and 10 min using simple akinesia score (0-8). If after 10 min score was >1, supplementary injection was given. Visual analogue scale (0-10) was used at the end of the procedure to assess surgeons' satisfaction and patients' intraoperative pain. No differences in akinesia score at 5 & 10 min (P = 0.34 and 0.36, resp.). Initial volume injected was comparable between groups (P = 0.31), however total volume of local anesthesia and supplementary injections were significantly higher in 12.5 mm group (P = 0.03 and 0.01, resp.). No difference as regard surgeons' satisfaction and patients' intraoperative pain (P = 1.0 and 0.18, resp.). Peribulbar block with 12.5 mm needle together with digital compression is a suitable alternative to the standard block with 25 mm needle length for retinal surgery. PMID- 22919377 TI - Autologous blood transfusion after local infiltration analgesia with ropivacaine in total knee and hip arthroplasty. AB - Aims. To study the safety of autotransfusion following local infiltration analgesia (LIA) with ropivacaine. Background. Knowledge of blood concentrations of ropivacaine after LIA and autotransfusion is crucial. However, very limited data are available for toxicological risk assessment. Methods. Autotransfusion was studied in patients after total knee arthroplasty (TKA: n = 25) and total hip arthroplasty (THA: n = 27) with LIA using 200 mg ropivacaine, supplemented with two postoperative bolus injections (150 mg ropivacaine). Drainage blood was reinfused within 6 h postoperatively. Results. Reinfusion caused a significant increase in the serum concentration of total ropivacaine for TKA from 0.54 +/- 0.17 (mean +/- SD) to 0.79 +/- 0.20 MUg/mL (P < 0.001) and a nonsignificant increase for THA from 0.62 +/- 0.17 to 0.63 +/- 0.18 MUg/mL. The maximum free (unbound) concentration after reinfusion was 0.038 MUg/mL. Peak total and free venous ropivacaine concentrations after 8 h and 16 h postoperative bolus injections were 2.6 MUg/mL and 0.11 MUg/mL, respectively. All concentrations observed were below the threshold for toxicity and no side effects were observed. Conclusion. Autotransfusion of patients undergoing knee or hip arthroplasty after local infiltration analgesia with 200 mg ropivacaine can be performed safely, even supplemented with 8 h and 16 h postoperative bolus injections. PMID- 22919375 TI - Predictive biomarkers of bacillus calmette-guerin immunotherapy response in bladder cancer: where are we now? AB - The most effective therapeutic option for managing nonmuscle invasive bladder cancer (NMIBC), over the last 30 years, consists of intravesical instillations with the attenuated strain Bacillus Calmette-Guerin (the BCG vaccine). This has been performed as an adjuvant therapeutic to transurethral resection of bladder tumour (TURBT) and mostly directed towards patients with high-grade tumours, T1 tumours, and in situ carcinomas. However, from 20% to 40% of the patients do not respond and frequently present tumour progression. Since BCG effectiveness is unpredictable, it is important to find consistent biomarkers that can aid either in the prediction of the outcome and/or side effects development. Accordingly, we conducted a systematic critical review to identify the most preeminent predictive molecular markers associated with BCG response. To the best of our knowledge, this is the first review exclusively focusing on predictive biomarkers for BCG treatment outcome. Using a specific query, 1324 abstracts were gathered, then inclusion/exclusion criteria were applied, and finally 87 manuscripts were included. Several molecules, including CD68 and genetic polymorphisms, have been identified as promising surrogate biomarkers. Combinatory analysis of the candidate predictive markers is a crucial step to create a predictive profile of treatment response. PMID- 22919378 TI - Generativity as a route to active ageing. AB - We elucidate the significance of active ageing from an individual as well as from a societal perspective. Taking an individual perspective, maintaining activity in later years is linked to successful ageing because of empirical relationships to positive self-perception, satisfaction with life, and development of competences, whereas from a societal perspective, active ageing implies usage of older people's life competences as a human capital of society-a societal imperative, particularly in times of demographic change but also more basically substantiated in an ethics of responsibility, intergenerational solidarity, and generation equity. We focus on the psychological construct of generativity which is interpreted as an aspect of the philosophical-anthropological category of joint responsibility. Our own research in Mexico and the Baltic States supports the notion that maintaining access to the public sphere and active engagement for others is a more basic individual concern than a life-stages specific developmental task. We report background and results of a Dialogue Forum Project Funding, a research cooperation between our institute and the Foundation Remembrance, Responsibility, and Future aimed to improve generativity in Belarus, Russia, and Ukraine by implementing and supporting local initiatives offering opportunities for intergenerational dialogue. PMID- 22919379 TI - Impact of inappropriate empiric antimicrobial therapy on mortality of septic patients with bacteremia: a retrospective study. AB - Background. Inappropriate empiric antimicrobials could be a major cause of unfavorable mortality rates in co-morbid patients. This study aimed to assess the prevalence and impact of first-dose and 24-hour inappropriate antimicrobials on mortality rates of bacteremic septic patients. Methods. A retrospective cohort study was employed. Case record forms of patients diagnosed as sepsis, severe sepsis, or septic shock with positive hemoculture during 2009 were retrieved from the medical wards, Siriraj Hospital. Demographic data, antimicrobial use, types of bacteria isolated from blood and susceptibilities, patients' comorbidities, 28 day and overall mortality rates were collected and analyzed. Results. There were 229 cases, mean age (SD) of 63.5 (17.2) years and mean (SD) APACHE II score of 24.7 (6.8). The prevalence of first-dose and 24-hour inappropriate antimicrobials was 29.7% and 25.3%, respectively. The 28-day and overall mortality rates between first-dose inappropriate and appropriate antimicrobial were 67.6% versus 60.2% (P = 0.301) and 75.0% versus 68.3% (P = 0.345), consequently. Patients with septic shock and inappropriate first-dose antimicrobials significantly had higher 28-day mortality rate (61.6% versus 41.9%; P = 0.017). Conclusion. Higher mortality rates in bacteremic septic patients were substantially associated with inappropriate first-dose antimicrobials and 3-hour delayed antimicrobial administration after sepsis diagnosis. PMID- 22919380 TI - Sequence Complexity of Chromosome 3 in Caenorhabditis elegans. AB - The nucleotide sequences complexity in chromosome 3 of Caenorhabditis elegans (C. elegans) is studied. The complexity of these sequences is compared with some random sequences. Moreover, by using some parameters related to complexity such as fractal dimension and frequency, indicator matrix is given a first classification of sequences of C. elegans. In particular, the sequences with highest and lowest fractal value are singled out. It is shown that the intrinsic nature of the low fractal dimension sequences has many common features with the random sequences. PMID- 22919382 TI - Thyroid peroxidase gene mutation in patients with congenital hypothyroidism in isfahan, iran. AB - Background. Thyroid peroxidase gene (TPO) mutations are one of the most common causes of thyroid dyshormonogenesis in patients with congenital hypothyroidism (CH). In this study, the prevalence of TPO gene mutations in patients with thyroid dyshormonogenesis in Isfahan was investigated. Methods. In this cross sectional study, genomic DNA of 41 patients with permanent CH due to thyroid dyshormonogenesis was extracted using the salting out method. The 17 exonic regions of the TPO gene were amplified. SSCP technique was performed for scanning of the exonic regions of the TPO gene, except exon 8. DNA sequencing was performed for those with different migration patterns in SSCP by chain termination method. Exon 8 was sequenced directly in all patients. In 4 patients, all fragments were also sequenced. Results. One missense mutation c.2669G > A (NM_000547.5) at exon 15 (14th coding exon) in one patient in homozygous form and seven different single nucleotide polymorphisms (SNPs) in exons 1, 7, 8, 11, and 15 of TPO gene. Conclusion. The TPO gene mutations among CH patients with dyshormonogenesis in Isfahan were less frequent in comparison with other similar studies. It may be due to the presence of other unknown gene mutations which could not be detected by SSCP and sequencing methods. PMID- 22919381 TI - Drug-induced oxidative stress and toxicity. AB - Reactive oxygen species (ROS) are a byproduct of normal metabolism and have roles in cell signaling and homeostasis. Species include oxygen radicals and reactive nonradicals. Mechanisms exist that regulate cellular levels of ROS, as their reactive nature may otherwise cause damage to key cellular components including DNA, protein, and lipid. When the cellular antioxidant capacity is exceeded, oxidative stress can result. Pleiotropic deleterious effects of oxidative stress are observed in numerous disease states and are also implicated in a variety of drug-induced toxicities. In this paper, we examine the nature of ROS-induced damage on key cellular targets of oxidative stress. We also review evidence implicating ROS in clinically relevant, drug-related side effects including doxorubicin-induced cardiac damage, azidothymidine-induced myopathy, and cisplatin-induced ototoxicity. PMID- 22919383 TI - Potential anticancer properties of grape antioxidants. AB - Dietary intake of foods rich in antioxidant properties is suggested to be cancer protective. Foods rich in antioxidant properties include grape (Vitis vinifera), one of the world's largest fruit crops and most commonly consumed fruits in the world. The composition and cancer-protective effects of major phenolic antioxidants in grape skin and seed extracts are discussed in this review. Grape skin and seed extracts exert strong free radical scavenging and chelating activities and inhibit lipid oxidation in various food and cell models in vitro. The use of grape antioxidants are promising against a broad range of cancer cells by targeting epidermal growth factor receptor (EGFR) and its downstream pathways, inhibiting over-expression of COX-2 and prostaglandin E2 receptors, or modifying estrogen receptor pathways, resulting in cell cycle arrest and apoptosis. Interestingly, some of these activities were also demonstrated in animal models. However, in vivo studies have demonstrated inconsistent antioxidant efficacy. Nonetheless, a growing body of evidence from human clinical trials has demonstrated that consumption of grape, wine and grape juice exerts many health promoting and possible anti-cancer effects. Thus, grape skin and seed extracts have great potential in cancer prevention and further investigation into this exciting field is warranted. PMID- 22919384 TI - Tumor angiogenesis 2012. PMID- 22919385 TI - Histopathological growth pattern, proteolysis and angiogenesis in chemonaive patients resected for multiple colorectal liver metastases. AB - The purpose of this study was to characterise growth patterns, proteolysis, and angiogenesis in colorectal liver metastases from chemonaive patients with multiple liver metastases. Twenty-four patients were included in the study, resected for a median of 2.6 metastases. The growth pattern distribution was 25.8% desmoplastic, 33.9% pushing, and 21% replacement. In 20 patients, identical growth patterns were detected in all metastases, but in 8 of these patients, a second growth pattern was also present in one or two of the metastases. In the remaining 4 patients, no general growth pattern was observed, although none of the liver metastases included more than two growth patterns. Overall, a mixed growth pattern was demonstrated in 19.3% of the liver metastases. Compared to metastases with pushing, those with desmoplastic growth pattern had a significantly up-regulated expression of urokinase-type plasminogen activator receptor (P = 0.0008). Angiogenesis was most pronounced in metastases with a pushing growth pattern in comparison to those with desmoplastic (P = 0.0007) and replacement growth pattern (P = 0.021). Although a minor fraction of the patients harboured metastases with different growth patterns, we observed a tendency toward growth pattern uniformity in the liver metastases arising in the same patient. The result suggests that the growth pattern of liver metastases is not a random phenomenon. PMID- 22919387 TI - Stress analysis of occlusal forces in canine teeth and their role in the development of non-carious cervical lesions: abfraction. AB - Non-carious cervical tooth lesions for many decades were attributed to the effects of abrasion and erosion mainly through toothbrush trauma, abrasive toothpaste, and erosive acids. However, though the above may be involved, more recently a biomechanical theory for the formation of these lesions has arisen, and the term abfraction was coined. The aim of this study was to investigate the biomechanics of abfraction lesions in upper canine teeth under axial and lateral loading conditions using a three-dimensional finite element analysis. An extracted human upper canine tooth was scanned by MUCT machine (Skyscan, Belgium). These MUCT scans were segmented, reconstructed, and meshed using ScanIP (Simpleware, Exeter, UK) to create a three-dimensional finite element model. A 100 N load was applied axially at the incisal edge and laterally at 45 degrees midpalatally to the long axis of the canine tooth. Separately, 200 N axial and non-axial loads were applied simultaneously to the tooth. It was found that stresses were concentrated at the CEJ in all scenarios. Lateral loading produced maximum stresses greater than axial loading, and pulp tissues, however, experienced minimum levels of stresses. This study has contributed towards the understanding of the aetiology of non-carious cervical lesions which is a key in their clinical management. PMID- 22919386 TI - The Interaction between Pesticide Use and Genetic Variants Involved in Lipid Metabolism on Prostate Cancer Risk. AB - Background. Lipid metabolism processes have been implicated in prostate carcinogenesis. Since several pesticides are lipophilic or are metabolized via lipid-related mechanisms, they may interact with variants of genes in the lipid metabolism pathway. Methods. In a nested case-control study of 776 cases and 1444 controls from the Agricultural Health Study (AHS), a prospective cohort study of pesticide applicators, we examined the interactions between 39 pesticides (none, low, and high exposure) and 220 single nucleotide polymorphisms (SNPs) in 59 genes. The false discovery rate (FDR) was used to account for multiple comparisons. Results. We found 17 interactions that displayed a significant monotonic increase in prostate cancer risk with pesticide exposure in one genotype and no significant association in the other genotype. The most noteworthy association was for ALOXE3 rs3027208 and terbufos, such that men carrying the T allele who were low users had an OR of 1.86 (95% CI = 1.16-2.99) and high users an OR of 2.00 (95% CI = 1.28-3.15) compared to those with no use of terbufos, while men carrying the CC genotype did not exhibit a significant association. Conclusion. Genetic variation in lipid metabolism genes may modify pesticide associations with prostate cancer; however our results require replication. PMID- 22919388 TI - Oral cancer awareness and knowledge in the city of valongo, portugal. AB - We conducted a questionnaire survey among 602 subjects in order to analyze the awareness and knowledge on oral cancer among residents of the city of Valongo in Portugal. The cancer that most subjects were aware of was breast cancer (99%). Oral cancer was the least mentioned cancer (68.6%). There was awareness of the relationship between oral cancer and smoking among 89.5% subjects, but less of the association with alcohol misuse (63.3%). Nonhealing mouth ulcers were identified as a sign or symptom of oral cancer by 90.0% and red or white patch by only 52.8% subjects. Whereas 94.5% agreed that early detection could improve the treatment outcome, a disheartening 28.1% believed that whether a person developed an oral cancer or not is a matter of luck and therefore is unavoidable. Surprisingly only 1.7% were ever submitted to or had knowledge of receiving a consultation regarding oral cancer. In conclusion, this survey demonstrates a general lack of awareness and knowledge on oral cancer in a population of Valongo. An oral health promotion strategy should involve elements of basic education on oral cancer for this population, and regular oral cancer screenings should be implemented in Valongo. PMID- 22919389 TI - A Nanomechanical Investigation of Three Putative Anti-Erosion Agents: Remineralisation and Protection against Demineralisation. AB - An increasing interest in dental erosion as a clinical and scientific phenomenon has led to concerted efforts to identify agents which might protect against erosion. In this study, nanoindentation was used to investigate inhibition of erosive enamel demineralisation over time scales with direct clinical relevance. Nanohardness of polished human enamel specimens (n = 8 per group) was measured at baseline (B), after demineralisation (D1: citric acid, 0.3% w/v, pH3.20, 20s), after treatment (T), and after a second demineralisation (D2: as above). Data were analysed using repeated measures ANOVA. All specimens exhibited a similar reduction in nanohardness B-D1 in the range 35.2-39.5%. The positive control solution (saturated hydroxyapatite solution) and 4500 mg/L fluoride as NaF significantly increased nanohardness D1-T by 19.9% and 24.1%, respectively, whereas 1400 mg/L fluoride as NaF, casein phosphopeptide-amorphous calcium phosphate mousse and negative control (deionised water) had no significant effect. Nanohardness at D2 was indistinguishable for all groups, with total reduction in nanohardness B-D2 of 31.6% (4500 mg/L fluoride), 35.2% (positive control), 39.9% (1400 mg/L fluoride), 42.4% (negative control), and 43.7% (CPP ACP product). In summary, 4500 mg/L fluoride significantly increased the nanohardness of previously demineralised enamel and resulted in the smallest total reduction in nanohardness but there were few statistically significant differences among the groups. PMID- 22919390 TI - The Effect of Zirconia in Hydroxyapatite on Staphylococcus epidermidis Growth. AB - Synthetic hydroxyapatite (HA) has been widely used and developed as the material for bone substitute in medical applications. The addition of zirconia is needed to improve the strength of hydroxyapatite as the bone substitute. One of the drawbacks in the use of biomedical materials is the occurrence of biomaterial centred infections. The recent method of limiting the presence of microorganism on biomaterials is by providing biomaterial-bound metal-containing compositions. In this case, S. epidermidis is the most common infectious organism in biomedical centred infection. Objective. This study was designed to evaluate the effect of zirconia concentrations in hydroxyapatite on the growth of S. epidermidis. Methods and Materials. The subjects of this study were twenty hydroxyapatite discs, divided into four groups in which one was the control and the other three were the treatment groups. Zirconia powder with the concentrations of 20%, 30%, and 40% was added into the three different treatment groups. Scanning electron microscope analysis was performed according to the hydroxyapatite and hydroxyapatite-zirconia specimens. All discs were immersed into S. epidermidis culture for 24 hours and later on they were soaked into a medium of PBS. The cultured medium was spread on mannitol salt agar. After incubation for 24 hours at 37 degrees C , the number of colonies was measured with colony counter. Data obtained were analyzed using the ANOVA followed by the pairwise comparison. Result. The statistical analysis showed that different concentrations of zirconia powder significantly influenced the number of S. epidermidis colony (P < 0.05) . Conclusion. The addition of zirconia into hydroxyapatite affected the growth of S. epidermidis. Hydroxyapatite with 20% zirconia proved to be an effective concentration to inhibit the growth of S. epidermidis colony. PMID- 22919391 TI - Cytotoxicity of Cricula triphenestrata Cocoon Extract on Human Fibroblasts. AB - Objectives. The aim of this paper was to evaluate the cytotoxicity of Indonesian silkworm cocoon extract of Cricula triphenestrata on human fibroblasts. Methods and Materials. The cocoon shells of the silkworm Cricula triphenestrata were degumming. The shells were mixed with an aqueous solution of 0.3% Na(2)CO(3) at 98 degrees C for 1 hour. The solution was then dialyzed in cellulose membranes against deionized water for 3 days. The cocoon shells extract powder was collected via rotary evaporation and dried under freeze dryer. Cell culture medium was exposed to Cricula triphenestrata cocoon extract (0.01-100 MUg/mL) for 24 hours. The primary human gingival fibroblasts were exposed to the treated cell culture medium for 24 hours. Cytotoxicity evaluation was done by MTT method. The data were analyzed by one-way ANOVA. Result. The result revealed no significant cytotoxicity of Cricula triphenestrata cocoon extract against human fibroblasts at a concentration up to 100 MUg/mL (P > 0.05). Conclusion. Cricula triphenestrata cocoon extract was not cytotoxic on human gingival fibroblast cells. PMID- 22919392 TI - BSA Nanoparticles for siRNA Delivery: Coating Effects on Nanoparticle Properties, Plasma Protein Adsorption, and In Vitro siRNA Delivery. AB - Developing vehicles for the delivery of therapeutic molecules, like siRNA, is an area of active research. Nanoparticles composed of bovine serum albumin, stabilized via the adsorption of poly-L-lysine (PLL), have been shown to be potentially inert drug-delivery vehicles. With the primary goal of reducing nonspecific protein adsorption, the effect of using comb-type structures of poly(ethylene glycol) (1 kDa, PEG) units conjugated to PLL (4.2 and 24 kDa) on BSA-NP properties, apparent siRNA release rate, cell viability, and cell uptake were evaluated. PEGylated PLL coatings resulted in NPs with zeta-potentials close to neutral. Incubation with platelet-poor plasma showed the composition of the adsorbed proteome was similar for all systems. siRNA was effectively encapsulated and released in a sustained manner from all NPs. With 4.2 kDa PLL, cellular uptake was not affected by the presence of PEG, but PEG coating inhibited uptake with 24 kDa PLL NPs. Moreover, 24 kDa PLL systems were cytotoxic and this cytotoxicity was diminished upon PEG incorporation. The overall results identified a BSA-NP coating structure that provided effective siRNA encapsulation while reducing zeta-potential, protein adsorption, and cytotoxicity, necessary attributes for in vivo application of drug-delivery vehicles. PMID- 22919393 TI - Porous biodegradable metals for hard tissue scaffolds: a review. AB - Scaffolds have been utilized in tissue regeneration to facilitate the formation and maturation of new tissues or organs where a balance between temporary mechanical support and mass transport (degradation and cell growth) is ideally achieved. Polymers have been widely chosen as tissue scaffolding material having a good combination of biodegradability, biocompatibility, and porous structure. Metals that can degrade in physiological environment, namely, biodegradable metals, are proposed as potential materials for hard tissue scaffolding where biodegradable polymers are often considered as having poor mechanical properties. Biodegradable metal scaffolds have showed interesting mechanical property that was close to that of human bone with tailored degradation behaviour. The current promising fabrication technique for making scaffolds, such as computation-aided solid free-form method, can be easily applied to metals. With further optimization in topologically ordered porosity design exploiting material property and fabrication technique, porous biodegradable metals could be the potential materials for making hard tissue scaffolds. PMID- 22919395 TI - Synergistic effect of anemia and red blood cells transfusion on inflammation and lung injury. AB - Anemia and resultant red blood cell transfusion may be associated with adverse long-term clinical outcomes. To investigate the mechanism(s) responsible, we profiled inflammatory biomarkers and circulating levels of the bioactive lysophospholipid mediator sphingosine-1-phosphate (S1P) in control and anemic mice with or without LPS-induced systemic inflammation. Acute anemia or lipopolysaccharide (LPS) challenge alone triggered an increase of circulating levels of the inflammatory markers IL-6 and keratinocyte-derived chemokine (CXCL1/KC). Moreover, administration of LPS to anemic mice reduced circulating S1P levels and augmented lung injury and pulmonary vascular permeability. Transfusion of aged, but not fresh, red blood cells (RBCs) worsened pulmonary vascular leak. S1P levels decline markedly during storage of mouse RBCs. Loading stored murine RBCs with S1P prior to transfusion partially attenuated anemia associated acute pulmonary vascular leak. Taken together, our results indicate that anemia and systemic inflammation can alter the S1P buffering capacity of RBCs, suggesting possible strategies for alleviating transfusion-related lung injury in clinical practice. PMID- 22919394 TI - Biological activity of lenalidomide and its underlying therapeutic effects in multiple myeloma. AB - Lenalidomide is a synthetic compound derived by modifying the chemical structure of thalidomide. It belongs to the second generation of immunomodulatory drugs (IMiDs) and possesses pleiotropic properties. Even if lenalidomide has been shown to be active in the treatment of several hematologic malignancies, this review article is mostly focalized on its mode of action in multiple myeloma. The present paper is about the direct and indirect antitumor effects of lenalidomide on malignant plasmacells, bone marrow microenvironment, bone resorption and host's immune response. The molecular mechanisms and targets of lenalidomide remain largely unknown, but recent evidence shows cereblon (CRBN) as a possible mediator of its therapeutical effects. PMID- 22919397 TI - Neurogenic pulmonary edema associated with underlying lung disease after a breakthrough seizure. AB - Neurogenic pulmonary edema (NPE) can result from various central nervous system disorders such as brain malignancies, traumatic brain injuries, infections, and seizures. Although the pathogenesis is not completely understood, NPE creates an increase in pulmonary interstitial and alveolar fluid. It has been reported with prolonged seizure activity. Treatment for NPE is largely supportive. If unrecognized, it can lead to hypoxia and respiratory arrest. We report a case of NPE in a middle-aged female patient following a breakthrough seizure in whom an immunological cause for respiratory findings was high on the differential list, based on her past medical history and chronicity of symptoms. Rapid symptomatic and radiological improvement following hospitalization led to the correct diagnosis. PMID- 22919396 TI - Sinonasal manifestations in cystic fibrosis. AB - Cystic fibrosis is a genetic disease, characterized by accumulation of thickened mucous secretions in exocrine glands. Although the major clinical manifestations of the disease are pancreatic and pulmonary disease, the majority of cystic fibrosis patients will develop sinonasal manifestations as well. This paper outlines the etiology, evaluation, and management of the nasal and sinus manifestations in patients with cystic fibrosis. PMID- 22919398 TI - Pediatric nasal lobular capillary hemangioma. AB - Background. LCH is a benign vascular growth of the skin and mucous membranes commonly affecting the head and neck. Since it was first described in the nineteenth century, this entity has been variously known as "human botryomycosis" and "pyogenic granuloma." The shifting nomenclature reflects an evolving understanding of the underlying pathogenesis. We review the histopathology of and current epidemiological data pertaining to LCH which suggests that the development of these lesions may involve a hyperactive inflammatory response influenced by endocrine factors. We report two new cases of pediatric lobular capillary hemangioma (LCH) of the nasal cavity and review current theories regarding the etiology, diagnosis, and treatment of nasal LCH. Methods. Retrospective case series. Case Series. Two adolescent females presented with symptoms of recurrent epistaxis, nasal obstruction, and epiphora. Both patients underwent computed tomography imaging and biopsy of their intranasal mass. The tumors were excised using image-guided transnasal endoscopic technique. Seven other cases of nasal LCH have been reported to date in the pediatric population. Conclusion. Nasal LCH is a rare cause of an intranasal mass and is associated with unilateral epistaxis, nasal obstruction, and epiphora. We advocate for image guided endoscopic excision of LCH in the adolescent population. PMID- 22919399 TI - Intraoral superficial angiomyxoma of the upper alveolus: report of a unique case. AB - Angiomyxomas are relatively a group of uncommon myxoid mesenchymal tumors characterized by frequent local recurrences and show lack of malignant potential. Basically three types of angiomyxomas are recognized superficial, aggressive, and angiomyofibroblastoma. Though the angiomyxomas are rarely reported in the head and neck region, the paper shows reported cases intraorally in the buccal mucosa and floor of the mouth. Here, the authors report a rare case of angiomyxoma presenting as a growth in the upper posterior alveolar mucosa. PMID- 22919400 TI - Aortic Valvuloplasty as Bridging for TAVI in High-Risk Patients with Heyde's Syndrome: A Case Report. AB - There is a frequent association between aortic valve stenosis and gastrointestinal bleeding, also known as Heyde's syndrome. In these patients, the aortic valve replacement should be recommended as "gold standard." In high surgical-risk patients, the Transcatheter Aortic Valve Implantation (TAVI) is an alternative option. However, the risk of bleeding recurrence, related to double antiplatelet therapy started after TAVI, cannot be excluded especially in the first months. We present a case of a patient with a severe aortic valve stenosis and a history of previously documented angiodysplasia and recurrence of gastrointestinal bleeding initially treated only with balloon aortic valvuloplasty that excluded recurrence of bleeding during the subsequent six months of followup. Therefore, a definite transfemoral Edwards XT valve implantation was planned to be performed in case of recurrence of aortic stenosis. PMID- 22919401 TI - Ion channels in hematopoietic and mesenchymal stem cells. AB - Hematopoietic stem cells (HSCs) reside in bone marrow niches and give rise to hematopoietic precursor cells (HPCs). These have more restricted lineage potential and eventually differentiate into specific blood cell types. Bone marrow also contains mesenchymal stromal cells (MSCs), which present multilineage differentiation potential toward mesodermal cell types. In bone marrow niches, stem cell interaction with the extracellular matrix is mediated by integrin receptors. Ion channels regulate cell proliferation and differentiation by controlling intracellular Ca(2+), cell volume, release of growth factors, and so forth. Although little evidence is available about the ion channel roles in true HSCs, increasing information is available about HPCs and MSCs, which present a complex pattern of K(+) channel expression. K(+) channels cooperate with Ca(2+) and Cl(-) channels in regulating calcium entry and cell volume during mitosis. Other K(+) channels modulate the integrin-dependent interaction between leukemic progenitor cells and the niche stroma. These channels can also regulate leukemia cell interaction with MSCs, which also involves integrin receptors and affects the MSC-mediated protection from chemotherapy. Ligand-gated channels are also implicated in these processes. Nicotinic acetylcholine receptors regulate cell proliferation and migration in HSCs and MSCs and may be implicated in the harmful effects of smoking. PMID- 22919403 TI - Play and be happy? Leisure participation and quality of life in school-aged children with cerebral palsy. AB - The objective of this study was to examine the association between leisure participation and quality of life (QoL) in school-age children with cerebral palsy (CP). Leisure participation was assessed using the Children's Assessment of Participation and Enjoyment (CAPE) and QoL using the Pediatric Quality of Life Inventory (PedsQL). Pearson correlation coefficients were calculated to examine the association between CAPE and PedsQL scores, and a multiple linear regression model was used to estimate QoL predictors. Sixty-three children (mean age 9.7 +/- 2.1 years; 39 male) in GMFCS levels I-V were included. Intensity of participation in active-physical activities was significantly correlated with both physical (r = 0.34, P = 0.007) and psychosocial well-being (r = 0.31, P = 0.01). Intensity and diversity of participation in skill-based activities were negatively correlated with physical well-being (r = -0.39, P = 0.001, and r = -0.41, P = 0.001, resp.). Diversity and intensity of participation accounted for 32% (P = 0.002) of the variance for physical well-being and 48% (P < 0.001) when age and gross motor functioning were added. Meaningful and adapted leisure activities appropriate to the child's skills and preferences may foster QoL. PMID- 22919402 TI - Emerging stem cell therapies: treatment, safety, and biology. AB - Stem cells are the fundamental building blocks of life and contribute to the genesis and development of all higher organisms. The discovery of adult stem cells has led to an ongoing revolution of therapeutic and regenerative medicine and the proposal of novel therapies for previously terminal conditions. Hematopoietic stem cell transplantation was the first example of a successful stem cell therapy and is widely utilized for treating various diseases including adult T-cell leukemia-lymphoma and multiple myeloma. The autologous transplantation of mesenchymal stem cells is increasingly employed to catalyze the repair of mesenchymal tissue and others, including the lung and heart, and utilized in treating various conditions such as stroke, multiple sclerosis, and diabetes. There is also increasing interest in the therapeutic potential of other adult stem cells such as neural, mammary, intestinal, inner ear, and testicular stem cells. The discovery of induced pluripotent stem cells has led to an improved understanding of the underlying epigenetic keys of pluripotency and carcinogenesis. More in-depth studies of these epigenetic differences and the physiological changes that they effect will lead to the design of safer and more targeted therapies. PMID- 22919404 TI - Morphologic features of extrahepatic manifestations of hepatitis C virus infection. AB - Cirrhosis and hepatocellular carcinoma are the prototypic complications of chronic hepatitis C virus infection in the liver. However, hepatitis C virus also affects a variety of other organs that may lead to significant morbidity and mortality. Extrahepatic manifestations of hepatitis C infection include a multitude of disease processes affecting the small vessels, skin, kidneys, salivary gland, eyes, thyroid, and immunologic system. The majority of these conditions are thought to be immune mediated. The most documented of these entities is mixed cryoglobulinemia. Morphologically, immune complex depositions can be identified in small vessels and glomerular capillary walls, leading to leukoclastic vasculitis in the skin and membranoproliferative glomerulonephritis in the kidney. Other HCV-associated entities include porphyria cutanea tarda, lichen planus, necrolytic acral erythema, membranous glomerulonephritis, diabetic nephropathy, B-cell non-Hodgkin lymphomas, insulin resistance, sialadenitis, sicca syndrome, and autoimmune thyroiditis. This paper highlights the histomorphologic features of these processes, which are typically characterized by chronic inflammation, immune complex deposition, and immunoproliferative disease in the affected organ. PMID- 22919405 TI - The involvement of microglial cells in Japanese encephalitis infections. AB - Despite the availability of effective vaccines, Japanese encephalitis virus (JEV) infections remain a leading cause of encephalitis in many Asian countries. The virus is transmitted to humans by Culex mosquitoes, and, while the majority of human infections are asymptomatic, up to 30% of JE cases admitted to hospital die and 50% of the survivors suffer from neurological sequelae. Microglia are brain resident macrophages that play key roles in both the innate and adaptive immune responses in the CNS and are thus of importance in determining the pathology of encephalitis as a result of JEV infection. PMID- 22919406 TI - Rituximab-based treatment, HCV replication, and hepatic flares. AB - Rituximab, a chimeric mouse-human monoclonal antibody directed to the CD20 antigen expressed on pre-B lymphocytes and mature lymphocytes, causes a profound B-cell depletion. Due to its peculiar characteristics, this drug has been used to treat oncohaematological diseases, B cell-related autoimmune diseases, rheumatoid arthritis, and, more recently, HCV-associated mixed cryoglobulinaemic vasculitis. Rituximab-based treatment, however, may induce an increased replication of several viruses such as hepatitis B virus, cytomegalovirus, varicella-zoster virus, echovirus, and parvovirus B19. Recent data suggest that rituximab-based chemotherapy induces an increase in HCV expression in hepatic cells, which may become a target for a cell-mediated immune reaction after the withdrawal of treatment and the restoration of the immune control. Only a few small studies have investigated the occurrence of HCV reactivation and an associated hepatic flare in patients with oncohaematological diseases receiving R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone). These studies suggest that the hepatic flares are frequently asymptomatic, but life-threatening liver failure occurs in nearly 10% of cases. PMID- 22919407 TI - Gelam Honey Inhibits the Production of Proinflammatory, Mediators NO, PGE(2), TNF alpha, and IL-6 in Carrageenan-Induced Acute Paw Edema in Rats. AB - Natural honey is well known for its therapeutic value and has been used in traditional medicine of different cultures throughout the world. The aim of this study was to investigate the anti-inflammatory effect of Malaysian Gelam honey in inflammation-induced rats. Paw edema was induced by a subplantar injection of 1% carrageenan into the rat right hind paw. Rats were treated with the nonsteroidal anti-inflammatory drug (NSAID) Indomethacin (10 mg/kg, p.o.) or Gelam honey at different doses (1 or 2 g/kg, p.o.). The increase in footpad thickness was considered to be edema, which was measured using a dial caliper. Plasma and paw tissue were collected to analyze the production of inflammatory mediators, such as NO, PGE(2), TNF-alpha, and IL-6, as well as iNOS and COX-2. The results showed that Gelam honey could reduce edema in a dose-dependent fashion in inflamed rat paws, decrease the production of NO, PGE(2), TNF-alpha, and IL-6 in plasma, and suppress the expression of iNOS, COX-2, TNF-alpha, and IL-6 in paw tissue. Oral pretreatment of Gelam honey at 2 g/kg of body weight at two time points (1 and 7 days) showed a significantly decreased production of proinflammatory cytokines, which was similar to the effect of the anti-inflammatory drug Indomethacin (NSAID), both in plasma and tissue. Thus, our results suggest that Gelam honey has anti-inflammatory effects by reducing the rat paw edema size and inhibiting the production of proinflammatory mediators. Gelam honey is potentially useful for treating inflammatory conditions. PMID- 22919408 TI - Isolation of Antidiabetic Principle from Fruit Rinds of Punica granatum. AB - Present study was aimed to isolate and evaluate the antidiabetic activity of phytoconstituents from fruit rinds of Punica granatum. With the above objectives Valoneic acid dilactone (VAD) was isolated from methanolic fruit rind extracts of Punica granatum (MEPG) and confirmed by (1)H-NMR, (13)C-NMR, and mass spectral data. Antidiabetic activity was evaluated by Aldose reductase, alpha-amylase and PTP1B inhibition assays in in vitro and Alloxan-induced diabetes in rats was used as an in vivo model. In bioactivity studies, MEPG and VAD have showed potent antidiabetic activity in alpha-amylase, aldose reductase, and PTP1B inhibition assays with IC(50) values of 1.02, 2.050, 26.25 MUg/mL and 0.284, 0.788, 12.41 MUg/mL, respectively. Furthermore, in alloxan-induced diabetes model MEPG (200 and 400 mg/kg, p.o.) and VAD (10, 25, and 50 mg/kg, p.o.) have showed significant and dose dependent antidiabetic activity by maintaining the blood glucose levels within the normal limits. Inline with the biochemical findings histopathology of MEPG (200 and 400 mg/kg, p.o.), VAD (10, 25, and 50 mg/kg, p.o.), and glibenclamide (10 mg/kg, p.o.) treated animals showed significant protection against alloxan-induced pancreatic tissue damage. These findings suggest that MEPG and VAD possess significant antidiabetic activity in both in vitro and in vivo models. PMID- 22919409 TI - Inhibition of Staphylococcus epidermidis Biofilm Formation by Traditional Thai Herbal Recipes Used for Wound Treatment. AB - Development of biofilm is a key mechanism involved in Staphylococcus epidermidis virulence during device-associated infections. We aimed to investigate antibiofilm formation and mature biofilm eradication ability of ethanol and water extracts of Thai traditional herbal recipes including THR-SK004, THR-SK010, and THR-SK011 against S. epidermidis. A biofilm forming reference strain, S. epidermidis ATCC 35984 was employed as a model for searching anti-biofilm agents by MTT reduction assay. The results revealed that the ethanol extract of THR SK004 (THR-SK004E) could inhibit the formation of S. epidermidis biofilm on polystyrene surfaces. Furthermore, treatments with the extract efficiently inhibit the biofilm formation of the pathogen on glass surfaces determined by scanning electron microscopy and crystal violet staining. In addition, THR-SK010 ethanol extract (THR-SK010E; 0.63-5 MUg/mL) could decrease 30 to 40% of the biofilm development. Almost 90% of a 7-day-old staphylococcal biofilm was destroyed after treatment with THR-SK004E (250 and 500 MUg/mL) and THR-SK010E (10 and 20 MUg/mL) for 24 h. Therefore, our results clearly demonstrated THR-SK004E could prevent the staphylococcal biofilm development, whereas both THR-SK004E and THR-SK010E possessed remarkable eradication ability on the mature staphylococcal biofilm. PMID- 22919410 TI - Green Tea Extract Ameliorates Learning and Memory Deficits in Ischemic Rats via Its Active Component Polyphenol Epigallocatechin-3-gallate by Modulation of Oxidative Stress and Neuroinflammation. AB - Ischemic stroke results in brain damage and behavioral deficits including memory impairment. Protective effects of green tea extract (GTex) and its major functional polyphenol (-)-epigallocatechin gallate (EGCG) on memory were examined in cerebral ischemic rats. GTex and EGCG were administered 1 hr before middle cerebral artery ligation in rats. GTex, EGCG, and pentoxifylline (PTX) significantly improved ishemic-induced memory impairment in a Morris water maze test. Malondialdehyde (MDA) levels, glutathione (GSH), and superoxide dismutase (SOD) activity in the cerebral cortex and hippocampus were increased by long-term treatment with GTex and EGCG. Both compounds were also associated with reduced cerebral infraction breakdown of MDA and GSH in the hippocampus. In in vitro experiments, EGCG had anti-inflammatory effects in BV-2 microglia cells. EGCG inhibited lipopolysaccharide- (LPS-) induced nitric oxide production and reduced cyclooxygenase-2 and inducible nitric oxide synthase expression in BV-2 cells. GTex and its active polyphenol EGCG improved learning and memory deficits in a cerebral ischemia animal model and such protection may be due to the reduction of oxidative stress and neuroinflammation. PMID- 22919411 TI - Inulae Flos and Its Compounds Inhibit TNF-alpha- and IFN-gamma-Induced Chemokine Production in HaCaT Human Keratinocytes. AB - The present study is to investigate which kinds of solvent extracts of Inulae Flos inhibit the chemokine productions in HaCaT cell and whether the inhibitory capacity of Inulae Flos is related with constitutional compounds. The 70% methanol extract showed comparatively higher inhibition of thymus and activation regulated chemokine (TARC/CCL17) in HaCaT cells, therefore this extract was further partitioned with n-hexane, chloroform, ethyl acetate, butanol, and water. The ethyl acetate fraction inhibited TARC, macrophage-derived chemokine (MDC/CCL22), and regulated on activation of normal T-cell-expressed and -secreted (RANTES/CCL5) production in HaCaT cells better than the other fractions. The compounds of Inulae Flos, such as 1,5-dicaffeoylquinic acid and luteolin, inhibited TARC, MDC, and RANTES production in HaCaT cells. 1,5-Dicaffeoylquinic acid was contained at the highest concentrations both in the 70% methanol extract and ethyl acetate fraction and inhibited the secretion of chemokines dose dependently more than the other compounds. Luteolin also represented dose dependent inhibition on chemokine productions although it was contained at lower levels in 70% methanol extract and solvent fractions. These results suggest that the inhibitory effects of Inulae Flos on chemokine production in HaCaT cell could be related with constituent compounds contained, especially 1,5-dicaffeoylquinic acid and luteolin. PMID- 22919412 TI - Quantitative analysis of sphingomyelin by high-performance liquid chromatography after enzymatic hydrolysis. AB - Sphingomyelin is the most abundant sphingolipid in mammalian cells and is mostly present in the plasma membrane. A new analytical method using high-performance liquid chromatography (HPLC) was developed to quantify sphingomyelin in mouse plasma and tissues, 3T3-L1 cells, rat aortic smooth muscle cells, and HT-29 cells. Sphingomyelin and dihydrosphingomyelin, an internal standard, were separated by high-performance thin-layer chromatography and simultaneously hydrolyzed with sphingolipid ceramide N-deacylase and sphingomyelinase to release sphingosine and dihydrosphingosine, respectively. Sphingomyelin content was measured by HPLC following o-phthalaldehyde derivatization. Sphingomyelin concentrations in 3T3-L1 cells, rat aortic smooth muscle cells, and HT-29 cells were 60.10 +/- 0.24, 62.69 +/- 0.08, and 58.38 +/- 0.37 pmol/MUg protein, respectively, whereas those in brain, kidney, and liver of ICR mice were 55.60 +/ 0.43, 43.75 +/- 0.21, and 22.26 +/- 0.14 pmol/MUg protein. The sphingomyelin concentration in mouse plasma was 407.40 +/- 0.31 MUM. The limits of detection and quantification for sphingomyelin were 5 and 20 pmol, respectively, in the HPLC analysis with fluorescence detection. This sensitivity was sufficient for analyzing sphingomyelin in biological samples. In conclusion, this analytical method is a sensitive and specific technique for quantifying sphingomyelin and was successfully applied to diverse biological samples with excellent reproducibility. PMID- 22919413 TI - Behavioral, neurochemical and neuroendocrine effects of abnormal savda munziq in the chronic stress mice. AB - Oral administration of Abnormal Savda Munsiq (ASMq), a herbal preparation used in Traditional Uighur Medicine, was found to exert a memory-enhancing effect in the chronic stressed mice, induced by electric foot-shock. The memory improvement of the stressed mice was shown by an increase of the latency time in the step through test and the decrease of the latency time in the Y-maze test. Treatment with ASMq was found to significantly decrease the serum levels of adrenocorticotropic hormone (ACTH), corticosterone (CORT) and beta-endorphin (beta-EP) as well as the brain and serum level of norepinephrine (NE). Furthermore, ASMq was able to significantly reverse the chronic stress by decreasing the brain and serum levels of the monoamine neurotransmitters dopamine (DA), 5-hydroxytryptamine (5-HT) and 3,4-dihydroxyphenylalanine (DOPAC). The results obtained from this study suggested that the memory-enhancing effect of ASMq was mediated through regulations of neurochemical and neuroendocrine systems. PMID- 22919415 TI - Effects of Thymol and Carvacrol, Constituents of Thymus vulgaris L. Essential Oil, on the Inflammatory Response. AB - Thyme (Thymus vulgaris L., Lamiaceae) is an aromatic and medicinal plant that has been used in folk medicine, phytopharmaceutical preparations, food preservatives, and as an aromatic ingredient. The effect of Thymus vulgaris essential oil (TEO) and its isolated constituents thymol and cavacrol (CVL) were studied in the following experimental models: ear edema, carrageenan-induced pleurisy, and chemotaxis in vitro. In the pleurisy model, TEO, CVL, and thymol significantly inhibited inflammatory edema. However, only TEO and CVL inhibited leukocyte migration. In the in vitro chemotaxis experiment, CVL inhibited leukocyte migration, whereas thymol exerted a potent chemoattractant effect. In the ear edema model, CVL (10 mg/ear), applied topically, reduced edema formation, exerting a topical anti-inflammatory effect. Thymol did not reduce edema formation but rather presented an irritative response, probably dependent on histamine and prostanoid release. Our data suggest that the antiinflammatory effects of TEO and CVL are attributable to the inhibition of inflammatory edema and leukocyte migration. PMID- 22919416 TI - Patterns and Determinants of Complementary and Alternative Medicine Practitioner Use among Adults with Diabetes in Queensland, Australia. AB - There is evidence that complementary and alternative medicine (CAM) use is common among people with diabetes. The role of CAM in the treatment or management of diabetes is an emerging health issue given the potential side effects and benefits associated with the use of this kind of medicine. This paper examined patterns and determinants of CAM practitioner use in Queensland, Australia, using a large population-based sample of people with type 1 and type 2 diabetes. The study found that within a 12-month period, 7.7% of people with diabetes used the services of CAM practitioners alongside or as a complement to conventional health care service. Younger age, female gender, a higher education, having private health insurance, and engagement in preventive health behaviours are significant predictors of individuals who are more likely to visit a CAM practitioner. There was no significant difference in CAM practitioner use between people with type 1, type 2 insulin requiring, or type 2 noninsulin requiring diabetes. The findings highlight the need for further research on the role of CAM in the prevention and management of diabetes. PMID- 22919414 TI - From omics to drug metabolism and high content screen of natural product in zebrafish: a new model for discovery of neuroactive compound. AB - The zebrafish (Danio rerio) has recently become a common model in the fields of genetics, environmental science, toxicology, and especially drug screening. Zebrafish has emerged as a biomedically relevant model for in vivo high content drug screening and the simultaneous determination of multiple efficacy parameters, including behaviour, selectivity, and toxicity in the content of the whole organism. A zebrafish behavioural assay has been demonstrated as a novel, rapid, and high-throughput approach to the discovery of neuroactive, psychoactive, and memory-modulating compounds. Recent studies found a functional similarity of drug metabolism systems in zebrafish and mammals, providing a clue with why some compounds are active in zebrafish in vivo but not in vitro, as well as providing grounds for the rationales supporting the use of a zebrafish screen to identify prodrugs. Here, we discuss the advantages of the zebrafish model for evaluating drug metabolism and the mode of pharmacological action with the emerging omics approaches. Why this model is suitable for identifying lead compounds from natural products for therapy of disorders with multifactorial etiopathogenesis and imbalance of angiogenesis, such as Parkinson's disease, epilepsy, cardiotoxicity, cerebral hemorrhage, dyslipidemia, and hyperlipidemia, is addressed. PMID- 22919417 TI - Assessment of Antiobesity Potential of Achyranthes aspera Linn. Seed. AB - The present study was designed to evaluate the quality control parameters, quantitative phytochemical analysis (total phenols, total flavonoids, and total saponin content), and the antiobesity effect of ethanol extract of Achyranthes aspera Linn. seed (EAA) by employing in vitro and in vivo models. In in vitro study, the inhibitory activity of EAA on pancreatic amylase and lipase was measured. The in vivo pancreatic lipase activity was evaluated by measurement of plasma triacylglycerol levels after oral administration of EAA along with lipid emulsion to Swiss albino mice. The EAA inhibited pancreatic amylase and lipase activity in vitro and elevations of plasma triacylglycerol level in mice. Furthermore, the antiobesity effect of EAA (900 mg/kg) was assessed in mice fed a high-fat diet with or without EAA for 6 weeks. EAA significantly suppressed the increase in body, retroperitoneal adipose tissue, liver weights, and serum parameters, namely; total cholesterol, total triglyceride, and LDL-cholesterol level. The anti obesity effects of EAA in high-fat-diet-treated mice may be partly mediated through delaying the intestinal absorption of dietary fat by inhibiting pancreatic amylase and lipase activity. Histopathological effects of EAA on the liver of mice were also assessed. PMID- 22919418 TI - Phenethyl Isothiocyanate (PEITC) Inhibits the Growth of Human Oral Squamous Carcinoma HSC-3 Cells through G(0)/G(1) Phase Arrest and Mitochondria-Mediated Apoptotic Cell Death. AB - Phenethyl isothiocyanate (PEITC), an effective anticancer and chemopreventive agent, has been reported to inhibit cancer cell growth through cell-cycle arrest and induction of apoptotic events in various human cancer cells models. However, whether PEITC inhibits human oral squamous cell carcinoma HSC-3 cell growth and its underlying mechanisms is still not well elucidated. In the present study, we evaluated the inhibitory effects of PEITC in HSC-3 cells and examined PEITC modulated cell-cycle arrest and apoptosis. The contrast-phase and flow cytometric assays were used for examining cell morphological changes and viability, respectively. The changes of cell-cycle and apoptosis-associated protein levels were determined utilizing Western blotting in HSC-3 cells after exposure to PEITC. Our results indicated that PEITC effectively inhibited the HSC-3 cells' growth and caused apoptosis. PEITC induced G(0)/G(1) phase arrest through the effects of associated protein such as p53, p21, p17, CDK2 and cyclin E, and it triggered apoptosis through promotion of Bax and Bid expression and reduction of Bcl-2, leading to decrease the levels of mitochondrial membrane potential (DeltaPsi(m)), and followed the releases of cytochrome c, AIF and Endo G then for causing apoptosis in HSC-3 cells. These results suggest that PEITC could be an antitumor compound for oral cancer therapy. PMID- 22919419 TI - Reversion of p-glycoprotein-mediated multidrug resistance in human leukemic cell line by diallyl trisulfide. AB - Multidrug resistance (MDR) is the major obstacle in chemotherapy, which involves multiple signaling pathways. Diallyl trisulfide (DATS) is the main sulfuric compound in garlic. In the present study, we aimed to explore whether DATS could overcome P-glycoprotein-(P-gp-)mediated MDR in K562/A02 cells, and to investigate whether NF-kappaB suppression is involved in DATS-induced reversal of MDR. MTT assay revealed that cotreatment with DATS increased the response of K562/A02 cells to adriamycin (the resistance reversal fold was 3.79) without toxic side effects. DATS could enhance the intracellular concentration of adriamycin by inhibiting the function and expression of P-gp, as shown by flow cytometry, RT PCR, and western blot. In addition, DATS resulted in more K562/A02 cell apoptosis, accompanied by increased expression of caspase-3. The expression of NF kappaB/p65 (downregulation) was significantly linked to the drug-resistance mechanism of DATS, whereas the expression of IkappaBalpha was not affected by DATS. Our findings demonstrated that DATS can serve as a novel, nontoxic modulator of MDR, and can reverse the MDR of K562/A02 cells in vitro by increasing intracellular adriamycin concentration and inducing apoptosis. More importantly, we proved for the first time that the suppression of NF-kappaB possibly involves the molecular mechanism in the course of reversion by DATS. PMID- 22919420 TI - Vitamin E as an Antiosteoporotic Agent via Receptor Activator of Nuclear Factor Kappa-B Ligand Signaling Disruption: Current Evidence and Other Potential Research Areas. AB - Osteoporosis is a growing healthcare burden that affects the quality of life in the aging population. Vitamin E is a potential prophylactic agent that can impede the progression of osteoporosis. Various in vivo studies demonstrated the antiosteoporotic potential of vitamin E, but evidence on its molecular mechanism of action is limited. A few in vitro studies showed that various forms of vitamin E can affect the receptor activator of nuclear factor kappa-B ligand (RANKL) signaling and their molecular targets, thus preventing the formation of osteoclasts in the early stage of osteoclastogenesis. Various studies have also shown that the effects of the different isoforms of vitamin E differ. The effects of single isoforms and combinations of isoforms on bone metabolism are also different. Vitamin E may affect bone metabolism by disruption of free radical mediated RANKL signaling, by its oestrogen-like effects, by its effects on the molecular mechanism of bone formation, by the anti-inflammatory effects of its long-chain metabolites on bone cells, and by the inhibition of 3-hydroxyl-3 methyglutaryl coenzyme A (HMG-CoA). In conclusion, the vitamin E isoforms have enormous potential to be used as prophylactic and therapeutic agents in preventing osteoporosis, but further studies should be conducted to elucidate their mechanisms of action. PMID- 22919421 TI - Hepatoprotective Potential of Caesalpinia crista against Iron-Overload-Induced Liver Toxicity in Mice. AB - The present study was carried out to evaluate the ameliorating effect of Caesalpinia crista Linn. (CCME) extract on iron-overload-induced liver injury. Iron overload was induced by intraperitoneal administration of iron dextran into mice. CCME attenuated the percentage increase in liver iron and serum ferritin levels when compared to control group. CCME also showed a dose-dependent inhibition of lipid peroxidation, protein oxidation, and liver fibrosis. The serum enzyme markers were found to be less, whereas enhanced levels of liver antioxidant enzymes were detected in CCME-treated group. In presence of CCME, the reductive release of ferritin iron was increased significantly. Furthermore, CCME exhibited DPPH radical scavenging and protection against Fe(2+)-mediated oxidative DNA damage. The current study confirmed the hepatoprotective effect of CCME against the model hepatotoxicant iron overload and the activity is likely related to its potent antioxidant and iron-chelating property. PMID- 22919422 TI - Cytomorphology of unusual infectious entities in the Pap test. AB - Rare entities in the Pap test, including neoplastic and non-neoplastic conditions, pose challenges due to their infrequent occurrence in the daily practice of cytology. Furthermore, these conditions give rise to important diagnostic pitfalls. Infections such as tuberculosis cervicitis may be erroneously diagnosed as carcinoma, whereas others, such as schistosomiasis, are associated with squamous cell carcinoma. These cases include granuloma inguinale (donovanosis), tuberculosis, coccidioidomycosis, schistosomiasis, taeniasis, and molluscum contagiosum diagnosed in Pap tests. Granuloma inguinale shows histiocytes that contain intracytoplasmic bacteria (Donovan bodies). Tuberculosis is characterized by necrotizing granulomatous inflammation with Langhans multinucleated giant cells. Coccidioidomycosis may show large intact or ruptured fungal spherules associated with endospores. Schistosoma haematobium is diagnosed by finding characteristic ova with a terminal spine. Molluscum contagiosum is characterized by the appearance of squamous cells with molluscum bodies. This article reviews the cytomorphology of selected rare infections and focuses on their cytomorphology, differential diagnosis, and role of ancillary diagnostic studies. PMID- 22919424 TI - Ossifying fibromyxoid tumor - Diagnostic challenge for a cytopathologist. PMID- 22919423 TI - An unusual case of Primary Effusion Lymphoma with aberrant T-cell phenotype in a HIV-negative, HBV-positive, cirrhotic patient, and review of the literature. AB - Primary effusion lymphoma (PEL) is an unusual, human herpes virus-8 (HHV-8) associated type of lymphoma, presenting as lymphomatous effusion in body cavities, without a detectable tumor mass. It primarily affects human immunodeficiency virus (HIV)-infected patients, but has also been described in other immunocompromised individuals. Although PEL is a B-cell lymphoma, the neoplastic cells are usually of the 'null' phenotype by immunocytochemistry. This report describes a case of PEL with T-cell phenotype in a HIV-negative patient and reviews all the relevant cases published until now. Our patient suffered from cirrhosis associated with Hepatitis B virus (HBV) infection and presented with a large ascitic effusion, in the absence of peripheral lymphadenopathy or solid mass within either the abdomen or the thorax. Paracentesis disclosed large lymphoma cells with anaplastic features consisting of moderate cytoplasm and single or occasionally multiple irregular nuclei with single or multiple prominent nucleoli. Immunocytochemically, these cells were negative for both CD3 and CD20, but showed a positive reaction for T-cell markers CD43 and CD45RO (VCHL 1). Furthermore, the neoplastic cells revealed strong positivity for EMA and CD30, but they lacked expression of ALK-1, TIA-1, and Perforin. The immune status for both HHV-8 and Epstein-Barr virus (EBV) was evaluated and showed positive immunostaining only for the former. The combination of the immunohistochemistry results with the existence of a clonal rearrangement in the immunoglobulin heavy chain gene (identified by PCR), were compatible with the diagnosis of PEL. The presence of T-cell markers was consistent with the diagnosis of PEL with an aberrant T-cell phenotype. PMID- 22919425 TI - Parakeratotic-like cells in effusions - A clue to diagnosis of malignant mesothelioma. AB - BACKGROUND: Malignant mesothelioma (MM) is an aggressive neoplasm with a poor prognosis. Its incidence has been increasing worldwide. Cytological examination of an effusion is often the first opportunity to diagnose MM. However, the cytological diagnosis of MM can be difficult. We have noticed that parakeratotic like cells, with orange cytoplasm and pyknotic nuclei, are present in many cases of mesothelioma on Papanicolaou-stained cytology slides. Although this cytological finding has been described previously, to our knowledge, there has been no systematic study of this finding. Our study is to determine whether the presence of small parakeratotic / orangeophilic cells (PK-like cells) is specific for the cytodiagnosis of mesothelioma. MATERIALS AND METHODS: A total of 90 body fluid cases were selected from our archived specimens in the Cytology Section at the University of Chicago Hospital accessioned between January 2000 to November 2011. They included 30 cases of mesothelioma, 30 cases of adenocarcinoma, and 30 cases of reactive mesothelial cells. RESULTS: PK-like cells were present in 83% of the mesothelioma cases, 13% of the adenocarcinoma cases, and 7% of the reactive cases. Our data showed that the presence of PK-like cells has a specificity of 90%, sensitivity of 83%, positive predictive value of 81%, and negative predictive value of 84% for the diagnosis of malignant mesothelioma in body cavity fluids. CONCLUSION: The presence of PK-like cells in the effusion specimen, especially in pleural effusions, is a highly specific and moderately sensitive cytological feature for diagnosis of mesothelioma. PMID- 22919426 TI - A novel method for simulating the extracellular matrix in models of tumour growth. AB - A novel hybrid continuum-discrete model to simulate tumour growth on a cellular scale is proposed. The lattice-based spatiotemporal model consists of reaction diffusion equations that describe interactions between cancer cells and their microenvironment. The fundamental ingredients that are typically considered are the nutrient concentration, the extracellular matrix (ECM), and matrix degrading enzymes (MDEs). The in vivo processes are very complex and occur on different levels. This in turn leads to huge computational costs. The main contribution of the present work is therefore to describe the processes on the basis of simplified mathematical approaches, which, at the same time, depict realistic results to understand the biological processes. In this work, we discuss if we have to simulate the MDE or if the degraded matrix can be estimated directly with respect to the cancer cell distribution. Additionally, we compare the results for modelling tumour growth using the common and our simplified approach, thereby demonstrating the advantages of the proposed method. Therefore, we introduce variations of the positioning of the nutrient delivering blood vessels and use different initializations of the ECM. We conclude that the novel method, which does not explicitly model the matrix degrading enzymes, provides means for a straightforward and fast implementation for modelling tumour growth. PMID- 22919428 TI - Correlation kernels for support vector machines classification with applications in cancer data. AB - High dimensional bioinformatics data sets provide an excellent and challenging research problem in machine learning area. In particular, DNA microarrays generated gene expression data are of high dimension with significant level of noise. Supervised kernel learning with an SVM classifier was successfully applied in biomedical diagnosis such as discriminating different kinds of tumor tissues. Correlation Kernel has been recently applied to classification problems with Support Vector Machines (SVMs). In this paper, we develop a novel and parsimonious positive semidefinite kernel. The proposed kernel is shown experimentally to have better performance when compared to the usual correlation kernel. In addition, we propose a new kernel based on the correlation matrix incorporating techniques dealing with indefinite kernel. The resulting kernel is shown to be positive semidefinite and it exhibits superior performance to the two kernels mentioned above. We then apply the proposed method to some cancer data in discriminating different tumor tissues, providing information for diagnosis of diseases. Numerical experiments indicate that our method outperforms the existing methods such as the decision tree method and KNN method. PMID- 22919427 TI - How the statistical validation of functional connectivity patterns can prevent erroneous definition of small-world properties of a brain connectivity network. AB - The application of Graph Theory to the brain connectivity patterns obtained from the analysis of neuroelectrical signals has provided an important step to the interpretation and statistical analysis of such functional networks. The properties of a network are derived from the adjacency matrix describing a connectivity pattern obtained by one of the available functional connectivity methods. However, no common procedure is currently applied for extracting the adjacency matrix from a connectivity pattern. To understand how the topographical properties of a network inferred by means of graph indices can be affected by this procedure, we compared one of the methods extensively used in Neuroscience applications (i.e. fixing the edge density) with an approach based on the statistical validation of achieved connectivity patterns. The comparison was performed on the basis of simulated data and of signals acquired on a polystyrene head used as a phantom. The results showed (i) the importance of the assessing process in discarding the occurrence of spurious links and in the definition of the real topographical properties of the network, and (ii) a dependence of the small world properties obtained for the phantom networks from the spatial correlation of the neighboring electrodes. PMID- 22919429 TI - Localizing true brain interactions from EEG and MEG data with subspace methods and modified beamformers. AB - To address the problem of mixing in EEG or MEG connectivity analysis we exploit that noninteracting brain sources do not contribute systematically to the imaginary part of the cross-spectrum. Firstly, we propose to apply the existing subspace method "RAP-MUSIC" to the subspace found from the dominant singular vectors of the imaginary part of the cross-spectrum rather than to the conventionally used covariance matrix. Secondly, to estimate the specific sources interacting with each other, we use a modified LCMV-beamformer approach in which the source direction for each voxel was determined by maximizing the imaginary coherence with respect to a given reference. These two methods are applicable in this form only if the number of interacting sources is even, because odd dimensional subspaces collapse to even-dimensional ones. Simulations show that (a) RAP-MUSIC based on the imaginary part of the cross-spectrum accurately finds the correct source locations, that (b) conventional RAP-MUSIC fails to do so since it is highly influenced by noninteracting sources, and that (c) the second method correctly identifies those sources which are interacting with the reference. The methods are also applied to real data for a motor paradigm, resulting in the localization of four interacting sources presumably in sensory motor areas. PMID- 22919430 TI - A general latent class model for performance evaluation of diagnostic tests in the absence of a gold standard: an application to Chagas disease. AB - We propose a new general Bayesian latent class model for evaluation of the performance of multiple diagnostic tests in situations in which no gold standard test exists based on a computationally intensive approach. The modeling represents an interesting and suitable alternative to models with complex structures that involve the general case of several conditionally independent diagnostic tests, covariates, and strata with different disease prevalences. The technique of stratifying the population according to different disease prevalence rates does not add further marked complexity to the modeling, but it makes the model more flexible and interpretable. To illustrate the general model proposed, we evaluate the performance of six diagnostic screening tests for Chagas disease considering some epidemiological variables. Serology at the time of donation (negative, positive, inconclusive) was considered as a factor of stratification in the model. The general model with stratification of the population performed better in comparison with its concurrents without stratification. The group formed by the testing laboratory Biomanguinhos FIOCRUZ-kit (c-ELISA and rec ELISA) is the best option in the confirmation process by presenting false negative rate of 0.0002% from the serial scheme. We are 100% sure that the donor is healthy when these two tests have negative results and he is chagasic when they have positive results. PMID- 22919431 TI - Voxel scale complex networks of functional connectivity in the rat brain: neurochemical state dependence of global and local topological properties. AB - Network analysis of functional imaging data reveals emergent features of the brain as a function of its topological properties. However, the brain is not a homogeneous network, and the dependence of functional connectivity parameters on neuroanatomical substrate and parcellation scale is a key issue. Moreover, the extent to which these topological properties depend on underlying neurochemical changes remains unclear. In the present study, we investigated both global statistical properties and the local, voxel-scale distribution of connectivity parameters of the rat brain. Different neurotransmitter systems were stimulated by pharmacological challenge (d-amphetamine, fluoxetine, and nicotine) to discriminate between stimulus-specific functional connectivity and more general features of the rat brain architecture. Although global connectivity parameters were similar, mapping of local connectivity parameters at high spatial resolution revealed strong neuroanatomical dependence of functional connectivity in the rat brain, with clear differentiation between the neocortex and older brain regions. Localized foci of high functional connectivity independent of drug challenge were found in the sensorimotor cortices, consistent with the high neuronal connectivity in these regions. Conversely, the topological properties and node roles in subcortical regions varied with neurochemical state and were dependent on the specific dynamics of the different functional processes elicited. PMID- 22919433 TI - Hemorrhage detection and segmentation in traumatic pelvic injuries. AB - Automated hemorrhage detection and segmentation in traumatic pelvic injuries is vital for fast and accurate treatment decision making. Hemorrhage is the main cause of deaths in patients within first 24 hours after the injury. It is very time consuming for physicians to analyze all Computed Tomography (CT) images manually. As time is crucial in emergence medicine, analyzing medical images manually delays the decision-making process. Automated hemorrhage detection and segmentation can significantly help physicians to analyze these images and make fast and accurate decisions. Hemorrhage segmentation is a crucial step in the accurate diagnosis and treatment decision-making process. This paper presents a novel rule-based hemorrhage segmentation technique that utilizes pelvic anatomical information to segment hemorrhage accurately. An evaluation measure is used to quantify the accuracy of hemorrhage segmentation. The results show that the proposed method is able to segment hemorrhage very well, and the results are promising. PMID- 22919432 TI - In silico modelling of tumour margin diffusion and infiltration: review of current status. AB - As a result of advanced treatment techniques, requiring precise target definitions, a need for more accurate delineation of the Clinical Target Volume (CTV) has arisen. Mathematical modelling is found to be a powerful tool to provide fairly accurate predictions for the Microscopic Extension (ME) of a tumour to be incorporated in a CTV. In general terms, biomathematical models based on a sequence of observations or development of a hypothesis assume some links between biological mechanisms involved in cancer development and progression to provide quantitative or qualitative measures of tumour behaviour as well as tumour response to treatment. Generally, two approaches are taken: deterministic and stochastic modelling. In this paper, recent mathematical models, including deterministic and stochastic methods, are reviewed and critically compared. It is concluded that stochastic models are more promising to provide a realistic description of cancer tumour behaviour due to being intrinsically probabilistic as well as discrete, which enables incorporation of patient-specific biomedical data such as tumour heterogeneity and anatomical boundaries. PMID- 22919434 TI - Investigating properties of the cardiovascular system using innovative analysis algorithms based on ensemble empirical mode decomposition. AB - Cardiovascular system is known to be nonlinear and nonstationary. Traditional linear assessments algorithms of arterial stiffness and systemic resistance of cardiac system accompany the problem of nonstationary or inconvenience in practical applications. In this pilot study, two new assessment methods were developed: the first is ensemble empirical mode decomposition based reflection index (EEMD-RI) while the second is based on the phase shift between ECG and BP on cardiac oscillation. Both methods utilise the EEMD algorithm which is suitable for nonlinear and nonstationary systems. These methods were used to investigate the properties of arterial stiffness and systemic resistance for a pig's cardiovascular system via ECG and blood pressure (BP). This experiment simulated a sequence of continuous changes of blood pressure arising from steady condition to high blood pressure by clamping the artery and an inverse by relaxing the artery. As a hypothesis, the arterial stiffness and systemic resistance should vary with the blood pressure due to clamping and relaxing the artery. The results show statistically significant correlations between BP, EEMD-based RI, and the phase shift between ECG and BP on cardiac oscillation. The two assessments results demonstrate the merits of the EEMD for signal analysis. PMID- 22919435 TI - Predictive Modeling and Integrative Physiology: The Physiome Projects. AB - The fundamental paradigm in physiological research is integration. Biological researchers are now ready to define for a species a mathematical construct, the Physiome, the all-encompassing quantitative model of an organism. The goal of the human Physiome project is improved health care, through deep understanding of the organism, all the way down to the genes, reconciling contradictions and clarifying cause and effect. The strategies for accomplishing this long term aim include the systematic gathering of old and new knowledge into shared databases, and integrating the information into self consistent, reproducible, mathematical models. Multiscale models, for practicality, cover only a few levels at a time. Beginning at the middle level, the cell, where the knowledge base is largest and most secure, and the elements well defined as functional biophysical/biochemical modules, the plan is to work up to the organism level and down to the gene level, in the end providing clear linkages between phenotype and the genome. PMID- 22919436 TI - Aging and vision: changes in function and performance from optics to perception. AB - Age-related declines in vision can have a major impact on the health and well being of an older population. A review of research on aging and vision indicates that these declines occur at multiple levels of the visual system including optics, sensory processing, and perceptual processing and are not likely due to a systemic change in brain function (e.g., generalized slowing; common cause hypothesis) as a result of normal aging. In addition, declines in sensory and perceptual processing are not due to low-level explanations such as the amount of light that reaches the retina. Declines in visual performance are due to a variety of distinct factors that include spatial integration and difficulty in processing visual information in the presence of noise. Neurophysiological studies suggest that processing declines may be due in part to changes in cortical inhibition mediated by changes in the level of neurotransmitters associated with inhibition. Despite the widespread declines in function with normal aging, recent research suggests that perceptual learning can be used to dramatically improve visual function for older individuals. This research suggests a high degree of plasticity of the visual system among older populations and suggests that perceptual learning is an important tool for the recovery of age-related declines in vision. WIREs Cogn Sci 2012, 3:403-410. doi: 10.1002/wcs.1167 For further resources related to this article, please visit the WIREs website. PMID- 22919437 TI - Antioxidant capacity of flavonoids in hepatic microsomes is not reflected by antioxidant effects in vivo. AB - Flavonoids are polyphenolic compounds with potential antioxidant activity via multiple reduction capacities. Oxidation of cellular lipids has been implicated in many diseases. Consequently, this study has assessed the ability of several dietary flavonoid aglycones to suppress lipid peroxidation of hepatic microsomes derived from rats deficient in the major lipid soluble antioxidant, dalpha tocopherol. Antioxidant effectiveness was galangin > quercetin > kaempferol > fisetin > myricetin > morin > catechin > apigenin. However, none of the flavonoids were as effective as dalpha-tocopherol, particularly at the lowest concentrations used. In addition, there appears to be an important distinction between the in vitro antioxidant effectiveness of flavonoids and their ability to suppress indices of oxidation in vivo. Compared with dalpha-tocopherol, repletion of vitamin E deficient rats with quercetin, kaempferol, or myricetin did not significantly affect indices of lipid peroxidation and tissue damage. Direct antioxidant effect of flavonoids in vivo was not apparent probably due to low bioavailability although indirect redox effects through stimulation of the antioxidant response element cannot be excluded. PMID- 22919438 TI - Curcumin induces Nrf2 nuclear translocation and prevents glomerular hypertension, hyperfiltration, oxidant stress, and the decrease in antioxidant enzymes in 5/6 nephrectomized rats. AB - Renal injury resulting from renal ablation induced by 5/6 nephrectomy (5/6NX) is associated with oxidant stress, glomerular hypertension, hyperfiltration, and impaired Nrf2-Keap1 pathway. The purpose of this work was to know if the bifunctional antioxidant curcumin may induce nuclear translocation of Nrf2 and prevents 5/6NX-induced oxidant stress, renal injury, decrease in antioxidant enzymes, and glomerular hypertension and hyperfiltration. Four groups of rats were studied: (1) control, (2) 5/6NX, (3) 5/6NX +CUR, and (4) CUR (n = 8-10). Curcumin was given by gavage to NX5/6 +CUR and CUR groups (60 mg/kg/day) starting seven days before surgery. Rats were studied 30 days after NX5/6 or sham surgery. Curcumin attenuated 5/6NX-induced proteinuria, systemic and glomerular hypertension, hyperfiltration, glomerular sclerosis, interstitial fibrosis, interstitial inflammation, and increase in plasma creatinine and blood urea nitrogen. This protective effect was associated with enhanced nuclear translocation of Nrf2 and with prevention of 5/6NX-induced oxidant stress and decrease in the activity of antioxidant enzymes. It is concluded that the protective effect of curcumin against 5/6NX-induced glomerular and systemic hypertension, hyperfiltration, renal dysfunction, and renal injury was associated with the nuclear translocation of Nrf2 and the prevention of both oxidant stress and the decrease of antioxidant enzymes. PMID- 22919439 TI - Coffee polyphenols change the expression of STAT5B and ATF-2 modifying cyclin D1 levels in cancer cells. AB - BACKGROUND: Epidemiological studies suggest that coffee consumption reduces the risk of cancer, but the molecular mechanisms of its chemopreventive effects remain unknown. OBJECTIVE: To identify differentially expressed genes upon incubation of HT29 colon cancer cells with instant caffeinated coffee (ICC) or caffeic acid (CA) using whole-genome microarrays. RESULTS: ICC incubation of HT29 cells caused the overexpression of 57 genes and the underexpression of 161, while CA incubation induced the overexpression of 12 genes and the underexpression of 32. Using Venn-Diagrams, we built a list of five overexpressed genes and twelve underexpressed genes in common between the two experimental conditions. This list was used to generate a biological association network in which STAT5B and ATF-2 appeared as highly interconnected nodes. STAT5B overexpression was confirmed at the mRNA and protein levels. For ATF-2, the changes in mRNA levels were confirmed for both ICC and CA, whereas the decrease in protein levels was only observed in CA-treated cells. The levels of cyclin D1, a target gene for both STAT5B and ATF 2, were downregulated by CA in colon cancer cells and by ICC and CA in breast cancer cells. CONCLUSIONS: Coffee polyphenols are able to affect cyclin D1 expression in cancer cells through the modulation of STAT5B and ATF-2. PMID- 22919440 TI - Induction of mitochondrial changes associated with oxidative stress on very long chain fatty acids (C22:0, C24:0, or C26:0)-treated human neuronal cells (SK-NB E). AB - In Alzheimer's disease, lipid alterations point towards peroxisomal dysfunctions. Indeed, a cortical accumulation of saturated very long chain fatty acids (VLCFAs: C22:0, C24:0, C26:0), substrates for peroxisomal beta-oxidation, has been found in Alzheimer patients. This study was realized to investigate the effects of VLCFAs at the mitochondrial level since mitochondrial dysfunctions play crucial roles in neurodegeneration. On human neuronal SK-NB-E cells treated with C22:0, C24:0, or C26:0 (0.1-20 MUM; 48 h), an inhibition of cell growth and mitochondrial dysfunctions were observed by cell counting with trypan blue, MTT assay, and measurement of mitochondrial transmembrane potential (Deltapsi(m)) with DiOC(6)(3). A stimulation of oxidative stress was observed with DHE and MitoSOX used to quantify superoxide anion production on whole cells and at the mitochondrial level, respectively. With C24:0 and C26:0, by Western blotting, lower levels of mitochondrial complexes III and IV were detected. After staining with MitoTracker and by transmission electron microscopy used to study mitochondrial topography, mass and morphology, major changes were detected in VLCFAs treated-cells: modification of the cytoplasmic distribution of mitochondria, presence of large mitochondria, enhancement of the mitochondrial mass. Thus, VLCFAs can be potential risk factors contributing to neurodegeneration by inducing neuronal damages via mitochondrial dysfunctions. PMID- 22919441 TI - Inhibition of mitochondrial cytochrome c release and suppression of caspases by gamma-tocotrienol prevent apoptosis and delay aging in stress-induced premature senescence of skin fibroblasts. AB - In this study, we determined the molecular mechanism of gamma-tocotrienol (GTT) in preventing cellular aging by focusing on its anti-apoptotic effect in stress induced premature senescence (SIPS) model of human diploid fibroblasts (HDFs). Results obtained showed that SIPS exhibited senescent-phenotypic characteristic, increased expression of senescence-associated beta-galactosidase (SA beta-gal) and promoted G(0)/G(1) cell cycle arrest accompanied by shortening of telomere length with decreased telomerase activity. Both SIPS and senescent HDFs shared similar apoptotic changes such as increased Annexin V-FITC positive cells, increased cytochrome c release and increased activation of caspase-9 and caspase 3 (P < 0.05). GTT treatment resulted in a significant reduction of Annexin V-FITC positive cells, inhibited cytochrome c release and decreased activation of caspase-9 and caspase-3 (P < 0.05). Gene expression analysis showed that GTT treatment down regulated BAX mRNA, up-regulated BCL2A1 mRNA and decreased the ratio of Bax/Bcl-2 protein expression (P < 0.05) in SIPS. These findings suggested that GTT inhibits apoptosis by modulating the upstream apoptosis cascade, causing the inhibition of cytochrome c release from the mitochondria with concomitant suppression of caspase-9 and caspase-3 activation. In conclusion, GTT delays cellular senescence of human diploid fibroblasts through the inhibition of intrinsic mitochondria-mediated pathway which involved the regulation of pro- and anti-apoptotic genes and proteins. PMID- 22919442 TI - Biomarkers of antioxidant status, inflammation, and cartilage metabolism are affected by acute intense exercise but not superoxide dismutase supplementation in horses. AB - Objectives were to evaluate effects of (1) repetitive arthrocentesis on biomarkers of inflammation (prostaglandin E(2), PGE(2)) and aggrecan synthesis (chondroitin sulfate-846; CS) in synovial fluid (SF); (2) exercise and superoxide dismutase (SOD) supplementation on biomarkers of inflammation, antioxidant status, and aggrecan synthesis, in horses. Preliminary trial. Standardbreds underwent four arthrocentesis procedures within 48 h and exhibited elevated CS and no changes in PGE(2). Exercise trial. this randomized crossover design used twelve Standardbred mares which received either treatment (3000 IU d(-1) oral SOD powder) or placebo (cellulose powder) for 6 wks which culminated with them running a repeated sprint exercise test (RSET). Samples were collected before (PRE), during (PEAK), and following exercise (POST). Exercise resulted in increased (P < 0.05) antioxidant defenses including erythrocyte SOD, total glutathione, glutathione peroxidase, gene transcripts for interferon-gamma, interleukin-10, and interleukin-1beta in blood, and decreased plasma nitric oxide. Exercise increased (P < 0.05) SF CS and adjusted-PGE(2), and higher (P < 0.05) CS and PGE(2) were found in hock versus carpus joints. No treatment effects were detected. Results suggest normal adaptive responses likely due to exercise induced tissue microdamage and oxidative stress. Additional research is needed to identify benefit(s) of SOD supplementation in horses. PMID- 22919444 TI - Fast Detection Allows Analysis of the Electronic Structure of Metalloprotein by X ray Emission Spectroscopy at Room Temperature. AB - The paradigm of "detection-before-destruction" was tested for a metalloprotein complex exposed at room temperature to the high x-ray flux typical of third generation synchrotron sources. Following the progression of the x-ray induced damage by Mn Kbeta x-ray emission spectroscopy, we demonstrated the feasibility of collecting room temperature data on the electronic structure of native Photosystem II, a trans-membrane metalloprotein complex containing a Mn(4)Ca cluster. The determined non-damaging observation timeframe (about 100 milliseconds using continuous monochromatic beam, deposited dose 1*10(7) photons/um(2) or 1.3*10(4) Gy, and 66 microseconds in pulsed mode using pink beam, deposited dose 4*10(7) photons/um(2) or 4.2*10(4) Gy) is sufficient for the analysis of this protein's electron dynamics and catalytic mechanism at room temperature. Reported time frames are expected to be representative for other metalloproteins. The described instrumentation, based on the short working distance dispersive spectrometer, and experimental methodology is broadly applicable to time-resolved x-ray emission analysis at synchrotron and x-ray free electron laser light sources. PMID- 22919443 TI - Quercetin and sesamin protect dopaminergic cells from MPP+-induced neuroinflammation in a microglial (N9)-neuronal (PC12) coculture system. AB - A growing body of evidence indicates that the majority of Parkinson's disease (PD) cases are associated with microglia activation with resultant elevation of various inflammatory mediators and neuroinflammation. In this study, we investigated the effects of 2 natural molecules, quercetin and sesamin, on neuroinflammation induced by the Parkinsonian toxin 1-methyl-4-phenylpyridinium (MPP(+)) in a glial-neuronal system. We first established that quercetin and sesamin defend microglial cells against MPP(+)-induced increases in the mRNA or protein levels of 3 pro-inflammatory cytokines (interleukin-6, IL-1beta and tumor necrosis factor-alpha), as revealed by real time-quantitative polymerase chain reaction and enzyme-linked immunoabsorbent assay, respectively. Quercetin and sesamin also decrease MPP(+)-induced oxidative stress in microglial cells by reducing inducible nitric oxide synthase protein expression as well as mitochondrial superoxide radicals. We then measured neuronal cell death and apoptosis after MPP(+) activation of microglia, in a microglial (N9)-neuronal (PC12) coculture system. Our results revealed that quercetin and sesamin rescued neuronal PC12 cells from apoptotic death induced by MPP(+) activation of microglial cells. Altogether, our data demonstrate that the phytoestrogen quercetin and the lignan sesamin diminish MPP(+)-evoked microglial activation and suggest that both these molecules may be regarded as potent, natural, anti inflammatory compounds. PMID- 22919445 TI - HLA-DQB1* alleles and genetic susceptibility to type 1 diabetes mellitus. AB - AIM: To determine human leukocyte antigen (HLA)-DQB1 allele association with susceptibility to type 1 diabetes (T1D) and to clinical and laboratory findings. METHODS: This study was conducted on 85 unrelated Egyptian children with T1D recruited consecutively from the Pediatric Diabetes Endocrinology outpatients Clinic; Mansoura University Children's Hospital, Egypt. Patient mean follow up period was 2.5 years. Patients were subdivided according to level of HbA1c (optimal/suboptimal control < 8.5% and poor control >= 8.5%). The control group consisted of 113 unrelated age- and sex-matched healthy subjects without T1D or other autoimmune diseases. Genomic DNA extraction was done for all subjects using a DNA isolation kit. HLA-Class II-DQB1 allele typing was carried out with a polymerase chain reaction-sequence-specific oligonucleotide probe using a INNO LiPA HLA-DQB1 update kit. RESULTS: Significant differences were detected between Egyptian patients with T1D and control groups in the frequencies of DQB1*02 [44.4% vs 18.6%, corrected P value (Pc) < 0.001] and DQB1*03 (41.2% vs 24.4%, Pc < 0.001). Significant differences were also observed between control groups and T1D patients in the frequencies of DQB1*05 (14.6% vs 7.2%, P = 0.029) and DQB1*06 (34.1% vs 7.2%, P < 0.001). However, after correction for multiple comparisons, the significance was retained for HLA-DQB1*06 (Pc < 0.001) but lost for HLA DQB1*05. HLA-DQB1*0201, *0202, *030201 were positively associated with T1D (Pc = 0.014, Pc < 0.001, and Pc < 0.001 respectively), while HLA-DQB1*060101 was negatively associated (Pc < 0.001) with the condition. Although the HLA-DQB1 alleles 030101 and 050101 were significantly higher in controls (P = 0.016, P = 0.025 respectively), both of them lost statistical significance after correction of P value. The frequency of the HLA-DQB1 genotypes 02/02, 02/03, and 03/03 was higher in T1D patients, and the frequency of the genotypes 03/06, 05/06, and 06/06 was higher in controls, these differences being statistically significant before correction. After correction, the genotypes 02/02, 02/03 in T1D, and the genotypes 03/06, 06/06 in controls were still significant (Pc = 0.01, Pc < 0.001, Pc < 0.001, and Pc = 0.04, respectively). Non-significant associations were found between the frequency HLA-DQB1 alleles and genotypes in T1D in relation to the grade of diabetic control, Microalbuminuria, age, gender, age of presentation, weight, height, frequency of diabetic ketoacidosis (P = 0.42), serum cholesterol, and fasting and post-prandial level of C-peptide (P = 0.83, P = 0.9, respectively). CONCLUSION: The Current work suggests that HLA-DQB1 alleles *030201, *0202, *0201, and genotypes 02/03, 02/02 may be susceptibility risk factors for development of T1D in Egyptian children, while the HLA-DQB1*060101 allele, and 03/06, 06/06 genotypes may be protective factors. HLA-DQB1 alleles and genotypes do not contribute to microalbuminuria or grade of diabetic control. PMID- 22919446 TI - Clinical Profile and Mortality of ST-Segment Elevation Myocardial Infarction Patients Receiving Thrombolytic Therapy in the Middle East. AB - OBJECTIVE: Little is known about thrombolytic therapy patterns in patients with ST-elevation myocardial infarction (STEMI) in the Middle East. The objective of this study was to evaluate the clinical profile and mortality of STEMI patients who arrived in hospital within 12 hours from pain onset and received thrombolytic therapy. PATIENTS AND METHODS: This was a prospective, multinational, multi centre, observational survey of consecutive acute coronary syndrome patients admitted to 65 hospitals in six Middle Eastern countries during the period between October 2008 and June 2009, as part of Gulf RACE-II (Registry of Acute Coronary Events). Analyses were performed using univariate statistics. RESULTS: Out of 2,465 STEMI patients, 66% (n = 1,586) were thrombolysed with namely: streptokinase (43%), reteplase (44%), tenecteplase (10%), and alteplase (3%). 22.7% received no reperfusion. Median age of the study cohort was 50 (45-59) years with majority being males (91%). The overall median symptom onset-to presentation and door-to-needle times were 165 (95- 272) minutes and 38 (24-60) minutes, respectively. Generally, patients presenting with higher GRACE risk scores were treated with newer thrombolytic agents (reteplase and tenecteplase) (P < 0.001). The use of newer thrombolytic agents was associated with a significantly lower mortality at both 1-month (0.8% vs. 1.7% vs. 4.2%; P = 0.014) and 1-year (0% vs. 1.7% vs. 3.4%; P = 0.044) compared to streptokinase use. CONCLUSIONS: Majority of STEMI patients from the Middle East were thrombolysed with streptokinase and reteplase in equal numbers. Nearly one-fifth of patients did not receive any reperfusion therapy. There was inappropriately long symptom onset to hospital presentation as well as door-to-needle times. Use of newer thrombolytic agents in high risk patients was appropriate. Newer thrombolytic agents were associated with significantly lower mortality at 1-month and 1-year compared to the older agent, streptokinase. PMID- 22919447 TI - Evaluation of QT Interval in beta Thalassemia Major Patients in Comparison with Control Group. AB - BACKGROUND: Cardiac complications are the primary cause of death in patients with b thalassemia major. QTc interval is an indicator of variability of ventricular repolarization and is supposed to be prominent in high risk patients. The aim of this investigation was to evaluate the relationship between QTc interval in beta thalassemia major in comparison with the control group. PATIENTS AND METHODS: Sixty beta thalassemia major and intermadia patients were enrolled in this analytical cross-sectional study. Thalassemia major and intermadia patients with no clinical symptoms of cardiac disease underwent echocardiographic and stress tests. QTc interval, blood pressure, heart rate, and average serum ferritin levels were measured. Statistical analysis was performed using version 15 SPSS. RESULTS: Although there was no clinical or echocardiographic sign of cardiac disease and QTc intervals measured before the test were not significantly different between patients and control group (421.7 +/- 29.6 vs. 412.4 +/- 28.2, P = 0.06), we found that, during stress test, QTc intervals (452.7 +/- 30.8 vs. 410.2 +/- 26.2, P < 0.001) and heart rate (105 +/- 15.1 vs. 89.7 +/- 12.3, P < 0.001) were notably greater in beta thalassemia major patients compared to the control group, respectively. CONCLUSION: We found augmented QTc intervals in this group of thalassemia major patients who have neither clinical nor electrocardiographic and gross echocardiographic signs of cardiac disease. QTc interval can be helpful in the cardiac assessment of thalassemia major patients. PMID- 22919448 TI - Giant left atrium: a review. AB - Giant left atrium is a rare condition, with a reported incidence of 0.3%, and following mainly rheumatic mitral valve disease. Although rheumatic heart disease represents the main cause of giant left atrium, other etiologies have been reported. Giant left atrium has significant hemodynamic effects and requires specific management. In this review, we present two cases, discuss the different definitions, etiologies, clinical presentation and management modalities. PMID- 22919450 TI - Vitamin e and omega-3: what to believe: observational studies or randomized controlled trials? AB - The practice of conventional medicine has markedly changed since the introduction of the concept of the evidence-based medicine. Randomized controlled study design and large sample size were the only justifications for level A or B evidence at the summit of what is called the evidence pyramid. A lot of medical interventions that were based on a plethora of basic researches and multiple large real world or observational studies in humans became questioned now by the results of even a single large sized randomized controlled trial (RCT). The conflicting evidences for the value of vitamin E and Omega-3 fatty acids in cardiovascular diseases are famous examples for such perplexity. This article discusses this problem on the basis of scientific, ethical, and statistical critical appraisal. To conclude, in this era of overwhelming flow of data, it should be emphasized in short, fast-to read articles that it is important to consider not only the level of evidence "as dictated by the study design and sample size" but also the relevance of evidence. Studies tell us about populations but we treat individuals. The type of the studied individuals, the enrollment criteria, the methodology, the dose of the studied drug and all the combined medications in the study should be clearly considered whenever the reported results are to be generalized beyond the specific situation studied. Comparing the effect of an active drug against placebo by giving either one of them to a group already treated with other multiple drugs (optimum medical therapy) could be a misleading indicator for the pure efficacy of the active drug. Many confounding variables such as known "or unknown" drug-drug interactions, sharing mechanisms of action or unexpected adverse drug reactions can afflict only the group randomized to take the active drug. These variables will not affect the control group simply because they add to their optimized multiple drug therapy an inert placebo. PMID- 22919451 TI - Left main coronary artery aneurysm: a rare presentation. AB - Left main coronary artery aneurysm is an uncommon coronary anomaly. We describe herein a male whose coronary angiogram revealed left main coronary artery aneurysm. The purpose of the case report is to highlight the clinical picture, workup, and treatment options for such patients. PMID- 22919452 TI - Successful pregnancy in a patient with univentricular heart and pulmonary stenosis. AB - Univentricular heart or single ventricle heart is a rare and complex congenital heart disease (CHD). We report the successful management of a parturient with a single ventricle, and pulmonary stenosis. The univentricular heart is discussed in detail and the maternal and fetal outcome in pregnant women with CHD is reviewed. PMID- 22919449 TI - Pregnancy-related Spontaneous Coronary Artery Dissection: Two Case Reports and a Comprehensive Review of Literature. AB - Spontaneous coronary artery dissection is a rare cause of acute coronary syndrome, particularly seen in women during pregnancy or in the puerperium. It has a high acute phase mortality. The etiology is uncertain. Hormonal changes during pregnancy, hemodynamic stress and changes in the autoimmune status have been considered as possible etiological factors. A timely diagnosis and institution of appropriate treatment is important for a successful outcome. There is no consensus of opinion for optimal treatment. Conservative management, coronary artery bypass graft surgery, and percutaneous coronary intervention, all have been described in the literature as possible therapeutic options. Spontaneous coronary artery dissection should be considered as a differential in any young woman presenting with chest pain associated with pregnancy. We report two cases of pregnancy-associated spontaneous coronary artery dissection, both successfully managed, along with a comprehensive review of the previously published literature. PMID- 22919453 TI - Massive calcification in the myocardium post infarction. PMID- 22919454 TI - Arab folk medicine and magic. PMID- 22919455 TI - Classics in cardiology: on cardiac murmurs(*) (part 3). PMID- 22919456 TI - Preoperative medical treatment in patients undergoing diabetic foot surgery with a Wagner Grade-3 or higher ulcer: a retrospective analysis of 52 patients. AB - Diabetic foot ulcers (DFU) are one of the most important complications in people with diabetes mellitus. The present study was aimed to retrospectively review the efficacy of at least 1-week medical treatment before any surgical intervention in patients with Grade-3 and higher DFU according to Wagner's classification. A total of 52 patients (36 males and 16 females) hospitalized and treated between June 2006 and February 2009 and had initially received therapeutic treatment (local wound care, antibiotic therapy and blood glucose regulation) for a period of at least 1 week were included in the study. The level of amputation, rates of reulceration and mortality in both groups were recorded in the following period of 2 years. Group 1 (did not respond to preoperative medical intervention) included 16 patients where a surgical debridement, flap or skin graft surgery was performed in 2 (12.5%) patients, major amputation was performed in another 2 (12.5%) patients and minor amputation was performed in the remaining 12 (75%) patients. Of 36 patients in Group 2 (did respond to preoperative medical intervention), 5 (13.9%) patients underwent the surgical debridement, flap or skin graft surgery, 8 (22.2%) patients had a major amputation and the remaining 23 (63.9%) patients lead to a minor amputation. The ulcer recurrence and mortality rates were obtained as 2 (12.5%) and 2 (12.5%) in Group 1 and 2 (5.6%) and 1 (2.8%) in Group 2, respectively. Despite the lower rates of ulcer recurrence and mortality in patients having adequate responses to initial treatment before surgical procedures were performed, no statistically significant difference was observed between the 2 groups. In addition, there was no statistically significant difference between the levels of amputation in both groups. PMID- 22919457 TI - Intervertebral disk-like biphasic scaffold-demineralized bone matrix cylinder and poly(polycaprolactone triol malate)-for interbody spine fusion. AB - Interbody fusion is an established procedure to preserve disk height and anterior fusion, but fusion with autografts, allografts, and metallic cages has its endogenous shortcomings. The objective of this study is to investigate whether a biphasic scaffold model, the native demineralized bone matrix cylinder in conjunction with degradable biomaterial poly(polycaprolactone triol malate), can be employed as a biological graft for interbody fusion. The poly(polycaprolactone triol malate) was synthesized by polycondensing malic acid and polycaprolactone and then the concentric sheet of poly(polycaprolactone triol malate) was fabricated into the demineralized bone matrix cylinder derived from rabbit femurs. Rabbit chondrocytes were loaded onto the three-dimensional constructs with 1-day in vitro culture and implanted into the subcutaneous dorsal pocket of nude mice. The chondrocytes/scaffold constructs are approximately two folds bigger than the scaffold-alone constructs after 12 weeks of implantation. X-ray and micro-computed tomography imaging showed endochondral bone formation in the chondrocytes/scaffold constructs as early as 4 weeks and showed that the bone intensity increased over time. Histological staining confirmed the above observation. By week 8, lamellar bone tissues were formed inside the demineralized bone matrix cylinder. In addition, the compression biomechanical test showed that the chondrocytes/scaffold constructs produced a significant higher compressive strength compared to the scaffold group. These results demonstrated that the inner-phase poly(polycaprolactone triol malate) degraded over time and was replaced by new bone in an in vivo environment. PMID- 22919458 TI - Electrical stimulation directs engineered cardiac tissue to an age-matched native phenotype. AB - Quantifying structural features of native myocardium in engineered tissue is essential for creating functional tissue that can serve as a surrogate for in vitro testing or the eventual replacement of diseased or injured myocardium. We applied three-dimensional confocal imaging and image analysis to quantitatively describe the features of native and engineered cardiac tissue. Quantitative analysis methods were developed and applied to test the hypothesis that environmental cues direct engineered tissue toward a phenotype resembling that of age-matched native myocardium. The analytical approach was applied to engineered cardiac tissue with and without the application of electrical stimulation as well as to age-matched and adult native tissue. Individual myocytes were segmented from confocal image stacks and assigned a coordinate system from which measures of cell geometry and connexin-43 spatial distribution were calculated. The data were collected from 9 nonstimulated and 12 electrically stimulated engineered tissue constructs and 5 postnatal day 12 and 7 adult hearts. The myocyte volume fraction was nearly double in stimulated engineered tissue compared to nonstimulated engineered tissue (0.34 +/- 0.14 vs 0.18 +/- 0.06) but less than half of the native postnatal day 12 (0.90 +/- 0.06) and adult (0.91 +/- 0.04) myocardium. The myocytes under electrical stimulation were more elongated compared to nonstimulated myocytes and exhibited similar lengths, widths, and heights as in age-matched myocardium. Furthermore, the percentage of connexin-43 positive membrane staining was similar in the electrically stimulated, postnatal day 12, and adult myocytes, whereas it was significantly lower in the nonstimulated myocytes. Connexin-43 was found to be primarily located at cell ends for adult myocytes and irregularly but densely clustered over the membranes of nonstimulated, stimulated, and postnatal day 12 myocytes. These findings support our hypothesis and reveal that the application of environmental cues produces tissue with structural features more representative of age-matched native myocardium than adult myocardium. We suggest that the presented approach can be applied to quantitatively characterize developmental processes and mechanisms in engineered tissue. PMID- 22919460 TI - Human responses to unfairness with primary rewards and their biological limits. AB - Humans bargaining over money tend to reject unfair offers, whilst chimpanzees bargaining over primary rewards of food do not show this same motivation to reject. Whether such reciprocal fairness represents a predominantly human motivation has generated considerable recent interest. We induced either moderate or severe thirst in humans using intravenous saline, and examined responses to unfairness in an Ultimatum Game with water. We ask if humans also reject unfair offers for primary rewards. Despite the induction of even severe thirst, our subjects rejected unfair offers. Further, our data provide tentative evidence that this fairness motivation was traded-off against the value of the primary reward to the individual, a trade-off determined by the subjective value of water rather than by an objective physiological metric of value. Our data demonstrate humans care about fairness during bargaining with primary rewards, but that subjective self-interest may limit this fairness motivation. PMID- 22919461 TI - Imaging limbal and scleral vasculature using Swept Source Optical Coherence Tomography. AB - We demonstrate an application of high-speed swept source optical coherence tomography for vessel visualization in the anterior segment of the human eye. The human corneo-scleral junction and sclera was imaged in vivo. Imaging was performed using a swept source OCT system operating at the 1050nm wavelength range and 100kHz A-scan rate. High imaging speed enables the generation of 3D depth-resolved vasculature maps. The vessel visualization method revealed a rich vascular system in the conjunctiva and episclera. PMID- 22919462 TI - Islet beta-Cell Mass Preservation and Regeneration in Diabetes Mellitus: Four Factors with Potential Therapeutic Interest. AB - Islet beta-cell replacement and regeneration are two promising approaches for the treatment of Type 1 Diabetes Mellitus. Indeed, the success of islet transplantation in normalizing blood glucose in diabetic patients has provided the proof of principle that cell replacement can be employed as a safe and efficacious treatment. Nonetheless, shortage of organ donors has hampered expansion of this approach. Alternative sources of insulin-producing cells are mandatory to fill this gap. Although great advances have been achieved in generating surrogate beta-cells from stem cells, current protocols have yet to produce functionally mature insulin-secreting cells. Recently, the concept of islet regeneration in which new beta-cells are formed from either residual beta cell proliferation or transdifferentiation of other endocrine islet cells has gained much interest as an attractive therapeutic alternative to restore beta cell mass. Complementary approaches to cell replacement and regeneration could aim at enhancing beta-cell survival and function. Herein, we discuss the value of Hepatocyte Growth Factor (HGF), Glucose-Dependent Insulinotropic Peptide (GIP), Paired box gene 4 (Pax4) and Liver Receptor Homolog-1 (LRH-1) as key players for beta-cell replacement and regeneration therapies. These factors convey beta-cell protection and enhanced function as well as facilitating proliferation and transdifferentiation of other pancreatic cell types to beta-cells, under stressful conditions. PMID- 22919463 TI - One-Haptic Fixation of Posterior Chamber Intraocular Lenses without Scleral Flaps. AB - Purpose. To assess visual results and complications of a modified technique of posterior chamber intraocular lenses (PC IOLs) in aphakic eyes without scleral flaps. Methods. Modified one-haptic scleral fixation was performed in one eye each of 25 patients with aphakia and insufficient capsule support. Follow-up period was six months. Outcome measures included best-corrected visual acuity, intraocular pressure (IOP), and postoperative complications. Results. The study included 15 males and 10 females. The preoperative best-corrected visual acuity (BCVA) ranged from 5/60 to 6/9. The operation time ranged from 25 to 45 minutes (mean 35.25 +/- 5.34 min). Anterior vitrectomy was performed in 12 cases (48%). There was no major IOL decentration. The final BCVA ranged from 6/36 to 6/9. Seven cases (28%) showed postoperative glaucoma, five cases (20%) had temporary hypotony, and hyphema in 2 eyes (8%). No cases of suture erosion, postoperative endophthalmitis, retinal detachment, or IOL dislocation were detected. Conclusion. This technique of one-haptic scleral fixation of posterior chamber IOLs is a good choice in presence of insufficient capsule support. It reduces the operation time, achieves the IOL stability, and minimizes postoperative suture related complications. PMID- 22919464 TI - Structural and Functional Characterization of RecG Helicase under Dilute and Molecular Crowding Conditions. AB - In an ATP-dependent reaction, the Escherichia coli RecG helicase unwinds DNA junctions in vitro. We present evidence of a unique protein conformational change in the RecG helicase from an alpha-helix to a beta-strand upon an ATP binding under dilute conditions using circular dichroism (CD) spectroscopy. In contrast, under molecular crowding conditions, the alpha-helical conformation was stable even upon an ATP binding. These distinct conformational behaviors were observed to be independent of Na(+) and Mg(2+). Interestingly, CD measurements demonstrated that the spectra of a frayed duplex decreased with increasing of the RecG concentration both under dilute and molecular crowding conditions in the presence of ATP, suggesting that RecG unwound the frayed duplex. Our findings raise the possibility that the alpha-helix and beta-strand forms of RecG are a preactive and an active structure with the helicase activity, respectively. PMID- 22919465 TI - Genetic predisposition for dermal problems in hexavalent chromium exposed population. AB - We studied the effect of genetic susceptibility on hexavalent chromium induced dermal adversities. The health status of population was examined from the areas of Kanpur (India) having the elevated hexavalent chromium levels in groundwater. Blood samples were collected for DNA isolation to conduct polymorphic determination of genes, namely: NQO1 (C609T), hOGG1 (C1245G), GSTT1, and GSTM1 (deletion). Symptomatic exposed subjects (n = 38) were compared with asymptomatic exposed subjects (n = 108) along with asymptomatic controls (n = 148) from a non contaminated reference community. Exposed symptomatic group consisted of 36.8% subjects who were GSTM1 null genotyped as compared to asymptomatic where only 19.4% subjects were null. The exposed subjects with GSTM1 null genotype were more susceptible to dermal adversities in comparison with wild genotyped subjects (OR = 2.42; 95% CI = 1.071-5.451). Age, smoking, gender or duration of residence were not found to have any confounding effect towards this association. Association with other genes was not statistically significant, nonetheless, possible contribution by these genes cannot be ruled out. In conclusion, variation in the polymorphic status of GSTM1 gene may influence dermal outcomes among residents from Cr(VI) contaminated areas. Further studies are therefore, needed to examine these observations among different population groups. PMID- 22919466 TI - Cardiovascular Risk Factors and Distributions of the Ankle-Brachial Index among Type 2 Diabetes Mellitus Patients. AB - Background. The aim of present study is to observe the association between the levels of ankle-brachial index (ABI) and cardiovascular risk factors among people with type 2 diabetes mellitus in north India. A cross-sectional study was carried out at a centre for heart and diabetic clinic in the state of Punjab on 1121 subjects (671 males and 450 females) with type 2 diabetes mellitus. History of symptoms related to cardiovascular diseases was noted, and blood pressure and anthropometric measurements were recorded. Ankle-brachial index (ABI) was measured using ultrasonic Doppler flow detector. Subjects with ABI <=0.9 and >=1.30 were classified as having low and high ABI, respectively. Females had a higher BMI and brachial-ankle pulse wave velocity (P < 0.001). Whereas, males had higher diastolic blood pressure and duration of type 2 diabetes mellitus. The differences of systolic blood pressure and ankle-brachial index were not found significant between the sexes. The prevalence of low ABI (<0.9) was 4.47% in men and 4.67% in women and high ABI (>=1.30) was prevalent in 14% of men and 10.45% of women. Age, BMI, baPWV, and blood pressures were significantly associated with ABI value in both sexes. The results suggested that the ABI might be used as a strong indicator for cardiovascular risk factors in type 2 diabetic subjects. PMID- 22919467 TI - A Thermostable Crude Endoglucanase Produced by Aspergillus fumigatus in a Novel Solid State Fermentation Process Using Isolated Free Water. AB - Aspergillus fumigatus was grown on chopped wheat straw in a solid state fermentation (SSF) process carried out in constant presence of isolated free water inside the fermentation chamber. The system allowed maintaining a constant vapor pressure inside the fermentor throughout the fermentation process. Crude endoglucanase produced by A. fumigatus under such conditions was more thermostable than previously reported enzymes of the same fungal strain which were produced under different conditions and was also more thermostable than a number of other previously reported endoglucanases as well. Various thermostability parameters were calculated for the crude endoglucanase. Half lives (T(1/2)) of the enzyme were 6930, 866, and 36 min at 60 degrees C, 70 degrees C, and 80 degrees C, respectively. Enthalpies of activation of denaturation (DeltaH(D)*) were 254.04, 253.96, and 253.88 K J mole(-1), at 60 degrees C, 70 degrees C and 80 degrees C, respectively, whereas entropies of activation of denaturation (DeltaS(D)*) and free energy changes of activation of denaturation (DeltaG(D)*) were 406.45, 401.01, and 406.07 J mole(-1) K(-1) and 118.69, 116.41, and 110.53 K J mole(-1) at 60 degrees C, 70 degrees C and 80 degrees C, respectively. PMID- 22919468 TI - Isolation and characterization of chitosan-producing bacteria from beaches of chennai, India. AB - Chitosan is a deacetylated product of chitin produced by chitin deacetylase, an enzyme that hydrolyses acetamido groups of N-acetylglucosamine in chitin. Chitosan is a natural polymer that has great potential in biotechnology and in the biomedical and pharmaceutical industries. Commercially, it is produced from chitin via a harsh thermochemical process that shares most of the disadvantages of a multistep chemical procedure. It is environmentally unsafe and not easily controlled, leading to a broad and heterogeneous range of products. An alternative or complementary procedure exploiting the enzymatic deacetylation of chitin could potentially be employed, especially when a controlled and well defined process is required. In this study, 20 strains of bacteria were isolated from soil samples collected from different beaches of Chennai, India. Of these 20 bacterial strains, only 2 strains (S3, S14) are potent degrader of chitin and they are also a good producer of the enzyme chitin deacetylase so as to release chitosan. PMID- 22919469 TI - Brain Levels of Catalase Remain Constant through Strain, Developmental, and Chronic Alcohol Challenges. AB - Catalase (EC 1.11.1.6) oxidizes ethanol to acetaldehyde within the brain and variations in catalase activity may underlie some consequences of ethanol consumption. The goals of this study were to measure catalase activity in subcellular fractions from rat brain and to compare the levels of this enzyme in several important settings. In the first series of studies, levels of catalase were compared between juvenile and adult rats and between the Long-Evans (LE) and Sprague-Dawley (SD) strains. Levels of catalase appear to have achieved the adult level by the preadolescent period defined by postnatal age (P, days) P25-P28, and there were no differences between strains at the developmental stages tested. Thus, variation in catalase activity is unlikely to be responsible for differences in how adolescent and adult rats respond to ethanol. In the second series of studies, periadolescent and adult rats were administered ethanol chronically through an ethanol-containing liquid diet. Diet consumption and blood ethanol concentrations were significantly higher for periadolescent rats. Catalase activities remained unchanged following ethanol consumption, with no significant differences within or between strains. Thus, the brain showed no apparent adaptive changes in levels of catalase, even when faced with the high levels of ethanol consumption characteristic of periadolescent rats. PMID- 22919470 TI - Osteonecrosis in systemic lupus erythematosus: an early, frequent, and not always symptomatic complication. AB - Osteonecrosis may complicate the course of systemic lupus erythematosus and may contemporaneously affect multiple joints. The major risk factor associated with the development of osteonecrosis is the use of glucocorticoid at high doses. Recent studies using serial MRI, which represents the "gold standard" for the early detection of osteonecrosis, yielded some interesting findings about the natural history of this clinical entity. Osteonecrosis in the majority of the cases is asymptomatic and occurs early in the course of the disease. Its later occurrence is associated with lupus flare that requires the increase of corticosteroid dose. The optimal treatment of osteonecrosis is controversial. In case of silent osteonecrosis involving a small area conservative strategy is usually adequate. When lesions are symptomatic surgical treatment as core decompression or free vascularized fibular grafting is required; extracorporeal shockwave treatment may represent an alternative therapeutic approach. When the lesion has a medium-large dimension or involves a weight-bearing area bone collapse is a common complication requiring total joint replacement. Coadministration of bisphosphonate or warfarin with high doses of corticosteroid might be a promising preventive strategy of osteonecrosis. PMID- 22919471 TI - Eating and psychological profiles of women with higher depressive symptoms who are trying to lose weight. AB - The aim of this study was to determine whether women with higher depressive symptoms differed from women with lower depressive symptoms on early weight-loss, eating behaviors and psychological profiles. Among a sample of 45 overweight/obese women who had undertaken a self-initiated weight-loss attempt, two groups were formed based on scores from the Beck Depression Inventory (BDI II), one with lower depressive symptoms (BDI-II < 10; n = 21) and one with higher depressive symptoms (BDI >= 10; n = 24). Even if some women in the higher depressive symptom group did not reach the clinical cut-off for depression (BDI = 14), this group tended to lose less weight in the first two months of their weight-loss attempt and to show a more disturbed eating and psychological profile compared to the group with lower depressive symptoms. In addition, among women with higher depressive symptoms, eating and psychological variables were systematically related to one another whereas these variables were not related among the other group. Results highlight the relevance of considering the presence of depressive symptoms as a marker of clinical severity among the overweight/obese population, and suggest that the BDI-II could be an interesting screening instrument to identify this particular subgroup. PMID- 22919472 TI - MicroRNA Regulation of Cholesterol Metabolism. AB - Disruption of cellular cholesterol balance results in pathologic processes including atherosclerosis, metabolic syndrome, type II diabetes and Alzheimer's disease. Maintenance of cholesterol homeostasis requires constant metabolic adjustment, achieved partly through the fine regulation of the classical transcription factors (e.g., by SREBP and LXR), but also through members of a class of noncoding RNAs termed miRNAs. Some miRNAs have now been identified to be potent post-transcriptional regulators of lipid metabolism genes, including miR 122, miR-33, miR-758, and miR-106b. Different strategies have been developed to modulate miRNA effects for therapeutic purposes. The promise demonstrated by the use of anti-miRs in human preclinical studies, in the case of miR-122, raises the possibility that miR-33, miR-758, and miR-106b may become viable therapeutic targets in future. This review summarizes the evidence for a critical role of some miRNAs in regulating cholesterol metabolism and suggests novel ways to manage dyslipidemias and cardiovascular diseases. PMID- 22919473 TI - Optimization of preload in severe sepsis and septic shock. AB - In sepsis both under- and overresuscitation are associated with increased morbidity and mortality. Moreover, sepsis can be complicated by myocardial dysfunction, and only half of the critically ill patients exhibit preload responsiveness. It is of paramount importance to accurately, safely, and rapidly determine and optimize preload during resuscitation. Traditional methods of determining preload based on measurement of pressure in a heart chamber or volume of a heart chamber ("static" parameters) are inaccurate and should be abandoned in favor of determining preload responsiveness by using one of the "dynamic parameters" based on respiratory variation in the venous or arterial circulation or based on change in stroke volume in response to an endogenous or exogenous volume challenge. The recent development and validation of a number of noninvasive technologies now allow us to optimize preload in an accurate, safe, rapid and, cost-effective manner. PMID- 22919474 TI - Depression treatment with duloxetine and reduction of inability to work. AB - Data on inability to work from an observational study in patients treated with duloxetine for major depressive disorder in clinical practice in Germany were collected. Ability to work was compared between baseline and up to 6 months after initiation of duloxetine. All patients with a working status at baseline other than retired or retired early were included. 2,825 patients were analyzed, 54.8% were able to work at baseline increasing to 83.8% at 6 months. Of those patients unable to work at baseline, 72.7% were able to work after 6 months. A relevant reduction of inability to work was also found for patient subgroups with moderate to severe pain at baseline and those with and without MDD pretreatment. As inability to work is one of the main cost drivers for depressive patients in Germany, the reduction of inability to work could potentially result in considerable cost savings for health insurance companies and society. PMID- 22919475 TI - The role of secondary surgery in recurrent ovarian cancer. AB - Despite optimal treatment (complete cytoreduction and adjuvant chemotherapy), 5 year survival for advanced ovarian cancer is approximately 30% and most patients succumb to their disease. Cytoreductive surgery is accepted as a major treatment of primary ovarian cancer but its role in recurrent disease is controversial and remains a field of discussion mainly owing to missing data from prospective randomized trials. A critical review of literature evidence on secondary surgery in recurrent ovarian cancer will be described. PMID- 22919476 TI - The Reliability of a Three-Dimensional Photo System- (3dMDface-) Based Evaluation of the Face in Cleft Lip Infants. AB - Ample data exists about the high precision of three-dimensional (3D) scanning devices and their data acquisition of the facial surface. However, a question remains regarding which facial landmarks are reliable if identified in 3D images taken under clinical circumstances. Sources of error to be addressed could be technical, user dependent, or patient respectively anatomy related. Based on clinical 3D photos taken with the 3dMDface system, the intra observer repeatability of 27 facial landmarks in six cleft lip (CL) infants and one non-CL infant was evaluated based on a total of over 1,100 measurements. Data acquisition was sometimes challenging but successful in all patients. The mean error was 0.86 mm, with a range of 0.39 mm (Exocanthion) to 2.21 mm (soft gonion). Typically, landmarks provided a small mean error but still showed quite a high variance in measurements, for example, exocanthion from 0.04 mm to 0.93 mm. Vice versa, relatively imprecise landmarks still provide accurate data regarding specific spatial planes. One must be aware of the fact that the degree of precision is dependent on landmarks and spatial planes in question. In clinical investigations, the degree of reliability for landmarks evaluated should be taken into account. Additional reliability can be achieved via multiple measuring. PMID- 22919477 TI - Acid-fast bacilli other than mycobacteria in tuberculosis patients receiving directly observed therapy short course in cross river state, Nigeria. AB - The information on the contribution of non tuberculous mycobacteria (NTM) to mycobacterial infections in Africa is scarce due to limited laboratory culture for its isolation and identification. One hundred and thirty-seven sputum smear positive patients were recruited into a study on the molecular epidemiology of Mycobacterium tuberculosis in Cross River State. Following sputum culture, 97 pure isolates were obtained and identified using Capilia TB-Neo and further confirmed by the GenoType Mycobacterium CM kit. Of the 97 isolates, 81 (83.5%) isolates were Capilia TB-Neo positive while 16 (16.5%) were Capilia TB-Neo negative. Further confirmation with the GenoType Mycobacterium CM kit revealed that 4 (25%) of the 16 isolates belonged to NTM and included M. fortuitum I, M. fortuitum II/M magaritense, M. abscessus, and M. avium ssp. The remaining 12 (75%) Capilia TB-Neo negative isolates were not members of the genus Mycobacterium despite their AFB appearance. Six (33.3%) of the Capilia TB-Neo negative were from HIV positive tuberculosis patients. All subjects in this study were placed on DOTS shortly after the AFB results were obtained. The implication of isolation of 16.5% nontuberculous isolates further emphasizes the need for culture of sputum specimen especially in HIV positive patients prior to administration of antituberculosis therapy. PMID- 22919478 TI - A new drug release method in early development of transdermal drug delivery systems. AB - In vitro drug release tests are a widely used tool to measure the variance between transdermal product performances and required by many authorities. However, the result cannot provide a good estimation of the in vivo drug release. In the present work, a new method for measuring drug release from patches has been explored and compared with the conventional USP apparatus 2 and 5 methods. Durogesic patches, here used as a model patch, were placed on synthetic skin simulator and three moisture levels (29, 57, 198 MUL cm(-2)) were evaluated. The synthetic skin simulators were collected after 1, 2, 3, 4, 6, and 24 hours and extracted with pH 1.0 hydrochloric acid solution. The drug concentrations in the extractions were measured by isocratic reverse phase high-pressure liquid chromatography. The results showed that, with the increasing moisture level on the synthetic skin simulator, the drug release rate increased. In comparison with the conventional USP method, the drug release results performed by the new method were in more correlation to the release rate claimed in the product label. This new method could help to differentiate the drug release rates among assorted formulations of transdermal drug delivery systems in the early stage of development. PMID- 22919479 TI - Concurrent dual contrast for cellular magnetic resonance imaging using gadolinium oxide and iron oxide nanoparticles. AB - Rationale and Objectives. Concurrent visualization of differential targets in cellular and molecular imaging is valuable for resolving processes spatially and temporally, as in monitoring different cell subtypes. The purpose of this study was to demonstrate concurrent, dual (positive and negative) contrast visualization on magnetic resonance imaging (MRI) of two colocalized cell populations labeled with Gadolinium "Gd" oxide and iron "Fe" oxide nanoparticles. Materials and Methods. Human aortic endothelial cells (EC) and smooth muscle cells (SMC) were labeled with various concentrations of Gd oxide and Fe oxide, respectively. MRI on single- or mixed-cell samples was performed at 7 tesla. Proper cell phenotype expressions, cell uptake of contrast agents, and the effect of labeling on cell viability and proliferation were also determined. Results. Both contrast agents were efficiently taken up by cells, with viability and proliferation largely unaffected. On MRI, the positive contrast associated with Gd oxide-labeled EC and negative contrast associated with Fe oxide-labeled SMC discriminated the presence of each cell type, whether it existed alone or colocalized in a mixed-cell sample. Conclusion. It is feasible to use Gd oxide and Fe oxide for dual contrast and concurrent discrimination of two colocalized cell populations on MRI at 7 tesla. PMID- 22919481 TI - "Discordant Airflow Obstruction: GOLD versus LLN". PMID- 22919480 TI - Dietary Flaxseed Oil Protects against Bleomycin-Induced Pulmonary Fibrosis in Rats. AB - Bleomycin, a widely used antineoplastic agent, has been associated with severe pulmonary toxicity, primarily fibrosis. Previous work has shown a reduction in bleomycin-induced lung pathology by long-chain omega-3 fatty acids. Treatment by short-chain omega-3 fatty acids, alpha-linolenic acid, found in dietary flaxseed oil may also reduce lung fibrosis, as previously evidenced in the kidney. To test this hypothesis, 72 rats were divided between diets receiving either 15% (w/w) flaxseed oil or 15% (w/w) corn oil (control). These groups were further divided to receive either bleomycin or vehicle (saline) via an oropharyngeal delivery, rather than the traditional intratracheal instillation. Lungs were harvested at 2, 7, and 21 days after bleomycin or saline treatment. Animals receiving flaxseed oil showed a delay in edema formation (P = 0.025) and a decrease in inflammatory cell infiltrate and vasculitis (P = 0.04 and 0.007, resp.). At days 7 and 21, bleomycin produced a reduction in pulmonary arterial lumen patency (P = 0.01), but not in rats that were treated with flaxseed oil. Bleomycin-treated rats receiving flaxseed oil had reduced pulmonary septal thickness (P = 0.01), signifying decreased fibrosis. Dietary flaxseed oil may prove beneficial against the side effects of this highly effective chemotherapeutic agent and its known toxic effects on the lung. PMID- 22919482 TI - Neuromuscular junction protection for the potential treatment of amyotrophic lateral sclerosis. AB - Amyotrophic lateral sclerosis (ALS) is a neuromuscular disease characterized by the progressive degeneration of upper and lower motor neurons (MNs), leading to muscular atrophy and eventual respiratory failure. ALS research has primarily focused on mechanisms regarding MN cell death; however, degenerative processes in the skeletal muscle, particularly involving neuromuscular junctions (NMJs), are observed in the early stages of and throughout disease progression. According to the "dying-back" hypothesis, NMJ degeneration may not only precede, but actively cause upper and lower MN loss. The importance of NMJ pathology has relatively received little attention in ALS, possibly because compensatory mechanisms mask NMJ loss for prolonged periods. Many mechanisms explaining NMJ degeneration have been proposed such as the disruption of anterograde/retrograde axonal transport, irregular cellular metabolism, and changes in muscle gene and protein expression. Neurotrophic factors, which are known to have neuroprotective and regenerative properties, have been intensely investigated for their therapeutic potential in both the preclinical and clinical setting. Additional research should focus on the potential of preserving NMJs in order to delay or prevent disease progression. PMID- 22919483 TI - RNA-Binding Proteins in Amyotrophic Lateral Sclerosis and Neurodegeneration. AB - Amyotrophic Lateral Sclerosis (ALS) is an adult onset neurodegenerative disease, which is universally fatal. While the causes of this devastating disease are poorly understood, recent advances have implicated RNA-binding proteins (RBPs) that contain predicted prion domains as a major culprit. Specifically, mutations in the RBPs TDP-43 and FUS can cause ALS. Cytoplasmic mislocalization and inclusion formation are common pathological features of TDP-43 and FUS proteinopathies. Though these RBPs share striking pathological and structural similarities, considerable evidence suggests that the ALS-linked mutations in TDP 43 and FUS can cause disease by disparate mechanisms. In a recent study, Couthouis et al. screened for protein candidates that were also involved in RNA processing, contained a predicted prion domain, shared other phenotypic similarities with TDP-43 and FUS, and identified TAF15 as a putative ALS gene. Subsequent sequencing of ALS patients successfully identified ALS-linked mutations in TAF15 that were largely absent in control populations. This study underscores the important role that perturbations in RNA metabolism might play in neurodegeneration, and it raises the possibility that future studies will identify other RBPs with critical roles in neurodegenerative disease. PMID- 22919484 TI - ALS and Frontotemporal Dysfunction: A Review. AB - Though once believed to be a disease that was limited to the motor system, it is now apparent that amyotrophic lateral sclerosis (ALS) may be associated with cognitive changes in some patients. Changes are consistent with frontotemporal dysfunction, and may range from mild abnormalities only recognized with formal neuropsychological testing, to profound frontotemporal dementia (FTD). Executive function, behavior, and language are the most likely areas to be involved. Screening helpful in detecting abnormalities includes verbal or categorical fluency, behavioral inventories filled out by the caregiver, and evaluation for the presence of depression and pseudobulbar affect. Patients with cognitive dysfunction have shortened survival and may be less compliant with recommendations regarding use of feeding tubes and noninvasive ventilation. Evolving knowledge of genetic and pathological links between ALS and FTD has allowed us to better understand the overlapping spectrum of ALS and FTD. PMID- 22919485 TI - Assessing Cerebrovascular Reactivity in Carotid Steno-Occlusive Disease Using MRI BOLD and ASL Techniques. AB - Impaired cerebrovascular reactivity (CVR), a predictive factor of imminent stroke, has been shown to be associated with carotid steno-occlusive disease. Magnetic resonance imaging (MRI) techniques, such as blood oxygenation level dependent (BOLD) and arterial spin labeling (ASL), have emerged as promising noninvasive tools to evaluate altered CVR with whole-brain coverage, when combined with a vasoactive stimulus, such as respiratory task or injection of acetazolamide. Under normal cerebrovascular conditions, CVR has been shown to be globally and homogenously distributed between hemispheres, but with differences among cerebral regions. Such differences can be explained by anatomical specificities and different biochemical mechanisms responsible for vascular regulation. In patients with carotid steno-occlusive disease, studies have shown that MRI techniques can detect impaired CVR in brain tissue supplied by the affected artery. Moreover, resulting CVR estimations have been well correlated to those obtained with more established techniques, indicating that BOLD and ASL are robust and reliable methods to assess CVR in patients with cerebrovascular diseases. Therefore, the present paper aims to review recent studies which use BOLD and ASL to evaluate CVR, in healthy individuals and in patients with carotid steno-occlusive disease, providing a source of information regarding the obtained results and the methodological difficulties. PMID- 22919486 TI - Cathepsin D Expression in Colorectal Cancer: From Proteomic Discovery through Validation Using Western Blotting, Immunohistochemistry, and Tissue Microarrays. AB - Despite recent advances in surgical techniques and therapeutic treatments, survival from colorectal cancer (CRC) remains disappointing with some 40-50% of newly diagnosed patients ultimately dying of metastatic disease. Current staging by light microscopy alone is not sufficiently predictive of prognosis and would benefit from additional support from biomarkers in order to stratify patients appropriately for adjuvant therapy. We have identified that cathepsin D expression was significantly greater in cells from invasive front (IF) area and liver metastasis (LM) than those from main tumour body (MTB). Cathepsin D expression was subsequently examined by immunohistochemistry in tissue microarrays from 119 patients with CRC. Strong expression in tumour cells at the IF did not correlate significantly with any clinico-pathological parameters examined or patient survival. However, cathepsin D expression in cells from the MTB was highly elevated in late stage CRC and showed significant correlation with subsequent distant metastasis and shorter cancer-specific survival. We also found that macrophages surrounding tumour cells stained strongly for cathepsin D but there was no significant correlation found between cathepsin D in macrophages at IF and MTB of CRC patient with the clinic-pathological parameters examined. PMID- 22919487 TI - Method for recovery and immunoaffinity enrichment of membrane proteins illustrated with metastatic ovarian cancer tissues. AB - Integral membrane proteins play key biological roles in cell signaling, transport, and pathogen invasion. However, quantitative clinical assays for this critical class of proteins remain elusive and are generally limited to serum soluble extracellular fragments. Furthermore, classic proteomic approaches to membrane protein analysis typically involve proteolytic digestion of the soluble pieces, resulting in separation of intra- and extracellular segments and significant informational loss. In this paper, we describe the development of a new method for the quantitative extraction of intact integral membrane proteins (including GPCRs) from solid metastatic ovarian tumors using pressure cycling technology in combination with a new (ProteoSolve-TD) buffer system. This new extraction buffer is compatible with immunoaffinity methods (e.g., ELISA and immunoaffinity chromatography), as well as conventional proteomic techniques (e.g., 2D gels, western blots). We demonstrate near quantitative recovery of membrane proteins EDG2, EDG4, FASLG, KDR, and LAMP-3 by western blots. We have also adapted commercial ELISAs for serum-soluble membrane protein fragments (e.g., sVEGFR2) to measure the tissue titers of their transmembrane progenitors. Finally, we demonstrate the compatibility of the new buffers with immunoaffinity enrichment/mass spectrometric characterization of tissue proteins. PMID- 22919488 TI - ASGR1 and ASGR2, the Genes that Encode the Asialoglycoprotein Receptor (Ashwell Receptor), Are Expressed in Peripheral Blood Monocytes and Show Interindividual Differences in Transcript Profile. AB - Background. The asialoglycoprotein receptor (ASGPR) is a hepatic receptor that mediates removal of potentially hazardous glycoconjugates from blood in health and disease. The receptor comprises two proteins, asialoglycoprotein receptor 1 and 2 (ASGR1 and ASGR2), encoded by the genes ASGR1 and ASGR2. Design and Methods. Using reverse transcription amplification (RT-PCR), expression of ASGR1 and ASGR2 was investigated in human peripheral blood monocytes. Results. Monocytes were found to express ASGR1 and ASGR2 transcripts. Correctly spliced transcript variants encoding different isoforms of ASGR1 and ASGR2 were present in monocytes. The profile of transcript variants from both ASGR1 and ASGR2 differed among individuals. Transcript expression levels were compared with the hepatocyte cell line HepG2 which produces high levels of ASGPR. Monocyte transcripts were 4 to 6 orders of magnitude less than in HepG2 but nonetheless readily detectable using standard RT-PCR. The monocyte cell line THP1 gave similar results to monocytes harvested from peripheral blood, indicating it may provide a suitable model system for studying ASGPR function in this cell type. Conclusions. Monocytes transcribe and correctly process transcripts encoding the constituent proteins of the ASGPR. Monocytes may therefore represent a mobile pool of the receptor, capable of reaching sites remote from the liver. PMID- 22919489 TI - Physical Activity across Frailty Phenotypes in Females with Parkinson's Disease. AB - Females with Parkinson's disease (PD) are vulnerable to frailty. PD eventually leads to decreased physical activity, an indicator of frailty. We speculate PD results in frailty through reduced physical activity. Objective. Determine the contribution of physical activity on frailty in PD (n = 15, 65 +/- 9 years) and non-PD (n = 15, 73 +/- 14 years) females. Methods. Frailty phenotype (nonfrail/prefrail/frail) was categorized and 8 hours of physical activity was measured using accelerometer, global positioning system, and self-report. Two-way ANCOVA (age as covariate) was used to compare physical activity between disease and frailty phenotypes. Spearman correlation assessed relationships, and linear regression determined associations with frailty. Results. Nonfrail recorded more physical activity (intensity, counts, self-report) compared with frail. Self reported physical activity was greater in PD than non-PD. In non-PD, step counts, light physical activity time, sedentary time, and self-reported physical activity were related to frailty (R = 0.91). In PD, only carbidopa-levodopa dose was related to frailty (r = 0.61). Conclusion. Physical activity influences frailty in females without PD. In PD females, disease management may be a better indicator of frailty than physical activity. Further investigation into how PD associated factors contribute to frailty is warranted. PMID- 22919490 TI - "Dead Cells Talking": The Silent Form of Cell Death Is Not so Quiet. AB - After more than twenty years of research, the molecular events of apoptotic cell death can be succinctly stated; different pathways, activated by diverse signals, increase the activity of proteases called caspases that rapidly and irreversibly dismantle condemned cell by cleaving specific substrates. In this time the ideas that apoptosis protects us from tumourigenesis and that cancer chemotherapy works by inducing apoptosis also emerged. Currently, apoptosis research is shifting away from the intracellular events within the dying cell to focus on the effect of apoptotic cells on surrounding tissues. This is producing counterintuitive data showing that our understanding of the role of apoptosis in tumourigenesis and cancer therapy is too simple, with some interesting and provocative implications. Here, we will consider evidence supporting the idea that dying cells signal their presence to the surrounding tissue and, in doing so, elicit repair and regeneration that compensates for any loss of function caused by cell death. We will discuss evidence suggesting that cancer cell proliferation may be driven by inappropriate or corrupted tissue-repair programmes that are initiated by signals from apoptotic cells and show how this may dramatically modify how we view the role of apoptosis in both tumourigenesis and cancer therapy. PMID- 22919491 TI - Activities-specific balance confidence in people with multiple sclerosis. AB - Objective. To evaluate the validity of the Activities-specific Balance Confidence scale (ABC) in people with multiple sclerosis (PwMS). Design. A multicentre, cross-sectional study. Setting. Six rural and urban Swedish sites, including specialized units at hospitals and primary care centers. Participants. A sample of 84 PwMS with subjective gait and balance impairment but still able to walk 100 m (comparable with EDSS 1-6). Outcome Measures. Timed Up and Go, Timed Up and Go(cog), 25-foot Timed Walk Test, Four Square Step Test, Dynamic Gait Index, Chair Stand Test, 12-item MS Walking Scale, self-reported falls, and use of assistive walking device were used for validation. Results. The concurrent convergent validity was moderate to good (0.50 to -0.75) with the highest correlation found for the 12-item MS Walking Scale. The ABC discriminated between multiple fallers and nonfallers but not between men and women. Ecological validity is suggested since ABC discriminated between users of assistive walking device and nonusers. The internal consistency was high at alpha = 0.95, and interitem correlations were between 0.30 and 0.83. Conclusion. This study supports the validity of the ABC for persons with mild-to-moderate MS. The participants lacked balance confidence in many everyday activities, likely restricting their participation in society. PMID- 22919492 TI - A Randomised, Double-Blind, Placebo-Controlled Trial with Vitamin D3 in MS: Subgroup Analysis of Patients with Baseline Disease Activity Despite Interferon Treatment. AB - We present a subgroup analysis of the first double-blind, placebo-controlled, randomised trial with vitamin D3 in MS. In the overall study population, there were 34 patients in the vitamin D arm and 32 patients in the placebo arm. All the patients were using interferon-beta-1b (IFNB) therapy. The subgroup consisted of 15 patients in the vitamin D arm and 15 patients in the placebo arm, who had either at least one relapse during the year preceding the study or enhancing T1 lesions at the baseline MRI scan. We measured the total number of MRI T1 enhancing lesions, the number of new/enlarging T2 lesions and T2 lesion volume (BOD) (mm(3)), EDSS (Expanded Disability Status Scale), annual relapse Rate (ARR), timed 25-foot walk (T25FW), and timed 10-foot tandem walk (TT10W) at baseline and at 12 months in the vitamin D-treated and in the placebo-treated patients. There was a statistically significant reduction in the number of T1 enhancing lesions, a smaller T2 lesion volume growth and less new/enlarging T2 brain MRI lesions in the vitamin D3-treated than in the placebo-treated subgroup patients. The MRI results were slightly more pronounced in the subgroup than in the overall study population. PMID- 22919493 TI - Application of Soft Tissue Artifact Compensation Using Displacement Dependency between Anatomical Landmarks and Skin Markers. AB - Soft tissue artifact is known to be one of the main sources of errors in motion analysis by means of stereophotogrammetry. Among many approaches to reduce such errors, one is to estimate the position of anatomical landmarks during a motion with joint angle or displacement of skin markers, which is the so-called compensation method of anatomical landmarks. The position of anatomical landmarks was modeled from the data of the so-called dynamic calibration, in which anatomical landmark positions are calibrated in an ad hoc motion. This study aimed to apply the compensation methods with joint angle and skin marker displacement to three lower extremity motions (walking, sit-to-stand/stand-to sit, and step up/down) in ten healthy males and compare their reliability. To compare the methods, two sets of kinematic variables were calculated using two different marker clusters, and the difference was obtained. Results showed that the compensation method with skin marker displacement had less differences by 30 60% compared to without compensation. In addition, it had significantly less difference in some kinematic variables (7 of 18) by 25-40% compared to the compensation method with joint angle. PMID- 22919494 TI - Further clinical validation of the walking impairment questionnaire for classification of walking performance in patients with peripheral artery disease. AB - The purpose of this study was to further validate the Walking Impairment Questionnaire (WIQ) as a self-report tool to aid in the clinical identification of walking ability of patients with peripheral artery disease (PAD). 132 patients with PAD and an ankle brachial index (ABI) <=0.90 were enrolled; 123 provided complete data for the WIQ and standardized graded treadmill test. The WIQ scores were consistent with reported scores in other studies. The absolute claudication distance (ACD) ranged from 42.3 to 1589.2 meters; the peak walking time (PWT) ranged from 68 to 1800 seconds. Adjusted WIQ scores were positively and moderately associated with the log transformed ACD and PWT (r > .53, P < .001). Based on the area under the curve analysis, an overall WIQ score of 42.5 or less identified low performers (sensitivity 0.90, specificity 0.73); the combined subscale score of distance and stair of 75.5 or more identified high performers (sensitivity 0.41, specificity 0.90). We conclude that WIQ cut-offs appropriately classify walking performance in PAD patients, making this a potentially useful clinical tool. Consideration needs to be given to incorporating a standardized WIQ version into practice guidelines and the use of innovative strategies to facilitate clinical uptake. PMID- 22919495 TI - Imaging-based biomarkers: characterization of post-kawasaki vasculitis in infants and hypertension phenotype in rat model. AB - Background. Investigating the mechanical properties of the arteries is essential in cardiovascular diseases. Recent imaging modalities allow mapping mechanical properties within the arterial wall. Aims. We report the potential of imaging based biomarker (ImBioMark) to investigate the effect of aging on the rat. We also present preliminary data with ImBioMark characterizing vascular sequelae of Kawasaki disease (KD) in young humans. Methods. We investigated in vivo the effect of aging on male Brown Norway (BN) rats' (n = 5) carotid stiffness. In a second experiment, the impact of KD on the ascending aorta (AA) was examined in KD children (n = 2) aged 13 +/- 1.41 years old compared to KD-free children (n = 5) aged 13.13 +/- 0.18 years old. Results. The stiffness of BN's carotid artery was three times stiffer in the old rats, with a turning point at 40 weeks old (P = 0.001). KD had a very significant impact on the AA stiffness with strain estimates of 2.39 +/- 0.51% versus 4.24 +/- 0.65% in controls (P < 0.001). Conclusion. ImBioMark phenotypes hypertension in rat models noninvasively in vivo without resorting to euthanasia. Quantifying aortic wall remodeling is also feasible in humans. Future investigations target human cardiovascular disease. PMID- 22919496 TI - Hyperemia-Related Changes in Arterial Stiffness: Comparison between Pulse Wave Velocity and Stiffness Index in the Vascular Reactivity Assessment. AB - Carotid-to-radial pulse wave velocity (PWV(cr)) has been proposed to evaluate endothelial function. However, the measurement of PWV(cr) is not without limitations. A new simple approach could have wide application. Stiffness index (SI) is obtained by analysis of the peripheral pulse wave and gives reproducible information about stiffness of large arteries. This study assessed the effects of hyperemia on SI and compared it with PWV(cr) in 14 healthy subjects. Both were measured at rest and during 8 minutes after ischemia. SI temporal course was determined. At 1 minute, SI and PWV(cr) decreased (5.58 +/- 0.24 to 5.34 +/- 0.23 m/s, P < 0.05; 7.8 +/- 1.0 to 7.2 +/- 0.9 m/s; P < 0.05, resp.). SI was positively related to PWV(cr) in baseline (r = 0.62 , P < 0.05), at 1 minute (r = 0.79, P < 0.05), and during the whole experimental session (r = 0.52, P < 0.05). Conclusion. Hyperemia significantly decreases SI in healthy subjects. SI was related to PWV(cr) and could be used to facilitate the evaluation of hyperemia related changes in arterial stiffness. PMID- 22919497 TI - Encountering anger in the emergency department: identification, evaluations and responses of staff members to anger displays. AB - Background. Anger manifestations in emergency departments (EDs) occur daily, interrupting workflow and exposing staff to risk. Objectives. How staff assess and recognize patients' angry outbursts in EDs and elucidate responses to anger expressions, while considering effects of institution guidelines. Methods. Observations of staff patient interaction in EDs and personal interviews of staff (n = 38) were conducted. Two questionnaires were administered (n = 80 & n = 144). Assessment was based mainly on regression statistic tests. Results. Staff recognizes two types of anger displays. Magnitude of anger expressions were correlated with staff's fear level. Staff's responses ranged from ignoring incidents, giving in to patients' requests or immediately calling security. When staff felt fear and became angry they tended to call security. Staff was more likely to ignore anger when incident responsibility was assigned to patients. Discussion. Anger encounters are differentiated according to intensity level, which influences interpretations and response. Organizational policy has an effect on staff's response. Conclusions. Staff recognizes anger at varying levels and responds accordingly. The level of danger staff feels is a catalyst in giving in or calling security. Call security is influenced by fear, and anger. Permanent guidelines can help staff in responding to anger encounters. PMID- 22919498 TI - Concerns of Indian Mothers with Children Having Severe-to-Profound Hearing Impairment at Diagnosis and after 1-3 Years of Therapy. AB - Counseling training in graduate programs continues to be underrepresented. If parental queries are not addressed adequately, they keep visiting one doctor after another. Objective. The aim of the study is to identify maternal needs of children with hearing impairment at two stages of habilitation, that is, just after diagnosis (group I) and after receiving 1 to 3 years of language therapy (group II). Methods. Two groups of mothers were asked to speak their queries about aural habilitation of their children. Queries were recorded, summarized, and categorized as per their priorities. Results. Group I mothers wanted to know about how the child would learn to listen and speak (45%), causes of hearing loss (33.7%), understanding the ear and hearing (10.2%), understanding the audiogram (7%), and coping with emotional aspects of hearing loss (5%), while group II parents had priorities concerning speech development (24.5%) followed by child independence and employment (17.3%), schooling (15.6%), problem behaviors (11%), amplification device (9.4%), duration of therapy (8%), future of the child (8%), and questions about how can my child get adjusted to the "normal" world (6%). Conclusions. Culture- and language-specific materials to explain these issues need to be developed. PMID- 22919499 TI - Electromyographical comparison of four common shoulder exercises in unstable and stable shoulders. AB - This study examines if electromyographic (EMG) amplitude differences exist between patients with shoulder instability and healthy controls performing scaption, prone horizontal abduction, prone external rotation, and push-up plus shoulder rehabilitation exercises. Thirty nine subjects were categorized by a single orthopedic surgeon as having multidirectional instability (n = 10), anterior instability (n = 9), generalized laxity (n = 10), or a healthy shoulder (n = 10). Indwelling and surface electrodes were utilized to measure EMG activity (reported as a % of maximum voluntary isometric contraction (MVIC)) in various shoulder muscles during 4 common shoulder exercises. The exercises studied effectively activated the primary musculature targeted in each exercise equally among all groups. The serratus anterior generated high activity (50-80% MVIC) during a push-up plus, while the infraspinatus and teres major generated moderate to-high activity (30-80% MVIC) during both the prone horizontal and prone external rotation exercises. Scaption exercise generated moderate activity (20 50% MVIC) in both rotator cuff and scapular musculature. Clinicians should feel confident in prescribing these shoulder-strengthening exercises in patients with shoulder instability as the activation levels are comparable to previous findings regarding EMG amplitudes and should improve the dynamic stabilization capability of both rotator cuff and scapular muscles using exercises designed to address glenohumeral joint instability. PMID- 22919500 TI - Design of an implantable device for ocular drug delivery. AB - Ocular diseases, such as, glaucoma, age-related macular degeneration (AMD), diabetic retinopathy, and retinitis pigmentosa require drug management in order to prevent blindness and affecting million of adults in USA and worldwide. There is an increasing need to develop devices for drug delivery to address ocular diseases. This study focuses on the design, simulation, and development of an implantable ocular drug delivery device consisting of micro-/nanochannels embedded between top and bottom covers with a drug reservoir made from polydimethylsiloxane (PDMS) which is silicon-based organic and biodegradable polymer. Several simulations were carried out with six different micro-channel configurations in order to see the feasibility for ocular drug delivery applications. Based on the results obtained, channel design of osmotic I and osmotic II satisfied the diffusion rates required for ocular drug delivery. Finally, a prototype illustrating the three components of the drug delivery design is presented. In the future, the device will be tested for its functionality and diffusion characteristics. PMID- 22919501 TI - Composite polylactic-methacrylic Acid copolymer nanoparticles for the delivery of methotrexate. AB - The purpose of this study was to develop poly(lactic acid)-methacrylic acid copolymeric nanoparticles with the potential to serve as nanocarrier systems for methotrexate (MTX) used in the chemotherapy of primary central nervous system lymphoma (PCNSL). Nanoparticles were prepared by a double emulsion solvent evaporation technique employing a 3-Factor Box-Behnken experimental design strategy. Analysis of particle size, absolute zeta potential, polydispersity (Pdl), morphology, drug-loading capacity (DLC), structural transitions through FTIR spectroscopy, and drug release kinetics was undertaken. Molecular modelling elucidated the mechanisms of the experimental findings. Nanoparticles with particle sizes ranging from 211.0 to 378.3 nm and a recovery range of 36.8-86.2 mg (Pdl <= 0.5) were synthesized. DLC values were initially low (12 +/- 0.5%) but were finally optimized to 98 +/- 0.3%. FTIR studies elucidated the comixing of MTX within the nanoparticles. An initial burst release (50% of MTX released in 24 hours) was obtained which was followed by a prolonged release phase of MTX over 84 hours. SEM images revealed near-spherical nanoparticles, while TEM micrographs revealed the presence of MTX within the nanoparticles. Stable nanoparticles were formed as corroborated by the chemometric modelling studies undertaken. PMID- 22919502 TI - Biodegradation of used motor oil in soil using organic waste amendments. AB - Soil and surface water contamination by used lubricating oil is a common occurrence in most developing countries. This has been shown to have harmful effects on the environment and human beings at large. Bioremediation can be an alternative green technology for remediation of such hydrocarbon-contaminated soil. Bioremediation of soil contaminated with 5% and 15% (w/w) used lubricating oil and amended with 10% brewery spent grain (BSG), banana skin (BS), and spent mushroom compost (SMC) was studied for a period of 84 days, under laboratory condition. At the end of 84 days, the highest percentage of oil biodegradation (92%) was recorded in soil contaminated with 5% used lubricating oil and amended with BSG, while only 55% of oil biodegradation was recorded in soil contaminated with 15% used lubricating oil and amended with BSG. Results of first-order kinetic model to determine the rate of biodegradation of used lubricating oil revealed that soil amended with BSG recorded the highest rate of oil biodegradation (0.4361 day(-1)) in 5% oil pollution, while BS amended soil recorded the highest rate of oil biodegradation (0.0556 day(-1)) in 15% oil pollution. The results of this study demonstrated the potential of BSG as a good substrate for enhanced remediation of hydrocarbon contaminated soil at low pollution concentration. PMID- 22919503 TI - Cellulosic Ethanol Production by Recombinant Cellulolytic Bacteria Harbouring pdc and adh II Genes of Zymomonas mobilis. AB - The ethanol fermenting genes such as pyruvate decarboxylase (pdc) and alcohol dehydrogenase II (adh II) were cloned from Zymomonas mobilis and transformed into three different cellulolytic bacteria, namely Enterobacter cloacae JV, Proteus mirabilis JV and Erwinia chrysanthemi and their cellulosic ethanol production capability was studied. Recombinant E. cloacae JV was found to produce 4.5% and 3.5% (v/v) ethanol, respectively, when CMC and 4% NaOH pretreated bagasse were used as substrates, whereas recombinant P. mirabilis and E. chrysanthemi with the same substrates could only produce 4%, 3.5%, 1%, and 1.5 % of ethanol, respectively. The recombinant E. cloacae strain produced twofold higher percentage of ethanol than the wild type. The recombinant E. cloacae strain could be improved further by increasing its ethanol tolerance capability through media optimization and also by combining multigene cellulase expression for enhancing ethanol production from various types of lignocellulosic biomass so that it can be used for industrial level ethanol production. PMID- 22919504 TI - Experimental Investigations on the Effects of Carbon and Nitrogen Sources on Concomitant Amylase and Polygalacturonase Production by Trichoderma viride BITRS 1001 in Submerged Fermentation. AB - The paper investigates the effects of different commercial carbon and nitrogen sources on the concomitant synthesis of amylase and polygalacturonase enzymes with the aim of optimizing them for maximal enzyme production. The microorganism used in this work was the fungus Trichoderma viride BITRS-1001, which had been previously identified as a highly active producer of amylase and polygalacturonase enzymes. The results showed that the different commercial carbon and nitrogen substrate significantly affected the concomitant syntheses of amylase and polygalacturonase in culture media supplemented with the different commercial carbon and nitrogen substrates. The result obtained suggested that for optimal and concomitant synthesis of the enzymes by Trichoderma viride BITRS-1001 in submerged fermentation, minimal medium supplemented with maltose and casein were the carbon and nitrogen substrates of choice. PMID- 22919505 TI - Tooth surface loss and associated risk factors in northern saudi arabia. AB - Aim. To evaluate tooth surface loss (TSL) severity and associated risk factors in a representative sample of Saudi adults. Materials and Methods. Four hundred TSL patients (200 females and 200 males) participated in this study. Each patient completed a comprehensive questionnaire interview (using a modified Tooth wear Assessment Questionnaire) and then examined for the severity of TSL (using ordinal scale). Results. Seventy-five percent of participants demonstrated attrition, 90% had erosion, 15% had abrasion, and 95% had more than one type of TSL. The most common risk factors were consumption of acidic food/drinks (78%), parafunctional habits (70%), and unilateral chewing (50%). 77% of participants demonstrated grade 2 TSL. Males demonstrated greater TSL severity (P <= 0.05). Age, systemic disease, number of remaining teeth, acidic food/drinks, bruxism/parafunction, biting objects, facial pain/tenderness, sour taste, exposure to dust, unilateral chewing, using dental abrasives, and brushing frequency/technique had significant relationship with TSL severity (P <= 0.05). Conclusions. TSL has a multifactorial aetiology. Parafunction, gastrointestinal problems, and diet were the most common aetiological factors reflecting changes to stressful modern life-styles, eating/drinking habits, and behaviours. Gender didn't influence the aetiology of TSL; however males demonstrated more TSL severity. Patients' age had significant correlation to TSL severity. PMID- 22919506 TI - A primer on network meta-analysis for dental research. AB - In the last decade, a new statistical methodology, namely, network meta-analysis, has been developed to address limitations in traditional pairwise meta-analysis. Network meta-analysis incorporates all available evidence into a general statistical framework for comparisons of all available treatments. A further development in the network meta-analysis is to use a Bayesian statistical approach, which provides a more flexible modelling framework to take into account heterogeneity in the evidence and complexity in the data structure. The aim of this paper is therefore to provide a nontechnical introduction to network meta analysis for dental research community and raise the awareness of it. An example was used to demonstrate how to conduct a network meta-analysis and the differences between it and traditional meta-analysis. The statistical theory behind network meta-analysis is nevertheless complex, so we strongly encourage close collaboration between dental researchers and experienced statisticians when planning and conducting a network meta-analysis. The use of more sophisticated statistical approaches such as network meta-analysis will improve the efficiency in comparing the effectiveness between multiple treatments across a set of trials. PMID- 22919507 TI - Thyroid and Hepatic Haemodynamic Alterations among Egyptian Children with Liver Cirrhosis. AB - Background. Alterations in thyroid hormones regulation and metabolism are frequently observed in patients with cirrhosis. Aims. To assess alterations in thyroid volume (TV), haemodynamics, and hormones in patients with cirrhosis and their relation to hepatic arterial haemodynamics, and disease severity. Methods. Forty cirrhotic patients were compared to 30 healthy subjects regarding TV, free triiodiothyronine (fT(3)), free tetraiodothyronine (fT(4)), thyroid stimulating hormone (TSH), and pulsatility and resistance indices in the inferior thyroid and hepatic arteries. Results. TV (P = 0.042), thyroid volume standard deviation score (TVSDS, P = 0.001), Inferior Thyroid Artery Pulsatility Index (ITAPI, P = 0.001), Inferior Thyroid Artery Resistance Index (ITARI, P = 0.041), Hepatic Artery Pulsatility Index (HAPI, P = 0.029) and Hepatic Artery Resistance Index (HARI, P = 0.035) were higher among cases being highest in Child-C patients. FT(3) was lower in patients than controls (P = 0.001) and correlated negatively with ITAPI (r = -0.71, P = 0.021) and ITARI (r = -0.79, P = 0.011). ITAPI and ITARI correlated directly with HAPI and HARI (r = 0.62, P = 0.03, and r = 0.42, P = 0.04, resp.). Conclusions. Thyroid is involved in the haemodynamic alterations of cirrhosis. Routine study of thyroid by Doppler and assessment of thyroid functions should be performed in patients with cirrhosis to offer proper treatment if needed. PMID- 22919508 TI - Intermittent iron folate supplementation: impact on hematinic status and growth of school girls. AB - In view of high iron needs for adolescent growth, this paper studied the impact of daily vs. intermittent (once and twice weekly) iron folic acid (IFA) supplementation on hemoglobin levels and pubertal growth among primary school girls in early adolescence (9-13 years) of Vadodara, India. Methods. Hemoglobin (Hb), height and weight of the girls were assessed using standard methods. In three experimental schools (ES) IFA tablets in a dose of 100 mg Fe + 0.5 mg folic acid was given either daily, once weekly or twice weekly for one year. The fourth school (control: CS) did not receive any intervention. Results. Hb levels significantly improved (P < 0.01) in all ES compared to CS. Body Mass Index (BMI) increment in ES vs CS was significant (P < 0.05) in twice weekly IFA and daily IFA. Within ES groups, mean Hb and BMI increments were comparable between twice weekly IFA and daily IFA. Anemic ES girls showed higher Hb and BMI increments vs. non-anemic girls. Better the Hb response, greater was the benefit on BMI. CONCLUSION: Twice-weekly IFA supplementation was comparable to daily IFA as regards impact on Hb and growth; at less cost and greater feasibility. Once weekly dose was inadequate to significantly improve growth. PMID- 22919509 TI - Bacterial bloodstream infections in neonates in a developing country. AB - Background. Ongoing surveillance of antimicrobial sensitivity patterns of bacteria isolated in bloodstream infections guides empiric antibiotic therapy in neonatal sepsis. Methods. Sensitivity profiles of neonatal bacterial bloodstream infections in a tertiary hospital were reviewed between 01/06/2009 and 30/06/2010 . Results. There were 246 episodes of bloodstream infection in 181 individuals (14.06 episodes in10.35 patients/1000 patient days or 14.4 episodes in 10.6 babies/1000 live births. The majority were (93.5%) were late onset and most (54.9%) were gram positive. There were 2.28 sepsis-related deaths /1000 patient days or 2.3/1000 live births. Death was significantly associated with gram negative infections (P < 0.001), multiple gestation (P < 0.001), shock (P = 0.008), NEC (P = 0.002), and shorter duration of hospital stay (P < 0.001). Coagulase-negative staphylococcus was isolated in 19.1%, K. pneumoniae ESBL in 12.1%, and A. baumanni in 10.9%. S. agalactiae predominated in early onset sepsis. Methicillin resistance was present in 86% of CoNS and 69.5% of S. aureus; 46% enterococcal isolates were ampicillin resistant. The majority (65%) of K. pneumoniae isolates were ESBL producers. Ampicillin resistance was present in 96% of E. coli. Conclusions. Penicillin and an aminoglycoside would be suitable empiric therapy for early onset sepsis and meropenem with gentamycin or ceftazidime with amikacin for late onset sepsis. PMID- 22919510 TI - Component-resolved diagnosis in pediatrics. AB - Component resolved diagnosis is a new concept in the investigation of pediatric allergic disease. The aim of the present paper is to review the available data on component resolved diagnosis with respect to implications for investigation of children with allergic disease. In most conditions head-to-head comparisons of component resolved diagnosis with traditional IgE testing have not been performed. Rather than alternatives the molecular methods should be seen as adjuncts to the cheaper traditional specific IgE tests. It may be appropriate to determine IgE antibodies to components as part of the diagnostic work-up in selected cases of peanut and birch pollen allergy and in hymenoptera allergy. However, cost benefit analyses of component resolved diagnosis compared with traditional work-up of allergy are needed. Prospectively planned protocols for assessment of the extent to which component resolved diagnosis may be able to improve the selection of children to immunotherapy and, thus, the efficacy of immunotherapy, are needed. Finally, studies of component resolved diagnosis with microarray technology in screening panels with hundreds of components should be undertaken before it can be determined to which extent such panel screening, if at all, may be helpful in children. PMID- 22919511 TI - Antioxidant, Antimicrobial, and Free Radical Scavenging Potential of Aerial Parts of Periploca aphylla and Ricinus communis. AB - Context. Many diseases are associated with oxidative stress caused by free radicals. Objective. The present study evaluated the in vitro antioxidant and antibacterial activities of various extracts of aerial parts of Periploca aphylla and Ricinus communis. Materials and Methods. In vitro antioxidant activities of the plant extract were determined by DPPH and NO scavenging method. Superoxide anion radical activity was measured by the reduction of nitro blue tetrazolium as compared with standard antioxidants. Total phenolic contents and antibacterial activities of these plants were determined by gallic acid equivalent (GAE) and serial tube dilution method, respectively. Results. Plants showed significant radical scavenging activity. The results were expressed as IC(50). n-Propyl gallate and 3-t-butyl-4-hydroxyanisole were used as standards for antioxidant assay. All the extracts of both plants showed comparable IC(50) to those of standards. Plants extract exhibited high phenolic contents and antibacterial activities were comparable with standard drug, Ciprofloxacin. Discussion and Conclusion. The present study provides evidence that Periploca aphylla and Ricinus communis prove to be potent natural antioxidants and could replace synthetic antioxidants. Plants can also be used against pathogenic bacterial strains. PMID- 22919512 TI - Predictors of Prolonged Stay in the Intensive Care Unit following Cardiac Surgery. AB - The prediction of intensive care unit length of stay (ICU-LOS) could contribute to more efficient ICU resources' allocation and better planning of care among cardiac surgery patients. The aim of this study was to identify the preoperative and intraoperative predictors for prolonged cardiac surgery ICU-LOS. An observational cohort study was conducted among 150 consecutive patients, who were admitted to the cardiac surgery ICU of a tertiary hospital of Athens, Greece from September 2010 to January 2011. Multivariate regression analysis revealed that patients with increased creatinine levels preoperatively (odds ratio (OR) 3.0, P = 0.049), history of atrial fibrillation (AF) (OR 6.3, P = 0.012) and high EuroSCORE values (OR 2.6, P = 0.017) had a significant greater probability to stay in the ICU for more than 2 days. In addition, intraoperative hyperglycemia (OR 3.0, P = 0.004) was strongly associated with longer ICU-LOS. In conclusion, the high perioperative risk, the history of AF and renal dysfunction, and the intraoperative hyperglycemia are significant predictors of prolonged ICU stay. The early identification of patients at risk could allow the efficient ICU resources' allocation and the reduction of healthcare costs. This would contribute to nursing care planning depending on the availability of healthcare personnel and ICU bed capacity. PMID- 22919513 TI - Organizational Interventions concerning Palliation in Community Palliative Care Services: A Literature Study. AB - Background. Studies indicate problems between different professional groups working with palliative care and the organisation of palliative home care at nursing homes. The purpose of this study is to examine international experiences and cooperative development initiatives regarding the organisation of community palliative care services. Method. The study has been carried out as a literature study based on bibliographic searches in international databases with selected key words. Results and Conclusion. The study of the literature identified 19 studies described in 20 articles that relate to development efforts and interventions regarding the organisation of palliative care in communities. Nearly, all of the studies were based on health care professionals' assessments of users (the relatives). However, it is unknown whether or how patients and relatives experience a positive effect of the interventions. The literature study shows that it is a great methodological challenge to complete and evaluate studies concerning organisation and cooperation using methods that make the results useful for others. PMID- 22919514 TI - The effect of pramipexole therapy on balance disorder and fall risk in Parkinson's disease at early stage: clinical and posturographic assessment. AB - The aim of this study was to determine balance problems and severity and ratio of postural instability of newly diagnosed, early stage Parkinson's patients who did not receive any antiparkinson treatment before, to evaluate fall risk clinically and posturographically and to examine the effects of pramipexole on these signs and symptoms. Detailed posturographic assessments which involved central vestibular, visual, peripheric vestibular somatosensory field tests were applied to both patient and control subjects and fall risk was determined. There was not statistically significant difference between patients and control subjects before and after drug therapy in the assesment of fall risk in posturography and there was not any improvement with drug usage in the patient group. However, in the analysis of subsystems separately, only the involvement in central vestibular field was more severe and could appear at all positions in Parkinson's patients comparing with the control group, and pramipexole was partially effective in improving this disorder. Central vestibular field is the subsystem that should be examined with first priority. Posturography is relatively reliable in defining fall risk and postural instability ratio in Parkinson's disease. But it should be considered that clinical assessment tools can be more sensitive in the evaluation of balance and postural disorders and in the follow-up of the response to drug therapy. PMID- 22919515 TI - Cardiovascular autonomic response to amlodipine in primary hypertension. AB - Sympathetic hyperactivity may be involved in primary hypertension. The purpose of this study was to evaluate both sympathetic and vagal activity responses in patients receiving amlodipine as antihypertensive agent. Patients and Methods. This prospective study included a group of primary hypertensive patients (N = 32, mean age 54.6 +/- 7.6 years). The cardiovascular autonomic tests performed in this group, before and after 3 months of daily oral administration of amlodipine, included deep breathing, hand-grip, and mental stress tests. Statistical analysis was done using the Student's t-test. Results. Cardiovascular autonomic reflexes responses before and after 3 months of amlodipine oral administration were as follows: the mental stress test stimulation method produced a central alpha adrenergic response of 23.9 +/- 8.7% versus 11.2 +/- 2.0% (P < 0.05), a central beta sympathetic response of 16.7 +/- 9.2% versus 10.4 +/- 1.3% (P < 0.05), a blood pressure increase in response to hand grip test of 20.5 +/- 7.3% versus 10.7 +/- 2.4% (P < 0.05), vagal response to deep breathing test was 21.2 +/- 6.5% versus 30.8 +/- 2.9%, (P < 0.05). Conclusion. The results attest that amlodipine may have an anti-sympathetic effect. PMID- 22919516 TI - Variable Resistance of RMS to Interferon gamma Signaling. AB - Aims. Chimeric T cells directed to the gamma-subunit of the fetal acetylcholine receptor (fAChR) produce large amounts of interferon-gamma (IFNgamma) on coculture with fAChR-expressing rhabdomyosarcoma (RMS) cells prior to RMS cell death. The aim of this study was to elucidate whether IFNgamma blocks proliferation and survival of RMS cells and modulates expression of genes with relevance for cytotoxicity of chimeric T cells. Methods. Expression levels of IFNgamma receptor (IFNGR), AChR, MHCI, MHCII, and CIITA (class II transactivator) by RMS were checked by flow cytometry, qRT-PCR, and western blot. Proliferation and cell survival were investigated by annexin V and propidium iodide staining and MTT (thiazolyl-blue-tetrazolium-bromide) assay. Key phosphorylation and binding sites of IFNGRs were checked by DNA sequencing. Results. IFNgamma treatment blocked proliferation in 3 of 6 RMS cell lines, but reduced survival in only one. IFNGR was expressed at levels comparable to controls and binding sites for JAK and STAT1 were intact. Induction of several target genes (e.g., AChR, MHCI, and MHCII) by IFNgamma was detected on the RNA level but not protein level. Conclusions. IFNgamma does not significantly contribute to the killing of RMS cells by fAChR directed chimeric T cells. Signalling downstream of the IFNR receptor, including the posttranscriptional level, is impaired in most RMS cell lines. PMID- 22919517 TI - The Distribution of PSA Age-Specific Profiles in Healthy Irish Men between 20 and 70. AB - Background. Ireland is estimated to have the highest European incidence rate of prostate cancer (Pca) in 2006 which will increase by 275% by 2025. This study aimed to determine PSA cutoff values in different age groups of healthy male patients without Pca. Methods. 660 men in a pilot men's health programme, aged 18 67, had PSA assayed. Men were grouped into 8 age groups at 5-year intervals: 30 34, 35-39, 40-44, 45-49, 50-54, 55-59, 60-64, and 64-70. Results. Linear regression demonstrates a PSA velocity of 0.024 ng/ml/year. The 95% confidence interval demonstrates a near flat line of PSA values from age 20 to 50 and rises after. When transformed logarithmically, PSA correlates highly with expected values from the normal distribution (0.98). A fractional polynomial quantile regression model was used to predict median and 95th percentile for PSA as follows: 30-34 (0.73, 1.57), 35-39 (0.71, 1.65), 40-44 (0.73, 1.85), 45-49 (0.78, 2.17), 50-54 (0.88, 2.63), 55-59 (1.01, 3.25), 60-64 (1.20, 4.02), and 64-70 (1.43, 4.96). Conclusions. PSA levels are similar to other racial groups but not as high as US Caucasians until 65 years. These data define the predicted PSA for the Irish population and provide a reference for future screening programmes. PMID- 22919519 TI - Nanofilled composite restorations with different adhesives strategies: clinical cases. AB - The esthetic procedures with composites are widely applied, both to posterior and anterior teeth to restore caries cavities, to replace failed restorations, or to make cosmetic procedures. The materials selected to each case may make the difference in the clinical result. This paper presents two clinical cases made with a nanofilled composite resin system used in different bond strategies. In the first, a wide posterior class I restoration, the self-etching strategy was used. The second, an esthetic anterior restoration, was made using the prior etching with phosphoric acid and a hydrophobic adhesive. PMID- 22919520 TI - Ingested fish bone: an unusual mechanism of duodenal perforation and pancreatic trauma. AB - Ingestion of gastrointestinal foreign bodies represents a challenging clinical scenario. Increased morbidity is the price for the delayed diagnosis of complications and timely treatment. We present a case of 57-year-old female patient which was admitted in the emergency room department complaining of a mid epigastric pain over the last twenty-four hours. Based on the patient's history, physical examination and elevated serum amylase levels, a false diagnosis of pancreatitis, was initially adopted. However, a CT scan confirmed the presence of a radiopaque foreign body in the pancreatic head and the presence of air bubbles outside the intestinal lumen. The patient was unaware of the ingestion of the foreign body. At laparotomy, after an oblique duodenotomy, a fish bone pinned in the pancreatic head after the penetration of the medial aspect of the second portion of the duodenal wall was identified and successfully removed. The patient had an uneventful postoperative recovery. Wide variation in clinical presentation characterizes the complicated fish bone ingestions. The strategically located site of penetration in the visceral wall is responsible for the often extraordinary gastrointestinal tract injury patterns. Increased level of suspicion is of paramount importance for the timely diagnosis and treatment. PMID- 22919518 TI - Hippocampal CA1 pyramidal neurons of Mecp2 mutant mice show a dendritic spine phenotype only in the presymptomatic stage. AB - Alterations in dendritic spines have been documented in numerous neurodevelopmental disorders, including Rett Syndrome (RTT). RTT, an X chromosome linked disorder associated with mutations in MECP2, is the leading cause of intellectual disabilities in women. Neurons in Mecp2-deficient mice show lower dendritic spine density in several brain regions. To better understand the role of MeCP2 on excitatory spine synapses, we analyzed dendritic spines of CA1 pyramidal neurons in the hippocampus of Mecp2(tm1.1Jae) male mutant mice by either confocal microscopy or electron microscopy (EM). At postnatal-day 7 (P7), well before the onset of RTT-like symptoms, CA1 pyramidal neurons from mutant mice showed lower dendritic spine density than those from wildtype littermates. On the other hand, at P15 or later showing characteristic RTT-like symptoms, dendritic spine density did not differ between mutant and wildtype neurons. Consistently, stereological analyses at the EM level revealed similar densities of asymmetric spine synapses in CA1 stratum radiatum of symptomatic mutant and wildtype littermates. These results raise caution regarding the use of dendritic spine density in hippocampal neurons as a phenotypic endpoint for the evaluation of therapeutic interventions in symptomatic Mecp2-deficient mice. However, they underscore the potential role of MeCP2 in the maintenance of excitatory spine synapses. PMID- 22919521 TI - Gonococcal subcutaneous abscess and pyomyositis: a case report. AB - Disseminated gonococcal infection (DGI) is an uncommon complication of Neisseria gonorrhoeae infection, its manifestation varies from a classic arthritis dermatitis syndrome to uncommon pyogenic infections of several organs. Herein, we reported atypical presentation of DGI with subcutaneous abscess of right knee, pyomyositis of right lower extremity, and subsequently complicated by Escherichia coli pyomyositis. This infection responded to appropriate antimicrobial therapy and prompt surgical management with good clinical outcome. PMID- 22919522 TI - Uterus didelphys: report of a puerperal torsion and a review of the literature. AB - A 29-year-old Para 2 was admitted to the emergency department with increasing lower abdominal pain. The patient had undergone an uncomplicated elective repeat caesarean section 7 days before being admitted to the emergency department. An emergency laparotomy revealed a uterus didelphys with a torsion of one of the uteri. PMID- 22919523 TI - Fallopian tube herniation: an unusual complication of surgical drain. AB - Background. Surgical drains have been used since time immemorial, but their use is not without complications. By presenting this case we aim to describe an uncommon complication of herniation of fallopian tube following the simple procedure of surgical drain removal. Case Presentation. This case describes a 23 year G2P1L1 who underwent an emergency cesarean section for obstructed labor with intraperitoneal drain insertion. The patient had an uneventful postoperative period, drain was removed on day 4, and she was discharged. She presented on day 8 with the complaint of soakage of drain site dressing. On examination an edematous, tubular structure with early sign of necrosis was seen coming out of drain site and a provisional diagnosis of appendix herniation was made. On emergency laparotomy fallopian tube was seen coming out through the drain site and salphingectomy was done. Conclusion. Drains are not a substitute for good surgical technique. Although herniation of intestine, omentum, appendix, gall bladder, and ovary have been reported, we could not find any case of fallopian tube herniation in the literature searched by us. PMID- 22919524 TI - Placental mesenchymal dysplasia: a case report. AB - Introduction. A rare case of histologically proven placental mesenchymal dysplasia (PMD) with fetal omphalocele in a 22-year-old patient is reported. Material and Methods. Antenatal ultrasound of this patient showed hydropic placenta with a live fetus of 17 weeks period of gestation associated with omphalocele. Cordocentesis detected the diploid karyotype of the fetus. Patient, when prognosticated, choose to terminate the pregnancy in view of high incidence of fetal and placental anomalies. Subsequent histopathological examination of placenta established the diagnosis to be placental mesenchymal dysplasia. Conclusion. On clinical and ultrasonic grounds, suspicion of P.M.D. arises when hydropic placenta with a live fetus presents in second trimester of pregnancy. Cordocentesis can detect the diploid karyotype of the fetus in such cases. As this condition is prognostically better than triploid partial mole, continuation of pregnancy can sometimes be considered after through antenatal screening and patient counseling. However, a definite diagnosis of P.M.D. is made only on placental histology by absence of trophoblast hyperplasia and trophoblastic inclusions. PMID- 22919525 TI - Massive delayed vaginal hemorrhage after laparoscopic supracervical hysterectomy. AB - Background. A known complication of supracervical hysterectomy is cyclical bleeding from the retained cervix when functioning endometrial tissue is not totally removed. We present a rare case of delayed postoperative vaginal hemorrhage after supracervical hysterectomy. Case. A 44-year-old woman presented on postoperative day 15 after laparoscopic supracervical hysterectomy with massive vaginal hemorrhage requiring emergent re-operation. Her bleeding was controlled with vaginally placed sutures. Ultrasound confirmed no intraperitoneal free fluid. The etiology was thought to be induced by postoperative tissue necrosis from cautery applied to the endocervical canal during the original surgery. Conclusion. Delayed vaginal hemorrhage from a retained cervix is a rare complication of laparoscopic supracervical hysterectomy. Caution should be exercised when cauterizing the endocervical canal as induced tissue necrosis may increase the risk of postoperative bleeding. PMID- 22919526 TI - Complete cervical avulsion with intravaginal misoprostol for second trimester pregnancy termination. AB - Intravaginal misoprostol, a synthetic PGE1 analogue, has largely replaced all other techniques for pregnancy termination in II trimester, because of its successful results. Incidence of II trimester pregnancy termination has also increased in the present days, because of prenatal diagnosis of pregnancies with serious fetal abnormalities like cardiovascular and skeletal malformations. But there are serious and life threatening complications reported with the use of intravaginal misoprostol. Here we are reporting a case of complete avulsion of cervix from lower part of the uterus, with the use of intravaginal misoprostol, for II trimester termination of pregnancy. So, clinicians dealing with II trimester termination of pregnancy should be aware of such complications. PMID- 22919527 TI - Perineal accessory scrotum with congenital lipoma: a rare case report. AB - A case of accessory scrotum in a 1-year-old boy is reported because of its rarity. A boy presented with a tumor mass attached with scrotum-like skin on its tip in the right side of perineum between the scrotum and anus. Both testes had descended into the scrotum. There was no other urological anomaly. Histological findings of the tumor indicated perineal lipoma, and the scrotum-like portion accessory scrotum. An overview of sequences during the normal development of male external genitalia has been provided and the deranged mechanism resulting in this anomaly has been reviewed with hypothesis regarding etiology of accessory scrotum. PMID- 22919528 TI - Chronic granulomatous herpes encephalitis in a child with clinically intractable epilepsy. AB - Most patients with herpes simplex virus Type I encephalitis experience an acute, monophasic illness. Chronic encephalitis is much less common, and few late relapses are associated with intractable seizure disorders. A 10-year-old boy was admitted to our institution for intractable epilepsy as part of an evaluation for epilepsy surgery. His history was significant for herpes meningitis at age 4 months. At that time, he presented to an outside hospital with fever for three days, with acyclovir treatment beginning on day 4 of his 40-day hospital course. He later developed infantile spasms and ultimately a mixed seizure disorder. Video electroencephalogram showed a Lennox-Gastaut-type pattern with frequent right frontotemporal spikes. Imaging studies showed an abnormality in the right frontal operculum. Based on these findings, he underwent a right frontal lobectomy. Neuropathology demonstrated chronic granulomatous inflammation with focal necrosis and mineralizations. Scattered lymphocytes, microglial nodules and nonnecrotizing granulomas were present with multinucleated giant cells. Immunohistochemistry for herpes simplex virus showed focal immunoreactivity. After undergoing acyclovir therapy, he returned to baseline with decreased seizure frequency. This rare form of herpes encephalitis has only been reported in children, but the initial presentation of meningitis and the approximate 10 year-time interval in this case are unusual. PMID- 22919529 TI - Menkes kinky hair syndrome: a rare neurodegenerative disease. AB - Menkes kinky hair disease is a rare X-linked recessive disease nearly exclusively affecting males who present at 2-3 months of age due to abnormal functioning of copper-dependent enzymes due to deficiency of copper. Here, we describe a completely worked-up case of a 4-month-old male infant with very typical history and radiological features confirmed by biochemical and trichoanalysis. The initially seen asymmetric cortical and subcortical T2 hyperintensities in cerebral and cerebellar hemispheres converted into symmetrical diffuse cerebral and predominantly cerebellar atrophy with uniform loss of both white and grey matter on follow-up MRI. Also, subdural hemorrhages of various sizes and different stages and tortuosity of larger proximal intracranial vessels with distal narrowing were identified. Ours is a completely worked-up proven case of Menkes kinky hair disease (MKHD) with history, electroencephalography, biochemical, trichoanalysis, and MRI findings. This is a good teaching case and shows importance of clinical examination and biochemistry as complimentary to MRI. Tortuous intracranial arteries with blocked major vessels are found only in this disease, thus stressing the value of MR Angiography in these patients. PMID- 22919530 TI - Beyond a gossypiboma. AB - Gossypiboma or a retained surgical sponge is a rare but avoidable surgical complication. It leads to considerable morbidity and at times even mortality. We report a case of a 24-year-old lady who presented one month after a Caesarean operation with complaints of fever, pain in abdomen, and vomiting. After the clinical examination a possibility of a retained surgical sponge was entertained. However a CT scan of abdomen revealed the complete diagnosis and helped in treating the patient surgically with a successful outcome. A review of the literature and all the relevant issues in the management of such a case have been discussed. PMID- 22919531 TI - Superior Mesenteric Artery Syndrome-Believe in it! Report of a Case. AB - We present a case of a man with amyotrophic lateral sclerosis who developed superior mesenteric artery syndrome (SMAS) following the confection of feeding jejunostomy. He was successfully managed by conservative treatment. Left lateral positioning during enteral feeding allowed quick resolution of the occlusive state. Various surgical interventions have been associated with SMAS, directly or indirectly, by reducing the width of the aortomesenteric angle. The operative stress was probably what triggered symptomatology in our patient thus to conclude that the surgical stress should be considered as a causal factor triggering the SMAS in a context of other predisposing factors. PMID- 22919532 TI - The heineke-mikulicz principle for hepaticojejunostomy stricture. AB - Benign anastomotic stricture after hepaticojejunostomy is one of the serious complications of biliary surgery. If left untreated, jaundice, cholangitis, or cirrhosis may develop. A 58-year-old male patient was admitted with benign hepaticojejunostomy stricture. The patient initially underwent an endoscopic retrograde cholangiography using double-balloon enteroscope, which was unsuccessful due to the sharp angle between the jejunal limb and the biliary tree. It was decided to perform surgery. During the operation, we performed Heineke-Mikulicz strictureplasty to the narrowed anastomosis. Patient's postoperative course was uneventful. At the end of followup, for 18 months, his liver enzymes were within normal ranges, and the ultrasound examination showed a patent hepaticojejunostomy anastomosis. The simplicity of the technique and the promising result support the applicability of the Heineke-Mikulicz principle in suitable cases as an alternative treatment approach for hepaticojejunostomy strictures. PMID- 22919533 TI - Posttraumatic parotid fistula treated with transdermal scopolamine: a case report. AB - A parotid fistula is a rare and extremely unpleasant condition. In this paper, we present the case of a 53-year-old woman with a diagnosis of posttraumatic fistula of the parotid gland. After exclusion of other therapeutic alternatives, it was decided to use transdermal scopolamine patches at sustained release (Scopoderm TTS). This technique consists in the application every three days of a patch with 1.5 mg of scopolamine in the area of the mastoid apophysis; the patch releases a dose of 0.5 mg of the active substance over each 24-hour period. The patient underwent periodic clinical followup over a period of three years, achieving satisfactory results with no significant adverse effects. PMID- 22919534 TI - Hypernephroma presenting with cutaneous leukocytoclastic vasculitis and lupus anticoagulant: resolution after nephrectomy. AB - Hypernephroma can present as a variety of paraneoplastic, nonmetastatic conditions, including vasculitis, and rarely a lupus-type anticoagulant. Nephrectomy leads to the resolution of the systemic complaints. Malignancy, in this case hypernephroma, can present as an immune-mediated paraneoplastic syndrome which resolves after removal of the underlying tumor. PMID- 22919535 TI - Renal Solid Mass as a Rare Presentation of Wagener's Granulomatosis: A Case Report. AB - Wagener's granulomatosis (WG) is a rheumatologic disease with unknown etiology which renal and pulmonary involvement is commonly seen. Renal involvement in Wagener's granulomatosis represents as a segmental necrotizing glomerulonephritis which is not visible with imaging techniques and usually presents with proteinuria, microhematuria, and hypertension. A rare presentation of the disease is a renal mass which can be mistaken as renal tumors, abscess, or lymphoma. We report a 22-year-old female with flank pain and fever who was admitted in our hospital. The patient underwent renal tumor biopsy and diagnosed with Wagener's granulomatosis in pathologic staining. The aim of this work is introduction of Wagener's granulomatosis as a differential diagnosis of renal tumors, to prevent unnecessary interventions and delayed treatment. PMID- 22919536 TI - Posterior nutcracker syndrome with left renal vein duplication: a rare cause of haematuria in a 12-year-old boy. AB - The nutcracker syndrome (NCS) is a rare cause of haematuria. It embraces an extended nonpathognomonic spectrum of symptoms that imply a difficult diagnosis. Ultimately it may be associated with substantial morbidity and even life threatening events. We report a rare cause if a 12-year-old boy who presented with a history of frequent intermittent episodes of painless constant haematuria. The cystoscopy showed a bloody urine ejaculate from the left ureter meatus. The Doppler ultrasonography showed turbulent pattern of venous blood flow of the posterior renal vein branch behind the aorta. The abdominopelvic computer tomography (apCT) revealed left renal vein (LRV) duplication with a dilated retroaortic branch, entrapped between the aorta and the vertebral column, promoting the renal nutcracker syndrome. The patient was initially hospitalized and managed with oral iron supplements and continuous saline bladder irrigation, not requiring additional treatment. The child is currently asymptomatic, with haemoglobin value returning to normal and therefore proposed to conservative management with close followup. The authors present a case report of episodic haematuria caused by a rare entity-posterior nutcracker syndrome with renal vein duplication. PMID- 22919537 TI - Cardiovascular risk in chronic kidney disease: role of the sympathetic nervous system. AB - Patients with chronic kidney disease are at significantly increased risk for cardiovascular disease and sudden cardiac death. One mechanism underlying increased cardiovascular risk in patients with renal failure includes overactivation of the sympathetic nervous system (SNS). Multiple human and animal studies have shown that central sympathetic outflow is chronically elevated in patients with both end-stage renal disease (ESRD) and chronic kidney disease (CKD). SNS overactivation, in turn, increases the risk of cardiovascular disease and sudden death by increasing arterial blood pressure, arrythmogenicity, left ventricular hypertrophy, and coronary vasoconstriction and contributes to the progression renal disease. This paper will examine the evidence for SNS overactivation in renal failure from both human and experimental studies and discuss mechanisms of SNS overactivity in CKD and therapeutic implications. PMID- 22919538 TI - Does depression impact cognitive impairment in patients with heart failure? AB - Prevalence studies have noted the cooccurrence of cognitive decline and depression in persons with heart failure. Cognitive impairment is associated with significant mortality and deteriorated quality of life, likely due to impairments in memory and executive function, which impact a patient's ability to understand and comply with prescribed treatment plans. This is especially true in complex diseases such as heart failure. Evidence from literature supports the possibility of a pathophysiological relationship between cognitive impairment, depression, and heart failure. Yet, very few studies have sought to investigate this relationship. This paper reviews current literature on the association between depression and cognitive impairment in persons with heart failure and explores possible mechanisms explaining this complex triad. PMID- 22919539 TI - Central mechanisms of abnormal sympathoexcitation in chronic heart failure. AB - It has been recognized that the sympathetic nervous system is abnormally activated in chronic heart failure, and leads to further worsening chronic heart failure. In the treatment of chronic heart failure many clinical studies have already suggested that the inhibition of the abnormal sympathetic hyperactivity by beta blockers is beneficial. It has been classically considered that abnormal sympathetic hyperactivity in chronic heart failure is caused by the enhancement of excitatory inputs including changes in peripheral baroreceptor and chemoreceptor reflexes and chemical mediators that control sympathetic outflow. Recently, the abnormalities in the central regulation of sympathetic nerve activity mediated by brain renin angiotensin system-oxidative stress axis and/or proinflammatory cytokines have been focused. Central renin angiotensin system, proinflammatory cytokines, and the interaction between them have been determined as the target of the sympathoinhibitory treatment in experimental animal models with chronic heart failure. In conclusion, we must recognize that chronic heart failure is a syndrome with an abnormal sympathoexcitation, which is caused by the abnormalities in the central regulation of sympathetic nerve activity. PMID- 22919541 TI - Evolution of the FGF Gene Family. AB - Fibroblast Growth Factors (FGFs) are small proteins generally secreted, acting through binding to transmembrane tyrosine kinase receptors (FGFRs). Activation of FGFRs triggers several cytoplasmic cascades leading to the modification of cell behavior. FGFs play critical roles in a variety of developmental and physiological processes. Since their discovery in mammals, FGFs have been found in many metazoans and some arthropod viruses. Efforts have been previously made to decipher the evolutionary history of this family but conclusions were limited due to a poor taxonomic coverage. We took advantage of the availability of many new sequences from diverse metazoan lineages to further explore the possible evolutionary scenarios explaining the diversity of the FGF gene family. Our analyses, based on phylogenetics and synteny conservation approaches, allow us to propose a new classification of FGF genes into eight subfamilies, and to draw hypotheses for the evolutionary events leading to the present diversity of this gene family. PMID- 22919542 TI - Mechanisms of Gene Duplication and Translocation and Progress towards Understanding Their Relative Contributions to Animal Genome Evolution. AB - Duplication of genetic material is clearly a major route to genetic change, with consequences for both evolution and disease. A variety of forms and mechanisms of duplication are recognised, operating across the scales of a few base pairs upto entire genomes. With the ever-increasing amounts of gene and genome sequence data that are becoming available, our understanding of the extent of duplication is greatly improving, both in terms of the scales of duplication events as well as their rates of occurrence. An accurate understanding of these processes is vital if we are to properly understand important events in evolution as well as mechanisms operating at the level of genome organisation. Here we will focus on duplication in animal genomes and how the duplicated sequences are distributed, with the aim of maintaining a focus on principles of evolution and organisation that are most directly applicable to the shaping of our own genome. PMID- 22919543 TI - Association between P2X7 Receptor Polymorphisms and Bone Status in Mice. AB - Macrophages from mouse strains with the naturally occurring mutation P451L in the purinergic receptor P2X7 have impaired responses to agonists (1). Because P2X7 receptors are expressed in bone cells and are implicated in bone physiology, we asked whether strains with the P451L mutation have a different bone phenotype. By sequencing the most common strains of inbred mice, we found that only a few strains (BALB, NOD, NZW, and 129) were harboring the wild allelic version of the mutation (P451) in the gene for the purinergic receptor P2X7. The strains were compared by means of dual energy X-ray absorptiometry (DXA), bone markers, and three-point bending. Cultured osteoclasts were used in the ATP-induced pore formation assay. We found that strains with the P451 allele (BALB/cJ and 129X1/SvJ) had stronger femurs and higher levels of the bone resorption marker C telopeptide collagen (CTX) compared to C57Bl/6 (B6) and DBA/2J mice. In strains with the 451L allele, pore-formation activity in osteoclasts in vitro was lower after application of ATP. In conclusion, two strains with the 451L allele of the naturally occurring mutation P451L, have weaker bones and lower levels of CTX, suggesting lower resorption levels in these animals, which could be related to the decreased ATP-induced pore formation observed in vitro. The importance of these findings for the interpretation of the earlier reported effects of P2X7 in mice is discussed, along with strategies in developing a murine model for testing the therapeutic effects of P2X7 agonists and antagonists upon postmenopausal osteoporosis. PMID- 22919544 TI - Rehabilitation of the Upper Extremity after Stroke: A Case Series Evaluating REO Therapy and an Auditory Sensor Feedback for Trunk Control. AB - Background and Purpose. Training in the virtual environment in post stroke rehab is being established as a new approach for neurorehabilitation, specifically, ReoTherapy (REO) a robot-assisted virtual training device. Trunk stabilization strapping has been part of the concept with this device, and literature is lacking to support this for long-term functional changes with individuals after stroke. The purpose of this case series was to measure the feasibility of auditory trunk sensor feedback during REO therapy, in moderate to severely impaired individuals after stroke. Case Description. Using an open label crossover comparison design, 3 chronic stroke subjects were trained for 12 sessions over six weeks on either the REO or the control condition of task related training (TRT); after a washout period of 4 weeks; the alternative therapy was given. Outcomes. With both interventions, clinically relevant improvements were found for measures of body function and structure, as well as for activity, for two participants. Providing auditory feedback during REO training for trunk control was found to be feasible. Discussion. The degree of changes evident varied per protocol and may be due to the appropriateness of the technique chosen, as well as based on patients impaired arm motor control. PMID- 22919540 TI - Fractalkine Mediates Communication between Pathogenic Proteins and Microglia: Implications of Anti-Inflammatory Treatments in Different Stages of Neurodegenerative Diseases. AB - The role of inflammation in neurodegenerative diseases has been widely demonstrated. Intraneuronal protein accumulation may regulate microglial activity via the fractalkine (CX3CL1) signaling pathway that provides a mechanism through which neurons communicate with microglia. CX3CL1 levels fluctuate in different stages of neurodegenerative diseases and in various animal models, warranting further investigation of the mechanisms underlying microglial response to pathogenic proteins, including Tau, beta-amyloid (Abeta), and alpha-synuclein. The temporal relationship between microglial activity and localization of pathogenic proteins (intra- versus extracellular) likely determines whether neuroinflammation mitigates or exacerbates disease progression. Evidence in transgenic models suggests a beneficial effect of microglial activity on clearance of proteins like Abeta and a detrimental effect on Tau modification, but the role of CX3CL1 signaling in alpha-synucleinopathies is less clear. Here we review the nature of fractalkine-mediated neuronmicroglia interaction, which has significant implications for the efficacy of anti-inflammatory treatments during different stages of neurodegenerative pathology. Specifically, it is likely that anti-inflammatory treatment in early stages of disease during intraneuronal accumulation of proteins could be beneficial, while anti inflammatory treatment in later stages when proteins are secreted to the extracellular space could exacerbate disease progression. PMID- 22919545 TI - Single intramammary infusion of recombinant bovine interleukin-8 at dry-off induces the prolonged secretion of leukocyte elastase, inflammatory lactoferrin derived peptides, and interleukin-8 in dairy cows. AB - A single intramammary infusion of recombinant bovine interleukin-8 (IL-8) at 50 MUg/quarter/head, but not 10 MUg/quarter/head, induced clinical mastitis in three of four cows during the dry-off period, resulting in an elevated rectal temperature, redness and swelling of the mammary gland, extensive polymorphonuclear leukocyte (PMNL) infiltration, and milk clot formation from 1 to 28 days post infusion (PI). In the mammary secretions of the mastitic glands, high levels of IL-8 were sustained from 8 hours to 28 days PI, peaking at 1-3 days PI. The levels of leukocyte-derived elastase and inflammatory 22 and 23 kDa lactoferrin derived peptides (LDP) were also increased in the mammary secretions from the mastitic glands. In addition to the experimentally induced mastitis, the mammary secretions from the glands of cattle with spontaneous Staphylococcus aureus dry-period mastitis displayed milk clot formations and significant increases in their levels of PMNL counts, elastase, LDP, and IL-8, compared with those of the mammary secretions from the uninfected glands. These results suggest that after an intramammary infusion of IL-8 has elicited inflammatory responses, it induces the prolonged secretion of elastase, inflammatory LDP, and IL-8, and that long-lasting IL-8-induced inflammatory reactions are involved in the pathogenesis of S. aureus dry-period mastitis. PMID- 22919546 TI - Seizure Mimicking Stroke: Role of CT Perfusion. AB - Stroke mimics constitute 15--20% of all cases presenting to the emergency department, prominent among them being seizures, hypoglycemia, tumors, migraines, and posterior reversible leucoencephalopathy. They have also abnormal computerized tomography perfusion (CTP) findings. We report a case where CTP helped us to diagnose and treat a seizure when initial presentation was that of a stroke. PMID- 22919547 TI - Imaging of Cystic and Cyst-like Lesions of the Mediastinum with Pathologic Correlation. AB - Cystic masses of the mediastinum are a heterogenous group of asymptomatic or symptomatic, congenital, infectious, or neoplastic lesions. For early and correct diagnosis, evaluation, and optimal patient management of cystic mediastinal masses in infants, children, or adults imaging plays an important role. A non invasive and sensitive imaging modality is an efficient and cost-effective tool. Multidetector computed tomography (MDTC) with volumetric acquisition provides fast acquisition of high resolution images and multiplanar reconstruction. Both 2D and 3D imaging in mediastinal imaging help in surgical planning and assessing resectability of mediastinal lesions. MR imaging has many advantages over other modalities for detecting and identifying cystic, or fluid-filled mediastinal masses, because of its intrinsic high soft tissue contrast and direct multiplanar imaging capabilities. However, histological tissue analysis may be required to differentiate a cystic lesion from other cyst-like or low-attenuation lesions. PMID- 22919548 TI - Radiographic study of the prevalence of dens invaginatus in a sample set of Turkish dental patients. AB - AIM: The aim of this study was to determine the prevalence of dens invaginatus in a sample of Turkish dental patients. MATERIALS AND METHODS: The sample included 6, 912 panoramic radiographs from different Turkish dental patients. The ages of the patients ranged from 18 to 50 years. A tooth was considered having dens invaginatus if an infolding of a radiopaque ribbon-like structure equal in density to enamel was seen extending from the cingulum into the root canal. Maxillary and mandibular teeth were evaluated on panoramic radiographs to determine the type of dens invaginatus using Oehlers' classification. RESULTS: The overall incidence of patients with dens invaginatus was 0.17%. Dens invaginatus were detected in 15 teeth of a total of 192 150 teeth to give a tooth prevalence of 0.008%. Maxillary lateral incisors were most commonly affected teeth in the mouth (80% of cases), followed by maxillary canine teeth (20% of cases). The bilateral incidence of a symmetrical distribution was 25%. CONCLUSION: The occurrence of dens invaginatus among this Turkish population was rare. Attention should be paid to the presence of dens invaginatus and the treatment problems associated with it. PMID- 22919549 TI - Primary endobronchial leiomyosarcoma of the lung: clinical, gross and microscopic findings of two cases. AB - Primary leiomyosarcoma of the lung is an unusual malignant tumor. Among this entity, the endobronchial form is very rare and the preoperative diagnosis is extremely difficult. We present two different presentations and outcomes of primary endobronchial leiomyosarcoma of the lung. In both cases, the histological study and the immunohistochemical stain, of the surgical resection, provided the final diagnosis. Through those cases we present the diagnostic and therapeutic difficulties encountered. PMID- 22919550 TI - "Knot stent": an unusual cause of acute renal failure in solitary kidney. AB - The insertion of indwelling ureteric stents is a routine procedure in urology practice. Complications secondary to the insertion of these stents have also increased, such as stent encrustation, stent fragmentation, stone formation, and recurrent urinary tract infections. Knot formation within the renal pelvis or in the coiled portion of the ureteral stent is an extremely rare condition, with less than 15 cases reported in literature. The authors report a rare case of knotted stent, complicated by an obstructive acute renal failure and urosepsis, in a patient with a solitary functioning kidney. PMID- 22919551 TI - Training for rural radiology and imaging in sub-saharan Africa: addressing the mismatch between services and population. AB - The objectives of this review are to outline the needs, challenges, and training interventions for rural radiology (RR) training in Sub-Saharan Africa (SSA). Rural radiology may be defined as imaging requirements of the rural communities. In SSA, over 80% of the population is rural. The literature was reviewed to determine the need for imaging in rural Africa, the challenges, and training interventions. Up to 50% of the patients in the rural health facilities in Uganda may require imaging, largely ultrasound and plain radiography. In Uganda, imaging is performed, on an average, in 50% of the deserving patients in the urban areas, compared to 10-13 % in the rural areas. Imaging has been shown to increase the utilization of facility-based rural health services and to impact management decisions. The challenges in the rural areas are different from those in the urban areas. These are related to disease spectrum, human resource, and socio economic, socio-cultural, infrastructural, and academic disparities. Countries in Sub-Saharan Africa, for which information on training intervention was available, included: Uganda, Kenya, Tanzania, Rwanda, Zambia, Ghana, Malawi, and Sudan. Favorable national policies had been instrumental in implementing these interventions. The interventions had been made by public, private-for-profit (PFP), private-not-for profit (PNFP), local, and international academic institutions, personal initiatives, and professional societies. Ultrasound and plain radiography were the main focus. Despite these efforts, there were still gross disparities in the RR services for SSA. In conclusion, there have been training interventions targeted toward RR in Africa. However, gross disparities in RR provision persist, requiring an effective policy, plus a more organized, focused, and sustainable approach, by the stakeholders. PMID- 22919552 TI - Shoulder ultrasonography: performance and common findings. AB - Ultrasound (US) of the shoulder is the most commonly requested examination in musculoskeletal US diagnosis. Sports injuries and degenerative and inflammatory processes are the main sources of shoulder pain and functional limitations. Because of its availability, low cost, dynamic examination process, absence of radiation exposure, and ease of patient compliance, US is the preferred mode for shoulder imaging over other, more sophisticated, and expensive methods. Operator dependence is the main disadvantage of US examinations. Use of high range equipment with high resolution transducers, adhering to a strict examination protocol, good knowledge of normal anatomy and pathological processes and an awareness of common pitfalls are essential for the optimal performance and interpretation of shoulder US. This article addresses examination techniques, the normal sonographic appearance of tendons, bursae and joints, and the main pathological conditions found in shoulder ultrasonography. PMID- 22919553 TI - Musculoskeletal disorders in the elderly. AB - Musculoskeletal disorders are among the most common problems affecting the elderly. The resulting loss of mobility and physical independence can be particularly devastating in this population. The aim of this article is to present some of the most frequent musculoskeletal disorders of the elderly, such as fractures, osteoporosis, osteoarthritis, microcrystal disorders, infections, and tumors. PMID- 22919554 TI - Prenatal Diagnosis of EEC Syndrome with "Lobster Claw" Anomaly by 3D Ultrasound. AB - THE EEC SYNDROME IS A GENETIC ANOMALY CHARACTERIZED BY THE TRIAD: ectodermal dysplasia (development of anomalies of the structures derived from the embryonic ectodermal layer), ectrodactyly (extremities, hands and feet malformations) and cleft lip and/or palate; these malformations can be seen together or in isolation. The prenatal diagnosis can be made by two-dimensional ultrasonography (2DUS) that identifies the facial and/or limb anomalies, most characteristic being the "lobster-claw" hands. The three-dimensional ultrasonography (3DUS) provides a better analysis of the malformations than the 2DUS. A 25-year-old primigravida, had her first transvaginal ultrasonography that showed an unique fetus with crow-rump length of 47 mm with poorly defined hands and feet,. She was suspected of having sporadic form of EEC syndrome. The 2DUS performed at 19 weeks confirmed the EEC syndrome, showing a fetus with lobster-claw hands (absence of the 2(nd) and 3(rd) fingers), left foot with the absence of the 3rd toe and the right foot with syndactyly, and presence of cleft lip/palate. The 3DUS defined the anomalies much better than 2DUS including the lobster-claw hands. PMID- 22919555 TI - Cerebral Blood and CSF Flow Patterns in Patients Diagnosed for Cerebral Venous Thrombosis - An Observational Study. AB - BACKGROUND AND PURPOSE: Recent studies of the organization of the cerebral venous system in healthy subjects using phase contrast magnetic resonance imaging (PC MRI) show its structural complexity and inter-individual variations. Our objective was to study the venous blood and CSF flows in cerebral venous thrombosis (CVT). MATERIALS AND METHODS: PC-MRI sequences were added to brain MRI conventional protocol in 19 patients suspected of CVT, among whom 6 patients had CVT diagnosis confirmed by MR venography. Results were compared with 18 healthy age-matched volunteers (HV). RESULTS: In patients without CVT (NoCVT) confirmed by venography, we found heterogeneous individual venous flows, and variable side dominance in paired veins and sinuses, comparable to those in healthy volunteers. In CVT patients, PC-MRI detected no venous flow in the veins and/or sinuses with thrombosis. Arterial flows were preserved. CSF aqueductal and cervical stroke volumes were increased in a patient with secondary cerebral infarction, and decreased in 4 patients with extended thrombosis in the superior sagittal and transverse sinuses. These results suggest the main role of the venous system in the regulation of the dynamic intracranial equilibrium. CONCLUSIONS: CVT produces highly individualized pattern of disturbance in venous blood drainage. Complementary to MRI venography, PC-MRI provides non-invasive data about venous blockage consequences on CSF flow disturbances. PMID- 22919557 TI - Radiological features of metastatic gastrointestinal stromal tumors. AB - The imaging features of 42 histopathologically confirmed cases of Gastrointestinal Stromal Tumors (GIST) were analyzed, to observe the pattern of metastasis. At presentation 22 of 42 patients (52.3%) showed metastasis. During follow-up, three more cases developed metastasis, within one year of resection. Mesentery, omentum, and liver were the most frequent sites for metastasis. Other sites that were rarely reported to be involved were increasingly recognized to show metastasis due to longer survival. The metastasis often showed attenuation and enhancement characteristics, similar to primary GIST, and frequently showed necrosis, hemorrhage, and calcification. PMID- 22919556 TI - Uterine cervical malignancy: diagnostic accuracy of MRI with histopathologic correlation. AB - OBJECTIVE: Cervical cancer is the third most common malignancy in women worldwide. Accurate staging of the disease is crucial in planning the optimal treatment strategy. The aim of this study was to evaluate the role of magnetic resonance imaging (MRI) in the assessment of extension and staging of cervical malignancy in correlation with histopathologic examination. MATERIALS AND METHODS: Thirty females with untreated pathologically proven uterine cervical carcinoma were included in this prospective study. The patients were 40 - 65 years of age and their average age was 45 years. All patients were subjected to routine clinical staging workup and underwent MRI for preoperative staging. Preoperative MRI findings were reviewed and compared with the final pathological staging that is the Gold Standard of reference. RESULTS: Histopathologic examination established that of the 30 tumors, 22 (73.3%) were squamous cell carcinoma. According to the International Federation of Gynecology and Obstetrics (FIGO) staging criteria, 2/30 patients (6.6%) were stage IB, 12/30 (40.3%) were IIA, 8/30 were IIB (26.6%), and 8/30 (26.6%) were IVA. MRI had a sensitivity of 100% and specificity 85.7% in the detection of parametrial infiltration, and a sensitivity of 100% and specificity of 90% in the detection of vaginal infiltration. It was sensitive (100%) and specific (100%) in detecting tumor extension to the stroma, urinary bladder, and rectum. Pathological examination demonstrated stage IB cervical carcinoma in 2/30 patients (6.6%), stage IIA disease in 10/30 patients (33.3%), stage IIB in 6/30 patients (20%), and stage IV disease in 8/30 patients (26.6%). MRI features demonstrated stage IB in 2/30 patients (6.6%), stage IIA disease in 12/30 patients (40%), stage IIB in 8/30 patients (26.6%), and stage IV disease in 8/30 patients (26.6%). MRI staging of cervical carcinoma was in concordance with histopathologic staging in stages IB and IVA and over-staging in IIA and IIB stages. CONCLUSION: MRI is an optimal non invasive modality for preoperative staging of uterine cervical malignancy, and crucial in subsequent more accurate treatment planning. PMID- 22919558 TI - Penile Metastases of Recurrent Prostatic Adenocarcinoma without PSA Level Increase: A Case Report. AB - We report a case of penile metastases from recurrent prostatic adenocarcinoma that was the first sign of a widespread metastatic disease in the absence of any increase in prostate-specific antigen (PSA) level. In April 2011, an 80-year-old man presented to our Radiotherapy Unit with multiple palpable hard nodules in the penis, dysuria, and moderate perineal pain, 7 years after he had received radiotherapy for prostate cancer. Nodules in the penis had appeared in February 2011. The ultrasound and magnetic resonance (MR) imaging suggested the diagnosis of multiple penile metastases. A total body computed tomography scan revealed a systemic spread of the disease, with multiple metastases in the liver, bones, and lungs. PSA level was 0.126 ng/ml. A fine needle aspiration biopsy of the liver lesion was undertaken, and the histopathologic examination revealed the prostatic origin of the metastases, so androgen deprivation therapy was started. The diagnosis of metastases should be considered in a patient with prior history of prostate malignancies presenting with solid nodules in the penis, even if the PSA level is low. PMID- 22919560 TI - Primary sarcoid of the breast with incidental malignancy. AB - Breast sarcoidosis is rare and usually presents in patients with known sarcoid involving other organ systems. In the breast, sarcoidosis may mimic malignancy which must be excluded by core biopsy. We report a very unusual case of primary breast sarcoidosis with incidentally discovered breast carcinoma. The roles of mammography, ultrasound, and MRI in the diagnosis as well as other potential differential diagnosis are discussed. PMID- 22919561 TI - Endovascular management of fusiform superior cerebellar artery aneurysms: a series of three cases with review of literature. AB - Distal superior cerebellar artery (SCA) aneurysms are rare. Fusiform aneurysms of SCA are rarer and more challenging to treat. Parent artery occlusion by endovascular coiling is the treatment option for these cases. Presence of good collateral circulation and paucity of perforators from S1 and S2 segments makes this a feasible option. From 2007 to 2010, we treated three patients (two men and one woman between the ages of 42 to 64 years) with distal fusiform SCA aneurysms using endovascular coiling. All the patients presented with symptoms of rupture and were treated in the acute phase. Informed and written high-risk consent was given by all patients prior to the procedure. Successful angiographic and clinical outcome was achieved in all three patients. Endovascular treatment of fusiform SCA aneurysms with coils is a safe and feasible option in the management of this rare entity. PMID- 22919559 TI - CAD May Not be Necessary for Microcalcifications in the Digital era, CAD May Benefit Radiologists for Masses. AB - OBJECTIVE: The aim of this study was to evaluate the effectiveness of computer aided detection (CAD) to mark the cancer on digital mammograms at the time of breast cancer diagnosis and also review retrospectively whether CAD marked the cancer if visible on any available prior mammograms, thus potentially identifying breast cancer at an earlier stage. We sought to determine why breast lesions may or may not be marked by CAD. In particular, we analyzed factors such as breast density, mammographic views, and lesion characteristics. MATERIALS AND METHODS: Retrospective review from 2004 to 2008 revealed 3445 diagnosed breast cancers in both symptomatic and asymptomatic patients; 1293 of these were imaged with full field digital mammography (FFDM). After cancer diagnosis, in a retrospective review held by the radiologist staff, 43 of these cancers were found to be visible on prior-year mammograms (false-negative cases); these breast cancer cases are the basis of this analysis. All cases had CAD evaluation available at the time of cancer diagnosis and on prior mammography studies. Data collected included patient demographics, breast density, palpability, lesion type, mammographic size, CAD marks on current- and prior-year mammograms, needle biopsy method, pathology results (core needle and/or surgical), surgery type, and lesion size. RESULTS: On retrospective review of the mammograms by the staff radiologists, 43 cancers were discovered to be visible on prior-year mammograms. All 43 cancers were masses (mass classification included mass, mass with calcification, and mass with architectural distortion); no pure microcalcifications were identified in this cohort. Mammograms with CAD applied at the time of breast cancer diagnosis were able to detect 79% (34/43) of the cases and 56% (24/43) from mammograms with CAD applied during prior year(s). In heterogeneously dense/extremely dense tissue, CAD marked 79% (27/34) on mammograms taken at the time of diagnosis and 56% (19/34) on mammograms with CAD applied during the prior year(s). At time of diagnosis, CAD marked lesions in 32% (11/34) on the craniocaudal (CC) view, 21% (7/34) on the mediolateral oblique (MLO) view. Lesion size of those marked by CAD or not marked were similar, the average being 15 and 12 mm, respectively. CONCLUSION: CAD marked cancers on mammograms at the time of diagnosis in 79% of the cases and in 56% of the cases from the mammograms with CAD applied in the prior year(s). Our review demonstrated that CAD can mark invasive breast carcinomas in even dense breast tissue. CAD marked a significant portion on the CC view only, which may be an indicator to radiologists to be especially vigilant when a lesion is marked on this view. PMID- 22919562 TI - Computed tomographic features of congenital left ventricular diverticulum. AB - Congenital left ventricular diverticulum is a rare cardiac malformation characterized by a localized out-pouching from the cardiac chamber. They are most often found in the left ventricle (LV) but have been reported to occur in all chambers of the heart. The patient is usually asymptomatic. However, complications like embolism, infective endocarditis, arrhythmia and, rarely, rupture may be the initial presentation. Diagnosis can be established by echocardiography (EKG), computed tomographic (CT) angiography, and magnetic resonance imaging (MRI). We report a case of congenital left ventricular diverticulum in an adult with no valvular abnormality as an incidental finding in an uncommon location. PMID- 22919563 TI - Critical paths in a metapopulation model of H1N1: Efficiently delaying influenza spreading through flight cancellation. AB - Disease spreading through human travel networks has been a topic of great interest in recent years, as witnessed during outbreaks of influenza A (H1N1) or SARS pandemics. One way to stop spreading over the airline network are travel restrictions for major airports or network hubs based on the total number of passengers of an airport. Here, we test alternative strategies using edge removal, cancelling targeted flight connections rather than restricting traffic for network hubs, for controlling spreading over the airline network. We employ a SEIR metapopulation model that takes into account the population of cities, simulates infection within cities and across the network of the top 500 airports, and tests different flight cancellation methods for limiting the course of infection. The time required to spread an infection globally, as simulated by a stochastic global spreading model was used to rank the candidate control strategies. The model includes both local spreading dynamics at the level of populations and long-range connectivity obtained from real global airline travel data. Simulated spreading in this network showed that spreading infected 37% less individuals after cancelling a quarter of flight connections between cities, as selected by betweenness centrality. The alternative strategy of closing down whole airports causing the same number of cancelled connections only reduced infections by 18%. In conclusion, selecting highly ranked single connections between cities for cancellation was more effective, resulting in fewer individuals infected with influenza, compared to shutting down whole airports. It is also a more efficient strategy, affecting fewer passengers while producing the same reduction in infections. PMID- 22919564 TI - The Good, The Bad and The Ugly: Disaster Risk Reduction (DRR) Versus Disaster Risk Creation (DRC). AB - In understanding and trying to reduce the risk from disasters, connections are often articulated amongst poverty, vulnerability, risk, and disasters. These are welcome steps, but the approach taken in top-down international documents is rarely to articulate explicitly that vulnerability accrues from a wide variety of dynamic and long-term processes. Neglecting these processes-and failing to explore their links with poverty, risk, and disasters-tends to encourage disaster risk creation. This paper identifies seven examples of on-the-ground realities of long-term vulnerability within two clusters: Endangerment: 1 Environmental degradation. 2 Discrimination. 3 Displacement. Impoverishment: 4 Self-seeking public expenditure. 5 Denial of access to resources. 6 Corruption. 7 Siphoning of public money. Examples are presented as vignettes, many contemporary and many rooted in historical contexts, to demonstrate the extent to which "vulnerability drivers" emanate from greed, the misuse of political and commercial power, mismanagement and incompetence amongst other behaviours. Moving forward to the tackling of disaster risk creation, instead of simply seeking disaster risk reduction, requires detailed investigation into these contemporary and historical realities of the causes of vulnerability. That would support the integration of disaster risk reduction within the many wider contexts that foment and perpetuate vulnerability. PMID- 22919565 TI - Protection by glia-conditioned medium in a cell model of Huntington disease. AB - The physiological role of huntingtin and the pathogenic mechanisms that produce the disease are unknown. Mutant huntingtin changes its normal localization and produces cytoplasmic and intranuclear inclusions, changes gene transcription, alters synaptic transmission, impairs mitochondrial activity and activates caspases and other pro-apoptotic molecules, promotes excitotoxicity, energy deficits, synthesis and release reduction of neurotrophic factors and oxidative stress. Previous studies confirm that the mutant huntingtin difficult neurotrophic function of astrocytes leading to neuronal dysfunction in Huntington's disease. Our objective was to study the neuroprotective potential role of glia-conditioned medium (GCM) in an in vitro model of Huntington's disease. We used conditionally-immortalized striatal neuronal progenitor cell lines (STHdhQ7/Q7 and STHdhQ111/Q111) expressing endogenous levels of normal and mutant huntingtin with 7 and 111 glutamines, respectively. We studied the protection of fetal and postnatal glia conditioned medium (GCM) on H2O2 (2 uM), glutamate (5 mM) and 3-nitropropionic acid (2.5 mM) related toxicity. We also compared the neuroprotective effects of GCM versus that of the growth factors bFGF, BDNF and GDNF. Fetal GCM protects from every toxin, reducing the cell death and increasing the cell survival. Fetal GCM reduces the caspases fragmentation of the protein PARP, the expression of chaperone Hsp70 and the accumulation of ROS and polyubiquitinated proteins. In addition, in Q111 striatal cells treated with H2O2 (2 uM) for 24 hours, the intracellular GSH levels are higher in the presence of GCM. Notably, the 13-day and 2-month postnatal GCM, totally protects from H2O2 induced cell death in mutant striatal cells. GCM neuroprotective effects are more potent than those of the already identified neurotrophic factors. We conclude that GCM protects Q111 cells from neuronal neurotoxins and the effects of GCM are more potent than those of any known neurotrophic factor. GCM may contain new and more potent, as yet unidentified, neurotrophic molecules, potentially useful in patients with Huntington's disease. PMID- 22919566 TI - Caspase-6 does not contribute to the proteolysis of mutant huntingtin in the HdhQ150 knock-in mouse model of Huntington's disease. PMID- 22919567 TI - Complications in the management of metastatic spinal disease. AB - Metastatic spine disease accounts for 10% to 30% of new cancer diagnoses annually. The most frequent presentation is axial spinal pain. No treatment has been proven to increase the life expectancy of patients with spinal metastasis. The goals of therapy are pain control and functional preservation. The most important prognostic indicator for spinal metastases is the initial functional score. Treatment is multidisciplinary, and virtually all treatment is palliative. Management is guided by three key issues; neurologic compromise, spinal instability, and individual patient factors. Site-directed radiation, with or without chemotherapy is the most commonly used treatment modality for those patients presenting with spinal pain, causative by tumours which are not impinging on neural elements. Operative intervention has, until recently been advocated for establishing a tissue diagnosis, mechanical stabilization and for reduction of tumor burden but not for a curative approach. It is treatment of choice patients with diseaseadvancement despite radiotherapy and in those with known radiotherapy-resistant tumors. Vertebral resection and anterior stabilization with methacrylate or hardware (e.g., cages) has been advocated.Surgical decompression and stabilization, however, along with radiotherapy, may provide the most promising treatment. It stabilizes the metastatic deposited areaand allows ambulation with pain relief. In general, patients who are nonambulatory at diagnosis do poorly, as do patients in whom more than one vertebra is involved. Surgical intervention is indicated in patients with radiation-resistant tumors, spinal instability, spinal compression with bone or disk fragments, progressive neurologic deterioration, previous radiation exposure, and uncertain diagnosis that requires tissue diagnosis. The main goal in the management of spinal metastatic deposits is always palliative rather than curative, with the primary aim being pain relief and improved mobility. This however, does not come without complications, regardless of the surgical intervention technique used. These complication range from the general surgical complications of bleeding, infection, damage to surrounding structures and post operative DT/PE to spinal specific complications of persistent neurologic deficit and paralysis. PMID- 22919568 TI - Instability after total hip arthroplasty. AB - Instability following total hip arthroplasty (THA) is an unfortunately frequent and serious problem that requires thorough evaluation and preoperative planning before surgical intervention. Prevention through optimal index surgery is of great importance, as the management of an unstable THA is challenging even for an experienced joints surgeon. However, even after well-planned surgery, a significant incidence of recurrent instability still exists. Non-operative management is often successful if the components are well-fixed and correctly positioned in the absence of neurocognitive disorders. If conservative management fails, surgical options include revision of malpositioned components; exchange of modular components such as the femoral head and acetabular liner; bipolar arthroplasty; tripolar arthroplasty; use of a larger femoral head; use of a constrained liner; soft tissue reinforcement and advancement of the greater trochanter. PMID- 22919569 TI - Hip joint center localisation: A biomechanical application to hip arthroplasty population. AB - AIM: To determine hip joint center (HJC) location on hip arthroplasty population comparing predictive and functional approaches with radiographic measurements. METHODS: The distance between the HJC and the mid-pelvis was calculated and compared between the three approaches. The localisation error between the predictive and functional approach was compared using the radiographic measurements as the reference. The operated leg was compared to the non-operated leg. RESULTS: A significant difference was found for the distance between the HJC and the mid-pelvis when comparing the predictive and functional method. The functional method leads to fewer errors. A statistical difference was found for the localization error between the predictive and functional method. The functional method is twice more precise. CONCLUSION: Although being more individualized, the functional method improves HJC localization and should be used in three-dimensional gait analysis. PMID- 22919570 TI - Non-typeable Haemophilus influenzae invasion and persistence in the human respiratory tract. AB - Non-typeable Haemophilus influenzae (NTHI) is an opportunistic bacterial pathogen of the human respiratory tract and is a leading cause of respiratory infections in children and adults. NTHI is considered to be an extracellular pathogen, but has consistently been observed within and between human respiratory epithelial cells and macrophages, in vitro and ex vivo. Until recently, few studies have examined the internalization, trafficking, and fate of NTHI in host cells. It is important to clarify this interaction because of a possible correlation between intracellular NTHI and symptomatic infection, and because NTHI infections frequently persist and recur despite antibiotic therapy and the development of bactericidal antibodies, suggesting a possible intracellular state or reservoir for NTHI. How does NTHI enter host cells? Can NTHI survive intracellularly and, if so, for how long? Strides have been made in the identification of host receptors, signaling, endocytosis, and trafficking pathways involved in the entry and persistence of NTHI in the respiratory tract. PMID- 22919571 TI - Structure and function of the Haemophilus influenzae autotransporters. AB - Autotransporters are a large class of proteins that are found in the outer membrane of Gram-negative bacteria and are almost universally implicated in virulence. These proteins consist of a C-terminal beta-domain that is embedded in the outer membrane and an N-terminal domain that is exposed on the bacterial surface and is endowed with effector function. In this article, we review and compare the structural and functional characteristics of the Haemophilus influenzae IgA1 protease and Hap monomeric autotransporters and the H. influenzae Hia and Hsf trimeric autotransporters. All of these proteins play a role in colonization of the upper respiratory tract and in the pathogenesis of H. influenzae disease. PMID- 22919572 TI - Extreme antimicrobial peptide and polymyxin B resistance in the genus Burkholderia. AB - Cationic antimicrobial peptides and polymyxins are a group of naturally occurring antibiotics that can also possess immunomodulatory activities. They are considered a new source of antibiotics for treating infections by bacteria that are resistant to conventional antibiotics. Members of the genus Burkholderia, which includes various human pathogens, are inherently resistant to antimicrobial peptides. The resistance is several orders of magnitude higher than that of other Gram-negative bacteria such as Escherichia coli, Salmonella enterica, or Pseudomonas aeruginosa. This review summarizes our current understanding of antimicrobial peptide and polymyxin B resistance in the genus Burkholderia. These bacteria possess major and minor resistance mechanisms that will be described in detail. Recent studies have revealed that many other emerging Gram-negative opportunistic pathogens may also be inherently resistant to antimicrobial peptides and polymyxins and we propose that Burkholderia sp. are a model system to investigate the molecular basis of the resistance in extremely resistant bacteria. Understanding resistance in these types of bacteria will be important if antimicrobial peptides come to be used regularly for the treatment of infections by susceptible bacteria because this may lead to increased resistance in the species that are currently susceptible and may also open up new niches for opportunistic pathogens with high inherent resistance. PMID- 22919573 TI - Comparative genomics evidence that only protein toxins are tagging bad bugs. AB - The term toxin was introduced by Roux and Yersin and describes macromolecular substances that, when produced during infection or when introduced parenterally or orally, cause an impairment of physiological functions that lead to disease or to the death of the infected organism. Long after the discovery of toxins, early genetic studies on bacterial virulence demonstrated that removing a certain number of genes from pathogenic bacteria decreases their capacity to infect hosts. Each of the removed factors was therefore referred to as a "virulence factor," and it was speculated that non-pathogenic bacteria lack such supplementary factors. However, many recent comparative studies demonstrate that the specialization of bacteria to eukaryotic hosts is associated with massive gene loss. We recently demonstrated that the only features that seem to characterize 12 epidemic bacteria are toxin-antitoxin (TA) modules, which are addiction molecules in host bacteria. In this study, we investigated if protein toxins are indeed the only molecules specific to pathogenic bacteria by comparing 14 epidemic bacterial killers ("bad bugs") with their 14 closest non-epidemic relatives ("controls"). We found protein toxins in significantly more elevated numbers in all of the "bad bugs." For the first time, statistical principal components analysis, including genome size, GC%, TA modules, restriction enzymes, and toxins, revealed that toxins are the only proteins other than TA modules that are correlated with the pathogenic character of bacteria. Moreover, intracellular toxins appear to be more correlated with the pathogenic character of bacteria than secreted toxins. In conclusion, we hypothesize that the only truly identifiable phenomena, witnessing the convergent evolution of the most pathogenic bacteria for humans are the loss of metabolic activities, i.e., the outcome of the loss of regulatory and transcription factors and the presence of protein toxins, alone, or coupled as TA modules. PMID- 22919575 TI - Influence of neutrophil defects on Burkholderia cepacia complex pathogenesis. AB - The Burkholderia cepacia complex (Bcc) is a group of Gram-negative bacteria that are ubiquitous in the environment and have emerged as opportunistic pathogens in immunocompromised patients. The primary patient populations infected with Bcc include individuals with cystic fibrosis (CF), as well as those with chronic granulomatous disease (CGD). While Bcc infection in CF is better characterized than in CGD, these two genetic diseases are not obviously similar and it is currently unknown if there is any commonality in host immune defects that is responsible for the susceptibility to Bcc. CF is caused by mutations in the CF transmembrane conductance regulator, resulting in manifestations in various organ systems, however the major cause of morbidity and mortality is currently due to bacterial respiratory infections. CGD, on the other hand, is a genetic disorder that is caused by defects in phagocyte NADPH oxidase. Because of the defect in CGD, phagocytes in these patients are unable to produce reactive oxygen species, which results in increased susceptibility to bacterial and fungal infections. Despite this significant defect in microbial clearance, the spectrum of pathogens frequently implicated in infections in CGD is relatively narrow and includes some bacterial species that are considered almost pathognomonic for this disorder. Very little is known about the cause of the specific susceptibility to Bcc over other potential pathogens more prevalent in the environment, and a better understanding of specific mechanisms required for bacterial virulence has become a high priority. This review will summarize both the current knowledge and future directions related to Bcc virulence in immunocompromised individuals with a focus on the roles of bacterial factors and neutrophil defects in pathogenesis. PMID- 22919574 TI - The influence of rickettsiologists on post-modern microbiology. AB - Many of the definitions in microbiology are currently false. We have reviewed the great denominations of microbiology and attempted to free microorganisms from the theories of the twentieth century. The presence of compartmentation and a nucleoid in Planctomycetes clearly calls into question the accuracy of the definitions of eukaryotes and prokaryotes. Archaea are viewed as prokaryotes resembling bacteria. However, the name archaea, suggesting an archaic origin of lifestyle, is inconsistent with the lifestyle of this family. Viruses are defined as small, filterable infectious agents, but giant viruses challenge the size criteria used for the definition of a virus. Pathogenicity does not require the acquisition of virulence factors (except for toxins), and in many cases, gene loss is significantly inked to the emergence of virulence. Species classification based on 16S rRNA is useless for taxonomic purposes of human pathogens, as a 2% divergence would classify all Rickettsiae within the same species and would not identify bacteria specialized for mammal infection. The use of metagenomics helps us to understand evolution and physiology by elucidating the structure, function, and interactions of the major microbial communities, but it neglects the minority populations. Finally, Darwin's descent with modification theory, as represented by the tree of life, no longer matches our current genomic knowledge because genomics has revealed the occurrence of de novo-created genes and the mosaic structure of genomes, the Rhizome of life is therefore more appropriate. PMID- 22919576 TI - Characterization of recombinant B. abortus strain RB51SOD toward understanding the uncorrelated innate and adaptive immune responses induced by RB51SOD compared to its parent vaccine strain RB51. AB - Brucella abortus is a Gram-negative, facultative intracellular pathogen for several mammals, including humans. Live attenuated B. abortus strain RB51 is currently the official vaccine used against bovine brucellosis in the United States and several other countries. Overexpression of protective B. abortus antigen Cu/Zn superoxide dismutase (SOD) in a recombinant strain of RB51 (strain RB51SOD) significantly increases its vaccine efficacy against virulent B. abortus challenge in a mouse model. An attempt has been made to better understand the mechanism of the enhanced protective immunity of RB51SOD compared to its parent strain RB51. We previously reported that RB51SOD stimulated enhanced Th1 immune response. In this study, we further found that T effector cells derived from RB51SOD-immunized mice exhibited significantly higher cytotoxic T lymphocyte activity than T effector cells derived from RB51-immunized mice against virulent B. abortus-infected target cells. Meanwhile, the macrophage responses to these two strains were also studied. Compared to RB51, RB51SOD cells had a lower survival rate in macrophages and induced lower levels of macrophage apoptosis and necrosis. The decreased survival of RB51SOD cells correlates with the higher sensitivity of RB51SOD, compared to RB51, to the bactericidal action of either Polymyxin B or sodium dodecyl sulfate (SDS). Furthermore, a physical damage to the outer membrane of RB51SOD was observed by electron microscopy. Possibly due to the physical damage, overexpressed Cu/Zn SOD in RB51SOD was found to be released into the bacterial cell culture medium. Therefore, the stronger adaptive immunity induced by RB51SOD did not correlate with the low level of innate immunity induced by RB51SOD compared to RB51. This unique and apparently contradictory profile is likely associated with the differences in outer membrane integrity and Cu/Zn SOD release. PMID- 22919578 TI - Long-term colonization of the cystic fibrosis lung by Burkholderia cepacia complex bacteria: epidemiology, clonal variation, and genome-wide expression alterations. AB - Long-term respiratory infections with Burkholderia cepacia complex (Bcc) bacteria in cystic fibrosis (CF) patients generally lead to a more rapid decline in lung function and, in some cases, to a fatal necrotizing pneumonia known as the "cepacia syndrome." Bcc bacteria are ubiquitous in the environment and are recognized as serious opportunistic pathogens that are virtually impossible to eradicate from the CF lung, posing a serious clinical threat. The epidemiological survey of Bcc bacteria involved in respiratory infections at the major Portuguese CF Treatment Center at Santa Maria Hospital, in Lisbon, has been carried out by our research group for the past 16 years, covering over 500 clinical isolates where B. cepacia and B. cenocepacia are the predominant species, with B. stabilis, B. contaminans, B. dolosa, and B. multivorans also represented. The systematic and longitudinal study of this CF population during such an extended period of time represents a unique case-study, comprehending 41 Bcc-infected patients (29 pediatric and 12 adult) of whom around 70% have been persistently colonized between 7 months and 9 years. During chronic infection, the CF airways represent an evolving ecosystem, with multiple phenotypic variants emerging from the clonal population and becoming established in the patients' airways as the result of genetic adaptation. Understanding the evolutionary mechanisms involved is crucial for an improved therapeutic outcome of chronic infections in CF. This review focuses on our contribution to the understanding of these adaptive mechanisms based on extensive phenotypic, genotypic, and genome-wide expression approaches of selected Bcc clonal variants obtained during long-term colonization of the CF airways. PMID- 22919579 TI - Trimeric autotransporter adhesins in members of the Burkholderia cepacia complex: a multifunctional family of proteins implicated in virulence. AB - Trimeric autotransporter adhesins (TAAs) are multimeric surface proteins exclusively found in bacteria. They are involved in various biological traits of pathogenic Gram-negative bacteria including adherence, biofilm formation, invasion, survival within eukaryotic cells, serum resistance, and cytotoxicity. TAAs have a modular architecture composed by a conserved membrane-anchored C terminal domain and a variable number of stalk and head domains. In this study, a bioinformatic approach has been used to analyze the distribution and architecture of TAAs among Burkholderia cepacia complex (Bcc) genomes. Fifteen genomes were probed revealing a total of 74 encoding sequences. Compared with other bacterial species, the Bcc genomes contain a large number of TAAs (two genes to up to eight genes, such as in B. cenocepacia). Phylogenetic analysis showed that the TAAs grouped into at least eight distinct clusters. TAAs with serine-rich repeats are clearly well separated from others, thereby representing a different evolutionary lineage. Comparative gene mapping across Bcc genomes reveals that TAA genes are inserted within conserved synteny blocks. We further focused our analysis on the epidemic strain B. cenocepacia J2315 in which seven TAAs were annotated. Among these, three TAA-encoding genes (BCAM019, BCAM0223, and BCAM0224) are organized into a cluster and are candidates for multifunctional virulence factors. Here we review the current insights into the functional role of BCAM0224 as a model locus. PMID- 22919577 TI - Clostridial binary toxins: iota and C2 family portraits. AB - There are many pathogenic Clostridium species with diverse virulence factors that include protein toxins. Some of these bacteria, such as C. botulinum, C. difficile, C. perfringens, and C. spiroforme, cause enteric problems in animals as well as humans. These often fatal diseases can partly be attributed to binary protein toxins that follow a classic AB paradigm. Within a targeted cell, all clostridial binary toxins destroy filamentous actin via mono-ADP-ribosylation of globular actin by the A component. However, much less is known about B component binding to cell-surface receptors. These toxins share sequence homology amongst themselves and with those produced by another Gram-positive, spore-forming bacterium also commonly associated with soil and disease: Bacillus anthracis. This review focuses upon the iota and C2 families of clostridial binary toxins and includes: (1) basics of the bacterial source; (2) toxin biochemistry; (3) sophisticated cellular uptake machinery; and (4) host-cell responses following toxin-mediated disruption of the cytoskeleton. In summary, these protein toxins aid diverse enteric species within the genus Clostridium. PMID- 22919580 TI - 3-Hydroxyphenylacetic acid induces the Burkholderia cenocepacia phenylacetic acid degradation pathway - toward understanding the contribution of aromatic catabolism to pathogenesis. AB - The phenylacetic acid (PA) degradative pathway is the central pathway by which various aromatic compounds (e.g., styrene) are degraded. Upper pathways for different aromatic compounds converge at common intermediate phenylacetyl-CoA (PA CoA), which is then metabolized to succinyl-CoA and acetyl-CoA. We previously made a link in Burkholderia cenocepacia between PA degradation and virulence by showing that insertional mutagenesis of paaA and paaE genes, that encode part of a multicomponent oxidase of PA-CoA, results in PA-conditional growth and an attenuated killing phenotype in the Caenorhabditis elegans model of infection. However, insertional mutagenesis of paaK1, which encodes a phenylacetate-CoA ligase, did not result in a PA-conditional growth probably due to the presence of a putative paralog gene paaK2. Recently published crystallographic and enzyme kinetics data comparing the two PaaK ligases showed that PaaK1 is more active than PaaK2 and that the larger binding pocket of PaaK1 can accommodate hydroxylated PA derived molecules such as 3-hydroxyphenylacetic (3-OHPA) acid and 4-hydroxyphenylacetic acid (4-OHPA). The higher activity and broader substrate specificity suggested a more active role in pathogenesis. In this work, we aimed to determine the relevance of PaaK1 activity to the killing ability of B. cenocepacia to C. elegans. Using reporter activity assays, we demonstrate that 3 OHPA activated PA degradation gene promoters of Burkholderia cenocepacia K56-2 in a paaK1-dependent manner, while 4-OHPA had no effect. We compared the pathogenicity of a paaK1 deletion mutant with that of the wild type in C. elegans and observed no differences in the killing ability of the strains. Taken together, these studies suggest that 3-OHPA, but not 4-OHPA, can induce the PA pathway and that this induction is dependent on the paaK1 gene. However, the more active PaaK1 does not play a distinct role in pathogenesis of B. cenocepacia as previously suggested. PMID- 22919581 TI - Burkholderia cenocepacia differential gene expression during host-pathogen interactions and adaptation to the host environment. AB - Members of the Burkholderia cepacia complex (Bcc) are important in medical, biotechnological, and agricultural disciplines. These bacteria naturally occur in soil and water environments and have adapted to survive in association with plants and animals including humans. All Bcc species are opportunistic pathogens including Burkholderia cenocepacia that causes infections in cystic fibrosis and chronic granulomatous disease patients. The adaptation of B. cenocepacia to the host environment was assessed in a rat chronic respiratory infection model and compared to that of high cell-density in vitro grown cultures using transcriptomics. The distribution of genes differentially expressed on chromosomes 1, 2, and 3 was relatively proportional to the size of each genomic element, whereas the proportion of plasmid-encoded genes differentially expressed was much higher relative to its size and most genes were induced in vivo. The majority of genes encoding known virulence factors, components of types II and III secretion systems and chromosome 2-encoded type IV secretion system were similarly expressed between in vitro and in vivo environments. Lower expression in vivo was detected for genes encoding N-acyl-homoserine lactone synthase CepI, orphan LuxR homolog CepR2, zinc metalloproteases ZmpA and ZmpB, LysR-type transcriptional regulator ShvR, nematocidal protein AidA, and genes associated with flagellar motility, Flp type pilus formation, and type VI secretion. Plasmid encoded type IV secretion genes were markedly induced in vivo. Additional genes induced in vivo included genes predicted to be involved in osmotic stress adaptation or intracellular survival, metal ion, and nutrient transport, as well as those encoding outer membrane proteins. Genes identified in this study are potentially important for virulence during host-pathogen interactions and may be associated with survival and adaptation to the host environment during chronic lung infections. PMID- 22919582 TI - Insights into the role of extracellular polysaccharides in Burkholderia adaptation to different environments. AB - The genus Burkholderia comprises more than 60 species able to adapt to a wide range of environments such as soil and water, and also colonize and infect plants and animals. They have large genomes with multiple replicons and high gene number, allowing these bacteria to thrive in very different niches. Among the properties of bacteria from the genus Burkholderia is the ability to produce several types of exopolysaccharides (EPSs). The most common one, cepacian, is produced by the majority of the strains examined irrespective of whether or not they belong to the Burkholderia cepacia complex (Bcc). Cepacian biosynthesis proceeds by a Wzy-dependent mechanism, and some of the B. cepacia exopolysaccharide (Bce) proteins have been functionally characterized. In vitro studies showed that cepacian protects bacterial cells challenged with external stresses. Regarding virulence, bacterial cells with the ability to produce EPS are more virulent in several animal models of infection than their isogenic non producing mutants. Although the production of EPS within the lungs of cystic fibrosis (CF) patients has not been demonstrated, the in vitro assessment of the mucoid phenotype in serial Bcc isolates from CF patients colonized for several years showed that mucoid to non-mucoid transitions are relatively frequent. This morphotype variation can be induced under laboratory conditions by exposing cells to stress such as high antibiotic concentration. Clonal isolates where mucoid to non-mucoid transition had occurred showed that during lung infection, genomic rearrangements, and mutations had taken place. Other phenotypic changes include variations in motility, chemotaxis, biofilm formation, bacterial survival rate under nutrient starvation and virulence. In this review, we summarize major findings related to EPS biosynthesis by Burkholderia and the implications in broader regulatory mechanisms important for cell adaptation to the different niches colonized by these bacteria. PMID- 22919583 TI - Major host factors involved in epithelial cell invasion of Campylobacter jejuni: role of fibronectin, integrin beta1, FAK, Tiam-1, and DOCK180 in activating Rho GTPase Rac1. AB - Host cell entry by the food-borne pathogen Campylobacter jejuni has been reported as one of the primary reasons of tissue damage in infected humans, however, molecular invasion mechanisms and cellular factors involved in this process are widely unclear. Here we used knockout cell lines derived from fibronectin(-/-), integrin beta1(-/-), and focal adhesion kinase (FAK)(-/-) deficient mice and corresponding wild-type (WT) controls, to study C. jejuni-induced signaling cascades involved in the bacterial invasion process. Using high resolution scanning electron microscopy, GTPase pull-downs, G-LISA, and gentamicin protection assays we found that each of these host cell factors is indeed required for activation of the small Rho GTPase member Rac1 and maximal host cell invasion of this pathogen. Interestingly, membrane ruffling, tight engulfment of bacteria and invasion were only seen during infection of WT control cells, but not in fibronectin(-/-), integrin beta1(-/-), and FAK(-/-) knockout cell lines. We also demonstrate that C. jejuni activates FAK autophosphorylation activity at Y-397 and phosphorylation of Y-925, which is required for stimulating two downstream guanine exchange factors, DOCK180 and Tiam-1, which are upstream of Rac1. Small interfering (si) RNA studies further show that DOCK180 and Tiam-1 act cooperatively to trigger Rac1 activation and C. jejuni invasion. Moreover, mutagenesis data indicate that the bacterial fibronectin-binding protein CadF and the intact flagellum are involved in Rho GTPase activation and host cell invasion. Collectively, our results suggest that C. jejuni infection of host epithelial target cells hijacks a major fibronectin -> integrin beta1 -> FAK -> DOCK180/Tiam-1 signaling cascade, which has a crucial role for Rac1 GTPase activity and bacterial entry into host target cells. PMID- 22919584 TI - Can early Burkholderia cepacia complex infection in cystic fibrosis be eradicated with antibiotic therapy? AB - INTRODUCTION: Organisms of the Burkholderia cepacia complex (BCC) are important pathogens in cystic fibrosis (CF). The majority of those who acquire BCC develop chronic infection but it can also result in rapid decline in a significant minority. In addition, chronic infection with Burkholderia cenocepacia in particular is regarded as a contraindication to lung transplantation in many units. Whilst aggressive antibiotic therapy is employed in CF to eradicate Pseudomonas aeruginosa before infection becomes irreversibly established, no formal assessment of such strategies has been previously reported for BCC, despite the apparent widespread adoption of this practice. METHODS: UK adult CF centers were surveyed about their current approach to new BCC infection. Outcomes of eradication therapy were assessed in patients attending the Manchester Adult CF Center with new BCC isolates between 1st January 2002 and 1st May 2011. Patients with previous infection with the same strain of BCC were excluded. BCC were identified at the national reference laboratories and confirmed by species specific PCR and RecA sequencing. RESULTS: Routine use of therapies to attempt eradication of new BCC is commonly used in the UK (12/17 centers who responded). This typically involves a combination of intravenous and nebulised antibiotics. Of 19 eligible cases of new BCC infection, the organism has been eradicated in 7 (37%). Three of these did not receive specific eradication therapy. Of 14 patients who have received eradication therapy and completed follow up, BCC were cleared in only 4 (29%). CONCLUSIONS: Attempted eradication of new BCC is a common practice in UK adult CF centers. A minority of patients clear the infection spontaneously and the effects of eradication therapies are at best modest. Early treatment may be associated with better outcomes, though there are insufficient data to support the use of any specific treatment regimen. A prospective, systematic evaluation of treatments and outcomes is required. PMID- 22919585 TI - Identification of a lactate-quinone oxidoreductase in Staphylococcus aureus that is essential for virulence. AB - Staphylococcus aureus is an important human pathogen commonly infecting nearly every host tissue. The ability of S. aureus to resist innate immunity is critical to its success as a pathogen, including its propensity to grow in the presence of host nitric oxide (NO.). Upon exogenous NO. exposure, S. aureus immediately excretes copious amounts of L-lactate to maintain redox balance. However, after prolonged NO.-exposure, S. aureus reassimilates L-lactate specifically and in this work, we identify the enzyme responsible for this L-lactate-consumption as a L-lactate-quinone oxidoreductase (Lqo, SACOL2623). Originally annotated as Mqo2 and thought to oxidize malate, we show that this enzyme exhibits no affinity for malate but reacts specifically with L-lactate (K(M) = ~330 MUM). In addition to its requirement for reassimilation of L-lactate during NO.-stress, Lqo is also critical to respiratory growth on L-lactate as a sole carbon source. Moreover, Deltalqo mutants exhibit attenuation in a murine model of sepsis, particularly in their ability to cause myocarditis. Interestingly, this cardiac-specific attenuation is completely abrogated in mice unable to synthesize inflammatory NO. (iNOS(-/-)). We demonstrate that S. aureus NO.-resistance is highly dependent on the availability of a glycolytic carbon sources. However, S. aureus can utilize the combination of peptides and L-lactate as carbon sources during NO.-stress in an Lqo-dependent fashion. Murine cardiac tissue has markedly high levels of L lactate in comparison to renal or hepatic tissue consistent with the NO. dependent requirement for Lqo in S. aureus myocarditis. Thus, Lqo provides S. aureus with yet another means of replicating in the presence of host NO.. PMID- 22919586 TI - Alpha-1 antitrypsin is markedly decreased following pulmonary F. tularensis challenge. AB - Neutrophils form the first line of defense during infection and are indispensable in this function. The neutrophil elastase is a key effector molecule of the innate immune system with potent antimicrobial activity against Gram-negative bacteria, spirochaetes, and fungi. However, the release of neutrophil elastase during bacterial infection must be checked otherwise its release in the extracellular milieu will result in damage to surrounding tissues. Alpha-1 antitrypsin is a small glycoprotein clade A serpine serine protease inhibitor and has been shown to increase in humans following bacterial and viral infection. Francisella tularensis is a Gram-negative facultative intracellular bacterium and the causative agent of tularemia. Type A strains are the most virulent with an infectious dose as low as 10 colony forming units and a mortality rate of 30-60% among untreated cases of pneumonic tularemia. We report here significant reduction of this major inhibitor of the neutrophil elastase in plasma of F. tularensis LVS and F. tularensis (type A) SCHU S4 infected animals following pulmonary challenge. Associated with an imbalance of protease-antiprotease function at the alveolar level in lungs of infected animals, increased elastase activity was observed in lung lavage fluids accompanied by decrease lung function, i.e., loss of lung elastance with concomitant increase of pulmonary hysteresivity. Consistent with a competent acute phase response following F. tularensis LVS and F. tularensis (type A) SCHU S4 pulmonary challenge and proposed up-regulation of plasma haptoglobin during the course of the acute phase reaction, haptoglobin was observed significantly increased. These data suggest that unchecked neutrophil serine protease activity may arise from F. tularensis targeted reduction of plasma alpha(1)-antitrysin promoting lung tissue damage facilitating increased dissemination of this bacterium in infected animals. PMID- 22919588 TI - Ehrlichia chaffeensis tandem repeat proteins and Ank200 are type 1 secretion system substrates related to the repeats-in-toxin exoprotein family. AB - Ehrlichia chaffeensis has type 1 and 4 secretion systems (T1SS and T4SS), but the substrates have not been identified. Potential substrates include secreted tandem repeat protein (TRP) 47, TRP120, and TRP32, and the ankyrin repeat protein, Ank200, that are involved in molecular host-pathogen interactions including DNA binding and a network of protein-protein interactions with host targets associated with signaling, transcriptional regulation, vesicle trafficking, and apoptosis. In this study we report that E. chaffeensis TRP47, TRP32, TRP120, and Ank200 were not secreted in the Agrobacterium tumefaciens Cre recombinase reporter assay routinely used to identify T4SS substrates. In contrast, all TRPs and the Ank200 proteins were secreted by the Escherichia coli complemented with the hemolysin secretion system (T1SS), and secretion was reduced in a T1SS mutant (DeltaTolC), demonstrating that these proteins are T1SS substrates. Moreover, T1SS secretion signals were identified in the C-terminal domains of the TRPs and Ank200, and a detailed bioinformatic analysis of E. chaffeensis TRPs and Ank200 revealed features consistent with those described in the repeats-in-toxins (RTX) family of exoproteins, including glycine- and aspartate-rich tandem repeats, homology with ATP-transporters, a non-cleavable C-terminal T1SS signal, acidic pIs, and functions consistent with other T1SS substrates. Using a heterologous E. coli T1SS, this investigation has identified the first Ehrlichia T1SS substrates supporting the conclusion that the T1SS and corresponding substrates are involved in molecular host-pathogen interactions that contribute to Ehrlichia pathobiology. Further investigation of the relationship between Ehrlichia TRPs, Ank200, and the RTX exoprotein family may lead to a greater understanding of the importance of T1SS substrates and specific functions of T1SS in the pathobiology of obligately intracellular bacteria. PMID- 22919587 TI - The role of microRNAs in Helicobacter pylori pathogenesis and gastric carcinogenesis. AB - Gastric carcinogenesis is a multistep process orchestrated by aberrancies in the genetic and epigenetic regulation of oncogenes and tumor suppressor genes. Chronic infection with Helicobacter pylori is the strongest known risk factor for the development of gastric cancer. H. pylori expresses a spectrum of virulence factors that dysregulate host intracellular signaling pathways that lower the threshold for neoplastic transformation. In addition to bacterial determinants, numerous host and environmental factors increase the risk of gastric carcinogenesis. Recent discoveries have shed new light on the involvement of microRNAs (miRNAs) in gastric carcinogenesis. miRNAs represent an abundant class of small, non-coding RNAs involved in global post-transcriptional regulation and, consequently, play an integral role at multiple steps in carcinogenesis, including cell cycle progression, proliferation, apoptosis, invasion, and metastasis. Expression levels of miRNAs are frequently altered in malignancies, where they function as either oncogenic miRNAs or tumor suppressor miRNAs. This review focuses on miRNAs dysregulated by H. pylori and potential etiologic roles they play in H. pylori-mediated gastric carcinogenesis. PMID- 22919589 TI - The emergence of severe pulmonary hemorrhagic leptospirosis: questions to consider. AB - Since the 1980s, the incidence of severe pulmonary hemorrhage caused by Leptospira spp. infection has increased. The mild, non-specific symptoms or the more classical form of severe disease with hepatorenal manifestations, Weil's syndrome, predominate world-wide. However, several regions of the world have seen increases in numbers of patients with pulmonary hemorrhage attributed to leptospirosis. The reasons behind the emergence of this syndrome, which carries a high mortality rate, are not known. Several avenues for future research may shed light on the mechanisms involved in development of pulmonary hemorrhage, and inform targeted therapeutics to improve outcomes. Possibilities to consider include: (1) emergence of new bacterial strains, (2) acquisition of virulence traits by strains in the endemic regions, (3) changes in underlying health of the affected human populations, and (4) increased recognition of the syndrome and better record keeping by the medical and veterinary communities. Determining the causes of emerging clinical manifestations presents challenges and opportunities for potentially life-saving research into the pathogenesis of a number of infectious diseases, including leptospirosis. PMID- 22919590 TI - Host evasion by Burkholderia cenocepacia. AB - Burkholderia cenocepacia is an opportunistic respiratory pathogen of individuals with cystic fibrosis (CF). Some strains of B. cenocepacia are highly transmissible and resistant to almost all antibiotics. Approximately one-third of B. cenocepacia infected CF patients go on to develop fatal "cepacia syndrome." During the last two decades, substantial progress has been made with regards to evasion of host innate defense mechanisms by B. cenocepacia. Almost all strains of B. cenocepacia have the capacity to survive and replicate intracellularly in both airway epithelial cells and macrophages, which are primary sentinels of the lung and play a pivotal role in clearance of infecting bacteria. Those strains of B. cenocepacia, which express both cable pili and the associated 22 kDa adhesin are also capable of transmigrating across airway epithelium and persist in mouse models of infection. In this review, we will discuss how this type of interaction between B. cenocepacia and host may lead to persistence of bacteria as well as lung inflammation in CF patients. PMID- 22919591 TI - Leishmania exosomes deliver preemptive strikes to create an environment permissive for early infection. AB - Herein, we review evidence supporting a role for Leishmania exosomes during early infection. We suggest a model in which Leishmania secreted microvesicles released into the extracellular milieu deliver effector cargo to host target cells. This cargo mediates immunosuppression and functionally primes host cells for Leishmania invasion. Leishmania ssp. release microvesicles and the amount of vesicle release and the specific protein cargo of the vesicles is sensitive to changes in environmental conditions that mimic infection. Leishmania exosomes influence the phenotype of treated immune cells. For example, wild-type (WT) exosomes attenuate interferon-gamma-induced pro-inflammatory cytokine production (TNF-alpha) by Leishmania-infected monocytes while conversely enhancing production of the anti-inflammatory cytokine IL-10. The Leishmania proteins GP63 and elongation factor-1alpha (EF-1alpha) are found in secreted vesicles and are likely important effectors responsible for these changes in phenotype. GP63 and EF-1alpha access host cell cytosol and activate multiple host protein-tyrosine phosphatases (PTPs). Activation of these PTPs negatively regulates interferon gamma signaling and this prevents effective expression of the macrophage microbicidal arsenal, including TNF-alpha and nitric oxide. In addition to changing macrophage phenotype, WT vesicles dampen the immune response of monocyte derived dendritic cells and CD4+ T lymphocytes. This capacity is lost when the protein cargo of the vesicles is modified, specifically when the amount of GP63 and EF-1alpha in the vesicles is reduced. It appears that exosome delivery of effector proteins results in activation of host PTPs and the negative regulatory effects of the latter creates a pro-parasitic environment. The data suggest that Leishmania exosomes secreted upon initial infection are capable of delivering effector cargo to naive target cells wherein the cargo primes host cells for infection by interfering with host cell signaling pathways. PMID- 22919592 TI - The promise of bacteriophage therapy for Burkholderia cepacia complex respiratory infections. AB - In recent times, increased attention has been given to evaluating the efficacy of phage therapy, especially in scenarios where the bacterial infectious agent of interest is highly antibiotic resistant. In this regard, phage therapy is especially applicable to infections caused by the Burkholderia cepacia complex (BCC) since members of the BCC are antibiotic pan-resistant. Current studies in BCC phage therapy are unique from many other avenues of phage therapy research in that the investigation is not only comprised of phage isolation, in vitro phage characterization and assessment of in vivo infection model efficacy, but also adapting aerosol drug delivery techniques to aerosol phage formulation delivery and storage. PMID- 22919593 TI - Antigen-specific acquired immunity in human brucellosis: implications for diagnosis, prognosis, and vaccine development. AB - Brucella spp., are Gram negative bacteria that cause disease by growing within monocyte/macrophage lineage cells. Clinical manifestations of brucellosis are immune mediated, not due to bacterial virulence factors. Acquired immunity to brucellosis has been studied through observations of naturally infected hosts (cattle, goats), mouse models (mice), and human infection. Even though Brucella spp. are known for producing mechanisms that evade the immune system, cell mediated immune responses drive the clinical manifestations of human disease after exposure to Brucella species, as high antibody responses are not associated with protective immunity. The precise mechanisms by which cell-mediated immune responses confer protection or lead to disease manifestations remain undefined. Descriptive studies of immune responses in human brucellosis show that TH(1) (interferon-gamma-producing T cells) are associated with dominant immune responses, findings consistent with animal studies. Whether these T cell responses are protective, or determine the different clinical responses associated with brucellosis is unknown, especially with regard to undulant fever manifestations, relapsing disease, or are associated with responses to distinct sets of Brucella spp. antigens are unknown. Few data regarding T cell responses in terms of specific recognition of Brucella spp. protein antigens and peptidic epitopes, either by CD4+ or CD8+ T cells, have been identified in human brucellosis patients. Additionally because current attenuated Brucella vaccines used in animals cause human disease, there is a true need for a recombinant protein subunit vaccine for human brucellosis, as well as for improved diagnostics in terms of prognosis and identification of unusual forms of brucellosis. This review will focus on current understandings of antigen-specific immune responses induced Brucella peptidic epitopes that has promise for yielding new insights into vaccine and diagnostics development, and for understanding pathogenetic mechanisms of human brucellosis. PMID- 22919594 TI - Analyses of Brucella pathogenesis, host immunity, and vaccine targets using systems biology and bioinformatics. AB - Brucella is a Gram-negative, facultative intracellular bacterium that causes zoonotic brucellosis in humans and various animals. Out of 10 classified Brucella species, B. melitensis, B. abortus, B. suis, and B. canis are pathogenic to humans. In the past decade, the mechanisms of Brucella pathogenesis and host immunity have been extensively investigated using the cutting edge systems biology and bioinformatics approaches. This article provides a comprehensive review of the applications of Omics (including genomics, transcriptomics, and proteomics) and bioinformatics technologies for the analysis of Brucella pathogenesis, host immune responses, and vaccine targets. Based on more than 30 sequenced Brucella genomes, comparative genomics is able to identify gene variations among Brucella strains that help to explain host specificity and virulence differences among Brucella species. Diverse transcriptomics and proteomics gene expression studies have been conducted to analyze gene expression profiles of wild type Brucella strains and mutants under different laboratory conditions. High throughput Omics analyses of host responses to infections with virulent or attenuated Brucella strains have been focused on responses by mouse and cattle macrophages, bovine trophoblastic cells, mouse and boar splenocytes, and ram buffy coat. Differential serum responses in humans and rams to Brucella infections have been analyzed using high throughput serum antibody screening technology. The Vaxign reverse vaccinology has been used to predict many Brucella vaccine targets. More than 180 Brucella virulence factors and their gene interaction networks have been identified using advanced literature mining methods. The recent development of community-based Vaccine Ontology and Brucellosis Ontology provides an efficient way for Brucella data integration, exchange, and computer-assisted automated reasoning. PMID- 22919596 TI - Campylobacter concisus - A new player in intestinal disease. AB - Over the last decade Campylobacter concisus, a highly fastidious member of the Campylobacter genus has been described as an emergent pathogen of the human intestinal tract. Historically, C. concisus was associated with the human oral cavity and has been linked with periodontal lesions, including gingivitis and periodontitis, although currently its role as an oral pathogen remains contentious. Evidence to support the role of C. concisus in acute intestinal disease has come from studies that have detected or isolated C. concisus as sole pathogen in fecal samples from diarrheic patients. C. concisus has also been associated with chronic intestinal disease, its prevalence being significantly higher in children with newly diagnosed Crohn's disease (CD) and adults with ulcerative colitis than in controls. Further C. concisus has been isolated from biopsy specimens of patients with CD. While such studies support the role of C. concisus as an intestinal pathogen, its isolation from healthy individuals, and failure of some studies to show a significant difference in C. concisus prevalence in subjects with diarrhea and healthy controls has raised contention as to its role in intestinal disease. Such findings could argue against the role of C. concisus in intestinal disease, however, the fact that C. concisus strains are genetically diverse raises the possibility that differences exist in their pathogenic potential. Evidence to support this view comes from studies showing strain specific differences in the ability of C. concisus to attach to and invade cells and produce virulence factors, including toxins and hemolytic phospholipase A. Further, sequencing of the genome of a C. concisus strain isolated from a child with CD (UNSWCD) and comparison of this with the only other fully sequenced strain (BAA-1457) would suggest that major differences exist in the genetic make up of this species which could explain different outcomes of C. concisus infection. PMID- 22919595 TI - Brucella ceti and brucellosis in cetaceans. AB - Since the first case of brucellosis detected in a dolphin aborted fetus, an increasing number of Brucella ceti isolates has been reported in members of the two suborders of cetaceans: Mysticeti and Odontoceti. Serological surveys have shown that cetacean brucellosis may be distributed worldwide in the oceans. Although all B. ceti isolates have been included within the same species, three different groups have been recognized according to their preferred host, bacteriological properties, and distinct genetic traits: B. ceti dolphin type, B. ceti porpoise type, and B. ceti human type. It seems that B. ceti porpoise type is more closely related to B. ceti human isolates and B. pinnipedialis group, while B. ceti dolphin type seems ancestral to them. Based on comparative phylogenetic analysis, it is feasible that the B. ceti ancestor radiated in a terrestrial artiodactyl host close to the Raoellidae family about 58 million years ago. The more likely mode of transmission of B. ceti seems to be through sexual intercourse, maternal feeding, aborted fetuses, placental tissues, vertical transmission from mother to the fetus or through fish or helminth reservoirs. The B. ceti dolphin and porpoise types seem to display variable virulence in land animal models and low infectivity for humans. However, brucellosis in some dolphins and porpoises has been demonstrated to be a severe chronic disease, displaying significant clinical and pathological signs related to abortions, male infertility, neurobrucellosis, cardiopathies, bone and skin lesions, strandings, and death. PMID- 22919597 TI - Nutrient acquisition and metabolism by Campylobacter jejuni. AB - The gastrointestinal pathogen Campylobacter jejuni is able to colonize numerous different hosts and compete against the gut microbiota. To do this, it must be able to efficiently acquire sufficient nutrients from its environment to support its survival and rapid growth in the intestine. However, despite almost 50 years of research, many aspects as to how C. jejuni accomplishes this feat remain poorly understood. C. jejuni lacks many of the common metabolic pathways necessary for the use of glucose, galactose, or other carbohydrates upon which most other microbes thrive. It does however make efficient use of citric acid cycle intermediates and various amino acids. C. jejuni readily uses the amino acids aspartate, glutamate, serine, and proline, with certain strains also possessing additional pathways allowing for the use of glutamine and asparagine. More recent work has revealed that some C. jejuni strains can metabolize the sugar l-fucose. This finding has upset years of dogma that C. jejuni is an asaccharolytic organism. C. jejuni also possesses diverse mechanisms for the acquisition of various transition metals that are required for metabolic activities. In particular, iron acquisition is critical for the formation of iron sulfur complexes. C. jejuni is also unique in possessing both molybdate and tungsten cofactored proteins and thus has an unusual regulatory scheme for these metals. Together these various metabolic and acquisition pathways help C. jejuni to compete and thrive in wide variety of hosts and environments. PMID- 22919598 TI - Staphylococcus aureus temperate bacteriophage: carriage and horizontal gene transfer is lineage associated. AB - Staphylococcus aureus is a major cause of human and animal infections. Bacteriophage are a class of mobile genetic element (MGE) that carry virulence genes and disseminate them horizontally, including Panton-Valentine leukocidin (PVL), the immune evasion cluster (IEC) associated with human specificity, and enterotoxin A the major toxin associated with food poisoning. S. aureus isolates group into major clonal complex (CC) lineages that largely evolve independently due to possession of different restriction-modification (RM) systems. We aimed to better understand the horizontal and vertical transmission dynamics of virulence and resistance genes by bacteriophage by using (i) bioinformatic approaches to analyze bacteriophage genomes from the first 79 sequenced S. aureus isolates and (ii) S. aureus microarrays to analyze the distribution of bacteriophage and virulence genes in S. aureus isolates from a broader range of lineages. The distribution of eight bacteriophage families was highly variable but lineage associated. Nevertheless, there was evidence of frequent acquisition and loss and not just vertical transmission. Most bacteriophage genes were dispensable, and extensive mosaicism was seen. Surprisingly, virulence genes were tightly associated with specific phage families. This data suggests S. aureus bacteriophage evolve rapidly, and the horizontal gene transfer (HGT) of virulence genes encoded by bacteriophage is restricted by bacteriophage family and the lineage of the host bacterium, delaying the evolution of fully resistant and virulent strains. PMID- 22919599 TI - Campylobacter polysaccharide capsules: virulence and vaccines. AB - Campylobacter jejuni remains a major cause of bacterial diarrhea worldwide and is associated with numerous sequelae, including Guillain Barre Syndrome, inflammatory bowel disease, reactive arthritis, and irritable bowel syndrome. C. jejuni is unusual for an intestinal pathogen in its ability to coat its surface with a polysaccharide capsule (CPS). These capsular polysaccharides vary in sugar composition and linkage, especially those involving heptoses of unusual configuration and O-methyl phosphoramidate linkages. This structural diversity is consistent with CPS being the major serodeterminant of the Penner scheme, of which there are 47 C. jejuni serotypes. Both CPS expression and expression of modifications are subject to phase variation by slip strand mismatch repair. Although capsules are virulence factors for other pathogens, the role of CPS in C. jejuni disease has not been well defined beyond descriptive studies demonstrating a role in serum resistance and for diarrhea in a ferret model of disease. However, perhaps the most compelling evidence for a role in pathogenesis are data that CPS conjugate vaccines protect against diarrheal disease in non human primates. A CPS conjugate vaccine approach against this pathogen is intriguing, but several questions need to be addressed, including the valency of CPS types required for an effective vaccine. There have been numerous studies of prevalence of CPS serotypes in the developed world, but few studies from developing countries where the disease incidence is higher. The complexity and cost of Penner serotyping has limited its usefulness, and a recently developed multiplex PCR method for determination of capsule type offers the potential of a more rapid and affordable method. Comparative studies have shown a strong correlation of the two methods and studies are beginning to ascertain CPS-type distribution worldwide, as well as examination of correlation of severity of illness with specific CPS types. PMID- 22919600 TI - Development of a multiplex PCR assay for detection of Shiga toxin-producing Escherichia coli, enterohemorrhagic E. coli, and enteropathogenic E. coli strains. AB - Escherichia coli O157:H7 and other pathogenic E. coli strains are enteric pathogens associated with food safety threats and which remain a significant cause of morbidity and mortality worldwide. In the current study, we investigated whether enterohemorrhagic E. coli (EHEC), Shiga toxin-producing E. coli (STEC), and enteropathogenic E. coli (EPEC) strains can be rapidly and specifically differentiated with multiplex PCR (mPCR) utilizing selected biomarkers associated with each strain's respective virulence genotype. Primers were designed to amplify multiple intimin (eae) and long polar fimbriae (lpfA) variants, the bundle-forming pilus gene bfpA, and the Shiga toxin-encoding genes stx1 and stx2. We demonstrated consistent amplification of genes specific to the prototype EHEC O157:H7 EDL933 (lpfA1-3, lpfA2-2, stx1, stx2, and eae-gamma) and EPEC O127:H6 E2348/69 (eae-alpha, lpfA1-1, and bfpA) strains using the optimized mPCR protocol with purified genomic DNA (gDNA). A screen of gDNA from isolates in a diarrheagenic E. coli collection revealed that the mPCR assay was successful in predicting the correct pathotype of EPEC and EHEC clones grouped in the distinctive phylogenetic disease clusters EPEC1 and EHEC1, and was able to differentiate EHEC1 from EHEC2 clusters. The assay detection threshold was 2 * 10(4) CFU per PCR reaction for EHEC and EPEC. mPCR was also used to screen Argentinean clinical samples from hemolytic uremic syndrome and diarrheal patients, resulting in 91% sensitivity and 84% specificity when compared to established molecular diagnostic procedures. In conclusion, our mPCR methodology permitted differentiation of EPEC, STEC and EHEC strains from other pathogenic E. coli; therefore, the assay becomes an additional tool for rapid diagnosis of these organisms. PMID- 22919601 TI - Glycoconjugates play a key role in Campylobacter jejuni Infection: interactions between host and pathogen. AB - Glycan based interactions between host and pathogen are critical in many bacterial and viral diseases. Glycan interactions range from initial receptor based adherence to protecting the infective agent from the host's immune response through molecular mimicry. Campylobacter jejuni is an ideal model for studying the role of glycans in host-pathogen interactions, as well as the role of bacterial surface glycoconjugates in infection. Using glycan array analysis, C. jejuni has been shown to interact with a wide range of host glycoconjugates. Mannose and sialic acid residues appear to play a role in initial interactions between host and pathogen following environmental exposure, whereas fucose and galactose based interactions are likely to be required for prolonged colonization. Other studies have highlighted potential decoy receptor type interactions between host's intestinal mucins and C. jejuni, demonstrating the importance of host glycoproteins as defense against C. jejuni infection as well as the role for glycoconjugates found in human breast milk in protection of breast feeding infants from infection with C. jejuni. C. jejuni can produce N- and O-linked glycoproteins, capsular polysaccharide (CPS) and/or lipooligosaccharide (LOS) which results in C. jejuni presenting its own diverse sugar coated displays on the cell surface. Bacterial glycans play an important and versatile role in infection and disease. Of these, the best understood is the molecular mimicry of human gangliosides presented by C. jejuni's LOS and its link to the onset of autoimmune neuropathies such as the Guillain Barre syndrome (GBS). However, the role of glycoconjugates presented by C. jejuni extends beyond expression of sialylated ganglioside structures involved in initiation of GBS. Expression of surface glycans by C. jejuni may also relate to the ability of this organism to interact with the glycoproteins for initial host-pathogen interactions and continued infectivity. PMID- 22919602 TI - The immunomodulatory properties of Helicobacter pylori confer protection against allergic and chronic inflammatory disorders. AB - Chronic infection with the gastric bacterial pathogen Helicobacter pylori causes gastritis and predisposes carriers to a high risk of developing gastric and duodenal ulcers, gastric cancer, and gastric lymphoma, but has also recently been shown to protect against certain allergic and chronic inflammatory disorders. The immunomodulatory properties that allow the bacteria to persist for decades in infected individuals in the face of a vigorous, yet ultimately non-protective, innate, and adaptive immune response may at the same time confer protection against allergies, asthma, and inflammatory bowel diseases. Experimental evidence from mouse models suggests that H. pylori has evolved to skew the adaptive immune response toward immune tolerance rather than immunity, which promotes persistent infection on the one hand, and inhibits auto-aggressive and allergic T-cell responses on the other. Regulatory T-cells mediating peripheral immune tolerance have emerged as key cellular players in facilitating persistent infection as well as protection from allergies, in both observational studies in humans and experimental work in mice. Recent data suggest that H. pylori actively targets dendritic cells to promote tolerance induction. The findings discussed in this review raise the possibility of harnessing the immunomodulatory properties of H. pylori for the prevention and treatment of allergic and auto-immune diseases, and also provide new insights relevant for H. pylori-specific vaccine development. PMID- 22919603 TI - Phase variable expression of capsular polysaccharide modifications allows Campylobacter jejuni to avoid bacteriophage infection in chickens. AB - Bacteriophages are estimated to be the most abundant entities on earth and can be found in every niche where their bacterial hosts reside. The initial interaction between phages and Campylobacter jejuni, a common colonizer of poultry intestines and a major source of foodborne bacterial gastroenteritis in humans, is not well understood. Recently, we isolated and characterized a phage F336 resistant variant of C. jejuni NCTC11168 called 11168R. Comparisons of 11168R with the wildtype lead to the identification of a novel phage receptor, the phase variable O-methyl phosphoramidate (MeOPN) moiety of the C. jejuni capsular polysaccharide (CPS). In this study we demonstrate that the 11168R strain has gained cross resistance to four other phages in our collection (F198, F287, F303, and F326). The reduced plaquing efficiencies suggested that MeOPN is recognized as a receptor by several phages infecting C. jejuni. To further explore the role of CPS modifications in C. jejuni phage recognition and infectivity, we tested the ability of F198, F287, F303, F326, and F336 to infect different CPS variants of NCTC11168, including defined CPS mutants. These strains were characterized by high-resolution magic angle spinning NMR spectroscopy. We found that in addition to MeOPN, the phase variable 3-O-Me and 6-O-Me groups of the NCTC11168 CPS structure may influence the plaquing efficiencies of the phages. Furthermore, co infection of chickens with both C. jejuni NCTC11168 and phage F336 resulted in selection of resistant C. jejuni bacteria, which either lack MeOPN or gain 6-O-Me groups on their surface, demonstrating that resistance can be acquired in vivo. In summary, we have shown that phase variable CPS structures modulate phage infectivity in C. jejuni and suggest that the constant phage predation in the avian gut selects for changes in these structures leading to a continuing phage host co-evolution. PMID- 22919605 TI - Mechanism of H. pylori intracellular entry: an in vitro study. AB - The majority of Helicobacter pylori reside on gastric epithelial cell surfaces and in the overlying mucus, but a small fraction of H. pylori enter host epithelial and immune cells. To explore the role of the nudA invasin in host cell entry, a DeltanudA deletion derivative of strain J99 was constructed and transformants were verified by PCR and by fluorescence in situ hybridization. AGS cells were inoculated with either wild type (WT) strain J99 or its DeltanudA mutant to determine the fraction of bacteria that were bound to the cells and were present inside these cells using the gentamicin protection assay. We observed no significant difference between either the density of H. pylori bound to AGS cell membranes or the density of intracellular H. pylori. To further explore this finding, separate chambers of each culture were fixed in glutaraldehyde for transmission electron microscopy (TEM) and immunogold TEM. This addition to the "classical" gentamicin assay demonstrated that there were significantly more intracellular, and fewer membrane-bound, H. pylori in WT infected AGS cells than in DeltanudA allele infected cells. Thus, the sum of intracellular and membrane-bound H. pylori was similar in the two groups. Since no other similar TEM study has been performed, it is at present unknown whether our observations can be reproduced by others Taken together however, our observations suggest that the "classical" gentamicin protection assay is not sufficiently sensitive to analyze H. pylori cell entry and that the addition of TEM to the test demonstrates that nudA plays a role in H. pylori entry into AGS cells in vitro. In addition, deletion of the invasin gene appears to limit H. pylori to the AGS cell surface, where it may be partly protected against gentamicin. In contrast, this specific environment may render H. pylori more vulnerable to host defense and therapeutic intervention, and less prone to trigger normal immune, carcinogenic, and other developmental response pathways. PMID- 22919604 TI - Staphylococcus aureus hemolysins, bi-component leukocidins, and cytolytic peptides: a redundant arsenal of membrane-damaging virulence factors? AB - One key aspect of the virulence of Staphylococcus aureus lies in its ability to target the host cell membrane with a large number of membrane-damaging toxins and peptides. In this review, we describe the hemolysins, the bi-component leukocidins (which include the Panton Valentine leukocidin, LukAB/GH, and LukED), and the cytolytic peptides (phenol soluble modulins). While at first glance, all of these factors might appear redundant, it is now clear that some of these factors play specific roles in certain S. aureus life stages and diseases or target specific cell types or species. In this review, we present an update of the literature on toxin receptors and their cell type and species specificities. Furthermore, we review epidemiological studies and animal models illustrating the role of these membrane-damaging factors in various diseases. Finally, we emphasize the interplay of these factors with the host immune system and highlight all their non-lytic functions. PMID- 22919606 TI - Transcriptome complexity and riboregulation in the human pathogen Helicobacter pylori. AB - The Gram-negative Epsilonproteobacterium Helicobacter pylori is considered as one of the major human pathogens and many studies have focused on its virulence mechanisms as well as genomic diversity. In contrast, only very little is known about post-transcriptional regulation and small regulatory RNAs (sRNAs) in this spiral-shaped microaerophilic bacterium. Considering the absence of the common RNA chaperone Hfq, which is a key-player in post-transcriptional regulation in enterobacteria, H. pylori was even regarded as an organism without riboregulation. However, analysis of the H. pylori primary transcriptome using RNA-seq revealed a very complex transcriptional output from its small genome. Furthermore, the identification of a wealth of sRNAs as well as massive antisense transcription indicates that H. pylori uses riboregulation for its gene expression control. The ongoing functional characterization of sRNAs along with the identification of associated RNA binding proteins will help to understand their potential roles in Helicobacter virulence and stress response. Moreover, research on riboregulation in H. pylori will provide new insights into its virulence mechanisms and will also help to shed light on post-transcriptional regulation in other Epsilonproteobacteria, including widespread and emerging pathogens such as Campylobacter. PMID- 22919607 TI - Defense and adaptation: the complex inter-relationship between Campylobacter jejuni and mucus. AB - Mucus colonization is an essential early step toward establishing successful infection and disease by mucosal pathogens. There is an emerging literature implicating specific mucin sub-types and mucin modifications in protecting the host from Campylobacter jejuni infection. However, mucosal pathogens have evolved sophisticated mechanisms to breach the mucus layer and C. jejuni in particular appears to harbor specific adaptations to better colonize intestinal mucus. For example, components of mucus are chemotactic for C. jejuni and the rheological properties of mucus promote motility of the organism. Furthermore, recent studies demonstrate that mucins modulate the pathogenicity of C. jejuni in a species specific manner and likely help determine whether these bacteria become pathogenic (as in humans), or adopt a commensal mode of existence (as in chickens and other animals). This review focuses on recent advances in understanding the complex interplay between C. jejuni and components of the mucus layer. PMID- 22919608 TI - Inferring reasons for the failure of Staphylococcus aureus vaccines in clinical trials. PMID- 22919609 TI - Alterations in Helicobacter pylori triggered by contact with gastric epithelial cells. AB - Helicobacter pylori lives within the mucus layer of the human stomach, in close proximity to gastric epithelial cells. While a great deal is known about the effects of H. pylori on human cells and the specific bacterial products that mediate these effects, relatively little work has been done to investigate alterations in H. pylori that may be triggered by bacterial contact with human cells. In this review, we discuss the spectrum of changes in bacterial physiology and morphology that occur when H. pylori is in contact with gastric epithelial cells. Several studies have reported that cell contact causes alterations in H. pylori gene transcription. In addition, H. pylori contact with gastric epithelial cells promotes the formation of pilus-like structures at the bacteria-host cell interface. The formation of these structures requires multiple genes in the cag pathogenicity island, and these structures are proposed to have an important role in the type IV secretion system-dependent process through which CagA enters host cells. Finally, H. pylori contact with epithelial cells can promote bacterial replication and the formation of microcolonies, phenomena that are facilitated by the acquisition of iron and other nutrients from infected cells. In summary, the gastric epithelial cell surface represents an important niche for H. pylori, and upon entry into this niche, the bacteria alter their behavior in a manner that optimizes bacterial proliferation and persistent colonization of the host. PMID- 22919610 TI - Comparison of Staphylococcus aureus strains for ability to cause infective endocarditis and lethal sepsis in rabbits. AB - Staphylococcus aureus is a major cause of infective endocarditis (IE) and sepsis. Both methicillin-resistant (MRSA) and methicillin-sensitive (MSSA) strains cause these illnesses. Common S. aureus strains include pulsed-field gel electrophoresis (PFGE) types USA200, 300, and 400 types where we hypothesize that secreted virulence factors contribute to both IE and sepsis. Rabbit cardiac physiology is considered similar to humans, and rabbits exhibit susceptibility to S. aureus superantigens (SAgs) and cytolysins. As such, rabbits are an excellent model for studying IE and sepsis, which over the course of four days develop IE vegetations and/or fatal septicemia. We examined the ability of MRSA and MSSA strains (4 USA200, 2 USA300, 2 USA400, and three additional common strains, FRI1169, Newman, and COL) to cause vegetations and lethal sepsis in rabbits. USA200, TSST-1(+) strains that produce only low amounts of alpha-toxin, exhibited modest LD(50) in sepsis (1 * 10(8) - 5 * 10(8)) colony-forming units (CFUs), and 3/4 caused significant IE. USA200 strain MNPE, which produces high-levels of alpha-toxin, was both highly lethal (LD(50) 5 * 10(6) CFUs) and effective in causing IE. In contrast, USA300 strains were highly effective in causing lethal sepsis (LD(50)s 1 * 10(6) and 5 * 10(7) CFUs) but were minimally capable of causing IE. Strain Newman, which is phylogenetically related to USA300 strains, was not highly lethal (LD(50) of 2 * 10(9) CFUs) and was effective in causing IE. USA400 strains were both highly lethal (LD(50)s of 1 * 10(7) and 5 * 10(7) CFUs) and highly effective causes of IE. The menstrual TSS isolate FRI1169, that is TSST-1(+), produces high-levels of alpha-toxin, but is not USA200, was both highly lethal and effective in causing IE. Additional studies showed that phenol soluble modulins (PSMs) produced by FRI1169 were important for sepsis but did not contribute to IE. Our studies show that these clonal groups of S. aureus differ in abilities to cause IE and lethal sepsis and suggest that secreted virulence factors, including SAgs and cytolysins, account for some of these differences. PMID- 22919611 TI - Nontypeable Haemophilus influenzae: the role of N-acetyl-5-neuraminic acid in biology. AB - Nontypeable Haemophilus influenzae (NTHi) is an exclusive human pathogen, which has evolved a number of unique mechanisms to survive within the human environment. An important part of this is the ability of the organism to take up and incorporate sialic acid into its surface structures. This protects the organism against host adaptive and innate immune factor as well as serving as a mechanism for sustaining itself within biofilms. Recent evidence suggests that this also may be the source of the evolution of human antibodies to non-human sialic acid structures, which can lead to inflammation in the host. In very rare instances, evolution of antibodies to sialylated lipooligosaccharide (LOS) mimics of human antigens can result in autoimmune disease. PMID- 22919612 TI - The 30th anniversary of Campylobacter, Helicobacter, and Related Organisms workshops-what have we learned in three decades? AB - As we commemorate the 30(th) anniversary of the Campylobacter, Helicobacter, and Related Organisms (CHRO) workshops with this special Frontiers edition, we look back upon three decades of research and provide some highlights from the 16(th) International CHRO meeting. Although Theodor Escherich himself provided drawings of campylobacters back in the 1880s, Campylobacter jejuni was not identified until the 1950s. Helicobacter pylori was first described to be the causative agent of stomach ulcers at a CHRO meeting by Barry Marshall and Robin Warren-who later received the Nobel Prize for their findings that bacteria could cause diseases previously believed to be caused by human factors. Now, several genome sequences for campylobacters, helicobacters, and related organisms are available and we have moved into an era examining the intersection between host microbial ecology and pathogen infection. Both pioneers and new investigators in the CHRO research field continue to obtain "unexpected results" demonstrating that campylobacters and helicobacters do not follow classic paradigms of other well characterized gastrointestinal pathogens and we are learning that there is a plethora of interesting related organisms beyond C. jejuni and H. pylori. This review summarizes recent discoveries in CHRO research and the exciting directions ahead. PMID- 22919613 TI - A fluoroquinolone resistance associated mutation in gyrA Affects DNA supercoiling in Campylobacter jejuni. AB - The prevalence of fluoroquinolone (FQ)-resistant Campylobacter has become a concern for public health. To facilitate the control of FQ-resistant (FQ(R)) Campylobacter, it is necessary to understand the impact of FQ(R) on the fitness of Campylobacter in its natural hosts as understanding fitness will help to determine and predict the persistence of FQ(R)Campylobacter. Previously it was shown that acquisition of resistance to FQ antimicrobials enhanced the in vivo fitness of FQ(R)Campylobacter. In this study, we confirmed the role of the Thr-86 Ile mutation in GyrA in modulating Campylobacter fitness by reverting the mutation to the wild-type (WT) allele, which resulted in the loss of the fitness advantage. Additionally, we determined if the resistance-conferring GyrA mutations alter the enzymatic function of the DNA gyrase. Recombinant WT gyrase and mutant gyrases with three different types of mutations (Thr-86-Ile, Thr-86 Lys, and Asp-90-Asn), which are associated with FQ(R) in Campylobacter, were generated in E. coli and compared for their supercoiling activities using an in vitro assay. The mutant gyrase with the Thr-86-Ile change showed a greatly reduced supercoiling activity compared with the WT gyrase, while other mutant gyrases did not show an altered supercoiling. Furthermore, we measured DNA supercoiling within Campylobacter cells using a reporter plasmid. Consistent with the results from the in vitro supercoiling assay, the FQ(R) mutant carrying the Thr-86-Ile change in GyrA showed much less DNA supercoiling than the WT strain and the mutant strains carrying other mutations. Together, these results indicate that the Thr-86-Ile mutation, which is predominant in clinical FQ(R)Campylobacter, modulates DNA supercoiling homeostasis in FQ(R)Campylobacter. PMID- 22919614 TI - LuxS and quorum-sensing in Campylobacter. AB - Several intercellular bacterial communication mechanisms have been identified in a broad range of bacterial species. These systems, collectively termed quorum sensing systems, have been demonstrated to play significant roles in a variety of bacterial processes including motility, biofilm formation, expression of virulence genes, and animal colonization. Campylobacter jejuni is known to possess a LuxS/ autoinducer-2 (AI-2) mediated system that have been partially characterized over the last decade. AI-2 is formed as a byproduct of the activated methyl recycling pathway, specifically by the LuxS enzyme. Previous work in our laboratory and that of others has demonstrated that this gene is involved in a variety of physiologic pathways of C. jejuni including motility, autoagglutination, cytolethal distending toxin (CDT) expression, flagellar expression, oxidative stress, and animal colonization. This review article will summarize the current research associated with LuxS in C. jejuni and will provide insights into the role of this system in the metabolism and intercellular communication of this organism. Additionally, the evidence for other quorum sensing pathways in Campylobacter will be discussed. PMID- 22919615 TI - Genome-scale approaches to identify genes essential for Haemophilus influenzae pathogenesis. AB - Haemophilus influenzae is a Gram-negative bacterium that has no identified natural niche outside of the human host. It primarily colonizes the nasopharyngeal mucosa in an asymptomatic mode, but has the ability to disseminate to other anatomical sites to cause otitis media, upper, and lower respiratory tract infections, septicemia, and meningitis. To persist in diverse environments the bacterium must exploit and utilize the nutrients and other resources available in these sites for optimal growth/survival. Recent evidence suggests that regulatory factors that direct such adaptations also control virulence determinants required to resist and evade immune clearance mechanisms. In this review, we describe the recent application of whole-genome approaches that together provide insight into distinct survival mechanisms of H. influenzae in the context of different sites of pathogenesis. PMID- 22919616 TI - Identification of genetic modifiers of CagA-induced epithelial disruption in Drosophila. AB - Helicobacter pylori strains containing the CagA protein are associated with high risk of gastric diseases including atrophic gastritis, peptic ulcers, and gastric cancer. CagA is injected into host cells via a Type IV secretion system where it activates growth factor-like signaling, disrupts cell-cell junctions, and perturbs host cell polarity. Using a transgenic Drosophila model, we have shown that CagA expression disrupts the morphogenesis of epithelial tissues such as the adult eye. Here we describe a genetic screen to identify modifiers of CagA induced eye defects. We determined that reducing the copy number of genes encoding components of signaling pathways known to be targeted by CagA, such as the epidermal growth factor receptor (EGFR), modified the CagA-induced eye phenotypes. In our screen of just over half the Drosophila genome, we discovered 12 genes that either suppressed or enhanced CagA's disruption of the eye epithelium. Included in this list are genes involved in epithelial integrity, intracellular trafficking, and signal transduction. We investigated the mechanism of one suppressor, encoding the epithelial polarity determinant and junction protein Coracle, which is homologous to the mammalian Protein 4.1. We found that loss of a single copy of coracle improved the organization and integrity of larval retinal epithelia expressing CagA, but did not alter CagA's localization to cell junctions. Loss of a single copy of the coracle antagonist crumbs enhanced CagA-associated disruption of the larval retinal epithelium, whereas overexpression of crumbs suppressed this phenotype. Collectively, these results point to new cellular pathways whose disruption by CagA are likely to contribute to H. pylori-associated disease pathology. PMID- 22919618 TI - The staphylococcal accessory regulator, SarA, is an RNA-binding protein that modulates the mRNA turnover properties of late-exponential and stationary phase Staphylococcus aureus cells. AB - The modulation of mRNA turnover is gaining recognition as a mechanism by which Staphylococcus aureus regulates gene expression, but the factors that orchestrate alterations in transcript degradation are poorly understood. In that regard, we previously found that 138 mRNA species, including transcripts coding for the virulence factors protein A (spa) and collagen-binding protein (cna), are stabilized in a sarA-dependent manner during exponential phase growth, suggesting that SarA directly or indirectly affects the RNA turnover properties of these transcripts. Herein, we expanded our characterization of the effects of sarA on mRNA turnover during late-exponential and stationary phases of growth. Results revealed that the locus affects the RNA degradation properties of cells during both growth phases. Further, using gel mobility shift assays and RIP-Chip, it was found that SarA protein is capable of binding mRNA species that it stabilizes both in vitro and within bacterial cells. Taken together, these results suggest that SarA post-transcriptionally regulates S. aureus gene expression in a manner that involves binding to and consequently altering the mRNA turnover properties of target transcripts. PMID- 22919617 TI - Host epithelial cell invasion by Campylobacter jejuni: trigger or zipper mechanism? AB - Campylobacter jejuni, a spiral-shaped Gram-negative pathogen, is a highly frequent cause of gastrointestinal foodborne illness in humans worldwide. Clinical outcome of C. jejuni infections ranges from mild to severe diarrheal disease, and some other complications including reactive arthritis and Guillain Barre syndrome. This review article highlights various C. jejuni pathogenicity factors, host cell determinants, and proposed signaling mechanisms involved in human host cell invasion and their potential role in the development of C. jejuni mediated disease. A model is presented which outlines the various important interactions of C. jejuni with the intestinal epithelium, and we discuss the pro's and con's for the "zipper" over the "trigger" mechanism of invasion. Future work should clarify the contradictory role of some previously identified factors, and should identify and characterize novel virulence determinants, which are crucial to provide fresh insights into the diversity of strategies employed by this pathogen to cause disease. PMID- 22919619 TI - Lateral gene transfers have polished animal genomes: lessons from nematodes. AB - It is now accepted that lateral gene transfers (LGT), have significantly contributed to the composition of bacterial genomes. The amplitude of the phenomenon is considered so high in prokaryotes that it challenges the traditional view of a binary hierarchical tree of life to correctly represent the evolutionary history of species. Given the plethora of transfers between prokaryotes, it is currently impossible to infer the last common ancestral gene set for any extant species. For this ensemble of reasons, it has been proposed that the Darwinian binary tree of life may be inappropriate to correctly reflect the actual relations between species, at least in prokaryotes. In contrast, the contribution of LGT to the composition of animal genomes is less documented. In the light of recent analyses that reported series of LGT events in nematodes, we discuss the importance of this phenomenon in the evolutionary history and in the current composition of an animal genome. Far from being neutral, it appears that besides having contributed to nematode genome contents, LGT have favored the emergence of important traits such as plant-parasitism. PMID- 22919620 TI - Toward a structural understanding of Clostridium difficile toxins A and B. AB - Clostridium difficile is a toxin-producing bacterium that is a frequent cause of hospital-acquired and antibiotic-associated diarrhea. The incidence, severity, and costs associated with C. difficile associated disease are substantial and increasing, making C. difficile a significant public health concern. The two primary toxins, TcdA and TcdB, disrupt host cell function by inactivating small GTPases that regulate the actin cytoskeleton. This review will discuss the role of these two toxins in pathogenesis and the structural and molecular mechanisms by which they intoxicate cells. A focus will be placed on recent publications highlighting mechanistic similarities and differences between TcdA, TcdB, and different TcdB variants. PMID- 22919622 TI - Polynucleotide phosphorylase has an impact on cell biology of Campylobacter jejuni. AB - Polynucleotide phosphorylase (PNPase), encoded by the pnp gene, is known to degrade mRNA, mediating post-transcriptional regulation and may affect cellular functions. The role of PNPase is pleiotropic. As orthologs of the two major ribonucleases (RNase E and RNase II) of Escherichia coli are missing in the Campylobacter jejuni genome, in the current study the focus has been on the C. jejuni ortholog of PNPase. The effect of PNPase mutation on C. jejuni phenotypes and proteome was investigated. The inactivation of the pnp gene reduced significantly the ability of C. jejuni to adhere and to invade Ht-29 cells. Moreover, the pnp mutant strain exhibited a decrease in C. jejuni swimming ability and chick colonization. To explain effects of PNPase on C. jejuni 81-176 phenotype, the proteome of the pnp mutant and parental strains were compared. Overall, little variation in protein production was observed. Despite the predicted role of PNPase in mRNA regulation, the pnp mutation did not induce profound proteomic changes suggesting that other ribonucleases in C. jejuni might ensure this biological function in the absence of PNPase. Nevertheless, synthesis of proteins which are involved in virulence (LuxS, PEB3), motility (N acetylneuraminic acid synthetase), stress-response (KatA, DnaK, Hsp90), and translation system (EF-Tu, EF-G) were modified in the pnp mutant strain suggesting a more specific role of PNPase in C. jejuni. In conclusion, PNPase deficiency induces limited but important consequences on C. jejuni biology that could explain swimming limitation, chick colonization delay, and the decrease of cell adhesion/invasion ability. PMID- 22919623 TI - The Campylobacter jejuni CiaC virulence protein is secreted from the flagellum and delivered to the cytosol of host cells. AB - Campylobacter jejuni is a leading cause of bacterial gastroenteritis worldwide. Acute C. jejuni-mediated disease (campylobacteriosis) involves C. jejuni invasion of host epithelial cells using adhesins (e.g., CadF and FlpA) and secreted proteins [e.g., the Campylobacter invasion antigens (Cia)]. The genes encoding the Cia proteins are up-regulated upon co-culture of C. jejuni with epithelial cells. One of the Cia proteins, CiaC, is required for maximal invasion of host cells by C. jejuni. Previous work has also revealed that CiaC is, in part, responsible for host cell cytoskeletal rearrangements that result in membrane ruffling. This study was performed to test the hypothesis that CiaC is delivered to the cytosol of host cells. To detect the delivery of CiaC into cultured epithelial cells, we used the adenylate cyclase domain (ACD) of Bordetella pertussis CyaA as a reporter. In this study, we found that export and delivery of the C. jejuni Cia proteins into human INT 407 epithelial cells required a functional flagellar hook complex composed of FlgE, FlgK, and FlgL. Assays performed with bacterial culture supernatants supported the hypothesis that CiaC delivery requires bacteria-host cell contact. We also found that CiaC was delivered to host cells by cell-associated (bound) bacteria, as judged by experiments performed with inhibitors that specifically target the cell signaling pathways utilized by C. jejuni for cell invasion. Interestingly, the C. jejuni flgL mutant, which is incapable of exporting and delivering the Cia proteins, did not induce INT 407 cell membrane ruffles. Complementation of the flgL mutant with plasmid-encoded flgL restored the motility and membrane ruffling. These data support the hypothesis that the C. jejuni Cia proteins, which are exported from the flagellum, are delivered to the cytosol of host cells. PMID- 22919624 TI - Identification of genetic loci that contribute to Campylobacter resistance to fowlicidin-1, a chicken host defense peptide. AB - Antimicrobial peptides (AMPs) are critical components of host defense limiting bacterial infections at the gastrointestinal mucosal surface. Bacterial pathogens have co-evolved with host innate immunity and developed means to counteract the effect of endogenous AMPs. However, molecular mechanisms of AMP resistance in Campylobacter, an important human food-borne pathogen with poultry as a major reservoir, are still largely unknown. In this study, random transposon mutagenesis and targeted site-directed mutagenesis approaches were used to identify genetic loci contributing Campylobacter resistance to fowlicidin-1, a chicken AMP belonging to cathelicidin family. An efficient transposon mutagenesis approach (EZ::TNTM Transposome) in conjunction with a microtiter plate screening identified three mutants whose susceptibilities to fowlicidin-1 were significantly increased. Backcrossing of the transposon mutations into parent strain confirmed that the AMP-sensitive phenotype in each mutant was linked to the specific transposon insertion. Direct sequencing showed that these mutants have transposon inserted in the genes encoding two-component regulator CbrR, transporter CjaB, and putative trigger factor Tig. Genomic analysis also revealed an operon (Cj1580c-1584c) that is homologous to sapABCDF, an operon conferring resistance to AMP in other pathogens. Insertional inactivation of Cj1583c (sapB) significantly increased susceptibility of Campylobacter to fowlicidin-1. The sapB as well as tig and cjaB mutants were significantly impaired in their ability to compete with their wild-type strain 81-176 to colonize the chicken cecum. Together, this study identified four genetic loci in Campylobacter that will be useful for characterizing molecular basis of Campylobacter resistance to AMPs, a significant knowledge gap in Campylobacter pathogenesis. PMID- 22919621 TI - Outer membrane biogenesis in Escherichia coli, Neisseria meningitidis, and Helicobacter pylori: paradigm deviations in H. pylori. AB - The bacterial pathogen Helicobacter pylori is capable of colonizing the gastric mucosa of the human stomach using a variety of factors associated with or secreted from its outer membrane (OM). Lipopolysaccharide (LPS) and numerous OM proteins have been shown to be involved in adhesion and immune stimulation/evasion. Many of these factors are essential for colonization and/or pathogenesis in a variety of animal models. Despite this wide array of potential targets present on the bacterial surface, the ability of H. pylori to vary its OM profile limits the effectiveness of vaccines or therapeutics that target any single one of these components. However, it has become evident that the proteins comprising the complexes that transport the majority of these molecules to the OM are highly conserved and often essential. The field of membrane biogenesis has progressed remarkably in the last few years, and the possibility now exists for targeting the mechanisms by which beta-barrel proteins, lipoproteins, and LPS are transported to the OM, resulting in loss of bacterial fitness and significant altering of membrane permeability. In this review, the OM transport machinery for LPS, lipoproteins, and outer membrane proteins (OMPs) are discussed. While the principal investigations of these transport mechanisms have been conducted in Escherichia coli and Neisseria meningitidis, here these systems will be presented in the genetic context of epsilon proteobacteria. Bioinformatic analysis reveals that minimalist genomes, such as that of Helicobacter pylori, offer insight into the smallest number of components required for these essential pathways to function. Interestingly, in the majority of epsilon proteobacteria, while the inner and OM associated apparatus of LPS, lipoprotein, and OMP transport pathways appear to all be intact, most of the components associated with the periplasmic compartment are either missing or are almost unrecognizable when compared to their E. coli counterparts. Eventual targeting of these pathways would have the net effect of severely limiting the delivery/transport of components to the OM and preventing the bacterium's ability to infect its human host. PMID- 22919626 TI - Systems biology and bioinformatics help decipher Brucella antigens involved in clinical manifestation of the disease. PMID- 22919627 TI - Immunogenic response of Brucella canis virB10 and virB11 mutants in a murine model. AB - The virB locus, which encodes the type IV secretion system, is a major component of virulence in Brucella. A non-polar virB10 mutant and a virB11 deletion mutant were constructed in Brucella canis. In the mouse model, both mutants were cleared at day 21 post-infection, indicating reduced virulence in mice. After challenging with wild-type B. canis, the amounts of CFU recovered at day 15 were significantly lower in the group previously vaccinated with the virB10 mutant. Levels of IgG1, IgG2a, IgG2b, and IgM, the induction of the cytokines IL-2, IL-4, IL-10, and the production of IFN-gamma were measured in lymphocyte cultures. All strains elicited similar levels of different antibody isotype profiles, and no significant differences were detected (P < 0.05). The wild-type strain induced a rapid and strong INF-gamma response at 24 h, while both mutants induced mild INF gamma responses at 24 h, which remained constant over the course of sampling. Our results suggest that the virB mutants elicit a protective immunity and may be considered as candidates for studies to be conducted in dogs against canine brucellosis. PMID- 22919628 TI - Characterization of the mechanism of protection mediated by CS-D7, a monoclonal antibody to Staphylococcus aureus iron regulated surface determinant B (IsdB). AB - We previously reported the development of a human monoclonal antibody (CS-D7, IgG(1)) with specificity and affinity for the iron regulated surface determinant B (IsdB) of Staphylococcus aureus. CS-D7 mediates opsonophagocytic killing in vitro and protection in a murine sepsis model. In light of recent data indicating that IsdB specific T cells (CD4+, Th17), not Ab, mediate protection after vaccination with IsdB, it is important to investigate the mechanism of protection mediated by CS-D7. The mAb was examined to determine if it blocked heme binding to IsdB in vitro. The mAb was not found to have heme blocking activity, nor did it prevent bacterial growth under in vivo conditions, in an implanted growth chamber. To assess the role of the mAb Fc a point mutation was introduced at aa 297 (CS-D7.N297A). This point mutation removes Fc effector functions. In vitro analysis of the mutein confirmed that it lacked measurable binding to FcgammaR, and that it did not fix complement. The mutein had dramatically reduced in vitro opsonic OP activity compared to CS-D7. Nonetheless, the mutein conferred protection equivalent to the wild type mAb in the murine sepsis model. Both wild type and mutein mAbs were efficacious in FcgammaR deletion mice (including both FcgammaRII(-/-) mice and FcgammaRIII(-/-) mice), indicating that these receptors were not essential for mAb mediated protection in vivo. Protection mediated by CS D7 was lost in Balb/c mice depleted of C3 with cobra venom factor (CFV), was lost in mice depleted of superoxide dismutase (SOD) in P47phox deletion mice, and as previously reported, was absent in SCID mice (Joshi et al., 2012). Enhanced clearance of S. aureus in the liver of CS-D7 treated mice and enhanced production of IFN-gamma, but not of IL17, may play a role in the mechanism of protection mediated by the mAb. CS-D7 apparently mediates survival in challenged mice through a mechanism involving complement, phagocytes, and lymphocytes, but which does not depend on interaction with FcgammaR, or on blocking heme uptake. PMID- 22919625 TI - Staphylococcal response to oxidative stress. AB - Staphylococci are a versatile genus of bacteria that are capable of causing acute and chronic infections in diverse host species. The success of staphylococci as pathogens is due in part to their ability to mitigate endogenous and exogenous oxidative and nitrosative stress. Endogenous oxidative stress is a consequence of life in an aerobic environment; whereas, exogenous oxidative and nitrosative stress are often due to the bacteria's interaction with host immune systems. To overcome the deleterious effects of oxidative and nitrosative stress, staphylococci have evolved protection, detoxification, and repair mechanisms that are controlled by a network of regulators. In this review, we summarize the cellular targets of oxidative stress, the mechanisms by which staphylococci sense oxidative stress and damage, oxidative stress protection and repair mechanisms, and regulation of the oxidative stress response. When possible, special attention is given to how the oxidative stress defense mechanisms help staphylococci control oxidative stress in the host. PMID- 22919630 TI - A coverslip-based technique for evaluating Staphylococcus aureus biofilm formation on human plasma. AB - The ability of the opportunistic pathogen, Staphylococcus aureus, to form biofilms is increasingly being viewed as an important contributor to chronic infections. In vitro methods for analyzing S. aureus biofilm formation have focused on bacterial attachment and accumulation on abiotic surfaces, such as in microtiter plate and flow cell assays. Microtiter plates provide a rapid measure of relative biomass levels, while flow cells have limited experimental throughput but are superior for confocal microscopy biofilm visualization. Although these assays have proven effective at identifying mechanisms involved in cell attachment and biofilm accumulation, the significance of these assays in vivo remains unclear. Studies have shown that when medical devices are implanted they are coated with host factors, such as matrix proteins, that facilitate S. aureus attachment and biofilm formation. To address the challenge of integrating existing biofilm assay features with a biotic surface, we have established an in vitro biofilm technique utilizing UV-sterilized coverslips coated with human plasma. The substratum more closely resembles the in vivo state and provides a platform for S. aureus to establish a robust biofilm. Importantly, these coverslips are amenable to confocal microscopy imaging to provide a visual reference of the biofilm growth stage, effectively merging the benefits of the microtiter and flow cell assays. We confirmed the approach using clinical S. aureus isolates and mutants with known biofilm phenotypes. Altogether, this new biofilm assay can be used to assess the function of S. aureus virulence factors associated with biofilm formation and for monitoring the efficacy of biofilm treatment modalities. PMID- 22919629 TI - Remodeling the host environment: modulation of the gastric epithelium by the Helicobacter pylori vacuolating toxin (VacA). AB - Virulence mechanisms underlying Helicobacter pylori persistence and disease remain poorly understood, in part, because the factors underlying disease risk are multifactorial and complex. Among the bacterial factors that contribute to the cumulative pathophysiology associated with H. pylori infections, the vacuolating cytotoxin (VacA) is one of the most important. Analogous to a number of H. pylori genes, the vacA gene exhibits allelic mosaicism, and human epidemiological studies have revealed that several families of toxin alleles are predictive of more severe disease. Animal model studies suggest that VacA may contribute to pathogenesis in several ways. VacA functions as an intracellular acting protein exotoxin. However, VacA does not fit the current prototype of AB intracellular-acting bacterial toxins, which elaborate modulatory effects through the action of an enzymatic domain translocated inside host cells. Rather, VacA may represent an alternative prototype for AB intracellular acting toxins that modulate cellular homeostasis by forming ion-conducting intracellular membrane channels. Although VacA seems to form channels in several different membranes, one of the most important target sites is the mitochondrial inner membrane. VacA apparently take advantage of an unusual intracellular trafficking pathway to mitochondria, where the toxin is imported and depolarizes the inner membrane to disrupt mitochondrial dynamics and cellular energy homeostasis as a mechanism for engaging the apoptotic machinery within host cells. VacA remodeling of the gastric environment appears to be fine-tuned through the action of the Type IV effector protein CagA which, in part, limits the cytotoxic effects of VacA in cells colonized by H. pylori. PMID- 22919631 TI - Haemophilus influenzae and oxidative stress. AB - Haemophilus influenzae is a commensal of the human upper respiratory tract. H. influenzae can, however, move out of its commensal niche and cause multiple respiratory tract diseases. Such diseases include otitis media in young children, as well as exacerbations of chronic obstructive pulmonary disease (COPD), sinusitis, conjunctivitis, and bronchitis. During the course of colonization and infection, H. influenzae must withstand oxidative stress generated by multiple reactive oxygen species produced endogenously, by other co-pathogens and by host cells. H. influenzae has, therefore, evolved multiple mechanisms that protect the cell against oxygen-generated stresses. In this review, we will describe these systems relative to the well-described systems in Escherichia coli. Moreover, we will compare how H. influenzae combats the effect of oxidative stress as a necessary phenotype for its roles as both a successful commensal and pathogen. PMID- 22919632 TI - The iron-regulated staphylococcal lipoproteins. AB - Lipoproteins fulfill diverse roles in antibiotic resistance, adhesion, protein secretion, signaling and sensing, and many also serve as the substrate binding protein (SBP) partner to ABC transporters for the acquisition of a diverse array of nutrients including peptides, sugars, and scarcely abundant metals. In the staphylococci, the iron-regulated SBPs are significantly upregulated during iron starvation and function to sequester and deliver iron into the bacterial cell, enabling staphylococci to circumvent iron restriction imposed by the host environment. Accordingly, this subset of lipoproteins has been implicated in staphylococcal pathogenesis and virulence. Lipoproteins also activate the host innate immune response, triggered through Toll-like receptor-2 (TLR2) and, notably, the iron-regulated subset of lipoproteins are particularly immunogenic. In this review, we discuss the iron-regulated staphylococcal lipoproteins with regard to their biogenesis, substrate specificity, and impact on the host innate immune response. PMID- 22919633 TI - SapF-mediated heme-iron utilization enhances persistence and coordinates biofilm architecture of Haemophilus. AB - Non-typeable Haemophilus influenzae (NTHI) is a common commensal bacterium that resides in the human upper respiratory tract of healthy individuals. NTHI is also a known causative agent of multiple diseases including sinusitis, otitis media, as well as exacerbates disease severity of patients with cystic fibrosis and chronic obstructive pulmonary disease. We have previously shown that the Sap transporter mediates resistance to host antimicrobial peptides (AMPs) and import of the iron-containing compound heme. Here, we analyzed the contribution of the Sap structural ATPase protein, SapF, in these essential functions. In contrast to SapD, SapF was dispensable for NTHI survival when exposed to AMPs in vitro. SapF was responsible for heme utilization and recovery of depleted internal heme-iron stores. Further, a loss of SapF resulted in morphological plasticity and enhanced community development and biofilm architecture, suggesting the potential role of heme-iron availability in coordinating the complexity of NTHI biofilm architecture. SapF was required for colonization of the nasopharynx and acute infection of the middle ear, as SapF deficiency correlated with a statistically significant decrease in NTHI persistence in vivo. These data suggest that SapF is required for proper heme utilization which directly impacts NTHI survival. Thus, these studies further support a role for the Sap complex in the transport of multiple substrates and further defines substrate specificity for the two ATPase subunits. Given the multiple essential functions provided by the Sap transporter, this complex could prove to be an effective therapeutic target for the treatment of NTHI diseases. PMID- 22919634 TI - Intracellular Staphylococcus aureus: live-in and let die. AB - Staphylococcus aureus uses a plethora of virulence factors to accommodate a diversity of niches in its human host. Aside from the classical manifestations of S. aureus-induced diseases, the pathogen also invades and survives within mammalian host cells.The survival strategies of the pathogen are as diverse as strains or host cell types used. S. aureus is able to replicate in the phagosome or freely in the cytoplasm of its host cells. It escapes the phagosome of professional and non-professional phagocytes, subverts autophagy, induces cell death mechanisms such as apoptosis and pyronecrosis, and even can induce anti apoptotic programs in phagocytes. The focus of this review is to present a guide to recent research outlining the variety of intracellular fates of S. aureus. PMID- 22919636 TI - Multilocus sequence typing methods for the emerging Campylobacter Species C. hyointestinalis, C. lanienae, C. sputorum, C. concisus, and C. curvus. AB - Multilocus sequence typing (MLST) systems have been reported previously for multiple food- and food animal-associated Campylobacter species (e.g., C. jejuni, C. coli, C. lari, and C. fetus) to both differentiate strains and identify clonal lineages. These MLST methods focused primarily on campylobacters of human clinical (e.g., C. jejuni) or veterinary (e.g., C. fetus) relevance. However, other, emerging, Campylobacter species have been isolated increasingly from environmental, food animal, or human clinical samples. We describe herein four MLST methods for five emerging Campylobacter species: C. hyointestinalis, C. lanienae, C. sputorum, C. concisus, and C. curvus. The concisus/curvus method uses the loci aspA, atpA, glnA, gltA, glyA, ilvD, and pgm, whereas the other methods use the seven loci defined for C. jejuni (i.e., aspA, atpA, glnA, gltA, glyA, pgm, and tkt). Multiple food animal and human clinical C. hyointestinalis (n = 48), C. lanienae (n = 34), and C. sputorum (n = 24) isolates were typed, along with 86 human clinical C. concisus and C. curvus isolates. A large number of sequence types were identified using all four MLST methods. Additionally, these methods speciated unequivocally isolates that had been typed ambiguously using other molecular-based speciation methods, such as 16S rDNA sequencing. Finally, the design of degenerate primer pairs for some methods permitted the typing of related species; for example, the C. hyointestinalis primer pairs could be used to type C. fetus strains. Therefore, these novel Campylobacter MLST methods will prove useful in differentiating strains of multiple, emerging Campylobacter species. PMID- 22919635 TI - Comparative genomics of the Staphylococcus intermedius group of animal pathogens. AB - The Staphylococcus intermedius group consists of three closely related coagulase positive bacterial species including S. intermedius, Staphylococcus pseudintermedius, and Staphylococcus delphini. S. pseudintermedius is a major skin pathogen of dogs, which occasionally causes severe zoonotic infections of humans. S. delphini has been isolated from an array of different animals including horses, mink, and pigeons, whereas S. intermedius has been isolated only from pigeons to date. Here we provide a detailed analysis of the S. pseudintermedius whole genome sequence in comparison to high quality draft S. intermedius and S. delphini genomes, and to other sequenced staphylococcal species. The core genome of the SIG was highly conserved with average nucleotide identity (ANI) between the three species of 93.61%, which is very close to the threshold of species delineation (95% ANI), highlighting the close-relatedness of the SIG species. However, considerable variation was identified in the content of mobile genetic elements, cell wall-associated proteins, and iron and sugar transporters, reflecting the distinct ecological niches inhabited. Of note, S. pseudintermedius ED99 contained a clustered regularly interspaced short palindromic repeat locus of the Nmeni subtype and S. intermedius contained both Nmeni and Mtube subtypes. In contrast to S. intermedius and S. delphini and most other staphylococci examined to date, S. pseudintermedius contained at least nine predicted reverse transcriptase Group II introns. Furthermore, S. pseudintermedius ED99 encoded several transposons which were largely responsible for its multi-resistant phenotype. Overall, the study highlights extensive differences in accessory genome content between closely related staphylococcal species inhabiting distinct host niches, providing new avenues for research into pathogenesis and bacterial host-adaptation. PMID- 22919637 TI - Conserved transcriptional unit organization of the cag pathogenicity island among Helicobacter pylori strains. AB - The Helicobacter pyloricag pathogenicity island (cag PAI) encodes a type IV secretion system that is more commonly found in strains isolated from patients with gastroduodenal disease than from those with asymptomatic gastritis. Genome wide organization of the transcriptional units in H. pylori strain 26695 was recently established using RNA sequence analysis (Sharma et al., 2010). Here we used quantitative reverse-transcription polymerase chain reaction of open reading frames and intergenic regions to identify putative cag PAI operons in H. pylori; these operons were analyzed further by transcript profiling after deletion of selected promoter regions. Additionally, we used a promoter-trap system to identify functional cag PAI promoters. The results demonstrated that expression of genes on the H. pyloricag PAI varies by nearly five orders of magnitude and that the organization of cag PAI genes into transcriptional units is conserved among several H. pylori strains, including, 26695, J99, G27, and J166. We found evidence for 20 transcripts within the cag PAI, many of which likely overlap. Our data suggests that there are at least 11 operons: cag1-4, cag3-4, cag10-9, cag8 7, cag6-5, cag11-12, cag16-17, cag19-18, cag21-20, cag23-22, and cag25-24, as well as five monocistronic genes (cag4, cag13, cag14, cag15, and cag26). Additionally, the location of four of our functionally identified promoters suggests they are directing expression of, in one case, a truncated version of cag26 and in the other three, transcripts that are antisense to cag7, cag17, and cag23. We verified expression of two of these antisense transcripts, those antisense to cag17 and cag23, by reverse-transcription polymerase chain reaction. Taken together, our results suggest that the cag PAI transcriptional profile is generally conserved among H. pylori strains, 26695, J99, G27, and J166, and is likely complex. PMID- 22919638 TI - The small protein CydX is required for function of cytochrome bd oxidase in Brucella abortus. AB - A large number of hypothetical genes potentially encoding small proteins of unknown function are annotated in the Brucella abortus genome. Individual deletion of 30 of these genes identified four mutants, in BAB1_0355, BAB2_0726, BAB2_0470, and BAB2_0450 that were highly attenuated for infection. BAB2_0726, an YbgT-family protein located at the 3' end of the cydAB genes encoding cytochrome bd ubiquinal oxidase, was designated cydX. A B. abortus cydX mutant lacked cytochrome bd oxidase activity, as shown by increased sensitivity to H(2)O(2), decreased acid tolerance and increased resistance to killing by respiratory inhibitors. The C terminus, but not the N terminus, of CydX was located in the periplasm, suggesting that CydX is an integral cytoplasmic membrane protein. Phenotypic analysis of the cydX mutant, therefore, suggested that CydX is required for full function of cytochrome bd oxidase, possibly via regulation of its assembly or activity. PMID- 22919639 TI - Evolutionary blueprint for host- and niche-adaptation in Staphylococcus aureus clonal complex CC30. AB - Staphylococcus aureus clonal complex CC30 has caused infectious epidemics for more than 60 years, and, therefore, provides a model system to evaluate how evolution has influenced the disease potential of closely related strains. In previous multiple genome comparisons, phylogenetic analyses established three major branches that evolved from a common ancestor. Clade 1, comprised of historic pandemic phage type 80/81 methicillin susceptible S. aureus (MSSA), and Clade 2 comprised of contemporary community acquired methicillin resistant S. aureus (CA-MRSA) were hyper-virulent in murine infection models. Conversely, Clade 3 strains comprised of contemporary hospital associated MRSA (HA-MRSA) and clinical MSSA exhibited attenuated virulence, due to common single nucleotide polymorphisms (SNP's) that abrogate production of alpha-hemolysin Hla, and interfere with signaling of the accessory gene regulator agr. We have now completed additional in silico genome comparisons of 15 additional CC30 genomes in the public domain, to assess the hypothesis that Clade 3 has evolved to favor niche adaptation. In addition to SNP's that influence agr and hla, other common traits of Clade 3 include tryptophan auxotrophy due to a di-nucleotide deletion within trpD, a premature stop codon within isdH encoding an immunogenic cell surface protein involved in iron acquisition, loss of a genomic toxin-antitoxin (TA) addiction module, acquisition of S. aureus pathogenicity islands SaPI4, and SaPI2 encoding toxic shock syndrome toxin tst, and increased copy number of insertion sequence ISSau2, which appears to target transcription terminators. Compared to other Clade 3 MSSA, S. aureus MN8, which is associated with Staphylococcal toxic shock syndrome, exhibited a unique ISSau2 insertion, and enhanced production of toxic shock syndrome toxin encoded by SaPI2. Cumulatively, our data support the notion that Clade 3 strains are following an evolutionary blueprint toward niche-adaptation. PMID- 22919640 TI - Genetic manipulation of Staphylococci-breaking through the barrier. AB - Most strains of Staphylococcus aureus and Staphylococcus epidermidis possess a strong restriction barrier that hinders exchange of DNA. Recently, major advances have been made in identifying and characterizing the restriction-modification (RM) systems involved. In particular a novel type IV restriction enzyme that recognizes cytosine methylated DNA has been shown to be the major barrier to transfer of plasmid DNA from Escherichia coli into S. aureus and S. epidermidis. While the conserved type I RM system provides a further barrier. Here we review the recent advances in understanding of restriction systems in staphylococci and highlight how this has been exploited to improve our ability to manipulate genetically previously untransformable strains. PMID- 22919641 TI - The rhizome of life: what about metazoa? AB - The increase in huge number of genomic sequences in recent years has contributed to various genetic events such as horizontal gene transfer (HGT), gene duplication and hybridization of species. Among them HGT has played an important role in the genome evolution and was believed to occur only in Bacterial and Archaeal genomes. As a result, genomes were found to be chimeric and the evolution of life was represented in different forms such as forests, networks and species evolution was described more like a rhizome, rather than a tree. However, in the last few years, HGT has also been evidenced in other group such as metazoa (for example in root-knot nematodes, bdelloid rotifers and mammals). In addition to HGT, other genetic events such as transfer by retrotransposons and hybridization between more closely related lineages are also well established. Therefore, in the light of such genetic events, whether the evolution of metazoa exists in the form of a tree, network or rhizome is highly questionable and needs to be determined. In the current review, we will focus on the role of HGT, retrotransposons and hybridization in the metazoan evolution. PMID- 22919642 TI - Insights on the trafficking and retro-translocation of glycosphingolipid-binding bacterial toxins. AB - Some bacterial toxins and viruses have evolved the capacity to bind mammalian glycosphingolipids to gain access to the cell interior, where they can co-opt the endogenous mechanisms of cellular trafficking and protein translocation machinery to cause toxicity. Cholera toxin (CT) is one of the best-studied examples, and is the virulence factor responsible for massive secretory diarrhea seen in cholera. CT enters host cells by binding to monosialotetrahexosylganglioside (GM1 gangliosides) at the plasma membrane where it is transported retrograde through the trans-Golgi network (TGN) into the endoplasmic reticulum (ER). In the ER, a portion of CT, the CT-A1 polypeptide, is unfolded and then "retro-translocated" to the cytosol by hijacking components of the ER associated degradation pathway (ERAD) for misfolded proteins. CT-A1 rapidly refolds in the cytosol, thus avoiding degradation by the proteasome and inducing toxicity. Here, we highlight recent advances in our understanding of how the bacterial AB(5) toxins induce disease. We highlight the molecular mechanisms by which these toxins use glycosphingolipid to traffic within cells, with special attention to how the cell senses and sorts the lipid receptors. We also discuss several new studies that address the mechanisms of toxin unfolding in the ER and the mechanisms of CT A1 chain retro-translocation to the cytosol. PMID- 22919643 TI - Staphylococcal superantigens in colonization and disease. AB - Superantigens (SAgs) are a family of potent immunostimulatory exotoxins known to be produced by only a few bacterial pathogens, including Staphylococcus aureus. More than 20 distinct SAgs have been characterized from different S. aureus strains and at least 80% of clinical strains harbor at least one SAg gene, although most strains encode many. SAgs have been classically associated with food poisoning and toxic shock syndrome (TSS), for which these toxins are the causative agent. TSS is a potentially fatal disease whereby SAg-mediated activation of T cells results in overproduction of cytokines and results in systemic inflammation and shock. Numerous studies have also shown a possible role for SAgs in other diseases such as Kawasaki disease (KD), atopic dermatitis (AD), and chronic rhinosinusitis (CRS). There is also now a rich understanding of the mechanisms of action of SAgs, as well as their structures and function. However, we have yet to discover what purpose SAgs play in the life cycle of S. aureus, and why such a wide array of these toxins exists. This review will focus on recent developments within the SAg field in terms of the molecular biology of these toxins and their role in both colonization and disease. PMID- 22919644 TI - Antimicrobial activities of isothiocyanates against Campylobacter jejuni isolates. AB - Food-borne human infection with Campylobacter jejuni is a medical concern in both industrialized and developing countries. Efficient eradication of C. jejuni reservoirs within live animals and processed foods is limited by the development of antimicrobial resistances and by practical problems related to the use of conventional antibiotics in food processes. We have investigated the bacteriostatic and bactericidal activities of two phytochemicals, allyl isothiocyanate (AITC), and benzyl isothiocyanate (BITC), against 24 C. jejuni isolates from chicken feces, human infections, and contaminated foods, as well as two reference strains NCTC11168 and 81-176. AITC and BITC displayed a potent antibacterial activity against C. jejuni. BITC showed a higher overall antibacterial effect (MIC of 1.25-5 MUg mL(-1)) compared to AITC (MIC of 50-200 MUg mL(-1)). Both compounds are bactericidal rather than bacteriostatic. The sensitivity levels of C. jejuni isolates against isothiocyanates were neither correlated with the presence of a GGT (gamma-Glutamyl Transpeptidase) encoding gene in the genome, with antibiotic resistance nor with the origin of the biological sample. However the ggt mutant of C. jejuni 81-176 displayed a decreased survival rate compared to wild-type when exposed to ITC. This work determined the MIC of two ITC against a panel of C. jejuni isolates, showed that both compounds are bactericidal rather than bacteriostatic, and highlighted the role of GGT enzyme in the survival rate of C. jejuni exposed to ITC. PMID- 22919645 TI - Selfishness, warfare, and economics; or integration, cooperation, and biology. AB - The acceptance of Darwin's theory of evolution by natural selection is not complete and it has been pointed out its limitation to explain the complex processes that constitute the transformation of species. It is necessary to discuss the explaining power of the dominant paradigm. It is common that new discoveries bring about contradictions that are intended to be overcome by adjusting results to the dominant reductionist paradigm using all sorts of gradations and combinations that are admitted for each case. In addition to the discussion on the validity of natural selection, modern findings represent a challenge to the interpretation of the observations with the Darwinian view of competition and struggle for life as theoretical basis. New holistic interpretations are emerging related to the Net of Life, in which the interconnection of ecosystems constitutes a dynamic and self-regulating biosphere: viruses are recognized as a macroorganism with a huge collection of genes, most unknown that constitute the major planet's gene pool. They play a fundamental role in evolution since their sequences are capable of integrating into the genomes in an "infective" way and become an essential part of multicellular organisms. They have content with "biological sense" i.e., they appear as part of normal life processes and have a serious role as carrier elements of complex genetic information. Antibiotics are cell signals with main effects on general metabolism and transcription on bacterial cells and communities. The hologenome theory considers an organism and all of its associated symbiotic microbes (parasites, mutualists, synergists, amensalists) as a result of symbiopoiesis. Microbes, helmints, that are normally understood as parasites are cohabitants and they have cohabited with their host and drive the evolution and existence of the partners. Each organism is the result of integration of complex systems. The eukaryotic organism is the result of combination of bacterial, virus, and eukaryotic DNA and it is the result of the interaction of its own genome with the genome of its microbiota, and their metabolism are intertwined (as a "superorganism") along evolution. The darwinian paradigm had its origin in the free market theories and concepts of Malthus and Spencer. Then, nature was explained on the basis of market theories moving away from an accurate explanation of natural phenomena. It is necessary to acknowledge the limitations of the dominant dogma. These new interpretations about biological processes, molecules, roles of viruses in nature, and microbial interactions are remarkable points to be considered in order to construct a solid theory adjusted to the facts and with less speculations and tortuous semantic traps. PMID- 22919646 TI - Host interferon-gamma inducible protein contributes to Brucella survival. AB - Brucella spp. are highly adapted intracellular pathogens of mammals that cause chronic infections while surving and replicating in host monocytes and macrophages. Although monocytes are normally susceptible to infection, pretreatment with pro-inflammatory cytokine interferon-gamma (IFN-gamma) activates cellular defense mechanisms that increase intracellular killing of Brucella and prevents bacterial replication. We examined the contribution of the IFN-gamma inducible GTPase, LRG-47, to B. abortus 2308 infection in in vitro and in vivo murine models. Infecting non-activated macrophages from LRG-47(-/-) mice revealed that loss of this host protein negatively effected the intracellular survival and replication of IgG opsonized B. abortus. In contrast, survival and replication of non-opsonized B. abortus was the same in both C57/B6 and LRG-47(-/ ) peritoneal macrophages. Following IFN-gamma activation of LRG-47(-/-) monocytes, IgG opsonized B. abortus survived better than non-opsonized bacteria. The differential fate of opsonized and non-opsonized B. abortus was only observed in macrophages collected from LRG-47(-/-) mice. Given the specific nature of the relationship between this host protein and the mechanism of Brucella internalization, LRG-47(-/-) mice were infected with B. abortus to assess whether the loss of the lrg47 protein would affect the ability of the bacteria to colonize or persist within the host. B. abortus were able to establish and maintain similar numbers of bacteria in both C57/B6 mice and LRG-47(-/-) through 3 weeks post intraperitoneal infection. By 9 weeks p.i. fewer B. abortus were recovered from LRG-47(-/-) mice than controls, suggesting that the host protein has a positive role in maintaining long term persistence of the bacteria within the host. These observations demonstrating a positive role for a host IFN-gamma induced protein defense protein has yet to be reported. These results provide interesting insight into the complex interaction between Brucella and their host. PMID- 22919648 TI - A framework for assessing the concordance of molecular typing methods and the true strain phylogeny of Campylobacter jejuni and C. coli using draft genome sequence data. AB - Tracking of sources of sporadic cases of campylobacteriosis remains challenging, as commonly used molecular typing methods have limited ability to unambiguously link genetically related strains. Genomics has become increasingly prominent in the public health response to enteric pathogens as methods enable characterization of pathogens at an unprecedented level of resolution. However, the cost of sequencing and expertise required for bioinformatic analyses remains prohibitive, and these comprehensive analyses are limited to a few priority strains. Although several molecular typing methods are currently widely used for epidemiological analysis of campylobacters, it is not clear how accurately these methods reflect true strain relationships. To address this, we have developed a framework and associated computational tools to rapidly analyze draft genome sequence data for the assessment of molecular typing methods against a "gold standard" based on the phylogenetic analysis of highly conserved core (HCC) genes with high sequence quality. We analyzed 104 publicly available whole genome sequences (WGS) of C. jejuni and C. coli. In addition to in silico determination of multi-locus sequence typing (MLST), flaA, and porA type, as well as comparative genomic fingerprinting (CGF) type, we inferred a "reference" phylogeny based on 389 HCC genes. Molecular typing data were compared to the reference phylogeny for concordance using the adjusted Wallace coefficient (AWC) with confidence intervals. Although MLST targets the sequence variability in core genes and CGF targets insertions/deletions of accessory genes, both methods are based on multi-locus analysis and provided better estimates of true phylogeny than methods based on single loci (porA, flaA). A more comprehensive WGS dataset including additional genetically related strains, both epidemiologically linked and unlinked, will be necessary to more comprehensively assess the performance of subtyping methods for outbreak investigations and surveillance activities. Analyses of the strengths and weaknesses of widely used typing methodologies in inferring true strain relationships will provide guidance in the interpretation of this data for epidemiological purposes. PMID- 22919647 TI - Host- and microbe determinants that may influence the success of S. aureus colonization. AB - Staphylococcus aureus may cause serious skin and soft tissue infections, deep abscesses, endocarditis, osteomyelitis, pneumonia, and sepsis. S. aureus persistently colonizes 25-30% of the adult human population, and S. aureus carriers have an increased risk for infections caused by the bacterium. The major site of colonization is the nose, i.e., the vestibulum nasi, which is covered with ordinary skin and hair follicles. Several host and microbe determinants are assumed to be associated with colonization. These include the presence and expression level of bacterial adhesins, which can adhere to various proteins in the extracellular matrix or on the cellular surface of human skin. The host expresses several antimicrobial peptides and lipids. The level of beta-defensin 3, free sphingosine, and cis-6-hexadecenoic acid are found to be associated with nasal carriage of S. aureus. Other host factors are certain polymorphisms in Toll like receptor 2, mannose-binding lectin, C-reactive protein, glucocorticoid-, and vitamin D receptor. Additional putative determinants for carriage include genetic variation and expression of microbial surface components recognizing adhesive matrix molecules and their interaction partners, as well as variation among humans in the ability of recognizing and responding appropriately to the bacteria. Moreover, the available microflora may influence the success of S. aureus colonization. In conclusion, colonization is a complex interplay between the bacteria and its host. Several bacterial and host factors are involved, and an increased molecular understanding of these are needed. PMID- 22919649 TI - Dps promotes survival of nontypeable Haemophilus influenzae in biofilm communities in vitro and resistance to clearance in vivo. AB - Nontypeable Haemophilus influenzae (NTHi) is a common airway commensal and opportunistic pathogen that persists within surface-attached biofilm communities. In this study, we tested the hypothesis that bacterial stress-responses are activated within biofilms. Transcripts for several factors associated with bacterial resistance to environmental stress were increased in biofilm cultures as compared to planktonic cultures. Among these, a homolog of the DNA-binding protein from starved cells (dps) was chosen for further study. An isogenic NTHi 86-028NP dps mutant was generated and tested for resistance to environmental stress, revealing a significant survival defects in high-iron conditions, which was mediated by oxidative stress and was restored by genetic complementation. As expected, NTHi 86-028NP dps had a general stress-response defect, exhibiting decreased resistance to many types of environmental stress. While no differences were observed in density and structure of NTHi 86-028NP and NTHi 86-028NP dps biofilms, bacterial survival was decreased in NTHi 86-028NP dps biofilms as compared to the parental strain. The role of dps persistence in vivo was tested in animal infection studies. NTHi 86-028NP dps had decreased resistance to clearance after pulmonary infection of elastase-treated mice as compared to NTHi 86-028NP, whereas minimal differences were observed in clearance from mock treated mice. Similarly, lower numbers of NTHi 86-028NP dps were recovered from middle-ear effusions and bullar homogenates in the chinchilla model for otitis media (OM). Therefore, we conclude that Dps promotes bacterial survival within NTHi biofilm communities both in vitro and in chronic infections in vivo. PMID- 22919650 TI - The influence of early neutrophil-Leishmania interactions on the host immune response to infection. AB - Neutrophils are the first cells recruited to the dermal site of Leishmania infection following injection by needle or sand fly bite. The role of neutrophils in either promoting or suppressing host immunity remains controversial. We discuss the events driving neutrophil recruitment, their interaction with the parasite and apoptotic fate, and the nature of their encounters with other innate cells. We suggest that the influence of the neutrophil response on infection outcome critically depends on the timing of their recruitment and the tissue environment in which it occurs. PMID- 22919651 TI - How microbiology helps define the rhizome of life. AB - In contrast to the tree of life (TOF) theory, species are mosaics of gene sequences with different origins. Observations of the extensive lateral sequence transfers in all organisms have demonstrated that the genomes of all life forms are collections of genes with different evolutionary histories that cannot be represented by a single TOF. Moreover, genes themselves commonly have several origins due to recombination. The human genome is not free from recombination events, so it is a mosaic like other organisms' genomes. Recent studies have demonstrated evidence for the integration of parasitic DNA into the human genome. Lateral transfer events have been accepted as major contributors of genome evolution in free-living bacteria. Furthermore, the accumulation of genomic sequence data provides evidence for extended genetic exchanges in intracellular bacteria and suggests that such events constitute an agent that promotes and maintains all bacterial species. Archaea and viruses also form chimeras containing primarily bacterial but also eukaryotic sequences. In addition to lateral transfers, orphan genes are indicative of the fact that gene creation is a permanent and unsettled phenomenon. Currently, a rhizome may more adequately represent the multiplicity and de novo creation of a genome. We wanted to confirm that the term "rhizome" in evolutionary biology applies to the entire cellular life history. This view of evolution should resemble a clump of roots representing the multiple origins of the repertoires of the genes of each species. PMID- 22919652 TI - O-antigen and virulence profiling of shiga toxin-producing Escherichia coli by a rapid and cost-effective DNA microarray colorimetric method. AB - Shiga toxin-producing Escherichia coli (STEC) is a leading cause of foodborne illness worldwide. The present study developed the use of DNA microarrays with the ampliPHOX colorimetric method to rapidly detect and genotype STEC strains. A low-density 30-mer oligonucleotide DNA microarray was designed to target O antigen gene clusters of 11 E. coli serogroups (O26, O45, O91, O103, O104, O111, O113, O121, O128, O145, and O157) that have been associated with the majority of STEC infections. In addition, the DNA microarray targeted 11 virulence genes, encoding adhesins, cytotoxins, proteases, and receptor proteins, which have been implicated in conferring increased ability to cause disease for STEC. Results from the validation experiments demonstrated that this microarray-based colorimetric method allowed for a rapid and accurate genotyping of STEC reference strains from environmental and clinical sources and from distinct geographical locations. Positive hybridization signals were detected only for probes targeting serotype and virulence genes known to be present in the STEC reference strains. Quantification analysis indicated that the mean pixel intensities of the signal for probes targeting O-antigen or virulence genes were at least three times higher when compared to the background. Furthermore, this microarray-based colorimetric method was then employed to genotype a group of E. coli isolates from watershed sediment and animal fecal samples that were collected from an important region for leafy-vegetable production in the central coast of California. The results indicated an accurate identification of O-type and virulence genes in the tested isolates and confirmed that the ampliPHOX colorimetric method with low-density DNA microarrays enabled a fast assessment of the virulence potential of STEC using low-cost reagents and instrumentation. PMID- 22919654 TI - Single-cell elemental analysis of bacteria: quantitative analysis of polyphosphates in Mycobacterium tuberculosis. AB - More than 1.8 million people die annually from infection with Mycobacterium tuberculosis, the causative agent of tuberculosis. The ability of M. tuberculosis to obtain and distribute micronutrients, including biometals, is known to play a role in its intracellular survival and virulence within a host. Techniques to detect elemental distributions within M. tuberculosis cells have previously been limited to bulk detection methods or low-resolution analyses. Here, we present a method for determining the elemental distribution within M. tuberculosis on a single-cell level, at high (individual nanometer) resolution, using scanning transmission electron microscopy (STEM) in concert with energy-dispersive X-ray spectroscopy (EDS). Results revealed the presence of large polyphosphate granules in all strains of Mycobacteria tested. These persisted even through starvation conditions, and might play a role connected to elemental homeostasis in M. tuberculosis. Associated with the polyphosphate granules were micronutrients such as calcium and magnesium. In addition, we expanded the technique beyond Mycobacteria to show that STEM and EDS could be used as a simple screen to detect the presence or absence of concentrated elements on a single-cell level within all six other bacterial types tested, with minimal processing to the bacteria. Overall, we believe that this technique represents a first step in developing a better understanding of the role that components of the intracellular milieu, including polyphosphates and biometals, play in the pathogenesis of M. tuberculosis, with potential future applications for in vivo analysis. PMID- 22919653 TI - Deciphering mechanisms of staphylococcal biofilm evasion of host immunity. AB - Biofilms are adherent communities of bacteria contained within a complex matrix. Although host immune responses to planktonic staphylococcal species have been relatively well-characterized, less is known regarding immunity to staphylococcal biofilms and how they modulate anti-bacterial effector mechanisms when organized in this protective milieu. Previously, staphylococcal biofilms were thought to escape immune recognition on the basis of their chronic and indolent nature. Instead, we have proposed that staphylococcal biofilms skew the host immune response away from a proinflammatory bactericidal phenotype toward an anti inflammatory, pro-fibrotic response that favors bacterial persistence. This possibility is supported by recent studies from our laboratory using a mouse model of catheter-associated biofilm infection, where S. aureus biofilms led to the accumulation of alternatively activated M2 macrophages that exhibit anti inflammatory and pro-fibrotic properties. In addition, relatively few neutrophils were recruited into S. aureus biofilms, representing another mechanism that deviates from planktonic infections. However, it is important to recognize the diversity of biofilm infections, in that studies by others have demonstrated the induction of distinct immune responses during staphylococcal biofilm growth in other models, suggesting influences from the local tissue microenvironment. This review will discuss the immune defenses that staphylococcal biofilms evade as well as conceptual issues that remain to be resolved. An improved understanding of why the host immune response is unable to clear biofilm infections could lead to targeted therapies to reverse these defects and expedite biofilm clearance. PMID- 22919655 TI - Alpha-toxin promotes Staphylococcus aureus mucosal biofilm formation. AB - Staphylococcus aureus causes many diseases in humans, ranging from mild skin infections to serious, life-threatening, superantigen-mediated Toxic Shock Syndrome (TSS). S. aureus may be asymptomatically carried in the anterior nares or vagina or on the skin, serving as a reservoir for infection. Pulsed-field gel electrophoresis clonal type USA200 is the most widely disseminated colonizer and the leading cause of TSS. The cytolysin alpha-toxin (also known as alpha hemolysin or Hla) is the major epithelial proinflammatory exotoxin produced by TSS S. aureus USA200 isolates. The current study aims to characterize the differences between TSS USA200 strains [high (hla(+)) and low (hla(-)) alpha toxin producers] in their ability to disrupt vaginal mucosal tissue and to characterize the subsequent infection. Tissue viability post-infection and biofilm formation of TSS USA200 isolates CDC587 and MN8, which contain the alpha toxin pseudogene (hla(-)), MNPE (hla(+)), and MNPE isogenic hla knockout (hlaKO), were observed via LIVE/DEAD(r) staining and confocal microscopy. All TSS strains grew to similar bacterial densities (1-5 * 10(8) CFU) on the mucosa and were proinflammatory over 3 days. However, MNPE formed biofilms with significant reductions in the mucosal viability whereas neither CDC587 (hla(-)), MN8 (hla( )), nor MNPE hlaKO formed biofilms. The latter strains were also less cytotoxic than wild-type MNPE. The addition of exogenous, purified alpha-toxin to MNPE hlaKO restored the biofilm phenotype. We speculate that alpha-toxin affects S. aureus phenotypic growth on vaginal mucosa by promoting tissue disruption and biofilm formation. Further, alpha-toxin mutants (hla(-)) are not benign colonizers, but rather form a different type of infection, which we have termed high density pathogenic variants (HDPV). PMID- 22919656 TI - Exoribonucleases as modulators of virulence in pathogenic bacteria. PMID- 22919657 TI - The staphylococci and staphylococcal pathogenesis. PMID- 22919658 TI - Serum susceptibility in clinical isolates of Burkholderia cepacia complex bacteria: development of a growth-based assay for high throughput determination. AB - Burkholderia cepacia complex (BCC) bacteria can cause devastating chronic infections in people with cystic fibrosis. Of particular concern is "cepacia syndrome," a rapidly progressive and usually fatal decline in health, characterized by a necrotizing bacteremic pneumonia. An important component of defense against bloodstream infections is the bactericidal action of serum. Traditional methods to determine the capacity of bacterial isolates to resist the bactericidal effects of serum are relatively low-throughput viability assays. In this study, we developed a novel growth-based assay for serum susceptibility, which allows for high throughput analysis. We applied this assay to a range of clinical isolates of BCC as well as isolates comprising the BCC experimental strain panel. Our data demonstrate that isolates from all species of BCC examined can possess serum resistant or serum sensitive/intermediate phenotypes. Of particular clinical significance, we also found no direct link between the last saved pulmonary isolate from patients who subsequently developed "cepacia syndrome" and their capacity to resist the inhibitory effects of human serum, suggesting serum resistance cannot be used as a marker of an isolate's capacity to escape from the lung and cause bacteremia. PMID- 22919659 TI - Genotyping markers used for multi locus VNTR analysis with ompA (MLVA-ompA) and multi sequence typing (MST) retain stability in Chlamydia trachomatis. AB - We aimed to evaluate the stability of the Chlamydia trachomatis multi locus VNTR analysis (MLVA-ompA) and multi sequence typing (MST) systems through multiple passages in tissue culture. Firstly, we analyzed the stability of these markers through adaptation of C. trachomatis to tissue culture and secondly, we examined the stability of a four-locus MLVA-ompA and a five-locus MST system after multiple passages in tissue culture. Marker sequences were monitored through successive chlamydial developmental cycles to evaluate the stability of the individual DNA markers through many bacterial divisions and this, in turn, informed us of the usefulness of using such typing systems for short and long term molecular epidemiology. Southampton genitourinary medicine (GUM) clinic isolates from endocervical swabs collected from C. trachomatis positive women were passaged through tissue culture. MLVA-ompA typing was applied to primary swab samples and to the same samples after C. trachomatis had been passaged through cell culture (eight passages). Sequence data from time-zero and passage eight isolates were aligned with reference sequences to determine the stability of the markers. The Swedish new variant (nvCT) underwent 72 passages in cell culture and the markers of the two schemes were similarly analyzed. Analysis of genetic markers of the MLVA-ompA typing system before and after the isolates were introduced to tissue culture showed no change in the dominant sequence. The nvCT that had been passaged 72 times over the duration of a year also showed no variation in the dominant sequence for both the genotyping schemes. MLVA-ompA and MST markers are stable upon adaptation of C. trachomatis to tissue culture following isolation of strains from primary endocervical swab samples. These markers remain stable throughout multiple rounds of cell-division in tissue culture, concomitant with the incubation period and appearance of symptoms normally associated with host-infection. Both genotyping schemes are, therefore, suitable for epidemiology of C. trachomatis. PMID- 22919660 TI - Natural killer cells in experimental and human leishmaniasis. AB - Infections with parasites of the genus Leishmania lead to a rapid, but transient activation of natural killer (NK) cells. In mice activation of NK cells requires a toll-like-receptor 9-dependent stimulation of dendritic cells (DC) which is followed by the production of IL-12. Although NK cells appear to be non-essential for the ultimate control of cutaneous and visceral leishmaniasis (VL) and can exhibit immunosuppressive functions, they form an important source of interferon (IFN)-gamma, which elicits antileishmanial activity in macrophages and helps to pave a protective T helper cell response. In contrast, the cytotoxic activity of NK cells is dispensable, because Leishmania-infected myeloid cells are largely resistant to NK-mediated lysis. In human cutaneous and VL, the functional importance of NK cells is suggested by reports that demonstrate (1) a direct activation or inhibition of NK cells by Leishmania promastigotes, (2) the suppression of NK cell numbers or activity during chronic, non-healing infections, and (3) the recovery of NK cell activity following treatment. This review aims to provide an integrated view on the migration, activation, inhibition, function, and therapeutic modulation of NK cells in experimental and human leishmaniasis. PMID- 22919661 TI - An RGD helper sequence in CagL of Helicobacter pylori assists in interactions with integrins and injection of CagA. AB - Helicobacter pylori is a specific gastric pathogen that colonizes the stomach in more than 50% of the world's human population. Infection with this bacterium can induce several types of gastric pathology, ranging from chronic gastritis to peptic ulcers and even adenocarcinoma. Virulent H. pylori isolates encode components of a type IV secretion system (T4SS), which form a pilus for the injection of virulence proteins such as CagA into host target cells. This is accomplished by a specialized adhesin on the pilus surface, the protein CagL, a putative VirB5 ortholog, which binds to host cell beta(1) integrin, triggering subsequent delivery of CagA across the host cell membrane. Like the human extracellular matrix protein fibronectin, CagL contains an RGD (Arg-Gly-Asp) motif and is able to trigger intracellular signaling pathways by RGD-dependent binding to integrins. While CagL binding to host cells is mediated primarily by the RGD motif, we identified an auxiliary binding motif for CagL-integrin interaction. Here, we report on a surface exposed FEANE (Phe-Glu-Ala-Asn-Glu) interaction motif in spatial proximity to the RGD sequence, which enhances the interactions of CagL with integrins. It will be referred to as RGD helper sequence (RHS). Competitive cell adhesion assays with recombinant wild type CagL and point mutants, competition experiments with synthetic cyclic and linear peptides, and peptide array experiments revealed amino acids essential for the interaction of the RHS motif with integrins. Infection experiments indicate that the RHS motif plays a role in the early interaction of H. pylori T4SS with integrin, to trigger signaling and to inject CagA into host cells. We thus postulate that CagL is a versatile T4SS surface protein equipped with at least two motifs to promote binding to integrins, thereby causing aberrant signaling within host cells and facilitating translocation of CagA into host cells, thus contributing directly to H. pylori pathogenesis. PMID- 22919662 TI - Achieving consistent multiple daily low-dose Bacillus anthracis spore inhalation exposures in the rabbit model. AB - Repeated low-level exposures to biological agents could occur before or after the remediation of an environmental release. This is especially true for persistent agents such as B. anthracis spores, the causative agent of anthrax. Studies were conducted to examine aerosol methods needed for consistent daily low aerosol concentrations to deliver a low-dose (less than 10(6) colony forming units (CFU) of B. anthracis spores) and included a pilot feasibility characterization study, acute exposure study, and a multiple 15 day exposure study. This manuscript focuses on the state-of-the-science aerosol methodologies used to generate and aerosolize consistent daily low aerosol concentrations and resultant low inhalation doses to rabbits. The pilot feasibility characterization study determined that the aerosol system was consistent and capable of producing very low aerosol concentrations. In the acute, single day exposure experiment, targeted inhaled doses of 1 * 10(2), 1 * 10(3), 1 * 10(4), and 1 * 10(5) CFU were used. In the multiple daily exposure experiment, rabbits were exposed multiple days to targeted inhaled doses of 1 * 10(2), 1 * 10(3), and 1 * 10(4) CFU. In all studies, targeted inhaled doses remained consistent from rabbit-to-rabbit and day to-day. The aerosol system produced aerosolized spores within the optimal mass median aerodynamic diameter particle size range to reach deep lung alveoli. Consistency of the inhaled dose was aided by monitoring and recording respiratory parameters during the exposure with real-time plethysmography. Overall, the presented results show that the animal aerosol system was stable and highly reproducible between different studies and over multiple exposure days. PMID- 22919663 TI - Impact of Leishmania metalloprotease GP63 on macrophage signaling. AB - The intramacrophage protozoan parasites of Leishmania genus have developed sophisticated ways to subvert the innate immune response permitting their infection and propagation within the macrophages of the mammalian host. Several Leishmania virulence factors have been identified and found to be of importance for the development of leishmaniasis. However, recent findings are now further reinforcing the critical role played by the zinc-metalloprotease GP63 as a virulence factor that greatly influence host cell signaling mechanisms and related functions. GP63 has been found to be involved not only in the cleavage and degradation of various kinases and transcription factors, but also to be the major molecule modulating host negative regulatory mechanisms involving for instance protein tyrosine phosphatases (PTPs). Those latter being well recognized for their pivotal role in the regulation of a great number of signaling pathways. In this review article, we are providing a complete overview about the role of Leishmania GP63 in the mechanisms underlying the subversion of macrophage signaling and functions. PMID- 22919664 TI - MiR-155 induction by microbes/microbial ligands requires NF-kappaB-dependent de novo protein synthesis. AB - MiR-155 regulates numerous aspects of innate and adaptive immune function. This miR is induced in response to Toll-like receptor ligands, cytokines, and microbial infection. We have previously shown that miR-155 is induced in monocytes/macrophages infected with Francisella tularensis and suppresses expression of the inositol phosphatase SHIP to enhance activation of the PI3K/Akt pathway, which in turn promotes favorable responses for the host. Here we examined how miR-155 expression is regulated during infection. First, our data demonstrate that miR-155 can be induced through soluble factors of bacterial origin and not the host. Second, miR-155 induction is not a direct effect of infection and it requires NF-kappaB signaling to up-regulate fos/jun transcription factors. Finally, we demonstrate that the requirement for NF-kappaB dependent de novo protein synthesis is globally shared by microbial ligands and live bacteria. This study provides new insight into the complex regulation of miR 155 during microbial infection. PMID- 22919665 TI - Development of a murine nose-only inhalation model of influenza: comparison of disease caused by instilled and inhaled A/PR/8/34. AB - Influenza continues to cause widespread disease and death during winter months. In preclinical studies to evaluate the potential efficacy of drugs and vaccines, influenza challenge virus is usually instilled into the noses of animals in the form of large liquid drops. Since inhalation of aerosolized influenza is commonly associated with human transmission, instillation of challenge virus raises uncertainty about the applicability of results. In order to compare the challenge methods, we established conditions to generate influenza aerosols with a mass median aerodynamic diameter (MMAD) of 1 MUm that were delivered to mice in a nose only inhalation system. In this report, we describe the system and compare the 50% lethal dose (LD(50)) of instilled and inhaled A/PR/8/34 (PR8) in BALB/c mice. The estimated LD(50) for inhaled virus was 8.7 plaque forming units (PFU) and the mean time to death was 7.7 days, whereas the estimated LD(50) for instilled virus was 51.6 PFU and the mean time to death was 8.2 days. Our results show that mice are more sensitive to inhaled virus than virus delivered by intranasal instillation. The murine nose-only inhalation model of influenza infection can be used to infect large numbers of animals simultaneously with well-characterized, homogenous PR8 bioaerosol in a controlled and reproducible manner. This model provides the means to evaluate the efficacy of drug and vaccine candidates against the relevant route of challenge, thereby providing data that may better predict clinical outcome. PMID- 22919666 TI - Bacterial toxin effector-membrane targeting: outside in, then back again. AB - Pathogenic bacteria utilize multiple approaches to establish infection and mediate their toxicity to eukaryotic cells. Dedicated protein machines deposit toxic effectors directly inside the host, whereas secreted toxins must enter cells independently of other bacterial components. Regardless of how they reach the cytosol, these bacterial proteins must accurately identify their intracellular target before they can manipulate the host cell to benefit their associated bacteria. Within eukaryotic cells, post-translational modifications and individual targeting motifs spatially regulate endogenous host proteins. This review focuses on the strategies employed by bacterial effectors to associate with a frequently targeted location within eukaryotic cells, the plasma membrane. PMID- 22919668 TI - Genomic stability of genotyping markers in Chlamydia trachomatis. PMID- 22919669 TI - Recovery efficiencies for Burkholderia thailandensis from various aerosol sampling media. AB - Burkholderia thailandensis is used in the laboratory as a surrogate of the more virulent B. pseudomallei. Since inhalation is believed to be a natural route of infection for B. pseudomallei, many animal studies with B. pseudomallei and B. thailandensis utilize the inhalation route of exposure. The aim of the present study was to quantify the recovery efficiency of culturable B. thailandensis from several common aerosol sampling devices to ensure that collected microorganisms could be reliably recovered post-collection. The sampling devices tested included 25 mm gelatin filters, 22 mm stainless steel disks used in Mercer cascade impactors, and two types of glass impingers. The results demonstrate that while several processing methods tested resulted in significantly lower physical recovery efficiencies than other methods, it was possible to obtain culturable recovery efficiencies for B. thailandensis and physical recovery efficiencies for 1 MUm fluorescent spheres of at least 0.95 from all of the sampling media tested given an appropriate sample processing procedure. The results of the present study also demonstrated that the bubbling action of liquid media in all-glass impingers (AGIs) can result in physical loss of material from the collection medium, although additional studies are needed to verify the exact mechanisms involved. Overall, the results of this study demonstrate that the collection mechanism as well as the post-collection processing method can significantly affect the recovery from and retention of culturable microorganisms in sampling media, potentially affecting the calculated airborne concentration and any subsequent estimations of risk or dose derived from such data. PMID- 22919667 TI - Cellular and physiological effects of anthrax exotoxin and its relevance to disease. AB - Bacillus anthracis, the causative agent of anthrax, secretes a tri-partite exotoxin that exerts pleiotropic effects on the host. The purification of the exotoxin components, protective antigen, lethal factor, and edema factor allowed the rapid characterization of their physiologic effects on the host. As molecular biology matured, interest focused on the molecular mechanisms and cellular alterations induced by intoxication. Only recently have researchers begun to connect molecular and cellular knowledge back to the broader physiological effects of the exotoxin. This review focuses on the progress that has been made bridging molecular knowledge back to the exotoxin's physiological effects on the host. PMID- 22919670 TI - Deep sequencing of Porphyromonas gingivalis and comparative transcriptome analysis of a LuxS mutant. AB - Porphyromonas gingivalis is a major etiological agent in chronic and aggressive forms of periodontal disease. The organism is an asaccharolytic anaerobe and is a constituent of mixed species biofilms in a variety of microenvironments in the oral cavity. P. gingivalis expresses a range of virulence factors over which it exerts tight control. High-throughput sequencing technologies provide the opportunity to relate functional genomics to basic biology. In this study we report qualitative and quantitative RNA-Seq analysis of the transcriptome of P. gingivalis. We have also applied RNA-Seq to the transcriptome of a DeltaluxS mutant of P. gingivalis deficient in AI-2-mediated bacterial communication. The transcriptome analysis confirmed the expression of all predicted ORFs for strain ATCC 33277, including 854 hypothetical proteins, and allowed the identification of hitherto unknown transcriptional units. Twelve non-coding RNAs were identified, including 11 small RNAs and one cobalamin riboswitch. Fifty-seven genes were differentially regulated in the LuxS mutant. Addition of exogenous synthetic 4,5-dihydroxy-2,3-pentanedione (DPD, AI-2 precursor) to the DeltaluxS mutant culture complemented expression of a subset of genes, indicating that LuxS is involved in both AI-2 signaling and non-signaling dependent systems in P. gingivalis. This work provides an important dataset for future study of P. gingivalis pathophysiology and further defines the LuxS regulon in this oral pathogen. PMID- 22919671 TI - Rho/ROCK-dependent inhibition of 3T3-L1 adipogenesis by G-protein-deamidating dermonecrotic toxins: differential regulation of Notch1, Pref1/Dlk1, and beta catenin signaling. AB - The dermonecrotic toxins from Pasteurella multocida (PMT), Bordetella (DNT), Escherichia coli (CNF1-3), and Yersinia (CNFY) modulate their G-protein targets through deamidation and/or transglutamination of an active site Gln residue, which results in activation of the G protein and its cognate downstream signaling pathways. Whereas DNT and the CNFs act on small Rho GTPases, PMT acts on the alpha subunit of heterotrimeric G(q), G(i), and G(12/13) proteins. We previously demonstrated that PMT potently blocks adipogenesis and adipocyte differentiation in a calcineurin-independent manner through downregulation of Notch1 and stabilization of beta-catenin and Pref1/Dlk1, key proteins in signaling pathways strongly linked to cell fate decisions, including fat and bone development. Here, we report that similar to PMT, DNT, and CNF1 completely block adipogenesis and adipocyte differentiation by preventing upregulation of adipocyte markers, PPARgamma and C/EBPalpha, while stabilizing the expression of Pref1/Dlk1 and beta catenin. We show that the Rho/ROCK inhibitor Y-27632 prevented or reversed these toxin-mediated effects, strongly supporting a role for Rho/ROCK signaling in dermonecrotic toxin-mediated inhibition of adipogenesis and adipocyte differentiation. Toxin treatment was also accompanied by downregulation of Notch1 expression, although this inhibition was independent of Rho/ROCK signaling. We further show that PMT-mediated downregulation of Notch1 expression occurs primarily through G(12/13) signaling. Our results reveal new details of the pathways involved in dermonecrotic toxin action on adipocyte differentiation, and the role of Rho/ROCK signaling in mediating toxin effects on Wnt/beta-catenin and Notch1 signaling, and in particular the role of G(q) and G(12/13) in mediating PMT effects on Rho/ROCK and Notch1 signaling. PMID- 22919672 TI - Shiga toxin in enterohemorrhagic E.coli: regulation and novel anti-virulence strategies. AB - Enterohemorrhagic Escherichia coli (EHEC) are responsible for major outbreaks of bloody diarrhea and hemolytic uremic syndrome (HUS) throughout the world. The mortality associated with EHEC infections stems from the production and release of a potent Shiga toxin (Stx) by these bacteria. Stx induces cell death in endothelial cells, primarily in the urinary tract, causing HUS. Stx was first described in Shigella dysenteriae serotype I by Kiyoshi Shiga and was discovered later in EHEC. Multiple environmental cues regulate the expression of Stx, including temperature, growth phase, antibiotics, reactive oxygen species (ROS), and quorum sensing. Currently, there is no effective treatment or prophylaxis for HUS. Because antibiotics trigger Stx production and their use to treat EHEC infections is controversial, alternative therapeutic strategies have become the focus of intense research. One such strategy explores quorum sensing inhibitors as therapeutics. These inhibitors target quorum sensing regulation of Stx expression without interfering with bacterial growth, leading to the hypothesis that these inhibitors impose less selective pressure for bacteria to develop drug resistance. In this review, we discuss factors that regulate Stx production in EHEC, as well as novel strategies to prevent and/or minimize the development of HUS in infected subjects. PMID- 22919673 TI - Differences in Shiga toxin and phage production among stx(2g)-positive STEC strains. AB - Shiga toxin-producing Escherichia coli (STEC) are characterized by the production of Shiga toxins (Stx) encoded by temperate bacteriophages. Stx production is linked to the induction of the phage lytic cycle. Several stx variants have been described and differentially associated with the risk of developing severe illness. The variant named stx(2g) was first identified in a STEC strain isolated from the faeces of healthy cattle. Analysis of stx(2g)-positive strains isolated from humans, animals, and environmental sources have shown that they have a close relationship. In this study, stx(2g)-positive STEC isolated from cattle were analyzed for phage and Stx production, with the aim to relate the results to differences observed in cytotoxicity. The presence of inducible phages was assessed by analyzing the bacterial growth/lysis curves and also by plaque assay. Bacterial growth curves in the absence of induction were similar for all isolates, however, notably differed among induced cultures. The two strains that clearly evidenced bacteriolysis under this condition also showed higher phage titers in plaque assays. However, only the phage plaques produced by one of these strains (FB 62) hybridized with a stx(2)-probe. Furthermore, the production of Stx was evaluated by enzyme immunoassay (EIA) and Western immunoblotting in overnight supernatants. By EIA, we detected Stx only in supernatants of FB 62, with a higher signal for induced than uninduced cultures. By immunoblotting, Stx2 could be detected after induction in all stx(2g)-positive isolates, but with lower amounts of Stx2B subunit in those supernatants where phages could not be detected. Taking into account all the results, several differences could be found among stx(2g)-positive strains. The strain with the highest cytotoxic titer showed higher levels of stx(2)-phages and toxin production by EIA, and the opposite was observed for strains that previously showed low cytotoxic titers, confirming that in stx(2g)-positive strains Stx production is phage-regulated. PMID- 22919674 TI - The early interaction of Leishmania with macrophages and dendritic cells and its influence on the host immune response. AB - The complicated interactions between Leishmania and the host antigen-presenting cells (APCs) have fundamental effects on the final outcome of the disease. Two major APCs, macrophages and dendritic cells (DCs), play critical roles in mediating resistance and susceptibility during Leishmania infection. Macrophages are the primary resident cell for Leishmania: they phagocytose and permit parasite proliferation. However, these cells are also the major effector cells to eliminate infection. The effective clearance of parasites by macrophages depends on activation of appropriate immune response, which is usually initiated by DCs. Here, we review the early interaction of APCs with Leishmania parasites and how these interactions profoundly impact on the ensuing adaptive immune response. We also discuss how the current knowledge will allow further refinement of our understanding of the interplay between Leishmania and its hosts that leads to resistance or susceptibility. PMID- 22919675 TI - Detection of Shiga toxin-producing Escherichia coli by sandwich enzyme-linked immunosorbent assay using chicken egg yolk IgY antibodies. AB - Enterohemorrhagic Escherichia coli (EHEC), a subset of Shiga toxin producing E. coli (STEC) is associated with a spectrum of diseases that includes diarrhea, hemorrhagic colitis and a life-threatening hemolytic-uremic syndrome (HUS). Regardless of serotype, Shiga toxins (Stx1 and/or Stx2) are uniformly expressed by all EHEC, and so exploitable targets for laboratory diagnosis of these pathogens. In this study, a sandwich ELISA for determination of Shiga toxin (Stx) was developed using anti-Stx2B subunit antibodies and its performance was compared with that of the Vero cell assay and a commercial immunoassay kit. Chicken IgY was used as capture antibody and a HRP-conjugated rabbit IgG as the detection antibody. The anti-Stx2B IgY was harvested from eggs laid by hens immunized with a recombinant protein fragment. Several parameters were tested in order to optimize the sandwich ELISA assay, including concentration of antibodies, type and concentration of blocking agent, and incubation temperatures. Supernatants from 42 STEC strains of different serotypes and stx variants, including stx(2EDL933), stx(2vha), stx(2vhb), stx(2g), stx(1EDL933), and stx(1d) were tested. All Stx variants were detected by the sandwich ELISA, with a detection limit of 115 ng/ml Stx2. Twenty three strains negative for stx genes, including different bacteria species, showed no activity in Vero cell assay and produced negative results in ELISA, except for two strains. Our results show that anti-Stx2B IgY sandwich ELISA could be used in routine diagnosis as a rapid, specific and economic method for detection of Shiga toxin-producing E. coli. PMID- 22919676 TI - Immunogenic recombinant Burkholderia pseudomallei MprA serine protease elicits protective immunity in mice. AB - Burkholderia pseudomallei is resistant to a diverse group of antimicrobials including third generation cephalosporins whilst quinolones and aminoglycosides have no reliable effect. As therapeutic options are limited, development of more effective forms of immunotherapy is vital to avoid a fatal outcome. In an earlier study, we reported on the B. pseudomallei serine MprA protease, which is relatively stable over a wide pH and temperature range and digests physiological proteins. The present study was carried out to evaluate the immunogenicity and protective efficacy of the MprA as a potential vaccine candidate. In BALB/c mice immunized with recombinant MprA protease (smBpF4), a significantly high IgG titer was detectable. Isotyping studies revealed that the smBpF4-specific antibodies produced were predominantly IgG(1), proposing that immunization with smBpF4 triggered a Th2 immune response. Mice were immunized with smBpF4 and subsequently challenged with B. pseudomallei via the intraperitoneal route. Whilst control mice succumbed to the infection by day 9, smBpF4-immunized mice were protected against the lethal challenge and survived beyond 25 days post-infection. In conclusion, MprA is immunogenic in melioidosis patients whilst also eliciting a strong immune response upon bacterial challenge in mice and presents itself as a potential vaccine candidate for the treatment of melioidosis. PMID- 22919677 TI - Lactic acid bacteria contribution to gut microbiota complexity: lights and shadows. AB - Lactic Acid Bacteria (LAB) are ancient organisms that cannot biosynthesize functional cytochromes, and cannot get ATP from respiration. Besides sugar fermentation, they evolved electrogenic decarboxylations and ATP-forming deiminations. The right balance between sugar fermentation and decarboxylation/deimination ensures buffered environments thus enabling LAB to survive in human gastric trait and colonize gut. A complex molecular cross-talk between LAB and host exists. LAB moonlight proteins are made in response to gut stimuli and promote bacterial adhesion to mucosa and stimulate immune cells. Similarly, when LAB are present, human enterocytes activate specific gene expression of specific genes only. Furthermore, LAB antagonistic relationships with other microorganisms constitute the basis for their anti-infective role. Histamine and tyramine are LAB bioactive catabolites that act on the CNS, causing hypertension and allergies. Nevertheless, some LAB biosynthesize both gamma-amino butyrate (GABA), that has relaxing effect on gut smooth muscles, and beta phenylethylamine, that controls satiety and mood. Since LAB have reduced amino acid biosynthetic abilities, they developed a sophisticated proteolytic system, that is also involved in antihypertensive and opiod peptide generation from milk proteins. Short-chain fatty acids are glycolytic and phosphoketolase end products, regulating epithelial cell proliferation and differentiation. Nevertheless, they constitute a supplementary energy source for the host, causing weight gain. Human metabolism can also be affected by anabolic LAB products such as conjugated linoleic acids (CLA). Some CLA isomers reduce cancer cell viability and ameliorate insulin resistance, while others lower the HDL/LDL ratio and modify eicosanoid production, with detrimental health effects. A further appreciated LAB feature is the ability to fix selenium into seleno-cysteine. Thus, opening interesting perspectives for their utilization as antioxidant nutraceutical vectors. PMID- 22919678 TI - Inhalational anthrax (Ames aerosol) in naive and vaccinated New Zealand rabbits: characterizing the spread of bacteria from lung deposition to bacteremia. AB - There is a need to better understand inhalational anthrax in relevant animal models. This understanding could aid risk assessment, help define therapeutic windows, and provide a better understanding of disease. The aim here was to characterize and quantify bacterial deposition and dissemination in rabbits following exposure to single high aerosol dose (> 100 LD(50)) of Bacillus anthracis (Ames) spores immediately following exposure through 36 h. The primary goal of collecting the data was to support investigators in developing computational models of inhalational anthrax disease. Rabbits were vaccinated prior to exposure with the human vaccine (Anthrax Vaccine Adsorbed, AVA) or were sham-vaccinated, and were then exposed in pairs (one sham and one AVA) so disease kinetics could be characterized in equally-dosed hosts where one group is fully protected and is able to clear the infection (AVA-vaccinated), while the other is susceptible to disease, in which case the bacteria are able to escape containment and replicate uncontrolled (sham-vaccinated rabbits). Between 4-5% of the presented aerosol dose was retained in the lung of sham- and AVA-vaccinated rabbits as measured by dilution plate analysis of homogenized lung tissue or bronchoalveolar lavage (BAL) fluid. After 6 and 36 h, >80% and >96%, respectively, of the deposited spores were no longer detected in BAL, with no detectable difference between sham- or AVA-vaccinated rabbits. Thereafter, differences between the two groups became noticeable. In sham-vaccinated rabbits the bacteria were detected in the tracheobronchial lymph nodes (TBLN) 12 h post exposure and in the circulation at 24 h, a time point which was also associated with dramatic increases in vegetative CFU in the lung tissue of some animals. In all sham-vaccinated rabbits, bacteria increased in both TBLN and blood through 36 h at which point in time some rabbits succumbed to disease. In contrast, AVA vaccinated rabbits showed small numbers of CFU in TBLN between 24 and 36 h post exposure with small numbers of bacteria in the circulation only at 24 h post exposure. These results characterize and quantify disease progression in naive rabbits following aerosol administration of Ames spores which may be useful in a number of different research applications, including developing quantitative models of infection for use in human inhalational anthrax risk assessment. PMID- 22919679 TI - Intelligibility in microbial complex systems: Wittgenstein and the score of life. AB - Knowledge in microbiology is reaching an extreme level of diversification and complexity, which paradoxically results in a strong reduction in the intelligibility of microbial life. In our days, the "score of life" metaphor is more accurate to express the complexity of living systems than the classic "book of life." Music and life can be represented at lower hierarchical levels by music scores and genomic sequences, and such representations have a generational influence in the reproduction of music and life. If music can be considered as a representation of life, such representation remains as unthinkable as life itself. The analysis of scores and genomic sequences might provide mechanistic, phylogenetic, and evolutionary insights into music and life, but not about their real dynamics and nature, which is still maintained unthinkable, as was proposed by Wittgenstein. As complex systems, life or music is composed by thinkable and only showable parts, and a strategy of half-thinking, half-seeing is needed to expand knowledge. Complex models for complex systems, based on experiences on trans-hierarchical integrations, should be developed in order to provide a mixture of legibility and imageability of biological processes, which should lead to higher levels of intelligibility of microbial life. PMID- 22919681 TI - Enterohemorrhagic E. coli (EHEC) pathogenesis. AB - Enterohemorrhagic Escherichia coli (EHEC) serotype O157:H7 is a human pathogen responsible for outbreaks of bloody diarrhea and hemolytic uremic syndrome (HUS) worldwide. Conventional antimicrobials trigger an SOS response in EHEC that promotes the release of the potent Shiga toxin that is responsible for much of the morbidity and mortality associated with EHEC infection. Cattle are a natural reservoir of EHEC, and approximately 75% of EHEC outbreaks are linked to the consumption of contaminated bovine-derived products. This review will discuss how EHEC causes disease in humans but is asymptomatic in adult ruminants. It will also analyze factors utilized by EHEC as it travels through the bovine gastrointestinal (GI) tract that allow for its survival through the acidic environment of the distal stomachs, and for its ultimate colonization in the recto-anal junction (RAJ). Understanding the factors crucial for EHEC survival and colonization in cattle will aid in the development of alternative strategies to prevent EHEC shedding into the environment and consequent human infection. PMID- 22919682 TI - Lamarckian evolution of the giant Mimivirus in allopatric laboratory culture on amoebae. AB - Acanthamoeba polyphaga Mimivirus has been subcultured 150 times on germ-free amoebae. This allopatric niche is very different from that found in the natural environment, where the virus is in competition with many other organisms. In this experiment, substantial gene variability and loss occurred concurrently with the emergence of phenotypically different viruses. We sought to quantify the respective roles of Lamarckian and Darwinian evolution during this experiment. We postulated that the Mimivirus genes that were down-regulated at the beginning of the allopatric laboratory culture and inactivated after 150 passages experienced Lamarckian evolution because phenotypic modifications preceded genotypic modifications, whereas we considered that genes that were highly transcribed in the new niche but were later inactivated obeyed Darwinian rules. We used the total transcript abundances and sequences described for the genes of Mimivirus at the beginning of its laboratory life and after 150 passages in allopatric culture on Acanthamoeba spp. We found a statistically significant positive correlation between the level of gene expression at the beginning of the culture and gene inactivation during the 150 passages. In particular, the mean transcript abundance at baseline was significantly lower for inactivated genes than for unchanged genes (165 +/- 589 vs. 470 +/- 1,625; p < 1e-3), and the mean transcript levels during the replication cycle of Mimivirus M1 were up to 8.5 fold lower for inactivated genes than for unchanged genes. In addition, proteins tended to be less frequently identified from purified virions in their early life in allopatric laboratory culture if they were encoded by variable genes than if they were encoded by conserved genes (9 vs. 15%; p = 0.062). Finally, Lamarckian evolution represented the evolutionary process encountered by 63% of the inactivated genes. Such observations may be explained by the lower level of DNA repair of useless genes. PMID- 22919680 TI - Gene flow and biological conflict systems in the origin and evolution of eukaryotes. AB - The endosymbiotic origin of eukaryotes brought together two disparate genomes in the cell. Additionally, eukaryotic natural history has included other endosymbiotic events, phagotrophic consumption of organisms, and intimate interactions with viruses and endoparasites. These phenomena facilitated large scale lateral gene transfer and biological conflicts. We synthesize information from nearly two decades of genomics to illustrate how the interplay between lateral gene transfer and biological conflicts has impacted the emergence of new adaptations in eukaryotes. Using apicomplexans as example, we illustrate how lateral transfer from animals has contributed to unique parasite-host interfaces comprised of adhesion- and O-linked glycosylation-related domains. Adaptations, emerging due to intense selection for diversity in the molecular participants in organismal and genomic conflicts, being dispersed by lateral transfer, were subsequently exapted for eukaryote-specific innovations. We illustrate this using examples relating to eukaryotic chromatin, RNAi and RNA-processing systems, signaling pathways, apoptosis and immunity. We highlight the major contributions from catalytic domains of bacterial toxin systems to the origin of signaling enzymes (e.g., ADP-ribosylation and small molecule messenger synthesis), mutagenic enzymes for immune receptor diversification and RNA-processing. Similarly, we discuss contributions of bacterial antibiotic/siderophore synthesis systems and intra-genomic and intra-cellular selfish elements (e.g., restriction modification, mobile elements and lysogenic phages) in the emergence of chromatin remodeling/modifying enzymes and RNA-based regulation. We develop the concept that biological conflict systems served as evolutionary "nurseries" for innovations in the protein world, which were delivered to eukaryotes via lateral gene flow to spur key evolutionary innovations all the way from nucleogenesis to lineage-specific adaptations. PMID- 22919683 TI - Vacuolating cytotoxin A (VacA), a key toxin for Helicobacter pylori pathogenesis. AB - More than 50% of the world's population is infected with Helicobacter pylori (H. pylori). Chronic infection with this Gram-negative pathogen is associated with the development of peptic ulcers and is linked to an increased risk of gastric cancer. H. pylori secretes many proteinaceous factors that are important for initial colonization and subsequent persistence in the host stomach. One of the major protein toxins secreted by H. pylori is the Vacuolating cytotoxin A (VacA). After secretion from the bacteria via a type V autotransport secretion system, the 88 kDa VacA toxin (comprised of the p33 and p55 subunits) binds to host cells and is internalized, causing severe "vacuolation" characterized by the accumulation of large vesicles that possess hallmarks of both late endosomes and early lysosomes. The development of "vacuoles" has been attributed to the formation of VacA anion-selective channels in membranes. Apart from its vacuolating effects, it has recently become clear that VacA also directly affects mitochondrial function. Earlier studies suggested that the p33 subunit, but not the p55 subunit of VacA, could enter mitochondria to modulate organelle function. This raised the possibility that a mechanism separate from pore formation may be responsible for the effects of VacA on mitochondria, as crystallography studies and structural modeling predict that both subunits are required for a physiologically stable pore. It has also been suggested that the mitochondrial effects observed are due to indirect effects on pro-apoptotic proteins and direct effects on mitochondrial morphology-related processes. Other studies have shown that both the p55 and p33 subunits can indeed be efficiently imported into mammalian-derived mitochondria raising the possibility that they could re assemble to form a pore. Our review summarizes and consolidates the recent advances in VacA toxin research, with focus on the outstanding controversies in the field and the key remaining questions that need to be addressed. PMID- 22919684 TI - Maternal factors pre- and during delivery contribute to gut microbiota shaping in newborns. PMID- 22919685 TI - Programmed cell death in Leishmania: biochemical evidence and role in parasite infectivity. AB - Demonstration of features of a programmed cell death (PCD) pathway in protozoan parasites initiated a great deal of interest and debate in the field of molecular parasitology. Several of the markers typical of mammalian apoptosis have been shown in Leishmania which suggested the existence of an apoptosis like death in these organisms. However, studies to elucidate the downstream events associated with phosphotidyl serine exposure, loss of mitochondrial membrane potential, cytochrome c release, and caspase-like activities in cells undergoing such cell death remain an ongoing challenge. Recent advances in genome sequencing, chemical biology should help to solve some of these challenges. Leishmania genetic mutants that lack putative regulators/effectors of PCD pathway should not only help to demonstrate the mechanisms of PCD but also provide tools to better understand the putative role for this pathway in population control and in the establishment of a successful infection of the host. PMID- 22919686 TI - Nontypeable Haemophilus influenzae biofilms: role in chronic airway infections. AB - Like many pathogens inhabiting mucosal surfaces, nontypeable Haemophilus influenzae (NTHi) forms multicellular biofilm communities both in vitro and in various infection models. In the past 15 years much has been learned about determinants of biofilm formation by this organism and potential roles in bacterial virulence, especially in the context of chronic and recurrent infections. However, this concept has not been without some degree of controversy, and in the past some have expressed doubts about the relevance of NTHi biofilms to disease. In this review, I will summarize the present information on the composition and potential role(s) of NTHi biofilms in different clinical contexts, as well as highlight potential areas for future work. PMID- 22919689 TI - Quorum signaling and sensing by nontypeable Haemophilus influenzae. AB - Quorum signals are diffusible factors produced by bacteria that coordinate communal responses. For nontypeable Haemophilus influenzae (NTHi), a series of recent papers indicate that production and sensing of quorum signals are determinants of biofilm formation/maturation and persistence in vivo. In this mini-review I will summarize the current knowledge about quorum signaling/sensing by this organism, and identify specific topics for additional study. PMID- 22919687 TI - Protein based molecular markers provide reliable means to understand prokaryotic phylogeny and support Darwinian mode of evolution. AB - The analyses of genome sequences have led to the proposal that lateral gene transfers (LGTs) among prokaryotes are so widespread that they disguise the interrelationships among these organisms. This has led to questioning of whether the Darwinian model of evolution is applicable to prokaryotic organisms. In this review, we discuss the usefulness of taxon-specific molecular markers such as conserved signature indels (CSIs) and conserved signature proteins (CSPs) for understanding the evolutionary relationships among prokaryotes and to assess the influence of LGTs on prokaryotic evolution. The analyses of genomic sequences have identified large numbers of CSIs and CSPs that are unique properties of different groups of prokaryotes ranging from phylum to genus levels. The species distribution patterns of these molecular signatures strongly support a tree-like vertical inheritance of the genes containing these molecular signatures that is consistent with phylogenetic trees. Recent detailed studies in this regard on the Thermotogae and Archaea, which are reviewed here, have identified large numbers of CSIs and CSPs that are specific for the species from these two taxa and a number of their major clades. The genetic changes responsible for these CSIs (and CSPs) initially likely occurred in the common ancestors of these taxa and then vertically transferred to various descendants. Although some CSIs and CSPs in unrelated groups of prokaryotes were identified, their small numbers and random occurrence has no apparent influence on the consistent tree-like branching pattern emerging from other markers. These results provide evidence that although LGT is an important evolutionary force, it does not mask the tree-like branching pattern of prokaryotes or understanding of their evolutionary relationships. The identified CSIs and CSPs also provide novel and highly specific means for identification of different groups of microbes and for taxonomical and biochemical studies. PMID- 22919690 TI - Particle-size dependent effects in the Balb/c murine model of inhalational melioidosis. AB - Deposition of Burkholderia pseudomallei within either the lungs or nasal passages of the Balb/c murine model resulted in different infection kinetics. The infection resulting from the inhalation of B. pseudomallei within a 12 MUm particle aerosol was prolonged compared to a 1 MUm particle aerosol with a mean time-to-death (MTD) of 174.7 +/- 14.9 h and 73.8 +/- 11.3 h, respectively. Inhalation of B. pseudomallei within 1 MUm or 12 MUm particle aerosols resulted in a median lethal dose (MLD) of 4 and 12 cfu, respectively. The 12 MUm particle inhalational infection was characterized by a marked involvement of the nasal mucosa and extension of bacterial colonization and inflammatory lesions from the olfactory epithelium through the olfactory nerves (or tracts) to the olfactory bulb (100%), culminating in abscessation of the brain (33%). Initial involvement of the upper respiratory tract lymphoid tissues (nasal-associated lymphoid tissue (NALT) and cervical lymph nodes) was observed in both the 1 and 12 MUm particle inhalational infections (80-85%). Necrotising alveolitis and bronchiolitis were evident in both inhalational infections, however, lung pathology was greater after inhalation of the 1 MUm particle aerosol with pronounced involvement of the mediastinal lymph node (50%). Terminal disease was characterized by bacteraemia in both inhalational infections with dissemination to the spleen, liver, kidneys, and thymus. Treatment with co-trimoxazole was more effective than treatment with doxycycline irrespective of the size of the particles inhaled. Doxycycline was more effective against the 12 MUm particle inhalational infection as evidenced by increased time to death. However, both treatment regimes exhibited significant relapse when therapy was discontinued with massive enlargement and abscessation of the lungs, spleen, and cervical lymph nodes observed. PMID- 22919688 TI - Leishmania RNA virus: when the host pays the toll. AB - The presence of an RNA virus in a South American subgenus of the Leishmania parasite, L. (Viannia), was detected several decades ago but its role in leishmanial virulence and metastasis was only recently described. In Leishmania guyanensis, the nucleic acid of Leishmania RNA virus (LRV1) acts as a potent innate immunogen, eliciting a hyper-inflammatory immune response through toll like receptor 3 (TLR3). The resultant inflammatory cascade has been shown to increase disease severity, parasite persistence, and perhaps even resistance to anti-leishmanial drugs. Curiously, LRVs were found mostly in clinical isolates prone to infectious metastasis in both their human source and experimental animal model, suggesting an association between the viral hyperpathogen and metastatic complications such as mucocutaneous leishmaniasis (MCL). MCL presents as chronic secondary lesions in the mucosa of the mouth and nose, debilitatingly inflamed and notoriously refractory to treatment. Immunologically, this outcome has many of the same hallmarks associated with the reaction to LRV: production of type 1 interferons, bias toward a chronic Th1 inflammatory state and an impaired ability of host cells to eliminate parasites through oxidative stress. More intriguing, is that the risk of developing MCL is found almost exclusively in infections of the L. (Viannia) subtype, further indication that leishmanial metastasis is caused, at least in part, by a parasitic component. LRV present in this subgenus may contribute to the destructive inflammation of metastatic disease either by acting in concert with other intrinsic "metastatic factors" or by independently preying on host TLR3 hypersensitivity. Because LRV amplifies parasite virulence, its presence may provide a unique target for diagnostic and clinical intervention of metastatic leishmaniasis. Taking examples from other members of the Totiviridae virus family, this paper reviews the benefits and costs of endosymbiosis, specifically for the maintenance of LRV infection in Leishmania parasites, which is often at the expense of its human host. PMID- 22919691 TI - Cationic antimicrobial peptides serve as activation signals for the Salmonella Typhimurium PhoPQ and PmrAB regulons in vitro and in vivo. AB - Salmonella enterica serovar Typhimurium uses two-component regulatory systems (TCRSs) to respond to environmental stimuli. Upon infection, the TCRSs PhoP-PhoQ (PhoPQ) and PmrA-PmrB (PmrAB) are activated by environmental signals detected in the lumen of the intestine and within host cells. TCRS-mediated gene expression leads to upregulation of genes involved in lipopolysaccharide (LPS) modification and cationic antimicrobial peptide (CAMP) resistance. This research expands on previous studies which have shown that CAMPs can activate Salmonella TCRSs in vitro. The focus of this work was to determine if CAMPs can act as environmental signals for PhoPQ- and PmrAB-mediated gene expression in vitro, during infection of macrophages and in a mouse model of infection. Monitoring of PhoPQ and PmrAB activation using recombinase-based in vivo expression technology (RIVET), alkaline phosphtase and beta-galactosidase reporter fusion constructs demonstrated that S. Typhimurium PhoQ can sense CAMPs in vitro. In mouse macrophages, the cathelecidin CRAMP does not activate the PhoPQ regulon. Acidification of the Salmonella-containing vacuole activates PhoP- and PmrA regulated loci but blocking acidification still does not reveal a role for CRAMP in TCRS activation in mouse macrophages. However, assays performed in susceptible wild type (WT), CRAMP knockout (KO), and matrilysin (a metalloproteinase necessary for activating murine alpha-defensins) KO mice suggest CRAMP, but not alpha-defensins, serve as a putative direct TCRS activation signal in the mouse intestine. These studies provide a better understanding of the in vivo environments that result in activation of these virulence-associated TCRSs. PMID- 22919692 TI - Yersinia pestis Ail: multiple roles of a single protein. AB - Yersinia pestis is one of the most virulent bacteria identified. It is the causative agent of plague-a systemic disease that has claimed millions of human lives throughout history. Y. pestis survival in insect and mammalian host species requires fine-tuning to sense and respond to varying environmental cues. Multiple Y. pestis attributes participate in this process and contribute to its pathogenicity and highly efficient transmission between hosts. These include factors inherited from its enteric predecessors; Y. enterocolitica and Y. pseudotuberculosis, as well as phenotypes acquired or lost during Y. pestis speciation. Representatives of a large Enterobacteriaceae Ail/OmpX/PagC/Lom family of outer membrane proteins (OMPs) are found in the genomes of all pathogenic Yersiniae. This review describes the current knowledge regarding the role of Ail in Y. pestis pathogenesis and virulence. The pronounced role of Ail in the following areas are discussed (1) inhibition of the bactericidal properties of complement, (2) attachment and Yersinia outer proteins (Yop) delivery to host tissue, (3) prevention of PMNL recruitment to the lymph nodes, and (4) inhibition of the inflammatory response. Finally, Ail homologs in Y. enterocolitica and Y. pseudotuberculosis are compared to illustrate differences that may have contributed to the drastic bacterial lifestyle change that shifted Y. pestis from an enteric to a vector-born systemic pathogen. PMID- 22919694 TI - Choice of inbred rat strain impacts lethality and disease course after respiratory infection with Rift Valley Fever Virus. AB - Humans infected with Rift Valley Fever Virus (RVFV) generally recover after a febrile illness; however, a proportion of patients progress to a more severe clinical outcome such as hemorrhagic fever or meningoencephalitis. RVFV is naturally transmitted to livestock and humans by mosquito bites, but it is also infectious through inhalational exposure, making it a potential bioterror weapon. To better understand the disease caused by inhalation of RVFV, Wistar-Furth, ACI, or Lewis rats were exposed to experimental aerosols containing virulent RVFV. Wistar-Furth rats developed a rapidly progressing lethal hepatic disease after inhalational exposure; ACI rats were 100-fold less susceptible and developed fatal encephalitis after infection. Lewis rats, which do not succumb to parenteral inoculation with RVFV, developed fatal encephalitis after aerosol infection. RVFV was found in the liver, lung, spleen, heart, kidney and brain of Wistar Furth rats that succumbed after aerosol exposure. In contrast, RVFV was found only in the brains of ACI or Lewis rats that succumbed after aerosol exposure. Lewis rats that survived s.c. infection were not protected against subsequent re-challenge by aerosol exposure to the homologous virus. This is the first side-by-side comparison of the lethality and pathogenesis of RVFV in three rat strains after aerosol exposure and the first step toward developing a rodent model suitable for use under the FDA Animal Rule to test potential vaccines and therapeutics for aerosol exposure to RVFV. PMID- 22919693 TI - The function of our microbiota: who is out there and what do they do? AB - Current meta-omics developments provide a portal into the functional potential and activity of the intestinal microbiota. The comparative and functional meta omics approaches have made it possible to get a molecular snap shot of microbial function at a certain time and place. To this end, metagenomics is a DNA-based approach, metatranscriptomics studies the total transcribed RNA, metaproteomics focuses on protein levels and metabolomics describes metabolic profiles. Notably, the metagenomic toolbox is rapidly expanding and has been instrumental in the generation of draft genome sequences of over 1000 human associated microorganisms as well as an astonishing 3.3 million unique microbial genes derived from the intestinal tract of over 100 European adults. Remarkably, it appeared that there are at least 3 clusters of co-occurring microbial species, termed enterotypes, that characterize the intestinal microbiota throughout various continents. The human intestinal microbial metagenome further revealed unique functions carried out in the intestinal environment and provided the basis for newly discovered mechanisms for signaling, vitamin production and glycan, amino-acid and xenobiotic metabolism. The activity and composition of the microbiota is affected by genetic background, age, diet, and health status of the host. In its turn the microbiota composition and activity influence host metabolism and disease development. Exemplified by the differences in microbiota composition and activity between breast- as compared to formula-fed babies, healthy and malnourished infants, elderly and centenarians as compared to youngsters, humans that are either lean or obese and healthy or suffering of inflammatory bowel diseases (IBD). In this review we will focus on our current understanding of the functionality of the human intestinal microbiota based on all available metagenome, metatranscriptome, and metaproteome results. PMID- 22919695 TI - Darwin's goldmine is still open: variation and selection run the world. AB - The scientific contribution of Darwin, still agonized in many religious circles, has now been recognized and celebrated by scientists from various disciplines. However, in recent years, several evolutionists have criticized Darwin as outdated, arguing that "Darwinism," assimilated to the "tree of life," cannot explain microbial evolution, or else was not operating in early life evolution. These critics either confuse "Darwinism" and old versions of "neo-Darwinism" or misunderstand the role of gene transfers in evolution. The core of Darwin explanation of evolution (variation/selection) remains necessary and sufficient to decipher the history of life. The enormous diversity of mechanisms underlying variations has been successfully interpreted by evolutionists in this framework and has considerably enriched the corpus of evolutionary biology without the necessity to kill the father. However, it remains for evolutionists to acknowledge interactions between cells and viruses (unknown for Darwin) as a major driving force in life evolution. PMID- 22919696 TI - The effect of low shear force on the virulence potential of Yersinia pestis: new aspects that space-like growth conditions and the final frontier can teach us about a formidable pathogen. AB - Manned space exploration has created a need to evaluate the effects of space-like stress (SLS) on pathogenic and opportunistic microbes. Interestingly, several Gram-negative enteric pathogens, e.g., Salmonella enterica serovar Typhimurium, have revealed a transient hyper-virulent phenotype following simulated microgravity (SMG) or actual space flight exposures. We have explored the virulence potential of Yersinia pestis KIM/D27 (YP) following exposure to mechanical low shear forces associated with SMG. Our experimental results demonstrated that SMG-grown YP was decreased in its induced HeLa cell cytotoxicity, suggesting that SMG somehow compromises T3SS functions. This was confirmed by an actual reduced amount of effector protein production and secretion through the T3SS injectisome. Also, SMG-grown YP proliferated less than their NG-grown counterparts did during an 8-h macrophage infection. Presently, we are evaluating the influence of SMG on various KIM/D27 mutant strains to further understanding of our initial phenomenology described above. Taken together, characterizing YP grown under the low shear forces of SMG can provide new insights into its pathogenesis and potentially uncover new targets that could be exploited for the development of novel antimicrobials as well as potential live attenuated vaccines. PMID- 22919698 TI - Subtyping of STEC by MLVA in Argentina. AB - Shiga toxin-producing Escherichia coli (STEC) causes serious human illness such as hemolytic uremic syndrome (HUS). Argentina has the world's highest rate of this syndrome, which is the leading cause of acute renal failure among children. E. coli O157:H7 is the most common cause of HUS, but a substantial and growing proportion of this illness is caused by infection due to non-O157 strains. Multiple-locus variable-number tandem repeat analysis (MLVA) has become an established technique to subtype STEC. This review will address the use of routine STEC subtyping by MLVA in order to type this group of isolates and to get insight into the genetic diversity of native STEC. With regard to these objectives we modified and adapted two MLVA protocols, one exclusive for O157 and the other, a generic E. coli assay. A total of 202 STEC isolates, from different sources and corresponding to 20 serotypes, have been MLVA genotyped in our laboratory. In our experience, MLVA constitutes a very sensitive tool and enables us to perform an efficient STEC subtyping. The diversity found in many serotypes may be useful for future epidemiological studies of STEC clonality, applied to O157 as well as to non-O157 isolates. PMID- 22919699 TI - Migration behaviour of discontinuous buffers in capillary electrophoresis during protein enrichment. AB - Capillary electrophoresis (CE) is not only an effective separation technique, but can also serve as a sample preparation tool for enrichment and purification at sub-microliter sample volumes. Our approach is based on the use of a discontinuous buffer system consisting of an acid and a base (acetate and ammonium). Proteins and/or peptides with isoelectric points between the pH values of these two buffers will become stacked at the neutralization reaction boundary (NRB). To understand the mechanism of the NRB formation and the electrophoretic migration of various ions during the enrichment, we performed experiments using myoglobin and mesityl oxide to reveal the ion migration patterns at the buffer junction, and utilized Simul 5 to computer simulate the process. The simulated results closely resembled the experimental data, and together, they effectively revealed the characteristics of the discontinuous buffers. Importantly, the discovery allowed the manipulation of NRB behaviours by controlling the discontinuous buffer composition. To illustrate this, the removal of urea as an unwanted background molecule from the enriched protein sample was achieved based on the acquired information. PMID- 22919700 TI - Investigating cellular responses to novel chemotherapeutics in renal cell carcinoma using SR-FTIR spectroscopy. AB - SR-FTIR spectroscopy was evaluated as a technique to discriminate spectral signals of cellular response at the single cell level, when cancer cells are exposed to chemotherapeutics. 5-Fluorouracil, an established drug of known mode of action, was tested against a renal carcinoma cell line (Caki-2), along with two experimental analogues of gold-based compounds. The use of unsupervised principal component analysis (PCA) failed to clearly define any distinction between control and drug treated cell spectra. Supervised principal component linear discriminant analysis (PC-LDA) did have some potential to reveal signatures of cell response and repair but again failed to distinctly discriminate groups of spectra with different drug treatments. Alternatively, clear PCA discrimination was observed in spectra from average cell populations via single point benchtop spectroscopy, probing several cells simultaneously with an increased aperture. The Caki-2 cell line initially appeared to be sensitive to the novel compounds, inducing a cellular response prior to subsequential cell recovery which was assessed by both PCA and cell viability assays. PMID- 22919697 TI - Lateral gene exchanges shape the genomes of amoeba-resisting microorganisms. AB - Based on Darwin's concept of the tree of life, vertical inheritance was thought to be dominant, and mutations, deletions, and duplication were streaming the genomes of living organisms. In the current genomic era, increasing data indicated that both vertical and lateral gene inheritance interact in space and time to trigger genome evolution, particularly among microorganisms sharing a given ecological niche. As a paradigm to their diversity and their survival in a variety of cell types, intracellular microorganisms, and notably intracellular bacteria, were considered as less prone to lateral genetic exchanges. Such specialized microorganisms generally have a smaller gene repertoire because they do rely on their host's factors for some basic regulatory and metabolic functions. Here we review events of lateral gene transfer (LGT) that illustrate the genetic exchanges among intra-amoebal microorganisms or between the microorganism and its amoebal host. We tentatively investigate the functions of laterally transferred genes in the light of the interaction with their host as they should confer a selective advantage and success to the amoeba-resisting microorganisms (ARMs). PMID- 22919701 TI - CTAB-capped Mn-doped ZnS quantum dots and label-free aptamer for room-temperature phosphorescence detection of mercury ions. AB - A new room-temperature phosphorescence (RTP) mercury ions sensor has been developed based on cetyltrimethylammonium bromide-capped Mn-doped ZnS quantum dots (CTAB/Mn-ZnS QDs) and label-free thymine (T)-rich aptamer. The formed T Hg(2+)-T dsDNA can linearly quench the RTP of Mn-ZnS QDs through electron transfer and aggregation effect, and give a detection limit of 1.5 nM. PMID- 22919702 TI - Functionalized shell-isolated nanoparticle-enhanced Raman spectroscopy for selective detection of trinitrotoluene. AB - Shell-isolated nanoparticle-enhanced Raman spectroscopy (SHINERS), which acts as the next generation of advanced spectroscopy, expands the versatility of surface enhanced Raman spectroscopy (SERS). Here we present a facile one-step method to prepare functionalized core-shell nanoparticles for selective detection of trinitrotoluene (TNT) through the formation of Meisenheimer complexes. A well designed type of tunable poly(2-aminothiophenol) (PAT) shells on gold nanoparticles was prepared for the first time and the shell thickness of 2 nm could be controlled by only adjusting the molar ratio of sodium dodecylsulfate (SDS) to 2-aminothiophenol. The polymer shells shows prominent advantages, including uniformity, better chemical stability, being free of pin-holes and amino-functionalized. PMID- 22919703 TI - A nanoscale graphene oxide-peptide biosensor for real-time specific biomarker detection on the cell surface. AB - A nanoscale RGD-pyrene-graphene oxide (GO) biosensor was prepared for real-time in situ detection of a cancer cell surface marker, integrin alphavbeta3. This nanoscale GO-based biosensor is simple, robust, sensitive and of high selectivity. It can also be adapted to other cancer cell surface marker evaluation systems. PMID- 22919704 TI - Differences in nucleotide excision repair capacity between newly diagnosed colorectal cancer patients and healthy controls. PMID- 22919705 TI - Corrigendum: Serotonin transporter gene, stress, and raphe-raphe interactions: a molecular mechanism of depression. PMID- 22919706 TI - [Personalized medicine - the next revolution in medicine?]. PMID- 22919707 TI - Career development: What's your type? PMID- 22919708 TI - Cancer: Resolving the stem-cell debate. PMID- 22919709 TI - Reply to van Hoorn: Converging lines of evidence. PMID- 22919710 TI - The interactome. By Caveman. PMID- 22919711 TI - [The letters from the exile of the academician S.S. Yudin]. AB - Unknown letters of the professor S.S. Yudin are presented in the article, written by him at period of the reference in Berdsk. They are addressed to his colleague in the Institute to ambulance named after the N.V. Sklifosovskiy. The authors give the estimation epistolary heritage known surgeon, considering its as an important source on study of the histories to domestic surgery. The noted role of the museum of clinical institution in conservation and presentations society monuments of the medical science. PMID- 22919712 TI - In Memoriam: Sergio Ragi-Eis, MD, CCD, CDT (April 8, 1962-February 22, 2012). PMID- 22919713 TI - Greiner Bio-One North America offers solutions in biotechnology, diagnostics, and pharmaceuticals. PMID- 22919714 TI - [Advances in the study of inhibitors of kinases and nuclear factors for treating allergic asthma]. AB - Currently, about 300 million people worldwide are affected by asthma. Most of these sufferers inhale immunosuppressants (ie corticosteroids) and beta adrenergic receptor agonists for their asthma treatment. However, about 5%-10% of patients of asthma have poor response to such treatment. Investigation of kinase signaling pathway and nuclear transcription factor as a target molecule in the treatment of allergic asthma has been the concern of scholars home and abroad. This paper reviewed inhibitors of kinase signaling pathway and nuclear transcription factors for the treatment of asthma. PMID- 22919715 TI - [Network pharmacology: new opportunity for the modernization of traditional Chinese medicine]. AB - Traditional Chinese medicine (TCM) with the characteristics of holistic view and treatment based on syndrome differentiation, has rich clinical experience thousands of years and demonstrates promising effects to cure complex disease. However, due to the features of multi-component, multi-target and synergistic effect existed in TCM, the effective substances and mechanisms of action are not clear, the qualities of TCM are out of control, and scientific and correct assess system is waiting to be established. The network pharmacology is a novel subject based on the construction of multi-layer networks of disease-phenotype-gene-drug to predict the drug targets in a holistic view, and promote efficiency of drug discovery. Methodologically, network pharmacology integrated the notions of comprehensive research and systematic assessment which agree with the characteristics of holistic view and treatment based on syndrome differentiation in Chinese medicine. Our paper reviewed the challenge and chance within the modernization of TCM, the concept and technology of network pharmacology, and its preliminary application in investigation of TCM. The theoretical system of network pharmacology is emphasized, and the potential prospect of its application in modernization in TCM is focused. PMID- 22919716 TI - [Progress in the ligands and their complex structures of farnesoid X receptor]. AB - Farnesoid X receptor (FXR) belongs to the nuclear receptor superfamily. It is highly related to the formation of metabolic syndrome and the glucose homeostasis, and therefore represents an important drug target against metabolic diseases and diabetes. In recent years, great progress has been made in the agonists, antagonists, and crystal structures of FXR. The diverse FXR ligands and their structure-activity relationship are reviewed in this article. The advances in the crystal structures of FXR in complex with different ligands are also introduced. PMID- 22919717 TI - [Research progress of sodium-glucose co-transporter 2 inhibitors for treatment of type 2 diabetes]. AB - Sodium-glucose co-transporters are a family of glucose transporter found in the intestinal mucosa of the small intestine (SGLT-2) and the proximal tubule of the nephron (SGLT-1 and SGLT-2). They contribute to renal glucose reabsorption and most of renal glucose (about 90%) is reabsorbed by SGLT-2 located in the proximal renal tubule. Selectively inhibiting activity of SGLT-2 is an innovative therapeutic strategy for treatment of type 2 diabetes by enhancing urinary glucose excretion from the body. Therefore SGLT-2 inhibitors are considered to be potential antidiabetic drugs with an unique mechanism. This review will highlight some recent advances and structure-activity relationships in the discovery and development of SGLT-2 inhibitors including O-glycoside, C-glycoside, C, O-spiro glycoside and non glycosides. PMID- 22919718 TI - [Research progress of the atypical kinetic profiles of cytochrome P450 enzymes]. AB - Cytochrome P450 enzymes are composed of many isozymes and involved in the biotransformation of both exogenous and endogenous substances. A growing number of studies have found that the P450 enzymes do not always follow the classical Michaelis-Menten kinetics, but show atypical kinetic behavior, which is also the current research hotspot. In this paper, the category and mechanisms of atypical kinetics of the P450 enzyme were reviewed, providing theoretical basis for the research of enzyme kinetics. PMID- 22919719 TI - [A study on the standard of influenza neuraminidase inhibition assay]. AB - In present study, standard method and standard operation practice for measuring the activities of influenza neuraminidase and its inhibitors have been established. The accuracy and stability of the method has been evaluated. Standard operation is as following: 10 microL sample, 30 microL neuraminidase and 60 microL substrate are added to one well of a 96-well plate, and then incubated at 37 degrees C for 1 h. The reaction was stopped with NaOH before fluorescence intensity determination. One unit of neuraminidase is defined as the amount of enzyme that produces 1 nmol 4-MU in 1 h under above conditions. The inhibition accuracy is indicated by an uncertainty measurement of 6.51 x 10(-12), and its stability was reaffirmed by determination of oseltamivir acid. In this study, systematic assessment of neuraminidase inhibitory assay not only provided theoretical basis of its application in drug discovery, but also made preliminary attempt to use uncertainty measurement as a parameter in biological measurement. PMID- 22919720 TI - [Trans-splicing of Cys mutated coagulation factor VIII]. AB - To investigate the improving effect of inter-chain disulfide formation on protein trans-splicing, we introduce a Cys point mutation at Tyr(664) in heavy chain and at Thr(1826) in light chain of B-domain-deleted FVIII (BDD-FVIII). By co transfection of COS-7 cell with the two Cys mutated chain genes, the intracellular protein splicing, inter-chain disulfide formation, secreted BDD FVIII and bioactivity in culture supernatant were observed. The data showed that a strengthened spliced BDD-FVIII with an inter-chain disulfide detected by Western blotting and an elevated secretion of spliced BDD-FVIII (128 +/- 24 ng mL(-1)) compared to control (89 +/- 15 ng mL(-1)), assayed by a sandwich ELISA. A Coatest was performed to assay the secretion of bioactivity in culture supernatant and shown a much higher value (0.94 +/- 0.08 u mL(-1)) compared to that of control (0.62 +/- 0.15 u mL(-1)). It suggests that inter-chain disulfide formation could improve protein trans-splicing based dual-vector delivery of BDD FVIII gene providing experimental evidence for ongoing in vivo study. PMID- 22919721 TI - [Blocking IL-17A protects against lung injury-induced pulmonary fibrosis through promoting the activation of p50NF-kappaB]. AB - This study is to determine the preventive effect and mechanism of targeting IL 17A on pulmonary inflammation and fibrosis after acute lung injury. Mice were treated with anti-IL-17A antibody on the day 7 and sacrificed on the day 14 after bleomycin lung injury. The pulmonary inflammatory status and the deposition of collagen were measured by HE and Sirius stains staining. The contents of hydroxyproline and collagen were measured by using commercial kits. The survival rate of mice was calculated by Kaplan-Meier methods. The inflammatory cytokines in bronchoalveolar lavage fluid were measured by ELISA and the expressions of inflammation-related molecules were detected by Western blotting assay. Targeting of IL-17A could prevent the development of lung inflammation, decrease collagen deposition and the contents of hydroxyproline, and protect against the development of pulmonary fibrosis, which together led to an increase in the animal survival. Moreover, blocking IL-17A decreased the expression ofpro fibrotic cytokines such as IL-17A, TGF-beta1 and IL-13; increased the expression of anti-fibrotic or anti-inflammatory factors such as IFN-gamma, COX-2, 5-LOX, 15 LOX. Indeed, IL-17A antagonism suppressed the activation of pro-inflammatory p65NF-kappaB but enhanced the activation of pro-resolving p50NF-kappaB. In conclusion, that blockade of IL-17A prevents the development of pulmonary fibrosis from acute lung injury, is because blocking IL-17A may prevent acute inflammation converting to chronic inflammation. PMID- 22919722 TI - Synthesis and anti-tubercular activity of novel alkyl substituted riminophenazine derivatives. AB - A series of novel riminophenazine derivatives bearing an alkyl substituent attached to N-5 and imino nitrogen at C-3 position of the phenazine ring were obtained through rational drug design, aiming to maintain high anti-tubercular activity, lower toxicity and reduce lipophilicity. All target compounds were prepared by utilizing simple and flexible synthetic route and evaluated against Mycobacterium tuberculosis H37Rv and screened for mammalian cytotoxicity. The results demonstrated that compounds with a cyclopropyl substituent at N-5 position were more active than the reference compound clofazimine. In particular, 2-(4-chloroanilino)-5-cyclopropyl-3-(4-methoxycyclohexyl) imino-3, 5 dihydrophenazine (25) was found to be the most potent compound with low cytotoxicity and lipophilicity. This compound could serve as a valuable lead molecule for further optimization. PMID- 22919723 TI - [Design, synthesis and bioactivity of aryl piperazine benzo[b][1,4]oxazine derivatives]. AB - Compounds with serotonin reuptake inhibition/5-HT(1A) dual activity were used to build 3D pharmacophore model as a training molecules by Discover Studio. Based on the model, 8 novel aryl piperazine benzo[b][1,4] oxazine derivatives were designed and synthesized, and their structures were confirmed by 1H NMR and HR MS. Biological evaluation illustrated that compounds VI(1) and VI(7) showed potent functional activities at both 5-HT transporter and 5-HT(1A) receptor, which can be used as lead compounds to guide future research of design and synthesis of potent novel compounds. PMID- 22919724 TI - [Chemical constituents of Rauvolfia verticillata]. AB - The study on the Rauvolfia verticillata (Lour.) Baill., which belongs to Apocynaceae, was carried out to look for its chemical constituents and pharmacological activity. The isolation and purification were performed by chromatography on silica gel, Sephadex LH-20 and ODS (octadecyl silane) open column. The structures of obtained compounds were elucidated on the basis of physicochemical properties and spectral analysis. Three indole alkaloids and one acridone alkaloid were isolated from chloroform layer extract and identified as ajmalicine B (1), sandwicine (2), raunescine (3) and 7-hydroxynoracronycine (4) separately. Ajmalicine B (1) is a new compound belonging to indole alkaloid. Compound 4 as an acridone alkaloid was a new type compound isolated from Rauvolfia genus for the first time. We also did some biological activity research on the new type compound (4) to explore other pharmacological activities in addition to antihypertensive activity. PMID- 22919725 TI - [Study on the proficiency testing program of pharmaceutical preparation analysis]. AB - This proficiency testing program is established to evaluate the pharmaceutical preparation analysis capacity of laboratories recommended by 18 countries and economies. It was authorized by Asia Pacific Laboratory Accreditation Cooperation (APLAC), and organized by Shanghai Institute for Food and Drug Control (SIFDC) and China National Accreditation Service for Conformity Assessment (CNAS). The 0.3sigma test is used to evaluate the homogeneity and stability of the proficiency testing sample. The results of the laboratories were assessed by Z score. The robust average and the robust standard deviation of the participants' results were calculated as assigned value and standard deviation for performance assessment of hydrochlorothiazide and captopril using robust statistics. Thirty three of 38 laboratories recommended by 18 countries and economies sent their results back. Twenty-four laboratories' results were observed as satisfactory. Five laboratories were identified as having reported at least one questionable result. Four laboratories were identified as having reported at least one unsatisfactory result. PMID- 22919726 TI - [Analysis of saponins in Panax notoginseng by UPLC-LTQ-Orbitrap MS/MS]. AB - A method for qualitative analysis of constituents in Panax notoginseng by UPLC LTQ-Orbitrap mass spectrometry was established. Based on the high-resolution mass information, MS/MS fragmentation behaviors and chemical components from literatures, 43 compounds were identified or tentatively characterized. New type saponin aglycone, combined with malonyl-substituted and acetyl-substituted saponins were discovered and plausibly identified in this study. This work could be helpful for the quality control and further phytochemical studies of Panax notoginseng, and provided a good example for the analysis of chemical constituents in traditional Chinese medicine. PMID- 22919727 TI - [Identification of the related substances in docetaxel injection by LC-MS/MS]. AB - The related substances in docetaxel injection were identified by LC-MS/MS. Ethyl acetate was used to extract the injection to remove the pharmaceutical excipients. HPLC separation was carried out on a Hedera ODS-2 column (150 mm x 2.1 mm, 5 microm) with a mobile phase consisting of acetonitrile - 0.1% acetate acid aqueous solution (40: 60). Electrospray ionization source was set in the positive mode for the LC-ESI-MS/MS, and the ion monitoring modes were full scan and product ion scan. According to the mass spectra of the related substances, the fragment profiles were explained, and the chemical structures were elucidated. Docetaxel and its main related substances were well separated. Nine related substances in docetaxel injection were detected by LC-MS/MS. Their chemical structures were proposed, and four of them were identified in the docetaxel injection for the first time. The established LC-MS/MS method is effective in the separation and identification of the related substances in docetaxel injection. The test results are useful for its quality control. PMID- 22919728 TI - [Cross-linking mechanism of the matrix of hydrogel patch]. AB - In this study, we prepared various matrices of hydrogel patches and studied their cross-linking mechanism by observing their rheological properties, which could provide theoretical basis and deep technical support for further industrial development of hydrogel patch. Rheology method was used to do the amplitude scanning and single-frequency scanning for various hydrogel matrix, under the condition of oscillation mode of the rheometer. Then the linear viscoelastic region, composite modulus value, as well as changes in slope with time of the composite modulus and phase angle of various hydrogel matrix were analyzed in detail. The results showed that the stability of matrix was mainly determined by hydrogel frame; only in acidic environment, the cross-linking reaction between cross-linker and hydrogel frame can occur; elasticity of matrix can be decreased by organic acid and the effect level was related to the ratio of the number of carboxyl and hydroxyl (-COO(-)/-OH) in adjusters: if the ratio was not equal, the higher -COO(-)/-OH in adjusters would be the less elasticity of matrix decreased; the cross-linking speed of matrix was determined by adjuster, the cross-linking speed of matrix contain different adjusters was ranged in following order: matrix containing tartaric acid > matrix containing lactic acid > matrix containing malic acid > matrix containing citric acid; the cross-linking speed of matrix was not uniform in the whole cross-linking process. PMID- 22919729 TI - [Preparation of ibuprofen/EC-PVP sustained-release composite particles by supercritical CO2 anti-solvent technology]. AB - Ibuprofen/ethyl-cellulose (EC)-polyvinylpyrrolidone (PVP) sustained-release composite particles were prepared by using supercritical CO2 anti-solvent technology. With drug loading as the main evaluation index, orthogonal experimental design was used to optimize the preparation process of EC PVP/ibuprofen composite particles. The experiments such as encapsulation efficiency, particle size distribution, electron microscope analysis, infrared spectrum (IR), differential scanning calorimetry (DSC) and in vitro dissolution were used to analyze the optimal process combination. The orthogonal experimental optimization process conditions were set as follows: crystallization temperature 40 degrees C, crystallization pressure 12 MPa, PVP concentration 4 mgmL(-1), and CO2 velocity 3.5 Lmin(-1). Under the optimal conditions, the drug loading and encapsulation efficiency of ibuprofen/EC-PVP composite particles were 12.14% and 52.21%, and the average particle size of the particles was 27.621 microm. IR and DSC analysis showed that PVP might complex with EC. The experiments of in vitro dissolution showed that ibuprofen/EC-PVP composite particles had good sustained release effect. Experiment results showed that, ibuprofen/EC-PVP sustained release composite particles can be prepared by supercritical CO2 anti-solvent technology. PMID- 22919730 TI - [Synthesis and characterization of N-octyl-N-arginine chitosan--a chitosan derivant with a mimetic structure of cell-penetrating peptides]. AB - A novel chitosan derivant, N-octyl-N-arginine chitosan (OACS) with a mimetic structure of cell-penetrating peptides was synthesized by introducing hydrophilic arginine groups and hydrophobic octyl groups to the amino-group on chitosan's side chain. Structure of the obtained polymer was characterized by FT-IR and 1H NMR. The substitution degree of octyl and arginine groups was calculated through element analysis and spectrophotometric method, separately. The critical micelle concentration of OACS was 0.12 - 0.27 mgmL(-1) tested by fluorescence spectrometry. The solubility test showed OACS could easily dissolve in pH 1 - 12 solutions and self-assemble to form a micelle solution with light blue opalescence. The OACS micelles have a mean size of 158.4 - 224.6 nm, polydisperse index of 0.038 - 0.309 and a zeta potential of +19.16 - +30.80 mV determined by malvern zetasizer. AFM images confirmed free OACS micelle has a regular sphere form with a uniform particle size. MTT test confirmed that OACS was safe in 50 - 1 000 micromol-L(-1). The result of HepG2 cell experiment showed that the cell internalization of OACS micelles enhanced with increased substitution degree of arginine by 40 folds compared to chitosan. Thus, OACS micelles were a promising nano vehicle with permeation enhancement and drug carrier capability. PMID- 22919731 TI - [EST-SSR identification of Lonicera japonica Thunb]. AB - Simple and effective methods are needed for the identification of Chinese medicinal material species and their variety. Lonicera japonica Thunb. is one of Chinese herbal medicines widely demanded. A total of 3 705 EST-SSRs of L. japonica and 2 818 EST-SSRs of L. japonica var. chinensis Thunb. were identified from EST database in our lab. In average, there was one EST-SSR per 4.05 kb in L. japonica ESTs and per 7.49 kb in L. japonica var. chinensis ESTs, separately. The identified SSRs in L. japonica were consisted of 51.98% dinucleotide and 34.61% trinucleotide repeats, while SSRs in L. japonica var. chinensis had 57.45% dinucleotide and 30.09% trinucleotide. The results reviewed that the classes AG/TC and GAG/TCT were predominant in the dinucleotide motifs and the trinucleotide motifs, respectively. Total 87 EST-SSRs were identified of significant difference between L. japonica and L. japonica var. chinensis. PCR products were obtained from 52 L. japonica samples in 13 out of 15 SSR markers tested. The polymorphism in L. japonica, L. japonica var. chinensis and other honeysuckles could be distinguished by three markers (jp.ssr4, jp.ssr64 and jp.ssr65) tested. PMID- 22919732 TI - [Effect of safflor yellow B on vascular endothelial cells injury induced by angiotensin-II]. AB - This study is to investigate protective effect of safflor yellow B (SYB) against vascular endothelial cells (VECs) injury induced by angiotensin-II (Ang-II). VECs were cultured and divided into six groups: control group, Ang-II group, Ang-II + SYB (1 micromolL(-1)) group, Ang-II + SYB (10 micromolL(-1)) group, Ang-II + SYB (100 micromolL(-1)) group and Ang- II + verapamil (10 micromolL(-1)) group. Except control group, all of VECs in other groups were treated with Ang- II at the final concentration of 0.1 micromolL(-1). Mitochondria membrane potential (MMP) and free calcium concentration ([Ca2+]i) were measured by laser scanning confocal microscopy, and mitochondria complex IV activity was detected by BCA method. The levels of reactive oxygen species (ROS) in VECs were analyzed by fluorescence detector and apoptosis of VECs was observed by flow cytometer. Caspase 3 was determined by Western blotting method. Comparing with control group, Ang-II was able to increase [Ca2+]i and ROS level, decrease MMP level, inhibit complex IV activity and enhance caspase 3 activity in VECs, as a result, enhance apoptosis of VECs. But SYB could significantly reduce the result induced by Ang- II relying on different dosages (P < 0.05 or P < 0.01). SYB was able to eliminate the effect of Ang-II on VECs via regulating [Ca2+]i, mitochondrial structure and function and inhibiting apoptosis. PMID- 22919733 TI - [Mechanisms of (2-methyl-n-butyl) shikonin induced apoptosis of gastric cancer SGC-7901 cells]. AB - This study is to investigate the effect of (2-methyl-n-butyl) shikonin (MBS) on inducing apoptosis of human gastric cancer cell line SGC-7901 and the role of ERK1/2 signal pathway in the apoptosis. MTT assay was used to detect SGC-7901 cell proliferation. DNA condensation was measured by DAPI stain. Cell apoptosis was analyzed by flow cytometry. Mitochondrial membrane potential (MMP) was analyzed by JC-1 staining. The protein expressions of Bcl-2, Bax, Survivin, cleaved caspase-9, cleaved caspase-3, cleaved PARP, p-ERK1/2, ERK1/2, p-JNK, JNK, p-p38 and p38 were detected by Western blotting. The results showed that MBS reduced the cell viability of SGC-7901 cells in a dose- and time-dependent manner. The IC50 at 24 h and 48 h for SGC-7901 cells was 10.113 and 4.196 micromolL(-1), respectively. After being treated with MBS, the typical nuclear condensation was observed in SGC-7901 cells by DAPI stain. Apoptosis in SGC-7901 cells was induced by MBS in a dose dependent manner. The protein expression of Bcl-2 was down-regulated, while the protein expressions of cleaved caspase-9, cleaved caspase-3, cleaved PARP, p-ERK1/2 and p-JNK were up-regulated after MBS treatment. U0126, a specific MAP kinase (MEK1/2) inhibitor, blocked the ERK1/2 activation by MBS. MMP was decreased by MBS treatment. It can be concluded that MBS could inhibit SGC-7901 cell proliferation and induce apoptosis. Mitochondrial apoptosis pathway, ERK1/2 signal pathway and JNK signal pathway might be involved in this process. PMID- 22919734 TI - [In vitro anti-proliferation effect of peptides from cinobufacini injection]. AB - Cinobufacini is an aqueous extract of Bufo bufo gargarizans Cantor dried skin, which has been widely used for cancer therapy in China. So far, its active components are still not very clear. In previous reports, bufadienolides with low concentration were usually studied because of their anticancer effects. However, the high polarity constituents in cinobufacini are less investigated. The present study found that more than 50% contents of cinobufacini were water-soluble peptides. Then, in vitro anticancer experiments were carried out, including human stomach cancer cell lines BGC823 and MCG803, human colon cancer cell lines DLD-1 and HT-29, and human pancreatic cancer cell line MIAPACA-2. The IC50 for these cell lines model were ranged from 25-123 microgmL(-1). The results indicated that these peptides showed similar activity with cinobufacini injection. As a conclusion, this study provides a new and further understanding of anticancer components in cinobufacini injection. PMID- 22919735 TI - [Legal criteria in ophthalmology]. PMID- 22919736 TI - Portal bilopathy. PMID- 22919737 TI - Global leprosy situation, 2012. PMID- 22919738 TI - [To enhance viral diarrhea surveillance in China]. PMID- 22919739 TI - [Molecular epidemiology of viral diarrhea in Chengdu infants and young children]. AB - OBJECTIVE: To investigated the molecular epidemiologic features of viral diarrhea in Chengdu infants and young children, and to establish baseline patterns of etiology, provides the scientific basis for the vaccine development and the epidemic situation control. METHODS: From March, 2006 to December, 2008, a total of 376 infants and young children from Chengdu area hospitalized for diarrhea in Chengdu Children's Hospital were enrolled in this study. The stool specimen collected from each patient was tested for rotavirus (RV), Calicivirus (CV), astrovirus (AstV) and adenovirus (Adv) by using enzyme linked immunosorbent assay (ELISA) and reverse transcription-polymerase chain reaction (RT-PCR) examination. RESULTS: Among those 376 cases,there were 142 cases (37.76%) of RV infections,which scattered predominantly in October to December. Among 234 cases RV negativity,there were 29 cases HuCV infections (15.85%), 5 cases AstV infections (1.64%), and 8 cases Adv infections (2.04%). CONCLUSION: RV appeared to be the main etiological agent of viral diarrhea in Chengdu infants and young children,the predominant serotype of RV were G3, P[8] and P[4],HuCV might be the important etiological agent besides RV. PMID- 22919740 TI - [Etiological and epidemiological study on viral diarrhea among children in Changchun]. AB - OBJECTIVE: To study the pathogen and characteristics of viral diarrhea in children in Changchun area. METHODS: 460 stools specimens were collected from children with acute diarrhea cured in the childrens, hospital of Changchun in 2010. Rotavirus were detected by ELISA, caliceverus and astrovirus were detected by reverse transcription-polymerase chain reactions (RT-PCR), adenovirus were detected by polymerase chain reactions (PCR). RESULTS: A total of 460 specimens were detected. The detection rate of rotavirus, caliceverus, astrovious, adenovious respectively is 35.22%, 20.43%, 9.78%, 3.70%, the detectablerate of mixed infection is 7.61%, children under 2 years old were the major patient. The main genotypes of the virus: rotavirus (G3P[8]), caliceverus (GII-4), astrovious (type I), adenovious (Ad41). CONCLUSION: Rotavirus is the main pathogen in Changchun. Followed by caliceverus, astrovious, adenovious. PMID- 22919741 TI - [Molecular epideiological and clinical feature of human calicivirus and adenovirus among children with diarrhea less than 5 years old from 2010 to 2011 in Lanzhou, Gansu province]. AB - OBJECTIVE: To investigate the clinical and molecular epidemiology characteristics of calicivirus and adenovirus in children for viral diarrhea in Lanzhou. METHODS: Stool samples were collected from 295 children with diarrhea at the First Hospital of Lanzhou University, Gansu Province,China, between July 2010 and June 2011. Reverse transcription-polymerase chain reaction (RT-PCR) or PCR were used to detected calicivirus and adenovirus. The adenovirus positive samples were typed by nested PCR and multiple PCR. RESULTS: Of the 295 specimens, 13.2% (39/295) were positive for calicivirus, and 5.1% (15/295) were adenovirus. Typing and Phylogenetic analysis revealed that novirus GII-3 and adenovirus 41 were the dominant strains. Both calicivirus and adenovirus predominately affect children under the age of 2. In seasonal distribution, there was no obvious peak. CONCLUSION: Human calicivirus and adenovirus are important pathogens of viral diarrhea,it is important to develop long-term systematic surveillance. PMID- 22919742 TI - [Detection and typing assay of norovirus in acute hospitalizations among children less than 5 years old from 2008 to 2009 in Lulong, Hebei province]. AB - OBJECTIVE: To investigate the molecular epidemiologic characteristics and genotypes of norovirus in children less than 5 years of age in Lulong area from 2008 to 2009. METHODS: 325 stool specimens and epidemiological data from hospitalized children with diarrhea less than 5 years of age were collected. Rotavirus was detected by using the ELISA kit. Norovirus, adenovirus and astrovirus were detected by multiple reverse transcription-polymerase chain reaction (RT-PCR). Partial norovirus strains were sequenced and the tree was conducted by using the phylogenetic analyses. RESULTS: Norovirus was detected in 37 out of 325 (11.3%) specimens,ranked only second to rotavirus (48.6%), and higher than adenovirus (6.5%) and astrovirus (4.3%). Norovirus predominantly infected children less than 2 years of age and the season peak of norovirus occurred in November. Phylogenetic analysis showed that the predominant strain was the GII. 4/2006b variant. Interestingly, a novel unreported GII-4 variant was found in this study. CONCLUSION: Norovirus was one of the most important pathogens causing acute gastroenteritis from 2008 to 2009 in Lulong area. The GII. 4/2006b vairant was still the predominant strain. It is important to keep on monitoring the novel GII. 4 variant. PMID- 22919743 TI - [Molecular and epidemiological study on among children under 5 years old in Nanjing]. AB - OBJECTIVE: To study the infected information, clinical symptom and molecular epidemiological characteristics of HuCV infection among children under 5 years old in Nanjing. METHODS: In Nanjing Children's Hospital of Nanjing Medical University from July 2010 to June 2011, we collected 428 stool specimens from children with diarrhea and 428 asymptomatic controls. Human Calicivirus were tested by using RT-PCR. Then we sequenced the nucleic acid of PCR amplifications and identified the genotype and gene group of prevalent strains. RESULTS: 63 (14.72%) out of 428 stool samples were detected as HuCV. 58 were norovirus and 5 were sapovirus, while GII-4 2006b was the predominant strain of NoV. In the 428 control samples, 19 samples were positive for calicivirus, there were 8 NoV and 13 SaV (Including 3 co-infection cases). CONCLUSION: Human caliciviruses with different genotypes circulated among children in Nanjing,and GII. 2006b is the dominant genotype. PMID- 22919744 TI - [Optimizing expression of the capsid protein VP2 from human Bocavirus and establish it's seroepidemiology assying methord]. AB - OBJECTIVE: To obtain sufficient recombinant VP2 protein of human Bocavirus and establish it's seroepidemiology assying metbord. METHORD: Tbe capsid protein VP2 DNA genes of HBoV1 and 2 were optimized in accordance with tbe usage of the favorite codons in K coil so as to enhance its protein expression in prokaryotic expressing system. The protein was purified by Ni-NTA column, and its antigenicity was determined by Western Blot. Then establish ELISA to detect the specific anti-VP2 IgG antibodies against HBoV1 and 2 in healthy children aged 3-6 years in Nanjing, China. RESULTS: The recombinant protein 6 x His-VP2 was produced in a larger quantity at 25 degrees C induced by IPTG (1 mmol/L) over night and purified by Ni-NTA column. Seropositive rates of HBoV1 and 2 were 62.2% and 55.5% and their mixed seropositivity was 37%. CONCLUSION: The optimizing expression of the capsid protein VP2 from human Bocavirus constructed successfully and get a high yield under certain conditions. The established ELISA could be used to further analyze seroepidemiology of HBoV in China. PMID- 22919745 TI - [Optimization of the codon strengthened the human rotavirus VP6 antigen's serum immune responses and protective responses in mice model]. AB - OBJECTIVE: To observe the serum immune responses and protection in mice model of the recombinant adenovirus vector mediated human rotavirus VP6 gene expression through coden optimization (rvAdVP6(o)) in comparison with the wild type (rvAdVP6). METHODS: 6-8 week female BALB/c mice were randomly grouped and immunized three times intranasally with 10(8) TCID50 rvAdVP6(o) and rvAdVP6, respectively, then detect the serum IgG level against rotavirus induced by rvAdVP6(o) and rvAdVP6. The amount of sheding viral antigens in feces was detectd after mice rotavirus was taked orally. RESULTS: The serum IgG level against rotavirus induced by rvAdVP6(o) was higher than that of rvAdVP6 after three times of immunization. The immunized mice shed lower amount of viral antigens in feces as compared with the rvAdVP6. CONCLUSION: The recombinant adenovirus which encode optimized human rotavirus VP6 proteins (rvAdVP6(o)) could induce stronger serum immune and protective responses against the challenge of the rotavirus than the wild type (rvAdVP6) at the same immunizing dosage. PMID- 22919746 TI - [Hepatitis B virus (HBV) mutation in enhancer I (HBV Enh I)/X-promoter and the relationship between chronic HBV-related disease spectrum]. AB - OBJECTIVE: To investigate the hepatitis B virus (HBV) mutation in the Enhancer I (HBV Enh I)/X-promoter and to analysis the relationship between chronic HBV related disease spectrum. METHODS: 275 patients were enrolled in this study, including 100 cases of chronic hepatitis B (CHB), 74 cases of liver cirrhosis (LC), 101 cases of hepatocellular carcinoma (HCC), grouping by different HBV genotypes, using semi-nested PCR amplification of HBV Enh I/X-promoter and sequencing DNA, the mutations were determined by alignment to HBV reference sequence, the data was compared by chi2 test and analyzed by multivariate logistic regression. RESULTS: (1) Genotyping results: 61.48% (158/257) were infected with HBV genotype B, including 70 cases of CHB, 36 cases of LC and 52 cases of HCC; 38.52% (117/257) were infected with HBV genotype C, including 30 cases of CHB, 38 cases of LC and 49 cases of HCC. (2) In the patients were infected with HBV genotype B, A1123Y mutation in LC was significantly higher than in CHB (30.56% vs. 8.58%, chi2 = 8.533, P = 0.005, A = 4.693, 95% CI [1.567 14.056]), HCC was significantly higher than in CHB (28.85% vs. 8.58%, chi2 = 8.607, P = 0.003, A = 4.324,95% CI [1.544-2.109]); A1317G mutation in HCC was significantly higher than in CHB (30.77% vs. 7.14%, chi2 = 11.687, P = 0.001, A = 5.778, 95% CI [1.955-17.076]). In the patients were infected with HBV genotype C, T1323C mutation in HCC was significantly higher than in CHB (30.61% vs. 6.67%, chi2 = 6.318, P = 0.12, A = 6.176, 95% CI [1.301-29.331]). (3) Multivariate regression analyses showed that A1317G (OR = 5.706, 95% CI [1.770-18.837], P = 0.004) and T1323C (A = 5.810, 95% CI [1.114-30.306], P = 0.037) mutation were risk factors for HCC. CONCLUSION: HBV Enh I/X-promoter mutations were associated with the development of LC and HCC, the mutations can help to predict the occurrence of LC and HCC. PMID- 22919747 TI - [Investigation of the relationship between apolipoprotein gene polymorphism and hepatitis B virus infection in China]. AB - OBJECTIVE: To explore the gene polymorphisms of ApoAI-75 Msp1, ApoB Msp1, ApoCIII Sst1, LRP5, and ApoE genotypes in two pairs of semi different modes of hepatitis B for HBV markers. METHODS: The patients are divided into 9 groups. There were a total of 720 cases, 80 patients in each group, The patients was carried out by SnaPshot method (single-base multilocus micro-sequencing), and different genotypes of each locus were conducted by the method of sequencing in order to support the final evidence of the accuracy of test results. RESULTS: There was association between gene polymorphisms of ApoAI-75Msp1 and ApoE and different modes of two pairs of semi-hepatitis B (P < 0.05), while there wasn't any association between gene polymorphisms of ApoB-Msp1, ApoCIII-Sst1, LRP5 and different modes of two pairs of semi-hepatitis B (P > 0.05). CONCLUSION: The gene polymorphism of ApoAI-75Msp1 and ApoE was associated with the different modes of HBV markers. PMID- 22919748 TI - [The coastal areas of Yantai human and swine hepatitis E virus genotyping analysis]. AB - OBJECTIVE: Survey of the coastal city of Yantai, from human and swine hepatitis E virus (HEV) genotype correlation. METHOD: Application of reverse transcription nested polymerase chain reaction (RT-nPCR) method for local acute sporadic hepatitis E patients,normal population of HEV-IgM positive and local pig farm pigs were HEV RNA detection. And HEV RNA positive samples for cloning sequencing and sequence analysis. RESULTS: In 16 patients with acute sporadic hepatitis E in 7 cases of RNA positive stool specimens of HEV; 51 IgM positive sera of normal people in specimens with 1 HEV RNA positive; 34 pig bile specimens with 1 HEV RNA positive. Sequence analysis revealed the region HEV strains and swine strains in the ORF2 region of nucleotide sequence homology is 87%-98.1%. 7 strains of hepatitis E virus genotype in patients and 1 strains of swine hepatitis E virus genotypes are type IV, gene sequence homology between the 87%-98.1%; there were 6 patients and porcine gene sequence homology in 93.9%-98.1% between,for type a subtype; 1 patients and porcine gene sequence homology in 87%, for the type D subtype. Normal population of 1 cases of hepatitis E virus genotype for I type D subtype. Human and porcine HEV ORF2 gene fragment and HEV part I-IV representative strains were compared, and the nucleotide sequence homology were 82.5%-100%, 81.7%-92.9%, 81.4%-93.9%, 84.9%-100%. CONCLUSION: The area population prevalence of HEV in the presence of 2 genotype 3 subtype genes, mainly to IV A, in pigs with popular HEV gene with a high homology; HEV type I in the crowd disperses in the presence of. PMID- 22919749 TI - [Comparative study on the HPV infection rate of different esophageal squamous cell carcinoma in Anyang China]. AB - OBJECTIVE: Comparative and statistical analysis the HPV infection rate between fresh tissue and Paraffin-embedded Specimens of esophageal squamous cell carcinoma,and comparative the testing results with others regions. METHODS: Extracted the total DNA from the novel fresh tissue and Paraffin-embedded Specimens; Detected the DNA by PCR with universal primer and Detected the HPV type with human papilloma virus nucleic acid amplification-based typing detection reagent kit (Hybribio); Compared the statistical result from the different specimens; analyzed the result between different region. RESULTS: HPV infection rate of fresh tissue is 82.6% with HPV16 (34.8%) and HPV18 (34.8%), and paraffin embedded specimens is 78.2% with HPV16 (30.4%) and HPV18 (17.4%). CONCLUSION: The results provides the first evidence that there wasn't noticeable difference between HPV infection rate of the two specimens. So broader specimen source could be used for HPV testing. PMID- 22919750 TI - [Genotyping and variability of HIV-1 in 26 cases of paid blood donors]. AB - OBJECTIVE: To analyze the genome mutations of HIV-1 gag, pol and env genes from HIV-infected paid blood donors in rural central China. METHODS: DNA was extracted from peripheral blood mononuclear cells, gag (p17-p24), pol (PR-RT), env (C2-V5) genes were amplified by nested polymerase chain reaction (PCR), purified products were sequenced, and sequence data was analyzed by MEGA5.0 soft wares. RESULTS: Twenty-three samples were subtype B, two samples were recombinant of subtype B and subtype C, one sample was recombinant of subtype CRF01_AE and subtype B. PI major resistance mutations were not found in the PR region. M184V, K101E and G190A were detected in the RT region, respectively. CONCLUSION: Subtype B was the major HIV circulating genetic forms in this area. Most strains were sensitive to high active anti-retroviral therapy (HARRT). 91.7% V3 loop tip motifs of X4 tropic strains was GPGR. It showed that GPGR might be associated with accelerate disease progression to AIDS. PMID- 22919751 TI - [Antigenicity characterization of six different fragments of SARS-CoV N protein expressed in E. coli]. AB - OBJECTIVE: To determine the antigen characteristics of different fragments of SARS-CoV N protein expressed in E. Coli and their application in the serological diagnosis. METHODS: Based on preliminary analysis of 39 different segments of the N protein, We choosed six purified N protein for further antigenicity characterization in this study, including that PN360 (1 -360aa), PN301 (1-301aa), PN199 (30-228aa), PN185 (30-214aa), PN155b (60-214aa), and PN125 (90-214aa). We developed Western-Bolt and ELISA to detect antibody reactivity between truncated N fragments with sera from SARS-CoV-negative normal adults or SARS-CoV patient convalescent sera. RESULTS: Western-Bolt results show that all the six fragments have reacted with the SARS patient convalescent sera, but the PN360 and PN301 showed obvious cross-reaction with sera from SARS-CoV-negative normal adults; sensitivity analysis using an ELISA coating with PN199, PN185, PN155b, PN125 as antigen showed that the PN185 and PN155b are better than PN125. CONCLUSION: Truncated N protein PN185 and PN155b expressed in E. Coli are better antigen candidates used for detection of SARS-CoV specific antibody. PMID- 22919752 TI - [Study in the killing effect of Myxoma virus to C6 glioma cell in vitro]. AB - OBJECTIVE: To evaluate the susceptibility of C6 glioma cells to Myxoma virus and the killing effect of Myxoma virus to the C6 glioma cells in vitro. METHODS: C6 glioma cells were infected with myxoma virus, used death virus as the negative control, 5-FU as the positive control, DEMD as blank control. The number of living cells were counted every 24 h, and Western-Blot method, inverted microscope and MTT assay were applicated to observe the cell morphology and survival rate in each group. RESULTS: The cell number were decreased rapidly in virus effected group and 5-FU group, with significant differences to the negative and blank control groups. And cells in virus effected group appeared cytopathic effect. CONCLUSIONS: C6 glioma cells were susceptible to myxoma virus and myxoma virus had killing effect to C6 glioma cells in vitro. PMID- 22919753 TI - [Antibody detection of hepatitis E virus in human population of different national in China]. AB - OBJECTIVE: To investigate the seroprevalence of HEV infection in different national human population in Han, Hui and Zang in China. METHODS: EIA was used for detecting anti-HEV IgG of the serum samples. All samples were collected in 2006-2008 in Sichuan, Beijing, Heilongjianin, Sandong, Gansuo, Ningxia and Qinghai areas. RESULTS: The total positive rate of anti-HEV IgG was 17.97% (1878/ 10448), 24.32% (1794/7376) in Han national, 3.59% (81/2258) of Hui national and 0.37% (3/814) of Zang national, respectively. The positive rate of Han human at different age group, was 5.19% of < or = 10 year, 11.64% of 11-20 year, 20.08% of 21-30 year, 34.17% of 31-40 year, 41.75% of 41-50 year, 48.58% of 51-60 year, 57.43% of > or = 61 year. The positive rate of Hui human at different age group, was 3.11%, 3.96%, 2.11%, 3.98, 2.52%, 4.57% and 6.67%, respectively. Three positive of Zang human was between 21-60 year. CONCLUSIONS: The HEV infection in Han national population was higher than the Hui and Zang national, significantly. The HEV infection was correlation with age significantly, the infection rate was increased with age. PMID- 22919754 TI - [Value of delta model for end-stage liver disease in evaluating the prognosis of liver failure patients with hepatitis B virus]. AB - OBJECTIVE: To evaluate the prognostic value of the model for end-stage liver disease (MELD) and deltaMELD in liver failure patients infected with hepatitis B virus. METHODS: Based on prospective study design, 98 hospitalized cases were studied and followed up for 24 weeks. The clinical data were recorded. We calculated the score of MELD and deltaMELD, and also compare the score between the survival group and death group. Using ROC curve plotting obtained the better decisive threshold. The case fatality rate were compared at different time points which the patients were classified by the best critical value of MELD and deltaMELD. We draw the Kaplan-Meier survival curve of different group and analyse the change of survival rate by log-rank analysis. RESULTS: 52 of 97 patients died and 46 survive during 24 weeks of followup. There was significant difference between the two groups for MELD and deltaMELD (P < 0.01). The case fatality rate in group which MELD > or = 23 was obviously higher than in that MELD < 23. The rate in group which deltaMELD > 4.5 was obviously higher than in that deltaMELD < 4.5 (P < 0.001). The area under curve (AUC) for the twelfth and 24th week's prognosis judgment of deltaMELD (0.823, 0.815) was larger than that of MELD (0.680, 0.684) (P < 0.05). Survival analyses (Kaplan-Meier) indicated that there were significant differences in cumulative survival rates among the groups which were grouped by optimization critical value ( P = 0. 000). CONCLUSIONS: The scoring system of MELD also applied to the forecasting of prognosis for severe hepatitis B patients in China. The accuracy of deltaMELD to predict the prognosis was higher than that of MELD. The combination of MELD and deltaMELD showed good clinical practical value. PMID- 22919755 TI - [The relationship of HBeAg status with HBV DNA loads, MELD scores in patients with acute-on-chronic hepatitis B liver failure during terminal phases]. AB - OBJECTIVE: To investigate the relationship and clinical significances of HBeAg status with serum HBV DNA loads, model for end-stage liver disease (MELD) scores in patients with acute-on-chronic hepatitis B liver failure during terminal phase. METHODS: 120 fatal patients were enrolled. At three phases of 0 -14 d, 15 28 d and 29-90 d before death, they were detected serum HBeAg, HBV DNA loads order meanwhile MELD scores were calculated. RESULTS: In 51 patients with HBeAg positive, HBV DNA levels were (5.25 +/- 1.99), (5.45 +/- 1.47) and (6.06 +/- 1.77) log10 copies/ml while MELD scores were (30.33 +/- 5.25), (26.36 +/- 6.43) and (20.13 +/- 6.47) respectively. In 69 patients with HBeAg negative,HBV DNA loads were (5.14 +/- 1.84), (5.49 +/- 1.75 ) and (4.62 +/- 1.65) log10 copies/ml while MELD scores were 32.38 +/- 9.95, 28.17 +/- 6.82 and 26.19 +/- 5.56 in sequence. Compared with the same phase between HBeAg-positive group and HBeAg negative group, significant differences in both HBV DNA loads and MELD scores were found only at the phase of 29-90 d (P < 0.05). In multiple comparisons among three phases, regardless of the HBeAg status,there wasn't significant difference for HBV DNA loads (P > 0.05). But increasing MELD scores are associated with the disease exacerbation and significant differences were found (P < 0.05). CONCLUSIONS: To initiate acute-on-chronic hepatitis B liver failure, serum HBV DNA loads of HBeAg-positive patients are higher than that of HBeAg-negative ones. Once ACLF has been initiated,sustained high HBV DNA loads may promote the disease worsened and be fatal regardless of the HBeAg status. PMID- 22919756 TI - [Evaluating the current protocol of influenza A (H1N1) based on the epidemic situations of Zhengzhou,a middle-sized city in China]. AB - OBJECTIVE: From May 2009-January 2010, a total of 3768 biosamples were tested for influenza A (H1N1) infection at Zhengzhou center for disease control and prevention, China. 1452 cases were laboratory confirmed H1N1 infection and 2316 were considered suspected victims. To evaluate the current protocol of influenza A (H1N1) based on the epidemic situations of Zhengzhou, relationships among features were explored and whether additional clinical characteristics should be part of H1N1 diagnosis protocols were determined. METHODS: Both clinical and epidemiologic findings as well as statistical analyses were described in this article. Test for independence between features related to the disease diagnosis has been proposed. Furthermore, logistic regression was carried out to measure the association among features and latent class analysis was performed to identify additional crucial features in laboratory confirmed H1N1 by building various latent models with different combinatorial features. RESULTS: The mean generation time for H1N1 was estimated as 3.59 +/- 1.41 days (range = 2.01-7.26). The estimated infection rate was 0.258 +/- 0.088 3, and reproduction number was 1.94 (95% CI = 1.12-3.18). Our results revealed that the six features, including molecular detections using three separate primer/probe sets, gender, age and temperature, are all associated with clinical diagnosis of H1N1, and that three separate primer/probe sets for laboratory confirmed H1N1, age and temperature are associated with each other. CONCLUSION: Additional clinical features applied into the H1N1 diagnosis with current three primers/probe sets can increase the diagnostic efficiency. PMID- 22919757 TI - [Different dosages Ganciclovir treatment of symptomatic congenital cytomegalovirus infection in neonatal]. AB - OBJECTIVE: Ganciclovir is a first line drug for treatment of cytomegalovirus (CMV) infection. This study aimed to compare the efficacy and side effects of relatively low and high doses of Ganciclovir in the treatment of neonatal congenital CMV infection. METHODS: 37 neonates with congenital CMV infection were randomly assigned to high-dose (n = 19) and low-dose Ganciclovir groups (n = 18). The high-dose Ganciclovir group was injected with Ganciclovir of 7.5 mg/kg in the inducement phase and of 10 mg/kg in the maintaining phase. The low-dose Ganciclovir group was injected with Ganciclovir of 5 mg/kg in the inducement and the maintaining phases. The efficacy and side effects were observed in the two groups. RESULTS: The results of different doses of GCV treatment of congenital CMV infection in symptomatic by the clinical symptoms were improved, high-dose treatment group CMV-IgM negative rate of 89.5%, CMV-DNA negative rate of 73.7%; low-dose treatment group CMV-IgM switch negative rate of 83.3%, CMV-DNA negative rate was 77.8%, no significant difference between the two groups. Low-dose GCV treatment of congenital CMV infection in newborns with symptomatic side effects than high dose GCV, the low dose group neutropenia, anemia, thrombocytopenia was lower than the high dose group, the difference was significant (P < 0.05). CONCLUSION: Low- dose GCV treatment of symptomatic congenital CMV infection with high-doses of the same clinical efficacy, and less side effects than high-doses of GCV. PMID- 22919758 TI - [Clinical study of tissue expression and serum contents of VEGF-C in cervical diseases of Uighur women]. AB - OBJECTIVE: To detect the VEGF-C expression in the serum and tissue of cervical diseases. To explore correlation of tissue and serum expression and the clinical significance of VEGF-C in the cervical intraepithelial neoplasia and cervical squamous-celled carcinoma of Uighur momen in Xinjiang. METHOD: (1) The VEGF- C expressions in tissue were tested by immunohistochemisty from the 22 chronic cervicitis, 24 CIN,and 43 squamous-celled carcinoma patients, (2) The VEGF-C contents in the serum were tested by enzyme-linked immunosorbent assay (ELISA) from the 15 chronic cervicitis, 23 CIN, and 40 squamous-celled carcinoma patients. RESULT: (1) The expression of VEGF-C in the tissue of cervicitis, CIN and cervical carcinoma were separately 9.1%, 87.50%, 100%, the differences had significance (P < 0.05). (2) The VEGF-C serum contents were gradually increased from cervicitis to CIN and cervical carcinoma, the differences had significance (P < 0.05). (3) The compartment of results of VEGF-C in serum and tissue showed that, there were correlation between to of them, the more tissue expressions, the more serum expressions will be (r = 0.27, F = 5.327, P < 0.05). CONCLUSION: VEGF C has played an facilitation rule in the transition process of CIN to cervical squamous cell carcinoma of the Uygure women in Xinjiang, there are correlation of VEGF-C expression between tissue and serum. PMID- 22919759 TI - [Preparation of the monoclonal antibody against human Bocavirus VP2 protein]. AB - OBJECTIVE: To express and purify HBoV VP2 protein, and the monoclonal antibody against HBoV VP2 protein was prepared with hybridoma technique. METHODS: The HBoV VP2 cloned into vector pET-30a was expressed in E. coil. After purified by immobilized metal affinity chromatography, the BALB/c mouse was immunized with purified protein as antigen. The positive hybridoma cells were screened with hybridoma technique and ELISA assay. Isotype and titer of the monoclonal antibody were detected. RESULTS: The recombinant HBoV VP2 protein was expressed and purified, and then the monoclonal antibody was obtained with hybridoma technique. The titer of the IgG monoclonal antibody was up to 1:4 x 10(5). CONCLUSION: Monoclonal antibody against recombinant HBoV VP2 protein was prepared and the antibody titer was high. This work may provide a new method in rapid diagnosis and study of HBoV. PMID- 22919760 TI - [The study of an in-house method for drug resistance genotyping testing on HIV-1 strains prevailing in China]. AB - OBJECTIVE: To evaluate the amplification rate and the lowestlower detection limit of an in-house HIV-1 Drug resistant (HIVDR) genotyping test. METHODS: A total of 30 plasma samples were selected, which covered all major HIV-1 subtypes predominating prevailing in China (B', CRF07_BC, CRF01 _AE). The viral loads of the 30 selected samples were detected in triplicate by Easy Q method and the average values were taken as the viral loads of the samples. Each sample was diluted to the concentration of > 1000 copies/ml, 401-1000 copies/ml, 101-400 copies/ml, 50-100 copies/ml and < 50 copies/ml with HIV-negative plasma. After extraction of nucleic acids, RT-PCR and nested PCR amplification were performed, the efficiency of amplification of each subtype and the minimum detection limit were determined statistically based on the PCR results. RESULTS: The viral loads of the selected samples ranged from 2.03 x 10(2)-5.92 x 10(4) copies/ml. The sample of 50-1000 copies/ml have a high amplification rate (86%). CONCLUSION: The In-house method for HIV-1 drug resistance genotyping has a high sensitivity with a high successful amplification rate, especially in the samples with low viral load. This method can be used to the detection of drug-resistant virus and to provide scientific data to treatment options for patients. PMID- 22919761 TI - [Comparison of three methods in construction fusion gene of influenza A virus Nucleoprotein]. AB - OBJECTIVE: To develop a best method of constructing influenza NP fusion gene containing enhanced green fluorescent protein (EGFP). METHODS: The full-length NP gene of influenza A was amplified by RT-PCR and was inserted into an eukaryotic expression vector pEGFP-N1 in order to construct a fusion gene of pEGFP-N1-NP using three different methods. Method one, NP gene containing restriction endonucleases and pEGFP-N1 were both digested using the same restrict enzymes and ligated, yielding the fusion gene of pEGFP-N1-NP. Method two, NP gene was cloned into pMD19-T Vector to construct a plasmid of pMD19-T-NP. The pMD19-T-NP cloned into pEGFP-N1 to construct the fusion gene of pEGFP-N1-NP; Method three, NP gene containing restriction endonucleases was cloned into pMD19-T Simple Vector to construct a plasmid of pMD19-T-NP. The pMD19-T-NP cloned into pEGFP-N1 to construct the fusion gene of pEGFP-N1-NP. RESULTS: The fusion gene of recombinant eukaryotic expression vector pEGFP-N1-NP was successfully constructed by using method three. CONCLUSIONS: The full-length NP gene is obtained and its fusion gene of recombinant eukaryotic expression plasmid is successfully constructed. This study provides foundation for further understanding the biological function of NP protein and the mechanism of diseases induced by influenza A virus. PMID- 22919763 TI - Don't just tick it, talk it! PMID- 22919762 TI - [Evaluation of norovirus rapid detection kit]. AB - OBJECTIVE: Evaluating the accuracy and safety as well as the equivalence compared with the control kit of RIDA QUICK Norovirus detection kit(R-Biopharm, Germany). METHODS: Based on the results of commercially available IDEA Norovirus detection kit (ELISA), the sensitivity and specificity and accuracy of RIDA QUICK Norovirus detection kit (immunochromatographic assay) were evaluated. RESULTS: The sensitivity and specificity of RIDA QUICK Norovirus detection kit were 98.4% and 92.4%, and the accuracy was 97.6% compared with the control kit. CONCLUSION: RIDA QUICK Norovirus detection kit has good sensitivity and specificity for the detection of norovirus antigens. PMID- 22919764 TI - Going for gold. PMID- 22919765 TI - Respect, compassion and dignity: the foundations of ethical and professional caring. AB - Throughout 2011, and for much of this year, the national and professional press have been dominated by reports of failures in health and social care. Stories have focussed on the avoidable harm and disturbing cruelty suffered by individuals and the distress of distraught families seeking answers in the light of systemic organisational failure on an incredible scale (Francis 2010, CQC 2011a, CQC 2011b). PMID- 22919766 TI - The relationship between continuing professional education and horizontal violence in perioperative practice. AB - Continuing professional development must be undertaken by all registered perioperative practitioners. However, interviews with 23 perioperative nurses employed by one NHS trust suggested a link between workplace culture and intra professional conflict which was associated with horizontal violence and perceived as a direct consequence of formal study. Such experiences appeared to affect participants' study and their psychological wellbeing. Further work is required to explore this concept. PMID- 22919767 TI - Ambulatory orthopaedic surgery patients' emotions when using different patient education methods. AB - A randomised controlled trial was used to evaluate elective ambulatory orthopaedic surgery patients' emotions during internet-based patient education or face-to-face education with a nurse. The internet-based patient education was designed for this study and patients used websites individually based on their needs. Patients in the control group participated individually in face-to-face patient education with a nurse in the ambulatory surgery unit. The theoretical basis for both types of education was the same. Ambulatory orthopaedic surgery patients scored their emotions rather low at intervals throughout the whole surgical process, though their scores also changed during the surgical process. Emotion scores did not decrease after patient education. No differences in patients' emotions were found to result from either of the two different patient education methods. PMID- 22919768 TI - Preventing surgical site infections. AB - In less enlightened times, the risk and impact of infection made surgical intervention virtually a last resort option. If the patient survived the operation, infection and death usually followed. In the late 19th century, Joseph Lister applied Pasteur's theories to surgical sterility, and the breakthrough in our understanding of infection prevention and control in the surgical setting had begun. PMID- 22919769 TI - Constrained procurement across Europe. AB - Most of us are aware that the financial climate across Europe at the moment is inevitably going to impact upon our way of working. This is particularly so in the area of procurement. Our surgeon 'gods' can no longer demand whatever they wish, and we as the new generation of 'Florences' cannot rub our lamps and produce the genies with their endless pots of gold. PMID- 22919770 TI - New strategy for NHS procurement Manchester Conference Centre, 17 April 2012. AB - Through the QIPP agenda, the NHS is expected to deliver procurement savings of pounds 1.2 bn by 2014/15. The question at the conference was--is that enough? The NHS as a whole is expected to deliver efficiencies of some pounds 20 bn, which implies that, if procurement was to take its fair share, savings of some pounds 3 bn-3.5 bn would be needed. PMID- 22919771 TI - Guidance aims to improve procurement across healthcare. PMID- 22919772 TI - Procurement decisions packed full of efficiency. PMID- 22919773 TI - Role of the mentor in the theatre setting. AB - Mentorship has been present in healthcare for many years and much has been written about it. This article will explore the role of the mentor in the operating theatre in light of the new standards of mentor preparation. PMID- 22919774 TI - Enhanced recovery after surgery (ERAS) workshop: effect on attitudes of the perioperative care team. AB - BACKGROUND: Enhanced recovery after surgery (ERAS) or 'fast track' surgery is heavily based on a multidisciplinary focused perioperative care model with all players being equally important for successful implementation. Several institutions run an ERAS course but few data are available on their effect on attitudes and perceptions to perioperative care principles. METHODS: A ten item survey was designed for perioperative care clinicians attending an annual ERAS workshop. The survey was administered one week before and three weeks after the workshop. RESULTS: Seventy seven eligible participants were identified. Forty four (57%) responded to the questionnaire prior to the course. On repeat administration of the survey three weeks after the course there were 28 (36%) responses. The results of the survey indicate that the majority of perioperative care staff were already aware of the evidence behind some of the principles applied in colectomy, with a high pre-course level of understanding shown. However the course significantly changed opinion regarding some other aspects of care to align opinion with evidence amongst the responders. CONCLUSION: There appears to be a high rate of evidence agreement with some interventions but not others amongst perioperative staff. Attending a multidisciplinary ERAS workshop seems to align opinion with evidence. PMID- 22919775 TI - Denis Burkitt: Burkitt's lymphoma. PMID- 22919776 TI - State Supreme Court ordered new trial after verdict for $5.1 million. Bedell v. Williams, 2012 Ark. 75-664 (2/23/2012)_S.W. 3.d _-AR. PMID- 22919777 TI - Failure to diagnose 17 year-old who died from pulmonary thromboembolism. Case on point: Ramnarine v. N. Y. City Health & Hospitals Corp., 201250992 (5/18/2012) NY. PMID- 22919778 TI - PA: CNA terminated: U I benefits denied: court found termination without just cause. Beaumont Retirement Home v. Unemployment Compensation Board of Review, 2076 C.D. 2011, 2077 C.D. 2011 (7 /6/2012)-PA. PMID- 22919779 TI - NY: Failure to diagnose & treat VAD: court affirmed judgment for defendants. Helfer v. Chapin, 2012 NY APP3 (6/21/2012)-NY. PMID- 22919780 TI - Mom smoked while pregnant: sued for cerebral palsy & injury to fetus. Case on point: Armagost v. Gunderson Clinic, Inc., 2011 AP522 (5/31/2012) -WI. PMID- 22919781 TI - Making a difference. PMID- 22919782 TI - Health visitors: look out for signs of neglect, urge NSPCC. PMID- 22919783 TI - NMC shows 'shocking lack of competence' reveals report--where next for the regulator and where next for registrants? PMID- 22919784 TI - The health visitor's role in the identification of domestic abuse. AB - Internationally, domestic abuse is a significant public health issue in terms of imposing physical and psychological distress upon victims, having a detrimental impact upon parenting and causing psychological problems for victim's children. Figures identify that one in four UK women experience domestic abuse. However, it is acknowledged that reported rates are gross underestimates of true figures and that multiple barriers exist that inhibit domestic abuse identification. This paper reviews the literature to explore these barriers and ascertain evidence based strategies that will help practitioners to identify domestic abuse more effectively. Particular attention is paid to domestic abuse screening tools, as research suggests their use increases disclosure rates. The paper concludes that routine and recurrent enquiry using a screening tool, information giving to all women, knowledgeable staff and supportive environments, are all potential facilitators to identification. PMID- 22919785 TI - Parental experiences of cleft lip and palate services. AB - In 1995 a cleft liaison service was developed in a health and social care trust which comprises primary and secondary care. The service team includes hospital and community midwives, health visitors and a consultant orthodontist who had a particular interest, and experience in the care of children born with a cleft and often this work was in addition to their existing roles. Anecdotal evidence indicated that the service was of great help to parents but it had never been formally evaluated. Therefore this evaluation was designed to explore the needs and views of parents who had a baby or child with a cleft of the lip and or palate, using a qualitative, cross sectional approach. Following 20 parents interviews responses were recorded, transcribed and a content analysis completed. Three main themes emerged relating to the parents' emotional experiences, their need for information and their experience of caring for a child with a cleft. This study has provided insight into the service delivered by the team and reiterates the need for retaining, maintaining and expanding this specialist service to other localities. Updating midwifery and health visiting staff in terms of knowledge and expertise was implicit to provide a responsive service to meet the needs of the child and family. PMID- 22919786 TI - The role of specialist community public health nurses: students' perceptions. AB - The article outlines the initial perceptions of student specialist community public health nurses (SCPHN) (health visitors, school nurses and sexual health advisers) on the role of the qualified health visitor, school nurse and sexual health advisor. It considers how students undertaking the BSc (hons)/Post Graduate Diploma specialist community public health nursing programme conceptualise their future public health role. The paper identifies themes drawn from a class-based teaching session with a large group of SCPHN students using the medium of art and student drawings. This was followed by classroom discussion and a subsequent mapping exercise. Several themes emerged with emphasis on the personal attributes and role of the public health nurse. The paper concludes that SCPHN students have a relevant knowledge base upon which to develop their future public health roles, as well as identifying clear gaps in their knowledge base at the early stage of the SCPHN programme. PMID- 22919787 TI - Optimising nutritional intake to promote growth and development in children. AB - Eating habits may be formed at a young age and once entrenched, tend to track across childhood and beyond (Tsuji et al, 2012). Although parents have a significant role in the development of their child's dietary intake (Clarke et al, 2007), Harris (2010) argues that the diets and feeding habits of young children are now no longer the sole responsibility of parents but other childcare professionals, including nannies and nursery staff. The aim of this article is to provide parents and professionals with guidance to help encourage parents, and other members of the multidisciplinary team, to provide children with a healthy diet. PMID- 22919788 TI - Newly qualified SCPHN? Tips for your first year in practice. PMID- 22919789 TI - Family Nurse Partnership programme in Scotland: an update. PMID- 22919790 TI - Initiating public health activities in Uganda. PMID- 22919791 TI - 68 is too late...for staff and patients. PMID- 22919792 TI - [Reviving the sentiment of group membership]. PMID- 22919793 TI - [The Geneva declaration and French-speaking nurses]. PMID- 22919794 TI - [A team of women working for the Minister of Social Affairs and Health]. PMID- 22919795 TI - [An assessment of healthcare networks in 2012]. AB - In twenty years, healthcare networks have developed specific new solutions in order to meet the population's healthcare needs. They enrich the general practice hospital link, notably in the coordination of complex patient pathways. However, neither their funding nor their position within the system are guaranteed. PMID- 22919796 TI - [Palliative care networks, players in the 24-hour provision of care]. AB - Palliative care networks ensure the coordination of patients' care in their homes and thereby contribute to the 24-hour provision of care. However, how is participation in round-the-clock care organised when the network's mobile coordination and expertise team does not perform care procedures? PMID- 22919797 TI - [The partnership at the heart of care across a territory]. AB - The coordinator nurse within a healthcare network plays a central role in the continuity of general practice/hospital care. The transfer of the information relating to the care and the care procedures themselves sometimes go beyond administrative borders and require proximity with the patient and reinforced partnerships between healthcare professionals for optimum care safety. PMID- 22919798 TI - [The community role of nurses with elderly people]. AB - The care of frail and dependent elderly people living at home has become a major healthcare issue. Following a multi-disciplinary approach, the gerontology healthcare network Giront'Emeraude in Saint-Malo offers support within the local community. Trained by the network, nurses play a pivotal role in the coordination of the personalised care projects of the elderly people within the network. PMID- 22919799 TI - [The health education nurse in a diabetology network]. AB - By providing global, multi-disciplinary and coordinated care, the Resodia67 network in the Bas-Rhin department aims to improve the quality of life of patients and their family and to reduce the complications and morbidity linked to type 2 diabetes. Nurses can implement their skills in therapeutic patient education. PMID- 22919800 TI - [Challenges and future perspectives of healthcare networks]. AB - Healthcare networks play a central role in the French healthcare system. A reflection on their future and the evolutions to be envisaged is currently in progress. Moreover, the French Directorate General for Healthcare Provision should soon publish a methodological guide concerning these networks. Three players in healthcare networks review the current status of the networks and consider their development. PMID- 22919801 TI - [Correctional health nursing]. PMID- 22919802 TI - [Care and acceptance of the elderly homeless person]. AB - Homeless people are even more vulnerable to the harsh conditions of life on the street when they are old and in poor health. Torn between respecting the individual's choice and performing its mission to provide care, the nursing team aims to find the most adapted solution. Seeking to convince without restraining it is guided by an attitude of care and concern. PMID- 22919803 TI - [The benefit of the telephone questionnaire the day after outpatient surgery]. AB - As outpatient surgery develops, the nursing teams involved find themselves creating innovative practices. These practices must be assessed. A telephone questionnaire carried out the day following surgery is one of the assessment tools used. While it constitutes a lever for the improvement of patient management, it also represents a means of ensuring the continuity of care. PMID- 22919804 TI - [On the road to hope with street children in Madagascar]. AB - On a four-month humanitarian mission to Madagascar, two young child care nurses were able to use their nursing skills, listening skills and their imagination to help orphaned children. They were able to discover the island's social and cultural reality. Here they look back at this experience of deep poverty which also included moments of sharing and hope. PMID- 22919805 TI - [Esthetics and social support, aids for oncology]. AB - Socio-aesthetic care is increasingly being offered to patients suffering from long-term illnesses such as cancer. Combined with support care, it is performed by a socio-aesthetician having received specific training and can be offered as soon as the diagnosis is announced and until the end of the treatment or the end of life. This comfort care helps patients to reclaim a body transformed by the disease and treatments. PMID- 22919806 TI - [The paradoxes and singularity of palliative care]. PMID- 22919807 TI - Caring for the patient with Alzheimer's disease. PMID- 22919808 TI - [Nursing care of heart arrest in a child]. PMID- 22919809 TI - "CNO has work cut out in restoring respect". PMID- 22919810 TI - CNO reveals new nursing vision. PMID- 22919811 TI - "Agreeing national changes is crucial to the survival of AfC". PMID- 22919812 TI - "Sunday madness is epitomised by stupid government leaks". PMID- 22919813 TI - "How news stories encourage people to learn resuscitation". PMID- 22919814 TI - Types of substance misuse and risk factors. AB - This first in a two-part series on substance misuse among older people discusses the pattern of misuse in this group and outlines the different types of misusers. It also explores the risk factors for alcohol misuse and its effects, as well as other types of substance misuse. PMID- 22919815 TI - Opioid prescribing in palliative care. PMID- 22919816 TI - Using multimedia to teach students essential skills. AB - The essential nursing skills team at the University of the West of Scotland's Hamilton Campus introduced a contemporary holistic integrated teaching approach in September 2010 to engage students with essential nursing skills (phase 1). This article explores how this approach was further developed by introducing media in the form of a video (phase 2). It also reports student and peer evaluation of the use of multimedia and preferred formats, with recommendations for further development. PMID- 22919817 TI - Individual treatment for irritable bowel syndrome. AB - Irritable bowel syndrome is a debilitating and distressing condition. This article explores the prevalence, causes, investigation and treatment of it. PMID- 22919818 TI - Skin cancer: causes and groups at risk. AB - This second in a two-part series focuses on the causes and risk factors of skin cancer, highlighting risk factors among the general population as well as in high risk groups. Part 1, published last week, outlined the main types of skin cancer and the treatment options available for each type; this article stresses the importance of early identification and patient education to prevent skin cancer. PMID- 22919819 TI - Bringing taboo to the tab. PMID- 22919820 TI - [Disease resistance signal transfer between roots of different tomato plants through common arbuscular mycorrhiza networks]. AB - Common mycorrhizal networks (CMNs) are the underground conduits of nutrient exchange between plants. However, whether the CMNs can serve as the underground conduits of chemical communication to transfer the disease resistance signals between plants are unknown. By inoculating arbuscular mycorrhizal fungus (AMF) Glomus mosseae to establish CMNs between 'donor' and 'receiver' tomato plants, and by inoculating Alternaria solani, the causal agent of tomato early blight disease, to the 'donor' plants, this paper studied whether the potential disease resistance signals can be transferred between the 'donor' and 'receiver' plants roots. The real time RT-PCR analysis showed that after inoculation with A. solani, the AMF-inoculated 'donor' plants had strong expression of three test defense-related genes in roots, with the transcript levels of the phenylalanine ammonia-lyase (PAL), lipoxygenase (LOX) and chitinase (PR3) being significantly higher than those in the roots of the 'donor' plants only inoculated with A. solani, not inoculated with both A. solani and AMF, and only inoculated with AMF. More importantly, in the presence of CMNs, the expression levels of the three genes in the roots of the 'receiver' plants were significantly higher than those of the 'receiver' plants without CMNs connection, with the connection blocking, and with the connection but the 'donor' plants not A. solani-inoculated. Compared with the control (without CMNs connection), the transcript level of the PAL, LOX and PR3 in the roots of the 'receiver' plants having CMNs connection with the 'donor' plants was 4.2-, 4.5- and 3.5-fold higher, respectively. In addition, the 'donor' plants activated their defensive responses more quickly than the 'receiver' plants (18 and 65 h vs. 100 and 140 h). These findings suggested that the disease resistance signals produced by the pathogen-induced 'donor' tomato plant roots could be transferred to the 'receiver' plant roots through CMNs. PMID- 22919821 TI - [Effects of extraneous inorganic nitrogen forms on the dynamics of soil amino sugars]. AB - Substrate availability affects microbial growth, whereas extraneous nitrogen forms can significantly affect microbial metabolic processes. As for soil amino sugars, the stable residues in microbial cell wall, their synthesis, decomposition and turnover are closely related to the availability of extraneous carbon and nitrogen. Using isotope tracing technique to study soil amino sugars can further understand the substrate utilization profiles by soil microorganisms. In this study, two incubation tests were conducted, with glucose plus 15N labelled NH4+ or NO3- as the substrates, respectively. The 15N enrichment in each kind of soil amino sugars was identified by gas chromatography/ mass spectrometry (GC/MS) to trace the dynamics of soil 15N-labelled and native amino sugars. During the incubation, the content of soil 15N-labelled amino sugars increased significantly, and the transformation rate from NH4+ to amino sugars was significantly higher than that from NO3-, suggesting the preferred utilization of NH4+ than NO3- by soil microorganisms. Significant changes in the amounts of soil unlabelled amino sugars were observed. The amount of unlabelled glucosamine increased with NH4+ addition, but decreased gradually with NO3- addition. The content of unlabelled muramic acid decreased gradually, especially with NO3- addition. Either the increase or the decrease of galactosamine did not exceed 20% to the original value. These compound-specific changes showed that the heterogeneous microbial residues played different roles on the turnover and stabilization of nitrogen in soil matrix. Fungal cell wall residues were easily accumulated in soil matrix, which benefited the stabilization of soil organic matter, while bacterial cell wall residues were easily degraded, playing an important role in the turnover of soil organic matter. PMID- 22919822 TI - [Characteristics of dominant tree species stem sap flow and their relationships with environmental factors in a mixed conifer-broadleaf forest in Dinghushan, Guangdong Province of South China]. AB - By the method of Granier' s thermal dissipation probe, the stem sap flow density of four dominant tree species (Pinus massoniana, Castanopsis chinensis, Schima superba, and Machilus kwangtungensis) in a mixed conifer-broadleaf forest in Dinghushan Reserve of South China was continuously measured in the dry season (November) and wet season (July) in 2010, and the environmental factors including air temperature, relative humidity, and photosynthetically active radiation (PAR) were measured synchronically, aimed to study the characteristics of the stem sap flow of the tree species in response to environmental factors. During the dry and wet seasons, the diurnal changes of the stem sap flow velocity of the tree species all presented a typical single-peak curve, with high values in the daytime and low values in the nighttime. The average and maximum sap flow velocities and the daily sap flow flux of broad-leaved trees (C. chinensis, S. superba, and M. kwangtungensis) were significantly higher than those of coniferous tree (P. massoniana), and the maximum sap flow velocity of P. massoniana, C. valueschinensis, S. superba, and M. kwangtungensis was 29.48, 38.54, 51.67 and 58.32 g H2O x m(-2) x s(-1), respectively. A time lag was observed between the sap flow velocity and the diurnal variations of PAR, vapor pressure deficiency, and air temperature, and there existed significant positive correlations between the sap flow velocity and the three environmental factors. The PAR in wet season and the air temperature in dry season were the leading factors affecting the stem sap flow velocity of the dominant tree species. PMID- 22919823 TI - [Profile distribution of soil aggregates organic carbon in primary forests in Karst cluster-peak depression region]. AB - Soil profiles were collected from three primary forests (Itoa orientalis, Platycladus orientalis, and Radermachera sinica) in Karst cluster-peak depression region to study the composition of soil aggregates, their organic carbon contents, and the profile distribution of the organic carbon. In the three forests, >2 mm soil aggregates were dominant, occupying about 76% of the total. The content of soil total organic carbon ranged from 12.73 to 68.66 g x kg(-1), with a significant difference among the forests. The organic carbon content in <1 mm soil aggregates was slightly higher than that in >2 mm soil aggregates, but most of soil organic carbon was stored in the soil aggregates with greater particle sizes. About 70% of soil organic carbon came from >2 mm soil aggregates. There was a significant positive relationship between the contents of 2-5 and 5-8 mm soil aggregates and the content of soil organic carbon. To increase the contents of 2-8 mm soil aggregates could effectively improve the soil carbon sequestration in Karst region. In Itoa orientalis forest, 2-8 mm soil aggregates accounted for 46% of the total, and the content of soil total organic carbon reached to 37.62 g x kg(-1), which implied that Itoa orientalis could be the suitable tree species for the ecological restoration in Karst region. PMID- 22919824 TI - [Carbon density and its spatial distribution in Quercus acutissima plantations under different thinning intensities]. AB - Quercus acutissima is a tree species widely planted in Jianghuai hilly lands. In this study, the Q. acutissima plantations after five years of different thinning [15% (T15), 30% (T30), 50% (T50) and un-thinning (CK)] were selected, and a sampling plot investigation was made to analyze the carbon density and its spatial distribution in these plantations. In treatments T15, T30 and T50, the tree carbon density increased by 9.1%, 29.6% and 28.4%, respectively, as compared with CK. The carbon density in tree organs was in the order of stem > root > branch > bark > leaf. With increasing thinning intensity, the carbon density in litters decreased while that in 0-50 cm soil layer had a slight increase, but no significant difference was observed between thinning and un-thinning. The total carbon density of the Q. acutissima stands under different thinning intensities was in the order of T30 > T50 > T15 > CK, with an increase of 16.3, 14.5 and 3.6 t C x hm(-2) in treatments T15, T30 and T50, respectively, as compared with CK, but there were no significant differences among the treatments. In treatments T15, T30 and T50, soil respiration was also higher than that in CK, and the difference was significant between treatments T30 and CK. Overall, thinning was helpful to the enhancement of carbon storage in the Q. acutissima plantations in Jianghuai hilly lands, and 30% thinning could be the best. PMID- 22919825 TI - [Photosynthetic functions and chlorophyll fast fluorescence characteristics of five Pinus species]. AB - A comparative study was made on the needle morphological characteristics, photosynthetic rate, and chlorophyll fast fluorescence induction curves of five representative Pinus species P. parvifiora, P. armandii, P. bungeana, P. tabuliformis, and P. densiflora. Significant differences were observed in the needle morphological characteristics among the five species. P. tabuliformis had the longest needle length and highest needle density, whereas P. bungeana had the highest chlorophyll content. P. densiflora and P. parvifiora had the maximum and minimum photosynthetic rate, respectively. There was a positive correlation between the photosynthetic rate and stomatal conductance across the five species. The differences in the chlorophyll fast fluorescence induction curves of the five species were mainly manifested in J-step and I-step. Although the five species had similar values of Fv/Fm, Fv/Fo and Tfm, P. parviflora had significantly higher values of dV/dt(o), dVG/d(o), V and Vi, but lower energy flux ratio psi(o), phiEo and phiRo, compared with the other four species. The low PSII activity and efficiency of P. parviflora might relate to its smallest Sm, Sm/Tfm and N. P. densiflora and P. parvifiora had the maximum and minimum vitality indices PI(ABS/CSo/CSm) and DF, respectively, and there existed significant positive correlations between the PI(CSo) and PI(CSm) and the net photosynthetic rate of the five species, suggesting that PI(CSo) and PI(CSm) could be used to estimate the photosynthetic activity of Pinus trees. PMID- 22919826 TI - [Effects of understory removal and nitrogen addition on the soil chemical and biological properties of Pinus sylvestris var. mongolica plantation in Keerqin Sandy Land]. AB - A full factorial experiment was conducted to study the effects of understory removal and nitrogen addition (8 g x m(-2)) on the soil NO(3-)-N and NH(4+)-N concentrations, potential net nitrogen mineralization rate (PNM) and nitrification rate (PNN), microbial biomass C (MBC) and N (MBN), MBC/MBN, urease and acid phosphomonoesterase activities, and Olsen-P concentration in a Pinus sylvestris var. mongolica plantation in Keerqin Sandy Land during a growth season. Understory removal decreased the soil NH(4+)-N concentration, PNM, MBC, and MBN/MBN significantly, increased the soil Olsen-P concentration, but had little effects on the soil NO(3-)-N concentration, PNN, and urease and acid phosphomonoesterase activities. Nitrogen addition increased the soil NO(3-)-N concentration, PNM and PNN significantly, but had little effects on the other test properties. The interaction between understory removal and nitrogen addition had significant effects on the soil NH(4+)-N concentration, but little effects on the soil NO(3-)-N concentration. However, the soil NO(3-)-N concentration in the plots of understory removal with nitrogen addition was increased by 27%, compared with the plots of nitrogen addition alone, which might lead to the leaching of NO3-. It was suggested that understory vegetation could play an important role in affecting the soil chemical and biological properties in Mongolian pine plantations, and hence, the importance of understory vegetation should not be neglected when the forest management and restoration were implemented. PMID- 22919827 TI - [Organic carbon storage in urban built-up areas of China in 1997-2006]. AB - With the increase of greenhouse gases emission in urban regions, urban carbon cycle plays a more and more important role in global carbon cycle. To estimate urban carbon emission and carbon storage is crucial for understanding urban carbon cycle. By using China's statistics data and the results from recent publications, this paper estimated the organic carbon storage in China's urban built-up areas in 1997-2006. From 1997 to 2006, the total organic carbon storage in the urban built-up areas increased from 0.13-0.19 Pg C (averagely 0.16 Pg C) to 0.28-0.41 Pg C (averagely 0.34 Pg C), and the organic carbon density increased from 9.86-14.03 kg C x m(-2) (averagely 11.95 kg C x m(-2)) to 10.54-15.54 kg C x m(-2) (averagely 13.04 kg C x m(-2)). The total organic carbon storage in the urban built-up areas was mainly contributed by soils (78% in 1997 and 73% in 2006), followed by buildings (12% in 1997 and 16% in 2006) and green spaces (9% in 1997 and 10% in 2006), while the carbon storage in resident bodies only accounted for less than 1%, which could be neglected. PMID- 22919828 TI - [Ecosystem service interactions and their affecting factors in Jinghe watershed at county level]. AB - Taking the multiple ecosystem services (grain supply, meat supply, fuel-wood supply, water resource conservation and soil retention) as test objects, this paper analyzed the interactions among these services, the interaction modes and the possible affecting factors in 31 counties of Jinghe watershed. At the county level, there existed great differences in the interactions among different pairs of the ecosystem services. The grain supply showed significant positive correlation with meat supply but negative correlation with soil retention, whereas the water resource conservation showed significant positive correlations with fuel-wood supply and soil retention. As for the interaction modes of the ecosystem services, 24 counties were primarily of regulation services, 3 counties were of supply and regulation services in balance, and 4 counties were primarily of grain supply. The total ecosystem service index of the interaction modes in each county varied greatly, with 5.1 times of difference between the maximum (Jingyuan County) and the minimum value (Yanchi County). The total ecosystem service index was significantly positively correlated with precipitation and soil total nitrogen, and negatively correlated with solar hours. The increase of farmland had negative effects, while that of shrub land and grassland had great positive effects on the total ecosystem service index, but the increase of forestland had less effects. PMID- 22919829 TI - [Responses of vegetations in Minqin desert area to climate change]. AB - Based on the phenological data in 1974-2009 and the plot vegetation data in 2002 2010 as well as the meteorological data, this paper analyzed the responses of the vegetations in Minqin desert area to climate change. In 1961-2010, the air temperature and air humidity in the study area increased, and the increasing rate of the mean annual air temperature was greater than the global level and China's level over the past century. The responses of the vegetations to the air temperature change were mainly manifested in the advance of spring phenology, delay of autumn phenology, and lengthening of growing duration, whereas the responses of the vegetations to precipitation change were mainly manifested in the decrease of vegetation coverage and pure coverage with the decreasing precipitation. The plant density and richness fluctuated with the variation of precipitation, and the vegetation coverage and pure coverage were positively correlated with the annual precipitation firstly, and the precipitation in Jun July and in April-May secondly. The plant density and richness were positively correlated with the precipitation in September. The advance of the spring phenology was in the order of bud-expansion > bud-opening > beginning of flowering > beginning of leaf-extension and leaf flourish > flower-bud appearance > flower flourishing > end of flowering > fruit-maturity, whereas the delay of autumn phenology was in the order of full leaf-discoloration > beginning of leaf fall > beginning of leaf-discoloration > end of leaf-fall. As compared with the increase of air temperature in autumn, the increase of air temperature in spring had greater effects on the plant phenology in Minqin desert area. PMID- 22919830 TI - [Spatiotemporal differentiation of land cover change and grassland degradation pattern in Yangtze River headwaters area]. AB - Based on field survey data, remote sensing images and statistical data, this paper analyzed the spatiotemporal differentiation of land use and grassland degradation patterns in Yangtze River headwaters area in 1987-2007, and discussed the main natural factors (elevation, position and slope) leading to the changes of this area's grassland ecological environment. In 1987-2007, the fragmentation of this area' s landscape patterns had an increasing trend, and natural environment and climate change were the main driving forces of land use pattern change. There existed significant differences in the areas of grassland degradation at different altitudes. Grassland degradation mainly occurred at altitudes 4800-5100 m. The grassland degradation area tended to increase with increasing elevation, and the proportions of the degradation area varied greatly over different slopes and aspects. The climate in the study area became warm and dry, and the spatial structure of regional land cover changed obviously. The distribution patterns of grassland degradation at different elevation, position and slope coincided with alpine environment and human disturbances, suggesting that alpine environment and climatic change were the decisive factors to the grassland ecosystem pattern in Yangtze River headwaters area. PMID- 22919831 TI - [Effects of snow cover on the decomposition and nutrient dynamics of Sibiraea angustata leaf litter in western Sichuan plateau, Southwest China]. AB - Soil-borne bag method was adopted to study the decomposition and nutrient dynamics of Sibiraea angustata leaf litter under different depths (0, 30 and 100 cm) of snow cover in western Sichuan plateau in January-May, 2010. In snow-free plot, the mass loss rate of the litter over the five months was 29.9%; in the plots with 30 and 100 cm snow cover, the litter mass loss rate was 33.8% and 35.2%, respectively. During the decomposition, definite N enrichment in the litter was observed, while the P enrichment fluctuated. The C content and C/N ratio of the litter decreased sharply at the early stage of decomposition, but increased gradually after then. Snow cover greatly contributed to the rapid decomposition of litter and the N enrichment in the litter, but had little effects on the litter C and P contents. In western Sichuan plateau, durable snow cover with a depth of > 30 cm could alter the litter decomposition pattern, and substantially affect the soil nutrient turnover and plant community composition. PMID- 22919832 TI - [Effects of controlled alternate partial root-zone drip irrigation on apple seedling morphological characteristics and root hydraulic conductivity]. AB - To investigate the effects of alternate partial root-zone drip irrigation (ADI) on the morphological characteristics and root hydraulic conductivity of apple seedlings, three irrigation modes, i.e., fixed partial root-zone drip irrigation (FDI, fixed watering on one side of the seedling root zone), controlled alternate partial root-zone drip irrigation (ADI, alternate watering on both sides of the seedling root zone), and conventional drip irrigation (CDI, watering cling to the seedling base), and three irrigation quotas, i. e., each irrigation amount of FDI and ADI was 10, 20 and 30 mm, and that of CDI was 20, 30 and 40 mm, respectively, were designed. In treatment ADI, the soil moisture content on the both sides of the root zone appeared a repeated alternation of dry and wet process; while in treatment CDI, the soil moisture content had less difference. At the same irrigation quotas, the soil moisture content at the watering sides had no significant difference under the three drip irrigation modes. At irrigation quota 30 mm, the root-shoot ratio, healthy index of seedlings, and root hydraulic conductivity in treatment ADI increased by 31.6% and 47.1%, 34.2% and 53.6%, and 9.0% and 11.0%, respectively, as compared with those in treatments CDI and FDI. The root dry mass and leaf area had a positive linear correlation with root hydraulic conductivity. It was suggested that controlled alternate partial root zone drip irrigation had obvious compensatory effects on the root hydraulic conductivity of apple seedlings, improved the soil water use by the roots, benefited the equilibrated dry matter allocation in seedling organs, and markedly enhanced the root-shoot ratio and healthy index of the seedlings. PMID- 22919833 TI - [Identification of plant species based on DNA barcode technology]. AB - It is crucial for the studies of taxonomy and biodiversity by using DNA barcode technology to fast and accurately make species identification in the forests across tropics and temperate zones. In this study, the 183 plant species in a 20 hm2 subtropical forest plot in Dinghushan (DHS) National Nature Reserve of South China were sampled and sequenced, and the matK, rbcL, and psbA-trnH were employed to generate multi-locus barcodes. For the plot, the psbA-trnH possessed the highest integral success rate, i. e., the product of sequencing recovery and correct species identification (75%), followed by matK (70%), and rbcL (56%). A combination of three-locus barcode (matK, rbcL and psbA-trnH) could identify greater than 87% of the total species, followed by two-locus barcode (85% for matK+psbA-trnH, 83% for rbcL+psbA-trnH, and 81% for matK+rbcL). A comparison was made with the previously published results from one subtropical forest plot (LFDP in Puerto Rico, 143 species) and two tropical forest plots (BCI in Panama, 296 species; and NRS in French Guiana, 254 species) to evaluate the universality and species identification correctness of the proposed DNA barcodes for these four forest plots. For the plots in tropics and subtropics, the sequencing success rate of rbcL, psbA-trnH and matK were 93% and 95.1%, 91.5% and 94.6%, and 68.5% and 79.7%, respectively. The combination of matK + rbcL showed a high identification capacity in geographically restricted regions in taxonomic groups, whereas the three-locus barcode had a high rate of correct species identification both in tropics (84%) and in subtropics (90%). PMID- 22919834 TI - [Features of calcium crystals and calcium components in 54 plant species in salinized habitats of Tianjin]. AB - Plant calcium (Ca) is composed of dissociated Ca2+ and easily soluble, slightly soluble, and hard soluble combined Ca salts. The hard soluble Ca salts can often engender Ca crystals. To understand the Ca status in different growth form plants in salinized habitats, 54 plant species were sampled from the salinized habitats in Tianjin, with the Ca crystals examined by microscope and the Ca components determined by sequential fractionation procedure. More Ca crystals were found in 38 of the 54 plant species. In 37 of the 38 plant species, drusy and prismatic Ca oxalate crystals dominated, whereas the cystolith of Ca carbonate crystal only appeared in the leaves of Ficus carica of Moraceae. The statistics according to growth form suggested that deciduous arbors and shrubs had more Ca oxalate crystal, liana had lesser Ca oxalate crystal, and herbs and evergreen arbors had no Ca oxalate crystal. From arbor, shrub, liana to herb, the concentration of HCl soluble Ca decreased gradually, while that of water soluble Ca was in adverse. The concentration of water soluble Ca in herbs was significantly higher than that in arbors and shrubs. This study showed that in salinized habitats, plant Ca crystals and Ca components differed with plant growth form, and the Ca oxalate in deciduous arbors and shrubs played an important role in withstanding salt stress. PMID- 22919835 TI - [Characteristics of sediment heavy metal pollution in three water supply reservoirs in Huizhou, Guangdong Province of South China]. AB - To understand the present status of the heavy metal (Cr, Cu, Zn, Cd, Pb and Hg) pollution of the sediments in water supply reservoirs in Huizhou, sediment cores were sampled from three representative reservoirs. The heavy metal concentrations were analyzed by ICP-MS, and the pollution status was assessed by geo accumulation index (Igeo) and potential ecological risk index (RI). In the meantime, the possible sources of the heavy metals were analyzed by the principal component analysis (PCA). In the sediments of the three reservoirs, the test heavy metals had different vertical distribution, some had less change, the others decreased or increased with depth, and the distribution patterns differed with the reservoirs. According to the Igeo, the sediments in the reservoirs were seriously polluted by Zn and Pb (Zn: 49.98-640.29 mg x kg(-1); Pb: 21.94-300.66 mg x kg(-1)), reaching slight to high pollution, and the middle or bottom part of the sediments was slightly polluted by Cu (16.85-45.46 mg x kg(-1)). On the whole, the sediments were not polluted by Cr, Cd and Hg. According to the RI and the potential ecological risk coefficient [Er(i)], the sediments in the three reservoirs were under low potential ecological risk. Based on the PCA and relevant information, the human activities such as mining and smelting, urbanization, and agriculture and forestry had great contribution to the heavy metal pollution. The Zn and Pb pollution mainly originated from mining and smelting, Pb pollution also came from motor vehicle exhaust emission and domestic wastes, and Cu pollution mainly derived from agriculture and forestry. PMID- 22919836 TI - [Effects of slope gradient on slope runoff and sediment yield under different single rainfall conditions]. AB - Based on the field observation data of runoff and sediment yield produced by single rainfall events in runoff plots, this paper analyzed the variation patterns of runoff and sediment yield on the slopes with different gradients under different single rainfall conditions. The differences in the rainfall conditions had little effects on the variation patterns of slope runoff with the gradient. Under the conditions of six different rainfall events in the study area, the variation patterns of slope runoff with the gradient were basically the same, i. e., the runoff increased with increasing gradient, but the increment of the runoff decreased slightly with increasing gradient, which was mainly determined by the infiltration flux of atmospheric precipitation. Rainfall condition played an important role on the slope sediment yield. Generally, there existed a critical slope gradient for slope erosion, but the critical gradient was not a fixed value, which varied with rainfall condition. The critical slope gradient for slope erosion increased with increasing slope gradient. When the critical slope gradient was greater, the variation of slope sediment yield with slope gradient always became larger. PMID- 22919837 TI - [Relationships of rice canopy PAR interception and light use efficiency to grain yield]. AB - Taking two rice cultivars (Liangyoupeijiu and Wuxiangjing 14) with different plant types as test materials, a 2-year field experiment was conducted to study the relationships of rice canopy photosynthetically active radiation (PAR) interception and light use efficiency to grain yield under three planting densities and five nitrogen (N) application rates. From tillering to maturing stage, the average PAR reflectance in all treatments was 3.45%. The ratio of reflected PAR to the total loss of PAR from tillering to heading stage was 10.90%, which was significantly lower than that (22.06%) from heading to maturiting stage. The PAR conversion efficiency from tillering to maturing stage decreased with increasing planting density but increased with increasing nitrogen rate, and the conversion efficiency was significantly higher from tillering to heading than from heading to maturing stage. The PAR use efficiency from tillering to maturing stage increased with the increase of planting density and nitrogen application rate, and the average PAR use efficiency of Liangyoupeijiu (1.83 g x MJ(-1)) was significantly higher than that of Wuxiangjing 14 (1.42 g x MJ(-1)). Due to the longer growth period of Wuxiangjing 14, its incident PAR and intercepted PAR under midium and high planting densities were higher, as compared with Liangyoupeijiu. The grain yield was significantly positively correlated with the canopy PAR interceptance and use efficiency at different growth stages, but less correlated with the PAR conversion efficiency. To increase the canopy PAR use efficiency and conversion efficiency on the basis of maintaining higher PAR interception rate could be an effective way to increase rice yield. PMID- 22919838 TI - [Drought resistance evaluation system for backcross lines of Dongxiang common wild rice (Oryza rufipogon Griff.)]. AB - A total of 79 rice materials containing Dongxiang wild rice (Oryza rufipogon Griff. ) backcross lines (Dwr)/Xie-qingzao B (Xqz B)//Xqz B and their parents were chosen as the test objects to study the relationships between the drought resistance of these materials and the 31 drought resistance indices at germinating stage, seedling stage, booting stage, and mature stage. The results showed that the drought resistance index or the drought resistance coefficient of these materials were significantly correlated to the relative germination energy (RGE) under 15% PEG-6000 drought stress, the germination drought resistance index (GDRI) and relative germination energy (RGE) under 20% PEG-6000 drought stress, and the relative value of maximum root length (MRL), seeding height (SH), fresh root mass (FRM), dry root mass (DRM), root relative water content (RRWC), wilting rate (WR), leaf soluble sugar content (LSSC), leaf proline content (LPC), leaf MDA content (LMDAC), leaf relative water content (LRWC), level of rolling leaf (RL), plant height (PH), tiller number per plant (TNP), productive tiller number per plant (PTNP), filled spikelets per panicle (FSP), panicle density (PD), seed setting rate (SR), and 1000-grain mass (TGM) under water stress. Through stepwise regression analysis, nine drought resistance indices including the RGE under 20% PEG-6000 drought stress and the relative values of DRM, RRWC, LSSC, LPC, LMDAC, ETNP, SR, and TGM under water stress were selected. Base on these indices and their partial correlation coefficients, the drought resistance evaluation equation (D value) and evaluation system were established, which could well assess the drought resistance of the Dongxiang common wild rice backcross lines at different growth stages. PMID- 22919839 TI - [Canopy light distribution and its correlation with photosynthetic production in super-high yielding cotton fields of Xinjiang, Northwest China]. AB - Taking the super-high yielding cotton fields (lint yield > or = 4000 kg x hm(-2)) in Xinjiang as the objects, this paper studied the canopy light distribution, photosynthetic rate, and dry matter accumulation at different growth stages, as well as the relationships between the characteristics of canopy light environment and the photosynthetic production. From full flowering stage to late full bolling stage, the light absorption proportion in the upper, middle and lower canopy layers in the super-high yielding cotton fields was 2:2:1, and the canopy transmission coefficients for radiation penetration and diffuse penetration were 0.20-0.55 and 0.22-0.56, respectively, being at reasonable level. The leaves in the middle and lower canopy layers could well accept light, and the leaf photosynthetic rate had little difference among different canopy layers. Compared with high yielding (3500 kg x hm(-2)) and generally high yielding (3000 kg x hm( 2)) cotton fields, super-high yielding cotton field had higher leaf area index and the highest canopy photosynthesis rate at early full boiling stage, and slowly decreased leaf area index, higher canopy photosynthesis rate, increased contribution of non-foliar organs to photosynthetic production, and larger dry matter accumulation from early boll-opening stage to full boll-opening stage. In cotton cultivation, to adjust the canopy structure for the equidistribution of light and canopy photosynthesis capacity in vertical direction could be the important strategy for the efficient utilization of absorbed light energy and the realization of super-high yielding. PMID- 22919840 TI - [Maize growth and its responses to heat condition in Northeast China]. AB - Taking 3 maize cultivars (Danyu 39, Yuandan 29, and Longdan 13) as test materials, a field experiment was conducted to study their growth characteristics and responses to air temperature under the conditions of early, medium and late sowing. For the three cultivars, the days from sowing to seedling emergence under early, medium and late sowing were averagely 13, 11 and 8 d, respectively, and the seedling emergence rate was the fastest when the mean air temperature was about 18 degrees C. Higher or lower air temperature would decrease the seedling emergence rate. The test cultivars had less difference in the days from seedling to jointing, which was slightly affected by air temperature. Compared with Danyu 39 and Yuandan 29, the late-maturing Longdan 13 had an increased growth rate from jointing to mature stage, and thus, the days for mature shortened markedly. For all the three maize cultivars, the days from jointing to mature tended to decrease with increasing air temperature. The dry matter accumulation rate in whole growth period, grain yield, and 100-seed mass were in the order of Danyu 39 > Yuandan 29 > Longdan 13. PMID- 22919841 TI - [Salt-alkaline tolerance of sorghum germplasm at seedling stage]. AB - A sand culture experiment with Hoagland solution plus NaCl and Na2CO3 was conducted to study the responses of sorghum seedlings to salt-alkaline stress. An assessment method for identifying the salt-alkaline tolerance of sorghum at seedling stage was established, and the salt-alkaline tolerance of 66 sorghum genotypes was evaluated. At the salt concentrations 8.0-12.5 g x L(-1), there was a great difference in the salt-alkaline tolerance between tolerant genotype 'TS 185' and susceptive 'Tx-622B', suggesting that this range of salt concentrations was an appropriate one to evaluate the salt-alkaline tolerance of sorghum at seedling stage. At the salt concentrations 10.0 and 12.5 g x L(-1), there existed significant differences in the relative livability, relative fresh mass, and relative height among the 66 genotypes, indicating a great difference in the salt alkaline tolerance among these genotypes. The genotype 'Sanchisan' was highly tolerant, 16 genotypes such as 'MN-2735' were tolerant, 32 genotypes such as 'EARLY HONEY' were mild tolerant, 16 genotypes such as 'Tx-622B' were susceptive, and genotype 'MN-4588' was highly susceptive to salt-alkaline stress. Most of the sorghum genotypes belonging to Sudangrasses possessed a high salt-alkaline tolerance, while the sorghum genotypes belonging to maintainer lines were in adverse. PMID- 22919842 TI - [Salt stress tolerance of cucumber-grafted rootstocks]. AB - Taking 4 different Cucurbita maxima x C. moschata rootstocks for cucumber (Cucumis sativus) as test materials, a solution culture experiment was conducted to study their growth and antioxidative enzyme activities under the stresses of Ca(NO3)2 and NaCl, with the salt stress tolerance of the rootstocks evaluated by subordinate function. At 30 mmol x L(-1) of Ca (NO3)2 or 45 mmol x L(-1) of NaCl, the growth of the rootstock seedlings was improved; but at 60 and 120 mmol x L( 1) of Ca(NO3)2 or 90 and 180 mmol x L(-1) of NaCl, the growth and the antioxidative systems of the seedlings were inhibited, and the salt injury index of 'Qingzhen No. 1' was the smallest, with the decrement of biomass and SOD, POD and CAT activities and the increment of relative conductance being significantly lower than those of the others. Under the stress of high concentration Ca(NO3)2, the SOD, POD and CAT activities of test rootstocks were higher, and the salt injury index and relative conductance were lower, as compared with those under high concentration NaCl, suggesting that the damage of Ca(NO3)2 stress to cucumber-grafted rootstock were smaller than that of NaCl stress. Among the 4 rootstocks, 'Qingzhen No. 1' had the strongest salt stress tolerance, followed by 'Zuomu Nangua', 'Fengyuan Tiejia', and 'Chaoba Nangua'. PMID- 22919843 TI - [Trait stability and test site representativeness of sugarcane varieties based on GGE-biplot analysis]. AB - Arithmetic mean method is commonly used to evaluate the yield stability and adaptability of sugarcane varieties, and variance analysis is applied to estimate the errors in regional trials. However, it is difficult to accurately evaluate the differences of the varieties due to the discrepancies across test sites and years. In this paper, GGE-biplot method was adopted to analyze the data from the regional trials with seven sugarcane varieties at five sites from 2008 to 2009, aimed to objectively evaluate the yield stability and adaptability of sugarcane varieties in China. Among the test sugarcane varieties, Funong No. 30 had higher cane yield and better yield stability, Yuegan No. 18 had higher sugar content and better trait stability, Funong No. 28 and Yunzhe 99-91 had high sucrose content and trait stability, while Yuegan No. 16 had the highest cane yield and sugar content but ordinary stability. In the test sites, Zhangzhou City in Fujian Province and Suixi City in Guangdong Province had the best representativeness and discrimination. This study showed that GGE-biplot analysis provided a simple and effective method to analyze the high yield and stability of sugarcane varieties in regional trials, and supplied the basis for the approval and extension of new sugarcane varieties. PMID- 22919844 TI - [Effects of sowing date and planting density on the seed yield and oil content of winter oilseed rape]. AB - A field experiment was conducted to investigate the effects of different sowing date and planting density on the seed yield and seed oil content of winter oilseed rape (Brassica napus). Sowing date mainly affected the seed yield of branch raceme, while planting density affected the seed yields of both branch raceme and main raceme. The seed oil content was less affected by sowing date. The proportion of the seed yield of main raceme to the seed yield per plant increased with increasing planting density, and the seed oil content of main raceme was about 1% higher than that of branch raceme. Consequently, the seed oil production per plot increased significantly with increasing planting density. In the experimental region, the sowing date of winter oilseed rape should be earlier than mid-October. When sowing in late October, the seed yield would be decreased significantly. A planting density of 36-48 plants x m(-2) could improve the seed yield and oil content of winter oilseed rape. PMID- 22919845 TI - [Effects of UV-B radiation on the growth and reproduction of Vicia angustifolia]. AB - A simulation experiment with supplementation and exclusion of solar ultraviolet-B (UV-B) radiation was conducted to study the effects of enhanced and near ambient UV-B radiation on the growth and reproduction of alpine annual pasture Vicia angustifolia on Qinghai-Tibet Plateau. Enhanced UV-B decreased the plant height and biomass, biomass allocation to fruit, flower number, and 100-seed mass significantly, delayed flowering stage, increased the concentration degree of flowering and success rate of reproduction, but had little effect on seed yield. Near ambient UV-B radiation made the plant height increased after an initial decrease, decreased biomass allocation to fruit and 100-seed mass, but little affected flowering duration, flower number, and seed yield. Both enhanced and near ambient UV-B radiation could inhibit the growth and production of V. angustifolia, and the effect of enhanced UV-B radiation was even larger. PMID- 22919846 TI - [Genetic diversity of 21 Fusarium strains in Section Martiella based on ISSR analysis]. AB - In order to understand the genetic difference and phylogenic relationship within and among the Fusarium species in Section Martiella, the genetic diversity of 21 Fusarium strains in the section was examined by inter-simple sequence repeats (ISSR). Fifteen selected ISSR primers were adopted to do amplification, and a total of 239 bands were amplified, among which, 230 (96.2%) were polymorphic, with an average of 15.3 polymorphic bands per primer. The genetic similarity ranged from 0.494 to 0.933, with an average of 0.640. All the test strains were clustered into two groups at genetic similarity of 0.593. The strains 1-17 were grouped into IG-I, belonging to Fusarium solani and F. solani var. coeruleum, while the strains 18-21 were grouped into IG-II, belonging to F. ventricosum. All the 21 strains could be entirely distinguished at genetic similarity of 0. 933. The SSR loci in the Fusarium genomes were rich in polymorphism. The ISSR grouping had definite correlation with the species classification, but less correlation with the geographic origin of the strains. Within the same ISSR groups, there existed definite correlation between the genetic similarity and the geographic origin of the strains. Within the same species collected from the same regions and same host plants, there existed definite genetic difference among the strains of the same species. PMID- 22919847 TI - [Urban heat island intensity and its grading in Liaoning Province of Northeast China]. AB - According to the recorded air temperature data and their continuity of each weather station, the location of each weather station, the numbers of and the distances among the weather stations, and the records on the weather stations migration, several weather stations in Liaoning Province were selected as the urban and rural representative stations to study the characteristics of urban heat island (UHI) intensity in the province. Based on the annual and monthly air temperature data of the representative stations, the ranges and amplitudes of the UHI intensity were analyzed, and the grades of the UHI intensity were classified. The Tieling station, Dalian station, Anshan station, Chaoyang station, Dandong station, and Jinzhou station and the 18 stations including Tai' an station were selected as the representative urban and rural weather stations, respectively. In 1980-2009, the changes of the annual UHI intensity in the 6 representative cities differed. The annual UHI intensity in Tieling was in a decreasing trend, while that in the other five cities was in an increasing trend. The UHI intensity was strong in Tieling but weak in Dalian. The changes of the monthly UHI intensity in the 6 representative cities also differed. The distribution of the monthly UHI intensity in Dandong, Jinzhou and Tieling took a "U" shape, with the maximum and minimum appeared in January and in May-August, respectively, indicating that the monthly UHI intensity was strong in winter and weak in summer. The ranges of the annual and monthly UHI intensity in the 6 cities were 0.57-2.15 degrees C and 0.70-4.60 degrees C, and the ranges of 0.5-2.0 degrees C accounted for 97.8% and 72.3%, respectively. The UHI intensity in the province could be classified into 4 grades, i. e., weak, strong, stronger and strongest. PMID- 22919848 TI - [Applications of 2D and 3D landscape pattern indices in landscape pattern analysis of mountainous area at county level]. AB - Landscape pattern indices are the commonly used tools for the quantitative analysis of landscape pattern. However, the traditional 2D landscape pattern indices neglect the effects of terrain on landscape, existing definite limitations in quantitatively describing the landscape patterns in mountains areas. Taking the Qixia City, a typical mountainous and hilly region in Shandong Province of East China, as a case, this paper compared the differences between 2D and 3D landscape pattern indices in quantitatively describing the landscape patterns and their dynamic changes in mountainous areas. On the basis of terrain structure analysis, a set of landscape pattern indices were selected, including area and density (class area and mean patch size), edge and shape (edge density, landscape shape index, and fractal dimension of mean patch), diversity (Shannon's diversity index and evenness index) , and gathering and spread (contagion index). There existed obvious differences between the 3D class area, mean patch area, and edge density and the corresponding 2D indices, but no significant differences between the 3D landscape shape index, fractal dimension of mean patch, and Shannon' s diversity index and evenness index and the corresponding 2D indices. The 3D contagion index and 2D contagion index had no difference. Because the 3D landscape pattern indices were calculated by using patch surface area and surface perimeter whereas the 2D landscape pattern indices were calculated by adopting patch projective area and projective perimeter, the 3D landscape pattern indices could be relative accurate and efficient in describing the landscape area, density and borderline, in mountainous areas. However, there were no distinct differences in describing landscape shape, diversity, and gathering and spread between the 3D and 2D landscape pattern indices. Generally, by introducing 3D landscape pattern indices to topographic pattern, the description of landscape pattern and its dynamic change would be relatively accurate. PMID- 22919849 TI - [Life table of Leptinotarsa decemlineata (Say) natural population and related affecting factors]. AB - In this study, the life table of the 2nd generation of Leptinotarsa decemlineata (Say) natural population on potato plants was constructed based on functional factor life table method, and the control effects of different factors on the population were analyzed by exclusion analysis method. It was shown that the survival rate of eggs and first instar (79.1% and 69.3%, respectively) was rather lower than that of the L. decemlineata at other growth stages, suggesting that the eggs and first instar larvae were the key stages to control L. decemlineata. Among the controlling factors, "natural death" was the most effective factor, its exclusive index of population control (EIPC) being 1.87, "predators and others" was in the second place, with the EIPC being 1.51, while "parasitism" had no control effect. The index of population trend of L. decemlineata would be increased 2.8 times if all natural factors were excluded. It was concluded that natural factors had a certain but weak action on the L. decemlineata population. PMID- 22919850 TI - [Effects of temperature stress on physiological indices of Chilo suppressalis Walker (Lepidoptera: Pyralidae) diapause larvae]. AB - To understand the physiological mechanisms of temperature stress on the diapause larvae of rice stem borer Chilo suppressalis Walker at physiological and biochemical levels, determinations were made on the contents of water, lipid, total sugar and low molecular mass carbohydrates and the activities of SOD, POD, CAT in the larvae after series temperature stress (STS) and gradient temperature stress (GTS). With the decrease of temperature, the water content in the larvae decreased, and the decrement below 0 degrees C was significantly larger in treatment GTS than in treatment STS. The lipid content in the larvae decreased gradually, but no significant difference was observed between treatments STS and GTS. The total sugar content in the larvae in treatment STS increased after an initial decrease, but that in treatment GTS continued to decline. Four species of low molecular carbohydrates, i. e. , trehalose, glucose, glycerol and fructose were detected in the larvae. In treatment STS, the contents of glycose, glycerol and fructose in the larvae decreased after an initial increase, while the trehalose content was in adverse. In treatment GTS, the trehalose content decreased first and increased then, the glucose and glycerol were in adverse, but the fructose content had little change. In the range from 14 to -14 degrees C, the SOD and POD activities in the larvae in treatment STS were significantly lower than those in treatment GTS, but the CAT activity was in adverse. The changes of these indices reflected the physiological responses of C. suppressalis diapause larvae to different temperature stress. PMID- 22919851 TI - [Impacts of urbanization on the water quality and macrobenthos community structure of the tributaries in middle reach of Qiantang River, East China]. AB - The 59 1st-3rd order tributaries in the middle reach of Qiantang River are negatively affected by different intensities of urbanization. In April 2010, an investigation was conducted on the water bodies' physical and chemical properties and macrobenthos communities of the tributaries, with the relationships between the tributaries' water quality and biological communities and the percentage of ground surface impervious area (PIA), an indicator of urbanization intensity. The Spearman correlation analysis showed that the water bodies' NH(4+)-N, PO4(3-)-P, TP, COD(Mn), conductivity, width, depth, and fine sand/silt ratio were positively correlated with PIA, and negatively correlated with forest land area. The fitted nonlinear regression equations revealed that all the test macro-benthic invertebrate's parameters had significant relationships with PIA, of which, the total number of taxa, Shannon diversity index, richness index, EPT (%), predators (%), shredders (%), filterers (%) and scrapers (%) were negatively correlated to PIA but positively correlated to forest land area, and the BI, collectors (%), tolerance taxa (%) and oligochaeta (%) were positively correlated to the PIA. Our study indicated that under the impact of urbanization, these tributaries presented the common features of degradation, i. e., high concentrations of nitrogen and phosphorus, degradation of physical habitat, disappearance of pollution-sensitive macro-benthic invertebrate species, and dramatic increase of pollution-tolerant species individuals. PMID- 22919852 TI - [Macrozoobenthos community structure and its indicative significance in water quality bioassessment of Fenshuijiang Reservoir, Zhejiang Province of East China]. AB - A monthly investigation was conducted on the macrozoobenthos at 7 stations of Fenshuijiang Reservoir in Zhejiang Province of East China from November 2008 to October 2009. A total of 37 taxa were collected, most of which belonged to Oligocheata and Chironomidae. Limnodrilus hoffmeisteri was dominant in spring, summer and autumn, and Chironomus gr. plumosus was prevailing in winter. The collector-gatherer was the predominant group in species number, density and biomass. The mean annual density and biomass of the community were (488.0 +/- 48.8) ind X m(-2) and (1.86 +/- 0.49) g X m(-2), respectively. There were no significant differences in the macrozoobenthic density among the stations and in the macrozoobenthic biomass among the stations and among the seasons, but the macrozoobenthic density had a significant seasonal variation, with the sequence of spring > summer > winter > autumn. Water temperature and water depth were the main factors affecting the spatial distribution of the macrozoobenthos. Shannon index and Goodnight-Whitley index were not suitable for the assessment, whereas the Wright index, Carlander index, Pielou index and trophic level index showed that this reservoir was slightly polluted. PMID- 22919853 TI - [Morphological and quality difference of adult Anguilla japonica under three aquaculture models]. AB - Anguilla japonica adults with a snout-vent length of (25.91 +/- 3.26) cm were randomly sampled from the ponds of monoculture A. japonica (M1) and polyculture A. japonica and Macrobrachium nipponense (M2) and the proliferation site in reservoir (M3) to compare the morphological and quality indices of the adults under the three aquaculture models. Discriminant analysis, cluster analysis, and factor analysis were applied to reveal the differences among the individuals of these three cultured populations. Among the test 21 biological traits and 23 morphological and quality indices, there were significant differences in 15 biological traits and 14 morphological and quality indices between M1 and M2, 19 and 18 between M1 and M3, and 11 and 8 between M2 and M3, respectively. The Euclidean distance between M1 and M2, M1 and M3, and M2 and M3 was 1.433, 3. 516, and 2. 167, respectively, and the differences were significant. The accumulative variance percentage of the first five principal components was 82.1%, and the eigenvalues of these components were all larger than 1. The principal components 1 and 2 could be regarded as fatness factor and movement factor, the other three principal components could be regarded as well-being factor, and the three populations could be clearly separated each other by principal component 1. In discriminant analysis, the five principal components, i. e., body width / anal length, body length / anal length, net volume coefficient, swim bladder coefficient, and liver coefficient, were served as independent variables to establish discriminant functions of the populations, which could clearly distinguish the populations, with the discriminant accuracy and synthetic discriminant accuracy being 100%. PMID- 22919854 TI - [Effects of nutritional condition on the competitive parameters of Prorocentrum donghaiense and Skeletonema costatum]. AB - By the methods of pure culture and mixed culture in laboratory, this paper studied the effects of different substrate nitrogen and phosphorus concentrations on the population growth and interspecific competitive parameters of two kinds of microalgae, Skeletonema costatum and Prorocentrum donghaiens. With the increasing concentrations of substrate nitrogen and phosphorus, the maximum biomass of the two kinds of microalgae increased, and their specific growth rate was higher in pure culture than in mixed culture. In mixed culture, S. costatum was dominant at the beginning, while P. donghaiense became dominant later. The time period when this change happened was related to the nutritional conditions, and the inflection point for S. costatum and P. donghaiense was about 0-2.6 and 0.5-4.9 d, respectively. Under the test nutritional conditions, the competitive parameter of P. donghaiense to S. costatum (beta) was higher than that of S. costatum to P. donghaiense (alpha). When the substrate nitrogen and phosphorous concentrations were 128 micromol N x L(-1) and 32 micromol P x L(-1), the competitive capability of P. donghaiense was 3.8 times of that of S. costatum, presenting the most obvious difference. PMID- 22919855 TI - [Water-saving mechanisms of intercropping system in improving cropland water use efficiency]. AB - Based on the multi-disciplinary researches, and in terms of the transformation efficiency of surface water to soil water, availability of cropland soil water, crop canopy structure, total irrigation volume needed on a given area, and crop yield, this paper discussed the water-saving mechanisms of intercropping system in improving cropland water use efficiency. Intercropping system could promote the full use of cropland water by plant roots, increase the water storage in root zone, reduce the inter-row evaporation and control excessive transpiration, and create a special microclimate advantageous to the plant growth and development. In addition, intercropping system could optimize source-sink relationship, provide a sound foundation for intensively utilizing resources temporally and spatially, and increase the crop yield per unit area greatly without increase of water consumption, so as to promote the crop water use efficiency effectively. PMID- 22919856 TI - [Roles of soil dissolved organic carbon in carbon cycling of terrestrial ecosystems: a review]. AB - Soil dissolved organic carbon (DOC) is an active fraction of soil organic carbon pool, playing an important role in the carbon cycling of terrestrial ecosystems. In view of the importance of the carbon cycling, this paper summarized the roles of soil DOC in the soil carbon sequestration and greenhouse gases emission, and in considering of our present ecological and environmental problems such as soil acidification and climate warming, discussed the effects of soil properties, environmental factors, and human activities on the soil DOC as well as the response mechanisms of the DOC. This review could be helpful to the further understanding of the importance of soil DOC in the carbon cycling of terrestrial ecosystems and the reduction of greenhouse gases emission. PMID- 22919857 TI - [Research advances in control of N2O emission from municipal solid waste landfill sites]. AB - Landfill is one of the main approaches for municipal solid waste treatment, and landfill site is a main emission source of greenhouse gases nitrous oxide (N2O) and methane (CH4). As a high-efficient trace greenhouse gas, N2O has a very high warming potential, with a warming capacity 296 times of CO2, and has a long-term stability in atmosphere, giving greater damage to the ozone layer. Aiming at the researches in the control of N2O emission from municipal solid waste landfill sites, this paper summarized the characteristics and related affecting factors of the N2O emission from the landfill sites, and put forward a series of the measures adaptable to the N2O emission control of present municipal solid waste landfill sites in China. Some further research focuses on the control of N2O emission from the landfill sites were also presented. PMID- 22919858 TI - [Measurement model of carbon emission from forest fire: a review]. AB - Forest fire is the main disturbance factor for forest ecosystem, and an important pathway of the decrease of vegetation- and soil carbon storage. Large amount of carbonaceous gases in forest fire can release into atmosphere, giving remarkable impacts on the atmospheric carbon balance and global climate change. To scientifically and effectively measure the carbonaceous gases emission from forest fire is of importance in understanding the significance of forest fire in the carbon balance and climate change. This paper reviewed the research progress in the measurement model of carbon emission from forest fire, which covered three critical issues, i. e., measurement methods of forest fire-induced total carbon emission and carbonaceous gases emission, affecting factors and measurement parameters of measurement model, and cause analysis of the uncertainty in the measurement of the carbon emissions. Three path selections to improve the quantitative measurement of the carbon emissions were proposed, i. e., using high resolution remote sensing data and improving algorithm and estimation accuracy of burned area in combining with effective fuel measurement model to improve the accuracy of the estimated fuel load, using high resolution remote sensing images combined with indoor controlled environment experiments, field measurements, and field ground surveys to determine the combustion efficiency, and combining indoor controlled environment experiments with field air sampling to determine the emission factors and emission ratio. PMID- 22919860 TI - [The percutaneous treatment of pulmonary atresia with intact ventricular septum]. AB - OBJECTIVE: Describe a mechanical method of perforation-dilatation of the pulmonary valve in pulmonary atresia with intact interventricular septum (PA IVS), with or without stenting the patent ductus arteriosus (PDA) and medium-term results. METHOD: Since 2007, all patients with PA-IVS and a right ventricle adequate for biventricular repair, benefited from a transcatheter attempt to perforate-dilate the valve with or without stenting the PDA, and were included in this retrospective study. TECHNIQUE: A catheter was percutaneously introduced through the femoral vein and positionned in front of the atretic pulmonary valve. A lasso catheter was introduced through the femoral artery to the other side of the pulmonary valve. The tip of a rigid guidewire was then pushed through the atretic valve and taken with the lasso, creating a loop that allowed for balloon valvuloplasty. If the child remained ductal dependant following PGE1 withdrawal, a stent is placed in the ductus arteriosus. RESULTS: Five patients were included in this series. Four patients were successfully dilated, and two patients necessitated stents. The procedure had to be interrupted in one patient. FOLLOW UP: One patient with a patent stent was operated at the age of one year and died in the postoperative period. The other patient with a stent is now 16 months old with a patent stent and an oxygen saturation of 98%. The two remaining patients without stent are now 3- and 18-month-old with oxygen saturation of 85% and 96% respectively. CONCLUSION: The percutaneous treatment of PA-IVS is feasible and avoids early high risk surgery. Stenting the ductus arteriosus may replace a Blalock shunt. However, the prognosis is still related to the severity of the anomaly. PMID- 22919859 TI - On the ethics of placebo-controlled trials. PMID- 22919861 TI - Influenza A (H1N1) 2009 pandemia. The experience of a tertiary care center in Beirut. AB - INTRODUCTION: In March 2009, a new influenza virus strain emerged, currently known as the 2009 pandemic H1N1 virus. The virus first appeared in Mexico and rapidly spread globally to reach a pandemic level in June of the same year. We describe here the experience of one major referral center in Beirut, Lebanon. MATERIALS AND METHODS: The laboratory department at St. George Hospital University Medical Center received respiratory specimens from hospital wards, the emergency department, in addition to a considerable proportion collected directly from "outpatients" in the lab. We used the real time RT-PCR as our main diagnostic test. We collected data about the patients from the laboratory information system and from the hospital medical records department. RESULTS: From mid-August 2009 till the end of January 2010, a total of 1771 specimens were analyzed, with 948 (53.5%) returning positive for influenza A (H1N1) by RT-PCR. Only 79 patients with H1N1 infection required hospitalization. Most of H1N1 confirmed patients were children and adolescents aged 5 to 17 years and young adults between 25 and 44 years. The most common symptoms at presentation were: fever, cough, shortness of breath, chills, rhinorrhea or nasal congestion, as well as gastrointestinal symptoms. Twenty-three patients required ICU care and eight patients died. The vast majority had an uncomplicated course of illness and was managed in an outpatient setting. CONCLUSION: The percentage of positive tests during the pandemia was significantly elevated, although few patients experienced drastic clinical outcomes. PMID- 22919862 TI - Integrating quality and patient safety concepts in medical curricula. Baseline assessment in Lebanon. AB - PURPOSE: Hospital accreditation places emphasis on the role of health professionals in quality of patient care. Training physicians in quality and patient safety influences quality improvement efforts in healthcare. Little is known about the attitudes and knowledge of medical students towards the concepts of quality of care, patient safety and accreditation. The objective of this study was to determine the extent to which Lebanese medical students are aware of and familiar with these aforementioned concepts. METHODS: The study adopted a cross sectional research design on a sample of (148 participants) graduating medical students from four major universities in Lebanon. A semi-structured self completion questionnaire was developed to assess students' knowledge towards: (A) quality concepts; (B) quality tools ; (C) patient safety & risk management; (D) accreditation ; and (E) policies & procedures/guidelines. Two statistical tests, MANOVA (parametric) and Kruskal-Wallis (nonparametric) were used to analyze the data. RESULTS: Study results showed that 85% of medical students did not receive any course about quality and patient safety, although 93% considered them to be important and called for their integration into curricula. Lowest mean scores were recorded for the theme on quality concepts and tools (1.60 +/- 0.81 and 1A.49 +/- 0.71 respectively). Respondents from sampled universities showed a general lack of knowledge of the themes studied. CONCLUSIONS: Quality, patient safety and accreditation are important disciplines that need to be incorporated into medical curricula. This would be a positive step towards enabling future physicians to meet the changing needs of the constantly evolving healthcare system. PMID- 22919863 TI - Chronic urticaria and autoimmune thyroiditis. AB - GOAL: Idiopathic chronic urticaria may be associated to other auto-immune diseases, in particular thyroiditis. The goal of our study is to show that this association is higher than the incidence of auto-immune thyroiditis in the general population. METHODS: It is a retrospective observational study including 90 patients with chronic urticaria. We calculated the proportion of patients having associated auto-immune thyroiditis based on a level of anti-TPO >220 mUI/ml. RESULTS: The mean age of patients was 36.7 years with a sex ratio F/H of 2.9/1. The anti-TPO antibodies were positive in 16 patients (17.7%). Eight were euthyroid, seven had hypothyroidism and one had hyperthyroidism with positive anti-TSH receptor antibodies. The percentage of anti-TPO antibodies in the chronic urticaria patients was higher than the control group (17.7 vs. 8.7; p < 0.01). CONCLUSION: This significant association between chronic urticaria and autoimmune thyroiditis may change the medical practice in Lebanon by including anti-TPO and anti-thyroglobulin antibodies in the workup of patients with chronic urticaria. PMID- 22919864 TI - Quality of palliative care. Perspective of Lebanese patients with cancer. AB - The number of cancer patients in Lebanon is increasing, and patients are living longer due to early detection and enhanced methods of treatment. The purpose of this study was to evaluate the quality of life, symptom management, functional ability, and the quality of palliative care in adult Lebanese cancer patients at the American University of Beirut-Medical Center. A cross sectional survey design was used. A number of internationally validated instruments were translated into Arabic. A total of 200 cancer patients participated in the study; the majority was female with breast cancer and mean age 54. The cognitive functioning domain of the Quality of Life scale was found to have the highest score and social functioning the lowest. The most prevalent symptom was lack of energy and the least prevalent was shortness of breath. Nausea and pain were the symptoms mostly treated. In conclusion, this sample reported a fair quality of life and social functioning with high prevalence of physical and psychological symptoms. Inadequate symptom management was reported especially for the psychological symptoms. Participants reported a satisfactory level with the quality of care. Based on these results, providing adequate symptom management and social support to Lebanese cancer patients is highly recommended. PMID- 22919865 TI - [Hospitalization due to skin diseases at Hotel-Dieu de France Hospital (Beirut), 1998-2007]. AB - OBJECTIVE: This study aims to determine retrospectively the nature and frequency of dermatological diseases leading to hospitalization at Hotel-Dieu de France Hospital (HDF) in Beirut, between 1998 and 2007 and to compare them with literature data. PATIENTS & METHODS: For the patients who were hospitalized in dermatology at HDF, we studied: demographics, diagnosis of hospitalization, length of stay, service, mode of financial support, in-hospital evolution, diagnostic tests and treatment. The data were processed by SPSS program. RESULTS: Alopecia areata, psoriatic erythroderma, acute urticaria and vasculitic purpura are the top four diagnoses (85% of hospitalizations). The third of the patients was admitted to same day care. The financial support of the hospitalization is based primarily on public insurance (57.6%). Corticosteroids are the most widely used treatment for patients in dermatology hospital with a frequency of 59.8%. The number of hospitalizations peaked at 44 in 2002 and since then has been declining (11 hospitalizations in 2007). DISCUSSION: Pathologies encountered in hospital are different from those encountered during consultation. Management of skin diseases on an outpatient basis is often insufficient. In the literature, no profile of skin diseases leading to hospitalization is similar to our study. PMID- 22919866 TI - Parkinsonian syndrome as a complication of systemic lupus erythematosus. Report of a case and review of the literature. AB - A 34-year-old woman has had systemic lupus erythematosus since 11 years, with multiple treatments and incomplete result. When examined in our department, she presented with a recent parkinsonian syndrome including bradykinesia, adiadochokinesia, cogwheel rigidity and postural tremor of hands. Deep tendon reflexes were increased. Brain MRI showed abnormal signal intensity in the periventricular white matter, internal capsule, brain stem, middle cerebellar peduncles and cerebellar hemispheres. She was treated with prednisone and mycophenolate for the lupus, and amantadine and benzhexol for the parkinsonian syndrome which resolved within ten months, while the lupus improved. There are 30 cases of Parkinson's disease as a complication of lupus reported in the literature. The pathogenesis may be cerebral vasculitis with ischemia, and antibodies against neurons, mainly dopaminergic. Twenty cases improved, eight of them with the treatment of the lupus alone. PMID- 22919867 TI - Large thymolipoma causing primarily respiratory distress. AB - Thymolipoma, is an anterior mediastinal tumor that is benign in origin. It is often asymptomatic, but can enlarge significantly prior to diagnosis. It consists of thymic and fatty tissue and is surrounded by a capsule. Less than a hundred cases have been reported worldwide. Although rare, it should be considered in the differential diagnosis of mediastinal tumors. In this paper, we report the case of a 44-year-old woman presenting with a giant thymolipoma causing symptoms of severe respiratory distress. The patient underwent surgical resection, which is the main treatment, and remains free of disease. PMID- 22919868 TI - Celiac disease presenting as acute colonic pseudo-obstruction. AB - Acute colonic pseudo-obstruction rarely presents in children. Upon diagnosis, initiating conservative management and identification of an underlying etiology is mandatory. We describe the case of an 8-year-old girl who presented with signs of acute abdominal distention with no evident etiology. The diagnosis of celiac disease was suspected and confirmed by intestinal biopsy. Based on this case and other reported cases in the literature, we discuss this unusual mode of presentation of celiac disease, the underlying etiology and suggest management options to avoid unnecessary aggressive interventions. PMID- 22919869 TI - Ewing sarcoma/primitive neuroectodermal tumor (PNET) of the vulva. Case report and review of the literature. AB - Ewing sarcoma is a rare highly malignant neoplasm that is mostly encountered as a primary bone tumor of childhood. Extra osseous occurrence is less frequent and cases involving the vulva are very rare with only twelve reported to date. We report the case of a Ewing sarcoma that presented as a vulvar mass in a 28-year old Lebanese lady and briefly review the differential diagnosis as well as the published literature regarding the clinical presentation and prognosis. PMID- 22919870 TI - [Rapidly progressing quadriparesis secondary to licorice (souss) intoxication]. AB - INTRODUCTION: Regular consumption of licorice based beverages can provoke pseudohyperaldosteronism with hypokalemia but can rarely lead to severe muscle weakness. CASE REPORT: A 62-year-old man was admitted for a one-week history of progressive weakness of the four limbs. Blood work revealed severe hypokalemia that was due to primary pseudo-hyperaldosteronism secondary to licorice intoxication. He became normal after correction of the electrolytes disturbances. DISCUSSION & CONCLUSION: In an area where a liquorice-based beverage (souss), is frequently and sometimes excessively consumed, pseudo-hyperaldosteronism secondary to licorice toxicity should be thought of in front of any muscle weakness accompanied by hypokalemia. A rapid correction of electrolytes disturbances leads to rapid improvement. PMID- 22919871 TI - Trans-omental hernia as a rare cause of small bowel obstruction. AB - Internal hernia is a very rare case of small bowel obstruction (incidence: 0.2 09%) with a significant mortality rate of about 45%. It has few different forms including congenital or acquired and persistent or intermittent. According to its anatomic location, internal hernia has multiple different types. Trans-omental type is the rarest one that only accounts for 1-4% of internal hernia cases. It can be discovered incidentally but can also cause small bowel strangulation and obstruction with very high mortality rate. Based on presentation, immediate diagnosis and urgent surgical intervention are crucial to save the patient's life. Only very seldom cases o f trans-omentalhernia were reported in the literature that always had acute presentation. We report a very rare case of trans-omental hernia that started with slow presentation over decades with vague abdominal symptoms but then developed acute small bowel obstruction that necessitated immediate surgery. PMID- 22919872 TI - Entamoeba histolytica pleuropulmonary infection. Case report and review of the literature. AB - Pleuropulmonary amebiasis is the 2nd most common extraintestinal site of amebiasis after liver abscess. We describe a man with pleuropulmonary amebiasis presenting with pulmonary consolidation and pleural effusion. In patients with pneumonia coming from endemic countries such as Lebanon, pleuropulmonary amebiasis should be considered in the setting of chocolate-colored sputum, negative respiratory cultures, and failure of antibacterial therapy. PMID- 22919873 TI - Why has COPE developed guidelines for cooperation between journals and research institutions? PMID- 22919874 TI - Reibergram and oligoclonal bands in diagnosis of multiple sclerosis. AB - INTRODUCTION: In this study authors have analyzed the correlation between the IgG immunoglobulins in cerebrospinal fluid and the findings of oligoclonal bands on gel. Immunoglobulin IgG in cerebrospinal fluid (CSF) can be detected in neurological diseasses (infections and inflammatory neurological diseases and in demyelinating diseases, like multiple sclerosis (MS)). Quantitative IgG in CSF can be expressed by different formulae Reiber (Reiber and Felgenhauer 1987), Tourtellotte (Tourtellotte 1970), Schuller (Schuller and Sagar 1983) and IgG Index (Link and Tibbling 1977). In this study we used Reibergram. Qualitative CSF IgG can be measured by electrophoresis and isoelectric focusing (IEF). We used IEF for analysig CSF and seum because of its higher sensitivity. AIMS OF THE STUDY: To determine the correlation of immunoglobulins IgG positivity in CSF with the finding of oligoclonal bands on the gel. MATERIAL AND METHODS: The retrospective study based on data processed in OJ Clinical Immunology KCUS. Patients were suspicious of multiple sclerosis according to clinical findings and magnetic resonance imaging. All CSF and serum samples were processed by nephelometry, isoelectric focusing on the gel. Statistical analysis of intrathecal synthesis was also performed according to Reibergram. RESULTS: Analyses were performed on 76 samples of cerebrospinal fluid and serum of patients from neurological clinic, suspected of multiple sclerosis. We received following results: 42 samples tested had type 1.25 samples tested showed type 2.3 samples had type 3.5 samples had type 4.1 sample had a fifth type. When we compare these results with values obtained by intrathecal synthesis of which is determined by Reibergram we obtained the following values: 16 samples had intrathecal synthesis of 20%-60%, 9 samples had a negative value of intrathecal synthesis of 10% or less. DISCUSSION AND CONCLUSION: For most patients with established MS we found intrathecal humoral response, type two, and the number and arrangement of IgG bands generally does not change during the disease, because they reflect long-term non-specific immune stimulation rather than a specific immune response that during infectious disease changes (quantitatively and qualitatively). PMID- 22919875 TI - Indirect serum fibrosis markers in hepatitis C virus (HCV) infection. AB - Assessment of liver fibrosis is important for making treatment decisions, as well as for predicting prognosis and therapeutic outcome in patients on chronic hemodialysis (HD) treatment and infected with hepatitis C virus (HCV). The aim of the present investigation was to evaluate changes in standard laboratory tests (AST, ALT, yGT, cholesterol and platelet count) and indirect serum fibrosis markers: AST-to-platelet ratio index (APRI), FIB-4 and Forns index, in chronically HCV-infected patients on maintenance HD with and without antiviral treatment. PATIENTS AND METHODS: A total of 38 patients on chronic HD program more than 3 months and with chronic hepatitis C, were included in the study. According to local legislature 14 patients receive antiviral therapy (24 or 48 weeks, according to HCV genotype) adjusted for patients on HD: eight of them achieved sustained virological response (SVR) and six did not. RESULTS: All treated patients were HCV genotype 1. Baseline blood samples for standard laboratory tests and indirect serum fibrosis markers were collected on the day of antiviral treatment initiation, as well as at the end of follow-up treatment, 36 month later. At the beginning of antiviral treatment there were no significant differences in APRI, FIB-4, Forns and its components between patients who will achieve SVR and those who did not. A significant decrease of AST, ALT, yGT and APRI, and moderate decrease FIB-4 and Forns index was found at the end of follow up in patients with SVR. In non-sustained responders group those three indexes and its components remained unchanged. Using cut-of values for APRI and FIB-4 (APRI < 0.5 and FIB-4 < 1.45) it was registered that raised percentage of patients with "no fibrosis" at the end of follow-up in those who achieved SVR. Absence of fibrosis measured by Forns index remained unchanged in all groups of patients. CONCLUSION: Simple indexes as APRI and FIB-4, successfully decrease after antiviral treatment of chronic hepatitis C in hemodialysis patients. These parameters seems to be useful in monitoring for liver fibrosis rate after antiviral treatment in patients on maintenance HD infected by HCV and can be used for estimation liver fibrosis progression in candidates for cadaveric renal transplantation. PMID- 22919876 TI - Clinical significance of haemostatic tests in chronic liver disease. AB - OBJECTIVE: To determine different haemostatic tests in patients with various degrees of liver parenchymal damage and to rule out their role in assessing parenchymal hepatocyte dysfunction. METHODS: Seventy-five patients with chronic liver disease were included and due to their degree of liver damage categorized into three groups: group one patients with chronic viral hepatitis and early stage of fibrosis (n=30), group two patients with compensated cirrhosis (n=17) and group three patients with decompensated liver cirrhosis (n=28). The following haemostatic tests were measured: activated partial thromboplastin time, prothrombin time, plasma fibrinogen, antithrombin III and protein C and plasma D dimer. RESULTS: Antithrombin III levels showed significant reduction in compensated (83.86 +/- 19.49%) and decompensated cirrhosis (52.64 +/- 14.31%; p < 0.001), while protein C activity exhibited significant decrease in all the patients group, including patients with chronic viral hepatitis (90.58 +/- 11.03, 74.65 +/- 19.56, 41.11 +/- 18.35%; p < 0.001) in comparison with controls. Correlation between antithrombin III (Pearson ro = -.931, p < 0.01) and protein C (Pearson ro = -.789, p < 0.01) and clinical degree of chronic liver disease were found. D-dimer levels were significantly increased in decompensated cirrhosis (832.26 +/- 537.19 microg/L; p < 0.001) and no significant difference was found in group two and three when compared with healthy controls. CONCLUSIONS: In advanced chronic liver disease anticoagulant activitiy may reflect hepatocellular dysfunction. Protein C activity may be used as a senstive marker of hepatocellular damage even in those patients with mild liver affection whereas D dimer levels may be considered as an important sign of decompensation in cirrhotic patients. Further studies are necessary to approve whether these parameters could be used as clinical routine markers of hepatocyte function in chronic liver disease. PMID- 22919877 TI - The efficacy of PPI after endoscopic hemostasis in patients with bleeding peptic ulcer and role of Helicobacter pylori. AB - BACKGROUND: Nowadays PPI present cornerstone in the medical therapy of bleeding peptic ulcer. Controlled pantoprazole data in peptic ulcer bleeding are few. AIM: To compare the effect of intravenous (iv) pantoprazole (PPI) with iv ranitidine (H2RA) for bleeding peptic ulcers after endoscopic therapy. METHODS: After endoscopic haemostasis, 122 patients were randomized to PPI 80 mg + 8 mg/h or H2RA 50 mg + 13 mg/h, both for 72 h and to continue with oral equivalent dose of these medicaments. Patients underwent second-look endoscopy on day 3 or earlier, if clinically indicated. The primary endpoint measure was rebleeding before discharge and <14 days of enrollment. Secondary endpoint measures included number of surgeries performed, volume of blood transfusion, mortality rate and hospital stay. All data were statistically analyzed and a value of 0.05 or less was considered to indicate statistical significance. RESULTS: In the group who were treated with PPI, re-bleeding rate was evidenced in 5 patients (8.33%) and in the groups who were treated with H2RA, re-bleeding rate was found in 9 patients (14.5%) with RR 0.27 and CI 0.12-0.60 and P < 0.05. The volume of transfused blood was lower in the group treated with PPI compared to the group treated with H2RA (930 ml vs. 1540 ml and P < 0.05). In this study there was not statistically significant difference in the hospital stay 15.00 vs. 17.80% (9 vs. 11 patients and P> 0.05), the need for surgical intervention 5.00 vs. 6.45% (3 vs. 4 patients and P= 1.00) and the mortality rate 1.66 vs. 3.22% (1 vs. 2 patients and P > 0.05). CONCLUSION: A high-dose pantoprazole infusion is more effective than a ranitidine infusion for prevention of re-bleeding after endoscopic epinephrine injection in patients with peptic ulcers and active bleeding or non-bleeding visible vessels (P < 0.05). In all bleeding peptic ulcer patients is needed to make the eradication of H. pylori infection with the aim to prevent re-bleeding in long term. PMID- 22919878 TI - Possibilities of infection and increase of intraocular pressure after intravitreal application of bevacizumab in treatment of exudative form of AMD. AB - THE GOAL: To establish the frequency increase of intraocular pressure (IOP) and endophthalmitis as well as other complications that may occur after intravitreal application of bevacizumab. SUBJECTS AND METHODOLOGY: The study included 45 patients and 75 eyes with exudative form of senile degeneration of macula lutea, who were treated in the General Hospital "Prim. Dr. Abdulah Nakas" from 2007. and 2010., the patients being aged between 55 and 75 years. The intraocular pressure (IOP) was measured before the application of bevacizumab, and then after 1st, 2nd and 3rd dose, and it was examined by the bio-microscope two days after the application of bevacuzimab. RESULT: The average age of the patients treated by bevacizumab was 71.27 years (71 years, 3 months, and 7 days); 28 patients were females and 17 were males. The examination by bio-microscope indicates changes at certain number of patients. After first dose of bevacizumab, there were 9 suffusions of the bulbar conjuctiva in the application area. After the second dose, there were 10 of them, while after the third dose of bevacizumab, there were 5 suffusions and 3 cases of inflammation of the anterior eye segment, anterior uveitis. As for the intraocular pressure, there is no statistically significant difference (p > 0.05) for any measuring period. CONCLUSION: Based on the results achieved in the intravitreal application of bevacizumab in treatment of senile degeneration of macula lutea, we can conclude that there is a possibility of infection after intravitreal application of bevacizumab, but it is minimal when working in a sterile environment. Increased intraocular pressure is possible, but not necessarily to happened after the intravitreal application of the drug. PMID- 22919879 TI - Idiosyncratic adverse reactions of most frequent drug combinations longterm use among hospitalized patients with polypharmacy. AB - GOAL: Inappropriate prescribing of a multiple therapeutic agents to patients with chronic conditions is very common in everyday practice. Adverse drug reactions (ADRs) are still considered as one of the main problems of drug therapy. We investigated idiosyncratic symptoms and signs of adverse drug reactions (ADRs) of the most frequent used combination of drugs among hospitalized patients prescribed polypharmacy. METHODOLOGY: A cross sectional study (design) was performed in Pharmacies "Eufarm Edal" in Tuzla from 2010 to 2011. Polypharmacy was defined as using > or =4 drugs. The total study sample of 166 examiners was interviewed with a questionnaire about ADRs which was developed special for study. Linear regression analyses was used to evaluate predictors of idiosyncratic signs of adverse drug reactions of the most prevalent drug combinations; using length of drugs in cases polypharmacy more than 6 months as independent variable. Age, sex, index of cumulative morbidity, drug number in polypharmacy, type of drug combination related pharmacological effects, type of hospital clinics were used as possible confounders. RESULTS: The most common exposures to various drug combinations were: medication for high blood pressure and heart (62%), psychotropic drugs (59%), antacids (47%) and antibiotics (46%) among hospitalized patients with polypharmacy. Our results indicated that from 9.6% to 90.4% of hospitalized patients with polypharmacy had at least one suspicious long-term idiosyncratic drug combination use symptoms. The ADRs prevalence often used psychotropic drug combination was initiated suspected idiosyncratic adverse reactions: confusion, depression, anxiety, decreased libido and insomnia. Linear regression analyses also showed that it remains a very strange, and negative idiosyncratic and lacking therapeutic effects of use of antacids in conditions of polypharmacy. CONCLUSION: The toxicity of some drug combinations may sometimes be synergistic and be greater than the sum of the risks of toxicity of either agent used alone. In order to recognize and to prevent ADRs (including drug interactions), good communication between pharmacist and patient and/or physicians and patient is crucial, and prescribers should develop an effective therapeutic partnership with the patient and with fellow health professionals. PMID- 22919880 TI - Choice of surgical approach with alloplastic hip surgery. AB - INTRODUCTION: From all deceases and injuries of femur, most surgical, medical, social and economical difficulties and problems are created by deceases and fractures of femur neck. AIM OF THE PAPER: Aims of this research lie in the value of surgical approach (Hueter, Mooro and Gibson's) when anchoring hip endoprosthesis. The following parameters were analyzed: Harris Hip Score before and after the surgery, the length of the surgical incision, duration of the surgery, the amount of transfusion used, post-surgery time of the first movement to the upright position and full weight bearing. MATERIALS AND METHODS: At the Orthopedic clinic in Travnik in the period from January 1st 2005 to December 31st 2009, 136 hip prosthesis were implanted. Out of that number, 56 hip prosthesis were implanted using Moor approach, 34 using Hueter approach and 46 patients were exposed to postero lateral (Gibson's) approach. All patients were treated in the same manner, operated by the same surgery team. RESULTS: Hueter approach has the highest quality of surgical treatment as none of the patients had the value of the score of surgical treatment below 8. Using Hueter's approach 16 patients had the value of the score of quality of the surgical treatment between 8 and 10, whereas 18 patients had the score of quality of surgical treatment above 10. The second quality surgical treatment is Gibson's posteolateral approach at which 29 patients had the score of quality surgical treatment below 8, and 17 patients had the quality surgical treatment between 8 and 10. The worst quality of surgical treatment is Moor's approach because all 56 patients had the quality surgical treatment below 8. DISCUSSION: Implantation of total endoprosthesis of dysplastic hip with adults is a demanding orthopedic surgery. The surgery of implanted hip as well as endoprosthetic materials have both improved at the satisfaction of both the patients and the surgeons. Excellent and extraordinary results were achieved over the time have become a standard. In spite of that huge surgery wound and long recovery have motivated surgeons to improve the surgery techniques. CONCLUSION: With proper instruments and endoprosthesis, Hueter approach has advantages compared to Gibson and Moor's approach of implantation of endoprosthesis of aligned hip. PMID- 22919881 TI - The importance of the first ultrasonic exam of newborn hips. AB - INTRODUCTION: Developmental hip disorder (DHD) is a disorder in development of the acetabulum which remains abrupt (dysplasia) and probably consequential cranialisation of the femur head (luxation). AIM OF THE PAPER: The aim of this paper is to establish the total number of DHD and its subtypes at the first clinical and ultrasound exam of newborns in a retrospective-prospective study made in the period from 1st Jan 2006 through to 31 Dec 2010 at the Clinic for orthopaedics and traumatology in Banja Luka. MATERIALS AND METHODS: In total 6132 patients were examined and 99 cases diagnosed with DHD (dysplasia and luxation). Ultrasonic exam was done by means of electronic probe of 5-12 MHz according to standard method after Graph. Girls were significantly more present (96%). Positive family anamnesis on DHD was present with 7.8% examinee, mainly with primiparas, and/ or with 77.8% children with DHD. Dominant intrauterine risk factors for DHD were: mal position of foetus in uterus (78.6%), oligoamnion (17.9%), malformation of the spinal column of the pregnant woman (3.6%), whereas with 38.4% of children with a certain form of DHD the following were found: breech presentation, caesarean section or twin pregnancy. The clinical exam indicated DHD with 8.87% examinee, out of which hip looseness was found with 5% examinees. Ultrasonic finding was positive with 99 examinee, that is with 1.61% of them (deficient and badly formed acetabulum, sleeked protrusion; 8 luxations and 91 dysplasia). Prophylactic measures were requested by 58.6% children (abductive bending and exercises), whereas 41.4 % needed non-intervention therapeutic measures (traction, Pavlik's straps, Graph's knickers, plastering), after which there were no children needing surgical correction of DHD. CONCLUSION: These data indicate that clinical exam is unreliable for DHD diagnostics, and that Ultrasonic diagnostics and treatment of DHD should start as early as possible applying atraumatic helping devices and procedures in the period when all structures are elastic, flexible and adaptable. PMID- 22919882 TI - Perinatal mortality during fifteen-year period in Tuzla Canton, Bosnia and Herzegovina. AB - THE AIM: To determine the incidence of perinatal mortality, as well as the frequency of premature deliveries. METHODS: We analyzed the data of birth protocol at the Clinics for Gynecology and Obstetrition at the University Clinical Centre in Tuzla in period 1992-2006. RESULTS: Perinatal mortality gradually declines in the period of 1992-2000. The decline owns mostly to early neonatal mortality more than to fetal which also shows the trend of decrease. During the first analyzed years (1992 and 1993) the incidence of premature deliveries was below 10% but that number increased during 1994 and 1995 (15.8%). The most interesting finding is that the highest level of incidence of premature deliveries was registered in the first postwar year--1996 (16.4%) when we also noted the largest number of deliveries for the analyzed period and most of which were finished between 32 and 36 weeks. The frequency of delivery of underweight babies (500-2499 g) was between 3.8 to 12.2%. The highest frequency was registered during the 1994 and 1995 when it reached 12.2%. The frequency of delivery of extremely underweight babies (500-999 g) for the analyzed period was about 0.1% with significant increase during the wartime (1995 even 0.6%). CONCLUSION: We found that during the period of 15 years a significant decline of perinatal mortality is registered, due to early neonatal death. Limited accessibility and quality of perinatal health care during the war period had detrimental effects on the healt and survival of newborns. PMID- 22919883 TI - Analysis of chemotherapy and molecular therapy efficiency in advanced or metastatic non-small cell lung cancer. AB - AIM: To compare a benefit of chemiotherapeutic protocols docetaxel with Tarceva molecular therapy in advanced or metastatic non-small cell lung cancer (NSCLC). Primary endpoint-OS (overall survival), toxicity, secondary endpoint-quality of life. PATIENTS AND METHODS: In this retrospective and -prospective study a total of 63 patients (two groups--30+33 patients) were analysed and treated for advanced or metastatic NSCLC during the period 2008-2010. One group was treated with molecular therapy Tarceva oral, and the other group was treated with chemiotherapy docetaxel monotherapy every three weeks. The chemotherapy was administered intravenously. Monitoring parameters included overall survival and toxicity. RESULTS: Statistical differencet was registered in histology type, total toxicity and total survival. Adenocarcinom occured as a more often pathohistologic type in both groups of patients (Tarceva 57, 6% vs. Docetaxel 83, 3%). The chemiotherapeutic protocol, Docetaxel monotherapy, demonstrated higher total toxicity than Tarceva molecular therapy (hematological toxicity grade II 69.0% Docetaxel vs. 12.5% Tarceva). Tarceva molecular therapy demonstrated longer overall survival (OS) than Docetaxel (Tarceva 26, 4 months vs. Docetaxel 15, 5 months). CONCLUSION: In this investigation of two groups of patients the molecular therapy Tarceva was showed better efficiency and toxicity profile. Preferred regimen could be molecular therapy Tarceva. PMID- 22919884 TI - Ankle distorsion. AB - INTRODUCTION: Despite enormous number of publications on classifications and treatment of ankle fractures, this problem remains actual till present days. Never the less, the ultimate goal remains the same--anatomically correct position of articular surfaces, painless and stabile ankle joint. MATERIAL AND METHODS: Through prospective study we processed over 50 patients from policlinic data of Orthopedic-Traumatology ward in Cantonal Hospital Zenica. Research lasted over one year and we collected tremendous data from patients which filled in surveys. These data were processed and presented in this study. From collected data we determined statistical incidence of so called "overseen" and poorly treated injuries of lateral ligaments, origin and mechanism of injuries, number of previous injuries of same nature and then compared with data on treatment method, whether conservative or operative. RESULTS AND DISCUSSION: We paid special attention and presented findings on age and gender groups that are most involved in ankle injuries. We've confirmed that RTG-Varus stress test is still the method of choice in diagnostics of ankle lateral ligaments injuries. We also determined how treatment duration correlates to time between injury and check in, number of recidivism and most importantly correlation between duration of symptoms and length of immobilization and physical therapy duration. We appeal to our colleagues to approach these injuries with higher level of interest and methodically during diagnosis and therapy because every oversight leads to increased risk of repeated injury, chronic instability of ankle joint, cartilage damage and progression of arthritic joint changes. All of those factors greatly impairs patient's life quality. Competent and quality examination will determine, with more accuracy, degree of injury and set basis for adequate therapy which will not leave any consequences for the patient. That would provide him to continue with normal everyday activaties. PMID- 22919885 TI - Influence of the physical activity on the cognitive functions with people depending on their age. AB - In comparison with the number of studies which have examined the physical activity influence on the cognitive capabilities with the adults (above 60 years of age), researches for children, adolescents and young adult population are rarely done. The examination of the potential connection, role or influence between Physical Activity and cognition during early age (the first third of the human life) is very complex and subtle due to a large number of external factors which are present in the period during which the cognitive capabilities are still being developed. Regular physical activity improves the physiological and psychological aspect of human health. Due to the well known advantages and benefits from the physical activity, one would expect it to be more present in the life of contemporary man. But it is a fact that the level of physical activity with people decreases in the course of lifetime, especially in the period when young people move from secondary school to university. The decrease of the physical activity additionally increases the pressure over the young academic persons. There is not enough literature which examines the connection of the neuropsychological indicators and physical activity with young adults. It is obvious the need for further researches in this field which will create a solid base for the connection of the physical activity and cognition, the same one that is found for the adult population. Within the frame of positive role the physical activity has over the cognitive health, it is suggested as a means of reducing the risk of developing cognitive decrease connected with getting old. Future vast randomized researches and interventions would have to test the quantity and the type of physical activity which would be recommended in order to prevent or postpone the cognitive decrease. PMID- 22919886 TI - Transumbilical single-port laparoscopic cholecystectomy. AB - Surgery of the gallbladder has evolved tremendously over the last century. Laparoscopic cholecystectomy is the gold standard for gallbladder removal and the most common laparoscopic procedure worldwide. In recent times, innovative techniques of natural orifice transluminal endoscopic surgery (NOTES) and transumbilical single-port (TUSP) or single-incision laparoscopic surgery (SILS), have been applied in gallbladder removal as a step towards even more less invasive procedures. We report a 49-year-old woman with calculosis which were submitted to a single-port transumbilical laparoscopic cholecystectomy, first time done on the Surgical Clinic of Tuzla, and first time in Bosnia and Herzegovina. PMID- 22919887 TI - Successful pregnancy and delivery after kidney transplantation. AB - The kidney transplantation is considered to be the best therapy for terminal kidney disease, nowadays. Numerous studies have shown that pregnancy may be successful and may result in a delivery of a healthy baby after the kidney transplantation. Pregnant women who are the recipients of a kidney transplant have increased chances of developing hypertension, preeclampsia, as well as going into premature labour and frequently giving birth to newborns of low birth weight. We present a case of a successful pregnancy and delivery in a 32-year-old kidney transplant recipient who conceived spontaneously four years posttransplantation. The kidney transplantation has been done due to the chronic hypertension and the consequential kidney atrophy. During the pregnancy, the patient underwent antihypertension and immunosupressive drugs therapy. She was also being monitored by the gynaecologist and the nephrologist. The pregnancy was terminated in the 40th week by an urgent Caesarean section due to the fetal bradycardia. The patient gave birth to the healthy baby girl. PMID- 22919888 TI - Lung hamartoma--diagnosis and treatment. AB - Pulmonary hamartoma, the most common benign tumor of the lung, is most often presented as a solitary pulmonary nodule of a peripheral localization. We report a case of a large, centrally located, invisible in chest X-ray, hystopathologicaly (PH) verified hamartoma. A 63-year-old male was admitted for hospital treatment with obvious symptoms and signs of right-sided lobar pneumonia. His treatment was started with a combination of antibiotics Ceftriaxone and Ciprofloxacin. Because of his obviously bad condition with wheezing and bronchial secret in his lungs, an urgent bronchoscopy was performed. A huge amount of bronchial secret was found in his bronchial tree and, surprisingly, a tumor in the upper left lobe. For further evaluation computed tomography (CT) scan was performed and it verified right pneumonia but, it also revealed large (13.3 x 11.2 mm) endobronchial tumor in upper left lobe which wasn't clinically or radiographically presented. From a bronchobiopsy, we received an inconclusive PH finding. It was concluded that the best treatment is a surgical sleeve resection lobectomy, which was performed. Definite pathohistological finding was hamartoma and the patient was successfully healed. PMID- 22919889 TI - Celiac artery aneurysm. AB - Coeliac artery aneurysms are rare and frequently detected incidentally. It is usually with associated aneurysms. Herein we present accidentally detected, asymptomatic coeliac aneurysm in a patient with acute myocardial infarction. Multi-slice tomography and invasive angiography images are provided along with brief discussion on clinical presentation, diagnostic tools and treatment options. PMID- 22919890 TI - Do hostile attribution biases in children and parents predict relationally aggressive behavior? AB - Relatively little is understood about the role of hostile attributions in children's use of relational aggression with peers, or about the impact of family processes on children's attributions about ambiguous provocations. This cross sectional study investigated associations among hostile attributions made by children, mothers, and fathers, and children's use of relational aggression with peers. The sample included 91 children in Grades 3-5 (43 girls), and their mothers (n = 90) and teachers (n = 88). Fathers also participated for a subsample of children (n = 53). Results showed that relational aggression is associated with a hostile attribution bias in children and parents, although findings varied as a function of gender of parent and child, provocation type, and informant of aggression. Overall, mothers' attributions were more closely related to daughters' attributions and aggressive behavior than to sons'. Implications of these findings for social information processing models and family-focused prevention of relational aggression are discussed. PMID- 22919892 TI - The association between self-reported mother-child attachment and social initiative and withdrawal in Chinese school-aged children. AB - The purpose of this study was to examine relations between mother-child attachment and social initiative and withdrawal in Chinese urban children. Participants were 487 school-aged children (247 boys, 240 girls) in Shanghai, the People's Republic of China. Data on mother-child attachment styles were collected from children's self-reports. Information concerning social initiative and social withdrawal (i.e., shyness and social disinterest) was obtained from peer nomination. Path analyses revealed that secure attachment was positively associated with social initiative, whereas ambivalent-insecure attachment was positively associated with shyness. However, avoidant-insecure attachment was not significantly associated with social disinterest. In addition, a number of gender and developmental differences were also observed. PMID- 22919891 TI - Observing preschoolers' social-emotional behavior: structure, foundations, and prediction of early school success. AB - Social-emotional behavior of 352 3- and 4-year-olds attending private child-care and Head Start programs was observed using the Minnesota Preschool Affect Checklist, Revised (MPAC-R). Goals of the investigation included (a) using MPAC-R data to extract a shortened version, MPAC-R/S, comparing structure, internal consistency, test-retest reliability, and stability of both versions; and, using the shortened measure, to examine (b) age, gender, and risk status differences in social-emotional behaviors; (c) contributions of emotion knowledge and executive function to social-emotional behaviors; and (d) contributions of social-emotional behaviors to early school adjustment and kindergarten academic success. Results show that reliability of MPAC-R/S was as good, or better, than the MPAC-R. MPAC R/S structure, at both times of observation, included emotionally negative/aggressive, emotionally regulated/prosocial, and emotionally positive/productive behaviors; MPAC-R structure was similar but less replicable over time. Age, gender, and risk differences were found. Children's emotion knowledge contributed to later emotionally regulated/prosocial behavior. Finally, preschool emotionally negative/aggressive behaviors were associated with concurrent and kindergarten school success, and there was evidence of social emotional behavior mediating relations between emotion knowledge or executive function, and school outcomes. The importance of portable, empirically supported observation measures of social-emotional behaviors is discussed along with possible applications, teacher utilization, and implementation barriers. PMID- 22919893 TI - Effect of visual field presentation on action planning (estimating reach) in children. AB - In this article, the authors examined the effects of target information presented in different visual fields (lower, upper, central) on estimates of reach via use of motor imagery in children (5-11 years old) and young adults. Results indicated an advantage for estimating reach movements for targets placed in lower visual field (LoVF), with all groups having greater difficulty in the upper visual field (UpVF) condition, especially 5- and 7-year-olds. Complementing these results was an overall age-related increase in accuracy. Based in part on the equivalence hypothesis suggesting that motor imagery and motor planning and execution are similar, the findings support previous work of executed behaviors showing that there is a LoVF bias for motor skill actions of the hand. Given that previous research hints that the UpVF may be bias for visuospatial (perceptual) qualities, research in that area and its association with visuomotor processing (LoVF) should be considered. PMID- 22919894 TI - Role of fault attributions and desire, effort, and outcome expectations in children's anticipated responses to hypothetical peers with various undesirable characteristics. AB - A total of 137 third- through eighth-grade students were asked to respond to a series of statements concerning 6 male peers described as having various undesirable characteristics (i.e., poor student, poor athlete, extremely overweight, extremely aggressive, extremely shy, or having the symptoms of attention deficit hyperactivity disorder). The aggressive peer and the overweight peer consistently elicited the least favorable reactions from the children. For all 6 peers included in the study, the more strongly the children agreed that a peer was at fault for his undesirable characteristic, the less favorably they anticipated responding to that peer. In contrast, the children's expectations concerning a peer's desire to change, effort to change, and success in changing an undesirable characteristic were generally unrelated to their anticipated responses to that peer. The children demonstrated the general belief that desire backed by effort leads to success in overcoming an undesirable characteristic, but lack of effort leads to failure regardless of the peer's desire or lack of desire to change the characteristic. PMID- 22919895 TI - Emergent literacy and early writing skills. AB - In the present study, the authors aimed to assess the short- and long-term predictive power of the various components of an emergent literacy model on early writing abilities in a language with a mainly transparent orthography (Italian). Emergent literacy skills were assessed in 72 children (M age = 5.05 years, SD = +/- .03) who were followed longitudinally from preschool to the end of the first grade of primary school. Their early writing abilities (orthographic correctness in writing individual words) and their advanced writing abilities (orthographic correctness in text writing) were tested at the beginning and at the end of the school year. Multiple stepwise and logistic regression analyses were conducted to evaluate the predictive capacities of emergent literacy abilities on early and advanced writing competences. Results show that notational competence is a strong predictor of early writing skills and that phonological competence only has an effect insofar as it is integrated with notational competence. Emergent literacy competences do not significantly predict orthographic errors in advanced text writing. This research allows for reconsideration of the importance of phonological awareness and gives a central role to notational competence in predicting early writing competence. PMID- 22919896 TI - An invasive riparian tree reduces stream ecosystem efficiency via a recalcitrant organic matter subsidy. AB - A disturbance, such as species invasion, can alter the exchange of materials and organisms between ecosystems, with potential consequences for the function of both ecosystems. Russian olive (Elaeagnus angustifolia) is an exotic tree invading riparian corridors in the western United States, and may alter stream organic matter budgets by increasing allochthonous litter and by reducing light via shading, in turn decreasing in-stream primary production. We used a before after invasion comparison spanning 35 years to show that Russian olive invasion increased allochthonous litter nearly 25-fold to an invaded vs. a control reach of a stream, and we found that this litter decayed more slowly than native willow. Despite a mean 50% increase in canopy cover by Russian olive and associated shading, there were no significant changes in gross primary production. Benthic organic matter storage increased fourfold after Russian olive invasion compared to pre-invasion conditions, but there were no associated changes in stream ecosystem respiration or organic matter export. Thus, estimated stream ecosystem efficiency (ratio of ecosystem respiration to organic matter input) decreased 14%. These findings show that invasions of nonnative plant species in terrestrial habitats can alter resource fluxes to streams with consequences for whole-ecosystem functions. PMID- 22919897 TI - A new approach to the "apparent survival" problem: estimating true survival rates from mark-recapture studies. AB - Survival estimates generated from live capture-mark-recapture studies may be negatively biased due to the permanent emigration of marked individuals from the study area. In the absence of a robust analytical solution, researchers typically sidestep this problem by simply reporting estimates using the term "apparent survival." Here, we present a hierarchical Bayesian multistate model designed to estimate true survival by accounting for predicted rates of permanent emigration. Initially we use dispersal kernels to generate spatial projections of dispersal probability around each capture location. From these projections, we estimate emigration probability for each marked individual and use the resulting values to generate bias-adjusted survival estimates from individual capture histories. When tested using simulated data sets featuring variable detection probabilities, survival rates, and dispersal patterns, the model consistently eliminated negative biases shown by apparent survival estimates from standard models. When applied to a case study concerning juvenile survival in the endangered Cape Sable Seaside Sparrow (Ammodramus maritimus mirabilis), bias-adjusted survival estimates increased more than twofold above apparent survival estimates. Our approach is applicable to any capture-mark-recapture study design and should be particularly valuable for organisms with dispersive juvenile life stages. PMID- 22919898 TI - Demographic stochasticity reduces the synchronizing effect of dispersal in predator-prey metapopulations. AB - Dispersal may affect predator-prey metapopulations by rescuing local sink populations from extinction or by synchronizing population dynamics across the metapopulation, increasing the risk of regional extinction. Dispersal is likely influenced by demographic stochasticity, however, particularly because dispersal rates are often very low in metapopulations. Yet the effects of demographic stochasticity on predator-prey metapopulations are not well known. To that end, I constructed three models of a two-patch predator-prey system. The models constitute a hierarchy of complexity, allowing direct comparisons. Two models included demographic stochasticity (pure jump process [PJP] and stochastic differential equations [SDE]), and the third was deterministic (ordinary differential equations [ODE]). One stochastic model (PJP) treated population sizes as discrete, while the other (SDE) allowed population sizes to change continuously. Both stochastic models only produced synchronized predator-prey dynamics when dispersal was high for both trophic levels. Frequent dispersal by only predators or prey in the PJP and SDE spatially decoupled the trophic interaction, reducing synchrony of the non-dispersive species. Conversely, the ODE generated synchronized predator-prey dynamics across all dispersal rates, except when initial conditions produced anti-phase transients. These results indicate that demographic stochasticity strongly reduces the synchronizing effect of dispersal, which is ironic because demographic stochasticity is often invoked post hoc as a driver of extinctions in synchronized metapopulations. PMID- 22919899 TI - Improved testing of species traits--environment relationships in the fourth corner problem. AB - The fourth-corner problem entails estimation and statistical testing of the relationship between species traits and environmental variables from the analysis of three data tables. In a 2008 paper, S. Dray and P. Legendre proposed and evaluated five permutation methods for statistical significance testing, including a new two-step testing procedure. However, none of these attained the correct type I error in all cases of interest. We solve this problem by showing that a small modification of their two-step procedure controls the type I error in all cases. The modification consists of adjusting the significance level from mean square root of alpha to alpha or, equivalently, of reporting the maximum of the individual P. values as the final one. The test is also applicable to the three-table ordination method RLQ. PMID- 22919900 TI - Uses and misuses of bioclimatic envelope modeling. AB - Bioclimatic envelope models use associations between aspects of climate and species' occurrences to estimate the conditions that are suitable to maintain viable populations. Once bioclimatic envelopes are characterized, they can be applied to a variety of questions in ecology, evolution, and conservation. However, some have questioned the usefulness of these models, because they may be based on implausible assumptions or may be contradicted by empirical evidence. We review these areas of contention, and suggest that criticism has often been misplaced, resulting from confusion between what the models actually deliver and what users wish that they would express. Although improvements in data and methods will have some effect, the usefulness of these models is contingent on their appropriate use, and they will improve mainly via better awareness of their conceptual basis, strengths, and limitations. PMID- 22919901 TI - The memory of spatial patterns: changes in local abundance and aggregation in a tropical forest. AB - The current spatial pattern of a population is the result of previous individual birth, death, and dispersal events. We present a simple model followed by a comparative analysis for a species-rich plant community to show how the current spatial aggregation of a population may hold information about recent population dynamics. Previous research has shown how locally restricted seed dispersal often leads to stronger aggregation in less abundant populations than it does in more abundant populations. In contrast, little is known about how changes in the local abundance of a species may affect the spatial distribution of individuals. If the level of aggregation within a species depends to some extent on the abundance of the species, then changes in abundance should lead to subsequent changes in aggregation. However, an overall change of spatial pattern relies on many individual birth and death events, and a surplus of deaths or births may have short-term effects on aggregation that are opposite to the long-term change predicted by the change in abundance. The change in aggregation may therefore lag behind the change in abundance, and consequently, the current aggregation may hold information about recent population dynamics. Using an individual-based simulation model with local dispersal and density-dependent competition, we show that, on average, recently growing populations should be more aggregated than shrinking populations of the same current local abundance. We tested this hypothesis using spatial data on individuals from a long-term tropical rain forest plot, and find support for this relationship in canopy trees, but not in understory and shrub species. On this basis we argue that current spatial aggregation is an important characteristic that contains information on recent changes in local abundance, and may be applied to taxonomic groups where dispersal is limited and within-species aggregation is observed. PMID- 22919902 TI - Biotic contexts alter metal sequestration and AMF effects on plant growth in soils polluted with heavy metals. AB - Investigating how arbuscular mycorrhizal fungi (AMF)-plant interactions vary with edaphic conditions provides an opportunity to test the context-dependency of interspecific interactions. The relationship between AMF and their host plants in the context of other soil microbes was studied along a gradient of heavy metal contamination originating at the site of zinc smelters that operated for a century. The site is currently under restoration. Native C3 grasses have reestablished, and C4 grasses native to the region but not the site were introduced. Interactions involving the native mycorrhizal fungi, non-mycorrhizal soil microbes, soil, one C3 grass (Deschampsia flexuosa), and one C4 grass (Sorghastrum nutans) were investigated using soils from the two extremes of the contamination gradient in a full factorial greenhouse experiment. After 12 weeks, plant biomass and root colonization by AMF and non-mycorrhizal microbes were measured. Plants from both species grew much larger in soil from low-contaminated (LC) origin than high-contaminated (HC) origin. For S. nutans, the addition of a non-AMF soil microbial wash of either origin increased the efficacy of AMF from LC soils but decreased the efficacy of AMF from HC soils in promoting plant growth. Furthermore, there was high mortality of S. nutans in HC soil, where plants with AMF from HC died sooner. For D. flexuosa, plant biomass did not vary with AMF source or the microbial wash treatment or their interaction. While AMF origin did not affect root colonization of D. flexuosa by AMF, the presence and origin of AMF did affect the number of non-mycorrhizal (NMF) morphotypes and NMF root colonization. Adding non-AMF soil biota reduced Zn concentrations in shoots of D. flexuosa. Thus the non-AMF biotic context affected heavy metal sequestration and associated NMF in D. flexuosa, and it interacted with AMF to affect plant biomass in S. nutans. Our results should be useful for improving our basic ecological understanding of the context-dependency of plant-soil interactions and are potentially important in restoration of heavy-metal contaminated sites. PMID- 22919903 TI - Herbivory reduces plant interactions with above- and belowground antagonists and mutualists. AB - Herbivores affect plants through direct effects, such as tissue damage, and through indirect effects that alter species interactions. Interactions may be positive or negative, so indirect effects have the potential to enhance or lessen the net impacts of herbivores. Despite the ubiquity of these interactions, the indirect pathways are considerably less understood than the direct effects of herbivores, and multiple indirect pathways are rarely studied simultaneously. We placed herbivore effects in a comprehensive community context by studying how herbivory influences plant interactions with antagonists and mutualists both aboveground and belowground. We manipulated early-season aboveground herbivore damage to Cucumis sativus (cucumber, Cucurbitaceae) and measured interactions with subsequent aboveground herbivores, root-feeding herbivores, pollinators, and arbuscular mycorrhizal fungi (AMF). We quantified plant growth and reproduction and used an enhanced pollination treatment to determine if plants were pollen limited. Increased herbivory reduced interactions with both antagonists and mutualists. Plants with high levels of early herbivory were significantly less likely to suffer leaf damage later in the summer and tended to be less attacked by root herbivores. Herbivory also reduced pollinator visitation, likely due to fewer and smaller flowers, and reduced AMF colonization. The net effect of herbivory on plant growth and reproduction was strongly negative, but lower fruit and seed production were not due to reduced pollinator visits, because reproduction was not pollen limited. Although herbivores influenced interactions between plants and other organisms, these effects appear to be weaker than the direct negative effects of early-season tissue loss. PMID- 22919904 TI - Urbanized landscapes favored by fig-eating birds increase invasive but not native juvenile strangler fig abundance. AB - Propagule pressure can determine the success or failure of invasive plant range expansion. Range expansion takes place at large spatial scales, often encompassing many types of land cover, yet the effect of landscape context on propagule pressure remains largely unknown. Many studies have reported a positive correlation between invasive plant abundance and human land use; increased propagule pressure in these landscapes may be responsible for this correlation. We tested the hypothesis that increased rates of seed dispersal by fig-eating birds, which are more common in urban habitats, result in an increase in invasive strangler fig abundance in landscapes dominated by human land use. We quantified abundance of an invasive species (Ficus microcarpa) and a native species (F. aurea) of strangler fig in plots spanning the entire range of human land use in South Florida, USA, from urban parking lots to native forest. We then compared models that predicted juvenile fig abundance based on distance to adult fig seed sources and fig-eating bird habitat quality with models that lacked one or both of these terms. The best model for juvenile invasive fig abundance included both distance to adult and fig-eating bird habitat terms, suggesting that landscape effects on invasive fig abundance are mediated by seed-dispersing birds. In contrast, the best model for juvenile native fig abundance included only presence/absence of adults, suggesting that distance from individual adult trees may have less effect on seed limitation for a native species compared to an invasive species undergoing range expansion. However, models for both species included significant effects of adult seed sources, implying that juvenile abundance is limited by seed arrival. This result was corroborated by a seed addition experiment that indicated that both native and invasive strangler figs were strongly seed limited. Understanding how landscape context affects the mechanisms of plant invasion may lead to better management techniques. Our results suggest that prioritizing removal of adult trees in sites with high fig eating bird habitat may be the most effective method to control F. microcarpa abundance. PMID- 22919905 TI - Tracing impacts of partner abundance in facultative pollination mutualisms: from individuals to populations. AB - Partner abundance affects costs and benefits in obligate mutualisms, but its role in facultative partnerships is less clear. We address this gap in a pollination web consisting of two clovers (Trifolium) that differ in specialization on a bumble bee pollinator Bombus balteatus. We examine how pollination niche breadth affects plant responses to pollinator abundance, comparing early-flowering (specialized) and late-flowering (generalized) cohorts of T. parryi and early T. parryi to T. dasyphyllum, a pollination generalist. Co-pollinators disrupt the link between B. halteatus visitation and pollination rate for both clovers. Only for early-flowering T. parryi do visitation, pollination, and seed set increase with density of B. balteatus. Bumble bee density also alters timing of seed germination in T. parryi, with seeds from plants receiving augmented B. balteatus germinating sooner than seeds of open-pollinated counterparts. Benefits saturate at intermediate bumble bee densities. Despite strong effects of B. balteatus density on individual plant fitness components, population models suggest little impact of B. balteatus density on lamda in T. parryi or T. dasyphyllum. Findings show that functional redundancy in a pollinator guild mediates host-plant responses to partner density. Unexpected effects of pollinator density on life history schedule have implications for recruitment under pollinator decline. PMID- 22919906 TI - Effects of sampling completeness on the structure of plant-pollinator networks. AB - Plant-animal interaction networks provide important information on community organization. One of the most critical assumptions of network analysis is that the observed interaction patterns constitute an adequate sample of the set of interactions present in plant-animal communities. In spite of its importance, few studies have evaluated this assumption, and in consequence, there is no consensus on the sensitivity of network metrics to sampling methodological shortcomings. In this study we examined how variation in sampling completeness influences the estimation of six network metrics frequently used in the literature (connectance, nestedness, modularity, robustness to species loss, path length, and centralization). We analyzed data of 186 flowering plants and 336 pollinator species in 10 networks from a forest-fragmented system in central Chile. Using species-based accumulation curves, we estimated the deviation of network metrics in undersampled communities with respect to exhaustively sampled communities and the effect of network size and sampling evenness on network metrics. Our results indicate that: (1) most metrics were affected by sampling completeness but differed in their sensitivity to sampling effort; (2) nestedness, modularity, and robustness to species loss were less influenced by insufficient sampling than connectance, path length, and centralization; (3) robustness was mildly influenced by sampling evenness. These results caution studies that summarize information from databases with high, or unknown, heterogeneity in sampling effort per species and should stimulate researchers to report sampling intensity to standardize its effects in the search for broad patterns in plant-pollinator networks. PMID- 22919907 TI - Role of climate and competitors in limiting fitness across range edges of an annual plant. AB - It is often assumed that the geographic distributions of species match their climatic tolerances, but this assumption is not frequently tested. Moreover, few studies examine the relative importance of abiotic and biotic factors for limiting species ranges. We combined multiple approaches to assess the extent to which fitness of a widespread native annual legume, Chamaecrista fasciculata, decreases at and beyond its northern and western range edges, and how this is influenced by the presence of neighbors. First, we examined plant fitness and the effect of neighbors in natural populations at different geographic range locations for three years. Fitness decreased toward the northern range edge, but not the western edge. Neighbor removal had a consistently positive effect on seedpod production across all years and sites. Second, we established experimental populations at sites within the range, and at and beyond the northern and western range edges. We tracked individual fitness and recorded seedling recruitment in the following year (a complete generation) to estimate population growth rate. Individual fitness and population growth declined to near zero beyond both range edges, indicating that C. fasciculata with its present genetic composition will not establish in these regions, given conditions currently. We also carried out a neighbor removal treatment. Consistent with the natural populations, neighbors reduced seedpod production of reproductive adults. However, neighbors also increased early-season survival, and this positive effect early in life history resulted in a net positive effect of neighbors on lifetime fitness at most range locations. Our data show that the population growth rate of C. fasciculata includes values above replacement, and populations are well adapted to conditions up to the edge of the range, whereas the severely compromised fitness at sites beyond the edge precludes immediate establishment of populations and thereby impedes adaptation to these conditions. PMID- 22919908 TI - Extrinsic regime shifts drive abrupt changes in regeneration dynamics at upper treeline in the Rocky Mountains, U.S.A. AB - Given the widespread and often dramatic influence of climate change on terrestrial ecosystems, it is increasingly common for abrupt threshold changes to occur, yet explicitly testing for climate and ecological regime shifts is lacking in climatically sensitive upper treeline ecotones. In this study, quantitative evidence based on empirical data is provided to support the key role of extrinsic, climate-induced thresholds in governing the spatial and temporal patterns of tree establishment in these high-elevation environments. Dendroecological techniques were used to reconstruct a 420-year history of regeneration dynamics within upper treeline ecotones along a latitudinal gradient (approximately 44-35 degrees N) in the Rocky Mountains. Correlation analysis was used to assess the possible influence of minimum and maximum temperature indices and cool-season (November-April) precipitation on regional age-structure data. Regime-shift analysis was used to detect thresholds in tree establishment during the entire period of record (1580-2000), temperature variables significantly Correlated with establishment during the 20th century, and cool-season precipitation. Tree establishment was significantly correlated with minimum temperature during the spring (March-May) and cool season. Regime-shift analysis identified an abrupt increase in regional tree establishment in 1950 (1950-1954 age class). Coincident with this period was a shift toward reduced cool-season precipitation. The alignment of these climate conditions apparently triggered an abrupt increase in establishment that was unprecedented during the period of record. Two main findings emerge from this research that underscore the critical role of climate in governing regeneration dynamics within upper treeline ecotones. (1) Regional climate variability is capable of exceeding bioclimatic thresholds, thereby initiating synchronous and abrupt changes in the spatial and temporal patterns of tree establishment at broad regional scales. (2) The importance of climate parameters exceeding critical threshold values and triggering a regime shift in tree establishment appears to be contingent on the alignment of favorable temperature and moisture regimes. This research suggests that threshold changes in the climate system can fundamentally alter regeneration dynamics within upper treeline ecotones and, through the use of regime-shift analysis, reveals important climate-vegetation linkages. PMID- 22919909 TI - Precipitation-driven carbon balance controls survivorship of desert biocrust mosses. AB - Precipitation patterns including the magnitude, timing, and seasonality of rainfall are predicted to undergo substantial alterations in arid regions in the future, and desert organisms may be more responsive to such changes than to shifts in only mean annual rainfall. Soil biocrust communities (consisting of cyanobacteria, lichen, and mosses) are ubiquitous to desert ecosystems, play an array of ecological roles, and display a strong sensitivity to environmental changes. Crust mosses are particularly responsive to changes in precipitation and exhibit rapid declines in biomass and mortality following the addition of small rainfall events. Further, loss of the moss component in biocrusts leads to declines in crust structure and function. In this study, we sought to understand the physiological responses of the widespread and often dominant biocrust moss Syntrichia caninervis to alterations in rainfall. Moss samples were collected during all four seasons and exposed to two rainfall event sizes and three desiccation period (DP) lengths. A carbon balance approach based on single precipitation events was used to define the carbon gain or loss during a particular hydration period. Rainfall event size was the strongest predictor of carbon balance, and the largest carbon gains were associated with the largest precipitation events. In contrast, small precipitation events resulted in carbon deficits for S. caninervis. Increasing the length of the DP prior to an event resulted in reductions in carbon balance, probably because of the increased energetic cost of hydration following more intense bouts of desiccation. The season of collection (i.e., physiological status of the moss) modulated these responses, and the effects of DP and rainfall on carbon balance were different in magnitude (and often in sign) for different seasons. In particular, S. caninervis displayed higher carbon balances in the winter than in the summer, even for events of identical size. Overall, our results suggest that annual carbon balance and survivorship in biocrust mosses are largely driven by precipitation, and because of the role mosses play in biocrusts, changes in intra-annual precipitation patterns can have implications for hydrology, soil stability, and nutrient cycling in dryland systems. PMID- 22919910 TI - Balancing the edge effects budget: bay scallop settlement and loss along a seagrass edge. AB - Edge effects are a dominant subject in landscape ecology literature, yet they are highly variable and poorly understood. Often, the literature suggests simple models for edge effects-positive (enhancement at the edge), negative (enhancement at the interior), or no effect (neutral)--on a variety of metrics, including abundance, diversity, and mortality. In the marine realm, much of this work has focused on fragmented seagrass habitats due to their importance for a variety of commercially important species. In this study, the settlement, recruitment, and survival of bay scallops was investigated across a variety of seagrass patch treatments. By simultaneously collecting settlers (those viable larvae available to settle and metamorphose) and recruits (those settlers that survive some period of time, in this case, 6 weeks) on the same collectors, we were able to demonstrate a "balance" between positive and negative edge effects, resulting in a net neutral effect. Scallop settlement was significantly enhanced along seagrass edges, regardless of patch type while survival was elevated within patch interiors. However, recruitment (the net result of settlement and post-settlement loss) did not vary significantly from edge to center, representing a neutral effect. Further, results suggest that post-settlement loss, most likely due to predation, appears to be the dominant mechanism structuring scallop abundance, not patterns in settlement. These data illustrate the complexity of edge effects, and suggest that the metric used to investigate the effect (be it abundance, survival, or other metrics) can often influence the magnitude and direction of the perceived effect. Traditionally, high predation along a habitat edge would have indicated an "ecological trap" for the species in question; however, this study demonstrates that, at the population level, an ecological trap may not exist. PMID- 22919911 TI - Tidal events and salt-marsh structure influence black mangrove (Avicennia germinans) recruitment across an ecotone. AB - Field experiments were conducted at a black mangrove-salt-marsh ecotone in southwest Florida (U.S.A.) to investigate retention of propagules of the black mangrove, Avicennia germinans, by salt-marsh plants as a mechanism of facilitation operating on recruitment success at landward boundaries. Buoyant A. germinans propagules are dispersed by tides, and stranding is required for establishment; therefore, processes that enable stranding should facilitate mangrove recruitment. We expected the physical structure of salt-marsh vegetation to define propagule retention capacity, and we predicted that salt-marsh plants with distinct growth forms would differentially retain propagules. Experimental monoculture plots (1 m2) of salt-marsh plants with different growth forms (Sporobolus virginicus [grass], Sesuvium portulacastrum [succulent forb], and Batis maritima [succulent scrub]) were created, and A. germinans propagules were emplaced into these plots and monitored over time. For comparison, propagules were also placed into natural polyculture plots (1 m2). Polyculture plots contained at least two of the salt-marsh plant taxa selected for monoculture treatments, and S. virginicus was always present within these polyculture plots. Natural polyculture plots retained 59.3% +/- 11.0% (mean +/- SE) of emplaced propagules. Monocultures varied in their propagule retention capacities with plots of S. virginicus retaining on average 65.7% +/- 11.5% of transplanted propagules compared to 7.2% +/- 1.8% by B. maritima and 5.0% +/- 1.9% by S. portulacastrum. Plots containing S. virginicus retained a significantly greater percentage of emplaced propagules relative to the two succulent salt-marsh taxa. Furthermore, propagule entrapment, across all treatments, was strongly correlated with salt-marsh structure (r2 = 0.6253, P = 0.00001), which was estimated using an indirect quantitative metric (lateral obstruction) calculated from digital images of plots. Overall, our findings imply that entrapment of propagules by salt-marsh plants may be facilitative if propagules are dispersed beyond the established tree line by spring or storm tides, and that facilitation may be sustained over time. We conclude that salt-marsh ecotone permeability may modulate landward encroachment by A. germinans, and that interactions among the early life history stages of black mangroves and neighboring plants may direct community responses to climate change. PMID- 22919912 TI - Microbial community phylogenetic and trait diversity declines with depth in a marine oxygen minimum zone. AB - Oxygen minimum zones (OMZs) are natural physical features of the world's oceans. They create steep physiochemical gradients in the water column, which most notably include a dramatic draw down in oxygen concentrations over small vertical distances (<100 m). Microbial communities within OMZs play central roles in ocean and global biogeochemical cycles, yet we still lack a fundamental understanding of how microbial biodiversity is distributed across OMZs. Here, we used metagenomic sequencing to investigate microbial diversity across a vertical gradient in the water column during three seasons in the Eastern Tropical South Pacific (ETSP) OMZ. Based on analysis of small subunit ribosomal RNA (SSU rRNA) gene fragments, we found that both taxonomic and phylogenetic diversity declined steeply along the transition from oxygen-rich surface water to the permanent OMZ. We observed similar declines in the diversity of protein-coding gene categories, suggesting a decrease in functional (trait) diversity with depth. Metrics of functional and trait dispersion indicated that microbial communities are phylogenetically and functionally more overdispersed in oxic waters, but clustered within the OMZ. These dispersion patterns suggest that community assembly drivers (e.g., competition, environmental filtering) vary strikingly across the oxygen gradient. To understand the generality of our findings, we compared OMZ results to two marine depth gradients in subtropical oligotrophic sites and found that the oligotrophic sites did not display similar patterns, likely reflecting unique features found in the OMZ. Finally, we discuss how our results may relate to niche theory, diversity-energy relationships and stress gradients. PMID- 22919913 TI - Multiple predators indirectly alter community assembly across ecological boundaries. AB - Models of habitat selection often assume that organisms choose habitats based on their intrinsic quality, regardless of the position of these habitats relative to low-quality habitats in the landscape. We created a habitat matrix in which high quality (predator-free) aquatic habitat patches were positioned adjacent to (predator-associated) or isolated from (control) patches with single or two species of caged predators. After 16 days of colonization, larval insect abundance was reduced by 50% on average in both the predator and predator associated treatments relative to isolated controls. Effects were largely similar among predator treatments despite variation in number of predator species, predator biomass, and whether predators were native or nonnative. Importantly, the strength of effects did not depend on whether predators were physically present. These results demonstrate that predator cues can cascade with equal strength across ecological boundaries, indirectly altering community assembly via habitat selection in intrinsically high-quality habitats. PMID- 22919914 TI - Above- and belowground responses of Arctic tundra ecosystems to altered soil nutrients and mammalian herbivory. AB - Theory and observation indicate that changes in the rate of primary production can alter the balance between the bottom-up influences of plants and resources and the top-down regulation of herbivores and predators on ecosystem structure and function. The exploitation ecosystem hypothesis (EEH) posited that as aboveground net primary productivity (ANPP) increases, the additional biomass should support higher trophic levels. We developed an extension of EEH to include the impacts of increases in ANPP on belowground consumers in a similar manner as aboveground, but indirectly through changes in the allocation of photosynthate to roots. We tested our predictions for plants aboveground and for phytophagous nematodes and their predators belowground in two common arctic tundra plant communities subjected to 11 years of increased soil nutrient availability and/or exclusion of mammalian herbivores. The less productive dry heath (DH) community met the predictions of EEH aboveground, with the greatest ANPP and plant biomass in the fertilized plots protected from herbivory. A palatable grass increased in fertilized plots while dwarf evergreen shrubs and lichens declined. Belowground, phytophagous nematodes also responded as predicted, achieving greater biomass in the higher ANPP plots, whereas predator biomass tended to be lower in those same plots (although not significantly). In the higher productivity moist acidic tussock (MAT) community, aboveground responses were quite different. Herbivores stimulated ANPP and biomass in both ambient and enriched soil nutrient plots; maximum ANPP occurred in fertilized plots exposed to herbivory. Fertilized plots became dominated by dwarf birch (a deciduous shrub) and cloudberry (a perennial forb); under ambient conditions these two species coexist with sedges, evergreen dwarf shrubs, and Sphagnum mosses. Phytophagous nematodes did not respond significantly to changes in ANPP, although predator biomass was greatest in control plots. The contrasting results of these two arctic tundra plant communities suggest that the predictions of EEH may hold for very low ANPP communities, but that other factors, including competition and shifts in vegetation composition toward less palatable species, may confound predicted responses to changes in productivity in higher ANPP communities such as the MAT studied here. PMID- 22919915 TI - Nitrogen niches revealed through species and functional group removal in a boreal shrub community. AB - Most theories attempting to explain the coexistence of species in local communities make fundamental assumptions regarding whether neighbors exhibit competitive, neutral, or positive resource-use interactions; however, few long term data from naturally assembled plant communities exist to test these assumptions. We utilized a 13-year experiment consisting of factorial removal of three shrub species (Vaccinium myrtillus, V. vitis-idaea, and Empetrum hermaphroditum) and factorial removal of two functional groups (tree roots and feather mosses) to assess how neighbors affect N acquisition and growth of each of the three shrub species. The removal plots were established on each of 30 lake islands in northern Sweden that form a natural gradient of resource availability. We tested the hypotheses that: (1) the presence of functionally similar neighbors would reduce shrub N acquisition through competition for a shared N resource; (2) the removal of functional groups would affect shrub N acquisition by altering the breadth of their niches; and (3) soil fertility would influence the effects of neighbor removals. We found that the removal of functionally similar neighbors (i.e., other shrub species) usually resulted in higher biomass and biomass N, with the strength of these effects varying strongly with site fertility. Shrub species removals never resulted in altered stable N isotope ratios (delta(15)N), suggesting that the niche breadth of the three shrubs was unaffected by the presence of neighboring shrub species. In the functional group removal experiment, we found positive effects of feather moss removal on V. myrtillus biomass and biomass N, and negative effects on E. hermaphrotium N concentration and V. vitis-idaea biomass and biomass N. Tree root removal also caused a significant shift in foliar delta(15)N of V. myrtillus and altered the delta(15)N, biomass, and biomass N of E. hermaphroditum. Collectively, these results show that the resource acquisition and niche breadth of the three shrub species are often affected by neighbors, and further that both the identity of neighbors and site fertility strongly determine whether these interactions are positive, negative, or neutral. These findings have implications for understanding species coexistence and the reciprocal relationships between productivity and species diversity in this ecosystem. PMID- 22919916 TI - Disentangling trophic relationships in a High Arctic tundra ecosystem through food web modeling. AB - Determining the manner in which food webs will respond to environmental changes is difficult because the relative importance of top-down vs. bottom-up forces in controlling ecosystems is still debated. This is especially true in the Arctic tundra where, despite relatively simple food webs, it is still unclear which forces dominate in this ecosystem. Our primary goal was to assess the extent to which a tundra food web was dominated by plant-herbivore or predator-prey interactions. Based on a 17-year (1993-2009) study of terrestrial wildlife on Bylot Island, Nunavut, Canada, we developed trophic mass balance models to address this question. Snow Geese were the dominant herbivores in this ecosystem, followed by two sympatric lemming species (brown and collared lemmings). Arctic foxes, weasels, and several species of birds of prey were the dominant predators. Results of our trophic models encompassing 19 functional groups showed that <10% of the annual primary production was consumed by herbivores in most years despite the presence of a large Snow Goose colony, but that 20-100% of the annual herbivore production was consumed by predators. The impact of herbivores on vegetation has also weakened over time, probably due to an increase in primary production. The impact of predators was highest on lemmings, intermediate on passerines, and lowest on geese and shorebirds, but it varied with lemming abundance. Predation of collared lemmings exceeded production in most years and may explain why this species remained at low density. In contrast, the predation rate on brown lemmings varied with prey density and may have contributed to the high-amplitude, periodic fluctuations in the abundance of this species. Our analysis provided little evidence that herbivores are limited by primary production on Bylot Island. In contrast, we measured strong predator-prey interactions, which supports the hypothesis that this food web is primarily controlled by top-down forces. The presence of allochthonous resources subsidizing top predators and the absence of large herbivores may partly explain the predominant role of predation in this low-productivity ecosystem. PMID- 22919917 TI - Genes and song: genetic and social connections in fragmented habitat in a woodland bird with limited dispersal. AB - Understanding the processes leading to population declines in fragmented landscapes is essential for successful conservation management. However, isolating the influence of disparate processes, and dispersal in particular, is challenging. The Grey Shrike-thrush, Colluricincla harmonica, is a sedentary woodland-dependent songbird, with learned vocalizations whose incidence in suitable habitat patches falls disproportionally with decline in tree cover in the landscape. Although it has been suggested that gaps in tree cover might act as barriers to its dispersal, the species remains in many remnants of native vegetation in agricultural landscapes, suggesting that it may have responded to habitat removal and fragmentation by maintaining or even increasing dispersal distances. We quantified population connectivity of the Grey Shrike-thrush in a system fragmented over more than 120 years using genetic (microsatellites) and acoustic (song types) data. First, we tested for population genetic and acoustic structure at regional and local scales in search of barriers to dispersal or gene flow and signals of local spatial structuring indicative of restricted dispersal or localized acoustic similarity. Then we tested for effects of habitat loss and fragmentation on genetic and acoustic connectivity by fitting alternative models of mobility (isolation-by-distance [the null model] and reduced and increased movement models) across treeless vs. treed areas. Birds within -5 km of each other had more similar genotypes and song types than those farther away, suggesting that dispersal and song matching are limited in the region. Despite restricted dispersal detected for females (but not males), populations appeared to be connected by gene flow and displayed some cultural (acoustic) connectivity across the region. Fragmentation did not appear to impact greatly the dispersal of the Grey Shrike-thrush: none of the mobility models fit the genetic distances of males, whereas for females, an isolation-by-distance model could not be rejected in favor of the models of reduced or increased movement through treeless gaps. However, dissimilarities of the song types were more consistent with the model of reduced cultural connectivity through treeless areas, suggesting that fragmentation impedes song type sharing in the Grey Shrike-thrush. Our paper demonstrates that habitat fragmentation hinders important population processes in an Australian woodland bird even though its dispersal is not detectably impacted. PMID- 22919918 TI - Decoupling of component and ensemble density feedbacks in birds and mammals. AB - A component density feedback represents the effect of change in population size on single demographic rates, whereas an ensemble density feedback captures that effect on the overall growth rate of a population. Given that a population's growth rate is a synthesis of the interplay of all demographic rates operating in a population, we test the hypothesis that the strength of ensemble density feedback must augment with increasing strength of component density feedback, using long-term censuses of population size, fertility, and survival rates of 109 bird and mammal populations (97 species). We found that compensatory and depensatory component feedbacks were common (each detected in approximately 50% of the demographic rates). However, component feedback strength only explained <10% of the variation in ensemble feedback strength. To explain why, we illustrate the different sources of decoupling between component and ensemble feedbacks. We argue that the management of anthropogenic impacts on populations using component feedbacks alone is ill-advised, just as managing on the basis of ensemble feedbacks without a mechanistic understanding of the contributions made by its components and environmental variability can lead to suboptimal decisions. PMID- 22919919 TI - Density estimation in tiger populations: combining information for strong inference. AB - A productive way forward in studies of animal populations is to efficiently make use of all the information available, either as raw data or as published sources, on critical parameters of interest. In this study, we demonstrate two approaches to the use of multiple sources of information on a parameter of fundamental interest to ecologists: animal density. The first approach produces estimates simultaneously from two different sources of data. The second approach was developed for situations in which initial data collection and analysis are followed up by subsequent data collection and prior knowledge is updated with new data using a stepwise process. Both approaches are used to estimate density of a rare and elusive predator, the tiger, by combining photographic and fecal DNA spatial capture-recapture data. The model, which combined information, provided the most precise estimate of density (8.5 +/- 1.95 tigers/100 km2 [posterior mean +/- SD]) relative to a model that utilized only one data source (photographic, 12.02 +/- 3.02 tigers/100 km2 and fecal DNA, 6.65 +/- 2.37 tigers/100 km2). Our study demonstrates that, by accounting for multiple sources of available information, estimates of animal density can be significantly improved. PMID- 22919920 TI - Ecological determinism increases with organism size. AB - After much debate, there is an emerging consensus that the composition of many ecological communities is determined both by species traits, as proposed by niche theory, as well as by chance events. A critical question for ecology is, therefore, which attributes of species predict the dominance of deterministic or stochastic processes. We outline two hypotheses by which organism size could determine which processes structure ecological communities, and we test these hypotheses by comparing the community structure in bromeliad phytotelmata of three groups of organisms (bacteria, zooplankton, and macroinvertebrates) that encompass a 10 000-fold gradient in body size, but live in the same habitat. Bacteria had no habitat associations, as would be expected from trait-neutral stochastic processes, but still showed exclusion among species pairs, as would be expected from niche-based processes. Macroinvertebrates had strong habitat and species associations, indicating niche-based processes. Zooplankton, with body size between bacteria and macroinvertebrates, showed intermediate habitat associations. We concluded that a key niche process, habitat filtering, strengthened with organism size, possibly because larger organisms are both less plastic in their fundamental niches and more able to be selective in dispersal. These results suggest that the relative importance of deterministic and stochastic processes may be predictable from organism size. PMID- 22919921 TI - First detection of hepatitis E virus in Austrian pigs by RT-qPCR. AB - Long known to cause disease outbreaks in man in countries with poor sanitary conditions, an increasing number of autochthonous HEV genotype 3 infections have been reported in industrialised countries. Genotype 3 poses an important potential zoonotic threat, with infected pigs functioning as the main reservoir. This study reports the first detected emergence of HEV in Austrian pigs. Five Austrian strains were partially sequenced and phylogenetic analysis demonstrates that they cluster within genotype 3. In addition, a reverse transcription quantitative real-time PCR (RT-qPCR) method using a MGB-hydrolysis probe was developed offering the possibility to detect the HEV genotype 3 in faeces, liquid and tissue-samples from domestic pigs. The method was adapted to the strains found in Austria. Sensitivity of the assay was tested with different pig organs (liver, mesenteric lymph nodes and kidney) as well as with serum, bile and faeces samples. Within the dynamic range of the assay, a quantitative determination of virus loads was performed. For specificity testing several common swine pathogens were used. Results demonstrated that the proposed method allows implementation of reliable high-throughput screening of Austrian swine samples in the future. PMID- 22919922 TI - Improving the sensitivity of the IBR-gE ELISA for testing IBR marker vaccinated cows from bulk milk. AB - The low sensitivity of the IBR-gE ELISA compared to other diagnostic ELISA tests for IBR is a major disadvantage of IBR control programmes based on IBR marker vaccination. Therefore the IBR-gE ELISA is not generally recommended for testing pooled or bulk milk samples.The aim of this study was to determine the performance of a commercially available kit for concentrating and purifying antibodies in milk in order to improve the sensitivity of detecting IBR-gE antibody positive cows from pooled and bulk milk samples. A single IBR-gE positive cow is likely to remain undetected in a pool of 49 negative milk samples without concentration. By contrast, the bulk milk concentration procedure improved sensitivity from 5.4% to 75.7% in a positive herd. Milk samples with a high or moderate positive signal are more likely to be detected after pool milk concentration compared to weak positive samples. Whereas a follow up study involving a monthly testing of bulk milk samples from three marker vaccinated IBR gE negative herds over a period of seven months yielded negative results each month, bulk milk from a herd containing <5% IBR-gE positive cows always detected positive after concentration. Although the milk concentration procedure had no impact on specificity, it significantly enhanced the sensitivity of the detection of IBR-gE positive milk in pooled and bulk milk samples. After further evaluation this procedure could allow a cost efficient and reliable method of monitoring IBR marker-vaccinated herds for IBR-gE antibodies. PMID- 22919923 TI - A brief summary of European legislation regarding animal welfare. AB - An overview of the current European legislation concerning animal welfare is given. The legal requirements concern the housing and care of production animals (poultry, calves and swine), the transport of animals and the killing of animals (not only in slaughterhouses, but also in case of contagious animal disease outbreaks). General information concerning the principles and contents of European pieces of legislation as well as detailed information concerning requirements for individual animal species is given. Furthermore, other elements concerning animal welfare such as castration of piglets, ritual slaughter and animals used for experimental purposes are also reviewed. Finally, some recent initiatives in the field of animal welfare are mentioned and useful links are provided for finding the various legislative acts and additional supportive information. PMID- 22919924 TI - Effects of meloxicam and flunixin on pain, stress and discomfort in male piglets during and after surgical castration. AB - Surgical castration of young male piglets is now a generally accepted cause of serious distress and impairment of animal welfare. Awareness of this problem has created the moral commitment to seek for practical and more humane alternatives. As one possible alternative, the application of analgesics has been installed in Germany as an interim solution by the QS system, thus mandatory for the majority of German pig producers.Two analgesics have been authorised for this purpose. Both have been shown a significant positive impact on cortisol levels if administered pre-operatively. However, their effects on pain, stress and discomfort during castration, and on the post-castration period are conflicting. Thus, the aim of the present study was to compare the effects of Meloxicam and Flunixin on cortisol levels, behavioural indices, vocalisation, and wound healing of surgical castrated piglets in the field. There was no difference in vocalisation during castration in analgesic treated and untreated piglets. Piglets castrated under analgesia still had significantly elevated serum cortisol levels 30 min post castration, when compared to the sham castrated group. Both analgesics led to a significant impairment of behavioural indices and wound healing. It is concluded that analgesics can improve the welfare of piglets during the first part of the post-castration period. However, the benefits may be considered small and may not meet the requirements of the EU. Hence it is of high importance to prevent the interim practice of surgical castration of male piglets under analgesics from becoming implemented as a permanent condition in pig production. PMID- 22919925 TI - [Comparison of three different anesthesia procedures in calves with respect to possible pain-associated reactions]. AB - The objective of this study was to compare the effects of three anaesthetic protocols with respect to possible pain-associated reactions: injection (INJE) with xylazine (0.2 mg/kg), ketamine (5 mg/kg) and local anaesthesia (procain 2%); a combination of injection and inhalation (KOMB) with xylazine (0.2 mg/kg), ketamine (2 mg/kg), and isoflurane (1.5-3.0 vol%); and inhalation with isoflurane (control group [o]) surgery. During the trial, the anaesthetic level was controlled, and signs of response to surgical stimulation or spontaneous movements, changes in heart rate, mean arterial pressure, plasma L-lactate and cortisol levels were recorded. The dosage of 5 mg ketamine/kg body mass was rarely sufficient to obtain surgical tolerance in group INJE. In order to attain surgical tolerance, it was necessary to administer an average of 8.4 mg ketamine/kg body mass. All animals of the INJEc/o groups started to show signs of spontaneous movements or response to surgical stimulation between five and twelve minutes after the last administration of ketamine. Signs of response to surgical stimulation at the time of skin incision were significantly most frequent (37%) in the INHAc group, while agitation or response to surgical stimulation at least once during the entire time of anaesthesia was significantly (p <0.01) most frequent in the INJEc group (100%). Changes in heart rate and mean blood pressure were not found to be related to surgical stress situations.Ten minutes after the incision, the highest increases in plasma cortisol levels above basal levels of the previous day were determined in the groups INJEc and INJEo (53.5 and 57.7 nmol/l, respectively). However, a significant increase of plasma cortisol levels between the previous day and ten minutes after incision was only found between INHAc and INHAo (30.1 versus 7.5 nmol/l, p < 0.01) but not in the other pairs of groups (INJEc/o and KOMBdc/o). Within the three experimental groups the increase of plasma cortisol levels between the previous day and ten minutes after incision was only significant between INJEc and KOMBc (53.5 versus 28.3 nmol/l, p < 0.01). Among the protocols tested in this study, the combination anaesthesia (KOMB) was associated with the least amount of pain-associated reactions by the calves. Therefore, this protocol should be used preferred to the other two protocols in order to minimise stress and pain for the animals as much as posssible. PMID- 22919926 TI - [Retrospective evaluation of data over five years of the BVDV prevention program using ear notch samples from the autonomous province of Bolzano (Italy)]. AB - In 2005 the Autonomous Province of Bolzano implemented a BVD-Virus control programme by testing all newborn calves for Bovine Viral Diarrhoea Virus (BVDV) antigen by analysing ear notch samples. In eradication programs between November 2005 and October 2010 a total of 344,108 newborn calves were ear notch sampled and analysed for BVDV by an antigen ELISA detecting the E(rns) (HerdCheck BVDV Antigen/Serum Plus, Idexx Laboratories, Switzerland). The tissue samples were collected during calf ear tagging (within the first 20 days of life) using two sampling devices (TypiFix-System, Agrobiogen GmbH [Germany] and Allflex [France]). 0.4% (1400) of the collected samples showed a positive result, and of these, 583 calves were subjected to a follow-up examination, analysing the samples again by ELISA as well blood samples by Reverse transcriptase-PCR. Blood samples were also collected from the dam, if still present on the farm by the time of sampling. These results suggest that a BVDV control programme testing all newborn calves sampled for BVDV antigen by analysing an ear notch sample in principle is practicable. However, due to the low positive predictive value (75%) of the E(rns)-ELISA used, not all persistently infected calves can be detected. PMID- 22919927 TI - Further characteristics of Actinomyces weissii, a novel species isolated from the oral cavity of dogs. AB - Comparable to previously conducted phenotypical and genotypical investigations (Hijazin et al., 2011c), three strains of the newly described species Actinomyces weissii, isolated from infections of the oral cavity of three dogs could be classified by matrix-assisted laser desorption ionization-time of flight mass spectrometry and by sequencing the target genes 23S rDNA and cpn60 as novel species of genus Actinomyces. The detection of peptidic spectra and both genotypic approaches might help to identify A. weissii in future and elucidate the role this species plays in infections of dogs. PMID- 22919928 TI - Prevalence of antibodies against Borrelia burgdorferi sensu lato and Anaplasma phagocytophilum and their clinical relevance in dogs in Munich, Germany. AB - Although prevalences of antibodies against Borrelia (B.) burgdorferi sensu lato (sl) and Anaplasma (A.) phagocytophilum have been reported to be high in the German dog population, the importance of the diseases caused by both agents is still not well characterized in a field situation.The aim of this study was (1) to determine the prevalence of antibodies to B. burgdorferi sl and A. phagocytophilum in dogs in Munich, Germany, and (2) to assess the clinical presentation and laboratory values of antibody-positive dogs and compare them to a negative control group. In total, 448 randomly selected dogs were screened for antibodies to B. burgdorferi sl and A. phagocytophilum with the SNAP 4Dx assay (IDEXX, Laboratories, Inc., USA). Dogs carrying antibodies against B. burgdorferi sl and/or A. phagocytophilum were classified as "positive"(n=100), the following 100 negative dogs served as control group. In both groups, physical examination and laboratory parameters were compared. 22 (4.9%) dogs had antibodies to B. burgdorferi sl, 78 (19.4%) to A. phagocytophilum, nine (2.0%) to both agents. Bernese Mountain Dogs had significantly more often antibodies against B. burgdorferi sl. Negative dogs were more often diagnosed as "healthy" compared to A. phagocytophilum antibody-positives that showed more often elevated body temperature and poor general condition; beyond that, there were no differences in clinical and laboratory abnormalities between both groups. Although dogs tested negative were more often considered healthy, there were no differences in parameters considered "specific" for both infections between dogs with and without antibodies. Hence, tests detecting antibodies against both agents are not able to detect animals with the clinical disease. PMID- 22919929 TI - Bulk milk-estimated seroprevalence of Fasciola hepatica in dairy herds and collecting of risk factor data in East Frisia, northern Germany. AB - The liver fluke Fasciola (F) hepatica is one of the most important trematodes in cattle farming worldwide. Fasciolosis in dairy cows is leading to production losses due to decreased milk yield, liver condemnation and impaired reproduction. The treatment of dairy cows is unsatisfactory, because available drugs are either effective against adult flukes only or have long withdrawal times or in some countries may not be used at all. In the present study the prevalence of F. hepatica in dairy farms located in East Frisia, which is part of the federal state Lower Saxony, was investigated. East Frisia is considered a high risk area for Fasciola hepatica infections, because of its coastal location, high precipitation and moist pastures. About 750 bulk milk samples were collected in January and November 2006 and analysed for F. hepatica antibodies using the Pourquier ELISA. In addition, questionnaires, which were answered by 260 of the participating farmers, were evaluated to analyse management-related factors associated with fasciolosis. In January and November, 52.1% and 53.6% of the bulk milk samples, respectively, showed positive results. Thereby, 88.1% of the examined farms showed an unchanged infection status, whereas 6.2% of the farms became seropositive during the grazing season and 5.8% of the dairy herds turned seronegative. Statistical analysis revealed a significant negative association between average annual milk production and the frequency of infections with F. hepatica. PMID- 22919931 TI - Life insurance policy loans: tax and other implications. PMID- 22919932 TI - Cutting "class". PMID- 22919930 TI - Feed restriction enhances the depressive effects of erythromycin on equine hindgut microbial metabolism in vitro. AB - Equine typholocolitis is a sporadic diarrheal disease causing high mortality rates. One of the risk factors responsible for this is the oral application of the macrolide antibiotic erythromycin. The aim of the present in vitro study was to investigate whether erythromycin in combination with feed restriction provokes changes in microbial hindgut metabolism and could therefore be involved in the pathogenesis of equine typhlocolitis. As application of erythromycin and feed restriction are risk factors for equine typhlocolitis, both factors were chosen to investigate their individual and combined effects on hindgut microbial metabolism. The colon simulation technique (Cositec) was used to evaluate biochemical parameters of microbial metabolism. Production rates of the acetate, proprionate and butyrate were measured as quantitative parameters of microbial fermentation. Application of erythromycin (10 mg/d) predominantly decreased the production rates of propionate. Reducing the fermentable substrate to 30% induced an even more pronounced impairment. The detrimental effects of feed restriction on the production rates of short-chain fatty acids (SCFA) were enhanced when feed restriction was combined with the application of erythromycin. Irrespective of erytrhomycin, the butyrate fermentation rate was completely inhibited by feed restriction within two days after start of restriction. The reduction in butyrate fermentation rate has to be discussed as a pathophysiological factor for the onset of acute typhlocolitis. PMID- 22919933 TI - What you don't know can hurt you: the importance of the dental office lease. PMID- 22919934 TI - Reflections on dental management service organizations. AB - There are a multitude of practice options for the young dentist today. First, many practicing clinicians remain in solo practice or small group settings; flexibility, autonomy, and the ability to control one's environment are important factors in deciding to practice privately. The modern dentist, in order to succeed, will have to learn the business side of dentistry quickly and apply it more strategically in this new economic environment. A second choice is working in a large clinic or clinic environment, which is an option for those interested in a group setting with related benefits but no ownership option. The third alternative is working for a DMSO that operates facilities and offers their staff commensurate salaries and benefits, professional pride, and the potential for ownership that will be a stable component of caregiving in the future. Lastly, joining the military as a dental practitioner is worth noting; 10 percent of the men and women of the TUSDM 2010 graduating class opted for this clinical setting. PMID- 22919935 TI - 2011 William McKenna Volunteer Heroes. PMID- 22919936 TI - Prescription writing for dentists: ethical and legal guidelines. PMID- 22919937 TI - The pregnant dental patient. AB - When dealing with a pregnant patient, the dental practitioner should keep in mind the various physiological changes that occur in the pregnant female and the potential effects on the fetus in using various types of local anesthesia. This article reviews the current considerations in the use of local anesthesia in the pregnant dental patient, and the safety of local anesthetics, their dosage, and any adverse effect on mother and fetus. It also discusses various dental procedures and the trimester during which they can be performed. Lastly, this article talks about the complications that can occur with a pregnant dental patient in the dental chair. PMID- 22919938 TI - Jaded smiles: ancient Mayan dental inlays and today's Central American patients. PMID- 22919939 TI - A clinico-pathologic correlation. Osteomyelitis. PMID- 22919940 TI - Lateral radicular radiolucencies. PMID- 22919941 TI - Molarball. PMID- 22919942 TI - The times they are a-changin'. PMID- 22919943 TI - Prescription writing for dentists: ethical and legal guidelines. PMID- 22919945 TI - How much do you know about Social Security? PMID- 22919944 TI - Health insurance tax credit for small businesses. PMID- 22919946 TI - Is your reputation at risk? PMID- 22919947 TI - Digital dental labs. PMID- 22919948 TI - Ropivacaine: the next dental local anesthetic? PMID- 22919949 TI - A conservative approach in the management of inflammatory dentigerous cyst in transitional dentition: a case report. AB - Dentigerous cysts are benign odontogenic cysts that develop from the reduced enamel epithelium related to the crown of an unerupted and/or impacted tooth. Inflammatory dentigerous cyst is a variety of dentigerous cyst that is mostly found in the mixed dentition, and the treatment modalities range from enucleation to marsupialization. By extracting the infected primary teeth, opening the cyst, and ensuring continuous drainage, spontaneous eruption of the involved permanent teeth occurs into the dental arch even if they are severely dislocated. The purpose of this report is to describe the successful treatment of a large dentigerous cyst by conservative surgical management. PMID- 22919951 TI - 10 Under Ten 2012. PMID- 22919950 TI - How many residents with disabilities are there in Massachusetts? AB - The availability of the U.S. Census Bureau data for 2010 provides an opportunity to review the increasing child, adult, and elderly populations with disabilities and the reality that there are individuals with disabilities not only in the larger population centers, but also in the small towns throughout the Commonwealth of Massachusetts. PMID- 22919952 TI - Iatrogenic damage to dental roots and paradental tissues. PMID- 22919953 TI - A clinico-pathologic correlation. Oral ranula. PMID- 22919954 TI - Screening for osteoporosis with panoramic radiographs. PMID- 22919955 TI - Osteosarcoma: how does it present? PMID- 22919956 TI - The Marius Bridge: a fixed restoration for the fully edentulous atrophic maxilla. PMID- 22919957 TI - A Yankee at home in Boston. PMID- 22919958 TI - Matariki--a time for reflection and renewal. PMID- 22919959 TI - Are ENs a dying breed? PMID- 22919960 TI - Time for action against apathy. PMID- 22919961 TI - I want a fair go! PMID- 22919962 TI - Management models--who gives an F? PMID- 22919963 TI - Regulatory authorities try to reach agreement. PMID- 22919964 TI - Boosting flu vaccination uptake. PMID- 22919965 TI - The journey from 'did not attend' to diagnosis and treatment. PMID- 22919966 TI - Good bowel cleaning vital for effective colonoscopy. PMID- 22919968 TI - Working to improve health literacy. PMID- 22919967 TI - Alzheimer's and other dementias. PMID- 22919969 TI - Passionate about gastroenterology. PMID- 22919970 TI - Bowel screening programme increases nursing skills. PMID- 22919971 TI - Ensuring patients are cared for with dignity. PMID- 22919972 TI - DHBS have an obligation to consult with NZNO. PMID- 22919973 TI - Getting involved--from apathy to integration. PMID- 22919974 TI - Cancer nurses think global, act local. PMID- 22919975 TI - Developing an endoscopy framework. PMID- 22919976 TI - Aged-care workers underpaid, undervalued and overworked. PMID- 22919977 TI - Does gestational weight gain in normal pre-pregnancy BMI pregnant women reflect fetal weight gain? AB - OBJECTIVE: To identify the correlation between gestational weight gain in pregnant women with normal pre-pregnancy body mass index (BMI) and fetal weight gain. MATERIAL AND METHOD: Uncomplicated normal pre-pregnancy BMI Thai singleton pregnant women with less than 16 weeks' gestation participated in this study between June 2008 and September 2009. Serial measurements of maternal and fetal weight using ultrasound examination were recorded every four weeks from 16 to 36 weeks' gestation. RESULTS: Two hundred seventy four uncomplicated pregnant women were included in this study of which 166 met inclusion criteria during a period of the study. There was a significant correlation between gestational weight gain and both estimated fetal weight gain and actual infant birth weight (p < 0.05). Using the multiple regression analysis, gestational weight gain between 16 to 28 weeks' gestation, multiparity, and male infants were independent factors and were significantly correlated with both fetal weight gain and actual infant birth weight (p < 0.05). CONCLUSION: For pregnant women with normal pre-pregnancy BM, gestational weight gain can predict intrauterine fetal weight as well as infant birth weight. PMID- 22919978 TI - Awareness of colorectal cancer screening in primary care physicians. AB - OBJECTIVE: Colorectal cancer is one of the leading causes of cancer related death worldwide. Primary care physicians play an important role in colorectal cancer screening. However the awareness and knowledge on the methods for colorectal cancer screening are still lacking. The authors aimed to assess Thai primary care physicians' knowledge and practice regarding colorectal cancer screening. MATERIAL AND METHOD: Between October and December 2010, questionnaires were distributed to 447 Thai physicians. The questionnaires included demographic data, self-responded knowledge, and practice. Their responses were analyzed. RESULTS: Three hundred eighty seven physicians completed the questionnaires (86.5% response rate). Of these, 44.7% were internists, 27.4% general practitioners (GPs), 11.9% surgeons, and 16.0% other specialists. Two hundred forty of physicians (62%) routinely recommended colorectal cancer screening to asymptomatic, average-risk patients. Only 43% gave the correct recommendation for the correct starting age. Colonoscopy (47.5%) and fecal occult blood test (40.0%) were preferred by the majority of physicians, whereas flexible sigmoidoscopy, double contrast barium enema, and CT colonoscopy were chosen by 5.7%, 4.4%, and 1.8% of physicians respectively. Surgeons had more knowledge of test efficacy and frequency. They also were more aware of colorectal cancer screening than internists. Patient ignorance (66.1%), unavailability of the test (64.6%), unawareness of physicians (57.9%), and financial problems (41.1%) were determinedas barriers for colorectal cancer screening. CONCLUSION: Although the majority of physicians are aware of colorectal cancer screening, the correct knowledge is lacking. Colonoscopy and FOBT are their most preferred tests. Patient ignorance, unavailability of the test, unawareness of physician, and financial problems are the main barriers for colorectal cancer screening. Improvement in academic support services and standard clinical practice guideline are needed to improve overall morbidity and mortality of colorectal cancer. PMID- 22919979 TI - In-hospital outcomes of primary percutaneous coronary intervention in King Chulalongkorn Memorial Hospital: 11 years of experience. AB - BACKGROUND: Primary percutaneous coronary intervention (PCI) appears to be the preferred reperf usion methodfor patients with ST-segment elevation myocardial infarction (STEMI). This method was introduced in our hospital before the year 2000. In Thailand, data showing long experience results in patients with STEMI who underwent primary percutaneous coronary intervention remain limited. OBJECTIVE: To demonstrate 11-yr experience of primary percutaneous coronary intervention at King Chulalongkorn Memorial Hospital. MATERIAL AND METHOD: This retrospective descriptive single-center study analyses clinical characteristics, angiographic features and in-hospital outcomes of 772 patients with STEMI who underwent primary percutaneous coronary intervention between 2000 and 2010. RESULTS: Seven hundred seventy two consecutive patients with STEMI were enrolled in the study. Three-fourth of the patients were male. Mean age was 60.13 years (range 28 to 96 years) and 12.6% were older than 75 years old. Forty-eight percent of patients were referred from hospital without cardiac catheterization facilities. Of these patients 94.4% underwent primary PCI and rescue PCI was done in 5.6% of patients. There were 27% ofpatients with left ventricular ejection fraction less than 40%, 21% of patients with Killip's class IV and 12% suffered cardiac arrest prior to angiography. Median door-to-balloon time in referred and non-referred patients was 28 and 104.5 minutes, respectively. Ninety-two percent of referred patients and 36% of non-referred patients, door to balloon time were within 90 minutes. About half ofthe patients had multi-vessels disease at that time of diagnosis. The overall angiographic success rate was 96%. Platelet glycoprotein llb/lla inhibitors were used in two-third ofpatients and stent placement in 82%. Post procedural thrombolysis in myocardial infarction (TII) 3 flow was documented in 87%. Intra-aortic balloon pump was used in 15% and thrombus aspiration device in 47%. During hospital stay, in-hospital mortality was 8.5% and 80% of those cases died from cardiac cause. One-third of patients died if they had Killip's class IV at presentation compared with 1.6% in patients with Killip's class I-III. In-hospital major adverse cardiovascular event was 10.4%. CONCLUSION: During 11 years of primary PCI experience in King Chulalongkorn Memorial Hospital, the angiographic success rate was high with acceptable in-hospital mortality and major adverse cardiac event. This strategy of treatment should be the treatment of choice for patients with STEMI in experienced PCI capable center with 24 hours/7 days availability. PMID- 22919980 TI - Leptospirosis among river water rafters in Satoon, southern Thailand. AB - OBJECTIVE: To assess epidemiology and risk factors for leptospirosis infection among the rafting participants in southern Thailand. MATERIAL AND METHOD: Prospective observation of the patients who participated in rafting in southern Thailand was conducted between January and December 2010. Demographic, clinical data as well as potential risk factors were collected Indirect immunofluorescent antibody test (IFAT) for specific leptospirosis IgG detection were examined immediately after rafting and two to three weeks after first samples. Microagglutination Test (MAT) was performed to confirm diagnosis in cases with seroconversion. RESULTS: One hundred fifty eight rafting participants enrolled to the present study of which 150 complied with the protocol and were analyzed Eleven patients had serological evidence of leptospirosis infection accounting for 7.3% while only three patients were symptomatic. Various serovars are responsible for infection while serovar Icterohemorrhagiae is most common. Persistence of abrasion wound/laceration wound were likely to be risk factors for infection with p < 0.05. CONCLUSION: The laboratory findings in the present study demonstrated that leptospirosis was associated with rafting and a contaminated environment. PMID- 22919981 TI - Clinical outcome of children with Henoch-Schonlein purpura nephritis. AB - OBJECTIVE: Evaluate the outcomes of pediatric patients with Henoch-Sch6nlein purpura nephritis andfind the parameters correlated with outcomes of treatment. MATERIAL AND METHOD: Review of medical records was performed in twenty patients diagnosed with Henoch-Schinlein purpura nephritis. Demographic data, clinical parameters and records of treatment at diagnosis and the last visit were collected and analyzed. RESULTS: Median age at diagnosis was 8-year-old and median follow-up time was 39 months. All patients had urine protein to creatinine ratio (UPCR) of more than 1.0 g/g while ten patients had hypoalbuminemia. Renal pathology results were class I, II, and III in 2, 14, and 4 patients respectively. Prednisolone was prescribed in all patients and cyclophosphamide was given in 13 patients. All patients had first resolution of proteinuria at median time of six months (range 2-47 months). At the last visit, 13 patients (65%) had remission of proteinuria (remission group), while seven patients (35%) became proteinuric relapse (relapse group) with UPCR > 0.2 g/g. Interestingly, the remission group had median time to first resolution of proteinuria shorter than the relapse group (6 months and 19 months, p < 0.001). Moreover, estimated glomerular filtration rate at diagnosis correlated negatively with UPCR at the last visit (r = -0.773, p = 0.001). CONCLUSION: Pediatric patients with Henoch Schonlein purpura nephritis who presented with heavy proteinuria had favorable outcome after treatment. The patients who had early resolution ofproteinuria remained in remission more than those who had late resolution. PMID- 22919982 TI - Effectiveness of conventional phototherapy versus Super light-emitting diodes phototherapy in neonatal hyperbilirubinemia. AB - BACKGROUND: Neonatal hyperbilirubinemia is very common. Phototherapy has been used for decades to prevent severe hyperbilirubinemia, which can cause kernicterus. OBJECTIVE: To compare the effectiveness of two phototherapy devices in reducing plasma bilirubin and duration of phototherapy in non-severe hyperbilirubinemia. MATERIAL AND METHOD: This was an open-label randomized controlled trial. Forty healthy infants aged between 1 and 5 days with non-severe hyperbilirubinemia, but to the level requiring phototherapy, were recruited. The phototherapy unit used in the "blue-light" group was the Siriraj Phototherapy Lamp with 6 special blue fluorescent tubes. The phototherapy unit used in the "light-emitting diodes (LEDs)" group was the Bilitron 3006 with 5 super LEDs. RESULTS: Twenty infants were included in each group. Demographic data and baseline clinical characteristics of infants in both groups were comparable. Median rate (25%, 75%tile) ofplasma bilirubin decreasing during phototherapy in the "blue light" was significantly higher than in the "LEDs" group [0.16 (0.09, 0.25) and 0.10 (0.02, 0.17) mg/dL/hour, respectively; p = 0.03]. Duration of phototherapy in "blue light" group was shorter than in "LEDs" group but was not statistically significant. CONCLUSION: A locally invented phototherapy device with special blue fluorescent tubes can be more effective than the more expensive commercial super LEDs phototherapy device in decreasing plasma bilirubin. PMID- 22919983 TI - Evaluation of short term integrated management of childhood illness training on the clinical competency of village doctors in Yunnan, China. AB - OBJECTIVE: Evaluate the clinical competency in detection and management complicated pneumonia, diarrhea, and measles cases of trainees who were village doctors in Puer city of Yunnan province, China. MATERIAL AND METHOD: One hundred fifty four village doctors working in the border areas were trainedfor 5-day Integrated Management of Childhood Illness (IMCI) training, which was adapted to World Health Organization (WHO) guidelines. Pre- and post-training assessment based on a modified WHO package was carried out. RESULTS: Statistically significant improvements in almost allperformances were observed. However, the level of post-training achievement was still low. Correct classifications of severe pneumonia, measles, and diarrhea were found in 63.0% 54.3% and 83.5%, respectively in the post-training period CONCLUSION: The training package needs to be further strengthened. PMID- 22919984 TI - Therapeutic effectiveness of the generic preparation of meropenem (Mapenem) in the treatment of moderate to severe infection in children. AB - OBJECTIVE: To compare treatment effectiveness and tolerability between generic meropenem (Mapenem, Siam Pharmaceutical) and the original formulation. MATERIAL AND METHOD: A retrospective review using historical control of children hospitalized at Queen Sirikit National Institute of Child Health was conducted. The demographics, clinical, and treatment outcomes of 180 children receiving generic meropenem were compared with that of 180 children receiving original meropenem. RESULTS: Baseline demographics, clinical characteristics were comparable between both groups. The treatment outcomes on day 3, 7, and 14 of treatment were comparable between the two groups with overall improvement rates of 73.9% and 71.7% for generic and original meropenem, respectively (absolute difference: 2.2%, 95% CI: -6.9%, 11.4%). Both drugs were well tolerated, with only 1.6% of patients in each group who experienced adverse reactions. CONCLUSION: Mapenem exhibited comparable therapeutic effectiveness and tolerability with that of the brand-name formulation in the treatment of moderate to severe infections in a pediatric population. PMID- 22919985 TI - Breast cancer cells in the afferent lymphatic tracts of sentinel lymph nodes. AB - BACKGROUND: To identify breast cancer cells in the afferent lymphatic tracts of axillary sentinel lymph nodes (SLNs). MATERIAL AND METHOD: The authors performed a prospective study of 1 00 breast cancer patients who underwent SLN biopsy between June 2009 and January 2010. The afferent lymphatic tracts of SLNs were identified by isosulfan blue or radiocolloid or both and were examined histologically. RESULTS: One hundred three SLNs and afferent lymphatic tracts were examined. The mean age of the patients was 53.2 years (range, 24 to 78 years). The median number of SLNs was 2 (range, 1 to 7). Twenty-four (24%) patients had positive SLNs. Most patients had stage I breast cancer (67%). Three patients with positive SLNs (13%) and stages IIB-IIIC breast cancers had tumor cells in the afferent tract tissue. There were no tumor cells in the afferent tracts of negative SLNs. CONCLUSION: Only a small proportion of operable breast cancer patients have tumor cells in the afferent lymphatic tract tissue of SLNs. There was a probable trend for more advanced stage breast cancer to harbor tumor cells in the afferent lymphatic tract tissue. PMID- 22919986 TI - A preliminary study of three and four levels degenerative cervical spondylosis treated with peek cages and anterior cervical plate. AB - OBJECTIVE: A retrospective study was performed in case with three and four levels degenerative cervical spondylosis that underwent anterior cervical discectomy and fusion (ACDF) with polyetheretherketone (PEEK) cages and anterior cervical plate to evaluate the efficacy and outcome. MATERIAL AND METHOD: Clinical and radiographic results of 16 patients (6 women and 10 men) between January 2006 and June 2009 with follow-up more than 24 months were evaluated Spinal curvature, segmental sagittal angulations, construct height and the radiographic fusion success rate were measured Odom's criteria, visual analog scale (VAS), Nurick and modified JOA (Japanese Orthopedic Association) score were used to assess the clinical results. RESULTS: There was significant difference between pre- and post operative in degree of lordosis, segmental Cobb angle and clinical outcomes (p < 0.01). Clinical outcomes were classified as 'excellent' or 'good' according to Odom's criteria in 14 patients (success rate: 87.5%). Mean follow-up period was 36 months. Flexion and extension lateral radiographs showed 100% fusion rate. The construct height and sagittal alignment were maintained on the final follow-up observations. No cage failure, subsiding or dislodgement was showed on follow-up radiographs. CONCLUSION: Interbody fusion with PEEK cages packed with bone substitute and aspirated bone marrow which additions of cervical plate eliminate the complications of graft harvest and is a good option for the treatment of patients with three and four levels degenerative cervical spondylosis. PMID- 22919987 TI - Patients with osteoporotic hip fractures: factors affecting length of hospital stay (LOS) and outcome. AB - OBJECTIVE: Identify risk factors associated with prolonged hospital stay (LOS more than 14 days) in patients with osteoporotic hip fracture. MATERIAL AND METHOD: One hundred and fifty out of 356 patients with fractured femur were selected between April 2008 and August 2009. Analysis of patient's LOS (group I equal or less than 14 days, group II more than 14 days) is performed by backward binary multiple logistic regression. RESULTS: LOS in group I (n=46) was 12.5 (+/- 4) days compared to 21 (+/- 11) days in group II (n=104). Patients were mainly female (74%) and about 50% were aged over 80 years. The 30-days mortality in group I and II was zero and two patients respectively. Time-to-surgery was three days (+/- 2) in group I and seven (+/- 5) days in group II. Significant predicting risk factors were waiting for investigation (odds ratio (OR) 3.77, confidence interval (CI) 1.12-12.69) and receiving systemic opioids (OR 3.44; CI 1.54-7.66). CONCLUSION: Unnecessary surgery delay after hip fracture should be avoided. Higher need for opioids in those patients might be the result of prolonged waiting for surgical treatment. PMID- 22919988 TI - Body surface area and age as a guidance of the dose of intrathecal 0.5% heavy bupivacaine and fentanyl in transurethral procedures. AB - OBJECTIVE: Observe the potency of various drugs doses as milliliters of 0.5% heavy bupivacaine with or without fentanyl for spinal block in transurethral cystoscopic procedures. These doses were calculated from patients and drugs 'characteristic risk factors that interfered with intrathecal drugs spread as weight, height, age, volume, and baricity. Various doses of fentanyl were also added to increase potency of block as necessary except the oldest group. MATERIAL AND METHOD: One hundred fifty two ASA I-III adult patients, of both sexes, aged 19 to 80 years, and scheduledfor elective transurethral cystoscopic surgery, were allocated into four groups of age and doses (formulated by earlier studies and the authors' own experiences). Group I was the 16 to 59-years-old, n=32, and received [0.5% hyperbaric bupivacaine in ml (= 5/4 body surface area) + 12.5 mcgfentanyl]. Group 2 was the 60 to 70-years-old group, n=65, and received [0.5% hyperbaric bupivacaine in ml (= I body surface area) + 10 mcgfentanyl]. Group 3 was the 71 to 75-years-old group, n=35, and received[0.5% hyperbaric bupivacaine in ml (= 3/4 body surface area) + 7.5 mcgfentanyl]. Finally, group 4 was the >75 years old, n=20, and received [0.5% hyperbaric bupivacaine in ml (= 3/4 body surface area) without fentanyl]. The statistical analysis included hemodynamic parameters and side effects. Post-hoc analysis was done using ANOVA among the four groups and logistic regression to find any association with successful outcomes. RESULTS: Eighty-eight percent of the blocks were successful without analgesic supplements (VAS <2). The mean onset time (sensation loss to T10) of patients started at 5.4 +/- 1.4 minutes, time to regress to T11 (expected duration of operable time) was 119.7 +/- 37.9 (45-255) minutes, time to leg up (expected ready to discharge) 132 +/- 39 (65-250) minutes. Hypotension was strikingly low in the study (8%), while bradycardia was 16%, similar to other reports. The other side effects were pruritus 2%, nausea 7%, and vomiting 1%. Total successful without any supplement was 87.5% but increase to 93.4% with low dose of fentanyl <50 mcg intravenously. The formulas predicted less successful blocks for the oldest age groups that LA dose less than 1 BSA, and fentanyl added had a significant weight on the outcomes (OR 1.2635, 95% CI 1.0719-1.4894). CONCLUSION: Age and body surface area guided spinal anesthesia is safe. The dose of bupivacaine is lower when combined with fentanyl. Furthermore, hemodynamic stability is better. The technique is suitable for transurethral procedure within 60 minutes but not in longer operation time. Additionally, it needs patients' cooperation due to less potent of motor and pressure sensation block. PMID- 22919989 TI - A comparative study in efficacy and safety of 0.1% tacrolimus and 0.05% clobetasol propionate ointment in discoid lupus erythematosus by modified cutaneous lupus erythematosus disease area and severity index. AB - OBJECTIVE: To compare the efficacy and safety between 0.1% Tacrolimus ointment twice a day and 0.05% clobetasol propionate. MATERIAL AND METHOD: Twenty-one Thai patients 18 to 60 years old with DLE lesions on both right and left sides of the body, without SLE, were included in the present study. Each patient was randomly allocated to determine the use of one side for twice-daily 0.1% topical tacrolimus ointment and the other side for once-daily 0.05% clobetasol propionate ointment for six weeks. Clinical outcomes were evaluated by modified cutaneous lupus erythematosus disease area and severity index (CLASI) and global assessment score for patient efficacy evaluation. RESULTS: Disease activity score were significantly decreased from baseline in both groups but clobetasol had better efficacy (p < 0.05). No significant change in disease damage score between the two groups. Both drugs were well tolerated. Transient pruritus and burning sensation were found in the tacrolimus group. Telangiectasia and acneiform eruption were found in the clobetasol group. CONCLUSION: The present study proved the efficacy of twice-daily tacrolimus and once-daily clobetasol treatment for DLE lesion. Clobetasol has significantly higher efficacy and tacrolimus may be an alternative treatment. PMID- 22919990 TI - Renal vascular variants in living related renal donors: evaluation with CT angiography. AB - BACKGROUND: Renal vascular variants may complicate the surgical techniques of living related renal transplantation. Renal computed tomographic (CT) angiography is now well accepted for preoperative renal vascular mapping in living related renal donors. OBJECTIVE: To study the prevalence of renal vascular variants in living related renal donors using CT angiography. MATERIAL AND METHOD: Preoperative renal CT angiography of 65 consecutive living related renal donors were retrospectively reviewed by two abdominal radiologists on a 3-D workstation. The number and branching patterns of bilateral renal arteries and veins, as well as the presence of renal arterial and venous variants were described. RESULTS: Supernumerary renal arteries and early branching were present in 18.5% and 12.8% respectively on the right kidneys and 27.7% and 22.4% respectively on the left kidneys. The prevalence of precaval right renal artery was 4.6%. Supernumerary renal veins were present in 35.4% and 1.5% on the right and left kidneys, respectively. Late confluences of left renal veins were identified in 1.5% of left kidneys. Other venous anomalies included 1.5% duplicated inferior vena cava (IVC), 1.5% circumaortic left renal vein, 1.5% retroaortic left renal vein, 1.5% outsized left gonadal veins drained into the left renal vein, and 6.2% right gonadal vein drained into the right renal vein. CONCLUSION: Renal vascular anatomical variants were common. The surgeons and the radiologists should be aware of these variants to prevent postoperative complications. PMID- 22919991 TI - The usage of proton magnetic resonance spectroscopy in Parkinson's disease. AB - BACKGROUND: Parkinson's disease is a degenerative disorder of the central nervous system resulting from neuronal loss in the substantia nigra (a region of the mid brain) and BSG. Proton magnetic resonance spectroscopy (1H-MRS) has been previously performed in Parkinson's disease (PD) to evaluate in vivo concentration of basal ganglia (BSG) and cerebral cortex metabolites. However this technique has never been used to evaluate the substantia nigra (SN) in PD patients. In this preliminary report, single voxel MRS of BSG and SN was performed in PD and normal control (non-PD) to evaluate the usage of MRS in PD patients. MATERIAL AND METHOD: Seventeen PD patients including 12 men and five women with a mean age 60.5 years (SD 9.4) and a mean duration of the disease 5.9 years (SD 4.2) based on Hoehn & Yahr stage I to III, and 14 healthy age-matched controls including eight men and six women with a mean age 55.5 years (SD 5.8) were enrolled. Patients with evidence of brain atrophy and cognitive impairment were excluded. RESULTS: A significant reduction in the NAA/Cr ratio was observed in the SN ofPD compared with controls (p < 0.05). BSG spectra did not allow any evaluation due to the presence of artifacts related to inorganic paramagnetic substances. CONCLUSION: 1H-MRS could be used as a sensitive tool for studying neuronal dysfunction in SN of PD patients and may be a useful technique to monitor the disease. The SN reduction of NAA/Cr ratio in PD patients may be the marker of neuronal loss in SN of patients with PD. PMID- 22919992 TI - Transrectal ultrasound (TRUS) findings of the prostate gland in late onset hypogonadism with testosterone supplementation in correlation with clinical outcome. AB - OBJECTIVE: To determine the TRUS findings of the prostate and correlation of ultrasoundfindings with clinical outcomes in late-onset hypogonadal (LOH) men with testosterone supplementation. MATERIAL AND METHOD: Between January 2007 and September 2010, TRUS findings and clinical outcomes of 16 from 226 subjects were studied The demographic data, ultrasound parameters as prostate volume and vascularity, and clinical parameters were evaluated Correlation between ultrasound and clinical parameters were analyzed using Pearson correlation analysis. RESULTS: During mean time follow-up of 6.48 months, the volume of the central gland (CG) significantly increased (p = 0.02), the volume of the total gland (TG) increased, and the volume of the peripheral zone (PZ) slightly decreased. The vascularity of the TG, CG, and PZ were significantly increased. The periurethral region vascularity was not significantly increased (p = 0.06), whereas total serum testosterone, prostate specific antigen (PSA), and PSA density were increased The International Prostate Symptom Score (IPSS) was significantly decreased (p < 0.001). There was a significant correlation between increased prostate volume and increased serum PSA. CONCLUSION: Testosterone supplementation in LOH men was found to cause an increase in TG volume during the first six months. The preferentially increased CG volume and prostatic vascularity might be due to exogenous testosterone. The authors observed a significantly increased PSA with a strong correlation between serum PSA and prostate volume. PMID- 22919993 TI - Successful management of methicillin-resistant Staphylococcus aureus bacteremia unresponsive to Vancomycin by adding fosfomycin: a case report. AB - BACKGROUND: Vancomycin is the drug of choice for the treatment of methicillin resistant Staphylococcus aureus (MRSA) bacteremia. However, vancomycin treatment failures are occasionally observed with some strains that are considered susceptible to vancomycin according to Clinical and Laboratory Standards Institute breakpoints (vancomycin minimum inhibitory concentration [MIC] < or =2 microg/mL). Although fosfomycin has in vitro activity against MRSA, clinical data regarding the use of fosfomycin either alone or in combination for the management of MRSA bacteremia is limited. CASE REPORT: A 57-year-old woman who was on regular hemodialysis for chronic kidney disease presented with sepsis associated with possible infection of arteriovenous fistula. Blood culture grew MRSA with vancomycin MIC of 1.5 microg/mL. Despite placement of a double-lumen catheter for hemodialysis and treatment with vancomycin and serum concentrations monitoring to keep trough levels of 15 to 20 microg/mL, her blood cultures still continued to grow MRSA for over 10 days. Later intravenous fosfomycin was added to the regimen along with vancomycin. After three days of this combination, suppression of bacteremia was achieved. CONCLUSION: Combination of fosfomycin and vancomycin might be another option for the treatment of bacteremia due to MRSA with vancomycin MIC of 1.5 microg/mL that is not responsive to vancomycin alone. PMID- 22919994 TI - A 13-year-old female with Xp11.2 translocation renal cell carcinoma; the first case diagnosed at Siriraj Hospital. AB - Xp11.2 translocation renal cell carcinomas are rare tumors characterized by translocations involving chromosome Xp11.2. These tumors are predominantly reported in pediatric patients. The authors report Xp11.2 translocation renal cell carcinoma in a 13-year-old girl who presented with asymptomatic palpable right renal mass. Right radical nephrectomy was performed and revealed a well defined solid mass at the lower pole of the kidney. Microscopically, the tumor was composed of sheets and nests of clear to pale eosinophilic cells with some alveolar growth pattern. Psammoma bodies were detected. Immunohistochemically, the tumor cells marked with TFE3, focally marked with smooth muscle actin, HMB 45, CD68, progesterone receptor (PR) and CD10 but did not mark with epithelial markers (AE1/AE3, EMA and CAM5.2), vimentin, S-100 and p53. The presence of psammoma bodies is an important diagnostic clue for these tumors. Cytogenetic study and/or immunohistochemistry for TFE3 protein are needed for confirming the diagnosis. Currently, surgery seems to be the most effective therapy Pediatric patients with these tumors are believed to have a favorable prognosis. PMID- 22919995 TI - Bullous systemic lupus erythematosus induced by UVB: report a case. AB - Bullous systemic lupus erythematosus (BSLE) is a rare blistering disease that dramatically responds to dapsone administration without leaving any scar. Generally, those patients with BSLE meet the criteria for systemic lupus erythematosus, but some have a widespread vesiculobullous eruption only as an initial manifestation without any specific clinical or laboratory findings that fulfill the American College of Rheumatology diagnostic criteria for SLE. The authors report here a middle-aged female patient, whose diagnosis of BSLE was suspected at first from the characteristic vesiculobullous eruption, histopathology, immunofluorescent pattern, and positive antinuclear antibody, who was later confirmed to have UVB photosensitivity that induced the typical skin lesions. PMID- 22919996 TI - Serum soluble OX40 in patients with amyotrophic lateral sclerosis. AB - Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease. Data from the literature show that systemic immune activation plays a role in ALS. OX40 (CD134) is member of the tumor necrosis factor receptor family and is expressed selectively on activated T lymphocytes. The aim of the study was to measure serum soluble OX40 (sOX40) levels in patients with ALS. The study included 25 ALS patients and 15 control subjects. Serum sOX40 levels were determined by the enzyme-linked immunosorbent method. Study showed that sOX40 levels were significantly decreased in serum of ALS patients compared with controls (P=0.05). There was no significant correlation between serum sOX40 levels and clinical parameters ofALS such as severity of the ALS patient clinical state and duration of the disease (P>0.05). In conclusion, decrease in serum sOX40 levels in patients with ALS suggests that this cytokine may be implicated in the pathomechanisms of this disease. PMID- 22919997 TI - Effects of nitrogen dioxide and meteorological conditions on the number of patients presenting to emergency department. AB - In recent years, there is ever more awareness about the impact of polluted air on the incidence of acute and chronic cardiac disease. The aim of this study was to evaluate the correlation of certain meteorological factors, NO2 concentration in the air and number of patients presenting to Emergency Department of Internal Medicine, Sestre milosrdnice University Hospital Center (ED), during a two-year period, with special reference to the incidence of patients with a cardiac referral diagnosis according to the International Classification of Diseases (ICD 10). The total number of patients was 44,245, of which 12,946 with a cardiac referral diagnosis. Meteorological parameters (temperature and air pressure) during the warm and cool periods of the year and NO2 concentrations during the study period were recorded. Study results showed the total number of patients presenting to ED to be greatest in summer, while the number of cardiac patients was highest in winter. There was positive correlation between the number of ED patients with cardiac referral diagnosis and increasing NO2 concentrations in the air. Despite the fact that the highest concentrations of NO2 were recorded in the cool period of the year when there were more traffic jams, the influence of the air NO2 concentration on the number of patients with cardiac diagnoses was statistically most significant in the warm period of the year when the slightest increase in the concentration of NO2 in the air significantly increased the number of cardiac patients presenting to ED. These results indicate the need for further research of the importance of photochemical processes and their impact on cardiovascular patients. PMID- 22919998 TI - Analysis of blood pressure changes in patients undergoing total hip or knee replacement in spinal and general anesthesia. AB - The aim of this study was to analyze hemodynamic changes in hypertensive and normotensive patients undergoing total hip or knee replacement in spinal and general anesthesia. Eighty patients who underwent total hip or knee replacement surgery in the period between July 2010 and February 2011 at Sveti Duh University Hospital were retrospectively evaluated. Seventeen patients underwent the operation in general anesthesia and 63 patients in regional anesthesia. They were allocated into groups of normotensive (n=24) or hypertensive patients (n=56). The anthropologic and hematologic parameters of normotensive and hypertensive patients were compared, as well as their blood pressures immediately before and during the operation. Blood pressure immediately before anesthesia induction, the highest and the lowest intraoperative blood pressures were recorded. Blood pressure immediately before anesthesia induction was significantly higher in hypertensive patients who underwent the operation in regional anesthesia compared to normotensive patients (158.48 mm Hg vs. 144.71 mm Hg, P<0.01). The highest intraoperative systolic blood pressure was also significantly higher in hypertensive patients operated on in regional anesthesia compared to normotensive patients (161.20 mm Hg vs. 146.76 mm Hg, P<0.01). The difference between the highest and the lowest intraoperative systolic blood pressure was significantly greater in hypertensive patients undergoing the operation in regional anesthesia compared to normotensive patients (46.41 mm Hg vs. 35.88 mm Hg, P<0.05). The results presented in this paper indicate that the fluctuations of intraoperative blood pressure were greater and the highest intraoperative systolic blood pressure was higher in hypertensive compared to normotensive patients undergoing the operation in regional anesthesia. In our study, there were no significant differences in intraoperative blood pressure between hypertensive and normotensive patients who underwent the operation in general anesthesia. PMID- 22919999 TI - Connection between inflammatory markers, antidepressants and depression. AB - The aim of this study was to explore the role of inflammatory markers in the occurrence of depression. The concentrations of inflammatory markers were analyzed in the groups of healthy subjects and subjects with major depressive disorder (MDD) initially and after one-month antidepressant therapy in the latter. The intention was to demonstrate the role of inflammatory markers in the development of MDD by differences in their concentrations and to explain the mechanism of depression development. This would help us expand our understanding of the occurrence of depression and enable introduction of some new methods in the treatment and diagnosis of depression. Study results showed a statistically significant difference in the concentrations of inflammatory markers (C-reactive protein (CRP), interleukin-6 and tumor necrosis factor alpha) between the group of MDD subjects and control group of healthy subjects. These concentrations were higher in MDD subjects. A statistically significant difference was also found in CRP concentration before and after antidepressant therapy administered to MDD patients, i.e. it was lower after antidepressant therapy. Study results pointed to the efficacy of antidepressant therapy for depression by reducing the concentration of this inflammatory marker. PMID- 22920000 TI - The role of nm23 gene in colorectal carcinogenesis. AB - The aim of this study was to investigate the correlation of immunohistochemical expression of nm23 gene in colorectal cancer cells with tumor stage according to Dukes, tumor differentiation, occurrence of distant metastases and patient survival. This retrospective study included 100 colorectal cancer patients who underwent surgical treatment. Both pathological and clinical data were analyzed according to sex, age, immunohistochemical expression of nm23, tumor stage, tumor differentiation, occurrence of distant metastases and patient survival. Overexpression of nm23 gene was related to both good tumor differentiation and Dukes' stage A, whereas no significant correlation was found between the occurrence of metastases and nm23 gene expression. There was no significant correlation between nm23 gene expression and 5-year survival of colorectal cancer patients either. Although the results of this study suggested that higher expression of nm23 gene correlated with an early stage of tumor and its good differentiation, this parameter cannot yet be taken as an independent and reliable prognostic indicator in colorectal cancer. PMID- 22920001 TI - All-inside arthroscopic suturing technique for meniscal ruptures. AB - The most frequent indication for surgical treatment of the knee is lesion of the meniscus. The "all inside" arthroscopic technique with bioresorptive material for meniscus lesion is becoming the most popular treatment. This prospective study included 10 patients with posterior meniscal horn lesion operatively treated at Sports Traumatology Department. The "all inside" technique was performed by intra articular application of bioresorptive pins-Darts sticks or Meniscus Viper and bioresorptive string. Patients were followed up for 2-6 months postoperatively and graded according to the IKDC 2000 scale. All surgical treatments showed satisfactory results. Young patients with acute longitudinal peripheral lesion posterior horn lesions, in the red-red or red-white meniscal zone, 1-2 centimeters long are most appropriate for this type of treatment. In these patients, this technique proved to be superior and free from the risk of neurovascular damage. For better authentication of this conclusion, additional prospective randomized studies should be performed. PMID- 22920002 TI - Phacoemulsification in eyes with posterior polar cataract. AB - The aim of the study was to evaluate the results of phacoemulsification in eyes with posterior polar cataract and to assess the risk factors for posterior capsular rupture during phaco surgery. This prospective study included 13 patients (14 eyes) undergoing phacoemulsification surgery with intraocular lens implantation. Intact posterior capsule was present in 10 (71.5%) eyes, posterior capsular rupture in 4 (28.5%) eyes, one of them with vitreal loss and requiring anterior vitrectomy. Of the eyes with intact posterior capsule, 5 (35%) had capsular plaque which was removed by gentle aspiration; in one case posterior capsulorrhexis was performed to remove the plaque; and postoperative capsule was clear in 4 (28.5%) eyes. In 3 eyes with capsular rupture, there was soft nucleus and capsular opacification greater than 3 mm in diameter, and the patients were under 40 years old. One capsular rupture occurred in dense cataract. The incidence of posterior capsular rupture in our study was 28.5%; other authors reported the incidence between 7.1% and 36%. Many different techniques have been described by other surgeons to avoid capsular rupture; however, in our opinion, posterior capsular rupture could not be avoided in some cases. In our study, the risk factors for capsular rupture in posterior polar cataract were soft nucleus with large capsular opacification and younger patient age. Our results of visual acuity after phacoemulsification in posterior polar cataracts are consistent with those reported by other authors: in 9 eyes, visual acuity was 0.8 or more (Snellen chart), and in 5 eyes there was no satisfactory improvement of visual acuity, probably due to amblyopia because the majority of the cataracts were unilateral. Accordingly, phacoemulsification in posterior polar cataracts, when done carefully, leads to good postoperative results and good visual improvement in most cases. PMID- 22920003 TI - The importance of ambulatory blood pressure monitoring in children and adolescents. AB - The objective of this study was to present our data on ambulatory blood pressure monitoring (ABPM) in children and adolescents referred to our Department because of casual BP elevation over the 95th percentile on at least 3 visits in primary care office. ABPM studies in 139 children, 94 boys and 45 girls, mean age 14.14 (range 4-19) years, were reviewed. A total of 107 (76.98%) children had hypertension according to the ABPM criteria. Primary hypertension (PH) was diagnosed in 89 (64.03%), secondary hypertension (SH) in 18 (12.95%) and white coat hypertension (WCH) in 32 (23.02%) children. In both PH and SH groups, hypertension was predominantly systolic (60.67% and 55.56%, respectively). There was no statistically significant difference in diurnal and nocturnal systolic and diastolic blood pressure (BP) loads between PH and SH groups. The non-dipping phenomenon was detected in 49.44%, 66.66% and 40.62% of children with PH, SH and WCH, respectively. The mean pulse pressure values were 60.41, 58.58 and 52.25 mm Hg in the PH, SH and WCH groups, respectively. A statistically significant difference was found in pulse pressure values between PH and WCH (df=55, t=6.15, P<0.01) groups and between SH and WCH groups (df=31, t=3.18, P=0.001). Target organ damage was diagnosed in 16 (17.98%) children with PH and in 5 (27.78%) children with SH. None of the children with WCH had target organ damage. ABPM is indispensable for establishing the diagnosis of hypertension in children. It is the only reliable method of WCH diagnosis. PMID- 22920004 TI - Neurologic manifestations of hypereosinophilic syndrome--review of the literature. AB - Hypereosinophilic syndrome is a rare disorder of the hematopoietic system. The disease is characterized by continuously high number of eosinophils (>1.5 x 10(9)/L) for more than six months. Other possible causes of hypereosinophilia, such as allergic and parasitic diseases, malignant disease, Churg-Strauss disease and infection should be eliminated. The most common manifestations of hypereosinophilic syndrome are pulmonary, skin, gastrointestinal, cardiac difficulties and neurologic lesions. Numerous neurologic lesions have been described, in particular of the central and peripheral nervous systems. Review of the literature revealed the following to have been recorded so far: mononeuritis multiplex, sensory polyneuropathy, radiculopathy, myalgia, myositis and perimyositis, neuropathy, ataxia, paraplegia, ophthalmologic abnormalities, optic neuritis, hemiplegia-hemiparesis, spasmodic quadriplegia, seizures, meningitis, cerebral infarction, organic psychosyndrome, other mental changes, stroke, temporal arteritis, leptomeningeal dissemination, memory deficits and dysarthria. PMID- 22920005 TI - Glucose metabolism disorders in patients with acute coronary syndromes. AB - Glucose metabolism disorders in acutely ill patients include oscillations in plasma glucose concentration outside the range of reference values. These disorders include both hyperglycemia and hypoglycemia, regardless of previous diagnosis of diabetes in a particular patient. Hyperglycemia is frequent in acute patients due to the increased release of stress hormones such as catecholamines and cortisol, but also as an effect of a cascade of proinflammatory cytokines in emergencies such as acute coronary syndrome, pulmonary edema, pulmonary embolism, injuries, severe infections and sepsis. Hyperglycemia occurs often even in patients in whom diabetes was not previously diagnosed, and in diabetic patients requirement for hypoglycemic medication may be temporarily increased. Hyperglycemia in cardiac emergencies is associated with more frequent adverse major cardiovascular events and worse prognosis. Hypoglycemia occurs seldom in these patients, its origin is almost always iatrogenic, and it worsens the patient's prognosis even more than moderate hyperglycemia. Good regulation of glycemia is necessary in the management of these patients; therefore plasma glucose determination and close monitoring are obligatory, and therapy with short acting insulin should be introduced if plasma glucose concentration exceeds 10 mmol/L, regardless of the risk of hypoglycemia. It is also useful to determine the acid-base status and blood or urine ketones. PMID- 22920006 TI - Secondary arterio-enteric fistula: case report and review of the literature. AB - Arterio-enteric fistula is a rare, but potentially deadly cause of gastrointestinal bleeding. The disease occurs in two forms: primary as a result of atherosclerotic aortic aneurysm, aortitis, trauma, radiation, tumor invasion or penetrating ulcer, and secondary as a consequence of surgical aortal reconstruction. The clinical manifestation is mostly gastrointestinal bleeding, rarely back pain, fever and sepsis. Computed tomography with contrast medium is the most suitable diagnostic test, however, the diagnosis frequently requires explorative laparotomy. A case is presented of secondary arterio-enteric fistula, found two years after surgical treatment of chronic pancreatitis with pseudocystojejunostomy, which clinically manifested with gastrointestinal bleeding. Although there was strong suspicion of arterio-enteric fistula, the diagnosis was not verified by routine workup, but only on explorative laparotomy. PMID- 22920007 TI - Primary bilateral iliopsoas abscess in an elderly man. AB - Primary bilateral iliopsoas abscesses in the elderly are very rare in Europe. We report a case of an elderly male misdiagnosed with rheumatic low back pain. The delay in accurate diagnosis and therapy led to severe worsening of his general condition and septic shock. The diagnosis was established by multi-slice computed tomography (MSCT) and the patient was successfully treated by MSCT-guided percutaneous drainage of both psoas muscles. Septic shock and miscellaneous complications required continuous intensive care. The patient was discharged after 42 days of hospital treatment. Antibiotic therapy continued for the next six weeks until his complete recovery. Pain remains the most frequent and predominant symptom of spinal pathology regardless of the etiology. Immunocompromised patients or signs suggestive of bacterial infection require caution and a more comprehensive diagnostic work-up. PMID- 22920008 TI - Sporadic Creutzfeldt-Jakob disease in a patient with episodes of nonconvulsive status epilepticus: case report. AB - Creutzfeldt-Jakob disease is the most common form of human prion diseases. A 57 year-old woman was transferred to our Department from a local hospital, where she had been treated for two weeks due to consciousness disorders and convulsive epileptic attacks that progressed to refractory status epilepticus. Electroencephalography showed diffuse spike-wave complex discharges and development of nonconvulsive status epilepticus. The causes of metabolic encephalopathy and paraneoplastic syndrome were ruled out. A combination of clinical features and findings of diagnostic procedures including electroencephalography, biomarkers in the cerebrospinal fluid and magnetic resonance imaging suggested with great probability that the patient was affected with sporadic Creutzfeldt-Jakob disease. PMID- 22920009 TI - Orthostatic intolerance: postural orthostatic tachycardia syndrome with overlapping vasovagal syncope. AB - A 28-year-old female with a history of situational syncope and a new-onset right sided hemiparesis is described. Tilt-up table test revealed the postural orthostatic tachycardia syndrome followed by vasovagal syncope. Neurological and internal medicine tests showed no particular disorders. The patient underwent autonomic physical training and the tilt-up test performed three months later showed improvement of the autonomic system in terms of lower heart beat rate of the postural orthostatic tachycardia syndrome and longer duration of the test. This case report describes longstanding idiopathic dysautonomia that can be improved by nonpharmacological treatment, while reminding that this medical condition may also be the cause of syncope. PMID- 22920010 TI - Giant mixed-type liposarcoma of the mesentery: case report. AB - Primary mesenteric liposarcomas are very rare, especially when they are of mixed histologic pattern. Patient prognosis is based upon the most aggressive histologic type of liposarcoma. A case is reported of a 77-year-old man with a history of slowly increasing abdominal volume over 3 years. The diagnosis of giant intra-abdominal mass suspect of liposarcoma was confirmed by computed tomography and ultrasound scans. The patient underwent resection of 24 tumor masses weighing together 23.5 kg. The microscopic diagnosis was mixed-type liposarcoma of the mesentery. Although this type of tumor is rare, tumor tissue should be thoroughly collected and analyzed on histologic examination to reach definitive diagnosis. Recognition of the underappreciated subtype of liposarcoma is important for proper prognosis and treatment of the patient. According to our knowledge, this is the largest size of mixed-type mesenteric liposarcoma described in the English literature. PMID- 22920011 TI - Outpatient simultaneous repair of ventral and groin hernias in local anesthesia: case report. AB - Umbilical and epigastric hernias are occasionally seen in patients with groin hernias, however, there is almost no published evidence about their simultaneous repair. In a 3-year period, 10 patients were subjected to simultaneous repair of groin hernias (7 unilateral, 2 bilateral inguinal and 1 femoral) and ventral hernias (7 primary, 2 recurrent umbilical and 1 epigastric) with local infiltration anesthesia and intravenous sedation. The mean total bupivacaine dose was 18 (10-30) mL and mean total lidocaine dose 21 (14-30) mL. The mean time to resuming normal daily activity was 5.5 days, whereas the time to car driving was 3-7 days. The oral analgesic (naproxen sodium) requirement was 6-10 tablets for 3 5 days. Patient acceptance was excellent. Simultaneous repair of groin and ventral hernias with local anesthesia in outpatient setting is feasible and associated with a low complication rate and maximum patient comfort. PMID- 22920012 TI - Eye drops preservative as the cause of corneal band keratopathy in long-term pilocarpine hydrochloride treatment. AB - The aim is to present a patient with severe bilateral corneal complications after long-term antiglaucoma treatment with 1% pilocarpine hydrochloride (Pilokarpin, Pliva, Zagreb, Croatia) and its management. A patient with narrow-angle glaucoma treated with 1% topical pilocarpine hydrochloride eye drops for the last twenty years complained of impaired vision, intermittent visual haloes and eye redness. Ophthalmologic examination showed bilateral band keratopathy, peripheral laser iridotomy, medicamentous myosis, brown nuclear cataract, and synchysis scintillans of his right eye. Band keratopathy was thought to have resulted from the presence of the preservative phenylmercuric nitrate in the pilocarpine hydrochloride eye drops. Treatment of the patient consisted of two separate procedures for both eyes, i.e. phaco trabeculectomy and six months later corneal procedure including abrasion of corneal epithelium followed by removal of the superficial stromal calcium deposits by means of a 3.75% ethylenediaminetetraacetic (EDTA) solution. After phaco trabeculectomy, visual acuity was 0.8 on both eyes. Bilateral visual improvement with visual acuity 1.0 was recorded after corneal treatment with EDTA. In conclusion, one must be aware of preservative complications in long-term topical use, such as band keratopathy that can be visually incapacitating. Surgical treatment using EDTA is safe and effective treatment for band keratopathy. PMID- 22920013 TI - Tumor-like multiple sclerosis. AB - Multiple sclerosis is a chronic demyelinating disease of the central nervous system. Tumor-like manifestation of multiple sclerosis is one of the rare clinical variants and it is frequently misdiagnosed. This is a report on a 45 year-old man who presented with right-sided hemiparesis. Initial computed tomography and magnetic resonance imaging studies of the brain revealed a large hyperintense signal lesion in the left hemisphere surrounding the cerebral edema. Low grade glioma was among the likely differential diagnoses. The patient underwent surgery. Brain biopsy showed demyelination. Lumbar puncture was performed and cerebrospinal fluid was positive for intrathecal synthesis of immunoglobulins. Other findings were compatible with the unusual form of multiple sclerosis. This case report illustrates a demyelinating process mimicking tumor lesions of the brain and it is of high importance to consider the diagnosis of multiple sclerosis on differential diagnosis of a tumor-like lesion of the central nervous system. PMID- 22920014 TI - Recommendations for diagnosis and management of multiple sclerosis. AB - Multiple sclerosis (MS) is a chronic demyelinating neurologic disorder that mainly affects young individuals (aged 20 to 50 years). Approximately 85% of patients experience an initial course with relapses and remissions (relapsing remitting multiple sclerosis). Guidelines for the management of MS should be focused on three main areas: (a) the diagnosis of MS; (b) treatment of relapses; and (c) long-term preventive treatment including clinical follow up, dose adjustment, drug switch, control of therapeutic efficacy, and disease progression. Diagnosis should be established according to clinical and paraclinical criteria. Discussion on therapeutic recommendations is focused on the disease-modifying agents in acute phases and drugs for long-term treatment and symptomatic treatment. Differential diagnoses must be taken into account on making the diagnosis of MS. Therefore, diagnosis of MS should be established on clinical and radiological diagnostic criteria, cerebrospinal fluid analysis and evoked potentials. PMID- 22920015 TI - Therapeutic plasma exchange in the neurologic intensive care setting recommendation for clinical practice. AB - Therapeutic plasma exchange (TPE) is a well-established therapeutic procedure commonly used in many neurologic immune-mediated disorders. It is thought that the beneficial effects of TPE occur through elimination of pathognomonic autoantibodies, immune complexes, inflammatory mediators, complement components and cytokines, which play a crucial role in many kinds of neurologic autoimmune disease. In various neurologic disorders, randomized controlled studies have demonstrated the efficacy of TPE (e.g., in acute inflammatory demyelinating polyneuropathy (Guillain-Barre syndrome), chronic inflammatory demyelinating polyradiculoneuropathy, myasthenia gravis and paraproteinemic polyneuropathies). For these disorders, TPE is accepted as first-line therapy, either as a primary standalone treatment or in conjunction with other modes of treatment. Although widely used, the potential benefit of TPE in the treatment of acute disseminated encephalomyelitis, chronic focal encephalitis (Rasmussen's encephalitis), Lambert Eaton myasthenic syndrome, multiple sclerosis and neuromyelitis optica (Devic's disease) is less clear. For these disorders, TPE is accepted as second-line therapy, either as a standalone treatment or in conjunction with other modes of treatment. PMID- 22920016 TI - What happens next? PMID- 22920017 TI - The meaningful conversation: a leadership skill for all times. AB - Would you like to generate more referrals, improve your staff's performance, and increase patient compliance? Master the meaningful conversation. The ability to build rapport and influence others is a leadership skill that will serve you at work, at home, and at play. PMID- 22920018 TI - You must have financial office policies in place to maximize your profits: part I. AB - In summary, it is clear that A/R and collections relate to the business side of medicine and are critical to your financial success. After patient care, your focus should be on getting paid for your services and collecting what is due, having a fine-tuned billing process with all its components working in a coordinated fashion, maximizing revenue, managing patient payments and overdue accounts, and ensuring that your employees are operating in a trustworthy manner. The key to managing your A/R is to be consistent while at the same time flexible with your patients. Staff training and continuing education must be a job requirement. Setting performance and expectation standards is necessary for each and every employee. In your training sessions, which must include all providers, staff members must understand the tasks for which they are accountable and how their individual roles contribute to the success of the entire practice. Remember that the overall goal in managing your A/R is to collect what is due you on a timely basis. The longer funds are due from the patient or insurance company, the longer the practice waits for the money. In some cases, you may never receive payment, so it is critical that you have a team in place to act on collections and everyone in your practice is on the same page. Your staff must learn to work smarter, not harder, when it comes to collecting what you have earned. PMID- 22920019 TI - Competing interests in healthcare: a conflict of quality. Part II: regulations, transparency, and policy implications. AB - This research explores the association of physician conflicts of interest with quality of care. Specifically, we discuss the role of some government regulations as policy alternatives. The need for further regulation has become more apparent as improprieties in the healthcare industry have come to light. The dominating theme in current and proposed legislation, as well as institutional policies, is the idea of ensuring that conflicts of interest are transparent, thereby increasing the likelihood that appropriate relationships will be maintained between healthcare providers and industry representatives. Much of the difficulty that organizations are going to have in implementing effective policies is the resistance that will be initiated by physicians. In order to decrease the frequency of negative effects from conflicts of interest, we suggest that each organization establish a committee to create and oversee strict policies governing expectations regarding conflicts of interest. PMID- 22920020 TI - Those boring, burdensome basics. PMID- 22920021 TI - The three most effective strategies for handling patients with overdue accounts. AB - Many medical practice employees find the collections tasks assigned to them to be a source of discomfort, reluctance, and even dread. This is understandable. Talking about overdue accounts is not something most people want to do. This article focuses on the three most effective strategies that medical practice employees can use to help them feel more confident when they handle patients who have overdue accounts. It provides a sample 135-day collection program and variations of it that many medical practices use. It offers medical practice employees 10 tips to help them develop a stronger, more businesslike attitude when they approach their collection duties. It provides a list of more than 15 daily affirmations that medical practice employees can use to develop a more positive attitude about making collection calls and having one-on-one collection meetings with patients. Finally, this article presents a worst-case scenario exercise to help medical practice employees face their worst fears about collection calls and meetings and to feel more at ease when they confront patients about their debts. PMID- 22920022 TI - Would evidence-based regulation improve the practice and management of patient care? AB - The use of evidence to achieve sound medical diagnoses and optimal treatment plans is considered a standard of practice for healthcare providers. Indeed, failure to do so is prima facie evidence of malpractice. Health and medical care managers have begun espousing a similar philosophy: to make decisions that are data-driven rather than based on logic, intuition, personal preference, or last experience. Unfortunately, regulatory policies and practices in patient care are not always founded upon strong evidence. As a result, unintended consequences often surface after the passage of legislation or the adoption of policies by nongovernmental entities. These dysfunctions might be avoided if policymakers embraced evidence-based protocols commonly found throughout medicine and its management. This paper reviews the dilemmas that unfold when policy is formed without giving sufficient attention, in advance, to "hard" evidence. PMID- 22920023 TI - Transition to change. PMID- 22920024 TI - Marketing and medicine: a questionable mix. AB - Historically, medicine has been an evolving art and science. It never remains the same. Only in the past few decades has it been acceptable for doctors to market and promote their practices. This article will review the history of medical marketing and provide ethical examples of marketing that might be available to any physician, in any practice, and in any geographic location. PMID- 22920025 TI - Patient collection strategies in a high-deductible world. PMID- 22920026 TI - Emergency medicine workforce issues affect hospital efficiency. AB - Improving efficiency and quality in emergency departments is a crucial issue for hospital leaders and depends on changing physician performance. Shortages of residency-trained emergency physicians results in a need for collaborative staffing models and a continued reliance on physicians who trained in other specialties, especially family medicine. Healthcare executives need to identify the unique needs of their institutions, but also be aware of the strengths that family physicians possess in patient-centered care. PMID- 22920027 TI - Recent developments on fee disclosure, IRS survey results, cafeteria plan limit changes, and required health plan summaries. PMID- 22920028 TI - Difficulties in consummating a meaningful hospital-physician collaboration. AB - Although there is a vast literature concerning the virtues of hospital-physician collaborative efforts, their actual performance to date in the United States according to rigorous research studies is far less than impressive. Hospitals are usually the party most interested in initiating such alignments, but physicians, as they respond to a patient's clinical needs, control almost all healthcare expenditures. Discussions between the parties have the potential of creating serious conflicts, primarily because of the lack of trust between physicians and hospital executives. The most frequent issues that arise are those relating to the sharing of ambulatory care revenues and who will be responsible for various clinical operations. PMID- 22920029 TI - Maintain workplace civility by sharing the vow of personal responsibility. AB - Office gossip, power struggles, employee burnout, and short fuses are becoming more the rule than the exception in running a medical practice. The difficult conversation avoided today can turn into the lawsuit 15 years later. Managers often find it hard to confront high performers and authority figures in the workplace. In order to deal with disruptive behavior and incivility before it ruins the medical practice, practice managers should institute the four steps outlined in this article plus the Vow of Personal Responsibility to improve clarity, teamwork, and personal performance. PMID- 22920030 TI - The elephant and the chains: breaking old habits and improving practice efficiency and productivity. AB - Doctors for the most part are creatures of habit. After training, they get into a comfort zone and may find it difficult to change the way they practice medicine or conduct their business. This article will provide a metaphor using small chains holding large elephants in place as an example of physician behaviors in regards to adopting new methods and technologies for running their practices. The article will also provide examples of how to break those chains and make a medical practice more effective and efficient. PMID- 22920031 TI - In search of the "V" codes (ICD-9-CM). PMID- 22920032 TI - Optimizing your reception area. AB - Through the optimization of reception areas (waiting rooms), physicians can improve the medical experiences of their patients. A qualitative investigation identified issues relevant to improving the quality of the reception area and was used to develop a thorough questionnaire. Most patients were satisfied with accessibility, reception area conditions, and performance of doctors and nurses. The main reasons for dissatisfaction were due to remediable points. No correlations were found between patient satisfaction and age, sex, or religion. A 36-item checklist for satisfaction with reception areas is offered as a useful tool for health quality self-assessment. PMID- 22920033 TI - How a medical practice can reduce labor costs with practical technologies. AB - Medical practices are struggling financially because of continually decreasing reimbursements and increasing expenses. Staff expenses are the largest category of expenses in any medical office. In order to preserve their compensation from shrinking further, doctors must learn how to use more of the office technologies that are already at their disposal to reduce the practice's reliance on manual effort. PMID- 22920034 TI - The business of medicine: how to overcome financial obstacles and secure financing for your private practice and ancillary services business. AB - Doctors across the country who operate private medical practices are facing increasing financial obstacles, namely shrinking income as a result of rising costs and lower reimbursements. In addition, as hospitals have become overburdened many physicians have opened up private surgical centers; magnetic resonance imaging and computed tomography and positron emission tomography scanning facilities; pathology labs; colonoscopy/endoscopy suites; lithotripsy centers; and other medical businesses typically performed within the hospital. Moreover, many doctors seek loans to purchase existing practices or for their capital contribution in medical partnerships. The past decade has thus seen a significant increase in the number of doctors taking out small business loans. Indeed, banks view the healthcare industry as a large growth market. This article includes practical information, advice, and resources to help doctors to secure bank financing for their practices, ancillary services business, real estate, and equipment on the best possible market terms. PMID- 22920035 TI - Computer briefs: M-health revisited. PMID- 22920037 TI - Review of Pt-based bimetallic catalysis: from model surfaces to supported catalysts. PMID- 22920036 TI - Mapping single-cell-substrate interactions by surface plasmon resonance microscopy. AB - We report the imaging of the cell-substrate adhesion of a single cell with subcellular spatial resolution. Osmotic pressure was introduced to provide a controllable mechanical stimulation to the cell attached to a substrate, and high resolution surface plasmon resonance microscopy was used to map the response of the cell, from which local cell-substrate adhesion was determined. In addition to high spatial resolution, the approach is noninvasive and fast and allows for the continuous mapping of cell-substrate interactions and single-cell movements. PMID- 22920038 TI - A study on the luminescence and energy transfer of single-phase and color-tunable KCaY(PO4)2:Eu2+,Mn2+ phosphor for application in white-light LEDs. AB - Novel single-phased white light-emitting KCaY(PO(4))(2):Eu(2+),Mn(2+) phosphors for light-emitting diode (LED) applications were synthesized by conventional solid-state reaction. The emission hue could be controlled by tuning the Eu(2+)/Mn(2+) ratio via the energy transfer; the the emission hue of KCaY(PO(4))(2):Eu(2+),Mn(2+) varied from blue (0.1853, 0.2627) to white-light (0.3350, 0.3203) and eventually to purple (0.3919, 0.2867). The mechanism of energy transfer from a sensitizer Eu(2+) to an activator Mn(2+) in KCaY(PO(4))(2):Eu(2+),Mn(2+) phosphors was demonstrated to be an electric dipole quadrupole interaction. Combining a NUV 405-nm chip and a white-emitting KCaY(PO(4))(2):1%Eu(2+),4%Mn(2+) phosphor produced a white-light NUV LED, demonstrating CIE chromaticity coordinates of (0.314, 0.329) and a color temperature of 6507 K. PMID- 22920041 TI - Update on emerging drugs for insomnia. AB - In recent years, there has been no evidence that the problem of chronic insomnia has faded in the least in US adults; on the contrary, a recent estimate of annual lost productivity due to insomnia was $63.2 billion dollars. However, the proportion of insomniacs who are treated continues to be low, indicating the need for continued development and dissemination of effective therapies. Hypnotic drug development has arguably become more focused in recent years, particularly upon the highly anticipated novel target, the orexin (hypocretin) system. Merck's suvorexant (MK-4305) is the first compound of the so-called dual orexin receptor antagonist (DORA) class expected to be submitted for FDA approval, with a new drug application anticipated in 2012. While there has also been some new activity in the modulation of well-characterized targets with well-characterized agents, such as CNS histamine receptors with low-dose doxepin, a decades-old antidepressant and GABA(A) with sublingual zolpidem, experience with melatonin and serotonin modulators suggests that other targets also exist. Diversifying insomnia drug targets may expand possibilities for customizing hypnotic administration to individualized patient presentation and mechanistic underpinnings. In addition, it may offer improved avenues for combining medications with non-drug treatments such as cognitive behavioral therapy for insomnia (CBT-I). PMID- 22920039 TI - Crystal structure of human aurora B in complex with INCENP and VX-680. AB - We present the structure of the human Aurora B kinase domain in complex with the C-terminal Aurora-binding region of human INCENP and the Aurora kinase inhibitor VX-680. The structure unexpectedly reveals a dimeric arrangement of the Aurora B:INCENP complex, which was confirmed to exist in solution by analytical ultracentrifugation. The dimerization involves a domain swap of the activation loop, resulting in a different conformation of the DFG motif as compared to that seen in other kinase complexes with VX-680. The binding of INCENP differs significantly from that seen in the Xenopus laevis Aurora B:INCENP complex currently used as a model for structure-based design for this important oncology target. PMID- 22920042 TI - Emerging biological insights and novel treatment strategies in multiple myeloma. AB - INTRODUCTION: Survival in multiple myeloma (MM) has improved significantly in the past 10 years due to new treatments, such as thalidomide and lenalidomide (immunomodulatory drugs or IMiDs) bortezomib and advances in supportive care. Nevertheless, almost all MM patients show disease relapse and develop drug resistance. AREAS COVERED: The authors review the therapeutic approach for untreated MM patients. Furthermore, the prognostic stratification of patients and the proposed risk-adapted strategy are discussed. Finally, preclinical and clinical data regarding newer antimyeloma agents, currently undergoing examination such as proteasome inhibitors (PIs, carfilzomib), IMiDs (pomalidomide), epigenetic agents (histone deacetylase inhibitors vorinostat and panobinostat), humanized monoclonal antibodies (elotuzumab and MOR03087) and targeted therapies (inhibitors of NF-kappaB, MAPK, HSP90 and AKT) are reported. EXPERT OPINION: MM patient outcome has remarkably improved due to the use of three to four drug combination therapies including PIs and IMiDs, which target the tumor in its bone marrow microenvironment, however MM treatment remains challenging. The use of high-throughput techniques has allowed to discover new insights into MM biology. The identification of candidate therapeutic targets and availability of respective investigative agents will allow for a substantial progress in the development and implementation of personalized medicine in MM. PMID- 22920044 TI - Matching women with binge eating disorder to group treatment based on attachment anxiety: outcomes and moderating effects. AB - We hypothesized that compared to therapy groups homogeneously composed of women with binge eating disorder (BED) and low attachment anxiety, groups with high attachment anxiety would have better outcomes and a greater alliance-outcome relationship. We assigned 102 women with BED to therapy groups homogeneously composed of low attachment anxiety (n =52) or high attachment anxiety participants (n=50) who received Group Psychodynamic Interpersonal Psychotherapy (GPIP). GPIP resulted in improved outcomes with large effects. Attachment anxiety condition did not moderate outcomes. However, attachment anxiety condition did moderate the alliance-outcome relationship: i.e., group alliance growth was associated with improved binge eating only in the high attachment anxiety condition. Clinicians should be attentive to and encourage the growth of group therapy alliance especially for anxiously attached individuals. PMID- 22920045 TI - Sugarcane bagasse pretreatment using three imidazolium-based ionic liquids; mass balances and enzyme kinetics. AB - BACKGROUND: Effective pretreatment is key to achieving high enzymatic saccharification efficiency in processing lignocellulosic biomass to fermentable sugars, biofuels and value-added products. Ionic liquids (ILs), still relatively new class of solvents, are attractive for biomass pretreatment because some demonstrate the rare ability to dissolve all components of lignocellulosic biomass including highly ordered (crystalline) cellulose. In the present study, three ILs, 1-butyl-3-methylimidazolium chloride ([C4mim]Cl), 1-ethyl-3 methylimidazolium chloride ([C2mim]Cl), 1-ethyl-3-methylimidazolium acetate ([C2mim]OAc) are used to dissolve/pretreat and fractionate sugarcane bagasse. In these IL-based pretreatments the biomass is completely or partially dissolved in ILs at temperatures greater than 130 degrees C and then precipitated by the addition of an antisolvent to the IL biomass mixture. For the first time mass balances of IL-based pretreatments are reported. Such mass balances, along with kinetics data, can be used in process modelling and design. RESULTS: Lignin removals of 10% mass of lignin in bagasse with [C4mim]Cl, 50% mass with [C2mim]Cl and 60% mass with [C2mim]OAc, are achieved by limiting the amount of water added as antisolvent to 0.5 water:IL mass ratio thus minimising lignin precipitation. Enzyme saccharification (24 h, 15FPU) yields (% cellulose mass in starting bagasse) from the recovered solids rank as: [C2mim]OAc(83%) > >[C2mim]Cl(53%) = [C4mim]Cl(53%). Composition of [C2mim]OAc-treated solids such as low lignin, low acetyl group content and preservation of arabinosyl groups are characteristic of aqueous alkali pretreatments while those of chloride IL-treated solids resemble aqueous acid pretreatments. All ILs are fully recovered after use (100% mass as determined by ion chromatography). CONCLUSIONS: In all three ILs regulated addition of water as an antisolvent effected a polysaccharide enriched precipitate since some of the lignin remained dissolved in the aqueous IL solution. Of the three IL studied [C2mim]OAc gave the best saccharification yield, material recovery and delignification. The effects of [C2mim]OAc pretreatment resemble those of aqueous alkali pretreatments while those of [C2mim]Cl and [C4mim]Cl resemble aqueous acid pretreatments. The use of imidazolium IL solvents with shorter alkyl chains results in accelerated dissolution, pretreatment and degradation. PMID- 22920043 TI - Prevalence of Campylobacter spp. in skinless, boneless retail broiler meat from 2005 through 2011 in Alabama, USA. AB - BACKGROUND: The prevalence of Campylobacter spp. in 755 skinless, boneless retail broiler meat samples (breast, tenderloins and thighs) collected from food stores in Alabama, USA, from 2005 through 2011 was examined. Campylobacter spp. were isolated using enrichment and plate media. Isolates were identified with multiplex PCR assays and typed with pulsed field gel electrophoresis (PFGE). Data were analyzed by nominal variables (brand, plant, product, season, state and store) that may affect the prevalence of these bacteria. RESULTS: The average prevalence of Campylobacter spp. in retail broiler meat for these years was 41%, with no statistical differences in the prevalence by year (P > 0.05). Seasons did not affect the prevalence of C. jejuni but statistically affected the prevalence of C. coli (P < 0.05). The prevalence by brand, plant, product, state and store were different (P < 0.05). Establishments from two states had the highest prevalence (P < 0.05). C. coli and C. jejuni had an average prevalence of 28% and 66%, respectively. The prevalence of C. coli varied by brand, plant, season, state, store and year, while the prevalence of C. jejuni varied by brand, product, state and store. Tenderloins had a lower prevalence of Campylobacter spp. than breasts and thighs (P < 0.05). Although no statistical differences (P > 0.05) were observed in the prevalence of C. jejuni by season, the lowest prevalence of C. coli was recorded from October through March. A large diversity of PFGE profiles was found for C. jejuni, with some profiles from the same processing plants reappearing throughout the years. CONCLUSIONS: The prevalence of Campylobacter spp. did not change during the seven years of the study; however, it did change when analyzed by brand, product and state. Seasons did not affect the prevalence of C. jejuni, but they did affect the prevalence of C. coli. Larger PFGE databases are needed to assess the temporal reoccurrence of PFGE profiles to help predict the risk associated with each profile. PMID- 22920046 TI - Antihypertensive effects of olmesartan compared with other angiotensin receptor blockers: a meta-analysis. AB - OBJECTIVES: Angiotensin II type 1 receptor antagonists (angiotensin receptor blockers [ARBs]) have been shown to be effective and well tolerated in hypertensive patients. Olmesartan is the seventh angiotensin receptor blocker licensed by the US Food and Drug Administration. The aim of this meta-analysis was to determine the efficacy and tolerability of olmesartan medoxomil in comparison with other ARBs. DATA SOURCES: Reports of randomized controlled trials (RCTs) of olmesartan versus other ARBs were identified through a systematic search of PubMed (up to July 2010), EMBASE (1980 to July 2010), SinoMed (up to July 2010), and the Cochrane Central Register of Controlled Trials (Cochrane Library Issue 7, 2010). REVIEW METHODS: Pertinent studies were selected through extensive searches of PubMed, EMBASE, Cochrane Central Register of Controlled Trials, and SinoMed. Two of the authors abstracted data from the identified studies independently. Criteria for inclusion in our meta-analyses were randomized clinical trials in which patients were receiving an ARB and outcome data for blood pressure reduction or the incidence of adverse events were available. Quantitative and qualitative analyses of data from all RCTs meeting the criteria were performed. Our meta-analysis was undertaken according to the Quality of Reporting Meta-analyses (QUOROM) statement. RESULTS: Twenty-two studies with data from 4892 patients were considered for analyses. Olmesartan provided greater diastolic blood pressure (DBP) and systolic blood pressure (SBP) reductions compared with losartan (DBP: 95% confidence interval [CI] 0.59, 2.62; SBP: 95% CI 0.46, 5.92). Olmesartan provided greater SBP reductions compared with valsartan (95% CI 0.29, 3.16). Similar blood pressure response rates and incidence of adverse events were found with losartan, valsartan, candesartan, and irbesartan. CONCLUSION: Olmesartan provides better antihypertensive efficacy than losartan and valsartan and has no association with an increased risk of adverse events in comparison with losartan, valsartan, candesartan, and irbesartan. PMID- 22920047 TI - Anticoagulation therapy for patients with non-valvular atrial fibrillation: comparison of decision analytic model recommendations and real-world warfarin prescription use. AB - BACKGROUND: Anticoagulation in patients with atrial fibrillation (AF) is challenging because stroke-risk reduction must be balanced against increased bleeding risk. OBJECTIVE: We developed a decision model integrating both stroke and bleeding risk schemes to guide optimal use of anticoagulation in AF, and compared model recommendations with warfarin use in a real-world database. METHODS: A Markov model based on demographics, CHADS(2) (Congestive Heart Failure, Hypertension, Age of 75 years and greater, Diabetes Mellitus and History of Stroke) stroke and ATRIA (Anticoagulation and Risk Factors in Atrial Fibrillation) bleed risk scores, and anticoagulation treatment effects from clinical trials simulated health state transitions for recently diagnosed AF patients. The model recommended the treatment with greater quality-adjusted life expectancy. Model recommendations were contrasted with actual warfarin use recorded in the Thomson Reuters MarketScan database (N = 64,946). RESULTS: 74.8% (n = 48,548) of the Marketscan AF cohort had CHADS(2) >=1, of whom 14.3% had moderate/high (>=4) ATRIA bleeding risk. While the model recommended warfarin for almost all patients with CHADS(2) >=1 who are at low bleeding risk, it recommended warfarin for fewer patients as bleeding risk increased. Of the 44,611 patients recommended warfarin, 63.4% of patients were considered warfarin exposed (concordant with model recommendation), and of the 20,335 patients recommended aspirin (acetylsalicylic acid), 59.7% received warfarin (discordant with model recommendations). Actual warfarin use decreased modestly with higher stroke risk (p < 0.0001) and with higher bleeding risk (p < 0.0001). CONCLUSION: High discordance between actual warfarin use and model recommendations suggests that anticoagulation decisions are not based on systematic evaluation of stroke and bleeding risks. Model-based clinical decision aids may improve oral anticoagulation decisions by more systematically weighing bleed and stroke risk. PMID- 22920048 TI - Efficacy of olmesartan medoxomil and hydrochlorothiazide fixed-dose combination therapy in patients aged 65 years and older with stage 1 and 2 hypertension or isolated systolic hypertension. AB - BACKGROUND: The incidence of hypertension, particularly isolated systolic hypertension, increases with increasing age, as does the risk of fatal cardiovascular disease. A combination antihypertensive therapy regimen may be required to reach recommended BP goals in older patients. OBJECTIVES: This study set out to report blood pressure (BP) data in elderly patients across the subgroups of stage 1 and stage 2 hypertension (prespecified subgroup) and isolated systolic hypertension (ISH) [post hoc]. DESIGN AND SETTING: This was a subgroup analysis of a prospective, open-label study carried out in a multicenter, outpatient setting (e.g. the BeniSILVER [Benicar Efficacy: New Investigation Shows OM Treatment Increasingly Leads to Various Elderly Populations to Safe BP Reductions; ClinicalTrials.gov identifier: NCT00412932] study). The study included 176 patients with a mean age of approximately 72 years; stage 1 hypertension, 60, stage 2 hypertension, 116, and ISH, 98. INTERVENTION: After a 2- to 3-week placebo run-in period, patients were uptitrated every 3 weeks from olmesartan medoxomil (OM) 20 mg daily to OM 40 mg, OM/hydrochlorothiazide (HCTZ) 40 mg/12.5 mg, and OM/HCTZ 40 mg/25 mg, if seated cuff BP (SeBP) was >=120/70 mmHg. MEASUREMENTS: Measurements included change from baseline in mean 24-hour ambulatory BP and SeBP after 12 weeks of treatment, percentage of patients achieving a cumulative SeBP goal of <140/90 mmHg (stage 1 and stage 2 cohorts) or seated cuff systolic BP (SeSBP) goal of <140 mmHg (ISH cohort), and the incidence of adverse events (AEs). RESULTS: Combination therapy was required by 159 patients. Changes from baseline in mean 24-hour ambulatory BP (+/- standard deviation [SD]) were -24.2 (+/- 11.8)/-11.8 (+/- 6.9) mmHg, -26.5 (+/- 11.8)/-12.6 (+/- 6.7) mmHg, and -24.7 (+/- 12.5)/-11.2 (+/- 6.4) mmHg in the stage 1, stage 2, and ISH cohorts, respectively (all p < 0.001 vs baseline). Mean SeBP changes (+/- SD) from baseline in patients titrated to OM/HCTZ 40 mg/25 mg were -24.6 (+/- 11.4)/-10.5 (+/- 7.3) mmHg in the stage 1 cohort, -26.4 (+/- 17.2)/-11.3 (+/- 9.7) mmHg in the stage 2 cohort, and -21.5 (+/- 15.6)/-6.8 (+/- 7.8) mmHg in the ISH cohort (all p < 0.001). The cumulative proportions of patients achieving an SeBP goal of <140/90 mmHg by week 12 were 88.3%, 56.0%, and 72.4% in the stage 1, stage 2, and ISH cohorts, respectively, while 72.4% of patients achieved an SeSBP of <140 mmHg in the ISH cohort. Treatment-emergent AEs ranged from 32.3% to 32.8%, with <3% of patients reporting drug-related hypotension. CONCLUSION: An OM/HCTZ-based titration regimen enabled elderly patients with hypertension to safely reduce BP throughout the 24-hour dosing interval and allowed the majority of these patients to achieve a BP target of <140/90 mmHg or <140 mmHg. PMID- 22920049 TI - How do compliance, convenience, and tolerability affect blood pressure goal rates? AB - Uncontrolled hypertension imposes a substantial global health burden, and poor patient compliance with prescribed antihypertensive medication makes a major contribution to the development of suboptimal blood pressure (BP) control. The asymptomatic nature of hypertension, side effects of medication, treatment complexity, and high pill burdens all have a negative impact on patient compliance. It is important to address the issue of poor patient compliance as studies have shown that good compliance is associated with improvement of BP control and positive health outcomes. As the majority of hypertensive patients require treatment with two or more agents to achieve goal BP, treatment guidelines have acknowledged the value of simplifying treatment through the use of fixed-dose combination (FDC) therapy. Triple FDC therapy comprising an angiotensin II type 1 receptor antagonist (angiotensin receptor blocker), calcium channel blocker, and thiazide diuretic is a novel treatment strategy for the improvement of BP control in hard-to-treat patients. PMID- 22920050 TI - Genome-wide association studies on HIV susceptibility, pathogenesis and pharmacogenomics. AB - Susceptibility to HIV-1 and the clinical course after infection show a substantial heterogeneity between individuals. Part of this variability can be attributed to host genetic variation. Initial candidate gene studies have revealed interesting host factors that influence HIV infection, replication and pathogenesis. Recently, genome-wide association studies (GWAS) were utilized for unbiased searches at a genome-wide level to discover novel genetic factors and pathways involved in HIV-1 infection. This review gives an overview of findings from the GWAS performed on HIV infection, within different cohorts, with variable patient and phenotype selection. Furthermore, novel techniques and strategies in research that might contribute to the complete understanding of virus-host interactions and its role on the pathogenesis of HIV infection are discussed. PMID- 22920052 TI - Progress in overcoming barriers to influenza immunization of pregnant women. PMID- 22920051 TI - Patients with acute exacerbation of chronic obstructive pulmonary disease feel safe when treated at home: a qualitative study. AB - BACKGROUND: The design of new interventions to improve health care for patients with chronic obstructive pulmonary disease (COPD) requires knowledge about what patients with an acute exacerbation experience as important and useful. The objective of the study was to explore patients' experiences of an early discharge hospital at home (HaH) treatment programme for exacerbations in COPD. METHODS: Six exacerbated COPD patients that were randomised to receiving HaH care and three patients randomised to receiving traditional hospital care were interviewed in semi-structured in-depth interviews. Four spouses were present during the respective patients' interviews. The interviews were audio-taped, transcribed and analysed by a four-step method for systematic text condensing. RESULTS: Despite limited assistance from the health care service, the patients and their spouses experienced the HaH treatment as safe. They expressed that information that was adapted to specific situations in their daily lives and given in a familiar environment had positive impact on their self-management of COPD. CONCLUSION: The results contribute to increased knowledge and awareness about what the patients experienced as important aspects of a HaH treatment programme. How adapted input from health services can make patients with exacerbation of COPD feel safe and better able to manage their disease, is important knowledge for developing new and effective health services for patients with chronic disease. PMID- 22920053 TI - Benefits of influenza vaccination during pregnancy for pregnant women. AB - Influenza vaccination is a cornerstone of influenza prevention efforts among pregnant women. Prior to 2005, data from studies conducted on pregnant women were limited, with much of the supporting evidence coming from influenza vaccine studies conducted among nonpregnant, age-matched populations. Since 2005, however, an increasing number of studies have demonstrated the safety and immunogenicity of influenza vaccine for pregnant women, including evidence of maternal transfer of antibody. In addition, the clinical benefit of influenza vaccination, both for the mother and infant, was demonstrated in a landmark randomized clinical trial conducted in Bangladesh. Additional randomized clinical trials with laboratory-confirmed influenza as the primary outcome are underway in countries without a current influenza vaccination program, but such trials are unlikely to be conducted in the United States or other countries that already recommend the vaccination of pregnant women. However, current evidence supports the safety and immunogenicity of inactivated influenza vaccine and its effectiveness in reducing the risk of influenza-related illness among pregnant women. PMID- 22920054 TI - A review of fetal and infant protection associated with antenatal influenza immunization. AB - The well-described burden of influenza morbidity in the pregnant woman and her young infant have led to increasing interest in the use of antenatal immunization to protect both the mother and the infant. In this review, we summarize the recent data on the effect of antenatal influenza infection, and influenza immunization, on mothers and infants. Antenatal influenza immunization can improve intrauterine growth in Asia and North America and reduce preterm deliveries. Studies of the pathogenetic process of influenza infection in the mother and fetus are needed. These findings suggest the wider use of antenatal immunization should be encouraged, including in low-resource regions. Creative approaches to antenatal influenza immunization policy should be developed to provide protection to the maternal, fetal, and infant triad in temperate and tropical regions. PMID- 22920055 TI - Immunogenicity and efficacy of influenza immunization during pregnancy: recent and ongoing studies. AB - Pregnant women and young infants are at increased risk from influenza. The World Health Organization and public health guidelines from Australia, Canada, and the United States recommend immunizing pregnant women with trivalent inactivated influenza vaccine. However, there are multiple barriers to the uptake of this recommendation. Additionally, current vaccines are not licensed for infants <6 months of age. Immunizing pregnant women would provide protection to both mothers and infants. The Bill & Melinda Gates Foundation (BMGF) and the National Institute of Allergy and Infectious Diseases (NIAID) are trying to address some of the issues associated with maternal immunization, which could be an effective intervention in both high- and low-resource settings to combat the significant maternal and infant morbidity and mortality due to influenza. BMGF and NIAID efforts are complementary to each other, focusing on evaluating the immunogenicity, efficacy, and safety of influenza vaccines during pregnancy; and the potential effect of maternal immunization on outcomes in infants in low resource populations. PMID- 22920056 TI - Effects of influenza on pregnant women and infants. AB - Influenza vaccination during pregnancy has been shown to decrease the risk of influenza and its complications among pregnant women and their infants up to 6 months old. To adequately assess the benefits and potential risks that are associated with the use of influenza vaccine during pregnancy, it is necessary to examine the influenza-associated complications that occur among pregnant women and their children. Pregnant women have been shown to be at increased risk for morbidity and death with influenza illness during seasonal epidemics and pandemics. Newborn infants born to mothers with influenza during pregnancy, especially mothers with severe illness, are at increased risk of adverse outcomes, such as preterm birth and low birthweight. Infants <6 months old who experience influenza virus infection have the highest rates of hospitalization and death of all children. Here we review the risks for influenza-associated complications among pregnant women and infants <6 months old. PMID- 22920057 TI - Safety of influenza vaccines in pregnant women. AB - Prevention of influenza in pregnant women and their newborns through maternal immunization is a safe and effective intervention during seasonal epidemics and a priority during a pandemic. While influenza vaccination of pregnant women has been routine in the United States since the 1950s, coverage rates increased significantly only after the 2009 H1N1 influenza pandemic. Epidemiologic and clinical studies support the safety of inactivated influenza vaccines in pregnant women and their infants. Safety barriers to the use of vaccines during pregnancy can be addressed through research, active surveillance, and education. PMID- 22920058 TI - Safety of influenza immunization during pregnancy for the fetus and the neonate. AB - Since the 1960s, pregnant women in the United States have been recommended to receive influenza vaccine. A maternal concern about the possibility of adverse fetal and neonatal outcomes after the vaccination of pregnant women has been cited as a reason for low maternal influenza vaccination coverage. Recent research has identified benefits to the fetus and neonate after maternal influenza vaccination that have prompted efforts to increase coverage in pregnant women. There is a long history of research findings that highlight the safety of vaccinating pregnant women. This review summarizes nearly 40 years of research on influenza vaccination of pregnant women and the lack of association with adverse fetal or neonatal outcomes. Future research should focus on vaccinations that are given in the first trimester of pregnancy and on product-specific analyses to account for differences in manufacturing processes. PMID- 22920059 TI - Assessing the safety of influenza immunization during pregnancy: the Vaccine Safety Datalink. AB - The influenza vaccine can reduce maternal and neonatal morbidity and mortality and thus is recommended for all pregnant women. However, concerns regarding safety of influenza vaccine remain a barrier to vaccination. We describe ongoing analyses of influenza vaccine safety during pregnancy within the Vaccine Safety Datalink that includes the evaluation of acute events, adverse pregnancy and birth outcomes, and congenital anomalies. In addition, we highlight unique challenges and strategies for the study of vaccine safety among pregnant women with the use of large linked databases. PMID- 22920060 TI - Manufacturers' postmarketing safety surveillance of influenza vaccine exposure in pregnancy. AB - Pregnant women are at increased risk for hospitalization and death with influenza infection. The limited data on safety and effectiveness of influenza immunization in pregnancy emphasizes the importance of developing new and well-designed studies and of enhancing safety surveillance in pregnant women who are vaccinated with licensed influenza vaccines. Pregnancy exposure registries aim to collect and maintain data on the effects of marketed drugs and vaccines, when prescribed in pregnancy or during breastfeeding, on the women themselves and their children. Women who are prescribed a medication or vaccine as part of their routine clinical care can be enrolled directly or through reporting health care providers on a voluntary basis. Such registries generally are established for products that are intended for use by adolescents and adults and are a key component of the safety monitoring of licensed products. This article reviews some of the pregnancy registries that have been established for US-licensed vaccines, which includes influenza vaccines, and other postlicensure safety surveillance efforts for monitoring safety in vaccinated pregnant women. PMID- 22920061 TI - Influenza immunization during pregnancy: US regulatory perspective. AB - Maternal immunization with inactivated influenza vaccines is an important public health strategy to protect mothers and young infants from the serious complications of influenza. Although not contraindicated in pregnant women, currently US-licensed influenza vaccines are not specifically labeled for use during pregnancy. Several postmarketing initiatives are ongoing to obtain maternal and infant safety and immunogenicity data on US-licensed inactivated influenza vaccines used in pregnant women. The Food and Drug Administration is revising its pregnancy labeling regulations to improve the characterization and communication of risks of drugs and biologics used during pregnancy. To obtain a specifically labeled indication for use of an influenza vaccine during pregnancy, adequate and well-controlled prelicensure studies are needed to obtain data on the product's safety and effectiveness and to demonstrate protection of the mother and/or infant against influenza illness. PMID- 22920062 TI - Liability and maternal immunization: in utero injury claims in the VICP. AB - Generally, under the National Childhood Vaccine Injury Act of 1986 (Vaccine Act), vaccine administrators and manufacturers are shielded from medical malpractice or products liability actions stemming from vaccine-related injuries and deaths. That said, as generous as these protections may be, they have boundaries, some of which are clear and others of which are unsettled. This is particularly so for in utero injuries stemming from immunization of pregnant women. The issue of whether in utero injuries are afforded such protections, vis a vis compensation by the National Vaccine Injury Compensation Program (VICP) under the Vaccine Act, has not definitively been resolved by the courts. Short of a decision by the Court of Appeals for the Federal Circuit or a statutory amendment by Congress specifically addressing this issue, the uncertainty remains. PMID- 22920063 TI - Influenza immunization in pregnancy: overcoming patient and health care provider barriers. AB - Seasonal influenza imparts disproportionate morbidity and death to pregnant women. Immunization against influenza is the most effective intervention to mitigate the burden of influenza disease during pregnancy; nevertheless, immunization rates remain suboptimal in this patient population. Therefore, there is a clear need for strategies to optimize influenza vaccination among pregnant women. We reviewed potential patient and health care provider barriers to influenza immunization and propose effective strategies for overcoming them. PMID- 22920064 TI - Programmatic and research priorities for improving influenza immunization of pregnant women. AB - Despite evidence regarding the benefits of influenza immunization during pregnancy for both the pregnant woman and her infant, as well as reassuring safety data, influenza vaccination rates in pregnancy have lagged. The 2009 influenza pandemic was accompanied by increased maternal vaccination rates. In this article, we review programmatic and research priorities with regard to overcoming barriers to influenza immunization of pregnant women. PMID- 22920065 TI - Monitoring seasonal influenza vaccination coverage among pregnant women in the United States. AB - This report describes surveillance systems used for assessing influenza vaccination coverage among pregnant women in the United States. Coverage estimates and factors associated with maternal vaccination are reviewed for internet panel surveys of pregnant women and the Pregnancy Risk Assessment Monitoring System (PRAMS); new estimates are reported from the Behavioral Risk Factor Surveillance System (BRFSS) and Internet panel surveys. Influenza vaccination coverage among pregnant women improved from 11% during the 2001-2002 influenza season to approximately 38% measured by BRFSS and 50% measured by Internet panel surveys during the 2010-2011 influenza season. Coverage varied by state, ranging from 26% to 68% among the states participating in PRAMS in 2009 2010. Provider recommendation increased a woman's likelihood of vaccination nearly 6-fold. Despite increases in influenza vaccination coverage among pregnant women, approximately half remain unvaccinated. Continued efforts are needed to ensure pregnant women receive recommendations and offers of vaccination from their health care providers. PMID- 22920066 TI - Type III hereditary angioedema: defined, but not understood. PMID- 22920067 TI - Is nerve growth factor involved in the symptoms of rhinitis? PMID- 22920068 TI - Biomarkers for eosinophilic esophagitis: a review. AB - BACKGROUND: The complex pathophysiology of eosinophilic esophagitis (EoE) provides several candidate biomarkers that could be used to establish diagnosis, assess response to therapy, and document disease recurrence. OBJECTIVE: To review the literature on various biomarkers of EoE, with respect to their correlation to disease activity and response to treatment. DATA SOURCES: A literature search was performed using PubMed and OVID with keyword combinations of EoE and various potential biomarkers. STUDY SELECTIONS: Between 2006 and 2012, 26 studies that investigated the correlation of various tissue and serum biomarkers with EoE were identified. RESULTS: The markers investigated included eotaxins-1,-2, and -3, interleukin-5 (IL-5), interleukin-13 (IL-13), eosinophil-derived neurotoxin, mast cell markers, absolute eosinophil count, and micro-RNAs. Several studies have shown a positive correlation between eotaxin-3, IL-5, and IL-13 messenger RNA (mRNA) expression in esophageal tissue and disease activity. Eotaxin-3 mRNA staining was found to have 89% sensitivity for diagnosing EoE. Staining for mast cells and their products has also shown promise. More recently, a microRNA signature that can potentially distinguish EoE from non-EoE esophagitis has been identified. CONCLUSION: The studies are quite heterogeneous with respect to their methodology and the biomarker(s) studied, but most have investigated tissue biomarkers. Eotaxin-3 and IL-13 have emerged as the most promising ones with respect to sensitivity and degree of positive correlation to disease process. Future research on biomarkers for EoE should include longitudinal studies, establishment of normal values, effects of concomitant atopic diseases, age and gender, and validation of methodology of the tests. PMID- 22920069 TI - Latex immunotherapy: state of the art. AB - OBJECTIVE: Latex allergy remains a significant problem, especially among certain professional categories, and specific immunotherapy has been suggested as a suitable therapeutic option. The objective of the this article is to review the available literature on clinical trials of specific immunotherapy in latex allergy. DATA SOURCES: Literature databases (PubMed, Embase, Google Scholar) were searched for latex immunotherapy clinical trials. STUDY SELECTIONS: Clinical trials (either open or randomized controlled) using subcutaneous or sublingual immunotherapy with latex extracts were selected. Only articles published in English in peer-reviewed journals were considered. Case reports quoted in the clinical trials were also described, when pertinent. RESULTS: Eleven clinical trials (3 with subcutaneous and 8 with sublingual immunotherapy) were identified. Two of the 3 randomized trials of subcutaneous immunotherapy reported some benefit in adults but a remarkable occurrence of side effects. Concerning sublingual immunotherapy (SLIT), there were 6 randomized placebo-controlled (1 in children), 1 randomized open, and 1 open trials. All but 1 trial reported positive results, and the safety profile was overall superior to injection immunotherapy. The overall quality of the study was moderate, and the number of subjects studied was low. CONCLUSION: Although guidelines do not consider allergy to latex as an accepted indication to desensitization, SLIT can be offered, in addition to symptomatic treatment, to selected patients, when avoidance measures are not feasible or effective. PMID- 22920070 TI - Climate change and allergic diseases. PMID- 22920071 TI - Clinical characteristics of chronic rhinitis patients with high vs low irritant trigger burdens. AB - BACKGROUND: Patients with chronic allergic rhinitis (AR) and nonallergic rhinitis (NAR) often experience irritant-induced symptoms. The clinical relevance of the magnitude of their symptoms in response to these nonspecific stimuli remains unclear. OBJECTIVE: To determine the internal consistency and validity of an irritant index questionnaire (IIQ) and whether reclassification of physician diagnosed rhinitis subtypes based on IIQ scores results in rhinitis subtypes with different clinical characteristics. METHODS: Patients 18 to 65 years old with physician-diagnosed AR (n = 404), mixed rhinitis (MR; n = 129), or NAR (n = 123) completed an IIQ that rated rhinitis symptom severity in response to 21 nonallergic irritant triggers on a 1- to 10-point scale. Multistage sex-specific statistical analyses were performed using IIQ responses to reclassify physician diagnosed AR, MR, and NAR into categories with high and low irritant burdens. RESULTS: The IIQ demonstrated good internal consistency and cross-validation. After reclassification, 48% and 52% of patients with physician-diagnosed AR patients (n = 533) were categorized as having low-burden AR and high-burden AR, respectively, whereas 64% and 36% of NAR (n = 123) patients were categorized as having low-burden NAR and high-burden NAR, respectively. Reclassified high-burden AR and high-burden NAR patients were more likely to have a physician diagnosis of asthma and a greater number of self-reported rhinitis symptoms and perennial symptoms with seasonal exacerbations than reclassified low-burden AR and low burden NAR patients, respectively (P < .01). CONCLUSION: The IIQ resulted in significant reclassification of physician-diagnosed rhinitis patients into different diagnostic categories with unique clinical characteristics. Further studies are necessary to confirm the IIQ's utility as a tool for characterizing rhinitis patients in clinical practice and research. PMID- 22920072 TI - The association between language proficiency and outcomes of elderly patients with asthma. AB - BACKGROUND: Asthma is a growing cause of morbidity for elderly Americans and is highly prevalent among Hispanic people in the United States. The inability to speak English poses a barrier to patient-provider communication. OBJECTIVE: To evaluate associations between limited English proficiency, asthma self management, and outcomes in elderly Hispanic patients. METHOD: Elderly patients with asthma receiving primary care at clinics in New York City and Chicago were studied. RESULTS: Of 268 patients in the study, 68% were non-Hispanic, 18% English-proficient Hispanic, and 14% Hispanic with limited English proficiency. Unadjusted analyses showed that Hispanic persons with limited English proficiency had worse asthma control (P = .0007), increased likelihood of inpatient visits (P = .002), and poorer quality of life (P < .0001). We also found significant associations between limited English proficiency and poorer medication adherence (P = .006). Similar results were obtained in multiple regression analyses adjusting for demographics, asthma history, comorbidities, depression, and health literacy. CONCLUSION: Limited English proficiency was associated with poorer self management and worse outcomes among elderly patients with asthma. Further understanding of mechanisms underlying this relationship is necessary to develop interventions that improve asthma outcomes in this vulnerable population. PMID- 22920073 TI - Are we overlooking persistent small airways dysfunction in community-managed asthma? AB - BACKGROUND: Whether small airways dysfunction persists in patients with asthma receiving standard community treatment is unknown. Impulse oscillometry (IOS) is a sensitive measure of small airways function. OBJECTIVE: To assess the degree of small airways dysfunction in a cross-section of patients with community-managed asthma. METHODS: We analyzed primary care referral data from patients with persistent asthma (n = 378) receiving standard community therapy, screened using spirometry and IOS. We compared patients by British Thoracic Society asthma treatment step (2-4). RESULTS: Step 2 patients were not different from step 3 patients receiving long-acting beta-agonist (LABA). Step 4 patients differed from step 2 by: higher inhaled corticosteroid (ICS) dose (P < .0001); lower forced expiratory volume in 1 second (FEV(1)%; P = .02) and forced mid-expiratory flow (FEF(25-75%); P = .001); higher frequency of resonance (F(res); P = .02) and peripheral airway resistance (R5-R20; P = .006); whereas for steps 3 vs 4 there were differences in F(res) (P < .05) and R5-R20 (P = .006). There were high proportions of abnormality for R5-R20 (>0.03 kPa/L/s) at steps 2, 3, and 4, respectively: 64.6%, 63.5%, and 69.9%. Step 2 patients receiving extra-fine particle ICS demonstrated lower total airway resistance at 5Hz (R5) vs patients receiving standard ICS (124.1% vs 138.3%, P < .05), with no difference in FEV(1). At step 4, R5 remained elevated at 141.3% despite concomitant LABA, with only 2.4% using extra-fine ICS. CONCLUSION: Persistent small airways dysfunction occurs despite treatment at steps 2 through 4 of current asthma guidelines. Extra fine ICS may reduce airway resistance at step 2. Prospective studies with extra fine ICS +/- LABA at steps 2 through 4 are required to discern whether improving small airways function might result in long-term improved control. PMID- 22920074 TI - Status of asthma control in children and the effect of parents' knowledge, attitude, and practice (KAP) in China: a multicenter study. AB - BACKGROUND: Asthma is the most common chronic respiratory disease seriously endangering the health of children. But disease awareness and self-management skills are relatively poor in children; parents play an important role in the control of childhood asthma. OBJECTIVE: To investigate the status of asthma control and severity of asthma in children and to identify impact factors. METHODS: We studied 1 tertiary hospital in each of the 29 provinces. A total of 2,960 parents with children with asthma who visited those hospitals were selected for the knowledge, attitude, and practice (KAP) questionnaire survey, and separated into the controlled asthma group and uncontrolled asthma group according to children's asthma conditions in the past 12 months. Multivariate analysis was carried out based on the answers to 28 tested factors. RESULTS: In the past 12 months, 66.0% of children with asthma had asthma attacks, 26.8% visited an emergency room, and 16.2% were hospitalized. The total cost for asthma was significantly higher in the uncontrolled group than controlled group (chi(2) = 23.14, P < .01). Twelve protective factors of asthma control were founded, such as older age of children, long disease course, high KAP scores of parents, compliance with using nasal steroids, and knowledge of "3 or more times recurrent wheezing suggesting asthma." The risk factors were eczema and family history of asthma. CONCLUSION: Children's asthma is poorly controlled. The cost of asthma is significantly higher in uncontrolled asthma than in controlled. The age of children, course of asthma, personal history of allergy, family history of asthma, parents' education level, and parents' KAP are factors that affect asthma control. PMID- 22920075 TI - Clinical, biochemical, and genetic characterization of type III hereditary angioedema in 13 Northwest Spanish families. AB - BACKGROUND: A new variant of hereditary angioedema has been reported during the last decade. Three main characteristics distinguish it from classic hereditary angioedema: normal C1 inhibitor activity, predominance in women, and different genetic alterations. OBJECTIVE: To assess the symptoms, laboratory findings, and treatment of a population with type III hereditary angioedema from Northwest Spain. METHODS: We studied 29 patients (26 female and 3 male) from 13 different families. RESULTS: The 26 female patients showed a similar clinical pattern to the classic forms of hereditary angioedema, and 22 of these patients had the estrogen-dependent phenotype. Three patients had a negative family history, and 1 of the parents was confirmed as an asymptomatic carrier in 2 of them. All had functional C1 inhibitor activity within the normal range in periods without high estrogen levels, but during attacks (in female patients) and pregnancy, activity decreased to below 50%. One male patient had normal C1 inhibitor activity during attacks, and he was initially diagnosed as having idiopathic angioedema. The C4 and antigenic C1 inhibitor levels were always normal. All studied patients had the c.1032C>A, Thr309Lys mutation in the factor XII gene. The mutation was also found in asymptomatic relatives: 5 of 6 men studied and 1 of 8 women studied. CONCLUSION: Positive family history is a diagnosis criterion, but it could be lacking because there may be asymptomatic relatives, primarily males. PMID- 22920076 TI - Effect of oral feeding with Clostridium leptum on regulatory T-cell responses and allergic airway inflammation in mice. AB - BACKGROUND: Allergic lung inflammation is mediated by allergen-specific T responses, which are negatively regulated by regulatory T cells (Tregs). Previous studies have reported that inoculation of indigenous Clostridium species in the early lives of mice can induce Tregs that colonize the colon. However, whether inoculation of C leptum alone in adult mice could induce systemic Treg responses and inhibit allergic airway inflammation remains unclear. OBJECTIVE: To investigate the effect of oral administration of C leptum on systemic Treg responses and allergic airway inflammation in a mouse model of asthma. METHODS: Adult BABL/c mice were injected with ovalbumin to induce asthma and treated orally with C leptum or vehicle daily for 2 weeks. The numbers of Foxp3(+)CD4(+)CD25(+) Tregs in both the spleen and mediastinal lymph nodes were examined by flow cytometry. After allergen challenge, the airway hyperresponsiveness of individual mice was measured, and the numbers of inflammatory infiltrates and the levels of cytokines in bronchoalveolar lavage fluids ere determined. RESULTS: Oral feeding with C leptum increased the percentage and total number of Tregs in the spleens and mediastinal lymph nodes at 14 days after inoculation and attenuated allergen-induced airway hyperresponsiveness and inflammation by inhibiting inflammatory cytokine production but enhancing interleukin 10 and transforming growth factor beta1 production in the lungs. CONCLUSION: Oral treatment with C leptum can attenuate induced allergic airway inflammation in adult mice. PMID- 22920077 TI - Pollen starch granules in bronchial inflammation. AB - BACKGROUND: Pollen grains with a diameter of more than 10 MUm preferentially deposit in the upper airways. Their contribution to lower airway inflammation is unclear. One hypothesis is that lower airway inflammation is mainly caused by allergen containing pollen starch granules, which are released from the pollen grains and can easily enter the peripheral airways because of their smaller size. OBJECTIVE: To investigate the differential effect of pollen grains and pollen starch granules on nasal symptoms and lower airway inflammation. METHODS: In a 2 period crossover design, 30 patients with allergic rhinitis and mild intermittent asthma underwent 2 allergen challenges on consecutive days in an environmental challenge chamber with either a mixture of pollen grains plus starch granules or starch granules only. End points were the total nasal symptom score (TNSS), nasal secretion weight, nasal flow, spirometry, and exhaled nitric oxide (eNO). RESULTS: The presence of pollen grains had a significant and considerable effect on increase in TNSS and secretion weight and on decrease in nasal flow. Starch granules alone only had minimal effects on nasal symptoms. Challenges with starch granules significantly increased eNO. Pollen had no effect on eNO. CONCLUSION: Pollen grains cause nasal symptoms but do not augment lower airway inflammation, whereas starch granules trigger lower airway inflammation but hardly induce nasal symptoms. PMID- 22920078 TI - Profilin cross-reactive panallergen causes latex sensitization in the pediatric population allergic to pollen. AB - BACKGROUND: Component-resolved diagnostics (CRD) has been demonstrated to be an excellent new tool for improving the current diagnosis of allergies, and it allows differentiation between polysensitization and cross-reactivity. OBJECTIVE: To demonstrate the role of cross-reactive pollen allergens in pediatric patients living in areas with large amounts of airborne grass pollen grains who are sensitive to grass pollen and latex. METHODS: Serum samples were obtained from 106 children between 3 and 14 years of age diagnosed with allergies to pollen based on clinical history, skin prick tests, and specific immunoglobulin E (IgE). None of them had allergy symptoms to latex or fruits. From these 106 children, 56 patients revealed positive results to Phleum-specific major allergens but not to cross-reactive allergens. The other 50 patients who showed positive specific IgE to Phleum-specific major allergens and to cross-reactive pollen allergens also showed positive results to latex allergens. CRD was carried out by specific IgE quantification using a fluoro-enzyme immunoassay (ImmunoCAPT System). RESULTS: Results demonstrated a positive significant relationship between the specific IgE to Hev b 8 and Phl p 12 and also between the specific IgE to Hev b 8 and latex extract in the group of patients sensitized to species-specific and cross reactive Phleum allergens. Positive significant relationships were also found between profilin and avocado or peach sensitizations. No other latex allergens gave positive results. CONCLUSION: The apparent sensitization to latex in pediatric patients allergic to grass pollen is caused by the cross-reactive profilin panallergen; however, it is appears not to be clinically relevant. PMID- 22920079 TI - Sensitization to bald cypress and cross-reactivity with red cedar in Northeastern Georgia. PMID- 22920080 TI - Poor utility of atopy patch test in predicting tolerance development in food protein-induced enterocolitis syndrome. PMID- 22920081 TI - Omalizumab treatment in a child with severe asthma and multiple steroid-induced morbidities. PMID- 22920082 TI - Lipid transfer proteins and thaumatins as relevant allergens in melon peel allergy. PMID- 22920083 TI - Hospital admissions for allergy and eczema varied across regions in England, 2008 2011. PMID- 22920084 TI - Ultrarush venom immunotherapy and the lipoxin a4 inflammation resolution pathway. PMID- 22920085 TI - Allergen of the month-English walnut. PMID- 22920086 TI - [Image-guided and adaptive radiotherapy]. AB - Image-guided radiotherapy (IGRT) aims to take into account anatomical variations occurring during irradiation by visualization of anatomical structures. It may consist of a rigid registration of the tumour by moving the patient, in case of prostatic irradiation for example. IGRT associated with intensity-modulated radiotherapy (IMRT) is strongly recommended when high-dose is delivered in the prostate, where it seems to reduce rectal and bladder toxicity. In case of significant anatomical deformations, as in head and neck tumours (tumour shrinking and decrease in volume of the salivary glands), replanning appears to be necessary, corresponding to the adaptive radiotherapy. This should ideally be "monitored" and possibly triggered based on a calculation of cumulative dose, session after session, compared to the initial planning dose, corresponding to the concept of dose-guided adaptive radiotherapy. The creation of "planning libraries" based on predictable organ positions (as in cervical cancer) is another way of adaptive radiotherapy. All of these strategies still appear very complex and expensive and therefore require stringent validation before being routinely applied. PMID- 22920087 TI - Combined target factor analysis and Bayesian soft-classification of interference contaminated samples: forensic fire debris analysis. AB - A bayesian soft classification method combined with target factor analysis (TFA) is described and tested for the analysis of fire debris data. The method relies on analysis of the average mass spectrum across the chromatographic profile (i.e., the total ion spectrum, TIS) from multiple samples taken from a single fire scene. A library of TIS from reference ignitable liquids with assigned ASTM classification is used as the target factors in TFA. The class-conditional distributions of correlations between the target and predicted factors for each ASTM class are represented by kernel functions and analyzed by bayesian decision theory. The soft classification approach assists in assessing the probability that ignitable liquid residue from a specific ASTM E1618 class, is present in a set of samples from a single fire scene, even in the presence of unspecified background contributions from pyrolysis products. The method is demonstrated with sample data sets and then tested on laboratory-scale burn data and large-scale field test burns. The overall performance achieved in laboratory and field test of the method is approximately 80% correct classification of fire debris samples. PMID- 22920088 TI - Sequential improvements in organ procurement increase the organ donation rate. AB - PURPOSE: Organ demand exceeds availability of transplantable organs. Organ procurement continues to suffer from failures to identify potential donors, inability to obtain consent for donation, as well as failures to retrieve certain organs as donor demographics change. The purpose of this article is to propose how sequentially introduced measures can increase organ donation rates as well as improve organ procurement. METHODS: We analysed the effect of stepwise improvements in the organ procurement process patients in a university-based surgical intensive care unit over a 20-year period. We related newly introduced measures in the organ retrieval process with changes in donation rates. We specifically targeted these three main steps in the donation process: donor identification, conversion of potential donors to actual donors, and organ protection during the procurement process. Finally, we assessed the effect of the same measures on organ procurement after introduction in other hospitals of the same organ procurement region. RESULTS: Introduction of quality improvement steps increased all of the observed parameters. The number of organ donors was stabilised due to a better identification of potential donors, a major increase in conversion from potential to actual donors, and an increase in extended criteria donor. Improvements in organ protection led to higher rates of organs transplanted per donor and increased recovery of lungs and hearts despite increasing donor age. The same measures were introduced successfully in other hospitals in our organ procurement region. CONCLUSION: Sequential improvements in organ procurement can increase the yield of retrieved organs. The same measures can be applied to other hospitals and lead to comparable improvements in organ donation. PMID- 22920089 TI - Fat Embolism Syndrome following minor trauma in Duchenne muscular dystrophy. AB - We describe five patients with Duchenne muscular dystrophy who presented with acute neurologic and respiratory symptoms following minor trauma. Four of the five deteriorated rapidly and died within 36 h after falling. X-rays for fractures were negative. Four of the five patients were taking corticosteroids daily. All five patients fulfilled the clinical criteria for Fat Embolism Syndrome. Autopsy findings were consistent with fat embolism in two cases. Fat Embolism Syndrome needs to be considered in patients with Duchenne muscular dystrophy following minor trauma even without fractures. Early recognition of Fat Embolism Syndrome and aggressive resuscitation are important to improve survival. This report serves as an important reminder that seatbelts need to be used at all times. PMID- 22920090 TI - Quantitative structure-activity relationships of imidazole-containing farnesyltransferase inhibitors using different chemometric methods. AB - Farnesyltranseferase inhibitors (FTIs) are one of the most promising classes of anticancer agents, but though some compounds in this category are in clinical trials there are no marketed drugs in this class yet. Quantitative structure activity relationship (QSAR) models can be used for predicting the activity of FTI candidates in early stages of drug discovery. In this study 192 imidazole containing FTIs were obtained from the literature, structures of the molecules were optimized using Hyperchem software, and molecular descriptors were calculated using Dragon software. The most suitable descriptors were selected using genetic algorithms-partial least squares (GA-PLS) and stepwise regression, and indicated that the volume, shape and polarity of the FTIs are important for their activities. 2D-QSAR models were prepared using both linear methods, i.e., multiple linear regression (MLR), and non-linear methods, i.e., artificial neural networks (ANN) and support vector machines (SVM). The proposed QSAR models were validated using internal and external validation methods. The results show that the proposed 2D-QSAR models are valid and that they can be applied to predict the activities of imidazole-containing FTIs. The prediction capability of the 2D-QSAR (linear and non-linear) models is comparable to and somewhat better than that of previous 3D-QSAR models and the non-linear models are more accurate than the linear models. PMID- 22920091 TI - QSAR and pharmacophore study of Dyrk1A inhibitory meridianin analogs as potential agents for treatment of neurodegenerative diseases. AB - Dual-specificity tyrosine phosphorylation-regulated kinase 1A (Dyrk1A) is a protein kinase with diverse functions in neuronal development and adult brain physiology. Elevated levels of Dyrk1A are associated with the pathology of neurodegenerative diseases and have been implicated in some neurobiological alterations of Down syndrome, such as mental retardation. Meridianins are marine derived indole alkaloids exhibiting anti-proliferative activity as well as are known to inhibit panel of kinases. In the present article, a descriptor based QSAR study was carried out for a series of meridianin analogs inhibiting Dyrk1A to find out structural features which are crucial for biological activity. Developed QSAR model showed good correlation coefficient (r > 0.9), higher F value (F > 20) and excellent predictive power (r2 cv and r2 pred > 0.6). Activity of naturally occurring meridianins was also predicted using developed model. The study indicated that kier Chi4 path/cluster, total lipole, VAMP polarization ZZ component, dipole moment Z component and log P plays important role in Dyrk1A inhibition. Further analysis of pharmacophore model using PHASE module of Schrodinger revealed that two hydrogen bond acceptors (A), two hydrogen bond donors (D) and two hydrophobic aromatic rings (R) are crucial molecular features that predict binding affinity for meridianins to the Dyrk1A enzyme. These observations provide important insights to the key structural requirements of meridianins for potent Dyrk1A inhibition. Excellent statistical results of developed models strongly suggest that these models are reasonable for prediction of the activity of new inhibitors and in future drug design. PMID- 22920092 TI - Chondromodulating chimeric prodrugs of diacetylrhein: synthesis and evaluation in monoiodoacetate-induced hyperalgesia. AB - Chondromodulating chimeric prodrugs of diacetylrhein were synthesized with an objective of potentiating its moderate anti-inflammatory effect and optimizing its hydrophilic/lipophilic balance by conjugating it with essential amino acids through a bioreversible amide linkage. In vitro release in HCl buffer (pH 1.2) showed insignificant release of diacetylrhein. However in phosphate buffer (pH 7.4), almost complete release of diacetylrhein was attained over a period of 4.5 h, following first order kinetics. The prodrug was screened extensively for therapeutic efficacy in monoiodoacetate induced rat hyperalgesia model for levels of various markers of osteoarthritis, knee diameter and locomotor activity over a period of three months. Amongst the three prodrugs synthesized, diacetylrhein-L tryptophan prodrug exhibited highest activity by reducing knee diameter, serum alkaline phosphatase and serum glucosaminoglycan to the baseline levels while increasing the spontaneous locomotor activity. It was found to provide maximum protection against Freund's adjuvant arthritis with minimum ulcerogenic potential and better chondroprotection than diacetylrhein. PMID- 22920094 TI - Modeling of LIM-Kinase 2 inhibitory activity of pyrrolopyrimidine analogues: useful in treatment of ocular hypertension and glaucoma. AB - The LIM-Kinase 2 (LIMK2) inhibitory activity of a series of pyrrolopyrimidine analogs has been analyzed through combinatorial protocol in multiple linear regressions (CP-MLR) and partial least square (PLS) using different descriptors obtained from DRAGON software. The empirical, topological and charge descriptors have led to statistically significant QSAR models and showed good external predictivity as reflected in test set R2 values (0.782 to 0.888). The obtained structure-activity correlations underlined the significance of bulkiness and molecular polarizability in improving the activity. The topological descriptors suggested that open chain or branched substituents are favorable while cyclic /ring substituents are unfavorable for the activity. The descriptors identified in the study showed that pyrrolopyrimidine scaffold holds scope for modulating LIMK2 inhibitory activity. The study gives a direction for further exploration of chemical space of pyrrolopyrimidine analogs as LIMK2 inhibitors. PMID- 22920093 TI - Synthesis and biological evaluation of novel pyrimido[4,5-b]quinoline-2,4- dione derivatives as MDM2 ubiquitin ligase inhibitors. AB - A series of pyrimido[4,5-b]quinoline-2,4-dione derivatives was synthesized and evaluated for their cytotoxic activities in vitro against five human cancer cell lines. Selected compounds were tested for their MDM2 E3 ligase inhibitory activities and p53-MDM2 binding inhibitory activities. Among tested compounds, four sulfur-containing compounds (4-7) displayed enhanced cytotoxic activities and better MDM2 E3 ligase inhibitoty activities in comparison with that of HLI98c. Three compounds (4-6) showed better p53-MDM2 binding inhibitory potency with IC50 values ranging from 1.3 MUM to 9.0 MUM. PMID- 22920095 TI - Newer approaches to the treatment of acne vulgaris. AB - The multifactorial etiology of acne vulgaris makes it challenging to treat. Current treatments include topical retinoids, benzoyl peroxide, topical and systemic antibiotics, azelaic acid, and systemic isotretinoin. Adjunctive and/or emerging approaches include topical dapsone, taurine bromamine, resveratrol, chemical peels, optical treatments, as well as complementary and alternative medications. The purpose of this paper is to discuss the therapies available for acne and their latest developments, including new treatment strategies (i.e. re evaluation of the use of oral antibiotics and avoidance of topical antibiotic monotherapy, use of subantimicrobial antibiotic dosing, use of low-dose isotretinoin, optical treatments), new formulations (microsponges, liposomes, nanoemulsions, aerosol foams), new combinations (fixed-combination products of topical retinoids and topical antibiotics [essentially clindamycin] or benzoyl peroxide), new agents (topical dapsone, taurine bromamine, resveratrol) and their rationale and likely place in treatment. Acne vaccines, topical natural antimicrobial peptides, and lauric acid represent other promising therapies. PMID- 22920096 TI - Luminescent nanocomposites made of finely dispersed Y3Ga5O12:Tb powder in a polymer matrix: promising candidates for optical devices. AB - This paper reports the initial results of an original and simple method to elaborate flexible, self-standing, and thick luminescent films suitable for optical devices. PVP/Y(3)Ga(5)O(12):Tb(3+) nanocomposite films have been successfully achieved from a sol-gel derived Y(3)Ga(5)O(12):Tb(3+) powder and an alcoholic solution of poly-N-vinylpyrrolidone (PVP). The structural, morphological, and optical properties of these nanocomposite films have been studied and compared to those of a pristine PVP film and Y(3)Ga(5)O(12):Tb(3+) powder. The nanocomposite films were characterized by infrared and Raman spectroscopies as well as scanning and transmission electron microscopies (SEM and TEM) and demonstrated good dispersion of the phosphor particles within the polymer matrix via an alveolar mesostructure. The optical properties of these nanocomposites were fully characterized, and both their excitation and emission spectra and decay curves were recorded. Furthermore, photostability of the nanocomposite films and of the luminescent raw powder has been studied after exposure to an accelerated artificial photoageing at wavelengths higher than 300 nm. The elaboration process used is both tunable and applicable to a large variety of powders and polymers because it does not require any additive to form homogeneous and easily shapeable phosphor/polymer nanocomposites applicable in a large variety of optical devices such as solid-state-lighting. PMID- 22920097 TI - Conical intersection seams in polyenes derived from their chemical composition. AB - The knowledge of conical intersection seams is important to predict and explain the outcome of ultrafast reactions in photochemistry and photobiology. They define the energetic low-lying reachable regions that allow for the ultrafast non radiative transitions. In complex molecules it is not straightforward to locate them. We present a systematic approach to predict conical intersection seams in multifunctionalized polyenes and their sensitivity to substituent effects. Included are seams that facilitate the photoreaction of interest as well as seams that open competing loss channels. The method is based on the extended two electron two-orbital method [A. Nenov and R. de Vivie-Riedle, J. Chem. Phys. 135, 034304 (2011)]. It allows to extract the low-lying regions for non-radiative transitions, which are then divided into small linear segments. Rules of thumb are introduced to find the support points for these segments, which are then used in a linear interpolation scheme for a first estimation of the intersection seams. Quantum chemical optimization of the linear interpolated structures yields the final energetic position. We demonstrate our method for the example of the electrocyclic isomerization of trifluoromethyl-pyrrolylfulgide. PMID- 22920098 TI - Self-consistent treatment of the local dielectric permittivity and electrostatic potential in solution for polarizable macromolecular force fields. AB - A self-consistent method is presented for the calculation of the local dielectric permittivity and electrostatic potential generated by a solute of arbitrary shape and charge distribution in a polar and polarizable liquid. The structure and dynamics behavior of the liquid at the solute/liquid interface determine the spatial variations of the density and the dielectric response. Emphasis here is on the treatment of the interface. The method is an extension of conventional methods used in continuum protein electrostatics, and can be used to estimate changes in the static dielectric response of the liquid as it adapts to charge redistribution within the solute. This is most relevant in the context of polarizable force fields, during electron structure optimization in quantum chemical calculations, or upon charge transfer. The method is computationally efficient and well suited for code parallelization, and can be used for on-the fly calculations of the local permittivity in dynamics simulations of systems with large and heterogeneous charge distributions, such as proteins, nucleic acids, and polyelectrolytes. Numerical calculation of the system free energy is discussed for the general case of a liquid with field-dependent dielectric response. PMID- 22920099 TI - A derivation of the master equation from path entropy maximization. AB - The master equation and, more generally, Markov processes are routinely used as models for stochastic processes. They are often justified on the basis of randomization and coarse-graining assumptions. Here instead, we derive nth-order Markov processes and the master equation as unique solutions to an inverse problem. We find that when constraints are not enough to uniquely determine the stochastic model, an nth-order Markov process emerges as the unique maximum entropy solution to this otherwise underdetermined problem. This gives a rigorous alternative for justifying such models while providing a systematic recipe for generalizing widely accepted stochastic models usually assumed to follow from the first principles. PMID- 22920100 TI - Formulation and implementation of a unitary group adapted state universal multi reference coupled cluster (UGA-SUMRCC) theory: excited and ionized state energies. AB - The traditional state universal multi-reference coupled cluster (SUMRCC) theory uses the Jeziorski-Monkhorst (JM) based Ansatz of the wave operator: Omega = Sigma(MU)Omega(MU)|phi(MU)> 0) embedding of mixed quantum mechanical (QM)/classical (or more precisely QM/electrodynamics) systems with a quantum sub-region, described by time-dependent density functional theory (TDDFT), within a classical sub-region, modeled here by the recently proposed near-field (NF) method. Both sub-systems are propagated simultaneously and are coupled through a common Coulomb potential. As a first step we implement the method to study the plasmonic response of a metal film which is half jellium-like QM and half classical. The resulting response is in good agreement with both full scale TDDFT and the purely classical NF method. The embedding method is able to describe the optical response of the whole system while capturing quantum mechanical effects, so it is a promising approach for studying electrodynamics in hybrid molecules-metals nanostructures. PMID- 22920110 TI - Response theory for confined systems. AB - In this work, we use the transient time correlation function (TTCF) method to evaluate the response of a fluid confined in a nanopore and subjected to shear. The shear is induced by the movement of the boundaries in opposite directions and is made of moving atoms. The viscous heat generated inside the pore is removed by a thermostat applied exclusively to the atomic walls, so as to leave the dynamics of the fluid purely Newtonian. To establish a link with nonlinear response theory and apply the TTCF formalism, dissipation has to be generated inside the system. This dissipation is then time correlated with a phase variable of interest (e.g., pressure) to obtain its response. Until recently, TTCF has been applied to homogeneous fluids whose equations of motion were coupled to a mechanical field and a thermostat. In our system dissipation is generated by a boundary condition rather than a mechanical field, and we show how to apply TTCF to these realistic confined systems, comparing the shear stress response so obtained with that of homogeneous systems at equivalent state points. PMID- 22920111 TI - Incorporation of quantum effects for selected degrees of freedom into the trajectory-based dynamics using spatial domains. AB - The approach of defining quantum corrections on nuclear dynamics of molecular systems incorporated approximately into selected degrees of freedom, is described. The approach is based on the Madelung-de-Broglie-Bohm formulation of time-dependent quantum mechanics which represents a wavefunction in terms of an ensemble of trajectories. The trajectories follow classical laws of motion except that the quantum potential, dependent on the wavefunction amplitude and its derivatives, is added to the external, classical potential. In this framework the quantum potential, determined approximately for practical reasons, is included only into the "quantum" degrees of freedom describing light particles such as protons, while neglecting with the quantum force for the heavy, nearly classical nuclei. The entire system comprised of light and heavy particles is described by a single wavefunction of full dimensionality. The coordinate space of heavy particles is divided into spatial domains or subspaces. The quantum force acting on the light particles is determined for each domain of similar configurations of the heavy nuclei. This approach effectively introduces parametric dependence of the reduced dimensionality quantum force, on classical degrees of freedom. This strategy improves accuracy of the quantum force and does not restrict interaction between the domains. The concept is illustrated for two-dimensional scattering systems, where the quantum force is required to reproduce vibrational energy of the quantum degree of freedom. PMID- 22920112 TI - Rapid topography mapping of scalar fields: large molecular clusters. AB - An efficient and rapid algorithm for topography mapping of scalar fields, molecular electron density (MED) and molecular electrostatic potential (MESP) is presented. The highlight of the work is the use of fast function evaluation by Deformed-atoms-in-molecules (DAM) method. The DAM method provides very rapid as well as sufficiently accurate function and gradient evaluation. For mapping the topography of large systems, the molecular tailoring approach (MTA) is invoked. This new code is tested out for mapping the MED and MESP critical points (CP's) of small systems. It is further applied to large molecular clusters viz. (H(2)O)(25), (C(6)H(6))(8) and also to a unit cell of valine crystal at MP2/6 31+G(d) level of theory. The completeness of the topography is checked by extensive search as well as applying the Poincare-Hopf relation. The results obtained show that the DAM method in combination with MTA provides a rapid and efficient route for mapping the topography of large molecular systems. PMID- 22920113 TI - Effect of strong electron correlation on the efficiency of photosynthetic light harvesting. AB - Research into the efficiency of photosynthetic light harvesting has focused on two factors: (1) entanglement of chromophores, and (2) environmental noise. While chromophores are conjugated pi-bonding molecules with strongly correlated electrons, previous models have treated this correlation implicitly without a mathematical variable to gauge correlation-enhanced efficiency. Here we generalize the single-electron/exciton models to a multi-electron/exciton model that explicitly shows the effects of enhanced electron correlation within chromophores on the efficiency of energy transfer. The model provides more detailed insight into the interplay of electron correlation within chromophores and electron entanglement between chromophores. Exploiting this interplay is assisting in the design of new energy-efficient materials, which are just beginning to emerge. PMID- 22920114 TI - Optical Zeeman spectroscopy of the (0,0) B4Gamma-X4Phi band systems of titanium monohydride, TiH, and titanium monodeuteride, TiD. AB - The Zeeman effect in the (0,0) bands of the B(4)Gamma(5/2)-X(4)Phi(3/2) system of titanium monohydride, TiH, and titanium monodeuteride, TiD, has been recorded and analyzed. Magnetic tuning of the spectral features recorded at high resolution (full width at half maximum ? 35 MHz) and at a field strength of 4.5 kG is accurately modeled using an effective Zeeman Hamiltonian. The determined magnetic g-factors for the X(4)Phi(3/2) (v = 0) state deviate only slightly from those expected for an isolated (4)Phi(3/2) state whereas those for the B(4)Gamma(5/2)(v = 0) deviate significantly from those of an isolated (4)Gamma(5/2) state. The rotational dependence of the magnetic tuning in the B(4)Gamma(5/2)(v = 0) state is attributed to perturbations from a nearby (4)Phi state. PMID- 22920115 TI - Direct measurement of S-branch N2-H2 Raman linewidths using time-resolved pure rotational coherent anti-Stokes Raman spectroscopy. AB - S-branch N(2)-H(2) Raman linewidths have been measured in the temperature region 294-1466 K using time-resolved dual-broadband picosecond pure rotational coherent anti-Stokes Raman spectroscopy (RCARS). Data are extracted by mapping the dephasing rates of the CARS signal temporal decay. The J-dependent coherence decays are detected in the time domain by following the individual spectral lines as a function of probe delay. The linewidth data set was employed in spectral fits of N(2) RCARS spectra recorded in binary mixtures of N(2) and H(2) at calibrated temperature conditions up to 661 K using a standard nanosecond RCARS setup. In this region, the set shows a deviation of less than 2% in comparison with thermocouples. The results provide useful knowledge for the applicability of N(2) CARS thermometry on the fuel-side of H(2) diffusion flames. PMID- 22920116 TI - A combined spectroscopic and theoretical study of propofol.(H2O)3. AB - Propofol (2,6-di-isopropylphenol) is probably the most widely used general anesthetic. Previous studies focused on its complexes containing 1 and 2 water molecules. In this work, propofol clusters containing three water molecules were formed using supersonic expansions and probed by means of a number of mass resolved laser spectroscopic techniques. The 2-color REMPI spectrum of propofol[middle dot](H(2)O)(3) contains contributions from at least two conformational isomers, as demonstrated by UV/UV hole burning. Using the infrared IR/UV double resonance technique, the IR spectrum of each isomer was obtained both in ground and first excited electronic states and interpreted in the light of density functional theory (DFT) calculations at M06-2X/6-311++G(d,p) and B3LYP/6-311++G(d,p) levels. The spectral analysis reveals that in both isomers the water molecules are forming cyclic hydrogen bond networks around propofol's OH moiety. Furthermore, some evidences point to the existence of isomerization processes, due to a complicated conformational landscape and the existence of multiple paths with low energy barriers connecting the different conformers. Such processes are discussed with the aid of DFT calculations. PMID- 22920117 TI - Differential cross sections for the electron impact excitation of pyrimidine. AB - We report on differential cross section (DCS) measurements for the electron impact excitation of the electronic states of pyrimidine. The energy range of the present measurements was 15-50 eV with the angular range of the measurements being 10 degrees -90 degrees . All measured DCSs displayed forward-peaked angular distributions, consistent with the relatively large magnitudes for the dipole moment and dipole polarizability of pyrimidine. Excitations to triplet states were found to be particularly important in some energy loss features at the lower incident electron energies. To the best of our knowledge there are no other experimental data or theoretical computations against which we can compare the present results. PMID- 22920118 TI - Ab initio ground state phenylacetylene-argon intermolecular potential energy surface and rovibrational spectrum. AB - We evaluate the phenylacetylene-argon intermolecular potential energy surface by fitting a representative number of ab initio interaction energies to an analytic function. These energies are calculated at a grid of intermolecular geometries, using the CCSD(T) method and the aug-cc-pVDZ basis set extended with a series of 3s3p2d1f1g midbond functions. The potential is characterized by two equivalent global minima where the Ar atom is located above and below the phenylacetylene plane at a distance of 3.5781 A from the molecular center of mass and at an angle of 9.08 degrees with respect to the axis perpendicular to the phenylacetylene plane and containing the center of mass. The calculated interaction energy is 418.9 cm(-1). To check further the potential, we obtain the rovibrational spectrum of the complex and the results are compared to the available experimental data. PMID- 22920119 TI - Optimal covering of C60 fullerene by rare gases. AB - Putative global energy minima of clusters formed by the adsorption of rare gases on a C(60) fullerene molecule, C(60)X(N) (X=Ne, Ar, Kr, Xe; N <= 70), are found using basin-hopping global optimization in an empirical potential energy surface. The association energies per rare gas atom as a function of N present two noticeable minima for Ne and Ar and just one for Kr and Xe. The minimum with the smallest N is the deepest one and corresponds to an optimal packing monolayer structure; the other one gives a monolayer with maximum packing. For Kr and Xe, optimal and maximum packing structures coincide. By using an isotropic average form of the X-C(60) interaction, we have established the relevance of the C(60) surface corrugation on the cluster structures. Quantum effects are relevant for Ne clusters. The adsorption of these rare gases on C(60) follows patterns that differ significantly from the ones found recently for He by means of experimental and theoretical methods. PMID- 22920120 TI - Fish-Bite structure by three-dimensional hydrogen-bond acceptor: IR spectroscopy of pyrrole and N-methylpyrrole binary clusters. AB - The N-H...pi hydrogen-bonded (H-bonded) structures of pyrrole (Py) and N methylpyrrole (NMPy) binary clusters have been studied by IR cavity ringdown spectroscopy and density functional theory calculations. The Py(1)-NMPy(1) cluster has an "L-shape" structure, which is formed by an ordinary H-bond between a N-H donor of Py and a pi-electron cloud acceptor of NMPy. The Py(2)-NMPy(1) cluster has a "Cyclic" structure, which is also formed by ordinary N-H...pi H bonds as well as the weak C-H...pi H-bond between the methyl CH group and the pi cloud acceptor of Py. On the other hand, the Py(1)-NMPy(2) cluster shows an extraordinary structure, in which the single donor NH group is surrounded by a three-dimensional H-bond acceptor formed by two aromatic pi electron clouds. We call the Py(1)-NMPy(2) cluster as the "Fish-Bite" structure. The Py(1)-NMPy(2) cluster exhibits a redshifted NH stretch by 157 cm(-1) from the Py monomer, which is larger than 94 cm(-1) of the Py(1)-NMPy(1) cluster. However, both Py(1) NMPy(1) and Py(1)-NMPy(2) clusters have calculated IR intensities of 169 and 163 km/mol, respectively. This result indicates that not only the N-H...pi H-bonds but also the dipole-dipole interaction between Py and NMPy contributes to the Fish-Bite Py(1)-NMPy(2) cluster formation. PMID- 22920121 TI - Finite temperature path integral Monte Carlo simulations of structural and dynamical properties of Ar(N)-CO2 clusters. AB - We report finite temperature quantum mechanical simulations of structural and dynamical properties of Ar(N)-CO(2) clusters using a path integral Monte Carlo algorithm. The simulations are based on a newly developed analytical Ar-CO(2) interaction potential obtained by fitting ab initio results to an anisotropic two dimensional Morse/Long-range function. The calculated distributions of argon atoms around the CO(2) molecule in Ar(N)-CO(2) clusters with different sizes are consistent to the previous studies of the configurations of the clusters. A first order perturbation theory is used to quantitatively predict the CO(2) vibrational frequency shift in different clusters. The first-solvation shell is completed at N = 17. Interestingly, our simulations for larger Ar(N)-CO(2) clusters showed several different structures of the argon shell around the doped CO(2) molecule. The observed two distinct peaks (2338.8 and 2344.5 cm(-1)) in the upsilon(3) band of CO(2) may be due to the different arrangements of argon atoms around the dopant molecule. PMID- 22920122 TI - Spectroscopy above the ionization threshold: dissociative recombination of the ground vibrational level of N2+. AB - Comprehensive theoretical calculations are reported for the dissociative recombination of the lowest vibrational level of the N(2)(+) ground state. Fourteen dissociative channels, 21 electron capture channels, and 48 Rydberg series including Rydberg states having the first excited state of the ion as core are described for electron energies up to 1.0 eV. The calculation of potential curves, electron capture and predissociation widths, cross sections and rate constants are described. The cross sections and rate constants are calculated using Multichannel Quantum Defect Theory which allows for efficient handling of the Rydberg series. The most important dissociative channel is 2(3)Pi(u) followed by 4(3)Pi(u). Dissociative states that do not cross the ion within the ground vibrational level turning points play a significant role in determining the cross section structure and at isolated energies can be more important than states having a favorable crossing. By accounting for autoionization, the interactions between resonances, between dissociative states, and between resonances and dissociative states it is found that the cross section can be viewed as a complex dissociative recombination spectrum in which resonances overlap and interfere. The detailed cross section exhibits a rapid variation in atomic quantum yields for small changes in the electron energy. A study of this rapid variation by future high resolution storage ring experiments is suggested. A least squares fit to the calculated rate constant from the ground vibrational level is 2.2(+0.2)/( 0.4) * 10(-7) * (T(e)/300)(-0.40) cm(3)/sec for electron temperatures, T(e), between 100 and 3000 K and is in excellent agreement with experimentally derived values. PMID- 22920123 TI - Cooperative effects of noncovalent bonds to the Br atom of halogen-bonded H3N...BrZ and HCN...BrZ (Z = F, Br) complexes. AB - A series of complexes formed between halogen-bonded H(3)N/HCN...BrZ (Z = Br, F) dimers and H(3)N/HCN...BrZ...XY (XY = HF, ClF, BeH(2), LiF) trimers were investigated at the MP2 and B3LYP levels of theory using a 6-31++G(d,p) basis set. Optimized structures, interaction energies, and other properties of interest were obtained. The addition of XY to the H(3)N/HCN...BrZ dyad leads to enhanced intermolecular binding with respect to the isolated monomers. This enhanced binding receives contributions from the electrostatic and inductive forces between the constituent pairs, with, in some instances, substantial three-body non-additive contributions to the binding energy. It was found that the XY = LiF interaction causes the greatest distortion of the H(3)N/HCN...BrZ halogen bond from the preferred linear orientation and also provides the strongest binding energy via the nonadditive energy. PMID- 22920124 TI - Scattering of N2O on electron impact over an extensive energy range (0.1 eV-2000 eV). AB - We report electron impact total cross sections, Q(T), for e-N(2)O scattering over an extensive range of impact energies approximately from 0.1 eV to 2000 eV. We employ an ab initio calculation using R-matrix formalism below the ionization threshold of the target and above it we use the well established spherical complex optical potential to compute the cross sections. Total cross section is obtained as a sum of total elastic and total electronic excitation cross sections below the ionization threshold and above the ionization threshold as a sum of total elastic and total inelastic cross sections. Ample cross section data for e N(2)O scattering are available at low impact energies and hence meaningful comparisons are made. Good agreement is observed with the available theoretical as well as experimental results over the entire energy range studied here. PMID- 22920125 TI - Room-temperature structures of solid hydrogen at high pressures. AB - By employing first-principles metadynamics simulations, we explore the 300 K structures of solid hydrogen over the pressure range 150-300 GPa. At 200 GPa, we find the ambient-pressure disordered hexagonal close-packed (hcp) phase transited into an insulating partially ordered hcp phase (po-hcp), a mixture of ordered graphene-like H(2) layers and the other layers of weakly coupled, disordered H(2) molecules. Within this phase, hydrogen remains in paired states with creation of shorter intra-molecular bonds, which are responsible for the very high experimental Raman peak above 4000 cm(-1). At 275 GPa, our simulations predicted a transformation from po-hcp into the ordered molecular metallic Cmca phase (4 molecules/cell) that was previously proposed to be stable only above 400 GPa. Gibbs free energy calculations at 300 K confirmed the energetic stabilities of the po-hcp and metallic Cmca phases over all known structures at 220-242 GPa and >242 GPa, respectively. Our simulations highlighted the major role played by temperature in tuning the phase stabilities and provided theoretical support for claimed metallization of solid hydrogen below 300 GPa at 300 K. PMID- 22920126 TI - Hydration structures of U(III) and U(IV) ions from ab initio molecular dynamics simulations. AB - We apply DFT+U-based ab initio molecular dynamics simulations to study the hydration structures of U(III) and U(IV) ions, pertinent to redox reactions associated with uranium salts in aqueous media. U(III) is predicted to be coordinated to 8 water molecules, while U(IV) has a hydration number between 7 and 8. At least one of the innershell water molecules of the hydrated U(IV) complex becomes spontaneously deprotonated. As a result, the U(IV)-O pair correlation function exhibits a satellite peak at 2.15 A associated with the shorter U(IV)-(OH(-)) bond. This feature is not accounted for in analysis of extended x-ray absorption fine structure and x-ray adsorption near edge structure measurements, which yield higher estimates of U(IV) hydration numbers. This suggests that it may be useful to include the effect of possible hydrolysis in future interpretation of experiments, especially when the experimental pH is close to the reported hydrolysis equilibrium constant value. PMID- 22920127 TI - Nonequilibrium molecular dynamics simulations of the thermal conductivity of water: a systematic investigation of the SPC/E and TIP4P/2005 models. AB - We report an extensive nonequilibrium molecular dynamics investigation of the thermal conductivity of water using two of the most accurate rigid nonpolarizable empirical models available, SPC/E and TIP4P/2005. Our study covers liquid and supercritical states. Both models predict the anomalous increase of the thermal conductivity with temperature and the thermal conductivity maximum, hence confirming their ability to reproduce the complex anomalous behaviour of water. The performance of the models strongly depends on the thermodynamic state investigated, and best agreement with experiment is obtained for states close to the liquid coexistence line and at high densities and temperatures. Considering the simplicity of these two models the overall agreement with experiments is remarkable. Our results show that explicit polarizability and molecular flexibility are not needed to reproduce the anomalous heat conduction of water. PMID- 22920128 TI - Neutron scattering studies of K3H(SO4)2 and K3D(SO4)2: the particle-in-a-box model for the quantum phase transition. AB - In the crystal of K(3)H(SO(4))(2) or K(3)D(SO(4))(2), dimers SO(4)...H...SO(4) or SO(4)...D...SO(4) are linked by strong centrosymmetric hydrogen or deuterium bonds whose O...O length is ~2.50 A. We address two open questions. (i) Are H or D sites split or not? (ii) Is there any structural counterpart to the phase transition observed for K(3)D(SO(4))(2) at T(c) ~ 85.5 K, which does not exist for K(3)H(SO(4))(2)? Neutron diffraction by single-crystals at cryogenic or room temperature reveals no structural transition and no resolvable splitting of H or D sites. However, the width of the probability densities suggest unresolved splitting of the wavefunctions suggesting rigid entities H(L1/2)-H(R1/2) or D(L1/2)-D(R1/2) whose separation lengths are l(H) ~ 0.16 A or l(D) ~ 0.25 A. The vibrational eigenstates for the center of mass of H(L1/2)-H(R1/2) revealed by inelastic neutron scattering are amenable to a square-well and we suppose the same potential holds for D(L1/2)-D(R1/2). In order to explain dielectric and calorimetric measurements of mixed crystals K(3)D((1-rho))H(rho)(SO(4))(2) (0 <= rho <= 1), we replace the classical notion of order-disorder by the quantum notion of discernible (e.g., D(L1/2)-D(R1/2)) or indiscernible (e.g., H(L1/2) H(R1/2)) components depending on the separation length of the split wavefunction. The discernible-indiscernible isostructural transition at finite temperatures is induced by a thermal pure quantum state or at 0 K by rho. PMID- 22920129 TI - Structural changes of filled ice Ic hydrogen hydrate under low temperatures and high pressures from 5 to 50 GPa. AB - Low-temperature and high-pressure experiments were performed on the filled ice Ic structure of hydrogen hydrate at previously unexplored conditions of 5-50 GPa and 30-300 K using diamond anvil cells and a helium-refrigeration cryostat. In situ x ray diffractometry revealed that the cubic filled ice Ic structure transformed to tetragonal at low temperatures and high pressures; the axis ratio of the tetragonal phase changed depending on the pressure and temperature. These results were consistent with theoretical predictions performed via first principle calculations. The tetragonal phase was determined to be stable above 20 GPa at 300 K, above 15 GPa at 200 K, and above 10 GPa at 100 K. Further changes in the lattice parameters were observed from about 45-50 GPa throughout the temperature region examined, which suggests the transformation to another high-pressure phase above 50 GPa. In our previous x-ray study that was performed up to 80 GPa at room temperature, a similar transformation was observed above 50 GPa. In this study, the observed change in the lattice parameters corresponds to the beginning of that transformation. The reasons for the transformation to the tetragonal structure are briefly discussed: the tetragonal structure might be induced due to changes in the vibrational or rotational modes of the hydrogen molecules under low temperature and high pressure. PMID- 22920130 TI - In situ Raman spectroscopic study of the pressure induced structural changes in ammonia borane. AB - The effect of static compression up to 65 GPa at ambient temperature on ammonia borane, BH(3)NH(3), has been investigated using in situ Raman spectroscopy in a diamond anvil cells. Two phase transitions were observed at approximately 12 GPa and previously not reported transition at 27 GPa. It was demonstrated that ammonia borane behaves differently under compression at quasi-hydrostatic and non hydrostatic conditions. The ability of BH(3)NH(3) to generate second harmonic of the laser light observed up to 130 GPa suggests that the non-centrosymmetric point group symmetry is preserved in the material up to very high pressures. PMID- 22920131 TI - The sticking probability of D2O-water on ice: isotope effects and the influence of vibrational excitation. AB - The present study measures the sticking probability of heavy water (D(2)O) on H(2)O- and on D(2)O-ice and probes the influence of selective OD-stretch excitation on D(2)O sticking on these ices. Molecular beam techniques are combined with infrared laser excitation to allow for precise control of incident angle, translational energy, and vibrational state of the incident molecules. For a translational energy of 69 kJ/mol and large incident angles (theta >= 45 degrees ), the sticking probability of D(2)O on H(2)O-ice was found to be 1% lower than on D(2)O-ice. OD-stretch excitation by IR laser pumping of the incident D(2)O molecules produces no detectable change of the D(2)O sticking probability (<10(-3)). The results are compared with other gas/surface systems for which the effect of vibrational excitation on trapping has been probed experimentally. PMID- 22920132 TI - A generalized kinetic model for heterogeneous gas-solid reactions. AB - We present a generalized kinetic model for gas-solid heterogeneous reactions taking place at the interface between two phases. The model studies the reaction kinetics by taking into account the reactions at the interface, as well as the transport process within the product layer. The standard unreacted shrinking core model relies on the assumption of quasi-static diffusion that results in a steady state concentration profile of gas reactant in the product layer. By relaxing this assumption and resolving the entire problem, general solutions can be obtained for reaction kinetics, including the reaction front velocity and the conversion (volume fraction of reacted solid). The unreacted shrinking core model is shown to be accurate and in agreement with the generalized model for slow reaction (or fast diffusion), low concentration of gas reactant, and small solid size. Otherwise, a generalized kinetic model should be used. PMID- 22920133 TI - Structural phases formed by NO2/CO co-adsorption on Au{111} surfaces. AB - Exposing a Au{111} surface to NO(2) and then to CO at temperatures around 120 K in ultra-high vacuum gives rise to molecular overlayers in which the two species are co-adsorbed, which we have investigated using low-temperature scanning tunnelling microscopy. Under NO(2)-rich conditions, a (?7 * ?7)R19.1 degrees phase with 3:1 NO(2):CO stoichiometry forms. Under CO-rich conditions, this phase co-exists with other phases having 2:1 and 1:1 NO(2):CO stoichiometries and different symmetries, and with bare Au surface. Structural models for these phases are discussed. Individual domains of the (?7 * ?7)R19.1 degrees phase are chiral, by virtue of the arrangement of their achiral components, an observation that may have more general implications. PMID- 22920134 TI - Coadsorption properties of CO2 and H2O on TiO2 rutile (110): a dispersion corrected DFT study. AB - Adsorption and reactions of CO(2) in the presence of H(2)O and OH species on the TiO(2) rutile (110)-(1*1) surface were investigated using dispersion-corrected density functional theory and scanning tunneling microscopy. The coadsorbed H(2)O (OH) species slightly increase the CO(2) adsorption energies, primarily through formation of hydrogen bonds, and create new binding configurations that are not present on the anhydrous surface. Proton transfer reactions to CO(2) with formation of bicarbonate and carbonic acid species were investigated and found to have barriers in the range 6.1-12.8 kcal/mol, with reactions involving participation of two or more water molecules or OH groups having lower barriers than reactions involving a single adsorbed water molecule or OH group. The reactions to form the most stable adsorbed formate and bicarbonate species are exothermic relative to the unreacted adsorbed CO(2) and H(2)O (OH) species, with formation of the bicarbonate species being favored. These results are consistent with single crystal measurements which have identified formation of bicarbonate type species following coadsorption of CO(2) and water on rutile (110). PMID- 22920135 TI - Structure simulation of ultrathin dichloromethane layer on a solid substrate by density functional theory and molecular dynamics simulations. AB - The method for prediction of structural properties of ultrathin liquid layers has been developed on the base of the atomistic molecular dynamics (AMD) and the density functional theory (DFT). A comparative analysis of ultrathin dichloromethane layer density profiles on three types of solid flat substrates showed that these approaches can be effectively used as mutually complementary procedures to describe the structural properties of nanometer scale surface layers. We used AMD calculations to predict the dichloromethane layer density profile on a solid substrate. However, it is difficult and computationally expensive to calculate structural and thermodynamic layers properties. At the same time, DFT can retain the microscopic details of macroscopic systems at the calculative cost significantly lower than that used in AMD. Therefore, in context of DFT, the substrate potential parameters are adjusted to reproduce AMD data. Thus, the obtained potential allows us to compute structural characteristics and, further, can be used to predict other physical properties of ultrathin films within the DFT framework. For instance, we calculated the coefficient of thermal expansion of dichloromethane in the case of three different substrates such as graphite, silicon oxide, and gold. PMID- 22920136 TI - Enhanced selectivity towards O2 and H2 dissociation on ultrathin Cu films on Ru(0001). AB - The reactivity of Cu monolayer (ML) and bilayer films grown on Ru(0001) towards O(2) and H(2) has been investigated. O(2) initial sticking coefficients were determined using the King and Wells method in the incident energy range 40-450 meV, and compared to the corresponding values measured on clean Ru(0001) and Cu(111) surfaces. A relative large O(2) sticking coefficient (~0.5-0.8) was measured for 1 ML Cu and even 2 ML Cu/Ru(0001). At low incident energies, this is one order of magnitude larger than the value observed on Cu(111). In contrast, the corresponding reactivity to H(2) was near zero on both Cu monolayer and bilayer films, for incident energies up to 175 meV. Water adsorption on 2 ML Cu/Ru(0001) was found to behave quite differently than on the Ru(0001) and Cu(111) surfaces. Our study shows that Cu/Ru(0001) is a highly selective system, which presents a quite different chemical reactivity towards different species in the same range of collision energies. PMID- 22920137 TI - Adsorption of ions on surfaces modified with brushes of polyampholytes. AB - We apply density functional theory to study adsorption of ions, treated in the framework of the restricted primitive model (RPM), on surfaces modified by tethered polyampholytes. The residual electrostatic contribution to the free energy functional is approximated by using the approach proposed by Wang et al. [J. Phys.: Condens. Matter 23, 175002 (2011)] for simple nonuniform RPMs systems. Our research concentrates on the problems how the distribution of the charges within chains of polyampholytes changes the selectivity of adsorption of ions species, the structure of the surface layer, and its electric properties. PMID- 22920138 TI - Substituent effects on packing entropy and film morphologies in the nucleation of functionalized pentacenes on SiO2 substrate: molecular dynamics simulations. AB - The changes in structural ordering, packing entropy, free energy, and film morphologies in the initial nucleation processes of pentacene (Pn), 6, 13-bis(t butylethynyl) pentacene (t-Bu Pn), and 6, 13-bis(triisopropylsilylethynyl) pentacene (TIPS Pn) on the SiO(2) substrate were investigated, by using the molecular dynamics simulations. During the nucleation, the rod-like Pn molecules tend to diffuse rapidly and have different orientations on the SiO(2) surface. At the low coverage, the t-Bu Pn and TIPS Pn molecules with the branched topological structures almost lie flat on the substrate. On the basis of statistical distribution of various packing configurations of the functionalized Pn pairs, the packing entropy is estimated according to the Boltzmann formula. The packing entropy abruptly decreases in the early stage of deposition. Once the critical nucleus size is reached, the packing entropy converges to a constant value. As the coverage increases, the monolayer films of Pn and its branched derivatives become more ordered. The TIPS Pn with the relatively larger molecular area would occasionally stand on the surface during the nucleation, resulting in the dramatic changes in free energy. In the monolayers, the functionalized Pn molecules are packing more orderly than those in amorphous solids, but less orderly than those in crystals. The degree of order of these monolayers increases as the size of the substituents increases. The understanding of substituent effects on nucleation processes and packing structures is helpful to fabricate organic thin films with well-predefined molecular orientations. PMID- 22920139 TI - The nature of the ordered phase of the confined self-assembled rigid rod model. AB - We investigate the nature of the ordered phase and the orientational correlations between adjacent layers of the confined three-dimensional self-assembled rigid rod model, on the cubic lattice. We find that the ordered phase at finite temperatures becomes uniaxial in the thermodynamic limit, by contrast to the ground state (partial) order where the orientation of the uncorrelated layers is perpendicular to one of the three lattice directions. The increase of the orientational correlation between layers as the number of layers increases suggests that the unconfined model may also exhibit uniaxial ordering at finite temperatures. PMID- 22920140 TI - Near critical electrolytes: are the charge-charge sum rules obeyed? AB - In an electrolyte solution the charge-charge structure factor obeys S(ZZ)(k;T,rho)=0+xi(Z,1)(2)k(2)-xi(Z,2)(4)k(4)+..., where xi(Z, 1) and xi(Z, 2) are the second- and fourth-moment charge-charge correlation lengths depending on the temperature T and the overall ion density rho. The vanishing of the leading term, the first Stillinger-Lovett (SL) sum rule, simply reflects bulk electroneutrality. The second SL rule, or second-moment condition, dictates that xi(Z, 1) = xi(D), where the Debye screening length xi(D) is proportional to ?(T/rho). In this paper we present results from grand canonical Monte Carlo simulations of a fully size and charge symmetric 1:1 (finely-discretized) hard sphere electrolyte, or restricted primitive model. By design, electroneutrality is imposed during the simulations, so satisfying the first sum rule automatically. However, careful finite-size scaling analyses of extensive histogram reweighted data indicate that the second-moment condition is violated at criticality, xi(Z,1)(c) exceeding xi(D)(c) by approximately 8%. It is also found that xi(Z,2)(4) diverges to +infinity as T -> T(c) in a manner closely mirroring the density-density fluctuations, S(NN)(0). These findings contradict generalized Debye-Huckel theory and also the exactly soluble charge-symmetric spherical models, both of which support the second-moment condition at criticality and the finiteness of the fourth-moment. Nevertheless, the observed behavior is strikingly similar to that of the charge-asymmetric spherical models. PMID- 22920141 TI - How a single stretched polymer responds coherently to a minute oscillation in fluctuating environments: an entropic stochastic resonance. AB - Within the cell, biopolymers are often situated in constrained, fluid environments, e.g., cytoskeletal networks, stretched DNAs in chromatin. It is of paramount importance to understand quantitatively how they, utilizing their flexibility, optimally respond to a minute signal, which is, in general, temporally fluctuating far away from equilibrium. To this end, we analytically study viscoelastic response and associated stochastic resonance in a stretched single semi-flexible chain to an oscillatory force or electric field. Including hydrodynamic interactions between chain segments, we evaluate dynamics of the polymer extension in coherent response to the force or field. We find power amplification factor of the response at a noise-strength (temperature) can attain the maximum that grows as the chain length increases, indicative of an entropic stochastic resonance (ESR). In particular for a charged chain under an electric field, we find that the maximum also occurs at an optimal chain length, a new feature of ESR. The hydrodynamic interaction is found to enhance the power amplification, representing unique polymer cooperativity which the fluid background imparts despite its overdamping nature. For the slow oscillatory force, the resonance behavior is explained by the chain undulation of the longest wavelength. This novel ESR phenomenon suggests how a biopolymer self-organizes in an overdamping environment, utilizing its flexibility and thermal fluctuations. PMID- 22920142 TI - Conformational dynamics of ATP/Mg:ATP in motor proteins via data mining and molecular simulation. AB - The conformational diversity of ATP/Mg:ATP in motor proteins was investigated using molecular dynamics and data mining. Adenosine triphosphate (ATP) conformations were found to be constrained mostly by inter cavity motifs in the motor proteins. It is demonstrated that ATP favors extended conformations in the tight pockets of motor proteins such as F(1)-ATPase and actin whereas compact structures are favored in motor proteins such as RNA polymerase and DNA helicase. The incorporation of Mg(2+) leads to increased flexibility of ATP molecules. The differences in the conformational dynamics of ATP/Mg:ATP in various motor proteins was quantified by the radius of gyration. The relationship between the simulation results and those obtained by data mining of motor proteins available in the protein data bank is analyzed. The data mining analysis of motor proteins supports the conformational diversity of the phosphate group of ATP obtained computationally. PMID- 22920143 TI - A density functional and quantum Monte Carlo study of glutamic acid in vacuo and in a dielectric continuum medium. AB - We present density functional theory (DFT) and quantum Monte Carlo (QMC) calculations of the glutamic acid and glutamate ion in vacuo and in various dielectric continuum media within the polarizable continuum model (PCM). In DFT, we employ the integral equation formalism variant of PCM while, in QMC, we use a PCM scheme we have developed to include both surface and volume polarization. We investigate the gas-phase protonation thermochemistry of the glutamic acid using a large set of structural conformations, and find that QMC is in excellent agreement with the best available theoretical and experimental results. For the solvated glutamic acid and glutamate ion, we perform DFT calculations for dielectric constants, epsilon, between 4 and 78. We find that the glutamate ion in the zwitterionic form is more stable than the non-zwitterionic form over the whole range of dielectric constants, while the glutamic acid is more stable in its non-zwitterionic form at epsilon = 4. The dielectric constant at which the two glutamic acid species have the same energy depends on the cavity size and lies between 5 and 12.5. We validate these results with QMC for the two limiting values of the dielectric constant, and find qualitative agreement with DFT even though the solvent polarization is less pronounced at the QMC level. PMID- 22920146 TI - Drug interactions with the dietary fiber Plantago ovata husk. AB - INTRODUCTION: Plantago ovata husk is a viscous water-soluble fiber obtained by milling the seed of Plantago ovata. The increased use of this compound for the treatment of diseases makes it necessary to know of its potential drug interactions. AREAS COVERED: The present paper reviews the literature concerning interactions between drugs and the dietary fiber Plantago ovata husk. All publications which might describe interactions between the dietetic fiber Plantago ovata husk and other drugs were identified by searches using databases such as MEDLINE or EMBASE. EXPERT OPINION: Drug interactions have been the subject of numerous studies, but few of them have been carried out with dietary fiber and the results obtained have often been variable. The incidence and importance of interactions between fiber and drugs has increased due to a worldwide rise in the use of dietary fiber. Plantago ovata husk has the potential for producing both benefits and risks with both desirable and undesirable effects when coadministered with drugs. More clinical studies are justifiably needed to improve treatments and to better evaluate patient safety. PMID- 22920147 TI - Characterization of a new myxozoan species (Myxozoa: Myxobolidae: Myxosporea) in largescale stonerollers (Campostoma oligolepis) from the Mobile River Basin (Alabama). AB - Myxobolus stanlii sp. n. was described from largescale stonerollers ( Campostoma oligolepis ) from the Mobile River Basin in Alabama. The parasite was described using critical identifying morphological features, and the 18S small subunit ribosomal RNA (SSU rRNA) gene sequence. The spore body was ovoid, 10.03 +/- 0.7 (7.5-11.0) MUm long and 8.8 +/- 1.5 (6.3-11.3) MUm wide in frontal view. Spore thickness was 6.3 +/- 2.7 (6.2-8.6) MUm in sutural view. Polar capsules were pyriform, of equal size, and oriented in plane with the sutural ridge. Polar capsules were 2.45 +/- 1.5 (range 2.1-4.3) MUm in width and 4.6 +/- 2.7 (range 4.5-6.9) MUm in length. Based on the SSU rRNA gene sequence of Myxobolus stanlii sp. n. is most closely related to M. pseudodispar. PMID- 22920149 TI - Tuning MOF stability and porosity via adding rigid pillars. AB - High stability and permanent porosity are the premise of general applicability for metal-organic framework materials (MOFs). By varying degrees of success on increasing the connectivity of the linear pillar 4,4'-bipyridine (bpy), two isostructural flexible frameworks [M(2)(obb)(2)(DMF)(2)].2DMF (1, M = Zn or Cu; H(2)obb = 4,4'-oxybis(benzoic acid), DMF = N,N-dimethylformamide) with no gas sorption are structurally modified into two rigid frameworks [Zn(2)(obb)(2)(bpy)].DMF (2) and [Cu(2)(obb)(2)(bpy)(0.5)(DMF)].2DMF (3) with notable gas sorption and separation properties. Especially for 3, it exhibits gas selective uptake for the adsorption of CO(2) over N(2) and CH(4) under 273 K and has an interesting physically lock effect in benzene and cyclohexane sorption. The results provide a successful strategy on tuning framework stability of flexible structures via adding rigid pillars. PMID- 22920150 TI - An aromatic region to induce a switch between agonism and inverse agonism at the ghrelin receptor. AB - The ghrelin receptor displays a high constitutive activity suggested to be involved in the regulation of appetite and food intake. Here, we have created peptides with small changes in the core binding motif -wFw- of the hexapeptide KwFwLL-NH(2) that can swap the peptide behavior from inverse agonism to agonism, indicating the importance of this sequence. Introduction of beta-(3-benzothienyl) d-alanine (d-Bth), 3,3-diphenyl-d-alanine (d-Dip) and 1-naphthyl-d-alanine (d-1 Nal) at position 2 resulted in highly potent and efficient inverse agonists, whereas the substitution of d-tryptophane at position 4 with 1-naphthyl-d-alanine (d-1-Nal) and 2-naphthyl-d-alanine (d-2-Nal) induces agonism in functional assays. Competitive binding studies showed a high affinity of the inverse agonist K-(d-1-Nal)-FwLL-NH(2) at the ghrelin receptor. Moreover, mutagenesis studies of the receptor revealed key positions for the switch between inverse agonist and agonist response. Hence, only minor changes in the peptide sequence can decide between agonism and inverse agonism and have a major impact on the biological activity. PMID- 22920151 TI - Synthesis, cytotoxicity, antibacterial and antileishmanial activities of imidazolidine and hexahydropyrimidine derivatives. AB - This paper describes the synthesis and in vitro biological activities of imidazolidine and hexahydropyrimidine derivatives against bacteria (Escherichia coli, Staphylococcus aureus and Mycobacterium tuberculosis) and Leishmania protozoa. Out of sixteen heterocyclic derivatives tested, none were cytotoxic against mammalian cells. The compounds showed significant bacterial effects and leishmanicidal activity. Compounds 4a and 4c were active against S. aureus and E. coli, respectively. Compounds 3a-3f, 4h and 4i presented promising results against M. tuberculosis, with MIC values ranging from 12.5 to 25.0 MUg/mL, comparable to the "first and second line" drugs used to treat tuberculosis. Compounds 4a, 4c and 4e were active against L major. Three of them were structurally characterized by single-crystal X-ray diffraction. PMID- 22920152 TI - QSAR study on a series of aryl carboxylic acid amide derivatives as potential inhibitors of dihydroorotate dehydrogenase (DHODH). AB - QSAR study was performed on a series of aryl carboxylic acid amide derivatives (62 analogs) to establish structural features required for human dihydroorotate dehydrogenase (hDHODH) inhibition. Statistical significant QSAR models were developed for the prediction of hDHODH inhibitory activity by applying MLR analysis (r2 = 0.851 and q2 = 0.795), PCR analysis (r2 = 0.713 and q2 = 0.667) and PLS analysis (r2 = 0.848 and q2 = 0.802). QSAR study emphasized the importance of topological, estate number, hydrophobic and alignment independent descriptors for the prediction of hDHODH inhibitory activity. SaasCcount descriptor suggested the presence of carbon atoms in five member aryl ring system. Positive impact of alignment independent descriptors reveals the presence of carbonyl oxygen and chloro group in this series of compounds. DistTopo signifies basic connectivity of atoms in the molecules. High degree of predictability of the proposed QSAR models offers a great potential for the design and development of potent hDHODH inhibitors. PMID- 22920153 TI - Synthesis and QSAR modeling of novel benzimidazolo thiazolidinones, thiazinones and 5-arylidene-2-imino thiazolidinones as antibacterial agents. AB - A novel series of benzimidazolo thiazolidinones, thiazinones and 5-arylidene-2 imino thiazolidinones were synthesized and evaluated for antibacterial activity. The compounds were synthesized in excellent yield and the structures were characterized on the basis of IR, 1H-NMR and MASS spectral data. Most of the synthesized compounds showed good antibacterial activity against Gram-positive and Gram-negative bacteria. QSAR study was carried out with synthesized compounds using molecular descriptors such as electronic, thermodynamic and steric. Molecular descriptors were used to derive QSAR models between antibacterial activity and structural properties. QSAR study suggested the need of a bulky group to enhance the antibacterial activity in these series of compounds. PMID- 22920154 TI - The synthesis, structural study and anticancer activity evaluation of emodin derivatives containing conjugative groups. AB - Eight new emodin derivatives that contain large conjugative system have been synthesized and their anticancer activities also have been evaluated. The result shows that large conjugative system can not enhance the anticancer activities of emodin derivatives, but the introduction of an alkylating center can make emodin derivative effective against cancer cell lines. Compound 12 has the highest alkylating ability, but its anticancer activity is not remarkable, which indicates that there is not a direct correlation between the chemical reactivity of the alkylating agent and the toxic effects. PMID- 22920155 TI - Design, synthesis, and in vitro antitumor evaluation of novel phenylaminopyrimidine derivatives. AB - Two series of novel phenylaminopyrimidine derivatives were designed and synthesized. All target compounds were determined against the human acute monocytic leukemia cell line U937 and the human chronic myeloid leukemia cell line K562 in vitro. Some of the target compounds demonstrated significant inhibitory activity against both cell lines. Compared with the control drug VX 680, 8a, 8e, 8g, 8h, 8j, and 8k demonstrated more potent antitumor activity. The structures of all target compounds were identified by 1H-NMR, 13C-NMR, IR, MS, and EA. PMID- 22920148 TI - The magic of bicelles lights up membrane protein structure. PMID- 22920156 TI - Effect of fasting for Ramadan on kidney graft function during the hottest month of the year (August) in Riyadh, Saudi Arabia. AB - OBJECTIVES: To assess the effect of fasting Ramadan during the hottest month of the year in Riyadh, Saudi Arabia. MATERIALS AND METHODS: This prospective cohort study was performed at the King Fahd National Guard Hospital in Riyadh, Saudi Arabia. We used the Modification of Diet in Renal Disease formula to estimate the glomerular filtration rate in renal transplant patients who fasted and did not fast before and after Ramadan. RESULTS: There were 43 fasters and 37 nonfasters of comparable ages, with fasters having longer posttransplant times compared with nonfasters (P = .0001). The 2 groups had similar mean estimated glomerular filtration rates before Ramadan: 75.6 +/- 29.2 and 65.9 +/- 25.9 mL/min (P = .1) and similar mean estimated glomerular filtration rates 6 months after Ramadan: 77.2 +/- 29.7 and 64.1 +/- 29 mL/min (P = .21). Mean changes in the estimated glomerular filtration rate were similar in the 2 groups: -1.5 +/- 10.9 and -2.8 +/- 19.3 (P = .7) as was the percentage change (-0.2.2 +/- 13.4 and 1.8 +/- 15.9; P = .4). In the fasting group, serum creatinine and estimated glomerular filtration rate were similar before and 6 months after Ramadan: 105.1 +/- 55 and 105.14 +/- 61 MUmol/L (P = 1.0) and 75.6 +/- 29 and 72.2 +/- 29.7 mL/min (P = .36). No significant changes were observed in the nonfasting group. No significant differences were detected regarding fasting in the estimated glomerular filtration rate before and 6 months after Ramadan in the 3 groups with the low, moderate, and high glomerular filtration rates at baseline. CONCLUSIONS: Fasting for Ramadan in August does not adversely affect graft function at a mean follow-up of 7.6 +/- 1.3 months. PMID- 22920157 TI - Input data quality control for NDNQI national comparative statistics and quarterly reports: a contrast of three robust scale estimators for multiple outlier detection. AB - BACKGROUND: To evaluate institutional nursing care performance in the context of national comparative statistics (benchmarks), approximately one in every three major healthcare institutions (over 1,800 hospitals) across the United States, have joined the National Database for Nursing Quality Indicators (NDNQI). With over 18,000 hospital units contributing data for nearly 200 quantitative measures at present, a reliable and efficient input data screening for all quantitative measures for data quality control is critical to the integrity, validity, and on time delivery of NDNQI reports. METHODS: With Monte Carlo simulation and quantitative NDNQI indicator examples, we compared two ad-hoc methods using robust scale estimators, Inter Quartile Range (IQR) and Median Absolute Deviation from the Median (MAD), to the classic, theoretically-based Minimum Covariance Determinant (FAST-MCD) approach, for initial univariate outlier detection. RESULTS: While the theoretically based FAST-MCD used in one dimension can be sensitive and is better suited for identifying groups of outliers because of its high breakdown point, the ad-hoc IQR and MAD approaches are fast, easy to implement, and could be more robust and efficient, depending on the distributional property of the underlying measure of interest. CONCLUSION: With highly skewed distributions for most NDNQI indicators within a short data screen window, the FAST-MCD approach, when used in one dimensional raw data setting, could overestimate the false alarm rates for potential outliers than the IQR and MAD with the same pre-set of critical value, thus, overburden data quality control at both the data entry and administrative ends in our setting. PMID- 22920158 TI - Sustainability of return to work in sick-listed employees with low-back pain. Two year follow-up in a randomized clinical trial comparing multidisciplinary and brief intervention. AB - BACKGROUND: Sick-listed employees with low back pain had similar return to work (RTW) rates at one-year follow-up in a randomized trial comparing two interventions, but the effects were modified by specific workplace related factors. The present study addressed the sustainability of the intervention effects by performing a two-year follow-up and by using different outcome measures. METHODS: A total of 351 employees sick-listed for 3-16 weeks due to LBP were recruited from their general practitioners and were randomly allocated to a hospital-based brief or multidisciplinary intervention. Outcome measures were based on sick leave registered in a national database of social and health related benefits. RTW rates, RTW status, sick leave weeks and sick leave relapse were studied. RESULTS: During the two-year follow-up 80.0% and 77.3% had RTW for at least four weeks continuously, and the percentages with RTW at the 104th week were 61.1% and 58.0% in the brief and multidisciplinary intervention groups, respectively. At the 104th week 16.6% and 18.8% were on sick leave in the two groups, respectively, and about 12% were employed in modified jobs or participated in job training. The number of weeks on sick leave in the first year was significantly lower in the brief intervention group (median 14 weeks) than in the multidisciplinary intervention group (median 20 weeks), but during the second year the number of weeks on sick leave were not significantly different between intervention groups. Subgroups characterised by specific work related factors modified the effect of the intervention groups on RTW rates (p = 0.017). No difference in sick leave relapse was found between the intervention groups. CONCLUSION: The effects of the brief and multidisciplinary interventions at the two-year follow-up were in general similar to the effects at one-year follow-up. TRIAL REGISTRATION: Current Controlled Trials ISRCTN18609003. PMID- 22920159 TI - Narrow band quantitative and multivariate electroencephalogram analysis of peri adolescent period. AB - BACKGROUND: The peri-adolescent period is a crucial developmental moment of transition from childhood to emergent adulthood. The present report analyses the differences in Power Spectrum (PS) of the Electroencephalogram (EEG) between late childhood (24 children between 8 and 13 years old) and young adulthood (24 young adults between 18 and 23 years old). RESULTS: The narrow band analysis of the Electroencephalogram was computed in the frequency range of 0-20 Hz. The analysis of mean and variance suggested that six frequency ranges presented a different rate of maturation at these ages, namely: low delta, delta-theta, low alpha, high alpha, low beta and high beta. For most of these bands the maturation seems to occur later in anterior sites than posterior sites. Correlational analysis showed a lower pattern of correlation between different frequencies in children than in young adults, suggesting a certain asynchrony in the maturation of different rhythms. The topographical analysis revealed similar topographies of the different rhythms in children and young adults. Principal Component Analysis (PCA) demonstrated the same internal structure for the Electroencephalogram of both age groups. Principal Component Analysis allowed to separate four subcomponents in the alpha range. All these subcomponents peaked at a lower frequency in children than in young adults. CONCLUSIONS: The present approaches complement and solve some of the incertitudes when the classical brain broad rhythm analysis is applied. Children have a higher absolute power than young adults for frequency ranges between 0-20 Hz, the correlation of Power Spectrum (PS) with age and the variance age comparison showed that there are six ranges of frequencies that can distinguish the level of EEG maturation in children and adults. The establishment of maturational order of different frequencies and its possible maturational interdependence would require a complete series including all the different ages. PMID- 22920160 TI - Adjusting kinematics and kinetics in a feedback-controlled toe walking model. AB - BACKGROUND: In clinical gait assessment, the correct interpretation of gait kinematics and kinetics has a decisive impact on the success of the therapeutic programme. Due to the vast amount of information from which primary anomalies should be identified and separated from secondary compensatory changes, as well as the biomechanical complexity and redundancy of the human locomotion system, this task is considerably challenging and requires the attention of an experienced interdisciplinary team of experts. The ongoing research in the field of biomechanics suggests that mathematical modeling may facilitate this task. This paper explores the possibility of generating a family of toe walking gait patterns by systematically changing selected parameters of a feedback-controlled model. METHODS: From the selected clinical case of toe walking we identified typical toe walking characteristics and encoded them as a set of gait-oriented control objectives to be achieved in a feedback-controlled walking model. They were defined as fourth order polynomials and imposed via feedback control at the within-step control level. At the between-step control level, stance leg lengthening velocity at the end of the single support phase was adaptively adjusted after each step so as to facilitate gait velocity control. Each time the gait velocity settled at the desired value, selected intra-step gait characteristics were modified by adjusting the polynomials so as to mimic the effect of a typical therapeutical intervention - inhibitory casting. RESULTS: By systematically adjusting the set of control parameters we were able to generate a family of gait kinematic and kinetic patterns that exhibit similar principal toe walking characteristics, as they were recorded by means of an instrumented gait analysis system in the selected clinical case of toe walking. We further acknowledge that they to some extent follow similar improvement tendencies as those which one can identify in gait kinematics and kinetics in the selected clinical case after inhibitory casting. CONCLUSIONS: The proposed walking model that is based on a two-level control strategy has the ability to generate different gait kinematics and kinetics when the set of control parameters that define walking premises change. Such a framework does not have only educational value, but may also prove to have practical implications in pathological gait diagnostics and treatment. PMID- 22920161 TI - Positively charged supported lipid bilayers as a biomimetic platform for neuronal cell culture. AB - The supported lipid bilayer (SLB) is a well-known system for studying the cell membrane and membrane proteins. It is also promising as a platform for studying cell processes: the cell adhesion, the cell membrane receptors, and the intercellular signaling processes. SLBs made of natural lipids appeared to be protein and cell repellent. Thus, to use the SLB as a substrate for cells, one should functionalize them to provide adhesion. In the present paper, we describe a simple approach to promote adhesion of neuronal cells to the SLB without using proteins or peptides, by introducing positively charged lipids 1,2-dioleoyl-3 trimethylammonium-propane (DOTAP) into the SLB made of 1-palmitoyl-2-oleoyl-sn glycero-3-phosphocholine (POPC). We show that neurons adhere to these bilayers and grow for at least 10 days. The SLBs themselves were found to degrade with time in cell culture conditions, but maintained fluidity (as revealed by fluorescence recovery after photobleaching), demonstrating the possibility of using SLBs for studying neuronal cells in culture. PMID- 22920162 TI - [Implication of bone marrow microenvironment in pathogenesis of multiple myeloma]. AB - Multiple myeloma is a hematooncological disease characterized by malignant proliferation of plasma cells. These cells accumulate in the bone marrow where they suppress physiological hematopoiesis; at the same time, these cells interact with a wide variety of cytokines, growth factors and adhesion molecules. It is obvious that the bone marrow microenvironment plays an important role in disease pathogenesis as well as treatment resistance. PMID- 22920163 TI - [CT colonography - evolution of methodology and indications]. AB - BACKGROUND: Advances in CT scanners technology and computing in 90s allowed visual reconstruction of hollow organs inner surface. This method which was mainly used for colon wall imaging had to deal with several limitations from the very first years caused by poorly developed methodology of colonic preparation and distension as well as high radiation exposure. DESIGN: Aim of the paper is to provide an overview of technical and methodological innovations that can at least partially overcome above mentioned shortcomings. Due to these changes, CT colonography became the recognized method after incomplete or impossible optical colonography. Specific patient subgroups which particularly benefit from this modality and unresolved role of the CT colonography in colorectal cancer screening are also mentioned. CONCLUSION: CT colonography is a relatively new method that can not completely replace optical colonoscopy. Thanks to advances in technology, however, it became a valid diagnostic tool with certain advantages over other imaging or invasive methods. These benefits can be handed over to a patient when the examination is carefully indicated. PMID- 22920164 TI - [Long non-coding RNAs and their relevance in cancer]. AB - A major portion of the eukaryotic genome is occupied by DNA sequences; transcripts of these sequences do not code for proteins. This part of the eukaryotic genome is transcribed in a developmentally regulated manner or as a response to external stimuli to produce large numbers of long non-coding RNAs (lncRNAs). Genome-wide studies indicate the existence of more than 3,300 lncRNAs. Long non-coding RNAs are tentatively defined as molecules of ncRNAs that are more than two hundred nucleotides long. Due to the complexity and diversity of their sequences, progress in the field of lncRNAs has been very slow. Nonetheless, lncRNAs have emerged as key molecules involved in the control of transcriptional and posttranscriptional gene regulatory pathways. Although limited numbers of functional lncRNAs have been identified so far, the immense regulatory potential of lncRNAs is already evident, emphasizing that a genome-wide characterization of functional lncRNAs is needed. The fact that many lncRNAs are deregulated in various human cancers, together with their functional characteristics, implies their eminent role in carcinogenesis. In this review, we summarize novel classes of lncRNAs, describe their biological functions emphasizing their roles in tumor biology and translational oncology research. PMID- 22920165 TI - [Treatment of Langerhans cells histiocytosis by cladribin reached long-term complete remission in 9 out of 10 adult patients]. AB - BACKGROUND: The effectiveness of cladribine depends on the ratio of activating (deoxycytidine kinase) and inactivating (5-nucleotidase) enzymes. Not only is this ratio high in resting lymphocytes but also in Langerhans cells as well in some other histiocytic cells. Therefore, cladribine shows high effectiveness in patients with Langerhans cell histiocytosis (LCH). In 2003, the first report on excellent results with cladribine in first line treatment of patients with multisystem or multifocal LCH was published. That is why we use cladribine for adult patients with relapsing form of LCH and also for first line treatment of multifocal and multisystem LCH at our department. PATIENTS AND METHODS: Since 2001, we have treated altogether 10 adults (9 male and 1 female) with cladribine. The median age at diagnosis was 31.5 years (range: 5-45). The multiorgan form of the disease was present in 8 patients, and 2 patients had the multifocal skeletal form with aggressive disease course. Cladribine at a dose of 5 mg/m2 SC per day was given as a 5-day course at 28-day intervals. In cases of insufficient effectiveness, in two patients after the 3rd cycle with cladribine monotherapy, we proceeded to combination therapy with cladribine of 5 mg/m2 per day, cyclophosphamide 150 mg/m2 per day and dexamethasone 20 mg per day, all on days 1 5. We planned 6 cycles at the most. RESULTS: The median of cladribine cycles was 5 (range: 4-6). Altogether, 10 patients finished therapy; out of them 9 are in complete remission with the follow-up median of 26 months (range: 16-94). Treatment failure was noted only in 1 patient - in 60 days after therapy cessation the disease progressed and required further treatment (CHOEP, high-dose BEAM chemotherapy with autologous transplantation followed by Revlimid treatment and allogeneic transplantation). Treatment response - disappearance of infiltrate in the pituitary infundibulum - was observed in 2 patients with LCH affecting the pituitary infundibulum. CONCLUSION: Cladribine is a suitable medication for multiorgan and multifocal forms of LCH. In our group of ten evaluated patients, cladribine therapy resulted in 90% of long-term complete remissions. Three patients had CNS involvement and in all three patients, treatment responses have been achieved. PMID- 22920166 TI - Comparision of histological types of primary and subsequent relapsing basal cell carcinomas of the skin. AB - BACKGROUND: Basal cell carcinoma (BCC) recurrences are relatively frequent event in a routine dermatologic practice. One of the most important factor which impacts risk of their development is a histomorphological appearance of tumor. DESIGN: The purpose of our study was to compare histological types of primary and corresponding relapsing BCCs of the skin. MATERIAL AND METHODS: The study included 36 cases of BCC recurrences from 34 patients, 17 women and 17 men. The patients ranged in age from 32 to 97 years, with a mean age of 67.1 years at the time of (the first) recurrence. RESULTS: Both tumor groups generally exhibited the same proportion of indolent and aggressive histological phenotype. In 21 cases (58.4%), we found an identical histological BCC type in primary and subsequent relapsing lesion. In 3 cases (8.3%), primary lesion showed indolent histological features without aggressive--growth component, while recurrent tumor already manifested it. Conversely, in next 3 cases (8.3%) primary tumor exhibited focal infiltrative-growth features and corresponding relapsing lesion did not. Of the remaining 9 cases (25%), histomorphological phenotype was not identical, but it showed the same prognostic histological tumor variant. CONCLUSION: Based on the results of our study it can be assumed that a BCC recurrence is a dynamic histogenetic process, during which the phenotypic transformation and the changes in histomorphological picture of lesions occur, probably as a result of the interactions between cancer cells and re-modulated surrounding stroma. PMID- 22920167 TI - [EGFR mutations in patients with advanced NSCLC]. AB - BACKGROUND: Molecular targeted therapy based on tyrosine kinase inhibitors, directed at the epidermal growth factor receptor (EGFR) is one of novel options for management of NSCLC. EGFR gene mutations, exon 19 deletions and exon 21 point mutations (L858R) are good predictors of response to EGFR-TKI treatment. The aim of this study was to assess the incidence of EGFR mutations in a large cohort of Europeans with advanced NSCLC and subsequently to evaluate their impact on the effect of EGFR-TKI treatment. PATIENTS AND METHODS: In total, 613 patients with advanced stage NSCLC (IIIB, IV) were genetically tested. The effect of treatment was evaluated in 410 patients treated with EGFR-TKI. Survival was evaluated using Kaplan-Meier method, and statistical comparison was performed using log-rank test. RESULTS: EGFR mutations were detected in 73 (11.9%) patients. Exon 19 deletions were detected in 49 patients, exon 21 point mutations (L858R) were detected in 22 patients, and both mutation types were detected in 2 patients. An increased incidence of EGFR mutations among patients with adenocarcinoma (14.9% vs 7.8%, p = 0.008), women (20.2% vs 7.1%, p < 0.001) and nonsmokers (29.9% vs 7.0%, p < 0.001) was demonstrated. Sixty patients with EGFR mutation and 350 patients with wild-type EGFR were treated with EGFR-TKI. Median PFS in patients harboring EGFR mutation was 7.2 vs 2.0 months in patients harboring wild-type EGFR (p < 0.001), median OS in patients harboring EGFR mutation was 14.5 vs 7.5 months in patients harboring wild-type EGFR (p = 0.019). CONCLUSION: The incidence of EGFR mutations in the studied population, their increased incidence among patients with adenocarcinoma, women and non-smokers correlated with data previously published. Results of survival analysis in patients treated with EGFR TKI confirmed high potential of EGFR mutations to predict good effect of the EGFR TKI treatment. Genetic testing in patients with NSCLC should be a standard part of diagnostic procedures PMID- 22920168 TI - [HARDROCK project: parametric data collection and analysis of patients with head and neck cancer in the comprehensive cancer centre of Ostrava - role of fractionation and target volume definition in radiotherapy]. AB - BACKGROUND: The HARDROCK project has been designed as a retrospective data collection study in a locally run database system, which fulfils the requirements on the basic version of electronic medical records of cancer patients. The diagnostic category of head and neck tumors has been selected on purpose, as it presents a major problem in the Comprehensive Cancer Centre of Ostrava, and it is relevant given the high incidence and mortality in the Moravian-Silesian Region. The target parameters of the assessment include short-term as well as long-term treatment results in patients with head and neck tumors, evaluated with standard indicators of treatment response and survival. A special emphasis is put on major treatment modalities, i.e. surgery and radiation therapy, and on related complications. PATIENTS AND METHODS: In this article, we present a sample of collected data. The data from patients has been separated into two groups based on the time of their acquisition: data from patients treated in 2004-2005 versus patients treated in 2006-2010. This division was given by the change of treatment protocols in 2006 introducing accelerated radiotherapy with concomitant boost and expanded lymph node irradiation field compared to normofractionation and hyperfractionation regimes used before 2006. RESULTS: Introduction of new irradiation techniques did not increase the rate of acute toxicity but slightly increased late toxicity. Further, we found a decrease of number of relapse and improved overall survival in patients with stage IV disease treated in 2006-2010. CONCLUSION: The project results will contribute methodically to the exact evaluation of diagnostics and treatment of patients with head and neck cancer and will help to optimize their medical care. PMID- 22920169 TI - [What is the prognostic importance of molecular genetic factors in endometrial carcinoma?]. AB - BACKGROUND: Evaluation of the importance of molecular genetic factors in endometrial carcinoma based on our review of available literature, and in the case of K- ras mutation based on our own data. The aim of the original part of our study was to compare the presence of K- ras mutation in early stages of endometroid carcinoma with normal endometrium and evaluate the role of the mutation in endometrial carcinogenesis. MATERIAL AND METHODS: Molecular bio logical analysis was performed to detect K- ras mutation in samples of endometrial tissue obtained from women treated in the past at the Department of Obstetrics and Gynecology, University Hospital Hradec Kralove. The detection was made from DNA isolated from paraffin embedded sections using K- ras -StripAssay, ViennaLab Diagnostics GmbH. RESULTS: K- ras mutation was found in 7 out of 30 specimens of endometroid carcinoma in stage I (23%) and in 3 of 20 specimens of normal endometrium in the control group (15%). K- ras mutations were more frequent in IA stage and grade 1 of endometroid carcinoma. CONCLUSION: The importance of molecular genetic factors in endometrial carcinoma differs depending on the type of carcinoma. In more common type 1 endometroid cancer, published data are not as clear as in type 2 carcinoma, in which prevalence of alteration of p53 reaches 90%. Results of our study performed on local population of women support the theory about the possible role of K- ras mutation as an early event in the process of endometrial carcinogenesis in type 1 tumors. PMID- 22920170 TI - [Hepatocellular carcinoma - long-term treatable disease]. AB - Case report - 30 months surviving patient with unresectable hepatocellular carcinoma treated with sorafenib. PMID- 22920171 TI - Paratesticular mesothelioma in young age. Case report. AB - BACKGROUND: Malignant mesothelioma is a neoplasm arising in serosal membranes in the body cavities. Usual presentation of the tumor is in the pleura, peritoneum and less frequently pericardium. Paratesticular mesothelioma is the rarest known form of malignant mesothelioma with only a limited number of reported cases. CASE: A case of malignant epithelial mesothelioma of the tunica vaginalis testis was reported with presentation of hydrocele and multinodular intrascrotal masses in a 20-year old male. The patient underwent surgery for post-traumatic long-term hydrocele with perioperative discovery of multiple small exophytic structures. After histological findings of the malignant mesothelioma of tunica vaginalis testis, he underwent left-side orchiectomy, followed by inguinal and pelvic lymph node dissection. Clinical staging did not reveal distant metastases. Regular follow-up visits based on physical examinations and imaging studies are to date negative for recurrence. CONCLUSION: Literature data were reviewed, and possible risk factors for the development of the neoplasm were analysed. PMID- 22920172 TI - [Treatment for volume upgrading of the low-grade supratentorial glioma after the subtotal neurosurgical resection]. AB - BACKGROUND: Low-grade gliomas WHO II (LGG) are mostly detected in patients with neurological symptomatology between 20 and 45 years of age very often as secondary epilepsy. We present two cases in which low-grade gliomas attacked neurological zones. Neurosurgical resection was subtotal because of the risk of the damage in neurocognitive functions in both these patients. After the operation, both patients were followed at neurosurgery department in regular intervals using different imaging methods (MRI, MRS and PET). After resections, the MRI detected the enlargement of the volumes of the tumor residua in both patients. PATIENTS AND METHODS: Owing to the risk of up-grading to high-grades glial tumors (overexpression of EGFR and VEGF), both patients were indicated for curative treatment by external beam radiotherapy combined with chemotherapy (Temodal(r)) and adjuvant chemotherapy. RESULTS: After the end of this treatment, the MRI proved considerable partial regressions in both patients. Moreover, three months later, the MRI did not prove any residual disease. CONCLUSION: Radiotherapy combined with the administration of Temodal should prolong the OS and TTP in patients with a high risk of up-grading of low-grade gliomas of the brain. Both the patients are in a follow-up program, also because of the risk of duplicite brain tumor. PMID- 22920173 TI - [The RENIS clinical registry]. PMID- 22920174 TI - Early-life disruption of epigenetic marks may contribute to the origins of mental illness. PMID- 22920175 TI - The importance of epigenomic studies in schizophrenia. PMID- 22920177 TI - Differential epigenetic regulation of GATA4 in gastric adenocarcinomas. PMID- 22920178 TI - miRNAs as mediators of drug resistance. AB - Chemoresistance of tumors is often reported to be due to overexpression of efflux transporters or genetic alterations of signaling pathways. More recently, there is increasing evidence that epigenetic modification contributes to the phenomenon of drug resistance. Despite alteration of DNA methylation or histone modifications, deregulated miRNA expression patterns of tumor cells have been identified as interfering with drug response. Attempts to modify the expression of selected miRNAs have partly led to intriguing improvements of chemotherapy response. This review focuses on the major epigenetic mechanisms, including the role of miRNA expression contributing to drug resistance and the role of epigenetic drugs to overcome nonresponse arising under conventional chemotherapy. PMID- 22920180 TI - Single-molecule, genome-scale analyses of DNA modifications: exposing the epigenome with next-generation technologies. AB - DNA modifications represent an integral part of the epigenome and they have a pivotal role in regulation of genome function. Despite the wide variety of analytical techniques that have been developed to detect DNA modifications, their investigation at the single-genome level is only beginning to emerge. In contrast to population-averaged analyses, single-molecule approaches potentially allow the mapping of epigenetic linkage between distantly located genomic regions, the locus-specific analysis of repetitive DNA elements, as well as determination of allele-specific DNA modification patterns. In this article, the properties of current single-molecule analyses of DNA modifications will be discussed and compared. In addition, the possible biomedical and discovery research applications of single-molecule epigenomics will be highlighted. PMID- 22920182 TI - The lasting legacy of social stress on the epigenome of the hypothalamic pituitary-adrenal axis. AB - Social stress is a major factor contributing to early-life adversity that has taken on an epidemic scale. Early social stress leads to long-lasting changes in behavior, cognition, mood and neuroendocrine responses predisposing to or sheltering from stress-related diseases later in life. Epigenetic mechanisms are thought to mediate the effects of early social stress on the epigenome, and can give rise to persistent memories hard coded by DNA methylation. The hypothalamic pituitary-adrenal axis canalizes early social stress, which leaves its footprints at key regulator sites of this highly plastic system. Thereby, social stress induced DNA memories mirror the complexity of the stress response and sex differences in brain epigenetics. Timely therapeutic interventions should aim to attenuate early social stress-derived DNA markings and their life-long consequences for mental health. PMID- 22920181 TI - Epigenetics and childhood asthma: current evidence and future research directions. AB - Asthma is the most common chronic disease of childhood, affecting one in eight children in the USA and worldwide. It is a complex disease, influenced by both environmental exposures and genetic factors. Although epigenetic modifications (DNA methylation, histone modification and miRNA) can affect transcriptional activity in multiple genetic pathways relevant for asthma development, very limited work has been carried out so far to examine the role of epigenetic variations on asthma development and management. This review provides a brief overview of epigenetic modifications, summarizes recent findings, and discusses some of the major methodological concerns that are relevant for asthma epigenetics. PMID- 22920179 TI - The epigenetic lorax: gene-environment interactions in human health. AB - Over the last decade, we have witnessed an explosion of information on genetic factors underlying common human diseases and disorders. This 'human genomics' information revolution has occurred as a backdrop to a rapid increase in the rates of many human disorders and diseases. For example, obesity, Type 2 diabetes, asthma, autism spectrum disorder and attention deficit hyperactivity disorder have increased at rates that cannot be due to changes in the genetic structure of the population, and are difficult to ascribe to changes in diagnostic criteria or ascertainment. A likely cause of the increased incidence of these disorders is increased exposure to environmental factors that modify gene function. Many environmental factors that have epidemiological association with common human disorders are likely to exert their effects through epigenetic alterations. This general mechanism of gene-environment interaction poses special challenges for individuals, educators, scientists and public policy makers in defining, monitoring and mitigating exposures. PMID- 22920186 TI - Enhanced detection and characterization of glutathione-trapped reactive metabolites by pseudo-MS(3) transition using a linear ion trap mass spectrometer. AB - We present a simple and label-free approach to characterize glutathione (GSH) trapped reactive metabolites from a single LC-MS analysis employing a linear ion trap mass spectrometer. The GSH specific fragment anion m/z 272 was first generated from the nonselective in-source fragmentation of intact conjugates. GSH conjugates were then detected by selected reaction monitoring (SRM) of the anion pair m/z 272 -> 179 or 210. The resultant SRM peaks represented putative GSH conjugates which were then further characterized from their MS and MS(2) data acquired in both positive and negative ion modes. The method is demonstrated with test compounds that are all known to form GSH conjugates. PMID- 22920183 TI - Sensitive periods in epigenetics: bringing us closer to complex behavioral phenotypes. AB - Genetic studies have attempted to elucidate causal mechanisms for the development of complex disease, but genome-wide associations have been largely unsuccessful in establishing these links. As an alternative link between genes and disease, recent efforts have focused on mechanisms that alter the function of genes without altering the underlying DNA sequence. Known as epigenetic mechanisms, these include DNA methylation, chromatin conformational changes through histone modifications, ncRNAs and, most recently, 5-hydroxymethylcytosine. Although DNA methylation is involved in normal development, aging and gene regulation, altered methylation patterns have been associated with disease. It is generally believed that early life constitutes a period during which there is increased sensitivity to the regulatory effects of epigenetic mechanisms. The purpose of this review is to outline the contribution of epigenetic mechanisms to genomic function, particularly in the development of complex behavioral phenotypes, focusing on the sensitive periods. PMID- 22920184 TI - DNA demethylation by TDG. AB - DNA methylation has long been considered a very stable DNA modification in mammals that could only be removed by replication in the absence of remethylation - that is, by mere dilution of this epigenetic mark (so-called passive DNA demethylation). However, in recent years, a significant number of studies have revealed the existence of active processes of DNA demethylation in mammals, with important roles in development and transcriptional regulation, allowing the molecular mechanisms of active DNA demethylation to be unraveled. In this article, we review the recent literature highlighting the prominent role played in active DNA demethylation by base excision repair and especially by TDG. PMID- 22920189 TI - Isolated ocular surface squamous neoplasia in a renal transplant recipient. AB - Ocular surface squamous neoplasia is a rare complication after a kidney transplant, related with increased risk and poor prognosis. Generally, ocular surface squamous neoplasia in kidney transplant patients is associated with skin lesions. We report a case of ocular surface squamous neoplasia without skin lesions in a kidney transplant recipient. Systematic periodic ophthalmic evaluation of recipients may help ensure the early diagnosis of subtle ocular surface squamous neoplasia. PMID- 22920187 TI - Generation and characterization of non-competitive furin-inhibiting nanobodies. AB - The PC (proprotein convertase) furin cleaves a large variety of proproteins and hence plays a major role in many pathologies. Therefore furin inhibition might be a good strategy for therapeutic intervention, and several furin inhibitors have been generated, although none are entirely furin-specific. To reduce potential side effects caused by cross-reactivity with other proteases, dromedary heavy chain-derived nanobodies against catalytically active furin were developed as specific furin inhibitors. The nanobodies bound only to furin but not to other PCs. Upon overexpression in cell lines, they inhibited the cleavage of two different furin substrates, TGFbeta (transforming growth factor beta) and GPC3 (glypican 3). Purified nanobodies could inhibit the cleavage of diphtheria toxin into its enzymatically active A fragment, but did not inhibit cleavage of a small synthetic peptide-based substrate, suggesting a mode-of-action based on steric hindrance. The dissociation constant of purified nanobody 14 is in the nanomolar range. The nanobodies were non-competitive inhibitors with an inhibitory constant in the micromolar range as demonstrated by Dixon plot. Furthermore, anti-furin nanobodies could protect HEK (human embryonic kidney)-293T cells from diphtheria toxin-induced cytotoxicity as efficiently as the PC inhibitor nona-D-arginine. In conclusion, these antibody-based single-domain nanobodies represent the first generation of highly specific non-competitive furin inhibitors. PMID- 22920188 TI - Diverse modulation of spa transcription by cell wall active antibiotics in Staphylococcus aureus. AB - BACKGROUND: The aim of this study was to investigate the effect of various classes of clinically relevant antibiotics at sub-lethal concentrations on virulence gene expression and biofilm formation in Staphylococcus aureus. FINDINGS: LacZ promoter fusions of genes related to staphylococcal virulence were used to monitor the effects of antibiotics on gene expression in a disc diffusion assay. The selected genes were hla and spa encoding alpha-hemolysin and Protein A, respectively and RNAIII, the effector molecule of the agr quorum sensing system. The results were confirmed by quantitative real-time PCR. Additionally, we monitored the effect of subinhibitory concentrations of antibiotics on the ability of S. aureus to form biofilm in a microtiter plate assay. The results show that sub-lethal antibiotic concentrations diversely modulate expression of RNAIII, hla and spa. Consistently, expression of all three genes were repressed by aminoglycosides and induced by fluoroquinolones and penicillins. In contrast, the beta-lactam sub-group cephalosporins enhanced expression of RNAIII and hla but diversely affected expression of spa. The compounds cefalotin, cefamandole, cefoxitin, ceftazidime and cefixine were found to up-regulate spa, while down regulation was observed for cefuroxime, cefotaxime and cefepime. Interestingly, biofilm assays demonstrated that the spa-inducing cefalotin resulted in less biofilm formation compared to the spa-repressing cefotaxime. CONCLUSIONS: We find that independently of the cephalosporin generation, cephalosporins oppositely regulate spa expression and biofilm formation. Repression of spa expression correlates with the presence of a distinct methyloxime group while induction correlates with an acidic substituted oxime group. As cephalosporines target the cell wall penicillin binding proteins we speculate that subtle differences in this interaction fine-tunes spa expression independently of agr. PMID- 22920190 TI - A Chinese herbal formula "Gan-Lu-Yin" suppresses vascular smooth muscle cell migration by inhibiting matrix metalloproteinase-2/9 through the PI3K/AKT and ERK signaling pathways. AB - BACKGROUND: This study was to explore the effects of Gan-Lu-Yin (GLY) on the migration of vascular smooth muscle cells (VSMCs) induced by fetal bovine serum and on neointima formation in a rat model of carotid artery balloon injury. METHODS: VSMCs were treated with different concentrations of GLY, and then analyzed with Flow cytometric analysis, zymography, transwell, and western blotting. SD rats received balloon-injury were analyzed with H&E staining. RESULTS: Our results showed that GLY significantly decreased the thickness of neointima. The inhibition by non-cytoxic doses of GLY of VSMCs migration was through its negative regulatory effects on phosphorylated ERK1/2, PI3K/AKT, and FAK. The data showed that GLY can inhibit the migration of VSMCs cells, and might block injury-induced neointima hyperplasia via the inhibition of VSMCs migration, without inducing apoptosis. CONCLUSIONS: These observations provide a mechanism of GLY in attenuating cell migration, thus as a potential intervention for restenosis. PMID- 22920191 TI - The neuroprotective effect of post ischemic brief mild hypothermic treatment correlates with apoptosis, but not with gliosis in endothelin-1 treated rats. AB - BACKGROUND: Stroke remains one of the most common diseases with a serious impact on quality of life but few effective treatments exist. Mild hypothermia (33 degrees C) is a promising neuroprotective therapy in stroke management. This study investigated whether a delayed short mild hypothermic treatment is still beneficial as neuroprotective strategy in the endothelin-1 (Et-1) rat model for a transient focal cerebral ischemia. Two hours of mild hypothermia (33 degrees C) was induced 20, 60 or 120 minutes after Et-1 infusion. During the experiment the cerebral blood flow (CBF) was measured via Laser Doppler Flowmetry in the striatum, which represents the core of the infarct. Functional outcome and infarct volume were assessed 24 hours after the insult. In this sub-acute phase following stroke induction, the effects of the hypothermic treatment on apoptosis, phagocytosis and astrogliosis were assessed as well. Apoptosis was determined using caspase-3 immunohistochemistry, phagocytic cells were visualized by CD-68 expression and astrogliosis was studied by glial fibrillary acidic protein (GFAP) staining. RESULTS: Cooling could be postponed up to 1 hour after the onset of the insult without losing its positive effects on neurological deficit and infarct volume. These results correlated with the caspase-3 staining. In contrast, the increased CD-68 expression post-stroke was reduced in the core of the insult with all treatment protocols. Hypothermia also reduced the increased levels of GFAP staining, even when it was delayed up to 2 hours after the insult. The study confirmed that the induction of the hypothermia treatment in the Et-1 model does not affect the CBF. CONCLUSIONS: These data indicate that in the Et-1 rat model, a short mild hypothermic treatment delayed for 1 hour is still neuroprotective and correlates with apoptosis. At the same time, hypothermia also establishes a lasting inhibitory effect on the activation of astrogliosis. PMID- 22920192 TI - Development and evaluation of an immunochromatographic strip for rapid detection of porcine hemagglutinating encephalomyelitis virus. AB - BACKGROUND: The incidence of PHE among pigs in many countries is on the rise, and it has caused great economic losses to the pig industry. Therefore, the development of a sensitive, specific, and easily-performed assay is crucial for the rapid detection and surveillance of PHE-CoV infection and transmission. RESULTS: An immunochromatographic strip was developed for the detection of PHE CoV. The colloidal gold-labeled MAb 4D4 was used as the detection reagent, and the MAb 1E2 and goat anti-mouse IgG coated the strip's test and control lines, respectively. The immunochromatographic strip was capable of specifically detecting PHE-CoV with a HA unit of 2 within 10 min. Storage of the strips at room temperature for 6 months or at 4 degrees C for 12 months did not change their sensitivity or specificity. Using RT-PCR as a reference test, the relative specificity and sensitivity of the immunochromatographic strip were determined to be 100% and 97.78%, respectively. There was an excellent agreement between the results obtained by RT-PCR and the immunochromatographic strips (kappa = 0.976). Additionally, there was a strong agreement between the sandwich enzyme-linked immunosorbent assay (ELISA) and immunochromatographic strips (Kappa = 0.976). When the immunochromatographic strips were used for diagnosing PHE-CoV infection in the Jilin Province, the PHE-CoV-positive rate ranged from 61.54% in the Jilin district to 17.95% in the Songyuan district. CONCLUSIONS: Based on its high specificity, sensitivity, and stability, the immunochromatographic strip would be suitable for on-site detection of PHE-CoV for surveillance and epidemiological purposes. PMID- 22920193 TI - Protein-glycosphingolipid interactions revealed using catch-and-release mass spectrometry. AB - Glycosphingolipids (GSL) on the surface of cells are important receptors in antigen/microbial recognition and cell adhesion. However, their functional characterization is often challenging. We have developed a catch-and-release electrospray ionization mass spectrometry (CaR-ESI-MS) assay for the identification of specific interactions between water-soluble proteins or protein complexes with GSL incorporated into nanodiscs. The specificity and sensitivity of the assay is demonstrated for interactions involving cholera toxin and Shiga toxin, with their natural GSL receptors, the ganglioside GM1, and the globotriaosylceramide Gb3, respectively. The detection of binding between cholera toxin and GM1 within a mixture of lipids extracted from cell membranes highlights the potential of this assay for the discovery of biologically relevant protein GSL interactions. PMID- 22920194 TI - Structural optimization and evaluation of butenolides as potent antifouling agents: modification of the side chain affects the biological activities of compounds. AB - A recent global ban on the use of organotin compounds as antifouling agents has increased the need for safe and effective antifouling compounds. In this study, a series of new butenolide derivatives with various amine side chains was synthesized and evaluated for their anti-larval settlement activities in the barnacle, Balanus amphitrite. Side chain modification of butenolide resulted in butenolides 3c-3d, which possessed desirable physico-chemical properties and demonstrated highly effective non-toxic anti-larval settlement efficacy. A structure-activity relationship analysis revealed that varying the alkyl side chain had a notable effect on anti-larval settlement activity and that seven to eight carbon alkyl side chains with a tert-butyloxycarbonyl (Boc) substituent on an amine terminal were optimal in terms of bioactivity. Analysis of the physico chemical profile of butenolide analogues indicated that lipophilicity is a very important physico-chemical parameter contributing to bioactivity. PMID- 22920195 TI - Photoinduced charge transfer properties and photocatalytic activity in Bi2O3/BaTiO3 composite photocatalyst. AB - A series of Bi(2)O(3)/BaTiO(3) composite photocatalysts with different mass ratios of Bi(2)O(3) vs BaTiO(3) were prepared by an impregnating-annealing method. X-ray diffraction (XRD), high-resolution transmission electron microscopic (HRTEM), and UV-vis diffuse reflection spectroscopy (DRS) confirmed that Bi(2)O(3) and BaTiO(3) coexisted in the composites. The results of surface photovoltage (SPV) experiments showed enhancements of photovoltaic response in composites, which indicated a higher separation efficiency of photoinduced charges due to the establishment of an efficient interfacial electric field between Bi(2)O(3) and BaTiO(3) in the composites. The consistency of phtocatalytic activity and photovoltaic response intensity of photocatalysts showed that the efficiency interfacial electric field between Bi(2)O(3) and BaTiO(3) played an important role in improving the degradation efficiency of Rhodamine B (RhB). The 60%-Bi(2)O(3)/BaTiO(3) sample with the best activity was found by optimizing the mass ratios of Bi(2)O(3) vs. BaTiO(3). On the basis of the work function (WF) measurements, a reasonable energy band diagram was proposed for BaTiO(3)/Bi(2)O(3) composite. It would be helpful in designing and constructing high efficiency heterogeneous semiconductor photocatalyst. PMID- 22920196 TI - [Editorial. Hereditary neoplastic diseases]. PMID- 22920199 TI - [The Claus model for estimating lifetime cumulative risk for breast cancer in women with a positive family anamnesis]. PMID- 22920200 TI - [Juvenile polyposis syndrome]. AB - Juvenile polyposis syndrome (JPS) is an autosomal dominant disorder characterized by the occurrence of juvenile polyps and predisposition to cancer of the gastrointestinal tract (GIT). Characteristic feature of juvenile polyps are irregular cystic glands filled with mucus not observed in other colorectal cancer syndromes. Germline mutations in the SMAD4 and BMPR1A genes are found in 40% of the JP individuals. Hereditary hemorrhagic telangiectasia (HHT) and higher frequency of gastric polyposis are associated mostly with SMAD4 mutations. PMID- 22920201 TI - [Birt-Hogg-Dube syndrome]. AB - Birt-Hogg-Dube syndrome (BHDS, MIM 135150) is an autosomal dominant condition characterized by presence of skin fibrofolliculomas, lung cysts, spontaneous pneumothorax and renal cancer. The disease is caused by germ-line mutations of the FLCN gene, which encodes protein folliculin. BHDS is a rare condition with high penetrance and variable expression. Clinical recommendations include increased care during general anesthesia due to a higher risk of pneumothorax, and long-term follow-up due to an elevated risk of renal cancer. Diagnostic and predictive DNA tests are available; prenatal and preimplantation diagnosis is possible. PMID- 22920202 TI - [Hereditary pheochromocytoma and paraganglioma]. AB - Pheochromocytomas and paragangliomas are tumors arising from chromaffin cells. These tumors produce catecholamines and are typically found with symptoms and signs that may include hypertension (persistent or episodic), palpitations, headache and sweating. So far, 10 different genes have been associated with both tumors and other genes are expected to be detected. Pheochromocytoma and paraganglioma can occur as a part of genetic syndromes - familial paragangliomas (SDH genes, SDHAF2 gene), von Hippel-Lindau syndrome (VHL gene), multiple endocrine neoplasia type 2 (RET gene), and neurofibromatosis type 1 (NF1 gene). These tumors may be the first and only manifestation of these genetic syndromes. Patients with SDHB mutations are at high risk to develop malignant disease and unfortunately current therapeutic options for malignant form of disease are poor. Genetic testing plays a key role in the management of these tumors and therefore not only index patients with pheochromocytoma but also relatives should be tested. Management of this disease requires multidisciplinary cooperation and should be performed in the specialized medical centres. PMID- 22920203 TI - [Rhabdoid tumours]. AB - Rhabdoid tumors (RT) are rare highly malignant tumors. They are part of the embryonic types of tumors and therefore occur in early childhood (between ages of 0-2 years). The most common locations are brain and kidney, but RTs arising usually from soft tissues have been reported widely at most anatomical sites in the body. These tumors are composed of rhabdoid cells alone or as a mixture with primitive neuroectodermal cells, mesenchymal cells and/or epithelial cells, commonly denoted as atypical teratoid/rhabdoid tumours (AT/RT). Based on extremely rare incidence and usually non-specific histological picture, molecular genetic studies are extremely helpful in confirming diagnosis of RT. Biallelic inactivation mutation of the SMARCB1 gene plays a crucial role in the pathogenesis of most RT. One third of mutations are germline mutations leading to the designation of the so-called rhabdoid predisposition syndrome. Molecular genetic analysis of the SMARCB1 gene might be beneficial in the establishment of correct diagnosis, genetic counselling and for epidemiologic studies. PMID- 22920204 TI - [Hereditary diffuse gastric cancer]. AB - Hereditary diffuse gastric cancer is an autosomal dominant syndrome with a high lifetime risk of diffuse gastric cancer and also a high risk of lobular breast carcinoma. Hereditary diffuse gastric cancer (HDGC) is characterized by late presentation and a poor prognosis. The average age of onset of HDGC is 38 years, with a range of 14-69 years. The estimated lifetime risk of developing gastric cancer by age 80 is 67% for men and 83% for women. Many families with HDGC have germline mutations in the E-cadherin (CDH1) gene. We describe indication for genetic testing of germline mutations in CDH1 gene, possibilities of predictive testing, preventive care, prophylactic gastrectomy and preimplantation diagnosis. PMID- 22920205 TI - [Constitutional mismatch repair-deficiency syndrome (CMMR-D) - a case report of a family with biallelic MSH6 mutation]. AB - This work gives comprehensive information about new recessively inherited syndrome characterized by development of childhood malignancies. Behind this new described syndrome, called Constitutional mismatch repair-deficiency syndrome (CMMR-D), there are biallelic mutations in genes, which cause adult cancer syndrom termed Lynch syndrom (Hereditary non-polyposis cancer syndrom-HNPCC) if they are heterozygous mutations. Biallelic germline mutations of genes MLH1, MSH2, MSH6 and PMS2 in CMMR-D are characterized by increased risk of hematological malignancies, atypical brain tumors and early onset of colorectal cancers. An accompanying manifestation of the disease are skin spots with diffuse margins and irregular pigmentation reminiscent of Cafe au lait spots of NF1. This paper reports a case of a family with CMMR-D caused by novel homozygous MSH6 mutations leading to gliomatosis cerebri, T-ALL in an 11-year-old female and glioblastoma multiforme in her 10-year-old brother, both with rapid progression of the diseases. A literature review of brain tumors in CMMR-D families shows that they are treatment-resistant and lead to early death. Therefore, this work highlights the importance of early identification of patients with CMMR-D syndrome - in terms of initiation of a screening program for early detection of malignancies as well as early surgical intervention. PMID- 22920206 TI - [Clinical dysmorphic syndromes with tumorigenesis]. AB - Genetic alterations cause predisposition to malignancy by increased cancer risk related to constitutional mutations in growth-regulating or DNA repair genes. Some pediatric malignancies are associated with dysmorphic features in several body areas. Through physical examination, we recognise characteristic signs of genetic dysmorphic disorders, such as somatic overgrowth, undergrowth, macrocephaly, microcephaly and dysmorphic changes of the face, eyes, mouth and lips, heart, gastrointestinal tract, urinary tract, genitalia and skeleton. Recognition of a cancer-associated dysmorphic syndrome allows intensive cancer screening and genetic counseling. Therefore, it is recommended that every child with cancer should be examined by a clinical geneticist. Molecular diagnostics of germinal mutations may very effectively detect families at high risk of malignancy and help provide primary prevention. This work presents clinical syndromes with genetic background and cancer screening recommendations for 18 syndromes with increased cancer risk. PMID- 22920207 TI - [Li-Fraumeni syndrome - a proposal of complex prevention care for carriers of TP53 mutation with total-body MRI]. AB - Li-Fraumeni syndrome (LFS) is one of the most serious hereditary cancer syndromes with high risk of malignancy already in childhood. Adrenocortical carcinoma, brain tumor, leukemia, sarcoma are the most frequent malignancies in children. Early breast cancer, brain tumor, sarcoma, skin cancer, gastrointestinal, lung, gynecological, hematological and other malignancies can be seen in adults. Predictive testing in families with detected LFS and TP53 mutation is offered from the age of 18 for various reasons. One of the most important reasons is a very limited effectivity of prevention especially in children, also the possible risk of psychological harm to the child and his family caused by the diagnosis of this syndrome. Progress in diagnostic methods, especially total body MRI, enables to propose preventive care for early cancer diagnoses for children and adults. Biochemical tests, ultrasound, MRI may improve survival of these high risk individuals and support the possibility of predictive testing in children. PMID- 22920208 TI - [Hereditary leiomyomatosis and renal cell cancer - HLRCC/multiple cutaneous and uterine leimomyomatosis - MCUL]. AB - Hereditary leiomyomatosis and renal cell cancer / multiple cutaneous and uterine leimomyomatosis is a relatively rare autosomal dominant condition which predisposes to the development of cutaneous and uterine leiomyomas and early onset renal cell carcinoma, typically papillary carcinoma type II. It is caused by germline mutations in the FH gene encoding the fumarate hydratase enzyme. The test of fumarate hydratase activity in lymphocytes may be used as a screening method with subsequent mutation analysis of the FH gene in persons with reduced enzyme activity. Persons with this syndrome should be followed to detect any occurrence of these diseases. Treatment of renal cancer associated with the hereditary leiomyomatosis and renal cell cancer syndrome should be radical with respect to its aggressive nature. PMID- 22920210 TI - [Genetic counselling in male carriers of BRCA1 and BRCA2 gene mutations]. AB - BRCA1 and BRCA2 gene mutations cause hereditary breast and ovarian cancer syndrome. The disease has autosomal dominant mode of inheritance, and both genders have the same probability of inheriting the trait. However, the phenotype is different in males and females, and the risk of cancer is significantly lower in males. Although the results of some studies are conflicting, it has been clearly shown that male BRCA mutation carriers are predisposed to an increased risk of breast, prostate, pancreas and stomach cancer when compared to the ge neral population. With respect to the routinely performed predictive testing of healthy persons in families with BRCA gene mutations, results of these studies are taken into consideration. Screening programs are offered to the patients with the goal of early detection of cancer. PMID- 22920209 TI - [The clinical importance of a genetic analysis of moderate-risk cancer susceptibility genes in breast and other cancer patients from the Czech Republic]. AB - BACKGROUND: Analysis of the major breast cancer (BC) predisposition genes BRCA1 and BRCA2 enables identification of high-risk individuals. Specialized programs enrolling the carriers of BRCA1/2 mutations facilitate an improvement in prevention and early diagnostics in asymptomatic individuals and rationalize the selection of individualized treatment in case of a BC onset. However, the carriers of mutations in the major predisposition genes represent only approximately 25% of cases among high-risk BC patients. Numerous candidate predisposing genes for breast and other cancers have recently been identified. The risk of cancer development associated with alterations in these genes is lower, and there is a considerable population variability in different regions worldwide. AIM: We have performed mutation analyses of moderate-risk cancer susceptibility genes to evaluate their clinical importance for genetic counseling in high-risk patients suffering from breast and other cancers in the Czech population. RESULTS: Czech oncological patients were analysed for mutation in ATM, CHEK2, NBS1 (NBN) and PALB2 genes. The majority of analyzed individuals represent the population of high-risk BRCA1/2-negative BC patients. CONCLUSIONS: Based on results of this study, we recommend an analysis of recurrent truncating mutations in the CHEK2 gene (the c.1100delC mutation and a large deletion affecting exons 9-10) in BRCA1/2-negative patients from high-risk BC families. A clinical assessment of missense variants in CHEK2 is not suitable. A routine mutation analysis of the ATM and NBS1 (NBN) genes is not recommended in BC patients due to the low frequency of alterations in these genes in the Czech Republic. An identification of truncating mutations in the PALB2 gene is important in BRCA1/2-negative BC patients from families with a strong history of BC (HBC families). The frequency of PALB2 mutations may be comparable to the frequency of mutations in the BRCA2 gene in Czech HBC families. PMID- 22920211 TI - [The effect of prophylactic mastectomy with recontruction on quality of life in BRCA positive women]. AB - It is presumed that bilateral mastectomy is so far the most efficient way how to prevent development of breast carcinoma among BRCA positive patients. This mutilating intervention might be unacceptable for cosmetic reasons for most women. The purpose of this study was to determine the influence of prophylactic mastectomy on the quality of life of BRCA positive patients by comparing results of psychodiagnostic questionnaire methods before surgical intervention and after it. Our data set consisted of 25 BRCA positive healthy women and 19 BRCA positive women in remission. All these patients underwent a reconstructive surgical intervention after mastectomy. Age of patients was 38-55 years. The following questionnaires were used: Life Satisfaction Questionnaire by J. Fahrenberg, M. Myrtek and E. Brahler, Clinical analysis questionnaire by S. E. Kruge and R. B. Cattel, Impact of Event Scale - Revised by D. S. Weiss and C. R. Marmar. RESULTS: Women in remission showed most significant decrease in Financial position category and minor decrease in Work and Employment category and Friends, Acquaintances and Relatives category. Improvement of quality of life was recorded especially in category of Health, Sexuality, Own person, Partnership and in Relationship with own children and there was also a significant improvement to overall life satisfaction. Among healthy patients, there was a significant improvement in category of Health and Own person. Most significant decrease was in dimension of Financial position and Work and employment. Prophylactic mastectomy with reconstruction might be the way of prevention of breast carcinoma because from psychological point of view there is the unambiguously significant fact that there was improvement of perception of own health and own person in both groups of women. These are the quality of life aspects that are considered to be basal and long term stabilizing from the perspective of dynamics of own self and they also systematically influence other aspects of quality of life which are derived from them. PMID- 22920212 TI - [Surgical prevention of breast carcinoma in patients with hereditary risk]. AB - BACKGROUND: Women with BRCA1 gene mutation have 85% risk of breast cancer; the risk for BRCA2 carriers is 45%. The aim of the study was to verify if prophylactic mastectomy with immediate breast reconstruction can prevent breast cancer in BRCA positive patients. MATERIAL: There were 100 BRCA positive women in which prophylactic mastectomy with immediate reconstruction, 75 dieps, 25 with implants, performed in period 2000-2011. Group A was composed of healthy, non affected 41 patients, group B of 59 patients in remission after breast cancer treatment. These groups were compared to group C that consisted of 219 healthy carriers of BRCA1/2, non-operated, from registry of genetic department of the Masaryk Memorial Cancer in Brno, from 2000-2011. METHOD: Follow-up for oncology status was done in September 2011 for all 3 groups. RESULTS: Average follow-up of 21 months revealed that in group A there was no breast cancer, in group B 4 patients died and 2 had treatment for metastases. In group C, there were 16 new cases of breast cancer. CONCLUSION: Bilateral prophylactic mastectomy with immediate reconstruction can be an effective way in breast cancer prevention in healthy carriers of BRCA1/2 mutation. In BRCA positive patients treated for breast cancer, the effect of prophylactic mastectomy is unclear. Their survival is more influenced by their previous disease than by a new tumor in the breast. PMID- 22920213 TI - [Preimplantation genetic diagnosis (PGD) of hereditary cancer syndromes]. AB - Advances in molecular biology techniques made possible genotype analysis from one or several cells. This can be used in preimplantation genetic diagnosis (PGD) not only of chromosomal aneuploidy but also of single gene diseases as well as hereditary cancer syndromes. PGD can be a benefit for those cases when the risk of transfer of pathological alteration from parent to offspring is unwelcome. We submit three cases of PGD with the results. PMID- 22920214 TI - [Evaluation of variants of unknown significance in the BRCA2 gene]. AB - BACKGROUND: Endogenous processes and exogenous agents cause constant DNA damage. DNA double-strand breaks are among the most serious types of damage. They are mainly repaired by homologous recombination, where the BRCA2 protein plays a dominant role. Heterozygous germline BRCA2 mutations predispose to breast, ovarian, pancreatic and other types of cancer. The presence of a pathogenic mutation in patients or their family members warrants close surveillance and prophylactic surgery. Apart from clearly pathogenic mutations, variants leading only to a single amino acid substitution are often identified. Since the influence of these variants on cancer risk is unknown, they represent a major clinical problem. AIMS: The aim of this paper is to summarize the current possibilities of predicting pathogenicity of BRCA2 variants. In some cases, genetic methods are able to classify variants with high probability; however, their use is often limited by low frequency of the variants or inaccessibility of samples for mRNA isolation or DNA from family members. Alternatively, functional assays performed in various cellular models may be employed. Multiple functional tests and cellular models are presented and characterized, including their advantages and limitations. A new model of human syngeneic cell lines developed by the authors is presented, in which one BRCA2 allele is deleted and the variant is introduced into the other allele by homologous recombination. This model has the potential to evaluate function of variants without some of the unwanted effects of the other models. Currently, this model is being applied to variants identified in patients with hereditary cancer predisposition in the Masaryk Memorial Cancer Institute. CONCLUSION: Functional assays in cellular models including a new model of syngeneic cell lines described by the authors have a great potential in evaluating clinical importance of unclassified variants in the BRCA2 gene, especially in cases where genetic tests are not applicable. PMID- 22920215 TI - [Diagnostics of breast cancer in high-risk women - our own experience]. AB - Preventive oncology clinic of MMCI provides complex preventive care for women with high hereditary risk of breast and ovarian cancer due to germline mutations in BRCA1 and BRCA2 genes. Clinical follow-up is also provided to women with mutations in other genes causing a higher risk of different tumors, and also to women with increased lifetime empirical risk of breast cancer due to positive family history. Our clinic was established in 2000 and takes care for about 700 women. The goal of the clinic is to extend the life expectancy of these women to the level of the regular population. The risk of breast cancer can be reduced by prophylactic surgeries. Prophylactic mastectomy and oophorectomy are offered to women at a high risk. Other modality in breast cancer risk reduction is a chemoprevention by Tamoxifen. Most women accept only secondary prevention with the goal of the detection of breast cancer in clinical stage I, where the tumor is smaller than 1 cm and the risk of recurrence is less than 10%. The algorithm of prevention care was changed over the time and our diagnostic methods were improved by magnetic resonance imaging of breasts. During the 11 years of clinical follow-up 32 breast cancers in 31 women were detected. High risk women are examined every 6 month by physical examination, breast ultrasound and MRI plus mammography yearly. PMID- 22920217 TI - One-pot in situ fabrication of stable nanocaterpillars directly from polyacetylene diblock copolymers synthesized by mild ring-opening metathesis polymerization. AB - We report a direct one-pot route for the preparation of supramolecules from simple polyacetylene diblock copolymers synthesized by mild ring-opening metathesis polymerization of cyclooctatetraene. This in situ nanoparticlization of conjugated polymer (INCP) approach is advantageous over conventional self assembly processes because this method does not require any tedious postsynthetic treatments. Also, this direct approach provides intriguing supramolecules with a unique nanostructure resembling a caterpillar. Furthermore, the new supramolecules are highly stable adducts because the polyacetylene core block provides an exceptionally strong driving force for the self-assembly. Even though pristine polyacetylene is unstable in air, the polyacetylene segment in the nanocaterpillar is very stable because it is protected within the shell of the supramolecule. PMID- 22920218 TI - Configurational preferences of arylamide alpha-helix mimetics via alchemical free energy calculations of relative binding affinities. AB - We use molecular docking and free energy calculations to estimate the relative free energy of binding of six arylamide compounds designed to inhibit the hDM2 p53 interaction. We show that using docking methods to predict or rank the binding affinity of a series of arylamide inhibitors of the hDM2-p53 interaction is problematic. However, using free energy calculations, we show that we can achieve levels of accuracy that can guide the development of novel arylamide compounds. We perform alchemical free energy calculations using the Desmond molecular dynamics package with the same arylamide inhibitors of the hDM2-p53 system and illustrate the challenges of performing accurate free energy calculations for realistic systems. To our knowledge, these are the first calculations for inhibitors of the hDM2 system that employ a full treatment of statistical mechanics including explicit water representation and full protein flexibility. We show that mutating three functional groups in a single transformation can be more efficient than mutating the groups one by one if proper intermediates are used. We also show that Hamiltonian exchanges can improve the efficiency of the calculation compared to standard alchemical methods, with a novel use of the phase space overlap to monitor sampling extent. We show that, despite sampling limitations, this approach can achieve levels of accuracy sufficient to bias further inhibitor modification toward binding, and identifies antiparallel configurations as stable or more stable than the parallel configurations that are typically considered. PMID- 22920219 TI - Li absorption and intercalation in single layer graphene and few layer graphene by first principles. AB - We present an exhaustive first-principles investigation of Li absorption and intercalation in single layer graphene and few layer graphene, as compared to bulk graphite. For single layer graphene, the cluster expansion method is used to systemically search for the lowest energy ionic configuration as a function of absorbed Li content. It is predicted that there exists no Li arrangement that stabilizes Li absorption on the surface of single layer graphene unless that surface includes defects. From this result follows that defect-poor single layer graphene exhibits significantly inferior capacity compared to bulk graphite. For few layer graphene, we calibrate a semiempirical potential to include the effect of van der Waals interactions, which is essential to account for the contribution of empty (no Li) gallery to the total energy. We identify and analyze the Li intercalation mechanisms in few layer graphene and map out the sequence in stable phases as we move from single layer graphene, through few layer, to bulk graphite. PMID- 22920216 TI - Toward an integration of cognitive and genetic models of risk for depression. AB - There is growing interest in integrating cognitive and genetic models of depression risk. We review two ways in which these models can be meaningfully integrated. First, information-processing biases may represent intermediate phenotypes for specific genetic influences. These genetic influences may represent main effects on specific cognitive processes or may moderate the impact of environmental influences on information-processing biases. Second, cognitive and genetic influences may combine to increase reactivity to environmental stressors, increasing risk for depression in a gene*cognition*environment model of risk. There is now growing support for both of these ways of integrating cognitive and genetic models of depression risk. Specifically, there is support for genetic influences on information-processing biases, particularly the link between 5-HTTLPR and attentional biases, from both genetic association and gene*environment (G*E) studies. There is also initial support for gene*cognition*environment models of risk in which specific genetic influences contribute to increased reactivity to environmental influences. We review this research and discuss important areas of future research, particularly the need for larger samples that allow for a broader examination of genetic and epigenetic influences as well as the combined influence of variability across a number of genes. PMID- 22920220 TI - Variation in phenolic content and antioxidant activity of fermented rooibos herbal tea infusions: role of production season and quality grade. AB - Data are required to calculate the dietary exposure to rooibos herbal tea flavonoids and phenolic acids. Representative content values for the principal phenolic compounds and total antioxidant capacity of fermented rooibos infusion, taking into account variation caused by production seasons (2009, 2010, and 2011) and quality grades (A, B, C, and D), were determined for samples (n = 114) from different geographical areas and producers. The major phenolic constituents were isoorientin and orientin (>10 mg/L), with quercetin-3-O-robinobioside, phenylpyruvic acid glucoside, and aspalathin present at >5 mg/L. Isovitexin, vitexin, and hyperoside were present at <3 mg/L. Rutin, ferulic acid, and isoquercitrin were present at <2 mg/L. Nothofagin was present at <1 mg/L. Only traces of luteolin-7-O-glucoside and the aglycones quercetin, luteolin, and chrysoeriol were present. Substantial variation was observed in the individual content values of the phenolic compounds and total antioxidant capacity within production seasons and quality grades. PMID- 22920221 TI - The complete mitochondrial genome of Macrotermes barneyi Light (Isoptera: Termitidae). AB - The complete nucleotide sequence of the mitochondrial genome of Macrotermes barneyi Light (Isoptera: Termitidae) was determined. This mitochondrial genome is 15,940 bp with 37 typical animal mitochondrial genes and an A+T-rich region. Gene positions and directions are identical to that of the pupative ancestral arrangement of insects. All protein-coding genes start with ATN codon. Seven protein-coding genes stop with termination codon TAA. Four protein-coding genes use incomplete stop codons TA and two use T. The base composition of M. barneyi mitochondrial genome is normal to most insects. All of the 22 tRNA genes, ranging from 63 to 76 bp, have a typical cloverleaf structure except for trnS2. In trnS2, D-stem pairings in the DHU (dihydrouridine) arm is absent as in many sequenced insect species. Five elements characterized by A+T-rich region of the insect mitochondrial genome are found on their conserved arrangement. However, no repeat sequence is present on the downstream of the A+T-rich region. PMID- 22920222 TI - Short communication: NKG2C+ NK cells contribute to increases in CD16+CD56- cells in HIV type 1+ individuals with high plasma viral load. AB - Chronic HIV-1 infection results in the expansion of both NKG2C+ and CD16+CD56- human natural killer cells. NKG2C+ cells proliferate in response to human cytomegalovirus (HCMV) and expansion of the dysfunctional CD56-CD16+ natural killer (NK) cells is associated with HIV-1 viremia. Here we report an association between increased proportions of CD56-CD16+ NK cells in viremic HIV-1+ individuals and an increased contribution of NKG2C+ cells to this subset. These data, in addition to anti-HCMV IgG serology, indicate a potential contribution of both HCMV and HIV-1 to NK cell dysfunction in HIV-1-infected individuals. PMID- 22920223 TI - A hero's tale of childbirth. AB - OBJECTIVES: to present a secondary analysis of the findings from an interpretive phenomenological study of women who had experienced a self-defined traumatic and subsequent positive birth experience. DESIGN: a re-interpretation of women's accounts through the conceptual lens of the hero narrative framework developed by Campbell (1993). SETTING: 12 women recruited from a large maternity trust in North-West England. FINDINGS: by drawing upon Campbell's analysis of myth and folklore, contextualised by the women's narratives, we illuminate the adversity and dysphoria of a distressing birth, and how through taking courage, drawing on inner strength and accessing targeted support, all of the participants went on to achieve a joyful, healing birth experience. This analysis reveals the power, courage and determination of the childbearing women in this study, and to re envision their journey as a 'hero's tale'. CONCLUSION: this paper uncovers how myth can illuminate existential accounts of a phenomenon as well as raise important practice based implications. Creating services based on these principles has the potential to translate the theoretical insights from this study into a new maternity care praxis. PMID- 22920224 TI - Renoprotective effects of a novel Nox1/4 inhibitor in a mouse model of Type 2 diabetes. AB - Nox (NADPH oxidase)-derived ROS (reactive oxygen species) have been implicated in the development of diabetic nephropathy. Of the Nox isoforms in the kidney, Nox4 is important because of its renal abundance. In the present study, we tested the hypothesis that GKT136901, a Nox1/4 inhibitor, prevents the development of nephropathy in db/db (diabetic) mice. Six groups of male mice (8-week-old) were studied: (i) untreated control db/m, (ii) low-dose GKT136901-treated db/m (30 mg/kg of body weight per day), (iii) high-dose GKT136901-treated db/m (90 mg/kg of body weight per day), (iv) untreated db/db; (v) low dose GKT136901-treated db/db; and (vi) high-dose GKT136901-treated db/db. GKT136901, in chow, was administered for 16 weeks. db/db mice developed diabetes and nephropathy as evidenced by hyperglycaemia, albuminuria and renal injury (mesangial expansion, tubular dystrophy and glomerulosclerosis). GKT136901 treatment had no effect on plasma glucose or BP (blood pressure) in any of the groups. Plasma and urine TBARSs (thiobarbituric acid-reacting substances) levels, markers of systemic and renal oxidative stress, respectively, were increased in diabetic mice. Renal mRNA expression of Nox4, but not of Nox2, increased, Nox1 was barely detectable in db/db. Expression of the antioxidant enzyme SOD-1 (superoxide dismutase 1) decreased in db/db mice. Renal content of fibronectin, pro-collagen, TGFbeta (transforming growth factor beta) and VCAM-1 (vascular cell adhesion molecule 1) and phosphorylation of ERK1/2 (extracellular-signal-regulated kinase 1/2) were augmented in db/db kidneys, with no change in p38 MAPK (mitogen-activated protein kinase) and JNK (c-Jun N-terminal kinase). Treatment reduced albuminuria, TBARS and renal ERK1/2 phosphorylation and preserved renal structure in diabetic mice. Our findings suggest a renoprotective effect of the Nox1/4 inhibitor, possibly through reduced oxidative damage and decreased ERK1/2 activation. These phenomena occur independently of improved glucose control, suggesting GKT136901-sensitive targets are involved in complications of diabetes rather than in the disease process. PMID- 22920225 TI - The study of radiosensitivity in left handed compared to right handed healthy women. AB - BACKGROUND: Radiosensitivity is an inheriting trait that mainly depends on genetic factors. it is well known in similar dose of ionizing radiation and identical biological characteristics 9-10 percent of normal population have higher radiation response. Some reports indicate that distribution of breast cancer, immune diseases including autoimmune diseases as example lupus, Myasthenia Gravies and even the rate of allergy are more frequent in left handed individuals compared to right handed individuals. The main goal of the present study is determination of radiosensitivity in left handed compared to right handed in healthy women by cytokinesis blocked micronuclei [CBMN] assay.5 ml peripheral fresh blood sample was taken from 100 healthy women including 60 right handed and 40 left handed. The age of participants was between 20-25 old years and they had been matched by sex. After blood sampling, blood samples were divided to 2 groups including irradiated and non-irradiated lymphocytes that irradiated lymphocytes were exposed to 2 Gy CO-60 Gama rays source then chromosomal aberrations was analyzed by CBMN [Cytokinesis Blocked Micronuclei Assay]. RESULTS: Our results have shown radiosensitivity index [RI] in left handers compared to right-handers is higher. Furthermore, the mean MN frequency is elevated in irradiated lymphocytes of left-handers in comparison with right handers. CONCLUSION: Our results from CBMN assay have shown radiosensitivity in the left handed is higher than right handed women but more attempts need to prove this hypothesis. PMID- 22920227 TI - Tunable fusion and aggregation of liposomes triggered by multifunctional surface cross-linked micelles. AB - Water-soluble organic nanoparticles were prepared by cross-linking the micelles of a tripropargylated cationic surfactant by a diazide cross-linker in the presence of Cu(I) catalysts. The nanoparticles were decorated with hydrophilic ligands of different lengths on the surface. By interacting with negatively charged liposomes through tunable electrostatic interactions, these nanoparticles induced fusion and leakage of large unilamellar vesicles (LUVs). Fusion or aggregation of the membranes was highly sensitive to the rigidity and phase structures of the membranes, enabling thermally gated fusion to occur within a very narrow window of temperature change. PMID- 22920228 TI - Spontaneous rupture of intracranial dermoid cyst with chemical meningitis. PMID- 22920226 TI - Sponsors' participation in conduct and reporting of industry trials: a descriptive study. AB - BACKGROUND: Bias in industry-sponsored trials is common and the interpretation of the results can be particularly distorted in favour of the sponsor's product. We investigated sponsors' involvement in the conduct and reporting of industry sponsored trials. METHODS: We included all industry-sponsored trials published in The Lancet in 2008 and 2009 and corresponding trial protocols provided by The Lancet. For each protocol and publication, we extracted information on trial conduct and reporting. RESULTS: We identified 169 publications of randomised trials and included 69 (41%) that were industry-sponsored, and 12 (7%) industry funded but seemingly independently conducted as a subsample. Entry of data into the study database was done independently by academic authors without the involvement of the sponsor or a contract research organisation in one of the 69 trials. Two trials had independent data analysis and one independent reporting of results. In 11 of the trials, there was a discrepancy between the information in the protocols and papers concerning who analysed the data. In four of the 12 seemingly independent trials, the protocol described sponsors' involvement in writing the report while the published paper explicitly stated that the sponsor was not involved. CONCLUSIONS: The sponsors are usually involved in the analysis and reporting of results in industry-sponsored trials, but their exact role is not always clear from the published papers. Journals should require more transparent reporting of the sponsors' role in crucial elements such as data processing, statistical analysis and writing of the manuscript and should consider requiring access to trial protocols, independent data analysis and submission of the raw data. PMID- 22920229 TI - Gallstone ileus. PMID- 22920230 TI - Liver transplant for adult hemophagocytic lymphohistiocytosis: case report and literature review. AB - We report the case of a middle-aged man who died from multiorgan failure 3 weeks after orthotopic liver transplant for fulminant hepatic failure, associated with a rare, often fatal, hematologic condition that usually presents in childhood. We discuss the importance of its diagnosis, treatment, and implications for liver transplant. PMID- 22920231 TI - Protective effect of guggulsterone against cardiomyocyte injury induced by doxorubicin in vitro. AB - BACKGROUND: Doxorubicin (DOX) is an effective antineoplastic drug; however, clinical use of DOX is limited by its dose-dependent cardiotoxicity. It is well known that reactive oxygen species (ROS) play a vital role in the pathological process of DOX-induced cardiotoxicity. For this study, we evaluated the protective effects of guggulsterone (GS), a steroid obtained from myrrh, to determine its preliminary mechanisms in defending against DOX-induced cytotoxicity in H9C2 cells. METHODS: In this study, we used a 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay, lactate dehydrogenase (LDH) release measurements, and Hoechst 33258 staining to evaluate the protective effect of GS against DOX-induced cytotoxicity in H9C2 cells. In addition, we observed the immunofluorescence of intracellular ROS and measured lipid peroxidation, caspase-3 activity, and apoptosis-related proteins by using Western blotting. RESULTS: The MTT assay and LDH release showed that treatment using GS (1-30 MUM) did not cause cytotoxicity. Furthermore, GS inhibited DOX (1 MUM)-induced cytotoxicity in a concentration-dependent manner. Hoechst 33258 staining showed that GS significantly reduced DOX-induced apoptosis and cell death. Using GS at a dose of 10-30 MUM significantly reduced intracellular ROS and the formation of MDA in the supernatant of DOX-treated H9C2 cells and suppressed caspase-3 activity to reference levels. In immunoblot analysis, pretreatment using GS significantly reversed DOX-induced decrease of PARP, caspase-3 and bcl-2, and increase of bax, cytochrome C release, cleaved-PARP and cleaved-caspase-3. In addition, the properties of DOX-induced cancer cell (DLD-1 cells) death did not interfere when combined GS and DOX. CONCLUSION: These data provide considerable evidence that GS could serve as a novel cardioprotective agent against DOX-induced cardiotoxicity. PMID- 22920232 TI - [Fetal heart rate variability and clozapine treatment]. AB - We report the 2 cases of schizophrenic patients with clozapine treatment and particularly, we underlined a reduced variability and low short-term variability, whereas biophysical ultrasound score, Dopplers and perception of fetal movements were acceptable and comfortable concerning the fetal vitality. Our aim is to show the limits of the analyzed fetal heart rate under clozapine. So, we may change our observation of fetus in chronic suffering that is usually mainly made with an informatics analysis of pregnants under clozapine. PMID- 22920233 TI - [Opinion: we all are excisers !]. PMID- 22920234 TI - [What is mild stimulation?]. AB - Mild stimulation is the administration of low doses (150 IU/day) of FSH, continuously, from the fifth day of the cycle, associated with the administration of GnRH antagonists. Despite the lower number of oocytes collected during mild stimulation, they are better for pregnancy rates on with an endometrium nearest closer to the natural cycle, and reducing the risk of ovarian hyperstimulation. Although the number of IVF +/- ICSI attempts is limited to 4 in France, the Mild stimulation may be proposed in young women, those with a polycystic ovary syndrome or "low responder" women. PMID- 22920236 TI - The role of multimodality imaging in the evaluation of Takayasu arteritis. AB - OBJECTIVES: Takayasu arteritis is a rare large vessel vasculitis of unknown etiology, in which both early diagnosis and follow-up present very significant challenges. The high incidence of disease-associated morbidity and significant risk of premature death-particularly in young adults-mandate the need to facilitate early diagnosis and aggressive treatment where appropriate. The aim of this review is to summarize the current level of knowledge regarding the usefulness of evolving imaging modalities in the diagnostic workup and management of patients suffering with Takayasu arteritis. We also propose an imaging algorithm for the evaluation of this population. METHODS: A MEDLINE search for articles published between January 1999 and December 2011 was conducted using the following keywords: Takayasu arteritis, imaging modalities, echocardiogram, cardiac magnetic resonance, positron emission tomography scan, diagnosis. RESULTS: Imaging studies-particularly cardiac magnetic resonance-can assist early diagnosis by demonstrating vascular lesions even when angiography is negative, by identifying the presence of vascular inflammation and/or wall thickening; they are also useful for monitoring purposes. However, availability, expertise, high cost, and radiation are considerable limitations. Magnetic resonance imaging, although it can detect both anatomic and pathophysiologic changes without radiation, is time-consuming, needs high expertise, and still remains an expensive tool, not widely available. CONCLUSIONS: Knowledge of the advantages and limitations of the various imaging procedures can complement the physicians' clinical assessment and, along with nonspecific serologic tests, can aid them in diagnosing active arteritis and commence relevant treatment early on, as well as monitor activity and tailor therapy subsequently. PMID- 22920235 TI - Serum soluble receptor for advanced glycation end products levels and aortic augmentation index in early rheumatoid arthritis--a prospective study. AB - OBJECTIVE: We assessed whether a serum soluble receptor for advanced glycation end product (sRAGE) levels were associated with a progression of carotid atherosclerosis and arterial stiffness indexes in a cohort of early rheumatoid arthritis (RA) patients. METHODS: RA patients with symptoms onset <2 years were recruited. Vascular assessments and serum sRAGE levels were measured at baseline and 1 year later. Arterial stiffness was determined by pulse wave velocity and aortic augmentation index (AIx). Carotid intima-media thickness was measured using high-resolution ultrasound. RESULTS: Ninety-four patients completed the 1 year study. Fifty-three (56.4%) achieved disease remission [28-joint disease activity score (DAS28 < 2.6)] at 12 months. Improvement in arterial stiffness was observed as reflected by the significant reductions in AIx and pulse wave velocity. At 12 months, the sRAGE levels increased significantly compared with baseline (939.8 +/- 517.7 pg/ml to 1272.1 +/- 567.3 pg/ml, P < 0.001). Changes in sRAGE levels were significantly higher in men compared to women (768 +/- 510 pg/ml versus 271 +/- 490 pg/ml, P < 0.05) and was negatively associated with the change in AIx (r = -0.259, P = 0.023). Changes in sRAGE level were not associated with other demographic, clinical, cardiovascular risk factors or treatment. Using multivariate analysis, the change in sRAGE levels and baseline high-density lipoprotein were independent predictors associated with the change in AIx. CONCLUSIONS: Arterial stiffness improved significantly in patients with early RA after effective control of inflammation. Increase in sRAGE level was associated with a decrease in AIx, suggesting that sRAGE may play an important role in the ligand-soluble receptor for advanced glycation end product interaction propagated inflammation and vascular stiffness in these patients. PMID- 22920237 TI - Barriers to participant retention in knee osteoarthritis clinical trials: a systematic review. AB - OBJECTIVE: We investigated the reasons and rates of attrition in knee osteoarthritis trials through a systematic review of randomized, placebo controlled, clinical trials. METHODS: Randomized trials were identified by searches conducted in MEDLINE, SCOPUS, and the Cochrane Central Register of Controlled Trials. We then attempted to identify and describe the reasons for attrition and their associated themes. For each theme, we calculated the rate of patients who discontinued a trial from the total number of dropouts in each trial. The rates obtained with different trials were combined using a random effects model. We also performed a random effects meta-regression analysis to identify sources associated with the rates. RESULTS: Overall, 259 studies consisting of 266 trials and 13,593 patients were included in the analysis. From these, we short-listed 54 attrition reasons and identified 21 key themes. "Ineffectiveness" and "adverse event" were the reasons frequently reported by >5% of the dropouts. On further investigation of the theme ineffectiveness, the attrition rate was associated with delivery routes of treatment, trial duration, flare design, prohibition of usual analgesics, and allowing the use of escape medication. In cases of adverse events, we found that the treatment type and delivery route affected the attrition rate. CONCLUSIONS: Our findings not only support the importance of the intention-to-treat analysis, but also suggest the possibility of controlling the attrition at the study level. PMID- 22920238 TI - Temporal and spatial expression of polygalacturonase gene family members reveals divergent regulation during fleshy fruit ripening and abscission in the monocot species oil palm. AB - BACKGROUND: Cell separation that occurs during fleshy fruit abscission and dry fruit dehiscence facilitates seed dispersal, the final stage of plant reproductive development. While our understanding of the evolutionary context of cell separation is limited mainly to the eudicot model systems tomato and Arabidopsis, less is known about the mechanisms underlying fruit abscission in crop species, monocots in particular. The polygalacturonase (PG) multigene family encodes enzymes involved in the depolymerisation of pectin homogalacturonan within the primary cell wall and middle lamella. PG activity is commonly found in the separation layers during organ abscission and dehiscence, however, little is known about how this gene family has diverged since the separation of monocot and eudicots and the consequence of this divergence on the abscission process. RESULTS: The objective of the current study was to identify PGs responsible for the high activity previously observed in the abscission zone (AZ) during fruit shedding of the tropical monocot oil palm, and to analyze PG gene expression during oil palm fruit ripening and abscission. We identified 14 transcripts that encode PGs, all of which are expressed in the base of the oil palm fruit. The accumulation of five PG transcripts increase, four decrease and five do not change during ethylene treatments that induce cell separation. One PG transcript (EgPG4) is the most highly induced in the fruit base, with a 700-5000 fold increase during the ethylene treatment. In situ hybridization experiments indicate that the EgPG4 transcript increases preferentially in the AZ cell layers in the base of the fruit in response to ethylene prior to cell separation. CONCLUSIONS: The expression pattern of EgPG4 is consistent with the temporal and spatial requirements for cell separation to occur during oil palm fruit shedding. The sequence diversity of PGs and the complexity of their expression in the oil palm fruit tissues contrast with data from tomato, suggesting functional divergence underlying the ripening and abscission processes has occurred between these two fruit species. Furthermore, phylogenetic analysis of EgPG4 with PGs from other species suggests some conservation, but also diversification has occurred between monocots and eudicots, in particular between dry and fleshy fruit species. PMID- 22920239 TI - Non-proteinogenic amino acids in lacticin 481 analogues result in more potent inhibition of peptidoglycan transglycosylation. AB - Lantibiotics are ribosomally synthesized and post-translationally modified peptide natural products that contain the thioether structures lanthionine and methyllanthionine and exert potent antimicrobial activity against Gram-positive bacteria. At present, detailed modes-of-action are only known for a small subset of family members. Lacticin 481, a tricyclic lantibiotic, contains a lipid II binding motif present in related compounds such as mersacidin and nukacin ISK-1. Here, we show that lacticin 481 inhibits PBP1b-catalyzed peptidoglycan formation. Furthermore, we show that changes in potency of analogues of lacticin 481 containing non-proteinogenic amino acids correlate positively with the potency of inhibition of the transglycosylase activity of PBP1b. Thus, lipid II is the likely target of lacticin 481, and use of non-proteinogenic amino acids resulted in stronger inhibition of the target. Additionally, we demonstrate that lacticin 481 does not form pores in the membranes of susceptible bacteria, a common mode of-action of other lantibiotics. PMID- 22920240 TI - The advantage of high-resolution MRI in evaluating basilar plaques: a comparison study with MRA. AB - OBJECTIVE: Intracranial atherosclerosis (ICAS) is a major cause of ischemic stroke; however it is rather neglected. Vessel wall visualization by high resolution magnetic resonance imaging (HRMRI) might provide more accurate information. METHODS: A total of 219 consecutive patients with acute ischemic stroke underwent MRI, MRA and proton-density weighted HRMRI. Using HRMRI, the patients were divided into 3 groups with respect to basilar plaques: no plaque (n = 85), minimal plaque (n = 72) and apparent plaque (n = 62). Demographics and characteristics were compared between the groups, and the extents of stenoses calculated from MRA versus HRMRI data were also compared. Factors potentially associated with basilar plaque were validated by multivariate analysis. RESULTS: Patients with apparent plaque had higher frequencies of diabetes mellitus, lower high-density lipoprotein and higher hemoglobin A1c, erythrocyte sedimentation rate and homocysteine. Of the 62 cases of apparent plaque, severe stenosis (>50%) was observed in 10 (16%) by MRA and in 27 (43%) by HRMRI, which points to overestimation of plaques by HRMRI. In addition, no stenosis was evident on MRA in 13 patients with apparent plaque even though they had up to 72% stenosis on HRMRI. After adjusting for covariates, basilar artery apparent plaque was independently associated with old age, previous stroke, diabetes mellitus, low HDL and high levels of homocysteine. CONCLUSIONS: Basilar artery stenosis with plaque is more accurately detected using HRMRI than MRA. In addition, the associated risk factors differ somewhat. The use of HRMRI for evaluating ICAS deserves more attention. PMID- 22920241 TI - Defining rules for the shape evolution of gold nanoparticles. AB - The roles of silver ions and halides (chloride, bromide, and iodide) in the seed mediated synthesis of gold nanostructures have been investigated, and their influence on the growth of 10 classes of nanoparticles that differ in shape has been determined. We systematically studied the effects that each chemical component has on the particle shape, on the rate of particle formation, and on the chemical composition of the particle surface. We demonstrate that halides can be used to (1) adjust the reduction potential of the gold ion species in solution and (2) passivate the gold nanoparticle surface, both of which control the reaction kinetics and thus enable the selective synthesis of a series of different particle shapes. We also show that silver ions can be used as an underpotential deposition agent to access a different set of particle shapes by controlling growth of the resulting gold nanoparticles through surface passivation (more so than kinetic effects). Importantly, we show that the density of silver coverage can be controlled by the amount and type of halide present in solution. This behavior arises from the decreasing stability of the underpotentially deposited silver layer in the presence of larger halides due to the relative strengths of the Ag(+)/Ag(0)-halide and Au(+)/Au(0)-halide interactions, as well as the passivation effects of the halides on the gold particle surface. We summarize this work by proposing a set of design considerations for controlling the growth and final shape of gold nanoparticles prepared by seed-mediated syntheses through the judicious use of halides and silver ions. PMID- 22920242 TI - A comparison of the biomechanical effects of valgus knee braces and lateral wedged insoles in patients with knee osteoarthritis. AB - Increases in the external knee adduction moment (EKAM) have been associated with increased mechanical load at the knee and progression of knee osteoarthritis. Valgus knee braces and lateral wedged insoles are common approaches to reducing this loading; however no study has directly compared the biomechanical and clinical effects of these two treatments in patients with medial tibiofemoral osteoarthritis. A cross-over randomised design was used where each intervention was worn by 28 patients for a two week period. Pre- and post-intervention gait kinematic/kinetic data and clinical outcomes were collected to evaluate the biomechanical and clinical effects on the knee joint. The valgus knee brace and the lateral wedged insole significantly increased walking speed, reduced the early stance EKAM by 7% and 12%, and the knee adduction angular impulse by 8.6 and 16.1% respectively. The lateral wedged insole significantly reduced the early stance EKAM compared to the valgus knee brace (p=0.001). The valgus knee brace significantly reduced the knee varus angle compared to the baseline and lateral wedged insole. Improvements in pain and function subscales were comparable for the valgus knee brace and lateral wedged insole. There were no significant differences between the two treatments in any of the clinical outcomes; however the lateral wedged insoles demonstrated greater levels of acceptance by patients. This is the first study to biomechanically compare these two treatments, and demonstrates that given the potential role of knee loading in osteoarthritis progression, that both treatments reduce this but lateral wedge insoles appear to have a greater effect. PMID- 22920245 TI - Brain, know thy transcriptome, know thyself. AB - In this issue of Neuron, Konopka et al. (2012) describe their comparison of transcriptomes from frontal pole, caudate nucleus, and hippocampus of multiple adult humans, chimpanzees, and rhesus monkeys. The data provide an initial opportunity for linking genomic and brain differences among these primate species. PMID- 22920244 TI - Virtual human hand: model and kinematics. AB - The human hand plays an important role in daily life. It is the interface between the human and the exterior world by positioning, orienting, touching and grasping objects. The human hand has multiple degrees of freedom (DOFs) to enable mobility and dexterity. A virtual human hand model can be inserted into CAD (Computer Aided Design) models to assess the manipulation capabilities in the early design stage to reduce design time and cost. Joystick assessment is one of the important design cases. This study is a first step towards a comprehensive hand simulation tool to simulate the manipulation and grasping of objects. This paper presents a novel 25 DOFs' hand skeletal model based on hand anatomy and hand kinematics: (1) joint range of motion, (2) Denavit-Hartenberg method to define the joint relationship and (3) finger workspace determination. Novelty for this hand model includes arching the palm with the four DOFs added in the carpometacarpal and wrist joints for the ring and small fingers. PMID- 22920243 TI - Bromophycoic acids: bioactive natural products from a Fijian red alga Callophycus sp. AB - Bioassay-guided fractionation of extracts from a Fijian red alga in the genus Callophycus resulted in the isolation of five new compounds of the diterpene benzoate class. Bromophycoic acids A-E (1-5) were characterized by NMR and mass spectroscopic analyses and represent two novel carbon skeletons, one with an unusual proposed biosynthesis. These compounds display a range of activities against human tumor cell lines, malarial parasites, and bacterial pathogens including low micromolar suppression of MRSA and VREF. PMID- 22920246 TI - Fear of the light or need for action: the IGL will judge. AB - Temporal adaptation of behaviors is of crucial importance for every organism. In this issue of Neuron, while elegantly establishing the developmental program of the subcortical visual shell (SVS), a group of retinorecipient nuclei, Delogu et al. (2012) also implicate one of its structures, the IGL, as a potential important player in the regulation of daily activity pattern. PMID- 22920247 TI - Slow gamma takes the reins in replay. AB - The mechanisms supporting hippocampal memory reactivation are puzzling. Reactivation occurs during ripple oscillations, yet ripples are not coordinated across regions. In this issue of Neuron, Carr et al. (2012) report that another oscillation, slow gamma, coordinates memory reactivation across the hippocampal network. PMID- 22920248 TI - Thalamic coordination of cortical communication. AB - Higher-order thalamic nuclei, like the pulvinar, have extensive connections with cortex, suggesting a role in the coordination of cortical communication. A recent study in Science by Saalmann et al. (2012) implicates the pulvinar in promoting cortical alpha-band synchronization that subserves communication of attended information. PMID- 22920250 TI - Rates and rhythms: a synergistic view of frequency and temporal coding in neuronal networks. AB - In the CNS, activity of individual neurons has a small but quantifiable relationship to sensory representations and motor outputs. Coactivation of a few 10s to 100s of neurons can code sensory inputs and behavioral task performance within psychophysical limits. However, in a sea of sensory inputs and demand for complex motor outputs how is the activity of such small subpopulations of neurons organized? Two theories dominate in this respect: increases in spike rate (rate coding) and sharpening of the coincidence of spiking in active neurons (temporal coding). Both have computational advantages and are far from mutually exclusive. Here, we review evidence for a bias in neuronal circuits toward temporal coding and the coexistence of rate and temporal coding during population rhythm generation. The coincident expression of multiple types of gamma rhythm in sensory cortex suggests a mechanistic substrate for combining rate and temporal codes on the basis of stimulus strength. PMID- 22920249 TI - The spike-timing dependence of plasticity. AB - In spike-timing-dependent plasticity (STDP), the order and precise temporal interval between presynaptic and postsynaptic spikes determine the sign and magnitude of long-term potentiation (LTP) or depression (LTD). STDP is widely utilized in models of circuit-level plasticity, development, and learning. However, spike timing is just one of several factors (including firing rate, synaptic cooperativity, and depolarization) that govern plasticity induction, and its relative importance varies across synapses and activity regimes. This review summarizes this broader view of plasticity, including the forms and cellular mechanisms for the spike-timing dependence of plasticity, and, the evidence that spike timing is an important determinant of plasticity in vivo. PMID- 22920251 TI - Neuromodulatory state and sex specify alternative behaviors through antagonistic synaptic pathways in C. elegans. AB - Pheromone responses are highly context dependent. For example, the C. elegans pheromone ascaroside C9 (ascr#3) is repulsive to wild-type hermaphrodites, attractive to wild-type males, and usually neutral to "social" hermaphrodites with reduced activity of the npr-1 neuropeptide receptor gene. We show here that these distinct behavioral responses arise from overlapping push-pull circuits driven by two classes of pheromone-sensing neurons. The ADL sensory neurons detect C9 and, in wild-type hermaphrodites, drive C9 repulsion through their chemical synapses. In npr-1 mutant hermaphrodites, C9 repulsion is reduced by the recruitment of a gap junction circuit that antagonizes ADL chemical synapses. In males, ADL sensory responses are diminished; in addition, a second pheromone sensing neuron, ASK, antagonizes C9 repulsion. The additive effects of these antagonistic circuit elements generate attractive, repulsive, or neutral pheromone responses. Neuronal modulation by circuit state and sex, and flexibility in synaptic output pathways, may permit small circuits to maximize their adaptive behavioral outputs. PMID- 22920252 TI - Sensation in a single neuron pair represses male behavior in hermaphrodites. AB - Pheromones elicit innate sex-specific mating behaviors in many species. We demonstrate that in C. elegans, male-specific sexual attraction behavior is programmed in both sexes but repressed in hermaphrodites. Repression requires a single sensory neuron pair, the ASIs. To repress attraction in adults, the ASIs must be present, active, and capable of sensing the environment during development. The ASIs release TGF-beta, and ASI function can be bypassed by experimental activation of TGF-beta signaling. Sexual attraction in derepressed hermaphrodites requires the same sensory neurons as in males. The sexual identity of both these sensory neurons and a distinct subset of interneurons must be male to relieve repression and release attraction. TGF-beta may therefore act to change connections between sensory neurons and interneurons during development to engage repression. Thus, sensation in a single sensory neuron pair during development reprograms a common neural circuit from male to female behavior. PMID- 22920253 TI - Human-specific transcriptional networks in the brain. AB - Understanding human-specific patterns of brain gene expression and regulation can provide key insights into human brain evolution and speciation. Here, we use next generation sequencing, and Illumina and Affymetrix microarray platforms, to compare the transcriptome of human, chimpanzee, and macaque telencephalon. Our analysis reveals a predominance of genes differentially expressed within human frontal lobe and a striking increase in transcriptional complexity specific to the human lineage in the frontal lobe. In contrast, caudate nucleus gene expression is highly conserved. We also identify gene coexpression signatures related to either neuronal processes or neuropsychiatric diseases, including a human-specific module with CLOCK as its hub gene and another module enriched for neuronal morphological processes and genes coexpressed with FOXP2, a gene important for language evolution. These data demonstrate that transcriptional networks have undergone evolutionary remodeling even within a given brain region, providing a window through which to view the foundation of uniquely human cognitive capacities. PMID- 22920254 TI - Tau promotes neurodegeneration via DRP1 mislocalization in vivo. AB - Mitochondrial abnormalities have been documented in Alzheimer's disease and related neurodegenerative disorders, but the causal relationship between mitochondrial changes and neurodegeneration, and the specific mechanisms promoting mitochondrial dysfunction, are unclear. Here, we find that expression of human tau results in elongation of mitochondria in both Drosophila and mouse neurons. Elongation is accompanied by mitochondrial dysfunction and cell cycle mediated cell death, which can be rescued in vivo by genetically restoring the proper balance of mitochondrial fission and fusion. We have previously demonstrated that stabilization of actin by tau is critical for neurotoxicity of the protein. Here, we demonstrate a conserved role for actin and myosin in regulating mitochondrial fission and show that excess actin stabilization inhibits association of the fission protein DRP1 with mitochondria, leading to mitochondrial elongation and subsequent neurotoxicity. Our results thus identify actin-mediated disruption of mitochondrial dynamics as a direct mechanism of tau toxicity in neurons in vivo. PMID- 22920255 TI - c-Jun reprograms Schwann cells of injured nerves to generate a repair cell essential for regeneration. AB - The radical response of peripheral nerves to injury (Wallerian degeneration) is the cornerstone of nerve repair. We show that activation of the transcription factor c-Jun in Schwann cells is a global regulator of Wallerian degeneration. c Jun governs major aspects of the injury response, determines the expression of trophic factors, adhesion molecules, the formation of regeneration tracks and myelin clearance and controls the distinctive regenerative potential of peripheral nerves. A key function of c-Jun is the activation of a repair program in Schwann cells and the creation of a cell specialized to support regeneration. We show that absence of c-Jun results in the formation of a dysfunctional repair cell, striking failure of functional recovery, and neuronal death. We conclude that a single glial transcription factor is essential for restoration of damaged nerves, acting to control the transdifferentiation of myelin and Remak Schwann cells to dedicated repair cells in damaged tissue. PMID- 22920256 TI - Subcortical visual shell nuclei targeted by ipRGCs develop from a Sox14+ GABAergic progenitor and require Sox14 to regulate daily activity rhythms. AB - Intrinsically photosensitive retinal ganglion cells (ipRGCs) and their nuclear targets in the subcortical visual shell (SVS) are components of the non-image forming visual system, which regulates important physiological processes, including photoentrainment of the circadian rhythm. While ipRGCs have been the subject of much recent research, less is known about their central targets and how they develop to support specific behavioral functions. We describe Sox14 as a marker to follow the ontogeny of the SVS and find that the complex forms from two narrow stripes of Dlx2-negative GABAergic progenitors in the early diencephalon through sequential waves of tangential migration. We characterize the requirement for Sox14 to orchestrate the correct distribution of neurons among the different nuclei of the network and describe how Sox14 expression is required both to ensure robustness in circadian entrainment and for masking of motor activity. PMID- 22920257 TI - The LIM-homeodomain protein islet dictates motor neuron electrical properties by regulating K(+) channel expression. AB - Neuron electrical properties are critical to function and generally subtype specific, as are patterns of axonal and dendritic projections. Specification of motoneuron morphology and axon pathfinding has been studied extensively, implicating the combinatorial action of Lim-homeodomain transcription factors. However, the specification of electrical properties is not understood. Here, we address the key issues of whether the same transcription factors that specify morphology also determine subtype specific electrical properties. We show that Drosophila motoneuron subtypes express different K(+) currents and that these are regulated by the conserved Lim-homeodomain transcription factor Islet. Specifically, Islet is sufficient to repress a Shaker-mediated A-type K(+) current, most likely due to a direct transcriptional effect. A reduction in Shaker increases the frequency of action potential firing. Our results demonstrate the deterministic role of Islet on the excitability patterns characteristic of motoneuron subtypes. PMID- 22920258 TI - Regulation of N-type voltage-gated calcium channels and presynaptic function by cyclin-dependent kinase 5. AB - N-type voltage-gated calcium channels localize to presynaptic nerve terminals and mediate key events including synaptogenesis and neurotransmission. While several kinases have been implicated in the modulation of calcium channels, their impact on presynaptic functions remains unclear. Here we report that the N-type calcium channel is a substrate for cyclin-dependent kinase 5 (Cdk5). The pore-forming alpha(1) subunit of the N-type calcium channel is phosphorylated in the C terminal domain, and phosphorylation results in enhanced calcium influx due to increased channel open probability. Phosphorylation of the N-type calcium channel by Cdk5 facilitates neurotransmitter release and alters presynaptic plasticity by increasing the number of docked vesicles at the synaptic cleft. These effects are mediated by an altered interaction between N-type calcium channels and RIM1, which tethers presynaptic calcium channels to the active zone. Collectively, our results highlight a molecular mechanism by which N-type calcium channels are regulated by Cdk5 to affect presynaptic function. PMID- 22920259 TI - Visual input modulates audiomotor function via hypothalamic dopaminergic neurons through a cooperative mechanism. AB - Visual cues often modulate auditory signal processing, leading to improved sound detection. However, the synaptic and circuit mechanism underlying this cross modal modulation remains poorly understood. Using larval zebrafish, we first established a cross-modal behavioral paradigm in which a preceding flash enhances sound-evoked escape behavior, which is known to be executed through auditory afferents (VIII(th) nerves) and command-like neurons (Mauthner cells). In vivo recording revealed that the visual enhancement of auditory escape is achieved by increasing sound-evoked Mauthner cell responses. This increase in Mauthner cell responses is accounted for by the increase in the signal-to-noise ratio of sound evoked VIII(th) nerve spiking and efficacy of VIII(th) nerve-Mauthner cell synapses. Furthermore, the visual enhancement of Mauthner cell response and escape behavior requires light-responsive dopaminergic neurons in the caudal hypothalamus and D1 dopamine receptor activation. Our findings illustrate a cooperative neural mechanism for visual modulation of audiomotor processing that involves dopaminergic neuromodulation. PMID- 22920262 TI - Learning about time: plastic changes and interindividual brain differences. AB - Learning the timing of rapidly changing sensory events is crucial to construct a reliable representation of the environment and to efficiently control behavior. The neurophysiological mechanisms underlying the learning of time are unknown. We used functional and structural magnetic resonance imaging to investigate neurophysiological changes and individual brain differences underlying the learning of time in the millisecond range. We found that the representation of a trained visual temporal interval was associated with functional and structural changes in a sensory-motor network including occipital, parietal, and insular cortices, plus the cerebellum. We show that both types of neurophysiological changes correlated with changes of performance accuracy and that activity and gray-matter volume of sensorimotor cortices predicted individual learning abilities. These findings represent neurophysiological evidence of functional and structural plasticity associated with the learning of time in humans and highlight the role of sensory-motor circuits in the perceptual representation of time in the millisecond range. PMID- 22920260 TI - Transient slow gamma synchrony underlies hippocampal memory replay. AB - The replay of previously stored memories during hippocampal sharp wave ripples (SWRs) is thought to support both memory retrieval and consolidation in distributed hippocampal-neocortical circuits. Replay events consist of precisely timed sequences of spikes from CA3 and CA1 neurons that are coordinated both within and across hemispheres. The mechanism of this coordination is not understood. Here, we show that during SWRs in both awake and quiescent states there are transient increases in slow gamma (20-50 Hz) power and synchrony across dorsal CA3 and CA1 networks of both hemispheres. These gamma oscillations entrain CA3 and CA1 spiking. Moreover, during awake SWRs, higher levels of slow gamma synchrony are predictive of higher quality replay of past experiences. Our results indicate that CA3-CA1 gamma synchronization is a central component of awake memory replay and suggest that transient gamma synchronization serves as a clocking mechanism to enable coordinated memory reactivation across the hippocampal network. PMID- 22920263 TI - Efficient solvent-free synthesis of phytostanyl esters in the presence of acid surfactant-combined catalyst. AB - An efficient approach based on the synthesis of phytostanyl esters with an acid surfactant-combined catalyst in a solvent-free system was developed. The effect of catalyst dose, substrate molar ratio, reaction temperature, and acyl donor was considered. The reaction conditions were further optimized by response surface methodology, and a high yield of phytostanyl laurate (>92%) was obtained under optimum conditions: 3.17:1 molar ratio of lauric acid to plant stanols, 4.01% catalyst dose (w/w), 119 degrees C, and 4.1 h. FT-IR, MS, and NMR were adopted to confirm the chemical structure of phytostanyl laurate. Meanwhile, the physiochemical properties of different phytostanyl esters were investigated. Compared with phytostanols, the prepared phytostanyl esters had much lower melting temperature and higher oil solubility. There was no obvious difference in melting and solidification properties between sunflower oil with phytostanyl laurate (<5%) or oleate (<10%) and the original sunflower oil, suggesting that the esterification of phytostanols greatly facilitated their corporation into oil based foods. PMID- 22920261 TI - Early cognitive experience prevents adult deficits in a neurodevelopmental schizophrenia model. AB - Brain abnormalities acquired early in life may cause schizophrenia, characterized by adulthood onset of psychosis, affective flattening, and cognitive impairments. Cognitive symptoms, like impaired cognitive control, are now recognized to be important treatment targets but cognition-promoting treatments are ineffective. We hypothesized that cognitive training during the adolescent period of neuroplastic development can tune compromised neural circuits to develop in the service of adult cognition and attenuate schizophrenia-related cognitive impairments that manifest in adulthood. We report, using neonatal ventral hippocampus lesion rats (NVHL), an established neurodevelopmental model of schizophrenia, that adolescent cognitive training prevented the adult cognitive control impairment in NVHL rats. The early intervention also normalized brain function, enhancing cognition-associated synchrony of neural oscillations between the hippocampi, a measure of brain function that indexed cognitive ability. Adolescence appears to be a critical window during which prophylactic cognitive therapy may benefit people at risk of schizophrenia. PMID- 22920264 TI - Comparison of a 2-step insulin-response test to conventional insulin-sensitivity testing in horses. AB - Equine insulin resistance is important because of its association with laminitis. The insulin-response test is described to diagnose insulin resistance in clinical settings. Practitioners may be reluctant to perform this test because of the time needed for the test and the fear of inducing hypoglycemia. The objective of the study was to compare a 2-step insulin-response test with a complete insulin response test. A complete insulin-response test was performed on 6 insulin resistant horses and 6 controls. A 2-step insulin-response test consisting of an intravenous injection of 0.1 IU/kg human insulin and blood glucose determination at 0 and 30 min after injection was performed on the same horses. Times to reach a 50% reduction of glucose baseline were compared between tests and horses. All the horses tolerated both tests well. No significant difference was observed between baseline glucose concentrations of insulin-resistant horses and controls (P = 0.09). Time to reach 50% reduction of glucose baseline for controls was not significantly different with the use of the complete insulin-response test or the 2-step test (P = 0.98). For insulin-resistant horses, the time to reach 50% reduction of glucose baseline with the use of the 2-step test was significantly longer than for controls (P = 0.004). With a cut-off time of 30 min, the 2-step test had the same characteristics as the complete test. The 2-step test provided a safe, rapid, and low-cost method to diagnose insulin resistance in horses in a clinical setting. PMID- 22920265 TI - Effects of the phytoestrogen, genistein, and protein tyrosine kinase inhibitor dependent mechanisms on steroidogenesis and estrogen receptor expression in porcine granulosa cells of medium follicles. AB - The use of soy-based products in pig diets had raised concerns regarding the reproductive toxicity of genistein, the predominant isoflavone in soybeans. Genistein was reported to exhibit weak estrogenic activity but its mechanism of action is not fully recognized. The aim of the study was to examine the in vitro effects of genistein on (1) progesterone (P(4)) and estradiol (E(2)) secretion by porcine granulosa cells harvested from medium follicles, (2) the viability of cultured granulosa cells, and (3) the mRNA and protein expression of estrogen receptors alpha and beta (ERalpha and ERbeta) in these cells. In addition, to verify the role of protein tyrosine kinase (PTK)-dependent mechanisms possibly involved in genistein biological action, we tested the effects of lavendustin C, the nonsteroidal PTK inhibitor, on granulosa cell steroidogenesis. We found that genistein inhibited (P < 0.05) basal P(4) secretion by granulosa cells harvested from medium follicles of pigs. In contrast, lavendustin C did not affect basal P(4) secretion by the cells. Moreover, genistein increased (P < 0.05) basal granulosal secretion of E(2). In contrast, lavendustin C did not alter basal E(2) secretion by porcine granulosa cells. In addition, we demonstrated that genistein increased mRNA and protein expression of ERbeta (P < 0.05) in the examined cells. The expression of ERalpha mRNA was not affected by genistein and ERalpha protein was not detected in the cultured granulosa cells of pigs. In summary, the genistein action on follicular steroidogenesis in pigs involved changes in the granulosal expression of ERbeta. However, the genistein action on P(4) and E(2) production by granulosa cells harvested from medium follicles did not seem to be associated with PTK. PMID- 22920266 TI - Interaction between melatonin and follicle-stimulating hormone promotes in vitro development of caprine preantral follicles. AB - The aim of this study was to investigate the effects of melatonin and follicle stimulating hormone (FSH) on the in vitro culture of goat preantral follicles. Ovarian fragments were cultured for 7 d in alpha-minimum essential medium (alpha MEM(+)) containing melatonin (100, 250, 500, or 1,000 pM), FSH (50 ng/mL), or a combination of the 2 hormones and further analyzed by histology and transmission electron and fluorescent microscopy. The results showed that after 7 d of culture, tissues cultured in alpha-MEM(+) alone or supplemented with FSH alone, melatonin (500 and 1,000 pM), or the combination of FSH and melatonin (1,000 pM) maintained percentages of normal preantral follicles similar to the fresh control. In contrast to the noncultured tissues, the percentage of developing follicles was increased under all culture conditions after 7 d (P < 0.05). The addition of 1,000 pM melatonin associated with FSH to the culture medium increased follicular and oocyte diameters compared with alpha-MEM(+) alone after 7 d of culture (P < 0.05). Ultrastructural and fluorescent analyses confirmed the integrity of follicles cultured with 1,000 pM of melatonin plus FSH for 7 d. In conclusion, this study demonstrated that the interaction between melatonin and FSH maintains ultrastructural integrity and stimulates further growth of cultured caprine preantral follicles. PMID- 22920267 TI - Occult traumatic loculated tension pneumothorax--a sonographic diagnostic dilemma. AB - This case outlines a rarely seen disease in prehospital emergency care-namely, a traumatic loculated tension pneumothorax. Prehospital thoracic ultrasound as part of a standard extended focused assessment with sonography in trauma (EFAST) algorithm failed to diagnose this life-threatening injury. We have subsequently added scanning the lateral chest wall in the fifth intercostal space to the algorithm. PMID- 22920269 TI - First principles pKa calculations on carboxylic acids using the SMD solvation model: effect of thermodynamic cycle, model chemistry, and explicit solvent molecules. AB - Aqueous pK(a) values are calculated from first principles for a set of carboxylic acids using the SMD solvation model with various model chemistries, thermodynamic cycles, and treatments of explicit solvation. In all, 108 unique theoretical protocols are examined. The direct (D) and water proton exchange (PX) cycles are trialled along with a new approach, termed the semidirect (SD) cycle. The SD thermodynamic cycle offers some improvements over the D and PX schemes, as it bypasses the gas-phase heterolytic bond dissociation calculation required in the conventional D approach while also avoiding an aqueous OH(-) calculation required by the PX method when using water as the reference acid. With all three cycles, the recommended model chemistry employs M05-2X/cc-pVTZ Gibbs energies of solvation with a single discrete water molecule and a high-level composite method for the gas-phase reaction energies. With the SD cycle, these calculations result in a mean unsigned error of less than 1 pK(a) units, with respective mean signed error and maximum unsigned error of less than 0.5 and 2 pK(a) units. Similar results are obtained with the D and PX cycles, and further improvement is required in both the gas and aqueous phase ab initio energy calculations before we can truly discriminate between the thermodynamic cycles investigated here. PMID- 22920268 TI - Patterns of gray and white matter changes in individuals at risk for Alzheimer's disease. AB - Structural brain changes precede cognitive and clinical symptoms in Alzheimer's disease (AD). We aimed to examine the gray and white matter tissue changes in individuals with memory decline over a 12-year period, who might be at risk for AD. The participants were selected from the longitudinal Maastricht Aging Study based on their scores on the verbal word learning task. A group with profound memory decline over a 12-year period (n = 20) was identified and matched with a group that did not meet this criterion (n = 20). All of the participants underwent MRI scanning. Diffusion tensor imaging and cortical thickness analyses were performed to investigate the white and gray matter differences respectively. We found decreased white matter integrity in the memory decline group compared to the control group in frontal and parietal brain regions and in several cortico cortical and cortico-subcortical tracts. Cortical thinning in the memory decline group was found in frontal, parietal, medial temporal and occipital areas. These results showed similarities with the structural brain changes observed in early AD. Thus, not only may cognitive changes be detected years before the clinical diagnosis, but typical gray and white matter changes appear to be present in older people with memory decline as well. This suggests that a combination of cognitive decline and structural brain changes might be an ideal biomarker for AD pathogenesis. PMID- 22920270 TI - Serologic host response to Helicobacter pylori and Campylobacter jejuni in socially housed Rhesus macaques (Macaca mulatta). AB - BACKGROUND: Helicobacter pylori are successful colonizers of the human gastric mucosa. Colonization increases the risk of peptic ulcer disease and adenocarcinoma. However, potential benefits of H. pylori colonization include protection against early-onset asthma and against gastrointestinal infections. Campylobacter jejuni are a leading cause of bacterial diarrhea and complications include Guillain-Barre syndrome. Here, we describe the development of reliable serological assays to detect antibodies against those two bacteria in Rhesus macaques and investigated their distribution within a social group of monkeys. METHODS: Two cohorts of monkeys were analyzed. The first cohort consisted of 30 monkeys and was used to establish an enzyme-linked immunosorbent assay (ELISA) for H. pylori antibodies detection. To evaluate colonization of those macaques, stomach biopsies were collected and analyzed for the presence of H. pylori by histology and culture. C. jejuni ELISAs were established using human serum with known C. jejuni antibody status. Next, plasma samples of the 89 macaques (Cohort 2) were assayed for antibodies and then statistically analyzed. RESULTS: An H. pylori IgG ELISA, which was 100% specific and 93% sensitive, was established. In contrast, the IgA ELISA was only 82% specific and 61% sensitive. The CagA IgG assay was 100% sensitive and 61% of the macaques were positive. In cohort 2, 62% macaques were H. pylori sero-positive and 52% were CagA positive. The prevalence of H. pylori IgG and CagA IgG increased with monkey age as described for humans. Of the 89 macaques 52% showed IgG against C. jejuni but in contrast to H. pylori, the sero-prevalence was not associated with increasing age. However, there was a drop in the IgG (but not in IgA) mean values between infant and juvenile macaques, similar to trends described in humans. CONCLUSIONS: Rhesus macaques have widespread exposure to H. pylori and C. jejuni, reflecting their social conditions and implying that Rhesus macaques might provide a model to study effects of these two important human mucosal bacteria on a population. PMID- 22920271 TI - Morphometric analysis, region of supply and microanatomy of the lenticulostriate arteries and their clinical significance. AB - The lenticulostriate arteries (LSA) and their microanatomy, region of supply and atherosclerosis were examined in 24 microdissected brains, arterial casts, and histological specimens. The LSA ranged from 2 to 12 in number and from 0.10 mm to 1.28 mm in diameter. They always arose from the initial segment of the middle cerebral artery (MCA), often from the MCA leptomeningeal branches (38.24%), and rarely from the insular segment (2.94%). They always originated as individual branches, often (61.76%) with their own common stems. In two hemispheres we found that the LSA supplied either a larger or a smaller portion of the basal ganglia and internal capsule than usual. The number of twigs to the innominate substance (substantia innominata) (3-11), and their diameters (0.07-0.30 mm), has been described for the first time, to our knowledge. Microatheromas were found in two LSA. Data about the LSA microanatomy and territory could form the basis of safer neurosurgery, more accurate neuroimaging evaluation, and precise neurological diagnosis in patients with focal ischemic lesions in the basal ganglia and internal capsule. PMID- 22920272 TI - The presence of long spinal muscles increases stiffness and hysteresis of the caprine spine in-vitro. AB - Long muscle-tendon-units are known to contribute to spinal stiffness and hysteresis in-vivo, yet their contribution as a passive structure in-vitro is less well defined. Twelve full length caprine spines including the head, pelvis and all spinal muscles were tested during displacement in Flexion-Extension (FE) and coupled Lateral and Rotational (LR) motion in a material testing machine. Hysteresis and modified stiffness (modST), i.e. mean force divided by the total displacement, were calculated. This was repeated following removal of dorsal muscles (longissimus dorsi and gluteus) and ventral muscles (iliopsoas), in a random order. ModST and hysteresis in the different dissection stages were identified. Correlations between modST, hysteresis, body mass, spine length and longissimus muscle thickness were calculated. Removal of dorsal musculature reduced extension modST significantly by 23%, and flexion modST by 40%. Ventral muscle removal reduced extension modST by 1% and flexion modSt by 13%. Hysteresis was reduced by 27% after dorsal and 2% after ventral muscle removal in FE hysteresis. Out of 105 correlation coefficients, five values were significantly correlated (p<0.05, range r(2): 0.61-0.71) and 10 values were highly significantly correlated (p<0.01, range r(2): 0.75-0.97). Strongest correlations were between hysteresis and modST for the same movement direction and dissection state. The results of this study demonstrate that the presence of muscles stiffens the spine with dorsal muscles showing more effect. This supports the concept that muscle volume even in a non-contractile state provides a stabilising function to the spine. PMID- 22920274 TI - Complete mitochondrial genome of the stone loach, Triplophysa stoliczkae (Teleostei: Cypriniformes: Balitoridae). AB - The complete mitochondrial genome of the stone loach Triplophysa stoliczkae is 16,571 bp in size, consisting of 13 protein-coding genes, 22 transfer RNA (tRNA) genes, two ribosomal RNA (rRNA) genes, and a noncoding control region. As in other vertebrates, most mitochondrial genes are encoded on the heavy strand, except for nd6 and eight tRNA genes which are encoded on the light strand. The overall base composition of the heavy strand of the T. stoliczkae mitochondrial genome is A: 28.1%, T: 29.0%, C: 25.0%, and G: 17.9%. The alignment of the Triplophysa species control regions exhibited high genetic variability and rich A+T content. PMID- 22920273 TI - Comparing the effectiveness of copper intrauterine devices available in Canada. Is FlexiT non-inferior to NovaT when inserted immediately after first-trimester abortion? Study protocol for a randomized controlled trial. AB - BACKGROUND: We describe the rationale and protocol for a randomized noninferiority controlled trial (RCT) to determine if the Flexi-T380(+) copper intrauterine contraceptive device (IUD) is comparable in terms of effectiveness and expulsion rates to the most common Canadian IUD currently in use, NovaT-200, when placed immediately after a first-trimester abortion. METHODS/DESIGN: Consenting women choosing to use an IUD after an abortion for a pregnancy of less than 12 weeks of gestation will be randomized to device-type groups to receive immediate post-abortion placement of either a Flexi-T380(+) IUD, a device for which no current evidence on expulsion or effectiveness rates is available, or the Nova-T200 IUD, the only other brand of copper IUD available in Canada at the time of study initiation. The primary outcome measure is IUD expulsion rate at 1 year. Secondary outcomes include: pregnancy rate, method continuation rate, complication rates (infection, perforation), and satisfaction with contraceptive method. A non-intervention group of consenting women choosing a range of other post-abortion contraception methods, including no contraception, will be included for comparison of secondary outcomes. Web-based contraception satisfaction questionnaires, clinical records, and government-linked health administrative databases will be used to assess primary and secondary outcomes. DISCUSSION: The RCT design, combined with access to clinical records at all provincial abortion clinics, and to information in provincial single-payer linked administrative health databases, birth registry, and hospital records, offers a unique opportunity to determine if a novel IUD has a comparable expulsion rate to that of the current standard IUD in Canada, in addition to the first opportunity to determine pregnancy rate and method satisfaction at 1 year post-abortion for women choosing a range of post-abortion contraceptive options. We highlight considerations of design, implementation, and evaluation of the first trial to provide rigorous evidence for the effectiveness of current Canadian IUDs when inserted after first-trimester abortion. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT01174225. PMID- 22920275 TI - Geographic distribution of healthcare resources, healthcare service provision, and patient flow in Japan: a cross sectional study. AB - Healthcare systems in developed countries are facing the challenge of dealing with changing social structures as a result of rapidly aging populations. This study examines the relationship among the geographical distribution of healthcare resources, healthcare service provision, and interregional patient flow in Japan. A cross-sectional study was performed using data from healthcare-related public surveys conducted in 2008, together with social, economic, and environmental variables. The geographical units of analysis were 348 Secondary Healthcare Service Areas, which provide and manage most healthcare services in Japan. The equity of the distribution of physicians among hospitals and clinics was evaluated using the Lorenz curve and the Gini coefficient. Multiple regression analysis was used to examine the relationships between the inpatient flow ratio and selected variables. Next, the 348 Secondary Healthcare Service Areas were divided into tertiles according to the inpatient flow ratio, and differences among these variables were examined using Bonferroni's correction for multiple comparisons. The Gini coefficient for physician distribution among hospitals was 0.209 and was 0.165 among clinics. Multiple regression analysis showed that hospital physician density, the elderly ratio, and hospital bed density were all correlated with the inpatient flow ratio (beta = 0.396, -0.576, 0.425, respectively; R(2) = 0.622, all ps < 0.001). Healthcare resources were significantly more scarce in the lowest tertile (outflow group) than in other groups in both hospitals and clinics. The provision of healthcare services was also imbalanced among tertiles. Our results imply that there is a need for reconstituting the geographical distribution of healthcare resources in Japan. Further research and healthcare-related databases are also needed to facilitate the creation of a more balanced geographical distribution and of a more effective healthcare system in Japan. PMID- 22920278 TI - Changing health care quality paradigms: the rise of clinical guidelines and quality measures in American medicine. AB - Clinical guidelines and quality measures are important new paradigms for conceptualizing and managing quality in the United States. Researchers have proposed that professional elites-including members of academic medicine-were an important cause of the shift to guidelines and measures. This paper draws on content analysis of abstracts focused on quality in major American medical journals between 1975 and 2009 to empirically assess whether and how paradigms for managing quality changed in academic medicine. The content analysis shows that guidelines- and measures-based approaches to quality increased in prominence. Individual expertise-based approaches to quality, however, remain important. Concurrent with changing paradigms in academic medicine, there was a reorientation of policy toward increased use of guidelines and measures the late 1980s and early 1990s in the United States. This policy reorientation was informed by earlier work by medical researchers proposing new approaches to quality. The policy reorientation was followed by an increase in the prominence of guidelines and measures in medical research. PMID- 22920277 TI - Using complexity theory to analyse the organisational response to resurgent tuberculosis across London. AB - We employ complexity theory to analyse the English National Health Service (NHS)'s organisational response to resurgent tuberculosis across London. Tennison (2002) suggests that complexity theory could fruitfully explore a healthcare system's response to this complex and emergent phenomenon: we explore this claim here. We also bring in established New Public Management principles to enhance our empirical analysis, which is based on data collected between late 2009 and mid-2011. We find that the operation of complexity theory based features, especially self-organisation, are significantly impacted by the macro context of a New Public Management-based regime which values control, measurement and risk management more than innovation, flexibility and lateral system building. We finally explore limitations and suggest perspectives for further research. PMID- 22920276 TI - Glitch in the gradient: additional education does not uniformly equal better health. AB - While the relationship between education and general health has been firmly established in the literature, surprisingly little research has analyzed individual components of the global health judgments, such as chronic conditions or pain. We present a systematic account of the health gradient for multiple health outcomes by detailed educational categories among U.S. working-age adults. Using the 1997-2010 National Health Interview Surveys (N = 204,764), we analyze individual health outcomes ranging from cardiovascular disease to vision problems with a series of logistic regression models. The results at the presecondary and baccalaureate levels are consistent with the health gradient. An unexpected finding occurs among adults with some college but no degree, and those with technical/vocational associate degrees: these groups report more pain and a higher prevalence of a broad range of conditions than high school graduates who never attended college. We discuss several explanations for the observed patterns. The findings challenge the broadly accepted educational gradient in health; additionally, the lower postsecondary groups comprise a quarter of American adults. Jointly, there is a clear research and policy impetus to understand the source of this 'glitch' in the health gradient. PMID- 22920279 TI - A synthetic chemomechanical machine driven by ligand-receptor bonding. AB - The ability to create synthetic chemomechanical machines with engineered functionality promises large technological rewards. However, current efforts in molecular chemistry are restrained by the formidable challenges faced in molecular structure and function prediction. An alternative approach to engineering machines with tailorable chemomechanical functionality is to design Brownian ratchet devices using molecular assemblies. We demonstrate this through the creation of autonomous molecular machines that sense, mechanically react, and extract energy from ligand-receptor binding. We present a specific instantiation, measuring approximately 100 nm in length, which actuates upon detection of a streptavidin ligand. Machines were designed through the tailoring of energy landscapes on 3D DNA origami motifs. We also analyzed the response over a logarithmic concentration ratio (device:ligand) range from 1:10(1) to 1:10(5). PMID- 22920280 TI - Positive predictive value of a case definition for diabetes mellitus using automated administrative health data in children and youth exposed to antipsychotic drugs or control medications: a Tennessee Medicaid study. AB - BACKGROUND: We developed and validated an automated database case definition for diabetes in children and youth to facilitate pharmacoepidemiologic investigations of medications and the risk of diabetes. METHODS: The present study was part of an in-progress retrospective cohort study of antipsychotics and diabetes in Tennessee Medicaid enrollees aged 6-24 years. Diabetes was identified from diabetes-related medical care encounters: hospitalizations, outpatient visits, and filled prescriptions. The definition required either a primary inpatient diagnosis or at least two other encounters of different types, most commonly an outpatient diagnosis with a prescription. Type 1 diabetes was defined by insulin prescriptions with at most one oral hypoglycemic prescription; other cases were considered type 2 diabetes. The definition was validated for cohort members in the 15 county region geographically proximate to the investigators. Medical records were reviewed and adjudicated for cases that met the automated database definition as well as for a sample of persons with other diabetes-related medical care encounters. RESULTS: The study included 64 cases that met the automated database definition. Records were adjudicated for 46 (71.9%), of which 41 (89.1%) met clinical criteria for newly diagnosed diabetes. The positive predictive value for type 1 diabetes was 80.0%. For type 2 and unspecified diabetes combined, the positive predictive value was 83.9%. The estimated sensitivity of the definition, based on adjudication for a sample of 30 cases not meeting the automated database definition, was 64.8%. CONCLUSION: These results suggest that the automated database case definition for diabetes may be useful for pharmacoepidemiologic studies of medications and diabetes. PMID- 22920282 TI - Solid-state combinatorial screening of ARSi4N7:Eu2+ (A = Sr, Ba, Ca; R = Y, La, Lu) phosphors. AB - A double-ternary combinatorial chemistry (combi-chem) library was visualized in terms of structure, PL intensity, and color chromaticity for a nitride phosphor system, ARSi4N7:Eu(2+) (A = Sr, Ca, Ba; R = Y, La, Lu), so as to obtain a quantitative structure and property relationship (QSPR) in a systematic manner. Most of the samples constituting the double-ternary combi-chem library turned out to have ARSi4N7 structures with a P63mc space group. However, several phases such as Ca2Si5N8 with a Cc space group, LaSi3N5 with a P212121 space group, R6Si11N20O with a P31c space group, etc., coexisted. Aside from the green luminescence from the well-known SrYSi4N7:Eu(2+) and BaYSi4N7:Eu(2+) phosphors, their solid solutions (Sr,Ba)Si4N7:Eu(2+) proved to possess better PL properties. In addition, novel phosphors with an acceptable green PL intensity and color chromaticity were discovered in the ALuSi4N7:Eu(2+) side of the double-ternary combi-chem library. The Ca-rich side did not constitute a single-phase ARSi4N7 structure with a P63mc space group, and therefore the red emission in the Ca-rich side proved to originate from well-known Ca2Si5N8:Eu(2+) phosphors, which resided in the sample as a minor phase. PMID- 22920281 TI - Nitric oxide-induced eosinophil apoptosis is dependent on mitochondrial permeability transition (mPT), JNK and oxidative stress: apoptosis is preceded but not mediated by early mPT-dependent JNK activation. AB - BACKGROUND: Eosinophils are critically involved in the pathogenesis of asthma. Nitric oxide (NO) is produced in high amounts in asthmatic lungs and has an important role as a regulator of lung inflammation. NO was previously shown to induce eosinophil apoptosis mediated via c-jun N-terminal kinase (JNK) and caspases. Our aim was to clarify the cascade of events leading to NO-induced apoptosis in granulocyte macrophage-colony stimulating factor (GM-CSF)-treated human eosinophils concentrating on the role of mitochondria, reactive oxygen species (ROS) and JNK. METHODS: Apoptosis was determined by flow cytometric analysis of relative DNA content, by Annexin-V labelling and/or morphological analysis. Immunoblotting was used to study phospho-JNK (pJNK) expression. Mitochondrial membrane potential was assessed by JC-1-staining and mitochondrial permeability transition (mPT) by loading cells with calcein acetoxymethyl ester (AM) and CoCl2 after which flow cytometric analysis was conducted. Statistical significance was calculated by repeated measures analysis of variance (ANOVA) or paired t-test. RESULTS: NO-donor S-nitroso-N-acetyl-D,L-penicillamine (SNAP) induced late apoptosis in GM-CSF-treated eosinophils. SNAP-induced apoptosis was suppressed by inhibitor of mPT bongkrekic acid (BA), inhibitor of JNK SP600125 and superoxide dismutase-mimetic AEOL 10150. Treatment with SNAP led to late loss of mitochondrial membrane potential. Additionally, we found that SNAP induces early partial mPT (1 h) that was followed by a strong increase in pJNK levels (2 h). Both events were prevented by BA. However, these events were not related to apoptosis because SNAP-induced apoptosis was prevented as efficiently when BA was added 16 h after SNAP. In addition to the early and strong rise, pJNK levels were less prominently increased at 20-30 h. CONCLUSIONS: Here we demonstrated that NO induced eosinophil apoptosis is mediated via ROS, JNK and late mPT. Additionally, our results suggest that NO induces early transient mPT (flickerings) that leads to JNK activation but is not significant for apoptosis. Thereby, we showed some interesting early events in NO-stimulated eosinophils that may take place even if the threshold for irreversible mPT and apoptosis is not crossed. This study also revealed a previously unknown physiological function for transient mPT by showing that it may function as initiator of non-apoptotic JNK signalling. PMID- 22920283 TI - Elevated expression of LSD1 (Lysine-specific demethylase 1) during tumour progression from pre-invasive to invasive ductal carcinoma of the breast. AB - BACKGROUND: Lysine-specific demethylase1 (LSD1) is a nuclear protein which belongs to the aminooxidase-enzymes playing an important role in controlling gene expression. It has also been found highly expressed in several human malignancies including breast carcinoma. Our aim was to detect LSD1 expression also in pre invasive neoplasias of the breast. In the current study we therefore analysed LSD1 protein expression in ductal carcinoma in situ (DCIS) in comparison to invasive ductal breast cancer (IDC). METHODS: Using immunohistochemistry we systematically analysed LSD1 expression in low grade DCIS (n = 27), intermediate grade DCIS (n = 30), high grade DCIS (n = 31) and in invasive ductal breast cancer (n = 32). SPSS version 18.0 was used for statistical analysis. RESULTS: LSD1 was differentially expressed in DCIS and invasive ductal breast cancer. Interestingly, LSD1 was significantly overexpressed in high grade DCIS versus low grade DCIS. Differences in LSD1 expression levels were also statistically significant between low/intermediate DCIS and invasive ductal breast carcinoma. CONCLUSIONS: LSD1 is also expressed in pre-invasive neoplasias of the breast. Additionally, there is a gradual increase of LSD1 expression within tumour progression from pre-invasive DCIS to invasive ductal breast carcinoma. Therefore upregulation of LSD1 may be an early tumour promoting event. PMID- 22920284 TI - Improvement in developmental stuttering following deep brain stimulation for Parkinson's disease. PMID- 22920285 TI - Torque-related changes in mechanomyographic intensity patterns for the superficial quadriceps femoris muscles. AB - The purpose of this study was to investigate changes in mechanomyographic (MMG) intensity patterns for the vastus lateralis (VL), rectus femoris (RF) and vastus medialis (VM) during submaximal to maximal concentric isokinetic, eccentric isokinetic and isometric muscle actions of the leg extensors. Eleven men (mean +/ SD age = 20.1 +/- 1.1 years) performed concentric, eccentric and isometric muscle actions of the dominant leg extensors on 3 separate days. Surface MMG signals were detected from the VL, RF and VM, processed with a wavelet analysis and examined with a trend plot. The results indicated that the trend plot was capable of tracking systematic changes in MMG amplitude and frequency with an increase in torque. However, these changes were statistically significant in only 26% of the cases. There were also no consistent differences between muscles or contraction types for the significance of the trend plots. PMID- 22920286 TI - Proline catalyzes direct C-H arylations of unactivated arenes. AB - Several amino acids were tested to catalyze the transition-metal-free direct C-H arylation of unactivated benzene derivatives. Among them, proline was found to be an excellent catalyst for the cross-coupling between aryl halides and unactivated arenes. The reaction presumably involves an aryl radical anion as the intermediate based on several experiments. The reaction using this catalyst system offers an option toward establishing an environmentally benign and cost effective route to biaryls. PMID- 22920287 TI - Physiological changes as a result of hip arthroscopy performed with traction. AB - PURPOSE: To evaluate the physiological effects of hip arthroscopy using traction on venous blood flow, nerve conduction, soft-tissue injury, fibrinolysis, and patient pain. METHODS: Thirty subjects were prospectively analyzed in an institutional review board-approved study. The visual analog scale pain score, creatine phosphokinase (CPK)-MM level, and D-dimer test were obtained preoperatively, postoperatively, and 5 days postoperatively. Doppler ultrasound (group A) (n = 15) of femoral and popliteal venous blood flow and somatosensory evoked potentials (SSEPs) (group B) (n = 15) of the posterior tibial nerve and superficial peroneal nerve were monitored intraoperatively. RESULTS: Mean operation and traction times were 131.7 and 27.3 minutes, respectively. During traction (mean, 57.7 lb), decreased blood flow was determined at the popliteal vein (15 of 15 subjects) and femoral vein (4 of 15 subjects). Blood flow returned to baseline after traction in all subjects. Mean CPK-MM levels were 86.0 +/- 29.6 mU/mL preoperatively, 232.1 +/- 224.6 mU/mL postoperatively, and 138.1 +/- 109.3 mU/mL at 5 days postoperatively. The number of subjects positive for D-dimer was 7 preoperatively, 12 postoperatively, and 21 at 5 days postoperatively. SSEPs showed a greater than 50% decrease in amplitude on the operative (8 of 15) and nonoperative (9 of 15) limbs. No significant correlations were determined between visual analog scale pain score, body mass index, CPK-MM level, traction time, or operating room time. CONCLUSIONS: Doppler ultrasound showed decreased blood flow of the popliteal vein with traction, which returned to normal after traction. SSEPs showed changes with and without traction on operative and nonoperative legs. Consideration should be given for knee flexion of the contralateral leg after traction to protect nerve function. Hip arthroscopy resulted in an increase in a positive D-dimer test from immediately postoperatively to postoperative day 5. There is variability in the soft-tissue damage with hip arthroscopy, which is independent of time (<2 hours), body mass index, or pain. Traction affects the vascular and neurologic structures of the operative and nonoperative extremity independent of time. LEVEL OF EVIDENCE: Level IV, therapeutic case series. PMID- 22920288 TI - Suture capsulorrhaphy versus capsulolabral advancement for shoulder instability. AB - PURPOSE: The purpose of this study was to test the strength of a suture capsulorrhaphy repair versus a capsulolabral repair with knotless suture anchors in a cadaveric model with anteroinferior shoulder instability. METHODS: Fourteen cadaveric shoulders were tested with either a suture capsulorrhaphy to the intact labrum or a capsulolabral advancement using a knotless suture anchor into the glenoid. Specimens were translated with the shoulder in an abducted, externally rotated position to failure. RESULTS: The capsulolabral advancement showed a significantly higher load to failure than did the suture capsulorrhaphy group (P = .030). CONCLUSIONS: Capsulolabral advancement with suture anchors may offer greater initial strength when compared with a suture capsulorrhaphy. In the setting of shoulder instability without evidence of a labral tear, the capsulolabral advancement technique may be considered biomechanically superior. CLINICAL RELEVANCE: In the setting of shoulder instability due to capsular insufficiency, the capsulolabral advancement may be considered biomechanically superior to a traditional suture capsulorrhaphy. PMID- 22920289 TI - Unwinding to recombine. AB - The MCM proteins are best known for their role in DNA replication, MCM2-7 forming the replicative helicase. Now, two reports in this issue of Molecular Cell, Nishimura et al. (2012) and Lutzmann et al. (2012) show the less well understood MCM8 and MCM9 to be crucial for effective homologous recombination. PMID- 22920290 TI - HuR and translation--the missing linc(RNA). AB - In this issue, Yoon et al. (2012) reveal that HuR influences decay of a long noncoding RNA (lincRNA-p21) that in turn hybridizes to mRNA targets and represses their translation-an indirect, but elegant explanation for the impact of HuR on translation efficiency. PMID- 22920291 TI - Playing the end game: DNA double-strand break repair pathway choice. AB - DNA double-strand breaks (DSBs) are highly toxic lesions that can drive genetic instability. To preserve genome integrity, organisms have evolved several DSB repair mechanisms, of which nonhomologous end-joining (NHEJ) and homologous recombination (HR) represent the two most prominent. It has recently become apparent that multiple layers of regulation exist to ensure these repair pathways are accurate and restricted to the appropriate cellular contexts. Such regulation is crucial, as failure to properly execute DSB repair is known to accelerate tumorigenesis and is associated with several human genetic syndromes. Here, we review recent insights into the mechanisms that influence the choice between competing DSB repair pathways, how this is regulated during the cell cycle, and how imbalances in this equilibrium result in genome instability. PMID- 22920292 TI - Lipase-catalyzed synthesis of starch palmitate in mixed ionic liquids. AB - Lipase-catalyzed synthesis of starch palmitate was investigated in ionic liquid mixtures consisting of 1-butyl-3-methyl-imidazolium acetic ([BMIm]Ac) and 1-butyl 3-methyl-imidazolium tetraflouroborate ([BMIm][BF(4)]). The effect of reaction parameters such as the amount of enzyme used, the reaction temperature, the mass ratio of [BMIm][BF(4)]/[BMIm]Ac, the molar ratio of methyl palmitate/anhydroglucose unit in starch, and the reaction time on the degree of substitution was studied. The formation of starch esters was confirmed by the presence of the carbonyl signal in the FT-IR and NMR spectra. Scanning electron microscopy and X-ray diffraction data showed that the morphology and crystallinity of starch esters were largely disrupted. Thermogravimetric analysis suggested thermal stability of starch palmitate decreased compared to native starch. Water contact angle measurements revealed that the hydrophobicity of starch esters was improved after modification. The successful lipase-catalyzed synthesis of starch palmitate in ionic liquids suggested that ionic liquids could be used as a potentially attractive green alternative to harmful organic solvents for synthesis of high fatty acid starch ester. PMID- 22920293 TI - Craniopharyngioma. PMID- 22920294 TI - Bilateral endoscopic craniectomies in the treatment of an infant with Apert syndrome. AB - Patients with Apert syndrome commonly present with ocular proptosis due to bilateral coronal craniosynostosis and midfacial hypoplasia. Severe proptosis can cause visual compromise and damage, which is most commonly treated with bilateral orbital frontal advancement. The authors present the case of a patient who was treated at 8 weeks of age with endoscope-assisted bilateral coronal craniectomies followed by treatment with a custom-made postoperative cranial orthosis. The patient underwent the procedure without any complications. Over the ensuing months, the patient's proptosis corrected, the forehead and orbital rims advanced without the need for an orbital frontal advancement and craniotomies. This approach may provide an alternative treatment modality for these patients. PMID- 22920295 TI - Treatment-related morbidity and the management of pediatric craniopharyngioma: a systematic review. AB - OBJECT: Craniopharyngiomas are benign tumors but their close anatomical relationship with critical neurological, endocrine, and vascular structures makes gross-total resection (GTR) with minimal morbidity difficult to achieve. Currently, there is controversy regarding the extent, timing, and modality of treatment for pediatric craniopharyngioma. METHODS: The authors performed a systematic review of the published literature on pediatric craniopharyngioma to determine patterns of clinical practice and the reported outcomes of standard treatment strategies. This yielded 109 studies, which contained data describing extent of resection for a total of 531 patients. Differences in outcome were examined based upon extent of resection and choice of radiation treatment. RESULTS: Gross-total resection was associated with increased rates of new endocrine dysfunction (OR 5.4, p < 0.001), panhypopituitarism (OR 7.8, p = 0.006), and new neurological deficits (OR 9.9, p = 0.03) compared with biopsy procedures. Subtotal resection (STR) was not associated with an increased rate of new neurological deficits. Gross-total was associated with increased rates of diabetes insipidus (OR 7.7, p = 0.05) compared with the combination of STR and radiotherapy (RT). The addition of RT to STR was associated with increased rates of panhypopituitarism (OR 9.9, p = 0.01) but otherwise similar rates of morbidities. CONCLUSIONS: Although subject to the limitations of a literature review, this report suggests that GTR is associated with increased rates of endocrinopathies compared with STR + RT, and this should be considered when planning goals of surgery. PMID- 22920296 TI - Clinical and radiological profiles and outcomes in pediatric patients with intracranial aneurysms. AB - OBJECT: Intracranial aneurysms are extremely uncommon in the pediatric population, their characteristics are not well studied, and certain features make them unique. The authors analyzed pediatric patients with aneurysms to try to understand their clinical, radiological, and outcome profile. METHODS: Sixty three pediatric patients (<= 18 years of age) with ages ranging from 4 to 18 years and features (clinical and radiological) suggestive of aneurysm presented to, and were treated at, the authors' center in the past 20 years (1991-2011). Included in the present study were only those patients who underwent surgical intervention, and thus data for 57 patients were analyzed. RESULTS: Seventy-three aneurysms in 57 patients were surgically treated. There was a slight female predominance (M/F 1:1.2), and the mean age among all patients was 12.69 +/- 3.75 years. Fifty patients (87.72%) presented with subarachnoid hemorrhage, 4 (7.02%) with mass effect, and 3 (5.26%) with seizure. On presentation the majority of patients (45 [78.95%]) had a good clinical grade. Eleven patients had multiple aneurysms. The internal carotid artery (ICA) bifurcation was the most common aneurysm site (18 cases [24.66%]), followed by the middle cerebral artery (MCA) bifurcation (11 cases [15.07%]). At a mean follow-up of 18.58 +/- 10.71 months (range 1.5-44 months), 44 patients (77.19%) had a favorable outcome, and 5 patients had died. CONCLUSIONS: Pediatric patients with intracranial aneurysms most commonly presented with subarachnoid hemorrhage, and there was a slight female predominance. The ICA bifurcation followed by the MCA bifurcation was the most common aneurysm site. The incidence of posterior circulation and giant aneurysms is higher in pediatric patients than in the adult population. Children tend to present with better clinical grades and have better overall survival results and good functional outcomes. PMID- 22920297 TI - The stability of bisulfite and sulfonate ions in aqueous solution characterized by hydration structure and dynamics. AB - The aqueous solutions of bisulfite (SO(3)H(-)) and sulfonate (HSO(3)(-)) were simulated by the ab initio quantum mechanical charge field molecular dynamics (QMCF MD) formalism. All superimposed trajectories for the atomic coordinates of solutes with three-dimensional alignment here illustrated the reactivities of the ions. Power spectra were evaluated on the basis of the velocity autocorrelation functions (VACFs) with the normal-mode analysis, presenting a higher frequency of the symmetric SO(3) deformation (delta(s)(SO(3))) than the asymmetric SO(3) deformation (delta(as)(SO(3))) modes for the sulfonate ion. The different influence of solvent on the frequency of the O-H and S-H stretching suggests a higher stability of hydrated sulfonate ion. The bisulfite shows a slightly stronger molecular hydration shell than the sulfonate ion with the average number of ion-solvent hydrogen bonds (H-bonds) of 5.3 and 5.0, respectively. Extra water molecules within the molecular hydration shell are found for bisulfite (1.2) and for sulfonate (1.6). The mean residence times for the water ligands classify each ion as a structure maker, while the S-H bond within the sulfonate ion displays a hydrophobic behavior. No tautomerization was observed within the simulation period. PMID- 22920298 TI - The V-line: a sonographic aid for the confirmation of pleural fluid. AB - BACKGROUND: Ultrasound is being used increasingly to diagnose pathological free fluid accumulation at the bedside. In addition to the detection of peritoneal and pericardial fluid, point-of-care ultrasound allows rapid bedside diagnosis of pleural fluid. FINDINGS: In this short report, we describe the sonographic observation of the vertebral or 'V-line' to help confirm the presence of pleural fluid in the supine patient. The V-line sign is a result of the fluid acting as an acoustic window to enable visualization of vertebral bodies and posterior thoracic wall, thus confirming the presence of pleural fluid. CONCLUSIONS: The V line is a useful sonographic sign to aid the diagnosis of pleural free fluid. PMID- 22920299 TI - New insights into the mechanism of JNK1 inhibition by glutathione transferase P1 1. AB - The role played by glutathione transferase P1-1 (GSTP1-1) in modulating the c-Jun N-terminal kinase (JNK) pathway has been extensively investigated using JNK isoforms known to exert opposite effects in the cells. We have expressed isoform JNK1alpha2, which has been reported to transmit a pro-apoptotic signal, and we have analyzed both the phosphorylation level and the activity of this kinase in the presence of GSTP1-1. Contrary to what previous studies suggest, we found that GSTP1-1 is able to form a complex with the unphosphorylated and inactive JNK1alpha2 isoform, even in the absence of the substrate. We also analyzed the consequences of this interaction on the activity of both enzymes. The complex strongly reduced the extent of activation of JNK1alpha2 and preserved GSTP1-1 from inactivation. Unexpectedly, glutathione (GSH) exerted a negative effect on the affinity of GSTP1-1 for JNK1alpha2, suggesting that the intracellular levels of this thiol may allow a fine-tuning of the MAPK signaling pathway. Moreover, we found that the adduct formed by GSH and the strong GSTP1-1 inhibitor NBDHEX abolishes the interaction between GSTP1-1 and JNK1alpha2. These data confirm and extend at the molecular level previous evidence obtained in tumor cell lines. PMID- 22920300 TI - Exploring reverse shape selectivity and molecular sieving effect of metal-organic framework UIO-66 coated capillary column for gas chromatographic separation. AB - Metal-organic frameworks (MOFs) which offer a variety of topologies, porous networks and high surface areas are promising and have potential for the applications of specific adsorption, isomerization, catalysis and separation. UIO 66 is the first MOF that has been observed to have reverse shape selectivity. However, such reverse shape selectivity of MOFs has never been explored for capillary gas chromatographic separation. Here we report the fabrication of MOF UIO-66 coated capillary column and exploration of the reverse shape selectivity and molecular sieving effect of such column for capillary gas chromatographic separation of alkane isomers and benzene homologues with excellent selectivity and precision. The adsorption enthalpies and entropies on the interaction between hydrocarbons and UIO-66 were measured to illustrate the energy effect on the separation of alkane isomers and benzene homologues on the UIO-66 coated capillary column. UIO-66 coated capillary column gave preferential retention of branched alkane isomers over their linear isomer, showing reverse shape selectivity, making UIO-66 coated capillary column attractive for capillary gas chromatographic separation of alkane isomers. iso-Propylbenzene (branched) eluted after n-propylbenzene on the UIO-66 coated capillary column again shows reverse shape selectivity. However, much bulkier 1,3,5-trimethylbenzene eluted earlier than n-propylbenzene and iso-propylbenzene on the UIO-66 coated capillary column, exhibiting molecular sieving effect. The combination of reverse shape selectivity with molecular sieving effect makes the UIO-66 coated capillary column promising for the separation of structural isomers. PMID- 22920301 TI - A versatile cryo-focussing flow switching gas chromatography inlet for trace analysis of intractable compounds. AB - A wide variety of samples that can be analysed by gas chromatography do not lend themselves to the usual preparation of solvent extracts for split-splitless injections, and are best handled by purge and trap or equilibrium headspace sampling. A cryo-focussing, flow switching gas chromatography inlet system that handles different types of sample without the need for hardware changes has been prototyped. It provides excellent repeatability and linearity with liquid injections, purge and trap, and equilibrium headspace samples, in both split and splitless modes. The performance of the system was tested with sub-nanogram quantities of challenging analytes such as free carboxylic acids, alcohols, diols, phenols and aldehydes, and volatiles purged from contaminated soil, mammal faeces, a pesticide formulation, and a spice. Repeatability RSDs for peak areas were consistently below 11% and repeatabilities of retention times below 0.05%, independently of sample type (liquid or gas phase) and nature or quantity of compound. Regression coefficients of peak areas vs. quantity were typically >= 0.999 over two orders of magnitude ranges extending down to below 0.01 ng, also independently of sample and analyte. Limits of quantitation were robustly below 0.1-0.2 ng. Peak shapes and resolution are the same with use of the cryo-trap and flow switch as they are with conventional injections. Performance is robust to flow rate and, for most compounds, to trapping and desorption temperature. The cryo-trapping flow switching inlet's performance parameters match those of other sample introduction systems, and are achieved with sub-nanogram quantities of intractable analytes. PMID- 22920302 TI - Valid internal standard technique for arson detection based on gas chromatography mass spectrometry. AB - The most popular procedures for the detection of residues of accelerants in fire debris are the ones published by the American Society for Testing and Materials (ASTM E1412-07 and E1618-10). The most critical stages of these tests are the conservation of fire debris from the sampling to the laboratory, the extraction of residues of accelerants from the debris to the activated charcoal strips (ACS) and from those to the final solvent, as well as the analysis of sample extract by gas chromatography-mass spectrometry (GC-MS) and the interpretation of the instrumental signal. This work proposes a strategy for checking the quality of the sample conservation, the accelerant residues transference to final solvent and GC-MS analysis, using internal standard additions. It is used internal standards ranging from a highly volatile compound for checking debris conservation to low volatile compound for checking GC-MS repeatability. The developed quality control (QC) parameters are not affected by GC-MS sensitivity variation and, specifically, the GC-MS performance control is not affected by ACS adsorption saturation that may mask test performance deviations. The proposed QC procedure proved to be adequate to check GC-MS repeatability, ACS extraction and sample conservation since: (1) standard additions are affected by negligible uncertainty and (2) observed dispersion of QC parameters are fit for its intended use. PMID- 22920303 TI - Chromatographic-nuclear magnetic resonance can provide a prediction of high pressure liquid chromatography shape selectivity tests. AB - NMR diffusometry has been recently demonstrated as a means of investigating the mobility variations of solutes induced by chromatographic phases (under the acronym chromatographic-NMR). Particularly, a given compound has its average diffusivity reduced proportionally to its affinity towards the solid. In this work we propose the first comparison of chromatographic-NMR and tests for assessment of column performance, to investigate to what measure the novel approach could provide an assay of the outcome of a given stationary phase without the need of packing the relative column. Specifically, using bulk materials, we reproduce with very good agreement a shape selectivity test as reported in the catalog of a column producer, consisting of four probe molecules, applied to two different stationary phases. PMID- 22920304 TI - Fabrication and evaluation of low-cost agarose-zinc nanoporous composite matrix: influence of adsorbent density and size distribution on the performance of expanded beds. AB - Expanded bed adsorption (EBA), a promising and practical separation technique for adsorption of nanobioproduct/bioproduct, has been widely studied in the past two decades. The development of adsorbent with the special design for expanded bed process is a challenging course. To reduce the costs of adsorbent preparation, fine zinc powder was used as the inexpensive densifier. A series of matrices named Ag-Zn were prepared by water-in-oil emulsification method. The structure and morphology of the prepared matrix were studied by the optical microscope (OM) and scanning electron microscopy (SEM). The physical properties as a function of zinc powder ratio to agarose slurry were measured. The prepared matrices had regular spherical shape, and followed logarithmic normal size distribution with the range of 75-330 MUm, mean diameter of 140.54-191.11 MUm, wet density of 1.33 2.01 g/ml, water content of 0.45-0.75, porosity of 0.86-0.97 and pore size of about 40-90 nm. The bed expansion factor at the range of 2-3 was examined. The obtained results indicated that the expansion factor was decreased with increasing of matrix density. In addition, it was found that matrices with large particle size were suitable for high operation flow rate. The hydrodynamic properties were determined in expanded bed by the residence time distribution method (RTD). The effects of flow velocity, expansion factor and density of matrix on the hydrodynamic properties were also investigated. Moreover, the influence of particle size distribution on the performance of expanded bed has been studied. Therefore, three different particle size fractions (65-140, 215-280 and 65-280 MUm) were assessed. The results indicated that dispersion in liquid solid expanded beds increased with increasing flow rate and expansion factor; and matrix with a wide particle size distribution leaded to a reduced axial dispersion compared to matrices with a narrow size distribution. The axial dispersion coefficient also enhanced with the increasing of matrix density. It was found that flow rate was the most essential factor to effect on the hydrodynamic characteristics in the bed. For all the prepared matrices, the values of axial mixing coefficients (D(axl)) were smaller than 1.0 * 10-5 m2/s when flow velocities in expanded bed were less than 700 cm/h. All the results indicate that the prepared matrix show good expansion and stability in expanded bed; and it is suitable for expanded bed processes as an economical adsorbent. PMID- 22920305 TI - High performance liquid chromatography-tandem mass spectrometry method for quantifying phenylurea herbicides and their main metabolites in amended and unamended soils. AB - A sensitive multiresidue method for the simultaneous determination of sixteen phenylurea herbicides and their main metabolites in amended soils has been developed. Liquid chromatography tandem-mass spectrometry (LC-MS2) in electrospray ionization positive mode was used for the separation, identification and quantification of these compounds. The procedure involves initial single phase extraction of soil sample with acetonitrile by sonication, followed by liquid-liquid partitioning formed by addition of NaCl. The average recovery by the LC-MS2 method obtained for these compounds varied from 76.2 to 107.9% with a relative standard deviation ranging from 2.1 to 5.8%. The method presents good linearity (R2>0.99) over the range assayed 10-1000 MUg L-1 (except N-phenylurea 50-1000 MUg L-1). The detection limits for the compounds studied varied from 0.1 to 9.0 ng g-1. PMID- 22920306 TI - Rapid quantification of protein-polyethylene glycol conjugates by multivariate evaluation of chromatographic data. AB - Size exclusion chromatography (SEC) is often applied for characterization of protein-polyethylene glycol (PEG) conjugates regarding the number of attached PEG chains (PEGamers). SEC analysis is advantageous as it is precise, robust, and straightforward to establish. However, most SEC based assays have a maximal throughput of a few samples per hour. We present a strategy to increase analytical throughput based on combining a short column with a fast flow rate, and finally multivariate calibration in order to compensate for the resolution lost in the trade off for speed. Different multivariate approaches were compared and multilinear regression was shown to result in the most precise calibrations. Further, a dynamic calibration approach was developed in order to account for changes in column performance over time. In this way, it was possible to establish a highly precise assay for protein PEGamer quantification with a throughput of 30 samples per hour. PMID- 22920308 TI - [The multifibrillar network of the tendon sliding system]. AB - After carrying out 215 in vivo dissections, 65 of which were video-recorded, the authors propose that the current representation of the notion of the tendon sliding is incorrect. It is suggested that tendon sliding is explained by the existence of a mechanical adaptable multimicrovacuolar and fibrillar tissue. This tissue enables complete sliding without any dynamic influence on the surrounding tissues. The new theory is based on a polyhedric fibrillar framework, apparently chaotic and complex, subtending the microvacuolar gel, a concept that is to be found everywhere in the human body. PMID- 22920307 TI - Dual antiplatelet therapy in patients with aspirin resistance following coronary artery bypass grafting: study protocol for a randomized controlled trial [NCT01159639]. AB - BACKGROUND: Coronary artery disease remains the dominant cause of mortality in developed countries. While platelets have been recognized to play a pivotal role in atherothrombosis, the ideal antiplatelet regime after coronary artery surgery remains elusive. The evolution of CABG has presently moved beyond technical improvements to involve modulation of pharmacologic management designed to improve patient outcomes. The aim of this trial will be to test the hypothesis that the addition of clopidogrel to patients with documented postoperative aspirin resistance will reduce the incidence of major cardiovascular events. METHODS: Patients scheduled for isolated coronary artery surgery will be eligible for the study. Patients in whom postoperative multiple electrode aggregometry documents aspirin resistance will be randomized into two groups. The control group will receive 300 mg of aspirin. The dual antiplatelet group will receive 75 mg of clopidogrel in addition to 300 mg of aspirin. Patients will be followed for 6 months. Major adverse cardiac and cerebrovascular events (death from any cause, myocardial infarction, stroke, hospitalization due to cardiovascular pathology) as well as bleeding events will be recorded. DISCUSSION: This will be the first trial that will specifically address the issue of dual antiplatelet therapy in patients undergoing coronary artery surgery who have been found to be aspirin resistant. In the event that the addition of clopidogrel proves to be beneficial in this subset of surgical patients, this study could significantly impact their future antiplatelet management. This randomized controlled trial has been registered at the ClinicalTrials.gov website (Identifier NCT01159639). PMID- 22920310 TI - The effect of playing surface on the incidence of ACL injuries in National Collegiate Athletic Association American Football. AB - BACKGROUND: Artificial playing surfaces are widely used for American football practice and competition and anterior cruciate ligament (ACL) injuries are common. This study analyzed the National Collegiate Athletic Association (NCAA) Injury Surveillance System (ISS) men's football ACL injury database from 2004 2005 through 2008-2009 to determine the effect of playing surface on ACL injury in NCAA football athletes. METHODS: This database was reviewed from the 2004-2005 through 2008-2009 seasons using the specific injury code, "Anterior cruciate ligament (ACL) complete tear." The injury rate was computed for competition and practice exposures. Ninety-five percent confidence intervals were calculated using assumptions of a Poisson distribution. Pair-wise, two-sample tests of equality of proportions with a continuity correction were used to estimate the associations of risk factors. RESULTS: There was an incidence rate of 1.73 ACL injuries per 10,000 athlete-exposures (A-Es) (95% CI 1.47-2.0) on artificial playing surfaces compared with a rate of 1.24 per 10,000 A-Es (1.05-1.45, p<0.001) on natural grass. The rate of ACL injury on artificial surfaces is 1.39 times higher than the injury rate on grass surfaces. Non-contact injuries occurred more frequently on artificial turf surfaces (44.29%) than on natural grass (36.12%). CONCLUSIONS: NCAA football players experience a greater number of ACL injuries when playing on artificial surfaces. PMID- 22920309 TI - An evaluation of insertion sites for mini-implants: a micro - CT study of human autopsy material. AB - OBJECTIVE: (1) To report the thickness of the cortical bone in insertion sites commonly used for orthodontic mini-implants, (2) to assess the impact of a change in insertion angle on primary cortical bone-to-implant contact, and (3) to evaluate the risk of maxillary sinus perforation. MATERIALS AND METHODS: At autopsy, 27 human samples containing three to five adjacent teeth were excised and scanned using a table-top micro-computed tomography system. Bone thickness measurements were taken at 45 degrees and 90 degrees to the long the axis of the adjacent teeth, simulating a mini-implant insertion at the mid-root level. RESULTS: In the maxilla, the overall mean cortical thickness at 90 degrees was 0.7 mm buccally in the lateral region, 1.0 mm buccally in the anterior region, and 1.3 mm palatally. In the mandible, the mean cortical thickness was 0.7 mm buccally and 1.8 mm lingually in the anterior region; 1.9 mm buccally and 2.6 mm lingually in the lateral region. Changing the insertion angle from 90 degrees to 45 degrees increased the cortical bone-to-implant contact by an average of 47%. Perpendicular insertion at the mid-root level only rarely interfered with the sinus, whereas apically inclined insertion increased the risk of sinus perforation. CONCLUSIONS: Buccally and palatally in the maxilla and buccally in the anterior mandible, the thickness of the alveolar cortical bone is often less than 1 mm. In contrast, the alveolar cortical bone is frequently thicker than 2 mm laterally in the mandible. Changing the insertion angle to 45 degrees will generally enhance implant stability but increase the risk of perforation to the maxillary sinus. PMID- 22920311 TI - The complete mitochondrial genome sequence of the Gracile shrew mole, Uropsilus gracilis (Soricomorpha: Talpidae). AB - The Gracile shrew mole (Uropsilus gracilis) belongs to the family Talpidae, which distributes in southwestern China, extending to northern Myanmar. In this study, the complete mitochondrial genome of U. gracilis was sequenced. It was determined to be of 16,533 bases. The nucleotide sequence data of 12 heavy-strand protein coding genes of U. gracilis and other 12 insectivores were used for phylogenetic analysis. Phylogenetic trees were constructed by using Bayesian and maximum likelihood methods, which showed that U. gracilis was clustered together with U. soricipes, and Urotrichus should be prior to Galemys. PMID- 22920312 TI - What's on the horizon: the future of pain medicine. PMID- 22920313 TI - A systematic review of the evidence for complete decongestive therapy in the treatment of lymphedema from 2004 to 2011. AB - OBJECTIVE: To critically analyze the contemporary published research that pertains to the individual components of complete decongestive therapy (CDT), as well as CDT as a bundled intervention in the treatment of lymphedema. DATA SOURCES: Publications were retrieved from 11 major medical indices for articles published from 2004-2010 by using search terms for lymphedema and management approaches. Literature archives of the authors and reference lists were examined through 2011. STUDY SELECTION: A research librarian assisted with initial literature searches by using search terms used in the Best Practice for the Management of Lymphoedema, plus expanded terms, for literature related to lymphedema. Authors sorted relevant literature for inclusion and exclusion; included articles were sorted into topical areas for data extraction and assessment of level of evidence by using a published grading system and consensus process. The authors reviewed 99 articles, of which 26 met inclusion criteria for individual studies and 1 case study did not meet strict inclusion criteria. In addition, 14 review articles and 2 consensus articles were reviewed. DATA EXTRACTION: Information on study design and/or objectives, participants, outcomes, intervention, results, and study strengths and weaknesses was extracted from each article. Study evidence was categorized according to the Oncology Nursing Society Putting Evidence into Practice level of evidence guidelines after achieving consensus among authors. DATA SYNTHESIS: Levels of evidence were only moderately strong, because there were few randomized controlled trials with control groups, well-controlled interventions, and precise measurements of volume, mobility and/or function, and quality of life. Treatment interventions were often bundled, which makes it difficult to determine the contribution of each individual component of treatment to the outcomes achieved. CONCLUSIONS: CDT is seen to be effective in reducing lymphedema. This review focuses on original research about CDT as a bundled intervention and 2 individual components, manual lymph drainage and compression bandages. Additional studies are needed to determine the value and efficacy of the other individual components of CDT. PMID- 22920314 TI - The business of health care reform. PMID- 22920315 TI - Cervical manipulation for neck pain. PMID- 22920316 TI - Severe nervous system complications after botulinum type A therapy: three case reports with reviews of FDA-reported nervous system adverse effects. PMID- 22920317 TI - Single-lead percutaneous peripheral nerve stimulation for the treatment of shoulder pain from subacromial impingement syndrome. AB - This case report demonstrates the feasibility of a single-lead peripheral nerve stimulation system for the treatment of pain secondary to chronic subacromial impingement syndrome. The participant was a 57-year-old man who experienced persistent pain from subacromial impingement syndrome for 20 months despite having undergone conservative therapy of steroid injection and physical therapy. After study enrollment, a single intramuscular lead was placed percutaneously into the deltoid muscle of the affected shoulder. He was treated 6 hours per day for 3 weeks and the lead was removed. The primary outcome measure was the Brief Pain Inventory (Short-form) Question 3 (BPI 3), which queries the worst pain in the last week on a 0-10 numerical rating scale. At baseline, BPI 3 was an 8. At the end of treatment and at 4 and 12 weeks after treatment, BPI 3 scores were 2, 0, and 0, respectively. Substantial improvements in shoulder impairment, quality of life, and shoulder disability measures were also observed. Additional studies are needed to further demonstrate safety and efficacy, determine optimal dose, define optimal prescriptive parameters, expand clinical indications, and demonstrate long-term effect. PMID- 22920318 TI - Use of an antigravity treadmill for rehabilitation of a pelvic stress injury. AB - Pelvic stress injuries are a relatively uncommon form of injury that require high index of clinician suspicion and usually MRI for definitive diagnosis. We present a case report of a 21-year-old female elite runner who was diagnosed with pelvic stress injury and used an antigravity treadmill during rehabilitation. She was able to return to pain-free ground running at 8 weeks after running at 95% body weight on the antigravity treadmill. Ten weeks from time of diagnosis, she competed at her conference championships and advanced to the NCAA Championships in the 10,000-meters. She competed in both races without residual pain. To our knowledge, this is the first published case report on use of an antigravity treadmill in rehabilitation of bone-related injuries. Our findings suggest that use of an antigravity treadmill for rehabilitation of a pelvic stress injury may result in appropriate bone loading and healing during progression to ground running and faster return to competition. Future research may identify appropriate protocols for recovery from overuse lower extremity injuries and other uses for this technology, including neuromuscular recovery and injury prevention. PMID- 22920319 TI - A ventral epidural facet cyst causing central canal stenosis and lumbar nerve compression in a woman with lumbar radicular pain. PMID- 22920320 TI - Re: hip strength and knee pain in high school runners: a prospective study. PMID- 22920322 TI - Sampling issues in quantitative analysis of dendritic spines morphology. AB - BACKGROUND: Quantitative analysis of changes in dendritic spine morphology has become an interesting issue in contemporary neuroscience. However, the diversity in dendritic spine population might seriously influence the result of measurements in which their morphology is studied. The detection of differences in spine morphology between control and test group is often compromised by the number of dendritic spines taken for analysis. In order to estimate the impact of dendritic spine diversity we performed Monte Carlo simulations examining various experimental setups and statistical approaches. The confocal images of dendritic spines from hippocampal dissociated cultures have been used to create a set of variables exploited as the simulation resources. RESULTS: The tabulated results of simulations given in this article, provide the number of dendritic spines required for the detection of hidden morphological differences between control and test groups in terms of spine head-width, length and area. It turns out that this is the head-width among these three variables, where the changes are most easily detected. Simulation of changes occurring in a subpopulation of spines reveal the strong dependence of detectability on the statistical approach applied. The analysis based on comparison of percentage of spines in subclasses is less sensitive than the direct comparison of relevant variables describing spines morphology. CONCLUSIONS: We evaluated the sampling aspect and effect of systematic morphological variation on detecting the differences in spine morphology. The results provided here may serve as a guideline in selecting the number of samples to be studied in a planned experiment. Our simulations might be a step towards the development of a standardized method of quantitative comparison of dendritic spines morphology, in which different sources of errors are considered. PMID- 22920323 TI - Sulfur K-edge X-ray absorption spectroscopy and time-dependent density functional theory of dithiophosphinate extractants: minor actinide selectivity and electronic structure correlations. AB - The dithiophosphinic acid HS(2)P(o-CF(3)C(6)H(4))(2) is known to exhibit exceptionally high extraction selectivities for trivalent minor actinides (Am and Cm) in the presence of trivalent lanthanides. To generate insight that may account for this observation, a series of [PPh(4)][S(2)PR(2)] complexes, where R = Me (1), Ph (2), p-CF(3)C(6)H(4) (3), m-CF(3)C(6)H(4) (4), o-CF(3)C(6)H(4) (5), o-MeC(6)H(4) (6), and o-MeOC(6)H(4) (7), have been investigated using sulfur K edge X-ray absorption spectroscopy (XAS) and time-dependent density functional theory (TDDFT). The experimental analyses show distinct features in the spectrum of S(2)P(o-CF(3)C(6)H(4))(2)(-) (5) that are not present in the spectrum of 4, whose conjugate acid exhibits reduced selectivity, or in the spectra of 2 and 3, which are anticipated to have even lower separation factors based on previous studies. In contrast, the spectrum of 5 is similar to those of 6 and 7, despite the significantly different electron-donating properties associated with the o CF(3), o-Me, and o-OMe substituents. The TDDFT calculations suggest that the distinct spectral features of 5-7 result from steric interactions due to the presence of the ortho substituents, which force the aryl groups to rotate around the P-C bonds and reduce the molecular symmetry from approximately C(2v) in 2-4 to C(2) in 5-7. As a consequence, the change in aryl group orientation appears to make the ortho-substituted S(2)PR(2)(-) anions "softer" extractants compared with analogous Ph-, p-CF(3)C(6)H(4)-, and m-CF(3)C(6)H(4)-containing ligands (2-4) by raising the energies of the sulfur valence orbitals and enhancing orbital mixing between the S(2)P molecular orbitals and the aryl groups bound to phosphorus. Overall, we report that sulfur K-edge XAS experiments and TDDFT calculations reveal unique electronic properties of the S(2)P(o-CF(3)C(6)H(4))(2)(-) anion in 5. These results correlate with the special extraction properties associated with HS(2)P(o-CF(3)C(6)H(4))(2), and suggest that ligand K-edge XAS and TDDFT can be used to guide separation efforts relevant to advanced fuel cycle development. PMID- 22920324 TI - PEGylated PRINT nanoparticles: the impact of PEG density on protein binding, macrophage association, biodistribution, and pharmacokinetics. AB - In this account, we varied PEGylation density on the surface of hydrogel PRINT nanoparticles and systematically observed the effects on protein adsorption, macrophage uptake, and circulation time. Interestingly, the density of PEGylation necessary to promote a long-circulating particle was dramatically less than what has been previously reported. Overall, our methodology provides a rapid screening technique to predict particle behavior in vivo and our results deliver further insight to what PEG density is necessary to facilitate long-circulation. PMID- 22920325 TI - The effect of sulindac, a non-steroidal anti-inflammatory drug, attenuates inflammation and fibrosis in a mouse model of chronic pancreatitis. AB - BACKGROUND: Chronic pancreatitis is characterized by progressive fibrosis, pain and loss of exocrine and endocrine functions. The long-standing chronic pancreatitis and its associated pancreatic fibrosis are the most common pathogenic events involved in human pancreatic carcinogenesis, but the therapeutic strategies to chronic pancreatitis and the chemoprevention of pancreatic carcinogenesis are very limited. METHODS: We investigated the effect of sulindac, a non-steroidal anti-inflammatory drug (NSAID), on inhibition of chronic pancreatitis in a caerulein induced chronic pancreatitis mouse model. RESULTS: Sulindac significantly reduced the severity of chronic pancreatitis including the extent of acini loss, inflammatory cell infiltration and stromal fibrosis. The protein expression of phosphorylation of MEK/ERK was inhibited in the chronic pancreatic tissues by sulindac treatment as measured by Western blot assay. The levels of inflammatory cytokines including TNF-alpha and MCP-1 were also significantly decreased with sulindac treatment, as well as the expression of TGF-beta, PDGF-beta, SHH and Gli in the chronic pancreatic tissue detected by qPCR assay and confirmed by western blot assay. The activation of pancreatic satellet cells was also inhibited by sulindac as measured by the activity of alpha-smooth muscle actin (alpha-SMA) in the pancreatic tissue of chronic pancreatitis. CONCLUSIONS: Sulindac is a promising reagent for the treatment of chronic pancreatitis via inhibition of inflammatory cell infiltration and stromal fibrosis, the inhibitory effect of sulindac on chronic pancreatitis may through targeting the activation ERK/MAPK signaling pathway. PMID- 22920326 TI - Targeted therapy for liver cancer: updated review in 2012. AB - In May 2007, sorafenib (Nexavar?) was approved for "unresectable hepatocellular carcinoma (HCC)", and was the first molecular targeted agent for use in HCC. To date, sorafenib is the only molecular-targeted agent, whose survival benefit has been demonstrated in two global phase III randomized controlled trials, and has now been approved worldwide. Phase III clinical trials of other molecular targeted agents comparing them with sorafenib as first-line treatment agents are now ongoing. Phase III clinical trials of several targeted agents comparing them with placebo as second-line treatment agents for patients who failed or was intolerable to sorafenib are also ongoing. In addition, combination of sorafenib with standard treatment such as resection, ablation, transarterial chemoembolization, and hepatic arterial infusion chemotherapy are ongoing.This review outlines the clinical utility of sorafenib in the treatment algorithm of HCC. Furthermore, it also reviews the current status of clinical trials of new agents or combination therapy with sorafenib and standard treatment. Finally, further prospect of the paradigm shift of the HCC treatment is also discussed. PMID- 22920327 TI - Healthcare system intervention for prevention of birth injuries - process evaluation of self-assessment, peer review, feedback and agreement for change. AB - BACKGROUND: Patient safety is fundamental in high quality healthcare systems but despite an excellent record of perinatal care in Sweden some children still suffer from substandard care and unnecessary birth injuries. Sustainable patient safety improvements assume changes in key actors' mental models, norms and culture as well as in the tools, design and organisation of work. Interventions positively affecting team mental models on safety issues are a first step to enhancing change. Our purpose was to study a national intervention programme for the prevention of birth injuries with the aim to elucidate how the main interventions of self-assessment, peer review, feedback and written agreement for change affected the teams and their mental model of patient safety, and thereby their readiness for change. Knowledge of relevant considerations before implementing this type of patient safety intervention series could thereby be increased. METHODS: Eighty participants in twenty-seven maternity units were interviewed after the first intervention sequence of the programme. A content analysis using a priori coding was performed in order to relate results to the anticipated outcomes of three basic interventions: self-assessment, peer review and written feedback, and agreement for change. RESULTS: The self-assessment procedure was valuable and served as a useful tool for elucidating strengths and weaknesses and identifying areas for improvement for a safer delivery in maternity units. The peer-review intervention was appreciated, despite it being of less value when considering the contribution to explicit outcome effects (i.e. new input to team mental models and new suggestions for actions). The feedback report and the mutual agreement on measures for improvements reached when signing the contract seemed exert positive pressures for change. CONCLUSIONS: Our findings are in line with several studies stressing the importance of self evaluation by encouraging a thorough review of objectives, practices and outcomes for the continuous improvement of an organisation. Even though effects of the peer review were limited, feedback from peers, or other change agents involved, and the support that a clear and well-structured action plan can provide are considered to be two important complements to future self-assessment procedures related to patient safety improvement. PMID- 22920328 TI - [Is nerve stimulation still necessary in ultrasound-guided regional anaesthesia]. PMID- 22920329 TI - [Analysis of output failures in an ambulatory surgery unit]. PMID- 22920330 TI - Oscillatory shear stress created by fluid pulsatility versus flexed specimen configurations. AB - Oscillatory shear stress (OSS), caused by time-varying flow environments, may play a critical role in the production of engineered tissue by bone marrow derived stem cells. This is particularly relevant in heart valve tissue engineering (HVTE), owing to the intense haemodynamic environments that surround native valves. In this study, we examined and quantified the role that (i) physiologically relevant scales of pulsatility and (ii) changes in geometry as a function of specimen flexure have in creating OSS conditions. A U-shaped bioreactor capable of producing flow, stretch and flexure was modelled with housed specimens, and computational fluid dynamic simulations were performed. We found that physiologically relevant OSS can be maximised by the application of pulsatile flow to straight, non-moving specimens in a uniform manner. This finding reduces a substantial layer of complexity in dynamic HVTE protocols in which traditionally, time-varying flow has been promoted through specimen movement in custom-made bioreactors. PMID- 22920331 TI - Transesterification for synthesis of carboxylates using aldehydes as acyl donors via C-H and C-O bond activations. AB - A new type of transesterification between aryl, heteroaryl, alkyl N-heteroarene-2 carboxylates and various aldehydes by C-H and C-O bond activations has been developed for the synthesis of versatile carboxylates. A possible mechanism containing oxidative addition of acyl-O bond in parent ester and radical cleavage of sp(2) C-H bond in aldehyde is proposed. PMID- 22920332 TI - [5 alpha-reductase inhibitors and prostate cancer: a statement of the Committee of Cancerology of the French Association of Urology]. AB - INTRODUCTION: Two randomised trials and negative conclusion of the FDA about inhibitors of 5 alpha-reductase in prevention of prostate cancer need a revision of the indications of these drugs. METHODS: After description of fundamentals data, review of the literature in PubMed library was performed to analyse the indications of these drugs according to the different stages of prostate cancer. RESULTS: Even if PCPT and REDUCE studies showed a decrease of cancers with the use of 5 alpha-reductase (5ARI) but with side effects, there is no indication for prostate cancer prevention by these drugs. In the same way, despite the results of REEDEM study, there is no indication of these drugs in active surveillance. CONCLUSION: Despite the large interest of these drugs, no recommendation can be given for indications of 5ARI in prevention or treatment of prostate cancer. PMID- 22920333 TI - [Assisted reproductive technologies with sperm donation]. AB - INTRODUCTION: The purpose of this review is to relate to the operating rules of CECOS in France and the legal, medical and ethical issues raised by sperm donation. MATERIAL AND METHODS: Review of articles and consensus conferences on this subject published in Medline (PubMed) selected from 1973 and 2011 according to their relevance and Acts recorded on official legislative French websites. RESULTS: The operating rules of CECOS were established by the Act of July 29, 2004, revised 6 August 2004 and July 7, 2011. Of the 21,759 children born of ART in France in 2009, 5.1% are from a sperm donation. From 1973 to 2006, 44,045 children are born after a sperm donation. Between 1973 and 2006, 16,971 donors are presented in the CECOS and only 10,347 donors have completely made their donation process. The main indication for use of donor sperm (75% of applications) is represented by men of infertile couples with nonobstructive azoospermia, the second indication is infertile men with oligospermia. In azoospermia, the application is usually performed after failure of testicular or epididymal surgical specimen. In oligozoospermia, claims made most often after several failures of intraconjugal ART. CONCLUSION: Many questions are still present around the conception of children by sperm donation. The legitimacy of maintaining anonymity in the gift remains widely debated. PMID- 22920334 TI - [Growing teratoma syndrome]. AB - Growing teratoma syndrome (GTS) is a rare entity, characterized by enlarging masses of the retroperitoneum or other location occurring during or after systemic chemotherapy for the treatment of non-seminomatous germ cell of the testis (NSGCT). Three criteria define this syndrome: enlarging metastatic masses, normalized serum markers and no component of viable germ cell tumor in this mature teratoma. Prognostic is excellent after the resection of these masses, but this surgery has to be as much complete as possible. Surgical excision of large GTS lesions is technically challenging, a serious intraoperative complications may occur, that's why the treatment must not be delayed. PMID- 22920335 TI - [Clinicopathological study and immunohistochemical expression of CA9 in cystic multilocular renal cell carcinomas]. AB - OBJECTIVE: Multilocular cystic renal cell carcinoma has been considered as a distinct subtype of clear cell renal cell carcinoma according to 2004 WHO classification. CA9 has proven to be a diagnostic and prognostic marker for clear cell renal cell carcinoma, but the study has been limited to solid tumors. The aim of this article was to analyse the clinical features of multilocular cystic renal cell carcinoma with focus on CA9 expression. PATIENTS AND METHODS: Nine multilocular cystic renal cell carcinomas were found. Their age was from 33 to 74 years old with a median of 54 years. There were five men and four women. The computerized tomography was analyzed. There were three total nephrectomies and six partial nephrectomies. The follow-up ranged from five to 102 months with a median 56 months. Immunohistochemical staining was performed on surgical samples to detect CA9 expression. RESULTS: There were seven pT1a, one pT1b and one pT2; four grade 1 and five grade 2. The Bosniak classification was: one B2F, six B3 and two B4. In CT examination, all tumors showed a hypodense mass. Seven out of nine showed multiple intern septa, more or less thick and vascularized with an enhancement after injection of contrast. No metastasis or relapse was found during follow-up. Eight out of nine multilocular cystic renal cell carcinomas expressed strongly CA9. CONCLUSION: Multilocular cystic renal cell carcinoma was a low malignant tumor with a good prognosis. The diagnostic criteria based on the WHO classification 2004 should be adopted in routine. CA9 could be a new diagnostic marker for this tumor. PMID- 22920336 TI - [Effect of plant extracts on the in vitro dissolution of cystine stones: a study at the mesoscopic scale]. AB - AIM: Assessing the efficacy to dissolve cystine stones in vitro of plant extracts used in traditional medicine to treat or prevent urolithiasis. MATERIAL AND METHOD: Pure cystine stones were incubated during 8 weeks under magnetic stirring in the presence of four plant extracts or of NaCl 9 g/l solution used as control. Plants under examination were Arenaria ammophila (leaves and stems), Parietaria officinalis (leaves and flowers studied separately), Paronychia argentea (flowers). Each experiment was performed in triplicate. The mass loss of the stones and the pH of the solution were measured after each two weeks period. Possible changes in the cystine crystals at the stone surface were assessed at the mesoscopic scale using a scanning electron microscope. RESULTS: None of the plant extracts has revealed a significant effect to dissolve cystine stones by comparison to the control during the time of the experiment. The best result was a mass loss of 99 mg at the end of experiment in the presence of A. ammophila vs. 43.7 mg for the NaCl solution (P=0.051). Considering the slopes of the dissolution, only that extract could have an actual efficacy on a more prolonged period. CONCLUSION: Our study failed to demonstrate a significant effect of the tested plant extracts to dissolve cystine stones in vitro. However, the examination of the dissolution curves suggests that a more prolonged test period could allow an efficacy of some extracts, especially A. ammophila. Further studies are needed to verify such hypothesis. However, we cannot recommend the use of the tested plants to treat cystine stones in vivo. PMID- 22920337 TI - [Prebiopsy multiparametric MRI of the prostate: the end of randomized biopsies?]. AB - OBJECTIVE: To evaluate the value of multiparametric MRI-targeted prostate biopsies in patients with suspected low-risk prostate cancer. PATIENTS AND METHOD: Patients with normal digital rectal examination and a PSA level between 4 and 10 ng/mL were prospectively included. A multiparametric MRI of the prostate was performed prospectively before the biopsies. 12-core randomized biopsies were performed, with additional targeted samples in each suspicious area identified on MRI. Detected cancers and their histological characteristics were compared between those two biopsy protocols. A micro focal cancer (MFC) was defined by the presence of less than 4mm of Gleason score 3+3 cancer on a single core. RESULTS: Seventy-one consecutive patients were included. The overall detection rate was of 53% (38/71). It was of 70% (26/37) in the presence of suspicious area on MRI versus 35% (12/34) in the absence of any suspicious area (P=0.004). MRI-targeted biopsies alone detected three cancers, none of which was a MFC. 12-core biopsies alone detected 14 cancers, including ten MFC (71%). In 21 patients, prostate cancer was detected by both the MRI-targeted and 12-core biopsies. The Gleason score in the MRI-targeted area was the highest Gleason score in 90% of the cases. It was high (>6) in 76% (16/21) of the patients. CONCLUSIONS: MRI-targeted biopsies detected less micro focal cancers than randomized 12-core biopsies. They did not seem however to decrease the detection of clinically significant cancers. PMID- 22920338 TI - [Intra-prostatic UroLift((r)) implants for benign prostatic hyperplasia: preliminary results of the four first cases performed in France]. AB - OBJECTIVES: To evaluate the feasibility, tolerance and short-term efficacy of intra-prostatic UroLift((r)) implants in four patients with symptomatic benign prostatic hyperplasia. PATIENTS AND METHOD: Four patients with symptomatic BPH, already treated with alpha-blockers, were consecutively treated with intra prostatic UroLift((r)) implants under general anaesthesia. A bladder catheter was placed postoperatively. Alpha-blocker therapy was withdrawn 7 days postoperatively. The clinical and morphological characteristics of the patients were noted. Low urinary tract (IPSS) and sexual symptoms (IIEF5, MSHQ-EjD), maximum urinary flow rate and post voiding residual volume were evaluated preoperatively and at 1 month. RESULTS: Median age was of 69 [52-74] years old and median prostatic volume of 50 cm(3) [40-80]. Median procedure time was of 11 minutes [6-15]. Intra- and postoperative outcomes were uneventful. At 1 month, the mean IPSS and IPSS-QOL improvement were of 46 % and 58 %, respectively. One patient reported no improvement in his urinary and sexual symptoms. In the other three patients, the maximum urinary flow rate was improved, the post voiding residual improved in two patients and similar in one. No alteration in erection or ejaculation functions was reported. CONCLUSIONS: In our initial experience, intra-prostatic UroLift((r)) implant procedure seemed feasible, efficacious for LUTS and well tolerated, especially concerning sexual outcomes. Further study of the UroLift((r)) implant in France is currently being planned. PMID- 22920339 TI - [A western cohort of urinary schistosomiasis]. AB - Urinary schistosomiasis is very frequent, but there are few data upon its epidemiology in western countries. We wanted to describe the cohort from Tenon hospital, in Paris, France, near a big subsaharian community. METHODS: We searched in our clinical files database for "urinary schistosomiasis" encoding. RESULTS: The cohort comprised 207 men and 34 women seen for the first time at the mean age of 34, mainly for haematuria or LUTS. Patients were mainly native from subsaharian Africa. The lost to follow up rate was 54%. Diagnosis was made on sole endoscopic finding in half of the cases. For non-tumor pathology, were made seven cystoplasties et 12 ureteral dilations. Tumoral pathology was frequent and severe (15/81 from the same age range), mainly represented by urothelial histology (8/14). Imported cases were rare (five cases). CONCLUSION: Despite its limitations, different characteristics from this cohort seemed noticeable: frequency of sole lower urinary tract symptoms, frequency and severity of tumoral diseases, mainly with urothelial carcinoma as histology. PMID- 22920340 TI - [Assessment of the transobturator male sling by a pelvic MRI]. AB - PURPOSE: To evaluate the usefulness of MRI to assess the anatomical and functional relationships between the transobturator male sling Advance((r)) and the uretral sphincter, in patients treated for postprostatectomy urinary incontinence. PATIENTS: For 12 patients treated for postprostatectomy urinary incontinence using the transobturator male sling Advance((r)), a pelvic real-time MRI was performed between 1 and 3 months postoperatively. A comparison between pre- and postoperative MRI was performed in eight patients. The static sequences studied the anatomical relationships between the sling and the uretral sphincter, as well as the impact on the location of the vesico-uretral anastomosis. The dynamic sequences by coughing looked for the existence of an uretral sphincter mobility. Finally, the voiding sequences studied the impact of the sling on the uretral lumen during the micturition. RESULTS: The position of the sling was always visible, located at a median distance of 5mm from the posterior wall of the uretra. On transverse sections, the angles between the transobturator arms and the horizontal line between the ischial tuberosities varied from 28 to 59 degrees. The vesico-uretral anastomosis location was not modificated between pre and postoperative MRI. On the preop sequences by coughing, four patients had uretral mobility, which didn't exist on postop sequences. To finish, the seven patients who were able to void during MRI, had micturition without uretral stenosis. CONCLUSION: Pelvic MRI was a useful tool to assess the positioning of the sling and the relationships with the uretral sphincter. When correctly positioned, the sling was retro-uretrally and no urethral stenosis was visible during the micturition. PMID- 22920341 TI - [Could gosereline acetate induce autoimmune-like hepatitis?]. AB - We report a case of acute icteric hepatitis attributed to goserelin acetate, occurred during prostate cancer treatment. Gosereline acetate could induce acute hepatitis, which characteristics are close to autoimmune hepatitis type I and may require hepatic monitoring. PMID- 22920342 TI - MRI and pelvic abscesses: a pictorial review. AB - OBJECTIVE: The purpose of our article was to review the magnetic resonance imaging (MRI) features of pelvic abscesses. Pelvic abscesses account for a wide range of abnormalities from various etiologies. CONCLUSION: MRI is being increasingly used for pelvic exploration. Radiologists must thus be aware of their features and characteristics. PMID- 22920343 TI - Spectrum of gastric malignancy on 18F-FDG PET/CT: a pictorial essay. AB - A wide variety of malignant gastric diseases can be detected, staged, and followed on (18)F-FDG PET/CT. Although the PET/CT findings are often nonspecific and some can be seen in certain benign gastric diseases, the aim of this atlas was to demonstrate that the wide histological spectrum of gastric tumors that can be evaluated, staged, and followed with PET/CT is much broader than current medical literature would suggest. PET/CT readers and oncologists should be aware of the utility of PET/CT in these tumors and the imaging characteristics and patterns of (18)F-FDG uptake that can be demonstrated in these cases. PMID- 22920344 TI - What is the role of plain radiography in patients with foreign bodies in the gastrointestinal tract? AB - Foreign bodies (FBs) in the gastrointestinal (GI) tract can show a wide range of clinical manifestations ranging from spontaneous evacuation to severe complication. Plain radiography is a straightforward and important initial imaging modality in cases of FB ingestion or insertion and is also helpful for follow-up purposes. Careful evaluations of the plain radiographs can determine the presence and nature of FBs, and help predict their precise locations and facilitate risk assessment. In this review, a wide variety of FBs in the GI tract are illustrated, and the role of plain radiography in patient management is discussed. PMID- 22920345 TI - Effect on examination ordering by physician attitude, common knowledge, and practice behavior regarding CT radiation exposure. AB - PURPOSE: We surveyed ordering physician attitudes, knowledge, and behavior with regard to computed tomography (CT)-related radiation exposure at a large medical center. METHODS: Sixteen questions were sent via electronic survey to 350 physicians. RESULTS AND CONCLUSION: The ability to quickly rule in or rule out conditions effectively strongly influenced the decision to order CT (85%-99%). Fear of litigation influenced CT ordering for those with less experience [odds ratio (OR)=2.3, P<.05]. Residents and primary care physicians were less likely to discuss risks/benefits of CT with patients (P <=.03) compared to those with >5 years of experience (OR=4.0, P=.04). PMID- 22920346 TI - Cerebral toxoplasmosis: unusual MRI findings. AB - BACKGROUND: Single cerebral toxoplasmic lesions are rarely explored. METHODS: Through magnetic resonance imaging, 10 lesions were analyzed regarding location, signal intensity, contrast enhancement, eccentric target, and meningeal uptake. RESULTS: Five lesions were corticosubcortical and in the deep three (60%) had infratentorial locations. Iso- or hypointense signal predominated in T1 sequence, but in T2, there was variability. Perilesional edema and ring contrast enhancement occurred in 100% of lesions, but eccentric targets and meningeal uptake were less frequent. CONCLUSION: Even in the presence of single lesions, iso- or hypointense signal in T1, perilesional edema, and ring enhancement are suggestive of cerebral toxoplasmosis. PMID- 22920347 TI - Extracranial skeletal Langerhans cell histiocytosis: MR imaging features according to the radiologic evolutional phases. AB - PURPOSE: The purpose was to describe the magnetic resonance (MR) findings of extracranial skeletal Langerhans cell histiocytosis according to the radiologic evolutional phases. MATERIALS AND METHODS: Twenty-two patients with pathologically confirmed extracranial skeletal Langerhans cell histiocytosis were included. The lesions were classified as early, mid, and late phases according to the radiologic evolutional phases. MR images were retrospectively analyzed regarding signal intensity, internal hypointense band, fluid levels, periosteal reaction, adjacent bone marrow and soft tissue abnormal signal, and patterns of contrast enhancement in each phase. RESULTS: According to the radiologic evolutional phases, there were 4 patients with early phase, 16 with mid phase, and 2 with late phase. All cases showed hypointense to intermediate signal intensity on T1-weighted images. On T2-weighted images, 12 (55%) of the 22 lesions were hyperintense, and 10 (45%) showed intermediate signal. All lesions showed diffusely heterogeneous signal on T2-weighted images. Internal low-signal bands of the lesions were observed in 13 cases (59%). There were two cases with fluid levels in mid phase. Periosteal reaction was observed in 13 (59%) cases. Adjacent bone marrow or soft tissue abnormal signal was observed in 20 cases (91%), respectively. According to early, mid, and late phases, bone marrow and soft tissue abnormal signals were observed in 100%, 100%, and 0% cases, respectively. Soft tissue mass was seen in eight cases (36%). Ten (46%) lesions showed cortical destruction, including one patient with a pathologic fracture. Among 21 patients with contrast infusion, diffuse enhancement was observed in 19 patients (90%), and marginal and septal enhancement was seen in 2 patients (10%). CONCLUSION: MR imaging was helpful in the diagnosis of extracranial skeletal Langerhans cell histiocytosis, particularly in early and mid phases. PMID- 22920348 TI - Computed tomography scan findings in refractory acute rhinosinusitis. AB - Several sinonasal anatomical variants may be related to the etiology of acute rhinosinusitis. The same is true with intrusion of teeth into the maxillary sinus cavity. Patients with acute rhinosinusitis not responding to maximal medical treatment were prospectively enrolled. Deviation of the nasal septum towards the infected sinus may be associated with the pathogenesis of refractory acute rhinosinusitis. Intrusion of teeth into the maxillary sinus is a common finding and is not necessarily associated with the formation of sinusitis. PMID- 22920349 TI - Clinical and imaging findings in thalassemia patients with extramedullary hematopoiesis. AB - The purpose was to analyze the imaging features of thalassemia with extramedullary hematopoiesis in 17 patients. The 17 patients were analyzed and examined retrospectively by X-ray, ultrasonography, computed tomography, and magnetic resonance imaging. Nine cases appeared with hepatic enlargement; 12 cases presented with megalocardia or hypodensity; 15 cases had skeletal manifestations, with involvement of the ribs (66.7%), spine vertebra (40.0%), skull (46.7%), and other bones (20%). Five cases showed nonskeletal manifestations, and extramedullary hematopoiesis was found in three cases. A case presented with cholelithiasis, and hemosiderosis of the liver was found in three cases. The signs of the skeletal manifestations and nonskeletal manifestations may be useful for clinical diagnosis. PMID- 22920350 TI - Magnetic resonance imaging in the evaluation of iron overload: a comparison of MRI, echocardiography and serum ferritin level in patients with beta-thalassemia major. AB - PURPOSE: This study aimed to evaluate iron levels in cardiac and hepatic tissues using magnetic resonance imaging (MRI) T2*. METHODS: Cardiac and hepatic MRI was performed for 93 patients with beta-thalassemia major. RESULTS: Cardiac T2* was in the range of 2.9-56.6 ms. Myocardial siderosis was detected in 44% of patients; 25 patients had moderate and severe siderosis with serum ferritin level (SFL) of 576-10,284 ng/ml. There was a significant correlation between SFL and cardiac T2* (p<.001). CONCLUSIONS: The effective role of MRI as a noninvasive producible method in measurement of iron concentration in tissues is not accessible with conventional techniques. PMID- 22920351 TI - Evolution of portal vein tumor thromboses in patients with hepatocellular carcinoma: CT findings and transition of serum tumor markers. AB - We investigated the patterns of evolution of portal vein tumor thromboses (PVTTs) and the changes in serum tumor marker levels in untreated hepatocellular carcinomas. The mean time required for the subsegmental or lower-order branch PVTTs and the segmental PVTTs to reach the large portal vein was 120 and 101 days, respectively. The mean values of the serum alpha-fetoprotein levels markedly increased after the appearance of PVTTs from 1858.7 ng/ml to 6795.2 ng/ml. PMID- 22920352 TI - Non-contrast-enhanced MR venography of the upper limb: a comparative study of acquisitions with fresh blood imaging vs. time-of-flight methods. AB - Non-contrast-enhanced magnetic resonance venography (MRV) of the upper limb acquired by fresh blood imaging (FBI) was compared with time-of-flight (TOF)-MRV. Visualization of three veins (basilic, brachial, and cephalic veins), small branches, and fat suppression was evaluated with a four-point scale (0-3). FBI MRV was significantly superior for the basilic veins and small venous branches and equivalent for the brachial and cephalic veins to TOF-MRV, with no difference in fat suppression. FBI-MRV would be useful in venous mapping and detection of thrombus. PMID- 22920353 TI - A new approach of extracting embolized venous catheters using a large-diameter steerable sheath under biplane fluoroscopy. AB - To report the efficacy of a new percutaneous technique for extraction of embolized catheters, five female patients (62 +/- 14 years) referred to our institution were analyzed. With the combination of a large-diameter steerable sheath with a sizeable snare system, three dislodged Port-A-Cath tubes and two ventriculoatrial shunts were retrieved successfully. Mean procedure time was 51 +/- 23 min, biplane fluoroscopy time was 22 +/- 21 min, and dose area product was 1188 +/- 992 dGy cm(2). Percutaneous extraction of embolized venous catheters is highly effective with the help of this novel, self-assembled system. The presented technique provides major advantages with respect to three-dimensional steerability and should be considered for complex cases. PMID- 22920354 TI - Shorter-time dual-phase FDG PET/CT in characterizing solid or ground-glass nodules based on surgical results. AB - OBJECTIVES: We compared the accuracy of shorter-time dual-phase (18)F-FDG PET/CT in evaluating 94 different lung nodules classified as solid or ground-glass nodules (GGNs). MATERIALS AND METHODS: Early and delayed maximum standardized uptake values (SUV(max)) as well as the retention index (RI) of each nodule were determined in 75 solid nodules and 19 GGNs. RESULTS: In solid nodules, early SUV(max), delayed SUV(max), and RI were higher in malignant than in benign lesions. In GGNs, these values were not significantly lower in the malignant than in the benign lesions. CONCLUSION: In the patient group with solid nodules, shorter-time dual-phase (18)F-FDG PET/CT could significantly differentiate the malignant from the benign ones. PMID- 22920355 TI - Gray-scale inversion radiographic display for the detection of pulmonary nodules on chest radiographs. AB - The purpose of this study was to investigate gray-scale inversion in nodule detection on chest radiography. Simulated nodules were superimposed randomly onto normal chest radiographs. Six radiologists interpreted 144 chest radiographs during three reading sessions: traditional presentation, inverted gray-scale, and a choice session allowing use of traditional and gray-scale inverted views. Sensitivity and specificity were used to assess accuracy based on presence or absence of a nodule. Gray-scale inversion and choice display sessions resulted in significantly higher nodule detection specificity and decreased sensitivity compared to traditional display. Gray-scale inversion may decrease false-positive nodule findings during chest X-ray interpretation. PMID- 22920356 TI - Clinical and multidetector computed tomography findings of patients with median arcuate ligament syndrome. AB - OBJECTIVES: The present study aimed to present the clinical and multidetector computed tomography (MDCT) findings of patients who were diagnosed with the median arcuate ligament (MAL) syndrome on MDCT retrospectively. METHODS: Seven hundred forty-four patients in whom MDCT angiography was performed were retrospectively analyzed for investigating incidental MAL syndrome. RESULTS: Twenty-one patients were shown to have MAL syndrome. Of 21 patients, 18 with MAL syndrome were asymptomatic. Three patients had some symptoms. On MDCT angiography, proximal narrowing of the arteries was observed in 21 patients. CONCLUSIONS: MDCT is a minimally invasive and useful tool for the diagnosis of MAL syndrome. PMID- 22920357 TI - Diagnostic accuracy of ultra-high-b-value 3.0-T diffusion-weighted MR imaging for detection of prostate cancer. AB - PURPOSE: To investigate the diagnostic accuracy of 3.0-T diffusion-weighted imaging (DWI) for detection of prostate cancer by using different b-values. METHODS: Seventy-three patients underwent magnetic resonance imaging (MRI) at 3.0 T. Three MRI sets were reviewed by two radiologists: MRI and DWI (b = 500 s/mm(2)) (protocol A), MRI and DWI (b = 1000 s/mm(2)) (protocol B), and MRI and DWI (b = 2000s/mm(2)) (protocol C). Areas under the receiver operating characteristic curve (AUCs) were calculated. RESULTS: The mean of the AUCs in protocol C was larger than those in protocol A and in protocol B (P<.05). CONCLUSION: DWI (b = 2000s/mm(2)) at 3.0 T can improve the diagnostic accuracy for detection of prostate cancer. PMID- 22920358 TI - Differentiation between pelvic abscesses and pelvic tumors with diffusion weighted MR imaging: a preliminary study. AB - PURPOSE: Use diffusion-weighted magnetic resonance imaging (MRI) in differentiating pelvic abscess from pelvic cystic tumor. MATERIALS AND METHODS: Patients with pelvic abscess (n=23) or pelvic cystic tumor (n=15) who underwent diffusion-weighted MRI were reviewed. RESULTS: Pelvic abscesses showed hyperintensity on diffusion-weighted MRI and hypointensity on apparent diffusion coefficient (ADC) map. The mean ADC values of fluid in pelvic abscess and pelvic tumors were 0.73 +/- 0.15 * 10(-3) and 2.27 +/- 0.45 * 10(-3) mm(2)/s, respectively. Pelvic abscesses had significantly lower ADC values than pelvic cystic tumors (P<.001). CONCLUSION: Diffusion-weighted MRI provides a noncontrast method for interpreting pelvic cystic lesions. PMID- 22920359 TI - Prevalence and imaging of hepatic involvement in malignant lymphoproliferative disease. AB - From January 2005 to January 2010, 668 consecutive patients with lymphoproliferative disease were retrospectively identified. Hepatic infiltration was present at initial staging in patients with non-Hodgkin's lymphoma [12 of 364=3.3%; age median=45; male:female (M:F)=10:2] but also Hodgkin's disease (5 of 41=12.2%; age median=19; M:F=0:5) and multiple myeloma (3 of 162=1.8%; age median=60; M:F=2:1). There were no cases of hepatic infiltration in 101 patients with leukemia. There are typical radiological patterns of hepatic involvement in lymphoproliferative disease with typical lesions characteristics. PMID- 22920360 TI - Local staging of prostate cancer: comparative accuracy of T2-weighted endorectal MR imaging and transrectal ultrasound. AB - OBJECTIVE: The objective of this study was to compare the accuracy of T2-weighted magnetic resonance (MR) imaging and transrectal ultrasound (TRUS) for staging of prostate cancer. MATERIAL AND METHODS: A total of 101 men with biopsy-proven prostate cancer undergoing both T2-weighted endorectal MR imaging and B-mode TRUS for local tumor staging prior to radical prostatectomy were retrospectively identified. Three MR readers rated the likelihood of locally advanced disease using a 5-point scale. An ultrasound reader performed the same rating. Staging accuracy was compared using receiver operating characteristic curves. RESULTS: Staging accuracy was not significantly different between MR imaging (A(z) = 0.69 0.70) and TRUS (A(z) = 0.81, P>.05). CONCLUSIONS: T2-weighted MR imaging demonstrates comparable accuracy to B-mode TRUS for depicting locally invasive prostate cancer. PMID- 22920361 TI - A feasibility study of unidirectional 240 degrees -angle 3D CT colonography. AB - In three-dimensional (3D) CT colonography (CTC), a wider viewing angle provides a larger field of view. The purpose of this study was to investigate the polyp detection rate and time efficiency of unidirectional 240 degrees -angle 3D CTC compared with bidirectional 120 degrees -angle CTC. CTC data sets of 40 patients were reviewed by two readers using the two methods. The unidirectional 240 degrees -angle CTC showed a performance in polyp detection similar to the bidirectional 120 degrees -angle CTC with improved time efficiency. PMID- 22920362 TI - Tomographic imaging of the spleen: the role of morphological and metabolic features in differentiating benign from malignant diseases. AB - To evaluate the tomographic features in differentiating benign from malignant splenic diseases, 54 patients with a cytohistological examination and a contrast enhanced multidetector computed tomography (ce-MDCT) and/or positron emission tomography/computed tomography (PET/CT) were retrospectively selected. Significant associations were observed between ce-MDCT Pattern 3 (focal hyperdense lesion) and Pattern 4 (infarcts/cysts) as well as PET/CT Pattern 3 (focal photopenia/diffuse uptake= liver) and Pattern 2 (focal increased uptake) and malignant diseases. No significant association between benign or malignant diseases and spleen volumes and maximum standardized uptake value (SUV(max)) as well as lesion characteristics was observed. The metabolic data do not improve the performance of morphological patterns. PMID- 22920363 TI - Comparison of inversion recovery and contrast-enhanced T1-weighted fat-suppressed sequences for the staging of cervical lymphoma. AB - In a retrospective analysis with two readers blinded to the clinical information, coronal short tau inversion recovery (STIR) images were compared to contrast enhanced fat-saturated T1-weighted imaging (T1 CEfs) in 51 cases of cervical lymphoma. Interrater reliability was good to excellent. Although sensitivity and subjective quality of the STIR sequence were higher than those of the T1 CEfs sequence (sensitivity 85%/72%, respectively), specificity (82%/95%) as well as positive likelihood ratio (4.65/15.93) was much lower. Therefore, contrast enhanced sequences should be included in the primary staging of lymphoma. PMID- 22920364 TI - An alternative technique for the exact sizing of glenoid bone defects. AB - In posttraumatic shoulder dislocation, the size of a glenoid rim defect can determine the probability of recurrent dislocations. Most attempts to assess the size of such defects are based on the width of a defect in relation to glenoid length or diameter. So far, no method exactly calculating the area of articular surface missing has been reported. With the use of software originally designed for architectural purposes, the exact percentage of a glenoid defect was measured on three-dimensional computed tomography images. PMID- 22920365 TI - Direct and Doppler angle-independent measurement of blood flow velocity in small diameter vessels using ultrasound microbubbles. AB - This article represents an initial attempt to demonstrate the feasibility of a novel method for measuring flow velocity in small vessels, which is a direct, noninvasive, ultrasound-guided, and Doppler angle-independent method. In vitro, experiments were designed to mimic blood flow inside tubes. Harmonic ultrasound imaging was used to track the movement of microbubbles, and the mean flow velocity was calculated. In vivo, the flow velocities were measured in the central arteries of rabbit ears. This method can be used whenever the Doppler ultrasound cannot measure the velocity in small vessels because of either low sensitivity or Doppler angle limitation. PMID- 22920366 TI - Transient global amnesia caused by hippocampal infarct: case report and review of literature. AB - BACKGROUND: Transient global amnesia is a fairly common occurrence in patients arriving to the emergency department. In most cases, transient global amnesia is benign, and the etiology remains unknown; however, it is important to exclude the rare but serious causes ensuring proper treatment and prevention of serious complication. CASE REPORT: We present a rare case in which a patient arrived with amnesia, and after full evaluation; a subtle ischemic region in the hippocampus was identified, allowing the patient to be treated. In most cases of transient global amnesia, the cause is seldom identified. CONCLUSIONS: We review the diagnostic criteria, risk factors, and imaging considerations associated. PMID- 22920367 TI - Inadvertent insertion of a nasogastric tube into the brain: case report and review of the literature. AB - The inadvertent insertion of a nasogastric tube (NGT) into the brain of a trauma patient with skull base fractures is reported. A 52-year-old male with head trauma was referred following a car accident with an NGT in situ. Serosanguineous fluid was withdrawn from the NGT, which was considered to be an indication of gastrointestinal bleeding, and cold saline lavage was performed. Skull X-rays revealed intracranial position and coiling of the NGT and pneumocranium. The NGT was immediately removed manually. The patient finally went through neurosurgical operation because of an extradural hematoma, with normal postoperative course and outcome. PMID- 22920368 TI - Branchial fistula arising from pyriform fossa: CT diagnosis of a case and discussion of radiological features. AB - Anomalies of third or fourth branchial apparatus origin are very uncommon and present as recurrent neck infections or thyroiditis with a predominant left-sided involvement. Radiological diagnosis requires a high index of suspicion and is critical for initiation of proper treatment. We describe a case of branchial sinus of pyriform fossa with external fistulization that presented in adulthood and was diagnosed on computed tomographic scan. The radiological features of this rare anomaly are revisited. PMID- 22920369 TI - MRI of cervical spinal cord infarction in a patient with sickle cell disease. AB - We report a patient with sickle cell disease who developed spinal cord ischemia. Initial conventional magnetic resonance imaging (MRI) was unremarkable, but diffusion-weighted imaging showed restricted diffusion in the cervical spinal cord. Follow-up MRI performed 3 days later showed development of findings on conventional images that confirmed the infarction. PMID- 22920370 TI - A rare case report of a primary large-cell neuroendocrine carcinoma of the breast with coexisting Paget disease. AB - Neuroendocrine carcinomas are malignancies deriving from neuroendocrine cells existing in various sites of the body, most commonly in the lungs and gastrointestinal tract. Primary neuroendocrine carcinomas of the breast are extremely rare, and their diagnosis is confirmed by positive neuroendocrine markers. We describe a case of a 46-year-old woman with a palpable mass in her left breast for the previous 3 months. The tumor was resected and a primary large cell neuroendocrine tumor of the breast was confirmed by histopathologic examination. Paget disease of the nipple was noted as well. PMID- 22920371 TI - Isolated interrupted aortic arch accompanied by type B aortic dissection and extensive collateral arteries diagnosed with MDCT angiography. AB - Interrupted aortic arch (IAA) is a rare congenital cardiovascular condition. A patient with uncorrected IAA accompanied by rich collateral arteries can survive to adulthood asymptomatically. However, IAA complicated by aortic dissection is life threatening. Herein, we report a rare case of an isolated IAA accompanied by type B aortic dissection and extensive collateral arteries detected by multidetector computed tomography in a 38-year-old man. The imaging findings of the case are presented, and the utility of multidetector computed tomography in the evaluation of this condition is discussed. PMID- 22920372 TI - Giant lymphatic malformations of the mediastinum in children: report of three cases. AB - Lymphatic malformations are vascular malformations and consist of masses of abnormal lymphatic channels. They are uncommon in the mediastinum. We report three cases of giant mediastinum lymphatic malformations in children. One case developed two episodes of cardiopulmonary arrests, and the other two were first diagnosed and treated as pneumonia. They all recovered well after surgery. The diagnosis is rather important in lymphatic malformations. A delay in diagnosis of mediastinum lymphatic malformation increases the risk of death and prolonged clinical course. Thus, mediastinum lymphatic malformations should be kept in mind as a differential diagnosis of pneumonia and mass in the neck. PMID- 22920373 TI - Delayed noninvasive reduction of large bullae following thoracic irradiation. AB - Chest radiotherapy is a mainstay of management of thoracic oncology patients. Radiotherapy also injures nontarget tissues such as the lungs, coronary arteries, and esophagus, and safe limits to the doses that can be delivered to tumors have been determined empirically. Patients afflicted with lung cancer due to smoking often have concomitant chronic obstructive pulmonary disease which, on occasion, manifests as bullous emphysema. We describe a case and course of treatment of lung cancer found incidentally in a patient followed for severe pulmonary emphysema. Treatment consisted of radiochemotherapy after induction chemotherapy. Three years after the end of antineoplastic treatment, a follow-up computed tomography scan revealed complete retraction of a large emphysematous bulla that had been present prior to treatment. PMID- 22920374 TI - CT demonstration of pulmonary embolism due to the rupture of a giant hepatic hydatid disease. AB - Hydatid disease can be seen anywhere in the body and presents with a variety of clinical symptoms and imaging features according to its location. In this article, computed tomography features of a giant hepatic hydatid cyst extending into the right atrium and causing pulmonary embolism are presented. PMID- 22920375 TI - Case report of systemic IgG-related disease affecting the pancreas and orbit. AB - PURPOSE: The purpose was to describe the magnetic resonance imaging appearance of the brain and spine in a patient. METHOD: A patient with pancreatitis and neurologic findings is described. RESULTS: Our patient had an inflammatory condition involving the pancreas and orbital muscles, a constellation of findings that should suggest systemic IgG-related disease (SIRD). CONCLUSIONS: Patients with multiorgan inflammatory disease, especially those involving the pancreas and other organs, should be evaluated for possible SIRD. PMID- 22920376 TI - Primary angiosarcoma of the spleen as depicted on computed tomography. AB - Primary angiosarcoma of the spleen is rare, usually widespread or has a splenic rupture by the time of presentation, and almost always has poor prognosis; early radiological diagnosis is necessary for improving the survival rate. We report two special cases of this disease. Both patients did not have pathologic metastasis or splenic rupture, but their computed tomography (CT) manifestations were distinct from each other and had uncommon characteristics. We compared the CT features with pathological findings. PMID- 22920377 TI - Incidental MRI finding of a pons tuberculoma in a patient with so-far-undiagnosed multisystemic tuberculosis infection. AB - Tuberculomas are routinely included in the differential diagnosis of newly detected intracranial lesions in patients with known systemic tuberculosis, but are rarely considered in patients without systemic disease. We report a 49-year old patient without any neurological symptoms whose magnetic resonance imaging examination showed a lesion in the pons that was suspected of being an opportunistic, DD granulomatous lesion, which prompted further laboratory examinations revealing systemic tubercle bacillus (TB) infection. Tuberculosis should be included in the differential diagnosis of an intracranial solitary lesion even in atypical locations and in asymptomatic patients without prior diagnosis of a TB. PMID- 22920378 TI - Antegrade retrieval of double J stents with capture of the bladder end in three young children. AB - A technique to retrieve double J stents was described in children in whom cystoscopic stent removal was not feasible. In three children, the caudal ends of the double J stents were retrieved via the percutaneous nephrostomy access. Capturing the caudal end of the double J stents for retrieval made removal feasible and easy. PMID- 22920379 TI - Delayed intrahepatic subcapsular hematoma after laparoscopic cholecystectomy. AB - Intrahepatic subcapsular hematoma after laparoscopic cholecystectomy is a rare complication and is potentially life threatening. When radiologic studies confirm the presence of the hematoma, the decision to follow a conservative treatment should involve clinical monitoring. If there are signs of infection, the collection can safely be drained percutaneously. If there are signs of active bleeding, a selective embolization should be attempted first. If unsuccessful, subsequent surgical evacuation should be performed. We report the case of a patient with an intrahepatic subcapsular hematoma after laparoscopic cholecystectomy, which occurred 6 weeks after surgery, and review the literature concerning the management of these bleedings. PMID- 22920380 TI - Magnetic resonance imaging features of angiomyofibroblastoma-like tumor of the scrotum with pathologic correlates. AB - Various tumors can occur in the scrotum. Among them, angiomyofibroblastoma-like tumors are very rare mesenchymal tumors. We report a case of an angiomyofibroblastoma-like tumor that arose in the right half of the scrotum in a 72-year-old man. It is difficult to separate angiomyofibroblastoma-like tumors from other malignant tumors invading the male genital tract on the basis of clinical characteristics and magnetic resonance imaging findings. PMID- 22920381 TI - Sonographic findings of uterine cervical lymphoma manifesting as multinodular lesions. AB - Uterine cervical lymphoma, a very rare condition, has rarely been reported in sonographic findings in the English medical literature. We describe a case of uterine cervical lymphoma which was detected initially and depicted on sonography as a multinodular smoothly lobulated heterogeneous mass with some posterior enhancements. PMID- 22920382 TI - Ultrasound and MR images of prenatally diagnosed bilateral congenital diaphragmatic hernia, a rare variation of CDH. AB - The patient referred to our hospital at 29 weeks. The detailed ultrasound study demonstrated the stomach behind the heart, the slight deviation of the heart, and the vascular connection between the right chest organ and inferior vena cava. Bilateral congenital diaphragmatic hernia was suggested and confirmed by magnetic resonance imaging. A baby was delivered at 37 weeks and immediately placed on high-frequency oscillation ventilation. Although a surgical correction of the bilateral hernia under extracorporeal membrane oxygenation was completed, he expired at 14 h of age. PMID- 22920383 TI - Muscular involvement of Behcet's disease: ultrasonography, computed tomography, and magnetic resonance imaging findings. AB - Behcet's disease (BD) is a form of systemic vasculitis with the classic triad of recurrent oral and genital ulcers along with uveitis. In BD, muscular involvement is very rare. We report a case of muscular involvement in BD with characteristic findings using ultrasonography, computed tomography, and magnetic resonance imaging. PMID- 22920384 TI - What is DIPNECH? AB - Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) is a rare disorder that is being diagnosed more frequently with the increasing availability of advanced imaging and more accurate histopathology. It occurs most commonly in nonsmoking, middle-aged women. High-resolution computed tomography (HRCT) findings include mosaic attenuation due to constrictive bronchiolitis and small (<5 mm) randomly distributed pulmonary nodules. It is important to recognize this condition as it is considered a precursor of peripheral carcinoid tumors. This article will present a case of this uncommon condition with review of the literature, imaging findings, and clinical presentation. PMID- 22920385 TI - FDG PET/CT of a benign ovarian Brenner tumor. AB - We present a case of an ovarian benign Brenner tumor identified in an 85-year-old woman. During an observation period of over 1 year, the tumor increased in size and showed newly appeared solid component. Magnetic resonance imaging was typical of a Brenner tumor; fluorine-18 fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT) findings revealed mild FDG uptake and calcification in the solid component. These findings of PET/CT are often found in ovarian mucinous carcinomas. Our case suggests that magnetic resonance imaging is superior to FDG PET/CT for the differential diagnosis of ovarian Brenner tumors from other malignant tumors. PMID- 22920386 TI - Preparation of human milk fat substitutes from palm stearin with arachidonic and docosahexaenoic acid: combination of enzymatic and physical methods. AB - Human milk fat substitutes (HMFSs) were prepared by a two-step process, namely, Lipozyme RM IM-catalyzed acidolysis of interesterified high-melting palm stearin with fatty acids from rapeseed oil and blending of the enzymatic product with the selected oils on the basis of the calculation model. The optimum conditions for the enzymatic reaction were a mole ratio of palm stearin/fatty acids 1:10, 60 degrees C, 8% enzyme load (wt % of substrates), 4 h, and 3.5% water content (wt % of enzyme); the enzymatic product contained 39.6% palmitic acid (PA), 83.7% of the fatty acids at sn-2 position were PA (sn-2 PA), and the distribution probability of PA at the sn-2 position among total PA (% sn-2 PA) was 70.5%. With the fatty acid profiles of human milk fat (HMF) as a preferable goal, a physical blending model was established for the second step to guarantee the maximum addition of selected oils. Based on the model prediction, a desirable formula constituted enzymatic product/rapeseed oil/sunflower oil/palm kernel oil/algal oil/microbial oil at a mole ratio of 1:0.28:0.40:0.36:0.015:0.017, and the final product had PA content, sn-2 PA, and %sn-2 PA at 23.5, 43.1, and 61.1%, respectively. The contents of arachidonic and docosahexaenoic acids were 0.4 and 0.3%, respectively. Relying on the total and sn-2 fatty acid compositions of HMF and "deducting score" principle, the score for the similarity between the final product and HMF was scaled as 89.2, indicating the potential as a fat substitute in infant formulas. PMID- 22920387 TI - Neuroprotective effect of an angiotensin receptor type 2 agonist following cerebral ischemia in vitro and in vivo. AB - BACKGROUND: Intracerebral administration of the angiotensin II type 2 receptor (AT2R) agonist, CGP42112, is neuroprotective in a rat model of ischemic stroke. To explore further its possible cellular target(s) and therapeutic utility, we firstly examined whether CGP42112 may exert direct protective effects on primary neurons following glucose deprivation in vitro. Secondly, we tested whether CGP42112 is effective when administered systemically in a mouse model of cerebral ischemia. METHODS: Primary cortical neurons were cultured from E17 C57Bl6 mouse embryos for 9 d, exposed to glucose deprivation for 24 h alone or with drug treatments, and percent cell survival assessed using trypan blue exclusion. Ischemic stroke was induced in adult male C57Bl6 mice by middle cerebral artery occlusion for 30 min, followed by reperfusion for 23.5 h. Neurological assessment was performed and then mice were euthanized and infarct and edema volume were analysed. RESULTS: During glucose deprivation, CGP42112 (1x10-8 M and 1x10-7 M) reduced cell death by ~30%, an effect that was prevented by the AT2R antagonist, PD123319 (1x10-6 M). Neuroprotection by CGP42112 was lost at a higher concentration (1x10-6 M) but was unmasked by co-application with the AT1R antagonist, candesartan (1x10-7 M). By contrast, Compound 21 (1x10-8 M to 1x10-6 M), a second AT2R agonist, had no effect on neuronal survival. Mice treated with CGP42112 (1 mg/kg i.p.) after cerebral ischemia had improved functional outcomes over vehicle-treated mice as well as reduced total and cortical infarct volumes. CONCLUSIONS: These results indicate that CGP42112 can directly protect neurons from ischemia-like injury in vitro via activation of AT2Rs, an effect opposed by AT1R activation at high concentrations. Furthermore, systemic administration of CGP42112 can reduce functional deficits and infarct volume following cerebral ischemia in vivo. PMID- 22920388 TI - A fly in the ointment: reassessing mitotane's role in the treatment of adrenocortical carcinoma. PMID- 22920389 TI - Warfarin anticoagulation in children: is there a role for a personalized approach to dosing? PMID- 22920390 TI - Clinical interest of point-of-care pharmacogenomic testing: clopidogrel behind warfarin. PMID- 22920392 TI - Predicting response to statins by pharmacogenetic testing. PMID- 22920394 TI - Validation of the acenocoumarol EU-PACT algorithms: similar performance in the Rotterdam Study cohort as in the original study. AB - AIM: To evaluate the performance of the European Pharmacogenetics of Anticoagulant Therapy (EU-PACT) acenocoumarol dose algorithms in an independent data set. The EU-PACT trial investigates the added value of pretreatment genotyping for use of warfarin, phenprocoumon and acenocoumarol. PATIENTS & METHODS: External validation was performed in the Rotterdam Study cohort using information about 707 acenocoumarol users. R(2), which measures the strength of correlation between the predicted and observed acenocoumarol dose, mean absolute error and mean squared error were calculated to evaluate the performance of the original algorithm. RESULTS: Validation resulted in a R(2) of 52.7 and 12.9% compared with an R(2) of 52.6 and 17.8% in the original study for the genotype guided and nongenotype-guided dose algorithm, respectively. For the genotype guided dose algorithm, the mean absolute error was 0.48 mg/day and the mean squared error was 0.38 (mg/day)(2). For the nongenotype-guided dose algorithm, the mean absolute error was 0.62 mg/day and the mean squared error was 0.63 (mg/day)(2). CONCLUSION: The EU-PACT acenocoumarol algorithm performs just as accurately in this study as in the original study, which implies applicability in various populations. PMID- 22920395 TI - The population attributable fraction as a measure of the impact of warfarin pharmacogenetic testing. AB - AIM: We aimed to estimate the population impact of warfarin pharmacogenetic testing (WPGT) across multiple populations. MATERIALS & METHODS: We used the expanded International Warfarin Pharmacogenetics Consortium data set and genotype frequencies from HapMap to simulate dose distributions for each CYP2C9/VKORC1 genotype combination in the different races, and calculated the population attributable fraction as a measure of population impact of WPGT. WPGT was compared to both clinical and fixed-dose algorithms to estimate the benefits of WPGT. RESULTS: Our dose simulation revealed different dose requirements in difference races and considerable overlap in dose distributions of different genotype combinations. Population attributable fraction calculations suggest that complete implementation of WPGT can reduce inaccurate dosing by 18-24% in white individuals. However black, Japanese and Chinese patients do not benefit from WPGT, especially when compared against a race-specific fixed dose. CONCLUSION: Our findings support WPGT in white individuals but not in black, Japanese and Chinese individuals. PMID- 22920393 TI - Targeted pharmacogenetic analysis of antipsychotic response in the CATIE study. AB - AIM: This study evaluated the impact of 6789 SNPs on treatment response to antipsychotics in Caucasian patients from the CATIE study. MATERIALS & METHODS: An Illumina (CA, USA) BeadChip was designed that targeted genes potentially impacting disease risk, disease presentation or antipsychotic response. SNPs tagged regions of linkage disequilibrium or functional variants not detectable using previous genotypes for CATIE. Change in Positive and Negative Syndrome scale total score was modeled using a mixed model repeated measures method that assumed a 30-day lag period. Genetic association analysis was performed using linear regression. RESULTS: Association analysis identified 20 SNPs with p-values of <=5 * 10(-4). Many of these are in genes previously implicated in schizophrenia and other neuropsychiatric diseases. CONCLUSION: The targeted approach identified SNPs possibly influencing response to antipsychotic drugs in Caucasian patients suffering from schizophrenia. The findings support a biological link between disease risk and presentation and antipsychotic response. PMID- 22920397 TI - Advances in treatment of chronic myeloid leukemia with tyrosine kinase inhibitors: the evolving role of Bcr-Abl mutations and mutational analysis. AB - Over the last decade, the treatment of chronic myeloid leukemia has progressed tremendously. The first-generation tyrosine kinase inhibitor imatinib is now flanked by two second-generation molecules, dasatinib and nilotinib - and others are in advanced clinical development. One of the reasons for such intensive research on novel compounds is the problem of resistance, that is thought to be caused, in a proportion of cases, by point mutations in Bcr-Abl. In this article, the authors review how the biological and clinical relevance of Bcr-Abl mutations has evolved in parallel with the availability of more and more therapeutic options. The authors also discuss the practical relevance of Bcr-Abl mutation analysis and how this tool should best be integrated in the optimal clinical management of chronic myeloid leukemia patients. PMID- 22920398 TI - HLA and pharmacogenetics of drug hypersensitivity. AB - Immunologically mediated drug reactions have been traditionally classified as unpredictable based on the fact that they cannot be predicted strictly on the pharmacological action of the drug. Such adverse drug reactions are associated with considerable morbidity and include severe cutaneous adverse reactions such as Stevens-Johnson syndrome/toxic epidermal necrolysis and the drug hypersensitivity syndromes (drug reaction with eosinophilia and systemic symptoms/drug-induced hypersensitivity syndrome). Over the last decade there have been many associations between these syndromes and Class I and II HLA alleles of the MHC, which have enriched and driven our knowledge of their immunopathogenesis. Significant translation has also occurred in the case of HLA B*5701 screening being used to exclude at risk patients from abacavir and prevent abacavir hypersensitivity. The ultimate translation of the knowledge of how drugs interact with HLA would be applicable to preclinical drug screening programs to improve the safety and cost-effectiveness of drug design and development. PMID- 22920396 TI - The clinically relevant pharmacogenomic changes in acute myelogenous leukemia. AB - Acute myelogenous leukemia (AML) is an extremely heterogeneous neoplasm with several clinical, pathological, genetic and molecular subtypes. Combinations of various doses and schedules of cytarabine and different anthracyclines have been the mainstay of treatment for all forms of AMLs in adult patients. Although this combination, with the addition of an occasional third agent, remains effective for treatment of some young-adult patients with de novo AML, the prognosis of AML secondary to myelodysplastic syndromes or myeloproliferative neoplasms, treatment related AML, relapsed or refractory AML, and AML that occurs in older populations remains grim. Taken into account the heterogeneity of AML, one size does not and should not be tried to fit all. In this article, the authors review currently understood, applicable and relevant findings related to cytarabine and anthracycline drug-metabolizing enzymes and drug transporters in adult patients with AML. To provide a prime-time example of clinical applicability of pharmacogenomics in distinguishing a subset of patients with AML who might be better responders to farnesyltransferase inhibitors, the authors also reviewed findings related to a two-gene transcript signature consisting of high RASGRP1 and low APTX, the ratio of which appears to positively predict clinical response in AML patients treated with farnesyltransferase inhibitors. PMID- 22920399 TI - NAVAGATE: a rubric to move from pharmacogenomics science to pharmacogenomics practice. AB - Integration of pharmacogenomic data at the point of care is the next essential step in translating years of research into evidence-based decisions that impact the care of an individual patient. The use of clinical recommendations for pharmacogenomic data help clinicians to better select and monitor drug therapy. However, a systematic rubric for utilizing the data ensures a thorough implementation of the information in a way that may improve the application of the new scientific discoveries. NAVAGATE is a set of eight questions to ask when considering a pharmacogenomic test or test result when caring for a patient. The series of questions are meant to inform prescribing or dispensing when obtaining or employing pharmacogenomic data for these steps within the medical-care framework. In this article two key examples are used to exemplify the benefits of following a systematic process to evaluate the utility of the new scientific data. PMID- 22920401 TI - Residues PsaB Asp612 and PsaB Glu613 of photosystem I confer pH-dependent binding of plastocyanin and cytochrome c(6). AB - The binding and electron transfer between plastocyanin (pc) or cytochrome c(6) (cyt c(6)) and photosystem I (PSI) can be described by hydrophobic as well as electrostatic interactions. The two alpha helices, l and l' in PsaB and PsaA, respectively, are involved in forming the hydrophobic interaction site at the oxidizing site of PSI. To obtain mechanistic insights into the function of the two negatively charged residues D612 and E613, present in alpha helix l of PsaB, we exchanged both residues by site-directed mutagenesis with His and transformed a PsaB deficient mutant of Chlamydomonas reinhardtii. Flash-induced absorption spectroscopy revealed that PSI harboring the changes D612H and E613H had a high affinity toward binding of the electron donors and possessed an altered pH dependence of electron transfer with pc and cyt c(6). Despite optimized binding and electron transfer between the altered PSI and its electron donors, the mutant strain PsaB-D612H/E613H exhibited a strong light sensitive growth phenotype, indicating that decelerated turnover between pc/cyt c(6) and PSI with respect to electron transfer is deleterious to the cells. PMID- 22920403 TI - Relative value unit impact of complex skin closures to academic surgical melanoma practices. AB - BACKGROUND: Melanoma excisions frequently are associated with significant soft tissue defects, creating the need for complex closures. These closures could be performed by either surgical oncologists or plastic surgeons. We sought to quantify the relative value units (RVUs) and describe the practice patterns of 2 academic surgical subspecialties after a melanoma excision. METHODS: After institutional review board approval, a retrospective data analysis of a billing database was conducted on all melanoma patients undergoing an excision and closure by surgical oncology and plastic surgery departments in 2007. Data were obtained using billing records for Current Procedural Terminology diagnosis codes. RVUs were used to quantify the value added to each practice from these closures. The surgical oncologist and patient decided if a plastic surgeon was needed. RESULTS: A total of 270 closures were performed, 53 (19.9%) primary and 217 (80.1%) complex. The surgical oncologists performed most complex closures (188; 86.6%), and the plastic surgeons performed the remainder (29; 13.4%), generating a total of 1,921 RVUs (1,630 by the surgical oncologists and 291 by the plastic surgeons). For analysis, complex closures were divided among 4 anatomic sites: trunk, upper extremity, lower extremity, and head and neck. Most closures by the surgical oncologists were adjacent tissue rearrangements (155; 82%) and the remainder were skin grafts (33; 18%). Closures by the plastic surgeons were more likely to be a full-thickness skin graft (P < .0027) in the head and neck region (P < .0001), with a higher associated median RVU/case (10.15 compared with 8.44 for the surgical oncologists; P < .0002). CONCLUSIONS: At our institution, the majority of melanoma closures were performed by surgical oncologists. However, plastic surgery often was involved in more complex closures in the head and neck. This data set quantifies the RVUs added and describes the types of closures performed in an academic melanoma practice. PMID- 22920402 TI - Randomized clinical trial of conventional versus cylindrical abdominoperineal resection for locally advanced lower rectal cancer. AB - BACKGROUND: An alternative treatment for low rectal cancer is the cylindrical technique. We aim to compare the outcomes of patients undergoing conventional abdominoperineal resection (APR) versus cylindrical APR. METHODS: A prospective, randomized, open-label, parallel controlled trial was conducted between January 2008 and December 2010. Sixty-seven patients with T3-T4 low rectal cancer were identified during the study period (conventional n = 32, cylindrical n = 35). RESULTS: Patients who received cylindrical APR had less operative time for the perineal portion (P < .001), larger perineal defect (P < .001), less intraoperative blood loss (P = .001), larger total cross-sectional tissue area (P < .001), similar total operative time (P = .096), and more incidence of perineal pain (P < .001). The local recurrence of the cylindrical APR group was improved statistically (P = .048). CONCLUSIONS: Cylindrical APR in the prone jackknife position has the potential to reduce the risk of local recurrence without increased complications when compared with conventional APR in the lithotomy position for the treatment of low rectal cancer. PMID- 22920405 TI - Targeted microbubbles in the experimental and clinical setting. AB - BACKGROUND: Microbubbles have improved ultrasonography imaging techniques over the past 2 decades. Their safety, versatility, and easiness of use have rendered them equal or even superior in some instances to other imaging modalities such as computed tomography and magnetic resonance imaging. Herein, we conducted a literature review to present their types, general behavior in tissues, and current and potential use in clinical practice. METHODS: A literature search was conducted for all preclinical and clinical studies involving microbubbles and ultrasonography. RESULTS: Different types of microbubbles are available. These generally improve the enhancement of tissues during ultrasonography imaging. They also can be attached to ligands for the target of several conditions such as inflammation, angiogenesis, thrombosis, apoptosis, and might have the potential of carrying toxic drugs to diseased sites, thereby limiting the systemic adverse effects. CONCLUSIONS: The use of microbubbles is evolving rapidly and can have a significant impact on the management of various conditions. The potential for their use as targeting agents and gene and drug delivery vehicles looks promising. PMID- 22920406 TI - Spontaneous erosion of ureterocele wall by stone: rare images. AB - The incidence of ureterocele at autopsy is estimated to be in 1/500 to 1/4000. A solitary stone in a single ureterocele is common, with a prevalence of 4%-39%. However, spontaneous rupture of the ureterocele wall by a stone has not been reported, to the best of our knowledge. We report the case of a 35-year-old man with right-side ureterocele, complicated by a stone that spontaneously eroded the ureterocele wall. PMID- 22920404 TI - Trials and tribulations: the professional development of surgical trialists. AB - BACKGROUND: Regulatory and professional bodies issue an ever-increasing number of guidance documents on the ethics and methods of clinical trials, but the quality of clinical trials of invasive therapeutic procedures continues to be a concern. We interviewed aspiring and accomplished surgical trialists to understand how they use guidance documents and other resources in their work. METHODS: We performed a qualitative research study involving semistructured interviews of a diverse sample of 15 surgical trialists. RESULTS: Professional development as a surgical trialist was haphazard, inefficient, and marked by avoidable mistakes. Four types of resources played constructive roles: formal education; written materials on clinical trials; experience with actual trials; and interpersonal interactions with peers, experts, collaborators, and mentors. Recommendations for improvement centered on education, mentoring, networking, participating in trials, and facilitation by department chairs. CONCLUSIONS: The haphazard and unstructured nature of the current system is adding unnecessarily to the numerous challenges faced by surgical trialists. PMID- 22920407 TI - Potential establishment of lung metastatic xenograft model of androgen receptor positive and androgen-independent prostate cancer (C4-2B). AB - OBJECTIVE: To establish a mouse xenograft model of metastatic prostate cancer (PCa) and investigate the relationship between metastasis and circulating tumor cells. METHODS: Flow cytometry (FACS) was used to detect suitable PCa cells and markers for detecting circulating tumor cells in vivo. We orthotopically injected androgen receptor-positive and androgen-independent C4-2B PCa cells into 12 severe combined immunodeficiency (SCID) mouse prostates, including 1 vehicle control. We measured the serum prostate-specific antigen levels biweekly after tumor inoculation. Circulating tumor cells (CTCs) were measured qualitatively by fluorescent microscopy immediately after the mice were sacrificed. The mouse prostates and lungs were examined for tumor formation using immunohistochemistry because we found no apparent metastasis, except in the lung. RESULTS: FACS analyses in vitro identified the marker, prostate-specific membrane antigen, and C4-2B cells to be appropriate for additional in vivo study. We confirmed that the serum prostate-specific antigen increase was dependent on time and prostate tumor weight in mice. Of the 11 mice, 6 could be used as the mouse PCa xenograft model. Fluorescent microscopy detected CTCs in the peripheral blood in 5 of the 6 mice constituting the PCa model. Human prostate-specific antigen expression was detected by immunohistochemistry in the prostates of all the mice and in the lung of 2 of the 6 mice, suggesting 2 mice with lung metastasis. CONCLUSION: We have shown the potential establishment of a mouse lung metastatic xenograft model of androgen receptor-positive and androgen-independent C4-2B PCa tumor. However, the present model requires improvement to be a more reproducible, accurate and complete experimental model. Additional study is necessary to verify the relationship between metastasis and CTCs. PMID- 22920409 TI - Preparation and characterization of composites built of poly(N-benzophenoyl methacrylamide-co-N-hydroxyethyl acrylamide) cores and silica raspberry-like shells with dual orthogonal functionality. AB - The design and fabrication of novel poly(N-benzophenoyl methacrylamide-co-N hydroxyethyl acrylamide)@SiO(2) composites are reported herein. These core-shell composites demonstrate orthogonal functionality, composed of photoreactive cores, containing a benzophenone (BPh) moiety and silica (SiO(2)) shells, enabling the utilization of the free hydroxyl groups via silane-based chemistry. The co polymer cores, which are 1.28MUm in diameter, are first obtained by dispersion polymerization of photoreactive (N-benzophenoyl methacrylamide) (polyBPMA) and N Hydroxyethyl acrylamide (HEAA). Next, silica seeds with a 42nm diameter are deposited onto the surfaces as a result of the hydrolysis and the condensation of tetraethyl orthosilicate (TEOS) in a basic condition. Scanning electron microscopy (SEM), transmission electron microscopy (TEM), FT-infrared spectroscopy (FT-IR), thermogravimetric analysis (TGA), UV-spectrophotometry, X ray photoelectron spectroscopy (XPS), and zeta-potential measurements were used to characterize the composites. The morphology and surface smoothness of the deposited silica nanoparticles (NPs) were found to strongly depend on a number of parameters such as the pH value of the medium, TEOS concentration, and the temperature. PMID- 22920408 TI - Brief intervention for alcohol misuse in people attending sexual health clinics: study protocol for a randomized controlled trial. AB - BACKGROUND: Over the last 30 years the number of people who drink alcohol at harmful levels has increased in many countries. There have also been large increases in rates of sexually transmitted infections. Available evidence suggests that excessive alcohol consumption and poor sexual health may be linked. The prevalence of harmful alcohol use is higher among people attending sexual health clinics than in the general population, and a third of those attending clinics state that alcohol use affects whether they have unprotected sex. Previous research has demonstrated that brief intervention for alcohol misuse in other medical settings can lead to behavioral change, but the clinical- and cost effectiveness of this intervention on sexual behavior have not been examined. METHODS: We will conduct a two parallel-arm, randomized trial. A consecutive sample of people attending three sexual health clinics in London and willing to participate in the study will be screened for excessive alcohol consumption. Participants identified as drinking excessively will then be allocated to either active treatment (Brief Advice and referral for Brief Intervention) or control treatment (a leaflet on healthy living). Randomization will be via an independent and remote telephone randomization service and will be stratified by study clinic. Brief Advice will comprise feedback on the possible health consequences of excessive alcohol consumption, written information about alcohol and the offer of an appointment for further assessment and Brief Intervention. Follow-up data on alcohol use, sexual behavior, health related quality of life and service use will be collected by a researcher masked to allocation status six months later. The primary outcome for the study is mean weekly alcohol consumption during the previous three months, and the main secondary outcome is the proportion of participants who report unprotected sex during this period. DISCUSSION: Opportunistic intervention for excessive alcohol use has been shown to be effective in a range of medical settings. The SHEAR study will examine whether delivering such interventions in sexual health clinics results in reductions in alcohol consumption and will explore whether this is associated with changes in sexual behavior. PMID- 22920410 TI - Complete mitochondrial genome of the blind cave barbel Sinocyclocheilus furcodorsalis (Cypriniformes: Cyprinidae). AB - Sinocyclocheilus furcodorsalis, a typical cavefish, has evolved some striking characters, for example loss of its eyes and reduction in melanin pigmentation, and can serve as a good model system in evolutionary adaptation developmental mechanisms. So we cloned the complete mitochondrial DNA of S. furcodorsalis (16,581 bp), which is similar to those reported from other fish mitochondrial genomes, containing 37 genes (13 protein-coding genes, 2 ribosomal RNAs, and 22 transfer RNAs) and a major noncoding control region. The complete mitogenome of the S. furcodorsalis provides an additional important data-set for the study in evolutionary adaptation developmental mechanisms. PMID- 22920411 TI - Novel diphenylmethyl-derived amide protecting group for efficient liquid-phase peptide synthesis: AJIPHASE. AB - An efficient method for the synthesis of peptides bearing an amide at the C terminal is described. This method involves the attachment of a C-terminal protecting group bearing long aliphatic chains, followed by the repetition of simple reaction and precipitation steps with the combined advantages of liquid phase peptide synthesis (LPPS) and solid-phase peptide synthesis (SPPS). Using this method, a hydrophobic peptide was successfully synthesized in good yield and high purity, which cannot be obtained satisfactorily by SPPS. PMID- 22920412 TI - Cognitive impairment is undetected in medical inpatients: a study of mortality and recognition amongst healthcare professionals. AB - BACKGROUND: Detecting cognitive impairment in medical inpatients is important due to its association with adverse outcomes. Our aim was to study recognition of cognitive impairment and its association with mortality. METHODS: 200 inpatients aged over 60 years were recruited at the Department of General Internal Medicine at University Hospital MAS in Malmo, Sweden. The MMSE (Mini-Mental State Examination) and the CDT (Clock-Drawing Test) were performed and related to recognition rates by patients, staff physicians, nurses and informants. The impact of abnormal cognitive test results on mortality was studied using a multivariable Cox proportional hazards regression. RESULTS: 55 patients (28%) had no cognitive impairment while 68 patients (34%) had 1 abnormal test result (on MMSE or CDT) and 77 patients (39%) had 2 abnormal test results. Recognition by healthcare professionals was 12% in the group with 1 abnormal test and 44-64% in the group with 2 abnormal test results. In our model, cognitive impairment predicted 12-month mortality with a hazard ratio (95% CI) of 2.86 (1.28-6.39) for the group with 1 abnormal cognitive test and 3.39 (1.54-7.45) for the group with 2 abnormal test results. CONCLUSIONS: Cognitive impairment is frequent in medical inpatients and associated with increased mortality. Recognition rates of cognitive impairment need to be improved in hospitals. PMID- 22920413 TI - FeCl3.6H2O-catalyzed alkenylation of indoles with aldehydes. AB - FeCl(3).6H(2)O-catalyzed efficient C3-alkenylation of indoles was realized through the condensation of aldehydes and indole derivatives in the presence of 2 equiv of ethanol at ambient temperature, forming 3-vinylindoles in up to 93% yields. Ethanol promoted formation of the desired products. An obvious solvent effect was observed, and bisindoles were identified as the reaction intermediates. PMID- 22920414 TI - Fibronectin expression is decreased in metastatic renal cell carcinoma following endostatin gene therapy. AB - Tumor cells induce the disruption of homeostasis between cellular and extracellular compartments to favor tumor progression. The expression of fibronectin (FN), a matrix glycoprotein, is increased in several carcinoma cell types, including renal cell carcinoma (RCC). RCC are highly vascularized tumors and are often amenable to antiangiogenic therapy. Endostatin (ES) is a fragment of collagen XVIII that possesses antiangiogenic activity. In this study, we examined the modulation of FN gene expression by ES gene therapy in a murine metastatic renal cell carcinoma (mRCC) model. Balb/C mice bearing Renca cells were treated with NIH/3T3-LXSN cells or NIH/3T3-LendSN cells. At the end of the experiment, the ES serum levels were measured, and the FN gene expression was assessed using real-time PCR. The tissue FN was evaluated by western blotting and by immunofluorescence analysis. The ES serum levels in treated mice were higher than those in the control group (P<0.05). ES treatment led to significant decreases at the FN mRNA (P<0.001) and protein levels (P<0.01). Here, we demonstrate the ES antitumor effect that is mediated by down-regulation of FN expression in mRCC. PMID- 22920416 TI - Sorting of cargos between axons and dendrites: modelling of differences in cargo transport in these two types of neurites. AB - Explaining how intracellular cargos are sorted between axons and dendrites is important for a mechanistic understanding of what happens in many neurodegenerative disorders. A simple model of cargo sorting relies on differences in microtubule (MT) orientation between axons and dendrites: in mammalian neurons all MTs in axons have their plus ends directed outward while in proximal regions of dendrites the MT polarity is mixed. It can therefore be assumed that cargos that need to be driven into axons associate with kinesin motors while cargos that need to be driven into dendrites associate with dynein motors. This paper develops equations of cargo transport in axons and dendrites based on the above assumptions. Propagation of a pulse of radiolabelled cargos entering an axon and dendrite is simulated. The model equations are solved utilising the Laplace transform method. Differences in cargo transport between axons and dendrites are discussed. PMID- 22920415 TI - Combining peak- and chromatogram-based retention time alignment algorithms for multiple chromatography-mass spectrometry datasets. AB - BACKGROUND: Modern analytical methods in biology and chemistry use separation techniques coupled to sensitive detectors, such as gas chromatography-mass spectrometry (GC-MS) and liquid chromatography-mass spectrometry (LC-MS). These hyphenated methods provide high-dimensional data. Comparing such data manually to find corresponding signals is a laborious task, as each experiment usually consists of thousands of individual scans, each containing hundreds or even thousands of distinct signals. In order to allow for successful identification of metabolites or proteins within such data, especially in the context of metabolomics and proteomics, an accurate alignment and matching of corresponding features between two or more experiments is required. Such a matching algorithm should capture fluctuations in the chromatographic system which lead to non linear distortions on the time axis, as well as systematic changes in recorded intensities. Many different algorithms for the retention time alignment of GC-MS and LC-MS data have been proposed and published, but all of them focus either on aligning previously extracted peak features or on aligning and comparing the complete raw data containing all available features. RESULTS: In this paper we introduce two algorithms for retention time alignment of multiple GC-MS datasets: multiple alignment by bidirectional best hits peak assignment and cluster extension (BIPACE) and center-star multiple alignment by pairwise partitioned dynamic time warping (CeMAPP-DTW). We show how the similarity-based peak group matching method BIPACE may be used for multiple alignment calculation individually and how it can be used as a preprocessing step for the pairwise alignments performed by CeMAPP-DTW. We evaluate the algorithms individually and in combination on a previously published small GC-MS dataset studying the Leishmania parasite and on a larger GC-MS dataset studying grains of wheat (Triticum aestivum). CONCLUSIONS: We have shown that BIPACE achieves very high precision and recall and a very low number of false positive peak assignments on both evaluation datasets. CeMAPP-DTW finds a high number of true positives when executed on its own, but achieves even better results when BIPACE is used to constrain its search space. The source code of both algorithms is included in the OpenSource software framework Maltcms, which is available from http://maltcms.sf.net. The evaluation scripts of the present study are available from the same source. PMID- 22920417 TI - Solid state TL detectors for in vivo dosimetry in brachytherapy. AB - In vivo dosimetry provides information about the actual dose delivered to the patient treated with radiotherapy and can be adopted within a routinary treatment quality assurance protocol. Aim of this study was to evaluate the feasibility of performing in vivo rectal dosimetry by placing thermoluminescence detectors directly on the transrectal ultrasound probe adopted for on-line treatment planning of high dose rate brachytherapy boosts of prostate cancer patients. A suitable protocol for TLD calibration has been set up. In vivo measurements resulted to be in good agreement with the calculated doses, showing that the proposed method is feasible and returns accurate results. PMID- 22920418 TI - Single- versus double-row arthroscopic rotator cuff repair: the complexity grows. PMID- 22920421 TI - The iHOT-33: how valid is it? PMID- 22920420 TI - Protrusio acetabuli: some questions. PMID- 22920423 TI - Quality and safety in home and ambulatory settings. AB - Much of the work in quality and patient safety has been based in hospitals and other acute care settings, yet it has become increasingly apparent that there are errors in delivery of care in other settings, all of which require attention. This article reviews sources of errors in 3 nonacute settings: the home, children's day care, and ambulatory surgery centers. Also described are standards that have been developed to guide practice, as well as specific regulatory agencies that are involved and some of the safeguards that have been instituted in each of the settings to protect against errors. PMID- 22920424 TI - NYU3T: teaching, technology, teamwork: a model for interprofessional education scalability and sustainability. AB - Interprofessional education is a critical precursor to effective teamwork and the collaboration of health care professionals in clinical settings. Numerous barriers have been identified that preclude scalable and sustainable interprofessional education (IPE) efforts. This article describes NYU3T: Teaching, Technology, Teamwork, a model that uses novel technologies such as Web based learning, virtual patients, and high-fidelity simulation to overcome some of the common barriers and drive implementation of evidence-based teamwork curricula. It outlines the program's curricular components, implementation strategy, evaluation methods, and lessons learned from the first year of delivery and describes implications for future large-scale IPE initiatives. PMID- 22920425 TI - Interprofessional education in action: the VA Quality Scholars fellowship program. AB - Although there are many examples of interprofessional education activities that focus on quality and safety, few include longitudinal experiences of teams working together over time. One exception is the Veterans Affairs Quality Scholars (VAQS) fellowship program. This article describes the integration of interprofessional education into the VAQS fellowship program, offers 2 examples of interprofessional projects conducted by the fellows, and discusses the VAQS program as a model for others to consider in developing interprofessional training programs in safety and quality improvement. PMID- 22920426 TI - Advancing the science of human patient simulation in nursing education. AB - The call to reform nursing education introduced new expectations and revived long standing questions about how nursing students learn to manage the complexities of patient care. As pressures mount to combine learning experiences from traditional clinical settings with those from simulated patient care environments, innovative studies are needed to explore the effectiveness of teaching strategies used in each area. This will require a renewed commitment to the scholarship of teaching and learning in nursing education. PMID- 22920427 TI - The role of constructive feedback in patient safety and continuous quality improvement. AB - Constructive feedback is essential for personal and professional growth. It is an integral part of continuous quality improvement and essential in maintaining patient safety in the clinical environment. The perception of feedback can interfere with professionals giving and receiving feedback, which can have negative consequences on patient outcomes. Delivering and receiving feedback effectively are learned skills that should be introduced early in prelicensure education. Faculty have the opportunity to influence the perception of feedback to be viewed as an opportunity so that students can learn to appreciate its value in maintaining patient safety and high-quality care in clinical practice. PMID- 22920428 TI - Alarm fatigue. AB - The number of false high alarms in the hospital setting remains a serious problem. False alarms have desensitized care providers and, at times, have led to dire consequences for patients. Efforts by both industry and clinicians are beginning to address this situation in collaborative approaches. Research is needed to establish an evidence base around issues such as which patients need to be monitored, and what the threshold settings and delay settings should be on devices. Initial and ongoing education needs to be considered for any new medical device, and be included in the hospital's annual budget. PMID- 22920429 TI - The second victim of adverse health care events. AB - Nurses and other professionals drawn to health care by their desire to help others may be traumatized because they are involved in situations that bring harm rather than healing to patients. Health systems should develop early warning systems to alert unit or team leaders when health workers are at risk of harm from adverse events. This article focuses on health professionals who become second victims of adverse events that occur to patients. PMID- 22920430 TI - The quality burden. AB - While the cost of care remains a major focus of attention in pursuing quality patient care, little recognition has been given to the costs of the quality improvement efforts themselves: the time, energy, infrastructure, and emotional stress associated with documenting, monitoring, reporting, implementing, and evaluating quality indicators and initiatives. This article describes an emerging phenomenon, the quality burden, which, though often unmeasured, is significant in size and impact and accompanies ongoing efforts to improve the quality and safety of health care. Recommendations are given to mitigate the impact of the quality burden in delivering care and improving quality and safety. PMID- 22920431 TI - A just culture for nurses and nursing students. AB - This article provides an overview of current safety science related to just cultures, the tracking of errors and near misses, and individual and system responsibilities for promoting safe practice; and applies these principles to schools of nursing. PMID- 22920432 TI - Second-generation quality and safety education for nurses. PMID- 22920433 TI - How do different aspects of self-regulation predict successful adaptation to school? AB - Self-regulation plays an important role in successful adaptation to preschool and school contexts as well as in later academic achievement. The current study relates different aspects of self-regulation such as temperamental effortful control and executive functions (updating, inhibition, and shifting) to different aspects of adaptation to school such as learning-related behavior, school grades, and performance in standardized achievement tests. The relationship between executive functions/effortful control and academic achievement has been established in previous studies; however, little is known about their unique contributions to different aspects of adaptation to school and the interplay of these factors in young school children. Results of a 1-year longitudinal study (N=459) revealed that unique contributions of effortful control (parental report) to school grades were fully mediated by children's learning-related behavior. On the other hand, the unique contributions of executive functions (performance on tasks) to school grades were only partially mediated by children's learning related behavior. Moreover, executive functions predicted performance in standardized achievement tests exclusively, with comparable predictive power for mathematical and reading/writing skills. Controlling for fluid intelligence did not change the pattern of prediction substantially, and fluid intelligence did not explain any variance above that of the two included aspects of self regulation. Although effortful control and executive functions were not significantly related to each other, both aspects of self-regulation were shown to be important for fostering early learning and good classroom adjustment in children around transition to school. PMID- 22920434 TI - Impact of age on the efficacy of bone marrow mononuclear cell transplantation in experimental stroke. AB - Bone marrow-derived mononuclear cells (BM MNC) have been effectively used to treat experimental stroke. Most of the preclinical trials have been performed in young and healthy laboratory animals, even though age and hypertension are major risk factors for stroke. To determine the influence of age on the properties of BM MNCs after cerebral ischemia, we compared the efficacy of aged and young BM MNC in an in vitro model of cerebral hypoxia and in an adapted in vivo model of stroke. Human BM MNCs were obtained from healthy young or aged donors and either co-cultured with rat hippocampal slices exposed to oxygen glucose deprivation (OGD), or transplanted intravenously 24 h after permanent middle cerebral artery occlusion in aged (18 months) spontaneously hypertensive rats (SHR). Efficacy was examined by quantification of hippocampal cell death, or respectively, by neurofunctional tests and MR investigations. Co-cultivation with young, but not with aged BM MNCs significantly reduced the hippocampal cell death after OGD. Transplantation of both young and old BM MNCs did not reduce functional deficits or ischemic lesion volume after stroke in aged SHR. These results suggest a significant impact of age on the therapeutic efficacy of BM MNCs after cerebral ischemia. PMID- 22920435 TI - The complete mitochondrial genome of the Oujiang color carp, Cyprinus carpio var. color (Cypriniformes, Cyprinidae). AB - The complete mitochondrial genome of Oujiang color carp was determined to be 16,581 bp in length accurately using the next generation sequencing technology and bioinformatics tools. The complete mitochondrial genome of Oujiang color carp shows typical circular molecule structure of vertebrate's mitochondrial genome, which consists of 13 protein-coding genes, 22 tRNA genes, 2 rRNA genes, and 1 control region. The whole genome base composition was estimated to be 31.89% A, 27.53% C, 15.76% G, and 24.82% T with A/T bias of 56.71%. The complete mitochondrial genome of Oujiang color carp provides the basis for genetic breeding and conservation studies. PMID- 22920437 TI - Editorial: recent advances in the prevention and therapy of hepatocellular carcinoma. PMID- 22920436 TI - Chagasic patients are able to respond against a viral antigen from influenza virus. AB - BACKGROUND: Trypanosoma cruzi, the etiological agent of Chagas' disease, is an obligate intracellular parasite which induces a CD8+ T cell immune response with secretion of cytokines and release of cytotoxic granules. Although an immune suppressive effect of T. cruzi on the acute phase of the disease has been described, little is known about the capacity of CD8+ T cell from chronic chagasic patients to respond to a non-T. cruzi microbial antigen. METHODS: In the present paper, the frequency, phenotype and the functional activity of the CD8+ T cells specific from Flu-MP*, an influenza virus epitope, were determined in 13 chagasic patients and 5 healthy donors. RESULTS: The results show that Flu-MP* peptide specific CD8+ T cells were found with similar frequencies in both groups. In addition, Flu-MP* specific CD8+ T cells were distributed in the early or intermediate/late differentiation stages without showing enrichment of a specific sub-population. The mentioned Flu-MP* specific CD8+ T cells from chagasic patients were predominately TEM (CCR7- CD62L-), producing IL-2, IFNgamma, CD107a/b and perforin, and did not present significant differences when compared with those from healthy donors. CONCLUSIONS: Our results support the hypothesis that there is no CD8+ T cell nonspecific immune-suppression during chronic Chagas disease infection. Nonetheless, other viral antigens must be studied in order to confirm our findings. PMID- 22920438 TI - Inhibition of Cdc42-interacting protein 4 (CIP4) impairs osteosarcoma tumor progression. AB - BACKGROUND: In patients with Osteosarcoma (OS), larger primary tumor size correlates with higher metastasis incidence and lower overall survival. Identifying the mechanisms that control primary tumor growth can lead to the new therapeutic approaches and improve prognosis. Cytoskeleton regulatory molecules play an important role in tumor cells proliferation and motility. In the current study, we investigated the role of scaffolding protein Cdc42-interacting protein 4 (CIP4) in OS. METHODS: Murine OS cells, DLM8 were stably transfected with shCIP4 plasmid and their tumorigenic activity was studied in vitro and in vivo. The effect of CIP4 downregulation on cytoskeleton was studied by immunohistochemical analysis. RESULTS: In vivo studies revealed that downregulation of CIP4 in OS tumor cells can inhibit primary subcutaneous tumor growth and delay spontaneous metastases growth in the animal lungs. In vitro studies confirmed that inhibiting CIP4 expression significantly reduced tumor cells invasiveness and migration. Changes in CIP4 expression altered its cellular localization pattern and tumor cell morphology, which could explain changes in OS cell behavior in vivo and in vitro. Cells with downregulated CIP4 showed lower levels of actin in cells along with fewer perinuclear actin stress filaments and actin bridges to the lipid bilayer of the cell membrane than control cells. CONCLUSIONS: This study presents compelling evidence that inhibition of CIP4 expression in OS cells impairs metastatic behavior of cells in vitro and prolongs survival of animals by inhibiting primary tumor growth. Although the lack of CIP4 in tumor cells did not prevent formation of metastasis, it did substantially delay their formation in the animals' lungs. PMID- 22920439 TI - Inhibition of STAT signalling in bladder cancer by diindolylmethane: relevance to cell adhesion, migration and proliferation. AB - Effective treatments to prevent recurrence or progression of non-muscle-invasive bladder cancer, or to inhibit metastasis of muscle-invasive forms of the disease, would deliver significant patient benefit. Here the involvement of STAT signalling and the chemopreventive potential of diindolylmethane (DIM) in human bladder cancer were investigated. Muscle-invasive bladder cancer tissues were characterised by nuclear expression of phosphorylated STAT1, 3 and 5. In E cadherin positive tumour cell lines (RT112, RT4, HT1376), STAT5 was constitutively phosphorylated, while E-cadherin negative lines (J82, T24, UMUC3) contained phosphoSTAT3. Knockdown of STAT3 induced G0/G1 arrest and inhibited adhesion in J82 cells. Knockdown of STAT1inhibited migration in J82 and RT112 lines. No significant increase in apoptosis was observed. In response to the Janus kinase inhibitor, AG490, RT112 and J82 cells initially underwent G0/G1 arrest, with RT112 cells subsequently exhibiting S phase arrest. Phosphorylation of STAT1(Tyr701), STAT3(Tyr705) and (Ser727) and STAT5(Tyr694) was inhibited by DIM, as was adhesion of J82 cells to collagen, an effect that was enhanced when STAT1 or 3 was reduced by siRNA. However, over-expression of STAT3C partially rescued the DIM inhibitory effect on collagen-mediated adhesion. Migration of both lines was inhibited by DIM, while transfection of constitutively active STAT3C enhanced migration of RT112 cells. DIM induced cell cycle arrest and apoptosis in three cell lines with different degrees of radioresistance. Taken together, these results suggest that inhibition of STAT signalling and/or treatment with DIM may decrease invasiveness of bladder cancer. DIM can induce apoptosis in cell lines which are radioresistant, so in combination with radiotherapy may be useful in overcoming such resistance. PMID- 22920440 TI - Apoptosis suppression by candidate oncogene PLAC8 is reversed in other cell types. AB - Targets for cancer therapy are conventionally selected by identification of molecules acting downstream of established tumour suppressors and oncoproteins, such as p53, c-Myc and Ras. However, the forward genetics approach provides an alternative, conceptually distinct, strategy for identifying target molecules de novo. This approach, which uses unbiased selection protocols relying directly on the effects of the genes themselves on cell fate, has the potential to identify novel cancer targets which have not been highlighted by conventional approaches. PLAC8, a small cysteine-rich protein with little homology to other proteins, has been identified by both these strategies. Here we confirm that PLAC8 overexpression protects some cancer cell lines from apoptosis, but we also demonstrate for the first time that, in other cell lines, the effect of PLAC8 overexpression is reversed, and, in this context, PLAC8 induces apoptosis. In both cases siRNA-mediated down-regulation of PLAC8 confirms that the activity of endogenously expressed PLAC8 is consistent with that shown by exogenous PLAC8. The striking reversal of the effects of PLAC8 in different cell types is not readily explained by the level of PLAC8 expressed within the cells, by the differential expression of PLAC8 splice variants observed, or by the p53 status of the host cells. This intriguing contrast in the effects of PLAC8 on cell fate in different cellular contexts presents attractive possibilities for the development of novel therapies for cancers, such as pancreatic cancers, where PLAC8 has been shown to be overexpressed. PMID- 22920441 TI - TRPC channels and their splice variants are essential for promoting human ovarian cancer cell proliferation and tumorigenesis. AB - TRPC channels are Ca2+-permeable cationic channels controlling Ca2+ influx response to the activation of G protein-coupled receptors and protein tyrosine kinase pathways or the depletion of Ca2+ stores. Here we aimed to investigate whether TRPC can act as the potential therapeutic targets for ovarian cancer. The mRNAs of TRPC1, TRPC3, TRPC4 and TRPC6 were detected in human ovarian adenocarcinoma. The spliced variants of TRPC1beta, TRPC3a, TRPC4beta, TRPC4gamma, and TRPC6 with exon 3 and 4 deletion were highly expressed in the ovarian cancer cells, and a novel spliced isoform of TRPC1 with exon 9 deletion (TRPC1(E9del)) was identified. TRPC proteins were also detected by Western blotting and immunostaining. The expression of TRPC1, TRPC3, TRPC4 and TRPC6 was significantly lower in the undifferentiated ovarian cancer cells, but all-trans retinoic acid up-regulated the gene expression of TRPCs. The expression level was correlated to the cancer differentiation grade. The non-selective TRPC channel blockers, 2-APB and SKF-96365, significantly inhibited the cell proliferation, whilst the increase of TRPC channel activity by trypsin promoted the cell proliferation. Transfection with siRNA targeting TRPC1, TRPC3, TRPC4 and TRPC6 or application of specific blocking antibodies targeting to TRPC channels inhibited the cell proliferation. On the contrary, overexpression of TRPC1, TRPC1(E9del), TRPC3, TRPC4, and TRPC6 increased the cancer cell colony growth. These results suggest that TRPCs and their spliced variants are important for human ovarian cancer development and alteration of the expression or activity of these channels could be a new strategy for anticancer therapy. PMID- 22920443 TI - A thematic analysis of the role of the organisation in building allied health research capacity: a senior managers' perspective. AB - BACKGROUND: Evidence-based practice aims to achieve better health outcomes in the community. It relies on high quality research to inform policy and practice; however research in primary health care continues to lag behind that of other medical professions. The literature suggests that research capacity building (RCB) functions across four levels; individual, team, organisation and external environment. Many RCB interventions are aimed at an individual or team level, yet evidence indicates that many barriers to RCB occur at an organisational or external environment level. This study asks senior managers from a large healthcare organisation to identify the barriers and enablers to RCB. The paper then describes strategies for building allied health (AH) research capacity at an organisational level from a senior managers' perspective. METHODS: This qualitative study is part of a larger collaborative RCB project. Semi-structured in-depth interviews were conducted with nine allied health senior managers. Recorded interviews were transcribed and NVivo was used to analyse findings and emergent themes were defined. RESULTS: The dominant themes indicate that the organisation plays an integral role in building AH research capacity and is the critical link in creating synergy across the four levels of RCB. The organisation can achieve this by incorporating research into its core business with a whole of organisation approach including its mission, vision and strategic planning. Critical success factors include: developing a co-ordinated and multidisciplinary approach to attain critical mass of research-active AH and enhance learning and development; support from senior managers demonstrated through structures, processes and systems designed to facilitate research; forming partnerships to increase collaboration and sharing of resources and knowledge; and establishing in internal framework to promote recognition for research and career path opportunities. CONCLUSIONS: This study identifies four key themes: whole of organisation approach; structures, processes and systems; partnerships and collaboration; and dedicated research centres, units and positions. These themes form the foundation of a model which can be applied to assist in achieving synergy across the four levels of RCB, overcome barriers and create an environment that supports and facilitates research development in AH. PMID- 22920444 TI - [For a more humane hospital: experience of medical mediators]. AB - The legislation on patient's rights has considerably evolved during these last ten years. Its appropriation by users and its perception by care providers occur progressively. An important gap appears between the progresses of the medical sciences and techniques and the humane approach of the patient. The complaints remain relatively scarce compared to the number of treated patients. More frequent are the complaints linked to the care management, to the communication and humane relations. The hospital has to day with the CRUQ a permanent structure of relation with users. Medical mediation allows to listen to, explain, advise impartially patients and families. Its main goal is not to avoid litigation with the hospital but to improve the quality of care and the risk prevention. With this objective, it is necessary to develop a patient-centered care and to modify the behaviors toward a more humane relation. PMID- 22920445 TI - [Towards a pedagogical e-learning approach to improve preparation for medical school curriculum in Grenoble: results over the 10 last years]. AB - INTRODUCTION: Before 2005, at Grenoble, the teaching of the first year of medicine satisfied neither the students, nor the teachers anxious to exempt a correctly targeted effective teaching. METHODS: By 2006, the Grenoble-native teaching method was reformed in-depth with the introduction of information and communication technology (ICT) in education. Each sequence was over 4 weeks connecting: self- learning using multi-media resources, questions submitted online, meetings with teaching staff for interactive question-answer sessions in the presence of the teacher,) tutorials animated by older students for Multiple Choice Question (MCQ) training in preparation for the exams. The whole health formation was structured in 12 cycles of this same structured sequence. Since 2010, this method was extended from the faculty of medicine to the faculty of pharmacy and maieutic. Each year, more than 1600 students, 40 teachers and 140 tutors are concerned. The ICT laboratory was responsible for the production of the multi-media support, of the management of the questions online, the collection and the treatment of the evaluations of the lesson by the students. It also took part in the preparation of the MCQ trainings and after each sequence, delivered to students their personal ranking. RESULTS: Staffs between teachers and students are organized for the 12 cycles. The teachers' and students' opinions were analyzed to evaluate the reforms and allow teaching methods to be adapted accordingly. The expressed satisfaction' rate vary from 85% with more than 91% by students and teachers. The intensive use of new information and communication technologies is well accepted, by both sides: teachers and students. After each tutorial, students had their results and their rank, which are linked with the contest result. The mean of the 12 notes obtained during the tutorials is correlated with the note with the contest (R of Spearman=0.75). Student profiles at registration and success in the exams following the reform are described. The keys to success (e.g. social background, high school specialization) seem to be modified by the reform providing greater equality of opportunity between students. CONCLUSION: Since 2006, the teachers have adopted this teaching reform. All the returns from the students but also the staff and the teachers, allowed us to improve teachings quality. This teaching reform modified the profiles and the characteristics of the students received with the contest as well as the nature of the factors of this success. PMID- 22920447 TI - Structures of the ozonolysis products and ozonolysis pathway of aflatoxin B1 in acetonitrile solution. AB - The ozonolysis of aflatoxin B(1) (400 MUg/mL) in acetonitrile solution was conducted with an ozone concentration of 6.28 mg/L at the flow rate of 60 mL/min for different times. The results showed that ozone was an effective detoxification agent because of its powerful oxidative role. Thin-layer chromatography and liquid chromatography-quadrupole time-of-flight mass spectra were applied to confirm and identify the ozonolysis products of aflatoxin B(1). A total of 13 products were identified, and 6 of them were main products. The structural identification of these products provided effective information for understanding the ozonolysis pathway of aflatoxin B(1). Two ozonolysis pathways were proposed on the basis of the accurate mass and molecular formulas of these product ions. Nine ozonolysis products came from the first oxidative pathway based on the Criegee mechanism, and the other four products were produced from the second pathway based on the oxidative and electrophilic reactions of ozone. According to the toxicity mechanism of aflatoxin B(1) to animals, the toxicity of aflatoxin B(1) was significantly reduced because of the disappearance of the double bond on the terminal furan ring or the lactone moiety on the benzene ring. PMID- 22920448 TI - Basic concepts of activity-based interventions for improved recovery of motor function after spinal cord injury. AB - Spinal cord injury (SCI) is a devastating condition that affects a large number of individuals. Historically, the recovery process after an SCI has been slow and with limited success. Recently, a number of advances have been made in the strategies used for rehabilitation, resulting in marked improved recovery, even after a complete SCI. Several rehabilitative interventions, that is, assisted motor training, spinal cord epidural stimulation, and/or administration of pharmacologic agents, alone or in combination, have produced remarkable recovery in motor function in both humans and animals. The success with each of these interventions appears to be related to the fact that the spinal cord is smart, in that it can use ensembles of sensory information to generate appropriate motor responses without input from supraspinal centers, a property commonly referred to as central pattern generation. This ability of the spinal cord reflects a level of automaticity, that is, the ability of the neural circuitry of the spinal cord to interpret complex sensory information and to make appropriate decisions to generate successful postural and locomotor tasks. Herein, we provide a brief review of some of the neurophysiologic rationale for the success of these interventions. PMID- 22920446 TI - Using novel Canadian resources to improve medication reconciliation at discharge: study protocol for a randomized controlled trial. AB - BACKGROUND: Adverse drug events are responsible for up to 7% of all admissions to acute care hospitals. At least 58% of these are preventable, resulting from incomplete drug information, prescribing or dispensing errors, and overuse or underuse of medications. Effective implementation of medication reconciliation is considered essential to reduce preventable adverse drug events occurring at transitions between community and hospital care. An electronically enabled discharge reconciliation process represents an innovative approach to this problem. METHODS/DESIGN: Participants will be recruited in Quebec and are eligible for inclusion if they are using prescription medication at admission, covered by the Quebec drug insurance plan, admitted from the community, 18 years or older, admitted to a general or intensive care medical or surgical unit, and discharged alive. A sample size of 3,714 will be required to detect a 5% reduction in adverse drug events. The intervention will comprise electronic retrieval of the community drug list, combined with an electronic discharge reconciliation module and an electronic discharge communication module. The primary outcomes will be adverse drug events occurring 30 days post-discharge, identified by a combination of patient self-report and chart abstraction. All emergency room visits and hospital readmission during this period will be measured as secondary outcomes. A cluster randomization approach will be used to allocate 16 medical and 10 surgical units to electronic discharge reconciliation and communication versus usual care. An intention-to-treat approach will be used to analyse data. Logistic regression will be undertaken within a generalized estimating equation framework to account for clustering within units. DISCUSSION: The goal of this prospective trial is to determine if electronically enabled discharge reconciliation will reduce the risk of adverse drug events, emergency room visits and readmissions 30 days post-discharge compared with usual care. We expect that this intervention will improve adherence to medication reconciliation at discharge, the accuracy of the community-based drug history and effective communication of hospital-based treatment changes to community care providers. The results may support policy-directed investments in computerizing and training of hospital staff, generate key requirements for future hospital accreditation standards, and highlight functional requirements for software vendors. TRIAL REGISTRATION: NCT01179867. PMID- 22920449 TI - Assessment of functional improvement without compensation reduces variability of outcome measures after human spinal cord injury. AB - OBJECTIVE: To develop a scale (Neuromuscular Recovery Scale [NRS]) for classification of functional motor recovery after spinal cord injury (SCI) based on preinjury movement patterns that would reduce variability of the populations' level of function within each class, because assessment of functional improvement after SCI is problematic as a result of high variability of the populations' level of function and the insensitivity to change within the available outcome measures. DESIGN: Prospective observational cohort with longitudinal follow-up. SETTING: Seven outpatient rehabilitation centers from the Christopher and Dana Reeve Foundation NeuroRecovery Network (NRN). PARTICIPANTS: Individuals (N=95) with American Spinal Injury Association Impairment Scale (AIS) grade C or AIS grade D having received at least 20 locomotor training treatment sessions in the NRN. INTERVENTIONS: Intensive locomotor training including stepping on a treadmill with partial body weight support and manual facilitation and translation of skills into home and community activities. MAIN OUTCOME MEASURES: Berg Balance Scale, six-minute walk test, and ten-meter walk test. RESULTS: Individuals classified within each of the 4 phases of the NRS were functionally discrete, as shown by significant differences in the mean values of balance, gait speed, and walking endurance, and the variability of these measurements was significantly reduced by NRS classification. The magnitude of improvements in these outcomes was also significantly different among phase groups. CONCLUSIONS: Assessment with the NRS provides a classification for functional motor recovery without compensation, which reduces variability in performance and improvements for individuals with injuries classified as AIS grades C and D. PMID- 22920450 TI - Relationship between ASIA examination and functional outcomes in the NeuroRecovery Network Locomotor Training Program. AB - OBJECTIVE: To determine the effects of locomotor training on: (1) the International Standards for Neurological Classification of Spinal Cord Injury examination; (2) locomotion (gait speed, distance); (3) balance; and (4) functional gait speed stratifications after chronic incomplete spinal cord injury (SCI). DESIGN: Prospective observational cohort. SETTING: Outpatient rehabilitation centers in the NeuroRecovery Network (NRN). PARTICIPANTS: Individuals (n=225) with American Spinal Injury Association Impairment Scale (AIS) grade C or D chronic motor incomplete SCI having completed locomotor training in the NRN. INTERVENTION: The NRN Locomotor Training Program consists of manual-facilitated body weight-supported standing and stepping on a treadmill and overground. MAIN OUTCOME MEASURES: AIS classification, lower extremity pin prick, light touch and motor scores, ten-meter walk and six-minute walk tests, and the Berg Balance Scale. RESULTS: Significant gains occurred in lower extremity motor scores but not in sensory scores, and these were only weakly related to gait speed and distance. Final Berg Balance Scale scores and initial lower extremity motor scores were positively related. Although 70% of subjects showed significantly improved gait speed after locomotor training, only 8% showed AIS category conversion. CONCLUSIONS: Locomotor training improves gait speed to levels sufficient for independent in-home or community ambulation after chronic motor incomplete SCI. Changes in lower extremity motor and sensory scores do not capture the full extent of functional recovery, nor predict responsiveness to locomotor training. Functional classification based on gait speed may provide an effective measure of treatment efficacy or functional improvement after incomplete SCI. PMID- 22920451 TI - Longitudinal patterns of functional recovery in patients with incomplete spinal cord injury receiving activity-based rehabilitation. AB - OBJECTIVE: To model the progression of 3 functional outcome measures from patients with incomplete spinal cord injury (SCI) receiving standardized locomotor training. DESIGN: Observational cohort. SETTING: The NeuroRecovery Network (NRN), a specialized network of treatment centers providing standardized, activity-based therapy for SCI patients. PARTICIPANTS: Patients (N=337) with incomplete SCI (grade C or D on the International Standards for Neurological Classification of Spinal Cord Injury scale) who were enrolled in the NRN between February 2008 and March 2011. INTERVENTION: All enrolled patients received standardized locomotor training sessions, as established by NRN protocol, and were evaluated monthly for progress. MAIN OUTCOME MEASURES: Berg Balance Scale, 6 minute walk test, and 10-meter walk test. Progression over time was analyzed via the fitting of linear mixed effects models. RESULTS: There was significant improvement on each outcome measure and significant attenuation of improvement over time. Patients varied significantly across groups defined by recovery status and American Spinal Injury Association Impairment Scale (AIS) grade at enrollment with respect to baseline performance and rates of change over time. Time since SCI was a significant determinant of the rate of recovery for all measures. CONCLUSIONS: Locomotor training, as implemented in the NRN, results in significant improvement in functional outcome measures as treatment sessions accumulate. Variability in patterns of recovery over time suggest that time since SCI and patient functional status at enrollment, as measured by the Neuromuscular Recovery Scale, are important predictors of performance and recovery as measured by the targeted outcome measures. PMID- 22920452 TI - Ambulation and balance outcomes measure different aspects of recovery in individuals with chronic, incomplete spinal cord injury. AB - OBJECTIVE: To evaluate relationships among ambulation and balance outcome measures over time for incomplete spinal cord injury (SCI) after locomotor training, in order to facilitate the selection of effective and sensitive rehabilitation outcomes. DESIGN: Prospective observational cohort. SETTING: Outpatient rehabilitation centers (N=7) from the Christopher and Dana Reeve Foundation NeuroRecovery Network. PARTICIPANTS: Patients with incomplete SCI (N=182) American Spinal Injury Association Impairment Scale level C (n=61) and D (n=121). INTERVENTIONS: Intensive locomotor training, including step training using body weight support and manual facilitation on a treadmill followed by overground assessment and community integration. MAIN OUTCOME MEASURES: Six minute and 10-meter walk tests, Berg Balance Scale, Modified Functional Reach, and Neuromuscular Recovery Scale collected at enrollment, approximately every 20 sessions, and on discharge. RESULTS: Walking and standing balance measures for all participants were strongly correlated (r>=.83 for all pairwise outcome correlations), standing and sitting balance measures were not highly correlated (r<=.48 for all pairwise outcome correlations), and walking measures were weakly related to sitting balance. The strength of relationships among outcome measures varied with functional status. Correlations among evaluation-to-evaluation changes were markedly reduced from performance correlations. Walk tests, when conducted with different assistive devices, were strongly correlated but had substantial variability in performance. CONCLUSIONS: These results cumulatively suggest that changes in walking and balance measures reflect different aspects of recovery and are highly influenced by functional status and the utilization of assistive devices. These factors should be carefully considered when assessing clinical progress and designing clinical trials for rehabilitation. PMID- 22920453 TI - Dynamic longitudinal evaluation of the utility of the Berg Balance Scale in individuals with motor incomplete spinal cord injury. AB - OBJECTIVES: To examine the utility of the Berg Balance Scale among patients with motor incomplete spinal cord injuries (SCIs), to determine how the utility of the Berg Balance Scale changes over time with activity-based therapy, and to identify differences in scale utility across patient groups defined by status of recovery. DESIGN: Prospective observational cohort. SETTING: The NeuroRecovery Network (NRN), a network of clinical centers for patients with motor incomplete SCI. PARTICIPANTS: Patients with motor incomplete SCI (n=124) with American Spinal Injury Association Impairment Scale grade C or D, who were enrolled in the NRN between February 2008 and June 2009. INTERVENTION: Standardized locomotor training. MAIN OUTCOME MEASURE: The Berg Balance Scale items were examined with longitudinal principal components analyses. Patients were categorized by phase using the Neuromuscular Recovery Scale. RESULTS: In the full sample, the first principal component explained a large percentage of overall scale variance (77%), items were loaded homogeneously on the first principal component, and item scores were well correlated with first principal component scores. In subgroups of low and high functioning of patients, first principal component variance accounting was reduced (49%) and only a few of the simplest and most difficult items substantially loaded onto the first principal component. Item loading coefficients evolved over time as patients recovered, with simpler items becoming less important to the full scale and difficult items more important. CONCLUSIONS: The utility of the Berg Balance Scale in patients with motor incomplete SCI in early and advanced phases of recovery is limited. Specific item utility changes as patients recover. Thus, a more comprehensive and dynamic instrument is necessary to adequately measure balance across the spectrum of patients with motor incomplete SCI. PMID- 22920454 TI - NeuroRecovery Network provides standardization of locomotor training for persons with incomplete spinal cord injury. AB - OBJECTIVE: To illustrate the continuity of care afforded by a standardized locomotor training program across a multisite network setting within the Christopher and Dana Reeve Foundation NeuroRecovery Network (NRN). DESIGN: Single patient case study. SETTING: Two geographically different hospital-based outpatient facilities. PARTICIPANTS: This case highlights a 25-year-old man diagnosed with C4 motor incomplete spinal cord injury with American Spinal Injury Association Impairment Scale grade D. INTERVENTION: Standardized locomotor training program 5 sessions per week for 1.5 hours per session, for a total of 100 treatment sessions, with 40 sessions at 1 center and 60 at another. MAIN OUTCOME MEASURES: Ten-meter walk test and 6-minute walk test were assessed at admission and discharge across both facilities. For each of the 100 treatment sessions percent body weight support, average, and maximum treadmill speed were evaluated. RESULTS: Locomotor endurance, as measured by the 6-minute walk test, and overground gait speed showed consistent improvement from admission to discharge. Throughout training, the patient decreased the need for body weight support and was able to tolerate faster treadmill speeds. CONCLUSIONS: Data indicate that the patient continued to improve on both treatment parameters and walking function. Standardization across the NRN centers provided a mechanism for delivering consistent and reproducible locomotor training programs across 2 facilities without disrupting training or recovery progression. PMID- 22920455 TI - Cardiovascular status of individuals with incomplete spinal cord injury from 7 NeuroRecovery Network rehabilitation centers. AB - OBJECTIVE: To examine cardiovascular (CV) health in a large cohort of individuals with incomplete spinal cord injury (SCI). The CV health parameters of patients were compared based on American Spinal Injury Association Impairment Scale (AIS), neurologic level, sex, central cord syndrome, age, time since injury, Neuromuscular Recovery Scale, and total AIS motor score. DESIGN: Cross-sectional study. SETTING: Seven outpatient rehabilitation clinics. PARTICIPANTS: Individuals (N=350) with incomplete AIS classification C and D were included in this analysis. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Heart rate, systolic and diastolic blood pressure during resting sitting and supine positions and after an orthostatic challenge. RESULTS: CV parameters were highly variable and significantly differed based on patient position. Neurologic level (cervical, high and low thoracic) and age were most commonly associated with CV parameters where patients classified at the cervical level had the lowest resting CV parameters. After the orthostatic challenge, blood pressure was highest for the low thoracic group, and heart rate for the high thoracic group was higher. Time since SCI was negatively related to blood pressure at rest but not after orthostatic challenge. Men exhibited higher systolic blood pressure than women and lower heart rate. The prevalence of orthostatic hypotension (OH) was 21% and was related to the total motor score and resting seated blood pressures. Cervical injuries had the highest prevalence. CONCLUSIONS: Resting CV parameters of blood pressure and heart rate are affected by position, age, and neurologic level. OH is more prevalent in cervical injuries, those with lower resting blood pressures and who are lower functioning. Results from this study provide reference for CV parameters for individuals with incomplete SCI. Future research is needed on the impact of exercise on CV parameters. PMID- 22920456 TI - Locomotor training: as a treatment of spinal cord injury and in the progression of neurologic rehabilitation. AB - Scientists, clinicians, administrators, individuals with spinal cord injury (SCI), and caregivers seek a common goal: to improve the outlook and general expectations of the adults and children living with neurologic injury. Important strides have already been accomplished; in fact, some have labeled the changes in neurologic rehabilitation a "paradigm shift." Not only do we recognize the potential of the damaged nervous system, but we also see that "recovery" can and should be valued and defined broadly. Quality-of-life measures and the individual's sense of accomplishment and well-being are now considered important factors. The ongoing challenge from research to clinical translation is the fine line between scientific uncertainty (ie, the tenet that nothing is ever proven) and the necessary burden of proof required by the clinical community. We review the current state of a specific SCI rehabilitation intervention (locomotor training), which has been shown to be efficacious although thoroughly debated, and summarize the findings from a multicenter collaboration, the Christopher and Dana Reeve Foundation's NeuroRecovery Network. PMID- 22920458 TI - Highly enantioselective conjugate addition of malononitrile to 2-enoylpyridines with bifunctional organocatalyst. AB - An efficient enantioselective conjugate addition of malononitrile to a range of beta-substituted 2-enoylpyridines catalyzed by cinchona alkaloid-based bifunctional urea catalysts has been developed. Both enantiomers of the products could be achieved with the same level of enantioselectivity by using pseudoenantiomeric catalysts in up to 97% ee and in excellent yields. One of the enantioenriched products has been transformed to a highly functionalized piperidone derivative. PMID- 22920457 TI - A peptide-based biosensor assay to detect intracellular Syk kinase activation and inhibition. AB - Spleen tyrosine kinase (Syk) has been implicated in a number of pathologies including cancer and rheumatoid arthritis and thus has been pursued as a novel therapeutic target. Because of the complex relationship between Syk's auto- and other internal phosphorylation sites, scaffolding proteins, enzymatic activation state and sites of phosphorylation on its known substrates, the role of Syk's activity in these diseases has not been completely clear. To approach such analyses, we developed a Syk-specific artificial peptide biosensor (SAStide) to use in a cell-based assay for direct detection of intracellular Syk activity and inhibition in response to physiologically relevant stimuli in both laboratory cell lines and primary splenic B cells. This peptide contains a sequence derived from known Syk substrate preference motifs linked to a cell permeable peptide, resulting in a biosensor that is phosphorylated in live cells in a Syk-dependent manner, thus serving as a reporter of Syk catalytic activity in intact cells. Because the assay is compatible with live, primary cells and can report pharmacodynamics for drug action on an intended target, this methodology could be used to facilitate a better understanding of Syk's function and the effect of its inhibition in disease. PMID- 22920459 TI - Molecules tell stories: Reactive Oxygen, Nitrogen, Carbonyl and Sulfur Species take center stage. PMID- 22920461 TI - Determination of the material parameters of four-fibre family model based on uniaxial extension data of arterial walls. AB - The four-fibre family constitutive relation has been used to capture the mechanical behaviour of arterial walls under biaxial loading conditions. This study shows that the material parameters of the four-fibre family model can be determined by uniaxial extension data from the arterial walls. Stochastic optimisation methods were used to determine the material parameters based on uniaxial extension data of the strip samples with circumferential and axial orientations from thoracic aortas and pulmonary arteries of two fresh donation bodies. Moreover, we implemented numerical experiments, in which stress-strain data generated according to different constitutive parameters were treated as mechanical experiment data and went through the same methods as mechanical test data to determine the constitutive parameters. The estimate-effect ratio, defined by the number of data with the precision of estimation less than 0.5% over whole size of data, was applied to demonstrate the feasibility of our method. The material parameters for Chinese thoracic aorta and pulmonary artery were given with [Formula: see text], and the minimal estimate-effect ratio in numerical simulations was 97.77%. In conclusion, the four-fibre family model of arterial walls can be determined from uniaxial extension data. Moreover, the four-fibre family six-parameter constitutive model is the best fit to the data from Chinese pulmonary arteries, and the four-fibre family eight-parameter constitutive model is the best fit to the data from Chinese thoracic aortas. PMID- 22920460 TI - Two glutamic acid residues in the DNA-binding domain are engaged in the release of STAT1 dimers from DNA. AB - BACKGROUND: In interferon-gamma-stimulated cells, the dimeric transcription factor STAT1 (signal transducer and activator of transcription 1) recognizes semi palindromic motifs in the promoter regions of cytokine-driven target genes termed GAS (gamma-activated sites). However, the molecular steps that facilitate GAS binding and the subsequent liberation of STAT1 homodimers from these promoter elements are not well understood. RESULTS: Using a mutational approach, we identified two critical glutamyl residues within the DNA-binding domain adjacent to the phosphodiester backbone of DNA which efficiently release phospho-STAT1 from DNA. The release of STAT1 dimers from DNA enhances transcriptional activity on both interferon-driven reporter and endogenous target genes. A substitution of either of the two glutamic acid residues broadens the repertoire of putative binding sites on DNA and enhances binding affinity to GAS sites. However, despite elevated levels of tyrosine phosphorylation and a prolonged nuclear accumulation period, the STAT1 DNA-binding mutants show a significantly reduced transcriptional activity upon stimulation of cells with interferon-gamma. This reduced transcriptional response may be explained by the deposition of oligomerized STAT1 molecules outside GAS sites. CONCLUSIONS: Thus, two negatively charged amino acid residues in the DNA-binding domain are engaged in the liberation of STAT1 from DNA, resulting in a high dissociation rate from non-GAS sites as a key feature of STAT1 signal transduction, which positively regulates cytokine-dependent gene expression probably by preventing retention at transcriptionally inert sites. PMID- 22920462 TI - History of pulmonary critical care nursing and where we are going. AB - Pulmonary critical care nurses have played a prominent role in the ICUs from the inception of critical care units. This article describes how the history of pulmonary critical care nursing has evolved and discusses a few of the challenges in the years to come: stress imposed by working in a critical care environment, enhancing the care of patients by altering patterns of sedation and promoting early mobilization, and dealing with increasing infection rates. PMID- 22920463 TI - Acute respiratory failure and intensive measures. AB - Critical patients presenting with acute respiratory failure (ARF) offer a plentiful, dynamic, and complex picture, which requires a deep understanding of gas exchange, pulmonary dynamics, and mechanical ventilation strategies. The most frequent cause of ARF is chronic disease with exacerbation. Interventions treating acute exacerbation, along with ventilatory support, physical therapy, and evidence-based strategies, may improve immediate outcomes. However, follow-up is essential and for the chronic obstructive pulmonary disease patient the goal is to avoid relapse or rehospitalization. This article discusses the evaluation of gas exchange failures, pulmonary mechanics, and the properties of obstructive airway disease as they relate to ARF. PMID- 22920464 TI - Current knowledge of acute lung injury and acute respiratory distress syndrome. AB - Acute lung injury/acute respiratory distress syndrome (ALI/ARDS) continues to be a major cause of mortality in adult and pediatric critical care medicine. This article discusses the pulmonary sequelae associated with ALI and ARDS, the support of ARDS with mechanical ventilation, available adjunctive therapies, and experimental therapies currently being tested. It is hoped that further understanding of the fundamental biology, improved identification of the patient's inflammatory state, and application of therapies directed at multiple sites of action may ultimately prove beneficial for patients suffering from ALI/ARDS. PMID- 22920466 TI - Management of COPD patients in the intensive care unit. AB - Chronic obstructive pulmonary disease (COPD) is characterized by expiratory airflow limitation that is not fully reversible. Acute exacerbations in patients with moderate to severe COPD can cause severe hypoxia and persistent or severe respiratory acidosis, resulting in respiratory failure and the need for ventilator support. Acute respiratory failure, altered mental status, and hemodynamic instability associated with acute exacerbations of COPD are commonly encountered and require careful management in the intensive care unit (ICU). Noninvasive and invasive ventilator support in conjunction with pharmacotherapy can be lifesaving, although mortality remains high. It is important also to consider pulmonary rehabilitation and palliative care. PMID- 22920467 TI - Community-acquired, health care-associated, and ventilator-associated pneumonia: three variations of a serious disease. AB - Pneumonia affects millions of people every year in the United States. Hospital acquired pneumonia is associated with a mortality rate as high as 50%. Pneumonia is classified according to where it was acquired or by the infecting organism. This article explores the similarities and differences in three types of pneumonia seen routinely in the intensive care unit: community-acquired pneumonia, ventilator-associated pneumonia, and health care-associated pneumonia. PMID- 22920465 TI - Pulmonary complications of transfused blood components. AB - Three transfusion complications are responsible for the majority of the morbidity and mortality in hospitalized patients. This article discusses the respiratory complications associated with these pathophysiologic processes, including definitions, diagnosis, mechanism, incidence, risk factors, clinical management, and strategies for prevention. It also explores how different patient populations and different blood components differentially affect the risk of these deadly transfusion complications. Lastly, the article discusses how health care providers can risk stratify individual patients or patient populations to determine whether a given transfusion is more likely to benefit or harm the patient based on the transfusion indication, risk, and expected result. PMID- 22920468 TI - Understanding advanced modes of mechanical ventilation. AB - Approaches to mechanical ventilation (MV) are consistently changing and the level of ventilator sophistication provides opportunities to improve pulmonary support for critically ill patients. Advanced MV modes are used in the treatment of patients with complex pulmonary conditions. To achieve optimal patient outcomes MV modes that best meet the needs of patient's evolving pulmonary conditions are necessary. It's essential for nurses to integrate pulmonary MV knowledge in the care of critically ill patients. The purpose of this article is to describe the evidence supporting lung protective modes of MV used in the care of critically ill adults. PMID- 22920469 TI - Weaning from mechanical ventilation: where were we then, and where are we now? AB - Weaning patients from long-term mechanical ventilation (LTMV) has been an important focus of clinical process improvement initiatives and research for decades. The purpose of this article is to describe the science that drives our current weaning practices, including (1) preweaning assessment, (2) individualized weaning plans, (3) weaning prediction, (4) the use of protocols and guidelines for weaning trials and sedation management, (5) timing of tracheostomy placement, and (6) system initiatives for the management of LTMV patients. Finally, this article discusses potential interventions for improving the outcomes of patients who require prolonged mechanical ventilation. PMID- 22920470 TI - Self/unplanned extubation: safety, surveillance, and monitoring of the mechanically ventilated patient. AB - The purpose of this article is to provide an appreciation for a significant risk to quality of care affecting patients receiving mechanical ventilation: unplanned extubation. A summary of the current literature provides evidence-based recommendations for how to minimize this potentially dangerous complication. In addition, recommendations for proceeding after unplanned extubation are made. PMID- 22920471 TI - Early mobilization in the management of critical illness. AB - Patients undergoing critical illness and mechanical ventilation are at risk of developing neuromuscular and neurocognitive impairments that can impact physical function and quality of life. Mobilizing patients early in the course of critical illness may improve outcomes. Recent literature on early mobilization is reviewed, suggestions for implementation are discussed, and areas for future research are identified. PMID- 22920472 TI - Telemedicine in the intensive care unit. AB - It is estimated if each hospital implemented intensivist physician staffing, approximately 55,000 lives and $4.3 billion dollars could be saved in the United States. However, there is a limited supply of new critical care specialists as teaching hospitals have decreased the size of critical care programs for financial reasons. Tele-ICU can be used to provide coverage in facilities that cannot support a full-time specialist in critical care medicine and as an adjunct to facilities without 24-hour intensivist coverage. This article discusses the benefits and challenges of tele-ICU and its implications for nursing practice. PMID- 22920473 TI - Pulmonary processes and mechanical ventilation in the ICU patient. PMID- 22920474 TI - Intracardiac origin of heart rate variability, pacemaker funny current and their possible association with critical illness. AB - Heart rate variability (HRV) is an indirect estimator of autonomic modulation of heart rate and is considered a risk marker in critical illness, particularly in heart failure and severe sepsis. A reduced HRV has been found in critically ill patients and has been associated with neuro-autonomic uncoupling or decreased baroreflex sensitivity. However, results from human and animal experimental studies indicate that intracardiac mechanisms might also be responsible for interbeat fluctuations. These studies have demonstrated that different membrane channel proteins and especially the so-called 'funny' current (If), an hyperpolarization-activated, inward current that drives diastolic depolarization resulting in spontaneous activity in cardiac pacemaker cells, are altered during critical illness. Furthermore, membrane channels kinetics seem to have significant impact upon HRV, whose early decrease might reflect a cellular metabolic stress. In this review article we present research findings regarding intracardiac origin of HRV, at the cellular level and in both isolated sinoatrial node and whole ex vivo heart preparations. In addition, we will review results from various experimental studies that support the interrelation between If and HRV during endotoxemia. We suggest that reduced HRV during sepsis could also be associated with altered pacemaker cell membrane properties, due to ionic current remodeling. PMID- 22920476 TI - Atrial fibrillation in acute ST-elevation myocardial infarction: clinical and prognostic features. AB - Atrial fibrillation (AF) is a common arrhythmia in the setting of acute coronary syndrome and acute ST-elevation myocardial infarction (STEMI). This review summarizes recent evidence on the clinical and prognostic significance of pre existent and new-onset AF in acute STEMI patients and highlights new emerging predictors of AF development in the era of contemporary treatment. PMID- 22920475 TI - Obesity, diabetes and atrial fibrillation; epidemiology, mechanisms and interventions. AB - The last few decades have witnessed a global rise in adult obesity of epidemic proportions. The potential impact of this is emphasized when one considers that body mass index (BMI) is a powerful predictor of death, type 2 diabetes (T2DM) and cardiovascular (CV) morbidity and mortality [1, 2]. Similarly we have witnessed a parallel rise in the incidence of atrial fibrillation (AF), the commonest sustained cardiac arrhythmia, which is also a significant cause of cardiovascular morbidity and mortality. Part of this increase is attributable to advances in the treatment of coronary heart disease (CHD) and heart failure (HF) improving life expectancy and consequently the prevalence of AF. However, epidemiological studies have demonstrated an independent association between obesity and AF, possibly reflecting common pathophysiology and risk factors for both conditions. Indeed, weight gain and obesity are associated with structural and functional changes of the cardiovascular system including left atrial and ventricular remodeling, haemodynamic alterations, autonomic dysfunction, and diastolic dysfunction. Moreover, diabetic cardiomyopathy is characterized by an adverse structural and functional cardiac phenotype which may predispose to the development of AF [3]. In this review, we discuss the pathophysiological and mechanistic relationships between obesity, diabetes and AF, and the challenges posed in the management of this high-risk group of individuals. PMID- 22920477 TI - Atrial fibrillation in heart failure: an innocent bystander? AB - Heart failure (HF) and atrial fibrillation (AF) frequently coexist and each complicates the course of the other. The purpose of this review is to analyse the prognostic impact of AF in patients with HF and assess whether there is an advantage in targeting therapies towards the maintenance of sinus rhythm (SR) in this cohort of patients. The presence of AF in patients with HF has been reported to be independently associated with an increase in mortality in many studies and this increased risk is observed in those with both preserved and impaired LV systolic function. The optimal strategy for targeting AF in patients with HF is unclear but recent randomised controlled studies indicate no significant prognostic advantage associated with a rhythm control strategy as compared to a rate control strategy. A number of small studies have investigated the role of both cardiac resynchronization therapy (CRT) and AF catheter ablation for the maintenance of / conversion to SR in patients with HF with initial promising results although larger randomised controlled studies will need to be performed to define the role of these modalities in the treatment of this cohort and whether preliminary benefits observed in these studies translate to improvements in longer term prognosis. Finally, there has been a focus on modifying the arrhythmogenic atrial substrate and neurohormonal milieu by pharmacological means in order to prevent AF although it remains to be seen whether this approach proves to be efficacious with improvements in clinically relevant outcomes. PMID- 22920478 TI - Cost of atrial fibrillation: invasive vs non-invasive management in 2012. AB - Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia. It places an enormous burden on the patients, caregivers and the society at large. As a chronic illness, AF accrues significant costs related to clinical presentation, complications and loss of productivity. Novel invasive approaches to AF promise a cure in some patients and a significant reduction in AF burden in others, but are very expensive. This paper will address the cost of conventional and invasive strategies in AF care and will review the evidence on the comparative cost effectiveness of these approaches. PMID- 22920479 TI - Long-term success and follow-up after atrial fibrillation ablation. AB - Atrial fibrillation (AF) is the most prevalent sustained arrhythmia in clinical practice. It is associated with significant morbidity and mortality and has been identified as an independent risk factor for ischemic stroke and thromboembolic events. Catheter ablation has become an established rhythm control therapy in patients with highly symptomatic drug-refractory AF. The definition of ablation success remains controversial since current symptom-based or intermittent electrocardiogram monitoring strategies fail to sufficiently disclose rhythm outcome. This failure is mainly related to the high incidence of asymptomatic AF recurrences, the unpredictable nature of arrhythmia relapses, and the poor correlation of symptoms and AF episodes. There is a clear correlation between the intensity of the monitoring strategy and the sensitivity for it to detect arrhythmia recurrences. Furthermore, several clinical studies assessing the long term efficacy of catheter ablation procedures have reported late AF recurrences in patients who were initially considered responders to catheter ablation. In certain subsets of patients, precise long-term monitoring may help to guide therapy, e.g. patients in whom withdrawal of antithrombotic therapy may be considered if they are free of arrhythmia recurrences. Recently, subcutaneous implantable cardiac monitors (ICM) have been introduced for prolonged and continuous rhythm monitoring. The performance of a leadless ICM equipped with a dedicated AF detection algorithm has recently been assessed in a clinical trial demonstrating a high sensitivity and overall accuracy for identifying patients with AF. The clinical impact of ICM-based follow-up strategies, however, has to be evaluated in prospective clinical trials. PMID- 22920481 TI - Ablation of complex fractionated atrial electrograms in catheter ablation for AF; where have we been and where are we going? AB - Catheter ablation for persistent AF remains a challenge to the ablator as the disease is now outside the veins and cannot be tackled by pulmonary vein isolation alone. In this article we describe targeting complex fractionated atrial electrograms (CFAE) as a method to guide atrial substrate modification. PMID- 22920480 TI - Stroke prevention in atrial fibrillation: concepts and controversies. AB - Atrial fibrillation (AF) is the commonest cardiac rhythm disorder worldwide, affecting 1% of the general population. It is estimated that up to 16 million people in the US will suffer from the arrhythmia by 2050. AF is an independent stroke risk factor and associated with more severe strokes. For six decades, warfarin has been the only truly effective therapy to protect against stroke for patients with atrial fibrillation. Despite the proven worth of warfarin, its limitations have seen reluctance amongst physicians and patients to utilise this efficacious agent. This has meant that substantial numbers of patients are either unprotected against stroke or suboptimally protected with antiplatelet therapy. Contemporary well-validated stroke risk factor schemes (CHA(2)DS(2)-VASc) now permit rapid but comprehensive evaluation of a patient's risk for thromboembolism, allowing better identification of low-risk patients who do not require antithrombotic therapy, and whilst for those with >=1 stroke risk factors require formal oral anticoagulation. Aspirin has been proven to be inferior to anticoagulation, and is not free of bleeding risk. We also have simple scores to easily evaluate a patient's risk of haemorrhage (e.g. HAS-BLED). The emergence of new oral anticoagulants should further improve stroke prevention in AF, and they successfully negotiate many of the hurdles to oral anticoagulation generated by warfarin's limitations. Monitoring, reversal, and perioperative management are areas which require further investigation to enhance our ability to safely and effectively utilise the new agents. PMID- 22920483 TI - Novel anti-arrhythmic medications in the treatment of atrial fibrillation. AB - Atrial fibrillation (AF) is a prevalent condition particularly amongst the elderly, which contributes to both morbidity and mortality. The burden of disease has lead to significant increases in health care utilization and cost in recent years. Treatment of Atrial fibrillation consists of either a rate or rhythm control strategy. Rhythm control is achieved using medical management and/or catheter ablation. In spite of major strides in catheter ablation, this procedure remains a second line treatment of AF. Anti-arrhythmic medications represent the main treatment modality for the maintenance of sinus rhythm. Amiodarone has been used for decades because of its efficacy and lack of pro-arrhythmia despite numerous extracardiac side effects. Novel agents such as Dronedarone were designed to emulate Amiodarone without the extra-cardiac side effects. Unfortunately recent trials have raised concerns for the safety of this medication in certain patients. Other agents such as Vernakalant and Ranolazine are in development that promise to be more atrial selective in their action, thereby potentially avoiding pro-arrhythmia and heart failure side effects. It remains to be seen however if one or more of these agents achieves the required high efficacy and safety threshold. This review summarizes the main anti arrhythmic clinical trials, early phase trials involving novel agents and examines the conflicting data relating to Dronedarone. PMID- 22920482 TI - Current hot potatoes in atrial fibrillation ablation. AB - Atrial fibrillation (AF) ablation has evolved to the treatment of choice for patients with drug-resistant and symptomatic AF. Pulmonary vein isolation at the ostial or antral level usually is sufficient for treatment of true paroxysmal AF. For persistent AF ablation, drivers and perpetuators outside of the pulmonary veins are responsible for AF maintenance and have to be targeted to achieve satisfying arrhythmia-free success rate. Both complex fractionated atrial electrogram (CFAE) ablation and linear ablation are added to pulmonary vein isolation for persistent AF ablation. Nevertheless, ablation failure and necessity of repeat ablations are still frequent, especially after persistent AF ablation. Pulmonary vein reconduction is the main reason for arrhythmia recurrence after paroxysmal and to a lesser extent after persistent AF ablation. Failure of persistent AF ablation mostly is a consequence of inadequate trigger ablation, substrate modification or incompletely ablated or reconducting linear lesions. In this review we will discuss these points responsible for AF recurrence after ablation and review current possibilities on how to overcome these limitations. PMID- 22920485 TI - Facilitated/pharmaco-invasive approaches in STEMI. AB - Primary percutaneous coronary intervention (PCI) is the preferred reperfusion method in patients with STelevation myocardial infarction (STEMI), when performed in a timely manner and by skilled operators. However, this strategy has shown to be limited in environments with lack of PCI facilities and delay in the first medical contact-toballoon time for logistic reasons. Pretreatment with fibrinolysis and/or glycoprotein IIb/IIIa inhibitors before PCI has the potential to provide early pharmacologic reperfusion before definitive PCI in STEMI patients. However, current data suggest that facilitated PCI does not offer any advantage over primary PCI. Conversely, a role for pharmacoinvasive recanalization, defined as pharmacological reperfusion followed by rapid transfer for routine delayed coronary angiography and PCI may still be considered in centers without on-site PCI capability. PMID- 22920484 TI - Triggers and anatomical substrates in the genesis and perpetuation of atrial fibrillation. AB - The definition of atrial fibrillation (AF) as a functional electrical disorder does not reflect the significant underlying structural abnormalities. Atrial and Pulmonary Vein (PV) muscle sleeve microstructural remodeling is present, and establishes a vulnerable substrate for AF maintenance. In spite of an incomplete understanding of the anatomo-functional basis for AF, current evidence demonstrates that this arrhythmia usually requires a trigger for initiation and a vulnerable electrophysiological and/or anatomical substrate for maintenance. It is still unclear whether the trigger mechanisms include focal enhanced automaticity, triggered activity and/or micro re-entry from myocardial tissue. Initiation of AF can be favored by both parasympathetic and sympathetic stimulation, which also seem to play a role in maintaining AF. Finally, evolving clinical evidence demonstrates that inflammation is associated with new-onset and recurrent AF through a mechanism that possibly involves cellular degeneration, apoptosis, and subsequent atrial fibrosis. PMID- 22920486 TI - Thrombus extraction catheters vs. angiojet rheolytic thrombectomy in thrombotic lesions/SV grafts. AB - Primary percutaneous coronary intervention, (pPCI), of native coronaries and saphenous vein grafts (SVGs), is the recommended reperfusion strategy for STEMI, and an early invasive approach is recommended for high risk patients with UA/NSTEMI. Although PCI effectively restores flow in the infarct related artery/culprit vessel in both situations, myocardial perfusion often remains suboptimal due to microvascular obstruction, partly attributed to distal embolization of thrombus. Hence, thrombectomy (manual or mechanical), prior to stenting may further reduce hard clinical end points in patients with ACS. This article discusses accumulated evidence regarding the safety and effectiveness of thrombectomy in culprit native coronaries and SVGs in such patients, as well as possible strategies for maximizing its benefits relative to the size of the thrombotic burden. PMID- 22920487 TI - Pathophysiology of coronary thrombus formation and adverse consequences of thrombus during PCI. AB - Atherosclerosis is a systemic vascular pathology that is preceded by endothelial dysfunction. Vascular inflammation "fuels" atherosclerosis and creates the milieu for episodes of intravascular thromboses. Thrombotic events in the coronary vasculature may lead to asymptomatic progression of atherosclerosis or could manifest as acute coronary syndromes or even sudden cardiac death. Thrombus encountered in the setting of acute coronary syndromes has been correlated with acute complications during percutaneous coronary interventions such as no-reflow, acute coronary occlusion and long term complications such as stent thrombus. This article reviews the pathophysiology of coronary thrombogenesis and explores the complications associated with thrombus during coronary interventions. PMID- 22920488 TI - Treating and preventing no reflow in the cardiac catheterization laboratory. AB - The no reflow phenomenon can happen during elective or primary percutaneous coronary intervention. This phenomenon is thought to be a complex process involving multiple factors that eventually lead to microvascular obstruction and endothelial disruption. Key pathogenic components include distal atherothrombotic embolization, ischemic injury, reperfusion injury, and susceptibility of coronary microcirculation to injury. Thus, pharmacologic and mechanical strategies to prevent and treat no reflow target these mechanisms. Specifically, pharmacologic therapy consisting of vasodilators and antiplatelet agents have shown benefit in the treatment of no-reflow and mechanical therapies such as distal protection and aspiration thrombectomy have also shown benefit. PMID- 22920490 TI - Embolic protection devices in saphenous vein graft and native vessel percutaneous intervention: a review. AB - The clinical benefit of percutaneous intervention (PCI) depends on both angiographic success at the site of intervention as well as the restoration of adequate microvascular perfusion. Saphenous vein graft intervention is commonly associated with evidence of distal plaque embolization, which is correlated with worse clinical outcomes. Despite successful epicardial intervention in the acute MI patient treated with primary PCI, distal tissue perfusion may still be absent in up to 25% of cases [1-3]. Multiple devices and pharmacologic regimens have been developed and refined in an attempt to protect the microvascular circulation during both saphenous vein graft intervention and primary PCI in the acute MI setting. We will review the evidence for various techniques for embolic protection of the distal myocardium during saphenous vein graft PCI and primary PCI in the native vessel. PMID- 22920491 TI - Exhaled nitric oxide measurement confirms 2 severe wheeze phenotypes in young children from the Trousseau Asthma Program. PMID- 22920489 TI - Appropriate anti-thrombotic/anti-thrombin therapy for thrombotic lesions. AB - Managing coronary thrombus is a challenging task and requires adequate knowledge of the various antithrombotic agents available. In this article, we will briefly analyze the risk-benefit profile of antithrombotic agents, with critical analysis of the scientific evidence available to support their use. Since thrombus consists of platelets and coagulation cofactors, an effective antithrombotic strategy involves using one anticoagulant with two or more antiplatelet agents. Unfractionated heparin traditionally has been the most commonly used anticoagulant but is fast being replaced by relatively newer agents like LMWH, direct thrombin inhibitors, and Factor Xa inhibitors. In recent years, the antiplatelet landscape has changed significantly with the availability of more potent and rapidly acting agents, like prasugrel and ticagrelor. These agents have demonstrated a sizeable reduction in ischemic outcomes in patients with ACS, who are treated invasively or otherwise, with some concern for an increased bleeding risk. Glycoprotein IIb/IIIa inhibitors have an established role in high risk NSTE ACS patients pretreated with dual antiplatelets, but its role in STEMI patients, treated with invasive approach and dual antiplatelets, has not been supported consistently across the studies. Additionally, in recent years, its place as a directly injected therapy into coronaries has been looked into with mixed results. In conclusion, a well-tailored antithrombotic strategy requires taking into account each patient's individual risk factors and clinical presentation, with an effort to strike balance between not only preventing ischemic outcomes but also reducing bleeding complications. PMID- 22920492 TI - Six-month in vitro validation of a metered-dose inhaler electronic monitoring device: implications for asthma clinical trial use. PMID- 22920493 TI - Do all asthmatics with atopy have atopic asthma? PMID- 22920494 TI - Evaluation of a skin test device designed to be less painful. PMID- 22920496 TI - Antineutrophil cytoplasmic autoantibodies and myeloperoxidase autoantibodies in clinical expression of Churg-Strauss syndrome. AB - BACKGROUND: The clinical significance of antineutrophil cytoplasmic antibodies (ANCAs) in the phenotypic expression of Churg-Strauss syndrome (CSS) is uncertain. OBJECTIVE: We sought to investigate the relationship between ANCA status and the clinical expression of CSS in a case series derived from the US Food and Drug Administration's adverse events database. METHODS: All cases of CSS reported to the US Food and Drug Administration from 1997 to April 2003 were reviewed. Information about basic demographics, suspect medication use, clinical manifestations, histologic findings, ANCA staining patterns, and the presence of antibodies to myeloperoxidase (anti-MPO) or proteinase 3 (anti-PR3) was recorded when available. RESULTS: There were 93 case reports of CSS with sufficient documentation, including ANCA status. There were 38 (40.9%) of 93 cases with positive ANCA results, of which 15 cases reported a positive ELISA, all of which were positive for anti-MPO. ANCA negativity was associated with an increased proportion of cardiac involvement (risk difference [RD], 38.2%; 95% CI, 25.3% to 51.0%), gastrointestinal involvement (RD, 25.5%; 95% CI, 13.9% to 37.0%), pulmonary infiltrates (odds ratio, 4.9; 95% CI, 1.5-16.2), and the outcome of a life-threatening event or death (RD, 30.9%; 95% CI, 18.7% to 43.1%) when compared with anti-MPO-positive cases. ANCA negativity was associated with a decreased proportion of peripheral neuropathy (odds ratio, 0.3; 95% CI, 0.07-0.9). CONCLUSION: These findings support the hypothesis that the presence or absence of autoantibodies influences the clinical expression and severity of CSS. PMID- 22920495 TI - Comparative transcriptomic analyses of atopic dermatitis and psoriasis reveal shared neutrophilic inflammation. AB - BACKGROUND: Atopic dermatitis (AD) and psoriasis are common inflammatory diseases canonically described as involving distinct T(H) polarization and granulocytic infiltration. Acute AD lesions are associated with T(H)2 and eosinophilic inflammation, whereas psoriatic lesions are associated with T(H)1/T(H)17 and neutrophilic inflammation. Despite intensive investigation, these pathways remain incompletely understood in vivo in human subjects. OBJECTIVE: Using AD and psoriatic lesional skin as exemplar T(H)2 and T(H)1/T(H)17 diseased tissue, we sought to clarify common and unique molecular and pathophysiologic features in inflamed skin with different types of inflammatory polarization. METHODS: We conducted gene expression microarray analyses to identify distinct and commonly dysregulated expression in AD (based on Hanifin and Rajka criteria) and psoriatic lesions. We defined gene sets (GSs) as comprising genes encoding cytokines, chemokines, and growth factors that were uniquely or jointly dysregulated in patients with AD and those with psoriasis and calculated aggregate GS expression scores for lesional skin of patients with these dermatoses and healthy control skin. RESULTS: The atopic dermatitis gene set (AD-GS) score correlated with systemic and local measures of allergic inflammation, including serum IgE levels, blood eosinophil counts, and tissue eosinophil counts. Unexpectedly, genes encoding neutrophil chemoattractants among the common GS were highly expressed in AD lesional skin. Hematoxylin and eosin and immunohistochemical analyses showed the numbers of neutrophils in AD lesional skin were comparable with those in psoriatic lesional skin, and both were correlated with the extent of expression of neutrophil chemoattractant genes. CONCLUSION: These data are evidence that neutrophilic inflammation is a feature of lesional AD pathology comorbid with allergic inflammation. PMID- 22920498 TI - Ab initio study of magnesium and magnesium hydride nanoclusters and nanocrystals: examining optimal structures and compositions for efficient hydrogen storage. AB - On the basis of the attractive possibility of efficient hydrogen storage in light metal hydrides, we have examined a large variety of Mg(n)H(m) nanoclusters and (MgH(2))(n) nanocrystals (n = 2-216, m = 2-436) using high level coupled cluster, CCSD(T), ab initio methods, and judicially chosen density functional calculations of comparable quality and (near chemical) accuracy. Our calculated desorption energies as a function of size and percentage of hydrogen have pinpointed optimal regions of sizes and concentrations of hydrogen which are in full agreement with recent experimental findings. Furthermore, our results reproduce the experimental desorption energy of 75.5 kJ/mol for the infinite system with remarkable accuracy (76.5 +/- 1.5 kJ/mol). PMID- 22920497 TI - Predictors of outcome in neck pain patients undergoing chiropractic care: comparison of acute and chronic patients. AB - BACKGROUND: Neck pain is a common complaint in patients presenting for chiropractic treatment. The few studies on predictors for improvement in patients while undergoing treatment identify duration of symptoms, neck stiffness and number of previous episodes as the strong predictor variables. The purpose of this study is to continue the research for predictors of a positive outcome in neck pain patients undergoing chiropractic treatment. METHODS: Acute (< 4 weeks) (n = 274) and chronic (> 3 months) (n = 255) neck pain patients with no chiropractic or manual therapy in the prior 3 months were included. Patients completed the numerical pain rating scale (NRS) and Bournemouth questionnaire (BQ) at baseline prior to treatment. At 1 week, 1 month and 3 months after start of treatment the NRS and BQ were completed along with the Patient Global Impression of Change (PGIC) scale. Demographic information was provided by the clinician. Improvement at each of the follow up points was categorized using the PGIC. Multivariate regression analyses were done to determine significant independent predictors of improvement. RESULTS: Baseline mean neck pain and total disability scores were significantly (p < 0.001and p < 0.008 respectively) higher in acute patients. Both groups reported significant improvement at all data collection time points, but was significantly larger for acute patients. The PGIC score at 1 week (OR = 3.35, 95% CI = 1.13-9.92) and the baseline to 1 month BQ total change score (OR = 1.07, 95% CI = 1.03-1.11) were identified as independent predictors of improvement at 3 months for acute patients. Chronic patients who reported improvement on the PGIC at 1 month were more likely to be improved at 3 months (OR = 6.04, 95% CI = 2.76-13.69). The presence of cervical radiculopathy or dizziness was not predictive of a negative outcome in these patients. CONCLUSIONS: The most consistent predictor of clinically relevant improvement at both 1 and 3 months after the start of chiropractic treatment for both acute and chronic patients is if they report improvement early in the course of treatment. The co-existence of either radiculopathy or dizziness however do not imply poorer prognosis in these patients. PMID- 22920499 TI - An improved allele-specific PCR primer design method for SNP marker analysis and its application. AB - BACKGROUND: Although Single Nucleotide Polymorphism (SNP) marker is an invaluable tool for positional cloning, association study and evolutionary analysis, low SNP detection efficiency by Allele-Specific PCR (AS-PCR) still restricts its application as molecular marker like other markers such as Simple Sequence Repeat (SSR). To overcome this problem, primers with a single nucleotide artificial mismatch introduced within the three bases closest to the 3'end (SNP site) have been used in AS-PCR. However, for one SNP site, nine possible mismatches can be generated among the three bases and how to select the right one to increase primer specificity is still a challenge. RESULTS: In this study, different from the previous reports which used a limited quantity of primers randomly (several or dozen pairs), we systematically investigated the effects of mismatch base pairs, mismatch sites and SNP types on primer specificity with 2071 primer pairs, which were designed based on SNPs from Brassica oleracea 01-88 and 02-12. According to the statistical results, we (1) found that the primers designed with SNP (A/T), in which the mismatch (CA) in the 3rd nucleotide from the 3' end, had the highest allele-specificity (81.9%). This information could be used when designing primers from a large quantity of SNP sites; (2) performed the primer design principle which forms the one and only best primer for every SNP type. This is never reported in previous studies. Additionally, we further identified its availability in rapeseed (Brassica napus L.) and sesame (Sesamum indicum). High polymorphism percent (75%) of the designed primers indicated it is a general method and can be applied in other species. CONCLUSION: The method provided in this study can generate primers more effectively for every SNP site compared to other AS-PCR primer design methods. The high allele-specific efficiency of the SNP primer allows the feasibility for low- to moderate- throughput SNP analyses and is much suitable for gene mapping, map-based cloning, and marker-assisted selection in crops. PMID- 22920501 TI - Molybdenum(VI) oxosulfato complexes in MoO3-K2S2O7-K2SO4 molten mixtures: stoichiometry, vibrational properties, and molecular structures. AB - The structural and vibrational properties of molybdenum(VI) oxosulfato complexes formed in MoO(3)-K(2)S(2)O(7) and MoO(3)-K(2)S(2)O(7)-K(2)SO(4) molten mixtures under an O(2) atmosphere and static equilibrium conditions were studied by Raman spectroscopy at temperatures of 400-640 degrees C. The corresponding composition effects were explored in the X(MoO)(3)(0) = 0-0.5 range. MoO(3) undergoes a dissolution reaction in molten K(2)S(2)O(7), and the Raman spectra point to the formation of molybdenum(VI) oxosulfato complexes. The Mo?O stretching region of the Raman spectrum provides sound evidence for the occurrence of a dioxo Mo(?O)(2) configuration as a core. The stoichiometry of the dissolution reaction MoO(3) + nS(2)O(7)(2-) -> C(2n-) was inferred by exploiting the Raman band intensities, and it was found that n = 1. Therefore, depending on the MoO(3 content, monomeric MoO(2)(SO(4))(2)(2-) and/or associated [MoO(2)(SO(4))(2)](m)(2m-) complexes are formed in the binary MoO(3)-K(2)S(2)O(7) molten system, and pertinent structural models are proposed in full consistency with the Raman data. A 6-fold coordination around Mo is inferred. Adjacent MoO(2)(2+) cores are linked by bidentate bridging sulfates. With increasing temperature at concentrated melts (i.e., high X(MoO)(3)(0)), the observed spectral changes can be explained by partial dissociation of [MoO(2)(SO(4))(2)](m)(2m-) by detachment of S(2)O(7)(2-) and formation of a Mo-O Mo bridge. Addition of K(2)SO(4) in MoO(3)-K(2)S(2)O(7) results in a "follow-up" reaction and formation of MoO(2)(SO(4))(3)(4-) and/or associated [MoO(2)(SO(4))(3)](m)(4m-) complexes in the ternary MoO(3)-K(2)S(2)O(7)-K(2)SO(4) molten system. The 6-fold Mo coordination comprises two oxide ligands and four O atoms linking to coordinated sulfate groups in various environments of reduced symmetry. The most characteristic Raman bands for the molybdenum(VI) oxosulfato complexes pertain to the Mo(?O)(2) stretching modes: (1) at 957 (polarized) and 918 (depolarized) cm(-1) for the nu(s) and nu(as) Mo(?O)(2) modes of MoO(2)(SO(4))(2)(2-) and [MoO(2)(SO(4))(2)](m)(2m-) and (2) at 935 (polarized) and 895 (depolarized) cm(-1) for the respective modes of MoO(2)(SO(4))(3)(4-) and [MoO(2)(SO(4))(3)](m)(4m-). The results were tested and found to be in accordance with ab initio quantum chemical calculations carried out on [MoO(2)(SO(4))(3)](4 ) and [{MoO(2)}(2)(SO(4))(4)(MU-SO(4))(2)](8-) ions, in assumed isolated gaseous free states, at the DFT/B3LYP (HF) level and with the 3-21G basis set. The calculations included determination of vibrational infrared and Raman spectra, by use of force constants in the Gaussian 03W program. PMID- 22920500 TI - The effects of levosimendan on brain metabolism during initial recovery from global transient ischaemia/hypoxia. AB - BACKGROUND: Neuroprotective strategies after cardiopulmonary resuscitation are currently the focus of experimental and clinical research. Levosimendan has been proposed as a promising drug candidate because of its cardioprotective properties, improved haemodynamic effects in vivo and reduced traumatic brain injury in vitro. The effects of levosimendan on brain metabolism during and after ischaemia/hypoxia are unknown. METHODS: Transient cerebral ischaemia/hypoxia was induced in 30 male Wistar rats by bilateral common carotid artery clamping for 15 min and concomitant ventilation with 6% O2 during general anaesthesia with urethane. After 10 min of global ischaemia/hypoxia, the rats were treated with an i.v. bolus of 24 MUg kg-1 levosimendan followed by a continuous infusion of 0.2 MUg kg-1 min-1. The changes in the energy-related metabolites lactate, the lactate/pyruvate ratio, glucose and glutamate were monitored by microdialysis. In addition, the effects on global haemodynamics, cerebral perfusion and autoregulation, oedema and expression of proinflammatory genes in the neocortex were assessed. RESULTS: Levosimendan reduced blood pressure during initial reperfusion (72 +/- 14 vs. 109 +/- 2 mmHg, p = 0.03) and delayed flow maximum by 5 minutes (p = 0.002). Whereas no effects on time course of lactate, glucose, pyruvate and glutamate concentrations in the dialysate could be observed, the lactate/pyruvate ratio during initial reperfusion (144 +/- 31 vs. 77 +/- 8, p = 0.017) and the glutamate release during 90 minutes of reperfusion (75 +/- 19 vs. 24 +/- 28 MUmol.L-1) were higher in the levosimendan group. The increased expression of IL-6, IL-1beta TNFalpha and ICAM-1, extend of cerebral edema and cerebral autoregulation was not influenced by levosimendan. CONCLUSION: Although levosimendan has neuroprotective actions in vitro and on the spinal cord in vivo and has been shown to cross the blood-brain barrier, the present results showed that levosimendan did not reduce the initial neuronal injury after transient ischaemia/hypoxia. PMID- 22920502 TI - Building health systems capacity in global health graduate programs: reflections from Australian educators. AB - There has been increasing focus on the role of health systems in low and middle income countries. Despite this, very little evidence exists on how best to build health systems program and research capacity in educational programs. The current experiences in building capacity in health systems in five of the most prominent global health programs at Australian universities are outlined. The strengths and weaknesses of various approaches and techniques are provided along with examples of global practice in order to provide a foundation for future discussion and thus improvements in global health systems education. PMID- 22920503 TI - Refractive lens exchange for a multifocal intraocular lens with a surface embedded near section in mild to moderate anisometropic amblyopic patients. AB - PURPOSE: To evaluate visual and refractive outcomes in amblyopic patients who had bilateral implantation of a multifocal intraocular lens (IOL) with a surface embedded near section. SETTING: Cathedral Eye Clinic, Belfast, Northern Ireland, United Kingdom. DESIGN: Comparative case series. METHODS: Anisometropic amblyopic patients having bilateral implantation of Lentis Mplus multifocal IOLs were examined for distance and near visual acuities, contrast sensitivity, defocus curves, extent of crowding, reading speed, stereoacuity, and Quality of Vision (QoV) questionnaire scores preoperatively and at 3-month intervals during 12 months. A +3.00 diopter (D) reading addition IOL was used in all eyes. RESULTS: Twenty-eight eyes (14 patients) (mean age 59.4 years) were included. In the nonamblyopic eye, the mean uncorrected distance visual acuity (UDVA) was 0.16 logMAR +/- 0.17 (SD), the mean corrected distance visual acuity (CDVA) was 0.02 +/- 0.07 logMAR, and the mean near acuity was M 0.5 (Jaeger [J] 2 = logRAD 0.1) or better. In the amblyopic eye, the means were 0.30 +/- 0.14 logMAR, 0.21 +/- 0.11 logMAR, and M 0.8 (J4 = logRAD 0.3) or better, respectively. Bilateral reading speeds (mean 137.73 +/- 28.7 words per minute [wpm]) surpassed unilateral nonamblyopic eye speeds (mean 130.6 +/- 29.4 wpm). The mean QoV scores improved from 7.78 +/- 10.23 preoperatively to 1.92 +/- 5.21 at 12 months. No glare or halos were reported; 1 patient had mild starburst symptoms at 1 year. Patients rated distance and near vision as excellent. CONCLUSION: Anisometropic amblyopic patients may benefit from bilateral implantation of the multifocal IOL; no unwanted side effects were detected. PMID- 22920504 TI - Evaluation of a new single-piece 4% water content hydrophobic acrylic intraocular lens in the rabbit model. AB - PURPOSE: To evaluate uveal and capsular biocompatibility of a 1-piece intraocular lens (IOL) manufactured from a new hydrophobic acrylic material that incorporates a barrier step at the optic-haptic junctions. SETTING: John A. Moran Eye Center, University of Utah, Salt Lake City, Utah, USA. DESIGN: Experimental study. METHODS: The study IOL (Eternity-Uni W-60) was implanted in the right eyes of 5 New Zealand rabbits and the control IOL (Acrysof SN60WF) in the left eyes. Slitlamp examination was performed 1 through 4 weeks postoperatively. After death, the globes were enucleated and fixed in formalin. Capsular bag opacification scoring (Miyake-Apple view) was then performed followed by complete histopathology. RESULTS: At the 4-week examination, the mean posterior capsule opacification (PCO) score was 1.5 +/- 1.0 (SD) in the study group and 2.2 +/- 1.09 in the control group (P=.02). Anterior capsule opacification (ACO) was not present in the study eyes and was mild in the control eyes. On gross examination, the mean central PCO score was 0.9 +/- 0.65 in the study group and 1.7 +/- 1.20 in the control group (P=.07); the mean peripheral PCO score was 1.3 +/- 0.67 and 2.4 +/- 1.14 (P=.01) and the mean Soemmerring ring score was 3.8 +/- 0.44 and 4.2 +/- 1.09, respectively (P=.47). Histopathology confirmed that both IOLs were equally tolerated by the rabbit eyes. CONCLUSIONS: In this rabbit study, the new hydrophobic acrylic material was biocompatible. The barrier step incorporated to the optic-haptic junctions has the potential to enhance PCO prevention. PMID- 22920505 TI - Clinical grading of post-LASIK ectasia related to visual limitation and predictive factors for vision loss. AB - PURPOSE: To evaluate and characterize the main clinical features of post-laser in situ keratomileusis (LASIK) ectasia, propose a grading system based on visual limitation, and identify predictive factors related to the degree of visual loss. SETTING: Vissum Corp., Alicante, Spain. DESIGN: Retrospective case series. METHODS: This study comprised consecutive eyes with corneal ectasia after LASIK from 1996 to 2010. Main outcomes were post-LASIK ectasia corrected distance visual acuity (CDVA), CDVA loss, spherical equivalent (SE), and the corneal bulge (delta K). These outcomes were correlated with the residual stromal bed, ablation depth, ablation ratio (ablation depth:pachymetry), corneal depth (flap + ablation depth), and corneal ratio (corneal depth:pachymetry) to characterize their role in the severity of the disease. RESULTS: The mean post-LASIK ectasia CDVA, CDVA loss, SE, and delta K were 0.20 logMAR +/- 0.18 (SD), -0.13 +/- 0.15 logMAR, 3.80 +/- 3.86 diopters (D), and 4.77 +/- 4.23 D, respectively. The ablation ratio had the strongest correlation with post-LASIK ectasia CDVA (rho = 0.477 and P<.001), whereas the corneal ratio had the strongest correlation with the post LASIK ectasia SE and delta K (rho = -0.614 and rho = 0.453, respectively: P<.001). The ablation ratio was the main predictive factor for post-LASIK ectasia CDVA loss (relative risk, 2.04; P=.049). CONCLUSIONS: The grading system based on visual limitation was consistently represented by differences in CDVA loss, SE, and delta K. A high amount of tissue removed by the refractive procedure was associated with greater corneal biomechanical destabilization, increased corneal steepening, and a worse prognosis. PMID- 22920506 TI - Comparative genomic analysis of Escherichia coli O104:H4 stx2 prophage reveals a potential new method to identify virulence factors. AB - This study investigated the process of virulence acquisition in a Shiga toxin producing Escherichia coli O104:H4 strain, TY-2482, by comparing the sequence of stx2 (Shiga toxin 2) prophage with the sequences of 1421 complete bacterial genomes and analyzing the evolutionary relationships of the stx2 prophage-like regions identified. The results showed a strong positive correlation between the evolutionary distance and the distance to switch sites of GC skew, suggesting that the loci near these sites are "hotspots" for insertions. These findings represent a potential new method to identify virulence factors in bacterial genomes. PMID- 22920507 TI - Pulmonary extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue associated with granulomatous inflammation in a child with chromosome 22q11.2 deletion syndrome (DiGeorge syndrome). AB - Patients with immunodeficiency disorders have an increased incidence of lymphoproliferative disorders; however, only 4 such patients with DiGeorge/chromosome 22q11.2 deletion syndrome have been reported. We report a case of a pulmonary Epstein-Barr virus-negative extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue in a child with this syndrome. PMID- 22920508 TI - Chorioamnionitis as a risk factor for necrotizing enterocolitis: a systematic review and meta-analysis. AB - OBJECTIVE: To accumulate available evidence regarding the association between antenatal inflammation and necrotizing enterocolitis (NEC). STUDY DESIGN: A systematic literature search was performed using Medline, Embase, Cochrane Library, ISI Web of Knowledge, and reference hand searches. Human studies published in English that reported associations between chorioamnionitis or other indicators of antenatal inflammation and NEC were eligible. Relevant associations were extracted and reported. Studies reporting associations between histological chorioamnionitis (HC) and NEC, HC with fetal involvement and NEC, and clinical chorioamnionitis and NEC were pooled in separate meta-analyses. RESULTS: A total of 33 relevant studies were identified. Clinical chorioamnionitis was significantly associated with NEC (12 studies; n = 22 601; OR, 1.24; 95% CI, 1.01 1.52; P = .04; I(2) = 12%), but the association between HC and NEC was not statistically significant (13 studies; n = 5889; OR, 1.39; 95% CI, 0.95-2.04; P = .09; I(2) = 49%). However, HC with fetal involvement was highly associated with NEC (3 studies; n = 1640; OR, 3.29; 95% CI, 1.87-5.78; P <= .0001; I(2) = 10%). Selection based on study quality did not affect the results. No indications of publication bias were apparent. Multivariate analyses in single studies generally attenuated the reported associations. Several associations between other markers of antenatal inflammation and NEC are reported. CONCLUSION: Currently available evidence supports a role for antenatal inflammation in NEC pathophysiology. This finding emphasizes the need to further study the underlying mechanisms and evaluate potential interventions to improve postnatal intestinal outcomes. PMID- 22920511 TI - Diverse mechanisms of antidiabetic effects of the different procyanidin oligomer types of two different cinnamon species on db/db mice. AB - The procyanidin oligomers are thought to be responsible for the antidiabetic activity of cinnamon. To investigate the hypoglycemic effects of different procyanidin oligomer types, the procyanidin oligomer-rich extracts were prepared from two different cinnamon species. Using high-performance liquid chromatography with purified procyanidin oligomers as reference compounds, we found that the Cinnamomum cassia extract (CC-E) and Cinnamomum tamala extract (CT-E) were rich in B- and A-type procyanidin oligomers, respectively. In the experiment, 8 week-old diabetic (db/db) mice were gavaged with CC-E and CT-E (both 200 mg/kg per day) for 4 weeks. Both CC-E and CT-E exhibited antidiabetic effects. Moreover, histopathological studies of the pancreas, liver, and adipose tissue showed that CC-E promoted lipid accumulation in the adipose tissue and liver, whereas CT-E mainly improved the insulin concentration in the blood and pancreas. PMID- 22920509 TI - The impact of the Clean Air Act. PMID- 22920512 TI - Phorone A and isophorbasone A, sesterterpenoids isolated from the marine sponge Phorbas sp. AB - A chemical investigation of a Korean marine sponge, Phorbas sp., yielded unprecedented sesterterpenoids phorone A (1) and isophorbasone A (2) along with ansellone B (3) and phorbasone A acetate (4). Their complete structures were elucidated by the combination of spectroscopic data and chemical manipulation. Phorone A (1) and isophorbasone A (2) have the new "phorane"(5) and "isophorbasane"(6) sesterterpenoid carbon skeletons, respectively. Ansellone B (3) and phorbasone A acetate (4) exhibited potent inhibitory activity on nitric oxide production in RAW 264.7 LPS-activated mouse macrophage cells with IC(50) values of 4.5 and 2.8 MUM, respectively. PMID- 22920513 TI - Travel, sex, and food: what's speciation got to do with it? AB - We discuss the potential interactions among travel (dispersal and gene flow), bacterial "sex" (mainly as horizontal gene transfer), and food (metabolic plasticity and responses to nutrient availability) in shaping microbial communities. With regard to our work at a unique desert oasis, the Cuatro Cienegas Basin in Coahuila, Mexico, we propose that diversification and low phosphorus availability, in combination with mechanisms for nutrient recycling and community cohesion, result in enhanced speciation through reproductive as well as geographic isolation. We also discuss these mechanisms in the broader sense of ecology and evolution. Of special relevance to astrobiology and central to evolutionary biology, we ask why there are so many species on Earth and provide a working hypothesis and a conceptual framework within which to consider the question. Key Words: Microbial ecology-Microbial mats-Evolution-Horizontal gene transfer-Metabolism. PMID- 22920514 TI - The Cuatro Cienegas Basin in Coahuila, Mexico: an astrobiological Precambrian Park. AB - The Cuatro Cienegas Basin (CCB) is a rare oasis in the Chihuahuan Desert in the state of Coahuila, Mexico. It has a biological endemism similar to that of the Galapagos Islands, and its spring-fed ecosystems have very low nutrient content (nitrogen or phosphorous) and are dominated by diverse microbialites. Thus, it has proven to be a distinctive opportunity for the field of astrobiology, as the CCB can be seen as a proxy for an earlier time in Earth's history, in particular the late Precambrian, the biological frontier when prokaryotic life yielded at least partial dominance to eukaryotes and multicellular life. It is a kind of ecological time machine that provides abundant opportunities for collaborative investigations by geochemists, geologists, ecologists, and population biologists in the study of the evolutionary processes that structured Earth-based life, especially in the microbial realm. The CCB is an object of investigation for the identification of biosignatures of past and present biota that can be used in our search for extraterrestrial life. In this review, we summarize CCB research efforts that began with microbial ecology and population biology projects and have since been expanded into broader efforts that involve biogeochemistry, comparative genomics, and assessments of biosignatures. We also propose that, in the future, the CCB is sanctioned as a "Precambrian Park" for astrobiology. PMID- 22920515 TI - Comparative metagenomics of two microbial mats at Cuatro Cienegas Basin I: ancient lessons on how to cope with an environment under severe nutrient stress. AB - The Cuatro Cienegas Basin (CCB) is an oasis in the desert of Mexico characterized by low phosphorus availability and by its great diversity of microbial mats. We compared the metagenomes of two aquatic microbial mats from the CCB with different nutrient limitations. We observed that the red mat was P-limited and dominated by Pseudomonas, while the green mat was N-limited and had higher species richness, with Proteobacteria and Cyanobacteria as the most abundant phyla. From their gene content, we deduced that both mats were very metabolically diverse despite their use of different strategies to cope with their respective environments. The red mat was found to be mostly heterotrophic, while the green mat was more autotrophic. The red mat had a higher number of transporters in general, including transporters of cellobiose and osmoprotectants. We suggest that generalists with plastic genomes dominate the red mat, while specialists with minimal genomes dominate the green mat. Nutrient limitation was a common scenario on the early planet; despite this, biogeochemical cycles were performed, and as a result the planet changed. The metagenomes of microbial mats from the CCB show the different strategies a community can use to cope with oligotrophy and persist. PMID- 22920517 TI - Divergence and phylogeny of Firmicutes from the Cuatro Cienegas Basin, Mexico: a window to an ancient ocean. AB - The Cuatro Cienegas Basin (CCB) has been identified as a center of endemism for many life-forms. Nearly half the bacterial species found in the spring systems have their closest relatives in the ocean. This raises the question of whether the high diversity observed today is the product of an adaptive radiation similar to that of the Galapagos Islands or whether the bacterial groups are "survivors" of an ancient sea, which would be of interest for astrobiology. To help answer this question, we focused on Firmicutes from Cuatro Cienegas (mainly Bacillus and Exiguobacterium). We reconstructed the phylogenetic relationships of Firmicutes with 28 housekeeping genes and dated the resulting tree using geological events as calibration points. Our results show that marine Bacillus diverged from other Bacillus strains 838 Ma, while Bacillus from Cuatro Cienegas have divergence dates that range from 770 to 202 Ma. The members of Exiguobacterium from the CCB conform to a much younger group that diverged from the Andes strain 60 Ma and from the one in Yellowstone 183 Ma. Therefore, the diversity of Firmicutes in Cuatro Cienegas is not the product of a recent radiation but the product of the isolation of lineages from an ancient ocean. Hence, Cuatro Cienegas is not a Galapagos Archipelago for bacteria but is more like an astrobiological "time machine" in which bacterial lineages survived in an oligotrophic environment that may be very similar to that of the Precambrian. Key Words: Firmicutes-Cuatro Cienegas-Precambrian-Molecular dating-Western Interior Seaway. PMID- 22920516 TI - Comparative metagenomics of two microbial mats at Cuatro Cienegas Basin II: community structure and composition in oligotrophic environments. AB - Microbial mats are self-sustained, functionally complex ecosystems that make good models for the understanding of past and present microbial ecosystems as well as putative extraterrestrial ecosystems. Ecological theory suggests that the composition of these communities might be affected by nutrient availability and disturbance frequency. We characterized two microbial mats from two contrasting environments in the oligotrophic Cuatro Cienegas Basin: a permanent green pool and a red desiccation pond. We analyzed their taxonomic structure and composition by means of 16S rRNA clone libraries and metagenomics and inferred their metabolic role by the analysis of functional traits in the most abundant organisms. Both mats showed a high diversity with metabolically diverse members and strongly differed in structure and composition. The green mat had a higher species richness and evenness than the red mat, which was dominated by a lineage of Pseudomonas. Autotrophs were abundant in the green mat, and heterotrophs were abundant in the red mat. When comparing with other mats and stromatolites, we found that taxonomic composition was not shared at species level but at order level, which suggests environmental filtering for phylogenetically conserved functional traits with random selection of particular organisms. The highest diversity and composition similarity was observed among systems from stable environments, which suggests that disturbance regimes might affect diversity more strongly than nutrient availability, since oligotrophy does not appear to prevent the establishment of complex and diverse microbial mat communities. These results are discussed in light of the search for extraterrestrial life. PMID- 22920519 TI - Microbial stowaways: inimitable survivors or hopeless pioneers? AB - The resiliency of prokaryotic life has provided colonization across the globe and in the recesses of Earth's most extreme environments. Horizontal gene transfer provides access to a global bank of genetic resources that creates diversity and allows real-time adaptive potential to the clonal prokaryotic world. We assess the likelihood that this Earth-based strategy could provide survival and adaptive potential, in the case of microbial stowaways off Earth. PMID- 22920520 TI - Substance risk, prevention treatments and the role of the environmental and cultural context in addressing Latinos and other ethnic/racial populations. PMID- 22920521 TI - Measuring what we value: quantifying the impact of the physician extender in surgical care. PMID- 22920518 TI - Bacterial communities and the nitrogen cycle in the gypsum soils of Cuatro Cienegas Basin, coahuila: a Mars analogue. AB - The OMEGA/Mars Express hyperspectral imager identified gypsum at several sites on Mars in 2005. These minerals constitute a direct record of past aqueous activity and are important with regard to the search of extraterrestrial life. Gale Crater was chosen as Mars Science Laboratory Curiosity's landing site because it is rich in gypsum, as are some desert soils of the Cuatro Cienegas Basin (CCB) (Chihuahuan Desert, Mexico). The gypsum of the CCB, which is overlain by minimal carbonate deposits, was the product of magmatic activity that occurred under the Tethys Sea. To examine this Mars analogue, we retrieved gypsum-rich soil samples from two contrasting sites with different humidity in the CCB. To characterize the site, we obtained nutrient data and analyzed the genes related to the N cycle (nifH, nirS, and nirK) and the bacterial community composition by using 16S rRNA clone libraries. As expected, the soil content for almost all measured forms of carbon, nitrogen, and phosphorus were higher at the more humid site than at the drier site. What was unexpected is the presence of a rich and divergent community at both sites, with higher taxonomic diversity at the humid site and almost no taxonomic overlap. Our results suggest that the gypsum-rich soils of the CCB host a unique microbial ecosystem that includes novel microbial assemblies. PMID- 22920523 TI - Anaortic coronary bypass surgery. AB - Review of the benefits and techniques for anaortic coronary bypass surgery. PMID- 22920522 TI - What is the optimal interval between chemoradiation and esophagectomy? AB - Locally advanced esophageal cancer requires multimodality therapy-most commonly induction chemoradiation followed by esophagectomy. There is a paucity of literature on the optimal time interval between induction treatment and resection. Patient readiness and healthy tissue, as well as tumor responses to radiation, are factors to consider. Two recent retrospective large-center studies on this topic are reviewed. PMID- 22920524 TI - Lung cancer resection volume: is procedure volume really an indicator of quality? AB - The majority of lung cancer resection studies indicate that hospital and surgeon procedure volume are inversely associated with mortality. It makes intuitive sense that performing large numbers of these procedures leads to better outcomes. However, controversy exists regarding the strength and validity of this volume outcome association. Because thresholds of procedure volume are used to recommend the regionalization of care, investigation of the volume-outcome relationship is imperative. This review will examine the methodology used in the volume-outcome relationship literature and highlight important areas of concern. Careful examination of the literature demonstrates that lung cancer resection volume is not strongly associated with mortality and should not be used as a proxy measure for quality. PMID- 22920525 TI - Specialty matters in the treatment of lung cancer. AB - The effect of surgeon volume, hospital volume, and surgeon specialty on operative outcomes has been reported in numerous studies. Short-term and long-term outcome comparisons for pulmonary resection for lung cancer have been performed between general surgeons (GS), cardiothoracic surgeons (CTS), and general thoracic surgeons (TS), using large administrative and inpatient databases. In the United States, general surgeons perform more pulmonary resection than thoracic surgeons. Studies have found that in cases involving thoracic surgeons, there is a lower operative mortality and morbidity, improved long-term survival, better adherence to established practice standards, and a lower cost compared with cases involving general surgeons. Some specific processes of care that account for these improved economic, operative, and oncological outcomes have been identified. Others are not yet specifically known and associated with specialization in thoracic surgery. PMID- 22920526 TI - Awake thoracic surgery--is it worth the trouble? AB - Awake thoracic surgery is performed by regional anesthesia techniques in spontaneously breathing, fully conscious patients to avoid side-effects of general anesthesia, fasten recovery, and reduce morbidity, particularly in high risk patients. Results of ongoing experience are promising, and this novel surgical approach has been successfully applied to several thoracoscopic procedures, including management of pleural effusion, wedge resections, lung volume reduction surgery, bullectomy, and thymectomy. In this article, the historical background, main pathophysiology features of the surgical pneumothorax, and the various regional anesthesia techniques as well as reported results are reviewed and critically discussed. PMID- 22920527 TI - Unilateral extended thoracoscopic thymectomy for nontumoral myasthenia gravis--a new standard. AB - Myasthenia gravis (MG) is a heterogeneous disorder with a fluctuating, clinical, pathologic, and immunobiological picture. Today, it is believed that effective treatment of MG must include both immunosuppression and surgery. Thymectomy is recommended by neurologists for patients with nontumoral MG as an option to increase the probability of remission or improvement. Currently, thoracoscopic thymectomy is considered a good alternative to the standard open approach because of its higher rate of acceptance, low morbidity, and high efficacy, as measured by complete stable remission rates. We present a review of the experience of unilateral extended thoracoscopic thymectomy for nontumoral MG, a technique that could became a new standard in the complex management of MG treatment. PMID- 22920528 TI - Cerebral protection for aortic arch surgery: mild hypothermia with selective cerebral perfusion. AB - Historically, reconstruction of the aortic arch has been exclusively performed during deep hypothermic circulatory arrest. Antegrade cerebral perfusion (ACP) has been popularized, offering a more physiologic method of perfusion and extending the safe limits for arch repair. Initially, deep hypothermia has been used as an adjunct to ACP almost universally. More recently, the absolute necessity for deep hypothermia during aortic surgery once ACP with flow rates and pressures within the physiologic range is provided has been questioned from our institution, as well as others. To our best knowledge we have been one of the pioneering centers to start such an aggressive temperature management in aortic arch surgery back in 2000. To date 426 patients underwent aortic arch replacement in our unit employing the standardized surgical protocol described herein. PMID- 22920529 TI - Cerebral protection for aortic arch surgery: deep hypothermia. AB - The technical aspects of arch surgery have evolved considerably during the last 2 decades. The use of deep hypothermic circulatory arrest has been embraced by many cardiac surgeons to approach aortic arch aneurysms around the world. The branched graft technique that we have been using since the late 1990s has improved surgical outcomes and simplified the treatment considerably. We describe our technique of total arch replacement by using deep hypothermia and selective cerebral perfusion in aortic arch surgery. PMID- 22920530 TI - Thoracoscopic mediastinal lymph node dissection for lung cancer. AB - Mediastinal lymph node staging is an important component of the assessment and management of patients with operable non-small cell lung cancer and is necessary to achieve complete resection. During minimally invasive surgery, performance of an equivalent oncologic resection, including adequate lymph node dissection similar in extent to open thoracotomy, is absolutely necessary. We describe our techniques for video-assisted thoracic surgery (VATS) and Robot-assisted VATS (R VATS) mediastinal lymph node dissection when performing thoracoscopic lobectomy for lung cancer. Between 2008 and 2011, 200 consecutive patients who underwent VATS or R-VATS lobectomies for early stage lung cancer were analyzed. In our series, we removed about 25 lymph nodes per case in both complete VATS and R VATS. A thorough lymph node dissection in lung cancer is possible with either VATS or R-VATS technique without oncological compromise. PMID- 22920531 TI - Implantation of total artificial heart in congenital heart disease. PMID- 22920532 TI - Minimally invasive approach for mitral valve repair in a patient with prior pentalogy of Fallot repair. PMID- 22920533 TI - The variability and complexity of ameloblastoma: carcinoma ex ameloblastoma or primary ameloblastic carcinoma. AB - Ameloblastoma is characterized by slow-growing, local invasiveness and high incidence of local recurrence. It usually presents with a benign histological appearance. However, ameloblastoma occasionally demonstrates a clinical course that is characteristic of malignant transformation. Here, we present a case of ameloblastoma with an aggressive clinical course, including multiple recurrences, a short disease-free interval, pulmonary metastasis and extensive skull-base infiltration. With a careful re-evaluation of the histology and cytology of the specimens of primary and recurrent ameloblastoma in 2006 and 2007, malignant transformation was observed and carcinoma ex ameloblastoma was ultimately diagnosed. PMID- 22920534 TI - An amputation resets positional information to a proximal identity in the regenerating zebrafish caudal fin. AB - BACKGROUND: Zebrafish has emerged as a powerful model organism to study the process of regeneration. This teleost fish has the ability to regenerate various tissues and organs like the heart, spinal cord, retina and fins. In this study, we took advantage of the existence of an excellent morphological reference in the zebrafish caudal fin, the bony ray bifurcations, as a model to study positional information upon amputation. We investigated the existence of positional information for bifurcation formation by performing repeated amputations at different proximal-distal places along the fin. RESULTS: We show that, while amputations performed at a long distance from the bifurcation do not change its final proximal-distal position in the regenerated fin, consecutive amputations done at 1 segment proximal to the bifurcation (near the bifurcation) induce a positional reset and progressively shift its position distally. Furthermore, we investigated the potential role of Shh and Fgf signalling pathways in the determination of the bifurcation position and observed that they do not seem to be involved in this process. CONCLUSIONS: Our results reveal that, an amputation near the bifurcation inhibits the formation of the regenerated bifurcation in the pre-amputation position, inducing a distalization of this structure. This shows that the positional memory for bony ray bifurcations depends on the proximal distal level of the amputation. PMID- 22920535 TI - Direct association of Mu-opioid and NMDA glutamate receptors supports their cross regulation: molecular implications for opioid tolerance. AB - In the nervous system, the interaction of opioids like morphine and its derivatives, with the G protein-coupled Mu-opioid receptor (MOR) provokes the development of analgesic tolerance, as well as physical dependence. Tolerance implies that increasing doses of the drug are required to achieve the same effect, a phenomenon that contributes significantly to the social problems surrounding recreational opioid abuse. In recent years, our understanding of the mechanisms that control MOR function in the nervous system, and that eventually produce opioid tolerance, has increased greatly. Pharmacological studies have identified a number of signaling proteins involved in morphine-induced tolerance, including the N-methyl-D-aspartate acid glutamate receptor (NMDAR), nitric oxide synthase (NOS), protein kinase C (PKC), protein kinase A (PKA), calcium (Ca2+)/calmodulin (CaM)-dependent kinase II (CaMKII), delta-opioid receptor (DOR) and the regulators of G-protein signaling (RGS) proteins. There is general agreement on the critical role of the NMDAR/nNOS/CaMKII pathway in this process, which is supported by the recent demonstration of a physical association between MORs and NMDARs in post-synaptic structures. Indeed, it is feasible that treatments that diminish morphine tolerance may target distinct elements within the same regulatory MOR-NMDAR pathway. Accordingly, we propose a model that incorporates the most relevant signaling components implicated in opioid tolerance in which, certain signals originating from the activated MOR are perceived by the associated NMDAR, which in turn exerts a negative feedback effect on MOR signaling. MOR- and NMDAR-mediated signals work together in a sequential and interconnected manner to ultimately induce MOR desensitization. Future studies of these phenomena should focus on adding further components to this signaling pathway in order to better define the mechanism underlying MOR desensitization in neural cells. PMID- 22920536 TI - Cation clock permits distinction between the mechanisms of alpha- and beta-O- and beta-C-glycosylation in the mannopyranose series: evidence for the existence of a mannopyranosyl oxocarbenium ion. AB - The use of a cationic cyclization reaction as a probe of the glycosylation mechanism has been developed and applied to the 4,6-O-benzylidene-protected mannopyranoside system. Cyclization results in the formation of both cis- and trans-fused tricyclic systems, invoking an intermediate glycosyl oxocarbenium ion reacting through a boat conformation. Competition reactions with isopropanol and trimethyl(methallyl)silane are interpreted as indicating that beta-O mannosylation proceeds via an associative S(N)2-like mechanism, whereas alpha-O mannosylation and beta-C-mannosylation are dissociative and S(N)1-like. Relative rate constants for reactions going via a common intermediate can be estimated. PMID- 22920537 TI - Stream invertebrate communities of Mongolia: current structure and expected changes due to climate change. AB - BACKGROUND: Mongolia's riverine landscape is divided into three watersheds, differing in extent of permafrost, amount of precipitation and in hydrological connectivity between sub-drainages. In order to assess the vulnerability of macroinvertebrate communities to ongoing climate change, we consider the taxonomic and functional structures of stream communities in two major watersheds: The Central Asian Internal Watershed (CAIW) and the Arctic Ocean Watershed (AOW), together covering 86.1% of Mongolia's surface area. We assess the consequences of the hydrological connectivity between sub-drainages on the nestedness and distinctness of the stream communities. And accordingly, we discuss the expected biotic changes to occur in each watershed as a consequence of climate change. RESULTS: Gamma and beta diversities were higher in the CAIW than the AOW. High community nestedness was also found in the CAIW along with a higher heterogeneity of macroinvertebrate assemblage structure. Assemblages characteristic of cold headwater streams in the CAIW, were typical of the drainages of the Altai Mountain range. Macroinvertebrate guilds of the CAIW streams exhibited traits reflecting a high stability and low resilience capacity for eutrophication. In contrast, the community of the AOW had lower nestedness and a combination of traits reflecting higher stability and a better resilience capacity to disturbances. CONCLUSION: Higher distinctness of stream communities is due to lower connectivity between the drainages. This was the case of the stream macroinvertebrate communities of the two major Mongolian watersheds, where connectivity of streams between sub-drainages is an important element structuring their communities. Considering differences in the communities' guild structure, hydrological connectivity and different magnitudes of upcoming impacts of climate change between the two watersheds, respective stream communities will be affected differently. The hitherto different communities will witness an increasing differentiation and divergent adaptations for the upcoming changes. Accordingly, in an increasing awareness to protect Mongolia's nature, our results encourage adapting conservation planning and management strategies specifically by watershed. PMID- 22920539 TI - Clinical relevance of tests on bond strength, microleakage and marginal adaptation. AB - Dental adhesive systems should provide a variety of capabilities, such as bonding of artificial materials to dentin and enamel, sealing of dentinal tubules, reduction of post-operative sensitivity and marginal sealing to reduce marginal staining and caries. In the laboratory, numerous surrogate parameters that should predict the performance of different materials, material combinations and operative techniques are assessed. These surrogate parameters include bond strength tests of various kinds, evaluation of microleakage with tracer penetration between restorative and tooth, two-dimensional analysis of marginal quality with microscopes and mapping of the micromorphology of the bonding interface. Many of these tests are not systematically validated and show therefore different results between different research institutes. The correlation with clinical phenomena has only partly been established to date. There is some evidence, that macrotensile and microtensile bond strength tests correlate better with clinical retention of cervical restorations than macroshear and microshear bond tests but only if data from different test institutes are pooled. Also there is some evidence that marginal adaptation has a moderate correlation in cervical restorations with clinical retention and in Class II restorations (proximal enamel) with clinical marginal staining. There is moderate evidence that microleakage tests with dye penetration does not correlate with any of the clinical parameters (post-operative hypersensitivity, retention, marginal staining). A rationale which helps the researcher to select and apply clinically relevant test methods in the laboratory is presented in the paper. PMID- 22920538 TI - Influences of implant neck design and implant-abutment joint type on peri-implant bone stress and abutment micromovement: three-dimensional finite element analysis. AB - OBJECTIVES: Occlusal overloading is one of the causes of peri-implant bone resorption, and many studies on stress distribution in the peri-implant bone by three-dimensional finite element analysis (3D FEA) have been performed. However, the FEA models previously reported were simplified and far from representing what occurs in clinical situations. In this study, 3D FEA was conducted with simulation of the complex structure of dental implants, and the influences of neck design and connections with an abutment on peri-implant bone stress and abutment micromovement were investigated. METHODS: Three types of two-piece implant CAD models were designed: external joint with a conical tapered neck (EJ), internal joint with a straight neck (IJ), and conical joint with a reverse conical neck (CJ). 3D FEA was performed with the setting of a "contact" condition at the component interface, and stress distribution in the peri-implant bone and abutment micromovement were analyzed. RESULTS: The shear stress was concentrated on the mesiodistal side of the cortical bone for EJ. EJ had the largest amount of abutment micromovement. While the von Mises and shear stresses around the implant neck were concentrated on the labial bone for IJ, they were distributed on the mesiodistal side of the cortical bone for CJ. CJ had the least amount of abutment micromovement. SIGNIFICANCE: Implants with a conical joint with an abutment and reverse conical neck design may effectively control occlusal overloading on the labial bone and abutment micromovement. PMID- 22920540 TI - Bioflotation of sulfide minerals with Acidithiobacillus ferrooxidans in relation to copper activation and surface oxidation. AB - Surface oxidation of sulfides and copper (Cu) activation are 2 of the main processes that determine the efficiency of flotation. The present study was developed with the intention to ascertain the role of the phenomena in the biomodification of sulfides by Acidithiobacillus ferrooxidans culture (cells and growth media) and their impact in bioflotation. Surface characteristics of chalcopyrite, sphalerite, and pyrrhotite, alone and in mixtures, after interaction with A. ferrooxidans were evaluated. Chalcopyrite floatability was increased substantially by biomodification, while bacteria depressed pyrrhotite floatability, favoring separation. The results showed that elemental sulfur concentration increased because of the oxidation generated by bacterial cells, the effect is intensified by the Fe(III) left in the culture and by galvanic contact. Acidithiobacillus ferrooxidans culture affects the Cu activation of sphalerite. The implications of elemental sulfur concentration and Cu activation of sphalerite are key factors that must be considered for the future development of sulfide bioflotation processes, since the depressive effect of cells could be counteracted by elemental sulfur generation. PMID- 22920541 TI - Precipitating and relieving factors of migraine versus tension type headache. AB - BACKGROUND: To determine the differences of precipitating and relieving factors between migraine and tension type headache. METHODS: This is a cross sectional study. We retrospectively reviewed the records of 250 migraine patients and 250 patients diagnosed as tension type headache from the specialized headache clinic in Dept. of Neurology, Dhaka Medical College Hospital. Data were collected through a predesigned questionnaire containing information on age, sex, social status and a predetermined list of precipitating and relieving factors. RESULTS: In this study, the female patients predominated (67%). Most of the patients were within 21-30 years age group (58.6%). About 58% of them belonged to middle class families. The common precipitating factors like stress, anxiety, activity, journey, reading, cold and warm were well distributed among both the migraine and tension type headache (TTH) patients. But significant difference was demonstrated for fatigue (p < 0.05), sleep deprivation (p < 0.05), sunlight (p < 0.01) and food (p < 0.05), which were common among migraineurs. In consideration of relieving factors of pain, different maneuvers were commonly tried by migraineurs and significant difference were observed for both analgesic drug and massage (p < 0.05), which relieved migraine headache. But maneuvers like sleep, rest and posture were used by both groups. CONCLUSION: The most frequent precipitating factors for headache appear to be identical for both migraine and TTH patients. Even though some factors like fatigue, sleep deprivation, sunlight and food significantly precipitate migraine and drug, massage are effective maneuver for relieving pain among migrianeurs. PMID- 22920542 TI - Trapping of p-coumaryl and coniferyl alcohol during soda-anthraquinone treatment: a means of estimating uncondensed beta-O-4 structures in native lignin. AB - In most native lignins, at least 50% of the phenylpropane (C(9)) units are involved in beta-O-4 linkages. It was recently observed that ethylguaiacol (EG) was efficient at trapping coniferyl alcohol generated from the cleavage of uncondensed beta-O-4 dimeric structures during soda-anthraquinone (AQ) or SAQ delignification of sugar maple wood meal. Some of the coniferyl alcohol was transformed to vinylguaiacol and isoeugenol, and the alpha-carbon atom in all three monomers formed C-C bonds with the C-5 position of EG. In the present research, eucalyptus and sugar cane bagasse meals were also investigated, and the yields of uncondensed beta-O-4 structures in the nonsyringyl fraction were quantitated. The estimates of the uncondensed fraction of the lignin in the three samples (assuming S units are 90-95% uncondensed) were in close agreement with results from traditional but more tedious methods such as permanganate oxidation or spectroscopic methods requiring a sample representative of native lignin. PMID- 22920543 TI - New method for quantifying and correcting underestimated cardiac Doppler blood flow velocities: in vitro and in vivo studies. AB - This study was aimed to quantify the underestimation of cardiac Doppler measurements and to explore a method for correction. A dual pulse wave (PW)/Doppler tissue imaging (DTI) mode echocardiographic technique was used in the in vitro and in vivo studies. In the in vitro experiment, we have demonstrated how cardiac valvular motion might interfere with blood velocity estimation using conventional Doppler. When examining the participants, we observed that adding valvular annulus velocity to determine the relative velocity between blood and valvular annulus would result in an increment of 9.3 +/- 1.3 cm/s and 6.3 +/- 0.9 cm/s for aortic and pulmonary blood flow, 12.8 +/- 1.9 cm/s and 8.9 +/- 1.4 cm/s for mitral E and A wave, 12.9 +/- 1.8 cm/s and 10.2 +/- 2.4 cm/s for tricuspid E and A wave. The underestimations of the Doppler measurements markedly influence the hemodynamic parameters commonly used in the clinical practices and researches. This study provides a quantitative method for the correction and would make the Doppler measurement accurate. PMID- 22920544 TI - Intracellular growth of nanoscale perfluorocarbon droplets for enhanced ultrasound-induced phase-change conversion. AB - Perfluorocarbon (PFC) nanodroplets (NDs) have been proposed as phase-change contrast agents for ultrasound imaging. Since the ultrasound energy required to convert PFC droplets to microbubbles is inversely related to size, the conversion of PFC NDs at clinically-relevant pressures is challenging. We propose that if PFC NDs can accumulate in a close-packed configuration and grow in size in situ, phase-change conversion can occur at lower ultrasound pressures compared with isolated NDs. In this article, we show that PFC NDs can be designed to grow in size after loading in cells, from 0.26 +/- 0.09 MUm to 1.7 +/- 0.6 MUm after 2 h. This growth allowed for a substantial decrease in the ultrasound conversion threshold (to 1.4 MPa and 4.8 MPa at 1 MHz and 18 MHz, respectively), whereas non coalesced NDs in cells and NDs alone were not converted up to the maximum applied pressure (2.1 MPa and 6.3 MPa at 1 MHz and 18 MHz, respectively). These results indicate that PFC NDs with conversion pressures too high for diagnostically feasible conversion can be used as phase-change agents if they can be induced to grow in size in situ. PMID- 22920545 TI - Is a visible (hypoechoic) lesion at biopsy an independent predictor of prostate cancer outcome? AB - The aim of this study was to evaluate the prognostic implications of the sonographic appearance of prostate cancers. All patients with biopsy-proven prostate cancer between January 2003 and July 2004 (and at least 5 years of follow-up) were selected retrospectively. After exclusions, 101 patients constituted our study population and were divided into isoechoic (or nonvisible) and hypoechoic (or visible) lesion. The clinical outcomes of these two groups were compared. The outcomes for the two groups were significantly different (p < 0.01). For nonvisible lesions, 37 of the 41 patients (90.2%) had no disease relapse and 2 (4.9%) had biochemical failure. For the visible lesions, 37 of the 60 (61.6%) patients were free of recurrence, 7 (11.7%) had systemic metastases and 10 (16.7%) died of complications related to prostate cancer. Our data show that patients with nonvisible prostate cancer had significantly better outcomes than patients with visible lesions during a five-year period of evaluation. PMID- 22920547 TI - Statistical analysis of high frequency ultrasonic backscattered signals from basal cell carcinomas. AB - A statistical approach was implemented in the study of histologic characteristics from ex vivo basal cell carcinomas, based on the properties of backscattered acoustic waves, for the purpose of evaluating the method as a diagnostic tool. The study was developed using an ultrasound biomicroscope working at a frequency of 45 MHz. The parameters examined were signal-to-noise ratio (SNR), and shape parameters from the Weibull (b(W)) and generalized gamma (c(GG) and upsilon(GG)) probability density functions. Twenty-seven carcinomatous skin samples were obtained from volunteer patients and classified into two groups (BCC1 and BCC2) based on the distribution patterns of their tumor nests; also, seven non-tumoral samples were used for comparative purposes. Significant differences between groups were obtained for all studied parameters. The successful differentiation between some tissue groups suggests its potential use for carcinoma characterization. PMID- 22920546 TI - Integrin-mediated mechanotransduction pathway of low-intensity continuous ultrasound in human chondrocytes. AB - Chondrocytes are mechanosensitive cells that require mechanical stimulation for proper growth and function in in vitro culture systems. Ultrasound (US) has emerged as a technique to deliver mechanical stress; however, the intracellular signaling components of the mechanotransduction pathways that transmit the extracellular mechanical stimulus to gene regulatory mechanisms are not fully defined. We evaluated a possible integrin/mitogen-activated protein kinase (MAPK) mechanotransduction pathway using Western blotting with antibodies targeting specific phosphorylation sites on intracellular signaling proteins. US stimulation of chondrocytes induced phosphorylation of focal adhesion kinase (FAK), Src, p130 Crk-associated substrate (p130Cas), CrkII and extracellular regulated kinase (Erk). Furthermore, pre-incubation with inhibitors of integrin receptors, Src and MAPK/Erk kinase (MEK) reduced US-induced Erk phosphorylation levels, indicating integrins and Src are upstream of Erk in an US-mediated mechanotransduction pathway. These findings suggest US signals through integrin receptors to the MAPK/Erk pathway via a mechanotransduction pathway involving FAK, Src, p130Cas and CrkII. PMID- 22920548 TI - Ultrasound findings of papillary thyroid microcarcinoma: a review of 113 consecutive cases with histopathologic correlation. AB - Papillary thyroid microcarcinoma (PTMC) is a malignant thyroid tumor of less than 1 cm in size. Ultrasound (US) is the preferred imaging modality for PTMC. This study retrospectively evaluated the US results from 113 consecutive cases of PTMC with 127 nodules and correlated the results with the histopathologic findings. The results showed none of the PTMC nodules had a cystic element. Half of the PTMC nodules had a well-defined boundary and the remaining half had an ill defined boundary. A percent (6.3%) of the nodules had a halo sign. Microcalcification was present in approximately half of the PTMC nodules. The cancerous tissue with a papillary structure was hypoechogenic and the amount of fibrous stroma determined whether the nodule echogenicity was heterogeneous or homogeneous. Heterogeneous echogenicity was associated with a fibrous stroma proportion of >20%. Only PTMC nodules with predominantly follicular structures containing a large proportion of colloid demonstrated isoechogenicity. Well defined boundaries on US were associated with well-defined histologic margins, with or without the presence of an intact fibrous pseudo-capsule. A halo sign with a well-defined boundary detected by US was associated with the presence of an intact fibrous pseudo-capsule. Half of the PTMC nodules with ill-defined boundaries exhibited infiltration into the surrounding thyroid tissue, while the remaining half of the PTMC nodules with ill-defined boundaries on US presented irregular nodule margins by histology, rather than nodule infiltration. Psammoma bodies detected at a frequency >=5 per *200 microscopic field of view were detectable on US as microcalcifications. PMID- 22920549 TI - Longitudinal displacement of the carotid wall and cardiovascular risk factors: associations with aging, adiposity, blood pressure and periodontal disease independent of cross-sectional distensibility and intima-media thickness. AB - The recently discovered longitudinal displacement of the common carotid arterial wall (i.e., the motion along the same plane as the blood flow), may be associated with incident cardiovascular events and represents a novel and relevant clinical information. At present, there have only been a few studies that have been conducted to investigate this longitudinal movement. We propose here a method to assess noninvasively the wall bi-dimensional (two-dimensional [2-D], cross sectional and longitudinal) motion and present an original approach that combines a robust speckle tracking scheme to guidance by minimal path contours segmentation. Our method is well suited to large clinical population studies as it does not necessitate strong imaging prerequisites. The aim of this study is to describe the association between the longitudinal displacement of the carotid arterial wall and cardiovascular risk factors, among which periodontal disease. Some 126 Indigenous Australians with periodontal disease, an emerging risk factor, and 27 healthy age- and sex-matched non-indigenous control subjects had high-resolution ultrasound scans of the common carotid artery. Carotid intima media thickness and arterial wall 2-D motion were then assessed using our method in ultrasound B-mode sequences. Carotid longitudinal displacement was markedly lower in the periodontal disease group than the control group (geometric mean (IQR): 0.15 mm (0.13) vs. 0.42 mm (0.30), respectively; p < 0.0001), independent of cardiovascular risk factors, cross-sectional distensibility and carotid intima media thickness (p < 0.0001). A multivariable model indicated that the strongest correlates of carotid longitudinal displacement in adults with periodontal disease were age (beta-coefficient = -.235, p = .03), waist (beta-coefficient = .357, p = 0.001), and pulse pressure (beta-coefficient = .175, p = 0.07), independent of other cardiovascular risk factors, cross-sectional distensibility and pulse wave velocity. Carotid longitudinal displacement, estimated with our approach, is impaired in the periodontal disease group, independent of established cardiovascular risk factors and other noninvasive measures of arterial stiffness, and may represent an important marker of cardiovascular risk. PMID- 22920551 TI - Low-intensity pulsed ultrasound inhibits messenger RNA expression of matrix metalloproteinase-13 induced by interleukin-1beta in chondrocytes in an intensity dependent manner. AB - The effect of low-intensity pulsed ultrasound (LIPUS) on articular cartilage metabolism has been characterized. However, the effect of LIPUS intensity on articular cartilage degradation factors remains unknown. This study aimed to investigate the immediate effect of LIPUS at several intensities on cultured chondrocytes treated with interleukin-1beta (IL-1beta) to induce an inflammatory response and on articular cartilage explants. Cultured chondrocytes and articular cartilage explants were treated by LIPUS at intensities of 0, 7.5, 30 and 120 mW/cm(2) or 0, 27 and 67 mW/cm(2), respectively. mRNA analysis revealed that LIPUS inhibited induction of MMP13 mRNA expression by 100 pg/mL IL-1beta in cultured chondrocytes in an intensity-dependent manner. LIPUS also inhibited MMP13 and MMP1 mRNA expression in articular cartilage explants. Our results indicate that LIPUS may potentially protect articular cartilage by inhibiting MMP mRNA expression in an intensity-dependent manner and should thus be considered a useful candidate for daily treatment of OA. PMID- 22920552 TI - Clinical application of extracorporeal shock wave therapy in orthopedics: focused versus unfocused shock waves. AB - For the past decade extracorporeal shock wave therapy has been applied to a wide range of musculoskeletal disorders. The many promising results and the introduction of shock wave generators that are less expensive and easier to handle has added to the growing interest. Based on their nature of propagation, shock waves can be divided into two types: focused and unfocused. Although several physical differences between these different types of shock waves have been described, very little is known about the clinical outcome using these different modalities. The aim of the present review is to investigate differences in outcome in select orthopaedic applications using focused and unfocused shock waves. PMID- 22920550 TI - Investigating the efficacy of subharmonic aided pressure estimation for portal vein pressures and portal hypertension monitoring. AB - The efficacy of using subharmonic emissions from Sonazoid microbubbles (GE Healthcare, Oslo, Norway) to track portal vein pressures and pressure changes was investigated in 14 canines using either slow- or high-flow models of portal hypertension (PH). A modified Logiq 9 scanner (GE Healthcare, Milwaukee, WI, USA) operating in subharmonic mode (f(transmit): 2.5 MHz, f(receive): 1.25 MHz) was used to collect radiofrequency data at 10-40% incident acoustic power levels with 2-4 transmit cycles (in triplicate) before and after inducing PH. A pressure catheter (Millar Instruments, Inc., Houston, TX, USA) provided reference portal vein pressures. At optimum insonification, subharmonic signal amplitude changes correlated with portal vein pressure changes; r ranged from -0.82 to -0.94 and from -0.70 to -0.73 for PH models considered separately or together, respectively. The subharmonic signal amplitudes correlated with absolute portal vein pressures (r: -0.71 to -0.79). Statistically significant differences between subharmonic amplitudes, before and after inducing PH, were noted (p <= 0.01). Portal vein pressures estimated using subharmonic aided pressure estimation did not reveal significant differences (p > 0.05) with respect to the pressures obtained using the Millar pressure catheter. Subharmonic-aided pressure estimation may be useful clinically for portal vein pressure monitoring. PMID- 22920553 TI - Active site-inactivated factor VIIa inhibits nuclear factor kappa B activation in intestinal ischemia and reperfusion. AB - BACKGROUND: Intestinal ischemia and reperfusion (I/R) injury is a pivotal mechanism in critical illness and in the development of multiple organ dysfunction syndrome, in which the nuclear factor kappa B (NF-kappaB) activation plays a central role. Intestinal I/R injury initiates the extrinsic tissue factor or factor VIIa-dependent pathway of coagulation, also of importance in multiple organ dysfunction syndrome. Our aim was to analyze NF-kappaB activation in I/R injury in the rat intestine and in two main "shock" organs, that is, the liver and lungs. Pretreatment with active site-inactivated factor VII (FVIIai), an inhibitor of the extrinsic pathway, was evaluated. MATERIALS AND METHODS: NF kappaB activation was analyzed using enzyme-linked immunosorbent assay (ELISA) and electrophoretic mobility shift assay (EMSA) studies of nuclear extracts from the intestine, liver, and lungs in rats subjected to intestinal I/R injury. FVIIai was given 90 min before the induction of intestinal ischemia. RESULTS: I/R induced NF-kappaB p65 activation in all three organs, especially in the liver. Pretreatment with FVIIai counteracted NF-kappaB activation in all three tissues studied. A commercially available ELISA for (human) NF-kappaB p65 and EMSA gave parallel results. CONCLUSIONS: I/R injury in the rat intestine induces a pronounced activation of NF-kappaB p50 or p65 in the small intestine and in the liver and lungs. The NF-kappaB activation is especially pronounced in the liver and plays a central role in the regulation of transcription of cytokines, adhesion molecules, and chemokines. ELISA for (human) NF-kappaB p65 and "gold standard" EMSA gave parallel results. Pretreatment with FVIIai completely counteracted NF-kappaB activation in the intestine and liver, although not in the lungs. PMID- 22920554 TI - Novel evidence demonstrates that epithelial-mesenchymal transition contributes to nephrolithiasis-induced renal fibrosis. AB - PURPOSE: To investigate fibrotic lesions in renal tissues obtained from patients with large calculi, and to selectively evaluate the expression and clinical significance of Twist and E-cadherin in nephrolithiasis patients. METHODS: We recruited 50 patients with kidney stone and 32 matched healthy controls. We determined plasma creatinine (Cr) and corrected Cr clearance (CCr). For the 50 patients, we detected daily urine protein excretion. At the end of percutaneous nephroscopic lithotomy, we performed puncture biopsy to acquire kidney tissue. We obtained normal control kidney tissues from non-nephrolithiasis patients who received a surgical biopsy during open surgery. We determined the expression of Twist and E-cadherin by immunohistochemical staining and scored it with clinical parameters. In addition, we analyzed the degree of expression of Twist and its correlation with long-term renal survival. RESULTS: Overall, the renal function of patients significantly decreased, as indicated by Cr and reduced CCr compared with healthy controls. Activated Twist was strongly expressed in tubular epithelial cells from kidneys of nephrolithiasis patients, whereas we found little positive staining of Twist in normal kidneys. Meanwhile, the expression of E-cadherin was significantly suppressed in kidneys of nephrolithiasis patients. Twist expression was inversely correlated with E-cadherin expression; using multivariate analysis, data showed that the factors influencing renal survival in patients were CCr (relative ratio, 4.39; 95% confidence interval, 1.34-14.38; P = 0.013) and the extent of Twist expression (relative ratio, 3.45; 95% confidence interval, 1.10-10.68; P = 0.033). CONCLUSIONS: Our data suggest that the possible novel EMT marker molecule Twist and Twist staining might be a valuable index predicting renal fibrosis progression in human nephrolithiasis. PMID- 22920555 TI - Genomics and transplantation: a brave new world is (almost) here. PMID- 22920556 TI - Modulation of ovine SBD-1 expression by 17beta-estradiol in ovine oviduct epithelial cells. AB - BACKGROUND: Mucosal epithelia, including those of the oviduct, secrete antimicrobial innate immune molecules (AIIMS). These have bactericidal/bacteriostatic functions against a variety of pathogens. Among the AIIMs, sheep beta-defensin-1 (SBD-1) is one of the most potent. Even though the SBD-1 is an important AIIM and it is regulated closely by estrogenic hormone, the regulation mechanism of 17beta-estradiol has not been clearly established. We investigated the effects of E2 and agonist or inhibitor on ovine oviduct epithelial cells in regard to SBD-1 expression using reverse transcription quantitative PCR (RT-qPCR). In addition, three different pathways were inhibited separately or simultaneously to confirm the effect of different inhibitors in the regulation mechanism. RESULTS: 17beta-estradiol (E2) induced release of SBD-1 in ovine oviduct epithelial cells. SBD-1 expression was mediated through G-protein coupled receptor 30 (GPR30) and Estrogen Receptors (ERs) activation in ovine oviduct epithelial cell. Inhibition of gene expression of protein kinase A (PKA), protein kinase C (PKC), and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappaB) led to a decreased SBD-1 expression. CONCLUSIONS: Taken together, E2-induced up-regulation of SBD-1 expressions were GPR30 dependent during prophase and ERs-dependent during later-stage in ovine oviduct epithelial cells, and we assume that the effect was completed by the PKA, PKC, and NF-kappaB pathways simultaneous. PMID- 22920557 TI - Implementing community participation through legislative reform: a study of the policy framework for community participation in the Western Cape province of South Africa. AB - BACKGROUND: Amidst an evolving post-apartheid policy framework for health, policymakers have sought to institutionalize community participation in Primary Health Care, recognizing participation as integral to realizing South Africa's constitutional commitment to the right to health. With evolving South African legislation supporting community involvement in the health system, early policy developments focused on Community Health Committees (HCs) as the principal institutions of community participation. Formally recognized in the National Health Act of 2003, the National Health Act deferred to provincial governments in establishing the specific roles and functions of HCs. As a result, stakeholders developed a Draft Policy Framework for Community Participation in Health (Draft Policy) to formalize participatory institutions in the Western Cape province. METHODS: With the Draft Policy as a frame of analysis, the researchers conducted documentary policy analysis and semi-structured interviews on the evolution of South African community participation policy. Moving beyond the specific and unique circumstances of the Western Cape, this study analyzes generalizable themes for rights-based community participation in the health system. RESULTS: Framing institutions for the establishment, appointment, and functioning of community participation, the Draft Policy proposed a formal network of communication - from local HCs to the health system. However, this participation structure has struggled to establish itself and function effectively as a result of limitations in community representation, administrative support, capacity building, and policy commitment. Without legislative support for community participation, the enactment of superseding legislation is likely to bring an end to HC structures in the Western Cape. CONCLUSIONS: Attempts to realize community participation have not adequately addressed the underlying factors crucial to promoting effective participation, with policy reforms necessary: to codify clearly defined roles and functions of community representation; to outline how communities engage with government through effective and accountable channels for participation; and to ensure extensive training and capacity building of community representatives. Given the public health importance of structured and effective policies for community participation, and the normative importance of participation in realizing a rights-based approach to health, this analysis informs researchers on the challenges to institutionalizing participation in health systems policy and provides practitioners with a research base to frame future policy reforms. PMID- 22920558 TI - Suppressive composts: microbial ecology links between abiotic environments and healthy plants. AB - Suppressive compost provides an environment in which plant disease development is reduced, even in the presence of a pathogen and a susceptible host. Despite the numerous positive reports, its practical application is still limited. The main reason for this is the lack of reliable prediction and quality control tools for evaluation of the level and specificity of the suppression effect. Plant disease suppression is the direct result of the activity of consortia of antagonistic microorganisms that naturally recolonize the compost during the cooling phase of the process. Thus, it is imperative to increase the level of understanding of compost microbial ecology and population dynamics. This may lead to the development of an ecological theory for complex ecosystems as well as favor the establishment of hypothesis-driven studies. PMID- 22920559 TI - Somatic hybridization in the Uredinales. AB - Rust fungi are cosmopolitan in distribution and parasitize a wide range of plants, including economically important crop species such as wheat. Detailed regional, national, and continental surveys of pathogenic variability in wheat attacking rust pathogens over periods of up to 90 years have shown that in the absence of sexual recombination, genetic diversity is generated by periodic introduction of exotic isolates, single-step mutation, and somatic hybridization. Laboratory studies have provided evidence for somatic hybridization between many rust species and formae speciales, and there is evidence for the process in nature within and between rust species on Linum, poplar, Senecio, wheat, and several grass species. Although the mechanisms involved in somatic hybridization are not well understood, they are thought to involve the fusion of dikaryotic vegetative hyphae, nuclear exchange, and possibly exchange of whole chromosomes between nuclei or parasexuality via the fusion of the two haploid nuclei, followed by mitotic crossing over and vegetative haploidization. In three cases, hybrid isolates rendered resistant plant genotypes susceptible because of new combinations of virulence. Implications for resistance breeding and future prospects in understanding the process are discussed. PMID- 22920560 TI - Mechanisms and evolution of virulence in oomycetes. AB - Many destructive diseases of plants and animals are caused by oomycetes, a group of eukaryotic pathogens important to agricultural, ornamental, and natural ecosystems. Understanding the mechanisms underlying oomycete virulence and the genomic processes by which those mechanisms rapidly evolve is essential to developing effective long-term control measures for oomycete diseases. Several common mechanisms underlying oomycete virulence, including protein toxins and cell-entering effectors, have emerged from comparing oomycetes with different genome characteristics, parasitic lifestyles, and host ranges. Oomycete genomes display a strongly bipartite organization in which conserved housekeeping genes are concentrated in syntenic gene-rich blocks, whereas virulence genes are dispersed into highly dynamic, repeat-rich regions. There is also evidence that key virulence genes have been acquired by horizontal transfer from other eukaryotic and prokaryotic species. PMID- 22920561 TI - Receptor kinase signaling pathways in plant-microbe interactions. AB - Plant receptor-like kinases (RLKs) function in diverse signaling pathways, including the responses to microbial signals in symbiosis and defense. This versatility is achieved with a common overall structure: an extracytoplasmic domain (ectodomain) and an intracellular protein kinase domain involved in downstream signal transduction. Various surfaces of the leucine-rich repeat (LRR) ectodomain superstructure are utilized for interaction with the cognate ligand in both plant and animal receptors. RLKs with lysin-motif (LysM) ectodomains confer recognitional specificity toward N-acetylglucosamine-containing signaling molecules, such as chitin, peptidoglycan (PGN), and rhizobial nodulation factor (NF), that induce immune or symbiotic responses. Signaling downstream of RLKs does not follow a single pattern; instead, the detailed analysis of brassinosteroid (BR) signaling, innate immunity, and symbiosis revealed at least three largely nonoverlapping pathways. In this review, we focus on RLKs involved in plant-microbe interactions and contrast the signaling pathways leading to symbiosis and defense. PMID- 22920563 TI - Synthesis of S-linked glycoconjugates and S-disaccharides by thiol-ene coupling reaction of enoses. AB - Free-radical hydrothiolation of the endocyclic double bond of enoses is reported. Reaction between 2-acetoxy-D-glucal and a range of thiols including amino acid, peptide, glycosyl thiols, and sugars with primary or secondary thiol functions gave S-linked alpha-glucoconjugates and S-disaccharides with full regio- and stereoselectivity. Addition of glycosyl thiols to a 2,3-unsaturated glycoside also proceeded with good selectivity and afforded a series of 3-deoxy-S disaccharides. PMID- 22920562 TI - Probing command following in patients with disorders of consciousness using a brain-computer interface. AB - OBJECTIVE: To determine if brain-computer interfaces (BCIs) could serve as supportive tools for detecting consciousness in patients with disorders of consciousness by detecting response to command and communication. METHODS: We tested a 4-choice auditory oddball EEG-BCI paradigm on 16 healthy subjects and 18 patients in a vegetative state/unresponsive wakefulness syndrome, in a minimally conscious state (MCS), and in locked-in syndrome (LIS). Subjects were exposed to 4 training trials and 10 -12 questions. RESULTS: Thirteen healthy subjects and one LIS patient were able to communicate using the BCI. Four of those did not present with a P3. One MCS patient showed command following with the BCI while no behavioral response could be detected at bedside. All other patients did not show any response to command and could not communicate with the BCI. CONCLUSION: The present study provides evidence that EEG based BCI can detect command following in patients with altered states of consciousness and functional communication in patients with locked-in syndrome. However, BCI approaches have to be simplified to increase sensitivity. SIGNIFICANCE: For some patients without any clinical sign of consciousness, a BCI might bear the potential to employ a "yes-no" spelling device offering the hope of functional interactive communication. PMID- 22920564 TI - Profile of beta-thalassemia and its prenatal diagnosis in Khorasan-e-Jonobi Province, Iran. AB - This study was performed to determine the molecular spectrum of beta-thalassemia (beta-thal) mutations in at-risk couples from Khorasan-e-Jonobi Province in East Iran. During the past 9 years, 106 couples were referred to our Center for detection of their beta-thal carrier status. Samples were initially tested for the most common Iranian alpha- and beta-thal mutations by gap-polymerase chain reaction (gap-PCR) and amplification refractory mutation system (ARMS)-PCR, respectively. In cases with negative results, direct DNA sequencing was used to identify additional beta-globin mutations. Fetal DNA was obtained from chorionic villus sampling (CVS) (n = 55), 47.2% were referred during pregnancy and 23.0% of couples underwent more than one prenatal diagnosis (PND). Of the 14 mutations that were detected in Khorasan-e-Jonobi Province, Iran, the IVS-I-5 (G>C) and codon 44 (-C) mutations were the most frequently identified variants, representing 45.9 and 24.8% of the total; these were followed by three mutations in the following order: -88 (C >T) (5.3%); codons 8/9 (+G), a rare mutation, and codons 37/38/39 [-7 nucleotides (nts)], each with a frequency of 4.5%. These findings provide complementary information on the region specific profile of beta thal in eastern Iran. PMID- 22920565 TI - Dual-band perfect absorber for multispectral plasmon-enhanced infrared spectroscopy. AB - Metamaterial-based perfect absorbers utilize intrinsic loss, with the aid of appropriate structural design, to achieve near unity absorption at a certain wavelength. For most of the reported absorbers, the absorption occurs only at a single wavelength where plasmon resonances are excited in the nanostructures. Here we introduce a dual-band perfect absorber based on a gold nanocross structure. Two bands of maximum absorption of 94% are experimentally accomplished by breaking the symmetry of the cross structure. Furthermore, we demonstrate the two bands can be readily tuned throughout the mid-infrared with their associated resonances giving rise to large near-field enhancements. These features are ideal for multiband surface-enhanced infrared spectroscopy applications. We experimentally demonstrate this application by simultaneously detecting two molecular vibrational modes of a 4 nm thick polymer film utilizing our proposed absorber. Furthermore, in response to variations in the interaction strength between the plasmonic and molecular dipoles, we observe an anticrossing behavior and modification in the spectral line shape of the molecular absorption peak, which are characteristic of the coupling between the two modes. PMID- 22920566 TI - A time-dependent density functional theory study of the structure and electronic spectroscopy of the group 7 mixed-metal carbonyls: MnTc(CO)10, MnRe(CO)10, and TcRe(CO)10. AB - A detailed study of the structure, infrared, and electronic spectra of the mixed metal group 7 carbonyls MnTc(CO)(10), MnRe(CO)(10), and TcRe(CO)(10) is presented using density functional theory, and time-dependent density functional theory, with a variety of modern density functionals. Long-range corrected density functionals are needed to accurately model the transitions in such complexes, and through calibration with data for known bimetallic carbonyls, DFT and TD-DFT can be used to predict the behavior of their as yet elusive counterparts. PMID- 22920567 TI - Championing the renal dietitian. PMID- 22920568 TI - Kidney-friendly frozen meal tips and suggestions "in a pinch". PMID- 22920569 TI - Rational design of proteolytically stable, cell-permeable peptide-based selective Mcl-1 inhibitors. AB - Direct chemical modifications provide a simple and effective means to "translate" bioactive helical peptides into potential therapeutics targeting intracellular protein-protein interactions. We previously showed that distance-matching bisaryl cross-linkers can reinforce peptide helices containing two cysteines at the i and i+7 positions and confer cell permeability to the cross-linked peptides. Here we report the first crystal structure of a biphenyl-cross-linked Noxa peptide in complex with its target Mcl-1 at 2.0 A resolution. Guided by this structure, we remodeled the surface of this cross-linked peptide through side-chain substitution and N-methylation and obtained a pair of cross-linked peptides with substantially increased helicity, cell permeability, proteolytic stability, and cell-killing activity in Mcl-1-overexpressing U937 cells. PMID- 22920571 TI - The consequences of enhanced cell-autonomous glucose metabolism. AB - The intake and metabolism of carbohydrates for the generation of energy and biomass is evolutionarily conserved, down to the most primitive of cells. Although a basal rate of glucose metabolism occurs in all cells, the processing rates of glucose can become dramatically enhanced when cells acquire malignant properties, or remain undifferentiated. This article investigates the consequences of how increased glucose metabolism affects cellular physiology by altering the physicochemical properties of the whole metabolic network. As a result, enhanced lactate production in the presence of oxygen (the Warburg effect) is required, and metabolism is consequently reconfigured, through multiple mechanisms, to confer numerous physiological and possibly regulatory properties to cells. PMID- 22920570 TI - Accurate discrimination of bHLH domains in plants, animals, and fungi using biologically meaningful sites. AB - BACKGROUND: The highly conserved bHLH (basic Helix-Loop-Helix) domain, found in many transcription factors, has been well characterized separately in Plants, Animals, and Fungi. While conserved, even functionally constrained sites have varied since the Eukarya split. Our research identifies those slightly variable sites that were highly characteristic of Plants, Animals, or Fungi. RESULTS: Through discriminant analysis, we identified five highly discerning DNA-binding amino acid sites. Additionally, by incorporating Kingdom specific HMMs, we were able to construct a tool to quickly and accurately identify and classify bHLH sequences using these sites. CONCLUSIONS: We conclude that highly discerning sites identified through our analysis were likely under functional constraints specific to each Kingdom. We also demonstrated the utility of our tool by identifying and classifying previously unknown bHLH domains in both characterized genomes and from sequences in a large environmental sample. PMID- 22920572 TI - Photo-cross-linked poly(ethylene carbonate) elastomers: synthesis, in vivo degradation, and determination of in vivo degradation mechanism. AB - Low-molecular-weight poly(ethylene carbonate) diols of varying molecular weight were generated through catalyzed thermal degradation of high-molecular-weight poly(ethylene carbonate). These polymers were then end functionalized with acrylate groups. The resulting alpha,omega-diacrylates were effectively photo cross-linked upon exposure to long-wave UV light in the presence of a photoinitiator to yield rubbery networks of low sol content. The degree of cross linking effectively controlled the in vivo degradation rate of the networks by adherent macrophages; higher cross-link densities yielded slower degradation rates. The cross-link density did not affect the number of adherent macrophages at the elastomer/tissue interface, indicating that cross-linking affected the susceptibility of the elastomer to degradative species released by the macrophages. The reactive species likely responsible for in vivo degradation appears to be superoxide anion, as the in vivo results were in agreement with in vitro degradation via superoxide anion, while cholesterol esterase, known to degrade similar poly(alkylene carbonate)s, had no affect on elastomer degradation. PMID- 22920573 TI - Anatomical, biochemical and physiological considerations of the colon in design and development of novel drug delivery systems. AB - The colon is composed of four distinct layers such as serosa, muscularis externa, sub mucosa and mucosa. There exists a difference in the anatomy, neural and blood supply and absorption characteristics as the length of the colon is traversed. At birth the mucosal surface of the colon is similar to that of the small intestine but rapid changes occur with the loss of the villi leaving flat mucosa with deep crypts. The existence of receptors like muscarinic M3, cholecystokinin1, Eph, Erb B, estrogen (alpha, beta), gastrin releasing peptide, killer Ig like receptor, lymphocyte-endothelial receptor, notch, pregnane X, substance P and peroxisome proliferator-activated gamma receptor can be utilized as a promising approach for targeting. The inner compact firm mucus is impervious to bacteria, making it a defensive barrier for the colossal bacterial load. The mucus thus provides innate immunity to maintain the homeostasis in colon. The physiological properties of the colon such as pH, transit time, luminal pressure of the colon, and the presence of microbial flora localized in the colon are utilized in the drug design. The drug delivery systems exploit enteric coating and biodegradable polymers to reach colon in an intact form by surpassing the barriers in the stomach and small intestine. The presence of azo-reductase, glucuronidase, dextranase, pectinase, glycosidase, polysaccharidase made it feasible to design prodrug and enzyme based drug delivery. Drug designing methodologies in colon specific drug delivery include pH- based systems, enzymedepended systems, timed- release systems and pressure/osmotically release systems. PMID- 22920574 TI - Development of novel gastroretentive floating particulate drug delivery system of gliclazide. AB - The objective of present project was to improve the dissolution profile of gliclazide by developing floating alginate beads using various biodegradable polymers like gelatin, pectin and hydroxypropylmethylcellulose (HPMC). The floating beads were prepared by a simple ionotropic gelatin method using calcium carbonate as gas generating agent. The developed beads were characterized by Fourier transform infrared spectroscopy analysis, differential scanning calorimetry, X-ray diffraction analysis and scanning electron microscopy (SEM). The prepared beads showed good in vitro floatation, which was dependent on the concentration of gas-forming agent. SEM photomicrographs confirmed that the developed beads were spherical in shape and had particle size in the range of 730 to 890 MUm. The incorporation efficiency was found to be in the range of 59.96 to 85.1%. The cumulative percent drug release from the beads after 10 h dissolution study at pH 1.2 and pH 5.8 was in the range of 33 to 46% and 82 to 95% respectively. The concentration of the gas generating agent was found to influence the release rate. The mechanism of drug release was Fickian diffusion with swelling. The in vivo sub-acute hypoglycemic study in high fat diet induced diabetic C57BL/6J mice demonstrated significant (p < 0.05) hypoglycemic effect over a period of 12 h and 24 h, respectively, with HPMC and pectin beads. A significant (p & 0.05) reduction in fasting and non-fasting blood glucose levels, reduction in fasting plasma insulin level and a significant improvement in glucose tolerance were observed in animals treated with formulations. The developed beads were suitable carriers for improving the systemic absorption of gliclazide and maintaining reduced blood glucose levels. PMID- 22920575 TI - Enhancement of hepatoprotective efficacy of propolis by fabrication of liposomes, as a platform nano-formulation for multi-component natural medicine. AB - Lack of suitable formulations often obscures the potential of natural medicine. Moreover, the presence of myriad of constituents with varied physicochemical properties makes fabrication of stable phyto-formulation extremely difficult. Bee propolis is one such material that suffers inadequate clinical application, despite having diverse pharmacological activities, solely attributed to deficit of appropriate formulations. In this study, we have presented a possibility of fabricating liposomes as a platform nano-formulation for enhancement of hepatoprotective activity of propolis. Hepatoprotective efficacy of the propolis is limited by its poor oral absorption. Moreover, the exact composition of the propolis being yet undefined, indeed unconfined, it cannot be administered parenterally. In order to address the foregoing issue, propolis liposomes suitable for oral administration and having higher entrapment efficiency were formulated through a modified ethanol injection method. Effect of phospholipids (PL) and cholesterol (CH) concentration on the formulation characteristics was checked statistically by 3(2) factorial approach. Liposomes were characterized for vesicle diameter (Dv), entrapment efficiency (EE), zeta potential (zeta p), TEM and drug release kinetics. Clinical efficacy of the formulation was assessed using acetaminophen induced hepatotoxicity in rat model. Biochemical parameters such as AST, ALT, ALP and TBARS, as well as histopathological aspects were studied. Stable unilamellar vesicles were formed according to 3(2) factorial approach. Dv, EE and zeta p were ranging between 216 to 437 nm, 79.53 to 93.01% & -27.8 to -31.2 mV, respectively. Marked positive effect of PL and CH and propolis concentrations was seen on Dv as well as EE. Release of propolis in acidic media followed zero order kinetics while in alkaline media it followed 1(st) order kinetics. Formulation was able to suppress AST, ALT, ALP & TBARS levels in hepatotoxicity induced experimental animals and promote tissue healing, in a manner more effective than plain EEP as well as silymarin. In conclusion, suitability of liposomes as a fundamental formulation for enhancing hepatoprotective activity of multi-component propolis was justified. PMID- 22920576 TI - Comprehensive review on oral disintegrating films. AB - Fast-dissolving drug-delivery systems were first developed in the late 1970s as an alternative to tablets, capsules, and syrups for pediatric and geriatric patients who experience difficulties swallowing traditional oral solid dosage forms. In response to this need, a variety of orally disintegrating tablet (ODT) formats were commercialized, which disintegrate within 1 min when placed in the mouth without drinking water or chewing. Oral drug delivery technology has improved from conventional dosage forms to modified release dosage forms to ODT to the recent oral disintegrating films (ODF). Oral disintegrating film or strip that employs a water dissolving polymer which allows the dosage form to quickly hydrate by saliva, adhere to mucosa, and disintegrate within a few seconds, dissolve and releases medication for oromucosal absorption when placed on the tongue or oral cavity. Oral strip technology provides an alternate route for drugs with first pass metabolism. This review give details of materials used in ODF, manufacturing aspects, technologies, evaluation tests and marketed products. PMID- 22920577 TI - In vitro glucocorticoid sensitivity is associated with clinical glucocorticoid therapy outcome in rheumatoid arthritis. AB - INTRODUCTION: Genetic and disease-related factors give rise to a wide spectrum of glucocorticoid (GC) sensitivity in rheumatoid arthritis (RA). In clinical practice, GC treatment is not adapted to these differences in GC sensitivity. In vitro assessment of GC sensitivity before the start of therapy could allow more individualized GC therapy. The aim of the study was to investigate the association between in vitro and in vivo GC sensitivity in RA. METHODS: Thirty eight early and 37 established RA patients were prospectively studied. In vitro GC sensitivity was assessed with dexamethasone-induced effects on interleukin-2 (IL-2) and glucocorticoid-induced leucine zipper (GILZ) messenger RNA expression in peripheral blood mononuclear cells (PBMCs). A whole-cell dexamethasone-binding assay was used to measure number and affinity (1/KD) of glucocorticoid receptors (GRs). RESULTS: GR number was positively correlated with improvement in DAS. IL-2 EC50 and GILZ-EC50 values both had weak near-significant correlations with clinical improvement in DAS in intramuscularly treated patients only. HAQ responders had lower GILZ-EC50 values and higher GR number and KD. CONCLUSIONS: Baseline cellular in vitro glucocorticoid sensitivity is modestly associated with in vivo improvement in DAS and HAQ-DI score after GC bridging therapy in RA. Further studies are needed to evaluate whether in vitro GC sensitivity may support the development of tailor-made GC therapy in RA. PMID- 22920578 TI - A large seroprevalence survey of brucellosis in cattle herds under diverse production systems in northern Nigeria. AB - BACKGROUND: This study was carried out to investigate the status of brucellosis in cattle under various management systems in Adamawa, Kaduna and Kano states, northern Nigeria. Using multi-stage sampling, serum samples of 4,745 cattle from 271 herds were tested using the Rose-Bengal plate-agglutination test (RBPT) and positives were confirmed using a competitive enzyme-linked immunosorbent assay (c ELISA). RESULTS: Prevalence estimates were calculated by adjusting for sampling weights and where possible for test sensitivity and specificity. Thirty-seven percent of all animals were RBPT positive, and after confirmation with c-ELISA the overall animal-level prevalence, adjusted for sampling weights, was 26.3% (95% CI, 22.1%-31.0%). Of the herds sampled, 210 (77.5%; 95% CI, 68.6%-84.5%) had at least one animal positive to both tests; this did not differ significantly between states (P = 0.538). Mean within-herd seroprevalence in positive herds was 30.2% (95% CI, 25.3%-35.1%) and ranged from 3.1% to 85.7%. Overall animal-level seroprevalences of 29.2% (95% CI, 22.5%-36.9%) n = 1,827, 23.3% (95% CI, 18.9% 28.3%) n = 1,870 and 26.7% (95% CI, 18.8%-36.7%) n = 1,048 were observed in Adamawa, Kaduna and Kano states, respectively (P = 0.496). A significantly higher seroprevalence was found in males (38.2%; 95% CI, 31.7%-45.2%) than in females (24.7%; 95% CI, 20.4%-29.5%) (P < 0.001) and in non-pregnant females (27.8%; 95% CI, 22.9%-33.5%) than in pregnant females (17.2%; 95% CI, 13.6%-21.5%) (P < 0.001). Seroprevalence increased with increasing age (P < 0.001), from 13.5% (95% CI, 8.9%-19.9%) in cattle <4 years to 35.0% (95% CI, 28.5%-42.3%) in cattle >7 years. Seroprevalence also varied between management systems (P < 0.001): pastoral systems 45.1% (95% CI, 38.6%-51.9%), zero-grazing systems 23.8% (95% CI, 6.8%-59.2%), agro-pastoral systems 22.0% (95% CI, 17.3%-27.8%), and commercial farms 15.9% (95% CI, 9.5%-25.5%). Seroprevalence did not differ significantly between breeds or lactation status. CONCLUSION: This is the first large study to assess the prevalence of bovine brucellosis over a wide geographic area of northern Nigeria, in a variety of management systems and using accurate tests. The seroprevalence of brucellosis was high, and higher than results of previous studies in northern Nigeria. The pastoral management systems of the traditional Fulanis may be encouraging the dissemination of the disease. Public enlightenment of the farmers about the disease, vaccination and appropriate national control measures are recommended. PMID- 22920579 TI - Structure and properties of collagen vitrigel membranes for ocular repair and regeneration applications. AB - The frequency of ocular injuries on the battlefield has been steadily increasing during recent conflicts. Combat-related eye injuries are difficult to treat and solutions requiring donor tissue are not ideal and are often not readily available. Collagen vitrigels have previously been developed for corneal reconstruction, but increased transparency and mechanical strength are desired for improved vision and ease of handling. In this study, by systematically varying vitrification temperature, relative humidity and time, the collagen vitrigel synthesis conditions were optimized to yield the best combination of high transparency and high mechanical strength. Optical, mechanical, and thermal properties were characterized for each set of conditions to evaluate the effects of the vitrification parameters on material properties. Changes in denaturing temperature and collagen fibril morphology were evaluated to correlate properties with structure. Collagen vitrigels with transmittance up to 90%, tensile strength up to 12 MPa, and denaturing temperatures that significantly exceed the eye/body temperature have been synthesized at 40 degrees C and 40% relative humidity for one week. This optimal set of conditions enabled improvements of 100% in tensile strength and 11% in transmittance, compared to the previously developed collagen vitrigels. PMID- 22920580 TI - High-resolution magnetic resonance imaging of prostatectomy specimens: a promising tool for virtual histology. PMID- 22920581 TI - Robotic intracorporeal orthotopic ileal neobladder: replicating open surgical principles. AB - BACKGROUND: Robotic radical cystectomy (RC) for cancer is beginning to gain wider acceptance. Yet, the concomitant urinary diversion is typically performed extracorporeally at most centers, primarily because intracorporeal diversion is perceived as technically complex and arduous. Previous reports on robotic, intracorporeal, orthotopic neobladder may not have fully replicated established open principles of reservoir configuration, leading to concerns about long-term functional outcomes. OBJECTIVE: To illustrate step-by-step our technique for robotic, intracorporeal, orthotopic, ileal neobladder, urinary diversion with strict adherence to open surgical tenets. DESIGN, SETTING, AND PARTICIPANTS: From July 2010 to May 2012, 24 patients underwent robotic intracorporeal neobladder at a single tertiary cancer center. This report presents data on patients with a minimum of 3-mo follow-up (n=8). SURGICAL PROCEDURE: We performed robotic RC, extended lymphadenectomy to the inferior mesenteric artery, and complete intracorporeal diversion. Our surgical technique is demonstrated in the accompanying video. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Baseline demographics, pathology data, 90-d complications, and functional outcomes were assessed and compared with patients undergoing intracorporeal ileal conduit diversion (n=7). RESULTS AND LIMITATIONS: Robotic intracorporeal urinary diversion was successfully performed in 15 patients (neobladder: 8 patients, ileal conduit: 7 patients) with a minimum 90-d follow-up. Median age and body mass index were 68 yr and 27 kg/m2, respectively. In the neobladder cohort, median estimated blood loss was 225 ml (range: 100-700 ml), median time to regular diet was 5 d (range: 4-10 d), median hospital stay was 8 d (range: 5-27 d), and 30- and 90-d complications were Clavien grade 1-2 (n=5 and 0), Clavien grade 3-5 (n=2 and 1), respectively. This study is limited by small sample size and short follow-up period. CONCLUSIONS: An intracorporeal technique of robot assisted orthotopic neobladder and ileal conduit is presented, wherein established open principles are diligently preserved. This step-wise approach is demonstrated to help shorten the learning curve of other surgeons contemplating robotic intracorporeal urinary diversion. PMID- 22920583 TI - Neuroprotective effects of longan ( Dimocarpus longan Lour.) flower water extract on MPP+-induced neurotoxicity in rat brain. AB - In this study, the neuroprotective effect of Dimocarpus longan Lour. flower water extract (LFWE) was investigated. First, an in vitro study showed that LFWE concentration-dependently inhibited lipid peroxidation of brain homogenates incubated at 37 degrees C. The antioxidative activity of LFWE was more potent than that of glutathione or Trolox. Furthermore, an ex vivo study found that the basal lipid peroxidation (0 degrees C) and lipid peroxidation incubated at 37 degrees C were lower in the brain homogenates of LFWE-treated (500 mg/day) rats, indicating that the brain of LFWE-treated rats was more resistant to oxidative stress. Moreover, a Parkinsonian animal model was employed to demonstrate that oral administration of LFWE (125-500 mg/kg/day) dose-dependently attenuated 1 methyl-4-phenylpyridinium (MPP(+))-induced neurotoxicity in the nigrostriatal dopaminergic system of rat brain. In conclusion, this study suggests that LFWE is antioxidative, anti-inflammatory, and anti-apoptotic. Furthermore, oral administration of LFWE appears to be useful in preventing and/or treating central nervous system neurodegenerative diseases, including Parkinsonism. PMID- 22920584 TI - Characteristic clinical presentation and CSF biomarker pattern in cerebral small vessel disease. AB - To be able to live a good, independent life cognitive functions need to be intact. Dementia, stroke and neuropsychiatric disorders are the major disorders underlying disability. Stroke is usually a consequence of an underlying vessel wall disease that has lasted for a longer period. This vessel wall disease is commonly silent or without prominent symptoms. Damage to the small penetrating arterioles of the brain, arteriolosclerosis, induced by aging and hypertension, as well as other factors such as diabetes and genetic vulnerability, plays an important role in the origin of white matter changes. The pathological vascular wall process leads to lumen constriction, impaired ability to change lumen diameter according to metabolic needs and possible ischemic-hypoxic tissue damage in the vulnerable vascular architectural terminal areas of the long penetrating arteries. The arteriolosclerotic blood vessels are associated with inflammation and remodelling of the extracellular matrix. Enzymes connected to this process have also been found to be involved in demyelination and blood brain barrier opening but also in the repair process of angiogenesis and neurogenesis. Biochemical changes reflecting these processes might be early indicators of small vessel disease and hence increase the knowledge about the disease characteristic mechanisms. Moreover, monitoring disease modifying treatment effects can be an important application for small vessel disease specific biochemical markers. PMID- 22920585 TI - Current status and emerging role of glutathione in food grade lactic acid bacteria. AB - Lactic acid bacteria (LAB) have taken centre stage in perspectives of modern fermented food industry and probiotic based therapeutics. These bacteria encounter various stress conditions during industrial processing or in the gastrointestinal environment. Such conditions are overcome by complex molecular assemblies capable of synthesizing and/or metabolizing molecules that play a specific role in stress adaptation. Thiols are important class of molecules which contribute towards stress management in cell. Glutathione, a low molecular weight thiol antioxidant distributed widely in eukaryotes and Gram negative organisms, is present sporadically in Gram positive bacteria. However, new insights on its occurrence and role in the latter group are coming to light. Some LAB and closely related Gram positive organisms are proposed to possess glutathione synthesis and/or utilization machinery. Also, supplementation of glutathione in food grade LAB is gaining attention for its role in stress protection and as a nutrient and sulfur source. Owing to the immense benefits of glutathione, its release by probiotic bacteria could also find important applications in health improvement. This review presents our current understanding about the status of glutathione and its role as an exogenously added molecule in food grade LAB and closely related organisms. PMID- 22920586 TI - Different associations of white matter lesions with depression and cognition. AB - BACKGROUND: To test the hypothesis that white matter lesions (WML) are primarily associated with regional frontal cortical volumes, and to determine the mediating effects of these regional frontal cortices on the associations of WML with depressive symptoms and cognitive dysfunction. METHODS: Structural brains MRIs were performed on 161 participants: cognitively normal, cognitive impaired but not demented, and demented participants. Lobar WML volumes, regional frontal cortical volumes, depressive symptom severity, and cognitive abilities were measured. Multiple linear regression analyses were used to identify WML volume effects on frontal cortical volume. Structural equation modeling was used to determine the MRI-depression and the MRI-cognition path relationships. RESULTS: WML predicted frontal cortical volume, particularly in medial orbirtofrontal cortex, irrespective of age, gender, education, and group status. WML directly predicted depressive score, and this relationship was not mediated by regional frontal cortices. In contrast, the association between WML and cognitive function was indirect and mediated by regional frontal cortices. CONCLUSIONS: These findings suggest that the neurobiological mechanisms underpinning depressive symptoms and cognitive dysfunction in older adults may differ. PMID- 22920587 TI - Comprehensive phenotypic characterization of human adipose-derived stromal/stem cells and their subsets by a high throughput technology. AB - The characterization of adipose-derived stromal/stem cells (ASCs) remains difficult due to the lack of a definitive and unique cellular marker. Therefore, a combination of markers is necessary to identify the cells. No comprehensive analysis of the immunophenotype of expanded plastic adherent ASCs has been published. Therefore, the aim of this study was to characterize the general phenotype of cultured ASCs and to further analyze cellular subsets. ASCs were isolated from lipoaspirates from patients undergoing cosmetic liposuction and cultured in standard cell culture. A comprehensive phenotype characterization was done with the BD LyoplateTM Human Cell Surface Marker Screening Panel containing 242 antibodies and isotype controls. Cultured ASCs not only showed the characteristic expression profile of mesenchymal stem cells (MSCs), but also revealed donor-specific variability in the expression of 49 other markers. We further detected markers with a scattering in the fluorescence intensity, indicating subpopulations with different expression profiles. Therefore, a multi color flow cytometric analysis was done after staining the cells with direct labeled antibodies against CD73, CD90, CD105, and either CD34, CD140b, CD200, CD201, or CD36 to verify the selected subpopulations of ASCs. We detected no CD34 CD36 double-positive population, but CD34(+)-CD36(-) and CD34(-)CD36(+) subpopulations, both of which are positive for the 3 main MSC markers, CD73, CD90, and CD105. All other detected subpopulations also co-expressed the 3 main MSC markers, and therefore fulfill the minimal phenotypic criteria for the definition of cultured MSCs. Our study demonstrates the first comprehensive phenotypic characterization of ASCs and clearly highlights donor-specific variability in ASC preparations. PMID- 22920588 TI - Is there a Trojan-horse effect during magnetic nanoparticles and metalloid cocontamination of human dermal fibroblasts? AB - This study investigates the issue of nanoparticles/pollutants cocontamination. By combining viability assays, physicochemical and structural analysis (to probe the As speciation and valence), we assessed how gammaFe(2)O(3) nanoparticles can affect the cytotoxicity, the intra- and extracellular speciation of As(III). Human dermal fibroblasts were contaminated with gammaFe(2)O(3) nanoparticles and As(III) considering two scenarios: (i) a simultaneous coinjection of the nanoparticles and As, and (ii) an injection of the nanoparticles after 24 h of As adsorption in water. In both scenarios, we did not notice significant changes on the nanoparticles surface charge (zeta potential ~ -10 mV) nor hydrodynamic diameters (~950 nm) after 24 h. We demonstrated that the coinjection of gammaFe(2)O(3) nanoparticles and As in the cellular media strongly affects the complexation of the intracellular As with thiol groups. This significantly increases at low doses the cytotoxicity of the As nonadsorbed at the surface of the nanoparticles. However, once As is adsorbed at the surface the desorption is very weak in the culture medium. This fraction of As strongly adsorbed at the surface is significantly less cytotoxic than As itself. On the basis of our data and the thermodynamics, we demonstrated that any disturbance of the biotransformation mechanisms by the nanoparticles (i.e., surface complexation of thiol groups with the iron atoms) is likely to be responsible for the increase of the As adverse effects at low doses. PMID- 22920590 TI - Iron-centered ten-vertex germanium clusters: the ubiquity of low energy pentagonal prismatic structures with various skeletal electron counts. AB - One of the most significant recent developments (in 2009) is the discovery of the clusters M@Ge10(3-) (M = Fe, Co) in which the outer Ge10 polyhedron is a pentagonal prism rather than a deltahedral structure of the type predicted by the Wade-Mingos rules. Consistent with this experimental observation, density functional theory shows the lowest energy structures to be pentagonal prisms for the iron-centered clusters Fe@Ge10(z) in all nine charge states ranging from -5 to +3. This contrasts with the previously studied cobalt-centered germanium clusters Co@Ge10(z) for which the lowest energy structures are pentagonal prisms only for the electron richest systems where z ranges from -3 to -5. The C3v structures derived from the tetracapped trigonal prism found as lowest energy structures of the electron poorer Co@Ge10(z) (z = 0, -1, -2) systems are higher energy structures for the iron-centered germanium clusters Fe@Ge10(z) (z = 0, -1, -2). The strong energetic preference for pentagonal prismatic structures in the Fe@Ge10(z) clusters can be attributed to the need for the larger volume of the pentagonal prism relative to other 10-vertex closed polyhedra to accommodate the interstitial iron atom. PMID- 22920589 TI - Efficient bioconversion of quercetin into a novel glycoside by Streptomyces rimosus subsp. rimosus ATCC 10970. AB - Incubation of quercetin with Streptomyces rimosus subsp. rimosus ATCC 10970 yielded an unusual glycosylated derivative. The structure of the product was determined to be quercetin-7-O-beta-4"-deoxy-hex-4"-enopyranosiduronic acid based on the spectral data. Quercetin was completely converted into the glycoside in 72 h. PMID- 22920591 TI - Effectiveness of omalizumab in a patient with severe asthma, low serum IgE level, and lack of sensitized allergens induced by oral steroid therapy: the usefulness of impulse oscillation for assessment of omalizumab therapy. AB - BACKGROUND: Omalizumab is a humanized monoclonal anti-IgE antibody that was recently approved for the treatment of severe allergic asthma. However, omalizumab is not licensed for allergic asthma in patients with a low serum IgE level (<30 IU/mL) or negative results for specific allergen tests. CASE HISTORY: We present a patient with severe asthma and low serum IgE levels who had negative results for specific allergens induced by oral steroid therapy. Omalizumab administration improved asthma exacerbated forced expiratory volume in 1 s (FEV(1)) and respiratory resistance measurements based on the impulse oscillation technique (Mostgraph-01). The response to omalizumab therapy was evidenced by a decrease in airway resistance at 1 month. CONCLUSIONS: The findings of this case report indicate that omalizumab treatment had beneficial effects in a patient with severe asthma and low total serum IgE levels with negative results for specific IgE, which may have been induced by long-term corticosteroid administration. PMID- 22920592 TI - Enhanced condensation and facilitated release of DNA using mixed cationic agents: a combined experimental and Monte Carlo study. AB - Efficient DNA condensation and decondensation, as well as low toxicity, are required for an efficient gene delivery vehicle. We report on the condensation of DNA by a mixture of cationic agents, low-molecular-weight polyethylenimine (PEI, 1.2 KDa) and Fe(III) ions, and respective decondensation, using experimental and theoretical methods. It was found that a significant reduction in the amount of PEI necessary to induce DNA condensation is achieved by the addition of the trivalent ions, which are very inefficient on their own. In addition, the mixture makes DNA decompaction by heparin easier, starting from similar degrees of condensation. The results obtained using simulations of coarse-grain models are coherent with those obtained experimentally. It was also found that the improved effect of the multivalent ions is related to the preferred positioning of the trivalent ions in the DNA areas less populated by the polycation chains, in between the polycation chains and at the ends of the DNA, which facilitates the overall condensation. PMID- 22920593 TI - Regulation of expression and role of leukemia inhibitory factor and interleukin-6 in the uterus of early pregnant pigs. AB - Cytokines, which are generally involved in the process of inflammation, may also play a critical role in conceptus implantation. We examined: (1) the expression profiles of leukemia inhibitory factor (LIF) and interleukin (IL)-6 mRNA and their protein content in the endometrium of cyclic and pregnant gilts on Days 10 to 18 after estrus; (2) the effect of conceptus-exposed medium on LIF and IL-6 synthesis in the endometrium; (3) the profiles of IL6R and LIFR mRNA expression in pig conceptuses collected on Days 10 to 18 of pregnancy; and (4) the effect of LIF and IL-6 on the attachment and proliferation of porcine trophoblast cells. The expression of LIF mRNA in the endometrium increased between Days 10 and 12 in both cyclic and pregnant gilts, and tended to be higher in Day 12 pregnant animals compared with nonpregnant ones. The LIF protein content in the uterine lumen peaked on Day 12 of pregnancy, and was higher than on Day 12 of the estrous cycle. Endometrial IL-6 mRNA expression was upregulated on Day 12 in pregnant gilts compared with nonpregnant animals. Moreover, a higher content of IL-6 protein was observed in pregnant than in cyclic gilts. The addition of conceptus exposed medium resulted in up-regulation of LIF and IL6 mRNA expression, and increased IL-6 content in endometrial slices. In conceptuses, increased mRNA expression was detected on Days 10 to 14 for IL6R and on Day 14 for LIFR, when compared with other days studied. LIF and IL-6 stimulated the attachment and proliferation of trophoblast cells in vitro. In summary, LIF and IL-6 are important components of embryo-uterine interactions during early pregnancy in the pig, and may contribute to successful conceptus implantation. PMID- 22920594 TI - The stage of ovarian development affects organ expression of vitellogenin as well as the morphometry and ultrastructure of germ cells in the freshwater prawn Macrobrachium amazonicum (Heller, 1862). AB - The objective was to characterize vitellogenin expression in the ovary and hepatopancreas, and to describe the morphometry and ultrastructure of oocytes, in the freshwater prawn Macrobrachium amazonicum at various stages of ovarian development. Five ovarian stages were defined: (I) immature, (II) maturing, (III) mature, (IV) spawned, and (V) reorganized. Ovaries and hepatopancreas were analyzed by immunohistochemistry for vitellogenin expression. Vitellogenin expression in both ovary and hepatopancreas was predominantly widespread, beginning at Stage I, peaking at Stage III, and decreasing in Stages IV and V. Characterization of the ovary included measurement of the following germ cell types: oogonia (OG), and previtellogenic (PV), early vitellogenesis (EV), advanced vitellogenesis (AV), and mature (M) oocytes. Mean +/- SD diameter of OG and EV oocytes in Stages I (14.2 +/- 5.5 and 119.8 +/- 15.7 MUm) and II (17.9 +/- 4.8 and 114.3 +/- 34.6 MUm), respectively, were significantly different from that in Stages IV (16.6 +/- 4.7 and 107.0 +/- 24.6 MUm) and V (14.4 +/- 4.1 and 101.0 +/- 25.2 MUm). Both scanning and transmission electron microscopy enabled identification of EV, AV and M oocytes based on the presence of a nucleus, and the organization and distribution of yolk in the cytoplasm. In summary, vitellogenesis occurred both in the hepatopancreas and ovary, with the ovary expressing vitellogenin starting as early as Stage I. This process promoted accumulation of yolk and growth of oocytes, thus favoring sexual maturation of females. This knowledge may be applied to improve production of farmed M. amazonicum. PMID- 22920595 TI - Dissecting the role of low-complexity regions in the evolution of vertebrate proteins. AB - BACKGROUND: Low-complexity regions (LCRs) in proteins are tracts that are highly enriched in one or a few amino acids. Given their high abundance, and their capacity to expand in relatively short periods of time through replication slippage, they can greatly contribute to increase protein sequence space and generate novel protein functions. However, little is known about the global impact of LCRs on protein evolution. RESULTS: We have traced back the evolutionary history of 2,802 LCRs from a large set of homologous protein families from H.sapiens, M.musculus, G.gallus, D.rerio and C.intestinalis. Transcriptional factors and other regulatory functions are overrepresented in proteins containing LCRs. We have found that the gain of novel LCRs is frequently associated with repeat expansion whereas the loss of LCRs is more often due to accumulation of amino acid substitutions as opposed to deletions. This dichotomy results in net protein sequence gain over time. We have detected a significant increase in the rate of accumulation of novel LCRs in the ancestral Amniota and mammalian branches, and a reduction in the chicken branch. Alanine and/or glycine rich LCRs are overrepresented in recently emerged LCR sets from all branches, suggesting that their expansion is better tolerated than for other LCR types. LCRs enriched in positively charged amino acids show the contrary pattern, indicating an important effect of purifying selection in their maintenance. CONCLUSION: We have performed the first large-scale study on the evolutionary dynamics of LCRs in protein families. The study has shown that the composition of an LCR is an important determinant of its evolutionary pattern. PMID- 22920597 TI - Surgical ablation of atrial fibrillation trends and outcomes in North America. AB - OBJECTIVE: Despite growing awareness of the clinical significance of atrial fibrillation (AF) and observational data demonstrating the safety and efficacy of surgical therapy, AF ablation is variably performed among patients with AF undergoing cardiac surgery. We examined the national trends of surgical ablation and perioperative outcomes for stand-alone surgical ablation of AF. METHODS: Using the Society of Thoracic Surgeons Adult Cardiac Surgery Database, 91,801 (2005-2010) surgical AF ablations were performed of which 4893 (5.3%) were stand alone procedures. The outcomes of 854 propensity-matched pairs having "on" versus "off" cardiopulmonary bypass stand-alone ablation were compared. RESULTS: The percentage of patients with preoperative AF increased from 2005 to 2010 (from 10.0% to 12.2%). Overall, 40.6% of patients with AF underwent concomitant surgical ablation-a significant decline of 1.6% from 2005 to 2010. The number of stand-alone surgical ablations increased significantly from 552 to 1041 cases (2005-2010). Overall, the stand-alone group had a mean age of 60 years, 71% were men, and 80% were treated "off" cardiopulmonary bypass. The "on" cardiopulmonary bypass group had significantly more pulmonary disease, diabetes, and congestive heart failure. Overall, the operative mortality and stroke rate was 0.7% for each. After propensity matching, the "off" cardiopulmonary bypass group underwent significantly fewer reoperations for bleeding and had a lower incidence of prolonged ventilation and shorter hospitalization. New pacemaker implantation was low, without group differences. CONCLUSIONS: The prevalence of AF in patients undergoing cardiac surgery has increased, as has the number of stand-alone surgical ablations. The treatment of concomitant disease declined slightly. Isolated surgical ablation is safe, performed "on" or "off" cardiopulmonary bypass. These results support consideration of surgical AF ablation as an alternative to percutaneous ablation for patients with lone AF. PMID- 22920598 TI - The reliability of lung function tests in a quadriplegic patient. PMID- 22920596 TI - Long-term outcomes of patients with diabetes receiving bilateral internal thoracic artery grafts. AB - OBJECTIVES: Bilateral internal thoracic artery (BITA) grafting in patients with diabetes are controversial because of increased risk of sternal infection. On the other hand, patients with diabetes may benefit from BITA grafts because of the associated improved survival. This study evaluated factors affecting early and long-term outcomes for better selection of patients with diabetes for BITA grafts. METHODS: Between 1996 and 2006, 69 patients with insulin-treated diabetes and 732 with orally treated diabetes received isolated skeletonized BITA grafts. Of these patients, 338 were younger than 65 years, 322 were between 65 and 74 years old, and 141 were 75 years or older. RESULTS: Operative mortality was lower than logistic EuroSCORE-calculated mortality (2.9% vs 7%, P < .001). Predictors of increased mortality were critical preoperative state (P < .001) and age (P = .008). There were 30 cases of sternal infection (3.7%); predictors were reoperation (P < .001), peripheral vascular disease (P = .009), obesity (P = .012), chronic lung disease (P = .009), and female sex (P = .020). Mean follow-up was 8.4 +/- 4 years. Kaplan-Meier 10-year survivals were 75%, 59%, and 39% for patients younger than 65, 65 to 74, and at least 75 years, respectively (P < .001). They were better than corresponding Charlson comorbidity index-predicted survivals (36%, 10%, and 3%, respectively; P < .001). Predictors of decreased survival were age (P < .001), congestive heart failure (P < .001), and peripheral vascular disease (P < .001). Off-pump surgery was independently associated with better long-term survival (P = .003). CONCLUSIONS: BITA grafts are safe in patients with diabetes. Favorable short- and long-term outcomes outweigh increased sternal infection risk. PMID- 22920600 TI - Highly enantioselective organocatalytic sulfenylation of 3-aryloxindoles. AB - An organocatalytic asymmetric sulfenylation of 3-aryloxindoles with N (sulfanyl)succinimides has been developed by using commercially available (DHQD)(2)PHAL as catalyst. Various chiral 3-benzylthio-, alkylthio-, and arylthio substituted oxindoles, containing 3,3-disubstituted quarternary carbon stereocenters, could be obtained in high enantioselectivities (85-97% ee). Furthermore, the opposite enantiomers of the sulfenylated products were readily accessible with equal excellent enantioselectivities (86-95% ee) by replacing the catalyst with (DHQ)(2)PHAL. PMID- 22920599 TI - Response of mean arterial pressure to temporary biventricular pacing after chest closure during cardiac surgery. AB - OBJECTIVES: We have previously demonstrated that biventricular pacing increased cardiac output within 1 hour of weaning from cardiopulmonary bypass in selected patients. To assess the possible sustained benefit, we reviewed in the present study the effects of biventricular pacing on the mean arterial pressure after chest closure. METHODS: A total of 30 patients (mean ejection fraction 35% +/- 15%, mean QRS 119 +/- 24 ms) underwent coronary bypass and/or valve surgery. The mean arterial pressure was maximized during biventricular pacing using atrioventricular delays of 90 to 270 ms and interventricular delays of +80 to -80 ms during 20-second intervals in random sequence. Optimized biventricular pacing was finally compared with atrial pacing at a matched heart rate and to a sinus rhythm during 30-second intervals. Vasoactive medication and fluid infusion rates were held constant. The arterial pressure was digitized, recorded, and integrated. Statistical significance was assessed using linear mixed effects models and Bonferroni's correction. RESULTS: Optimized atrioventricular delay, ranging from 90 to 270 ms, increased the mean arterial pressure 4% versus nominal and 7% versus the worst (P < .001). Optimized interventricular delay increased pressure 3% versus nominal and 7% versus the worst. Optimized biventricular pacing increased the mean arterial pressure 4% versus sinus rhythm (78.5 +/- 2.4 vs 75.1 +/- 2.4 mm Hg; P = .002) and 3% versus atrial pacing (76.4 +/- 2.7 mm Hg; P = .017). CONCLUSIONS: Temporary biventricular pacing improves the hemodynamics after chest closure, with effects similar to those within 1 hour of bypass. Individualized optimization of atrioventricular delay is warranted, because the optimal delay was longer in 80% of our patients than the current recommendations for temporary postoperative pacing. PMID- 22920602 TI - A complete family of terminal uranium chalcogenides, [U(E)(N{SiMe3}2)3]- (E = O, S, Se, Te). AB - Addition of 1 equiv of E (E = 0.125 S(8), Se, Te) to U(H(2)C?PPh(3))(NR(2))(3) (R = SiMe(3)) (1) in Et(2)O results in generation of the terminal chalcogenide complexes, [Ph(3)PCH(3)][U(E)(NR(2))(3)] (E = S, 2; Se, 3; Te, 4; R = SiMe(3)), in modest yield. Complexes 2-4 represent extremely rare examples of terminal uranium monochalcogenides. Synthesis of the oxo analogue, [Cp*(2)Co][U(O)(NR(2))(3)] (5), was achieved by reduction of [U(O)(NR(2))(3)] with Cp*(2)Co. All complexes were fully characterized, including analysis by X ray crystallography. In the solid state, complexes 2-5 feature short U-E bond lengths, suggestive of actinide-ligand multiple bonding. PMID- 22920601 TI - Releasable layer-by-layer assembly of stabilized lipid nanocapsules on microneedles for enhanced transcutaneous vaccine delivery. AB - Here we introduce a new approach for transcutaneous drug delivery, using microneedles coated with stabilized lipid nanocapsules, for delivery of a model vaccine formulation. Poly(lactide-co-glycolide) microneedle arrays were coated with multilayer films via layer-by-layer assembly of a biodegradable cationic poly(beta-amino ester) (PBAE) and negatively charged interbilayer-cross-linked multilamellar lipid vesicles (ICMVs). To test the potential of these nanocapsule coated microneedles for vaccine delivery, we loaded ICMVs with a protein antigen and the molecular adjuvant monophosphoryl lipid A. Following application of microneedle arrays to the skin of mice for 5 min, (PBAE/ICMV) films were rapidly transferred from microneedle surfaces into the cutaneous tissue and remained in the skin following removal of the microneedle arrays. Multilayer films implanted in the skin dispersed ICMV cargos in the treated tissue over the course of 24 h in vivo, allowing for uptake of the lipid nanocapsules by antigen presenting cells in the local tissue and triggering their activation in situ. Microneedle mediated transcutaneous vaccination with ICMV-carrying multilayers promoted robust antigen-specific humoral immune responses with a balanced generation of multiple IgG isotypes, whereas bolus delivery of soluble or vesicle-loaded antigen via intradermal injection or transcutaneous vaccination with microneedles encapsulating soluble protein elicited weak, IgG(1)-biased humoral immune responses. These results highlight the potential of lipid nanocapsules delivered by microneedles as a promising platform for noninvasive vaccine delivery applications. PMID- 22920603 TI - Stromal proteome expression profile and muscle-invasive bladder cancer research. AB - BACKGROUND: To globally characterize the cancer stroma expression profile of muscle-invasive transitional cell carcinoma and to discuss the cancer biology as well as biomarker discovery from stroma. Laser capture micro dissection was used to harvest purified muscle-invasive bladder cancer stromal cells and normal urothelial stromal cells from 4 paired samples. Two-dimensional liquid chromatography tandem mass spectrometry was used to identify the proteome expression profile. The differential proteins were further analyzed using bioinformatics tools and compared with the published literature. RESULTS: We identified 868/872 commonly expressed proteins and 978 differential proteins from 4 paired cancer and normal stromal samples using laser capture micro dissection coupled with two-dimensional liquid chromatography tandem mass spectrometry. 487/491 proteins uniquely expressed in cancer/normal stroma. Differential proteins were compared with the entire list of the international protein index (IPI), and there were 42/42 gene ontology (GO) terms exhibited as enriched and 8/5 exhibited as depleted in cellular Component, respectively. Significantly altered pathways between cancer/normal stroma mainly include metabolic pathways, ribosome, focal adhesion, etc. Finally, descriptive statistics show that the stromal proteins with extremes of PI and MW have the same probability to be a biomarker. CONCLUSIONS: Based on our results, stromal cells are essential component of the cancer, biomarker discovery and network based multi target therapy should consider neoplastic cells itself and corresponding stroma as whole one. PMID- 22920604 TI - Canine mesenchymal stem cells are effectively labeled with silica nanoparticles and unambiguously visualized in highly autofluorescent tissues. AB - BACKGROUND: Development of a method for long-term labeling of cells is critical to elucidate transplanted cell fate and migration as well as the contribution to tissue regeneration. Silica nanoparticles have been recently developed and demonstrated to be biocompatible with a high labeling capacity. Thus, our study was designed to assess the suitability of silica nanoparticles for labeling canine mesenchymal stem cells (MSCs) and the fluorescence afficiency in highly autofluorescent tissue. RESULTS: We examined the effect of silica nanoparticle labeling on stem cell morphology, viability and differentiation as compared with those of unlabeled control cells. After 4 h of incubation with silica nanoparticles, they were internalized by canine MSCs without a change in the morphology of cells compared with that of control cells. The viability and proliferation of MSCs labeled with silica nanoparticles were evaluated by a WST-1 assay and trypan blue exclusion. No effects on cell viability were observed, and the proliferation of canine MSCs was not inhibited during culture with silica nanoparticles. Furthermore, adipogenic and osteogenic differentiation of silica nanoparticle-labeled canine MSCs was at a similar level compared with that of unlabeled cells, indicating that silica nanoparticle labeling did not alter the differentiation capacity of canine MSCs. Silica nanoparticle-labeled canine MSCs were injected into the kidneys of BALB/c mice after celiotomy, and then the mice were sacrificed after 2 or 3 weeks. The localization of injected MSCs was closely examined in highly autofluorescent renal tissues. Histologically, canine MSCs were uniformly and completely labeled with silica nanoparticles, and were unambiguously imaged in histological sections. CONCLUSIONS: The results of the current study showed that silica nanoparticles are useful as an effective labeling marker for MSCs, which can elucidate the distribution and fate of transplanted MSCs. PMID- 22920605 TI - Indications and performance of pelvic radiography in patients with blunt trauma. AB - OBJECTIVES: The objectives of this study are to validate a set of clinical variables to identify patients with pelvic fractures and to determine the sensitivity of anteroposterior (AP) pelvic radiographs in patients with pelvic fractures. METHODS: We conducted a prospective observational cohort study of adults (>18 years) with blunt torso trauma evaluated with abdominal/pelvic computed tomography. Physicians providing care in the emergency department documented history and physical examination findings after initial evaluation. High-risk variables included any of the following: hypotension (systolic blood pressure <90 mm Hg), Glasgow Coma Scale score less than 14, pelvic bone tenderness, or instability. Pelvic fractures were present if the orthopedic faculty documented a fracture to the pubis, ilium, ischium, or sacrum. RESULTS: We enrolled 4737 patients, including 289 (6.1%; 95% confidence interval [CI], 5.4%-6.8%) with pelvic fractures. Of the 289 patients, 256 (88.6%; 95% CI, 84.3% 92.0%) had at least one of the high-risk variables identified. Initial plain AP radiographs identified 234 (81.0%; 95% CI, 76.0%-85.3%) of 289 patients with pelvic fractures. The high-risk variables identified all 87 patients (100%; 95% CI, 96.6%-100%) undergoing surgery, whereas plain AP pelvic radiography identified a fracture in 83 patients (95.4%; 95% CI, 88.6%-98.7%) undergoing surgery. CONCLUSION: Previously identified high-risk variables for pelvic fracture identify most but not all patients with pelvic fractures. However, these high-risk variables identify all patients undergoing surgery and may be implemented as screening criteria for pelvic radiography. Anteroposterior pelvic radiographs fail to demonstrate a fracture in a substantial number of patients with pelvic fracture including patients who undergo surgery. PMID- 22920606 TI - Hydrolysis of chicoric and caftaric acids with esterases and Lactobacillus johnsonii in Vitro and in a gastrointestinal model. AB - Chicoric acid (ChA) and caftaric acid (CafA) were identified as bioactive components of chicory and have been ascribed a number of health benefits. This study investigated the hydrolysis of ChA and CafA with enzymes and a probiotic bacterium Lactobacillus johnsonii (La1). Esterase from Aspergillus japonicus (24 U/mg) hydrolyzed 100% of ChA (5 mM) and CafA (5 mM) after 3 h, at pH 7.0 and 37 degrees C. Under the same reaction conditions, 100% hydrolysis of ChA and CafA was achieved with a spray-dried preparation of La1. The addition of La1 (100 mg/mL, 3.3 E9 cfu/g) to CafA solution in a gastrointestinal model (GI model) resulted in 65% hydrolysis of CafA. This model simulates the physicochemical conditions of the human gastrointestinal tract. No hydrolysis of CafA was observed after passage through the GI model in the absence of La1. The results of this study support the hypothesis that ChA and CafA are degraded by gut microflora before absorption and metabolization. PMID- 22920607 TI - Antinociceptive interaction of (+/-)-CPP and propentofylline in monoarthritic rats. AB - INTRODUCTION: Multiple studies have shown that glial cells of the spinal cord, such as astrocytes and microglia, have close contact with neurons, suggesting the term tripartite synapse. In these synapses, astrocytes surrounding neurons contribute to neuronal excitability and synaptic transmission, thereby increasing nociception and thus the persistence of chronic pain. Conversely, the N-methyl-D aspartate (NMDA) receptor is crucial in the generation and maintenance of chronic pain. It has multiple sites of modulation. One is the site of recognition of extracellular neurotransmitter (glutamate), which can be blocked by competitive antagonists such as (3-(2-carboxipiperazin-4)1-propyl phosphonic acid), (+/-) CPP, resulting in a blockade of the calcium current and thus the intracellular transduction process. In the present study, we investigated whether the potential antinociceptive effect of glial inhibition produced by propentofylline (PPF) can be enhanced when combined with an NMDA-receptor inhibitor such as (+/-)-CPP. METHODS: We used Sprague-Dawley monoarthritic rats. The monoarthritis was induced by injection of complete Freund adjuvant in the right tibiotarsal joint. Four weeks later, rats were treated with PPF (1, 10, 30, and 100 MUg/10 MUl) intrathecally (i.t.) for 10 days, injected once with (+/-)-CPP (2.5, 5, 12.5, 25, 50, and 100 MUg/10 MUl, i.t.), or both treatments combined. The antinociceptive effect was evaluated on day 11 for PPF and immediately to (+/-)-CPP, by assessing the vocalization threshold to mechanical stimulation of the arthritic paw. RESULTS: The data indicate that intrathecal administration of increasing concentrations of (+/-)-CPP or PPF produced a significant dose-dependent antinociceptive effect with respect to monoarthritic rats receiving saline. The linear regression analysis showed that the dose that produces 30% of maximal effect (ED30) for i.t. (+/-)-CPP was 3.97 MUg, and 1.42 MUg for i.t. PPF. The administration of the PPF and (+/-)-CPP combination in fixed proportions of ED30 produced a dose-dependent antinociceptive effect, showing an interaction of the supraadditive type. CONCLUSIONS: The results suggest that glia inhibitors can synergically potentiate the effect of glutamate blockers for the treatment of chronic inflammatory pain. PMID- 22920608 TI - Subcutaneous implantation of a new intravenous pump system for prostacyclin treatment in patients with pulmonary arterial hypertension. AB - BACKGROUND: Intravenous prostacyclin treatment is a well recognized option in patients suffering from pulmonary arterial hypertension (PAH), and remains the gold standard of treatment. However, intravenous prostacyclin treatment involves several limitations, because the available battery-driven pump systems carry the risk of line infections, catheter-related embolisms, thrombosis, and delivery system malfunctions. CASE REPORT: We report for the first time, to the best of our knowledge, on the safe transition procedure from subcutaneous to intravenous treprostinil in a 74-year-old woman suffering from severe PAH (New York Heart Association functional class III), using a new implantable, gas-driven, intravenous pump device (LenusPro, Tricumed/OMT, Frittlingen, Germany). CONCLUSIONS: This implantable pump system may overcome the well-known limitations and risks of commonly used delivery systems, and thus may provide a new option for continuous intravenous prostacyclin treatment in patients with PAH. PMID- 22920610 TI - Primary chordomas of the cervical spine: a consecutive series of 14 surgically managed cases. AB - OBJECT: Cervical chordomas are rare lesions and usually bring about challenges in treatment planning because of their wide extension and complicated adjacent anatomy. There are few large published series at present focusing on cervical chordomas. The authors studied a consecutive series of 14 patients with primary cervical chordomas who underwent surgical treatment and were observed between 1989 and 2008. By reviewing the clinical patterns and follow-up data, they sought to investigate the clinical characters, tailor the appropriate surgical techniques, and establish prognosis factors for cervical chordomas. METHODS: Hospitalization and follow-up data in the 14 patients were collected. All patients underwent piecemeal tumor excision and reconstruction for stability; total spondylectomy was achieved in 5 cases. Postoperative radiotherapy was administered in all patients. Kaplan-Meier plots were used to represent tumor recurrence and patient survival, and log-rank testing was used to determine the risk factors of local recurrence. RESULTS: Follow-up ranged from 8 to 120 months (mean 58.6 months). Symptom and neural status in most patients improved after surgery. The 1- and 5-year disease-free survival rates were 78.6% and 50%, respectively, and the 1- and 5-year survival rates were 92.9% and 85.7%, respectively. Log-rank tests revealed that the following variables were significantly associated with a high rate of tumor recurrence: age less than 40 years or greater than 70 years (p = 0.006) and an upper cervical tumor location (p = 0.019). CONCLUSIONS: Chordomas in the cervical spine are usually neoplasms that exhibit insidious growth and a wide extension by the time of diagnosis. Radical intralesional debulking surgery and postoperative radiotherapy have been effective treatment. A limited application of en bloc tumor resection and the highly likely intraoperative intralesional tumor seeding may partially explain the high local recurrence rate, whereas the chance of distant metastases, fortunately, is very low. Most recurrence were documented within 3 years. Some specific surgical techniques should be emphasized to minimize tumor seeding. Patients with upper cervical chordomas, younger adults, and elderly adults have worse prognosis. For patients with chordoma extending to both the anterior and posterior spinal columns, total spondylectomy combined with piecemeal excision is recommended for a better prognosis. PMID- 22920609 TI - Social support among African Americans with heart failure: is there a role for community health advisors? AB - OBJECTIVE: The study had 2 objectives: (1) to gather the observations of community health advisors (CHAs) on the role of social support in the lives of African Americans; and (2) to develop a lay support intervention framework, on the basis of the existing literature and observations of CHAs, depicting how social support may address the needs of African American patients with heart failure. METHODS: Qualitative data were collected in semistructured interviews among 15 CHAs working in African American communities in Birmingham, Alabama. RESULTS: Prominent themes included the challenge of meeting clients' overlapping health care and general life needs, the variation in social support received from family and friends, and the opportunities for CHAs to provide multiple types of social support to clients. CHAs also believed that their support activities could be implemented among populations with heart failure. CONCLUSION: The experience of CHAs with social support can inform a potential framework of a lay support intervention among African Americans with heart failure. PMID- 22920611 TI - Infection risk for primary and revision instrumented lumbar spine fusion in the Medicare population. AB - OBJECT: This retrospective analysis of Medicare administrative data was performed to evaluate the risk of infection following instrumented lumbar fusion over a 10 year follow-up period in the Medicare population. Although infection can be a devastating complication, due to its rarity it is difficult to characterize infection risk except in large patient populations. METHODS: Using ICD-9-CM and CPT4 procedure codes, the Medicare 5% analytical research files for inpatient, outpatient, and physician carrier claims were checked to identify patients who were treated between 1997 and 2009 with lumbar spine fusion in which cages or posterior instrumentation were used. Patients younger than 65 years old were excluded. Patients were followed continuously by using the matching denominator file until they withdrew from Medicare or died. The authors identified 15,069 patients with primary fusion procedures and 605 with revision of instrumented lumbar fusion. Infections were identified by the related ICD-9 codes (998.59 or 996.67) after fusion. Kaplan-Meier survival analysis and Cox regression were performed to determine adjusted infection risk for each type of spine procedure (primary vs revision) and surgical approach (anterior, posterior, combined anteroposterior), accounting for patient (for example, age, sex, comorbidities/Charlson Comorbidity Index [CCI], and state buy-in) and hospital (census region) characteristics. RESULTS: At 10 years, the overall infection incidence, including superficial and deep infections, was 8.5% in primary procedures and 12.2% in revisions. Among the factors considered, infection risk within 10 years was most influenced by comorbidities: for a CCI of 5 versus 0, the adjusted hazard ratio (AHR) was 2.48 (95% CI 1.93-3.19, p < 0.001); for >= 9 versus 2-3 fused vertebrae, the AHR was 2.39 (95% CI 1.20-4.76, p < 0.001); for revision versus primary fusion procedures, the AHR was 1.66 (95% CI 1.28-2.15, p < 0.001). Other significant predictors of 10-year infection risk included diagnosis of obesity (p < 0.001); state buy-in--a proxy for socioeconomic status (p = 0.02); age (p = 0.003); surgical approach (p = 0.03); census region (p = 0.02); and the year of the index procedure (p = 0.03). CONCLUSIONS: Patient comorbidities were the greatest predictor of infection risk for the Medicare population. The high incidence of infection following instrumented fusion warrants increased focus on infection risk mitigation, especially for patients with comorbid conditions. PMID- 22920612 TI - Temporal trends and spatial variation characteristics of hazardous air pollutant emission inventory from municipal solid waste incineration in China. AB - A multiple-year emission inventory of hazardous air pollutants (HAPs), including particulate matter (PM), SO(2), NO(x), CO, HCl, As, Cd, Cr, Hg, Ni, Pb, Sb, and polychlorinated dibenzo-p-dioxins and polychlorinated dibenzofurans (PCDD/Fs), discharged from municipal solid waste (MSW) incineration in China has been established for the period 2003-2010 by using the best available emission factors and annual activity data. Our results show that the total emissions have rapidly amounted to 28,471.1 t of NO(x), 12,062.1 t of SO(2), 6500.5 t of CO, 4654.6 t of PM, 3609.1 t of HCl, 69.5 t of Sb, 36.7 t of Hg, 9.4 t of Pb, 4.4 t of Cr, 2.8 t of Ni, 926.7 kg of Cd, 231.7 kg of As, and 23.6 g of PCDD/Fs as TEQ (toxic equivalent quantity) by the year 2010. The majority of HAP emissions are concentrated in the eastern central and southeastern areas of China where most MSW incineration plants are built and put into operation. Between 2003 and 2010, provinces always ranking in the top three with largest HAPs emissions are Zhejiang, Guangdong, and Jiangsu. To better understand the emissions of these HAPs and to adopt effective measures to prevent poisoning risks, more specific field-test data collection is necessary. PMID- 22920613 TI - An unequal burden: risk factors for severe complications following unsafe abortion in Tigray, Ethiopia. AB - Unsafe abortion is a leading cause of maternal mortality and morbidity worldwide. A total of 266 women seeking care at health facilities for the treatment of incomplete abortion in Tigray, Ethiopia were studied, and factors associated with severe complications related to unsafe abortion were assessed. Women had significantly higher odds of experiencing severe clinical complications if they were married compared with unmarried (odds ratio 3.98; 95% confidence interval, 1.75-9.04) or were seen in a mid- or low-level health facility (a health center or health post) compared with a high-level facility (a hospital) (odds ratio 4.77; 95% confidence interval, 1.87-12.19). The findings support the need to provide family planning programs that involve men and the need to expand access to confidential, safe abortion services by mid-level providers so that pregnancy termination no longer means placing women's lives and health in danger. PMID- 22920614 TI - Pathways and consequences of unsafe abortion: a comparison among women with complications after induced and spontaneous abortions in Madhya Pradesh, India. AB - This study aimed to understand women's pathways of seeking care for postabortion complications in Madhya Pradesh, India. The study recruited 786 women between July and November 2007. Data were collected on service provision, abortion related complications, care-seeking behavior, knowledge about abortion legality and availability, methods used, symptoms, referral source, and out-of-pocket costs. Women seeking care for complications from induced abortion followed more complex pathways to treatment than women with complications of spontaneous abortion. More complex pathways were associated with higher out-of-pocket costs. Improving community awareness on legal aspects, safe abortion methods, and trained providers are necessary to reduce morbidity associated with unsafe abortion. PMID- 22920615 TI - Outcome of an intervention to improve the quality of private sector provision of postabortion care in northern Nigeria. AB - The outcomes of an intervention aimed at improving the quality of postabortion care provided by private medical practitioners in 8 states in northern Nigeria are reported. A total of 458 private medical doctors and 839 nurses and midwives were trained to offer high-quality postabortion care, postabortion family planning, and integrated sexually transmitted infection/HIV care. Results showed that among the 17009 women treated over 10 years, there was not a single case of maternal death. In a detailed analysis of 2559 women treated during a 15-month period after the intervention was established, only 33 women experienced mild complications, while none suffered major complications of abortion care. At the same time, there was a reduction in treatment cost and a doubling of the contraceptive uptake by the women. Building the capacity of private medical providers can reduce maternal morbidity and mortality associated with induced abortion in northern Nigeria. PMID- 22920616 TI - The health system cost of postabortion care in Ethiopia. AB - To address the knowledge gap that exists in costing unsafe abortion in Ethiopia, estimates were derived of the cost to the health system of providing postabortion care (PAC), based on research conducted in 2008. Fourteen public and private health facilities were selected, representing 3 levels of health care. Cost information on drugs, supplies, material, personnel time, and out-of-pocket expenses was collected using an ingredients approach. Sensitivity analysis was used to determine the most likely range of costs. The average direct cost per client, across 5 types of abortion complications, was US $36.21. The annual direct cost nationally ranged from US $6.5 to US $8.9 million. Including indirect costs and satisfying all demand increased the annual national cost to US $47 million. PAC consumes a large portion of the total expenditure in reproductive health in Ethiopia. Investing more resources in family planning programs to prevent unwanted pregnancies would be cost-beneficial to the health system. PMID- 22920617 TI - Public hospital costs of treatment of abortion complications in Nigeria. AB - Unsafe abortion is a significant contributor to maternal mortality in Nigeria, and treatment of postabortion complications drains public healthcare resources. Provider estimates of medications, supplies, and staff time spent in 17 public hospitals were used to estimate the per-case and annual costs of postabortion care (PAC) provision in Ogun and Lagos states and the Federal Capital Territory. PAC with treatment of moderate complications (US $112) cost 60% more per case than simple PAC (US $70). In cases needing simple PAC, treatment with dilation and curettage (D&C, US $80) cost 18% more per case than manual vacuum aspiration (US $68). Annually, all public hospitals in these 3 states spend US $807 442 on PAC. This cost could be reduced by shifting service provision to an outpatient basis, allowing service provision by midwives, and abandoning the use of D&C. Availability of safe, legal abortion would further decrease cost and reduce preventable deaths from unsafe abortion. PMID- 22920618 TI - Quality and efficiency of care for complications of unsafe abortion: a case study from Bangladesh. AB - Treating complications of unsafe abortion can be financially draining for health systems. This analysis assessed incremental health system costs of service delivery for abortion-related complications in the Bangladesh public health system and confirmed that providing postabortion care with vacuum aspiration is less expensive than using dilation and curettage (D&C). Implementing several evidence-based best practices, such as replacing D&C with vacuum aspiration, reducing use of high-level sedation, authorizing midlevel providers to offer postabortion care, and providing postabortion contraceptive counseling and services to women while still at the health facility, could increase the quality and cost efficiency of postabortion care in Bangladesh. PMID- 22920619 TI - Attitudes toward abortion in Zambia. AB - Despite Zambia's relatively progressive abortion law, women continue to seek unsafe, illegal abortions. Four domains of abortion attitudes - support for legalization, immorality, rights, and access to services - were measured in 4 communities. A total of 668 people were interviewed. Associations among the 4 domains were inconsistent with expectations. The belief that abortion is immoral was widespread, but was not associated with lack of support for legalization. Instead, it was associated with belief that women need access to safe services. These findings suggest that increasing awareness about abortion law in Zambia may be important for encouraging more favorable attitudes. PMID- 22920620 TI - Correlates of perceived and internalized stigma among abortion patients in the USA: an exploration by race and Hispanic ethnicity. AB - This study estimated the proportion of abortion patients in the USA reporting perceived and internalized stigma, and assessed associations between those outcomes and women's sociodemographic, reproductive, and situational characteristics by race/ethnicity from a nationally representative dataset. Two thirds of women reported that some people would look down on them if they knew about the abortion, and more than half of the respondents reported needing to keep their abortion a secret from friends and family. Associations between women's characteristics and abortion stigma varied by race/ethnicity. Results indicate that many abortion patients in the USA perceive and internalize stigma; certain subgroups of women are more likely to perceive or internalize stigma than others. PMID- 22920621 TI - Public opinion about abortion-related stigma among Mexican Catholics and implications for unsafe abortion. AB - A nationally representative survey was conducted among 3000 Catholics in Mexico during 2009 and 2010. Respondents were presented with a hypothetical situation about a young woman who decided to have an abortion and were asked their personal opinion of her. On the basis of a stigma index, it was found that the majority (61%) had stigmatizing attitudes about abortion; however, 81% believed that abortion should be legal in at least some circumstances. Respondents were significantly more likely to stigmatize abortion if they disagreed with the Mexico City law legalizing the procedure (odds ratio 1.66; 95% CI, 1.30-2.11) and believed that abortion should be prohibited in all cases (odds ratio 3.13; 95% CI, 2.28-4.30). Such stigma can lead women to seek unsafe abortions to avoid judgment by society. PMID- 22920622 TI - Investigating social consequences of unwanted pregnancy and unsafe abortion in Malawi: the role of stigma. AB - Malawian women in all sectors of society are suffering from social implications of unwanted pregnancy and unsafe abortion. Unwanted pregnancies occur among women who have limited access to family planning and safe abortion. A legally restrictive setting for safe abortion services leads many women to unsafe abortion, which has consequences for them and their families. In-depth interviews were conducted with 485 Malawian stakeholders belonging to different political and social structures. Interviewees identified the impact of unwanted pregnancy and unsafe abortion to be the greatest on young women. Premarital and extramarital pregnancies were highly stigmatized; stigma directly related to abortion was also found. Community-level discussions need to focus on reduction of stigma. PMID- 22920623 TI - Social and psychological consequences of abortion in Iran. AB - Iran has had replacement fertility since 2000. Upholding a small family size has led some couples to terminate unwanted pregnancies. Abortion is, however, permitted only on medical grounds in Iran. Using data from the Iran Low Fertility Survey, this study assessed sociodemographic correlates of abortion among a random sample of 5526 ever-married women aged 15-54 years, and used in-depth interviews to explore reasons for and psychological consequences of abortion among 40 women who had experienced an unintended pregnancy. Although social and economic concerns were the main reasons cited for seeking abortion, women experienced anxiety and depression when seeking pregnancy termination and thereafter. Social stigmatization arose from a belief that abortion is sinful and that misfortune experienced thereafter is punishment. Inadequate knowledge and misunderstanding of relevant Sharia laws discouraged women from seeking care when they experienced complications. Iran's reproductive health policies should be revised to integrate pre- and postabortion counseling. PMID- 22920624 TI - The health, social, and economic consequences of unsafe abortion: papers presented at an IUSSP Seminar, Mexico, 2010. PMID- 22920625 TI - Quantifying the global burden of morbidity due to unsafe abortion: magnitude in hospital-based studies and methodological issues. AB - The global burden of complications from unsafe abortion is thought to be high, but difficult to measure. A systematic review was conducted to describe the prevalence and type of complications of abortion among women hospitalized for treatment of abortion complications in settings where abortion is generally considered unsafe. There were 43 hospital-based studies reporting on severity and type of complications of abortions, but definitions varied substantially. The proportion of women treated in facilities for severe complications ranged from a median of 1.6% (range, 0.1%-10.8%) for renal failure to 7.2% (range, 0.1%-43.9%) for severe trauma. Heterogeneity of study designs and definitions makes comparisons difficult. Therefore, it is recommended that standardized designs and definitions are used in future studies of abortion complications. (c) 2012 Published by Elsevier Ireland Ltd. on behalf of International Federation of Gynecology and Obstetrics. PMID- 22920626 TI - Analysis of maternal and abortion-related mortality in Mexico over the last two decades, 1990-2008. AB - To document the relative contribution of abortion-related deaths to overall maternal deaths in Mexico, official mortality data were analyzed according to International Classification of Diseases (ICD) codes. During 1990-2008, among 24 805 maternal deaths, 1786 (7.2%) were abortion related. Of these, 13.2% occurred in adolescents and 65% in uninsured women; 60% were probably associated with unsafely induced procedures. The study calculated the number of abortion-related deaths per 100,000 abortion-related hospitalizations, expressed as a modified abortion case-fatality rate. During 2000-2008, this rate was 48 at the national level, with wide variations among states: from 140 deaths in Guerrero to 8 in Baja California Sur per 100,000 abortion hospitalizations. Unsafe abortion continues to represent a significant proportion of all maternal deaths in Mexico. PMID- 22920627 TI - Stories behind the statistics: a review of abortion-related deaths from 2005 to 2007 in Mexico City. AB - Evidence suggests that restricting abortion does not reduce its occurrence but increases health risk. A qualitative analysis was performed, reviewing the medical charts of 12 women who died from unsafe induced abortions in Mexico City; most deaths occurred before abortion was decriminalized. Women resorted to using unsafe techniques, without medical guidance or under incorrect recommendations by providers, ultimately resulting in the loss of their lives. Postabortion care in private and public health facilities was often inadequate. The cases illustrate the importance of liberalizing abortion laws and improving postabortion care to protect the life and health of women seeking to terminate pregnancy. PMID- 22920628 TI - Health consequences of unsafe abortion in Colombia, 1989-2008. AB - The number of Colombian women hospitalized for the treatment of induced abortion complications increased from 57 679 in 1989 to 93 336 in 2008; the hospitalization rate also rose: from 7.2 to 9.1 cases per 1000 women aged 15-44 years. Factors that likely underlie the increase include improved access to postabortion care (although 1 in 5 women still do not obtain the care they need) and the growing role of misoprostol, often used incorrectly and to some extent replacing the use of surgical abortion by doctors. Efforts are evidently needed to improve access to safe abortion and effective contraception. PMID- 22920629 TI - Trends in hospitalization for abortion-related complications in Brazil, 1992 2009: why the decline in numbers and severity? AB - Brazil offers a unique opportunity to analyze trends in abortion-related morbidity over time with high-quality data. National data on facility-based treatment of abortion complications from 1992-2009 were analyzed. Large declines occurred in the number and rate of women treated for abortion complications: the national number of treated cases declined by 41% (from 282 000 in 1992 to 165000 in 2009), and the abortion treatment rate declined by 57% (from 7.1 to 3.1 per 1000 women) over the same period. The decline in this rate was more striking for more serious complications than for less serious ones (69% compared with 52%). Possible reasons for these overall declines include increasing use and greater availability of safer abortion methods, and greater ability to pay for such methods as well as a possible decline in incidence of unintended pregnancy and abortion through more widespread use of modern contraception. PMID- 22920631 TI - Innate immunity in the pathogenesis of cholangiopathy: a recent update. AB - Biliary innate immunity is involved in the pathogenesis of cholangiopathies in patients with various biliary diseases. Biliary epithelial cells possess an innate immune system consisting of the Toll-like receptor (TLR) family and recognize pathogen-associated molecular patterns (PAMPs). Recently, regulatory mechanisms by intracellular negative regulators including peroxisome proliferator activated receptor-gamma and micro-RNA have been clarified. In primary biliary cirrhosis (PBC) and primary sclerosing cholangitis, dysregulated biliary innate immunity, namely hyper-responsiveness to PAMPs, is associated with the histopathogenesis of cholangiopathy. Moreover, biliary epithelial cells produce monocyte chemotactic protein-1 (MCP-1/CCL2) as a result of the innate immune response and bile ductules play a role in hepatic fibrosis caused by hepatic stellate cells (HSCs). Also, biliary innate immune responses induce the production of two chemokines, fractalkine and macrophage inflammatory protein 3alpha (MIP-3alpha), causing the migration of inflammatory cells and a population of antigen-presenting cell found in epithelium, Langerhans cell, and involve chronic cholangitis associated with biliary epithelium-specific innate and acquired immunity in PBC. PMID- 22920632 TI - JCV-negative natalizumab-associated progressive multifocal leukoencephalopathy: a clinico-radiological diagnosis. PMID- 22920633 TI - Muscle biopsy findings predictive of malignancy in rare infiltrative dermatomyositis. AB - OBJECTIVE: The characteristic pathological muscular findings of polymyositis (PM) and dermatomyositis (DM) have been shown to reflect their different pathogeneses. Here, we characterized the muscle biopsy findings of PM and DM patients with or without malignancy. METHODS: We evaluated the muscle biopsy findings of 215 consecutive PM and DM patients admitted to our hospital between 1970 and 2009. Pathology of the lesion biopsy sections was classified into 3 types: endomysial infiltration-type, perivascular infiltration-type, and rare-infiltrative-type. RESULTS: There was no difference between the muscle pathology of PM patients with and without malignancy. However, the incidence of rare-infiltrative type muscle pathology in DM patients with malignancy was significantly higher than in those without such tumors (p=0.0345). CONCLUSION: The incidence of rare-infiltrative type muscle pathology may be a predictive marker of DM with malignancy. PMID- 22920634 TI - Solid phase excitation-emission fluorescence method for the classification of complex substances: Cortex Phellodendri and other traditional Chinese medicines as examples. AB - A novel, simple and direct fluorescence method for analysis of complex substances and their potential substitutes has been researched and developed. Measurements involved excitation and emission (EEM) fluorescence spectra of powdered, complex, medicinal herbs, Cortex Phellodendri Chinensis (CPC) and the similar Cortex Phellodendri Amurensis (CPA); these substances were compared and discriminated from each other and the potentially adulterated samples (Caulis mahoniae (CM) and David poplar bark (DPB)). Different chemometrics methods were applied for resolution of the complex spectra, and the excitation spectra were found to be the most informative; only the rank-ordering PROMETHEE method was able to classify the samples with single ingredients (CPA, CPC, CM) or those with binary mixtures (CPA/CPC, CPA/CM, CPC/CM). Interestingly, it was essential to use the geometrical analysis for interactive aid (GAIA) display for a full understanding of the classification results. However, these two methods, like the other chemometrics models, were unable to classify composite spectral matrices consisting of data from samples of single ingredients and binary mixtures; this suggested that the excitation spectra of the different samples were very similar. However, the method is useful for classification of single-ingredient samples and, separately, their binary mixtures; it may also be applied for similar classification work with other complex substances. PMID- 22920635 TI - Monoclonal gammopathies: disambiguation. PMID- 22920630 TI - Characterization of genetic rearrangements in esophageal squamous carcinoma cell lines by a combination of M-FISH and array-CGH: further confirmation of some split genomic regions in primary tumors. AB - BACKGROUND: Chromosomal and genomic aberrations are common features of human cancers. However, chromosomal numerical and structural aberrations, breakpoints and disrupted genes have yet to be identified in esophageal squamous cell carcinoma (ESCC). METHODS: Using multiplex-fluorescence in situ hybridization (M FISH) and oligo array-based comparative hybridization (array-CGH), we identified aberrations and breakpoints in six ESCC cell lines. Furthermore, we detected recurrent breakpoints in primary tumors by dual-color FISH. RESULTS: M-FISH and array-CGH results revealed complex numerical and structural aberrations. Frequent gains occurred at 3q26.33-qter, 5p14.1-p11, 7pter-p12.3, 8q24.13-q24.21, 9q31.1 qter, 11p13-p11, 11q11-q13.4, 17q23.3-qter, 18pter-p11, 19 and 20q13.32-qter. Losses were frequent at 18q21.1-qter. Breakpoints that clustered within 1 or 2 Mb were identified, including 9p21.3, 11q13.3-q13.4, 15q25.3 and 3q28. By dual-color FISH, we observed that several recurrent breakpoint regions in cell lines were also present in ESCC tumors. In particular, breakpoints clustered at 11q13.3 q13.4 were identified in 43.3% (58/134) of ESCC tumors. Both 11q13.3-q13.4 splitting and amplification were significantly correlated with lymph node metastasis (LNM) (P = 0.004 and 0.022) and advanced stages (P = 0.004 and 0.039). Multivariate logistic regression analysis revealed that only 11q13.3-q13.4 splitting was an independent predictor for LNM (P = 0.026). CONCLUSIONS: The combination of M-FISH and array-CGH helps produce more accurate karyotypes. Our data provide significant, detailed information for appropriate uses of these ESCC cell lines for cytogenetic and molecular biological studies. The aberrations and breakpoints detected in both the cell lines and primary tumors will contribute to identify affected genes involved in the development and progression of ESCC. PMID- 22920636 TI - Evolving strategies in the diagnosis, treatment, and monitoring of myeloma kidney. PMID- 22920637 TI - The pathogenesis of acute kidney impairment in patients with multiple myeloma. AB - Acute kidney injury in myeloma, a serious complication associated with poor prognosis, is generally mediated by the toxic and inflammatory effects of monoclonal free light chains (FLCs) on kidney proximal tubule cells and by the formation of intratubular casts through interaction with Tamm-Horsfall proteins. Production of excessive quantities of FLCs is seen in most cases of FLC associated kidney injury, although a direct relation between quantity and nephrotoxicity does not exist, indicating variable toxicity among light chain species. Toxic effects of FLCs include inhibition of transport functions, Fanconi syndrome, generation of reactive oxygen species, cytoskeletal abnormalities, and apoptosis and necrosis in proximal tubule cells. Excessive endocytosis of FLCs in proximal tubule cells also induces cell stress responses that result in stimulation of inflammatory pathways through activation of nuclear transcription factors kappaB and mitogen-activated protein kinases, induction of proinflammatory cytokines, and epithelial to mesenchymal transition. The mechanisms of nephrotoxicity of FLC described here explain the basis of acute kidney injury seen in patients with multiple myeloma and provide the rationale for eliminating or reducing the FLC burden in myeloma patients with renal involvement. The inflammatory pathways that are activated as a result of FLC toxicity also show clearly how severe chronic tubulointerstitial nephritis can occur in patients with myeloma kidney and identify several attractive opportunities for novel therapeutic interventions. PMID- 22920638 TI - The role of immunological assessment in patients with acute kidney injury and possible myeloma. AB - Acute kidney injury (AKI) in plasma cell multiple myeloma (MM) is a medical emergency requiring a rapid, accurate diagnosis because prompt commencement of therapy and supportive care are essential. Most cases of AKI in MM are caused by cast nephropathy secondary to high levels of nephrotoxic serum free light chains (FLCs). This article reviews the role and relevance of FLC as an immunological biomarker for AKI and MM. We discuss the utility of FLC measurement as a screening tool in the cast nephropathy clinical setting. We present its analytical pitfalls and evolving evidence for the integration of an FLC assay into clinical algorithms. PMID- 22920639 TI - Monoclonal gammopathy of undetermined significance: an update for nephrologists. AB - Screening for a monoclonal protein is a common part of the assessment of patients presenting with a renal injury. While in the settings of acute kidney injury, chronic kidney disease and proteinuria monoclonal proteins can be associated with significant pathologies such as cast nephropathy, amyloidosis, and light chain deposition disease, they can also be an unrelated finding. The purpose of this review is to provide the nephrologist with an update to the diagnostic assessment and risk stratification of monoclonal proteins to avoid unnecessary investigation and monitoring of those patients with low-risk monoclonal gammopathies. PMID- 22920640 TI - Current approach to diagnosis and management of acute renal failure in myeloma patients. AB - Renal impairment is a serious complication of multiple myeloma. The primary cause of renal failure in myeloma is damage to the kidney by excessive amounts of light chain produced by the myeloma tumor, giving rise to cast nephropathy (myeloma kidney), although there are several other important precipitants. Significantly poor prognosis is observed in patients who do not recover their renal function; however, with the advent of more effective therapies and a greater understanding of the pathogenesis of the underlying process, it has become possible to reverse renal impairment in greater numbers of patients. Determining whether the renal impairment is due to cast nephropathy should be the first priority, and once the diagnosis is confirmed, appropriate treatment should be initiated without delay. Reduction of serum free light chain is the key to recovery of renal function in these patients. The role of chemotherapy and extracorporeal removal of light chain are discussed. PMID- 22920641 TI - Achieving an early myeloma response in patients with kidney impairment. AB - There is increasing evidence, particularly in severe acute kidney injury, that treatment of multiple myeloma with regimens that include dexamethasone in combination with novel chemotherapy agents are associated with an early disease response in most patients. However, the evidence to guide the optimal chemotherapy regimen in patients with kidney impairment is limited, and treatment choices are complicated by the effect of kidney function on drug dosing. Here, we summarize the current status of this field, with a particular focus on chemotherapy regimens that are based on dexamethasone and novel agents and an outline of those areas in which further work is needed to improve the evidence base. PMID- 22920642 TI - Evolving chemotherapy options for the treatment of myeloma kidney: a 40-year perspective. AB - Kidney impairment (KI) at the time of initial diagnosis is common in myeloma. The improvement of kidney function and the reversal of KI are of utmost importance. Recent advances have made it possible to reverse acute kidney damage due to myeloma in most patients, at least if treatment is immediately implemented. Immediate antimyeloma therapy and appropriate hydration are the most commonly used treatment modalities for the management of acute KI related to myeloma. Mechanical approaches can only temporarily reduce the free light-chain load, and without effective chemotherapy they are probably not able to significantly improve kidney function. However, the role of mechanical approaches together with effective chemotherapy is still being explored. Thalidomide, lenalidomide, and bortezomib have improved the survival of myeloma patients, but they have also improved the outcome of patients presenting with KI. Thalidomide is safe to use on patients with KI without dose adjustments. Lenalidomide needs dose modification, but it can improve kidney function in many patients. Bortezomib seems to be the agent of choice for most patients presenting with KI without dose modifications. This review focuses on the management of patients presenting with "myeloma kidney" using modern chemotherapy approaches, especially novel agents. PMID- 22920643 TI - The rationale and evidence base for the direct removal of serum-free light chains in the management of myeloma kidney. AB - Myeloma kidney (cast nephropathy) causing severe acute kidney injury occurs in up to 10% of patients with multiple myeloma. The lesion is caused by exposure of the kidneys to high serum levels of free clonal immunoglobulin light chains (LCs) and is associated with very high morbidity and mortality. The current focus on the management of this complication is on early and aggressive treatment to rapidly reduce the serum levels of the immunoglobulin LC clone and protect the kidneys from continuing injury. This has promoted intense interest in the role of direct (extracorporeal) removal of free LCs from serum by plasma exchange or high cut off (protein permeable) hemodialysis. However, it remains uncertain whether direct removal provides an additional measurable clinical benefit over the current standard of care; rapid institution of treatment with a dexamethasone- and bortezomib-based chemotherapy regime. In this article, we review the rationale for direct removal of free LCs and the current clinical evidence base for plasma exchange and high cut-off hemodialysis. PMID- 22920644 TI - Optimizing treatment strategies in myeloma cast nephropathy: rationale for a randomized prospective trial. AB - Renal failure is a frequent complication of multiple myeloma (MM) that strongly affects patient survival. Although a variety of renal diseases may be observed in MM, myeloma cast nephropathy (MCN), a tubulo-interstitial disorder related to precipitation of a monoclonal light chain (LC) within tubular distal lumens, is the main cause of severe and persistent renal failure. To date, the respective frequency and initial evolution of renal disorders associated with monoclonal LC in MM remain poorly defined. Treatment of MCN relies on urgent symptomatic measures and rapid introduction of chemotherapy to reduce the production of monoclonal LC. The introduction of novel chemotherapy regimens based on the association of bortezomib with dexamethasone is likely to have improved the prognosis of MM patients with renal failure. In addition, the combination of novel agents with efficient removal of circulating LC through high cut-off hemodialysis membrane may further increase renal response rate. However, the impact on patient and renal outcomes of these potential therapeutic advances has not been evaluated in prospective studies. The randomized trials EuLITE in the UK and Germany and MYRE in France should help to answer these issues. MYRE is a randomized controlled phase III trial (NCT01208818) that aims to better define the epidemiology and typology of inaugural renal failure in MM and to optimize therapy of MCN patients with and without dialysis-dependent renal failure. PMID- 22920645 TI - Myeloma kidney: improving clinical outcomes? AB - Renal impairment is a common complication of multiple myeloma, affecting 20% to 40% of new cases (depending on the definition). Most cases are mild and easily reversible, but it may manifest as severe acute renal injury requiring dialysis. Renal impairment is associated with a large tumor mass and consequently confers a poor prognosis. The prognosis of myeloma has improved with the introduction of novel agents and autologous stem cell transplantation. These improvements appear to apply equally to patients with renal impairment, although the risk of complication is usually higher in this group of patients. In addition to improved overall survival, there is some evidence that novel therapies have improved the renal prognosis. Treatment with high-dose dexamethasone and bortezomib can rapidly reduce light chain production and provide an opportunity for renal recovery. Although trials of plasma exchange (to remove the nephrotoxic light chain) have shown a disappointing lack of benefit, high cutoff dialysis removes larger quantities of light chain; therefore, trials are underway to investigate whether this can improve the renal prognosis independently of chemotherapy. Outcomes in patients with myeloma kidney do appear to be improving, but more trials are needed (some of which are in progress). There is cause for optimism for physicians and for patients suffering from this condition. PMID- 22920646 TI - Development and reproducibility of a 3D stereophotogrammetric reference frame for facial soft tissue growth of babies and young children with and without orofacial clefts. AB - The aim of this study was to develop a reference frame for three dimensional (3D) facial soft tissue growth analysis in children and to determine its reproducibility. Two observers twice placed the reference frame on 39 3D stereophotogrammetry facial images of children with orofacial clefts and control children. The observers' performances were analyzed by calculating mean distance, distance variability, and P95 between the same facial surfaces at two different time points. Correlations between observers were analyzed with Pearson's correlation coefficient. The influence of presence of a cleft, absence of one ear in the photograph, and age on the reproducibility of the reference frame was checked using Student's t test. Results of intraobserver comparisons showed a mean distance of <0.40 mm, distance variability of <0.51 mm, and P95 of <0.80 mm. For interobserver reliability, the mean distance was <0.52 mm, distance variability was <0.53 mm, and P95 was <1.10 mm. Presence of a cleft, age, and absence of one ear on the 3D photograph did not have a significant influence on the reproducibility of placing the reference frame. The children's reference frame is a reproducible method to superimpose on 3D soft tissue stereophotogrammetry photographs of growing individuals with and without orofacial clefts. PMID- 22920647 TI - Reinforced self-assembly of donor-acceptor pi-conjugated molecules to DNA templates by dipole-dipole interactions together with complementary hydrogen bonding interactions for biomimetics. AB - One of the most important criteria for the successful DNA-templated polymerization to generate fully synthetic biomimetic polymers is to design the complementary structural monomers, which assemble to the templates strongly and precisely before carrying polymerization. In this study, water-soluble, laterally thymine-substituted donor-acceptor pi-conjugated molecules were designed and synthesized to self-assemble with complementary oligoadenines templates, dA(20) and dA(40), into stable and tubular assemblies through noncovalent interactions including pi-pi stacking, dipole-dipole interactions, and the complementary adenine-thymine (A-T) hydrogen-bonding. UV-vis, fluorescence, circular dichroism (CD), atomic force microscopy (AFM), and transmission electron microscopy (TEM) techniques were used to investigate the formation of highly robust nanofibrous structures. Our results have demonstrated for the first time that the dipole dipole interactions are stronger and useful to reinforce the assembly of donor acceptor pi-conjugated molecules to DNA templates and the formation of the stable and robust supramolecular nanofibrous complexes together with the complementary hydrogen bonding interactions. This provides an initial step toward DNA-templated polymerization to create fully synthetic DNA-mimetic polymers for biotechnological applications. This study also presents an opportunity to precisely position donor-acceptor type molecules in a controlled manner and tailor-make advanced materials for various biotechnological applications. PMID- 22920648 TI - Application of the QuantiFERON(r)-TB Gold test in erythema induratum. AB - Erythema induratum (EI) was originally described by Ernest Bazin in 1861 as nodular lesions on the legs in association with tuberculosis (TB). A 33-year-old woman was referred to our hospital with tender ulcerative nodules on her legs. Skin biopsies revealed lobular inflammation of the subcutaneous fat with vasculitis. Although conservative treatment was given, the lesions did not improve. Several months later as the lesions persisted, we suspected a TB infection and additional tests were performed. The chest roentgenogram results were normal. The skin biopsies were negative for acid-fast bacilli (AFB). Mycobacterial cultures of the blood and skin were negative. However, the QuantiFERON(r)-TB Gold test was positive, which led to a diagnosis of latent TB infection being made. The patient was treated with multidrug antituberculosis therapy, which successfully resolved her skin lesions. Therefore, reported herein is the application of the QuantiFERON(r)-TB Gold test for the confirmation of latent TB infection in EI patients. PMID- 22920649 TI - Unexpected genetic diversity of Mycoplasma agalactiae caprine isolates from an endemic geographically restricted area of Spain. AB - BACKGROUND: The genetic diversity of Mycoplasma agalactiae (MA) isolates collected in Spain from goats in an area with contagious agalactia (CA) was assessed using a set of validated and new molecular typing methods. Validated methods included pulsed field gel electrophoresis (PFGE), variable number of tandem repeats (VNTR) typing, and Southern blot hybridization using a set of MA DNA probes, including those for typing the vpma genes repertoire. New approaches were based on PCR and targeted genomic regions that diverged between strains as defined by in silico genomic comparisons of sequenced MA genomes. RESULTS: Overall, the data showed that all typing tools yielded consistent results, with the VNTR analyses being the most rapid method to differentiate the MA isolates with a discriminatory ability comparable to that of PFGE and of a set of new PCR assays. All molecular typing approaches indicated that the Spanish isolates from the endemic area in Murcia were very diverse, with different clonal isolates probably restricted to separate, but geographically close, local areas. CONCLUSIONS: The important genetic diversity of MA observed in infected goats from Spain contrasts with the overall homogeneity of the genomic background encountered in MA from sheep with CA in Southern France or Italy, suggesting that assessment of the disease status in endemic areas may require different approaches in sheep and in goats. A number of congruent sub-typing tools are now available for the differentiation of caprine isolates with comparable discriminatory powers. PMID- 22920650 TI - Delineating the degree of association between biomarkers of arsenic exposure and type-2 diabetes mellitus. AB - Non-carcinogenic effects in low-level (< 100 MUgL(-1)) arsenic (As)-impacted populations, such as the development and progression of type-2 diabetes mellitus (T2DM), are often neglected given the primary emphasis of public health authorities on As carcinogenicity. We gathered studies reporting urinary biomarkers of As exposure (U-As) and biomarkers associated with T2DM and its complications (U-T2DM), such as renal damage, oxidation stress, low-grade inflammation, and endothelial damage. Studied U-T2DM biomarkers were: 8-hydroxy 2'deoxyguanosine, N-acetyl-beta-d-glucosaminidase, beta2-microglobulin, and albumin. Data was expressed as: either arithmetic means and standard deviations, or geometric means and geometric standard deviations, or correlation coefficients of U-As and U-T2DM. Urinary As concentrations were consistently associated with the aforementioned biomarkers of T2DM pathologic complications. Despite the limited selectivity of the selected T2DM biomarkers, a per unit change in As exposure level was reflected in the corresponding T2DM biomarker urinary concentrations. Our systematic review provides new evidence on the role of environmental As exposures influencing the T2DM disease process. Additional epidemiologic studies onto the association between As and T2DM should incorporate both urinary As and T2DM biomarkers, as suggested in this study, in order to evaluate subclinical effects of low-level As exposures. PMID- 22920651 TI - Synthesis of tri-O-acetyl-D-allal from levoglucosenone. AB - Tri-O-acetyl-D-allal has been enantiospecifically synthesized in six steps from levoglucosenone in 55% overall yield. A key step in the synthesis is the anhydro bridge ring-opening with concomitant formation of a 1,3-oxathiolane-2-thione ring. PMID- 22920652 TI - Contraction and expansion of the silicon scaffold of stable Si6R6 isomers. AB - The reactivity of two stable Si(6)R(6) clusters (4 and 5, R = 2,4,6 (i)Pr(3)C(6)H(2)) with unsymmetrical substitution patterns (including Si, SiR, and SiR(2) vertices) is reported. In order to account for the importance of such clusters as model systems for transient intermediates in the deposition of elemental silicon, we here propose the term "siliconoids" for silicon clusters with unsaturated valencies. With the hexasilaprismane 8a, a saturated-i.e., non siliconoid-Si(6)R(6) isomer is accessible from a suitable Si(3) precursor. Thermal redistribution of the substituents converts 1,1,2-trichlorocyclotrisilane 6 into the corresponding 1,2,3-derivative 7 prior to the requisite reductive coupling step leading to 8a. On the other hand, a stable expanded Si(11) siliconoid 9 was isolated as a minor side product of the thermal isomerization of 4 to 5, thus providing a first example of siliconoid cluster expansion in the condensed phase. In the solid-state structure, the two unsubstituted vertices of 9 strongly interact in a staggered propellane-like fashion. Oxidative cluster contraction of a siliconoid scaffold is observed upon treatment of siliconoid 5 with a large excess of iodine in refluxing toluene, thus providing access to a highly functionalized hexaiodocyclopentasilane 11 in high yield. Conversely, chlorination of the isomeric 4 with BiCl(3) as a mild source of Cl(2) results in a complex mixture of products from chlorination of the unsubstituted vertices as well as sigma-bonds of the cluster framework of 4. The main product, 1,2 dichlorotricyclo[2.2.0.0(2,5)]hexasilane 12, undergoes thermal cluster contraction to give tricyclo[2.1.0.0(2,5)]pentasilane 14 with an exohedral chlorosilyl group. PMID- 22920653 TI - Giant viruses coexisted with the cellular ancestors and represent a distinct supergroup along with superkingdoms Archaea, Bacteria and Eukarya. AB - BACKGROUND: The discovery of giant viruses with genome and physical size comparable to cellular organisms, remnants of protein translation machinery and virus-specific parasites (virophages) have raised intriguing questions about their origin. Evidence advocates for their inclusion into global phylogenomic studies and their consideration as a distinct and ancient form of life. RESULTS: Here we reconstruct phylogenies describing the evolution of proteomes and protein domain structures of cellular organisms and double-stranded DNA viruses with medium-to-very-large proteomes (giant viruses). Trees of proteomes define viruses as a 'fourth supergroup' along with superkingdoms Archaea, Bacteria, and Eukarya. Trees of domains indicate they have evolved via massive and primordial reductive evolutionary processes. The distribution of domain structures suggests giant viruses harbor a significant number of protein domains including those with no cellular representation. The genomic and structural diversity embedded in the viral proteomes is comparable to the cellular proteomes of organisms with parasitic lifestyles. Since viral domains are widespread among cellular species, we propose that viruses mediate gene transfer between cells and crucially enhance biodiversity. CONCLUSIONS: Results call for a change in the way viruses are perceived. They likely represent a distinct form of life that either predated or coexisted with the last universal common ancestor (LUCA) and constitute a very crucial part of our planet's biosphere. PMID- 22920654 TI - Performance of "VIKIA Malaria Ag Pf/Pan" (IMACCESS(r)), a new malaria rapid diagnostic test for detection of symptomatic malaria infections. AB - BACKGROUND: Recently, IMACCESS(r) developed a new malaria test (VIKIA Malaria Ag Pf/PanTM), based on the detection of falciparum malaria (HRP-2) and non falciparum malaria (aldolase). METHODS: The performance of this new malaria rapid diagnostic test (RDT) was assessed using 1,000 febrile patients seeking malaria treatment in four health centres in Cambodia from August to December 2011. The results of the VIKIA Malaria Ag Pf/Pan were compared with those obtained by microscopy, the CareStart MalariaTM RDT (AccessBio(r)) which is currently used in Cambodia, and real-time PCR (as "gold standard"). RESULTS: The best performances of the VIKIA Malaria Ag Pf/PanTM test for detection of both Plasmodium falciparum and non-P. falciparum were with 20-30 min reading times (sensitivity of 93.4% for P. falciparum and 82.8% for non-P. falciparum and specificity of 98.6% for P. falciparum and 98.9% for non-P. falciparum) and were similar to those for the CareStart MalariaTM test. CONCLUSIONS: This new RDT performs similarly well as other commercially available tests (especially the CareStart MalariaTM test, used as comparator), and conforms to the World Health Organization's recommendations for RDT performance. It is a good alternative tool for the diagnosis of malaria in endemic areas. PMID- 22920656 TI - Using the teach-back method to increase maternal immunization literacy among low income pregnant women in Jamaica: a pilot study. AB - The purpose of this pilot study was to assess maternal health literacy of pregnant women in Jamaica and evaluate their ability to communicate the benefits, risks, and safety of the Bacillus Calmette-Guerin (BCG) and Hepatitis B (hep B) vaccines after using the teach back method. REALM scores were moderately, positively correlated with identification of the BCG vaccine risks (r = .43, p = .01) and with hep B vaccine benefits (r = .34, p = .05) and risks (r = .42, p = .01). Women who gave incorrect responses about the benefits or risks of the vaccines had lower REALM scores than women who gave completely correct or partially correct responses. PMID- 22920655 TI - The First Tomoh Masaki Award (2011). AB - Professor Tomoh Masaki, a Japanese physician-scientist born in 1934, is particularly known for the discovery of endothelium-derived peptide endothelin and its receptors, among many other scientific achievements. In recognition of his work, the Tomoh Masaki Award was established in 2011 by the Endothelin International Advisory Board of The International Conferences on Endothelin as a biannual scientific prize in recognition of Masaki's innovative and ground breaking work that has led to new clinical applications. The inaugural Tomoh Masaki Award was presented at The Twelfth International Conference on Endothelin held in Cambridge, UK, to one his former graduate students, Professor Masashi Yanagisawa as the first recipient of this award, who played an instrumental role in the discovery of endothelin at the University of Tsukuba, Japan. The article summarizes the scientific achievements of Masaki and the awardee, Masashi Yanagisawa, also including personal reflections of two of Masaki's former graduate students on their teacher as well as on the awardee of The First Tomoh Masaki Award 2011 and their work as scientists and their role as mentors. PMID- 22920657 TI - The health care experiences of the preschool child with autism. AB - It is known that children with autism spectrum disorder (ASD) visit health care providers (HCPs) more frequently than typically developing peers, and mothers experience barriers in this process. The purpose of this interpretive phenomenological study was to gain a better understanding of a mother's experiences of taking her child with ASD to the HCP. Two themes related to the health care experience of the child surfaced from the study. These themes included feelings that HCPs do not "get" the complexity of caring for the child and marginalization of mothers by the HCP. The need for creation of child specific profiles emerged from this study. PMID- 22920658 TI - Nurses' role in the prevention of infant mortality in 1884-1925: health disparities then and now. AB - Nursing has a strong historical precedence in the treatment of health disparities. This article evaluates the public health nurses' (PHNs') role with infant mortality during 1884-1920, specifically how nursing care impacted on conditions of poverty, poor nutrition, poor living conditions, lack of education, and lack of governmental policies that contributed to the poor health of infants a century ago. The historical significance of the early PHNs' role can improve our understanding of nursing practice with childhood health issues today. Suggestions are made for nursing to focus on health disparities in childhood obesity, in areas of environmental and policy changes, and the development of social programs and education for families to support healthier living. PMID- 22920659 TI - Support needs and preferences of young adolescents with asthma and allergies: "just no one really seems to understand". AB - The objectives of this study were to identify support needs, support resources, and support barriers for young adolescents with asthma and allergies and to describe preferences for an accessible support intervention. Adolescents (N = 57) completed a survey questionnaire. Eight young adolescents, 10 parents, and 5 older adolescents participated in separate group interviews. Young adolescents' challenges included transition to self-care, balancing restrictions with safety, social isolation, and loneliness. Young teens recommended supportive networks facilitated by older adolescent peers and wanted to meet with other young adolescents living with asthma and allergies online and share information, advice, and encouragement with them. PMID- 22920660 TI - Is rural school-aged children's quality of life affected by their responses to asthma? AB - The unpredictable nature of asthma makes it stressful for children and can affect their quality of life (QOL). An exploratory analysis of 183 rural school-aged children's data was conducted to determine relationships among demographic factors, children's responses to asthma (coping and asthma self-management), and their QOL. Coping frequency, asthma severity, and race/ethnicity significantly predicted children's asthma-related QOL. Children reported more frequent coping as asthma-related QOL worsened (higher scores). Children with more asthma severity had worse asthma-related QOL. Post hoc analyses showed that racial/ethnic minorities reported worse asthma-related QOL scores than did non Hispanic Whites. PMID- 22920662 TI - Integrative review: parent perspectives on care of their child at the end of life. AB - This integrative review aims to describe parents' perspectives on end-of-life care for their children. Fifteen publications from a literature search of the Cochrane databases, CINAHL, MEDLINE, and PSYCHinfo were included in the review. Recurring themes included poor communication/lack of information, strained relationships/inadequate emotional support, parental need to maintain parent/child relationships in life and death, quality of care continues after the death of the child, influence of services/planning on parent/child impacts quality of life, and the difficult decision to terminate life support. No studies were identified that focused on parents' perspectives on the care their child received at the end of life. Further research that focuses on the special needs of parents at this difficult time is needed. PMID- 22920661 TI - Caring for children with life-threatening illnesses: impact on White, African American, and Latino families. AB - We describe the racial and ethnic variation in family impact resulting from caring for a child with a life-threatening illness. Parents of children aged 2-21 years diagnosed with a potentially life-threatening illness and enrolled in Florida's Medicaid and Children's Medical Services Network programs were surveyed. Two hundred sixty-six telephone surveys were conducted in English and Spanish between November 2007 and April 2008. In adjusted models, compared with Whites, Latinos reported that their child's illness resulted in a greater negative impact on the family. Continued study of this group of parents is critical to developing culturally appropriate interventions to reduce strain and burden and improve the quality of life for families. PMID- 22920663 TI - What level of knowledge do elementary school teachers possess concerning the care of children with asthma? A pilot study. AB - A self-report questionnaire was used to assess the level of knowledge among a convenience sample of 34 elementary school teachers in a rural school district in Illinois. The questionnaire addressed general asthma knowledge and management, including signs and symptoms, triggers, and treatment. The results suggest a knowledge deficit among this sample of elementary school teachers; the average score was 75%. Teachers with an increased exposure/experience with asthma scored significantly higher than did those with limited exposure. Implications of these findings for schools in rural areas are discussed. PMID- 22920664 TI - Emancipated minors: health policy and implications for nursing. AB - Emancipation is a process that offers adolescents a solution to serve in the role of an adult in circumstances that warrant the need for more autonomy. The process and definitions of emancipation are often ambiguous for adolescents, nurses, and other health care providers that provide services for these individuals. Emancipation can be additionally perplexing with the lack of overarching federal guidelines and the fragmented definitions among various states. Nursing has a significant and legal role in providing care for emancipated minors and a more global duty to advocate for adolescents in situations that necessitate emancipation. This article explores the emancipation process, the laws of each state that govern emancipation, the facilitators and barriers, and the role of nursing in the emancipation process. PMID- 22920665 TI - The integration of a specialized eating disorders nurse on a general inpatient pediatric unit. AB - Eating disorders (EDs) affect approximately 5% of Canadian adolescents. Patients experiencing acute medical complications of their illness are often treated on a general pediatric ward with mixed populations. Twenty-one health care providers shared their experiences caring for youth with EDs and provided feedback regarding the integration of a specialized ED nurse (ED-RN). Findings suggest that an RN and ED-RN model produces consistent care for ED patients and satisfying therapeutic relationships for nurses. ED-RNs caring for youth with EDs need support from their peers, whereas other nurses need training regarding this population. Suggestions for the integration of specialized RN roles are discussed. PMID- 22920666 TI - Challenges in treating oppositional defiant disorder in a pediatric medical setting: a case study. AB - The following case study is presented to highlight the importance of consistency in identifying and treating oppositional defiant disorder in a pediatric patient with a life-threatening medical illness. A pediatric transplant patient's oppositional behaviors are described, as well as the educational behavioral training program provided to the patient's caregivers and medical staff. As a result of the training, the patient engaged in less oppositional behavior, was more cooperative and pleasant with staff, and was more compliant with her treatment. Subjective reports from caregivers indicated that the training with its emphasis on consistency effectively reduced the patient's symptoms and enhanced the caregivers' ability to care for the patient. PMID- 22920667 TI - Selective photoelectrocatalytic degradation of recalcitrant contaminant driven by an n-P heterojunction nanoelectrode with molecular recognition ability. AB - With in situ molecular imprinting technique, a novel nanoelectrode (MI, n-P) TiO(2) with n-P heterojunction and molecular recognition ability was fabricated by liquid phase deposition at low temperature. Using bisphenol A (BPA) as template, the spindle-like TiO(2) particles 40-80 nm in size compactly grew on the boron-doped diamond (BDD) substrate. Several spectroscopy measurements demonstrate that the BPA molecules were successfully imprinted on the TiO(2) matrix and numerous specific recognition sites to template were formed after calcination. The transient photocurrent response experiments have confirmed that the (MI, n-P)-TiO(2) nanoelectrode displays outstanding photoelectrocatalytic (PEC) activity and selectivity. The (MI, n-P)-TiO(2) is further employed in degrading the mixture containing BPA and interference 2-naphthol (2-NP). After 2 h, BPA removal reaches 97%, and corresponding kinetic constant is 1.76 h(-1), which is 4.6 times that of 2-NP removal even if 2-NP is much more concentrated. On the electrode without molecular imprint, the removal rate constants of BPA and 2-NP approximately equal, only about 0.5 h(-1). The results indicate that selective PEC oxidation can be realized readily on the (MI, n-P)-TiO(2) nanoelectrode due to the synergetic effects including strong recognition adsorption, formation of n-P heteojunction, and external electrostatic field. The effect of formation of n-P heterojunction on the enhanced PEC performances is also discussed. PMID- 22920668 TI - Reversal by RARalpha agonist Am580 of c-Myc-induced imbalance in RARalpha/RARgamma expression during MMTV-Myc tumorigenesis. AB - INTRODUCTION: Retinoic acid signaling plays key roles in embryonic development and in maintaining the differentiated status of adult tissues. Recently, the nuclear retinoic acid receptor (RAR) isotypes alpha, beta and gamma were found to play specific functions in the expansion and differentiation of the stem compartments of various tissues. For instance, RARgamma appears to be involved in stem cell compartment expansion, while RARalpha and RARbeta are implicated in the subsequent cell differentiation. We found that over-expressing c-Myc in normal mouse mammary epithelium and in a c-Myc-driven transgenic model of mammary cancer, disrupts the balance between RARgamma and RARalpha/beta in favor of RARgamma. METHODS: The effects of c-Myc on RAR isotype expression were evaluated in normal mouse mammary epithelium, mammary tumor cells obtained from the MMTV Myc transgenic mouse model as well as human normal immortalized breast epithelial and breast cancer cell lines. The in vivo effect of the RARalpha-selective agonist 4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)carboxamido]benzoic acid (Am580) was examined in the MMTV-Myc mouse model of mammary tumorigenesis. RESULTS: Modulation of the RARalpha/beta to RARgamma expression in mammary glands of normal mice, oncomice, and human mammary cell lines through the alteration of RAR-target gene expression affected cell proliferation, survival and tumor growth. Treatment of MMTV-Myc mice with the RARalpha-selective agonist Am580 led to significant inhibition of mammary tumor growth (~90%, P<0.001), lung metastasis (P<0.01) and extended tumor latency in 63% of mice. Immunocytochemical analysis showed that in these mice, RARalpha responsive genes such as Cyp26A1, E cadherin, cellular retinol-binding protein 1 (CRBP1) and p27, were up-regulated. In contrast, the mammary gland tumors of mice that responded poorly to Am580 treatment (37%) expressed significantly higher levels of RARgamma. In vitro experiments indicated that the rise in RARgamma was functionally linked to promotion of tumor growth and inhibition of differentiation. Thus, activation of the RARalpha pathway is linked to tumor growth inhibition, differentiation and cell death. CONCLUSIONS: The functional consequence of the interplay between c Myc oncogene expression and the RARgamma to RARalpha/beta balance suggests that prevalence of RARgamma over-RARalpha/beta expression levels in breast cancer accompanied by c-Myc amplification or over-expression in breast cancer should be predictive of response to treatment with RARalpha-isotype-specific agonists and warrant monitoring during clinical trials. PMID- 22920670 TI - Vascular endothelial growth factor in patients with exudative age-related macular degeneration treated with ranibizumab. AB - OBJECTIVES: To analyze the temporal correlations of vascular endothelial growth factor (VEGF) suppression, morphologic recurrence of choroidal neovascularization (CNV), and visual acuity loss in eyes with exudative age-related macular degeneration (AMD) treated with ranibizumab. DESIGN: Nonrandomized, prospective, clinical study. PARTICIPANTS: Forty-seven eyes of 47 patients with exudative AMD undergoing intravitreal ranibizumab injections. METHODS: Aqueous humor specimens were taken before each intravitreal ranibizumab injection. Visual acuity testing, spectral domain optical coherence tomography (SD-OCT), and fundoscopy were performed before each injection. Vascular endothelial growth factor A was measured by Luminex multiplex bead analysis (Luminex Inc., Austin, TX). MAIN OUTCOME MEASURES: Intraocular VEGF concentration, recurrence of CNV activity shown by SD-OCT, and vision loss. RESULTS: Ranibizumab resulted in complete VEGF suppression within a mean period of 37.8 days (standard deviation [SD] +/- 4.8 days; range, 26-49 days). Recurrences of CNV activity as determined by SD-OCT occurred 93.7 days (SD +/- 69.9 days; range, 57-368 days) after the last ranibizumab treatment. The VEGF levels were never suppressed when a recurrence occurred. Functional recurrence (visual acuity) occurred 114.3 days (SD +/- 81.4 days; range, 57-398 days) after previous treatment. The VEGF levels did not differ significantly between baseline and recurrence (69.3 pg/ml vs. 74.14 pg/ml; 95% confidence interval, -18.87 to 9.12). CONCLUSIONS: A monthly intravitreal injection of 0.5 mg ranibizumab yields a durable VEGF inhibition. The recurrences of CNV as determined by SD-OCT are always preceded by a loss of intraocular VEGF suppression and usually followed by loss of visual acuity in the further course. PMID- 22920669 TI - An educational cartoon accelerates amblyopia therapy and improves compliance, especially among children of immigrants. AB - PURPOSE: We showed previously that an educational cartoon that explains without words why amblyopic children should wear their eye patch improves compliance, especially in children of immigrant parents who speak Dutch poorly. We now implemented this cartoon in clinics in low socioeconomic status (SES) areas with a large proportion of immigrants and clinics elsewhere in the Netherlands. DESIGN: Clinical, prospective, nonrandomized, preimplementation, and postimplementation study. PARTICIPANTS: Amblyopic children aged 3 to 6 years who started occlusion therapy. METHODS: Preimplementation, children received standard orthoptic care. Postimplementation, children starting occlusion therapy received the cartoon in addition. At implementation, treating orthoptists followed a course on compliance. In low SES areas, compliance was measured electronically during 1 week. MAIN OUTCOME MEASURES: The clinical effects of the cartoon electronically measured compliance, outpatient attendance rate, and speed of reduction in interocular-acuity difference (SRIAD)-averaged over 15 months of observation. RESULTS: In low SES areas, 114 children were included preimplementation versus 65 children postimplementation; elsewhere in the Netherlands, 335 versus 249 children were included. In low SES areas, mean electronically measured compliance was 52.0% preimplementation versus 62.3% postimplementation (P=0.146); 41.8% versus 21.6% (P=0.043) of children occluded less than 30% of prescribed occlusion time. Attendance rates in low SES areas were 60.3% preimplementation versus 76.0% postimplementation (P=0.141), and 82.7% versus 84.5%, respectively, elsewhere in the Netherlands. In low SES areas, the SRIAD was 0.215 log/year preimplementation versus 0.316 log/year postimplementation (P=0.025), whereas elsewhere in the Netherlands, these were 0.244 versus 0.292 log/year, respectively (P=0.005; the SRIAD's improvement was significantly better in low SES areas than elsewhere, P=0.0203). This advantage remained after adjustment for confounding factors. Overall, 25.1% versus 30.1% (P=0.038) had completed occlusion therapy after 15 months. CONCLUSIONS: After implementation of the cartoon, electronically measured compliance improved, attendance improved, acuity increased more rapidly, and treatment was shorter. This may be due, in part, to additional measures such as the course on compliance. However, that these advantages were especially pronounced in children in low SES areas with a large proportion of immigrants who spoke Dutch poorly supports its use in such areas. PMID- 22920671 TI - Antiallergic asthma properties of brazilin through inhibition of TH2 responses in T cells and in a murine model of asthma. AB - This study aimed to determine whether brazilin exhibits anti-inflammatory effects that inhibit T helper cell type II (T(H)2) responses and whether it suppresses allergic inflammation reactions in a murine model of asthma. We found that brazilin inhibited the mRNA and protein expression of interleukin (IL)-4 and IL-5 induced by phorbol myristate acetate (PMA) and cAMP in EL-4 T cells in a dose dependent manner. Following the intratracheal instillation of brazilin in ovalbumin (OVA)-immunized mice, we found that brazilin-treated mice exhibited decreases in the release of IL-4, IL-5, IL-13, eotaxin-1, and tumor necrosis factor-alpha in bronchoalveolar lavage fluid (BALF); inhibited T(H)2 functioning via a decrease in IL-4 production; and exhibited attenuation of OVA-induced lung eosinophilia, airway hyperresponsiveness, and airway remodeling. These results suggest that brazilin exhibits anti-T(H)2 effects both in vitro and in vivo and may possess therapeutic potential for allergic diseases. PMID- 22920672 TI - An inverse relation between the Simplified Menopausal Index and biological antioxidant potential. AB - BACKGROUND: Inasmuch as female sex hormones can exhibit antioxidative activity, the oxidative-antioxidative imbalance is mechanistically postulated to be involved in menopausal symptoms. OBJECTIVES: The objectives of this study were to investigate the correlation between the established menopausal index and blood levels of the in vivo antioxidative potential in women. METHOD: Blood antioxidant levels were examined by the biological antioxidative potential (BAP) test and menopausal-like symptoms were determined using the Simplified Menopausal Index (SMI) in 160 healthy Japanese women (mean age 52 years). RESULTS: A correlation analysis revealed a significant inverse relationship between the BAP and SMI levels, independent of age and the body mass index. CONCLUSIONS: The data suggest that menopausal symptoms may be associated with a decrease in antioxidant potential as assessed by the BAP test. PMID- 22920673 TI - Reovirus exerts potent oncolytic effects in head and neck cancer cell lines that are independent of signalling in the EGFR pathway. AB - BACKGROUND: Reovirus exploits aberrant signalling downstream of Ras to mediate tumor-specific oncolysis. Since ~90% squamous cell carcinomas of the head and neck (SCCHN) over-express EGFR and SCCHN cell lines are sensitive to oncolytic reovirus, we conducted a detailed analysis of the effects of reovirus in 15 head and neck cancer cell lines. Both pre- and post-entry events were studied in an attempt to define biomarkers predictive of sensitivity/resistance to reovirus. In particular, we analysed the role of EGFR/Ras signalling in determining virus mediated cytotoxicity in SCCHN. METHODS: To test whether EGFR pathway activity was predictive of increased sensitivity to reovirus, correlative analyses between reoviral IC50 by MTT assay and EGFR levels by western blot and FACS were conducted. Inhibition or stimulation of EGFR signalling were analysed for their effect on reoviral oncolysis by MTT assay, and viral growth by TCID50 assay. We next analysed the effects of inhibiting signalling downstream of Ras, by specific inhibitors of p38MAPK, PI3-K or MEK, on reoviral killing examined by MTT assay. The role of PKR in reoviral killing was also determined by blockade of PKR using 2-aminopurine and assaying for cell survival by MTT assay. The apoptotic response of SCCHN to reovirus was examined by western blot analysis of caspase 3 cleavage. RESULTS: Correlative analyses between reoviral sensitivity and EGFR levels revealed no association. Intermediate sub-viral and core particles showed the same infectivity/cytotoxicity as intact reovirus. Therefore, sensitivity was not determined by cell entry. In 4 cell lines, oncolysis and viral growth were both unaffected by inhibition or stimulation of EGFR signalling. Inhibition of signalling downstream of Ras did not abrogate reoviral oncolysis and, in addition, modulation of PKR using 2-aminopurine did not alter reovirus sensitivity in resistant cell lines. Caspase 3 cleavage was not detected in infected cells and oncolysis was observed in pan-caspase inhibited cells. CONCLUSIONS: In summary, reovirus is potently oncolytic in a broad panel of SCCHN cell lines. Attempts to define sensitivity/resistance by analysis of the EGFR/Ras/MAPK pathway have failed to provide a clear predictive biomarker of response. Further analysis of material from in vitro and clinical studies is ongoing in an attempt to shed further light on this issue. PMID- 22920674 TI - Synthesis and transformation of linear adamantane assemblies inside carbon nanotubes. AB - We report the assembly and thermal transformation of linear diamondoid assemblies inside carbon nanotubes. Our calculations and observations indicate that these molecules undergo selective reactions within the narrow confining space of a carbon nanotube. Upon vacuum annealing of adamantane molecules encapsulated in a carbon nanotube, we observe a sharp Raman feature at 1857 cm(-1), which we interpret as a stretching mode of carbon chains formed by thermal conversion of adamantane inside a carbon nanotube. Introduction of pure hydrogen during thermal annealing, however, suppresses the formation of carbon chains and seems to keep adamantane intact. PMID- 22920675 TI - A computational study of lithium cuprate mixed aggregates. AB - Lithium dialkylcuprates may potentially form mixed aggregates with many species in solution. Those include excess alkyllithium used to prepare the cuprate, lithium halide, and lithium cyanide from cuprate preparation and from coupling reactions with alkyl halides, higher order cuprates, and species resulting from incomplete cuprate reactions. The M06 DFT method was used to elucidate the structures and energies of formation of potential mixed aggregates. A comparison was made to available experimental data. PMID- 22920676 TI - [Impact of the financial crisis and health workforce crisis on the sustainability of the healthcare system: what's next?]. PMID- 22920677 TI - [Efficiency of clinical pathways of integrated care for adults and children in clinical practice centers]. PMID- 22920678 TI - High-frequency EEG oscillations in hyperthermia-induced seizures of Scn1a mutant rats. AB - We examined high-frequency oscillations (HFOs) in the ictal cortical EEGs of hyperthermia-induced seizures in a rat model of febrile seizures with an SCN1A mutation as a means of investigating the pathophysiological mechanisms underlying the generation of febrile seizures. We used 13 male homozygous Scn1a-N1417H mutant rats (F344/NSlc-Scn1a(Kyo811)) and 10 wild-type control rats. Generalized tonic-clonic seizures were induced in all mutant rats, and HFOs with frequencies ranging from 200 to 400 Hz were found to precede spikes during the clonic phases of these seizures in the ictal EEGs. The proportion of all spikes in each seizure that were associated with HFOs increased with age. In time-frequency spectra of the EEG data, the HFOs had a mean peak frequency of 301.1 +/- 65.4 Hz (range: 156.3-468.8Hz) and a mean peak power of 24.6 +/- 3.8 dB (range: 11.4-33.4 dB); the peak power increased with age. Regarding the wild-type rats, a brief seizure without unmistakable HFOs was exceptionally induced in only one rat. The generation mechanism of febrile seizures is still an unanswered question. The detection of HFOs from the ictal EEGs of hyperthermia-induced seizures may provide a cue to answering this open question, although in this research we were unable to provide sufficient evidence to prove that the generation of HFOs depended on the mutation. PMID- 22920679 TI - Cerebrospinal fluid ubiquitin C-terminal hydrolase as a novel marker of neuronal damage after epileptic seizure. AB - BACKGROUND: Ubiquitin carboxy-terminal hydrolase (UCH-L1) has been established as a reliable and potential biomarker of neuronal damage after acute neurologic insults such as ischemic stroke, subarachnoid hemorrhage, and traumatic brain injury. The effects of seizures on UCH-L1 levels in cerebrospinal fluid (CSF) has not been investigated in epileptic patients. The aim of the present study was to evaluate whether CSF UCH-L1 levels are a reliable marker of brain damage from epileptic seizures. METHODS: Thirty-three patients with epilepsy (mean age 45 years) participated. Twenty-five patients had generalized seizures and eight had partial seizures. CSF was sampled by lumbar puncture. The control samples were obtained from 23 adult patients on whom lumbar puncture was performed to exclude neurological disease. CSF UCH-L1 levels were determined using an enzyme-linked immunosorbent assay (ELISA) kit. RESULTS: Patients with epilepsy had significantly elevated CSF levels of UCH-L1 after seizures compared with controls (p<0.001). CSF UCH-L1 levels were significantly higher in patients with generalized seizures than in patients with partial seizures and controls (p<0.001). Moreover, patients with repetitive generalized tonic-clonic (GTC) seizures had higher CSF UCH-L1 levels than those with a single GTC seizure (p<0.001). CSF UCH-L1 levels in seizure patients showed strong correlation with severity of seizures (r=0.56) and seizure duration (r=0.77). Conversely, CSF UCH L1 levels in seizure patients did not correlate with the age of patients, duration of epilepsy, age of first seizure, time from last seizure or number of seizures. CONCLUSIONS: Our results suggest that UCH-L1 may serve as a novel biomarker for neuronal damage after epileptic seizure. PMID- 22920681 TI - Mucin multilayers assembled through sugar-lectin interactions. AB - Multilayer films of biopolymers are attractive tools to exploit the extraordinary properties of certain biomacromolecules and introduce new functionalities to surfaces. Mucins, the gel-forming constituents of mucus, are versatile glycoproteins that have potential as new building blocks for biomaterial surface coatings. Multilayer films have mostly been assembled through the electrostatic pairing of polyelectrolytes, which results in limited pH and salt stability and screens charges otherwise available for useful payload binding. Here, we aim at assembling mucin multilayer films that differ from conventional paired polyelectrolyte assemblies to obtain highly stable and functional surface modifications. Using the lectin wheat germ agglutinin (WGA) to cross-link mucin bound sugar residues, we show that (Mucin/WGA) films can grow into hydrated films and sustain exceptional resistance to extreme salt conditions and a large range of pH. Furthermore, we show that the addition of soluble N-acetyl-d-glucosamine can induce the controlled release of WGA from (Mucin/WGA) films. Last, we show that (Mucin/WGA) films can repeatedly incorporate and release a positively charged model cargo. The lubricating, hydration, barrier, and antimicrobial properties of mucins open multiple applicative perspectives for these highly stable mucin-based multilayer films. PMID- 22920680 TI - Correlation between EGFr expression and accelerated proliferation during radiotherapy of head and neck squamous cell carcinoma. AB - PURPOSE: To investigate the correlation between the expression of Epidermal Growth Factor receptor (EGFr) and the reduction of the effective doubling time (TD) during radiotherapy treatment and also to determine the dose per fraction to be taken into account when the overall treatment time (OTT) is reduced in accelerated radiotherapy of head and neck squamous cell carcinoma (HNSCC). METHODS: A survey of the published papers comparing 3-years of local regional control rate (LCR) for a total of 2162 patients treated with conventional and accelerated radiotherapy and with a pretreatment assessment of EGFr expression, was made. Different values of TD were obtained by a model incorporating the overall time corrected biologically effective dose (BED) and a 3-year clinical LCR for high and low EGFr groups of patients (HEGFr and LEGFr), respectively. By obtaining the TD from the above analysis and the sub-sites' potential doubling time (Tpot) from flow cytometry and immunohistochemical methods, we were able to estimate the average TD for each sub-site included in the analysis. Moreover, the dose that would be required to offset the modified proliferation occurring in one day (Dprolif), was estimated. RESULTS: The averages of TD were 77 (27-90)95% days in LEGFr and 8.8 (7.3-11.0)95% days in HEGFr, if an onset of accelerated proliferation TK at day 21 was assumed. The correspondent HEGFr sub-sites' TD were 5.9 (6.6), 5.9 (6.6), 4.6 (6.1), 14.3 (12.9) days, with respect to literature immunohistochemical (flow cytometry) data of Tpot for Oral-Cavity, Oro pharynx, Hypo-pharynx, and Larynx respectively. The Dprolif for the HEGFr groups were 0.33 (0.29), 0.33 (0.29), 0.42 (0.31), 0.14 (0.15) Gy/day if alpha = 0.3 Gy 1 and alpha/beta = 10 Gy were assumed. CONCLUSIONS: A higher expression of the EGFr leads to enhanced proliferation. This study allowed to quantify the extent of the effect which EGFr expression has in terms of reduced TD and Dprolif for each head and neck sub-site. PMID- 22920682 TI - Manganese nitride complexes in oxidation states III, IV, and V: synthesis and electronic structure. AB - The synthesis and characterization of a series of manganese nitrides in a tripodal chelating tris(carbene) ligand framework is described. Photolysis of [(TIMEN(xyl))Mn(N(3))](+) (where TIMEN(xyl) = tris[2-(3-xylylimidazol-2 ylidene)ethyl]amine) yields the isolable molecular Mn(IV) nitride, [(TIMEN(xyl))Mn(N)](+). Spectroscopic and DFT studies indicate that this Mn(IV) d(3) complex has a doublet electronic ground state. The metal-centered one electron oxidation of this Mn(IV) species results in formation of the pentavalent Mn(V) nitride, [(TIMEN(xyl))Mn(N)](2+). Unlike previously reported, tetragonal Mn(V) nitrides with a d(2), nonmagnetic S = 0 ground state, this trigonal bipyramidal complex has a triplet ground state S = 1. One-electron reduction of [(TIMEN(xyl))Mn(N)](+) produces the neutral, nonmagnetic trivalent [(TIMEN(xyl))Mn(N)] species with a d(4) low-spin, S = 0, ground state. PMID- 22920683 TI - Development of Sendai virus vectors and their potential applications in gene therapy and regenerative medicine. AB - Gene delivery/expression vectors have been used as fundamental technologies in gene therapy since the 1980s. These technologies are also being applied in regenerative medicine as tools to reprogram cell genomes to a pluripotent state and to other cell lineages. Rapid progress in these new research areas and expectations for their translation into clinical applications have facilitated the development of more sophisticated gene delivery/expression technologies. Since its isolation in 1953 in Japan, Sendai virus (SeV) has been widely used as a research tool in cell biology and in industry, but the application of SeV as a recombinant viral vector has been investigated only recently. Recombinant SeV vectors have various unique characteristics, such as low pathogenicity, powerful capacity for gene expression and a wide host range. In addition, the cytoplasmic gene expression mediated by this vector is advantageous for applications, in that chromosomal integration of exogenous genes can be undesirable. In this review, we introduce a brief historical background on the development of recombinant SeV vectors and describe their current applications in gene therapy. We also describe the application of SeV vectors in advanced nuclear reprogramming and introduce a defective and persistent SeV vector (SeVdp) optimized for such reprogramming. PMID- 22920684 TI - Protein transduction domains: applications for molecular medicine. AB - Protein transduction domains (PTD) or cell penetrating peptides (CTPs) are small peptides able to carry proteins, peptides, nucleic acid, and nanoparticles, including viral particles, across the cellular membranes into cells. In general, PTDs can be classified into 3 types: cationic peptides of 6-12 amino acids in length, comprised predominantly of arginine, ornithine and/or lysine residues; hydrophobic peptides such as leader sequences of secreted growth factors and cytokines; and cell-type specific peptides, identified by screening of peptide phage display libraries. These three types of transduction peptides have many different applications including delivery of therapeutic proteins and drugs, delivery of fluorescent or radioactive compounds for imaging, and improving uptake of DNA, RNA and even viral particles. Here we review the potential applications of protein transduction domains. PMID- 22920685 TI - Holmium-166 radioembolisation in patients with unresectable, chemorefractory liver metastases (HEPAR trial): a phase 1, dose-escalation study. AB - BACKGROUND: The efficacy of radioembolisation for the treatment of liver tumours depends on the selective distribution of radioactive microspheres to tumorous tissue. The distribution of holmium-166 ((166)Ho) poly(L-lactic acid) microspheres can be visualised in vivo by both single-photon-emission CT (SPECT) and MRI. In this phase 1 clinical trial, we aimed to assess the safety and the maximum tolerated radiation dose (MTRD) of (166)Ho-radioembolisation in patients with liver metastases. METHODS: Between Nov 30, 2009, and Sept 19, 2011, patients with unresectable, chemorefractory liver metastases were enrolled in the Holmium Embolization Particles for Arterial Radiotherapy (HEPAR) trial. Patients were treated with intra-arterial (166)Ho-radioembolisation in cohorts of three patients, with escalating aimed whole-liver absorbed doses of 20, 40, 60, and 80 Gy. Cohorts were extended to a maximum of six patients if dose-limiting toxicity occurred. Patients were assigned a dose in the order of study entry, with dose escalation until dose-limiting toxicity was encountered in at least two patients of a dose cohort. Clinical or laboratory toxicities were scored according to the National Cancer Institute's Common Terminology Criteria for Adverse Events version 3.0. The primary endpoint was the MTRD. Analyses were per protocol. This study is registered with ClinicalTrials.gov, number NCT01031784. FINDINGS: 15 patients underwent (166)Ho-radioembolisation at doses of 20 Gy (n=6), 40 Gy (n=3), 60 Gy (n=3), and 80 Gy (n=3). Mean estimated whole-liver absorbed doses were 18 Gy (SD 2) for the 20 Gy cohort, 35 Gy (SD 1) for the 40 Gy cohort, 58 Gy (SD 3) for the 60 Gy cohort, and 73 Gy (SD 4) for the 80 Gy cohort. The 20 Gy cohort was extended to six patients because of the occurrence of dose-limiting toxicity in one patient (pulmonary embolism). In the 80 Gy cohort, dose-limiting toxicity occurred in two patients: grade 4 thrombocytopenia, grade 3 leucopenia, and grade 3 hypoalbuminaemia in one patient, and grade 3 abdominal pain in another patient. The MTRD was identified as 60 Gy. The most frequently encountered laboratory toxicities (including grade 1) were lymphocytopenia, hypoalbuminaemia, raised alkaline phosphatase, raised aspartate aminotransferase, and raised gamma-glutamyltransferase, which were all noted in 12 of 15 patients. Stable disease or partial response regarding target lesions was achieved in 14 of 15 patients (93%, 95% CI 70-99) at 6 weeks and nine of 14 patients (64%, 95% CI 39-84) at 12 weeks after radioembolisation. Compared with baseline, the average global health status and quality of life scale score at 6 weeks after treatment had decreased by 13 points (p=0.053) and by 14 points at 12 weeks (p=0.048). In all patients, technetium-99m ((99m)Tc)-macro-aggregated albumin SPECT, (166)Ho scout dose SPECT, and (166)Ho treatment dose SPECT showed similar patterns of the presence or absence of extrahepatic deposition of activity. INTERPRETATION: (166)Ho-radioembolisation is feasible and safe for the treatment of patients with unresectable and chemorefractory liver metastases and enables image-guided treatment. Clinical (166)Ho-radioembolisation should be done with an aimed whole liver absorbed dose of 60 Gy. PMID- 22920686 TI - Co-occurrence of arsenic and fluoride in groundwater of semi-arid regions in Latin America: genesis, mobility and remediation. AB - Several million people around the world are currently exposed to excessive amounts of arsenic (As) and fluoride (F) in their drinking water. Although the individual toxic effects of As and F have been analyzed, there are few studies addressing their co-occurrences and water treatment options. Several studies conducted in arid and semi-arid regions of Latin America show that the co occurrences of As and F in drinking water are linked to the volcaniclastic particles in the loess or alluvium, alkaline pH, and limited recharge. The As and F contamination results from water-rock interactions and may be accelerated by geothermal and mining activities, as well as by aquifer over-exploitation. These types of contamination are particularly pronounced in arid and semi-arid regions, where high As concentrations often show a direct relationship with high F concentrations. Enrichment of F is generally related to fluorite dissolution and it is also associated with high Cl, Br, and V concentrations. The methods of As and F removal, such as chemical precipitation followed by filtration and reverse osmosis, are currently being used at different scales and scenarios in Latin America. Although such technologies are available in Latin America, it is still urgent to develop technologies and methods capable of monitoring and removing both of these contaminants simultaneously from drinking water, with a particular focus towards small-scale rural operations. PMID- 22920687 TI - Augmenting intraoperative ultrasound with preoperative magnetic resonance planning models for percutaneous renal access. AB - BACKGROUND: Ultrasound (US) is a commonly-used intraoperative imaging modality for guiding percutaneous renal access (PRA). However, the anatomy identification and target localization abilities of the US imaging are limited. This paper evaluates the feasibility and efficiency of a proposed image-guided PRA by augmenting the intraoperative US with preoperative magnetic resonance (MR) planning models. METHODS: First, a preoperative surgical planning approach is presented to define an optimal needle trajectory using MR volume data. Then, a MR to US registration is proposed to transfer the preoperative planning into the intraoperative context. The proposed registration makes use of orthogonal US slices to avoid local minima while reduce processing time. During the registration, a respiratory gating method is used to minimize the impact of kidney deformation. By augmenting the intraoperative US with preoperative MR models and a virtual needle, a visual guidance is provided to guarantee the correct execution of the surgical planning. The accuracy, robustness and processing time of the proposed registration were evaluated by four urologists on human data from four volunteers. Furthermore, the PRA experiments were performed by the same four urologists on a kidney phantom. The puncture accuracy in terms of the needle-target distance was measured, while the perceptual quality in using the proposed image guidance was evaluated according to custom scoring method. RESULTS: The mean registration accuracy in terms of the root mean square (RMS) target registration error (TRE) is 3.53 mm. The RMS distance from the registered feature points to their average is 0.81 mm. The mean operating time of the registration is 6'4". In the phantom evaluation, the mean needle-target distance is 2.08 mm for the left lesion and 1.85 mm for the right one. The mean duration for all phantom PRA tests was 4'26". According to the custom scoring method, the mean scores of the Intervention Improvement, Workflow Impact, and Clinical Relevance were 4.0, 3.3 and 3.9 respectively. CONCLUSIONS: The presented image guidance is feasible and promising for PRA procedure. With careful setup it can be efficient for overcoming the limitation of current US-guided PRA. PMID- 22920688 TI - New insights into family relationships within the avian superfamily Sylvioidea (Passeriformes) based on seven molecular markers. AB - BACKGROUND: The circumscription of the avian superfamily Sylvioidea is a matter of long ongoing debate. While the overall inclusiveness has now been mostly agreed on and 20 families recognised, the phylogenetic relationships among the families are largely unknown. We here present a phylogenetic hypothesis for Sylvioidea based on one mitochondrial and six nuclear markers, in total ~6.3 kbp, for 79 ingroup species representing all currently recognised families and some species with uncertain affinities, making this the most comprehensive analysis of this taxon. RESULTS: The resolution, especially of the deeper nodes, is much improved compared to previous studies. However, many relationships among families remain uncertain and are in need of verification. Most families themselves are very well supported based on the total data set and also by indels. Our data do not support the inclusion of Hylia in Cettiidae, but do not strongly reject a close relationship with Cettiidae either. The genera Scotocerca and Erythrocercus are closely related to Cettiidae, but separated by relatively long internodes. The families Paridae, Remizidae and Stenostiridae clustered among the outgroup taxa and not within Sylvioidea. CONCLUSIONS: Although the phylogenetic position of Hylia is uncertain, we tentatively support the recognition of the family Hyliidae Bannerman, 1923 for this genus and Pholidornis. We propose new family names for the genera Scotocerca and Erythrocercus, Scotocercidae and Erythrocercidae, respectively, rather than including these in Cettiidae, and we formally propose the name Macrosphenidae, which has been in informal use for some time. We recommend that Paridae, Remizidae and Stenostiridae are not included in Sylvioidea. We also briefly discuss the problems of providing a morphological diagnosis when proposing a new family-group name (or genus-group name) based on a clade. PMID- 22920689 TI - Quantity vs quality. PMID- 22920691 TI - Evaluating airway volume with CBCT. PMID- 22920692 TI - With gratitude. PMID- 22920694 TI - Long-term stability of alveolar bone grafts in cleft palate patients. AB - INTRODUCTION: Many authors have examined the surgical bone treatment of cleft palate patients, but no study has emphasized the role of orthodontic therapy. The aims of this study were to evaluate the long-term stability of bone grafts when using an orthodontic-surgical protocol, to determine the success of bone grafts in minor vs severe clefts, and to develop a qualitative method for assessing the success of bone grafting. METHODS: Forty-nine patients were included in this study. Occlusal x-rays were taken before (T0), immediately after (T1), and at least 1 year after bone grafting (T2). Two radiographic parameters were analyzed adjacent to the cleft side: the vertical bone level (Bergland scale) and the horizontal bone level (Witherow-derived scale). RESULTS: The bone graft success at T2 was 91.84% (95% confidence interval, 84.55-96.41). The severity of the cleft before grafting was not statistically correlated with success at T2 (P <0.05). The concordance rate between Bergland and Witherow values was 87.07% (95% confidence interval, 82.69-90.69). The variables analyzed (sex, age, type of cleft, lateral incisor agenesis) were not statistically correlated (P <0.05) with the stability of bone graft. Based on the results, the only factor involved in the stability of the graft seems to be dental age at the time of bone grafting and the orthodontic therapy before and after grafting. CONCLUSIONS: It seems appropriate to recommend early application of a surgical-orthodontic protocol to treat cleft lip and palate patients, prevent postoperative bone resorption, and guarantee correct positioning of the teeth. PMID- 22920695 TI - Cone-beam computed tomography transverse analysis. Part I: Normative data. AB - INTRODUCTION: The application of cone-beam computed tomography (CBCT) in orthodontics ushered in a new era in 3-dimensional analysis that promises to provide more comprehensive understanding of craniofacial skeletal anatomy. That promise is now being realized in multiple studies. The purposes of this study were to investigate a portion of transverse dimension relationships by using CBCT and to propose a transverse analysis to assist practitioners with treatment decisions. METHODS: The CBCT scans of 241 patients with and without crossbite were analyzed to assess the width of the jaws and the inclination of the first molars. The dental and skeletal measurements were compared between the noncrossbite and the crossbite groups. RESULTS: The noncrossbite group included patients who had apparently normal transverse relationships, but also a surprising number of patients with an obvious skeletal transverse discrepancy masked by dental compensation. The noncrossbite patients with molar inclinations within 1 SD of the mean were defined as the control group, and those with dental compensations were identified as either superior convergent or inferior convergent. The obvious unilateral crossbite patients demonstrated dental compensation in the maxillary first molar on the noncrossbite side, whereas the obvious bilateral crossbite patients had normal dental inclinations. CONCLUSIONS: Skeletally, both the bilateral and unilateral crossbite groups had narrower maxillary widths than did the controls, but also wider mandibles, with more severe bilateral crossbites. Dentally, the unilateral crossbite group had more upright teeth on the noncrossbite side. In the noncrossbite groups with dental compensations, the superior convergent and inferior convergent differences in both dental and skeletal characteristics were marked. Patients without crossbites can have significant discrepancies that might warrant treatment. PMID- 22920696 TI - Dental models made with an intraoral scanner: a validation study. AB - INTRODUCTION: Our objectives were to determine the validity and reproducibility of measurements on stereolithographic models and 3-dimensional digital dental models made with an intraoral scanner. METHODS: Ten dry human skulls were scanned; from the scans, stereolithographic models and digital models were made. Two observers measured transversal distances, mesiodistal tooth widths, and arch segments on the skulls and the stereolithographic and digital models. All measurements were repeated 4 times. Arch length discrepancy and tooth size discrepancy were calculated. Statistical analysis was performed by using paired t tests. RESULTS: For the measurements on the stereolithographic and digital models, statistically significant differences were found. However, these differences were considered to be clinically insignificant. Digital models had fewer statistically significant differences and generally the smallest duplicate measurement errors compared with the stereolithographic models. CONCLUSIONS: Stereolithographic and digital models made with an intraoral scanner are a valid and reproducible method for measuring distances in a dentition. PMID- 22920697 TI - Archwire vibration and stick-slip behavior at the bracket-archwire interface. AB - INTRODUCTION: It is unknown whether or not intraoral vibrations affect stick-slip behavior at orthodontic bracket-archwire interfaces. In this study, we evaluated bracket-archwire stick-slip behavior as a function of ligation method and archwire vibration. METHODS: In-vivo archwire vibrations were measured to obtain frequencies and amplitudes for ex-vivo testing. A piezoresistive accelerometer ligated to the maxillary right canines of 6 subjects transduced the intraoral vibrations. All subjects gave informed consent to participate. Amplitude and frequency of the vibrations were quantified and used in a bench-top friction testing apparatus. Active and passive ligation methods were compared for 9 vibration scenarios. The amount of time to move the bracket along a stainless steel wire was recorded in 90 trials. Analysis of variance and post-hoc tests were used for statistical analyses of the data. RESULTS: During carrot biting, orthodontic wire vibrations had a mean frequency of 98 Hz and a peak-to-peak mean amplitude of 151 mV. The bench-top stick-slip measurement trials containing medium (150 mV) and high (190 mV) amplitude vibrations had significantly less friction (ln, s), 4.81 +/- 2.08 and 4.67 +/- 2.00, respectively, than those subjected to low (110 mV) amplitudes, 5.80 +/- 1.39 (P = 0.04). There were no significant differences between passive and active ligation methods. CONCLUSIONS: Amplitudes of archwire vibrations affect stick-slip behavior at the bracket archwire interfaces. PMID- 22920698 TI - Three-dimensional interpretation of intercanine width change in children: a 9 year longitudinal study. AB - INTRODUCTION: The immutability of intercanine width has long been the subject of discussion. The aims of this study were to describe the longitudinal intercanine width changes of children from 6 to 14 years of age and to interpret them with a 3-dimensional method. METHODS: Complete dental stone casts were annually prepared for 66 subjects (50 girls, 16 boys) from 6 to 14 years of age. By using 3 dimensional laser scanning and reconstruction software, virtual casts were constructed. Intercanine width was measured as well as the related 3-dimensional measurements, such as the area of the intercanine triangle, the intercanine angle, the radius of the inscribed circle, and the angles formed by the virtual axes of the canines and the occlusal plane. The measurement changes over time were analyzed by using mixed-effects analysis for longitudinal data. RESULTS: There were slight decreases in intercanine widths for both sexes and both arches. However, the amounts of change were relatively small when compared with the initial values and individual random variability. The values of area, the angles formed by the virtual axes of the canines and the occlusal plane, and the radius showed decreasing trends, whereas the intercanine angle exhibited increasing trends during the observation period. Although the intercanine width changed over time, it was not clinically significant, showing relative stability. CONCLUSIONS: The intercanine width of an untreated subject after stabilization in the mouth is considered to be quite stable, even though individual variation is great. PMID- 22920699 TI - Histomorphometric study of the periodontal ligament in the initial period of orthodontic movement in Wistar rats with induced allergic asthma. AB - INTRODUCTION: Asthma is a common systemic disease occurring in infancy and adolescence, time periods that could encompass orthodontic treatment. Asthma is an inflammatory disease; therefore, it might interfere with orthodontic tooth movement. The purpose of the study was to analyze the histomorphologic aspects of the periodontal ligament of asthmatic Wistar rats in the initial period of orthodontic movement. METHODS: Thirty-two Wistar rats were divided into 4 groups: 2 control groups consisting of rats without induced allergic asthma, and 2 experimental groups consisting of rats with induced allergic asthma. The animals of the first control and experimental groups did not receive orthodontic forces, whereas those in the second control and experimental groups were subjected to mesial movement of the maxillary left first molar for 3 days. The samples were prepared for histomorphometric analysis of the periodontal ligament. The area of the periodontal ligament was calculated as a function of root length in the cervical and apical regions of the distal face of the maxillary first molar mesial root. The Student t test and the Welch correlation test were applied to the data obtained. RESULTS: There was a statistically significant difference (P <0.05) between the control and experimental groups. An enhanced response to orthodontic force was observed in the asthmatic animals: the periodontal ligament was more compressed at the pressure area and more stretched in the traction area. CONCLUSIONS: Our findings indicate that experimental allergic asthma seems to exacerbate orthodontic movement in rats. PMID- 22920700 TI - Association analysis of clinical aspects and vitamin D receptor gene polymorphism with external apical root resorption in orthodontic patients. AB - INTRODUCTION: Vitamin D is responsible for the regulation of certain genes at the transcription level, via interaction with the vitamin D receptor, and influences host immune responses and aspects of bone development, growth, and homeostasis. Our aim was to investigate the association of TaqI vitamin D receptor gene polymorphism with external apical root resorption during orthodontic treatment. METHODS: Our subjects were 377 patients with Class II Division 1 malocclusion, divided into 3 groups: (1) 160 with external apical root resorption <=1.43 mm, (2) 179 with external apical root resorption >1.43 mm), and (3) 38 untreated subjects. External apical root resorption of the maxillary incisors was evaluated on periapical radiographs taken before and after 6 months of treatment. After DNA collection and purification, vitamin D receptor TaqI polymorphism analysis was performed by polymerase chain reaction-restriction fragment length polymorphism. Univariate and multivariate analyses were performed to verify the association of clinical and genetic variables with external apical root resorption (P <0.05). RESULTS: There was a higher proportion of external apical root resorption in orthodontically treated patients compared with the untreated subjects. In patients orthodontically treated, age higher than 14 years old, initial size of the maxillary incisor root superior to 30 mm, and premolar extraction were associated with increased external apical root resorption. Genotypes containing the C allele were weakly associated with protection against external apical root resorption (CC + CT * TT [odds ratio, 0.29; 95% confidence interval, 0.07-1.23; P = 0.091]) when treated orthodontic patients were compared to untreated individuals. CONCLUSIONS: Clinical factors and vitamin D receptor TaqI polymorphism were associated with external apical root resorption in orthodontic patients. PMID- 22920701 TI - Management of the American Heart Association's guidelines for orthodontic treatment of patients at risk for infective endocarditis. AB - INTRODUCTION: For over 50 years, the American Heart Association has made recommendations for the prevention of infective endocarditis. The first guidelines were published in 1955; since then, they have been updated 9 times, most recently in 2007. There is still confusion about which orthodontic procedures are most prone to generate bacteremias and lead to infective endocarditis in susceptible patients. The aim of this study was to conduct a survey to determine orthodontists' knowledge, attitudes, and in-office behaviors regarding the American Heart Association's guidelines. METHODS: A 4-page online survey consisting of 3 sections was sent to members of the American Association of Orthodontists by using a random number generator. The first section consisted of demographic information, the second consisted of questions about the respondents' practice characteristics, and the third included questions about the respondents' knowledge and management of the treatment of patients at risk for infective endocarditis. There were 78 responses. RESULTS AND CONCLUSIONS: Orthodontists are screening for cardiac problems in the patient's medical history but to a lesser extent are requesting written medical clearance from the patient's physician before starting orthodontic treatment. Many of the orthodontists surveyed believed that their knowledge of the American Heart Association's guidelines and management of high-risk patients was in the good-to excellent range. Orthodontists recommend antibiotic prophylaxis most frequently during band placement and removal. Patients at risk for infective endocarditis are somewhat likely to inquire about possible treatment sequelae associated with previous cardiac problems. PMID- 22920702 TI - Dental light curing and its effects on color perception. AB - INTRODUCTION: Light curing has become increasingly popular for orthodontic bonding, partly as a result of improvements in light-curing unit technology and higher light intensities. The aim of this study was to determine orthodontists' knowledge of dental light-curing units, their safety aspects, and the possible effects on color perception. METHODS: Questionnaires were administered to 120 specialists or trainees to assess their knowledge of light curing and safety issues. In addition, 15 orthodontists and 15 nonorthodontists were asked to complete the Farnsworth Munsell 100 hue test to assess color perception. RESULTS: One hundred four questionnaires were returned, giving a response rate of 86.6%. Light-emitting diode lights were the most popular (73.4%), followed by quartz halogen (9.2%) and plasma lights (5.5%); 11.9% were unsure of the type of light used, 84% did not know the intensity, and 67% did not know the wavelength of the lights. Although most used safety equipment-eg, paddles-7% used no safety measures. Seventy-six percent were either unsure or took no precautions during light curing for staff or patients who had previous cataract surgery, and up to 99% were either unsure or took no precautions during light curing for staff or patients taking photosensitizing medications. With the Farnsworth Munsell test, 28 participants had average color discrimination, with 2 demonstrating superior discrimination. There were no differences between the orthodontists and the controls, or between men and women. CONCLUSIONS: Orthodontists' knowledge of dental light-curing units and hazards is poor. Although potential risks are associated with the long-term use of these light-curing units, no effect on color discrimination was detected. PMID- 22920704 TI - Impaction of both maxillary central incisors and a canine. AB - This case report describes the treatment of a 14-year-old adolescent patient who had 2 impacted maxillary central incisors with distoangular root dilacerations. He also had an impacted maxillary left canine, with the crown completely overlapping the root of the lateral incisor, and insufficient space. The general dentist referred this patient because the maxillary central incisors had still not erupted 2 years after extraction of the retained deciduous incisors. A unilateral expander with a modified vestibular arch and an attachment spring on the right side was used to correct the posterior crossbite on the right side and improve the positions of the teeth. The expansion appliance was also applied as a high anchorage device to move the central incisors and the left canine into position during the initial stages. After this phase, fixed appliances were used to redistribute the space in the anterior maxillary region to create enough space for repositioning the impacted teeth. This procedure restored the normal appearance of the maxillary arch, with good periodontal health and without evidence of root resorption, apart from the distoangular root dilacerations of the 2 maxillary central incisors. PMID- 22920703 TI - Correlation of the arch forms of male and female subjects with those of preformed rectangular nickel-titanium archwires. AB - INTRODUCTION: This investigation was carried out to correlate the normal arch forms of male and female subjects derived mathematically by the beta function with commercially available preformed rectangular nickel-titanium archwires. METHODS: The mathematical beta function was used to derive planar projections of natural archforms by using the spatial coordinates of the labial bracket interfacing surfaces in the maxillary and mandibular arches of both sexes. Graphic planar representations of corresponding bracket base spatial coordinates of archforms of 30 popular rectangular nickel-titanium archwire-bracket assemblies (derived through the same mathematical function) were superimposed on relevant maxillary and mandibular arches. RESULTS: The rectangular nickel titanium archwire-bracket assemblies exceeded the intercanine width by averages of 7.159 mm in the maxillary arches of females, 6.289 mm in the maxillary arches of males, 6.667 mm in the mandibular arches of females, and 5.337 mm in the mandibular arches of males. The average intermolar width exceeded the natural width by 2.893 mm in the maxillary arches and 1.861 mm in the mandibular arches. The average intermolar-intercanine width ratios for natural arches (2.11 for mandibular and 1.75 for maxillary) were greater than the ratios for the wire bracket assemblies (1.78 for mandibular and 1.53 for maxillary). CONCLUSIONS: The prefomed rectangular nickel-titanium archwires might result in wider arch forms. The intercanine width difference is greater than the intermolar width. The differences were more pronounced for arches in female subjects compared with those in males. These findings influence posttreatment retention, stability, and facial esthetics. A subsequent change to stainless steel wires to restore a more natural form and size can lead to round tripping and increased treatment duration. PMID- 22920705 TI - Angle Class III malocclusion treated with mandibular first molar extractions. AB - A Class III malocclusion associated with dental asymmetry is a complex diagnostic and treatment problem in orthodontics. The goals of maintaining or improving the facial profile and achieving good function are decisive factors when considering whether to plan a surgical or a nonsurgical treatment approach. A fixed appliance in combination with extractions could be considered for nonsurgical management of this type of malocclusion in the permanent dentition. This article presents the results of an orthodontic approach to a Class III subdivision malocclusion in an adult treated with mandibular first molar extractions. The extractions provided the space needed to correct the overjet and overbite and to improve the intercuspation. PMID- 22920706 TI - Orthodontic-restorative treatment as an option for biologic replacement of a maxillary central incisor: 5-year follow-up. AB - The maxillary central incisor is the tooth most often affected by trauma, especially in the age range of 7 to 10 years, when high-impact sports are prevalent. The options for conservative treatment should be prioritized in these patients, aiming to achieve a biologic response that might provide continuity of growth of the alveolus, to provide functional and esthetic development of the affected region. This case report describes a patient with a history of trauma during the deciduous dentition with consequent intrusion, root dilaceration, and retention of the maxillary left central incisor. The treatment involved extraction of the traumatized tooth and mesial movement of the lateral incisor and posterior segments. PMID- 22920707 TI - Tooth separation: a risk-free procedure? AB - This article reports the case of a 12-year-old patient with tooth extrusion, pain, gingival bleeding, and localized periodontitis near the maxillary second premolar. Despite probing and radiographic examination, it was not possible to establish the etiology. Tooth extraction was indicated because of the severe tooth mobility and extrusion. Curettage of the tooth socket revealed a rubber separator. Preventive approaches are suggested to avoid iatrogenesis and legal problems. PMID- 22920708 TI - Severe complication of a bonded mandibular lingual retainer. AB - Bonding a flexible spiral wire retainer to the lingual surfaces of all 6 anterior mandibular teeth is a commonly used type of retention. Complications are rare but can be serious enough to produce biologic damage. This article presents a serious complication of a lingual flexible spiral wire retainer. Four years after the orthodontic treatment, a 20-year-old man sought treatment for a broken flexible spiral wire retainer. The clinical examination showed about 35 degrees of buccal root torque of that tooth. A cone-beam computed tomography image showed that the root and the apex of the tooth were almost completely out of the bone on its buccal side. Surprisingly, the tooth's vitality was preserved. The tooth was moved back, nearly to its original position; clinically, only a gingival recession remained. Orthodontists and dentists should be aware of possible complications of bonded retainers. Patients should be clearly informed how to detect problems at an early stage. PMID- 22920710 TI - Litigation and legislation. In the beginning. PMID- 22920709 TI - Three-dimensional evaluation of changes in lip position from before to after orthodontic appliance removal. AB - INTRODUCTION: Our objectives were to develop a reproducible method of superimposing 3-dimensional images for measuring soft-tissue changes over time and to use this method to document changes in lip position after the removal of orthodontic appliances. METHODS: Three-dimensional photographs of 50 subjects were made in repose and maximum intercuspation before and after orthodontic appliance removal with a stereo camera. For reliability assessment, 2 photographs were repeated for 15 patients. The images were registered on stable areas, and surface-to-surface measurements were made for defined landmarks. RESULTS: Mean changes were below the level of clinical significance (set at 1.5 mm). However, 51% and 18% of the subjects experienced changes greater than 1.5 mm at the commissures and lower lips, respectively. CONCLUSIONS: The use of serial 3 dimensional photographs is a reliable method of documenting soft-tissue changes. Soft-tissue changes after appliance removal are not clinically significant; however, there is great individual variability. PMID- 22920711 TI - Cluster-randomized controlled trials: Part 2. PMID- 22920712 TI - Is the incidence of candidemia caused by Candida glabrata increasing in Brazil? Five-year surveillance of Candida bloodstream infection in a university reference hospital in southeast Brazil. AB - From 2006 to 2010, a retrospective study was conducted in a university referral tertiary care hospital to study the frequency and distribution of Candida species in different medical specialties. The use of mechanical ventilation, central venous catheter, and urinary catheter were recorded per 1,000 patient-days and the use of antifungals was calculated using defined daily dose (DDD). A total of 313 episodes were identified and the overall incidence was 0.54 (0.41-0.71) episodes per 1,000 patient-days. Candida albicans caused 44% of the overall episodes, followed by C. tropicalis (21.7%), C. parapsilosis (14.4%), C. glabrata (11.2%), and C. krusei (3.5%). The incidence of C. glabrata significantly increased from 2006-2010 (range: 4.8-23.5%) (P = 0.024). Candida glabrata was associated with malignancies (P = 0.004) and C. krusei with hematologic malignancies (P < 0.0001). The use of antifungals was higher in the hematology/bone marrow transplant units and represented 40% of all fluconazole prescription in the hospital. There was no correlation with the use of fluconazole and the increasing ratio of C. glabrata (r = 0.60). The use of invasive devices was significantly higher in the intensive care units (ICUs) than the medical and surgical emergencies units (P < 0.001). In contrast, the emergencies had higher incidence of candidemia (2-2.1 episodes/1,000 patient days) than the ICUs (1.6 episodes 1,000 patient-days). Candida glabrata candidemia showed a significant increase in contrast to the current national literature where C. parapsilosis remained the most important non-C. albicans Candida species in Brazilian hospitals. Our findings suggested that the increasing incidence of C. glabrata was not associated with use of fluconazole and other risk factors might play an important role. PMID- 22920713 TI - An efficient synthesis of pyrrolo[2,3,4-kl]acridin-1-one derivatives catalyzed by L-proline. AB - An efficient domino approach for the synthesis of novel pyrrolo[2,3,4-kl]acridin 1-one derivatives has been established. This reaction represents the first facile conversion of an isatin to a pyrrolo[2,3,4-kl]acridin-1-one via a C-N bond cleavage reaction without the need for a multistep reaction process. PMID- 22920714 TI - Air-water fluxes of N2O and CH4 during microalgae (Staurosira sp.) cultivation in an open raceway pond. AB - The industrial-scale production of biofuels from cultivated microalgae has gained considerable interest in the last several decades. While the climate benefits of microalgae cultivation that result from the capture of atmospheric CO(2) are known, the counteracting effect from the potential emission of other greenhouse gases has not been well quantified. Here, we report the results of a study conducted at an industrial pilot facility in Hawaii to determine the air-water fluxes of N(2)O and CH(4) from open raceway ponds used to grow the marine diatom Staurosira sp. as a feedstock for biofuel. Dissolved O(2), CH(4), and N(2)O concentrations were measured over a 24 h cycle. During this time, four SF(6) tracer release experiments were conducted to quantify gas transfer velocities in the ponds, and these were then used to calculate air-water fluxes. Our results show that pond waters were consistently supersaturated with CH(4) (up to 725%) resulting in an average emission of 19.9 +/- 5.6 MUmol CH(4) m(-2) d(-1). Upon NO(3)(-) depletion, the pond shifted from being a source to being a sink of N(2)O, with an overall net uptake during the experimental period of 3.4 +/- 3.5 MUmol N(2)O m(-2) d(-1). The air-water fluxes of N(2)O and CH(4) expressed as CO(2) equivalents of global warming potential were 2 orders of magnitude smaller than the overall CO(2) uptake by the microalgae. PMID- 22920715 TI - Onshore ballast water treatment: a viable option for major ports. AB - Ballast water treatment consists of the elimination of exotic species. Currently, the development of alternative methods for this process is directed toward treatment onboard ships. However, we present onshore treatment as a viable alternative for ballast water treatment. We investigated onshore treatment in two iron ore ports with movement capacities of 25 and 90 million tons annually (Mta) that receive 7.5 and 25 million cubic meters annually (Mm(3)) of ballast water, respectively. Discrete event simulation was used as the method of analysis, considering the processes of arrival, berthing, ship loading and capture and treatment of ballast water. We analyzed data from 71 ships operating in these ports to validate our simulation model. We were able to demonstrate that onshore treatment does not impact the cargo capacity, occupation rate or average queuing time of ships at these ports. We concluded that implementation of onshore ballast water treatment may be practicable in ports that receive high volumes of ballast water. PMID- 22920716 TI - Rapid assessment of the bryozoan, Zoobotryon verticillatum (Delle Chiaje, 1822) in marinas, Canary Islands. AB - A rapid assessment, using the abundance and distribution range method, was used to evaluate the status of a large branching bryozoan, Zoobotryon verticillatum attached to the immersed part of marina pontoons in the Canary Islands. Colonies were also found attached to the hulls of leisure craft berthed alongside pontoons at three marinas in Lanzarote during 2012. Low levels of abundance and distribution of the bryozoan occurred in marinas with a freshwater influence whereas in a sheltered marina lacking direct freshwater inputs colonies occurred at ~2 per metre of combined pontoon length. While the occurrence of this bryozoan is recent it may be expected to occur elsewhere in Macaronesia most probably spread by leisure craft. PMID- 22920717 TI - Heart rate as a target of treatment of chronic heart failure. AB - Cardiovascular risk of increased heart rate (HR) was first reported in the Framingham study. Thereafter, the risk of increased HR for mortality has been extensively studied, suggesting the higher risk in clinical outcomes with increased HR in the general population and in patients with coronary artery disease or heart failure (HF). In a long-term follow-up study in Framingham, the general population in this cohort showed an increase in all-cause mortality by 14% at every 10 bpm increase in HR. In patients with heart failure, resting HR of more than 80 bpm could cause myocardial dysfunction which further deteriorates HF. Downregulation of beta-adrenoreptor receptors with suppressed signal transductions, impaired intracellular Ca homeostasis, and excitation-contraction coupling may play a role in myocardial dysfunction. These subcellular alterations are mimicked in the pacing-induced HF in large animals; however, exact mechanisms of cardiac deterioration by increased HR are not fully understood. beta-Blocker treatment is the most effective therapy for long-term survival of patients with chronic HF. Meta-analysis of HR reduction and improvement in survival in patients with chronic HF indicates that HR reduction is more important than the titrated dose of beta-blockers, although the relative importance of HR reduction in improvement of prognosis is not clear. A recent study in which ivabradine decreased the hospitalization from HR deterioration in patients with chronic HF, demonstrated that further HR reduction with optimal treatment for HF is beneficial for clinical outcomes of the patients. These findings strongly suggest that HR reduction should be a pivotal target of the treatment in patients with HF. PMID- 22920718 TI - Randomized, placebo-controlled trial of quetiapine XR and divalproex ER monotherapies in the treatment of the anxious bipolar patient. AB - BACKGROUND: Anxiety disorders complicate the treatment of bipolar disorder but are seldom the focus of bipolar treatment studies. METHODS: The anxiolytic effect of quetiapine XR 50-300 mg/day compared to divalproex ER (500-3000 mg/day) was tested in an 8-week, double-blind, placebo-controlled, randomized clinical trial in 149 patients with bipolar disorder and a co-occurring panic disorder or GAD. The primary efficacy measure was the Clinician Global Improvement-21 Anxiety Scale (CGI-21). Secondary measures included the Hamilton Anxiety Scale (HAM-A) and Sheehan Panic Disorder Scale (SPS). RESULTS: Repeated measures last observation-carried-forward (LOCF) analyses of variance demonstrated significant treatment-by-time interaction effects on 3 of the 4 anxiety measures. Quetiapine XR at a mean endpoint dose of 186 mg/day produced rapid sustained improvements relative to baseline, divalproex ER and placebo on anxiety. Mean baseline-to endpoint improvement was significantly greater for quetiapine XR compared to divalproex ER and placebo on the HAM-A and SPS. Both active medications were well tolerated, but weight gain was higher on quetiapine XR. LIMITATIONS: The study was limited to 8 weeks and to patients with bipolar disorder and comorbid panic disorder or GAD. The results may not be applicable to quetiapine XR as an add-on treatment to mood stabilizers or to bipolar disorder comorbid with other anxiety disorders. CONCLUSIONS: Quetiapine XR in a dose range of 50-300 mg/day appears to reduce anxiety in bipolar patients with comorbid panic disorder or GAD treated for 8 weeks. The efficacy of other second-generation antipsychotics and mood stabilizers in patients with bipolar disorder and a co-occurring anxiety disorder should be investigated in double-blind, placebo-controlled studies. PMID- 22920719 TI - Polymorphisms in seizure 6-like gene are associated with bipolar disorder I: evidence of gene * gender interaction. AB - BACKGROUND: Previous reports have suggested that there may be gene * gender interaction for bipolar disorder (BD)-associated genes/loci at 22q11-13. This study aimed to investigate the associations of SEZ6L genetic variants with bipolar disorder I (BD-I) and to examine gender-specific genetic associations. METHODS: 605 BD-I Caucasian cases and 1034 controls were selected from the publicly available data of the Whole Genome Association Study of BD. To increase power, an additional 362 Caucasian controls were added to this study from the Genome-Wide Association Study of Schizophrenia. In total, 605 BD-I cases and 1396 controls (934 males and 1067 females) were available for genetic association analysis of 118 SNPs within the SEZ6L gene using PLINK software. RESULTS: 16 SNPs showed significant gene x gender interactions influencing BD-I (P<0.01). In addition, significant differences in the distribution of the alleles for these 16 SNPs were observed between the female BD-I patients and healthy controls (P<0.015) but no significant associations were found for the male sample (P>0.05). The SNP rs4822691 showed the strongest association with BD-I in the female sample (P=2.18 * 10(-4)) and the strongest gene * gender interaction in influencing BD-I (P=9.16 * 10(-5)). LIMITATIONS: The findings of this study need to be replicated in independent samples. CONCLUSIONS: This is the first demonstration that genetic variants in the SEZ6L gene are associated with BD-I in female patients and provides additional compelling evidence for genetic variation at 22q11-13 that influences BD-I risk. The present findings highlight the gene x gender interactions modifying BD-I susceptibility. PMID- 22920720 TI - Erratum: (13)C NMR-Distance Matrix Descriptors: Optimal Abstract 3D Space Granularity for Predicting Estrogen Binding. PMID- 22920722 TI - Self-amplification mechanisms of mast cell activation: a new look in allergy. AB - Allergic diseases are major diseases involving approximately 22% of world population. In recent years, accumulated evidence suggests that apart from IgE, allergens may provoke immediate allergic reactions via other pathways such as IgG, toll like receptor (TLR) dependent ones. In addition, large numbers of low molecular weight molecules (LMWM) such as sphingosine-1-phosphate and iodinated contrast agents have been observed to cause allergy. Therefore, the current definition of allergy, a group of IgE mediated diseases appears difficult to cover all allergic reactions. Since even IgE dependent allergic reactions are carried out through activation of mast cells and basophils, and all allergens mentioned above can activate these cells, we hypothesize that allergic reactions are mast cell and basophil mediated inflammatory process as it is the activated mast cells and basophils that initiate the pathological process of the immediate allergic reactions, whereas IgE only serves as one of the activators of these cells. PMID- 22920721 TI - Deregulation of miR-100, miR-99a and miR-199b in tissues and plasma coexists with increased expression of mTOR kinase in endometrioid endometrial carcinoma. AB - BACKGROUND: Alterations of mTOR gene expression have been implicated in the pathogenesis of endometrioid endometrial cancer however only few studies explored the cause of increased mTOR activation in this malignancy. miRNAs are small, noncoding RNAs, which were proven to regulated gene expression at the posttranscriptional level. The study aimed to explore deregulation of miRNAs targeting mTOR kinase (miR-99a, miR-100 and miR-199b) as a possible cause of its altered expression in EEC tissues. In addition expression of the three miRNAs was investigated in plasma of EEC patients and was assessed in terms of diagnostic and prognostic utility. METHODS: We investigated expression of mTOR kinase transcripts in 46 fresh tissue samples. Expression of miR-99a, miR-100 and miR 199b was investigated in the same group of fresh samples, and in additional 58 FFPE sections as well as in 48 plasma samples using qPCR. Relative quantification was performed using experimentally validated endogenous controls. RESULTS: mTOR kinase expression was increased in EEC tissues and was accompanied by decreased expression of all three miRNAs. Down-regulation of the investigated miRNAs was discovered in plasma of EEC patients and miRNA signatures classified EEC tissues (miR-99a/miR-100/miR-199b) and plasma (miR-99a/miR-199b) samples with higher accuracy in comparison to single miRNAs. We also revealed that miR-100 was an independent prognostic marker of overall survival. CONCLUSIONS: We conclude that increased expression of mTOR kinase coexists with down-regulation of its targeting miRNAs, which could suggest a new mechanism of mTOR pathway alterations in EEC. In addition, our findings implicate that miRNA signatures can be considered promising biomarkers for early detection and prognosis of endometrioid endometrial carcinoma. PMID- 22920723 TI - Efficacy of porcine placental extract on climacteric symptoms in peri- and postmenopausal women. AB - OBJECTIVES: Injections of human placental extract have long been used to treat menopausal symptoms. Recently, porcine placental extract (PPE), an oral supplement, has been developed for this purpose. The aim of this study was to assess whether PPE has an impact on climacteric symptoms in perimenopausal and postmenopausal women. METHODS: Seventy-six women with climacteric symptoms were enrolled into this open-label, randomized, controlled study. The control group (n = 38) underwent 24 weeks of open treatment with Toki-shakuyaku-san (TJ23), an oral herbal remedy used to alleviate climacteric symptoms. The PPE group (n = 38) received three capsules of PPE/day orally for the initial 12 weeks and six capsules/day for the next 12 weeks. Climacteric symptoms were evaluated in both groups using the Simplified Menopausal Index (SMI) score, Zung's Self-Rating Depression Scale (ZSDS) and the Spielberger State-Trait Anxiety Inventory (STAI) before commencing treatment, after 12 weeks of treatment and on completion of treatment. RESULTS: Treatment with PPE was significantly (p < 0.01) more effective in reducing the SMI, ZSDS and STAI measures at 12 and 24 weeks than TJ23 treatment alone. Treatment with PPE was also significantly effective (p < 0.01) in reducing the subscale scores of the SMI for items such as hot flushes, insomnia, irritability, depression, fatigue and joint pain. PPE treatment had no significant adverse effects. CONCLUSION: Oral PPE treatment is another possible option for treating perimenopausal and postmenopausal women with climacteric symptoms. PMID- 22920724 TI - Adipose stem cells can secrete angiogenic factors that inhibit hyaline cartilage regeneration. AB - INTRODUCTION: Adipose stem cells (ASCs) secrete many trophic factors that can stimulate tissue repair, including angiogenic factors, but little is known about how ASCs and their secreted factors influence cartilage regeneration. Therefore, the aim of this study was to determine the effects ASC-secreted factors have in repairing chondral defects. METHODS: ASCs isolated from male Sprague Dawley rats were cultured in monolayer or alginate microbeads supplemented with growth (GM) or chondrogenic medium (CM). Subsequent co-culture, conditioned media, and in vivo cartilage defect studies were performed. RESULTS: ASC monolayers and microbeads cultured in CM had decreased FGF-2 gene expression and VEGF-A secretion compared to ASCs cultured in GM. Chondrocytes co-cultured with GM cultured ASCs for 7 days had decreased mRNAs for col2, comp, and runx2. Chondrocytes treated for 12 or 24 hours with conditioned medium from GM-cultured ASCs had reduced sox9, acan, and col2 mRNAs; reduced proliferation and proteoglycan synthesis; and increased apoptosis. ASC-conditioned medium also increased endothelial cell tube lengthening whereas conditioned medium from CM cultured ASCs had no effect. Treating ASCs with CM reduced or abolished these deleterious effects while adding a neutralizing antibody for VEGF-A eliminated ASC-conditioned medium induced chondrocyte apoptosis and restored proteoglycan synthesis. FGF-2 also mitigated the deleterious effects VEGF-A had on chondrocyte apoptosis and phenotype. When GM-grown ASC pellets were implanted in 1 mm non critical hyaline cartilage defects in vivo, cartilage regeneration was inhibited as evaluated by radiographic and equilibrium partitioning of an ionic contrast agent via microCT imaging. Histology revealed that defects with GM-cultured ASCs had no tissue ingrowth from the edges of the defect whereas empty defects and defects with CM-grown ASCs had similar amounts of neocartilage formation. CONCLUSIONS: ASCs must be treated to reduce the secretion of VEGF-A and other factors that inhibit cartilage regeneration, which can significantly influence how ASCs are used for repairing hyaline cartilage. PMID- 22920726 TI - Circularly polarized luminescence of curium: a new characterization of the 5f actinide complexes. AB - A key distinction between the lanthanide (4f) and the actinide (5f) transition elements is the increased role of f-orbital covalent bonding in the latter. Circularly polarized luminescence (CPL) is an uncommon but powerful spectroscopy which probes the electronic structure of chiral, luminescent complexes or molecules. While there are many examples of CPL spectra for the lanthanides, this report is the first for an actinide. Two chiral, octadentate chelating ligands based on orthoamide phenol (IAM) were used to complex curium(III). While the radioactivity kept the amount of material limited to micromole amounts, spectra of the highly luminescent complexes showed significant emission peak shifts between the different complexes, consistent with ligand field effects previously observed in luminescence spectra. PMID- 22920725 TI - beta-catenin/Wnt signaling controls progenitor fate in the developing and regenerating zebrafish retina. AB - BACKGROUND: The zebrafish retina maintains two populations of stem cells: first, the germinal zone or ciliary marginal zone (CMZ) contains multipotent retinal progenitors that add cells to the retinal periphery as the fish continue to grow; second, radial glia (Muller cells) occasionally divide asymmetrically to generate committed progenitors that differentiate into rod photoreceptors, which are added interstitially throughout the retina with growth. Retinal injury stimulates Muller glia to dedifferentiate, re-enter the cell cycle, and generate multipotent retinal progenitors similar to those in the CMZ to replace missing neurons. The specific signals that maintain these two distinct populations of endogenous retinal stem cells are not understood. RESULTS: We used genetic and pharmacological manipulation of the beta-catenin/Wnt signaling pathway to show that it is required to maintain proliferation in the CMZ and that hyperstimulation of beta-catenin/Wnt signaling inhibits normal retinal differentiation and expands the population of proliferative retinal progenitors. To test whether similar effects occur during regeneration, we developed a method for making rapid, selective photoreceptor ablations in larval zebrafish with intense light. We found that dephosphorylated beta-catenin accumulates in Muller glia as they re-enter the cell cycle following injury, but not in Muller glia that remain quiescent. Activation of Wnt signaling is required for regenerative proliferation, and hyperstimulation results in loss of Muller glia from the INL as all proliferative cells move into the ONL. CONCLUSIONS: beta-catenin/Wnt signaling is thus required for the maintenance of retinal progenitors during both initial development and lesion-induced regeneration, and is sufficient to prevent differentiation of those progenitors and maintain them in a proliferative state. This suggests that the beta-catenin/Wnt cascade is part of the shared molecular circuitry that maintains retinal stem cells for both homeostatic growth and epimorphic regeneration. PMID- 22920727 TI - Computational studies of CO2 activation via photochemical reactions with reduced sulfur compounds. AB - Reactions between CO(2) and reduced sulfur compounds (RSC), H(2)S and CH(3)SH, were investigated using ground and excited state density functional theory (DFT) and coupled cluster (CC) methods to explore possible RSC oxidation mechanisms and CO(2) activation mechanisms in the atmospheric environment. Ground electronic state calculations at the CR-CC(2,3)/6-311+G(2df,2p)//CAM-B3LYP/6-311+G(2df,2p) level show proton transfer as a limiting step in the reduction of CO(2) with activation energies of 49.64 and 47.70 kcal/mol, respectively, for H(2)S and CH(3)SH. On the first excited state surface, CR-EOMCC(2,3)/6-311+G(2df,2p)//CAM B3LYP/6-311+G(2df,2p) calculations reveal that energies of <250 nm are needed to form H(2)S-CO(2) and CH(3)SH-CO(2) complexes allowing facile hydrogen atom transfer. Once excited, all reaction intermediates and transition states are downhill energetically showing either C-H or C-S bond formation in the excited state whereas only C-S bond formation was found in the ground state. Environmental implications of these data are discussed with a focus on tropospheric reactions between CO(2) and RSC, as well as potential for carbon sequestration using photocatalysis. PMID- 22920729 TI - Diagnosis to a "T". PMID- 22920728 TI - Rab31 expression levels modulate tumor-relevant characteristics of breast cancer cells. AB - BACKGROUND: Rab proteins constitute a large family of monomeric GTP-binding proteins that regulate intracellular vesicle transport. Several Rab proteins, including rab31, have been shown to affect cancer progression and are related with prognosis in various types of cancer including breast cancer. Recently, the gene encoding rab31 was found to be overexpressed in estrogen receptor-positive breast cancer tissue. In a previous study we found a significant association of high rab31 mRNA expression with poor prognosis in node-negative breast cancer patients. In the present study, we aimed to investigate the impact of rab31 (over)-expression on important aspects of tumor progression in vitro and in vivo. METHODS: Breast cancer cells displaying low (MDA-MB-231) or no (CAMA-1) endogenous rab31 expression were stably transfected with a rab31 expression plasmid. Batch-transfected cells as well as selected cell clones, expressing different levels of rab31 protein, were analyzed with regard to proliferation, cell adhesion, the invasive capacity of tumor cells, and in vivo in a xenograft tumor model. Polyclonal antibodies directed to recombinantly expressed rab31 were generated and protein expression analyzed by immunohistochemistry, Western blot analysis, and a newly developed sensitive ELISA. RESULTS: Elevated rab31 protein levels were associated with enhanced proliferation of breast cancer cells. Interestingly, weak to moderate overexpression of rab31 in cell lines with no detectable endogenous rab31 expression was already sufficient to elicit distinct effects on cell proliferation. By contrast, increased expression of rab31 in breast cancer cells led to reduced adhesion towards several extracellular matrix proteins and decreased invasive capacity through Matrigel(TM). Again, the rab31 mediated effects on cell adhesion and invasion were dose-dependent. Finally, in a xenograft mouse model, we observed a significantly impaired metastatic dissemination of rab31 overexpressing MDA-MB-231 breast cancer cells to the lung. CONCLUSIONS: Overexpression of rab31 in breast cancer cells leads to a switch from an invasive to a proliferative phenotype as indicated by an increased cell proliferation, reduced adhesion and invasion in vitro, and a reduced capacity to form lung metastases in vivo. PMID- 22920730 TI - Cementoplasty of metastases of the proximal femur: is it a safe palliative option? AB - PURPOSE: Percutaneous cementoplasty has proved very effective for the palliation of pain from bone metastases. However, several studies argue that it should be contraindicated for metastases that are located in the proximal femur because of inadequate bone consolidation. The aim of this study was to evaluate the risk factors for fracture despite performing cementoplasty for metastases of the proximal femur. METHODS: We retrospectively analyzed all consecutive patients who underwent cementoplasty for metastases of the proximal femur who had a high risk for fracture (N = 21) from June 2003 to October 2010. Cementoplasty was performed for preventive consolidation as well as for pain palliation in 16 patients. The risk factors studied were the patient characteristics, the Mirels score, the maximal size and cortical involvement of the lesion, and a history of a previous fracture of the lesser trochanter. RESULTS: The 1-year pathologic fracture rate was 40.6% (seven fractures). The risk of fracture was significantly higher for cortical involvement greater than 30 mm (n = 7/11 vs n = 0/10; P = .0005) and a history of a previous fracture of the lesser trochanter (n = 3/3 vs 4/18; P = .0009). CONCLUSIONS: Percutaneous cementoplasty can be considered for patients with metastases of the proximal femur under certain conditions: cortical involvement less than 30 mm and no history of a fracture of the lesser trochanter. Otherwise, the risk of fracture is too high, and cementoplasty is contraindicated. PMID- 22920731 TI - Tortuous iliac systems--a significant burden to conventional cannulation in the visceral segment: is there a role for robotic catheter technology? AB - PURPOSE: To attempt to quantify the effect of varying degrees of iliac tortuosity on maneuverability and "torquability" of endovascular catheters in the visceral segment, comparing conventional and robotic cannulation techniques. MATERIALS AND METHODS: In a fenestrated endograft within a pulsatile phantom, 10 experienced operators cannulated the renal arteries via three different access vessels of varying iliac tortuosity with the use of conventional and robotic techniques. All procedures were performed in the angiography suite and recorded for blinded video assessment for quantitative (time, catheter-tip movements) and qualitative metrics (operator performance scores). RESULTS: In total, 120 cannulations were observed. With increasing iliac tortuosity, median time and number of catheter movements required for renal cannulation with conventional techniques increased in stepwise fashion for mild, moderate, and severe iliac tortuosity (times, 7.6 min [interquartile range (IQR), 4.6-9.3 min] vs 6.9 min [4.2-11.4 min] vs 17.7 min [13.3-22.6 min], respectively; movements, 184 [IQR, 110-351] vs 251 [207-395] vs 569 [409-616], respectively). Median renal cannulation times were significantly reduced with the use of the robotic system irrespective of mild, moderate, or severe tortuosity (times, 1.4 min [IQR, 1.1-1.9 min] vs 3 min [2.3 3.3 min] vs 2.8 min [1.5-3.9 min], respectively; movements, 19 [IQR, 14-27] vs 46 [43-58] vs 45 [40-66], respectively; P < .005). Overall operator performance scores improved significantly with the use of the robotic system irrespective of iliac tortuosity severity. CONCLUSIONS: In cases of moderate to severe iliac tortuosity, conventional catheter manipulation and control becomes an issue. The improvement in positional control and predictability seen with advanced catheter designs may be amplified in cases of severe iliac tortuosity. PMID- 22920732 TI - Monoclonal antibody therapeutics: history and future. AB - Over the last three decades, monoclonal antibodies have made a dramatic transformation from scientific tools to powerful human therapeutics. At present, approximately 30 therapeutic monoclonal antibodies are marketed in the United States and Europe in a variety of indications, with sales in the US alone reaching approximately $18.5 billion in 2010. This review describes how antibody engineering has revolutionized drug discovery and what are considered the key areas for future development in the monoclonal antibody therapy field. PMID- 22920733 TI - Investigation of endocannabinoid system genes suggests association between peroxisome proliferator activator receptor-alpha gene (PPARA) and schizophrenia. AB - Schizophrenia (SZ) is a complex psychiatric disorder with a large genetic burden and an estimated hereditability of 80%. A large number of neuroanatomical and psychopharmacological studies suggest a central role of the endocannabinoid (eCB) system in the susceptibility of the disease. To further investigate this hypothesis, we performed an association study with genes codifying for key elements of the eCB system in a sample of 170 schizophrenic patients and 350 healthy controls of Italian ancestry. A total of 57 Tag SNPs (tSNPs) were selected using HapMap CEU population SNP database spanning the following genes: cannabinoid receptor 1 (CNR1), peroxisome proliferator activator receptor-alpha (PPARA), fatty acid amide hydrolase (FAAH) and N-acyl phosphatidylethanolamine phospholipase D (NAPE-PLD). Seven out of the 32 tSNPs within PPARA (rs4253765, rs4263776, rs6007662, rs1800206, rs4253763, rs6008197 and rs4253655) and 3 out of 12 tSNPs within CNR1 (rs1049353, rs7766029 and rs806366) were nominally associated with SZ (uncorrected p<0.05). The same pattern of association was observed in the genotype analysis, with rs4253765 showing the highest level of significance (uncorrected p=2*10(-3)). None of these associations survived after permutation test. Our findings suggest a potential role for PPARA in the susceptibility to SZ, but further studies on larger independent samples are warranted in order to clarify the involvement of this gene in the pathophysiology of SZ. PMID- 22920734 TI - Modeling the impact of alcohol dependence on mortality burden and the effect of available treatment interventions in the European Union. AB - Alcohol consumption is a major risk factor for the burden of disease, and Alcohol Dependence (AD) is the most important disorder attributable to this behavior. The objective of this study was to quantify mortality associated with AD and the potential impact of treatment. For the EU countries, for the age group 15-64 years, mortality attributable to alcohol consumption in general, to heavy drinking, and to AD were estimated based on the latest data on exposure and mortality. Potential effects of AD treatment were modeled based on Cochrane and other systematic reviews of the effectiveness of the best known and most effective interventions. In the EU 88.9% of men and 82.1% of women aged 15-64 years were current drinkers; and 15.3% of men and 3.4% of women in this age group were heavy drinkers. AD affected 5.4% of men and 1.5% of women. The net burden caused by alcohol consumption was 1 in 7 deaths in men and 1 in 13 deaths in women. The majority of this burden was due to heavy drinking (77%), and 71% of this burden was due to AD. Increasing treatment coverage for the most effective treatments to 40% of all people with AD was estimated to reduce alcohol attributable mortality by 13% for men and 9% for women (annually 10,000 male and 1700 female deaths avoided). Increasing treatment rates for AD was identified as an important issue for future public health strategies to reduce alcohol attributable harm and to complement the current focus of alcohol policy. PMID- 22920735 TI - Dark modes and Fano resonances in plasmonic clusters excited by cylindrical vector beams. AB - Control of the polarization distribution of light allows tailoring the electromagnetic response of plasmonic particles. By rigorously extending the generalized multiparticle Mie theory, we show that focused cylindrical vector beams (CVB) can be used to efficiently excite dark plasmon modes in nanoparticle clusters. In addition to the small radiative damping and large field enhancement associated to dark modes, excitation with CVB can give place to unusual phenomenology like the formation of electromagnetic cold spots and the generation of Fano resonances in highly symmetric clusters. Overall, the results show the potential of CVB to tailor the plasmonic response of nanoparticle clusters in a unique way. PMID- 22920737 TI - Opening the door on gender-based violence. PMID- 22920736 TI - Where we are today: prioritizing women's health services and health policy. A report by the Women's Health Expert Panel of the American Academy of Nursing. AB - There has been a recent resurgence of interest in women's health as evidenced by several federal and international policy-shaping reports that will impact women's health services. These reports include the 2010 Affordable Care Act, the formation of the National Prevention Council and Strategy, the 2011 IOM report on clinical preventives services for women, and the World Health Organization strategic plan for 2010-2015. In this paper, we summarize and discuss these reports and discuss implications of enacting the suggested health policies. We highlight policy strategies and recommendations that will extend national and global recommendations to improve women's health and wellness across the lifespan and emphasize the urgent need for preventive services. We conclude this paper by detailing our broad recommendations for putting prevention into practice illustrated by specific recommendations related to unintended pregnancy prevention and management. PMID- 22920738 TI - Australia's plain tobacco packaging. PMID- 22920739 TI - Gluten-free diets: vital or vogue? PMID- 22920740 TI - 40 years of innovation in sexual and reproductive health. PMID- 22920741 TI - Jeanette Vega: putting equity and resilience into global health. PMID- 22920743 TI - Pharmacogenetic guidance for antiplatelet treatment. PMID- 22920744 TI - Pharmacogenetic guidance for antiplatelet treatment. PMID- 22920745 TI - Breathlessness, night sweats, and weight loss on natalizumab. PMID- 22920746 TI - WHO's undermining tobacco control. PMID- 22920747 TI - Global core competencies for clinical trials. PMID- 22920748 TI - Global health in UK postgraduate medical training. PMID- 22920749 TI - Implantable device regulation in Europe. PMID- 22920750 TI - TDR: a time to live. PMID- 22920751 TI - Fear of genetic discrimination in Japan. PMID- 22920752 TI - Secondary rise in blood pressure after renal denervation. PMID- 22920753 TI - Knock-down of NDRG2 sensitizes cervical cancer Hela cells to cisplatin through suppressing Bcl-2 expression. AB - BACKGROUND: NDRG2, a member of N-Myc downstream regulated gene family, plays some roles in cellular stress, cell differentiation and tumor suppression. We have found that NDRG2 expression in cervical cancer Hela cells increases significantly upon stimulation with cisplatin, the most popular chemotherapeutic agent currently used for the treatment of advanced cervical cancer. This interesting phenomenon drove us to evaluate the role of NDRG2 in chemosensitivity of Hela cells. METHODS: In the present study, RNA interference was employed to down regulate NDRG2 expression in Hela cells. RT-PCR and Western blot were used to detect expression of NDRG2, Bcl-2 and Bax in cancer cells. Real-time PCR was applied to detect miR-15b and miR-16 expression levels. Drug sensitivity was determined with MTT assay. Cell cloning efficiency was evaluated by Colony forming assay. Apoptotic cells were detected with annexin V staining and flow cytometry. RESULTS: In vitro drug sensitivity assay revealed that suppression of NDRG2 could sensitize Hela cells to cisplatin. Down-regulation of NDRG2 didn't influence the colony-forming ability but promoted cisplatin-induced apoptosis of Hela cells. Inhibition of NDRG2 in Hela cells was accompanied by decreased Bcl-2 protein level. However, Bcl-2 mRNA level was not changed in Hela cells with down regulation of NDRG2. Further study indicated that miR-15b and miR-16, two microRNAs targetting Bcl-2, were significantly up-regulated in NDRG2-suppressed Hela cells. CONCLUSIONS: These data suggested that down-regulation of NDRG2 could enhance sensitivity of Hela cells to cisplatin through inhibiting Bcl-2 protein expression, which might be mediated by up-regulating miR-15b and miR-16. PMID- 22920754 TI - Using multilevel growth curve modeling to examine emotional modulation of temporal summation of pain (TS-pain) and the nociceptive flexion reflex (TS-NFR). AB - Emotion can modulate pain and spinal nociception, and correlational data suggest that cognitive-emotional processes can facilitate wind-up-like phenomena (ie, temporal summation of pain). However, there have been no experimental studies that manipulated emotion to determine whether within-subject changes in emotion influence temporal summation of pain (TS-pain) and the nociceptive flexion reflex (TS-NFR, a physiological measure of spinal nociception). The present study presented a series of emotionally charged pictures (mutilation, neutral, erotic) during which electric stimuli at 2 Hz were delivered to the sural nerve to evoke TS-pain and TS-NFR. Participants (n=46 healthy; 32 female) were asked to rate their emotional reactions to pictures as a manipulation check. Pain outcomes were analyzed using statistically powerful multilevel growth curve models. Results indicated that emotional state was effectively manipulated. Further, emotion modulated the overall level of pain and NFR; pain and NFR were highest during mutilation and lowest during erotic pictures. Although pain and NFR both summated in response to the 2-Hz stimulation series, the magnitude of pain summation (TS pain) and NFR summation (TS-NFR) was not modulated by picture-viewing. These results imply that, at least in healthy humans, within-subject changes in emotions do not promote central sensitization via amplification of temporal summation. However, future studies are needed to determine whether these findings generalize to clinical populations (eg, chronic pain). PMID- 22920756 TI - The European Commission's recommendation on the definition of nanomaterial makes an impact. PMID- 22920757 TI - Interference of tobacco smoke with immunochromatography assay for urinary drug detection. AB - BACKGROUND: This study aimed to evaluate the interference of tobacco smoke on immunochromatography assay of urinary drug detection. METHODS: Our study included 256 voluntary subjects (143 passive smokers and 113 current smokers). Cotinine was measured by immunoenzymatic method and thiocyanates (SCN(-)) by selective electrode. Urinary drug was detected by immunochromatography assay. A positive result is completed by an analytical method with an immunometric assay. RESULTS: False positive results for benzodiazepines are significantly more frequent in smokers compared with passive smokers (90.2% Vs 22.4%; chi(2) = 116.62, p < 10( 3)). For smokers, the number of cigarettes was significantly higher in subjects with falsely positive results for benzodiazepines compared with subjects with negative results (32 +/- 11 Vs 20 +/- 10; p = 0.04). Between these two groups, we established a significant difference for urinary cotinine (345 +/- 211 Vs 117 +/- 54 MUg/MUmol; p < 10(-3)) and for plasma SCN(-) (101.6 +/- 3.4 Vs 98.8 +/- 2.1 MUmol/L; p = 10(-3)). Urinary cotinine and consumption duration present the highest values of areas under curves (AUC) of the receiver-operating characteristic (ROC) curves. The cut-off of 167.6 MUg/MUmol and 10.5 years were found as predictive factors of false positive results. CONCLUSION: Tobacco smoke interferes with immunochromatography assay of urinary drug detection; therefore, all subjects must be questioned about their smoking status to avoid such false results during results interpretation. PMID- 22920755 TI - Quantitative criteria for improving performance of buccal DNA for high-throughput genetic analysis. AB - BACKGROUND: DNA from buccal brush samples is being used for high-throughput analyses in a variety of applications, but the impact of sample type on genotyping success and downstream statistical analysis remains unclear. The objective of the current study was to determine laboratory predictors of genotyping failure among buccal DNA samples, and to evaluate the successfully genotyped results with respect to analytic quality control metrics. Sample and genotyping characteristics were compared between buccal and blood samples collected in the population-based Genetic and Environmental Risk Factors for Hemorrhagic Stroke (GERFHS) study (https://gerfhs.phs.wfubmc.edu/public/index.cfm). RESULTS: Seven-hundred eight (708) buccal and 142 blood DNA samples were analyzed for laboratory-based and analysis metrics. Overall genotyping failure rates were not statistically different between buccal (11.3%) and blood (7.0%, p = 0.18) samples; however, both the Contrast Quality Control (cQC) rate and the dynamic model (DM) call rates were lower among buccal DNA samples (p < 0.0001). The ratio of double stranded to total DNA (ds/total ratio) in the buccal samples was the only laboratory characteristic predicting sample success (p < 0.0001). A threshold of at least 34% ds/total DNA provided specificity of 98.7% with a 90.5% negative predictive value for eliminating probable failures. After genotyping, median sample call rates (99.1% vs. 99.4%, p < 0.0001) and heterozygosity rates (25.6% vs. 25.7%, p = 0.006) were lower for buccal versus blood DNA samples, respectively, but absolute differences were small. Minor allele frequency differences from HapMap were smaller for buccal than blood samples, and both sample types demonstrated tight genotyping clusters, even for rare alleles. CONCLUSIONS: We identified a buccal sample characteristic, a ratio of ds/total DNA <34%, which distinguished buccal DNA samples likely to fail high-throughput genotyping. Applying this threshold, the quality of final genotyping resulting from buccal samples is somewhat lower, but compares favorably to blood. Caution is warranted if cases and controls have different sample types, but buccal samples provide comparable results to blood samples in large-scale genotyping analyses. PMID- 22920758 TI - The application of CamScan 2 in forensic dentistry. AB - Forensic dentistry plays a major role in body identification. The dental examination is very accurate and also, nowadays, in the time of a comprehensive fingerprint and DNA assessment, objectively supported. The identification, which is based on the dental documentation, leads up to 43-89% of a successful process. The purpose of the study is to describe the techniques employed by forensic odontology to identify human remains and also to provide details of some of the novel developments within this area. Comparative methods of dental identification of the unknown subject with pre-mortem clinical records, X-ray images, implant presence, superimposition and DNA analysis confirm the identity of the individual. It was shown that dental identification of a person is based on unique individual characteristics of the dentition and dental restorations, relative resistance of the mineralised dental tissues and dental restorations to changes resulting from decomposition and harsh environmental extremes such as conditions of temperature and violent physical forces. PMID- 22920760 TI - Assessing the presence of female DNA on post-coital penile swabs: Relevance to the investigation of sexual assault. AB - During the investigation of sexual assault, penile swabs from an alleged perpetrator are processed as part of the routine procedure. The results of the forensic DNA analysis may subsequently be presented in court. Documentation on the expectancy of finding female cells on post-coital penile swabs is scarce. Reviews from assault cases show that retrieval of female cells from penile swabs is generally reported for less than 50% of the cases. The perception may therefore be that female cells are not expected to be recovered on penile swabs, even few hours after vaginal penetration. However, these reviews do not provide certainty that penetration of body cavities had taken place. Furthermore, the alleged perpetrator may have washed himself before the examination. In the present study, eleven couples provided fourteen sets of post-coital penile swabs collected between 5 and 24 h after vaginal intercourse. At time intervals between 5 and 12 h, the full female DNA profiles were recovered in 90% of the samples. At the lowest, 67% of the full female profile was typed as an average of two swabs sampled at each time point. Samples collected from three couples at 20, 22 and 24 h post-coital, retrieved 100% (15 AMPFlSTR((r))Identifiler markers, in addition to the amelogenin gene) of the female DNA profile from one couple, and 37% and 30% of the full female DNA profiles from the other two couples. For the majority of samples, male DNA was present in slightly greater abundance than female DNA. In this study, female DNA was recovered on all post-coital penile swabs taken at 5-24 h intervals. PMID- 22920759 TI - Sex determination using anthropometric dimensions of the clavicle in Iranian population. AB - OBJECTIVE: Sometimes only skeletal remains are available for forensic identification. Therefore, sex determination using human skeletal remains is one of the most important components in forensic identification. Different levels of accuracy for sex determination using clavicle have been reported in various studies, and on the other hand, anthropometric dimensions of different bones are unique in each race and geographical region. This study was carried out to assess the accuracy of this bone for sex determination in Iranian population. Based on the results of this research, by using the anthropometric dimensions of the clavicle bone, gender can be estimated with a high accuracy. MATERIALS AND METHODS: This research was carried out on 120 Iranian cadavers. Maximum of length and midshaft circumference of clavicle was measured. SPSS (Version 13.5) was used for statistical analysis. RESULTS: The mean of maximum of the length and the midshaft circumference of clavicle was larger in men (P < 0.001). Using claviclular anthropometric parameters, we could determine sex with 73.3%-88.3% accuracy. CONCLUSION: The results of this research indicate that sex can be determined using clavicle dimensions with relatively high accuracy, when only the clavicle bone is available due to explosion, plane crashes, mutilated bodies, etc. PMID- 22920761 TI - A study of lip print pattern in Goan dental students - A digital approach. AB - AIM: To find the incidence of different types of lip patterns, the dominant pattern, quadrant wise, amongst the Goan population. To assess, the quadrant wise differences in lip patterns among males and females and to report new lip print pattern in Goan population. METHODOLOGY: Lip prints of 100 students studying in Goa Dental College & Hospital were taken using 14 mm wide and 50 mm long Scotch tape without any distortion. These prints were then scanned (256 gray shades at a resolution of 300 dpi.) for the digital analysis. Using various applications of Adobe Photoshop 7 software an attempt was made to trace each and every line. K. Suzuki and Y. Tsuchihashi's classification was followed to define the patterns of the grooves. RESULTS: The current study has found the most predominant pattern in Quadrant I to be Type V (580 lines; 52.39%) followed in order by Type I' (196 lines; 17.70%), Type I (166 lines; 14.99%), Type II (166 lines; 10.47%), Type IV (40 lines; 3.61%), Type III (9 lines; 0.81%). In Quadrant II of this study the most predominant pattern recorded was Type V (589 lines; 50.47%) followed in order by Type I' (209 lines; 17.90%), Type I (204 lines; 17.48%), Type II (130 lines; 11.13%), Type IV (34 lines; 2.91%), Type III (1 line; 0.08%). In Quadrant III of this study the most predominant pattern recorded was again Type V (484 lines; 52.09%) followed in order by Type I' (174 lines; 18.72%), Type I (155 lines; 16.68%), Type II (102 lines; 10.97%), Type IV (9 lines; 0.96%), Type III (5 lines; 0.53%). In Quadrant IV of this study the most predominant pattern recorded was Type V (543 lines; 58.19%) followed in order by Type I (151 lines; 16.18%), Type I' (138 lines; 14.79%), Type II (85 lines; 9.11%), Type III (9 lines; 0.96%), Type IV (7 line; 0.75%). In all four Quadrants the most predominant pattern found in males and females was Type V. The present study recorded the following types of type V patterns for the first time; Trifurcations, Bridge or 'H' pattern, Horizontal Lines, Cartwheel, Pineapple Skin and Multiple Branching Appearance. CONCLUSION: The digital method of analyzing the Lip Print images using Adobe Photoshop 7 software serves as a convenient method that provides better visualization and ease in identification and recording of the Lip Print pattern. Predominant pattern in all four quadrants was Type V followed by the linear pattern i.e. Type I' in quadrants I, II, and III and Type I in quadrant IV in the studied population. Distribution of pattern is not affected by the sex. Although type V is the most predominant pattern found in Goan population, the sub-classification of this type defines the more defined term and aids in accuracy of the classification. PMID- 22920762 TI - Hypothalamic transcript profiling in hypothermia using SuperSAGE. AB - Understanding of molecular mechanisms underlying hypothermia is of primary importance in devising strategies to diagnose hypothermia. We investigated the hypothalamic transriptome in hypothermia. For transcriptomic analyses, SuperSAGE, an improved method of serial analysis of gene expression, was used. Totally, 62,208 and 54,084 tags were collected from the hypothalami of normal and hypothermia, respectively. And 367 transcripts were differentially expressed at a statistically significant level. That is, 157 and 210 transcripts among them were expressed at a higher level in normal and hypothermic hypothalami. Results obtained by SuperSAGE and quantitative PCR were consistent in 6 selected genes, although levels of differences detected by the 2 methods were not exactly the same. mRNA expressions in the hypothalamus were considered to be useful for hypothermic diagnosis. Various methods have been applied for gene expression analyses and biomarker detections. However in forensic pathology, SuperSAGE would be a promising method, especially in gene discoveries and transcriptomic analyses. PMID- 22920763 TI - Experience of violence perpetration and victimization in alcohol-dependent patients hospitalized for alcohol withdrawal. AB - BACKGROUND: Alcohol use has long been associated with aggression. However, no causal relationship has been established. Few data are available on both expressed and received violence in problem drinkers or alcohol-dependent patients. This study examined the link between acute alcohol use in dependent drinkers and their experience of violent acts as assailants or victims. METHODS: Face-to-face interviews were conducted in 100 unselected heavy drinkers, admitted to hospital for planned alcohol withdrawal. Questions were directed to: (1) socio economic status, (2) history of alcohol use, (3) family life, (4) professional events, (5) lifetime experiences of physical and psychological harm, as author or as victim, and (6) other addictive behaviors. Violence was considered when the patient considered it to be related to alcohol intake. RESULTS: A total of 69 males and 31 females participated in the study. Forty-six patients (46%, 32 men [46%], 14 women [45%]) reported to be victims of violent acts while they were under the influence of alcohol. Twenty-five patients (25%, 18 men [26%] and 7 women [23%]) reported to be the author of physical or sexual assaults, or thefts or robberies under the influence of alcohol. Insults to strangers were reported by 21 patients (21%, 18 men [26%], 3 women [10%]). Thirty-five patients (35%, 23 men [32%], 13 women [42%]) were detained in police custody while intoxicated. CONCLUSION: In this study, received and expressed violence related to alcohol consumption was a common finding, one side of which can be evaluated through interview of hospitalized patients. PMID- 22920764 TI - Dental age assessment of young Iranian adults using third molars: A multivariate regression study. AB - BACKGROUND: In recent years, a noticeable increase in forensic age estimations of living individuals has been observed. Radiologic assessment of the mineralisation stage of third molars is of particular importance, with regard to the relevant age group. To attain a referral database and regression equations for dental age estimation of unaccompanied minors in an Iranian population was the goal of this study. Moreover, determination was made concerning the probability of an individual being over the age of 18 in case of full third molar(s) development. MATERIALS AND METHODS: Using the scoring system of Gleiser and Hunt, modified by Kohler, an investigation of a cross-sectional sample of 1274 orthopantomograms of 885 females and 389 males aged between 15 and 22 years was carried out. Using kappa statistics, intra-observer reliability was tested. With Spearman correlation coefficient, correlation between the scores of all four wisdom teeth, was evaluated. We also carried out the Wilcoxon signed-rank test on asymmetry and calculated the regression formulae. RESULTS: A strong intra-observer agreement was displayed by the kappa value. No significant difference (p-value for upper and lower jaws were 0.07 and 0.59, respectively) was discovered by Wilcoxon signed-rank test for left and right asymmetry. The developmental stage of upper right and upper left third molars yielded the greatest correlation coefficient. The probability of an individual being over the age of 18 is 95.6% for males and 100.0% for females in case four fully developed third molars are present. Taking into consideration gender, location and number of wisdom teeth, regression formulae were arrived at. CONCLUSION: Use of population-specific standards is recommended as a means of improving the accuracy of forensic age estimates based on third molars mineralisation. To obtain more exact regression formulae, wider age range studies are recommended. PMID- 22920765 TI - Dilemmas concerning the diffuse axonal injury as a clinicopathological entity in forensic medical practice. AB - Dilemmas and discussions concerning the diffuse axonal injury (DAI) and still existing in forensic medical practice are as it follows: 1. Whether the occurrence of DAI can indicate the type of traumatic event that has caused the head trauma, 2. Whether the presence of axonal damage in cases of hypoxia, ischaemia and other pathological conditions casts a shadow on the post-mortem pathological diagnosis of DAI and totally negates it, or there are certain clues in the findings that can point to the aetiology of the axonal damage. This paper discusses our findings based on neuropathological examination of 60 forensic cases of closed head injury. The neuropathological examination included: a macroscopic examination of the coronal sections and a microscopic examination involving an immunohistochemical method with antibody against beta-amyloid precursor protein. Our findings indicate that DAI, as a clinicopathological entity, is undoubtedly an acceleration-deceleration injury, predominant in road traffic accidents as it is classically outlined, and cases of falling from a considerable height. Our findings point to a certain difference between the features of traumatic and ischaemic axonal damage. In this paper we also investigate the correlation between pathological grades of DAI and the impairment of the brain function before death. PMID- 22920766 TI - How reliable is external examination in identifying internal injuries - Casper's sign revisited. AB - It has been proposed that the absence of injuries to the outside of a body that has been subject to blunt trauma indicates that the forces involved were relatively minor. It has also been suggested that an autopsy will be unlikely to uncover any significant injuries. A series of cases involving lethal blunt trauma from vehicle crashes and falls are described where minimal external injuries were associated with major disruption of internal organs. Skin is both resilient and elastic enabling it to resist injury, while allowing considerable forces to be transmitted to the musculoskeletal system and internal organs beneath. The absence of external injury is not, therefore, synonymous with lesser degrees of force, and should not discourage full medicolegal investigation of cases where occult trauma may be a possibility. As Casper was one of the earliest to describe this phenomenon, perhaps the term 'Casper's sign' should be used when massive internal injuries from blunt trauma are found in the absence of significant injuries to the skin. PMID- 22920767 TI - A fatal intoxication case involving ropinirole. AB - Ropinirole, a specific non-ergoline dopamine D2-receptor agonist, belongs to the drugs applied in treatment of Parkinson's disease (PD) and restless legs syndrome (RLS) and acts as a D2, D3, and D4 dopamine receptor agonist with highest affinity for D3. Therapeutic ropinirole plasma levels in adults are defined between 0.4 and 6 ng/mL. This case report documents a fatal intoxication involving ropinirole. Information about lethal ropinirole concentrations is hitherto lacking in the literature and the assessed ropinirole levels of this case may present a step towards defining potentially lethal concentrations. A 37 year-old man without medical history was found dead in a converted van used as place of residence and an autopsy was performed. The pathological findings did not reveal an apparent cause of death but the toxicological analysis revealed the presence of ropinirole, paracetamol, and alcohol in the peripheral blood sample. Quantitative analysis revealed that ropinirole was present at a peripheral blood concentration of 64 ng/mL. The ropinirole concentrations determined in vitreous humor, urine and bile were respectively, 11 ng/mL, 2670 ng/mL and 826 ng/mL. Paracetamol was detected at a blood level of <2 MUg/mL. Based on the autopsy findings and toxicological results, the cause of death was primarily attributed to intoxication with ropinirole in combination with alcohol. PMID- 22920768 TI - The donating capacity of the elderly: A case report of vascular dementia. AB - Seniors may be more vulnerable to the influence of others, being less able to make judicious decisions. The legal legitimacy of donating capacity is based on the clinical assumption that, at the time of the event, the donor is able to understand the nature of the transaction, weigh its consequences and determine his/her actions according to it. From the point of view of forensic psychiatry, the evaluation of such premises is a challenge, reflecting the difficulty in assessing, retrospectively, the subject's cognitive functions at the time of the event. In cases where the cross-sectional evaluation favours the diagnosis of dementia it is crucial to objectify the onset and course of the illness. The authors report and discuss the case of a donation from father to sons, involving a great deal of money, made by an 85-year-old man, who had suffered an ischaemic cerebrovascular accident 5 years before. PMID- 22920769 TI - A case of a serial sexual offender: The first ever report from Turkey. AB - There have been cases of serial sexual offenders and studies dealing with such cases in the literature. However, no serial sexual offender case was reported in Turkey, to the best of our knowledge. In this article, as the first report from Turkey, we present a serial sexual offender who assaulted 27 women. The assailant entered a total of 29 houses, and assaulted victims in 27 of them, and he failed to assault two individuals. The 'modus operandi' of the offender was identical in all assault cases and led the police towards a hypothesis that these assaults were all committed by the same individual. The offender did not admit the assaults and strictly refused a forensic psychiatric examination. Being an individual with a high level of education, having a respected position and profession, choosing women aged older than 18 years as victims were among distinctive features of the presented offender. PMID- 22920770 TI - Collision victim travels for "seven kilometres" on top of the car that hit him. AB - CASE REPORT: A 26-year-old man, after a drinking binge, drove into a tram building site and collided with a track-grinding machine which left a fist-size hole in his windscreen. He then hit a construction worker who was catapulted onto the car roof. The worker held on to the antenna and the windscreen hole, while the car drove on for 7 km, reaching speeds of 90 km h(-1). The victim suffered several fractures and survived with relatively little consequential damage. The investigation showed the driver to have been under the influence of alcohol and cannabis. In trial, he claimed loss of memory and stated that he had noticed neither the accident nor the man on his car roof. PMID- 22920771 TI - An unusual case of self-strangulation by ligature. AB - Self-strangulation is an uncommon method of suicide. We report an unusual case of self-strangulation where the body was found in an open area with a ligature around neck and another around the feet. The case was initially taken up as homicide. The manner was determined as suicide later based on detailed investigations. The deceased had used two ligatures tied to heavy stones, one secured around the feet and the other around the neck to strangulate him. The case is reported for its rarity and the unusual method adopted by the victim to commit suicide by self-strangulation in an open area. In cases where it is difficult to reach a definitive conclusion as to manner of death, it is of utmost importance that a systematic death scene investigation, a meticulous post mortem examination and an intelligent interpretation of the findings is carried out. PMID- 22920772 TI - Medical error reporting should it be mandatory in Scotland? AB - Healthcare professionals have an ethical and professional responsibility to report medical errors. Doctors in particular are duty bound to consider the best interests of their patients and 'do no harm'. Medical errors are rarely due to individual human error but are often systems based and in many cases are avoidable. Reporting and learning from medical errors improves the safety of patients. It has been over ten years since the reports To Err Is Human and An Organisation with a Memory highlighted the scale of preventable medical errors. These statistics, stimulated worldwide health organisations to prioritise patient safety. Both reports recommended the implementation of a voluntary near-miss reporting system and mandatory reporting of serious adverse incidents that had caused physical or psychological harm or death. Currently in Scotland reporting of all errors is voluntary and there is no sharing of information between Health Boards. Studies have demonstrated failings of the voluntary system and preventable medical errors are still occurring in Scotland. The UK Government in England as of April 2010 has changed the voluntary system of reporting serious adverse events to a mandatory obligation. Failure to report may result in a fine of L4000 to the Trust. Patient groups wish the system in Scotland to become mandatory with public disclosure. This would ensure openness, honesty and autonomy for patients. This article reviews the controversial issue of mandatory reporting and whether or not this would improve the safety of patients. In conclusion, Scotland would benefit from mandatory reporting of serious adverse events and voluntary near-miss reporting. PMID- 22920773 TI - The range of scientific misconduct. PMID- 22920775 TI - An integrative review of adolescent smoking cessation using the Transtheoretical Model of Change. AB - INTRODUCTION: The purpose of this literature review is to report the effectiveness of trials using the Transtheoretical Model of Change for achieving smoking cessation among adolescents. METHOD: An integrative literature review was performed. Two reviewers searched the Internet for randomized, controlled trials or observational studies of adolescent smoking cessation trials reported between 1999 and June 2009 that used the Transtheoretical Model of Change. RESULTS: Six randomized controlled trials remained after all inclusion and exclusion criteria were met. Each study was reviewed qualitatively and odds ratio and quit rates were calculated. Four studies demonstrated an odds ratio of greater than 1.0, and in four studies significantly better quit rates were found in the intervention arm versus the control arm at the endpoint evaluation. DISCUSSION: Evidence exists for the effectiveness of stage-based interventions in promoting smoking cessation in adolescents. PMID- 22920774 TI - Evidence-based care of the child with deformational plagiocephaly, part II: management. AB - Non-synostotic deformational plagiocephaly (DP) is a common condition that affects as many as one in five infants in the first 2 months of life. The purpose of this article, the second in a two-part series, is to present a synthesis of the evidence related to management of deformational plagiocephaly and an evidence based clinical decision tool for multidisciplinary management of DP. We systematically reviewed and graded the literature on management of DP from 2000 to 2011 based on level of evidence and quality. The evidence suggests that although many cases of DP will improve over time, conservative management strategies such as repositioning, physical therapy, and cranial molding devices can safely and effectively minimize the degree of skull asymmetry when implemented in the first year of life. Outcomes are best when the timing of diagnosis and severity of asymmetry guide decision making related to interventions and referrals for DP. Prevention and management of early signs of DP are best achieved in a primary care setting, with multidisciplinary management based on the needs of the child and the goals of the family. PMID- 22920776 TI - Risk and protective factors associated with stress in mothers whose children are enrolled in early intervention services. AB - INTRODUCTION: Although considerable research has addressed children with special health care needs enrolled in early intervention (EI) services, little is known about families' needs. This study provides baseline data on factors informing health promotion and prevention interventions for mothers of children enrolled in EI services who are experiencing high levels of stress. METHODS: A non experimental descriptive-correlational study measured the following risk and protective factors in mothers of children enrolled in EI services: parent stress, severity of child's behavior, stressful life events, family functioning, appraisal of the situation, resources, and social support. RESULTS: More than one third of mothers had stress and family-functioning scores necessitating referral. Services for cognitive or social-emotional delays, unhealthy family functioning, and many co-existing stress events were significantly associated with increased stress. Mothers did not find caring for a child with a disability stressful and were satisfied with their social support. Higher incomes and levels of education were significantly associated with less stress; however, this sample was highly educated with middle-class incomes. DISCUSSION: Many mothers with children enrolled in EI services could be helped by specific primary, secondary, and tertiary interventions by pediatric nurse practitioners and primary health care providers. PMID- 22920778 TI - Issues in research integrity: deciding what is mine, yours, and ours. PMID- 22920779 TI - The medical home: the debate over who is qualified to drive the bus. PMID- 22920777 TI - Puerto Rican families' experiences of asthma and use of the emergency department for asthma care. AB - Puerto Ricans have been found to have higher asthma prevalence rates than non Hispanic whites, blacks, and all other Hispanic subgroups. They also have the highest rates of emergency department (ED) use for the management of their asthma. Using a hermeneutic phenomenological approach, the aim of this study was to describe the lived experience of Puerto Rican families caring for their child's asthma and using the ED for asthma care. Six themes were generated from in-depth interviews with 10 Puerto-Rican caregivers: (1) The Folklore of Asthma, (2) Culture and the Medicine Woman, (3) In Awe of Asthma, (4) Praying to God, (5) The Decision-Time to Go, and (6) The ED Environment. The findings emphasize the necessity of establishing and maintaining a therapeutic partnership between primary care providers and families of children with asthma. The results may be used as a foundation for understanding motivations for seeking asthma care in the ED. PMID- 22920780 TI - The effects of health insurance and a usual source of care on a child's receipt of health care. AB - INTRODUCTION: Although recent health care reforms will expand insurance coverage for U.S. children, disparities regarding access to pediatric care persist, even among the insured. We investigated the separate and combined effects of having health insurance and a usual source of care (USC) on children's receipt of health care services. METHODS: We conducted secondary analysis of the nationally representative 2002-2007 Medical Expenditure Panel Survey data from children (<= 18 years of age) who had at least one health care visit and needed any additional care, tests, or treatment in the preceding year (n = 20,817). RESULTS: Approximately 88.1% of the study population had both a USC and insurance; 1.1% had neither one; 7.6% had a USC only, and 3.2% had insurance only. Children with both insurance and a USC had the fewest unmet needs. Among insured children, those with no USC had higher rates of unmet needs than did those with a USC. DISCUSSION: Expansions in health insurance are essential; however, it is also important for every child to have a USC. New models of practice could help to concurrently achieve these goals. PMID- 22920781 TI - The Barcelona Symposium: electrocardiography and the need for consensus. PMID- 22920782 TI - Current electrocardiographic criteria for diagnosis of Brugada pattern: a consensus report. AB - Brugada syndrome is an inherited heart disease without structural abnormalities that is thought to arise as a result of accelerated inactivation of Na channels and predominance of transient outward K current (I(to)) to generate a voltage gradient in the right ventricular layers. This gradient triggers ventricular tachycardia/ventricular fibrillation possibly through a phase 2 reentrant mechanism. The Brugada electrocardiographic (ECG) pattern, which can be dynamic and is sometimes concealed, being only recorded in upper precordial leads, is the hallmark of Brugada syndrome. Because of limitations of previous consensus documents describing the Brugada ECG pattern, especially in relation to the differences between types 2 and 3, a new consensus report to establish a set of new ECG criteria with higher accuracy has been considered necessary. In the new ECG criteria, only 2 ECG patterns are considered: pattern 1 identical to classic type 1 of other consensus (coved pattern) and pattern 2 that joins patterns 2 and 3 of previous consensus (saddle-back pattern). This consensus document describes the most important characteristics of 2 patterns and also the key points of differential diagnosis with different conditions that lead to Brugada-like pattern in the right precordial leads, especially right bundle-branch block, athletes, pectus excavatum, and arrhythmogenic right ventricular dysplasia/cardiomyopathy. Also discussed is the concept of Brugada phenocopies that are ECG patterns characteristic of Brugada pattern that may appear and disappear in relation with multiple causes but are not related with Brugada syndrome. PMID- 22920783 TI - Interatrial blocks. A separate entity from left atrial enlargement: a consensus report. AB - Impaired interatrial conduction or interatrial block is well documented but is not described as an individual electrocardiographic (ECG) pattern in most of ECG books, although the term atrial abnormalities to encompass both concepts, left atrial enlargement (LAE) and interatrial block, has been coined. In fact, LAE and interatrial block are often associated, similarly to what happens with ventricular enlargement and ventricular block. The interatrial blocks, that is, the presence of delay of conduction between the right and left atria, are the most frequent atrial blocks. These may be of first degree (P-wave duration >120 milliseconds), third degree (longer P wave with biphasic [+/-] morphology in inferior leads), and second degree when these patterns appear transiently in the same ECG recording (atrial aberrancy). There are evidences that these electrocardiographic P-wave patterns are due to a block because they may (a) appear transiently, (b) be without associated atrial enlargement, and (c) may be reproduced experimentally. The presence of interatrial blocks may be seen in the absence of atrial enlargement but often are present in case of LAE. The most important clinical implications of interatrial block are the following: (a) the first degree interatrial blocks are very common, and their relation with atrial fibrillation and an increased risk for global and cardiovascular mortality has been demonstrated; (b) the third degree interatrial blocks are less frequent but are strong markers of LAE and paroxysmal supraventricular tachyarrhythmias. Their presence has been considered a true arrhythmological syndrome. PMID- 22920784 TI - Electrocardiographic manifestation of the middle fibers/septal fascicle block: a consensus report. AB - There are fibers in the left ventricle (LV) (LV middle network) that in around one third of cases may be considered a true septal fascicle that arises from the common left bundle. Its presence and the evidence that there are 3 points of activation onset in the LV favor the quadrifascicular theory of the intraventricular activation of both ventricles. Since the 70s, different authors have suggested that the block of the left middle fibers (MS)/left septal fascicle may explain different electrocardiographic (ECG) patterns. The 2 hypothetically based criteria that are in some sense contradictory include: a) the lack of septal "q" wave due to first left and later posteriorly shifting of the horizontal plane loop and b) the presence of RS in lead V(2) (V(1)-V(2)) due to some anterior shifting of the horizontal plane vectorcardiogram loop. However, there are many evidence that the lack of septal q waves can be also explained by predivisional first-degree left bundle-branch block and that the RS pattern in the right precordial leads may be also explained by first-degree right bundle branch block. The transient nature of these patterns favor the concept that some type of intraventricular conduction disturbance exists but a doubt remains about its location. Furthermore, the RS pattern could be explained by many different normal variants. To improve our understanding whether these patterns are due to MF/left septal fascicle block or other ventricular conduction disturbances (or both), it would be advisable: 1) To perform more histologic studies (heart transplant and necropsy) of the ventricular conduction system; 2) To repeat prior experimental studies using new methodology/technology to isolate the MF; and 3) To change the paradigm: do not try to demonstrate if the block of the fibers produces an ECG change but to study with new electroanatomical imaging techniques, if these ECG criteria previously described correlate or not with a delay of activation in the zone of the LV that receives the activation through these fibers or in other zones. PMID- 22920785 TI - Common pitfalls in the interpretation of electrocardiograms from patients with acute coronary syndromes with narrow QRS: a consensus report. AB - Acute coronary syndromes (ACS) with narrow QRS are divided into 2 groups: ST elevation ACS that requires emergency percutaneous coronary intervention, and non ST elevation ACS. The classification of ACS into these 2 groups is not always straightforward. In this document, we discuss several electrocardiogram patterns of acute ischemia that are often misinterpreted. We suggest that any new recommendations or guidelines from the Scientific Societies should acknowledge these aspects of electrocardiogram interpretation by including appropriate diagnostic criteria that should prove helpful for the optimal management of patients with ACS. PMID- 22920786 TI - Importance of defining left bundle branch block. PMID- 22920787 TI - Sleep apnea: what does that really mean? A commentary on Baranchuk: "Sleep apnea, cardiac arrhythmias, and conduction disorders". PMID- 22920788 TI - The electrocardiographic features of complete and partial left anterior and left posterior hemiblock. AB - The aim of this study is to present the criteria for the diagnosis of incomplete or partial block within the anterior and posterior divisions of the left bundle branch (LBB). To disclose incomplete left anterior hemiblock (LAH) and incomplete left posterior hemiblock (LPH), clinical cases of pathologic and physiologic intermittent or transient block in the divisions of the LBB are analyzed. When dealing with the diagnosis of incomplete LAH, an AQRS shift in the same or in successive tracings in a patient, showing electrical axis at +50 degrees , +40 degrees , +30 degrees , and 0 degrees covering the whole range up to -45 degrees or even more negative, makes the diagnosis of incomplete to complete block in the anterior division of the LBB. Conversely, when LPH is the case, a progressive change of the AQRS from a normal axis to the right, up to +120 degrees in the same or subsequent tracings in a short period, can only be explained by increasing the degrees of LPH. When a partial or incomplete LAH or LPH is present and the AQRS direction can be considered normal in clinical practice, it is difficult or even impossible to reach a diagnosis. That is, small degrees of block in the divisions of the LBB totally overlap normal variants. PMID- 22920789 TI - Autoinhibitory mechanism for the mutation-induced impaired FGF9 signaling. AB - Fibroblast growth factor 9 (FGF9), an important member of the fibroblast growth factor (FGF) family, can bind with high affinity to FGFR3 in a heparin-dependent approach. In humans, the deletions and mutations resulting in dysfunction of the FGF9 signaling can cause human skeletal dysplasia and cancers. A mutation (S99N) in this protein has been identified to be associated with significantly impaired FGF signaling considered as a potential cause of synostoses syndrome. However, the detailed mechanism for this observation still remains unknown. In this study, we used molecular dynamics simulations and free energy calculations to study the interactions of FGF9(WT/S99N), FGFR3c, and heparin, with an aim of providing atomic sights into the detailed mechanism for the impaired FGF signaling caused by the S99N mutation. We found that the S99N mutation has a well-ordered C terminal structure, which can reduce its homodimerization ability so as to break the monomer-dimer equilibrium in the FGF signaling, which is considered as a key factor to regulate extracellular matrix affinity and tissue diffusion in the FGF signaling pathway. The FGF9(WT) monomer can preferentially form a homodimer owing to its comparatively favorable binding free energy. In contrast, the FGF9(S99N) monomer is preferred to bind with the FGFR3c receptor to form an inactive complex, leading to impair FGF signaling. To support our computational findings, we also performed biochemical experiments, which confirm the computational results mentioned above. The impaired FGF signaling is believed to be a potential cause of human synostoses syndrome, implicating an important role for FGF9 in normal joint development. PMID- 22920790 TI - Human serum is a suitable supplement for the osteogenic differentiation of human adipose-derived stem cells seeded on poly-3-hydroxibutyrate-co-3-hydroxyvalerate scaffolds. AB - Human adipose-derived stem cells (hASCs) are currently a point of focus for bone tissue engineering applications. However, the ex vivo expansion of stem cells before clinical application remains a challenge. Fetal bovine serum (FBS) is largely used as a medium supplement and exposes the recipient to infections and immunological reactions. In this study, we evaluated the osteogenic differentiation process of hASCs in poly-3-hydroxybutyrate-co-3-hydroxyvalerate (PHB-HV) scaffolds with the osteogenic medium supplemented with pooled allogeneic human serum (aHS). The hASCs grown in the presence of FBS or aHS did not show remarkable differences in morphology or immunophenotype. The PHB-HV scaffolds, which were developed by the freeze-drying technique, showed an adequate porous structure and mechanical performance as observed by micro-computed tomography, scanning electron microscopy (SEM), and compression test. The three-dimensional structure was suitable for allowing cell colonization, which was revealed by SEM micrographs. Moreover, these scaffolds were not toxic to cells as shown by 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. The differentiation capacity of hASCs seeded on scaffolds was confirmed by the reduction of the proliferation, the alkaline phosphatase (AP) activity, expression of osteogenic gene markers (AP, collagen type I, Runx2, and osteocalcin), and the expression of bone markers, such as osteopontin, osteocalcin, and collagen type I. The osteogenic capacity of hASCs seeded on PHB-HV scaffolds indicates that this scaffold is adequate for cell growth and differentiation and that aHS is a promising supplement for the in vitro expansion of hASCs. In conclusion, this strategy seems to be useful and safe for application in bone tissue engineering. PMID- 22920791 TI - Cannabis use and schizotypy: the role of social anxiety and other negative affective states. AB - Emerging research suggests that cannabis use might be related to psychosis onset in people vulnerable to developing schizophrenia-spectrum disorders. Furthermore, individuals with high-positive and disorganized schizotypy traits report more cannabis use and cannabis-related problems than controls. Social anxiety, a frequently co-occurring schizotypal feature, is related to increased cannabis related problems in the general population. Building on this research, we explored the impact of social anxiety, measured by the Social Interaction Anxiety Scale (SIAS), and depression and trait anxiety reported on the Brief Symptom Inventory (BSI), on the relationship of schizotypy, measured by the Schizotypy Personality Questionnaire-Brief Revised (SPQ-BR), to cannabis use (n=220 schizotypy, 436 controls) and frequent use and cannabis-related problems among users (n=88 schizotypy, 83 controls) in college undergraduates. Among cannabis users, social anxiety moderated the relationships of schizotypy to frequent cannabis use and more cannabis-related problems in the total schizotypy group, and across high-positive, negative, and disorganized schizotypy subgroups. Depression and trait anxiety also moderated the relationship of schizotypy to frequent cannabis use and more cannabis-related problems, but results varied across high-positive, negative, and disorganized schizotypy subgroups. Results suggest therapeutically targeting negative affective states may be useful in psychosocial intervention for cannabis-related problems in schizotypy. PMID- 22920792 TI - Response confidence for emotion perception in schizophrenia using a Continuous Facial Sequence Task. AB - Deficits in emotion perception and overconfidence in errors are well-documented in schizophrenia but have not been examined concurrently. The present study aimed to fill this gap. Twenty-three schizophrenia patients and twenty-nine healthy subjects underwent a Continuous Facial Sequence Task (CFST). The CFST comprised two blocks: a female (1st block) and a male protagonist (2nd block) displayed the six basic emotions postulated by Ekman as well as two more complex mental states and a neutral expression. Participants were first asked to identify the affect displayed by the performer and then to judge their response confidence. No group differences emerged regarding overall emotion perception. Follow-up analyses showed that patients were less correct in detecting some negative emotions but performed better for neutral or positive emotions. Regarding confidence, incorrect decisions in patients were associated with higher confidence than in controls (statistical trend level, moderate effect size). Patients displayed significant overconfidence in errors for negative emotions. In addition, patients were more prone to high-confident errors for emotions that were displayed in weak emotional intensity. While the study supports the view that the examination of confidence adds unique information to our understanding of social cognition, several methodological limitations render its findings preliminary. PMID- 22920793 TI - Pore-scale investigation of nanoparticle transport in saturated porous media using laser scanning cytometry. AB - Knowledge of nanoparticle transport and retention mechanisms is essential for both the risk assessment and environmental application of engineered nanomaterials. Laser scanning cytometry, an emerging technology, was used for the first time to investigate the transport of fluorescent nanoparticles in a microfluidic flow cell packed with glass beads. The laser scanning cytometer (LSC) was able to provide the spatial distribution of 64 nm fluorescent nanoparticles attached in a domain of 12 mm long and 5 mm wide. After 40 pV of injection at a lower ionic strength condition (3 mM NaCl, pH 7.0), fewer fluorescent nanoparticles were attached to the center of the flow cell, where the pore-scale velocity is relatively higher. After a longer injection period (300 PV), more were attached to the center of the flow cell, and particles were attached to both the upstream and downstream sides of a glass bead. Nanoparticles attached under a higher ionic strength condition (100 mM NaCl, pH 7.0) were found to be mobilized when flushed with DI water. The mobilized particles were later reattached to some favorable sites. The attachment efficiency factor was found to reduce with an increase in flow velocity. However, torque analysis based on the secondary energy minimum could not explain the observed hydrodynamic effect on the attachment efficiency factor. PMID- 22920795 TI - Metal-free N-H insertions of donor/acceptor carbenes. AB - Synthetically useful transformations arise from the thermal decomposition of aryldiazoacetates in the presence of primary and secondary amines without the use of a metal catalyst. Thermally generated, free donor/acceptor carbenes directly undergo N-H insertion with amines through selective aza-ylide formation to afford a variety of alpha-amino esters in 53-96% yields. PMID- 22920794 TI - Localized delivery of dexamethasone from electrospun fibers reduces the foreign body response. AB - Synthetic scaffolds are crucial to applications in regenerative medicine; however, the foreign body response can impede regeneration and may lead to failure of the implant. Herein we report the development of a tissue engineering scaffold that allows attachment and proliferation of regenerating cells while reducing the foreign body response by localized delivery of an anti-inflammatory agent. Electrospun fibers composed of poly(l-lactic) acid (PLLA) and poly(epsilon caprolactone) (PCL) were prepared with and without the steroid anti-inflammatory drug, dexamethasone. Analysis of subcutaneous implants demonstrated that the PLLA fibers encapsulating dexamethasone evoked a less severe inflammatory response than the other fibers examined. They also displayed a controlled release of dexamethasone over a period of time conducive to tissue regeneration and allowed human mesenchymal stem cells to adhere to and proliferate on them in vitro. These observations demonstrate their potential as a building block for tissue engineering scaffolds. PMID- 22920796 TI - Future of diabetes-technology: certificate of competency for insulin pumps and continuous glucose monitors. PMID- 22920797 TI - Ultrafast-acting insulins: state of the art. AB - Optimal coverage of prandial insulin requirements remains an elusive goal. The invention of rapid-acting insulin analogs (RAIAs) was a big step forward in reducing postprandial glycemic excursions in patients with diabetes in comparison with using regular human insulin; however, even with these, the physiological situation cannot be adequately mimicked. Developing ultrafast-acting insulins (UFIs)-showing an even more rapid onset of action and a shorter duration of action after subcutaneous (SC) administration-is another step forward in achieving this goal. The need for UFIs has been gradually recognized over the years, and subsequently, a number of different approaches to cover this need are in clinical development. A rapid increase in circulating insulin levels can be achieved by different measures: modification of the primary structure of insulin molecule (as we know from RAIAs), addition of excipients that enhance the appearance in the monomeric state post-injection, or addition of enzymes that enable more free spreading of the insulin molecules in the SC tissue. Other measures to increase the insulin absorption rate increase the local blood flow nearby the insulin depot in the SC tissue, injecting the insulin intradermally or applying via another route, e.g., the lung. The development of these approaches is in different stages, from quite early stages to nearing market authorization. In time, daily practice will show if the introduction of UFIs will fulfill their clinical promise. In this review, the basic idea for UFIs will be presented and the different approaches will be briefly characterized. PMID- 22920798 TI - Pharmacokinetics and postprandial glycemic excursions following insulin lispro delivered by intradermal microneedle or subcutaneous infusion. AB - BACKGROUND: Intradermal (ID) delivery has been shown to accelerate insulin pharmacokinetics (PK). We compared the PK and pharmacodynamic (PD) effects of insulin lispro administered before two daily standardized solid mixed meals (breakfast and lunch), using microneedle-based ID or traditional subcutaneous (SC) delivery. METHOD: The study included 22 subjects with type 1 diabetes in an eight-arm full crossover block design. One arm established each subject's optimal meal dose. In six additional arms, the optimal, higher, and lower doses (+30%, 30%) were each given ID and SC delivery, in random order. The final arm assessed earlier timing for the ID optimal dose (-12 versus -2 min). The PK/PD data were collected for 6 h following meals. Intravenous basal regular insulin was given throughout, and premeal blood glucose (BG) adjusted to 115 mg/dl. RESULTS: The primary end point, postprandial time in range (70-180 mg/dl), showed no route based differences with a high level of overall BG control for both SC and ID delivery. Secondary insulin PK end points showed more rapid ID availability versus SC across doses and meals (?Tmax -16 min, ?T50rising -7 min, ?T50falling 30 min, all p < .05). Both intrasubject and intersubject variability for ID Tmax were significantly lower. Intradermal delivery showed modest, statistically significant secondary PD differences across doses and meals, generally within 90 120 min postprandially (?12 mg/dl BG at 90 min, ?7 mg/dl BGmax, ?7 mg/dl mean BG 0-2 h, all p < .05). CONCLUSIONS: This study indicates that ID insulin delivery is superior to SC delivery in speed of systemic availability and PK consistency and may improve postprandial glucose control. PMID- 22920799 TI - Ultra-rapid absorption of recombinant human insulin induced by zinc chelation and surface charge masking. AB - BACKGROUND: In order to enhance the absorption of insulin following subcutaneous injection, excipients were selected to hasten the dissociation rate of insulin hexamers and reduce their tendency to reassociate postinjection. A novel formulation of recombinant human insulin containing citrate and disodium ethylenediaminetetraacetic acid (EDTA) has been tested in clinic and has a very rapid onset of action in patients with diabetes. In order to understand the basis for the rapid insulin absorption, in vitro experiments using analytical ultracentrifugation, protein charge assessment, and light scattering have been performed with this novel human insulin formulation and compared with a commercially available insulin formulation [regular human insulin (RHI)]. METHOD: Analytical ultracentrifugation and dynamic light scattering were used to infer the relative distributions of insulin monomers, dimers, and hexamers in the formulations. Electrical resistance of the insulin solutions characterized the overall net surface charge on the insulin complexes in solution. RESULTS: The results of these experiments demonstrate that the zinc chelating (disodium EDTA) and charge-masking (citrate) excipients used in the formulation changed the properties of RHI in solution, making it dissociate more rapidly into smaller, charge-masked monomer/dimer units, which are twice as rapidly absorbed following subcutaneous injection than RHI (Tmax 60 +/- 43 versus 120 +/- 70 min). CONCLUSIONS: The combination of rapid dissociation of insulin hexamers upon dilution due to the zinc chelating effects of disodium EDTA followed by the inhibition of insulin monomer/dimer reassociation due to the charge-masking effects of citrate provides the basis for the ultra-rapid absorption of this novel insulin formulation. PMID- 22920800 TI - Accelerating and improving the consistency of rapid-acting analog insulin absorption and action for both subcutaneous injection and continuous subcutaneous infusion using recombinant human hyaluronidase. AB - Rapid-acting insulin analogs were introduced to the market in the 1990s, and these products have improved treatment of diabetes by shortening the optimum delay time between injections and meals. Compared with regular human insulin, rapid-acting insulin formulations also reduce postprandial glycemic excursions while decreasing risk of hypoglycemia. However, the current prandial products are not fast enough for optimum convenience or control. Recombinant human hyaluronidase (rHuPH20) has been used to increase the dispersion and absorption of other injected drugs, and in the case of prandial insulin analogs, it confers both ultrafast absorption and action profiles. Animal toxicology studies have demonstrated excellent tolerability of rHuPH20, and human studies, involving over 60,000 injections of prandial insulin + rHuPH20 to date, have similarly shown excellent safety and tolerability. Studies using rapid-acting analog insulin with rHuPH20 have included clinic-based pharmacokinetic and glucodynamic euglycemic glucose clamp studies, test meal studies, and take-home treatment studies. Administration methods have included subcutaneous injection of coformulations of rapid-acting insulin + rHuPH20 as well as continuous subcutaneous infusion of coformulations or use of pretreatment of newly inserted infusion sets with rHuPH20 followed by standard continuous subcutaneous insulin infusion therapy. These studies have demonstrated acceleration of insulin absorption and action along with improvement in postprandial glycemic excursions and reduction in hypoglycemia risks. Further, rHuPH20 reduces intrasubject variability of insulin absorption and action and provides greater consistency in absorption and action profiles over wear time of an infusion set. Further studies of rHuPH20 in the take-home treatment setting are underway. PMID- 22920801 TI - Coverage of prandial insulin requirements by means of an ultra-rapid-acting inhaled insulin. AB - Barriers to the use of prandial insulin regimens include inadequate synchronization of insulin action to postprandial plasma glucose excursions as well as a significant risk of hypoglycemia and weight gain. Technosphere(r) insulin (TI) is an inhaled ultra-rapid-acting human insulin that is quickly absorbed in the alveoli. With a time to maximum plasma drug concentration of approximately 14 min and a time to maximum effect of 35 to 40 min, TI more closely matches the postprandial insulin concentrations seen in nondiabetic individuals. Studies have shown that long-term administration of prandial TI in combination with long-acting basal insulin results in reductions in hemoglobin A1c comparable to conventional subcutaneously injected prandial insulins but with improved control of early postprandial BG. Furthermore, TI has been associated with less weight gain and a lower incidence of hypoglycemia, which may enhance patient satisfaction and acceptability of insulin therapy. This review discusses the clinical properties of TI and proposes strategies for optimal use. PMID- 22920802 TI - Increasing local blood flow by warming the application site: beneficial effects on postprandial glycemic excursions. AB - The absorption profile of rapid-acting insulin analogs delivered subcutaneously is slow compared with physiological insulin. Shorter time to peak and shorter duration of insulin action are important steps toward reducing high postprandial blood glucose concentrations in diabetes therapy and are critical for the development of a closed-loop insulin delivery system. Many attempts have been made to develop more rapid-acting insulins. Since the 1950s, different approaches, such as jet injectors and sprinkler needles, which try to increase the absorption areas of injected insulin, have been developed; however, none of them are commonly used in diabetes therapy. Massage and heat increase tissue blood perfusion and, thereby, the absorption of subcutaneously applied insulin. The main focus of this article is a novel device that allows local application of heat to human skin. The device can be connected to a regular insulin pump. This device could demonstrate a significant effect on insulin absorption and postprandial glucose excursions in multiple clinical trials. PMID- 22920803 TI - A review of a family of ultra-rapid-acting insulins: formulation development. AB - This review summarizes the clinical development of a family of ultra-rapid-acting recombinant human insulin formulations. These formulations use ethylenediaminetetraacetic acid (EDTA) to chelate zinc and thereby destabilize insulin hexamers. In addition, insulin monomer surface charges are chemically masked with citrate to prevent reaggregation. The first phase 1 trials were performed using BIOD-090, an acidic 25 unit U/ml insulin formulation, which contained disodium-EDTA (NaEDTA). When compared with regular human insulin (RHI) and/or insulin lispro in multiple phase 1 studies, BIOD-090 consistently showed more rapid absorption and/or onset of action. A standard meal challenge study also demonstrated improved postprandial glucose profiles associated with BIOD 090. However, increased patient exposure in larger phase 3 trials showed that this formulation was associated with an increased incidence of local injection site reactions, most commonly pain. A next generation formulation, BIOD-100, contained the same excipients as a standard insulin concentration of 100 U/ml. BIOD-100 maintained an ultra-rapid action profile and was associated with modest but significantly improved toleration when compared with BIOD-090. In order to further improve toleration, the hypothesis that NaEDTA contributed to discomfort by chelating endogenous calcium was tested by either substituting calcium-EDTA for NaEDTA or by adding calcium chloride to the NaEDTA formulation. These calcium formulations essentially eliminated the excess discomfort associated with BIOD 090 but were associated with less optimal pharmacokinetic profiles in humans. Recent efforts have succeeded in developing ultra-rapid-acting human insulin formulations with acceptable injection site toleration by optimizing concentrations of calcium (BIOD-125) and with the use of magnesium sulfate to mitigate discomfort (BIOD-123). Similar formulation technology has also been shown to accelerate absorption of insulin analogs in animal models. PMID- 22920804 TI - Undeniable need for ultrafast-acting insulin: the pediatric perspective. AB - Insulin therapy in youth with type 1 diabetes mellitus (T1DM) poses a special challenge because childhood is an unsteady state with increasing weight, height, and caloric needs, leading to varying insulin requirements. The current rapid acting insulin analogs are not as fast and short-acting as needed to meet these challenges. This review describes the unique characteristics of insulin action in youth with T1DM based on previously published euglycemic clamp studies. It also explains the rationale behind the need for ultrafast-acting insulins to advance open- and closed-loop insulin therapy for the pediatric population with diabetes. Lastly, it briefly summarizes ongoing and future projects to accelerate insulin action in youth with T1DM. PMID- 22920805 TI - Video games for diabetes self-management: examples and design strategies. AB - The July 2012 issue of the Journal of Diabetes Science and Technology includes a special symposium called "Serious Games for Diabetes, Obesity, and Healthy Lifestyle." As part of the symposium, this article focuses on health behavior change video games that are designed to improve and support players' diabetes self-management. Other symposium articles include one that recommends theory based approaches to the design of health games and identifies areas in which additional research is needed, followed by five research articles presenting studies of the design and effectiveness of games and game technologies that require physical activity in order to play. This article briefly describes 14 diabetes self-management video games, and, when available, cites research findings on their effectiveness. The games were found by searching the Health Games Research online searchable database, three bibliographic databases (ACM Digital Library, PubMed, and Social Sciences Databases of CSA Illumina), and the Google search engine, using the search terms "diabetes" and "game." Games were selected if they addressed diabetes self-management skills. PMID- 22920806 TI - Designing serious video games for health behavior change: current status and future directions. AB - Serious video games for health are designed to entertain while changing a specific health behavior. This article identifies behavioral principles that can guide the development of serious video games focused on changing a variety of health behaviors, including those attempting to decrease risk of obesity and type 2 diabetes. Guidelines discussed include how to develop video games that provide a solid foundation for behavior change by enhancing a player's knowledge and skill, ways in which personal mastery experiences can be incorporated into a video game environment, using game characters and avatars to promote observational learning, creating personalized experiences through tailoring, and the importance of achieving a balance between "fun-ness" and "seriousness." The article concludes with suggestions for future research needed to inform this rapidly growing field. PMID- 22920807 TI - Motivating effects of cooperative exergame play for overweight and obese adolescents. AB - BACKGROUND: Exergames (i.e., video games that require gross motor activity) may provide intrinsically motivating experiences that engage youth in sustained physical activity. METHOD: Thirty-one low-income 15- to 19-year-old overweight and obese African American adolescents were randomly assigned to a competitive exergame (n = 17) or a cooperative exergame (n = 14) condition. Participants played a preassigned Wii Active exergame routine that took between 30 and 60 min each school day, and sessions occurred during lunch time or an after-school program over a 6 month period. Participation was voluntary, so students decided whether to come or not on a given day. Cooperative exergame players worked together with a peer to expend calories and earn points, while competitive exergame players competed individually against a peer to expend calories and earn points. Motivation was measured through surveys and interviews at the end of the intervention, and energy expenditure was measured by accelerometry during game play. RESULTS: Compared with the competitive group, the cooperative players were significantly more intrinsically motivated to play (p = .034, partial eta-squared = 0.366) and more psychologically attracted to the design of the exergame (p = .034, partial eta-squared = 0.320). Intrinsic motivation was significantly positively correlated with energy expenditure during game play: individuals who were motivated by control/choice had higher energy expenditure (p = .026), and those who were more goal motivated (p = .004) and more immersed in game play (p = .024) had lower energy expenditure during game play. CONCLUSIONS: Cooperative exergame play produced higher intrinsic motivation to play the exergame than competitive exergame play did. Intrinsic motivation that came from a desire for control/choice was related to higher energy expenditure during game play. Cooperative exergame play holds promise as a method for engaging overweight and obese youth in physical activity. PMID- 22920808 TI - Two-player partnered exergame for obesity prevention: using discrepancy in players' abilities as a strategy to motivate physical activity. AB - BACKGROUND: Physical inactivity is associated with obesity and type 2 diabetes. A key obstacle to physical activity is lack of motivation. Although some interactive exercise games (i.e., exergames--video games that require physical exertion in order to play) motivate players to exercise more, few games take advantage of group dynamics to motivate players' duration of exercise. In a test of the Kohler motivation gain effect, this study varied the ability level of a virtually presented partner in an interactive exergame that focused on abdominal strength to identify effects on a subject's (S') persistence with the task. METHOD: Male (n = 63) and female (n = 72) undergraduate students were randomly assigned to one of four conditions (individual control or low-, moderate-, or high- partner discrepancy) in a conditions * gender factorial design and tested on a series of isometric abdominal exercises using PlayStation 2 EyeToy: Kinetic software. They performed the first series of five exercises alone (trial block 1), and after a rest period, those in the partner conditions performed remaining trials (trial block 2) with a same-sex virtually presented partner whom they could observe during their performance, while those in the individual control condition performed the remaining trials alone. In the partner conditions, the partner's performance was manipulated to be always better than the S's, the exact difference depending on the discrepancy condition. The partnered tasks were conjunctive; that is, success in the game depended on the performance of the weaker team member. Persistence, the outcome measure for this study, consisted of the total number of seconds the S held the exercise position. RESULTS: Using planned orthogonal contrasts on difference scores between blocks 1 and 2, results showed that persistence was significantly (p < .001) greater in all experimental conditions with a virtually presented partner (M = 33.59 s) than in the individual control condition (M = -49.04 s). Subjects demonstrated more persistence in the moderate-discrepancy condition (M = 51.36 s) than in the low discrepancy condition (M = 22.52 s) or the high-discrepancy condition (M = 26.89 s). A significant quadratic trend confirmed the expected inverted-U function relating partner discrepancy and persistence (p = .025). Although Ss persisted longer and had higher heart rate in partnered conditions, they did not perceive their exertion to be any higher than those in the individual condition. CONCLUSIONS: Virtually presented partners who are moderately more capable than participants are the most effective at improving persistence in exergame tasks. PMID- 22920809 TI - Using an alternate reality game to increase physical activity and decrease obesity risk of college students. AB - BACKGROUND: This quasi-experimental study investigated a game intervention- specifically, an alternate reality game (ARG)--as a means to influence college students' physical activity (PA). An ARG is an interactive narrative that takes place in the real world and uses multiple media to reveal a story. METHOD: Three sections of a college health course (n = 115 freshman students) were assigned either to a game group that played the ARG or to a comparison group that learned how to use exercise equipment in weekly laboratory sessions. Pre- and post intervention measures included weight, waist circumference, body mass index (BMI), percentage body fat (PBF), and self-reported moderate physical activity (MPA) and vigorous physical activity (VPA), and PA (steps/week). RESULTS: A significant group x time interaction (p = .001) was detected for PA, with a significant increase in PA for the game (p < .001) versus a significant decrease (p = .001) for the comparison group. Significant within-group increases for weight (p = .001), BMI (p = .001), and PBF (p = .001) were detected. A significant group x time interaction (p = .001) was detected when analyzing self reported VPA, with both groups reporting decreases in VPA over time; however, the decrease was only significant for the comparison group (p < .001). No significant group differences were found for MPA. CONCLUSIONS: It is important that any intervention meet the needs and interests of its target population. Here, the ARG was designed in light of the learning preferences of today's college students- collaborative and social, experiential and media-rich. Our results provide preliminary evidence that a game intervention can positively influence PA within the college student population. PMID- 22920810 TI - Novel approaches to obesity prevention: effects of game enjoyment and game type on energy expenditure in active video games. AB - BACKGROUND: Some active video games have been found to promote physical activity adherence because of enjoyment. However, many active games are exercise themed, which may interfere with the distracting properties that make game-based exercise more enjoyable than traditional exercise. This study compared exercise-themed and game-themed active games to investigate differences in energy expenditure and enjoyment. METHOD: Young adults (N = 100, 50 female, 55 overweight, aged 18-35 years) played two of four Wii Fit games (one aerobic game and one balance game per person) for 10 min each. Of the two aerobic games, one was exercise themed (jogging) and the other was game themed (hula hooping). Both balance games were game themed. Energy expenditure and enjoyment were measured. RESULTS: After adjustment for gender and weight, aerobic games produced 2.70 kcal/kg(-1)/h(-1) (95% confidence interval 2.41, 3.00) greater energy expenditure than balance games (p < .001), but balance games were more enjoyable (p < .001). In aerobic games, jogging produced greater energy expenditure than hula hooping in normal weight and male participants (p < .001); in overweight and female participants, no differences were found (p > .17). Hula hooping was enjoyed more than jogging (p = .008). Enjoyment predicted energy expenditure in aerobic games (B = 0.767, p = .010). CONCLUSIONS: Aerobic games produced greater energy expenditure but lower enjoyment than balance games, and a game-themed aerobic game was found more enjoyable than an exercise-themed aerobic game. Integrating more strenuous activity into entertaining games instead of games that simply simulate exercise may be a fruitful avenue for active game development. PMID- 22920811 TI - Neuropsychological benefits of stationary bike exercise and a cybercycle exergame for older adults with diabetes: an exploratory analysis. AB - OBJECTIVE: This quasi-experimental exploratory study investigated neuropsychological effects of exercise among older adults with diabetes mellitus (DM) compared with adults without diabetes (non-DM), and it examined the feasibility of using a stationary bike exergame as a form of exercise for older adults with and without diabetes. It is a secondary analysis that uses a small dataset from a larger randomized clinical trial (RCT) called the Cybercycle Study, which compared cognitive and physiological effects of traditional stationary cycling versus cybercycling. METHODS: In the RCT and the secondary analysis, older adults living in eight independent living retirement facilities in the state of New York were enrolled in the study and assigned to exercise five times per week for 45 min per session (two times per week was considered acceptable for retention in the study) by using a stationary bicycle over the course of 3 months. They were randomly assigned to use either a standard stationary bicycle or a "cybercycle" with a video screen that displayed virtual terrains, virtual tours, and racing games with virtual competitors. For this secondary analysis, participants in the RCT who had type 2 DM (n = 10) were compared with age-matched non-DM exercisers (n = 10). The relationship between exercise and executive function (i.e., Color Trials 2, Digit Span Backwards, and Stroop C tests) was examined for DM and non-DM patients. RESULTS: Older adults with and without diabetes were able to use cybercycles successfully and complete the study, so the feasibility of this form of exercise for this population was supported. However, in contrast with the larger RCT, this small subset did not demonstrate statistically significant differences in executive function between the participants who used cybercycles and those who used stationary bikes with no games or virtual content on a video screen. Therefore, the study combined the two groups and called them "exercisers" and compared cognitive outcomes for DM versus non-DM patients. As predicted, exercisers with DM exhibited significant gains in executive function as measured by the Color Trails 2 test, controlling for age and education, while non-DM exercisers did not significantly gain in this measure [group * time interaction, F(1,16]) = 9.75; p = .007]. CONCLUSIONS: These preliminary results support the growing literature that finds that exercise may improve cognition among older adult with DM. Additional research is needed to clarify why certain aspects of executive function might be differentially affected. The current findings may encourage physicians to prescribe exercise for diabetes management and may help motivate DM patients' compliance for engaging in physical activity. PMID- 22920812 TI - Increased risk of acute hepatitis B among adults with diagnosed diabetes mellitus. AB - INTRODUCTION: The risk of acute hepatitis B among adults with diabetes mellitus is unknown. We investigated the association between diagnosed diabetes and acute hepatitis B. METHODS: Confirmed acute hepatitis B cases were reported in 2009 2010 to eight Emerging Infections Program (EIP) sites; diagnosed diabetes status was determined. Behavioral Risk Factor Surveillance System respondents residing in EIP sites comprised the comparison group. Odds ratios (ORs) comparing acute hepatitis B among adults with diagnosed diabetes versus without diagnosed diabetes were determined by multivariate logistic regression, adjusting for age, sex, and race/ethnicity, and stratified by the presence or absence of risk behaviors for hepatitis B virus (HBV) infection. RESULTS: During 2009-2010, EIP sites reported 865 eligible acute hepatitis B cases among persons aged >=23 years; 95 (11.0%) had diagnosed diabetes. Comparison group diabetes prevalence was 9.1%. Among adults without hepatitis B risk behaviors and with reported diabetes status, the OR for acute hepatitis B comparing adults with and without diabetes was 1.9 (95% confidence interval [CI] = 1.4, 2.6); ORs for adults ages 23-59 and >=60 years were 2.1 (95% CI = 1.6, 2.8) and 1.5 (95% = CI 0.9, 2.5), respectively. CONCLUSIONS: Diabetes was independently associated with an increased risk for acute hepatitis B among adults without HBV risk behaviors. PMID- 22920813 TI - Effects of simulated altitude on blood glucose meter performance: implications for in-flight blood glucose monitoring. AB - BACKGROUND: Most manufacturers of blood glucose monitoring equipment do not give advice regarding the use of their meters and strips onboard aircraft, and some airlines have blood glucose testing equipment in the aircraft cabin medical bag. Previous studies using older blood glucose meters (BGMs) have shown conflicting results on the performance of both glucose oxidase (GOX)- and glucose dehydrogenase (GDH)-based meters at high altitude. The aim of our study was to evaluate the performance of four new-generation BGMs at sea level and at a simulated altitude equivalent to that used in the cabin of commercial aircrafts. METHODOLOGY/PRINCIPAL FINDINGS: Blood glucose measurements obtained by two GDH and two GOX BGMs at sea level and simulated altitude of 8000 feet in a hypobaric chamber were compared with measurements obtained using a YSI 2300 blood glucose analyzer as a reference method. Spiked venous blood samples of three different glucose levels were used. The accuracy of each meter was determined by calculating percentage error of each meter compared with the YSI reference and was also assessed against standard International Organization for Standardization (ISO) criteria. Clinical accuracy was evaluated using the consensus error grid method. The percentage (standard deviation) error for GDH meters at sea level and altitude was 13.36% (8.83%; for meter 1) and 12.97% (8.03%; for meter 2) with p = .784, and for GOX meters was 5.88% (7.35%; for meter 3) and 7.38% (6.20%; for meter 4) with p = .187. There was variation in the number of time individual meters met the standard ISO criteria ranging from 72-100%. Results from all four meters at both sea level and simulated altitude fell within zones A and B of the consensus error grid, using YSI as the reference. CONCLUSIONS: Overall, at simulated altitude, no differences were observed between the performance of GDH and GOX meters. Overestimation of blood glucose concentration was seen among individual meters evaluated, but none of the results obtained would have resulted in dangerous failure to detect and treat blood glucose errors or in giving treatment that was actually contradictory to that required. PMID- 22920814 TI - First clinical evaluation of a new long-term subconjunctival glucose sensor. AB - BACKGROUND: To evaluate the feasibility of an implantable subconjunctival glucose monitoring system (SGMS) for glucose monitoring in humans, we investigated the in vivo performance of the sensor in a clinical trial with five patients. METHODS: The new SGMS consists of an implantable ocular mini implant (OMI) and a hand-held fluorescence photometer. The implantable subconjunctival glucose sensor is composed of a fluorescence resonance energy transfer system based on Concanavalin A chemistry, embedded in a nelfilcon polymer hydrogel disk. Blood glucose changes in humans were induced by oral glucose intake and insulin injections. RESULTS: The in vivo response of the new SGMS was tested in a first human clinical study with five diabetes patients. The OMI was well tolerated in the eyes of the patients. The SGMS exhibited high correlation coefficients (>0.88) with blood glucose changes and a good stability of the sensor response to glucose for the study period of 2 weeks. Lag times were in the range of 5-10 min. A total of 98% of all data pairs was in the clinical acceptable ranges A and B of the consensus error grid. CONCLUSIONS: For the first time, the possibility to measure glucose in vivo in the subconjunctival interstitial fluid for a period of 2 weeks was demonstrated in a human clinical trial. PMID- 22920815 TI - Determinants of the accuracy of continuous glucose monitoring in non-critically ill patients with heart failure or severe hyperglycemia. AB - BACKGROUND: The accuracy of continuous glucose monitoring (CGM) in non-critically ill hospitalized patients with heart failure or severe hyperglycemia (SH) is unknown. METHODS: Hospitalized patients with congestive heart failure (CHF) exacerbation (receiving IV or subcutaneous insulin) or SH requiring insulin infusion were compared to outpatients referred for retrospective CGM. RESULTS: Forty-three patients with CHF, 15 patients with SH, and 88 outpatients yielded 470, 164, and 2150 meter-sensor pairs, respectively. Admission glucose differed (188 versus 509 mg/dl in CHF and SH, p < .001) but not the first sensor glucose (p = .35). In continuous glucose error grid analysis, 67-78% of pairs during hypoglycemia were in zones A+B (p = .63), compared with 98-100% in euglycemia (p < .001) and 98%, 92%, and 99% (p = .001) during hyperglycemia for the CHF, SH, and outpatient groups, respectively. Mean absolute relative difference (MARD) was lower in the CHF versus the SH group in glucose strata above 100 mg/dl, but there was no difference between the CHF and outpatient groups. Linear regression models showed that CHF versus outpatient, SH versus CHF, and coefficient of variation were significant predictors of higher MARD. Among subjects with CHF, MARD was not associated with brain natriuretic peptide or change in plasma volume, but it was significantly higher in subjects randomized to IV insulin (p = .04). CONCLUSIONS: The results suggest that SH and glycemic variability are more important determinants of CGM accuracy than known CHF status alone in hospitalized patients. PMID- 22920816 TI - A fluorescent responsive hybrid nanogel for closed-loop control of glucose. AB - BACKGROUND: The concept of closed-loop control of glucose, in which continuous glucose sensing is coupled to a fully automated insulin delivery device, without human input, has been an attractive idea for diabetes management. This study presents a new class of hybrid nanogels that can integrate glucose sensing and glucose-responsive insulin release into a single nano-object. METHODS: Zinc oxide@poly[N-isopropylacrylamide (NIPAM)-acrylamide (AAm)- 2-aminomethyl-5 fluorophenylboronic acid (FPBA)] hybrid nanogels were synthesized and investigated for size, morphology, volume phase transition, photoluminescence properties, and in vitro insulin release under different glucose concentrations. Glucose sensing was performed both in phosphate-buffered saline (PBS) and in blood samples. The insulin release in PBS of varying glucose levels, as well as a stepwise treatment between two glucose levels (126.0 and 270.0 mg/dl), was performed to test the glucose-responsive insulin release ability of the hybrid nanogels. RESULTS: Zinc oxide@poly(NIPAM-AAm-FPBA) hybrid nanogels can sensitively and selectively detect glucose in highly reproducible fluorescent signals over the clinically relevant glucose concentration range of 18-540 mg/dl. The glucose-responsive volume phase transition of the nanogels can further regulate the release of the preloaded insulin. The insulin release from the nanogels exhibits the slowest rate (~5% released in 76 h) at a normal glucose level (108.0 mg/dl) but becomes quicker and quicker as the glucose increases to higher and higher levels. CONCLUSIONS: The rationally designed hybrid nanogel can optically signal the glucose level with high sensitivity and selectivity and simultaneously regulate the insulin release rate in response to the glucose reading, which shows a promising concept toward the development of a miniaturized closed-loop glycemic control system. PMID- 22920817 TI - Feasibility of overnight closed-loop control based on hourly blood glucose measurements. AB - INTRODUCTION: Safe and effective closed-loop control (artificial pancreas) is the ultimate goal of insulin delivery. In this study, we examined the performance of a closed-loop control algorithm used for the overnight time period to safely achieve a narrow target range of blood glucose (BG) concentrations prior to breakfast. The primary goal was to compare the quality of algorithm control during repeated overnight experiments. MATERIALS AND METHODS: Twenty-three subjects with type 1 diabetes performed 2 overnight experiments on each of three visits at the study site, resulting in 138 overnight experiments. On the first evening, the subject's insulin therapy was applied; on the second, the insulin was delivered by an algorithm based on subcutaneous continuous glucose measurements (including meal control) until midnight. Overnight closed-loop control was applied between midnight and 6 a.m. based on hourly venous BG measurements during the first and second nights. RESULTS: The number of BG values within the target range (90-150 mg/dl) increased from 52.9% (219 out of 414 measurements) during the first nights to 72.2% (299 out of 414 measurements) during the second nights (p < .001, chi2-test). The occurrence of hypoglycemia interventions was reduced from 14 oral glucose interventions, the latest occurring at 2:36 a.m. during the first nights, to 1 intervention occurring at 1:02 a.m. during the second nights (p < .001, chi2-test). CONCLUSIONS: Overnight controller performance improved when optimized initial control was given; this was suggested by the better metabolic control during the second night. Adequate controller run-in time seems to be important for achieving good overnight control. In addition, the findings demonstrate that hourly BG data are sufficient for the closed-loop control algorithm tested to achieve appropriate glycemic control. PMID- 22920818 TI - Comparison of patient preference for two insulin injection pen devices in relation to patient dexterity skills. AB - BACKGROUND: Impaired dexterity has been reported to be prevalent in diabetes patients independent from the existence of diabetic neuropathy. This study was performed to investigate the impact of dexterity impairment on patient preference for two insulin pen injection devices (InnoLet and FlexTouch). METHODS: Ninety patients [54 male/36 female; age (mean +/- standard deviation), 62 +/- 8 years; disease duration, 18 +/- 11 years; hemoglobin A1c, 7.2 +/- 1.0%] were included in this investigation and were stratified into four different groups based on the results of a dexterity test (Jebsen-Taylor Hand Function Test) and assessment of visual impairment: 15 type 1 (group A) and 30 type 2 (group B) patients with impaired dexterity, 30 type 1/type 2 patients with visual impairment (group C), and 15 type 1/type 2 patients without any impairment (group D). The patients performed a cognitive function test (number connection test), were introduced to the devices in random order, and were asked to perform some mock injections before completing a six-item standardized preference questionnaire. RESULTS: There was a strong preference for FlexTouch in all groups. All unimpaired patients (100%, group D) preferred FlexTouch, as did the vast majority in all other groups. Only 11% of the patients with impaired cognitive function preferred InnoLet, as did a few patients with more severely impaired dexterity or with visual impairment (group A, 13%; group B, 3%; group C, 14%). CONCLUSIONS: Patient dexterity skills may have an influence on device preference, especially if the impairment is more pronounced. PMID- 22920819 TI - Analysis of comparison of patient preference for two insulin injection pen devices in relation to patient dexterity skills. AB - Insulin therapy is the cornerstone of medical treatment for many patients with diabetes. Self-administration of this life-saving medication is no longer limited to the traditional vial and syringe. Instead, more and more patients worldwide are using prefilled insulin pen devices. Ease of use, convenience, confidence in dosing accuracy, and improved quality of life are just a few of their advantages. As with any medical technology, safe and proper use is vital. Many studies have examined pen device preference and usability. Until now, no study has included patients with both visual and dexterity impairments. To ensure safe and simple self-administration of insulin for all patients, it is time for the special needs of patients with diabetes to be considered not only during product development, but during postmarketing studies as well. PMID- 22920820 TI - Importance of blood glucose meter and carbohydrate estimation accuracy. AB - BACKGROUND: The clinical significance of blood glucose meter (BGM) error in the presence of increasing carbohydrate errors in diabetes patients who use both the BGM result and the carbohydrate estimation to dose insulin is unknown. METHODS: This Monte Carlo simulation modeled diabetes patients who calculate insulin dosages based on BGM results and carbohydrate estimations. It evaluated the likelihood of on-target insulin dosing and clinically significant insulin dose errors based on data from five BGMs with different levels of performance (expressed as bias and imprecision [coefficient of variation (%CV)]) and increasing levels of carbohydrate estimation errors. The study was performed across three separate preprandial glucose (PPG) ranges (90-150, 150-270, and 270 450 mg/dl). RESULTS: When carbohydrate estimation is accurate (%CV = 0%), the likelihood for on-target insulin doses ranged 50.1-98.5%. The likelihood depended on BGM performance and PPG range. In the presence of carbohydrate estimation errors (%CV = 5-20%), the likelihood of on-target insulin dosages markedly decreased (range, 27.2-80.1%) for all BGMs, the likelihood of insulin underdosing (range, 0-12.8%) and overdosing (range, 0-32.3%) increased, and the influence of BGM error on insulin dosing accuracy was blunted. Even in the presence of carbohydrate error, the BGM with the best performance (bias 1.35% and %CV = 4.84) had the highest probability for on-target insulin dosages. CONCLUSIONS: Both BGM and carbohydrate estimation error contribute to insulin dosing inaccuracies. The BGM with the best performance was associated with the most on-target insulin dosages. PMID- 22920821 TI - Performance of a new speech translation device in translating verbal recommendations of medication action plans for patients with diabetes. AB - BACKGROUND: Language barriers are significant hurdles for chronic disease patients in achieving self-management goals of therapy, particularly in settings where practitioners have limited nonprimary language skills, and in-person translators may not always be available. S-MINDS(c) (Speaking Multilingual Interactive Natural Dialog System), a concept-based speech translation approach developed by Fluential Inc., can be applied to bridge the technologic gaps that limit the complexity and length of utterances that can be recognized and translated by devices and has the potential to broaden access to translation services in the clinical settings. METHODS: The prototype translation system was evaluated prospectively for accuracy and patient satisfaction in underserved Spanish-speaking patients with diabetes and limited English proficiency and was compared with other commercial systems for robustness against degradation of translation due to ambient noise and speech patterns. RESULTS: Accuracy related to translating the English-Spanish-English communication string from practitioner to device to patient to device to practitioner was high (97-100%). Patient satisfaction was high (means of 4.7-4.9 over four domains on a 5-point Likert scale). The device outperformed three other commercial speech translation systems in terms of accuracy during fast speech utterances, under quiet and noisy fluent speech conditions, and when challenged with various speech disfluencies (i.e., fillers, false starts, stutters, repairs, and long pauses). CONCLUSIONS: A concept-based English-Spanish speech translation system has been successfully developed in prototype form that can accept long utterances (up to 20 words) with limited to no degradation in accuracy. The functionality of the system is superior to leading commercial speech translation systems. PMID- 22920822 TI - Integrated self-monitoring of blood glucose system: handling step analysis. AB - Self-monitoring of blood glucose (SMBG) implicates a number of handling steps with the meter and the lancing device. Numerous user errors can occur during SMBG, and each step adds to the complexity of use. This report compares the required steps to perform SMBG of one fully integrated (the second generation of the Accu-Chek(r) Mobile), three partly integrated (Accu-Chek Compact Plus, Ascensia(r) Breeze(r)2, and Accu-Chek Aviva), and six conventional (Bayer Contour(r), Bayer Contour USB, BGStarTM, FreeStyle Lite(r), OneTouch(r) Ultra(r) 2, and OneTouch VerioTMPro) systems. The results show that the fully integrated system reduces the number of steps to perform SMBG. The mean decrease is approximately 70% compared with the other systems. We assume that a reduction of handling steps also reduces the risk of potential user errors and improves the user-friendliness of the system. PMID- 22920823 TI - Insulin delivery device technology 2012: where are we after 90 years? AB - Since the first successful use of insulin in 1921 to treat diabetes at Toronto General Hospital, the major advances in development of the medication itself have taken place in parallel with equally significant developments in the means of delivery. Administration of insulin remains parenteral. This article reviews the main variants in prescription-available delivery technology: vial and syringe, pen injector, needle-free injection, and continuous subcutaneous insulin infusion pumps. For each of these, the background and major milestones are covered briefly and followed by a discussion of the latest product innovations, technologies, and implementations, which are all considered in the context of the interaction with users. The article concludes by reflecting upon how the progress in the technology of diabetes management can best serve the patient. The spectacular technological advances in medication, monitoring, and delivery since 1922 have transformed the lives of millions. However, the fact that we can add sophisticated technology to delivery devices and accessories does not mean it is always the best thing for the patient. Electronic sophistication may be welcomed by a young, eager type 1 diabetes patient, while a senior citizen who discovers he has type 2 diabetes may yearn for simplicity. Technology continues to provide great solutions, but the type of solution delivered must be matched to the user if the maximum benefit is to be achieved for all. PMID- 22920824 TI - Insulin infusion set: the Achilles heel of continuous subcutaneous insulin infusion. AB - Continuous subcutaneous insulin infusion from an insulin pump depends on reliable transfer of the pumped insulin to the subcutaneous insulin depot by means of an insulin infusion set (IIS). Despite their widespread use, the published knowledge about IISs and related issues regarding the impact of placement and wear time on insulin absorption/insulin action is relatively small. We also have to acknowledge that our knowledge is limited with regard to how often patients encounter issues with IISs. Reading pump wearer blogs, for instance, suggests that these are a frequent source of trouble. There are no prospective clinical studies available on current IIS and insulin formulations that provide representative data on the type and frequency of issues with infusion sets. The introduction of new IISs and patch pumps may foster a reassessment of available products and of patient problems related to their use. The aim of this review is to summarize the current knowledge and recommendations about IISs and to highlight potential directions of IIS development in order to make insulin absorption safer and more efficient. PMID- 22920825 TI - Screening for diabetic cardiac autonomic neuropathy using a new handheld device. AB - BACKGROUND: Cardiac autonomic neuropathy (CAN) is a serious complication of longstanding diabetes and is associated with an increased morbidity and reduced quality of life in patients with diabetes. The present study evaluated the prevalence of CAN diagnosed by reduced heart rate variability (HRV) using a newly developed device in a large, unselected, hospital-based population of patients with diabetes. METHODS: The study examined 323 patients consisting of 206 type 1 diabetes (T1DM) patients and 117 type 2 diabetes (T2DM) patients. The new handheld prototype VagusTM was used to screen for CAN. Three different standardized cardiac reflex tests were performed to calculate HRV: 30:15 ratio, E:I ratio, and the Valsalva maneuver. An abnormal HRV in one test is indicative of early CAN, and if two or more tests show abnormal HRV, the diagnosis of CAN is established. RESULTS: In total, 86% of examined patients completed all three tests. Each test was completed by more than 90% of the patients. The prevalence of established CAN was 23%, whereas 33% of the patients had early signs of CAN. The prevalence was higher in T2DM patients (27.8%) than in T1DM patients (20.6 %), p = .02. Patients with CAN were older and had a longer duration of diabetes, higher systolic blood pressure, more nephropathy and retinopathy, and a higher vibration threshold. CONCLUSIONS: Cardiac autonomic neuropathy is frequent in both T2DM and T1DM patients, especially in those with other late diabetes complications. Screening for CAN with the new device is feasible. PMID- 22920826 TI - Full neurological recovery after extreme hypoglycemia during intensive insulin therapy: a case report. AB - Since 2000, there has been an ongoing debate regarding tightness of glycemic control in critically ill patients. An increased risk of hypoglycemia is observed in patients treated with an intensive insulin protocol targeting "normoglycemia," probably accounting for a reduction of the overall benefit. Hypoglycemia is associated with neurological side effects and is found to be an independent predictor of mortality in most trials; however, long-term sequelae are rare if glucose is administered early. We describe a case of prolonged, extreme hypoglycemia in a critically ill patient treated according to an intensive insulin protocol who recovered without any neurological deficit at discharge. PMID- 22920827 TI - Self-monitoring of blood glucose: one STeP forward? AB - INTRODUCTION: In times of short health care budgets, reimbursement for self monitoring of blood glucose (SMBG) in diabetes patients without insulin treatment is subject to debate. The Structured Testing Program (STeP) trial found a positive correlation of test frequency and improved hemoglobin A1c (HbA1c) levels in poorly controlled type 2 diabetes patients not treated with insulin. METHODS: A structured literature search for other clinical studies reporting on SMBG frequency was performed. RESULTS: There is scarce evidence: three trials, including STeP, noted a significant and relevant correlation between testing frequency and improved HbA1c levels (FA effect), whereas two studies did not. The comparability between the identified studies is problematic. CONCLUSION: Future research should consider correlations between testing frequency and level of glycemic control. More emphasis should be placed on a structured approach to use SMBG and to address adherence to testing and therapy. PMID- 22920828 TI - DialBetics: smartphone-based self-management for type 2 diabetes patients. PMID- 22920829 TI - Psychosocial factors and adherence to continuous glucose monitoring in type 1 diabetes. PMID- 22920830 TI - Creatinine measurement and stability in dried serum. PMID- 22920831 TI - Direct arylation/alkylation/magnesiation of benzyl alcohols in the presence of Grignard reagents via Ni-, Fe-, or Co-catalyzed sp3 C-O bond activation. AB - Direct application of benzyl alcohols (or their magnesium salts) as electrophiles in various reactions with Grignard reagents has been developed via transition metal-catalyzed sp(3) C-O bond activation. Ni complex was found to be an efficient catalyst for the first direct cross coupling of benzyl alcohols with aryl/alkyl Grignard reagents, while Fe, Co, or Ni catalysts could promote the unprecedented conversion of benzyl alcohols to benzyl Grignard reagents in the presence of (n)hexylMgCl. These methods offer straightforward pathways to transform benzyl alcohols into a variety of functionalities. PMID- 22920832 TI - Editorial: Resistance in gram-negative pathogens: a threat to global health. PMID- 22920833 TI - Effects of alpha-mangostin on the expression of anti-inflammatory genes in U937 cells. AB - BACKGROUND: alpha-Mangostin (alpha-MG) is a main constituent of the fruit hull of the mangosteen. Previous studies have shown that alpha-MG has pharmacological activities such as antioxidant, antitumor, anti-inflammatory, antiallergic, antibacterial, antifungal and antiviral effects. This study aims to investigate the anti-inflammatory molecular action of alpha-MG on gene expression profiles. METHODS: U937 and EL4 cells were treated with different concentrations of alpha MG in the presence of 0.1 ng/mL lipopolysaccharide (LPS) for 4 h. The anti inflammatory effects of alpha-MG were measured by the levels of tumor necrosis factor (TNF)-alpha and interleukin (IL)-4 in cell culture media, which were determined with enzyme-linked immunosorbent assay kits. The gene expression profiles of all samples were analyzed with a whole human genome microarray, Illumina BeadChip WG-6 version 3, containing 48804 probes. The protein levels were determined by Western blotting analyses. RESULTS: alpha-MG decreased the LPS induction of the inflammatory cytokines TNF-alpha (P = 0.038) and IL-4 (P = 0.04). alpha-MG decreased the gene expressions in oncostatin M signaling via mitogen-activated protein kinase (MAPK) pathways, including extracellular signal regulated kinases (P = 0.016), c-Jun N-terminal kinase (P = 0.01) , and p38 (P = 0.008). alpha-MG treatment of U937 cells reduced the phosphorylation of MAPK kinase 3 / MAPK kinase 6 (P = 0.0441), MAPK-activated protein kinase-2 (P = 0.0453), signal transducers and activators of transcription-1 (STAT1) (P = 0.0012), c-Fos (P = 0.04), c-Jun (P = 0.019) and Ets-like molecule 1 (Elk-1) (P = 0.038). CONCLUSION: This study demonstrates that alpha-MG attenuates LPS-mediated activation of MAPK, STAT1, c-Fos, c-Jun and EIK-1, inhibiting TNF-alpha and IL-4 production in U937 cells. PMID- 22920834 TI - Study of the thermal nitridation of nanocrystalline Ti(OH)4 by X-ray and in situ neutron powder diffraction. AB - In situ neutron diffraction measurements of nanocrystalline titanium oxynitrides were performed, as a function of temperature and time, to explore the nitrogen/oxygen substitution mechanism occurring during their synthesis by reaction of gaseous ammonia with nanocrystalline Ti(OH)(4). These neutron diffraction experiments are supported by chemical analysis and X-ray diffraction, allowing the description of the structural variations and ordering process between the Ti(O/N)(2) anatase and the Ti(O/N) rock-salt phases. Our results show that the formation of the Ti(O/N) rock-salt phase goes along with the creation of vacancies on the Ti sites and that the N/O substitution proceeds but without N/O ordering. PMID- 22920835 TI - [Intracranial hypertension related to sedation with sevoflurane using the AnaConDa((r)) device in a patient with severe traumatic brain injury]. AB - Sedation in neurocritical patients remains a challenge as there is no drug that meets all the requirements. Since the appearance of the AnaConDa((r)) device, and according to the latest recommendations, sevoflurane has become an alternative for patients with brain injury. The use of AnaConDa((r)) produces an increase in the anatomical dead space that leads to a decrease in alveolar ventilation. If the decrease in the alveolar ventilation is not offset by an increase in minute volume, there will be an increase in PaCO2. We report the case of a patient with severe traumatic brain injury who suffered an increase in intracranial pressure as a result of increased PaCO2 after starting sedation with the AnaConDa((r)) device. PMID- 22920836 TI - Hippocampal volume reduction in chromosome 22q11.2 deletion syndrome (22q11.2DS): a longitudinal study of morphometry and symptomatology. AB - Recent studies observed an association between the structural integrity of the hippocampal structure and the manifestations of clinically significant psychotic symptoms in participants at high risk for psychosis. The present study sought to investigate the longitudinal trajectory of the hippocampal volume and its subregions among a sample of participants affected by 22q11.2 deletion syndrome (22q11.2DS), a neurogenetic disorder associated with elevated risk for psychosis. We specifically investigated possible correlations between hippocampal volumes, as measured by magnetic resonance imaging (MRI), and the manifestation of positive psychotic symptoms (hallucinations and delusions). Regional hippocampal volumes were measured twice with cerebral MRI obtained at 3-year intervals in 30 healthy participants and 31 gender-matched 22q11.2 microdeletion carriers aged 6 to 22. We examined potential associations between psychotic symptom manifestations and volumetric parameters at both time points. We found a hippocampal body-driven significant reduction in hippocampal volume among patients with 22q11DS compared to controls. No significant group by time interaction for the total or the subregional volumes were observed. In patients, larger hippocampal head at baseline was associated with the presence of hallucinations at follow-up. We first discuss the reduced hippocampal body finding in light of potentially abnormal mesiocortical circuits. We further discuss the association between baseline hippocampal head volume in participants with 22q11DS as a possible marker related to the later unfolding of psychotic symptoms. PMID- 22920837 TI - Array-based sensing of metastatic cells and tissues using nanoparticle fluorescent protein conjugates. AB - Rapid and sensitive methods of discriminating between healthy tissue and metastases are critical for predicting disease course and designing therapeutic strategies. We report here the use of an array of gold nanoparticle-green fluorescent protein elements to rapidly detect metastatic cancer cells (in minutes), as well as to discriminate between organ-specific metastases and their corresponding normal tissues through their overall intracellular proteome signatures. Metastases established in a new preclinical non-small-cell lung cancer metastasis model in athymic mice were used to provide a challenging and realistic testbed for clinical cancer diagnosis. Full differentiation between the analyte cell/tissue was achieved with as little as 200 ng of intracellular protein (~1000 cells) for each nanoparticle, indicating high sensitivity of this sensor array. Notably, the sensor created a distinct fingerprint pattern for the normal and metastatic tumor tissues. Moreover, this array-based approach is unbiased, precluding the requirement of a priori knowledge of the disease biomarkers. Taken together, these studies demonstrate the utility of this sensor for creating fingerprints of cells and tissues in different states and present a generalizable platform for rapid screening amenable to microbiopsy samples. PMID- 22920838 TI - The alleviation of acute and chronic kidney injury by human Wharton's jelly derived mesenchymal stromal cells triggered by ischemia-reperfusion injury via an endocrine mechanism. AB - BACKGROUND AIMS: The effects of human Wharton's jelly-derived mesenchymal stromal cells (WJ-MSC) on acute and chronic kidney injury induced by ischemia-reperfusion injury (IRI) were assessed. METHODS: WJ-MSC were injected intravenously immediately after solitary kidney ischemia for 45 min. Cells were labeled with 5 bromo-2'deoxy-uridine (BrdU) for tracing in vivo. At 48 h post-IRI, serum creatinine and blood urea nitrogen (BUN) were measured. Tubular cell proliferation and apoptosis as well as activation of the Akt signal were identified by immunostaining. Real-time polymerase chain reaction (PCR) was employed to determine gene expression of inflammation-related cytokines and hepatocyte growth factor (HGF). Levels of human HGF were assayed by enzyme-linked immunosorbant assay (ELISA). Twenty-two weeks later, renal fibrosis was assessed by Masson's tri-chrome staining, collagen content and alpha-smooth muscle actin (alpha-SMA) staining. RESULTS: There was no sign of labeled cells residing in the damaged kidney. Acute renal dysfunction elicited by IRI was considerably improved by WJ-MSC, in parallel with a stronger proliferative response and less apoptotic events. Additionally, phosphoAkt staining in injured tubular cells was substantially intensified. Cell treatment also caused a remarkable up-regulation of kidney interleukin (IL)-10, heme oxygenase (HO)-1 and HGF expression. Human HGF was detected in cell supernatants and the serum of cell-infused rats. Moreover, IRI-initiated fibrosis was abrogated by cell therapy, coincident with function amelioration. CONCLUSIONS: WJ-MSC alleviate acute kidney injury, thereby rescuing the ensuing fibrotic lesions in an endocrine manner. The Akt signal in impaired tubular cells is reinforced by WJ-MSC, facilitating cell resistance to apoptosis and cell proliferation. HGF, either delivered or induced by WJ-MSC, is an important contributor. PMID- 22920839 TI - Effects of physical therapy on quality of life in osteoporosis patients - a randomized clinical trial. AB - SUMMARY: The aim of this prospective randomized single-center study was to investigate whether sling exercise therapy is superior to conventional exercises in osteoporosis patients. BACKGROUND: Patients with osteoporosis frequently experience fractures of the vertebral body, which may cause chronic back pain and other symptoms. These, in turn, may lead to immobilization, muscular atrophy, and restrictions in activities of daily living. The situation can be improved with specific medication and physiotherapy. We explored the effects of a variety of physical treatments on activities of daily living in patients with osteoporosis. METHOD: Fifty patients were randomly allocated to two treatment groups. Group A received traditional physiotherapy (PT) while group B underwent sling exercise therapy (ST). Both treatments were given twice a week for three months. The results of the treatment were registered on the quality of life questionnaire (Qualeffo-41) devised by the International Osteoporosis Foundation. After a further three months with no specific exercise treatment, we again tested all patients in order to draw conclusions about the long-term effects of both types of exercise. RESULTS: Forty-four patients (88%) completed the study. Patients were assigned to small groups (a maximum of 5 patients in each group) and thus received individual attention and motivation. Quality of life was improved in both groups; a significantly greater improvement was registered in patients who performed sling exercises (Global score Qualeffo: p = 0.002). CONCLUSION: The test results confirm the known positive effects of physical therapy on the quality of life of osteoporosis patients, as well as the fact that sling exercises are a sound alternative treatment for this condition. PMID- 22920840 TI - The patient with the human immunodeficiency virus-1 in the cardiovascular operative setting. PMID- 22920841 TI - Focused transthoracic echocardiography predicts perioperative cardiovascular morbidity. AB - OBJECTIVES: The aim of this study was to assess the risk and predictive value of cardiac pathology detected on an anesthesiologist-performed focused transthoracic echocardiogram with adverse cardiac outcomes in the perioperative period. DESIGN: A retrospective review of 222 patients having a focused transthoracic echocardiogram and evaluating the incidence and echocardiographic risk factors associated with perioperative adverse cardiac events. SETTING: A single tertiary referral university teaching hospital. PARTICIPANTS: Two hundred twenty patients who had a focused transthoracic echocardiogram performed by an anesthesiologist. INTERVENTIONS: All patients who had a focused transthoracic echocardiogram had their discharge summary and any perioperative troponin levels reviewed, looking for evidence of adverse cardiac events, including cardiac death before discharge, myocardial infarction, pulmonary edema, hypotension requiring vasoactive drug infusion, or new arrhythmia. MEASUREMENTS AND MAIN RESULTS: Data were collected on the 222 patients who had an anesthesiologist-performed focused transthoracic echocardiogram, with 39 (18%) having an adverse cardiac event. There were 24 (11%) myocardial infarctions, 6 (2.7%) new arrhythmias, 5 (2.3%) deaths, and 4 (1.8%) episodes of severe hypotension. High-risk pathology detected on echocardiography included adverse cardiac events in 64% of the patients with pulmonary hypertension, 56% of the patients with left or right ventricular dysfunction, and 17% of the patients with stenotic valvular disease. In particular, patients with a combination of pulmonary hypertension, ventricular dysfunction, and/or stenotic valvular disease had a 77% risk of an adverse cardiac event. In contrast, no patients with a completely normal study, flow murmur, or isolated regurgitant valvular disease had adverse cardiac events. CONCLUSIONS: Anesthesiologist-performed focused transthoracic echocardiography predicts perioperative adverse cardiac events in noncardiac surgical patients. PMID- 22920842 TI - The complications of uncomplicated acute type-B dissection: the introduction of the Penn classification. AB - Uncomplicated acute type-B aortic dissection (ATBAD) is a misnomer because it has subgroups with excessive mortality risk. The Penn classification has designated these ATBAD presentations as class-A because they initially are characterized by the absence of malperfusion and/or aortic rupture. The Penn classification also has designated class-A high-risk subgroups as type I and low-risk subgroups as type II. The risk factors for Penn class-A type-I presentations relate to medical therapy; aortic anatomy, and dissection extent as outlined by the DeBakey classification. Tight medical therapy significantly protects against aortic complications. Beta-blockade, angiotensin inhibition, and calcium channel antagonists may reduce mortality. The details of optimal medical therapy require further research. The aortic risk factors for type-I presentations include false lumen size and patency, ulcer-like projections, aortic diameter >40 mm, and intimal tear characteristics such as size and proximal location. The prognostic role of dissection extent in ATBAD remains unclear, requiring further investigation to determine its effect on natural history. Future trials in Penn class-A ATBAD should focus on type-I presentations. The Penn classification can serve as a clinical framework for trial design, laying the groundwork for future management advances. It also may provide a common language to facilitate standardized definitions, trial design, and management approaches for this high risk patient cohort. PMID- 22920843 TI - Heterogeneity in the differentiation and function of memory B cells. AB - Vaccines that induce neutralizing antibodies have led to the eradication of small pox and have severely reduced the prevalence of many other infections. However, even the most successful vaccines do not induce protective antibodies in all individuals, and can fail to induce lifelong immunity. A key to remedying these shortcomings may lie in a better understanding of long-lived memory B cells. Recent studies have revealed novel insights into the differentiation and function of these cells, and have shown that the memory B cell pool is much more heterogeneous than previously appreciated. PMID- 22920844 TI - Toxoplasma gondii prevalence in Israeli crows and Griffon vultures. AB - A cross-sectional Toxoplasma gondii seroprevalence study was performed on free ranging crows (Corvus cornis, Corvus monedula, Corvus splendens) and Griffon vultures (Gyps fulvus) from Israel in order to assess exposure to this pathogen in scavenger birds that feed on animal carcasses and their possible role in the epidemiology of toxoplasmosis. Using the modified agglutination test (MAT) with a cutoff titer of 1:25, 52 of 122 crows (42.6%) and 40 of 101 Griffon vultures (39.6%) were found to be T. gondii seropositive. Crow T. gondii seroprevalence was significantly higher in northern areas of Israel (p=0.007) where annual precipitation is higher and annual summer maximum temperatures are lower than in the drier and warmer south. Seroprevalence in crows was positively associated with higher human population densities possibly related to the increased cat population in these areas. PCR analysis of brain extracts from crows resulted in the detection of T. gondii DNA in 1 seropositive crow from northern Israel. Genetic analysis of DNA from the positive crow brain confirmed infection with T. gondii type 2 using a multiplex multilocus nested PCR-RFLP (Mn-PCR-RFLP) of the SAG1, 5-3' SAG2, alt.SAG2, SAG3, BTUB, GRA6, C22-8, c29-2, L358, PK1 and Apico loci. The high T. gondii seroprevalence in these bird species suggests that infected carrion may be responsible for widespread infection of carcass scavenger birds which may further transmit infection to other carnivorous intermediate hosts or feline definitive hosts when consumed post-mortally. PMID- 22920845 TI - The prevalence and correlates of behavioral risk factors for cardiovascular health among Southern Brazil adolescents: a cross-sectional study. AB - BACKGROUND: The adoption of health-related behaviors is an important part of adolescence. This study examined the prevalence and correlates of the isolated and simultaneous presence of behavioral risk factors for cardiovascular health (BRFCH) among adolescents in Curitiba, Southern Brazil. METHODS: A cross sectional study was performed with 1,628 adolescents (aged 11-17.9 years, 52.5% males) that were randomly selected from 44 public schools. Self-report instruments were used to assess the variables. Six BRFCH were analyzed: insufficiently active, excessive TV watching, current alcohol and tobacco use, daily soft drinks consumption and inadequate fruit and vegetable consumption. Sociodemographic and behavioral variables were studied as possible correlates of the presence of BRFCH. RESULTS: The BRFCH with the highest prevalence were insufficiently active (50.5%, 95% confidence interval [95% CI]: 48.0-52.9) and daily soft drinks consumption (47.6%, 95% CI: 45.1-50.0). Approximately 30% of the adolescents presented three or more BRFCH simultaneously. Girls, adolescents who did not participate in organized physical activity, and who used computer/video games daily were the main high-risk subgroups for insufficiently active. Boys and those who used computer/video games daily were the high-risk subgroups for daily soft drinks consumption. For excessive TV watching, we identified to be at risk those who were from a high economic class, unemployed, and who used computer/video games daily. For current alcohol use, we identified older adolescents, who were from a high economic class and who worked to be at risk. Older adolescents, who worked and who spent little active time during a physical education class were the high-risk subgroups for current tobacco use. For inadequate fruit and vegetable consumption, we identified those who did not participate in organized physical activity to be at risk. Older adolescents, who were from a high economic class, who did not participate in organized physical activity and who used computer/video games daily were the high-risk subgroups for simultaneous BRFCH. CONCLUSIONS: We found a high prevalence of BRFCH among adolescents, both isolated and simultaneously. The correlates of the presence of BRFCH can contribute to healthy policies among Brazilian adolescents, mainly focusing on high-risk subgroups for a health risk behavior. PMID- 22920846 TI - The basal ganglia optimize decision making over general perceptual hypotheses. AB - The basal ganglia are a subcortical group of interconnected nuclei involved in mediating action selection within cortex. A recent proposal is that this selection leads to optimal decision making over multiple alternatives because the basal ganglia anatomy maps onto a network implementation of an optimal statistical method for hypothesis testing, assuming that cortical activity encodes evidence for constrained gaussian-distributed alternatives. This letter demonstrates that this model of the basal ganglia extends naturally to encompass general Bayesian sequential analysis over arbitrary probability distributions, which raises the proposal to a practically realizable theory over generic perceptual hypotheses. We also show that the evidence in this model can represent either log likelihoods, log-likelihood ratios, or log odds, all leading proposals for the cortical processing of sensory data. For these reasons, we claim that the basal ganglia optimize decision making over general perceptual hypotheses represented in cortex. The relation of this theory to cortical encoding, cortico basal ganglia anatomy, and reinforcement learning is discussed. PMID- 22920847 TI - Adaptive metric learning vector quantization for ordinal classification. AB - Many pattern analysis problems require classification of examples into naturally ordered classes. In such cases, nominal classification schemes will ignore the class order relationships, which can have a detrimental effect on classification accuracy. This article introduces two novel ordinal learning vector quantization (LVQ) schemes, with metric learning, specifically designed for classifying data items into ordered classes. In ordinal LVQ, unlike in nominal LVQ, the class order information is used during training in selecting the class prototypes to be adapted, as well as in determining the exact manner in which the prototypes get updated. Prototype-based models in general are more amenable to interpretations and can often be constructed at a smaller computational cost than alternative nonlinear classification models. Experiments demonstrate that the proposed ordinal LVQ formulations compare favorably with their nominal counterparts. Moreover, our methods achieve competitive performance against existing benchmark ordinal regression models. PMID- 22920848 TI - Neural relax. AB - We propose a new self-organizing algorithm for a feedforward network inspired to an electrostatic problem that turns out to have intimate relations with information maximization. PMID- 22920849 TI - The hippocampus as a stable memory allocator for cortex. AB - It is suggested here that mammalian hippocampus serves as an allocator of neurons in cortex for memorizing new items. A construction of a shallow feedforward network with biologically plausible parameters is given that possesses the characteristics needed for such an allocator. In particular, the construction is stabilizing in that for inputs within a range of activity levels spanning more than an order of magnitude, the output will have activity levels differing as little as 1%. It is also noise tolerant in that pairs of input patterns that differ little will generate output patterns that differ little. Further, pairs of inputs that differ by much will be mapped to outputs that also differ sufficiently that they can be treated by cortex as distinct. PMID- 22920850 TI - Regulation of ambient GABA levels by neuron-glia signaling for reliable perception of multisensory events. AB - Activities of sensory-specific cortices are known to be suppressed when presented with a different sensory modality stimulus. This is referred to as cross-modal inhibition, for which the conventional synaptic mechanism is unlikely to work. Interestingly, the cross-modal inhibition could be eliminated when presented with multisensory stimuli arising from the same event. To elucidate the underlying neuronal mechanism of cross-modal inhibition and understand its significance for multisensory information processing, we simulated a neural network model. Principal cell to and GABAergic interneuron to glial cell projections were assumed between and within lower-order unimodal networks (X and Y), respectively. Cross-modality stimulation of Y network activated its principal cells, which then depolarized glial cells of X network. This let transporters on the glial cells export GABA molecules into the extracellular space and increased a level of ambient (extrasynaptic) GABA. The ambient GABA molecules were accepted by extrasynaptic GABA(a) receptors and tonically inhibited principal cells of the X network. Cross-modal inhibition took place in a nonsynaptic manner. Identical modality stimulation of X network activated its principal cells, which then activated interneurons and hyperpolarized glial cells of the X network. This let their transporters import (remove) GABA molecules from the extracellular space and reduced tonic inhibitory current in principal cells, thereby improving their gain function. Top-down signals from a higher-order multimodal network (M) contributed to elimination of the cross-modal inhibition when presented with multisensory stimuli that arose from the same event. Tuning into the multisensory event deteriorated if the cross-modal inhibitory mechanism did not work. We suggest that neuron-glia signaling may regulate local ambient GABA levels in order to coordinate cross-modal inhibition and improve neuronal gain function, thereby achieving reliable perception of multisensory events. PMID- 22920851 TI - Shared and specific independent components analysis for between-group comparison. AB - Independent component analysis (ICA) has been extensively used in individual and within-group data sets in real-world applications, but how can it be employed in a between-groups or conditions design? Here, we propose a new method to embed group membership information into the FastICA algorithm so as to extract components that are either shared between groups or specific to one or a subset of groups. The proposed algorithm is designed to automatically extract the pattern of differences between different experimental groups or conditions. A new constraint is added to the FastICA algorithm to simultaneously deal with the data of multiple groups in a single ICA run. This cost function restricts the specific components of one group to be orthogonal to the subspace spanned by the data of the other groups. As a result of performing a single ICA on the aggregate data of several experimental groups, the entire variability of data sets is used to extract the shared components. The results of simulations show that the proposed algorithm performs better than the regular method in both the reconstruction of the source signals and classification of shared and specific components. Also, the sensitivity to detect variations in the amplitude of shared components across groups is enhanced. A rigorous proof of convergence is provided for the proposed iterative algorithm. Thus, this algorithm is guaranteed to extract and classify shared and specific independent components across different experimental groups and conditions in a systematic way. PMID- 22920852 TI - On convergence rates of mixtures of polynomial experts. AB - In this letter, we consider a mixture-of-experts structure where m experts are mixed, with each expert being related to a polynomial regression model of order k. We study the convergence rate of the maximum likelihood estimator in terms of how fast the Hellinger distance of the estimated density converges to the true density, when the sample size n increases. The convergence rate is found to be dependent on both m and k, while certain choices of m and k are found to produce near-optimal convergence rates. PMID- 22920853 TI - A network of spiking neurons for computing sparse representations in an energy efficient way. AB - Computing sparse redundant representations is an important problem in both applied mathematics and neuroscience. In many applications, this problem must be solved in an energy-efficient way. Here, we propose a hybrid distributed algorithm (HDA), which solves this problem on a network of simple nodes communicating by low-bandwidth channels. HDA nodes perform both gradient-descent like steps on analog internal variables and coordinate-descent-like steps via quantized external variables communicated to each other. Interestingly, the operation is equivalent to a network of integrate-and-fire neurons, suggesting that HDA may serve as a model of neural computation. We show that the numerical performance of HDA is on par with existing algorithms. In the asymptotic regime, the representation error of HDA decays with time, t, as 1/t. HDA is stable against time-varying noise; specifically, the representation error decays as 1/?t for gaussian white noise. PMID- 22920855 TI - The therapeutic effect of bone marrow-derived stem cell implantation after epiphyseal plate injury is abrogated by chondrogenic predifferentiation. AB - The goal of this study was to determine the effects of chondrogenic predifferentiation on the ability of bone marrow-derived stromal cells (BMSCs) delivered to growth plate defects to restore growth function. Chondrogenesis was induced with transforming growth factor (TGF)-beta1 treatment in high-density monolayer cultures of BMSCs in vitro. The predifferentiated or undifferentiated BMSCs were either seeded into agarose gels for continued in vitro culture, or injected into growth plate defects via an in situ gelling agarose. Predifferentiated BMSCs had higher Sox-9, type II collagen, and aggrecan mRNA levels compared to undifferentiated cells after high-density monolayer culture. After transfer to agarose gels, predifferentiated cells did not produce a cartilaginous matrix, even with continued TGF-beta1 stimulation, whereas undifferentiated cells produced a cartilaginous matrix in this system. Three dimensional images of the growth plate created from microcomputed tomography scans showed that delivery of either predifferentiated or undifferentiated cells to defects resulted in a decrease in mineralized tether formation (fusion) in the growth plate tissue surrounding the defect to normal levels. Limb length discrepancy between injured and control limbs was corrected after treatment with undifferentiated, but not predifferentiated, cells. These results indicate that cell therapy may be an effective treatment to reduce growth dysfunction after growth plate injury, perhaps by maintaining the health of the uninjured growth plate tissue, and that the cell differentiation state plays a role in restoring the growth potential of the injured limb. PMID- 22920854 TI - Identification of miRNAs and their targets from Brassica napus by high-throughput sequencing and degradome analysis. AB - BACKGROUND: MicroRNAs (miRNAs) are endogenous regulators of a broad range of physiological processes and act by either degrading mRNA or blocking its translation. Oilseed rape (Brassica napus) is one of the most important crops in China, Europe and other Asian countries with publicly available expressed sequence tags (ESTs) and genomic survey sequence (GSS) databases, but little is known about its miRNAs and their targets. To date, only 46 miRNAs have been identified in B. napus. RESULTS: Forty-one conserved and 62 brassica-specific candidate B. napus miRNAs, including 20 miRNA* sequences, were identified using Solexa sequencing technology. Furthermore, 33 non-redundant mRNA targets of conserved brassica miRNAs and 19 new non-redundant mRNA targets of novel brassica specific miRNAs were identified by genome-scale sequencing of mRNA degradome. CONCLUSIONS: This study describes large scale cloning and characterization of B. napus miRNAs and their potential targets, providing the foundation for further characterization of miRNA function in the regulation of diverse physiological processes in B. napus. PMID- 22920856 TI - Influence of surface coating of PLGA particles on the internalization and functions of human endothelial cells. AB - This study is focused on the uptake of PLGA particles with different coatings and its influences on the functions and toxicity of human endothelial cells. The PLGA particles coated with polyethyleneimine (PEI) or bovine serum albumin (BSA) were prepared via a one-step emulsion method, which had a similar diameter of ~420 nm in water and ~170 nm in a dry state but oppositely charged surfaces. Both types of the particles were readily internalized into cells within a short time regardless of their surface chemistry. Uptake of the positively charged particles caused apparently a decrease in cell viability, but did not significantly influence mitochondrial membrane potential and activity of caspase-3. The cell adhesion and migration were significantly affected, especially after uptake of the PLGA-PEI particles. The secretion levels of von Willebrand factor (vWF) and 6 k-PGF(1alpha) were not significantly influenced regardless of the surface coating. PMID- 22920858 TI - Total synthesis of (+/-)-hirsutine: application of phosphine-catalyzed imine allene [4 + 2] annulation. AB - The total synthesis of the indole alkaloid hirsutine has been achieved, with a key step being the application of our phosphine-catalyzed [4 + 2] annulation of an imine with ethyl alpha-methylallenoate. From commercially available indole-2 carboxaldehyde, the target was synthesized in 14 steps and 6.7% overall yield. PMID- 22920860 TI - Intake fraction for the indoor environment: a tool for prioritizing indoor chemical sources. AB - Reliable exposure-based chemical characterization tools are needed to evaluate and prioritize in a rapid and efficient manner the more than tens of thousands of chemicals in current use. This study applies intake fraction (iF), the integrated incremental intake of a chemical per unit of emission, for a suite of indoor released compounds. A fugacity-based indoor mass-balance model was used to simulate the fate and transport of chemicals for three release scenarios: direct emissions to room air and surface applications to carpet and vinyl. Exposure through inhalation, dermal uptake, and nondietary ingestion was estimated. To compute iF, cumulative intake was summed from all exposure pathways for 20 years based on a scenario with two adults and a 1-year-old child who ages through the simulation. Overall iFs vary by application modes: air release (3.1 * 10(-3) to 6.3 * 10(-3)), carpet application (3.8 * 10(-5) to 6.2 * 10(-3)), and vinyl application (9.0 * 10(-5) to 1.8 * 10(-2)). These iF values serve as initial estimates that offer important insights on variations among chemicals and the potential relative contribution of each pathway over a suite of compounds. The approach from this study is intended for exposure-based prioritization of chemicals released inside homes. PMID- 22920861 TI - [Riding dangerous roads]. PMID- 22920859 TI - Exosomal cell-to-cell transmission of alpha synuclein oligomers. AB - BACKGROUND: Aggregation of alpha-synuclein (alphasyn) and resulting cytotoxicity is a hallmark of sporadic and familial Parkinson's disease (PD) as well as dementia with Lewy bodies, with recent evidence implicating oligomeric and pre fibrillar forms of alphasyn as the pathogenic species. Recent in vitro studies support the idea of transcellular spread of extracellular, secreted alphasyn across membranes. The aim of this study is to characterize the transcellular spread of alphasyn oligomers and determine their extracellular location. RESULTS: Using a novel protein fragment complementation assay where alphasyn is fused to non-bioluminescent amino-or carboxy-terminus fragments of humanized Gaussia Luciferase we demonstrate here that alphasyn oligomers can be found in at least two extracellular fractions: either associated with exosomes or free. Exosome associated alphasyn oligomers are more likely to be taken up by recipient cells and can induce more toxicity compared to free alphasyn oligomers. Specifically, we determine that alphasyn oligomers are present on both the outside as well as inside of exosomes. Notably, the pathway of secretion of alphasyn oligomers is strongly influenced by autophagic activity. CONCLUSIONS: Our data suggest that alphasyn may be secreted via different secretory pathways. We hypothesize that exosome-mediated release of alphasyn oligomers is a mechanism whereby cells clear toxic alphasyn oligomers when autophagic mechanisms fail to be sufficient. Preventing the early events in alphasyn exosomal release and uptake by inducing autophagy may be a novel approach to halt disease spreading in PD and other synucleinopathies. PMID- 22920862 TI - [What planarians tell us about cilia, centrioles and centrosomes]. PMID- 22920863 TI - [Olfactory dysfonction in multiple sclerosis: role for subventricular zone progenitors]. PMID- 22920864 TI - [When our metabolic health depends on our internal clocks]. PMID- 22920865 TI - [Nuclear receptors REVERBalpha and REVERBbeta set the clock]. PMID- 22920866 TI - [Regulation of erythropoiesis mediated by immunoglobulin A1]. PMID- 22920867 TI - [Healing the tree of life with lateral gene transfers]. PMID- 22920868 TI - [When human cytomegalovirus says STOP to autophagy: an antiviral defense mechanism]. PMID- 22920869 TI - [TMC1 and TMC2: key partners in hearing and vestibular function]. PMID- 22920870 TI - [KLHL3 and CULLIN-3: new genes involved in familial hypertension]. PMID- 22920871 TI - [Impact of new antiretroviral therapy in HIV infected patients with virologic failure]. PMID- 22920872 TI - [Deciphering functional activity of TLX homeodomain oncogenes in T-ALL: a clue for a differentiating therapy?]. PMID- 22920873 TI - [Alternative genetic system supports the hypothesis of an RNA precursor]. PMID- 22920874 TI - [DNA repair: finding the perfect match]. PMID- 22920875 TI - [Management of biofilm-associated infections: what can we expect from recent research on biofilm lifestyles?]. AB - Biofilms are surface-associated microbial communities present in all environments. Although biofilms play important ecological roles, they also lead to negative or deleterious effects in industrial and medical settings. In the latter, high levels of antibiotic tolerance of bacterial biofilms developing on medical devices and during chronic infections determine the physiopathology of many healthcare-associated infections. Original approaches have been developed to avoid bacterial adhesion or biofilm development targetting specific mechanisms or pathways. We herein review recent data about biofilm lifestyle understanding and ways to fight against related infections. PMID- 22920876 TI - [Could antifungal lock be useful in the management of candidiasis linked with catheters?]. AB - Fungal biofilms associated with inserted medical devices such as catheters, represent a major risk factor for candidemia. In addition, these biofilm yeasts show a decreased susceptibility to antifungal agents. Recently, a new therapeutic approach has emerged, the "lock therapy", based on the use of high concentrations of antimicrobials, instilled into the lumen of the catheter and left in place for 8 to 12 h. In vitro or in vivo studies have evaluated the interest of antifungal locks using amphotericin B, an azole or echinocandins. The promising results will permit us to discuss the relevance of this technique. PMID- 22920878 TI - [Use of regulatory T cells in cellular therapies in autoimmune diseases]. AB - Self tolerance is dependent on regulatory T cells (Treg) which suppress effector T cells, avoiding autoimmunity. Functional and quantitative deficits of Treg have been reported in autoimmune diseases. A new therapeutic approach consisting in Treg adoptive transfer has proved to be efficient and safe in murine models. Two populations seem to be available for a clinical application: CD4(+)CD25(+)Foxp3(+) natural Treg derived from the thymus and induced regulatory T cells. First clinical trials have been applied to patients with autoimmune diseases. Classical treatments of autoimmune diseases are usually non-curative and require long-term administration. Treg cellular therapy may have a long-term effect and offers an alternative attractive approach. PMID- 22920877 TI - [Nuclear-power-plant accidents: thyroid cancer incidence and radiation-related health effects from the Chernobyl accident]. AB - Following the Chernobyl accident, enormous amounts of radioisotopes were released in the atmosphere and have contaminated surrounding populations in the absence of rapid protective countermeasures. The highest radiation doses were delivered to the thyroid gland, and the only direct consequence of radiation exposure observed among contaminated population is the increased incidence of thyroid cancers among subjects who were children in 1986 and who lived at that time in Belarus, Ukraine or Russia. PMID- 22920879 TI - [Synesthesia as a neuronal palimpsest]. AB - Synesthetes, a small fraction of the population, experience systematic, additional associations. For example, they may arbitrarily associate a specific color to each letter or number. Synesthesia has offered for the last ten years to cognitive science a unique opportunity to study the neural bases of subjective experience, drawing on individual differences just like in neuropsychology, but with healthy people. Here we review the current knowledge and propose a new theory, the "palimpsest hypothesis", a variant of the recycling hypothesis for reading. The neural development of written language expertise (a recent cultural invention acquired without any genetic modification) requires indeed the recycling of brain regions predisposed to expertise acquisition into reading regions. The palimpsest hypothesis supposes that for synesthetes recycling involves neuronal networks that were already specialized for color perception. Synesthetic colors would be the remains of this former expertise. PMID- 22920882 TI - [CaV rebels]. PMID- 22920881 TI - [Lymphocytes are endowed with molecular complexes looking like voltage-dependent calcium channels but that are not channels]. PMID- 22920880 TI - [Calcium signaling in T lymphocytes]. AB - Calcium signaling is essential for all the functions of T lymphocytes, including those of Th2 cells. Th2 lymphocytes producing interleukins 4, 5 and 13 orchestrate allergic diseases including asthma. T-cell activation induces an influx of Ca(2+) from the external medium through ORAI calcium channels although other calcium channels are likely to be involved. Among them, voltage-gated calcium (Ca(v)1) channels have been reported in some T-cell subsets including Th2 cells. The inhibition of Ca(v)1 channels abrogates T-cell receptor-driven calcium influx and interleukin production by Th2 cells. From a therapeutic point of view, the inhibition of Ca(v)1 channels prevents Th2-dependent experimental allergic asthma. In this review, we will discuss the singularities of calcium responses depending upon the T-cell subset and its state of activation. PMID- 22920883 TI - [Is our genome predictive?]. PMID- 22920884 TI - Fragmentation pathways in the uracil radical cation. AB - We investigate pathways for fragmentation in the uracil radical cation using ab initio electronic structure calculations. We focus on the main fragments produced in pump-probe dissociative ionization experiments. These are fragments with mass to charge ratios (m/z) of 69, 28, 41, and 42. Barriers to dissociation along the ground ionic surface are reported, which provide an estimate of the energetic requirements for the production of the main fragments. Direct and sequential fragmentation mechanisms have been analyzed, and it is concluded that sequential fragmentation after production of fragment with m/z 69 is the dominant mechanism for the production of the smaller fragments. PMID- 22920885 TI - Structural insights into the molecular basis of the ligand promiscuity. AB - Selectivity is a key factor in drug development. In this paper, we questioned the Protein Data Bank to better understand the reasons for the promiscuity of bioactive compounds. We assembled a data set of >1000 pairs of three-dimensional structures of complexes between a "drug-like" ligand (as its physicochemical properties overlap that of approved drugs) and two distinct "druggable" protein targets (as their binding sites are likely to accommodate "drug-like" ligands). Studying the similarity between the ligand-binding sites in the different targets revealed that the lack of selectivity of a ligand can be due (i) to the fact that Nature has created the same binding pocket in different proteins, which do not necessarily have otherwise sequence or fold similarity, or (ii) to specific characteristics of the ligand itself. In particular, we demonstrated that many ligands can adapt to different protein environments by changing their conformation, by using different chemical moieties to anchor to different targets, or by adopting unusual extreme binding modes (e.g., only apolar contact between the ligand and the protein, even though polar groups are present on the ligand or at the protein surface). Lastly, we provided new elements in support to the recent studies which suggest that the promiscuity of a ligand might be inferred from its molecular complexity. PMID- 22920887 TI - [What are the effects and management of short sleep duration in adolescents?]. AB - Sleep deprivation is highly prevalent in the general population and related to lifestyle in industrialized countries. There has been an increase in this reduction of sleep for half a century and adolescents are particularly affected. Given the magnitude of this sleep restriction, it seems important to focus its mechanisms and its neurocognitive, endocrine, metabolic, weight, psychological and school consequences on adolescents. This sleep deprivation is described and the solutions that can be proposed to adolescents and their family or school environment to increase sleep duration and decrease the negative consequences of their current sleep deprivation are reviewed. PMID- 22920888 TI - [Nontuberculous mycobacterial epitrochlear adenitis]. AB - We report the case of a 2-year-old girl referred for unilateral epitrochlear lymphadenitis caused by Mycobacterium avium. Adenitis is the most frequent presentation of non tuberculous mycobacteria in children. Typical locations are the cervical, submandibular, axillar, inguinal, mediastinal, and parotid regions. To our knowledge, this is the first observation of an epitrochlear location. The diagnosis was made by evidencing the causal bacterium but also by the exclusion of other causes such as Bartonella henselae and Mycobacterium tuberculosis infections. Treatment is based on surgical excision, which provides a cure rate of 90%. Macrolides are reserved for extended lesions and/or relapsing lesions despite surgical management. PMID- 22920886 TI - The bidirectional interation between pancreatic cancer and diabetes. AB - The bidirectional interation between pancreatic cancer (PanCa) and diabetes has been confirmed by epidemiological studies, which provide evidence-based medical support for further research into the mechanisms involved in the interaction. We reviewed the literature regarding the role of diabetes in the generation and progression of PanCa and the mechanism by which PanCa induces diabetes for its malignant progression. The effect of antidiabetic drugs on the occurrence and prognosis of PanCa was also reviewed. Diabetes may directly promote the progression of PanCa by pancreatic duct enlargement and hypertension, as well as by enabling an increased tumor volume. Hyperinsulinemia, insulin resistance, cytokines, hyperglycemia and genotype change are also important factors in the progression of PanCa with diabetes. Hyperglycemia may be the first clinical manifestation and is helpful in the early diagnosis of PanCa. Furthermore, antidiabetic drugs can have different effects on the occurrence and prognosis of PanCa. The bidirectional interation between PanCa and diabetes is involved in the occurrence, proliferation, invasion, metastasis and prognosis of PanCa with diabetes. The discovery of biomarkers for the early diagnosis of PanCa, as well as the novel usage of metformin for its antitumor effects and determining the potential mechanisms of these effects, may be the next direction for PanCa research and treatment. PMID- 22920889 TI - [Bacteriological study of urinary tract infections in infants at the Brazzaville University Hospital]. PMID- 22920890 TI - [Establishment of the intestinal microflora and regulation of bacterial translocation after caffeine citrate treatment during postnatal period in rat]. AB - To relieve respiratory problems such as apnea in newborns, caffeine citrate is the drug of choice because of its good tolerance and therapeutic index. However, its impact on the intestinal microbial ecosystem and on bacterial translocation in the neonatal period remains insufficiently investigated. Therefore, the objective of this study was to evaluate the effects of caffeine citrate on the establishment of the intestinal microflora and bacterial translocation in rats from birth to the 30th day of life. Newborn Wistar rats were divided into four groups of 14 animals, each subdivided into a control group receiving a placebo (12mL tap water/kg/day) and another treated with caffeine citrate (12mg/kg/day). The animals were nursed by their mothers and weighed daily. A group of 14 rats was killed at birth and after 10, 20, or 30 days of life. Organs in which translocation was assessed (liver, lungs, spleen, and kidneys) and various fragments of intestine (duodenum, jejunum, ileum, and colon) were surgically removed. The bacteriological analysis performed involved enumeration of the total microflora, staphylococci, enterobacteria, and lactobacilli. From the 10th day, caffeine was shown to significantly decrease the weight of treated animals as compared with controls (P<0.05). However, caffeine treatment did not drastically alter the kinetics of establishment of the intestinal microflora as only enterobacteria were found to be significantly lower in any intestinal segment of the treated group (P<0.05). Moreover, from the 20th day of life, caffeine citrate significantly downregulated bacterial translocation of both Gram-positive and negative bacteria (P<0.05). This preliminary study on the effects of treatment with caffeine citrate may open opportunities in clinical pediatrics; the treatment will remain partially effective in preventing bacterial translocation in the neonatal period. PMID- 22920891 TI - [Zygomatic anchorage concept in full edentulism]. AB - The zygoma anchorage concept for severe atrophy of the maxilla was developed by Branemark in the 1980s. It concerned patients having undergone maxillectomy as well as patients with edentulous upper jaws and mild to severe maxillary atrophy. The concept was created and clinically developed in 1997, by placing two zygomatic implants and four standard ones to compensate sub-sinus bone resorption. It was applied later to patients presenting extremely severe maxillary atrophy, using the "zygoma quad" concept with the placement of four zygomatic implants. Zygoma anchorage is reliable in terms of osseo-integration and biomechanical support of screwed prostheses, according to frequently published data (overall survival rate ranging between 91 and 100%). The increasing practice of immediate loading makes it the treatment of choice for oral rehabilitation. It decreases surgical invasiveness and the delay between surgery and oral rehabilitation. It allows a quick social and professional reinsertion and increases the comfort and quality of life for patients with fully edentulous maxilla with mild, moderate, or severe atrophy. PMID- 22920892 TI - [Pre-implantation bone graft coffering technique for posterior mandibular edentulism: between onlay grafting and regeneration]. AB - BACKGROUND: Pre-implant placement posterior mandibular bone grafts remain a challenge for maxillofacial surgeons. We present a coffering technique we prefer using in this localization. SURGICAL PROCEDURE: This original technique involves creating a sagittal mandibular groove in which a graft harvested from the retromolar region is wedged vertically, after being sharpened in a bone mill. Reconstruction of the alveolar region itself is achieved by filling up the space between this vestibular coffer and the residual alveolar ridge with particulate bone graft from the bone mill. RESULTS: A hundred patients were operated with this technique by the same team from 2005 to 2010. The treatment failed for four patients at 3 post-operative months. No alteration of inferior alveolar nerve was observed. DISCUSSION: This coffering technique seems to be fully adequate in case of a posterior mandibular atrophy with a narrow ridge and sufficient bone height. This technique has several assets. Guided bone regeneration is associated with the use of exclusively autologous bone grafts. It may be performed under local anesthesia. The donor site is close, and the regenerated bone is of good quality. Implant placement must be achieved from 4 to 6 months after graft surgery. The drawbacks of the technique are related to donor site possibilities, and to the alveolar ridge height. Morbidity is low. PMID- 22920893 TI - [Implant insertion in distracted bone for reconstruction after gunshot injury]. AB - Distraction osteogenesis is a tissue engineering technique with two clinical applications in maxillofacial surgery: alveolar distraction and basal bone distraction. Even if it appears to be a binding and major surgery, distraction osteogenesis applied to facial bone, and especially to the mandible, has the great advantage of producing a pluritissular reconstruction of ideal quality and quantity, suitable for the ultimate goal of dental implant rehabilitation management. This technique had some drawbacks due to technical constraints related to the material. Distraction osteogenesis is well placed in the armamentarium of reconstructive surgery techniques for bone defects caused by trauma or tumor. It allows rapid restoration of adequate physiological conditions for mandibular dental implant placement. We reviewed the various modifications of this technique. PMID- 22920895 TI - Netrin-1 in the developing enteric nervous system and colorectal cancer. AB - Netrin-1 is a well-characterised chemoattractant involved in neuronal guidance in the developing enteric nervous system (ENS), but it is also a regulator of tumorigenesis. Two of its well-characterised receptors, deleted in colorectal cancer (DCC) and uncoordinated-5 homolog (UNC-5H), belong to a family of dependence receptors that transmit either pro- or anti-apoptosis signals depending on the availability of ligand, in this case netrin-1. This review summarises these two effects of netrin-1 and highlights the additional research needed information about to allow better utilisation of netrin-1 as a therapeutic target for axonal regeneration in the context of colorectal cancer. PMID- 22920894 TI - Xenobiotics and autoimmunity: does acetaminophen cause primary biliary cirrhosis? AB - The serologic hallmark of primary biliary cirrhosis (PBC) is the presence of antimitochondrial autoantibodies (AMAs) directed against the E2 subunit of the pyruvate dehydrogenase complex (PDC-E2). The PBC-related autoepitope of PDC-E2 contains lipoic acid, and previous work has demonstrated that mimics of lipoic acid following immunization of mice lead to a PBC-like disease. Furthermore, approximately one-third of patients who have ingested excessive amounts of acetaminophen (paracetamol) develop AMA of the same specificity as patients with PBC. Quantitative structure-activity relationship (QSAR) data indicates that acetaminophen metabolites are particularly immunoreactive with AMA, and we submit that in genetically susceptible hosts, electrophilic modification of lipoic acid in PDC-E2 by acetaminophen or similar drugs can facilitate a loss of tolerance and lead to the development of PBC. PMID- 22920896 TI - Chaperonopathies and chaperonotherapy. Hsp60 as therapeutic target in cancer: potential benefits and risks. AB - In this minireview we focus on Hsp60 as a target for anticancer therapy. We discuss the new concepts of chaperonopathies and chaperonotherapy and present information on Hsp60 localization in the cell membrane of human tumor cells. We describe novel mechanisms for Hsp60 reaching the extracellular environment that involve membrane-associated stages, as well as data on anti-Hsp60 antibodies found in human sera, both in normal subjects and patients affected by autoimmune diseases. Finally, we discuss possible therapeutic applications of anti-Hsp60 antibodies in cancer treatment, evaluating also side effects on non-tumor cells. In conclusion, the way for investigating Hsp60-targeted anti-tumor therapy is open, at least for those tumors that express Hsp60 on its surface and/or secrete it outside the cell, as is the search for the molecular mechanisms involved in Hsp60 translocation from cytosol to cell membrane: elucidation of this mechanism will greatly facilitate the optimization of chaperonotherapy centered on Hsp60 with anti-tumor efficacy and minimal side effects. PMID- 22920898 TI - Hsp70s and J proteins of Plasmodium parasites infecting rodents and primates: structure, function, clinical relevance, and drug targets. AB - Human malaria is an economically important disease caused by single-celled parasites of the Plasmodium genus whose biology displays great evolutionary adaptation to both its mammalian host and transmitting vectors. While the parasite has multiple life cycle stages, it is in the blood stage where clinical symptoms of the disease are manifested. Following erythrocyte entry, the parasite resides in the parasitophorous vacuole and actively transports its own proteins to the erythrocyte cytosol. This host-parasite "cross-talk" results in tremendous modifications of the infected erythrocyte imparting properties that allow it to adhere to the endothelium preventing splenic clearance. The Hsp70-J protein (DnaJ/Hsp40) molecular chaperone machinery, involved in cellular protein homeostasis, is being investigated as a novel drug target in various cellular systems including malaria. In Plasmodium the diverse chaperone complement is intimately involved in infected erythrocyte remodelling associated with the development and pathogenesis of malaria. In this review, we provide an overview of the Hsp70-J protein chaperone complement in Plasmodium falciparum and compare it with other Plasmodium species including the ones that serve as experimental study models for malaria. We propose that the unique traits possessed by this machinery not only provide avenues for drug targeting but also inform the evolutionary fitness of this parasite to its environment. PMID- 22920899 TI - HSP60 as a drug target. AB - Heat shock proteins (HSPs) are ubiquitous and evolutionary conserved proteins induced by cell stress. HSP60, in particular, is a typical mitochondrial molecular chaperone that is known to assist nascent polypeptides to reach a native conformation. HSP60 is also known to interact with HSP10. In the last decade, HSP60 has been detected in the cytosol, the cell surface, the extracellular space, and biological fluids. HSP60 elicits potent proinflammatory response in cells of the innate immune system and serves as a danger signal of stressed or damaged cells. As cytosolic HSP60 levels gradually increase or decrease during carcinogenesis in various organs, HSP60 can be used as a biomarker for the diagnosis and prognosis of preneoplastic and neoplastic lesions. In this review, we summarize recent discoveries on the important roles of HSP60 in various diseases ranging from autoimmune diseases to tumors. Furthermore, small molecules targeting HSP60, which were the target of intensive investigations in the last few years, are also summarized. The possibility of utilizing HSP60 as a new drug target for the treatment of certain diseases is examined. PMID- 22920897 TI - Lysosomal rerouting of Hsp70 trafficking as a potential immune activating tool for targeting melanoma. AB - Tumor specific cell surface localization and release of the stress inducible heat shock protein 70 (Hsp70) stimulate the immune system against cancer cells. A key immune stimulatory function of tumor-derived Hsp70 has been exemplified with the murine melanoma cell model, B16 overexpressing exogenous Hsp70. Despite the therapeutic potential mechanism of Hsp70 transport to the surface and release remained poorly understood. We investigated principles of Hsp70 trafficking in B16 melanoma cells with low and high level of Hsp70. In cells with low level of Hsp70 apparent trafficking of Hsp70 was mediated by endosomes. Excess Hsp70 triggered a series of changes such as a switch of Hsp70 trafficking from endosomes to lysosomes and a concomitant accumulation of Hsp70 in lysosomes. Moreover, lysosomal rerouting resulted in an elevated concentration of surface Hsp70 and enabled active release of Hsp70. In fact, hyperthermia, a clinically applicable approach triggered immediate active lysosomal release of soluble Hsp70 from cells with excess Hsp70. Furthermore, excess Hsp70 enabled targeting of internalized surface Hsp70 to lysosomes, allowing in turn heat-induced secretion of surface Hsp70. Altogether, we show that excess Hsp70 expressed in B16 melanoma cells diverts Hsp70 trafficking from endosomes to lysosomes, thereby supporting its surface localization and lysosomal release. Controlled excess-induced lysosomal rerouting and secretion of Hsp70 is proposed as a promising tool to stimulate anti-tumor immunity targeting melanoma. PMID- 22920900 TI - High-throughput screening identifies small molecule inhibitors of molecular chaperones. AB - Heat shock proteins (HSPs) are involved in a number of cellular processes, including cell cycle, growth, and survival, apoptosis, stress responses, angiogenesis, and oncogenesis. Among the characterized HSPs, the molecular chaperone HSP90 has emerged as an exciting molecular target for cancer therapy since its discovery as the target protein of the antibiotic geldanamycin. The stress-inducible HSP70, which is upregulated in many cancers, contributing to tumor cell survival and resistance to therapy, has important roles as a housekeeper in the cell, assisting in the correct folding, trafficking, and degradation of many proteins. 2-Phenylethynesulfonamide (PES) physically interacts with HSP70 and disrupts the association between HSP70 and several of its cofactors and client proteins, leading to cancer cell death that is selectively mediated through caspase-independent mechanisms involving increased protein aggregation, impairment of lysosomal functions, and inhibition of autophagy. Mammalian HSP60 has several functions in the cell, including apoptosis, an immune-regulatory function, and cell spreading. HSP60 is a mitochondrial protein that is essential for the folding and assembly of newly imported proteins in the mitochondria. Epolactaene/ETB covalently binds to HSP60, inhibiting its chaperone activity. Molecular chaperone inhibitors are significantly valuable not only as tools to reveal the unknown cellular functions of molecular chaperones, but also as lead compounds for drug discovery. Thus, high-throughput screening systems are necessary for the discovery of more effective inhibitors. Here, we describe the methodology for 4 characteristic types of high-throughput screening systems for inhibitors of molecular chaperones, mainly HSP90 and HSP70: the colorimetric method, the fluorescence polarization method, the chemical array method, and the AlphaScreen(r) method. PMID- 22920902 TI - Hydroximic acid derivatives: pleiotropic HSP co-inducers restoring homeostasis and robustness. AB - According to the "membrane sensor" hypothesis, the membrane's physical properties and microdomain organization play an initiating role in the heat shock response. Clinical conditions such as cancer, diabetes and neurodegenerative diseases are all coupled with specific changes in the physical state and lipid composition of cellular membranes and characterized by altered heat shock protein levels in cells suggesting that these "membrane defects" can cause suboptimal hsp-gene expression. Such observations provide a new rationale for the introduction of novel, heat shock protein modulating drug candidates. Intercalating compounds can be used to alter membrane properties and by doing so normalize dysregulated expression of heat shock proteins, resulting in a beneficial therapeutic effect for reversing the pathological impact of disease. The membrane (and lipid) interacting hydroximic acid (HA) derivatives discussed in this review physiologically restore the heat shock protein stress response, creating a new class of "membrane-lipid therapy" pharmaceuticals. The diseases that HA derivatives potentially target are diverse and include, among others, insulin resistance and diabetes, neuropathy, atrial fibrillation, and amyotrophic lateral sclerosis. At a molecular level HA derivatives are broad spectrum, multi-target compounds as they fluidize yet stabilize membranes and remodel their lipid rafts while otherwise acting as PARP inhibitors. The HA derivatives have the potential to ameliorate disparate conditions, whether of acute or chronic nature. Many of these diseases presently are either untreatable or inadequately treated with currently available pharmaceuticals. Ultimately, the HA derivatives promise to play a major role in future pharmacotherapy. PMID- 22920903 TI - S-nitrosation/denitrosation in cardiovascular pathologies: facts and concepts for the rational design of S-nitrosothiols. AB - Nitric oxide (*NO) is a physiological mediator of vasorelaxation constitutively synthesized by endothelial nitric oxide synthase. Because *NO has a short half life, it is stored by proteins through S-nitrosation reactions. S-nitrosation was recently defined as a post-translational modification of proteins for cellular signalling, as important as glycosylation and phosphorylation. Disulfide forming/ isomerizing enzymes like thioredoxin (Trx), protein disulfide isomerase (PDI), which are chaperone proteins, are implicated into transnitrosation reactions, which are the transfer of *NO from one cysteine residue to another one. Furthermore, Trx has been shown to denitrosate S-nitrosoproteins depending on its redox status. S-nitrosation of Trx on Cys residues apart from active site, under nitrosative or oxidative stresses, enhances its activity, thereby reducing intracellular reactive oxygen species. Trx and PDI have therefore an essential role for cell signalling control which leads, among other actions, to cardio and vasculo-protection. The diminution of either *NO synthesis or bioavailability is implicated into a large number of cardiovascular pathologies associated to hypoxia or vasoconstriction like, endothelial dysfunction, arterial hypertension and atherosclerosis. In order to mimic the physiological storage of *NO as S nitrosothiols, the development of *NO donors should be based on the covalent S-NO bond. The chemical stabilisation of the S-NO bond and protection against enzymatically active proteins such as PDI//Trx are major points for the design of stable compounds. S-nitrosothiols entrapment in innovative formulations (films, gels, microparticles, nanoparticles) is an emerging field in order to stabilise and protect them, and to deliver *NO under a sustained release at the targeted site. PMID- 22920904 TI - Druggability of mortalin for cancer and neuro-degenerative disorders. AB - Mortalin is a member of Hsp70 family of stress chaperones. It was first identified as a protein involved in the senescence of mouse cells. Genetic studies revealed that there are two mouse mortalin alleles coding for two proteins (mot-1 and mot-2) that differ in only two amino acids in the carboxy terminus, but have contrasting activities. Whereas mot-1 accelerated senescence, mot-2 extended the lifespan of mouse cells in culture. In human cells, only one kind of mortalin protein has been identified so far and is shown to be functionally equivalent to mouse mot-2. Whereas mortalin is enriched in cancer cells and contributes to carcinogenesis, the old age brain disorders show its deficiency. As we demystify its deux de machina, accumulating evidence reveal that mortalin may be "druggable" bidirectionally to either treat cancer or neuro degenerative disorders. PMID- 22920901 TI - Hsp70 protein complexes as drug targets. AB - Heat shock protein 70 (Hsp70) plays critical roles in proteostasis and is an emerging target for multiple diseases. However, competitive inhibition of the enzymatic activity of Hsp70 has proven challenging and, in some cases, may not be the most productive way to redirect Hsp70 function. Another approach is to inhibit Hsp70's interactions with important co-chaperones, such as J proteins, nucleotide exchange factors (NEFs) and tetratricopeptide repeat (TPR) domain containing proteins. These co-chaperones normally bind Hsp70 and guide its many diverse cellular activities. Complexes between Hsp70 and co-chaperones have been shown to have specific functions, including roles in pro-folding, pro-degradation and pro-trafficking pathways. Thus, a promising strategy may be to block protein- protein interactions between Hsp70 and its co-chaperones or to target allosteric sites that disrupt these contacts. Such an approach might shift the balance of Hsp70 complexes and re-shape the proteome and it has the potential to restore healthy proteostasis. In this review, we discuss specific challenges and opportunities related to these goals. By pursuing Hsp70 complexes as drug targets, we might not only develop new leads for therapeutic development, but also discover new chemical probes for use in understanding Hsp70 biology. PMID- 22920905 TI - Heat shock protein 90 inhibitors as broad spectrum anti-infectives. AB - Combating stress is one of the prime requirements for any organism. For parasitic microbes, stress levels are highest during the growth inside the host. Their survival depends on their ability to acclimatize and adapt to new environmental conditions. Robust cellular machinery for stress response is, therefore, both critical and essential especially for pathogenic microorganisms. Microbes have cleverly exploited stress proteins as virulence factors for pathogenesis in their hosts. Owing to its ability to sense and respond to the stress conditions, Heat shock protein 90 (Hsp90) is one of the key stress proteins utilized by parasitic microbes. There are growing evidences for the critical role played by Hsp90 in the growth of pathogenic organisms like Candida, Giardia, Plasmodium, Trypanosoma, and others. This review, therefore, explores potential of exploiting Hsp90 as a target for the treatment of infectious diseases. This molecular chaperone has already gained attention as an effective anti-cancer drug target. As a result, a lot of research has been done at laboratory, preclinical and clinical levels for several Hsp90 inhibitors as potential anti-cancer drugs. In addition, lot of data pertaining to toxicity studies, pharmacokinetics and pharmacodynamics studies, dosage regime, drug related toxicities, dose limiting toxicities as well as adverse drug reactions are available for Hsp90 inhibitors. Therefore, repurposing/ repositioning strategies are also being explored for these compounds which have gone through advanced stage clinical trials. This review presents a comprehensive summary of current status of development of Hsp90 as a drug target and its inhibitors as candidate anti-infectives. A particular emphasis is laid on the possibility of repositioning strategies coupled with pharmaceutical solutions required for fulfilling needs for ever growing pharmaceutical infectious disease market. PMID- 22920906 TI - The therapeutic target Hsp90 and cancer hallmarks. AB - Hsp90 is a major molecular chaperone that is expressed abundantly and plays a pivotal role in assisting correct folding and functionality of its client proteins in cells. The Hsp90 client proteins include a wide variety of signal transducing molecules such as protein kinases and steroid hormone receptors. Cancer is a complex disease, but most types of human cancer share common hallmarks, including self-sufficiency in growth signals, insensitivity to growth inhibitory mechanism, evasion of programmed cell death, limitless replicative potential, sustained angiogenesis, and tissue invasion and metastasis. A surprisingly large number of Hsp90-client proteins play crucial roles in establishing cancer cell hallmarks. We start the review by describing the structure and function of Hsp90 since conformational changes during the ATPase cycle of Hsp90 are closely related to its function. Many co-chaperones, including Hop, p23, Cdc37, Aha1, and PP5, work together with Hsp90 by modulating the chaperone machinery. Post-translational modifications of Hsp90 and its cochaperones are vital for their function. Many tumor-related Hsp90-client proteins, including signaling kinases, steroid hormone receptors, p53, and telomerase, are described. Hsp90 and its co-chaperones are required for the function of these tumor-promoting client proteins; therefore, inhibition of Hsp90 by specific inhibitors such as geldanamycin and its derivatives attenuates the tumor progression. Hsp90 inhibitors can be potential and effective cancer chemotherapeutic drugs with a unique profile and have been examined in clinical trials. We describe possible mechanisms why Hsp90 inhibitors show selectivity to cancer cells even though Hsp90 is essential also for normal cells. Finally, we discuss the "Hsp90-addiction" of cancer cells, and suggest a role for Hsp90 in tumor evolution. PMID- 22920907 TI - Hsp90 inhibitors as anti-cancer agents, from basic discoveries to clinical development. AB - Heat shock protein (Hsp) 90 is an ATP-dependent molecular chaperone which stabilizes various oncogenic kinases, including HER2, EGFR, BCR-ABL, B-Raf and EML4-ALK, which are essential for tumor growth. Several monoclonal antibodies and small molecule kinase inhibitors which target these kinases have been identified as potential new molecular target therapeutics. Previous reports have shown that many oncogenic proteins essential for cancer transformation are chaperoned by the Hsp90 complex, and some of these client proteins have been discovered by using Hsp90 inhibitors, such as geldanamycin (GA) and radicicol (RD).Thus far more than 200 client proteins have been identified. In past derivatives of these natural products have been evaluated in clinical trials, but none of the 1st generation of Hsp90 inhibitors has been approved yet because of their limitations in physico chemical properties and/or safety profiles. However, recent reports have indicated that more than 10 new agents, 2nd generation of Hsp90 inhibitors with different chemotypes from GA and RD, have entered clinical trials and some of them showed clinical efficacy. In this review article, we describe the discoveries of major Hsp90 client proteins in the cancer field by RD derivatives, the history of KW-2478 discovery and development by Kyowa Hakko Kirin, and gave an update on the current status of new Hsp90 inhibitors in clinical trials. PMID- 22920908 TI - Molecular chaperones as drug targets. PMID- 22920909 TI - Gene carrier showing all-or-none response to cancer cell signaling. AB - In this work we designed a novel nano carrier, a linear polyethylenimine (LPEI) peptide conjugate, for cancer-specific expression of transgenes. The conjugate was easily synthesized by using a click chemistry scheme orthogonal to the reactive side groups of the peptide, which is the substrate of protein kinase Calpha (PKCalpha). Polyplexes of the conjugates with plasmid DNA (pDNA) were intact and stably dispersed even in the presence of cell lysate. Despite this stability, the polyplexes readily dissociated upon phosphorylation of the grafted peptides by PKCalpha. Because of its endosomal escape ability and adequate susceptibility to PKCalpha, the polyplexes showed an all-or-none type response to PKCalpha activity in transgene expression in vitro. The polyplexes achieved cancer tissue-specific transgene expression even for a tumor with a relatively low PKCalpha activity. Thus the LPEI-peptide conjugate has high potential as a nanocarrier for cancer-targeted gene therapy. PMID- 22920910 TI - Exploring the role of intra-nasal oxytocin on the partner preference effect in humans. AB - Previous studies with prairie voles suggest that the hormone oxytocin is crucial for bond formation - indicated when a partner preference is formed towards the target vole. In this study, we conduct the first empirical test of whether oxytocin likewise promotes partner preferences in humans. Seventy-six undergraduate students received either oxytocin or placebo before being introduced to a male and female persona (via pre-recorded videoclips). One day later, participants were assessed for a partner preference towards the personae: across three situations, participants were asked to choose as company one of the personae they had been introduced to, or an opposite- or same-gendered person they had not been introduced to before; participants were additionally offered a choice to have no company. We found evidence suggesting oxytocin increases preference for persons introduced under the influence of oxytocin; however, this was not targeted at persons of the opposite-gender, and was found in only one aspect of social interaction (finding out more information about the person, but not in choice of company to work with or for a date). Taken together, our findings suggest that oxytocin might not promote human bond formation in ways analogous to prairie voles - that is, by inducing a partner preference effect. PMID- 22920911 TI - The cortisol awakening response in infants: ontogeny and associations with development-related variables. AB - The cortisol awakening response (CAR) is a frequently used measure in psychoneuroendocrinological research, however, some of its more fundamental aspects still require attention. An important question in this respect concerns the ontogeny of the CAR. Data from two recent reports suggest that the CAR may only emerge relatively late during child development (>=16 months of age). However, as both enquiries did not use objective means of verifying participant adherence or infants' awakening times, it is unclear whether methodological factors may have contributed to these results. Here, we report data from a study on 33 infants aged 2-12 months with close care being taken to ensure the accuracy of sampling times by using wrist actigraphy and electronic monitoring containers. Salivary cortisol levels were assessed at 0 and 30 min post-awakening over three study days. Results revealed evidence for a significant CAR (>=2.5 nmol/L) in 32 (out of 33) infants and on a total 86.9% of study days, with a marked magnitude of the CAR across infants (mean estimated increase=12.54 nmol/L). In addition, the cortisol level on awakening and the CAR were found to be associated with different aspects of infant's physical and sleep-related development as well as with their weight and body mass index (BMI) at birth. Contrary to previous reports, the current results thus indicate that the ontogeny of the CAR occurs at an early stage of development and that it is present from as early as two months of life. The data also suggest that post-awakening cortisol secretion may undergo considerable changes during the first year of life associated with different aspects of infant development. PMID- 22920913 TI - Evidence for overturning the guidelines in cardiogenic shock. PMID- 22920912 TI - Intraaortic balloon support for myocardial infarction with cardiogenic shock. AB - BACKGROUND: In current international guidelines, intraaortic balloon counterpulsation is considered to be a class I treatment for cardiogenic shock complicating acute myocardial infarction. However, evidence is based mainly on registry data, and there is a paucity of randomized clinical trials. METHODS: In this randomized, prospective, open-label, multicenter trial, we randomly assigned 600 patients with cardiogenic shock complicating acute myocardial infarction to intraaortic balloon counterpulsation (IABP group, 301 patients) or no intraaortic balloon counterpulsation (control group, 299 patients). All patients were expected to undergo early revascularization (by means of percutaneous coronary intervention or bypass surgery) and to receive the best available medical therapy. The primary efficacy end point was 30-day all-cause mortality. Safety assessments included major bleeding, peripheral ischemic complications, sepsis, and stroke. RESULTS: A total of 300 patients in the IABP group and 298 in the control group were included in the analysis of the primary end point. At 30 days, 119 patients in the IABP group (39.7%) and 123 patients in the control group (41.3%) had died (relative risk with IABP, 0.96; 95% confidence interval, 0.79 to 1.17; P=0.69). There were no significant differences in secondary end points or in process-of-care measures, including the time to hemodynamic stabilization, the length of stay in the intensive care unit, serum lactate levels, the dose and duration of catecholamine therapy, and renal function. The IABP group and the control group did not differ significantly with respect to the rates of major bleeding (3.3% and 4.4%, respectively; P=0.51), peripheral ischemic complications (4.3% and 3.4%, P=0.53), sepsis (15.7% and 20.5%, P=0.15), and stroke (0.7% and 1.7%, P=0.28). CONCLUSIONS: The use of intraaortic balloon counterpulsation did not significantly reduce 30-day mortality in patients with cardiogenic shock complicating acute myocardial infarction for whom an early revascularization strategy was planned. (Funded by the German Research Foundation and others; IABP SHOCK II ClinicalTrials.gov number, NCT00491036.). PMID- 22920914 TI - Self-reported leisure time physical activity: a useful assessment tool in everyday health care. AB - BACKGROUND: The individual physical activity level is an independent risk factor for cardiovascular disease and death, as well as a possible target for improving health outcome. However, today's widely adopted risk score charts, typically do not include the level of physical activity. There is a need for a simple risk assessment tool, which includes a reliable assessment of the level of physical activity. The aim of this study was therefore, to analyse the association between the self-reported levels of physical activity, according to the Saltin-Grimby Physical Activity Level Scale (SGPALS) question, and cardiovascular risk factors, specifically focusing on the group of individuals with the lowest level of self reported PA. METHODS: We used cross sectional data from the Intergene study, a random sample of inhabitants from the western part of Sweden, totalling 3588 (1685 men and 1903 women, mean age 52 and 51). Metabolic measurements, including serum-cholesterol, serum-triglycerides, fasting plasma-glucose, waist circumference, blood pressure and resting heart rate, as well as smoking and self reported stress were related to the self-reported physical activity level, according to the modernized version of the SGPALS 4-level scale. RESULTS: There was a strong negative association between the self-reported physical activity level, and smoking, weight, waist circumference, resting heart rate, as well as to the levels of fasting plasma-glucose, serum-triglycerides, low-density lipoproteins (LDL), and self-reported stress and a positive association with the levels of high-density lipoproteins (HDL). The individuals reporting the lowest level of PA (SGPALS, level 1) had the highest odds-ratios (OR) for having pre defined levels of abnormal risk factors, such as being overweight (men OR 2.19, 95% CI: 1.51-3.19; women OR 2.57, 95 % CI: 1.78-3.73), having an increased waist circumference (men OR 3.76, 95 % CI: 2.61-5.43; women OR 2.91, 95% CI: 1.94-4.35) and for reporting stress (men OR 3.59, 95 % CI: 2.34-5.49; women OR 1.25, 95% CI: 0.79-1.98), compared to the most active individuals, but also showed increased OR for most other risk factors analyzed above. CONCLUSION: The self-reported PA level according to the modernized Saltin-Grimby Physical Activity Level Scale, SGPALS, is associated with the presence of many cardiovascular risk factors, with the most inactive individuals having the highest risk factor profile, including self-reported stress. We propose that the present SGPALS may be used as an additional, simple tool in a routine risk assessment in e.g. primary care, to identify inactive individuals, with a higher risk profile. PMID- 22920916 TI - Direct laser pruning of CdS(x)Se1-x nanobelts en route to a multicolored pattern with controlled functionalities. AB - CdS(x)Se(1-x) nanobelts are interesting nanostructured materials with a tunable band gap from 1.7 to 2.4 eV depending on the nanobelts' stoichiometry. On the basis of their chemical compositions, these nanobelts give out strong photoluminescence with unique color. In this work, we demonstrate that a direct focused laser beam irradiation was able to achieve localized modification of the chemical composition of the nanobelts. As a result, we could locally change the optical properties of these nanobelts. With a scanning laser beam, micropatterns with a wide range of fluorescence color could be created on a substrate covered with ternary nanobelts without a prepatterned mask. The laser modified nanobelts showed higher resistance to acid corrosion and these nanobelts exhibited more superior photoconductivity. The construction of micropatterns with functionality/color control within the sample would provide greater building blocks for photoelectronic applications. PMID- 22920915 TI - Genetic diversity within the genus Francisella as revealed by comparative analyses of the genomes of two North American isolates from environmental sources. AB - BACKGROUND: Francisella tularensis is an intracellular pathogen that causes tularemia in humans and the public health importance of this bacterium has been well documented in recent history. Francisella philomiragia, a distant relative of F. tularensis, is thought to constitute an environmental lineage along with Francisella novicida. Nevertheless, both F. philomiragia and F. novicida have been associated with human disease, primarily in immune-compromised individuals. To understand the genetic relationships and evolutionary contexts among different lineages within the genus Francisella, the genome of Francisella spp. strain TX07 7308 was sequenced and compared to the genomes of F. philomiragia strains ATCC 25017 and 25015, F. novicida strain U112, and F. tularensis strain Schu S4. RESULTS: The size of strain ATCC 25017 chromosome was 2,045,775 bp and contained 1,983 protein-coding genes. The size of strain TX07-7308 chromosome was 2,035,931 bp and contained 1,980 protein-coding genes. Pairwise BLAST comparisons indicated that strains TX07-7308 and ATCC 25017 contained 1,700 protein coding genes in common. NUCmer analyses revealed that the chromosomes of strains TX07-7308 and ATCC 25017 were mostly collinear except for a few gaps, translocations, and/or inversions. Using the genome sequence data and comparative analyses with other members of the genus Francisella (e.g., F. novicida strain U112 and F. tularensis strain Schu S4), several strain-specific genes were identified. Strains TX07-7308 and ATCC 25017 contained an operon with six open reading frames encoding proteins related to enzymes involved in thiamine biosynthesis that was absent in F. novicida strain U112 and F. tularensis strain Schu S4. Strain ATCC 25017 contained an operon putatively involved in lactose metabolism that was absent in strain TX07-7308, F. novicida strain U112, and F. tularensis strain Schu S4. In contrast, strain TX07-7308 contained an operon putatively involved in glucuronate metabolism that was absent in the genomes of strain ATCC 25017, F. novicida strain U112, and F. tularensis strain Schu S4. The polymorphic nature of polysaccharide biosynthesis/modification gene clusters among different Francisella strains was also evident from genome analyses. CONCLUSIONS: From genome comparisons, it appeared that genes encoding novel functions have contributed to the metabolic enrichment of the environmental lineages within the genus Francisella. The inability to acquire new genes coupled with the loss of ancestral traits and the consequent reductive evolution may be a cause for, as well as an effect of, niche selection of F. tularensis. Sequencing and comparison of the genomes of more isolates are required to obtain further insights into the ecology and evolution of different species within the genus Francisella. PMID- 22920918 TI - Synthetic peptide-acrylate surface for self-renewal of human retinal progenitor cells. AB - Human retinal progenitor cells (hRPCs), isolated from fetal retina, require extracellular matrix proteins such as fibronectin or laminin for successful attachment and self-renewal in vitro. Here we have shown that a novel synthetic vitronectin-mimicking surface supports self-renewal and multipotency of hRPCs in a chemically defined culture system. The morphology, adhesion, and proliferation of hRPC were equivalent on a novel vitronectin-mimicking surface (Synthemax) compared to a fibronectin-coated surface. When evaluated using real-time polymerase chain reaction, Western blotting, and flow cytometry, both surfaces maintained self-renewal of hRPCs, as shown by similar expression levels of Sox2, Nestin, cMyc, Klf4, and Pax6, with no change in integrin beta1 and integrin alpha5 expression. We suggest that the use of synthetic, xeno-free surfaces such as Synthemax will be useful for basic research studies, as well as development of translational strategies aimed at using stem cell transplantation to treat disease. PMID- 22920917 TI - Nanoceria facilitates the synthesis of poly(o-phenylenediamine) with pH-tunable morphology, conductivity, and photoluminescent properties. AB - Poly(ortho-phenylenediamine) synthesis enabled by the catalytic oxidase-like activity of nanoceria was accomplished for applications in electronics, medicine, and biotechnology. The polymer shows unique morphology, conductivity, and photoluminescence based on pH of the solution during synthesis. The various poly(ortho-phenylenediamine) preparations were characterized by UV-visible spectroscopy, scanning electron microscopy, fluorescence spectroscopy, fluorescence microscopy, high-pressure liquid chromatography, and cyclic voltammetry. Poly(ortho-phenylenediamine) synthesized at pH 1.0 by nanoceria was selected to be extensively studied on the basis of the fast synthetic kinetics and the resulting conductive and photoluminescent properties for various applications. PMID- 22920919 TI - Ankle distraction arthroplasty combined with joint resurfacing for management of an osteochondral defect of the talus and concomitant osteoarthritis: a case report. AB - There are many treatment options for patients with ankle osteochondral defects and subsequent osteoarthritis. Although ankle arthrodesis remains the gold standard to definitive treatment of this condition, its permanent sequelae demands an alternative. In this article we discuss a case report from a 61-year old woman with a history of a previous ankle sprain resulting in an osteochondral defect that progressed to develop ankle osteoarthritis. After multiple attempts at conservative management, the patient underwent placement of an articulating external ring fixator for arthrodiastasis, as well as ankle joint resurfacing using allograft. The fixator was kept in place for a total of 12 weeks, with the patient performing range-of-motion exercises throughout the treatment course. We feel that this treatment presents as a promising treatment alternative based on the success demonstrated by this patient's 6-month follow-up. The patient has reported a decease in ankle joint pain, increased range of motion, and a return to normal daily activity without limitation. PMID- 22920920 TI - Coronenediimides synthesized via ICl-induced cyclization of diethynyl perylenediimides. AB - Treating diethynyl-substituted perylenediimides with ICl successfully induced an annulation reaction and generated a series of coronenediimide derivatives. Instead of the expected iodine-substituted cyclization product, chlorine substituted analogues were produced. The mechanism of this annulation reaction thus necessarily involved a chlorine addition step prior to the aromatic substitution reaction. With facile subsequent transformations, various tetraaryl coronenediimides could be obtained via the annulated chloro-substituted coronenediimide. PMID- 22920921 TI - The battle against ALK resistance: successes and setbacks. AB - Chromosomal translocations and single point mutations involving the Anaplastic Lymphoma Kinase (ALK) gene have been described in several human tumors, including anaplastic large cell lymphoma (ALCL), non-small cell lung cancer (NCSLC), inflammatory myofibroblastic tumor (IMT) and neuroblastoma. Cancer cells are "addicted" to ALK constitutive activation and are highly sensitive to the treatment with small-molecule inhibitors. Crizotinib, an oral ALK inhibitor, has proved to provide dramatic clinical benefit in patients with NSCLC harboring ALK rearrangements. Nonetheless, acquired drug resistance inevitably develops and leads to tumor progression and relapse. Different mechanisms of crizotinib acquired drug resistance, resembling those reported for other tyrosine kinase targeted therapies, have been recently reported both in cell lines and in patients. Thus, the identification of the molecular mechanisms of crizotinib resistance will be strictly required in order to pursue the appropriate therapeutic options for patients with ALK-rearranged tumors. PMID- 22920922 TI - Well-defined vanadium organoazide complexes and their conversion to terminal vanadium imides: structural snapshots and evidence for a nitrene capture mechanism. AB - We report the synthesis and structural characterization of a family of well defined organoazide complexes supported by a three-fold-symmetric pyrrolide scaffold and their conversion to the corresponding terminal imido congeners. Kinetic measurements on a series of structurally homologous but electronically distinct vanadium organoazide complexes reveal that the azido-to-imido transformations proceed via a process that is first-order in the metal complex and has a positive entropy of activation. Further studies suggest that these reactions may involve metal-mediated generation and capture of nitrene fragments. PMID- 22920923 TI - Performing discovery-driven neonatal research by transcriptomic analysis of routinely discarded biofluids. AB - OBJECTIVE: To perform discovery-driven research on the neonatal salivary and cord blood transcriptomes. METHODS: Two separate cohorts of infants were enrolled in this study. In one, cord blood (n = 10) and in the other, saliva samples (n = 10) were collected at term gestation. Total RNA was extracted, amplified and hybridized onto Affymetrix HG U133a gene expression microarrays. Following normalization, genes expressed in the highest quintile (>= 80%) across all subjects in each biofluid were analyzed with Ingenuity Pathway Analysis. Over represented pathways relating to organ specific development and physiological functions in the newborn were explored. RESULTS: There were 303 genes in neonatal saliva and 282 genes in umbilical cord blood that met statistical criteria. Of these, 114 were common to both biofluids. Pathway analyses revealed the important roles of redox balance, cellular proliferation, and smooth muscle relaxation. In blood, hematopoiesis and immune response pathways predominated. In saliva, pathways associated with the gastrointestinal system were highlighted. CONCLUSIONS: Neonatal cord blood and saliva provide a wealth of transcriptomic information. These normally discarded biofluids should be considered an important source of real-time gene expression data that may elucidate key pathways in neonatal physiology and pathology. PMID- 22920925 TI - BODIPY-labeled DC-SIGN-targeting glycodendrons efficiently internalize and route to lysosomes in human dendritic cells. AB - Glycodendrons bearing nine copies of mannoses or fucoses have been prepared by an efficient convergent strategy based on Cu(I) catalyzed azide-alkyne cycloaddition (CuAAC). These glycodendrons present a well-defined structure and have an adequate size and shape to interact efficiently with the C-type lectin DC-SIGN. We have selected a BODIPY derivative to label these glycodendrons due to its interesting physical and chemical properties as chromophore. These BODIPY-labeled glycodendrons were internalized into dendritic cells by mean of DC-SIGN. The internalized mannosylated and fucosylated dendrons are colocalized with LAMP1, which suggests routing to lysosomes. The interaction of these glycodendrons with DC-SIGN at the surface of dendritic cells did not induce maturation of the cells. Signaling analysis by checking different cytokines indicated also the lack of induction the expression of inflammatory and noninflammatory cytokines by these second generation glycodendrons. PMID- 22920924 TI - Exploring the genetic control of glycolytic oscillations in Saccharomyces cerevisiae. AB - BACKGROUND: A well known example of oscillatory phenomena is the transient oscillations of glycolytic intermediates in Saccharomyces cerevisiae, their regulation being predominantly investigated by mathematical modeling. To our knowledge there has not been a genetic approach to elucidate the regulatory role of the different enzymes of the glycolytic pathway. RESULTS: We report that the laboratory strain BY4743 could also be used to investigate this oscillatory phenomenon, which traditionally has been studied using S. cerevisiae X2180. This has enabled us to employ existing isogenic deletion mutants and dissect the roles of isoforms, or subunits of key glycolytic enzymes in glycolytic oscillations. We demonstrate that deletion of TDH3 but not TDH2 and TDH1 (encoding glyceraldehyde 3-phosphate dehydrogenase: GAPDH) abolishes NADH oscillations. While deletion of each of the hexokinase (HK) encoding genes (HXK1 and HXK2) leads to oscillations that are longer lasting with lower amplitude, the effect of HXK2 deletion on the duration of the oscillations is stronger than that of HXK1. Most importantly our results show that the presence of beta (Pfk2) but not that of alpha subunits (Pfk1) of the hetero-octameric enzyme phosphofructokinase (PFK) is necessary to achieve these oscillations. Furthermore, we report that the cAMP-mediated PKA pathway (via some of its components responsible for feedback down-regulation) modulates the activity of glycoytic enzymes thus affecting oscillations. Deletion of both PDE2 (encoding a high affinity cAMP-phosphodiesterase) and IRA2 (encoding a GTPase activating protein- Ras-GAP, responsible for inactivating Ras-GTP) abolished glycolytic oscillations. CONCLUSIONS: The genetic approach to characterising the glycolytic oscillations in yeast has demonstrated differential roles of the two types of subunits of PFK, and the isoforms of GAPDH and HK. Furthermore, it has shown that PDE2 and IRA2, encoding components of the cAMP pathway responsible for negative feedback regulation of PKA, are required for glycolytic oscillations, suggesting an enticing link between these cAMP pathway components and the glycolysis pathway enzymes shown to have the greatest role in glycolytic oscillation. This study suggests that a systematic genetic approach combined with mathematical modelling can advance the study of oscillatory phenomena. PMID- 22920926 TI - Structure and reactivity of homocysteine radical cation in the gas phase studied by ion-molecule reactions and infrared multiple photon dissociation. AB - The reactivity of the cysteine (Cys) and homocysteine (Hcy) radical cation was studied using ion-molecule reactions. The radical cations were generated via collision-induced dissociation (CID) of their S-nitrosylated precursors. Cleavage of the S-NO bond led to the formation of the radical initially positioned on the sulfur atom. The reactions of the radical cations with dimethyl disulfide revealed that the cysteine radical cation reacts more quickly than the homocysteine radical cation. Infrared multiple photon dissociation (IRMPD) spectroscopy and density functional theory (DFT) calculations were used to determine the structure of the homocysteine radical cation, which was compared to the previously published structure of the cysteine radical cation (Sinha et al. Phys. Chem. Chem. Phys. 2010, 12, 9794-9800). IRMPD spectroscopy and DFT calculations revealed that this difference in radical reactivity was not a result of a radical rearrangement for the homocysteine radical cation but rather that the reactivity was modulated by stronger hydrogen bonding. PMID- 22920927 TI - Application of the Seattle heart failure model in patients >80 years of age enrolled in a tertiary care heart failure clinic. AB - The Seattle Heart Failure Model (SHFM) is 1 of the most widely used tools to predict survival in patients with heart failure. However, it does not accommodate very elderly patients. We decided to assess the applicability of the SHFM in patients >80 years old enrolled in a tertiary care heart failure clinic. We evaluated the difference between observed survival and mean life expectancy as predicted by the SHFM on 261 patients >80 years old enrolled in a heart failure clinic at the Jewish General Hospital, Montreal, Quebec, Canada from January 2002 through March 2010. Average age of the patient population was 85 +/- 4 years (range 80 to 105). Sixty-two percent of the population consisted of men, 63% had ischemic cardiomyopathy (ICM), and average ejection fraction was 36 +/- 18%. Median observed survival was 1.91 years (interquartile range 0.68 to 5.53) for the total population (n = 261). The SHFM (predicted median survival 6.7 years, interquartile range 3.8 to 11.2) overestimated life expectancy by an average of 4.79 years. For patients with ICM (n = 164) versus non-ICM (n = 97), the score overestimated survival by 4.29 versus 5.69 years, respectively. In conclusion, the SHFM overestimates life expectancy in elderly patients followed in a tertiary care heart failure clinic. Further studies are needed to more accurately estimate prognosis in this patient population. PMID- 22920928 TI - Relative prognostic value of baseline Q wave and time from symptom onset among men and women with ST-elevation myocardial infarction undergoing percutaneous coronary intervention. AB - Q waves have been shown to be a stronger prognostic marker than time from symptom onset to percutaneous coronary intervention (PCI) in ST-segment elevation myocardial infarction. We examined whether the relative importance of these 2 measurements is modulated by patient gender. Q waves in the area of ST-segment elevation on baseline electrocardiogram were evaluated at a central core laboratory in 4,530 patients with ST-segment elevation myocardial infarction (3,468 men and 1,062 women) without previous infarction and who underwent PCI in the Assessment of Pexelizumab in Acute Myocardial Infarction (APEX-AMI) trial. Women were older and had higher rates of diabetes, hypertension, Killip class >I, and lower creatinine clearance compared to men. Time from symptom onset to PCI >3 hours was associated with a trend toward worse 90-day mortality (adjusted hazard ratio 1.5, 95% confidence interval 0.9 to 2.2) in men but not in women (0.8, 0.5 to 1.4). In contrast, presence of Q waves on baseline electrocardiogram was associated with significantly higher 90-day mortality in men (adjusted hazard ratio 1.7, 95% confidence interval 1.0 to 2.7) and women (2.3, 1.2 to 4.2). In conclusion, in this gender-specific analysis, baseline Q wave was found be a better marker of risk of 90-day mortality than time from symptom onset to PCI, overall, and especially in women. PMID- 22920929 TI - Wenckebach periodicity at rest that normalizes with tachycardia in a family with a NKX2.5 mutation. AB - A family with asymptomatic Wenckebach atrioventricular block (Wenckebach periodicity [WP]) has been followed at the investigators' institution for >4 decades. In contrast to all reported cases of WP (except in top-ranking athletes) family members have WP at rest that promptly converts to regular sinus tachycardia with exercise. They also have mild apical noncompaction that has been quite stable. Because of apparent autosomal dominant inheritance of the structural and arrhythmia disorders, deoxyribonucleic acid was obtained from 4 affected family members in 2 generations for sequence analysis of the cardiac transcription factor gene NKX2.5. A novel frame-shift mutation (c.959delC) was identified that would result in premature truncation of the protein at residue 293, with loss of the C-terminal 31 amino acids. The responsiveness of WP to exercise, the long-term stability of the WP rhythm, and the mild asymptomatic structural features expand the phenotypic presentation of diseases related to mutations in NKX2.5. In addition, the physiology of WP is reviewed in these subjects and in highly conditioned athletes. In conclusion, the investigators report familial stable WP and ventricular noncompaction caused by a mutation in NKX2.5. PMID- 22920931 TI - Evaluation of serological markers to monitor the disease status of Indian post kala-azar dermal leishmaniasis. AB - Post kala-azar dermal leishmaniasis (PKDL), a dermal sequel of visceral leishmaniasis presents with macular or polymorphic lesions. As immunological variations between these two forms have not been delineated, we evaluated levels of antileishmanial total Ig, IgG and its subclasses, IgM, IgE, IgG avidity, cytokines IL-10, IL-4, IL-13 and expression of CD19. The levels of Ig and IgG in polymorphic PKDL were higher than macular PKDL, while significant curtailment in levels of Ig, IgM and IgG following treatment was evident only in polymorphic PKDL. With regard to IgG subclasses, IgG1 and IgG3 were significantly raised in polymorphic PKDL, whereas in macular PKDL only IgG1 was elevated; treatment decreased levels of IgG1, IgG2 and IgG3 only in polymorphic PKDL; IgE levels were raised in both groups but no marked alterations occurred following treatment. The avidity of IgG was higher in polymorphic PKDL and correlated with duration of disease. IL-10 was higher in polymorphic PKDL and decreased significantly after treatment, whereas in macular PKDL IL-4 predominated. Taken together, in PKDL the humoral immune response was greater in the polymorphic variant than the macular form suggesting that serological markers may have a role in monitoring polymorphic PKDL. PMID- 22920933 TI - Blood donations motivators and barriers: a descriptive study of African American and white voters. AB - African American adults are half as likely to donate blood than whites. In order to understand this difference, African American and white participants completed a survey regarding demographics, medical and donation history, and motivators and barriers. The most agreed upon motivators to blood donation were more convenient place and times, being asked and taking less than hour. Motivator responses which differed by race included donating for infectious disease test and reward, and assurance donating is safe. The most agreed upon barriers were not having a convenient place, not knowing where (response differed by race) and fear of needles, pain and feeling faint. PMID- 22920932 TI - Tea consumption and risk of bladder cancer: a meta-analysis. AB - BACKGROUND: Tea consumption has been reported to be associated with an decreased risk of several types of cancers. However, the results based on epidemiological studies on the association of tea consumption with bladder cancer were inconsistent. This meta-analysis was undertaken to evaluate the relationship between tea consumption and bladder cancer risk. METHODS: Eligible studies were retrieved via both computer searches and review of references. The summary relative risk (RR) with 95% confidence interval (CI) was calculated. RESULTS: Twenty three studies met the inclusion criteria of the meta-analysis. No association with bladder cancer was observed in either overall tea consumption group (OR =0.94, 95% CI 0.85-1.04) or subgroups stratified by sex, study design, geographical region or tea types. CONCLUSIONS: Our findings did not support that tea consumption was related to the decreased risk of bladder cancer. PMID- 22920935 TI - Marine downscaling of a future climate scenario in the North Sea and possible effects on dinoflagellate harmful algal blooms. AB - Two hydrodynamic and ecological models were used to investigate the effects of climate change-according to the IPCC A1b emission scenario - on the primary productivity of the North Sea and on harmful algal blooms. Both models were forced with atmospheric fields from a regional downscaling of General Circulation Models to compare two sets of 20-year simulations representative of present climate (1984-2004) conditions and of the 2040s. Both models indicated a general warming of the North Sea by up to 0.8 degrees C and a slight freshening by the 2040s. The models suggested that the eastern North Sea would be subjected to more temperature and salinity changes than the western part. In addition, the ecological modules of the models indicated that the warming up of the sea would result in a slightly earlier spring bloom. The one model that also computes the distribution of four different phytoplankton groups suggests an increase in the abundance of dinoflagellates, whereas the abundance of diatoms, flagellates and Phaeocystis sp. remains comparable to current levels, or decrease. Assuming that Dinophysis spp. would experience a similar increase in abundance as the modelled group of dinoflagellates, it is hypothesised that blooms of Dinophysis spp. may occur more frequently in the North Sea by 2040. However, implications for shellfish toxicity remain unclear. PMID- 22920936 TI - Changes in work situation and work ability in young female and male workers. A prospective cohort study. AB - BACKGROUND: Good work ability is very important in young workers, but knowledge of work situations that influence work ability in this group is poor. The aim of this study was to assess whether changes in self-reported work factors are associated with self-reported work ability among young female and male workers. METHODS: A sample of 1,311 (718 women and 593 men) was selected from a Swedish cohort of workers aged 21-25 years. At baseline and at 1-year follow-up, participants completed a self-administrated questionnaire including ratings of physical and psychosocial work factors and current work ability. Prevalence ratios were calculated to assess univariate and multivariate associations between changes in work factors and changes in work ability. RESULTS: Decreased job control (PR 1.7, 95% CI 1.49-2.12) and increased negative influence of job demands on private life (PR 1.5, 95% CI 1.25-1.69) were associated with reduced work ability for both female and male workers in the multivariate analyses. Among female workers, an association was found between improved work ability and increased social support at work (PR 2.4, CI 1.43-3.95). For male workers, increased job control (PR 2.3, 95% CI 1.21-4.54) and decreased negative influence of job demands on private life (PR 2.1, 95% CI 1.10-3.87) were associated with improved work ability in the multivariate analyses. CONCLUSIONS: Decreased job control and increased negative influence of job demands on private life over time seem to be the most important work factors associated with reduced work ability among young workers of both sexes. Increased social support at work, increased job control, and decreased negative influence of job demands on private life were also found to be the main work factors associated with improved work ability, although with possible gender differences. PMID- 22920937 TI - Emergence of bimodal cell population responses from the interplay between analog single-cell signaling and protein expression noise. AB - BACKGROUND: Cell-to-cell variability in protein expression can be large, and its propagation through signaling networks affects biological outcomes. Here, we apply deterministic and probabilistic models and biochemical measurements to study how network topologies and cell-to-cell protein abundance variations interact to shape signaling responses. RESULTS: We observe bimodal distributions of extracellular signal-regulated kinase (ERK) responses to epidermal growth factor (EGF) stimulation, which are generally thought to indicate bistable or ultrasensitive signaling behavior in single cells. Surprisingly, we find that a simple MAPK/ERK-cascade model with negative feedback that displays graded, analog ERK responses at a single cell level can explain the experimentally observed bimodality at the cell population level. Model analysis suggests that a conversion of graded input-output responses in single cells to digital responses at the population level is caused by a broad distribution of ERK pathway activation thresholds brought about by cell-to-cell variability in protein expression. CONCLUSIONS: Our results show that bimodal signaling response distributions do not necessarily imply digital (ultrasensitive or bistable) single cell signaling, and the interplay between protein expression noise and network topologies can bring about digital population responses from analog single cell dose responses. Thus, cells can retain the benefits of robustness arising from negative feedback, while simultaneously generating population-level on/off responses that are thought to be critical for regulating cell fate decisions. PMID- 22920939 TI - Divalent N(I) character in 2-(thiazol-2-yl)guanidine: an electronic structure analysis. AB - Several medicinally important compounds carry a 2-(thiazol-2-yl)guanidine unit. These species are generally (erroneously) represented as 1-(thiazol-2 yl)guanidine species. Quantum chemical studies were performed to identify the appropriate tautomeric state of this class of compounds. B3LYP/6-31+G(d) calculations indicate the preferred tautomeric state of these species is associated with the 2-(thiazol-2-yl)guanidine structure rather than the 1 (thiazol-2-yl)guanidine structure. G2MP2 calculations on the model system were carried out to study the electronic structure, electron delocalization, and protonation energy; MESP, ELF, HOMA, AIM, and NBO analyses were also carried out. The results indicate that this class of compounds may be treated as species with hidden ::N(<-L)R character. Upon protonation of the thiazole ring nitrogen, these systems show the electronic structure as in ::N(<-L)2(?) systems with divalent N(I) oxidation state. PMID- 22920938 TI - NVP-BEZ235 alone and in combination in mantle cell lymphoma: an effective therapeutic strategy. AB - OBJECTIVES: Mantle cell lymphoma (MCL) is a distinct subtype of B-cell lymphoma; the complete response rate for standard therapies in use today is 85 - 90%. NVP BEZ235 inhibits the PI3K/Akt/mTOR signaling axis at the level of both PI3K and mTOR. In this study, we analyzed the inhibitory effects of NVP-BEZ235 on mantle cell lines and its effects in combination with enzastaurin, everolimus and perifosine. METHODS: The effects of NVP-BEZ235 on cell proliferation and apoptosis were evaluated using MTT assay and flow cytometry analysis. The cell cycle analysis was performed applying BrdU incorporation. Western blot analysis was utilized for phosphorylation status evaluation of protein kinases. The interaction between NVP-BEZ235 and enzastaurin, everolimus and perifosine was examined by Chou-Talalay method. RESULTS: NVP-BEZ235 induced significant increase of apoptosis, both via intrinsic and extrinsic pathways. We found that NVP-BEZ235 inhibited mantle cells growth by induction of G1 arrest. NVP-BEZ235 exerts its antitumor activity even when mantle cells were in contact with bone marrow microenvironment. Enzastaurin, everolimus and perifosine enhanced the cytotoxicity triggered by NVP-BEZ235. CONCLUSIONS: The above results encourage clinical development of NVP-BEZ235 in combination and the possible inclusion of patients with mantle lymphoma in Phase I/II clinical trials. PMID- 22920940 TI - World Diabetes Day 2012--expanding the circle of influence. PMID- 22920941 TI - DNA extraction and molecular analysis of non-tumoral liver, spleen, and brain from autopsy samples: the effect of formalin fixation and paraffin embedding. AB - The use of molecular biology in combination with morphological analysis is increasing because of the treatments by target therapies. However, to improve the methods for obtaining DNA for molecular analyses from formalin-fixed, paraffin embedded (FFPE) tissue is a challenge. The aim of this study was to evaluate the DNA extracted from FFPE tissue blocks (non-tumoral liver, spleen, and brain), obtained from autopsy, 8-24 h post mortem, using three methods of DNA extraction. PCR of the beta-actin (136 pb) and human amelogenin (AMEL 212-218 bp/106-112 bp) genes, as well as short tandem repeat (STR) (100-400 bp fragments), reported in forensic scientific analysis, was performed to evaluate the effectiveness of the methods of DNA extraction. We used 28 archived (1 and 5 years) and 12 recent autopsy cases. The commercial kit showed reproducible and consistent results in the PCR amplification of the beta-actin and AMEL genes and in analysis by STR used in forensic analysis. This is the first report using non-tumoral samples from FFPE autopsy tissues, comparing the three most common methods of DNA extraction and using the STR previously described in forensics. Our study has clarified the challenges for pathologists in applying the molecular biology approach in combination with methods suited for morphology, which must be improved. The data provided here should be used in other molecular studies in FFPE samples. PMID- 22920942 TI - Does timing of surgery affect hospitalization costs and length of stay for acute care following a traumatic spinal cord injury? AB - Although there is a trend toward performing early surgery for traumatic spinal cord injury (SCI), it remains unclear whether this tendency leads to decreased costs and length of stay (LOS) for acute care. This study determined the impact of surgical timing on costs and LOS after a traumatic SCI. A total of 477 consecutive patients sustaining an acute traumatic SCI and receiving surgery at a level I trauma center were included. A general linear model was used to assess the relationship among costs, LOS, and surgical delay, while accounting for various sociodemographic and clinical covariables. The analysis was also repeated with surgical delay dichotomized within 24 h or later after the trauma. Mean costs and LOS for all patients were respectively 24,156 +/- 17,244 $CAD and 35.0 +/- 39.4 days. The costs of acute care hospitalization were related to the surgical delay between the trauma and the surgery, in addition to age, injury severity score (ISS), American Spinal Injury Association (ASIA) grade, and neurological level. LOS was associated with the surgical delay dichotomized into two groups (<24 vs. >=24 h), as well as with age, ISS, ASIA grade, and neurological level. This study suggests that resource utilization in terms of costs and LOS for the acute hospitalization is decreased with early surgery after an acute traumatic SCI, particularly if the procedure is performed within 24 h following the trauma. Performing the surgery as early as possible when the patient is cleared for surgery could lower the financial burden on the healthcare system, while optimizing the neurological recovery. PMID- 22920943 TI - Delay in taking the American Board of Surgery qualifying examination affects examination performance. AB - BACKGROUND: The American Board of Surgery (ABS) Qualifying Examination (QE) represents an important step along the pathway to board certification. We investigated whether candidates who delayed taking the QE had worse performance on the examination. METHODS: QE pass rates and equated scaled scores for all first-time examinees from 2006 to 2010 (n = 5,193) were reviewed. After eliminating examinees who could not be matched to final ABS In-Training Examination (ABSITE) scores, the remaining cohort (n = 4,909) was analyzed by comparing those who took the exam immediately after residency (Immediate, n = 4,488) to those who delayed for 1 or more years (Delay, n = 421). RESULTS: The Immediate group had a mean first-time QE pass rate of 87% compared to 57% for those who delayed 1 year and 48% for those who delayed 2 or more years (P < .001). Regression analysis demonstrated that delay in taking the QE remained a significant determinant of exam failure after controlling for ABSITE scores (odds ratio = 0.35; 95% CI, 0.29-0.43; P = .001). Undergraduate medical education and postresidency training did not affect the results. The Delay group had lower equated scaled scores, a greater ultimate failure rate on the QE, and was more likely to fail the ABS Certifying Examination on the first attempt. CONCLUSION: These results demonstrate that candidates who delayed taking the QE immediately are at extremely high risk for exam failure and failure to achieve board certification. These findings presumably are due to deterioration of knowledge over time, but they also may represent characteristics of the Delay group that are currently undefined. PMID- 22920944 TI - Compartment syndrome of the hand and rhabdomyolysis. PMID- 22920945 TI - Vitelline artery remnant causing intestinal obstruction in an adult. PMID- 22920946 TI - Copper levels in patients with hematological malignancies. AB - BACKGROUND: Copper levels are elevated in cancer patients compared to normal subjects. However, few studies have investigated the relationship between copper and hematological malignancies. METHODS: 84 patients with hematological diseases were studied, along with 50 healthy individuals. Copper was measured by flame atomic absorption spectrometry. The patients were classified to 2 homogeneous groups, acute and chronic hematological neoplasms, respectively. For the patients with acute hematological malignancies, relapse and remission were investigated in relation to serum copper levels. For chronic hematological neoplasms, serum copper was connected either with stable or progressive disease. Zeta-chain associated protein kinase 70 (ZAP70) and CD38 expression, along with the unmutated VH immunoglobulin genes (IgVH) status were also determined for the 22 chronic lymphocytic leukemia (CLL) patients. RESULTS: 54 patients with relapse or progressive disease had elevated copper levels (mean value 1.8 mg/l), whereas 30 patients either in remission or in stable disease had normal copper levels (mean value 1.01 mg/l) (normal range 0.8-1.3mg/l). CONCLUSION: Hence, our study indicates that serum elevated copper levels are associated with hematological malignancies either in relapse or in disease progression, whereas normal copper levels are linked with hematological neoplasms in remission or in stable disease. Furthermore, we report for the first time an association between high serum copper levels and several adverse prognostic markers in CLL, such as increased expression of ZAP70 and CD38, along with elevated percentage of unmutated IgVH. PMID- 22920948 TI - Synthesis and characterization of highly water-soluble dendrofulleropyrrolidine bisadducts with DNA binding activity. AB - The synthesis, characterization and DNA binding studies of a series of polycationic fullerene adducts are reported. These cationic species, exhibiting reasonably high water solubility and a heterogeneous distribution of positive charges, can efficiently complex plasmid DNA. Electrophoresis studies show different DNA binding efficiencies for different adducts, some of which can be considered excellent candidates for DNA binding therapies. PMID- 22920947 TI - H3K9 and H3K14 acetylation co-occur at many gene regulatory elements, while H3K14ac marks a subset of inactive inducible promoters in mouse embryonic stem cells. AB - BACKGROUND: Transcription regulation in pluripotent embryonic stem (ES) cells is a complex process that involves multitude of regulatory layers, one of which is post-translational modification of histones. Acetylation of specific lysine residues of histones plays a key role in regulating gene expression. RESULTS: Here we have investigated the genome-wide occurrence of two histone marks, acetylation of histone H3K9 and K14 (H3K9ac and H3K14ac), in mouse embryonic stem (mES) cells. Genome-wide H3K9ac and H3K14ac show very high correlation between each other as well as with other histone marks (such as H3K4me3) suggesting a coordinated regulation of active histone marks. Moreover, the levels of H3K9ac and H3K14ac directly correlate with the CpG content of the promoters attesting the importance of sequences underlying the specifically modified nucleosomes. Our data provide evidence that H3K9ac and H3K14ac are also present over the previously described bivalent promoters, along with H3K4me3 and H3K27me3. Furthermore, like H3K27ac, H3K9ac and H3K14ac can also differentiate active enhancers from inactive ones. Although, H3K9ac and H3K14ac, a hallmark of gene activation exhibit remarkable correlation over active and bivalent promoters as well as distal regulatory elements, a subset of inactive promoters is selectively enriched for H3K14ac. CONCLUSIONS: Our study suggests that chromatin modifications, such as H3K9ac and H3K14ac, are part of the active promoter state, are present over bivalent promoters and active enhancers and that the extent of H3K9 and H3K14 acetylation could be driven by cis regulatory elements such as CpG content at promoters. Our study also suggests that a subset of inactive promoters is selectively and specifically enriched for H3K14ac. This observation suggests that histone acetyl transferases (HATs) prime inactive genes by H3K14ac for stimuli dependent activation. In conclusion our study demonstrates a wider role for H3K9ac and H3K14ac in gene regulation than originally thought. PMID- 22920949 TI - One-year clinical outcome after primary stenting for Trans-Atlantic Inter-Society Consensus (TASC) C and D femoropopliteal lesions (the STELLA "STEnting Long de L'Artere femorale superficielle" cohort). AB - OBJECTIVE: The study aims to evaluate the safety and the efficacy of primary stenting for Trans-Atlantic Inter-Society Consensus Document II on Management of Peripheral Arterial Disease (TASC) C and D femoropopliteal lesions. DESIGN: Prospective cohort study. METHODS: Patients with TASC C and D de novo femoropopliteal lesions were treated with the same endovascular technique by implanting a primary nitinol self-expanding stent (LifeStent((r)), Bard Peripheral Vascular, Tempe, AZ, USA). Patients were included in a single-centre registry and prospectively followed up. The primary end point was primary sustained clinical improvement after 12 months. Secondary end points were secondary sustained clinical improvement, primary and secondary patency rates, freedom from target lesion revascularisation (TLR), freedom from target extremity revascularisation (TER) and stent fracture rate. RESULTS: We enrolled 58 patients (62 limbs) suffering from either claudication (40.3%) or critical limb ischaemia (59.7%). Lesions were either TASC C (62.9%) or TASC D (37.1%). Median length of the treated segment was 220 +/- 160 mm. The mean number of stents was 2.2. Mean follow-up was 17 months, with one patient lost to follow-up. At 1 year, the primary end point was 68.6% while secondary sustained clinical improvement was 82.6%. Freedom from TLR and TER rates were 81.1% and 96.3%. Primary and secondary patencies were 66% and 80.9%. One-year primary and secondary sustained clinical improvement rates were 76.7% +/- 7.2 for TASC C and 46.3% +/- 11.1 for TASC D (p = 0.03) and 87.6% +/- 5.9 for TASC C and 67.3% +/- 11.3 for TASC D (p = 0.09), respectively. The ankle-brachial pressure index increased from 0.58 to 0.94 (p = 0.001) at 1 year and the incidence of in-stent restenosis (ISR) was 19.3%. Stent fracture and disconnection rate was 17.7%. CONCLUSIONS: Primary stenting of TASC C and D lesions appears to be safe and efficient given the high-sustained clinical improvement and the low rate of ISR observed in our study. Endovascular treatment of such long and severe lesions exposes to high rate of stent fractures, which should not be a concern given their low clinical impact. PMID- 22920950 TI - Synthesis, characterization, and biocompatibility of biodegradable hyperbranched polyglycerols from acid-cleavable ketal group functionalized initiators. AB - Herein we report the synthesis of biodegradable hyperbranched polyglycerols (BHPGs) having acid-cleavable core structure by anionic ring-opening multibranching polymerization (ROMBP) of glycidol using initiators bearing dimethyl and cyclohexyl ketal groups. Five different multifunctional initiators carrying one to four ketal groups and two to four hydroxyl groups per molecule were synthesized. The hydroxyl carrying initiators containing one ketal group per molecule were synthesized from ethylene glycol. An alkyne-azide click reaction was used for synthesizing initiators containing multiple cyclohexyl ketal linkages and hydroxyl groups. The synthesized BHPGs exhibited monomodal molecular weight distributions and polydispersity in the range of 1.2 to 1.6, indicating the controlled nature of the polymerizations. The polymers were relatively stable at physiological pH but degraded at acidic pH values. The polymer degradation was dependent on the type of ketal structure present in the BHPG; polymers with cyclohexyl ketal groups degraded at much slower rates than those with dimethyl ketal groups at a given pH. Good control of polymer degradation was achieved under mild acidic conditions by changing the structure of ketal linkages. A precise control of the molecular weight of the degraded HPG was achieved by controlling the number of ketal groups within the core, as revealed from the gel permeation chromatography (GPC) analyses. The decrease in the polymer molecular weights upon degradation was correlated well with the number of ketal groups in their core structure. Our data support the suggestion that glycidol was polymerized uniformly from all hydroxyl groups of the initiators. BHPGs and their degradation products were highly biocompatible, as measured by blood coagulation, complement activation, platelet activation, and cell viability assays. The controlled degradation profiles of these polymers together with their excellent biocompatibility make them suitable for drug delivery and bioconjugation applications. PMID- 22920951 TI - Neoadjuvant versus adjuvant treatment: which one is better for resectable esophageal squamous cell carcinoma? AB - Esophageal cancer is the eighth most common cancer worldwide, and especially in some areas of China is the fourth most common cause of death and is of squamous cell carcinoma (SCC) histology in >90% of cases. Surgery alone was the mainstay of therapeutic intervention in the past, but high rates of local and systemic failure have prompted investigation into multidisciplinary management. In this review, we discuss the key issues raised by the recent availability of esophageal SCC treatment with the addition of chemotherapy, radiotherapy, and chemoradiotherapy to the surgical management of resectable disease and discuss how clinical trials and meta-analysis inform current clinical practice. None of the randomized trials that compared neoadjuvant radiotherapy or chemotherapy with surgery alone in esophageal SCC has demonstrated an increase in overall survival in those patients treated with neoadjuvant radiotherapy or chemotherapy. Neoadjuvant chemoradiotherapy has been accepted recently for esophageal cancer because such a regimen offers great opportunity for margin negative resection, improved loco-regional control and increased survival. The majority of the available evidence currently reveals that only selected locally advanced esophageal SCC are more likely to benefit from the adjuvant therapy. The focus of future trials should be on identification of the optimum regimen and should aim to minimize treatment toxicities and effect on quality of life, as well as attempt to identify and select those patients most likely to benefit from specific treatment options. PMID- 22920952 TI - Cross-protection is crucial for prophylactic HPV vaccination. PMID- 22920953 TI - Cross-protective efficacy of two human papillomavirus vaccines: a systematic review and meta-analysis. AB - BACKGROUND: The extent of cross-protection is a key element in the choice of human papillomavirus (HPV) vaccine to use in vaccination programmes. We compared the cross-protective efficacy of the bivalent vaccine (HPV 16 and 18; Cervarix, GlaxoSmithKline Biologicals, Rixensart, Belgium) and quadrivalent vaccine (HPV 6, 11, 16, and 18; Gardasil, Merck, Whitehouse Station, NJ, USA) against non-vaccine type HPVs. METHODS: We searched Medline and Embase databases, conference abstracts, and manufacturers' websites for randomised clinical trials assessing the efficacy of bivalent and quadrivalent vaccines against persistent infections (lasting >=6 months) and cervical intraepithelial neoplasia (CIN) associated with the non-vaccine type HPVs (types 31, 33, 45, 52, and 58). We included studies of participants who were HPV DNA negative before vaccination for all HPV types assessed. We assessed heterogeneity in vaccine efficacy estimates between trials with I(2) and chi(2) statistics. FINDINGS: We identified two clinical trials (Females United to Unilaterally Reduce Endo/Ectocervical Disease [FUTURE] I and II) of the quadrivalent vaccine and three (Papilloma Trial Against Cancer In Young Adults [PATRICIA], HPV007, and HPV-023) of the bivalent vaccine. Analysis of the most comparable populations (pooled FUTURE I/II data vs PATRICIA) suggested that cross-protective vaccine efficacy estimates against infections and lesions associated with HPV 31, 33, and 45 were usually higher for the bivalent vaccine than the quadrivalent vaccine. Vaccine efficacy in the bivalent trial was higher than it was in the quadrivalent trial against persistent infections with HPV 31 (77.1% [95% CI 67.2 to 84.4] for bivalent vaccine vs 46.2% [15.3 to 66.4] for quadrivalent vaccine; p=0.003) and HPV 45 (79.0% [61.3 to 89.4] vs 7.8% [ 67.0 to 49.3]; p=0.0003), and against CIN grade 2 or worse associated with HPV 33 (82.3% [53.4 to 94.7] vs 24.0% [-71.2 to 67.2]; p=0.02) and HPV 45 (100% [41.7 to 100] vs -51.9% [-1717.8 to 82.6]; p=0.04). We noted substantial heterogeneity between vaccine efficacy in bivalent trials against persistent infections with HPV 31 (I(2)=69%, p=0.04) and HPV 45 (I(2)=70%, p=0.04), with apparent reductions in cross-protective efficacy with increased follow-up. INTERPRETATION: The bivalent vaccine seems more efficacious against non-vaccine HPV types 31, 33, and 45 than the quadrivalent vaccine, but the differences were not all significant and might be attributable to differences in trial design. Efficacy against persistent infections with types 31 and 45 seemed to decrease in bivalent trials with increased follow-up, suggesting a waning of cross-protection; more data are needed to establish duration of cross-protection. FUNDING: Public Health Agency of Canada. PMID- 22920954 TI - Parasite-based malaria diagnosis: are health systems in Uganda equipped enough to implement the policy? AB - BACKGROUND: Malaria case management is a key strategy for malaria control. Effective coverage of parasite-based malaria diagnosis (PMD) remains limited in malaria endemic countries. This study assessed the health system's capacity to absorb PMD at primary health care facilities in Uganda. METHODS: In a cross sectional survey, using multi-stage cluster sampling, lower level health facilities (LLHF) in 11 districts in Uganda were assessed for 1) tools, 2) skills, 3) staff and infrastructure, and 4) structures, systems and roles necessary for the implementing of PMD. RESULTS: Tools for PMD (microscopy and/or RDTs) were available at 30 (24%) of the 125 LLHF. All LLHF had patient registers and 15% had functional in-patient facilities. Three months' long stock-out periods were reported for oral and parenteral quinine at 39% and 47% of LLHF respectively. Out of 131 health workers interviewed, 86 (66%) were nursing assistants; 56 (43%) had received on-job training on malaria case management and 47 (36%) had adequate knowledge in malaria case management. Overall, only 18% (131/730) Ministry of Health approved staff positions were filled by qualified personnel and 12% were recruited or transferred within six months preceding the survey. Of 186 patients that received referrals from LLHF, 130(70%) had received pre-referral anti-malarial drugs, none received pre-referral rectal artesunate and 35% had been referred due to poor response to antimalarial drugs. CONCLUSION: Primary health care facilities had inadequate human and infrastructural capacity to effectively implement universal parasite-based malaria diagnosis. The priority capacity building needs identified were: 1) recruitment and retention of qualified staff, 2) comprehensive training of health workers in fever management, 3) malaria diagnosis quality control systems and 4) strengthening of supply chain, stock management and referral systems. PMID- 22920956 TI - The role of decompressive craniectomy in cerebral venous sinus thrombosis. AB - OBJECT: Studies on the role of decompressive craniectomy for cerebral venous sinus thrombosis (CVST) in the literature are scanty. Randomized trials face a lot of drawbacks, including ethical issues. In this article the authors discuss their experience with this procedure for CVST and review the available literature. METHODS: This study was a retrospective analysis of all patients who underwent decompressive craniectomy for CVST between August 2006 and June 2008 at the National Institute of Mental Health and Neurosciences. The cases were evaluated for demographic and clinicoradiological features, operative findings, and outcome of surgery. Ethical clearance was obtained from the institutional ethics committee. The data for each patient were obtained from the database of the department. Follow-up data were obtained either through direct clinical evaluation or mailed self-report questionnaire. The Glasgow Outcome Scale (GOS) and the Rankin Disability Scale were used to assess the outcome. RESULTS: A total of 34 patients (13 men and 21 women) were included; their mean age was 31.6 years, with a range from 18 to 65 years. In univariate analysis, the Glasgow Coma Scale (GCS) score prior to surgery and that in the immediate postoperative period had a statistically significant correlation with poor outcome. The GCS score immediately postoperatively was the only independent, significant predictor of poor outcome on multivariate analysis. CONCLUSIONS: Decompressive craniectomy in a selected cohort of patients had a good outcome in a majority of the patients: 26 of 34 in this study had a GOS score of 4 or 5. In this series, which is the largest in the available literature, the authors review their experience and recommend usage of this procedure in selected patients. PMID- 22920955 TI - The role of radiotherapy following gross-total resection of atypical meningiomas. AB - OBJECT: Atypical (WHO Grade II) meningiomas comprise a heterogeneous group of tumors, with histopathology delineated under the guidance of the WHO and a spectrum of clinical outcomes. The role of postoperative radiotherapy for patients with atypical meningiomas who have undergone gross-total resection (GTR) remains unclear. In this paper, the authors sought to clarify this role by reviewing their experience over the past 2 decades. METHODS: The authors retrospectively analyzed all patients at their institution who underwent GTR between 1992 and 2011 with a final histology demonstrating atypical meningioma. Information regarding patients, tumor characteristics, and postoperative adjuvant therapy was gleaned from medical records. Time to recurrence and overall survival were analyzed using univariate, multivariate, and Kaplan-Meier survival analyses. RESULTS: Forty-five patients who met the inclusion criteria underwent GTR for atypical meningiomas. By a median follow-up of 44.1 months, 22% of atypical meningiomas had recurred. There was no recurrence in 12 (92%) of 13 patients who received postoperative radiotherapy or in 19 (59%) of 32 patients who did not undergo postoperative radiotherapy (p = 0.085), demonstrating a strong trend toward improved local control with postoperative radiotherapy. No other factors were significantly associated with recurrence in univariate or multivariate analyses. CONCLUSIONS: This retrospective series supports the observation that postoperative radiotherapy likely results in lower recurrence rates of gross totally resected atypical meningiomas. Although a multicenter prospective trial will ultimately be needed to fully define the role of radiotherapy in managing gross totally resected atypical meningiomas, the authors' results contribute to a growing number of series that support routine postoperative radiotherapy as an adjuvant treatment for these lesions. PMID- 22920957 TI - The deleterious effects of methamphetamine use on initial presentation and clinical outcomes in aneurysmal subarachnoid hemorrhage. AB - OBJECT: The objective of this study was to retrospectively look at methamphetamine (MA) use in patients with aneurysmal subarachnoid hemorrhage (SAH) to determine if MA use affects clinical presentation and outcomes after aneurysmal SAH. METHODS: A retrospective review of patients admitted to the Oregon Health & Science University neurosurgical service with aneurysmal SAH during the past 6 years was undertaken. Variables analyzed included MA use, age, sex, cigarette use, Hunt and Hess grade, Fisher grade, admission blood pressure, aneurysm characteristics, occurrence of vasospasm, hospital length of stay (LOS), cerebral infarction, aneurysm treatment, and Glasgow Outcome Scale (GOS) score. Data differences between MA users and nonusers were statistically analyzed using multivariate logistic regression analysis. A separate comparison with randomly selected age-matched nonuser controls was also performed. RESULTS: Twenty-eight (7%) of 374 patients with aneurysmal SAH were identified as MA users. Methamphetamine users were younger than nonusers (45.2 vs 55.9 years, respectively; p <0.001). Despite a younger age, MA users had significantly higher Hunt and Hess grades than nonusers (3.0 vs 2.5, respectively; p <0.020) and age matched controls (3.0 vs 2.0, respectively; p <0.001). Earliest available mean arterial pressure was significantly higher in MA users (122.1 vs 109.7, respectively; p = 0.005) than all nonusers but not age-matched controls. Methamphetamine users had significantly higher vasospasm rates than nonusers (92.9% vs 71.1%, respectively; p = 0.008) but similar rates as age-matched controls (92.9% vs 89.3%, respectively; p = 0.500). Glasgow Outcome Scale score did not differ significantly between users and nonusers (3 vs 4, respectively; p = 0.170), but users had significantly lower GOS scores than age-matched controls (3 vs 5, respectively; p <0.001). There was no statistically significant difference in the LOS between users and nonusers (18 days vs 16 days, respectively; p = 0.431) or users and age-matched controls (18 days vs 14 days, respectively; p = 0.250). In the multivariate analysis, MA use (OR 3.777, p = 0.018), age (p <0.001), Fisher grade (p = 0.011), Hunt and Hess grade (p <0.001), and cerebral infarction (p <0.001) were predictors of poor GOS score. The only predictor of vasospasm was age (p <0.001), although a strong predictive trend in MA use (p = 0.149) was found. Predictors of a hospital LOS >15 days included age (p = 0.002), Fisher grade (p = 0.002), Hunt and Hess grade (p <0.001), and cerebral infarction (p <0.001). Predictors of cerebral infarction include male sex (p = 0.022) and Hunt and Hess grade (p = 0.006), with vasospasm demonstrating a strong trend (p = 0.056). CONCLUSIONS: A history of MA use may predict poorer outcomes in patients who present with aneurysmal SAH. Methamphetamine users have significantly worse presentations and outcomes when compared with age-matched controls. PMID- 22920958 TI - Editorial: I am become misery, the spoiler of lives? I think not. PMID- 22920959 TI - Editorial: radiosurgery and atypical meningiomas. PMID- 22920960 TI - Distinctive flow pattern of wall shear stress and oscillatory shear index: similarity and dissimilarity in ruptured and unruptured cerebral aneurysm blebs. AB - OBJECT: The difference in the hemodynamics of wall shear stress (WSS) and oscillatory shear index (OSI) between ruptured and unruptured aneurysms is not well understood. The authors investigated the hemodynamic similarities and dissimilarities in ruptured and thin-walled unruptured aneurysm blebs. METHODS: Magnetic resonance imaging-based fluid dynamics analysis was used to calculate WSS and OSI, and hemodynamic and intraoperative findings were compared. The authors also compared ruptured and unruptured thin-walled blebs for the magnitude of WSS and OSI. RESULTS: Intraoperatively, 13 ruptured and 139 thin-walled unruptured aneurysm blebs were identified. Twelve of the ruptured (92.3%) and 124 of the unruptured blebs (89.2%) manifested low WSS and high OSI. The degree of WSS was significantly lower in ruptured (0.49 +/- 0.12 Pa) than in unruptured (0.64 +/- 0.15 Pa; p < 0.01) blebs. CONCLUSIONS: Ruptured and unruptured blebs shared a distinctive pattern of low WSS and high OSI. The degree of WSS at the rupture site was significantly lower than in the unruptured thin-walled blebs. PMID- 22920961 TI - Editorial: venous thrombosis. PMID- 22920962 TI - Decompressive hemicraniectomy for malignant middle cerebral artery territory infarction: is life worth living? AB - OBJECT: Although decompressive hemicraniectomy has been shown to reduce death and improve functional outcome following malignant middle cerebral artery territory infarction, there is ongoing debate as to whether surgery should be routinely performed, considering the very high rates of disability and functional dependence in survivors. Through a systematic review of the literature, the authors sought to determine the outcome from a patient's perspective. METHODS: In September 2010, a MEDLINE search of the English-language literature was performed using various combinations of 12 key words. A total of 16 papers were reviewed and individual study data were extracted. RESULTS: There was significant variability in study design, patient eligibility criteria, timing of surgery, and methods of outcome assessment. There were 382 patients (59% male, 41% female) with a mean age of 50 years, 25% with dominant-hemisphere infarction. The mortality rate was 24% and the mean follow-up in survivors was 19 months (range 3 114 months). Of 156 survivors with available modified Rankin Scale (mRS) scores, 41% had favorable functional outcome (mRS Score <= 3), whereas 47% had moderately severe disability (mRS Score 4). Among 157 survivors with quality of life assessment, the mean overall reduction was 45%: 67% for physical aspect and 37% for psychosocial aspect. Of 114 screened survivors, depression affected 56% and was moderate or severe in 25%. Most patients and/or caregivers (77% of the 209 interviewed) were satisfied and would give consent again for the procedure. CONCLUSIONS: Despite high rates of physical disability and depression, the vast majority of patients are satisfied with life and do not regret having undergone surgery. PMID- 22920963 TI - Prognosis of patients with multifocal glioblastoma: a case-control study. AB - OBJECT: The prognosis of patients with glioblastoma who present with multifocal disease is not well documented. The objective of this study was to determine whether multifocal disease on initial presentation is associated with worse survival. METHODS: The authors retrospectively reviewed records of 368 patients with newly diagnosed glioblastoma and identified 47 patients with multifocal tumors. Each patient with a multifocal tumor was then matched with a patient with a solitary glioblastoma on the basis of age, Karnofsky Performance Scale (KPS) score, and extent of resection, using a propensity score matching methodology. Radiation and temozolomide treatments were also well matched between the 2 cohorts. Kaplan-Meier estimates and log-rank tests were used to compare patient survival. RESULTS: The incidence of multifocal tumors was 12.8% (47/368). The median age of patients with multifocal tumors was 61 years, 76.6% had KPS scores >= 70, and 87.2% underwent either a biopsy or partial resection of their tumors. The 47 patients with multifocal tumors were almost perfectly matched on the basis of age (p = 0.97), extent of resection (p = 1.0), and KPS score (p = 0.80) compared with 47 patients with a solitary glioblastoma. Age (>65 years), partial resection or biopsy, and low KPS score (<70) were associated with worse median survival within the multifocal group. In the multifocal group, 19 patients experienced tumor progression on postradiation therapy MRI, compared with 11 patients (26.8%) with tumor progression in the unifocal group (p = 0.08). Patients with multifocal tumors experienced a significantly shorter median overall survival of 6 months (95% CI 4-10 months), compared with the 11-month median survival (95% CI 10-19 months) of the matched solitary glioblastoma group (p = 0.02, log-rank test). Two-year survival rates were 4.3% for patients with multifocal tumors and 29.0% for the unifocal cohort. Patients with newly diagnosed multifocal tumors were found to have an almost 2-fold increase in the hazard of death compared with patients with solitary glioblastoma (hazard ratio 1.8, 95% CI 1.1-3.1; p = 0.02). Tumor samples were analyzed for expression of phosphorylated mitogen-activated protein kinase, phosphatase and tensin homolog, O(6)-methylguanine-DNA methyltransferase, laminin beta1 and beta2, as well as epidermal growth factor receptor amplification, and no significant differences in expression profile between the multifocal and solitary glioblastoma groups was found. CONCLUSIONS: Patients with newly diagnosed multifocal glioblastoma on presentation experience significantly worse survival than patients with solitary glioblastoma. Patients with multifocal tumors continue to pose a therapeutic challenge in the temozolomide era and magnify the challenges faced while treating patients with malignant gliomas. PMID- 22920964 TI - Interplay between vibrational energy transfer and excited state deactivation in DNA components. AB - Femtosecond laser spectroscopies are used to examine a thymine family of systems chosen to expose the interplay between excited state deactivation and two distinct vibrational energy transfer (VET) pathways: (i) VET from the base to the deoxyribose ring; (ii) VET between neighboring units in a dinucleotide. We find that relaxation in the ground electronic state accelerates markedly as the molecular sizes increase from the nucleobase to the dinucleotide. This behavior directly reflects growth in the density of vibrational quantum states on the substituent of the base. Excited state lifetimes are studied at temperatures ranging from 100 to 300 K to characterize the thermal fluctuations that connect the Franck-Condon geometries and the conical intersections leading back to the ground state. An Arrhenius analysis yields an approximate excited state energy barrier of 13 meV in the thymine dinucleotide. In addition, we find that the transfer of vibrational energy from the base to the substituent suppresses thermal fluctuations across this energy barrier. The possibility that the solvent viscosity imposes friction on the reaction coordinate is examined by comparing thymine and adenine systems. Experiments suggest that the solvent viscosity has little effect on barrier crossing dynamics in thymine because the conical intersection is accessed through relatively small out-of-plane atomic displacements. Overall, we conclude that the transfer of vibrational quanta from thymine to the deoxyribose ring couples significantly to the internal conversion rate, whereas the neighboring unit in the dinucleotide serves as a secondary heat bath. In natural DNA, it follows that (local) thermal fluctuations in the geometries of subunits involving the base and deoxyribose ring are most important to this subpicosecond relaxation process. PMID- 22920965 TI - Psychopathology before surgery in the longitudinal assessment of bariatric surgery-3 (LABS-3) psychosocial study. AB - BACKGROUND: Current and previous psychopathology in bariatric surgery candidates is believed to be common. Accurate prevalence estimates, however, are difficult to obtain given that bariatric surgery candidates often wish to appear psychiatrically healthy when undergoing psychiatric evaluation for approval for surgery. Also, structured diagnostic assessments have been infrequently used. METHODS: The present report concerned 199 patients enrolled in the longitudinal assessment of bariatric surgery study, who also participated in the longitudinal assessment of bariatric surgery-3 psychopathology substudy. The setting was 3 university hospitals, 1 private not-for-profit research institute, and 1 community hospital. All the patients were interviewed independently of the usual preoperative psychosocial evaluation process. The patients were explicitly informed that the data would not be shared with the surgical team unless certain high-risk behaviors, such as suicidality, that could lead to adverse perioperative outcomes were reported. RESULTS: Most of the patients were women (82.9%) and white (nonwhite 7.6%, Hispanic 5.0%). The median age was 46.0 years, and the median body mass index was 44.9 kg/m2. Of the 199 patients, 33.7% had >=1 current Axis I disorder, and 68.8% had >=1 lifetime Axis I disorder. Also, 38.7% had a lifetime history of a major depressive disorder, and 33.2% had a lifetime diagnosis of alcohol abuse or dependence. All these rates were much greater than the population-based prevalence rates obtained for this age group in the National Comorbidity Survey-Replication Study. Also, 13.1% had a lifetime diagnosis and 10.1% had a current diagnosis of a binge eating disorder. CONCLUSION: The current and lifetime rates of psychopathology are high in bariatric surgery candidates, and the lifetime rates of affective disorder and alcohol use disorders are particularly prominent. Finally, binge eating disorder is present in approximately 1 in 10 bariatric surgery candidates. PMID- 22920930 TI - Prasugrel versus clopidogrel for acute coronary syndromes without revascularization. AB - BACKGROUND: The effect of intensified platelet inhibition for patients with unstable angina or myocardial infarction without ST-segment elevation who do not undergo revascularization has not been delineated. METHODS: In this double-blind, randomized trial, in a primary analysis involving 7243 patients under the age of 75 years receiving aspirin, we evaluated up to 30 months of treatment with prasugrel (10 mg daily) versus clopidogrel (75 mg daily). In a secondary analysis involving 2083 patients 75 years of age or older, we evaluated 5 mg of prasugrel versus 75 mg of clopidogrel. RESULTS: At a median follow-up of 17 months, the primary end point of death from cardiovascular causes, myocardial infarction, or stroke among patients under the age of 75 years occurred in 13.9% of the prasugrel group and 16.0% of the clopidogrel group (hazard ratio in the prasugrel group, 0.91; 95% confidence interval [CI], 0.79 to 1.05; P=0.21). Similar results were observed in the overall population. The prespecified analysis of multiple recurrent ischemic events (all components of the primary end point) suggested a lower risk for prasugrel among patients under the age of 75 years (hazard ratio, 0.85; 95% CI, 0.72 to 1.00; P=0.04). Rates of severe and intracranial bleeding were similar in the two groups in all age groups. There was no significant between-group difference in the frequency of nonhemorrhagic serious adverse events, except for a higher frequency of heart failure in the clopidogrel group. CONCLUSIONS: Among patients with unstable angina or myocardial infarction without ST-segment elevation, prasugrel did not significantly reduce the frequency of the primary end point, as compared with clopidogrel, and similar risks of bleeding were observed. (Funded by Eli Lilly and Daiichi Sankyo; TRILOGY ACS ClinicalTrials.gov number, NCT00699998.). PMID- 22920967 TI - A simple gold plate electrode modified with Gd-doped TiO2 nanoparticles used for determination of trace nitrite in cured food. AB - A simple gold plate electrode (GPE) based on a gadolinium-doped titanium dioxide (Gd/TiO2) ultrathin film was successfully constructed by using a surface sol-gel technique, and used for the detection of trace amounts of nitrite in cured foods. The Gd/TiO2 nanoparticles were synthesised and characterised via scanning electron microscopy (SEM) and X-ray diffraction (XRD), indicating that the Gd doped TiO2 formed an anatase phase through roasting at 450 degrees C, generating actively interstitial oxygen at the interface of the surface of TiO2 lattice surrounded by Gd3+. The electro-catalytic effect for oxidation of nitrite on the modified electrode was investigated by cyclic voltammetry in 0.10 mol l-1 sulfuric acid media solution, showing that the modified electrode exhibited excellent response performance to nitrite with good reproducibility, selectivity and stability. The catalytic peak current was found to be linear with nitrite concentrations in the range of 8.0 * 10-7 to 4.0 * 10-4) mol l-1, with a detection limit of 5.0 * 10-7 mol l-1 (S/N = 3). The modified electrode could be used for the determination of nitrite in the cured sausage samples with a satisfactory recovery in the range of 95.5-104%, showing its promising application for food safety monitoring. PMID- 22920968 TI - Topological effects of data incompleteness of gene regulatory networks. AB - BACKGROUND: The topological analysis of biological networks has been a prolific topic in network science during the last decade. A persistent problem with this approach is the inherent uncertainty and noisy nature of the data. One of the cases in which this situation is more marked is that of transcriptional regulatory networks (TRNs) in bacteria. The datasets are incomplete because regulatory pathways associated to a relevant fraction of bacterial genes remain unknown. Furthermore, direction, strengths and signs of the links are sometimes unknown or simply overlooked. Finally, the experimental approaches to infer the regulations are highly heterogeneous, in a way that induces the appearance of systematic experimental-topological correlations. And yet, the quality of the available data increases constantly. RESULTS: In this work we capitalize on these advances to point out the influence of data (in)completeness and quality on some classical results on topological analysis of TRNs, specially regarding modularity at different levels. CONCLUSIONS: In doing so, we identify the most relevant factors affecting the validity of previous findings, highlighting important caveats to future prokaryotic TRNs topological analysis. PMID- 22920966 TI - Weight loss at first postoperative visit predicts long-term outcome of Roux-en-Y gastric bypass using Duke weight loss surgery chart. AB - BACKGROUND: Roux-en-Y gastric bypass has been used for >3 decades. However, no normative data are available to aid the bariatric surgeon in assessing the adequacy of weight loss at each postoperative visit. The objective of the present study was to construct nomograms to aid in the assessment of weight loss. The setting was a university hospital in the United States. METHODS: We used data prospectively collected from 1216 patients who had undergone Roux-en-Y gastric bypass at Duke University from April 2000 to September 2007. The percentage of excess weight loss (%EWL) was determined at each follow-up visit (1, 3, 6, 12, and 36 mo). The %EWL velocity was also determined using the postoperative data collected at the 1- and 3-month visits. Multivariate analysis was used to determine the predictive factors that influence the long-term results. RESULTS: At 12 months of follow-up, most patients, especially those in the first and fourth quartiles (P = .01), continued to be in the same weight loss quartile they had initially been in at 1 month postoperatively. The positive and negative predictive value for the first quartile %EWL at 1 month resulting in a first quartile %EWL at 12 months was 39% and 81%, respectively. Multivariate analysis indicated that gender, preoperative body mass index, %EWL at 1 month, and %EWL velocity were statistically significant predictors of the %EWL at 12 months postoperatively. CONCLUSION: We are the first group to determine that weight loss performance in the early period is a significant predictor of the long-term outcomes. The clinical utility of the weight loss chart is to identify underperformers early in the postoperative period to potentially improve their outcomes. PMID- 22920971 TI - Building practice-based evidence. PMID- 22920970 TI - Professional autobiography of Professor Leif Svanstrom - with a focus on injury prevention and safety promotion. AB - Professor Svanstrom has spent about forty-five years in the field of Social Medicine and Health and Safety Promotion. His main lines of research and teaching are Injury Epidemiology and Safety Promotion. In the 1960s, he conducted a number of descriptive and analytical studies, and in the 1970s began to address home and occupational injuries. In 1974, he introduced the community approach to safety promotion, encapsulated in the Falkoping Model, which has heavily influenced Swedish and international community safety work. Under his leadership of the Research Group on Injury Prevention and Safety Promotion at the Karolinska Institutet in Stockholm, Sweden, more than 30 doctorates have been awarded. His work as Head of the WHO Collaborating Centre on Community Safety Promotion has led to the establishment of Safe Communities worldwide. PMID- 22920972 TI - The taxon-specific paralogs of grapevine PRLIP genes are highly induced upon powdery mildew infection. AB - PRLIP (pathogenesis-related lipase) is a gene family encoding class 3 lipase-like proteins originally described and first characterized in Arabidopsis thaliana. Nine paralog genes of Arabidopsis can be separated into two groups based on expression characteristics and pathogen responses. Genes of Group 1 are clustered on chromosome 5 and show either high inducibility to different stress hormones and in response to pathogen attack or are undetectable at the transcript level. Group 2 contains the remaining genes, spread over the genome and are expressed constitutively in all the tissues tested. The aim of the present study was to determine the distribution of these two groups among plants, and to verify their differential expression. Orthologs of constitutively active members (Group 2) were found in all angiosperms, with available genome sequences. They are referred to as "core PRLIPs". In contrast, the gene cluster containing the pathogen inducible PRLIPs (Group 1) was unique for Arabidopsis. Among other angiosperms, grapevine also possesses such a unique genome-specific group of PRLIP genes. To investigate whether these genes are also counterparts in pathogen responses, their expression pattern was tested under stress conditions. Two of the specific Vitis PRLIPs were highly induced in response to both powdery mildew infection and benzothiadiazole (BTH) treatment. Core Vitis PRLIPs, however, were not responsive to either pathogen attack or the chemical inducer. Our data provide insights into the distribution of a pathogenesis-related gene family in different plant lineages, and might reveal common characteristics with other inducible defense related gene families. PMID- 22920973 TI - GFP-tagging of Arabidopsis acyl-activating enzymes raises the issue of peroxisome chloroplast import competition versus dual localization. AB - Protein sequence analysis of a subfamily of 18 Arabidopsis acyl-activating enzymes (AAE) for organelle targeting signals revealed that eight of them possessed putative peroxisomal targeting signals (PTS1), five of which belonged to Clade VI of the AAE superfamily. Peroxisomal localization was confirmed by confocal microscopy of green fluorescent protein (GFP)-AAE fusion proteins co localizing with peroxisomal RFP. The sequence analysis also revealed that all enzymes of Clade VI possess N-terminal regions indicative of chloroplast transit peptides (cTP). Among the five Clade VI peroxisomal enzymes tested, masking the PTS1 signal with GFP redirected three to plastids. In addition, three other peroxisomal AAEs appeared to be redirected to plastids in AAE-GFP fusion constructs. Due to the lack of evidence supporting plastid localization, we propose that competition dictates the exclusive localization to peroxisomes. AAE2 of Clade VI was the only enzyme with a putative mitochondrial targeting sequence, and it appeared to be targeted to mitochondria. The remainder of the AAEs appeared to be localized to plastids or cytosol. The AAE9-GFP fusion protein appeared to be located within discreet structures within plastids that may be plastoglobules. AAE15-GFP, but not AAE16-GFP appeared to be located in the chloroplast envelope. The number of examples is increasing whereby proteins located within other compartments contribute to plastid function. We provide an example of this through the light-sensitive phenotype of mutants of AAE2. PMID- 22920975 TI - The 28th Annual Dr. Charles T. Dotter Lecture: IR 360-the external and internal forces that shape our specialty. PMID- 22920974 TI - Predictors of high-grade esophagitis after definitive three-dimensional conformal therapy, intensity-modulated radiation therapy, or proton beam therapy for non small cell lung cancer. AB - INTRODUCTION: We analyzed the ability of various patient- and treatment-related factors to predict radiation-induced esophagitis (RE) in patients with non-small cell lung cancer (NSCLC) treated with three-dimensional conformal radiation therapy (3D-CRT), intensity-modulated radiation therapy (IMRT), or proton beam therapy (PBT). METHODS AND MATERIALS: Patients were treated for NSCLC with 3D CRT, IMRT, or PBT at MD Anderson from 2000 to 2008 and had full dose-volume histogram (DVH) data available. The endpoint was severe (grade>=3) RE. The Lyman Kutcher-Burman (LKB) model was used to analyze RE as a function of the fractional esophageal DVH, with clinical variables included as dose-modifying factors. RESULTS: Overall, 652 patients were included: 405 patients were treated with 3D CRT, 139 with IMRT, and 108 with PBT; corresponding rates of grade>=3 RE were 8%, 28%, and 6%, respectively, with a median time to onset of 42 days (range, 11-93 days). A fit of the fractional DVH LKB model demonstrated that the fractional effective dose was significantly different (P=.046) than 1 (fractional mean dose) indicating that high doses to small volumes are more predictive than mean esophageal dose. The model fit was better for 3D-CRT and PBT than for IMRT. Including receipt of concurrent chemotherapy as a dose-modifying factor significantly improved the LKB model (P=.005), and the model was further improved by including a variable representing treatment with >30 fractions. Examining individual types of chemotherapy agents revealed a trend toward receipt of concurrent taxanes and increased risk of RE (P=.105). CONCLUSIONS: Fractional dose (dose rate) and number of fractions (total dose) distinctly affect the risk of severe RE, estimated using the LKB model, and concurrent chemotherapy improves the model fit. This risk of severe RE is underestimated by this model in patients receiving IMRT. PMID- 22920976 TI - Catheter-based arterial sympathectomy: hypertension and beyond. AB - Transluminal ablation of renal artery sympathetic nerves has been shown to provide a significant and durable reduction in blood pressure with very low complication rates. Additional publications have documented improvement in insulin sensitivity, obstructive sleep apnea indices, and frequency and severity of congestive heart failure in subgroups undergoing the procedure. This technology may provide effective management of other diseases in which there is autonomic imbalance. Available data are reviewed with the intent to provoke interest within the interventional radiology community in this novel technology, which may allow minimally invasive treatment of many important chronic medical conditions. PMID- 22920977 TI - CT fluoroscopy-guided percutaneous osteoplasty for the treatment of osteolytic lung cancer bone metastases to the spine and pelvis. AB - PURPOSE: To retrospectively assess the results of computed tomographic (CT) fluoroscopy-guided percutaneous osteoplasty (PO) of osteolytic lung cancer bone metastases, focusing on pain reduction, improved quality of life, and patient mobility. MATERIALS AND METHODS: Over a 43-month interval, 92 patients with lung cancer bone metastases underwent PO, including vertebroplasty and acetabuloplasty. A total of 261 lesions of the vertebral column and 22 lesions of the pelvis, ilium, and femur were treated with the use of CT fluoroscopic guidance. Clinical outcomes were assessed, including pain, quality of life, and mobility, 24 hours before, 24 hours after, and 1 and 3 months after osteoplasty. RESULTS: Pain reduction and improved quality of life and patient mobility were observed in most patients. Visual analog scale and Karnofsky Performance Scale scores changed significantly (P < .05), from 6.1 +/- 1.4 and 69.3 +/- 5.5 at 24 hours before osteoplasty, respectively, to 3.5 +/- 1.2 and 75.2 +/- 5.4 at 24 hours after the procedure, 3.3 +/- 1.2 and 76.5 +/- 5.8 at 1 month, and 2.9 +/- 1.5 and 79.6 +/- 5.8 at 3 months after PO. Mobility scale score, Frankel classification of spinal cord injury, and Harris hip score also changed significantly (P < .05) after osteoplasty. No major complications occurred. CONCLUSIONS: PO was shown to be a highly effective and safe palliative therapy to reduce pain and improve quality of life and patient mobility, not only in vertebral metastases, but also in pelvic, iliac, and femoral metastases. PMID- 22920978 TI - Risk factors for new vertebral fractures after percutaneous vertebroplasty in patients with osteoporosis: a prospective study. AB - PURPOSE: To determine the risk factors for new vertebral compression fractures (VCFs) following percutaneous vertebroplasty (PV) in patients with osteoporosis. MATERIALS AND METHODS: This prospective study included 132 consecutive patients with osteoporosis treated with PV in a single institution over 46 months from March 2005 to December 2008. Multivariable logistic regression and univariate analysis were employed to identify risk factors for new VCFs after PV, including patient demographic data, parameters of the initial and new fractured vertebrae, procedure-related information, and follow-up data. RESULTS: During the follow-up period (22.4 months +/- 12.1), 80 new vertebral fractures occurred in 36 (27.3%) patients. Multivariate analysis showed that number of VCFs per time frame, computed tomography (CT) value of nonfractured vertebrae (T11-L2), activity level after discharge, duration of follow-up, and cement distribution in the inferior part of the vertebral body or close to the endplate were statistically correlated with new fractures (odds ratios, 2.63, 0.96, 3.59, 1.00, 0.30, and 0.05; P = .006, P = .001, P = .007, P = .004, P = .021 and P = .029). Univariate analysis showed preexisting old VCFs were correlated with new VCFs (P = .045). Subsequent compression fractures in adjacent vertebrae (45 of 80) occurred more frequently and sooner than nonadjacent vertebral fractures (both P < .05). CONCLUSIONS: The incidence of new VCFs after PV is relatively high and affected by several risk factors that are related to both the PV procedure and the natural course of osteoporosis. PMID- 22920979 TI - Osteoporotic vertebral compression fractures after vertebroplasty: a frustrating controversy. PMID- 22920980 TI - Contrast-enhanced MR angiography of uterine arteries for the prediction of ovarian artery embolization in 349 patients. AB - PURPOSE: To assess contrast-enhanced magnetic resonance (MR) angiographic findings of uterine arteries (UAs) and to evaluate the diagnostic utility of this imaging modality for the prediction of ovarian artery (OA) embolization (OAE). MATERIALS AND METHODS: The authors retrospectively evaluated 349 patients who underwent contrast-enhanced MR angiography before UA embolization (UAE) for symptomatic fibroid tumors or adenomyosis. The diameters of the UAs were compared with those of the inferior mesenteric arteries (IMAs) and classified into two groups: group I, in which the diameters of both UAs were the same as or greater than that of the IMA; and group II, in which at least one UA was smaller than the IMA or was not visible. The presence of an enlarged OA was also evaluated. Sensitivity and specificity were calculated for UA diameter, enlarged OA, and the combination of the two. RESULTS: Nine of 22 patients (40.9%) in group II underwent OAE, which was a significantly higher incidence (P < .001) than in group I (nine of 327; 2.8%). Among eight patients with enlarged OAs, six (75%) underwent OAE. Relative UA diameter had a sensitivity of 50% and specificity of 96.1%; the respective values for enlarged OAs were 33.3% and 99.3%. The combination of UA diameter and enlarged OAs showed a sensitivity and specificity of 72.2% and 95.4%, respectively. CONCLUSIONS: In addition to the identification of enlarged OAs, contrast-enhanced MR angiography allows a comparison between UA and IMA diameters and therefore can be helpful for the prediction of OAE. PMID- 22920981 TI - Properties of N-butyl cyanoacrylate-iodized oil mixtures for arterial embolization: in vitro and in vivo experiments. AB - PURPOSE: To examine the properties of N-butyl cyanoacrylate (NBCA) and iodized oil (lipiodol [Lip]) in vitro and in vivo for safe and effective embolization. MATERIALS AND METHODS: Viscosity, polymerization time, and diffusing capacity were evaluated according to the NBCA/Lip ratio in vitro. Additionally, the effect of the NBCA/Lip ratio on arterial embolization was evaluated in vivo; various ratios of NBCA/Lip were injected into the renal arteries of adult beagles, after which the embolization effect following transcatheter arterial embolization was quantitatively investigated histopathologically and using computed tomography (CT) volumetry. RESULTS: The viscosity of NBCA/Lip increased, polymerization time was prolonged, and diffusing capacity increased as the NBCA density decreased. As the NBCA density decreased, embolic material was recognized in smaller diameter arteries, and embolization of a larger vascular bed was accomplished. The NBCA/Lip mixture with a low density of NBCA was located more peripherally from the catheter tip, and embolization of more peripheral and smaller diameter arteries was achieved. CONCLUSIONS: The relationships of properties of NBCA/Lip in vitro and embolization effects in vivo of various ratios of NBCA/Lip were quantitatively examined and compared. The results of this study are useful for safe and effective embolization. PMID- 22920982 TI - Fibrin cap disruption: an adjunctive technique for inferior vena cava filter retrieval. AB - Various adjunctive techniques have been reported for challenging inferior vena cava (IVC) filter retrievals (1-4). One particularly challenging obstacle to successful IVC filter retrieval is the formation of a radiolucent fibrin cap over the embedded apex of the IVC filter. This obstacle is a result of filter tilting that creates turbulent blood flow, which promotes fibrin cap formation. The aim of this brief report is to depict a novel technique for IVC filter retrieval: guide wire-manipulated disruption of the fibrin cap. PMID- 22920983 TI - Use of endobronchial valves for the treatment of bronchopleural fistulas after thermal ablation of lung neoplasms. AB - Persistent air leaks resulting from bronchopleural fistulas (BPFs) are a rare but serious side effect of thermal ablation. Traditionally, BPFs are treated with surgery; however, patients receiving ablation are often poor surgical candidates and require minimally invasive treatment. The present report describes four cases of BPFs following ablation, which were treated with endobronchial valves (EBVs). In three of the four patients, the pneumothoraces resolved after valve placement. One patient required further treatment with pleurodesis. EBVs can selectively block inspiratory airflow while allowing expiratory flow with drainage of air and secretions. In select patients, EBVs are a viable treatment option for BPFs. PMID- 22920984 TI - Treatment of ureteroarterial fistula with an endoureteral stent graft. AB - A patient with a history of total cystectomy for bladder cancer, cutaneous ureterostomy, irradiation, and long-term indwelling urinary catheters presented with an aortoureteral fistula (UAF), which was treated with an endoureteral stent graft. The described ureteral approach using stent grafts may be considered for the management of UAFs when more traditional approaches are unavailable. PMID- 22920985 TI - Balloon-occluded venography of a gastrorenal shunt with carbon dioxide to visualize access route to gastric varices during selective balloon-occluded retrograde transvenous obliteration. PMID- 22920986 TI - Cardiac pacemaker lead dislodgment during insertion of hemodialysis catheter. PMID- 22920987 TI - CT-guided microcoil localization before surgical management of an intraorbital abscess. PMID- 22920988 TI - Acute uterine inversion: case report and angiographic features. PMID- 22920989 TI - Simple technique for transjugular intrahepatic portosystemic shunt reduction using a flared stent graft. PMID- 22920990 TI - Inadvertent subclavian arteriotomy closure using the Mynx vascular closure device. PMID- 22920991 TI - A randomized controlled trial to assess the efficacy of an interactive mobile messaging intervention for underserved smokers: Project ACTION. AB - BACKGROUND: Despite a significant decrease in smoking prevalence over the past ten years, cigarette smoking still represents the leading cause of preventable morbidity and mortality in the United States. Moreover, smoking prevalence is significantly higher among those with low levels of education and those living at, or below, the poverty level. These groups tend to be confronted with significant barriers to utilizing more traditional smoking cessation intervention approaches. The purpose of the study, Project ACTION (Adult smoking Cessation Treatment through Innovative Outreach to Neighborhoods), is to utilize a mobile clinic model, a network of community sites (i.e., community centers and churches) and an interactive mobile messaging system to reach and deliver smoking cessation treatment to underserved, low-income communities. METHODS/DESIGN: We are using a group-randomized design, with the community site as the sampling unit, to compare the efficacy of three smoking cessation interventions: 1) Standard Care--brief advice to quit smoking, nicotine replacement therapy (NRT), and self-help materials; 2) Enhanced Care--standard care components plus a cell phone-delivered text/graphical messaging component; and 3) Intensive Care--enhanced care components plus a series of 11 cell phone-delivered proactive counseling sessions. An economic evaluation will also be performed to evaluate the relative cost effectiveness of the three treatment approaches. We will recruit 756 participants (252 participants in each of the 3 intervention groups). At the time of randomization, participants complete a baseline assessment, consisting of smoking history, socio-demographic, and psychosocial variables. Monthly cell phone assessments are conducted for 6 months-post enrollment, and a final 12 month follow-up is conducted at the original neighborhood site of enrollment. We will perform mixed-model logistic regression to compare the efficacy of the three smoking cessation intervention treatment groups. DISCUSSION: It is hypothesized that the intensive care approach will most successfully address the needs of the target population and result in the highest smoking cessation rates. In addition to increasing cessation rates, the intervention offers several features (including neighborhood outreach and use of mHealth technology) that are likely to reduce treatment barriers while enhancing participant engagement and retention to treatment. TRIAL REGISTRATION: This randomized controlled trial is registered with clinicaltrials.gov registration number NCT00948129. PMID- 22920993 TI - Synthesis of imidazopyridines from the Morita-Baylis-Hillman acetates of nitroalkenes and convenient access to Alpidem and Zolpidem. AB - A variety of functionalized imidazo[1,2-a]pyridines have been synthesized through a one-pot, room temperature, and reagent-free reaction between MBH acetates of nitroalkenes and 2-aminopyridines. The reaction involves a cascade inter intramolecular double aza-Michael addition of 2-aminopyridines to MBH acetates. Our methodology is marked by excellent yield, regioselectivity and, above all, adaptability to synthesize imidazopyridine-based drug molecules such as Alpidem and Zolpidem. PMID- 22920992 TI - Yellow lupin (Lupinus luteus L.) transcriptome sequencing: molecular marker development and comparative studies. AB - BACKGROUND: Yellow lupin (Lupinus luteus L.) is a minor legume crop characterized by its high seed protein content. Although grown in several temperate countries, its orphan condition has limited the generation of genomic tools to aid breeding efforts to improve yield and nutritional quality. In this study, we report the construction of 454-expresed sequence tag (EST) libraries, carried out comparative studies between L. luteus and model legume species, developed a comprehensive set of EST-simple sequence repeat (SSR) markers, and validated their utility on diversity studies and transferability to related species. RESULTS: Two runs of 454 pyrosequencing yielded 205 Mb and 530 Mb of sequence data for L1 (young leaves, buds and flowers) and L2 (immature seeds) EST- libraries. A combined assembly (L1L2) yielded 71,655 contigs with an average contig length of 632 nucleotides. L1L2 contigs were clustered into 55,309 isotigs. 38,200 isotigs translated into proteins and 8,741 of them were full length. Around 57% of L. luteus sequences had significant similarity with at least one sequence of Medicago, Lotus, Arabidopsis, or Glycine, and 40.17% showed positive matches with all of these species. L. luteus isotigs were also screened for the presence of SSR sequences. A total of 2,572 isotigs contained at least one EST-SSR, with a frequency of one SSR per 17.75 kbp. Empirical evaluation of the EST-SSR candidate markers resulted in 222 polymorphic EST-SSRs. Two hundred and fifty four (65.7%) and 113 (30%) SSR primer pairs were able to amplify fragments from L. hispanicus and L. mutabilis DNA, respectively. Fifty polymorphic EST-SSRs were used to genotype a sample of 64 L. luteus accessions. Neighbor-joining distance analysis detected the existence of several clusters among L. luteus accessions, strongly suggesting the existence of population subdivisions. However, no clear clustering patterns followed the accession's origin. CONCLUSION: L. luteus deep transcriptome sequencing will facilitate the further development of genomic tools and lupin germplasm. Massive sequencing of cDNA libraries will continue to produce raw materials for gene discovery, identification of polymorphisms (SNPs, EST-SSRs, INDELs, etc.) for marker development, anchoring sequences for genome comparisons and putative gene candidates for QTL detection. PMID- 22920994 TI - Dynamic proteomic profile of potato tuber during its in vitro development. AB - Potato tuberization is a complicated biochemical process, which is dependent on external environmental factors. Tuber development in potato consists of a series of biochemical and morphological processes at the stolon tip. Signal transduction proteins are involved in the source-sink transition during potato tuberization. In the present study, we examined protein profiles under in vitro tuber-inducing conditions using a shotgun proteomic approach involving denaturing gel electrophoresis and liquid chromatography-mass spectrometry. A total of 251 proteins were identified and classified into 9 groups according to distinctive expression patterns during the tuberization stage. Stolon stage-specific proteins were primarily involved in the photosynthetic machinery. Proteins specific to the initial tuber stage included patatin. Proteins specific to the developing tuber stage included 6-fructokinase, phytoalexin-deficient 4-1, metallothionein II-like protein, and malate dehydrogenase. Novel stage-specific proteins identified during in vitro tuberization were ferredoxin-NADP reductase, 34 kDa porin, aquaporin, calmodulin, ripening-regulated protein, and starch synthase. Superoxide dismutase, dehydroascorbate reductase, and catalase I were most abundantly expressed in the stolon; however, the enzyme activities of these proteins were most activated at the initial tuber. The present shotgun proteomic study provides insights into the proteins that show altered expression during in vitro potato tuberization. PMID- 22920996 TI - Genome-wide transcriptional response of Populus euphratica to long-term drought stress. AB - Populus euphratica is native to semi-arid regions of the Xinjiang Uyghur Autonomous Region of China, and studying its drought responses will greatly increase the understanding of how trees acclimate to drought. Water was withheld for seven weeks in four different drought stress treatments, with regime 1 being the least drought stressed and regime 4 being the most, and the poplar's transcriptional profiles examined with Affymetrix Poplar GeneChip microarrays. The number of significantly up or down transcriptional changes increased with the severity of drought stress, with regime 1, 2, 3 and 4 showing 952, 1354, 2138 and 2360 altered transcripts, respectively. Only 277 of these were found in common across all four regimes, while 1938 transcripts were found to be unique to the individual treatments. Genes with altered transcript abundance included members of the transcription factor families AP2/EREPB, bZIP, NAC, NF-Y, WRKY, MYB and Homeobox, as well as genes for the small HSP, HSP70 and HSP90 heat shock protein families. Analysis of the transcript data from these experiments indicated that P. euphratica activates specific regulatory pathways according to the degree of drought stress it receives. These results provide important insights into the molecular mechanisms underpinning the drought stress responses of poplar, as well as providing candidates for future experimentation. PMID- 22920997 TI - The Arabidopsis F-box protein AtFBS1 interacts with 14-3-3 proteins. AB - AtFBS1 is an F-box protein whose transcript accumulates in response to biotic and abiotic stresses. Previous evidence suggests that a postranscriptional event regulates AtFBS1 expression [1]. We now found that AtFBS1 interacts with 14-3-3 proteins through its amino-terminus and the F-box motif. Deletion of any of these regions abolishes the interaction between AtFBS1 and 14-3-3 proteins. On the other hand, the treatment with the proteasome inhibitor MG132 or the deletion of the F-box from AtFBS1 increases beta-glucuronidase (GUS) activity in plants containing a translational fusion of AtFBS1 with the GUS reporter gene, indicating that AtFBS1 is degraded by the 26S proteasome. MG132 treatment of seedlings containing a gene fusion between AtFBS1 and the TAP (Tandem Affinity Purification) cassette causes an increase in the half-life of the protein. In an attempt to understand the role of 14-3-3 interactions, we treated Arabidopsis seedlings with 5-aminoimidazole-4-carboxamide-1-beta-d-ribofuranosyl 5' monophosphate (AICAR), an inhibitor of 14-3-3 client interactions. We observed an increase in AtFBS1-TAP stability as a consequence of AICAR treatment. Based on these data we propose that 14-3-3 proteins promote the dimerization of SCF(AtFBS1). This also may enhance the AtFBS1 autoubiquitination activity and its degradation by the 26S proteasome. AICAR also affects Cullin1 (CUL1) modification by RUB1, which would provide an additional element to the effect of this compound on AtFBS1 stability. PMID- 22920995 TI - Some like it hot, some like it warm: phenotyping to explore thermotolerance diversity. AB - Plants have evolved overlapping but distinct cellular responses to different aspects of high temperature stress. These responses include basal thermotolerance, short- and long-term acquired thermotolerance, and thermotolerance to moderately high temperatures. This 'thermotolerance diversity' means that multiple phenotypic assays are essential for fully describing the functions of genes involved in heat stress responses. A large number of genes with potential roles in heat stress responses have been identified using genetic screens and genome wide expression studies. We examine the range of phenotypic assays that have been used to characterize thermotolerance phenotypes in both Arabidopsis and crop plants. Three major variables differentiate thermotolerance assays: (1) the heat stress regime used, (2) the developmental stage of the plants being studied, and (3) the actual phenotype which is scored. Consideration of these variables will be essential for deepening our understanding of the molecular genetics of plant thermotolerance. PMID- 22920998 TI - Hydraulic safety margins and embolism reversal in stems and leaves: why are conifers and angiosperms so different? AB - Angiosperm and coniferous tree species utilize a continuum of hydraulic strategies. Hydraulic safety margins (defined as differences between naturally occurring xylem pressures and pressures that would cause hydraulic dysfunction, or differences between pressures resulting in loss of hydraulic function in adjacent organs (e.g., stems vs. leaves) tend to be much greater in conifers than angiosperms and serve to prevent stem embolism. However, conifers tend to experience embolism more frequently in leaves and roots than angiosperms. Embolism repair is thought to occur by active transport of sugars into empty conduits followed by passive water movement. The most likely source of sugar for refilling is from nonstructural carbohydrate depolymerization in nearby parenchyma cells. Compared to angiosperms, conifers tend to have little parenchyma or nonstructural carbohydrates in their wood. The ability to rapidly repair embolisms may rely on having nearby parenchyma cells, which could explain the need for greater safety margins in conifer wood as compared to angiosperms. The frequent embolisms that occur in the distal portions of conifers are readily repaired, perhaps due to the abundant parenchyma in leaves and roots, and these distal tissues may act as hydraulic circuit breakers that prevent tension-induced embolisms in the attached stems. Frequent embolisms in conifer leaves may also be due to weaker stomatal response to changes in ambient humidity. Although there is a continuum of hydraulic strategies among woody plants, there appear to be two distinct 'behaviors' at the extremes: (1) embolism prevention and (2) embolism occurrence and subsequent repair. PMID- 22920999 TI - Phytoalexin transgenics in crop protection--fairy tale with a happy end? AB - Phytoalexins are pathogen induced low molecular weight compounds with antimicrobial activities derived from secondary metabolism. Following their identification, phytoalexins were directly incorporated into the network of plant defense responses. Due to their heterogeneity, the metabolic pathways involved in phytoalexin formation and in particular the regulatory mechanisms remained elusive. Consequently, research focus shifted to the characterization of other components of plant immunity such as defense signaling and resistance mechanisms, including components of systemic acquired and induced systemic resistance, effector and pathogen-associated molecular pattern triggered immunity as well as R-gene resistance. Despite the obtained knowledge on these immunity mechanisms, genetic engineering employing these mechanisms and classical breeding reached too low improvements in crop protection, probably because classical breeding focused on yield performance and taste, rather than pathogen resistance. The increasing demand for disease resistant crop species and the aim to reduce pesticide application therefore requires alternative approaches. Recent advances in the understanding of phytoalexin function, biosynthesis and regulation, in combination with novel methods of molecular engineering and advances in instrumental analysis, returned attention to phytoalexins as a potent target for improving crop protection. Based on this, the advantages as well as potential bottlenecks for molecular approaches of modulating inducible phytoalexins to improve crop protection are discussed. PMID- 22921000 TI - Hydrogen peroxide induced phenylpropanoids pathway eliciting a defensive response in plants micropropagated in Temporary Immersion Bioreactors (TIBs). AB - The relation between the oxidative burst and phenylpropanoid pathways has been studied using the sugarcane cultivar C86-56, which does not release phenolics in agar-base micropropagation systems. In stationary liquid culture, a significant production of phenolic compounds and plant survival were determined in sugarcane plants treated with 5mM H(2)O(2). The spectrophotometer determinations and the gene expression analysis corroborated that releasing of phenolics and soluble theta-quinones was induced during the first 24h of treatment. In comparison with the control treatments, sugarcane plants treated with H(2)O(2) demonstrated differences in the micropropagation-related variables when multiplied in Temporary Immersion Bioreactors (TIBs) supplemented with polyethyleneglycol (PEG 20%). Expression of selected genes related to photosynthesis, ethylene, auxins, oxidative burst, and defense pathways were confirmed during the entire PEG 20% stress in the plants coming from the 5mM H(2)O(2) treatment; whereas, much more heterogeneous expression patterns were evidenced in plants stressed with PEG but not previously treated with H(2)O(2). RT-PCR expression analysis supports the hypothesis that while H(2)O(2) induces the oxidative burst, the phenylpropanoids pathways elicit and maintain the defensive response mechanism in micropropagated sugarcane plants. PMID- 22921001 TI - Glutathione improves early somatic embryogenesis in Araucaria angustifolia (Bert) O. Kuntze by alteration in nitric oxide emission. AB - In this work, it was observed a straight relationship between the manipulation of the reduced glutathione (GSH)/glutathione disulfide (GSSG) ratio, nitric oxide emission and quality and number of early somatic embryos in Araucaria angustifolia, a Brazilian endangered native conifer. In low concentrations GSH (0.01 and 0.1mM) is a potential NO scavenger in the culture medium. Furthermore, it can increase the number of early SE formed in cell suspension culture media in a few days. However, the maintenance in this low redox state lead to a loss of early somatic embryos polarization. In gelled culture medium, high levels of GSH (5mM) allows the development of globular embryos presenting a high NO emission on embryo apex, stressing its importance in the differentiation and cell division. Taken together these results indicate that the modification of the embryogenic cultures redox state might be an effective strategy to develop more efficient embryogenic systems in A. angustifolia. PMID- 22921002 TI - Plant defense using toxic inorganic ions: conceptual models of the defensive enhancement and joint effects hypotheses. AB - The concept of plant defense using toxic mineral elements originated as an explanation for extremely elevated concentrations of some elements (termed hyperaccumulation) in some plant tissues. The Defensive Enhancement Hypothesis suggests that hyperaccumulation evolved because, after an initial defensive benefit accrued from a relatively low initial concentration, increased concentration of an element provided increased plant fitness and drove evolution of higher element concentrations until hyperaccumulation was achieved. The Joint Effects Hypothesis postulates that additive or synergistic effects between element-based defenses, or between toxic element and organic chemical defenses, may have contributed to the evolution of hyperaccumulation. By lessening the concentration of an element necessary to provide an initial defensive benefit to a plant, joint effects could decrease the level of an element that provides an initial defensive benefit, allowing additive or synergistic defensive enhancement to take effect. Recent experimental tests have demonstrated defense at relatively low element concentrations, and tests of metal/metal and metal/organic compound combinations have shown joint effects. These hypotheses suggest how hyperaccumulator plants may have evolved in response to plant-herbivore interactions, and suggest that toxic element levels below those used to define hyperaccumulation may be ecologically effective. PMID- 22921003 TI - Functional validation of Capsicum frutescens aminotransferase gene involved in vanillylamine biosynthesis using Agrobacterium mediated genetic transformation studies in Nicotiana tabacum and Capsicum frutescens calli cultures. AB - Capsaicinoid biosynthesis involves the participation of two substrates viz. vanillylamine and C(9)-C(11) fatty acid moieties. Vanillylamine which is a derivative of vanillin is synthesized through a transaminase reaction in the phenylpropanoid pathway of capsaicinoid synthesis. Here we report the functional validation of earlier reported putative aminotransferase gene for vanillylamine biosynthesis in heterologous system using Agrobacterium mediated genetic transformation studies in Nicotiana tabacum and Capsicum frutescens calli cultures. Molecular analysis tools comprising PCR and Southern blot analysis have shown the integration of the foreign gene in N. tabacum and C. frutescens calli cultures. The study shows the production of vanillylamine in transformed N. tabacum callus cultures and also the reduction of vanillylamine production when whole gene based antisense binary vector construct was used in transformation of C. frutescens callus cultures. Vanillylamine production, aminotransferase assay with Western blot analysis for crude proteins of transformants established the production of putative aminotransferase (pAMT) protein in alternate plant. The result is a clear evidence of involvement of the reported putative aminotransferase responsible for vanillylamine biosynthesis in capsaicinoid biosynthesis pathway, confirming the gene function through functional validation. PMID- 22921004 TI - Kinetic transcriptomic approach revealed metabolic pathways and genotoxic-related changes implied in the Arabidopsis response to ionising radiations. AB - Plants exposed to ionising radiation (IR) have to face direct and indirect (oxidative stress) deleterious effects whose intensity depends on the dose applied and led to differential genome regulation. Transcriptomic analyses were conducted with CATMA microarray technology on Arabidopsis thaliana plantlets, 2 and 26h after exposure to the IR doses 10Gy and 40Gy. 10Gy treatment seemed to enhance antioxidative compound biosynthetic pathways whereas the 40Gy dose up regulated ROS-scavenging enzyme genes. Transcriptomic data also highlighted a differential regulation of chloroplast constituent genes depending on the IR dose, 10Gy stimulating and 40Gy down-regulating. This probable 40Gy decrease of photosynthesis could help for the limitation of ROS production and may be coupled with programmed cell death (PCD)/senescence phenomena. Comparisons with previous transcriptomic studies on plants exposed to a 100Gy dose revealed 60 dose dependent up-regulated genes, including notably cell cycle checkpoints to allow DNA repairing phenomena. Furthermore, the alteration of some cellular structure related gene expression corroborated a probable mitotic arrest after 40Gy. Finally, numerous heat-shock protein and chaperonin genes, known to protect proteins against stress-dependent dysfunction, were up-regulated after IR exposure. PMID- 22921006 TI - Overexpression of OsTLP27 in rice improves chloroplast function and photochemical efficiency. AB - The thylakoid lumen proteins are highly associated with photosynthesis functionally. In this study, we characterized the OsTLP27 gene from rice (Oryza sativa), which encodes a 27-kDa of 257-amino acid with 53% homology to the AtTLP gene from Arabidopsis thaliana. OsTLP27 was predicted to encode a thylakoid lumen protein of unknown function in chloroplast, and chloroplast targeting of OsTLP27 was confirmed by transient expression of a fusion protein with green fluorescent protein (GFP). OsTLP27 transcripts accumulated specifically in green tissues such as the leaf blade and leaf sheath, and the levels of its transcripts followed a circadian rhythm. Constitutive expression of OsTLP27 under the control of CaMV 35S promoter resulted in increased pigment content and enhanced photochemical efficiency in terms of the values of maximal photochemical efficiency of photosystem II (PSII) (F(v)/F(m)), effective quantum yield of PSII (PhiPSII), electron transport rate (ETR) and photochemical quenching (qP). Overexpression of OsTLP27 also enhanced transcript levels of genes related to chloroplast function and caused changes in the grana size and number. Further study showed that the structure and polypeptide composition of the photosynthetic apparatus were altered in transgenic lines overexpressing OsTLP27. These data suggested that OsTLP27 encodes a protein with a novel function in photosynthesis and chloroplast development in rice. PMID- 22921005 TI - Mini-review: what nuclear magnetic resonance can tell us about protective tissues. AB - The epidermis and periderm protect plants from water and solute loss, pathogen invasion, and UV radiation. The cell walls of these protective tissues deposit the insoluble lipid biopolyesters cutin and suberin, respectively. These biopolymers interact in turn with polysaccharides, waxes and aromatic compounds to create complex assemblies that are not yet well defined at the molecular level. Non-destructive approaches must be tailored to the insoluble and noncrystalline character of these assemblies to establish the polymer and inter component interactions needed to create functional barriers and structural supports. In the present mini-review, we illustrate the contribution of solid state NMR methodology to compare the architecture of intact fruit cuticular polymers in wild-type and single-gene mutant tomatoes. We also show the potential of NMR-based metabolomics to identify the soluble metabolites that contribute to barrier formation in different varieties of potato tubers. Finally, we outline the challenges of these spectroscopic approaches, which include limited spectral resolution in solid state, differential swelling capabilities in solution, and incomplete dissolution in ionic liquids. Given the many genetically modified plants with altered suberin and cutin polymers that are now available, NMR nonetheless offers a promising tool to gain molecular insight into the complexity of these protective materials. PMID- 22921007 TI - Dissimilar sweet proteins from plants: oddities or normal components? AB - The fruits of a few tropical plants contain intensely sweet proteins. Their common property points to a protein family. Generally, proteins belonging to the same family share similar folds, similar sequences and, at least in part, similar function but sweet proteins constitute an exception to this rule. Apart from sharing the rather unusual taste function, they show no obvious similarities either in their sequences or in three-dimensional structures. In this review we describe the nature, structure and mechanism of action of the best known sweet tasting proteins, including two taste modifying proteins. Sweet proteins stand out among sweet molecules because their volume is not compatible with an interaction with orthosteric active sites of the sweet taste receptor. The best explanation of their mechanism of action is the interaction with the external surface of the sweet taste receptor, according to a model that has been named "wedge model". It is hypothesized that this mode of action may be related to the ability of other members of their protein families to inhibit different enzymes. PMID- 22921008 TI - Mitochondrial mutation impairs cytoplasmic male sterility rice in response to H2O2 stress. AB - Cytoplasmic male sterility (CMS) is a phenomenon widely observed in various plant species characterized with disrupted anther development caused by mitochondrial mutation. CMS is becoming a model system for the investigations of nucleus cytoplasmic interaction. To reveal the possible effects of CMS genes on plant growth in adverse environment, plant development and biochemical characters of mitochondria from Honglian (HL)-CMS line Yuetai A and maintainer Yuetai B treated with H(2)O(2) were analyzed. Results showed that 40-60mM H(2)O(2) significantly inhibits rice seedling development and growth. When treated with H(2)O(2), ATP content and mitochondrial membrane potential in Yuetai A decreased significantly faster than those of Yuetai B. These biochemical changes were accompanied by the severe nuclear DNA fragmentation and the release of mitochondrial cytochrome c in the leaf cells of Yuetai A. In addition, the antioxidative enzyme activities and mitochondrial electron transfer chain complexes were significantly down regulated. Disturbance of the biochemical indexes indicate that HL-CMS line is more susceptible to H(2)O(2) stress than the maintainer line, the deleterious effects caused by the CMS-related ORFH79 peptide compromises the adaptability of HL-CMS line to the adverse environment. PMID- 22921009 TI - Segregation distortion in a region containing a male-sterility, female-sterility locus in soybean. AB - In diploid segregation, each alternative allele has a 50% chance of being passed on to the offspring. Mutations in genes involved in the process of meiotic division or early stages of reproductive cell development can affect allele frequency in the gametes. In addition, competition among gametes and differential survival rates of gametes can lead to segregation distortion. In a recent transformation study, a male-sterile, female-sterile (MSFS) mutant was identified in the soybean cultivar, Williams. The mutant in heterozygous condition segregated 3 fertile:1 sterile in the progeny confirming monogenic inheritance. To map the lesion, we generated an F(2) mapping population by crossing the mutant (in heterozygous condition) with Minsoy (PI 27890). The F(2) progeny showed strong segregation distortion against the MSFS phenotype. The objectives of our study were to molecularly map the gene responsible for sterility in the soybean genome, to determine if the MSFS gene is a result of T-DNA insertion during Agrobacterium-mediated transformation, and to map the region that showed distorted segregation. The fertility/sterility locus was mapped to molecular linkage group (MLG) D1a (chromosome Gm01) using bulked segregant analysis. The closest marker, Satt531, mapped 9.4cM from the gene. Cloning of insertion sites for T-DNA in the mutant plants revealed that there are two copies of T-DNA in the genome. Physical locations of these insertion sites do not correlate with the map location of the MSFS gene, suggesting that MSFS mutation may not be associated with T-DNA insertions. Segregation distortion was most extreme at or around the st_A06-2/6 locus suggesting that sterility and segregation distortion are tightly linked attributes. Our results cue that the distorted segregation may be due to a gamete elimination system. PMID- 22921010 TI - Detect thy neighbor: identity recognition at the root level in plants. AB - Some plant species increase root allocation at the expense of reproduction in the presence of non-self and non-kin neighbors, indicating the capacity of neighbor identity recognition at the root level. Yet in spite of the potential consequences of root identity recognition for the relationship between plant interactions and community structure and functioning, this phenomenon still remains poorly understood. We first critically assess the evidence for the existence of self/non-self and kin recognition at the root level in plants. While root identity recognition most likely exists to some degree, there remain valid points of criticism regarding experiments that have documented this, particularly concerning the effects of pot volume in self/non-self recognition experiments and the roles of size inequality and asymmetric competition in kin recognition studies. Subsequently we review and propose some plausible physiological mechanisms that may underlie these responses. Finally we briefly discuss the relation between under- and aboveground interactions and the potential consequences of root identity recognition for agriculture, and conclude with raising several questions for future studies. PMID- 22921011 TI - Ultracold molecules under control! PMID- 22921012 TI - Non-invasive assessment of the reproductive cycle in free-ranging female African elephants (Loxodonta africana) treated with a gonadotropin-releasing hormone (GnRH) vaccine for inducing anoestrus. AB - BACKGROUND: In southern Africa, various options to manage elephant populations are being considered. Immunocontraception is considered to be the most ethically acceptable and logistically feasible method for control of smaller and confined populations. In this regard, the use of gonadotropin-releasing hormone (GnRH) vaccine has not been investigated in female elephants, although it has been reported to be safe and effective in several domestic and wildlife species. The aims of this study were to monitor the oestrous cycles of free-ranging African elephant cows using faecal progestagen metabolites and to evaluate the efficacy of a GnRH vaccine to induce anoestrus in treated cows. METHODS: Between May 2009 June 2010, luteal activity of 12 elephant cows was monitored non-invasively using an enzyme immunoassay detecting faecal 5alpha-reduced pregnanes (faecal progestagen metabolites, FPM) on a private game reserve in South Africa. No bulls of breeding age were present on the reserve prior to and for the duration of the study. After a 3-month control period, 8 randomly-selected females were treated twice with 600 micrograms of GnRH vaccine (Improvac(r), Pfizer Animal Health, Sandton, South Africa) 5-7 weeks apart. Four of these females had been treated previously with the porcine zona pellucida (pZP) vaccine for four years (2004 2007). RESULTS: All 12 monitored females (8 treated and 4 controls) showed signs of luteal activity as evidenced by FPM concentrations exceeding individual baseline values more than once. A total of 16 oestrous cycles could be identified in 8 cows with four of these within the 13 to 17 weeks range previously reported for captive African elephants. According to the FPM concentrations the GnRH vaccine was unable to induce anoestrus in the treated cows. Overall FPM levels in samples collected during the wet season (mean 4.03 micrograms/gram dry faeces) were significantly higher (P<0.002) than the dry season (mean 2.59 micrograms/gram dry faeces). CONCLUSIONS: The GnRH vaccination protocol failed to induce anoestrus in the treated female elephants. These results indicate that irregular oestrous cycles occur amongst free-ranging elephants and are not restricted to elephants in captivity. The relationship between ecological conditions and endocrine activity were confirmed. Free-ranging female elephants were observed to not cycle continuously throughout the year in the absence of adult bulls. PMID- 22921013 TI - Relationship of bladder dysfunction with upper urinary tract deterioration in cerebral palsy. AB - Although lower urinary tract dysfunction (LUTD) in patients with cerebral palsy (CP) has been previously documented by clinical observations and urodynamic tests, its correlation with upper urinary tract deterioration (UUTD) has not been demonstrated. This paper documents symptoms and urodynamic findings of LUTD and their relationship with UUTD in 33 children with CP. By sonography, 4 of these children were found to have UUTD. Age was found to correlate with UUTD, but gender difference and mental or motor functions did not. When comparing urinary symptoms with UUTD, incontinence (n = 31) did not correlate, but on the other hand symptoms of detrusor sphincter dyssynergia (interrupted voiding, urinary retention, hesitancy; n = 5) and culture proven febrile urinary tract infections (n = 4) did. Abnormal urodynamics findings were not diagnostic. We conclude that, apart from incontinence, dysfunctional voiding symptoms and febrile urinary tract infections are valuable indicators of UUTD. PMID- 22921015 TI - Improved overall survival trends of men with newly diagnosed M1 prostate cancer: a SWOG phase III trial experience (S8494, S8894 and S9346). AB - PURPOSE: Frequent prostate specific antigen testing for screening and monitoring prostate cancer has led to significant stage migration. We evaluated whether overall survival in hormone naive patients with metastatic prostate cancer has improved during the era of prostate specific antigen use. We also assessed whether any patient subsets benefited differentially during this period. MATERIALS AND METHODS: We compared overall survival in 3 sequential phase III trials of 3,096 men with hormone naive, metastatic prostate cancer who received similar androgen deprivation therapy, including 2 trials performed before the prostate specific antigen era (S8494 and S8894) and the other done during this era (S9346). Overall survival was adjusted for patient and disease risk factors in the latter 2 trials. Subgroups were evaluated by interactions of risk factors with trial. RESULTS: Median overall survival was 30 months in S8494, 33 months in S8894 and 49 months in S9346. Adjusting for risk factors, there was a 22% lower risk of death in S9346 than in S8894 (HR 0.78, 95% CI 0.70, 0.87, p <0.001). The improvement in overall survival was greater in black American men (test of interaction p = 0.008). In S8494 and S8894 median survival for black men was 27 months, and 34 and 35 months for nonblack men, respectively. This racial difference disappeared in S9346 with overall survival of 48 and 49 months in black and nonblack men, respectively. CONCLUSIONS: Adjusting for risk factors, overall survival was significantly improved in the post-prostate specific antigen era trial. However, it cannot be concluded that this was attributable only to prostate specific antigen monitoring. Black men now have overall survival comparable to that of white men. Current estimates of survival should be used to design new trials in this population. PMID- 22921016 TI - Magnetic molecularly imprinted nanoparticles based on dendritic-grafting modification for determination of estrogens in plasma samples. AB - In order to resolve the low imprinting efficiency of surface molecularly imprinted polymers (MIPs), a dendritic-grafting method introducing more functional groups was proposed to modify the SiO(2)-coated magnetic nanoparticles (SiO(2)-coated MNPs). And then magnetic MIPs (MMIPs) were obtained using 17-ethyl estradiol (EE2) as a pseudo template with dendronized SiO(2)-coated MNPs as the supporter, aiming to avoid residual template leakage and to increase the imprinting efficiency. The resulting MMIPs showed high adsorption capacity, quick binding kinetics and good selectivity for trace estrogens. Meanwhile, MMIPs were used as magnetic dispersive solid-phase extraction (MDSPE) materials coupled with HPLC-UV for the detection of trace estrogens. The amounts of three estrogens which were detected from the plasma samples of pregnant women were 5.28, 5.31 and 4.17 ng mL(-1), and the average recoveries were 87.8%, 93.1% and 90.6% for the spiked samples with RSDs in the range of 1.4-6.3%, respectively. All these results reveal that MMIPs as MDSPE materials has good applicability to selective extraction and separation of trace estrogens from complex samples. PMID- 22921017 TI - Longstanding underweight eating disorder: associated features and treatment outcome. AB - The clinical features and the response to inpatient cognitive-behavior treatment (I-CBT) of underweight individuals with either longstanding or more recent-onset eating disorder have rarely been compared. We compared the psychopathological profile and the response to I-CBT of 37 female patients with longstanding eating disorder (>=10 years, L-ED) and 58 with shorter disease duration. Individuals with L-ED had higher age, baseline BMI, higher frequency of self-induced vomiting, laxative and diuretic misuse, but not different personality traits at baseline and not different psychopathological changes, outcome, and dropout rates in response to I-CBT. This study provides preliminary evidence that I-CBT may be useful to treat L-ED and improve their eating disorder psychopathology. PMID- 22921018 TI - Clinical importance of SF3B1 mutations in Chinese with myelodysplastic syndromes with ring sideroblasts. AB - Recent studies report SF3B1 mutations in about 20% of persons of European descent with myelodysplastic syndromes (MDS). Mutations are especially common in persons with ring sideroblasts (RS). SF3B1 mutation state was determined in 104 Chinese with MDS-RS. SF3B1 mutations were found in 55 subjects (53%) including 25 of 39 with refractory anemia and RS (RARS), 26 of 45 (58%) of those with refractory cytopenia with multi-lineage dysplasia and RS (RCMD-RS), 3 of 6 with refractory anemia with excess blasts-1-RS (RAEB1-RS) and 1 of 14 with RAEB2-RS. There were significant correlations between SF3B1 mutation state and platelet levels (P=0.007), mean RBC corpuscular volume (MCV; (P<0.001), proportion of RS (P<0.001) and percent bone marrow erythroblasts (P=0.012) and myeloblasts (P=0.044). Multivariate analyses using a Cox proportional hazards regression model including sex, age, SF3B1 mutation state, hemoglobin concentration, absolute neutrophil level, platelet level, MCV, international prognostic scoring system (IPSS) cytogenetics category, WHO morphologic category and treatment showed SF3B1 mutation state to independently predict survival. These data increase our knowledge of the impact of SF3B1 mutations in persons with MDS. They indicate a similar favorable impact of SF3B1 mutation on survival in Chinese with MDS as reported for persons of European descent. PMID- 22921019 TI - Historical perspectives on myelodysplastic syndromes. AB - Although Georg Hegel quipped, "We learn from history that we do not learn from history", Aldous Huxley expressed a more nuanced view: "The charm of history and its enigmatic lesson consist in the fact that, from age to age, nothing changes and yet everything is completely different." In order to understand present-day positions and peculiarities in any field of human endeavor, familiarity with the past is essential. Those of us who study myelodysplastic syndromes (MDS) or care for patients diagnosed with these troublesome conditions may wonder also how the current state of affairs evolved with respect to our narrow area of focus, and how we know what we think we know now about these still-enigmatic bone marrow diseases. Here, I review a number of developments that collectively represent a brief "history of MDS." I first highlight a few landmark observations that preceded any concept of MDS by hundreds of years. Twentieth-century case descriptions and series with hypotheses about the etiology and nature of disorders described as "refractory anemia", "preleukemia", and with other terminology culminated in the efforts of the French-American-British (FAB) Co operative Group of morphologists, whose landmark 1976 and 1982 papers provided the first widely-used classification of MDS. More recent developments in the MDS field include new mechanistic biological insights, regulatory approval of several somewhat-effective treatments, and improved organizational support and advocacy. The history of a disease concept like MDS, as for history in general, provides both inspiration and cautionary tales that can inform present and future work. PMID- 22921020 TI - Analysis of single nucleotide polymorphisms in the SFRS3 and FKBP4 genes in corticosteroid-induced ocular hypertension. AB - BACKGROUND: The use of intravitreal triamcinolone acetonide (IVTA) can cause ocular hypertension. This steroid response appears to be heritable and alleles in the SFRS3 and FKBP4 genes have recently been suggested to play a role. The purpose of the present study was to perform an independent replication study to determine whether single nucleotide polymorphisms (SNPs) in SFRS3 and FKBP4 are involved in the steroid response. MATERIALS AND METHODS: A retrospective case control study of native Dutch patients was performed who were treated with 4.0mg IVTA. The patients were divided into an intraocular hypertension group (intraocular pressure > 21 mmHg within a year after IVTA) and a non-intraocular hypertension group. The cohort was genotyped for three SNPs: rs7759778 and rs1406945 in SFRS3, and rs2968909 in FKBP4. RESULTS: A total of 102 patients was included: 58 steroid responders and 44 non-responders. No significant differences in demographic parameters or medical history were observed between the study groups. None of the SNPs were found to be significantly associated with the disease as no difference was revealed either in the genotype or allele frequencies between responders and non-responders. CONCLUSIONS: This study does not confirm a role for genetic variants in the SFRS3 and FKBP4 genes in the pathogenesis of corticosteroid-induced ocular hypertension. However, our limited sample size may have restricted the power of our study, and we therefore cannot exclude the involvement of these genetic variants in steroid response. PMID- 22921021 TI - [Combined phacoemulsification and pars plana vitrectomy]. AB - Cataract is frequently associated with vitreoretinal diseases. Moreover, cataract is also a constant complication of vitrectomy in patients over 50 years. Its occurrence may be very early, especially when internal tamponade is used. For these reasons, a combined procedure including phacoemulsification and vitrectomy accelerates functional rehabilitation of patients, avoiding the need for a second operation. Interventions, their tricks and indications, are described for epimacular membranes, macular holes, diabetic retinopathy and macular hematoma. Combined surgery is a safe and effective procedure whose results are comparable to those of sequential surgery. PMID- 22921022 TI - [Foreword]. PMID- 22921023 TI - [Keratoplasty combined with cataract surgery]. AB - Corneal pathologies leading to keratoplasty are often associated with cataract and combined surgery is therefore mandatory. Triple procedure with penetrating keratoplasty and concurrent cataract extraction followed by intra ocular lens (IOL) implantation is usually the preferential choice because visual rehabilitation is theoretically more rapid. Surgeons have to be aware of surgical conditions during open-sky surgery because vitreous pressure is not counterbalanced by anterior chamber pressure. Today, many surgeons prefer non simultaneous procedures with cataract surgery performed months after grafting because of the improvement in spherical refractive error. More recently, new triple procedures, Descemet's stripping automated keratoplasty and concurrent cataract surgery have gained popularity, especially in patients with Fuchs dystrophy associated with cataract. Surgery starts with phacoemulsification, followed by endothelium exchange through a 3 to 5 mm incision. Advantages against classic triple procedure are quick visual rehabilitation, fewer induced refractive errors, minimal postoperative discomfort and corneal integrity. Surgeons have to consider an eventual postoperative hyperopic shift secondary to corneal lenticule shape when choosing adequate intraocular lens. PMID- 22921024 TI - Comment on "Emergency water supply: A review of potential technologies and selection criteria.". AB - In a recent review by Loo et al. (2012) an examination of potential technologies for emergency water supply was presented alongside selection criteria for such technologies to be used by humanitarian relief agencies. Some fundamental concerns were raised with regards to their work and is presented here. PMID- 22921025 TI - Anaerobic treatment of municipal wastewater at ambient temperature: Analysis of archaeal community structure and recovery of dissolved methane. AB - Anaerobic treatment is an attractive option for the biological treatment of municipal wastewater. In this study, municipal wastewater was anaerobically treated with a bench-scale upflow anaerobic sludge blanket (UASB) reactor at temperatures from 6 to 31 degrees C for 18 months to investigate total chemical oxygen demand (COD) removal efficiency, archaeal community structure, and dissolved methane (D-CH(4)) recovery efficiency. The COD removal efficiency was more than 50% in summer and below 40% in winter with no evolution of biogas. Analysis of the archaeal community structures of the granular sludge from the UASB using 16S rRNA gene-cloning indicated that after microorganisms had adapted to low temperatures, the archaeal community had a lower diversity and the relative abundance of acetoclastic methanogens decreased together with an increase in hydrogenotrophic methanogens. D-CH(4), which was detected in the UASB effluent throughout the operation, could be collected with a degassing membrane. The ratio of the collection to recovery rates was 60% in summer and 100% in winter. For anaerobic treatment of municipal wastewater at lower temperatures, hydrogenotrophic methanogens play an important role in COD removal and D-CH(4) can be collected to reduce greenhouse gas emissions and avoid wastage of energy resources. PMID- 22921026 TI - Introduction: devising a prognostic score for pulmonary arterial hypertension. PMID- 22921027 TI - Echocardiography in pulmonary arterial hypertension. AB - In the context of pulmonary arterial hypertension (PAH), echocardiographic assessment of right ventricular (RV) function is key to determining disease severity and prognosis. Using Doppler echocardiography (ECHO) there are numerous ways that RV function can be measured, either directly or indirectly, to capture the triad of changes in RV geometry, right-to-left interaction, and RV systolic dysfunction in response to high pulmonary vascular resistance states, such as PAH. To fully evaluate and characterize the nature and extent of the impact of PAH on the RV in an individual patient, it is critical to assess a combination of these direct and indirect measures of RV function. In order to predict changes in status and have prognostic significance, the variables used must be easy to measure, reproducible, and clinically relevant. This review assesses the relative value of different ECHO parameters and looks at what the future holds for ECHO imaging of the right heart in PAH. PMID- 22921028 TI - Cardiac magnetic resonance imaging: what can it add to our knowledge of the right ventricle in pulmonary arterial hypertension? AB - Pulmonary arterial hypertension (PAH) is a disease of the pulmonary vasculature characterized by vasoconstriction and vascular remodeling leading to a progressive increase in pulmonary vascular resistance (PVR). It is becoming increasingly recognized that it is the response of the right ventricle (RV) to the increased afterload resulting from this increase in PVR that is the most important determinant of patient outcome. A range of hemodynamic, structural, and functional measures associated with the RV have been found to have prognostic importance in PAH and, therefore, have potential value as parameters for the evaluation and follow-up of patients. If such measures are to be used clinically, there is a need for simple, reproducible, accurate, easy-to-use, and noninvasive methods to assess them. Cardiac magnetic resonance imaging (CMRI) is regarded as the "gold standard" method for assessment of the RV, the complex structure of which makes accurate assessment by 2-dimensional methods, such as echocardiography, challenging. However, the majority of data concerning the use of CMRI in PAH have come from studies evaluating a variety of different measures and using different techniques and protocols, and there is a clear need for the development of standardized methodology if CMRI is to be established in the routine assessment of patients with PAH. Should such standards be developed, it seems likely that CMRI will become an important method for the noninvasive assessment and monitoring of patients with PAH. PMID- 22921029 TI - Characterizing the right ventricle: advancing our knowledge. AB - Our ability to evaluate the right ventricle (RV) in pulmonary hypertension has traditionally been quite limited: the RV's complex anatomy is not adequately represented by 2-dimensional imaging, and our understanding of what is an adaptive and maladaptive RV response is incomplete. However, measures of RV function appear to be a strong predictor of survival in pulmonary hypertension. This is, therefore, a promising area for future study. To more fully understand the challenges and opportunities in this area, this article provides a review of RV embryology and anatomy, current assessment of the RV function, animal models of RV function, RV-pulmonary artery coupling, and how translating lessons from studies of the left ventricle may increase our knowledge of the RV. PMID- 22921030 TI - The potential of biomarkers in pulmonary arterial hypertension. AB - Effective management of patients with pulmonary arterial hypertension (PAH) requires comprehensive prognostic evaluation in order to determine optimal management strategies. Although a number of clinical and hemodynamic parameters linked to PAH prognosis have been identified, some are associated with significant limitations (eg, invasive techniques, subjective measures). There is a need for noninvasive and objective measures to be established that function as biomarkers for the diagnosis and assessment of disease prognosis, and that determine response to therapy in patients with PAH. Reflecting the highly complex etiology of the disease, a large number of potential biomarkers have been, and continue to be, investigated in PAH, including those reflecting right heart function, endothelial dysfunction, and markers of inflammation and second organ failure. However, it has become clear that scientifically interesting biomarkers may not necessarily be clinically useful. Of the range of biomarkers investigated in PAH to date, only brain natriuretic peptide and its N-terminal cleavage product have been included as prognostic parameters in treatment guidelines. It is unlikely that any single biomarker will provide all the relevant information required for an individual patient, and the potential for combining markers is currently of considerable interest. Future studies are required to determine the optimal combination of existing and emerging biomarkers in the clinical setting. PMID- 22921031 TI - Cardiovascular modeling in pulmonary arterial hypertension: focus on mechanisms and treatment of right heart failure using the CircAdapt model. AB - In recent years, increased understanding of cardiovascular system dynamics has led to the development of mathematical models of the heart and circulation. Models that enable realistic simulation of ventricular mechanics and interactions under a range of conditions have the potential to provide an ideal method with which to investigate the effects of pulmonary arterial hypertension and its treatment on cardiac mechanics and hemodynamics. Such mathematical models have the potential to contribute to a personalized, patient-specific treatment approach and allow more objective diagnostic decision-making, patient monitoring, and assessment of treatment outcome. This review discusses the development of mathematical models of the heart and circulation, with particular reference to the closed-loop CircAdapt model, and how the model performs under both normal and pathophysiological (pulmonary hypertensive) conditions. PMID- 22921032 TI - Developing a heart score: next steps. AB - The meeting of the Advisory Board of Experts in Pulmonary Hypertension (ABEPH) in 2011 discussed the potential development of a prognostic score for pulmonary arterial hypertension (PAH) based on parameters associated with right ventricular function. During the discussion, a shortlist of parameters derived from hemodynamic, echocardiography, magnetic resonance imaging, and biomarker analysis was developed. This shortlist is the starting point for developing a score that reflects heart function; such a score could have potential in the future clinical management of patients with PAH. PMID- 22921033 TI - Hemodynamics in pulmonary arterial hypertension: current and future perspectives. AB - Right heart catheterization (RHC)-determined pulmonary hemodynamics are mandatory for the diagnosis and classification of pulmonary hypertension (PH) and can be used to assess response to PH-specific therapy and inform clinical decision making. PH is diagnosed in patients with a mean pulmonary arterial pressure of >=25 mm Hg at rest, with a further classification of pulmonary arterial hypertension (PAH) in patients with a pulmonary artery wedge pressure of <=15 mm Hg and, often, reduced cardiac output. In addition, a number of hemodynamic variables, either measured directly with RHC or subsequently derived, have been shown to have prognostic significance in PAH, with different variables having more prognostic significance in specific patient populations. Although there is no hemodynamic definition of exercise-induced PAH, measurement of certain hemodynamic variables during exercise may identify an intermediary phenotype between healthy individuals and overt PAH at rest and may have prognostic implications. However, although exercise hemodynamics may be a closer reflection of the true resistive component of the pulmonary vasculature and its ability to respond to therapy, the lack of standardized protocols limits application in routine clinical practice. PMID- 22921034 TI - Quantitative assessment of cerebral hemodynamics using single photon emission computed tomography with venous blood sampling. AB - OBJECTIVE: Quantitative cerebral blood flow (CBF) measured by single photon emission computed tomography (SPECT) with arterial blood sampling is one of the most reliable methods to assess the hemodynamics in individual patients. SPECT with venous blood sampling is less invasive. The present study compared the measurement of CBF using N-isopropyl-p-(iodine-123)-iodoamphetamine SPECT with venous blood sampling and with arterial blood sampling in patients with major cerebral artery occlusive disease. METHODS: Two normal subjects and 14 patients with major cerebral artery occlusive disease underwent SPECT with arterial and venous blood sampling. The microsphere method was used for quantitative SPECT imaging. Whole brain radioactivity was corrected when the detectors rotated in the forward direction (F1-F7). Venous sampling was performed 30min after radiotracer injection. Arterial blood radioactivity was estimated by multiple regression analysis from these parameters. The cerebrovascular reactivity to acetazolamide was also measured. RESULTS: Multiple regression analysis established the following formula:(where Ca10 is the arterial blood radioactivity at 10min, F1-F7 are the whole brain radioactivity in the forward direction, Cv30 is the venous blood radioactivity at 30min). Mean CBF values were 32.2+/ 6.6ml/100g/min for measured arterial radioactivity and 42.2+/-7.8ml/100g/min for calculated arterial radioactivity based on venous radioactivity. CONCLUSIONS: The present modified method of calculating quantitative CBF from whole brain and venous blood radioactivities correlated well with values determined with arterial blood radioactivity. PMID- 22921035 TI - Multiple sclerosis in Sistan and Baloochestan, South East Iran. PMID- 22921036 TI - Perioperative complications of superficial temporal artery to middle cerebral artery bypass for the treatment of complex middle cerebral artery aneurysms. AB - OBJECT: Only a few studies have reported the risk of ischemic complications occurring when superficial temporal artery (STA) to middle cerebral artery (MCA) anastomosis is performed during surgery for complex MCA aneurysms. SUBJECTS AND METHODS: This is a retrospective study of 10 patients (age 52-73) with MCA aneurysms treated with revascularization surgery. The aneurysms were 10-50mm in size (mean: 21mm). We studied the causes and frequency of ischemic complications by analyzing postoperative magnetic resonance imaging. RESULTS: Postoperative diffusion-imaging confirmed ischemic complications in six of the 10 patients (in two of the five ruptured aneurysms and in four of the five unruptured). The ischemic complications that observed were infarction of the lenticulostriate artery territory in three cases, cortical infarction in two cases, and cerebral infarction that was likely to be due to cerebral vasospasm in one case. In one case, both cortical infarction and infarction of the lenticulostriate artery territory were observed. The Glasgow Outcome Scale (GOS) scores at the time of discharge indicated good recovery (GR) and moderate disability (MD) in seven cases, severe disability (SD) in two cases, and death (D) in one case. CONCLUSIONS: The present study suggests the possibility that STA-MCA anastamosis in surgeries for MCA aneurysms can be performed with comparatively better safety. However, the temporary occlusion time with this surgery is longer than that with a temporary clipping for aneurysmal surgery; thus, we believe that adequate countermeasures are required to prevent ischemic complications. PMID- 22921037 TI - The prognostic impact of the stroke unit concept after transient ischemic attack. AB - BACKGROUND AND PURPOSE: Transient ischemic attack (TIA) is associated with high short-term risk of stroke, especially in the early phase following the event. Data about the impact of the early hospitalization in a stroke unit on patients with TIA are sparse. This study compares the prognostic impact of the stroke unit concept with conventional care on patients with TIA. METHODS: During a 30-month period (beginning April 2005), 878 patients (mean age, 70+/-12years; 44.3% female) with TIA admitted within 24h of symptom onset were prospectively evaluated. The adjusted logistic regression analyses were used to estimate the odds ratio for the stroke risk during hospitalization and the 90-day mortality. RESULTS: Of 878 patients, 591 (67.3%) were treated in the stroke unit, and 287 (32.7%) underwent conventional care. Patients receiving stroke-unit care had significantly higher rates of cranial computed tomography (96.3% vs. 88.1%; P<.001) and brain-supplying artery ultrasound (97.1% vs. 91.3%; P<.001) investigations. The stroke risk during hospitalization was 1.7% in patients treated in stroke unit and 2.4% in patients received a conventional care. A relevant difference between the groups was not found (1.7% vs. 2.4%; P=.45). The 90-day mortality rate was 1.7% in the stroke unit group compared to 2.2% in the conventional care group (1.7% vs. 2.2%; P=.66). The adjusted logistic regression analyses revealed no difference in stroke rates (odds ratio, 0.68; 95% confidence interval, 0.24-1.9) and in the 90-day mortality (odds ratio, 0.63; 95% confidence interval, 0.2-1.96) between the stroke unit concept and conventional care. CONCLUSION: The prognostic impact of the stroke unit care for patients with transient ischemic attack appears to be similar to that of the conventional care. Further randomized studies are needed to investigate the impact of stroke-unit care on patients with transient ischemic attack. PMID- 22921038 TI - A case of vestibular and oculomotor pathology from bilateral AICA watershed infarcts treated with basilar artery stenting. PMID- 22921039 TI - Granulomatous encephalitis due to Balamuthia mandrillaris is not limited to immune-compromised patients. PMID- 22921040 TI - Risk factors for multiple intracranial aneurysms rupture: a retrospective study. AB - BACKGROUND AND PURPOSE: The presence of predicting the rupture risk of intracranial aneurysms has recently generated considerable controversy. We retrospectively investigated the risk factors for multiple intracranial aneurysms related to rupture. METHODS: Between July 2007 and July 2011, 134 patients with 294 aneurysms were identified after review. Every patient had two or more aneurysms. Univariate and multivariate logistic regression models were used to analyze the risk factors for multiple intracranial aneurysms with age, gender, site and size. RESULTS: 134 patients were divided into three groups according to patient age category (<45, 45-65, >65 years of age). The incidence of aneurysms ruptured in the second group was significantly higher. Three groups showed significant difference (P=0.001 versus >65 years of age). Thirteen of 35 AComA aneurysms were ruptured, accounting for 26% of all ruptured aneurysms, and the rate of rupture at AComA aneurysms in patients was 37.1%. The rate of aneurysm rupture in the AComA was significantly higher than that in other sites (P=0.001). In all 294 aneurysms, 88.1% of the aneurysms were 5mm or less, of which 58.2% were less than 3mm. In the ruptured aneurysms, 68% were 5mm or less. CONCLUSIONS: Our study reveals the pattern of ruptured multiple intracranial aneurysms, in terms of age, size and location of aneurysms. Age, size, and site of aneurysm should be considered in the decision whether to treat an unruptured aneurysm or not. Especially, in cases of multiple aneurysm, the AComA aneurysm is most prone to hemorrhage. PMID- 22921041 TI - [Combined glaucoma cataract surgeries]. AB - The combined cataract-glaucoma surgery is a procedure gaining a higher role in the surgical treatment for patients having both cataract and glaucoma. Both these pathologies are strongly related to the age. A good knowledge of surgical indications and techniques, complications and postoperative follow-up can improve the outcome of this surgery, which is considered to be the best technique in the treatment of combined cataract and glaucoma. The combined glaucoma and cataract surgery enables us to lower the intraocular pressure and gain in visual acuity in one surgery, with the treatment of two distinct disorders. This kind of surgery requires a close follow-up to spot and manage the post-operative complications. PMID- 22921042 TI - Survival analysis of patients with stage I non-small-cell lung cancer using clinical and DNA repair pathway expression variables. AB - BACKGROUND: Lung cancer is the leading cause of cancer-related mortality. Understanding patient attributes that enhance survival and predict recurrence is necessary to individualize treatment options. METHODS: Patients (N = 162) were dichotomized into favorable (n = 101) and unfavorable (n = 61) groups based on survival characteristics. Ku86 and poly(ADP-ribose) polymerase (PARP) expression measures were incorporated into the analyses. LR, Kaplan-Meier analysis, and Cox regression were used to investigate intervariable relationships and survival. Odds ratios (ORs) and hazard ratios (HRs) with 95% confidence intervals (CIs) were used to assess associations. RESULTS: Sex (OR, 0.32; CI-0.14, 0.76), squamous cell carcinoma (SCC) (OR, 0.41; CI-0.17, 0.98), and recurrence (OR, 0.04; CI-0.01, 0.20) confer an unfavorable outcome with area under the receiver operating characteristic curve (Az) = 0.788. Patients with increased tumor grade (OR = 1.84; CI-1.06, 3.19) or increased Ku86 intensity (OR, 2.03; CI-1.08, 3.82) were more likely to be male individuals, and older patients (OR, 1.70; CI-(1.14, 2.52) were more likely to have SCC. Patients older than the median age (HR, 1.86; CI-1.11, 3.12), patients with SCC (HR, 1.78; CI-1.05, 3.01), patients with recurrence (HR, 4.16; CI-2.37, 7.31), and male patients (HR, 2.03; CI-1.20, 3.43) have a higher hazard. None of the DNA repair measures were associated with significant HRs. CONCLUSION: Clinical and pathologic factors that enhance and limit survival for patients with stage I NSCLC were quantified. The DNA repair measures showed little association. These findings are important given that certain clinical and pathologic features are related to better long-term survival outcome than others. PMID- 22921043 TI - The American Society for Gastrointestinal Endoscopy (ASGE) diagnostic algorithm for obscure gastrointestinal bleeding: eight burning questions from everyday clinical practice. AB - The diagnosis and management of patients with obscure gastrointestinal bleeding are often long and challenging processes. Over the last 10 years the introduction in clinical practice of new diagnostic and therapeutic procedures (i.e. Capsule Endoscopy, Computed Tomographic Enterography, Magnetic Resonance Enterography, and Device Assisted Enteroscopy) has revolutionized the diagnostic/therapeutic work-up of these patients. Based on evidence published in the last 10 years, international scientific societies have proposed new practice guidelines for the management of obscure gastrointestinal bleeding, which include these techniques. However, although these algorithms (the most recent ones are endorsed by the American Society for Gastrointestinal Endoscopy - ASGE) allow the management of the large majority of patients, some issues still remain unsolved. The present paper reports the results of the discussion, based on the literature published up to September 2011, among a panel of experts and gastroenterologists, working with Capsule Endoscopy and with Device Assisted Enteroscopy, attending the 6th annual meeting of the Italian Club for Capsule Endoscopy and Enteroscopy. Eight unresolved issues were selected: each of them is presented as a "Burning question" and the "Answer" is the strategy proposed to manage it, according to both the available evidence and the discussion among participants. PMID- 22921044 TI - Variation of quality of colonoscopy in Italy over five years: a nation-wide observational study. AB - BACKGROUND/AIM: A nation-wide survey of colonoscopy practice carried out in 2004 showed disappointing data on colonoscopy quality in Italy. Present study was aimed prospectively at re-evaluating quality indicators of colonoscopy and their changes over a five-year-period. METHODS: The main features of each Endoscopy Unit and performance indicators on consecutive colonoscopies performed in a 2 week period were recorded. Variation of colonoscopy quality was assessed by comparing caecal-intubation and polyp-detection rates in present survey with those collected five-years before; statistical analysis was restricted to centres participating in both data collections. RESULTS: 6158 colonoscopies from 116 centres were evaluated; unadjusted caecal-intubation rate was 83.0%, with 21.6% centres reporting a value >90%; mean polyp-detection rate was 32.0% (range 9.6 71.2% across centres). To assess variation of performance indicators, 4452 procedures from 77 centres were compared to 3589 procedures performed five-years before, in the same centres. A significant difference between the two rounds of data collections was observed for both caecal-intubation (82.6% versus 80.9%, p=0.043) and polyp-detection (31.3% versus 28.1%, p=0.002). However, 52 centres maintained a caecal-intubation rate constantly <90%. CONCLUSIONS: Present data show that colonoscopy in Italy is still far below quality standards and that a significant improvement of practice did not occur over the last five years. Strategies to enhance colonoscopy quality should be pursued by professional societies. PMID- 22921046 TI - Point-of-care ultrasonography in assessing fluid responsiveness in sepsis patients: sonographer characteristics, noninferential statistics, and study design. PMID- 22921045 TI - Images in emergency medicine. Woman with painful purpura. Propylthiouracil related ANCA-positive vasculitis. PMID- 22921048 TI - Clinical policy: Critical issues in the initial evaluation and management of patients presenting to the emergency department in early pregnancy. AB - This clinical policy from the American College of Emergency Physicians is the revision of the 2003 Clinical Policy: Critical Issues in the Initial Evaluation and Management of Patients Presenting to the Emergency Department in Early Pregnancy.(1) A writing subcommittee reviewed the literature to derive evidence based recommendations to help clinicians answer the following critical questions: (1) Should the emergency physician obtain a pelvic ultrasound in a clinically stable pregnant patient who presents to the emergency department (ED) with abdominal pain and/or vaginal bleeding and a beta human chorionic gonadotropin (beta-hCG) level below a discriminatory threshold? (2) In patients who have an indeterminate transvaginal ultrasound, what is the diagnostic utility of beta-hCG for predicting possible ectopic pregnancy? (3) In patients receiving methotrexate for confirmed or suspected ectopic pregnancy, what are the implications for ED management? Evidence was graded and recommendations were developed based on the strength of the available data in the medical literature. A literature search was also performed for a critical question from the 2003 clinical policy.(1) Is the administration of anti-D immunoglobulin indicated among Rh-negative women during the first trimester of pregnancy with threatened abortion, complete abortion, ectopic pregnancy, or minor abdominal trauma? Because no new, high-quality articles were found, the management recommendations from the previous policy are discussed in the introduction. PMID- 22921049 TI - Change of shift. What it's like. PMID- 22921050 TI - Images in emergency medicine. Male with abdominal pain. Abdominal wall pseudocyst. PMID- 22921051 TI - Acute otitis media treatment research: choosing outcome measures, adhering to protocol, and reporting results. PMID- 22921052 TI - A cap and trade approach to improve patients' access to emergency services and health care. PMID- 22921054 TI - Lean health care: the success of a toolkit depends also on the people who use the tools. PMID- 22921056 TI - Images in emergency medicine. Man with sudden onset of bilateral flank pain. Polyarteritis nodosa. PMID- 22921058 TI - Evolution in microfluidic droplet. AB - High-throughput screening (HTS) of enzymatic activity is important for directed evolution-based enzyme engineering. However, substrate and product diffusion can severely compromise these HTS assays. In this issue of Chemistry & Biology, Kintses and coworkers describe a microfluidic platform for the directed evolution of enzymes in droplets that allows for the screening of 10(7) mutants per round of evolution. PMID- 22921057 TI - The business of genome analysis and interpretation. PMID- 22921059 TI - Mass spectrometry of immunolabeled neurons--the best of both techniques. AB - Peptides perform a wide number of physiological roles as signaling molecules between cells as well as other functions. The detection of peptides has generally relied on one of two distinct techniques: immunohistochemistry and mass spectrometry. In this issue of Chemistry & Biology, Neupert and colleagues describe an approach to combine these techniques. PMID- 22921060 TI - A magic bullet for antibiotic discovery. AB - Activation/exploitation of biosynthetic pathways for useful metabolites is a major current interest. The metabolism remodeling approach developed by Craney and colleagues in this issue of (Chemistry & Biology), in which small molecule probes alter the secondary metabolites produced by streptomycetes, could lead to discovery of a multitude of novel antibiotics and other drugs. PMID- 22921061 TI - Disarming bacterial type IV secretion. AB - With common bacterial pathogens becoming increasingly resistant to the current therapeutic arsenal, there is a growing need to utilize alternative strategies when developing new antibacterial drugs. In this issue of Chemistry & Biology, Smith et al. explore the idea of antivirulence drugs by developing inhibitors of the type IV secretion system in Brucella. PMID- 22921062 TI - Designing chemically modified oligonucleotides for targeted gene silencing. AB - Oligonucleotides (ONs), and their chemically modified mimics, are now routinely used in the laboratory as a means to control the expression of fundamentally interesting or therapeutically relevant genes. ONs are also under active investigation in the clinic, with many expressing cautious optimism that at least some ON-based therapies will succeed in the coming years. In this review, we will discuss several classes of ONs used for controlling gene expression, with an emphasis on antisense ONs (AONs), small interfering RNAs (siRNAs), and microRNA targeting ONs (anti-miRNAs). This review provides a current and detailed account of ON chemical modification strategies for the optimization of biological activity and therapeutic application, while clarifying the biological pathways, chemical properties, benefits, and limitations of oligonucleotide analogs used in nucleic acids research. PMID- 22921063 TI - Synthetically accessible non-secosteroidal hybrid molecules combining vitamin D receptor agonism and histone deacetylase inhibition. AB - 1,25-Dihydroxyvitamin D(3) (1,25D), the hormonal form of vitamin D, and several analogs have failed as monotherapies for cancer because of poor efficacy or acquired resistance. However, 1,25D analogs are amenable to bifunctionalization. Preclinical studies have revealed combinatorial effects of 1,25D analogs and histone deacetylase inhibitors (HDACi). Secosteroidal hybrid molecules combining vitamin D receptor (VDR) agonism with HDACi displayed enhanced efficacy but are laborious to synthesize. Here, we have developed easily assembled, fully integrated, non-secosteroidal VDR agonist/HDACi hybrids. The most promising are full VDR agonists with ~10-fold lower potency than 1,25D. Structure/function studies revealed that antiproliferative activity against 1,25D-resistant squamous carcinoma cells required VDR agonism and HDACi. Remarkably, modeling and X-ray crystallography reveal non-secosteroidal hybrids bind in the VDR ligand binding domain in the opposite orientation of their secosteroidal counterparts. PMID- 22921064 TI - Glucocorticoid compounds modify smoothened localization and hedgehog pathway activity. AB - The Hedgehog signaling pathway is linked to a variety of diseases, notably a range of cancers. The first generation of drug screens identified Smoothened (Smo), a membrane protein essential for signaling, as an attractive drug target. Smo localizes to the primary cilium upon pathway activation, and this transition is critical for the response to Hedgehog ligands. In a high content screen directly monitoring Smo distribution in Hedgehog-responsive cells, we identified different glucocorticoids as specific modulators of Smo ciliary accumulation. One class promoted Smo accumulation, conferring cellular hypersensitivity to Hedgehog stimulation. In contrast, a second class inhibited Smo ciliary localization and signaling activity by both wild-type Smo, and mutant forms of Smo, SmoM2, and SmoD473H, that are refractory to previously identified Smo antagonists. These findings point to the potential for developing glucocorticoid-based pharmacological modulation of Smo signaling to treat mutated drug-resistant forms of Smo, an emerging problem in long-term cancer therapy. They also raise a concern about potential crosstalk of glucocorticoid drugs in the Hedgehog pathway, if therapeutic administration exceeds levels associated with on-target transcriptional mechanisms of glucocorticoid action. PMID- 22921065 TI - A Role for the 2' OH of peptidyl-tRNA substrate in peptide release on the ribosome revealed through RF-mediated rescue. AB - The 2' OH of the peptidyl-tRNA substrate is thought to be important for catalysis of both peptide bond formation and peptide release in the ribosomal active site. The release reaction also specifically depends on a release factor protein (RF) to hydrolyze the ester linkage of the peptidyl-tRNA upon recognition of stop codons in the A site. Here, we demonstrate that certain amino acid substitutions (in particular those containing hydroxyl or thiol groups) in the conserved GGQ glutamine of release factor RF1 can rescue defects in the release reaction associated with peptidyl-tRNA substrates lacking a 2' OH. We explored this rescue effect through biochemical and computational approaches that support a model where the 2' OH of the P-site substrate is critical for orienting the nucleophile in a hydrogen-bonding network productive for catalysis. PMID- 22921066 TI - Euphohelioscopin A is a PKC activator capable of inducing macrophage differentiation. AB - To identify small molecules that selectively control hematopoietic stem cell differentiation, we performed an unbiased screen using primary human CD34(+) cells. We identified a plant-derived natural product, euphohelioscopin A, capable of selectively differentiating CD34(+) cells down the granulocyte/monocytic lineage. Euphohelioscopin A also inhibits proliferation and induces differentiation of the myeloid leukemia cell lines THP-1 and HL-60. Mechanistic studies revealed that euphohelioscopin A is an activator of protein kinase C (PKC), and that the promonocytic effects of this natural product are mediated by PKC activation. In addition to shedding insights into normal hematopoiesis, this work may ultimately facilitate the application of stem cell therapies to a host of myeloid dysfunctions. PMID- 22921067 TI - Picoliter cell lysate assays in microfluidic droplet compartments for directed enzyme evolution. AB - We demonstrate the utility of a microfluidic platform in which water-in-oil droplet compartments serve to miniaturize cell lysate assays by a million-fold for directed enzyme evolution. Screening hydrolytic activities of a promiscuous sulfatase demonstrates that this extreme miniaturization to the single-cell level does not come at a high price in signal quality. Moreover, the quantitative readout delivers a level of precision previously limited to screening methodologies with restricted throughput. The sorting of 3 * 10(7) monodisperse droplets per round of evolution leads to the enrichment of clones with improvements in activity (6-fold) and expression (6-fold). The detection of subtle differences in a larger number of screened clones provides the combination of high sensitivity and high-throughput needed to rescue a stalled directed evolution experiment and make it viable. PMID- 22921069 TI - Chemical perturbation of secondary metabolism demonstrates important links to primary metabolism. AB - Bacterially produced secondary metabolites are used as antibiotics, anticancer drugs, and for many other medicinal applications. The mechanisms that limit the production of these molecules in the laboratory are not well understood, and this has impeded the discovery of many important compounds. We have identified small molecules that remodel the yields of secondary metabolites in many actinomycetes and show that one set of these molecules does so by inhibiting fatty acid biosynthesis. This demonstrates a particularly intimate relationship between this primary metabolic pathway and secondary metabolism and suggests an approach to enhance the yields of metabolites for discovery and biochemical characterization. PMID- 22921068 TI - Targeted single-cell microchemical analysis: MS-based peptidomics of individual paraformaldehyde-fixed and immunolabeled neurons. AB - Pinpointing a specific cell from within a relatively uniform cell population to determine its chemical content presents a challenging bioanalytical task. Immunocytochemistry is the classical method used to localize specific molecules and, hence, selected cells. Mass spectrometry also probes endogenous molecules such as neuropeptides within a cell. Here, these two approaches are hyphenated to allow microchemical analysis of immunocytochemical-selected peptidergic neurons. This two-step strategy utilizes antibody-based localization of cells containing selected biomarkers to isolate the cell(s) of interest, followed by peptidomic analysis via mass spectrometry. Applicable to a broad range of analyte and cell types, the strategy was used to successfully profile neuropeptides from individual immunostained insect neurons stored for up to 2 weeks as well as from tissues preserved for 42 weeks. PMID- 22921070 TI - An integrated chemical biology approach provides insight into Cdk2 functional redundancy and inhibitor sensitivity. AB - Cdk2 promotes DNA replication and is a promising cancer therapeutic target, but its functions appear redundant with Cdk1, an essential Cdk affected by most Cdk2 inhibitors. Here, we present an integrated multidisciplinary approach to address Cdk redundancy. Mathematical modeling of enzymology data predicted conditions allowing selective chemical Cdk2 inhibition. Together with experiments in Xenopus egg extracts, this supports a rate-limiting role for Cdk2 in DNA replication. To confirm this we designed inhibitor-resistant (ir)-Cdk2 mutants using a novel bioinformatics approach. Bypassing inhibition with ir-Cdk2 or with Cdk1 shows that Cdk2 is rate-limiting for replication in this system because Cdk1 is insufficiently active. Additionally, crystal structures and kinetics reveal alternative binding modes of Cdk1-selective and Cdk2-selective inhibitors and mechanisms of Cdk2 inhibitor resistance. Our approach thus provides insight into structure, functions, and biochemistry of a cyclin-dependent kinase. PMID- 22921071 TI - Identification of the binding site of Brucella VirB8 interaction inhibitors. AB - Secretion systems translocate virulence factors of many bacterial pathogens, enabling their survival inside the host organism. Consequently, inhibition strongly attenuates pathogenicity and can be considered a target for novel antimicrobial drugs. The type IV secretion system (T4SS) of the intracellular pathogen Brucella is a prerequisite for its virulence, and in this work we targeted the interactions of the essential assembly factor protein, VirB8, using small-molecule inhibitors. High-throughput screening identified several potent and specific inhibitors, and the target-binding site of these inhibitors was identified by X-ray crystallography, in silico docking, and analysis of the derivates of the inhibitor B8I-2. VirB8 interaction inhibitors bind to a surface groove opposite to the dimerization interface, and by varying the binding-site residues, we were able to determine which residues are required for inhibitor activity. E115 and K182 were found to be especially important, and changes at R114, Y229, and L151 also reduced inhibitor efficiency. PMID- 22921072 TI - Characterization of a silent azaphilone gene cluster from Aspergillus niger ATCC 1015 reveals a hydroxylation-mediated pyran-ring formation. AB - Azaphilones are a class of fungal metabolites characterized by a highly oxygenated pyrano-quinone bicyclic core and exhibiting a broad range of bioactivities. Although widespread among various fungi, their biosynthesis has not been thoroughly elucidated. By activation of a silent (aza) gene cluster in Aspergillus niger ATCC 1015, we discovered six azaphilone compounds, azanigerones A-F (1, 3-7). Transcriptional analysis and deletion of a key polyketide synthase (PKS) gene further confirmed the involvement of the aza gene cluster. The biosynthetic pathway was shown to involve the convergent actions of a highly reducing PKS and a non-reducing PKS. Most significantly, in vitro reaction of a key flavin-dependent monooxygenase encoded in the cluster with an early benzaldehyde intermediate revealed its roles in hydroxylation and pyran-ring formation to afford the characteristic bicylic core shared by azaphilones. PMID- 22921073 TI - Firefly luciferase in chemical biology: a compendium of inhibitors, mechanistic evaluation of chemotypes, and suggested use as a reporter. AB - Firefly luciferase (FLuc) is frequently used as a reporter in high-throughput screening assays, owing to the exceptional sensitivity, dynamic range, and rapid measurement that bioluminescence affords. However, interaction of small molecules with FLuc has, to some extent, confounded its use in chemical biology and drug discovery. To identify and characterize chemotypes interacting with FLuc, we determined potency values for 360,864 compounds found in the NIH Molecular Libraries Small Molecule Repository, available in PubChem. FLuc inhibitory activity was observed for 12% of this library with discernible SAR. Characterization of 151 inhibitors demonstrated a variety of inhibition modes, including FLuc-catalyzed formation of multisubstrate adduct enzyme inhibitor complexes. As in some cell-based FLuc reporter assays, compounds acting as FLuc inhibitors yield paradoxical luminescence increases, thus data on compounds acquired from FLuc-dependent assays require careful analysis as described here. PMID- 22921074 TI - Metabolic profiling of follicular fluid and plasma from natural cycle in vitro fertilization patients--a pilot study. AB - OBJECTIVE: To investigate changes in follicular fluid (FF) and plasma composition during the follicular and periovulatory phases of the menstrual cycle in patients undergoing assisted conception, using proton nuclear magnetic resonance ((1)H NMR) spectroscopy-based metabolite profiling. DESIGN: A pilot prospective laboratory study. SETTING: Assisted conception clinic in a university hospital. PATIENT(S): Ten women undergoing natural-cycle (NC) in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) with either male factor subfertility or unexplained subfertility. INTERVENTION(S): FF and plasma were collected during the midfollicular phase or at the LH-surge and at the time of oocyte collection. MAIN OUTCOME MEASURE(S): (1)H-NMR spectroscopy was performed on the fluids and the metabolic profiles compared across the phases with the use of principal components analysis (PCA). RESULT(S): LH-surge FF resembled periovulatory FF more than midfollicular FF, with higher levels of lactate and pyruvate and lower glucose. Periovulatory plasma contained higher levels of glucose and acetate and lower glycoprotein, trimethylamine, and glycine compared with midfollicular and LH-surge plasma. CONCLUSION(S): NMR-based metabolite profiling of FF and plasma has potential for identifying changes across menstrual stages, studying the impact of exogenous hCG administration, and in the pursuit of biomarkers to predict fertility treatment outcome. PMID- 22921075 TI - Blastocyst preimplantation genetic diagnosis (PGD) of a mitochondrial DNA disorder. AB - OBJECTIVE: To evaluate the utility of trophectoderm biopsy for preimplantation genetic diagnosis (PGD) of mitochondrial (mt) DNA mutation load. DESIGN: A PGD case and analysis of blastocyst mosaicism. SETTING: Academic center for reproductive medicine. PATIENT(S): A 30-year-old carrier of 35% 3243A>G mtDNA mutation load with a daughter affected by mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome. INTERVENTION(S): Blastocyst biopsy for PGD of mutation load and gender. MAIN OUTCOME MEASURE(S): Variation in mutation load within and among embryos, and newborn mutation load after PGD-based selection. RESULT(S): Oocytes and embryos were found to possess a variety of 3243A>G mutation loads from 9% to 90% in oocytes and 7% to 91% in embryos, demonstrating that PGD would be a relevant procedure. Highly consistent results were obtained within multiple biopsies of both cleavage- and blastocyst-stage embryos. Importantly, mutation loads observed in trophectoderm were predictive of the inner cell mass (r(2) = 0.97). Transfer of a male embryo, predicted to possess 12% mutation load by analysis of a trophectoderm biopsy, resulted in the delivery of a boy with tissue-specific mutation loads ranging from undetectable to 15%. CONCLUSION(S): This study represents the first successful clinical application of PGD to reduce the transgenerational risk of transmitting an mtDNA disorder and supports the applicability of blastocyst trophectoderm PGD for carriers of mtDNA mutations attempting reproduction. PMID- 22921076 TI - Refining the measurement of sperm DNA fragmentation. PMID- 22921077 TI - Interpreting human follicular recruitment and antimullerian hormone concentrations throughout life. AB - The changes in the relationships between circulating antimullerian hormone, the size of the primordial follicle pool, and follicular recruitment before and through the reproductive years have now been clarified, and show dynamic changes through sexual development. The constant relationship between the number of follicles and circulating antimullerian hormone exists only after the age of 25 years, implying that the association between follicular recruitment and follicular survival to the later stages of development is not constant across the reproductive life course. This commentary assesses the factors that may underlie these relationships and their clinical implications for reproductive health. PMID- 22921078 TI - Effect of antiangiogenic treatment on peritoneal endometriosis-associated nerve fibers. AB - OBJECTIVE: To investigate the effect of antiangiogenic treatment on experimental endometriotic lesion nerve fibers. DESIGN: Heterologous mouse model of endometriosis. SETTING: University Institute IVI, University Hospital La Fe. ANIMAL(S): Ovariectomized nude mice (n = 16) receiving human endometrial fragments from oocyte donors (n = 4). INTERVENTION(S): Endometrium fragments stuck in the peritoneum of 5-week-old female nude mice treated with vehicle (n = 8) and antiangiogenic agent cabergoline (n = 8; Cb(2,) 0.05 mg/kg/day) for 14 days. MAIN OUTCOME MEASURE(S): Immunofluorescence analysis of von-Willebrand factor (vWF) and vascular smooth muscle cells (alphaSMA) for evaluating the number of immature blood vessels (IBV) and microvascular density (MVD); immunochemical analysis of protein-gene product 9.5 (PGP 9.5) to assess nerve fibers density (NFD), and blue toluidine staining to confirm presence of mast cells and macrophages in endometriotic lesions. RESULT(S): All the results were quantified by morphometric techniques. The IBV, NFD, and number of macrophages and mast cells were statistically significantly decreased in the Cb2-treated group when compared with controls. CONCLUSION(S): Antiangiogenic treatment statistically significantly diminishes new blood vessel formation after macrophage, mast cell, and nerve fiber reduction, providing a rationale to test antiangiogenic agents as a novel therapeutic approach to severe pelvic pain associated with human peritoneal endometriosis. PMID- 22921079 TI - Structure based molecular design, synthesis and biological evaluation of alpha pyrone analogs as anti-HSV agent. AB - Several options for treating Herpes Simplex Virus type 1 and type 2 are available. However, non-specific inhibition and drug resistance warrants the discovery of new anti-herpetic compounds with better therapeutic profile or different mode of action. The non-nucleoside inhibitors of HSV DNA polymerase target the site that is less important for the binding of a natural nucleoside or nucleoside inhibitors. In the present study, we have explored the possibility to find a new lead molecule based on alpha-pyrone analogs as non-nucleoside inhibitors using structure based modeling approach. The designed molecules were synthesized and evaluated for anti-HSV activity using MTT assay. The compound 5h with EC(50) 7.4MUg/ml and CC(50) 52.5MUg/ml was moderately active against HSV when compared to acyclovir. A plaque reduction assay was also carried out and results reveal that 5h is more effective against HSV-1 with better selective index of 12.8 than against HSV-2 (SI=3.6). The synthesized compounds were also evaluated for anti-HIV activity, but none were active. PMID- 22921080 TI - 2-Substituted 4,5-dihydrothiazole-4-carboxylic acids are novel inhibitors of metallo-beta-lactamases. AB - Bacterial resistance to beta-lactam antibiotics caused by class B metallo-beta lactamases (MBL), especially for certain hospital-acquired, Gram-negative pathogens, poses a significant threat to public health. We report several 2 substituted 4,5-dihydrothiazole-4-carboxylic acids to be novel MBL inhibitors. Structure activity relationship (SAR) and molecular modeling studies were performed and implications for further inhibitor design are discussed. PMID- 22921081 TI - Apoptosis-inducing effects of distichamine and narciprimine, rare alkaloids of the plant family Amaryllidaceae. AB - Several of the Amaryllidaceae alkaloids are known for their cytotoxic properties, of which the lycorine group representatives are prominent for potent and cell line specific antiproliferative activities. As a distinct niche within the lycorine group, the phenanthridones, exemplified by narciclasine and pancratistatin, have shown much promise as remarkably selective cytotoxic agents and are presently at various stages of development, with a clinical candidate likely to appear on the market within the next decade. The crinane group of the Amaryllidaceae has also spawned several molecules, such as crinamine and haemanthamine, with promising cytotoxic activities. In the present study, the beta-crinane distichamine as well as the phenanthridone narciprimine, both rare constituents of the Amaryllidaceae, are revealed as novel antiproliferative agents. Apoptosis-inducing effects are demonstrated for distichamine in human acute lymphoblastic leukemia (CEM) cells. These findings provide further insights to the structural details of the apoptosis-inducing pharmacophores resident within both series of alkaloids. PMID- 22921082 TI - Skeletal morphology and morphometry of the lumbosacral junction in German shepherd dogs and an evaluation of the possible genetic basis for radiographic findings. AB - The aim of this study was to identify skeletal variations in the lumbosacral junction (LSJ) of the German shepherd dog (GSD) compared with other large breeds. The radiographic traits of the LSJ were investigated in a group of 733 GSDs and a control group of 334 dogs of other breeds that were matched in terms of size. Nine morphological and 17 morphometric traits were recorded and analysed. Furthermore, the possibility of a genetic basis for these radiographic features was evaluated by calculation of genetic variance components. Five of the morphological and 14 of the morphometric traits varied significantly between the GSD group and the control group (P<0.05). Osteochondrosis of the sacral endplate (SOC) had a higher prevalence in the GSDs (10.1%) compared with controls (5.7%). The majority of LSJ degenerative changes recorded from the radiographs occurred in the GSDs. The extent and relative proportion of lumbosacral step formations were greater in the GSD group compared with controls (P<0.001). The lumbosacral vertebral canal height was reduced in the GSD compared with the control dogs (P<0.001) suggesting a primary stenosis. This was accentuated by an abrupt tapering of the vertebral canal at the level of the LSJ indicated by a lumbosacral ratio of 1.51 in the GSD. The skeletal morphology and morphometry of the LSJ in the GSD seem to be different from that found in other large dogs. For multiple traits frequently observed in GSD such as SOC, step formations, and LSJ stenosis, moderate to high non-zero heritabilities were noted. As these features are also assumed to promote lumbosacral disease, selection against these traits is suggested. PMID- 22921083 TI - Observations on the design and use of footbaths for the control of infectious hoof disease in dairy cattle. AB - A survey of 65 freestall-housed dairy herds in five different countries, with an average of 1023 milking cows, found that footbaths were used 1-4 times per day for 1-7 days per week, with between 80 and 3000 cows passing through the bath between chemical changes. The most common agents used were copper sulfate (41/65) and formalin (22/65). Twenty-seven herds (42%) used more than one chemical. The median footbath measured 2.03 m long by 0.81m wide, and was filled to a depth of 0.11 m with a volume of 189 L (range 80-1417 L). An observational behavioral study was conducted using a custom-designed footbath to test four different bath dimensions, with two different step-in heights. The number of immersions per rear foot was counted for each footbath design for each cow passing through the bath on two consecutive days. While a higher step-in height significantly increased the number of foot immersions, the effect was small compared to the effect of length. The probability of each rear foot receiving at least two immersions reached 95% at a bath length of 3.0m, and a significant increase in the frequency of three and four immersions per foot was observed between 3.0 and 3.7 m. In order to optimize the number of foot immersions per cow pass, while limiting the footbath volume, this study recommends a bath 3.0-3.7 m long, 0.5-0.6m wide, with a 28 cm step-in height. PMID- 22921084 TI - Recent patents on bacteriocins: food and biomedical applications. AB - Most types of bacteria produce bacteriocins, which are proteinaceous extracellular compounds that can inhibit the growth of other undesirable microorganisms. Bacteriocins are receiving increasing attention, due to their many applications, ranging from their initial application in strategies for food preservation to more recent proposed uses in biomedical strategies aimed at fighting certain bacterial infections. Thus, while nisin has a long history of use as a safe additive in certain food products for the purpose of food preservation, certain bacteriocin-producing lactic acid bacteria, which are generally recognised as safe microorganisms, or their extracellular extracts are receiving increased attention as protective cultures or antimicrobial extracts in minimally processed food products. More recently, a number of these bacteriocinproducing cultures have been proposed for use in other applications, such as in probiotics, for the inhibition of biofilms in the food industry, or even as coadjuvants of combined therapeutical strategies along with other antimicrobial agents in biomedical applications. This review aims to provide a brief overview of the most relevant recent patents in this field. PMID- 22921085 TI - [Pathophysiology of ANCA-associated vasculitides]. AB - ANCA-associated vasculitides comprise granulomatosis with polyangiitis (GPA) (formerly names Wegener's granulomatosis), Churg-Strauss syndrome (SCS) (which will be renamed GPA and eosinophilia) and microscopic polyangiitis (MPA). Immune cells (dendritic and non dendritic cells) and inflammatory cells (neutrophils, monocytes, macrophages) and resident cells (endothelial cells, fibroblasts) are implicated in the pathophysiology of ANCA-associated vasculitides. One of the targets of ANCA, myeloperoxydase, is only present in the azurophil granules of neutrophils, whereas the other target of these antibodies, proteinase 3, is also present at the internal face of cytoplasmic membrane of neutrophils, as well as at their surface. Anti-myeloperoxydase ANCA are pathogenicin vitroandin vivo, whereas the pathogenicity of anti-proteinase 3 ANCA has only been demonstrated in vitro and recent studies suggest a pathogenic role of ANCA anti-PR3 in mouse model. Two phenotypes of GPA can be distinguished: a granulomatous form, localized to the respiratory tract with Th1 immune response features, and a vasculitic form with Th2 immune response features. Recently, an increase in TH17 lymphocytes at the acute phase and a defect in T regulatory cells at the chronic phase have been identified in GPA. The role of B-lymphocytes in the pathogenesis of ANCA-associated vasculitides is now well documented by the effectiveness of rituximab in the treatment of this condition. PMID- 22921086 TI - [Eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome)]. AB - Eosinophilic granulomatosis with polyangiitis (EGPA) (Churg-Strauss), is a rare necrotizing vasculitis of small-sized vessels, associated to antimyeloperoxydase ANCA in 40% of patients. EGPA occurs in patients with asthma. Asthma is sever, associated with eosinophilia and extrapulmonary symptoms. Among them, mononeuritis multiplex is the most frequent symptom. When cardiac involvement is present, prognosis is poor. Despite a good overall prognosis, deaths are caused by vasculitis activity, gastrointestinal and cardiac involvement. Treatment is well codified based on steroids, which are quickly effective. Immunosuppressants combined with corticosteroids are compulsory to treat the most sever forms, mainly when cardiac and gastrointestinal or renal symptoms are present. PMID- 22921087 TI - [Vasculitis: Time of changes]. PMID- 22921088 TI - Emtricitabine/rilpivirine/tenofovir disoproxil fumarate single-tablet regimen: a guide to its use in HIV-1 infection. AB - The once-daily, single-tablet regimen of emtricitabine/rilpivirine/tenofovir disoproxil fumarate (EvipleraTM [EU]; CompleraTM [US]) provides a convenient option for antiretroviral therapy in treatment-naive patients with HIV-1 infection. In well designed trials in this patient population, rilpivirine plus emtricitabine/tenofovir disoproxil fumarate was noninferior to efavirenz plus emtricitabine/tenofovir disoproxil fumarate in terms of reducing viral HIV-1 RNA level to <50 copies/mL and was generally better tolerated than efavirenz plus emtricitabine/tenofovir disoproxil fumarate. PMID- 22921089 TI - Structural sweet spot for A1 adenosine receptor activation by truncated (N) methanocarba nucleosides: receptor docking and potent anticonvulsant activity. AB - A(1) adenosine receptor (AR) agonists display antiischemic and antiepileptic neuroprotective activity, but peripheral cardiovascular side effects impeded their development. SAR study of N(6)-cycloalkylmethyl 4'-truncated (N) methanocarba-adenosines identified 10 (MRS5474, N(6)-dicyclopropylmethyl, K(i) = 47.9 nM) as a moderately A(1)AR-selective full agonist. Two stereochemically defined N(6)-methynyl group substituents displayed narrow SAR; groups larger than cyclobutyl greatly reduced AR affinity, and those larger or smaller than cyclopropyl reduced A(1)AR selectivity. Nucleoside docking to A(1)AR homology model characterized distinct hydrophobic cyclopropyl subpockets, the larger "A" forming contacts with Thr270 (7.35), Tyr271 (7.36), Ile274 (7.39), and carbon chains of glutamates (EL2) and the smaller subpocket "B" forming contacts between TM6 and TM7. 10 suppressed minimal clonic seizures (6 Hz mouse model) without typical rotarod impairment of A(1)AR agonists. Truncated nucleosides, an appealing preclinical approach, have more druglike physicochemical properties than other A(1)AR agonists. Thus, we identified highly restricted regions for substitution around N(6) suitable for an A(1)AR agonist with anticonvulsant activity. PMID- 22921090 TI - Ultra-sensitive detection of Ag+ ions based on Ag+-assisted isothermal exponential degradation reaction. AB - Ag(+) ions are greatly toxic to a lot of algae, fungi, viruses and bacteria, which can also induce harmful side-effects to environments and human health. Herein we report an ultra-sensitive method for the selective detection of Ag(+) ions with electrochemical technique based on Ag(+)-assisted isothermal exponential degradation reaction. In the presence of Ag(+), mismatched trigger DNA can transiently bind to template DNA immobilized on an electrode surface through the formation of C-Ag(+)-C base pair, which then initiates the isothermal exponential degradation reaction. As a result, the mismatched trigger DNA may melt off the cleaved template DNA to trigger rounds of elongation and cutting. After the cyclic degradation reactions, removal of the template DNA immobilized on the electrode surface can be efficiently monitored by using electrochemical technique to show the status of the electrode surface, which can be then used to determine the presence of Ag(+). Further studies reveal that the proposed method can be ultra-sensitive to detect Ag(+) at a picomolar level. The selectivity of the detection can also be satisfactory, thus the proposed method for the Ag(+) ions detection may be potentially useful in the future. PMID- 22921091 TI - Volatile general anesthetic sensing with organic field-effect transistors integrating phospholipid membranes. AB - The detailed action mechanism of volatile general anesthetics is still unknown despite their effect has been clinically exploited for more than a century. Long ago it was also assessed that the potency of an anesthetic molecule well correlates with its lipophilicity and phospholipids were eventually identified as mediators. As yet, the direct effect of volatile anesthetics at physiological relevant concentrations on membranes is still under scrutiny. Organic field effect transistors (OFETs) integrating a phospholipid (PL) functional bio inter layer (FBI) are here proposed for the electronic detection of archetypal volatile anesthetic molecules such as diethyl ether and halothane. This technology allows to directly interface a PL layer to an electronic transistor channel, and directly probe subtle changes occurring in the bio-layer. Repeatable responses of PL FBI-OFET to anesthetics are produced in a concentration range that reaches few percent, namely the clinically relevant regime. The PL FBI-OFET is also shown to deliver a comparably weaker response to a non-anesthetic volatile molecule such as acetone. PMID- 22921092 TI - Hybridization assay of insect antifreezing protein gene by novel multilayered porous silicon nucleic acid biosensor. AB - A fabrication of a novel simple porous silicon polybasic photonic crystal with symmetrical structure has been reported as a nucleic acid biosensor for detecting antifreeze protein gene in insects (Microdera puntipennis dzhungarica), which would be helpful in the development of some new transgenic plants with tolerance of freezing stress. Compared to various porous silicon-based photonic configurations, porous silicon polytype layered structure is quite easy to prepare and shows more stability; moreover, polybasic photonic crystals with symmetrical structure exhibit interesting optical properties with a sharp resonance in the reflectance spectrum, giving a higher Q factor which causes higher sensitivity for sensing performance. In this experiment, DNA oligonucleotides were immobilized into the porous silicon pores using a standard crosslink chemistry method. The porous silicon polybasic symmetrical structure sensor possesses high specificity in performing controlled experiments with non complementary DNA. The detection limit was found to be 21.3nM for DNA oligonucleotides. The fabricated multilayered porous silicon-based DNA biosensor has potential commercial applications in clinical chemistry for determination of an antifreeze protein gene or other genes. PMID- 22921093 TI - Bimetallic AuPt nanochains: Synthesis and their application in electrochemical immunosensor for the detection of carcinoembryonic antigen. AB - The recent development in the nanotechnology has paved the way for a large number of alloyed nanomaterials and devices of desirable properties which have useful functions for electrochemical sensor and biosensor applications. In this paper, bimetallic AuPt nanochains were synthesized through a mild chemical method, with which anti-horseradish peroxidase-conjugated anti-carcinoembryonic antigen (HRP anti-CEA-NCAuPt) was developed for electrochemical detection of carcinoembryonic antigen (CEA) in a sandwich-type immunoassay format. The alloyed nanocrystals exhibit not only sound signal amplification effect of Au nanoparticles, but also further new combination of interfacial, electrical and structural properties arising from the disparate AuPt components. As a result, the electrochemical signal was significantly amplified by using the HRP-anti-CEA-NCAuPt as tracer and hydrogen peroxide as enzyme substrate. The linear range of the developed immunosensor is 0.01-200ng/mL and the detection limit is 0.11pg/mL of CEA, which makes the biometallic nanochains promising candidates for the next-generation sandwich-type electrochemical immunoassays. PMID- 22921094 TI - Nutrient sensor-mediated programmed nonalcoholic fatty liver disease in low birthweight offspring. AB - OBJECTIVE: We hypothesized that gestationally programmed nonalcoholic fatty liver disease in low-birthweight offspring is mediated through nutrient sensors nicotinamide adenine dinucleotide+-dependent histone deacetylase (SIRT1) and AMP activated protein kinase (AMPK). STUDY DESIGN: Pregnant dams received ad libitum food or were 50% food restricted from pregnancy days 10-21 to produce control and low-birthweight newborn offspring, respectively. All pups were nursed by control dams and weaned to ad libitum feed. We determined hepatic SIRT1 and AMPK activities and protein expression of lipid targets in low-birthweight and control fetuses, newborns, and adult offspring (3 months). RESULTS: Low-birthweight fetuses demonstrated increased prenatal hepatic SIRT1 activity, although with increased lipogenesis. After birth, low-birthweight newborn offspring undergo postnatal suppression of hepatic SIRT1 and AMPK activities in conjunction with increased lipogenesis, decreased lipolysis, and increased fat stores. CONCLUSION: These findings suggest that undernutrition stress in utero may program hepatic nutrient sensors to perceive normal postnatal nutrition as a state of nutrient excess with the induction of hepatic lipid storage. PMID- 22921095 TI - Preconceptional laparoscopic abdominal cerclage: a multicenter cohort study. AB - OBJECTIVE: The purpose of this study was to evaluate the effectiveness of laparoscopic abdominal cerclage placement in the prevention of recurrent preterm birth. STUDY DESIGN: We conducted a multicenter cohort study with retrospective Dutch (32 patients) and Boston (34 patients) cohorts who had undergone preconceptional laparoscopic abdominal cerclage placement. Eligible patients had at least 1 second/third trimester fetal loss or delivered at <34 weeks of gestation because of cervical insufficiency and/or a short or absent cervix. Primary outcome was delivery of an infant at >= 34 weeks of gestation with neonatal survival. Secondary outcome measures included surgical and pregnancy outcomes and patients' satisfaction (Dutch cohort). RESULTS: Surgical outcomes of 66 patients were excellent, with 3 minor complications. After preconceptional laparoscopic abdominal cerclage, 35 pregnancies were evaluated. Twenty-five patients (71.4%) delivered at >= 34 weeks of gestation; 3 patients (8.6%) experienced a second-trimester fetal loss. The total fetal survival rate was 90.0%. CONCLUSION: Preconceptional laparoscopic abdominal cerclage shows encouraging and favorable perinatal outcomes in patients with a poor obstetric history. PMID- 22921096 TI - Practices of obstetrician-gynecologists regarding nonvaccine-related public health recommendations during the 2009 H1N1 influenza pandemic. AB - OBJECTIVE: We examined practices of obstetrician-gynecologists regarding nonvaccine-related public health recommendations during the 2009 H1N1 influenza pandemic. STUDY DESIGN: From February to May 2010, a survey was sent to a random sample of members of the American College of Obstetricians and Gynecologists involved in obstetric care. RESULTS: Obstetrician-gynecologists varied in their adherence to 2009 H1N1 influenza public health recommendations. Nearly all reported prescribing antiviral medications to pregnant women with suspected influenza. Most obstetrician-gynecologists reported using preventive practices in the outpatient setting to reduce exposure of well patients to ill ones. A wide range of responses was provided regarding postpartum infection control practices, suggesting lack of awareness of, disagreement with, or difficulty adhering to these recommendations. CONCLUSION: Obstetrician-gynecologists reported that they adhered to some recommendations related to 2009 H1N1 influenza, but not to others. These data provide insight into strategies for development and dissemination of recommendations in a future pandemic. PMID- 22921097 TI - Prevalence of polycystic ovary syndrome among the privately insured, United States, 2003-2008. AB - OBJECTIVE: The purpose of this study was to estimate the prevalence of polycystic ovary syndrome (PCOS) and its phenotypes as defined by the National Institutes of Health, Rotterdam criteria, and Androgen Society. STUDY DESIGN: Thomson Reuters MarketScan Commercial databases (Thomson Reuters Healthcare Inc, New York, NY) for 2003-2008 were used to calculate the prevalence of PCOS and to assess differences in demographic characteristics and comorbid conditions among women who were 18-45 years old with and without PCOS. RESULTS: The prevalence of PCOS was 1585.1 per 100,000; women with phenotype A or classic PCOS were most prevalent at 1031.5 per 100,000. Women with PCOS were more likely than those without PCOS to be 25-34 years old, be from the South, be infertile, have metabolic syndrome, have been seen by an endocrinologist, and have taken oral contraceptives. CONCLUSION: This is the first study to use all available criteria to estimate the prevalence of PCOS. Providers should evaluate women with menstrual dysfunction for the presence of PCOS. PMID- 22921100 TI - Electrocardiogram beat detection enhancement using independent component analysis. AB - Beat detection is a basic and fundamental step in electrocardiogram (ECG) processing. In many ECG applications strong artifacts from biological or technical sources could appear and cause distortion of ECG signals. Beat detection algorithm desired property is to avoid these distortions and detect beats in any situation. Our developed method is an extension of Christov's beat detection algorithm, which detects beat using combined adaptive threshold on transformed ECG signal (complex lead). Our offline extension adds estimation of independent components of measured signal into the transformation of ECG creating a signal called complex component, which enhances ECG activity and enables beat detection in presence of strong noises. This makes the beat detection algorithm much more robust in cases of unpredictable noise appearances, typical for holter ECGs and telemedicine applications of ECG. We compared our algorithm with the performance of our implementation of the Christov's and Hamilton's beat detection algorithm. PMID- 22921098 TI - Gas embolism during hysteroscopic surgery using bipolar or monopolar diathermia: a randomized controlled trial. AB - OBJECTIVE: The objective of the study was to determine the incidence and amount of gas embolism during hysteroscopic surgery using either monopolar or bipolar diathermia and to investigate the relationship between the severity of gas embolism and the amount of intravasation of distension fluid. STUDY DESIGN: This was a randomized, observer-blinded trial. Fifty patients, scheduled for hysteroscopic surgery, were assigned to either monopolar or bipolar diathermia. Transesophageal echocardiography was used to detect and classify gas embolism (grade 0-IV). Intravasation of distension fluid was measured. RESULTS: Venous gas embolism was observed in all but 1 patient. A higher incidence of more extensive (grade IV) was seen during bipolar diathermia (42% vs 13%; P = .031). Paradoxical embolism was observed in 2 patients. When intravasation exceeded 1000 mL, significantly more grade IV venous gas embolism was seen (P = .049). CONCLUSION: During hysteroscopic surgery, gas embolism was equally observed irrespective of the type of diathermia. However, more extensive embolism was observed when intravasation of distension fluid exceeded 1 L. These results question the acceptance of up to 2500 mL intravasation of distension fluid if bipolar diathermia is used. PMID- 22921101 TI - [Helicobacter pylori eradication frequency with the conventional triple therapy in adult patients at the Centro Medico Issemym]. AB - BACKGROUND: In Mexico, the prevalence of Helicobacter pylori (H. pylori) infection is high. The bacterial eradication rate with the administration of antibiotic regimens recommended by international guidelines is not yet clear. AIMS: To determine the eradication frequency of H. pylori infection in the adult Mexican population that underwent treatment with the conventional triple regimen. MATERIAL AND METHODS: A cross-sectional study was carried out that evaluated the effectiveness of the triple regimen in individuals with confirmed infection that received consensual treatment and then underwent tests to corroborate eradication. RESULTS: From a total of 249 potential case records, 26 did not meet the inclusion criteria. Two hundred and twenty-three patients were enrolled for analysis, 64,00% women and 36,00% men, with a mean age of 49,4 years (range 17 86). Comorbidities presented in 55,60% of the patients and 28,60% referred to chronic use of nonsteroidal anti-inflammatory drugs (NSAIDs). Bacterial eradication with the triple regimen was 65,50% (146/223); of the 77 patients with no eradication, 11 received a quadruple regimen as second-line treatment resulting in bacterial eradication in 5/11 (45,45%) patients, for an overall eradication of 67,70%. CONCLUSIONS: The eradication rate in our study population was suboptimal due to the probability of multiple factors that are difficult to identify, given the retrospective design of the study. A prospective and controlled evaluation of the recommended regimens needs to be carried out in order to determine their true effectiveness. PMID- 22921102 TI - [Are we doing the right thing with Helicobacter pylori?]. PMID- 22921103 TI - [Esophageal duplication cyst: an unusual finding]. PMID- 22921104 TI - Review of a major epidemic of methicillin-resistant Staphylococcus aureus: the costs of screening and consequences of outbreak management. AB - BACKGROUND: A major outbreak of methicillin-resistant Staphylococcus aureus (MRSA) occurred in locations C and Z of our hospital and lasted for several years. It affected 1,230 patients and 153 personnel. METHODS: Outbreak management was installed according to the Dutch "search and destroy" policy. A rapid, high throughput method for molecular screening of potential MRSA carriers was implemented. Outbreak isolates were retrospectively genotyped by pulsed field gel electrophoresis. Costs of molecular screening were compared with screening by culture. RESULTS: Genotyping results revealed 4 distinct epidemic MRSA clones. Three were present in hospital C. Because of a merger of hospitals, these clones spread to hospital Z. Another clone of MRSA affected other health care-related institutions in the region. Because of the implementation of strict containment measures of the "search and destroy" policy, the annual number of tests decreased from 100,000 to 18,000. The disposables and reagents used in polymerase chain reaction technology are more expensive than those of conventional methods. However, the clinical and economic benefits of fast results in regard to expenses of the hospital clearly outweigh the higher costs of screening. CONCLUSION: The implementation of a rapid, high-throughput molecular screening system greatly contributed to the effectiveness of strict containment measures of the "search and destroy" policy. The major epidemic clones of MRSA in the outbreak were eradicated by this strategy. PMID- 22921106 TI - Decreased prevalence of atopic features in patients with psoriatic arthritis, but not in psoriasis vulgaris. AB - BACKGROUND: The prevalence of atopic disorders is reduced in patients with various autoinflammatory diseases but, to our knowledge, this association has not been studied in psoriasis vulgaris or psoriatic arthritis (PSA). OBJECTIVE: Prevalence of hay fever, asthma, and sensitization to common aeroallergens was compared in patients with psoriasis vulgaris to patients with PSA and control subjects; we also investigated whether atopy influences the arthritis activity and severity scores in patients with PSA. METHODS: In a cross-sectional cohort study design, the differences in patient-reported lifetime prevalence of atopic disorders and serum IgE directed against common aeroallergens were compared. The effect of atopy on arthritis severity was assessed using the 28-joint Disease Activity Score and Health Assessment Questionnaire. Logistic regression models were used to calculate crude and adjusted odds ratios with 95% confidence intervals (CI) for presence of atopy. RESULTS: A total of 168 patients with PSA, 133 patients with psoriasis vulgaris, and 147 control subjects were included. The lifetime prevalence of hay fever did not differ across groups. Patients with PSA were less likely to have had asthma than control subjects (adjusted odds ratio 0.20; 95% CI 0.04-0.92) and they were less likely to be sensitized (adjusted odds ratio 0.50; 95% CI 0.25-0.99). Health Assessment Questionnaire-visual analog scales for pain and for patient global score were significantly reduced by sensitization to common aeroallergens (beta-coefficients -0.54 [95% CI -0.84 to 0.25] and -18.4 [95% CI -28.5 to -8.25], respectively.) LIMITATIONS: This was a cross-sectional, small-numbered study. CONCLUSION: Atopy may protect against development of PSA and diminish its severity. PMID- 22921105 TI - SNPs in stress-responsive rice genes: validation, genotyping, functional relevance and population structure. AB - BACKGROUND: Single nucleotide polymorphism (SNP) validation and large-scale genotyping are required to maximize the use of DNA sequence variation and determine the functional relevance of candidate genes for complex stress tolerance traits through genetic association in rice. We used the bead array platform-based Illumina GoldenGate assay to validate and genotype SNPs in a select set of stress-responsive genes to understand their functional relevance and study the population structure in rice. RESULTS: Of the 384 putative SNPs assayed, we successfully validated and genotyped 362 (94.3%). Of these 325 (84.6%) showed polymorphism among the 91 rice genotypes examined. Physical distribution, degree of allele sharing, admixtures and introgression, and amino acid replacement of SNPs in 263 abiotic and 62 biotic stress-responsive genes provided clues for identification and targeted mapping of trait-associated genomic regions. We assessed the functional and adaptive significance of validated SNPs in a set of contrasting drought tolerant upland and sensitive lowland rice genotypes by correlating their allelic variation with amino acid sequence alterations in catalytic domains and three-dimensional secondary protein structure encoded by stress-responsive genes. We found a strong genetic association among SNPs in the nine stress-responsive genes with upland and lowland ecological adaptation. Higher nucleotide diversity was observed in indica accessions compared with other rice sub-populations based on different population genetic parameters. The inferred ancestry of 16% among rice genotypes was derived from admixed populations with the maximum between upland aus and wild Oryza species. CONCLUSIONS: SNPs validated in biotic and abiotic stress-responsive rice genes can be used in association analyses to identify candidate genes and develop functional markers for stress tolerance in rice. PMID- 22921107 TI - Phosphoproteome profiling of the sexually transmitted pathogen Trichomonas vaginalis. AB - BACKGROUND/PURPOSE(S): Trichomoniasis caused by Trichomonas vaginalis is the most common non-viral sexually transmitted infection. Morphological transformation from the trophozoite stage to the amoeboid or pseudocyst stage is crucial for T. vaginalis infection and survival. Protein phosphorylation is a key post translational modification involved in the regulation of several biological processes in various prokaryotes and eukaryotes. More than 880 protein kinases have been identified in the T. vaginalis genome. However, little is known about the phosphorylation of specific proteins and the distribution of phosphorylated proteins in different stages of the morphological transformation of T. vaginalis. METHODS: To obtain a more comprehensive understanding of the T. vaginalis phosphoproteome, we analyzed phosphorylated proteins in the three morphological stages using titanium dioxide combined with LC-MS/MS. RESULTS: A total of 93 phosphopeptides originating from 82 unique proteins were identified. Among these proteins, 21 were detected in all stages, 29 were identified in two different stages, and 32 were stage specific. CONCLUSION: Identification of stage-specific phosphorylated proteins indicates that phosphorylation of these proteins may play a key role in the morphological transformation of T. vaginalis. PMID- 22921108 TI - New quinolinyl-1,3,4-oxadiazoles: synthesis, in vitro antibacterial, antifungal and antituberculosis studies. AB - In order to generate hybrid antimicrobial remedies with novel mode of action, two series of quinoline based 1,3,4-oxadiazole derivatives condensed with N aryl/benzothiazolyl acetamides were synthesized and the MIC values of the compounds towards eight reference bacterial strains (S. aureus, B. cereus, E. coli, P. aeruginosa, K. pneumoniae, S. typhi, P. vulgaris, S. flexneri), four fungi (A. niger, A. fumigatus, A. clavatus, C. albicans) and Mycobacterium tuberculosis H37Rv were assayed in vitro. Quinoline-6-carboxlic acid was treated with thionyl chloride in refluxing methanol to obtain the corresponding ester derivative to be hydrazinolyzed by 99% hydrazine hydrate in ethanol to produce carbohydrazide intermediate. The carbohydrazide precursor underwent cyclization by carbon disulfide and ethanolic KOH to construct 5-quinolinyl-6-yl-1,3,4 oxadiazol-2-thiol. Substituted 2-chloro-N-phenyl(benzothiazolyl)aceta-mide derivatives were then condensed to 1,3,4-oxadiazole nucleus via sulphur linkage to yield the desired products. Target products bearing N-benzothiazolyl-2 chloroacetamides displayed good inhibitory potential. The biological screening identified that many final analogues exhibited a significant inhibition of the growth of microorganisms at 3.12-25 MUg/mL of MIC, which were comparable to control drugs. The influence of the presence of various functional groups to the phenyl/benzothiazolyl ring on activity profiles was investigated. The proposed structures of the newly prepared products were confirmed with the aid of IR, 1H NMR, 13C NMR spectroscopy and elemental analysis. These results may provide new insights in the design of a novel pool of bioactive templates. PMID- 22921109 TI - Synthesis, molecular docking and antiamnesic activity of selected 2- naphthyloxy derivatives. AB - The present paper describes the design and synthesis of a series of some 2 naphthyloxy derivatives with their antiamnesic activity using mice as the animal model and piracetam as the reference drug. All the synthesized compounds were characterized by spectroscopic techniques and were screened for their efficacy as cognition enhancers by elevated plus maze test and acetylcholinestrase inhibitory assay. Molecular modeling and docking studies of the selected compounds into the crystal structure of acetylcholinestrase complexed with functional ligand succinylcholine using GRAMM software was performed in order to predict the affinity and orientation of the synthesized derivatives at the active site. The binding energy of ligands was calculated using ArgusLab software. The docking score and hydrogen bonds formed with surrounding amino acids show the good agreement with predicted binding affinities obtained by molecular docking studies, as verified by acetylcholinestrase activity. PMID- 22921110 TI - Synthesis, antifungal activity, and molecular docking studies of novel triazole derivatives. AB - In order to meet the urgent need for novel antifungal agents with improved activity and broader spectrum, a series of 3/4-[[N-alkyl-2-(2,4-difluorophenyl)-2 hydroxy-3-(1H-1, 2, 4-triazole)] propylamino] benzylethyl carbonate were designed, synthesized and evaluated as antifungal agents. The MIC80 values indicate that all the compounds showed only moderate or even no antifungal activities against nearly all the tested fungal pathogens. Moreover, the interactions of the most active compounds in the drug binding site of CACYP51 were also explored with the help of docking studies. PMID- 22921111 TI - [1st Community Health Conference: promoting health and the challenge of chronic diseases]. PMID- 22921112 TI - [Fibreoptic clinical training in anaesthesia. Course design and results based on a self-assessment survey]. AB - BACKGROUND AND OBJECTIVE: Fibreoptic intubation is the technique of choice for resolving complications related to a difficult airway. Our aim was to determine whether a clinical-practice-based, individualized course provides sufficient training and confidence to allow anaesthetists to routinely practice fibreoptic intubation. METHODS: Our hospital developed a clinical-practice-based, individualized course on fibreoptic intubation in general anaesthesia that provided practice in sedated spontaneously breathing patients and insertion through supraglottic devices. From 2005 to 2009, we e-mailed participants for response to an anonymous online self-assessment survey. We asked participants about the training outcomes and their overall degree of satisfaction. RESULTS: Seventy-seven participants were sent the questionnaire six months after the course and 61% responded. All respondents considered themselves skilled in handling the bronchoscope at the end of the course and 97% used it in their routine practice in patients with difficult airways. CONCLUSIONS: These results suggest a high success rate can be expected from individually tailored fibreoptic intubation courses that supplement theory and mannequin experience with clinical practice. PMID- 22921113 TI - Galectin-1 for neuroprotection? AB - Classically activated microglia (M1) are believed to play a key role in neuronal degeneration in multiple sclerosis (MS). In this issue of Immunity, Starossom et al. (2012) show that Galectin-1 exerts a neuroprotective function through glycosylation-dependent inactivation with M1 cells. PMID- 22921114 TI - Regulate globally, act locally: adrenergic nerves promote leukocyte recruitment. AB - In this issue of Immunity, Scheiermann et al. (2012) demonstrate that circadian regulation of the expression of endothelial cell adhesion molecules via adrenergic innervation of local vasculature promotes clinically significant changes in leukocyte homing and bone marrow engraftment. PMID- 22921115 TI - Guanylate-binding proteins: niche recruiters for antimicrobial effectors. AB - There are fundamental questions regarding how IFN-gamma activates host cells to eliminate intracellular pathogens. In this issue of Immunity, Yamamoto et al. (2012) demonstrate a critical role for the p65 guanylate-binding proteins (GBPs) in this process during infection with Toxoplasma gondii. PMID- 22921116 TI - Semaphorins: new cues for skin healing by gammadelta T cells. AB - In this issue of Immunity, Witherden et al. (2012) demonstrate a crucial role for CD100-plexin B2 interactions in the wound healing response mediated by murine gammadelta T cells and in the T cell morphological changes associated with this process. PMID- 22921117 TI - Interleukin-22, the guardian of the intestinal stem cell niche? AB - Our molecular understanding of how immune cells protect epithelial cells against damage is limited. In this issue of Immunity, Hanash et al. (2012) report that interleukin-22 produced by innate lymphoid cells provides protection to the stem cell niche of the intestinal epithelium. PMID- 22921118 TI - Regulation of humoral immunity by complement. AB - The complement system of innate immunity is important in regulating humoral immunity largely through the complement receptor CR2, which forms a coreceptor on B cells during antigen-induced activation. However, CR2 also retains antigens on follicular dendritic cells (FDCs). Display of antigen on FDCs is critical for clonal selection and affinity maturation of activated B cells. This review will discuss the role of complement in adaptive immunity in general with a focus on the interplay between CR2-associated antigen on B cells with CR2 expressed on FDCs. This latter interaction provides an opportunity for memory B cells to sample antigen over prolonged periods. The cocrystal structure of CR2 with its ligand C3d provides insight into how the complement system regulates access of antigen by B cells with implications for therapeutic manipulations to modulate aberrant B cell responses in the case of autoimmunity. PMID- 22921119 TI - STAT3 transcription factor promotes instability of nTreg cells and limits generation of iTreg cells during acute murine graft-versus-host disease. AB - Acute graft-versus-host disease (GvHD) is a major cause of mortality in allogeneic bone marrow transplantation (BMT), for which administration of FoxP3(+) regulatory T (Treg) cells has been proposed as a therapy. However, the phenotypic stability of Treg cells is controversial, and STAT3-dependent cytokines can inhibit FoxP3 expression. We assessed whether the elimination of STAT3 in T cells could limit the severity of GvHD. We found STAT3 limited FoxP3(+) Treg cell numbers following allogeneic BMT by two pathways: instability of natural Treg (nTreg) cells and inhibition of induced Treg (iTreg) cell polarization from naive CD4(+) T cells. Deletion of STAT3 within only the nTreg cell population was not sufficient to protect against lethal GvHD. In contrast, transfer of STAT3-deficient naive CD4(+) T cells increased FoxP3(+) Treg cells post-BMT and prevented lethality, suggesting that the consequence of STAT3 signaling may be greater for iTreg rather than nTreg cells during GvHD. PMID- 22921122 TI - WITHDRAWN: First observation of diffusion-diffraction pattern in neuronal tissue by double-pulsed-field-gradient NMR. AB - This article has been withdrawn at the request of the author(s) and/or editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy. PMID- 22921120 TI - TBK-1 promotes autophagy-mediated antimicrobial defense by controlling autophagosome maturation. AB - Autophagy is a fundamental biological process of the eukaryotic cell contributing to diverse cellular and physiological functions including cell-autonomous defense against intracellular pathogens. Here, we screened the Rab family of membrane trafficking regulators for effects on autophagic elimination of Mycobacterium tuberculosis var. bovis BCG and found that Rab8b and its downstream interacting partner, innate immunity regulator TBK-1, are required for autophagic elimination of mycobacteria in macrophages. TBK-1 was necessary for autophagic maturation. TBK-1 coordinated assembly and function of the autophagic machinery and phosphorylated the autophagic adaptor p62 (sequestosome 1) on Ser-403, a residue essential for its role in autophagic clearance. A key proinflammatory cytokine, IL-1beta, induced autophagy leading to autophagic killing of mycobacteria in macrophages, and this IL-1beta activity was dependent on TBK-1. Thus, TBK-1 is a key regulator of immunological autophagy and is responsible for the maturation of autophagosomes into lytic bactericidal organelles. PMID- 22921121 TI - Interleukin-22 protects intestinal stem cells from immune-mediated tissue damage and regulates sensitivity to graft versus host disease. AB - Little is known about the maintenance of intestinal stem cells (ISCs) and progenitors during immune-mediated tissue damage or about the susceptibility of transplant recipients to tissue damage mediated by the donor immune system during graft versus host disease (GVHD). We demonstrate here that deficiency of recipient-derived IL-22 increased acute GVHD tissue damage and mortality, that ISCs were eliminated during GVHD, and that ISCs as well as their downstream progenitors expressed the IL-22 receptor. Intestinal IL-22 was produced after bone marrow transplant by IL-23-responsive innate lymphoid cells (ILCs) from the transplant recipients, and intestinal IL-22 increased in response to pretransplant conditioning. However, ILC frequency and IL-22 amounts were decreased by GVHD. Recipient IL-22 deficiency led to increased crypt apoptosis, depletion of ISCs, and loss of epithelial integrity. Our findings reveal IL-22 as a critical regulator of tissue sensitivity to GVHD and a protective factor for ISCs during inflammatory intestinal damage. PMID- 22921123 TI - Downregulation of PMCA2 or PMCA3 reorganizes Ca(2+) handling systems in differentiating PC12 cells. AB - Changes in PMCA2 and PMCA3 expression during neuronal development are tightly linked to structural and functional modifications in Ca(2+) handling machinery. Using antisense strategy we obtained stably transfected PC12 lines with reduced level of PMCA2 or PMCA3, which were then subjected to dibutyryl-cAMP differentiation. Reduced level of neuron-specific PMCAs led to acceleration of differentiation and formation of longer neurites than in control PC12 line. Treatment with dibutyryl-cAMP was associated with retraction of growth cones and intensified formation of varicosities. In PMCA2-reduced cells development of apoptosis and DNA laddering were detected. Higher amounts of constitutive isoforms PMCA1 and PMCA4, their putative extended location to gaps left after partial removal of PMCA2 or PMCA3, together with increased SERCA may indicate the induction of compensatory mechanism in modified cells. Functional studies showed altered expression of certain types of VDCCs in PMCA-reduced cells, which correlated with their higher contribution to Ca(2+) influx. The cell response to PMCAs suppression suggests the interplay between transcription level of two opposite calcium-transporting systems i.e. voltage- and store depletion-activated channels facilitating Ca(2+) influx and calcium pumps responsible for Ca(2+) clearance, as well highlights the role of both neuron-specific PMCA isoforms in the control of PC12 cells differentiation. PMID- 22921125 TI - Washing of metal contaminated soil with EDTA and process water recycling. AB - We demonstrate here, in a laboratory scale experiment, the feasibility of using the base/acid pair Ca(OH)(2)/H(2)SO(4) to impose a pH gradient for EDTA recycling and, coupled with an electrochemical advanced oxidation process using a graphite anode, of recycling process water as part of a novel remediation technology for multi-metal contaminated soils. In the first batch, 60 mmol EDTA kg(-1) of soil removed 72, 27, and 71% of Pb, Zn, and Cd, respectively, from soil contaminated with 5329+/-685, 3401+/-193, and 35+/-6 mg kg(-1) of Pb, Zn, and Cd, respectively. In the subsequent four batches, we demonstrated that up to 88% of EDTA was recycled from each batch, with the potential to extract up to 98, 94, and 109% of Pb, Zn, and Cd, respectively, that the fresh EDTA extracted. Accumulation of salts in the process water through multiple remediation batches/recycles was prevented by CaSO(4) precipitation. Recycled process water toxicity testing indicated no significant effect on plant seed germination but some inhibition of root elongation. PMID- 22921126 TI - Proteomic profiling of the acid tolerance response (ATR) during the enhanced biomethanation process from Taihu Blue Algae with butyrate stress on anaerobic sludge. AB - Enhanced biomethanation with acid stress on anaerobic sludge, dehydrogenase activity, protein expression, and the primary proteomic profiling of microbial communities during the enhanced anaerobic digestion process from Taihu Blue Algae were investigated. It was found that the accumulation of organic acids and the specific biogas accumulation rate were 1.8 and 1.3 times of the control, when 10 g/L and 7.5 g/L of butyrate were selected for acid stress, respectively. Meanwhile, dehydrogenase activity of the 7.5 g/L acid stress group exhibited an increase of 1.6 times of the control, and protein expression was also found to be enhanced sharply as revealed by 1D-PAGE. Finally, twenty of the matched protein spots through 2D-PAGE from both the control and the 7.5 g/L stress groups were identified by MALDI-TOF MS, and five of which were proved to be involved in bioenergy metabolism. Significantly, ATR related proteins might be induced as the pIs of which were acidic as 5.92, 5.51 and 5.54, respectively. PMID- 22921127 TI - Text messaging and adolescents: clues to promoting sexual rights. PMID- 22921128 TI - Workplace strategies are needed to protect youth across the globe from starting to smoke. PMID- 22921129 TI - The intersection of youth, technology, and new media with sexual health: moving the research agenda forward. AB - Youth bear a significant proportion of the sexually transmitted infection (STI)/HIV burden in the United States, CDC, 2010. Available at: http://www.cdc.gov/std/stats09/default.htm, with rates of some STIs increasing among youth of color and young men who have sex with men. Technology use among youth also continues to increase. The ubiquitous nature of technology use among youth offers a multitude of opportunities to promote youth sexual health and to prevent disease transmission and unplanned pregnancies. To date, there have been a handful of peer-reviewed articles published regarding the feasibility, acceptability, and effectiveness of using new media and technology for sexual health promotion. Despite recent publications, there is still a real need for high-quality research to understand the impact of different forms of new media use on youth sexual health, as well as to determine the best ways to harness technology to promote safer sex behaviors, both for the short- and long-term. In March 2011, Internet Sexuality Information Services (ISIS), National Institute of Mental Health (NIMH), and the Ford Foundation convened a meeting of scientists and technology experts to discuss how to effectively conduct sexual health promotion research using new forms of technology. The meeting was structured to cover the following topic areas: (i) research-community partnerships, (ii) institutional review board and ethical issues, (iii) theoretical frameworks, (iv) intervention approaches, (v) recruitment methods, and (vi) assessing impact. Presentations included case studies of successful technology-based HIV/STI prevention interventions for youth, which led to broader discussions on how to conduct research in this area. This article summarizes the meeting proceedings, highlights key points, offers recommendations, and outlines future directions. PMID- 22921130 TI - Health care transition for youth with special health care needs. AB - PURPOSE: Youth with special health care needs (YSHCN) increasingly live into adulthood, and approximately 500,000 U.S. youth transition from pediatric to adult health care systems annually. Through a systematic literature review, we sought to (1) determine adult outcomes for YSHCN who have no special transition interventions and (2) identify evidence for strategies that lead to better outcomes, in particular, access to adult health care. METHODS: We searched the medical, nursing, psychology, and social science literature and reviewed selected articles' reference lists. Transition experts also recommended relevant articles. Search criteria included health conditions, transition-related activities, and health care and related outcomes. We selected English-language articles published from 1986 to 2010, with an abstract, description of transition-related interventions (objective 2), and posttransition outcomes. Investigators abstracted study design, population, sample size, description of intervention, data collection methods, and findings. RESULTS: The search yielded 3,370 articles, of which 15 met study criteria. Although many YSHCN appear to make the transition to adult health providers successfully, some experience serious gaps in outcomes; those with more complex conditions or with conditions affecting the nervous system appear to have less good transitions. Some evidence supports introducing YSHCN to adult providers before leaving the pediatric system; one study supports using care coordinators to improve outcomes. CONCLUSIONS: Evidence regarding programs to facilitate transition for YSHCN is inconclusive. Weak evidence suggests that meeting adult providers before transfer may facilitate posttransition access to care. We recommend additional studies with strong research designs to guide best practice in preparing YSHCN for adulthood. PMID- 22921131 TI - Adolescents' perspectives on the use of a text messaging service for preventive sexual health promotion. AB - PURPOSE: To understand adolescents' perspectives on the use of a preventive sexual health text messaging service. METHODS: Twenty-six adolescents aged 15-20 years old were recruited from two teen clinics in Los Angeles County to participate in focus groups. Three focus groups were held. Discussions focused on the content of the weekly text messages sent by a service called the Hookup, as well as the acceptability of using text messaging to relay sexual health education to adolescents. Codes and themes were developed from transcripts using standard constant comparison methods. RESULTS: Participants enjoyed receiving weekly text messages related to sexual health. They linked their enjoyment to the message content being informative (providing relevant and new information), simple (automatically limited to small words and short phrases), and sociable (easily able to be shared with friends). Participants also pointed to the convenience and ubiquity of text messaging and generally felt that cost of messages was not a concern. Most felt that text messaging provided a sense of privacy for learning about sensitive health topics, although a few expressed concerns about stigma from peers' seeing the messages. CONCLUSIONS: Teens may face several barriers to accessing reliable, useful, and age-appropriate information and services for their health. The use of text messaging is an innovative way to engage teens in preventive health learning and practices. Text messaging may allow efficient delivery of health messages and may offer a discreet way for teens to learn important health information, especially for sensitive topics like sexual health. PMID- 22921132 TI - Youth employment, income, and smoking initiation: results from Korean panel data. AB - PURPOSE: To estimate the effect of youth employment and income on smoking initiation, this study tests whether youth with higher incomes from either employment or allowance are more likely to smoke, and, if so, whether it is the employment effect or the income effect that affects youth smoking initiation. METHODS: Data from the 2003-2007 Korea Youth Panel Study were used to estimate the effect of youth employment and income on smoking initiation. A fixed-effects linear probability model was estimated to control for unobserved individual heterogeneity, which may affect both youth employment/income and smoking initiation. RESULTS: Even after controlling for unobserved individual heterogeneity, youth employment raised the probability of smoking initiation by 4.4% points, but neither employment income nor allowance was significantly associated with youth smoking initiation. CONCLUSIONS: Youth employment is an important risk factor for smoking initiation in South Korea, suggesting that workplaces that hire youth may be an appropriate target for antismoking interventions. PMID- 22921133 TI - Cash, cars, and condoms: economic factors in disadvantaged adolescent women's condom use. AB - PURPOSE: Evaluate whether adolescent women who received economic benefits from their boyfriends were more likely never to use condoms. METHODS: Data are obtained from a longitudinal HIV prevention intervention study with 715 African American adolescent women in urban Atlanta surveyed at baseline, 6 months, and 12 months. The primary outcome was never using condoms in the past 14 and 60 days at 6 and 12 months. The primary predictor was having a boyfriend as primary spending money source at baseline. Analysis minimized confounding using propensity weighting to balance respondents on 81 variables. RESULTS: A boyfriend was the primary spending money source for 24% of respondents, who did not differ in neighborhood or family context but had lower education, more abuse history, riskier sex, and more sexually transmitted infections. After propensity score weighting, no statistically significant differences for 81 evaluated covariates remained, including age distributions. Women whose boyfriend was their primary spending money source were 50% more likely never to use condoms at 6 and 12 months and less likely to respond to the intervention at 12 months. Women whose boyfriend had been their primary spending money source but found another spending money source were more likely to start using condoms than women who continued. Women whose boyfriends owned cars were more likely never to use condoms. CONCLUSIONS: Receiving spending money from a boyfriend is common among adolescent women in populations targeted by pregnancy and sexually transmitted infection prevention interventions, and may undermine interventions' effectiveness. Clinicians and reproductive health interventions need to address females' economic circumstances. PMID- 22921134 TI - Predictors of antiretroviral medication adherence among a diverse cohort of adolescents with HIV. AB - PURPOSE: To compare prevalence and describe predictors of antiretroviral treatment adherence among adolescents with HIV acquired perinatally (PIY) or through risk behaviors (BIY). METHODS: Data were obtained from the baseline assessment of Adolescent Impact, an intervention for HIV-infected adolescents receiving care in three U.S. cities. Patients self-reported missed medication doses as well as medication factors, HIV knowledge, disclosure, substance use, mental health, and social support through face-to-face or computer-assisted interviews. RESULTS: Of 104 participants, 68 (65.4%) reported full adherence. Compared with BIY, PIY were younger, had greater HIV disease severity, and had more structural supports. Adjusting for transmission mode (PIY vs. BIY), nonadherence by self-report was associated with higher viral load (VL) (adjusted odds ratio [AOR] = 1.5, confidence interval [CI] = 1.03, 2.18). Nonadherent adolescents were significantly likely to have had AIDS, discussed HIV disease with providers, reported difficulty with medication routine, experienced internalizing behavior problems, and used drugs. In multivariate analyses, independent predictors of nonadherence included acquiring HIV behaviorally (AOR = 4.378, CI = 1.055, 18.165), ever having AIDS (AOR = 4.78, CI = 1.31, 17.49), perceiving difficult medication routine (AOR = 1.84, CI = 1.07, 3.16), discussing disease indicators with provider (AOR = 4.57, CI = 1.74, 11.98), and missing doses because of forgetting (AOR = 2.53, CI = 1.29, 4.96). Adjusting for transmission mode, detectable VL was associated with lower recent CD4(+) lymphocyte counts, discussing disease indicators with providers, and missing doses because of forgetting or being depressed. Low recent CD4(+) lymphocyte counts (AOR = .988, p = .024) but fewer HIV symptoms (AOR = .466, p = .032) and missing doses because of forgetting (AOR = 1.76, p = .05) were independently associated with detectable VL in multivariate analysis. CONCLUSIONS: Despite differences between groups, nonadherence was associated with severity of illness, difficult medication routine, and forgetfulness. Beyond individual needs, both groups of adolescents had suboptimal adherence and would benefit from simplified medication routines and organizational skills. PMID- 22921135 TI - Predicting adolescent asthma research participation decisions from a structural equations model of protocol factors. AB - PURPOSE: To examine similarities and differences in the process that parents and adolescents use to make decisions concerning participation in an asthma clinical trial. We hypothesized that a single conceptual model, tested through structural equations modeling, could explain adolescent assent and parent consent for adolescent research participation. METHODS: One hundred nine adolescents enrolled with at least one parent and received an asthma evaluation from a pediatric asthma specialist and then evaluated a hypothetical asthma research protocol. Family members independently evaluated the protocol and made research participation decisions. RESULTS: Perceived risk, benefit, and compensation were direct predictors of participation decisions for parents and adolescents. Adolescents perceived direct study benefit from the relationship with the physician, however parents did not. Parent decisions were most strongly associated with perceived risk, and parents associated discomfort with risk more strongly than did adolescents. Protocol procedures contributed to perceptions of benefit and discomfort for parents and adolescents. CONCLUSIONS: Parent and adolescent research participation decisions are influenced by protocol variables in similar ways, although there are differences that account for disagreements within families. Findings may help investigators develop protocols that appeal to parents and adolescents and highlight issues of particular importance to address during the process of informed consent. PMID- 22921136 TI - Sustainability of the Communities That Care prevention system by coalitions participating in the Community Youth Development Study. AB - PURPOSE: Community prevention coalitions are a common strategy to mobilize stakeholders to implement tested and effective prevention programs to promote adolescent health and well-being. This article examines the sustainability of Communities That Care (CTC) coalitions approximately 20 months after study support for the intervention ended. METHODS: The Community Youth Development Study is a community-randomized trial of the CTC prevention system. Using data from 2007 and 2009 coalition leader interviews, this study reports changes in coalition activities from a period of study support for CTC (2007) to 20 months following the end of study support for CTC (2009), measured by the extent to which coalitions continued to meet specific benchmarks. RESULTS: Twenty months after study support for CTC implementation ended, 11 of 12 CTC coalitions in the Community Youth Development Study still existed. The 11 remaining coalitions continued to report significantly higher scores on the benchmarks of phases 2 through 5 of the CTC system than did prevention coalitions in the control communities. At the 20-month follow-up, two-thirds of the CTC coalitions reported having a paid staff person. CONCLUSIONS: This study found that the CTC coalitions maintained a relatively high level of implementation fidelity to the CTC system 20 months after the study support for the intervention ended. However, the downward trend in some of the measured benchmarks indicates that continued high quality training and technical assistance may be important to ensure that CTC coalitions maintain a science-based approach to prevention, and continue to achieve public health impacts on adolescent health and behavior outcomes. PMID- 22921137 TI - Co-occurrence of obesogenic risk factors among adolescents. AB - PURPOSE: The purpose of this study was to determine the prevalence, sociodemographic distribution, and co-occurrence of five potentially obesogenic behavioral risk factors (low physical activity, high screen time, low fruit and vegetable intake, high soft drink consumption, and high snack intake) among adolescents. METHODS: Cross-sectional representative population survey (n = 1,568) of grade 6, 8, and 10 students (49% male) randomly selected from 70 primary and secondary schools in New South Wales, Australia, between February and May 2007. Co-occurrence was assessed using an observed-to-expected ratio (O/E) method. RESULTS: Only 5% of boys and 9% of girls had none of the five obesogenic behavioral risk factors studied. Overall, 51.4% of boys and 42.9% of girls had three or more risk factors. Prevalence of multiple risk factors (3+) was higher among boys and girls from lower income households and among girls whose mothers had less than grade 12 education. For both boys and girls, the occurrence of all five risk factors was 160% greater than expected (O/E ratio: 2.6). CONCLUSIONS: There was clear evidence of a co-occurrence of obesogenic risk factors among adolescents, especially among those from lower socioeconomic backgrounds, indicating this group would benefit from targeted prevention strategies. PMID- 22921138 TI - Assessing the health, functional characteristics, and health needs of youth attending a noncategorical transition support program. AB - PURPOSE: To assess the health, functional characteristics, and health care service needs of youth and young adults with special health care needs attending a comprehensive, noncategorical transition program. METHODS: A self-administered survey was developed from national health surveys and clinical experience to assess concepts identified as important for successful transition to adulthood. Surveys were mailed to 198 parents of youth and young adults with special health care needs attending the transition clinic. Parents were asked about the youth's health, functional status, and health care services needed. The clinical database provided demographic and patient health characteristics. Results were compared against the 2005-2006 National Survey of Children with Special Health Care Needs. RESULTS: Forty-four percent of surveys were returned. Average age of youth was 17.5 (11-22) years old and diagnoses included cerebral palsy (36%), spina bifida (10%), developmental delay or Down syndrome (17%), and autism (6%). Most youth needed assistance with personal care (69%) and routine needs (91%) and used assistive devices (59%). Compared with the 2005-2006 National Survey of Children with Special Health Care Needs, parents reported higher needs for all services except mental health care and tobacco or substance use counseling. Forty three percent reported at least one unmet health need. Few parents reported the need for counseling on substance use (1%), sexual health screening (16%), nutrition (34%), and exercise (41%). CONCLUSIONS: Youth attending our transition program had more functional limitations, poorer reported health status, different diagnosis distribution, and higher levels of needed health services. Few parents identified needs for other recommended adolescent preventive services. Transition programs should assess patient health characteristics and service needs to design effective patient-centered services. PMID- 22921139 TI - National estimates of the pubertal milestones among urban and rural Chinese girls. AB - PURPOSE: To provide clinically meaningful, normative reference data that describe pubertal timing indicators among urban and rural Chinese girls. METHODS: Girls of Chinese Han ethnicity from grade 1 in elementary schools through grade 12 in junior high schools in eight regions participated in China Puberty Research Collaboration from October 2010 to May 2011. At examination, stages of breast and pubic hair development were assessed by trained physicians. Data on menses were collected through questionnaire survey. RESULTS: A total of 15,388 girls aged 6.0 18.9 years participated in this collaboration study. Among them, approximately 53.5% (8,238) came from rural areas. The median ages at stage 2 of breast development of Chinese girls were 9.18 (95% confidence interval: 8.91-9.44) years and at stage 2 for pubic hair growth were 11.65 (95% confidence interval: 11.41 11.90) years. Girls with body mass index >=85th percentile had earlier age for B2 (Tanner stage 2 for breast development), B3 (Tanner stage 3 for breast development), PH2 (Tanner stage 2 for pubic hair development), PH3 (Tanner stage 3 for pubic hair development), and menarche compared with girls with body mass index < 85th percentile. Urban girls achieved PH2, PH3, and menarche at a much earlier age than rural girls, except for B2 and B3 attainment. Mean menarcheal age is 12.43 years. CONCLUSIONS: This study presented up-to-date data on female pubertal timing in a national sample of Chinese Han ethnicity girls and separately for urban and rural areas. PMID- 22921140 TI - Access to private and confidential health care among secondary school students in New Zealand. AB - PURPOSE: Private and confidential health care is an important indicator of the quality of health care for adolescents. The objective of this study was to determine the prevalence of health care utilization and private and confidential health care among a nationally representative population of high school students. METHODS: A two-stage cluster sample of 9,107 students (grades 8-12, response rate 73%) from 96 New Zealand high schools (response rate 84%) participated in a 2007 health survey using Internet tablets. Questions included when and where they had accessed health care, if their health care provider had explained that their health care was confidential, and if they had been seen in private by their health care provider. RESULTS: Although 83% of students had accessed health care in the previous 12 months, only 27% of students reported receiving private and confidential health care. Students who had accessed health care from a school based health center (adjusted relative risk [95% confidence interval] 1.54 [1.42 1.66]) or family planning/sexual health clinics (adjusted relative risk = 2.1 [1.9-2.26]) were more likely to report receiving private and confidential health care compared with students who had not accessed health care from these settings. CONCLUSIONS: While most young people access health care from their family doctor or general practitioner's clinic, rates of private and confidential health care were low suggesting that opportunities to adequately explore and respond to important yet sensitive topics are compromised in primary care settings. PMID- 22921142 TI - Medical student performance on an adolescent medicine examination. AB - PURPOSE: To examine the performance of third-year medical students on an adolescent medicine clinical practice examination. METHODS: The participants were third-year medical students (2010 [n = 145] and 2011 [n = 134]) at the University of Colorado School of Medicine. Student performance on adolescent contraceptive management was measured in three domains following Accreditation Council for Graduate Medical Education (ACGME) competencies in professionalism, communication, and history-taking skills. RESULTS: With regard to professionalism and communication skills, students performed very well, scoring >95% correct in both years. Students demonstrated relatively poorer performance in history-taking competency in 2010 and 2011 (66% and 67% correct, respectively). CONCLUSION: In the adolescent Objective Structured Clinical Examination case, third-year medical students demonstrated extremely high performance in communication and professionalism skills. However, performance was lower for history-taking skill in contraceptive management. PMID- 22921141 TI - A cluster analysis of physical activity and sedentary behavior patterns in middle school girls. AB - PURPOSE: To identify similar patterns of physical activity (PA) and sedentary behavior in sixth-grade girls using cluster analysis; to determine which clusters of girls were associated with greater daily minutes of objectively measured PA; and to examine whether girls in these clusters experienced change in PA from sixth to eighth grade. METHODS: An adventitious cohort of girls (n = 957) from the Trial of Activity for Adolescent Girls were measured at sixth and eighth grade. Activities were identified using the 3-day physical activity recall and a self-report survey and used to create clusters of sixth-grade girls who had similar PA/sedentary behaviors. Accelerometry was used to assess PA in sixth and eighth grade. Data analysis consisted of FASTCLUS procedure and mixed model repeated measures analyses in SAS statistical software. RESULTS: Cluster analysis yielded six clusters (C1: educational sedentary; C2: sports and play; C3: organized sports teams/classes/lessons in past year; C4: active transport and chores; C5: electronic media; C6: sleep). Sixth-grade girls in C2 and C3 had greater average daily minutes of moderate-to-vigorous physical activity (MVPA), metabolic equivalent of a physical activity-weighted MVPA, and vigorous physical activity compared with other clusters (p < .05). In eighth grade, sedentary time increased and PA declined among girls in all clusters (p < .05). Girls in C2 had the greatest decline in PA, whereas girls' PA in C3 declined less. CONCLUSIONS: Encouraging participation in organized sports teams/class/lessons in middle school girls may promote greater MVPA and vigorous physical activity than other activities and may help to better sustain PA levels over time. PMID- 22921143 TI - The role of social networks in influenza vaccine attitudes and intentions among college students in the Southeastern United States. AB - PURPOSE: To investigate whether support for vaccines among one's health discussants is associated with beliefs in vaccine safety and intention to vaccinate among college students. METHODS: Ordered logistic regression analysis was conducted of data collected from 1,019 undergraduates at a large public university in 2009 and 2010. RESULTS: Having health discussion networks that support vaccination is a significant predictor of beliefs of H1N1 vaccine safety (adjusted odds ratio [aOR] = 2.32) and intention (aOR = 1.78) in 2009 and of influenza vaccine safety (aOR = 1.85) and intention (aOR = 1.74) in 2010. These relationships are strongest among parents, friends, and spouses. CONCLUSIONS: Perceptions of flu vaccine attitudes among health discussants were strongly related to vaccination intent and beliefs about flu vaccine safety among survey respondents. PMID- 22921144 TI - Enhancement of surface graft density of MPEG on alginate/chitosan hydrogel microcapsules for protein repellency. AB - Alginate/chitosan/alginate (ACA) hydrogel microcapsules were modified with methoxy poly(ethylene glycol) (MPEG) to improve protein repellency and biocompatibility. Increased MPEG surface graft density (n(S)) on hydrogel microcapsules was achieved by controlling the grafting parameters including the buffer layer substrate, membrane thickness, and grafting method. X-ray photoelectron spectroscopy (XPS) model was employed to quantitatively analyze n(S) on this three-dimensional (3D) hydrogel network structure. Our results indicated that neutralizing with alginate, increasing membrane thickness, and in situ covalent grafting could increase n(S) effectively. ACAC(PEG) was more promising than ACC(PEG) in protein repellency because alginate supplied more COO(-) negative binding sites and prevented MPEG from diffusing. The n(S) increased with membrane thickness, showing better protein repellency. Moreover, the in situ covalent grafting provided an effective way to enhance n(S), and 1.00 +/- 0.03 chains/nm(2) was achieved, exhibiting almost complete immunity to protein adsorption. This antifouling hydrogel biomaterial is expected to be useful in transplantation in vivo. PMID- 22921145 TI - [Arterial hypertension: a French resurrection]. PMID- 22921146 TI - Parent, sibling and peer associations with subtypes of psychiatric and substance use disorder comorbidity in offspring. AB - BACKGROUND: Parental substance use disorder (SUD) is associated with a range of negative offspring outcomes and psychopathology, but the clustering of these outcomes into subtypes has seldom been examined, nor have the familial and environmental contexts of these subtypes been reported. The present study examines the clustering of offspring lifetime substance use and psychiatric disorders into subtypes and characterizes them in terms of familial and non familial influences using an offspring-of-twins design. METHOD: Telephone administered diagnostic interviews were used to collect data on psychiatric disorders and SUD from 488 twin fathers, 420 biological mothers and 831 offspring. Latent class analysis (LCA) was used to derive subtypes of lifetime comorbidity in offspring. Familial risk and environmental variables associated with each subtype (i.e., parenting, childhood physical or sexual abuse, perceived sibling and peer substance use) were identified using multinomial logistic regression. RESULTS: Four classes identified by LCA were characterized as (1) unaffected, (2) alcohol abuse/dependence, (3) alcohol abuse/dependence comorbid with anxiety and depression, and (4) alcohol, cannabis abuse/dependence and nicotine dependence comorbid with conduct disorder. Inconsistent parenting, childhood physical/sexual abuse, and perceived sibling and peer substance use were significantly associated with profiles of offspring comorbidity after adjusting for familial vulnerability. Some associations were specific (i.e., perceived peer alcohol use to the AUD class), while others were general (peer smoking to all 3 comorbidity classes). CONCLUSIONS: We observed distinct subtypes of psychiatric and SUD comorbidity in adolescents and young adults. Subtypes of offspring psychopathology have varied associations with parental psychopathology, family environment, and sibling and peer behaviors. PMID- 22921147 TI - Occurrence and partitioning of endocrine-disrupting compounds in the marine environment of Thermaikos Gulf, Northern Aegean Sea, Greece. AB - An integrated study was conducted to determine the presence of phenolic and steroid endocrine-disrupting compounds (EDCs), in the marine environment of Thermaikos Gulf, Northern Aegean Sea, Greece. Seawater, suspended particulate matter, sediments and biota were examined for nonylphenol, octylphenol, their mono- and diethoxylate oligomers, bisphenol A, estrone, 17alpha-estradiol, 17beta estradiol, estriol, mestranol and 17 alpha -ethynylestradiol. Phenolic compounds were detected in all of the compartments, with nonylphenol and its ethoxylates being the dominant pollutants. The occurrence of nonylphenol in sediments presents a significant risk to the biota. Mussels exhibited relatively low concentrations and low bioconcentration factors for NP and OP. The effect of terrestrial sources of the EDCs on the marine environment is discussed. The influence of suspended particulate matter and organic carbon in the partition of the EDCs between the dissolved and the particulate phase was investigated. PMID- 22921148 TI - Pneumatic balloon dilation in pediatric achalasia: efficacy and factors predicting outcome at a single tertiary pediatric gastroenterology center. AB - BACKGROUND: The use of pneumatic dilation (PD) is well established in adults with achalasia; however, it is less commonly used in children. OBJECTIVE: To evaluate the efficacy of PD in pediatric achalasia and to define predictive factors for its treatment failure. DESIGN: Single-center, prospective cohort study. SETTING: Academic tertiary referral center. PATIENTS: Twenty-four patients with achalasia were enrolled from January 2004 to November 2009 and were followed for a median of 6 years. INTERVENTION: PD was performed with the patients under general anesthesia. MAIN OUTCOME MEASUREMENTS: Efficacy and safety of PD. Follow-up was performed by using the Eckardt score, barium swallow contrast studies, and esophageal manometry at baseline; 1, 3, and 6 months after dilation; and every year thereafter. A Cox regression model was used to identify independent predictors of failure after the first PD. RESULTS: The PD success rate was 67%. In 8 patients, the first PD failed, but the parents of one patient refused a second PD and requested surgery. Of the 7 patients who underwent repeated treatment, the second PD failed in 3 (43%). Overall, only 3 of the 24 patients underwent surgery (overall success rate after a maximum of 3 PDs was 87%). Multivariate analysis showed that only older age was independently associated with a higher probability of the procedure success (hazard ratio [HR] 0.66; 95% CI, 0.45-0.97). LIMITATIONS: Small sample size, single-center study. CONCLUSIONS: PD is a safe and effective technique in the management of pediatric achalasia. Young age is an independent negative predictive factor for successful clinical outcome. PMID- 22921149 TI - Liquid chromatography-tandem mass spectrometry to determine the stability of collagen pentapeptide (KTTKS) in rat skin. AB - The objective of this study was to develop a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method to determine the stability of collagen pentapeptide (KTTKS), which is a subfragment of collagen and has been proved to promote the extracellular release of collagen in skin fibroblast, in rat skin. The chromatographic condition was optimized on an Acclaim C-18 column (2.1 mm * 150 mm, 3 MUm) under isocratic elution using a mobile phase consisting of deionized water and acetonitrile (87:13, v/v) mixture containing 5mM pentafluoropropionic acid as an ion-pairing reagent. The quantitation of KTTKS was performed on a triple quadrupole mass spectrometer in multiple reaction monitoring mode. The calibration curve showed good linearity in the concentration range of 0.05-10.0 MUg/mL (r(2)>0.999). The intra- and inter-day precisions were 0.8-6.5% and 2.4-5.8%, respectively, and the intra- and inter-day accuracies were 96.3-102.7% and 92.8-98.5%, respectively. The developed LC-MS/MS method was successfully applied to investigate the degradation rate and sites of KTTKS in rat skin homogenate. KTTKS was found to be very susceptible to the peptide bond cleavage by aminopeptidases present in the skin. PMID- 22921150 TI - Establishment of a transcatheter aortic valve program and heart valve team at a Veterans Affairs facility. AB - BACKGROUND: The US Food and Drug Administration recently approved a transcatheter aortic valve for patients for whom open heart surgery is prohibitively risky. METHODS: A multidisciplinary heart valve team partnered with administration to launch a transcatheter aortic valve replacement (TAVR) program. Clinical registries were used to show robust valve caseloads and outcomes at our Veterans Affairs (VA) facility and to project future volumes. A TAVR business plan was approved by the VA leadership as part of a multiphase project to upgrade and expand our surgical facilities. RESULTS: The heart valve team completed a training program that included simulations and visits to established TAVR centers. Patients were evaluated and screened through a streamlined process, and the program was initiated successfully. CONCLUSIONS: Establishing a TAVR program at a VA facility requires a multidisciplinary team with experience in heart valve and endovascular therapies and a supportive administration willing to invest in a sophisticated infrastructure. PMID- 22921151 TI - Gastroesophageal reflux disease in lung transplant patients with cystic fibrosis. AB - BACKGROUND: Gastroesophageal reflux disease (GERD) in lung transplant patients is being increasingly investigated because of its reported association with chronic rejection. However, information concerning the characteristics of GERD in cystic fibrosis (CF) patients is scarce. METHODS: We compared esophageal pH monitoring, manometry, gastric emptying studies, and barium swallow of 10 lung transplant patients with CF with those of 78 lung transplant patients with other end-stage pulmonary diseases. RESULTS: In lung transplant patients with CF, the prevalence of GERD was 90% (vs 54% controls, P = .04), of whom 70% had proximal reflux (vs 29% controls, P = .02). CONCLUSIONS: Lung transplant patients with CF have a significantly higher prevalence and proximal extent of GERD than do other lung transplant recipients. These data suggest that CF patients in particular should be routinely screened for GERD after transplantation to identify those who may benefit from antireflux surgery, especially given the risks of GERD-related aspiration and chronic allograft injury. PMID- 22921152 TI - Longitudinal comparison of three depression measures in adult cancer patients. AB - CONTEXT: Although a number of depression measures have been used with cancer patients, longitudinal comparisons of several measures in the same patient population have been infrequently reported. OBJECTIVES: To compare the Hopkins Symptom Checklist 20-item depression scale, Short-Form 36 Mental Health Inventory five-item distress scale, and Patient Health Questionnaire nine-item depression scale in adults with cancer. METHODS: Of the 309 cancer patients enrolled in a telecare management trial for depression, 247 completed the three depression measures at both baseline and at three months and a retrospective assessment of global rating of change in depression at three months. Internal consistency and construct validity of each measure were evaluated. Responsiveness was compared by calculating standardized response means and receiver operating characteristic area under the curve, using global rating of change as the external comparator measure. Differences between intervention and control groups in depression change scores were compared by calculating standardized effect sizes (SESs). RESULTS: Internal reliability coefficients for the three measures were >=0.77 at baseline and >=0.84 at three months. Construct validity was supported with strong correlations of the depression measures among themselves, moderately strong correlations with other measures of mental health, and moderate correlations with vitality and disability. In terms of responsiveness, standardized response means for all measures significantly differentiated between three groups (improved, unchanged, and worse) as classified by patient-reported global rating of change in depression at three months. The three measures were able to detect a modest treatment effect in the intervention group compared with the control group (SES ranging from 0.21 to 0.43) in the full sample, whereas detecting a greater treatment effect in depressed participants with comorbid pain (SES ranging from 0.30 to 0.58). Finally, the three measures performed similarly in detecting patients with improvement. CONCLUSION: The Hopkins Symptom Checklist 20-item depression scale, Mental Health Inventory five-item distress scale, and Patient Health Questionnaire nine-item depression scale were established as reliable, valid, and responsive depression measures in adults with cancer. Given the current recommendations for measurement-based care, our study shows that clinicians treating depressed cancer patients have several measures from which to choose. PMID- 22921153 TI - Physical health and incident late-life depression: modification by cytokine genes. AB - Inflammatory cytokines have been implicated in the pathophysiology of depression, potentially underlying its association with worse physical health. Cytokine production is influenced by the transcriptional activity of several polymorphisms. We hypothesized that alleles related to higher proinflammatory and/or lower anti-inflammatory cytokine production would strengthen the association between physical disorders and late-life depression. In a 2-year prospective study of a community sample of 521 older people, information on number of physical disorders, diagnosis of depression (Geriatric Mental State), and genotypes for 6 pro-inflammatory (tumor necrosis factor-alpha -850C/T and 308G/A, interleukin (IL)-1beta -511C/T and +3953C/T, IL-6 -174G/C, IL-8 -251T/A) and 2 anti-inflammatory (IL-4 +33T/C, IL-10 -1082G/A) cytokine polymorphisms were ascertained. Total numbers of potential risk alleles were calculated for pro- and anti-inflammatory cytokine genes. Interactions between baseline physical disorders and cytokine genotypes were investigated for incident depression. The associations between physical disorders and incident depression were significant in the presence of 2 alleles related to higher proinflammatory cytokine production (tumor necrosis factor-alpha -850T and IL-8 -251A), and 1 allele related to lower anti-inflammatory cytokine production (IL-4 +33C). Significant gene-environment interactions, independent of all covariates, were found for total number of risk alleles on both pro- and anti-inflammatory cytokine genes in addition to the above 3 individual single nucleotide polymorphisms. The present findings support cytokine-mediated inflammatory pathways underlying at least some of the well-recognized association between worse physical health and late-life depression, and provide novel evidence of a genetic basis for this. PMID- 22921154 TI - Leptin prevents hippocampal synaptic disruption and neuronal cell death induced by amyloid beta. AB - Accumulation of amyloid-beta (Abeta) is a key event mediating the cognitive deficits in Alzheimer's disease (AD) as Abeta promotes synaptic dysfunction and triggers neuronal death. Recent evidence has linked the hormone leptin to AD as leptin levels are markedly attenuated in AD patients. Leptin is also a potential cognitive enhancer as it facilitates the cellular events underlying hippocampal learning and memory. Here we show that leptin prevents the detrimental effects of Abeta(1-42) on hippocampal long-term potentiation. Moreover leptin inhibits Abeta(1-42)-driven facilitation of long-term depression and internalization of the 2-amino-3-(5-methyl-3-oxo-1,2- oxazol-4-yl)propanoic acid (AMPA) receptor subunit, GluR1, via activation of PI3-kinase. Leptin also protects cortical neurons from Abeta(1-42)-induced cell death by a signal transducer and activator of transcription-3 (STAT-3)-dependent mechanism. Furthermore, leptin inhibits Abeta(1-42)-mediated upregulation of endophilin I and phosphorylated tau in vitro, whereas cortical levels of endophilin I and phosphorylated tau are enhanced in leptin-insensitive Zucker fa/fa rats. Thus leptin benefits the functional characteristics and viability of neurons that degenerate in AD. These novel findings establish that the leptin system is an important therapeutic target in neurodegenerative conditions. PMID- 22921155 TI - ENMD-2076, an oral inhibitor of angiogenic and proliferation kinases, has activity in recurrent, platinum resistant ovarian cancer. AB - PURPOSE: The purpose was to assess the activity and side effect profile of ENMD 2076, an oral anti-angiogenic and anti-proliferative kinase inhibitor, in platinum-resistant recurrent epithelial ovarian cancer (EOC), fallopian tube or peritoneal cancer. Archival tumour tissue was obtained for correlative analyses. EXPERIMENTAL DESIGN: This was an open-label single-arm Phase II study of single agent ENMD-2076 taken daily orally (PO). The primary objective was to determine the progression free survival (PFS) rate at 6 months of ENMD-2076 in platinum resistant cancer based on RECIST v1.1. Secondary objectives included response rate (RR), duration of response, overall survival (OS) and safety. An exploratory analysis of archival tissue for mitotic index and angiogenesis was conducted in an attempt to identify a sensitive or resistant patient phenotype. RESULTS: 64 patients were enrolled, and the PFS rate at 6 months was 22% with a median time to progression of 3.6 months. The median number of prior regimens was 2. The most common adverse events were fatigue, hypertension and diarrhoea with the most common Grade 3/4 events being hypertension and fatigue. None of the markers of mitotic index or angiogenesis evaluated in the archival tissue samples were predictive of greater benefit or resistance to ENMD-2076 treatment. CONCLUSIONS: ENMD-2076 has activity in platinum-resistant ovarian cancer, and observed toxicities were similar to other PO kinase inhibitors. Additional studies with ENMD-2076 are warranted, especially in combination with active chemotherapeutic agents in platinum-resistant patients. Further work to determine appropriate biomarkers for ENMD-2076 should be incorporated into new clinical studies. PMID- 22921156 TI - The feasibility of nipple aspiration and duct lavage to evaluate the breast duct epithelium of women with increased breast cancer risk. AB - AIM: Nipple aspiration (NA) and duct lavage (DL) are modalities for obtaining breast duct fluid for biomarker analyses. The aim of this study was to assess the feasibility of obtaining serial NA and DL samples at consecutive patient visits for cytology assessment and the creation of a biobank. METHODS: Seventy eligible subjects were enroled at a single institution in the United Kingdom as part of an international multicentre study. Entry criteria were based on a 5-year Gail model risk of >=2% or Claus score lifetime risk of >=26%. Women underwent NA and DL in an outpatient clinic under local anaesthesia. RESULTS: The mean patient age was 48 (range 41-69)years. Sixty seven out of 70 women (96%) attended three consecutive 6 monthly visits and follow-up for 2 years. Three women withdrew due to intolerance of the DL procedure. 56/67 (83%) women produced NA fluid from at least one duct. 204/264 (77%) of ducts declared by NA were cannulated for DL. 170/204 (83%) produced DL samples with adequate cellularity. By the final visit 52/67 (78%) women produced DL, 28/52 (54%) of whom were premenopausal and 24/52 (46%) were postmenopausal. 50/52 women (96%) underwent repeated DL of 81 ducts on 3 consecutive visits. CONCLUSION: NA and DL are well tolerated for repeated assessment to obtain material for cytology and to create a biobank for future biomarker studies in women at high breast cancer risk. PMID- 22921157 TI - Support of the 'fallopian tube hypothesis' in a prospective series of risk reducing salpingo-oophorectomy specimens. AB - OBJECTIVE: To determine the prevalence, localisation and type of occult (non)invasive cancer in risk-reducing salpingo-oophorectomy (RRSO) specimens in BRCA-mutation carriers and high-risk women from BRCA-negative families. METHODS: A consecutive series of RRSO specimens of asymptomatic, screen-negative high-risk women were prospectively collected in our tertiary multidisciplinary cancer clinic from January 2000 until March 2012. All high-risk women in this study underwent genetic testing on BRCA-mutations. The surgico-pathological protocol comprised complete resection of ovaries and fallopian tubes, transverse sectioning at 2-3 mm (sectioning and extensively examining the fimbrial end [SEE FIM] protocol from 2006) and double independent pathology review of morphologically deviant sections. RESULTS: Three hundred and sixty RRSOs were performed in 188 BRCA1-carriers, 115 BRCA2-carriers and 57 BRCA-negative women at a median age of 44.0 years. Four occult invasive cancers were detected in BRCA carriers (1.3%, 95%-confidence interval (CI) 0.03-2.61), all in BRCA1-carriers >40 years of age. All cancers, of which two tubal and two ovarian cancers, were FIGO-stage I/II. Three non-invasive serous intraepithelial carcinomas (STICs) were detected in BRCA-carriers (1.0%, 95%-CI 0.00-2.10). In BRCA-negative women one STIC was found (1.8%, 95%-CI 0.00-5.16), however she carried an unclassified variant in BRCA2. Total follow-up after RRSO was 1691 woman-years, in which one BRCA1-carrier developed peritoneal cancer (0.3%, 95%-CI 0.00-0.82). CONCLUSIONS: A low prevalence of occult invasive cancer (1.1%) was found in young asymptomatic, screen-negative women at increased ovarian cancer risk undergoing RRSO. This study adds to the advice to perform RRSO in BRCA1-carriers before the age of 40. Our findings support the hypothesis of the fallopian tube as the primary site of origin of pelvic high-grade serous cancer. PMID- 22921158 TI - [Cervical pregnancy: a rare case of reimplantation after abortion. A case report]. AB - Cervical pregnancy is a rare form of ectopic pregnancy defined by the implantation of the blastocyst in the cervical canal. Most of the cervical pregnancies have been reported in patients with a history of vacuum curettage or caesarean section. The authors report a case of cervical pregnancy occurred after a failure of medical abortion. A literature review discusses the possibility of a cervical secondary implantation and describes the management of such pregnancies. PMID- 22921159 TI - Interventional study to strengthen the health promoting behaviours of pregnant women to prevent anaemia in southern India. AB - OBJECTIVES: to determine the effectiveness of a health information package in terms of empowering the pregnant women to modify their health-care behaviour and take appropriate action to combat anaemia in pregnancy. DESIGN: the study was conceptualized based on Rosenstock and Becker's health belief model. A quasi experimental pretest-posttest control group design was used. The sample consists of 225 anaemic pregnant women randomly allocated in experimental (n=75), control group A (n=75) and control group B (n=75). The health seeking behaviour outcome measure included knowledge regarding anaemia, food selection ability, increase in haemoglobin level and compliance to iron supplementation. Intervention was a validated planned educational programme with visual aids and iron supplementation. FINDINGS: the results show the mean gain of knowledge scores of experimental group was comparatively higher and control groups A and B showed that F ratio was (F(2,190)=11.910, p<0.01) indicating that the pregnant women learned more about anaemia prevention than others. With regard to food selection ability scores of experimental, control groups A and B the F ratio was also significant (F(2,190)=20.92, p<0.01). Nearly 61.2% of the subjects in experimental group became non-anaemic after the intervention when compared to control group A. This indicated that inspite of iron supplementation received by the three groups health education contributed significantly in modifying their health seeking behaviour and their perception about significance of anaemia has a problem. CONCLUSION: developing countries still face the critical problem of anaemia in pregnancy. These are the socio-cultural priority problems that demand immediate attention by the policy makers and health professionals. The national anaemia control programme focuses on iron supplementation, but nutritional education and supervision of iron supplementation has failed in different regions. The study implies that economic empowerment; strengthening health literacy through planned educational programs will definitely improve the health behaviour of individual and community at large. PMID- 22921160 TI - Preferred place of birth: characteristics and motives of low-risk nulliparous women in the Netherlands. AB - OBJECTIVE: to explores preferences, characteristics and motives regarding place of birth of low-risk nulliparous women in the Netherlands. DESIGN: a prospective cohort study of low-risk nulliparous women and their partners starting their pregnancy in midwifery-led care or in obstetric-led care. Data were collected using a self-administered questionnaire, including questions on demographic, psychosocial and pregnancy factors and statements about motives with regard to place of birth. Depression, worry and self-esteem were explored using the Edinburgh Depression Scale (EDS), the Cambridge Worry Scale (CWS) and the Rosenberg Self Esteem Scale (RSE). SETTING: participants were recruited in 100 independent midwifery practices and 14 hospitals from 2007 to 2011. PARTICIPANTS: 550 low-risk nulliparous women; 231 women preferred a home birth, 170 women a hospital birth in midwifery-led care and 149 women a birth in obstetric-led care. FINDINGS: Significant differences in characteristics were found in the group who preferred a birth in obstetric-led care compared to the two groups who preferred midwifery-led care. Those women were older (F (2,551)=16.14, p<0.001), had a higher family income (chi(2) (6)=18.87, p=0.004), were more frequently pregnant after assisted reproduction (chi(2)(2)=35.90, p<0.001) and had a higher rate of previous miscarriage (chi(2)(2)=25.96, p<0.001). They also differed significantly on a few emotional aspects: more women in obstetric-led care had symptoms of a major depressive disorder (chi(2)(2)=6.54, p=0.038) and were worried about health issues (F (2,410)=8.90, p<0.001). Women's choice for a home birth is driven by a desire for greater personal autonomy, whereas women's choice for a hospital birth is driven by a desire to feel safe and control risks. KEY CONCLUSIONS: the characteristics of women who prefer a hospital birth are different than the characteristics of women who prefer a home birth. It appears that for women preferring a hospital birth, the assumed safety of the hospital is more important than type of care provider. This brings up the question whether women are fully aware of the possibilities of maternity care services. Women might need concrete information about the availability and the characteristics of the services within the maternity care system and the risks and benefits associated with either setting, in order to make an informed choice where to give birth. PMID- 22921161 TI - Place of birth. PMID- 22921162 TI - Weight-related actual and ideal self-states, discrepancies, and shame, guilt, and pride: examining associations within the process model of self-conscious emotions. AB - The aim of this study was to examine the associations between women's actual:ideal weight-related self-discrepancies and experiences of weight-related shame, guilt, and authentic pride using self-discrepancy (Higgins, 1987) and self conscious emotion (Tracy & Robins, 2004) theories as guiding frameworks. Participants (N=398) completed self-report questionnaires. Main analyses involved polynomial regressions, followed by the computation and evaluation of response surface values. Actual and ideal weight self-states were related to shame (R2 = .35), guilt (R2 = .25), and authentic pride (R2 = .08). When the discrepancy between actual and ideal weights increased, shame and guilt also increased, while authentic pride decreased. Findings provide partial support for self-discrepancy theory and the process model of self-conscious emotions. Experiencing weight related self-discrepancies may be important cognitive appraisals related to shame, guilt, and authentic pride. Further research is needed exploring the relations between self-discrepancies and a range of weight-related self-conscious emotions. PMID- 22921163 TI - The problem of orthodoxy in safety research: time for a reformation. PMID- 22921164 TI - Prediction value of the Canadian CT head rule and the New Orleans criteria for positive head CT scan and acute neurosurgical procedures in minor head trauma: a multicenter external validation study. AB - STUDY OBJECTIVE: The New Orleans Criteria and the Canadian CT Head Rule have been developed to decrease the number of normal computed tomography (CT) results in mild head injury. We compare the performance of both decision rules for identifying patients with intracranial traumatic lesions and those who require an urgent neurosurgical intervention after mild head injury. METHODS: This was an observational cohort study performed between 2008 and 2011 on patients with mild head injury who were aged 10 years or older. We collected prospectively clinical head CT scan findings and outcome. Primary outcome was need for neurosurgical intervention, defined as either death or craniotomy, or the need of intubation within 15 days of the traumatic event. Secondary outcome was the presence of traumatic lesions on head CT scan. New Orleans Criteria and Canadian CT Head Rule decision rules were compared by using sensitivity specifications and positive and negative predictive value. RESULTS: We enrolled 1,582 patients. Neurosurgical intervention was performed in 34 patients (2.1%) and positive CT findings were demonstrated in 218 patients (13.8%). Sensitivity and specificity for need for neurosurgical intervention were 100% (95% confidence interval [CI] 90% to 100%) and 60% (95% CI 44% to 76%) for the Canadian CT Head Rule and 82% (95% CI 69% to 95%) and 26% (95% CI 24% to 28%) for the New Orleans Criteria. Negative predictive values for the above-mentioned clinical decision rules were 100% and 99% and positive values were 5% and 2%, respectively, for the Canadian CT Head Rule and New Orleans Criteria. Sensitivity and specificity for clinical significant head CT findings were 95% (95% CI 92% to 98%) and 65% (95% CI 62% to 68%) for the Canadian CT Head Rule and 86% (95% CI 81% to 91%) and 28% (95% CI 26% to 30%) for the New Orleans Criteria. A similar trend of results was found in the subgroup of patients with a Glasgow Coma Scale score of 15. CONCLUSION: For patients with mild head injury, the Canadian CT Head Rule had higher sensitivity than the New Orleans Criteria, with higher negative predictive value. The question of whether the use of the Canadian CT Head Rule would have a greater influence on head CT scan reduction requires confirmation in real clinical practice. PMID- 22921165 TI - Comparison of the test characteristics of procalcitonin to C-reactive protein and leukocytosis for the detection of serious bacterial infections in children presenting with fever without source: a systematic review and meta-analysis. AB - STUDY OBJECTIVE: We determine the usefulness of the procalcitonin for early identification of young children at risk for severe bacterial infection among those presenting with fever without source. METHODS: The design was a systematic review and meta-analysis of diagnostic studies. Data sources were searches of MEDLINE and EMBASE in April 2011. Included were diagnostic studies that evaluated the diagnostic value of procalcitonin alone or compared with other laboratory markers, such as C-reactive protein or leukocyte count, to detect severe bacterial infection in children with fever without source who were aged between 7 days and 36 months. RESULTS: Eight studies were included (1,883 patients) for procalcitonin analysis, 6 (1,265 patients) for C-reactive protein analysis, and 7 (1,649 patients) for leukocyte analysis. The markers differed in their ability to predict serious bacterial infection: procalcitonin (odds ratio [OR] 10.6; 95% confidence interval [CI] 6.9 to 16.0), C-reactive protein (OR 9.83; 95% CI 7.05 to 13.7), and leukocytosis (OR 4.26; 95% CI 3.22 to 5.63). The random-effect model was used for procalcitonin analysis because heterogeneity across studies existed. Overall sensitivity was 0.83 (95% CI 0.70 to 0.91) for procalcitonin, 0.74 (95% CI 0.65 to 0.82) for C-reactive protein, and 0.58 (95% CI 0.49 to 0.67) for leukocyte count. Overall specificity was 0.69 (95% CI 0.59 to 0.85) for procalcitonin, 0.76 (95% CI 0.70 to 0.81) for C-reactive protein, and 0.73 (95% CI 0.67 to 0.77) for leukocyte count. CONCLUSION: Procalcitonin performs better than leukocyte count and C-reactive protein for detecting serious bacterial infection among children with fever without source. Considering the poor pooled positive likelihood ratio and acceptable pooled negative likelihood ratio, procalcitonin is better for ruling out serious bacterial infection than for ruling it in. Existing studies do not define how best to combine procalcitonin with other clinical information. PMID- 22921166 TI - Harnessing genomic approaches for infectious disease diagnosis in emergency medicine: getting closer to prime time. PMID- 22921167 TI - [Introduction]. PMID- 22921168 TI - [Cardiovascular risk in the 21st century: identifying risk in primary prevention. Controlling risk in secondary prevention]. AB - If a primary prevention strategy for cardiovascular disease is to be implemented successfully, it is essential to have some knowledge of the level of risk in the general population, long before clinical disease appears. Traditionally, risk stratification has been based on risk factors that were first described some 50 years ago. However, we know that we are not able to identify all individuals who could present with a cardiovascular condition. in recent years, various techniques, principally imaging techniques, have been developed for detecting subclinical vascular disease, but they have not yet been approved for general use. While we will clearly witness changes in cardiovascular risk assessment in the future, until then we must make use of every available tool to ensure that any patient who needs our expertise does not escape our attention. Once a patient presents with clinical symptoms of cardiovascular disease or is known to have silent disease, we must implement secondary prevention measures to avoid the appearance of additional clinical conditions. in addition to strictly controlling risk factors, we must also make use of both drug treatment and surgical revascularization, strategies that have been demonstrated to be effective but which are underutilized. Above all, there is the unfinished business of modifying lifestyles to encourage healthier habits. Considerable medical progress will be lost if we do not improve our diet, exercise regularly and completely ban smoking. PMID- 22921169 TI - [An alarming threat to secondary prevention: low compliance (lifestyle) and poor adherence (drugs)]. AB - The deteriorating health of the general population and the increasing prevalence of chronic disease combine to present a problem of global proportions whose causes are both multifactorial and complex. The consumer society we live in does not encourage healthy living, and the consequences are even most devastating when social inequalities, the economic situation and the population explosion in recent decades are taken into account. The growth of poor eating habits, obesity, and hypertension are relentlessly contributing to the development of an epidemic of cardiovascular disease. In this context, the ability of national and international bodies and regulatory agencies to have an effect on commercial interests is very limited and alternative ways of reducing the disease burden are needed. Recent studies on patient compliance with lifestyle changes and on adherence to prescribed medication have produced alarming findings. Over 50% of patients, on average, choose to abandon the treatment they have been prescribed, and the percentage that achieve the targets proposed for improving habitual behaviors (e.g. quitting smoking, losing weight or increasing physical activity) is similar or lower. It is essential that solutions to these problems are found because, in addition to their implications for the health of the individual, poor compliance and adherence threaten to undermine the relevance of clinical study findings and are associated with substantial economic costs, given that they result in the failure to achieve therapeutic goals and increase rates of hospitalization and death. Improved communication between doctors and patients, the active participation of other health professionals and the development of combination drug formulations (e.g. the polypill) appear to be the most promising strategies for improving patient adherence to treatment and reducing the economic burden. PMID- 22921170 TI - [Risk stratification in Chagas disease]. AB - Chagas disease is the leading cause of infectious myocarditis worldwide and its associated high morbidity and mortality result in a substantial public health burden. The most common clinical manifestations of the disease are congestive heart failure, thromboembolism and sudden cardiac death. However, both the clinical course of the disease and prognosis vary widely. Therefore, clinical decision-making depends on the identification of markers of a poor prognosis. This article contains a concise review of risk stratification in Chagas disease, with a focus on echocardiographic predictors of mortality. PMID- 22921171 TI - [Atrial fibrillation ablation in the real world: the less we know, the more we ablate?]. AB - Catheter ablation is now well established as an alternative or complementary therapeutic approach to the use of anti-arrhythmic drugs in selected patients with atrial fibrillation. Although pulmonary vein isolation is very effective in patients with paroxysmal atrial fibrillation, it is still not possible to identify the arrhythmogenic substrate responsible for fibrillation in a large number of patients, principally those with persistent atrial fibrillation. As a result, anatomic areas in the atrium that are not involved in either the initiation or maintenance of atrial fibrillation may undergo ablation. Until we have a better understanding of the pathophysiology of the different stages of atrial fibrillation, it would be wise to treat arrhythmias early, before anatomic or electrical deterioration of the atrium occurs. PMID- 22921172 TI - [Percutaneous aortic valve replacement. A multidisciplinary approach. The key to success]. AB - Recently transcatheter aortic valve implantation (TAVI) has been offered to selected patients and results have been good. In Europe, for example, TAVI is an established, evidence-based, alternative to open aortic valve replacement for patients with aortic stenosis in whom conventional cardiac surgery would pose a high risk. Studies in the United States demonstrated that, in patients with severe aortic stenosis who are not candidates for surgery, TAVI using the Edwards SAPIEN valve resulted in significantly lower mortality than standard treatment. However, TAVI was associated with a nonsignificantly higher incidence of stroke and major vascular complications compared to standard aortic valve replacement. Moreover, when strokes and transient ischemic attacks were considered together, there was a significant benefit in favor of surgery at both 30 days and 1 year (P=.04). Clearly, optimal patient selection is critical for the success of TAVI. In addition, it has been shown that the adoption of a multidisciplinary approach improves outcomes in complex procedures like these. To ensure successful outcomes with TAVI, a multidisciplinary heart valve team must collaborate at all stages of the program: during screening, during and after the procedure, and throughout follow-up. In particular, patients should be screened for inclusion in a TAVI program by a member of the multidisciplinary team, and not by an external individual specialist. Moreover, the selection of candidates for treatment should involve consultation between the different disciplines (i.e. between cardiologists, surgeons, imaging specialists, anesthesiologists, pulmonologist, and other specialists, if necessary). PMID- 22921173 TI - Metal-mediated controllable creation of secondary, tertiary, and quaternary carbon centers: a powerful strategy for the synthesis of iron, cobalt, and copper complexes with in situ generated substituted 1-pyridineimidazo[1,5-a]pyridine ligands. AB - An efficient strategy for the synthesis of a wide variety of coordination complexes has been developed. The synthetic protocol involves a solvothermal in situ metal-ligand reaction of picolinaldehyde, ammonium acetate, and transition metal ions, leading to the generation of 12 coordination complexes supported by a novel class of substituted 1-pyridineimidazo[1,5-a]pyridine ligands (L1-L5). The ligands L1-L5 were afforded by metal-mediated controllable conversion of the aldehyde group of picolialdehyde into a ketone and secondary, tertiary, and quaternary carbon centers, respectively. Complexes of various nuclearities were obtained: from mono-, di-, and tetranuclear to 1D chain polymers. The structures of the in situ formed complexes could be controlled rationally via the choice of appropriate starting materials and tuning of the ratio of the starting materials. The plausible mechanisms for the formation of the ligands L1-L5 were proposed. PMID- 22921174 TI - Factors associated with the provision of hospice care for children. AB - CONTEXT: Children at the end of life often lack access to hospice care at home or in a dedicated facility. The factors that may influence whether or not hospices provide pediatric care are relatively unknown. OBJECTIVES: The purpose of this study was to understand the institutional and resource factors associated with provision of pediatric hospice care. METHODS: This study used a retrospective, longitudinal design. The main data source was the 2002 to 2008 California State Hospice Utilization Data Files. The sample size was 311 hospices or 1368 hospice observations over seven years. Drawing on institutional and resource dependence theory, this study used generalized estimating equations to examine the institutional and resource factors associated with provision of pediatric hospice care. Interaction terms were included to assess the moderating effect of resource factors on the relationship between institutional factors and provision of care. RESULTS: Membership in professional groups increased the probability (19%) of offering hospice services for children. Small- (-22%) and medium-sized (-11%) hospices were less likely to provide care for children. The probability of providing pediatric hospice care diminished (-23%) when competition increased in the prior year. Additionally, small size attenuated the accreditation-provision relationship and medium size magnified the membership-provision relationship. CONCLUSION: Professional membership may promote conformity to industry standards of pediatric care and remove the unknowns of providing hospice care for children. Hospices, especially medium-sized hospices, interested in developing or expanding care for children may benefit by identifying a pediatric champion to join a professional group. PMID- 22921175 TI - Oxygen is nonbeneficial for most patients who are near death. AB - CONTEXT: Clinicians prescribe and administer oxygen in response to reports of dyspnea, in the face of dropping oxygen saturation, as a "routine" comfort intervention, or to support anxious family members. Oxygen may produce nasal irritation and increase the cost of care. OBJECTIVES: To determine the benefit of administering oxygen to patients who are near death. METHODS: A double-blind, repeated-measure observation with the patient as his/her own control was conducted. The Respiratory Distress Observation Scale((c)) measured presence and intensity of distress at baseline and at every gas or flow change. Medical air, oxygen, and no flow were randomly alternated every 10 minutes via nasal cannula with patients who were near death, at risk for respiratory distress, with no distress at the baseline of testing. Each patient had two encounters under each condition, yielding six encounters per patient. RESULTS: Patients were 66% female, 34% white, and 66% African American, and ages 56-97 years. Patients had heart failure (25%), chronic obstructive pulmonary disease (34%), pneumonia (41%), or lung cancer (9%). Most (91%) patients tolerated the protocol with no change in respiratory comfort. Three patients (9%) displayed distress and were restored to baseline oxygen; one patient died during the protocol while displaying no distress. Repeated-measure analysis of variance revealed no differences in the Respiratory Distress Observation Scale under changing gas and flow conditions. CONCLUSION: The routine application of oxygen to patients who are near death is not supported. The n-of-1 trial of oxygen in clinical practice is appropriate in the face of hypoxemic respiratory distress. PMID- 22921176 TI - "It makes you feel that somebody is out there caring": a qualitative study of intervention and control participants' perceptions of the benefits of taking part in an evaluation of dignity therapy for people with advanced cancer. AB - CONTEXT: Participants in a Phase II randomized controlled trial of Dignity Therapy felt that the intervention had helped them; however, the processes underlying this are not known. OBJECTIVES: To explore intervention and control participants' perceptions of the benefits of taking part in an evaluation of Dignity Therapy within the frame of the underlying model of the intervention. METHODS: We interviewed 29 patients at one-week follow-up and 20 at four-week follow-up. We also interviewed nine family members of patients in the intervention group. We used the Framework approach to qualitative analysis. This comprised five stages: familiarization, identifying a thematic framework, indexing, charting, and mapping and interpretation. The analysis was both deductive (a priori themes from the model informing the content and therapeutic tone of the intervention) and inductive (from participants' views). RESULTS: There was support for five of the seven themes from the model underlying Dignity Therapy: "generativity," "continuity of self," "maintenance of pride," "hopefulness," and "care tenor." With the exception of generativity, all were evident in both groups. Prevalent emergent themes for the intervention group were "reminiscence" and "pseudo life review." "Making a contribution" was prevalent in the control group. CONCLUSION: Patients with advanced cancer and their families found that Dignity Therapy had helped them in many ways; however, patients in the control group sometimes perceived similar benefits from taking part in the study, highlighting elements of Dignity Therapy that are common to dignity conserving care. PMID- 22921178 TI - Management of end-of-life care and of difficult behaviors associated with borderline personality disorder. PMID- 22921177 TI - Coming to your senses: detecting taste and smell alterations in chemotherapy patients. A systematic review. AB - CONTEXT: Taste alterations (TAs) and smell alterations (SAs) are frequently observed, yet understudied side effects in chemotherapy patients, considerably affecting patients' quality of life. OBJECTIVES: This review provides a systematic evaluation of the literature on TAs and SAs in cancer chemotherapy patients and discloses understudied research questions. METHODS: A systematic methodology based on the PRISMA guidelines was applied to identify original research articles with TAs and SAs as primary outcomes in chemotherapy patients. MEDLINE and Embase were searched using Medical Subject Heading and free-text terms. Study extraction and evaluation were done by three reviewers using predefined criteria. RESULTS: The search revealed 22 eligible studies, including three randomized controlled trials. Different measurement approaches were identified, with a clear trend toward self-report measures during the past decade. The methodological quality of the included studies varied, especially reports on SAs, which were inconsistent and hard to interpret. Regarding TAs, there is evidence that taste thresholds increase during chemotherapy. Qualitative changes, for example, metallic taste, are frequent but cannot be attributed to specific chemotherapy regimens. There are large research gaps regarding TAs and SAs in different patient populations and the impact of different chemotherapy regimens. Adequate management strategies are rare. CONCLUSION: Current research results do not allow firm conclusions concerning the occurrence, severity, and quality of TAs and SAs under different chemotherapy regimens. Patient information on TAs and SAs, therefore, largely is based on the clinician's experience. In the palliative care setting, TAs and SAs need further investigation in the light of their importance in preventing food-related problems and maintaining a reasonable quality of life. PMID- 22921180 TI - Episodic breathlessness in patients with advanced disease: a systematic review. AB - CONTEXT: Although episodic breathlessness (EB) is reported to be highly prevalent in advanced disease, our understanding about it is limited. OBJECTIVES: The aim of this study was to systematically review and synthesize the evidence on EB regarding definition, characteristics, and patients' experiences. METHODS: Systematic review using searches in six databases, hand search, and personal contacts with authors in the field. Search terms included the combination of "episodic" and "breathlessness" (and synonyms) with five different diseases. Selection criteria included patients with advanced disease and information about EB based on original research. All retrieved studies were reviewed by two independent investigators. RESULTS: Twenty-seven studies (of 7584) were included in this review. Only eight studies explored EB as a primary outcome. EB is poorly defined. It is characterized by high prevalence (81%-85%), high frequency (daily), short duration (often less than 10 minutes), and severe peak intensity. EB either develops without any known trigger or is triggered by physical exertion, emotions, or environmental influences. CONCLUSION: EB is a common symptom in patients with advanced disease, but information about characteristics and experiences is limited. As there is no common terminology, an agreed definition is needed to foster research to develop effective treatments for EB. PMID- 22921181 TI - [Pre-implant posterior mandibular reconstruction]. AB - INTRODUCTION: We present a literature reviewed of pre-implant posterior mandible reconstruction, and report our experience with 107 patients exclusively reconstructed with cranial bone grafts. MATERIAL AND METHODS: Over a period of 15 years, 167 patients presenting with sometimes extremely severe bone resorption were grafted using various techniques depending on the type of resorption. RESULTS: The mean bone augmentation was 7.83 mm vertically and 7.16 mm horizontally respectively for patients with vertical and horizontal resorption. It was 6.66 mm vertically and 8.11 mm horizontally for patients with combined horizontal and vertical resorption. The postoperative complications were: mental nerve dysesthesia in 6.5% of patients, graft exposure in 1.8%, and +/- complete graft resorption in 4.2%. Implant placement was possible 3 months after reconstruction and bridge placement 6 months after reconstruction. DISCUSSION: The posterior mandible is the most difficult area to reconstruct, according to our experience. The vertical expansion technique, called "sandwich" osteotomy, frequently cannot be used. Alveolar distraction has a lot of drawbacks: patient constraints, uncertain outcome, and high risk of complications. Guided bone regeneration is restricted to small deficits. The onlay graft technique is poorly documented although it has many assets as demonstrated by our study. It may be used in any situation, even the most severe cases, except for rare cases of reduced occlusal space. PMID- 22921182 TI - Absence of global hypomethylation in promoter hypermethylated Mixed Lineage Leukaemia-rearranged infant acute lymphoblastic leukaemia. AB - BACKGROUND: Mixed Lineage Leukaemia (MLL)-rearranged acute lymphoblastic leukaemia (ALL) in infants represents a highly aggressive type of leukaemia that is often characterised by severe promoter CpG island hypermethylation. Consequently, MLL-rearranged ALL cells respond well to demethylating cytosine analogue drugs. In human cancer cells, enhanced promoter methylation is typically accompanied by global loss of methylation in non-promoter regions of the genome. In turn, global hypomethylation usually leads to genomic instability, which may have contributed to cancer development. DESIGN AND METHODS: Here we examined global methylation densities in MLL-rearranged infant ALL (n=45) samples in comparison with germline MLL infant ALL (n=11), non-infant B-cell precursor ALL (n=11) and normal paediatric bone marrow (n=9) samples. For this we performed high-resolution bisulfite pyrosequencing to determine methylation levels at the repetitive elements LINE-1, Alu and satellite alpha (SAT-alpha). As an additional measure of global methylation levels we used the LUminometric Methylation Assay (LUMA). RESULTS: We found that MLL-rearranged infant ALL is not characterised by global hypomethylation, despite its characteristic promoter CpG hypermethylation patterns. Instead we observed a moderate trend towards global hypermethylation and demonstrated that these methylated non-promoter sequences are responsive to demethylating agents. CONCLUSIONS: MLL-rearranged infant ALL cells are characterised by an overall methylated genomic state, and both promoter and non promoter methylation responds to demethylating agents, which may further explain the remarkable sensitivity of these cells for the methylation-inhibiting therapeutics. PMID- 22921179 TI - Trajectories of sleep disturbance and daytime sleepiness in women before and after surgery for breast cancer. AB - CONTEXT: Sleep disturbance is a problem for oncology patients. OBJECTIVES: To evaluate how sleep disturbance and daytime sleepiness (DS) changed from before to six months following surgery and whether certain characteristics predicted initial levels and/or the trajectories of these parameters. METHODS: Patients (n=396) were enrolled prior to surgery and completed monthly assessments for six months following surgery. The General Sleep Disturbance Scale was used to assess sleep disturbance and DS. Using hierarchical linear modeling, demographic, clinical, symptom, and psychosocial adjustment characteristics were evaluated as predictors of initial levels and trajectories of sleep disturbance and DS. RESULTS: All seven General Sleep Disturbance Scale scores were above the cutoff for clinically meaningful levels of sleep disturbance. Lower performance status; higher comorbidity, attentional fatigue, and physical fatigue; and more severe hot flashes predicted higher preoperative levels of sleep disturbance. Higher levels of education predicted higher sleep disturbance scores over time. Higher levels of depressive symptoms predicted higher preoperative levels of sleep disturbance, which declined over time. Lower performance status; higher body mass index; higher fear of future diagnostic tests; not having had sentinel lymph node biopsy; having had an axillary lymph node dissection; and higher depression, physical fatigue, and attentional fatigue predicted higher DS prior to surgery. Higher levels of education, not working for pay, and not having undergone neo adjuvant chemotherapy predicted higher DS scores over time. CONCLUSION: Sleep disturbance is a persistent problem for patients with breast cancer. The effects of interventions that can address modifiable risk factors need to be evaluated. PMID- 22921183 TI - Phase I dose-escalation study of intravenous aflibercept administered in combination with irinotecan, 5-fluorouracil and leucovorin in patients with advanced solid tumours. AB - BACKGROUND: To determine dose-limiting toxicities (DLTs), recommended phase II trial dose (RPTD), safety, preliminary antitumour activity and pharmacokinetics of intravenous aflibercept with irinotecan, 5-fluorouracil and leucovorin (LV5FU2). PATIENTS AND METHODS: In this open-label study, 38 patients with advanced solid tumours received aflibercept 2, 4, 5, or 6 mg/kg on day 1, then irinotecan and LV5FU2 on days 1 and 2 every 2 weeks. RESULTS: Two grade 3/4 aflibercept-associated DLTs occurred with 4 mg/kg: proteinuria lasting >2 weeks and acute nephrotic syndrome with thrombotic microangiopathy. Two DLTs with 5mg/kg (grade 3 stomatitis and grade 3 oesophagitis reflux) and three with 6 mg/kg (febrile neutropenia, grade 3 stomatitis and grade 3 abdominal pain) were considered related to concurrent chemotherapy and underlying disease. The most common grade 3/4 adverse events were neutropenia, hypertension and diarrhoea. Nine patients had partial responses, five with 4 mg/kg. Twenty-two patients had stable disease (five with 4 mg/kg), lasting >3 months in 17 patients. No anti aflibercept antibodies were detected. Free aflibercept was in excess of bound in most patients on 4 mg/kg. CONCLUSION: Based on pharmacokinetics, acceptable safety and encouraging antitumour activity, aflibercept 4 mg/kg was selected as the RPTD with irinotecan and LV5FU2 every 2 weeks. PMID- 22921184 TI - Phase I pharmacokinetic and pharmacodynamic study of the pan-PI3K/mTORC vascular targeted pro-drug SF1126 in patients with advanced solid tumours and B-cell malignancies. AB - BACKGROUND: SF1126 is a peptidic pro-drug inhibitor of pan-PI3K/mTORC. A first-in human study evaluated safety, dose limiting toxicities (DLT), maximum tolerated dose (MTD), pharmacokinetics (PK), pharmacodynamics (PD) and efficacy of SF1126, in patients with advanced solid and B-cell malignancies. PATIENTS AND METHODS: SF1126 was administered IV days 1 and 4, weekly in 28day-cycles. Dose escalation utilised modified Fibonacci 3+3. Samples to monitor PK and PD were obtained. RESULTS: Forty four patients were treated at 9 dose levels (90-1110 mg/m(2)/day). Most toxicity was grade 1 and 2 with a single DLT at180 mg/m(2) (diarrhoea). Exposure measured by peak concentration (C(max)) and area under the time concentration curve (AUC(0-)(t)) was dose proportional. Stable disease (SD) was the best response in 19 of 33 (58%) evaluable patients. MTD was not reached but the maximum administered dose (MAD) was 1110 mg/m(2). The protocol was amended to enrol patients with CD20+ B-cell malignancies at 1110 mg/m(2). A CLL patient who progressed on rituximab [R] achieved SD after 2 months on SF1126 alone but in combination with R achieved a 55% decrease in absolute lymphocyte count and a lymph node response. PD studies of CLL cells demonstrated SF1126 reduced p-AKT and increased apoptosis indicating inhibition of activated PI3K signalling. CONCLUSION: SF1126 is well tolerated with SD as the best response in patients with advanced malignancies. PMID- 22921187 TI - Eye gaze reveals a fast, parallel extraction of the syntax of arithmetic formulas. AB - Mathematics shares with language an essential reliance on the human capacity for recursion, permitting the generation of an infinite range of embedded expressions from a finite set of symbols. We studied the role of syntax in arithmetic thinking, a neglected component of numerical cognition, by examining eye movement sequences during the calculation of arithmetic expressions. Specifically, we investigated whether, similar to language, an expression has to be scanned sequentially while the nested syntactic structure is being computed or, alternatively, whether this structure can be extracted quickly and in parallel. Our data provide evidence for the latter: fixations sequences were stereotypically organized in clusters that reflected a fast identification of syntactic embeddings. A syntactically relevant pattern of eye movement was observed even when syntax was defined by implicit procedural rules (precedence of multiplication over addition) rather than explicit parentheses. While the total number of fixations was determined by syntax, the duration of each fixation varied with the complexity of the arithmetic operation at each step. These findings provide strong evidence for a syntactic organization for arithmetic thinking, paving the way for further comparative analysis of differences and coincidences in the instantiation of recursion in language and mathematics. PMID- 22921186 TI - Highlights of the EORTC St. Gallen International Expert Consensus on the primary therapy of gastric, gastroesophageal and oesophageal cancer - differential treatment strategies for subtypes of early gastroesophageal cancer. AB - The 1st St. Gallen EORTC Gastrointestinal Cancer Conference 2012 Expert Panel clearly differentiated treatment and staging recommendations for the various gastroesophageal cancers. For locally advanced gastric cancer (>=T3N+), the preferred treatment modality was pre- and postoperative chemotherapy. The majority of panel members would also treat T2N+ or even T2N0 tumours with a similar approach mainly because pretherapeutic staging was considered highly unreliable. It was agreed that adenocarcinoma of the gastroesophageal junction (AEG) is classified best according to Siewert et al. Preoperative radiochemotherapy (RCT) is the preferred treatment for AEG type I and II tumours. For AEG type III, i.e. tumours which may be considered as gastric cancer, perioperative chemotherapy is the majority approach. For resectable squamous cell cancer of the oesophagus a clear majority recommended radiochemotherapy followed by surgery as optimal approach, irrespective of tumour size. In contrast, definitive RCT was judged appropriate for advanced tumours with extended lymph node involvement (N2) or for cancers of the upper oesophagus. Additional recommendations are presented on the use of endosonography, PET-CT scan and laparoscopy for staging and on the preferred approach to surgery. PMID- 22921185 TI - Prognostic impact of the time interval between surgery and chemotherapy in advanced ovarian cancer: analysis of prospective randomised phase III trials. AB - BACKGROUND AND AIMS: Surgery followed by platinum-taxane chemotherapy is the current standard approach to treat advanced ovarian cancer. The impact of the time interval between surgery and initiation of chemotherapy for clinical outcome has not been clarified yet. METHODS: Individual patient data analysis of 3326 patients from three prospective randomised phase III trials conducted between 1995 and 2002 to investigate platinum-taxane based chemotherapy regimens in advanced ovarian cancer. Time to chemotherapy (TTC) was analysed and correlated with outcome. RESULTS: Median TTC was 19 days (range 1-56). The effect of TTC differed significantly for patients with or without residual disease for progression-free (PFS; interaction p=0.004) and for overall survival (OS; interaction p=0.028). A delayed start of chemotherapy was associated with earlier disease recurrence (HR 1.038, 95% CI 0.973; 1.106, p=0.257 per week delay) and a significantly decreased OS (HR 1.087, 95% CI 1.005; 1.176 p=0.038) in patients with no residual tumour after surgery. In contrast, in patients with residual disease, a longer TTC was significantly associated with later progression (HR 0.931, 95% CI 0.895; 0.969, p<0.001) and no effect towards OS (HR 0.983, 95% CI 0.940; 1.028, p=0.452). CONCLUSIONS: Our results provide evidence that early initiation of chemotherapy might result in slightly improved survival in patients with complete cytoreduction while patients with residual disease after surgery did not benefit from earlier chemotherapy. A prospective study randomising patients to different time intervals could clarify the definitive relevance of the time between surgery and chemotherapy. PMID- 22921188 TI - The labial-coronal effect revisited: Japanese adults say pata, but hear tapa. AB - The labial-coronal effect has originally been described as a bias to initiate a word with a labial consonant-vowel-coronal consonant (LC) sequence. This bias has been explained with constraints on the human speech production system, and its perceptual correlates have motivated the suggestion of a perception-production link. However, previous studies exclusively considered languages in which LC sequences are globally more frequent than their counterpart. The current study examined the LC bias in speakers of Japanese, a language that has been claimed to possess more CL than LC sequences. We first conducted an analysis of Japanese corpora that qualified this claim, and identified a subgroup of consonants (plosives) exhibiting a CL bias. Second, focusing on this subgroup of consonants, we found diverging results for production and perception such that Japanese speakers exhibited an articulatory LC bias, but a perceptual CL bias. The CL perceptual bias, however, was modulated by language of presentation, and was only present for stimuli recorded by a Japanese, but not a French, speaker. A further experiment with native speakers of French showed the opposite effect, with an LC bias for French stimuli only. Overall, we find support for a universal, articulatory motivated LC bias in production, supporting a motor explanation of the LC effect, while perceptual biases are influenced by distributional frequencies of the native language. PMID- 22921189 TI - Motivating inhibition - reward prospect speeds up response cancellation. AB - Reward prospect has been demonstrated to facilitate various cognitive and behavioral operations, particularly by enhancing the speed and vigor of processes linked to approaching reward. Studies in this domain typically employed task regimes in which participants' overt responses are facilitated by prospective rewards. In contrast, we demonstrate here that even the cancellation of a motor response can be accelerated by reward prospect, thus signifying reward-related benefits on restraint rather than approach behavior. Importantly, this facilitation occurred independent of strategy-related adjustments of response speed, which are known to systematically distort the estimation of response cancellation speed. The fact that motivational factors can indeed facilitate response inhibition is not only relevant for understanding how motivation and response inhibition interact in healthy participants but also for work on various patient groups that display response-inhibition deficits, suggesting that core differences in the ability to inhibit motor responses have to be differentiated from motivational factors. PMID- 22921190 TI - Introduction of Lihua Xiao, recipient of the Henry Baldwin Ward Medal for 2012. PMID- 22921191 TI - Improved survival with iron chelation therapy for red blood cell transfusion dependent lower IPSS risk MDS may be more significant in patients with a non-RARS diagnosis. AB - Retrospective analyses suggest iron overload is associated with inferior survival (OS) in lower risk MDS and iron chelation therapy (ICT) with improvement. However, an analysis of RARS patients found no such association. We analyzed subtypes of lower risk MDS. Median OS for non-RARS without and with ICT was 44 months and not reached (P<0.001), and for RARS 99 and 134.4 months (P=NS); in red blood cell (RBC) transfusion dependent RARS patients not receiving ICT, median OS was 73.8 months (P=0.025). These results suggest a stronger association between ICT and OS in non-RARS MDS than in RARS, with significantly superior OS in transfusion dependent patients receiving ICT. PMID- 22921192 TI - Wilderness first aid: is it time to revisit course content? PMID- 22921193 TI - Medical and sporting ethics of high altitude mountaineering: the use of drugs and supplemental oxygen. PMID- 22921194 TI - Performance-enhancing drugs-commentaries. PMID- 22921195 TI - Ultrasound use in ski clinics. PMID- 22921196 TI - Poly(2-hydroxyethyl methacrylate) brush surface for specific and oriented adsorption of glycosidases. AB - We present a detailed picture to screen general ligands from simple chemicals for fabricating affinity surface to glycosidase enzymes. The surface was constructed by grafting poly(2-hydroxyethyl methacrylate) (PHEMA) brush on SPR gold chip via surface-initiated atom-transfer radical polymerization, after which poly(methoxyethyl methacrylate) (PMEMA) and poly(oligo(ethylene glycol) methacrylate) (POEGMA) brushes were also prepared for comparison. SPR measurements were adopted to monitor the early-stage adsorption of two glycosidases and three other typical proteins. PHEMA resists the adsorption of lysozyme, bovine serum albumin, and fibrinogen, while it is capable of specifically adsorbing beta-glucosidase (GLU) and beta-galactosidase (GAL). These are quite different from the nonspecific adsorption of PMEMA and the anti nonspecific adsorption of POEGMA to the studied proteins, because PHEMA is the acceptor substrate of the glycosidases. About 69.6 and 93.7 ng/cm(2) of GAL and GLU are adsorbed on the PHEMA brush surface, of which more than 49.6 ng/cm(2) is remained after washing with PBS. The specific adsorption process is appropriately described by Freundlich isothermal model rather than Langmuir one, and is also indicated to be spontaneous, endothermic, and entropy driven through thermodynamic studies. Taking into account all stated results above, we propose that molecular recognition takes place between the hydroxyl groups of PHEMA and the active sites of glycosidases, which subsequently enables the oriented adsorption of glycosidases on the brush surface. The adsorbed enzyme can be effectively eluted with 1.0 M aqueous solution of ethanol. Our findings open the door to the further development in the design of novel acceptor substrate-ligand affinity chromatography for enzyme purification. PMID- 22921197 TI - Listing requirements for a prospective crossmatch in pediatric heart transplantation: analysis of Organ Procurement and Transplantation Network data from 1996 to 2009. PMID- 22921198 TI - Does smoke-free legislation and smoking outside bars increase feelings of stigmatization among smokers? Findings from the International Tobacco Control (ITC) Netherlands Survey. AB - This study examined whether smokers' perceived level of stigmatization changed after the implementation of smoke-free hospitality industry legislation and whether smokers who smoked outside bars reported more perceived stigmatization. Longitudinal data from the International Tobacco Control (ITC) Netherlands Survey was used, involving a nationally representative sample of 1447 smokers aged 15 years and older. Whether smoke-free legislation increases smokers' perceived stigmatization depends on how smokers feel about smoking outside. The level of perceived stigmatization did not change after the implementation of smoke-free hospitality industry legislation in the Netherlands, possibly because most Dutch smokers do not feel negatively judged when smoking outside. PMID- 22921199 TI - Arginine dehydrolase and beta-gentiobiose cannot discriminate within the Staphylococcus intermedius group. PMID- 22921200 TI - Predisposing factors for oropharyngeal colonization of yeasts in human immunodeficiency virus-infected patients: a prospective cross-sectional study. AB - BACKGROUND: Oropharyngeal candidiasis continues to be a major opportunistic infection in human immunodeficiency virus (HIV)-infected patients. The objectives of this study were to investigate the prevalence, associated factors, and microbiologic features for oropharyngeal yeast colonization in HIV-infected patients. METHODS: From October to December 2009, consecutive HIV-infected patients older than 18 years were recruited in this study. Demographic information, underlying conditions, and clinical histories were collected. Oropharyngeal swab cultures for yeasts and antifungal drug susceptibilities of the isolates were performed. RESULTS: Of the 105 HIV-infected patients, 54 (51.4%) were colonized with yeasts, including 11 patients (20.4%) with more than one species. Among the 68 isolates, Candida albicans accounted for 73.5%, followed by Candida tropicalis (5.9%), Candida glabrata (5.9%), and Candida dubliniensis (4.4%). There were 7.5% and 6% Candida isolates resistant to fluconazole and voriconazole, respectively. All of the Candida isolates were susceptible to amphotericin B. A higher prevalence of yeast colonization was noted in patients with a CD4 cell count <=200 cells/MUL (p = 0.032). Multivariate regression analysis showed that intravenous drug use was an independent associated factor for oropharyngeal yeast colonization (odds ratio, 5.35; 95% confidence interval, 1.39-20.6; p = 0.015), as well as protease inhibitor containing antiretroviral therapy (odds ratio, 3.59; 95% confidence interval, 1.41-9.12; p = 0.007). CONCLUSION: Despite previous studies showing that protease inhibitors decreased Candida adhesion to epithelial cells in vitro, the current study found protease inhibitor-containing antiretroviral therapy predisposed to oropharyngeal yeast colonization in HIV-infected patients. PMID- 22921201 TI - Planar polarized protrusions break the symmetry of EGFR signaling during Drosophila bract cell fate induction. AB - Secreted signaling molecules typically float in the outer leaflet of the plasma membrane or freely diffuse away from the signaling cell, suggesting that a signal should be sensed equally by all neighboring cells. However, we demonstrate that Spitz (Spi)-mediated epidermal growth factor receptor (EGFR) signaling is spatially biased to selectively determine the induction of a single bract cell on the proximal side of each mechanosensory organ on the Drosophila leg. Dynamic and oriented cellular protrusions emanating from the socket cell, the source of Spi, robustly favor the Spi/EGFR signaling response in a particular cell among equally competent neighbors. We propose that these protrusive structures enhance signaling by increasing contact between the signaling and responding cells. The planar polarized direction of the protrusions determines the direction of the signaling outcome. This asymmetric cell signaling serves as a developmental mechanism to generate spatially patterned cell fates. PMID- 22921203 TI - Glycolaldehyde impairs neutrophil biochemical parameters by an oxidative and calcium-dependent mechanism--protective role of antioxidants astaxanthin and vitamin C. AB - AIM: The present study examined the effects of glycolaldehyde (GC) on biochemical parameters of human neutrophils and whether the antioxidant astaxanthin associated with vitamin C can modulate these parameters. METHODS: Neutrophils from healthy subjects were treated with GC (1mM) followed or not by the antioxidants astaxanthin (2 MUM) and vitamin C (100 MUM). We examined the phagocytic capacity, hypochlorous acid, myeloperoxidase (MPO) and glucose-6 phosphate dehydrogenase (G6PDH) activities, cytokines and [Ca(2+)](i). Also, superoxide anion, hydrogen peroxide, nitric oxide production, antioxidant enzyme activities and glutathione-recycling system were evaluated. RESULTS: GC promoted a marked reduction on the phagocytic capacity, maximal G6PDH and MPO activities, hypochlorous acid production and release of IL-1beta, IL-6 and TNF-alpha cytokines. Some impairment in the neutrophils biochemical parameters appears to be mediated by oxidative stress through ROS/RNS production and calcium reduction. Oxidative stress was evidenced by reduction in the activities of the main antioxidant enzymes, GSH/GSSG ratio and in the increment of O(2)(-) and H(2)O(2) and NO. CONCLUSIONS: Treatment of cells with the combination of the antioxidants astaxanthin and vitamin C was able to restore some neutrophils function mainly by decreasing ROS/RNS production and improving the redox state. Overall, our findings demonstrate that GC modulates several neutrophils biochemical parameters in vitro. PMID- 22921202 TI - MOZ regulates the Tbx1 locus, and Moz mutation partially phenocopies DiGeorge syndrome. AB - DiGeorge syndrome, caused by a 22q11 microdeletion or mutation of the TBX1 gene, varies in severity greatly, even among monozygotic twins. Epigenetic phenomena have been invoked to explain phenotypic differences in individuals of identical genetic composition, although specific chromatin modifications relevant to DiGeorge syndrome are elusive. Here we show that lack of the histone acetyltransferase MOZ (MYST3/KAT6A) phenocopies DiGeorge syndrome, and the MOZ complex occupies the Tbx1 locus, promoting its expression and histone 3 lysine 9 acetylation. Importantly, DiGeorge syndrome-like anomalies are present in mice with homozygous mutation of Moz and in heterozygous Moz mutants when combined with Tbx1 haploinsufficiency or oversupply of retinoic acid. Conversely, a Tbx1 transgene rescues the heart phenotype in Moz mutants. Our data reveal a molecular mechanism for a specific chromatin modification of the Tbx1 locus intersecting with an environmental determinant, modeling variability in DiGeorge syndrome. PMID- 22921204 TI - Cortical fragment penetration into distal joints after intramedullary nailing - a rare complication. PMID- 22921205 TI - Extra- and intramedullary implants for the treatment of pertrochanteric fractures -- results from a Finnish National Database Study of 14,915 patients. AB - We analysed registry-based data on 14,915 patients treated for pertrochanteric fracture obtained from the Finnish Health Care Register during the years 1999 2009. Data on the comorbidities, residential status and deaths of the cohort were extracted from several Finnish registries using patients' unique personal identification numbers. The use of intramedullary implants increased substantially during the study period. One-year mortality was slightly higher in the patients treated with intramedullary implant (26.6% vs. 24.9%; P=0.011). In the first year after the fracture, there were more new operations on hip and thigh in patients treated with an intramedullary implant (11.1% vs. 8.9%; P<0.0001). Similarly, there were more new subtrochanteric and diaphyseal fractures of the femur in patients treated with intramedullary implants (3.2% vs. 1.05%; P<0.0001). Our findings suggest that more expensive intramedullary implants do not lead to better clinical outcomes than extramedullary implants for the treatment of pertrochanteric fractures. PMID- 22921206 TI - [Jejunal metastasis from choriocarcinoma. A three-case report]. AB - Five per cent of patients presenting with choriocarcinoma develop small bowel metastasis. Tumors of the small bowel are rare and the metastases are generally from lung and breast carcinoma or from melanoma. Clinical presentation is vague and the majority of cases are autopsy findings. The main symptoms are related to the presence of abdominal tumor or hemorrhage, or bowel obstruction or perforation. We present the cases of three patients with small bowel metastasis from choriocarcinoma. A 24-year-old woman with bowel obstruction secondary to intussusception caused by a metastatic choriocarcinoma polypoid mass and two men, one 18 years old and the other 24 years old, with a history of testicular tumor, who presented with gastrointestinal bleeding due to small bowel metastasis from choriocarcinoma, 2 and 10 months after orchiectomy, respectively. Management was endoscopic in one case and surgical in the other two. Two patients died in the early postoperative period and one patient died during the first year of follow up. Choriocarcinoma metastases are very rare and their main clinical manifestations are hemorrhage and bowel obstruction. Management can be either medical or surgical. The majority of patients with choriocarcinoma respond to chemotherapy but prognosis is worse for those patients presenting with small bowel metastasis. PMID- 22921207 TI - [Intussusception in the adult: a rare cause of mechanical obstruction]. AB - Intussusception is an infrequent cause of mechanical intestinal obstruction in the adult. We present herein two clinical cases of intussusception with different etiologies. In the first case, the underlying cause was a lipoma, and in the second, it was metastasis from melanoma. In both cases the intussusception was identified through computed tomography and treatment was intestinal resection. Pathologic anatomy provided the definitive diagnosis. Etiology is diverse and it is more common for obstruction to be due to organic lesions that are malignant at the level of the colon and benign at the level of the small bowel. Currently there are more preoperative diagnoses thanks to the advances made in imaging study techniques. Intestinal resection continues to be the treatment of choice in the majority of cases, because of the high percentage of malignant lesions as the underlying cause. PMID- 22921208 TI - [Endoscopic retrograde cholangiopancreatography at a regional hospital of the Instituto Mexicano del Seguro Social, 2002-2011: risk factors and complications]. AB - BACKGROUND: Endoscopic retrograde cholangiopancreatography (ERCP) is a valuable study in the approach to diseases of the biliary and pancreatic ducts. It was first used for diagnostic purposes, but today its use is mainly therapeutic. It can present a variety of complications. AIMS: To determine the frequency of complications and the risk factors associated with ERCP. MATERIAL AND METHODS: A prolective study was carried out to analyze ERCP that was performed on 1.145 patients over a 10-year period of time (2.002-2.011). Complications were determined at the time of the procedure, through the personal communication of relatives, and/or when the patient was admitted to the emergency room. Follow-up was carried out for one month after ERCP in the out-patient service of the Department of Gastroenterology. Complications were evaluated with a multiple logistic regression model. RESULTS: The sample included 1.145 patients. Mean age was 55,3 years (SD=18,7; CI 95%: 54,2-56,3). Women made up 60,5% (n=693) of the study participants. Therapeutic endoscopy was performed in 51,0% of the total number of procedures. Complications presented in 2,1% (n=24) of the patients; the most frequent was hemorrhage (n=14, 1,2%), followed by acute pancreatitis (n=6, 0,5%), respiratory distress (n=3, 0,3%), and cholangitis (n=1, 0,1%). There was a 1,4 times higher complication risk in patients that underwent precut/sphincterotomy, adjusted by age (CI 95%: OR 1,02-5,43; p=0,045). CONCLUSIONS: This study shows a complication frequency similar to that published by other authors. However, this figure could be further reduced if ERCP were performed only for therapeutic purposes by highly qualified endoscopy physicians. PMID- 22921209 TI - [Perforated peptic ulcer: is the form of methamphetamine known as "crystal meth" a new risk factor?]. AB - BACKGROUND: The emergence of new synthetic drugs related to peptic ulcer perforation has been reported. Recently an increase in the use of inhaled methamphetamine has been observed and we have described an association of frequent use with peptic disease symptomatology and perforation. AIMS: To determine whether methamphetamine use is a factor related to peptic acid disease and perforation and to establish its demographic variables. MATERIAL AND METHODS: A retrospective, comparative, descriptive, and observational study was carried out through the evaluation of medical records of patients admitted to the Surgery Service with perforated ulcer, within the time frame of January 2002 to March 2005. A descriptive analysis was carried out, along with the Z test, odds ratio, confidence interval, p value and the Student's t test. RESULTS: Forty-two patients were divided into 2 groups: methamphetamine users (n=25) and nonusers (n=17). There was a statistically significant difference in relation to age, which was lower in the methamphetamine user group (38,7 years vs 58,88 years, p=0.0001). In addition, there was a trend in the user group to develop peptic ulcer perforation at earlier ages compared with the nonuser group (p=0.0001). There were no statistically significant differences between the two groups in regard to clinical presentation. CONCLUSIONS: Methamphetamine use is related to ulcer perforation in age groups of younger patients when compared with nonuser patients. PMID- 22921210 TI - [Short bowel syndrome in children: a diagnosis and management update]. AB - Short bowel syndrome (SBS) refers to the sum of the functional alterations that are the result of a critical reduction in the length of the intestine, which in the absence of adequate treatment, presents as chronic diarrhea, chronic dehydration, malnutrition, weight loss, nutriment and electrolyte deficiency, along with a failure to grow that is present with greater frequency during the neonatal period. The aim was to carry out a review of the literature encompassing the definition and the most frequent causes of SBS, together with an understanding of its physiopathology, prognostic factors, and treatment. An Internet search of PubMed articles was carried out for the existing information published over the last 20 years on SBS in children, using the keywords "short bowel syndrome". From a total of 784 potential articles, 82 articles were chosen for the literature review. The treatment of patients presenting with SBS is quite a challenge and therefore it is necessary to establish multidisciplinary management with a focus on maintaining optimal nutritional support that covers the necessities of growth and development and at the same time provides a maximum reduction of short, medium, and long-term complications. The diagnosis and treatment of a child with SBS require a team of professionals that are experts in gastroenterologic, pediatric, and nutritional management. The outcome for the child will be directly related to opportune management, as well as to the length of the intestinal resection and the presence or absence of the ileocecal valve. PMID- 22921231 TI - Reading performance and patient satisfaction after corneal inlay implantation for presbyopia correction: two-year follow-up. AB - PURPOSE: To evaluate change in reading performance parameters after monocular Kamra corneal inlay implantation for the surgical correction of presbyopia. SETTING: University surgical outpatient center. DESIGN: Prospective interventional case series. METHODS: A corneal inlay was implanted in the nondominant eye. Naturally emmetropic and presbyopic patients between 45 years and 60 years old with an uncorrected distance visual acuity of at least 20/20 in both eyes without additional ocular pathology were eligible for inclusion. Bilateral uncorrected reading acuity, reading distance, mean and maximum reading speed, and the smallest log-scaled print size (lower case letter of a Radner reading chart) were evaluated using the Salzburg Reading Desk. The minimum postoperative follow-up was 24 months. RESULTS: Twenty-four patients were enrolled. The mean reading distance was 46.7 cm +/- 6.3 (SD) preoperatively and 39.5 +/- 6.4 cm 24 months postoperatively (P<.001). The mean reading acuity at best distance improved (0.33 +/- 0.13 logRAD versus 0.23 +/- 0.11 logRAD) (P=.004). The mean reading speed increased from 141 +/- 20 words per minute (wpm) to 146 +/- 20 wpm, respectively (P=.261), and the mean maximum reading speed from 171 +/- 28 wpm to 180 +/- 22 wpm, respectively (P=.110). The smallest print size improved from 1.50 +/- 0.42 mm to 1.01 +/- 0.22 mm, respectively (P<.001). CONCLUSION: Improving the depth of focus by monocular implantation of a small aperture optic caused statistically significant changes in all tested reading performance parameters except reading speed metrics in emmetropic presbyopic patients. PMID- 22921230 TI - Ca(2+) influx through L-type Ca(2+) channels and transient receptor potential channels activates pathological hypertrophy signaling. AB - Common cardiovascular diseases such as hypertension and myocardial infarction require that myocytes develop greater than normal force to maintain cardiac pump function. This requires increases in [Ca(2+)]. These diseases induce cardiac hypertrophy and increases in [Ca(2+)] are known to be an essential proximal signal for activation of hypertrophic genes. However, the source of "hypertrophic" [Ca(2+)] is not known and is the topic of this study. The role of Ca(2+) influx through L-type Ca(2+) channels (LTCC), T-type Ca(2+) channels (TTCC) and transient receptor potential (TRP) channels on the activation of calcineurin (Cn)-nuclear factor of activated T cells (NFAT) signaling and myocyte hypertrophy was studied. Neonatal rat ventricular myocytes (NRVMs) and adult feline ventricular myocytes (AFVMs) were infected with an adenovirus containing NFAT-GFP, to determine factors that could induce NFAT nuclear translocation. Four millimolar Ca(2+) or pacing induced NFAT nuclear translocation. This effect was blocked by Cn inhibitors. In NRVMs Nifedipine (Nif, LTCC antagonist) blocked high Ca(2+)-induced NFAT nuclear translocation while SKF-96365 (TRP channel antagonist) and Nickel (Ni, TTCC antagonist) were less effective. The relative potency of these antagonists against Ca(2+) induced NFAT nuclear translocation (Nif>SKF-96365>Ni) was similar to their effects on Ca(2+) transients and the LTCC current. Infection of NRVM with viruses containing TRP channels also activated NFAT-GFP nuclear translocation and caused myocyte hypertrophy. TRP effects were reduced by SKF-96365, but were more effectively antagonized by Nif. These experiments suggest that Ca(2+) influx through LTCCs is the primary source of Ca(2+) to activate Cn-NFAT signaling in NRVMs and AFVMs. While TRP channels cause hypertrophy, they appear to do so through a mechanism involving Ca(2+) entry via LTCCs. PMID- 22921232 TI - Clear corneal incisions in bimanual microincision cataract surgery: long-term wound-healing architecture. AB - PURPOSE: To evaluate bimanual microincision cataract surgery (MICS) clear corneal incision (CCI) architectural features over the long-term using anterior segment optical coherence tomography (AS-OCT). DESIGN: Case series. SETTING: Institute of Ophthalmology, University of Modena, Modena, Italy. METHODS: Patients who had uneventful bimanual MICS in the previous 2 to 16 months were examined using AS OCT. Images were used to measure corneal thickness, incision length, incision angle, incidence of epithelial or endothelial gaping, misalignment, Descemet membrane detachment, and posterior wound retraction. RESULTS: Fifty-two eyes (33 patients) were enrolled. Mean incision length and incision angle were, respectively, 1427.91 MUm and 31.19 degrees for the right hand, 1440.63 MUm and 31.54 degrees for the left hand, 1474.13 MUm and 31.27 degrees for temporal incisions, and 1394.41 MUm and 31.46 degrees for nasal CCIs. Posterior wound retraction was the only architectural feature found. Its prevalence was 7.10% at 2 to 3 months, 31.8% at 4 to 11 months, and 33.3% at 12 months. Fifty-three percent of posterior wound retractions were in 1.8 mm CCIs and 47% in 1.4 mm CCIs. CONCLUSIONS: Bimanual MICS was not related to particular morphologic features of CCIs. The enlargement of 1 incision or construction of the incision with the dominant or the nondominant hand did not affect long-term wound architecture. Posterior wound retraction was the only architectural feature; however, its prevalence seems substantially lower than with other surgical techniques. PMID- 22921233 TI - Salvage esophagectomy after failed definitive chemoradiation for esophageal adenocarcinoma. AB - BACKGROUND: Outcomes of salvage esophagectomy after definitive chemoradiation (CRT) for squamous cell carcinoma are well defined. Previous reports of salvage esophagectomy in patients with recurrent adenocarcinoma after definitive CRT are limited by small numbers and high morbidity and mortality rates. METHODS: We reviewed our experience of 65 patients with esophageal adenocarcinoma treated from 1997 to 2010 who underwent salvage esophagectomy after failed definitive CRT. We then compared this group to 65 matched patients of 521 total patients with esophageal adenocarcinoma who received preoperative CRT followed by planned esophagectomy. Propensity matching and multivariable analysis were performed. RESULTS: Median time to surgery from completion of therapy for the salvage group was 216 days. Major postoperative events (major pulmonary event, conduit loss, leak, readmission to intensive care unit) occurred in 35% (23 of 65) of salvage patients and 31% (20 of 65) of the planned resection matched group. Anastomotic leak occurred in 18.5% (12 of 65) and 11.3 (59 of 521) of salvage and planned groups, respectively. Thirty-day mortality was 3.1% (2 of 65) after salvage resection and 4.6% (3 of 65) after planned resection. There was no difference in 3-year overall or median survival between the two groups of patients (32 months, 48% salvage, versus 40 months, 57% planned resection). Multivariable analysis did not identify salvage strategy or time from completion of therapy to resection as a predictor of major event or death. CONCLUSIONS: Postoperative morbidity, mortality, and overall survival of patients after salvage esophagectomy are comparable to matched patients after planned resection. These results suggest that patients with esophageal adenocarcinoma who fail definitive CRT and recur locoregionally should be considered for salvage esophagectomy at experienced esophageal centers. PMID- 22921234 TI - Surgical experience with aggressive aortic pathologic process in Loeys-Dietz syndrome. AB - BACKGROUND: Loeys-Dietz syndrome (LDS) is a recently recognized connective tissue disorder (CTD) caused by mutations in transforming growth factor-beta receptor (TGFBR)1 and TGFBR2. Surgical outcomes of aortic repair in patients with LDS are poorly known. METHODS: We enrolled 16 patients with TGFBR mutations identified by gene analysis in this study. Between 1993 and 2011, they underwent 41 aortic surgical procedures. Ten patients (group D: dissection group) underwent aortic repair for acute or chronic aortic dissection as a first surgical intervention, and 6 patients (group N: nondissection group) underwent surgical treatment for aortic root dilatation. The mean follow-up period was 103.7 +/- 92.3 months (range, 2- 276 months). RESULTS: There were no in-hospital deaths. In group N, valve-sparing root replacement (VSRR) was performed in all patients. The residual aorta in 9 patients (90%) from group D required further repairs, 3 times on average. Moreover, in 4 patients (40%), the aorta was entirely replaced in serial procedures. In group N, aortic dissection occurred in only 1 patient (17%). The aortic event-free rates at 5 years were 40% in group D and 80% in group N, respectively (p = 0.819). One late death due to arrhythmia occurred 1 month after VSRR. The cumulative survival rates at 5 years were 100% in group D and 83% in group N, respectively (p = 0.197). CONCLUSIONS: Surgical outcomes for patients with LDS were satisfactory. Once aortic dissection occurred, the aorta expanded rapidly, requiring further operations. Therefore, early surgical intervention may improve prognosis by preventing a fatal aortic event. PMID- 22921235 TI - Benefits of high-pitch 128-slice dual-source computed tomography for planning of transcatheter aortic valve implantation. AB - BACKGROUND: Transcatheter aortic valve implantation (TAVI) has emerged as an alternative treatment for high-risk and inoperable patients. Advanced multimodality imaging, including computed tomography (CT), plays a key role for optimized planning of TAVI. METHODS: Forty-nine patients (25 women; age, 82.3+/ 8.8 year) with severe aortic stenosis scheduled for TAVI were examined with 128 slice high-pitch dual-source prospective aortoiliac CT angiography (CTA). The 3 coronary-sinus-alignment (3-CSA) plane, comprising left and right anterior oblique and craniocaudal projection, was defined from three-dimensional volume rendered technique data sets and compared with the intraoperative angiographic plane (deployment plane) used for device implantation. A tolerance level of +/-5 degree deviation was acceptable. Volume of intraoperative iodine contrast agent was compared before and after the implementation of the 3-CSA plane estimation by CT. RESULTS: All 49 patients underwent TAVI, during which 6 CoreValves (Medtronic, Minneapolis, MN) and 43 Sapien valves (Edwards Lifesciences, Irvine, CA) were successfully implanted using transapical (n=29), transfemoral (n=17), and transaxillary access (n=4). No severe complications occurred. In 47 patients (96%), CTA correctly predicted the 3-CSA plane used for device implantation. Mean left anterior oblique by CTA was 5.3+/-6.5 degrees and craniocaudal was -1.3+/ 10.1 degrees. Mean left anterior oblique deviation between CTA and the intraoperative projection was 2.1+/-2.7 degrees and craniocaudal was 1.7+/-3.0 degrees. Ostium heights of the right and left coronary arteries were 12+/-1.9 and 12.9+/-3.3 mm. No over-stenting occurred in left coronary artery ostia of 8 mm or more. Contrast volume was reduced from 81.8+/-25.6 to 59.4+/-40.2 mL (p=0.05) when using 3-CSA plane estimation by CT for final prosthesis implantation plane. CONCLUSIONS: Aortoiliac high-pitch 128-slice dual-source CT contributes to TAVI planning, including reliable prediction of the 3-CSA valve deployment plane, which saves contrast volume during the procedure and may facilitate correct valve placement. PMID- 22921236 TI - Outcomes of neonates undergoing extracorporeal membrane oxygenation support using centrifugal versus roller blood pumps. AB - BACKGROUND: Advances in centrifugal blood pump technology have led to increased use of centrifugal pumps in extracorporeal membrane oxygenation (ECMO) circuits. Their efficacy and safety in critically ill neonates remains unknown. Blood cell trauma leading to hemolysis may result in end-organ injury in critically ill neonates receiving centrifugal pump ECMO. We hypothesized that neonates undergoing ECMO support using centrifugal pumps were at increased odds of hemolysis and subsequent end-organ injury. METHODS: Children 30 days of age or younger who received support with venoarterial ECMO and were reported to the Extracorporeal Life Support Registry during 2007 to 2009 underwent propensity score matching (Greedy matching 1:1) using pre-ECMO support characteristics. RESULTS: A total of 1,592 neonates receiving ECMO (centrifugal pump = 163 and roller pump = 1,492) were identified. Significant differences in demographic, presupport, and cannulation variables were present before matching. One hundred seventy-six neonates who were supported using either centrifugal (n = 88) or roller pumps (n = 88) were matched using propensity scoring. No significant differences in demographic, presupport, or cannulation variables were present after matching. Neonates undergoing support using centrifugal pumps had increased odds of hemolysis (odds ratio [OR], 7.7 [2.8-21.2]), hyperbilirubinemia (OR, 20.8 [2.7-160.4]), hypertension (OR, 3.2 [1.3-8.0]), and acute renal failure (OR, 2.4 [1.1-5.6]). Survival to discharge was not different between pump types. CONCLUSIONS: Use of ECMO using centrifugal pumps is associated with increased odds of hemolysis that likely contributes to other end-organ injury. Research into the optimal use of centrifugal pumps and strategies to prevent support related complications need to be investigated. PMID- 22921237 TI - Predictive risk factors for patients with cirrhosis undergoing heart surgery. AB - BACKGROUND: Empiric experiences suggest higher mortality and complication risk for patients with cirrhosis of the liver after cardiac surgery. However, cirrhosis is not considered a risk factor in either the EuroSCORE or The Society of Thoracic Surgeons score. We report a large single-center experience of patients with cirrhosis undergoing cardiac surgery with extracorporeal circulation and aimed to evaluate the severity of cirrhosis as a predictor of outcome. METHODS: During 2001 and 2011, we operated on 109 consecutive patients (average age, 64 years; 82 male) diagnosed for cirrhosis with cardiopulmonary bypass for different indications. Thirty-day mortality and long-term mortality were set as primary study end points. RESULTS: Thirty-day mortality was 26%, and 5-year survival was 19%. Patients categorized as Child-Turcotte-Pugh (CHILD) C (n=6; 67% 30-day survival; 0% 5-year survival) and B (n=30; 60%; 5%) had worse 30 day and 5-year survival compared with patients categorized as CHILD A (n=73; 80%; 25%). For 30-day mortality, preoperative EuroSCORE (p=0.015), model for end-stage liver disease (MELD) score (p=0.006), albumin (p=0.023), total protein (p=0.01), and myocardial infarction (p=0.049) revealed significant differences between survivors and nonsurvivors. Multivariate logistic regression identified only MELD score (odds ratio [OR], 1.12; 95% confidence interval [CI], 1.03 to 1.23; p=0.011) and total protein (OR, 0.97; 95% CI, 0.95 to 1; p=0.049) were connected with increased 30-day mortality. Cox regression analysis revealed EuroSCORE (OR, 1.02; 95% CI, 1.01 to 1.03; p<0.0001) and MELD (OR, 1.06; 95% CI, 1.01 to 1.12; p=0.016) predicting the overall mortality. Receiver operating characteristic analysis indicated significant predictive power of MELD (p=0.001) and EuroSCORE (p=0.027) for 30-day mortality. CONCLUSIONS: Patients with cirrhosis undergoing heart surgery with extracorporeal circulation have a poor prognosis. Several preoperative factors are related to outcome. EuroSCORE and MELD score may help to evaluate operation risk and indication. PMID- 22921238 TI - Perventricular device closure of doubly committed subarterial ventral septal defect through left anterior minithoracotomy on beating hearts. AB - BACKGROUND: Surgical repair of doubly committed subarterial ventricular septal defect (VSD) under cardiopulmonary bypass has been the gold standard with full median sternotomy, complicated by skin scarring and potential mortalities and morbidities from cardiopulmonary bypass. Perventricular device closure of muscular and then perimembranous VSD on beating heats with a small subxiphoid or inferior sternotomy has been attempted in the past few years with good results. We have tried perventricular closure of doubly committed subarterial VSD through a left anterior minithoracotomy as an alternative procedure with a modified occluder. METHODS: Between January 2008 and December 2010, 6 selected patients with doubly committed subarterial VSD were recruited for modified device closure on beating hearts without cardiopulmonary bypass through left anterior minithoracotomy involving a short incision through the third intercostal space. Their ages ranged from 18 to 46 months and their body weights from 11 to 23 kg. A single per-right ventricular "U" like suture under pulmonic annulus was established, and a delivery system was introduced, aided by an 18G trocar, including a guidewire, delivery sheath, and loading sheath. A proper device was selected according to the VSD size established by transesophageal echocardiography (TEE), and then the device was released under real-time monitoring of TEE if no residual shunt, increased aortic prolapse or regurgitation, abnormal atrioventricular valvular motion appeared. RESULTS: In 5 of the 6 children, the device was successfully closed through a left minithoracotomy with satisfactory cosmetic effects. In the other child, the procedure was converted to conventional open-heart repair because the relatively larger occluder induced significantly increased aortic regurgitation. There was no operative or late mortality or major morbidity. All children were followed up for 10 to 21 months. No residual shunt, increased aortic prolapse or regurgitation, or serious atrioventricular block was recorded until the most recent follow-up. CONCLUSIONS: Selected doubly committed subarterial VSD can be safely closed with a proper occluder through left anterior minithoracotomy. The Cosmetic results are highly satisfactory. PMID- 22921239 TI - Outcomes of infants weighing three kilograms or less requiring extracorporeal membrane oxygenation after cardiac surgery. AB - BACKGROUND: Extracorporeal membrane oxygenation (ECMO) is the most common form of cardiac support for postcardiotomy cardiac failure in children. While its benefits have been thoroughly explored in infants weighing more than 3 kg, similar analyses are lacking in lower weight neonates. This single-center study investigated outcomes and risks for poor survival among infants weighing 3 kg or less. METHODS: A retrospective review of infants 3 kg or less who required postcardiotomy ECMO support was performed (January 1, 1999 to December 31, 2010). Primary outcome was 30-day survival after decannulation. Factors analyzed for association with poor outcome included demographics, cardiac anatomy, bypass and circulatory arrest times, total ECMO support time, postoperative lactate, inotrope use, and need for renal replacement therapy. RESULTS: During the study period, 64 patients weighing 3 kg or less required postcardiotomy ECMO. Median gestational age and age at ECMO initiation were 38 weeks (interquartile range, 36 to 39) and 7 days (interquartile range, 4 to 9), respectively, with median ECMO support time of 164 hours (interquartile range, 95 to 231). Overall 30-day survival after decannulation was 33%. Factors associated with poor outcome were longer duration of support (231 hours or more, 12% survival, versus less than 231 hours, 40% survival; p = 0.05) and renal replacement therapy (n = 36, survival 17% versus 54%; p = 0.002). Multivariable regression analysis identified renal replacement therapy as the only independent factor associated with poor survival (odds ratio 4.3, 95% confidence interval: 1.3 to 14.9, p = 0.02). CONCLUSIONS: For infants weighing 3 kg or less, 30-day survival after decannulation after cardiac ECMO is poor. Factors associated with poor prognosis were need for renal replacement therapy and longer duration of ECMO support. These findings may provide a useful guide for medical decision making among this unique, high-risk patient group. PMID- 22921240 TI - Mechanical circulatory support pathways that maximize post-heart transplant survival. AB - BACKGROUND: Heart transplant (HTx) recipients reach transplantation through increasing numbers of support pathways, including transition from one pathway to another. Outcomes of patients successfully bridged with various support pathways are unknown. We sought to identify mechanical circulatory support pathways that maximize survival after HTx. METHODS: A supplemented United Network Organ Sharing Dataset tracked status 1 HTx outcomes from 2000 to 2010. Recipients were grouped based on support pathway before HTx, including those transitioning from one pathway to another. Multivariable factors for time-related death were sought using Cox proportional hazard regression models. RESULTS: We identified 13,250 status 1 HTx recipients. Initial support pathways were inotropes (n = 7,607), left ventricular assist device (LVAD [n = 4,034]), intraaortic balloon pump (n = 729), biventricular assist device (n = 521), extracorporeal membrane oxygenation (ECMO [n = 316]), and right ventricular assist device (n = 43). Multivariable analysis demonstrated that LVAD use conferred a survival advantage (hazard ratio [HR] 0.71; p < 0.001), whereas all other support pathways, including inotropes (HR 1.1; p = 0.02), right ventricular assist device (HR 1.9; p = 0.01), and ECMO (HR 2.2; p < 0.001) increased the risk of post-HTx death. Support pathway transition (both escalation and reduction) occurred in 2,175 patients. Patients who transitioned from either ECMO or biventricular assist device support at listing to LVAD-only support at HTx had improved post-HTx survival that was comparable to patients who had LVAD-only therapy throughout their course (p = 0.74). CONCLUSIONS: The LVAD supported HTx recipients have better posttransplant survival than patients after all other mechanical support pathways. Survival after HTx is optimized when ECMO or biventricular assist device support can be transitioned to LVAD-only support. Our findings should aid clinical decision making and inform organ allocation policy development intended to maximize societal benefits of HTx. PMID- 22921241 TI - Quality of life after radical pleurectomy decortication for malignant pleural mesothelioma. AB - BACKGROUND: Malignant pleural mesothelioma is an aggressive malignancy in which radical surgical treatment appears to improve survival. It is unknown, however, if radical surgical treatment affects quality of life (QoL) adversely. Our objective was to assess patient-reported symptoms of health-related QoL after radical pleurectomy decortication (PD). METHODS: Patients with malignant pleural mesothelioma were prospectively enrolled between 2010 and 2011 to determine the effects of PD on baseline QoL. Health-related QoL was assessed using the European Organization for Research and Treatment of Cancer core Quality of Life Questionnaire-C30 tool (EORTC QLQ-C30) before operation and at 1, 5 to 6, and 8 to 9 months postoperatively. Patients were grouped based on World Health Organization baseline performance status (PS) and compared. RESULTS: Of the 28 patients enrolled, 16 (57.1%) and 12 (42.9%) were World Health Organization PS 0 and PS 1, respectively. At baseline, PS 1 patients had significantly worse global QoL functional and symptom scores at baseline. At 5 to 6 months' follow-up, PS 0 patients had no significant change in global QoL or functional domain scores. PS 1 patients had significant improvement in global QoL (p=0.038), symptoms of fatigue (p=0.05), and dyspnea (p=0.048). At 8 to 9 months' follow-up, PS 0 patients showed significant improvement in symptoms of fatigue (p=0.026) from baseline and PS 1 maintained the improvements in symptoms of fatigue (p=0.049) and dyspnea (p=0.048). CONCLUSIONS: Radical PD does not negatively impact minimally symptomatic patients at intermediate follow-up. Patients who have symptoms at baseline can have significant improvement in their QoL after surgical treatment. PMID- 22921242 TI - Transcanal surgical excision of an intracochlear schwannoma. AB - An intracochlear schwannoma is a rare cause of sensorineural hearing loss, which is little discussed in the literature. This case report details the presentation of a patient with a sensorineural hearing loss due to an intracochlear schwannoma. The patient was initially managed conservatively; however, as her symptoms and serial imaging indicated progression, the lesion was surgically resected via a transcanal/transotic approach. Diagnosis and management of this unusual schwannoma are reviewed. PMID- 22921243 TI - Fatal complications of percutaneous dilatational tracheostomy. AB - OBJECTIVES: Fatal complications of percutaneous dilatational tracheostomy (PDT) are rare and intraoperative fatal complications of PDT even more so. We present the unique case of a fatal nonvascular intraoperative complication of PDT, previously unreported in the medical literature. We also present a review of all previously reported fatal complications of PDT. METHODS: A review of all previously reported fatal complications of PDT was conducted in order to examine the prevalent causes of death and to attempt to recommend measures designed to prevent similar fatal complications in the future. RESULTS: Cases of death during or following PDT in which the technique is related to the cause of death have only been reported in a small number of cases. Almost all fatal complications of PDT result from vascular injury. CONCLUSIONS: Any vascular pulsation palpated over the tracheostomy site mandates preoperative ultrasound or conversion to open surgical tracheostomy. Patients with previous neck surgery, radiotherapy or unclear surgical anatomy should be regarded with caution. If a difficult intubation or a difficult procedure is anticipated, it may be preferable not to attempt PDT with a plan to convert to surgical tracheostomy if necessary but instead to perform surgical tracheostomy without attempting PDT. PMID- 22921245 TI - Paying for performance and the social relations of health care provision: an anthropological perspective. AB - Over the past decade, the use of financial incentive schemes has become a popular form of intervention to boost performance in the health sector. Often termed "paying for performance" or P4P, they involve "...the transfer of money or material goods conditional upon taking a measurable action or achieving a predetermined performance target" (Eldridge & Palmer, 2009, p.160). P4P appear to bring about rapid improvements in some measured indicators of provider performance, at least over the short term. However, evidence for the impact of these schemes on the wider health system remains limited, and even where evaluations have been positive, unintended effects have been identified. These have included: "gaming" the system; crowding out of "intrinsic motivation"; a drop in morale where schemes are viewed as unfair; and the undermining of social relations and teamwork through competition, envy or ill feeling. Less information is available concerning how these processes occur, and how they vary across social and cultural contexts. While recognizing the potential of P4P, the authors argue for greater care in adapting schemes to particular local contexts. We suggest that insights from social science theory coupled with the focused ethnographic methods of anthropology can contribute to the critical assessment of P4P schemes and to their adaptation to particular social environments and reward systems. We highlight the need for monitoring P4P schemes in relation to worker motivation and the quality of social relations, since these have implications both for health sector performance over the long term and for the success and sustainability of a P4P scheme. Suggestions are made for ethnographies, undertaken in collaboration with local stakeholders, to assess readiness for P4P; package rewards in ways that minimize perverse responses; identify process variables for monitoring and evaluation; and build sustainability into program design through linkage with complementary reforms. PMID- 22921244 TI - Salvage endoscopic nasoseptal flap repair of persistent cerebrospinal fluid leak after open skull base surgery. AB - PURPOSE: Persistent cerebrospinal fluid (CSF) rhinorrhea after open skull base surgery can be challenging to manage due to the risk of meningitis, brain abscess, surgical morbidity associated with revision craniotomy, and the lack of available healthy autologous tissue after failure of a pericranial flap. Given the recent success of the vascularized pedicled nasoseptal flap (PNSF) for reconstruction after endoscopic skull base surgery, we have adopted this technique as a salvage method to treat recalcitrant CSF rhinorrhea after previous open skull base surgery in order to avoid revision craniotomy. To our knowledge, use of the PNSF in this setting has not been previously described in the literature. METHODS: A retrospective analysis was performed on 4 patients who underwent endoscopic endonasal PNSF repair of persistent CSF rhinorrhea after having undergone previous open transcranial skull base operation. Pathologies consisted of one sinonasal anterior skull base squamous cell carcinoma, one recurrent petrosal skull base meningioma, and 2 traumatic gunshot wounds to the head. RESULTS: All 4 patients underwent successful repair of CSF rhinorrhea without complications using the salvage endoscopic endonasal PNSF technique after a mean follow-up of 21.5 months. CONCLUSIONS: In patients who have undergone previous open skull base surgery as the primary approach, persistent CSF rhinorrhea can be safely repaired using the vascularized PNSF via an endoscopic endonasal approach. This minimally invasive strategy has the advantage of providing new healthy vascularized tissue for skull base reconstruction while avoiding revision craniotomy. PMID- 22921246 TI - Dependence of the reduction products of platinum(IV) prodrugs upon the configuration of the substrate, bulk of the carrier ligands, and nature of the reducing agent. AB - Most evidence indicates that platinum(IV) prodrugs are rapidly reduced under physiological conditions by biologically relevant reducing agents, such as ascorbic acid and glutathione; however, the precise mechanisms of reduction are not fully understood, thus preventing rational design of compounds with better pharmacological properties. In the present study, reduction of three all-trans platinum(IV) compounds of formula [PtCl(2)(CH(3)COO)(2)LL'] (LL' = {E HN?C(CH(3))OCH(3)}(2), 1c, (H(3)N)(cyclohexylamine), 2c, and (H(3)N)(1 adamantylamine), 3c) by two biologically relevant reductants (ascorbic acid and glutathione) and by a classical coordination chemistry reductant (triphenylphosphine) has been investigated. Reduction by triphenylphosphine and glutathione leads, in all cases examined, to loss of the two chlorides and formation of the diacetato species trans-[Pt(CH(3)COO)(2)LL']. This is in accord with an "inner-sphere" redox process in which a chlorido ligand bridges the reductant with the platinum(IV) center. In contrast, reduction by ascorbic acid/sodium ascorbate 1:1 leads, in addition to the diacetato complex, also to formation of a significant amount of dichlorido species, particularly in the case of 1c (31%) and to a lesser extent of 3c (16%). The latter results indicate that ascorbic acid is less efficient to promote an inner-sphere redox process (attack on a chlorido ligand), therefore allowing participation of an "outer-sphere" mechanism, ultimately leading to formation of the more stable dichlorido species. The dependence of the yield of diacetato species upon the steric hindrance of the carrier ligand (69%, 84%, and 95% for 1c, 3c, and 2c, respectively) points to the possible participation of a second type of inner-sphere mechanism in which the interaction between the ascorbate and a chlorido ligand of the platinum(IV) substrate is mediated by a platinum(II) catalyst, the transition state resembling that of a platinum(II)-catalyzed ligand substitution at a platinum(IV) center. This investigation demonstrates that different species can be obtained by reduction of a platinum(IV) prodrug (depending upon the configuration of the substrate and the nature of the intervening reducing agent) and can explain some lack of correlation between prodrug and putative active species as well as contrasting literature results. PMID- 22921247 TI - Addictive behaviors and Parkinson's disease. AB - INTRODUCTION: In Parkinson's disease, the degeneration of the dopaminergic system and the longstanding exposure to dopamine replacement therapy (DRT) may cause, in a group of vulnerable patients, dysregulation of the brain reward system. STATE OF THE ARTS: These patients develop DRT-related compulsions, which include addiction to levodopa or dopamine dysregulation syndrome (DDS), punding, and impulse control disorders (ICDs). ICDs or behavioral addiction reported in Parkinson's disease include pathological gambling, hypersexuality, compulsive buying and binge eating. Although the underlying pathophysiology is still poorly understood, these behaviors are linked by their reward-based and repetitive nature. Such behaviors may result in devastating psychosocial impairment for the patients and are often hidden. PERSPECTIVE AND CONCLUSIONS: The recognition of these behaviors is important and allows a better clinical management. Although the limited data do not permit particular therapeutic strategies, some approaches are worth considering: DRT reduction, trials of non-dopaminergic medications and subthalamic chronic stimulation. PMID- 22921248 TI - Apathy: a pathology of goal-directed behaviour: a new concept of the clinic and pathophysiology of apathy. AB - We propose to defined apathy as a quantitative reduction of goal-directed behaviour. As such, the neural bases of apathy rely on lesions or dysfunctions of the brain structures that generate and control goal-directed behaviour: the frontal lobes, the basal ganglia and the frontal-basal ganglia circuits. Lesions or dysfunctions of the limbic territories of the frontal lobes (the orbital mesial prefrontal cortex) and the basal ganglia (e.g., the ventral striatum) lead to apathy through difficulties to provide the affective value of a given behavioural context. We also suggest that lesions or dysfunctions of the associative ("cognitive") territories of the frontal lobes (the dorsal prefrontal cortex) and the basal ganglia (e.g., the dorsal caudate) contribute to apathy via a "cognitive inertia" - an inability to generate or activate strategies required to successfully complete a given program of actions. The most severe forms of apathy ("auto-activation deficit" syndrome), due to bilateral lesions in the prefrontal-basal ganglia circuits can be explained either by the addition of lesions in the cognitive and limbic territories or by a more general and elementary impairment that mirrored the presumed normal functions of the prefrontal-basal ganglia circuits, that is to selectively amplified the behaviour that one considers as the most adapted to one's personal needs or environmental demands. These lesions may limit the selective amplification of the signal that represents relevant thoughts and actions, leading to difficulties to disambiguate decision-making at the level of the prefrontal cortex. PMID- 22921249 TI - [Apathy and deep brain stimulation in Parkinson's disease]. AB - Apathy was defined by Marin as diminished motivation not attributable to diminished level of consciousness, cognitive impairment, or emotional distress. Up to 42% of Parkinson's disease patients could be concerned. It has a pejorative impact on quality of life and could be predictive of cognitive decline. It has been shown that deep brain stimulation in Parkinson's disease may induce apathy. It seems directly related to the stimulation target, i.e. the subthalamic nucleus, since such an effect has not been observed so far in thalamic and pallidal stimulation. It should certainly not make us question the remarkable effectiveness of subthalamic stimulation in Parkinson's disease patients, but encourages us to be very careful about operability criteria. We must, in this sense, improve identification of at risk patients, seeking a thoroughly diminished motivation, loss of interest or blunting affects. PMID- 22921250 TI - [Imaging non motor signs in Parkinson's disease]. AB - Parkinson's disease is mainly considered as a motor disorder defined by a motor triad. However, various non-motor manifestations may be encountered in Parkinson's disease, including hyposmia, pain, fatigue, sleep disorders, cognitive and behavioral disorders. The pathophysiology of these signs is complex, not univocal and remains poorly understood. Functional imaging techniques either by positron emission tomography, single photon emission tomography or functional magnetic resonance imaging provide an invaluable opportunity to better understand the pathophysiology of these signs. In this paper, we present a review of the recent advances provided by functional imaging in this area. PMID- 22921251 TI - Kraft lignin biodegradation by Novosphingobium sp. B-7 and analysis of the degradation process. AB - This study focused on the biodegradation of kraft lignin (KL) by Novosphingobium sp. B-7 using KL as sole carbon source. Results revealed that Novosphingobium sp. B-7 reduced the chemical oxygen demand (COD) by 34.7% in KL mineral salt medium after 7days of incubation. Additionally, the maximum activities of manganese peroxidase (MnP) of 3229.8Ul(-1) and laccase (Lac) of 1275Ul(-1) were observed at 4th and 5th day, respectively. GC-MS analysis indicated that after incubated with Novosphingobium sp. B-7, low molecular weight alcohols and lignin-related monomer compounds such as ethanediol, p-hydroxy benzoic acid and vanillic acid were formed in the system, which strongly confirmed the degradation of KL by Novosphingobium sp. B-7. PMID- 22921252 TI - Generation of electricity from FeCl3 pretreatment of rice straw using a fuel cell system. AB - This study explored a new approach to the pretreatment of lignocellulosic biomass using FeCl3 combined with a fuel cell system to generate electricity. After pretreatment, ferric iron (Fe(3+)), a strong catalyst in the hydrolysis of carbohydrate, was found to be reduced to ferrous iron (Fe(2+)) by means of the oxidation of xylose and lignin. Ferrous iron, as a fuel, was employed to the anode part of a fuel cell, generating power of 1110 mW/m(2). During the fuel cell operation, ferrous iron was completely removed through oxidation to ferric iron and precipitated out. The optimal conditions for the operation of the fuel cell were found to be a pH of 7.0 and ferrous iron concentration of above 0.008 M. These results clearly show that a fuel cell system could be used not only to remove ferrous iron from liquid hydrolysate, but also to produce electricity. PMID- 22921253 TI - Musks and organochlorine pesticides in breast milk from Shanghai, China: levels, temporal trends and exposure assessment. AB - The concentrations of musks (polycyclic musks and nitro musks) and traditional organochlorine pesticides (OCPs), including dichlorodiphenyltrichloroethane and its metabolites (DDT, DDE, DDD, and total DDTs), hexachlorobenzene (HCB), and hexachlorocyclohexanes (HCHs) in breast milk collected in Shanghai, China during the period 2006-2010, were determined. The total concentrations ranged from 4.7 to 276.2 (median: 58.4) ng/glipid weight (lw) for musks and from 88.3 to 2532.9 (median: 1003.8) ng/glw for OCPs. 4,4'-DDE (median: 655.4 ng/glw) was the predominant OCP, followed by beta-HCH (median: 172.5 ng/g lw), and HHCB (1,3,4,6,7,8-hexahydro-4,6,6,7,8,8-hexamethylcyclopenta[gamma]-2-benzopyran) (median: 17.7 ng/g lw) was the dominant musk. There was no statistical correlation between total musk concentrations, and HCB, HCHs, DDTs or total OCP concentrations, indicating their different exposure routes and metabolism in humans (p=0.182-0.325). Clear reductions in temporal trends in the levels of DDTs and HCB, especially HCHs (p<0.01) were observed during the sampling period, and the high DDE/DDT ratios in the samples indicated past exposure to DDTs. The relatively high median concentrations of HHCB and HHCB-lactone in 2010 suggested a probably increasing tendency. There were statistically significant influences regarding maternal age and parity on OCP accumulation (p=0.001-0.002), but no significant effect on musks was found (p=0.542-0.919). Musk exposure in neonates via breast milk was 2-3 orders of magnitude lower than suggested provisional tolerable daily intakes (PTDI). The estimated daily intakes for HCB and DDTs were below the PTDI in Canada, however, 56% of those for HCHs exceeded the Canadian PTDI. OCP contamination of breast milk requires further attention. PMID- 22921254 TI - Using the enzymatic and non-enzymatic antioxidant defense system of the land snail Eobania vermiculata as biomarkers of terrestrial heavy metal pollution. AB - The present study aimed to investigate the efficacy of antioxidant defense system of the land snail Eobania vermiculata as biomarkers for terrestrial heavy metal pollution. For this reason, a set of biomarkers was performed on land snails E. vermiculata collected from polluted and non-polluted areas in the field. The biomarkers used were lactate dehydrogenase activity, level of lipid peroxidation, activities of catalase, glutathione peroxidase, glutathione-S-transferase, gamma glutamyl transferase and content of glutathione, metalothionines, total proteins and total lipid in the digestive gland tissue. The correlation between the bioaccumulation of heavy metal in gland tissue and all the biomarkers in the digestive gland was determined. The results revealed appreciable alterations in the biomarker values in field, accompanied by significant correlations among the biomarkers. Therefore, this study suggests E. vermiculata is a suitable sentinel organism and the selected biomarkers show efficacy for terrestrial heavy metal biomonitoring. PMID- 22921255 TI - Application of biomarkers in mudskipper (Boleophthalmus dussumieri) to assess polycyclic aromatic hydrocarbons (PAHs) pollution in coastal areas of the Persian Gulf. AB - In this study, selected biomarkers-The retention time (RT) performed on haemocytes, the Erythrocyte Osmotic Fragility (EOF) and the Glutathione-S Transferase (GST) activity in the liver- were measured in mudskipper (i.e., Boleophthalmus dussumieri) obtained from the Persian Gulf. Chemical analyses included the assessment of the polycyclic aromatic hydrocarbons (PAHs) in the sediment and mudskipper liver. Total PAH concentrations in the sediment and the liver tissues ranged between 113.50-3384.34 ng g(-1) dw and 3.99-46.64 ng g(-1) dw, respectively. Spatial evaluation indicated that RT had a significant difference (p<0.05) among sampling sites except Arvand and Zangi. The mean erythrocyte fragility was significantly differ between various locations (p<0.05). GST activity in the liver of mudskippers showed significant differences (p<0.05) among Jafari, Bahrakan, and with other sites. No significant difference (p>0.05) was observed between Arvand, Zangi and Samayeli. Additionally, significant correlations were found between total PAHs levels and selected biomarkers (p<0.01). The biomarkers measured in this study were useful as a first investigation into the biological effects of PAHs pollution as well as in determining the bioavailability of pollution. PMID- 22921256 TI - Transfer of wastewater associated pharmaceuticals and personal care products to crop plants from biosolids treated soil. AB - The plant uptake of emerging organic contaminants such as pharmaceuticals and personal care products (PPCPs) is receiving increased attention. Biosolids from municipal wastewater treatment have been previously identified as a major source for PPCPs. Thus, plant uptake of PPCPs from biosolids applied soils needs to be understood. In the present study, the uptake of carbamazepine, diphenhydramine, and triclocarban by five vegetable crop plants was examined in a field experiment. At the time of harvest, three compounds were detected in all plants grown in biosolids-treated soils. Calculated root concentration factor (RCF) and shoot concentration factor (SCF) are the highest for carbamazepine followed by triclocarban and diphenhydramine. Positive correlation between RCF and root lipid content was observed for carbamazepine but not for diphenhydramine and triclocarban. The results demonstrate the ability of crop plants to accumulate PPCPs from contaminated soils. The plant uptake processes of PPCPs are likely affected by their physico-chemical properties, and their interaction with soil. The difference uptake behavior between plant species could not solely be attributed to the root lipid content. PMID- 22921257 TI - Potential risk effect from elevated levels of soil heavy metals on human health in the Niger delta. AB - An analysis of the soil quality in the Niger Delta Area (NDA) was carried out to determine the severity of soil contamination. The United States Environmental Protection Agency (US EPA) risk assessment model was used in determining the potential health risk due to lifetime exposure (by means of ingestion, dermal contact and inhalation) of the population to heavy metal contents in the soil. Substantial levels of contamination were found indicating elevated levels of heavy metals above background concentrations from controlled samples in the areas. Median topsoil metal concentrations (0-15cm) in the NDA measured in mg/kg were: Zn 58.3+/-37.0, Cd 1.3+/-1.0, Cr(VI) 13.2+/-5.5, Cu 28.3+/-31.5, Pb 895.1+/ 423.9, Ni 42.7+/-20.3, Mn 201.8+/-77.5 and Fe 1303.5+/-2028.6. Pb, Ni, Zn, Cd, Cr(VI), Fe and Mn exceeded some guideline and standard values; while the comprehensive levels of total metals contamination exceeded the environmental action level for soils, which could potentially affect human health. The collective total risk (carcinogenic and non-carcinogenic) for minors and adults were established from the model using the slope factors and reference dose of the compounds respectively. The study has shown that soil contamination in the industrial and residential regions are similarly significant; while the risk assessment proved that based on the pollutants concentration in the soil, metals with the highest cancer risk values (Pb=2.62E-02 and Cr(VI)=1.52E-02) have the potential of affecting the health status of the residents, especially for children in the region. The chronic daily intake of the metals are of major concern as their cumulative effect could result to several health complications of children and adults in the region. PMID- 22921258 TI - National pertussis surveillance in South Korea 1955-2011: epidemiological and clinical trends. AB - BACKGROUND: Although there has been substantial progress in controlling pertussis in South Korea, the reported number of pertussis case-patients has gradually been increasing during the last decade. To address this, we summarized the surveillance data on pertussis collected during the period 1955-2011. Detailed epidemiologic and clinical data were determined, primarily using data from recent years. METHODS: We analyzed data from the national surveillance system to describe the occurrence of pertussis. The annual numbers of reported pertussis case-patients were identified for the period 1955-2000. For 2001-2009, information including limited demographic characteristics and the date of onset of symptoms were identified. For 2010-2011, detailed epidemiologic and clinical information of reported pertussis case-patients were collected. RESULTS: During 1955-2011, the secular trend was characterized by a gradual decrease in the reported number of cases from 1955 to the late 1990s, then a recent increase starting in the early 2000s. In 2009, a large number of reported cases occurred in infants <1 year of age. In 2011, an increase in reported cases among adolescents and adults aged >=15 years was observed. During 2010-2011, 29.8% of reported cases were not immunized and 11.3% had not been immunized in a timely manner. Of adolescents and adults aged >=15 years, 91.7% did not have a record of immunization. CONCLUSIONS: During 2010-2011, a shift in age group was observed in pertussis case-patients: 33.8% were young infants <3 months of age and 29.0% were adolescents and adults >=15 years of age. Considering that infants without timely vaccination may be vulnerable to an increased risk of pertussis infection, steps to provide timely vaccination to infants, to provide Tdap vaccination to adolescents and adults, and to enhance surveillance to capture adult pertussis cases should be taken in South Korea. PMID- 22921259 TI - Immunogenicity and protective efficacy of heterologous prime-boost regimens with mycobacterial vaccines and recombinant adenovirus- and poxvirus-vectored vaccines against murine tuberculosis. AB - OBJECTIVES: To evaluate regimens using bacillus Calmette-Guerin (BCG) or recombinant BCG (rBCG) overexpressing Ag85B for priming, followed by boosting with a modified vaccinia virus Ankara strain (MVA) and/or adenovirus vector (AD) expressing an Ag85B-ESAT6 fusion protein. METHODS: Cellular and humoral immune responses were determined after subcutaneous vaccination, which was employed to trigger systemic immunity against intravenous infection in a mouse model of tuberculosis (TB). Bacterial loads and lung histology were evaluated. RESULTS: The relative IgG2a and IgG1 antibody levels indicated that the viral-vectored vaccines generated a T-helper type 1 (Th1)-biased response after two doses of viral boost vaccinations. Boosting BCG-primed mice with viral vaccines induced a Th1 immune response that included both CD4 and CD8 T-cells generating antigen specific interferon-gamma (IFN-gamma) and CD8 T cytotoxic activity. Only mice vaccinated with two different viral boosters after BCG priming exhibited a significant reduction in bacterial burden in the lung after challenge. Histology examinations confirmed the attenuation of lung damage and more compact granulomas. After mycobacteria priming, boosting with AD85B-E6 followed by MVA85B E6 afforded better protection than the reverse order of administration of the viral vectors. CONCLUSIONS: This study demonstrates the potential of multiple heterologous viral booster vaccines, although the exact correlates of protection and optimal regimens should be further investigated for the rational design of future vaccine strategies. PMID- 22921260 TI - An enriched-enrolment, randomized withdrawal, flexible-dose, double-blind, placebo-controlled, parallel assignment efficacy study of nabilone as adjuvant in the treatment of diabetic peripheral neuropathic pain. AB - Cannabinoids are emerging as potential options for neuropathic pain treatment. This study evaluated an oral cannabinoid, nabilone, in the treatment of refractory human diabetic peripheral neuropathic pain (DPN). We performed a single-center, randomized, double-blind, placebo-controlled, flexible-dose study with an enriched enrollment randomized withdrawal design. DPN subjects with a pain score >= 4 (0-10 scale) continued regular pain medications and were administered single-blinded adjuvant nabilone for 4 weeks. Subjects achieving >= 30% pain relief (26/37) were then randomized and treated with either flexible dose nabilone 1-4 mg/day (n=13) or placebo (n=13) in a further 5-week double blind treatment period, with 30% (11/37) of subjects deemed run-in-phase nabilone nonresponders. For nabilone run-in-phase responders, there was an improvement in the change in mean end-point neuropathic pain vs placebo (mean treatment reduction of 1.27; 95% confidence interval 2.29-0.25, P=0.02), with an average nabilone dose at end point of 2.9 +/- 1.1mg/day, and improvements from baseline for the anxiety subscale of the Hospital Anxiety and Depression Scale, the Medical Outcomes Study sleep scale problems index, and the European Quality of Life-5-Domains index score (each P<0.05). Nabilone run-in-phase responders reported greater global end-point improvement with nabilone than with placebo (100% vs 31%; P<0.05). Medication-related confusion led to discontinuation in 2/37 subjects during single-blind nabilone treatment. Potential unmasking occurred in 62% of both groups. Flexible-dose nabilone 1-4 mg/day was effective in relieving DPN symptoms, improving disturbed sleep, quality of life, and overall patient status. Nabilone was well tolerated and successful as adjuvant in patients with DPN. PMID- 22921261 TI - Experimental hypoglycemia is a human model of stress-induced hyperalgesia. AB - Hypoglycemia is a physiological stress that leads to the release of stress hormones, such as catecholamines and glucocorticoids, and proinflammatory cytokines. These factors, in euglycemic animal models, are associated with stress induced hyperalgesia. The primary aim of this study was to determine whether experimental hypoglycemia in humans would lead to a hyperalgesic state. In 2 separate 3-day admissions separated by 1 to 3 months, healthy study participants were exposed to two 2-hour euglycemic hyperinsulinemic clamps or two 2-hour hypoglycemic hyperinsulinemic clamps. Thermal quantitative sensory testing and thermal pain assessments were measured the day before and the day after euglycemia or hypoglycemia. In contrast to prior euglycemia exposure, prior hypoglycemia exposure resulted in enhanced pain sensitivity to hot and cold stimuli as well as enhanced temporal summation to repeated heat-pain stimuli. These findings suggest that prior exposure to hypoglycemia causes a state of enhanced pain sensitivity that is consistent with stress-induced hyperalgesia. This human model may provide a framework for hypothesis testing and targeted, mechanism-based pharmacological interventions to delineate the molecular basis of hyperalgesia and pain susceptibility. PMID- 22921262 TI - Experimental pelvic pain facilitates pain provocation tests and causes regional hyperalgesia. AB - The extra-articular sacroiliac joint (SIJ) structure is a potential source for low back and pelvic pain. This study hypothesised that experimental pain induced in a superficial pelvic ligament causes (1) hyperalgesia to pressure, (2) distinct pain referral, and (3) an increased frequency of positive pain provocation tests of the SIJ complex. Thirty healthy subjects (15 females) participated in this study designed as a randomised crossover trial. Pain was induced in the long posterior sacroiliac ligament by injection of hypertonic saline, with the contralateral ligament injected with isotonic saline as control. Pain intensity was assessed on an electronic visual analogue scale (VAS). Pressure pain thresholds (PPTs) and pain provocation tests were assessed on 3 occasions: at baseline, after injection, and when pain had subsided. PPT sites were located bilaterally at the injection site, lateral to spinous processes of S2 and L5, and at the gluteus medius and gastrocnemius muscles. Hypertonic saline caused significantly higher VAS scores and more extended pain referral than isotonic saline (P<0.001). PPTs at the injection site and lateral to S2 were significantly reduced after hypertonic saline compared with baseline and isotonic saline (P<0.002). Significantly more subjects had positive pain provocation tests after hypertonic (67% of subjects) compared with isotonic saline (20%; P<0.001). These data demonstrate that the extra-articular SIJ structure accommodates nociceptors that are capable of inducing pain referral and regional hyperalgesia sensitive to manual pain provocation tests similar to what previously have been found in pelvic girdle pain patients. PMID- 22921263 TI - Metamorphosis of the Basidiomycota Ustilago maydis: transformation of yeast-like cells into basidiocarps. AB - Ustilago maydis (DC) Cda., a phytopathogenic Basidiomycota, is the causal agent of corn smut. During its life cycle U. maydis alternates between a yeast-like, haploid nonpathogenic stage, and a filamentous, dikaryotic pathogenic form that invades the plant and induces tumor formation. As all the members of the Subphylum Ustilaginomycotina, U. maydis is unable to form basidiocarps, instead it produces teliospores within the tumors that germinate forming a septate basidium (phragmobasidium). We have now established conditions allowing a completely different developmental program of U. maydis when grown on solid medium containing auxins in dual cultures with maize embryogenic calli. Under these conditions U. maydis forms large hemi-spheroidal structures with all the morphological and structural characteristics of gastroid-type basidiocarps. These basidiocarps are made of three distinct hyphal layers, the most internal of which (hymenium) contains non-septate basidia (holobasidia) from which four basidiospores develop. In basidiocarps meiosis and genetic recombination occur, and meiotic products (basidiospores) segregate in a Mendelian fashion. These results are evidence of sexual cycle completion of an Ustilaginomycotina in vitro, and the demonstration that, besides its quasi-obligate biotrophic pathogenic mode of life, U. maydis possesses the genetic program to form basidiocarps as occurs in saprophytic Basidiomycota species. PMID- 22921264 TI - Tools for high efficiency genetic manipulation of the human pathogen Penicillium marneffei. AB - Penicillium marneffei is an opportunistic pathogen of humans and displays a temperature dependent dimorphic transition. Like many fungi, exogenous DNA introduced by DNA mediated transformation is integrated randomly into the genome resulting in inefficient gene deletion and position-specific effects. To enhance successful gene targeting, the consequences of perturbing components of the non homologous end joining recombination pathway have been examined. The deletion of the KU70 and LIG4 orthologs, pkuA and ligD, respectively, dramatically enhanced the observed homologous recombination frequency leading to efficient gene deletion. While DeltapkuA was associated with reduced genetic stability over time, DeltaligD represents a suitable recipient strain for downstream applications and combined with a modified GatewayTM system for the rapid generation of gene deletion constructs, this represents an efficient pipeline for characterizing gene function in P. marneffei. PMID- 22921265 TI - The role of microRNAs in mammalian oocytes and embryos. AB - Advanced genomic analysis has revealed an enormous inventory of non-coding RNAs (ncRNAs), which are functionally important at transcriptional and post transcriptional level for different cellular processes. Among the ncRNAs, microRNAs (miRNAs) have recently been highlighted extensively for their pivotal role in disease, fertility and development through post-transcriptional regulation of gene expression. The presence and spatio-temporal expression of miRNAs and miRNA processing machinery genes in oocytes and preimplantation embryos has evidenced the involvement of miRNAs for growth and maturation of mammalian oocytes, early embryonic development, stem cell lineage differentiation and implantation. Therefore, this article aims to highlight primary evidences on the importance of miRNAs and their mediated translational reprogramming in the physiology and development of mammalian oocytes and embryos. PMID- 22921266 TI - Placental expression and localization of endothelin-1 system and nitric oxide synthases during bovine pregnancy. AB - This study aimed to investigate mRNA expression of the endothelin-1 (EDN1) system (preproEDN1; precursor, ECE-1; converting enzyme, EDNRA and EDNRB; receptor subtypes A and B) and endothelial and inducible nitric oxide synthases (eNOS and iNOS) in the bovine utero-placental unit during pregnancy. We also investigated the cellular localization of mRNA and protein of components of the EDN1 system in the placentome. The bovine utero-placental unit on Day 60, 100, 150, 200 and 250 of gestation was separated into carunclar areas (CAR), intercaruncular areas (ICAR), cotyledonary villi (COT) and intercotyledonary areas (ICOT). PreproEDN1, ECE1, EDNRA, EDNRB, eNOS and iNOS mRNA expression was determined by real-time quantitative RT-PCR. In situ hybridization and immunohistochemistry were performed using placentomes on Day 94 or Day 250 of gestation. PreproEDN1 and ECE1 mRNA expression was higher on Day 100 than on other gestation days. The mRNA expression for EDNRA in COT and ICOT and eNOS in COT, CAR and ICAR were higher on Day 150 than on other gestation days. EDNRB mRNA expression increased from Day 60 to Day 150 then decreased. iNOS mRNA expression in COT and CAR was higher on Day 250 than on other gestation days. PreproEDN1, ECE1 and EDNRA mRNA was localized in the caruncular epithelial cells (CEs) and the COT. EDNRB mRNA was found in the CEs and the trophoblast binucleate giant cells (BNCs). PreproEDN1, EDNRA and EDNRB proteins were detected in COT and CEs, whereas ECE-1 was found in the BNCs. Our results demonstrate that differential cell-specific and spatiotemporal expression of the EDN1 system and NOS in the bovine utero-placental unit may be associated with regulation of vascular and cellular functions during pregnancy. PMID- 22921267 TI - Conceptus elongation in cattle: genes, models and questions. AB - In ruminants, more than 30% of the embryonic loss observed after artificial insemination has an early origin that is coincident with the marked elongation of the conceptus that occurs before implantation. During this developmental phase, physiological interactions are established between the conceptus and the uterus which are essential for the establishment of pregnancy and the elongation process. Our molecular knowledge of elongating conceptuses in cattle has long been focused on its analysis in view of its interactions with the uterus with the elongating stages being defined, like the uterus stages, by days post insemination or conception. The gene clusters reported so far indicate important pathways, some being shared by the non-elongating conceptuses of other mammals. However, to identify the key components of the elongation process - that could be specific to ungulates - new models are needed. Somatic nuclear transfer could be one of them as it provides complementary insights on differentiation beyond the blastocyst stage. Nonetheless, other models are necessary to convert gene lists or networks in elongating phenotypes. This review partly summarizes information on these topics, but data on the impact of the uterus on the elongation process or on the differentiation of the embryonic tissues are reviewed elsewhere. PMID- 22921268 TI - Role of nanoparticle surface functionality in the disruption of model cell membranes. AB - Lipid bilayers are biomembranes common to cellular life and constitute a continuous barrier between cells and their environment. Understanding the interaction of engineered nanomaterials (ENMs) with lipid bilayers is an important step toward predicting subsequent biological effects. In this study, we assess the effect of varying the surface functionality and concentration of 10-nm diameter gold (Au) and titanium dioxide (TiO(2)) ENMs on the disruption of negatively charged lipid bilayer vesicles (liposomes) using a dye-leakage assay. Our findings show that Au ENMs having both positive and negative surface charge induce leakage that reaches a steady state after several hours. Positively charged particles with identical surface functionality and different core compositions show similar leakage effects and result in faster and greater leakage than negatively charged particles, which suggests that surface functionality, not particle core composition, is a critical factor in determining the interaction between ENMs and lipid bilayers. The results suggest that particles permanently adsorb to bilayers and that only one positively charged particle is required to disrupt a liposome and trigger the leakage of its entire contents in contrast to mellitin molecules, the most widely studied membrane lytic peptide, which requires hundred of molecules to generate leakage. PMID- 22921269 TI - UNC13A influences survival in Italian amyotrophic lateral sclerosis patients: a population-based study. AB - The common variant rs12608932, located within an intron of UNC13A gene on chromosome 19p13.3, has been suggested to influence susceptibility to amyotrophic lateral sclerosis (ALS), as well as survival, in patients of north European descent. To examine this possibility further, we evaluated the association of rs12608932 with susceptibility and survival in a population-based cohort of 500 Italian ALS patients and 1457 Italian control samples. Although rs12608932 was not associated with ALS susceptibility in our series (p = 0.124), it was significantly associated with survival under the recessive model (median survival for AA/AC genotypes = 3.5 years [interquartile range, 2.2-6.4]; CC = 2.5 years [interquartile range, 1.6-4.2]; p = 0.017). Furthermore, rs12608932 genotype remained an independent prognostic factor in Cox multivariable analysis adjusting for other factors known to influence survival (p = 0.023). Overall, minor allele carrier status of rs12608932 was strongly associated with an approximate 1-year reduction of survival in ALS patients, making it a significant determinant of phenotype variation. The identification of UNC13A as a modifier of prognosis among sporadic ALS patients potentially provides a new therapeutic target aimed at slowing disease progression. PMID- 22921270 TI - Influence of body dissatisfaction on 1-year change in nutrient intake of overweight and obese inner-city African American children. AB - This analysis aimed to examine the relationship of baseline body dissatisfaction with 1-year change in nutrient intake of inner-city, overweight and obese, African American children. This is a secondary analysis of 1-year pre-post data available for a convenience sample of 88 children. After adjusting for baseline intake of dietary variables and intervention group status, baseline body dissatisfaction was associated with 1-year increases in intake of energy, and all macronutrients in girls, but not in boys. These relationships were not substantially altered after adjusting for baseline BMIz and global self-worth. After including all adjustment factors, increasing baseline body dissatisfaction in girls was associated with 1-year increased intake of total energy, total sugars, total fat, discretionary fat, and total carbohydrates. This analysis suggests that, in girls but not necessarily in boys, body dissatisfaction might need to be targeted during interventions that aim to improve nutrient intake. PMID- 22921271 TI - Twenty-one years of experience with ovarian ectopic pregnancy at one institution in Taiwan. AB - OBJECTIVE: To review the experience with patients with ovarian ectopic pregnancy (OEP) at Chang Gung Memorial Hospital, Lin-Kou Medical Center, Tao-Yuan, Taiwan, between 1989 and 2009. METHODS: A retrospective review of the presentation, prevalence, diagnosis, and trends in treatment of patients with OEP, and the use of assisted reproductive technology (ART) procedures and intrauterine devices (IUD). The incidence rate ratios (IRR) of ectopic pregnancies (EPs) per live births, OEPs per EPs, and OEPs per live births were analyzed. RESULTS: The 110 OEPs diagnosed comprised 2.0% of all EPs (n=5408) and 1:1543 of all live births, leading to a mean OEP per year of 5.24. Seventy-eight patients were managed with laparoscopy and 32 underwent laparotomy. Twenty-six (23.6%) patients used an IUD and 12 (10.9%) had undergone ART. OEP associated with ART increased in the last 10 years of the study period. The IRR of EPs per live births, OEPs per EPs, and OEPs per live births all increased between 1989 and 2009. Management of OEP tended to favor laparoscopy in the later years. CONCLUSION: There was a trend toward better management of OEP with laparoscopy. ART has become a risk factor for OEP. The IRR of EPs per live births, OEPs per EPs, and OEPs per live births all increased over the 21-year period. PMID- 22921272 TI - A Turkish Gynecologic Oncology Group study of fertility-sparing treatment for early-stage endometrial cancer. AB - OBJECTIVE: To analyze the results of fertility-sparing treatment of early-stage endometrial cancer (EC) in patients treated at Turkish gynecologic oncology centers, and to present a review of the literature. METHODS: Thirteen healthcare centers in Turkey were contacted to determine if they were eligible to participate in the study. Centers that were eligible and agreed to participate were sent a database form to record the demographic characteristics, clinicopathologic findings, and follow-up results for their EC patients. RESULTS: Eleven Turkish healthcare centers provided data on 43 EC patients. Mean duration of treatment was 5 months and mean follow-up was 49 months. In total, 35 (81.4%) patients were tumor free following primary progesterone therapy. Mean time from the end of progesterone therapy to pregnancy was 10.6 +/- 4.3 months (range, 3-18 months). Two patients had tumor recurrence during follow-up. The pregnancy rate among the 31 women who actively sought pregnancy was 41.9% (n=13). CONCLUSION: Conservative management of early-stage EC in women of reproductive age using oral progestins was effective and did not compromise oncological outcome. Pregnancy in the study patients was achieved spontaneously and artificially. PMID- 22921273 TI - Effect of prior hysterectomy on the anterior and posterior vaginal compartments of women presenting with pelvic organ prolapse. AB - OBJECTIVE: To describe the effects of hysterectomy on the anterior and posterior vaginal compartments and specific pelvic organ prolapsed quantification (POP-Q) data points. METHODS: In a retrospective case-control study, data were analyzed from patients presenting at a urogynecologic center in Manhasset, USA, with urogenital prolapse between January 1, 2008, and December 31, 2010. Patients who underwent hysterectomy for indications not including prolapse were compared with age- and parity-matched women without prior hysterectomy. POP-Q points were measured and converted to stages for each vaginal compartment. The t test, Wilcoxon rank sum, and Fisher exact tests were used to compare normally distributed variables, nonparametric data, and categoric variables, respectively. RESULTS: Seventy-one patients who underwent prior hysterectomy were matched to 71 patients with intact uteri. Women with prior hysterectomy had significantly greater prolapse at POP-Q point Bp and worse overall posterior compartment prolapse compared with those without prior hysterectomy. Women who underwent hysterectomy were more likely to have stage 2 or greater prolapse (OR 2.6, 95% CI, 1.3-5.2; P=0.01). CONCLUSION: When matched for age and parity, women with prior hysterectomy had significantly greater posterior compartment prolapse compared with those without. Prior hysterectomy had no significant effect on the anterior vaginal compartment. PMID- 22921274 TI - Risk factors for perinatal mortality at Souissi Maternity Hospital, Rabat, Morocco. PMID- 22921275 TI - A comparison of vital registration and reproductive-age mortality survey in Bukidnon, Philippines, 2008. AB - OBJECTIVE: To determine the accuracy of reported maternal deaths for 2008 in a province in the Philippines. METHODS: A reproductive-age mortality survey (RAMOS) was conducted to identify deaths of women aged 15-49 years from Bukidnon, Philippines, in 2008. Sources included various health and community reporting units. Verbal autopsies were carried out to ascertain maternal deaths. RESULTS: The survey found 58 pregnancy-related deaths in 2008, of which 52 were maternal deaths. Of the 52, 14 were found in local civil registries but 4 were not classified as maternal deaths. No single reporting unit identified all deaths. Local civil registries provided an estimated maternal mortality ratio (MMR) of 49 per 100000 live births. The present RAMOS estimated an MMR of 209 (95% confidence interval, 191-226) per 100000 live births. CONCLUSION: Official reports led people using the data to believe that the MMR in the province was on track for Millennium Development Goal 5 (to reduce MMR by three-quarters by 2015). The present survey showed that local civil registries missed three-quarters of all maternal deaths. All countries engaged in addressing maternal mortality reduction should consider similar approaches to improve data quality. PMID- 22921276 TI - Risk factors for relaparotomy after cesarean delivery. AB - OBJECTIVE: To identify risk factors for relaparotomy after cesarean delivery. METHODS: Cases of exploratory laparotomy at Lis Maternity Hospital, Tel Aviv, Israel, following cesarean delivery between 2000 and 2010 were reviewed retrospectively. Each case in the study group was matched randomly with 5 control cases in which the patient underwent cesarean delivery only. Demographic and clinical data before and during the primary procedure were compared. RESULTS: Twenty-eight (0.2%) of 17482 cesarean deliveries were followed by exploratory relaparotomy. Significant differences between the study and the control (n=140) groups were found in: placental abruption as an indication for cesarean (17.8% vs 0.6%; P=0.004); duration of primary operation (45.3 +/- 21.1 vs 29.9 +/- 11.8 minutes; P=0.007; 95% CI, 5.1-19.2); and experience of chief surgeon (10.1 +/- 1.6 vs 5.8 +/- 0.4 years; P=0.02; 95% CI, 0.0-5.0). Findings during relaparotomy were: abdominal wall bleeding/hematoma (n=4 [14.2%]); uterine scar bleeding (n=4 [14.2%]); retroperitoneal bleeding (n=1 [3.5%]); adhesions causing bowel obstruction (n=1 [3.5%]); and uterine scar gangrene (n=1 [3.5%]). There were no findings for 17 (60.7%) patients. CONCLUSION: The incidence of relaparotomy following cesarean was 0.2% (1 per 624 cesarean deliveries). Significant risk factors were placental abruption and longer operative time. PMID- 22921277 TI - Sonogenetics in fetal neurology. AB - Fetal imaging technology has been advancing remarkably and prenatal detection and diagnoses have been moved forward from the second and third trimesters to the first trimester. Structural abnormalities detected by fetal imaging often lead to prenatal diagnoses of genetic disorders. However, there are still dilemmas in fetal diagnoses in normal karyotype cases with strong suspicion of congenital genetic disorders from sonographic findings. When fetal sonography reveals multiple minor abnormalities originating from various organs, counseling dilemmas and parental anxieties become greater than before karyotyping. Array-comparative genomic hybridization (aCGH) was developed as a high-resolution analysis of DNA copy number variations (CNVs). In seven cases presenting with abnormal brain structures by fetal imaging, abnormal CNVs were confirmed by aCGH but conventional karyotyping yielded normal results. Although careful patient selection is required in order to deal with microarray results and parental counseling, 'sonogenetics' - incorporating the idea of 'fetuses first' - will play an important role in the era of molecular genetics. Recent advances in non invasive prenatal testing by using fetal cell-free DNA in maternal plasma has the potential to generate misleading prenatal diagnoses without the observation of fetuses. However, no fetal diagnoses should be made without observing fetuses and we must not forget 'the fetus as a patient'. PMID- 22921278 TI - Antibacterial action of 4,4'-bipyrazolyl-based silver(I) coordination polymers embedded in PE disks. AB - Coupling the rigid spacer 4,4'-bipyrazole (H(2)BPZ), in its anionic or neutral form, to different silver(I) salts allowed isolation of the novel coordination polymers [Ag(2)(BPZ)] (1) and [Ag(H(2)BPZ)(X)] (X = NO(3), 2; ClO(4), 3; BF(4), 4; PF(6), 5; CH(3)SO(3), 6; CF(3)SO(3), 7), which were fully characterized by infrared and emission spectroscopies, thermal analysis, and X-ray powder diffraction. The crystal structure of 1 consists of 2-D layers containing 1-D chains of Ag(I) ions bridged by exo-tetradentate bipyrazolato moieties. The crystal structures of the [Ag(H(2)BPZ)(X)] species 2-7 feature 1-D chains of [Ag(H(2)BPZ)] stoichiometry, along which the metal centers are bridged by exo bidentate bipyrazolyl spacers. Contacts among adjacent chains are mediated by the counterions through nonbonding interactions involving the Ag(I) ions and the pyrazolyl N-H groups. Thermogravimetric analyses disclosed the good thermal stability of these materials, decomposing in the range 200-300 degrees C. Under UV irradiation at room temperature, all the species showed a yellow-green emission centered in the range 520-522 nm. When embedded into polyethylene disks, 1, 2, and 4-7 demonstrated their activity as topical antibacterial agents against suspensions of E. coli, P. aeruginosa, and S. aureus: complete reduction of the three bacterial strains was achieved in 24 h, reduction of S. aureus reaching ca. 90% in only 2 h. Biocidal action was expressed also by contact susceptibility tests. PMID- 22921279 TI - Armeniaspiroles, a new class of antibacterials: Antibacterial activities and total synthesis of 5-chloro-Armeniaspirole A. AB - Armeniaspiroles, a novel class of natural products isolated from Streptomyces armeniacus, are characterized by a novel spiro[4.4]non-8-ene scaffold. Various derivatives of Armeniaspiroles could be obtained by halogenation, alkylation, addition/elimination or reductions. A total synthesis of the 5-chloro analog of Armeniaspirole A has been accomplished in a linear six-step sequence. 5-Chloro Armeniaspirole A exhibits good activity against a range of multidrug-resistant, Gram-positive bacterial pathogens. PMID- 22921280 TI - The increased maternal serum levels of IL-6 are associated with the severity and onset of preeclampsia. AB - Preeclampsia is a complex disease of pregnancy with both feto-placental and maternal factors contributing to its pathogenesis. Although the cause of this disease is uncertain, imbalance between pro-and anti-inflammatory cytokines has been implicated in the pathogenesis of preeclampsia. Increased levels of the inflammatory cytokine IL-6 has been postulated to be involved in some ways in the pathogenesis of preeclampsia. However studies investigating whether levels of IL 6 in the maternal circulation differ between the disease severities or between times of onset of preeclampsia, or between preeclamptic pregnancies that are or are not complicated by fetal growth restriction (FGR) are limited. 104 women with preeclampsia and 75 health pregnant women were included into this study. The levels of IL-6 in maternal circulation were measured by enzyme-linked immunosorbent assay (ELISA). The levels of IL-6 in serum were significantly increased in women with preeclampsia in early onset and late onset preeclampsia compared to gestation matched health pregnant women. In addition, the levels of IL-6 were significantly increased in women with severe preeclampsia, but not with mild preeclampsia compared to gestation matched health pregnant women. Furthermore there was no correlation in IL-6 levels between preeclamptic with or without FGR. Our data shows increased level of circulating IL-6 levels in both women with early onset or late onset preeclampsia and in women with severe preeclampsia. These results suggest the excessive maternal inflammatory response in preeclampsia. PMID- 22921281 TI - One Health in the shrinking world: experiences with tuberculosis at the human livestock-wildlife interface. AB - Tuberculosis (TB) is a global anthropozoonotic infection that has raised awareness of the impact of disease at the human-livestock-wildlife interface. There are examples of transmission from livestock resulting in establishment of reservoirs in wildlife populations, and exposures from interactions between humans and wildlife that have resulted in disease outbreaks. A One Health approach is crucial to managing and protecting the health of humans, livestock, wildlife and the environment. Although still in its infancy in many areas of the world, the use of transdisciplinary teams to address wildlife-human-livestock boundary diseases will broaden the scope of options for solutions. This paper reviews some less commonly known examples of threats and outcomes using lessons learned from tuberculosis. PMID- 22921282 TI - A new TB vaccine: fact or fiction? AB - Vaccination has been spectacularly successful in eradicating or controlling some infectious diseases, and is particularly attractive as an approach to tackling other infectious diseases. Although vaccination against tuberculosis has been done for nearly 100 years, it is clearly not that successful since the disease still occurs at epidemic levels in animals and humans in many areas. New approaches to vaccination against TB in humans and animals are currently in the pipeline, but none show either complete protection or sterilization. However, there is evidence to suggest that vaccination may deliver some positive outcomes. Not only should we be investigating new vaccines, but also how vaccines and candidates are used and delivered. There are many reasons to think that this task will not be simple, or perhaps not possible in some cases. We present different aspects of the development of vaccines against TB, outline some complications and suggest some new ways to consider this problem. PMID- 22921283 TI - Conditioned taste aversion and drugs of abuse: history and interpretation. AB - Conditioned taste aversion (CTA) learning describes a phenomenon wherein an animal learns to avoid consumption of a particular taste or food following its pairing with an aversive stimulus. Although initially demonstrated with radiation and classical emetics, CTAs have also been shown with drugs of abuse. The ability of rewarding drugs to support CTA learning was described as paradoxical by many investigators, and a number of attempts have been made to resolve this paradox. The present review offers a historical perspective on the CTA literature with a particular focus on CTAs induced by self-administered drugs. Specifically, this review describes and summarizes several interpretations of CTA learning that offer possible mechanisms by which drugs of abuse support CTAs, including sickness, drug novelty, reward comparison and conditioned fear. It is concluded that the reported "paradox" is no paradox at all in that drugs of abuse are complex pharmacological compounds that produce multiple stimulus effects, not all of which are positive reinforcing. Finally, a possible role of drug aversion in drug self-administration is discussed. PMID- 22921284 TI - Neurocognitive networks: findings, models, and theory. AB - Through its early history, cognitive neuroscience largely followed a modular paradigm wherein high-level cognitive functions were mapped onto locally segregated brain regions. However, recent evidence drives a continuing shift away from modular theories of cognitive brain function, and toward theories which hold that cognition arises from the integrated activity of large-scale, distributed networks of brain regions. A growing consensus favors the fundamental concept of this new paradigm: the large-scale cognitive brain network, or neurocognitive network. This consensus was the motivation for Neurocognitive Networks 2010 (NCN 2010), a conference sponsored by the Cognitive Neuroscience Program of the National Science Foundation, organized by Drs. Steven Bressler and Craig Richter of Florida Atlantic University (FAU), and held at FAU in Boca Raton, FL on January 29-30, 2010. NCN 2010 gathered together some of today's leading investigators of neurocognitive networks. This paper serves to review their presentations as they relate to the paradigm of neurocognitive networks, as well as to compile the emergent themes, questions, and possible future research directions that arose from the conference. PMID- 22921286 TI - Relationship between diabetic retinopathy, microalbuminuria and overt nephropathy, and twenty-year incidence follow-up of a sample of type 1 diabetic patients. AB - PURPOSE: To determine the incidence and relationship of diabetic retinopathy (DR), microalbuminuria and overt nephropathy (ON). METHOD: A 20-year prospective study, in a cohort of 110 consecutive type 1 diabetes mellitus (DM) patients, without diabetic retinopathy or microalbuminuria at enrolment in 1990. RESULTS: The 20-year incidence of any DR was 70.91%, microalbuminuria 42.72%, and ON was 23.63%. Regarding the risk factors: pre pubertal age at diagnosis was significant for DR and ON, LDL-cholesterol and CT/HDL-cholesterol were significant for DR but not for microalbuminuria or ON. The relationship between DR and ON demonstrated that DR was a significant risk factor for ON, but ON was significant for sight threatening DR. At the end of the study, two major groups of patients were formed: patients with DR only and patients with DR and ON. For the development of only DR we can assume that the most important risk factor is the duration of DM, followed by the high levels of HbA1c, pre-pubertal age at onset, and arterial hypertension; and for the development of ON and DR simultaneously, risk factors are higher levels of HbA1c, arterial hypertension, DM duration and pre-pubertal age at onset. CONCLUSIONS: In the current study, two major groups of patients have been formed, those who developed only DR and those who developed DR and ON. For the former, incidence increased as DM duration increased, and for the latter incidence appeared to be closely related to levels of HbA1c. PMID- 22921288 TI - [Is the multifibrillar system the structuring architecture of the extracellular matrix?]. PMID- 22921287 TI - Assessment of the effect of mirodenafil on the hemodynamics of healthy male Korean volunteers administered tamsulosin: a randomized, double-blind, placebo controlled, 2-period crossover study. AB - BACKGROUND: Both mirodenafil, a phosphodiesterase type 5 inhibitor for the treatment of erectile dysfunction, and tamsulosin, a selective alpha(1A) adrenergic receptor antagonist for the treatment of benign prostatic hyperplasia, have mild vasodilational effects. OBJECTIVE: The aim of this study was to investigate the effect of mirodenafil on the hemodynamics of healthy volunteers who were administered tamsulosin. METHODS: Healthy, Korean normotensive male volunteers were enrolled in a randomized, placebo-controlled, double-blind, 2 sequence, 2-period crossover study. Mirodenafil 100 mg or placebo was administered orally after pretreatment with tamsulosin 0.2 mg once daily for 7 days in each period, with a 1-week washout period. Blood pressure (BP) and pulse rate (PR) in supine and standing positions were measured repeatedly before and until 24 hours after the administration of mirodenafil or placebo. The mean differences from the baseline values of the maximum changes of BP and PR, which were measured at 4 and 24 hours, were analyzed by using a mixed-effects model. RESULTS: Eighteen subjects (mean [SD] age, 26.8 [3.9] years; weight, 65.5 [7.0] kg) were administered any trial medication, and 16 of them completed the study. For 4 hours/24 hours after mirodenafil administration, the mean maximal changes from baseline versus placebo in supine systolic BP, diastolic BP, and PR were 1.0 mm Hg (95% CI, -4.2 to 2.2) (P = 0.53)/-1.2 mm Hg (95% CI, -5.3 to 2.9) (P = 0.56), -2.1 mm Hg (95% CI, -4.6 to 0.4) (P = 0.10)/-1.1 mm Hg (95% CI, -3.9 to 1.6) (P = 0.39), and 7.2 beats/min (95% CI, 4.7 to 9.6) (P < 0.05)/4.8 beats/min (95% CI, 1.4 to 8.1) (P < 0.05), respectively. Those changes in a standing position were -4.0 mm Hg (95% CI, -8.9 to 0.9) (P = 0.10)/-4.3 mm Hg (95% CI, 10.0 to 1.5) (P = 0.13), -1.1 mm Hg (95% CI, -4.9 to 2.7) (P = 0.54)/-1.9 mm Hg (95% CI, -5.5 to 1.7) (P = 0.27), and 10.7 beats/min (95% CI, 4.4 to 16.9) (P < 0.05)/6.0 beats/min (95% CI, 0.7 to 11.3) (P < 0.05), respectively. A total of 33 adverse events (AEs) were reported in 9 of 18 subjects. The number of subjects with AEs (P = 0.13) and the number of AEs (P = 0.26) were not significantly different between the 2 groups. The most common AEs were vasodilational symptoms, such as nasal congestion, headache, and flushing. CONCLUSIONS: The coadministration of mirodenafil 100 mg did not induce a significant decrease in BP when associated with an increase in PR in these healthy male Korean volunteers administered tamsulosin 0.2 mg compared with placebo. (Clinical Trial Registry, http://cris.cdc.go.kr/cris/en/: KCT0000117). PMID- 22921289 TI - [Towards a structuring fibrillar ontology]. AB - Over previous decades and centuries, the difficulty encountered in the manner in which the tissue of our bodies is organised, and structured, is clearly explained by the impossibility of exploring it in detail. Since the creation of the microscope, the perception of the basic unity, which is the cell, has been essential in understanding the functioning of reproduction and of transmission, but has not been able to explain the notion of form; since the cells are not everywhere and are not distributed in an apparently balanced manner. The problems that remain are those of form and volume and also of connection. The concept of multifibrillar architecture, shaping the interfibrillar microvolumes in space, represents a solution to all these questions. The architectural structures revealed, made up of fibres, fibrils and microfibrils, from the mesoscopic to the microscopic level, provide the concept of a living form with structural rationalism that permits the association of psychochemical molecular biodynamics and quantum physics: the form can thus be described and interpreted, and a true structural ontology is elaborated from a basic functional unity, which is the microvacuole, the intra and interfibrillar volume of the fractal organisation, and the chaotic distribution. Naturally, new, less linear, less conclusive, and less specific concepts will be implied by this ontology, leading one to believe that the emergence of life takes place under submission to forces that the original form will have imposed and oriented the adaptive finality. PMID- 22921290 TI - Invasive pneumococcal diseases in birth cohorts vaccinated with PCV-7 and/or PHiD CV in the province of Quebec, Canada. AB - BACKGROUND: The 10-valent protein D pneumococcal conjugate vaccine (PHiD-CV) was licensed on the basis of immunogenicity studies and there are no published data on its effectiveness to prevent invasive pneumococcal disease (IPD). In the province of Quebec, Canada, PHiD-CV was introduced in the summer of 2009, replacing the 7-valent CRM197 vaccine (PCV-7). Transition to the new vaccine was recommended regardless of the number of PCV7 doses already administered. METHODS: IPD rates in children born in 2007-2010 and observed up to the end of 2010 were computed from laboratory surveillance data. The main vaccine used for the infant primary immunization series (mainly 2 doses at 2-4 months) and the toddler (12 months) booster dose was inferred from the Quebec City Immunization Registry data. RESULTS: IPD rates were significantly lower in the cohorts exposed to PHiD CV (35/100,000 person-years) as compared with those exposed to PCV-7 (64/100,000 person-years; p=0.03). There was no breakthrough vaccine-type IPD case among children who had received >=2 PHiD-CV doses for the primary series or a single PHiD-CV dose as a booster. There was also a statistically non-significant lower frequency of 19A and other non-vaccine types IPD cases in children exposed to 2+1 PHiD-CV doses as compared with those exposed to PCV-7. INTERPRETATION: Results are compatible with a high level of protection induced by PHiD-CV against IPD caused by homologous serotypes. PMID- 22921291 TI - The effectiveness of a voice training program for telemarketers. AB - PURPOSE: To use a randomized design to evaluate the effectiveness of voice training programs for telemarketers via multidimensional analysis. METHODS: Forty eight telemarketers were randomly assigned to two groups: voice training group (n=14) who underwent training over an 8-week period and a nontraining control group (n=34). Before and after training, recordings of the sustained vowel /E/ and connected were collected for acoustic and perceptual analyses. RESULTS: Based on pre- and posttraining comparisons, the voice training group presented with a significant reduction in percent jitter (P=0.044). No other significant differences were observed, and inter-rater reliability varied from poor to fair. CONCLUSIONS: These findings suggest that voice training improved a single acoustic dimension, but do not change perceptual dimension of telemarketers' voices. PMID- 22921292 TI - Can listeners hear how many singers are singing? The effect of listener's experience, vibrato, onset, and formant frequency on the perception of number of simultaneous singers. AB - OBJECTIVE/HYPOTHESIS: This study investigated whether listener's experience, presence/absence of vibrato, formant frequency difference, or onset delay affect the ability of experienced and inexperienced listeners to segregate complex vocal stimuli. STUDY DESIGN: Repeated measures factorial design. METHODS: Two sets of stimuli were constructed: one with no vibrato and another with vibrato. For each set, each stimulus was synthesized at four pitches: A3, E4, B4, and F5. Stimuli were synthesized using formant patterns appropriate for the vowel |alpha|. Frequencies for formants one through four were systematically varied from lower to higher in an attempt to simulate the acoustic results of corresponding changes in vocal tract length. Four formant patterns were synthesized (patterns A-D). Three pairs were created at each pitch, pairing the formants AB (mezzo soprano/mezzo-soprano), CD (soprano/soprano), and AD (mezzo-soprano/soprano). Each of these three pairs was constructed in three separate conditions: simultaneous onset; the first voice in the pair with an onset delay of 100 milliseconds; and the second voice in the pair with an onset delay of 100 milliseconds. Using a scroll bar, listeners rated how difficult it was for them to hear each stimulus pair as two separate voices. RESULTS: The most difficult combinations to segregate were produced with no vibrato and used simultaneous onset. The easiest conditions to segregate were combinations including a "soprano like" formant pattern (D) in the vibrato condition. Overall, listener's experience did not affect the perceived difficulty of segregation; however, in the presence of vibrato cues, inexperienced listeners did not use delay cues as an aid in segregation in the same manner as did experienced listeners. Once vibrato was removed from the experimental context, inexperienced listeners were able to use delay to aid in segregation in a similar manner to experienced listeners. CONCLUSION: Presence/absence of vibrato, formant pattern difference, and onset delay interact in a complex manner to affect the perceived difficulty of voice segregation. PMID- 22921293 TI - An acoustic-perceptual study of vocal tremor. AB - BACKGROUND: Essential tremor of the voice (ETV) is an involuntary intention tremor of the vocal folds that causes fluctuations in fundamental frequency (f(0)) and/or intensity leading to an unsteady voice. There is limited data on how different acoustic variables affect perception of severity of tremor. AIM: The purpose of the study was to determine if systematic changes in f(0), rate or modulation frequency (f(f0m)), extent or depth of modulation (d(f0m)), and signal to-noise ratio (SNR) affect perception of severity of tremor. METHOD: Vowel phonations of four speakers (two male and two female) with a clinical diagnosis of ETV were selected from the Kay Elemetrics Disordered Voice Database (Lincoln Park, NJ). A high fidelity speech vocoder (STRAIGHT; Kawahara, 1997) was used to synthesize the f(0) contour for each of these voices, which were varied in mean f(0), f(f0m), and d(f0m). The f(0) contour was modified 30 Hz above and below the mean f(0) for each speaker. f(f0m) ranged from 3 to 12 Hz in steps of 3 Hz. d(f0m) ranged from 2 to 32 Hz in steps of 6 Hz. Six (three experts and three naive) listeners rated the "severity" of tremor on a seven-point rating scale. RESULTS: Significant main effects and interactions were found between the study variables. Perceived severity of tremor increased with f(f0m) and d(f0m). There was no systematic effect of SNR on perceived tremor severity. CONCLUSION: The perception of severity for steady-state tremor results from a complex interaction of multiple acoustic cues with d(f0m) acting as the primary acoustic cue. PMID- 22921294 TI - An examination of intrasubject variability on the Dysphonia Severity Index. AB - OBJECTIVES/HYPOTHESIS: The purpose of this study was to expand on previous literature regarding the intrasubject variability of the Dysphonia Severity Index (DSI) by incorporating a larger sample of participants and by examining the test retest mean differences and intrasubject variability not only in the DSI but also within its component measures. STUDY DESIGN: Longitudinal and within-subject design. METHODS: The DSI and component measures of jitter, maximum phonation time (MPT), lowest vocal intensity, and highest phonational frequency (F(0)) were obtained from 49 normal voiced participants (21 males and 28 females) between the ages of 18-25 years. Each participant was tested in three testing sessions with an approximate 1-week interval between each testing session. RESULTS: These results indicated that the mean DSI and its component measures of high F(0) and MPT are quite stable across time (ie, no significant differences across time and strong intraclass correlation coefficients [ICCs]), whereas Bland-Altman analyses indicated that the within-subject 1-week test-retest variability on the DSI for normal voiced subjects may be expected to be within +/-2.27, and the 2-week test retest variability may be expected to be within +/-2.66. In addition, weak ICC results indicated that increased variability may also be expected in the DSI component measures of low decibel and jitter. No evidence of a test-practice effect on repeated DSI measurements was observed. CONCLUSIONS: The findings of this study are in agreement with previous data regarding the intrasubject variability of the DSI. Changes in DSI that exceed +/-2.27-2.66 may be necessary to reflect significant changes in voice function. The observed test-retest variability in the DSI is relatively large in relation to the initially reported DSI range of +5 (normal voice) to -5 (severely disordered voice). Rather than the use of +/-2 standard deviations (SDs) as a guideline for significant change (+/ 2.27-2.66), DSI change of +/-1.5 SDs may be clinically useful, resulting in a more liberal level of +/-1.74 (within 1 week) to 2.04 (within 2 weeks) as a guideline for significant changes in voice function. PMID- 22921295 TI - Coblation of the canine vocal fold: a histologic study. AB - Controlled ablation (coblation) is a radiofrequency bipolar method of tissue ablation, which destroys tissue at very low temperatures. It has been used in a variety of clinical settings and is most frequently used by the otolaryngologist for tonsillectomy. In this study, we have examined the effect of coblation on the canine larynx by applying coblation to the vocal fold and harvesting the larynx on postoperative days (PODs) 0, 4, and 7. Histologic examination was performed with a variety of stains to examine the healing process. Coblation injury demonstrated complete epithelialization by POD 7. No injury to the underlying vocalis muscle was seen. The inflammatory response demonstrates less inflammation than previously reported with CO(2) laser injury. Coblation is a viable method for removal of tissue from the vocal fold resulting in minimal scar formation and a controlled depth of injury. Further studies should be performed to determine clinical utility in the removal of lesions such as respiratory papillomatosis. PMID- 22921296 TI - Influence of obligatory mouth breathing, during realistic activities, on voice measures. AB - OBJECTIVE: Low humidity environments and mouth breathing may contribute to superficial vocal fold dehydration. The purpose of this study was to investigate the effects of obligatory mouth breathing, during daily activities in low- and high-humidity environments, on voice measures. The activities included 15 minutes of obligatory mouth breathing alone, during loud reading and during exercise. The effects of mouth breathing and humidity were compared in subjects who either reported or did not report vocal worsening after heavy voice use. STUDY DESIGN: Prospective, between-group, repeated-measures design. METHODS: Sixty-three healthy adults with normal respiratory function and perceptually normal voice participated in this study. Thirty-one subjects reported symptoms of voice worsening with heavy voice use. Thirty-two subjects who did not report these symptoms participated as controls. Phonation threshold pressure and perceived phonatory effort were measured at baseline and after each obligatory mouth breathing challenge. Ambient humidity was set to either low or high humidity. RESULTS: Obligatory mouth breathing in loud reading and exercise significantly increased phonation threshold pressure when compared with mouth breathing alone. This increase in phonation threshold pressure was observed at low and high humidity, in both subject groups. There were no significant effects for perceived phonatory effort. CONCLUSIONS: Obligatory mouth breathing during loud reading and exercise negatively impact phonation threshold pressure. Future investigations that include longer challenge durations, and subjects with voice disorders, are needed to elucidate the underlying mechanisms for increases in phonation threshold pressure. PMID- 22921297 TI - Preliminary data on prevention and treatment of voice problems in student teachers. AB - OBJECTIVES/HYPOTHESES: To assess the utility of a targeted voice hygiene (VH) program compared to VH plus voice training intervention (VH+VT) for the prevention and treatment of voice problems in student teachers. STUDY DESIGN: Prospective, randomized. METHODS: Thirty-one student teachers with low (good) and high (poor) voice handicap index (VHI) scores in Pittsburgh and Hong Kong were randomly assigned to (1) a targeted, individually tailored VH program, (2) the VH program plus resonant VT (VH+VT), or (c) a control group. Participants assigned to intervention groups were monitored for their adherence to their programs for their first 4 weeks of student teaching. VHI data were collected again 4 weeks postintervention (both sites) and 8 weeks postintervention, following a no contact washout period (Pittsburgh). RESULTS: Descriptive data analysis indicated that across both sites, for initially healthy participants, the VH program was sufficient to prevent worsening of VHI scores that occurred in all control participants over the first 4-8 weeks of student teaching. The addition of VT did not consistently enhance protective benefits over VH alone. In contrast, for participants with initially poor VHI scores, the VH program failed to produce VHI benefits over the control condition. The addition of VT was required to optimize results for that cohort. CONCLUSIONS: Preliminary data suggest that a minimalist, individually tailored VH program may be sufficient to prevent voice problems from teaching in healthy student teachers. However, for student teachers with existing voice problems, VT may be required to optimize results of intervention. PMID- 22921298 TI - Aquaporin changes in compound 48/80 induced inflammatory sublaryngeal edema in rat. AB - OBJECTIVES/HYPOTHESIS: Laryngeal edema is a common clinical condition. However, the underlying molecular mechanisms remain elusive. Aquaporins (AQPs) are small integral plasma membrane proteins that transport water across the plasma membrane. In this study, we explore the relationship between inflammatory laryngeal edema induced by compound 48/80 and the expression of AQPs. STUDY DESIGN: Prospective, controlled, experimental animal study. METHODS: Healthy adult male SD rats were injected with either sterile water, compound 48/80 (2 mg/kg), or compound 48/80 plus dexamethasone (3 mg/kg) via the tail vein. The larynxes were harvested 10, 30 minutes, and 1 hour after the injection for the measurement of sublaryngeal water content and histological and molecular evaluations. RESULTS: Ten and 30 minutes after the compound 48/80 injection compared with the sterile water injection control groups, the water content in subglottic larynx increased significantly and the tissues were markedly swollen accompanied with inflammatory cell infiltration. AQP1 and AQP5 mRNA decreased significantly. One hour after the compound 48/80 injection, the edema was diminished, but the inflammatory cell infiltration remained. AQP1 was elevated but AQP5 was still lower than controls. Dexamethasone did not significantly reduce laryngeal edema, but significantly reduced inflammatory cells infiltration induced by compound 48/80 injection. Dexamethasone increased the AQP5 level but not AQP1. CONCLUSIONS: AQP1 and AQP5 might play key roles in inflammatory subglottic edema caused by compound 48/80 in rats. AQP1 and AQP5 might be useful molecular targets of clinical treatment of inflammatory laryngeal edema. PMID- 22921299 TI - Measurement of vocal folds elastic properties for continuum modeling. AB - OBJECTIVE: This study aimed to quantify the major elastic properties of human vocal fold's lamina propria, including longitudinal and transverse Young's modulus, shear modulus, and Poisson's ratio. METHODS: Samples were obtained from cadaveric human larynges that were snap frozen within 48 hours postmortem and kept at -82 degrees F and thawed overnight in saline solution. Once the sample was tested in the longitudinal direction, two special brackets were glued to the side of each sample and the sample was mounted with brackets in the transverse direction. The shear modulus was obtained from samples mounted between two parallel plates applying shear forces. The Poisson ratio was obtained using high speed video imaging of two-dimensional samples with markers for longitudinal and transverse strain measurements. RESULTS: Results indicate that human vocal fold elasticity is very nonlinear with slope that increases 10-15 times from low- to high-strain values. Its average low-strain Young's modulus is approximately 30 kPa in the longitudinal direction and 1 kPa in the transverse direction. The vocal fold longitudinal shear modulus is in the same order of magnitude of its transverse shear modulus (less than 1 kPa). The average Poisson ratio is approximately 0.57. CONCLUSIONS: The present study provides quantitative data for the longitudinal and transverse elastic properties of the human vocal fold tissue and indicates that nonlinear behavior and relative difference of these properties may lead to wide ranges of oscillation frequency and amplitude in human larynges. PMID- 22921300 TI - Outcomes following total laryngectomy for squamous cell carcinoma: one centre experience. AB - OBJECTIVES: To evaluate the clinical outcomes of total laryngectomy (TL), complications and factors affecting survival. DESIGN: Retrospective review of hospital electronic database for head and neck squamous cell carcinoma (SCCa). SETTING: Large district general hospital in England, United Kingdom. PARTICIPANTS: Patients who had TL between January 1994 and January 2008. MAIN OUTCOME MEASURES: 5-year disease specific survival (DSS) and disease-free survival (DFS). RESULTS AND CONCLUSIONS: Seventy-one patients were reviewed, of whom 38 (54%) had laryngeal SCCa and 33 (46%) hypopharyngeal SCCa. The overall mean survival period following TL was 42.4 months. The 5-year DSS and DFS was better for laryngeal SCCa compared to hypopharyngeal SCCa, although not statistically significant (P=0.090, P=0.54 respectively). Patients treated for laryngeal SCCa had a mean survival period of 47.5 months compared to 36.5 months for hypopharyngeal disease. Those who had laryngeal recurrence after primary radiotherapy (RT) demonstrated statistically better survival probability than those who had hypopharyngeal recurrence (P=0.011). Patients without cervical lymphadenopathy had statistically better survival (P=0.049). The most common early complication was related to the cardiorespiratory system. One fatal complication of erosion of the brachiocephalic artery due to the laryngectomy tube was noted. The most common late complication was neopharyngeal stenosis. The commonest cause of death was due to locoregional recurrence, followed by medical co-morbidities. Patients referred to specialised head and neck clinic had a better survival probability than those referred to a general ENT clinic (P=0.37). While there is increasing tendency towards laryngeal conservation, total laryngectomy remains a robust treatment option in selected patients. PMID- 22921301 TI - Nasal cavity lobular capillary hemangioma due to insect sting. AB - INTRODUCTION: Lobular capillary hemangioma is a frequent benign vascular inflammatory lesion of the skin tissue. It rarely reaches the mucous membrane, and the nasal fossa involvement is exceptional. CASE REPORT: A 68-year-old woman presented with an ulcerous hemorrhagic mass blocking the left nasal fossa, which had appeared a few weeks after a wasp sting in the nose. The insect was evacuated only three weeks after the sting. The clinical and radiological data suggested malignancy. Biopsy under local anesthesia proved non-contributory and was complicated by 1 week's hospitalization for severe nosebleed. Surgical excision under video-endoscopy confirmed diagnosis. At 31 months' follow-up, the patient was free of recurrence. DISCUSSION/CONCLUSION: The pathogeny of lobular capillary hemangioma is uncertain. No previous cases affecting the mucous membrane after insect sting have been reported. Except in the typical contexts of long-term packing or pregnancy, diagnosis can be difficult and misleading. It can mimic a malignant pathology. Its rich vascularization requires caution during biopsy, and the risk of recurrence requires excision to be complete. PMID- 22921302 TI - Sonic aerosol therapy to target maxillary sinuses. AB - AIM: Intranasal aerosol administration of drugs is widely used by ENT specialists. Although clinical evidence is still lacking, intranasal nebulization appears to be an interesting therapeutic option for local drug delivery, targeting anatomic sites beyond the nasal valve. The sonic nebulizer NL11SN associates a 100Hertz (Hz) sound to the aerosolization to improve deposition in the nasal/paranasal sinuses. The aim of the present study was: to evaluate in vivo the influence of associating a 100Hz sound on sinus ventilation and nasal and pulmonary aerosol deposition in normal volunteers, and; to quantify in vitro aerosol deposition in the maxillary sinuses in a plastinated head model. MATERIAL AND METHODS: Scintigraphic analysis of (81m)Kr gas ventilation and of sonic aerosol ((99m)Tc-DTPA) deposition using the NL11SN was performed in vivo in seven healthy volunteers. In parallel, NL11SN gentamicin nebulization was performed, with or without associated 100Hz sound, in a plastinated human head model; the gross amount of gentamicin delivered to the paranasal sinuses was determined by fluorescence polarization immunoassay. RESULTS: Associating the 100Hz sound to (81m)Kr gas ensured paranasal sinus ventilation in healthy volunteers. (99m)Tc DTPA particles nebulized with the NL11SN were deposited predominantly in the nasal cavities (2/3, vs 1/3 in the lungs). In vitro, the use of NL11SN in sonic mode increased gentamicin deposition threefold in the plastinated model sinuses (P<0.002); the resulting antibiotic deposit would be sufficient to induce a local therapeutic effect. CONCLUSION: The NL11SN nebulizer ensured preferential nasal cavity aerosol deposition and successfully targeted the maxillary sinuses. PMID- 22921303 TI - Lycium barbarum polysaccharide stimulates proliferation of MCF-7 cells by the ERK pathway. AB - AIMS: The aim of this study was to investigate the anti-proliferative effect of Lycium barbarum polysaccharide (LBP) on MCF-7 cells. MAIN METHODS: MCF-7 cells were treated with 0, 10, 30, 100, and 300 MUg/ml LBP for 24 h. The cell cycle distribution was analyzed by flow cytometry. MEK inhibitor, U1206 also was added in MCF-7 cells to deal with LBP (300 MUg/ml) for different times (0, 2, 4, 6, 8, 16, 24 h). Western blotting was used to indicate changes in the levels of ERK (extracellular signal-regulated protein kinase) and phosphorylation-ERK (p-ERK) to compare the relationship between ERK activity and LBP. The expressions of p53, p-p53 and p21 were observed by western blotting to analyze the relationship between p53 and ERK which was under the treatment of LBP. KEY FINDINGS: The MCF-7 cell cycle was arrested in S phase with the treatment of LBP. The LBP can also activate ERK, which may be associated with p53 pathway. There was a dose dependent increase in the relation between the degree of ERK activation and LBP. SIGNIFICANCE: LBP induces the anti-proliferation of MCF-7 cells by activating ERK. PMID- 22921305 TI - Morphology-driven automatic segmentation of MR images of the neonatal brain. AB - The segmentation of MR images of the neonatal brain is an essential step in the study and evaluation of infant brain development. State-of-the-art methods for adult brain MRI segmentation are not applicable to the neonatal brain, due to large differences in structure and tissue properties between newborn and adult brains. Existing newborn brain MRI segmentation methods either rely on manual interaction or require the use of atlases or templates, which unavoidably introduces a bias of the results towards the population that was used to derive the atlases. We propose a different approach for the segmentation of neonatal brain MRI, based on the infusion of high-level brain morphology knowledge, regarding relative tissue location, connectivity and structure. Our method does not require manual interaction, or the use of an atlas, and the generality of its priors makes it applicable to different neonatal populations, while avoiding atlas-related bias. The proposed algorithm segments the brain both globally (intracranial cavity, cerebellum, brainstem and the two hemispheres) and at tissue level (cortical and subcortical gray matter, myelinated and unmyelinated white matter, and cerebrospinal fluid). We validate our algorithm through visual inspection by medical experts, as well as by quantitative comparisons that demonstrate good agreement with expert manual segmentations. The algorithm's robustness is verified by testing on variable quality images acquired on different machines, and on subjects with variable anatomy (enlarged ventricles, preterm- vs. term-born). PMID- 22921304 TI - Increased plasma levels of big-endothelin-2 and big-endothelin-3 in patients with end-stage renal disease. AB - AIMS: Big endothelins (pro-endothelin; inactive-precursor) are converted to biologically active endothelins (ETs). Mammals and humans produce three ET family members: ET-1, ET-2 and ET-3, from three different genes. Although ET-1 is produced by vascular endothelial cells, these cells do not produce ET-3, which is produced by neuronal cells and organs such as the thyroid, salivary gland and the kidney. In patients with end-stage renal disease, abnormal vascular endothelial cell function and elevated plasma ET-1 and big ET-1 levels have been reported. It is unknown whether big ET-2 and big ET-3 plasma levels are altered in these patients. The purpose of the present study was to determine whether endogenous ET 1, ET-2, and ET-3 systems including big ETs are altered in patients with end stage renal disease. MAIN METHODS: We measured plasma levels of ET-1, ET-3 and big ET-1, big ET-2, and big ET-3 in patients on chronic hemodialysis (n=23) and age-matched healthy subjects (n=17). KEY FINDINGS: In patients on hemodialysis, plasma levels (measured just before hemodialysis) of both ET-1 and ET-3 and big ET-1, big ET-2, and big ET-3 were markedly elevated, and the increase was higher for big ETs (Big ET-1, 4-fold; big ET-2, 6-fold; big ET-3: 5-fold) than for ETs (ET-1, 1.7-fold; ET-3, 2-fold). SIGNIFICANCE: In hemodialysis patients, plasma levels of the inactive precursors big ET-1, big ET-2, and big ET-3 levels are markedly increased, yet there is only a moderate increase in plasma levels of the active products, ET-1 and ET-3. This suggests that the activity of endothelin converting enzyme contributing to circulating levels of ET-1 and ET-3 may be decreased in patients on chronic hemodialysis. PMID- 22921306 TI - Conceptual models to guide best practices in organization and development of State Action Coalitions. AB - The RWJF/AARP National Campaign for Action established a goal of establishing Action Coalitions in every state by 2012. Last year, a small Steering Committee formed in Nebraska and used two conceptual models to guide the organization and development of its Action Coalition. The purpose of this article is to present the Internal Coalition Outcome Hierarchy (ICOH) model that guided development of partnership and coalition building. The second model, Determining Program Feasibility, provided a framework for data collection and analysis to identify the opportunities and challenges for strategic program planning to accomplish identified key priorities for Nebraska. A discussion of the models' applications is included and offered as best practices for others seeking to form partnership/coalitions and establish action plans and priorities. PMID- 22921307 TI - Evaluation of the introduction of a diagnosis procedure combination system for patient outcome and hospitalisation charges for patients with hip fracture or lung cancer in Japan. AB - OBJECTIVES: To evaluate the effects of introducing the Diagnosis Procedure Combination (DPC) system on outcomes, length of stay (LOS) and hospitalisation charges for patients with hip fractures or lung cancer. Patient outcome was evaluated by inpatient mortality, condition at discharge, and readmission within 42 days after discharge. METHODS: DPC data were collected from 92 Japanese Red Cross Medical Centres and community hospitals between April 2005 and December 2008. Pre- and post-DPC outcomes were compared by multivariate regression with difference-in-difference analysis. RESULTS: For hip fractures, the percentage of patients in worse condition at discharge was 150% higher when DPC was used [odds ratio (OR)=2.556, P<0.001]. For lung cancer, the percentage of patients in worse condition at discharge was about 30% lower when DPC was used (OR=0.697, P=0.001). The number of lung cancer diagnosis groups that did not require a long LOS increased. Inpatient mortality and readmission rates and hospitalisation charges did not change for either diagnosis, though the average LOS decreased. CONCLUSIONS: Under the DPC system in Japan, some patients would be discharged 'quicker' and 'sicker', but other patients' outcome at discharge improved. Although LOS decreased, hospitalisation charges did not decrease, and the readmission rate did not increase. PMID- 22921308 TI - Back to basics: a case series of angular dermoid cyst excision. AB - Angular dermoid cysts are common peri-orbital tumours in children. Characteristically benign and slow growing, they are tumours of embryonic origin that arise along bony sutures as a result of abnormal ectodermal sequestration during development. Early surgical excision is recommended and performed in the majority of cases, particularly to restore facial cosmesis. We present a review of 25 cases, managed by our unit over the past 9 years, which underwent surgical excision by a single-stage procedure using the superior eyelid crease approach only. We show that despite the evolution of many techniques, including endoscopy, the superior eyelid crease remains superior in our opinion, affording simple complete excision with a well-concealed scar. Therefore, we recommend this technique as the optimal technique for lateral eyebrow dermoid cyst excision. PMID- 22921309 TI - The role of choline in prostate cancer. AB - Choline is an essential nutrient that is necessary for cell membrane synthesis and phospholipid metabolism and functions as an important methyl donor. Multiple roles for choline in cancer development have been suggested. Choline can affect DNA methylation and lead to a disruption of DNA repair. It can also modify cell signaling that is mediated by intermediary phospholipid metabolites, and it can support the synthesis of cell membranes and thus support cell proliferation. A higher intake or status of choline in plasma and tissues has been related to higher cancer risks. Prostate cancer shows elevated levels of choline uptake and levels of certain choline metabolites. Choline metabolites can be used as potential prognostic biomarkers for the management of prostate cancer patients. Targeting certain enzymes, which are related to choline metabolism, provides promising therapeutic opportunities for tumor growth arrest. This review summarizes the potential role of choline metabolism in cancer, especially in prostate cancer. PMID- 22921310 TI - Reconstruction of the (Crico)trachea for malignancy in the virgin and irradiated neck. AB - BACKGROUND: Reconstruction of the trachea following resection for malignancy is challenging. We present our experience over a 5-year period, and a reconstruction algorithm with particular emphasis on minimising complications associated with radiotherapy. METHODS: A maximum of six tracheal rings can be resected and anastomosed primarily with acceptable tension. A more conservative approach is required in an irradiated trachea. For a limited defect localised anteriorly or laterally, a tracheal flap can be fashioned. As for more eccentric defects, an option is to convert the defect into an asymmetrical segmental defect, and to primarily anastomose the trachea with rotation of the distal stump. Our workhorse loco-regional flaps for patch reconstruction or suture line reinforcement include the sternocleidomastoid, internal mammary artery perforator and pectoralis major myocutaneous flaps. For extensive defects, a radial forearm free flap (RFFF) with rib cartilage struts for rigidity provides a good solution. RESULTS: Fifteen patients (M:F = 4:11, median age 69 years) were identified. Six cases were locally aggressive papillary thyroid cancer. Mean follow-up was 17 months. Five and two patients had had radiotherapy prior to and following tracheal resection, respectively. Nine patients were extubated at the end of surgery, two were successfully decannulated from their T tube subsequently, and one from his tracheostomy. The two surgical complications included a partial RFFF dehiscence causing minor air leak, and major haemorrhage that warranted urgent operation and pectoralis major flap reconstruction. CONCLUSION: Reconstruction of the trachea requires individualised techniques suited to the patient's body habitus, co morbidity, previous treatment and the configuration of the defect. PMID- 22921311 TI - Reliable and sensitive detection of fragile X (expanded) alleles in clinical prenatal DNA samples with a fast turnaround time. AB - This study evaluated a large set of blinded, previously analyzed prenatal DNA samples with a novel, CGG triplet-repeat primed (TP)-PCR assay (Amplidex FMR1 PCR Kit; Asuragen, Austin, TX). This cohort of 67 fetal DNAs contained 18 full mutations (270 to 1100 repeats, including 1 mosaic), 12 premutations (59 to 150 repeats), 9 intermediate mutations (54 to 58 repeats), and 28 normal samples (17 to 50 repeats, including 3 homozygous female samples). TP-PCR accurately identified FMR1 genotypes, ranging from normal to full- mutation alleles, with a 100% specificity (95% CI, 85.0% to 100%) and a 97.4% sensitivity (95% CI, 84.9% to 99.9%) in comparison with Southern blot analysis results. Exact sizing was possible for a spectrum of normal, intermediate, and premutation (up to 150 repeats) alleles, but CGG repeat numbers >200 are only identified as full mutations. All homozygous alleles were correctly resolved. The assay is also able to reproducibly detect a 2.5% premutation and a 3% full-mutation mosaicism in a normal male background, but a large premutation in a full male mutation background was masked when the amount of the latter was >5%. Implementation of this TP-PCR will significantly reduce reflex testing using Southern blot analyses. Additional testing with methylation-informative techniques might still be needed for a few cases with (large) premutations or full mutations. PMID- 22921312 TI - Development of a next-generation sequencing method for BRCA mutation screening: a comparison between a high-throughput and a benchtop platform. AB - In a clinical setting, next-generation sequencing (NGS) approaches for the enrichment and resequencing of DNA targets may have limitations in throughput, cost, or accuracy. We evaluated an NGS workflow for targeted DNA sequencing for mutation detection. Targeted sequence data of the BRCA1 and BRCA2 genes, generated using a PCR-based, multiplexed NGS approach using the SOLiD 4 (n = 24) and Ion Torrent PGM (n = 20) next-generation sequencers, were evaluated against sequence data obtained by Sanger sequencing. The overall sensitivity for SOLiD and PGM were 97.8% (95% CI = 94.7 to 100.0) and 98.9% (95% CI = 96.8 to 100.0) respectively. The specificity for the SOLiD platform was high, at 100.0% (95% CI = 99.3 to 100.0). PGM correctly identified all 3 indels, but 68 false-positive indels were also called. Equimolar normalization of amplicons was not necessary for successful NGS. Both platforms are highly amenable to scale-up, potentially reducing the reagent cost for BRCA testing to TC (Gly190Ser) pathogenic mutation in CLCN1 gene. Occurrence of two different neurological conditions in the same patient, both manifesting with stiffness, is quite unusual and suggests the opportunity of an accurate differential diagnosis. PMID- 22921320 TI - Influence of cervical spine position, turning time, and cervical segment on cadaver intradiscal pressure during cervical spinal manipulative therapy. AB - OBJECTIVE: The purpose of this study was to determine influences of cervical spine positions, turning times, and cervical segments on cadaver intradiscal pressure (IDP) during cervical spinal manipulative therapy (SMT). METHODS: We simulated cervical SMT with stretching and rotation on 7 fresh adult cadaver specimens in the material test system machine. The changes in IDP for cervical intervertebral disks (C3/4, C4/5, and C5/6) during 4 different stages of cervical SMT (physiologic state, end of the traction stage, turning stage, and finish time) were monitored. Five different cervical positions (extension 20 degrees , extension 10 degrees , neutral position, flexion 10 degrees , flexion 20 degrees ) and 3 different turning times (0.06, 0.11, 0.16 second) of IDP were monitored, using micropressure sensors. RESULTS: The variable tendency of cervical IDP presents a "V"-shaped curve during SMT. The 4 stages of SMT had significantly different IDP (F=5498.956; P<.001). There were also significant differences in IDP between 5 cervical positions ([F=1371.216; P<.001], [flexion 20 degrees >flexion 10 degrees >neutral position>extension 10 degrees >extension 20 degrees ]), 3 turning times ([F=419.530; P<.001], [0.06>0.11>0.16 seconds]), and 3 cervical segments ([F=84.282; P<.001], [C3/4= 3 g/dL) and/or clinical signs of hemodynamic compromise, and categorized as early or late (<24 hours or >24 hours from operation). Demographics and operative and perioperative outcomes were analyzed using standard descriptive statistics. RESULTS: Overall incidence of PPH was 3% (33 of 1,122 pancreatectomies) and was similar for pancreaticoduodenectomy (25 of 739 [3%]), distal (6 of 350 [2%]), and central pancreatectomy (2 of 31 [6%]) (p = 0.26). Early hemorrhage was seen in 21% (7 of 33) and was always extraluminal; these patients underwent reoperation and recovered fully. Late hemorrhage (26 of 33 [79%]) was predominantly intraluminal (18 of 26 [69%]), occurring at a median of 12 days postoperatively (4 to 23 days), and was treated endoscopically (13 of 26 [50%]), angiographically (10 of 26 [38%]), or surgically (3 of 26 [10%]). Postpancreatectomy hemorrhage was associated with longer hospitalization (10 [range 8 to 17] days vs 7 [range 6 to 9] days; p < 0.01); mortality, however, was not increased (1 of 33 [3%] vs 17 of 1,089 [2%]; p = 0.95). Hemorrhage began after discharge in 39% of patients (13 of 33), with the only death occurring in a patient from this group. CONCLUSIONS: Postpancreatectomy hemorrhage can be managed successfully with low mortality (3%). Early hemorrhage requires urgent reoperation, and management of delayed hemorrhage should be guided by location (intra- vs extraluminal). Greater pressure to reduce length of hospital stay appears to have increased the likelihood of PPH occurring after discharge; patients and physicians should be aware of this possibility. PMID- 22921326 TI - Hospital surgical volume and cost of inpatient surgery in the elderly. AB - BACKGROUND: Strong relationships between hospital volume and quality with inpatient surgery have prompted calls for volume-based referral. However, many are concerned that such policies would steer patients toward higher-cost hospitals. STUDY DESIGN: Using 2005-2007 national Medicare claims, we identified all US hospitals performing elective colectomy for cancer, coronary artery bypass surgery, and abdominal aortic aneurysm repair. Patients were sorted into quintiles based on procedure volumes of the hospital in which they had surgery. For each quintile, we assessed overall 30-day Medicare episode payments adjusted for hospital case mix, including the index hospitalization, readmissions, physician services, and post-discharge ancillary care. RESULTS: Hospitals in the lowest-volume quintile had considerably higher case-mix-adjusted episode payments than those in the highest-volume quintile for coronary artery bypass surgery ($960; 2.2% higher) and abdominal aortic aneurysm ($2,796; 8.5% higher), but differences were small for colectomy ($350; 1.3% higher). For coronary artery bypass surgery and abdominal aortic aneurysm repair, the index hospitalization was the largest source of higher overall payments at very low-volume hospitals. For all 3 procedures, very low-volume hospitals had higher payments for both 30 day readmissions and post-discharge ancillary care. CONCLUSIONS: Volume-based referral policies would not steer patients toward hospitals with high mean costs around episodes of inpatient surgery in the elderly. Minimizing the use of very low-volume hospitals has the potential to reduce costs as well as improve outcomes, particularly for operations with strong volume-outcomes associations. PMID- 22921327 TI - Have we expanded the equitable delivery of postmastectomy breast reconstruction in the new millennium? Evidence from the national cancer data base. AB - BACKGROUND: Studies examining patterns of cancer care before 2000 have shown underuse of postmastectomy breast reconstruction as well as racial and socioeconomic disparities in its delivery. These findings prompted legislation designed to broaden use at the turn of the millennium. However, little is known about trends in these findings over the past decade. STUDY DESIGN: Patients who underwent mastectomy for stage 0 to III breast cancer between 1998 and 2007 (n = 452,903) were studied using the National Cancer Data Base to evaluate trends in the receipt of immediate and early delayed breast reconstruction. Those who underwent mastectomy between 1998 and 2000 (n = 150,177) and between 2005 and 2007 (n = 123,518) were compared using logistic regression to identify factors influencing the use of breast reconstruction and how they changed over time. RESULTS: The use of postmastectomy breast reconstruction increased from 13% to 26% from 1998 to 2007. This increase was statistically significant in almost all patient subsets. Independent factors associated with breast reconstruction included age less than 50 years old; higher census-derived household income; private or managed care insurance; non-African American race; and treatment in an academic hospital setting. Treatment in an academic hospital and higher income became stronger predictors of breast reconstruction over the study period, while age became less of a predictor. CONCLUSIONS: Although the use of breast reconstruction has increased from 1998 to 2007, it is still underused among many patient populations. Furthermore, racial and socioeconomic disparities in its delivery have persisted or widened. Additional effort is necessary to broaden the use of breast reconstruction and to ensure equitable access to it. PMID- 22921328 TI - Patient readmission and mortality after surgery for hepato-pancreato-biliary malignancies. AB - BACKGROUND: The incidence and associated risk factors for readmission after hepato-pancreato-biliary surgery are poorly characterized. The objective of the current study was to compare readmission after pancreatic vs hepatobiliary surgical procedures, as well as to identify potential factors associated with higher readmission within 30 days of discharge. STUDY DESIGN: Using Surveillance, Epidemiology and End Results-Medicare linked data from 1986-2005, we identified 9,957 individuals aged 66 years and older who underwent complex hepatic, biliary, or pancreatic procedures for cancer treatment and were eligible for analysis. In hospital morbidity, mortality, and 30-day readmission were examined. RESULTS: Primary surgical treatment consisted of a pancreatic (46.7%), hepatic (50.0%), or biliary (3.4%) procedure. Mean patient age was 72.6 years and most patients were male (53.2%). The number of patients with multiple preoperative comorbidities increased over time (patients with Elixhauser's comorbidity score >13: 1986-1990, 47.0% vs 2001-2005, 62.9%; p < 0.001). Pancreatic operations had higher inpatient mortality vs hepatobiliary procedures (9.2% vs 7.3%; p < 0.001). Mean length of stay after pancreatic procedures was longer compared with hepatobiliary procedures (19.7 vs 10.3 days; p < 0.001). The proportion of patients readmitted after a pancreatic (1986-1990, 17.7%; 1991-1995, 16.1%; 1996-2000, 18.6%; 2001 2005, 19.6%; p = 0.15) or hepatobiliary (1986-1990, 14.3%; 1991-1995, 14.1%; 1996 2000, 15.2%; 2001-2005, 15.5%; p = 0.69) procedure did not change over time. Factors associated with increased risk of readmission included preoperative Elixhauser comorbidities >13 (odds ratio = 1.90) and prolonged index hospital stay >=10 days (odds ratio = 1.54; both p < 0.05). During the readmission, additional morbidity and mortality were 46.5% and 8.0%, respectively. CONCLUSIONS: Although the incidence of readmission did not change across the time periods examined, readmission was higher among patients undergoing a pancreatic procedure vs a hepatobiliary procedure. Other factors associated with risk of readmission included number of patient comorbidities and prolonged hospital stay. Readmission was associated with additional short-term morbidity and mortality. PMID- 22921329 TI - Hepatic resection for primary hepatolithiasis: a single-center Western experience. AB - BACKGROUND: The incidence (0.6% to 1.3%) of primary hepatolithiasis (PHL), also known as Oriental cholangiohepatitis, is increasing in Western countries and the treatment remains challenging. We analyzed the outcomes of patients undergoing hepatic resection (HR) for PHL at a single Western center. STUDY DESIGN: The records of all patients undergoing HR for PHL between August 1998 and January 2012 were reviewed. Patients were required to have preserved liver function (Child-Pugh class A) with no evidence of portal hypertension. Diagnosis of disease recurrence was based on radiographic and clinical findings. RESULTS: Of the 30 patients who underwent HR, 63.3% presented with earlier failed therapeutic strategies. The majority of the patients were female (63.3%), presented with cholangitis (66.6%), left-sided (66.6%), and unilateral (90.0%) disease, and underwent left-sided hepatic resection (76.6%). Previously created choledochoduodenostomies (13.3%) were all revised into Roux-en-Y hepaticojejunostomy anastomoses in conjunction with the HR. The incidence of concomitant cholangiocarcinoma was 23.3%, with a mean tumor size of 4.2 cm. Perioperative morbidity and mortality rates were 6.6% and 0%, respectively. At a median follow-up of 35 months, all patients had complete intrahepatic stone clearance. One patient required postoperative ERCP. Of the 7 patients with cholangiocarcinoma, 2 had cancer recurrence within the first year of the HR. The remaining patients are disease-free at a median follow-up of 21 months. CONCLUSIONS: Hepatic resection is a safe and definitive treatment option in the management of PHL. It achieves excellent short- and long-term results. The high incidence of concomitant cholangiocarcinoma makes a compelling argument for resection of all involved hepatic segments, when possible. PMID- 22921330 TI - Ethics education in chiropractic colleges: a North American survey. AB - OBJECTIVE: The purposes of this study were to survey Council on Chiropractic Education-accredited chiropractic colleges in North America and to describe curricular details on the teaching of bioethics. METHODS: A custom-designed survey was sent to chiropractic colleges. Total number of contact hours, whether the ethics was a stand-alone course or integrated elsewhere, type of instructor, and if there was a required or recommended course text were queried. RESULTS: Of 19 surveys sent by mail, 15 surveys were returned. The average time in ethics instruction was 18.7 hours including lecture format, small group tutorial, and self-study. Chiropractic ethics education includes 8 areas of content (boundaries, law and jurisprudence, professionalism, basic ethic tenets/principles, ethical codes of conduct, prevention of financial and of sexual abuse, and resolving an ethical dilemma). Some colleges include content taught to students under the domain of law and jurisprudence. CONCLUSION: The results of this survey indicate that there are opportunities to further develop the educational ethics program at Council on Chiropractic Education-accredited colleges. All colleges currently offer bioethics teaching. An expanded role for this content is recommended so as to offer optimal benefit for students and practitioners. PMID- 22921331 TI - Shoulder pain in Iranian elite athletes: the prevalence and risk factors. AB - OBJECTIVE: Shoulder sports injuries are relatively common in athletes who perform highly repetitive motions. The purposes of this study were to determine the prevalence of and risk factors for shoulder injuries and to analyze how individual and other sport characteristics contribute to the risk of shoulder injuries among 6 overhead sports, those being swimming, rowing, wrestling, basketball, volleyball, and handball. METHODS: A cross-sectional study was carried out on 613 Iranian overhead sports athletes in different collegiate sport fields. Data were collected using different questionnaires. A structured questionnaire including demographics, sport characteristics, and also prevalence and risk factors of shoulder pain was used. Visual analogue scale and Disability of the Arm, Shoulder, and Hand questionnaires were used to determine the pain intensity and functional disability, respectively. RESULTS: Point, last 6-month, last year, and lifetime prevalences of shoulder pain were 21.4%, 29%, 38.8%, and 41.6%, respectively. The highest point prevalence was related to the rowing athletes with 31.9% and the lowest for swimming athletes (12.3%). Sex, body mass index, sport level, days of practice per week, and satisfaction with income were found to be significantly correlated with the prevalence of shoulder pain (P < .05 in all instances). For those with shoulder pain, the mean pain intensity and functional disability were 53.8 mm and 15.46%, respectively. CONCLUSIONS: The prevalence of shoulder pain in athletes with highly repetitive overhead motions seems to be high. PMID- 22921332 TI - Mobilization with movement and kinesiotaping compared with a supervised exercise program for painful shoulder: results of a clinical trial. AB - OBJECTIVE: The purpose of this study was to compare the efficacy of Mobilization with Movement (MWM) and kinesiotaping (KT) techniques with a supervised exercise program in participants with patients with shoulder pain. METHODS: Twenty subjects with shoulder pain were included if subjects were diagnosed by the referring physician with either rotator cuff lesion with impingement syndrome or impingement shoulder syndrome. Participants were randomly assigned to 1 of 2 groups after clinical and radiologic assessment: group 1 was treated with MWM and KT techniques, whereas group 2 was treated with a supervised exercise program. The main outcome measures were active pain-free shoulder abduction and flexion tested on days 0, 5, and 10. RESULTS: Improvement in active pain-free shoulder range of motion was significantly higher in the group treated with MWM and KT. Repeated-measures analysis of variance indicated significant effects of treatment, time, and treatment*time interaction. CONCLUSION: This study suggests that MWM and KT may be an effective and useful treatment in range of motion augmentation of subjects with rotator cuff lesion and impingement syndrome or impingement shoulder syndrome. PMID- 22921333 TI - Obstacles to communication in children with cri du chat syndrome. AB - BACKGROUND: Cri du chat syndrome (CCS) is a genetic disorder resulting from the deletion of the short arm of chromosome 5. Perhaps the most distinctive characteristic of this syndrome is the congenital high-pitched cry, which frequently brings these patients to the attention of an otolaryngologist. Speech and language development in children with CCS is notable for a reduced receptive vocabulary and a profound deficit in expressive language. Currently, no clear guidelines have been established for the treatment of the speech and language difficulties exhibited by these patients. In this article, we present a case report and discuss the current literature regarding the challenges to effective communication in CCS. METHODS: Case report. CASE: We present a 7-year-old girl with CCS who sought help to improve her ability to communicate. The patient presented with a persistent high-pitched voice unchanged since birth and a breathy dysphonia. Findings on examination were significant for an abnormally oriented larynx with atrophic vocal folds. She continues to undertake intensive speech therapy to assist in her language development. CONCLUSION: CCS is a genetic disorder that universally results in profound deficits in expressive speech. Although patients with CCS commonly present with a high-pitched voice and marked laryngeal abnormalities, they are unlikely to benefit from surgical intervention. Speech and language therapy, including augmentative communication devices, may enhance effective communication and improve the quality of life of these patients. PMID- 22921334 TI - Interleukin-6 induces the generation of IL-10-producing Tr1 cells and suppresses autoimmune tissue inflammation. AB - Compared with its pro-inflammatory function, the mechanisms underlying the anti inflammatory effect of IL-6 are poorly understood. IL-6 can cooperate with TGF beta to induce IL-10 production in Th17 cells in vitro. However, the effect of IL 6 on generation of Tr1 cells and the in vivo importance of this effect are mostly uncharacterized. In this study, we showed that in vitro, IL-6 can induce the generation of IL-10-producing Tr1 cells from naive CD4 T cells, independently of IL-27 and TGF-beta. IL-6 induces IL-21 production in CD4 T cells and IL-10 inducing effect of IL-6 requires both IL-21 and IL-2. Although IL-6 cannot induce IL-10 production in CD8 T cells in a cell-autonomous manner, it can do so indirectly through promoting CD4 T cell IL-21 production. The IL-10-producing T cells induced by IL-6 have phenotypic, genetic and functional traits of Tr1 cells and can suppress LPS-induced in vivo inflammatory response in an IL-10-dependent fashion. Blockade of IL-6 in two autoimmune inflammation models, induced respectively by anti-CD3 antibody or Treg-depletion, led to reduction in IL-10 producing T cells and exacerbated inflammation of lung and intestine. Thus, we delineated critical pathways involved in IL-6-induced generation of Tr1 cells and demonstrated the importance of this event in restraining autoimmune tissue inflammation. PMID- 22921336 TI - Video capsule retention--endoscopic or surgical problem? PMID- 22921335 TI - Nuclear orphan receptor NR2F6 directly antagonizes NFAT and RORgammat binding to the Il17a promoter. AB - Interleukin-17A (IL-17A) is the signature cytokine produced by Th17 CD4(+) T cells and has been tightly linked to autoimmune pathogenesis. In particular, the transcription factors NFAT and RORgammat are known to activate Il17a transcription, although the detailed mechanism of action remains incompletely understood. Here, we show that the nuclear orphan receptor NR2F6 can attenuate the capacity of NFAT to bind to critical regions of the Il17a gene promoter. In addition, because NR2F6 binds to defined hormone response elements (HREs) within the Il17a locus, it interferes with the ability of RORgammat to access the DNA. Consistently, NFAT and RORgammat binding within the Il17a locus were enhanced in Nr2f6-deficient CD4(+) Th17 cells but decreased in Nr2f6-overexpressing transgenic CD4(+) Th17 cells. Taken together, our findings uncover an example of antagonistic regulation of Il17a transcription through the direct reciprocal actions of NR2F6 versus NFAT and RORgammat. PMID- 22921337 TI - MRI features of oriental cholangiohepatitis. PMID- 22921338 TI - A novel minicircle vector based system for inhibting the replication and gene expression of enterovirus 71 and coxsackievirus A16. AB - Enterovirus 71 (EV 71) and Coxsackievirus A16 (CA 16) are two major causative agents of hand, foot and mouth disease (HFMD). They have been associated with severe neurological and cardiological complications worldwide, and have caused significant mortalities during large-scale outbreaks in China. Currently, there are no effective treatments against EV 71 and CA 16 infections. We now describe the development of a novel minicircle vector based RNA interference (RNAi) system as a therapeutic approach to inhibiting EV 71 and CA 16 replication. Small interfering RNA (siRNA) molecules targeting the conserved regions of the 3C(pro) and 3D(pol) function gene of the EV 71 and CA 16 China strains were designed based on their nucleotide sequences available in GenBank. This RNAi system was found to effectively block the replication and gene expression of these viruses in rhabdomyosarcoma (RD) cells and virus-infected mice model. The inhibitory effects were confirmed by a corresponding decrease in viral RNA, viral protein, and progeny virus production. In addition, no significant adverse off-target silencing or cytotoxic effects were observed. These results demonstrated the potential and feasibility of this novel minicircle vector based RNAi system for antiviral therapy against EV 71 and CA 16 infection. PMID- 22921339 TI - Breast cancer mortality in Spain: has it really declined for all age groups? AB - OBJECTIVES: In recent years, the incidence of breast cancer has increased in Spain but mortality has decreased, particularly since 1992. Despite the general decrease in mortality, the intensity of this disease differs between age groups. The main objective of this study was to examine mortality due to breast cancer for different age groups in Spain from 1981 to 2007, and to forecast the mortality rate in 2023. STUDY DESIGN: Ecological study. METHODS: Trends in mortality due to breast cancer were analysed using the Lee-Carter model, which is the typical analysis for mortality in the general population but is rarely used to analyse specific causes of death. RESULTS: This study found a decreasing trend in mortality due to breast cancer from 1993 to 2007, and it is predicted that this trend will continue. However, mortality rates varied between age groups: a decreasing trend was seen in younger and middle-aged women, whereas mortality rates remained stable in older women. CONCLUSIONS: Preventive breast cancer practices should differ by patient age. PMID- 22921340 TI - [Fever and persistent cough in a 65-year-old patient]. PMID- 22921342 TI - Economic perspective of marine reserves in fisheries: a bioeconomic model. AB - The present paper describes a prey-predator type fishery model with prey dispersal in a two-patch environment, one of which is a free fishing zone and other is protected zone. The objective of the paper is to maximize the net economic revenue earn from the fishery through implementing the sustainable properties of the fishery to keep the ecological balance. Biological measures are introduced to increase the understanding of the mechanisms in the bioeconomic system. The importance of marine reserve is analyzed through the obtained results of the numerical simulations of proposed model system. The results depict that reserves will be most effective when coupled with harvesting controls in adjacent fisheries. The paper also incorporates the induced cost and premium from establishing a marine protected area in a fishery. It is found that premium of marine protected area (MPA) increases with the increasing size of the reserve. Results are analyzed with the help of graphical illustrations. PMID- 22921345 TI - Surgical correction of transverse skeletal abnormalities in the maxilla and mandible. AB - The correction of transverse skeletal abnormalities occupies a special place in orthognathic surgery. Maxillofacial surgeons employ a variety of techniques, but treatment stability remains a common problem. This paper presents a range of therapeutic options with special emphasis on two little-known techniques for correcting transverse skeletal abnormalities: symphyseal distraction and mandibular constriction. These techniques are described and their indications discussed. PMID- 22921347 TI - Assessment of lower lip changes following incisor displacement in 92 orthodontically-treated adults. AB - AIM: A retrospective assessment of the lower lip changes consequent to incisor displacement in correction of malocclusion in a sample of 92 post-adolescent subjects. METHODS: The study sample comprised two groups, subdivided according to the direction of incisor movement achieved during orthodontic treatment: the retraction group (Group 1), made up of 41 patients in which the maxillary incisor had been moved in a palatal direction (palatal tipping); and the protraction group (Group 2), composed of 51 patients who had undergone labial movement of the upper incisors (labial tipping). In order to evaluate the mean changes in lower lip position, and consequent alterations in the quality of the patients' profiles, between T1 (prior to orthodontic displacement of the incisors) and T2 (following treatment), the following parameters were measured on lateral head film X rays: variation in lower lip vermilion thickness (dLVT); variation in lower lip sulcus depth (dLLSD); variation in lower vermilion height (dLVH); variation in exposure of the upper and lower incisors in relation to the lower stomion (dIs-STOi and dIi-STOi, respectively); variation in upper and lower incisor tipping with respect to the palatal plane (d1/PP and dinf1/PP); and variation in lower facial height (dLFH). RESULTS: Assessment of the changes due to incisor translocation revealed significant differences between Group 1 and Group 2 in all lower lip soft tissue parameters, except for dLVT, dLVH and dIi STOi. Furthermore, using multiple linear regression analysis to predict the behaviour of the dependent (cutaneous) lower lip variables, a good coefficient of determination (r-square) value was only obtained for the horizontal variation of the labrale inferius point (dxLi), found to be dependent on horizontal movement of the upper and lower incisors (dxIs and dxIi) and thickness of the lower vermilion (LVT). CONCLUSIONS: The results of this study highlight great variability among the patients studied, and suggest that the behaviour of the soft tissues (lower lip changes) following displacement of the upper and lower incisors is multifactorial and very difficult to predict. PMID- 22921348 TI - Therapeutic decisions in the presence of decayed permanent first molars in young subjects: a descriptive inquiry. AB - The aim of this exhaustive descriptive epidemiological study was to determine the clinical approach to be adopted by practitioners specializing exclusively in pediatric odontology and by orthodontists when confronted with decayed molars in children and adolescents. MATERIAL AND METHOD: A questionnaire was sent out to all corresponding practitioners (n=2076). Six questions related to treatment decisions taken when faced with decayed permanent first molars (unfavorable short or middle-term prognosis) in patients needing, or not, orthodontic care. The Chi(2) test was used to compare responses. RESULTS: Thirty-eight per cent of pedodontists (n=38) and 12.5% (n=246) of orthodontists answered the questionnaire. Faced with a permanent first molar with an unfavorable middle-term prognosis, 75.7% needed criteria to help them reach their treatment decision. In decreasing order of importance, these criteria were: presence of the third molar, patient motivation, inter-arch relationship, patient's oral hygiene, facial type, anterior jaw-teeth discrepancy and the number of molars to be extracted. Faced with a permanent first molar requiring extraction and when orthodontic treatment was not required, 31.7% of practitioners decided to close the maxillary space immediately as opposed to 13.4% who closed the space at the mandible. In the presence of a single decayed first molar, 68.7% of practitioners did not extract the antagonist or contralateral first molars. CONCLUSION: These treatment decisions were not always unanimous and call for a combined approach between dental surgeon and orthodontist. PMID- 22921349 TI - Collaborative study to establish a proficiency panel of hepatitis B surface antigens for evaluating in vitro diagnostics. AB - Hepatitis B virus (HBV) infection is a critical health issue. In hospitals, in vitro diagnostic devices (IVDs) are used to detect HBV infections. The Taiwan Food and Drug Administration has prepared a candidate hepatitis B surface antigen (HBsAg) proficiency panel as an analytical standard to evaluate the sensitivity of the postmarketing surveillance of HBV IVDs. The sensitivity and stability of the proficiency panel, which comprises 5 HBsAg positive sera (SN-A to E) and 1 negative serum, was determined by a collaborative study involving 8 collaboratories. The potency of the candidate proficiency panel was consistent among all collaboratories. The potencies of sera SN-A to E in semiquantitative and quantitative analyses were 2.823-0.011 and 2.229-0.009 IU/mL, respectively. The mean coefficients of variation (CV) of intra and interday precision among the collaboratories were <7%. Accelerated degradation and long-term storage tests were used as stability assays. The candidate HBsAg proficiency panel exhibited good stability under different storage conditions, while all CVs were <6%. In conclusion, this candidate HBsAg proficiency panel is credible and reliable. Therefore, it can be used for postmarketing surveillance of HBV IVDs and quality assessment by clinical researchers and IVD manufacturers. PMID- 22921350 TI - In vitro protective effects of Thymus quinquecostatus Celak extracts on t-BHP induced cell damage through antioxidant activity. AB - The purpose of this study was to evaluate the antioxidative activities of water and 70% ethanolic extracts from the Thymus quinquecostatus Celak (TQC) for natural antioxidant source. The antioxidant activities were compared with other natural and synthetic antioxidants. The levels of total polyphenols and flavonoids were also determined. The extracts were found to have different levels of antioxidant properties in a few kind of assay. The results showed that higher radical scavenging activity, reducing power and antioxidant capacity in FRAP than those of BHT as a positive control. In addition, the extracts from the TQC leaf and stem showed stronger antioxidant activity than that of vitamin C, alpha tocopherol in ferric thiocyanate (FTC) and thiobarbituric acid (TBA) methods. Cytoprotective and anti-apoptotic effect of water extracts from TQC was also prevented t-BHP-induced toxicity in Chang liver cells. Therefore, these results indicate that TQC extracts have antioxidant properties through its ability to enhance the cell viability, reduction of production of ROS, inhibition of oxidative damage, mitochondria dysfunction and ultimately inhibition of cell apoptosis. Based on the results described above, it is suggested that TQC has the potential to protect liver on t-BHP-induced cell damage and should be considered as a prospective functional food. PMID- 22921351 TI - Ergothioneine protects against neuronal injury induced by beta-amyloid in mice. AB - beta-Amyloid peptides (Abeta) are neurotoxic and contribute to the development of Alzheimer's disease (AD). Ergothioneine (EGT) has been shown to protect against loss of memory and learning abilities in mice. In this study, mice were orally fed EGT (0.5 or 2 mg/kg body weight) for 16 days before treatment (i.c.v) with a single dose of Abeta1-40 in the hippocampus. After resting for 12 days to restore the body weight, the mice were again fed EGT for additional 39 days. Active avoidance tests were conducted on days 37-39 (short-memory avoidance) and on days 37, 44 and 51 (long-memory avoidance). Water maze task was used to evaluate learning and memory abilities by acquisition test and retention test. In both long-memory avoidance and water maze tests, EGT significantly decreased the escape latency and increased the frequency of successful avoidance. Furthermore, EGT significantly prevented Abeta accumulation in the hippocampus and brain lipid peroxidation, restored acetylcholinesterase (AChE) activity, maintained glutathione/glutathione disulfide ratio and superoxide dismutase activity in brain tissues of Abeta1-40-teated mice. Thus, EGT can protect against Abeta induced loss of memory and learning abilities in mice. Further studies are required to confirm the protective effects of EGT on the development or progression of AD. PMID- 22921352 TI - Genotoxicity studies of glycidol fatty acid ester (glycidol linoleate) and glycidol. AB - Glycidol fatty acid esters (GEs) are found in refined edible oils. Safety concerns have been alleged due to the possible release of glycidol (G), an animal carcinogen. We evaluated the genotoxic potential of glycidol linoleate (GL), a primary GE found in an edible oil (diacylglycerol oil), and G, using three established genotoxicity tests (a bacterial reverse mutation test, an in vitro chromosomal aberration test, and an in vivo bone marrow micronucleus test) under GLP conditions complying with all OECD guidelines. In the bacterial reverse mutation test, GL and G showed positive responses. The positive responses of GL were less than those of G and observed only in strains detecting point mutations where G showed remarkably positive responses. G was involved in the positive response of GL. In the chromosomal aberration test, GL did not induce chromosome aberrations whereas G induced structural chromosome aberrations in the presence and absence of metabolic activation. In the bone marrow micronucleus test, neither GL nor G induced significant increases of micronucleated immature (polychromatic) erythrocytes in bone marrow of test animals. Based on the above results as well as pertinent information on toxicokinetics, GL itself does not play a key role in genotoxic action. PMID- 22921353 TI - Characterization of heat-labile toxin-subunit B from Escherichia coli by liquid chromatography-electrospray ionization-mass spectrometry and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. AB - The possibilities of characterizing the heat-labile enterotoxin (LT) of enterotoxigenic Escherichia coli (ETEC) by liquid chromatography electrospray mass spectrometry (LC/ESI-MS) and matrix-assisted laser desorption with time-of flight mass spectrometry (MALDI-TOF-MS) were investigated. The B subunit from recombinant E. coli (expression in Pichia pastoris) can be detected by LC/ESI-MS expressed in P. pastoris and the charge envelope signals can be observed; LC/ESI MS and MALDI-TOF-MS analysis allowed the acquisition of labile toxin subunit B (LTB) molecular weight and preliminary structural characterization of LTB toxin. MALDI-TOF analysis after reduction and alkylation of the protein evidenced the presence of one disulfide bond in the structure of the protein. Confirmatory analysis was carried out by detection of most of the tryptic fragments of the B subunit by MALDI-TOF-MS, obtaining total coverage of the protein sequence. Possible biovariations in the toxin can mostly be determined by sequencing, where an increase of molecular mass in the N-terminal side of the protein was identified. This modification may be due to an O-GlcNAc-1-phosphorylation. PMID- 22921354 TI - Speeding with control: codon usage, tRNAs, and ribosomes. AB - Codon usage and tRNA abundance are critical parameters for gene synthesis. However, the forces determining codon usage bias within genomes and between organisms, as well as the functional roles of biased codon compositions, remain poorly understood. Similarly, the composition and dynamics of mature tRNA populations in cells in terms of isoacceptor abundances, and the prevalence and function of base modifications are not well understood. As we begin to decipher some of the rules that govern codon usage and tRNA abundances, it is becoming clear that these parameters are a way to not only increase gene expression, but also regulate the speed of ribosomal translation, the efficiency of protein folding, and the coordinated expression of functionally related gene families. Here, we discuss the importance of codon-anticodon interactions in translation regulation and highlight the contribution of non-random codon distributions and post-transcriptional base modifications to this regulation. PMID- 22921355 TI - Xylose isomerase overexpression along with engineering of the pentose phosphate pathway and evolutionary engineering enable rapid xylose utilization and ethanol production by Saccharomyces cerevisiae. AB - Xylose is the main pentose and second most abundant sugar in lignocellulosic feedstocks. To improve xylose utilization, necessary for the cost-effective bioconversion of lignocellulose, several metabolic engineering approaches have been employed in the yeast Saccharomyces cerevisiae. In this study, we describe the rational metabolic engineering of a S. cerevisiae strain, including overexpression of the Piromyces xylose isomerase gene (XYLA), Pichia stipitis xylulose kinase (XYL3) and genes of the non-oxidative pentose phosphate pathway (PPP). This engineered strain (H131-A3) was used to initialize a three-stage process of evolutionary engineering, through first aerobic and anaerobic sequential batch cultivation followed by growth in a xylose-limited chemostat. The evolved strain H131-A3-AL(CS) displayed significantly increased anaerobic growth rate (0.203+/-0.006 h-1) and xylose consumption rate (1.866 g g-1 h-1) along with high ethanol conversion yield (0.41 g/g). These figures exceed by a significant margin any other performance metrics on xylose utilization and ethanol production by S. cerevisiae reported to-date. Further inverse metabolic engineering based on functional complementation suggested that efficient xylose assimilation is attributed, in part, to the elevated expression level of xylose isomerase, which was accomplished through the multiple-copy integration of XYLA in the chromosome of the evolved strain. PMID- 22921356 TI - [Adenocarcinoma of the uterine cervix: particularities in diagnosis and treatment]. AB - INTRODUCTION: The adenocarcinoma of the uterine cervix accounts for 10 to 20% of the premalignant and malignant lesions and is different from the cervical intraepithelial neoplasia and invasive squamous cell carcinoma. MATERIALS AND METHODS: Recent literature review (from 1985 to 2012) based on the literature available. RESULTS AND DISCUSSION: Adenocarcinoma in situ is an induced HPV lesion (role of HPV 18) of the glandular epithelium: its preferential endocervical situation explains the difficulties in the diagnosis and follow-up after conservative treatment. If the hysterectomy remains the gold standard for treatment, the conservative treatments (resection in sano of the lesions with margins of more than 1cm, meticulous study of the operative specimen, compliance with the follow-up) are possible in the young patients who desire to preserve their fertility. The invasive adenocarcinoma is characterized by a more difficult diagnosis because of its endocervical development, and a prognosis less favorable when compared to squamous cell carcinoma with a greater frequency of the lymphatic node involvement and metastatic diffusion. Its treatment must take into account the particular gravity of the factors of worse prognosis (FIGO stage, tumor size, lymphatic node spreading, adenosquamous histological subtype) in particular in the advanced stages and includes beside the surgery, radiotherapy and chemotherapy. PMID- 22921357 TI - [Immunological aspect of pregnancy]. AB - Pregnancy is a temporary semi-allograft that survives for nine months. The importance of this event for the survival of the species justifies several tolerance mechanisms that are put into place at the beginning of pregnancy, some of which occur even at the time of implantation. The presence of multiple tolerance mechanisms and the richness of the means employed underline the central importance of the trophoblast. Understanding these mechanisms, and in particular, their integration into an overall scheme, enables the anomalies encountered in certain pathologies of pregnancy to be placed into context. Understanding these mechanisms and their interruption at the end of pregnancy should improve our understanding of disappointing results from current immunological treatments facilitate the implementation of new prophylactic and therapeutic strategies. PMID- 22921358 TI - Hemimicelles/admicelles supported on magnetic graphene sheets for enhanced magnetic solid-phase extraction. AB - In this work, superparamagnetic nanoparticle-decorated graphene (MG) sheets were synthesized and used as support for hemimicelles/admicelles for solid-phase extraction (SPE) of different compounds from environmental water samples for the first time. The MG sheets were facilely synthesized by a one-step, one-pot redox reaction between graphene oxide and Fe(II). Due to the large surface area and unique nanosheet morphology, MG served as an excellent nano-scaled support material for hemimicelles and admicelles, exhibiting higher loading capacity than conventional materials and pure Fe3O4 nanoparticles. The MG sheets could be negatively or positively charged depending on solution pH, allowing the extraction to be conducted in different modes. In cationic mode, cetyltrimethylammonium bromide (CTAB) was used as micelle-forming reagent, and perfluoroalkyl and polyfluoroalkyl substances (PFASs) and alkylphenols were used as model analytes. In anionic mode, sodium dodecyl sulfate (SDS) was used as micelle-forming reagent and alkyltrimethylammonium salts were selected as analytes. In both modes, the formation processes of hemimicelles/admicelles on MG sheets were studied and the extraction conditions were optimized. For PFASs, the analytical sensitivity was enhanced by 50-113-fold by the extraction, and the method detection limits (MDLs) ranged from 0.15 to 0.50 ng/L. For alkyltrimethylammonium salts, the MDLs were in the range of 1.4-8.0 ng/L. In both modes, good recoveries (56.3-93.9%) and reproducibility (run-to-run RSDs<9.3%) were obtained. The results from this work show a potential new role of graphene in analytical sample preparation. PMID- 22921359 TI - From random sphere packings to regular pillar arrays: analysis of transverse dispersion. AB - We study the impact of microscopic order on transverse dispersion in the interstitial void space of bulk (unconfined) chromatographic beds by numerical simulations of incompressible fluid flow and mass transport of a passive tracer. Our study includes polydisperse random sphere packings (computer-generated with particle size distributions of modern core-shell and sub-2 MUm particles), the macropore space morphology of a physically reconstructed silica monolith, and computer-generated regular pillar arrays. These bed morphologies are analyzed by their velocity probability density distributions, transient dispersion behavior, and the dependence of asymptotic transverse dispersion coefficients on the mobile phase velocity. In our work, the spherical particles, the monolith skeleton, and the cylindrical pillars are all treated as impermeable solid phase (nonporous) and the tracer is unretained, to focus on the impact of microscopic order on flow and (particularly transverse) hydrodynamic dispersion in the interstitial void space. The microscopic order of the pillar arrays causes their velocity probability density distributions to start and end abruptly, their transient dispersion coefficients to oscillate, and the asymptotic transverse dispersion coefficients to plateau out of initial power law behavior. The microscopically disordered beds, by contrast, follow power law behavior over the whole investigated velocity range, for which we present refined equations (i.e., Eq.(13) and the data in Table 2 for the polydisperse sphere packings; Eq.(17) for the silica monolith). The bulk bed morphologies and their intrinsic differences addressed in this work determine how efficient a bed can relax the transverse concentration gradients caused by wall effects, which exist in all confined separation media used in chromatographic practice. Whereas the effect of diffusion on transverse dispersion decreases and ultimately disappears at increasing velocity with the microscopically disordered chromatographic beds, it dominates in the pillar arrays. The pillar arrays therefore become the least forgiving bed morphology with macroscopic heterogeneities and the engendered longitudinal dispersion in chromatographic practice. Wall effects in pillar arrays and the monolith caused by their confinement impact band broadening, which is traditionally observed on a macroscopic scale, more seriously than in the packings. PMID- 22921360 TI - Capillary electrophoresis as a tool for the characterization of pentosan nanoparticles. AB - Because capillary zone electrophoresis (CZE) showed higher resolution for highly charged large carbohydrates and complex structures when compared to other chromatographic separation methods, it was chosen for the characterization of nanoparticles (NPs) of pentosan polysulfate (PPS). Thus, using the CZE technique, we developed a reliable, sensitive and rapid protocol that allowed the detection and characterization of PPS NPs. This protocol was able to determine the profile of both the NPs and the species of PPS entrapped into them, and to quantify free and bound PPS showing high reproducibility, acceptable accuracy and a good degree of precision. Moreover, it allowed the evaluation of the size and charge of the NPs. This protocol might be suitable for the characterization of other kinds of NPs also. PMID- 22921361 TI - An approach based on ultra-high pressure liquid chromatography-tandem mass spectrometry to quantify O6-methyl and O6-carboxymethylguanine DNA adducts in intestinal cell lines. AB - O6-methylguanine (O6-MeG) and O6-carboxymethylguanine (O6-CMG) are characteristic promutagenic and toxic DNA adducts formed by nitrosated glycine derivates and N nitrosopeptides. Since endogenous nitrosation has been hypothesised as a plausible origin for the association between red and processed meat intake and colorectal cancer, a highly sensitive, fast and specific quantitative assay is needed to correlate the dose of individual DNA adducts with the effects of food consumption and individual digestive and metabolic processes. An ultra-high pressure liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) assay for quantitation of O6-MeG and O6-CMG, using the deuterated analogues as internal standards (ISTD), was developed. Samples of calf thymus DNA containing O6-MeG and O6-CMG were purified by acid hydrolysis and solid phase extraction prior to quantification by UHPLC-MS/MS in the selected reaction monitoring mode. The method was successfully validated in terms of repeatability (RSD<10%), reproducibility (RSD<15%) and linearity (99.9%) by incubating 0.1mg calf thymus DNA with the known N-nitroso compound potassium diazoacetate (KDA). The limit of quantitation was 30 fmol mg-1 DNA for O6-MeG or 1 adduct per 108 nucleotides and 50 fmol mg-1 DNA for O6-CMG or 1.7 adducts per 108 nucleotides. Subsequently, the method was applied to human colon carcinoma cell lines, Caco-2 and HT-29, treated with KDA to illustrate its capability to quantify O6-MeG and O6-CMG DNA adducts using biological relevant models in vitro. This method will support further research to unravel the mechanistic basis of endogenous nitrosation processes upon consumption of red and processed meat products. PMID- 22921362 TI - Chiral separations in reversed-phase liquid chromatography: evaluation of several polysaccharide-based chiral stationary phases for a separation strategy update. AB - By application of the reversed-phase generic screening conditions of a separation strategy defined in Matthijs et al. (2004) [18], the chiral discrimination abilities of six recently commercialized polysaccharide-based columns, Lux Cellulose-1, Lux Cellulose-2, Lux Cellulose-3, Lux Cellulose-4, Lux Amylose-2 and Sepapak-5, and of three classic ones, Chiralpak AD-RH, Chiralcel OD-RH and Chiralcel OJ-RH, were evaluated using a set of 58 compounds. Two mobile phases, an acidic and a basic, were sequentially applied on the columns. Using both mobile phases, a column set of Chiralcel OD-RH (or Lux Cellulose-1), Lux Cellulose-3 and Lux Amylose-2 gave the maximal number of cumulative separations, i.e. 51/58 (or 50), of which 35 (or 32) had baseline resolutions. Therefore, this set of systems was selected to update the screening step of the existing separation strategy. The selected columns were subsequently used to evaluate the applicability of the initial optimization steps, part of the existing RPLC strategy, using 66 different optimization cases. The existing optimization steps increased both the number of separations and of baseline separations by eight and by 18, respectively, relative to the screening results. Introduction of some modifications to the existing steps added eight more separations and three more baseline separations. In addition, a new optimization step for late eluting compounds was proposed and implemented. Based on these results, an updated chiral separation strategy in RPLC was defined. PMID- 22921363 TI - 3-methylcyclohexanone thiosemicarbazone: determination of E/Z isomerization barrier by dynamic high-performance liquid chromatography, configuration assignment and theoretical study of the mechanisms involved by the spontaneous, acid and base catalyzed processes. AB - Here, we report on the simultaneous direct HPLC diastereo- and enantioseparation of 3-methylcyclohexanone thiosemicarbazone (3-MCET) on a polysaccharide-based chiral stationary phase under normal-phase conditions. The optimized chromatographic system was employed in dynamic HPLC experiments (DHPLC), as well as detection technique in a batch wise approach to determine the rate constants and the corresponding free energy activation barriers of the spontaneous, base- and acid-promoted E/Z diastereomerization of 3-MCET. The stereochemical characterization of four stereoisomers of 3-MCET was fully accomplished by integrating the results obtained by chemical correlation method with those derived by theoretical calculations and experimental investigations of circular dichroism (CD). As a final goal, a deepened analysis of the perturbing effect exercised by the stationary phase on rate constant values measured through DHPLC determinations as a function of the chromatographic separation factor alpha of the interconverting species was successfully accomplished. This revealed quite small deviations from the equivalent kinetic values obtained by off-column batch wise procedure, and suggested a possible effective correction of rate constants measured by DHPLC approach. PMID- 22921364 TI - The origin of the plant body axis. AB - During embryogenesis, the basic body plan of an organism develops from a unicellular zygote. In most flowering plants, the polar zygote divides asymmetrically, making visible the apical-basal axis in the early embryo. The molecular mechanisms governing how the zygote polarizes and how this polarity is linked to embryo axis formation have been obscure, mainly owing to the difficulties to access the zygote that is deeply embedded in the maternal tissue. In this review, we summarize recent findings identifying key regulators in Arabidopsis and developing novel approaches in various plant species, which altogether set the stage for unraveling embryo axis formation. PMID- 22921365 TI - Determination of endothelial stalk versus tip cell potential during angiogenesis by H2.0-like homeobox-1. AB - Tissue branching morphogenesis requires the hierarchical organization of sprouting cells into leading "tip" and trailing "stalk" cells [1, 2]. During new blood vessel branching (angiogenesis), endothelial tip cells (TCs) lead sprouting vessels, extend filopodia, and migrate in response to gradients of the secreted ligand, vascular endothelial growth factor (Vegf) [3]. In contrast, adjacent stalk cells (SCs) trail TCs, generate the trunk of new vessels, and critically maintain connectivity with parental vessels. Here, we establish that h2.0-like homeobox-1 (Hlx1) determines SC potential, which is critical for angiogenesis during zebrafish development. By combining a novel pharmacological strategy for the manipulation of angiogenic cell behavior in vivo with transcriptomic analyses of sprouting cells, we identify the uniquely sprouting-associated gene, hlx1. Expression of hlx1 is almost entirely restricted to sprouting endothelial cells and is excluded from adjacent nonangiogenic cells. Furthermore, Hlx1 knockdown reveals its essential role in angiogenesis. Importantly, mosaic analyses uncover a cell-autonomous role for Hlx1 in the maintenance of SC identity in sprouting vessels. Hence, Hlx1-mediated maintenance of SC potential regulates angiogenesis, a finding that may have novel implications for sprouting morphogenesis of other tissues. PMID- 22921366 TI - Generalized perceptual learning in the absence of sensory adaptation. AB - Repeated performance of visual tasks leads to long-lasting increased sensitivity to the trained stimulus, a phenomenon termed perceptual learning. A ubiquitous property of visual learning is specificity: performance improvement obtained during training applies only for the trained stimulus features, which are thought to be encoded in sensory brain regions [1-3]. However, recent results show performance decrements with an increasing number of trials within a training session [4, 5]. This selective sensitivity reduction is thought to arise due to sensory adaptation [5, 6]. Here we show, using the standard texture discrimination task [7], that location specificity is a consequence of sensory adaptation; that is, it results from selective reduced sensitivity due to repeated stimulation. Observers practiced the texture task with the target presented at a fixed location within a background texture. To remove adaptation, we added task-irrelevant ("dummy") trials with the texture oriented 45 degrees relative to the target's orientation, known to counteract adaptation [8]. The results indicate location specificity with the standard paradigm, but complete generalization to a new location when adaptation is removed. We suggest that adaptation interferes with invariant pattern-discrimination learning by inducing network-dependent changes in local visual representations. PMID- 22921368 TI - Decision making during the psychological refractory period. AB - In spite of its massively parallel architecture [1], the human brain is fundamentally limited if required to perform two tasks at the same time [2, 3]. This limitation can be studied with the psychological refractory period (PRP) paradigm, where two stimuli that require speeded responses occur in close succession [4]. Interference generally takes the form of a delay in the time to respond to the second stimulus [5]. Previous studies suggested that sensory decisions require the accumulation of sensory evidence [6, 7] and that the PRP reflects the inability to form more than one decision at a time [4, 8]. In the present study, we used a psychophysical reverse-correlation technique [9, 10] to measure the time-course of evidence accumulation during the PRP. We found that the accumulation of evidence could occur during the PRP albeit with a reduced efficiency, which implies that multiple decision processes can occur in parallel in the human brain. In addition to the reduced efficiency of evidence accumulation, our results uncover an additional delay in the routing of the decision to motor structures during the PRP, which implies that the process of sensory decision making is separable from the preparation of a motor response [11 13]. PMID- 22921367 TI - Axon regrowth during development and regeneration following injury share molecular mechanisms. AB - BACKGROUND: The molecular mechanisms that determine axonal growth potential are poorly understood. Intrinsic growth potential decreases with age, and thus one strategy to identify molecular pathways controlling intrinsic growth potential is by studying developing young neurons. The programmed and stereotypic remodeling of Drosophila mushroom body (MB) neurons during metamorphosis offers a unique opportunity to uncover such mechanisms. Despite emerging insights into MB gamma neuron axon pruning, nothing is known about the ensuing axon re-extension. RESULTS: Using mosaic loss of function, we found that the nuclear receptor UNF (Nr2e3) is cell autonomously required for the re-extension of MB gamma-axons following pruning, but not for the initial growth or guidance of any MB neuron type. We found that UNF promotes this process of developmental axon regrowth via the TOR pathway as well as a late axon guidance program via an unknown mechanism. We have thus uncovered a novel developmental program of axon regrowth that is cell autonomously regulated by the UNF nuclear receptor and the TOR pathway. CONCLUSIONS: Our results suggest that UNF activates neuronal re-extension during development. Taken together, we show that axon growth during developmental remodeling is mechanistically distinct from initial axon outgrowth. Due to the involvement of the TOR pathway in axon regeneration following injury, our results also suggests that developmental regrowth shares common molecular mechanisms with regeneration following injury. PMID- 22921369 TI - Temperature field reconstruction for minimally invasive cryosurgery with application to wireless implantable temperature sensors and/or medical imaging. AB - There is an undisputed need for temperature-field reconstruction during minimally invasive cryosurgery. The current line of research focuses on developing miniature, wireless, implantable, temperature sensors to enable temperature-field reconstruction in real time. This project combines two parallel efforts: (i) to develop the hardware necessary for implantable sensors, and (ii) to develop mathematical techniques for temperature-field reconstruction in real time-the subject matter of the current study. In particular, this study proposes an approach for temperature-field reconstruction combining data obtained from medical imaging, cryoprobe-embedded sensors, and miniature, wireless, implantable sensors, the development of which is currently underway. This study discusses possible strategies for laying out implantable sensors and approaches for data integration. In particular, prostate cryosurgery is presented as a developmental model and a two-dimensional proof-of-concept is discussed. It is demonstrated that the lethal temperature can be predicted to a significant degree of certainty with implantable sensors and the technique proposed in the current study, a capability that is yet unavailable. PMID- 22921370 TI - AMP-activated kinase relaxes agonist induced contractions in the mouse aorta via effects on PKC signaling and inhibits NO-induced relaxation. AB - Adenosine monophosphate activated kinase (AMPK), a regulator of cellular metabolism, has been shown to relax arterial smooth muscle via endothelium dependent and independent mechanisms. We have examined the role of AMPK in different smooth muscles using the activating compound, 5-amino-4 imidazolecarboxamide riboside-1-beta-d-ribofuranoside (AICAR). Isolated preparations of mouse aorta, saphenous artery, ileum and urinary bladder were compared. AICAR produced a reversible dose-dependent relaxation in aortic rings pre-incubated with AICAR and activated with phenylephrine. Less prominent relaxation was noted in the other tissues. This difference in sensitivity to AICAR was not due to differences in the expression levels of AMPK alpha1 mRNA. In the aorta, AICAR had a greater effect on contractions induced by phenylephrine, compared to high-K(+) induced contractions. Contractions of the aorta in response to the protein kinase C activator PDBu were prominently inhibited by AICAR. The AICAR relaxation observed in the aorta was not prevented by the NOS inhibitor L NAME, Indomethacin or endothelium removal. Nitric oxide (NO) mediated relaxations in aortic preparations induced by acetylcholine or sodium nitroprusside (SNP) were attenuated by AICAR. In conclusion, AMPK induced relaxation of smooth muscle is tissue-dependent and most prominent in large elastic arteries. The smooth muscle relaxation is NO-independent and occurs downstream of PKC activation and is associated with attenuated relaxant responses to NO. PMID- 22921371 TI - Use of totally implantable vascular access port with mini-invasive Seldinger technique in 12 dogs undergoing chemotherapy. AB - Vascular access ports (VPAs) are totally implantable devices designed to provide repeated access to the vascular system. Port access is performed by percutaneous needle insertion using a noncoring needle. VAPs have been placed in 12 dogs affected by different tumors and needing long lasting chemotherapy. Using the non invasive Seldinger technique a silicone catheter was inserted from the jugular vein up to the junction of the cranial vena cava and the right atrium. The catheter then was connected to the port previously placed in a subcutaneous pocket over the scapula. 7/12 dogs showed no clinical complications. Port was removed in 4/12 dogs for post-operative complications as fistula formation (n.2) and infection/mal-position (n.2). One patient had mild complications shortly after implantation. VPAs were left in site until the death in the rest of patients. VAPs are useful for dogs undergoing long-lasting chemotherapy protocols as these devices allow peripheral veins to be spared and not seriously damaged for repeated infusion of vesicant drugs. In most cases VPAs are well tolerated and may be left in site for several months. PMID- 22921372 TI - Morbillivirus infection in cetaceans stranded along the Italian coastline: pathological, immunohistochemical and biomolecular findings. AB - Morbilliviruses are recognized as biological agents highly impacting the health and conservation status of free-ranging cetaceans worldwide, as clearly exemplified by the two Dolphin Morbillivirus (DMV) epidemics of 1990-1992 and 2006-2008 among Mediterranean striped dolphins (Stenella coeruleoalba). After these two epidemics, morbilliviral infection (MI) cases with peculiar neurobiological features were reported in striped dolphins stranded along the Spanish coastline. Affected cetaceans showed a subacute-to-chronic, non suppurative encephalitis, with brain lesions strongly resembling those found in human "subacute sclerosing panencephalitis" and "old dog encephalitis". Brain was the only tissue in which morbilliviral antigen and/or genome could be detected. Beside a case of morbilliviral encephalitis in a striped dolphin's calf stranded in 2009, we observed 5 additional MI cases in 2 striped dolphins, 1 bottlenose dolphin (Tursiops truncatus) and 2 fin whales (Balaenoptera physalus), all stranded in 2011 along the Italian coastline. Noteworthy, 3 of these animals (2 striped dolphins and 1 bottlenose dolphin) showed immunohistochemical (IHC) and/or biomolecular (PCR) evidence of morbilliviral antigen and/or genome exclusively in their brain, with 1 striped dolphin and 1 bottlenose dolphin also exhibiting a non-suppurative encephalitis. Furthermore, simultaneous IHC and PCR evidence of a Toxoplasma gondii coinfection was obtained in 1 fin whale. The above results are consistent with those reported in striped dolphins after the two MI epidemics of 1990-92 and 2006-2008, with evidence of morbilliviral antigen and/or genome being found exclusively in the brain tissue from affected animals. PMID- 22921373 TI - Transcranial magnetic stimulation of visual cortex in memory: cortical state, interference and reactivation of visual content in memory. AB - Memory for perceptual events includes the neural representation of the sensory information at short or longer time scales. Recent transcranial magnetic stimulation (TMS) studies of human visual cortex provided evidence that sensory cortex contributes to memory functions. In this review, we provide an exhaustive overview of these studies and ascertain how well the available evidence supports the idea of a causal role of sensory cortex in memory retention and retrieval. We discuss the validity and implications of the studies using a number of methodological and theoretical criteria that are relevant for brain stimulation of visual cortex. While most studies applied TMS to visual cortex to interfere with memory functions, a handful of pioneering studies used TMS to 'reactivate' memories in visual cortex. Interestingly, similar effects of TMS on memory were found in different memory tasks, which suggests that different memory systems share a neural mechanism of memory in visual cortex. At the same time, this neural mechanism likely interacts with higher order brain areas. Based on this overview and evaluation, we provide a first attempt to an integrative framework that describes how sensory processes contribute to memory in visual cortex, and how higher order areas contribute to this mechanism. PMID- 22921374 TI - Effect of dietary fish oil supplementation on the exploratory activity, emotional status and spatial memory of the aged mouse lemur, a non-human primate. AB - The data are inconsistent about the ability of dietary omega-3 fatty acids to prevent age-associated cognitive decline. Indeed, most clinical trials have failed to demonstrate a protective effect of omega-3 fatty acids against cognitive decline, and methodological issues are still under debate. In contrast to human studies, experiments performed in adult rodents clearly indicate that omega-3 fatty acids supplement can improve behavioural and cognitive functions. The inconsistent observations between human and rodent studies highlight the importance of the use of non-human primate models. The aim of the present study was to address the impact of omega-3 fatty acids (given in the form of dietary fish oil) on exploratory activity, emotional status and spatial reference memory in the aged mouse lemur, a non-human primate. Aged animals fed fish oil exhibited decreased exploratory activity, as manifested by an increase in the latency to move and a reduced distance travelled in an open-field. The fish oil-supplemented animals exhibited no change in the anxiety level, but they were more reactive to go into the dark arms of a light/dark plus-maze. In addition, we found that fish oil supplementation did not significantly improve the spatial memory performance in the Barnes maze task. This study demonstrated for the first time that a fish oil diet initiated late in life specifically modifies the exploratory behaviour without improving the spatial memory of aged non-human primates. Omega-3 fatty acid supplementation may be effective when started early in life but less effective when started at later ages. PMID- 22921375 TI - Psychosis risk screening in youth: a validation study of three self-report measures of attenuated psychosis symptoms. AB - Brief self-report questionnaires that assess attenuated psychosis symptoms have the potential to quickly and effectively screen many people who may benefit from clinical monitoring or early intervention. The current study sought to examine and compare the criterion validities of attenuated symptoms screening tools with diagnoses obtained from the clinician-administered Structured Interview for Psychosis Risk Syndromes (SIPS). Three screening questionnaires (Prime Screen, Prodromal Questionnaire-Brief, and Youth Psychosis At-Risk Questionnaire-Brief) were administered just prior to the SIPS interview in a sample of adolescents and young adults seeking mental health services. Using thresholds recommended by instrument authors as well as empirically derived optimal thresholds, the sensitivity, specificity, positive predictive value, and overall accuracy of each self-report measure with regard to SIPS diagnosis were obtained. Screeners correlated highly with the SIPS and demonstrated equivalent overall efficiency in capturing psychosis risk status. All three screeners appear to be useful and valid assessment tools for attenuated symptoms, with each instrument demonstrating relative benefits. The validation of attenuated symptoms screening tools is an important step toward enabling early, wide-reaching identification of individuals on a course toward psychotic illness. PMID- 22921376 TI - Dry coating of micronized API powders for improved dissolution of directly compacted tablets with high drug loading. AB - Motivated by our recent study showing improved flow and dissolution rate of the active pharmaceutical ingredient (API) powders (20 MUm) produced via simultaneous micronization and surface modification through continuous fluid energy milling (FEM) process, the performance of blends and direct compacted tablets with high drug loading is examined. Performance of 50 MUm API powders dry coated without micronization is also considered for comparison. Blends of micronized, non micronized, dry coated or uncoated API powders at 30, 60 and 70% drug loading, are examined. The results show that the blends containing dry coated API powders, even micronized ones, have excellent flowability and high bulk density compared to the blends containing uncoated API, which are required for direct compaction. As the drug loading increases, the difference between dry coated and uncoated blends is more pronounced, as seen in the proposed bulk density-FFC phase map. Dry coating led to improved tablet compactibility profiles, corresponding with the improvements in blend compressibility. The most significant advantage is in tablet dissolution where for all drug loadings, the t(80) for the tablets with dry coated APIs was well under 5 min, indicating that this approach can produce nearly instant release direct compacted tablets at high drug loadings. PMID- 22921377 TI - Higuchi's equation and beyond: overview of the formulation and application of a generalized model of drug release from polymeric matrices. AB - An account is presented of modeling and experimental work, which complements, in many useful ways, the excellent coverage, afforded by a recent dedicated issue edited by Siepmann and Peppas (Int. J. Pharm. 2011, 418(1)), of the theoretical background and many ramifications, as well as practical applications, of the Higuchi equation. The main notable feature of the said modeling work is formulation and successful practical application, of an ab initio generalized approach, based on solving the fundamental transport equations applicable to the operation of typical matrix-controlled release (MCR) devices. This approach (i) reduces to the Higuchi equation under the pertinent restrictive conditions but can duly handle most of its more complex ramifications and (ii) can be parameterized (by the use of appropriate data from the literature or from independent experiments) to adapt itself to the physics of the particular matrix solvent-solute system under consideration; as demonstrated here with examples from our laboratory or from the literature. A distinctive feature of the experimental work is the extensive use of simpler "model" MCR systems, chosen so as to promote better understanding of the effect of various physicochemical parameters and mechanisms on drug MCR rate and kinetics. A concept of MCR device efficiency is also discussed. PMID- 22921378 TI - Peer-supported review of teaching: making the grade in midwifery and nursing education. AB - This paper outlines the value of peer-supported review of teaching for nurse and midwifery educators in an academic environment. Reflection and continuing professional development are important tenets of an educators' practice and can be addressed via peer observation. Definitions and models of peer observation are presented. The strengths and challenges associated with peer-supported review of teaching are discussed. The reasons why peer observation is underutilised are explored with some suggestions on how to overcome these challenges. Recent developments in relation to peer observation and peer-supported review are outlined. The need for tangible evidence of development and enhancement of existing teaching expertise is very pronounced in the current economic climate, it is concluded that peer-supported review of teaching can provide such evidence. PMID- 22921380 TI - Ultrasound to perimortem caesarean delivery in prehospital settings. PMID- 22921379 TI - A broad range of self-reactivity drives thymic regulatory T cell selection to limit responses to self. AB - The degree of T cell self-reactivity considered dangerous by the immune system, thereby requiring thymic selection processes to prevent autoimmunity, is unknown. Here, we analyzed a panel of T cell receptors (TCRs) with a broad range of reactivity to ovalbumin (OVA(323-339)) in the rat insulin promoter (RIP)-mOVA self-antigen model for their ability to trigger thymic self-tolerance mechanisms. Thymic regulatory T (Treg) cell generation in vivo was directly correlated with in vitro TCR reactivity to OVA-peptide in a broad ~1,000-fold range. Interestingly, higher TCR affinity was associated with a larger Treg cell developmental "niche" size, even though the amount of antigen should remain constant. The TCR-reactivity threshold to elicit thymic negative selection and peripheral T cell responses was ~100-fold higher than that of Treg cell differentiation. Thus, these data suggest that the broad range of self-reactivity that elicits thymic Treg cell generation is tuned to secure peripheral tolerance to self. PMID- 22921381 TI - International comparison of regional trauma registries. AB - BACKGROUND: A regional trauma registry (RTR) collects injury data from multiple hospitals in a given region; however, the differences among RTRs have not yet been thoroughly investigated. AIM: The objective of this study was to identify RTRs worldwide and describe the structural differences, inclusion criteria and demographics among RTRs, as well as to investigate the effect of the inclusion criteria on patient demographics. MATERIALS AND METHODS: We included state, national and multinational trauma registries in this study. We searched for RTRs using the MEDLINE database and a general Internet search engine. We abstracted the funding sources, AIS versions, data submission methods, inclusion criteria and patient demographics of each RTR. We selected the following three outcome measures for comparison: the number of case registrations per year per hospital, proportion of cases with an Injury Severity Score (ISS)>15 and crude mortality rate. We compared the outcome measures for RTRs that included 'an ISS>15', 'an admission to the Intensive Care Unit (ICU)' or 'a transferred patient for higher care' with those of RTRs that did not. RESULTS: We identified 17 RTRs (11 national, 4 state and 2 multinational). Government funding was the most common funding source. The RTRs most frequently used the AIS 98 or AIS 2008. Web-based data submission was the most common. A significantly increased crude mortality rate was seen with 'an admission to the ICU' and 'an ISS>15'. CONCLUSION: We identified 17 RTRs, analysed the differences among RTRs and investigated the effect of the inclusion criteria on patient demographics. These findings may be useful when improving or developing RTRs. PMID- 22921382 TI - Locking plate and fibular allograft augmentation in unstable fractures of proximal humerus. AB - INTRODUCTION: The use of an intramedullary fibular allograft together with a locking plate fixation has been recently described in biomechanical studies to provide additional medial support and prevent varus malalignment for displaced proximal humeral fractures with promising results. The aim of this study was to evaluate the clinical and radiographic outcome of a locking plate with fibular allograft augmentation in unstable humeral fractures. METHODS: We prospectively assessed the functional outcome and complications in 17 patients with proximal humeral fractures with disrupted medial column, treated with a locking plate and a fibular strut graft. The median patient age was 62 years. Postoperative assessments included radiographic imaging, range of motion, pain according to the visual analogue scale (VAS), Short Form (SF36) Health Survey, Constant-Murley and Disabilities of the Arm, Shoulder and Hand (DASH) shoulder scores as well as return to previous occupation and complications. RESULTS: No patients were lost to follow-up and no major complications were recorded. There was no collapse of the humeral head more than 2mm, osteonecrosis or screw penetration of the articular surface. All fractures healed clinically and radiographically. After an average follow-up of 13 months, the mean Constant score was 79 points. The mean active flexion was 149 degrees ; extension, 47 degrees ; internal rotation, 40 degrees ; external rotation, 65 degrees ; and abduction, 135 degrees . The median VAS pain level was 1 point. The median DASH score was 33 points, and the median SF36 was 83 points. CONCLUSION: Locking plate with fibular graft augmentation is a safe and promising technique to support the humeral head and maintain reduction in the proximal humeral fracture with medial comminution. PMID- 22921383 TI - Applied anatomy of the calcaneocuboid articular surface for internal fixation of calcaneal fractures. AB - BACKGROUND: Many types of steel plates are used for internal fixation of calcaneal fractures through extensive lateral approach. The fixation screw at the anterior calcaneal process must be placed into the dense compression trabeculae located directly under the calcaneocuboid articular surface to achieve a stable fixation. METHODS: The transverse diameter and inner tilt angle of the calcaneocuboid articular surface were measured and the inner structures near the calcaneocuboid articular surface were observed in forty adult calcaneus bone specimens to provide an anatomical basis for internal fixation of calcaneal fractures. RESULTS: The transverse diameter was 22.67 +/- 2.14 mm and the inner tilt angle was 60.4 +/- 7.1 degrees . CONCLUSION: Screws should be implanted under the calcaneocuboid articular surface and the length and direction of the screw should be selected according to the transverse diameter of the calcaneal articular surface and the inner tilt angle, respectively. PMID- 22921384 TI - Endovascular management of axillo-subclavian arterial injury: a review of published experience. AB - BACKGROUND: The role of endovascular treatment for vascular trauma, including injury to the subclavian and axillary arteries, continues to evolve. Despite growing experience with the utilization of these techniques in the setting of artherosclerotic and aneurysmal disease, published reports in traumatic subclavian and axillary arterial injuries remain confined to sporadic case reports and case series. METHODS: We conducted a review of the medical literature from 1990 to 2012 using Pubmed and OVID Medline databases to search for all reports documenting the use of endovascular stenting for the treatment of subclavian or axillary artery injuries. Thirty-two published reports were identified. Individual manuscripts were analysed to abstract data regarding mechanism, location and type of injury, endovascular technique and endograft type utilized, follow-up, and radiographic and clinical outcomes. RESULTS: The use of endovascular stenting for the treatment of subclavian (150) or axillary (10) artery injuries was adequately described for only 160 patients from 1996 to the present. Endovascular treatment was employed after penetrating injury (56.3%; 29 GSW; 61 SW), blunt trauma (21.3%), iatrogenic catheter-related injury (21.8%) and surgical injury (0.6%). Injuries treated included pseudoaneurysm (77), AV fistula (27), occlusion (16), transection (8), perforation (22), dissection (6), or other injuries otherwise not fully described (4). Initial endovascular stent placement was successful in 96.9% of patients. Radiographic and clinical follow-up periods ranging from hospital discharge to 70 months revealed a follow-up patency of 84.4%. No mortalities related to endovascular intervention were reported. New neurologic deficits after the use of endovascular modalities were reported in only one patient. CONCLUSION: Endovascular treatment of traumatic subclavian and axillary artery injuries continues to evolve. Early results are promising, but experience with this modality and data on late follow-up remain limited. Additional multicenter prospective study and capture of data for these patients is warranted to further define the role of this treatment modality in the setting of trauma. PMID- 22921385 TI - Head injuries in children under 3 years. AB - BACKGROUND: A significant number of children under 3 years sustain a head injury every year. Despite this few studies have provided detailed information about these injuries. METHODS: A retrospective review of the medical files all children aged 0-3 years who attended a paediatric emergency department for treatment over a 2-year period. RESULTS: Children aged 0-6 months had the highest rate of moderate head injury. Children under 12 months were at the greatest risk of injury. Falls were the most common cause of injury including falls from caregiver's arms. CONCLUSIONS: Children under 12 months are at significant risk of head injury, many of these injuries could be prevented by increased parental supervision or improved home safety. PMID- 22921386 TI - Effectiveness of a short message reminder in increasing compliance with pediatric cataract treatment: a randomized trial. AB - OBJECTIVE: Regular follow-up is essential to successful management of childhood cataract. We sought to assess whether a mobile phone short message service (SMS) for parents of children with cataract could improve follow-up adherence and the proportion of procedures performed in timely fashion. DESIGN: Randomized, controlled trial. This trial is registered with ClinicalTrials.gov, NCT01417819. PARTICIPANTS: We included 258 parent-child pairs involved in the Childhood Cataract Program of the Chinese Ministry of Health. METHODS: Participants were randomized (1:1) to a mobile phone SMS intervention or standard follow-up appointments. All participants were scheduled to attend >= 4 follow-up appointments according to the protocol. Parents in the intervention group received SMS automated reminders before scheduled appointments. The control group parents did not receive SMSs or any alternative reminder of scheduled appointments. Regular ocular examinations and analyses were performed by investigators masked to group allocation; however, study participants and the manager in charge of randomization and sending SMSs were not masked. MAIN OUTCOME MEASURES: Number of follow-up appointments attended, additional surgeries, laser treatments, changes in eyeglasses prescription, and occurrence of secondary ocular hypertension. RESULTS: Among parent-child participants, 135 were randomly assigned to the SMS intervention and 123 to standard appointments. Attendance rates for the SMS group (first visit, 97.8%; second, 91.9%; third, 92.6%; fourth, 83%) were significantly higher than those for the control group (first visit, 87.8%; second, 69.9%; third, 56.9%; fourth, 33.3%). The increase in attendance rate for total number of follow-up visits with SMS reminders was 47.2% (relative risk [RR] for attendance, 1.47; 95% confidence interval [CI], 1.16-1.78; P = 0.003). The number needed to remind (NNR) to gain 1 additional visit by 1 child was 3 (95% CI, 1.8-4.2). A total of 247 clinical interventions were carried out in the SMS group and 134 in the control group (RR, 1.68; 95% CI, 1.37-1.99; P = 0.007). The NNR to result in 1 additional clinical intervention was 5 (95% CI, 3.5-6.5). CONCLUSIONS: The SMS reminders significantly improved follow-up adherence in pediatric cataract treatment. Using readily available mobile phone resources may be an effective and economic strategy to improve management of childhood cataract in China. FINANCIAL DISCLOSURE(S): The authors have no proprietary or commercial interest in any of the materials discussed in this article. PMID- 22921387 TI - Comparison of vitrectomy with brilliant blue G or indocyanine green on retinal microstructure and function of eyes with macular hole. AB - PURPOSE: To evaluate the microstructure of the inner and outer retina and the visual function after macular hole (MH) surgery using brilliant blue G (BBG) or indocyanine green (ICG) to make the internal limiting membrane (ILM) more visible. DESIGN: Comparative, retrospective, interventional case series. PARTICIPANTS: Sixty-three eyes of 63 consecutive cases with MH were studied. Thirty-five eyes of 35 cases were treated with BBG between January and August 2011. Twenty-eight eyes of 28 MH cases were treated with ICG from April 2009 through April 2010. METHODS: Vitrectomy was performed with a 23-gauge system and 0.25 mg/ml BBG or with 0.125% ICG. MAIN OUTCOME MEASURES: The best-corrected visual acuity (BCVA) and the microperimetry-determined retinal sensitivity were measured at baseline and at 3 and 6 months after surgery. The length of the defect of the photoreceptor inner segment/outer segment (IS/OS) junction and external limiting membrane (ELM), the central foveal thickness (CFT), and the thickness of the ganglion cell complex (GCC) were measured in the spectral-domain optical coherence tomographic images. RESULTS: The average BCVA was significantly better in the BBG group than in the ICG group at 3 months (P = 0.021) and 6 months (P = 0.045) after surgery. The mean retinal sensitivity in the BBG group was improved significantly in the central 2 degrees at 3 and 6 months (P = 0.001 and P = 0.030, respectively), but was not significantly improved in the adjacent 10 degrees . The length of IS/OS junction defect was significantly shorter in the BBG group at 3 months (P = 0.048), but was not significantly different at 6 months (P = 0.135). The length of ELM defect and the GCC thickness were not significantly different between the 2 groups at 3 and 6 months. The CFT was significantly thinner in the ICG group than in the BBG group at 3 and 6 months (P = 0.013 and P = 0.001, respectively). CONCLUSIONS: The postoperative BCVA and retinal sensitivity in the central 2 degrees were better in eyes after BBG assisted vitrectomy. The restoration of IS/OS junction was faster in the BBG group, and the CFT was significantly thinner in eyes after ICG. Brilliant blue G may be a better agent than ICG to make the ILM more visible. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article. PMID- 22921388 TI - Choroidal volume variations with age, axial length, and sex in healthy subjects: a three-dimensional analysis. AB - PURPOSE: To demonstrate the 3-dimensional choroidal volume distribution in healthy subjects using enhanced depth imaging (EDI) spectral-domain optical coherence tomography (SD-OCT) and to evaluate its association with age, sex, and axial length. DESIGN: Retrospective case series. PARTICIPANTS: A total of 176 eyes from 114 subjects with no retinal or choroidal disease. METHODS: The EDI SD OCT imaging studies of healthy patients who had undergone a 31-raster scanning protocol on a commercial SD-OCT device were reviewed. Manual segmentation of the choroid was performed by 2 retinal specialists. A macular choroidal volume map and 3-dimensional topography were automatically created by the built-in software of the device. Mean choroidal volume was calculated for each Early Treatment Diabetic Retinopathy Study (ETDRS) subfield. Regression analyses were used to evaluate the correlation between macular choroidal volume and age, sex, and axial length. MAIN OUTCOME MEASURES: Three-dimensional topography and ETDRS-style volume map of the choroid. RESULTS: Three-dimensional topography of the choroid and volume map was obtained in all cases. The mean choroidal volume was 0.228 +/- 0.077 mm(3) for the center ring and 7.374 +/- 2.181 mm(3) for the total ETDRS grid. The nasal quadrant showed the lowest choroidal volume, and the superior quadrant showed the highest choroidal volume. The temporal and inferior quadrants did not show different choroidal volume values. Choroidal volume in all the EDTRS rings was significantly correlated with axial length after adjustment for age (P < 0.0001), age after adjustment for axial length (P < 0.0001), and sex after adjustment for axial length (P < 0.05). Choroidal volume decreases by 0.54 mm(3) (7.32%) for every decade and by 0.56 mm(3) (7.59%) for every millimeter of axial length. Male subjects have a 7.37% greater choroidal volume compared with that of female subjects. CONCLUSIONS: Enhanced depth imaging SD-OCT is a noninvasive and well-tolerated procedure with an excellent ability to visualize 3-dimensional topography of the choroid and to measure choroidal volume at the posterior pole using manual segmentation. Age and axial length are inversely correlated with choroidal volume, most likely leading to changes in retinal metabolic support in elderly, highly myopic patients. Sexual differences should be considered when interpreting an EDI SD-OCT scan of the choroid. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article. PMID- 22921389 TI - Five-year incidence of age-related macular degeneration: the Beijing Eye Study. AB - PURPOSE: To examine the incidence of age-related macular degeneration (AMD) and its associated factors in an adult Chinese population. DESIGN: Population-based study. PARTICIPANTS: The Beijing Eye Study, which included 4439 subjects (age >= 40 years) in 2001, was repeated in 2006 with 3251 (73.2%) subjects participating. METHODS: Fundus photographs were graded using the International Age-related Maculopathy Epidemiological Study Group grading system. MAIN OUTCOME MEASURES: Incidence of AMD. RESULTS: Gradable slides were available on 3049 (93.9%) subjects who participated in the survey of 2001 and again in 2006. The incidence of early, late, and neovascular AMD per eye was 2.6% (95% confidence interval [CI], 2.2-3.0), 0.1% (95% CI, 0.00-0.2), and 0.1% (95% CI, 0.00-0.2), respectively. The incidence of early, late, and neovascular AMD per person was 4.2 +/- 0.4% (95% CI, 3.5-5.0), 0.1 +/- 0.1% (95% CI, 0.0-0.2), and 0.1 +/- 0.1% (95% CI, 0.0-0.2), respectively. By multivariate analysis, incident early AMD was associated significantly with greater age at baseline (P = 0.01; odds ratio [OR], 1.03; 95% CI, 1.01-1.06), smaller optic disc size (P = 0.007; OR, 0.50; 95% CI, 0.30-0.83), smaller scleral spur distance (P = 0.04; OR, 0.59; 95% CI, 0.36 0.98), and hyperopic refractive error (P = 0.057; OR, 1.15; 95% CI, 1.00-1.33), with the latter being significant only marginally. It was not associated with the systemic parameters of gender, body height, body mass index, region of habitation, level of education, profession, smoking, arterial blood pressure, diabetes mellitus, fasting blood concentrations of glucose, triglycerides, high density or low-density lipoproteins; or the ocular parameters of intraocular pressure, retinal arterial and vein diameters, retinal microvascular abnormalities, amount of nuclear cataract, cortical cataract or subcapsular cataract, pseudophakia, glaucoma, nonglaucomatous optic neuropathy, retinal vein occlusions, size of the beta zone of parapapillary atrophy, or progression of the zone of atrophy during the follow-up from 2001 to 2006. CONCLUSIONS: Hyperopia, short interscleral spur distance, and small optic disc size were, beside older age, the main factors associated with incident early AMD. This may point to a small globe size, potentially in relation to a firmly attached vitreous, playing a role in early incident AMD. FINANCIAL DISCLOSURE(S): The authors have no proprietary or commercial interest in any of the materials discussed in this article. PMID- 22921390 TI - Novel needle-in-straw vitrification can effectively preserve the follicle morphology, viability, and vascularization of ovarian tissue in Japanese quail (Coturnix japonica). AB - Cryopreservation of ovarian tissue has been the only effective way of ex situ conservation of female germplasm in avian species. A novel needle-in-straw (NIS) vitrification method was developed to store tissue in straws instead of cryovials. Fragments of ovarian tissue from one-week old Japanese quail were transfixed on an acupuncture needle. They were immersed in equilibration and vitrification solutions containing dimethyl sulphoxide, ethylene glycol and sucrose. A layer of tin foil was rolled over the tissue fragments and the tin foil package was plunged into liquid nitrogen and inserted into a pre-cooled, 0.5 ml straw which was stored in liquid nitrogen. Tissue was also preserved using a needle immersed vitrification (NIV) method, in which tissue fragments transfixed on needles without tin foil and were stored in cryovials filled with liquid nitrogen. Cryopreserved tissue was warmed at room temperature (RT) or 37 degrees C and the ratio of normal follicles to total visible follicles was determined by histological methods. In addition, cryopreserved and warmed tissue was cultured on the chorioallantoic membranes of fertilized chicken eggs for 5-6 days. The viability and vascularization of the grafts were evaluated. The tissue cryopreserved by NIS and warmed at RT showed comparable follicle morphology to fresh tissue and to that preserved by NIV and warmed at RT. No significant impairment on the viability or vascularization of the grafted tissue was observed. The NIS method allows tissue to be stored and transported safely and efficiently and can be used instead of cryovials in tissue cryobanking. PMID- 22921391 TI - Reactions between bacterial exopolymers and goethite: A combined macroscopic and spectroscopic investigation. AB - The adsorption to goethite of extracellular polymeric substances (EPS) isolated from Pseudomonas putida was investigated using batch adsorption experiments, electrophoretic mobility (EM) measurements, Fourier transform infrared (FTIR) spectroscopy, isothermal titration calorimetry (ITC) and X-ray absorption fine structure (XAFS) spectroscopy. The adsorption of EPS decreased the point of zero charge of goethite from 7.6 to 3.2, suggesting the formation of negatively charged inner-sphere surface complexes. The adsorption isotherms of EPS on goethite conformed to the Langmuir equation. The adsorption energy constant (K) of EPS on goethite was in the sequence of EPS phosphate-containing moieties > nitrogen-containing moieties > carbon-containing moieties, indicating those containing phosphate were the most strongly adsorbed. FTIR showed ligand exchange of phosphate groups of EPS with surface hydroxyls on goethite. Extended X-ray absorption fine structure (EXAFS) and X-ray absorption near edge structure (XANES) spectroscopy results further demonstrated phosphate groups of EPS can form monodentate inner-sphere complexes at lower pH 3.0, while form bidentate inner-sphere complexes at higher pH 9.0. The oxidation state of iron in goethite was not changed after the reaction with EPS at different pH values. The information obtained in this study is of fundamental significance for the understanding of the interaction mechanisms between bacteria and minerals in soil and aquatic environments. PMID- 22921392 TI - Mechanism of phenol photodegradation in the presence of pure and modified-TiO2: A review. AB - In recent years, the application of heterogeneous photocatalytic water purification processes has gained wide attention due to its effectiveness in degrading and mineralizing the recalcitrant organic compounds as well as the possibility of utilizing the solar UV and visible-light spectrum. By far, titania has played a much larger role in this scenario compared to other semiconductor photocatalysts due to its costly effectiveness, inert nature and photostability. A substantial amount of research has focused on the enhancement of TiO(2) photocatalysis by modification with metal, non-metal and ion doping. This paper aims to review and summarize the recent works on the titanium dioxide (TiO(2)) photocatalytic oxidation of phenol and discusses various mechanisms of phenol photodegradation (indicating the intermediates products) and formation of OH radicals. Phenol degradation pathway in both systems, TiO(2)/UV and doped TiO(2)/Vis, are described. PMID- 22921393 TI - Competition between kaolinite flocculation and stabilization in divalent cation solutions dosed with anionic polyacrylamides. AB - Divalent cations have been reported to develop bridges between anionic polyelectrolytes and negatively-charged colloidal particles, thereby enhancing particle flocculation. However, results from this study of kaolinite suspensions dosed with various anionic polyacrylamides (PAMs) reveal that Ca(2+) and Mg(2+) can lead to colloid stabilization under some conditions. To explain the opposite but coexisting processes of flocculation and stabilization with divalent cations, a conceptual flocculation model with (1) particle-binding divalent cationic bridges between PAM molecules and kaolinite particles and (2) polymer-binding divalent cationic bridges between PAM molecules is proposed. The particle-binding bridges enhanced flocculation and aggregated kaolinite particles in large, easily settleable flocs whereas the polymer-binding bridges increased steric stabilization by developing polymer layers covering the kaolinite surface. Both the particle-binding and polymer-binding divalent cationic bridges coexist in anionic PAM- and kaolinite-containing suspensions and thus induce the counteracting processes of particle flocculation and stabilization. Therefore, anionic polyelectrolytes in divalent cation-enriched aqueous solutions can sometimes lead to the stabilization of colloidal particles due to the polymer binding divalent cationic bridges. PMID- 22921394 TI - Determination of copper speciation in highway stormwater runoff using competitive ligand exchange - Adsorptive cathodic stripping voltammetry. AB - Low concentrations of dissolved copper have been shown to adversely affect the olfactory system of salmonid species, impairing their ability to avoid predators and likely increasing mortality. These studies have resulted in increased regulatory scrutiny of stormwater discharges to surface waters inhabited by threatened and endangered salmonid species. Because it is primarily the free ionic (Cu(2+)) and weakly complexed forms of copper that are bioavailable, it is critical to understand the speciation of copper in stormwater. This paper reports on the characterization of copper binding ligands and copper speciation in composite samples of highway stormwater runoff collected at four sites in Oregon, USA using competitive ligand exchange - adsorptive cathodic stripping voltammetry (CLE-ACSV). Although the concentration and strength of copper binding ligands in stormwater varied considerable between sites and storms, the vast majority (>99.9%) of the total dissolved copper in composite samples was complexed by organic ligands in stormwater. Although total dissolved copper concentrations range from 2 to 20 MUg/L, the analytically determined free ionic copper concentrations did not exceed 10(-10) M (6.3 ng/L) in any of the fully characterized samples, suggesting that much of the copper in highway stormwater is not bioavailable. Analytically determined free ionic copper concentrations were compared with those predicted by a readily available chemical equilibrium models and found to be in reasonable agreement. PMID- 22921395 TI - Comparative study of simultaneous removal of As, Cu, and Pb using different combinations of electrokinetics with bioleaching by Acidithiobacillus ferrooxidans. AB - Different designs of electrokinetics were applied to simultaneously remove arsenic, copper, and lead from contaminated soils. Single electrokinetics (control) resulted in superior removal efficiencies for Cu (73.5%) and Pb (88.5%), though the removal of As (3.11%) was relatively little. Sequential bioelectrokinetics of bioleaching with Acidithiobacillus ferrooxidans and electrokinetics enhanced the removal of As (25%), while Pb exhibited a significant decrease in removal efficiency (10.6%), due to the formation of insoluble compounds. In order to improve the overall performance, integrated bioelectrokinetics was designed by inoculating A. ferrooxidans into the electrolyte after 5 or 15 days of electrokinetics. Lead (75.8%) and copper (72%) were effectively removed through electrokinetics, after which arsenic (35%) was more efficiently removed by bioleaching-enhanced electrokinetics. A pilot-scale experiment indicated that integrated bioelectrokinetics is an effective means of remediation of soils contaminated with multiple heavy metals and arsenic. PMID- 22921396 TI - Further examination of polysaccharides causing membrane fouling in membrane bioreactors (MBRs): Application of lectin affinity chromatography and MALDI TOF/MS. AB - Membrane fouling remains a major obstacle for wider application of membrane bioreactors (MBRs) to wastewater treatment. Polysaccharides in mixed liquor suspensions in the reactors are thought to be mainly responsible for the evolution of membrane fouling in MBRs. However, details of polysaccharides causing membrane fouling in MBRs are still unknown. In this study, polysaccharides in a mixed liquor suspension of a pilot-scale MBR treating municipal wastewater were fractionated by using lectins, special proteins that bind to specific polysaccharides depending on their properties. Fouling potentials of the fractionated polysaccharides were assessed by bench-scale dead end filtration tests. It was clearly shown that the degrees of fouling caused by fractionated polysaccharides were significantly different. The amounts of polysaccharides in each fraction could not explain the variations in the fouling, indicating the presence of polysaccharides with high specific fouling potentials. To investigate structures and origins of the polysaccharides with high fouling potentials, matrix-assisted laser desorption/ionization (MALDI)-time of flight (TOF)/mass spectrometry (MS) analysis was applied to the fractionated polysaccharides after partial hydrolysis. Several mass peaks obtained could be assigned to fragments of structures of polysaccharides (i.e., oligosaccharides) reported in a database/literature. This is the first report showing the plausible structures of polysaccharides in MBRs based on MS. A deeper understanding and effective control of membrane fouling in MBRs could be achieved with information obtained by the approach used in this study. PMID- 22921397 TI - Determination of rate constants and half-lives for the simultaneous biodegradation of several cyanobacterial metabolites in Australian source waters. AB - The fate of five cyanobacterial metabolites was assessed in water sourced from Lake Burragorang (Warragamba Dam) in New South Wales, Australia. All of the studied metabolites were shown to be biodegradable in this water source. For some metabolites, biodegradation was influenced by factors, including temperature, location (within the water body) and seasonal variations. The biodegradation of the metabolites was shown to follow pseudo-first-order kinetics with rate constants ranging from 8.0 * 10(-4) to 1.3 * 10(-2) h(-1). Half-lives of the metabolites were also estimated and ranged from 2.2 to 36.1 d. The order of ease of biodegradability in this water source followed the trend: microcystin-LR >= cylindrospermopsin > saxitoxins > geosmin >= 2-methylisoborneol. The lack of detection of the mlrA gene during microcystin biodegradation suggests that these toxins may be degraded via a different pathway. While no metabolite-degrading organisms were isolated in this study, the inoculation of previously isolated geosmin- and microcystin-degrading bacteria into Lake Burragorang water resulted in efficient biodegradation of the respective metabolites. For example, microcystin-degrading isolate TT25 was able to degrade three microcystin variants to concentrations below analytical detection within 24 h, suggesting that inoculation of such bacteria has the potential to enhance biodegradation in Lake Burragorang. PMID- 22921398 TI - Targeting glioma stem cells by functional inhibition of a prosurvival oncomiR-138 in malignant gliomas. AB - Malignant gliomas are the most aggressive forms of brain tumors, associated with high rates of morbidity and mortality. Recurrence and tumorigenesis are attributed to a subpopulation of tumor-initiating glioma stem cells (GSCs) that are intrinsically resistant to therapy. Initiation and progression of gliomas have been linked to alterations in microRNA expression. Here, we report the identification of microRNA-138 (miR-138) as a molecular signature of GSCs and demonstrate a vital role for miR-138 in promoting growth and survival of bona fide tumor-initiating cells with self-renewal potential. Sequence-specific functional inhibition of miR-138 prevents tumorsphere formation in vitro and impedes tumorigenesis in vivo. We delineate the components of the miR-138 regulatory network by loss-of-function analysis to identify specific regulators of apoptosis. Finally, the higher expression of miR-138 in GSCs compared to non neoplastic tissue and association with tumor recurrence and survival highlights the clinical significance of miR-138 as a prognostic biomarker and a therapeutic target for treatment of malignant gliomas. PMID- 22921399 TI - Direct differentiation of human pluripotent stem cells into haploid spermatogenic cells. AB - Human embryonic stem cells (hESCs) and induced pluripotent stem cells (hiPSCs) have been shown to differentiate into primordial germ cells (PGCs) but not into spermatogonia, haploid spermatocytes, or spermatids. Here, we show that hESCs and hiPSCs differentiate directly into advanced male germ cell lineages, including postmeiotic, spermatid-like cells, in vitro without genetic manipulation. Furthermore, our procedure mirrors spermatogenesis in vivo by differentiating PSCs into UTF1-, PLZF-, and CDH1-positive spermatogonia-like cells; HIWI- and HILI-positive spermatocyte-like cells; and haploid cells expressing acrosin, transition protein 1, and protamine 1 (proteins that are uniquely found in spermatids and/or sperm). These spermatids show uniparental genomic imprints similar to those of human sperm on two loci: H19 and IGF2. These results demonstrate that male PSCs have the ability to differentiate directly into advanced germ cell lineages and may represent a novel strategy for studying spermatogenesis in vitro. PMID- 22921400 TI - Identification of cytoplasmic capping targets reveals a role for cap homeostasis in translation and mRNA stability. AB - The notion that decapping leads irreversibly to messenger RNA (mRNA) decay was contradicted by the identification of capped transcripts missing portions of their 5' ends and a cytoplasmic complex that can restore the cap on uncapped mRNAs. In this study, we used accumulation of uncapped transcripts in cells inhibited for cytoplasmic capping to identify the targets of this pathway. Inhibition of cytoplasmic capping results in the destabilization of some transcripts and the redistribution of others from polysomes to nontranslating messenger ribonucleoproteins, where they accumulate in an uncapped state. Only a portion of the mRNA transcriptome is affected by cytoplasmic capping, and its targets encode proteins involved in nucleotide binding, RNA and protein localization, and the mitotic cell cycle. The 3' untranslated regions of recapping targets are enriched for AU-rich elements and microRNA binding sites, both of which function in cap-dependent mRNA silencing. These findings identify a cyclical process of decapping and recapping that we term cap homeostasis. PMID- 22921402 TI - Role of S5b/PSMD5 in proteasome inhibition caused by TNF-alpha/NFkappaB in higher eukaryotes. AB - The ubiquitin-proteasome system is essential for maintaining protein homeostasis. However, proteasome dysregulation in chronic diseases is poorly understood. Through genome-wide cell-based screening using 5,500 cDNAs, a signaling pathway leading to NFkappaB activation was selected as an inhibitor of 26S proteasome. TNF-alpha increased S5b (HGNC symbol PSMD5; hereafter S5b/PSMD5) expression via NFkappaB, and the surplus S5b/PSMD5 directly inhibited 26S proteasome assembly and activity. Downregulation of S5b/PSMD5 abolished TNF-alpha-induced proteasome inhibition. TNF-alpha enhanced the interaction of S5b/PSMD5 with S7/PSMC2 in nonproteasome complexes, and interference of this interaction rescued TNF-alpha induced proteasome inhibition. Transgenic mice expressing S5b/PSMD5 exhibited a reduced life span and premature onset of aging-related phenotypes, including reduced proteasome activity in their tissues. Conversely, S5b/PSMD5 deficiency in Drosophila melanogaster ameliorated the tau rough eye phenotype, enhanced proteasome activity, and extended the life span of tau flies. These results reveal the critical role of S5b/PSMD5 in negative regulation of proteasome by TNF alpha/NFkappaB and provide insights into proteasome inhibition in human disease. PMID- 22921401 TI - Inflammatory signals enhance piezo2-mediated mechanosensitive currents. AB - Heightened nociceptor function caused by inflammatory mediators such as bradykinin (BK) contributes to increased pain sensitivity (hyperalgesia) to noxious mechanical and thermal stimuli. Although it is known that sensitization of the heat transducer TRPV1 largely subserves thermal hyperalgesia, the cellular mechanisms underlying mechanical hyperalgesia have been elusive. The role of the mechanically activated (MA) channel piezo2 (known as FAM38B) present in mammalian sensory neurons is unknown. We test the hypothesis that piezo2 activity is enhanced by BK, an algogenic peptide that induces mechanical hyperalgesia within minutes. Piezo2 current amplitude is increased and inactivation is slowed by bradykinin receptor beta 2 (BDKRB2) activation in heterologous expression systems. Protein kinase A (PKA) and protein kinase C (PKC) agonists enhance piezo2 activity. BDKRB2-mediated effects are abolished by PKA and PKC inhibitors. Finally, piezo2-dependent MA currents in a class of native sensory neurons are enhanced 8-fold by BK via PKA and PKC. Thus, piezo2 sensitization may contribute to PKA- and PKC-mediated mechanical hyperalgesia. PMID- 22921403 TI - Terminal, but not concurrent prism exposure produces perceptual aftereffects in healthy young adults. AB - A short period of prism adaptation (PA) has been shown to reduce spatial neglect symptoms. Recent evidence suggests that the positive effects of PA might be restricted to visually guided actions, with PA having little effect on perception. However, the majority of studies have adopted a concurrent exposure technique that fosters the development of a change in felt arm position (proprioceptive straight ahead, PSA). Few studies have used terminal exposure that promotes a change in the perceived visual direction (visual straight ahead, VSA). The positive effects of PA might appear to be primarily action based because studies have adopted an exposure technique that promotes a change in proprioception. Here, we compare the effects of the two exposure types on a perceptual and a manual line bisection task in healthy young adults. Before and after seven minutes of exposure to leftward displacing prisms we measured performance on two line bisection tasks (manual and perceptual) and perceived straight ahead (PSA and VSA). During the exposure period participants made pointing movements while the view of their pointing arm was either (i) restricted to the second half of the pointing movement (concurrent exposure) or (ii) restricted to the final part of the pointing movement (terminal exposure). In line with the previous research, concurrent exposure produced a large shift in PSA and a shift on the manual line bisection task. Interestingly, terminal exposure produced a large shift in VSA and a shift in performance on the perceptual line bisection task. Our results shed light on the underlying mechanisms of prism-induced neglect recovery and help to address an apparent discrepancy within the literature. PMID- 22921404 TI - Donors with a history of cocaine use and lung transplant outcomes. PMID- 22921405 TI - Protective effect of pre-recovery surfactant inhalation on lungs donated after cardiac death in a canine lung transplantation model. AB - BACKGROUND: Warm ischemia-reperfusion injury related to donation after cardiac death is a crucial issue in transplantation. Because surfactant function deteriorates in lungs during warm ischemia, we hypothesized pre-recovery surfactant inhalation would mitigate warm ischemia-reperfusion injury. METHODS: We rendered donor dogs cardiac dead and left them at room temperature. All animals received ventilation for 60 minutes starting at 240 minutes after cardiac arrest. The animals were divided into 2 groups: NS (normal saline, n = 7) group, which received aerosolized normal saline, and SF (surfactant; n = 5), which received aerosolized surfactant. The lungs were flushed and procured, and the left lung was transplanted into recipient dogs. At 45 minutes of reperfusion, the right pulmonary artery was ligated, and the left transplanted lung function was evaluated. RESULTS: In the NS group, 2 of 7 dogs died at 75 minutes after reperfusion, whereas all 5 animals in the SF group survived for 240 minutes after reperfusion. The SF group showed significantly better dynamic compliance, oxygenation, and wet-to-dry weight ratio. Furthermore, the SF group had higher levels of high-energy phosphates in the lung tissues and lower levels of interleukin-8, tumor necrosis factor-alpha, and protein in the bronchoalveolar lavage fluid. Histologically, the lungs in the SF group showed fewer signs of interstitial edema and hemorrhage and significantly less neutrophilic sequestration than those of the NS group. CONCLUSIONS: Our results indicated pre recovery surfactant inhalation improved graft function, maintained adenine nucleotide levels, and prevented alveolar-capillary barrier leakage, resulting in the attenuation of warm ischemia-reperfusion injury. PMID- 22921407 TI - Micelles of polybutadiene-b-poly(ethylene oxide) in deuterated methanol and deuterated cyclohexane. AB - Micellization of the diblock copolymer poly(ethylene oxide)-b-polybutadiene, PEO(132)-PB(89), where the subscripts denote the number of monomers in each block, has been studied in solution in deuterated methanol and in deuterated cyclohexane, in order to compare the micellar assembly in deuterated solvents to that in protonated solvents. The methods used were dynamic light scattering and small angle neutron scattering. In CD(3)OD, PEO(132)-PB(89) forms only spherical micelles that change little in size or shape over the temperature range 21-68 degrees C. In CH(3)OH, PEO(132)-PB(89) forms coexisting cylindrical and spherical structures over the entire temperature range. Thus cylindrical micelles form in CH(3)OH, but do not form in CD(3)OD. In C(6)D(12), the copolymer forms flexible, cylindrical micelles at lower temperatures; above about 40 degrees C, spherical micelles and free copolymers appear and coexist with the cylindrical micelles. The behavior in C(6)H(12) is the same as in C(6)D(12), except that no free copolymers are observed in C(6)H(12). The stronger hydrogen bonding in deuterated methanol as compared to protonated methanol is assumed to be the source of the difference in assembly. PMID- 22921406 TI - Fluorescent probes for sensing and imaging biological hydrogen sulfide. AB - Hydrogen sulfide (H(2)S) has long been recognized as a toxic molecule in biological systems. However, emerging studies now link controlled fluxes of this reactive sulfur species to cellular regulation and signaling events akin to other small molecule messengers, such as nitric oxide, hydrogen peroxide, and carbon monoxide. Progress in the development of fluorescent small-molecule indicators with high selectivity for hydrogen sulfide offers a promising approach for studying its production, trafficking, and downstream physiological and/or pathological effects. PMID- 22921408 TI - Hematite nanoparticle monolayers on mica electrokinetic characteristics. AB - Electrokinetic properties of alpha-Fe(2)O(3) (hematite) nanoparticle monolayers on mica were thoroughly characterized using the streaming potential method. Hematite suspensions were obtained by acidic hydrolysis of ferric chloride. The average size of particles (hydrodynamic diameter), determined by dynamic light scattering (DLS) and AFM, was 22 nm (pH=5.5, I=10(-2)M). The hematite monolayers on mica were produced under diffusion-controlled transport from the suspensions of various bulk concentration. The monolayer coverage, quantitatively determined by AFM and SEM, was regulated within broad limits by adjusting the nanoparticle deposition time. This allowed one to uniquely express zeta potential of hematite monolayers, determined by the streaming potential measurements, in terms of the particle coverage. Such dependencies, obtained for various pH, were successfully interpreted in terms of the three-dimensional electrokinetic model. A universal calibrating graph was produced enabling one to determine hematite monolayer coverage from the measured value of the streaming potential. The influence of the ionic strength, varied between 10(-4) and 10(-2)M, on the zeta potential of hematite monolayers was also studied. Additionally, the stability of monolayers (desorption kinetics) was determined under in situ conditions using the streaming potential method. Our experimental data prove that it is feasible to produce uniform and stable hematite particle monolayers of well-controlled coverage. Such monolayers may find practical applications as universal substrates for protein immobilization (biosensors) and in electrocatalytic applications. PMID- 22921409 TI - Anomalous dependence of particle size on supersaturation in the preparation of iron nanoparticles from iron pentacarbonyl. AB - Iron nanoparticles were prepared by decomposing iron pentacarbonyl (Fe(CO)(5)) at 170-220 degrees C in the presence of amine surfactant and alkane solvent and under 1-12 bar carbon monoxide (CO) pressure. It was found that the amine not only acted as a stabilizer for the growing particles but also had a critical role as a promotor in the decomposition reaction. Relatively small changes in the CO pressure had anomalous effects on the particle size distribution. Typically, monodisperse particles were obtained at 1 bar, while pressures in the 2-6 bar range led to wider and even bimodal size distributions due to an emergence of smaller particles. At still higher pressures, the larger particle size disappeared leaving the distribution monodisperse again. The CO pressure, at which the bimodal transition took place, increased with the reaction temperature. Polycrystalline particles were formed at lower pressures and monocrystalline particles at higher pressures. This indicates that increased CO pressure inhibits aggregation. PMID- 22921410 TI - A displacement principle for mercury detection by optical waveguide and surface enhanced Raman spectroscopy. AB - A novel displacement principle of metal nanoparticles for target analysis, differing from the usual target-induced aggregation principle, was proved feasible by the use of para-aminothiophenol coupled Au nanoparticles (PATP-Au) multilayer as probes to detect Hg(2+). The PATP-Au multilayer was fabricated through layer-by-layer assembly of Au nanoparticles on optical waveguide (OWG) chip surface using para-aminothiophenol (PATP) as coupling molecules. The localized surface plasmon resonance (LSPR) extinction from Au nanoparticles and the PATP as a Raman reporter enable to easily capture changes in PATP-Au multilayer by OWG and of surface enhanced Raman spectroscopy, respectively. The introduction of the Hg(2+), which has a higher binding affinity to the thiol group of PATP, greatly destroyed the multilayer structure, and produced a large change, several folds higher than the noise, in LSPR features and Raman signals of PATP-Au multilayer probes, and resulted in an excellent selectivity for Hg(2+) detection at a low level of 1 nM. This investigation provides us more ideas on the future development of surface analysis techniques for the detection of various target analytes. PMID- 22921411 TI - Egfr signaling regulates distal as well as medial fate in the embryonic leg of Tribolium castaneum. AB - The evolution of a mechanism to generate a proximal-distal axis perpendicular to the anterior-posterior body axis was a key event in arthropod evolution and facilitated the formation of multi-functional limbs. The study of proximodistal limb patterning in extant arthropods can provide insight into the origin and evolution of the proximal-distal axis. In Drosophila melanogaster, proximal distal patterning is mainly organized by Wg/Dpp signaling. Egfr signaling is also involved, but is restricted to late stages and distal leg parts (tarsus and pretarsus). Here we study the role of Epidermal growth factor receptor (Egfr), spitz (spi), and pointed (pnt) in leg development in the beetle Tribolium castaneum. We show that Egfr signaling has a more complex role in T. castaneum than in D. melanogaster and is not only required in the distal leg, but is also involved in formation of the medial leg (including femur and tibia). Egfr and spi are required for the regulation of clawless (cll), Distal-less (Dll) and dachshund (dac), and RNAi leads to thickened and fused leg segments. Intriguingly, regulation of Dll and dac by Egfr signaling appears functionally separate from its role in cll regulation, because it is not mediated by the transcription factor Pnt. This suggests that Egfr signaling has a dual role with separate mediators in proximodistal axis patterning. While the regulation of distal factors like cll is evolutionarily conserved, regulation of Dll and dac appears to function in parallel or redundant with Wg/Dpp signaling, thus providing a possible explanation why this role is less evolutionarily conserved in the insects. PMID- 22921412 TI - Significant rate of hepatitis B reactivation following kidney transplantation in patients with resolved infection. AB - BACKGROUND: Limited data is available on the risk of hepatitis B virus (HBV) reactivation in patients with resolved infection undergoing kidney transplantation. It is generally thought that this risk is negligible. OBJECTIVES: To evaluate the incidence of HBV reactivation in such patients, and the potential risk factors for reactivation. STUDY DESIGN: Retrospective cohort study including 93 patients transplanted with a kidney between 1995 and 2007 who had evidence of resolved HBV infection (HBsAg negative, anti-HBc positive, anti HBs positive or negative, and normal liver enzymes). HBV reactivation was defined as HBsAg reversion with HBV DNA>2000 IU/mL. RESULTS: Six patients experienced HBsAg reversion followed by HBV reactivation, 3 within the first post-transplant year. Immunosuppression regimen was similar in patients with and without reactivation. Among patients with reactivation only one was positive for anti-HBs antibodies at time of transplantation; these were progressively lost before reactivation. The odds ratio for reactivation in patients without anti-HBs antibodies at transplantation compared to those with anti-HBs antibodies was 26 (95% CI [2.8-240.5], p=0.0012). In patients with anti-HBs antibody titer above 100 IU/L, no reactivation was observed. CONCLUSIONS: Reactivation rate of resolved hepatitis B is not negligible in patients without anti-HBs antibodies at transplantation. We suggest monitoring of liver tests and HBV serology including HBsAg and anti-HBs antibodies after transplantation as well as vaccination pre- and post-transplantation in all patients, including those with resolved hepatitis B, aiming at maintaining anti-HBs antibody level above 100 IU/L. PMID- 22921413 TI - Molecular evolution of HA gene of the influenza A H1N1 pdm09 strain during the consecutive seasons 2009-2011 in Hangzhou, China: several immune-escape variants without positively selected sites. AB - BACKGROUND: Even under immune pressure, the highly active influenza A H1N1 pdm09 variants emerged again in December 2010. Did the variability lead to poor vaccine effectiveness? OBJECTIVES: To study the genetic distance and antigenic drift of the influenza A H1N1 pdm09 strains based on the sequence analysis of HA virus gene segments during consecutive seasons 2009-2011 in Hangzhou, China. STUDY DESIGN: 39 Clinical samples from influenza-like-illness patients with culture confirmed influenza A H1N1 pdm09 infections were collected over seasons in routine influenza surveillance. The HA gene was amplified and sequenced. A perspective analysis of genetic distance, antigenic drift and positively selected sites were conducted. RESULTS: Analyses of human influenza A H1N1 pdm09 strains isolated in Hangzhou revealed that during the seasons 2009-2011, the antigenic drift had occurred, away from the northern hemisphere 2010/2011 influenza vaccine strain A/California/07/2009. The 2010/2011 viruses cluster in two main branches with a significant genetic distance, characterized by either S202T and S468N, or K180T/I, V216A, P288S, I312V and I389F. Interestingly, the epitopes corresponding to the immune-escape characteristic have altered much, but none of the amino acid substitutions in 2010/2011 variants were positively selected. CONCLUSIONS: The results of genetic surveillance in this study might account for frequent outbreaks of the influenza A H1N1 pdm09 strains since December 2010 and the disappearance after three months circulation. It facilitates early detection of antigenic sites for the virus to escape immunological restraint in 2010/2011 season. Continuous monitoring of antigenic changes is recommended. PMID- 22921414 TI - Mechanical feedback between membrane tension and dynamics. AB - The plasma membrane represents a physical inelastic barrier with a given area that adheres to the underlying cytoskeleton. The tension in the membrane physically affects cell functions and recent studies have highlighted that this physical signal orchestrates complex aspects of trafficking and motility. Despite its undeniable importance, little is known about the mechanisms by which membrane tension regulates cell functions or stimulates signals. The maintenance of membrane tension is also a matter of debate, particularly the nature of the membrane reservoir and trafficking pathways that buffer tension. In this review we discuss the importance of membrane area and of tension as a master integrator of cell functions, particularly for membrane traffic. PMID- 22921415 TI - Increased levels of hydrogen peroxide induce a HIF-1-dependent modification of lipid metabolism in AMPK compromised C. elegans dauer larvae. AB - Cells have evolved numerous mechanisms to circumvent stresses caused by the environment, and many of them are regulated by the AMP-activated kinase (AMPK). Unlike most organisms, C. elegans AMPK-null mutants are viable, but they die prematurely in the "long-lived" dauer stage due to exhaustion of triglyceride stores. Using a genome-wide RNAi approach, we demonstrate that the disruption of genes that increase hydrogen peroxide levels enhance the survival of AMPK mutant dauers by altering both the abundance and the nature of the fatty-acid content in the animal by increasing the HIF-1-dependent expression of several key enzymes involved in fatty-acid biosynthesis. Our data provide a mechanistic foundation to explain how an optimal level of an often vilified ROS-generating compound such as hydrogen peroxide can provide cellular benefit, a phenomenon described as hormesis, by instructing cells to readjust their lipid biosynthetic capacity through downstream HIF-1 activation to correct cellular energy deficiencies. PMID- 22921416 TI - The role of PARP-1 and PARP-2 enzymes in metabolic regulation and disease. AB - While originally described as DNA damage repair agents, recent data suggest a role for poly(ADP-ribose) polymerase (PARP) enzymes in metabolic regulation by influencing mitochondrial function and oxidative metabolism. Here we review how PARP activity has a major metabolic impact and the role of PARP-1 and PARP-2 in diverse metabolic complications. PMID- 22921417 TI - Objective measures, sensors and computational techniques for stress recognition and classification: a survey. AB - Stress is a major growing concern in our day and age adversely impacting both individuals and society. Stress research has a wide range of benefits from improving personal operations, learning, and increasing work productivity to benefiting society - making it an interesting and socially beneficial area of research. This survey reviews sensors that have been used to measure stress and investigates techniques for modelling stress. It discusses non-invasive and unobtrusive sensors for measuring computed stress, a term we coin in the paper. Sensors that do not impede everyday activities that could be used by those who would like to monitor stress levels on a regular basis (e.g. vehicle drivers, patients with illnesses linked to stress) is the focus of the discussion. Computational techniques have the capacity to determine optimal sensor fusion and automate data analysis for stress recognition and classification. Several computational techniques have been developed to model stress based on techniques such as Bayesian networks, artificial neural networks, and support vector machines, which this survey investigates. The survey concludes with a summary and provides possible directions for further computational stress research. PMID- 22921418 TI - Progress in endovascular management of type A dissection. AB - Proximal acute aortic dissection [type A] remains a disease with a poor prognosis. High peri-operative open surgical mortality [up to 30%] and a significant turn-down rate [up to 40%] substantiate the bleak prospects for patients with this disease. Thoracic endovascular stent grafting has revolutionized the treatment of distal [type B] acute aortic dissection. Endovascular surgeons are now looking to improve the treatment of type A dissection by offering endovascular techniques to supplement conventional surgical therapy. Less invasive endovascular therapy, obviates the need for sternotomy and cardiopulmonary bypass, may reduce perioperative morbidity and offers a solution for those patients declined conventional intervention due to co morbidity or severe complications of the disease. Thoracic stent grafting in the ascending aorta presents specific challenges due to proximity to the aortic valve, navigation over the steep aortic arch and pulsatile aortic movement. Endovascular surgeons have treated type A dissection off-license using aortic cuffs and stents designed for infra-renal aortic surgery. Now grafts specifically designed for treating type A dissection are being developed and deployed under trial [compassionate license] in patients deemed unfit for open surgery. This paper explores how endovascular solutions may fit into the future care of patients with acute type A dissection. PMID- 22921419 TI - Low phase angle determined by bioelectrical impedance analysis is associated with malnutrition and nutritional risk at hospital admission. AB - BACKGROUND & AIMS: This study determined the association between phase angle (PhA), by bioelectrical impedance analysis (BIA) and nutritional risk by Nutritional Risk Screening (NRS-2002), Subjective Global Assessment (SGA), hospital length of stay (LOS) and 30 day non-survival in patients at hospital admission compared to healthy controls. METHODS: PhA was determined by BIA in patients (n = 983, 52.7 +/- 21.5 yrs, M 520) and compared to healthy age-, sex- and height-matched controls. Low PhA was set at <5.0 degrees (men) and <4.6 degrees (women) as previously determined (Kyle, in press). RESULTS: PhA was lower in patients (men 6.0 +/- 1.4 degrees , women 5.0 +/- 1.3 degrees ) than controls (men 7.1 +/- 1.2 degrees , women 6.0 +/- 1.2 degrees , un-paired t-test p < 0.001). Patients were more likely to have low PhA than controls: NRS-2002: no risk (relative risk (RR) 1.7, 95th confidence interval (CI) 1.2-2.3), moderate risk (RR 4.5, CI 3.4-5.8) and severe risk (RR 7.5, CI 5.9-9.4); similar results were obtained by SGA; LOS >=21 days (RR 6.9, CI 5.1-9.1) and LOS 5-20 days (RR 5.2, CI 3.9-6.9) and non-survivors (RR 3.1, CI 2.1-3.4) compared to survivors. CONCLUSIONS: There is a significant association between low PhA and nutritional risk, LOS and non-survival. PhA is helpful to identify patients who are at nutritional risk at hospital admission in order to limit the number of in-depth nutritional assessments. PMID- 22921420 TI - Genetic and chemical components analysis of Papaver setigerum naturalized in Korea. AB - Of the 110 species of genus Papaver, only Papaver somniferum and P. setigerum are controlled poppies in Korea. All poppy samples share similar morphology therefore it is important to check if they contain controlled substances such as morphine and codeine for forensic purpose. Since the alkaloid content of Papaver plants varies according to their growing stage, chemical components analysis alone is not enough to identify exact species. In 2010, hundreds of poppy plants suspected to be P. somniferum were found in Jeju Island, South Korea. They had a slightly different but overall similar appearance to P. somniferum. Using GC-MS analysis, codeine, rhoeadine, papaverine, protopine, noscapine, setigeridine and trace amounts of morphine were detected in these samples. Although their chemical components were different from what has been described in literatures for P. setigerum, they could be assumed to be P. setigerum based on their morphological features and GC-MS results. Also, chromosome numbers using their seeds showed 2n=44 and the numbers were in accordance with those of P. setigerum. Nucleotide substitution or insertion/deletion of ITS (internal transcribed spacer), 18S rRNA (ribosomal RNA), rbcL (large subunit of ribulose 1,5-bisphosphate carboxylase), trnL-trnF IGS (intergenic spacer), trnL intron and psbA-trnH were assessed as universal genetic markers for P. setigerum. Also, genetic analysis using six target genes involved in the biosynthesis of benzylisoquinoline alkaloids, including TYDC (tyrosine/dopa decarboxylase), SAT (salutaridinol-7-O acetyltransferase), BBE (berberine bridge enzyme), COR (codeinone reductase), CYP80B1 ((S)-N-methylcoclaurine 3'-hydroxylase) and NCS (norcoclaurine synthase) were tested as Papaver-specific genetic markers by the existence of their PCR products. From the results, the sequences of the 6 universal genetic markers and 6 Papaver-specific genetic markers for P. setigerum were identified and then Genbank accession numbers of them were registered in NCBI. Also, the trnL intron and psbA-trnH nucleic acid sequences of the 7 Papaver species were identified and registered. PMID- 22921421 TI - The laying of live larvae by the blowfly Calliphora varifrons (Diptera: Calliphoridae). AB - This study examined larviposition in Calliphora varifrons Malloch (Diptera: Calliphoridae), an ovoviviparous blowfly of forensic importance in Western Australia. Females took 1.5 min (mean 89+/-10.0s, n=42) to deposit their live, first instar larvae (average body length 2.5 mm) on fresh liver in the laboratory. Females laid an average of 30 live larvae (mean of 29.9+/-1.2, n=50) at a rate of 1 larva every 2 s (mean of 0.46+/-0.05 larvae/s, n=42). Most females (66%) laid live larvae only, but 18% laid fully developed eggs (half of the egg masses laid by individual females were viable) and 16% laid live larvae and some eggs at the same time. Females laying only eggs laid a mean of 24.1+/-3.0, n=10 eggs on each occasion. Field females carried between 20 and 44 live larvae (mean of 33.4+/-1.0, n=49) with a strong linear relationship between female size and number of live larvae. In the laboratory, females typically laid larvae in multiple locations. Very few females (<8%) retained some larvae in their ovisacs, retaining on average, half of their complement of developed larvae. Those larvae retained had begun to be resorbed by the female with necrosis evident on the posterior segments. PMID- 22921422 TI - Comparison of antimicrobial pharmacokinetic/pharmacodynamic breakpoints with EUCAST and CLSI clinical breakpoints for Gram-positive bacteria. AB - This study compared the susceptibility breakpoints based on pharmacokinetic/pharmacodynamic (PK/PD) models and Monte Carlo simulation with those defined by the Clinical and Laboratory Standards Institute (CLSI) and the European Committee on Antimicrobial Susceptibility Testing (EUCAST) for antibiotics used for the treatment of infections caused by Gram-positive bacteria. A secondary objective was to evaluate the probability of achieving the PK/PD target associated with the success of antimicrobial therapy. A 10,000 subject Monte Carlo simulation was executed to evaluate 13 antimicrobials (47 intravenous dosing regimens). Susceptibility data were extracted from the British Society for Antimicrobial Chemotherapy database for bacteraemia isolates. The probability of target attainment and the cumulative fraction of response (CFR) were calculated. No antibiotic was predicted to be effective (CFR>=90%) against all microorganisms. The PK/PD susceptibility breakpoints were also estimated and were compared with CLSI and EUCAST breakpoints. The percentages of strains affected by breakpoint discrepancies were calculated. In the case of beta lactams, breakpoint discrepancies affected <15% of strains. However, higher differences were detected for low doses of vancomycin, daptomycin and linezolid, with PK/PD breakpoints being lower than those defined by the CLSI and EUCAST. If this occurs, an isolate will be considered susceptible based on CLSI and EUCAST breakpoints although the PK/PD analysis predicts failure, which may explain treatment failures reported in the literature. This study reinforces the idea of considering not only the antimicrobial activity but also the dosing regimen to increase the probability of clinical success of an antimicrobial treatment. PMID- 22921423 TI - [Computer-assisted implantology]. AB - We had for aim to present the three applications of computer-assisted implantology: preoperative exploration of the surgery site, guided surgery, and preparation of the temporization prosthesis before surgery. Cases are presented for each indication and their clinical relevance is discussed. PMID- 22921424 TI - The role of vitamin D in cardiovascular disease: from present evidence to future perspectives. AB - Vitamin D and its metabolites have wide-spread physiological roles far beyond the well described effects in skeletal biology. Many physiological processes are directly or indirectly regulated by vitamin D and in consequence, vitamin D deficiency is implicated in numerous disease conditions. Summarizing previous assumptions on the optimal vitamin D levels in humans these data point towards calcidiol levels of approximately 30 ng/ml as being sufficient. The role of vitamin D deficiency in cardiovascular disease is a relatively novel field of interest. Well substantiated experimental data describe convincingly regulatory effects of vitamin D regarding various cardiovascular risk factors such as hypertension and diabetes mellitus. Activation of the vitamin D receptor suppresses e.g. the renin-angiotensin system. These experimental data are strongly supported by epidemiological and observational human data that link vitamin D deficiency to the incidence, degree and prevalence of cardiovascular risk factors and disease conditions. In contrast to the in vivo data and to the homogenous non-interventional observations, we know much less about controlled prospectively evaluated supplementation of vitamin D as a potentially therapeutic agent on cardiovascular events. High quality, large, and randomized controlled trials aiming primarily on cardiovascular end-points are absent. Speculations about the vitamin D usage in prevention or therapy of cardiovascular disease need to take potential drawbacks of vitamin D overdosing into account: Vitamin D overdosing might induce hypercalcemia, hyperphosphatemia, and increases in fibroblast growth-factor 23. The limited evidence regarding vitamin D therapy currently prevents general recommendations for vitamin D application in cardiology. PMID- 22921425 TI - Transglutaminase activity regulates atherosclerotic plaque composition at locations exposed to oscillatory shear stress. AB - OBJECTIVE: Atherosclerosis preferentially develops at sites of disturbed blood flow. We tested the hypothesis that transglutaminase activity plays a role in plaque development at these locations. METHODS AND RESULTS: Exposure of endothelial cells to steady flow (7 dynes/cm(2)) was associated with relatively low transglutaminase activity, whereas under low oscillatory flow (1.3 +/- 2.6 dynes/cm(2)) endothelial cells showed a >4-fold higher level of transglutaminase activity. Under oscillatory flow, transglutaminase activity increased the expression of the chemokine MCP-1 (CCL2). In vivo, oscillatory flow was induced by placement of a tapered perivascular cast around the carotid artery of type 2 transglutaminase (TGM2) knockout mice and WT counterparts. After 2 days, significantly less monocytes adhered to the endothelium in TGM2 knockout mice as compared to WT. In a more chronic setting, ApoE knockout mice that were equipped with the flow-modifying cast developed lesions proximal to the cast (low shear stress), and distal to the cast (oscillatory shear stress). Inhibition of transglutaminase induced a marked reduction in macrophage and fat content in distal lesions only. In addition, lesion size was increased in this area, which was attributed to an increase in smooth muscle content. CONCLUSION: Oscillatory shear stress increases endothelial transglutaminase activity. In turn, transglutaminase activity affects the expression of MCP-1 in vitro and monocyte recruitment in vivo. In a mouse model of atherosclerosis, transglutaminase activity has a major effect on plaque composition under oscillatory shear stress. PMID- 22921426 TI - Lead-induced ER calcium release and inhibitory effects of methionine choline in cultured rat hippocampal neurons. AB - Lead, a ubiquitous neurotoxicant, can result in learning and memory dysfunction. Long term potentiation in the hippocampus, a potential neural substrate for learning and memory, is thought to be linked to calcium-triggered intracellular events. In this study, laser scanning confocal microscopy was used to examine the effects of Pb(2+) on intracellular and endoplasmic reticulum free calcium concentration ([Ca(2+)](i) and [Ca(2+)](ER)) in cultured neonatal rat hippocampal neurons and their possible antagonism by methionine choline; understanding these effects would help explain the lead-induced cognitive and learning dysfunction and explore efficient safety and relief strategies. The results showed that Pb(2+) increased [Ca(2+)](i) and decreased [Ca(2+)](ER) linearly in a time- and concentration-dependant manner, and Pb(2+) addition after the applying of a ryanodine receptor (RyR) antagonist and an inositol-1,4,5-triphosphate receptor (IP(3)R) antagonist did not increase [Ca(2+)](i). The addition of 10, 20, or 40 mmol/L methionine choline simultaneously with addition of 10 MUmol/L Pb(2+) decreased [Ca(2+)](i) in Ca(2+)-free culture medium by 39.0%, 66.0%, and 61.6%, respectively, in a concentration-dependant manner in a certain dose range. Our results suggest that Pb(2+) induces ER calcium release to increase the resting [Ca(2+)](i); and methionine choline inhibit this increase in [Ca(2+)](i). PMID- 22921427 TI - Interactions between bufadienolides derived from toad venom and verapamil in langendorff-perfused guinea-pig hearts. AB - Drug toxicity may occur due to dangerous drug combination. We aimed to investigate the influence of verapamil (a P-gp inhibitor)--bufadienolides interaction on cardiotoxicity and bufadienolide uptake by the isolated heart. The study was performed in Langendorff isolated perfused guinea-pig hearts by bufadienolides infusion in the absence and presence of verapamil (250, 500ng/ml). Arrhythmia parameters were evaluated by ECG and the content of bufadienolides in heart were measured by ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS). In the present of verapamil, the wide QRS duration and lightly rapid heart rate (HR) were markedly reduced in the early stage of bufadienolide intoxication. However, the ECG changes characterized by prolonged P R interval, and slow heart rate and low QRS amplitude in the late stage of bufadienolide intoxication were significantly enhanced. Furthermore, the contents of a variety of bufadienolide compounds in the verapamil+bufadienolide group were significantly higher when cardiac arrest occurred. Although verapamil reduced the bufadienolide-induced ventricular arrhythmias, verapamil worsened heart block and lethal bradycardia of bufadienolides partly via increasing the uptake of bufadienolides in heart tissue, which could compromise the protective effects of verapamil against bufadienolide intoxication. These results suggested that the verapamil may produce dangerous interactions with drugs containing bufadienolides. PMID- 22921428 TI - A robust plate assay for detection of extracellular microbial protease activity in metagenomic screens and pure cultures. AB - A robust, efficient and cost-effective agar that utilises lactose free milk powder for identification of bacterial protease activity in pure cultures and metagenomic screens has been developed and tested on protease positive bacteria, selected strains and false protease positives isolated from a previously constructed metagenomic library. PMID- 22921429 TI - Trans and cis influences and effects in cobalamins and in their simple models. AB - The interligand interactions in coordination compounds have been principally interpreted in terms of cis and trans influences and effects, which can be defined as the ability of a ligand X to affect the bond of another ligand, cis or trans to X, to the metal. This review analyzes these effects/influences in cobalamins (XCbl) and their simple models cobaloximes, LCo(chel)X. Important properties of these complexes, such as geometry, stability, and reactivity, can be rationalized in terms of steric and electronic factors of the ligands. Experimental evidence of normal and inverse trans influence is described in alkylcobaloximes for the first time. The study of simple B(12) models has complemented that on the more complex cobalamins, with particular emphasis on the properties of the axial L-Co-X moiety. Some of the conclusions reached for the axial fragment of simple models have also been qualitatively detected in cobalamins and have furnished new insight into the as yet unestablished mechanism for the homolytic cleavage of the Co - C bond in the AdoCbl-based enzymes. PMID- 22921430 TI - Systematic differences in electrochemical reduction of the structurally characterized anti-cancer platinum(IV) complexes [Pt{((p-HC6F4)NCH2)2} (pyridine)2Cl2], [Pt{((p-HC6F4)NCH2)2}(pyridine)2(OH)2], and [Pt{((p HC6F4)NCH2)2}(pyridine)2(OH)Cl]. AB - The putative platinum(IV) anticancer drugs, [Pt{((R)NCH(2))(2)}(py)(2)XY] (X,Y=Cl, R=p-HC(6)F(4) (1a), C(6)F(5) (1b); X,Y=OH, R=p-HC(6)F(4) (2); X=Cl, Y=OH, R=p-HC(6)F(4) (3), py = pyridine) have been prepared by oxidation of the Pt(II) anticancer drugs [Pt{((R)NCH(2))(2)}(py)(2)] (R=p-HC(6)F(4) (4a) or C(6)F(5) (4b)) with PhICl(2) (1a,b), H(2)O(2) (2) and PhICl(2)/Bu(4)NOH (3). NMR spectroscopy and the X-ray crystal structures of 1b, 2 and 3 show that they have octahedral stereochemistry with the X,Y ligands in the trans-position. The net two electron electrochemical reduction of 1a, 2 and 3 has been studied by voltammetric, spectroelectrochemical and bulk electrolysis techniques in acetonitrile. NMR and other data reveal that reduction of 1a gives pure 4a via the elimination of both axial chloride ligands. In the case of 2, one end of the diamide ligand is protonated and the resulting -NH(p-HC(6)F(4)) group dissociated giving a [Pt{N(p-HC(6)F(4))CH(2)CH(2)NH(p-HC(6)F(4))}] arrangement, one pyridine ligand is lost and a hydroxide ion retained in the coordination sphere. Intriguingly, in the case of reduction of 3, a 50% mixture of the reduction products of pure 1a and 2 is formed. The relative ease of reduction is 1>3>2. Testing of 1a, 2 and 3 against L1210 and L1210(DDP) (DDP = cis-diamine dichloroplatinum(II)) mouse leukaemia cells shows all to be cytotoxic with IC(50) values of 1.0-3.5 MUM. 2 and 3 are active in vivo against AHDJ/PC6 tumor line when delivered in peanut oil despite being hard to reduce electrochemically, and notably are more active than 4a delivered in this medium whilst comparable with 4a delivered in saline/Tween. PMID- 22921431 TI - Inhibition of SOX17 by microRNA 141 and methylation activates the WNT signaling pathway in esophageal cancer. AB - In this study, we explored the possibility of SOX17 promoter region methylation as an esophageal cancer detection marker, the regulation of SOX17 expression, and the function of SOX17 in the WNT signaling pathway in esophageal cancer. Eight esophageal cancer cell lines, 9 normal esophageal mucosa samples, 60 cases of dysplasia, and 169 cancer tissue samples were included. Methylation-specific PCR, semiquantitative reverse transcription-PCR, immunohistochemistry, luciferase reporter assay, colony formation, and Western blot analysis were used to analyze methylation and function of SOX17 in esophageal cancer. MicroRNA-related detection methods were performed to evaluate microRNA regulation of SOX17. SOX17 methylation was found in progression tendency with 0% of normal mucosa, 39% of grade 1 dysplasia, 48% of grades 2 and 3 dysplasia, and 65% of primary cancer. SOX17 methylation is related to esophageal cancer patients' history of alcohol use and may induce beta-catenin expression and redistribution. Loss of SOX17 expression is correlated to promoter region hypermethylation, and re-expression was activated by 5-aza-2'-deoxycytidine treatment in esophageal cancer cell lines. Restoration of SOX17 expression suppresses TCF/beta-catenin-dependent transcription and colony formation. MicroRNA 141 was also found to down-regulate SOX17 expression and activate the WNT signal pathway. SOX17 is frequently methylated in esophageal cancer and in a progression tendency during esophageal carcinogenesis. Loss of SOX17 removes the normal inhibition of WNT signaling and promotes esophageal tumorigenesis. PMID- 22921432 TI - Skin biopsy is a practical approach for the clinical diagnosis and molecular genetic analysis of X-linked Alport's syndrome. AB - A total of 209 unrelated patients of predominantly Han Chinese ethnicity and with X-linked Alport's syndrome, a clinically heterogeneous hereditary nephritis, were enrolled in the present study to evaluate the ability to make a clinical diagnosis and perform molecular genetics analysis using skin biopsy. A negative or mosaic alpha5(IV) chain staining in the epidermal basement membrane was detected in 86.2% of male and 93.5% of female patients. COL4A5 mutations were identified in 85% of male patients with a negative alpha5(IV) chain staining pattern in the epidermal basement membrane. With use of skin biopsy and immunostaining, 16.4% of our patients were diagnosed before 3 years of age, and the youngest was diagnosed at 1 year of age. COL4A5 mutations were detected in 22 patients with normal epidermal basement membrane staining for the alpha5(IV) chain. Analysis of COL4A5 cDNA fragments from skin fibroblasts yielded a mutation detection rate of 83%, which was particularly valuable for identification of cryptic splicing mutations. Furthermore, 83% of COL4A5 mutations identified in the present study were novel. Thus, skin biopsy is a practical approach for the clinical diagnosis and molecular genetic analysis of X-linked Alport's syndrome. PMID- 22921433 TI - Early and late neurodegeneration and memory disruption after intracerebroventricular streptozotocin. AB - Glucose metabolism and insulin signaling disruptions in the brain have been proposed as a likely etiology of Alzheimer's disease. The aim of the present study was to investigate the time course of cognitive impairments induced by intracerebroventricular injection of streptozotocin (STZ) in rats and correlate them with the ensuing neurodegenerative process. Early and late effects of STZ were evaluated by using the reference and working memory versions of the Morris' water maze task and the evaluation of neurodegenerative markers by immunoblotting and the Fluoro-Jade C histochemistry. The results revealed different types of behavioral and neurodegenerative responses, with distinct time courses. We observed an early disruption on the working memory as early as 3h after STZ injections, which was followed by degenerative processes in the hippocampus at 1 and 15 days after STZ injections. Memory disruption increases over time and culminates with significant changes in amyloid-beta peptide and hyperphosphorylated Tau protein levels in distinct brain structures. These findings add information on the Alzheimer's disease-like STZ animal model and on the mechanisms underlying neurodegenerative processes. PMID- 22921434 TI - Intercalation of trichloroethene by sediment-associated clay minerals. AB - The objective of this research was to examine the potential for intercalation of trichloroethene (TCE) by clay minerals associated with aquifer sediments. Sediment samples were collected from a field site in Tucson, AZ. Two widely used Montmorillonite specimen clays were employed as controls. X-ray diffraction, conducted with a controlled-environment chamber, was used to characterize smectite interlayer d-spacing for three treatments (bulk air-dry sample, sample mixed with synthetic groundwater, sample mixed with TCE-saturated synthetic groundwater). The results show that the d-spacing measured for the samples treated with TCE-saturated synthetic groundwater are larger (~26%) than those of the untreated samples for all field samples as well as the specimen clays. These results indicate that TCE was intercalated by the clay minerals, which may have contributed to the extensive elution tailing observed in prior miscible displacement experiments conducted with this sediment. PMID- 22921435 TI - Comprehensive mass flow analysis of Swedish sludge contaminants. AB - A screening of metals, persistent organic pollutants, pharmaceuticals and personal care products (PPCPs), and other organic contaminants in sludge from seven Swedish sewage treatment plants (STPs) was performed in this study. This extensive screening provides information on mass flows of 282 compounds used in the Swedish society to sewage sludge. It reveals constant relative contaminant concentrations (ng mg kg(-1) d.w.), except for some pesticides and perfluorinated compounds, indicating that these originate from broad usage and diffuse dispersion rather than (industrial) point sources. There was a five order of magnitude difference in the sum concentrations of the most and least abundant species (metals and polychlorinated dibenzo-p-dioxins and -furans, respectively). Lower total concentrations were found in sludge from STPs processing primarily food industry or household sewage. Proportions of the amounts used (in Sweden) found in sludge were lower for compounds that are present in consumer goods or are diffusely dispersed into the environment (0.01-1% recovered in sludge) than for compounds used as detergents or PPCPs (17-63%). In some cases, the recovery seemed to be affected by evaporation (e.g. octamethylcyclotetrasiloxane) or biotransformation (e.g. adipates) losses, while polychlorinated alkanes and brominated diphenyl ethers were recovered to disproportionately high degree (ca. 4%); likely due to incomplete statistics for imported goods. PMID- 22921436 TI - Compound specific carbon and hydrogen stable isotope analyses of volatile organic compounds in various emissions of combustion processes. AB - This study presents carbon (delta(13)C) and hydrogen (deltaD) isotope values of volatile organic compounds (VOCs) in various emission sources using thermal desorption-gas chromatography-isotope ratio mass spectrometry (TD-GC-irMS). The investigated VOCs ranged from C6 to C10. Samples were taken from (i) car exhaust emissions as well as from plant combustion experiments of (ii) various C3 and (iii) various C4 plants. We found significant differences in delta values of analysed VOCs between these sources, e.g. delta(13)C of benzene ranged between (i) -21.7 +/- 0.2 0/00, (ii) -27.6 +/- 1.6 0/00 and (iii) -16.3 +/- 2.2 0/00, respectively and deltaD of benzene ranged between (i) -73 +/- 13 0/00, (ii) -111 +/- 10 0/00 and (iii) -70 +/- 24 0/00, respectively. Results of VOCs present in investigated emission sources were compared to values from the literature (aluminium refinery emission). All source groups could be clearly distinguished using the dual approach of delta(13)C and deltaD analysis. The results of this study indicate that the correlation of compound specific carbon and hydrogen isotope analysis provides the potential for future research to trace the fate and to determine the origin of VOCs in the atmosphere using thermal desorption compound specific isotope analysis. PMID- 22921437 TI - Seasonal variations in the levels of PCDD/Fs, PCBs and PBDEs in cows' milk. AB - The first detailed investigation into seasonal variations in PCDD/F, PCB and PBDE concentrations in cows' milk from individual farms was conducted. From August 2009 milk samples were taken at 6 weeks intervals from the bulk tank of 2 farms over a period of one year. Samples of dietary inputs including commercial feed, grass, silage and soil were also collected at 6 weekly intervals from each farm. Detailed animal husbandry information was additionally obtained. For all these samples total TEQ, ?ICES6 and the ?7 PBDE congeners was calculated. The results demonstrated that the concentrations of these sets of compounds fluctuate notably over short periods in cows' milk. This variability was such that the highest observed concentrations were nearly double the lowest concentrations detected for both PCDD/Fs and PCBs and PBDEs. Fluctuations between extremes were observed over time periods as short as 6 weeks. Some, but not all, of these variations may be explained by changes in the contaminant concentrations of dietary inputs consumed by the cattle. Changes in contaminant inputs from grass and silage were identified as being the most important source of these fluctuations. Given this variability, the results from PCDD/F and PCB and PBDE monitoring studies may be highly dependent upon when the individual samples were taken. The results have important implications for total diet studies and sampling design. PMID- 22921438 TI - Mucociliary clearance impairment after zygomaticomaxillary-orbital fractures. AB - OBJECTIVE: The purpose of this study was to examine the influence of zygomaticomaxillo-orbitalis (ZMO) fracture and its symptoms on mucociliary transport (MCT). STUDY DESIGN: The study encompassed 144 patients who sustained ZMO fracture. A saccharine test was conducted in every patient both on the side of fracture and on the unaffected side. The results were analyzed in connection with the patients' age, sex, degree of injury, method of treatment, time since fracture, and duration of surgery. RESULTS: It was shown that MCT was considerably impaired on the affected side compared with the control side. However, the degree of impairment did not vary significantly in the patients regardless of the analyzed parameters. CONCLUSIONS: ZMO fracture induces the disorder of MCT. Balloon Foley catheter in the open reduction of ZMO fracture impairs MCT. The analyzed parameters do not affect the disorders of MCT. PMID- 22921439 TI - Effects of surgically assisted rapid palatal expansion with and without pterygomaxillary disjunction on dental and skeletal structures: a retrospective review. AB - OBJECTIVE: The aim of this study was to evaluate and compare dental and skeletal changes in surgically assisted rapid palatal expansion (SARPE) patients with (+PP) and without (-PP) pterygomaxillary disjunction. STUDY DESIGN: The study casts of 18 maxillary constriction patients indicated for SARPE formed the sample of this retrospective review. The sample was divided into 2 groups. Twenty linear and 2 angular measurements were performed on the study models. RESULTS: All transversal measurements increased after expansion in both the +PP and -PP groups. The -PP group showed greater expansion at the midpalatal and gingival levels, while the +PP group exhibited a greater increase of 0.78 mm at the apical base level and 11.25 degrees less tipping in the molar teeth. A greater expansion of nearly 0.7 mm was measured in the premolar region of the +PP group. CONCLUSIONS: Both SARPE techniques resulted in significant maxillary expansion. PMID- 22921440 TI - Unusual case of a sialolith: a case report. AB - Sialoliths are a common cause of salivary gland obstruction, usually affecting the submandibular gland. Although many theories are postulated for their formation (dehydration, medications that reduce salivary flow, increased salivary viscosity), no one aspect is clearly the primary etiology. This case report details an unusual case in which a facial hair of the patient apparently became entrapped in Wharton's duct, causing a nidus for the formation of a sialolith. PMID- 22921441 TI - Effects of Ginkgo biloba on experimental rapid maxillary expansion model: a histomorphometric study. AB - OBJECTIVE: We aimed to investigate the effect of systemic Ginkgo biloba in rapid maxillary expansion (RME). STUDY DESIGN: We randomly divided 24 rats into 3 groups: expansion only (EO), expansion plus Ginkgo biloba (GB), and no expansion (NE). Expansion appliances were affixed to the maxillary incisors. After a 5-day expansion period, there was a consolidation period of 15 days, following which the rats were killed. Histomorphometric examination was performed to determine the number of osteoclasts, osteoblasts, and capillaries, the number and intensity of inflammatory cells, and new bone formation. RESULTS: New bone formation, number of capillaries, and the ratio of inflammatory cells in maxillary sutures were higher in the GB group than in the other groups. Statistical analysis demonstrated that the GB group had more osteoblasts and osteoclasts than the other groups. CONCLUSIONS: GB may hasten new bone regeneration in RME and prevent relapse after RME. PMID- 22921442 TI - Cyclic nucleotide phosphodiesterase activity in stem cells of human periodontal ligament (PDL-MSCs) before and after osteogenic induction. AB - OBJECTIVE: The aim of this work was to evaluate both the level of endogenous cyclic nucleotides cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cAMP) and phosphodiesterase activity in mesenchymal stem cells (MSCs) before and during the osteogenic induction. STUDY DESIGN: Samples were organized into control (nondifferentiated) and test groups which were analyzed at 3 different time points: 1, 2, and 4 weeks. Periodontal ligament MSCs were isolated and then expanded in an MSCM medium while cyclic nucleotide levels and phosphodiesterase activity were assessed. RESULTS: cAMP and cGMP levels were markedly higher in the first week than in the following stages. Similarly, PDE activity increased during the first week and reached the peak in the second week. CONCLUSIONS: This work validates that cAMP, cGMP, and PDE activities are important factors in the first phase of the osteogenic induction of a human stem cell. PMID- 22921443 TI - Distribution of diagnoses in a population of patients with temporomandibular disorders. AB - OBJECTIVES: The objective of this study was to describe the frequency of TMD diagnoses in a patient population for comparison with the available literature. METHODS: Five hundred twenty consecutive patients seeking TMD treatment underwent a Research Diagnostic Criteria for Temporomandibular Disorders (RDC/TMD) assessment. The prevalence and age distribution of the different RDC/TMD axis I and II diagnoses were described. RESULTS: Muscle disorders, disk displacements, and other joint disorders were diagnosed respectively in 56.4%, 42.0%, and 57.5% of patients. Sixty percent of patients had depression symptoms, 76.6% had somatization, and 21.8% presented high levels of pain-related impairment. Disk displacements were more frequently diagnosed in the younger-aged, other joint disorders in the older-aged, and muscle disorders in the middle-aged subjects (ANOVA for mean age comparison, F = 3.355; P = .002). CONCLUSIONS: These distribution frequencies of TMD diagnoses provide insight into the epidemiology of this disease. PMID- 22921444 TI - Relation between initial implant stability quotient and bone-implant contact percentage: an in vitro model study. AB - OBJECTIVE: This study evaluated the correlation between the initial stability of a dental implant, quantified as the implant stability quotient (ISQ), and the bone-implant contact percentage ( BIC%). STUDY DESIGN: Dental implants were inserted into specimens comprising an artificial cortical shell representing cortical bone and foam bone representing cancellous bone with 4 elastic moduli. Each specimen with an implant was subjected to microcomputed tomography (micro CT) scanning, from which the 2D and 3D BIC% values were calculated. The values of the Spearman correlation coefficient (r) were calculated between the ISQ and the 2D and 3D BIC% values. RESULTS: Increasing the elasticity of the specimen enhanced the ISQ. There was statistically significant correlation between the ISQ and 3D BIC% values (r = 0.85, P < .0001). However, the correlation between ISQ and 2D BIC% values was not statistically significance (r = 0.42, P = .062). CONCLUSIONS: The initial implant stability was strongly positively correlated with the 3D BIC%. PMID- 22921445 TI - Intraosseous carcinoma arising from an odontogenic cyst: a case report. AB - Carcinomas from an odontogenic cyst are not common, yet when they occur, squamous cell carcinomas are the most often seen. Among these cysts, the malignancy of keratocysts or dentigerous cysts are most likely. In contrast, a malignant transformation of a radicular cyst to an intraosseous carcinoma is extremely rare. In this case report, an intraosseous carcinoma arising from an odontogenic cyst in a 26-year-old male patient is presented. This case report clearly demonstrates the importance of the clinician's awareness of the malignant potential of apparently innocuous cystic lesions. PMID- 22921446 TI - Short-term clinical outcomes of two different flap techniques in impacted mandibular third molar surgery. AB - OBJECTIVE: The aim of this study was to estimate the influence of flap design on alveolar osteitis (AO) and postoperative side effects following third molar surgery. STUDY DESIGN: This study was designed as a randomized single-blind clinical trial. The predictor variable was flap type. Envelope flap and modified triangular flap techniques were used. The primary outcome variable was AO. The secondary outcome variables were pain, swelling, and trismus. Descriptive and bivariate statistics were computed. Statistical significance was set at P <= .05. RESULTS: Eighty patients with impacted mandibular third molars participated in the study. The envelope flap design was associated with a higher incidence of AO that was not statistically significant. On the second day, postoperative pain and swelling was observed as significantly different with the envelope flap technique. CONCLUSIONS: The modified triangular flap had the advantage of less postoperative pain and swelling but had the disadvantage of AO. PMID- 22921447 TI - Treatment of mandible fractures using resorbable plates with a mean of 3 weeks maxillomandibular fixation: a prospective study. AB - PURPOSE: In this study, a 2.5-mm resorbable plating system (Inion CPS, Tampere Finland) was assessed for the fixation of mandibular fractures with 3 weeks of maxillomandibular fixation. PATIENTS AND METHODS: Fifty mandibular fractures in 34 patients (32 males, 2 females) with a mean of 20.8 days of maxillomandibular fixation (MMF) were included in this study. The 2.5-mm resorbable plates were adapted along Champy's line of ideal osteosynthesis and secured with four 8 * 2.5 mm monocortical resorbable screws. All patients were followed for a minimum of 6 weeks with an average long-term follow-up of 10 months. The incidence of soft tissue infection, nonunion, malunion, malocclusion, osteomyelitis, nerve injury, and tooth damage was prospectively assessed. RESULTS: Primary bone healing was achieved in 100% of cases. Ten minor complications (20%) were observed: 5 soft tissue infections (10%), 4 plate dehiscences (8%), and 1 malocclusion (2%). No evidence of malunion, nonunion, osteomyelitis, plate fracture, or iatrogenic dental or nerve injury was noted; no readmission or reoperation was necessary. CONCLUSION: The Inion 2.5-mm resorbable plating system along Champy's line of ideal osteosynthesis plus 3 weeks of MMF is a viable option for the treatment of mandible fractures. PMID- 22921448 TI - Surgical management of head and neck vascular anomalies in children: a retrospective analysis of 42 patients. AB - OBJECTIVE: This article aimed to present a series of surgically treated head and neck vascular anomalies during a 12-year period, highlighting the epidemiology, diagnostic approach, indications for surgery, and final clinical outcome. STUDY DESIGN: The medical records of all patients with head and neck vascular anomalies, surgically treated at our department from 1998 to 2010, were reviewed retrospectively. RESULTS: A total of 42 patients with 46 vascular anomalies were identified. Patients' diagnoses included vascular tumors, hemangiomas mainly (18 cases), and various vascular malformations (26 cases). All patients were submitted to surgical treatment (excision-resection) to resolve main clinical symptoms (ulceration, bleeding, impaired mastication and feeding, airway obstruction) and/or esthetic issues. Recurrence was noted in 3 patients. CONCLUSION: Accurate differential diagnosis based on history, physical examination, and imaging, is the key to optimal treatment. Surgical intervention is warranted for small to moderately extended lesions to avoid complications and/or esthetic concerns and psychosocial distress. PMID- 22921449 TI - [Acute renal failure after cardiac surgery: evaluation of the RIFLE criteria]. AB - INTRODUCTION: Acute renal failure is a common complication is a common complication in cardiac surgery under cardiopulmonary bypass. It is associated with increased morbidity and mortality. Acute kidney injury (AKI) is a clinical entity encompassing the entire spectrum of acute renal failure, since minor alterations to the need for renal replacement therapy. The RIFLE criteria have been proposed for defining and classifying AKI. The aim of our study was to apply the RIFLE to a population of patients undergoing cardiac surgery with cardiopulmonary bypass (CPB) and to assess its relevance in terms of risk factor for hospital mortality compared to other risk factors. METHODS: In this prospective observational study, we included patients who were operated for programmed cardiac surgery. The assay of blood creatinine was performed at admission, after surgery and daily for 5 days post-surgery. The AKI was evaluated according to the criteria of classification RIFLE. The patients were divided into three levels of severity based on plasmatic creatinine (R: Risk=creatinine*1.5; I: Injury=creatinine*2; F: Failure=creatinine*3). We have analyzed the different perioperative parameters and we sought associations with the occurrence of AKI. We also studied the impact of AKI on length of stay in ICU and mortality early and late. RESULTS: One hundred and thirty-six patients were included. AKI was diagnosed in 17.6% of patients (RIFLE-R: 8.8%, RIFLE-I: 5.9% and RIFLE-F: 2.9%). AKI significantly prolongs the duration of ICU stay (7+/-3.8 versus 5+/-2.3 days; P=0.02). RIFLE-R patients had a mortality of 8.3%, compared to 12.5% for I and 50% for F. Patients without PORD had a mortality of 1.8%. In univariate analysis, age, the EURO score, preoperative renal dysfunction, duration of aortic clamping, duration of CPB and C-reactive protein (CRP) were significantly associated with the occurrence of AKI. In multivariate analysis only preoperative renal dysfunction (clearance less than 63 mL/min) and CRP greater than 158 mg/L were found as independent factors of occurrence of AKI. CONCLUSION: RIFLE classification seems to be a reliable way to detect acute renal failure and to classify its severity. The AKI is a common complication and is associated with increased morbidity and mortality. Identifying the risk factors allows a better prevention strategy. PMID- 22921450 TI - Cholesterol depletion by methyl-beta-cyclodextrin enhances cell proliferation and increases the number of desmin-positive cells in myoblast cultures. AB - Skeletal myogenesis comprises myoblast replication and differentiation into striated multinucleated myotubes. Agents that interfere with myoblast replication are important tools for the understanding of myogenesis. Recently, we showed that cholesterol depletion by methyl-beta-cyclodextrin (MCD) enhances the differentiation step in chick-cultured myogenic cells, involving the activation of the Wnt/beta-catenin signaling pathway. However, the effects of cholesterol depletion on myoblast replication have not been carefully studied. Here we show that MCD treatment increases cell proliferation in primary chick myogenic cell cultures. Treatment of myogenic cells with the anti-mitotic reagent cytosine arabinoside, immediately following cholesterol depletion, blocks the MCD-induced effects on proliferation. Cholesterol depletion induced an increase in the number of desmin-positive mononucleated cells, and an increase in desmin expression. MCD induces an increase in the expression of the cell cycle regulator p53 and the master switch gene MyoD1. Treatment with BIO, a specific inhibitor of GSK3beta, induced effects similar to MCD on cell proliferation; while treatment with Dkk1, a specific inhibitor of the Wnt/beta-catenin pathway, neutralized the effects of MCD. These findings indicate that rapid changes in the cholesterol content in cell membranes of myoblasts can induce cell proliferation, possibly by the activation of the Wnt/beta-catenin signaling pathway. PMID- 22921451 TI - Cardiac metastasis of head and neck squamous cell carcinoma. AB - Two patients with cardiac metastasis from head and neck cancer are reported. Cardiac metastasis located in the left atrium was detected on a follow-up computed tomography (CT) scan 15 months after partial glossectomy for a tongue carcinoma in a 60-year-old man. The diagnosis was confirmed as cardiac metastasis of squamous cell carcinoma (SCC) by surgical excision of the cardiac lesion. The patient died 3 weeks after surgery. In a 69-year-old man with a partial maxillectomy for primary soft palate cancer, a follow-up CT scan 5 months after surgery revealed a mass in the right atrium and ventricle, and multiple lung metastases. He died of heart failure 3 weeks after the diagnosis of cardiac metastasis. Information on these cases should add to knowledge about rarely encountered cardiac metastasis. PMID- 22921452 TI - Prediction of OSCC using biomarkers: methodological mistake. PMID- 22921453 TI - Impact of a preventive programme on the occurrence of incidents during the transport of critically ill patients. AB - OBJECTIVE: Incidents related to transport of critically ill patients have been extensively reported. The objective of this study was to determine the effect of an interdisciplinary preventive programme used by all intensive care unit team members involved in patients' transport on the rate of these incidents. METHODS: A clinical quality improvement audit using a prospective pre and post intervention design was performed among medical and surgical patients hospitalised in intensive care who required intra or inter-hospital transport. RESULTS: A total of 180 transports occurred in the pre-implementation phase of the study and 187 transports in the post-implementation phase. A 20% absolute reduction of incidents was observed (57.2% vs. 37.4%, p<0.001). Statistically significant reductions were obtained for the technical problems category of incidents (25% vs. 7.5%, p<0.001) as well as the problems related to patient's mobilisation category (14.4% vs. 7.5%, p=0.05). Clinically significant trends were also observed for the clinical deterioration (24.4% vs. 17.1%, p=0.11) and undesired delay before test (23.9% vs. 17.6%, p=0.14) categories but did not reach statistical significance. CONCLUSIONS: A preventive programme applied by all care providers involved in transport of critically ill patients was associated with a reduction of incidents. The application of such a programme should be acknowledged as a standard of care considering the risks inherent to the transportation of ICU patients. PMID- 22921454 TI - Effect of cognitive-behavioral therapy on neural correlates of fear conditioning in panic disorder. AB - BACKGROUND: Learning by conditioning is a key ability of animals and humans for acquiring novel behavior necessary for survival in a changing environment. Aberrant conditioning has been considered a crucial factor in the etiology and maintenance of panic disorder with agoraphobia (PD/A). Cognitive-behavioral therapy (CBT) is an effective treatment for PD/A. However, the neural mechanisms underlying the effects of CBT on conditioning processes in PD/A are unknown. METHODS: In a randomized, controlled, multicenter clinical trial in medication free patients with PD/A who were treated with 12 sessions of manualized CBT, functional magnetic resonance imaging (fMRI) was used during fear conditioning before and after CBT. Quality-controlled fMRI data from 42 patients and 42 healthy subjects were obtained. RESULTS: After CBT, patients compared to control subjects revealed reduced activation for the conditioned response (CS+ > CS-) in the left inferior frontal gyrus (IFG). This activation reduction was correlated with reduction in agoraphobic symptoms from t1 to t2. Patients compared to control subjects also demonstrated increased connectivity between the IFG and regions of the "fear network" (amygdalae, insulae, anterior cingulate cortex) across time. CONCLUSIONS: This study demonstrates the link between cerebral correlates of cognitive (IFG) and emotional ("fear network") processing during symptom improvement across time in PD/A. Further research along this line has promising potential to support the development and further optimization of targeted treatments. PMID- 22921457 TI - Comparison of stress cardiomyopathy in Hispanic and non-Hispanic patients. PMID- 22921455 TI - alpha2-containing GABA(A) receptors: a target for the development of novel treatment strategies for CNS disorders. AB - GABA(A) receptors have important physiological functions, as revealed by pharmacological studies and experiments involving gene-targeted mouse models, and are the target of widely used drugs such as the benzodiazepines. In this review, we are summarizing current knowledge about the function of alpha2-containing GABA(A) receptors, a receptor subtype representing approximately 15-20% of all GABA(A) receptors. This receptor subtype mediates anxiolytic-like, reward enhancing, and antihyperalgesic actions of diazepam, and has antidepressant-like properties. Secondary insufficiency of alpha2-containing GABA(A) receptors has been postulated to play a role in the pathogenesis of schizophrenia, and may be involved in cognitive impairment in other disorders. Moreover, polymorphisms in the GABRA2 gene encoding the GABA(A) receptor alpha2 subunit have been found to be linked to chronic alcohol dependence and to polydrug abuse. Thus, alpha2 containing GABA(A) receptors are involved in the regulation and/or modulation of emotional behaviors and of chronic pain, and appear to be a valid target for novel therapeutic approaches for the treatment of anxiety, depression, schizophrenia and chronic pain. PMID- 22921456 TI - A closer look at diabetes remission after gastric bypass surgery: a case study. PMID- 22921458 TI - Experimental modeling of recombinant tissue plasminogen activator effects after ischemic stroke. AB - Recombinant tissue plasminogen activator (rt-PA) is currently the only approved drug for ischemic stroke treatment, with a dose of 0.9 mg/kg. Since the fibrinolytic activity of rt-PA has been reported in vitro to be 10-fold less potent in rodent than in human, in most in vivo experimental models of cerebral ischemia rt-PA is used at 10 mg/kg. The purpose of this study was to compare the effects of the "human" (0.9 mg/kg) and "rodent" (10 mg/kg) doses of rt-PA given at an early or a delayed time point in a mouse model of cerebral ischemia. Cerebral ischemia was induced by thrombin injection into the left middle cerebral artery of mice. Rt-PA (0.9 or 10 mg/kg) was intravenously administered 30 min or 4 h after the onset of ischemia. The degree of reperfusion after rt-PA was followed for 90 min after its injection. The neurological deficit, infarct volumes, edema and hemorrhagic transformations (HT) were assessed at 24 h. Reperfusion was complete after early administration of rt-PA at 10 mg/kg but partial with rt-PA at 0.9 mg/kg. Both doses given at 4 h induced partial reperfusion. Early administration of both doses of rt-PA reduced the neurological deficit, lesion volume and brain edema, without modifying post-ischemic HT. Injected at 4 h, rt-PA at 0.9 and 10 mg/kg lost its beneficial effects and worsened HT. In conclusion, in the mouse thrombin stroke model, the "human" dose of rt-PA exhibits effects close to those observed in clinic. PMID- 22921459 TI - RNA interference against repulsive guidance molecule A improves axon sprout and neural function recovery of rats after MCAO/reperfusion. AB - Repulsive guidance molecule a (RGMa) is a neurite growth inhibitor that is of great interest in the study of CNS neuronal regeneration. We adopted RNA interference (RNAi) as a means of suppressing the expression of RGMa and observed the improvement in axonal regeneration and neurological function of rats after cerebral ischemic injury. Recombinant adenovirus rAd5-shRNA-RGMa was constructed and prepared for animal experimentation. RGMa and neurofilament protein 200 (NF200) in the ischemic cortex and ipsilateral hippocampus were detected by reverse transcription polymerase chain reaction (RT-PCR) and immunohistochemistry. The ischemic regions were examined by triphenyltetrazolium chloride (TTC) staining and the newborn neurite branches by Biotinylated Dextran Amine (BDA) neuronal tracing. Behavior tests were adopted to evaluate neurologic function recovery. Results showed RGMa was down-regulated and axonal growth was improved in the RNAi treated group (P<0.01). The number of axonal sprouts of corticospinal tract from the uninjured side to the ischemic side in the RNAi treated group was increased (P<0.01). Behavior test scores in the RNAi treated group were significantly better than other groups after 6 weeks (P<0.01). RGMa in rat brains after middle cerebral artery occlusion (MCAO) can be down-regulated by RNAi successfully, which may lead to improved axonal growth and neural anatomy plasticity, as well as neuron functional recovery. PMID- 22921460 TI - Up-regulation of brain-derived neurotrophic factor is regulated by extracellular signal-regulated protein kinase 5 and by nerve growth factor retrograde signaling in colonic afferent neurons in colitis. AB - Brain-derived neurotrophic factor (BDNF) plays an essential role in sensory neuronal activation in response to visceral inflammation. Here we report that BDNF up-regulation in the primary afferent neurons in the dorsal root ganglia (DRG) in a rat model of colitis is mediated by the activation of endogenous extracellular signal-regulated protein kinase (ERK) 5 and by nerve growth factor (NGF) retrograde signaling. At 7 days of colitis, the expression level of BDNF is increased in conventional neuronal tracing dye Fast Blue labeled primary afferent neurons that project to the distal colon. In these neurons, the phosphorylation (activation) level of ERK5 is also increased. In contrast, the level of phospho ERK1/2 is not changed in the DRG during colitis. Prevention of the ERK5 activation in vivo with an intrathecal application of the MEK inhibitor PD98059 significantly attenuates the colitis-induced increases in BDNF expression in the DRG. Further studies show that BDNF up-regulation in the DRG is triggered by NGF retrograde signaling which also involves activation of the MEK/ERK pathways. Application of exogenous NGF exclusively to the compartment containing DRG nerve terminals in an ex vivo ganglia-nerve preparation markedly increases the BDNF expression level in the DRG neuronal cell body that is placed in a different compartment; this BDNF elevation is attenuated by U0126, PD98059 and a specific ERK5 inhibitor BIX02188. These results demonstrate the mechanisms and pathways by which BDNF expression is elevated in primary sensory neurons following visceral inflammation that is mediated by increased activity of ERK5 and is likely to be triggered by the elevated NGF level in the inflamed viscera. PMID- 22921462 TI - Apnea produces excitotoxic hippocampal synapses and neuronal apoptosis. AB - Obstructive sleep apnea (OSA) results in the degeneration of neurons in the hippocampus that eventuates in neurocognitive deficits. We were therefore interested in determining the effects of apnea on monosynaptic excitatory processes in a hippocampal pathway (cornu ammonis 3-cornu ammonis 1, CA3-CA1) that has been shown to mediate the processing of cognitive information. In addition, to substantiate an anatomical basis for the cognitive dysfunction that occurs in OSA patients, we examined the effects of apnea with respect to neurodegenerative changes (apoptosis) in the same hippocampal pathway. In order to determine the effects of apnea, an automated system for the generation and analysis of single and recurrent periods of apnea was developed. Utilizing this system, the field excitatory postsynaptic potential (fEPSP) generated by pyramidal neurons in the CA1 region of the hippocampus was monitored in alpha chloralose anesthetized rats following stimulation of glutamatergic afferents in the CA3 region. A stimulus-response (input-output) curve for CA3-CA1 synaptic activity was determined. In addition, a paired-pulse paradigm was employed to evaluate, electrophysiologically, the presynaptic release of glutamate. Changes in the synaptic efficacy were assessed following single episodes of apnea induced by ventilatory arrest (60 to 80 s duration, mean=72 s; mean oxygen desaturation was 53% of normoxia level). Apnea resulted in a significant potentiation of the amplitude (mean=126%) and slope (mean=117%) of the baseline CA1 fEPSP. This increase in the fEPSP was accompanied by a significant decrease in the amplitude (71%) and slope (81%) of normalized paired-pulse facilitation (PPF) ratios. Since the potentiation of the fEPSP is inversely proportional to changes in PPF ratio, the potentiated fEPSP accompanied by the reduced PPF reveals that apnea produces an abnormal increase in the preterminal release of glutamate that results in the over-activation (and calcium overloading) of hippocampal CA1 neurons. Thus, we conclude that individual episodes of apnea result in the development of excitotoxic processes in the hippocampal CA3-CA1 pathway that is critically involved in the processing of cognitive information. Morphologically, the deleterious effect of recurrent apnea was substantiated by the finding of apoptosis in CA1 neurons of apneic (but not normoxic) animals. PMID- 22921461 TI - TNF-alpha triggers rapid membrane insertion of Ca(2+) permeable AMPA receptors into adult motor neurons and enhances their susceptibility to slow excitotoxic injury. AB - Excitotoxicity (caused by over-activation of glutamate receptors) and inflammation both contribute to motor neuron (MN) damage in amyotrophic lateral sclerosis (ALS) and other diseases of the spinal cord. Microglial and astrocytic activation in these conditions results in release of inflammatory mediators, including the cytokine, tumor necrosis factor-alpha (TNF-alpha). TNF-alpha has complex effects on neurons, one of which is to trigger rapid membrane insertion of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) type glutamate receptors, and in some cases, specific insertion of GluA2 lacking, Ca(2+) permeable AMPA receptors (Ca-perm AMPAr). In the present study, we use a histochemical stain based upon kainate stimulated uptake of cobalt ions ("Co(2+) labeling") to provide the first direct demonstration of the presence of substantial numbers of Ca-perm AMPAr in ventral horn MNs of adult rats under basal conditions. We further find that TNF-alpha exposure causes a rapid increase in the numbers of these receptors, via a phosphatidylinositol 3 kinase (PI3K) and protein kinase A (PKA) dependent mechanism. Finally, to assess the relevance of TNF-alpha to slow excitotoxic MN injury, we made use of organotypic spinal cord slice cultures. Co(2+) labeling revealed that MNs in these cultures possess Ca perm AMPAr. Addition of either a low level of TNF-alpha, or of the glutamate uptake blocker, trans-pyrrolidine-2,4-dicarboxylic acid (PDC) to the cultures for 48 h resulted in little MN injury. However, when combined, TNF-alpha+PDC caused considerable MN degeneration, which was blocked by the AMPA/kainate receptor blocker, 2,3-Dihydroxy-6-nitro-7-sulfamoylbenzo (F) quinoxaline (NBQX), or the Ca perm AMPAr selective blocker, 1-naphthyl acetylspermine (NASPM). Thus, these data support the idea that prolonged TNF-alpha elevation, as may be induced by glial activation, acts in part by increasing the numbers of Ca-perm AMPAr on MNs to enhance injurious excitotoxic effects of deficient astrocytic glutamate transport. PMID- 22921463 TI - Deficits in auditory, cognitive, and motor processing following reversible middle cerebral artery occlusion in mice. AB - Middle cerebral artery occlusion(1) (MCAO) is a widely used experimental technique in rodents to model both the short-term pathological events and longer term neuroanatomical and functional damage associated with focal ischemia. Various neurobehavioral tasks have been developed to assess the motor and cognitive dysfunctions associated with MCAO in rodents, and these studies have revealed deficits related to long-term sensorimotor function, as well as retention of spatial memory. Assessment of auditory processing in a MCAO model has not been undertaken, despite findings suggesting an auditory processing deficit in humans with stroke induced-aphasia, a common post-stroke deficit. Using a modified pre-pulse inhibition paradigm, and other behavioral tasks thought to tap "language-related processing", adult male C57Bl/6 mice were subjected to 60 minute MCAO or Sham surgery and were behaviorally assessed from P58 to P124 (2 to 65 days post-surgery). Tasks were selected based on evidence that rapid auditory processing(2) (RAP) skills are associated with language processing indices in clinical populations. Cognitive and sensorimotor ability was evaluated using the Morris water maze, non-spatial water maze, and a post injury rotarod task administered over multiple days (motor learning). Combined behavioral results from post-MCAO mice provide evidence of a RAP deficit as well as deficits in spatial, non-spatial, and motor learning. Overall results support a fuller characterization of behavioral deficits in auditory processing after MCAO. PMID- 22921464 TI - National differences in ulcerative colitis experience and management among patients from five European countries and Canada: an online survey. AB - BACKGROUND AND AIMS: Patients' and physicians' perceptions of ulcerative colitis and its management are important for developing and guiding appropriate therapies. This study explored national differences in patients' and physicians' experiences, expectations, and beliefs about ulcerative colitis. METHODS: Structured, cross-sectional, online surveys evaluating various indices were completed by 775 adult patients with ulcerative colitis and 475 physicians actively managing ulcerative colitis patients from France, Germany, Ireland, Spain, the United Kingdom, and Canada. RESULTS: Patients' classification of their symptom severity differed across countries (mild, 16%-45%; moderate, 46%-58%; severe, 4%-36%). Expectations of disease control also varied, with 26% (Ireland) to 65% (Spain) describing that remission realistically involves "living without symptoms." Within each country, more patients (45%-69%) than physicians (28%-45%) considered ulcerative colitis symptoms to affect patients' quality of life. Mean number of patient-reported flares during the past year ranged from 2.5 in Ireland to 8.0 in France. Self-reported adherence with oral 5-aminosalicylic acid (during remission) was highest in Spain (91% vs 50%-73% across other countries). Spanish patients were more likely to self-adjust their medications (54% vs 2%-5%), but reported the most dissatisfaction with therapy (42% vs 9%-27%). Irish patients were least likely to arrange physician/specialist nurse visits (14% vs 36%-49%) and least open to discussion of their condition. CONCLUSIONS: Important national differences in ulcerative colitis patients' attitudes and perceptions were observed, which may help physicians improve patient care based on country specific needs and influence self-assessments in clinical trials. The results suggest a need for structured patient education to improve adherence and outcomes. PMID- 22921466 TI - The prevalence of inflammatory bowel disease in an Israeli Arab population. AB - AIMS: To determine the prevalence of inflammatory bowel disease among the 1.5 million Arab residents in Israel who represent 20% of the total population. METHODS: Family physicians in all Arab towns and villages were contacted to obtain information on patients with inflammatory bowel disease. Relevant clinical data were retrieved and updated to December 31, 2009. RESULTS: Information was obtained from 23/71 municipalities approached (representing 200,000 out of 1.5 million Arabs). There were 64 confirmed cases of Crohn's disease indicating a prevalence rate of 32/100,000. The rate of smoking within this cohort was lower than in the general population (1.5% vs. 40%; P<0.001). There were 44 confirmed cases of ulcerative colitis with a prevalence rate of 22/100,000. The percentage of active smokers in this cohort was 18%. Clinical remission or mild activity was observed in 75% of patients in both cohorts at the time of the survey. Fourteen patients (21%) had undergone surgery for Crohn's disease, whereas none had undergone surgery for ulcerative colitis. Twenty-eight (42%) patients with Crohn's disease and 20 (45%) with ulcerative colitis were on maintenance therapy with 5-aminosalicylic acid. Only 18% with Crohn's disease and 6.8% with ulcerative colitis had received anti-tumor necrosis factor. The most prevalent extra-intestinal manifestations were perianal disease (18%) in Crohn's disease, and arthralgia or arthritis (6.8%) in ulcerative colitis. CONCLUSIONS: We found a low prevalence rate of inflammatory bowel disease in the Israeli Arab population. PMID- 22921465 TI - Plasminogen activator inhibitor-1 is increased in colonic epithelial cells from patients with colitis-associated cancer. AB - BACKGROUND: Patients with long-term ulcerative colitis are at risk for developing colorectal cancer. METHODS: Archival formalin-fixed paraffin-embedded tissue from ulcerative colitis patients who underwent a colectomy for high-grade dysplasia or carcinoma was examined for changes in expression of plasminogen activator inhibitor-1 (PAI-1) as well as other mediators of inflammation-associated cancer. Epithelia from areas of colons that showed histologic evidence of carcinoma, high grade dysplasia, and epithelia that were not dysplastic or malignant but did contain evidence of prior inflammation (quiescent colitis) was microdissected using laser capture microscopy. mRNA was extracted from the microdissected tissue and PCR array analysis was performed. To extend our findings, PAI-1 protein levels were determined using immunohistochemistry. RESULTS: The mRNA expression of PAI-1 is increased 6-fold (p=0.02) when comparing the carcinoma group to the quiescent colitis group; increases were also observed in NFKB2, REL, SRC, and VEGFA. The protein levels of PAI-1 are increased by 50% (p<0.001) in high-grade dysplasia and by 60% (p<0.001) in carcinoma when compared to the quiescent colitis group. CONCLUSIONS: The increase in PAI-1 in high-grade dysplasia and carcinoma suggests a functional role for PAI-1 in malignant transformation in colitis-associated cancer. PAI-1 could also prove a useful diagnostic marker to identify patients at risk for neoplasia and it may be a useful therapeutic target to treat colitis-associated cancer. PMID- 22921467 TI - Reply to Dr. Katsanos et al.'s letter. PMID- 22921468 TI - Electro-clinical features and magnetic resonance imaging correlates in Menkes disease. AB - BACKGROUND: Epilepsy is an early and important feature in Menkes disease (MD), an X-linked recessive neurodegenerative disorder of childhood with defect in copper metabolism. There are only few reports on the electro-clinical and magnetic resonance imaging correlates in Menkes disease. The current study describes the electro-clinical features in MD in relation with the structural findings on MRI. PATIENTS AND METHODS: Six patients from five families were evaluated between 2005 and 2011. Their diagnosis was based on the characteristic morphological features, microscopic evidence of pili torti and low copper and ceruloplasmin levels. All the patients underwent MRI and EEG as part of the evaluation. RESULTS: All patients had classical form of MD with typical morphological features. All but one patient had refractory seizures. Seizure types included multifocal clonic seizures (n=3), myoclonic jerks (n=4) and tonic spasms (n=1). EEG was markedly abnormal in all except in the patient without clinical seizures. While focal epileptiform discharges predominated before six months of age modified hypsarrhythmia was characteristically noted thereafter. MR Imaging revealed abnormalities in all patients, with cerebral atrophy and delayed myelination being the most common observations. Other features noted were subdural effusion (n=3), leukoencephalopathy (n=3) and basal ganglia signal changes (n=1). Follow up imaging in three patients showed resolution of white matter signal intensity changes. CONCLUSIONS: Electro-clinical features in Menkes disease are age dependent and evolve sequentially. White matter changes coincided with acute exacerbation of seizures. There was fair correlation between the electro-clinical features and structural findings on MRI. PMID- 22921469 TI - Protein domain repetition is enriched in Streptococcal cell-surface proteins. AB - Tandem repetition of domain in protein sequence occurs in all three domains of life. It creates protein diversity and adds functional complexity in organisms. In this work, we analyzed 52 streptococcal genomes and found 3748 proteins contained domain repeats. Proteins not harboring domain repeats are significantly enriched in cytoplasm, whereas proteins with domain repeats are significantly enriched in cytoplasmic membrane, cell wall and extracellular locations. Domain repetition occurs most frequently in S. pneumoniae and least in S. thermophilus and S. pyogenes. DUF1542 is the highest repeated domain in a single protein, followed by Rib, CW_binding_1, G5 and HemolysinCabind. 3D structures of 24 repeat containing proteins were predicted to investigate the structural and functional effect of domain repetition. Several repeat-containing streptococcal cell surface proteins are known to be virulence-associated. Surface-associated tandem domain containing proteins without experimental functional characterization may be potentially involved in the pathogenesis of streptococci and deserve further investigation. PMID- 22921470 TI - Trajectory in obsessive-compulsive disorder comorbidities. AB - The main goal of this study is to contribute to the understanding of the trajectory of comorbid disorders associated with obsessive-compulsive disorder (OCD) according to the first manifested psychiatric disorder and its impact in the clinical course of OCD and subsequent psychiatric comorbidities. One thousand and one OCD patients were evaluated at a single time point. Standardized instruments were used to determine the current and lifetime psychiatric diagnoses (Structured Clinical Interview for DSM-IV Axis I and for impulse-control disorders) as well as to establish current obsessive-compulsive, depressive and anxiety symptom severity (Yale-Brown Obsessive-Compulsive Scale; Dimensional Yale Brown Obsessive-Compulsive Scale, Beck Depression and Anxiety Inventories and the OCD Natural History Questionnaire). To analyze the distribution of comorbidities according to age at onset Bayesian approach was used. Five hundred eight patients had the first OC symptom onset till the age of 10 years old. The first comorbidity to appear in the majority of the sample was separation anxiety disorder (17.5%, n=175), followed by ADHD (5.0%, n=50) and tic disorders (4.4%, n=44). OCD patients that presented with separation anxiety disorder as first diagnosis had higher lifetime frequency of post-traumatic stress disorder (p=0.003), higher scores in the Sexual/Religious dimension (p=0.04), Beck Anxiety (p<0.001) and Depression (p=0.005) Inventories. OCD patients that initially presented with ADHD had higher lifetime frequencies of substance abuse and dependence (p<0.001) and worsening OCD course (p=0.03). OCD patients that presented with tic disorders as first diagnosis had higher lifetime frequencies of OC spectrum disorders (p=0.03). OCD is a heterogeneous disorder and that the presence of specific comorbid diagnoses that predate the onset of OCD may influence its clinical presentation and course over the lifetime. PMID- 22921471 TI - Cell-specific regulation of Ferroportin transcription following experimentally induced acute anemia in mice. AB - Ferroportin (FPN), the sole characterized iron exporter, is mainly controlled by the peptide hormone hepcidin in response to iron, erythroid factors, hypoxia, and inflammation. In addition, intracellular iron level controls FPN translation by modulating the binding of Iron Responsive Proteins at the 5'UTR of FPN mRNA. Recently, hypoxia inducible factor (HIF)2alpha has been shown to regulate FPN expression in intestinal cells. Here we show that, during experimentally-induced acute anemia in mice, FPN is regulated at transcriptional level in a cell specific manner. FPN mRNA level increases in duodenum and spleen macrophages, whereas it does not change in liver and is strongly down-regulated in erythroid precursors. These results were confirmed in Caco2, Raw264.7 and K562 cells treated with a hypoxic stimulus. Moreover, we found a differential expression of HIF1alpha and HIF2alpha in cells and tissues that might account for the specificity of FPN regulation. Thus, hypoxia, by directly controlling hepcidin and its target FPN, orchestrates a complex regulatory network aimed at ensuring rapid iron recovery from the periphery and efficient iron utilization in the erythroid compartment. PMID- 22921472 TI - [Editorial]. PMID- 22921473 TI - Molecular aspects of thymic carcinoma. AB - Thymic carcinomas are tumors of the anterior mediastinum derived from the epithelial cells of the thymic gland. Due to their low incidence they are often investigated in combination with thymomas under the rubric of "thymic epithelial neoplasms" and studies exclusively addressing thymic carcinomas are sparse. Thymic carcinomas are characterized by their histologic variability, often resembling tumors seen in other organ systems. This morphologic variation coupled with their rarity has prevented large scale research of these tumors and little is known about the etiology, biologic behavior or best treatment for thymic carcinoma. In recent years, attempts have been made to investigate the molecular characteristics of these tumors in the hope that molecular profiling can be used to predict the prognosis or lead to the development of new treatment strategies. Herein we provide an overview of the recent advances of the molecular analysis of thymic carcinoma with particular emphasis on the potential use for molecularly targeted therapies. PMID- 22921474 TI - The dose effects of short-term dronabinol (oral THC) maintenance in daily cannabis users. AB - BACKGROUND: Prior studies have separately examined the effects of dronabinol (oral THC) on cannabis withdrawal, cognitive performance, and the acute effects of smoked cannabis. A single study examining these clinically relevant domains would benefit the continued evaluation of dronabinol as a potential medication for the treatment of cannabis use disorders. METHODS: Thirteen daily cannabis smokers completed a within-subject crossover study and received 0, 30, 60 and 120mg dronabinol per day for 5 consecutive days. Vital signs and subjective ratings of cannabis withdrawal, craving and sleep were obtained daily; outcomes under active dose conditions were compared to those obtained under placebo dosing. On the 5th day of medication maintenance, participants completed a comprehensive cognitive performance battery and then smoked five puffs of cannabis for subjective effects evaluation. Each dronabinol maintenance period occurred in a counterbalanced order and was separated by 9 days of ad libitum cannabis use. RESULTS: Dronabinol dose-dependently attenuated cannabis withdrawal and resulted in few adverse side effects or decrements in cognitive performance. Surprisingly, dronabinol did not alter the subjective effects of smoked cannabis, but cannabis-induced increases in heart rate were attenuated by the 60 and 120mg doses. CONCLUSIONS: Dronabinol's ability to dose-dependently suppress cannabis withdrawal may be therapeutically beneficial to individuals trying to stop cannabis use. The absence of gross cognitive impairment or side effects in this study supports safety of doses up to 120mg/day. Continued evaluation of dronabinol in targeted clinical studies of cannabis treatment, using an expanded range of doses, is warranted. PMID- 22921475 TI - Assessment of riboflavin as a tracer substance: comparison of a qualitative to a quantitative method of riboflavin measurement. AB - BACKGROUND: Noncompliance with medications may have major impacts on outcomes measured in research, potentially distorting the validity of controlled clinical trials. Riboflavin is frequently used in trials as a marker of adherence. It can be combined with study medication and is excreted in urine where it fluoresces under UV light. This study compares qualitative visual inspection of fluorescence to quantitative fluorometric analysis of riboflavin concentration in its ability to detect the presence of riboflavin in urine. METHODS: Twenty-four volunteers received 0mg, 25mg, and 50mg doses of riboflavin under single-blind conditions, with 20 also receiving a 100mg dose. Five serial urine samples were collected over the following 36h. Quantitative measurement of riboflavin by fluorometric analysis and qualitative assessment of each sample using visual inspection were performed. RESULTS: The overall false positive rate for qualitative assessment was 53%. For quantitative assessment, a riboflavin concentration of 900ng/mL was established to classify positive samples. More than 80% of samples were positive 2-24h following ingestion of 25mg and 50mg, and less than 80% were positive at 36h. At least 95% of observations for the 100mg dose were above 900ng/mL at all timepoints. CONCLUSIONS: Quantitative fluorometric assessment is superior to qualitative visual inspection alone in determining medication adherence. The combination of 25-50mg of daily riboflavin and a cut-off level of 900ng/mL allows for the acceptable sensitivity of missing detection of non-compliant participants while preserving a high level of power to detect all cases of medication compliance. PMID- 22921476 TI - Buprenorphine/Naloxone and methadone effects on laboratory indices of liver health: a randomized trial. AB - BACKGROUND: Buprenorphine/naloxone (BUP) and methadone (MET) are efficacious treatments for opioid dependence, although concerns about a link between BUP and drug-induced hepatitis have been raised. This study compares the effects of BUP and MET on liver health in opioid-dependent participants. METHODS: This was a randomized controlled trial of 1269 opioid-dependent participants seeking treatment at 8 federally licensed opioid treatment programs and followed for up to 32 weeks between May 2006 and August 2010; 731 participants met "evaluable" criteria defined as completing 24 weeks of medication and providing at least 4 blood samples for transaminase testing. Participants were randomly assigned to receive BUP or MET for 24 weeks. Shift table analysis determined how many evaluable participants moved between categories of low and elevated transaminase levels. Predictors of moving from low to high transaminase levels were identified. RESULTS: Changes in transaminase levels did not differ by medication condition. Baseline infection with hepatitis C or B was the only significant predictor of moving from low to elevated transaminase levels; 9 BUP and 15 MET participants showed extreme liver test elevations and were more likely than those without extreme elevations to have seroconverted to both hepatitis B and C during the study, or to use illicit drugs during the first 8 weeks of treatment. MET participants were retained longer in treatment than BUP participants. CONCLUSIONS: This study demonstrated no evidence of liver damage during the initial 6 months of treatment in either condition. Physicians can prescribe either medication without major concern for liver injury. PMID- 22921477 TI - 3D models of human ERalpha and ERbeta complexed with 5-androsten-3beta,17beta diol. AB - Recently, binding of 5-androsten-3beta,17beta-diol (Delta(5)-androstenediol) to human estrogen receptor-beta (ERbeta) was found to repress microglia-mediated inflammation, which is associated with various neurodegenerative diseases, such as multiple sclerosis. In contrast, binding of estradiol to ERbeta resulted in little or no repression of microglia-mediated inflammation. Binding of Delta(5) androstenediol to ERbeta, as well as to ERalpha, is unexpected because unlike estradiol, Delta(5)-androstenediol has a saturated A ring and a C19 methyl group. To begin to elucidate the interaction of Delta(5)-androstenediol with both ERs, we constructed 3D models of Delta(5)-androstenediol with human ERalpha and ERbeta for comparison with the crystal structures of estradiol in ERalpha and ERbeta. Conformational flexibility in human ERalpha and ERbeta accommodates the C19 methyl on Delta(5)-androstenediol. This conformational flexibility may be relevant for binding of other Delta(5)-steroids with C19 methyl substituents, such as 25-hydroxycholesterol and 27-hydroxycholesterol, to ERs. PMID- 22921478 TI - New foot remains from the Gran Dolina-TD6 Early Pleistocene site (Sierra de Atapuerca, Burgos, Spain). AB - This paper presents and describes new foot fossils from the species Homo antecessor, found in level TD6 of the site of Gran Dolina (Sierra de Atapuerca, Burgos, Spain). These new fossils consist of an almost complete left talus (ATD6 95) and the proximal three-quarters of a right fourth metatarsal (ATD6-124). The talus ATD6-95 is tentatively assigned to Hominin 10 of the TD6 sample, an adult male specimen with which the second metatarsal ATD6-70+107 (already published) is also tentatively associated. Analysis of these fossils and other postcranial remains has made possible to estimate a stature similar to those of the specimens from the Middle Pleistocene site of Sima de los Huesos (Sierra de Atapuerca, Burgos, Spain). The morphology of the TD6 metatarsals does not differ significantly from that of modern humans, Neanderthals and the specimens from Sima de los Huesos. Talus ATD6-95, however, differs from the rest of the comparative samples in being long and high, having a long and wide trochlea, and displaying a proportionally short neck. PMID- 22921479 TI - The expression of affective temperaments in daily life. AB - BACKGROUND: Numerous validation studies have examined the TEMPS-A in both clinical and nonclinical samples. However, the majority of these studies utilized cross-sectional assessments in laboratory or clinical settings. The present study is the first to examine the expression of affective temperaments in daily life using experience sampling methodology (ESM). METHODS: 138 participants completed the TEMPS-A and received a personalized digital assistant that signaled them eight times daily for one week to complete questionnaires that assessed affect, cognition, behavior, sense of self, and social interaction. RESULTS: As expected, cyclothymic/irritable temperament was positively associated with negative affect, risky behavior, and restlessness, and was negatively associated with positive affect and preference to be with others in daily life. In contrast, hyperthymic temperament was associated with positive affect, fullness of thought, doing many and exciting things, grandiosity, and preference to be with others in daily life. Dysthymic temperament was modestly associated with worry, and was positively associated with trouble concentrating, fullness of thought, and a preference for social contact. Cross-level interactions indicated that cyclothymic/irritable temperament was associated with elevated stress reactivity in daily life. LIMITATIONS: ESM data collection was limited to one week. Longer assessment periods might better capture the cyclical nature of affective temperaments. CONCLUSIONS: This was the first study to examine affective temperaments in daily life. The findings offer further validation of the TEMPS-A, as well as the maladaptive nature of the cyclothymic/irritable temperament. PMID- 22921480 TI - Is coping well a matter of personality? A study of euthymic unipolar and bipolar patients. AB - BACKGROUND: Euthymic bipolar disorder (BD) patients often demonstrate better clinical outcomes than remitted patients with unipolar illness (UP). Reasons for this are uncertain, however, personality and coping styles are each likely to play a key role. This study examined differences between euthymic BD and UP patients with respect to the inter-relationship between personality, coping style, and clinical outcomes. METHODS: A total of 96 UP and 77 BD euthymic patients were recruited through the CADE Clinic, Royal North Shore Hospital in Sydney, and assessed by a team comprising Psychiatrists and Psychologists. They underwent a structured clinical diagnostic interview, and completed self-report measures of depression, anxiety, stress, personality, coping, social adjustment, self-esteem, dysfunctional attitudes, and fear of negative evaluation. RESULTS: Compared to UP, BD patients reported significantly higher scores on levels of extraversion, adaptive coping, self-esteem, and lower scores on trait anxiety and fear of negative evaluation. Extraversion correlated positively with self-esteem, adaptive coping styles, and negatively with trait anxiety and fear of negative evaluation. Trait anxiety and fear of negative evaluation correlated positively with eachother, and both correlated negatively with self-esteem and adaptive coping styles. Finally, self-esteem correlated positively with adaptive coping styles. LIMITATIONS: The results cannot be generalised to depressive states of BD and UP, as differences in the course of illness and types of depression are likely to impact on coping and clinical outcomes, particularly for BD. CONCLUSIONS: During remission, functioning is perhaps better 'preserved' in BD than in UP, possibly because of the protective role of extraversion which drives healthier coping styles. PMID- 22921481 TI - Different levels of lack of improvement at 4 weeks of escitalopram treatment as predictors of poor 8-week outcome in MDD. AB - BACKGROUND: Several post-hoc studies have shown that lack of early improvement reduces the chance of later response or remission. This post-hoc analysis evaluates different cut-off points of non-improvement at 4 weeks of escitalopram treatment to predict 8-week non-response and non-remission. METHOD: This study consisted of MDD patients with an absence of improvement (<30% reduction in baseline score of the HAMD-17) at Week 4 of escitalopram treatment (10mg/day) that continued escitalopram treatment (10-20mg/day) for a further 4-week period (n=251). Predictive, sensitivity and specificity values for the several definitions of non-improvement (<= 25%, <= 20% and <= 15% reduction in the HAMD 17 baseline total score) at 4 weeks were calculated. RESULTS: Overall, 70.1% (176/251) of patients did not achieve response at Week 8 and 84.5% (212/251) did not achieve remission. The predictive value for non-response was high (71.4 74.3%) for all cut-off points of non-improvement tested. The respective values for non-remission were placed between 85.0% and 87.2%. LIMITATIONS: This was a post-hoc subgroup analysis. The only drug assessed was escitalopram. CONCLUSIONS: Our data indicate that an absence of improvement, <30% reduction in the HAMD-17, after 4 weeks of escitalopram treatment should prompt clinicians to consider a change in treatment strategy. Similar findings were previously reported for other antidepressants. PMID- 22921482 TI - Intolerance of uncertainty as a vulnerability factor for hoarding behaviors. AB - BACKGROUND: Intolerance of uncertainty (IU) has been identified as a key vulnerability factor among numerous anxiety related conditions. It has been suggested that individuals engage in uncertainty-motivated behaviors such as avoidance, as a way to cope with ambiguous and potentially distressing situations. Patterns of behavioral avoidance have also been observed in a substantial number of hoarding patients and are thought to directly contribute to the avoidance of discarding. However, no studies to date have examined the potential relationship between IU and hoarding. The primary aim of the current investigation was to examine the association between IU and hoarding behaviors. METHOD: Participants consisted of 279 college students from a large southern university. RESULTS: Results revealed that IU was a significant predictor of hoarding severity after controlling for relevant covariates. Moreover, when looking at the relationships among IU subfactors and hoarding, results indicated that Factor 1 was significantly associated with hoarding severity whereas Factor 2 was not. LIMITATIONS: Future research should attempt to replicate the findings within clinical populations. Additionally, due to the cross sectional nature of the study, future work should utilize a longitudinal design. CONCLUSIONS: The current study provides additional evidence that IU is an important individual difference variable associated with various anxiety related conditions. Moreover, our findings revealed that IU is a unique and robust predictor of hoarding behaviors. Increasing our knowledge of vulnerability factors in compulsive hoarding has important implications for the classification of this disorder within DSM-V. Additionally, this information could inform future research and treatment programs. PMID- 22921483 TI - Developmental validation of the PowerPlex(r) 18D System, a rapid STR multiplex for analysis of reference samples. AB - As short tandem repeat markers remain the foundation of human identification throughout the world, new STR multiplexes require rigorous testing to ensure the assays are sufficiently robust and reliable for genotyping purposes. The PowerPlex((r)) 18D System was created for the direct amplification of buccal and blood samples from FTA((r)) storage cards and reliably accommodates other sample materials. The PowerPlex((r)) 18D System allows simultaneous amplification of the 13 CODIS loci and amelogenin along with four additional loci: Penta E, Penta D, D2S1338, and D19S433. To demonstrate suitability for human identification testing, the PowerPlex((r)) 18D System was tested for sensitivity, concordance, inhibitor tolerance, and performance with thermal cycling and reaction condition variation following SWGDAM developmental validation guidelines. Given these results, PowerPlex((r)) 18D System can confidently be used for forensic and human identification testing. PMID- 22921484 TI - Progressive axonal dysfunction and clinical impairment in amyotrophic lateral sclerosis. AB - OBJECTIVE: To elucidate longitudinal changes in axonal function in amyotrophic lateral sclerosis (ALS) patients, and to relate such changes with motor unit loss and functional impairment. METHODS: 37 ALS patients (age, 53.7 +/- 1.7 years; 22 males) were studied using axonal excitability techniques at baseline and 12 weeks follow-up. RESULTS: Longitudinal measurements across excitability parameters suggested increasing K(+) channel dysfunction, with further increases in depolarising threshold electrotonus (90-100 ms, baseline, 46.8 +/- 1.0%; follow up, 48.7 +/- 0.8%; P=0.02) and superexcitability (baseline, -24.0 +/- 1.2%; 12 weeks, -26.0 +/- 1.2%; P=0.04). Patients with preserved compound muscle action potential (CMAP) amplitude at follow-up developed more severe changes in axonal excitability than those in whom CMAP decreased from baseline, suggesting that the most pronounced disease effects were on motor axons immediately prior to axonal loss in ALS patients. Fine motor decline was associated with more severe changes in axonal excitability, suggesting that functional impairment was related to axonal dysfunction. CONCLUSIONS: Longitudinal changes in axonal excitability in ALS patients suggest increasing K(+) channel dysfunction in motor axons. SIGNIFICANCE: Axonal excitability studies enable investigation of longitudinal changes in axonal ion channel dysfunction, and thereby the processes that potentially contribute to axonal degeneration in ALS. PMID- 22921485 TI - The effect of electronic medical record-based clinical decision support on HIV care in resource-constrained settings: a systematic review. AB - BACKGROUND: It is estimated that one million people infected with HIV initiate anti-retroviral therapy (ART) in resource-constrained countries annually. This occurs against a background of overburdened health workers with limited skills to handle rapidly changing treatment standards and guidelines hence compromising quality of care. Electronic medical record (EMR)-based clinical decision support systems (CDSS) are considered a solution to improve quality of care. Little evidence, however, exists on the effectiveness of EMR-based CDSS on quality of HIV care and treatment in resource-constrained settings. OBJECTIVE: The aim of this systematic review was to identify original studies on EMR-based CDSS describing process and outcome measures as well as reported barriers to their implementation in resource-constrained settings. We characterized the studies by guideline adherence, data and process, and barriers to CDSS implementation. METHODS: Two reviewers independently assessed original articles from a search of the MEDLINE, EMBASE, CINAHL and Global Health Library databases until January 2012. The included articles were those that evaluated or described the implementation of EMR-based CDSS that were used in HIV care in low-income countries. RESULTS: A total of 12 studies met the inclusion criteria, 10 of which were conducted in sub-Saharan Africa and 2 in the Caribbean. None of the papers described a strong (randomized controlled) evaluation design. Guideline adherence: One study showed that ordering rates for CD4 tests were significantly higher when reminders were used. Data and process: Studies reported reduction in data errors, reduction in missed appointments, reduction in missed CD4 results and reduction in patient waiting time. Two studies showed a significant increase in time spent by clinicians on direct patient care. Barriers to CDSS implementation: Technical infrastructure problems such as unreliable electric power and erratic Internet connectivity, clinicians' limited computer skills and failure by providers to comply with the reminders are key impediments to the implementation and effective use of CDSS. CONCLUSION: The limited number of evaluation studies, the basic and heterogeneous study designs, and varied outcome measures make it difficult to meaningfully conclude on the effectiveness of CDSS on quality of HIV care and treatment in resource-limited settings. High quality evaluation studies are needed. Factors specific to implementation of EMR-based CDSS in resource-limited setting should be addressed before such countries can demonstrate its full benefits. More work needs to be done to overcome the barriers to EMR and CDSS implementation in developing countries such as technical infrastructure and care providers' computer illiteracy. However, simultaneously evaluating and describing CDSS implementation strategies that work can further guide wise investments in their wider rollout. PMID- 22921486 TI - Construction and validation of lentiviral vector carrying rat neuronal nitric oxide synthase in vitro and in vivo. AB - In the present study, we developed a lentiviral vector with human cytomegalovirus promoter permitting high-level of nNOS expression. Neuronal cell line NG108 was used as an in vitro model to check the validity of gene transfer. The cells were infected with lenti-EGFP or lenti-nNOS particles for 24h. Lenti-nNOS infection in the NG108 cells induced dose dependent increase in mRNA and protein for nNOS; with a dose of 2.5 * 104 pfu/ml, nNOS mRNA expression increased by 40-fold while protein expression was increased by 2.5-fold compared to lenti-EGFP. Moreover, lenti-nNOS infection caused a greater increase in nNOS immunoreactivity in NG108 cells compared to lenti-EGFP as shown by immonocytochemistry. nNOS expression showed time dependent increases with lenti-nNOS infection with maximum up regulation observed after two weeks of infection. Moreover, in vivo, unilateral injection of lenti-nNOS into the paraventricular nucleus (PVN) of rats induced a 27-fold increase of nNOS protein level in the injected side compared to non injected side and this escalation was sustained up to three weeks. Overall, lenti EGFP injection in the PVN did not show any significant change in nNOS expression. Furthermore, NADPH-diaphorase staining of nNOS in the PVN infected with lenti nNOS induced a visible increase in nNOS expression compared with contralateral non-injected side up to three weeks. These results indicate that this approach of lentiviral mediated gene transfer of nNOS may provide a new means to up-regulate the nNOS expression for longer periods of time compared to adenoviral transfection and can be used as a research tool and potentially a therapy for chronic diseases involving impaired nNOS expression. PMID- 22921487 TI - A new percutaneous model of Subarachnoid Haemorrhage in rats. AB - OBJECTIVE: Describe the results obtained with a new percutaneous, intracisternal model of Subarachnoid Haemorrhage (SAH) in Wistar rats by a single injection of non-heparinised, autologous blood. METHODS: Once anaesthetized the rat was fixed prone in a stereotaxic frame. After identifying the projection of the occipital bone, the needle of the stereotaxic frame aspirated towards the foramen magnum until it punctured through the atlanto-occipital membrane and obtained cerebrospinal fluid. Autologous blood (100 MUl) was withdrawn from the tail and injected intracisternally. This procedure was repeated in the sham group, injecting 100 MUl of isotonic saline. On the fifth day post-intervention, the rats were anaesthetized and the brain was exposed. After a lethal injection of ketamine the brain was explanted and fixed in paraformaldehyde. Gross and microscopic inspection of the slices revealed the existence or non-existence of pathological findings. RESULTS: A total of 26 rats were operated on (13 in the SAH group/13 in the sham group). The average time between obtaining the blood and the start of the intracisternal injection was 10 (+/-1.2)s. The mortality rate was 16.12%. Intra- and extraparenchymal ischemic-haemorrhagic lesions were found in three animals (23.07%)--all from the SAH group--with ischemic neuronal cell injury detected in two of the three. CONCLUSIONS: The new murine model of SAH is easy to perform, with low mortality, minimally invasive, which makes it interesting for future studies on vasospasm-related delayed SAH complications. PMID- 22921488 TI - Highlights in clinical autonomic neurosciences: Orthostatic hypotension: insights into risks and causes. PMID- 22921489 TI - Baroreflex control of renal sympathetic nerve activity in mice with cardiac hypertrophy. AB - Altered renal sympathetic nerve activity (RSNA) plays a major role in the progression of cardiac hypertrophy. We aimed to evaluate the baroreflex control of RSNA in mice with cardiac hypertrophy. Swiss Webster mice were treated with isoproterenol (15 MUg/g/day, s.c.) or vehicle and the baroreflex evaluation was performed by measuring changes in RSNA in response to changes in arterial pressure. The maximal gain of the reflex changes in RSNA was reduced in isoproterenol-treated animals (1.39 +/- 0.08%/mm Hg) in comparison with vehicle treated animals (1.77 +/- 0.10%/mm Hg). Therefore, we can conclude that cardiac hypertrophy led to a reduced sensitivity of baroreflex control of RSNA. PMID- 22921490 TI - Postural responses during volitional and perturbed dynamic balance tasks in new lower limb amputees: a longitudinal study. AB - This study examined the adaptation of postural responses in transtibial amputees during both perturbed and volitional dynamic balance tasks during a five-month period following discharge from inpatient rehabilitation. Seven unilateral transtibial amputees performed the sensory organisation test (SOT) and the limits of stability (LOS) test protocols on the NeuroCom Equitest((r)) at one, three and six months post-discharge from in-patient rehabilitation. Overall balance ability improved significantly (p=0.01) following discharge as did utilisation of somatosensory input (p=0.01), with hip strategy use decreasing. Reaction time and movement velocity did not change significantly in the majority of target directions for the LOS test. However, endpoint COG excursion and directional control were significantly increased in a number of directions (p<=0.05). Although balance ability improved following discharge from rehabilitation, participants were heavily reliant upon vision in order to maintain balance. Following discharge from rehabilitation, amputees were seemingly able to increase the spatial and accuracy aspects of volitional exploration of their LOS. However, temporal aspects did not display any adaptation, suggesting a trade-off between these aspects of postural control. Further practice of performing volitional postural movements under increasing time pressure, for example using low-cost gaming tools, may improve balance ability and postural control. PMID- 22921491 TI - The effect of varying the plantarflexion resistance of an ankle-foot orthosis on knee joint kinematics in patients with stroke. AB - Ankle-foot orthoses (AFOs) can improve gait in patients with hemiplegia. However, it is anecdotally known that excessive plantarflexion resistance of an AFO could induce undesired knee flexion at early stance. The aim of this study was to systematically investigate the effect of varying the degrees of plantarflexion resistance of an AFO on knee flexion angles at early stance in five subjects with chronic stroke who demonstrated two clear knee flexion peaks at early stance and swing. Each subject wore an experimental AFO constructed with an oil-damper type ankle joint and was instructed to walk at their self-selected walking speed under five plantarflexion resistance conditions. The sagittal plane ankle and knee joint kinematics and gait speed were analyzed using a 3-D Motion Analysis System. A number of significant differences (P<0.005) in maximum knee flexion angles at early stance amongst different plantarflexion resistance conditions were revealed. The knee flexion angle was 23.80 (3.25) degrees under the free hinge joint condition (condition 1), while that was 26.09 (3.79) degrees under the largest resistance condition (condition 5). It was therefore demonstrated that increasing the plantarflexion resistance of an AFO would induce more knee flexion at early stance phase in patients with stroke. PMID- 22921492 TI - Examining anticipatory turn signaling in typically developing 4- and 5-year-old children for applications in active orthotic devices. AB - To develop active pediatric orthotics, it is important to accurately predict alterations to a straight path, such as turns. In this study we examine anticipatory signals prior to a pre-defined turn in seven healthy children. Subjects walked along a predefined 4.25m straight path and then made either a 40 degree turn left or right, or continued straight based on a pre-set color panel at the endpoint. The forward center of mass (COM) velocity for the stride prior to the turn region was 1.16+/-0.22m/s (no significant difference was seen with respect to turn direction, p>0.05). In the stride prior to landing in the turn region, subjects showed a significant difference in the mediolateral COM velocity with respect to the turn direction (p=0.003 for 30% and p<0.0005 for 40-100% of the gait cycle). No significant differences were observed in the sagittal plane kinematics of the hip, knee, or ankle during the preparatory stride with respect to turn direction (p>0.05) when compared at 10% gait increments. However, significant differences were observed in pelvic rotation for 10-30% (p<0.05) and 70-100% (p<0.0005) of the gait cycle. The subjects were inconsistent in strategy used to perform a turn. In trials to the left and right, 66% and 56% of the trials were step turns, respectively. The varying turn strategy may be a function of limited instructions provided to the child, or ongoing development in the children's COM control. Yet even with the varying strategies, there exist anticipatory signals that can be used to design real-time controllers for assistive devices with readily available sensor systems. PMID- 22921493 TI - Diagnostic issues in Moroccan immigrants to the Netherlands. PMID- 22921494 TI - The Preschool Pediatric Symptom Checklist (PPSC): development and initial validation of a new social/emotional screening instrument. AB - OBJECTIVE: This article describes the development and initial validation of the Preschool Pediatric Symptom Checklist (PPSC), a social/emotional screening instrument for children 18 to 60 months of age. The PPSC was created as part of a comprehensive screening instrument designed for pediatric primary care and is modeled after the Pediatric Symptom Checklist. METHOD: Items for the PPSC were developed by a team of experts who reviewed existing assessment instruments and relevant research literature. Scale construction and initial validation (including factor analysis and tests of construct validity) were conducted with 292 families from pediatric primary care sites and 354 families from referral clinics. One hundred seventy-one additional families were recruited from primary care sites to obtain an independent replication sample. RESULTS: Exploratory factor analysis revealed 4 dimensions of the PPSC: Externalizing, Internalizing, Attention Problems, and Parenting Challenges. These dimensions were incorporated into a bifactor model that displayed a strong general factor, thus supporting the use of a total score. The PPSC total score shows strong internal and retest reliability, and it identifies children who score in the clinical range of a longer, well-validated, and more comprehensive parent-report instrument (the Child Behavior Checklist), as well as children who are reported to have a range of behavioral diagnoses. Moreover, sensitivity and specificity with respect to these criteria were comparable to those of another well-accepted but longer screener, the Ages & Stages Questionnaire: Social/Emotional. Finally, results for the PPSC total scale remained consistent when replicated in an independent sample. CONCLUSION: The PPSC shows promise as a social/emotional screening instrument for use in pediatric primary care. PMID- 22921495 TI - Exploring the choice to refuse or delay vaccines: a national survey of parents of 6- through 23-month-olds. AB - OBJECTIVE: The purpose of this study was to assess respondents' self-reported choices for vaccinating their young children; knowledge, attitudes, and beliefs (KABs) about vaccination; and communication with their child's vaccination provider. METHODS: A national telephone survey of 1500 parents of children aged 6 to 23 months was conducted in 2010. We calculated proportions of parents who had chosen-or planned-to refuse or delay 1 or more recommended vaccines, and proportions for responses to KABs and communication questions, stratified by vaccination choice (ie, refuse or delay). RESULTS: The response rate was 46%. Among the 96.6% of respondents (95% confidence interval [CI], 95.5%-97.4%; weighted n = 1453) who had chosen for their child to receive at least 1 vaccine, 80.6% (95% CI, 78.8%-83.0%) reported that their child had received all vaccines when recommended and 86.5% (95% CI, 84.7%-88.2%) reported that their child would receive remaining vaccines when recommended. Respondents who considered not following recommendations, but ultimately did, cited the physician's recommendation as the reason for vaccinating. Most vaccinators who reported past or planned deviations from recommendations cited only 1 vaccine that they would refuse and/or delay; all vaccines were mentioned. These parents reported approaching vaccination with serious concerns, while believing other parents did not. All parents cited "vaccine side effects" as their top question or concern. Almost all parents talked to a doctor or nurse about vaccines and, overall, satisfaction with communication was high. CONCLUSIONS: Communication about vaccines is important to most parents, but may be challenging for providers, because parental choices vary; thus, efforts to improve and support vaccine communication by providers should continue. PMID- 22921496 TI - Immunological mechanisms involved in the protection against intestinal taeniosis elicited by oral immunization with Taenia solium calreticulin. AB - Oral immunization with functional recombinant Taenia solium calreticulin (rTsCRT) induces 37% reduction in tapeworm burden in the experimental model of intestinal taeniosis in hamsters. Furthermore, tapeworms recovered from vaccinated animals exhibit diminished length, being frequently found in more posterior parts of the small intestine. The aim of this study was to analyze the immunological mechanisms involved in protection in response to rTsCRT oral immunization. Hamsters were orally immunized with rTsCRT using cholera toxin (CT) as adjuvant, weekly for 4 weeks. Fifteen days after the last boost animals were challenged with four T. solium cysticerci. Reduction in the adult worm recovery and increased transcription of mRNA for IL-4 and IFN-gamma in the mucosa of rTsCRT+CT immunized animals were observed. Immunization also induced goblet cell hyperplasia in the mucosa surrounding the implantation site of the parasite. Specific IgG and IgA antibodies in serum and fecal supernatants were detected after the second immunization, being more pronounced after challenge. Our data suggest that oral vaccination with rTsCRT+CT regulates a local expression of IL-4 and IFN-gamma, stimulating secretion of IgA that, together with the increase of goblet cells and mucin production, could result in an unfavorable environment for T. solium promoting an impaired tapeworm development. PMID- 22921497 TI - Leishmania (Viannia) braziliensis nucleoside triphosphate diphosphohydrolase (NTPDase 1): localization and in vitro inhibition of promastigotes growth by polyclonal antibodies. AB - Nucleoside triphosphate diphosphohydrolase (NTPDase) activity was recently characterized in Leishmania (Viannia) braziliensis promastigotes (Lb), and an antigenic conserved domain (r82-121) from the specific NTPDase 1 isoform was identified. In this work, mouse polyclonal antibodies produced against two synthetic peptides derived from this domain (LbB1LJ, r82-103; LbB2LJ, r102-121) were used. The anti-LbB1LJ or anti-LbB2LJ antibodies were immobilized on protein A-sepharose and immunoprecipitated the NTPDase 1 of 48 kDa and depleted approximately 40% of the phosphohydrolytic activity from detergent-homogenized Lb preparation. Ultrastructural immunocytochemical microscopy identified the NTPDase 1 on the parasite surface and in its subcellular cytoplasmic vesicles, mitochondria, kinetoplast and nucleus. The ATPase and ADPase activities of detergent-homogenized Lb preparation were partially inhibited by anti-LbB1LJ antibody (43-79%), which was more effective than that inhibition (18-47%) by anti LbB2LJ antibody. In addition, the immune serum anti-LbB1LJ (67%) or anti-LbB2LJ (33%) was cytotoxic, significantly reducing the promastigotes growth in vitro. The results appoint the conserved domain from the L. braziliensis NTPDase as an important target for inhibitor design and the potential application of these biomolecules in experimental protocols of disease control. PMID- 22921498 TI - Serum of Babesia rodhaini infected mice down regulates catalase activity of healthy erythrocytes. AB - Hemolytic activity for animals infected with various Babesia species is well reported. In this study, we confirmed that serum of Babesia rodhaini-infected mice also showed hemolytic activity. Erythrocytes from non-infected mice were lysed by co-incubation with B. rodhaini-infected serum. Catalase activity of the non-infected target erythrocytes was suppressed after this co-incubation with the hemolytic serum of B. rodhaini-infected mice. Furthermore, serum hemolytic activity was inhibited when target erythrocytes were incubated with hemolytic serum in the presence of exogenous catalase. Our study indicated that hemolytic serum can down-regulate the antioxidant capacity of non-infected healthy erythrocytes, possibly as a result of catalase activity, thereby leading to hemolysis. PMID- 22921499 TI - Insights into origins of Human T-cell Lymphotropic Virus Type 1 based on new strains from aboriginal people of Canada. AB - The causes of the worldwide distribution of Human T-cell Lymphotropic Virus Type 1 (HTLV-1) remain incompletely understood, with competing hypotheses regarding the number and timing of events leading to intercontinental spread on historical and prehistoric timescales. Ongoing discovery of this virus in aboriginal populations of Asia and the Americas has been the main source of evidence for the latter. We conducted molecular phylogenetic and dating analyses for 13 newly reported HTLV-1 strains from Canada. We analyzed two full-length proviral genomes from aboriginal residents of Nunavut (an autonomous territory in Northern Canada including most of the Canadian Arctic), 11 long-terminal-repeat (LTR) sequences from aboriginal residents of British Columbia's Pacific coast, and 2 LTR sequences from non-aboriginal Canadians. Phylogenetic analysis demonstrated a well-supported affinity between the two Nunavut strains and two East Asian strains, suggesting the presence of an Asian-American sublineage within the widespread "transcontinental" subgroup A clade of HTLV-1 Cosmopolitan subtype a. This putative sublineage was estimated to be 5400-11,900 years in age, consistent with a long-term presence of HTLV-1 in aboriginal populations of the Canadian Arctic. Phylogenetic affinities of the other 11 Canadian HTLV-1 aboriginal strains were diverse, strengthening earlier evidence for multiple incursions of this virus into coastal aboriginal populations of British Columbia. Our results are consistent with the hypothesis of ancient presence of HTLV-1 in aboriginal populations of North America. PMID- 22921500 TI - Molecular characterization of Giardia psittaci by multilocus sequence analysis. AB - Multilocus sequence analyses targeting small subunit ribosomal DNA (SSU rDNA), elongation factor 1 alpha (ef1alpha), glutamate dehydrogenase (gdh), and beta giardin (beta-giardin) were performed on Giardia psittaci isolates from three Budgerigars (Melopsittacus undulates) and four Barred parakeets (Bolborhynchus lineola) kept in individual households or imported from overseas. Nucleotide differences and phylogenetic analyses at four loci indicate the distinction of G. psittaci from the other known Giardia species: Giardia muris, Giardia microti, Giardia ardeae, and Giardia duodenalis assemblages. Furthermore, G. psittaci was related more closely to G. duodenalis than to the other known Giardia species, except for G. microti. Conflicting signals regarded as "double peaks" were found at the same nucleotide positions of the ef1alpha in all isolates. However, the sequences of the other three loci, including gdh and beta-giardin, which are known to be highly variable, from all isolates were also mutually identical at every locus. They showed no double peaks. These results suggest that double peaks found in the ef1alpha sequences are caused not by mixed infection with genetically different G. psittaci isolates but by allelic sequence heterogeneity (ASH), which is observed in diplomonad lineages including G. duodenalis. No sequence difference was found in any G. psittaci isolates at the gdh and beta giardin, suggesting that G. psittaci is indeed not more diverse genetically than other Giardia species. This report is the first to provide evidence related to the genetic characteristics of G. psittaci obtained using multilocus sequence analysis. PMID- 22921501 TI - An automated multiplex specific IgE assay system using a photoimmobilized microarray. AB - An automated microarray diagnostic system for specific IgE using photoimmobilized allergen has been developed. Photoimmobilization is useful for preparing microarrays, where various types of biological components are covalently immobilized on a plate. Because the immobilization is based on a photo-induced radical cross-linking reaction, it does not require specific functional groups on the immobilized components. Here, an aqueous solution of a photoreactive poly(ethylene glycol)-based polymer was spin-coated on a plate, and an aqueous solution of each allergen was microspotted on the coated plate and allowed to dry in air. Finally, the plate was irradiated with an ultraviolet lamp for covalent immobilization. An automated machine using these plates was developed for the assay of antigen-specific IgE. Initially, the patient serum was added to the microarray plate, and after reaction of the microspotted allergen with IgE, the adsorbed IgE was detected by a peroxidase-conjugated anti-IgE-antibody. The chemical luminescence intensity of the substrate decomposed by the peroxidase was automatically detected using a sensitive charge-coupled device camera. All the allergens were immobilized stably using this method, which was used to screen for allergen-specific IgE. The results were comparable with those using conventional specific IgE. Using this system, six different allergen-specific IgE were assayed using 10 MUL of serum within a period of 20 min. PMID- 22921502 TI - Updates for the antibiotic treatment of legionellosis in adults. Agence francaise de securite sanitaire des produits de sante. PMID- 22921503 TI - Metacommunities and symbiosis: hosts of challenges. PMID- 22921504 TI - Effect of silica gel modification with cyclofructans on properties of hydrophilic interaction liquid chromatography stationary phases. AB - Hydrophilic interaction liquid chromatography (HILIC) offers very good possibilities for separation of polar compounds as an alternative to reversed phase HPLC where polar compounds are not sufficiently retained. HILIC is becoming more popular for the analysis of biologically interesting (active) analytes. Various stationary phases are commercially available however, development of new materials (sorbents) suitable for HILIC systems still continues. Silica gel columns can be used directly but their modification can improve separation ability of the stationary phases. Cyclofructan-based stationary phases are demonstrated as possible HILIC columns in this work. The effect of silica gel modification by cyclofructan and a derivatized cyclofructan was studied in detail. HILIC separation systems with silica gel, cyclofructan and isopropyl cyclofructan modified silica stationary phases were compared. The detailed study of chromatographic behavior of peptides revealed that multimodal retention mechanism is present in systems with these stationary phases. Mobile phase composition changes the types of interactions and their strengths. It appears that ability to donate protons and dispersion forces are the main interactions that affect retention in HILIC with cyclofructan-based columns while they are less important in separation systems with bare silica stationary phase. Suitability of cyclofructan-based stationary phases in HILIC for separation of pentapeptides and nonapeptides was demonstrated. PMID- 22921505 TI - Methoxyquinoline labeling--a new strategy for the enantioseparation of all chiral proteinogenic amino acids in 1-dimensional liquid chromatography using fluorescence and tandem mass spectrometric detection. AB - The determination of trace amounts of d-amino acids (d-AAs) even in tissue samples of higher developed animals, mammals and humans has opened a wide field of biological questions to be investigated. d-Ala, d-Asp and d-Ser have already been identified to exhibit key functions in cellular regulation processes [1-4]. The abundance of trace amounts of these and also of other d-AAs in various biological fluids and in tissue samples is still being investigated. We herein present a facile derivatization method for amino acids using 6-methoxyquinoline-4 carboxylic acid-succinimide ester (MQ-OSu) to yield the corresponding stable N acyl-amino acids (MQ-AAs). Labeling with the MQ tag supports the enantioseparation of all 19 chiral proteinogenic amino acids on anion exchanger type chiral stationary phases, introduces fluorescence activity and particularly promotes sensitive electrospray tandem mass spectrometric detection. Limit of detection values (LOD) for MQ-l-Ala in water were 1.25 MUmol L(-1) with fluorescence detection and 0.015 MUmol L(-1) with MS in selected reaction monitoring (SRM) mode. The applicability of this method for the analysis of MQ-d AAs in biological fluids has been demonstrated. PMID- 22921506 TI - Extending the utility of the Depression Anxiety Stress scale by examining its psychometric properties in Chinese settings. AB - The Depression Anxiety Stress scale (DASS) is a widely used instrument for assessing mental health status, but the construct validity of the Chinese version of the test has not been demonstrated. The current study recruited three independent samples of Chinese participants to examine its reliability, factor structure, and utility in differentiating groups expected to show high and low scores on the scales. The first sample comprised 605 undergraduate student volunteers from Beijing, the second sample comprised 138 residents from the Sichuan Province who had experienced the 2008 earthquake there, and the third sample comprised 86 Beijing residents. Cronbach's alpha values in excess of 0.80 were found for all samples and all scales. Confirmatory factor analysis with the student sample supported a three-factor latent structure for the DASS (depression, anxiety, and stress). Substantially higher scores on all scales were found for the Sichuan earthquake sample compared with the Beijing resident's sample. Implications of these findings for the assessment of mental status using the DASS in China are discussed. PMID- 22921507 TI - Never-depressed females with a family history of depression demonstrate affective bias. AB - According to cognitive theories of depression, individuals susceptible to depression attend selectively to negative information. The purpose of the study was to examine if such an affective processing bias is present in never-depressed individuals with a family history of major depressive disorder (MDD). Formerly depressed female patients having at least one first-degree relative with a history of MDD (n=23), their never-depressed female siblings (n=21) and never depressed female controls (n=21) performed a conventional and an emotional Stroop task using negative, positive and neutral words. A significant effect was found of group on negative processing bias; post hoc comparisons indicated that never depressed siblings showed a larger negative processing bias than never-depressed controls. No significant differences were observed in positive bias or conventional interference between the three groups. Our findings suggest that never-depressed females with a family history of depression, like depressed patients, have more difficulties to inhibit negative material and to direct their attention towards task-specific material. This adds to the existing evidence that affective processing bias is a trait characteristic that contributes to the onset of depression and that could be a useful endophenotype for MDD. PMID- 22921508 TI - Association between serotonin transporter promoter polymorphisms and psychological distress in a diabetic population. AB - Investigations into serotonin transporter and anxiety and depression have shown an association between stress, depression onset and genotype. We investigated the relationship between 5-HTTLPR genotype and depression and anxiety in a population with diabetes mellitus, a condition associated with high rates of stress and depression. Participants were classified according to 'S' and 'L' alleles as well as the modification of the single nucleotide polymorphism (SNP) rs25531. The 5 HTTLPR low-expression genotype group (S or L(G) allele carriers) had significantly higher psychological distress (K10) scores (N=234, P=0.047). Subsequent analysis revealed that the effect of genotype was related to anxiety symptoms rather than depression symptoms. Furthermore, the main effect of genotype was not observed when the modification of the SNP polymorphism was not taken into account. Findings suggest that 5-HTTLPR/rs25531 genotype is associated with psychological distress in a sample of subjects with diabetes. PMID- 22921509 TI - The role of the atmosphere in the provision of ecosystem services. AB - Solving the environmental problems that we are facing today requires holistic approaches to analysis and decision making that include social and economic aspects. The concept of ecosystem services, defined as the benefits people obtain from ecosystems, is one potential tool to perform such assessments. The objective of this paper is to demonstrate the need for an integrated approach that explicitly includes the contribution of atmospheric processes and functions to the quantification of air-ecosystem services. First, final and intermediate air ecosystem services are defined. Next, an ecological production function for clean and clear air is described, and its numerical counterpart (the Community Multiscale Air Quality model) is introduced. An illustrative numerical example is developed that simulates potential changes in air-ecosystem services associated with the conversion of evergreen forest land in Mississippi, Alabama and Georgia to commercial crop land. This one-atmosphere approach captures a broad range of service increases and decreases. Results for the forest to cropland conversion scenario suggest that although such change could lead to increased biomass (food) production services, there could also be coincident, seasonally variable decreases in clean and clear air-ecosystem services (i.e., increased levels of ozone and particulate matter) associated with increased fertilizer application. Metrics that support the quantification of these regional air-ecosystem changes require regional ecosystem production functions that fully integrate biotic as well as abiotic components of terrestrial ecosystems, and do so on finer temporal scales than are used for the assessment of most ecosystem services. PMID- 22921510 TI - Toxic metals in WEEE: characterization and substance flow analysis in waste treatment processes. AB - Waste electrical and electronic equipment (WEEE) has received extensive attention as a secondary source of metals. Because WEEE also contains toxic substances such as heavy metals, appropriate management of these substances is important in the recycling and treatment of WEEE. As a basis for discussion toward better management of WEEE, this study characterizes various types of WEEE in terms of toxic metal contents. The fate of various metals contained in WEEE, including toxic metals, was also investigated in actual waste treatment processes. Cathode ray tube televisions showed the highest concentration and the largest total amount of toxic metals such as Ba, Pb, and Sb, so appropriate recycling and disposal of these televisions would greatly contribute to better management of toxic metals in WEEE. A future challenge is the management of toxic metals in mid sized items such as audio/visual and ICT equipment because even though the concentrations were not high in these items, the total amount of toxic metals contained in them is not negligible. In the case of Japan, such mid-sized WEEE items as well as small electronic items are subject to municipal solid waste treatment. A case study showed that a landfill was the main destination of toxic metals contained in those items in the current treatment systems. The case study also showed that changes in the flows of toxic metals will occur when treatment processes are modified to emphasize resource recovery. Because the flow changes might lead to an increase in the amount of toxic metals released to the environment, the flows of toxic metals and the materials targeted for resource recovery should be considered simultaneously. PMID- 22921511 TI - Detectability of secretagogin in human erythrocytes. AB - Secretagogin is a six EF-hand calcium-binding protein that can identify granule cells in the dentate gyrus of hippocampus. The aim of this study was to determine if secretagogin can be detected in human blood cells. Eight adult males were recruited for blood analysis. Whole blood was separated into plasma, peripheral mononuclear cells and erythrocytes with Ficoll-Paque and probed for secretagogin using reverse-transcription polymerase chain reaction and Western blot. While secretagogin mRNA was detected in both peripheral mononuclear cells and erythrocytes using reverse-transcription polymerase chain reaction, SCGN protein was only detected in erythrocytes. Interestingly, peripheral mononuclear cells secretagogin mRNA expression levels showed significant negative correlation with age. This begets the question on the function of secretagogin in blood cells and if it is correlated to neurodegeneration associated with ageing. This remains our impetus for further research. PMID- 22921512 TI - The SOCS and STAT from JAK/STAT signaling pathway of kuruma shrimp Marsupenaeus japonicus: molecular cloning, characterization and expression analysis. AB - Signal transducer and activators of transcription (STAT) gene, suppressors of cytokine signaling (SOCS) has been isolated from kuruma shrimp, Marsupenaeus japonicus and characterized. The kuruma shrimp STAT (MjSTAT) cDNA was composed of 2901 bp consisting of 801 amino acid residues which includes a protein interaction domain, all alpha domain, DNA binding domain and SH2 domain. Homology analysis of MjSTAT showed 94.1% and 34.0% identities with Penaeus monodon STAT (PmSTAT) and Drosophila melanogaster STAT92E (DmSTAT), respectively. The kuruma shrimp SOCS (MjSOCS) cDNA was composed of 1675 bp consisting of 342 amino acid residues including a SH2 domain and C-terminal SOCS domain. Homology analysis of MjSOCS showed 52.6% and 21.3% identities with Chinese mitten crab (Eriocheir sinensis) SOCS2 and fruit fly (D. melanogaster) SOCS44A, respectively. The MjSTAT and MjSOCS genes are constitutively expressed in the muscle, stomach, brain and gill of kuruma shrimp. In lymphoid organ cells, an enhanced expression of both MjSTAT and MjSOCS genes are observed following stimulation with peptidoglycan and polycytidylic acid. These observations suggest that MjSTAT and MjSOCS might play a major role in the innate immune defense of kuruma shrimp. The discovery of JAK/STAT signaling pathway in shrimp will allow a complete and concrete understanding of shrimp cytokine signaling. PMID- 22921513 TI - Estimation of paracrine signaling using quantitative RT-PCR from multiple patchy lesion samples. AB - We investigated whether correlations between mRNA levels of cytokines versus other proteins from patchy lesion could estimate cytokine paracrine signaling in vivo. Experiments with rat experimental autoimmune myocarditis (EAM), a patchy myocarditis model, indicated IL-1 and other protein levels were correlated, indicating paracrine signaling pathways in vivo. PMID- 22921514 TI - Lennox-Gastaut syndrome in south Iran: electro-clinical manifestations. AB - PURPOSE: Lennox-Gastaut syndrome (LGS) is an uncommon epileptic encephalopathy. In this study, we tried to determine the clinical and EEG characteristics of patients with LGS in south Iran. METHODS: In this retrospective study, all patients with a clinical diagnosis of LGS were recruited at the outpatient epilepsy clinic at Shiraz University of Medical Sciences from 2008 through 2012. Age, gender, age at seizure onset, seizure type(s), epilepsy risk factors, EEG and imaging findings of all patients were registered routinely. RESULTS: During the study period, 2500 patients with epilepsy were registered at our epilepsy clinic. One-hundred and thirty-five patients (5.4%) were diagnosed as having LGS. Age of onset (mean+/-standard deviation) was 3.2+/-3.8 years. In 14 (10.4%) patients, age of onset was above 8 years. Eighty-three patients (61.5%) were male and 52 (38.5%) were female. The most common seizure type was tonic, followed by generalized tonic-clonic and myoclonic seizures. The most common EEG finding was slow spike-wave complexes. The most common abnormal MRI finding was brain atrophy. CONCLUSION: LGS is an uncommon epileptic encephalopathy characterized by multiple seizure types, a specific electroencephalographic pattern and psychomotor retardation, beginning in childhood. However, variants of this classical triad including atypical EEG findings, normal psychomotor function, and late-onset disease could be seen in some patients. These atypical findings in a patient with typical history for LGS should not deter from the correct diagnosis. The mainstay for making a correct syndromic diagnosis is a detailed clinical history. PMID- 22921515 TI - Early detection of influenza A and B infection in infants and children using conventional and fluorescence-based rapid testing. AB - BACKGROUND: The appropriate management of infants and children with influenza depends on the accurate and timely diagnosis, ideally at the point of care (POC). OBJECTIVES: To evaluate the use of simultaneous RSV/influenza rapid testing with QuickVueTM test strips as well as (the use of) novel, fluorescence-based, rapid influenza antigen testing (SOFIATM) in infants and children with influenza-like illness (ILI). STUDY DESIGN: The Study was conducted in a real-time surveillance program at the Charite Department of Pediatrics in collaboration with the National Reference Centre for Influenza at the Robert Koch Institute (RKI) in Berlin, Germany (Charite Influenza-Like Disease=ChILD Cohort). RESULTS: During the 2010/2011 influenza season, 395 infants and children were simultaneously tested using QuickVueTM FluA&B and RSV10 rapid tests at POC compared to independent RT-PCR. Sensitivities were 62.7/67.8% for Influenza/RSV overall, but highest in infants <1 year with 76.0/76.2%. The evaluation of the fluorescence based rapid test SOFIATM with frozen laboratory samples (derived from the 2008/2009 and 2010/2011 national surveillance) yielded sensitivities of 97.7/86.7/86.7/81.7% for influenza A(H1N1)pdm09/A(H3N2)/B-Victoria/B-Yamagata in samples with CT values <34, and 80.2/79.8/67.5/62.5% for all CT values combined. The same method used at POC with 649 consecutive ChILD patients in 2011-2012 yielded sensitivity/specificity/PPV/NPV values of 78.9/99.7/96.6/97.3%. Again, sensitivities were highest in infants (85.7%) and small children <2 years (88%). CONCLUSIONS: Fluorescence-based rapid antigen testing provides a highly sensitive and specific tool for POC diagnostics of acute influenza in the paediatric age group, especially in infants and small children <2 years, when viral loads are at their peak and treatment decisions are imminent. PMID- 22921516 TI - Is it true that pre-conization high-risk HPV DNA load is a significant factor of persistence of HPV infection after conization? PMID- 22921517 TI - Comparison of real-time PCR quantitative analysis of the cytomegalovirus DNA level using LightCycler 2.0 and LightCycler 480 instruments. AB - Cytomegalovirus infection is a frequent complication after transplantation. It is commonly believed that the level of CMV viraemia, usually measured with real-time PCR, is directly correlated with the risk of developing a serious cytomegaloviral disease. OBJECTIVES: The aim was the comparison of results obtained with a commercial test for the quantitative diagnostics of CMV infections, using LightCycler 2.0 and LightCycler 480 real-time PCR systems. STUDY DESIGNS: Study comprised 97 samples of nucleic acids isolated from serum, in which the CMV DNA was detected during routine tests. Measurement in both analysers was performed simultaneously for paired serum samples. Comparison and of the results obtained with two types of thermocyclers included regression analysis, Spearman correlation, Friedman test and Bland-Altman analysis (p<0.05). RESULTS: CMV DNA was detected in all samples with use of both thermocyclers. Correlation coefficient of results obtained with both analysers was 0.94. According to Friedman and Bland-Altman tests' results, there were significant differences in measurements between instruments (p<0.001 and p=0.017, respectively). Difference of median values was 0.137 log(10)CMV viral load/ml, and difference of mean values was 0.215 log(10)CMV viral load/ml. Clear threshold of fluorescence crossing point of 1.4-1.8 cycles in advantage of LightCycler 480 was an apparent difference between both analysers. CONCLUSIONS: There was good overall correlation between both analysers, as detected shift in both median and mean values was close to intra-assay variability declared by its producer. Observed differences were probably due to different fluorescence excitation and detection systems used in both instruments. PMID- 22921518 TI - Microneedle-mediated transcutaneous immunization with plasmid DNA coated on cationic PLGA nanoparticles. AB - Previously, it was shown that microneedle-mediated transcutaneous immunization with plasmid DNA can potentially induce a stronger immune response than intramuscular injection of the same plasmid DNA. In the present study, we showed that the immune responses induced by transcutaneous immunization by applying plasmid DNA onto a skin area pretreated with solid microneedles were significantly enhanced by coating the plasmid DNA on the surface of cationic nanoparticles. In addition, the net surface charge of the DNA-coated nanoparticles significantly affected their in vitro skin permeation and their ability to induce immune responses in vivo. Transcutaneous immunization with plasmid DNA-coated net positively charged nanoparticles elicited a stronger immune response than with plasmid DNA-coated net negatively charged nanoparticles or by intramuscular immunization with plasmid DNA alone. Transcutaneous immunization with plasmid DNA-coated net positively charged nanoparticles induced comparable immune responses as intramuscular injection of them, but transcutaneous immunization was able to induce specific mucosal immunity and a more balanced T helper type 1 and type 2 response. The ability of the net positively charged DNA-coated nanoparticles to induce a strong immune response through microneedle-mediated transcutaneous immunization may be attributed to their ability to increase the expression of the antigen gene encoded by the plasmid and to more effectively stimulate the maturation of antigen-presenting cells. PMID- 22921519 TI - Degradation of microcrystalline cellulose and non-pretreated plant biomass by a cell-free extracellular cellulase/hemicellulase system from the extreme thermophilic bacterium Caldicellulosiruptor bescii. AB - Caldicellulosiruptor bescii is a cellulolytic/hemicellulolytic anaerobe, which extracellularly secretes various proteins, including multidomain cellulases with two-catalytic domains, for plant biomass degradation. Degradation by C. bescii cells has been well characterized, but degradation by the cell-free extracellular cellulase/hemicellulase system (CEC) of C. bescii has not been as well studied. In the present study, C. bescii CEC was prepared from cell-free culture supernatant, and the degradation properties for defined substrates and non pretreated plant biomass were characterized. Four multidomain cellulases (Cbes_1857, Cbes_1859, Cbes_1865, and Cbes_1867), composed of the glycoside hydrolase families 5, 9, 10, 44, and 48, were the major enzymes identified in the CEC by mass spectrometry. The CEC degraded xylan, mannose-based substrates, beta 1,4-linked glucans, including microcrystalline cellulose (Avicel), and non pretreated timothy grass and rice straw. However, degradation of chitin, pectin, dextran, and wheat starch was not observed. The optimum temperatures for degradation activities were 75 degrees C for timothy grass and Avicel, 85 degrees C for carboxylmethyl cellulose, and >85 degrees C for xylan. The optimum pH for these substrates was 5-6. The degradation activities were compared with a CEC derived from the fungus Trichoderma reesei, the most common enzyme used for plant biomass saccharification. The amounts of degraded Avicel, timothy grass, and rice straw by C. bescii CEC were 2.2-2.4-fold larger than those of T. reesei CEC. The high hydrolytic activity of C. bescii CEC might be attributed to the two catalytic domain architecture of the cellulases. PMID- 22921520 TI - It's not just bones anymore: the new and exciting world of vitamin D. PMID- 22921522 TI - Genome-wide association data provide further support for an association between 5 HTTLPR and major depressive disorder. AB - BACKGROUND: Dysfunctions of serotonergic neurotransmission are supposed to be involved in the pathogenesis of psychiatric disorders such as major depressive disorder (MDD). The concentration of serotonin (5-hydroxytryptamine, 5-HT) in the synaptic cleft is essentially regulated by the 5-HT transporter (5-HTT). A length polymorphism repeat in the 5-HTT promoter region, termed 5-HTTLPR, has been commonly investigated for an association with psychiatric disorders. METHODS: Genotyping of the 5-HTTLPR is time-consuming and technically challenging. Recently, a two-SNP haplotype was identified that tags the 5-HTTLPR at r(2)=0.775. This allows extraction of 5-HTTLPR genotype information from large genome-wide association study (GWAS) data sets. In the present study we performed haplotype analysis using a German GWAS case-control dataset to test for an association between MDD and the two-SNP tagging haplotype for 5-HTTLPR. RESULTS: We detected a significant association between the TA haplotype (tagging the S allele of the 5-HTTLPR) and MDD. Our result is consistent with previous findings of an association between the 5-HTTLPR S-allele and MDD. LIMITATIONS: Using the two-SNP tagging haplotype did not allow testing of the tri-allelic genotype (but only the two-allelic genotype). This and the fact that the haplotype tags the 5 HTTLPR with an imperfect linkage disequilibrium of r(2)=0.775 may lead to some loss of power. CONCLUSIONS: Our results provide further support for an involvement of the 5-HTTLPR in MDD and represent the first example of demonstrating association between MDD and the S-allele of the length polymorphism repeat using common SNP information from SNP-array data. PMID- 22921521 TI - Sensation seeking as risk factor for suicidal ideation and suicide attempts in adolescence. AB - BACKGROUND: High sensation seeking in adolescence is associated with engagement in risk-taking behaviors, especially substance use. Although depressed adolescents are prone to increased risk-taking, and suicidal behavior can be considered within the spectrum of risk-taking behaviors, the relationships between sensation seeking, depression, and suicidal behavior have not been explored. METHODS: A self-report questionnaire assessing sensation seeking, depression, substance use problems, and suicidal ideation and suicide attempts was completed by 9th- through 12th-grade students (n=2189) in six New York State high-schools from 2002 through 2004. Logistic regression analyses were conducted to examine main and interaction effects between sensation seeking and the four clinical variables. RESULTS: High sensation seeking was positively associated with depressive symptoms and substance use problems. The main effects of sensation seeking on suicidal ideation and suicide attempts remained significant after controlling for depression and substance use. The association between sensation seeking and suicide attempts was moderated by substance use problems. LIMITATIONS: The schools were suburban and predominantly white, limiting the generalizability of the results. Other mental disorders with potential implications for sensation seeking and for suicidal behavior, such as bipolar disorders, were not assessed. CONCLUSIONS: The finding that sensation seeking makes an independent contribution to the risk of suicidal ideation and attempts is consistent with findings in literature on novelty seeking and impulsivity. The associations between sensation seeking, depressive symptoms and suicidal behavior may be compatible with the presence of an underlying temperamental dysregulation. Screening for sensation seeking may contribute to the reduction of adolescent suicide risk. PMID- 22921524 TI - WITHDRAWN: Chemokines and chemokine receptors in the nervous system. AB - This article has been withdrawn at the request of the author(s) and/or editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at (http://www.elsevier.com/locate/withdrawalpolicy). PMID- 22921523 TI - Pharmacological evaluation of SN79, a sigma (sigma) receptor ligand, against methamphetamine-induced neurotoxicity in vivo. AB - Methamphetamine is a highly addictive psychostimulant drug of abuse, causing hyperthermia and neurotoxicity at high doses. Currently, there is no clinically proven pharmacotherapy to treat these effects of methamphetamine, necessitating identification of potential novel therapeutic targets. Earlier studies showed that methamphetamine binds to sigma (sigma) receptors in the brain at physiologically relevant concentrations, where it "acts in part as an agonist." SN79 (6-acetyl-3-(4-(4-(4-florophenyl)piperazin-1-yl)butyl)benzo[d]oxazol-2(3H) one) was synthesized as a putative sigma receptor antagonist with nanomolar affinity and selectivity for sigma receptors over 57 other binding sites. SN79 pretreatment afforded protection against methamphetamine-induced hyperthermia and striatal dopaminergic and serotonergic neurotoxicity in male, Swiss Webster mice (measured as depletions in striatal dopamine and serotonin levels, and reductions in striatal dopamine and serotonin transporter expression levels). In contrast, di-o-tolylguanidine (DTG), a well established sigma receptor agonist, increased the lethal effects of methamphetamine, although it did not further exacerbate methamphetamine-induced hyperthermia. Together, the data implicate sigma receptors in the direct modulation of some effects of methamphetamine such as lethality, while having a modulatory role which can mitigate other methamphetamine-induced effects such as hyperthermia and neurotoxicity. PMID- 22921526 TI - Right upper quadrant pain with mild jaundice: is it always what it looks like? PMID- 22921527 TI - A rare cause of anemia. PMID- 22921528 TI - The Short Health Scale: a valid and reliable measure of health related quality of life in English speaking inflammatory bowel disease patients. AB - BACKGROUND: Health related quality of life in inflammatory bowel disease is influenced both by disease activity as well as by the psychosocial characteristics of the individual patient. The Short Health Scale (SHS) is a four part visual analogue scale questionnaire using open-ended questions that are designed to assess the impact of inflammatory bowel disease on a health related quality of life. The four dimensions include bowel symptoms, activities of daily life, worry and general wellbeing. It has previously been validated in Swedish and Norwegian speaking patients. AIM: To evaluate the SHS in an English speaking inflammatory bowel disease population. METHODS: Four hundred and ninety Crohn's disease and ulcerative colitis patients completed the SHS. Individual SHS items were correlated with Inflammatory Bowel Disease Questionnaire (IBDQ) dimensions and with disease activity to assess validity. Test-retest reliability was assessed in 38 patients who completed the Short Health Scale two weeks apart. RESULTS: All four items correlated with corresponding IBDQ dimensions with correlation coefficients ranging from -0.66 to -0.74 (all p values<0.001). In addition, total SHS scores correlated with total IBDQ scores in both Crohn's disease (-0.836) and ulcerative colitis (0.797). There was a stepwise increase in Short Health Scale scores with increasing disease activity (all p values<0.001). Reliability was confirmed with test-retest correlations ranging from 0.70 to 0.89 (all p values<0.005). CONCLUSIONS: The Short Health Scale is a valid and reliable measure of health related quality of life in English speaking inflammatory bowel disease patients. PMID- 22921529 TI - Are there specific endosonographic features in Crohn's patients with perianal fistulae? AB - Both 2-dimensional and 3-dimensional endoanal ultrasounds have been shown to be accurate in the definition of the anatomy of complex fistulae-in-ano in patients with perianal Crohn's disease. Recently, a Crohn's Ultrasound Fistula Sign (CUFS) has been suggested as a discriminating feature of perianal Crohn's disease as has the presence of fistulous debris and fistular bifurcation. We blindly assessed 197 patients (39 Crohn's fistulae and 158 cryptogenic fistulae) to determine if these signs differentiated fistula types. The incidence of CUFS in Crohn's cases was 17/39 (43.6%) and in cryptogenic cases was 4/158 (2.5%) (P<0.0001). The sensitivity, specificity, positive and negative predictive values and accuracy for CUFS were 43.6%, 97.5%, 80.9%, 87.5% and 86.8%, respectively. The presence of debris and fistula bifurcation in evaluable cases had a high specificity (87.2% and 81.8%, respectively) but poor sensitivity. The kappa values for or against CUFS, debris and bifurcation in Crohn's cases between 2 observers blinded to the diagnosis were 0.85, 0.72 and 0.93, respectively and in cryptogenic fistulae were 0.89, 0.85 and 0.80, respectively. The kappa values of an agreed consensus for CUFS in Crohn's disease, cryptogenic fistulae and overall with a third observer with no ultrasound experience were 0.62, 0.85 and 0.77, respectively. The presence of CUFS differentiates Crohn's-related from cryptogenic fistulae-in-ano with a high level of agreement for this sign between experienced and inexperienced observers blinded to the underlying diagnosis. PMID- 22921530 TI - Feasibility of patient recruitment into clinical trials of experimental treatments for acute spinal cord injury. AB - Clinical trials of experimental neuroprotective and neuroregenerative therapies for acute spinal cord injury (SCI) typically require large numbers of patients to be enrolled. An important factor in designing such trials is the number of patients that can be realistically recruited at a given institution. The total number of patients with acute SCI treated at a neurotrauma centre is typically considered when such a site becomes a recruiting centre for a clinical trial. However, only a fraction of patients may be truly eligible due to the inclusion and exclusion criteria of the trial. This study was conducted to estimate the proportion of patients with acute SCI who would theoretically satisfy basic inclusion criteria for such a hypothetical clinical trial. Using a local prospective database, we reviewed 406 patients with acute traumatic SCI admitted between 2005 and 2009. 259 of 406 patients (64%) presented within 12 hours of injury, 53 patients (13%) between 12 hours and 24 hours, and 30 patients (7%) between 24 hours and 48 hours. Patients were assessed on admission using the American Spinal Injury Association Impairment Scale: category A, 39% of patients; B, 11%; C, 17%; and D, 28%. The number of patients who presented with injuries or other conditions that would likely exclude them from enrolment was 30%. Thus, of a total of 406 patients with SCI admitted over four years, the number who would have been eligible for an acute clinical trial was disappointingly small. This study is the first to quantify this challenging aspect of conducting acute SCI clinical trials, and provides guidance for those planning such initiatives. PMID- 22921531 TI - A controlled study of personality and affect in Tourette syndrome. AB - OBJECTIVE: Tourette syndrome (TS) can increase the likelihood of social and emotional difficulties which may shape an individual's personality and self perception. We investigated personality and affect in patients with TS. METHODS: Twenty-five adults with TS (2 with co-morbid obsessive compulsive disorder, 4 with co-morbid attention-deficit hyperactivity disorder and 4 with both co morbidities), who were not clinically depressed, and 25 matched controls participated in the study. They completed the Ten-Item Personality Index, the Positive and Negative Affect Scale and the Beck Depression Inventory. RESULTS: Adults with TS exhibited no differences from controls in reported emotional experience or depressive symptoms but did differ for four of the five assessed personality dimensions; extraversion, conscientiousness, openness and emotional stability. Individuals with pure TS (who had no co-morbid conditions) exhibited reduced extraversion and emotional stability compared to controls. Personality scores were not related to tic severity, yet lower emotional stability scores were associated with higher ratings of negative affect. CONCLUSIONS: This study is limited by a restricted sample in terms of size and source. However, our findings indicate that in the absence of depression and common co-morbidities, people with TS differ from controls in indices of personality, which are linked to negative affectivity. PMID- 22921533 TI - Analysis of the genome of leporid herpesvirus 4. AB - The genome of a herpesvirus highly pathogenic to rabbits, leporid herpesvirus 4 (LHV-4), was analyzed using high-throughput DNA sequencing technology and primer walking. The assembled DNA sequences were further verified by restriction endonuclease digestion and Southern blot analyses. The total length of the LHV-4 genome was determined to be about 124 kb. Genes encoded in the LHV-4 genome are most closely related to herpesvirus of the Simplexvirus genus, including human herpesviruses (HHV-1 and HHV-2), monkey herpesviruses including cercopithicine (CeHV-2 and CeHV-16), macacine (McHV-1), bovine herpesvirus 2 (BHV-2), and a lineage of wallaby (macropodid) herpesviruses (MaHV-1 and -2). Similar to other simplexvirus genomes, LHV-4 has a high overall G+C content of 65-70% in the unique regions and 75-77% in the inverted repeat regions. Orthologs of ICP34.5 and US5 were not identified in the LHV-4 genome. This study shows that LHV-4 has the smallest simplexvirus genome characterized to date. PMID- 22921534 TI - Glycosylation of CM2 is important for efficient replication of influenza C virus. AB - CM2 is the second membrane protein of influenza C virus and possesses a conserved motif for N-glycosylation. To investigate the role(s) of CM2 glycosylation in the virus replication, we generated rN11A, a recombinant influenza C virus lacking the glycosylation site. The rN11A virus grew less efficiently than the wild-type (WT) virus, although the biochemical characteristics of the mutant CM2 were similar to those of authentic CM2. The amount of the genome (GFP-vRNA) in the CM2 N11A-virus-like particles (VLPs) was 13% of that found in WT-VLPs. The incoming GFP-vRNA was less efficiently transported to the nucleus in CM2-N11A-VLP-infected cells than WT-VLP-infected cells, leading to the reduced reporter gene expression in CM2-N11A-VLP-infected cells. Thus the glycosylation of CM2 is required for efficient replication of influenza C virus, and the obtained findings confirmed and extended the previous observation that CM2 is involved in the genome packaging and uncoating processes. PMID- 22921535 TI - Axonopathy in Huntington's disease. AB - Personality changes, psychiatric disturbances and cognitive abnormalities frequently characterise the prodromal phase in Huntington's disease (HD), a devastating monogenic neurodegenerative disorder manifesting with abnormal motor movements and early death. Selective loss of medium-sized spiny striatal neurons has been related to the onset of motor symptoms but it does not completely explain the psychiatric and cognitive changes that often precede motor abnormalities. Here we review the evidence of synaptic and axonal dysfunction and neurite dystrophy preceding neuronal loss in HD patients and models. We discuss possible mechanisms leading to dysfunction of the axonal and synaptic compartments and identify potential novel targets for effective therapeutic intervention. PMID- 22921537 TI - beta oscillations in the cortico-basal ganglia loop during parkinsonism. AB - In the normal brain beta band oscillatory activity has been associated with retaining of ongoing motor activities. In Parkinson's disease, enhanced beta band oscillatory activity is displayed across the cortico-basal ganglia pathway and is one of the prominent neurophysiological phenomena associated with the disorder. Intraoperative and postoperative recordings of neural activity in patients undergoing stereotactic neurosurgery combined with studies in animal models of parkinsonism have led to the accumulation of complementary data regarding these oscillations. In this review we address some of the key issues facing researchers in the field. These issues encompass existing agreements as well as open debates in modern studies of beta band oscillations, including their defining characteristics, links to clinical symptoms and the functional properties of their formation and effects on behavior. We address these questions by comparing and contrasting the results of neurophysiological observations in human patients, MPTP primate model and 6-OHDA rat model with conceptual and computational models of the normal and parkinsonian basal ganglia. Defining a unifying scheme of beta band oscillations and their relation to neurophysiological, functional and clinical phenomena will enable future targeting of these oscillations for both diagnosis and treatment of Parkinson's disease. PMID- 22921538 TI - On the use of a natural peat for the removal of Cr(VI) from aqueous solutions. AB - A natural peat has been used as an adsorbent for the removal of hexavalent chromium from aqueous solution. The peat was firstly characterized in terms of particle size and chemical composition (ash content, pH of the point of zero charge, FT-IR and thermal analysis). Next, the kinetic and equilibrium aspects of the adsorption of Cr(VI) by this adsorbent were studied. The kinetic data were satisfactorily fitted to a kinetic law of partial order in C equal to one. The specific adsorption rates are around 10(-4)s(-1), increasing as temperature does. A noticeable influence of diffusion on the global adsorption process has been demonstrated. Finally, the equilibrium isotherms were satisfactorily fitted to a previously proposed model. The adsorption capacity of Cr(VI) was similar to some other previously reported and the affinity of Cr(VI) towards the active sites of the adsorbent increases as temperature rises. PMID- 22921536 TI - Ubiquitin proteasome system in Parkinson's disease: a keeper or a witness? AB - OBJECTIVE: The aim of this work was to evaluate the role of ubiquitin-proteasome system (UPS) on mitochondrial-driven alpha-synuclein (aSN) clearance in in vitro, ex vivo and in vivo Parkinson's disease (PD) cellular models. METHOD: We used SH SY5Y ndufa2 knock-down (KD) cells, PD cybrids and peripheral blood mononuclear cells (PBMC) from patients meeting the diagnostic criteria for PD. We quantified aSN aggregation, proteasome activity and protein ubiquitination levels. In PBMC of PD patient population we evaluated the aSN levels in the plasma and the influence of several demographic characteristics in the above mentioned determinations. RESULTS: We found that ubiquitin-independent proteasome activity was up-regulated in SH-SY5Y ndufa2 KD cells while a downregulation was observed in PD cybrids and PBMC. Moreover, we observed an increase in protein ubiquitination that correlates with a decrease in ubiquitin-dependent proteasome activity. Accordingly, proteasome inhibition prevented ubiquitin-dependent aSN clearance. Ubiquitin-independent proteasome activity was positively correlated with ubiquitination in PBMC. We also report a negative correlation of chymotrypsin-like activity with age in control and late-onset PD groups. Total ubiquitin content is positively correlated with aSN oligomer levels, which leads to an age-dependent increase of aSN ubiquitination in LOPD. Moreover, aSN levels are increased in the plasma of PD patients. INTERPRETATION: aSN oligomers are ubiquitinated and we identified a ubiquitin-dependent clearance insufficiency with the accumulation of both aSN and ubiquitin. However, SH-SY5Y ndufa2 KD cells showed a significant up-regulation of ubiquitin-independent proteasomal enzymatic activity that could mean a cell rescue attempt. Moreover, we identified that UPS function is age-dependent in PBMC. PMID- 22921539 TI - Fabrication of macroporous titanium dioxide film using PMMA microspheres as template. AB - A novel synthetic procedure is described for the fabrication of macroporous titanium dioxide (TiO(2)) films with an ordered, uniform pore framework comprised of nanocrystalline anatase mainly. The synthetic approach involved several processes. First, polymethyl methacrylate (PMMA) microspheres (87 nm) were synthesized by using a dispersion polymerization technique in the presence of Fenton reagent (FeSO(4)/H(2)O(2)) as a novel initiator, which has advantages such as simple and fast polymerization process without deoxygenation. Next, the templates of PMMA microspheres were assembled on clean substrates by dip-drawing technique. Finally, the macroporous TiO(2) films with the average size of pores about 87 nm were obtained by sol-dipping template method and calcination to remove the templates at 550 degrees C. The test results of X-ray diffraction indicate that the nanocrystalline of anatase formed after calcination. The mechanisms of PMMA polymerization and template formation were proposed. Furthermore, both structures and morphologies of the composite films were investigated with field emission scanning electron microscope, and the processes of the thermal decomposition of PMMA and TiO(2) gel were also discussed with thermo gravimetric analysis. This ordered and uniform pore framework could be used as the promising ultrafilter membranes showing active photocatalysis without intensive fouling. PMID- 22921540 TI - Molecular dynamics computations of brine-CO2 interfacial tensions and brine-CO2 quartz contact angles and their effects on structural and residual trapping mechanisms in carbon geo-sequestration. AB - In the context of carbon geo-sequestration projects, brine-CO(2) interfacial tension gamma and brine-CO(2)-rock surface water contact angles theta directly impact structural and residual trapping capacities. While gamma is fairly well understood there is still large uncertainty associated with theta. We present here an investigation of gamma and theta using a molecular approach based on molecular dynamics computer simulations. We consider a system consisting of CO(2)/water/NaCl and an alpha-quartz surface, covering a brine salinity range between 0 and 4 molal. The simulation models accurately reproduce the dependence of gamma on pressure below the CO(2) saturation pressure at 300 K, and over predict gamma by ~20% at higher pressures. In addition, in agreement with experimental observations, the simulations predict that gamma increases slightly with temperature or salinity. We also demonstrate that for non-hydroxylated quartz surfaces, theta strongly increases with pressure at subcritical and supercritical conditions. An increase in temperature significantly reduces the contact angle, especially at low-intermediate pressures (1-10 MPa), this effect is mitigated at higher pressures, 20 MPa. We also found that theta only weakly depends on salinity for the systems investigated in this work. PMID- 22921541 TI - Power at hip, knee and ankle joints are compromised in women with mild and moderate knee osteoarthritis. AB - BACKGROUND: Analyses of the biomechanical characteristics of gait of women with mild and moderate knee osteoarthritis may identify parameters that could be targeted by physical therapy interventions. Therefore, the purpose of the present study was to compare the joint power profiles during gait between a group of elderly women with mild and moderate levels of knee osteoarthritis and a group of age-matched asymptomatic women. METHODS: Thirty-nine women diagnosed with osteoarthritis at the medial compartment of the knee and 39 healthy women with no diagnosis of knee osteoarthritis participated in the study. Joint power profiles of the hip, knee and ankle joints in the sagittal plane during gait were performed using video and force data obtained using Qualisys ProReflex System synchronized with two force plates. Principal component analysis was applied to extract features from the joint power waveforms characterizing their main modes of temporal variation. The extracted features were compared between groups. FINDINGS: Women with knee osteoarthritis absorbed and generated less energy at the hip and ankle joints, and absorbed less energy at the knee when compared to the asymptomatic group. INTERPRETATION: The observed power pattern in women with knee osteoarthritis may be related to their reduced gait speed, a suboptimal strategy possibly used to reduce reaction forces at the knee. Clinical studies should investigate whether interventions designed to improve muscular resources, as a means to control the flow of forces at the knee, would optimize power patterns and gait performance in women with knee osteoarthritis. PMID- 22921557 TI - Effects of a home-based rehabilitation program in obese type 2 diabetics. AB - OBJECTIVE: To assess, in obese type 2 diabetics (T2D), the impact of a home-based effort training program and the barriers to physical activity (PA) practice. METHOD: Twenty-three obese T2D patients (52.7 +/- 8.2 years, BMI = 38.5 +/- 7.6 kg/m(2)) were randomized to either a control group (CG), or an intervention group (IG) performing home-based cyclergometer training during 3 months, 30 min/day, with a monthly-supervised session. The initial and final measurements included: maximal graded effort test on cyclergometer, 6-minute walk test (6MWT) and 200 meter fast walk test (200mFWT), quadriceps maximal isometric strength, blood tests and quality of life assessment (SF- 36). A long-term assessment of the amount of physical activity (PA) and the barriers to PA practice was conducted using a questionnaire by phone call. RESULTS: Patients in the CG significantly improved the maximal power developed at the peak of the cyclergometer effort test (P < 0.05) as well as the quadriceps strength (P < 0.01). There were no significant changes in the other physical and biological parameters, neither in quality of life. At a mean distance of 17 +/- 6.4 months, the PA score remained low in the two groups. The main barriers to PA practice identified in both groups were the perception of a low exercise capacity and a poor tolerance to effort, lack of motivation, and the existence of pain associated to PA. CONCLUSION: This home-based intervention had a positive impact on biometrics and physical ability in the short term in obese T2D patients, but limited effects in the long term. The questionnaires completed at a distance suggest considering educational strategies to increase the motivation and compliance of these patients. PMID- 22921570 TI - Blood pressure surges in REM sleep: A mini review. AB - Blood pressure displays large fluctuations during REM sleep, a period when skeletal muscle loses activity systemically. Blood pressure rises spontaneously in spike-like surges even with no body movement. The mechanism underlying this unique characteristic of cardiovascular control during REM sleep remains unclear. Where does the source for this blood pressure surge during REM sleep exist? Is it related to dreaming, which is one of the primary characteristics of REM sleep? Are peripheral mechanisms involved in this phenomenon? Here, evidence related to the above-mentioned questions is reviewed. PMID- 22921571 TI - SUMO ligase activity of vertebrate Mms21/Nse2 is required for efficient DNA repair but not for Smc5/6 complex stability. AB - Nse2/Mms21 is an E3 SUMO ligase component of the Smc5/6 complex, which plays multiple roles in maintaining genome stability. To study the functions of the vertebrate Nse2 orthologue, we generated Nse2-deficient chicken DT40 cells. Nse2 was dispensable for DT40 cell viability and required for efficient repair of bulky DNA lesions, although Nse2-deficient cells showed normal sensitivity to ionising radiation-induced DNA damage. Homologous recombination activities were reduced in Nse2(-/-/-) cells. Nse2 deficiency destabilised Smc5, but not Smc6. In rescue experiments, we found that the SUMO ligase activity of Nse2 was required for an efficient response to MMS- or cis-platin-induced DNA damage, and for homologous recombination, but not for Smc5 stability. Gel filtration analysis indicated that Smc5 and Nse2 remain associated during the cell cycle and after DNA damage and Smc5/Smc6 association is independent of Nse2. Analysis of Nse2(-/ /-)Smc5(-) clones, which were viable although slow-growing, showed no significant increase in DNA damage sensitivity. We propose that Nse2 determines the activity, but not the assembly, of the Smc5/6 complex in vertebrate cells, and this activity requires the Nse2 SUMO ligase function. PMID- 22921572 TI - 14th International Workshop on Ataxia-Telangiectasia ATW2012. AB - The fourteenth international Ataxia-Telangiectasia Workshop 2012 (ATW2012) (www.atw2012.com) on ataxia-telangiectasia (AT) and the role of the ataxia telangiectasia mutated (ATM) gene in DNA repair, neurological disease, cancer and related topics was held from February 07 to 11, 2012 in Delhi, India. The international ATW2012 meeting reported the latest advances in ATM research as well as potential therapeutic treatments for A-T. The meeting was attended by a productive mix of scientists, ranging from those prominent in the initial characterization of the underlying genetic defect to young scientists just entering the field. In broad terms, three main themes were discussed at the meeting: first, a wealth of new details emerged on DNA damage signaling/repair mechanisms for which ATM is a critical element; secondly, important functions for ATM in previously unrelated cellular pathways were identified; and thirdly, new physiological effects and potential therapeutic treatments related to A-T were presented. This report summarizes below a sampling of the many interesting results from the meeting. PMID- 22921573 TI - Unwinding of synthetic replication and recombination substrates by Srs2. AB - The budding yeast Srs2 protein possesses 3' to 5' DNA helicase activity and channels untimely recombination to post-replication repair by removing Rad51 from ssDNA. However, it also promotes recombination via a synthesis-dependent strand annealing pathway (SDSA). Furthermore, at the replication fork, Srs2 is required for fork progression and prevents the instability of trinucleotide repeats. To better understand the multiple roles of the Srs2 helicase during these processes, we analysed the ability of Srs2 to bind and unwind various DNA substrates that mimic structures present during DNA replication and recombination. While leading or lagging strands were efficiently unwound, the presence of ssDNA binding protein RPA presented an obstacle for Srs2 translocation. We also tested the preferred directionality of unwinding of various substrates and studied the effect of Rad51 and Mre11 proteins on Srs2 helicase activity. These biochemical results help us understand the possible role of Srs2 in the processing of stalled or blocked replication forks as a part of post-replication repair as well as homologous recombination (HR). PMID- 22921574 TI - Prevention of adhesion formation in Wistar-albino rats by increased bowel movements achieved with oral Ricinus oil use for 8 days postoperatively: an experimental study. AB - OBJECTIVE: Adhesion formation frequently occurs after abdominopelvic surgery and can cause significant morbidity for patients. Meticulous hemostasis, minimal access surgery and utilization of surgical adjuvants intraoperatively are clinically useful measures to minimize adhesion formation. We investigated the clinical efficiency of oral Ricinus oil treatment for 8 days postoperatively to decrease adhesion formation in this case-control study in a rat model. STUDY DESIGN: Following computer-generated randomization, 24 female Wistar-albino rats were operated on, with 10 standard cautery lesions on the right uterine horn and two simple suture lesions on left uterine horn generated with absorbable material. Half (n=12) the rats received 0.13 g (0.2 ml) Ricinus oil emulsion (40 g/60 ml) via the oral route during the first 8 days postoperatively, and the remaining rats (n=11) were considered as controls. The extent, severity, degree, total adhesion scores and histopathological features of the adhesions were the main outcome measures. RESULTS: The degree and total adhesion formation scores in the Ricinus oil group and control group revealed significant differences in adhesion extent and severity. The total adhesion scores of the Ricinus oil and control groups were 3.00 +/- 2.21 and 5.18 +/- 2.78 respectively (P<0.05). Differences in type of inflammation, extent of inflammation and vascularization were statistically insignificant for suture and cautery lesions individually (P>0.05). CONCLUSIONS: Ricinus oil treatment following abdominopelvic surgery for the 8-day period that covers the completion of tissue healing process may be a promising, cheap and cost-effective treatment strategy for patients. PMID- 22921575 TI - Cytogenetic evaluation of pre-pregnancy smoking in maternal and newborn lymphocytes. AB - OBJECTIVE: To study cytogenetic damage in order to estimate the effect of pre pregnancy smoking on pregnant women and their foetuses. STUDY DESIGN: Lymphocyte cultures were obtained from peripheral blood of 20 women who quit smoking during pregnancy, and umbilical cord blood of their newborns at delivery. Cytogenetic analyses were performed for sister chromatid exchanges (SCEs), proliferation rate index (PRI) and mitotic index (MI) using the Fluorescence Plus Giemsa staining technique. Twenty non-smoking women and their newborns were evaluated as controls. CPT-11, a known antineoplastic, was used as a positive genotoxic agent in order to correlate non-smoking women with smoking women and reveal any underlying chromosome instability. Statistical evaluation of SCE frequencies, PRI and MI was based on independent samples t-test in order to estimate the effect of pre-pregnancy smoking on mothers and their newborns. RESULTS: SCEs were induced in the cord blood lymphocytes of newborns whose mothers smoked before pregnancy when they were exposed to the mutagenic agent CPT-11 (p<0.01). A similar increase in SCEs was observed in both non-smoking and smoking mothers exposed to CPT-11. Newborns in both groups had significantly lower SCE levels than their mothers (p<0.01). CONCLUSION: Pre-pregnancy smoking results in cytogenetic damage for both mothers and newborns, and is an important risk factor for cancer and/or other genetic-related diseases. Smoking cessation needs to occur well before conception in order to avoid the strong cytogenetic association between pre pregnancy smoking by mothers and their newborns. PMID- 22921576 TI - Predictive value of serum human chorionic gonadotropin ratio, progesterone and inhibin A for expectant management of early pregnancies of unknown location. AB - OBJECTIVE: To evaluate serum human chorionic gonadotropin (hCG) ratio, progesterone and inhibin A as single parameters and in combination for the prediction of spontaneous resolution of pregnancies of unknown location (PUL). STUDY DESIGN: Prospective observational study of 105 consecutive patients with a diagnosis of PUL. Serum levels of hCG, progesterone and inhibin A were determined at the first visit and after 2 days. Patients were followed clinically until a final diagnosis of spontaneously resolving PUL, viable or non-viable intrauterine pregnancy, or ectopic pregnancy with need of laparoscopic intervention had been reached. Different combinations of hCG ratio (hCG at 48 h/hCG at 0 h), s progesterone and s-inhibin A were investigated to find the best predictor for successful expectant management. RESULTS: The final pregnancy outcomes were: 52 spontaneously resolving PUL (49.5%), 37 viable intrauterine pregnancies (35.2%), 8 non-viable intrauterine pregnancies (7.6%), 7 ectopic pregnancies (6.7%), and one molar pregnancy (1.0%). An hCG ratio<0.80 predicted spontaneously resolving PUL with positive and negative predictive values (PPV and NPV), sensitivity, and specificity of 0.98, 0.78, 0.72, and 0.99, respectively. In patients with hCG ratio >= 0.80, a combination of s-progesterone < 20 nmol/l and s-inhibin A < 30 pg/ml predicted spontaneously resolving PUL with PPV, NPV, sensitivity and specificity of 0.92, 0.96, 0.85, and 0.98 respectively. CONCLUSION: Our results suggest that patients with PUL and hCG ratio < 0.80 display a high probability of spontaneously resolving PUL with minimum need of follow-up. In cases of hCG ratio >= 0.80, a combination of s-progesterone < 20 nmol/l and s-inhibin A < 30 pg/ml, may be a reliable predictor of spontaneously resolving PUL. The safety of this approach should be tested in large prospective studies. PMID- 22921577 TI - Who defaults from colposcopy? A multi-centre, population-based, prospective cohort study of predictors of non-attendance for follow-up among women with low grade abnormal cervical cytology. AB - OBJECTIVE: The success of cervical screening relies on women with abnormal cervical cytology attending for follow-up by colposcopy and related procedures. Failure to attend for colposcopy, however, is a common problem in many countries. The objective of this study was to identify factors associated with non attendance at an initial colposcopy examination among women with low-grade abnormal cervical cytology. STUDY DESIGN: A cohort study was conducted within one arm of a multi-centre population-based randomised controlled trial nested within the UK NHS Cervical Screening Programmes. The trial recruited women aged 20-59 years with recent low-grade cervical cytology; women randomised to immediate referral for colposcopy were included in the current analysis (n=2213). At trial recruitment, women completed a socio-demographic and lifestyle questionnaire; 1693 women in the colposcopy arm were also invited to complete a psychosocial questionnaire, including the Hospital Anxiety and Depression Scale. Women were sent up to two colposcopy appointments. A telephone number was provided to reschedule if necessary. Defaulters were defined as those who failed to attend after two appointments. Logistic regression methods were used to compute multivariate odds ratios (OR) to identify variables significantly associated with default. RESULTS: 148 women defaulted (6.7%, 95%CI 5.7-7.8%). In multivariate analysis, risk of default was significantly raised in those not in paid employment (OR=2.70, 95%CI 1.64-4.43) and current smokers (OR=1.62, 95%CI 1.12 2.34). Default risk deceased with increasing age and level of post-school education/training and was lower in women with children (OR=0.59, 95%CI 0.35 0.98). Among the sub-group invited to complete psychosocial questionnaires, women who were not worried about having cervical cancer were significantly more likely to default (multivariate OR=1.56, 95%CI 1.04-2.35). Anxiety and depression were not significantly associated with default. CONCLUSIONS: Women at highest risk of default from colposcopy are younger, not in paid employment, smoke, lack post school education, have not had children and are not worried about having cervical cancer. Findings such as these could inform the development of tools to predict the likelihood that an individual woman will default from follow-up. Interventions to minimise default also deserve consideration, but a better understanding of reasons for default is needed to inform intervention development. PMID- 22921578 TI - TGF-beta and renal fibrosis: a Pandora's box of surprises. PMID- 22921579 TI - Transformation of paralytic shellfish poisoning toxins in Crassostrea gigas and Pecten maximus reference materials. AB - Matrix reference materials are an important requirement for the assessment of method performance characteristics and for routine quality control. In the field of marine toxin testing where biological assays have been used and where modern analytical testing methods are now becoming available, this requirement has become an urgent one. Various approaches are utilised for preparation of such materials in the absence of available naturally occurring toxic shellfish samples. Toxin-free shellfish may be artificially fortified through the addition of cultured toxic phytoplankton or shellfish may be incurred through natural feeding on toxic algae in a laboratory environment. Both of these approaches may be potentially affected by issues relating to the degradation or transformation of toxin analytes, so studies were conducted to assess these effects within our laboratory. A range of PSP-toxic shellfish tissues were prepared using the two approaches, in both Pacific oyster (Crassostrea gigas) and king scallops (Pecten maximus). Additionally, sub-samples of incurred Pacific oyster tissue were further treated, through addition of artificial chemical stabilisers and gamma irradiation. Two separate month-long stability trials were conducted at +4 degrees C on each material. Results highlighted clear evidence for improved stability of materials following shellfish feeding experiments in comparison with the tissues which had been spiked with plankton. In addition, there were clear differences in stability of toxins between the two shellfish species studied. There was evidence for good stability of C1&2 toxins in both the incurred tissues and improved stability of some toxins in tissues which had been subjected to either gamma irradiation or treatment with chemical additives. The results therefore highlighted the benefits of conducting shellfish feeding if suitable stable reference materials are to be prepared containing a full range of PSP toxin analytes. The study also highlighted the benefits of post-production treatment to prolong the stability of the materials. Work is ongoing to assess the full characteristics of candidate reference materials prepared with these approaches with the aim of producing a homogenous and stable PSP reference material in Pacific oysters. PMID- 22921580 TI - Horse IgG- and ostrich IgY-F(ab')2 groups have different affinities for mice erythrocytes and lymphocytes. Implications for avian immunoglobulin therapeutic usefulness. AB - We used high sensitivity and resolution fluorescence microscopy to study the interaction of ostrich IgY, horse F(ab')2 and horse IgG with mice lymphocyte and erythrocyte plasma membrane. The immunoglobulins were labeled with fluorescein isotiocyanate (FITC). Our results show an interaction of IgY with lymphocyte plasma membrane which does not result in endocytosis of the labeled protein. Less IgG and its F(ab')2 fraction bind to lymphocytes, and this binding seems to be followed by endocytosis producing a diffuse cytoplasmic fluorescence in most lymphocytes exposed to FITC-IgG or FITC-F(ab')2. Cytoplasmic fluorescence resembling FITC was not observed in lymphocytes exposed to FITC-IgY. Receptors in the erythrocyte membrane also differentiate between avian and horse Ig; while erythrocytes exposed to horse Igs became intensely fluorescent for at least 5 h, no erythrocyte labeling occurred when FITC-IgY was used. Our results suggest that IgY may be a stronger activator of adaptive immunity than horse IgG in mammals. Adaptive immunity against IgY is detrimental to its IV therapeutic use in humans and other mammals. PMID- 22921581 TI - Co-exposure of Fusarium mycotoxins: in vitro myelotoxicity assessment on human hematopoietic progenitors. AB - Mycotoxins such as beauvericin (BEA), deoxynivalenol (DON), enniatin B (ENB), fumonisin B1 (FB1), T-2 toxin and zearalenone (ZEA) can co-occur in food commodities. This aim of this study was to assess the myelotoxicity of these mycotoxins in couple using in vitro human granulo-monocytic (Colony Forming Unit Granulocyte and Macrophage, CFU-GM) hematopoietic progenitors. Clonogenic assays have been performed in the presence of the following couples of fusariotoxins: DON + BEA, DON + FB1, DON + T-2, DON + ZEA, T-2 + ZEA and BEA + ENB. Co-exposure of human CFU-GM to DON + BEA resulted in synergic myelotoxic effects. The combination of DON + T-2 presented additive or synergic myelotoxic effects. The couples DON + ZEA, T-2 + ZEA and BEA + ENB had additive myelotoxic effects, while the combination of DON + FB1 showed antagonist myelotoxic effects. These in vitro results suggested that the simultaneous presence of mycotoxins in food commodities and diet may be more myelotoxic than the presence of one mycotoxin alone. Diminution of hematopoietic progenitors could give rise to a decrease number of mature blood cells, inducing agranulocytosis and/or thrombocytopenia and in severe cases aplastic anemia. PMID- 22921582 TI - Kinetic modeling and synergy quantification in sono and photooxidative treatment of simulated dyehouse effluent. AB - The aim of this work was to explore the application of sulfate radical based advanced oxidation processes: photooxidation (UV/PMS/PS), sonooxidation (US/PMS/PS) and combined sono-photooxidation (US/UV/PMS/PS) for the mineralization of simulated dyehouse effluent (WW); using peroxymonosulfate (PMS) and persulfate (PS) as oxidants. Experiments were performed in a reaction vessel of a defined geometry and axially positioned source of UV-C radiation, all placed in the ultrasonic bath (35 kHz). Mathematical model of the process was developed according to the proposed degradation scheme. Decomposition of dyestuff (C.I. Reactive Violet 2, RV2 and C.I. Reactive Blue 7, RB7), surfactant (linear alkylbenzene sulfonate; hereafter: LAS) and auxiliary organic components was explored in three types of model wastewater: WW, simulated effluent excluding inorganic species (WW-IS) and model solution that consists of a specific compound (hereafter: compound model solutions). The influence of inorganic matrix (Cl(-), CO(3)(2-)/HCO(3)(-)) was studied due to the corresponding quenching affinity toward HO and SO(4)(-) radicals. The efficiency of applied processes was evaluated and the response to combined phenomena (cavitation and irradiation) was quantified as synergy index, f(Syn). Sono-photooxidative treatment (US/UV/PMS/PS) of WW resulted in a partial mineralization and partial decolourization; approximately 40% of initial TOC and 30% of initial RB7 remained after 60 min of treatment, while RV2 and LAS molecule were completely decomposed. Circumstantially, the combined process increased the mineralization efficiency by a factor of 3 (f(Syn) = 3.026). PMID- 22921583 TI - Removal of ethinylestradiol (EE2) from water via adsorption on aliphatic polyamides. AB - This study demonstrates the use of aliphatic polyamides (PAs) as efficient adsorbents for the removal of ethinylestradiol (EE2), a synthetic hormone and high-potency estrogenic contaminant, from water via strong adsorptive interactions. PA612 and PA12 showed significantly higher adsorption capacities than PA6 for EE2 adsorption from water. Isothermal adsorption studies showed that PA612 had an adsorption capacity for EE2 comparable to the benchmark macroreticular polymeric adsorbent, AMBERLTIE XAD4 (XAD4), despite its nonporous structure and far smaller surface area. The substantial adsorption of EE2 on PA612 is predominantly driven by Lewis acid-base interactions between EE2 and PA612 amide functionalities and facilitated by the hydrophobic partitioning of EE2 solutes in water. Rapid column adsorption tests demonstrated efficient removal of EE2 from water on a continuous flow basis. With an empty bed contact time of 0.8-1.0 min, the fixed-bed column with 1.0 g PA612 particles removed the EE2 from 24.1 L of 30 MUg L(-1) EE2 spiked solution to non-detectable levels by HPLC analysis. Regeneration was readily effected by rinsing the exhausted column with 4 wt.% NaOH solution at room temperature. Regenerated PA612 particles showed consistent performance to fresh PA612 particles in subsequent batch and column adsorption studies. PMID- 22921584 TI - Waste to resource: Converting paper mill wastewater to bioplastic. AB - In this study we investigated the feasibility of producing polyhydroxyalkanoate (PHA) by microbial enrichments on paper mill wastewater. The complete process includes (1) paper mill wastewater acidogenic fermentation in a simple batch process, (2) enrichment of a PHA-producing microbial community in a selector operated in sequencing batch mode with feast-famine regime, (3) Cellular PHA content maximization of the enrichment in an accumulator in fed-batch mode. The selective pressure required to establish a PHA-producing microbial enrichment, as derived from our previous research on synthetic medium, was validated using an agro-industrial waste stream in this study. The microbial enrichment obtained could accumulate maximum up to 77% PHA of cell dry weight within 5 h, which is currently the best result obtained on real agro-industrial waste streams, especially in terms of biomass specific efficiency. Biomass in this enrichment included both Plasticicumulans acidivorans, which was the main PHA producer, and a flanking population, which exhibited limited PHA-producing capacity. The fraction of P. acidivorans in the biomass was largely dependent on the fraction of volatile fatty acids in the total soluble COD in the wastewater after acidification. Based on this observation, one simple equation was proposed for predicting the PHA storage capacity of the enrichment. Moreover, some crucial bottlenecks that may impede the successful scaling-up of the process are discussed. PMID- 22921585 TI - A shallow lake remediation regime with Phragmites australis: Incorporating nutrient removal and water evapotranspiration. AB - Shallow lake eutrophication has been an important issue of global water environment. Based on the simulation and field sampling experiments in Baiyangdian Lake, the largest shallow lake in North China, this study proposed a shallow lake remediation regime with Phragmites australis (reed) incorporating its opposite effects of nutrient removal and water evapotranspiration on water quality. The results of simulation experiments showed that both total nitrogen (TN) and phosphorus (TP) removal efficiencies increased with the increasing reed coverage. The TN removal efficiencies by reed aboveground uptake and rhizosphere denitrification were 11.2%, 13.8%, 22.6%, 28.4%, and 29.6% for the reed coverage of 20%, 40%, 60%, 80%, and 100%, respectively. Correspondingly, TP removal efficiencies by aboveground reed uptake were 1.4%, 2.5%, 4.4%, 7.4% and 7.9%, respectively. However, the water quality was best when the reed coverage was 60% (72 plants m(-2)). This was due to the fact that the concentration effect of reed evapotranspiration on nutrient increased with reed coverage. When the reed coverage was 100% (120 plants m(-2)), the evapotranspiration was approximately twice that without reeds. The field sampling results showed that the highest aboveground nutrient storages occurred in September. Thus, the proposed remediation regime for Baiyangdian Lake was that the reed coverage should be adjusted to 60%, and the aboveground biomass of reeds should be harvested in each September. With this remediation regime, TN and TP removal in Baiyangdian Lake were 117.8 and 4.0 g m(-2), respectively, and the corresponding removal efficiencies were estimated to be 49% and 8.5% after six years. This study suggests that reed is an effective plant for the remediation of shallow lake eutrophication, and its contrasting effects of nutrient removal and evapotranspiration on water quality should be considered for establishing the remediation regime in the future. PMID- 22921586 TI - The mycobacterial cord factor adjuvant analogue trehalose-6,6'-dibehenate (TDB) activates the Nlrp3 inflammasome. AB - The success of a vaccine consists in the induction of an innate immune response and subsequent activation of the adaptive immune system. Because antigens are usually not immunogenic, the addition of adjuvants that activate innate immunity is required. The mycobacterial cord factor trehalose-6,6'-dimycolate (TDM) and its synthetic adjuvant analogue trehalose-6,6'-dibehenate (TDB) rely on the C type lectin Mincle and the signaling molecules Syk and Card9 to trigger innate immunity. In this study, we show that stimulation of bone marrow-derived dendritic cells (BMDCs) with TDB induces Nlrp3 inflammasome-dependent IL-1beta secretion. While Card9 is required for NF-kappaB activation by TDB, it is dispensable for TDB-induced activation of the Nlrp3 inflammasome. Additionally, efflux of intracellular potassium, lysosomal rupture, and oxygen radical (ROS) production are crucial for caspase-1 processing and IL-1beta secretion by TDB. In an in vivo inflammation model, we demonstrate that the recruitment of neutrophils by TDB is significantly reduced in the Nlrp3-deficient mice compared to the wild type mice, while the production of chemokines in vitro is not influenced by the absence of Nlrp3. These results identify the Nlrp3 inflammasome as an essential mediator for the induction of an innate immune response triggered by TDB. PMID- 22921587 TI - Bcl-rambo induces apoptosis via interaction with the adenine nucleotide translocator. AB - The Bcl-2 family proteins plays a central role in apoptosis. The pro- or anti apoptotic activities of Bcl-2 family are dependent on the Bcl-2 homology (BH) regions. Bcl-rambo, a new pro-apoptotic member, is unusual in that its pro apoptotic activity is independent of its BH domains. However, the mechanism underlying Bcl-rambo-induced apoptosis is largely unknown. Mitochondrial localization is indispensable for the pro-apoptotic function of Bcl-rambo. Bcl rambo interacts physically with the adenine nucleotide translocator (ANT), suppresses the ADT/ATP-dependent translocation activity of ANT. Collectively, our data indicate Bcl-rambo is a pro-apoptotic member of the Bcl-2 family, induces the permeability transition via interaction with ANT. PMID- 22921588 TI - Sleep and cardiometabolic function in obese adolescent girls with polycystic ovary syndrome. AB - OBJECTIVE: To compare the polysomnography findings and cardiometabolic function among adolescent girls with polycystic ovary syndrome (PCOS) and matched female and male controls. METHOD: Retrospective chart review of electronic medical records of 28 girls with PCOS (age: 16.8+/-1.9 years, body mass index (BMI) Z score 2.4+/-0.4), 28 control females (age: 17.1+/-1.8, BMI Z-score 2.4+/-0.3) and 28 control males (age: 16.6+/-1.6, BMI Z-score 2.5+/-0.5) in a tertiary care centre. RESULTS: The prevalence of obstructive sleep apnoea (OSA) was higher in girls with PCOS compared to control females (16/28 (57%) vs. 4/28(14.3%), p<0.01); however, it was comparable to that of the control males (16/28(57%) vs. 21/28(75%), p=0.4). Girls with PCOS had a significantly higher prevalence of insulin resistance compared to control females and control males (20/28 (71.4%) vs. 9/22 (41.0%) (p=0.04) vs. 8/23 (34.8%) (p=0.01). Among girls with PCOS, those with OSA had significantly higher proportions of metabolic syndrome (MetS) (9/16 (56.3%) vs. 1/12 (8.3%) p=0.03), higher insulin resistance (14/16 (87.5%) vs. 6/12 (50%), p=0.04), elevated daytime systolic blood pressure (128.4+/-12.8 vs. 115.6+/-11.4, p<0.01), lower high-density lipoprotein (HDL) (38.6+/-8.7 vs. 49+/ 10.9, p=0.01) and elevated triglycerides (TG) (149.7+/-87.7 vs. 93.3+/-25.8, p=0.03) compared to those without OSA. CONCLUSIONS: We report a higher prevalence of OSA and metabolic dysfunction in a selected group of obese girls with PCOS referred with sleep-related complaints compared to BMI-matched control girls without PCOS. We also report higher prevalence of cardiometabolic dysfunction in girls with PCOS and OSA compared to girls with PCOS without OSA. PMID- 22921589 TI - The H2O2-sensitive HyPer protein targeted to the endoplasmic reticulum as a mirror of the oxidizing thiol-disulfide milieu. AB - Oxidative protein folding in the endoplasmic reticulum (ER) is associated with the formation of native disulfide bonds, which inevitably results in the formation of hydrogen peroxide (H(2)O(2)). Particularly in pancreatic beta-cells with their high secretory activity and extremely low antioxidant capacity, the H(2)O(2) molecules generated during oxidative protein folding could represent a significant oxidative burden. Therefore this study was conducted to elucidate the H(2)O(2) generation during disulfide bond formation in insulin-producing RINm5F cells by targeting and specifically expressing the H(2)O(2)-sensitive biosensor HyPer in the ER (ER-HyPer). In addition the influence of overexpression of the H(2)O(2)-metabolizing ER-resident peroxiredoxin IV (PRDXIV) on H(2)O(2) levels was examined. The ER-HyPer fluorescent protein was completely oxidized, whereas HyPer expressed in cytosol, peroxisomes, and mitochondria was prevalently in the reduced state, indicating a high basal H(2)O(2) concentration in the ER lumen. These results could also be confirmed in non-insulin-producing COS-7 cells. Overexpression of PRDXIV in RINm5F cells effectively protected against H(2)O(2) mediated toxicity; however, it did not affect the fluorescence signal of ER HyPer. Moreover, the inhibition of de novo protein synthesis and the associated H(2)O(2) generation by cycloheximide had no influence on the ER-HyPer redox state. Taken together, these findings strongly suggest that the H(2)O(2) sensitive biosensor reflects exclusively the oxidative milieu in the ER and not the H(2)O(2) concentration in the ER lumen. PMID- 22921590 TI - The mechanism of redox sensing in Mycobacterium tuberculosis. AB - Tuberculosis epidemics have defied constraint despite the availability of effective treatment for the past half-century. Mycobacterium tuberculosis, the causative agent of TB, is continually exposed to a number of redox stressors during its pathogenic cycle. The mechanisms used by Mtb to sense redox stress and to maintain redox homeostasis are central to the success of Mtb as a pathogen. Careful analysis of the Mtb genome has revealed that Mtb lacks classical redox sensors such as FNR, FixL, and OxyR. Recent studies, however, have established that Mtb is equipped with various sophisticated redox sensors that can detect diverse types of redox stress, including hypoxia, nitric oxide, carbon monoxide, and the intracellular redox environment. Some of these sensors, such as heme based DosS and DosT, are unique to mycobacteria, whereas others, such as the WhiB proteins and anti-sigma factor RsrA, are unique to actinobacteria. This article provides a comprehensive review of the literature on these redox-sensory modules in the context of TB pathogenesis. PMID- 22921591 TI - Low molecular weight heparin or semuloparin should not be recommended for thromboprophylaxis in ambulatory solid cancer patients undergoing chemotherapy. PMID- 22921592 TI - Clinical features and short term outcomes of patients with acute pulmonary embolism. The Italian Pulmonary Embolism Registry (IPER). AB - BACKGROUND: Registries are essential to obtain information on the whole spectrum of patients with pulmonary embolism (PE). The aim of the Italian Pulmonary Embolism Registry (IPER) is to report on demographics, clinical features, management, and outcomes of patients diagnosed with PE in everyday clinical practice. METHODS: Patients with confirmed acute PE were enrolled in a web-based registry, in Cardiology, Emergency or Internal Medicine Departments in 47 hospitals in Italy. RESULTS: Overall, 1716 patients were included, mean age 70 +/ 15 years, (14% of the patients were <50 and 43% >75 year old); 57% of female gender and 11.7% hemodynamically unstable at presentation/diagnosis. D-dimer was performed in 1358 patients (80%). Computerized tomographic pulmonary angiogram (CT) was used for diagnosis in the majority of the patients (82.1%), followed by perfusion lung scan (8.6%). Thrombolytic agents were used in 185 (10.8%) patients, percutaneous thrombectomy in 14 (0.8%) and surgery in 2 (0.1%). One hundred sixteen patients died while in-hospital (6.7%), 68 (3.9%) due to PE. Death or clinical deterioration occurred in 138 patients (8.0%). All-cause mortality was 31.8% in hemodynamically unstable patients and 3.4% in hemodynamically stable patients; the corresponding PE-related deaths were 23.3% and 1.4% respectively. Age >75 (HR 1.50, 95% CI 1.01-2.25), immobilization > 3 days before diagnosis of PE (HR 2.54, 95% CI 1.72-3.77) and hemodynamic impairment (HR 6.38, 95% CI 4.26-9.57) were independent predictors for in hospital death. CONCLUSIONS: Patients with PE have a considerable risk of death during the hospital stay, PE being the most common cause of early mortality. PMID- 22921593 TI - Estimated insulin sensitivity and cardiovascular disease risk factors in adolescents with and without type 1 diabetes. AB - OBJECTIVE: To test the hypothesis that cardiovascular disease (CVD) risk factors are similar in nondiabetic (non-DM) adolescents compared with those with type 1 diabetes (T1D) in the most insulin-sensitive (IS) tertile, and that CVD risk factors are more atherogenic with decreasing IS in adolescents with T1D. STUDY DESIGN: IS for adolescents with T1D (n = 292; age = 15.4 +/- 2.1 years; duration = 8.8 +/- 3.0 years, hemoglobin A1c = 8.9% +/- 1.6%) and non-DM controls (n = 89; age = 15.4 +/- 2.1 years) was estimated using the model: log(e)IS = .64725 - 0.02032 (waist [cm]) - 0.09779 (hemoglobin A1c [%]) - 0.00235 (triglycerides [mg/dL]). CVD risk factors (blood pressure, fasting total and low- and high density lipoprotein-cholesterol (HDL-c), high sensitivity C-reactive protein, and body mass index z score) were compared between all non-DM adolescents and those with T1D in the most IS tertile, and then examined for a linear trend by IS tertile in adolescents with T1D, adjusted for sex, race/ethnicity, and Tanner stage. RESULTS: Estimated IS was significantly lower in adolescents with T1D compared with those without (T1D = 7.8 +/- 2.4, non-DM = 11.5 +/- 2.9; P < .0001). CVD risk factors were similar for non-DM compared with the adolescents with T1D with the most IS, except for higher (HDL-c) and diastolic blood pressure in adolescents with T1D (P < .05). Among adolescents with T1D, all CVD risk factors except for (HDL-c), were more atherogenic across decreasing IS tertiles in linear regression analysis (P < .05). CONCLUSION: Adolescents with T1D who are the most IS have similar CVD risk factors compared with non-DM adolescents. CVD risk factors are inversely associated with IS in adolescents with T1D. IS may be an important therapeutic target for reducing CVD risk factors in adolescents with T1D. PMID- 22921594 TI - Imaging exosome transfer from breast cancer cells to stroma at metastatic sites in orthotopic nude-mouse models. AB - Exosomes play an important role in cell-to-cell communication to promote tumor metastasis. In order to image the fate of cancer-cell-derived exosomes in orthotopic nude mouse models of breast cancer, we used green fluorescent protein (GFP)-tagged CD63, which is a general marker of exosomes. Breast cancer cells transferred their own exosomes to other cancer cells and normal lung tissue cells in culture. In orthotopic nude-mouse models, breast cancer cells secreted exosomes into the tumor microenvironment. Tumor-derived exosomes were incorporated into tumor-associated cells as well as circulating in the blood of mice with breast cancer metastases. These results suggest that tumor-derived exosomes may contribute to forming a niche to promote tumor growth and metastasis. Our results demonstrate the usefulness of GFP imaging to investigate the role of exosomes in cancer metastasis. PMID- 22921596 TI - Molecular fabrications of smart nanobiomaterials and applications in personalized medicine. AB - Recent advances in nanotechnology adequately address many of the current challenges in biomedicine. However, to advance medicine we need personalized treatments which require the combination of nanotechnological progress with genetics, molecular biology, gene sequencing, and computational design. This paper reviews the literature of nanoscale biomaterials described to be totally biocompatible, non-toxic, non-immunogenic, and biodegradable and furthermore, have been used or have the potential to be used in personalized biomedical applications such as drug delivery, tissue regeneration, and diagnostics. The nanobiomaterial architecture is discussed as basis for fabrication of novel integrated systems involving cells, growth factors, proteins, cytokines, drug molecules, and other biomolecules with the purpose of creating a universal, all purpose nanobiomedical device for personalized therapies. Nanofabrication strategies toward the development of a platform for the implementation of nanotechnology in personalized medicine are also presented. In addition, there is a discussion on the challenges faced for designing versatile, smart nanobiomaterials and the requirements for choosing a material with tailor made specifications to address the needs of a specific patient. PMID- 22921597 TI - Templated high density lipoprotein nanoparticles as potential therapies and for molecular delivery. AB - High density lipoproteins (HDLs) are dynamic natural nanoparticles best known for their role in cholesterol transport and the inverse correlation that exists between blood HDL levels and the risk of developing coronary heart disease. In addition, enhanced HDL-cholesterol uptake has been demonstrated in several human cancers. As such, the use of HDL as a therapeutic and as a vehicle for systemic delivery of drugs and as imaging agents is increasingly important. HDLs exist on a continuum from the secreted HDL-scaffolding protein, apolipoprotein A-1 (Apo A1), to complex, spherical "mature" HDLs. Aspects of HDL particles including their size, shape, and surface chemical composition are being recognized as critical to their diverse biological functions. Here we review HDL biology; strategies for synthesizing HDLs; data supporting the clinical use and benefit of directly administered HDL; a rationale for developing synthetic methods for spherical, mature HDLs; and, the potential to employ HDLs as therapies, imaging agents, and drug delivery vehicles. Importantly, methods that utilize nanoparticle templates to control synthetic HDL size, shape, and surface chemistry are highlighted. PMID- 22921598 TI - Mesoporous silica nanoparticles in medicine--recent advances. AB - MSNs have attracted increasing interest as drug carriers due to promising in vivo results in small-animal disease models, especially related to cancer therapy. In most cases small hydrophobic drugs have been used, but recent in vitro studies demonstrate that MSNs are highly interesting for gene delivery applications. This review covers recent advances related to the therapeutic use of mesoporous silica nanoparticles (MSNs) administered intravenously, intraperitoneally or locally. We also cover the use of MSNs in alternative modes of therapy such as photodynamic therapy and multidrug therapy. We further discuss the current understanding about the biodistribution and safety of MSNs. Finally, we critically discuss burning questions especially related to experimental design of in vivo studies in order to enable a fast transition to clinical trials of this promising drug delivery platform. PMID- 22921595 TI - Epigenetics advancing personalized nanomedicine in cancer therapy. AB - Personalized medicine aims to deliver the right drug to a right patient at the right time. It offers unique opportunities to integrate new technologies and concepts to disease prognosis, diagnosis and therapeutics. While selective personalized therapies are conceptually impressive, the majority of cancer therapies have dismal outcome. Such therapeutic failure could result from no response, drug resistance, disease relapse or severe side effect from improper drug delivery. Nanomedicine, the application of nanotechnology in medicine, has a potential to advance the identification of diagnostic and prognostic biomarkers and the delivery of right drug to disease sites. Epigenetic aberrations dynamically contribute to cancer pathogenesis. Given the individualized traits of epigenetic biomarkers, epigenetic considerations would significantly refine personalized nanomedicine. This review aims to dissect the interface of personalized medicine with nanomedicine and epigenetics. I will outline the progress and highlight challenges and areas that can be further explored perfecting the personalized health care. PMID- 22921599 TI - Cognitive disorganisation in schizotypy is associated with deterioration in visual backward masking. AB - To understand the causes of schizophrenia, a search for stable markers (endophenotypes) is ongoing. In previous years, we have shown that the shine through visual backward masking paradigm meets the most important characteristics of an endophenotype. Here, we tested masking performance differences between healthy students with low and high schizotypy scores as determined by the self report O-Life questionnaire assessing schizotypy along three dimensions, i.e. positive schizotypy (unusual experiences), cognitive disorganisation, and negative schizotypy (introvertive anhedonia). Forty participants performed the shine-through backward masking task and a classical cognitive test, the Wisconsin Card Sorting Task (WCST). We found that visual backward masking was impaired for students scoring high as compared to low on the cognitive disorganisation dimension, whereas the positive and negative schizotypy dimensions showed no link to masking performance. We also found group differences for students scoring high and low on the cognitive disorganisation factor for the WCST. These findings indicate that the shine-through paradigm is sensitive to differences in schizotypy which are closely linked with the pathological expression in schizophrenia. PMID- 22921600 TI - Escherichia coli strongly supports the growth of Histomonas meleagridis, in a monoxenic culture, without influence on its pathogenicity. AB - Based on clonal cultures of Histomonas meleagridis, monoxenic cultures have, to our knowledge for the first time, been established in a liquid medium. The faecal flora was exchanged for defined bacterial strains by selective destruction of the initial bacteria with a variety of antibiotics, keeping the flagellate alive. The growth of the protozoan parasite was found to depend on the bacteria, especially on their energy metabolism. Escherichia coli was found to strongly support the growth of the parasite, whereas Salmonella enterica serovar Typhimurium and Pseudomonas aeruginosa were less efficient. Confocal laser microscopy showed that H. meleagridis could take up green fluorescent protein-tagged E. coli DH5alpha, suggesting that bacteria serve as a food supply for the protozoa. By exchanging the bacterial flora for E. coli strain DH5alpha in H. meleagridis cultures that underwent continuous in vitro passages, it was possible to show that the in vivo attenuation process was independent of the bacteria. Furthermore, the gut flora in infected turkeys had no negative effect on the protozoan's virulence. Consequently, attenuation depends not on the bacteria in the culture but on the in vitro passages. Finally, the experiments provided evidence that the infection of turkeys with H. meleagridis enabled infection of the liver with E. coli. PMID- 22921602 TI - Spatial structure of the helminth parasite communities of the tonguefish, Symphurus plagiusa, from the Campeche coast, southern Mexico. AB - The goals of this paper were to determine whether the helminth communities of the blackcheek tonguefish, Symphurus plagiusa, exhibit a spatial structure and, if so, to determine the relative influence of selected environmental and spatial variables. The parasite communities of tonguefish and environmental data (e.g., temperature, salinity, oxygen) were sampled monthly over a network of 37 stations over 1 year (February 2006 to January 2007). Analysis of similarities (ANOSIM), non-metric multidimensional scaling (NMDS) and redundancy analysis (RDA) were used. Spatial variables were generated using the analysis of principal coordinates of neighbour matrices (PCNM) method. A total of 1,010 flatfishes and nine helminth taxa were collected. For the environmental variables, hierarchical cluster analyses produced groups of stations associated with the Yucatan dry, rainy and winter seasons. At the infracommunity level, there was no group formation as indicated by ANOSIM and NMDS nor association with environmental or spatial variables. At the component community level, there was significant group formation, and RDA analyses of core, satellite and all species produced significant associations with environmental variables. However, model fit improved substantially (from 17-52% to 49-83% of explained variance) when the spatial variables (variables generated with PCNM method) were added. Thus, the helminth component communities of S. plagiusa were affected by associated environmental variables and unknown ecological processes captured by the spatial variables acting at different spatial scales over time. In contrast, at the infracommunity level there was apparently a very fine spatial grain, where the numerical dominance of core species resulted in biased group formation. PMID- 22921603 TI - The role of maternal socioeconomic factors in the commitment to universal newborn hearing screening in the Northeastern region of Brazil. AB - OBJECTIVE: The implementation of early hearing detection in developing countries remains elusive. The fragile health care system along with insufficient funding for health care services leads to inadequate universal newborn hearing screening programs. There is a high incidence of loss to follow-up, at different stages of the program, in these countries, compromising the effect of early hearing screening programs. Strategies must be developed to improve family commitment to such programs. The objective of the present study was to examine factors that predict loss to second-stage follow-up at a municipal based, universal newborn hearing screening program in the Northeastern region of Brazil. METHOD: The current cross sectional study includes 577 newborns who underwent hearing screening and failed. The population was divided into two groups: those who returned and those who were lost to second-stage screening. Differences between groups were explored and adjusted odds ratios were derived. RESULTS: There was a significantly increased risk of non-adherence to the universal newborn hearing screening program in mothers with low income, few prenatal care visits, minimal education and with a multiparous child. CONCLUSION: Socioeconomic factors may have a significant influence on the effectiveness of hearing screening programs in poorer regions of Brazil and other low-income countries. Improvements in health care politics, tracking system and public awareness is crucial for successful program implementation. PMID- 22921604 TI - Antibiotic therapy for pediatric deep neck abscesses: a systematic review. AB - OBJECTIVE: To evaluate the current evidence regarding the safety and efficacy of medical management for deep neck abscesses in children. DATA SOURCES: Pubmed and Embase databases accessed 3/27/2012. REVIEW METHODS: An a priori protocol defining inclusion and exclusion criteria was developed to identify all articles addressing medical therapy of pediatric deep neck abscesses where details regarding diagnostic criteria, specifics of medical therapy and definitions of failure were presented. The search included electronic databases to identify candidate articles as well as a manual crosscheck of references. The level of evidence was assessed and data extracted by three authors independently. Data were pooled using a random effects model due to significant study heterogeneity. RESULTS: Eight articles met inclusion criteria. The overall level of evidence was grade C. There was significant heterogeneity among the studies (I(2)=98.8%; p<.001). However, each article uniformly presented cases suggesting that medical therapy may be a viable alternative to surgical drainage in some patients. The pooled success rate of medical therapy in avoiding surgical drainage in children with deep neck infections was 0.517 (95%CI: 0.335, 0.700). When patients taken immediately to surgery were excluded and patients were placed on author defined medical protocols, the success rate increased to 0.951 (95%CI: 0.851, 1.051). Subgroup analysis by duration of intravenous antibiotic trial greater than 48h demonstrated a pooled success rate of 0.740 (95%CI: 0.527, 0.953). CONCLUSION: The current literature suggests medical management may be a safe alternative to surgical drainage of deep neck abscesses in children. However, the level of evidence lacks strength and further investigation is warranted. PMID- 22921605 TI - Operator-controlled imaging significantly reduces radiation exposure during EVAR. AB - INTRODUCTION: Adoption of endovascular aneurysm repair (EVAR) has led to significant reductions in the short-term morbidity and mortality associated with abdominal aortic aneurysm (AAA) repair. However, EVAR may expose both patient and interventionalist to potentially harmful levels of radiation, particularly as more complex procedures are undertaken. The aim of this study was to assess whether changing from radiographer-controlled imaging to a system of operator controlled imaging (OCI) would influence radiation exposure, screening time or contrast dose during EVAR. METHOD: Retrospective analysis identified patients that had undergone elective EVAR for infra-renal AAA before or after the change to operator-controlled imaging. Data were collected for radiation dose (measured as dose area product; DAP), screening time, total delivered contrast volume and operative duration. Data were also collected for maximum aneurysm diameter, patient age, gender and body mass index. RESULTS: 122 patients underwent EVAR for infra-renal AAA at a single centre between January 2011 and December 2011. 57 of these were prior to installation of OCI and 65 after installation. Median DAP was significantly lower after installation of OCI (4.9 mGy m(2); range 1.25-13.3) than it had been before installation (6.9 mGy m(2); range 1.91-95.0) (p = 0.005). Median screening times before and after installation of OCI were 20.0 min and 16.2 min respectively (p = 0.027) and median contrast volumes before and after the change to OCI were 100 ml and 90 ml respectively (p = 0.21). CONCLUSION: Introduction of operator-controlled imaging can significantly reduce radiation exposure during EVAR, with particular reduction in the number of 'higher-dose' cases. PMID- 22921610 TI - MicroRNA turnover: when, how, and why. AB - MicroRNAs (miRNAs) are short (~22 nucleotide) RNAs that are important for the regulation of numerous biological processes. Accordingly, the expression of miRNAs is itself tightly controlled by mechanisms acting at the level of transcription as well as processing of miRNA precursors. Recently, active degradation of mature miRNAs has been identified as another mechanism that is important for miRNA homeostasis. Here we review the molecular factors and cellular conditions that promote miRNA turnover. We also discuss what is known about the physiological relevance of miRNA decay. PMID- 22921612 TI - Cardiac autonomic nerve abnormalities in chronic heart failure are associated with presynaptic vagal nerve degeneration. AB - BACKGROUND: Understanding of the functional and structural disturbances of cardiac autonomic nerves in ventricular hypertrophy and eventual chronic heart failure (CHF) remains unclear. METHODS AND RESULTS: ECG signals were obtained by a radio transmitter from male Wistar rats that received monocrotaline (MCT) via subcutaneous injection. Heart rate (HR) and HR variability (HRV) were analyzed. The RR interval, total power (TP), low frequency (LF) power, high frequency (HF) power, and LF/HF (L/H) power ratio were measured. Ultrastructural changes in cardiac autonomic nerves at the sinoatrial (SA) node region were studied using an electron microscope. TP and HF powers in MCT-induced right ventricular hypertrophy (RVH) and eventual CHF were significantly decreased, and HR was significantly increased at week 5 or later after the MCT injection. The electron microscopic findings indicated the depletion of neurotransmitter vesicles and degradation of parasympathetic but not sympathetic nerve endings in the SA node region of the heart. CONCLUSION: MCT-induced RVH and CHF rats showed presynaptic vagal nerve degradation prior to sympathetic nerve derangement in the heart. PMID- 22921601 TI - Trichinella patagoniensis n. sp. (Nematoda), a new encapsulated species infecting carnivorous mammals in South America. AB - Until a few years ago, Trichinella spiralis was the only taxon of the genus Trichinella detected in both domestic and wild animals of South America. Recently, a new genotype, named Trichinella T12, was identified in cougars (Puma concolor) from Argentina, on the basis of molecular studies using mitochondrial and nuclear ribosomal markers. In the present study, cross-breeding experiments indicated that Trichinella T12 is reproductively isolated from all other encapsulated Trichinella spp. and suggested that it is biologically more similar to Trichinella britovi and Trichinella murrelli than to the other encapsulated species/genotypes. Biological assays revealed that the reproductive capacity index of Trichinella T12 was ~4 and >2000 times lower than those of T. spiralis in mice and rats, respectively. The reproductive capacity index of Trichinella T12 in domestic pigs ranged from 0.0 to 0.05. Larvae parasitising the muscles of carnivores were infective to mice after freezing at -5 degrees C for 3 months, but they lost infectivity after freezing at -18 degrees C for 1 week. The region within the rDNA, known as the expansion segment V, showed a unique sequence which differs from those of all other known Trichinella spp./genotypes. The biological, geographical and molecular data support the classification of the genotype Trichinella T12 as a new species widespread in the Neotropical region, for which we propose the name Trichinella patagoniensis n. sp. PMID- 22921611 TI - Flagging and docking: dual roles for N-glycans in protein quality control and cellular proteostasis. AB - Nascent polypeptides entering the endoplasmic reticulum (ER) are covalently modified with pre-assembled oligosaccharides. The terminal glucose and mannose residues are immediately removed after transfer of the oligosaccharide onto newly synthesized polypeptides. This processing determines whether the polypeptide will be retained in the ER, transported along the secretory pathway, or dislocated across the ER membrane for destruction. New avenues of research and some issues of controversy have recently been opened by the discovery that lectin oligosaccharide interactions stabilize supramolecular complexes between regulators of ER-associated degradation (ERAD). In this Opinion article, we propose a unified model that depicts carbohydrates acting both as flags signaling the fitness of a maturing protein and as docking sites that regulate the assembly and stability of the ERAD machinery. PMID- 22921613 TI - A multi-physics and multi-scale lumped parameter model of cardiac contraction of the left ventricle: a conceptual model from the protein to the organ scale. AB - In cardiovascular computational physiology the importance of understanding cardiac contraction as a multi-scale process is of paramount importance to understand causality across different scales. Within this study, a multi-scale and multi-physics model of the left ventricle that connects the process of cardiac excitation and contraction from the protein to the organ level is presented in a novel way. The model presented here includes the functional description of a cardiomyocyte (cellular scale), which explains the dynamic behaviour of the calcium concentration within the cell whilst an action potential develops. The cell domain is coupled to a domain that determines the kinetics of the sliding filament mechanism (protein level), which is at the basis of cardiac contraction. These processes are then linked to the generation of muscular force and from there to the generation of pressure inside the ventricle. This multi scale model presents a coherent and unified way to describe cardiac contraction from the protein to the organ level. PMID- 22921614 TI - Comparative genomics between fly, mouse, and cattle identifies genes associated with sire conception rate. AB - The decline in reproductive performance in cattle is of major concern to farmers and the dairy industry worldwide. Most fertility studies in cattle have focused on fertility of the cow, whereas the genetics of male fertility have not been thoroughly investigated. The present study hypothesizes that the high conservation of spermatogenesis genes from fly to human implies important roles of these genes in male fertility in cattle. To test this hypothesis, we performed an association analysis between highly conserved spermatogenesis genes and sire conception rate (SCR) in US Holsteins as a measure of bull fertility. Sequencing analysis revealed 24 single nucleotide polymorphisms (SNP) in 9 genes in the bull population using the pooled DNA sequencing approach. Five SNP previously identified in 5 genes from the POU1F1 pathway were also included in this study because they have shown significant associations with female and male fertility traits. Overall, 29 SNP located in 14 candidate genes were tested for association with sire conception rate in a population of 1,988 bulls. Three SNP located in MAP1B and 1 SNP in PPP1R11 showed significant associations with SCR. For the POU1F1 pathway, single gene analysis revealed significant associations of POU1F1 and STAT5A with SCR. Analysis of genotypic interactions between adjacent genes in the pathway revealed significant associations of STAT5A and UTMP genotypic combinations with SCR. The most significant spermatogenesis gene, MAP1B, was found to be associated with fertilization and blastocyst rates. Thus, the association of these genes with bull fertility testifies to the usefulness of the comparative genomics approach in selecting candidate male fertility genes. PMID- 22921615 TI - Effects of beta-hydroxybutyrate and different calcium and potassium concentrations on the membrane potential and motility of abomasal smooth muscle cells in cattle. AB - The left displacement of the abomasum (LDA) is a common disease in periparturient dairy cows. Plasma beta-hydroxybutyrate (BHBA) levels above the reference range are regarded as risk factors for the occurrence of LDA. Additionally, hypokalemia and hypocalcemia have been observed in LDA cows. The aim of the present study was to characterize the membrane potential and the slow waves in abomasal smooth muscle cells by a microelectrode technique and to determine possible effects of BHBA and of various calcium and potassium concentrations on the membrane potential. Subsequently, the results obtained by the microelectrode technique were combined with in vitro motility experiments of abomasal smooth muscles. Strips of the abomasal circular smooth muscles were prepared and incubated in different buffer solutions. For the microelectrode technique, healthy bulls and cows that underwent surgery for LDA were sampled. These measurements showed a frequency of the slow waves between 3.5 and 10.9 per minute (for amplitudes >= 3mV) and between 0.6 and 4.5 per minute (for amplitudes >= 5mV). The frequency of contractions (1.8 to 3.1 per minute) were in the same order as the frequency of the slow waves with amplitudes >= 5 mV. Blocking potassium conductance with barium chloride induced a depolarization of the basal membrane potential (from 43+/-2.9 to -37+/-4.1mV; mean +/- standard error of the mean) without affecting the frequency or the height of the slow waves. The reduction in the potassium concentration from 5.4 to 2 mmol/L resulted in a nominal decrease in the activity of contractions (from 22.2 to 18.6 mN/min). The subsequent addition of 1 mmol of KCl/L induced a nominal increase in contraction activity (from 18.6 to 25.7 mN/min). An effect of BHBA (5 mmol/L) could not be demonstrated, neither on the electric nor on the motility parameters. A simulated hypocalcemia (1.2 mmol/L total, 0.9 mmol/L ionized Ca) did not change slow waves and motility. In conclusion, changes in membrane potential >= 5 mV correlated with contractions of abomasal muscles. Hypokalemic conditions may reduce abomasal contraction activity via an effect on the membrane potential. An exclusive increase in BHBA or a slight hypocalcemia (0.9 mmol/L ionized Ca) had no effects on the motility of healthy abomasal smooth muscle cells. A prolonged or severe exposition of muscles to a combination of low Ca and high BHBA concentrations might nevertheless be able to affect abomasal motility. PMID- 22921616 TI - Disappearance of infused phytate from the large intestine of dairy heifers. AB - The objective of this study was to investigate the disappearance of phytate from the large intestine of dairy heifers. Uncertainty about the availability of phosphorus (P) in different feeds may limit implementation of dietary strategies to reduce fecal P excretion by dairy cows. Increased understanding of the dynamics of phytate degradation and disappearance of P in the large intestine may improve prediction of intestinal P digestion and absorption. Eight ruminally- and ileally-cannulated crossbred dairy heifers were used in two 4*4 Latin square designs with 9-d periods, including 3d of washout. All heifers were fed a high forage diet containing 0.14% P throughout the study. Ytterbium-labeled corn silage and Co-EDTA were dosed to the rumen 4 times daily as particulate and liquid phase markers, respectively, to measure ileal digesta flow. Ond 4 to 7 of each period, each heifer was infused ileally with 0, 5, 15, or 25 g/d of phytate (phytic acid) in solution and total fecal collection was conducted. When infusion ceased (d 8 and 9) ileal digesta was sampled to measure P flow to the ileum from the basal diet. Feed, digesta, and feces were dried, ground, and analyzed for phytate P, inorganic P, and total P using high performance ion chromatography, inductively coupled plasma atomic emission spectroscopy, and the molybdovanadate yellow method, respectively. Phytate degradation in the large intestine was observed but was not complete, and the amount of infused phytate did not influence the degradability of phytate. Fecal excretion of total P increased with increasing total P infused. The slope coefficient for ileal P flow (dietary only) to feces was 0.56 +/- 0.26 (mean +/- SE), whereas the slope coefficient for infused P was 0.75 +/- 0.13. These indicate net absorption of P from the large intestine and greater disappearance of P from dietary P flowing to the ileum than from the infused pure phytate (44 vs. 25%). This data will support mechanistic modeling efforts to improve prediction of P digestion, allowing more accurate estimation of P bioavailability in feeds. PMID- 22921617 TI - Effects of Saccharomyces cerevisiae fermentation product on ruminal starch digestion are dependent upon dry matter intake for lactating cows. AB - This experiment was conducted to evaluate ruminal digestion responses to Saccharomyces cerevisiae fermentation product (SCFP) supplementation and to determine if responses are influenced by voluntary feed intake. Fifteen ruminally and duodenally cannulated Holstein cows with a wide range in preliminary dry matter intake (pDMI; 20.1 to 31.0 kg/d) measured during a 14-d preliminary period were used in a crossover design experiment. Treatments were SCFP and control (a mix of dry ground corn and soybean meal), top-dressed at the rate of 56 g/d per head. The base diet contained 28% NDF, 30% starch, and 16.5% CP and included corn silage, alfalfa silage, high-moisture corn, protein supplement, and a mineral and vitamin supplement. Treatment periods were 28 d, with the final 8d used for sample and data collection. Voluntary dry matter intake was determined during the last 4d of the preliminary period. Ruminal digestion kinetics were determined using the pool-and-flux method. Main effects of SCFP treatment and their interaction with pDMI were tested by ANOVA. An interaction was detected between SCFP treatment and pDMI for ruminal digestion rate of starch; SCFP increased the rate of starch digestion compared with the control for cows with pDMI below 26 kg/d and decreased it for cows with higher pDMI. This resulted in an interaction between treatment and pDMI for turnover rate of starch in the rumen and true and apparent ruminal starch digestibility because passage rate of starch from the rumen was not affected by treatment (mean=24.3%/h). Ruminal pH (mean=6.0), dry matter intake, milk yield and component percentages were not affected by treatment or its interaction with pDMI. Supplementation of SCFP reduced the rate of ruminal starch digestion for cows with higher feed intake, which could help stabilize the ruminal environment when large amounts of starch are consumed to support higher milk production. PMID- 22921618 TI - Differentiation of mixtures of co-product blend with barley grain based on Fourier transform infrared attenuated total reflection molecular spectroscopy: carbohydrate molecular spectral profiles and nutritive characteristics in dairy cattle. AB - The objectives of this study were to (1) differentiate mixtures of a co-product blend (70:30% mixture of wheat:corn before bioethanol fermentation) from bioethanol processing with barley grain based on Fourier transform infrared attenuated total reflection molecular spectroscopy with cluster analysis, (2) elucidate the effects of the co-product blend on the molecular structure spectral profile and nutritive characteristics of the hull-less barley carbohydrate (CHO) in dairy cattle, and (3) quantify the relationship between the CHO molecular structure spectral profiles and CHO nutritive characteristics of the mixtures in dairy cattle. The parameters assessed for CHO molecular structure spectral profiles included molecular spectral peak area and height intensities of lignin, structural CHO (STCHO), cellulosic compounds, and total CHO. The parameters assessed for CHO nutritive characteristics included the CHO nutrient profiles, CHO subfractions, energy values, and rumen-fermentable organic matter supply. Hull-less barley grains and the co-product blend were mixed according to the ratio of 100:0 (B100), 75:25, 50:50, 25:75, and 0:100 (BD100). The results showed that when the co-product blend was included at the different ratios, the predicted rumen-fermentable organic matter supply in the rumen was significantly decreased from 632 (B100) to 518 g/kg of dry matter (DM; BD100). The effective degradable dry matter in the rumen and the effective degradable starch in the rumen were also significantly decreased from 672 and 482 g/kg of DM (B100) to 475 and 43 g/kg of DM (BD100), respectively. By using Fourier transform infrared attenuated total reflection spectroscopy, we identified were significant changes in the spectral profiles of the CHO molecular structure in terms of lignin, STCHO, cellulosic compounds, and total CHO spectral peak area and height and their ratios. Pearson analysis results suggested strong correlations between lignin peak area, cellulosic compound area, and total CHO peak area and CHO nutrient profiles except energy values (net energy for lactation at 3 times maintenance intake, net energy for maintenance, and net energy for gain). No correlation was observed between STCHO peak area and CHO nutrient profiles in the mixture samples. PMID- 22921619 TI - Goat alpha(s1)-casein genotype affects milk fat globule physicochemical properties and the composition of the milk fat globule membrane. AB - Milk fat secretion is a complex process that initiates in the endoplasmic reticulum of the mammary epithelial cell by the budding of lipid droplets. Lipid droplets are finally released as fat globules in milk enveloped by the apical plasma membrane of the mammary epithelial cell. The milk fat globule membrane (MFGM) thus comprises membrane-specific proteins and polar lipids (glycerophospholipids and sphingolipids) surrounding a core of neutral lipids (mainly triacylglycerols and cholesterol esters). We have recently described major proteins of the MFGM in the goat and we have highlighted prominent differences between goats and bovine species, especially regarding lactadherin, a major MFGM protein. Here, we show that, in the goat species, the well-documented genetic polymorphism at the alpha(s1)-casein (CSN1S1) locus affects both structure and composition of milk fat globules. We first evidenced that both milk fat globule size and zeta-potential are related to the alpha(s1)-casein genotype. At midlactation, goats displaying strong genotypes for alpha(s1)-casein (A/A goats) produce larger fat globules than goats with a null genotype at the CSN1S1 locus (O/O goats). A linear relationship (R(2)=0.75) between fat content (g/kg) in the milk and diameter of fat globules (MUm) was established. Moreover, we found significant differences with regard to MFGM composition (including both polar lipids and MFGM proteins) from goats with extreme genotype at the CSN1S1 locus. At midlactation, the amount of polar lipids is significantly higher in the MFGM from goats with null genotypes for alpha(s1)-casein (O/O goats; 5.97+/ 0.11mg/g of fat; mean +/- standard deviation) than in the MFGM from goats with strong genotypes for alpha(s1)-casein (A/A goats; 3.96+/-0.12mg/g of fat; mean +/ standard deviation). Two MFGM-associated proteins, namely lactadherin and stomatin, are also significantly upregulated in the MFGM from goats with null genotype for alpha(s1)-casein at early lactation. Our findings are discussed with regard to techno-functional properties and nutritional value of goat milk. In addition, the genetic polymorphism in the goat species appears to be a tool to provide clues to the lipid secretion pathways in the mammary epithelial cell. PMID- 22921620 TI - Validation of RNA isolated from milk fat globules to profile mammary epithelial cell expression during lactation and transcriptional response to a bacterial infection. AB - Mastitis, an inflammation of the mammary gland, is the most costly infectious disease of dairy ruminants worldwide. Although it receives considerable attention, the early steps of the host response remain poorly defined. Here, we report a noninvasive method using milk fat globules (MFG) as a source of mammary RNA to follow the dynamics of the global transcriptional response of mammary epithelial cells (MEC) during the course of a bacterial infection. We first assessed that RNA isolated from MFG were representative of MEC RNA; we then evaluated whether MFG RNA could be used to monitor the MEC response to infection. Sufficiently high yields of good-quality RNA (RNA integrity numbers ranging between 6.7 and 8.7) were obtained from goat MFG for subsequent analyses. Contamination of MFG by macrophages and neutrophils, which can be trapped during creaming, was assessed and when using quantitative real-time PCR for cell-type specific markers, was shown to be weak enough (<8%) to affect MFG gene expression profiling. Using microarrays, we showed that RNA extracted from MFG and from mammary alveolar parenchyma shared approximately 90% of the highlighted probes corresponding in particular to genes encoding milk proteins (CSN, BLG, LALBA) and enzymes involved in milk fat synthesis and secretion (FASN, XDH, ADRP, SCD, and DGAT1). In addition, a gene involved in the acute-phase reaction, coding for the serum amyloid A3 (SAA3) protein, was found within the first 50 most highly expressed genes in a noninfectious context in both mammary alveolar parenchyma and MFG, strongly suggesting that SAA3 is expressed in MEC. We took advantage of this noninvasive RNA sampling to follow the early proinflammatory response of MEC during the course of a bacterial infection and showed that the levels of mRNA encoding SAA3 sharply increased at 24h postinfection. Taken together, our results demonstrate that MFG represent a unique source of MEC RNA to noninvasively sample sufficient amounts of high-quality RNA to assess the dynamics of MEC gene expression in vivo, especially during the first steps of infection, thereby paving the way for the discovery of early biomarkers for the control of intramammary infections. Furthermore, this noninvasive technique could be used to provide mammary transcriptomic data on a large scale, thus filling the gap between genomic and phenotypic data. PMID- 22921621 TI - The effect of reproductive performance on the dairy cattle herd value assessed by integrating a daily dynamic programming model with a daily Markov chain model. AB - The objective of this study was to determine the effect of reproductive performance on dairy cattle herd value. Herd value was defined as the herd's average retention payoff (RPO). Individual cow RPO is the expected profit from keeping the cow compared with immediate replacement. First, a daily dynamic programming model was developed to calculate the RPO of all cow states in a herd. Second, a daily Markov chain model was applied to estimate the herd demographics. Finally, the herd value was calculated by aggregating the RPO of all cows in the herd. Cow states were described by 5 milk yield classes (76, 88, 100, 112, and 124% with respect to the average), 9 lactations, 750 d in milk, and 282 d in pregnancy. Five different reproductive programs were studied (RP1 to RP5). Reproductive program 1 used 100% timed artificial insemination (TAI; 42% conception rate for first TAI and 30% for second and later services) and the other programs combined TAI with estrus detection. The proportion of cows receiving artificial insemination after estrus detection ranged from 30 to 80%, and conception rate ranged from 25 to 35%. These 5 reproductive programs were categorized according to their 21-d pregnancy rate (21-d PR), which is an indication of the rate that eligible cows become pregnant every 21 d. The 21-d PR was 17% for RP1, 14% for RP2, 16% for RP3, 18% for RP4, and 20% for RP5. Results showed a positive relationship between 21-d PR and herd value. The most extreme herd value difference between 2 reproductive programs was $77/cow per yr for average milk yield (RP5 - RP2), $13/cow per yr for lowest milk yield (RP5 - RP1), and $160/cow per yr for highest milk yield (RP5 - RP2). Reproductive programs were ranked based on their calculated herd value. With the exception of the best reproductive program (RP5), all other programs showed some level of ranking change according to milk yield. The most dramatic ranking change was observed in RP1, which moved from being the worst ranked for lowest milk yield to the second ranked for highest milk yield. Within a reproductive program, RPO changed based on the stage of lactation at pregnancy. Cows getting pregnant in the early stage of a lactation had higher RPO compared with getting pregnant later in the lactation. However, the RPO at calving was similar for early and late lactation pregnancies. PMID- 22921622 TI - Duodenal infusion of alpha-linolenic acid affects fatty acid metabolism in the mammary gland of lactating dairy cows. AB - Increasing the concentration of alpha-linolenic acid (LNA; 18:3 cis-9,cis-12,cis 15) in blood might affect fatty acid (FA) metabolism in the mammary gland of dairy cows. The objective was to determine the effects of different arterial concentrations of 18:3 cis-9,cis-12,cis-15 (18:3n-3) achieved via duodenal infusions with LNA on mammary uptake [assessed via arterial-rectificative venous concentration (AC-RVC) differences], synthesis of FA, and mammary gland FA balance in lactating dairy cows. Four primiparous lactating Chinese Holstein cows fitted with duodenal cannulas were administered 2 treatments in a crossover design: LNA-rich FA infusion at varying concentrations (0, 100, 200, and 300 g/d) versus basal infusate control. Arterial concentration of 18:3n-3 increased quadratically (29.24, 134.1, 218.3, and 219.3mg/L of plasma) as LNA infusion levels increased from 0 to 300 g/d. The mammary extraction rate and uptake of 18:3n-3 increased linearly as LNA infusion increased. The AC-RVC difference of total FA and 18:3n-3 increased more rapidly than arterial concentrations with all treatments. Increasing LNA infusion increased linearly the balance of 10:0 and 12:0, whereas it decreased linearly the 14:1 and 15:0 balances. Increasing arterial concentration of 18:3n-3 affects uptake and synthesis of FA in the mammary gland of lactating dairy cows. It is also suggested that the use of AC RVC difference maybe an acceptable way to investigate mammary gland uptake and synthesis of FA. PMID- 22921623 TI - A meta-analysis of the effects of feeding yeast culture produced by anaerobic fermentation of Saccharomyces cerevisiae on milk production of lactating dairy cows. AB - The purpose of this study was to use meta-analytic methods to estimate the effect of a commercially available yeast culture product on milk production and other production measures in lactating dairy cows using a meta-analysis of randomized controlled trials. Sixty-one research publications (published journal articles, published abstracts, and technical reports) were identified through a review of literature provided by the manufacturer and a search of published literature using 6 search engines. Thirty-six separate studies with 69 comparisons met the criteria for inclusion in the meta-analysis. The fixed-effect meta-analysis showed substantial heterogeneity for milk yield, energy-corrected milk, 3.5% fat corrected milk, milk fat yield, and milk protein yield. Sub-group analysis of the data showed much less heterogeneity in peer-reviewed studies versus non-peer reviewed abstracts and technical reports, and tended to show higher, but not significantly different, treatment effects. A random-effects meta-analysis showed estimated raw mean differences between treated and untreated cattle reported in peer-reviewed publications of 1.18 kg/d [95% confidence interval (CI): 0.55 to 1.81], 1.61 kg/d (95% CI: 0.92 to 2.29), and 1.65 kg/d (95% CI: 0.97 to 2.34) for milk yield, 3.5% fat-corrected milk, and energy-corrected milk, respectively. Milk fat yield and milk protein yield for peer-reviewed studies showed an increase in the raw mean difference of 0.06 kg/d (95% CI: 0.01 to 0.10) and 0.03 kg/d (95% CI: 0.00 to 0.05), respectively. Estimated raw mean dry matter intake of the peer-reviewed studies during early lactation (<70 d in milk) and not-early lactation were 0.62 kg/d (95% CI: 0.21 to 1.02) and a decrease of 0.78 kg/d (95% CI: -1.36 to -0.21), respectively. These findings provide strong evidence that this commercially available yeast culture product provides significant improvement in several important milk production outcomes as evaluated in production settings typical for commercial dairies in North America. Utilizing meta-analytic methods to study the complete breadth of information relating to a specific treatment by studying multiple overcomes of all eligible studies can reduce the uncertainty often seen in small individual studies designed without sufficient power to detect differences in treatments. PMID- 22921624 TI - Insertion depth of oral stomach tubes may affect the fermentation parameters of ruminal fluid collected in dairy cows. AB - Six rumen-fistulated dairy cows were used in 2 trials to validate the technique for the collection of ruminal fluid by an oral stomach tube (OST). Trial 1 was conducted to compare the differences of ruminal fermentation parameters among rumen sites (cranial dorsal, cranial ventral, central, ventral, caudal dorsal, and caudal ventral). The ruminal fluid was collected once per day for 3 consecutive days through rumen cannula (RC). The samples were analyzed for pH, volatile fatty acids (VFA), ammonia N, sodium, potassium, calcium, chloride, and phosphorus concentrations. The ruminal fermentation parameters varied significantly among rumen sites. Compared with the central or ventral rumen, the cranial dorsal rumen had significantly higher pH, ammonia, and sodium concentrations and lower acetate, propionate, and butyrate concentrations, indicating that the sampling site may be one of the main factors contributing to the difference in ruminal fermentation parameters between the samples collected via the OST and RC. In trial 2, the fermentation parameters of ruminal fluid collected via OST at 2 insertion depths (180 or 200 cm) were compared with those of ruminal fluid collected via RC (ventral sac). Ruminal fluid was collected once per week at 5 to 6h after morning feeding. When the OST was inserted to a depth of 180 cm, the OST head was located in the cranial dorsal (atrium) of the rumen. The ruminal fluid collected via the OST had higher pH and sodium concentrations but lower VFA, potassium, calcium, and phosphorus concentrations than that collected via RC. However, when the OST was inserted to a depth of 200 cm, the OST head could pass through the front rumen pillar and reach the central rumen for sampling. No differences were found in pH, VFA, ammonia N, and ion concentrations between the samples collected via the 2 sampling methods. These results indicated that the OST should be inserted to reach the central rumen to obtain representative rumen fluid samples. PMID- 22921625 TI - Influence of social dominance on the secondary sex ratio and factors affecting hierarchy in Holstein dairy cows. AB - In several studies of different species, the proportions of male and female offspring did not match the statistical assumption of 50:50. Aside from environmental and genetic factors, biological parameters were found to influence the sex ratio. Three hypotheses (Trivers-Willard, advantaged daughter, and the local resource competition hypothesis) have been proposed, stating that the sex of progeny might be influenced by sex-biased maternal investment in the raising of offspring. The results of existing studies are still conflicting, even within studies on the same species. The aim of the present study was to investigate whether the dominance status of cows influences the secondary sex ratio. A herd of lactating cows was observed directly for 126 h, and a dominance index (DI) was established for 71 individuals (aged between 2.6 and 9.8 yr) for which at least 8 encounters had been observed to categorize individuals as subordinate, intermediate, or dominant. Furthermore, the number and sex of calves were assessed, and further individual characteristics of the animals (e.g., age, milk yield, body condition, and lameness scores) were analyzed for interrelationships with dominance status as well as the influence of the DI on the secondary sex ratio. The results indicated that the DI was independent of age, but a negative correlation was found between DI and lameness, whereas a positive correlation was shown for DI and body condition score. In general, more dominant animals had lower lameness scores and better body conditions. No sex ratio bias was found for primi- or for pluriparous animals and no seasonal influences were detected. The proportion of male offspring was significantly correlated with the DI of lactating cows, where animals with a higher social rank produced a lower proportion of male progeny. The pairwise comparison between dominant and subordinate lactating cows revealed a significant difference in the sex ratios of progeny, with subordinate animals having more male calves. These results indicate that the maternal dominance rank was associated with the secondary sex ratio in cattle. These observations are generally in agreement with the advantaged daughter hypothesis. PMID- 22921626 TI - Free ferulic acid uptake in lactating cows. AB - Ferulic acid (FRA), a phenolic compound with antioxidant and anticancer activities, naturally occurs in plants as a lignin precursor. Many veins of research have been devoted to releasing FRA from the lignin complex to improve digestibility of ruminant feeds. Thus, the objective of this research was to investigate the transfer of a given dosage of the free form of FRA into the milk of dairy cattle. Six mid- to late-lactation Holstein cows at the Cornell Research Farm (Harford, NY) were given 14-d adaptation to diet and stall position. Ad libitum access to a total mixed ration based on haylage and maize silage (31.1% neutral detergent fiber containing 5.52 mg of FRA/g) was provided during the study. A crossover design was implemented so that each cow alternated weekly between FRA-dosed and control. On d 1, jugular cannulas and urine catheters were placed in all cows. On d 2, FRA-dosed cows received a single dosage of 150 g of pure FRA powder at 0830 h via their fistula (n=4) or a balling gun for nonfistulated cows (n=2). Plasma, urine, feces, feed, orts, milk, and rumen fluid were sampled intensively for the next 36 h and analyzed for FRA concentration. On d 8, the cows crossed over and the experiment was repeated. When compared with the control, FRA administration did not have an effect on dry matter intake, milk yield, milk fat yield, milk protein yield, somatic cell count, or neutral detergent fiber content of orts and feces. The concentration of FRA in the feces did not change as a result of FRA dosage. As expected, FRA concentration increased dramatically upon FRA dosage and decreased over time until returning to basal levels in rumen fluid (4 h after dosage), plasma (5.5 h after dosage), urine (10 h after dosage), and milk (14 h after dosage). Baseline values for FRA in urine and rumen fluid were variable among cows and had an effect on FRA concentration in FRA-dosed cows. From this study, it is observed that orally ingested FRA can be transported into the milk and that the physiological transfer of FRA occurs from rumen to milk within 6.5 h or the first milking after dosage. Ferulic acid may affect the functionality of milk due to its antioxidant, anticancer, and antibacterial activities. Future research will be required to elucidate whether FRA in milk is bioavailable and bioactive, and to evaluate the complete sensory and microbiological effects of increased FRA and FRA degradation products in milk. PMID- 22921627 TI - Effects of methionine hydroxy copper supplementation on lactation performance, nutrient digestibility, and blood biochemical parameters in lactating cows. AB - The objective of this study was to investigate the effects of methionine hydroxy Cu [(HMTBA)(2)-Cu] supplementation on lactation performance, nutrient digestibility, and blood biochemical parameters in lactating cows. Thirty lactating Holstein cows were assigned to 1 of 3 treatments in a randomized block design: (1) Cu sulfate only (S): 12 mg of Cu provided by CuSO(4) per kilogram of concentrate; (2) Cu sulfate and (HMTBA)(2)-Cu (SM): 6 mg of Cu provided by CuSO(4) and 6 mg of Cu provided by (HMTBA)(2)-Cu per kilogram of concentrate; or (3) (HMTBA)(2)-Cu only (M): 12 mg of Cu provided by (HMTBA)(2)-Cu per kilogram of concentrate. The level of dietary Cu was determined according to the NRC (2001) requirement. This experiment lasted for 120 d, with the first 20 d for adaptation and with sample and data collection beginning on d 21. The milk yield and 4% fat corrected milk yield of cows in the SM treatment tended to increase compared with those in the S and M treatments. Cows fed SM also tended to have higher NDF and ADF apparent digestibility values than did cows fed S or M. Plasma Cu concentration significantly increased for the SM treatment compared with the S and M treatments. Cows fed S had higher plasma K concentration than did cows in the other 2 treatments. In conclusion, replacing one-half of the dietary Cu sulfate with (HMTBA)(2)-Cu increased plasma Cu concentration and tended to improve the neutral and acid detergent fiber apparent digestibility values and the lactation performance of lactating dairy cattle. PMID- 22921628 TI - Short communication: grain-induced subacute ruminal acidosis is associated with the differential expression of insulin-like growth factor-binding proteins in rumen papillae of lactating dairy cattle. AB - The objective of this study was to characterize the mRNA expression of genes involved in the insulin-like growth factor (IGF) axis in the rumen epithelium during grain-induced ruminal acidosis. Eight lactating dairy cattle were randomly assigned to a control (38% concentrate) or a high-grain (HG; 57% concentrate) diet in a randomized study. Dry matter intake, milk production, ruminal pH, and rumen papillae gene expression were measured before treatment allocation (d 0) and on the fourth day of treatment. On d 4, no differences were observed in total feed intake and milk production; however, the cattle fed the HG diet displayed lower ruminal pH (587 +/- 130 min/d below 5.6; mean +/- SE) compared with cattle receiving the control diet (169 +/- 145 min/d below 5.6). No change in the relative mRNA expression of IGF-1, IGF-1 receptor (IGF-1R), and IGF-binding protein 6 (IGFBP6) was detected between treatments. However, the relative expression value of IGF-binding protein 3 (IGFBP3) decreased (0.73 +/- 0.07 fold, mean +/- SE), whereas IGF-binding protein 5 (IGFBP5) expression increased (1.53 +/- 0.20 fold). These results indicate that the IGF axis may play a role in rumen epithelial adaptation to HG diets. PMID- 22921629 TI - Hyperinsulinemic clamp modulates milk fat globule lipid composition in goats. AB - We determined the effect of insulin on milk fatty acid (FA) and lipid composition in goats. Four dairy goats, 150 d in milk, were subjected to hyperinsulinemic clamp (treatment) or saline (control) infusion for 4d in a crossover design study. Composition and concentration of plasma and milk FA, triglycerides, phospholipids, sphingolipids, and cholesterol were determined. Mammary gland biopsies were taken at the end of each experimental period and lipogenic gene expression was determined. Plasma insulin was elevated 3.5-fold, whereas plasma glucose remained constant during the treatment period. Feed intake decreased by 26% and fat yield decreased by 17% relative to controls. No change in nonesterified FA concentration was found between controls and treatment. Compared with controls, insulin decreased yield of long-chain saturated FA by 14%. Milk concentration of long-chain FA was reduced by 3%, whereas that of medium-chain FA increased by 5% during the treatment compared with controls. Hyperinsulinemic clamps increased the yields of milk phospholipids by 9% and cholesterol by 16%, whereas it only tended to decrease triglyceride yields (by 11%). Hyperinsulinemic treatment resulted in compositional changes in the milk fat globule membrane, as reflected by 15 and 9% decreases in phosphatidylethanolamine and phosphatidylcholine concentrations, respectively. Lipogenic gene expression of acyl coenzyme A carboxylase, stearoyl coenzyme A desaturase, and FA synthase did not change, whereas lipoprotein lipase gene expression tended toward an increase in the treatment period compared with controls. Hyperinsulinemic clamps reduce the availability of long-chain FA, which are considered to originate from the diet and adipose lipolysis for milk lipid synthesis by the mammary gland of goats. Under these conditions, long-chain FA might be preferentially channeled to phospholipid rather than triglyceride synthesis, hence increasing phospholipid yields. Mechanisms determining FA distribution among milk lipid components and the consequences of altered milk fat globule membrane lipid composition remained to be elucidated. PMID- 22921630 TI - Effects of glucogenic and ketogenic feeding strategies on splanchnic glucose and amino acid metabolism in postpartum transition Holstein cows. AB - Nine periparturient Holstein cows catheterized in major splanchnic vessels were used in a complete randomized design with repeated measurements to investigate effects of glucogenic and ketogenic feeding strategies on splanchnic metabolism of glucose and amino acids. At parturition, cows were assigned to 1 of 3 feeding strategies: a glucogenic diet (GLCG) based on sodium hydroxide treated wheat grain (56.5% of diet dry matter); a ketogenic diet (KETO) based on fodder beets (40.5% of diet dry matter); or an alfalfa-glucogenic strategy (ALF-GLCG) supplying 100% alfalfa (Medicago sativa L.) haylage at the day of parturition, followed by a 6-d linear shift to the GLCG diet. Samples were obtained 14 d before expected parturition as well as at 4, 15, and 29 d in milk (DIM). The net portal release of glucose was greatest with GLCG, reflecting the higher intake of ruminal escape starch with GLCG, as compared with a lower starch intake with KETO. Postpartum, the portal recovery of feed starch was greater (28 +/- 3%, mean +/- SEM) with KETO as compared with GLCG (15 +/- 4%). At 4 DIM, the net hepatic release of glucose was greatest with KETO and least with ALF-GLCG, whereafter it increased as lactation progressed with ALF-GLCG and GLCG, but not with KETO. The high alfalfa haylage allowance at 4 DIM with the ALF-GLCG treatment induced the lowest net release of nutrients from the splanchnic tissues at 4 DIM. The hepatic removal of lactate as percent of total influx (mean +/- SEM) increased from 27 +/ 3% prepartum to 56 +/- 3% at 4 DIM. The hepatic removal of lactate as percent of net portal release increased from 144 +/- 10% prepartum to 329 +/- 17% at 4 DIM with ALF-GLCG and KETO as compared with 242 +/- 20% in GLCG. No clear evidence for an amino acid sparing effect in splanchnic tissues from increasing small intestinal glucose absorption was observed. In conclusion, the glucogenic feeding strategy induced the highest glucogenic status among the tested feeding strategies due to greater release of glucose from splanchnic tissues. In contrast, the immediate postpartum high allowance of alfalfa haylage provided the lowest amount of nutrients from the splanchnic tissues, inducing low glucogenic status, pointing to the importance of allocating highly digestible diets to postpartum transition cows. Salvaging glucogenic carbon via interorgan transfer of lactate from peripheral tissues supported the immediate postpartum incremental increase in hepatic glucose release rather than hepatic catabolism of amino acids. PMID- 22921631 TI - Quality of bulk tank milk samples from Danish dairy herds based on real-time polymerase chain reaction identification of mastitis pathogens. AB - Results of a commercial real-time PCR analysis for 11 mastitis pathogens from bulk tank milk (BTM) samples from all 4,258 Danish dairy herds in November 2009 to January 2010 were compared with somatic cell count (SCC) and total bacteria count (TBC) estimates in BTM. For Streptococcus agalactiae, Streptococcus dysgalactiae, and Streptococcus uberis, a low real-time PCR cycle threshold (Ct) value (corresponding to high bacterial DNA quantity) was correlated with higher SCC and higher TBC. For Staphylococcus aureus, low Ct values were correlated only with higher SCC. For the environmental mastitis pathogens Klebsiella spp., Enterococcus spp., and Escherichia coli, low Ct values had a correlation with higher TBC. Staphylococcus spp. were found in the BTM from all herds, Strep. uberis in 95%, Staph. aureus in 91%, and Strep. dysgalactiae in 86%, whereas E. coli, Klebsiella, and Strep. agalactiae were found in 61, 13, and 7% of the herds. It is concluded that the real-time PCR used provides results that are related to the milk quality in the herds. Real-time PCR can be used in the same way as culture for monitoring BTM samples, and is especially useful for bacteria with low prevalence (e.g., Strep. agalactiae). PMID- 22921632 TI - [Iatrogenic intrathoracic infusion complicating catheterization of the external jugular vein]. PMID- 22921633 TI - [Papillar thyroid cancer: a rare case of a second primary tumor in retinoblastoma]. AB - Retinoblastoma is the most common primary cancer of the eye in children. The prognosis for survival is excellent. The current therapy includes an improved survival rate and decreased iatrogenic sequelae. The relative risk of a second tumor in survivors of retinoblastoma is documented, especially in those who carry a germline RB mutation. It is strongly increased in case of radiation therapy. The most common types of second primary tumor are sarcoma of soft tissues and osteosarcoma. We present here a rare case of a retinoblastoma patient who received radiation therapy as a part of his treatment and developed a papillar thyroid cancer as a second malignancy. Papillar thyroid cancer has a good prognosis. Systematic screening for thyroid carcinoma should be undertaken in patients irradiated for congenital retinoblastoma. PMID- 22921634 TI - Breath biomarkers of liver cirrhosis. AB - The diagnosis of asymptomatic cirrhosis in patients with liver disease is of importance to start screening for complications in due time. Liver biopsy is neither sensitive nor practical enough to be used as a frequent follow-up test in patients with chronic liver disease. The volatile organic compounds present in exhaled breath offer the possibility of exploring internal physiologic and pathologic process in a non invasive way. This study examined whether a specific pattern of biomarkers can be found in breath samples of patients with cirrhosis. To this aim samples of alveolar breath from patients with cirrhosis and healthy volunteers were analyzed using gas chromatography-mass spectrometry. When linear discriminant analysis was used to search for a model(s)/pattern of compounds characteristic for liver cirrhosis, 24 models of 8 independent compounds could distinguish between the groups. The sensitivity and specificity (between 82% and 88%, and 96% and 100%, respectively) of the models suggest that a specific pattern of breath biomarkers can be found in patients with cirrhosis, which may allow detecting this complication of chronic liver disease in an early stage. PMID- 22921635 TI - Fast liquid chromatography/tandem mass spectrometry determination of cannabinoids in micro volume blood samples after dabsyl derivatization. AB - Due to the non-polar nature and the absence of an ionizable group on the cannabinoids, the ionization efficiency in electrospray is low and leads to poor limits of detection (LOD). The reaction of chloride dabsyl with the phenolic OH group of cannabinoids results in a product containing a tertiary amine, which is easily protonated in positive electrospray mode and can significantly improve the cannabinoids LOD. A rapid, selective and sensitive LC/MS-MS method was developed for quantitative determination of Delta(9)-tetrahydrocannabinol (THC), 11-hydroxy Delta(9)-tetrahydrocannabinol (11-OH-THC), 11-nor-9-carboxy-Delta(9) tetrahydrocannabinol (THC-COOH), cannabinol (CBN) and cannabidiol (CBD), in micro volume blood samples following dabsyl derivatization to enhance signal intensity. The method comprised protein precipitation followed by derivatization with dabsyl chloride and subsequent analysis using liquid chromatography-tandem mass spectrometry (LC/MS-MS). Chromatographic separation was achieved using a 150 mm * 2.1 mm C18 analytical column maintained at 65 degrees C and eluted with a gradient of water and acetonitrile, both containing 0.2% formic acid. The run time was 8 min. The assay was successfully validated using the approach based on the accuracy profile. Lower limits of quantification (LOQ) were 0.25 ng/mL for THC and THC-COOH, 0.30 ng/mL for 11-OH-THC, 0.40 ng/mL for CBN and 0.80 ng/mL for CBD. A comparative study of cannabinoids in blood and plasma, as determined by the developed LC/MS-MS method or the in-house GC/MS-MS technique, demonstrated an excellent correlation between the two methods. Dabsylation was also tested on line with a spiral of peek tubing placed in the LC/MS-MS column heater at 65 degrees C before the analytical column. The results obtained with on-line dabsyl derivatization were similar to those observed off-line. PMID- 22921636 TI - Virus population bottlenecks during within-host progression and host-to-host transmission. AB - Despite rapidly growing to immense sizes, virus populations suffer repeated severe bottlenecks, both within hosts and when transmitted from host to host. The potential effect of bottlenecks has been theoretically and experimentally documented, but formal estimations of their actual sizes in natural situations are scarce. Bottlenecks during colonization of organs and during transmission are influenced by those occurring at the cellular level. The study of the multiplicity of cellular infection (MOI) thus appears central, and this trait may be differentially regulated by different virus species. The values of MOI and their putative regulation deserve important future efforts, in order to disentangle the complex interactions between the control of gene copy numbers and the populations dynamics/genetics of viruses. PMID- 22921637 TI - Distinctive neurological phenotype associated with partial trisomy of chromosome 16. AB - We present a case of a live born female infant who presented in early life with a movement disorder, lack of developmental progress and neutropenia. Extensive neuro-metabolic investigation was non-diagnostic. Chromosome analysis of cultured lymphocyte cells showed an abnormal chromosome 16 with additional material noted in the proximal long arm. Additional fluorescence in situ hybridisation studies identified this additional material to represent a duplication of the long arm of chromosome 16 between 16q11.2 and 16q21. There was progressive decline and death by 10 months. Dystonia cortical blindness and neutropenia have not been a reported feature of trisomy 16 to date. PMID- 22921638 TI - Factors influencing the decision to start renal replacement therapy: results of a survey among European nephrologists. AB - BACKGROUND: Little is known about the criteria nephrologists use in the decision of when to start renal replacement therapy (RRT) in early referred adult patients. We evaluated opinions of European nephrologists on the decision for when to start RRT. STUDY DESIGN: European web-based survey. PREDICTORS: Patient presentations described as uncomplicated patients, patients with unfavorable clinical and unfavorable social conditions, or patients with specific clinical, social, and logistical factors. SETTING & PARTICIPANTS: Nephrologists from 11 European countries. OUTCOMES & MEASUREMENTS: We studied opinions of European nephrologists about the influence of clinical, social, and logistical factors on decision making regarding when to start RRT, reflecting practices in place in 2009. Questions included target levels of kidney function at the start of RRT and factors accelerating or postponing RRT initiation. Using linear regression, we studied determinants of target estimated glomerular filtration rate (eGFR) at the start of RRT. RESULTS: We received 433 completed surveys. The median target eGFR selected to start RRT in uncomplicated patients was 10.0 (25th-75th percentile, 8.0-10.0) mL/min/1.73 m(2). Level of excretory kidney function was considered the most important factor in decision making regarding uncomplicated patients (selected by 54% of respondents); in patients with unfavorable clinical versus social conditions, this factor was selected by 24% versus 32%, respectively. Acute clinical factors such as life-threatening hyperkalemia refractory to medical therapy (100%) and uremic pericarditis (98%) elicited a preference for an immediate start, whereas patient preference (69%) and vascular dementia (66%) postponed the start. Higher target eGFRs were reported by respondents from high- versus low-RRT-incidence countries (10.4 [95% CI, 9.9-10.9] vs 9.1 mL/min/1.73 m(2)) and from for-profit versus not-for-profit centers (10.1 [95% CI, 9.5-10.7] vs 9.5 mL/min/1.73 m(2)). LIMITATIONS: We were unable to calculate the exact response rate and examined opinions rather than practice for 433 nephrologists. CONCLUSIONS: Only for uncomplicated patients did half the nephrologists consider excretory kidney function as the most important factor. Future studies should assess the weight of each factor affecting decision making. PMID- 22921639 TI - Dose of erythropoiesis-stimulating agents and adverse outcomes in CKD: a metaregression analysis. AB - BACKGROUND: Targeting higher hemoglobin levels with erythropoiesis-stimulating agents (ESAs) to treat the anemia of chronic kidney disease (CKD) is associated with increased cardiovascular risk. STUDY DESIGN: Metaregression analysis examining the association of ESA dose with adverse outcomes independent of target or achieved hemoglobin level. SETTING & POPULATION: Patients with anemia of CKD irrespective of dialysis status. SELECTION CRITERIA FOR STUDIES: We searched MEDLINE (inception to August 2010) and bibliographies of published meta-analyses and selected randomized controlled trials assessing the efficacy of ESAs for the treatment of anemia in adults with CKD, with a minimum 3-month duration. Two authors independently screened citations and extracted relevant data. Individual study arms were treated as cohorts and constituted the unit of analysis. PREDICTORS: ESA dose standardized to a weekly epoetin alfa equivalent, and hemoglobin levels. OUTCOMES: All-cause and cardiovascular mortality, cardiovascular events, kidney disease progression, or transfusion requirement. RESULTS: 31 trials (12,956 patients) met the criteria. All-cause mortality was associated with higher (per epoetin alfa-equivalent 10,000-U/wk increment) first 3-month mean ESA dose (incidence rate ratio [IRR], 1.42; 95% CI, 1.10-1.83) and higher total-study-period mean ESA dose (IRR, 1.09; 95% CI, 1.02-1.18). First-3 month ESA dose remained significant after adjusting for first-3-month mean hemoglobin level (IRR, 1.48; 95% CI, 1.02-2.14), as did total-study-period mean ESA dose adjusting for target hemoglobin level (IRR, 1.41; 95% CI, 1.08-1.82). Parameter estimates between ESA dose and cardiovascular mortality were similar in magnitude and direction, but not statistically significant. Higher total-study period mean ESA dose also was associated with increased rate of hypertension, stroke, and thrombotic events, including dialysis vascular access-related thrombotic events. LIMITATIONS: Use of study-level aggregated data; use of epoetin alfa-equivalent doses; lack of adjustment for confounders. CONCLUSIONS: In patients with CKD, higher ESA dose might be associated with all-cause mortality and cardiovascular complications independent of hemoglobin level. PMID- 22921640 TI - Ciliary signaling cascades in photoreceptors. AB - For being a polarized neuron and having a sensory cilium, photoreceptors attract remarkable attention. This is due their highly polarized structure and active visual signal transduction cascades and for the enrichment of complex networks of proteins in the cilium. Structural and functional maintenance of the photoreceptor sensory cilium, also called outer segment, ensures that light signal is received and relayed appropriately to the brain. Any perturbations in the protein content of the outer segment result in photoreceptor dysfunction, degeneration and eventually, blindness. This review focuses on the importance of photoreceptor sensory cilium to carry out signal transduction cascade for vision. PMID- 22921641 TI - Applying the ecological model of behavior change to a physical activity trial in retirement communities: description of the study protocol. AB - OBJECTIVES: To describe the intervention protocol for the first multilevel ecological intervention for physical activity in retirement communities that addresses individual, interpersonal and community influences on behavior change. DESIGN: A cluster randomized controlled trial design was employed with two study arms: a physical activity intervention and an attention control successful aging condition. SETTING: Sixteen continuing care retirement communities in San Diego County. PARTICIPANTS: Three hundred twenty older adults, aged 65 years and older, are being recruited to participate in the trial. In addition, peer leaders are being recruited to lead some study activities, especially to sustain the intervention after study activities ceased. INTERVENTION: Participants in the physical activity trial receive individual, interpersonal and community intervention components. The individual level components include pedometers, goal setting and individual phone counseling. The interpersonal level components include group education sessions and peer-led activities. The community level components include resource audits and enumeration, tailored walking maps, and community improvement projects. The successful aging group receives individual and group attention about successful aging topics. MEASUREMENTS: The main outcome is light to moderate physical activity, measured objectively by accelerometry. Other objective outcomes included physical functioning, blood pressure, physical fitness, and cognitive functioning. Self report measures include depressive symptoms and health related quality of life. RESULTS: The intervention is being delivered successfully in the communities and compliance rates are high. CONCLUSION: Ecological Models call for interventions that address multiple levels of the model. Previous studies have not included components at each level and retirement communities provide a model environment to demonstrate how to implement such an intervention. PMID- 22921642 TI - Circulating levels of persistent organic pollutants are related to retrospective assessment of life-time weight change. AB - BACKGROUND: Persistent organic pollutants (POPs) have been suggested to be linked to obesity. We have previously shown that less-chlorinated PCBs were positively related to fat mass, while highly-chlorinated PCBs were inversely related to obesity. OBJECTIVE: The aim of the present evaluation is to investigate the relationship between retrospective assessed life-time change in body weight (20 70 years) with circulating POP levels measured at age 70 years. METHODS: 1016 subjects aged 70 years were investigated in the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUSs) study. 16 PCBs and 3 OC pesticides were analyzed using HRGC/HRMS. Current body weight was measured and participants self reported their weight at age 20. RESULTS: The average estimated weight change over 50 years was 14.4 kg. Both the sum of OC pesticide concentrations (4.3 kg more weight gain in quintile 5 vs. quintile 1, p<0.0001) and the sum of the less chlorinated PCBs were positively related to the estimated weight change (3.7 kg more weight gain in quintile 2 vs. quintile 1, non-linear relationship p=0.0015). In contrast, the sum of concentrations of highly-chlorinated PCBs were inversely related to estimated weight change (8.4 kg less weight gain in quintile 5 vs. quintile 1, p<0.0001). CONCLUSION: High levels of OC pesticides and the less chlorinated PCBs at age 70 were associated with a pronounced estimated weight change over the previous 50 years. However, the opposite was seen for highly chlorinated PCBs. Differences in mode of action, toxicokinetics, non-linear relationships and reverse causation might explain these discrepancies. PMID- 22921643 TI - Improving Anammox start-up with bamboo charcoal. AB - Three Upflow Anaerobic Sludge Blanket (UASB) reactors were compared for Anammox enrichment using synthetic wastewater with Spherical Plastic (SP) and Bamboo Charcoal (BC) addition, and without carrier (CK). After four months of operation, the Anammox activity occurred in all reactors allowing continuous removal of ammonium and nitrite. Ammonium and nitrite removal efficiencies were all higher than 98% in steady phase with the effluent concentrations below 1 mg L(-1). The start-up time could be shortened from 117 to 97 d in CK and SP reactor to 85 d in BC amendment reactor. Quantitative PCR (q-PCR) analyses indicated a significant increase in the number of Anammox bacteria in BC amended reactor as compared with CK and SP during the entire start-up periods. The copy numbers of Anammox of 16S rRNA gene in the reactor with BC amendment could reach up to 6*10(9)copies g(-1) Volatile Suspended Solids, around 22.5 times and 12.3 times greater than that in CK and SP reactor, respectively. BC addition could accelerate the start-up of Anammox and significantly increase the Anammox bacteria number. PMID- 22921644 TI - Hazardous organic chemicals in rubber recycled tire playgrounds and pavers. AB - In this study, the presence of hazardous organic chemicals in surfaces containing recycled rubber tires is investigated. Direct material analyses using solvent extraction, as well as SPME analysis of the vapour phase above the sample, were carried out. Twenty-one rubber mulch samples were collected from nine different playgrounds. In addition, seven commercial samples of recycled rubber pavers were acquired in a local store of a multinational company. All samples were extracted by ultrasound energy, followed by analysis of the extract by GC-MS. The analysis confirmed the presence of a large number of hazardous substances including PAHs, phthalates, antioxidants (e.g. BHT, phenols), benzothiazole and derivatives, among other chemicals. The study evidences the high content of toxic chemicals in these recycled materials. The concentration of PAHs in the commercial pavers was extremely high, reaching values up to 1%. In addition, SPME studies of the vapour phase above the samples confirm the volatilisation of many of those organic compounds. Uses of recycled rubber tires, especially those targeting play areas and other facilities for children, should be a matter of regulatory concern. PMID- 22921645 TI - Transformation of polychlorinated biphenyls by persulfate at ambient temperature. AB - Increasing attention has been paid to persulfate due to its high efficiency in degrading organic pollutants. This paper investigated the transformation of a selected polychlorinated biphenyl (PCB) by sodium persulfate without activators at near ambient temperature (10-40 degrees C). The results showed that 2,4,4'-CB was completely decomposed by persulfate at 30 degrees C in 8 h. The products were identified by gas chromatography-mass spectrometry (GC-MS), and transformation pathways could be divided into two steps as dechlorination and hydroxylation. Electron paramagnetic resonance (EPR) technique was used to identify the generated radical species at different pH values at ambient temperature. The results showed that sulfate radicals (SO(4)(*-)) were predominant under acidic condition and hydroxyl radicals ((*)OH) were predominant under basic condition. This behavior was also confirmed by the quenching studies and kinetic model. Decreasing the solution pH resulted in increasing the degradation efficiency of 2,4,4'-CB. Moreover, the degradation of other PCBs such as 2-CB, 4-CB, 2,4-CB, 2,4'-CB, and 2,4,6-CB with persulfate was examined. The findings of this study can provide guidance in the remediation of PCBs contaminated soil and water with persulfate. PMID- 22921646 TI - Photodecomposition of humic acid and natural organic matter in swamp water using a TiO(2)-coated ceramic foam filter: potential for the formation of disinfection byproducts. AB - This paper reports on the photodecomposition of aqueous humic acid (HA) by a TiO(2)-coated ceramic foam filter (TCF) reactor and on the potential for the formation of disinfection byproducts (DBPs) upon chlorination of the photocatalytically treated solutions. This photocatalytic reactor can also be applied to the removal of natural organic matter (NOM) in swamp waters. The proposed photocatalytic reaction system was operated as per standardized methodologies. First, the ability of the TCF to decompose HA (a representative compound of NOM) was evaluated from the changes in the total organic carbon (TOC) and UV(254) with the reaction time. Remarkably, TOC removal and UV(254) values ranging from 44% to 61% and from 60% to 83%, respectively, were achieved. The potential for the formation of DBPs (total trihalomethane and total haloacetic acid) by chlorination of the phototreated solution was strongly dependent on the TOC removal and UV(254) values in the solution. The degree of photodecomposition of NOMs in the swamp water samples and the DBP formation potential showed similar trends as in the case of the standard solutions containing HA. The method used in this study could be effectively used to evaluate the efficiency of TCF for reducing HA and NOM, while suppressing the formation of DBP products. PMID- 22921647 TI - Polychlorinated dibenzodioxins, dibenzofurans, and biphenyls in fresh water fish from Campania Region, southern Italy. AB - Twenty-eight fish muscle specimens from the main water bodies of the Campania Region were analyzed in our laboratory. On average, results showed a low contamination by PCDDs+PCDFs and a relatively more important presence of DL-PCBs. All specimens were compliant with EU regulatory maximum levels. Cumulative PCDD+PCDF+DL-PCB concentrations (TEQ(TOT)) were comprised in the range 0.223-11.4 pgWHO(97)-TEQ g(-1) fresh weight (fw). DL-PCB contribution to TEQ(TOT) was on average greater than 86% (range, 50.2-97.1%). The cumulative concentrations of 30 non-dioxin-like PCB congeners (Sigma(30)(NDL-PCBs)) and of the six indicators (Sigma(6)(NDL-PCBs)) were respectively in the ranges 3.30-515 and 1.30-195 ng g( 1) fw. The hybrid clustering approach adopted to analyze the sample-specific congener profiles indentified the main analytical patterns present in the database and, in particular, two main diverse exposure macro-areas that seem to exist north and south of the city of Naples. The distribution of PCDD and PCDF congeners among different species showed significant variations from chub (Leuciscus cephalus), characterized by a higher proportion of low-chlorinated congeners (e.g. 2,3,7,8-T(4)CDD), to eel (Anguilla anguilla), whose contamination consisted mainly of highly chlorinated congeners (e.g. O(8)CDD). To have a more complete perspective in relation to the contaminants present in the environment, the study suggestion is to use benthic as well as pelagic species to obtain an integrated characterization of fish tissue contamination. PMID- 22921648 TI - Transformation of 2,4,6-trimethylphenol and furfuryl alcohol, photosensitised by Aldrich humic acids subject to different filtration procedures. AB - Suspended particles in a system made up of Aldrich humic acids (HAs) in water account for about 13% of the total HA mass, 10-11% of the organic carbon and 9 11% of radiation extinction in the UVA region. Extinction would be made up of radiation scattering (less than one third) and absorption (over two thirds). The contribution of particles to the degradation rates of trimethylphenol and furfuryl alcohol (FFA) (probes of triplet states and (1)O(2), respectively) was lower than 10% and possibly negligible. The results indicate that triplet states and (1)O(2) occurring in the solution bulk are mostly produced by the dissolved HA fraction. Experimental data would not exclude production of (1)O(2) in particle hydrophobic cores, unavailable for reaction with FFA. However, the limited to negligible particle fluorescence places an upper limit to particle core photoactivity. PMID- 22921649 TI - CORAL: QSPR model of water solubility based on local and global SMILES attributes. AB - Water solubility is an important characteristic of a chemical in many aspects. However experimental definition of the endpoint for all substances is impossible. In this study quantitative structure-property relationships (QSPRs) for negative logarithm of water solubility-logS (mol L(-1)) are built up for five random splits into the sub-training set (~55%), the calibration set (~25%), and the test set (~20%). Simplified molecular input-line entry system (SMILES) is used as the representation of the molecular structure. Optimal SMILES-based descriptors are calculated by means of the Monte Carlo method using the CORAL software (http://www.insilico.eu/coral). These one-variable models for water solubility are characterized by the following average values of the statistical characteristics: n(sub_train)=725-763; n(calib)=312-343; n(test)=231-261; r(sub_train)(2)=0.9211+/-0.0028; r(calib)(2)=0.9555+/-0.0045; r(test)(2)=0.9365+/ 0.0073; s(sub_train)=0.561+/-0.0086; s(calib)=0.453+/-0.0209; s(test)=0.520+/ 0.0205. Thus, the reproducibility of statistical quality of suggested models for water solubility confirmed for five various splits. PMID- 22921650 TI - PCB and organochlorine pesticide concentrations in eel increase after frying. AB - In several countries such as the Netherlands, consumption of eel from polluted waters is not allowed because the concentrations of polychlorinated biphenyls (PCBs) exceed official tolerance limits. Few experiments have been carried out to assess if pre-treatment, such as cooking and frying would alter the PCB concentrations and maybe bring them under the tolerance limits. We have carried out a frying and cooking experiment, which has shown that the concentrations of PCBs and organochlorine pesticides (OCPs) increase in eel after frying. The effect of boiling is negligible. This shows that preparation methods for eel as food product do not help in bringing PCB and OCP concentrations down to safe values. PMID- 22921651 TI - Persulfate oxidation regeneration of granular activated carbon: reversible impacts on sorption behavior. AB - Chemical oxidation regeneration of granular activated carbon (GAC) is a developing technology that can be carried out utilizing thermally-activated persulfate. During chemical regeneration of GAC, aggressive oxidative conditions lead to high acidity (pH<2) and the accumulation of sodium persulfate residuals in the GAC. In this study, we investigated the impact of chemical oxidation on the sorption characteristics of methyl-tert butyl ether (MTBE) in GAC. Loss of MTBE sorption was measured in thermally-activated persulfate regenerated GAC. The accumulation of sulfur was partially responsible for the blockage of sorption sites, but sorption loss was amplified under oxidizing and acidic conditions and attributed to the formation of acidic surface oxides and enhanced electrostatic attraction and accumulation of SO(4)(2-) in GAC. Raising the pH in the GAC slurry resulted in the removal of the residual sulfate and improved MTBE sorption indicating that the mechanisms responsible for MTBE sorption loss were reversible. These results establish baseline conditions and parameters that can be used to optimize pilot- and full-scale deployment of thermally-activated persulfate regeneration of GAC. PMID- 22921652 TI - Comparing the desorption and biodegradation of low concentrations of phenanthrene sorbed to activated carbon, biochar and compost. AB - Carbonaceous soil amendments are applied to contaminated soils and sediments to strongly sorb hydrophobic organic contaminants (HOCs) and reduce their freely dissolved concentrations. This limits biouptake and toxicity, but also biodegradation. To investigate whether HOCs sorbed to such amendments can be degraded at all, the desorption and biodegradation of low concentrations of (14)C labelled phenanthrene (<=5 MUg L(-1)) freshly sorbed to suspensions of the pure soil amendments activated carbon (AC), biochar (charcoal) and compost were compared. Firstly, the maximum abiotic desorption of phenanthrene from soil amendment suspensions in water, minimal salts medium (MSM) or tryptic soy broth (TSB) into a dominating silicone sink were measured. Highest fractions remained sorbed to AC (84+/-2.3%, 87+/-4.1%, and 53+/-1.2% for water, MSM and TSB, respectively), followed by charcoal (35+/-2.2%, 32+/-1.7%, and 12+/-0.3%, respectively) and compost (1.3+/-0.21%, similar for all media). Secondly, the mineralization of phenanthrene sorbed to AC, charcoal and compost by Sphingomonas sp. 10-1 (DSM 12247) was determined. In contrast to the amounts desorbed, phenanthrene mineralization was similar for all the soil amendments at about 56+/ 11% of the initially applied radioactivity. Furthermore, HPLC analyses showed only minor amounts (<5%) of residual phenanthrene remaining in the suspensions, indicating almost complete biodegradation. Fitting the data to a coupled desorption and biodegradation model revealed that desorption did not limit biodegradation for any of the amendments, and that degradation could proceed due to the high numbers of bacteria and/or the production of biosurfactants or biofilms. Therefore, reduced desorption of phenanthrene from AC or charcoal did not inhibit its biodegradation, which implies that under the experimental conditions these amendments can reduce freely dissolved concentration without hindering biodegradation. In contrast, phenanthrene sorbed to compost was fully desorbed and biodegraded. PMID- 22921653 TI - Extraction of raw sewage sludge containing iron phosphate for phosphorus recovery. AB - The objective of the present study was to establish an alkali extraction technology for FePO(4)-containing sewage sludge obtained from a wastewater treatment system that includes phosphorous removal by iron electrolysis. By clarifying the extraction properties of phosphorous, organic matter, and inorganic matter, conditions for alkali extraction were optimized. As a result, it was suggested that unheated phosphorous extraction would be superior for FePO(4)-containing sewage sludge. And, extraction methods and sewage sludge properties were also compared, and the noteworthy result that extraction of metals can be suppressed to extremely low amounts with alkali extraction as compared with acid extraction was obtained. A new insight was also gained that, as compared with the use of incinerated ash reported in previous studies, alkali extraction was more efficient when raw sewage sludge was used. PMID- 22921654 TI - Effects of simulated acid rain, EDTA, or their combination, on migration and chemical fraction distribution of extraneous metals in Ferrosol. AB - A laboratory repacked soil-leaching column experiment was conducted to study the effects of simulated acid rain or EDTA by themselves or in combination, on migration and chemical speciation distribution of Pb and its alternative rare metals including Ag, Bi, In, Sb, and Sn. Experimental results demonstrate that leaching with simulated acid rain promoted the migration of Bi, In and Pb, and their migration reached down to 8 cm in the soil profile, no enhancement of Sb, Ag or Sn migration was observed. Addition of EDTA significantly enhanced the migration of all six metals, especially Bi, In and Pb. The migration of metals was in the order Pb>Bi>In>Sb>Sn>Ag. The individual and combined effects of acid rain and EDTA increased the environmental risk of metals, by increasing the soluble content of metals in soil solutions and the relative distribution of the exchangeable fraction. Leaching risks of Bi, In and Pb were higher than other three metals. PMID- 22921655 TI - Effect of acid and alcohol network forces within functionalized multiwall carbon nanotubes bundles on adsorption of copper (II) species. AB - The adsorptive capacity of multiwall CNTs for copper species in water depends on the type of functional group present on their surface. The alcohol (OH) and acid (COOH) network forces formed by van der Waals bonds within the CNT bundles can define their aggregate state and available sites for copper adsorption. Copper is attracted to different oxygen radicals on the surface and within the bundles of CNTs. The effect of initial concentration shown on isotherm curves was investigated as an impact of different network forces and the presence of impurities leached from as-received CNTs. Deprotonation of CNTs reduced the COOH network forces, improved adsorption capacity and removed the effect of initial concentration. Impurities leached from CNTs under the effect of pH were less than 1 mg g(-1) for each metal, which was insignificant compared to copper in solution. Pristine CNTs were acid washed and purified (Ox-CNTs), improving their adsorption capacity, but the effect of initial concentration was still present. Adsorption of copper is stronger for OH-functionalized CNTs, followed by deprotonated COOH-functionalized CNTs, as-received COOH-functionalized CNT, Ox CNTs and finally pristine CNTs. FTIR, XPS and zeta potential measurements were used to identify and quantify the different surface functional groups present on CNTs. PMID- 22921656 TI - Development of sensitive determination method for fungicides from environmental water samples with Titanate nanotube array micro-solid phase extraction prior to high performance liquid chromatography. AB - Fungicides have been widely used throughout the world, and the resulted pollution has absorbed great attention in recent years. Present study described an effective measurement technique for fungicides including thiram, metalaxyl, diethofencarb, myclobutanil and tebuconazole in environmental water samples. A micro-solid phase extraction (MUSPE) was developed utilizing ordered TiO(2) nanotube array for determination of target fungicides prior to a high performance liquid chromatography (HPLC). The experimental results indicated that TiO(2) nanotube arrays demonstrated excellent merits on the preconcentration of fungicides, and excellent linear relationship between peak area and the concentration of fungicides was obtained in the range of 0.1-50 MUg L(-1). The detection limits for the targeted fungicides were in the range of 0.016-0.086 MUg L(-1) (S/N=3). Four real environmental water samples were used to validate the applicability of the proposed method, and good spiked recoveries in the range of 73.9-114% were achieved. A comparison of present method with conventional solid phase extraction was made and the results exhibited that proposed method resulted in better recoveries. The results demonstrated that this MU-SPE technique was a viable alternative for the analysis of fungicides in complex samples. PMID- 22921657 TI - Decabromodiphenyl ether in indoor dust from different microenvironments in a university in the Philippines. AB - This study was conducted to develop a method for the determination of decabromodiphenyl ether (BDE-209) in indoor dust from different microenvironments in a university in the Philippines. BDE-209 was extracted from dust samples by ultrasonication and determined by HPLC-UV. The determination was performed using external calibration and internal standard calibration. Internal standard calibration was shown to be more precise and sensitive than external calibration. The linearity for the concentration range of 0-300 MUg L(-1) BDE-209 was good (R(2)=0.993). The % absolute recovery and the % RSD for n=8 spiked dust analysis based on a 0.2 g dust sample was 57% and 19%, respectively. The method detection limit was 285 ng g(-1). All dust samples showed detectable levels of BDE-209 with some at levels below the quantification limits. The concentrations of BDE-209 in the quantified samples are within the range of 1103-4117 ng g(-1) with an average concentration of 2172 ng g(-1). The levels of BDE-209 found in the dust samples are comparable to those reported in house and workplace dusts from other Asian countries. Although not conclusive, it has been shown empirically that BDE-209 concentrations are higher in sampling sites containing more possible BDE-209 sources like electrical and electronic equipment. PMID- 22921658 TI - Spectrophotometric measurement of Cu(DDTC)2 for the simultaneous determination of zinc and copper. AB - A spectrophotometric procedure for the simultaneous determination of zinc(II) and copper(II) in a mixture using diethyldithiocarbamate (DDTC) as ligand has been described. Complexes formed with DDTC was extracted with CHCl(3)/CCl(4) and the absorbance was measured at 435 nm which is equivalent of Cu(II) in sample only as Zn(DDTC)(2) has no absorption. Zinc measurement is based on the quantitative displacement of zinc from Zn(DDTC)(2) by Cu(II) with the addition of excess copper(II) to the extract. The absorbance is measured again where additional absorbance is equivalent to zinc. The molar absorptivity and sandall's sensitivity at this wavelength are 2.86*10(5) mol(-1) L cm(-1) and 3.076 ng cm( 2), respectively. Reproducibility with in 4% and detection limits of 0.29 MUg mL( 1) was obtained. Linear calibration range was 0.2-14 MUg mL(-1) for zinc and 0.2 12 MUg mL(-1) for copper with the regression coefficient (r(2)) 0.998 for each. In the presence of a suitable masking agent (EDTA) very good selectivity was achieved. The method was extended to the determination of zinc and copper in a number of environmental water and soil samples, biological, pharmaceutical, fertilizer and food samples. PMID- 22921659 TI - Sulfide production and consumption in degrading wood in the marine environment. AB - Woody debris is known to be transported to the seas and accumulate on the seafloor, however, little is known on the consequences of its degradation in the marine environment. In this study we monitored the degradation product sulfide with Au/Hg voltammetric microelectrodes on the surface and interior of an experimentally immersed wood for 200 d. After 5 weeks of immersion, the interior became sulfidic, and steady-state conditions were established after 13 weeks with sulfide concentration reaching about 300 MUM. Although sulfide was briefly detected at the surface of wood, its concentration remained lower than 20 MUM, indicating that this compound was effectively oxidized within the substrate. Fitting these data to a kinetic model lead to an estimated microbial sulfide production rate in the range of 19-28 MUM d(-1) at steady state. As much as 24 MUM d(-1) nitrate could be consumed by this process in the steady-state period. Before the establishment of the steady state conditions, steep fluctuations in sulfide concentration (between 1mM and several MUM) were observed in the wood interior. This study is the first to document the temporal dynamics of this unsteady process, characterized by fast sulfide fluctuation and consumption. Our results point to the complex mechanisms driving the dynamics of wood biogeochemical transformations, and reveal the capacity of woody debris to generate sulfidic conditions and act as a possible sink for oxygen and nitrate in the marine environment. PMID- 22921660 TI - Effects of flow field on the metabolic characteristics of Streptomyces lincolnensis in the industrial fermentation of lincomycin. AB - In this work, the flow field in the existing fermentor with radial-flow impellers (C1) was studied using the computational fluid dynamics (CFD) software package Fluent, then the fermentor with radial-axial flow impellers (C2) was constructed and was compared with the C1 fermentor by CFD and experimental research. The simulation results revealed that the flow field in C2 fermentor had characteristics such as higher turbulent kinetic energy, gas holdup and shear rates. Metabolic variables of Streptomyces lincolnensis in the two fermentors such as carbon and nitrogen source consumption rates, specific growth rates (MU), hyphae morphologies, and lincomycin productivities were further explored. The correlation analysis between the experimental measurements and the simulation results indicated that the hyphae clustering and dry cell weight (DCW) decreasing at production stage were eliminated in C2 fermentor, which had higher gas volumetric mass transfer coefficient (K(L)a), dissolved oxygen (DO) concentration and consumption rates of nutrient materials. When C2 was employed in the fermentor, the specific growth rate of S. lincolnensis at growth stage was higher, and the maintenance metabolism together with secondary metabolism at production stage was kept at higher levels. As a result, the yield of lincomycin was achieved 7039 MUg ml(-1) when the 60 m(3) industrial fermentor was equipped with C2, which was increased by 46% compared to that obtained in the C1 fermentor. PMID- 22921661 TI - Pou2, a class V POU-type transcription factor in zebrafish, regulates dorsoventral patterning and convergent extension movement at different blastula stages. AB - Zebrafish pou2, which encodes a class V POU transcription factor considered to be an orthologue of mouse Oct-3/4, has been implicated by mutant analysis in dorsoventral (DV) patterning, gastrulation, and endoderm formation in early embryos and later in the regionalization of the neural plate. A series of gain-of function experiments were conducted in the present study to directly reveal the roles pou2 plays in embryogenesis. We first revealed that injecting low-dose wild type pou2 mRNA ventralizes embryos. Similar overexpression of activated (vp-) pou2 resulted in the same effects, whereas repressive (en-) pou2 caused dorsalization, supporting the previously proposed idea that pou2 is involved in DV patterning and that pou2 is a transcriptional activator. In contrast, high dose mRNA for pou2 and its modified genes affected convergent extension (CE) movement. We observed similar activities for mouse Oct-3/4, suggesting conservation of the roles of this POU family in vertebrate development. To determine the critical stage for the functions of pou2 in embryos, we established a transgenic (Tg) fish line harboring en-pou2 under regulation of a heat-shock promoter (HEP) and found that the exposure of HEP Tg embryos to heat shock at the midblastula (sphere) stage dorsalized embryos, whereas induction of HEP at the late blastula stage (30-50% epiboly) affected CE movement. The defects due to HEP induction were rescued by introducing wild-type pou2 mRNA before the heat treatments. Collectively, these data demonstrated that pou2 regulates DV patterning and CE movement in zebrafish embryos at the midblastula and late blastula stages, respectively. PMID- 22921662 TI - Abdominal radiation and diabetes: one more piece in the puzzle. PMID- 22921663 TI - Radiation dose to the pancreas and risk of diabetes mellitus in childhood cancer survivors: a retrospective cohort study. AB - BACKGROUND: Children and young adults treated with total body or abdominal radiotherapy have an increased risk of insulin resistance and diabetes mellitus. However, little is known of the effect of pancreas irradiation on the risk of diabetes. We assessed the relation between radiation exposure and occurrence of diabetes in a large cohort of long-term childhood cancer survivors. METHODS: We sent a questionnaire to 3468 survivors of a childhood cancer treated in eight centres in France and the UK between 1946 and 1985, of which 2520 were returned. Each self-declaration of diabetes was confirmed by contacting the patients' medical doctors. We estimated the radiation dose received by the tail, head, and body of the pancreas and 185 other anatomical sites during each course of radiotherapy from 1990 to 1995 for each child after reconstruction of the conditions in which irradiation was delivered. We investigated the relation between radiation dose to the pancreas and the risk of a subsequent diabetes diagnosis. FINDINGS: 65 cases of diabetes were validated. The risk of diabetes increased strongly with radiation dose to the tail of the pancreas, where the islets of Langerhans are concentrated, up to 20-29 Gy and then reached a plateau for higher radiation doses. The estimated relative risk at 1 Gy was 1.61 (95% CI 1.21-2.68). The radiation dose to the other parts of the pancreas did not have a significant effect. Compared with patients who did not receive radiotherapy, the relative risk of diabetes was 11.5 (95% CI 3.9-34.0) in patients who received 10 Gy or more to the tail of the pancreas. Results were unchanged after adjustment for body-mass index, despite its strong independent effect (p<0.0001), and were similar between men and women. Children younger than 2 years at time of radiotherapy were more sensitive to radiation than were older patients (relative risk at 1 Gy 2.1 [95% CI 1.4-4.3] vs 1.4 [95% CI 1.1-2.2] in older patients; p=0.02 for the difference). For the 511 patients who had received more than 10 Gy to the tail of the pancreas, the cumulative incidence of diabetes was 16% (95% CI 11-24). INTERPRETATION: Our study provides evidence of a dose-response relation between radiation exposure of pancreas and subsequent risk of diabetes. Because of the risks observed and the frequency of diabetes in general population, this finding raises important public health issues. The pancreas needs to be regarded as a critical organ when planning radiation therapy, particularly in children. Follow-up of patients who received abdominal irradiation should include diabetes screening. PMID- 22921664 TI - Persistent hypertension after adrenalectomy for an aldosterone-producing adenoma: weight as a critical prognostic factor for aldosterone's lasting effect on the cardiac and vascular systems. AB - BACKGROUND: Primary aldosteronism caused by an aldosterone producing adrenal tumor/aldosteronoma (APA), is a potentially curable form of hypertension, via unilateral adrenalectomy. Resolution of hypertension (HTN) is not as prevalent after tumor resection, as are the normalization of aldosterone secretion, hypokalemia, and other metabolic abnormalities. Here, we review the immediate and long-term medical outcomes of laparoscopic adrenalectomy in patients with an APA, and attempt to identify any distinctive sex differences in the management of resistant HTN. METHODS: We performed a retrospective review of the prospective adrenal database at the University of Wisconsin between January 2001 and October 2010. Of the 165 adrenalectomies performed, 32 were for the resection of an APA. Patients were grouped according to their postoperative HTN status. Those patients with normal blood pressure (<=120/80 mm Hg) and on no antihypertensive medication (CURE) were compared with those who continued to require medication for blood pressure control (HTN). We evaluated sex, age, body mass index, tumor size, duration of time with high blood pressure, and the differences in systolic and diastolic blood pressure following adrenalectomy. Statistical analysis was performed using Student's t-test. Statistical significance was defined as a P value of <0.05. RESULTS: We identified 32 patients with an APA based on biochemical and radiographic studies, two patients were excluded, due to missing data. There were 19 males (63%) and 11 (37%) females, with a mean age was 48.3 +/ 2.1 y, and mean tumor size was 24 +/- 3 mm. Postoperatively, patients required significantly fewer antihypertensive medications (1.5 +/- 0.2 versus 3.3 +/- 0.3, P < 0.001). Nine patients (31%) had complete resolution of their HTN, requiring no postoperative antihypertensive medication. The only significant difference between the sexes, was a lower body mass index in women (27.6 +/- 1.7 versus 33.4 +/- 2.1 kg/m(2), P = 0.04). Ninety percent of the cohort had at least a 20 mm Hg decline in their systolic blood pressure postoperatively, placing them in the prehypertensive or normal blood pressure categories. Sixty-six percent of the CURE patients required at least 6 mo for resolution of their HTN. All 20 patients who presented with hypokalemia, had immediate resolution postoperatively and did not require continuance of the preoperative spironolactone or potassium supplementation. CONCLUSIONS: Laparoscopic adrenalectomy for aldosterone producing adenoma results in the normalization of, or more readily manageable blood pressure in 90% of patients, within 6 mo. Metabolic disturbances are immediately corrected with tumor resection. Weight is an important contributing factor in resolving HTN. PMID- 22921665 TI - A large shin ulcer after minor trauma: please do not debride! PMID- 22921666 TI - Dysphagia in a patient with small-caliber esophagus. PMID- 22921669 TI - A pregnant patient with hypoglycemia. PMID- 22921670 TI - The relevance of weakly acidic reflux in patients with Barrett's esophagus. PMID- 22921671 TI - Elevated gamma-glutamyltransferase. PMID- 22921672 TI - Spleen stiffness measured by transient elastography accurately predicts esophageal varices in liver cirrhosis. PMID- 22921673 TI - Genomic and genetic characterization of cholangiocarcinoma identifies therapeutics targets for tyrosine kinase inhibitors. PMID- 22921675 TI - Alcohol based fixatives provide excellent tissue morphology, protein immunoreactivity and RNA integrity in paraffin embedded tissue specimens. AB - Fixation techniques preserving morphological fidelity, protein antigenicity and integrity of nucleic acids can have a high impact on both basic and applied biomedical sciences and diagnostic pathology. Different types of mouse tissues were fixed with neutral buffered formalin, ethanol supplemented with acetic acid and modified methacarn (methanol-Carnoy) fixative. The alcohol-fixed samples were processed in an Autotechnicon tissue processor or in an incubator. The preservation of tissue morphology was assessed in all specimens and the immunoreactivity was evaluated with antibodies specific for proteins with nuclear, membrane or cytoplasmic localization. RNA was extracted from all groups of fixed hind limb skeletal muscle specimens and was assessed versus unfixed tissue for preservation of its quantity and quality by amplification of gene specific fragments of different lengths. Both alcohol-based fixatives preserved the tissue architecture and the specificity of immunoreactivity in excellent quality; the trimming approach did not result in detectable differences. Oligonucleotide fragments of length between 108 and 577 base pairs were amplified from all groups of alcohol-fixed skeletal muscle specimens in amounts comparative to the unfixed muscle tissue. We conclude that both alcohol-based fixatives are an excellent tool for storage of tissue samples designed for immunohistochemical and mRNA expression studies when the access to fresh samples is limited. PMID- 22921676 TI - The GmCLC1 protein from soybean functions as a chloride ion transporter. AB - Soil salinization is a global issue that hampers agricultural production. Chloride is one of the prominent anions on saline land that cause toxicity to the plant. We previously identified the GmCLC1 gene from soybean (Glycine max) that encodes a putative tonoplast-localized chloride transporter. In this study, using electrophysiological analysis, we demonstrated the chloride transport function of GmCLC1. Interestingly, this chloride transport activity is pH dependent, suggesting that GmCLC1 is probably a chloride/proton antiporter. When the cDNA of GmCLC1 was expressed in tobacco BY-2 cells under the control of a constitutive promoter, the protective effect against salinity stress in transgenic tobacco BY 2 cells was also found to be pH sensitive. In the native host soybean, the expression of GmCLC1 gene is regulated by pH. All these findings support the notion that the function of GmCLC1 is regulated by pH. PMID- 22921677 TI - Salt-dependent increase in triterpenoids is reversible upon transfer to fresh water in mangrove plants Kandelia candel and Bruguiera gymnorrhiza. AB - This study examined the salinity dependence of triterpenoid content and triterpenoid synthase gene expression in mangrove plants, Kandelia candel and Bruguiera gymnorrhiza (Rhizophoraceae) after long-term exposure to salinity and subsequent re-adaptation. Seedlings of the two mangrove species grown in varying salt concentrations for 4 months were divided into two treatment groups and grown for another 4 months, one group continued under the respective saline condition and the other in fresh water for re-adaptation. The total content of triterpenoids increased with increasing salinity in roots and leaves of K. candel, but only in roots in B. gymnorrhiza. This increase was reversed to a variable extent, depending on the species and organ, after transfer to fresh water. In contrast, the total content of phytosterols showed no correlation with salinity throughout the experiment. The increase in total triterpenoids was accompanied by an up-regulation of several triterpenoid synthase genes: KcMS, a multifunctional triterpenoid synthase, in roots and leaves of K. candel and BgLUS, a lupeol synthase, and BgbAS, a beta-amyrin synthase, in roots of B. gymnorrhiza. The expression of root KcCAS, a cycloartenol synthase, which is involved in phytosterol biosynthesis, was not modulated by the salinity conditions but decreased with increasing salinity in leaves, followed by the restoration to the initial level after transfer to fresh water. The concentrations of individual triterpenoids, but not of phytosterols, in the roots positively correlated with the salinity. These results reinforced the importance of triterpenoids in the adaptation of mangroves to withstand salt and/or water stress. PMID- 22921678 TI - Transcriptome profile analysis of resistance induced by burdock fructooligosaccharide in tobacco. AB - Burdock fructooligosaccharide (BFO), isolated from the roots of Arcitum lappa, is a novel potential elicitor. Previous studies have shown that BFO induces various defense responses in plants. However, little is known about the mechanism of BFO induced plant responses. The transcriptome profiles in tobacco leaves after treatment with BFO or distilled water were analyzed using Solexa technology. The profiling analysis revealed numerous changes in gene expression after BFO treatment, which resulted in the up-regulation of 169 genes and the down regulation of 243 genes. The data were confirmed by reverse transcription polymerase chain reaction (RT-PCR) and real-time quantitative RT-PCR. Gene ontology analysis revealed that the differentially expressed genes were mainly involved in stress responses, defense responses, biosynthetic processes, hormone responses, RNA biosynthetic processes, signaling pathways and other processes. The results of this study suggested two important concepts. First, the differential expression of genes involved in plant hormone signaling pathways are related to defense, especially salicylic acid-mediated pathways, such as the genes encoding pathogen related proteins, WRKY transcription factors, Avr9/Cf-9 rapidly elicited protein, SA-activated MAP kinase, jasmonic acid/ethylene-related genes encoding jasmonate ZIM-domain protein and ethylene-responsive transcription factor, gibberellin-related genes encoding flowering promoting factor-like 1 and GA-insensitive dwarf 2, and abscisic acid related gene encoding ABA 8' hydroxylase CYP707A, indicated that plant hormones and their crosstalk might play a critical role in the defense response to BFO treatment in tobacco. Second, the genes involved in the biosynthesis of secondary metabolites were increased after BFO treatment including epiaristolochene synthase and cinnamoyl-CoA reductase, which serve as attractants in defense against pathogens and herbivores. PMID- 22921679 TI - Dimerization and protease resistance: new insight into the function of PR-1. AB - The group 1 pathogenesis-related (PR-1) proteins have long been considered hallmarks of hypersensitive response/defense pathways in plants, but their biochemical functions are still obscure despite resolution of the NMR/X-ray structures of several PR-1-like proteins, including P14a (the prototype PR-1). We report here the characterization of two basic PR-1 proteins (PR-1-1 and PR-1-5) recently identified from hexaploid wheat (Triticum aestivum). Both proteins were expressed in Pichia pastoris as a single major species of ~15 kDa. Sequence identity of the expressed PR-1 proteins was verified by MALDI-TOF/TOF analysis. Accumulation of the native PR-1-5 protein in pathogen-challenged wheat was confirmed by protein gel blot analysis. Low-temperature SDS-PAGE and yeast two hybrid assays revealed that PR-1-1 exists primarily as a monomer whereas PR-1-5 forms homodimers. Both PR-1 proteins are resistant to proteases compared to bovine serum albumin, but PR-1-1 shows resistance mainly to subtilisin and protease K (serine proteases) whereas PR-1-5 shows resistance to subtilisin, protease K and papain (a cysteine protease). Site-specific mutations at the five putative active sites in the PR-1 domain all affected dimerization, with the mutations at Glu-72 and Glu-102 (in the PR-1-5 numeration) also diminishing protease resistance. Sequence analysis revealed that the Glu-72 and Glu-102 residues are located in motif-like sequences that are conserved in both PR-1 and the human apoptosis-related caspase proteins. These findings prompt us to examine the function of PR-1 for a role in protease-mediated programmed cell death pathways in plants. PMID- 22921680 TI - The clinical value of antiplatelet therapy for patients with hemorrhage after thrombolysis based on susceptibility-weighted imaging: a prospective pilot study. AB - PURPOSE: To evaluate treatment decision-making based on susceptibility-weighted imaging (SWI) in patients with hemorrhage after thrombolysis. MATERIALS AND METHODS: One hundred and forty-six patients without intracranial hemorrhage on CT after receiving recombinant tissue plasminogen activator (rt-PA) were allocated to two groups: antiplatelets (n=72), who received antiplatelet therapy 24h after rt-PA for 10 days; and non-antiplatelets (n=74), who received no antiplatelet therapy. Twenty-two patients with SWI-detected microbleeds (MBs) or hemorrhagic transformation (HT) in the antiplatelets group (Group A) and 28 with MB or HT in the non-antiplatelets group (Group B) were included in this study. RESULTS: Sixteen patients had MB and six HT in Group A; 18 had MB, six HT, and four parenchymal hemorrhage (PH) in Group B. National Institutes of Health Stroke Scale (NIHSS) scores at 7 and 14 days and the Modified Rankin Scale (mRS) at 90 days post-rt-PA were significantly lower in Group B than in Group A, duration of hospitalization was significantly shorter, and the favorable outcome rate was higher at 90 days (P<0.05). There were no other significant differences. SWI evaluation at 14 days revealed eight patients with MB, 11 HT, and three PH in Group A; in Group B, 16 had MB, five HT, and one PH, with resolution of hemorrhage in six patients. CONCLUSIONS: Treatment decision-making based on SWI in acute stroke after thrombolysis was validated by the significantly reduced NIHSS score after 7/14 days, improved outcome, and reduced mRS in hemorrhage patients without antiplatelet therapy. PMID- 22921681 TI - Sonography of intrathyroid parathyroid adenomas: are there distinctive features that allow for preoperative identification? AB - OBJECTIVE: The purpose of our study was to determine if intra-thyroid parathyroid adenomas can be accurately identified by applying proposed criteria to preoperative ultrasound examinations in patients with primary hyperparathyroidism. MATERIALS/METHODS: Fifty-three patients with pathology proven intra-thyroid parathyroid adenomas and pre-operative ultrasounds were identified from a surgical database for a blinded, retrospective review. A contemporary, age-matched cohort of 54 patients with extra-thyroid parathyroid adenomas was identified as a control. A total of 64 patients within these cohorts had co-existing thyroid nodules. Proposed ultrasound criteria for identifying a parathyroid adenoma included solid composition, profound hypoechogenicity, and presence of a feeding polar vessel. Parathyroid adenomas were classified as extra thyroid or intra-thyroid (partial or complete) based on their relationship with the thyroid gland during ultrasound evaluation and results were compared to surgical and histopathology reports as the gold standard. The results from the blinded, retrospective review during which the proposed, specific ultrasound criteria were applied were compared to the initial, pre-operative reports during which the proposed criteria were not applied. The sensitivity, specificity, positive predictive value, negative predictive value and accuracy of the blinded, retrospective review and initial, pre-operative reports were calculated. Additionally, in patients with co-existing thyroid nodules, an attempt was made to differentiate parathyroid adenomas from the thyroid nodules. RESULTS: Application of the proposed ultrasound criteria during blinded retrospective review yielded a sensitivity and specificity for detecting intra-thyroid parathyroid adenomas of 76% and 92%, respectively. The sensitivity and specificity of ultrasound for detecting intra-thyroid parathyroid adenomas on the initial reports was 29% and 95%, respectively. The sensitivity and specificity for differentiating an intra-thyroid parathyroid adenoma from a thyroid nodule was 78% and 86%, respectively. CONCLUSION: Application of specific ultrasound criteria facilitates pre-operative diagnosis of intra-thyroid parathyroid adenomas and facilitates surgical planning. This large series confirms previous, largely anecdotal reports of ultrasound's utility in detecting intra-thyroid parathyroid adenomas. PMID- 22921682 TI - Neck ultrasonography as preoperative localization of primary hyperparathyroidism with an additional role of detecting thyroid malignancy. AB - OBJECTIVE: To evaluate and compare the diagnostic performances of high-resolution ultrasonography and (99m)Tc-sestamibi scintigraphy for the preoperative localization of abnormal parathyroid glands and to evaluate the ability of US for additional diagnostic roles in detecting thyroid malignancy in patients with pHPT. MATERIALS AND METHODS: Preoperative localization images of 115 parathyroid adenomas from high-resolution ultrasonography (US) and (99m)Tc-sestamibi scintigraphy (SS) were studied from 105 patients, who had undergone parathyroidectomy. Sensitivity, accuracy, and positive predictive value were calculated for the identification of adenomas in lesions and patients for both US and SS, respectively, and US and SS diagnostic performances were compared using generalized estimating equation. RESULTS: Preoperative imaging by both modalities localized 105 (93.8%) of the 112 parathyroid lesions confirmed at surgery and histology. Sensitivity, accuracy, and positive predictive value were 93.1% and 92.2%, 90.4% and 89.5%, and 96.9% and 96.9% by US and SS, respectively, without any statistically significant differences (P=0.796, 0.796, 0.879). US found incidental thyroid nodules in 47 patients (47/107, 43.9%), and 7 patients (7/107, 6.5%) were confirmed to have malignancy based on pathology results (all had papillary thyroid carcinoma). CONCLUSION: Neck ultrasonography and (99m)Tc sestamibi scintigraphy are complementary methods of the preoperative localization of parathyroid adenomas. Neck ultrasounds add an additional thyroid gland evaluation, and can be useful in the detection of incidental thyroid gland lesions, especially malignant nodules. PMID- 22921683 TI - Contrast enhanced MRI and 18F-FDG PET-CT in the assessment of multiple myeloma: a comparison of results in different phases of the disease. AB - OBJECTIVES: The aim of our study was to compare the accuracy of contrast enhanced MRI and FDG PET-CT in the staging, treatment evaluation and follow-up of multiple myeloma. METHODS: We retrospectively reviewed 210 PET-CT and 210 MRI studies of patients affected by multiple myeloma. MRI was always performed within 15 days of PET-CT. All the images have been evaluated by two expert oncologic radiologists. RESULTS: Patient population included 81 females and 110 males (age 61.9 +/- 9.9 years-old). Sixty-two patients have been evaluated at diagnosis, 58 at the end of therapies and 90 during follow-up. In 12/62 patients (19.4%) at diagnosis, differences between MRI and PET-CT findings determined changes in the staging: PET-CT was responsible for 11 down-staging (17.7%) and MRI only for one (1.6%). In 27/40 patients (67.5%) with good or complete clinical response to therapies the normalization of findings was faster for PET-CT than MRI. Ten out of 90 patients (10/90 - 11.1%) in follow-up protocol presented clinical recurrence of the disease: MRI detected active lesions in 8 of them (80.0%) and PET-CT in 5 patients (50.0%, all detected by MRI too). CONCLUSIONS: MRI achieved better results than PET-CT in the staging and in patients with multiple myeloma recurrence. PET-CT, showed prompt change of imaging findings, faster than MRI, in patients with positive response to therapy. PMID- 22921684 TI - Development of a lion-specific interferon-gamma assay. AB - The ongoing spread of bovine tuberculosis (BTB) in African free-ranging lion populations, for example in the Kruger National Park, raises the need for diagnostic assays for BTB in lions. These, in addition, would be highly relevant for zoological gardens worldwide that want to determine the BTB status of their lions, e.g. for translocations. The present study concerns the development of a lion-specific IFN-gamma assay, following the production and characterization of monoclonal antibodies specific for lion interferon-gamma (IFN-gamma). Recombinant lion IFN-gamma (rLIFN-gamma) was produced in mammalian cells and used to immunize mice to establish hybridoma cell lines producing monoclonal antibodies. These were used to develop a sensitive, lion IFN-gamma-specific capture ELISA, able to detect rLIFN-gamma to the level of 160 pg/ml. Recognition of native lion IFN gamma was shown in an initial assessment of supernatants of mitogen stimulated whole blood cultures of 11 known BTB-negative lions. In conclusion, the capture ELISA shows potential as a diagnostic assay for bovine tuberculosis in lions. Preliminary results also indicate the possible use of the test for other (feline) species. PMID- 22921685 TI - Simultaneous detection of the two main proliferation driving EBV encoded proteins, EBNA-2 and LMP-1 in single B cells. AB - Epstein Barr virus (EBV) is carried by almost all adults, mostly without clinical manifestations. Latent virus infection of B lymphocytes induces activation and proliferation that can be demonstrated in vitro. In healthy individuals, generation of EBV induced malignant proliferation is avoided by continuous immunological surveillance. The proliferation inducing set of the virally encoded genes is expressed exclusively in B cells in a defined differentiation window. It comprises nine EBV encoded nuclear proteins, EBNA 1-6, and three cell membrane associated proteins, LMP-1, 2A and 2B, designated as latency Type III. Outside this window the expression of the viral genes is limited. Healthy carriers harbor a low number of B lymphocytes in which the viral genome is either silent or expresses one virally encoded protein, EBNA-1, latency Type I. In addition, EBV genome carrying B cells can lack either EBNA-2 or LMP-1, latency Type IIa or Type IIb respectively. These cells have no inherent proliferation capacity. Detection of both EBNA-2 and LMP-1 can identify B cells with growth potential. We devised therefore a method for their simultaneous detection in cytospin deposited cell populations. Simultaneous detection of EBNA-2 and LMP-1 was reported earlier in tissues derived from infectious mononucleosis (IM), postransplantation lymphoproliferative disorders (PTLD) and from "humanized" mice infected with EBV. We show for the first time the occurrence of Type IIa and Type IIb cells in cord blood lymphocyte populations infected with EBV in vitro. Further, we confirm the variation of EBNA-2 and LMP-1 expression in several Type III lines and that they vary independently in individual cells. We visualize that in Type III LCL, induced for plasmacytoid differentiation by IL-21 treatment, EBV protein expression changes to Type IIa (EBNA-2 negative LMP-1 positive). We also show that when the proliferation of EBV infected cord blood lymphocyte culture is inhibited by the immunomodulator, PSK, the majority of the cells express latency Type IIa pattern. These results show that by modifying the differentiation state, the proliferating EBV positive B cells can be "curbed". Type IIa expression is a characteristic for EBV positive Reed-Sternberg (R/S) cells in EBV positive Hodgkin's lymphomas. For survival and proliferation, the R/S cells require the contribution of the in vivo microenvironment. Consequently, Type IIa lines could not be established from Hodgkin's lymphoma in vitro. We propose that these experimental cultures can be exploited for study of the Type IIa cells. PMID- 22921686 TI - Computer-assisted provision of hormonal contraception in acute care settings. AB - BACKGROUND: We evaluated whether computerized counseling about contraceptive options and screening for contraindications increased women's subsequent knowledge and use of hormonal contraception. METHODS: For the study 814 women aged 18-45 years were recruited from the waiting rooms of three emergency departments and an urgent care clinic staffed by non-gynecologists and asked to use a randomly selected computer module before seeing a clinician. RESULTS: Women in the intervention group were more likely to report receiving a contraceptive prescription when seeking acute care than women in the control group (16% vs. 1%, p=.001). Women who requested contraceptive refills were not less likely than women requesting new prescriptions to have potential contraindications to estrogen (75% of refills vs. 52% new, p=.23). Three months after visiting the clinic, women in the intervention group tended to be more likely to have used contraception at last intercourse (71% vs. 65%, p=.91) and to correctly answer questions about contraceptive effectiveness, but these differences were not statistically significant. CONCLUSION: Patient-facing computers appear to increase access to prescription contraception for women seeking acute care. PMID- 22921687 TI - Development and implementation of a quality assurance program for a hormonal contraceptive implant. AB - BACKGROUND: The importance of the distribution of safe, effective and cost effective pharmaceutical products in resource-constrained countries is the subject of increasing attention. FHI 360 has developed a program aimed at evaluating the quality of a contraceptive implant manufactured in China, while the product is being registered in an increasing number of countries and distributed by international procurement agencies. The program consists of (1) independent product testing; (2) ongoing evaluation of the manufacturing facility through audits and inspections; and (3) post-marketing surveillance. STUDY DESIGN: This article focuses on the laboratory testing of the product. The various test methods were chosen from the following test method compendia, the United States Pharmacopeia (USP), British Pharmacopeia (BP), International Organization for Standardization (ISO), the American Society for Testing and Materials (ASTM), or lot release tests mandated by Chinese regulatory requirements. Each manufactured lot is independently tested prior to its distribution to countries supported by this program. In addition, a more detailed annual testing program includes evaluation of the active ingredient (levonorgestrel), the final product and the packaging material. RESULTS: Over the first 4 years of this 5-year project, all tested lots met the established quality criteria. CONCLUSIONS: The quality assurance program developed for this contraceptive implant has helped ensure that a safe product was being introduced into developing country family planning programs. This program provides a template for establishing quality assurance programs for other cost-effective pharmaceutical products that have not yet received stringent regulatory approval and are being distributed in resource-poor settings. PMID- 22921688 TI - A physiotherapist-delivered, combined exercise and pain coping skills training intervention for individuals with knee osteoarthritis: a pilot study. AB - BACKGROUND: Osteoarthritis (OA) of the knee is associated with a number of physical and psychological impairments. Unfortunately, very few treatment strategies are capable of addressing both types of impairments concurrently. We performed a pilot, randomized controlled, proof of principle trial investigating the feasibility and effects of an intervention combining physical exercise and pain coping skills training (PCST). METHODS: Twenty patients with a clinical and radiographical diagnosis of tibiofemoral OA were randomized to receive either 10 weeks of physiotherapist supervised exercises (lower limb strengthening and walking) combined with non-directive counseling (NDC) or the same exercise program delivered concurrently with PCST. Primary outcomes included self-reported pain and pain coping, while secondary outcomes included self efficacy and self reported physical function. RESULTS: Ten participants were randomized to each group and both groups exhibited significant improvements in isometric knee strength, self-reported knee pain and physical function, self efficacy for control of pain management and other arthritis symptoms. Only those in the exercise + PCST group reported statistically significant improvements in pain control coping and rational thinking. No between-group differences existed in any outcome (0.07 < p < 0.98). Based on our findings, 63 participants per group would be needed for future large-scale studies using similar outcome measures and design. CONCLUSIONS: Our study showed that an intervention that combines exercise and PCST within the same treatment session and delivered by specially-trained physiotherapists is feasible and can improve both physical and psychological outcomes in individuals with knee OA. LEVEL OF EVIDENCE: Level II Clinical Trials Registry number: ACTRN12609000623291. PMID- 22921689 TI - Placement of metallic biliary endoprostheses in complex hilar tumours. AB - PURPOSE: To assess the technical success, clinical success and complications after 1 month of percutaneous biliary drainage with the placement of several metallic endoprostheses in complex hilar liver tumours. MATERIALS AND METHODS: This is a retrospective study, on a homogenous target population of 68 consecutive patients, who underwent multiple percutaneous biliary drainage for complex hilar tumour (Bismuth type II, III and IV) between August 1998 and August 2010. Patients benefiting from previous endoscopic drainage were excluded from the study. The clinical data, biological data, imaging and interventional radiology procedures were studied. RESULTS: The rate of success of the technique was 98.5% and the clinical rate of success was 84% after 1 week and 93% after 1 month. The rate of minor and major complications was 25 and 13% respectively. CONCLUSION: Multiple percutaneous biliary drainage in complex hilar tumour is a safe and effective first intention procedure. PMID- 22921690 TI - Interventional musculoskeletal ultrasonography of the lower limb. AB - In this case series, out of 823 ultrasound-guided injections carried out over a period of one and a half years, 60% were of the lower limb (LL). In the hip (61% of LL injections), the main indications were pathologies of the gluteal tendons and bursae (80%) and pathologies of periprosthetic soft tissue; in the knee (15% of LL punctures), these procedures were for cysts (51%), tendinopathies and bursopathies (18%), and joint aspirations (7%); in the calf, haematoma drainage; in the foot and the ankle (24% of LL punctures), Morton's neuroma (47%), tenosynovitis (22%), pathologies of the plantar fascia (13%), cysts (7%), joint aspirations (5%), and bursopathies. For each of these indications, we will detail the specific technique and equipment used, useful tips, and post-procedure care. PMID- 22921691 TI - Pfeiffer syndrome type II discovered perinatally: Report of an observation and review of the literature. PMID- 22921692 TI - Musculoskeletal interventional ultrasonography: the upper limb. AB - Forty percent of the 823 ultrasound-guided injections performed in our centre over a year and a half concerned the upper limb, injections involving the shoulder, for subacromial bursitis and the treatment of calcific tendinitis, being the prime indications (24%). The wrist represented 8% of the prescriptions, for treatment of tendinopathy, ganglion cysts, carpal tunnel syndrome and rhizarthrosis. Trigger finger, tenosynovitis and pulley ganglia made up 6% of the indications and the elbow 2.5%. Ultrasound improves the accuracy of the procedure by helping guide the path of the needle and allowing the distribution of the substance injected to be visualised. We shall give details of the technique used for each indication, with advice and hints and post-procedure recommendations. PMID- 22921693 TI - The dynamics of the non-heme iron in bacterial reaction centers from Rhodobacter sphaeroides. AB - We investigate the dynamical properties of the non-heme iron (NHFe) in His-tagged photosynthetic bacterial reaction centers (RCs) isolated from Rhodobacter (Rb.) sphaeroides. Mossbauer spectroscopy and nuclear inelastic scattering of synchrotron radiation (NIS) were applied to monitor the arrangement and flexibility of the NHFe binding site. In His-tagged RCs, NHFe was stabilized only in a high spin ferrous state. Its hyperfine parameters (IS=1.06+/-0.01mm/s and QS=2.12+/-0.01mm/s), and Debye temperature (theta(D0)~167K) are comparable to those detected for the high spin state of NHFe in non-His-tagged RCs. For the first time, pure vibrational modes characteristic of NHFe in a high spin ferrous state are revealed. The vibrational density of states (DOS) shows some maxima between 22 and 33meV, 33 and 42meV, and 53 and 60meV and a very sharp one at 44.5meV. In addition, we observe a large contribution of vibrational modes at low energies. This iron atom is directly connected to the protein matrix via all its ligands, and it is therefore extremely sensitive to the collective motions of the RC protein core. A comparison of the DOS spectra of His-tagged and non-His-tagged RCs from Rb. sphaeroides shows that in the latter case the spectrum was overlapped by the vibrations of the heme iron of residual cytochrome c(2), and a low spin state of NHFe in addition to its high spin one. This enabled us to pin point vibrations characteristic for the low spin state of NHFe. PMID- 22921694 TI - Acquired labial sinechiae and hydrocolpos secondary to Stevens-Johnson syndrome. AB - Stevens-Johnson syndrome frequently affects the genitalia. Vaginal problems have been recognized in female patients; however, reports about the problem and its treatment are rare. Labial sinechiae have not yet been reported as sequelae of Stevens-Johnson syndrome. Amenorrhea, cyclical abdominal pain, and a hypogastric mass in girls affected by Stevens-Johnson syndrome could indicate acquired vaginal obstruction. Extensive labial sinechiae in such patients can cause dysuria, urinary tract infection, and sexual dysfunction. After a diagnosis of Stevens-Johnson syndrome in girls, it is prudent to schedule a prepubertal genital examination to diagnose genital disease preemptively and avoid obstructed menstruation and future sexual problems. PMID- 22921695 TI - High dietary magnesium intake decreases hyperoxaluria in patients with nephrolithiasis. AB - OBJECTIVE: To examine the relationship between urine magnesium and hyperoxaluria in a cohort of patients with recurrent stone formation. METHODS: A total of 311 patients with nephrolithaisis were evaluated. The patients were divided into quintiles of urine magnesium excretion, an accepted surrogate of dietary magnesium intake. Multivariate analysis was used to examine the relationship between magnesium and hyperoxaluria. RESULTS: The mean patient age was 50.0 +/- 14.9 years, the body mass index was 28.0 +/- 5.9 kg/m(2), and 130 were women and 181 were men. The mean urine magnesium excretion was 100.8 +/- 42.0 mg/d (range 17.8-224.8). On multivariate analysis, an increasing quintile of urine magnesium was associated with decreasing hyperoxaluria (beta = -0.37, 95% confidence interval -0.6 to -0.14, P < .05 for trend). When analyzed as separate quintiles with the lowest quintile of magnesium as the referent, only the greatest quintile demonstrated a statistically significant decrease in hyperoxaluria (beta = -1.7, 95% confidence interval -2.7 to -0.7, P < .05 for trend). CONCLUSION: Increasing magnesium intake was associated with decreasing hyperoxaluria in this population of patients with stone formation. Our findings showed that high magnesium intake might be required to observe clinically significant effects from magnesium. PMID- 22921696 TI - Abnormalities of 24-hour urine composition in first-time and recurrent stone formers. AB - OBJECTIVE: To examine differences in 24-hour urine composition between recurrent and first-time stone-formers. METHODS: A retrospective review of patients evaluated in 2 metabolic stone clinics was performed. Recurrent stone formation was defined as patients with a history of more than 1 stone episode and first time stone-formers were those with a history of a single-stone episode. Frequencies of urine metabolic abnormalities were noted. Multivariate linear regression was performed to evaluate the likelihood of abnormalities of 24-hour urine composition. RESULTS: Three-hundred eleven patients met inclusion criteria: 71 (22.8%) were first-time stone-formers and 240 (77.1%) were recurrent stone formers. On univariate analysis, the likelihood of having a single abnormality of 24-hour urine composition (ie, hypercalciuria, hyperoxaluria, hyperuricosuria, or hypocitraturia) was similar between the 2 groups (83.1% for first-time vs 88.8% for recurrent, P = NS). In addition, there were similar rates of hypercalciuria (39.4% vs 43.3%, P = NS), hyperoxaluria (32.4% vs 33.3%, P = NS), hyperuricosuria (29.6% vs 23.3%, P = NS), and hypocitraturia (45.0% vs 45.0%, P = NS). On multivariate logistic regression, there was no difference in detection of any urine abnormality (ie, hypercalciuria or hyperoxaluria or hypocitraturia or hyperuricosuria) between first-time (referent) or recurrent stone-formers (OR 1.68, 95% CI .8-3.5, P = .2). CONCLUSION: In this study, detection of urine abnormalities was similar in first-time and recurrent stone-formers. Given the strong patient preference for stone prevention and the high success of directed therapy in the literature, we believe it is not unreasonable to offer comprehensive metabolic evaluation to first-time stone-formers who express a desire to undergo evaluation. PMID- 22921697 TI - Low prostate-specific antigen and no Gleason score upgrade despite more extensive cancer during active surveillance predicts insignificant prostate cancer at radical prostatectomy. AB - OBJECTIVE: To identify parameters that predict insignificant prostate cancer in 67 radical prostatectomies after biopsy reclassification to worse disease on active surveillance. METHODS: Parameters evaluated at diagnosis and at biopsy reclassification included serum prostate-specific antigen, prostate-specific antigen density, number of positive cores, maximum percent involvement of cancer per core, and any interval negative biopsies. Gleason upgrading at biopsy reclassification was also assessed to predict insignificant cancer. RESULTS: Mean time between diagnosis and radical prostatectomies was 30.3 months with a median of 3 biopsies (range 2-9). Nineteen of 67 (28.4%) had clinically insignificant cancer at radical prostatectomy. In the entire group, there were no variables significantly associated with insignificant cancer at radical prostatectomy. In a subgroup analysis of 37 patients without Gleason pattern 4/5 at biopsy reclassification, 16/37 (43.2%) showed insignificant cancer at radical prostatectomy. In this subgroup, prostate-specific antigen at diagnosis was significantly lower in men with insignificant cancer (3.7 ng/mL) vs significant cancer (5.4 ng/mL) (P = .0005). With prostate-specific antigen <4 ng/mL at diagnosis or at biopsy reclassification, 12/13 (92.3%) men showed insignificant cancer, whereas only 4/24 (16.7%) men with prostate-specific antigen >4 ng/mL both at diagnosis and at biopsy reclassification showed insignificant cancer. CONCLUSION: Most men with biopsy reclassification while on active surveillance have significant disease at radical prostatectomy, justifying their treatment. Low prostate-specific antigen at diagnosis or at biopsy reclassification can predict a high probability of insignificant cancer in the absence of Gleason pattern 4/5 on biopsy. These men may be candidates for continuing active surveillance. PMID- 22921698 TI - Response to on-demand vardenafil was improved by its daily usage in hypertensive men. AB - OBJECTIVE: To evaluate whether the response to on-demand vardenafil could be improved by its daily usage in hypertensive men with erectile dysfunction (ED) who previously did not answer to on-demand regime. METHODS: Our main efficacy criterion was per patient percentage of positive answers on the Sexual Encounter Profile question 3 (SEP3). Carotid intima-media thickness (IMT), flow-mediated dilation (FMD), and nitrate-mediated dilation on brachial artery were considered as vascular parameters. A total of 74 hypertensive men with ED aged 50 to 70 years with no major cardiovascular disease were selected from 284 patients initially referred. After vardenafil on-demand usage during 4 weeks, patients with more than 50% of positive answers on the SEP3, or 50% and more than 6 points on the International Index of Erectile Function-Erection Function Domain (IIEF EF) basal score or positive answer to global evaluation question were considered "responders." "Nonresponders" (n = 35) were randomized to daily vardenafil 10 mg or placebo during 5 weeks along with open 10 mg of vardenafil before intercourse. RESULTS: In the active group, 38.8% of patients became responders to vardenafil (P < .05). Clinical response to continuous vardenafil correlated with sexual frequency (r = .68, P < .01), Framingham risk score (r = -.65, P < .01), carotid IMT (r = -.61, P = .01) and low-density lipoprotein (LDL)-cholesterol (r = -.64, P < .01). CONCLUSION: Daily vardenafil during 5 weeks rescued response to on demand regime among ED hypertensive men with no major cardiovascular disease. Further clinical trials and cost-effectiveness studies are necessary to confirm these findings. PMID- 22921699 TI - Renal pelvic recurrence of renal cell carcinoma. AB - An 85-year-old man was referred for gross hematuria and a recurrent renal pelvic mass in a solitary left kidney, status post right nephrectomy for renal cell carcinoma 11 years previously. Three years before referral he had undergone ureteroscopic fulguration of a renal pelvis mass that had proved to be metastatic renal cell carcinoma on biopsy. We performed percutaneous resection of the renal pelvic mass, with no local recurrence at 1-year follow up. Contralateral renal pelvic recurrence is a rare form of renal cell carcinoma metastasis. PMID- 22921700 TI - Percutaneous nephrostolithotomy: an assessment of costs for prone and Galdakao modified supine Valdivia positioning. AB - OBJECTIVE: To examine the relative costs of prone percutaneous nephrostolithotomy (PCNL) versus PCNL performed with the patient in the Galdakao-modified supine Valdivia (GMSV) position to determine whether a cost differential exists. METHODS: We compared prone PCNL with PCNL using GMSV positioning. Cost data were obtained from the urology departmental and hospital billing offices at our institution and from the 2011 local Medicare reimbursement scales. The costs were divided into 5 major categories: surgeon fees, anesthesia fees, surgical supplies, hospital-related fees, and lost revenue. RESULTS: The overall cost of prone PCNL ranged from $23 423 to $24 463, and the cost for PCNL performed with GMSV positioning ranged from $24 725 to $25 830. The difference between the 2 positions ranged from approximately $1302 for stones <= 2 cm to $1367 for stones >2 cm. The lost office revenue because of the requirement for a second surgeon was estimated at $1987. CONCLUSION: Our assessment of the cost for prone versus GMSV PCNL technique found GMSV positioning to be more costly. The presence of 2 surgeons was the main driver of the cost differential, because it resulted in more equipment use, with greater instrument repair costs and higher surgeon fees. It also brings into consideration the opportunity cost of having a second surgeon in the operating room and not in the office. PMID- 22921701 TI - Editorial comment. PMID- 22921702 TI - Determination of ureter stent appearance on dual-energy computed tomography scan. AB - OBJECTIVE: To examine the dual-energy computed tomography (DECT) properties of 7 commonly used ureteral stents to optimize stent selection for calculi monitored using DECT. The use of DECT to evaluate renal and ureteral calculi has recently increased. METHODS: Seven stents were individually placed in a fish bowl phantom and imaged using a Siemens Somatom Definition Flash CT scanner. DECT peak tube potentials of 80 and 140 kVp and 100 and 140 kVp were used, reflecting our current dual-energy protocols. These were compared to 31 in vivo stents of known composition. The data were reconstructed on a multimodality WorkPlace (Siemens) using CT syngo Post-Processing Suite software. RESULTS: The average patient age was 64 years (range 27-90). The average body mass index was 31.9 kg/m(2) (range 24-51.6). Of the 27 patients, 4 had uric acid stones and 22 had calcium-based stones; 1 patient had undergone renal transplantation. No difference was seen in the dual-energy characterization of stents from the same manufacturer. All imaged Cook and Bard stents had a dual-energy characterization that approached that of calcium stones (blue). All Boston Scientific and Gyrus ACMI stents had a dual energy characterization resembling that of uric acid stones (red). CONCLUSION: The present study evaluated the stent appearance on DECT for various stent manufacturers. This information will aid in the optimal stent selection for patients undergoing treatment of renal calculi and followed up with DECT. PMID- 22921703 TI - Adult prepuceplasty: comparison of outcomes of standard prepuceplasty and foreskin Z-plasty. AB - OBJECTIVE: To compare the clinical and patient-reported outcomes from standard prepuceplasty and foreskin Z-plasty. METHODS: Consecutive standard prepuceplasty (n = 22) and Z-plasty (n = 12) procedures performed from September 2005 to December 2010 were analyzed. The patient and operative data were collated, together with the results of a patient questionnaire inquiring about the postoperative complications, postoperative pain, remaining foreskin tightness in the flaccid or erect penis, cosmetic appearance after surgery, and the need for later circumcision. RESULTS: The median follow-up period was 26 months for standard prepuceplasty and 16 months for Z-plasty. Of the 22 patients in the standard prepuceplasty group and 12 patients in the Z-plasty group, 5 (22.7%) and 1 (9.1%) requested circumcision (P = .33), respectively. One man in each group underwent revision standard prepuceplasty. Patients undergoing the 2 procedures reported no significant differences for the questions relating to postoperative pain and foreskin tightness in the flaccid or erect penis. However, the cosmetic appearance after Z-plasty, assessed using a Likert scale question, were "good" or "very good" compared with "acceptable" for the standard group (P = .005). CONCLUSION: Prepuceplasty can be used successfully in well-selected patients. In the present series, 82% of men avoided circumcision. Z-plasty resulted in fewer circumcisions and a significantly better cosmetic appearance than standard prepuceplasty. PMID- 22921706 TI - Editorial comment. PMID- 22921704 TI - Renal functional and perioperative outcomes of off-clamp versus clamped robot assisted partial nephrectomy: matched cohort study. AB - OBJECTIVE: To evaluate the potential benefit of performing off-clamp robot assisted partial nephrectomy as it relates to renal functional outcomes, while assessing the safety profile of this unconventional surgical approach. METHODS: Twenty-nine patients who underwent off-clamp robot-assisted partial nephrectomy for suspected renal cell carcinoma at Washington University between March 2008 and September 2011 (group 1) were matched to 29 patients with identical nephrometry scores and comparable baseline renal function who underwent robot assisted partial nephrectomy with hilar clamping during the same period (group 2). The matched cohorts' perioperative and renal functional outcomes were compared at a mean 9-month follow-up. RESULTS: Mean estimated blood loss was 146.4 mL in group 1, versus 103.9 mL in group 2 (P = .039). Mean hilar clamp time was 0 minutes in group 1 and 14.7 minutes in group 2. No perioperative complications were encountered in group 1; 1 Clavien-2 complication (3.4%) occurred in group 2 (P = 1.000). At 9-month follow-up, mean estimated glomerular filtration rate in group 1 was 79.9 versus 84.8 mL/min/1.73 m(2) preoperatively (P = .013); mean estimated glomerular filtration rate in group 2 was 74.1 versus 85.8 mL/min/1.73 m(2) preoperatively (P < .001). Hence, estimated glomerular filtration rate declined by a mean of 4.9 mL/min/1.73 m(2) in group 1 versus 11.7 mL/min/1.73 m(2) in group 2 (P = .033). CONCLUSION: Off-clamp robot-assisted partial nephrectomy is associated with a favorable morbidity profile and relatively greater renal functional preservation compared to clamped robot assisted partial nephrectomy. Nevertheless, the benefit is small in renal functional terms and may have very limited clinical relevance. PMID- 22921707 TI - An alternative and inexpensive percutaneous access needle in pediatric patients. AB - INTRODUCTION: The most important factor that increases the cost of percutaneous surgery is the disposable instruments used for the surgery. In this study we present the advantages of using an intravenous cannula instead of a percutaneous access needle for renal access. TECHNICAL CONSIDERATIONS: Recently, percutaneous stone surgery has grown in use in pediatric cases and is considered a minimally invasive surgery. The most important step in this surgery is access to the renal collecting systems. Although fluoroscopy has been used frequently at this stage, the use of ultrasound has recently increased. During percutaneous accesses under all types of imaging techniques, disposable 11- to 15-cm-long 18-ga needles are used. In pediatric cases, these longer needles are difficult to use. Using disposable materials in percutaneous nephrolithotomy increases the cost of the procedure. Therefore, we asserted that percutaneous access especially in pediatric cases could be performed using a 16-ga intravenous cannula (angiocath). Indeed, percutaneous access was performed successfully, especially in pediatric preschool patients. Shorter needle length, easy skin entry, comfort of manipulation, clear visualization of the metal needle on ultrasound, and wide availability can be considered advantages of this method. The angiocath is also less expensive than a percutaneous access needle. CONCLUSION: Angiocath is inexpensive, easily available, and practical, and it is the shortest needle to perform percutaneous access in pediatric patients. PMID- 22921708 TI - Efficacy of BloodSTOP iX, surgicel, and gelfoam in rat models of active bleeding from partial nephrectomy and aortic needle injury. AB - OBJECTIVE: To compare the bleeding time using 3 different hemostatic agents in a rat model of partial nephrectomy and aortic needle injury. METHODS: Bilateral partial nephrectomy was performed in 20 rats with a total bleeding surface of 1.5 cm(2) without vascular clamping. Surgicel (n = 10) or BloodSTOP iX (n = 10) matrix was applied on each kidney cut surface. Finger pressure was applied to the parenchyma with transparent plastic bubble wrap to allow for visualization of the site and monitor the bleeding time. Pressure was applied until the bleeding stopped and then released to assess the presence of active bleeding for 5 minutes. An additional 24 rats underwent aortic trauma with a 25-gauge needle puncture, and the efficacy of the topical hemostatic agents were compared among Gelfoam (n = 8), Surgicel (n = 8), and BloodSTOP iX (n = 8). RESULTS: After partial nephrectomy, the mean bleeding time with BloodSTOP iX and Surgicel treatment was 83.70 +/- 13.73 seconds and 168.8 +/- 19.41 seconds, respectively, a statistically significant difference (P = .002). After aortic injury, the mean bleeding time was 157.5 +/- 31.44 seconds, 187.5 +/- 23.20 seconds, and 66.00 +/- 13.74 seconds in the Gelfoam, Surgicel, and BloodSTOP groups, respectively, which was statistically significant (P = .004). CONCLUSION: The BloodSTOP iX hemostatic surgical matrix was more effective in reducing the bleeding time than Surgicel in a rat model of partial nephrectomy. Similarly, in an aortic needle injury model, BloodSTOP iX achieved hemostasis faster than Gelfoam or Surgicel. PMID- 22921710 TI - Glutamatergic neurons in the lateral periaqueductal gray innervate neurokinin-1 receptor-expressing neurons in the ventrolateral medulla of the rat. AB - The neural pathways underlying the respiratory responses elicited by electrical or chemical stimulation of the lateral part of the periaqueductal gray (lPAG) remain unsettled. In the present study, we examined the lPAG projection to neurokinin-1 receptor (NK1R)-immunoreactive (ir) neurons in the ventrolateral medulla (VLM) which have been implicated in the control of respiration. After biotinylated dextranamine (BDA) injection into the lPAG, NK1R-ir neurons in the rostral VLM were embedded in the plexus of BDA-labeled fibers. At the electron microscopic level, the BDA-labeled terminals made asymmetrical synaptic contacts predominantly with dendrites and additionally with somata of the NK1R-ir neurons. Using retrograde tracing combined with in situ hybridization, we demonstrated that the vast majority of the lPAG neurons projecting to the rostral VLM were positive for vesicular glutamate transporter 2 (VGLUT2) mRNA, but not for glutamic acid decarboxylase 67 mRNA. Using a combination of anterograde tracing and immunohistochemistry, we further demonstrated that the lPAG axon terminals with VGLUT2 immunoreactivity made close apposition with the NK1R-ir neuronal profiles in the rostral VLM. These data suggest that lPAG neurons exert an excitatory influence on NK1R-expressing neurons in the rostral VLM for the control of respiration. PMID- 22921711 TI - [Upper limb pain in an adolescent]. PMID- 22921709 TI - Neural responsivity to food cues in fasted and fed states pre and post gastric bypass surgery. AB - Reductions in mesolimbic responsivity have been noted following Roux-en-Y gastric bypass (RYGB; Ochner et al., 2011a). Given potential for postoperative increases in postprandial gut (satiety) peptides to affect mesolimbic neural responsivity, we hypothesized that: (1) post RYGB changes in mesolimbic responsivity would be greater in the fed relative to the fasted state and; (2) fasted vs. fed state differences in mesolimbic responsivity would be greater post-relative to pre surgery. fMRI was used to asses neural responsivity to high- and low-calorie food cues in five women 1 mo pre- and 1 mo post-RYGB. Scans were repeated in fasted and fed states. Significant post RYGB decreases in the insula, ventromedial prefrontal cortex (vmPFC) and dorsolateral prefrontal cortex (dlPFC) responsivity were found in the fasted state. These changes were larger than neural changes in the fed state, which were non-significant. Preoperatively, fasted vs. fed differences in neural responsivity were greater in the precuneus, with large but nonsignificant clusters in the vmPFC and dlPFC. Postoperatively, however, no fasted vs. fed differences in neural responsivity were noted. Results were opposite to that predicted and appear inconsistent with the initial hypothesis that postoperative increases in postprandial gut peptides are the primary driver of postoperative changes in neural responsivity. PMID- 22921712 TI - [Kawasaki disease: what you need to know]. AB - Kawasaki disease (KD) is an acute systemic vasculitis syndrome occurring mostly in children younger than 5 years of age. Especially young infants (<1 year) have an increased risk of coronary artery lesions (CAL). Whereas the etiology of KD is still unknown, progress in treatment during its acute phase has decreased the incidence of CAL from 25-30% to 3-5%. In "atypical KD", the clinical picture is dominated by an unusual symptom as seizure, bloody diarrhea, compressive cervical adenopathy, nephrotic syndrome or hyponatremia. To make a diagnosis in case of "incomplete KD", the supplementary criteria (clinical and biological) suggested by the American Heart Association can be helpful. Once the diagnosis established, the treatment of choice is the intravenous administration of immunoglobulin associated to aspirin at anti-inflammatory dose. However, some patients remain feverish within 36 hours following the end of immunoglobulin administration. This treatment resistance seems increasing in some regions of the globe and can touch up 20% of patients. The unsatisfactory answer to the initial treatment is associated to a higher risk of CAL. Predictive criteria of resistance have been identified and allow to strengthen the medical treatment with a second administration of immunoglobulins. Moreover, methylprednisolone pulse therapy and tumor necrosis factor-alpha blockade (infliximab) appear to be interesting therapeutic options in the future. At last, other treatments have not been the object of controlled studies yet but are alternatives in refractory forms e.g. cytotoxic agents (cyclosporine A, cyclophosphamide, methotrexate), plasmapheresis, plasma exchange or abciximab, especially in patients with aneurysms. Sclerotic vascular changes are often observed in post-Kawasaki disease patients, including those without coronary lesions during the acute phase. Indeed, endothelial dysfunction and risk factors for the development of atherosclerosis, such as dyslipidemia, decreased vascular elasticity, increased C reactive protein, oxidative stress, and inflammatory cytokines, are known to be present in the late phase of KD. However, it is not clearly established that the survivors of KD carry a higher risk of coronary disease. The epidemiological studies of the next decade should give clearer answers as far as these patients henceforth achieved the age of the atherosclerosis. In conclusion, the diagnosis of KD imposes a strict supervision by a pediatric cardiologist initially. The follow-up is organized according to the existence or non-existence of coronary artery lesions. Late complications as stenosis or coronary thrombosis can occur but remain rare. Thus, it is necessary to be reassuring with the parents, especially for those whose children had no or regressive CAL, while recommending a prevention of the cardiovascular risk factors in the adulthood. PMID- 22921713 TI - Training traditional birth attendants to use misoprostol and an absorbent delivery mat in home births. AB - A 50-fold disparity in maternal mortality exists between high- and low-income countries, and in most contexts, the single most common cause of maternal death is postpartum hemorrhage (PPH). In Bangladesh, as in many other low-income countries, the majority of deliveries are conducted at home by traditional birth attendants (TBAs) or family members. In the absence of skilled birth attendants, training TBAs in the use of misoprostol and an absorbent delivery mat to measure postpartum blood loss may strengthen the ability of TBAs to manage PPH. These complementary interventions were tested in operations research among 77,337 home births in rural Bangladesh. The purpose of this study was to evaluate TBAs' knowledge acquisition, knowledge retention, and changes in attitudes and practices related to PPH management in home births after undergoing training on the use of misoprostol and the blood collection delivery mat. We conclude that the training was highly effective and that the two interventions were safely and correctly used by TBAs at home births. Data on TBA practices indicate adherence to protocol, and 18 months after the interventions were implemented, TBA knowledge retention remained high. This program strengthens the case for community-based use of misoprostol and warrants consideration of this intervention as a potential model for scale-up in settings where complete coverage of skilled birth attendants (SBAs) remains a distant goal. PMID- 22921714 TI - Association between urinary concentrations of bisphenol A and type 2 diabetes in Korean adults: a population-based cross-sectional study. AB - Bisphenol A (BPA) is a synthetic phenolic compound to which the general public may be exposed via consumer products and environmental contamination. We assessed the association between urinary BPA concentration and the prevalence of type 2 diabetes. This cross-sectional study included Korean adult participants (n=1210) aged 40-69 years and was based on the 2009 Korean National Human Biomonitoring Survey. Demographic characteristics and medical history of type 2 diabetes were collected from the participants by questionnaire, and BPA levels were determined by analysis of urine samples. The mean age of the participants was 53.4 years and 41.6% were men; the prevalence of type 2 diabetes differed according to demographic characteristics. The geometric mean urinary BPA levels of participants with and without type 2 diabetes were 2.03 and 2.40ng/mL, respectively. Among BPA quartiles, no clear association was found between BPA levels and type 2 diabetes. Although the adjusted odds ratio of type 2 diabetes was slightly increased for participants in the upper BPA quartile, the association was not statistically significant. These findings suggest that a high body BPA burden may not be associated with an increased prevalence of type 2 diabetes in Korean adults. PMID- 22921715 TI - Impact of imperfect Mycobacterium avium subsp. paratuberculosis vaccines in dairy herds: a mathematical modeling approach. AB - The objective of this study was to investigate the potential impacts of imperfect Mycobacterium avium subsp. paratuberculosis (MAP) vaccines on the dynamics of MAP infection in US dairy herds using a mathematical modeling approach. Vaccine-based control programs have been implemented to reduce the prevalence of MAP infection in some dairy herds; however, MAP vaccines are imperfect. Vaccines can provide partial protection for susceptible calves, reduce the infectiousness of animals shedding MAP, lengthen the latent period of infected animals, slow the progression from low shedding to high shedding in infectious animals, and reduce clinical disease. To quantitatively study the impacts of imperfect MAP vaccines, we developed a deterministic multi-group vaccination model and performed global sensitivity analyses. Our results explain why MAP vaccination might have a beneficial, negligible, or detrimental effect in the reduction of prevalence and show that vaccines that are beneficial to individual animals may not be useful for a herd-level control plan. The study suggests that high efficacy vaccines that are aimed at reducing the susceptibility of the host are the most effective in controlling MAP transmission. This work indicates that MAP vaccination should be integrated into a comprehensive control program that includes test-and-cull intervention and improved calf rearing management. PMID- 22921716 TI - Reply to Jai Prakash, Apul Goel and Manish Garg's Letter to the Editor re: Anobel Y. Odisho, Anna B. Berry, Ardalan E. Ahmad, Matthew R. Cooperberg, Peter R. Carroll, Badrinath R. Konety. Reflex ImmunoCyt Testing for the Diagnosis of Bladder Cancer in Patients with Atypical Urine Cytology. Eur Urol. In press. http://dx.doi.org/10.1016/j.eururo.2012.04.019. PMID- 22921717 TI - Collaborative research networks as a platform for virtual multidisciplinary, international approach to managing difficult clinical cases: an example from the Upper Tract Urothelial Carcinoma Collaboration. PMID- 22921718 TI - Re: Serdar Tekgul, Hubertus Riedmiller, Piet Hoebeke, et al. EAU guidelines on vesicoureteral reflux in children. Eur Urol 2012;62;534-42. PMID- 22921719 TI - Intravesical bacille Calmette-Guerin eradicates bacteriuria in antibiotic-naive bladder cancer patients. AB - BACKGROUND: Intravesical bacille Calmette-Guerin (BCG) therapy is safe and effective in bladder cancer patients who have asymptomatic bacteriuria. BCG induces robust immune responses in the bladder that are responsible for its antitumor effect. We hypothesize that BCG-induced inflammation may eradicate bacterial infection. OBJECTIVE: To investigate whether intravesical BCG therapy alone can eradicate bacterial infection in antibiotic-naive bladder tumor patients who have asymptomatic bacteriuria. DESIGN, SETTING, AND PARTICIPANTS: A single-institution prospective cohort study of bacteriuric adults with non-muscle invasive bladder tumors who underwent outpatient BCG therapy or surveillance cystoscopy. INTERVENTION: Ninety high-risk patients received induction intravesical BCG without maintenance BCG, and 95 low-risk patients who had not received BCG underwent outpatient surveillance cystoscopy. Each patient had significant bacteriuria on urine culture, and none received routine antibiotics before, during, or after procedures. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Urine cultures were repeated after 3, 6, and 12 mo. All patients had follow-up cystoscopy every 3 mo and were followed for a minimum of 1 yr. The end point was number of BCG-treated and cystoscopy patients who became bacteria free at 3, 6, and 12 mo. RESULTS AND LIMITATIONS: Two BCG-treated patients (2.2%) and six patients after cystoscopy (6%) developed febrile urinary tract infection (p=0.21). All resolved with antibiotics. No patient was admitted for sepsis. Of 88 infected patients who received BCG without routine antibiotics, 58 (66%) were continuously bacteria free at 1 yr compared with 16 of 89 cystoscopy patients (18%; p=0.001). The prospective observational study design prohibits causal inference of antibacterial effects attributed to BCG over cystoscopy. CONCLUSIONS: Intravesical BCG therapy is associated with clearance of uropathogens in bladder cancer patients, possibly due to augmented innate host immunity. PMID- 22921720 TI - Enhanced gene transfection using calcium phosphate co-precipitates and low intensity pulsed ultrasound. AB - The capability to controllably disrupt the cell membrane by ultrasound (US), thus facilitating entry of exogenous species, has now reached a state of some maturity. However, a compelling question asks whether there is a residual role for US in enhancing transfection: that is, once the genetic material has been delivered to the cytosol, can US assist in its transport into the nucleus? The present experiment was designed with a view to addressing this question. As such, our experimental setup discriminates between: (i) the precursor cell membrane permealization step, and (ii) any subsequent intracellular trafficking into the nucleus. In this study, calcium phosphate co-precipitates (CaP) were used to internalize plasmid DNA encoding for luciferase (pDNA-Luc) (>90%) in HeLa cells. After 2h incubation with the CaP-pDNA-Luc, cells were washed and insonated for varying durations. The results showed that US can indeed enhance the intracellular trafficking of previously internalized genes when longer insonation periods are implemented, culminating with an increased probability for successful nuclear localization, as inferred from an enhanced luciferase expression. Moreover, the results suggest that the intracellular role of US might be mediated through a pathway that appears not to be limited to destabilizing the endosomal vesicles. The study thus provides new information regarding the intracellular effects of US, and in effect represents a new modality combining US and CaP carriers for improved efficiency in gene delivery. PMID- 22921721 TI - Inverted papilloma of the middle ear. AB - INTRODUCTION: Inverted papilloma (IP) of the middle ear is a very rare lesion, as less than 20 cases have been reported in the literature. CASE REPORT: The authors report the case of a 73-year-old male with IP of the middle and external ear that had already been operated many times. Treatment consisted of creating a large resection cavity. No recurrence was observed on clinical examination or MRI with a follow-up of 2 years. DISCUSSION AND CONCLUSION: This case is analysed in the light of a review of published cases with a discussion of the pathophysiological and treatment problems raised by these lesions. PMID- 22921722 TI - Chromatin and epigenetic modifications during early mammalian development. AB - In mammals, the embryonic genome is transcriptionally inactive after fertilization and embryonic gene expression is initiated during the preimplantation developmental period, during so-called "embryonic genome activation (EGA)". EGA is dependent on the presence of the basal transcriptional machinery components but also on the parental genome reorganization after fertilization. Indeed, during the first cell cycles, the embryonic nuclei undergo intense remodelling that participates in the regulation of embryonic development. Among the mechanisms of this remodeling, it appears that modifications of epigenetic marks are essential especially at the time of embryonic genome activation. This review will focus on DNA methylation and histone modifications such as acetylation or methylation which are important to produce healthy embryos. We will also consider nuclear higher-order structures, such as chromosomes territories and pericentric heterochromatin clusters. The relevance of these chromatin epigenetic modifications has been sustained by the work performed on cloned embryos produced through nuclear transfer of somatic donor cells. It is indeed believed that incomplete reprogramming of the somatic nucleus, in other words, the incomplete re-establishment of the embryonic epigenetic patterns and peculiar nuclear organization may be among the causes of development failure of cloned animals. This will also be discussed in this review. PMID- 22921723 TI - Transgenic RNAi in mouse oocytes: the first decade. AB - RNA interference (RNAi), a sequence-specific mRNA degradation induced by double stranded RNA (dsRNA), is a common approach employed to specifically silence genes. Experimental RNAi in plant and invertebrate models is frequently induced by long dsRNA. However, in mammals, short RNA molecules are used preferentially since long dsRNA can provoke sequence-independent type I interferon response. A notable exception are mammalian oocytes where the interferon response is suppressed and long dsRNA is a potent and specific trigger of RNAi. Transgenic RNAi is an adaptation of RNAi allowing for inducing sequence-specific silencing upon expression of dsRNA. A decade ago, we have developed a vector for oocyte specific expression of dsRNA, which has been used to study gene function in mouse oocytes on numerous occasions. This review provides an overview and discusses benefits and drawbacks encountered by us and our colleagues while working with the oocytes-specific transgenic RNAi system. PMID- 22921724 TI - Quantitative proteomic analysis of differentially expressed proteins in the toxicity-lost mutant of Alexandrium catenella (Dinophyceae) in the exponential phase. AB - Alexandrium catenella is a widely spread dinoflagellate species which can produce potent neurotoxins and result in paralytic shellfish poisoning. To date, the molecular mechanisms regulating toxin biosynthesis remain unclear. This study compared protein profiles of a toxicity-lost mutant of A. catenella, ACHK-NT and its wild-type, ACHK-T in the exponential phase, using two dimensional differential gel electrophoresis and MALDI-TOF-TOF mass spectrometry. Morphological analysis showed that both subcultures were morphologically identical with the distinctive taxonomic characteristics of A. catenella. Sequence analyses of ITS1, 5.8S, ITS2 and 18S demonstrated that the mutant and wild subcultures were genetically identical for these markers. 90 differentially expressed protein spots were identified from ACHK-NT, of which 34 were down regulated and 56 were up-regulated. Using a multilayered strategy for de novo protein sequence analysis, 67 proteins assigned to different functional categories were identified. Among them, 25 involved in bioluminescence, secondary metabolite biosynthesis, protein modification and toxin biosynthesis were down regulated, while 42 participating in carbon fixation, stress response, transporter and protein folding were up-regulated. This study indicated that the strengthening of certain biological processes coupled with the depression of essential reactions upstream or downstream of the toxin biosynthetic pathway might have blocked toxin production and resulted in the loss of toxicity in the mutant A. catenella. PMID- 22921726 TI - Ovarian serous cystadenofibromas associated with a low-grade serous carcinoma of the peritoneum. AB - Ovarian serous cystadenofibromas are benign neoplasms that sometimes have focal areas of borderline serous tumor and rarely have been associated with epithelial proliferations in the peritoneum, resembling implants. We are reporting 2 cases of ovarian serous cystadenofibromas with serous peritoneal lesions of higher grade than the ovarian tumor: 1 case had a serous carcinoma and another 1 a serous borderline tumor. PMID- 22921725 TI - Alveolar soft part sarcoma of the paranasal sinuses masquerading as a giant invasive pituitary adenoma. AB - Alveolar soft part sarcoma (ASPS) is a relatively rare tumor that mostly presents as a slow growing mass in the deep soft tissue of the extremities. A substantial number of cases in children occur in the head and neck region; however, in any age group, it is very rarely reported in the sinonasal region. We report a case of ASPS of the paranasal sinuses with sellar extension in a 25-year-old man that masqueraded as a giant invasive pituitary adenoma. This is only the fifth case of sinonasal ASPS in literature. The clinical and radiological diagnoses were misleading, but an extensive pathology workup including electron microscopy helped reach an accurate diagnosis in this unusual case. PMID- 22921727 TI - Analysis of the scalp of women with AIDS subjected to autopsy: epithelial, follicular, and immunologic aspects. AB - Hair keeps the scalp warmer and slightly moister than the rest of the skin, which contributes to a favorable environment for mycotic, bacterial, and parasitic infections. It is well established that AIDS makes the patient more susceptible to opportunistic infections and cutaneous manifestations. Because of this, the aim of this study was to analyze scalp fragments of autopsied women with AIDS. Twenty-eight scalp samples of women aged between 18 and 46 years were observed. These women were divided into 2 groups: with AIDS (n = 14) and without AIDS (n = 14). We conducted histochemical (hematoxylin-eosin, Picrosirius, and Verhoeff), morphometric (Image J; National Institutes of Health, Hamilton, ON, Canada and KS 300 Kontron-Zeiss; Kontron Elektronik, Carl-Zeiss, Germany), and immunohistochemical (S-100) analyses of the scalp. In patients with AIDS, epithelial thickness, number of epithelial cell layers, number of immature Langerhans cells in the epidermis, and percentages of elastic fibers in the dermis were significantly lower, whereas telogen hair follicles were significantly higher. The percentage of collagen fibers in the dermis and the diameter of the epithelial cells were smaller in patients with AIDS, without significant difference. AIDS possibly causes immunologic and morphologic alterations in the scalp. This study may establish parameters for better clinical and morphologic diagnostic in patients with AIDS. PMID- 22921728 TI - Multispectral MRI segmentation of age related white matter changes using a cascade of support vector machines. AB - White matter changes (WMC) are the focus of intensive research and have been linked to cognitive impairment and depression in the elderly. Cumbersome manual outlining procedures make research on WMC labor intensive and prone to subjective bias. We present a fast, fully automated method for WMC segmentation using a cascade of reduced support vector machines (SVMs) with active learning. Data of 102 subjects was used in this study. Two MRI sequences (T1-weighted and FLAIR) and masks of manually outlined WMC from each subject were used for the image analysis. The segmentation framework comprises pre-processing, classification (training and core segmentation) and post-processing. After pre-processing, the model was trained on two subjects and tested on the remaining 100 subjects. The effectiveness and robustness of the classification was assessed using the receiver operating curve technique. The cascade of SVMs segmentation framework outputted accurate results with high sensitivity (90%) and specificity (99.5%) values, with the manually outlined WMC as reference. An algorithm for the segmentation of WMC is proposed. This is a completely competitive and fast automatic segmentation framework, capable of using different input sequences, without changes or restrictions of the image analysis algorithm. PMID- 22921729 TI - Clonal nature and diversity of resistance, toxins and adhesins genes of meticillin-resistant Staphylococcus aureus collected in a Spanish hospital. AB - In this study we determined the prevalence of genes coding for antimicrobial resistance, toxins, enzymes, immunoevasion and adhesins factors among 189 meticillin-resistant Staphylococcus aureus (MRSA) strains isolated from a third level hospital in Valladolid (Spain) between 2005 and 2008 in order to examine the relationship between these pathogenicity determinants, both individually and in combination, and the genetic background of main MRSA strains that are presents in Spanish hospitals. MRSA isolates were first characterised epidemiologically by a combination of molecular typing strategies like spa, SCCmec and multilocus sequence typing, and then, a cluster analysis based on pathogenicity factors genes was performed according to the hybridisation pattern of 65 virulence, 36 resistance, 15 adhesins, and 11 set/ssl genes on a Diagnostic DNA microarray (Alere StaphyType DNA microarray Jena, Germany). CC5-agr type II [ST125 SCCmecIV/VI (32.2%) or ST125-IV (19.1%), ST228-I (19.1%), ST146-IV (13.7%) and ST5- IV (0.5%)] isolates was widely distributed. CC8-agr type I [ST8-IV (11.5%), USA300 clone (0.5%), and ST239-III (1.1%)]; CC45-agr type II [ST45- IV (1.6%)], and the CC97-agr type I [ST97-IV] were also detected. We identified 42 different resistance genes profiles, 22 set/ssl genes profiles, and 91 different virulence profiles. However although the high genetic diversity of MRSA strains, mainly with respect to virulence factors genes, the results of the simultaneous assessment of resistance and virulence genes and the genetic background illustrated a correspondence relationship (p<0.001) between the different clones and same resistance and virulence genes or clusters of them. During the study period we observed changes in molecular epidemiology of MRSA isolates and as a consequence we report the changes of the resistance and virulence potential of MRSA strains produced over time in our institution. PMID- 22921730 TI - Host selection and parasite infection in Aedes taeniorhynchus, endemic disease vector in the Galapagos Islands. AB - Host selection in blood-sucking arthropods has important evolutionary and ecological implications for the transmission dynamics, distribution and host specificity of the parasites they transmit. The black salt-marsh mosquito (Aedes taeniorhynchus Wiedemann) is distributed throughout tropical to temperate coastal zones in the Americas, and continental populations are primarily mammalphilic. It is the only indigenous mosquito in the Galapagos Islands, having colonised the archipelago around 200,000 years ago, potentially adapting its host selection, and in the process, altering the dynamics of vector mediated pathogen interactions in the archipelago. Here, we use blood-meal analysis and PCR-based parasite screening approach to determine the blood-feeding patterns of A. taeniorhynchus in the Galapagos Islands and identify potential parasite transmission with which this mosquito could be involved. Our results show that A. taeniorhynchus feeds equally on mammals and reptiles, and only one avian sample was observed in 190 successful PCR amplifications from blood meals. However, we detected endemic filarial worms and Haemoproteus parasites known to infect various Galapagos bird species in mosquito thoraces, suggesting that feeding on birds must occur at low frequency, and that A. taeniorhynchus may play a role in maintaining some avian vector-borne pathogens, although more work is needed to explore this possibility. We also isolated three different DNA sequences corresponding to hemogregarine parasites of the genus Hepatozoon from mosquito and iguana blood samples, suggesting that more than one species of Hepatozoon parasites are present in Galapagos. Phylogenetic analysis of Hepatozoon 18sRNA sequences indicates that A. taeniorhynchus may have facilitated a recent breakdown in host-species association of formerly isolated Hepatozoon spp. infecting the reptile populations in the Galapagos Islands. PMID- 22921731 TI - Emerging trends in the epidemiology of human astrovirus infection among infants, children and adults hospitalized with acute watery diarrhea in Kolkata, India. AB - Human astroviruses (HAstVs) have now emerged as another common cause of non bacterial acute gastroenteritis (AGE) in humans worldwide. This study investigated the epidemiology and genetic diversity of human astrovirus strains circulating among infants, younger children (up to 6 years), older children and adolescents (>6-17 years) and adults (18 years and above) hospitalized for diarrhea and their role in AGE in Kolkata, India. A total of 2535 fecal samples were screened for the presence of known enteric viral, bacterial and parasitic etiologies by conventional microbiological assays and molecular methods. The overall incidences of sole or mixed infection of HAstV with known enteric viral, bacterial and parasitic pathogens were detected in 60 cases (2.4%) among all age groups. The clinical symptoms of astrovirus-associated acute watery diarrhea cases were recorded for all sole and mixed infection cases. A high number of sole (n = 13/60 [21.7%]) and mixed infection cases (n = 22/60 [36.7%]) were observed in adults (18 years old or more). Considering all age groups, 18 sole infection cases (n = 18/60 [30%]) and 42 mixed infection cases (n = 42/60 [70%]) with Rotavirus (n = 11/25 [44%]), Vibrio cholerae O1 (n = 6/24 [25%]) Cryptosporidium spp and Giardia lamblia (n = 5/13 [38.4%]) were observed. Further, eleven HAstV samples from infants and children (up to 6 years), children and adolescents (>6 17 years) and adults (18 years and above) were analyzed for their sequences of overlap region between ORF1b (RdRp) and ORF2 (capsid). Among these, ten strains were found to have close genetic relatedness to the Japanese strain HAstV_G1 [AB009985]. Additionally, the IDH2211 Kolkata strain showed a close genetic match with the Thai HAstV_G3 strain [EU363889]. Our study reports show that HAstVs as the sole agent and as mixed infection with other known enteric viral, bacterial, parasitic pathogens are also responsible for AGE among infants, children, adolescents and adults in Kolkata, India. PMID- 22921732 TI - Development of a microarray-based method to detect exposure of human basophils to IL-3. AB - Human basophils are an accessible participant of the human allergic reaction. There is natural variation in various functional endpoints and in signaling molecule expression but there has been only a limited effort to place this information in the context of mRNA expression profiles. The goal of these studies was to develop gene transcript profiles associated with IL-3 exposure for use in probing basophil phenotypes. Highly purified human basophils were cultured under several conditions and the cells subsequently analyzed by microarray analysis of gene transcript expression. Basophils were cultured with or without IL-3 for 24 h and the expression profile, relative to pre-culture, analyzed for transcripts that act in a reciprocal fashion depending on the condition. A 51-gene transcript set was identified that was composed of 34 transcripts that increased with IL-3 and decreased without IL-3 and a further 17 transcripts that did the reverse. This set of transcripts was validated on two microarray chips. The changes induced by IL-3 were stable in time, with 3 day cultures generating a signature concordant with 1 day cultures. The inverted nature of the response to +/-IL-3 suggested that the normal circulating basophil is balanced between a state of high and low IL-3 exposure and thus is very sensitive to changes in IL-3. For example, the basophil could detect the early generation of IL-3 that follows IgE mediated stimulation of basophils. When this signature tool was applied to freshly isolated basophils, it was observed that the signature was similar for the same subjects' basophil sampled weeks apart. It was also shown that the 51 gene transcript was insensitive to the method of preparing purified basophils. Finally, these studies provided an estimate for the normal in vivo exposure of circulating basophils to IL-3 or IL-3-like functionality. These studies identified an IL-3 signature to probe changes in basophils occurring in vivo. PMID- 22921733 TI - Sexual violence. Preface. PMID- 22921734 TI - Signal fluctuations in fMRI data acquired with 2D-EPI and 3D-EPI at 7 Tesla. AB - Segmented three-dimensional echo planar imaging (3D-EPI) provides higher image signal-to-noise ratio (SNR) than standard single-shot two-dimensional echo planar imaging (2D-EPI), but is more sensitive to physiological noise. The aim of this study was to compare physiological noise removal efficiency in single-shot 2D-EPI and segmented 3D-EPI acquired at 7 Tesla. Two approaches were investigated based either on physiological regressors (PR) derived from cardiac and respiratory phases, or on principal component analysis (PCA) using additional resting-state data. Results show that, prior to physiological noise removal, 2D-EPI data had higher temporal SNR (tSNR), while spatial SNR was higher in 3D-EPI. Blood oxygen level dependent (BOLD) sensitivity was similar for both methods. The PR-based approach allowed characterization of relative contributions from different noise sources, confirming significant increases in physiological noise from 2D to 3D prior to correction. Both physiological noise removal approaches produced significant increases in tSNR and BOLD sensitivity, and these increases were larger for 3D-EPI, resulting in higher BOLD sensitivity in the 3D-EPI than in the 2D-EPI data. The PCA-based approach was the most effective correction method, yielding higher tSNR values for 3D-EPI than for 2D-EPI postcorrection. PMID- 22921735 TI - [Anterior segment imaging of congenital ectropion uveae: case report]. PMID- 22921736 TI - The switch between relapse and remission in multiple sclerosis: continuous inflammatory response balanced by Th1 suppression and neurotrophic factors. AB - Multiple sclerosis (MS) is characterized in most patients by a relapsing remitting disease course. However, the trigger of relapse and the transformation that switches relapse into remission are not clearly understood. To evaluate the key molecular pathways operating in MS relapse and remission we performed peripheral blood gene-expression profiling in 123 MS patients either in relapse (n=34) or remission (n=89) and in comparison with 41 matched healthy subjects using Affymetrix microarray technology. Our findings suggest that the relapsing remitting pattern of MS is an ongoing process where inflammation is persistently active in the background of a changing magnitude of processes associated with TBX21-mediated immune suppression and activation of BDNF-related neuroprotection. PMID- 22921737 TI - Individual variation in biomarkers of health: influence of persistent organic pollutants in Great skuas (Stercorarius skua) breeding at different geographical locations. AB - Persistent organic pollutants (POPs) have been shown to cause adverse effects on a number of biomarkers of health in birds. POPs may impair immune function and alter the stress response, defined as a suite of behavioral and physiological responses to environmental perturbations. Recent studies have also proposed that POPs can induce oxidative stress. Nevertheless, there is a lack of studies simultaneously assessing the potential damaging effects of POPs on the latter biomarkers. In this study, we examined the contribution of legacy (organochlorines; (OCs)) and emerging (flame retardants; PBDEs) POPs to individual variations in stress levels (feather corticosterone), humoral immunity (plasma immunoglobulin Y levels) and oxidative stress occurring in three breeding colonies of a top predator seabird, the Great skua (Stercorarius skua), distributed from temperate regions to the high Arctic: Shetland (60 degrees N), Iceland (63 degrees N) and Bjornoya (74 degrees N). Our results demonstrated that plasma concentrations of OCs in Great skuas from Bjornoya are among the highest in North Atlantic seabirds, with up to 7900 MUg/kg (ww) ?OCs. Yet, a latitudinal gradient in POP levels was observed with all compounds being significantly higher in Bjornoya than in Iceland and Shetland (on average 4-7 fold higher for OCs and 2.5-4.5 for PBDEs, respectively). Contrary to our predictions, skuas breeding at the least contaminated site (i.e., Shetland) experienced the poorest physiological condition; i.e., the highest levels of stress hormones (25% higher) and oxidative stress (50% higher) and the lowest immunoglobulin levels (15% lower) compared to the two other colonies. Finally, our results failed to point out consistent within-colony relationships between biomarkers of health and POPs. Overall, it is suggested that other ecological factors such as food availability could constrain physiological indicators more than anthropogenic contaminants. PMID- 22921738 TI - Very small size proteoliposomes (VSSP) and Montanide combination enhance the humoral immuno response in a GnRH based vaccine directed to prostate cancer. AB - Very small size proteoliposomes (VSSP) constitute a complex of very small size proteoliposomes that includes proteins, lipids, CpG and gangliosides tumor associated that provides a potential target for cancer immunotherapy. This compound has been described to stimulate the humoral and cellular response, dendritic cells (DC) activation and differentiation of T-helper cells, specially, in immunocompromised patients with cancer status. This work deals with the stimulating capacity of the VSSP to reach a humoral response when they are used as a component in a peptidic vaccine based on the gonadotrophin releasing hormone (GnRH). This study was carried out in male Copenhagen rats, which were immunized with 750MUg of the GnRH mimetic peptide (GnRHm1-TT) with or without the VSSP. The mixtures were always emulsified with the oil adjuvant Montanide ISA 51. The anti GnRH seroconversion analysis revealed that the group immunized with the peptide GnRHm1-TT/VSSP developed a strong anti GnRH seroconversion. These antibody levels proved to be significant superior to those reached by the use of the GnRHm1-TT peptide solely emulsified in Montanide. Post-mortem analysis on the Testosterone ablation target organs (prostate and testicles) yielded a sudden decrease in their size and weight in respect to the control group. On the other hand, the group submitted to the use of GnRHm1-TT/VSSP, showed a significant difference in the reduction of these target organs in comparison with the group only immunized with GnRHm1-TT adjuvated in Montanide ISA 51. These values turned to be of p=0.023 and p=0.009 in the prostate and testicles respectively. These findings foreground the VSSP as a useful immunopotentiator to be used as part of a GnRH based vaccine to treat prostate cancer. PMID- 22921739 TI - Acute exercise enhancement of pneumococcal vaccination response: a randomised controlled trial of weaker and stronger immune response. AB - Acute exercise at the time of vaccination can enhance subsequent immune responses. However, the potential benefit of this effect will be its efficacy in boosting poor responses, and thus protection in at-risk populations. The current study tested the effect of exercise on the response to either a full- or half dose Pneumococcal (Pn) vaccination to elicit stronger and weaker responses. Subjects were 133 young healthy adults, randomised to one of four groups: exercise or control task, receiving a full- or half-dose Pn vaccination. Prior to vaccination, exercise groups completed a 15 min arm and shoulder exercise task, control groups rested quietly. Antibody levels to 11 Pn strains were evaluated at baseline and 1-month. Across all participants, exercise groups showed significantly greater increase in antibody levels than control groups. When doses were compared, it emerged that those who exercised had significantly larger responses than those who rested in the half-dose group, but in the full-dose groups responses were similar. This data indicates the effectiveness of exercise as a vaccine adjuvant, particularly in weaker responses. Thus, given the potential public health benefits of no-cost behavioural intervention to enhance response to vaccination, testing in at-risk populations should be pursued. PMID- 22921740 TI - Effects of route and coadministration of recombinant raccoon poxviruses on immune responses and protection against highly pathogenic avian influenza in mice. AB - We previously demonstrated that recombinant raccoonpox (RCN) virus could serve as a vector for an influenza vaccine. RCN constructs expressing the hemagglutinin (HA) from H5N1 viruses were immunogenic in chickens. In the current study, we generated several recombinant RCN constructs expressing influenza (H5N1) antigens and a molecular adjuvant (Heat-Labile enterotoxin B from E. coli: RCN-LTB), demonstrated their expression in vitro, and evaluated their ability to protect mice against H5N1 virus challenge. RCN-HA provided strong protection when administered intradermally (ID), but not intranasally (IN). Conversely, the RCN neuraminidase (NA) construct was highly efficacious by the IN route and elicited high titers of neutralizing antibodies in mice. Vaccination by combined ID (RCN HA) and IN (RCN-NA) routes offered mice the best protection against an IN challenge with heterologous H5N1 virus. However, protection was reduced when the different RCN constructs were pre-mixed, perhaps due to reduced expression of antigen. PMID- 22921741 TI - Relative stability of meningococcal serogroup A and X polysaccharides. AB - Prior to the introduction of the MenAfriVacTM serogroup A glycoconjugate vaccine in September 2010, serogroup A was the major epidemic disease-causing meningococcal serogroup in the African meningitis belt. However, recently serogroup X meningococcal (MenX) disease has received increased attention because of outbreaks recorded in this region, with increased endemic levels of MenX disease over the past 2 years. Whereas polysaccharide-protein conjugate vaccines against meningococcal serogroups A, C, W and Y (MenA, MenC, MenW, MenY) are on the market, a vaccine able to protect against MenX has never been achieved. The structure of serogroup A, C, W and Y meningococcal polysaccharides has been already fully elucidated by NMR. MenX capsular polysaccharide (MenX CPS) structure is also documented but fewer characterization data have been published. We have applied here (1)H NMR, (31)P NMR and HPLC to evaluate the stability of MenX CPS in aqueous solution as compared to MenA capsular polysaccharide (MenA CPS). The stability study demonstrated that MenA CPS is more susceptible to hydrolytic degradation than MenX CPS. The different stereochemistry of the N acetyl group at position C(2) of mannosamine (MenA CPS) and glucosamine (MenX CPS) respectively might play a fundamental role in this susceptibility to polysaccharide chain degradation. The satisfactory stability of MenX CPS predicts the possibility that a stable fully-liquid MenX polysaccharide or glycoconjugate vaccine could be developed. PMID- 22921742 TI - Protective effects of caffeoylquinic acids on the aggregation and neurotoxicity of the 42-residue amyloid beta-protein. AB - Alzheimer's disease (AD), a neurodegenerative disorder, is characterized by aggregation of 42-mer amyloid beta-protein (Abeta42). Abeta42 aggregates through beta-sheet formation and induces cytotoxicity against neuronal cells. Abeta42 oligomer, an intermediate of the aggregates, causes memory loss and synaptotoxicity in AD. Inhibition of Abeta42 aggregation by small molecules is thus a promising strategy for the treatment of AD. Caffeoylquinic acid (CQA), a phenylpropanoid found widely in natural sources including foods, shows various biological activities such as anti-oxidative ability. Previously, our group reported that 3,5-di-O-caffeoylquinic acid (3,5-di-CQA) rescued the cognitive impairment in senescence-accelerated-prone mice 8. However, structure-activity relationship of CQA derivatives on the aggregation and neurotoxicity of Abeta42 remains elusive. To evaluate the anti-amyloidogenic property of CQA-related compounds for AD therapy, we examined the effect of CQA and its derivatives on the aggregation and neurotoxicity of Abeta42. In particular, 4,5-di-O caffeoylquinic acid (4,5-di-CQA) and 3,4,5-tri-O-caffeoylquinic acid (3,4,5-tri CQA) strongly inhibited the aggregation of Abeta42 in a dose-dependent manner. Structure-activity relationship studies suggested that the caffeoyl group in CQA is essential for the inhibitory activity. These CQAs also suppressed the transformation into beta-sheet and cytotoxicity against human neuroblastoma cells of Abeta42. Furthermore, 3,4,5-tri-CQA blocked the formation of Abeta42 oligomer. These results indicate that 3,4,5-tri-CQA could be a potential agent for the prevention of AD. PMID- 22921744 TI - Design, synthesis, and biological evaluation of the analogues of glaziovianin A, a potent antitumor isoflavone. AB - Various analogues of glaziovianin A, an antitumor isoflavone, were synthesized, and their biological activities were evaluated. O(7)-modified glaziovianin A showed strong cytotoxicity against HeLa S(3) cells. Compared to glaziovianin A, the O(7)-benzyl and O(7)-propargyl analogues were more cytotoxic against HeLa S(3) cells and more potent M-phase inhibitors. Furthermore, O(7)-modified molecular probes of glaziovianin A were synthesized for biological studies. PMID- 22921743 TI - Discovery of structurally-diverse inhibitor scaffolds by high-throughput screening of a fragment library with dimethylarginine dimethylaminohydrolase. AB - Potent and selective inhibitors of the enzyme dimethylarginine dimethylaminohydrolase (DDAH) are useful as molecular probes to better understand cellular regulation of nitric oxide. Inhibitors are also potential therapeutic agents for treatment of pathological states associated with the inappropriate overproduction of nitric oxide, such as septic shock, selected types of cancer, and other conditions. Inhibitors with structures dissimilar to substrate may overcome limitations inherent to substrate analogs. Therefore, to identify structurally-diverse inhibitor scaffolds, high-throughput screening (HTS) of a 4000-member library of fragment-sized molecules was completed using the Pseudomonas aeruginosa DDAH and human DDAH-1 isoforms. Use of a substrate concentration equal to its K(M) value during the primary screen allowed for the detection of inhibitors with different modes of inhibition. A series of validation tests were designed and implemented in the identification of four inhibitors of human DDAH-1 that were unknown prior to the screen. Two inhibitors share a 4-halopyridine scaffold and act as quiescent affinity labels that selectively and covalently modify the active-site Cys residue. Two inhibitors are benzimidazole-like compounds that reversibly and competitively inhibit human DDAH 1 with Ligand Efficiency values >=0.3 kcal/mol/heavy (non-hydrogen) atom, indicating their suitability for further development. Both inhibitor scaffolds have available sites to derivatize for further optimization. Therefore, use of this fragment-based HTS approach is demonstrated to successfully identify two novel scaffolds for development of DDAH-1 inhibitors. PMID- 22921745 TI - [18F]FE@SNAP-A new PET tracer for the melanin concentrating hormone receptor 1 (MCHR1): microfluidic and vessel-based approaches. AB - Changes in the expression of the melanin concentrating hormone receptor 1 (MCHR1) are involved in a variety of pathologies, especially obesity and anxiety disorders. To monitor these pathologies in-vivo positron emission tomography (PET) is a suitable method. After the successful radiosynthesis of [(11)C]SNAP 7941-the first PET-Tracer for the MCHR1, we aimed to synthesize its [(18)F]fluoroethylated analogue: [(18)F]FE@SNAP. Therefore, microfluidic and vessel-based approaches were tested. [(18)F]fluoroethylation was conducted via various [(18)F]fluoroalkylated synthons and direct [(18)F]fluorination. Only the direct [(18)F]fluorination of a tosylated precursor using a flow-through microreactor was successful, affording [(18)F]FE@SNAP in 44.3 +/- 2.6%. PMID- 22921746 TI - Curcumin suppresses the TPA-induced invasion through inhibition of PKCalpha dependent MMP-expression in MCF-7 human breast cancer cells. AB - Curcumin (diferuloylmethane) is a polyphenol derived from the plant turmeric (Curcuma longa), which is commonly used as a spice. Although anti-carcinogenic, anti-oxidant, anti-inflammation, and anti-angiogenic properties have been reported, the effect of curcumin on breast cancer metastasis is unknown. Matrix metalloproteinase-9 (MMP-9) is a major component in cancer cell invasion. In this study, we investigated the inhibitory effect of curcumin on 12-O tetradecanoylphorbol-13-acetate (TPA)-induced MMP-9 expression and cell invasion and the molecular mechanisms involved in MCF-7 cells. Our results showed that curcumin inhibits TPA-induced MMP-9 expression and cell invasion through suppressing NF-kappaB and AP-1 activation. Also, curcumin strongly repressed the TPA-induced phosphorylation of p38 and JNK and inhibited TPA-induced translocation of PKCalpha from the cytosol to the membrane, but did not affect the translocation of PKCdelta. These results indicate that curcumin-mediated inhibition of TPA-induced MMP-9 expression and cell invasion involves the suppression of the PKCalpha, MAPK and NF-kappaB/AP-1 pathway in MCF-7 cells. Curcumin may have potential value in restricting breast cancer metastasis. PMID- 22921747 TI - Moutan cortex radicis improves lipopolysaccharide-induced acute lung injury in rats through anti-inflammation. AB - Moutan cortex radicis (MCR) is a Chinese herbal medicine that was widely used over a long period as an analgesic, antipyretic, and anti-inflammatory agent in China. Lipopolysaccharide (LPS)-induced acute lung injury (ALI) in rat models is considered similar to adult respiratory distress syndrome (ARDS) in humans. Therefore, the present study investigates the effect of MCR on ALI. The ALI model was developed through the intra-tracheal (IT) administration of LPS (16mg/kg) to Sprague-Dawley (SD) rats, which formed the LPS group. MCR was orally administered before and after LPS was introduced into rats (MCR-LPS group and LPS-MCR group, respectively). In the MCR-LPS group, rats received MCR 2g/kg/times 3 times before LPS challenge; the LPS-MCR group received MCR 2g/kg/times 3 times after LPS challenge. The results of this experiment indicate that the number of total cells and neutrophils and the concentration of protein exudation in bronchoalveolar lavage fluid (BALF) significantly decreased in the MCR-LPS group. Cytokine levels, including levels of interleukin (IL)-1beta, macrophage-inflammatory peptide (MIP)-2, IL-6, and IL-10, in BALF were also significantly inhibited at 16h after LPS administration in the MCR-LPS group. Myeloperoxidase (MPO) activity in lung tissue was reduced in the MCR-LPS and LPS-MCR groups at 16h after LPS administration. Furthermore, leukocyte infiltration and protein exudation in the alveolar space were less severe in the MCR-LPS group than in the LPS group. Therefore, the findings of this study suggest that the administration of MCR prior to LPS improves ALI, possibly mediating ALI through anti-inflammation. PMID- 22921748 TI - Chemical composition of three Parmelia lichens and antioxidant, antimicrobial and cytotoxic activities of some their major metabolites. AB - The aim of this study is to investigate chemical composition of acetone extracts of the lichens Parmelia caperata, P. saxatilis and P. sulcata and antioxidant, antimicrobial and anticancer activities of some their major metabolites. The phytochemical analysis of acetone extracts of three Parmelia lichens were determined by HPLC-UV method. The predominant phenolic compounds in these extracts were protocetraric and usnic acids (P. caperata) and depsidone salazinic acid (other two species). Besides these compounds, atranorin and chloroatranorin, were also detected in some of these extracts. Antioxidant activity of their isolated metabolites was evaluated by free radical scavenging, superoxide anion radical scavenging and reducing power. As a result of the study salazinic acid had stronger antioxidant activity than protocetraric acid. The antimicrobial activity was estimated by determination of the minimal inhibitory concentration by the broth microdilution method. Both compounds were highly active with minimum inhibitory concentration values ranging from 0.015 to 1mg/ml. Anticancer activity was tested against FemX (human melanoma) and LS174 (human colon carcinoma) cell lines using MTT method. Salazinic acid and protocetraric acid were found to be strong anticancer activity toward both cell lines with IC(50) values ranging from 35.67 to 60.18MUg/ml. The present study shows that tested lichen compounds demonstrated a strong antioxidant, antimicrobial, and anticancer effects. That suggest that these lichens can be used as new sources of the natural antimicrobial agents, antioxidants and anticancer compounds. PMID- 22921749 TI - Wound healing activity of ent-kaura-9(11),16-dien-19-oic acid isolated from Wedelia trilobata (L.) leaves. AB - Wedelia trilobata (L.) Hitchc (Asteraceae) has been used in traditional medicine in the Caribbean and Central America for stubborn wounds, sores, swelling, arthritic painful joints. The present study was carried out to derive bioactive compounds from ethanolic extracts of W. trilobata (L.) leaves that could influence wound healing. W. trilobata leaves extract were subjected to bioassay guided fractionation. The five fractions (WEA1-A, B, C, D, and E) obtained were tested for antimicrobial activity. Out of the five fractions only the fraction (WEA1-B) containing ent-kaura-9(11),16-dien-19-oic acid showed promising antibacterial activity with MIC value of 15.62MUg/ml against S. aureus and 7.81MUg/ml against S. epidermidis. It was then further assessed for its possible activity on fibroblasts by measuring their percentage cell viability and on oxidative stress induced by hydrogen peroxide. WEA1-B (2.5-0.08MUg/ml) produced an increase in the percentage viability of mouse fibroblast L929 cells from 97 to 117% and protection of the fibroblast L929 cells against oxidative stress induced by hydrogen peroxide (94-80%). The present study provides some scientific evidence for the traditional use of W. trilobata in the management of wound healing due to a combination of antimicrobial, stimulation of fibroblast growth and protection of the cells from hydrogen peroxide-induced injury, all of which could play some role in its effect on tissue repair. PMID- 22921750 TI - Metastatic spread to the mandibular condyle as initial clinical presentation: radiographic diagnosis and surgical experience. AB - PURPOSE: Metastatic spread to the mandibular condyle is uncommon. The authors retrospectively evaluated a series of consecutive cases of condylar metastases presenting as the initial clinical event to increase awareness and provide a better understanding of this occurrence. PATIENTS AND METHODS: This study consisted of 6 cases of metastatic tumor of the mandibular condyle presenting as the initial clinical event from July 2004 to May 2011. Primary sites included the bladder, prostate, lung, penis, colon, and breast. In 3 cases, positron emission tomographic/computed tomographic scans were performed to detect the primary lesions, which stayed occult at presentation. Surgical removal of the metastatic condylar lesions was performed in 3 patients, and palliative therapy was provided to all patients except a patient with a solitary metastasis. RESULTS: Five patients developed disseminated systemic metastases and died within 12 months. Only the patient with a solitary metastasis stayed alive, without any sign or symptom of tumor recurrence or metastasis at the most recent follow-up visit. CONCLUSIONS: For adult patients without a history of cancer, metastasis should be taken into consideration when the mandibular condyle is irregularly disrupted. Positron emission tomography/computed tomography is effective for detecting occult malignant lesions, whereas surgery might be indicated only for a solitary condylar metastasis. PMID- 22921751 TI - Versatility of supraclavicular artery island flap in head and neck reconstruction of vessel-depleted and difficult necks. AB - PURPOSE: The advent of microvascular free tissue transfer has given reconstructive surgeons a vast repertoire of treatment options for reconstruction of head and neck defects. However, the success of free flaps in head and neck reconstruction depends on the presence and quality of the recipient vessels in the neck for microvascular anastomosis. The supraclavicular artery island flap can be used to reconstruct a variety of head and neck defects, allowing the reconstructive surgeons to circumvent some of the problems inherent in vessel depleted necks. The present study reports the use of the supraclavicular artery flap (SCAF) in the reconstruction of vessel-depleted neck and in difficult necks. MATERIALS AND METHODS: The present study was a retrospective study of patients who had undergone reconstruction with an SCAF and who also had a difficult neck or vessel-depleted neck in the head and neck surgery section from 2011 to 2012. Our inclusion criteria were patients treated at our institution with an SCAF who also had undergone multiple previous neck surgeries or patients with severely restricted donor options for soft tissue reconstruction. We excluded any patient for whom we did not have adequate follow-up or if the flap procedure was not performed by the faculty of the head and neck section. RESULTS: We identified 8 patients with a total of 9 SCAFs. One patient received bilateral SCAFs. Of the 8 patients, 6 were men and 2 were women. With the exception of 1 patient, all had received previous radiotherapy to the head and neck region. All the patients had undergone multiple surgical procedures. The flap survival was 100%. However, 2 patients had partial loss of the flap, and 2 had partial donor site wound dehiscence. Our overall complication rate was 38%, including dehiscence of the flap and partial loss of the flap. CONCLUSIONS: The SCAF is a sound option for reconstructing defects in the head and neck region in patients with previous radiotherapy and in multiple neck surgeries. The surgeon and patient should be aware of the high incidence of complications associated with this reconstructive option. PMID- 22921752 TI - Long-term follow-up of severely resorbed mandibles reconstructed using tent pole technique without platelet-rich plasma. AB - PURPOSE: To investigate the results of edentulous patients with severely resorbed mandibles who were treated with a modified tent pole procedure. PATIENTS AND METHODS: Twenty-two edentulous patients (3 men, 19 women; mean age, 62 yr; range, 51 to 72 yr) with a history of conservative prosthodontic treatment failures were included this study. Using a transcutaneous submental approach, 4 endosseous dental implants were placed in the anterior mandible of each patient and covered with autogenous bone grafts harvested from the posterior iliac crest without the addition of platelet-rich plasma. Follow-up ranged from 3 to 9 years. RESULTS: The postoperative course of the patients was uneventful, without any surgical infections. At 3 months postoperatively, the density of the grafted bone appeared to closely resemble that of the surrounding alveolar bone on panoramic radiographs. The average alveolar augmentation was 6.3 mm (standard deviation, 1.59 mm; range, 4 to 10 mm) and long-term follow-up showed no bone resorption around the endosseous implants. CONCLUSIONS: The modified tent pole technique without the addition of platelet-rich plasma is a safe and effective method to reconstruct the severely resorbed mandible. PMID- 22921753 TI - Follicular variant of papillary carcinoma arising from lingual thyroid with orthotopic hypoplasia of thyroid lobes. PMID- 22921754 TI - Application of acellular dermal matrix in reconstruction of oral mucosal defects in 36 cases. AB - PURPOSE: Artificial grafts have been investigated for use in the repair of oral mucosal defects. The aim of this retrospective study was to present the outcomes of the use of acellular dermal matrix (ADM) grafts to repair oral mucosal defects. MATERIALS AND METHODS: Data from 36 patients with oral mucosal defects reconstructed with ADM grafts from 2003 through 2009 were reviewed. All patients were followed-up for at least 6 months to observe the graft repair, wound-healing time, contracture, color, infection, pain, immunologic reaction, texture of the graft, and clinical course. Graft success was defined as the ADM graft being replaced by new mucosa-like tissue and the oral mucosal defect being covered with the new mucosa-like tissue. Any evidence of incomplete graft re-epithelialization or graft sloughing was considered a graft failure (complete or incomplete). RESULTS: Of the 36 cases, 34 grafts (94.4%) were successfully replaced with new mucosa-like tissues and only 2 grafts (5.6%) failed. No complaints such as pain, immunologic reaction, or infection were observed during the follow-up. Mild graft contraction occurred in 7 patients with lip or buccal defects, especially at approximately 3 to 5 weeks after the reconstructive surgery. CONCLUSIONS: The ADM grafts for oral mucosal defects were safe and effective. The present data support the clinical application of ADM grafts in reconstructing oral mucosal defects caused by various oral diseases. PMID- 22921755 TI - Towards the miniaturization of GPCR-based live-cell screening assays. AB - G protein-coupled receptors (GPCRs) play a key role in many physiological or disease-related processes and for this reason are favorite targets of the pharmaceutical industry. Although ~30% of marketed drugs target GPCRs, their potential remains largely untapped. The discovery of new leads calls for the screening of thousands of compounds with high-throughput cell-based assays. Although microtiter plate-based high-throughput screening platforms are well established, microarray and microfluidic technologies hold potential for miniaturization, automation, and biosensor integration that may well redefine the format of GPCR screening assays. This paper reviews the latest research efforts directed to bringing microarray and microfluidic technologies into the realm of GPCR-based, live-cell screening assays. PMID- 22921756 TI - Escherichia coli for biofuel production: bridging the gap from promise to practice. AB - The anticipated shift of biofuel feedstocks from maize to lignocellulose presents challenges in developing effective biomass pretreatment approaches, which impacts the selection and capabilities of fuel-producing organisms. For a viable biofuel production process, the ideal fuel-producing organism must be able to efficiently convert a variety of sugars to fuels anaerobically at near-theoretical yields, resist inhibitors generated by biomass pretreatment and exhibit low product toxicity. Escherichia coli finds extensive use as a model system, but has not been widely used as an industrial host. This review highlights recent advances in metabolic engineering of biofuel-synthesis pathways in E. coli and summarizes insights gained into regulation of those pathways, and describes progress toward overcoming the challenges facing its adoption as a biofuel-production strain. PMID- 22921757 TI - Oligomeric state study of prokaryotic rhomboid proteases. AB - Rhomboid peptidases (proteases) play key roles in signaling events at the membrane bilayer. Understanding the regulation of rhomboid function is crucial for insight into its mechanism of action. Here we examine the oligomeric state of three different rhomboid proteases. We subjected Haemophilus influenzae, (hiGlpG), Escherichia coli GlpG (ecGlpG) and Bacillus subtilis (YqgP) to sedimentation equilibrium analysis in detergent-solubilized dodecylmaltoside (DDM) solution. For hiGlpG and ecGlpG, rhomboids consisting of the core 6 transmembrane domains without and with soluble domains respectively, and YqgP, predicted to have 7 transmembrane domains with larger soluble domains at the termini, the predominant species was dimeric with low amounts of monomer and tetramers observed. To examine the effect of the membrane domain alone on oligomeric state of rhomboid, hiGlpG, the simplest form from the rhomboid class of intramembrane proteases representing the canonical rhomboid core of six transmembrane domains, was studied further. Using gel filtration and crosslinking we demonstrate that hiGlpG is dimeric and functional in DDM detergent solution. More importantly co-immunoprecipitation studies demonstrate that the dimer is present in the lipid bilayer suggesting a physiological dimer. Overall these results indicate that rhomboids form oligomers which are facilitated by the membrane domain. For hiGlpG we have shown that these oligomers exist in the lipid bilayer. This is the first detailed oligomeric state characterization of the rhomboid family of peptidases. PMID- 22921758 TI - Differential mode of attack on membrane phospholipids by an acidic phospholipase A2 (RVVA-PLA2-I) from Daboia russelli venom. AB - An acidic phospholipase A2 (RVVA-PLA2-I) purified from Daboia russelli venom demonstrated dose-dependent catalytic, mitochondrial and erythrocyte membrane damaging activities. RVVA-PLA2-I was non-lethal to mice at the tested dose, however, it affected the different organs of mice particularly the liver and cardiac tissues as deduced from the enzymatic activities measured in mice serum after injection of this PLA2 enzyme. RVVA-PLA2-I preferentially hydrolyzed phospholipids (phosphatidylcholine) of erythrocyte membrane compared to the liver mitochondrial membrane. Interestingly, RVVA-PLA2-I failed to hydrolyze membrane phospholipids of HT-29 (colon adenocarcinoma) cells, which contain an abundance of phosphatidylcholine in its outer membrane, within 24h of incubation. The gas chromatographic (GC) analysis of saturated/unsaturated fatty acids' release patterns from intact mitochondrial and erythrocyte membranes after the addition of RVVA-PLA2-I showed a distinctly different result. The results are certainly a reflection of differences in the outer membrane phospholipid composition of tested membranes owing to which they are hydrolyzed by the venom PLA2s to a different extent. The chemical modification of essential amino acids present in the active site, neutralization study with polyvalent antivenom and heat inactivation of RVVA-PLA2-I suggested the correlation between catalytic and membrane damaging activities of this PLA2 enzyme. Our study advocates that the presence of a large number of PLA2-sensitive phospholipid domains/composition, rather than only the phosphatidylcholine (PC) content of that particular membrane may determine the extent of membrane damage by a particular venom PLA2 enzyme. PMID- 22921759 TI - The number and position of N-linked glycosylation sites in the hemagglutinin determine differential recognition of seasonal and 2009 pandemic H1N1 influenza virus by porcine surfactant protein D. AB - C-type lectins are important molecules of the innate immune system. These molecules, like surfactant protein D (SP-D) can recognize glycans on pathogens and neutralize these. Also influenza viruses are recognized by SP-D and their susceptibility to neutralization by SP-D is dependent on the number of N-linked glycosylation sites in the hemagglutinin in particular. Porcine SP-D displayed stronger neutralizing activity to human influenza A viruses than to swine influenza A viruses. Although viruses from these species differ with regard to the number of glycosylation sites in the hemagglutinin, the mechanism underlying the differential recognition by porcine SP-D is poorly understood. Here we investigated the molecular basis for the differential recognition of a seasonal H1N1 and a 2009 pandemic H1N1 virus by porcine SP-D. We demonstrated that the number and position of glycosylation sites determine viral susceptibility to the neutralizing activity of porcine SP-D. However, predicting the effect remains difficult as it was shown to be dependent on the strain and the position of the glycosylation sites. PMID- 22921760 TI - Citrus psorosis and Mirafiori lettuce big-vein ophiovirus coat proteins localize to the cytoplasm and self interact in vivo. AB - Citrus psorosis (CPsV) and Mirafiori lettuce big-vein virus (MiLBVV) belong to the family Ophioviridae, plant viruses with filamentous nucleocapsids and segmented genomes of negative polarity, causing the worldwide distributed citrus psorosis and lettuce big-vein diseases, respectively. To gain insight into the replication cycle of these viruses, the subcellular localization of the viral coat proteins (CP) was studied. Immunoblot analysis of fractionated extracts derived from natural and experimental infected hosts indicated that the CP of CPsV occurs in the soluble cytoplasmic fraction. The cytoplasmic localization of this protein was confirmed by confocal microscopy of fluorescent protein (FP) tagged CP following its expression in either CPsV-infected and healthy Citrus sinensis plants or in Nicotiana benthamiana plants. The same localization was observed for FP-tagged CP of MiLBVV. The CPs of CPsV and MiLBBV can undergo homologous and heterologous interactions as revealed by fluorescent lifetime imaging microscopy and co-immunoprecipitation analysis. A putative leucine zipper motif that is conserved among ophiovirus CP sequences may account for these interactions. PMID- 22921761 TI - Isolation of alveolar plates from Coleps hirtus. AB - In the ciliate Coleps hirtus, the alveoli contain rigid alveolar plates that are almost unstudied so far. Neither the exact composition nor the genesis and function are known. A necessary step to study the alveolar plates is to isolate these structures in an adequate amount. Therefore, culture conditions of C. hirtus were optimized to obtain an axenic and dense long-time culture. The protocol we developed to isolate C. hirtus alveolar plates is presented and clean alveolar plates were documented via scanning electron microscopy. The described procedure delivers alveolar plates of very good structure and integrity with preserved filigree details in sufficient amount. They can be analysed via a range of different material and biological characterisations. Since there are indications of a mineral phase within the alveolar plates, the presented results will allow to study C. hirtus alveolar plates also in the context of biomineralisation. PMID- 22921762 TI - A redescription of the oxytrichid Tetmemena pustulata (Muller, 1786) Eigner, 1999 and notes on morphogenesis in the marine urostylid Metaurostylopsis salina Lei et al., 2005 (Ciliophora, Hypotrichia). AB - Two hypotrichous ciliates from China were investigated. The common oxytrichid species Tetmemena pustulata (Muller, 1786) Eigner, 1999, isolated from the estuary of the Pearl River in southern China, was investigated with emphasis on its living morphology and infraciliature. Tetmemena pustulata is characterized as follows: body elliptical to obovoid in shape; 75-115 * 40-60 MUm in vivo; two macronuclear nodules and two micronuclei; one contractile vacuole left of midline and somewhat ahead of midbody positioned; three frontal, four frontoventral, one buccal, three postoral ventral, two pretransverse ventral and five transverse cirri; cirrus III/2 ahead of level of cirrus IV/3; cirrus IV/2 arranged more anteriorly than cirrus V/4; transverse cirri not forming two distinct groups; three prolonged and widely separated caudal cirri; six dorsal kineties in Oxytricha-pattern with dorsal kineties 3 and 4 bipolar. The marine urostylid species Metaurostylopsis salina Li et al., 2005, isolated from an aquarium in Qingdao, northern China, was investigated with emphasis on its morphogenesis which is characterized by the de novo formation of the oral primordium in the proter and the development of the marginal rows from two anlagen that form within each parental structure separately in both dividers. PMID- 22921763 TI - Differences in kinetic variables between injured and noninjured novice runners: a prospective cohort study. AB - OBJECTIVES: This prospective study examined differences in kinetic variables between injured and noninjured novice female and male runners and their potential contribution to RRIs. DESIGN: A prospective cohort study. METHODS: At baseline vertical ground reaction forces were assessed with an instrumented treadmill equipped with three force measuring transducers. Female participants ran at 8 and 9kmh(-1) and male runners ran at 9 and 10kmh(-1). Primary outcome measure was a running related injury (RRI). Participants were novice female and male recreational runners and were followed during a 9-week running program with three running sessions a week. RESULTS: One hundred thirty three female and seventy seven male runners participated in this study. Mean age was 37.2years and the BMI was 23.9kgm(-2). During the nine week running program 16.2% of the participants sustained an injury and no difference in incidence between female and male runners was seen. In injured male runners loading rate was significantly higher compared to noninjured male runners at both running speeds and contact time in the injured male group was significantly shorter at 9kmh(-1). In the group of female injured and noninjured runners no differences on kinetic or spatio temporal variables were observed. Female runners had significantly higher loading rates compared to male runners but this did not have an effect on the incidence of RRIs. CONCLUSIONS: This study showed that male injured runners had higher loading rates and shorter contact times than noninjured male runners. In female runners, however, no differences in kinetic or spatio-temporal variables were observed between injured and noninjured novice runners. PMID- 22921764 TI - Duodenal haemosiderosis using narrow-band imaging. PMID- 22921765 TI - Effectiveness of deep transcranial magnetic stimulation combined with a brief exposure procedure in post-traumatic stress disorder--a pilot study. AB - BACKGROUND: Post-traumatic stress disorder (PTSD) is a debilitating anxiety disorder induced by traumatic experiences. To date, psychotherapy and drug treatment achieve only partial success, indicating need for further development of treatment strategies. Recent research has found that impaired acquired fear extinction capability serves as an important factor at the pathogenesis of the disorder. Medial prefrontal cortex (mPFC) hypo-activity has been implicated in this extinction impairment, providing insight as to why some trauma exposed individuals will develop PTSD. OBJECTIVE: To test whether fear extinction can be facilitated and therapeutic effect achieved by repeated mPFC deep transcranial magnetic stimulation (DTMS) of PTSD patients resistant to standard treatment. METHODS: In a double-blind study, 30 PTSD patients were enrolled and randomly assigned into 3 treatment groups: A) DTMS after brief exposure to the traumatic event with the script-driven imagery procedure; B) DTMS after brief exposure to a non-traumatic event; C) sham stimulation after brief exposure to the traumatic event. RESULTS: Significant improvement was demonstrated in the intrusive component of the CAPS scale in patients administered DTMS after exposure to the traumatic event script, while patients in the control groups showed no significant improvement. Similar trend was demonstrated in the Total-CAPS score as in the other rating scales. A significant reduction in the HR response to the traumatic script was evident in group A, further supporting the above results. CONCLUSIONS: Combining brief script-driven exposure with DTMS can induce therapeutic effects in PTSD patients. A wide multi-center study is suggested to substantiate these findings. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00517400. PMID- 22921767 TI - Repeated cocaine administration in marmoset monkeys induces hypervigilance related behaviors, but no changes in locomotion and cortisol levels. AB - Although cocaine induces several behavioral and hormonal effects, little is known about non-contingent repeated administrations in non-human primates. Therefore, we analyzed behavioral (locomotion, vigilance) and hormonal (cortisol) responses of adult black tufted-ear marmosets during repeated administrations and withdrawal trials. The subjects were divided into two groups (saline or cocaine 5mg/kg, ip) and submitted to nine treatment trials and four withdrawal trials in the absence of any treatment in an open-field arena. Blood samples were obtained on five different time points of the procedure to evaluate the effects of repeated cocaine treatment on basal cortisol levels. Cocaine repeatedly administered to drug-naive marmosets induced a slow-onset hypervigilance effect (i.e., scan - long-lasting sweeping movements of the head directed at the environment; and glance - single rapid movement of the head directed at the environment), with no concomitant change in locomotion. Treatment cessation during withdrawal immediately reversed the cocaine-induced hypervigilance effect. Cortisol levels remained constant throughout the procedure. Therefore, marmosets seem to have a similar behavioral - but not hormonal - response as humans and other nonhuman primates repeatedly injected with cocaine, but differ from rats in their absence of hyperlocomotor activity. The development of hypervigilance with repeated application may constitute a unique measure to assess cocaine-induced changes in behavior in the marmoset and other nonhuman primates. PMID- 22921766 TI - CDKL5, a novel MYCN-repressed gene, blocks cell cycle and promotes differentiation of neuronal cells. AB - Mutations in the CDKL5 (cyclin-dependent kinase-like 5) gene are associated with a severe epileptic encephalopathy (early infantile epileptic encephalopathy type 2, EIEE2) characterized by early-onset intractable seizures, infantile spasms, severe developmental delay, intellectual disability, and Rett syndrome (RTT)-like features. Despite the clear involvement of CDKL5 mutations in intellectual disability, the function of this protein during brain development and the molecular mechanisms involved in its regulation are still unknown. Using human neuroblastoma cells as a model system we found that an increase in CDKL5 expression caused an arrest of the cell cycle in the G(0)/G(1) phases and induced cellular differentiation. Interestingly, CDKL5 expression was inhibited by MYCN, a transcription factor that promotes cell proliferation during brain development and plays a relevant role in neuroblastoma biology. Through a combination of different and complementary molecular and cellular approaches we could show that MYCN acts as a direct repressor of the CDKL5 promoter. Overall our findings unveil a functional axis between MYCN and CDKL5 governing both neuron proliferation rate and differentiation. The fact that CDKL5 is involved in the control of both neuron proliferation and differentiation may help understand the early appearance of neurological symptoms in patients with mutations in CDKL5. PMID- 22921769 TI - The CB2-preferring agonist JWH015 also potently and efficaciously activates CB1 in autaptic hippocampal neurons. AB - The G protein coupled receptors CB(1) and CB(2) are targets for the psychoactive constituents of cannabis, chief among them Delta(9)-THC. They are also key components of the multifunctional endogenous cannabinoid signaling system. CB(1) and CB(2) receptors modulate a wide variety of physiological systems including analgesia, memory, mood, reward, appetite and immunity. Identification and characterization of selective CB(1) and CB(2) receptor agonists and antagonists will facilitate understanding the precise physiological and pathophysiological roles of cannabinoid receptors in these systems. This is particularly necessary in the case of CB(2) because these receptors are sparsely expressed and problematic to detect using traditional immunocytochemical approaches. 1-Propyl-2 methyl-3-(1-naphthoyl)indole (JWH015) is an aminoalkylindole that has been employed as a "CB(2)-selective" agonist in more than 40 published papers. However, we have found that JWH015 potently and efficaciously activates CB(1) receptors in neurons. Using murine autaptic hippocampal neurons, which express CB(1), but not CB(2) receptors, we find that JWH015 inhibits excitatory postsynaptic currents with an EC50 of 216nM. JWH015 inhibition is absent in neurons from CB(1)(-/-) cultures and is reversed by the CB(1) antagonist, SR141716 [200nM]. Furthermore, JWH015 partially occludes CB(1)-mediated DSE (~35% remaining), an action reversed by the CB(2) antagonist, AM630 [1 and 3MUM], suggesting that high concentrations of AM630 also antagonize CB(1) receptors. We conclude that while JWH015 is a CB(2)-preferring agonist, it also activates CB(1) receptors at experimentally encountered concentrations. Thus, CB(1) agonism of JWH015 needs to be considered in the design and interpretation of experiments that use JWH015 to probe CB(2)-signaling. PMID- 22921768 TI - Acute illness-induced behavioral alterations are similar to those observed during withdrawal from acute alcohol exposure. AB - Exposure to an immunogen results in a constellation of behavioral changes collectively referred to as "sickness behaviors," with alterations in cytokine expression previously shown to contribute to this sickness response. Since behaviors observed during ethanol withdrawal are strikingly similar to sickness behaviors, we hypothesized that behavioral manifestations of ethanol withdrawal might be an expression of sickness behaviors induced by ethanol-related changes in peripheral and/or central cytokine expression. Accordingly, behaviors exhibited during a modified social investigation test were first characterized in male rats following an acute injection of lipopolysaccharide (LPS; 100MUg/kg). Subsequently, behavioral changes after either a high (4-g/kg; Experiment 2) or low dose (0.5g/kg; Experiment 3) of ethanol were also examined in the same social investigation test, as well as in the forced-swim test (FST; Experiment 4). Results from these experiments demonstrated similar reductions in both exploration and social investigatory behavior during acute illness and ethanol withdrawal, while a seemingly paradoxical decrease in immobility was observed in the FST during acute ethanol withdrawal. In follow-up studies, neither indomethacin (Experiment 5) nor interleukin-1 receptor antagonist (Experiment 6) pre-exposure reversed the ethanol withdrawal-induced behavioral changes observed in this social investigation test. Taken together, these studies demonstrate that the behavioral sequelae of acute illness and ethanol withdrawal are similar in nature, while antagonist studies suggest that these behavioral alterations are not reversed by blockade of IL-1 receptors or inhibition of prostaglandin synthesis. Though a direct mechanistic link between cytokines and the expression of acute ethanol withdrawal-related behaviors has yet to be found, future studies examining the involvement of brain cytokines as potential mediators of ethanol effects are greatly needed. PMID- 22921770 TI - Estimation of bone strength parameters and response to treatment using peripheral quantitative computed tomography. PMID- 22921771 TI - Total body DXA: on the cusp of clinical care. PMID- 22921773 TI - Is osteoporosis an obesity paradox? PMID- 22921774 TI - Do we need to fine-tune the Spanish version of the FRAX predictive tool? PMID- 22921775 TI - Vertebral fracture assessment: is lateral spine imaging in the supine or decubitus position better? PMID- 22921776 TI - Simultaneous measurement of adenosine, dopamine, acetylcholine and 5 hydroxytryptamine in cerebral mice microdialysis samples by LC-ESI-MS/MS. AB - A rapid and sensitive liquid chromatography/tandem mass spectrometry (LC-MS/MS) method has been developed for the simultaneous measurement of adenosine (ADE), dopamine (DA), acetylcholine (ACh) and 5-hydroxytryptamine (5-HT) in mouse brain microdialysates. High method sensitivity (LLOQ of 0.05nM) was achieved by optimization of chromatographic and mass spectrometric parameters. The method was fully validated for its sensitivity, selectivity, matrix effect and stability. The LC-MS/MS method was successfully applied to evaluate the effect of the systemic administration of cocaine or amphetamine on the extracellular levels of ADE, DA, ACh and 5-HT in the mouse nucleus accumbens by microdialysis. PMID- 22921777 TI - Hearing impairments among Saudi preschool children. AB - BACKGROUND: Hearing loss among school-entrant children in the developing world has been widely reported as a significant health problem. Failure to detect hearing loss, either congenital or acquired, in children may result in lifelong deficits in speech and language acquisition. The aims of this study were: (1) to estimate the prevalence of hearing loss and (2) to identify its different types. METHODS: This is a cross-sectional study that included all children (n=2574) aged 4-8 years who attended the obligatory health examination for kindergarten (=370) and primary school (n=2204) entry at the school health center of King Abdulaziz Medical City, Riyadh, Saudi Arabia, from March 2009 to December 2010. Pure-tone air conduction audiometry was conducted for each child in a sound-treated room followed by a diagnostic test. Tympanometry was performed as a complement to the overall objectives of a hearing screening program. RESULTS: A total of 45 children were diagnosed with hearing impairment (84.4% conductive and 15.6% sensori-neural), with an overall prevalence of 1.75% (95% C.I.: 1.25, 2.25). The majority of cases were females (71.1%), of school age (80.0%), with conductive deafness (84.4%). More than one-half of cases had bilateral deafness (55.6%) of mild degree (57.8%). As for conductive deafness, otitis media with effusion ranked first as a cause of deafness (34.9%), followed by wax and chronic otitis media (23.3% each), while traumatic perforated drum came last (2.3%). Sensorineural deafness constituted 16.2% of all cases. CONCLUSION: Conductive hearing loss is the primary type of hearing loss among children and is easy to correct. The urgent development of audiological services in other school health centers in the country, particularly those with good referral systems to Ministry of Health hospitals, is needed. Evidence-based guidelines to identify, monitor, and manage otitis media with effusion (OME) in children in the primary healthcare setting and a strategy to prevent hearing loss are recommended. PMID- 22921778 TI - Fractured tracheostomy tube as foreign body bronchus: our experience with three cases. AB - OBJECTIVE: Tracheostomy tubes are extensively used in paediatric age group for airway issues. Their fracture and lodgement into trachea is an acute emergency requiring urgent intervention. CASES: We report three such paediatric cases having tracheostomy tube fracture and aspiration into trachea with different presentations and treatment outcomes. RESULTS: One patient was successfully managed with bronchoscopy and fractured tube removal. One patient succumbed to asphyxia before any intervention. The third patient was having supratubal tracheal stenosis making things more dangerous, but was managed successfully by tracheoscopy through tracheostomy opening with removal of fractured tube. CONCLUSION: Immediate identification is the key to successful management of this rare but life threatening situation. In the presence of tracheal stenosis above the tracheostomy opening, situation becomes more dangerous with very limited options for management. PMID- 22921779 TI - Pediatric cochlear implantation of children with eighth nerve deficiency. AB - OBJECTIVE: To evaluate the auditory outcomes of children implanted in an ear with eighth nerve hypoplasia or aplasia and to determine whether preoperative characteristics are predictive of auditory performance achieved. METHODS: STUDY DESIGN: retrospective case review. SETTING: tertiary care medical center. PATIENTS: ten children implanted in an ear with eighth nerve hypoplasia or aplasia, as determined by high resolution magnetic resonance imaging. MAIN OUTCOME MEASURES: Neural response test measurements, detection and speech awareness thresholds, Meaningful Auditory Integration Scale scores, as well as speech perception level achieved. RESULTS: Post-implantation, three children demonstrated little to no detection of sound, three had improved detection and awareness of environmental sounds, one developed closed-set speech perception and spoken language, and three developed open-set speech perception and spoken language. No imaging findings appeared related to outcomes. Significantly better implant detection thresholds and Meaningful Auditory Integration Scale scores were found in children who had preoperative aided auditory detection (p's <= 0.02 0.05). CONCLUSION: Some children with eighth nerve hypoplasia or aplasia may derive significant benefit from a cochlear implant. In our study high resolution magnetic resonance imaging was more sensitive than high resolution computer tomography in detecting neural deficiency. However, no imaging findings were predictive of auditory performance level achieved post-implantation. PMID- 22921780 TI - A translational study of urine miRNAs in acute myocardial infarction. AB - The currently used biomarkers for acute myocardial infarction (AMI) are blood creatinine phosphokinase-muscle band (CPK-MB), troponin-T (TnT), and troponin I (TnI). However, no good biomarkers are identified in urine after AMI, because these blood protein biomarkers are difficult to be filtered into urine. In this study, the role of urine microRNAs in the diagnosis of AMI and the mechanism involved were determined. We found that urine miR-1 was quickly increased in rats after AMI with peak at 24h after AMI, in which an over 50-fold increase was demonstrated. At 7 days after AMI, the urine miR-1 level was returned to the basal level. No miR-208 was found in normal urine. In urine from rats with AMI, miR-208 was easily detected. To determine the mechanism involved, we determined the levels of heart-released miR-1 in the liver, spleen and kidney after AMI in rats and found that the kidney was an important metabolic organ. To determine the renal elimination of blood miRNAs, we isolated serum exosomes from rats after AMI and injected these exosomes into the circulating blood of normal rats. We found that the urine miR-1 was significantly increased in exosome-injected animals. Moreover, PKH67-labeled exosomes injected into circulating blood could enter into the kidney tissues and cells, as well as urine. Furthermore, the levels of urine miR-1 were significantly increased in patients with AMI. The results suggest that urine miRNAs such as miR-1 could be novel urine biomarkers for AMI. PMID- 22921781 TI - Polydatin modulates Ca(2+) handling, excitation-contraction coupling and beta adrenergic signaling in rat ventricular myocytes. AB - Polydatin (PD), a resveratrol glucoside, has recently been suggested to have cardioprotective effects against heart diseases, including ischemia-reperfusion injury and pressure-overload induced ventricular remodeling. However, the mechanisms are poorly understood. This study aims to investigate the direct effects of PD on cardiac Ca(2+) handling and excitation-contraction (EC) coupling to explore the potential role of which in PD-mediated cardioprotection. We found that micromolar PD decreased action potential-elicited Ca(2+) transient, but slightly increased cell shortening. The contradictory response could be attributed to PD increasing myofilament Ca(2+) sensitivity. Exploring the activities of the two types of Ca(2+) channels, L-type Ca(2+) channels (LCCs) and ryanodine receptors (RyRs), reveals that PD dose-dependently decreased LCC current (I(Ca)), but increased frequency of spontaneous Ca(2+) sparks, the elementary Ca(2+) releasing events reflecting RyR activity in intact cells. PD dose-dependently increased the gain of EC coupling. In contrast, PD dose dependently decreased SR Ca(2+) content. Furthermore, PD remarkably negated beta adrenergic receptor (AR) stimulation-induced enhancement of I(Ca) and Ca(2+) transients, but did not inhibit beta-AR-mediated inotropic effect. Inhibition of nitric oxide synthase (NOS) with L-NAME abolished PD regulation of I(Ca) and Ca(2+) spark rate, and significantly inhibited the alteration of Ca(2+) transient and myocyte contractility stimulated by PD. These results collectively indicate that PD modulated cardiac EC coupling mainly by inversely regulating LCC and RyR activity and increasing myofilament Ca(2+) sensitivity through increasing intracrine NO, resulting in suppression of Ca(2+) transient without compromising cardiac contractility. The unique regulation of PD on cardiac EC coupling and responsiveness to beta-AR signaling implicates that PD has potential cardioprotective effects against Ca(2+) mishandling related heart diseases. PMID- 22921782 TI - Role of brain serotonin dysfunction in the pathophysiology of congestive heart failure. AB - Inherited or non-inherited dilated cardiomyopathy (DCM) patients develop varied disease phenotypes leading to death after developing congestive heart failure (HF) or sudden death with mild or no overt HF symptoms, suggesting that environmental and/or genetic factors may modify the disease phenotype of DCM. In this study, we sought to explore unknown genetic factors affecting the disease phenotype of monogenic inherited human DCM. Knock-in mice bearing a sarcomeric protein mutation that causes DCM were created on different genetic backgrounds; BALB/c and C57Bl/6. DCM mice on the BALB/c background showed cardiac enlargement and systolic dysfunction and developed congestive HF before died. In contrast, DCM mice on the C57Bl/6 background developed no overt HF symptoms and died suddenly, although they showed considerable cardiac enlargement and systolic dysfunction. BALB/c mice have brain serotonin dysfunction due to a single nucleotide polymorphism (SNP) in tryptophan hydroxylase 2 (TPH2). Brain serotonin dysfunction plays a critical role in depression and anxiety and BALB/c mice exhibit depression- and anxiety-related behaviors. Since depression is common and associated with poor prognosis in HF patients, we examined therapeutic effects of anti-depression drug paroxetine and anti-anxiety drug buspirone that could improve the brain serotonin function in mice. Both drugs reduced cardiac enlargement and improved systolic dysfunction and symptoms of severe congestive HF in DCM mice on the BALB/c background. These results strongly suggest that genetic backgrounds involving brain serotonin dysfunction, such as TPH2 gene SNP, may play an important role in the development of congestive HF in DCM. PMID- 22921783 TI - Intelligent geocoding system to locate traffic crashes. AB - State agencies continue to face many challenges associated with new federal crash safety and highway performance monitoring requirements that use data from multiple and disparate systems across different platforms and locations. On a national level, the federal government has a long-term vision for State Departments of Transportation (DOTs) to report state route and off-state route crash data in a single network. In general, crashes occurring on state-owned or state maintained highways are a priority at the Federal and State level; therefore, state-route crashes are being geocoded by state DOTs. On the other hand, crashes occurring on off-state highway system do not always get geocoded due to limited resources and techniques. Creating and maintaining a statewide crash geographic information systems (GIS) map with state route and non-state route crashes is a complicated and expensive task. This study introduces an automatic crash mapping process, Crash-Mapping Automation Tool (C-MAT), where an algorithm translates location information from a police report crash record to a geospatial map and creates a pinpoint map for all crashes. The algorithm has approximate 83 percent mapping rate. An important application of this work is the ability to associate the mapped crash records to underlying business data, such as roadway inventory and traffic volumes. The integrated crash map is the foundation for effective and efficient crash analyzes to prevent highway crashes. PMID- 22921784 TI - Aging and the impact of distraction on an intersection crossing assist system. AB - It is known that distraction reduces the benefits of collision avoidance systems by slowing a driver's response. The current study examined the impact of a drivers' use of an in-vehicle intersection crossing assist system under demanding cognitive load conditions. Forty eight drivers crossed a busy rural intersection in a simulated environment while completing four blocks of trials, in half of which they used the assist system and engaged in a working memory task. Participants were dichotomized into older and younger age groups. The results showed a tendency towards conservative driving in a single-task condition when only using the assist system. A similar shift in driving style was observed when drivers crossed the intersection while engaged in a secondary task. Using the in vehicle intersection crossing assist system under cognitively demanding conditions did not result in adverse consequences-the impact of distraction was different compared to a typical collision avoidance system. Older drivers showed some evidence of more conservative intersection crossing, however they also appeared to rely more on the in-vehicle assist system when presented with an extraneous additional task. PMID- 22921785 TI - Mesenchymal stem cells ameliorate postpyelonephritic renal scarring in rats. AB - OBJECTIVE: To evaluate the efficiency of mesenchymal stem cells in ameliorating renal scarring in a rat pyelonephritis model. METHODS: Three groups each, including 8 Sprague-Dawley rats were formed: Group 1 = sham operated (4 were given mesenchymal stem cells); group 2 = pyelonephritis induced by Escherichia coli; and group 3 = pyelonephritis and mesenchymal stem cells. Rats not given mesenchymal stem cells in group 1 and 4 rats in groups 2 and 3 were sacrificed on the eighth day for evaluation of inflammation, and the remaining rats were sacrificed at the sixth week to determine renal scarring along with migration of mesenchymal stem cells to renal tubules and differentiation to tubular cells expressing aquaporin-1. RESULTS: Rats in group 3 had lower scores of both acute (8th day) and chronic (6th week) histopathological alterations compared with rats in group 2. By contrast, although rats in group 3 were shown to have mesenchymal stem cells expressing aquaporin-1 in their renal tubules, these cells were not detected in kidney tissue of mesenchymal stem cells-treated sham rats. CONCLUSION: These results indicate that mesenchymal stem cells migrated to renal tissues and ameliorated renal scarring in this rat model of pyelonephritis. PMID- 22921786 TI - IL-33 promotes the migration and proliferation of circulating fibrocytes from patients with allergen-exacerbated asthma. AB - The release of IL-33 increases in the bronchial mucosa of asthmatic patients in relation to disease severity and several studies have demonstrated that IL-33 may enhance airway inflammation in asthma. This study tested the hypothesis that IL 33 may also contribute to the development of irreversible structural changes in asthma by favoring the airway recruitment and profibrotic function of circulating fibrocytes during episodes of allergen-induced asthma exacerbation. The circulating fibrocytes from patients with allergen-exacerbated asthma (PwAA) showed increased expression of the specific IL-33 receptor component ST2L in comparison with the cells from non-asthmatic individuals (NAI). Recombinant IL-33 induced the migration of circulating fibrocytes from PwAA at clinically relevant concentrations and stimulated their proliferation in a concentration-dependent manner between 0.1 and 10 ng/ml, without affecting the constitutive release of type I collagen. The recombinant protein did not induce similar responses in circulating fibrocytes from NAI. This study uncovers an important mechanism through which fibrocytes may accumulate in the airways of allergic asthmatics when their disease is not adequately controlled by current treatment and provides novel information on the function of IL-33 in asthma. PMID- 22921787 TI - Cancer cell growth suppression by a 62nt AU-rich RNA from C/EBPbeta 3'UTR through competitive binding with HuR. AB - AU-rich elements are functional motifs in the 3'untranslated region of mRNA and are binding sites for the RNA binding protein HuR, an mRNA stabilizer and translation enhancer implicated in carcinogenesis. It is not clear whether, and, if so, how the AU-rich elements function in cells when they are separated from their mRNA and form an independent RNA species. Here, we show that a short RNA with AU-rich elements derived from C/EBPbeta 3'UTR suppressed growth in a human liver cancer cell line. It specifically bound HuR, and it competed with C/EBPbeta mRNA in order to bind to HuR. Our results provide evidence that the cancer cell growth suppression by this 62nt RNA containing AU-rich elements may be due to competitive binding to HuR. This work may open new options for the development of novel anti-cancer drugs. PMID- 22921788 TI - Electron microscopy of pharmaceutical systems. AB - During the last decades, the focus of research in pharmaceutical technology has steadily shifted towards the development and optimisation of nano-scale drug delivery systems. As a result, electron microscopic methods are increasingly employed for the characterisation of pharmaceutical systems such as nanoparticles and microparticles, nanoemulsions, microemulsions, solid lipid nanoparticles, different types of vesicles, nanofibres and many more. Knowledge of the basic properties of these systems is essential for an adequate microscopic analysis. Classical transmission and scanning electron microscopic techniques frequently have to be adapted for an accurate analysis of formulation morphology, especially in case of hydrated colloidal systems. Specific techniques such as environmental scanning microscopy or cryo preparation are required for their investigation. Analytical electron microscopic techniques such as electron energy-loss spectroscopy or energy-dispersive X-ray spectroscopy are additional assets to determine the elemental composition of the systems, but are not yet standard tools in pharmaceutical research. This review provides an overview of pharmaceutical systems of interest in current research and strategies for their successful electron microscopic analysis. Advantages and limitations of the different methodological approaches are discussed and recent findings of interest are presented. PMID- 22921789 TI - An ultrastructural study of the ovary cord organization and oogenesis in Erpobdella johanssoni (Annelida, Clitellata: Hirudinida). AB - The aims of the present study were to analyze the ovary cord structure and oogenesis in Erpobdella johanssoni under light, fluorescent and transmission electron microscopy and to compare the obtained results with other clitellate annelids, especially with other arhynchobdellid leeches. Each of the paired ovaries is composed of the ovary wall (ovisac) and several (7-8) short, cone shaped ovary cords. The ovary cords are of the "Erpobdella" type, i.e. they are short and polarized and five zones containing germ cells at consecutives stages of their development can be distinguished along their long axis. One, huge somatic cell (the apical cell), oogonia and premeiotic germ cells occur at the tip of the apical part of the ovary cord - zone I. Below, in zone II germ cells enter meiosis, whereas in zone III only a few cells continue meiosis and gather nutrients (oocytes), while the rest become nurse cells. In zone IV, huge vitellogenic oocytes form protuberances on the surface of the cord, and degenerating germ cells were observed at the base of the ovary cord (zones IV and V). The germline cells form syncytial cysts in zones I-III. The germline cysts have broadly the same architecture as in the ovaries of all of the clitellate annelids that have been described to date. Each germ cell in a cyst has only one cytoplasmic bridge connecting it to the common cytoplasmic mass - the cytophore. The cytophore is poorly developed, and it has the form of thin, long cytoplasmic strands. The presence of two categories of germ cells suggests a meroistic mode of oogenesis. The germline cysts are closely associated with somatic, follicular cells. There are two subpopulations of follicular cells: one envelops the growing oocytes, while the second is distributed between other germ cells. The entire ovary cord is additionally enveloped by a layer of somatic cells with a spongy appearance - the spongiosa cells. A characteristic feature of vitellogenic oocytes is the condensation of the chromosomes into a karyosome. Fully grown oocytes are excluded from the ovary cords and float freely in the ovisac lumen. PMID- 22921790 TI - Anti-neutrophil cytoplasmic autoantibodies: methodological aspects and clinical significance in systemic vasculitis. AB - Antineutrophil cytoplasmic antibodies (ANCA) are the serological hallmark of some idiopathic systemic vasculitides, such as granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA) and, to a lesser extent, Churg-Strauss syndrome (CCS), the so-called ANCA-associated vasculitides (AAV). ANCA were first detected by immunofluorescence (IIFT), subsequently the target antigens myeloperoxidase (MPO) and proteinase 3 (PR3) were identified, allowing the development of the quantitative, antigen-specific assays. According to the guidelines, combining IIFT and PR3-ANCA/MPO-ANCA assures the optimal diagnostic specificity. Antigen specificity does not effectively differentiate among the different AAV, however C ANCA/PR3-ANCA are mainly found in GPA, while P-ANCA/MPO-ANCA are more prevalent in MPA and CSS. Despite their diagnostic value, the performance of the widespread immunometric assays for ANCA testing is disappointing, particularly for the low sensitivity. In recent years, more "sensitive" assays have been developed, using the microplate as well as fully the automated technologies, with promising preliminary results. ANCA, may be detected in a number of pathological conditions other than small vessel vasculitis. However, in most of these non-vasculitic patients ANCA do not recognize MPO or PR3 as target antigens, but other granulocyte components, often multiple or unknown specificities. A positive ANCA result by itself is not diagnostic for AAV, clinical evidence and possibly histological confirmation are always required. On the other hand, a negative test result cannot completely rule out a diagnosis of AAV, as AAV without detectable ANCA exist. The appropriate use of ANCA testing strongly improves the diagnostic accuracy and clinical usefulness of the results. PMID- 22921791 TI - Renal involvement in anti-neutrophil cytoplasmic autoantibody associated vasculitis. AB - Renal involvement is a common and often severe complication of anti-neutrophil cytoplasmic autoantibody (ANCA) associated vasculitides (AAV). With the exception of Churg-Strauss syndrome (CSS), where kidney involvement is not a prominent feature, renal disease is present in about 70% of patients with Wegener's granulomatosis, now called granulomatosis with polyangiitis (GPA) and in almost 100% of patients with microscopic polyangiitis (MPA). Kidney involvement is generally characterized by a pauci-immune necrotizing and crescentic glomerulonephritis with a very rapid decline of renal function (rapidly progressive glomerulonephritis). Even though there are not qualitative differences in glomerular lesions in patients with GPA or with MPA, chronic damage is significantly higher in MPA (and/or P-ANCA positive patients) than in GPA (and/or C-ANCA positive patients). If untreated necrotizing and crescentic glomerulonephritis has an unfavorable course leading in a few weeks or months to end stage renal disease. Serum creatinine at diagnosis, sclerotic lesions and the number of normal glomeruli at kidney biopsy are the best predictors of renal outcome. Corticosteroids and cyclophosphamide (with the addition of plasma exchange in the most severe cases) are the cornerstone of induction treatment of ANCA-associated renal vasculitis, followed by azathioprine for maintenance. Rituximab is as effective as cyclophosphamide in inducing remission in AAV and probably superior to cyclophosphamide in patients with severe flare, and could be preferred in younger patients in order to preserve fertility and in patients with serious relapses. PMID- 22921792 TI - Treatment of ANCA-associated vasculitides (AAV). AB - Treatment of AAV follows the principle of a combined remission induction and maintenance strategy and is adapted in a stage and activity-adapted fashion. So far the combination therapy of glucocorticoids and conventional immunosuppressive drugs has mainly been used to control disease. This approach has led to a significant improvement in outcome in spite of persistently high early mortality rates of nearly 11% within the first year. Besides conventional treatment, biologics have emerged as a new treatment option. The paper summarizes the current evidence for the use of conventional therapy and biologics in AAV. PMID- 22921793 TI - Advancing toxicology in RiskMAPP: setting ADEs based on the subsequent drug substance. AB - Cleaning validation programs are developed to demonstrate acceptable carryover of drug substances/products when multiple drug substances are manufactured in shared process equipment. The International Society of Pharmaceutical Engineers (ISPE) developed a guidance document in 2010 describing the Risk-Based Manufacture of Pharmaceutical Products (referred to as RiskMAPP) (ISPE, 2010). This guidance document developed the concept of an acceptable daily exposure (ADE), which is the toxicologically acceptable daily dose for the first drug substance used in processing drug equipment (DS(A)) without prior knowledge of the subsequent drug substance (DS(B)). This paper discusses an extension of the ADE methodology called the product-specific ADE (PSADE) which is derived when DS(B) is known. Four case studies demonstrate examples in which the PSADE can be scientifically supported in lieu of the ADE and highlight some limitations in its application. The PSADE approach can be used to justify higher acceptance limits for cleaning validation when the ADE based acceptance limits are below the process capability limit of the cleaning process or limit of quantitation of the analytical method. PMID- 22921794 TI - Biosynthesis of eoxin C4 by porcine leukocytes. AB - Human 15-lipoxygenase-1 (LO) possesses mainly 15-lipoxygenase activity whereas the animal ortholog 12/15-LO possesses mainly 12-lipoxygenase activity. These findings have raised the question if studies on animals can predict the function of 15-LO-1 in human. In this study we have characterized the arachidonic acid metabolites formed by porcine 12/15-LO. Mini pigs were infected with a parasite to increase the number of blood eosinophils, which highly express 12/15-LO. Isolated porcine polymorphonuclear leukocytes (PMNL) were incubated with arachidonic acid and the produced metabolites were analysed with HPLC and mass spectrometry (MS). The cells were found to produce 15-hydroxyeicosatetraenoic acid (HETE) and 12-HETE at a ratio of 1:5. Furthermore 8,15 dihydroxyeicosatetraenoic acids (DiHETEs) and 14,15-DiHETE were formed. Based on HPLC, UV-spectroscopy and MS analysis it was found that porcine PMNL also produced eoxin (EX) C4. These results demonstrate that although porcine 12/15-LO possesses primarily 12-lipoxygenase activity, the enzyme can catalyse the formation of EXC(4). PMID- 22921795 TI - Analysis of patient claims data to determine the prevalence of hidradenitis suppurativa in the United States. AB - BACKGROUND: Recent prevalence estimates for hidradenitis suppurativa (HS), a chronic inflammatory skin condition, are limited by timeliness, population size, and generalizability. OBJECTIVE: We sought to develop prevalence estimates for HS in the United States using large health care claims databases. METHODS: A retrospective analysis used PharMetrics Integrated Database to gather health care claims information for HS among patients with 12 or more months of continuous enrollment in a commercial health care plan throughout 2007. Included patients had: 1 or more diagnoses with International Classification of Diseases, Ninth Revision, Clinical Modification code 705.83 for HS during 2007 without a Current Procedural Terminology code for HS; 1 or more Current Procedural Terminology codes of 11450, 11451, 11462, 11463, 11470, or 11471 during 2007 without International Classification of Diseases, Ninth Revision, Clinical Modification code 705.83; or both. Age- and gender-specific prevalence projections were calculated. RESULTS: Among included patients (n = 7927), mean age (SD) was 38.2 (14.73) years, and 5834 (74%) were women. Most patients (n = 5205; 66%) were aged 30 to 64 years. The overall prevalence estimate was 0.053% (95% confidence interval 0.051-0.054). When adjusted for gender and age, prevalence rates were 0.052% and 0.051%, respectively. The most common procedures for HS were excision of skin and subcutaneous tissue axillary/inguinal simple or intermediate repair. LIMITATIONS: Limitations were a health insured-only population; 12-month enrollment period for 2007; HS-specific procedural codes; and possible HS misclassifications. CONCLUSION: We found a low rate of clinically detected HS (0.053%; approximately 146,000-162,000 patients in the United States in 2007), with affected persons almost 3 times as likely to be female and the highest prevalence in those aged 18 to 44 years. PMID- 22921796 TI - Increased psychosocial stress in Greek-born immigrants compared to Anglo Australians with coronary heart disease: the healthy heart, healthy mind study. AB - OBJECTIVE: To compare measures of depression and anxiety, physical health status, quality of life, and social support in Greek-born and Anglo-Australian outpatients with coronary heart disease (CHD). METHODS: A cross-sectional study of 61 Greek-born immigrants and 62 Anglo-Australian outpatients with CHD recruited between 2009 and 2011 was undertaken. We administered the Beck Depression Inventory-2 and the Cardiac Depression Scale, the State Trait Anxiety Inventory, the SF-12, the World Health Organisation Quality of Life (brief version), and the Perceived Social Support Scale and Social Enriched Social Support Instrument. RESULTS: Compared to Anglo-Australians, the Greek-born immigrants had higher depression and anxiety scores, lower reported physical health status, lower perceived social support and lower quality of life on the physical, psychological and environmental health subdomains (p values<.05). Birthplace differences remained for level of depression and anxiety when adjustments were made for other CHD risk factors. CONCLUSION: Greek-born immigrants were found to have more psychosocial risk factors for CHD compared to the Anglo-Australians. We suggest that differences in depression and anxiety may help explain differences in CHD risk and morbidity between Greek-born immigrants and other ethnic groups living in Australia. PMID- 22921797 TI - Imaging of an atypical pericardial cyst. AB - Pericardial cysts are uncommon mediastinal lesions that are usually congenital in origin. Patients are usually asymptomatic and the cysts are generally discovered on routine radiography for unrelated purposes. This case illustrates a symptomatic presentation of a haemorrhagic pericardial cyst in which radiographic, echocardiographic and multislice (MRI and CT) imaging were performed. The imaging findings were not typical of pericardial cysts leading to a diagnostic quandary despite the varied imaging techniques. In conclusion, it is important to appreciate that the imaging findings of pericardial cysts can be varied. Radiologists and clinicians alike should be aware of this variability. PMID- 22921798 TI - Extraluminal atherosclerosis: an under-recognised finding in human aortocoronary venous bypass grafts. AB - BACKGROUND: Coronary artery bypass grafting (CABG) is commonly compromised by graft atherosclerosis. Histopathologic studies confirm various forms of atherosclerosis, including positively remodelled lesions in native coronary arteries but there are no histopathologic reports of extraluminal atherosclerosis in vein grafts. METHODS: We prospectively investigated the histopathologic presence and pattern of extraluminal atherosclerosis in human old vein grafts in a two-year interval among patients undergoing redo-CABG at three university hospitals in Tehran. We separately documented clinical and angiographic findings. RESULTS: We evaluated 100 segments from 20 human old vein grafts obtained during the redo CABG. All but four segments demonstrated some degrees of luminal narrowing. Luminal atherosclerotic plaques were detectable in 61 segments. We detected extraluminal atheroscleoris in seven segments. Mean vessel wall thickness was greater in segments containing extraluminal plaques (1.41+/-0.26 mm versus 0.91+/-0.04 mm, P=0.008). Angiographic findings had a modest correlation with presence or absence of luminal atheromatous lesions (Spearman's rho: 0.331, P=0.007). Angiographic degree of stenosis could not predict the presence of positively remodelled atherosclerotic plaques (Spearman's rho: -2.21, P=0.073). CONCLUSION: Previous studies suggested positive remodelling in vein grafts. Out study provides histopathologic evidence on extraluminal atherosclerosis in human aortocoronary vein grafts. PMID- 22921799 TI - The glutathione-S-transferase mu 1 (GSTM1) null genotype and increased neutrophil response to low-level ozone (0.06 ppm). PMID- 22921800 TI - Navigating the site for embryo implantation: biomechanical and molecular regulation of intrauterine embryo distribution. AB - The distribution of intrauterine embryo implantation site(s) in most mammalian species shows remarkably constant patterns: in monotocous species such as humans, an embryo tends to implant in the uterine fundus; in polytocous species such as rodents, embryos implant evenly along the uterine horns. These long-time evolved patterns bear great biological significance because disruption of these patterns can have adverse effects on pregnancies. However, lack of suitable models and in vivo monitoring techniques has impeded the progress in understanding the mechanisms of intrauterine embryo distribution. These obstacles are being overcome by genetically engineered mouse models and newly developed high resolution ultrasound. It has been revealed that intrauterine embryo distribution involves multiple events including uterine sensing of an embryo, fine-tuned uterine peristaltic movements, time-controlled uterine fluid reabsorption and uterine luminal closure, as well as embryo orientation. Diverse molecular factors, such as steroid hormone signaling, lipid signaling, adrenergic signaling, developmental genes, ion/water channels, and potentially embryonic signaling are actively involved in intrauterine embryo distribution. This review covers the biomechanical and molecular aspects of intrauterine embryo distribution (embryo spacing at the longitudinal axis and embryo orientation at the vertical axis), as well as its pathophysiological roles in human reproductive medicine. Future progress requires multi-disciplinary research efforts that will integrate in vivo animal models, clinical cases, physiologically relevant in vitro models, and biomechanical/computational modeling. Understanding the mechanisms for intrauterine embryo distribution could potentially lead to development of therapeutics for treating related conditions in reproductive medicine. PMID- 22921801 TI - Prostatic hydatid cyst: a case study. PMID- 22921802 TI - Focused ultrasound for targeted delivery of siRNA and efficient knockdown of Htt expression. AB - RNA interference is a promising strategy for the treatment of Huntington's disease (HD) as it can specifically decrease the expression of the mutant Huntingtin protein (Htt). However, siRNA does not cross the blood-brain barrier and therefore delivery to the brain is limited to direct CNS delivery. Non invasive delivery of siRNA through the blood-brain barrier (BBB) would be a significant advantage for translating this therapy to HD patients. Focused ultrasound (FUS), combined with intravascular delivery of microbubble contrast agent, was used to locally and transiently disrupt the BBB in the right striatum of adult rats. 48h following treatment with siRNA, the right (treated) and the left (control) striatum were dissected and analyzed for Htt mRNA levels. We demonstrate that FUS can non-invasively deliver siRNA-Htt directly to the striatum leading to a significant reduction of Htt expression in a dose dependent manner. Furthermore, we show that reduction of Htt with siRNA-Htt was greater when the extent of BBB disruption was increased. This study demonstrates that siRNA treatment for knockdown of mutant Htt is feasible without the surgical intervention previously required for direct delivery to the brain. PMID- 22921803 TI - Cost-effectiveness of a modified two-step algorithm using a combined glutamate dehydrogenase/toxin enzyme immunoassay and real-time PCR for the diagnosis of Clostridium difficile infection. AB - The analytical performance and cost-effectiveness of the Wampole Toxin A/B EIA, the C. Diff. Quik Chek Complete (CdQCC) (a combined glutamate dehydrogenase antigen/toxin enzyme immunoassay), two RT-PCR assays (Progastro Cd and BD GeneOhm) and a modified two-step algorithm using the CdQCC reflexed to RT-PCR for indeterminate results were compared. The sensitivity of the Wampole Toxin A/B EIA, CdQCC (GDH antigen), BD GeneOhm and Progastro Cd RT-PCR were 85.4%, 95.8%, 100% and 93.8%, respectively. The algorithm provided rapid results for 86% of specimens and the remaining indeterminate results were resolved by RT-PCR, offering the best balance of sensitivity and cost savings per test (algorithm ~US$13.50/test versus upfront RT-PCR ~US$26.00/test). PMID- 22921804 TI - Increased proportion of CD4(+)CD25(+)Foxp3(+) regulatory T cells during early stage sepsis in ICU patients. AB - BACKGROUND/PURPOSE(S): We investigated whether CD4(+)CD25(+)Foxp3(+) regulatory T cells (Tregs) are induced in patients suffering from early-stage septic shock and distinguish them from noninfectious patients with systemic inflammatory response. METHODS: The study included 37 patients with early-stage septic shock, 15 patients with noninfectious systemic inflammatory response syndrome (SIRS), and 24 heath controls. We prospectively assayed the fraction of Tregs expressing high levels of CD25 and forkhead box P3 (Foxp3) as well as the plasma levels of interferon-gamma (IFN-gamma), interleukin-4 (IL-4), and soluble CD25 in all the subjects studied. RESULTS: Compared with the control groups, the plasma levels of IFN-gamma [66.10 (45.23-85.08) pg/mL vs. 20.97 (17.58-26.21) pg/mL, p < 0.001] and IL-4 [100.69 (77.41-127.68) pg/mL vs. 70.40 (64.14-80.15) pg/mL, p < 0.001] as well as the IFN-gamma/IL-4 ratio [0.66 (0.62-0.67) vs. 0.30 (0.27-0.33), p < 0.001] were significantly elevated in the patients with early-stage septic shock, but there was no difference between patients with sepsis and patients with SIRS. We found that the proportion of CD4(+)CD25(+)Foxp3(+) T cells was significantly increased in the patients with early-stage septic shock [(66.82 +/- 21.79%) vs. (51.79 +/- 21.79%) vs. (56.45 +/- 10.68%), p = 0.003] in comparison with the SIRS and control groups, which could be differentiated from the patients with SIRS. The plasma levels of soluble CD25 were also increased, and positively correlated with the proportion of Tregs in patients with early-stage septic shock (Spearman correlation coefficient = 0.390, p = 0.003). CONCLUSION: Our findings indicate that the proportion of CD4(+)CD25(+)Foxp3(+) T cells could be an indicator for the early diagnosis of sepsis. This proportion can also facilitate the evaluation of the patient's immune status and guide suitable immunoregulatory therapy. PMID- 22921805 TI - Recurrent abdominal pain as the presentation of tumor necrosis factor receptor associated periodic syndrome (TRAPS) in an Asian girl: a case report and review of the literature. AB - Tumor necrosis factor receptor-associated periodic syndrome (TRAPS) is characterized by periodic fever, cutaneous rash, conjunctivitis, lymphadenopathy, abdominal pain, myalgia, and arthralgia. It is a rare autosomal dominant disease and strongly associated with heterozygous mutations in the tumor necrosis factor (TNF) receptor super family 1A (TNFRSF1A) gene. It is believed to be more common in Western countries than in Asian countries. Here, we present the case of a 14 year-old girl with periodic fever and abdominal pain with elevation of inflammatory markers for 2 years. After extensive work-up of infectious etiology with negative results, the diagnosis of TRAPS was made although no gene mutations were identified in the TNFRSF1A gene, MVK gene, and NALP3/CIAS1 gene. She had partial clinical response to corticosteroids and immunomodulatory agents. However, the treatment response to TNF-alpha inhibitor etanercept was dramatic. She has remained symptom free under regular weekly to biweekly etanercept treatment for 2 years. We also reviewed the related literature and summarized the data of 10 Asian cases of TRAPS. PMID- 22921806 TI - The feasibility of laminar screw placement in the subaxial spine: analysis using 215 three-dimensional computed tomography scans and simulation software. AB - BACKGROUND CONTEXT: There have been several reports describing the usage of subaxial cervical laminar screws. However, the anatomic feasibility of placing such screws has not been thoroughly evaluated yet. PURPOSE: To determine the feasibility of the laminar screw placement in the subaxial cervical spine using a large number of computed tomography (CT) scans and three-dimensional screw trajectory software. STUDY DESIGN: Three-dimensional simulation study of screw placement. PATIENT SAMPLE: Computed tomography scans of 215 consecutive patients were examined, for a total of 430 screws at each level of the subaxial cervical spine. OUTCOME MEASURES: Successful screw placement without laminar cortical breach, facet joint violation, and collision between two screws in the same level. METHODS: We simulated the placement of 4.0-mm subaxial (C3-C7) cervical laminar screws. Unilateral and bilateral screw placement was simulated, and their success rates were evaluated at each level of the subaxial cervical spine. This study was not supported by any financial sources. One of the authors received royalties for a posterior cervical fixation system, which is not the topic of this article and is not used or mentioned in this article. RESULTS: The success rate of unilateral screw placement was the highest at C7 (91.4%), followed by C6 (31.9%), C3 (30.2%), C4 (6.3%), and C5 (4.0%). It was significantly higher (p<.001) in men than in women at C6 and C7 but not at the other levels. The success rate of bilateral screw placement was the highest at C7 (68.8%), followed by C3 (13.5%), C6 (8.8%), C4 (1.9%), and C5 (0.9%). It was significantly higher in men (83.5%) than in women (52.0%) at C7 (p<.001) but not at the other levels. CONCLUSIONS: The relatively high success rate at C7, particularly of unilateral placement, suggests that laminar screw placement can be a sound alternative method for fixation at this level. However, careful preoperative CT scan evaluation and patient selection are required, particularly for bilateral fixation in women. At C3 and C6, unilateral screw placement can be considered in approximately 30% of patients after careful selection using preoperative CT scans. At C4 and C5, neither unilateral nor bilateral screw fixation is recommended for most patients. PMID- 22921808 TI - Diabetes insipidus following resection of pituitary tumors. AB - Diabetes insipidus (DI) is a common complication following pituitary surgery and can be transient or permanent. Neurogenic DI occurs following injury to the magnocellular neurons in the hypothalamus that produce and transport arginine vasopressin (AVP) and form the hypothalamo-hypophyseal tract. DI is defined by a constellation of signs and symptoms resulting in dilute high-volume urine output and increasing serum osmolality. The body's inability to concentrate urine leaves the patient dehydrated and leads to metabolic abnormalities that can be life threatening if not recognized and treated in a timely manner with an exogenous AVP analog. The reported incidence of postsurgical central DI varies from 1 to 67%. This wide range likely reflects inconsistencies in the working definition of DI across the literature. Factors affecting the rate of DI include pituitary tumor size, adherence to surrounding structures, surgical approach, and histopathology of pituitary lesion. The likelihood of postoperative DI can be reduced by careful preservation of the neurovascular structures of the hypothalamus, infundibulum, and neurohypophysis. Vigilance and meticulous surgical technique are essential to minimize injury to these critical regions that can lead to postsurgical DI. PMID- 22921809 TI - Intensity-modulated radiotherapy in anal cancer: where do we go from here? PMID- 22921807 TI - RGS2 overexpression or G(i) inhibition rescues the impaired PKA signaling and slow AP firing of cultured adult rabbit pacemaker cells. AB - Freshly isolated adult rabbit sinoatrial node cells (f-SANC) are an excellent model for studies of autonomic signaling, but are not amenable to genetic manipulation. We have developed and characterized a stable cultured rabbit SANC (c-SANC) model that is suitable for genetic manipulation to probe mechanisms of spontaneous action potential (AP) firing. After 48 h in culture, c-SANC generate stable, rhythmic APs at 34+/-0.5 degrees C, at a rate that is 50% less than f SANC. In c- vs. f-SANC: AP duration is prolonged; phosphorylation of phospholamban at Ser(16) and type2 ryanodine receptor (RyR2) at Ser(2809) are reduced; and the level of type2 regulator of G-protein signaling (RGS2), that facilitates adenylyl cyclases/cAMP/protein kinase A (PKA) via G(i) inhibition, is substantially reduced. Consistent with the interpretation that cAMP/PKA signaling becomes impaired in c-SANC, acute beta-adrenergic receptor stimulation increases phospholamban and RyR2 phosphorylation, enhances RGS2-labeling density, and accelerates the AP firing rate to the similar maximum in c- and f-SANC. Specific PKA inhibition completely inhibits all beta-adrenergic receptor effects. Adv-RGS2 infection, or pertussis toxin treatment to disable G(i)-signaling, each partially rescues the c-SANC spontaneous AP firing rate. Thus, a G(i)-dependent reduction in PKA-dependent protein phosphorylation, including that of Ca(2+) cycling proteins, reduces the spontaneous AP firing rate of c-SANC, and can be reversed by genetic or pharmacologic manipulation of PKA signaling. PMID- 22921810 TI - Biochemistry and biology: heart-to-heart to investigate cardiac progenitor cells. AB - BACKGROUND: Cardiac regenerative medicine is a rapidly evolving field, with promising future developments for effective personalized treatments. Several stem/progenitor cells are candidates for cardiac cell therapy, and emerging evidence suggests how multiple metabolic and biochemical pathways strictly regulate their fate and renewal. SCOPE OF REVIEW: In this review, we will explore a selection of areas of common interest for biology and biochemistry concerning stem/progenitor cells, and in particular cardiac progenitor cells. Numerous regulatory mechanisms have been identified that link stem cell signaling and functions to the modulation of metabolic pathways, and vice versa. Pharmacological treatments and culture requirements may be exploited to modulate stem cell pluripotency and self-renewal, possibly boosting their regenerative potential for cell therapy. MAJOR CONCLUSIONS: Mitochondria and their many related metabolites and messengers, such as oxygen, ROS, calcium and glucose, have a crucial role in regulating stem cell fate and the balance of their functions, together with many metabolic enzymes. Furthermore, protein biochemistry and proteomics can provide precious clues on the definition of different progenitor cell populations, their physiology and their autocrine/paracrine regulatory/signaling networks. GENERAL SIGNIFICANCE: Interdisciplinary approaches between biology and biochemistry can provide productive insights on stem/progenitor cells, allowing the development of novel strategies and protocols for effective cardiac cell therapy clinical translation. This article is part of a Special Issue entitled Biochemistry of Stem Cells. PMID- 22921811 TI - Cytosolic ascorbate peroxidase 1 protects organelles against oxidative stress by wounding- and jasmonate-induced H(2)O(2) in Arabidopsis plants. AB - BACKGROUND: Reactive oxygen species (ROS) are not only cytotoxic compounds leading to oxidative damage, but also signaling molecules for regulating plant responses to stress and hormones. Arabidopsis cytosolic ascorbate peroxidase 1 (APX1) is thought to be a central regulator for cellular ROS levels. However, it remains unclear whether APX1 is involved in plant tolerance to wounding and methyl jasmonate (MeJA) treatment, which are known to enhance ROS production. METHODS: We studied the effect of wounding and MeJA treatment on the levels of H(2)O(2) and oxidative damage in the Arabidopsis wild-type plants and knockout mutants lacking APX1 (KO-APX1). RESULTS: The KO-APX1 plants showed high sensitivity to wounding and MeJA treatment. In the leaves of wild-type plants, H(2)O(2) accumulated only in the vicinity of the wound, while in the leaves of the KO-APX1 plants it accumulated extensively from damaged to undamaged regions. During MeJA treatment, the levels of H(2)O(2) were much higher in the leaves of KO-APX1 plants. Oxidative damage in the chloroplasts and nucleus was also enhanced in the leaves of KO-APX1 plants. These findings suggest that APX1 protects organelles against oxidative stress by wounding and MeJA treatment. GENERAL SIGNIFICANCE: This is the first report demonstrating that H(2)O(2) scavenging in the cytosol is essential for plant tolerance to wounding and MeJA treatment. PMID- 22921812 TI - Antimicrobial peptide pleurocidin synergizes with antibiotics through hydroxyl radical formation and membrane damage, and exerts antibiofilm activity. AB - BACKGROUND: Pleurocidin, a 25-mer antimicrobial peptide (AMP), is known to exert bactericidal activity. However, the synergistic activity and mechanism(s) of pleurocidin in combination with conventional antibiotics, and the antibiofilm effect of the peptide are poorly understood. METHODS: The interaction between pleurocidin and antibiotics was evaluated using checkerboard assay. To study the mechanism(s) involved in their synergism, we detected hydroxyl radical formation using 3'-(p-hydroxyphenyl) fluorescein, measured the NAD(+)/NADH ratio by NAD(+) cycling assay, observed change in bacterial viability with the hydroxyl radical scavenger thiourea, and investigated cytoplasmic membrane damage using propidium iodide. Also, the antibiofilm effect of pleurocidin was examined with the tissue culture plate method. RESULTS: All combinations of pleurocidin and antibiotics showed synergistic interaction against bacterial strains (fractional inhibitory concentration index (FICI)<=0.5) except for Enterococcus faecium treated with a combination of the peptide and ampicillin (FICI=0.75). We identified that pleurocidin alone and in combinations with antibiotics induced formation of hydroxyl radicals. The oxidative stress was caused by a transient NADH depletion and the addition of thiourea prevented bacterial death, especially in the case of the combined treatment of pleurocidin and ampicillin showing synergisms. The combination of pleurocidin and erythromycin increased permeability of bacterial cytoplasmic membrane. Additionally, pleurocidin exhibited a potent inhibitory effect on preformed biofilm of bacterial organisms. In conclusion, pleurocidin synergized with antibiotics through hydroxyl radical formation and membrane active mechanism, and exerted antibiofilm activity. GENERAL SIGNIFICANCE: The synergistic effect between pleurocidin and antibiotics suggests the AMP is a potential therapeutic agent and adjuvant for antimicrobial chemotherapy. PMID- 22921813 TI - Pneumococcal carriage in children attending a hospital outpatient clinic in the era of pneumococcal conjugate vaccines in Barcelona. AB - Between April 2004 and March 2006 an oropharyngeal swab was obtained from 502 asymptomatic children, aged 6 months to 6 years, at a tertiary children's hospital outpatient department to assess the pneumococcal colonisation rate, risk factors, serotype distribution and antimicrobial susceptibility. Only 126 (25.3%) children had received >= 1 dose of PCV7. The pneumococcal carriage rate was 23.5%. Carrier rates were significantly higher in children aged >= 24 months and children attending daycare center. Thirty six (31.0%) of the isolates were contained in PCV7, 39 (33.6%) in PCV10 and 62 (53.4%) in PCV13. Forty-four strains (37.9%) were resistant to penicillin. Vaccine serotype (VT) strains were more likely to be penicillin-nonsusceptible S. pneumoniae than non-PCV7 serotype (NVT) strains (66.7% vs. 21.6%; P < 0.001). In our pediatric population, NVT were predominant among pneumococcal carriers whereas antibiotic resistance was significantly associated with VT. PCV13 can substantially increase the serotype coverage of S.pneumoniae in healthy carriers. PMID- 22921814 TI - Quantification of Helicobacter pylori in gastric mucosa by real-time polymerase chain reaction: comparison with traditional diagnostic methods. AB - The aim of this study was to determine the main diagnostic validity parameters of a quantitative real-time polymerase chain reaction (PCR) system for detecting Helicobacter pylori in gastric biopsies. Prospective study. The real-time PCR has an internal control for eliminating the false negatives. Our system has a good diagnostic capacity compared with the gold standard and was superior in antral mucosa: area under the curve was 0.91 for antrum (95% confidence interval [CI] 0.87 to 0.96) and 0.83 for corpus (95% CI 0.77 to 0.9). The optimum cut-off point was 3.56 microorganisms/cell for antrum (sensitivity 83.5% [95% CI 74.2 to 89.9]; specificity 91.3% [95% CI 82.3 to 96.0]; positive predictive value 92.2%; negative predictive value 81.8%). The positive likelihood ratios were 9.61 and 8.52 for antrum and corpus, respectively. With the cut-off point that maximises the Youden index, 8.7% false positives were obtained. Our methodology is useful for diagnosing infection due to H. pylori and the false positives detected probably correspond to patients who were actually infected but the infection was not detected by traditional techniques. The clinical importance of these cases should be studied in greater detail since they may involve colonisations unrelated to the patient's digestive pathology. PMID- 22921815 TI - Cytomegalovirus ventriculoencephalitis with compartmentalization of antiviral resistant cytomegalovirus in a T cell-depleted haploidentical peripheral blood stem cell transplant recipient. AB - We describe a case of cytomegalovirus (CMV) ventriculoencephalitis and retinitis with compartmentalization of antiviral drug-resistant CMV across the blood-brain barrier after T cell-depleted haploidentical peripheral blood stem cell transplantation. PMID- 22921816 TI - Phaeoacremonium parasiticum invasive infections and airway colonization characterized by agar block smear and ITS and beta-tubulin gene sequencing. AB - Phaeoacremonium parasiticum is an environmental dematiaceous mold rarely associated with human infections. We present here 2 cases of P. parasiticum invasive infections, including the first report of P. parasiticum respiratory tract infection, and 1 case of airway colonization, which all 3 strains of P. parasiticum were identified using agar block smear and ITS and beta-tubulin gene sequencing. All 3 isolates grew initially as white to creamy, yeast-like colonies. After 21 days of incubation at 25 degrees C, 1 isolate remained light brown, atypical of P. parasiticum. Microscopic examination of agar block smear preparations of all 3 isolates showed thick-walled, medium brown conidiophores that were branched and slightly swollen at the base. The sequences of the ITS and beta-tubulin genes of the 3 isolates were identical to those of P. parasiticum. Cases of P. parasiticum infections should be confirmed by a polyphasic approach using morphologic characterization and ITS and beta-tubulin gene sequencing. PMID- 22921818 TI - Mobile Nodules on the Legs. PMID- 22921817 TI - A combination of increased Rho kinase activity and N-terminal pro-B-type natriuretic peptide predicts worse cardiovascular outcome in patients with acute coronary syndrome. AB - BACKGROUND: Recent experimental evidence suggests that the Rho/Rho-kinase (ROCK) system may play an important role in the pathogenesis of acute coronary syndrome (ACS) but there are little clinical data. This study examined if ROCK activity is increased in patients with acute coronary syndrome and if ROCK activity predicts long-term cardiovascular event. METHOD: Blood samples were collected from 188 patients within 12h after admission for ACS (53% men; aged 70 +/- 13) and from 61 control subject. The main outcome measures were all cause mortality, readmission with ACS or congestive heart failure (CHF) from presentation within around 2 years (mean:14.4 +/- 7.2 months; range: 0.5 to 26 months). RESULTS: ROCK activity increased in ST elevation myocardial infarction (STEMI, n=90) (3.33 +/- 0.93), non-STEMI (NSTEMI, n=68) (3.37 +/- 1.04) and unstable angina (UA, n=30) (2.53 +/- 0.59) groups when compared with disease controls (n=31) (2.06 +/- 0.38, all p<0.001) and healthy controls (n=30) (1.54 +/- 0.43, all p<0.001). There were 24 deaths, 34 readmissions with ACS and 15 admissions with CHF within 2 years. Patients with a high N-terminal pro-B-type natriuretic peptide (NT-proBNP) and high ROCK activity on admission had a five-fold risk of a cardiovascular event (RR: 5.156; 95% CI: 2.180-12.191) when compared to those with low NT-proBNP and low ROCK activity. CONCLUSION: ROCK activity was increased in patients with ACS, particularly in those with myocardial infarction. The combined usage of both ROCK activity and NT-proBNP might identify a subset of ACS patients at particularly high risk. PMID- 22921819 TI - Aortic valve replacement in neonates and infants: an analysis of the Society of Thoracic Surgeons Congenital Heart Surgery Database. AB - OBJECTIVE: We sought to describe early outcomes of aortic valve replacement in neonates and infants across a large multicenter cohort. METHODS: Neonates and infants in the Society of Thoracic Surgeons Congenital Heart Surgery Database undergoing nontruncal aortic valve replacement with the Ross-Konno procedure, Ross procedure, or homograft replacement from 2000 to 2009 were included. Preoperative characteristics, operative data, and early outcomes are described. RESULTS: A total of 160 patients (43 neonates, 117 infants) from 47 centers were included. Society of Thoracic Surgeons-defined preoperative risk factors were present in 76 patients (48%) and were most prevalent in neonates (67%) and patients undergoing homograft aortic valve replacement (93%). Concomitant arch repair or mitral valve surgery was performed in 30 patients (19%) and 19 patients (12%), respectively. Postoperative mechanical circulatory support was used in 17 patients (11%). Overall in-hospital mortality was 18% and was highest for neonates (28%) and patients undergoing homograft aortic valve replacement (40%). Concomitant arch repair was associated with higher in-hospital mortality (33% vs 15%, P = .02), whereas concurrent mitral valve surgery was not (21% vs 18%, P = .73). Postoperative mechanical circulatory support was also associated with increased in-hospital mortality (65% vs 13%, P < .0001). CONCLUSIONS: Neonates and infants undergoing aortic valve replacement are a high-risk group, with hospital mortality comparable with some of the highest risk procedures in this age group. The requirement for arch repair or postoperative mechanical circulatory support was associated with an increased risk of death in this cohort. PMID- 22921820 TI - Discussion. PMID- 22921821 TI - Anticoagulation early after mechanical valve replacement: improved management with patient self-testing. AB - OBJECTIVE: Self-testing to determine the international normalized ratio improves management with warfarin and reduces the risks of adverse events. Self-testing usually begins several weeks after hospital dismissal after valve replacement. We aimed to compare the in-hospital initiation of international normalized ratio self-testing with usual care in mechanical heart valve recipients. METHODS: A total of 200 adult mechanical heart valve recipients were randomly assigned to in hospital international normalized ratio self-testing instruction or usual care. Instruction for self-testing patients began on the fourth postoperative day. The patients were followed up for 3 months to compare the number of international normalized ratio tests, percentage of time in the therapeutic range, and adverse events. RESULTS: The baseline characteristics were similar between the 2 groups. During the first 3 postoperative months, the usual-care group underwent an average of 10 international normalized ratio tests, and the self-testing group completed 14 international normalized ratio tests. The mean +/- SD percentage of international normalized ratio tests within the therapeutic range was 45% +/- 22% for the usual-care group and 52% +/- 22% for the self-testing group (P = .05). Within 90 days after dismissal, transient ischemic attack occurred in 1 patient in the usual-care group and 2 patients in the self-testing group. Bleeding complications occurred in 3 patients in the usual-care group and 5 patients in the self-testing group. CONCLUSIONS: Management of anticoagulation with warfarin after mechanical valve replacement is improved with self-testing, even during the early postoperative phase when international normalized ratio testing is performed frequently. Although the incidence of adverse events was similar in the 2 groups, better control of the international normalized ratio would be expected to improve outcome in large populations of patients. PMID- 22921822 TI - Recurrence of mitral regurgitation after partial versus complete mitral valve ring annuloplasty for functional mitral regurgitation. AB - OBJECTIVES: Both partial and complete annuloplasty rings are used for mitral valve repair for patients with functional mitral regurgitation (FMR). We sought to determine if recurrence of mitral regurgitation (MR) is affected by the type of ring used. METHODS: Five hundred forty-eight patients diagnosed with FMR underwent mitral valve repair with ring annuloplasty between 1998 and 2008 in our institution. Medical records were reviewed retrospectively for clinical and echocardiographic data to determine the presence of recurrent MR (defined as moderate or severe). RESULTS: Among 479 patients for whom postoperative echocardiographic data were available, recurrent MR occurred less frequently in the complete versus partial ring group (20 of 209 [10%] vs 56 of 270 [21%] patients; P = .001), despite lower preoperative ejection fractions in the complete ring group (median, 35%; interquartile range, 25%-45% vs median, 40%; interquartile range, 30%-55%; P < .001). Kaplan-Meier analysis demonstrated greater freedom from recurrent MR in the complete ring group (108 vs 103 months; P = .001). Risk-matched propensity analysis of 102 patients per group (area under the curve, 0.824; 95% confidence interval, 0.788-0.861; P < .001) also demonstrated that complete ring recipients had greater freedom from recurrent MR than partial ring recipients by univariate analysis (7 [7%] vs 17 [17%] patients; P = .049), and a trend toward greater freedom by Kaplan-Meier analysis (110 vs 104 months; P = .068). CONCLUSIONS: The use of complete mitral annuloplasty rings provides improved freedom from recurrent MR in patients with FMR. PMID- 22921823 TI - Percutaneous coronary intervention of the left main coronary artery in a patient with extrinsic compression caused by massive pulmonary artery enlargement. PMID- 22921824 TI - Epidemiology, treatment trends and outcomes of acromegaly. PMID- 22921825 TI - Impact of participation in the California Healthcare-Associated Infection Prevention Initiative on adoption and implementation of evidence-based practices for patient safety and health care-associated infection rates in a cohort of acute care general hospitals. AB - BACKGROUND: In 2008, hospitals were selected to participate in the California Healthcare-Associated Infection Prevention Initiative (CHAIPI). This research evaluates the impact of CHAIPI on hospital adoption and implementation of evidence-based patient safety practices and reduction of health care-associated infection (HAI) rates. METHODS: Statewide computer-assisted telephone surveys of California's general acute care hospitals were conducted in 2008 and 2010 (response rates, 80% and 76%, respectively). Difference-in-difference analyses were used to compare changes in process and HAI rate outcomes in CHAIPI hospitals (n = 34) and non-CHAIPI hospitals (n = 149) that responded to both waves of the survey. RESULTS: Compared with non-CHAIPI hospitals, CHAIPI hospitals demonstrated greater improvements between 2008 and 2010 in adoption (P = .021) and implementation (P = .012) of written evidence-based practices for overall patient safety and prevention of HAIs and in assessing their compliance (P = .033) with these practices. However, there were no significant differences in the changes in HAI rates between CHAIPI and non-CHAIPI hospitals over this time period. CONCLUSIONS: Participation in the CHAIPI collaborative was associated with significant improvements in evidence-based patient safety practices in hospitals. However, determining how evidence-based practices translate into changes in HAI rates may take more time. Our results suggest that all hospitals be offered the opportunity to participate in an active learning collaborative to improve patient safety. PMID- 22921826 TI - Parents' perspectives on their children's health insurance: plight of the underinsured. AB - OBJECTIVES: To determine the prevalence and correlates of children's underinsurance within a primary care, practice-based research network. STUDY DESIGN: A survey of 13 practices within the Southwestern Ohio Ambulatory Research Network using the Medical Expenses for Children Survey in 2009 and 2010 yielded a sample of 2972 parents of children >6 months old with health insurance in the previous 12 months. Data were analyzed using bivariate and loglinear model analyses. RESULTS: Of the study children, 17.2% were classified as underinsured because of their inability to pay for >= 1 of their pediatrician's recommendations for care in the past 12 months. In addition, 15.5% reported it was harder to get medical care for their child in the past 3 years, and 6.5% indicated that their child's health had suffered. Multivariate analysis reveals complex relationships among the 3 factors related to ability to obtain care and between these factors and sociodemographic and health status factors. Across education and income categories, the underinsured rate ranged from 57% to 93% for parents who reported their child's health had suffered. CONCLUSIONS: One in 6 parents reported that their child was underinsured. A similar percentage reported that it had become more difficult to get needed medical care over the past 3 years. The relationship between the perception that an underinsured child's health has suffered is much stronger for the highest socioeconomic category in this sample than for the other categories; 93% of these families were underinsured in 2009. It is possible that high deductible features of insurance plans contribute to these circumstances. PMID- 22921827 TI - Pediatric traumatic brain injury and radiation risks: a clinical decision analysis. AB - OBJECTIVE: To determine the optimal imaging strategy for young children with minor head injury considering health-related quality of life and radiation risk. In children with minor head trauma, the risk of missing a clinically important traumatic brain injury (ciTBI) must be weighed against the risk of radiation induced malignancy from computed tomography (CT) to assess impact on public health. STUDY DESIGN: We included children <2 years old with minor blunt head trauma defined by a Glasgow Coma Scale score of 14-15. We used decision analysis to model a CT-all versus no-CT strategy and assigned values to clinical outcomes based on a validated health-related quality of life scale: (1) baseline health; (2) non-ciTBI; (3) ciTBI without neurosurgery, death, or intubation; and (4) ciTBI with neurosurgery, death, or intubation >24 hours with probabilities from a prospective study of 10000 children. Sensitivity analysis determined the optimal management strategy over a range of ciTBI risk. RESULTS: The no-CT strategy resulted in less risk with the expected probability of a ciTBI of 0.9%. Sensitivity analysis for the probability of ciTBI identified 4.8% as the threshold above which CT all becomes the preferred strategy and shows that the threshold decreases with less radiation. The CT all strategy represents the preferred approach for children identified as high-risk. CONCLUSION: Among children <2 years old with minor head trauma, the no-CT strategy is preferable for those at low risk, reserving CT for children at higher risk. PMID- 22921828 TI - Enterohaemorrhagic Escherichia coli exploits a tryptophan switch to hijack host f actin assembly. AB - Intrinsically disordered protein (IDP)-mediated interactions are often characterized by low affinity but high specificity. These traits are essential in signaling and regulation that require reversibility. Enterohaemorrhagic Escherichia coli (EHEC) exploit this situation by commandeering host cytoskeletal signaling to stimulate actin assembly beneath bound bacteria, generating "pedestals" that promote intestinal colonization. EHEC translocates two proteins, EspF(U) and Tir, which form a complex with the host protein IRTKS. The interaction of this complex with N-WASP triggers localized actin polymerization. We show that EspF(U) is an IDP that contains a transiently alpha-helical N terminus and dynamic C-terminus. Our structure shows that single EspF(U) repeat forms a high-affinity trimolecular complex with N-WASP and IRTKS. We demonstrate that bacterial and cellular ligands interact with IRTKS SH3 in a similar fashion, but the bacterial protein has evolved to outcompete cellular targets by utilizing a tryptophan switch that offers superior binding affinity enabling EHEC-induced pedestal formation. PMID- 22921829 TI - Structural basis for the versatile interactions of Smad7 with regulator WW domains in TGF-beta Pathways. AB - Transforming growth factor (TGF)-beta and BMP signaling is mediated by Smads 1-5 (R-Smads and Co-Smads) and inhibited by Smad7, a major hub of regulation of TGF beta and BMP receptors by negative feedback and antagonistic signals. The transcription coactivator YAP and the E3 ubiquitin ligases Smurf1/2 and Nedd4L target R-Smads for activation or degradation, respectively. Pairs of WW domain in these regulators bind PY motifs and adjacent CDK/MAPK and GSK3 phosphorylation sites in R-Smads in a selective and regulated manner. In contrast, here we show that Smad7 binds YAP, Smurf1, Smurf2, and Nedd4L constitutively, the binding involving a PY motif in Smad7 and no phosphorylation. We also provide a structural basis for how regulators that use WW domain pairs for selective interactions with R-Smads, resort to one single versatile WW domain for binding Smad7 to centralize regulation in the TGF-beta and BMP pathways. PMID- 22921830 TI - The crystal structure of the catalytic domain of the NF-kappaB inducing kinase reveals a narrow but flexible active site. AB - The NF-kappaB inducing kinase (NIK) regulates the non-canonical NF-kappaB pathway downstream of important clinical targets including BAFF, RANKL, and LTbeta. Despite numerous genetic studies associating dysregulation of this pathway with autoimmune diseases and hematological cancers, detailed molecular characterization of this central signaling node has been lacking. We undertook a systematic cloning and expression effort to generate soluble, well-behaved proteins encompassing the kinase domains of human and murine NIK. Structures of the apo NIK kinase domain from both species reveal an active-like conformation in the absence of phosphorylation. ATP consumption and peptide phosphorylation assays confirm that phosphorylation of NIK does not increase enzymatic activity. Structures of murine NIK bound to inhibitors possessing two different chemotypes reveal conformational flexibility in the gatekeeper residue controlling access to a hydrophobic pocket. Finally, a single amino acid difference affects the ability of some inhibitors to bind murine and human NIK with the same affinity. PMID- 22921831 TI - In-situ spectroscopic investigation of ultrasonic assisted unfolding and aggregation of insulin. AB - It is well-known that fibrillogenesis of proteins can be influenced by diverse external parameters, such as temperature, pressure, agitation or chemical agents. The present preliminary study suggests that ultrasonic excitation at moderate intensities has a significant influence on the unfolding and aggregation behaviour of insulin. Irradiation with an average sound intensity of even as low as 70mW/cm(2) leads to a lowering of the unfolding and aggregation temperature up to 7K. The effect could be explained by an increase of the aggregation kinetics due to ultrasonically induced acoustic micro-streaming in the insulin solution that most probably enhances the aggregation rate. The clear and remarkable effect at relatively low sound intensities offers interesting options for further applications of ultrasound in biophysics and biochemistry. On the other hand, a process that causes a change of kinetics equivalent to 7K also gives a warning signal concerning the safety of those medical ultrasonic devices that work in this intensity range. PMID- 22921832 TI - The clinical, histologic, and treatment spectrum in necrotizing sialometaplasia. AB - OBJECTIVES: The aim of this report was the clinical and histologic characterization of necrotizing sialometaplasia. STUDY DESIGN: We performed a retrospective case series analysis. RESULTS: The study included 4 women 29-71 years old. Possible contributing factors (drugs, alcohol abuse, bulimia, smoking, and pancreatic cancer) were identified. Patients presented with unilateral or bilateral rapidly progressing painful palatal ulcers. Necrotic salivary glands and inflammation were universal microscopic features; ductal metaplasia was present in only 1 case. Thrombosis and heavy fungal and bacterial overgrowth were observed in 1 case. In 3 of the cases the lesions healed within 4-6 weeks under conservative supportive care, whereas in 1 case persistent enlargement up to 25 mm diameter was observed. Surgical debridement combined with a palatal guard resulted in complete healing within 12 weeks. CONCLUSIONS: Significant variations may be observed in both clinical and microscopic manifestations of necrotizing sialometaplasia. Although this disease is considered to be self-limiting in the majority of cases, surgical intervention can be considered in unusually large cases. PMID- 22921833 TI - The relative risk of neurosensory deficit following removal of mandibular third molar teeth: the influence of radiography and surgical technique. AB - OBJECTIVE: The aim of this study was to identify the relative risk of damage to the inferior dental (ID) and lingual nerves in patients undergoing lower third molar removal. STUDY DESIGN: A single surgeon reviewed 1,000 patients. RESULTS: Temporary ID neurosensory deficit was highest (11%) when root apices were intimate to the ID nerve and lowest (0.9%) when close or distant from the nerve. Permanent ID neurosensory deficit was 0.4% per tooth but only when intimate to the canal. Bone removal, tooth division, and lingual split technique increase the risk of excessive hemorrhage which appears to be linked to the highest risk of temporary ID neurosensory deficit (20%). Permanent lingual nerve injury was rare (0.06%) and not related to lingual retraction. CONCLUSIONS: Preoperative warning for lower third molar removal can be individually tailored depending on the intimacy of the ID canal to the root apices and the anticipated surgical technique. PMID- 22921834 TI - Regioselective synthesis of isotopically labeled Delta9-tetrahydrocannabinolic acid A (THCA-A-D3) by reaction of Delta9-tetrahydrocannabinol-D3 with magnesium methyl carbonate. AB - For the reliable quantification of Delta9-tetrahydrocannabinolic acid A (THCA-A), the biogenetic precursor of Delta9-tetrahydrocannabinol (THC), in biological matrices by LC-MS/MS and GC-MS(/MS), an isotopically labeled internal standard was synthesized starting from Delta9-tetrahydrocannabinol-D(3) (THC-D(3)). Synthesis strategy was based on a method reported by Mechoulam et al. in 1969 using magnesium methyl carbonate (MMC) as carboxylation reagent for the synthesis of cannabinoid acids. Preliminary experiments with THC to optimize yield of the product (THCA-A) resulted in the synthesis of the positional isomer tetrahydrocannabinolic acid B (THCA-B) as a byproduct. Using the optimized conditions for the desired isomer, THCA-A-D(3) was prepared and isolated with a yield of approx. 10% after two synthesis cycles. Isotope purity was estimated to be >99% by relative abundance of the molecular ions. The synthesized compound proved to be suitable as an internal standard for quantification of THCA-A in serum and hair samples of cannabis consumers. PMID- 22921835 TI - D6: the 'crowd controller' at the immune gateway. AB - The chemokine-scavenging receptor, D6, is reported to regulate resolution of inflammatory responses. However, recent data also point to an unanticipated role for D6 in coordinating innate and adaptive immune responses. Here, we propose that D6 is essential for preventing inflammatory leukocyte association with lymphatic vasculature. In the absence of D6, inappropriate inflammatory leukocyte accumulation around lymphatic endothelium congests the lymphatic system, impairing fluid and cellular flow from inflamed sites to lymph nodes and reducing efficiency of antigen presentation. Thus, the inability of D6-deficient mice to resolve inflammation may be a byproduct of impaired fluid drainage from inflamed sites and thus we provide a model unifying D6 function in innate and adaptive immune responses. PMID- 22921836 TI - cDNA cloning and characterization of the antibacterial peptide cecropin 1 from the diamondback moth, Plutella xylostella L. AB - Cecropins are linear cationic antibacterial peptides that have potent activities against microorganisms. In the present study, a 480bp full-length cDNA encoding diamondback moth (Plutella xylostella) cecropin 1 (designated as Px-cec1) was obtained using RT-PCR. A Northern blot analysis showed that the Px-cec1 transcript was predominantly expressed in fat bodies, hemocytes, midgut and epidermis with the highest expression level in fat bodies. The expression of Px cec1 mRNA in fat bodies was significantly increased 24h after microbial challenge, with the highest induced expression by Staphylococcus aureus. A circular dichroism (CD) analysis revealed that the recombinant Px-cec1 mainly contained alpha-helixes. Antimicrobial assays demonstrated that recombinant Px cec1 exhibited a broad spectrum of anti-microbial properties against fungi, Gram positive and Gram-negative bacteria, but it did not exhibit hemolytic activity against human erythrocytes. Furthermore, Px-cec1 caused significant morphological alterations of S. aureus, as shown by scanning electron microscopy and transmission electron microscopy. These results demonstrated that Px-cec1 exerts its antibacterial activity by acting on the cell membrane to disrupt bacterial cell structures. PMID- 22921837 TI - Protective effects of sinapic acid on lysosomal dysfunction in isoproterenol induced myocardial infarcted rats. AB - In the pathology of myocardial infarction, lysosomal lipid peroxidation and resulting enzyme release play an important role. We evaluated the protective effects of sinapic acid on lysosomal dysfunction in isoproterenol induced myocardial infarcted rats. Male Wistar rats were treated with sinapic acid (12 mg/kg body weight) orally daily for 10 days and isoproterenol (100 mg/kg body weight) was injected twice at an interval of 24 h (9th and 10th day). Then, lysosomal lipid peroxidation, lysosomal enzymes in serum, heart homogenate, lysosomal fraction and myocardial infarct size were measured. Isoproterenol induced myocardial infarcted rats showed a significant increase in serum creatine kinase-MB and lysosomal lipid peroxidation. The activities of beta-glucuronidase, beta-galactosidase, cathepsin-B and D were significantly increased in serum, heart and the activities of beta-glucuronidase and cathepsin-D were significantly decreased in lysosomal fraction of myocardial infarcted rats. Pre-and-co treatment with sinapic acid normalized all the biochemical parameters and reduced myocardial infarct size in myocardial infarcted rats. In vitro studies confirmed the free radical scavenging effects of sinapic acid. The possible mechanisms for the observed effects are attributed to sinapic acid's free radical scavenging and membrane stabilizing properties. Thus, sinapic acid has protective effects on lysosomal dysfunction in isoproterenol induced myocardial infarcted rats. PMID- 22921838 TI - C-reactive protein and erythrocyte sedimentation rate discordance: frequency and causes in adults. AB - C-reactive protein (CRP) levels and the erythrocyte sedimentation rate (ESR) are widely used tests of inflammation that sometimes show opposite results. We performed a retrospective cohort study to clarify the frequency and causes of CRP/ESR discordance in adults. Between January and December of 2011, the laboratories of Texas Health Presbyterian Hospital performed 2150 paired CRP/ESR measurements in 1753 patients, 1731 of whom were nonpregnant adults aged >= 18 years. Initial CRP and ESR results for each patient were divided into quartiles. CRP/ESR discordance, predefined as results differing by 2 or 3 quartiles, occurred in 212 patients (12%), 105 of whom had high CRP/low ESR discordance (6%) and 107 of whom had high ESR/low CRP discordance (6%). The 212 patients in the CRP/ESR-discordant group (128 women and 84 men) were subdivided into 1 of 6 diagnostic categories, and the causes of discordances were compared. The high CRP/low ESR-discordant group had more patients with infections than the high ESR/low CRP-discordant group (P = 0.001), particularly infections in the urinary tract (P = 0.03), gastrointestinal tract (P = 0.001), lungs (P = 0.005), and bloodstream (P = 0.03). However, they had fewer bone and joint infections than the high ESR/low CRP-discordant group (P = 0.001). Connective tissue diseases, such as systemic lupus erythematosus, were less common in the high CRP/low ESR discordant group than in the high ESR/low CRP-discordant group (P = 0.001). Ischemic strokes or transient ischemic attacks almost invariably occurred in the high ESR/low CRP-discordant group (P = 0.001), whereas myocardial infarction or venous thromboembolism was limited to the high CRP/low ESR-discordant group (P = 0.001). Our findings provide information to physicians who order these 2 tests together and receive discordant results, which occurs in approximately 1 in 8 patients. PMID- 22921840 TI - Exosomes for targeted siRNA delivery across biological barriers. AB - Using oligonucleotide-based drugs to modulate gene expression has opened a new avenue for drug discovery. In particular small interfering RNAs (siRNAs) are being rapidly recognized as promising therapeutic tools, but their poor bioavailability limits the full realization of their clinical potential. In recent years, cumulating evidence has emerged for the role of membrane vesicles, secreted by most cells and found in all body fluids, as key mediators of information transmission between cells. Importantly, a sub-group of these termed exosomes, have recently been shown to contain various RNA species and to mediate their horizontal transfer to neighbouring- or distant recipient cells. Here, we provide a brief overview on membrane vesicles and their role in exchange of genetic information. We also describe how these natural carriers of genetic material can be harnessed to overcome the obstacle of poor delivery and allow efficient systemic delivery of exogenous siRNA across biological barriers such as the blood-brain barrier. PMID- 22921839 TI - Fatty acids as therapeutic auxiliaries for oral and parenteral formulations. AB - Many drugs have decreased therapeutic activity due to issues with absorption, distribution, metabolism and excretion. The co-formulation or covalent attachment of drugs with fatty acids has demonstrated some capacity to overcome these issues by improving intestinal permeability, slowing clearance and binding serum proteins for selective tissue uptake and metabolism. For orally administered drugs, albeit at low level of availability, the presence of fatty acids and triglycerides in the intestinal lumen may promote intestinal uptake of small hydrophilic molecules. Small lipophilic drugs or acylated hydrophilic drugs also show increased lymphatic uptake and enhanced passive diffusional uptake. Fatty acid conjugation of small and large proteins or peptides has exhibited protracted plasma half-lives, site-specific delivery and sustained release upon parenteral administration. These improvements are most likely due to associations with lipid binding serum proteins, namely albumin, LDL and HDL. These molecular interactions, although not fully characterized, could provide the ability of using the endogenous carrier systems for improving therapeutic outcomes. PMID- 22921842 TI - A method for testing the performance and the accuracy of the binary MLC used in helical tomotherapy. AB - During a helical tomotherapy a binary MLC is used for fluence modulation. The 64 pneumatically driven leaves of the MLC are either completely open or closed. The fast and frequent leaf movements result in a high demand of accuracy and stability of the MLC. This article is based on the analytical investigation of the accuracy and the stability of the MLC. Different patterns of MLC movements were generated to investigate the characteristics of the MLC. One of the considered aspects contains the friction between the leaves. The influence of variations of the compressed air on the MLC was also explored. The integrated MVCT detector of the tomotherapy system deposits the treatment data in a matrix. The detector is triggered with the linear accelerator, which is pulsed by 300Hz. The data matrix is available after the treatment. An IDL (Interactive Data Language) routine was programmed in order to analyse the matrix. The points of time, at which the leaves open (POT), and the period, in which the leaves stay open (LOT), were measured and compared with the desired values. That procedure has been repeated several times a week for approximately 6 months to investigate the stability of the MLC. Relative deviations of the LOT from -0.4% to -5.4% were measured. The friction between the leaves had no significant influence on the LOT. The available compressed air, that is used to move the leaves, depends on the number of moving leaves and also on the previous movements of the MLC. Variations of the compressed air resulted in deviations of the LOT from -1.8% to 3.7%. The measured POT deviates from the programmed POT up to -18.4ms+/-0.7ms. This maximal deviation correlates with a shift of the gantry angle of 0.52 which is negligible. The MLC has shown a stable behaviour over the 6 months. A separate consideration of the leaves showed no higher standard deviation of the LOT than +/-0.7ms during the investigated time. The variation between the different leaves is much higher than the deviations of LOT caused by friction and changes of compressed air. The deviations of the LOT vary between -2.6ms and -11.0ms. The developed method is feasible in order to recognize a deterioration of the MLC performance. PMID- 22921843 TI - Development of a Geant4 based Monte Carlo Algorithm to evaluate the MONACO VMAT treatment accuracy. AB - A method to evaluate the dosimetric accuracy of volumetric modulated arc therapy (VMAT) treatment plans, generated with the MONACOTM (version 3.0) treatment planning system in realistic CT-data with an independent Geant4 based dose calculation algorithm is presented. Therefore a model of an Elekta Synergy linear accelerator treatment head with an MLCi2 multileaf collimator was implemented in Geant4. The time dependent linear accelerator components were modeled by importing either logfiles of an actual plan delivery or a DICOM-RT plan sequence. Absolute dose calibration, depending on a reference measurement, was applied. The MONACO as well as the Geant4 treatment head model was commissioned with lateral profiles and depth dose curves of square fields in water and with film measurements in inhomogeneous phantoms. A VMAT treatment plan for a patient with a thoracic tumor and a VMAT treatment plan of a patient, who received treatment in the thoracic spine region including metallic implants, were used for evaluation. MONACO, as well as Geant4, depth dose curves and lateral profiles of square fields had a mean local gamma (2%, 2mm) tolerance criteria agreement of more than 95% for all fields. Film measurements in inhomogeneous phantoms with a global gamma of (3%, 3mm) showed a pass rate above 95% in all voxels receiving more than 25% of the maximum dose. A dose-volume-histogram comparison of the VMAT patient treatment plans showed mean deviations between Geant4 and MONACO of -0.2% (first patient) and 2.0% (second patient) for the PTVs and (0.5+/-1.0)% and (1.4+/-1.1)% for the organs at risk in relation to the prescription dose. The presented method can be used to validate VMAT dose distributions generated by a large number of small segments in regions with high electron density gradients. The MONACO dose distributions showed good agreement with Geant4 and film measurements within the simulation and measurement errors. PMID- 22921844 TI - Foam-oil interaction in porous media: implications for foam assisted enhanced oil recovery. AB - The efficiency of a foam displacement process in enhanced oil recovery (EOR) depends largely on the stability of foam films in the presence of oil. Experimental studies have demonstrated the detrimental impact of oil on foam stability. This paper reviews the mechanisms and theories (disjoining pressure, coalescence and drainage, entering and spreading of oil, oil emulsification, pinch-off, etc.) suggested in the literature to explain the impact of oil on foam stability in the bulk and porous media. Moreover, we describe the existing approaches to foam modeling in porous media and the ways these models describe the oil effect on foam propagation in porous media. Further, we present various ideas on an improvement of foam stability and longevity in the presence of oil. The outstanding questions regarding foam-oil interactions and modeling of these interactions are pointed out. PMID- 22921845 TI - Thermal properties of nanofluids. AB - Colloidal suspensions of fine nanomaterials in the size range of 1-100 nm in carrier fluids are known as nanofluids. For the last one decade, nanofluids have been a topic of intense research due to their enhanced thermal properties and possible heat transfer applications. Miniaturization and increased operating speeds of gadgets warranted the need for new and innovative cooling concepts for better performance. The low thermal conductivity of conventional heat transfer fluid has been a serious impediment for improving the performance and compactness of engineering equipments. Initial studies on thermal conductivity of suspensions with micrometer-sized particles encountered problems of rapid settling of particles, clogging of flow channels and increased pressure drop in the fluid. These problems are resolved by using dispersions of fine nanometer-sized particles. Despite numerous experimental and theoretical studies, it is still unclear whether the thermal conductivity enhancement in nanofluids is anomalous or within the predictions of effective medium theory. Further, many reports on thermal conductivity of nanofluids are conflicting due to the complex issues associated with the surface chemistry of nanofluids. This review provides an overview of recent advances in the field of nanofluids, especially the important material properties that affect the thermal properties of nanofluids and novel approaches to achieve extremely high thermal conductivities. The background information is also provided for beginners to better understand the subject. PMID- 22921846 TI - Strategies to enhance assessment of the fetal head position before instrumental delivery: a survey of obstetric practice in the United Kingdom and Ireland. AB - OBJECTIVE: To establish the current practice of obstetricians with regard to assessment of women in labour before instrumental delivery. STUDY DESIGN: A national postal survey of obstetricians in consultant-led obstetric units in the United Kingdom and Ireland. Clinical assessment before instrumental delivery, factors associated with difficulty in determining the fetal head position, approaches used to enhance determination of the fetal head position, perceived accuracy rates in assessment of the fetal head position and willingness to participate in a clinical trial of ultrasound assessment of the fetal head position before instrumental delivery were explored. RESULTS: The response rate was 75%. The majority of obstetricians assess women clinically before instrumental delivery as recommended by guidelines. Both consultants and trainees reported the following factors as being associated with difficulty in diagnosing the fetal head position: inadequate maternal pain relief, fetal caput and clinical inexperience. Strategies used when experiencing difficulty in determining the fetal head position varied, with trainees more likely than consultants to seek a second opinion (40% vs. 5%, p<0.0001), reassess in an operating theatre (80% vs. 68%, p=0.048) or abandon the procedure in favour of caesarean section (14% vs. 6%, p=0.035). One in five obstetricians reported using abdominal ultrasound to aid diagnosis, with some consultants reporting the use of ultrasound as 'a great idea' and others being 'appalled'. One in eight consultants perceived that they made an incorrect diagnosis of the fetal head position at instrumental delivery in more than 10% of deliveries compared to one in four trainees. CONCLUSION: The contrasting views on the role of ultrasound to enhance the assessment of the fetal head position before instrumental delivery suggest that it should be evaluated in a randomised clinical trial. PMID- 22921847 TI - Maternal and neonatal copeptin levels at cesarean section and vaginal delivery. AB - OBJECTIVE: The objective of the study was to measure the copeptin levels in maternal serum and umbilical cord serum at cesarean section and vaginal delivery in normotensive pregnancy and pre-eclamptic women. STUDY DESIGN: This was a prospective study at Mansoura University Hospital, Egypt. Ninety cases were included. They were divided into six groups: (1) normal pregnancy near term, as a control group, (2) primiparas who had vaginal delivery, (3) primiparas who had vaginal delivery and mild preeclampsia, (4) elective repeat cesarean section, (5) intrapartum cesarean section for indications other than fetal distress, and (6) intrapartum cesarean section for fetal distress. Serum copeptin concentrations were quantified with an enzyme-linked immunosorbent assay (ELISA). Mean, standard deviation, and paired t-test were used to test for significant change in quantitative data. RESULTS: The vaginal delivery groups had higher levels of maternal serum copeptin than the elective cesarean section group (P<0.01). Higher maternal serum copeptin levels were found in cases with pre-eclampsia as compared with the normotensive cases. The maternal copeptin levels during intrapartum cesarean section were higher than that during elective repeat cesarean section. There was a significant correlation between maternal copeptin levels and the duration of the first stage. In the presence of fetal distress, umbilical cord serum copeptin levels were significantly higher than other groups. CONCLUSION: Vaginal delivery can be very painful and stressful, and is accompanied by a marked increase of maternal serum copeptin. Increased maternal levels of serum copeptin were found in cases with pre-eclampsia as compared with the normotensive cases, and it may be helpful in assessing the disease. Intrauterine fetal distress is a strong stimulus to the release of copeptin into the fetal circulation. PMID- 22921841 TI - Nanotopography-guided tissue engineering and regenerative medicine. AB - Human tissues are intricate ensembles of multiple cell types embedded in complex and well-defined structures of the extracellular matrix (ECM). The organization of ECM is frequently hierarchical from nano to macro, with many proteins forming large scale structures with feature sizes up to several hundred microns. Inspired from these natural designs of ECM, nanotopography-guided approaches have been increasingly investigated for the last several decades. Results demonstrate that the nanotopography itself can activate tissue-specific function in vitro as well as promote tissue regeneration in vivo upon transplantation. In this review, we provide an extensive analysis of recent efforts to mimic functional nanostructures in vitro for improved tissue engineering and regeneration of injured and damaged tissues. We first characterize the role of various nanostructures in human tissues with respect to each tissue-specific function. Then, we describe various fabrication methods in terms of patterning principles and material characteristics. Finally, we summarize the applications of nanotopography to various tissues, which are classified into four types depending on their functions: protective, mechano-sensitive, electro-active, and shear stress-sensitive tissues. Some limitations and future challenges are briefly discussed at the end. PMID- 22921848 TI - Event-related near-infrared spectroscopy detects conflict in the motor cortex in a Stroop task. AB - The Stroop effect is one of the most popular models of conflict processing in neuroscience and psychology. The response conflict theory of the Stroop effect explains decreased performance in the incongruent condition of Stroop tasks by assuming that the task-relevant and the task-irrelevant stimulus features elicit conflicting response tendencies. However, to date, there is not much explicit neural evidence supporting this theory. Here we used functional near-infrared imaging (fNIRS) to examine whether conflict at the level of the motor cortex can be detected in the incongruent relative to the congruent condition of a Stroop task. Response conflict was determined by comparing the activity of the hemisphere ipsilateral to the response hand in the congruent and incongruent conditions. First, results provided explicit hemodynamic evidence supporting the response conflict theory of the Stroop effect: there was greater motor cortex activation in the hemisphere ipsilateral to the response hand in the incongruent than in the congruent condition during the initial stage of the hemodynamic response. Second, as fNIRS is still a relatively novel technology, it is methodologically significant that our data shows that fNIRS is able to detect a brief and transient increase in hemodynamic activity localized to the motor cortex, which in this study is related to subthreshold motor response activation. PMID- 22921849 TI - Bi-lateral changes to hippocampal cholesterol levels during epileptogenesis and in chronic epilepsy following focal-onset status epilepticus in mice. AB - Brain cholesterol homeostasis has been shown to be disrupted in neurodegenerative conditions such as Alzheimer's and Huntington's diseases. Investigations in animal models of seizure-induced brain injury suggest that brain cholesterol levels are altered by prolonged seizures (status epilepticus) and are a feature of the pathophysiology of temporal lobe epilepsy. The present study measured hippocampal sterol levels in a model of unilateral hippocampal injury triggered by focal-onset status epilepticus, and in chronically epileptic mice. Status epilepticus was induced by intra-amygdala microinjection of kainic acid and ipsilateral and contralateral hippocampus analyzed. No significant changes were found for ipsilateral or contralateral hippocampal levels of desmosterol or lathosterol at any time after SE as measured by gas chromatography-mass spectrometry. 24S-hydroxycholesterol and cholesterol levels were unchanged up to 24h after status epilepticus but were decreased in the ipsilateral hippocampus during early epileptogenesis and in chronically epileptic mice. Levels of cholesterol were also reduced in the contralateral hippocampus during epileptogenesis and in chronic epileptic mice. Treatment of mice with the anti inflammatory cholesterol synthesis inhibitor lovastatin did not alter seizures during status epilepticus or seizure-induced neuronal death. Thus, changes to hippocampal cholesterol homeostasis predominantly begin during epileptogenesis, occur bi-laterally even when the initial precipitating injury is unilateral, and continue into the chronic epileptic period. PMID- 22921850 TI - Selenium reduces cadmium uptake and mitigates cadmium toxicity in rice. AB - Hydroponic experiments were performed to investigate physiological mechanisms of selenium (Se) mitigation of Cd toxicity in rice. Exogenous Se markedly reduced Cd concentration in leaves, roots, and stems. Addition or pretreatment of 3 MUM Se in 50 MUM Cd solution significantly addressed Cd-induced growth inhibition, recovered root cell viability, and dramatically depressed O(2)(-), H(2)O(2), and malondialdehyde (MDA) accumulation. Supplemental Se counteracted 50 MUM Cd induced alterations of certain antioxidant enzymes, and uptake of nutrients, e.g. depressed Cd-induced increase in leaf and root superoxide dismutase (SOD) and leaf peroxidase (POD) activities, but elevated depressed catalase (CAT) activity; decreased Cd-induced high S and Cu concentrations in both leaves and roots. External Se counteracted the pattern of alterations in ATPase activities induced by Cd, e.g. significantly elevated the depressed root H(+)- and Ca(2+)-ATPase activities, but decreased the ascent root Na(+)K(+)-ATP activity. Results indicate that alleviated Cd toxicity by Se application is related to reduced Cd uptake and ROS accumulation, balanced nutrients, and increased H(+)- and Ca(2+) ATPase activities in rice. PMID- 22921851 TI - Ultrasound-assisted extraction for total sulphur measurement in mine tailings. AB - A sample preparation method for percentage recovery of total sulphur (%S) in reactive mine tailings based on ultrasound-assisted digestion (USAD) and inductively coupled plasma-optical emission spectroscopy (ICP-OES) was developed. The influence of various methodological factors was screened by employing a two level and three-factor (2(3)) full factorial design and using KZK-1, a sericite schist certified reference material (CRM), to find the optimal combination of studied factors and %S. Factors such as the sonication time, temperature and acid combination were studied, with the best result identified as 20 min of sonication, 80 degrees C temperature and 1 ml of HNO(3):1 ml of HCl, which can achieve 100% recovery for the selected CRM. Subsequently a fraction of the 2(3) full factorial design was applied to mine tailings. The percentage relative standard deviation (%RSD) for the ultrasound method is less than 3.0% for CRM and less than 6% for the mine tailings. The investigated method was verified by X-ray diffraction analysis. The USAD method compared favorably with existing methods such as hot plate assisted digestion method, X-ray fluorescence and LECOTM-CNS method. PMID- 22921852 TI - Assessment of the efficacy and quality of evidence for five on-farm interventions for Salmonella reduction in grow-finish swine: a systematic review and meta analysis. AB - Five on-farm practices for reduction of Salmonella shedding or sero-prevalence in grow-finish swine were selected through scoping study and expert consultation. Specific examples were selected based on supporting evidence from at least one controlled trial (CT), and availability to Canadian swine producers. Efficacy was evaluated using systematic review and meta-analysis (SR-MA) methodology. A modified Grading of Recommendations, Assessment, and Evaluation (GRADE) approach was applied to assess the quality of evidence for each intervention, and a 'summary of findings' table was developed to present findings 'at-a-glance'. MA of the small dataset of CTs investigating feeding meal, and measuring serology, yielded a significant summary estimate of efficacy (odds ratio (OR)=0.21; 95% confidence intervals (CI): 0.14, 0.31) with non-significant heterogeneity (P>0.10). MA of the dataset investigating inclusion of organic acids in the ration, measuring serology, yielded a significant summary estimate with significant heterogeneity across studies (P<0.001, I(2)=91%) precluding presentation of a single summary estimate; a range of results were reported (OR Range: 28 (1.6, 498); 0.07 (CI: 0.042, 0.33)). Pen disinfection between batches of finishers was studied in one large CT measuring both fecal culture (OR 0.84 (0.68, 1.1)) and serology (OR 0.48 (0.40, 0.58)) outcomes. The dataset investigating Salmonella spp. vaccination contained inconsistent findings (OR Range: 4.5 (1.3, 15); 0.07 (0.008, 0.68)), with significant heterogeneity across studies (P=0.005, I(2)=82), assessed measuring fecal culture. MA of the dataset investigating inclusion of in-feed tetracyclines yielded a significant OR indicating a potential harmful effect, measuring fecal culture, (OR Range: 14 (1.9, 108); 1.0 (0.43, 2.5)) with significant heterogeneity (P=0.003, I(2)=82%) across studies, suggesting some potential for withdrawal of in-feed tetracyclines to reduce Salmonella shedding. Therefore our ranking of intervention efficacy is: feeding meal>inclusion of acids in ration, feeder pen disinfection or Salmonella spp. vaccination>in-feed tetrayclines. Study design characteristics increasing risk of bias, including failure to justify sample size (19 of 31 studies) and failure to report random or systematic sampling (13 of 31 studies), resulted in modified GRADE evidence rankings of 'low' for these interventions. This suggests that further research is likely to affect our findings. Field CTs investigating herd-level interventions with measurements at the herd- and individual-levels are recommended. Overall, SR-MA was a useful approach for ranking efficacy, and GRADE offered a transparent method for ranking quality of evidence, although both were limited by the small number of comparable studies available. PMID- 22921853 TI - Improving the validity of peripheral venous blood gas analysis as an estimate of arterial blood gas by correcting the venous values with SvO2. AB - BACKGROUND: Peripheral venous blood gas (pVBG) analysis in replacement of arterial blood gas (ABG) is limited by the unpredictable differences between arterial and venous values, especially for PCO2 and pH (DeltaPCO2 and DeltapH). OBJECTIVES: We hypothesized that, using the theoretical relationship linking SvO2 and blood flow, we could diminish the effect of local circulatory conditions on DeltaPCO2 and DeltapH and thereby increase pVBG validity. METHODS: This was a prospective cross-sectional study performed in emergency patients requiring a blood gas analysis in which ABG and pVBG were performed simultaneously. The data of 50 randomly selected patients (model group) were used for developing two equations to correct PvCO2 and pHv according to the peripheral SvO2 (SpvO2) level. The formulas derived were PvCO2cor = PvCO2 - 0.30 * (75 - SpvO2), and pHvcor = pHv + 0.001 * (75 - SpvO2). The validity of the corrected values was then tested on the remaining population (validation group). RESULTS: There were 281 patients included in the study, mainly for dyspnea. DeltaPCO2 and DeltapH were strongly correlated with SpvO2 (r(2) = 0.62 and r(2) = 0.53, respectively, p < 0.001). Using the data of the model group, we developed equations that we applied on the validation group. We found that the corrected values were more valid than the raw values for detecting a PaCO2 > 45 mm Hg (AUC ROC = 0.96 +/- 0.01 vs. 0.89 +/- 0.02, p < 0.001), a PaCO2 < 35 mm Hg (AUC = 0.95 +/- 0.02 vs. 0.84 +/- 0.03, p < 0.001), a pHa < 7.35 (AUC = 0.97 +/- 0.01 vs. 0.95 +/- 0.02, p < 0.05), or a pHa > 7.45 (AUC = 0.91 +/- 0.02 vs. 0.81 +/- 0.04, p < 0.001). CONCLUSIONS: The variability of DeltaPCO2 and DeltapH is significantly lowered when the venous values are corrected according to the SpvO2 value, and pVBG is therefore more accurate and valid for detecting an arterial abnormality. PMID- 22921854 TI - Impact of a computerized order set on adherence to Centers for Disease Control guidelines for the treatment of victims of sexual assault. AB - BACKGROUND: Care of the sexual assault patient in the Emergency Department can be challenging due to complex pharmacologic interventions, evidence-collection procedures, and concomitant injury. OBJECTIVE: We sought to determine the effect of a standard, computerized order set for the treatment of adult victims of sexual assault on compliance with current Centers for Disease Control and Prevention (CDC) guidelines for the treatment of this population. METHODS: This study utilized a pretest-post-test design to evaluate the implementation of a standardized order set that provided clinicians with treatment recommendations consistent with CDC guidelines. Comparison of the rate of compliance with CDC guidelines before (n = 322) and after (n = 131) implementation of the order set was the primary outcome. Additional analyses examined for differences in compliance based upon evaluation by a sexual assault nurse/forensic examiner (SANE/SAFE), sex, and race. RESULTS: Pre-intervention phase compliance was 14 of 322 cases (4.4%) and post-intervention compliance was 108 of 131 cases (82.4%). This difference was statistically significant, chi(2) = 291.635, df = 1, p < 0.001. Overall, compliance with CDC pharmacologic recommendations was achieved in 122 (26.9%) cases. Evaluation by a SANE/SAFE nurse conferred no statistically significant difference in compliance. No statistically significant differences were noted based upon sex or race. CONCLUSIONS: The implementation of a standard, computerized order set for the treatment of adult victims of sexual assault significantly improved medical provider compliance with CDC treatment guidelines. This research demonstrates that electronic order sets can promulgate evidence based practices in clinical medicine. PMID- 22921855 TI - Terlipressin decreases vascular endothelial growth factor expression and improves oxygenation in patients with acute respiratory distress syndrome and shock. AB - BACKGROUND: Recent clinical data suggest that treatment with terlipressin (TP) may be more advantageous for septic shock than catecholamines. However, it is unknown whether TP would be effective for acute respiratory distress syndrome (ARDS) patients with shock. OBJECTIVES: The aim of this study was to compare the impact of TP vs. dopamine on hemodynamic variables and vascular endothelial growth factor (VEGF) in ARDS patients with shock. METHODS: We studied 32 ARDS patients with shock despite fluid loading, who were randomized to receive TP (16 patients) or dopamine (16 patients). TP was administered as a continuous intravenous dose of 1.3 MUg/kg/h and dopamine was administered in doses up to 20 MUg/kg/min to maintain a mean arterial pressure of 70 +/- 5 mm Hg for 48 h. Hemodynamic changes, ratio of partial pressure of arterial oxygen to fraction of inspired oxygen (PaO(2)/FiO(2)), and VEGF were recorded prospectively. RESULTS: There was a significant correlation between the plasma VEGF level and the lung injury score at baseline (r = 0.387, p < 0.01). VEGF concentrations significantly decreased from baseline levels in the TP group (p < 0.05) at 48 h; there was no difference in the dopamine group (p > 0.05) at 48 h vs. baseline. There was no significant difference in the tumor necrosis factor-alpha concentration between the groups. CONCLUSIONS: TP treatment has the potential to inhibit VEGF and improve oxygenation in patients with shock in the early stage of ARDS. PMID- 22921856 TI - Gas-producing cellulitis from injection of spot remover fluid (n-Hexane). AB - BACKGROUND: Subcutaneous administration of hydrocarbons, categorized according to their toxicological profiles, is rare compared to oral, inhalational, and cutaneous routes of exposure. Furthermore, injection of n-hexane in humans has not been described. OBJECTIVES: This report demonstrates a singular case of subcutaneous administration of n-hexane. CASE REPORT: A 21-year-old man presented to the Emergency Department (ED) 7 h after injecting his left antecubital fossa with approximately 5 cc of spot remover fluid, which contained more than 95% n hexane, in a suicide attempt. There was redness in the left forearm, but no apparent swelling was observed. He was administered tetanus prophylaxis and discharged with follow-up. However, the patient returned to the ED 14 h later, complaining of progression of the swelling around the injection site extending to the axilla. Significant volume of air in the soft tissue of the affected extremity was noted on both the radiograph and computed tomography scan; therefore, an immediate extensive incision and debridement of the diseased limb was performed. The postoperative course was uneventful, and a complete resolution of emphysema without any functional deficits was obtained for 5 months of follow up. CONCLUSION: In patients suffering from n-hexane injection, initial physical examination findings may not be apparent. Thus, the patient must be monitored closely for evidence of a spread of subcutaneous gas with elevation and immobilization. If increase in tissue pressure or spread of gas is not prevented, as in our case, immediate incision and removal of the toxic substances should be planned. PMID- 22921857 TI - Relationship between near infrared spectroscopy and intra-compartmental pressures. AB - BACKGROUND: Near infrared spectroscopy (NIRS) has been suggested as a possible means for detecting perfusion deficits in patients with acute compartment syndrome (ACS). STUDY OBJECTIVES: To longitudinally examine NIRS in an ACS model to determine its responsiveness to decreasing perfusion pressure. METHODS: A NIRS sensor pad was placed under a tourniquet over the anterior compartment in the mid tibia region on 20 volunteers. Initial perfusion pressures and NIRS values were recorded. The tourniquet pressure was sequentially raised by 10 mm Hg in 10-min intervals until systolic pressure was surpassed. NIRS values and perfusion pressure were determined at the end of each 10-min interval. RESULTS: There was no change in mean NIRS values from the initial baseline until 30 mm Hg of perfusion pressure was reached. Additionally, a statistically significant drop in mean NIRS values was observed as perfusion pressures dropped from 10 mm Hg to 0 mm Hg, and again with subsequent decreases of 10 mm Hg perfusion pressure until systolic pressure was surpassed. CONCLUSIONS: These results coincide with previously published studies using alternative methods of measuring blood flow or perfusion. NIRS values were responsive to decreasing perfusion pressures over a longitudinal period of time in an ACS model. These results suggest that NIRS may be useful for continuous, non-invasive monitoring of patients for whom ACS is a concern. Additional studies on traumatized patients are required. PMID- 22921858 TI - No diversion in Western Massachusetts. AB - BACKGROUND: Massachusetts (MA) instituted a moratorium on ambulance diversion ("No Diversion") on January 1, 2009. STUDY OBJECTIVES: Determine whether No Diversion was associated with changes in Emergency Department (ED) throughput measures. DESIGN: Comparison of three 3-month periods. Period 1: 1 year prior (January-March 2008); Period 2: 3 months prior (October-December 2008); Period 3: 3 months after (January-March 2009). SETTING: Seven EDs in Western MA; two - including the only Level I Trauma Center - were "high" diversion (>=562 h/year) and 5 were "low" diversion (<=260 h/year). For "all," "high" diversion and "low" diversion ED groups, we compared mean monthly throughput measures, including: 1) total volume, 2) number of admissions, 3) number of elopements, 4) length of stay for all, admitted and discharged patients. Mean absolute and percent changes were estimated using mixed-effects regression analysis. Linear mixed models were run for "all," "high" and "low" diversion EDs comparing means of changes between periods. Results are presented as mean change per month in number and percent, and 95% confidence intervals were calculated. We specified that a clinically significant effect of No Diversion had to meet two criteria: 1) there was a consistent difference in the means for both the Period 1 vs. Period 3 comparison and the Period 2 vs. Period 3 comparison, and 2) both comparisons had to achieve statistical significance at p <= 0.01. RESULTS: According to pre-determined criteria, no clinically significant changes were found in any ED group in mean monthly volume, admissions, elopements, or length-of-stay for any patient disposition group. CONCLUSION: No Diversion was not associated with significant changes in throughput measures in "all," "high" diversion and "low" diversion EDs. PMID- 22921859 TI - Respiratory distress and abdominal pain in a bed-bound nursing home patient. PMID- 22921860 TI - Rupture of ectopic pelvic dysplastic kidney after blunt abdominal trauma presenting as left lower quadrant pain. AB - BACKGROUND: Ectopic pelvic dysplastic kidney is very rare. To our knowledge, there is no case report in the literature that discusses the diagnosis and management of ectopic pelvic dysplastic kidney in trauma. OBJECTIVES: To report an unusual organ injury after abdominal blunt trauma. CASE REPORT: A 23-year-old man presented to the Emergency Department with complaints of left lower quadrant pain after blunt abdominal trauma. Rupture of an ectopic pelvic dysplastic kidney was suspected from ultrasonography and then confirmed by a computed tomography scan. The patient was managed successfully with conservative therapy. CONCLUSIONS: The focused assessment with sonography for trauma examination is beneficial to hemodynamically stable blunt abdominal trauma patients because unusual organ injuries can be detected early. PMID- 22921861 TI - Increased gamma oscillations during voluntary selection processes in adult patients with attention deficit/hyperactivity disorder. AB - Executive dysfunctions (regarding behavioural inhibition, decision making, flexibility or voluntary selection) rank among the core symptoms of attention deficit/hyperactivity disorder. Several studies demonstrated functional variations in patients with ADHD especially during response inhibition and flexibility. However, information about functional correlates of other aspects of executive functions such as voluntary selection processes is limited. A group of thirty adult patients with attention deficit/hyperactivity disorder (ADHD) and 30 healthy controls, matched for age and education, participated in the present study. Electrophysiological responses (event-related potentials, gamma oscillations) and behavioural data were acquired during the voluntary selection between various response alternatives. ADHD patients demonstrated increased responses in the gamma frequency band especially in frontal and fronto-central brain areas during voluntary response selection processes compared to healthy subjects. In addition, the error rate was increased in patients. Given that gamma band responses have been related to GABAergic and glutamatergic responses these results may indicate accordant dysfunction in patients with ADHD. PMID- 22921862 TI - Regional cerebral blood flow and abnormal eating behavior in Prader-Willi syndrome. AB - BACKGROUND: Prader-Willi syndrome (PWS) is a genetically determined neurodevelopmental disorder and is generally regarded as a genetic model of obesity. Individuals with PWS exhibit behavioral symptoms including temper tantrums, rigid thinking, and compulsive behavior. The most striking feature of PWS is abnormal eating behavior, including hyperphagia, intense preoccupation with food, and incessant food seeking. To explore brain regions associated with the behavioral symptoms of PWS, we investigated differences in resting-state regional cerebral blood flow (rCBF) between individuals with PWS and healthy controls. Correlation analyses were also performed to examine the relationship between rCBF and altered eating behavior in PWS individuals. METHODS: Twelve adults with PWS and 13 age- and gender-matched controls underwent resting-state single photon emission computerized tomography (SPECT) with N-isopropyl-p [(123)I] iodoamphetamine (IMP). The rCBF data were analyzed on a voxel-by-voxel basis using SPM5 software. RESULTS: The results demonstrated that compared with controls, individuals with PWS had significantly lower rCBF in the right thalamus, left insular cortex, bilateral lingual gyrus, and bilateral cerebellum. They had significantly higher rCBF in the right inferior frontal gyrus, left middle/inferior frontal gyrus (anterior and posterior clusters), and bilateral angular gyrus. Additionally, rCBF in the left insula, which was significantly lower in PWS individuals, was negatively correlated with the eating behavior severity score. CONCLUSIONS: These results suggest that specific brain regions, particularly the left insula, may be partly responsible for the behavioral symptoms in PWS. PMID- 22921863 TI - Pulmonary hypertension in mitochondrial disorders. PMID- 22921864 TI - Molecular mechanisms mediating metastasis of hypoxic breast cancer cells. AB - Breast cancers contain regions of intratumoral hypoxia in which reduced O(2) availability activates the hypoxia-inducible factors HIF-1 and HIF-2, which increase the transcription of genes encoding proteins that are required for many important steps in cancer progression. Recently, HIFs have been shown to play critical roles in the metastasis of breast cancer to the lungs through the transcriptional activation of genes encoding angiopoietin-like 4 and L1 cell adhesion molecule, which promote the extravasation of circulating cancer cells from the lung vasculature, and the lysyl oxidase family members LOX, LOXL2, and LOXL4, which promote invasion and metastatic niche formation. Digoxin, a drug that inhibits HIF-1 activity, blocks primary tumor growth, vascularization, invasion, and metastasis in ex vivo and in vivo assays. PMID- 22921865 TI - Development and validation of the Patient Asthma Concerns Tool (PACT) to identify the needs of older people with asthma. AB - BACKGROUND: Tools which assist practitioners to identify patient concerns and increase understanding of their needs can improve both the delivery of care and adherence to treatment. The aim of this study was to test the validity and reliability of a 14-item tool, to identify the unmet needs and concerns of older people with asthma. METHODS: The Patient Asthma Concerns Tool (PACT) was developed from a pool of 55 items derived from a comprehensive literature review. After pilot and field testing, the initial 55 item questionnaire was administered to a community sample (n = 193), psychometrically tested, and refined to a 14 item PACT tool which was evaluated by a group of clinicians. RESULTS: The PACT was shown to have good content and construct validity and was well received by clinicians. The PACT also correlated well with the Juniper ACQ and Brooks' adherence score on related variables and showed good reliability with good excellent Kappa and ICC scores. Internal consistency of factors was high, and the overall Cronbach's alpha was 0.70. CONCLUSION: The PACT questionnaire was shown to be a valid and reliable tool clinically and psychometrically. We intend to test it in primary care settings and anticipate that its use will assist health professionals to identify the needs and concerns of older patients with asthma and direct tailored asthma management accordingly. PMID- 22921866 TI - Event-related potentials dissociate perceptual from response-related age effects in visual search. AB - Attentional decline plays a major role in cognitive changes with aging. However, which specific aspects of attention contribute to this decline is as yet little understood. To identify the contributions of various potential sources of age decrements in visual search, we combined response time measures with lateralized event-related potentials of younger and older adults performing a compound-search task, in which the target-defining dimension of a pop-out target (color/shape) and the response-critical target feature (vertical/horizontal stripes) varied independently across trials. Slower responses in older participants were associated with age differences in all analyzed event-related potentials from perception to response, indicating that behavioral slowing originates from multiple stages within the information-processing stream. Furthermore, analyses of carry-over effects from one trial to the next revealed repetition facilitation of the target-defining dimension and of the motor response-originating from preattentive perceptual and motor execution stages, respectively-to be independent of age. Critically, we demonstrated specific age deficits on intermediate processing stages when intertrial changes required more executively controlled processes, such as flexible stimulus-response (re-)mapping across trials. PMID- 22921868 TI - Skin barrier abnormality caused by filaggrin (FLG) mutations is associated with increased serum 25-hydroxyvitamin D concentrations. PMID- 22921869 TI - Future of allergy/immunology task force report. PMID- 22921867 TI - Fibroblast growth factor 23: state of the field and future directions. AB - Fibroblast growth factor 23 (FGF23) is a bone-derived hormone that regulates and is regulated by blood levels of phosphate and active vitamin D. Post translational glycosylation by the enzyme GALNT3 and subsequent processing by furin have been demonstrated to be a regulated process that plays a role in regulating FGF23 levels. In physiologic states, FGF23 signaling is mediated by an FGF receptor and the coreceptor, Klotho. Recent work identifying a role for iron/hypoxia pathways in FGF23 physiology and their implications are discussed. Beyond its importance in primary disorders of mineral metabolism, recent work implicates FGF23 in renal disease-associated morbidity, as well as possible roles in cardiovascular disease and skeletal fragility. PMID- 22921870 TI - Utility of casein-specific IgE levels in predicting reactivity to baked milk. PMID- 22921871 TI - Oral exposure to Mal d 1 affects the immune response in patients with birch pollen allergy. AB - BACKGROUND: Antibodies and T cells specific for the major birch pollen allergen Bet v 1 cross-react with structurally related food allergens, such as Mal d 1 in apple. OBJECTIVE: We sought to evaluate the effects of oral uptake of Mal d 1 on the allergen-specific immune response in patients with birch pollen allergy. METHODS: Patients received 50 MUg of rBet v 1 sublingually on 2 consecutive days outside of the birch pollen season. One year later, equal amounts of rMal d 1 were administered. Blood samples were collected before and after oral exposure, as well as before and after the intermediate birch pollen season. Allergen specific IgE levels were determined by using ImmunoCAP. Proliferation of allergen stimulated PBMCs was assessed, as well as the expression of IL-5, IL-13, IL-10, IFN-gamma, and forkhead box protein 3 (Foxp3) in isolated T cells (real-time PCR). Allergen-specific T-cell lines were analyzed for epitope recognition. RESULTS: Orally administered Bet v 1 transiently reduced Bet v 1-specific serum IgE levels, as well as Bet v 1- and Mal d 1-induced T-cell proliferation, and enhanced the expression of IL-5, IL-10, and Foxp3. Orally applied Mal d 1 significantly decreased Bet v 1- and Mal d 1-specific IgE levels and induced IL-5 and IL-10 but no Foxp3 expression. In contrast to Bet v 1, Mal d 1 triggered IFN gamma production and T cells with a different epitope repertoire. Inhalation of birch pollen significantly enhanced allergen-specific IgE levels, T-cell proliferation, and IL-5, IL-10, IL-13, and Foxp3 expression. CONCLUSION: Two sublingual administrations of 50 MUg of Mal d 1 were well tolerated and induced transient immune responses seen during peripheral tolerance development. Thus recombinant Mal d 1 might be suitable and relevant for sublingual treatment of birch pollen-related apple allergy. PMID- 22921872 TI - Plasma levels of soluble MICA and ULBP2 are increased in children allergic to dust mites. PMID- 22921874 TI - Acute toxicity of crude oil water accommodated fraction on marine copepods: the relative importance of acclimatization temperature and body size. AB - Recent oil spillage accidents around the world greatly increase harmful risks to marine ecology. This study evaluated the influences of petroleum water accommodated fraction (WAF) on 15 typical species of marine copepods collected from a subtropical bay in East China Sea at different seasons. Copepods showed impaired swimming ability, restlessness, loss of balance, anoxic coma, and even death when they were acutely exposed to the crude oil WAF under laboratory conditions. The LC(50) values (expressed in total petroleum hydrocarbon concentration) indicated that the tolerances of copepods to WAF decreased significantly (P < 0.05) with increased exposure duration and natural water temperatures (acclimatization temperature). The sensitivity of the copepods was species-specific (P < 0.01), and there was a significant (P < 0.05) positive correlation between the 48-h LC(50) and body size. Therefore, the small copepod species confront more survival challenges under oil contamination stress, especially in the warm months or regions. PMID- 22921873 TI - Relation between objective measures of atopy and myocardial infarction in the United States. AB - BACKGROUND: Although rodent studies indicate that atherosclerosis is a T(H)1 mediated disease and that atopic T(H)2 immunity is atheroprotective, findings in humans are conflicting. Total IgE (tIgE) is associated with atherosclerotic disease but has limited specificity for atopy. OBJECTIVE: Our aim was to determine the relation between atopy, as indicated by a broad panel of serum allergen-specific IgE (sIgE), and past myocardial infarction (MI) in a sample representative of the US population. METHODS: Data were analyzed from 4002 participants aged >= 20 years from the 2005-2006 National Health and Nutrition Examination Survey. RESULTS: Subjects reporting a history of MI had lower summed sIgE (5.51 vs 7.71 kU/L; P < .001) and were less likely to have >= 1 positive sIgE test (29.9% vs 44.6%; P = .02) or current hay fever (3.3% vs 7.6%; P = .002). After adjustment for age, sex, race/ethnicity, diabetes mellitus, hypertension, family history of MI, smoking, total/high-density lipoprotein cholesterol, body mass index, and C-reactive protein, the odds ratio (OR) for MI was 0.91 (95% CI, 0.85-0.97) per positive sIgE; 0.70 (95% CI, 0.57-0.85) per 2 fold increase in sum[sIgE]; and 0.82 (95% CI, 0.69-0.98) per 10% increase in the ratio of sum[sIgE] to tIgE. Analysis with 7 data-driven, prespecified allergen clusters found that house dust mite is the only allergen cluster for which sIgE is associated with reduced odds for MI (fully adjusted OR, 0.36; 95% CI, 0.20 0.64). CONCLUSION: Serum sIgE is inversely related to MI in the US population in a manner independent of multiple coronary risk factors. PMID- 22921875 TI - Clinical characteristics, bone mineral density and non-vertebral osteoporotic fracture outcomes among post-menopausal U.S. South Asian Women. AB - PURPOSE: There is limited data pertaining to osteoporotic fractures among North American women of South Asian (SA) descent. This study examines fracture incidence and risk factors among post-menopausal SA, Chinese and White women undergoing mineral density (BMD) testing within a large healthcare organization in Northern California. METHODS: Using data from a retrospective study of women aged 50-85 years with femoral neck BMD measured between 1997 and 2003, we identified a subset of women of SA race and an age-matched subgroup of Chinese (1:5) and White (1:10) women and examined rates of incident wrist, humerus and hip fractures up to 10 years following BMD. Clinical and demographic risk factors were identified using health plan databases. Multivariable Cox regression analyses were conducted to examine predictors of incident fractures. RESULTS: The study cohort included 449 SA, 2245 Chinese and 4490 White women, with an average age of 58.4 +/- 6.1 years. The prevalence of femoral neck osteoporosis was higher among SA (8.9%) compared to White (6.5%) women and tended to be lower than Chinese (11.9%) women. More SA (7.1%) and White (9.6%) women had prior fracture compared to Chinese women (4.5%) and racial differences in smoking, rheumatoid arthritis, glucocorticoid use and hormone replacement therapy were seen. During a median of 8.4 years follow-up, wrist fracture incidence was similar among SA and White women (286 and 303 per 100,000 person-years, respectively) but significantly lower among Chinese women (130 per 100,000 person-years). In multivariable analyses, lower BMD, prior fracture and White and SA race (compared to Chinese race), were associated with a higher relative rate of wrist fracture. Lower BMD, prior fracture, older age and White but not SA race were also associated with a higher relative rate of non-vertebral (wrist, humerus or hip) fractures. CONCLUSIONS: Post-menopausal South Asian women differed from Chinese and White women with respect to prevalence of femoral neck osteoporosis, certain risk factors and site of osteoporotic fracture. These findings support the need for more studies examining fracture risk and outcomes specific to SA women residing in the U.S. to inform clinical decisions relevant to fracture risk. PMID- 22921876 TI - The genetics of being human. PMID- 22921877 TI - Stability switches and multistability coexistence in a delay-coupled neural oscillators system. AB - In this paper, we present a neural network system composed of two delay-coupled neural oscillators, where each of these can be regarded as the dynamical system describing the average activity of neural population. Analyzing the corresponding characteristic equation, the local stability of rest state is studied. The system exhibits the switch phenomenon between the rest state and periodic activity. Furthermore, the Hopf bifurcation is analyzed and the bifurcation curve is given in the parameters plane. The stability of the bifurcating periodic solutions and direction of the Hopf bifurcation are exhibited. Regarding time delay and coupled weight as the bifurcation parameters, the Fold-Hopf bifurcation is investigated in detail in terms of the central manifold reduction and normal form method. The neural system demonstrates the coexistence of the rest states and periodic activities in the different parameter regions. Employing the normal form of the original system, the coexistence regions are illustrated approximately near the Fold-Hopf singularity point. Finally, numerical simulations are performed to display more complex dynamics. The results illustrate that system may exhibit the rich coexistence of the different neuro-computational properties, such as the rest states, periodic activities, and quasi-periodic behavior. In particular, some periodic activities can evolve into the bursting-type behaviors with the varying time delay. It implies that the coexistence of the quasi-periodic activity and bursting-type behavior can be obtained if the suitable value of system parameter is chosen. PMID- 22921879 TI - Estimation of glomerular filtration rate in acute kidney injury. PMID- 22921878 TI - Porous silicon antibody microarrays for quantitative analysis: measurement of free and total PSA in clinical plasma samples. AB - The antibody microarrays have become widespread, but their use for quantitative analyses in clinical samples has not yet been established. We investigated an immunoassay based on nanoporous silicon antibody microarrays for quantification of total prostate-specific-antigen (PSA) in 80 clinical plasma samples, and provide quantitative data from a duplex microarray assay that simultaneously quantifies free and total PSA in plasma. To further develop the assay the porous silicon chips was placed into a standard 96-well microtiter plate for higher throughput analysis. The samples analyzed by this quantitative microarray were 80 plasma samples obtained from men undergoing clinical PSA testing (dynamic range: 0.14-44 ng/ml, LOD: 0.14 ng/ml). The second dataset, measuring free PSA (dynamic range: 0.40-74.9 ng/ml, LOD: 0.47 ng/ml) and total PSA (dynamic range: 0.87-295 ng/ml, LOD: 0.76 ng/ml), was also obtained from the clinical routine. The reference for the quantification was a commercially available assay, the ProStatus PSA Free/Total DELFIA. In an analysis of 80 plasma samples the microarray platform performs well across the range of total PSA levels. This assay might have the potential to substitute for the large-scale microtiter plate format in diagnostic applications. The duplex assay paves the way for a future quantitative multiplex assay, which analyzes several prostate cancer biomarkers simultaneously. PMID- 22921880 TI - MRI measurements of vessel calibre in tumour xenografts: comparison with vascular corrosion casting. AB - Vessel size index (R(v), MUm) has been proposed as a quantitative magnetic resonance imaging (MRI) derived imaging biomarker in oncology, for the non invasive assessment of tumour blood vessel architecture and vascular targeted therapies. Appropriate pre-clinical evaluation of R(v) in animal tumour models will improve the interpretation and guide the introduction of the biomarker into clinical studies. The objective of this study was to compare R(v) measured in vivo with vessel size measurements from high-resolution X-ray computed tomography (MUCT) of vascular corrosion casts measured post mortem from the same tumours, with and without vascular targeted therapy. MRI measurements were first acquired from subcutaneous SW1222 colorectal xenografts in mice following treatment with 0 (n=6), 30 (n=6) or 200 mg/kg (n=3) of the vascular disrupting agent ZD6126. The mice were then immediately infused with a low viscosity resin and, following polymerisation and maceration of surrounding tissues, the resulting tumour vascular casts were dissected and subsequently imaged using an optimised MUCT imaging approach. Vessel diameters were not measurable by MUCT in the 200 mg/kg group as the high dose of ZD6126 precluded delivery of the resin to the tumour vascular bed. The mean R(v) for the three treatment groups was 24, 23 and 23.5 MUm respectively; the corresponding MUCT measurements from corrosion casts from the 0 and 30 mg/kg cohorts were 25 and 28 MUm. The strong association between the in vivo MRI and post mortem MUCT values supports the use of R(v) as an imaging biomarker in clinical trials of investigational vascular targeted therapies. PMID- 22921881 TI - The effect of HMG-CoA reductase inhibitors on cognition in patients with Alzheimer's dementia: a prospective withdrawal and rechallenge pilot study. AB - BACKGROUND: Statins are well-known for their cardiovascular benefits. However, the cognitive effects of statins are not well understood. We hypothesized that individuals with preexisting dementia would be more vulnerable to statin-related cognitive effects. OBJECTIVE: The aim of this study was to evaluate the impact on cognition of 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor (statin) discontinuation and rechallenge in individuals with Alzheimer's dementia (AD) on statins at baseline. METHODS: A 12-week prospective, open-label study was conducted in a geriatric clinic setting. Eighteen older subjects underwent a 6 week withdrawal phase of statins followed by a 6-week rechallenge. The primary outcome measure was cognition, measured by the Mini-Mental State Examination (MMSE); secondary outcome measures were the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) neuropsychological battery, Activities of Daily Living (ADL) scale, Instrumental ADL (IADL) scale, and fasting cholesterol. The change in outcome measures was assessed using repeated-measures ANOVA and paired t tests. RESULTS: At the end of the intervention, there was a significant difference across time for MMSE score (P = 0.018), and total cholesterol (P = 0.0002) and a trend toward change across time for ADL (P = 0.07) and IADL (P = 0.06) scale scores. Further analyses using paired t tests indicated improvement in MMSE scores (Delta1.9 [3.0], P = 0.014) with discontinuation of statins and a decrease in MMSE scores (Delta1.9 [2.7], P = 0.007) after rechallenge. Total cholesterol increased with statin discontinuation (P = 0.0003) and decreased with rechallenge (P = 0.0007). The CERAD score did not show a change across time (P = 0.31). There was a trend toward improvement in ADL (P = 0.07) and IADL (P = 0.06) scale scores with discontinuation of statins, but no change with rechallenge. CONCLUSIONS: This pilot study found an improvement in cognition with discontinuation of statins and worsening with rechallenge. Statins may adversely affect cognition in patients with dementia. PMID- 22921882 TI - The mesenchyme in malignancy: a partner in the initiation, progression and dissemination of cancer. AB - The tumor microenvironment presents an exciting opportunity for innovative prognostic and therapeutic approaches to human cancer. The diverse cellular and extracellular contribution to tumor growth argues that prevention and cure of human cancers will result only from a multifaceted approach to cancer therapy. In this review we provide a foundation for considering the mesenchymal contribution to the tumor microenvironment. We address normal mesenchymal development, physiological interactions between the epithelium and stroma and the cellular hierarchy within these compartments. We focus on cancer-associated fibroblasts in gastrointestinal malignancy but our models have also been informed by other tumor systems. The review provides a framework for characterizing the overall biological contribution of the mesenchyme to human disease. Understanding the biological heterogeneity of specific mesenchymal cells in cancer will provide new opportunities for targeted cancer prevention and therapy. PMID- 22921883 TI - Exercise induces renin-angiotensin system unbalance and high collagen expression in the heart of Mas-deficient mice. AB - The renin-angiotensin system (RAS) is involved in the cardiac and vascular remodeling associated with cardiovascular diseases. Angiotensin (Ang) II/AT(1) axis is known to promote cardiac hypertrophy and collagen deposition. In contrast, Ang-(1-7)/Mas axis opposes Ang II effects in the heart producing anti trophic and anti-fibrotic effects. Exercise training is known to induce cardiac remodeling with physiological hypertrophy without fibrosis. We hypothesize that cardiac remodeling induced by chronic exercise depends on the action of Ang-(1 7)/Mas axis. Thus, we evaluated the effect of exercise training on collagen deposition and RAS components in the heart of FVB/N mice lacking Mas receptor (Mas-KO). Male wild-type and Mas-KO mice were subjected to a moderate-intense swimming exercise training for 6 weeks. The left ventricle (LV) of the animals was sectioned and submitted to qRT-PCR and histological analysis. Circulating and tissue angiotensin peptides were measured by RIA. Sedentary Mas-KO presented a higher circulating Ang II/Ang-(1-7) ratio and an increased ACE2 expression in the LV. Physical training induced in Mas-KO and WT a similar cardiac hypertrophy accompanied by a pronounced increase in collagen I and III mRNA expression. Trained Mas-KO and trained WT presented increased Ang-(1-7) in the blood. However, only in trained-WT there was an increase in Ang-(1-7) in the LV. In summary, we showed that deletion of Mas in FVB/N mice produced an unbalance in RAS equilibrium increasing Ang II/AT(1) arm and inducing deleterious cardiac effects as deposition of extracellular matrix proteins. These data indicate that Ang-(1-7)/Mas axis is an important counter-regulatory mechanism in physical training mediate cardiac adaptations. PMID- 22921884 TI - Scattered dose to radiosensitive organs and associated risk for cancer development from head and neck radiotherapy in pediatric patients. AB - The purpose of this study was to measure the scattered dose to out-of-field organs from head and neck radiotherapy in pediatric patients and to estimate the risk for second cancer induction to individual organs. Radiotherapy for thalamic tumor, brain tumor, acute leukemia and Hodgkin's disease in the neck region was simulated on 5 and 10-year-old pediatric phantoms with a 6 MV photon beam. The radiation dose to thyroid, breast, lung, stomach, ovaries, bladder, liver, uterus, prostate and colon was measured using thermoluminescent dosimeters. The methodology, provided by the BEIR VII report was used for the second cancer risk estimations. Peripheral dose range for a simulated 5-year-old patient was 0.019% 1.572% of the given tumor dose. The corresponding range at the advanced patient age was reduced to 0.018%-1.468%. The second cancer risk per fraction for male patients varied from 3 to 215 per 1,000,000 patients depending upon the age at the time of exposure, primary cancer site and organ scattered dose. The corresponding risk for females was 1-1186 per 1,000,000 patients. The higher risk values were found for breast, thyroid and lung cancer development. The current data concerning the risk magnitude for developing subsequent neoplasms to various out-of-field organs may be of value for health care professionals in the follow up studies of childhood cancer survivors. PMID- 22921885 TI - Pathophysiology of lower extremity edema in acute heart failure revisited. AB - BACKGROUND: The pathophysiology and key determinants of lower extremity edema in patients with acute heart failure are poorly investigated. METHODS: We prospectively enrolled 279 unselected patients presenting to the Emergency Department with acute heart failure. Lower extremity edema was quantified at predefined locations. Left ventricular ejection fraction, central venous pressure quantifying right ventricular failure, biomarkers to quantify hemodynamic cardiac stress (B-type natriuretic peptide), and the activity of the arginine-vasopressin system (copeptin) also were recorded. RESULTS: Lower extremity edema was present in 218 (78%) patients and limited to the ankle in 22%, reaching the lower leg in 40%, reaching the upper leg in 11%, and was generalized (anasarca) in 3% of patients. Patients in the 4 strata according to the presence and extent of lower leg edema had comparable systolic blood pressure, left ventricular ejection fraction, central venous pressure, and B-type natriuretic peptide levels, as well as copeptin and glomerular filtration rate (P=NS for all). The duration of dyspnea preceding the presentation was longer in patients with more extensive edema (P=.006), while serum sodium (P=.02) and serum albumin (P=.03) was lower. CONCLUSION: Central venous pressure, hemodynamic cardiac stress, left ventricular ejection fraction, and the activity of the arginine-vasopressin system do not seem to be key determinants of the presence or extent of lower extremity edema in acute heart failure. PMID- 22921886 TI - Hospital length of stay in patients with non-ST-segment elevation myocardial infarction. AB - PURPOSE: Substantial heterogeneity in hospital length of stay exists among patients admitted with non-ST-segment elevation myocardial infarction. Furthermore, little is known about the factors that impact length of stay. METHODS: We examined 39,107 non-ST-segment elevation myocardial infarction patients admitted to 351 Acute Coronary Treatment Intervention Outcomes Network Registry-Get With The Guidelines hospitals from January 1, 2007-March 31, 2009 who underwent cardiac catheterization and survived to discharge. Length of stay was categorized into 4 groups (<=2, 3-4, 5-7, and >=8 days), where prolonged length of stay was defined as >4 days. RESULTS: The overall median (25(th), 75(th)) length of stay was 3 (2, 5) days. Patients with a length of stay of >2 days were older with more comorbidities, but were less likely to receive evidence based therapies or percutaneous coronary intervention. Among the factors associated with prolonged length of stay >4 days were delay to cardiac catheterization >48 hours, heart failure or shock on admission, female sex, insurance type, and admission to the hospital on a Friday afternoon or evening. Hospital characteristics such as academic versus nonacademic or urban versus rural setting, were not associated with prolonged length of stay. CONCLUSION: Patients with longer length of stay have more comorbidities and in-hospital complications, yet paradoxically, are less often treated with evidence-based medications and are less likely to receive percutaneous coronary intervention. Hospital admission on a Friday afternoon or evening and delays to catheterization appear to significantly impact length of stay. A better understanding of factors associated with length of stay in patients with non-ST-segment elevation myocardial infarction is needed to promote safe and early discharge in an era of increasingly restrictive health care resources. PMID- 22921887 TI - Effects of supplementation on food intake, body weight and hepatic metabolites in the citrin/mitochondrial glycerol-3-phosphate dehydrogenase double-knockout mouse model of human citrin deficiency. AB - The C57BL/6:Slc23a13(-/-);Gpd2(-/-) double-knockout (a.k.a., citrin/mitochondrial glycerol 3-phosphate dehydrogenase double knockout or Ctrn/mGPD-KO) mouse displays phenotypic attributes of both neonatal intrahepatic cholestasis (NICCD) and adult-onset type II citrullinemia (CTLN2), making it a suitable model of human citrin deficiency. In the present study, we show that when mature Ctrn/mGPD KO mice are switched from a standard chow diet (CE-2) to a purified maintenance diet (AIN-93M), this resulted in a significant loss of body weight as a result of reduced food intake compared to littermate mGPD-KO mice. However, supplementation of the purified maintenance diet with additional protein (from 14% to 22%; and concomitant reduction or corn starch), or with specific supplementation with alanine, sodium glutamate, sodium pyruvate or medium-chain triglycerides (MCT), led to increased food intake and body weight gain near or back to that on chow diet. No such effect was observed when supplementing the diet with other sources of fat that contain long-chain fatty acids. Furthermore, when these supplements were added to a sucrose solution administered enterally to the mice, which has been shown previously to lead to elevated blood ammonia as well as altered hepatic metabolite levels in Ctrn/mGPP-KO mice, this led to metabolic correction. The elevated hepatic glycerol 3-phosphate and citrulline levels after sucrose administration were suppressed by the administration of sodium pyruvate, alanine, sodium glutamate and MCT, although the effect of MCT was relatively small. Low hepatic citrate and increased lysine levels were only found to be corrected by sodium pyruvate, while alanine and sodium glutamate both corrected hepatic glutamate and aspartate levels. Overall, these results suggest that dietary factors including increased protein content, supplementation of specific amino acids like alanine and sodium glutamate, as well as sodium pyruvate and MCT all show beneficial effects on citrin deficiency by increasing the carbohydrate tolerance of Ctrn/mGPD-KO mice, as observed through increased food intake and maintenance of body weight. PMID- 22921888 TI - Structure and function of the mammalian fibrillin gene family: implications for human connective tissue diseases. AB - Fibrillins and latent transforming growth factor beta binding proteins (LTBPs) are components of the extracellular matrix of connective tissue. While fibrillins are integral to the 10nm microfibrils, and often associated with elastin, all family members are likely to have an additional role in regulating the bioavailability of transforming growth factor beta (TGBbeta). Both fibrillins and LTBPs are large glycoproteins, containing a series of calcium binding epidermal growth factor domains as well as a number of copies of a unique 8 cysteine domain found only in this protein superfamily. There are three mammalian fibrillins and four LTBPs. Fibrillin monomers link head to tail in microfibrils which can then form two and three dimensional structures. In some tissues elastin is recruited to the fibrillin microfibrils to provide elasticity to the tissue. LTBPs are part of the TGBbeta large latent complex which sequesters TGBbeta in the extracellular matrix. Fibrillin-1 appears to bind to LTBPs to assist in this process and is thus involved in regulating the bioavailability of TGBbeta. Mutation of fibrillin genes results in connective tissue phenotypes which reflect both the increased level of active TGBbeta and the structural failure of the extracellular matrix due to the absence or abnormality of fibrillin protein. Fibrillinopathies include Marfan syndrome, familial ectopia lentis, familial thoracic aneurysm (mutations of FBN1) and congenital contractural arachnodactyly (mutation of FBN2). There are no diseases currently associated with mutation of FBN3 in humans, and this gene is no longer active in rodents. Expression patterns of fibrillin genes are consistent with their role in extracellular matrix structure of connective tissue. FBN1 expression is high in most cell types of mesenchymal origin, particularly bone. Human and mouse FBN2 expression is high in fetal cells and has more restricted expression in mesenchymal cell types postnatally. FBN3 is expressed early in development (embryonic and fetal tissues) in humans. The fibrillins are thus important in maintaining the structure and integrity of the extracellular matrix and, in combination with their sequence family members the LTBPs, also contribute to the regulation of the TGFbeta family of major growth factors. PMID- 22921889 TI - Gadoxetic acid-enhanced 3.0T MRI for the evaluation of hepatic metastasis from colorectal cancer: metastasis is not always seen as a "defect" on the hepatobiliary phase. AB - PURPOSE: To determine specific imaging features of hepatic metastasis from colorectal cancer, focusing on the hepatobiliary phase (HBP) of gadoxetic acid enhanced MRI. MATERIALS AND METHODS: Over a 2-year period, 79 hepatic metastatic lesions were identified from 32 patients (22 men and 10 women) who proven colorectal cancer and underwent gadoxetic acid-enhanced 3.0T MRI. Hepatic metastases were proven pathologically in 16 patients: by surgical liver resection (n=14) and by US-guided biopsy (n=2). The remaining 16 patients were considered to have hepatic metastasis based on imaging studies and clinical information. Two radiologists evaluated the imaging features of each MRI sequence, including high resolution T2WI, dynamic contrast enhancement study with hepatobiliary phase, and diffusion weighted image. We also compared SI of the lesions on T2WI and HBP. RESULTS: T2WI showed homogeneous high SI (n=25; 31.7%), target appearance (n=3; 3.8%), reversed target appearance (n=2; 2.6%), and heterogeneously high SI (n=49; 62%). On HBP, homogeneous defect were seen in 22 lesions (27.9%), target appearance in five lesions (6.4%), reversed target appearance in two lesions (2.5%), and heterogeneous defect in 50 lesions (63.3%); including reticular (70%), partially globular (26%), and diffuse GGO-like (4%) patterns. According to the imaging features on HBP, the homogeneous defect and heterogeneous defect groups had a mean ADC value of 0.99 * 10(-3) and 1.07 * 10(-3)mm(2)/s, respectively, without statistically significant difference. CONCLUSION: Hepatic metastasis from colorectal cancer usually showed as a heterogeneous defect on HBP and a heterogeneous high SI on T2WI. The generally accepted "true defect" was not a common finding in hepatic metastasis from colorectal cancer. PMID- 22921890 TI - Validation and absolute quantification of MR perfusion compared with CT perfusion in patients with unilateral cerebral arterial stenosis. AB - OBJECTIVE: The aim of the study was to assess absolute quantification of dynamic susceptibility contrast-enhanced magnetic resonance perfusion (MRP) comparing with computed tomography perfusion (CTP) in patients with unilateral stenosis. MATERIALS AND METHODS: We retrospectively post-processed MRP in 20 patients with unilateral occlusion or stenosis of >79% at the internal carotid artery or the middle cerebral artery (MCA). Absolute quantification of MRP was performed after applying the following techniques: cerebrospinal fluid removal, vessel removal, and automatic segmentation of brain to calculate the scaling factors to convert relative cerebral blood volume (rCBV) and relative cerebral blood flow (rCBF) values to absolute values. For comparison between MRP and CTP, we manually deposited regions of interest in bilateral MCA territories at the level containing the body of the lateral ventricle. RESULTS: The correlation between MRP and CTP was best for mean transit time (MTT) (r=0.83), followed by cerebral blood flow (CBF) (r=0.52) and cerebral blood volume (CBV) (r=0.43). There was no significant difference between CTP and MRP for CBV, CBF, and MTT on the lesion side, the contralateral side, the lesion-contralateral differences, or the lesion to-contralateral ratios (P>0.05). The mean differences between MRP and CTP were as follows: CBV -0.57 mL/100g, CBF 2.50 mL/100g/min, and MTT -0.90 s. CONCLUSION: Absolute quantification of MRP is possible. Using the proposed method, measured values of MRP and CTP had acceptable linear correlation and quantitative agreement. PMID- 22921891 TI - Is there any association of apolipoprotein E gene polymorphism with obesity status and lipid profiles? Tehran Lipid and Glucose Study (TLGS). AB - AIMS: Considering the key role played by the apolipoprotein E (Apo E) gene in the regulation of lipid metabolism and obesity, the current study has evaluate the association between abdominal obesity and Apo E gene polymorphism in a population of Tehran. MATERIALS AND METHODS: A cross-sectional study was performed on 345 men and 498 women, aged 19-86 years, selected from among participants of the Tehran Lipid and Glucose Study. The RFLP-PCR technique was employed to investigate polymorphism in the gene fragments. Based on the national survey of risk factors for non-communicable diseases of Iran, waist circumference (WC) cut off was set at 89 cm for men and 91 cm for women. The risk effect of obesity related variables and lipid profiles in two groups of WC were examined by logistic regression. For body mass index (BMI), waist to hip ratio (WHR), high density lipoprotein-cholesterol (HDL-C), triglyceride (TG), fasting blood sugar (FBS), total cholesterol (TC), low-density lipoprotein-cholesterol (LDL-C), and blood pressure (BP), the standard risk cut-offs were applied. RESULTS: Frequencies of E2, E3, and E4 alleles were 9.7, 73, and 14.6%, respectively. The presence of the E3 allele was significantly associated with higher TG level in subjects with high WC, while, the presence of E4 allele decreased the plasma HDL C (E2:52.1+/-13.1 vs., E3:48.9+/-11.2 vs., E4:44.6+/-10.6 mg/dl, p<0.05), HDL-C2 (E2:20.4+/-9.2 vs., E3:19.1+/-8.8 vs., E4:16.3+/-7.9 mg/dl, p<0.05), and HDL-C3 (E2:32.1+/-7.4 vs., E3:30.3+/-6.2 vs., E4:28.3+/-6.1 mg/dl, p<0.05) in normal WC subjects. The presence of the E3 carrier increased the risk of having higher plasma TG, compared with the E2 carrier (95% CI OR=1.91, 1.02-3.57; p=0.04). CONCLUSION: According to the results of this study, the E3 carrier, caused an approximately 90% increase in the levels of TG in the group with abdominal obesity. PMID- 22921892 TI - Association of P213S polymorphism of the L-selectin gene with type 2 diabetes and insulin resistance in Chinese population. AB - AIMS: L-selectin belongs to selectin family of adhesion molecule and participates in the generation and development of type 2 diabetes (T2D). In this study, we evaluated the relationship between the P213S polymorphism of L-selectin gene and T2D and insulin resistance in the Chinese population. METHODS: We genotyped P213S polymorphism in 801 patients with T2D and 834 healthy controls in the Chinese population using polymerase chain reaction-ligase detection reaction (PCR-LDR) technique. Plasma glucose, insulin, lipid, blood urea nitrogen, creatinine and uric acid levels were measured by biochemical technique. RESULTS: The frequency of 213PP genotype and P allele of the L-selectin gene in patients with T2D was significantly higher than that in controls (P=0.007; P=0.019, respectively). The relative risk of allele P suffered from T2D was 1.191 times higher than that of allele S. Moreover, the levels of FPG and HOMA-IR of PP and PS genotype carriers were significantly higher than those of SS genotype carriers in the T2D group (P<0.05). CONCLUSION: These findings indicated that the P213S polymorphism of L selectin gene may contribute to susceptibility to T2D and insulin resistance in the Chinese population, and P allele appears to be a risk factor for T2D. PMID- 22921893 TI - The impact of transposable elements on eukaryotic genomes: from genome size increase to genetic adaptation to stressful environments. AB - Transposable elements (TEs) are present in roughly all genomes. These mobile DNA sequences are able to invade genomes and their impact on genome evolution is substantial. The mobility of TEs can induce the appearance of deleterious mutations, gene disruption and chromosome rearrangements, but transposition activity also has positive aspects and the mutational activities of TEs contribute to the genetic diversity of organisms. This short review aims to give a brief overview of the impact TEs may have on animal and plant genome structure and expression, and the relationship between TEs and the stress response of organisms, including insecticide resistance. PMID- 22921894 TI - Novel homozygous p.Y395X mutation in the CYP11B1 gene found in a Vietnamese patient with 11beta-hydroxylase deficiency. AB - CONTEXT: The deficiency of steroid 11beta-hydroxylase is caused by mutations in the CYP11B1 gene and is the second major form of congenital adrenal hyperplasia associated with hypertension. OBJECTIVE: The objective of this study was to screen the CYP11B1 gene for mutations in one Vietnamese male suffering from congenital adrenal hyperplasia. PATIENT: The patient (46,XY) had congenital adrenal hyperplasia. The clinical manifestations presented precocious puberty, hyper-pigmentation and high blood pressure at 4 years. RESULTS: The patient was a homozygous carrier of a novel mutation located in exon 7 containing a premature stop codon instead of tyrosine at 395 (p.Y395X). CONCLUSION: We have identified a novel mutant of the CYP11B1 gene in one Vietnamese family associated with phenotypes of congenital adrenal hyperplasia. The mutant gene p.Y395X produces a truncated form of the polypeptide and abolishes the enzyme activities, leading to a severe phenotype of congenital adrenal hyperplasia. PMID- 22921896 TI - Impact of copper on the abundance and diversity of sulfate-reducing prokaryotes in two chilean marine sediments. AB - We studied the abundance and diversity of the sulfate-reducing prokaryotes (SRPs) in two 30-cm marine chilean sediment cores, one with a long-term exposure to copper-mining residues, the other being a non-exposed reference sediment. The abundance of SRPs was quantified by qPCR of the dissimilatory sulfite reductase gene beta-subunit (dsrB) and showed that SRPs are sensitive to high copper concentrations, as the mean number of SRPs all along the contaminated sediment was two orders of magnitude lower than in the reference sediment. SRP diversity was analyzed by using the dsrB-sequences-based PCR-DGGE method and constructing gene libraries for dsrB-sequences. Surprisingly, the diversity was comparable in both sediments, with dsrB sequences belonging to Desulfobacteraceae, Syntrophobacteraceae, and Desulfobulbaceae, SRP families previously described in marine sediments, and to a deep branching dsrAB lineage. The hypothesis of the presence of horizontal transfer of copper resistance genes in the microbial population of the polluted sediment is discussed. PMID- 22921897 TI - Analysis of Pacific oyster larval proteome and its response to high-CO2. AB - Most calcifying organisms show depressed metabolic, growth and calcification rates as symptoms to high-CO(2) due to ocean acidification (OA) process. Analysis of the global expression pattern of proteins (proteome analysis) represents a powerful tool to examine these physiological symptoms at molecular level, but its applications are inadequate. To address this knowledge gap, 2-DE coupled with mass spectrophotometer was used to compare the global protein expression pattern of oyster larvae exposed to ambient and to high-CO(2). Exposure to OA resulted in marked reduction of global protein expression with a decrease or loss of 71 proteins (18% of the expressed proteins in control), indicating a wide-spread depression of metabolic genes expression in larvae reared under OA. This is, to our knowledge, the first proteome analysis that provides insights into the link between physiological suppression and protein down-regulation under OA in oyster larvae. PMID- 22921895 TI - Chemosensory behaviors of parasites. AB - Many multicellular parasites seek out hosts by following trails of host-emitted chemicals. Host seeking is a characteristic of endoparasites such as parasitic worms as well as of ectoparasites such as mosquitoes and ticks. For host location, many of these parasites use CO(2), a respiration byproduct, in combination with host-specific chemicals. Recent work has begun to elucidate the behavioral responses of parasites to CO(2) and other host chemicals, and to unravel the mechanisms of these responses. Here we discuss recent findings that have greatly advanced our understanding of the chemosensory behaviors of host seeking parasites. We focus primarily on well-studied parasites such as nematodes and insects, but also note broadly relevant findings in a few less well studied parasites. PMID- 22921898 TI - Effects of intertidal seagrass habitat fragmentation on turbulent diffusion and retention time of solutes. AB - An in-depth knowledge of solutes advection and turbulent diffusion is crucial to estimate dispersion area and retention time (t(R)) of pollutants within seagrass habitats. However, there is little knowledge on the influence of seagrass habitat fragmentation on such mechanisms. A set of dye tracer experiments and acoustic Doppler velocimeter measurements (ADV) were conducted. Solute transport conditions were compared in between fragmented (FM) vs homogeneous (HM) intertidal meadows, and in vertical gradients (canopy vs overlaying flow). Results showed the highest horizontal diffusion coefficient (K(y), c.a. 10( 3)m(2)s(-1)) on FM and at the canopy-water column interface, whereas t(R) (2.6 5.6 min) was not affected by fragmentation. It suggests that (1) FM are more vulnerable to pollution events in terms of dispersion area and (2) at low tide, advection rather than turbulent diffusion determines t(R). Furthermore, Taylor's theorem is revealed as a powerful tool to analyze vertical gradients on K(y) within seagrass canopies. PMID- 22921899 TI - Management of waste electrical and electronic equipment in two EU countries: a comparison. AB - The paper presents some data regarding waste electrical and electronic (WEEE) management in one of the founding countries of the EU, Italy, and in a recent entry into the EU, Romania. The aim of this research was to analyze some problems that countries entering the EU will have to solve with respect to WEEE management. The experiences of Italy and Romania could provide an interesting reference point. The strengths and weaknesses that the two EU countries have encountered can be used in order to give a more rational plan for other countries. In Italy the increase of WEEE collection was achieved in parallel with the increase of the efficiency of selective Municipal Solid Waste collection. In Romania, pilot experiences were useful to increase the awareness of the population. The different interests of the two populations towards recyclable waste led to a different scenario: in Romania all types of WEEE have been collected since its entrance into the EU; in Italy the "interest" in recycling is typically related to large household appliances, with a secondary role of lighting equipment. PMID- 22921900 TI - Compartmentalization and regulation of arylsulfatase activities in Streptomyces sp., Microbacterium sp. and Rhodococcus sp. soil isolates in response to inorganic sulfate limitation. AB - Arylsulfatases allow microorganisms to satisfy their sulfur (S) requirements as inorganic sulfate after sulfate ester hydrolysis. Our objectives were to investigate the arylsulfatase activities among soil isolates, especially Streptomyces sp., Microbacterium sp. and Rhodococcus sp., because such investigations are limited for these bacteria, which often live in sulfate limited conditions. Physiological and biochemical analyses indicated that these isolates possessed strong specific arylsulfatase activities ranging from 6 to 8 U. Moreover, for Streptomyces sp., an arylsulfatase localization study revealed 2 forms of arylsulfatases. A first form was located in the membrane, and a second form was located in the intracellular compartment. Both arylsulfatases had different patterns of induction. Indeed, the intracellular arylsulfatase was strictly induced by inorganic sulfate limitation, whereas the membrane arylsulfatase was induced both by substrate presence or S demand independently. For Microbacterium and Rhodococcus isolates, only a membrane arylsulfatase was found. Consequently, our results suggest the presence of a previously undescribed arylsulfatase in these microorganisms that allows them to develop an alternative strategy to fulfill their S requirements compared to bacteria previously studied in the literature. PMID- 22921901 TI - Osteoblasts detect pericellular calcium concentration increase via neomycin sensitive voltage gated calcium channels. AB - The mechanisms underlying the detection of critically loaded or micro-damaged regions of bone by bone cells are still a matter of debate. Our previous studies showed that calcium efflux originates from pre-failure regions of bone matrix and MC3T3-E1 osteoblasts respond to such efflux by an increase in the intracellular calcium concentration. The mechanisms by which the intracellular calcium concentration increases in response to an increase in the pericellular calcium concentration are unknown. Elevation of the intracellular calcium may occur via release from the internal calcium stores of the cell and/or via the membrane bound channels. The current study applied a wide range of pharmaceutical inhibitors to identify the calcium entry pathways involved in the process: internal calcium release from endoplasmic reticulum (ER, inhibited by thapsigargin and TMB-8), calcium receptor (CaSR, inhibited by calhex), stretch activated calcium channel (SACC, inhibited by gadolinium), voltage-gated calcium channels (VGCC, inhibited by nifedipine, verapamil, neomycin, and omega conotoxin), and calcium-induced-calcium-release channel (CICRC, inhibited by ryanodine and dantrolene). These inhibitors were screened for their effectiveness to block intracellular calcium increase by using a concentration gradient induced calcium efflux model which mimics calcium diffusion from the basal aspect of cells. The inhibitor(s) which reduced the intracellular calcium response was further tested on osteoblasts seeded on mechanically loaded notched cortical bone wafers undergoing damage. The results showed that only neomycin reduced the intracellular calcium response in osteoblasts, by 27%, upon extracellular calcium stimulus induced by concentration gradient. The inhibitory effect of neomycin was more pronounced (75% reduction in maximum fluorescence) for osteoblasts seeded on notched cortical bone wafers loaded mechanically to damaging load levels. These results imply that the increase in intracellular calcium occurs by the entry of extracellular calcium ions through VGCCs which are sensitive to neomycin. N-type and P-type VGCCs are potential candidates because they are observed in osteoblasts and they are sensitive to neomycin. The calcium channels identified in this study provide new insight into mechanisms underlying the targeted repair process which is essential to bone adaptation. PMID- 22921902 TI - The methionine 196 arginine polymorphism of the TNF receptor 2 gene (TNFRSF1B) is not associated with worse outcomes in heart failure. AB - Tumor necrosis factor alpha (TNFalpha) may contribute to the pathologic process of congestive heart failure (CHF). TNFalpha signaling occurs through two receptors; TNFR1 (TNFRSF1A) and TNFRII (TNFRSF1B). In humans a single nucleotide polymorphism (rs1061622 in TNFRSF1B exon 6; T587G) encodes two different amino acids (M196R) in the transmembrane region. The 587G allele is associated with greater severity and/or prevalence of some inflammatory diseases, but its role in CHF in unknown. This study sought to test the hypothesis that the 587G allele is associated with a worse outcome or more severe phenotype in CHF. Peripheral blood DNA was isolated and genotyped from 379 heart failure patients enrolled in a genetic outcome study (GRACE); (44.7% ischemic, 70.4% male, 8.5% black race, age 55.6 +/- 11.7 yr (SD), LVEF 24.5 +/- 8.3%, NYHA 2.53 +/- 0.64). Genotyping was performed by PCR-RFLP. Cardiac function was assessed from medical records at study entry. The distribution of genotypes in this population was 54% T/T, 38.4% G/T and 7.7% G/G. Mean LV ejection fraction (T/T 24.4 +/- 8.2, T/G 25.0 +/- 8.4, G/G 23.3 +/- 8.6, n=352, p=ns) and LV end-diastolic dimensions (T/T 6.57 +/- 0.93, T/G 6.53 +/- 1.0, G/G 6.57 +/- 0.78, n=211, p=ns) were comparable in all groups. Transplant-free survival (median 23 months (range 1-62 months) did not vary by genotype (p=0.95). A lack of effect (p=0.74) on transplant-free survival was also observed in a subset of patients with ischemic heart failure (n=169). The TNFRSF1B 587G allele is not associated with the severity of heart failure phenotype or clinical outcomes in patients with chronic CHF. PMID- 22921903 TI - Correlation between IL-7 and MCP-1 in diabetic chronic non healing ulcer patients at higher risk of coronary artery disease. AB - Cytokines play an extremely important role in the pathogenesis of coronary artery disease (CAD) in which interleukin (IL)-7 is a major regulator of T-cell homeostasis which is conced in the stimulation of leukocyte-endothelial cell adhesion during inflammatory events. Circulating IL-7 is associated with activation of monocyte and natural killer cells, leading to enhanced production of inflammatory cytokines and chemokines observed in atherosclerosis and acute coronary syndromes. Plasma levels of IL-7, hs-CRP and monocyte chemoattractant protein (MCP)-1 were measured by an immunoenzymatic ELISA technique. Ninety neuropathic diabetic foot patients were divided into two groups: group B [those without CAD (n=45)] and group C [those with higher risk of CAD (n=45)]. Thirty five healthy subjects were included as control (group H). Plasma concentration of IL-7, MCP-1 and hs-CRP were significantly higher in group C as compare with group H and B. Plasma IL-7 levels also showed significant positive correlations with plasma levels of hs-CRP and MCP-1. Abnormalities in lipid profile were also observed. In conclusion the positive correlation between plasma concentration of IL-7, MCP-1 and hs-CRP in diabetic foot patients observed herein, suggests a plausible role for IL-7 in the promotion of clinical instability in coronary artery disease. PMID- 22921904 TI - Impairment of hepatic NK cell development in IFN-gamma deficient mice. AB - It is already clearly demonstrated that IFN-gamma plays important roles in differentiation and maturation of T cells, B cells and macrophages; however, it is not clear whether NK cell development is regulated by IFN-gamma. In our study by using IFN-gamma-deficient mice (GKO), we observed that the percentage and number of NK1.1(+)CD3(-) cells were declined significantly in the liver, but not in the spleen, bone marrow and lymph node, of adult IFN-gamma(-/-) mice. However, Lin(-)CD122(+) NK progenitor cells developed normally both in liver and bone marrow in IFN-gamma(-/-) mice. Moreover, more mature CD27(-)CD11b(+) NK cells accumulated in the liver of IFN-gamma(-/-) mice. Deficiency of IFN-gamma resulted in the lower expression of CD69, GranzymeB and TRAIL by hepatic NK1.1(+)CD3(-) cells and the phenotypes of IFN-gamma(-/-) hepatic NK1.1(+)CD3(-) cells were altered from WT hepatic NK cells. When stimulated with Poly (I:C) in vivo, attenuated accumulating in the liver and weaker expression of GranzymeB, TRAIL and FasL of NK1.1(+)CD3(-) cells were observed of IFN-gamma(-/-) mice. Accordingly, these results demonstrate that IFN-gamma plays important role in mounting liver environment for development of hepatic NK cells. PMID- 22921905 TI - Facing uncertainty in ecosystem services-based resource management. AB - The concept of ecosystem services is increasingly used as a support for natural resource management decisions. While the science for assessing ecosystem services is improving, appropriate methods to address uncertainties in a quantitative manner are missing. Ignoring parameter uncertainties, modeling uncertainties and uncertainties related to human-environment interactions can modify decisions and lead to overlooking important management possibilities. In this contribution, we present a new approach for mapping the uncertainties in the assessment of multiple ecosystem services. The spatially explicit risk approach links Bayesian networks to a Geographic Information System for forecasting the value of a bundle of ecosystem services and quantifies the uncertainties related to the outcomes in a spatially explicit manner. We demonstrate that mapping uncertainties in ecosystem services assessments provides key information for decision-makers seeking critical areas in the delivery of ecosystem services in a case study in the Swiss Alps. The results suggest that not only the total value of the bundle of ecosystem services is highly dependent on uncertainties, but the spatial pattern of the ecosystem services values changes substantially when considering uncertainties. This is particularly important for the long-term management of mountain forest ecosystems, which have long rotation stands and are highly sensitive to pressing climate and socio-economic changes. PMID- 22921906 TI - The DNA topoisomerase II catalytic inhibitor merbarone is genotoxic and induces endoreduplication. AB - In the last years a number of reports have shown that the so-called topoisomerase II (topo II) catalytic inhibitors are able to induce DNA and chromosome damage, an unexpected result taking into account that they do not stabilize topo II-DNA cleavable complexes, a feature of topo II poisons such as etoposide and amsacrine. Merbarone inhibits the catalytic activity of topo II by blocking DNA cleavage by the enzyme. While it was first reported that merbarone does not induce genotoxic effects in mammalian cells, this has been challenged by reports showing that the topo II inhibitor induces efficiently chromosome and DNA damage, and the question as to a possible behavior as a topo II poison has been put forward. Given these contradictory results, and the as yet incomplete knowledge of the molecular mechanism of action of merbarone, in the present study we have tried to further characterize the mechanism of action of merbarone on cell proliferation, cell cycle, as well as chromosome and DNA damage in cultured CHO cells. Merbarone was cytotoxic as well as genotoxic, inhibited topo II catalytic activity, and induced endoreduplication. We have also shown that merbarone induced DNA damage depends upon ongoing DNA synthesis. Supporting this, inhibition of DNA synthesis causes reduction of DNA damage and increased cell survival. PMID- 22921907 TI - Child restraint use in low socio-economic areas of urban Sydney during transition to new legislation. AB - Child restraints protect a young child against injury in crashes but best practice child restraint use is low in Australia, particularly among lower socio economic groups. We investigated factors associated with restraint use to inform the development of education and distribution programmes to support new Australian legislation on child passengers among families in low socio-economic areas of metropolitan Sydney. We interviewed a parent or carer of 1160 children aged 2-5 years enrolled at one of 28 early childhood centres in low socio economic areas of urban Sydney. Appropriate child restraint use was defined as a forward facing child restraint (FFCR) for 2-3 year olds and a FFCR or booster seat for children aged 4 years or more. Predictors of self-reported appropriate use were explored using logistic regression. Analysis was conducted on one child from each family in the target age range (2-5 years): 586 (51%) were male and the mean age was 3.5 (Standard Deviation 0.8) years. There were 432 (45%) families with annual income below $60,000, 248 (22%) spoke a language other than English at home and 360 (33%) had 3 or more children. Fifty-four percent of carers indicated that their 2-3 year old children travelled in a FFCR. Inappropriate use among children in this age group was more likely when the carer was <36 years (odds ratio (OR) 1.62, 95% confidence interval (CI) 1.08-2.45), in families with >=3 children (OR 1.64, 95% CI 1.10-2.44) and when the carer believed that a booster seat was just as safe as a FFCR (OR 2.98, 2.05-4.32). Eight-eight percent of carers of 4-5 year olds reported use of a booster seat or FFCR. Non-use was associated with low household income (OR 3.10, 95% CI 1.67-5.75), in families with >=3 children (OR 2.03, 95% CI 1.09-3.76) and families where a language other than English is spoken at home (OR 2.39, 95% CI 1.10-5.21). Non-English speaking families had less awareness of the new law and poorer knowledge of safety benefits of child restraints. They also had lower household incomes and more concerns about cost of child restraints and booster seats. These findings can inform development of interventions to promote best practice child restraint use, which will reach non-English speaking families in this region. They also confirm the importance of economic and logistic barriers to best practice child restraint use. PMID- 22921908 TI - Sleep-related collisions in United Arab Emirates. AB - INTRODUCTION: Road traffic collisions (RTC) are a major health problem in UAE. Sleep as a contributing factor to RTC is not well-studied in the Middle East. OBJECTIVE: We aimed to study to the proportion of RTC caused by sleep behind the wheel and the factors contributing to sleep related collisions (SRC). METHODS: Data of all hospitalized drivers who were involved in RTC in Al-Ain city were prospectively collected during the period of April 2006-October 2007. Variables studied included, driver's demographic data, time, date, location, mechanism of collision, speed at collision and whether sleepiness was a contributing factor as reported by the drivers. A direct logistic regression model was performed to define factors related to sleep while driving. RESULTS: 444 drivers (92% males) were involved in RTC during the study period. Sleepiness of drivers was a contributing factor in 5%. Most of the drivers experiencing SRC (79%) reported speeds of 100km/h or more during the collision. SRC was strongly over-represented during the month of Ramadan (42%) and in driving on highways (83%). A logistic regression model has shown that driving during the lunar month of Ramadan (p<0.0001, OR=6.36) and on highways (p=0.037, OR=3.75) were the most significant independent contributors to increasing the odds of SRC. CONCLUSION: Sleep is an important contributing factor to RTC in UAE. Drivers should be advised to discontinue driving when feeling sleepy especially during the lunar month of Ramadan and while driving on highways. PMID- 22921909 TI - Application of a ready-to-use calcium ionophore increases rates of fertilization and pregnancy in severe male factor infertility. AB - OBJECTIVE: To analyze whether a ready-to-use calcium ionophore improves outcomes, from fertilization to live birth, in patients with severe male factor infertility. DESIGN: Artificial oocyte activation offered to applicable patients over a 20-month period. SETTING: Specialized in vitro fertilization (IVF) centers in Austria and Germany. PATIENT(S): Twenty-nine azoospermic and 37 cryptozoospermic men. INTERVENTION(S): Mature oocytes treated with a ready-to-use Ca(2+)-ionophore (GM508 Cult-Active) immediately after intracytoplasmic sperm injection (ICSI). MAIN OUTCOME MEASURE(S): Rates of fertilization, implantation, clinical pregnancy, and live birth. RESULT(S): Patients had had 88 previous cycles without artificial activation that resulted in a fertilization rate of 34.7%, 79 transfers (89.8%), and 5 pregnancies, which all spontaneously aborted except one. After artificial oocyte activation, the fertilization rate was 56.9%. In terms of fertilization rate, both azoospermic (64.4%) and cryptozoospermic (48.4%) men statistically significantly benefited from use of the ionophore. In 73 transfer cycles, positive beta-human chorionic gonadotropin levels were observed in 34 cases (46.6%) and 29 cycles (39.7%) that ended with a clinical pregnancy. The corresponding implantation rate was 33.3%. Four spontaneous abortions occurred (11.8%), and 32 healthy children were born. CONCLUSION(S): This is the first prospective multicenter study on artificial oocyte activation in severe male factor infertility. Present data indicate that a ready-to-use calcium ionophore can yield high fertilization and pregnancy rates for this particular subgroup. In addition to fertilization failure after ICSI, severe male factor infertility is an additional area for application of artificial oocyte activation. PMID- 22921910 TI - The effect of the new 2010 World Health Organization criteria for semen analyses on male infertility. AB - OBJECTIVE: To quantify the effect of the new 2010 World Health Organization (WHO) semen analysis reference values on reclassifying previous semen analysis parameters and definition of patients with male factor infertility. DESIGN: A multi-institutional retrospective chart review. SETTING: University and private male infertility clinics. PATIENT(S): Men referred for infertility evaluation. INTERVENTION(S): Comparison of semen analysis values based on 2010 versus 1999 reference criteria. MAIN OUTCOME MEASURE(S): Quantification of the change based on individual sperm parameters and as a whole. RESULT(S): A total of 184 men had at least two semen analyses; 13 (7%), 17 (9.2%), 34 (18.4%), and 29 (15.7%) patients changed classification to being at or above the reference values by the 2010 criteria for semen volume, sperm concentration, motility, and morphology, respectively. A total of 501 men had one semen analysis on file; 40 (7.9%), 31 (6.2%), 50 (9.9%), and 74 (19.3%) would change classification for volume, concentration, motility, and morphology, respectively. Overall, 103 patients (15.1%) who had one or more parameter below the reference value on the original analysis were converted to having all parameters at or above the 2010 reference values. CONCLUSION(S): The 2010 reference values result in some infertile men being reclassified as fertile if status is based on semen analysis alone. This may lead to fewer men being referred for proper infertility evaluation or treatment. PMID- 22921912 TI - Turner syndrome: new insights into an old disorder. AB - There have been marked advances in the understanding and treatment of Turner syndrome since its initial description in 1938. Greater knowledge of the heterogeneity of phenotypes, early treatment interventions with growth hormone and hormonal replacement, the risks of reproduction, spontaneous and assisted, and the long-term health of women with Turner syndrome has been achieved in the interim. But many perplexing ethical and clinical issues persist. PMID- 22921911 TI - Contribution of the rate of change of antimullerian hormone in estimating time to menopause for late reproductive-age women. AB - OBJECTIVE: To determine the rate of change of antimullerian hormone (AMH) level in the late reproductive years and its associations with time to menopause (TTM). We hypothesized that the rate of change between two measures of AMH reflects follicular atresia and varies among women independent of age. DESIGN: A14-year follow-up. SETTING: A randomly identified, population-based cohort (Penn Ovarian Aging Study). PATIENT(S): Two measures of AMH were evaluated in survival analysis of 293 women. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Time to menopause. RESULT(S): The rate of AMH change was a strong independent predictor of TTM in multivariable analysis after adjusting for AMH baseline, age, and smoking (hazard ratio for 1 SD change = 1.82, 95% confidence interval 1.56-2.14). Among women with similar AMH levels, TTM differed by approximately 2 years when compared between a slow and fast rate of AMH change. A significant interaction of AMH rate of change and age indicated that a faster decrease in AMH level was associated with an increased risk of menopause in women aged 35-39 years (hazard ratio 6.97, 95% confidence interval 3.81-12.72), with less dramatic but significant associations in women aged 40-44 and 45-48 years. CONCLUSION(S): The AMH rate of change was independently associated with TTM in late reproductive-age women and increased the precision of estimates of TTM when included with an AMH baseline level and age. The rate of AMH change may be a more direct surrogate than age and increases the precision of estimates of TTM during this clinically important time period. PMID- 22921913 TI - Epithelial cell protein milk fat globule-epidermal growth factor 8 and human chorionic gonadotropin regulate stromal cell apoptosis in the human endometrium. AB - OBJECTIVE: To study the regulation of apoptosis in human endometrial cells. The specific aims were to determine whether milk fat globule-epidermal growth factor 8 (MFG-E8), a novel endometrial epithelial protein, modulates caspase activation and DNA fragmentation; and to examine whether hCG, an early embryonic product, regulates Bax and Bcl-2 equilibrium, as well as MFG-E8 expression. DESIGN: Primary cultures of human endometrial epithelial cells (EECs) and endometrial stromal cells (ESCs). SETTING: Academic center. PATIENT(S): Ovulatory women aged 21-30 years. INTERVENTION(S): Treatment with MFG-E8 and hCG. MAIN OUTCOME MEASURE(S): Apoptotic activity was quantified using a luciferase assay. Deoxyribonucleic acid fragmentation was detected by TUNEL assay. Bax, Bcl-2, and MFG-E8 messenger RNA expression levels were determined by quantitative reverse transcription-polymerase chain reaction. Immunocytochemistry was used to establish cell purity and presence of MFG-E8 and hCG-R (receptor) proteins. RESULT(S): Endometrial epithelial cells were cytokeratin(+), vimentin(-), MFG E8(+), and hCG-R(+), whereas ESC were vimentin(+), cytokeratin(-), MFG-E8(-), and hCG-R(+). Treatment of ESC with MFG-E8 resulted in a 13-fold increase in caspase activity and a 30-fold increase in TUNEL. On the other hand, hCG decreased messenger RNA expression of Bax in ESC. CONCLUSION(S): Milk fat globule-epidermal growth factor 8 has proapoptotic activity, suggesting participation in endometrial remodeling via an epithelial-stromal cell paracrine effect. Conversely, pregnancy levels of hCG has opposite effects on stromal cells. PMID- 22921914 TI - A bistable circuit involving SCARECROW-RETINOBLASTOMA integrates cues to inform asymmetric stem cell division. AB - In plants, where cells cannot migrate, asymmetric cell divisions (ACDs) must be confined to the appropriate spatial context. We investigate tissue-generating asymmetric divisions in a stem cell daughter within the Arabidopsis root. Spatial restriction of these divisions requires physical binding of the stem cell regulator SCARECROW (SCR) by the RETINOBLASTOMA-RELATED (RBR) protein. In the stem cell niche, SCR activity is counteracted by phosphorylation of RBR through a cyclinD6;1-CDK complex. This cyclin is itself under transcriptional control of SCR and its partner SHORT ROOT (SHR), creating a robust bistable circuit with either high or low SHR-SCR complex activity. Auxin biases this circuit by promoting CYCD6;1 transcription. Mathematical modeling shows that ACDs are only switched on after integration of radial and longitudinal information, determined by SHR and auxin distribution, respectively. Coupling of cell-cycle progression to protein degradation resets the circuit, resulting in a "flip flop" that constrains asymmetric cell division to the stem cell region. PMID- 22921916 TI - T1/T2 non-small-cell lung cancer treated by lobectomy: does tumor anatomic location matter? AB - BACKGROUND: The effect of tumor location on long-term survival after lobectomy for stage I non-small-cell lung cancer is unclear. Current data are limited to a retrospective single-institution series. We sought to determine if tumor anatomic location (i.e., the particular lobe that was involved) confers a survival advantage based on population-based data. METHODS: Using the Surveillance, Epidemiology and End Results database (1988-2007), we identified patients who underwent lobectomy for pathologic T1/T2 adenocarcinoma or squamous cell carcinomas. Wedge resections, segmentectomies, and pneumonectomies were excluded. We evaluated the association between the particular lobe that was involved, lymph node (LN) yield, and survival using the Kaplan-Meier method. To adjust for potential confounders, we used a Cox proportional hazards regression model. RESULTS: We identified 13,650 patients who met our inclusion criteria. There were significant differences in unadjusted overall (P=0.03) and cancer-specific survivals (P=0.03) based on tumor location. However, after adjusting for patient factors, geographic location of treatment, and tumor characteristics, we found that tumor location was not associated with significant differences in survival. We found that male gender, black race, squamous cell histology, increasing grade, and age were independent negative predictors of survival. Higher LN yields were independently associated with improved survival. Although adjusted survival rates were not significantly different, there were significant differences (P<0.0001) in LN yield based on tumor location; right middle lobe had the lowest yield (5.1 nodes), and left upper lobe had the highest yield (eight nodes). CONCLUSIONS: LN counts are independent predictors of survival. Although it is associated with significant difference in LN yield, tumor location is not an independent predictor of survival. Age, race, gender, tumor size, histology, and grade appear to be more important prognostic factors. These data suggest that treatment of T1/T2 non-small-cell lung cancer should be dictated by the same oncologic principles, regardless of tumor location. PMID- 22921915 TI - TrxG and PcG proteins but not methylated histones remain associated with DNA through replication. AB - Propagation of gene-expression patterns through the cell cycle requires the existence of an epigenetic mark that re-establishes the chromatin architecture of the parental cell in the daughter cells. We devised assays to determine which potential epigenetic marks associate with epigenetic maintenance elements during DNA replication in Drosophila embryos. Histone H3 trimethylated at lysines 4 or 27 is present during transcription but, surprisingly, is replaced by nonmethylated H3 following DNA replication. Methylated H3 is detected on DNA only in nuclei not in S phase. In contrast, the TrxG and PcG proteins Trithorax and Enhancer-of-Zeste, which are H3K4 and H3K27 methylases, and Polycomb continuously associate with their response elements on the newly replicated DNA. We suggest that histone modification enzymes may re-establish the histone code on newly assembled unmethylated histones and thus may act as epigenetic marks. PMID- 22921917 TI - Development of a lethal, closed-abdomen grade V hepato-portal injury model in non coagulopathic swine. AB - BACKGROUND: Hemorrhage within an intact abdominal cavity remains a leading cause of preventable death on the battlefield. Despite this need, there is no existing closed-cavity animal model to assess new hemostatic agents for the preoperative control of intra-abdominal hemorrhage. METHODS: We developed a novel, lethal liver injury model in non-coagulopathic swine by strategic placement of two wire loops in the medial liver lobes including the hepatic and portal veins. Distraction resulted in grade V liver laceration with hepato-portal injury, massive bleeding, and severe hypotension. Crystalloid resuscitation was started once mean arterial pressure (MAP) fell below 65 mm Hg. Monitoring continued for up to 180 min. RESULTS: We demonstrated 90% lethality (9/10) in swine receiving injury and fluid resuscitation, with a mean survival time of 43 min. Previous efforts in our laboratory to develop a consistently lethal swine model of abdominal solid organs, including preemptive anticoagulation, a two-hit injury with controlled hemorrhage prior to liver trauma, and the injury described above without resuscitation, consistently failed to result in lethal injury. CONCLUSION: This model can be used to screen other interventions for pre hospital control of noncompressible. PMID- 22921918 TI - Hemin induction of HO-1 protects against LPS-induced septic ileus. AB - BACKGROUND: Heme oxygenase (HO-1) protects against inflammation. In this study, we investigated the protective function of hemin-induced HO-1 against lipopolysaccharide (LPS)-induced ileus. METHODS: Rats received LPS intraperitoneally 24 h after intraperitoneal hemin pretreatment or placebo. We also injected zinc protoporphyrin (ZnPP, 3rd group), an inhibitor of HO-1, intraperitoneally 2 h before LPS administration. To assess intestinal muscle function, we examined muscularis strip contractility in an organ bath and measured gastrointestinal transit in vivo. We investigated inflammation within the muscularis using polymerase chain reaction (interleukin [IL]-6, inducible nitric oxide synthase (iNOS), HO-1 and IL-10) 6 and 24 h after LPS. RESULTS: Hemin significantly improved in vitro intestinal muscularis contractility (P < 0.001). In addition, hemin prevented LPS-induced dysmotility in vivo (gastrointestinal transit, geometric center: 8.39 +/- 0.33 versus 5.68 +/- 0.44; P < 0.001). In Zinc protoporphyrin (ZnPP)-treated animals, both parameters were significantly decreased compared with the hemin group. Messenger RNA expression demonstrated a significant reduction in IL-6 (6 h, hemin: 127.6 +/- 36.7 versus LPS: 14,431 +/- 5407; 24 h: 1.58 +/- 0.39 versus 11.15 +/- 2.59; P < 0.01) and iNOS (6 h: 2516 +/- 985 versus 50,771 +/- 13,321; 24 h: 55.11 +/- 10.55 versus 257.1 +/- 43.18; P < 0.001) in hemin-treated animals. Anti-inflammatory HO-1 messenger RNA levels (6 h, hemin: 116.3 +/- 18.55 versus LPS: 26.02 +/- 3.64; 24 h: 18.46 +/- 2.69 versus 2.80 +/- 0.32; P < 0.001) were increased. There was no significant difference in IL-10 levels at 6 and 24 h. ZnPP reversed the anti inflammatory hemin effects. CONCLUSIONS: Hemin induction of HO-1 diminishes LPS induced sepsis. Heme oxygenase-1 has a central role in preventing sepsis-induced ileus. This benefit is reversed by HO-1 inhibition with ZnPP. PMID- 22921919 TI - Unplanned reoperations: is emergency surgery a risk factor? A cohort study. AB - BACKGROUND: Unplanned reoperations have been proposed as a quality indicator in surgery but have not been studied extensively, especially concerning risk factors. METHODS: This was a prospective cohort study in a third-level general surgery service. Data regarding patients operated on between July 2007 and February 2008 and followed up for 30 postoperative days were collected. Unplanned reoperations were the primary end point. The secondary end points were 30-d mortality and length of stay. A multivariate logistic regression analysis evaluated the hypothesis that patients operated on in emergency conditions had a greater chance of being reoperated on, after adjusting for relevant covariates. RESULTS: There was a 5.9% cumulative incidence of unplanned reoperations. Patients operated on in emergency conditions had a 1.79 crude relative risk (RR) (95% confidence interval [CI], 1.15-2.78) of reoperation. Reoperated patients' RR of mortality was 8.94 (95% CI, 6.11-13.07). The mean postoperative hospital stay was 3d for patients who were not reoperated on and 19d for those who were reoperated on (P=0.00001). The logistic regression model gave a 2.83 odds ratio (95% CI, 1.65-4.87) for reoperation on emergency patients when adjusted for age, gender, body mass index, American Society of Anesthesiology classification, intraoperative inotropic use, and operation complexity. CONCLUSIONS: Tertiary general surgery service patients had a significantly increased risk of being reoperated on if the initial surgery was an emergency surgery compared with elective surgery. Unplanned reoperations led to a significantly increased mortality risk and a longer postoperative hospital stay, which could be regarded as warning signs in the care of surgical patients. PMID- 22921920 TI - Ischemic preconditioning decreased leukotriene C4 formation by depressing leukotriene C4 synthase expression and activity during hepatic I/R injury in rats. AB - BACKGROUND: Extensive experimental and clinical studies have shown that ischemic preconditioning (IP) can produce protective effects during hepatic ischemia reperfusion (I/R) injury. Our recent studies indicate that rat liver I/R injury is related to an abnormal increase in leukotriene (LT) C4 production. However, the mechanisms underlying IP actions on LTC4 generation during hepatic I/R injury remain to be explored. METHODS: We randomly divided adult male Sprague-Dawley rats into sham (control), I/R, and IP groups (n = 6). We subjected rat liver to 60 min partial hepatic ischemia followed by 5 h reperfusion with saline administered intravenously. We detected protein expression of LTC4 synthase (LTC4S) with Western blot, and measured LTC4 synthesis enzymes' activities and content by reverse-phase high-performance liquid chromatography. We assessed tissue injury using serum aspartate aminotransferase and aspartate aminotransferase activities and histologic changes. We examined liver tissue glutathione levels by a biochemical method. RESULTS: Ischemic preconditioning markedly decreased LTC4 content, reduced LTC4S protein expressions, and inhibited LTC4 synthesis enzymes' activities in rat liver compared with the I/R group (P < 0.05). We also observed a decline in serum alanine aminotransferase and aspartate aminotransferase activities (P < 0.05), together with hepatic tissue glutathione elevation (P < 0.05) in the IP groups. Positive expression of LTC4S on hepatocytes and sinusoidal endothelial cells in the IP group was significantly lower than that in the I/R group. CONCLUSIONS: These findings demonstrate that reduced LTC4 production by IP treatment during hepatic I/R injury could partially result from the down-regulation of LTC4S protein expression and the depression of LTC4 synthesis enzyme activity. They suggest that the beneficial effects of IP may be involved in repression of LTC4 generation during hepatic I/R injury. PMID- 22921922 TI - Linking planning performance and gray matter density in mid-dorsolateral prefrontal cortex: moderating effects of age and sex. AB - Planning of behavior relies on the integrity of the mid-dorsolateral prefrontal cortex (mid-dlPFC). Yet, only indirect evidence exists on the association of protracted maturation of dlPFC and continuing gains in planning performance post adolescence. Here, gray matter density of mid-dlPFC in young, healthy adults (18 32 years) was regressed onto performance on the Tower of London planning task while accounting for moderating effects of age and sex on this interrelation. Multiple regression analysis revealed an association of planning performance and mid-dlPFC gray matter density that was especially strong in late adolescence and early twenties. As expected, for males better planning performance was linked to reduced gray matter density of mid-dlPFC, possibly due to maturational processes such as synaptic pruning. Most surprisingly, females showed an inverted, positive interrelation of planning performance and mid-dlPFC gray matter density, indicating that sexually dimorphic development of dlPFC continues during early adulthood. Age and sex are hence important moderators of the link between planning performance and gray matter density in mid-dlPFC. Consequently, the assessment of moderator effects in regression designs can significantly enhance understanding of brain-behavior relationships. PMID- 22921921 TI - Extraocular ectoderm triggers dorsal retinal fate during optic vesicle evagination in zebrafish. AB - Dorsal retinal fate is established early in eye development, via expression of spatially restricted dorsal-specific transcription factors in the optic vesicle; yet the events leading to initiation of dorsal fate are not clear. We hypothesized that induction of dorsal fate would require an extraocular signal arising from a neighboring tissue to pattern the prospective dorsal retina, however no such signal has been identified. We used the zebrafish embryo to determine the source, timing, and identity of the dorsal retina-inducing signal. Extensive cell movements occur during zebrafish optic vesicle morphogenesis, however the location of prospective dorsal cells within the early optic vesicle and their spatial relationship to early dorsal markers is currently unknown. Our mRNA expression and fate mapping analyses demonstrate that the dorsolateral optic vesicle is the earliest region to express dorsal specific markers, and cells from this domain contribute to the dorsal retinal pole at 24 hpf. We show that three bmp genes marking dorsal retina at 25 hpf are also expressed extraocularly before retinal patterning begins. We identified gdf6a as a dorsal initiation signal acting from the extraocular non-neural ectoderm during optic vesicle evagination. We find that bmp2b is involved in dorsal retina initiation, acting upstream of gdf6a. Together, this work has identified the nature and source of extraocular signals required to pattern the dorsal retina. PMID- 22921924 TI - Individual profiles of spatio-temporal coordination in high intensity swimming. AB - The aim of the present study was to examine the inter-subject variability in inter-arm coordination during front crawl swimming at high intensity. Ten male competitive swimmers swam 200m front crawl at race pace. Two above water and four underwater cameras videotaped the test and APAS was used to assess the 3D anatomical points position and to calculate, afterwards, the angular position, velocity and the continuous relative phase, which was used to analyze upper limbs coupling during two arm stroke cycles for each 50 m lap of the 200 m front crawl event. The kinematics of the two arm stroke cycles was filtered and normalized to the total cycle duration. A significant decrease, caused by fatigue, was observed in the biomechanical and coordinative (temporal) parameters. The topography of the mean continuous relative phase curve showed a higher inter-subject variability between two groups (63.1 degrees vs. 76.0 degrees ; p<.05), suggesting that several profiles of inter-limb coordination exist. Two clusters arose from the coordination profiling, which mainly stemmed from organismic constraints (i.e., the swimmer's technique). PMID- 22921925 TI - Transfection of VEGF(165) genes into endothelial progenitor cells and in vivo imaging using quantum dots in an ischemia hind limb model. AB - Endothelial progenitor cells (EPCs) were transfected with fluorescently labeled quantum dot nanoparticles (QD NPs) with or without VEGF(165) plasmid DNA (pDNA) to probe the EPCs after in vivo transplantation and to test whether they presented as differentiated endothelial cells (ECs). Bare QD NPs and QD NPs coated with PEI or PEI + VEGF(165) genes were characterized by dynamic light scattering, scanning electron microscopy, and atomic force microscopy. Transfection of EPCs with VEGF(165) led to the expression of specific genes and proteins for mature ECs. A hind limb ischemia model was generated in nude mice, and VEGF(165) gene-transfected EPCs were transplanted intramuscularly into the ischemic limbs. At 28 days after transplantation, the VEGF(165) gene-transfected EPCs significantly increased the number of differentiated ECs compared with the injection of medium or bare EPCs without VEGF(165) genes. Laser Doppler imaging revealed that blood perfusion levels were increased significantly by VEGF(165) gene-transfected EPCs compared to EPCs without VEGF(165). Moreover, the transplantation of VEGF(165) gene-transfected EPCs increased the specific gene and protein expression levels of mature EC markers and angiogenic factors in the animal model. PMID- 22921926 TI - In vivo biocompatibility and osteogenesis of electrospun poly(epsilon caprolactone)-poly(ethylene glycol)-poly(epsilon-caprolactone)/nano hydroxyapatite composite scaffold. AB - A flexible and fibrous composite scaffold composed of poly(epsilon-caprolactone) poly(ethylene glycol)-poly(epsilon-caprolactone) (PCL-PEG-PCL, PCEC) and 30 wt.% nano-hydroxyapatite (n-HA) was fabricated through electrospinning. In the present study, we investigated its in vitro and in vivo performance by means of hydrolytic degradation, muscle pouch implantation, as well as repair the calvarial defects in New Zealand white rabbits. The results demonstrated that the degradable scaffold held good biocompatibility. Qualitative analysis of bone regeneration process was performed by radiological examination and histological analysis. The results indicated that new bone formed originally from the margin of host bone, and then grew toward the center of defects. Moreover, the quantitative determination of newly formed bone was performed using statistical analysis of histological sections at predetermined time points. At 20th week, the defects of treatment group were covered with the new solid cortical bone. In comparison, the control group was filled with a large amount of cancelous bone and bone marrow. It suggested that the composite scaffold had better activity of guided bone regeneration than that of self-healing. So the electrospun PCEC/n-HA fibrous scaffold had the great potential application in bone tissue engineering. PMID- 22921923 TI - Effects of nicotinic acetylcholine receptor agonists on cognition in rhesus monkeys with a chronic cocaine self-administration history. AB - Cocaine use is associated with impaired cognitive function, which may negatively impact treatment outcomes. One pharmacological strategy to improve cognition involves nicotinic acetylcholine receptor (nAChR) stimulation. However, the effects of chronic cocaine exposure on nAChR distribution and function have not been characterized. Thus, one goal of this study was to examine nAChR availability in rhesus monkeys with an extensive cocaine self-administration history (n = 4; ~6 years, mean intake, 1463 mg/kg) compared to age-matched cocaine-naive control monkeys (n = 5). Using [11C]-nicotine and positron emission tomography (PET) imaging, cocaine-experienced monkeys showed significantly higher receptor availability in the hippocampus compared to cocaine-naive monkeys. A second goal was to examine the effects of nAChR agonists on multiple domains of cognitive performance in these same monkeys. For these studies, working memory was assessed using a delayed match-to-sample (DMS) task, associative learning and behavioral flexibility using stimulus discrimination and reversal learning tasks. When administered acutely, the nonselective high-efficacy agonist nicotine, the low-efficacy alpha4beta2* subtype-selective agonist varenicline and the high efficacy alpha7 subtype-selective agonist, PNU-282987 significantly improved DMS performance in both cocaine-naive and cocaine-experienced monkeys. Individual doses of nicotine and varenicline that engendered maximum cognitive enhancing effects on working memory did not affect discrimination or reversal learning, while PNU-282987 disrupted reversal learning in the cocaine-naive monkeys. These findings indicate that a cocaine self-administration history influenced nAChR distribution and the effects of nAChR agonists on cognitive performance, including a reduced sensitivity to the disrupting effects on reversal learning. The cognitive enhancing effects of nAChR agonists may be beneficial in combination with behavioral treatments for cocaine addiction. This article is part of a Special Issue entitled 'Cognitive Enhancers'. PMID- 22921927 TI - Neuroprotective effects of agmatine in mice infused with a single intranasal administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). AB - We have recently demonstrated that rodents treated intranasally with 1-methyl-4 phenyl-1,2,3,6-tetrahydropyridine (MPTP) suffered impairments in olfactory, cognitive, emotional and motor functions associated with time-dependent disruption of dopaminergic neurotransmission in different brain structures conceivably analogous to those observed during different stages of Parkinson's disease (PD). Agmatine, an endogenous arginine metabolite, has been proposed as a novel neuromodulator that plays protective roles in several models of neuronal cellular damage. In the present study we demonstrated that repeated treatment with agmatine (30 mg/kg, i.p.) during 5 consecutive days increased the survival rate (from 40% to 80%) of 15-month-old C57BL/6 female mice infused with a single intranasal (i.n.) administration of MPTP (1 mg/nostril), improving the general neurological status of the surviving animals. Moreover, pretreatment with agmatine was found to attenuate short-term social memory and locomotor activity impairments observed at different periods after i.n. MPTP administration. These behavioral benefits of exogenous agmatine administration were accompanied by a protection against the MPTP-induced decrease of hippocampal glutamate uptake and loss of dopaminergic neurons in the substantia nigra pars compacta of aging mice, without altering brain monoamine oxidase B (MAO-B) activity. These results provide new insights in experimental models of PD, indicating that agmatine represents a potential therapeutic tool for the management of cognitive and motor symptoms of PD, together with its neuroprotective effects. PMID- 22921928 TI - Neuropeptide Y is associated with changes in appetite-associated hypothalamic nuclei but not food intake in a hypophagic avian model. AB - While neuropeptide Y (NPY) has been studied extensively per its pronounced role in food intake stimulation as well as its role in central pathways governing eating disorders, it has to our knowledge not been studied in polygenic models of hypo- and hyperphagia. Thus, the present study was designed to measure central NPY-associated food intake in lines of chickens that have undergone long-term genetic selection for low (LWS) or high (HWS) body weight and exhibit hypo- and hyperphagia, respectively. LWS chicks did not respond with any magnitude of altered food intake to any dose of NPY tested, while HWS chicks responded to all doses of NPY at similar magnitudes throughout the duration of observation. Both lines responded with similar increases in c-Fos immunoreactivity in the lateral hypothalamus and both divisions of the paraventricular nucleus; there were no significant line or line by treatment interactions. These data support the hypothesis that differences exist in the central NPY system of chicks from LWS and HWS lines and may provide novel insight for understanding NPY control of appetite. PMID- 22921929 TI - Acute and sustained effects of a metabotropic glutamate 5 receptor antagonist in the novelty-suppressed feeding test. AB - Accumulated evidence indicates that metabotropic glutamate 5 (mGlu5) receptor blockade exerts antidepressant-like and anxiolytic-like effects in several animal models. The novelty-suppressed feeding (NSF) test is used to measure anxiety induced hypophagia in rodents. Anxiogenic-like behavior can be counteracted by acute treatment with anxiolytics or chronic treatment with antidepressants. The objective of the present study was to investigate the effect of an mGlu5 receptor antagonist, 2-methyl-6-(phenylethynyl)-pyridine (MPEP), using the NSF test and to investigate the mechanisms underlying the effects of MPEP. The administration of MPEP at 1 h prior to testing significantly shortened the latency period until feed (an acute effect), and this effect lasted for 24 h (a sustained effect), similar to the results observed using the N-methyl-D-aspartate receptor antagonist ketamine. Pretreatment with a protein synthesis inhibitor, anisomycin, blocked the sustained, but not the acute, effects of MPEP, suggesting the involvement of new protein synthesis in the sustained effect of MPEP. In addition, the sustained effect of MPEP in the NSF test was partially abolished by pretreatment with a mammalian target of rapamycin (mTOR) antagonist, rapamycin. In contrast, a tropomyosin-related kinase, the tyrosine kinase inhibitor K252a, did not counteract the sustained effects of MPEP in this test. Taken together, these results are the first report to demonstrate that the blockade of the mGlu5 receptor exerted acute and sustained effects in the NSF test and that new protein synthesis may contribute to the sustained effects of MPEP, which may not mediate brain-derived neurotrophic factor-mTOR signaling. PMID- 22921930 TI - Risk factors for development of Clostridium difficile infection due to BI/NAP1/027 strain: a meta-analysis. AB - OBJECTIVE: To identify risk factors for the development of Clostridium difficile infection (CDI) due to C. difficile BI/NAP1/027 strain. METHODS: PubMed and Scopus databases were searched for studies that sought to identify risk factors for CDI due to the BI/NAP1/027 strain. The technique of meta-analysis was applied. RESULTS: Five studies compared CDI BI/NAP1/027 patients to CDI patients infected with non-BI/NAP1/027 strains, one compared CDI BI/NAP1/027 patients to non-CDI patients, and one provided data for both comparisons. The meta-analysis showed that fluoroquinolones were associated with a higher risk of CDI due to BI/NAP1/027 when compared to non-BI/NAP1/027 CDI (odds ratio (OR) 1.96, 95% confidence interval (95% CI) 1.37-2.80). A trend towards a lower risk for CDI due to BI/NAP1/027 was observed with cephalosporins when compared to non-BI/NAP1/027 CDI (OR 0.70, 95% CI 0.46-1.07). Prior macrolides were not associated with a higher risk for CDI BI/NAP1/027 when compared with non-BI/NAP1/027 CDI controls (OR 0.88, 95% CI 0.44-1.78). Clindamycin administration was associated with a lower risk for CDI due to BI/NAP1/027 when compared to non-BI/NAP1/027 CDI (OR 0.24, 95% CI 0.12-0.48). Age over 65 years was associated with an increased risk of CDI BI/NAP1/027 compared to non-BI/NAP1/027 CDI (OR 1.77, 95% CI 1.31-2.38). CONCLUSIONS: Fluoroquinolones and age over 65 years were associated with a higher risk of CDI due to the BI/NAP1/027 strain. Clindamycin was associated with a lower risk of CDI due to BI/NAP1/027. PMID- 22921931 TI - Impact on disease incidence of a routine universal and catch-up vaccination strategy against Neisseria meningitidis C in Tuscany, Italy. AB - BACKGROUND: Invasive infections due to Neisseria meningitidis are still an important public health issue worldwide. In Europe, meningococcal meningitis is differently distributed in the EU countries, but most cases of meningococcal diseases are caused by serogroups B and C. In Italy, each year about 900 cases of bacterial meningitis occur, of whom one third are caused by N. meningitidis. In March 2005, the Regional Health Authority of Tuscany approved a policy of active offer of conjugate meningococcus C (MCC) vaccination with three doses to all newborns at 3, 5 and 13 months of age (subsequently turning to a single dose at 13 months as of 2008) and a catch-up until age 6 years with a single dose. OBJECTIVE: The aim of the present study was to evaluate the effectiveness of the vaccination strategy adopted by Tuscany in preventing cases of invasive meningococcal C disease. METHODS: Surveillance data for the calculation of disease incidence, immunization coverage with MCC vaccine and vaccination status of meningitis cases were collected from 2005 to 2011. RESULTS: Incidence rates of meningococcal meningitis and septicemia decreased in all age groups involved in the immunization campaign, as a result of the progressively increasing vaccination coverage. Since 2006, no cases of invasive meningococcal C infection in vaccinated subjects were observed in Tuscany. A herd immunity effect was measured in unvaccinated age groups. CONCLUSION: MCC vaccination implementation in Tuscany was successful in the prevention of meningococcal C disease. Our results should prompt all Italian Regions to consider introducing MCC vaccination in order to protect their population. PMID- 22921932 TI - Chicago exploration days. AB - Single heavy atoms supported on thin carbon film were first imaged by Crewe, Wall and Langmore with their dark-field STEM. This glimpse into a hitherto invisible world we owe undeniably to Crewe's vision and determination, and to his gift to electrify, engage and encourage talented students. Since this successful event happened during my sabbatical stay in Crewe's group, the editors of this memorial volume asked me to write an account of its early history, which I gladly composed mostly from memory. The circumstances that led to my collaboration with Albert Crew in Chicago are reviewed, and the main project that we jointly embarked on the Chicago 1MeV STEM is described. It is shown that the project was nearing completion and would have likely been successful, had funding been continued. The paper concludes with a tribute to Albert I wrote many years ago. PMID- 22921933 TI - Three-dimensional structure of laser-modified Ti6Al4V and bone interface revealed with STEM tomography. AB - The early interaction between an implant's surface and bone is a leading factor for implant success, where multiple surface properties contribute to improved bone anchorage. An important parameter is surface topography, both on the micron and nanoscale. Laser-modification has been performed in the thread valleys of Ti6Al4V screws to alter their surface chemistry and topography to form a nanostructured surface titanium-dioxide. Implants were placed in the rabbit tibia, removed with surrounding bone after 8 weeks, fixated, dried and resin embedded. Focused ion beam milling (FIB) was used to prepare specimens from the resin blocks for transmission electron microscopy (TEM). Z-contrast electron tomography offered the possibility to explore the interfacial structure with high resolution in three-dimensions. With this technique, collagen fibers of the surrounding bone appear to have been laid down parallel to the implant surface. Accordingly, visualization of the laser-modified interface with nanoscale three dimensional resolution, as offered by Z-contrast electron tomography, gives new insights into bone bonding mechanisms between roughened titanium-dioxide surfaces and bone. PMID- 22921934 TI - Control of proinflammatory gene programs by regulated trimethylation and demethylation of histone H4K20. AB - Regulation of genes that initiate and amplify inflammatory programs of gene expression is achieved by signal-dependent exchange of coregulator complexes that function to read, write, and erase specific histone modifications linked to transcriptional activation or repression. Here, we provide evidence for the role of trimethylated histone H4 lysine 20 (H4K20me3) as a repression checkpoint that restricts expression of toll-like receptor 4 (TLR4) target genes in macrophages. H4K20me3 is deposited at the promoters of a subset of these genes by the SMYD5 histone methyltransferase through its association with NCoR corepressor complexes. Signal-dependent erasure of H4K20me3 is required for effective gene activation and is achieved by NF-kappaB-dependent delivery of the histone demethylase PHF2. Liver X receptors antagonize TLR4-dependent gene activation by maintaining NCoR/SMYD5-mediated repression. These findings reveal a histone H4K20 trimethylation/demethylation strategy that integrates positive and negative signaling inputs that control immunity and homeostasis. PMID- 22921935 TI - Reciprocal control between a bacterium's regulatory system and the modification status of its lipopolysaccharide. AB - Gram-negative bacteria often modify their lipopolysaccharide (LPS), thereby increasing resistance to antimicrobial agents and avoidance of the host immune system. However, it is unclear how bacteria adjust the levels and activities of LPS-modifying enzymes in response to the modification status of their LPS. We now address this question by investigating the major regulator of LPS modifications in Salmonella enterica. We report that the PmrA/PmrB system controls expression of a membrane peptide that inhibits the activity of LpxT, an enzyme responsible for increasing the LPS negative charge. LpxT's inhibition and the PmrA-dependent incorporation of positively charged L-4-aminoarabinose into the LPS decrease Fe(3+) binding to the bacterial cell. Because Fe(3+) is an activating ligand for the sensor PmrB, transcription of PmrA-dependent LPS-modifying genes is reduced. This mechanism enables bacteria to sense their cell surface by its effect on the availability of an inducing signal for the system regulating cell-surface modifications. PMID- 22921936 TI - Nuclear retention prevents premature cytoplasmic appearance of mRNA. AB - In S. cerevisiae cells debilitated in mRNA nuclear export, transcripts are retained in nuclear foci ("dots"). The ultimate fate of dot-mRNA has remained elusive. Here, we use single molecule counting microscopy and (35)S-methionine pulse-labeling assays to quantify cytoplasmic HSP104 RNA levels and estimate HSP104 RNA translation status. HSP104 transcripts, retained in dots as a consequence of the mex67-5 mutation, are slowly released over time for cytoplasmic translation. Thus, dot-mRNA retains function. However, forcing its nuclear export, by overexpressing the Sub2p mRNA export factor, does not elevate Hsp104p protein levels but is instead paralleled by growth deficiency. Nuclear export and growth phenotypes are both counteracted by coexpressing the nuclear RNA quality control factor Rrp6p. Thus, prematurely released dot-mRNA is translationally inactive and possibly toxic. Accordingly, nuclear retention of mRNA may serve a precautionary role during stressful situations such as, e.g., decreased mRNA maturation competence. PMID- 22921937 TI - Concerted action of the ribosome and the associated chaperone trigger factor confines nascent polypeptide folding. AB - How nascent polypeptides emerging from ribosomes fold into functional structures is poorly understood. Here, we monitor disulfide bond formation, protease resistance, and enzymatic activity in nascent polypeptides to show that in close proximity to the ribosome, conformational space and kinetics of folding are restricted. Folding constraints decrease incrementally with distance from the ribosome surface. Upon ribosome binding, the chaperone Trigger Factor counters folding also of longer nascent chains, to extents varying between different chain segments. Trigger Factor even binds and unfolds pre-existing folded structures, the unfolding activity being limited by the thermodynamic stability of nascent chains. Folding retardation and unfolding activities are not shared by the DnaK chaperone assisting later folding steps. These ribosome- and Trigger Factor specific activities together constitute an efficient mechanism to prevent or even revert premature folding, effectively limiting misfolded intermediates during protein synthesis. PMID- 22921938 TI - Quantifying hepatic fibrosis using a biexponential model of diffusion weighted imaging in ex vivo liver specimens. AB - The purpose of this study was to evaluate the non-Gaussian behavior of diffusion related signal decay of the ex vivo murine liver tissues from a dietary model of hepatic fibrosis. To this end, a biexponential formalism was used to model high b value diffusion imaging (up to 3500 s/mm(2)), the findings of which were correlated with liver histopathology and compared to a simple monoexponential model. The presence of a major, fast diffusing component and a minor, slow diffusing component was demonstrated. With increasing hepatic fibrosis, the fractional contribution of the fast diffusing component decreased, as did the diffusion coefficient of the fast diffusing component. Strong correlation between the degrees of liver fibrosis and a two-predictor regression model incorporating parameters of the biexponential model was found. Using Akaike's Information Criterion analyses, the biexponential model resulted in an improved fit of the high b-value diffusion data when compared to the monoexponential model. PMID- 22921939 TI - Sexual dimorphism in the human brain: evidence from neuroimaging. AB - In recent years, more and more emphasis has been placed on the investigation of sex differences in the human brain. Noninvasive neuroimaging techniques represent an essential tool in the effort to better understand the effects of sex on both brain structure and function. In this review, we provide a comprehensive summary of the findings that were collected in human neuroimaging studies in vivo thus far: we explore sexual dimorphism in the human brain at the level of (1) brain structure, in both gray and white matter, observed by voxel-based morphometry (VBM) and diffusion tensor imaging (DTI), respectively; (2) baseline neural activity, studied using resting-state functional magnetic resonance imaging (rs fMRI) and positron emission tomography (PET); (3) neurochemistry, visualized by means of neuroreceptor ligand PET; and (4) task-related neural activation, investigated using fMRI. Functional MRI findings from the literature are complemented by our own meta-analysis of fMRI studies on sex-specific differences in human emotional processing. Specifically, we used activation likelihood estimation (ALE) to provide a quantitative approach to mapping the consistency of neural networks involved in emotional processing across studies. The presented evidence for sex-specific differences in neural structure and function highlights the importance of modeling sex as a contributing factor in the analysis of brain related data. PMID- 22921940 TI - The effects of respiratory CO2 fluctuations in the resting-state BOLD signal differ between eyes open and eyes closed. AB - Resting fluctuations in arterial CO2 (a cerebral vasodilator) are believed to be an important source of low-frequency blood oxygenation level dependent (BOLD) signal fluctuations. In this study we focus on the two commonly used resting states in functional magnetic resonance imaging experiments, eyes open and eyes closed, and quantify the degree to which measured spontaneous fluctuations in the partial pressure of end-tidal CO2 (Petco2) relate to BOLD signal time series. A significantly longer latency of BOLD signal changes following Petco2 fluctuations was found in the eyes closed condition compared to with eyes open, which may reveal different intrinsic vascular response delays in CO2 reactivity or an alteration in the net BOLD signal arising from Petco2 fluctuations and altered neural activity with eyes closed. By allowing a spatially varying time delay for the compensation of this temporal difference, a more spatially consistent CO2 correlation map can be obtained. Finally, Granger-causality analysis demonstrated a "causal" relationship between Petco2 and BOLD. The identified dominant Petco2 >BOLD directional coupling supports the notion that Petco2 fluctuations are indeed a cause of resting BOLD variance in the majority of subjects. PMID- 22921941 TI - What causes the hyperintense T2-weighting and increased short T2 signal in the corticospinal tract? AB - The corticospinal tract (CST) appears hyperintense on both T2-weighted images and myelin water maps. Here, an extended multiecho T2 relaxation sequence with echoes out to 1120 ms was used to characterize the longer T2 times present in the CST. The T2 distribution from the CST was compared to other white matter structures in 14 healthy subjects. The intra-/extracellular T2 peak of the CST was broadened relative to other white matter structures and often split into two distinct peaks. In the CST, it appeared that the intracellular and extracellular water environments had unique T2 times, causing the intracellular water peak to be pushed down into the myelin water T2 regime and the extracellular peak to be pushed up to longer T2 times. The conventional myelin water T2 limits of 5-40 ms resulted in an artificial increase in myelin water fraction (MWF), causing the CST to be bright on myelin water images. When the upper limit for MWF was decreased to 25 ms, the CST regions exhibited MWF values similar to those found for adjacent anterior and posterior regions. The CST has unique magnetic resonance characteristics, which should be taken into consideration when being examined, especially when compared to pathological tissue. PMID- 22921942 TI - Improved in vivo human carotid artery wall T2 estimation. AB - T(2) quantification has been shown to noninvasively and accurately estimate tissue iron content in the liver and heart; applying this to thin-walled carotid arteries introduces a new challenge to the estimation process. With most imaging voxels in a vessel being along its boundaries, errors in parameter estimation may result from partial volume mixing and misregistration due to motion in addition to noise and other common error sources. To minimize these errors, we propose a novel technique to reliably estimate T(2) in thin regions of vessel wall. The technique weights data points to reduce the influence of expected error sources. It uses neighborhoods of data to increase the number of points for fitting and to assess lack of fit for automated outlier detection and deletion. The performance of this method was observed in simulations, phantom and in vivo patient studies and compared to results obtained using a pixelwise linear least squares estimation of T(2). The new proposed method showed a closer match to the expected results, and a 4.2-fold decrease in interobserver variability for in vivo studies. This increased confidence in estimation should improve the ability to reliably quantify iron noninvasively in the arterial wall. PMID- 22921943 TI - Evaluation of primary care: The "Primary Care Assessment Tools - Facility version" for the Spanish health system. AB - OBJECTIVE: To obtain versions of the Primary Care Assessment Tools (PCAT) Facility version to evaluate primary care (PC) in the Spanish context, and to analyze its feasibility, reliability and validity. METHODS: Cultural adaptation was performed through the use of forward and backward translations into Spanish and Catalan, observations and opinions of a panel of experts, and cognitive interviews with target users (PC team managers). A pilot phase was carried out in a sample of 130 managers of PC teams in Catalonia. A post-test questionnaire was sent 4-5 months later to all 194 managers of PC teams in the Barcelona health region. Analysis of metric properties included: 1) description of items and verification of Likert assumptions, since domain scores are obtained by summing item scores; 2) reliability analysis (Cronbach's alpha coefficient, Pearson's correlation coefficient, test-retest analysis); and 3) validity analysis (expert panel, cognitive interviews, and convergent and discriminant validity). RESULTS: Substantial adaptation was required for the accessory section of the questionnaire, but less was required in PC domain measurements. Items were added to the comprehensiveness domain to reflect services usually available in Spain. The lowest Cronbach's alpha scores were found for Access (0.62) and Coordination (0.59 and 0.65), while values were >0.70 for the remaining domains. CONCLUSION: The Spanish version of the PCAT-Facility questionnaire is now available and shows adequate reliability and validity. The Spanish PCAT version will facilitate national and international comparisons of PC and analysis of the determinants of quality of service provision. PMID- 22921944 TI - Metabolic syndrome, mild cognitive impairment and Alzheimer's disease--the emerging role of systemic low-grade inflammation and adiposity. AB - The past decade has shed new light on the etiology of Alzheimer's disease (AD), which is the consequence of interactions between numerous lesions. There is a growing body of evidence that the most beneficial effects of treatment might only be achieved in the preclinical stage of dementia, prior to the immense hallmarks of neurodegeneration. In view of this, several studies have focused on mild cognitive impairment (MCI) as a state, which represents a less severe form of the neuropathological process. However, early treatment interventions initiated in MCI have failed to slow down progression of the disease. Thus, great effort has been made to indicate modifiable risk factors for MCI. Consistent with the role of vascular malfunction in AD, this approach has shown the predictive value of the metabolic syndrome (MetS), which is a multidimensional entity and includes visceral obesity, dyslipidemia, hyperglycemia and hypertension. Despite the positive results of several epidemiological studies, the exact mechanisms underlying the connection between MetS and AD remain uncertain and various theories are being assessed. MetS, similarly to AD, has been attributed to a low grade chronic inflammation. There is a general consensus that the aberrant inflammatory response underlying MetS may arise from a deregulation of the endocrine homeostasis of adipose tissue. Hence, it might be assumed that the subclinical inflammation of adipose tissue may interact with the impaired central inflammatory response, leading to neurodegeneration. This article reviews the role of low-grade inflammation of adipose tissue in the pathophysiology of cognitive impairment and translates several considerable and unexplored findings from studies focused on subjects with MetS and animal models mimicking the phenotype of MetS into the etiology of AD. PMID- 22921945 TI - New evidence for assessing tetrahydrobiopterin (BH(4)) responsiveness. AB - OBJECTIVE: To evaluate the protocol we propose for detecting BH(4)-responsive patients and the possibility of delimiting more precisely the population to be tested. METHODS: We recruited 102 phenylketonuric patients on a phenylalanine (Phe)-restricted diet. The initial stage of the protocol was a 24-h BH(4) loading test involving Phe loading and subsequent ingestion of the cofactor, a 50% fall in blood Phe levels being considered a positive response. The non-responders at this stage then completed a one-week therapeutic test combining BH(4) administration and daily protein intake meeting recommended dietary allowances, to assess whether the 24-h test had detected all responders. RESULTS: The 24-h test detected almost all BH(4) responders (30.3% of the 99 patients included in the analysis), with just two patients (2.0%) subsequently responding positively to the therapeutic test. The 24-h test did not give any false positive results. CONCLUSIONS: The 24-h BH(4) loading test is clinically useful for screening phenylketonuric patients. Specifically, 95% of patients with Phe levels <700 MUmol/L, and none with Phe levels >1500 MUmol/L were BH(4)-responsive. Given these results, we conclude that patients with Phe levels<700 MUmol/L or>1500 MUmol/L probably do not need to be tested, prioritising the identification of BH(4)-responsiveness among individuals with intermediate Phe concentrations, between the aforementioned values. Additionally, our results suggest that the therapeutic test only needs to be performed in cases where the reduction in blood Phe levels after cofactor administration is within the range 40%-50%. PMID- 22921946 TI - Ammonium metabolism in humans. AB - Free ammonium ions are produced and consumed during cell metabolism. Glutamine synthetase utilizes free ammonium ions to produce glutamine in the cytosol whereas glutaminase and glutamate dehydrogenase generate free ammonium ions in the mitochondria from glutamine and glutamate, respectively. Ammonia and bicarbonate are condensed in the liver mitochondria to yield carbamoylphosphate initiating the urea cycle, the major mechanism of ammonium removal in humans. Healthy kidney produces ammonium which may be released into the systemic circulation or excreted into the urine depending predominantly on acid-base status, so that metabolic acidosis increases urinary ammonium excretion while metabolic alkalosis induces the opposite effect. Brain and skeletal muscle neither remove nor produce ammonium in normal conditions, but they are able to seize ammonium during hyperammonemia, releasing glutamine. Ammonia in gas phase has been detected in exhaled breath and skin, denoting that these organs may participate in nitrogen elimination. Ammonium homeostasis is profoundly altered in liver failure resulting in hyperammonemia due to the deficient ammonium clearance by the diseased liver and to the development of portal collateral circulation that diverts portal blood with high ammonium content to the systemic blood stream. Although blood ammonium concentration is usually elevated in liver disease, a substantial role of ammonium causing hepatic encephalopathy has not been demonstrated in human clinical studies. Hyperammonemia is also produced in urea cycle disorders and other situations leading to either defective ammonium removal or overproduction of ammonium that overcomes liver clearance capacity. Most diseases resulting in hyperammonemia and cerebral edema are preceded by hyperventilation and respiratory alkalosis of unclear origin that may be caused by the intracellular acidosis occurring in these conditions. PMID- 22921947 TI - A simple route to fabricate controllable and stable multilayered all-MWNTs films and their applications for the detection of NADH at low potentials. AB - This study demonstrates a polyelectrolyte-free method to fabricate controllable and stable all-MWNTs films via a covalent layer-by-layer (LBL) deposition. Aminated MWNTs and carboxylated MWNTs were prepared by surface functionalization, allowing the incorporation of MWNTs into highly tunable thin films through the formation of covalent amide bonds. Fourier transform infrared spectroscopy (FTIR) analysis demonstrated the formation of covalent linkages between MWNTs layers. Scanning electron microscopy (SEM) and ultraviolet-visible spectroscopy (UV-vis) were used to characterize the assembly process. Electrochemical studies indicated that the all-MWNTs film possessed a remarkable electrocatalytic activity toward dihydronicotinamide adenine dinucleotide (NADH) at relatively low potentials, without the need for redox mediators. The film thickness and the amount of assembled MWNTs were readily adjusted by simply changing the number of cycles in the LBL assembly process, which also effectively tuned the electrocatalytic activity of the film toward NADH. The film constructed with four bilayers showed a high sensitivity of 223.8MUA mM(-1)cm(-2) and a detection limit of 1.5MUM, with a fast response of less than 3s. Furthermore, the all-MWNTs film also showed good selectivity and excellent stability for the determination of NADH. PMID- 22921948 TI - A three-way junction aptasensor for lysozyme detection. AB - A well-designed three-way junction (TWJ) aptasensor for lysozyme detection was developed based on target-binding-induced conformational change of aptamer complementary DNA (cDNA) as probe. A ferrocene (Fc)-tagged cDNA is partially hybridized with an anti-lysozyme aptamer to form a folded structure where there is a coaxial stacking of two helices and the third one at an acute angle. In addition, the fabrication of the sensor was achieved via the single-step method, which offered a good condition for sensing. In the absence of lysozyme, electron transfer (eT), through the coaxial two helices called "conductive path", is allowed between Fc-labeled moiety and the electrode. The binding of lysozyme to the aptamer blocks eT, leading to diminished redox signal. This aptasensor with an instinct signal attenuation factor shows a high sensitivity to lysozyme, and the response data is fitted by nonlinear least-squares to Hill equation. Detection limit is 0.2nM with a dynamic range extending to 100nM. Compared with existing electrochemical impedance spectroscopy (EIS)-based approaches, TWJ-DNA aptasensor was demonstrated to be more specific for detection and simpler for regeneration procedure. PMID- 22921949 TI - Label-free G-quadruplex-specific fluorescent probe for sensitive detection of copper(II) ion. AB - An effective G-quadruplex-based probe has been constructed for rapid and sensitive detection of Cu(2+). In this probe, an anionic porphyrin, protoporphyrin IX (PPIX) served as a reference signal, which binds to G quadruplex specifically and the fluorescence intensity increases sharply. While, in the presence of Cu(2+), the G-quadruplex can catalyze the related Cu(2+) insertion into the protoporphyrin, the fluorescent intensity is decreased. The fluorescence of the response ligand could be selectively quenched in the presence of Cu(2+) and not interfered by other metal ions. The probe provided an effective platform for reliable detection of Cu(2+) with a detection limit as low as 3.0nM, the high sensitivity was attributed to the strong metalation of PPIX with Cu(2+) catalyzed by G-quadruplex (PS5.M). Linear correlations were obtained over the logarithm of copper ion concentration in the range from 8*10(-9)M to 2*10(-6)M (R=0.998). The G-quadruplex-based probe also could be used to detect Cu(2+) in real water samples. Additionally, these striking properties endow the G quadruplex-ligand with a great promise for analytical applications. PMID- 22921950 TI - Treatment with Azadirachta indica in diabetic pregnant rats: negative effects on maternal outcome. AB - ETHNOPHARMACOLOGICAL RELEVANCE: The role of Azadirachta indica (neem) against Chagas disease and its antibiotic and antidiabetic action have been demonstrated in non-pregnant animals. However, the effects of neem on lipid metabolism and oxidative stress during pregnancy remain to be investigated. The objective of this study was to evaluate the effects of Azadirachta indica (neem) on maternal reproductive performance and biochemical parameters in non-diabetic and streptozotocin-induced mild diabetic rats (MD). MATERIALS AND METHODS: Pregnant rats were randomly distributed into six experimental groups: ND=non-treated non diabetic (n=13); NDOil=non-diabetic treated with 1.2 mL/day neem seed oil (n=12); NDPA=non-diabetic treated with 1.0mg/mL/day azadirachtin (n=12); D=non-treated diabetic (n=13); DOil: diabetic treated with neem seed oil (n=12), and DPA=diabetic treated with azadirachtin, n=13. Treatment with either neem oil (1.2 mL/day) or azadirachtin (1.0mg/mL/day) was orally administered throughout pregnancy. Glucose test tolerance (GTT) was performed at day 17 of pregnancy and used as an inclusion criterion. At term pregnancy, maternal reproductive outcomes, lipid profile and oxidative stress status were assessed. RESULTS: Treatment with neem oil and azadirachtin during pregnancy (1) had no hypoglycemic and anti-hyperglycemic effects on non-diabetic and diabetic rats, respectively; (2) affected OGTT glycemic levels in diabetic rats; (3) increased the proportion of fetuses classified as small for pregnancy age (SPA) in all groups; and (4) did not interfere with the lipid profile in non-diabetic dams. Neem oil reduced the rate of total cholesterol and NEFA in diabetic animals. Both neem oil and azadirachtin increased lipoperoxidation, characterized by increased MDA levels in non-diabetic rats. CONCLUSION: Both neem seed oil and azadirachtin impaired intrauterine development and altered antioxidant/oxidative status during pregnancy. PMID- 22921951 TI - Therapeutic battle against larval toxocariasis: are we still far behind? AB - Toxocariasis is a widespread zoonotic helminthic disease. Human infection is acquired by ingestion of embryonated eggs of Toxocara which reach the environment via stools of dogs and cats. In paratenic hosts, such as humans and mice, the hatched larvae migrate systematically in the body and could reach critical sites such as the eye and the central nervous system. The clinical expression of toxocariasis includes two main forms of varying intensity: visceral and ocular, as well as several organ-specific clinical manifestations. The issue of treatment is a matter of great controversy not only because of limited efficacy of anthelmintic drugs in terms of parasite eradication, but also because of doubts about the benefits of therapy as most Toxocara infections are self-limiting. Many animal studies were conducted employing different drugs and regimens, yet the results were variable and inconsistent. On the other hand, experience in human therapy is unfortunately limited due to paucity of clinical trials. Herein, the problems and pitfalls of treatment of toxocariasis are addressed, and new trends in therapy are discussed. PMID- 22921952 TI - Prevalence of Toxoplasma gondii infection in antenatal population in Menoufia governorate, Egypt. AB - Knowledge of the prevalence of Toxoplasma gondii infection in pregnant women would be a valuable approach for planning appropriate preventive strategies. However, no enough data currently exist as to the magnitude of T. gondii infection among pregnant women in Egypt. In view of paucity of reports on this issue, the current cross-sectional study aimed to determine the rate of T. gondii infection and maternal-fetal transmission in antenatal population in Menoufia governorate, Egypt. Out of 323 pregnant women who were screened for Toxoplasma specific IgG and IgM antibodies with ELFA, 218 samples were IgG seropositive, of which, 9 samples were IgM seropositive. Therefore, seropositivity rates of 67.5% (95% CI: 62.39%, 72.61%), and 2.8% (95% CI: 1%, 4.6%) for IgG and IgM, respectively were found. Analysis of serological patterns revealed that a large proportion of subjects were immune to Toxoplasma infection (IgG+/IgM-), as prevalence of chronic infection was 64.7% (209 cases), and 32.5% of cases were susceptible to primary infection (IgG-/IgM-). Meanwhile, the rate of probable acute Toxoplasma infection (IgG+/IgM+) was 2.8%, with one case (0.3%) confirmed for recent infection, as she had low avidity index with positive amniotic fluid analysis with both PCR and mouse inoculation. Significant relations were seen between Toxoplasma-specific IgG and knowledge about transmission modes, consumption of milk/milk products and unwashed raw vegetable/fruit, hand hygiene, contact with soil and farm animals. In conclusion, we reported high prevalence for T. gondii infection among antenatal population in Menoufia governorate. Thus, the susceptibility for toxoplasmosis is relatively low. Sources of infection revealed herein might represent potential threats for primary infection in seronegative women. Accordingly, there is urgent need for implementation of health education programs as an appropriate approach for prevention. PMID- 22921953 TI - Hendra virus: an emerging paramyxovirus in Australia. AB - Hendra virus, first identified in 1994 in Queensland, is an emerging zoonotic pathogen gaining importance in Australia because a growing number of infections are reported in horses and people. The virus, a member of the family Paramyxoviridae (genus Henipavirus), is transmitted to horses by pteropid bats (fruit bats or flying foxes), with human infection a result of direct contact with infected horses. Case-fatality rate is high in both horses and people, and so far, more than 60 horses and four people have died from Hendra virus infection in Australia. Human infection is characterised by an acute encephalitic syndrome or relapsing encephalitis, for which no effective treatment is currently available. Recent identification of Hendra virus infection in a domestic animal outside the laboratory setting, and the large range of pteropid bats in Australia, underpins the potential of this virus to cause greater morbidity and mortality in both rural and urban populations and its importance to both veterinary and human health. Attempts at treatment with ribavirin and chloroquine have been unsuccessful. Education, hygiene, and infection control measures have hitherto been the mainstay of prevention, while access to monoclonal antibody treatment and development of an animal vaccine offer further opportunities for disease prevention and control. PMID- 22921954 TI - Familial aggregation of idiopathic normal pressure hydrocephalus: novel familial case and a family study of the NPH triad in an iNPH patient cohort. AB - OBJECTIVE: Idiopathic normal pressure hydrocephalus (iNPH) is considered sporadic, yet familial cases involving single pedigrees are being increasingly recognized. As current evidence does not extend beyond isolated pedigrees, we aimed to determine the putative heritability of iNPH by examining the prevalence of the iNPH triad among the family members of iNPH probands. METHOD: We present a case-control family study of the iNPH symptom triad among the relatives of iNPH patients (n=20) identified from a cohort of patients undergoing CSF diversion and matched comparison subjects (n=21). A total of 291 first-degree relatives from 41 families were characterized using semi-structured family history interviews. Independent from the family study, we present a novel well-characterized familial case of iNPH. RESULTS: >= 2 insidious, progressive and idiopathic iNPH symptoms were identified among first degree relatives in 6 iNPH pedigrees (2 multiply affected) and 1 control pedigree, with an incidence of 7.1% among iNPH relatives and 0.7% among control relatives (OR=11.53). Gait disturbance and memory impairment began at a younger age among the relatives of iNPH probands. Independent of our family study, we present a novel case report of a large iNPH pedigree with multiple affected relatives. INTERPRETATION: Our family study and novel familial case suggest familial aggregation of iNPH. A larger family study with full characterization of affected and unaffected relatives is warranted. Confirmation of heritability may allow identification of individuals at high-risk for iNPH, early intervention, and improved aetiological elucidation. PMID- 22921955 TI - The association between low alcohol use and traffic risk behaviors among Brazilian college students. AB - Although there are a large number of studies focused on binge drinking and traffic risk behaviors (TRB), little is known regarding low levels of alcohol consumption and its association to TRB. The aim of this cross-sectional study is to examine the association of low to moderate alcohol intake pattern and TRB in college students in Brazil. 7037 students from a National representative sample were selected under rigorous inclusion criteria. All study participants voluntarily fulfilled a structured, anonymous, and self-questionnaire regarding alcohol and drug use, social-demographic data, and TRB. Alcohol was assessed according to the average number of alcoholic units consumed on standard occasions over the past 12 months. The associations between alcohol intake and TRB were summarized with odds ratio and their confidence interval obtained from logistic regression. Compared with abstainers students who consumed only one alcohol unit had the risk of being a passenger in a car driven by a drunk driver increased by almost four times, students who reported using five or more units were increased by almost five times the risk of being involved in a car crash. Compared with students who consumed one alcohol unit, the risk of driving under the influence of alcohol increased four times in students using three alcohol units. Age group, use of illicit drugs, employment status, gender, and marital status significantly influenced occurrence of TRB among college students. Our study highlights the potential detrimental effects of low and moderate pattern of alcohol consumption and its relation to riding with an intoxicated driver and other TRB. These data suggest that targeted interventions should be implemented in order to prevent negative consequences due to alcohol use in this population. PMID- 22921957 TI - The relation between fearfulness in young and stress-response in adult laying hens, on individual and group level. AB - Fearfulness of an individual can affect its sensitivity to stress, while at the same time the social situation in which an animal lives can affect its fear level. It is however unknown what the long-term effects of high fearfulness on sensitivity to stress are, on individual or group level in laying hens. We hypothesize that increased fearfulness at a young age results in increased sensitivity to stress at an adult age, and that this relation can differ between groups, due to differences in group composition. Therefore, we studied the relation between fearfulness in an Open Field (OF) test at six weeks of age and plasma-corticosterone (CORT) levels after a 5-min Manual Restraint test (MR) at 33 weeks of age, and assessed behavior in the home pen. We used birds from a low mortality line, selected for four generations on low mortality due to feather pecking and cannibalism and a control line (n=153 in total, eight pens/line). These lines are known to differ in fearfulness and stress physiology. Chicks from the low mortality line were more active in the OF compared to chicks from the control line. Chicks that showed a fearful response (no walking, no vocalizing) in the OF test had higher CORT at 33 weeks of age than chicks that walked and/or vocalized in the OF test and had higher activity in the home pen as adults. On group level, a passive response in the OF was related to high CORT levels after MR. Presence of at least one fearful bird in a group led to higher CORT in the other group mates compared to birds from groups with no fearful birds present. Birds from groups in which more than 50% of birds had severe comb lesions had higher CORT levels compared to birds from groups with less than 50% of birds affected. High fearfulness of laying hen chicks can on individual level have a long-term effect on stress sensitivity. The presence of fearful birds in a group as well as signs of social instability in a group, indicated by comb lesions, can affect sensitivity to stress of birds from the same group. The mechanism by which this occurs can lie in social transmission of (fear related) behavior, but this suggestion needs further investigation. PMID- 22921956 TI - Reinforcement learning in young adults with developmental language impairment. AB - The aim of the study was to examine reinforcement learning (RL) in young adults with developmental language impairment (DLI) within the context of a neurocomputational model of the basal ganglia-dopamine system (Frank, Seeberger, & O'Reilly, 2004). Two groups of young adults, one with DLI and the other without, were recruited. A probabilistic selection task was used to assess how participants implicitly extracted reinforcement history from the environment based on probabilistic positive/negative feedback. The findings showed impaired RL in individuals with DLI, indicating an altered gating function of the striatum in testing. However, they exploited similar learning strategies as comparison participants at the beginning of training, reflecting relatively intact functions of the prefrontal cortex to rapidly update reinforcement information. Within the context of Frank's model, these results can be interpreted as evidence for alterations in the basal ganglia of individuals with DLI. PMID- 22921958 TI - Analysis of Investigator HDplex markers in Swedish and Somali populations. PMID- 22921959 TI - Modelling heterozygote balance in forensic DNA profiles. AB - In this paper we investigate the relationship between heterozygous balance (h) and average peak height (phi-) in a set of IdentifilerTM data. The mean of heterozygote balance is unaffected by average peak height but the variance about this mean is much lower at high average peak heights. PMID- 22921960 TI - [The impact of radiation therapy on sexual function]. AB - The aim of this study was to evaluate the impact of radiation therapy on sexual life. The analysis was based on a Pubmed literature review. The keywords used for this research were "sexual, radiation, oncology, and cancer". After a brief reminder on the anatomy and physiology, we explained the main complications of radiation oncology and their impact on sexual life. Preventive measures and therapeutic possibilities were discussed. Radiation therapy entails local, systematic and psychological after-effects. For women, vaginal stenosis and dyspareunia represent the most frequent side effects. For men, radiation therapy leads to erectile disorders for 25 to 75% of the patients. These complications have an echo often mattering on the patient quality of life of and on their sexual life post-treatment reconstruction. The knowledge of the indications and the various techniques of irradiation allow reducing its potential sexual morbidity. The information and the education of patients are essential, although often neglected. In conclusion, radiation therapy impacts in variable degrees on the sexual life of the patients. Currently, there are not enough preventive and therapeutic means. Patient information and the early screening of the sexual complications are at stake in the support of patients in the reconstruction of their sexual life. PMID- 22921961 TI - [Image-guided radiotherapy in prostate cancer: concepts and implications]. AB - Intensity modulated radiotherapy (IMRT) and image-guided radiotherapy (IGRT) are technological developments, which when applied in a model of prostate cancer, led to a significant reduction in the toxicity and digestive and urinary sequelae of 3D conformational radiotherapy. The major clinical benefits of these techniques with regard to reduced digestive and urinary toxicity are unequivocal since very few sequelae have been reported at 10 years (2% of grade 2 and 1% of grade 3 digestive toxicity; 11% of grade 2 and 5% of grade 3 urinary toxicity). Even when these two techniques are combined, IG-IMRT significantly diminishes late genitourinary toxicity. In the absence of adaptive radiotherapy, there are many IGRT protocols and repositioning techniques, and every step in the IGRT process must be carried out with extreme rigor: installing the patient and contention system, repositioning technique with or without fiduciary markers, type of repositioning imaging, definition of margins inherent in each technique (prostate, seminal vesicles and/or pelvic lymph nodes), frequency of repositioning during treatment, dietary constraints with or without rectal lavage. For these reasons, every centre that performs IGRT must carefully and rigorously assess the uncertainties of repositioning linked to the IGRT technique. In this review, we analyzed data from the literature based on dosimetric studies and the proven clinical impact in order to answer the different questions asked by radiation oncologists at every step of the IGRT process for cancer of the prostate. Recommendations are made for the repositioning protocols according to the most widely used repositioning techniques: fiduciary markers or soft tissues, kV-CBCT or MV-CBCT, 3D ultrasonography. PMID- 22921962 TI - [Ablation of liver metastases by radiofrequency]. AB - Radiofrequency is a thermal ablative technique that is most often used percuteanously under image guidance. Thermal damage is obtained through frictional heating of a high frequency current. The maximal volume of destruction obtained in one radiofrequency delivery is around 4 cm and consequently, best indication for treatment are tumours below 3 cm. When compared, radiofrequency and surgical removal for tumours below 25 mm in diameter demonstrated a rate of incomplete resection/ablation of 6% and 7.3% respectively. Median survival after the first radiofrequency of a liver metastasis of CRC is reported to be 24 to 52 months with a 5 years overall survival of 18 to 44%. The median overall survival increases from 22 to 48 months depending on the use of radiofrequency ablation as rescue treatment after failure of others, or as a first line treatment. For patients with a single tumour, less than 4 cm, the survival rates at 1, 3, and 5 years are respectively 97%, 84% and 40%, with a median survival of 50 months. Follow-up imaging requires to use contrast-enhanced CT or MRI, looking for local recurrences evidenced by local foci of enhancement at the periphery of the ablation zone. PMID- 22921963 TI - Intermittent androgen deprivation therapy in prostate cancer: is everything so clear? PMID- 22921964 TI - Obesity, prostate-specific antigen nadir, and biochemical recurrence after radical prostatectomy: biology or technique? Results from the SEARCH database. AB - BACKGROUND: Obesity is associated with an increased risk of biochemical recurrence (BCR) after radical prostatectomy (RP). It is unclear whether this is due to technical challenges related to operating on obese men or other biologic factors. OBJECTIVE: To examine whether obesity predicts higher prostate-specific antigen (PSA) nadir (as a measure of residual PSA-producing tissue) after RP and if this accounts for the greater BCR risk in obese men. DESIGN, SETTING, AND PARTICIPANTS: A retrospective analysis of 1038 RP patients from 2001 to 2010 in the multicenter US Veterans Administration-based Shared Equal Access Regional Cancer Hospital database with median follow-up of 41 mo. INTERVENTION: All patients underwent RP. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: We evaluated the relationship between body mass index (BMI) and ultrasensitive PSA nadir within 6 mo after RP. Adjusted proportional hazards models were used to examine the association between BMI and BCR with and without PSA nadir. RESULTS AND LIMITATIONS: Mean BMI was 28.5 kg/m2. Higher BMI was associated with higher PSA nadir on both univariable (p=0.001) and multivariable analyses (p<0.001). Increased BMI was associated with increased BCR risk (hazard ratio [HR]: 1.06; p=0.007). Adjusting for PSA nadir slightly attenuated, but did not eliminate, this association (HR: 1.04, p=0.043). When stratified by PSA nadir, obesity only significantly predicted BCR in men with an undetectable nadir (p=0.006). Unfortunately, other clinically relevant end points such as metastasis or mortality were not available. CONCLUSIONS: Obese men are more likely to have a higher PSA nadir, suggesting that either more advanced disease or technical issues confound an ideal operation. However, even after adjusting for the increased PSA nadir, obesity remained predictive of BCR, suggesting that tumors in obese men are growing faster. This provides further support for the idea that obesity is biologically associated with prostate cancer progression. PMID- 22921966 TI - Synthesis and biological activity evaluation of emodin quaternary ammonium salt derivatives as potential anticancer agents. AB - Twenty-six emodin derivatives (17 novel) which attach quaternary ammonium salt were synthesized and evaluated for their anticancer activities in vitro and in vivo. Compounds 11g + 12g and 11h + 12h had more significant antiproliferative ability against three cancer cell lines and low cytotoxicity to HELF. 11g + 12g and 11h + 12h induced AGS cell apoptosis and arrested cell cycle at the G(0)/G(1) phase in a dose-dependent manner. Furthermore, the activities of the caspase-3, 9 enzymes were increased in the treated cells. In vivo studies revealed that compounds 11g + 12g and 11h + 12h showed significant anti-tumor activity compared with controlled group. PMID- 22921965 TI - Exendin-4 reverses biochemical and behavioral deficits in a pre-motor rodent model of Parkinson's disease with combined noradrenergic and serotonergic lesions. AB - Research on Parkinson's disease (PD) has mainly focused on the degeneration of the dopaminergic neurons of nigro-striatal pathway; however, post-mortem studies have demonstrated that other brain regions such as the locus coeruleus (LC) and raphe nuclei (RN) are significantly affected as well. Degeneration of these crucial neuronal cell bodies may be responsible for depressive behavior and cognitive decline present in the pre-motor stage of PD. We have thus set out to create a pre-motor rodent model of PD which mimics the early stages of the condition. N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4), a selective noradrenergic neurotoxin, and parachloroampetamine (pCA), a selective serotonergic neurotoxin, were utilized concomitantly with bilateral 6 hydroxydopamine (6-OHDA) injections into the striatum to produce a pre-motor rodent model of PD with partial deficits in the dopaminergic, noradrenergic, and serotonergic systems. Our model exhibited a depressive/anhedonic condition as assessed using sucrose preference testing and the forced swim test. Our model also demonstrated deficits in object memory. These behavioral impairments were accompanied by a decline in both tissue and extracellular levels of all three neurotransmitters in both the frontal cortex and striatum. Immunohistochemistry also revealed a decrease in TH+ cells in the LC and substantia nigra. Exendin-4 (EX-4), a glucagon-like peptide-1 receptor (GLP-1R) agonist, promoted recovery of both the biochemical and behavioral dysfunction exhibited by our model. EX-4 was able to preserve the functional integrity of the dopaminergic, noradrenergic, and serotonergic systems. In conclusion, we have generated a novel animal model of PD that recapitulates certain pre-motor symptomology. These symptoms and causative physiology are ameliorated upon treatment with EX-4 and thus it could be used as a possible therapy for the non-motor symptoms prominent in the early stages of PD. PMID- 22921967 TI - Formation of pyranoanthocyanins by Schizosaccharomyces pombe during the fermentation of red must. AB - Schizosaccharomyces pombe is a non-Saccharomyces yeast strain that can ferment grape musts with high sugar contents - but it also has other metabolic and physiological properties that render it of great interest to wine biotechnologists. This work compares the production of pyranoanthocyanins by S. pombe, Saccharomyces cerevisiae and Saccharomyces uvarum during fermentation. Total pyranoanthocyanins ranged from 11.9 to 19.4 mg/l depending on the strain of S. pombe used. On average, S. pombe produced more pyruvic acid than did either Saccharomyces species; as a consequence it also formed more vitisin A-type pigments. S. pombe 938 produced the largest quantity of vitisin A (11.03+/-0.82 mg/l). The formation of large amounts of pyranoanthocyanins intensifies the post fermentation colour of wines somewhat, a phenomenon that helps them maintain their colour over ageing as the natural grape anthocyanins become degraded. Some of the S. pombe strains showed hydroxycinnamate decarboxylase activity, which favours the formation of vinylphenolic pyranoanthocyanins. Fermentation with S. pombe therefore provides an interesting way of increasing the overall pyranoanthocyanin content of red wines, and of stabilising their colour during ageing. PMID- 22921968 TI - Environmental factors affect the activity of biocontrol agents against ochratoxigenic Aspergillus carbonarius on wine grape. AB - The influence of temperature and relative humidity (RH) on the activity of three biocontrol agents-the yeast Metschnikowia pulcherrima LS16 and two strains of the yeast-like fungus Aureobasidium pullulans LS30 and AU34-2-against infection by A. carbonarius and ochratoxin A (OTA) accumulation in wine grape berries was investigated in lab-scale experiments. The presence of wounds on grape skin dramatically favored infection of berries by A. carbonarius strain A1102, since unwounded berries showed very low levels of infection at all conditions of RH and temperature tested. Artificially wounded berries pre-treated with the biocontrol agents were inoculated with the ochratoxigenic A. carbonarius strain A1102 and were incubated for 5 days at two levels of RH (60% and 100%) and three different temperatures (20, 25 and 30 degrees C). The three biocontrol agents were able to prevent infections at 60% RH and 20 degrees C. At 60% RH and 25 degrees C only strain AU34-2 achieved some protection on day 5, whereas at 30 degrees C a limited biocontrol efficacy was evident only up to day 2. At 100% RH, LS16, LS30 and AU34-2 showed effective protection of grape berries at 20 degrees C until the 5th day of incubation. The three biocontrol agents achieved significant protection at higher temperatures only until the 2nd day after the beginning of the experiment: all three strains at 25 degrees C, and only strain LS16 at 30 degrees C. After 5 days, the three biocontrol agents were able to significantly reduce the level of OTA in berries at all the conditions tested. This occurred even when protection from infection was not significant, except at 30 degrees C and 100% of RH for all the three strains, and at 25 degrees C and 100% of RH for strain LS16. The biocontrol agents displayed a higher rate of colonization on grape berries at 20 and 25 degrees C than at 30 degrees C. The higher value of RH (100%) appeared to increase the rate of colonization, in particular at 20 and 25 degrees C. Taken together, our results emphasize the significant influence of environmental factors on the effectiveness of biocontrol against A. carbonarius as well as on OTA contamination in wine grape berries, and the need for biocontrol agents that can cope with the environmental conditions that are conducive to attack by A. carbonarius. PMID- 22921969 TI - Outcomes of pulmonary valve replacement in 170 patients with chronic pulmonary regurgitation after relief of right ventricular outflow tract obstruction: implications for optimal timing of pulmonary valve replacement. AB - OBJECTIVES: The objectives of this study were to evaluate outcomes of pulmonary valve replacement (PVR) in patients with chronic pulmonary regurgitation (PR) and to better define the optimal timing of PVR. BACKGROUND: Although PVR is effective in reducing right ventricular (RV) volume overload in patients with chronic PR, the optimal timing of PVR is not well defined. METHODS: A total of 170 patients who underwent PVR between January 1998 and March 2011 for chronic PR were retrospectively analyzed. To define the optimal timing of PVR, pre-operative and post-operative cardiac magnetic resonance imaging (MRI) data (n = 67) were analyzed. RESULTS: The median age at the time of PVR was 16.7 years. Follow-up completeness was 95%, and the median follow-up duration was 5.9 years. Overall and event-free survival at 10 years was 98% and 70%, respectively. Post-operative MRI showed significant reduction in RV volumes and significant improvement in biventricular function. Receiver-operating characteristic curve analysis revealed a cutoff value of 168 ml/m(2) for non-normalization of RV end-diastolic volume index (EDVI) and 80 ml/m(2) for RV end-systolic volume index (ESVI). Cutoff values for optimal outcome (normalized RV volumes and function) were 163 ml/m(2) for RV EDVI and 80 ml/m(2) for RV ESVI. Higher pre-operative RV ESVI was identified as a sole independent risk factor for suboptimal outcome. CONCLUSIONS: Midterm outcomes of PVR in patients with chronic PR were acceptable. PVR should be considered before RV EDVI exceeds 163 ml/m(2) or RV ESVI exceeds 80 ml/m(2), with more attention to RV ESVI. PMID- 22921970 TI - Timing of pulmonary valve replacement in tetralogy of fallot using cardiac magnetic resonance imaging: an evolving process. PMID- 22921971 TI - Improving the primary prevention of cardiovascular events by using biomarkers to identify individuals with silent heart disease. AB - OBJECTIVES: The aim of this study was to examine whether biomarkers can identify silent cardiac target organ damage (cTOD) in a primary prevention population. BACKGROUND: One possible way to improve primary prevention of cardiovascular events is to identify those patients who already harbor silent cTOD (i.e., myocardial ischemia, left ventricular hypertrophy, systolic dysfunction, diastolic dysfunction, or left atrial enlargement). This might be possible by screening with a biomarker (e.g. high sensitivity cardiac troponin T [hs-cTnT] or B-type natriuretic peptide [BNP]). METHODS: We prospectively recruited 300 asymptomatic individuals already receiving primary prevention therapy. Transthoracic echocardiography, stress echocardiography, and/or myocardial perfusion imaging were performed to identify silent cTOD. RESULTS: One hundred two (34%) patients had evidence of cTOD. Left ventricular hypertrophy was the most prevalent (29.7%) form of cTOD, followed by diastolic dysfunction (21.3%), left atrial enlargement (15.3%), systolic dysfunction (6.3%), and ischemia (6.3%). The area under the curve (AUC) for BNP to identify any form of silent cTOD was 0.78 overall and 0.82 in men. The equivalent figures for hs-cTnT were 0.70 and 0.75 in women. The AUC for BNP and hs-cTnT together was 0.81 and 0.82 in men. However, the discrimination power of other markers was poor, with AUCs of 0.61 for microalbuminuria, 0.49 for uric acid, and 0.58 for eGFR. CONCLUSIONS: In asymptomatic treated primary prevention patients, BNP screening is able to identify existing silent cTOD. The performance of hs-cTnT was not as good as that of BNP. B-type natriuretic peptide plus hs-cTnT together performed best. Prescreening with BNP +/- cTnT followed by targeted phenotyping is worth exploring further as a possible way to improve primary prevention. PMID- 22921972 TI - Biomarkers and silent cardiac disease in primary prevention: time to unmask the damage? PMID- 22921973 TI - Early anticoagulation of bioprosthetic aortic valves in older patients: results from the Society of Thoracic Surgeons Adult Cardiac Surgery National Database. AB - OBJECTIVES: The aim of this study was to evaluate the risks and benefits of short term anticoagulation in patients receiving aortic valve bioprostheses. BACKGROUND: Patients receiving aortic valve bioprostheses have an elevated early risk of thromboembolic events; however, the risks and benefits of short-term anticoagulation have been debated with limited evidence. METHODS: Our cohort consisted of 25,656 patients >=65 years of age receiving aortic valve bioprostheses at 797 hospitals within the Society of Thoracic Surgeons Adult Cardiac Surgery Database (2004 to 2006). The associated 3-month incidences of death or readmission for embolic (cerebrovascular accident, transient ischemic attack, and noncerebral arterial thromboembolism) or bleeding events were compared across discharge anticoagulation strategies with propensity methods. RESULTS: In this cohort (median age, 77 years), the 3 most common discharge anticoagulation strategies included: aspirin-only (49%), warfarin-only (12%), and warfarin plus aspirin (23%). Among those receiving aspirin-only, 3-month adverse events were low (death, 3.0%; embolic events, 1.0%; bleeding events, 1.0%). Relative to aspirin-only, those treated with warfarin plus aspirin had a lower adjusted risk of death (relative risk [RR]: 0.80, 95% confidence interval [CI]: 0.66 to 0.96) and embolic event (RR: 0.52, 95% CI: 0.35 to 0.76) but a higher risk of bleeding (RR: 2.80, 95% CI: 2.18 to 3.60). Relative to aspirin-only, warfarin-only patients had a similar risk of death (RR: 1.01, 95% CI: 0.80 to 1.27), embolic events (RR: 0.95, 95% CI: 0.61 to 1.47), and bleeding (RR: 1.23, 95% CI: 0.85 to 1.79). These results were generally consistent across patient subgroups. CONCLUSIONS: Death and embolic events were relatively rare in the first 3 months after bioprosthetic aortic valve replacement. Compared with aspirin-only, aspirin plus warfarin was associated with a reduced risk of death and embolic events, but at the cost of an increased bleeding risk. PMID- 22921974 TI - Prevention of thromboembolic events after bioprosthetic aortic valve replacement: what is the optimal antithrombotic strategy? PMID- 22921975 TI - [In room delivered doses during image-guided radiotherapy courses]. AB - Image-guided radiotherapy is defined by the use of images acquired in the treatment room to improve the accuracy of patient positioning. Most of imaging devices use X-rays and deliver an additional dose to the patients. These non negligible doses have to be evaluated and reported. Several studies have investigated organ-absorbed dose due to in-room imaging. Some organ doses are reported to give an idea of the magnitude, in particular for prostate cancer. Then, principles based on the as low as reasonably achievable (ALARA) concept are described and adapted to image-guided radiotherapy. Justification (what is the patient outcome?) and optimisation (image modality, acquisition frequency, treatment site...) are two main issues. They have a really big impact on patient treatment and staff organization. PMID- 22921976 TI - [Non-small cell lung cancer with oligometastases: treatment with curative intent]. AB - Published series suggest that, in carefully selected patients, long-term survival can be obtained when a complete resection of the primary site and metastasis is achieved. It comprises resection of additional malignant nodules in the contralateral lung (at present classified as M1a, but the additional nodule may be a second primary lung cancer), complete resection of the primary associated with limited metastatic pleural involvement (M1a), and resection of the primary with an isolated extrathoracic metastasis (mostly a single brain or adrenal). All these topics are discussed. PMID- 22921977 TI - [Oligometastatic bone disease. Can limited metastatic bone disease be cured? Is there room for local ablative treatments?]. AB - Solitary metastases have been reported in up to 30% of cases in imaging series. Local treatment aims at consolidating the injured bone and to prevent neurologic complications. Since the prognosis of bony metastatic disease is about 30 months and includes some long survivors, the multisdisciplinary committee in charge of the patient should ask the question and decide on the type of radical/ablative intervention in case of oligometastases. A literature search was performed using MESH terms (bone, metastases, radiotherapy, radiology, cement, radiofrequency ablation, chemoembolisation). Local ablative treatments can yield symptomatic relief and local control rates of about 90%. Stereotactic hypofractionated irradiation and cementoplasty are increasingly used. In conclusion, local ablative treatment of bony oligometastases is an efficient treatment. Its potential impact on survival remains to be demonstrated prospectively in clinical trials. PMID- 22921978 TI - [Radiotherapy of invasive breast cancer: French national guidelines]. AB - The French National Cancer Institute (INCa) and Societe francaise de senologie et pathologie mammaire (SFSPM), in collaboration with a multidisciplinary experts group, have published the French national clinical practice guidelines on a selection of 11 currently debated questions regarding the management of invasive breast cancer. Those guidelines are based on a comprehensive analysis of the current published evidence dealing with those issues, secondly reviewed by 100 reviewers. Radiotherapy was concerned by five of the 11 questions: indications for the boost after whole gland irradiation; hypofractionated radiotherapy; partial breast irradiation; indications for mammary internal nodes irradiation, and indications of radiotherapy after neo-adjuvant chemotherapy. PMID- 22921979 TI - [Stereotactic radiotherapy of intracranial benign tumors]. AB - Stereotactic radiotherapy can be delivered in one fraction or in multiple fractions schedule. It is used in benign tumours such as meningiomas, mainly localized in the base of the skull, for acoustic schwannoma and pituitary tumours. Whatever the tumour, results with the Gamma Knife((r)) are the most numerous, but those obtained by linear accelerators, adapted or dedicated, are comparable. The peripheral dose is preferred to the dose delivered to the isocentre. One fraction stereotactic irradiation should be proposed in small lesions and fractionated treatment for tumours larger. Whatever the tumour, the results are satisfactory with a control rate of 90%. However, this value reflects a disparity assessment, radiological stability for meningiomas, radiological stability and preservation of useful hearing in schwannoma and radiological stability and a decrease in hormonal secretions for pituitary adenomas. Overall complication rates are low. In total, the treatment of benign lesions with stereotactic irradiation gives satisfactory results with few complications. PMID- 22921980 TI - [Oligometastatic disease, a new concept: stereotactic irradiation for lung metastases. Literature review]. AB - Metastatic lung disease has long been the preserve of systemic treatments, local treatments being considered in a purely palliative intention. Several studies have objectified benefit to the local treatment of metastases, especially oligometastases. Surgery then took an important place in this setting, but the development of techniques for stereotactic radiotherapy on the one hand and the refusal or contraindication for surgery on the other hand led authors to conduct studies in this direction. This literature review describes the realization of stereotactic radiotherapy in treating pulmonary oligometastases and evaluates criteria for the selection of patients who would benefit. A comparison between the results of different studies on this technique allowed to show its effectiveness for local control, overall survival and tolerance. Stereotactic radiotherapy has emerged as a viable alternative, effective and well tolerated with local control rates comparable to that obtained by surgery (74 to 100%). Quality of life after stereotactic radiotherapy should be in a near future an important parameter to support this therapeutic choice, and needs to be precisely assessed. PMID- 22921981 TI - [Radiation-induced proctitis: symptoms, pathophysiology and treatment]. AB - Radiotherapy is a major treatment of pelvic tumours. It exposes to the risk of acute and long-term side effects, such as radiation proctitis. Radiation proctitis is a complex disease requiring support ranging from initial contact with the patient until several years after completion of radiotherapy. This care includes preventive measures (clinical and dosimetric factors), detection and medical and surgical treatments. This article aims to make a review of radiation proctitis induced during the treatment of pelvic cancers. PMID- 22921982 TI - [Is there a curative treatment for oligometastases? Lung radiofrequency ablation]. AB - Percutaneous ablation allows to treat tumours with temperature modifications. These non-invasive techniques are useful to treat metastatic lung tumours in patients with a slowly evolving disease, which requires multiple local treatment. Ablation is therefore proposed as a locoregional treatment because it has a minimal impact on the lung. Other advantages are its efficacy and a low morbidity. Limits may be the tumour size and its location. PMID- 22921983 TI - [Image guidance for the evaluation of setup accuracy]. AB - Information obtained by different methods of image-guided radiotherapy now allows us to reposition the target volume. This evolution causes a change in practice and positioning control. In order to control positioning errors, a systematic control during the first three to five sessions is required. Random repositioning errors and clinical target volume motions can be mastered only by performing a daily imaging. Finally, image-guided radiotherapy allows assessing anatomical changes occurring during treatment, and opens the field of adaptive radiotherapy. PMID- 22921984 TI - [Accelerated partial breast irradiation for early breast cancer]. AB - Hypofractionated and accelerated partial breast irradiation are more and more widely used for early breast cancer. Here, this short communication would expose the role of hypofractionated radiotherapy in adjuvant breast radiotherapy, rational, techniques and indications of accelerated partial breast irradiation. PMID- 22921985 TI - Challenges in medical applications of whole exome/genome sequencing discoveries. AB - Despite the well-documented influence of genetics on susceptibility to cardiovascular diseases, delineation of the full spectrum of the risk alleles had to await the development of modern next-generation sequencing technologies. The techniques provide unbiased approaches for identification of the DNA sequence variants (DSVs) in the entire genome (whole genome sequencing [WGS]) or the protein-coding exons (whole exome sequencing [WES]). Each genome contains approximately 4 million DSVs and each exome approximately 13,000 single nucleotide variants. The challenge facing researchers and clinicians alike is to decipher the biological and clinical significance of these variants and harness the information for the practice of medicine. The common DSVs typically exert modest effect sizes, as evidenced by the results of genome-wide association studies, and hence have modest or negligible clinical implications. The focus is on the rare variants with large effect sizes, which are expected to have stronger clinical implications, as in single gene disorders with Mendelian patterns of inheritance. However, the clinical implications of the rare variants for common complex cardiovascular diseases remain to be established. The most important contribution of WES or WGS is in delineation of the novel molecular pathways involved in the pathogenesis of the phenotype, which would be expected to provide for preventive and therapeutic opportunities. PMID- 22921986 TI - Serotonin involvement in Rhodiola rosea attenuation of nicotine withdrawal signs in rats. AB - Rhodiola rosea has been used for centuries in the traditional medicine to stimulate nervous system, to enhance physical and mental performance and to treat fatigue. It is known that administration of Rhodiola rosea extract elicits antidepressant activity, but the mechanism of action still remains unclear. Evidence from animal models and human studies show that nicotine reduces symptoms of depression and that nicotine cessation induces depressive-like symptoms. We investigated the effects of Rhodiola rosea on nicotine withdrawal signs. Nicotine dependence was induced by subcutaneous nicotine injection (2 mg/kg, four times daily) for 14 days. Another group of animals treated with nicotine (for 14 days) and successively with Rhodiola rosea extract was co-administered with selective 5 HT receptorial antagonist WAY 100635 (1 mg/kg). After nicotine withdrawal animals were evaluated for behavioural parameters (locomotor activity, abstinence signs, marble burying test), diencephalic serotonin metabolism and serotonin receptor-1A expression. Results show a significant increase of 5-HT content in N treated with R. rosea, with a significant increase of serotonin receptor 1A, suggesting an involvement of serotonin in beneficial effects of R. rosea on suffering produced by nicotine withdrawal. PMID- 22921987 TI - Repair efficiency and PUVA therapeutic response variation in patients with vitiligo. AB - Vitiligo is an acquired depigmentation disorder affecting 0.1% to >8.8% in Indian population. Psoralen and ultraviolet A radiation (PUVA) is a gold standard treatment for vitiligo, however, response is still empirical. In order to investigate whether drug response variation is influenced by the repair ability of PUVA treated vitiligo subjects, single cell gel electrophoresis (SCGE) for genotoxicity and serum malonaldehyde (MDA) for cytotoxicity were performed on 107 subjects (77 cases and 30 healthy controls) in South Indian population. In vitro repair ability was assessed by considering the residual damage. A significant difference was observed between the patients and controls with regard to their mean values of DNA damage and MDA levels (p<0.05). On categorization to fast and slow responders based on the time of response, patients exhibited a significant deviation in residual DNA damage, suggestive of variation with respect to DNA repair efficiency (p<0.05). This is the first study to our knowledge with respect to PUVA drug response variation in vitiligo in relation to DNA repair. Large systematic studies on DNA repair may help in a better understanding of the mechanisms involved in the PUVA drug response variation. PMID- 22921988 TI - Nurses and dietitians differ in food safety information provided to highly susceptible clients. AB - OBJECTIVE: To determine content, education channels, and motivational factors that influence what health professionals teach about safe food handling to populations who are highly susceptible for foodborne illnesses. To assess the differences in information provided by health professionals to highly susceptible populations. DESIGN: Descriptive, cross-sectional, Web-based survey. SETTING: National convenience sample from across the United States. PARTICIPANTS: Registered nurses (RNs; n = 232) and registered dietitians (RDs; n = 267). MAIN OUTCOME MEASURE(S): Content, motivation, and education channels used to educate highly susceptible populations. ANALYSIS: Various nonparametric tests were applied to measure differences. Significance was declared at P < .05. RESULTS: Although both RDs and RNs were providing some food safety information to their high-risk clients, RDs had more training than RNs in safe food handling and were more likely to provide comprehensive food safety messages to their highly susceptible clients; however, neither professional type provided consistent food safety information to patients at high risk for foodborne illness. CONCLUSIONS AND IMPLICATIONS: There is a need for more information about what motivates the health professional to teach safe food handling and a need for a universally adopted, evidence-based practice for teaching safe food handling to patients at high risk for foodborne illness. PMID- 22921989 TI - Follicular degeneration in the ovaries of goats experimentally infected with Trypanosoma vivax from the Brazilian semi-arid region. AB - Infection by Trypanosoma vivax and other African trypanosomes plays an important role in reproductive disorders in male and female livestock. Outbreaks of T. vivax in the semi-arid region of northeastern Brazil are characterized by wasting disease in cattle, sheep and goats with hematological, cardiac and nervous compromises in addition to reproductive failures. Similar to reports from Africa, we previously observed a reduction in fertility rates and severe testicular degeneration and epididymitis in male sheep infected with T. vivax from this region. Although anestrus is frequently reported in goats and sheep infected with T. vivax, the effects of this infection on the female reproductive organs need clarification. In this study, we addressed this issue through a histopathological evaluation of ovarian follicular morphology and classification in goats experimentally infected with a T. vivax isolate from the Brazilian semi-arid region. The infected animals presented typical clinical signs of trypanosomosis by T. vivax, including anemia, hyperthermia, pallor of the mucous membranes, enlarged lymph nodes, and progressive loss of weight. All the infected goats remained anestrus throughout the experimental period and exhibited important disturbances in the ovaries, evidenced by reduced size and a smooth surface without follicles or corpora lutea, and abnormal follicular development. In addition, through PCR, we detected T. vivax DNA in the ovarian tissues of the infected goats. Our findings contributed to understand the female reproductive failure associated with trypanosomosis caused by T. vivax. PMID- 22921990 TI - Drug-coated balloons--the new gold standard for treatment of coronary in-stent restenosis? PMID- 22921991 TI - Is there a role for neuronal nitric oxide synthase (nNOS) in cytokine toxicity to pancreatic beta cells? AB - Nitric oxide (NO), produced by the action of the inducible NO synthase, plays a crucial role in cytokine toxicity to pancreatic beta cells during type 1 diabetes development. It was the aim of this study to analyze the role of the neuronal NOS (nNOS) in proinflammatory cytokine-mediated beta cell toxicity. Expression of different isoforms of nitric oxide synthase in insulin-secreting INS1E cells and rat islets was analyzed by quantitative real-time PCR and Western blotting. The expression of nNOS in insulin-secreting INS1E cells was similar to that found in rat brain, while two other isoforms, namely the endothelial eNOS and inducible iNOS were not expressed in untreated cells. IL-1beta alone or in combination with TNF-alpha and/or IFNgamma induced iNOS but not eNOS expression. In contrast, nNOS expression was strongly decreased by the mixture of the three proinflammatory cytokines (IL-1beta, TNF-alpha and IFNgamma) both on the gene and protein level in INS1E cells and rat islet cells. The effects of cytokines on glucose-induced insulin-secretion followed the pattern of nNOS expression reduction and, on the other hand, of the iNOS induction. The data indicate that a low level of nitric oxide originating from the constitutive expression of nNOS in pancreatic beta cells is not deleterious. In particular since proinflammatory cytokines reduce this expression. This nNOS suppression can compensate for NO generation by low concentrations of IL-1beta through iNOS induction. Thus, this basal nNOS expression level in pancreatic beta cells represents a protective element against cytokine toxicity. PMID- 22921992 TI - Wireless platform for controlled nitric oxide releasing optical fibers for mediating biological response to implanted devices. AB - Despite the documented potential to leverage nitric oxide generation to improve in vivo performance of implanted devices, a key limitation to current NO releasing materials tested thus far is that there has not been a means to modulate the level of NO release after it has been initiated. We report the fabrication of a wireless platform that uses light to release NO from a polymethylmethacrylate (PMMA) optical fiber coated with an S-nitroso-N acetylpenicillamine derivatized polydimethylsiloxane (SNAP-PDMS). We demonstrate that a VAOL-5GSBY4 LED (lambda(dominant)=460 nm) can be used as a dynamic trigger to vary the level of NO released from 500 MUm diameter coated PMMA. The ability to generate programmable sequences of NO flux from the surface of these coated fibers offers precise spatial and temporal control over NO release and provides a platform to begin the systematic study of in vivo physiological response to implanted devices. NO surface fluxes up to 3.88 +/- 0.57 * 10(-10)mol cm(-2)min( 1) were achieved with -100 MUm thick coatings on the fibers and NO flux was pulsed, ramped and held steady using the wireless platform developed. We demonstrate the NO release is linearly proportional to the drive current applied to the LED (and therefore level of light produced from the LED). This system allow the surface flux of NO from the fibers to be continuously changed, providing a means to determine the level and duration of NO needed to mediate physiological response to blood contacting and subcutaneous implants and will ultimately lead to the intelligent design of NO releasing materials tailored to specific patterns of NO release needed to achieve reliable in vivo performance for intravascular and subcutaneous sensors and potentially for a wide variety of other implanted biomedical devices. PMID- 22921994 TI - Usefulness of hemoglobin level to predict long-term mortality in patients with asymptomatic carotid narrowing by ultrasonography. AB - Anemia is associated with the cardiovascular outcome in healthy subjects but its impact on outcome in patients with cardiovascular disease has not yet been fully understood. Therefore, we assessed the long-term influence of hemoglobin on all cause and cardiovascular mortality in patients with atherosclerotic disease. We prospectively studied 1,065 of 1,286 consecutive patients with asymptomatic carotid narrowing. During a median follow-up of 6.2 years, corresponding to 5,551 overall person-years, 275 patients (25.8%) died. Continuous measures of hemoglobin displayed a significant inverse effect on all-cause mortality and cardiovascular mortality (adjusted hazard ratio [HR] for increase of 1 SD of hemoglobin 0.73, 95% confidence interval [CI] 0.64 to 0.83; p <0.001) and adjusted HR 0.76, 95% CI 0.64 to 0.89; p = 0.001, respectively). The cumulative 6 year survival rate was 61%, 79%, 80%, and 81% in the first, second, third, and fourth quartile of hemoglobin (log-rank p <0.001). Patients within the first quartile (<12.9 g/dl) had a significantly increased risk of all-cause mortality (adjusted HR 1.93, 95% CI 1.46 to 2.54, p <0.001) and cardiovascular mortality (adjusted HR 1.68, 95% CI 1.19 to 2.36, p = 0.003) compared to patients with greater levels. In conclusion, our study has demonstrated a significant association with hemoglobin levels and all-cause and cardiovascular mortality in patients with carotid narrowing. Nevertheless, additional research, in terms of randomized controlled trials, is needed to warrant these findings and to evaluate potential therapeutic interventions. PMID- 22921993 TI - Effects of short-term exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin on microRNA expression in zebrafish embryos. AB - Although many drugs and environmental chemicals are teratogenic, the mechanisms by which most toxicants disrupt embryonic development are not well understood. MicroRNAs, single-stranded RNA molecules of ~22 nt that regulate protein expression by inhibiting mRNA translation and promoting mRNA sequestration or degradation, are important regulators of a variety of cellular processes including embryonic development and cellular differentiation. Recent studies have demonstrated that exposure to xenobiotics can alter microRNA expression and contribute to the mechanisms by which environmental chemicals disrupt embryonic development. In this study we tested the hypothesis that developmental exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a well-known teratogen, alters microRNA expression during zebrafish development. We exposed zebrafish embryos to DMSO (0.1%) or TCDD (5nM) for 1h at 30hours post fertilization (hpf) and measured microRNA expression using several methods at 36 and 60hpf. TCDD caused strong induction of CYP1A at 36hpf (62-fold) and 60hpf (135-fold) as determined by real time RT-PCR, verifying the effectiveness of the exposure. MicroRNA expression profiles were determined using microarrays (Agilent and Exiqon), next-generation sequencing (SOLiD), and real-time RT-PCR. The two microarray platforms yielded results that were similar but not identical; both showed significant changes in expression of miR-451, 23a, 23b, 24 and 27e at 60hpf. Multiple analyses were performed on the SOLiD sequences yielding a total of 16 microRNAs as differentially expressed by TCDD in zebrafish embryos. However, miR-27e was the only microRNA to be identified as differentially expressed by all three methods (both microarrays, SOLiD sequencing, and real-time RT-PCR). These results suggest that TCDD exposure causes modest changes in expression of microRNAs, including some (miR-451, 23a, 23b, 24 and 27e) that are critical for hematopoiesis and cardiovascular development. PMID- 22921995 TI - Determining the risks of magnetic resonance imaging at 1.5 tesla for patients with pacemakers and implantable cardioverter defibrillators. AB - Conventional pacemaker and implantable cardioverter-defibrillator product labeling currently cautions against exposure to magnetic resonance imaging (MRI). However, there is a growing clinical need for MRI, without an acceptable alternative imaging modality in many patients with cardiac devices. The purpose of this study was to determine the risk of MRI at 1.5 T for patients with cardiac devices by measuring the frequency of device failures and clinically relevant device parameter changes. Data from a single-center retrospective review of 109 patients with pacemakers and implantable cardioverter-defibrillators (the MRI group) who underwent 125 clinically indicated MRI studies were compared to data from a prospective cohort of 50 patients with cardiac devices who did not undergo MRI (the control group). In the MRI group, there were no deaths, device failures requiring generator or lead replacement, induced arrhythmias, losses of capture, or electrical reset episodes. Decreases in battery voltage of >=0.04 V occurred in 4%, pacing threshold increases of >=0.5 V in 3%, and pacing lead impedance changes of >=50 Omega in 6%. Although there were statistically significant differences between the MRI and control groups for the mean change in pacing lead impedance (-6.2 +/- 23.9 vs 3.0 +/- 22.1 Omega) and left ventricular pacing threshold (-0.1 +/- 0.3 vs 0.1 +/- 0.2 V), these differences were not clinically important. In conclusion, MRI in patients with cardiac devices resulted in no device or lead failures. A small number of clinically relevant changes in device parameter measurements were noted. However, these changes were similar to those in a control group of patients who did not undergo MRI. PMID- 22921996 TI - Validation of functional state of coronary tandem lesions using computational flow dynamics. AB - Functional lesion assessment for coronary tandem lesions and its clinical applications have not been thoroughly studied. The aim of this study was to test the hypothesis that the fractional flow reserve (FFR) gradient across an individual stenosis (DeltaFFR) during pressure-wire pullback is a surrogate of the relative functional severity of each stenosis in coronary tandem lesions. For in vitro validation, computational flow dynamic modeling of coronary tandem lesion with various degree of stenosis was constructed. For clinical validation, a total of 52 patients (104 lesions) with coronary tandem lesions (2 stenoses along 1 coronary artery) were consecutively enrolled, and tailored stent procedures based on DeltaFFR was performed, at first treating the lesion with large DeltaFFR and then subsequently reassessing the FFR for the remaining lesion. The coronary stenosis was considered functionally significant and stenting was performed when the FFR of a lesion was <=0.80. Using in vitro computational flow dynamic modeling, the lesion with the large DeltaFFR of the coronary tandem lesion was indicated as the lesion with the greater degree of simulated diameter stenosis. In the clinical cohort, 28 patients (53.8%) had only single-lesion treatment, and stent implantation for 28 lesions (26.9%) was deferred according to the proposed strategy. During the 9-month follow-up period, only 1 repeat revascularization occurred among the deferred lesions. In conclusion, for the treatment of coronary tandem lesions, DeltaFFR may be a useful index for prioritizing the treatment sequence and optimizing the stenting procedure. In this way, unnecessary stent implantation can be avoided, with the achievement of favorable functional and clinical outcomes. PMID- 22921997 TI - Relation of body mass index to late survival after valvular heart surgery. AB - Limited data have suggested that an "obesity paradox" exists for mortality and cardiovascular outcomes in patients undergoing coronary artery bypass grafting. Much less is known about the role of the preoperative body mass index (BMI) in patients undergoing valve surgery. We evaluated 2,640 consecutive patients who underwent valve surgery between April 2004 and March 2011. The patients were classified by the World Health Organization standards as "underweight" (BMI 11.5 to 18.4 kg/m(2), n = 61), "normal weight" (BMI 18.5 to 24.9 kg/m(2), n = 865), "overweight" (BMI 25 to 29.9 kg/m(2), n = 1,020), and "obese" (BMI 30 to 60.5 kg/m(2), n = 694). Mortality was ascertained using the Social Security Death Index. Hazard ratios (HRs), adjusted for known preoperative risk factors, were obtained using Cox regression models. The mean follow-up was 31.9 +/- 20.5 months. The long-term mortality rate was 1.21, 0.52, 0.32, and 0.44 per 10 years of person-time for underweight, normal, overweight, and obese patients, respectively. Compared to the normal BMI category, overweight patients (adjusted HR 0.60, 95% confidence interval 0.46 to 0.79, p <0.001) and obese patients (adjusted HR 0.67, 95% confidence interval 0.50 to 0.91, p = 0.009) were at a lower hazard of long-term all-cause mortality. Underweight patients remained at a greater adjusted risk of long-term mortality than normal weight patients (adjusted HR 1.69, 95% confidence interval 1.01 to 2.85, p = 0.048). Similar patterns of mortality outcomes were noted in the subset of patients undergoing isolated valve surgery. In conclusion, overweight and obese patients had greater survival after valve surgery than patients with a normal BMI. Very lean patients undergoing valve surgery are at a greater hazard for mortality and might require more rigorous preoperative candidate screening and closer postoperative monitoring. PMID- 22921998 TI - Cardiac magnetic resonance evaluation of the impact of interventricular and intraventricular dyssynchrony on cardiac ventricular systolic and diastolic function in patients with isolated left bundle branch block. AB - Ventricular dyssynchrony significantly impairs cardiac performance. However, the independent role of interventricular dyssynchrony (interVD) and intraventricular dyssynchrony (intraVD) in the development of abnormalities of systolic and diastolic performance is unclear. Cardiac magnetic resonance imaging was performed in 39 patients with left bundle branch block and 13 healthy patients. Structural and functional parameters of the left ventricle and degrees of interVD and intraVD were measured. We found that interVD was inversely correlated with left ventricular (LV) ejection fraction (r = -0.8, p <0.0001) and positively correlated with LV end-diastolic volume (r = 0.4, p <0.01), LV end-systolic volume (r = 0.6, p <0.0001), and LV mass (r = 0.4, p <0.01), thus indicating that interVD significantly affects systolic function and favors ventricular remodeling. Multivariate analysis further confirmed that interVD was an independent predictor of systolic dysfunction. Interestingly, we found that interVD was not associated with abnormalities of diastolic performance. Conversely, we found that intraVD significantly impaired diastolic function, whereas it had no effect on systolic function. IntraVD was inversely correlated with peak filling rate (r = -0.7, p <0.0001) and 1/2 filling fraction (r = 0.4, p = 0.04) and positively correlated with time to peak filling rate (r = 0.6, p <0.0001), validated parameters of diastolic function. Multivariate analysis confirmed that intraVD was an independent predictor of diastolic dysfunction. In conclusion, our study suggests that the 2 components of ventricular dyssynchrony differently affect cardiac performance. If confirmed in prospective studies, our results may help to predict the prognosis of patients with left bundle branch block and different degrees of interVD and intraVD, particularly those subjects undergoing cardiac resynchronization therapy. PMID- 22921999 TI - Multi-ethnic study of atherosclerosis arterial age versus framingham 10-year or lifetime cardiovascular risk. AB - Methods to improve coronary heart disease (CHD) risk prediction include incorporation of coronary artery calcium (CAC) within risk models and considering longer time horizons such as evaluation of lifetime cardiovascular risk (LTR). We compared the accuracy of 10-year Framingham risk score (FRS), LTR, and Multi Ethnic Study of Atherosclerosis (MESA) arterial age-adjusted 10-year risk for prediction of incident CHD events in men in the Prospective Army Coronary Calcium Project. We studied 1,633 healthy men (mean age 43 years, range 40 to 50 years, mean FRS 4.6%) with electron-beam computed tomography for CAC. Events (CHD death, myocardial infarction, acute coronary syndrome with nonelective coronary revascularization) were prospectively assessed over 5.6 +/- 1.5 years. Predicted risk using 10-year FRS for CHD and cardiovascular disease, LTR, and MESA arterial age were evaluated in relation with CAC and CHD events. CAC prevalence was strongly related to LTR, increasing in a graded fashion from 10.1% to 66.7% across 8 categories of increasing LTR. On receiver operating characteristic analysis, MESA arterial age (area under curve 0.78, 95% confidence interval 0.64 to 0.93) had the largest area under the curve but similar areas under the curve were observed for 10-year risk (CHD 0.74, 0.61 to 0.86; cardiovascular disease 0.70, 0.59 to 0.82), LTR (0.68, 0.49 to 0.76), and LTR with CAC as a covariate (0.76, 0.63 to 0.89). Inclusion of family history of CHD or body mass index did not improve model accuracy. In conclusion, increasing LTR was associated with increasingly prevalent CAC in this low-risk cohort and inclusion of CAC improved the accuracy of LTR for short-term event prediction. PMID- 22922000 TI - Race-specific impact of atrial fibrillation risk factors in blacks and whites in the southern community cohort study. AB - Despite a greater burden of traditional risk factors, atrial fibrillation (AF) is less common among blacks than whites for reasons that are unclear. The aim of this study was to examine race- and gender-specific influences of demographic, lifestyle, anthropometric, and medical factors on AF in a large cohort of blacks and whites. Among white and black participants in the Southern Community Cohort Study (SCCS) aged >=65 years receiving Medicare coverage from 1999 to 2008 (n = 8,836), diagnoses of AF (International Classification of Diseases, Ninth Revision, Clinical Modification code 427.3) were ascertained. Multivariate logistic regression was used to compute AF odds ratios associated with participant characteristics, including histories of hypertension, diabetes, stroke, and myocardial infarction or coronary artery bypass graft surgery, ascertained at cohort entry. Over an average of 5.7 years of Medicare coverage, AF was diagnosed in 1,062 participants. AF prevalence was significantly lower among blacks (11%) than whites (15%) (p <0.0001). Odds ratios for AF increased with age and were higher among men, the tall and obese, and patients with each of the co-morbid conditions, but the AF deficit among blacks compared to whites persisted after adjustment for these factors (odds ratio 0.64, 95% confidence interval 0.55 to 0.73). The patterns of AF risk were similar for blacks and whites, although associations with hypertension, diabetes, and stroke were somewhat stronger among blacks. In conclusion, these findings confirm the lower prevalence of AF among blacks than whites and suggest that traditional risk factors for AF apply similarly to the 2 groups and thus do not appear to explain the AF paradox in blacks. PMID- 22922001 TI - A tiger man. PMID- 22922003 TI - Phosphorus recovery from wastewater through microbial processes. AB - Waste streams offer a compelling opportunity to recover phosphorus (P). 15-20% of world demand for phosphate rock could theoretically be satisfied by recovering phosphorus from domestic waste streams alone. For very dilute streams (<10 mg PL( 1)), including domestic wastewater, it is necessary to concentrate phosphorus in order to make recovery and reuse feasible. This review discusses enhanced biological phosphorus removal (EBPR) as a key technology to achieve this. EBPR relies on polyphosphate accumulating organisms (PAOs) to take up phosphorus from waste streams, so concentrating phosphorus in biomass. The P-rich biosolids can be either directly applied to land, or solubilized and phosphorus recovered as a mineral product. Direct application is effective, but the product is bulky and carries contaminant risks that need to be managed. Phosphorus release can be achieved using either thermochemical or biochemical methods, while recovery is generally by precipitation as struvite. We conclude that while EBPR technology is mature, the subsequent phosphorus release and recovery technologies need additional development. PMID- 22922002 TI - Transport and localization of signaling proteins in ciliated cells. AB - Most cells in the human body elaborate cilia which serve a wide variety of functions, including cell and tissue differentiation during development, sensing physical and chemical properties of the extracellular milieu and mechanical force generation. Common among cilia is the transduction of external stimuli into signals that regulate the activities of the cilia and the cells that possess them. These functions require the transport and localization of specialized proteins to the cilium, a process that many recent studies have shown to be vital for normal cell function and, ultimately, the health of the organism. Here we discuss several mechanisms proposed for the transport and localization of soluble and peripheral membrane proteins to, or their exclusion from the ciliary compartment with a focus on how the structure of the cytoplasm and the size and shape of proteins influence these processes. Additionally, we examine the impact of cell and protein structure on our ability to accurately measure the relative concentrations of fluorescently tagged proteins amongst various cellular domains, which is integral to our understanding of the molecular mechanisms underlying protein localization and transport. PMID- 22922004 TI - A systematic approach for diagnosing subscapularis tendon tears with preoperative magnetic resonance imaging scans. AB - PURPOSE: To determine and propose a systematic approach to evaluating magnetic resonance imaging (MRI) scans for subscapularis tears and compares preoperative MRI interpretations with findings of the same shoulders at arthroscopy. METHODS: The study was composed of 202 patients who underwent shoulder arthroscopy by 1 of 5 orthopaedic surgeons during a 3-month period. All patients had MRI scans performed within 6 months before arthroscopy. RESULTS: Of the 202 patients, 82 had subscapularis tendon tears confirmed at the time of arthroscopy. The orthopaedic surgeons correctly diagnosed 60 of 82 patients (73%) with subscapularis tendon tears on preoperative MRI that were subsequently identified by arthroscopy. The orthopaedic surgeons correctly diagnosed 113 of 120 patients (94%) as not having subscapularis tendon tears. This resulted in an overall sensitivity of 73%, specificity of 94%, positive predictive value of 90%, negative predictive value of 84%, and accuracy of 86%. The frequency of subscapularis tears was highest when the long head of the biceps was displaced from the groove (88%), a combined supraspinatus/infraspinatus tear existed (71%), or the long head of the biceps tendon was torn (69%). CONCLUSIONS: Preoperative MRI scans of the shoulder interpreted by orthopaedic surgeons with the described systematic approach resulted in improved accuracy in diagnosing subscapularis tendon tears compared with previous studies. A consistent finding is that larger subscapularis tendon tears are more easily detected using MRI scans whereas smaller tears are more frequently missed. LEVEL OF EVIDENCE: Level III, development of diagnostic criteria with universally applied reference (nonconsecutive patients). PMID- 22922005 TI - Post-translational modification of the RhoGTPase activating protein 21, ARHGAP21, by SUMO2/3. AB - ARHGAP21 is a 217 kDa RhoGAP protein shown to modulate cell migration through the control of Cdc42 and FAK activities. In the present work a 250 kDa-ARHGAP21 was identified by mass spectrometry. This modified form is differentially expressed among cell lines and human primary cells. Co-immunoprecipitations and in vitro SUMOylation confirmed ARHGAP21 specific modification by SUMO2/3 and mapped the SUMOylation site to ARHGAP21 lysine K1443. Immunofluorescence staining revealed that ARHGAP21 co-localizes with SUMO2/3 in the cytoplasm and membrane compartments. Interestingly, our results suggest that ARHGAP21 SUMOylation may be related to cell proliferation. Therefore, SUMOylation of ARHGAP21 may represent a way of guiding its function. PMID- 22922006 TI - Correlation between serum serotonin and endoscopy inflammation scores in patients with ileal pouches. AB - BACKGROUND: Inflammatory and functional complications are common in patients with inflammatory bowel disease (IBD) after restorative proctocolectomy with ileal pouch-anal anastomosis (IPAA). The pathogenesis of these complications remains poorly understood, and there is discrepancy between the clinical symptoms and objective endoscopic inflammation scores in these patients. While serum serotonin level has been reported to be associated with symptoms of irritable bowel syndrome, its association with ileal pouch disorders has not been studied. AIM: To investigate the association between serum serotonin level and symptoms and endoscopic inflammation in patients with IPAA. METHODS: A total of 185 consecutive eligible IPAA patients who presented to a specialized Pouchitis Clinic from Jan 2009 to May 2009 were prospectively recruited. Patients were divided into 4 groups: normal pouch, irritable pouch syndrome (IPS), inflammatory pouch disorders (Crohn's disease, acute and chronic pouchitis, and cuffitis), and surgical complications. Serum serotonin level was measured and analyzed for correlation with clinical and endoscopic inflammation scores. RESULTS: Demographic and clinical variables were evaluated, including age, gender, smoking history, duration of UC, duration of the pouch, and disease category of the pouch. The median fasting serum serotonin level was comparable among the 4 groups: 94.0 ng/ml (interquartile range [IQR], 70.0, 128.1), 89.2 ng/ml (IQR 54.2, 155.9), 90.3 ng/ml (IQR 49.7, 164.1), 77.9 ng/ml (IQR 54.7, 129.0), for normal pouch, irritable pouch, inflammatory pouch disorders, and surgical complication groups, respectively (p=0.91). A significant association between serum serotonin level and the Pouchitis Disease Activity Index (PDAI) endoscopy subscore of the pouch (odds ratio [OR]=1.9, 95% confidence interval [CI]: 1.2, 2.9, p<0.05) and total PDAI endoscopy score (OR=1.8; 95% CI: 1.2, 2.8, p<0.05) in the inflammatory complication group were noted. CONCLUSIONS: Serum serotonin level appears to correlate with the PDAI endoscopy subscores and total PDAI score in patients with inflammatory complications suggesting that the hormone may be involved in mechanisms of mucosal inflammation. These findings may promote future treatment strategies for patients with pouch inflammation. PMID- 22922007 TI - Acute low-dose melamine affects hippocampal synaptic plasticity and behavior in rats. AB - Foods contaminated with melamine potentially cause risk to human health. However, the neurotoxicity of melamine has not been adequately assessed. Here, we aimed to examine the effects of acute low-dose exposure to melamine on hippocampal synaptic plasticity and behaviors in rats. We found that bath application of 50 500MUg/ml melamine decreased basal synaptic transmission in the Schaffer collateral-CA1 pathway of hippocampal slices from postnatal days (P) 10-14 rats in a concentration-dependent manner; furthermore, this decrease in transmission was related to the reduction of presynaptic function as indicated by the increased paired-pulse facilitation ratio. Rats at 2-3months old were less vulnerable to the effects of 500MUg/ml melamine on basal synaptic transmission when compared with P10-14 and P21-28 rats. Melamine (50MUg/ml) significantly impaired long-term potentiation (LTP), without affecting long-term depression (LTD), in both P10-14 and 2-3month-old rats. Oral treatment with melamine (5 and 25mg/kg) 1h before behavioral tests significantly decreased the immobility time of the forced swim test in 2-3month-old rats and had no effect on locomotor activity in the open field test in both P21-28 and 2-3month-old rats. Our findings reveal some of the aspects of neurotoxicity induced by acute low-dose of melamine in hippocampal synaptic plasticity and behavior. PMID- 22922008 TI - Evaluation of the effects of resveratrol and bevacizumab on experimental corneal alkali burn. AB - PURPOSE: To evaluate the effects of resveratrol and bevacizumab on experimental corneal neovascularization. METHOD: A corneal alkali burn was performed in 62 eyes of 31 male white Vienna rabbits. Resveratrol (group 1), dimethyl sulfoxide (group 2), bevacizumab (group 3) and 0.9% NaCl (group 4) were administered to both eyes of the rabbits by subconjunctival injection for 7 days. Corneal photos were taken at 15 days after alkali injury. Inflammatory index scores and neovascularization areas were calculated. RESULTS: In bevacizumab group both inflammatory index scores and the calculation of the corneal neovascularization area was significantly less than the groups. CONCLUSION: The subconjunctival administration of bevacizumab inhibits corneal neovascularization effectively in the rabbit corneal alkali burn model. No effect of resveratrol to the corneal neovascularization on experimental model of the corneal alkali burn was seen at the doses of usage. PMID- 22922009 TI - Burn survivors' perceptions of rehabilitation. AB - BACKGROUND: The perspectives of burn survivors offer a powerful tool in assessing the efficacy of burn therapy interventions and methods. Despite this potential wealth of data, comprehensive analysis of burn survivor feedback remains largely uninvestigated and underdocumented. The aim of this study was to evaluate specific burn therapy interventions based on the opinions of a sample of the burn community. METHODS: The survey was distributed to a convenience sample drawn from burn survivors attending the Phoenix Society's 21st Annual World Burn Congress in New York City, New York. Items of inquiry focused on therapeutic intervention and reintegration. The 164 surveys (a 44% response rate) returned included burn survivors from a variety of demographic segments and with burn injuries of disparate size, location, and severity. Interventions of interest included splinting and positioning, pressure garments, therapeutic exercise, group therapy, and nontraditional therapy. Respondents also rated the contribution of acute burn rehabilitation toward reintegration into familial, societal, and professional roles. RESULTS: The vast majority of respondents felt that the rehabilitative interventions they experienced positively affected their long-term physical and psychosocial outcomes. In the areas of improving movement and scarring and expediting reintegration and usefulness, the majority of applicable interventions generated "strongly agree" or "agree" as the most popular responses. CONCLUSIONS: These findings support the efficacy of many practices employed by burn rehabilitation specialists and offer a glimpse into the inherent benefits found in assessment of burn survivors' perspectives. PMID- 22922010 TI - [Euthanasia, assisted suicide and palliative care: a review by the Ethics Committee of the French Society of Anaesthesia and Intensive Care]. AB - CONTEXT: Management of the end of life is a major social issue which was addressed in France by law, on April 22nd 2005. Nevertheless, a debate has emerged within French society about the legalization of euthanasia and/or assisted suicide (E/AS). This issue raises questions for doctors and most especially for anesthetists and intensive care physicians. OBJECTIVE: To highlight, dispassionately and without dogmatism, key points taken from the published literature and the experience of countries which have legislated for E/AS. RESULTS: The current French law addresses most of the end of life issues an intensive care physician might encounter. It is credited for imposing palliative care when therapies have become senseless and are withdrawn. However, this requirement for palliative care is generally applied too late in the course of a fatal illness. There is a great need for more education and stronger incentives for early action in this area. On the rare occasions when E/AS is requested, either by the patient or their loved-ones, it often results from a failure to consider that treatments have become senseless and conflict with patient's best interest. The implementation of E/AS cannot be reduced to a simple affirmation of the Principle of autonomy. Such procedures present genuine difficulties and the risk of drift. CONCLUSION: We deliver a message of prudence and caution. Should we address painful end of life and moral suffering issues, by suppressing the subject, i.e. ending the patient's life, when comprehensive palliative care has not first been fully granted to all patients in need of it ? PMID- 22922011 TI - Subtoxic product levels limit the epoxidation capacity of recombinant E. coli by increasing microbial energy demands. AB - The utilization of the cellular metabolism for cofactor regeneration is a common motivation for the application of whole cells in redox biocatalysis. Introduction of an active oxidoreductase into a microorganism has profound consequences on metabolism, potentially affecting metabolic and biotransformation efficiency. An ambitious goal of systems biotechnology is to design process-relevant and knowledge-based engineering strategies to improve biocatalyst performance. Metabolic flux analysis (MFA) has shown that the competition for NAD(P)H between redox biocatalysis and the energy metabolism becomes critical during asymmetric styrene epoxidation catalyzed by growing Escherichia coli containing recombinant styrene monooxygenase. Engineering TCA-cycle regulation allowed increased TCA cycle activities, a delay of acetate formation, and enhanced NAD(P)H yields during batch cultivation. However, at low biomass and product concentrations, the cellular metabolism of both the mutants as well as the native host strains could cope with increased NADH demands during continuous two-liquid phase biotransformations, whereas elevated but still subtoxic product concentrations were found to cause a significantly increased NAD(P)H demand and a compromised efficiency of metabolic operation. In conclusion, operational conditions determine cellular energy and NAD(P)H demands and thus the biocatalytic efficiency of whole-cell redox biocatalysts. PMID- 22922012 TI - Production of active single-chain antibodies in seeds using trimeric polyoleosin fusion. AB - A variety of single-chain variable fragments (scFv) that had been previously developed to the surface epitopes of infective Trichostrongylus colubriformis L3 pathogenic gut nematodes of sheep were fused to a trimeric version of polyoleosin (three head-to-tail repeats of oleosin) and expressed in planta under the control of an Arabidopsis oleosin promoter. The fusion products were found to accumulate in oil bodies (OBs) at the range of 0.25-0.9% of the total seed protein which is comparable with the main 18 kDa isoform of Arabidopsis seed oleosin. Immunofluorescence microscopy and immuno-binding were used to demonstrate that it is possible to both purify the recombinant protein via enrichment for OBs as well as use the OBs emulsion to deliver functional recombinant scFv. This work presents a novel fusion strategy platform to boost the productivity and simplify the delivery of recombinant single chain antibodies and other like proteins. PMID- 22922013 TI - Liver progenitor cells yield functional hepatocytes in response to chronic liver injury in mice. AB - BACKGROUND & AIMS: Self-renewal of mature hepatocytes promotes homeostasis and regeneration of adult liver. However, recent studies have indicated that liver progenitor cells (LPC) could give rise to hepatic epithelial cells during normal turnover of the liver and after acute injury. We investigated the capacity of LPC to differentiate into hepatocytes in vivo and contribute to liver regeneration. METHODS: We performed lineage tracing experiments, using mice that express tamoxifen-inducible Cre recombinase under control of osteopontin regulatory region crossed with yelow fluorescent protein reporter mice, to follow the fate of LPC and biliary cells. Adult mice received partial (two-thirds) hepatectomy, acute or chronic administration of carbon tetrachloride (CCl(4)), choline deficient diet supplemented with ethionine, or 3,5-diethoxycarbonyl-1,4 dihydrocollidine diet. RESULTS: LPC and/or biliary cells generated 0.78% and 2.45% of hepatocytes during and upon recovery of mice from liver injury, respectively. Repopulation efficiency by LPC and/or biliary cells increased when extracellular matrix and laminin deposition were reduced. The newly formed hepatocytes integrated into hepatic cords, formed biliary canaliculi, expressed hepato-specific enzymes, accumulated glycogen, and proliferated in response to partial hepatectomy, as neighboring native hepatocytes. By contrast, LPC did not contribute to hepatocyte regeneration during normal liver homeostasis, in response to surgical or toxic loss of liver mass, during chronic liver injury (CCl(4)-induced), or during ductular reactions. CONCLUSIONS: LPC or biliary cells terminally differentiate into functional hepatocytes in mice with liver injury. PMID- 22922015 TI - [Lung ultrasound: clinical applications and perspectives in intensive care unit]. AB - OBJECTIVE: To describe the use of lung ultrasound in clinical practice and the new opportunities offered by this technology in intensive care unit (ICU) patients. METHOD: Review of signs identified by lung ultrasound and systematic analysis of data published within the last 5 years on its use in ICU. The literature has been extracted from the database PubmedTM. Specific keywords were used to select relevant publications. Clinical studies published in French and English languages were assessed. RESULTS: Lung ultrasound serves to diagnose, quantify, drain and monitor pleural effusions. In patients with acute respiratory failure, lung ultrasound participates to the diagnosis, the implementation of treatments and their follow-up. It helps to manage patients with pneumonia and acute lung injury. Finally, the investigation of the interstitial edema brings information about hemodynamics that can serve to manage our patients. CONCLUSION: Lung ultrasound is an easy, non-invasive, and non-irradiant technology. It brings lot of useful information at the patient's bedside. PMID- 22922016 TI - Oxygen dependent electron transfer in the cytochrome bc(1) complex. AB - The effect of molecular oxygen on the electron transfer activity of the cytochrome bc(1) complex was investigated by determining the activity of the complex under the aerobic and anaerobic conditions. Molecular oxygen increases the activity of Rhodobacter sphaeroides bc(1) complex up to 82%, depending on the intactness of the complex. Since oxygen enhances the reduction rate of heme b(L), but shows no effect on the reduction rate of heme b(H), the effect of oxygen in the electron transfer sequence of the cytochrome bc(1) complex is at the step of heme b(L) reduction during bifurcated oxidation of ubiquinol. PMID- 22922017 TI - Controlled attention allocation mediates the relation between goal-oriented pursuit and approach-avoidance reactions to negative stimuli. AB - Approach and avoidance are two basic behavioural principles. The current study investigated neuropsychological mechanisms underlying the influence of the personality characteristic goal-oriented pursuit on the efficiency of regulating such approach-avoidance reactions. Therefore, the P3 event-related potential (ERP) reflecting controlled attention allocation was assessed during the Approach Avoidance Task (AAT) with positive and negative pictures in 36 healthy participants. For negative pictures, analyses revealed the neuropsychological mechanism of controlled attention allocation to mediate the relation between personality and behaviour: Stronger goal-oriented pursuit was associated with higher controlled attention allocation to the incompatible compared to the compatible condition and--thereby--with less automatic avoidance tendencies in response to negative pictures, i.e., with higher efficiency of regulation. Results are discussed in terms of their implications for future studies on mechanisms determining the influence of personality traits, situational factors and their interaction on approach-avoidance behaviour. PMID- 22922018 TI - Epitope mapping of botulinum neurotoxins light chains. AB - Botulinum neurotoxins (BoNTs) are listed among the most potent biothreat agents. Simultaneously, two out of seven known serotypes of these toxins are used in medicine and cosmetics. This situation calls for development of detailed epitope maps of these toxins. Such maps will help to develop new ways for decreasing damage caused by these toxins if they were to be used as weapons while retaining the therapeutic effect of these toxins used as medicine. Here, we used a library of random fragments of DNA encoding the catalytic domain of botulinum neurotoxin serotype A to identify short epitope-forming sequences. We demonstrated that knowledge of such sequences in a BoNT of one serotype can be used for identification of epitope-forming sequences in other serotypes of BoNTs. We also demonstrated a serodiagnostic value of identified sequences and their ability to retain epitope-specific structures and trigger production of corresponding antibodies, even when they are transferred into a background of a completely alien carrier protein. PMID- 22922019 TI - RNA-seq transcriptome analysis of male and female zebra finch cell lines. AB - The derivation of stably cultured cell lines has been critical to the advance of molecular biology. We profiled gene expression in the first two generally available cell lines derived from the zebra finch. Using Illumina RNA-seq, we generated ~93 million reads and mapped the majority to the recently assembled zebra finch genome. Expression of most Ensembl-annotated genes was detected, but over half of the mapped reads aligned outside annotated genes. The male-derived G266 line expressed Z-linked genes at a higher level than did the female-derived ZFTMA line, indicating persistence in culture of the distinctive lack of avian sex chromosome dosage compensation. Although these cell lines were not derived from neural tissue, many neurobiologically relevant genes were expressed, although typically at lower levels than in a reference sample from auditory forebrain. These cell lines recapitulate fundamental songbird biology and will be useful for future studies of songbird gene regulation and function. PMID- 22922021 TI - The influence of delayed compressive stress on TGF-beta1-induced chondrogenic differentiation of rat BMSCs through Smad-dependent and Smad-independent pathways. AB - Mechanical stimuli play important roles in regulating chondrogenic differentiation, but seldom studies have focused on when and how mechanical stimuli should be initiated. We have previously shown that Col2alpha1 mRNA was increased by delayed dynamic compressive stress initiated at the 8th day of chondrogenic culture. The current work is to further study the possibility of using delayed mechanical stress to relay chondrogenesis initiated by exogenous TGF-beta1. Mechanical stimulation was delivered from day 8 to day 14 of chondrogenic culture. It showed that delayed compressive stress not only stimulated gene expression and protein synthesis of chondrocyte-specific markers, but also stimulated the endogenous TGF-beta1 gene transcription, protein expression and the subsequent activation even when exogenous TGF-beta1 was discontinued. Furthermore, mechanical stress also promoted protein phosphorylation and nuclear translocation of Smad2/3, the TGF-beta1 downstream effectors. Inhibition TGF-beta with SB431542 significantly affected the stress induced chondrogenic gene expression. In addition, phosphorylated-p38 and RhoB were upregulated by delayed loading in a TGF-beta-related manner. Phosphorylated ERK1/2 and Wnt7a were also increased, but in a TGF-beta-independent way. It indicates that delayed compressive stress can be used as an effective substitute for TGF-beta1 supplement in inducing chondrogenic differentiation. PMID- 22922020 TI - Differential effects of soluble epoxide hydrolase inhibition and CYP2J2 overexpression on postischemic cardiac function in aged mice. AB - Cardioprotective effects of epoxyeicosatrienoic acids (EETs) have been demonstrated in models of young mice with either the cardiomyocyte specific over expression of cytochrome P450 2J2 (CYP2J2 Tr) or deletion of soluble epoxide hydrolase (sEH null). In this study we examined differences in EET-induced cardioprotection in young (2 months) and aged (12 months) CYP2J2 Tr and sEHnull mice using Langendorff isolated perfused heart model. Improved postischemic functional recovery was observed in both young and aged sEH null mice compared to age matched WT. Conversely, the cardioprotective effect observed in young CYP2J2 Tr was lost in aged CYP2J2 Tr mice. The loss of cardioprotection in aged CYP2J2 Tr was regained following perfusion with the sEH inhibitor t-AUCB. Data demonstrated increased levels of leukotoxin diol (DiHOME) and oxidative stress as well decreased protein phosphatase 2A (PP2A) activation in aged CYP2J2 Tr. In conclusion, inhibition of sEH and EET-induced cardioprotection is maintained in aged mice. However, the loss of protective effects observed in aged CYP2J2 Tr might be attributed to increased levels of DiHOME, oxidative stress and/or decreased PP2A activity. PMID- 22922022 TI - Comparison of micro- vs. nanostructured colloidal gelatin gels for sustained delivery of osteogenic proteins: Bone morphogenetic protein-2 and alkaline phosphatase. AB - Colloidal gels have recently emerged as a promising new class of materials for regenerative medicine by employing micro- and nanospheres as building blocks to assemble into integral scaffolds. To this end, physically crosslinked particulate networks are formed that are injectable yet cohesive. By varying the physicochemical properties of different particle populations, the suitability of colloidal gels for programmed delivery of multiple therapeutic proteins is superior over conventional monolithic gels that lack this strong capacity for controlled drug release. Colloidal gels made of biodegradable polymer micro- or nanospheres have been widely investigated over the past few years, but a direct comparison between micro- vs. nanostructured colloidal gels has not been made yet. Therefore, the current study has compared the viscoelastic properties and capacity for drug release of colloidal gels made of oppositely charged gelatin microspheres vs. nanospheres. Viscoelastic properties of the colloidal gelatin gels were characterized by rheology and simple injectability tests, and in vitro release of two selected osteogenic proteins (i.e. bone morphogenetic protein-2 (BMP-2) and alkaline phosphatase (ALP)) from the colloidal gelatin gels was evaluated using radiolabeled BMP-2 and ALP. Nanostructured colloidal gelatin gels displayed superior viscoelastic properties over microsphere-based gels in terms of elasticity, injectability, structural integrity, and self-healing behavior upon severe network destruction. In contrast, microstructured colloidal gelatin gels exhibited poor gel strength and integrity, unfavorable injectability, and did not recover after shearing, resulting from the poor gel cohesion due to insufficiently strong interparticle forces. Regarding the capacity for drug delivery, sustained growth factor (BMP-2) release was obtained for both micro- and nanosphere-based gels, the kinetics of which were mainly depending on the particle size of gelatin spheres with the same crosslinking density. Therefore, the optimal gelatin carrier for drug delivery in terms of particle size and crosslinking density still needs to be established for specific clinical indications that require either short-term or long-term release. It can be concluded that nanostructured colloidal gelatin gels show great potential for sustained delivery of therapeutic proteins, whereas microstructured colloidal gelatin gels are not sufficiently cohesive as injectables for biomedical applications. PMID- 22922024 TI - Inhibitory effects of trolox-encapsulated chitosan nanoparticles on tert butylhydroperoxide induced RAW264.7 apoptosis. AB - A nanocarrier, namely, hydroxylethyl-chitosan nanoparticles was developed in this research for delivering antioxidants with 6-hydroxy-2, 5, 7, 8-tetra methylchromane-2-carboxylic acid (trolox) as a model antioxidant. The trolox encapsulated chitosan nanoparticles (trolox-CS NPs) were prepared by modifying chitosan with epoxyethane, which self-assembled into NPs and entrapped trolox, and then characterized by their size, size distribution, morphology and in vitro trolox release profile. Intracellular trafficking of CS NPs was observed. The anti-oxidant effect and potential mechanism of trolox-CS NPs were subsequently investigated in RAW264.7 cells. The effects of trolox-CS NPs on RAW264.7 cells damaged by tert-butylhydroperoxide (t-BHP) were determined by MTT assay for cell viability, MDA assay for membrane lipid peroxidation, JC-1 probe and Annexin V FITC/PI double staining for mitochondria membrane potential (MMP) and RAW264.7 apoptosis, respectively. The trolox-CS NPs significantly improved cell viability and reduced MDA content compared with those of cells treated with free trolox. The trolox-CS NPs treatment inhibited MMP collapse and RAW264.7 apoptosis more obviously than free trolox. Molecular basis of apoptosis studied by western blotting revealed that trolox-CS NPs may block mitochondria-mediated apoptosis pathway through up-regulation of Bcl-2 and down-regulation of Bax and inhibiting the activation of pro-caspase 3, PARP and Bid. PMID- 22922023 TI - Suppression of inflammation in a mouse model of rheumatoid arthritis using targeted lipase-labile fumagillin prodrug nanoparticles. AB - Nanoparticle-based therapeutics are emerging technologies that have the potential to greatly impact the treatment of many human diseases. However, drug instability and premature release from the nanoparticles during circulation currently preclude clinical translation. Herein, we use a lipase-labile (Sn 2) fumagillin prodrug platform coupled with a unique lipid surface-to-surface targeted delivery mechanism, termed contact-facilitated drug delivery, to counter the premature drug release and overcome the inherent photo-instability of fumagillin, an established anti-angiogenic agent. We show that alpha(v)beta(3)-integrin targeted fumagillin prodrug nanoparticles, administered at 0.3 mg of fumagillin prodrug/kg of body weight suppress the clinical disease indices of KRN serum-mediated arthritis in a dose-dependent manner when compared to treatment with the control nanoparticles with no drug. This study demonstrates the effectiveness of this lipase-labile prodrug nanocarrier in a relevant preclinical model that approximates human rheumatoid arthritis. The lipase-labile prodrug paradigm offers a translatable approach that is broadly applicable to many targeted nanosystems and increases the translational potential of this platform for many diseases. PMID- 22922025 TI - Doxorubicin-loaded silk films: drug-silk interactions and in vivo performance in human orthotopic breast cancer. AB - Breast cancer is the most common of all malignant diseases in women. Systemic chemotherapy provides low clinical benefit for locoregional control of the disease, while localised chemotherapy may provide a therapeutic advantage. In this study, doxorubicin-loaded silk films were directly applied to tumours. Affinity binding studies demonstrated that the adsorption of doxorubicin onto silk was partially dependent on crystallinity. By manipulating silk crystallinity, or beta-sheet content, the doxorubicin release rate could be controlled ranging from immediate release to prolonged release over >4 weeks. The therapeutic impact of doxorubicin-loaded silk films on primary tumour growth and metastasis was assessed in mice using a humanised orthotopic breast cancer model (adenocarcinoma). Both soluble and stabilised silk films loaded with doxorubicin had a significantly greater primary tumour response than the equivalent dose of doxorubicin administered intravenously in the absence of the silk film carrier. In addition to reducing primary tumour growth, stabilised silk films loaded with doxorubicin also reduced metastatic spread and autopsy indicated that these films were not associated with any local or systemic toxicities. Collectively, these results suggest that the future use of this approach for localised chemotherapy is promising. PMID- 22922026 TI - Data to guide the "test and treat era" of hepatitis C. PMID- 22922027 TI - Nurse to educator? Academic roles and the formation of personal academic identities. AB - This aim of this research was to investigate the academic role of the nurse educator and its contribution to the formation of personal academic identity. Data was gathered using in-depth interviews (n=14) with experienced nurse educators employed within pre-1992 and post-1992 universities. Prolonged analysis, reflection and theorisation of the findings indicated that participants experienced multiple challenges when seeking to assimilate personal academic identity, adopting, and adapting a variety of identities over time. A conceptual model of identity transformation encompassing five stages: pre-entry, reaffirming, surmounting, stabilising and actualising, provides a useful analytical framework to inform and shape the professional development of nurse educators. PMID- 22922028 TI - Intergenerational conflict in nursing preceptorship. AB - BACKGROUND: Within the preceptorship model of clinical teaching/learning, the creation of a cohesive relationship between a preceptor and a nursing student highly influences the overall success of the experience. Invariably, preceptors and students tend to be of different generations and as such, there exists within this context the potential for generational misunderstandings and conflict. DESIGN: A phenomenological study guided by van Manen's approach to human science research was conducted. OBJECTIVE: The aim of this study is to explore the phenomenon of preceptorship in the intergenerational context. PARTICIPANTS: A purposive sample of seven preceptors and seven nursing students was recruited from an undergraduate nursing program. FINDINGS: The collective experience of all participants was illuminated through three key themes: being affirmed, being challenged, and being on a pedagogical journey. In this article we focus on encountering conflict, a key subtheme of being challenged, and one that emerged from the participants' narratives. CONCLUSIONS: The study findings suggest that interpersonal conflict continues to be a reality in our profession, owing to which a collective effort must be made by nurse educators, practicing nurses, and nursing students to effect change and create a more cohesive culture. The findings have the potential to enhance generational understanding and foster a more cohesive culture in clinical practice settings. PMID- 22922029 TI - Effective pedagogies for teaching math to nursing students: a literature review. AB - Improving mathematical competency and problem-solving skills in undergraduate nursing students has been an enduring challenge for nurse educators. A number of teaching strategies have been used to address this problem with varying degrees of success. This paper discusses a literature review which examined undergraduate nursing student challenges to learning math, methods used to teach math and problem-solving skills, and the use of innovative pedagogies for teaching. The literature was searched using the Cumulative Index of Nursing and Allied Health Literature and Education Resource Information Center databases. Key search terms included: math*, nurs*, nursing student, calculation, technology, medication administration, challenges, problem-solving, personal response system, clickers, computer and multi-media. Studies included in the review were published in English from 1990 to 2011. Results support four major themes which include: student challenges to learning, traditional pedagogies, curriculum strategies, and technology and integrative methods as pedagogy. The review concludes that there is a need for more innovative pedagogical strategies for teaching math to student nurses. Nurse educators in particular play a central role in helping students learn the conceptual basis, as well as practical hands-on methods, to problem solving and math competency. It is recommended that an integrated approach inclusive of technology will benefit students through better performance, increased understanding, and improved student satisfaction. PMID- 22922030 TI - Inhibition of Staphylococcus aureus adherence to Caco-2 cells by lactobacilli and cell surface properties that influence attachment. AB - Staphylococcus aureus is an opportunistic pathogen that can colonize human and animal intestinal tracts, causing certain gastrointestinal diseases. The adherence of enteric pathogens to host intestinal epithelial cells is important for their pathogenesis. In the present study, Lactobacillus salivarius and Lactobacillus plantarum were investigated in vitro to examine their ability to competitively exclude S. aureus. Various factors involved in attachment, including bacterial status and cell concentration, growth phase, competition patterns, and surface-layer protein extracts, were also investigated. Live lactobacilli in the mid-log growth phase exhibited maximum inhibitory activity when lactobacilli were pre- or co-incubated with S. aureus. However, the inhibitory activity was significantly reduced when the lactobacilli were inactivated by heating or treated with LiCl. Furthermore, both lactobacilli possessed certain cell surface properties, such as hydrophobicity, autoaggregation, and coaggregation ability. L. salivarius and L. plantarum strongly inhibited S. aureus adherence to Caco-2 cells and their inhibition activity was significantly influenced by several factors that affect adhesion inhibition. PMID- 22922031 TI - Genomic profiling of a human organotypic model of AEC syndrome reveals ZNF750 as an essential downstream target of mutant TP63. AB - The basis for impaired differentiation in TP63 mutant ankyloblepharon-ectodermal dysplasia-clefting (AEC) syndrome is unknown. Human epidermis harboring AEC TP63 mutants recapitulated this impairment, along with downregulation of differentiation activators, including HOPX, GRHL3, KLF4, PRDM1, and ZNF750. Gene set enrichment analysis indicated that disrupted expression of epidermal differentiation programs under the control of ZNF750 and KLF4 accounted for the majority of disrupted epidermal differentiation resulting from AEC mutant TP63. Chromatin immunoprecipitation (ChIP) analysis and ChIP-sequencing of TP63 binding in differentiated keratinocytes revealed ZNF750 as a direct target of wild-type and AEC mutant TP63. Restoring ZNF750 to AEC model tissue rescued activator expression and differentiation, indicating that AEC TP63-mediated ZNF750 inhibition contributes to differentiation defects in AEC. Incorporating disease causing mutants into regenerated human tissue can thus dissect pathomechanisms and identify targets that reverse disease features. PMID- 22922032 TI - Divergent whole-genome methylation maps of human and chimpanzee brains reveal epigenetic basis of human regulatory evolution. AB - DNA methylation is a pervasive epigenetic DNA modification that strongly affects chromatin regulation and gene expression. To date, it remains largely unknown how patterns of DNA methylation differ between closely related species and whether such differences contribute to species-specific phenotypes. To investigate these questions, we generated nucleotide-resolution whole-genome methylation maps of the prefrontal cortex of multiple humans and chimpanzees. Levels and patterns of DNA methylation vary across individuals within species according to the age and the sex of the individuals. We also found extensive species-level divergence in patterns of DNA methylation and that hundreds of genes exhibit significantly lower levels of promoter methylation in the human brain than in the chimpanzee brain. Furthermore, we investigated the functional consequences of methylation differences in humans and chimpanzees by integrating data on gene expression generated with next-generation sequencing methods, and we found a strong relationship between differential methylation and gene expression. Finally, we found that differentially methylated genes are strikingly enriched with loci associated with neurological disorders, psychological disorders, and cancers. Our results demonstrate that differential DNA methylation might be an important molecular mechanism driving gene-expression divergence between human and chimpanzee brains and might potentially contribute to the evolution of disease vulnerabilities. Thus, comparative studies of humans and chimpanzees stand to identify key epigenomic modifications underlying the evolution of human-specific traits. PMID- 22922033 TI - Mutation of membrane type-1 metalloproteinase, MT1-MMP, causes the multicentric osteolysis and arthritis disease Winchester syndrome. AB - The "vanishing bone" syndromes represent a group of rare skeletal disorders characterized by osteolysis and joint destruction, which can mimic severe rheumatoid arthritis. Winchester syndrome was one of the first recognized autosomal-recessive, multicentric forms of the disorder. It was originally described nearly 50 years ago in two sisters with a severe crippling osteolysis. Using cultured fibroblasts from the proband, we have now identified homozygous mutations in membrane type-1 metalloproteinase (MT1-MMP or MMP14). We demonstrate that the resulting hydrophobic-region signal-peptide substitution (p.Thr17Arg) decreases MT1-MMP membrane localization with consequent impairment of pro-MMP2 activation, and we propose a structure-based mechanism for this effect. PMID- 22922034 TI - Clinical effectiveness and sensitivity with overnight use of 22% carbamide peroxide gel. AB - OBJECTIVE: To evaluate clinical effectiveness, color rebound and sensitivity of 22% carbamide peroxide (CP) with 3% potassium nitrate. METHODS: Twenty-one participants were enrolled and treated overnight for 2 weeks with 22% CP (Venus White, Heraeus Kulzer). Visual color measurement was performed and expressed in shade guide units (SGU) of Vita Classical (VC) and Vita Bleachedguide 3D Master (BG) shade guides. Instrumental color measurements were performed using an intraoral spectrophotometer (Vita Easyshade Compact, EC). Color measurements were taken on a canine and central incisor at baseline, 2, 3, and 4 weeks. Participants documented sensitivity and data were analysed with Wilcoxon and Bonferroni correction at the 0.05 level of significance. RESULTS: Mean BG SGU difference immediately, 1 and 2 weeks postbleaching compared to baseline was 4.9 (2.1), 4.5 (2.2) and 4.6 (2.0), respectively. Corresponding VC values were 7.0 (3.5), 6.4 (3.3) and 6.5 (3.4), while corresponding DeltaE* values were 8.3 (4.1), 8.1 (4.0) and 7.9 (3.5). For visual shade evaluation there was a significant decrease in SGU from baseline and each subsequent week, p<0.001. There was no difference between week 3 and week 4 using VC or BG. For instrumental color measurements, there was no difference from week 2 to week 3 for canines and generally no difference between week 3 and week 4 for incisors. CONCLUSIONS: Visual and instrumental evaluation showed rebound occurred 1 week postbleaching with 22% carbamide peroxide and 3% potassium nitrate. In general, color was stable at 2 weeks postbleaching. Participants reported low sensitivity levels with a mean value of below 2 on a 0-10 scale. CLINICAL SIGNIFICANCE: This study demonstrates efficacy with overnight usage of 22% carbamide peroxide with 3% potassium nitrate and demonstrates postbleaching color is stable at two weeks with low tooth sensitivity. PMID- 22922035 TI - Michelia alba extract attenuates UVB-induced expression of matrix metalloproteinases via MAP kinase pathway in human dermal fibroblasts. AB - Solar ultraviolet (UV) radiation can cause skin photoaging by inducing secretion of matrix metalloproteinases (MMPs). It has been reported that MMPs, especially MMP-1, -3 and -9, reduce elasticity of the dermis by degrading collagen. Polyphenols are a group of compounds that exist mainly in glycosides in the plants and they may transform to aglycone after hydrolysis. Polyphenols can inhibit MMP expression and elastase activity. In this study, we investigated the effects of Michelia alba extract (MAE) on expression and activity of MMPs in human skin fibroblast cultures after UVB exposure. The results showed that MAE and its hydrolysates (MAH) inhibited collagenase and elastase activities. In addition, MAE exhibited antioxidant activity, elevated hyaluronic acid content and inhibited UVB-induced MMP-1, MMP-3 and MMP-9 expression. In addition, the zymography assay revealed that MAE also inhibited MMP-9 activity. We also found that MAE inhibited UVB-induced ERK and JNK kinase but not p38 kinase expression, suggesting that MAE may regulate the UVB-induced expression of MMP-1, MMP-3 and MMP-9 via the ERK and JNK kinase pathway. MAE could restore total collagen synthesis reduced by UVB. The results also suggest that MAE treatment may prevent UVB-induced extracellular matrix damage by inhibiting the expression of MMP-1, MMP-3 and MMP-9 through the MAP kinase pathway. Our findings imply that MAE is an effective agent against UVB-induced photodamage. PMID- 22922036 TI - Introduction of poly(4-vinylpyridinium) perchlorate as a new, efficient, and versatile solid acid catalyst for one-pot synthesis of substituted coumarins under ultrasonic irradiation. AB - Poly(4-vinylpyridinium) perchlorate, is a supported, recyclable, eco-benign catalyst for synthesis of substituted coumarins via Pechmann reaction using ultrasound irradiation at room temperature and neat condition in high yields with short reaction times. The catalyst was studied by FT-IR, X-ray diffraction, scanning electron microscope, thermo-gravimetric and energy dispersion X-ray analyses. All the products were extensively characterized by (1)H NMR, FT-IR, MS and melting point analyses. This methodology offers momentous improvements over various options for the synthesis of coumarins with regard to yield of products, simplicity in operation and green aspects by avoiding toxic catalysts and solvents. Further, the catalyst can be reused and recovered for several times without loss of activity. PMID- 22922037 TI - Kinetic modeling and optimization of maceration and ultrasound-extraction of resinoid from the aerial parts of white lady's bedstraw (Galium mollugo L.). AB - In this paper, extraction of resinoid from the aerial parts of white lady's bedstraw (Galium mollugo L.) using an aqueous ethanol solution (50% by volume) was studied at different temperatures in the absence and the presence of ultrasound. This study indicated that ultrasound-assisted extraction was effective for extracting the resinoid and gave better resinoid yields at lower extraction temperature and in much shorter time than the maceration. A phenomenological model was developed for modeling the kinetics of the extraction process. The model successfully describes the two-step extraction consisting of washing followed by diffusion of extractable substances and shows that ultrasound influences only the first step. The extraction process was optimized using response surface methodology (RMS) and artificial neural network (ANN) models. For the former modeling, the second-order polynomial equation was applied, while the second one was performed by an ANN-GA combination. The high coefficient of determination and the low MRPD between the ANN prediction and the corresponding experimental data proved that modeling the extraction process in the absence and the presence of ultrasound using ANN was more accurate than RSM modeling. The optimum extraction temperature was determined to be 80 and 40 degrees C, respectively for the maceration and the ultrasound-assisted extraction, ensuring the highest resinoid yield of 22.0 g/100g in 4h and 25.1g/100g in 30 min, which agreed with the yields obtained experimentally for the same time (21.7 and 25.3g/100g, respectively). PMID- 22922038 TI - Synthesis of NaP zeolite at room temperature and short crystallization time by sonochemical method. AB - NaP zeolite nano crystals were synthesized by sonochemical method at room temperature with crystallization time of 3h. For comparison, to insure the effect of sonochemical method, the hydrothermal method at conventional synthesis condition, with same initial sol composition was studied. NaP zeolites are directly formed by ultrasonic treatment without the application of autogenous pressure and also hydrothermal treatment. The effect of ultrasonic energy and irradiation time showed that with increasing sonication energy, the crystallinity of the powders decreased but phase purity remain unchanged. The synthesized powders were characterized by XRD, IR, DTA TGA, FESEM, and TEM analysis. FESEM images revealed that 50 nm zeolite crystals were formed at room temperature by using sonochemical method. However, agglomerated particles having cactus/cabbage like structure was obtained by sonochemical method followed by hydrothermal treatment. In sonochemical process, formation of cavitation and the collapsing of bubbles produced huge energy which is sufficient for crystallization of zeolite compared to that supplied by hydrothermal process for conventional synthesis. With increasing irradiation energy and time, the crystallinity of the synthesized zeolite samples increased slightly. PMID- 22922039 TI - Radioembolization with infusion of yttrium-90 microspheres into a right inferior phrenic artery with hepatic tumor supply is feasible and safe. AB - PURPOSE: To evaluate the feasibility and safety of yttrium-90 ((90)Y) radioembolization through the inferior phrenic arteries (IPAs). MATERIALS AND METHODS: Retrospective analysis of 108 patients referred for radioembolization to treat primary (n = 103) or secondary (n = 5) liver malignancy was performed. Five patients had malignant hepatic tumors supplied by the IPA and met criteria for infusion of (90)Y spheres into the IPA. Digital subtraction angiography (DSA), catheter-directed computed tomographic (CT) angiography, and technetium-99m ((99m)Tc) macroaggregated albumin (MAA) single photon emission CT (SPECT)/CT were used to plan treatment. Bremsstrahlung SPECT/CT was performed 1 day after radioembolization. Follow-up included clinical and biochemical tests and cross sectional CT or magnetic resonance imaging. RESULTS: Parasitized extrahepatic arteries were detected in 37% of patients (n = 40). Of these, 62.5% (n = 25) had tumor supply through an IPA. Of the patients with IPA supply, 20% (n = 5) underwent infusion of (90)Y into the right IPA. Reasons for disqualifying patients from infusion into the IPA were less than 10% tumor supply (n = 11), failed catheterization of IPA (n = 3), arterioportovenous shunt (n = 2), failed identification of IPA on pretreatment angiography (n = 1), and gastric or esophageal enhancement on catheter-directed CT angiography (n = 3). In all five patients, technical success was demonstrated on (90)Y imaging, with no significant extrahepatic radionuclide activity. No adverse events related to IPA radioembolization occurred at mean follow-up of 4.5 months (range, 2.2-10.1 mo). CONCLUSIONS: Delivery of (90)Y microspheres through the right IPA is feasible and safe with the use of catheter-directed CT angiography in addition to DSA and (99m)Tc MAA SPECT/CT in patients with tumors with greater than 10% IPA supply. PMID- 22922040 TI - Phase I/II study of radiologic hepatic arterial infusion of fluorouracil plus systemic irinotecan for unresectable hepatic metastases from colorectal cancer: Japan Clinical Oncology Group Trial 0208-DI. AB - PURPOSE: Treatment of patients who have metastatic colorectal cancer (CRC) by using a combination of hepatic arterial infusion chemotherapy (HAIC) and systemic chemotherapy has resulted in promising clinical outcomes. Additionally, image guided HAIC is reported to be less invasive and distribute drugs more accurately than surgical HAIC. The purpose of this study was to assess the combination of image-guided delivery of fluorouracil through HAIC and systemic irinotecan in a multicenter phase I/II study. MATERIALS AND METHODS: Twenty-five patients with unresectable liver metastases from CRC were fitted with hepatic arterial catheter and port systems by using image-guided methods. Intraarterial fluorouracil (1,000 mg/m(2)) was administered on days 1, 8, and 15 of each treatment cycle. The dose of systemic irinotecan on days 1 and 15 was escalated from 75 mg/m(2). RESULTS: No dose-limiting toxicity was encountered during phase I, and the recommended dose of irinotecan was set at 150 mg/m(2). Grade 3 or higher adverse events included hyperglycemia (15%), elevated gamma-glutamyl transpeptidase levels (15%), and neutropenia (9%). The response rate and median survival time were 72% and 49.8 months (95% CI, 27.5-78.1 mo), respectively. CONCLUSIONS: The combination of image-guided delivery of fluorouracil through HAIC and systemic irinotecan yielded favorable safety, response rate, and survival results. This combination should be evaluated in a large study. PMID- 22922041 TI - Phase I/II multicenter study of transarterial chemoembolization with a cisplatin fine powder and porous gelatin particles for unresectable hepatocellular carcinoma: Japan Interventional Radiology in Oncology Study Group Study 0401. AB - PURPOSE: A multicenter phase I/II study of transarterial chemoembolization with a fine cisplatin powder and gelatin particles (GPs) for multifocal hepatocellular carcinoma (HCC) was conducted. Primary endpoints were dose-limiting toxicity (DLT) and recommended dose (RD). Secondary endpoints were the incidence and severity of adverse events and tumor response. MATERIALS AND METHODS: Nonselective transarterial chemoembolization was performed until all tumor enhancement disappeared. Lipiodol was not used. In the phase I study, the cisplatin dose was escalated from 35 mg/m(2) to 65 mg/m(2) in 15-mg/m(2) increments to determine DLT and RD. In the phase II study, 40 patients were treated with the RD. Toxicity was assessed by Common Toxicity Criteria for Adverse Effects (version 3.0), and tumor response was evaluated by Response Evaluation Criteria in Solid Tumors (RECIST; version 1.0) and European Association for the Study of the Liver (EASL) criteria. RESULTS: A total of 46 patients were enrolled. As no DLT occurred at any dose level in the phase I study, RD was determined as 65 mg/m(2). In the phase II study, the treatment was discontinued in one patient as a result of vasovagal response. Toxicities of grade 3 or higher included nausea (2.2%), pancreatitis (2.2%), cholecystitis (2.2%), thrombocytopenia (8.7%), hyperbilirubinemia (2.2%), and increased aspartate aminotransferase (28.3%) and alanine aminotransferase (21.7%) levels. Tumor response rates under RD were 25.6% and 64.1% by RECIST and EASL criteria, respectively. CONCLUSIONS: Nonselective transarterial chemoembolization with fine cisplatin powder and GPs was well tolerated and effective in patients with multifocal HCC at the RD of 65 mg/m(2). PMID- 22922043 TI - Rural-urban disparities in the prevalence of diabetes and coronary heart disease. AB - OBJECTIVES: To examine the rural-urban differences in the prevalence of diabetes and coronary heart disease, and the extent to which they are explained by the presence of established risk factors including poverty. STUDY DESIGN: Cross sectional study of more than 214,000 respondents using data from the US Centers for Disease Control and Prevention's (CDC's) 2008 Behavioral Risk Factor Surveillance System. METHODS: Logistic regression models were utilized; prevalence odds ratios with corresponding confidence intervals and P-values are provided. RESULTS: The crude prevalence rates of diabetes and coronary heart disease were 8.6% (P = 0.001) and 38.8% (P < 0.001) higher among respondents living in rural areas compared with urban areas, respectively. The higher prevalence in rural areas of many of the common risk factors for these conditions, including poverty (P < 0.001), obesity (P < 0.001) and tobacco use (P < 0.001), may contribute to these findings. After controlling for these and other risk factors, the prevalence of diabetes was lower among respondents living in rural areas [prevalence odds ratio (POR) = 0.94, P = 0.032], but the prevalence of coronary heart disease was higher (POR = 1.09, P = 0.011). CONCLUSIONS: The higher prevalence of diabetes and coronary heart disease in rural populations in the USA presents a formidable public health challenge. It exacerbates many of the pre-existing rural health disparities, including a lack of access to financial resources and primary care providers. PMID- 22922042 TI - Emerging opportunities in structural biology with X-ray free-electron lasers. AB - X-ray free-electron lasers (X-FELs) produce X-ray pulses with extremely brilliant peak intensity and ultrashort pulse duration. It has been proposed that radiation damage can be 'outrun' by using an ultra intense and short X-FEL pulse that passes a biological sample before the onset of significant radiation damage. The concept of 'diffraction-before-destruction' has been demonstrated recently at the Linac Coherent Light Source, the first operational hard X-ray FEL, for protein nanocrystals and giant virus particles. The continuous diffraction patterns from single particles allow solving the classical 'phase problem' by the oversampling method with iterative algorithms. If enough data are collected from many identical copies of a (biological) particle, its three-dimensional structure can be reconstructed. We review the current status and future prospects of serial femtosecond crystallography (SFX) and single-particle coherent diffraction imaging (CDI) with X-FELs. PMID- 22922044 TI - Estimating the prevalence of medically unexplained symptoms from primary care records. AB - OBJECTIVES: To develop models to estimate the likely prevalence of medically unexplained symptoms (MUS) and severe MUS in a primary care practice from existing patient electronic records collected in the previous 2 years for secondary prevention and commissioning of psychological treatment. STUDY DESIGN: Cross-sectional survey comparing general practitioners' (GPs) assessment of the presence or absence of MUS and severe MUS with clinical, demographic and service use variables associated with MUS or functional somatic syndromes from previous research in the patient's routine electronic record over the previous 2 years. METHODS: Seventeen GPs from eight practices identified cases of MUS and severe MUS in 828 consecutive consulters in primary care. Models of variables associated with MUS and severe MUS were constructed using multivariate multilevel logistic regression. The predictive validity of the final models was tested, comparing predicted with observed data and expected prevalence rates from the literature. RESULTS: Models to predict MUS and severe MUS had areas under the receiver operating characteristic curve of 0.70 [95% confidence interval (CI) 0.65-0.74] and 0.76 (95% CI 0.70-0.82), respectively. Both models showed adequate goodness of fit with observed data, and had good predictive validity compared with the expected prevalence of MUS, severe MUS, and anxiety or depression. CONCLUSION: Models to predict the prevalence of MUS and severe MUS from routine practice records for commissioning purposes were successfully developed, but they require independent validation before general use. The sensitivity of these models was too low for use in clinical screening. PMID- 22922045 TI - Keeping you in the loop. PMID- 22922046 TI - Selective killing of cancer cells by peptide-targeted delivery of an anti microbial peptide. AB - Antimicrobial peptides selectively kill bacteria while maintaining low mammalian cell cytotoxicity. However, they become cytotoxic subsequent to internalization. Here we have conjugated the lytic peptide (KLAKLAK)(2) to either a cancer-cell binding peptide (LTVSPWY) selected from peptide libraries or to a gastrin releasing peptide (GNHWAVGHLM) in order to direct the lytic peptide to cancer cells. Peptide cytotoxicity was tested in breast MCF-7 and MDA-MB-231 cancer cells. The fusion peptides were internalized by cancer cells, disintegrated the cell membrane and induced rapid killing of the cells with IC50 values as low as 4 7 MUM. Peptide cytotoxicity was dependent on the targeting receptor. Indeed, addition of free targeting peptide reduced cell killing. Blood lymphocytes and normal human mammary epithelial cells were less sensitive to the fusion peptides. Although most of the cells were killed by necrosis, fusion peptides branched with DNA oligonucleotides induced apoptosis as assayed by annexin V staining and activation of caspase 3. Therefore, the new designed drug peptides might provide a potent and selective anticancer therapy. PMID- 22922048 TI - Review of comparative LCAs of food waste management systems--current status and potential improvements. AB - Twenty-five comparative cycle assessments (LCAs) addressing food waste treatment were reviewed, including the treatment alternatives landfill, thermal treatment, compost (small and large scale) and anaerobic digestion. The global warming potential related to these treatment alternatives varies largely amongst the studies. Large differences in relation to setting of system boundaries, methodological choices and variations in used input data were seen between the studies. Also, a number of internal contradictions were identified, many times resulting in biased comparisons between alternatives. Thus, noticed differences in global warming potential are not found to be a result of actual differences in the environmental impacts from studied systems, but rather to differences in the performance of the study. A number of key issues with high impact on the overall global warming potential from different treatment alternatives for food waste were identified through the use of one-way sensitivity analyses in relation to a previously performed LCA of food waste management. Assumptions related to characteristics in treated waste, losses and emissions of carbon, nutrients and other compounds during the collection, storage and pretreatment, potential energy recovery through combustion, emissions from composting, emissions from storage and land use of bio-fertilizers and chemical fertilizers and eco-profiles of substituted goods were all identified as highly relevant for the outcomes of this type of comparisons. As the use of LCA in this area is likely to increase in coming years, it is highly relevant to establish more detailed guidelines within this field in order to increase both the general quality in assessments as well as the potentials for cross-study comparisons. PMID- 22922047 TI - Hospital charges of potentially preventable pediatric hospitalizations. AB - OBJECTIVES: Reducing the number of preventable hospitalizations represents a possible source of health care savings. However, the current literature lacks a description of the extent of potentially preventable pediatric hospitalizations. The study objectives are to (1) identify the charges and (2) demographic characteristics associated with potentially preventable pediatric hospitalizations. METHODS: Secondary analysis of the 2006 Kids' Inpatient Database (weighted N = 7,558,812). International Classification of Diseases, Ninth Revision, Clinical Modification codes for 16 previously validated pediatric ambulatory care-sensitive (ACS) conditions identified potentially preventable hospitalizations; seven additional conditions reflected updated care guidelines. Outcome variables included number of admissions, hospitalization days, and hospital charges. Demographic and diagnostic variables associated with an ACS condition were compared with regression analyses by the use of appropriate person level weights. RESULTS: Pediatric ACS hospitalizations totaled $4.05B in charges and 1,087,570 hospitalization days in 2006. Two respiratory conditions-asthma and bacterial pneumonia-comprised 48.4% of ACS hospital charges and 46.7% of ACS hospitalization days. In multivariate analysis, variables associated with an ACS condition included: male gender (odds ratio [OR] 1.10; 95% confidence interval [95% CI] 1.07-1.13); race/ethnicity of black (OR 1.22; 95% CI 1.16-1.27) or Hispanic (OR 1.12; 95% CI 1.06-1.18); and emergency department as admission source (OR 1.37; 95% CI 1.27-1.48). CONCLUSIONS: Respiratory conditions comprised the largest proportion of potentially preventable pediatric hospitalizations, totaling as much as $1.96B in hospital charges. Children hospitalized with an ACS condition tend to be male, non-white, and admitted through the emergency department. Future research to prevent pediatric hospitalizations should examine targeted interventions in the primary care setting, specifically around respiratory conditions and minority populations. PMID- 22922049 TI - Effect of inoculum to substrate ratio (I/S) on municipal solid waste anaerobic degradation kinetics and potential. AB - The goal of this study is to evaluate the impact of the inoculum to substrate ratio (I/S) on the anaerobic degradation potential of municipal solid waste (MSW). Reconstituted MSW samples were thus incubated under batch anaerobic conditions and inoculated with an increasing amount of inoculum originating from a mesophilic sludge digester. I/S tested values were 0 (no inoculum added), 0.015, 0.03, 0.06, 0.12, 0.25, 1, 2 and 4 (gVM(inoculum)/gVM(waste)). The results indicate that the apparent maximal rate of dissolved organic carbon accumulation is reached at I/S=0.12. Under this level, the hydrolysis process is limited by the concentration of biomass and can thus be described as first order kinetics phenomena with respect to biomass for I/S ratios below 0.12. The maximum methane production rate and the minimal latency are reached at a ratio of 2. In addition to that, both methane signature and ARISA show a shift in the methanogenic populations from hydrogenotrophic to acetoclastic. PMID- 22922050 TI - Design and characterization of novel cell-penetrating peptides from pituitary adenylate cyclase-activating polypeptide. AB - The discovery of cell-penetrating peptide opened up new promising avenues for the non-invasive delivery of non-permeable biomolecules within the intracellular compartment. However, some setbacks such as possible toxic effects or unexpected immunological responses have limited their use in clinic. To overcome these obstacles, we investigated the use of novel cell-penetrating peptides (CPPs) derived from the endogenous neuropeptide Pituitary adenylate cyclase-activating polypeptide (PACAP). First, we demonstrated the propensity of native PACAP isoforms (PACAP27 and PACAP38) to efficiently deliver a large and non-permeable molecule, i.e. streptavidin, into cells. An inactive modified fragment of PACAP38, i.e. [Arg(17)]PACAP(11-38), with preserved cell-penetrating physico chemical properties, was also synthesized and successfully use for the intracellular delivery of various cargoes such as small molecules, peptides, proteins, and polynucleotides. Especially, its effectiveness as a transfection agent was comparable to Lipofectamine 2000 while being non-toxic for cells. Uptake mechanism studies demonstrated that direct translocation, caveolae dependent endocytosis and macropinocytosis were involved in the internalization of [Arg(17)]PACAP(11-38). This study not only opened up a new aspect in the usefulness of PACAP and its derivatives for therapeutic application but also contributed to the identification of new members of the CPP family. As such, inactive PACAP-related analogs could represent excellent vectors for in vitro and in vivo applications. PMID- 22922051 TI - The degree of compression of spherical granular solids controls the evolution of microstructure and bond probability during compaction. AB - The effect of degree of compression on the evolution of tablet microstructure and bond probability during compression of granular solids has been studied. Microcrystalline cellulose pellets of low (about 11%) and of high (about 32%) porosity were used. Tablets were compacted at 50, 100 and 150 MPa applied pressures and the degree of compression and the tensile strength of the tablets determined. The tablets were subjected to mercury intrusion measurements and from the pore size distributions, a void diameter and the porosities of the voids and the intra-granular pores were calculated. The pore size distributions of the tablets had peaks associated with the voids and the intra-granular pores. The void and intra-granular porosities of the tablets were dependent on the original pellet porosity while the total tablet porosity was independent. The separation distance between pellets was generally lower for tablets formed from high porosity pellets and the void size related linearly to the degree of compression. Tensile strength of tablets was higher for tablets of high porosity pellets and a scaled tablet tensile strength related linearly to the degree of compression above a percolation threshold. In conclusion, the degree of compression controlled the separation distance and the probability of forming bonds between pellets in the tablet. PMID- 22922052 TI - Serotonergic and tryptaminergic overstimulation on refeeding implicated in "enlightenment" experiences. AB - The classic "enlightenment" experience is that of Siddhartha Gautama (a.k.a. Buddha) who fasted and meditated intensely for years but failed to attain his goal of "enlightenment." He gave up his fast, ate rice pudding, and immediately meditated again, whereupon he attained "enlightenment." The hypothesis is that this altered state was a symptom of refeeding after prolonged starvation resulting from the combination of monoamine oxidase (MAO) inhibition followed by tryptophan and carbohydrate intake. Intense fasting inhibited Gautama's MAO activity; eating rice pudding constituted an intake of dietary tryptophan with carbohydrates. Carbohydrates trigger insulin release, which increases unbound tryptophan while reducing levels of competing amino acids at the blood-brain barrier. These effects allow significant amounts of tryptophan into the brain, where it converts into serotonin. Without MAO, serotonin does not degrade, and methyl-transferases convert excess tryptophan and serotonin into endogenous psychoactive tryptamines. The endogenous serotonin and tryptamines cause altered mental states. The absence of psychoactive substances and the prolonged fasting gives this experience its perceived spiritual power. Subjects may have no option but to assume that their experiences were due to either divine intervention or to values and techniques that took many years of hard work to acquire. If validated, this mechanism implicates a specific effect of refeeding syndrome as the trigger for these altered states, and offers an approach to study this phenomenon in untrained subjects from within a scientific framework. PMID- 22922053 TI - Imbalances in the neurotrophic effects of noradrenaline, favouring the positive in the child and the negative in the mother, are the cause of preeclampsia. AB - Preeclampsia is an inflammatory condition, involving the pregnant mother and complicated by the presence of a growing child and a disfunctional placenta; such is its complexity that so far no one has been able to fully elucidate its pathophysiology. Varicose veins are an inflammatory condition also, but far simpler and localised, whose pathophysiology has recently been virtually fully established by a combination of clinical observation, animal experiment and analysis of stripped veins. They have indicated the immediate cause of inflammation is stimulation of a tissue by increased levels of plasma noradrenaline, at basal concentration, diffusing into it from its microcirculation. The hypothesis offered here applies that information and proposes the changes in the uteroplacental tissues in preeclampsia are a result of a decreased level of microcirculatory noradrenaline stimulation, and the changes in the maternal tissues are a result of an increased level. The dichotomy means any treatment likely to benefit the mother in preeclampsia is likely to harm the child and vice versa. That may explain why the spectacular therapeutic advances of the past 50-60 years have had, relatively, so little impact on the treatment of preeclampsia. However, experiments aimed at finding tissue specific drugs to treat different aspects of HIV and individual types of cancer offer some slight hope that in the long term it may be possible to at least alleviate preeclampsia, if not cure it. PMID- 22922054 TI - beta-Diketone modified trastuzumab: a next-generation of Herceptin for resistant breast cancer cells? AB - Despite the initial efficacy of trastuzumab (commercially named Herceptin), acquired resistance in a majority of patients remains the biggest hurdle in breast cancer therapy. Recently, the Scripps Research Institute developed a method termed "instant immunity", in which antibodies (chemical programmed antibody) are rapidly induced by chemicals like beta-diketone. When beta-diketone is chemically linked to peptides specifically targeting cancer cells, the instant chemical programmed antibody would clear the cancer cells through antibody dependent cellular cytotoxicity (ADCC) and complement-directed cytotoxicity (CDC). This novel strategy has a super advantage over passive immunization or immunization with recombinant or vectored vaccines because it induces a universal immune response and memory. Theoretically, combination of the cancer cell specific recognition advantage of trastuzumab and cancerous cell clearance of active immunization would be an option for trastuzumab resistant patients, which harbors both the advantages of cancer specific targeting of trastuzumab and active immunization of the "instant immunity", implicating a better clinical outcome. Further studies are needed to verify our hypothesis, which is worth validating. PMID- 22922055 TI - Can a plant-based vaccine treat hypertension? AB - Vaccines against hypertension constitute a viable approach to decrease blood pressure. In particular, two vaccines against hypertension (HP) targeting angiotensin II (AgII) have showed promising results and these are currently on evaluation in clinical trials. In parallel, plant-based vaccines have become a biotechnological application that has been assessed in clinical trials for some cases. This report proposes a hypothesis that involves developing a plant-based vaccine against HP. It is hypothesized that a plant-based vaccine having AgII or its AT1 receptor (ATR1) as targets, constitutes a safe, suitable and efficient therapeutic approach for HP. It is known that a number of carrier proteins can be produced in plants retaining its adjuvanticity. Therefore the production in plants of chimeric proteins where either AgII or ATR1 domains are fused to these carriers would be a promising approach to be investigated. Mucosal immunization using plant-derived AgII/ATR1 chimeric proteins would imply several advantages such as low cost and friendly delivery. However due to the lack of a detailed knowledge on the physiological role of AgII at the gastrointestinal tract, the effects of partially blocking the AgII action must be extensively evaluated. An alternative related to this aspect would be the use of transient expression systems where productivity is sufficiently high to allow the purification of the antigen of interest at convenient yields, so that it can constitute a parenteral vaccine. Proving the concept for a plant-based vaccine against HP may have profound implications on the development of a new HP therapy which offers convenient features such as low cost and easier compliance in comparison to pharmacological treatment. PMID- 22922056 TI - Nicotinamide phosphoribosyl-transferase/visfatin: a missing link between overweight/obesity and postmenopausal breast cancer? Potential preventive and therapeutic perspectives and challenges. AB - Worldwide breast cancer (BC) constitutes a significant public health concern. Excess body weight is associated with postmenopausal BC (PBC) risk. Recent studies have shown that the constellation of obesity, insulin resistance and serum adipokine levels are associated with the risk and prognosis of PBC. Nicotinamide phosphoribosyl-transferase (Nampt), also known as visfatin and pre-B cell-colony-enhancing factor, found in the visceral fat, represents a novel pleiotropic adipokine acting as a cytokine, a growth factor and an enzyme. It plays an important role in a variety of metabolic and stress responses as well as in the cellular energy metabolism, particularly NAD biosynthesis. Nampt exhibits proliferative, anti-apoptotic, pro-inflammatory and pro-angiogenic properties. Nampt's insulin-mimetic function remains a controversial issue. Circulating Nampt levels are increased in obese women. Also, Nampt levels are significantly elevated in women suffering from PBC than in healthy controls independently from known risk factors of BC, anthropometric and metabolic parameters as well as serum concentrations of well known adipokines. High expression of Nampt in BC tissues was reported to be associated with more malignant cancer behavior as well as adverse prognosis. Taking into account the mitogenicity of Nampt as well as its proliferative, anti-apoptotic and pro-angiogenic properties, a novel hypothesis is proposed whereas Nampt may be involved in the etiopathogenesis of PBC and may represent a missing link between overweight/obesity and PBC. Nampt could exert its effects on the normal and neoplastic mammary tissue by endocrine and paracrine mechanisms; Nampt could also be secreted by tumor epithelial cells in an autocrine manner. It could stimulate mammary epithelial cell proliferation, invasion, metastasis, and angiogenesis, which is essential for BC development and progression. Serum Nampt might be a novel risk factor as well as a potential diagnostic and prognostic biomarker in PBC. In addition, pharmacologic agents that neutralize biochemically Nampt or medications that decrease Nampt levels or downregulate signaling pathways downstream of Nampt may prove to be useful anti cancer agents. The potential harmful effect on PBC risk due to vitamin B3 (nicotinic acid, a natural NAD precursor in the biosynthetic route leading to NAD) intake is speculated for the first time. In this hypothesis, the role of Nampt in BC carcinogenesis and progression is explored as well as the pathophysiological mechanisms that underlie the association between Nampt and PBC in the context of a dysfunctional adipose tissue in obesity. Understanding of these mechanisms may be important for the development of preventive and therapeutic strategies against PBC. PMID- 22922057 TI - A new design of the retrievable vena cava filter. AB - Retrievable vena cava filters are invented to minimize surgical traumas to patients. However, in reality the deployed filter may firmly adhere to the vena cava due to tissue in-growth into the filter, which will breach the original concept of retrieving the filter by minimal invasive surgery. We hypothesize that if we can invent a filter with a part of supporting feet that is made of biodegradable materials and can be detached from the main body of the filter during the filter retrieval, the retrieval damage problem to the vena cava might be solved. PMID- 22922058 TI - Lysophosphatidic acid as a potential trigger of atrial fibrillation. AB - Atrial fibrillation (AF) is the most common arrhythmia in clinical practice, but its pathogenesis is incompletely understood. Current evidences have highlighted the progression of atrial fibrosis and electrophysiological remodeling in AF development. Lysophosphatidic acid (LPA), the simplest phospholipid, is associated with fibrotic disease and promotes proliferation of a wide variety of fibroblast. It was demonstrated that LPA stimulation in many cell types such as human endothelial cells, human renal fibroblasts, and myoblasts, significantly upregulates connective tissue growth factor (CTGF) expression, which acts as a downstream signaling effector for transforming growth factor-beta1 (TGF-beta1) to drive fibrosis. We hypothesized that LPA could also evoke growth factor-like responses to atrial fibroblast, and subsequently induce atrial fibrosis to trigger AF. LPA is also verified to involve in numerous electrophysiological activities in non-myocardiocytes. So LPA is a possible cause of AF by initiating fibrosis response and altering electrophysiological properties in atrium. If the hypothesis is confirmed, LPA will act as a new target for AF treatment and administration of LPA receptor blockers may be applied in the prophylaxis of AF. PMID- 22922059 TI - [Orthostatic hypotension: which initial cardiovascular and biological explorations? Which therapeutic solutions? The place of recommendations]. AB - Orthostatic hypotension (OHT) is a common symptom that affects about 1% of the population. Its prevalence increases with age. In addition to the morbidity related to falls and syncope, OHT is a risk factor for cognitive decline and cerebrovascular morbidity and mortality. In most cases, its cause is easily found by the examination and some simple explorations. For severe and/or less obvious mechanism, some paraclinical methods of investigation can be proposed. These include head upright tilt-test and Valsalva maneuver. Both explore the entire baroreflex arc, and are realised by non-invasive measurements of heart rate and blood pressure. Other tests explore more specifically the parasympathetic outflow tract or sympathetic. In some situations cardiac MIBG scintigraphy and urinary catecholamines may be useful. The respective choice of these tests depends on the clinical setting and suspected type of dysautonomic lesion. Identifying the cause and assessment of functional impairment guide the therapeutic choices, which are primarily based on non-pharmacological approach. PMID- 22922060 TI - [Involuntary movements in infantile cobalamin deficiency appearing during treatment]. PMID- 22922061 TI - Microenvironments and different nanoparticle dynamics in living cells revealed by a standard nanoparticle. AB - For quantitative analysis of nanoparticle diffusions and submicro-environments in living cells, use of newly synthesized silica-based fluorescent nanoparticle (Si FNP) as a standard nanoprobe is successfully demonstrated. The appropriate characteristics of a standard probe were fully analyzed in vitro by single molecule detection, transmission electron microscopy, and dynamic light scattering. Using fluorescence correlation analysis in single living cells, we quantitatively compared the diffusional properties of the standard Si-FNP with a diameter of 50 nm, peptide coated Si-FNP, streptavidin coated Qdot, and GFP molecule which have different sizes and surface properties. The result demonstrates that the standard Si-FNP without coat is minimally trapped in the vesicles in the process of cellular endocytosis. Interestingly, a large proportion of Si-FNP introduced into the cells by electroporation diffuses freely in the cells during a cell cycle suggesting free diffusing NPs are hardly trapped in the vesicles. The simple but highly sensitive method will provide insight into strategies to understanding the hydrodynamic process of nanoparticle delivery into living cells as well as the cellular microenvironment in the view of submicro-size. PMID- 22922062 TI - A comparative analysis of models of Na+ channel gating for mammalian and invertebrate nonmyelinated axons: relationship to energy efficient action potentials. AB - The rapidly activating, voltage gated Na(+) current, INa, has recently been measured in mammalian nonmyelinated axons. Those results have been incorporated in simulations of the action potential, results that demonstrate a significant separation in time during the spike between INa and the repolarizing K(+) current, IK. The original Hodgkin and Huxley (1952) model of Na(+) channel gating, m(3)h, where m and h are channel activation and inactivation, respectively, has been used in this analysis. This model was originally developed for invertebrate nonmyelinated axons, squid giant axons in particular. The model has not survived challenges based on results from invertebrate preparations using a double-step voltage clamp protocol and measurements of gating currents, results that demonstrate a kinetic link between activation and inactivation leading to a delayed onset of inactivation following a voltage step. These processes are independent of each other in the Hodgkin and Huxley (1952) model. Application of the double-step protocol to the m(3)h model for mammalian INa results reveals a surprising prediction, an apparent delay in onset of inactivation even though activation and inactivation are uncoupled in the model. Other results, most notably gating currents, will be required to demonstrate such a link, if indeed it exists for mammalian Na(+) channels. The information obtained will be significant in determining the way in which the Na(+) channel is sequestered away from its open state during repolarization, thereby allowing for a separation in time between INa and IK during a spike, an energetically efficient mechanism of neuronal signaling in the mammalian brain. PMID- 22922063 TI - ArfA recruits RF2 into stalled ribosomes. AB - During translation in Escherichia coli, the ribosome rescue factor YaeJ and the alternative ribosome rescue factor (ArfA, previously called YhdL) can release stalled ribosomes from mRNA. Here, I used a reconstituted cell-free protein synthesis system to examine YaeJ- and ArfA-dependent recycling of stalled ribosomes, in which mRNA lacks in-frame stop codons. It is shown that YaeJ alone could recycle the ribosome but that ArfA required the presence of release factor 2 (RF2). Furthermore, I show that RF2 binds to stalled ribosomes only in the presence of ArfA, demonstrating that ArfA recruits RF2 into the A site of the ribosome to facilitate peptidyl-tRNA hydrolysis. It is also demonstrated that the efficiency of the ArfA-dependent process decreases rapidly with an increase in mRNA length downstream of the A site of the ribosome whereas YaeJ function is maintained on mRNA with sufficient length. From the results, I discuss differences of in vivo roles of these two systems in addition to the well-known tmRNA-dependent trans-translation system. PMID- 22922064 TI - Are ParM filaments polar or bipolar? AB - A recent perspective [Erickson, H. (2012). Bacterial actin homolog ParM: arguments for an apolar, antiparallel double helix. J. Mol. Biol., 422, 461-463] by Harold Erickson has suggested that published reconstructions of bacterial ParM filaments from three different laboratories may have artifactually imposed polarity upon a filament that is really bipolar, with the two strands running in opposite directions. We show that Erickson's model of a bipolar filament can be easily distinguished from a polar filament by helical diffraction, since the asymmetric unit in a bipolar filament would be twice the size as that in a polar filament. Existing data from both electron cryo-microscopy and X-ray diffraction exclude a bipolar model. We adopt the suggestion put forward by Erickson to process filaments, assuming that they are bipolar, and show that the resulting filaments are polar. PMID- 22922065 TI - The structural domains of Pseudomonas aeruginosa phosphorylcholine phosphatase cooperate in substrate hydrolysis: 3D structure and enzymatic mechanism. AB - Pseudomonas aeruginosa is an opportunistic Gram-negative pathogen. It colonizes different tissues by the utilization of diverse mechanisms. One of these may involve the breakdown of the host cell membrane through the sequential action of hemolytic phospholipase C and phosphorylcholine phosphatase (PchP). The action of hemolytic phospholipase C on phosphatidylcholine produces phosphorylcholine, which is hydrolyzed to choline (Cho) and inorganic phosphate by PchP. The available biochemical data on this enzyme demonstrate the involvement of two Cho binding sites in the catalytic cycle and in enzyme regulation. The crystal structure of P. aeruginosa PchP has been determined. It folds into three structural domains. The first domain harbors all the residues involved in catalysis and is well conserved among the haloacid dehalogenase superfamily of proteins. The second domain is characteristic of PchP and is involved in the recognition of the Cho moiety of the substrate. The third domain stabilizes the relative position of the other two. Fortuitously, the crystal structure of PchP captures molecules of Bistris (2-[bis(2-hydroxyethyl)amino]-2 (hydroxymethyl)propane-1,3-diol) at the active site and at an additional site. This represents two catalytically relevant complexes with just one or two inhibitory Bistris molecules and provides the basis of the PchP function and regulation. Site-directed mutagenesis along with biochemical experiments corroborates the structural observations and demonstrates the interplay between different sites for Cho recognition and inhibition. The structural comparison of PchP with other phosphatases of the haloacid dehalogenase family provides a three dimensional picture of the conserved catalytic cycle and the structural basis for the recognition of the diverse substrate molecules. PMID- 22922066 TI - Cell micropatterning on superhydrophobic diamond nanowires. AB - Cell micropatterning was achieved in a spatially controlled manner based on heterogeneously wetted superhydrophilic/superhydrophobic diamond nanowire (NW) surfaces. Diamond NWs were synthesized on boron-doped diamond substrates using reactive ion etching and functionalized with octadecyltrichlorosilane to achieve superhydrophobicity. Superhydrophilic motifs of 400*400 MUm(2) and 10*10 MUm(2) single cell-sized motifs, surrounded by superhydrophobic regions, were then generated by selectively exposing the substrates to UV light. This design allowed successful patterning of single HeLa and MCF-10A cells within the superhydrophilic regions without additional surface modification. To add a further level of complexity, micropatterned co-cultures were obtained using bovine serum albumin to promote cell adhesion. This method is simple and does not require any complicated processing steps such as mask deposition or template removal. Potential applications are in the development of cell-based biological assays in well-controlled and biologically relevant environments. PMID- 22922067 TI - R-Models: a mathematical framework for capturing notions of abstraction and assistance in reproductive systems. AB - R-Models are an approach to capturing notions of assistance and abstraction in reproductive systems, based on labelled transition systems and Gibson's theory of affordances. R-Models incorporate a labelled transition system that describes how a reproductive system changes over the course of reproduction. The actors in the system are represented by a set of entities together with a relation describing the states in which those entities are present, and an affordance-modelling function mapping actions to sets of entities which enable those actions to be performed. We show how R-models can be classified based on whether the reproducer is assisted or unassisted in reproduction, and whether or not the reproducer is active during reproduction. We prove that all assisted and unassisted R-models have a related R-model which has the opposite classification. We discuss the relevance to the field of artificial life, give a potential application to the fields of computer virology, and demonstrate reproduction modelling and classification in action using examples. PMID- 22922068 TI - Of mice and men--NAIP homologues face Legionella pneumophila. PMID- 22922069 TI - ABC drug transporter and nuclear receptor expression in human cytotrophoblasts: influence of spontaneous syncytialization and induction by glucocorticoids. AB - OBJECTIVES: ABC transporters in the human placenta play a major role in protecting the fetus against potential toxic drugs. The glucocorticoid dexamethasone has been shown to induce ABCB1 expression in enterocytes and hepatocytes. However, in placental cells, little data exists either for dexamethasone, betamethasone or prednisone while these three glucocorticoids may be used during pregnancy. We investigated the modulation of placental ABC transporter and nuclear receptor expression by these drugs. METHODS: Cytotrophoblasts were isolated from normal full-term placentas. We first assessed the influence of spontaneous syncytialization on transporter and nuclear receptor gene expression by taking samples of cytotrophoblasts after 24, 48 and 72 h of cell culture (n = 7 placentas). Incubations were then conducted with dexamethasone (50 nM-1 MUM), betamethasone (20-400 nM) and prednisone (50 nM-1 MUM) versus no drug for 24 h (n = 6). mRNA expression was determined by qRT-PCR. RESULTS: Influence of syncytialization was observed only for ABCB1, ABCC2 and ABCC5 gene expression between t = 24 and 48 h (p < 0.05). Therefore, the following induction studies were conducted between t = 48 h and 72 h. Dexamethasone and betamethasone significantly induced ABCB1 gene expression by around 4-fold (p < 0.01 and 0.001, respectively). In parallel, 100 nM betamethasone decreased the glucocorticoid receptor gene expression by 22% (p < 0.01). Prednisone showed no effect on transporter or receptor expression. CONCLUSIONS: These results suggest that dexamethasone or betamethasone administration may decrease the maternal-fetal transfer of an associated treatment being ABCB1 substrate, which may be either protective or deleterious for the fetus depending on the treatment's therapeutic aim. PMID- 22922070 TI - Optimization of biodiesel production in a hydrodynamic cavitation reactor using used frying oil. AB - The present work demonstrates the application of a hydrodynamic cavitation reactor for the synthesis of biodiesel with used frying oil as a feedstock. The synthesis involved the transesterification of used frying oil (UFO) with methanol in the presence of potassium hydroxide as a catalyst. The effect of geometry and upstream pressure of a cavitating orifice plate on the rate of transesterification reaction has been studied. It is observed that the micro level turbulence created by hydrodynamic cavitation somewhat overcomes the mass transfer limitations for triphasic transesterification reaction. The significant effects of upstream pressure on the rate of formation of methyl esters have been seen. It has been observed that flow geometry of orifice plate plays a crucial role in process intensification. With an optimized plate geometry of 2mm hole diameter and 25 holes, more than 95% of triglycerides have been converted to methyl esters in 10 min of reaction time with cavitational yield of 1.28 * 10(-3) (Grams of methyl esters produced per Joule of energy supplied). The potential of UFO to produce good quality methyl esters has been demonstrated. PMID- 22922071 TI - Ultrasound assisted polymerization of N-vinyl imidazole under phase-transfer catalysis condition--a kinetic study. AB - The kinetics of phase-transfer catalyzed radical polymerization of N-vinyl imidazole (NVI) using potassium peroxy disulfate (PDS) as water soluble initiator and tetraoctylammonium chloride (TOAC) as PTC has been investigated in ethyl acetate/water two phase system assisted by ultrasound irradiation at constant temperature 60 + 1 degrees C under nitrogen atmosphere. and. The rate of polymerization increases with an increase in concentrations of NVI, PTC and PDS. The order with respect to [NVI], [PTC], and [PDS] were found to be 1.01, 1.03 and 0.52 respectively. Based on the observed results a suitable mechanism has been proposed to account for the experimental observations followed by a discussion on its significance. PMID- 22922072 TI - Hyperfibrinolysis is common in out-of-hospital cardiac arrest: results from a prospective observational thromboelastometry study. AB - BACKGROUND: Cardiocirculatory arrest (CCA) activates procoagulant pathways. It has also been reported to inhibit fibrinolysis, resulting in fibrin deposition and further impairment of blood flow. Until now, no studies have used whole-blood viscoelastic tests to characterize coagulation and the impact of fibrinolysis in out-of-hospital cardiac arrest (OHCA). METHODS: Patient with established OHCA who underwent cardiopulmonary resuscitation (CPR) were enrolled. Blood samples were obtained immediately after placement of an intravenous line at the scene, for full blood cell count, standard coagulation tests and rotational thromboelastometric (ROTEM((r))) analyses. Patients with return of spontaneous circulation (ROSC) were compared to non-ROSC patients. RESULTS: Fifty-three patients (median age 67 years, interquartile range: 56-73 years) were included in the study. ROSC was established in 25 patients. Prothrombin time index (PTI) was significantly lower and activated partial thromboplastin time (aPTT) was significantly prolonged in non-ROSC patients compared to ROSC patients. Clotting time (CT) in the extrinsically activated ROTEM test (EXTEM) was significantly longer in non-ROSC versus ROSC patients. For the remaining EXTEM parameters, there were no significant differences between ROSC and non-ROSC patients. Hyperfibrinolysis (maximum lysis>15% according to ROTEM test results) was observed in 19 patients (35.8%). There was no difference between ROSC and non ROSC patients in the incidence of hyperfibrinolysis. CONCLUSIONS: PTI, aPTT and EXTEM CT revealed significant differences between ROSC and non-ROSC patients. Hyperfibrinolysis according to ROTEM test results was much more common than previously assumed. Routine use of fibrinolytic therapy in all patients with prolonged CPR cannot therefore be recommended. PMID- 22922073 TI - Retraining basic life support skills using video, voice feedback or both: a randomised controlled trial. AB - INTRODUCTION: The optimal strategy to retrain basic life support (BLS) skills on a manikin is unknown. We analysed the differential impact of a video (video group, VG), voice feedback (VFG), or a serial combination of both (combined group, CG) on BLS skills in a self-learning (SL) environment. METHODS: Two hundred and thirteen medicine students were randomly assigned to a VG, a VFG and a CG. The VG refreshed the skills with a practice-while-watching video (abbreviated Mini AnneTM video, Laerdal, Norway) and a manikin, the VFG with a computer-guided manikin (Resusci Anne Skills StationTM, Laerdal, Norway) and the CG with a serial combination of both. Each student performed two sequences of 60 compressions, 12 ventilations and three complete cycles of BLS (30:2). The proportions of students achieving adequate skills were analysed using generalised estimating equations analysis, taking into account pre-test results and training strategy. RESULTS: Complete datasets were obtained from 192 students (60 VG, 69 VFG and 63 CG). Before and after training, >=70% of compressions with depth >=50 mm were achieved by 14/60 (23%) vs. 16/60 (27%) VG, 24/69 (35%) vs. 50/69 (73%) VFG and 19/63 (30%) vs. 41/63 (65%) CG (P<0.001). Compression rate 100-120/min was present in 27/60 (45%) vs. 52/60 (87%) VG, 28/69 (41%) vs. 44/69 (64%) VFG and 27/63 (43%) vs. 42/63 (67%) CG (P=0.05). Achievement of >=70% ventilations with a volume 400-1000 ml was present in 29/60 (49%) vs. 32/60 (53%) VG, 32/69 (46%) vs. 52/69 (75%) VFG and 25/63 (40%) vs. 51/63 (81%) CG (P=0.001). There was no between-groups difference for complete release. CONCLUSIONS: Voice feedback and a sequential combination of video and voice feedback are both effective strategies to refresh BLS skills in a SL station. Video training alone only improved compression rate. None of the three strategies resulted in an improvement of complete release. PMID- 22922074 TI - Cervical spine injury resulting from low impact fall following cardiac arrest. PMID- 22922075 TI - Assessing learned associations between conditioned cocaine reward and environmental stimuli in the Wistar Kyoto rat. AB - Clinical studies demonstrate that anxiety disorders increase the risk of substance use disorder. However, few studies have directly assessed anxiety as a vulnerability factor in processing of rewarding stimuli. The Wistar-Kyoto (WKY) rat has been proposed as a model of anxiety vulnerability because it exhibits extreme behavioral inhibition in novel and social environments; yet, it displays paradoxical rapid active avoidance learning that is resistant to extinction. The present study was designed to characterize the acquisition and persistence of cocaine conditioned place preference (CPP) in WKY rats. In the first of a series of three experiments, adult male WKY and Sprague Dawley (SD) rats were given six pairings of cocaine (3, 5, 10, 15 mg/kg) or saline on alternating days. SD rats developed cocaine-induced CPP to each of the four doses of cocaine tested. In contrast, WKY rats demonstrated CPP when conditioned with 3, 5, and 10 mg/kg, but displayed no preference to the 15 mg/kg dose. Next, separate groups of rats were subject to an extended CPP paradigm, which included acquisition, extinction and reinstatement phases. Rats were conditioned with cocaine and saline on alternating days using either a 6/6 (as above) or 4/4 conditioning regimen. Both SD and WKY rats acquired a lasting CPP with the 6/6 conditioning regimen. Results from the 4/4 conditioning regimen show that SD, but not WKY, rats acquired CPP. Preference scores for SD rats during the cocaine primed reinstatement test were significantly different from pretest scores indicating reinstatement of CPP in this group. Paradoxically, WKY rats demonstrated a latent sensitization to the conditioned rewarding effects of cocaine during the drug-primed reinstatement test. Taken together, WKY rats appear to be more sensitive to high doses of cocaine and need more experience with the drug to acquire a preference than SD rats. PMID- 22922076 TI - Semantic priming in remitted patients with bipolar disorder. AB - BACKGROUND AND OBJECTIVES: Semantic priming disturbances are increasingly recognized as a feature of schizophrenia, and increased priming has been suggested to constitute a "cognitive correlate" of positive formal thought disorder (FTD). The present study aimed to investigate semantic priming in patients with bipolar disorder (BD). METHODS: A primed lexical decision task with strongly related (STR), weakly related (WR), or unrelated (UR) prime-target pairs (SOA = 250 ms) was administered to fourteen remitted patients with BD and twelve control subjects matched on key demographic variables. FTD was measured by means of the Scale for Thought, Language and Communication (TLC). RESULTS: Control subjects showed a robust (59.6 ms) and statistically significant priming effect for STR words, while priming for UR words was non-significant. In patients there was no evidence of priming in either condition. In patients, there were no significant correlations between priming magnitude and TLC scores. However, the only patient with a positive score on the TLC disorganization factor exhibited evidence of hyperpriming. LIMITATIONS: The present patient sample exhibited very low TLC scores, and no direct comparison to patients with schizophrenia was possible. CONCLUSIONS: The finding of decreased priming in patients with BD raises the possibility that semantic processing abnormalities in BD are of a different nature than those encountered in schizophrenia. Due to the small size and very low TLC scores of the present patient sample, no definite conclusions can be drawn as to the relationship of formal thought disorder and semantic processing abnormalities in BD. PMID- 22922077 TI - Beliefs regarding child anxiety and parenting competence in parents of children with separation anxiety disorder. AB - BACKGROUND AND OBJECTIVES: Despite the fact that numerous developmental models have highlighted the role of parental cognitive processes in connection with anxiety disorders in children and adolescents, the role of parents' beliefs about their children and parenting remains largely unexplored. This study investigated the specific association between parental beliefs and child separation anxiety. METHOD: Parents of children with a diagnosis of Separation Anxiety Disorder (SAD) reported on beliefs and expectations related to their child's fears and own parenting competence. To study the potential specificity of relationships, a clinical control group of mothers of children with social phobia (SoP) and a group of mothers of children without a mental disorder (healthy controls, HC) were included. RESULTS: Results indicated that parents of anxious children had significantly higher levels of dysfunctional beliefs than the parents in the HC group. Mothers of children with SAD showed lower levels of parenting self efficacy than mothers of children with SoP. They also demonstrated lower parenting self-efficacy and satisfaction compared to mothers of healthy children. Parental dysfunctional beliefs about child anxiety and paternal parenting self efficacy were significantly positively associated with child anxiety. The effects remained significant after controlling for parental anxiety and depression. LIMITATIONS: Due to the cross-sectional design of the study, causality of the found effects cannot be inferred. DISCUSSION: Data suggest that children's anxiety and parents' beliefs about their child's anxiety, coping skills and parenting are strongly associated. Further research is needed to investigate whether addressing parental cognitions in addition to parents' anxiety may improve prevention and intervention of child anxiety. PMID- 22922078 TI - The role of experiential avoidance, psychopathology, and borderline personality features in experiencing positive emotions: a path analysis. AB - BACKGROUND AND OBJECTIVES: Experiential avoidance (EA) is an important factor in maintaining different forms of psychopathology including borderline personality pathology (BPD). So far little is known about the functions of EA, BPD features and general psychopathology for positive emotions. In this study we investigated three different anticipated pathways of their influence on positive emotions. METHODS: A total of 334 subjects varying in general psychopathology &/or BPD features completed an online survey including self-ratings of BPD features, psychopathology, negative and positive emotions, and EA. Measures of positive emotions included both a general self-rating (PANAS) and emotional changes induced by two positive movie clips. Data were analyzed by means of path analysis. RESULTS: In comparing the three path models, one model was found clearly superior: In this model, EA acts as a mediator of the influence of psychopathology, BPD features, and negative emotions in the prediction of both measures of positive emotions. DISCUSSION: EA plays a central role in maintaining lack of positive emotions. Therapeutic implications and study limitations are discussed. PMID- 22922079 TI - Trauma-related reactivity and regulation of emotion: associations with posttraumatic stress symptoms. AB - BACKGROUND AND OBJECTIVES: Both emotional reactivity to traumatic event cues and difficulties regulating emotion have been linked to posttraumatic stress symptom severity. The current study uniquely extended these two lines of research by examining the degree to which these two factors alone, and in combination, account for variability in posttraumatic stress symptom severity. METHOD: Self reported emotion regulation difficulties, and both subjective and physiological reactivity in response to a script-driven imagery procedure, were assessed among a community sample of 21 adult women with a history of interpersonal assault. Relationships with an interview-based measure of posttraumatic stress symptom severity were examined. RESULTS: Results were consistent with hypotheses. Both traumatic event-related emotional reactivity and emotion regulation difficulties independently predicted posttraumatic stress symptom severity. A significant interaction also emerged such that traumatic event-related emotional reactivity and posttraumatic stress symptom severity were only significantly associated at relatively elevated levels of emotion regulation difficulties. LIMITATIONS: Limitations included the use of a self-report questionnaire to assess emotion regulation difficulties, relatively small sample size, and lack of evidence regarding generalizability across gender or other traumatic event types. CONCLUSIONS: These results highlight that the interaction of heightened emotional reactivity and difficulties regulating emotion may be particularly influential in posttraumatic stress symptom severity. PMID- 22922081 TI - T regulatory cell number and function: the autoimmune traits in liver diseases. PMID- 22922080 TI - Developments in the synthesis of a water compatible molecularly imprinted polymer as artificial receptor for detection of 3-nitro-L-tyrosine in neurological diseases. AB - A highly selective water compatible molecularly imprinted polymer (MIP) for 3 nitro-L-tyrosine (3NT), an oxidative stress marker associated with neurodegenerative disorders, was prepared and its use as solid-phase extraction (SPE) sorbent material was demonstrated. The MIP was prepared by bulk polymerization using methacrylic acid as functional monomer and acetonitrile as porogen with traces of acetic acid and trifluoroacetic acid. In order to evaluate its binding properties, the MIP was analyzed by batch rebinding experiments and subsequently used as SPE sorbent for the selective clean-up and pre-concentration of 3NT from standard solutions and spiked human urine samples. The results obtained from batch rebinding experiments showed the presence of two association constants corresponding to high-affinity (Ka 4.20*10(3) M(-1)) and low-affinity (Ka 0.79*10(3) M(-1)) binding sites. Standard mixture solution loaded on MIP-SPE cartridge gave a recovery of 95% for 3NT, while the other compounds were totally eluted during washing step. Percentage of recovery higher than 90%, with relative standard deviation of 2%, was also obtained when a maximum of 55 MUg of 3NT is used in spiked urine sample and loaded into the cartridge. Validation of the analytical method for 3NT quantification in human urine gave 0.7 MUg mL(-1) of limit of detection, a linear range of 2.5-55 MUg mL(-1) with a relative standard deviation of 2%. PMID- 22922083 TI - Antagonism of orexin-1 receptors attenuates swim- and restraint stress-induced antinociceptive behaviors in formalin test. AB - Orexin (ORX) plays an important role in pain modulation. ORX receptors have been found in many brain structures and are known to be involved in pain processing. It is well-established that the acute and chronic forms of stress could induce hormonal and neuronal changes that affect both pain threshold and nociceptive behaviors. The role of OX1R receptors in stress-induced analgesia (SIA) has not been fully elucidated. In the present study, using the formalin test, attempts were made to evaluate the effects of acute immobilization restraint stress and swimming stress on pain behavioral responses following OX1R antagonist administration in rats. Animals received OX1R antagonist (SB-334867), vehicle, or naloxone before exposure to acute restraint stress (30min) or swimming stress test (6min, 20+/-1 degrees C), and immediately submitted to hind paw formalin injection (50MUl, 2%). Acute 30-min exposure to restraint stress as well as 6-min exposure to swim stress could significantly reduce the formalin-induced nociceptive behaviors in rats. This antinociceptive effect with either restraint stress or swim stress was fully prevented by OX1R antagonist (SB-334867), while the SB-334867 alone had no effect. However, the opioid receptor antagonist naloxone could not totally reverse the antinociception effect with either form of stress. It is suggested that OX1R might be involved in antinociception behaviors induced by these two forms of stress. These data highlight the significant role of OX1R as a novel target for treatment of stress-related disorders. PMID- 22922084 TI - Effects of food ingredients and oxygen exposure on premature browning in cooked beef. AB - Premature browning (PMB) in the centre of cooked hamburgers and beef loin (M. longissimus dorsi) steaks was assessed visually and instrumentally. Rosemary extract, ascorbic acid, sodium lactate, polyphosphate or lingonberry juice were added to freshly ground beef with predominant oxymyoglobin, and hamburgers were cooked to 62 degrees C. In general, the tested ingredients did not reduce the extent of PMB in hamburgers, but polyphosphate tended to reduce PMB due to increased pH. Control burgers made of vacuum packaged meat with deoxymyoglobin were cooked to 62, 69 and 75 degrees C, and did not express PMB. Beef loins were injected with a solution of sodium lactate, polyphosphate and sodium chloride. Loin steaks were stored under 75% O(2)/25% CO(2) for 5 days and also cooked to 62 degrees C. Injected steaks had less PMB than non-injected controls, but of a low magnitude unlikely to influence the perception of doneness. The study demonstrated that anaerobic packaging is the most efficient measure to avoid PMB in beef. PMID- 22922085 TI - Camel urine components display anti-cancer properties in vitro. AB - ETHNOPHARMACOLOGICAL RELEVANCE: While camel urine (CU) is widely used in the Arabian Peninsula to treat various diseases, including cancer, its exact mechanism of action is still not defined. The objective of the present study is to investigate whether camel urine has anti-cancer effect on human cells in vitro. MATERIALS AND METHODS: The annexinV/PI assay was used to assess apoptosis, and immunoblotting analysis determined the effect of CU on different apoptotic and oncogenic proteins. Furthermore, flow cytometry and Elispot were utilized to investigate cytotoxicity and the effect on the cell cycle as well as the production of cytokines, respectively. RESULTS: Camel urine showed cytotoxicity against various, but not all, human cancer cell lines, with only marginal effect on non-tumorigenic epithelial and normal fibroblast cells epithelial and fibroblast cells. Interestingly, 216 mg/ml of lyophilized CU inhibited cell proliferation and triggered more than 80% of apoptosis in different cancer cells, including breast carcinomas and medulloblastomas. Apoptosis was induced in these cells through the intrinsic pathway via Bcl-2 decrease. Furthermore, CU down regulated the cancer-promoting proteins survivin, beta-catenin and cyclin D1 and increased the level of the cyclin-dependent kinase inhibitor p21. In addition, we have shown that CU has no cytotoxic effect against peripheral blood mononuclear cells and has strong immuno-inducer activity through inducing IFN-gamma and inhibiting the Th2 cytokines IL-4, IL-6 and IL-10. CONCLUSIONS: CU has specific and efficient anti-cancer and potent immune-modulator properties in vitro. PMID- 22922086 TI - The roots of Salvia miltiorrhiza (Danshen) and Pueraria lobata (Gegen) inhibit atherogenic events: a study of the combination effects of the 2-herb formula. AB - ETHNOPHARMACOLOGICAL RELEVANCE: The roots of Salvia miltiorrhiza (Danshen) and Pueraria lobata (Gegen) are principle herbs of Chinese herbal formulae which have long been used to treat cardiovascular diseases. AIM OF STUDY: The present study validated the anti-atherogenic effects of three extracts, Danshen alone (DE), Gegen alone (GE) as well as DGE and interpreted their combination effects statistically. MATERIALS AND METHODS: The anti-atherogenic effects of the three extracts were studied in three assays with regards to inflammation, foam cell formation and vascular smooth muscle cell (vSMC) proliferation using lipopolysaccharide (LPS)-induced nitric oxide production model, macrophage foam cell formation model and platelet-derived growth factor (PDGF)-induced vSMC proliferation model, respectively. The combination effects of DGE were statistically analyzed using combination index (CI) and fixed-ratio experimental design. RESULTS: The anti-atherogenic effects of the three extracts including anti-inflammation, anti-foam cell formation and anti-vSMC proliferation were demonstrated in this study. Their combination effects in anti-inflammation, anti foam cell formation and anti-vSMC proliferation were found to be synergistic, additive and antagonistic, respectively. CONCLUSIONS: This study provided scientific support for the combination use of DGE on atherosclerosis and presented one of the first applications of statistical interpretations of the combination effects of the 2-herb formula. PMID- 22922087 TI - An R-peak detection method that uses an SVD filter and a search back system. AB - In this paper, we present a method for detecting the R-peak of an ECG signal by using an singular value decomposition (SVD) filter and a search back system. The ECG signal was detected in two phases: the pre-processing phase and the decision phase. The pre-processing phase consisted of the stages for the SVD filter, Butterworth High Pass Filter (HPF), moving average (MA), and squaring, whereas the decision phase consisted of a single stage that detected the R-peak. In the pre-processing phase, the SVD filter removed noise while the Butterworth HPF eliminated baseline wander. The MA removed the remaining noise of the signal that had gone through the SVD filter to make the signal smooth, and squaring played a role in strengthening the signal. In the decision phase, the threshold was used to set the interval before detecting the R-peak. When the latest R-R interval (RRI), suggested by Hamilton et al., was greater than 150% of the previous RRI, the method of detecting the R-peak in such an interval was modified to be 150% or greater than the smallest interval of the two most latest RRIs. When the modified search back system was used, the error rate of the peak detection decreased to 0.29%, compared to 1.34% when the modified search back system was not used. Consequently, the sensitivity was 99.47%, the positive predictivity was 99.47%, and the detection error was 1.05%. Furthermore, the quality of the signal in data with a substantial amount of noise was improved, and thus, the R-peak was detected effectively. PMID- 22922088 TI - Anesthesia for cardiac surgery under cardiopulmonary bypass in pregnant patients: experience with nine cases. PMID- 22922089 TI - Anesthetic management of a parturient with neuromyelitis optica. AB - Women with neuromyelitis optica, an acute inflammatory demyelinating condition of the central nervous system, have an unpredictable clinical course in pregnancy. Providing neuraxial anesthesia for these patients is controversial, although relapses may occur after exposure to either general or neuraxial anesthesia and are common. We report the successful obstetric anesthesia management of a parturient with neuromyelitis optica, review the medical literature, and discuss specific considerations for obstetric anesthesia in patients with underlying demyelinating disease. PMID- 22922090 TI - Altered behavioral phenotypes in soluble epoxide hydrolase knockout mice: effects of traumatic brain injury. AB - After traumatic brain injury (TBI), arachidonic acid (ArA) is released from damaged cell membranes and metabolized to many bioactive eicosanoids, including several epoxyeicosatrienoic acids (EETs). Soluble epoxide hydrolase (Ephx2, sEH) appears to be the predominant pathway for EET metabolism to less active dihydroxyeicosatrienoates (DHETs). Prior studies indicate that brain levels of EETs increase transiently after TBI and EETs have antiinflammatory and neuroprotective activities which may benefit the injured brain. If the net effect of increased EET levels in the injured brain is beneficial to recovery, then Ephx2 gene disruption would be expected to enhance elevated EET levels and improve recovery in the injured brain. Thus, Ephx2-KO (Ephx2(-/-) bred onto pure C57Bl/6 background) mice were compared to wild-type controls in a unilateral controlled cortical impact model of TBI. Before injury, animals behaved comparably in open field activity and neurologic reflexes. Interestingly, the Ephx2-KO mice showed improved motor coordination on a beam walk task, yet showed indications of defective learning in a test of working spatial memory. After surgery, brain-injured Ephx2-KO mice again had less of a deficit in the beam walk than wild-type, and the difference in latency (post-pre) showed a trend of protection for Ephx2-KO mice after TBI. Brain-injured mice showed no genotype differences in working memory. Surprisingly, sham-operated Ephx2-KO mice exhibited an injured phenotype for working memory, compared to sham-operated wild type mice. Brain eicosanoid levels were measured using liquid chromatography with tandem mass spectrometry. Of the 20 eicosanoids evaluated, only 8,9-EET was elevated in the Ephx2-KO cerebral cortex (37 d post-surgery, in both sham and injured). Tissue DHET levels were below the limit of quantification. These results reflect a significant contribution of sEH deficiency in coordination of ambulatory movements and working spatial memory in the mouse. Further investigation of differential sEH expression and EET levels at earlier time points and across other brain regions may shed light on these behavioral differences. PMID- 22922091 TI - A cancer/testis antigen microarray to screen autoantibody biomarkers of non-small cell lung cancer. AB - Cancer/testis antigens (CTAs) are highly immunogenic in many tumors, especially in non-small cell lung cancer (NSCLC). A low-density protein microarray, which consisted of 72 CTAs and six non-CTAs, was used to screen for lung cancer-related autoantibodies. The CTA panel of NY-ESO-1, XAGE-1, ADAM29 and MAGEC1, had sensitivity and specificity values of 33% and 96%, respectively. When examined in a test set, this panel of markers had sensitivity and specificity values of 36% and 89%, respectively. This array of markers preferentially detected NSCLC, but did not detect breast cancer, and non-cancer lung disease. PMID- 22922092 TI - Quantitative simulation tools to analyze up- and downstream interactions of soil and water conservation measures: supporting policy making in the Green Water Credits program of Kenya. AB - Upstream soil and water conservation measures in catchments can have positive impact both upstream in terms of less erosion and higher crop yields, but also downstream by less sediment flow into reservoirs and increased groundwater recharge. Green Water Credits (GWC) schemes are being developed to encourage upstream farmers to invest in soil and water conservation practices which will positively effect upstream and downstream water availability. Quantitative information on water and sediment fluxes is crucial as a basis for such financial schemes. A pilot design project in the large and strategically important Upper Tana Basin in Kenya has the objective to develop a methodological framework for this purpose. The essence of the methodology is the integration and use of a collection of public domain tools and datasets: the so-called Green water and Blue water Assessment Toolkit (GBAT). This toolkit was applied in order to study different options to implement GWC in agricultural rainfed land for the pilot study. Impact of vegetative contour strips, mulching, and tied ridges were determined for: (i) three upstream key indicators: soil loss, crop transpiration and soil evaporation, and (ii) two downstream indicators: sediment inflow in reservoirs and groundwater recharge. All effects were compared with a baseline scenario of average conditions. Thus, not only actual land management was considered but also potential benefits of changed land use practices. Results of the simulations indicate that especially applying contour strips or tied ridges significantly reduces soil losses and increases groundwater recharge in the catchment. The model was used to build spatial expressions of the proposed management practices in order to assess their effectiveness. The developed procedure allows exploring the effects of soil conservation measures in a catchment to support the implementation of GWC. PMID- 22922093 TI - Low-density lipoprotein cholesterol and risk of gallstone disease: a Mendelian randomization study and meta-analyses. AB - BACKGROUND & AIMS: Drugs which reduce plasma low-density lipoprotein cholesterol (LDL-C) may protect against gallstone disease. Whether plasma levels of LDL-C per se predict risk of gallstone disease remains unclear. We tested the hypothesis that elevated LDL-C is a causal risk factor for symptomatic gallstone disease. METHODS: We used a Mendelian randomization approach and genotyped 63,051 individuals from a prospective cohort study of the general Danish population, including 3323 subjects with symptomatic gallstones. We selected eight genetic variants in APOE, APOB, LDLR, and PCSK9 affecting LDL-C. Furthermore, studies of APOE rs429358/rs7412 (defining epsilon2/epsilon3/epsilon4 alleles; 12 studies) and APOB rs693 (eight studies) were included in meta-analyses. RESULTS: The observational hazard ratio (HR) for symptomatic gallstone disease for the fifth versus first quintile of LDL-C was 0.94 (95% confidence interval: 0.76-1.17), despite a corresponding 134% increase in LDL-C. Furthermore, although individual genetic variants in APOE, APOB, LDLR, and PCSK9 associated with stepwise increases/decreases in LDL-C of up to +59% compared with non-carriers (p <0.001), none predicted the risk of symptomatic gallstone disease. Combining all variants into 10 genotypes, carriers of 9 versus ?3 LDL-C increasing alleles associated with 41% increased LDL-C (p <0.001), but predicted a HR for symptomatic gallstone disease of 1.09 (0.70-1.69). Finally, in meta-analyses, random effects odds ratios for gallstone disease were 0.91 (0.78-1.06) for carriers of APOE epsilon4 versus non-carriers, and 1.25 (0.95-1.63) for APOB rs693 CT+TT versus CC. CONCLUSIONS: Results from the observational study, genetic studies, and meta analyses suggest that elevated plasma levels of LDL-C are not causally associated with increased risk of symptomatic gallstone disease. PMID- 22922094 TI - Beyond plasma bilirubin: the effects of phototherapy and albumin on brain bilirubin levels in Gunn rats. AB - BACKGROUND & AIMS: Severe unconjugated hyperbilirubinemia, as occurs in Crigler Najjar disease and neonatal jaundice, carries the risk of neurotoxicity. This neurotoxicity is related to the increased passage of free bilirubin (UCB(free)), the fraction of bilirubin that is not bound to plasma proteins, into the brain. We hypothesized that albumin treatment would lower the UCB(free) fraction, and thus decrease bilirubin accumulation in the brain. METHODS: We treated chronic (e.g., as a model for Crigler-Najjar disease) and acute hemolytic (e.g., as a model for neonatal jaundice) moderate hyperbilirubinemic Gunn rats with phototherapy, human serum albumin (HSA) or phototherapy+HSA. RESULTS: In the chronic model, adjunct HSA increased the efficacy of phototherapy; it decreased plasma UCB(free) and brain bilirubin by 88% and 67%, respectively (p<0.001). In the acute model, adjunct HSA also increased the efficacy of phototherapy; it decreased plasma UCB(free) by 76% (p<0.001) and completely prevented the hemolysis-induced deposition of bilirubin in the brain. Phototherapy alone failed to prevent the deposition of bilirubin in the brain during acute hemolytic jaundice. CONCLUSIONS: We showed that adjunct HSA treatment decreases brain bilirubin levels in phototherapy-treated Gunn rats. We hypothesize that HSA decreases these levels by lowering UCB(free) in the plasma. Our results support the feasibility of adjunct albumin treatment in patients with Crigler-Najjar disease or neonatal jaundice. PMID- 22922096 TI - Definition and evaluation of testing scenarios for knee wear simulation under conditions of highly demanding daily activities. AB - The objective of our study was the definition of testing scenarios for knee wear simulation under various highly demanding daily activities of patients after total knee arthroplasty. This was mainly based on a review of published data on knee kinematics and kinetics followed by the evaluation of the accuracy and precision of a new experimental setup. We combined tibio-femoral load and kinematic data reported in the literature to develop deep squatting loading profiles for simulator input. A servo-hydraulic knee wear simulator was customised with a capability of a maximum flexion of 120 degrees , a tibio femoral load of 5000N, an anterior-posterior (AP) shear force of +/-1000N and an internal-external (IE) rotational torque of +/-50Nm to simulate highly demanding patient activities. During the evaluation of the newly configurated simulator the ability of the test machine to apply the required load and torque profiles and the flexion kinematics in a precise manner was examined by nominal-actual profile comparisons monitored periodically during subsequent knee wear simulation. For the flexion kinematics under displacement control a delayed actuator response of approximately 0.05s was inevitable due to the inertia of masses in movement of the coupled knee wear stations 1-3 during all applied activities. The axial load and IE torque is applied in an effective manner without substantial deviations between nominal and actual load and torque profiles. During the first third of the motion cycle a marked deviation between nominal and actual AP shear load profiles has to be noticed but without any expected measurable effect on the latter wear simulation due to the fact that the load values are well within the peak magnitude of the nominal load amplitude. In conclusion the described testing method will be an important tool to have more realistic knee wear simulations based on load conditions of the knee joint during activities of daily living. PMID- 22922095 TI - Progestin modulates the lipid profile and sensitivity of breast cancer cells to docetaxel. AB - Progestins induce lipid accumulation in progesterone receptor (PR)-positive breast cancer cells. We speculated that progestin-induced alterations in lipid biology confer resistance to chemotherapy. To examine the biology of lipid loaded breast cancer cells, we used a model of progestin-induced lipid synthesis. T47D (PR-positive) and MDA-MB-231 (PR-negative) cell lines were used to study progestin response. Oil red O staining of T47D cells treated with progestin showed lipid droplet formation was PR dependent, glucose dependent and reduced sensitivity to docetaxel. This protection was not observed in PR-negative MDA-MB 231 cells. Progestin treatment induced stearoyl CoA desaturase-1 (SCD-1) enzyme expression and chemical inhibition of SCD-1 diminished lipid droplets and cell viability, suggesting the importance of lipid stores in cancer cell survival. Gas chromatography/mass spectroscopy analysis of phospholipids from progestin-treated T47D cells revealed an increase in unsaturated fatty acids, with oleic acid as most abundant. Cells surviving docetaxel treatment also contained more oleic acid in phospholipids, suggesting altered membrane fluidity as a potential mechanism of chemoresistance mediated in part by SCD-1. Lastly, intact docetaxel molecules were present within progestin induced lipid droplets, suggesting a protective quenching effect of intracellular lipid droplets. Our studies suggest the metabolic adaptations produced by progestin provide novel metabolic targets for future combinatorial therapies for progestin-responsive breast cancers. PMID- 22922097 TI - Uncovering patients' concerns in routine head and neck oncology follow up clinics: an exploratory study. AB - The Patient Concerns Inventory (PCI) is a tool that enables patients to highlight issues they wish to discuss, and helps to uncover concerns that might otherwise be missed. Previous PCI studies have involved direct observation of a consultation by one assessor using a coding method based rigidly on items listed on the inventory. This pilot study explores the feasibility of developing a standardised method of scoring which can be used to evaluate it. We prospectively recruited 40 disease-free patients attending 42 routine outpatient consultations after treatment for head and neck cancer. Before the consultation they completed the University of Washington quality of life questionnaire and the PCI. Nineteen consultations were audio-recorded and transcribed, and 2 assessors used a thematic framework to analyse the content of the consultation to find the number and types of concerns, the professionals involved, and the clinical outcomes. The assessors were in agreement about 80% (65/81) of the audio-recordings. The mean number of items of concern highlighted on the PCI before consultation was 5.95, median (IQR) 4(3-8) in contrast to 6.47, median (IQR) 6(4-9) for those discussed; for involvement of professionals it was 0.74, median (IQR) 0(0-1) in contrast to 2.63, median (IQR) 3(1-4), respectively. We identified 4 new themes for the working thematic framework, which provided a dynamic, standardised, and comprehensive approach based on the observation and responses of those studied. This approach gave an insight into the way the PCI mediates consultations, and how patients do not always understand the support that specific professionals can provide. Overall, patients were satisfied with the consultations. PMID- 22922098 TI - Chitosan coated sodium alginate-chitosan nanoparticles loaded with 5-FU for ocular delivery: in vitro characterization and in vivo study in rabbit eye. AB - The objective of the study was to develop chitosan (CH) coated sodium alginate chitosan (SA-CH) nanoparticles, i.e. CH-SA-CH NPs loaded with 5-FU for ophthalmic delivery. Drug loaded nanoparticles (DNPs) were prepared by ionic gelation technique using sodium alginate (SA) and chitosan (CH) and then suspended in chitosan solution. The mean size of nanoparticles and morphology were characterized by dynamic light scattering, scanning electron microscopy, atomic force microscopy and zeta potential. The in vitro release was studied by dialysis membrane technique. The size and drug encapsulation efficiency were dependent on molar ratio of SA and CH. The size of SA-CH nanoparticles was significantly increased with changed morphology after CH coating. SA-CH nanoparticles did not show any interaction with mucin while an enhanced viscosity was observed on coating of nanoparticles with CH. CH-SA-CH DNPs presented a sustained release of 5-FU compared to the 5-FU solution with high burst effect. In vivo study in rabbit eye showed significantly greater level of 5-FU in aqueous humor compared to 5-FU solution. The enhanced mucoadhesiveness of CH-SA-CH DNPs results in higher bioavailability as compared to the uncoated nanoparticles. Optimized formulation was found non-irritant and tolerable when tested by modified Draize test in rabbit eye. PMID- 22922099 TI - Molecular dynamics simulations of UC781-cyclodextrins inclusion complexes in aqueous solution. AB - The inclusion complexes of highly potent anti-HIV agent, UC781, with beta cyclodextrin (betaCD), 2,6-dimethyl-beta-cyclodextrin (MbetaCD), and 2 hydroxypropyl-beta-cyclodextrin (HPbetaCD) in aqueous solution were investigated by molecular dynamics simulations. Simulations show that the phenyl ring of UC781 is trapped inside CD cavities, while the NH group of UC781 interacts with secondary hydroxyl groups at the wider rim of CDs. The different types of CDs directly affect the binding energy and the stability of the inclusion complexes. MbetaCD provides the most stable inclusion complex of UC781 among all CDs in this study due to the effect of methoxy groups (-OCH(3)) at C2 and C6 positions on the glucopyranose of CDs. Structure analysis of CDs and the orientation of UC781 inside CD cavities as well as the effects of aqueous solution to the inclusion complexes of UC781/CDs are discussed. Results of this study have provided an agreeable output; therefore, a reliable prediction method for other drug/CD inclusion complex formations is introduced. PMID- 22922100 TI - Roles of SAM and DDHD domains in mammalian intracellular phospholipase A1 KIAA0725p. AB - Members of the intracellular phospholipase A1 family of proteins have been implicated in organelle biogenesis and membrane trafficking. The mammalian family comprises three members: phosphatidic acid-preferring phospholipase A1 (PA PIA1)/DDHD1, p125/Sec23ip and KIAA0725p/DDHD2, all of which have a DDHD domain. PA-PLAI is mostly cytosolic, while KIAA0725p and p125 are more stably associated with the Golgi/endoplasmic reticulum (ER)-Golgi intermediate compartment (ERGIC) and ER exit sites, respectively. Here we show that KIAAO725p and p125 are novel phosphoinositide-binding proteins. Deletion and mutational analyses of KIAAO725p suggested that a sterile alpha-motif (SAM), which is also present inp125, but not in cytosolic PA-PLAI, and the following DDHD domain comprise a minimal region for phosphatidylinositol 4-phosphate (Pl(4)P)-binding. A construct with mutations in the positively charged cluster of the SAM domain is defective in both phosphoinositide-binding and Golgi/ERGIC targeting. Consistent with the view that the Pl(4)P-binding is important for the membrane association of KIAA0725p, expression of phosphoinositide phosphatase Sacd reduces the association of expressed KIAAO725p with membranes. In addition, we show that deletion of the DDHD domain or introduction of point mutations at the conserved aspartate or histidine residues in the domain abolishes the phospholipase activity of KIAAO725p and PA-PLA1. Together, our results suggest that KIAAO725p is targeted to specific organelle membranes in a phosphoinositide-dependent manner, and that its SAM and DDHD domains are essential for its phosphoinositide-binding and phospholipase activity. PMID- 22922101 TI - Phosphatidylcholine biosynthesis and function in bacteria. AB - Phosphatidylcholine (PC) is the major membrane-forming phospholipid in eukaryotes and is estimated to be present in about 15% of the domain Bacteria. Usually, PC can be synthesized in bacteria by either of two pathways, the phospholipid N methylation (Pmt) pathway or the phosphatidylcholine synthase (Pcs) pathway. The three subsequent enzymatic methylations of phosphatidylethanolamine are performed by a single phospholipid N-methyltransferase in some bacteria whereas other bacteria possess multiple phospholipid N-methyltransferases each one performing one or several distinct methylation steps. Phosphatidylcholine synthase condenses choline directly with CDP-diacylglycerol to form CMP and PC. Like in eukaryotes, bacterial PC also functions as a biosynthetic intermediate during the formation of other biomolecules such as choline, diacylglycerol, or diacylglycerol-based phosphorus-free membrane lipids. Bacterial PC may serve as a specific recognition molecule but it affects the physicochemical properties of bacterial membranes as well. This article is part of a Special Issue entitled Phospholipids and Phospholipid Metabolism. PMID- 22922102 TI - Glycogen synthase kinase-3beta activation mediates rotenone-induced cytotoxicity with the involvement of microtubule destabilization. AB - Rotenone, a mitochondrial complex I inhibitor, has been used to generate animal and cell culture models of Parkinson's disease. Recent studies suggest that microtubule destabilization causes selective dopaminergic neuronal loss. In this study, we investigated glycogen synthase kinase-3beta (GSK3beta) involvement in rotenone-induced microtubule destabilization. Rotenone-induced cytotoxicity in SH SY5Y cells was attenuated by the GSK3beta inhibitor SB216763. Tau, a microtubule associated protein and substrate for GSK3beta, has been implicated in the pathogenesis of tauopathies such as Alzheimer's disease. Rotenone induced an increase in phosphorylated tau, the effect of which was attenuated by concomitant treatment with SB216763. Rotenone treatment also decreased tau expression in the microtubule fraction and increased tau expression in the cytosol fraction. These effects were suppressed by SB216763, which suggests that rotenone reduces the capacity of tau to bind microtubules. Rotenone treatment increased the amount of free tubulin and reduced the amount of polymerized tubulin, indicating that rotenone destabilizes microtubules. Rotenone-induced microtubule destabilization was suppressed by SB216763 and taxol, a microtubule stabilizer. Taxol prevented rotenone-induced cytotoxicity and morphological changes. Taken together, these results suggest that rotenone-induced cytotoxicity is mediated by microtubule destabilization via GSK3beta activation, and that microtubule destabilization is caused by reduction in the binding capacity of tau to microtubules, which is a result of tau phosphorylation via GSK3beta activation. PMID- 22922103 TI - RGS2 is a component of the cellular stress response. AB - Regulator of G protein signaling (RGS) proteins are GTPase accelerating proteins for heterotrimeric G protein alpha-subunits. RGS2 has recently been shown to have additional G protein-independent functions including control of ion channel currents, microtubule polymerization, and protein synthesis. Cellular levels of RGS2 mRNA and protein are upregulated in response to various forms of stress suggesting that it may be a stress-adaptive protein; however, direct evidence to support this notion has remained elusive. In this report, we show that thermal stress upregulates RGS2 expression and this serves to arrest de novo protein synthesis. The latter is an established cellular response to stress. Inhibiting the stress-induced RGS2 upregulation by way of siRNA knockdown diminished the repression of global protein synthesis. The collective results of our study implicate RGS2 upregulation as a cellular mechanism of controlling de novo protein synthesis in response to stress. This work provides greater insight into the stress proteome and the role of RGS2. PMID- 22922104 TI - Stimulus-induced expression of the ABCG2 multidrug transporter in HepG2 hepatocarcinoma model cells involves the ERK1/2 cascade and alternative promoters. AB - The ATP-binding cassette G subfamily member ABCG2 protein is involved in drug resistance of various types of cancer including hepatocellular carcinoma (HCC). The transcriptional regulation of the ABCG2 gene was shown to depend on various transcription factors, and three alternative promoters were described. Here we aimed to decipher the role of hepatocyte growth factor (HGF) and the related kinase cascades on the expression of ABCG2 and the role of the different promoters in this process in the HepG2 human HCC cell line. We observed that HGF treatment increased the amount of ABCG2 on the cell surface in parallel with an increased ABCG2 transcription. ABCG2 mRNA expression was also increased by EGF, oxidative stress or activation of the aryl hydrocarbon receptor, while decreased by TGFb. Treatment with U0126, a specific inhibitor of the ERK1/2 cascade, prevented the HGF and the oxidative stress induced ABCG2 upregulation. We also show that the regulation of ABCG2 by various modulators involve specific alternative promoters. In conclusion, we demonstrate a unique role of the ERK1/2 cascade on ABCG2 modulation in HepG2, and the differential use of the alternative ABCG2 promoters in this cell line. This study reveals the molecular participants of ABCG2 overexpression as new potential treatment targets in HCC. PMID- 22922105 TI - Evaluation of a computer-assisted navigation system for anterior cruciate ligament reconstruction: prospective non-randomized cohort study versus conventional surgery. AB - BACKGROUND: Conventional reconstruction of the anterior cruciate ligament (ACL) is associated with a 15% failure rate. Computer-assisted navigation systems (CANS) have been developed to improve the accuracy of tunnel positioning. HYPOTHESIS: The use of a CANS for ACL reconstruction decreases the rate of failure, defined as IKDC grade C or D, compared to conventional ACL reconstruction. MATERIALS AND METHODS: This prospective multicentre observational non-randomised open study compared two groups of patients requiring arthroscopic ACL reconstruction: one group was managed with a CANS and the other (control group) without a CANS. The primary evaluation criterion was based on the subjective and objective IKDC scores. Inclusion criteria were age older than 18 years and first ACL reconstruction procedure using autologous semitendinosus and gracilis tendons or an autologous bone-patellar tendon-bone graft. Of the 272 included patients, 214 were analysed; 100 were in the control group and 114 in the CANS group. RESULTS: No significant between-group differences were found for the fraction of patients having an IKDC grade A or B (P=0.953), the subjective IKDC score (P=0.77), differential knee laxity at 150 N (1.38 +/- 1.79 mm in the control group and 1.77 +/- 2.06 mmin the CANS group, P=0.384), graft-type, or graft positioning. DISCUSSION: Our results establish the large-scale feasibility of computer-assisted navigation for ACL reconstruction. However, the main outcomes at 1 year showed no significant differences between patients managed with and without computer-assisted navigation. PMID- 22922106 TI - Chitosan-based hydrogels to induce neuronal differentiation of rat muscle-derived stem cells. AB - In this study, we used a chitosan hydrogel as a 3-dimensional substrate for the attachment, proliferation, and differentiation of rat muscle-derived stem cells (rMDSCs) in the presence of valproic acid (VA). Chitosan solutions containing glycerol phosphate disodium salt form a hydrogel at body temperature. The chitosan hydrogel exhibited a porous 3-dimensional network that allowed the culture medium to penetrate. The chitosan hydrogel acted as a suitable biocompatible substrate for the attachment and proliferation of rMDSCs. On chitosan hydrogel in the presence of VA, rMDSCs exhibited higher expression of the neural markers, neuron-specific enolase (NSE) and beta tubulin III (Tuj-1), the oligodendrocyte marker, oligodendrocyte transcription factor 2 (Olig-2), and the astrocyte marker, glial fibrillary acidic protein (GFAP) than those in the absence of VA. Our results suggest that rMDSCs on a chitosan hydrogel in the presence of VA can differentiate into cells with a neural-like phenotype. PMID- 22922107 TI - Photosynthetic and physiological analysis of the rice high-chlorophyll mutant (Gc). AB - Chlorophyll (Chl) molecules are essential for harvesting light energy in photosynthesis. A rice high-chlorophyll mutant (Gc) with significantly increased Chl b was identified previously in Zhenshan 97B (Oryza sativa indica). However, the mechanism underlying this higher Chl b content and its effects on photosynthetic efficiency are still unclear. Immunoblot and blue native polyacrylamide gel electrophoresis (BN-PAGE) with a second dimension electrophoresis followed by the matrix-assisted laser-desorption/ionization time of-flight (MALDI-TOF) analysis showed that a few core proteins of photosystem I (PSI) and photosystem II (PSII), and light-harvesting complex II (LHCII) proteins were overexpressed in the mutant plants. Remarkable differences in chloroplast ultrastructure were observed between the wild-type and mutant plants, with the latter having more highly stacked and larger grana. Chl florescence analysis demonstrated that Gc had markedly increased quantum efficiency of photosystem II (PhiPSII), photochemical quenching (qP), non-photochemical quenching (qN) and electron transport rate (ETR). This morphological and physiological adaptation might confer a higher photosynthetic capacity in Gc than the wild-type. PMID- 22922108 TI - Loss of membrane fluidity and endocytosis inhibition are involved in rapid aluminum-induced root growth cessation in Arabidopsis thaliana. AB - Aluminum (Al) toxicity is the main limiting factor in crop production on acid soils. The main symptom of Al toxicity is a rapid inhibition of root growth, but the mechanism of root growth cessation remains unclear. Here we examined the earliest changes in the plasma membrane and processes related to the membrane in the Arabidopsis thaliana root tip cells of roots grown in a hydropony. Al suppressed root growth within 2 min, inhibited endocytosis within 10 min of exposure and stabilized cortical microtubules within the first 30 min. Spectrofluorometric measurements of the plasma membrane isolated from Arabidopsis plants and labeled with the fluorescent probe laurdan showed that Al induced a reduction in membrane fluidity. Application of the membrane fluidizer, benzyl alcohol, restored partially membrane fluidity and also partially restored root growth during first 30 min of Al treatment. We concluded that Al-induced loss of membrane fluidity and endocytosis inhibition occurred very early during Al toxicity in plant roots and could be the earliest targets of Al treatment. PMID- 22922109 TI - Ectopic expression of dehydration responsive element binding proteins (StDREB2) confers higher tolerance to salt stress in potato. AB - Dehydration responsive element binding proteins (DREB) are members of a larger family of transcription factors, many of which have been reported to contribute to plant responses to abiotic stresses in several species. While, little is known about their role in potato (Solanum tuberosum). This report describes the cloning and characterization of a DREB transcription factor cDNA, StDREB2, isolated from potato (cv Nicola) plants submitted to salt treatment. Based on a multiple sequence alignment, this protein was classified into the A-5 group of DREB subfamily. Expression studies revealed that StDREB2 was induced in leaves, roots and stems upon various abiotic stresses and in response to exogenous treatment with abscisic acid (ABA). In agreement with this expression pattern, over expression of StDREB2 in transgenic potato plants resulted in enhanced tolerance to salt stress. These data suggest that the isolated StDREB2 encodes a functional protein involved in plant response to different abiotic stresses. An electrophoretic mobility shift assay (EMSA) indicated that the StDREB2 protein bound specifically to the DRE core element (ACCGAGA) in vitro. Moreover, Semi quantitative RT-PCR analysis revealed that the transcript level of a putative target gene i.e. delta(1)-pyrroline-5-carboxylate synthase (P5CS) was up regulated in transgenic plants submitted to salt stress conditions. A concomitant increase in proline accumulation was also observed under these conditions. Taking together, all these data suggest that StDREB2 takes part in the processes underlying plant responses to abiotic stresses probably via the regulation of ABA hormone signaling and through a mechanism allowing proline synthesis. PMID- 22922110 TI - The carnitine biosynthetic pathway in Arabidopsis thaliana shares similar features with the pathway of mammals and fungi. AB - Carnitine is an essential quaternary ammonium amino acid that occurs in the microbial, plant and animal kingdoms. The role and synthesis of this compound are very well documented in bacteria, fungi and mammals. On the contrary, although the presence of carnitine in plant tissue has been reported four decades ago and information about its biological implication are available, nothing is known about its synthesis in plants. We designed experiments to determine if the carnitine biosynthetic pathway in Arabidopsis thaliana is similar to the pathway in mammals and in the fungi Neurospora crassa and Candida albicans. We first checked for the presence of trimetyllysine (TML) and gamma-butyrobetaine (gamma BB), two precursors of carnitine in fungi and in mammals, using liquid chromatography-electrospray ionization tandem mass spectrometry (LC-ESI-MS/MS). Both compounds were shown to be present in plant extracts at concentrations in the picomole range per mg of dry weight. We next synthesized deuterium-labeled TML and transferred A. thaliana seedlings on growth medium supplemented with 1 mM of the deuterated precursor. LC-ESI-MS/MS analysis of plant extracts clearly highlighted the synthesis of deuterium labeled gamma-BB and labeled carnitine in deuterated-TML fed plants. The similarities between plant, fungal and mammalian pathways provide very useful information to search homologies between genomes. As a matter of fact the analysis of A. thaliana protein database provides homology for several enzymes responsible for carnitine synthesis in fungi and mammals. The study of mutants affected in the corresponding genes would be very useful to elucidate the plant carnitine biosynthetic pathway and to investigate further the role of carnitine in plant physiology. PMID- 22922111 TI - NO loading: Efficiency assessment of five commonly used application methods of sodium nitroprusside in Medicago truncatula plants. AB - Nitric oxide (NO) is a bioactive, diffusible molecule involved in a multitude of physiological and developmental processes in plants, which has been reported to display both antioxidant and pro-oxidant properties in plants. Several reports exist highlighting the protective action of sodium nitroprusside (SNP), an NO donor, which demonstrate its important role as a signal molecule in plants responsible for the expression regulation of antioxidant and other defense enzymes. However, the mode of application of this compound varies greatly between studies. The present study provides a comprehensive efficiency comparison of the most commonly used application methods using 2.5mM SNP on mature (40 day) Medicago truncatula plants. Measurement of NO content in both leaves and roots suggests that vacuum infiltration is the most efficient method for NO donation in leaf tissue, whereas hydroponic application resulted in highest NO content in roots. NO content correlated with activity levels of nitrate reductase (NR; EC 1.7.99.4), a key enzyme involved in the generation of NO in plants and which is known to be regulated by NO itself. PMID- 22922112 TI - Effects of glucans and eicosapentaenoic acid on differential regulation of phenylpropanoid and mevalonic pathways during potato response to Phytophthora infestans. AB - The effects of Phytophthora infestans glucans, eicosapentaenoic acid (EPA) and isolates of this pathogen, on the differential expression of eight genes from the phenylpropanoid and the mevalonate (Ac-MVA) pathways were analyzed in potato by semi-quantitative RT-PCR and qRT-PCR. The application of EPA had an elicitor effect in Russet Burbank (RB) and Defender (DF) in response to inoculation with a US8 isolate of P. infestans, thereby reducing symptoms of late blight. Such effect was associated with the expression of PAL-1 and PAL-2, since the latter occurred only when EPA was followed by inoculation, whereas these genes were down regulated in individual treatments RB + EPA, RB + US8, DF + EPA, and DF + US8. The glucan fraction did not by itself suppress phenylpropanoid genes, but its combination with the pathogen resulted in a down-regulation of PAL-1, PAL-2 and CHS. The addition of the glucan fraction to the elicitor EPA, had a negative effect (RB + EPA + GL + US8) since plants showed higher disease symptoms than the ones pretreated with water then infected with US8, and in comparison with RB + EPA + US8 and RB + GL + US8. Exclusive up-regulation of 4CL in DF + US11 and of CHS in DF + EPA + GL + US8, DF + EPA + US11, DF + GL + US11 and DF + EPA + GL + US11, where late blight lesions were not detected, could be associated with potato protection against late blight. Along with previous findings in this pathosystem, these data suggest that genetic resistance in potato against P. infestans is not the result of isolated reactions against the pathogen, but rather the combination of many factors in-line with a polygenic/horizontal resistance. PMID- 22922113 TI - An amperometric glutathione biosensor based on chitosan-iron coated gold nanoparticles modified Pt electrode. AB - A method is described for development of an amperometric biosensor for determination of glutathione (GSH), by immobilizing covalently a glutathione oxidase (GSHOx) onto the surface of gold coated magnetic nanoparticles (Fe@AuNPs) modified Pt electrode. Chitosan was used to introduce amino groups onto the surface of Fe@AuNPs. The morphology and covalent linkage of GSHOx led to high enzyme loading and better shelf life. The enzyme electrode was characterized by scanning electron microscopy (SEM), cyclic voltammetry (CV), Fourier transform infrared (FTIR) and electrochemical impedance spectroscopy (EIS). The electrode showed maximum response within 4s, when polarized at +0.4V, pH 7.0 and 25 degrees C. There was a linear relationship between electrode response and glutathione concentrations in the range 5.0-4000 MUmol L(-1) with a detection limit of 0.1 MUmol L(-1). An amperometric method of GSH determination was developed using this biosensor. The evaluation studies showed that the method was reliable as mean analytic recoveries of 50 MUM and 100 MUM of GSH were 97.5+/-1.7 and 96.1+/-1.3 respectively and within and between CVs for glutathione determination in blood RBCs were <2.14% and <2.39% respectively. The biosensor showed 50% loss in its initial activity after its 150 uses over a period 4 months, when stored at 4 degrees C. GSH concentration in hemolysated erythrocytes as measured by the present biosensor was 2.8 mmol L(-1) in apparently healthy persons. PMID- 22922114 TI - Immobilization of beta-galactosidase on modified polypropilene membranes. AB - A new immobilized system: beta-galactosidase-modified polypropylene membrane was created. It was obtained 13 different carriers by chemical modification of polypropylene membranes by two stages. The first stage is treatment with K(2)Cr(2)O(7) to receive carboxylic groups on membrane surface. The second stage is treatment with different modified agents ethylendiamine, hexamethylenediamine, hydrazine dihydrochloride, hydroxylamine, o-phenylenediamine, p-phenylenediamine, N,N'-dibenzyl ethylenediamine diacetate to receive amino groups. The quantity of the amino groups, carboxylic groups and the degree of hydrophilicity of unmodified and modified polypropilene membranes were determined. beta Galactosidase was chemically immobilized on the obtained carries by glutaraldehyde. The highest relative activity of immobilized enzyme was recorded at membrane modified with 10% hexamethylenediamine (Membrane 5) - 92.77%. The properties of immobilized beta-galactosidase on different modified membranes - pH optimum, temperature optimum, pH stability and thermal stability were investigated and compared with those of free enzyme. The storage stability of all immobilized systems was studied. It was found that the most stable system is immobilized enzyme on Membrane 5. The system has kept 90% of its initial activity at 300th day (pH=6.8; 4 degrees C). The stability of the free and immobilized beta-galactosidase on the modified membrane 5 with 10% HMDA in aqueous solutions of alcohols - mono-, diol and triol was studied. The kinetics of enzymatic reaction of free and immobilized beta-galactosidase on the modified membrane 5 at 20 degrees C and 40 degrees C and at the optimal pH for both forms of the enzyme were investigated. It was concluded that the modified agent - hexamethylenediamine, with long aliphatic chain ensures the best immobilized beta galactosidase system. PMID- 22922115 TI - A step toward the reactivation of aged cholinesterases--crystal structure of ligands binding to aged human butyrylcholinesterase. AB - Organophosphorus nerve agents irreversibly inhibit cholinesterases. Phosphylation of the catalytic serine can be reversed by the mean of powerful nucleophiles like oximes. But the phosphyl adduct can undergo a rapid spontaneous reaction leading to an aged enzyme, i.e., a conjugated enzyme that is no longer reactivable by oximes. One strategy to regain reactivability is to alkylate the phosphylic adduct. Specific alkylating molecules were synthesized and the crystal structures of the complexes they form with soman-aged human butyrylcholinesterase were solved. Although the compounds bind in the active site gorge of the aged enzyme, the orientation of the alkylating function appears to be unsuitable for efficient alkylation of the phosphylic adduct. However, these crystal structures provide key information to design efficient alkylators of aged-butyrylcholinesterase and specific reactivators of butyrylcholinesterase. PMID- 22922116 TI - Host specificity and local infection dynamics of Kudoa leptacanthae n. sp. (Multivalvulida: Kudoidae) from the pericardial cavity of two Zoramia spp. (Perciformes: Apogonidae) at Lizard Island lagoon, Queensland, Australia. AB - Kudoa leptacanthae n. sp. was identified within the pericardial cavities of two apogonid species, Zoramia leptacantha and Zoramia viridiventer, from waters off Lizard Island on the Great Barrier Reef. The species shows a close taxonomic affinity, both morphologically and genetically, to Kudoa shiomitsui Egusa & Shiomitsu 1983 reported from a tetraodontid and scombrid, both from Japan. The infection was at high prevalences (average = 75.8% +/- 0.63, n = 343) within schools of the two host species. Different sporogonic stages ('developing' and 'fully-developed') were observed in pseudocysts within the pericardium of the hosts. Kudoa leptacanthae n. sp. appears to be a persistent infection within the Zoramia species hosts. No seasonal variation was detected for this host/parasite system and the parasite did not affect host condition, when assessed using host length/weight ratio as a coarse indicator. We hypothesise that a source of infection in close proximity to the home patch reef of apogonid schools may lead to the high prevalence and intensity of infection reported in this study. PMID- 22922117 TI - Multifaceted applications of nanomaterials in cell engineering and therapy. AB - Nanomaterials with superior physiochemical properties have been rapidly developed and integrated in every aspect of cell engineering and therapy for translating their great promise to clinical success. Here we demonstrate the multifaceted roles played by innovatively-designed nanomaterials in addressing key challenges in cell engineering and therapy such as cell isolation from heterogeneous cell population, cell instruction in vitro to enable desired functionalities, and targeted cell delivery to therapeutic sites for prompting tissue repair. The emerging trends in this interdisciplinary and dynamic field are also highlighted, where the nanomaterial-engineered cells constitute the basis for establishing in vitro disease model; and nanomaterial-based in situ cell engineering are accomplished directly within the native tissue in vivo. We will witness the increasing importance of nanomaterials in revolutionizing the concept and toolset of cell engineering and therapy which will enrich our scientific understanding of diseases and ultimately fulfill the therapeutic demand in clinical medicine. PMID- 22922118 TI - Physical training is well tolerated, leads to improvements in cardiopulmonary fitness and is not associated with adverse outcomes in people with asthma. PMID- 22922119 TI - Correlation between coronary plaque burden and heart weight. AB - It is unclear if the extent of coronary atherosclerosis is associated with increase in heart muscle mass. We retrospectively reviewed autopsy reports of sudden coronary deaths occurring in a statewide medical examiner system over a one-year period. Cardiomegaly was assessed by height, and given a score of 0-4 based on amount above the upper limit of normal range. Coronary disease was quantitated as number of epicardial arteries with >=75% cross sectional luminal narrowing. There were 100 hearts with one-vessel disease, 77 with two-vessel disease, and 59 with three- or four-vessel diseases. The extent of disease was less in women than men (P=0.002). Healed infarcts were present in 21% of women and 36% of men. Cardiomegaly was present in 50% of women and 69% of men. By univariate analysis, in patients without hypertension, cardiomegaly score in the three- or four-vessel disease group was significantly greater than in the one vessel disease group (P=0.005), as well as the frequency of cardiomegaly (P=0.001). Hearts with myocardial scar had a more frequent cardiomegaly (P=0.0004) and higher cardiomegaly score (P=0.004) than without myocardial scar. Moreover, by multivariate analysis, body mass index (P<0.0001), extent of coronary disease (P=0.02) and healed infarct (P=0.04) were positively associated with cardiomegaly. We conclude that there is a significant correlation between the extent of coronary atherosclerosis and cardiac hypertrophy independent of age and body mass index in sudden coronary deaths as well as healed infarct. These data support a causative association between chronic ischemia and cardiomegaly. PMID- 22922120 TI - Ectopic uterine tissue as a chronic pain generator. AB - While chronic pain is a main symptom in endometriosis, the underlying mechanisms and effective therapy remain elusive. We developed an animal model enabling the exploration of ectopic endometrium as a source of endometriosis pain. Rats were surgically implanted with autologous uterus in the gastrocnemius muscle. Within two weeks, visual inspection revealed the presence of a reddish-brown fluid filled cystic structure at the implant site. Histology demonstrated cystic glandular structures with stromal invasion of the muscle. Immunohistochemical studies of these lesions revealed the presence of markers for nociceptor nerve fibers and neuronal sprouting. Fourteen days after surgery rats exhibited persistent mechanical hyperalgesia at the site of the ectopic endometrial lesion. Intralesional, but not contralateral, injection of progesterone was dose dependently antihyperalgesic. Systemic administration of leuprolide also produced antihyperalgesia. In vivo electrophysiological recordings from sensory neurons innervating the lesion revealed a significant increase in their response to sustained mechanical stimulation. These results are consistent with clinical and pathological findings observed in patients with endometriosis, compatible with the ectopic endometrium as a source of pain. This model of endometriosis allows mechanistic exploration at the lesion site facilitating our understanding of endometriosis pain. PMID- 22922121 TI - Dynamic plasticity: the role of glucocorticoids, brain-derived neurotrophic factor and other trophic factors. AB - Brain-derived neurotrophic factor (BDNF) is a secreted protein that has been linked to numerous aspects of plasticity in the central nervous system (CNS). Stress-induced remodeling of the hippocampus, prefrontal cortex and amygdala is coincident with changes in the levels of BDNF, which has been shown to act as a trophic factor facilitating the survival of existing and newly born neurons. Initially, hippocampal atrophy after chronic stress was associated with reduced BDNF, leading to the hypothesis that stress-related learning deficits resulted from suppressed hippocampal neurogenesis. However, recent evidence suggests that BDNF also plays a rapid and essential role in regulating synaptic plasticity, providing another mechanism through which BDNF can modulate learning and memory after a stressful event. Numerous reports have shown BDNF levels are highly dynamic in response to stress, and not only vary across brain regions but also fluctuate rapidly, both immediately after a stressor and over the course of a chronic stress paradigm. Yet, BDNF alone is not sufficient to effect many of the changes observed after stress. Glucocorticoids and other molecules have been shown to act in conjunction with BDNF to facilitate both the morphological and molecular changes that occur, particularly changes in spine density and gene expression. This review briefly summarizes the evidence supporting BDNF's role as a trophic factor modulating neuronal survival, and will primarily focus on the interactions between BDNF and other systems within the brain to facilitate synaptic plasticity. This growing body of evidence suggests a more nuanced role for BDNF in stress-related learning and memory, where it acts primarily as a facilitator of plasticity and is dependent upon the coactivation of glucocorticoids and other factors as the determinants of the final cellular response. PMID- 22922123 TI - The role of basolateral amygdala in the regulation of stress-induced phosphorylated extracellular signal-regulated kinase expression in the hippocampus. AB - Previous studies have shown that the amygdala plays a key role in the modulation of uncontrollable stress effect on hippocampal long-term potentiation and memory in rats. This study aimed to determine the effects of selective neurotoxic lesions of the basolateral amygdala (BLA) on stress-induced glucocorticoid receptor (GR) translocation and alteration of phosphorylated extracellular signal regulated kinases (pERK) in the hippocampus. Intrinsic neurons of the BLA in rats were destroyed using N-methyl-d-aspartate and the rats were subjected to uncontrollable stress induced by restraint and electrical tail shocks. Western blot analyses showed that stress-induced GR translocation occurred in both rats with sham-operated surgery and rats with BLA lesions. As in the Western blot analyses, immunohistological analyses revealed stress-induced reduction of GR expression in CA1 and dentate gyrus (DG) of the hippocampi in control rats and rats with BLA lesions. In addition, the Western blot analyses showed that, in response to stress, the levels of hippocampal pERK were reduced in the sham operated controls, but not in the rats with BLA lesions. Interestingly, the immunohistological analyses showed that BLA lesions prevented the stress-induced reductions in hippocampal pERK levels, only in the DG. These results suggested that the amygdala modulates stress-induced cognitive impairments by regulating the ERK signaling pathway in the hippocampus. PMID- 22922122 TI - Differential distribution of serotonin receptor subtypes in BNST(ALG) neurons: modulation by unpredictable shock stress. AB - The bed nucleus of the stria terminalis (BNST) plays a critical role in regulating the behavioral response to stress. Stressors that activate the BNST also activate serotonergic (5-HT) systems. Hence, maladaptive changes of 5-HT receptor expression may contribute to stress-induced anxiety disorders. The BNST contains three neuronal types, Type I-III neurons. However, little is known about 5-HT receptor subtypes mRNA expression in these neurons, or whether it can be modulated by stress. Whole-cell patch clamp recording from Type I-III neurons was used in conjunction with single cell reverse transcriptase polymerase chain reaction (RT-PCR) to characterize 5-HT receptor mRNA expression, and examine the effects of stress on this expression. We report that Type I neurons expressed mRNA transcripts predominantly for 5-HT(1A) and 5-HT(7) receptors. Type II neurons expressed transcripts for every 5-HT receptor except the 5-HT(2C) receptor. Type II neurons were divided into three sub-populations: Type IIA in which transcripts for 5-HT(3) and 5-HT(7) receptors predominate, Type IIB that mainly express 5-HT(1B) and 5-HT(4) receptor transcripts, and Type IIC in which transcripts for 5-HT(1A) and 5-HT(2A) receptors predominate. Type III neurons were also subdivided into two sub-populations; one that predominantly expressed transcripts for 5-HT(1A), 5-HT(1B) and 5-HT(2A) receptors, and another that mainly expressed transcripts for 5-HT(2C) receptor. Unpredictable shock stress (USS) caused a long-lasting increase in anxiety-like behavior, and a concomitant decrease in 5-HT(1A) transcript expression in Type I-III neurons, as well as an up-regulation of a transcriptional repressor of 5-HT(1A) gene expression, deformed epidermal autoregulatory factor 1 (Deaf-1). Significantly USS decreased 5-HT(1A) protein level, and increased the level of Deaf-1. USS also increased 5 HT(1B) transcript expression in Type III neurons, as well as 5-HT(7) expression in Type I and II neurons. These data suggest that cell type-specific disruption of 5-HT receptor expression in BNST(ALG) neurons may contribute to stress-induced anxiety disorders. PMID- 22922124 TI - Selective Fos induction in hypothalamic orexin/hypocretin, but not melanin concentrating hormone neurons, by a learned food-cue that stimulates feeding in sated rats. AB - Associative learning can enable cues from the environment to stimulate feeding in the absence of physiological hunger. How learned cues are integrated with the homeostatic regulatory system is unknown. Here we examined whether the underlying mechanism involves the hypothalamic orexigenic neuropeptide regulators orexin/hypocretin (ORX) and melanin-concentrating hormone (MCH). We used a Pavlovian conditioning procedure to train food-restricted rats to associate a discrete cue, a tone, with food pellets distinct from their regular lab chow diet. Rats in the conditioned group (Paired) received presentations of a tone immediately prior to food delivery, while the rats in the control group (Unpaired) received random presentations of the same number of tones and food pellets. After conditioning rats were allowed ad libitum access to lab chow for at least 10days before testing. At test sated rats were presented with the tones in their home cages, and then one group was allowed to consume food pellets, while another group was left undisturbed until sacrifice for Fos induction analysis. The tone cue stimulated food consumption in this setting; rats in the Paired group consumed larger amounts of food pellets than rats in the Unpaired group. To examine Fos induction we processed the brain tissue using fluorescent immunohistochemistry methods for combined detection of Fos and characterization of ORX and MCH neurons. We found a greater percentage of ORX and Fos double labeled neurons in the Paired compared to the Unpaired condition, specifically in the perifornical area. In contrast, there were very few MCH neurons with Fos induction in both the Paired and Unpaired conditions. Thus, the food-cue selectively induced Fos in ORX but not in MCH neurons. These results suggest a role for ORX in cue-induced feeding that occurs in the absence of physiological hunger. PMID- 22922125 TI - Sodium caprate augments the hypoglycemic effect of berberine via AMPK in inhibiting hepatic gluconeogenesis. AB - Berberine (BER), a natural product and active ingredient of genera Berberis and Coptis, has been demonstrated to possess anti-diabetic activities. However, the poor bioavailability of this agent greatly limits its clinical application. In our previous study, we demonstrated that co-administration of sodium caprate, an absorption enhancer, with BER could significantly increase the bioavailability of BER without any serious mucosal damage. Here, we investigated the effects of BER on AMP-activated protein kinase (AMPK)/gluconeogenesis pathway and the effects of sodium caprate on hypoglycemic action of BER. The ability of BER co-administered with sodium caprate to reduce insulin resistance was investigated in diabetic rat model induced by high-fat diet and low dose STZ. Western blot was performed to evaluate effects of BER on AMPK signaling proteins involved in hepatic gluconeogenesis in diabetic rat and HepG2 hepatocytes. BER reduced body weight and caused a significant improvement in glucose tolerance without altering food intake in diabetic rats. Similarly, BER reduced plasma triglycerides and improved insulin action in diabetic rats. BER down-regulated the elevated expressions of gluconeogenesis key enzymes PEPCK and G6Pase, inhibited the translocation of TORC2 from cytoplasm to nucleus and increased AMPK activity in liver tissues. The effect of BER was higher when co-administered with sodium caprate. BER treatment resulted in reduced glucose production in HepG2 hepatocytes. BER increased AMPK activity, reduced the expression of PEPCK, and the nuclear transcription factors PGC-1, HNF-4alpha and FOXO1. The effect of BER on gluconeogenesis could be partly blocked by AMPK inhibitor, Compound C. BER could suppress hepatic gluconeogenesis in rat model of diabetes at least in part via stimulation of AMPK activity and this action of BER is augmented by sodium caprate. PMID- 22922126 TI - Quantitative modifications of TNM staging, clinical staging and therapeutic intent by FDG-PET/CT in patients with non small cell lung cancer scheduled for radiotherapy--a retrospective study. AB - It is obvious that FDG-PET has added value to CT, but there is still insufficient data to define the role of FDG-PET/CT in clinical practice. Usually data are gathered from multiple sources and in consequence the information obtained is heterogeneous and not always comparable between patients. To alleviate this lack of data, we attempted to investigate the differences in staging and therapeutic intent as compared with conventional staging in non small cell lung cancer (NSCLC) patients scheduled for RT after adding FDG-PET/CT to conventional staging in 104 included subjects. In contrary to the multicentric studies relying on patients medical records from outside institutions, these data were generated entirely with the institution's PET/CT unit. Significant modifications of both, M stage and clinical stage were detected after inclusion of FDG-PET/CT data (p<0.001), while there was no statistically significant T- and N-stage modification. Overall implenting FDG-PET/CT revised RT intention decision in 34% of patients. FDG-PET/CT provides enhanced staging capabilities compared to conventional CT in staging of non small cell lung carcinoma and allows improved selection of patients suitable for curative intention, while avoiding unnecessary irradiation and costs in patients eligible to palliative intention. PMID- 22922127 TI - Role of HLA-G 14bp deletion/insertion and +3142C>G polymorphisms in the production of sHLA-G molecules in relapsing-remitting multiple sclerosis. AB - HLA-G is believed to act as an anti-inflammatory molecule in Multiple Sclerosis (MS). The 3' untranslated region of the HLA-G gene is characterized by two polymorphisms, DEL/INS14bp and +3142C>G, which control soluble HLA-G (sHLA-G) production. The influence of these two HLA-G variants on sHLA-G serum and cerebrospinal fluid (CSF) levels was investigated in 69 Relapsing-Remitting MS patients grouped in magnetic resonance imaging (MRI) inactive and active disease. Serum and CSF sHLA-G levels were more elevated in high than in low DEL/INS 14bp and +3142C>G sHLA-G producers and were different among the various combined HLA-G genotypes in both MRI inactive and active diseases. The highest and the lowest sHLA-G values were identified in MS patients with C/C,DEL/DEL and G/G,INS/INS genotypes, respectively. Our preliminary findings suggest that serum and CSF sHLA G levels in MS could be influenced by HLA-G polymorphisms irrespective of the inflammatory microenvironment. PMID- 22922128 TI - Early and persistent up-regulation of hypothalamic orexigenic peptides in rat offspring born to dams fed a high-carbohydrate supplement during gestation. AB - Maternal diet ingested during gestation can profoundly alter production and action of hypothalamic neuropeptides involved in feeding and body weight regulation. In this study, we set out to simulate, in a rat model, modifications to feeding habit often observed in pregnant women. Gestating dams were fed a restricted normal diet with the opportunity to complete their energy requirements with either a high-fat (HF) or a high-carbohydrate (HC) diet. Growth and hypothalamic feeding peptides were measured in the offspring at 3 (weaning) and 20 weeks of age. At weaning, body weight was lower in HC pups than in HF pups or control (Ca) pups born to dams fed control diet ad libitum. Expression of neuropeptide Y (NPY) and AgRP mRNA in the arcuate nucleus were increased in HC pups vs Ca and HF pups. By 20 weeks of age, body weight differentials had disappeared, and there was no differences in NPY and AgRP gene expression, although POMC expression was lower in HC rats than in HF rats. NPY and orexin peptide concentrations in the paraventricular nucleus at this age were higher in HC rats than in Ca and HF rats. In HC rats, there was also a greater positive gradient of peptide concentration between the zone of release and the zone of synthesis for NPY and orexin. The early up-regulation of orexigenic peptides in HC rats may be a compensatory adjustment to low body weight. This persisting overactive orexigenic drive might have deleterious metabolic effects in an obesogenic environment at adulthood. PMID- 22922130 TI - A GC-wave correction algorithm that improves the analytical performance of aCGH. AB - Array-based comparative genome hybridization (aCGH) is a powerful, data-intensive technique used to identify genomic copy number variation throughout the human genome. The use of aCGH clinically to identify pathogenic copy number aberrations is becoming common, and the statistical and mathematical algorithms used in aCGH data analysis play an important role in determining the performance of these platforms. Interpretation of aCGH data can be complicated by a platform independent technical artifact described as GC-waves, which are wave patterns in CGH data correlating to regional GC-content of the human genome that can reduce the clinical specificity and sensitivity of aCGH platforms. We describe an automated GC-wave correction algorithm and techniques to understand how the correction affects the analytical performance of aCGH. This GC-correction algorithm was effective at mitigating GC-wave effects. After correction, array data were measurably improved by the algorithm, demonstrating improvements in specificity and sensitivity and in overall data quality. PMID- 22922129 TI - Dissecting the effects of endogenous brain IL-2 and normal versus autoreactive T lymphocytes on microglial responsiveness and T cell trafficking in response to axonal injury. AB - IL-2 is essential for T-helper regulatory (Treg) cell function and self tolerance, and dysregulation of both endogenous brain and peripheral IL-2 gene expression may have important implications for neuronal injury and repair. We used an experimental approach combining mouse congenic breeding and immune reconstitution to test the hypothesis that the response of motoneurons to injury is modulated by the combined effects of IL2-mediated processes in the brain that modulate its endogenous neuroimmunological milieu, and IL2-mediated processes in the peripheral immune system that regulate T cell function (i.e., normal versus autoreactive Treg-deficient T cells). This experimental strategy enabled us to test our hypothesis by disentangling the effect of normal versus autoreactive T lymphocytes from the effect of endogenous brain IL-2 on microglial responsiveness (microglial phagocytic clusters normally associated with dead motoneurons and MHC2(+) activated microglia) and T cell trafficking, using the facial nerve axotomy model of injury. The results demonstrate that the loss of both brain and peripheral IL-2 had an additive effect on numbers of microglial phagocytic clusters at day 14 following injury, whereas the autoreactive status of peripheral T cells was the primary factor that determined the degree to which T cells entered the injured brain and contributed to increased microglial phagocytic clusters. Changes in activated MHC2(+) microglial in the injured FMN were associated with loss of endogenous brain IL-2 and/or peripheral IL-2. This model may provide greater understanding of the mechanisms involved in determining if T cells entering the injured central nervous system (CNS) have damaging or proregenerative effects. PMID- 22922131 TI - Environmental optimization of continuous flow ozonation for urban wastewater reclamation. AB - Wastewater samples from the secondary clarifier of two treatment plants were spiked in the microgram-to-tens-of-microgram per liter range with diuron (herbicide), ibuprofen and diclofenac (anti-inflammatory drugs), sulfamethoxazole and erythromycin (antibiotics), bezafibrate and gemfibrozil (lipid regulators), atenolol (beta-blocker), carbamazepine (anti-epileptic), hydrochlorothiazide (diuretic), caffeine (stimulant) and N-acetyl-4-amino-antipiryne, a metabolite of the antipyretic drug dypirone. They were subsequently ozonated in continuous flow using 1.2L lab-scale bubble columns. The concentration of all spiking compounds was monitored in the outlet stream. The effects of varying ozone input, expressed as energy per unit volume, and water flow rate, and of using single or double column were studied in relation to the efficiency of ozone usage and the ratio of pollutant depletion. The ozone dosage required to treat both wastewaters with pollutant depletion of >90% was in the 5.5-8.5 mg/L range with ozone efficiencies greater than 80% depending on the type of wastewater and the operating conditions. This represented 100-200 mol of ozone transferred per mole of pollutant removed. Direct and indirect environmental impacts of ozonation were assessed according to Life Cycle Assessment, a technique that helped identify the most effective treatments in terms of potential toxicity reduction, as well as of toxicity reduction per unit mass of greenhouse-gas emissions, which were used as an indicator of environmental efficiency. A trade-off between environmental effectiveness (toxicity reduction) and greenhouse-gas emissions was observed since maximizing toxicity removal led to higher greenhouse-gas emissions, due to the latter's relatively high ozone requirements. Also, there is an environmental trade-off between effectiveness and efficiency. Our results indicate that an efficient use of ozone was not compatible with a full pollutant removal. PMID- 22922132 TI - The use of biochar to reduce soil PCB bioavailability to Cucurbita pepo and Eisenia fetida. AB - Biochar is a carbon rich by-product produced from the thermal decomposition of organic matter under low oxygen concentrations. Currently many researchers are studying the ability of biochar to improve soil quality and function in agricultural soils while sustainably sequestering carbon. This paper focuses on a novel but complimentary application of biochar - the reduced bioavailability and phytoavailability of organic contaminants in soil, specifically polychlorinated biphenyls (PCBs). In this greenhouse experiment, the addition of 2.8% (by weight) biochar to soil contaminated with 136 and 3.1 MUg/g PCBs, reduced PCB root concentration in the known phytoextractor Cucurbita pepo ssp. pepo by 77% and 58%, respectively. At 11.1% biochar, even greater reductions of 89% and 83% were recorded, while shoot reductions of 22% and 54% were observed. PCB concentrations in Eisenia fetida tissue were reduced by 52% and 88% at 2.8% and 11.1% biochar, respectively. In addition, biochar amended to industrial PCB-contaminated soil increased both aboveground plant biomass, and worm survival rates. Thus, biochar has significant potential to serve as a mechanism to decrease the bioavailability of organic contaminants (e.g. PCBs) in soil, reducing the risk these chemicals pose to environmental and human health, and at the same time improve soil quality and decrease CO(2) emissions. PMID- 22922133 TI - Stream ecosystem integrity is impaired by logging and shifting agriculture in a global megadiversity center (Sarawak, Borneo). AB - In common with most of Borneo, the Bakun region of Sarawak is currently subject to heavy deforestation mainly due to logging and, to a lesser extent, traditional slash-and-burn farming practices. This has the potential to affect stream ecosystems, which are integrators of environmental change in the surrounding terrestrial landscape. This study evaluated the effects of both types of deforestation by using functional and structural indicators (leaf litter decomposition rates and associated detritivores or 'shredders', respectively) to compare a fundamental ecosystem process, leaf litter decomposition, within logged, farmed and pristine streams. Slash-and-burn agricultural practices increased the overall rate of decomposition despite a decrease in shredder species richness (but not shredder abundance) due to increased microbial decomposition. In contrast, decomposition by microbes and invertebrates was slowed down in the logged streams, where shredders were less abundant and less species rich. This study suggests that shredder communities are less affected by traditional agricultural farming practices, while modern mechanized deforestation has an adverse effect on both shredder communities and leaf breakdown. PMID- 22922134 TI - Relative influence of prey mercury concentration, prey energy density and predator sex on sport fish mercury concentrations. AB - Mercury (Hg) bioaccumulation in aquatic food webs has created a human health concern for anglers who consume fish. Variability in sport fish Hg concentration adds to the uncertainty of the amount of fish an angler can safely consume, so predicting where variability arises is useful. We evaluated the relative influence of diet (prey Hg concentration and energy density) and sex on sport fish Hg concentrations using a bioenergetics approach. Our results indicated that sport fish diets (prey Hg concentration followed by energy density) were the most important factors for determining sport fish Hg concentration followed by sex. Although physiological and behavioral differences based on sex may lead to differences in gross growth efficiency, resulting in different Hg concentrations in male and female sport fish, evaluating the relative importance of these differences will require sex-specific parameterization of bioenergetics models. Our results support previous findings that knowledge of sport fish diets (prey Hg concentration followed by energy density) and sex could aid in the prediction of sport fish Hg concentrations. Thus, basic knowledge of system-specific food web structure could provide valuable information for developing sport fish consumption advisories to better protect anglers and their families from Hg contamination. PMID- 22922135 TI - A numerical investigation of vapor intrusion--the dynamic response of contaminant vapors to rainfall events. AB - The U.S. government and various agencies have published guidelines for field investigation of vapor intrusion, most of which suggest soil gas sampling as an integral part of the investigation. Contaminant soil gas data are often relatively more stable than indoor air vapor concentration measurements, but meteorological conditions might influence soil gas values. Although a few field and numerical studies have considered some temporal effects on soil gas vapor transport, a full explanation of the contaminant vapor concentration response to rainfall events is not available. This manuscript seeks to demonstrate the effects on soil vapor transport during and after different rainfall events, by applying a coupled numerical model of fluid flow and vapor transport. Both a single rainfall event and seasonal rainfall events were modeled. For the single rainfall event models, the vapor response process could be divided into three steps: namely, infiltration, water redistribution, and establishment of a water lens atop the groundwater source. In the infiltration step, rainfall intensity was found to determine the speed of the wetting front and wash-out effect on the vapor. The passage of the wetting front led to an increase of the vapor concentration in both the infiltration and water redistribution steps and this effect is noted at soil probes located 1m below the ground surface. When the mixing of groundwater with infiltrated water was not allowed, a clean water lens accumulated above the groundwater source and led to a capping effect which can reduce diffusion rates of contaminant from the source. Seasonal rainfall with short time intervals involved superposition of the individual rainfall events. This modeling results indicated that for relatively deeper soil that the infiltration wetting front could not flood, the effects were damped out in less than a month after rain; while in the long term (years), possible formation of a water lens played a larger role in determining the vapor intrusion risk. In addition, soil organic carbon retarded the transport process, and damped the contaminant concentration fluctuations. PMID- 22922136 TI - BTEX removal from aqueous solutions by HDTMA-modified Y zeolite. AB - Various technologies have been used for the treatment and remediation of areas contaminated by BTEX (benzene, toluene, ethylbenzene and xylenes), which are organic compounds that are of particular concern due to their toxicity. Potential applications of synthetic zeolites for environmental fieldwork have also been reported worldwide. In this work, a hexadecyltrimethyl ammonium (HDTMA) surfactant-modified synthetic zeolite was investigated for its efficiency in removing BTEX from aqueous solutions. Three surfactant-modified zeolites were synthesized, with amounts of surfactant corresponding to 50%, 100%, and 200% of the total cation-exchange capacity (CEC) of the synthetic zeolite Y. The results of the BTEX adsorption experiments onto both synthetic zeolite and surfactant modified zeolites (SMZ) showed that the SMZ-100 (zeolite modified with surfactant levels at 100% of CEC) was the most efficient modified zeolite for BTEX removal. Kinetics studies indicated that the multicomponent adsorption equilibrium was reached within 6 h and followed pseudo-second-order kinetics. The Langmuir, Freundlich, Redlich-Peterson and Temkin models were used to evaluate the BTEX adsorption capacity by SMZ-100. The Temkin model was found to be suitable for all BTEX compounds in a multicomponent system. Regeneration cycles of the modified zeolite were also performed, and the results showed that the adsorbent could be used efficiently in as many as four adsorption cycles, except for benzene. PMID- 22922137 TI - [Gene and environmental interactions of food allergy]. AB - Food allergy is now looming as a major health issue with significant implications. In westernized countries, recent reports show a rise in allergic diseases, in particular food allergy. It affects approximately 5-8% of children and 1-5% of adults. Despite this, our current understanding of the immunological and biological mechanisms of food allergy is still incomplete. It is generally believed that food allergy is determined by both genetic and environmental factors. There is some evidence that epigenetic modifications may affect the prevalence of food allergies. This paper discusses the current state of knowledge regarding genetic, epigenetic and environmental factors of food allergy. PMID- 22922138 TI - [Age-related changes of skeletal muscles: physiology, pathology and regeneration]. AB - This review provides a short presentation of the aging-related changes of human skeletal muscles. The aging process is associated with the loss of skeletal muscle mass (sarcopenia) and strength. This results from fibre atrophy and apoptosis, decreased regeneration capacity, mitochondrial dysfunction, gradual reduction of the number of spinal cord motor neurons, and local and systemic metabolic and hormonal alterations. The latter involve age-related decrease of the expression and activity of some mitochondrial and cytoplasmic enzymes, triacylglycerols and lipofuscin accumulation inside muscle fibres, increased proteolytic activity, insulin resistance and decreased serum growth hormone and IGF-1 concentrations. Aging of the skeletal muscles is also associated with a decreased number of satellite cells and their proliferative activity. The age related reduction of skeletal muscle mass and function may be partially prevented by dietary restriction and systematic physical exercises. PMID- 22922139 TI - Identification of the genes expression profile associated with the ex vivo resistance to etoposide in childhood acute leukemias. AB - INTRODUCTION: Drug resistance and the gene expression profiles might discriminate the therapy outcome, and indicate the subgroup of patients with poor prognosis. In this study we analyzed the gene expression profile in correlation with the profile of ex vivo resistance to etoposide in children with acute leukemias. METHODS: The ex vivo drug resistance profile was determined by the MTT cytotoxicity assay performed on leukemic blasts of 56 patients. Gene expression profiles were obtained from the results of hybridization of cRNA to Human Genome U133A 2.0 ologonucleotide arrays. The following analyses were performed: correlation analysis, hierarchical clustering, the assignment of location and function. Verification of data for four selected genes (MNDA, GH1, NUDT21, RHOG) was performed by quantitative real time polymerase chain reaction in the studied population and in an independent group of 54 leukemic patients. RESULTS: Using the permutation Spearman correlation test, a set of 233 probes/209 genes was selected. The global test confirmed the significance of the correlation of gene expression profile and resistance to etoposide (p<0.001). The NUDT21 (nudix, nucleoside diphosphate linked moiety X-type, motif 21) gene showed the strongest correlation with resistance to etoposide (FDR<0.0001%). CONCLUSIONS: Profiling of transcriptome may help in assessing the sensitivity to drugs used in chemotherapy. Resistance to etoposide is possibly associated with a change of expression of a large number of biologically important genes that influence several cellular mechanisms. PMID- 22922140 TI - The impact of IL18 gene polymorphisms on mRNA levels and interleukin-18 release by peripheral blood mononuclear cells. AB - INTRODUCTION: Interleukin-18 (IL-18) is a pleiotropic cytokine playing an important role as a modulator of immune responses, found to play a role in pathogenesis of numerous inflammatory-associated disorders. In the present study a potential association between 7 common single-nucleotide polymorphisms (SNPs) spanning the whole IL18 gene, gene expression and the release of IL-18 from the stimulated peripheral blood mononuclear cells (PBMCs) was investigated. MATERIALS/METHODS: PBMCs were isolated from peripheral blood of 29 healthy volunteers, genotyped for the presence of IL18 SNPs: rs1946518: A>C, rs187238: G>C, rs360718: A>C, rs360722: C>T, rs360721: C>G, rs549908: T>G, and rs5744292: A>G. IL-18 concentration and IL18 mRNA levels were investigated after incubation of cells for 48 h with different stimulants (PHA, LPS, and anti-CD3/CD28 antibodies). RESULTS: After treatment with LPS and antibodies IL-18 concentrations were significantly lower in rs1946518AA homozygotes than in C allele carriers. When differences in IL18 mRNA levels between non-stimulated and stimulated cells were analyzed, significantly decreased gene expression was noted in rs1946518 AA homozygotes (as compared with C allele carriers) in samples treated with PHA and LPS. Similar trends were observed in the case of rs187238 SNP; however, the differences reached statistical significance only after PHA treatment. CONCLUSIONS: Our study supports the role of rs1946518 (-607A>C) and rs187238 (-137G>C) SNPs as genetic determinants of the observed variability in IL18 expression. PMID- 22922141 TI - [Selected mice models based on APP, MAPT and presenilin gene mutations in research on the pathogenesis of Alzheimer's disease]. AB - The research conducted on animal models of Alzheimer's disease (AD) has provided valuable information about the pathogenesis of this disease and associated behavioral and cognitive deficits as well as the disease-associated anatomical and histopathological lesions of the brain. Transgenic technologies have enabled the creation of animal models based on mutations in APP, MAPT, presenilin genes, tau protein and apoE. Due to economic reasons studies are mainly conducted on mice. Their brain tissue, depending on the mutation, is characterized by histopathological changes, such as the presence of amyloid plaques, tau protein deposits and dystrophic neurites, gliosis, hippocampal atrophy and amyloid accumulation in vessels. Animal cognitive impairment and behavior, which can be demonstrated in behavioral tests, primarily relate to the working and reference memory, alternation and anxiety. Unfortunately, despite the various modifications specific to AD in the genome of animals, scientists have failed to create an animal model characterized by all the pathological changes that can occur in Alzheimer's disease. Nevertheless, the role of transgenic animals is undeniable, both in research on AD neuropathology and for testing new therapies, such as immunotherapy. Despite the occurrence of abundant Alzheimer's disease mice models this article is dedicated to selected models with mutations in the APP, MAPT and presenilin genes and their application for behavioral studies. PMID- 22922142 TI - [Kynurenic acid--a new tool in the treatment of hiperhomocysteinemia and its consequences?]. AB - Atherosclerosis together with its cardiovascular consequences is the most common and significant cause of death, particularly in highly developed countries. The process of atherogenesis begins as soon as in childhood and depends on classical risk factors. Atherosclerosis also results from a chronic inflammatory-immune process which takes place in the vascular walls. Furthermore, it has been known for a number of years that the development of atherosclerotic lesions is closely connected with the concentration of homocysteine in serum. Homocysteine is a sulfur amino acid originating from methionine. An increased concentration of homocysteine in blood harmfully influences blood vessels, leading to a higher risk of ischemic heart disease and stroke. Since tackling classical atherosclerosis risk factors is not efficient enough when it comes to protecting the cardiovascular system from diseases, new substances possessing anti atherogenic properties, especially endogenous ones, are sought. Recently, researchers have paid attention to a connection between homocysteine and an endogenous tryptophan derivative, kynurenic acid. Recently, it was revealed that kynurenic acid counteracts the harmful effects of homocysteine on endothelium cells in vitro. The hypothesis assuming homocysteine-kynurenate interplay suggests the existence of a new mechanism of atherogenesis and gives us an opportunity to use this knowledge in both prevention and treatment of cardiovascular diseases. PMID- 22922143 TI - [NET and NETosis--new phenomenon in immunology]. AB - Neutrophils are one of the first cells of the immune system recruited to the site of infection, representing the host's most effective and numerous front-line defenders. Recently, a novel antimicrobial mechanism of neutrophils has been described: upon activation, they release DNA and a subset of their granule content, forming neutrophil extracellular traps (NETs). These extracellular, chromatin structures, which contain histones and neutrophil granule proteins, can trap and kill a broad spectrum of microbes, including Gram-positive and Gram negative bacteria, fungi, protozoa and viruses. Some of the pathogens, which are trapped and exposed to high local concentrations of antimicrobial compounds, employ strategies against NET binding, including surface modification and/or degradation of NET by DNases. It has been suggested that NETs are formed during active cell death, recently named NETosis. New data indicate that this novel mechanism of cell death requires interaction between three processes--reactive oxygen species generation, histone citrullination and autophagy--and significantly differs from previously known types of cell death, including apoptosis and necrosis. Moreover, the release of nuclear chromatin was also described for other types of cells--mast cells and eosinophils. Mast cells, like neutrophils, under certain conditions release nuclear chromatin and may undergo a similar active cell death program, while eosinophils release only mitochondrial chromatin, and its release does not lead to the death of these cells. PMID- 22922144 TI - [Salmonella multiphasic flagellar antigen]. AB - In the Salmonella antigenic pattern, more than one phase of flagellar antigen is observed. The phase of flagellar antigen depends of the gene which encodes the protein building the filament of flagella. The fliC gene encodes the 1st phase of flagellar antigen and the fljB gene encodes the 2nd phase of flagellar antigen. The third phase of flagellar antigen is encoded by one of the genes localized on the plasmid. Expression of the fljB gene (part of the hinfljBA operon) is regulated by a mechanism of DNA fragment sequence inversion. The hin gene, which encodes Hin invertase, flanked by two regions - hixL and hixR - is inverted by Hin invertase together with Fis protein. This process turns on or turns off of the hinfljBA operon. When this operon is turned on, FljB protein is produced (structural protein of flagella filament), and also FljA protein, which is a transcriptional repressor of the fliC gene. This means that one Salmonella cell could have only one phase flagellar antigen--1st or 2nd phase. Sometimes, due to mutation in one of the mentioned genes, naturally diphasic Salmonella strains have the ability to produce only one phase of flagellar antigen. Mostly monophasic Salmonella with an active fliC gene are observed. In recent years such a strain, Salmonella enterica with the antigenic formula 1,4,[5],12: i: -, is one of the most often isolated strains from human cases in many European countries. PMID- 22922145 TI - [Methods of detection of selected respiratory viruses]. AB - Respiratory viruses contribute to significant morbidity and mortality in healthy and immunocompromised individuals and are considered as a significant economic burden in the healthcare system. The similar clinical symptoms in the course of different viral and bacterial respiratory infections make the proper diagnosis difficult. An accurate and prompt diagnostics is crucial for infection control and patient management decisions, especially regarding the use of antibacterial or antiviral therapy and hospitalization. Moreover, the identification of the causative agent eliminates inappropriate use of antibiotics and may reduce the cost of healthcare. A wide variety of diagnostic procedures is applied for the detection of viral agents responsible for respiratory tract infections. For many years, the viral antigen detection and standard isolation technique in cell culture was the main method used in routine diagnostics. However, in recent years the nucleic acid amplification techniques have become widely used and have significantly improved the sensitivity of viral detection in clinical specimens. Molecular diagnostic assays have contributed to revealing high rates of co infection (multiplex reactions) and allow identification of agents that are difficult to culture. This paper discusses a number of technical aspects of the current most commonly used techniques, their general principles, main benefits and diagnostic value, but also some of their limitations. PMID- 22922146 TI - [Mycolic acids--potential biomarkers of opportunistic infections caused by bacteria of the suborder Corynebacterineae]. AB - Mycolic acids are one of the basic elements of the cell wall structure of bacteria belonging to the suborder Corynebacterineae, constituting from 20% to 40% of dry weight. Additionally, they show high structural diversity within each family and species. Nowadays, profiles of mycolic acids are widely described for the genus Mycobacterium, the causative agent of tuberculosis. However, the suborder Corynebacterineae also includes many representatives of opportunistic human pathogens, e.g. Dietzia, Gordonia, Nocardia and Rhodococcus. Currently, an increased infection risk caused by this group of microorganisms especially in immunocompromised patients has been observed. Better knowledge of mycolic acid profiles for Corynebacterineae may allow identification of mycolic acids as diagnostic markers in the detection of opportunistic bacterial infections. Modern techniques of chemical analysis, including mass spectrometry, may enable the development of new chemotaxonomic methods for the detection and differentiation of bacteria within the suborder Corynebacterineae. PMID- 22922147 TI - Evaluation of the humoral and cellular immune responses after implantation of a PTFE vascular prosthesis. AB - INTRODUCTION: The experiment was designed in order to determine the immunological processes that occur during the healing in synthetic vascular grafts, especially to establish the differences in the location of the complement system proteins between the proximal and distal anastomosis and the differences in the arrangement of inflammatory cells in those anastomoses. The understanding of those processes will provide a true basis for determining risk factors for complications after arterial repair procedures. MATERIAL/METHODS: The experiment was carried out on 16 dogs that underwent implantation of unilateral aorto femoral bypass with expanded polytetrafluoroethylene (ePTFE). After 6 months all animals were euthanized to dissect the vascular grafts. Immunohistochemical assays and electron microscopic examinations were performed. RESULTS: Immunohistochemical findings in the structure of neointima between anastomoses of vascular prostheses demonstrated significant differences between humoral and cellular responses. The area of proximal anastomosis revealed the presence of fibroblasts, but no macrophages were detected. The histological structure of the proximal anastomosis indicates that inflammatory processes were ended during the prosthesis healing. The immunological response obtained in the distal anastomosis corresponded to the chronic inflammatory reaction with the presence of macrophages, myofibroblasts and deposits of complement C3. DISCUSSION: The identification of differences in the presence of macrophages and myofibroblasts and the presence of the C3 component between the anastomoses is the original achievement of the present study. In the available literature, no such significant differences have been shown so far in the humoral and cellular immune response caused by the presence of an artificial vessel in the arterial system. PMID- 22922148 TI - [Molecular mimicry in the etiology of autoimmune diseases]. AB - There are currently more than 80 different autoimmune diseases, affecting approximately 100 million people worldwide. The etiology of most autoimmune diseases is unknown. The highest incidence of these diseases is in the developed countries and they are more common in women than in men. Among the most often listed factors responsible for the onset of autoimmunity are genetic predisposition and the phenomenon known as molecular mimicry. The latter stems from a similarity between microbial antigens and antigens present in the human body (self antigens). It is believed that such homology is responsible for the production of auto-antibodies and in consequence attack of the immune system against host tissues and organs. However, the main molecular factors responsible for these diseases in most cases remain unknown. While pathogenesis of many autoimmune diseases indicates the presence of molecular mimicry, at the same time the similarities between the own and foreign structures do not always result in autoimmunity. Therefore, prediction of such crucial homology responsible for the development of autoimmune disease is extremely difficult. In this paper we present examples of autoimmune diseases such as type 1 diabetes, multiple sclerosis, reactive arthritis and the potential contribution of micro-organisms to the mechanism of molecular mimicry. PMID- 22922149 TI - [Phosphodiesterase 3 mediates cross-talk between the protein kinase- and cGMP- dependent pathways and cyclic AMP metabolism]. AB - PDE3 is a dual-substrate phosphodiesterase responsible for hydrolyzing both cAMP and cGMP whilst being simultaneously inhibited by cGMP. This feature is related to presence of the 44 amino acid insert in the catalytic domain, which determines the mechanism of introduction of the cyclic nucleotide into the catalytic pocket of the enzyme. Once bound in the catalytic site cGMP results in steric hindrance for cAMP to enter the site. The regulatory domain of PDE3 consists of two hydrophobic regions: NHR1 and NHR2. Their presence defines the enzyme's intracellular localization, thus determining its participation in particular signaling cascades. Due to the properties of PDE3 this enzyme has exceptional importance for the cross-talk between cAMP-dependent signaling and other cascades. There are two different mechanisms of action of PDE3 enzymes in cell signaling pathways. In many signaling cascades assembly of a signalosome is necessary for phosphorylation and activation of the PDE3 proteins. In response to certain hormones and growth factors, PDE3 merges the metabolism of cAMP with protein kinase-dependent signaling pathways. PDE3 also controls the level of cAMP with regard to the alternating concentration of cGMP. This effect occurs in signaling cascades activated by natriuretic peptide. PMID- 22922150 TI - [The role of complement factor H in the pathogenesis of Borrelia infection]. AB - Complement factor H (CFH) is one of the most important negative regulators of the alternative pathway of the complement system. It is a glycoprotein belonging to the protein H family, which is synthesized mainly in the liver and is composed into a globular protein consisting of 60 amino acid domains in the serum. It shows specificity for C3b molecule of the complement system present in the serum or bound to the cell surface. It inhibits the steady formation of C3 convertase enzymes and the binding of C2 to C4b and factor B to C3b. It accelerates the decomposition of C2a into C4b and the displacement of Bb from C3b. The present paper discusses the composition, properties and functions of the complement factor and the family it belongs to. The paper focuses in particular on its role in the pathogenesis of an infection caused by the spirochetes of the Borrelia genus. Through binding CFH and other related proteins, bacteria of the Borrelia species inhibit the key effect of the alternative pathway of the complement system - the lysis of spirochete cells dependent on the complement's activation. The mechanism enables pathogens to spread in the host organism and facilitates the evolution of the disease. Discovering the immune mechanisms of the infection caused by the spirochetes of the Borrelia genus may allow for implementing a therapy blocking the binding of complement factor H early enough, apart from the standard treatment of the disease. PMID- 22922151 TI - [The biological activity of macrophages in health and disease]. AB - Macrophages are involved in immune response as phagocytes, antigen presenting cells and as effector cells of delayed-type hypersensitivity. Moreover, the activity of macrophages is associated with modulation of many biological processes during the whole life and depends on the actual macrophage phenotype induced under the influence of various microenvironmental stimuli. In pregnancy, placental macrophages induce the development of maternal tolerance to fetal antigens, while fetal macrophages are responsible for proper formation of tissues and organs. Residual macrophages play a very important role in tissue homeostasis, apoptotic cell clearance to prevent autoimmunization and first defense in infections. The inflammatory response of macrophages may be modulated by pathogens. Their suppressive activity is observed in immunologically privileged organs such as testes. In pathologies, macrophages are responsible for tissue damage in a case of nonspecific activation followed by overproduction of proinflammatory factors. Suppression of a specific immune response against tumors is mainly the effect of tumor associated macrophage (TAM) action. On the other hand, presentation of allergens or self-antigens by macrophages and their nonspecific activation by necrotic adipocytes leads to the induction of a chronic inflammatory response and impairment of immunity. Therefore, modulation of macrophage functions may be the key for improvement of therapy of cancer and allergic, autoimmune, metabolic, cardiovascular and Alzheimer's diseases. PMID- 22922152 TI - [Human carcinoembryonic antigen family proteins, structure and function]. AB - The CEA related cell adhesion molecules (CEACAM) contain variable and constant immunoglobulin-like domains and are classified as a member of the immunoglobulin supergene family, IgSF. The seven CEACAM (CD66) antigens (CEACAM1, CEACAM3, CEACAM4, CEA, CEACAM6, CEACAM7 and CEACAM8) differ in the number of Ig-like domains, sugar content, presence of isoforms, tissue distribution and form of membrane attachment (transmembrane region or GPI anchor). CEACAMs with a transmembrane region possess a cytoplasmic domain with or without the immunoreceptor motifs. The structural diversity of CEACAMs results in their multifunctionality, especially displayed in calcium independent homo- and heterotypic adhesion interactions. The scientific data, collected mainly for CEA, strongly confirm involvement of this molecule in colorectal cancer. Recent research also indicates that CEACAMs play an important role in signal transduction, recognition and binding of pathogenic bacteria belonging to Neisseria and Escherichia genera. PMID- 22922153 TI - Oxidative stress modulates the organization of erythrocyte membrane cytoskeleton. AB - BACKGROUND: Apart from their main role in transporting oxygen and carbon dioxide, erythrocytes play also an important role in organism antioxidative defence. Direct exposure to reactive oxygen species (ROS) results in shortening of their half-life, even by 50%. The presence of glucose, being the substrate in pentose phosphate pathway (PPP) cycle, is one of the factors that can have influence on the level of oxidative stress. The activity of PPP increases during oxidative stress. Glucose guarantees normal PPP functioning with the production of reductive equivalents in the amounts necessary to reproduction of glutathione- nonenzymatic free radical scavenger. In available literature there are no reports regarding the changes in protein contents of erythrocyte cytoskeleton exposed to t-butyl hydroperoxide in relation to glucose presence in incubation medium. MATERIAL/METHODS: Erythrocytes taken from 10 healthy subjects were used to assess the influence of generated free radicals on erythrocyte proteins and chosen parameters of oxidative stress. Erythrocytes were incubated in the solutions containing deferent concentrations of t-butyl hydroperoxide and glucose. Electrophoresis was performed on polyacrylamide gel in denaturating conditions. The contents of tryptophan in membranes was evaluated spectrofluorometrically. RESULTS/CONCLUSIONS: In vitro conditions oxidative stress leads to protein damage in erythrocyte cytoskeleton, both in proteins inside the cell as well as having contact with extracellular environment. In consequence, the amount of low molecular proteins--mainly globin, which bind to cytoskeleton, increases. This process takes place independently of glucose presence in incubation medium. One of the element of protein cytoskeleton, tryptophan, also undergoes degradation. The decrease of its contents is higher during erythrocyte exposure to t-BOOH in environment containing glucose, what can suggest prooxidative influence of glucose in conditions in vitro. PMID- 22922154 TI - [TSG-6 protein and its role during maturation of ovarian follicles]. AB - TSG-6 is an ~35 kDa glycoprotein belonging to the hyaluronan binding family. Its expression is induced as a result of an inflammatory condition and during ovulation. TSG-6 is a crucial protein engaged in extracellular matrix synthesis and organization of cumulus-oophorus-complexes (COCs) in preovulatory ovarian follicles. TSG-6 catalyzes cross-linking via heavy chains of trypsin alpha inhibitor and hyaluronan. This reaction is essential for proper cumulus cell expansion. This process is correlated with purchasing competence by the oocyte. Disorders of the synthesis of TSG-6 cause irregularities in expansion of cumulus cells during ovarian follicle maturation. Therefore, TSG-6 is a potential molecular marker of oocyte maturation. PMID- 22922155 TI - The role of manganese in etiopathogenesis and prevention of selected diseases. AB - Manganese (Mn) is an essential trace element, necessary for development and growth of the organism. The adequate content of this element in the body determines proper metabolism of amino acids, cholesterol and carbohydrates. This mineral influences activity of several enzymes involved in metabolic and redox processes. Mn absorption and retention disturbances may participate in etiopathogenesis of some diseases and disorders. This article is a review of knowledge about the role of Mn in etiopathogenesis and prevention of selected diseases: brain disorders, diabetes, lipid disturbances and cancers. PMID- 22922156 TI - [Oncogenic osteomalacia and its symptoms: hypophosphatemia, bone pain and pathological fractures]. AB - Oncogenic osteomalacia (OOM) is a rare paraneoplastic syndrome induced by tumor produced phosphaturic factors, i.e. phosphatonins. The disorder is characterized by renal tubular phosphate loss, secondary to this process hypophosphatemia and defective production of active form of vitamin D. The clinical course of oncogenic osteomalacia is characterized by bone pain, pathological fractures, muscle weakness and general fatigue. Osteomalacia-associated tumors are usually located in the upper and lower limbs, with half of the lesions primarily situated in the bones. Most of them are small, slow-growing tumors. Their insignificant size and various location coupled with rare occurrence of the disease and non specificity of clinical symptoms lead to difficulties in reaching a diagnosis, which is often time-consuming and requires a number of additional tests. The average time between the appearance of the first symptoms and the establishment of an accurate diagnosis and the beginning of treatment is over 2.5 years. The aim of this study is to discuss the pathophysiology of disease symptoms, pathomorphology of tumors, diagnostic methods and treatment of oncogenic osteomalacia. PMID- 22922157 TI - [Biological therapies in systemic lupus erythematosus]. AB - The prevention of chronic organic damage and complete inhibition of inflammatory activity of the disease are the main goals in the treatment of systemic lupus erythematosus (SLE). Current therapies of SLE are not effective enough and they may cause various serious side effects. Biological therapies, affecting important pathogenetic disturbances in the immunological system of SLE patients, give hope for the development of a new treatment for SLE. Currently the most advanced clinical trials are being conducted with anti-lymphocyte B drugs, such as rituximab, belimumab and epratuzumab. Belimumab as the first biological agent was registered for treatment of the active, seropositive form of SLE. The advances in immunology and rheumatology nowadays raise the hope of finding effective and safe treatment for SLE. In our article we present an overview of data concerning perspectives of biological treatment in SLE. PMID- 22922158 TI - [Role of CEACAM in neutrophil activation]. AB - Neutrophils express many surface adhesion molecules, including CEACAM1, CEACAM3, CEACAM4, CEACAM6 and CEACAM8 glycoproteins, which play an important role in biological functions of neutrophils such as adhesion, phagocytosis, oxidative burst and degranulation. CEACAM3 activates neutrophils and initiates phagocytosis as a result of binding to bacterial Opa protein. In addition, CEACAM1 and CEACAM6 can delay apoptosis. All neutrophil CEACAMs, except for CEACAM3, can stimulate adhesion of neutrophils to endothelium. One CEACAM family member, CEA, which is not expressed by neutrophils, displays strong chemotactic activity, and probably can prime and/or activate neutrophils to adhesion. Induction of CEACAM signaling can be initiated by dimerization of CEACAMs and/or phosphorylation of their cytoplasmic domains. CEACAM signaling is often associated with an increase in the cytoplasmic calcium level. PMID- 22922159 TI - Restless legs syndrome outside the blood-brain barrier--exacerbation by domperidone in Parkinson's disease. AB - INTRODUCTION: Models of dopaminergic function in restless legs focus on central dopaminergic neurons. Domperidone, a peripheral dopamine blocker that cannot cross the blood-brain barrier, is commonly used in Parkinson's disease. After encountering a case of restless legs syndrome that dramatically worsened with domperidone, we assessed whether Parkinson's patients may have exacerbation of restless legs with domperidone. METHODS: From two Parkinson's disease cohorts, we assessed restless legs prevalence according to standard criteria, in patients taking vs. not taking domperidone. Regression analysis was performed, adjusting for age, sex, disease duration, UPDRS, dopaminergic medications and other medications. RESULTS: One hundred eighty four patients were assessed, of whom 46 (25%) had restless legs. Thirteen out of twenty seven (48%) patients on domperidone had restless legs compared to 33/157 (21%) without (p = 0.010). Other medications were not associated with restless legs. CONCLUSION: This unexpected finding suggests that dopaminergic neurons outside of the blood-brain barrier may be important in restless legs syndrome pathophysiology. PMID- 22922160 TI - Antifungal properties of Canavalia ensiformis urease and derived peptides. AB - Ureases (EC 3.5.1.5) are metalloenzymes that hydrolyze urea into ammonia and CO(2). These proteins have insecticidal and fungicidal effects not related to their enzymatic activity. The insecticidal activity of urease is mostly dependent on the release of internal peptides after hydrolysis by insect digestive cathepsins. Jaburetox is a recombinant version of one of these peptides, expressed in Escherichia coli. The antifungal activity of ureases in filamentous fungi occurs at submicromolar doses, with damage to the cell membranes. Here we evaluated the toxic effect of Canavalia ensiformis urease (JBU) on different yeast species and carried out studies aiming to identify antifungal domain(s) of JBU. Data showed that toxicity of JBU varied according to the genus and species of yeasts, causing inhibition of proliferation, induction of morphological alterations with formation of pseudohyphae, changes in the transport of H(+) and carbohydrate metabolism, and permeabilization of membranes, which eventually lead to cell death. Hydrolysis of JBU with papain resulted in fungitoxic peptides (~10 kDa), which analyzed by mass spectrometry, revealed the presence of a fragment containing the N-terminal sequence of the entomotoxic peptide Jaburetox. Tests with Jaburetox on yeasts and filamentous fungi indicated a fungitoxic activity similar to ureases. Plant ureases, such as JBU, and its derived peptides, may represent a new alternative to control medically important mycoses as well as phytopathogenic fungi, especially considering their potent activity in the range of 10(-6)-10(-7)M. PMID- 22922162 TI - Penetration enhancer-containing vesicles: composition dependence of structural features and skin penetration ability. AB - In this work, we focused on how composition and preparation method of vesicles might affect their morphological features and delivery performances. Penetration Enhancer-containing Vesicles, PEVs, vesicles containing a water miscible penetration enhancer (Transcutol(r) P; 10%, 20%, 30% v/v) and encapsulating diclofenac sodium, were formulated and compared with conventional liposomes. A cheap and unpurified commercial mixture of phospholipids, fatty acids, and triglycerides (Phospholipon(r) 50) was used, and the effects of this heterogeneous composition (along with the presence or absence of transcutol and the production method) on vesicle morphology, size, surface charge, drug loading, and stability were investigated. The variations in vesicle structure, bilayer thickness, and number of lamellae were assessed by TEM and Small and Wide Angle X ray Scattering, which also proved the liquid state of the vesicular bilayer. Further, vesicles were evaluated for ex vivo (trans)dermal delivery, and their mode of action was studied performing a pre-treatment test and confocal laser scanning microscopy analyses. Results showed the formation of multi- and unilamellar vesicles that provided improved diclofenac delivery to pig skin, influenced by vesicle lipid composition and structure. Images of the qualitative CLSM analyses support the conclusion that PEVs enhance drug transport by penetrating intact the stratum corneum, thanks to a synergic effect of vesicles and penetration enhancer. PMID- 22922161 TI - Epigenetic obstacles encountered by transcription factors: reprogramming against all odds. AB - Reprogramming of a somatic nucleus to an induced pluripotent state can be achieved in vitro through ectopic expression of Oct4 (Pou5f1), Sox2, Klf4 and c Myc. While the ability of these factors to regulate transcription in a pluripotent context has been studied extensively, their ability to interact with and remodel a somatic genome remains underexplored. Several recent studies have begun to provide mechanistic insights that will eventually lead to a more rational design and improved understanding of nuclear reprogramming. PMID- 22922163 TI - Meta-analysis of fMRI studies of timing in attention-deficit hyperactivity disorder (ADHD). AB - Attention-deficit hyperactivity disorder (ADHD) is associated with deficits in timing functions with, however, inconclusive findings on the underlying neurofunctional deficits. We therefore conducted a meta-analysis of 11 functional magnetic resonance imaging (fMRI) studies of timing in ADHD, comprising 150 patients and 145 healthy controls. Peak coordinates were extracted from significant case-control activation differences as well as demographic, clinical, and methodological variables. In addition, meta-regression analyses were used to explore medication effects. The most consistent deficits in ADHD patients relative to controls were reduced activation in typical areas of timing such as left inferior prefrontal cortex (IFC)/insula, cerebellum, and left inferior parietal lobe. The findings of left fronto-parieto-cerebellar deficits during timing functions contrast with well documented right fronto-striatal dysfunctions for inhibitory and attention functions, suggesting cognitive domain-specific neurofunctional deficits in ADHD. The meta-regression analysis showed that right dorsolateral prefrontal cortex (DLPFC) activation was reduced in medication-naive patients but normal in long-term stimulant medicated patients relative to controls, suggesting potential normalization effects on the function of this prefrontal region with long-term psychostimulant treatment. PMID- 22922166 TI - Interleukin-18: a potent pro-inflammatory cytokine in atherosclerosis. PMID- 22922164 TI - Two functional domains in C. elegans glypican LON-2 can independently inhibit BMP like signaling. AB - Glypicans are multifunctional proteoglycans with regulatory roles in several intercellular signaling pathways. Here, we examine the functional requirements for glypican regulation of bone morphogenetic protein (BMP)-mediated body length in C. elegans. We provide evidence that two parts of C. elegans glypican LON-2 can independently inhibit BMP signaling in vivo: the N-terminal furin protease product and the C-terminal region containing heparan sulfate attachment sequences. While the C-terminal protease product is dispensable for LON-2 minimal core protein activity, it does affect the localization of LON-2. Cleavage of LON 2 into two parts at the conserved furin protease site is not required for LON-2 to inhibit BMP-like signaling. The glycosyl-phosphatidylinositol (GPI) membrane anchor is also not absolutely required for LON-2 activity. Finally, we show that an RGD protein-protein interaction motif in the LON-2 N-terminal domain is necessary for LON-2 core protein activity, suggesting that LON-2 inhibits BMP signaling by acting as a scaffold for BMP and an RGD-binding protein. PMID- 22922167 TI - Postnatal growth hormone deficiency in growing rats causes marked decline in the activity of spinal cord acetylcholinesterase but not butyrylcholinesterase. AB - The effects of growth hormone (GH) deficiency on the developmental changes in the abundance and activity of cholinesterase enzymes were studied in the developing spinal cord (SC) of postnatal rats by measuring the specific activity of acetylcholinesterase (AChE), a marker for cholinergic neurons and their synaptic compartments, and butyrylcholinesterase (BuChE), a marker for glial cells and neurovascular cells. Specific activities of these two enzymes were measured in SC tissue of 21- and 90 day-old (P21, weaning age; P90, young adulthood) GH deficient spontaneous dwarf (SpDwf) mutant rats which lack anterior pituitary and circulating plasma GH, and were compared with SC tissue of normal age-matched control animals. Assays were carried out for AChE and BuChE activity in the presence of their specific chemical inhibitors, BW284C51 and iso-OMPA, respectively. Results revealed that mean AChE activity was markedly and significantly reduced [28% at P21, 49% at P90, (p<0.01)] in the SC of GH deficient rats compared to age-matched controls. GH deficiency had a higher and more significant effect on AChE activity of the older (P90) rats than the younger ones (P21) ones. In contrast, BuChE activity in SC showed no significant changes in GH deficient rats at either of the two ages studied. Results imply that, in the absence of pituitary GH, the postnatal proliferation of cholinergic synapses in the rat SC, a CNS structure, where AChE activity is abundant, is markedly reduced during both the pre- and postweaning periods; more so in the postweaning than preweaning ages. In contrast, the absence of any effects on BuChE activity implies that GH does not affect the development of non-neuronal elements, e.g., glia, as much as the neuronal and synaptic compartments of the developing rat SC. PMID- 22922168 TI - Relationship between strength, power and balance performance in seniors. AB - BACKGROUND: Deficits in strength, power and balance represent important intrinsic risk factors for falls in seniors. OBJECTIVE: The purpose of this study was to investigate the relationship between variables of lower extremity muscle strength/power and balance, assessed under various task conditions. METHODS: Twenty-four healthy and physically active older adults (mean age: 70 +/- 5 years) were tested for their isometric strength (i.e. maximal isometric force of the leg extensors) and muscle power (i.e. countermovement jump height and power) as well as for their steady-state (i.e. unperturbed standing, 10-meter walk), proactive (i.e. Timed Up & Go test, Functional Reach Test) and reactive (i.e. perturbed standing) balance. Balance tests were conducted under single (i.e. standing or walking alone) and dual task conditions (i.e. standing or walking plus cognitive and motor interference task). RESULTS: Significant positive correlations were found between measures of isometric strength and muscle power of the lower extremities (r values ranged between 0.608 and 0.720, p < 0.01). Hardly any significant associations were found between variables of strength, power and balance (i.e. no significant association in 20 out of 21 cases). Additionally, no significant correlations were found between measures of steady-state, proactive and reactive balance or balance tests performed under single and dual task conditions (all p > 0.05). CONCLUSION: The predominately nonsignificant correlations between different types of balance imply that balance performance is task specific in healthy and physically active seniors. Further, strength, power and balance as well as balance under single and dual task conditions seem to be independent of each other and may have to be tested and trained complementarily. PMID- 22922169 TI - Conditions for quantitative evaluation of injured spinal cord by in vivo diffusion tensor imaging and tractography: preclinical longitudinal study in common marmosets. AB - Conventional magnetic resonance imaging (MRI) can detect hemorrhage, edema, syrinx, and spinal cord atrophy, but not axonal disruption after spinal cord injury (SCI). We previously demonstrated that diffusion tensor tractography (DTT) could depict axonal disruption after hemisection SCI in common marmosets. In the present study, to determine the relationship between DTT results and functional recovery after contusive SCI, we performed longitudinal DTT, behavioral, and histological analyses before and after contusive SCI in common marmosets. By comparing the tract fiber estimate depicted by DTT with neuronal fibers labeled with RT97 and SMI-31, anti-neurofilament antibodies, we determined the optimal fractional anisotropy (FA) threshold for fiber tracking to be 0.40. The ratio of the number of tract fiber estimates at the lesion site to the number before SCI, determined by DTT, was significantly correlated with the functional recovery after SCI. Moreover, comparison of the longitudinal pre- and post-SCI FA and axial diffusivity (lambda(||)) values revealed that they decreased after injury at the sites caudal to the lesion epicenter in the corticospinal tract and rostral to the lesion epicenter in the dorsal column. The FA values, then, showed partial recovery in the dorsal column. FA-value-oriented color DTT was used to represent axonal sparing or regeneration of the different tracts. These findings indicated that DTT analysis might be a versatile non-invasive tool for evaluating the axonal disruption after SCI. PMID- 22922170 TI - Reduced translocation of cadmium from roots is associated with increased production of phytochelatins and their precursors. AB - Cadmium (Cd) is a non-essential trace element and its environmental concentrations are approaching toxic levels, especially in some agricultural soils. Understanding how and where Cd is stored in plants is important for ensuring food safety. In this study, we examined two plant species that differ in the distribution of Cd among roots and leaves. Lettuce and barley were grown in nutrient solution under two conditions: chronic (4 weeks) exposure to a low, environmentally relevant concentration (1.0 MUM) of Cd and acute (1 h) exposure to a high concentration (5.0 mM) of Cd. Seedlings grown in solution containing 1.0 MUM CdCl2 did not show symptoms of toxicity and, at this concentration, 77% of the total Cd was translocated to leaves of lettuce, whereas only 24% of the total Cd was translocated to barley leaves. We tested the hypothesis that differential accumulation of Cd in roots and leaves is related to differential concentrations of phytochelatins (PCs), and its precursor peptides. The amounts of PCs and their precursor peptides in the roots and shoots were measured using HPLC. Each of PC2-4 was synthesized in the barley root upon chronic exposure to Cd and did not increase further upon acute exposure. In the case of lettuce, no PCs were detected in the root given either Cd treatment. The high amounts of PCs produced in barley root could have contributed to preferential retention of Cd in barley roots. PMID- 22922171 TI - Decline of health status sub-domains by exacerbations of chronic obstructive pulmonary disease: a prospective survey. AB - BACKGROUND: Exacerbations of chronic obstructive pulmonary disease (COPD) are held responsible for a decline in health status (HS). This may not apply equally to all exacerbations, because different definitions are required for quite different illnesses. Selection of definitions and the sensitivity of the HS instrument may affect results regarding the impact of exacerbations. Sensitivity of a new HS instrument, which covers different and more aspects, has not yet been tested, with respect to exacerbations. OBJECTIVES: Confirmation of the negative HS effect of exacerbations by using a highly differentiated instrument, and to evaluate which aspects of HS are affected most. METHODS: One hundred and sixty eight ambulatory patients with COPD were evaluated prospectively with regard to a wide range of HS aspects, at the beginning and end of a 1-year follow-up. Recording of symptom changes and treatment on monthly diary cards resulted in the identification of event-based exacerbations. HS was assessed via a newly validated instrument integrating both physiological and non-physiological sub domains. Parametric correlations were calculated between exacerbation frequency and HS scores at the end of the study. Partial corre-lations were then explored using HS scores at baseline to correct for prior HS levels. RESULTS: Correlations between -exacerbation frequency and HS sub-domains were found to be frequent, predominantly in non-physiological sub--domains. After correction for hs scores at baseline, only 2 sub-domains (belonging to the main domain 'complaints') remained significantly but weakly correlated. CONCLUSION: Exacerbation frequency and HS show weak correlations after a year, but most of these disappear after correction for prior HS levels. In such exacerbations, aggravated HS probably takes much longer to manifest itself. PMID- 22922172 TI - Vaccine adverse event text mining system for extracting features from vaccine safety reports. AB - OBJECTIVE: To develop and evaluate a text mining system for extracting key clinical features from vaccine adverse event reporting system (VAERS) narratives to aid in the automated review of adverse event reports. DESIGN: Based upon clinical significance to VAERS reviewing physicians, we defined the primary (diagnosis and cause of death) and secondary features (eg, symptoms) for extraction. We built a novel vaccine adverse event text mining (VaeTM) system based on a semantic text mining strategy. The performance of VaeTM was evaluated using a total of 300 VAERS reports in three sequential evaluations of 100 reports each. Moreover, we evaluated the VaeTM contribution to case classification; an information retrieval-based approach was used for the identification of anaphylaxis cases in a set of reports and was compared with two other methods: a dedicated text classifier and an online tool. MEASUREMENTS: The performance metrics of VaeTM were text mining metrics: recall, precision and F-measure. We also conducted a qualitative difference analysis and calculated sensitivity and specificity for classification of anaphylaxis cases based on the above three approaches. RESULTS: VaeTM performed best in extracting diagnosis, second level diagnosis, drug, vaccine, and lot number features (lenient F-measure in the third evaluation: 0.897, 0.817, 0.858, 0.874, and 0.914, respectively). In terms of case classification, high sensitivity was achieved (83.1%); this was equal and better compared to the text classifier (83.1%) and the online tool (40.7%), respectively. CONCLUSION: Our VaeTM implementation of a semantic text mining strategy shows promise in providing accurate and efficient extraction of key features from VAERS narratives. PMID- 22922174 TI - Extra-corporeal cardiopulmonary resuscitation--miracle cure or expensive futility? PMID- 22922173 TI - Clinical decision support for genetically guided personalized medicine: a systematic review. AB - OBJECTIVE: To review the literature on clinical decision support (CDS) for genetically guided personalized medicine (GPM). MATERIALS AND METHODS: MEDLINE and Embase were searched from 1990 to 2011. The manuscripts included were summarized, and notable themes and trends were identified. RESULTS: Following a screening of 3416 articles, 38 primary research articles were identified. Focal areas of research included family history-driven CDS, cancer management, and pharmacogenomics. Nine randomized controlled trials of CDS interventions for GPM were identified, seven of which reported positive results. The majority of manuscripts were published on or after 2007, with increased recent focus on genotype-driven CDS and the integration of CDS within primary clinical information systems. DISCUSSION: Substantial research has been conducted to date on the use of CDS to enable GPM. In a previous analysis of CDS intervention trials, the automatic provision of CDS as a part of routine clinical workflow had been identified as being critical for CDS effectiveness. There was some indication that CDS for GPM could potentially be effective without the CDS being provided automatically, but we did not find conclusive evidence to support this hypothesis. CONCLUSION: To maximize the clinical benefits arising from ongoing discoveries in genetics and genomics, additional research and development is recommended for identifying how best to leverage CDS to bridge the gap between the promise and realization of GPM. PMID- 22922175 TI - Challenges in using high-fidelity simulation to improve learning and patient safety. PMID- 22922176 TI - The impact of therapeutic hypothermia as adjunctive therapy in a regional primary PCI program. AB - BACKGROUND: Therapeutic hypothermia (TH) is associated with improved neurologic outcomes in comatose survivors of out-of-hospital cardiac arrest (OHCA). There are currently limited data on the outcomes of patients presenting with resuscitated OHCA in the setting of ST-segment elevation myocardial infarction (STEMI). We conducted a retrospective study to determine the outcomes of patients treated with TH for OHCA in a large regionalized STEMI program. METHODS: Patients referred for primary PCI and TH between July 2004 and April 2011 were identified from the University of Ottawa Heart Institute STEMI database. The primary endpoint was survival to hospital discharge with sufficient neurologic recovery to enable discharge home. RESULTS: Among 2467 consecutive patients referred for primary PCI, we identified 50 patients treated with TH following OHCA. Forty-nine underwent PCI, of which 47 (96%) received a stent. Median door-to-balloon time was 113min (IQR 91-151). Patients with good neurologic recovery were younger, mean 51 +/- 9 years versus 64 +/- 12, p<0.001, and had higher baseline creatinine clearance, 70 +/- 19 mL/min/1.73 m(2) versus 53 +/- 23 mL/min/1.73 m(2), p=0.007. The primary endpoint of survival with sufficient neurologic recovery to enable discharge home was reached in 30 patients (60%). Four survivors required levels of assistance that precluded discharge home. CONCLUSIONS: Therapeutic hypothermia in conjunction with primary PCI is associated with a favorable neurologic outcome in the majority of STEMI patients surviving OHCA. Our results suggest that TH is an important adjunctive therapy for STEMI patients suffering OHCA. PMID- 22922177 TI - Factors influencing the decision to ICD implantation in survivors of OHCA and its influence on long term survival. AB - BACKGROUND: Knowledge is insufficient of the long-term benefit of an implantable cardioverter defibrillator (ICD) after out of hospital cardiac arrest (OHCA). AIM: To describe the use and factors of importance for outcome in relation to ICD use among survivors of ventricular fibrillation (VF). METHODS: In consecutive patients discharged alive after OHCA in Gothenburg between 1988 and 2008 the long term prognosis was followed. RESULTS: In all, there were 5443 OHCAs of which 1489 (27%) were hospitalized alive. Of those, 495 (33%) were discharged alive, of which 390 (79%) had shockable rhythm. The use of ICDs increased, but only 58 of 390 (15%) had an ICD. Among patients who received an ICD, the 2-year mortality was 2%, versus 25% of those who did not (p<0.0001). In follow-up (mean 5.5 years; maximum 10 years), the use of an ICD showed a borderline association with mortality (adjusted hazard ratio 0.49; 95% confidence interval, 024-1.01; p=0.052). Patients who had ICD were younger and had better cerebral function compared with patients without. Predictors for mortality were cerebral function at discharge, age, history of heart failure and myocardial infarction and no coronary angiography during hospitalization. CONCLUSION: Among survivors of OHCA caused by VT/VF who had ICD during hospitalization only 2% died during the subsequent 2 years. The use of ICDs was low but increasing. Factors of importance for mortality were cerebral function at the time of discharge, age, history of heart failure and myocardial infarction and no coronary angiography during hospitalization. PMID- 22922178 TI - The neuropsychological sequelae of a 14-year-old girl following successful resuscitation from ventricular fibrillation and collapse secondary to butane gas inhalation. PMID- 22922179 TI - Effect of antifungal genes expressed in transgenic pea (Pisum sativum L.) on root colonization with Glomus intraradices. AB - Pathogenic fungi have always been a major problem in agriculture. One of the effective methods for controlling pathogen fungi to date is the introduction of resistance genes into the genome of crops. It is interesting to find out whether the induced resistance in crops will have a negative effect on non-target organisms such as root colonization with the AM fungi. The objective of the present research was to study the influence of producing antifungal molecules by four transgenic pea (Pisum sativum L.) lines expressing PGIP gene from raspberry, VST-stilbene synthase from vine, a hybrid of PGIP/VST and bacterial Chitinase gene (Chit30) from Streptomyces olivaceoviridis respectively on the colonization potential of Glomus intraradices. Four different experiments were done in greenhouse and climate chamber, colonization was observed in all replications. The following parameters were used for evaluation: frequency of mycorrhization, the intensity of mycorrhization, the average presence of arbuscules within the colonized areas and the presence of arbuscules in the whole root system which showed insignificant difference between transgenic and non-transgenic plants. The root/shoot ratio exhibited different values according to the experiment condition. Compared with negative non-transgenic control all transgenic lines showed the ability to establish symbiosis and the different growth parameters had insignificant effect due to mycorrhization. The results of the present study proved that the introduced pathogen resistance genes did not affect the mycorrhization allocations in pea. PMID- 22922181 TI - Probing the probe: AFM tip-profiling via nanotemplates to determine Hamaker constants from phase-distance curves. AB - A method to determine the van der Waals forces from phase-distance curves recorded by atomic force microscopy (AFM) in tapping mode is presented. The relationship between the phase shift and the tip-sample distance is expressed as a function of the product of the Hamaker constant by tip radius. Silica-covered silicon tips are used to probe silica-covered silicon substrate in dry conditions to avoid capillary effects. Tips being assumed spherical, radii are determined in situ by averaging profiles recorded in different directions on hematite nanocrystals acting as nanotemplates, thus accounting for tip anisotropy. Through a series of reproducible measurements performed with tips of various radii (including the in-situ characterization of a damaged tip), a value of (6.3+/ 0.4)*10(-20) J is found for the Hamaker constant of interacting silica surfaces in air, in good agreement with tabulated data. The results demonstrate that the onset of the tip-surface interaction is dominated by the van der Waals forces and that the total force can be modeled in the framework of the harmonic approximation. Based on the tip radius and the Hamaker constant associated to the tip-substrate system, the model is quite flexible. Once the Hamaker constant is known, a direct estimate of the tip size can be achieved whereas when the tip size is known, a quantitative evaluation of the van der Waals force becomes possible on different substrates with a spatial resolution at the nanoscale. PMID- 22922180 TI - Reduced exposure evaluation of an Electrically Heated Cigarette Smoking System. Part 2: Smoke chemistry and in vitro toxicological evaluation using smoking regimens reflecting human puffing behavior. AB - Chemical analysis of up to 49 harmful and potentially harmful constituents (HPHC) in mainstream smoke, in vitro cytotoxicity of the particulate and gas/vapor phase of mainstream smoke determined in the Neutral Red Uptake assay, and in vitro bacterial mutagenicity of the particulate phase determined in the Salmonella typhimurium Reverse Mutation (Ames) assay are reported for three Electrically Heated Cigarette Smoking System (EHCSS) series-K cigarettes, the University of Kentucky Reference Cigarette 2R4F, and a number of comparator commercial conventional lit-end cigarettes (CC) under ISO machine-smoking conditions and a total of 25 additional smoking regimens reflecting 'human puffing behavior' (HPB). The smoking machines were set to deliver nicotine yields for the EHCSS and comparator CC derived from the 10th percentile to the 90th percentile of nicotine uptake distributions in smokers determined in two clinical studies. Duplication of the smoking intensity 'per cigarette' on a smoking machine may provide an insight into product performance that is directly relevant to obtaining scientific evidence for reduced exposure substantiation based on mainstream cigarette smoke HPHC-to-nicotine regressions. The reported data support an overall evaluation of reduced exposure to HPHC and biological activity. PMID- 22922182 TI - Perioperative stroke risk in nonvascular surgery. AB - BACKGROUND: Perioperative stroke is an ischemic or hemorrhagic cerebrovascular accident that can arise intraoperatively or from 3 to 30 days after surgery. This relatively rare complication deserves attention because of its high mortality and serious disability, the latter of which can lead to prolonged hospital stay as well as discharge to long-term care facilities. The aim of this article was to review the literature on perioperative stroke in general surgery, excluding carotid and cardiac surgeries because these have already been thoroughly investigated in previous papers. METHODS: A search strategy was designed to identify all relevant studies on perioperative stroke in the English language. This search was restricted to papers published up to December 5, 2011. Studies were initially identified from the Medline/PubMed database, EMBASE and the Cochrane Database using the search terms 'surgery', 'perioperative stroke', 'risk factors', 'anticoagulation treatment' and 'antiplatelet treatment'. RESULTS: The incidence of perioperative stroke among patients who undergo nonvascular surgery is reported to be about 0.08-0.7%. This depends on the type and complexity of the surgical procedure along with patient risk factors. The reported perioperative mortality is 18-26%. One of the main issues is the management of patients taking anticoagulant or antiplatelet drugs, as the risk of bleeding has to be counterbalanced with the risk of arterial thrombosis due to discontinuation. Additionally, the presence of symptomatic carotid stenosis should be taken into account in the risk evaluation. CONCLUSIONS: To date, current guidelines are incomplete regarding the management of patients with vascular disease undergoing nonvascular surgery. It is recommended to stop oral anticoagulation approximately 5 days before major surgery to adequately allow the INR to normalize, and at the same time subcutaneous low-molecular-weight heparin or intravenous unfractionated heparin should be started. Regarding new anticoagulants, dabigatran does not need to be withheld for minor procedures. Currently, there are no clear recommendations on the use of rivaroxaban and apixaban. Data concerning the management of patients undergoing antiplatelet therapy are lacking. To date, neurologists discourage the perioperative withdrawal of aspirin (acetylsalicylic acid, ASA) especially in patients in secondary prevention. The 'Antiplatelet Agents in the Perioperative Management of Patients Trial' is ongoing to assess the safety and determine the optimal use of ASA in the perioperative management of patients undergoing general and abdominal surgery. In the meantime an individualized, accurate, multidisciplinary (surgical, neurological, cardiological and anesthesiological) risk/benefit assessment remains the best basis for treatment decision. PMID- 22922183 TI - Green-carding the referee, and Haldane's spell. PMID- 22922184 TI - Monotremes and marsupials: comparative models to better understand the function of milk. PMID- 22922185 TI - Making sense of ocean biota: how evolution and biodiversity of land organisms differ from that of the plankton. AB - The oceans cover 70% of the planet's surface, and their planktonic inhabitants generate about half the global primary production, thereby playing a key role in modulating planetary climate via the carbon cycle. The ocean biota have been under scientific scrutiny for well over a century, and yet our understanding of the processes driving natural selection in the pelagic environment - the open water inhabited by drifting plankton and free-swimming nekton - is still quite vague. Because of the fundamental differences in the physical environment, pelagic ecosystems function differently from the familiar terrestrial ecosystems of which we are a part. Natural selection creates biodiversity but understanding how this quality control of random mutations operates in the oceans - which traits are selected for under what circumstances and by which environmental factors, whether bottom-up or top-down - is currently a major challenge. Rapid advances in genomics are providing information, particularly in the prokaryotic realm, pertaining not only to the biodiversity inventory but also functional groups. This essay is dedicated to the poorly understood tribes of planktonic protists (unicellular eukaryotes) that feed the ocean's animals and continue to run the elemental cycles of our planet. It is an attempt at developing a conceptually coherent framework to understand the course of evolution by natural selection in the plankton and contrast it with the better-known terrestrial realm. I argue that organism interactions, in particular co-evolution between predators and prey (the arms race), play a central role in driving evolution in the pelagic realm. Understanding the evolutionary forces shaping ocean biota is a prerequisite for harnessing plankton for human purposes and also for protecting the oceanic ecosystems currently under severe stress from anthropogenic pressures. PMID- 22922186 TI - What history tells us XXVIII. What is really new in the current evolutionary theory of cancer? PMID- 22922187 TI - Morse potential in DNA molecule - an experiment proposal. AB - We rely on the helicoidal Peyrard-Bishop model for DNA dynamics. Interaction between nucleotides at a same site belonging to different strands is modelled by a Morse potential energy. This potential depends on two parameters that are different for AT and CG pairs, which is a possible source for inhomogeneity. It was shown recently (Zdravkovic and Sataric 2011) that certain values of these parameters bring about a negligible influence of inhomogeneity on the solitonic dynamics. We propose an experiment that should be carried out in order to determine the values of both of these parameters. PMID- 22922188 TI - Recombinant E. coli expressing Vitreoscilla haemoglobin prefers aerobic metabolism under microaerobic conditions: a proteome-level study. AB - Vitreoscilla haemoglobin (VHb) expression in heterologous host was shown to enhance growth and oxygen utilization capabilities under oxygen-limited conditions. The exact mechanism by which VHb enhances the oxygen utilization under oxygen-limiting conditions is still unknown. In order to understand the role of VHb in promoting oxygen utilization, changes in the total protein profile of E. coli expressing the vgb gene under its native promoter was analysed. Two dimensional difference gel electrophoresis (2D DIGE) was employed to quantify the differentially expressed proteins under oxygen-limiting conditions. Overexpression of proteins involved in aerobic metabolic pathways and suppression of proteins involved in non-oxidative metabolic pathways shown in this study indicates that the cells expressing VHb prefer aerobic metabolic pathways even under oxygen limitation. Under these conditions, the expression levels of proteins involved in central metabolic pathways, cellular adaptation and cell division were also found to be altered. These results imply that Vitreoscilla haemoglobin expression alters aerobic metabolism specifically, in addition to altering proteins involved in other pathways, the significance of which is not clear as of now. PMID- 22922189 TI - Changes in membrane lipids and carotenoids during light acclimation in a marine cyanobacterium Synechococcus sp. AB - Time course of carotenoid and membrane lipid variation during high light (HL) acclimation (about 85 meu mol m-2 s-1), after transfer from low light (LL) (5-10 meu mol m-2 s-1), was determined in a marine Synechococcus strain. Highperformance liquid chromatography (HPLC) coupled to diode array detector (DAD) or electrospray ionization mass spectrometry (ESI-MS) was used for compound separation and detection. Myxoxanthophyll rose within a time interval of 8 h to 24 h after the onset of exposure to HL. Beta -carotene content started to decrease after 4 h of the onset of exposure to HL. Zeaxanthin content rose with exposure to HL, but it was only significant after 24 h of exposure. Carotenoid changes are in agreement with a coordinated activity of the enzymes of the myxoxanthophyll biosynthetic pathway, with no rate-limiting intermediate steps. Lipid analysis showed all species with a C18:3/C16:0 composition increased their content, the changes of PG (18:3/16:0) and MGDG(18:3/16:0) being primarily significant. Major lipid changes were also found to occur within 24 h. These changes might suggest reduction and reorganization of the thylakoid membrane structure. Hypotheses are also drawn on the role played by lipid molecule shape and their possible effect in membrane fluidity and protein accommodation. PMID- 22922190 TI - Molecular analysis of gut microbiota in obesity among Indian individuals. AB - Obesity is a consequence of a complex interplay between the host genome and the prevalent obesogenic factors among the modern communities. The role of gut microbiota in the pathogenesis of the disorder was recently discovered; however, 16S-rRNA-based surveys revealed compelling but community-specific data. Considering this, despite unique diets, dietary habits and an uprising trend in obesity, the Indian counterparts are poorly studied. Here, we report a comparative analysis and quantification of dominant gut microbiota of lean, normal, obese and surgically treated obese individuals of Indian origin. Representative gut microbial diversity was assessed by sequencing fecal 16S rRNA libraries for each group (n=5) with a total of over 3000 sequences. We detected no evident trend in the distribution of the predominant bacterial phyla, Bacteroidetes and Firmicutes. At the genus level, the bacteria of genus Bacteroides were prominent among the obese individuals, which was further confirmed by qPCR (P less than 0.05). In addition, a remarkably high archaeal density with elevated fecal SCFA levels was also noted in the obese group. On the contrary, the treated-obese individuals exhibited comparatively reduced Bacteroides and archaeal counts along with reduced fecal SCFAs. In conclusion, the study successfully identified a representative microbial diversity in the Indian subjects and demonstrated the prominence of certain bacterial groups in obese individuals; nevertheless, further studies are essential to understand their role in obesity. PMID- 22922191 TI - The hnRNP A1 homolog Hrp36 is essential for normal development, female fecundity, omega speckle formation and stress tolerance in Drosophila melanogaster. AB - Hrp36/Hrb87F is one of the most abundant and well-characterized hnRNP A homolog in Drosophila and is shown to have roles in regulation of alternative splicing, heterochromatin formation, neurodegeneration, etc. Yet, hrp36 null individuals were reported to be viable and without any apparent phenotype, presumably because of overlapping functions provided by Hrp38 and related proteins. Here we show that loss of both copies of hrp36 gene slows down development with significant reduction in adult life span, decreased female fecundity and high sensitivity to starvation and thermal stresses. In the absence of Hrp36, the nucleoplasmic omega speckles are nearly completely disrupted. The levels of nuclear matrix protein Megator and the chromatin remodeller ISWI are significantly elevated in principal cells of larval Malpighian tubules, which also display additional endoreplication cycles and good polytene chromosomes. We suggest that besides the non-coding hsr omega-n transcripts, the Hrp36 protein is also a core constituent of omega speckles. The heat-shock-induced association of other hnRNPs at the hsr omega locus is affected in hrp36 null cells, which may be one of the reasons for their high sensitivity to cell stress. Therefore, in spite of the functional redundancy provided by Hrp38, Hrp36 is essential for normal development and for survival under conditions of stress. PMID- 22922193 TI - The present Pyrenean population of bearded vulture (Gypaetus barbatus): its genetic characteristics. AB - The Pyrenean population of the endangered bearded vulture (Gypaetus barbatus) is the largest natural population in Europe. In this study, its current genetic variability was assessed using 110 animals of the recent population in order to know what the present situation. Sex identification by DNA methodology in the 110 bearded vultures, mitochondrial DNA (mtDNA) and eight microsatellite markers in 87 bearded vultures have been analysed. Our results for sex identification present a number of 49 males and 61 females; no significant differences for number of males and females in this population have been observed. mtDNA studies indicate that nucleotide and haplotype diversities and number of variable sites were low. Tajima's D test and Fu and Li's D* and F* tests suggest that mutations are selectively neutral and the population is expanding. A mean number of alleles per locus and a mean observed heterozygosity have been obtained by microsatellite analysis. FIS is not high, and inbreeding depression could be discarded in the near future. The results suggest that the Pyrenean population of bearded vultures have to be controlled in order to avoid the loss of genetic variability. This data should be taken into account when considering conservation plans for the species. PMID- 22922192 TI - Effect of chronic exposure to aspartame on oxidative stress in the brain of albino rats. AB - This study was aimed at investigating the chronic effect of the artificial sweetener aspartame on oxidative stress in brain regions of Wistar strain albino rats. Many controversial reports are available on the use of aspartame as it releases methanol as one of its metabolite during metabolism. The present study proposed to investigate whether chronic aspartame (75 mg/kg) administration could release methanol and induce oxidative stress in the rat brain. To mimic the human methanol metabolism, methotrexate (MTX)-treated rats were included to study the aspartame effects. Wistar strain male albino rats were administered with aspartame orally and studied along with controls and MTX-treated controls. The blood methanol level was estimated, the animal was sacrificed and the free radical changes were observed in brain discrete regions by assessing the scavenging enzymes, reduced glutathione, lipid peroxidation (LPO) and protein thiol levels. It was observed that there was a significant increase in LPO levels, superoxide dismutase (SOD) activity, GPx levels and CAT activity with a significant decrease in GSH and protein thiol. Moreover, the increases in some of these enzymes were region specific. Chronic exposure of aspartame resulted in detectable methanol in blood. Methanol per se and its metabolites may be responsible for the generation of oxidative stress in brain regions. PMID- 22922194 TI - Enantioselective hydrolysis of epichlorohydrin using whole Aspergillus niger ZJB 09173 cells in organic solvents. AB - The enantioselective hydrolysis of racemic epichlorohydrin for the production of enantiopure (S)-epichlorohydrin using whole cells of Aspergillus niger ZJB-09173 in organic solvents was investigated. Cyclohexane was used as the reaction medium based on the excellent enantioselectivity of epoxide hydrolase from A. niger ZJB- 09173 in cyclohexane. However, cyclohexane had a negative effect on the stability of epoxide hydrolase from A. niger ZJB-09173. In the cyclohexane medium, substrate inhibition, rather than product inhibition of catalysis, was observed in the hydrolysis of racemic epichlorohydrin using A. niger ZJB-09173. The racemic epichlorohydrin concentration was markedly increased by continuous feeding of substrate without significant decline of the yield. Ultimately, 18.5% of (S)-epichlorohydrin with 98 percent enantiomeric excess from 153.6 mM of racemic epichlorohydrin was obtained by the dry cells of A. niger ZJB-09173, which was the highest substrate concentration in the production of enantiopure (S)-epichlorohydrin by epoxide hydrolases using an organic solvent medium among the known reports. PMID- 22922195 TI - Oxyradicals and PSII activity in maize leaves in the absence of UV components of solar spectrum. AB - The regulation of oxyradicals and PSII activity by UV-B (280-315 nm) and UV-A (315-400 nm) components were investigated in the leaves of maize [Zea mays L. var: HQPM.1]. The impact of ambient UV radiation on the production of superoxide (O(2)(.-)) and hydroxyl ((.)OH) radicals were analysed in the leaves of 20-day old plants. The amount of O(2)(.-) and (.)OH radicals and the radical scavenging activity were significantly higher in the leaves exposed to ambient UV radiation as compared to the leaves of the plants grown under UV exclusion filters. Smaller amount of oxyradicals in the leaves of UV excluded plants was accompanied by a substantial increase in quantum yield of electron transport (phi(Eo)), rate of electron transport (psi(o)) and performance index (PI(ABS)), as indicated by chlorophyll a fluorescence transient. Although higher amounts of oxyradicals invoked higher activity of antioxidant enzymes like superoxide dismutase and peroxidase under ambient UV, they also imposed limitation on the photosynthetic efficiency of PSII. Exclusion of UV components (UV-B 280-315 nm; UV-A 315-400 nm) translated to enhanced photosynthesis, growth and biomass. Thus, solar UV components, especially in the tropical region, could be a major limiting factor in the photosynthetic efficiency of the crop plants. PMID- 22922196 TI - Ion distribution measured by electron probe X-ray microanalysis in apoplastic and symplastic pathways in root cells in sunflower plants grown in saline medium. AB - Little is known about how salinity affects ions distribution in root apoplast and symplast. Using x-ray microanalysis, ions distribution and the relative contribution of apoplastic and symplastic pathways for delivery of ions to root xylem were studied in sunflower plants exposed to moderate salinity (EC=6). Cortical cells provided a considerably extended Na(+) and Cl(-) storage facility. Their contents are greater in cytoplasm (root symplast) as compared to those in intercellular spaces (root apoplast). Hence, in this level of salinity, salt damage in sunflower is not dehydration due to extracellular accumulation of sodium and chloride ions, as suggested in the Oertli hypothesis. On the other hand, reduction in calcium content due to salinity in intercellular space is less than reduction in the cytoplasm of cortical cells. It seems that sodium inhibits the radial movement of calcium in symplastic pathway more than in the apoplastic pathway. The cell wall seems to have an important role in providing calcium for the apoplastic pathway. Redistribution of calcium from the cell wall to intercellular space is because of its tendency towards xylem through the apoplastic pathway. This might be a strategy to enhance loading of calcium to xylem elements and to reduce calcium deficiency in young leaves under salinity. This phenomenon may be able to increase salt tolerance in sunflower plants. Supplemental calcium has been found to be effective in reducing radial transport of Na(+) across the root cells and their loading into the xylem, but not sodium absorption. Supplemental calcium enhanced Ca(2+) uptake and influx into roots and transport to stele. PMID- 22922197 TI - Simple luminosity normalization of greenness, yellowness and redness/greenness for comparison of leaf spectral profiles in multi-temporally acquired remote sensing images. AB - Observation of leaf colour (spectral profiles) through remote sensing is an effective method of identifying the spatial distribution patterns of abnormalities in leaf colour, which enables appropriate plant management measures to be taken. However, because the brightness of remote sensing images varies with acquisition time, in the observation of leaf spectral profiles in multi temporally acquired remote sensing images, changes in brightness must be taken into account. This study identified a simple luminosity normalization technique that enables leaf colours to be compared in remote sensing images over time. The intensity values of green and yellow (green+red) exhibited strong linear relationships with luminosity (R2 greater than 0.926) when various invariant rooftops in Bangkok or Tokyo were spectralprofiled using remote sensing images acquired at different time points. The values of the coefficient and constant or the coefficient of the formulae describing the intensity of green or yellow were comparable among the single Bangkok site and the two Tokyo sites, indicating the technique's general applicability. For single rooftops, the values of the coefficient of variation for green, yellow, and red/green were 16% or less (n=6 11), indicating an accuracy not less than those of well-established remote sensing measures such as the normalized difference vegetation index. After obtaining the above linear relationships, raw intensity values were normalized and a temporal comparison of the spectral profiles of the canopies of evergreen and deciduous tree species in Tokyo was made to highlight the changes in the canopies' spectral profiles. Future aspects of this technique are discussed herein. PMID- 22922198 TI - Transcriptome response to nitrogen starvation in rice. AB - Nitrogen is an essential mineral nutrient required for plant growth and development. Insufficient nitrogen (N) supply triggers extensive physiological and biochemical changes in plants. In this study, we used Affymetrix GeneChip rice genome arrays to analyse the dynamics of rice transcriptome under N starvation. N starvation induced or suppressed transcription of 3518 genes, representing 10.88 percent of the genome. These changes, mostly transient, affected various cellular metabolic pathways, including stress response, primary and secondary metabolism, molecular transport, regulatory process and organismal development. 462 or 13.1 percent transcripts for N starvation expressed similarly in root and shoot. Comparative analysis between rice and Arabidopsis identified 73 orthologous groups that responded to N starvation, demonstrated the existence of conserved N stress coupling mechanism among plants. Additional analysis of transcription profiles of microRNAs revealed differential expression of miR399 and miR530 under N starvation, suggesting their potential roles in plant nutrient homeostasis. PMID- 22922199 TI - Metabolic response to exogenous ethanol in yeast: an in vivo statistical total correlation NMR spectroscopy approach. AB - In vivo NMR spectroscopy, together with selectively 13C-labelled substrates and 'statistical total correlation spectroscopy' analysis (STOCSY), are valuable tools to collect and interpret the metabolic responses of a living organism to external stimuli. In this study, we applied this approach to evaluate the effects of increasing concentration of exogenous ethanol on the Saccharomyces cerevisiae fermentative metabolism. We show that the STOCSY analysis correctly identifies the different types of correlations among the enriched metabolites involved in the fermentation, and that these correlations are quite stable even in presence of a stressing factor such as the exogenous ethanol. PMID- 22922200 TI - Molecular characterization of 'Bhut Jolokia' the hottest chilli. AB - The northeast region of India, considered as 'hot spot' of biodiversity, having unique ecological environment with hot and high-humidity conditions, has given rise to the world's hottest chilli, 'Bhut Jolokia', which is at least two times hotter than Red Savina Habanero in terms of Scoville heat units (SHU). This study was undertaken to determine the distinctiveness of 'Bhut Jolokia' from Capsicum frutescens or Capsicum chinense through sequencing of the ribosomal RNA (rRNA) gene-internal transcribed ((ITS) region along with its phylogenetic analysis. Although a compensatory base change (CBC) in the ITS2 region was not observed between the closely related species of C. frutescens and C. chinense when compared with Bhut Jolokia; phylogenetic analysis using ITS1, 5.8S and ITS2 sequences indicated a distinct clade for all the accessions of 'Bhut Joloikia', while C. frutescens and C. chinense occupied discrete lineages. Further, a unique 13-base deletion was observed in all the representative accessions of 'Bhut Jolokia', making it distinct from all other members within the genus and beyond. The degree of genetic variations along with its extreme pungency might be related to ambient environmental factors of northeastern India. PMID- 22922201 TI - Cocos sahnii Kaul: a Cocos nucifera L.-like fruit from the Early Eocene rainforest of Rajasthan, western India. AB - Cocos sahnii Kaul, a fossil palm fruit, is validated and described from the Fuller's earth deposits of Kapurdi village of Rajasthan considered as Early Eocene in age. The fossil best resembles the genus Cocos, particularly Cocos nucifera L., which is now a common coastal element thriving in highly moist conditions. The recovery of this coconut-like fruit, along with earlier described evergreen taxa from the same formation, suggests the existence of typical tropical, warm and humid coastal conditions during the depositional period. The present arid to semi-arid climatic conditions occurring in Rajasthan indicate drastic climate change in the region during the Cenozoic. The possible time for the onset of aridity in the region which caused the total eradication of semi evergreen to evergreen forests is discussed, as well as the palaeobiogeography of coconuts. PMID- 22922202 TI - Emergent patterns of social organization in captive Cercocebus torquatus: testing the GrooFiWorld agent-based model. AB - We empirically applied the GrooFiWorld agent-based model (Puga-Gonzalez et al. 2009) in a group of captive redcapped mangabeys (Cercocebus torquatus). We analysed several measurements related to aggression and affiliative patterns. The group adopted a combination of despotic and egalitarian behaviours resulting from the behavioural flexibility observed in the Cercopithecinae subfamily. Our study also demonstrates that the GrooFiWorld agent-based model can be extended to other members of the Cercopithecinae subfamily generating parsimonious hypotheses related to the social organization. PMID- 22922203 TI - BIND - an algorithm for loss-less compression of nucleotide sequence data. AB - Recent advances in DNA sequencing technologies have enabled the current generation of life science researchers to probe deeper into the genomic blueprint. The amount of data generated by these technologies has been increasing exponentially since the last decade. Storage, archival and dissemination of such huge data sets require efficient solutions, both from the hardware as well as software perspective. The present paper describes BIND-an algorithm specialized for compressing nucleotide sequence data. By adopting a unique 'block-length' encoding for representing binary data (as a key step), BIND achieves significant compression gains as compared to the widely used general purpose compression algorithms (gzip, bzip2 and lzma). Moreover, in contrast to implementations of existing specialized genomic compression approaches, the implementation of BIND is enabled to handle non-ATGC and lowercase characters. This makes BIND a loss less compression approach that is suitable for practical use. More importantly, validation results of BIND (with real-world data sets) indicate reasonable speeds of compression and decompression that can be achieved with minimal processor/ memory usage. BIND is available for download at http://metagenomics.atc.tcs.com/compression/BIND. No license is required for academic or non-profit use. PMID- 22922204 TI - Begomovirus research in India: a critical appraisal and the way ahead. AB - Begomoviruses are a large group of whitefly-transmitted plant viruses containing single-stranded circular DNA encapsidated in geminate particles. They are responsible for significant yield losses in a wide variety of crops in India. Research on begomoviruses has focussed on the molecular characterization of the viruses, their phylogenetic analyses, infectivities on host plants, DNA replication, transgenic resistance, promoter analysis and development of virus based gene silencing vectors. There have been a number of reports of satellite molecules associated with begomoviruses. This article aims to summarize the major developments in begomoviral research in India in the last approximately 15 years and identifies future areas that need more attention. PMID- 22922206 TI - Lineage-specific growth inhibition of NK cell lines by FOXO3 in association with Akt activation status. AB - FOXO3 and PRDM1 are located on 6q21, one of the most frequently deleted regions among natural killer (NK) cell neoplasms. We previously demonstrated that forced expression of each gene suppresses the proliferation of NK cell lines with the 6q deletion. In this study, the forced expression of FOXO3 or PRDM1 was performed in various cell lines to clarify these suppressive effects. Forced expression of PRDM1 suppressed the proliferation of not only NK cell lines, but also other broad lineage cell lines. On the other hand, forced expression of FOXO3 was only effective on NK cell lines. FOXO3 functions as a transcriptional factor when it is localized in nuclei. Akt is known to induce cytoplasmic localization of FOXO3 as a result of phosphorylation. Transduced FOXO3 was predominantly localized in nuclei of NK cell lines, while it was localized in the cytoplasm of all non-NK cell lines. NK cell lines showed significantly lower Akt activity compared to other lineage cell lines. The low Akt activity and nucleic localization of FOXO3 in NK cell neoplasms seemed to cause NK cell-specific suppression. These findings indicate the "functional lineage specificity" of FOXO3 and the possibility for NK cell-specific gene therapy with minimal unexpected effects. PMID- 22922205 TI - Engineering influenza viral vectors. AB - The influenza virus is a respiratory pathogen with a negative-sense, segmented RNA genome. Construction of recombinant influenza viruses in the laboratory was reported starting in the 1980s. Within a short period of time, pioneer researchers had devised methods that made it possible to construct influenza viral vectors from cDNA plasmid systems. Herein, we discuss the evolution of influenza virus reverse genetics, from helper virus-dependent systems, to helper virus-independent 17-plasmid systems, and all the way to 3- and 1- plasmid systems. Successes in the modification of different gene segments for various applications, including vaccine and gene therapies are highlighted. PMID- 22922207 TI - PDCD2 knockdown inhibits erythroid but not megakaryocytic lineage differentiation of human hematopoietic stem/progenitor cells. AB - Programmed cell death-2 (PDCD2) protein is enriched in embryonic, hematopoietic, and neural stem cells, however, its function in stem/progenitor cell differentiation is unclear. We investigated the effects of PDCD2 knockdown on the development and differentiation of hematopoietic progenitor cells (HPC). CD34(+) cells derived from normal human bone marrow and K562 leukemic cells were effectively transduced with short-hairpin RNA to knockdown PDCD2. Colony-forming assays were used to investigate the effects of PDCD2 loss on HPC clonogenic potential and on 12-O-tetradecanoyl-phorbol-13-acetate-and arabinofuranosylcytosine-induced terminal differentiation. In CD34(+) clonogenic progenitors, PDCD2 knockdown decreased the total number of colony-forming units, increased the number of colony-forming units-granulocyte-erythroid-macrophage megakaryocyte and burst-forming unit-erythroid primitive colonies, and decreased the number of burst-forming unit-erythroid mature colonies. Similar results were observed in K562 cells, suggesting that PDCD2 is important for HPC differentiation and/or survival, and for erythroid lineage commitment. Furthermore, 12-O-tetradecanoyl-phorbol-13-acetate-induced megakaryocytic differentiation and proliferation of K562 cells was not affected by PDCD2 knockdown. In contrast, arabinofuranosylcytosine-induced erythroid differentiation of K562 cells was significantly reduced with PDCD2 knockdown, with no effect on cell proliferation. The effects of PDCD2 knockdown were attributed to a cell cycle arrest at G(0)/G(1), along with increased messenger RNA expression of early progenitor factors c-MYB and GATA-2, and decreased expression of erythroid factors GATA-1, EpoR, and gamma-globin. We conclude that PDCD2 loss of function(s) impedes erythroid differentiation by inducing cell cycle arrest and increasing expression of early hematopoietic progenitor factors. These findings suggest that PDCD2 has a novel regulatory role in human hematopoiesis and is essential for erythroid development. PMID- 22922208 TI - Tyroservatide therapy for tumor invasion and metastasis of human ovarian carcinoma and colon carcinoma. AB - Tyroservatide (YSV) is an active, low-molecular-weight peptide shown to have antimetastasic effects on experimental melanoma and lung carcinoma. This study was carried out to evaluate the therapeutic effects of YSV on tumor invasion and metastasis of ovarian carcinoma and colon carcinoma and explore its antitumor mechanism of action. In vivo, three metastasis models were established, and YSV inhibited abdominal cavity metastasis of human ovarian carcinoma, and liver metastasis after spleen implantation of human colon carcinoma, in mice. In vitro, YSV inhibited the proliferation, promoted the death of SKOV-3, HT-29, and SW620 cells, and inhibited the adhesion and invasion of these three types of cells. Through zymography, western blot, and reverse transcription-PCR methods, YSV was found to reduce the activity, expression, and mRNA level of matrix metalloproteinase (MMP)-2 and MMP-9. The results showed that YSV can inhibit tumor growth and metastasis of human ovarian carcinoma SKOV-3 and human colon carcinoma HT-29 and SW620. The mechanism of action of YSV may involve the inhibition of proliferation, promotion of death, inhibition of the adhesion and invasion of SKOV-3, HT-29, and SW620 cells by downregulating the expression and activity of MMP-2 and MMP-9. PMID- 22922209 TI - Cancer vaccines and immunotherapeutics: challenges for pricing, reimbursement and market access. AB - Public payment is key to market access for new therapeutics including cancer vaccines and cancer immunotherapeutics. However, the methodology for economic evaluation aimed at informing decisions about pricing and reimbursement is different for cancer vaccines, such as HPV for preventing the occurrence or incidence of cancer, and immunotherapeutics for treatment of patients with manifest cancer. Vaccination against HPV is a traditional public health intervention, where the role of economic evaluation is to inform decisions about optimal vaccination strategies. The decision is about funding for a vaccination program, aimed at vaccinating a defined population at risk, either at a national or regional level. The methodology of economic evaluation is based on statistical modeling of number of cases prevented over a long time period, and the costs and health outcome related to this, for different vaccination strategies For immunotherapeutics, the role of economic evaluation is to assist decisions about reimbursement and guidelines for treatment of patients with establish disease, very often at advanced stages with short life expectancy. The focus is on alternative treatment options, and the costs and outcomes associated with these. Alternatives may be best supportive care, immunotherapeutics or other treatments like surgery, radiotherapy and other anti-cancer drugs. From an economic perspective the type of therapy does not matter, only costs and outcome associated with the relevant alternatives. The main controversy about reimbursement of immunotherapeutics, as with other new cancer drugs, has been the cost of treatment, mainly determined by the price of the therapy, in relation to the expected benefits in terms of survival and quality of life. This paper reviews the evidence on cost-effectiveness, the reimbursement decisions made, and the impact on market access for new immunotherapeutics. Sipuleucel-T (Provenge((r))) and abiraterone (Zytiga((r))) for treatment of prostate cancer and ipilimumab (Yervoy((r))) as well as vemurafenib (Zelboraf((r))) for treatment of metastatic melanoma are used as examples of the economic issues involved in analysis and decision-making. PMID- 22922210 TI - Social determinants for recurrent diabetic ketoacidosis in children with diabetes. PMID- 22922211 TI - Cost-effectiveness analysis of a risk-adapted algorithm of plerixafor use for autologous peripheral blood stem cell mobilization. AB - Historically, up to 30% of patients were unable to collect adequate numbers of peripheral blood stem cells (PBSCs) for autologous stem cell transplantation (ASCT). Plerixafor in combination with granulocyte colony-stimulating factor (G CSF) has shown superior results in mobilizing peripheral blood (PB) CD34+ cells in comparison to G-CSF alone, but its high cost limits general use. We developed and evaluated risk-adapted algorithms for optimal utilization of plerixafor. In plerixafor-1, PBSC mobilization was commenced with G-CSF alone, and if PB CD34 on day 4 or day 5 was <10/MUL, plerixafor was administered in the evening, and apheresis commenced the next day. In addition, if on any day, the daily yield was <0.5 * 10(6) CD34/kg, plerixafor was added. Subsequently, the algorithm was revised (plerixafor-2) with lower thresholds. If day-4 PB CD34 <10/MUL for single or <20/MUL for multiple transplantations, or day-1 yield was <1.5 * 10(6) CD34/kg, or any subsequent daily yield was <0.5 * 10(6) CD34/kg, plerixafor was added. Three time periods were analyzed for results and associated costs: January to December 2008 (baseline cohort; 319 mobilization attempts in 278 patients); February to November 2009 (plerixafor-1; 221 mobilization attempts in 216 patients); and December 2009 to June 2010 (plerixafor-2; 100 mobilization attempts in 98 patients). Plerixafor-2 shows a significant improvement in PB CD34 collection, increased number of patients reaching minimum and optimal goals, fewer days of apheresis, and fewer days of mobilization/collection, albeit at increased costs. In conclusion, although the earlier identification of ineffective PBSC mobilization and initiation of plerixafor (plerixafor-2) increases the per-patient costs of PBSC mobilization, failure rates, days of apheresis, and total days of mobilization/collection are lower. PMID- 22922212 TI - Is it safe to proceed with thrombolytic therapy for acute ischemic stroke in a patient with cardiac myxoma? Case report and review of the literature. PMID- 22922214 TI - Increased expression of beta-glucosidase A in Clostridium thermocellum 27405 significantly increases cellulase activity. AB - beta-glucosidase A (bglA) in Clostridium thermocellum 27405 was increased by expression from shuttle vector pIBglA in attempts to increase cellulase activity and ethanol titer by lowering the end product inhibition of cellulase. Through a modified electrotransformation protocol C. thermocellum transformant (+MCbglA) harbouring pIBglA was produced. The beta-glucosidase activity of +MCbglA was 2.3- and 1.6-fold greater than wild-type (WT) during late log and stationary phases of growth. Similarly, total cellulase activity of +MCbglA was shown to be 1.7-, 2.3- and 1.6-fold greater than WT during, log, late log and stationary phases of growth. However, there was no significant correlation found between increased cellulase activity and increased ethanol titers for +MCbglA compared with the WT. C. thermocellum has industrial potential for consolidated bioprocessing (CBP) to make a more cost effective production of biofuels; however, the hydrolysis rate of the strain is still hindered by end product inhibition. We successfully increased total cellulase activity by increased expression of bglA and thereby increased the productivity of C. thermocellum during the hydrolysis stage in CBP. Our work also lends insights into the complex metabolism of C. thermocellum for future improvement of this strain. PMID- 22922215 TI - The PI3K/Akt/mTOR signaling pathway mediates insulin-like growth factor 1-induced E-cadherin down-regulation and cell proliferation in ovarian cancer cells. AB - Insulin-like growth factor 1 (IGF1) is produced by ovarian cancer cells and it has been suggested that it plays an important role in tumor progression. In this study, we report that IGF1 treatment down-regulated E-cadherin by up-regulating E cadherin transcriptional repressors, Snail and Slug, in human ovarian cancer cells. The pharmacological inhibition of phosphatidylinositol-3-kinase (PI3K) and mammalian target of rapamycin (mTOR) suggests that PI3K/Akt/mTOR signaling is required for IGF1-induced E-cadherin down-regulation. Moreover, IGF1 up-regulated Snail and Slug expression via the PI3K/Akt/mTOR signaling pathway. Finally, IGF1 induced cell proliferation was abolished by inhibiting PI3K/Akt/mTOR signaling. This study demonstrates a novel mechanism in which IGF1 down-regulates E-cadherin expression through the activation of PI3K/Akt/mTOR signaling and the up regulation of Snail and Slug in human ovarian cancer cells. PMID- 22922216 TI - G1/S checkpoint proteins in peripheral blood lymphocytes are potentially diagnostic biomarkers for Alzheimer's disease. AB - The recognition that G(1)/S checkpoint dysfunctions in Alzheimer's disease (AD) has opened a novel avenue for better understanding the pathogenesis of AD, as well as for searching for new biomarkers for early diagnosis of AD. In present study, we investigated Cyclin E, Rb, CDK2 and E(2)F-1, four G1/S checkpoint proteins, in the lymphocytes from AD and non-AD individuals, and explored their potential for diagnosis application. A total of 176 age-matched subjects were enrolled, including 74 AD patients, 80 cognitively normal individuals, 11 patients with Parkinson's disease (PD) and 11 patients with vascular dementia (VaD). Peripheral blood lymphocytes were collected from each individual, and Cyclin E, Rb, CDK2, E(2)F-1 were analyzed by enzyme-linked immunosorbent assay, western blot, confocal microscopy and flow cytometry. The results showed that four proteins increased in AD compared with other three groups (P<0.05), with CDK2 and E(2)F-1 showing higher statistical significance (P<0.01). Their specificity/sensitivity (Cyclin E 84%/81%; Rb 74%/89%, CDK2 80%/78%, E(2)F-1 85%/85%) were acceptable, suggesting their potential as biomarkers for AD. Furthermore, these four proteins had the best sensitivity/specificity and highest Area Under the Curve (AUC) in mild-moderate AD compared with the severe AD. PMID- 22922217 TI - Exposure of Wistar rats to 24-h psycho-social stress alters gene expression in the inferior colliculus. AB - Recently, we have demonstrated that the exposure of Wistar rats to psycho-social stress results in a transient auditory hypersensitivity. Here, to learn more about modifications occurring in auditory brainstem, we have analyzed gene expression pattern in inferior colliculus using quantitative RT-PCR. As targets, we have chosen genes associated with: neural activity (FBJ osteosarcoma viral oncogene, cFos), hypoxia (nitric oxide synthase inducible, iNos; superoxide dismutase 2, Sod2), neuroprotection (nerve growth factor beta, Ngfb; heat shock factor 1, Hsf1; heat shock protein 70, Hsp70) and inflammation (tumor necrosis factor alpha, Tnfa; tumor necrosis factor alpha receptor, Tnfar; substance P, Sp; cyclooxygenase 2, Cox2). We found that the expression of all genes was modified following stress, as compared to the controls. Immediately after stress, the number of transcripts encoding iNos, Sod2, Hsf1, Ngfb, Tnfa, Tnfar and Sp was significantly increased, suggesting possible modulation during exposure to stressor. Interestingly, we found that expression of Hsf1 and Ngfb at this particular time was left-right asymmetrical: there were more transcripts of both genes found in the left colliculi, as compared to the right colliculi. Three hours post-stress, iNos, Hsf1, Tnfa and Tnfar were still upregulated, Sod2, Ngfb and Sp went back to baseline and Cox2 was upregulated. Six hours post-stress, cFos mRNA became downregulated. The number of Hsp70 mRNA increased 24h post stress. Except for the reduced number of cFos transcripts, expression of all other genes tested reached the baseline seven days post-stress. Presented results corroborate the concept of auditory system responding to the psycho-social stress. Post-stress changes in the IC gene expression could likely indicate shift from allostasis to homeostasis in the auditory brainstem. PMID- 22922218 TI - Effect of ageing on the passive and active tension and pharmacodynamic characteristics of rat coronary arteries: age-dependent increase in sensitivity to 5-HT and K+. AB - The influence of ageing on the passive and active tension and pharmacodynamic characteristics of intramural coronary arteries from 3-month-old and 2-year-old male Wistar rats was investigated using an isometric myograph. The passive vessel wall tension measured in Ca(2+)-free physiological salt solution at L(0) was significantly greater in arteries from old rats (1.46 +/- 0.10 Nm(-1), n = 7) than in young rats (1.13 +/- 0.13 Nm(-1), n = 6). However, the maximal active tension at L(0) was similar. The spontaneous myogenic tone was increased by age and the vasorelaxation induced by extracellular K(+) was significantly higher in coronary arteries of old rats. The sensitivity (pD(2)) to 5-HT was significantly higher in arteries from old (6.43 +/- 0.11, n = 22) than from young rats (6.16 +/ 0.08, n = 29). Ketanserin induced a concentration-dependent rightward shift of the 5-HT concentration-response curve in arteries from both young and old rats. The slopes of the regression lines of the Schild plots were not significantly different from unity and the estimated pK(B) values for ketanserin were similar. In conclusion, ageing is associated with changes in passive mechanical characteristics as well as changes in pharmacological properties in rat coronary small arteries. PMID- 22922220 TI - Lack of CCR5 modifies glial phenotypes and population of the nigral dopaminergic neurons, but not MPTP-induced dopaminergic neurodegeneration. AB - Constitutive expression of C-C chemokine receptor (CCR) 5 has been detected in astrocytes, microglia and neurons, but its physiological roles in the central nervous system are obscure. The bidirectional interactions between neuron and glial cells through CCR5 and its ligands were thought to be crucial for maintaining normal neuronal activities. No study has described function of CCR5 in the dopaminergic neurodegeneration in Parkinson's disease. In order to examine effects of CCR5 on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced dopaminergic neurodegeneration, we employed CCR5 wild type (WT) and knockout (KO) mice. Immunostainings for tyrosine hydroxylase (TH) exhibited that CCR5 KO mice had lower number of TH-positive neurons even in the absence of MPTP. Difference in MPTP (15mg/kg*4 times, 2hr interval)-mediated loss of TH-positive neurons was subtle between CCR5 WT and KO mice, but there was larger dopamine depletion, behavioral impairments and microglial activation in CCR5 deficient mice. Intriguingly, CCR5 KO brains contained higher immunoreactivity for monoamine oxidase (MAO) B which was mainly localized within astrocytes. In agreement with upregulation of MAO B, concentration of MPP+ was higher in the substantia nigra and striatum of CCR5 KO mice after MPTP injection. We found remarkable activation of p38 MAPK in CCR5 deficient mice, which positively regulates MAO B expression. These results indicate that CCR5 deficiency modifies the nigrostriatal dopaminergic neuronal system and bidirectional interaction between neurons and glial cells via CCR5 might be important for dopaminergic neuronal survival. PMID- 22922221 TI - Thymosin beta4 promotes the recovery of peripheral neuropathy in type II diabetic mice. AB - Peripheral neuropathy is one of the most common complications of diabetes mellitus. Using a mouse model of diabetic peripheral neuropathy, we tested the hypothesis that thymosin beta4 (Tbeta4) ameliorates diabetes-induced neurovascular dysfunction in the sciatic nerve and promotes recovery of neurological function from diabetic peripheral neuropathy. Tbeta4 treatment of diabetic mice increased functional vascular density and regional blood flow in the sciatic nerve, and improved nerve function. Tbeta4 upregulated angiopoietin-1 (Ang1) expression, but suppressed Ang2 expression in endothelial and Schwann cells in the diabetic sciatic nerve. In vitro, incubation of Human Umbilical Vein Endothelial Cells (HUVECs) with Tbeta4 under high glucose condition completely abolished high glucose-downregulated Ang1 expression and high glucose-reduced capillary-like tube formation. Moreover, incubation of HUVECs under high glucose with conditioned medium collected from Human Schwann Cells (HSCs) treated with Tbeta4 significantly reversed high glucose-decreased capillary-like tube formation. PI3K/Akt signaling pathway is involved in Tbeta4-regulated Ang1 expression on endothelial and Schwann cells. These data indicate that Tbeta4 likely acts on endothelial cells and Schwann cells to preserve and/or restore vascular function in the sciatic nerve which facilitates improvement of peripheral nerve function under diabetic neuropathy. Thus, Tbeta4 has potential for the treatment of diabetic peripheral neuropathy. PMID- 22922222 TI - Temporal monitoring of liver and kidney lesions in contaminated East Greenland polar bears (Ursus maritimus) during 1999-2010. AB - Organohalogen contaminants bioaccumulate to high concentrations in tissues of polar bears (Ursus maritimus). The exposure levels are in the order to be toxic to inner organs like liver and kidney. We therefore investigated the temporal development of lesions in liver (n=115) and kidney (n=122) samples from East Greenland polar bears taken over the 12 year period from 1999 to 2010. Seven liver and seven kidney lesions were observed of which six were age-related. Controlling for this, the analyses showed that hepatic steatosis and renal cell infiltrations, glomerular sclerosis and tubular hyperplasia decreased over the investigated time period (all p<0.05). Similarly, hypertrophy of hepatic Ito cells, renal glomerular capillary wall thickening and interstitial fibrosis increased over the study period (all p<0.05). Regarding contaminant, concentrations of polybrominated diphenyl ethers in adipose tissue were negatively associated with hepatic mononuclear cell infiltrations (p=0.05) and a similar trend was found for Hg (p=0.09). Hexachlorobenzene was positively associated with portal cell infiltrations and hepatic lipid granulomas, while polychlorinated biphenyls were negatively associated with the prevalence of steatosis (both p<0.05) and a similar trend was found for hexachlorocyclohexanes (p=0.08). Mercury was positively correlated with the frequencies of hypertrophic Ito cells (p=0.002) and a similar trend was found for perfluorooctanesulfonic acid (p=0.07). In renal tissue, hexachlorocyclohexanes were positively associated with medullar hyaline casts (p=0.03) and a similar trend was found for cell infiltrations (p=0.08). There was a trend of trans-nonachlor being positively associated with glomerular sclerosis (p=0.06) while dichlorodiphenyltrichloroethanes were negatively associated with tubular hyperplasia (p=0.02). These results suggest that specific liver and renal lesions have decreased or increased over time and that long-range transported organohalogen contaminants and mercury may be among the co-factors responsible for these observations. These relationships are important to take into account when biomonitoring health and pollution in wildlife species such as polar bears. PMID- 22922223 TI - Manufacture, characterisation and properties of novel fluorcanasite glass ceramics. AB - OBJECTIVE: The aim of this study was to investigate the manufacture and characterisation of different compositions of fluorcanasite glass-ceramics with reduced fluorine content and to assess their mechanical and physical properties. METHODS: Three compositional variations (S80, S81 and S82) of a fluorcanasite glass were investigated. Differential thermal analysis (DTA) and X-ray diffraction (XRD) identified crystallisation temperatures and phases. X-ray fluorescence (XRF) determined the element composition in the glass-ceramics. Different heat treatments [2 h nucleation and either 2 or 4 h crystallisation] were used for the glasses. Scanning electron microscopy (SEM) examined the microstructure of the cerammed glass. The chemical solubility, biaxial flexural strength, fracture toughness, hardness and brittleness index of S81 and S82 fluorcanasite were investigated with lithium disilicate (e.max CAD, Ivoclar Vivadent) as a commercial comparison. Statistical analysis was performed using one-way ANOVA with Tukey's multiple comparison tests (P<0.05). Weibull analysis was employed to examine the reliability of the strength data. RESULTS: All compositions successfully produced glasses. XRD analysis confirmed fluorcanasite formation with the S81 and S82 compositions, with the S82 (2+2h) showing the most prominent crystal structure. The chemical solubility of the glass-ceramics was significantly different, varying from 2565 +/- 507 MUg/cm(2) for the S81 (2+2 h) to 722 +/- 177 MUg/cm(2) for the S82 (2+2 h) to 37.4 +/- 25.2 MUg/cm(2) for the lithium disilicate. BFS values were highest for the S82 (2+2 h) composition (250 +/- 26 MPa) and lithium disilicate (266 +/- 37 MPa) glass-ceramics. The fracture toughness was higher for the S82 compositions, with the S82 (2+2h) attaining the highest value of 4.2 +/- 0.3 MPa m(1/2)(P=0.01). The S82 (2+2 h) fluorcanasite glass-ceramic had the lowest brittleness index. CONCLUSION: The S82 (2+2 h) fluorcanasite glass-ceramic has acceptable chemical solubility, high biaxial flexural strength, fracture toughness and hardness. CLINICAL SIGNIFICANCE: A novel glass-ceramic has been developed with potential as a restorative material. The S82 (2+2 h) has mechanical and physical properties that would allow the glass ceramic to be used as a machinable core material for veneered resin-bonded ceramic restorations. PMID- 22922224 TI - An analytical Micro CT methodology for quantifying inorganic dentine debris following internal tooth preparation. AB - OBJECTIVES: MicroCT allows the complex canal network of teeth to be mapped but does not readily distinguish between structural tissue (dentine) and the debris generated during cleaning. The aim was to introduce a validated approach for identifying debris following routine instrumentation and disinfection. METHODS: The mesial canals of 12 mandibular molars were instrumented, and irrigated with EDTA and NaOCl. MicroCT images before and after instrumentation and images were assessed qualitatively and quantitatively. RESULTS: Debris in the canal space was identified through morphological image analysis and superimposition of the images before and after instrumentation. This revealed that the removal of debris is prohibited by protrusions and micro-canals within the tooth creating areas which are inaccessible to the irrigant. Although the results arising from the analytical methodology did provide measurements of debris produced, biological differences in the canals resulted in variances. Both irrigants reduced debris compared to the control which decreased with EDTA and further with NaOCl. However, anatomical variation did not allow definitive conclusions on which irrigant was best to use although both reduced debris build up. CONCLUSIONS: This work presents a new approach for distinguishing between debris and structural inorganic tissue in root canals of teeth. The application may prove useful in other calcified tissue shape determination. CLINICAL SIGNIFICANCE: Remaining debris may contain bacteria and obstruct the flow of irrigating solutions into lateral canal anatomy. This new approach for detecting the amount of remaining debris in canal systems following instrumentation provides a clearer methodology of the identification of such debris. PMID- 22922225 TI - Elder abuse and psychological well-being: a systematic review and implications for research and policy--a mini review. AB - Elder abuse and psychological distress are both important geriatric syndromes and are independently associated with premature morbidity and mortality. Despite recent advances, there has been little systematic exploration of the association between elder abuse and psychological distress. This systematic review synthesizes the qualitative and quantitative studies on the relationship between elder abuse and psychological distress, namely psychological distress as a risk factor and/or a consequence of elder abuse. Moreover, through this review, future research directions for elder abuse and psychological distress and their implications for practice and policy to improve the health and aging of vulnerable populations are also highlighted. PMID- 22922226 TI - Outcome of cystic fibrosis-related diabetes two years after lung transplantation. AB - BACKGROUND: Although transplantation is known to impair glucose tolerance, evolution of pre-existing diabetes after lung transplantation (LT) in cystic fibrosis (CF) has never been described. OBJECTIVES: We aimed to assess the outcome of CF-related diabetes (CFRD) after LT, with the hypothesis that suppressing chronic inflammatory foci may improve glucose tolerance in some patients. METHODS: In a retrospective study of 29 CF diabetic patients treated with insulin and undergoing LT, CFRD control was assessed 3 months before LT and 1 (n = 27) and 2 (n = 18) years after LT by measuring insulin dosage, fasting blood glucose and glycosylated hemoglobin (HbA1c) levels. Patients with HbA1c <=7% and an insulin dose <=1 UI/kg/day were defined as having controlled CFRD (group A). Other patients were assigned to group B. RESULTS: Before LT, 19 (65.5%) patients were in group A. At 2 years, 6 of 10 (60%) patients who were in group B prior to LT had moved into group A, which then comprised 77.8% of all patients. Insulin could have been stopped in 5 patients. Uncontrolled CFRD before LT (OR = 16) and a long delay between the diagnosis of CFRD and LT (OR = 1.3) were significant predictors of uncontrolled CFRD at 1 year. CONCLUSIONS: LT does not seem to worsen CFRD in some patients, suggesting that in some cases, glucose tolerance may be improved by the suppression of chronic pulmonary infection. PMID- 22922227 TI - Is there an interaction of the effects of salinity and pesticides on the community structure of macroinvertebrates? AB - Salinization of freshwater ecosystems is a global problem affecting many regions worldwide and can co-occur with pesticides in agricultural regions. Given that both stressors are potent to affect macroinvertebrate communities, their effects could interact. We investigated the effects of salinity and pesticides at 24 sites in an agricultural region of southern Victoria, South-East Australia. We used distance-based redundancy analysis to determine the influence of pesticides, salinity and other environmental variables on the composition of macroinvertebrate communities. Salinity and pesticide toxicity had a statistically significant effect on communities as had the substrate composition and the percentage of pool and riffle sections in the sampled stream reaches. We did not find evidence for interactive effects between salinity and pesticides, i.e. the effect of one of these variables did not depend on the level of the other. Nevertheless, our results show that salinization and exposure to pesticides can be major factors for the structure of macroinvertebrate communities in agricultural regions. Pesticide toxicity acted on a lower taxonomic level compared to salinity, potentially indicating evolutionary adaptation to salinity stress. PMID- 22922228 TI - PDGF-B-mediated downregulation of miR-21: new insights into PDGF signaling in glioblastoma. AB - Glioblastoma (GBM) is a highly heterogeneous type of tumor characterized by genomic and signaling abnormalities affecting pathways involved in control of cell fate, including tumor-suppressor- and growth factor-regulated pathways. An aberrant miRNA expression has been observed in GBM, being associated with impaired cellular functions resulting in malignant transformation, proliferation and invasion. Here, we demonstrate for the first time that platelet-derived growth factor-B (PDGF-B), a potent angiogenic growth factor involved in GBM development and progression, promotes downregulation of pro-oncogenic (miR-21) and anti-oncogenic (miR-128) miRNAs, as well as upregulation/downregulation of several miRNAs involved in GBM pathology. Retrovirally mediated overexpression of PDGF-B in U87 human GBM cells or their prolonged exposure, as well as that of F98 rat glioma cells to this ligand, resulted in decreased miR-21 and miR-128 levels, which was associated with increased cell proliferation. Furthermore, siRNA mediated PDGF-B silencing led to increased levels of miR-21 and miR-128, while miRNA modulation through overexpression of miR-21 did not alter the levels of PDGF-B. Finally, we demonstrate that modulation of tumor suppressors PTEN and p53 in U87 cells does not affect the decrease in miR-21 levels associated with PDGF-B overexpression. Overall, our findings suggest that, besides its role in inducing GBM tumorigenesis, PDGF-B may enhance tumor proliferation by modulating the expression of oncomiRs and tumor suppressor miRNAs in U87 human GBM cells. PMID- 22922231 TI - IKAP expression levels modulate disease severity in a mouse model of familial dysautonomia. AB - Hereditary sensory and autonomic neuropathies (HSANs) encompass a group of genetically inherited disorders characterized by sensory and autonomic dysfunctions. Familial dysautonomia (FD), also known as HSAN type III, is an autosomal recessive disorder that affects 1/3600 live births in the Ashkenazi Jewish population. The disease is caused by abnormal development and progressive degeneration of the sensory and autonomic nervous systems and is inevitably fatal, with only 50% of patients reaching the age of 40. FD is caused by a mutation in intron 20 of the Ikbkap gene that results in severe reduction in the expression of its encoded protein, inhibitor of kappaB kinase complex-associated protein (IKAP). Although the mutation that causes FD was identified in 2001, so far there is no appropriate animal model that recapitulates the disorder. Here, we report the generation and characterization of the first mouse models for FD that recapitulate the molecular and pathological features of the disease. Important for therapeutic interventions is also our finding that a slight increase in IKAP levels is enough to ameliorate the phenotype and increase the life span. Understanding the mechanisms underlying FD will provide insights for potential new therapeutic interventions not only for FD, but also for other peripheral neuropathies. PMID- 22922230 TI - Bezafibrate administration improves behavioral deficits and tau pathology in P301S mice. AB - Peroxisome proliferator-activated receptors (PPARs) are ligand-mediated transcription factors, which control both lipid and energy metabolism and inflammation pathways. PPARgamma agonists are effective in the treatment of metabolic diseases and, more recently, neurodegenerative diseases, in which they show promising neuroprotective effects. We studied the effects of the pan-PPAR agonist bezafibrate on tau pathology, inflammation, lipid metabolism and behavior in transgenic mice with the P301S human tau mutation, which causes familial frontotemporal lobar degeneration. Bezafibrate treatment significantly decreased tau hyperphosphorylation using AT8 staining and the number of MC1-positive neurons. Bezafibrate treatment also diminished microglial activation and expression of both inducible nitric oxide synthase and cyclooxygenase 2. Additionally, the drug differentially affected the brain and brown fat lipidome of control and P301S mice, preventing lipid vacuoles in brown fat. These effects were associated with behavioral improvement, as evidenced by reduced hyperactivity and disinhibition in the P301S mice. Bezafibrate therefore exerts neuroprotective effects in a mouse model of tauopathy, as shown by decreased tau pathology and behavioral improvement. Since bezafibrate was given to the mice before tau pathology had developed, our data suggest that bezafibrate exerts a preventive effect on both tau pathology and its behavioral consequences. Bezafibrate is therefore a promising agent for the treatment of neurodegenerative diseases associated with tau pathology. PMID- 22922232 TI - 2-aminoethyl diphenyl borinate (2-APB) inhibits TRPM7 channels through an intracellular acidification mechanism. AB - 2-APB is a widely used compound in ion channel research. It affects numerous channels including inositol 1,4,5-trisphosphate receptors, store-operated calcium channels and TRP channels, TRPV3 and TRPM7 among them. A characteristic property of TRPM7 channels is their sensitivity to intracellular Mg ( 2+) and pH. Using patch clamp electrophysiology we find that in Jurkat T lymphocytes, 100-300 uM extracellular 2-APB reversibly inhibits TRPM7 channels when internal HEPES concentration is low (1 mM). Increasing the concentration to 140 mM abolishes the 2-APB effect. Using single-cell fluorescence pH video imaging, we show that at concentrations of 100 uM and higher, 2-APB potently acidifies the cytoplasm. We conclude that TRPM7 sensitivity to 2-APB is not direct but rather, can be explained by cytoplasmic acidification and a resulting channel inhibition. PMID- 22922233 TI - Anxiety and depression in Marines sent to war in Iraq and Afghanistan. AB - Although the effects of combat deployment on posttraumatic stress disorder have been extensively studied, little is known about the effects of combat deployment on depression and anxiety. This study examined the factors associated with anxiety and depression in a sample of 1560 US Marines who were deployed to Iraq and Afghanistan. Eleven demographic and psychosocial factors were studied in relation to depression and anxiety. Five factors emerged as significant in relation to depression: deployment-related stressors, combat exposure, attitudes toward leadership, mild traumatic brain injury symptoms, and marital status. The same factors, with the exception of marital status, emerged as significant in relation to anxiety. Deployment-related stressors had a stronger association with both depression and anxiety than any other variable, including combat exposure. This finding is important because deployment-related stressors are potentially modifiable by the military. PMID- 22922229 TI - Seven newly identified loci for autoimmune thyroid disease. AB - Autoimmune thyroid disease (AITD), including Graves' disease (GD) and Hashimoto's thyroiditis (HT), is one of the most common of the immune-mediated diseases. To further investigate the genetic determinants of AITD, we conducted an association study using a custom-made single-nucleotide polymorphism (SNP) array, the ImmunoChip. The SNP array contains all known and genotype-able SNPs across 186 distinct susceptibility loci associated with one or more immune-mediated diseases. After stringent quality control, we analysed 103 875 common SNPs (minor allele frequency >0.05) in 2285 GD and 462 HT patients and 9364 controls. We found evidence for seven new AITD risk loci (P < 1.12 * 10(-6); a permutation test derived significance threshold), five at locations previously associated and two at locations awaiting confirmation, with other immune-mediated diseases. PMID- 22922234 TI - Perceived quality of early paternal relationships and mental health in adulthood. AB - We aimed to determine the association between perceived paternal relationships and mental health and social functioning among adults in the community. Data were drawn from the National Comorbidity Survey (N = 8098), a nationally representative sample of adults aged 15 to 54 years in the United States. Multiple logistic regression analyses were used to assess the relationships between quality of paternal relationship in childhood and current mental disorders, quality of current social relationships, and attachment style. Poor paternal relationship was associated with a significantly increased likelihood of mood and anxiety disorders. Poorer quality of paternal relationships was also associated with poorer current social functioning and avoidant and dependent attachment styles. Our findings suggest that quality of paternal relationships is associated with mental health and social functioning in adulthood and highlight a need for increased understanding of the role of paternal relationships in social/emotional development. PMID- 22922235 TI - Group therapy with male asylum seekers and refugees with posttraumatic stress disorder: a controlled comparison cohort study of three day-treatment programs. AB - Studies on group treatment of posttraumatic stress disorder (PTSD) in asylum seekers and refugees are scarce. The aim of this study was to evaluate the effectiveness of three different trauma-focused day-treatment group programs for treatment of PTSD in male asylum seekers and refugees. Three treatment groups (n = 56) and a waitlisted control group (n = 16) of help-seeking Iranian and Afghani patients were assessed with a set of self-rated symptom checklists for PTSD, anxiety, depression, and psychoticism 1 week before and 2 weeks after treatment. There are no indications that the 2 days' group program with three nonverbal and two group psychotherapy sessions per week is less effective in reducing symptoms than the program with the same amount of sessions spread over 3 days per week. The trauma-focused day-treatment group seems a promising approach for treatment of PTSD among asylum seekers and refugees in industrialized settings. PMID- 22922236 TI - Voice identity recognition failure in patients with schizophrenia. AB - Cognitive models propose that auditory verbal hallucinations arise through inner speech misidentification. However, such models cannot explain why the voices in hallucinations often have identities different from the hearer. This study investigated whether a general voice identity recognition difficulty might be present in schizophrenia and related to auditory verbal hallucinations. Twenty five schizophrenia patients and 13 healthy controls were tested on recognition of famous voices. Signal detection theory was used to calculate perceptual sensitivity and response criterion measures. Schizophrenia patients obtained fewer hits and had lower perceptual sensitivity to detect famous voices than healthy controls did. There were no differences between groups in false alarm rate or response criterion. A symptom-based analysis demonstrated that especially those patients with auditory verbal hallucinations performed poorly in the task. The results indicate that patients with hallucinations are impaired at voice identity recognition because of decreased sensitivity, which may result in inner speech misidentification. PMID- 22922237 TI - Rater evaluations for psychiatric instruments and cultural differences: the positive and negative syndrome scale in China and the United States. AB - This article compares Positive and Negative Syndrome Scale (PANSS) data from Chinese and American inpatients with chronic schizophrenia to show how differences in item ratings may reflect cultural attitudes of raters. The Chinese sample (N = 504) came from Beijing Huilongguan Hospital. The American sample came from 268 PANSS assessments of Clinical Antipsychotic Trials of Intervention Effectiveness subjects hospitalized for 15 days or more to optimize equivalence of the samples. When controlling for age and sex, the Chinese sample scored significantly lower for total score by 25% (p < 0.0001), for the positive subscale by 35% (p < 0.0001), and on the general subscale by 32% (p < 0.0001) but not significantly different on the negative subscale score (+0.26%; p = 0.76). However, the Chinese sample scored 26% higher on the item on poor rapport (p < 0.0001), 10.2% higher on passive social withdrawal (p = 0.003), and most notably 46% higher on the item on lack of judgment and insight (p < 0.0001). These results remain broadly consistent across sex subgroup analyses. Differences seem to be best explained by both cultural differences in patient clinical presentations and varying American and Chinese cultural values affecting rater judgment. PMID- 22922238 TI - Why do people with eating disorders drop out from inpatient treatment?: the role of personality factors. AB - Dropout rates from inpatient treatment for eating disorders are very high and have a negative impact on outcome. The purpose of this study was to identify personality factors predictive of dropout from hospitalization. A total of 64 adult patients with anorexia nervosa consecutively hospitalized in a specialized unit were included; 19 patients dropped out. The dropout group and the completer group were compared for demographic variables, clinical features, personality dimensions, and personality disorders. There was no link between clinical features and dropout, and among demographic variables, only age was associated with dropout. Personality factors, comorbidity with a personality disorder and Self-transcendence dimension, were statistically predictive of premature termination of hospitalization. In a multivariate model, these two factors remain significant. Personality traits (Temperament and Character Inventory personality dimension and comorbid personality disorder) are significantly associated with dropout from inpatient treatment for anorexia nervosa. Implications for clinical practice, to diminish the dropout rate, will be discussed. PMID- 22922239 TI - Dynamics of self-esteem in "poor-me" and "bad-me" paranoia. AB - The dynamics of self-esteem and paranoia were examined in 41 patients with past or current paranoia and 23 controls using questionnaires and the Experience Sampling Method (a structured diary technique). For some analyses, patients were further divided into three groups: a) individuals who believed that persecution is underserved ("poor me"; PM), b) individuals who believed that persecution is justified ("bad me"; BM), and c) remitted patients. The results revealed that PM and especially BM patients had highly unstable psychological profiles. Beliefs about deservedness of persecution fluctuated over 6 days. BM beliefs were associated with low self-esteem and depression. Measured concurrently, paranoia predicted lower self-esteem in the BM patients. Prospectively, paranoia predicted lower subsequent self-esteem in BM patients but higher subsequent self-esteem in PM patients. Our results suggest that paranoia can serve a defensive function in some circumstances. The reasons for inconsistencies in self-esteem research in relation to paranoia are discussed. PMID- 22922240 TI - Are there meaningful differences between major depressive disorder, dysthymic disorder, and their subthreshold variants? AB - A number of researchers have proposed adding an increasing number of subthreshold variants of major depressive disorder (MDD) as new mood disorder. However, this research has suffered from a number of theoretical and methodological flaws that the current investigation has attempted to address. Individuals with MDD (n = 470) were compared with individuals with subthreshold MDD (n = 57). Individuals with MDD reported consistently more severe symptoms, albeit of small magnitude, as well as differences in comorbidity with only two disorders. Results also indicated that diagnosis did not significantly predict rate of symptom change when MDD was compared with its subthreshold variant. Taken together, the aforementioned evidence suggests that small differences exist between MDD and its subthreshold variant. In addition, the extent to which the latter serves as useful analogs for the former may depend upon the variables under study. PMID- 22922241 TI - Conditional reasoning in Asperger's syndrome and depersonalization disorder. AB - Conditional reasoning premises can be systematically manipulated to elicit specific response patterns. This is useful for investigating the reasoning style of people who report clinical symptoms. We administered a standardized conditional reasoning task to 16 participants with a diagnosis of Asperger's syndrome (AS), 16 participants with a diagnosis of depersonalization disorder (DPD), and 32 intelligence-quotient-matched controls. Premises were manipulated for a) context, with some being embedded within extra statements, and b) content, neutral or emotional. Both the AS and DPD participants were less likely to incorporate exceptions to the given premises than the controls, indicating difficulties with mental flexibility, although this effect was less marked in the DPD group. It seems the AS participants were also less influenced than the controls by statements that highlight possible alternative consequences. However, this effect was less robust than that observed with statements detailing exceptions, suggesting it may be because of general problems with executive function rather than difficulties in processing contextual information. We did not observe the expected difference between the DPD participants and the controls when reasoning with emotional premises. Overall, these data suggest that the DPD and AS participants have distinct reasoning styles, which may be of use for interventions based on cognitive change. PMID- 22922242 TI - Sustained cognitive impairments after clinical recovery of severe depression. AB - Neuropsychological impairment is prominent in patients with depression, but it is unclear whether deficits persist after clinical response. This study aimed to investigate neuropsychological functions in the course of the illness. Depressive patients were investigated in the acute state and after clinical response using an extensive neuropsychological test battery. After clinical response, there was only a partial improvement in learning and memory and there were no changes regarding working memory, executive functions, and attention. Transient impairments in visual learning and memory suggest a depression-related state effect. The continuing deficits in attention, working memory, and executive function might be considered a trait marker. PMID- 22922243 TI - Variables mediating the linkage between loss centrality and postloss psychopathology. AB - Event centrality refers to the degree to which the memory of a negative life event is a core component of a person's identity. There is evidence that greater event centrality is associated with more intense psychopathology after different events, including the death of a loved one. This study sought to advance our understanding of the variables mediating the linkage between loss centrality and postloss psychopathology. Specifically, using multiple mediation analyses, we examined the role of a) intrusiveness of memories about the loss event, b) negative future cognitions and catastrophic misinterpretations of one's own grief reactions, and c) depressive avoidance and rumination in mediating the associations between loss centrality and postloss psychopathology. The outcomes showed that memory intrusiveness, the two cognitive variables, and the two behavioral strategies emerged as unique, independent mediators of the linkages between loss centrality and the indices of postloss psychopathology when controlling for the shared variance between the proposed mediators. The implications of these findings are discussed. PMID- 22922245 TI - The E-coach transition support computer telephony implementation study: protocol of a randomized trial. AB - BACKGROUND: Patients requiring complex care are at high risk during the transition from one setting of care to another. Effective interventions to support care transitions have been designed but are very resource intensive. Telemonitoring has been considered as an approach to enhance care transition support, but many telemonitoring systems require special equipment or web-based interfaces to interact with patients and caregivers. METHODS/DESIGN: In this paper we report our protocol for developing and testing E-Coach, an interactive voice response (IVR)-enhanced care transition intervention that monitors patients at home using their personal phone. The elements described include 1) development of an IVR monitoring system that will be based on Coleman's four pillars of care transition support; 2) development of a web-based "dashboard" of IVR responses that alert care transition nurses (CTN) of patient/caregiver concerns after discharge and allow documentation by the CTN when patients/caregivers are called; 3) pilot testing of the IVR system by patients and providers with refinement of the system based on patient/provider input; and 4) a pragmatic protocol for formal testing through a randomized controlled trial (RCT) of the E-Coach intervention in congestive heart failure (CHF) and chronic obstructive pulmonary disease (COPD) patients admitted to a large tertiary hospital. TRIAL REGISTRATION: CT.gov#: NCT01135381. PMID- 22922244 TI - Antibiotic retreatment of Lyme disease in patients with persistent symptoms: a biostatistical review of randomized, placebo-controlled, clinical trials. AB - INTRODUCTION: Lyme disease (Lyme borreliosis) is caused by the tick-borne spirochete Borrelia burgdorferi. Long-term persistent illness following antibiotic treatment is not uncommon, particularly when treatment is delayed. Current treatment guidelines for persistent disease primarily rely on findings from four randomized, controlled trials (RCTs), strongly advising against retreatment. METHODS: We performed a biostatistical review of all published RCTs evaluating antibiotic retreatment, focusing on trial design, analysis and conclusions. RESULTS: Four RCTs met the inclusion criteria; all examined the efficacy of intravenous ceftriaxone versus placebo at approximately 3 or 6 months. Design assumptions for the primary outcomes in the two Klempner trials and two outcomes in the Krupp trial were unrealistic and the trials were likely underpowered to detect clinically meaningful treatment effects. The Klempner trials were analyzed using inefficient statistical methods. The Krupp RCT was well-designed and analyzed for fatigue, finding statistically significant and clinically meaningful improvement. Fallon corroborated this finding. Fallon also found improvement in cognitive functioning, a primary outcome, at 12 weeks which was not sustained at 24 weeks; improvements in physical functioning and pain were demonstrated at week 24 as an interaction effect between treatment and baseline symptom severity with the drug effect increasing with higher baseline impairment. DISCUSSION: This biostatistical review reveals that retreatment can be beneficial. Primary outcomes originally reported as statistically insignificant were likely underpowered. The positive treatment effects of ceftriaxone are encouraging and consistent with continued infection, a hypothesis deserving additional study. Additional studies of persistent infection and antibiotic treatment are warranted. PMID- 22922246 TI - The value of selected in vitro and in silico methods to predict acute oral toxicity in a regulatory context: results from the European Project ACuteTox. AB - ACuteTox is a project within the 6th European Framework Programme which had as one of its goals to develop, optimise and prevalidate a non-animal testing strategy for predicting human acute oral toxicity. In its last 6 months, a challenging exercise was conducted to assess the predictive capacity of the developed testing strategies and final identification of the most promising ones. Thirty-two chemicals were tested blind in the battery of in vitro and in silico methods selected during the first phase of the project. This paper describes the classification approaches studied: single step procedures and two step tiered testing strategies. In summary, four in vitro testing strategies were proposed as best performing in terms of predictive capacity with respect to the European acute oral toxicity classification. In addition, a heuristic testing strategy is suggested that combines the prediction results gained from the neutral red uptake assay performed in 3T3 cells, with information on neurotoxicity alerts identified by the primary rat brain aggregates test method. Octanol-water partition coefficients and in silico prediction of intestinal absorption and blood-brain barrier passage are also considered. This approach allows to reduce the number of chemicals wrongly predicted as not classified (LD50>2000 mg/kg b.w.). PMID- 22922247 TI - Procurement regimens to reduce ischemia reperfusion injury of vascular grafts. AB - BACKGROUND: Ischemia reperfusion injury is an important nonimmunological factor contributing to the development of chronic rejection. The aim of this study was to compare different cell culture media in terms of vascular lesion formation after ischemia reperfusion injury. METHODS: BALB/c aortic grafts were incubated in different cell media (endothelial cell growth, ECG, RPMI-1640 and Waymouth/Ham's F12) for various time spans (5, 6.5 and 8.5 h) at 37 degrees C and implanted into syngeneic BALB/c recipients. On day 30 after implantation, histology, immunofluorescence and morphometric measurements were performed. RESULTS: A total of 36 transplants were performed for this study with an overall survival rate of 72.2%. The most frequent complication was thrombosis of the aortic graft (n = 9) and there was one late death due to other courses. All the recipients with vascular grafts incubated in the ECG medium survived and showed no signs of intimal proliferation independent of the time of ischemia. Aortic grafts incubated in the RPMI medium resulted in a reduced recipient survival rate of 66.7% and grafts incubated in the Waymouth medium showed only a 50% survival by day 30. Analysis of the vascular morphology revealed moderate amounts of intimal proliferation within two aortic grafts in this group. CD31 staining revealed superior endothelial cell integrity after incubation with the ECG medium. CONCLUSIONS: Data from the current study suggest that under optimized conditions vascular grafts can be safely kept in tissue culture up to 8.5 h without significant ischemic damage. Differences in vascular integrity and animal survival depended mostly on the respective tissue culture medium used for the storage of the vessel. PMID- 22922248 TI - Simvastatin prevents the induction of interleukin-6 gene expression by titanium particles in human osteoblastic cells. AB - One of the most important complications of total joint arthroplasty is failure associated with periprosthetic osteolysis, a process mainly initiated by the biological response to wear-derived products from the biomaterials in service. The inflammatory mediator interleukin-6 (IL-6) plays a key role in the establishment and progression of aseptic loosening. Metal particles specifically up-regulate IL-6 production in bone-forming cells and implant-bone interfacial tissues. The use of statins has been recently associated with a significantly reduced risk of revision in patients that undergo total hip arthroplasty. We hypothesized that simvastatin (Simv) could modulate the osteoblastic response to titanium particles (Ti) by attenuating the production of IL-6. Pre-treatment of human osteoblastic cells with Simv down-regulated Ti particle-induced IL-6 gene expression at mRNA and protein levels. The effect of Simv on Ti-induced IL-6 production in osteoblastic cells could not be explained by inhibition of the internalization of metal particles. The mechanism involved in this down regulation is based in the inhibition of the HMG-CoA/GGPP/RhoA/ROCK pathway, independently of Simv effects in the cholesterol synthesis. The cytokine-lowering property of Simv has been observed in Saos-2 cells and human primary osteoblasts (hOBs) exposed to Ti particles, and was further enhanced when hOBs were co cultured with macrophages. PMID- 22922249 TI - Long-term in vivo degradation behaviour and biocompatibility of the magnesium alloy ZEK100 for use as a biodegradable bone implant. AB - Magnesium alloys are the focus of research as resorbable materials for osteosynthesis, as they provide sufficient stability and would make surgery to remove implants unnecessary. The new degradable magnesium alloy ZEK100 was developed to improve the stability and corrosion resistance by alloying with zinc, rare earth metals and zirconium. As the implants were degraded to only a limited extent after 6 months implantation in a previous in vivo study the present study was conducted to evaluate the long-term degradation behaviour and biocompatibility in the same animal model over 9 and 12 months. Five rabbits each with intramedullary tibia implants were examined over 9 and 12 months. Three legs were left without an implant to serve as negative controls. Numerous examinations were performed in the follow-up (clinical examinations, serum analysis, and radiographic and in vivo micro-CT investigations) and after death (ex vivo micro CT, histology, and implant analysis) to assess the in vivo degradation and biocompatibility. It could be shown that favourable in vivo degradation behaviour is not necessarily associated with good biocompatibility. Although ZEK100 provided a very high initial stability and positive biodegradation, it must be excluded from further biomedical testing as it showed pathological effects on the host tissue following complete degradation. PMID- 22922250 TI - Heterogeneous structure and in vitro degradation behavior of wet-chemically derived nanocrystalline silicon-containing hydroxyapatite particles. AB - Nanocrystalline hydroxyapatite (HAp) and silicon-containing hydroxyapatite (SiHAp) particles were synthesized by a wet-chemical procedure and their heterogeneous structures involving a disordered phase were analyzed in detail by X-ray diffractometry (XRD), transmission electron microscopy (TEM), Fourier transform infrared (FTIR) spectroscopy and solid-state magic-angle spinning (MAS) nuclear magnetic resonance (NMR) spectroscopy. The effects of heterogeneous structure on in vitro biodegradability and the biologically active Ca(II)- and Si(IV)-releasing property of SiHAp particles were discussed. The (29)Si NMR analysis revealed that the Si(IV) was incorporated in the HAp lattice in the form of Q(0)(SiO(4)(4-)orHSiO(4)(3-)) species, accompanied by the formation of condensed silicate units outside the HAp lattice structure, where the fraction and amount of Q(0) species in the HAp lattice depends on the Si content. The (31)P and (1)H NMR results agreed well with the XRD, TEM and FTIR results. NMR quantitative analysis results were explained by using a core-shell model assuming a simplified hexagonal shape of HAp covered with a disordered layer, where Si(IV) in Q(0) was incorporated in the HAp lattice and a disordered phase consisted of hydrated calcium phosphates involving polymeric silicate species and carbonate anions. With the increase in the Si content in the HAp lattice, the in vitro degradation rate of the SiHAps increased, while their crystallite size stayed nearly unchanged. The biologically active Ca(II)- and Si(IV)-releasing ability of the SiHAps was remarkably enhanced at the initial stage of reactions by an increase in the amount of Si(IV) incorporated in the HAp lattice but also by an increase of the amount of polymeric silicate species incorporated in the disordered phase. PMID- 22922251 TI - Bone regeneration in strong porous bioactive glass (13-93) scaffolds with an oriented microstructure implanted in rat calvarial defects. AB - There is a need for synthetic bone graft substitutes to repair large bone defects resulting from trauma, malignancy and congenital diseases. Bioactive glass has attractive properties as a scaffold material but factors that influence its ability to regenerate bone in vivo are not well understood. In the present work, the ability of strong porous scaffolds of 13-93 bioactive glass with an oriented microstructure to regenerate bone was evaluated in vivo using a rat calvarial defect model. Scaffolds with an oriented microstructure of columnar pores (porosity=50%; pore diameter=50-150 MUm) showed mostly osteoconductive bone regeneration, and new bone formation, normalized to the available pore area (volume) of the scaffolds, increased from 37% at 12 weeks to 55% at 24 weeks. Scaffolds of the same glass with a trabecular microstructure (porosity=80%; pore width=100-500 MUm), used as the positive control, showed bone regeneration in the pores of 25% and 46% at 12 and 24 weeks, respectively. The brittle mechanical response of the as-fabricated scaffolds changed markedly to an elastoplastic response in vivo at both implantation times. These results indicate that both groups of 13-93 bioactive glass scaffolds could potentially be used to repair large bone defects, but scaffolds with the oriented microstructure could also be considered for the repair of loaded bone. PMID- 22922252 TI - HIV and T follicular helper cells: a dangerous relationship. AB - HIV infection leads to progressive destruction of infected CD4 T cells, hypergammaglobulinemia, and loss of memory B cells. Germinal centers, which are key to memory B cell formation and protective antibody responses, are major HIV reservoirs in which the virus replicates within T follicular helper (TFH) cells. In this issue of the JCI, the Koup and Streeck groups report that chronic SIV/HIV infection promotes TFH cell accumulation, which may drive B cell dysregulation. Their discoveries suggest that HIV harnesses TFH cells to evade the antibody response. PMID- 22922253 TI - Mining the secrets of the CSF: developing biomarkers of neurodegeneration. AB - Our ability to track the progression of neurological disorders like Parkinson's disease (PD) is hampered by a lack of biomarkers, rendering the neuronal changes that underlie clinical symptoms largely a mystery. In this issue of the JCI, Fanara et al. report the development of an innovative approach to biomarker development. They describe a method to measure axonal microtubule function via cerebrospinal fluid (CSF) sampling and use this technique to provide evidence of deficiencies in this process in PD patients. This both sheds light on the pathophysiology of PD and has implications for the more general problem of developing biomarkers for any brain process. PMID- 22922254 TI - Cerebrospinal fluid-based kinetic biomarkers of axonal transport in monitoring neurodegeneration. AB - Progress in neurodegenerative disease research is hampered by the lack of biomarkers of neuronal dysfunction. We here identified a class of cerebrospinal fluid-based (CSF-based) kinetic biomarkers that reflect altered neuronal transport of protein cargo, a common feature of neurodegeneration. After a pulse administration of heavy water (2H2O), distinct, newly synthesized 2H-labeled neuronal proteins were transported to nerve terminals and secreted, and then appeared in CSF. In 3 mouse models of neurodegeneration, distinct 2H-cargo proteins displayed delayed appearance and disappearance kinetics in the CSF, suggestive of aberrant transport kinetics. Microtubule-modulating pharmacotherapy normalized CSF-based kinetics of affected 2H-cargo proteins and ameliorated neurodegenerative symptoms in mice. After 2H2O labeling, similar neuronal transport deficits were observed in CSF of patients with Parkinson's disease (PD) compared with non-PD control subjects, which indicates that these biomarkers are translatable and relevant to human disease. Measurement of transport kinetics may provide a sensitive method to monitor progression of neurodegeneration and treatment effects. PMID- 22922255 TI - Inhibition of CXCR2 profoundly suppresses inflammation-driven and spontaneous tumorigenesis. AB - The chemokine receptor CXCR2 is a key mediator of neutrophil migration that also plays a role in tumor development. However, CXCR2 influences tumors through multiple mechanisms and might promote or inhibit tumor development depending on context. Here, we used several mouse models of spontaneous and inflammation driven neoplasia to define indispensable roles for CXCR2 in benign and malignant tumors. CXCR2-activating chemokines were part of the secretome of cultured primary benign intestinal adenomas (ApcMin/+) and highly expressed by all tumors in all models. CXCR2 deficiency profoundly suppressed inflammation-driven tumorigenesis in skin and intestine as well as spontaneous adenocarcinoma formation in a model of invasive intestinal adenocarcinoma (AhCreER;Apcfl/+;Ptenfl/fl mice). Pepducin-mediated CXCR2 inhibition reduced tumorigenesis in ApcMin/+ mice. Ly6G+ neutrophils were the dominant source of CXCR2 in blood, and CXCR2 deficiency attenuated neutrophil recruitment. Moreover, systemic Ly6G+ cell depletion purged CXCR2-dependent tumor-associated leukocytes, suppressed established skin tumor growth and colitis-associated tumorigenesis, and reduced ApcMin/+ adenoma formation. CXCR2 is thus a potent protumorigenic chemokine receptor that directs recruitment of tumor-promoting leukocytes into tissues during tumor-inducing and tumor-driven inflammation. Similar leukocyte populations were also found in human intestinal adenomas, which suggests that CXCR2 antagonists may have therapeutic and prophylactic potential in the treatment of cancer. PMID- 22922256 TI - Mouse fukutin deletion impairs dystroglycan processing and recapitulates muscular dystrophy. AB - Dystroglycan is a transmembrane glycoprotein that links the extracellular basement membrane to cytoplasmic dystrophin. Disruption of the extensive carbohydrate structure normally present on alpha-dystroglycan causes an array of congenital and limb girdle muscular dystrophies known as dystroglycanopathies. The essential role of dystroglycan in development has hampered elucidation of the mechanisms underlying dystroglycanopathies. Here, we developed a dystroglycanopathy mouse model using inducible or muscle-specific promoters to conditionally disrupt fukutin (Fktn), a gene required for dystroglycan processing. In conditional Fktn-KO mice, we observed a near absence of functionally glycosylated dystroglycan within 18 days of gene deletion. Twenty week-old KO mice showed clear dystrophic histopathology and a defect in glycosylation near the dystroglycan O-mannose phosphate, whether onset of Fktn excision driven by muscle-specific promoters occurred at E8 or E17. However, the earlier gene deletion resulted in more severe phenotypes, with a faster onset of damage and weakness, reduced weight and viability, and regenerating fibers of smaller size. The dependence of phenotype severity on the developmental timing of muscle Fktn deletion supports a role for dystroglycan in muscle development or differentiation. Moreover, given that this conditional Fktn-KO mouse allows the generation of tissue- and timing-specific defects in dystroglycan glycosylation, avoids embryonic lethality, and produces a phenotype resembling patient pathology, it is a promising new model for the study of secondary dystroglycanopathy. PMID- 22922257 TI - C/EBPepsilon mediates nicotinamide-enhanced clearance of Staphylococcus aureus in mice. AB - The myeloid-specific transcription factor, CCAAT/enhancer-binding protein epsilon (C/EBPepsilon) is a critical mediator of myelopoiesis. Mutation of this gene is responsible for neutrophil-specific granule deficiency in humans, a condition that confers susceptibility to Staphylococcus aureus infection. We found that C/EBPepsilon-deficient mice are severely affected by infection with S. aureus, and C/EBPepsilon deficiency in neutrophils contributes to the infectious phenotype. Conversely, exposure to the epigenetic modulator nicotinamide (vitamin B3) increased expression of C/EBPepsilon in WT myeloid cells. Further, nicotinamide increased the activity of C/EBPepsilon and select downstream antimicrobial targets, particularly in neutrophils. In a systemic murine infection model as well as in murine and human peripheral blood, nicotinamide enhanced killing of S. aureus by up to 1,000 fold but had no effect when administered to either C/EBPepsilon-deficient mice or mice depleted of neutrophils. Nicotinamide was efficacious in both prophylactic and therapeutic settings. Our findings suggest that C/EBPepsilon is an important target to boost killing of bacteria by the innate immune system. PMID- 22922258 TI - CD4 T follicular helper cell dynamics during SIV infection. AB - CD4 T follicular helper (TFH) cells interact with and stimulate the generation of antigen-specific B cells. TFH cell interaction with B cells correlates with production of SIV-specific immunoglobulins. However, the fate of TFH cells and their participation in SIV-induced antibody production is not well understood. We investigated the phenotype, function, location, and molecular signature of TFH cells in rhesus macaques. Similar to their human counterparts, TFH cells in rhesus macaques represented a heterogeneous population with respect to cytokine function. In a highly differentiated subpopulation of TFH cells, characterized by CD150lo expression, production of Th1 cytokines was compromised while IL-4 production was augmented, and cells exhibited decreased survival, cycling, and trafficking capacity. TFH cells exhibited a distinct gene profile that was markedly altered by SIV infection. TFH cells were infected by SIV; yet, in some animals, these cells actually accumulated during chronic SIV infection. Generalized immune activation and increased IL-6 production helped drive TFH differentiation during SIV infection. Accumulation of TFH cells was associated with increased frequency of activated germinal center B cells and SIV-specific antibodies. Therefore, chronic SIV does not disturb the ability of TFH cells to help B cell maturation and production of SIV-specific immunoglobulins. PMID- 22922259 TI - Expansion of HIV-specific T follicular helper cells in chronic HIV infection. AB - HIV targets CD4 T cells, which are required for the induction of high-affinity antibody responses and the formation of long-lived B cell memory. The depletion of antigen-specific CD4 T cells during HIV infection is therefore believed to impede the development of protective B cell immunity. Although several different HIV-related B cell dysfunctions have been described, the role of CD4 T follicular helper (TFH) cells in HIV infection remains unknown. Here, we assessed HIV specific TFH responses in the lymph nodes of treatment-naive and antiretroviral treated HIV-infected individuals. Strikingly, both the bulk TFH and HIV-specific TFH cell populations were significantly expanded in chronic HIV infection and were highly associated with viremia. In particular, GAG-specific TFH cells were detected at significantly higher levels in the lymph nodes compared with those of GP120-specific TFH cells and showed preferential secretion of the helper cytokine IL-21. In addition, TFH cell expansion was associated with an increase of germinal center B cells and plasma cells as well as IgG1 hypersecretion. Thus, our study suggests that high levels of HIV viremia drive the expansion of TFH cells, which in turn leads to perturbations of B cell differentiation, resulting in dysregulated antibody production. PMID- 22922261 TI - NPARM in PHOX2B: why some things just should not be expanded. AB - Although the neural crest and its derivatives have been studied for a very long time, disorders of derivatives of the crest, the neurocristopathies, are not well understood. In this issue of the JCI, Nagashimada et al. provide an elegant analysis of one neurocristopathy, the association of neuroblastoma (NB) with Hirschsprung disease (HSCR) (aganglionosis of the terminal bowel) and congenital central hypoventilation syndrome (CCHS) (also known as NB-HSCR-CCHS), linked to mutations in PHOX2B. In a mouse model, Nagashimada et al. demonstrate that a disease-linked mutation promotes tumorigenesis and disrupts neurogenesis, sympathetic gangliogenesis, and crest cell colonization of the terminal bowel. They also show that mutant PHOX2B results in decreased proliferation of crest derived cells and the development of glia at the expense of neurons. The work raises intriguing issues about the possible common origin of sympathetic and enteric nervous systems and provides new hope that we may someday understand the vexing abnormalities in gastrointestinal function that persist after the surgical treatment of HSCR. PMID- 22922260 TI - Autonomic neurocristopathy-associated mutations in PHOX2B dysregulate Sox10 expression. AB - The most common forms of neurocristopathy in the autonomic nervous system are Hirschsprung disease (HSCR), resulting in congenital loss of enteric ganglia, and neuroblastoma (NB), childhood tumors originating from the sympathetic ganglia and adrenal medulla. The risk for these diseases dramatically increases in patients with congenital central hypoventilation syndrome (CCHS) harboring a nonpolyalanine repeat expansion mutation of the Paired-like homeobox 2b (PHOX2B) gene, but the molecular mechanism of pathogenesis remains unknown. We found that introducing nonpolyalanine repeat expansion mutation of the PHOX2B into the mouse Phox2b locus recapitulates the clinical features of the CCHS associated with HSCR and NB. In mutant embryos, enteric and sympathetic ganglion progenitors showed sustained sex-determining region Y (SRY) box10 (Sox10) expression, with impaired proliferation and biased differentiation toward the glial lineage. Nonpolyalanine repeat expansion mutation of PHOX2B reduced transactivation of wild-type PHOX2B on its known target, dopamine beta-hydroxylase (DBH), in a dominant-negative fashion. Moreover, the introduced mutation converted the transcriptional effect of PHOX2B on a Sox10 enhancer from repression to transactivation. Collectively, these data reveal that nonpolyalanine repeat expansion mutation of PHOX2B is both a dominant-negative and gain-of-function mutation. Our results also demonstrate that Sox10 regulation by PHOX2B is pivotal for the development and pathogenesis of the autonomic ganglia. PMID- 22922263 TI - Studies claiming efficacy of CPR training interventions: which skills should be assessed and how should data be reported to allow comparison? PMID- 22922262 TI - The attachment disorders of muscle: failure to carb-load. AB - Dystroglycan is a prominent cell surface protein that mediates attachment to the extracellular matrix. Although broadly expressed, glycosylated dystroglycan is critically important for muscle cell adherence to its surrounding matrix. A subgroup of muscular dystrophies, which often manifest in infancy, is associated with reduced glycosylation of dystroglycan. In this issue of the JCI, Beedle et al. used conditional gene targeting of Fktn, the gene responsible for Fukuyama congenital muscular dystrophy, to investigate a developmental requirement for glycosylation of dystroglycan. PMID- 22922264 TI - Benefit of an early and systematic imaging procedure after cardiac arrest: insights from the PROCAT (Parisian Region Out of Hospital Cardiac Arrest) registry. AB - AIMS: Identification of the cause of out-of-hospital cardiac arrest (OHCA) is of paramount importance. We investigated the ability of our imaging strategy to provide an early etiological diagnosis of OHCA and the influence of this strategy on ICU survival. METHODS: Retrospective review of a prospectively acquired ICU database (01/2000-12/2010) including all OHCA patients without obvious extracardiac cause, for which an early diagnosis research was conducted (coronary angiography and/or brain and chest CT scan) within 24h after resuscitation. These procedures could be performed separately or be combined, according to a decision algorithm. RESULTS: Of the 1274 patients admitted after OHCA during this 10-year period, the imaging strategy was applied in 896 patients. Patients who benefited from coronary angiography and/or CT scan were admitted to our ICU after a median delay of 180 [130-220]min after resuscitation. Seven hundred and forty-five coronary angiographies were performed, of which 452 (61%) identified at least one significant coronary lesion deemed responsible for the OHCA. CT-scan was performed in 355 patients and provided a diagnosis in 72 patients (20%), mainly stroke (n=38) and pulmonary embolism (n=19). Overall, this strategy allowed early diagnosis in 524 patients (59%). ICU survival was significantly higher for patients with a diagnosis identified by coronary angiography as compared with CT scan (43% vs 10%, p<0.001). CONCLUSION: The use of an early diagnosis protocol with immediate coronary angiography and/or CT scan provided the etiology of nearly two thirds of OHCA cases. In this large retrospective database, coronary angiography yielded a better diagnostic value than brain and/or chest CT-scan. PMID- 22922266 TI - Hippocampal synaptic dysregulation of exo/endocytosis-associated proteins induced in a chronic mild-stressed rat model. AB - Although major depressive disorder (MDD) is a serious neuropsychiatric illness, it's pathogenesis remains unclear. Current evidence suggests that the abnormal transmission and plasticity of hippocampal synapses play an important role in the pathogenesis of MDD. In this study, a two-dimensional gel-based proteomic approach to profile alterations of synaptosome protein expression was applied in the hippocampus of rats subjected to chronic mild stress. Through mass spectrometry and database searching, 19 differentially expressed proteins were identified, of which 5 were up-regulated and 14 were down-regulated in the chronic mild-stressed group as compared with the control group. Subsequently, several proteins of interest were further validated by Western blotting. A detailed analysis of protein functions and disease relevance revealed that synaptic exo/endocytosis-associated proteins were dysregulated in the chronic mild-stressed rats. The present study is the first reported synaptoproteomic analysis of the chronic mild-stressed rat hippocampus. The synaptic exo/endocytosis-associated proteins may participate in a central mechanism that underlies the abnormal transmission and plasticity of hippocampal synapses found in the chronic mild-stressed rats, and provides guidance to advance our understanding of the pathogenesis of MDD. PMID- 22922267 TI - Central pontine myelinolysis in the hyperosmolar hyperglycaemic state. AB - OBJECTIVE: To report a rare association of central pontine myelinolysis (CPM) with hyperosmolar hyperglycaemic state (HHS). CLINICAL PRESENTATION AND INTERVENTION: A diabetic female presented with HHS and prolonged severe hypernatraemia. The metabolic derangement was adequately treated with proper correction of both hyperglycaemia and hypernatraemia. Lack of improvement in the presenting confusional state and the development of a fresh neurological deterioration led to the suspicion of CPM that was confirmed with magnetic resonance imaging. She fully recovered after 4 weeks with no specific medical treatment. CONCLUSION: This case report showed that osmotic demyelination was linked to hypernatraemia and that CPM could result from severe hypernatraemia of HHS. PMID- 22922269 TI - Methods for validation of miRNA sequence variants and the cleavage of their targets. AB - MicroRNA (miRNA) variants that share the sequences with other closely related miRNAs have been identified by deep sequencing and have been implicated in the diverse regulation of their target genes. The miRNA variants that originate from the same miRNA precursor are among the most common and have been termed "isomiRs." IsomiRs can be generated by several mechanisms such as differential processing by DICER, RNA degradation, or RNA editing. Members of the same miRNA family that have distinct sequences also contribute to the diversity of miRNA variants. Although many miRNA variants are lowly expressed and may function redundantly with their reference miRNAs, some miRNA variants are highly and/or differentially expressed. In addition, slight differences in sequence among miRNA variants can affect their specificity in target selection. Here, we describe two methods for detecting or validating miRNA variants and the target events they mediate. PMID- 22922268 TI - Light-mediated control of DNA transcription in yeast. AB - A variety of methods exist for inducible control of DNA transcription in yeast. These include the use of native yeast promoters or regulatory elements that are responsive to small molecules such as galactose, methionine, and copper, or engineered systems that allow regulation by orthogonal small molecules such as estrogen. While chemically regulated systems are easy to use and can yield high levels of protein expression, they often provide imprecise control over protein levels. Moreover, chemically regulated systems can affect many other proteins and pathways in yeast, activating signaling pathways or physiological responses. Here, we describe several methods for light mediated control of DNA transcription in vivo in yeast. We describe methodology for using a red light and phytochrome dependent system to induce transcription of genes under GAL1 promoter control, as well as blue light/cryptochrome dependent systems to control transcription of genes under GAL1 promoter or LexA operator control. Light is dose dependent, inexpensive to apply, easily delivered, and does not interfere with cellular pathways, and thus has significant advantages over chemical systems. PMID- 22922270 TI - TACI mutation in Good's Syndrome: in search of a genetic basis. PMID- 22922271 TI - High IL-10 production by aged AIDS patients is related to high frequency of Tr-1 phenotype and low in vitro viral replication. AB - This work aims to elucidate the effects of age and HIV-1 infection on the frequency and function of T cell subsets in response to HIV-specific and non specific stimuli. As compared with the younger AIDS group, the frequencies of naive and central memory T cells were significantly lower in aged AIDS patients. Although there was also a dramatic loss of classical CD4(+)FoxP3(+)CD25(+)Treg cells in this patient group, high frequencies of IL-10-producing CD4(+)FoxP3(-) T cells were observed. In our system, the increased production of IL-10 in aged AIDS patients was mainly derived from Env-specific CD4(+)FoxP3(-)CD152(+) T cells. Interestingly, while the blockade of IL-10 activity by monoclonal antibody clearly enhanced the release of IL-6 and IL-1beta by Env-stimulated PBMC cultures from aged AIDS patients, this monoclonal antibody enhanced in vitro HIV-1 replication. In conclusion, HIV infection and aging undoubtedly contribute synergistically to a complex immune dysfunction in T cell compartment of HAART treated older HIV-infected individuals. PMID- 22922272 TI - Determination of the optical GAP in thin films of amorphous dilithium phthalocyanine using the Tauc and Cody models. AB - Semiconducting thin films were grown on quartz substrates and crystalline silicon wafers, using dilithium phthalocyanine and the organic ligands 2,6 dihydroxyanthraquinone and 2,6-diaminoanthraquinone as the starting compounds. The films, thus obtained, were characterized by Fourier Transform infrared (FTIR), fast atomic bombardment (FAB+) mass and ultraviolet-visible (UV-Vis) spectroscopies. The surface morphology of these films was analyzed by means of atomic force microscopy (AFM) and scanning electron microscopy (SEM). It was found that the temperature-dependent electric current in all cases showed a semiconductor behavior with conductivities on the order of 10-6.S cm-1, whereas the highest value corresponded to the thin film based upon the bidentate amine. The Tauc and Cody optical band gap values of thin films were calculated from the absorption coefficients and were found to be around 1.5 eV, with another strong band between 2.3 and 2.43 eV, arising from non-direct transitions. The curvature in the Tauc plot influencing the determination of the optical gap, the Tauc optical gap corresponding to the thicker film is smaller. The dependence of the Cody optical gap on the film thickness was negligible. PMID- 22922273 TI - Synthesis and biological activity evaluation of novel beta-substituted nitromethylene neonicotinoid analogues. AB - The structure-based design and synthesis of a series of novel neonicotinoid analogues are described. The novel neonicotinoid analogues were designed based upon the reaction of enamine derivatives with electron-withdrawing beta substituents with electrophilic thiocyanogen reagents. These compounds were characterized by spectroscopic methods. Bioassays indicated that some of the synthesized compounds exhibited excellent bioactivity against cowpea aphids (Aphis craccivora). The LC50 values of compounds 7, 9,12, 13, 15, 17, 19, 20 and commercial imidacloprid were 0.01567, 0.00974, 0.02494, 0.01893, 0.02677, 0.01778, 0.0220, 0.02447 and 0.03502 mmol L-1, respectively, which suggested that they could be used as leads for future development of new insecticides. PMID- 22922274 TI - Synthesis of oligonucleotides carrying thiol groups using a simple reagent derived from threoninol. AB - Oligonucleotides carrying thiol groups are useful intermediates for a remarkable number of applications involving nucleic acids. In this study, DNA oligonucleotides carrying tert-butylsulfanyl protected thiol groups have been prepared. A building block derived from threoninol has been developed to introduce a thiol group at any predetemined position of an oligonucleotide. The resulting thiolated oligonucleotides have been used for the preparation of oligonucleotide conjugates and for the functionalization of gold nanoparticles using the reactivity of the thiol groups. PMID- 22922276 TI - Formononetin attenuates IL-1beta-induced apoptosis and NF-kappaB activation in INS-1 cells. AB - Several studies suggest that the inflammation plays a role in the pathogenesis of some glucose disorders in adults. Exposure of pancreatic beta-cells to cytokines, such as interleukin-1beta (IL-1beta), is thought to contribute to beta-cell apoptosis. One important event triggered by IL-1beta is induction of nitric oxide synthase (iNOS), an enzyme that catalyzes intracellular generation of the cytotoxic free radical NO. Recent work have suggested that formononetin, as an O methylated isoflavone found in a number of plants and herbs like Astragalus membranaceus, inhibited some pro-inflammatory cytokine production in macrophages. However, the roles of formononetin in pancreatic beta cells have not been fully established. The aim of the present study was to assess possible in vitro effects of formononetin on cell apoptosis induced by IL-1beta in the rat insulinoma cell line, INS-1. Our results demonstrate that formononetin significantly prevents IL 1beta-increased INS-1 cell death and blocks cytokine-induced apoptotic signaling (the reduction of Bax/Bcl-2 ratio and caspase-3 activity). Formononetin also inhibited the activation of nuclear factor-kappaB (NF-kappaB), which is a significant transcription factor for iNOS, so as to decease nitric oxide (NO) formation in a dose dependent manner in vitro. Our observations indicated that formononetin could protect against pancreatic beta-cell apoptosis caused by IL 1beta and therefore could be used in the future as a new drug improving diabetes mellitus. PMID- 22922275 TI - Two new daucane sesquiterpenoids from Daphne aurantiaca. AB - Two new daucane sesquiterpenoids 1beta,2beta-epoxy-10(H)alpha-dauca-11(12)-ene 7alpha,14-diol and 1alpha,2alpha-epoxy-10(H)alpha-dauca-11(12)-ene-7alpha,14-diol were isolated from the plateau medicinal plant Daphne aurantiaca Diels. (Thymelaeceae). Their structures were elucidated by 1D and 2D NMR spectroscopy, as well as HR-ESI-MS data. PMID- 22922277 TI - Inhibition of Burkholderia multivorans adhesion to lung epithelial cells by bivalent lactosides. AB - Burkholderia cepacia complex (Bcc) is an opportunistic pathogen in cystic fibrosis patients which is inherently resistant to antimicrobial agents. The mechanisms of attachment and pathogenesis of Bcc, a group of 17 species, are poorly understood. The most commonly identified Bcc species in newly colonised patients, Burkholderia multivorans, continues to be acquired from the environment. Development of therapies which can prevent or reduce the risk of colonization on exposure to Bcc in the environment would be a better alternative to antimicrobial agents. Previously, it has been shown that Bcc strains bound to many glycolipid receptors on lung epithelia. Using a real-time PCR method to quantify the levels of binding of B. multivorans to the lung epithelial cells, we have examined glycoconjugate derivatives for their potential to inhibit host cell attachment. Bivalent lactosides previously shown to inhibit galectin binding significantly reduced the attachment of B. multivorans to CF lung epithelial cells at micromolar concentrations. This was in contrast to monosaccharides and lactose, which were only effective in the millimolar range. Development of glycoconjugate therapies such as these, which inhibit attachment to lung epithelial cells, represent an alternative means of preventing infection with inherently antimicrobially resistant pathogens such as B. multivorans. PMID- 22922279 TI - 4-Ferrocenylpyridine- and 4-ferrocenyl-3-ferrocenylmethyl-3,4-dihydropyridine-3,5 dicarbonitriles: multi-component synthesis, structures and electrochemistry. AB - The reactions of 2-cyano-3-ferrocenylacrylonitrile (1) with malononitrile (2) in a MeOH/H2O or 2-PrOH/H2O medium in the presence of Na2CO3 afforded 6-alkoxy-2 amino-4-ferrocenylpyridine-3,5-dicarbonitriles 3a,b (multi-component condensation) and 6-alkoxy-2-amino-4-ferrocenyl-3-ferrocenylmethyl-3,4 dihydropyridine-3,5-dicarbonitriles 4a,b (multi-component cyclodimerization). Analogous reactions of 1 with 2 in an MeOH/H2O medium in the presence of NaOH, piperidine, or morpholine gave compounds 3a, 4a and 2-amino-4-ferrocenyl-6 hydroxy-, 6-piperidino- and 6-morpholinopyridine-3,5-dicarbonitriles 3c-e, respectively. The structures of the compounds 3b, 4a and 4b were established by the spectroscopic data and X-ray diffraction analysis. The electrochemical behaviour of compounds 3b, 3d and 4b was investigated by means of cyclic voltammetry. PMID- 22922278 TI - A new cubitane diterpenoid from the soft coral Sinularia crassa. AB - A new cubitane diterpenoid, crassalone A (1), was isolated from the marine soft coral Sinularia crassa. The structure was determined by extensive spectroscopic analyses. Compound 1 is not cytotoxic (IC50 > 20 MUg/mL) toward the four human cancer cell lines tested (HL60, MDA-MB-231, HCT-116 and DLD-1). PMID- 22922280 TI - Activity of spray-dried microparticles containing pomegranate peel extract against Candida albicans. AB - Pomegranate has attracted interest from researchers because of its chemical composition and biological properties. It possesses strong antioxidant activity, with potential health benefits, and also antimicrobial properties. The aim of this study was to produce microparticles containing pomegranate extract by the spray-drying technique, utilizing alginate or chitosan as encapsulating agents. Characterization and antifungal assays were carried out. Production yields were about 40% for alginate microparticles and 41% for chitosan. Mean diameters were 2.45 um and 2.80 um, and encapsulation efficiencies were 81.9% and 74.7% for alginate and chitosan microparticles, respectively. The spray-drying process preserved the antifungal activity against Candida albicans. These results could be useful for developing dosage forms for treating candidiasis, and should be further investigated in in vivo models. PMID- 22922281 TI - Ameliorative effects of curculigoside from Curculigo orchioides Gaertn on learning and memory in aged rats. AB - This study was designed to evaluate the ameliorating effects of curculigoside from Curculigo orchioides Gaertn on learning and memory in aged rats. In the present study, the ameliorating effects of curculigoside were determined through animal behaviour studies (including step-down test and Y-maze test), and the possible mechanisms were explored by evaluation of the activity of acetylcholinesterase (AchE) and determination of the expression of BACE1. Oral adminstration of the curculigoside (20, 40 mg/kg/day) for 14 days can significantly improve the latency and number of errors in aged rats based on the behaviour study results. In addition, the activity of AchE can be decreased by treatment of the curculigoside (10, 20, 40 mg/kg/day). Moreover, the expression of BACE1 can be down-regulated in the hippocampus of aged rats treated with curculigoside. The results of our present work have indicated that curculigoside can improve cognitive function in aged animals, possibly by decreasing the activity of AchE in the cerebra and inhibiting the expression of BACE1 in the hippocampus. In conclusion, our results suggested that curculigoside can be possible developed as a new drug for the treatment of Alzheimer's disease in the future. PMID- 22922282 TI - Dry etching of copper phthalocyanine thin films: effects on morphology and surface stoichiometry. AB - We investigate the evolution of copper phthalocyanine thin films as they are etched with argon plasma. Significant morphological changes occur as a result of the ion bombardment; a planar surface quickly becomes an array of nanopillars which are less than 20 nm in diameter. The changes in morphology are independent of plasma power, which controls the etch rate only. Analysis by X-ray photoelectron spectroscopy shows that surface concentrations of copper and oxygen increase with etch time, while carbon and nitrogen are depleted. Despite these changes in surface stoichiometry, we observe no effect on the work function. The absorbance and X-ray diffraction spectra show no changes other than the peaks diminishing with etch time. These findings have important implications for organic photovoltaic devices which seek nanopillar thin films of metal phthalocyanine materials as an optimal structure. PMID- 22922283 TI - Mechanistic study of the spiroindolones: a new class of antimalarials. AB - During the synthesis of the new antimalarial drug candidate NITD609, a high degree of diastereoselectivity was observed in the Pictet-Spengler reaction. By isolating both the 4E and 4Z imine intermediates, a systematic mechanistic study of the reaction under both kinetic and thermodynamic conditions was conducted. This study provides insight into the source of the diastereoselectivity for this important class of compounds. PMID- 22922284 TI - Acetylcholinesterase-inhibiting activity of salicylanilide N-alkylcarbamates and their molecular docking. AB - A series of twenty-five novel salicylanilide N-alkylcarbamates were investigated as potential acetylcholinesterase inhibitors. The compounds were tested for their ability to inhibit acetylcholinesterase (AChE) from electric eel (Electrophorus electricus L.). Experimental lipophilicity was determined, and the structure activity relationships are discussed. The mode of binding in the active site of AChE was investigated by molecular docking. All the discussed compounds expressed significantly higher AChE inhibitory activity than rivastigmine and slightly lower than galanthamine. Disubstitution by chlorine in C'(3,4) of the aniline ring and the optimal length of hexyl-undecyl alkyl chains in the carbamate moiety provided the most active AChE inhibitors. Monochlorination in C'(4) exhibited slightly more effective AChE inhibitors than in C'(3). Generally it can be stated that compounds with higher lipophilicity showed higher inhibition, and the activity of the compounds is strongly dependent on the length of the N-alkyl chain. PMID- 22922285 TI - Distribution of primary and specialized metabolites in Nigella sativa seeds, a spice with vast traditional and historical uses. AB - Black cumin (Nigella sativa L., Ranunculaceae) is an annual herb commonly used in the Middle East, India and nowadays gaining worldwide acceptance. Historical and traditional uses are extensively documented in ancient texts and historical documents. Black cumin seeds and oil are commonly used as a traditional tonic and remedy for many ailments as well as in confectionery and bakery. Little is known however about the mechanisms that allow the accumulation and localization of its active components in the seed. Chemical and anatomical evidence indicates the presence of active compounds in seed coats. Seed volatiles consist largely of olefinic and oxygenated monoterpenes, mainly p-cymene, thymohydroquinone, thymoquinone, gamma-terpinene and alpha-thujene, with lower levels of sesquiterpenes, mainly longifolene. Monoterpene composition changes during seed maturation. gamma-Terpinene and alpha-thujene are the major monoterpenes accumulated in immature seeds, and the former is gradually replaced by p-cymene, carvacrol, thymo-hydroquinone and thymoquinone upon seed development. These compounds, as well as the indazole alkaloids nigellidine and nigellicine, are almost exclusively accumulated in the seed coat. In contrast, organic and amino acids are primarily accumulated in the inner seed tissues. Sugars and sugar alcohols, as well as the amino alkaloid dopamine and the saponin alpha-hederin accumulate both in the seed coats and the inner seed tissues at different ratios. Chemical analyses shed light to the ample traditional and historical uses of this plant. PMID- 22922286 TI - A synthetic method to access symmetric and non-symmetric 2-(N,N' disubstituted)guanidinebenzothiazoles. AB - Symmetric and non-symmetric 2-(N-H, N-methyl, N-ethylenyl and N aryl)guanidinebenzothiazoles were synthesized from the reaction of ammonia, methylamine, pyrrolidine and aniline with dimethyl benzo[d]thiazol-2-yl carbonodithioimidate as intermediate. The products were characterized by 1H-, 13C NMR spectroscopy and three of them by X-ray diffraction analysis. HN-phenyl protons formed intramolecular hydrogen bonds that assist the stereochemistry of the second substituent, whereas the HN-alkyl protons were involved in intermolecular hydrogen bonding. PMID- 22922287 TI - Oxygen atom transfer mediated by an iron(IV)/iron(II) macrocyclic complex containing pyridine and tertiary amine donors. AB - A new non-heme iron model complex containing a high-spin iron(II) complexed with N-methylated pyridine-containing macrocycle was synthesized and crystallographically characterized. The complex generates peroxo- and high-valent iron-oxo intermediates in reactions with tert-butylhydroperoxide and isopropyl 2 iodoxybenzoate, respectively, allowing to gain insight into the formation and reactivity of enzyme-like intermediates related to biological oxygen activation. The formation and reactivity of these intermediate species were investigated by the stopped-flow methodology. The mechanism of oxygen transfer to organic substrates involving reaction of oxoiron(IV) intermediate was elucidated on the basis of spectroscopic and kinetic data. Incorporation of a pyridine ring into the macrocycle increased the reactivity of the Fe(IV)=O intermediates in comparison with polyamine tetraaza macrocyclic complexes: ferryl (Fe(IV)=O) species derived from 3 demonstrated electrophilic reactivity in transferring an oxygen atom to substituted triarylphosphines and to olefins (such as cyclooctene). However, iron(III) alkylperoxo intermediate was unreactive with cyclooctene. PMID- 22922288 TI - Platinum(II) complexes containing long-chain hydrophobic N-alkyl-diamine ligands: synthesis, characterization, molecular modeling, and cytotoxic activity. AB - A series of novel platinum(II) complexes derived from N-alkyl-ethanediamine and N alkyl-propanediamine ligands were prepared and characterized. These complexes contain a long chain aliphatic diamine where the carbon length is variable and present a hydroxyl group in two different positions. The complexes with the ethanediamine derivatives were prepared from K(2)PtCl(4). Interestingly, the propanediamine derivatives did not react well with this platinum salt under the experimental conditions normally employed and could only be obtained from the more reactive K(2)PtI(4). A theoretical molecular modeling study was performed to understand this difference in reactivity and it showed that the conformation around the diamine plays an important role in the ring closure step of complex formation. The complexes had their cytotoxicity investigated in B16F1, CT26, B16F10, and MDA cell lines. Some of them demonstrated superior activity when compared to cisplatin and carboplatin. We were also able to confirm a structure activity relationship between cytotoxicity and carbon chain length. PMID- 22922289 TI - The interplay of peptide sequence and local structure in TiO2 biomineralization. AB - Using cyclic constrained TiO(2) binding peptides STB1 (CHKKPSKSC), RSTB1 (CHRRPSRSC) and linear peptide LSTB1 (AHKKPSKSA), it was shown that while affinity of the peptide to TiO(2) is essential to enable TiO(2) biomineralization, other factors such as biomineralization kinetics and peptide local structure need to be considered to predict biomineralization efficacy. Cyclic and linear TiO(2) binding peptides show significantly different biomineralization activities. Cyclic STB1 and RSTB1 could induce TiO(2) precipitation in the presence of titanium(IV)-bis-ammonium-lactato-dihydroxide (TiBALDH) precursor in water or tris buffer at pH 8. In contrast, linear LSTB1 was unable to mineralize TiO(2) under the same experimental conditions despite its high affinity to TiO(2) comparable with STB1 and/or RSTB1. LSTB1 being a flexible molecule could not render the stable condensation of TiBALDH precursor to form TiO(2) particles. However, in the presence of phosphate buffer ions, the structure of LSTB1 is stabilized, leading to efficient condensation of TiBALDH and TiO(2) particle formation. This study demonstrates that peptide-mediated TiO(2) mineralization is governed by a complicated interplay of peptide sequence, local structure, kinetics and the presence of mineralizing aider such as phosphate ions. PMID- 22922291 TI - Tumor necrosis factor alpha stimulates Her-2 cleavage by activated caspase-8. AB - BACKGROUND/AIM: Her-2 over-expression has been correlated with a poor prognosis in patients with breast cancer. Now, we explored the effect of TNF-alpha treatment and/or NFKB activation on Her-2 expression in MCF-7 breast adenocarcinoma cells. METHODS: Stably transfected MCF-7 cell lines with pcDNA3.0, IKBalpha MT, c-FLIP/control shRNA were established by FuGENE with the supplementation of G418 (500 ug /ml). Western blot and Real-time PCR were applied to assess the expression levels of protein and mRNA of target gene. In addition, caspase-8 activity was evaluated by the incubation with a caspase-8 fluorogenic substrate, Ac-IEPD-AMC using a spectrofluorometer. RESULTS: It was uncovered that Her-2 was a new substrate for caspase-8 and that tumor necrosis factor alpha (TNF alpha) stimulation resulted in a caspase-8-dependent Her-2 cleavage in MCF-7 breast adenocarcinoma cells defective for nuclear factor KB (NFKB) activation. We demonstrated that the antiapoptotic transcription factor NFKB counteracted this cleavage through the induction of caspase-8 inhibitor, c-FLIP. CONCLUSION: we propose a novel mechanism in which NFKB functions as a new antiapoptotic factor by counteracting TNF-alpha-triggered Her-2 cleavage. PMID- 22922292 TI - Effect of umbilical cord bleeding following mid-pregnancy cordocentesis on pregnancy outcomes. AB - OBJECTIVES: To compare the adverse pregnancy outcomes among the three groups of umbilical cord bleeding following cordocentesis; a group of no bleeding (group 1), transient bleeding (group 2), and persistent bleeding (>60 s: group 3). METHODS: Consecutive cases of cordocentesis were prospectively recorded and followed up. The inclusion criteria for analysis consisted of (1) singleton pregnancies; (2) gestational age of 18-22 weeks; (3) no fetal anomalies; (4) no previous invasive procedures; (5) performed by experienced operators, and (6) known pregnancy outcomes. The main outcomes were rates of fetal loss, low birth weight and preterm birth. RESULTS: Of 2,174 procedures, 1,614 were in group 1, 509 were in group 2, and 51 were in group 3. The mean birth weight and gestational age at delivery were significantly lower in group 3 than those in groups 1 and 2. The fetal loss rate was significantly higher in group 3. Rates of low birth weight and preterm birth were significantly higher in group 3 whereas the rates in group 2 had a tendency to be higher than those in group 1. CONCLUSION: This study suggests that cord bleeding during cordocentesis carries a higher risk of fetal loss, low birth weight and preterm birth. PMID- 22922293 TI - Double aortic arch. PMID- 22922294 TI - PET/CT and SPECT/CT cardiac fusion imaging in a patient with takotsubo cardiomyopathy. PMID- 22922290 TI - Major signaling pathways in intestinal stem cells. AB - BACKGROUND: The discovery of markers to identify the intestinal stem cell population and the generation of powerful transgenic mouse models to study stem cell physiology have led to seminal discoveries in stem cell biology. SCOPE OF REVIEW: In this review we give an overview of the current knowledge in the field of intestinal stem cells (ISCs) highlighting the most recent progress on markers defining the ISC population and pathways governing intestinal stem cell maintenance and differentiation. Furthermore we review their interaction with other stem cell related pathways. Finally we give an overview of alteration of these pathways in human inflammatory gastrointestinal diseases. MAJOR CONCLUSIONS: We highlight the complex network of interactions occurring among different pathways and put in perspective the many layers of regulation that occur in maintaining the intestinal homeostasis. GENERAL SIGNIFICANCE: Understanding the involvement of ISCs in inflammatory diseases can potentially lead to new therapeutic approaches to treat inflammatory GI pathologies such as IBD and celiac disease and could reveal the molecular mechanisms leading to the pathogenesis of dysplasia and cancer in inflammatory chronic conditions. This article is part of a Special Issue entitled Biochemistry of Stem Cells. PMID- 22922295 TI - Are the significant effects really significant? PMID- 22922296 TI - Molecular genetic analysis of influenza A/H3N2 virus strains isolated in Western Siberia in the 2010-2011 epidemic season. AB - Molecular genetic and antigenic features of influenza A/H3N2 virus strains isolated in Western Siberia in 2011 are similar to those of the vaccine strain A/Perth/16/2009 despite a number of unique amino-acid changes. The strains lack specific amino-acid changes in NA protein providing decrease of sensibility to NA inhibitors activity that used in medical practice. Based on phylogenic analysis of HA protein amino-acid sequences examined strains are similar to influenza A/H3N2 virus strains circulating at the moment in Eurasia. PMID- 22922297 TI - Mitochondrial genome of Angiostrongylus vasorum: comparison with congeners and implications for studying the population genetics and epidemiology of this parasite. AB - Angiostrongylus vasorum is a strongylid nematode of major clinical relevance in canids, causing angiostrongylosis. In spite of its increasing importance, the genetics, epidemiology and biology of this parasite are not entirely understood. Mitochondrial (mt) DNA provides useful markers for studies of these areas, but genetic data are scant for A. vasorum and its congeners. Here, the mitochondrial genome was amplified by long-range polymerase chain reaction (long-PCR) from a portion of a single male adult of A. vasorum, sequenced using 454 technology and annotated employing a semi-automated bioinformatic pipeline. This circular mitochondrial genome is 13,422 bp and contains 12 protein-encoding, 22 transfer RNA, and two ribosomal RNA genes, consistent with its congeners and other secernentean nematodes. This mt genome represents a rich source of markers for future investigations of the population genetics and epidemiology of A. vasorum. Molecular tools, employing such mt markers, should be useful for explorations into host specificity and for prospecting for cryptic species, and might also underpin the diagnosis of canine angiostrongylosis. PMID- 22922298 TI - Using different methods to evaluate the efficacy of olmesartan medoxomil in Chinese patients with mild to moderate essential hypertension according to ambulatory blood pressure monitoring. AB - OBJECTIVE: To evaluate the efficacy of olmesartan medoxomil in Chinese patients with mild to moderate essential hypertension using different methods according to ambulatory blood pressure monitoring. METHODS: Chinese patients 18-75 years of age with clinic diastolic blood pressure (BP) 90-109 mmHg and systolic BP less than 180 mmHg were treated with olmesartan medoxomil 20-40 mg once daily for 24 weeks to reach the goal BP (< 140/90 and < 130/80 mmHg in diabetes) in a multicenter study. The trough-to-peak ratio (T/P ratio) and the smoothness index (SI) for systolic/diastolic BP were calculated using different methods according to ambulatory blood pressure monitoring. RESULT: Olmesartan medoxomil 20-40 mg once daily reduced the systolic/diastolic ambulatory BP for 24-h, daytime, and night-time by 13.3 +/- 16.3/7.6 +/- 9.5, 13.9 +/- 17.4/8.0 +/- 10.4, and 12.3 +/- 18.1/6.8 +/- 10.2 mmHg in all eligible patients at week 24 from baseline (n = 87, P < 0.0001). The global and individual T/P ratios were 0.64/0.62 and 0.32/0.30 (n = 87) for systolic/diastolic BP, whereas these were 0.71/0.70 and 0.31/0.39 in fair responders (n = 71). Global and individual SI were 6.81/5.37 and 0.92/0.67 (n = 87) for systolic/diastolic BP, whereas these were 7.04/5.44 and 1.03/1.03 in fair responders (n = 71). Global and individual T/P ratios for systolic/diastolic BP were 0.75/0.82 and 0.45/0.46 in the 20 mg subgroup (n = 41), whereas these were 0.44/0.59 and 0.30/0.29 in the 40 mg subgroup (n = 30). Global and individual SI were 5.70/5.32 and 1.03/0.87 for systolic/diastolic BP in the 20 mg subgroup (n = 41), but these were 3.64/2.46 and 1.01/0.60 in the 40 mg subgroup (n = 30). CONCLUSION: The duration of the antihypertensive action of olmesartan medoxomil with 20-40 mg once daily can be assessed by the global T/P ratio and SI rather than the individual values, even in different populations and dosages. PMID- 22922300 TI - Country factors associated with the risk of hospitalization and aeromedical evacuation among expatriate workers. AB - OBJECTIVE: To assess country factors associated with the risk of requiring aeromedical evacuation and hospitalization among expatriate workers and their dependents. METHODS: The 2009-2010 data including 5725 aeromedical evacuations and 17,828 hospitalizations, and 2009 data of hospitalizations and aeromedical evacuations among 94,651 at-risk expatriates, were analyzed to assess 2 country risk rating tools. Each tool utilized four risk categories and reflected level of development and medical capabilities. RESULTS: Country risk category was strongly associated with risk of evacuation and/or hospitalization for each risk rating tool (eg, 46-fold increase from lowest to highest country risk category). CONCLUSION: Country risk tools strongly associate hospitalization and aeromedical evacuation with country risk category, and thus can be important indicators of relative medical risk. Employers may use these results to implement targeted prevention programs to support expatriate workers and their families. PMID- 22922299 TI - Bioengineering: a bacteriocin perspective. AB - While the bacteriocin Nisin has been employed by the food industry for 60 y, it remains the only bacteriocin to be extensively employed as a food preservative. This is despite the fact that the activity of Nisin against several food spoilage and pathogenic bacteria is poor and the availability of many other bacteriocins with significant potential in this regard. An alternative route to address the deficiencies of Nisin is the application of bioengineered derivatives of the peptide which, despite differing only subtly, possess enhanced capabilities of commercial value. The career path which has taken me from learning for the first time what bacteriocins are to understanding the potential of bacteriocin bioengineering has been a hugely enjoyable experience and promises to get even more interesting in the years to come. PMID- 22922301 TI - Intracranial sarcoma metastasizing along distal shunt tubing. PMID- 22922302 TI - Genome walking by Klenow polymerase. AB - Genome walking procedures are all based on a final polymerase chain reaction amplification, regardless of the strategy employed for the synthesis of the substrate molecule. Here we report a modification of an already established genome walking strategy in which a single-strand DNA substrate is obtained by primer extension driven by Klenow polymerase and which results suitable for the direct sequencing of complex eukaryotic genomes. The efficacy of the method is demonstrated by the identification of nucleotide sequences in the case of two gene families (chiA and P1) in the genomes of several maize species. PMID- 22922303 TI - Angiopoietins in angiogenesis. AB - Tie-1 and Tie-2 tyrosine kinase receptors are expressed specifically on vascular endothelial cells and on a certain subtype of macrophages implicated in angiogenesis, thus, they have been a major focus of angiogenesis research. Tie-1 and Tie-2 are essential for vascular maturation during developmental, physiological and pathological angiogenesis. Angiopoietin 1-4 (Ang-1-4) have been identified as bona fide ligands of the Tie-2 receptor, while Tie-1 remains an orphan receptor which is able to heterodimerize with Tie-2 and to modulate Tie-2 signal transduction. The most exhaustively studied angiopoietins are Ang-1 and Ang-2. Ang-1 is a critical player in vessel maturation and it mediates migration, adhesion and survival of endothelial cells. Ang-2 disrupts the connections between the endothelium and perivascular cells and promotes cell death and vascular regression. Yet, in conjunction with VEGF, Ang-2 promotes neo vascularization. Hence, angiopoietins exert crucial roles in the angiogenic switch during tumor progression, and increased expression of Ang-2 relative to Ang-1 in tumors correlates with poor prognosis. Its central role in the regulation of physiological and pathological angiogenesis makes the angiopoietin/Tie signaling pathway a therapeutically attractive target for the treatment of vascular disease and cancer. PMID- 22922304 TI - Towards a turning point of neuroblastoma therapy. AB - In 1983, the MYCN oncogene amplification was discovered in neuroblastoma cells and few years later its prognostic role was clearly demonstrated. The first European study, in which MYCN gene status is taken as prognostic factor for therapeutic decision, was released by SIOPEN and GPOH in 1995. Afterward, other trials were released by SIOPEN, GPOH, COG, and JNBSG in which MYCN gene amplification was employed as prognostic risk factor. However, since MYCN is abnormal in about 20% of tumors and is a reliable prognostic marker for only some subgroups of patients, additional chromosomal abnormalities have been introduced for clinical decisions: 1p deletions/imbalances (GPOH), 11q deletions/imbalances (COG), and structural copy number aberrations (SIOPEN). MYCN gene status and chromosome aberrations improved patients' risk evaluation and helped to develop tailored therapy for diverse subgroups of patients. Unfortunately, high risk patients still have an unfavorable prognosis and are the major challenge for oncologists. In the last decade, the advent of genome-wide analysis and the next generation sequencing technique have given the opportunity to deeply investigate the genome of neuroblastoma to identify both candidate genes associated with tumor progression and druggable target genes. ALK gene is an actual candidate for the therapy with small molecule inhibitors, but others as mTOR, Aurora, and TRK, are suitable targets for subgroups of high risk patients. The huge amount of clinical and biological information collected in the last 20 years suggests that it is time to turn on for new and more personalized therapies of neuroblastoma. PMID- 22922305 TI - Pharmacokinetic and toxicological evaluation of multi-functional thiol-6-fluoro-6 deoxy-D-glucose gold nanoparticles in vivo. AB - We synthesized a novel, multi-functional, radiosensitizing agent by covalently linking 6-fluoro-6-deoxy-D-glucose (6-FDG) to gold nanoparticles (6-FDG-GNPs) via a thiol functional group. We then assessed the bio-distribution and pharmacokinetic properties of 6-FDG-GNPs in vivo using a murine model. At 2 h, following intravenous injection of 6-FDG-GNPs into the murine model, approximately 30% of the 6-FDG-GNPs were distributed to three major organs: the liver, the spleen and the kidney. PEGylation of the 6-FDG-GNPs was found to significantly improve the bio-distribution of 6-FDG-GNPs by avoiding unintentional uptake into these organs, while simultaneously doubling the cellular uptake of GNPs in implanted breast MCF-7 adenocarcinoma. When combined with radiation, PEG-6-FDG-GNPs were found to increase the apoptosis of the MCF-7 breast adenocarinoma cells by radiation both in vitro and in vivo. Pharmacokinetic data indicate that GNPs reach their maximal concentrations at a time window of two to four hours post-injection, during which optimal radiation efficiency can be achieved. PEG-6-FDG-GNPs are thus novel nanoparticles that preferentially accumulate in targeted cancer cells where they act as potent radiosensitizing agents. Future research will aim to substitute the (18)F atom into the 6-FDG molecule so that the PEG-6-FDG-GNPs can also function as radiotracers for use in positron emission tomography scanning to aid cancer diagnosis and image guided radiation therapy planning. PMID- 22922306 TI - Randomized controlled clinical trial on proximal caries infiltration: three-year follow-up. AB - We report the 3-year efficacy of resin infiltration (Icon, pre-product; DMG, Hamburg) to arrest progression of proximal non-cavitated caries lesions as compared with placebo treatment. In 22 young adults, 29 lesion pairs with radiographic extensions into the inner half of enamel up to the outer third of dentin were included (split-mouth design). All subjects received risk-related instructions for diet, flossing and fluoridation. No unwanted effects could be observed. Radiographically 1/26 test lesions (4%) and 11/26 control lesions (42%) had progressed (p = 0.002, McNemar). After 3-year follow-up, infiltration of proximal caries lesions can be said to be efficacious to reduce lesion progression. PMID- 22922307 TI - Complications from inflammatory bowel disease during pregnancy and delivery. AB - BACKGROUND & AIMS: Little is known about complications from ulcerative colitis (UC) or Crohn's disease (CD) during pregnancy and delivery. We assessed complications by using data from a large, population-based cohort. METHODS: We analyzed data from 1209 women with UC, 787 women with CD, and 10,773 women without these diseases (the comparison group) by using the Medical Birth, Patient, and Prescribed Drug Registers of all residents in Sweden. All the women included in the analysis gave birth to a single infant between October 2006 and December 2009. We used data on medical treatment, surgery, and hospital admissions to assess disease activity. Risks of pregnancy and delivery complications were determined from adjusted odds ratios (aORs) with 95% confidence intervals (CIs). RESULTS: The risk of venous thromboembolism was increased among women with UC (aOR, 3.78; 95% CI, 1.52-9.38), particularly for those with flaring disease. Women with CD had a higher risk of antepartum hemorrhage (aOR, 1.66; 95% CI, 1.12-2.45), with the highest risks among those with no disease activity. Risks of elective cesarean delivery were more than doubled among women with UC (aOR, 2.44; 95% CI, 2.06-2.88) or CD (aOR, 2.31; 95% CI, 1.89-2.83). Women with UC (aOR, 1.39; 95% CI, 1.13-1.70) or CD (aOR, 1.50; 95% CI, 1.17-1.92) had increased risk for emergency cesarean delivery. Women with an inactive UC or flaring CD had the highest risks of cesarean delivery. CONCLUSIONS: Women with UC or CD have more complications during pregnancy and delivery than women without these diseases. Disease activity affects mode of delivery, and thrombophilic events present differently in women with UC vs CD. PMID- 22922308 TI - Femtomolar Zn2+ affinity of LIM domain of PDLIM1 protein uncovers crucial contribution of protein-protein interactions to protein stability. AB - An individual LIM domain has approximately 55 amino acids with 8 highly conserved residues responsible for binding of two Zn(2+) into two distinct zinc finger motifs. We examined LIM domain stability of PDLIM1 protein (known also as Elfin protein), its C-terminally extended constructs as well as separate zinc fingers, and several full domain mutants in terms of Zn(2+) affinity and domain stability. Thermal denaturation, mass spectrometry, limited proteolysis, protein oxidation and circular dichroism techniques were used to determine a set of thermodynamic stability parameters. The results demonstrate unambiguously very high (femtomolar) affinity of both Zn(2+) to the conserved LIM domain (K(d)(av)=2.5*10(-14) M) and its additional elevation in the C-terminally extended domain construct (K(d)(av)=3.1*10(-15) M). We demonstrate in the example of PDLIM1 using a set of LIM protein constructs and its zinc finger peptides that stability of the entire zinc-containing domain is not only defined by the Zn(2+) coordination environment but significantly depends on the set of protein-protein interactions with the C-terminus of the protein. We discuss structural similarities of LIM domains and suggest the prolongation of the conserved LIM sequence to its C-terminal helix that has a significant impact on domain stability. We also discuss the functionality of LIM domains in terms of different physiological zinc and redox buffering capacity. PMID- 22922309 TI - Synthesis, crystal structure, characterisation, and antifungal activity of 3 thiophene aldehyde semicarbazone (3STCH), 2,3-thiophene dicarboxaldehyde bis(semicarbazone) (2,3BSTCH2) and their nickel (II) complexes. AB - The reaction of nickel (II) chloride and bromide with 3-thiophene aldehyde semicarbazone (3STCH) and 2,3-thiophene dicarboxaldehyde bis(semicarbazone) (2,3BSTCH(2)) leads to the formation of a series of new complexes: [NiCl(2)(3STCH)(2)], [NiBr(2)(3STCH)(2)], [NiCl(2,3BSTCH(2))(H(2)O)]Cl, and [NiBr(2,3BSTCH(2))(H(2)O)]Br respectively. The crystal structures of the two ligands 3STCH, 2,3BSTCH(2) and of the complex [NiBr(2,3BSTCH(2))(H(2)O)]Br have been determined by X-ray diffraction methods. For all these complexes, the central ion is coordinated through the oxygen atom of the carbonyle and the azomethine nitrogen atom of the semicarbazone. The antifungal activity of the complexes and their corresponding ligands was evaluated against some strains of respectively, Candida albicans, Candida glabrata and Aspergillus fumigatus. The complexes with 3STCH and 2,3BSTCH(2) revealed interesting CMI(80) values specifically against C. glabrata. Cytotoxicity assay was also carried out in vitro on MRC5 cells. PMID- 22922310 TI - VO(dmpp)2 normalizes pre-diabetic parameters as assessed by in vivo magnetic resonance imaging and spectroscopy. AB - Type 2 diabetes mellitus has been associated with obesity, metabolic syndrome, cardiovascular diseases and cancer. Attempts have been made for early diagnosis and finding effective drugs to prevent severe consequences and ameliorate the symptoms of this disorder. In this work, the pharmacological properties of VO(dmpp)(2), [bis(1,2-dimethyl-3-hydroxy-4-pyridinonato)oxovanadium(IV)], were in vivo evaluated. For 4 weeks fatty Zucker rats were subjected to a daily dose of VO(dmpp)(2) (44 MUmol/kg) and their metabolic profile was followed by assessing different biological parameters at established time points: body weight, subcutaneous fat width and hepatic triglyceride content determined by magnetic resonance imaging and spectroscopy, respectively. A glucose tolerance test was performed at the end of the experiment. After treatment, treated obese rats presented a weight significantly lower than the non-treated obese animals (359.0+/-11.1 vs. 433.5+/-6.2g, P<0.05), a thinner subcutaneous fat width, and a statistically significant decrease in hepatic triglyceride content (5.41+/-0.59 vs. 21.03+/-1.40%, P<0.0005). Additionally, the glucose intolerant profile of fatty Zucker rats was completely reversed in treated animals (102.3+/-2.1 vs. 172.4+/-1.3 mg/100 mL; P<0.0005). These results reinforce the therapeutic action of VO(dmpp)(2) which shows particular effects on lipid metabolism. PMID- 22922312 TI - How to modify 7-azaindole to form cytotoxic Pt(II) complexes: highly in vitro anticancer effective cisplatin derivatives involving halogeno-substituted 7 azaindole. AB - The platinum(II) dichlorido and oxalato complexes of the general formula cis [PtCl(2)(nHaza)(2)] (1-3) [Pt(ox)(nHaza)(2)] (4-6) involving 7-azaindole halogeno derivatives (nHaza) were prepared and thoroughly characterized. A single-crystal X-ray analysis of cis-[PtCl(2)(3ClHaza)(2)].DMF (1.DMF; 3ClHaza symbolizes 3 chloro-7-azaindole) revealed a distorted square-planar arrangement with both the 3ClHaza molecules coordinated through their N7 atoms in a cis fashion. In vitro cytotoxicity of the complexes was evaluated by an MTT [3-(4,5-dimethylthiazol-2 yl)-2,5-diphenyltetrazolium bromide] assay against the HOS (osteosarcoma), MCF7 (breast adenocarcinoma) and LNCaP (prostate adenocarcinoma) human cancer cell lines. The dichlorido complexes 1-3 (IC(50)=3.8, 3.9, and 2.5 MUM, respectively) showed significantly higher in vitro anticancer effect against HOS as compared with cisplatin, whose IC(50)=37.7 MUM. The biological effect of cisplatin against MCF7 (IC(50)=24.5 MUM) and LNCaP (IC(50)=3.8 MUM) was also exceeded by 1-3 (except for 2 against LNCaP), but the difference can be classified as significant only in the case of 1 (IC(50)=3.4 MUM) and 3 (IC(50)=2.0 MUM) against MCF7. The molecular pharmacological studies (RNA synthesis by T7 RNA polymerase in vitro) proved that 1-3 bind to DNA in a similar manner as cisplatin, since the RNA synthesis products of 1-3 and cisplatin showed a similar sequence profile of major bands. PMID- 22922313 TI - Mn(II) complexes with sulfonamides as ligands. DNA interaction studies and nuclease activity. AB - Sulfonamides derived from 8-aminoquinoline react with Mn(II) and Mn(III) salts to form Mn(II) complexes; the Mn(III) species are reduced to the divalent state in the presence of 1,10 phenanthroline and bipyridine. Their molecular structure, determined by single crystal X-ray diffraction, show that all the complexes present a distorted octahedral geometry, in which the deprotonated sulfonamide acts as a bidentate ligand. UV-visible spectroscopy and changes in the melting temperature (Tm) of calf thymus DNA show a strong interaction of these complexes with DNA. The significant hypochromicity of the charge transfer transition at 370 nm without an appreciable change in wavelength and the minor changes in the relative viscosity of calf thymus DNA have been attributed to an interaction between the surface of DNA and the complexes. [Mn(qbsa)(2)(MeOH)(2)], [Mn(qbsa)(2)(phen)], [Mn(qtsa)(2)(H(2)O)(2)] and [Mn(qtsa)(2)(phen)] (where qbsa=N-quinolin-8-yl-bencenesulfonamide, qtsa=N-quinolin-8-yl-p toluenesulfonamide and qnsa=N-quinolin-8-yl-naftalenesulfonamide) exhibit a prominent nuclease activity and the mechanism of DNA cleavage is investigated. PMID- 22922311 TI - A series of hybrid P450 BM3 enzymes with different catalytic activity in the light-initiated hydroxylation of lauric acid. AB - We have developed a series of hybrid P450 BM3 enzymes to perform the light activated hydroxylation of lauric acid. These enzymes contain a Ru(II)-diimine photosensitizer covalently attached to single cysteine residues of mutant P450 BM3 heme domains. The library of hybrid enzymes includes four non-native single cysteine mutants (K97C, Q397C, Q109C and L407C). In addition, mutations around the heme active site, F87A and I401P, were inserted in the Q397C mutant. Two heteroleptic Ru(II) complexes, Ru(bpy)(2)phenA (1) and Ru(phen)(2)phenA (2) (bpy=bipyridine, phen=1,10-phenanthroline, and phenA=5-acetamido-1,10 phenanthroline), are used as photosensitizers. Upon visible light irradiation, the hybrid enzymes display various total turnover numbers in the hydroxylation of lauric acid, up to 140 for the L407C-1 mutant, a 16-fold increase compared to the F87A/Q397C-1 mutant. CO binding studies confirm the ability of the photogenerated Ru(I) compound to reduce the fraction of ferric high spin species present in the mutants upon substrate binding. PMID- 22922314 TI - Another case of genitopatellar syndrome: a case report with additional rare coexistences. PMID- 22922315 TI - Proximal femoral focal deficiency and fibular hemimelia associated with misoprostol use: a case report. PMID- 22922316 TI - Mesenchymal stem cell prevention of vascular remodeling in high flow-induced pulmonary hypertension through a paracrine mechanism. AB - Pulmonary arterial hypertension (PAH) is characterized by functional and structural changes in the pulmonary vasculature, and despite the drug treatment that made significant progress, the prognosis of patients with advanced PH remains extremely poor. In the present study, we investigated the early effect of bone marrow mesenchymal stem cells (BMSCs) on experimental high blood flow induced PAH model rats and discussed the mechanism. BMSCs were isolated, cultured from bone marrow of Sprague-Dawley (SD) rat. The animal model of PAH was created by surgical methods to produce a left-to-right shunt. Following the successful establishment of the PAH model, rats were randomly assigned to three groups (n=20 in each group): sham group (control), PAH group, and BMSC group (received a sublingual vein injection of 1-5 * 10(6) BMSCs). Two weeks after the administration, BMSCs significantly reduced the vascular remodeling, improved the hemodynamic data, and deceased the right ventricle weight ratio to left ventricular plus septal weight (RV/LV+S) (P<0.05). Real-time reverse transcription-polymerase chain reaction (RT-PCR) and immunohistochemistry analysis results indicated that the inflammation factors such as interleukin 1beta (IL-1beta), IL-6, and tumor necrosis factor-alpha (TNF-alpha) were reduced (P<0.05); the expression of matrix metallo proteinase-9 (MMP-9) was lower (P<0.05); vascular endothelial growth factor (VEGF) was higher in BMSC group than those in PAH group (P<0.05). CONCLUSION: Sublingual vein injection of BMSCs for 2 weeks, significantly improved the lung and heart injury caused by left-to-right shunt-induced PAH; decreased pulmonary vascular remodeling and inflammation; and enhanced angiogenesis. PMID- 22922317 TI - Ac-SDKP ameliorates the progression of lupus nephritis in MRL/lpr mice. AB - N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP) is an endogenous tetrapeptide which can inhibit the differentiation, migration and activation of macrophages and suppress the proliferation of fibroblast. This study examined the effects of Ac-SDKP on the progression of lupus nephritis (LN). MRL/lpr mice received subcutaneous infusion of Ac-SDKP (1.0 mg kg(-1) d(-1)) or vehicle through implanted osmotic mini-pumps from 12 to 20 weeks until being euthanized. MRL/MpJ mice served as normal controls. The data indicative of renal inflammation and fibrosis were evaluated before and after treatment. Ac-SDKP-treated MRL/lpr mice showed reduced proteinuria and improved renal function compared with vehicle treated controls. Ac-SDKP-treated mice demonstrated decreased inflammatory infiltrates of T cells and macrophages in the kidneys as compared to vehicle treated animals. The treatment also inhibited the activation of NF-kappaB and production of TNF-alpha. Despite this, immune complex deposition and plasma anti dsDNA levels were not statistically different between the two groups. In addition, the treatment inhibited renal expression of TGF-beta1, alpha-SMA and fibronectin as well as the phosphorylation of Smad2/3. Ac-SDKP treatment ameliorated LN through exerting anti-inflammatory and anti-fibrotic effects on MRL/lpr mice, providing therapeutic potential for halting the progression of LN. PMID- 22922318 TI - Mapping of CGRP in the alpaca diencephalon. AB - We report the distribution of immunoreactive cell bodies and fibers containing calcitonin gene-related peptide in the alpaca diencephalon. This study was carried out in alpacas that lived from birth to death at 0 m above sea level. Immunoreactive fibers were widely distributed throughout the thalamus and hypothalamus. A moderate density of these fibers was found in the zona incerta, the central medial, subparafascicular, reuniens and rhomboid thalamic nuclei, in the preoptic, anterior, lateral and dorsal hypothalamic areas, around the fornix, in the posterior, ventromedial and paraventricular hypothalamic nuclei and in the lateral mammillary nucleus. Cell bodies were only found in the hypothalamus: a high density in the paraventricular and supraoptic hypothalamic nuclei and a low density in the anterior, lateral and dorsal hypothalamic areas, around the fornix, and in the posterior and ventromedial hypothalamic nuclei. The widespread distribution of calcitonin gene-related peptide in the alpaca diencephalon suggests that it is involved in many physiological actions that must be investigated in-depth in the future, since alpacas lives from 0 m above sea level to altitudes of up to 5000 m altitude and hence the involvement of neuropeptides in special and unique regulatory physiological mechanisms could be suggested. PMID- 22922319 TI - Long-term cross-sex hormone treatment is safe in transsexual subjects. AB - The European Journal of Endocrinology recently published a paper (Asscheman et al.) presenting mortality data from more than a thousand transsexuals followed for a median time of 18 years and who had undergone previous or were currently on long term cross-sex hormonal treatment. Transsexualism is a rare condition and in scientific literature there are few reports on the long-term safety of different treatment protocols and on the physical and psychological outcomes of medical treatments. The safety of long-term high doses oestrogen or testosterone in subjects of the opposite sex has been debated and data on long term effects are scant at best. The Asscherman paper therefore represents a very important and reassuring reference for professionals working in this field suggesting that mortality is increased among transsexuals although due to causes unrelated to cross sex replacement therapy. These results will benefit the care and treatment of these subjects. PMID- 22922320 TI - Influence of reproductive tract obstruction on expression of epididymal proteins and their restoration after patency. AB - Vasectomy is a simple and reliable method of male contraception. A growing number of men after vasectomy request vasectomy reversal due to various reasons. The pregnancy rate is lower than the patency rate after vasovasostomy and the pregnancy rate is time dependent. In this study, we evaluated the influence of reproductive tract obstruction on expression of epididymal proteins and their restoration after patency. Adult male Wistar rats were studied 30, 60 and 120 days after vasectomy, 30 days after vasovasostomy or after sham operations. Two dimensional gel electrophoresis, mass-spectrometric technique, multidatabase search, Western blotting and real-time PCR were used to analyze the expression regulation of epididymal proteins. Total integrated intensity and total spot area of autoradiograms showed a consistent downward trend with time after obstruction, and this trend remained after patency. The intensity of the autoradiographic spots in three patency groups showed three trends: a downward trend, similar intensity and an upward trend compared with the correspondent obstruction group, respectively. Further verified experiments on human epididymis 2 (HE2), fertilization antigen-1 (FA-1), clusterin and PH20 demonstrated that compared with the correspondent obstruction group, the translation levels of HE2 and the mRNA transcription levels of HE2 showed an upward trend in patency groups, especially in the groups of obstruction for 60 days where the expression levels of HE2 were significantly upregulated after patency (P<0.05). Reproductive tract obstruction provokes a disregulation of gene expression in the epididymis and this disregulation remained after patency. Successful reversal may recover some proteins and the recovery is time dependent. Obstruction differentially alters mRNA transcription of different proteins and the content of proteins seemed to be easier to be influenced than the gene transcription. PMID- 22922321 TI - Unsatisfactory outcomes of prolonged ischemic priapism without early surgical shunts: our clinical experience and a review of the literature. AB - Ischemic priapism is a rare occurrence which can cause severe erectile dysfunction (ED) without timely treatment. This retrospective study reports our experience in treating prolonged ischemic priapism and proposes our further considerations. In this paper, a total of nine patients with prolonged ischemic priapism underwent one to three types of surgical shunts, including nine Winter shunts, two Al-Ghorab shunts and one Grayhack shunt. During the follow-up visit (after a mean of 21.11 months), all patients' postoperative characters were recorded, except one patient lost for death. Six postoperative patients accepted a 25-mg oral administration of sildenafil citrate. The erectile function of the patients was evaluated by their postoperative 5-item version of International Index of Erectile Function Questionnaire (IIEF-5), which were later compared with their premorbid scores. All patients had complete resolutions, and none relapsed. The resolution rate was 100%. Seven patients were resolved with Winter shunts, one with an Al-Ghorab shunt and one with a Grayhack shunt. The mean hospital stay was 8.22 days. There was only one urethral fistula, and the incidence of postoperative ED was 66.67%. Four patients with more than a 72-h duration of priapism had no response to the long-term phosphodiesterase type 5 (PDE-5) inhibitor treatment. These results suggest that surgical shunts are an efficient approach to make the penis flaccid after prolonged priapism. However, the severe ED caused by prolonged duration is irreversible, and long-term PDE-5 inhibitor treatments are ineffective. Thus, we recommend early penile prosthesis surgeries for these patients. PMID- 22922322 TI - DNA damage, NF-kappaB and accelerated aging. AB - The aging process is the major risk factor for disease and disability yet the cellular mechanisms for aging are uncertain. By studying transgenic mice with altered expression of the DNA repair enzyme, ERCC1, it was concluded that DNA damage is an important, if not the primary mechanism for aging. Moreover it was established that altered activity of the transcription factor, NF-kappaB (nuclear factor kappa B) mediates the effects of DNA damage on aging. Therefore inhibition of NF-kappaB might have a role in delaying aging. PMID- 22922324 TI - A rare case of ventricular diverticulum in a child with occipital encephalocele. AB - Ventricular diverticula are dilatations of the ventricular system caused by stretching and protrusion of the ventricular wall as a result of severe chronic obstructive hydrocephalus. We report a case of lateral ventricular diverticulum arising from the occipital horn in a patient with occipital encephalocele. To the best of our knowledge, this is a first case of ventricular diverticulum in a patient with occipital encephalocele. PMID- 22922323 TI - Extracellular DNA within a nontypeable Haemophilus influenzae-induced biofilm binds human beta defensin-3 and reduces its antimicrobial activity. AB - Biofilms formed by nontypeable Haemophilus influenzae (NTHI) are associated with multiple chronic infections of the airway, including otitis media. Extracellular DNA (eDNA) is part of the biofilm matrix and serves as a structural component. Human beta-defensin-3 (hBD-3) is a cationic antimicrobial host defense protein (AMP) critical to the protection of the middle ear. We hypothesized that anionic eDNA could interact with and bind hBD-3 and thus shield NTHI in biofilms from its antimicrobial activity. We demonstrated that recombinant hBD-3 [(r)hBD-3] bound eDNA in vitro and that eDNA in biofilms produced by NTHI in the chinchilla middle ear co-localized with the orthologue of this AMP. Incubation of physiological concentrations of (r)hBD-3 with NTHI genomic DNA abrogated the ability of this innate immune effector to prevent NTHI from forming robust biofilms in vitro. Establishment of NTHI biofilms in the presence of both DNase I and (r)hBD-3 resulted in a marked reduction in the overall height and thickness of the biofilms and rescued the antimicrobial activity of the AMP. Our results demonstrated that eDNA in NTHI biofilms sequestered hBD-3 and thus diminished the biological activity of an important effector of innate immunity. Our observations have important implications for chronicity of NTHI-induced diseases. PMID- 22922325 TI - Nicotine alters the expression of molecular markers of endocrine disruption in zebrafish. AB - Nicotine, a drug of abuse, has been reported to have many adverse effects on the developing nervous system. In rodents, chronic nicotine exposure inhibits estrogen-mediated neuroprotection against cerebral ischemia in females suggesting that nicotine could disrupt endocrine targets. Zebrafish have been used as a model system for examining mechanisms underlying nicotinic effects on neuronal development. Here, using zebrafish embryos, we demonstrate that nicotine alters the expression of the validated endocrine disruption (ED) biomarkers, vitellogenin (vtg 1 and vtg 2) and cytochrome p450 aromatase (cyp19a1a and cyp19a1b) at the transcriptional level. Increased expression of three of these molecular markers (vtg 1, vtg 2 and cyp19a1b) in response to 17beta-estradiol (E2) was more pronounced in 48hpf (hours post-fertilization) embryos than in the 24hpf embryos. While 24hpf embryos were non-responsive in this regard to 25MUM nicotine, a similar exposure of the 48hpf embryos for 24h significantly down regulated the expression of all four ED biomarker genes indicating that nicotine's anti-estrogenic effects are detectable in the 48hpf zebrafish embryos. These results provide direct molecular evidence that nicotine is an endocrine disruptor in zebrafish. PMID- 22922326 TI - A narrative history of the International Society for Psychiatric Surgery: 1970 1983. AB - In order to reconcile the present resurgence of psychiatric neurosurgery with the not-too-distant historic transgressions in the field, one needs to examine the era of transition from crude art to regulated science. In large part, this transition took place in the 1970s with the continued development and widespread acceptance of stereotactic techniques in functional neurosurgery and several hard fought ideological and academic victories by proponents of the much-maligned field. Established in 1970, the International Society for Psychiatric Surgery (ISPS) sought to gather like-minded surgeons, psychiatrists and other neuroscientists to counter the rising pressure from special interest groups, as well as some in the public and medical realm, who attempted to abolish all forms of surgical management of psychiatric disease. We reviewed the archives of the ISPS, including letters from its founding members and active participants, conference proceedings and minutes from organizational meetings, from throughout its existence from 1970 to 1983. The archives provide a unique insight into the organization and objectives of the society that kept psychiatric surgery alive in the face of persistent and staunch opposition. We also outline the lessons that current and future functional neurosurgeons can learn from the ISPS, whose key figures, structure and communication, in the non-electronic era, were instrumental for the survival of psychiatric surgery during that critical period. PMID- 22922327 TI - Effects of carrier frequency of interferential current on pressure pain threshold and sensory comfort in humans. AB - OBJECTIVE: To assess the effect of carrier frequency of interferential current (IFC) on pressure pain threshold (PPT) and sensory comfort in healthy subjects. DESIGN: A double-blind randomized trial. SETTING: University research laboratory. PARTICIPANTS: Healthy subjects (N=150). INTERVENTIONS: Application of the IFC for 20 minutes and measures of PPT collected in the regions of the nondominant hand and forearm. MAIN OUTCOMES MEASURES: We measured PPT and comfort at frequencies of 1kHz, 2kHz, 4kHz, 8kHz, and 10kHz. RESULTS: There was a significant increase in PPT in the 1-kHz group when compared with the 8-kHz and 10-kHz groups. There was a greater discomfort in the 1-kHz and 2-kHz groups. CONCLUSIONS: IFC with a carrier frequency of 1kHz promotes a higher hypoalgesic response during and after stimulation than IFC with carrier frequencies of 8kHz and 10kHz. Carrier frequencies of 1kHz and 2kHz are perceived as more uncomfortable than carrier frequencies of 4kHz, 8kHz, and 10kHz. PMID- 22922328 TI - Bibliometric analysis of literature in cerebrovascular and cardiovascular diseases rehabilitation: growing numbers, reducing impact factor. AB - OBJECTIVES: To explore temporal trends, geographic distribution, and socioeconomic determinants of scientific production in the field of cerebrovascular and cardiovascular disease (CCD) rehabilitation. DATA SOURCES: Citations from 1967 to 2008 were downloaded from the PubMed database. Core of the search strategy was the key word cardiovascular diseases in the Medical Subject Headings major field with the subheading rehabilitation. Journal Citation Reports was used to assign an impact factor (IF). Demographic and economic data were retrieved from the International Monetary Fund. STUDY SELECTION: All articles retrieved were included in the bibliometric analysis. DATA EXTRACTION: The search strategy was validated on a random sample of the articles retrieved. The search quality reflected the level of error of the PubMed database. DATA SYNTHESIS: Publications retrieved were 10,379 and have grown 8.6 times in 40 years, faster than the all-diseases rehabilitation field (7.8 times), with a particularly steep growth for cerebrovascular diseases in the last 15 years (5 times). However, in the last decade, the articles' quality (IF) decreased. From 1994 to 2008, 3466 citations were retrieved; 44.4% came from the European Union and 30.3% from the United States. The highest mean IF was reported for France (4.127). The United Kingdom and some relatively small northern European Union countries had the best ratio of IF (sum) to resident population or to gross domestic product. The most frequently used key word was stroke, and 3 journals (Archives of Physical Medicine and Rehabilitation, Clinical Rehabilitation, and Stroke) published one quarter of the articles. CONCLUSIONS: The overall scientific production in the field of CCD rehabilitation showed a steep growth in the last decade, especially because of cerebrovascular research. In the same period, a decrease in the overall IF was observed. The European Union and the United States contributed 3 of every 4 articles in the field, although some Asian countries showed promising performance. PMID- 22922329 TI - Changes in hospitalization, physician visits, and self-reported fitness after spinal cord injury: a cross-sequential analysis of age, years since injury, and age at injury onset. AB - OBJECTIVE: To identify changes in hospitalizations, days hospitalized, nonroutine physician visits, and self-reported fitness over 4 measurements separated by 4- to 5-year intervals among participants with spinal cord injury (SCI), while testing for the effects of age, time since injury, and age at injury onset. DESIGN: A mixed model was used to analyze the cross-sequential data that include cross-sectional and longitudinal elements. The data were collected in 1993, 1998, 2003, and 2008. SETTING: Data were collected at 2 Midwestern hospitals and a Southeastern specialty hospital in the United States. PARTICIPANTS: Adult participants (N=1032) with SCI of at least 1-year duration who participated during at least 1 of 4 times of measurement dating back to 1993. Of these, 463 participated on all 4 occasions. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: The outcome measures were 3 indicators of medical treatments hospitalization, days hospitalized, and nonroutine physician visits. A fourth outcome was self-reported fitness. RESULTS: Results of the growth model indicated some limited cohort effects for chronologic age, years since injury, and age at injury onset at baseline. However, significant time effects were observed for each of the health indices, with hospitalizations and physician visits increasing and self-reported fitness decreasing. Significant cohort by time interactions were observed for both number of hospitalizations and days hospitalized with years postinjury and chronologic age. CONCLUSIONS: The natural course of change in the health indices was in the direction of a greater need for treatment and reduced fitness over time. Aging effects, as defined by cohort by time interactions, indicated the greater need for hospitalization increased over time at a greater rate for those with more years postinjury and of older ages. PMID- 22922331 TI - Review of bioactive glass: from Hench to hybrids. AB - Bioactive glasses are reported to be able to stimulate more bone regeneration than other bioactive ceramics but they lag behind other bioactive ceramics in terms of commercial success. Bioactive glass has not yet reached its potential but research activity is growing. This paper reviews the current state of the art, starting with current products and moving onto recent developments. Larry Hench's 45S5 Bioglass(r) was the first artificial material that was found to form a chemical bond with bone, launching the field of bioactive ceramics. In vivo studies have shown that bioactive glasses bond with bone more rapidly than other bioceramics, and in vitro studies indicate that their osteogenic properties are due to their dissolution products stimulating osteoprogenitor cells at the genetic level. However, calcium phosphates such as tricalcium phosphate and synthetic hydroxyapatite are more widely used in the clinic. Some of the reasons are commercial, but others are due to the scientific limitations of the original Bioglass 45S5. An example is that it is difficult to produce porous bioactive glass templates (scaffolds) for bone regeneration from Bioglass 45S5 because it crystallizes during sintering. Recently, this has been overcome by understanding how the glass composition can be tailored to prevent crystallization. The sintering problems can also be avoided by synthesizing sol-gel glass, where the silica network is assembled at room temperature. Process developments in foaming, solid freeform fabrication and nanofibre spinning have now allowed the production of porous bioactive glass scaffolds from both melt- and sol-gel-derived glasses. An ideal scaffold for bone regeneration would share load with bone. Bioceramics cannot do this when the bone defect is subjected to cyclic loads, as they are brittle. To overcome this, bioactive glass polymer hybrids are being synthesized that have the potential to be tough, with congruent degradation of the bioactive inorganic and the polymer components. Key to this is creating nanoscale interpenetrating networks, the organic and inorganic components of which have covalent coupling between them, which involves careful control of the chemistry of the sol-gel process. Bioactive nanoparticles can also now be synthesized and their fate tracked as they are internalized in cells. This paper reviews the main developments in the field of bioactive glass and its variants, covering the importance of control of hierarchical structure, synthesis, processing and cellular response in the quest for new regenerative synthetic bone grafts. The paper takes the reader from Hench's Bioglass 45S5 to new hybrid materials that have tailorable mechanical properties and degradation rates. PMID- 22922332 TI - Three-dimensional structural niches engineered via two-photon laser polymerization promote stem cell homing. AB - A strategy to modulate the behavior of stem cells in culture is to mimic structural aspects of the native cell/extracellular matrix interaction. We applied femtosecond laser two-photon polymerization (2PP) to fabricate three dimensional (3-D) microscaffolds, or "niches", using a hybrid organic-inorganic photoresist called SZ2080. The niches, of sizes fitting in a volume of 100*100*100 MUm(3), were made by an external containment grid of horizontal parallel elements and by an internal 3-D lattice. We developed two niche heights, 20 and 80-100 MUm, and four lattice pore dimensions (10, 20, 30 MUm and graded). We used primary rat mesenchymal stem cells (MSCs) to study cell viability, migration and proliferation in the niches, up to 6 culture days. MSCs preferentially stayed on/in the structures once they ran into them through random migration from the surrounding flat surface, invaded those with a lattice pore dimension greater than 10 MUm, and adhered to the internal lattice while the cell nuclei acquired a roundish morphology. In the niches, the highest MSC density was found in those areas where proliferation was observed, corresponding to the regions where the scaffold surface density available for cell adhesion was highest. The microgeometry inducing the highest cell density was 20 MUm high with graded pores, in which cell invasion was favored in the central region of large porosity and cell adhesion was favored in the lateral regions of high scaffold surface density. Cell density in the niches, 17+/-6 cells/(100*100 MUm(2)), did not significantly differ from that of the flat surface colonies. This implies that MSCs spontaneously homed and established colonies within the 3-D niches. This study brings to light the crucial role played by the niche 3-D geometry on MSC colonization in culture, with potential implications for the design of biomaterial scaffolds for synthetic niche engineering. PMID- 22922333 TI - Rectal suction biopsy to exclude the diagnosis of Hirschsprung disease. AB - OBJECTIVES: Hirschsprung disease (HD) is defined as the absence of ganglion cells in the Meissner and Auerbach plexuses. Diagnosis depends on demonstrating the absence of ganglion cells in rectal biopsy specimens. Rectal suction biopsy is widely employed as the method of choice in obtaining such specimens. Classically, the diagnosis was made until the 1990s by using the Multipurpose Suction Biopsy Kit, or Rubin Tube. This device was replaced by the Model SBT-100 Suction Biopsy Kit as the exclusive device used to procure rectal tissue. Because the suction devices are known to occasionally yield tissue that is insufficient, the present study was undertaken to determine the efficacy of using this technique to make or exclude the diagnosis of HD. METHODS: The last 50 biopsy sessions using the Multipurpose Suction Biopsy Kit and the first 46 sessions using the Model SBT-100 were included for review. RESULTS: Both groups had similar yields (24%) of biopsy sessions with insufficient tissue to allow meaningful interpretation. The predictive value of rectal suction biopsy in excluding HD at the first biopsy session was 65%. CONCLUSIONS: We conclude that HD can be excluded with a single rectal suction biopsy 65% of the time. A second biopsy session will exclude the diagnosis in an additional 11% of patients. Both devices yield biopsies of comparable quality and are equally useful in excluding the diagnoses of HD. PMID- 22922334 TI - Innate immune response of silver catfish (Rhamdia quelen) exposed to atrazine. AB - The impact of agrichemicals on aquatic vertebrate species has been a matter of increasing concern to researchers and environmentalist. In the present study, we evaluated the effects of a sublethal concentration of atrazine (10% of the LC(50 96 h)), a world-wide used herbicide, on the innate immune system of silver catfish (Rhamdia quelen). A significant reduction on phagocytic index, bacteria agglutination and bactericidal activity of the serum, serum lysozyme and total serum peroxidase activity was observed in fish exposed to atrazine for 24 h. After 10 days exposure to atrazine, only bactericidal activity of the serum, bacteria agglutination and total serum peroxidase activity were significantly reduced. Atrazine had no effect on the natural complement hemolytic activity. Our results demonstrate that atrazine decreases the innate immune response of fingerlings, which might increase its susceptibility to opportunistic pathogens. PMID- 22922335 TI - The influence of the surface chemistry of silver nanoparticles on cell death. AB - The influence of the surface chemistry of silver nanoparticles (AgNPs) on p53 mediated cell death was evaluated using human dermal fibroblast (HDF) and lung cancer (A549) cells. The citrate reduced AgNPs (C-AgNPs) were modified with either lactose (L-AgNPs) or a 12-base long oligonucleotide (O-AgNPs). Both unmodified and modified AgNPs showed increased concentration and time dependent cytotoxicity and genotoxicity causing an increased p53 up-regulation within 6 h and led to apoptotic or necrotic cell deaths. The C-AgNPs induced more cytotoxicity and cellular DNA damage than the surface modified AgNPs. Modifying the C-AgNPs with lactose or the oligonucleotide reduced both necrotic and apoptotic cell deaths in the HDF cells. The C-AgNPs caused an insignificant necrosis in A549 cells whereas the modified AgNPs caused necrosis and apoptosis in both cell types. Compared to the O-AgNPs, the L-AgNPs triggered more cellular DNA damage, which led to up-regulation of p53 gene inducing apoptosis in A549 cells compared to HDF cells. This suggests that the different surface chemistries of the AgNPs cause different cellular responses that may be important not only for their use in medicine but also for reducing their toxicity. PMID- 22922336 TI - Shear bond strength comparison between conventional porcelain fused to metal and new functionally graded dental restorations after thermal-mechanical cycling. AB - OBJECTIVES: The aim of this study was to evaluate the effect of thermo-mechanical cycling on the metal-ceramic bond strength of conventional porcelain fused to metal restorations (PFM) and new functionally graded metal-ceramic dental restorations (FGMR). METHODS: Two types of specimens were produced: PFM and FGMR specimens. PFM specimens were produced by conventional PFM technique. FGMR specimens were hot pressed and prepared with a metal/ceramic composite interlayer (50 M, vol%) at the metal-ceramic interface. They were manufactured and standardized in cylindrical format and then submitted to thermal (3000, 6000 and 12,000 cycles; between 5 degrees C and 60 degrees C; dwell time: 30s) and mechanical (25,000, 50,000 and 100,000 cycles under a load of 50 N; 1.6 Hz) cycling. The shear bond strength tests were performed in a universal testing machine (crosshead speed: 0.5mm/min), using a special device to concentrate the tension at the metal-ceramic interface and the load was applied until fracture. The metal-ceramic interfaces were examined with SEM/EDS prior to and after shear tests. The Young's modulus and hardness were measured across the interfaces of both types of specimens using nanoindentation tests. Data was analyzed with Shapiro-Wilk test to test the assumption of normality. The 2-way ANOVA was used to compare shear bond strength results (p<0.05). RESULTS: FGMR specimens showed significantly (p<0.001) higher shear bond strength results than PFM specimens, irrespective of fatigue conditions. Fatigue conditions significantly (p<0.05) affected the shear bond strength results. The analysis of surface fracture revealed adhesive fracture type for PFM specimens and mixed fracture type for FGMR specimens. Nanoindentation tests showed differences in mechanical properties measured across the metal-ceramic interface for the two types of specimens, namely Young's Modulus and hardness. SIGNIFICANCE: This study showed significantly better performance of the new functionally graded restorations relative to conventional PFM restorations, under fatigue testing conditions and for the materials tested. PMID- 22922337 TI - Experimental evaluation of the bond strength between a CoCrMo dental alloy and porcelain through a composite metal-ceramic graded transition interlayer. AB - OBJECTIVES: The purpose of this study was to evaluate the shear bond strength between CoCrMo dental alloy and porcelain restorations by application of different metal-ceramic transitional interfaces aiming at improvement of the bond strength and fracture tolerances. METHODS: Several metal-ceramic specimens with different composite interlayers were produced. The interlayers consisted of metal/ceramic composites with different metal volume fractions (20 M; 40 M; 60 M; 80 M). The metal-ceramic bond strength as well as the fracture strength of the composites and monolithic base materials were assessed by the means of a shear test performed in a universal test machine. The interfaces of fractured and untested specimens were examined by the means of optical microscopy. The microstructures of monolithic base materials were analyzed using SEM/EDS. The elastic and inelastic properties of the homogeneous compositions were additionally evaluated using dynamic mechanical analysis. RESULTS: The bond strength results obtained for metal-ceramic gradated specimens were the highest (261+/-38 MPa) for 40 vol% metal in the interlayer [40 M] vs. 109+/-27 MPa for a direct metal-ceramic joint. The Young's moduli and the fracture resistance of the composites revealed an increasing trend for increasing metal contents. SIGNIFICANCE: This study shows that a graded transition between metal and ceramic, provided by a metal/ceramic composite interlayer, is regarded for an increase by 2.5 times in the bond strength between the two materials relative to conventional sharp transitions. The elastic modulus of the composites used as interlayers might be very reasonably approximated by a micromechanical model. PMID- 22922339 TI - H2O2 lowers the cytosolic Ca2+ concentration via activation of cGMP-dependent protein kinase Ialpha. AB - The cGMP-dependent protein kinase I (cGKI) is a key mediator of cGMP signaling, but the specific functions of its two isoforms, cGKIalpha and cGKIbeta, are poorly understood. Recent studies indicated a novel cGMP-independent role for cGKIalpha in redox sensing. To dissect the effects of oxidative stress on the cGKI isoforms, we used mouse embryonic fibroblasts and vascular smooth muscle cells (VSMCs) expressing both, one, or none of them. In cGKIalpha-expressing cells, but not in cells expressing only cGKIbeta, incubation with H2O2 induced the formation of a disulfide bond between the two identical subunits of the dimeric enzyme. Oxidation of cGKIalpha was associated with increased phosphorylation of its substrate, vasodilator-stimulated phosphoprotein. H2O2 did not stimulate cGMP production, indicating that it activates cGKIalpha directly via oxidation. Interestingly, there was a mutual influence of H2O2 and cGMP on cGKI activity and disulfide bond formation, respectively; preoxidation of the kinase with H2O2 slightly impaired its activation by cGMP, whereas preactivation of the enzyme with cGMP attenuated its oxidation by H2O2. To evaluate the functional relevance of the noncanonical H2O2-cGKIalpha pathway, we studied the regulation of the cytosolic Ca2+ concentration ([Ca2+](i)). H2O2 suppressed norepinephrine-induced Ca2+ transients in cGKIalpha-expressing VSMCs and, to a lower extent, in VSMCs expressing only cGKIbeta or none of the isoforms. Thus, H2O2 lowers [Ca2+](i) mainly via a cGKIalpha-dependent pathway. These results indicate that oxidative stress selectively targets the cGKIalpha isoform, which then modulates cellular processes in a cGMP-independent manner. A decrease in [Ca2+](i) in VSMCs via activation of cGKIalpha might be a major mechanism of H2O2 induced vasodilation. PMID- 22922338 TI - Capsazepine, a TRPV1 antagonist, sensitizes colorectal cancer cells to apoptosis by TRAIL through ROS-JNK-CHOP-mediated upregulation of death receptors. AB - A major problem in clinical trials of tumor necrosis factor-related apoptosis inducing ligand (TRAIL) as cancer therapy is the development of resistance to TRAIL. Therefore, agents that can overcome TRAIL resistance have great therapeutic potential. In this study, we evaluated capsazepine, a TRPV1 antagonist, for its ability to sensitize human colon cancer cells to TRAIL induced apoptosis. Capsazepine potentiated the effect of TRAIL, as shown by its effect on intracellular esterase activity; activation of caspase-8,-9, and -3; and colony-formation assay. Capsazepine induced death receptors (DRs) DR5 and DR4, but not decoy receptors, at the transcriptional level and in a non-cell-type specific manner. DR induction was dependent on CCAAT/enhancer-binding protein homologous protein (CHOP), as shown by (a) the induction of CHOP by capsazepine and (b) the abolition of DR- and potentiation of TRAIL-induced apoptosis by CHOP gene silencing. CHOP induction was also reactive oxygen species (ROS)-dependent, as shown by capsazepine's ability to induce ROS and by the quenching of ROS by N acetylcysteine or glutathione, which prevented induction of CHOP and DR5 and consequent sensitization to TRAIL. Capsazepine's effects appeared to be mediated via JNK, as shown by capsazepine's ability to induce JNK and by the suppression of both CHOP and DR5 activation by inhibition of JNK. Furthermore, ROS sequestration abrogated the activation of JNK. Finally, capsazepine downregulated the expression of various antiapoptotic proteins (e.g., cFLIP and survivin) and increased the expression of proapoptotic proteins (e.g., Bax and p53). Together, our results indicate that capsazepine potentiates the apoptotic effects of TRAIL through downregulation of cell survival proteins and upregulation of death receptors via the ROS-JNK-CHOP-mediated pathway. PMID- 22922340 TI - Lobolide, a diterpene, blockades the NF-kappaB pathway and p38 and ERK MAPK activity in macrophages in vitro. AB - AIM: Recent studies have shown that constitutive activation of the nuclear factor kappaB (NF-kappaB) plays a key role in chronic inflammation and cancers. The aim of this study was to characterize lobolide, a cembrane diterpene, as a drug candidate targeting the NF-kappaB signaling pathway. METHODS: A HEK 293/NF-kappaB Luc stable cell line was constructed to evaluate the effect of lobolide on NF kappaB activation. THP-1 human monocytes and peripheral blood mononuclear cells (PBMCs) from healthy volunteers were tested. Lipopolysaccharide (LPS)-induced TNFalpha and IL-1beta production and activation of the TAK1-IKK-NF-kappaB pathway were studied using ELISA and Western blot analysis. RESULTS: In HEK 293/NF-kappaB Luc stable cells, lobolide (0.19-50 MUmol/L) inhibited NF-kappaB activation in a concentration-dependent manner with an IC(50) value of 4.2 +/- 0.3 MUmol/L. Treatment with lobolide (2.5-10 MUmol/L) significantly suppressed LPS-induced production of TNFalpha and IL-1beta in both THP-1 cells and PBMCs. In THP-1 cells, the suppression was partially caused by blockade of the translocation of NF-kappaB from the cytoplasm to the nucleus via affecting the TAK1-IKK-NF-kappaB pathway and p38 and ERK MAPK activity. CONCLUSION: Lobolide is a potential inhibitor of the NF-kappaB pathway, which blocks the translocation of NF-kappaB from the cytoplasm to the nucleus. Lobolide inhibits LPS-stimulated TNFalpha and IL-1beta release, suggesting that the compound might be an anti-inflammatory compound. PMID- 22922341 TI - Emodin, an 11beta-hydroxysteroid dehydrogenase type 1 inhibitor, regulates adipocyte function in vitro and exerts anti-diabetic effect in ob/ob mice. AB - AIM: Emodin (1,3,8-trihydroxy-6-methylanthraquinone) is a potent and selective inhibitor of 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) with the ability to ameliorate metabolic disorders in diet-induced obese mice. In the present study, we investigated the effects of emodin on adipocyte function and the underlying mechanisms in vitro, and its anti-diabetic effects in ob/ob mice. METHODS: 3T3-L1 adipocytes were used for in vitro studies. 11beta-HSD1A activity was evaluated with a scintillation proximity assay. The adipogenesis, glucose uptake, lipolysis and adiponectin secretion were investigated in 3T3-L1 adipocytes treated with emodin in the presence of active (corticosterone) or inactive glucocorticoid (11-dehydrocorticosterone). For in vivo studies, ob/ob mice were administered emodin (25 and 50 mg.kg-1.d-1, ip) for 26 d. On the last day of administration, the serum was collected and the mesenteric and perirenal fat were dissected for analyses. RESULTS: Emodin inhibited the 11beta-HSD1 activity in 3T3-L1 adipocytes in concentration- and time-dependent manners (the IC50 values were 7.237 and 4.204 MUmol/L, respectively, after 1 and 24 h treatment. In 3T3-L1 adipocytes, emodin (30 MUmol/L) suppressed 11 dehydrocorticosterone-induced adipogenesis without affecting corticosterone induced adipogenesis; emodin (3 MUmol/L) reduced 11-dehydrocorticosterone stimulated lipolysis, but had no effect on corticosterone-induced lipolysis. Moreover, emodin (3 MUmol/L) partly reversed the impaired insulin-stimulated glucose uptake and adiponectin secretion induced by 11-dehydrocorticosterone but not those induced by corticosterone. In ob/ob mice, long-term emodin administration decreased 11beta-HSD1 activity in mesenteric adipose tissues, lowered non-fasting and fasting blood glucose levels, and improved glucose tolerance. CONCLUSION: Emodin improves the inactive glucocorticoid-induced adipose tissue dysfunction by selective inhibition on 11beta-HSD1 in adipocyte in vitro and improves glycemic control in ob/ob mice. PMID- 22922342 TI - Discovery of N-(3,5-bis(1-pyrrolidylmethyl)-4-hydroxybenzyl)-4 methoxybenzenesulfamide (sulcardine) as a novel anti-arrhythmic agent. AB - AIM: To investigate the anti-arrhythmic effects of sulfamide analogues of changrolin and to characterize the sulfate of compound 6f (sulcardine sulfate, Sul) as a novel anti-arrhythmic agent. METHODS: The anti-arrhythmic effects of compounds were studied against aconitine-induced arrhythmias in rats and ouabain induced arrhythmias in guinea pigs. The effects of Sul on transmembrane action potentials were investigated in isolated rabbit sinoatrial nodes and guinea-pig papillary muscles using intracellular recording. With a whole-cell recording technique, the effects of Sul on sodium current, calcium current, and potassium currents were examined in isolated single guinea-pig ventricular myocytes. RESULTS: In aconitine-induced arrhythmias of rats, sulfamide analogues of changrolin (4, 5, and 6a-6p) exhibited various anti-arrhythmic activities. The sulfate of compound 6f (Sul) increased the amount of aconitine required to induce arrhythmias in each treated animal. The ED50 value of Sul in rats was 196 mg/kg. In ouabain-induced arrhythmias of guinea pigs, 25, 50, and 100 mg/kg doses of Sul increased the dose of ouabain required to induce VP, VT, and VF in a dose dependent manner. In papillary preparations, Sul produced a concentration dependent decrease in APA and V(max), prolonged APD(90) and ERP, whereas RP was unaffected. In the spontaneously beating sinus nodes, Sul reduced APA and V(max) in a concentration-dependent manner. The whole-cell recording studies revealed that Sul produced a reversible reduction in I(Na) (IC50=26.9 MUmol/L) and I(Ca,L)(IC50=69.2 MUmol/L), whereas the inward rectifier (I(K1)) and the delayed rectifier potassium currents (I(K)) were unaffected. CONCLUSION: As a multi-ion channel blocker, Sul may have potent efficacy in anti-atrial and ventricular arrhythmias. PMID- 22922343 TI - Differential effects of short- and long-term zolpidem treatment on recombinant alpha1beta2gamma2s subtype of GABA(A) receptors in vitro. AB - AIM: Zolpidem is a non-benzodiazepine agonist at benzodiazepine binding site in GABA(A) receptors, which is increasingly prescribed. Recent studies suggest that prolonged zolpidem treatment induces tolerance. The aim of this study was to explore the adaptive changes in GABA(A) receptors following short and long-term exposure to zolpidem in vitro. METHODS: Human embryonic kidney (HEK) 293 cells stably expressing recombinant alpha1beta2gamma2s GABA(A) receptors were exposed to zolpidem (1 and 10 MUmol/L) for short-term (2 h daily for 1, 2, or 3 consecutive days) or long-term (continuously for 48 h). Radioligand binding studies were used to determine the parameters of [(3)H]flunitrazepam binding sites. RESULTS: A single (2 h) or repeated (2 h daily for 2 or 3 d) short-term exposure to zolpidem affected neither the maximum number of [(3)H]flunitrazepam binding sites nor the affinity. In both control and short-term zolpidem treated groups, addition of GABA (1 nmol/L-1 mmol/L) enhanced [(3)H]flunitrazepam binding in a concentration-dependent manner. The maximum enhancement of [(3)H]flunitrazepam binding in short-term zolpidem treated group was not significantly different from that in the control group. In contrast, long-term exposure to zolpidem resulted in significantly increase in the maximum number of [(3)H]flunitrazepam binding sites without changing the affinity. Furthermore, long-term exposure to zolpidem significantly decreased the ability of GABA to stimulate [(3)H]flunitrazepam binding. CONCLUSION: The results suggest that continuous, but not intermittent and short-term, zolpidem-exposure is able to induce adaptive changes in GABA(A) receptors that could be related to the development of tolerance and dependence. PMID- 22922344 TI - Immunosuppressant discovery from Tripterygium wilfordii Hook f: the novel triptolide analog (5R)-5-hydroxytriptolide (LLDT-8). AB - The Chinese traditional herb Tripterygium wilfordii Hook f (TwHF) has been widely used in the treatment of autoimmune and inflammatory diseases. Over the past few decades, great efforts have been made to explore modern preparations of TwHF with higher efficacy, solubility, and lower toxicity. In this study, we reviewed several examples both of naturally occurring compounds and their derivatives in TwHF, and summarized the preclinical evaluations with regard to autoimmune and inflammatory diseases. All of the candidate compounds described herein have been or are currently in clinical trials. Although some studies encountered problems, the data still provided valuable references for future studies. (5R)-5 hydroxytriptolide (LLDT-8, Leitengshu) is a novel triptolide derivative with potent immunosuppressive and anti-inflammatory activities developed at Shanghai Institute of Materia Medica. Indeed, a Phase I clinical trial for this compound has been completed in rheumatoid arthritis patients. The results will provide the basis for the further exploration of this ancient herb and encourage the research and development of valuable traditional Chinese medicine. PMID- 22922345 TI - Qinghaosu (artemisinin): chemistry and pharmacology. AB - Qinghaosu and its derivatives are widely used in the world as a new generation of antimalarial drug. Up to now, some important progresses of Qinghaosu research have been made, including synthesis of new qinghaosu derivatives and analogs, investigation on their bioactivities and mode of actions. The present review briefly describes these efforts made by researchers in China, particularly in this Institute. PMID- 22922347 TI - Newly discovered angiogenesis inhibitors and their mechanisms of action. AB - In the past decade, the success of angiogenesis inhibitors in clinical contexts has established the antiangiogenic strategy as an important part of cancer therapy. During that time period, we have discovered and reported 17 compounds that exert potent inhibition on angiogenesis. These compounds exhibit tremendous diversity in their sources, structures, targets and mechanisms. These studies have generated new models for further modification and optimization of inhibitory compounds, new information for mechanistic studies and a new drug candidate for clinical development. In particular, through studies on the antiangiogenic mechanism of pseudolaric acid B, we discovered a novel mechanism by which the stability of hypoxia-inducible factor 1alpha is regulated by the transcription factor c-Jun. We also completed a preclinical study of AL3810, a compound with the potential to circumvent tumor drug resistance to a certain extent. All of these findings will be briefly reviewed in this article. PMID- 22922348 TI - Free p-cresol sulfate is associated with survival and function of vascular access in chronic hemodialysis patients. AB - BACKGROUND: Protein-bound uremic toxins indoxyl sulfate (IS) and p-cresol sulfate (p-CS) have been implicated as an important factor in uremic syndrome. Recent evidence indicates that both IS and p-CS are predictors of cardiovascular as well as all-cause mortality among chronic dialysis patients. We conducted a study to analyze the relationship between IS and p-CS and vascular access (VA) outcome in chronic hemodialysis (HD) patients. METHODS: A total of 91 chronic stable HD patients were divided into groups according to survival of VA and frequency of VA dysfunction. Demographic and biochemical data were reviewed and recorded. Serum levels of intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1, and the total and free forms of IS and p-CS were determined. RESULTS: Patients with a history of frequent VA failure and dysfunction had lower albumin and higher levels of ICAM-1, free IS, free and total p-CS. Diabetes was associated with higher IS and p-CS. Logistic regression revealed that diabetes and free p-CS were independent factors associated with poor outcome of VA. CONCLUSION: Endothelial dysfunction and uremic toxins were associated with survival and function of VA. Diabetes and free p-CS were significantly related to the outcome of VA among chronic HD patients. PMID- 22922346 TI - Computational drug discovery. AB - Computational drug discovery is an effective strategy for accelerating and economizing drug discovery and development process. Because of the dramatic increase in the availability of biological macromolecule and small molecule information, the applicability of computational drug discovery has been extended and broadly applied to nearly every stage in the drug discovery and development workflow, including target identification and validation, lead discovery and optimization and preclinical tests. Over the past decades, computational drug discovery methods such as molecular docking, pharmacophore modeling and mapping, de novo design, molecular similarity calculation and sequence-based virtual screening have been greatly improved. In this review, we present an overview of these important computational methods, platforms and successful applications in this field. PMID- 22922349 TI - Caesarean delivery in south-western Iran: trends and determinants in a community based survey. AB - OBJECTIVE: To assess trends in caesarean delivery and its associated factors in south-western Iran. SUBJECTS AND METHODS: This cross-sectional study was conducted from January 2007 to January 2010 in Fars province, Iran. All deliveries recorded in public and private hospitals were included. The Mann Whitney U test, chi2 test and multivariate logistic regression models were used for analysis of data. A p value less than 0.05 was considered significant. RESULTS: The rate of caesarean section for the whole sample of 139,159 increased from 51.6% in 2007 to 53.3% in 2009, which was statistically and clinically significant. The rate of caesarean delivery was significantly higher in primiparous compared to multiparous mothers. The rate increased steadily with the mother's age. The most prevalent recorded reason for caesarean delivery was maternal request. Logistic regression analysis showed that maternal age, previous abortions, underlying maternal disease, gestational age and number of living children were key contributing factors to the choice of mode of delivery. CONCLUSION: This study showed an increasing rate of caesarean delivery which should draw the attention of policymakers to factors associated with this mode of delivery. PMID- 22922352 TI - Brain-derived neurotrophic factor increases the motility of a particular N-methyl D-aspartate /GABA-responsive subset of neural progenitor cells. AB - Neurotrophins like brain-derived neurotrophic factor (BDNF) promote the migration of subsets of neural progenitor cells. The mechanism by which motility is increased and the functional properties of BDNF-responsive cells are not very well known. We have used the neurosphere model, combining time-lapse microscopy, immunocytochemistry, and Ca(2+) imaging, to study the effect of BDNF on parameters such as motility and neurotransmitter responsiveness of migrating neural progenitors. At the initiation of differentiation thick glial glutamate aspartate transporter (GLAST)-positive radial processes emerged from the neurosphere, followed by the exit of neuron-like cells. The neuron-like cells moved outside the radial processes in a phasic manner with intermittent surges of motility and stationary periods. BDNF increased the number and promoted the progress of the neuron-like cells by prolonging surges and decreasing the length of stationary phases. The average rate of cellular movement during surges was unaffected by BDNF. BDNF also caused a several fold increase in positive staining for tropomyosin-related kinase B (TrkB) receptors and neuronal markers such as Calbindin, microtubule-associated protein-2 (MAP-2), and neuron-specific nuclear protein (NeuN) in cells outside the radial network. Calcium imaging allowed for further characterization of the BDNF-responsive cell population. Kainate responsive cells, denoting the expression of AMPA/kainate receptors, dominated in the outer migration layers while cells responding to (S)-3,5 dihydroxyphenylglycine (DHPG) via metabotropic glutamate receptor 5 (mGluR5) dominated in the inner migration layers. BDNF did not appreciably affect the distribution of these cells but promoted the redistribution of a small subpopulation (about 20%) of N-methyl-D-aspartate (NMDA)- and GABA-responsive cells to the outermost layers of migration. The results demonstrate that BDNF does not affect cell motility per se but alters the phasic behavior of cell movement by promoting periods of high motility in a defined subpopulation of cells which give a robust Ca(2+) response to NMDA and GABA. PMID- 22922351 TI - Distribution of angiotensin type 1a receptor-containing cells in the brains of bacterial artificial chromosome transgenic mice. AB - In the central nervous system, angiotensin II (AngII) binds to angiotensin type 1 receptors (AT(1)Rs) to affect autonomic and endocrine functions as well as learning and memory. However, understanding the function of cells containing AT(1)Rs has been restricted by limited availability of specific antisera, difficulties discriminating AT(1)R-immunoreactive cells in many brain regions and, the identification of AT(1)R-containing neurons for physiological and molecular studies. Here, we demonstrate that an Agtr1a bacterial artificial chromosome (BAC) transgenic mouse line that expresses type A AT(1)Rs (AT1aRs) identified by enhanced green fluorescent protein (EGFP) overcomes these shortcomings. Throughout the brain, AT1aR-EGFP was detected in the nuclei and cytoplasm of cells, most of which were neurons. EGFP often extended into dendritic processes and could be identified either natively or with immunolabeling of GFP. The distribution of AT1aR-EGFP cells in brain closely corresponded to that reported for AngII binding and AT1aR protein and mRNA. In particular, AT1aR-EGFP cells were in autonomic regions (e.g., hypothalamic paraventricular nucleus, central nucleus of the amygdala, parabrachial nucleus, nuclei of the solitary tract and rostral ventrolateral medulla) and in regions involved in electrolyte and fluid balance (i.e., subfornical organ) and learning and memory (i.e., cerebral cortex and hippocampus). Additionally, dual label electron microscopic studies in select brain areas demonstrate that cells containing AT1aR-EGFP colocalize with AT(1)R-immunoreactivity. Assessment of AngII-induced free radical production in isolated EGFP cells demonstrated feasibility of studies investigating AT1aR signaling ex vivo. These findings support the utility of Agtr1a BAC transgenic reporter mice for future studies understanding the role of AT(1)R-containing cells in brain function. PMID- 22922353 TI - Angio-oedema induced by oestrogen contraceptives is mediated by bradykinin and is frequently associated with urticaria. AB - BACKGROUND: Hereditary C1-inhibitor (C1-Inh) deficiency is associated with 'bradykinin-mediated angio-oedema' (BK-AO) and is believed not to be associated with urticaria. Acquired AO has been related to oestrogen contraceptives. OBJECTIVE: To demonstrate that AO precipitated by oestrogens and characterized by nonfunctional C1-Inh is mediated by BK and to evaluate the occurrence of urticaria in these patients. METHODS: A retrospective evaluation of patients referred for AO related to oestrogen was undertaken. Circulating C1-Inh, high molecular weight kininogen (HK) and enzymes involved in the metabolism of bradykinin were investigated. RESULTS: Fifteen patients were included. HK cleavage concurrent to oestrogen intake was demonstrated in 10 patients with available plasma. Eight patients reported recurrent or chronic urticaria. Discontinuation of the contraceptive resulted in a return to native C1-Inh and HK in all cases studied and to normal kininogenase activity in all but one. The clinical manifestations completely disappeared in 6 patients and improved in 7 after the withdrawal of oestrogen. CONCLUSION: Patients display extensive cleavage of HK in the plasma, which supports that AO precipitated by oestrogen contraception is BK-mediated. Recurrent urticaria may have been underestimated in this context. The presence of recurrent urticaria should not systematically rule out the diagnosis of BK-AO when the history is suggestive. PMID- 22922354 TI - Selective interactions of spinophilin with the C-terminal domains of the delta- and MU-opioid receptors and G proteins differentially modulate opioid receptor signaling. AB - Previous studies have shown that the intracellular domains of opioid receptors serve as platforms for the formation of a multi-component signaling complex consisting of various interacting partners (Leontiadis et al., 2009, Cell Signal. 21, 1218-1228; Georganta et al., 2010, Neuropharmacology, 59(3), 139-148). In the present study we demonstrate that spinophilin a dendritic-spine enriched scaffold protein associates with delta- and MU-opioid receptors (delta-OmicronR, MU-OR) constitutively in HEK293 an interaction that is altered upon agonist administration and enhanced upon forskolin treatment for both MU-OR and delta OmicronR. Spinophilin association with the opioid receptors is mediated via the third intracellular loop and a conserved region of the C-terminal tails. The portion of spinophilin responsible for interaction with the delta-OR and MU-OR is narrowed to a region encompassing amino acids 151-444. Spinophilin, RGS4, Galpha and Gbetagamma subunits of G proteins form a multi-protein complex using specific regions of spinophilin and a conserved amino acid stretch of the C-terminal tails of both delta-MU-ORs. Expression of spinophilin in HEK293 cells potentiated DPDPE mediated adenylyl-cyclase inhibition of delta-OR leaving unaffected the levels of cAMP accumulation mediated by the MU-OR. Moreover, measurements of extracellular signal regulated kinase (ERK1,2) phosphorylation indicated that the presence of spinophilin attenuated agonist-driven ERK1,2 phosphorylation mediated upon activation of the delta-OR but not the MU-OR. Collectively, these findings suggest that spinophilin associates with both delta- and MU-OmicronR and G protein subunits in HEK293 cells participating in a multimeric signaling complex that displays a differential regulatory role in opioid receptor signaling. PMID- 22922355 TI - Fsy1, the sole hexose-proton transporter characterized in Saccharomyces yeasts, exhibits a variable fructose:H(+) stoichiometry. AB - In the model yeast Saccharomyces cerevisiae, hexose uptake is mediated exclusively by a family of facilitators (Hxt, hexose transporters). Some other Saccharomyces species (e.g. Saccharomyces bayanus and Saccharomyces pastorianus) possess, in addition, a specific fructose transporter (Fsy1, fructose symporter) that has been previously described to function as a proton symporter. In the present work, we compared growth of a yeast strain in which FSY1 occurs naturally in anaerobic, fructose- and glucose-limited chemostat cultures. Especially at low specific growth rates, fructose-proton symport was shown to have a strong impact on the biomass yield on sugar. We subsequently employed energized hybrid plasma membrane vesicles to confirm previous observations concerning the mode of operation and specificity of Fsy1 mediated transport. Surprisingly, these experiments suggested that the carrier exhibits an unusual fructose:H(+) stoichiometry of 1:2. This energetically expensive mode of operation was also found consistently in vivo, in shake flask and in chemostat cultures, and both when Fsy1 is the sole transporter and when the Hxt carriers are present. However, it is observed only when Fsy1 is operating at higher glycolytic fluxes, a situation that is normally prevented by downregulation of the gene. Taken together, our results suggest the possibility that fructose symport with more than one proton may constitute an energetically unfavorable mode of operation of the Fsy1 transporter that, in growing cultures, is prevented by transcriptional regulation. PMID- 22922356 TI - The role of zinc vacancies in bipolar resistance switching of Ag/ZnO/Pt memory structures. AB - We have presented a study of the bipolar resistance switching characteristics in the Ag/ZnO/Pt cell. This switching is accompanied by a change in intensity of the photoluminescence emission at 3.33 eV which is attributed to zinc vacancy related transitions in ZnO film. Besides voltage-driven resistance switching phenomena, a transition from a high-resistance state to a lower one is observed under laser illumination at low temperature. These results demonstrate that the bipolar resistance switching can originate due to an electron trapping/de-trapping process at zinc-vacancy defects localized in the interface layer. The Mott metal insulator transition is proposed as a possible mechanism of the memory effect. PMID- 22922357 TI - Ovarian undifferentiated carcinoma with voluminous mesenteric presentation. AB - INTRODUCTION: About 5% of ovarian cancers are so poorly differentiated and difficult to classify that they are called undifferentiated carcinomas and usually have disseminated disease at presentation. Extra pelvic debulking it is difficult to complete. PRESENTATION OF CASE: We report a case of a rare ovarian tumor presented as a large mesenteric tumor of 14cm diameter in a 73 years old woman. DISCUSSION: Undifferentiated carcinomas are usually large, solid with hemorrhage and necrosis, bilateral and most are difficult to classify histologically. Rarely are pure, generally identified through the extensive sampling of lesions, some other components of surface epithelial carcinoma and usually the predominant element is the latter. Cases with predominantly undifferentiated component are rare. CONCLUSION: The treatment and diagnostic approach is the same as for other high-grade epithelial tumors of the ovary, but in this particular case the differential diagnosis and diagnostic approach is that of a mesenteric tumor. PMID- 22922358 TI - Extra-hepatic portal vein aneurysm: A case report, overview of the literature and suggested management algorithm. AB - INTRODUCTION: Portal venous aneurysms are a rare finding. The reported incidence is on the rise with increasing use of modern imaging techniques in clinical practice. However, there is still much to be elicited regarding their aetiology, natural history, and management. PRESENTATION OF CASE: An 80-year-old woman presented with abdominal pain and nausea. Investigations showed a hypoechoic area in the region of the head of pancreas on ultrasound, which was found to be a portal venous aneurysm on CT. In view of her multiple comorbidities, a conservative approach was taken. DISCUSSION: Portal venous aneurysms represent approximately 3% of all venous aneurysms with a reported prevalence of 0.43%. They may be congenital, due to failure of complete regression of the right vitelline vein, or acquired secondary to portal hypertension. The primary presentation of portal vein aneurysm is abdominal pain, followed by incidental detection on imaging, with a minority of patients presenting with gastrointestinal bleeding. Complications of PVA include thrombosis, biliary tract obstruction, inferior vena cava obstruction, and duodenal compression. On the whole PVAs are stable and have a low risk of complications with 88% of patients showing no progression of aneurysm size or complications on subsequent follow up scans. CONCLUSION: We recommend that portal venous aneurysms be assessed using colour Doppler ultrasonography in the first instance with CT scans reserved for indeterminate cases or symptomatic patients. Due to the slow progression of such aneurysms, surgery is recommended only for symptomatic patients or those with complications secondary to portal venous aneurysms. PMID- 22922359 TI - Acute appendicitis in a duplicated appendix. AB - INTRODUCTION: Double appendix represents an extremely rare and commonly "missed" diagnosis, often with life threatening consequences. PRESENTATION OF CASE: In this case report we present an interesting case of operative treatment of acute appendicitis in a doubled vermiform appendix stemming operative pitfalls. A 23 year-old female was admitted to the emergency room department complaining of diffuse abdominal pain, nausea, and vomiting over the past 36h. As soon as the diagnosis of acute appendicitis was established a laparotomy via a McBurney incision was decided. Intraoperative findings included the presence of mild quantity of free fluid and surprisingly a thin non-inflamed appendiceal process. It was the preoperative ultrasound findings suggestive of acute appendicitis that dictated a more thorough investigation of the lower abdomen that led to the discovery of a second retrocecal inflamed appendix. Formal appendectomy was then performed for both processes. The patient had an uneventful recovery and was discharged on the fourth postoperative day. DISCUSSION: Double appendix represents a challenging clinical scenario in cases of right lower quadrant pain. CONCLUSION: Life threatening consequences with legal extensions can arise from the incomplete removal of both stumps. PMID- 22922360 TI - A case of giant inguinal hernia with intestinal malrotation. AB - INTRODUCTION: Giant inguinal hernia is uncommon nowadays. PRESENTATION OF CASE: A 75-year-old man with schizophrenia presented with complaints of episodic abdomen pain and constipation accompanied by a huge right scrotal mass. Physical examination revealed a large, irreducible, non-tender right inguinoscrotal hernia. The hernial mass was about 30cm and extended to the midpoint of the inner thigh. At laparotomy, the intestine from the proximal transverse colon to the terminal ileum with mesentery was found to have herniated through the right inguinal tract without evidence of ischemia or strangulation. The ascending colon showed no adherence to the retroperitoneum and the third and fourth parts of the duodenum descended vertically without Treitz's ligament. The inguinal defect was closed without complications. Ladd's procedure and appendectomy were performed simultaneously. DISCUSSION: Several techniques such as distending the abdominal wall progressively or debulking the abdominal contents have been reported. However, no consensus has been reached on a standard surgical procedure for the management of giant inguinoscrotal hernias. CONCLUSION: This was the first reported case of giant inguinal hernia containing malrotated intestine. PMID- 22922361 TI - DREZotomy in the treatment of cancer pain: a review. AB - BACKGROUND: Cancer-related pain is a common problem that may be intractable by medical and neuromodulatory treatment. The dorsal root entry zone (DREZ) is a hyperactive focus in neuropathic pain syndromes, and DREZotomy has been used in selective cases of neuropathic cancer pain. OBJECTIVE: The aim of this study was to describe the technique of spinal DREZotomy in the treatment of cancer pain and review the relevant published literature. METHODS: A PubMed database search for 'DREZ', 'dorsal root entry zone' and 'cancer', and a search of the references of these manuscripts, was undertaken. RESULTS: 14 papers were identified and reviewed that described a total of 123 patients with cancer pain or radiation induced pain who have been treated with DREZotomy. Though heterogeneous, these studies reported an overall favorable outcome in carefully selected patients with topographically limited pain syndromes. CONCLUSION: For patients with well localized neuropathic cancer pain intractable to medical and first-line surgical management, DREZotomy is a viable treatment option. Further prospective studies are needed to evaluate the outcomes of this procedure. PMID- 22922362 TI - Transcription factor Foxp3 and its protein partners form a complex regulatory network. AB - The transcription factor Foxp3 is indispensible for the differentiation and function of regulatory T cells (T(reg) cells). To gain insights into the molecular mechanisms of Foxp3-mediated gene expression, we purified Foxp3 complexes and explored their composition. Biochemical and mass-spectrometric analyses revealed that Foxp3 forms multiprotein complexes of 400-800 kDa or larger and identified 361 associated proteins, ~30% of which were transcription related. Foxp3 directly regulated expression of a large proportion of the genes encoding its cofactors. Some transcription factor partners of Foxp3 facilitated its expression. Functional analysis of the cooperation of Foxp3 with one such partner, GATA-3, provided additional evidence for a network of transcriptional regulation afforded by Foxp3 and its associates to control distinct aspects of T(reg) cell biology. PMID- 22922363 TI - Lymphotoxin regulates commensal responses to enable diet-induced obesity. AB - Microbiota are essential for weight gain in mouse models of diet-induced obesity (DIO), but the pathways that cause the microbiota to induce weight gain are unknown. We report that mice deficient in lymphotoxin, a key molecule in gut immunity, were resistant to DIO. Ltbr(-/-) mice had different microbial community composition compared to their heterozygous littermates, including an overgrowth of segmented filamentous bacteria (SFB). Furthermore, cecal transplantation conferred leanness to germ-free recipients. Housing Ltbr(-/-) mice with their obese siblings rescued weight gain in Ltbr(-/-) mice, demonstrating the communicability of the obese phenotype. Ltbr(-/-) mice lacked interleukin 23 (IL 23) and IL-22, which can regulate SFB. Mice deficient in these pathways also resisted DIO, demonstrating that intact mucosal immunity guides diet-induced changes to the microbiota to enable obesity. PMID- 22922365 TI - Pitfalls in using BMI as a selection criterion for bariatric surgery. AB - PURPOSE OF REVIEW: Because obesity was thought to be an important independent predictor for mortality, the eligibility criteria for bariatric procedures are all indexed to some minimum level of BMI. Recent evidence suggests that BMI is a poor correlate of mortality, suggesting that BMI should not serve as the basis for bariatric surgery approval. RECENT FINDINGS: Longevity studies of patients who have undergone bariatric operations have shown either a little or no improvement in survival. The distribution of fat is a far greater predictor of complications of obesity then the degree of obesity itself. When excessive amounts of calories are deposited into muscle it causes insulin resistance and diabetes. Consequently, weight loss induced by any means is an extremely effective treatment for obesity-related diabetes. SUMMARY: BMI is used as a criterion for bariatric surgery because it was thought that weight loss would be associated with greater longevity. This is not been the case and BMI should no longer be used to select patients for bariatric procedures. Bariatric operations should be offered to patients with complications of obesity that would be expected to resolve with weight loss such as diabetes. PMID- 22922364 TI - Type I interferon induces necroptosis in macrophages during infection with Salmonella enterica serovar Typhimurium. AB - Salmonella enterica serovar Typhimurium (S. Typhimurium) is a virulent pathogen that induces rapid host death. Here we observed that host survival after infection with S. Typhimurium was enhanced in the absence of type I interferon signaling, with improved survival of mice deficient in the receptor for type I interferons (Ifnar1(-/-) mice) that was attributed to macrophages. Although there was no impairment in cytokine expression or inflammasome activation in Ifnar1(-/ ) macrophages, they were highly resistant to S. Typhimurium-induced cell death. Specific inhibition of the kinase RIP1 or knockdown of the gene encoding the kinase RIP3 prevented the death of wild-type macrophages, which indicated that necroptosis was a mechanism of cell death. Finally, RIP3-deficient macrophages, which cannot undergo necroptosis, had similarly less death and enhanced control of S. Typhimurium in vivo. Thus, we propose that S. Typhimurium induces the production of type I interferon, which drives necroptosis of macrophages and allows them to evade the immune response. PMID- 22922366 TI - Fructose consumption and cancer: is there a connection? AB - PURPOSE OF REVIEW: Cancer cell metabolism is characterized by high rates of glucose uptake and anaerobic glycolysis. Sugar consumption has increased dramatically in the industrialized world, with refined fructose intake skyrocketing upwards in the USA over the past 30 years. Fructose provides an alternative carbon source for glycolysis, entering downstream of glucose and bypassing two key rate-limiting steps. Considering that glycolysis is the major pathway which fuels cancer growth, this review will focus on regulation and flux of glucose versus fructose through this pathway, and consider whether epidemiologic and experimental data support a mechanism whereby fructose might potentiate cancer growth in transformed cells.(Figure is included in full-text article.) RECENT FINDINGS: Fructose intake is associated with increased risk of pancreatic and small intestinal cancers, and possibly others. Fructose promotes flux through the pentose phosphate, which enhances protein synthesis and may indirectly increase tumor growth. Fructose treatment is associated with more aggressive cancer behavior and may promote metastasis. SUMMARY: Whereas glucose favors overall growth kinetics, fructose enhances protein synthesis and appears to promote a more aggressive cancer phenotype. Fructose has become ubiquitous in our food supply, with the highest consumers being teens and young adults. Therefore, understanding the potential health consequences of fructose and its role in chronic disease development is of critical importance. PMID- 22922367 TI - Hyperthyroidism in pregnancy. AB - PURPOSE OF REVIEW: Successful outcome in pregnancy hyperthyroidism depends on the cause, interpretation of laboratory tests, and careful use of antithyroid drug (ATD) therapy. Planning of a pregnancy in a woman with active or past history of Graves' hyperthyroidism is mandatory in order to avoid complications. RECENT FINDINGS: Fetal health may be affected by three factors: poor control of maternal hyperthyroidism, titer of maternal TRAb, and inappropriate use of ATD. Careful assessment of thyroid function through pregnancy and evaluation of fetal development by ultrasonography is the cornerstone for a successful outcome. In a subgroup of women previously treated with ablation therapy, those whose serum TSRAb titers remained elevated, are at risk of having a fetus/neonate with Graves' hyperthyroidism. Use of ATD during lactation is well tolerated, if recommended guidelines are followed. SUMMARY: Women during their childbearing age with active Graves' hyperthyroidism should plan their pregnancy. Causes of hyperthyroidism in pregnancy include Graves' disease or autonomous adenoma, and transient gestational thyrotoxicosis as a consequence of excessive production of human chroionic gonadotropin by the placenta. Careful interpretation of thyroid function tests and frequent adjustment of ATD is of utmost importance in the outcome of pregnancy. Graves' hyperthyroidism may relapse early in pregnancy or at the end of the first year postpartum. PMID- 22922368 TI - Human visual and parietal cortex encode visual choices independent of motor plans. AB - Perceptual decision-making entails the transformation of graded sensory signals into categorical judgments. Often, there is a direct mapping between these judgments and specific motor responses. However, when stimulus-response mappings are fixed, neural activity underlying decision-making cannot be separated from neural activity reflecting motor planning. Several human neuroimaging studies have reported changes in brain activity associated with perceptual decisions. Nevertheless, to date it has remained unknown where and how specific choices are encoded in the human brain when motor planning is decoupled from the decision process. We addressed this question by having subjects judge the direction of motion of dynamic random dot patterns at various levels of motion strength while measuring their brain activity with fMRI. We used multivariate decoding analyses to search the whole brain for patterns of brain activity encoding subjects' choices. To decouple the decision process from motor planning, subjects were informed about the required motor response only after stimulus presentation. Patterns of fMRI signals in early visual and inferior parietal cortex predicted subjects' perceptual choices irrespective of motor planning. This was true across several levels of motion strength and even in the absence of any coherent stimulus motion. We also found that the cortical distribution of choice-selective brain signals depended on stimulus strength: While visual cortex carried most choice-selective information for strong motion, information in parietal cortex decreased with increasing motion coherence. These results demonstrate that human visual and inferior parietal cortex carry information about the visual decision in a more abstract format than can be explained by simple motor intentions. Both brain regions may be differentially involved in perceptual decision-making in the face of strong and weak sensory evidence. PMID- 22922369 TI - Decoding the perception of pain from fMRI using multivariate pattern analysis. AB - Pain is known to comprise sensory, cognitive, and affective aspects. Despite numerous previous fMRI studies, however, it remains open which spatial distribution of activity is sufficient to encode whether a stimulus is perceived as painful or not. In this study, we analyzed fMRI data from a perceptual decision-making task in which participants were exposed to near-threshold laser pulses. Using multivariate analyses on different spatial scales, we investigated the predictive capacity of fMRI data for decoding whether a stimulus had been perceived as painful. Our analysis yielded a rank order of brain regions: during pain anticipation, activity in the periaqueductal gray (PAG) and orbitofrontal cortex (OFC) afforded the most accurate trial-by-trial discrimination between painful and non-painful experiences; whereas during the actual stimulation, primary and secondary somatosensory cortex, anterior insula, dorsolateral and ventrolateral prefrontal cortex, and OFC were most discriminative. The most accurate prediction of pain perception from the stimulation period, however, was enabled by the combined activity in pain regions commonly referred to as the 'pain matrix'. Our results demonstrate that the neural representation of (near threshold) pain is spatially distributed and can be best described at an intermediate spatial scale. In addition to its utility in establishing structure function mappings, our approach affords trial-by-trial predictions and thus represents a step towards the goal of establishing an objective neuronal marker of pain perception. PMID- 22922370 TI - Cerebral injury and neurodevelopmental impairment after amnioreduction versus laser surgery in twin-twin transfusion syndrome: a systematic review and meta analysis. AB - OBJECTIVE: To estimate the odds of severe cerebral injury and long-term neurodevelopmental impairment in monochorionic twins treated with amnioreduction versus laser surgery for twin-twin transfusion syndrome. METHODS: A systematic review and meta-analysis of studies on cerebral injury and long-term impairment after amnioreduction versus laser surgery were conducted. Odds ratios (OR) with their 95% confidence interval (CI) were computed. RESULTS: Electronic and manual search identified 63 references. Five studies were included for analysis. We found an ample seven-fold higher risk of severe cerebral injury in live-born children treated with amnioreduction compared to laser (OR 7.69, 95% CI 2.78 20.0, p = 0.00). In children surviving the neonatal period, the odds were three times higher following amnioreduction (OR 3.23, 95% CI 1.45-7.14, p = 0.00). Although not significant, monochorionic twins treated with amnioreduction had higher odds of periventricular leukomalacia and intraventricular hemorrhage (OR 2.08, 95% CI 0.86-5.00, p = 0.10 and OR 3.56, 95% CI 0.82-14.29, p = 0.09). Unfortunately, there were insufficient long-term outcome data available to estimate the odds of neurodevelopmental impairment. CONCLUSION: Amnioreduction is associated with an increased risk of severe cerebral injury compared to laser surgery in twin-twin transfusion syndrome. Our study highlights a lack of studies focusing on long-term neurodevelopmental outcome. Follow-up into childhood is indispensable to determine outcome in terms of motor, cognitive and socioemotional development. PMID- 22922371 TI - Colon manometry proves that perception of the urge to defecate is present in children with functional constipation who deny sensation. AB - BACKGROUND AND OBJECTIVE: Children with functional constipation often state an inability to sense an urge to defecate and/or inability to feel incontinence. We used colon manometry to assess whether there was a sensory abnormality in patients who denied sensation. METHODS: A physician observed all of the colon manometries in the preceding 20 years, and included behavioral observations in the procedure reports. We reviewed the charts of these patients. RESULTS: Of 150 subjects with normal manometry and a diagnosis of functional constipation, 56 volunteered that they had no urge to defecate or complained of abdominal pain. For all who denied sensation, the first high-amplitude propagating colonic contraction (HAPC) was associated with retentive posturing and facial grimaces. When queried, all reported they felt nothing. The examiner explained the HAPC was causing pain, and informed the child that the pain would resolve if they defecated. With subsequent HAPCs, every patient acknowledged an urge to defecate and successfully defecated. Most agreed that a similar pain sensation was present daily, but was misinterpreted to be abdominal pain. CONCLUSIONS: Colon manometry may be useful not only for objective findings to discriminate neuromuscular disease from functional symptoms but also to understand psychological issues and aid in helping the child and family understand the maladaptive behaviors in functional constipation. PMID- 22922372 TI - Transient elastography is a useful noninvasive tool for the evaluation of fibrosis in paediatric chronic liver disease. AB - BACKGROUND: Outcome of liver disease in children is mainly determined by severity and progression of liver fibrosis. Liver biopsy is the accepted standard for evaluating fibrosis but is limited by the need for sedation in children, sampling error, and risks including bleeding. The aim of the present study was to compare tools for noninvasive assessment of liver fibrosis in a paediatric cohort. METHODS: Children undergoing liver biopsy for chronic liver disease were recruited and underwent transient elastography (TE). Liver biopsies were scored by a hepatohistopathologist from F0 (no fibrosis) to F4 (cirrhosis). TE was compared with biopsy score. RESULTS: During the study period, 104 children (62 boys) were enrolled (median age 13.6 years). Diagnosis was autoimmune liver disease in 27; nonalcoholic fatty liver disease in 37; posttransplant in 16; hepatitis B/C in 8; Wilson disease in 5; and the remainder, miscellaneous. TE was successful in all but 7 patients and was a good discriminator of significant fibrosis (>= F2) (P < 0.001), severe fibrosis (>= F3) (P < 0.001), and cirrhosis (F4) (P = 0.003). The area under the receiver operating characteristic curve for the prediction of >= F2, >= F3, and F4 using TE was 0.78, 0.79, and 0.96, respectively. TE performed best in children with autoimmune liver disease and in those posttransplant. CONCLUSIONS: The present study demonstrates that TE is a reliable tool in distinguishing different stages of liver fibrosis in paediatric patients. Thus, TE may serve as a useful adjunct to liver biopsy for diagnostic purposes providing a reliable method of noninvasively monitoring liver disease progression in children. PMID- 22922373 TI - Comparison of diagnostic methods for pancreatic insufficiency in infants with cystic fibrosis. AB - OBJECTIVE: The objective of the present study is to compare daily weight gain and laboratory analysis (72-hour fecal fat and steatocrit) with fecal elastase-1 (EL 1) when diagnosing pancreatic insufficiency (PI) in infants with cystic fibrosis (CF). METHODS: A total of 39 infants with CF, diagnosed consecutively by newborn screening at 2 referral centers, were included in the study. Daily weight gain and results of laboratory analysis of stool samples were compared using the kappa coefficient and the receiver operator characteristic (ROC) curve. RESULTS: Using the criterion of low daily weight gain, the frequency of PI was 92.3%; using the 72-hour fecal fat, steatocrit, and fecal EL-1 tests, the frequency was 42.3%, 86.2%, and 84.6%, respectively. EL-1 was used as the reference test. It was observed that the criteria of low daily weight gain (<50th percentile) and abnormal steatocrit, used together, showed the highest sensitivity (91.3%) and specificity (83.3%) for the diagnosis of PI. CONCLUSIONS: When fecal EL-1 analysis is not immediately available, low daily weight gain associated with abnormal steatocrit can be adopted as a criterion for initiating pancreatic enzyme replacement therapy in infants with CF; however, EL-1 testing should be performed later for confirmation of PI. PMID- 22922374 TI - Abdominal plain film before gastrostomy tube placement to predict success of percutaneous endoscopic procedure. AB - OBJECTIVES: Percutaneous endoscopic gastrostomy (PEG) tube feeding is a convenient method for children requiring long-term enteral nutrition. Preoperative fitness of the majority of pediatric PEG candidates is graded as American Society of Anesthesiologists physical status >= III, indicating increased risk for peri- and postoperative morbidity. The success rate of endoscopic insertion is high, but variations in the anatomy may lead to failure of PEG placement and repeated exposure to anesthesia for surgical gastrostomy. We evaluated the efficiency of using abdominal plain film with gastric insufflation in the preparatory phase to predict a successful PEG insertion and avoid rescheduling. METHODS: A single-center cohort of candidates for PEG underwent abdominal plain film with gastric insufflation in the preparatory phase before tube insertion. The x-ray film was considered normal when the stomach projected distal to the costal margin. Primary endpoint was the success rate of PEG insertion. Multivariate logistic regression analysis was used to identify factors associated with PEG insertion failure. RESULTS: A total of 303 candidates for PEG underwent abdominal plain film (age range 0.3-18.1 years). PEG tube insertion succeeded in 287 cases (95%). In case of an abnormal abdominal film, the probability of successful PEG insertion dropped to 67% (95% confidence interval 46%-87%). In a multivariate logistic regression model, significant predictors for PEG insertion failure were spinal deformities (odds ratio [OR] 12.1), previous abdominal surgery (OR 8.5), neurological impairment (OR 4.1), and abnormal plain abdominal film (OR 10.3). CONCLUSIONS: Assessment of the gastric anatomy by abdominal plain film in PEG candidates with spinal deformities, previous abdominal surgery, or neurological impairment may help to identify children with a high likelihood of PEG insertion failure. This strategy enables the endoscopist to notify the surgeon in advance for a potential conversion and avoids repeated exposure to anesthesia. PMID- 22922375 TI - Fumarase deficiency associated with noninflammatory biliary atresia. PMID- 22922376 TI - Benign hepatic nodular lesions after treatment for childhood cancer. AB - BACKGROUND: Benign nodular hepatic regenerating lesions such as focal nodular hyperplasia (FNH) have been reported as rare complications of the antineoplastic therapy received during infancy. Little is known about the risk factors associated with the onset of these lesions and their diagnostic management. METHODS: We have analyzed a series of benign hepatic nodular lesions occurring in children previously treated for malignant tumors in our institution in a period of 11 years. An extensive description of the imaging presentation of the lesions has been provided to facilitate the differential diagnosis, and a risk factor analysis has been conducted. RESULTS: A total of 14 diagnoses (10 FNH and 4 hemangiomas) of benign nodular hepatic lesions have been found. Hematopoietic stem cell transplantation is the most important statistically independent risk factor associated with the development of these lesions, especially for FNH. No malignant transformation of nodules has been recorded during a median follow-up time of 4 years. CONCLUSIONS: In our experience, FNH is the most frequent benign nodular hepatic lesions occurring after treatment for childhood cancer. Hematopoietic stem cell transplantation is the most important risk factor to be taken in account. After a secure diagnosis of these benign lesions, only a close imaging follow-up is recommended. PMID- 22922377 TI - Retinal microvascular signs are associated with chronic kidney disease in persons with and without diabetes. AB - BACKGROUND/AIMS: In persons with diabetes, retinal microvascular abnormalities are associated with chronic kidney disease (CKD). However, it is not clear if the same relationship applies in persons without diabetes. METHODS: We examined 2,971 participants from a population-based study (240 with, 2,731 without diabetes). Retinal photographs were masked graded for retinal microvascular signs, and CKD was defined as estimated glomerular filtration rate (eGFR(MDRD)) <60 ml/min/1.73 m(2). RESULTS: Retinal microvascular signs were more frequent in persons with CKD. After adjusting for age, gender, systolic blood pressure and fasting plasma glucose, CKD was associated with both presence of retinopathy (odds ratio, OR, 1.2, 95% confidence interval, CI 1.0-1.5) and venular dilation (OR 1.2, 95% CI 1.0-1.5). These associations were similar in persons with and without diabetes. There was a significant trend for increasing magnitude of associations of retinopathy with increasing severity levels of CKD (p for trend 0.03). CONCLUSIONS: Retinal microvascular signs, namely retinopathy lesions and venular dilation, are associated with CKD both in persons with, and without diabetes. This supports the concept that retinal microvascular signs are indicators of generalized microvascular disease even in the absence of diabetes, and reinforces the link between retinal and renal microcirculations. PMID- 22922378 TI - Bortezomib action in multiple myeloma: microRNA-mediated synergy (and miR 27a/CDK5 driven sensitivity)? PMID- 22922379 TI - Is re-breathe diffusing capacity better than single breath in emphysema patients? PMID- 22922381 TI - Pediatric primary anaplastic ganglioglioma: a case report and review of the literature. AB - Gangliogliomas with anaplastic features are classified as grade III tumors by the World Health Organization. The clinical course and optimal treatment of anaplastic gangliogliomas have not been well understood to date. We report a case of a primary pure anaplastic ganglioglioma in a 14-year-old male treated with surgery and radiotherapy, who is disease-free 6 years after the diagnosis. A review of primary pure anaplastic gangliogliomas in children (between 3 and 21 years of age) is presented. Gross total removal and focal radiotherapy with a total dose of 54 Gy are recommended. The addition of chemotherapy should be evaluated. Prospective studies are needed to identify an appropriate chemotherapy schedule and to define biological factors in order to select those patients with a poor prognosis, who are to be treated with a more aggressive therapy. PMID- 22922382 TI - Determination of cathepsin S abundance and activity in human plasma and implications for clinical investigation. AB - There is strong experimental evidence associating cathepsin S with the pathogenesis of atherosclerosis, with emerging data to support its role in diseases such as abdominal aortic aneurysm, obesity, and type 2 diabetes. To further our understanding of cathepsin S, we have developed a novel sandwich immunoassay to measure the mature form of cathepsin S in plasma (mean values from 12 healthy donors of 53+/-17ng/ml, range=39-102). We also developed a targeted liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay to measure in vitro cathepsin S activity to compare activity levels with the protein mass levels determined by enzyme-linked immunosorbent assay (ELISA). Interestingly, we observed that only 0.4 to 1.1% of circulating cathepsin S was enzymatically active. We subsequently demonstrated that the attenuated activity we observed resulted from binding between cathepsin S and its endogenous inhibitor cystatin C in plasma. These data were obtained through immunoprecipitation coupled with either Western blotting analysis or in-gel tryptic digestion and LC-MS/MS characterization of Coomassie-stained gel bands. Although many laboratories have explored the relationship between cathepsin S and cystatin C, this is the first study to demonstrate their association in human circulation, a finding that could prove to be important in furthering our understanding of cathepsin S biology. PMID- 22922383 TI - Synthesis of radiolabeled nicotinamide cofactors from labeled pyridines: versatile probes for enzyme kinetics. AB - (14)C-labeled nicotinamide cofactors are widely employed in biomedical investigations, for example, to delineate metabolic pathways, to elucidate enzymatic mechanisms, and as substrates in kinetic isotope effect (KIE) experiments. The (14)C label has generally been located remote from the reactive position, frequently at the adenine ring. Rising costs of commercial precursors and disruptions in the availability of enzymes required for established syntheses have recently made the preparation of labeled nicotinamides such as [Ad (14)C]NADPH unviable. Here, we report the syntheses and characterization of several alternatives: [carbonyl-(14)C]NADPH, 4R-[carbonyl-(14)C, 4-(2)H]NADPH, and [carbonyl-(14)C, 4-(2)H(2)]NADPH. The new procedures use [carbonyl (14)C]nicotinamide as starting material, because it is significantly cheaper than other commercial (14)C precursors of NADPH, and require only one commercially available enzyme to prepare NAD(P)(+) and NAD(P)H. The proximity of carbonyl (14)C to the reactive center raises the risk of an inopportune (14)C isotope effect. This concern has been alleviated via competitive KIE measurements with Escherichia coli dihydrofolate reductase (EcDHFR) that use this specific carbonyl (14)C NADPH. A combination of binding isotope effect and KIE measurements yielded no significant (12)C/(14)C isotope effect at the amide carbonyl (KIE=1.003+/ 0.004). The reported procedure provides a high-yield, high-purity, and cost effective alternative to labeled nicotinamide cofactors synthesized by previously published routes. PMID- 22922384 TI - Electrochemical sensing based on gold nanoparticle-decorated halloysite nanotube composites. AB - Novel gold nanoparticle-decorated halloysite nanotube (AuNP-HNT) composites were effectively synthesized and then used for electrochemical sensing applications. The AuNP-HNT nanocomposites were characterized by transmission electron microscopy, field emission scanning electron microscopy, zeta potential, and UV Vis spectroscopy. The AuNP-HNT composite-based modified electrode exhibited high eletrocatalytic activity to the reduction of hydrogen peroxide (H(2)O(2)) with a linear range of 5.0*10(-6) to 2.55*10(-4)M and a detection limit of 1*10(-6)M (signal/noise=3), indicating that it could be used as a novel nonenzymatic electrochemical H(2)O(2) sensor. Furthermore, the Ru(bpy)(3)(2+)/AuNP-HNT/Nafion composite film modified electrode exhibited good electrochemiluminescence activity for determining tripropylamine. PMID- 22922385 TI - Simultaneous high-performance liquid chromatography determination of coenzyme A, dephospho-coenzyme A, and acetyl-coenzyme A in normal and pantothenic acid deficient rats. AB - We describe here a simultaneous high-performance liquid chromatography method for practical and rapid determination of coenzyme A (CoA), dephospho-CoA, and acetyl CoA in tissues. These coenzymes are biosynthesized from the vitamin pantothenic acid (PaA), which is involved in the metabolism of fatty acids, amino acid catabolism, and several other nutrients. The method employed a Tosoh TSK-GEL ODS 100 V column (250*4.6mm i.d., particle size 5MUm) eluted with 100mmol/L NaH(2)PO(4) and 75mmol/L CH(3)COONa (pH was adjusted to 4.6 by the addition of concentrated H(3)PO(4))-acetonitrile (94:6, v/v) at a flow rate of 1.0ml/min. The ultraviolet detector was set at 259nm. The limits of detection for CoA, dephospho CoA, and acetyl-CoA all were 10pmol. The method was applied to the analysis of several tissues of rats fed normal and PaA-free diets. The results clearly showed that the method was suitable for the simultaneous determination of CoA, dephospho CoA, and acetyl-CoA in the liver, heart, kidney, spleen, testis, large colon, and muscle, but not for the small intestine, of rats. PMID- 22922386 TI - Coupling purification and on-column PEGylation of tumor necrosis factor alpha analogue. AB - Trends in preparation of PEGylated protein drugs strive for simple, fast, and cheap processes, resulting in well-defined homogeneous products. We investigated the on-column PEGylation of tumor necrosis factor alpha (TNF-alpha), where purification and conjugation were performed in one step by using immobilized metal affinity chromatography (IMAC). The same quality of the PEGylated product was obtained by the on-column approach starting from either the crude Escherichia coli protein extract or the purified protein. In comparison with the PEGylation in solution, the on-column approach resulted in more homogeneous PEGylated product. The on-column PEGylation reduces the number of production steps, costs, and preparation time. PMID- 22922387 TI - Ectopic pleural thymoma mimicking a giant solitary fibrous tumour of the pleura. AB - Thymoma is the commonest tumour of the anterior mediastinum in adults. Ectopic thymoma sometimes occurs, usually affecting the neck, mediastinal compartments, the lung and, very rarely, the pleura. We describe the case of a giant right sided pleural thymoma (14 13 8 cm), preoperatively suspected to be a solitary fibrous tumour; a complete surgical resection was achieved and a postoperative diagnosis of type AB Masaoka stage II B tumour was attained. PMID- 22922388 TI - Cupping of the left atrial disc: a new echocardiographic pointer towards atrial septal defect-device mismatch. AB - We report a case of percutaneous atrial septal defect closure (ASD) in which, despite careful device selection and successful shunt closure, a number of adverse echocardiographic features developed, necessitating surgical extraction of the device and patch closure of the defect. Lessons regarding case selection, device choice, appropriate follow-up and recognition of adverse echocardiographic features can be learned from this experience. PMID- 22922389 TI - Retrosternal goiter located in the mediastinum: surgical approach and operative difficulties. AB - Most retrosternal goiters are situated in the anterior mediastinal compartment, but according to the literature, 10-15% are located in the posterior mediastinum. Although most of the anterior mediastinal goiters can be removed by a transcervical approach, posterior mediastinal goiters may require additional extracervical incisions. We report the case of a huge posterior mediastinal goiter extending from the neck retrotracheally beyond the aortic arch and azygous vein with crossover from the left to the right side and ending at the level of the lower part of the left cardiac atrium, nearly reaching the diaphragm. Surgical removal is the treatment of choice in such cases. We performed an operation using a transcervical and right thoracotomy approach. Histopathological examination confirmed the diagnosis of the large goiter. The patient recovered well and was discharged in 1 week. PMID- 22922390 TI - A global view of gene activity at the flowering transition phase in precocious trifoliate orange and its wild-type [Poncirus trifoliata (L.) Raf.] by transcriptome and proteome analysis. AB - Most of what we know about the molecular genetics of flowering time regulation comes from studies in the model plants. However, little is known about the regulation of flowering transition in perennial species or in species with particular growth habits compared with model plants. Here comparative transcriptome and proteome profiling of spring shoots was performed on an early flowering trifoliate orange mutant (precocious trifoliate orange, Poncirus trifoliata) and its wild-type. A total of 19,215 read-mapped genes were observed in two genotypes by RNA-Seq. Of these, 1450 and 1159 genes were specifically observed in the mutant and wild-type libraries, respectively. There were 355 genes that were expressed differently in the two genotypes. A total of 1664 proteins were identified by the iTRAQ technique, and transcript and protein profiles were parallel across the time course for 50% of the comparisons made, but divergent patterns were also observed, indicative of post-transcriptional events. In addition, a global survey of messenger RNA splicing events identified 16,343 splice junctions among 12,688 genes and showed that alternative 3' splice is the most prevalent form of alternative splicing. We further identify 5698 novel transcribed regions that are not overlapping with annotated citrus transcriptome in two genotypes. Understanding of the regulation of flowering transition in citrus can help in the development of new genetic or management strategies to improve fruit production. PMID- 22922391 TI - Hsa-miR-499 polymorphism (rs3746444) and cancer risk: a meta-analysis of 17 case control studies. AB - INTRODUCTION: MicroRNAs (miRNAs) are a family of endogenous, small and noncoding RNAs that negatively regulate gene expression by suppressing translation or degrading mRNAs. Recently, many studies investigated the association between hsa miR-499 rs3746444 polymorphism and cancer risk, which showed inconclusive results. METHODOLOGY/MAIN RESULTS: We conducted a meta-analysis of 17 studies that included 7842 cancer cases and 8989 case-free controls and assessed the strength of the association, using odds ratios (ORs) with 95% confidence intervals (CIs). Overall, hsa-miR-499 rs3746444 polymorphism was associated with higher cancer risk in heterozygote model (AG vs AA, OR=1.15, 95%CI=1.01-1.30, P(heterogeneity)<0.001), dominant genetic model (GG/AG vs AA, OR=1.18, 95% CI=1.04-1.33, P(heterogeneity)<0.001) and allele contrast (G vs A, OR=1.09, 95% CI=1.01-1.18, P(heterogeneity)=0.021). In the stratified analyses, we observed that the GG/AG genotype might modulate breast cancer risk (OR=1.13, 95% CI=1.01 1.26, P(heterogeneity)=0.111) comparing with the AA genotype. Moreover, a significantly increased risk was found among Asian populations in heterozygote model (AG vs AA, OR=1.23, 95% CI=1.06-1.43, P(heterogeneity)<0.001), homozygote model (GG vs AA, OR=1.22, 95% CI=1.02-1.46, P(heterogeneity)=0.319), dominant model (GG/AG vs AA, OR=1.25, 95% CI=1.06-1.39, P(heterogeneity)<0.001) and allele contrast (G vs A, OR=1.14, 95% CI=1.04-1.25, P(heterogeneity)=0.021). CONCLUSIONS: These findings supported that hsa-miR-499 rs3746444 polymorphism contributes to the susceptibility of cancers. PMID- 22922392 TI - Factors regulating the bioavailability of methylmercury to breeding rusty blackbirds in northeastern wetlands. AB - Rusty blackbirds are undergoing rapid population decline and have elevated Hg concentrations while breeding in the Acadian ecoregion of North America. Factors regulating the bioavailability of methyl-Hg (MeHg) within this population's habitat were determined using water, invertebrates, and blood from adult rusty blackbirds collected for Hg-speciation, along with additional water column parameters: MeHg and THg, dissolved organic carbon, pH, dissolved oxygen, conductivity, redox potential, and temperature. Both DO(2) and pH were negatively related to biota MeHg, while water MeHg concentrations were positively related. Both invertebrate MeHg concentration and %MeHg increased with trophic level. Invertebrate MeHg concentrations were among the greatest reported when compared with those reported elsewhere for wetlands and waterbodies-often several times greater for similar taxa-while percent MeHg of THg were similar. An environment with high bioavailability of MeHg in combination with a high trophic position best explains elevated Hg concentrations for this species regional population. PMID- 22922393 TI - Polybrominated diphenyl ethers (PBDEs) in sediments of the coastal East China Sea: occurrence, distribution and mass inventory. AB - Polybrominated diphenyl ethers (PBDEs) of sixty-three sediment samples from the coastal East China Sea (ECS), extending ~1000 km from the Yangtze River Estuary to the south, were measured. The levels of BDE-209 and ?PBDE(7) (sum of BDE-28, 47, 99, 100, 153, 154, 183) were 0.3-44.6 ng/g (dry weight) and nd-8.0 ng/g, respectively. BDE-209 was the predominant congener, followed by BDE-99/100. This was consistent with the historical and current usage of PBDE mixtures in China. The compositions and distribution of PBDEs suggest that the PBDEs in this area could be mainly from the coastal electronic waste dismantling/recycling and Yangtze River input. The poor correlations between TOC, grain size of sediments with PBDEs imply that the PBDE distribution is more related to their land-based inputs rather than the sediment characters in the area. The coastal ECS is an important sink of PBDEs (7.5 t/yr) in the world. PMID- 22922394 TI - Near-infrared quantum dot light emitting diodes employing electron transport nanocrystals in a layered architecture. AB - PbSe quantum dot light emitting diodes (QD-LEDs) of a multi-layer architecture are reported in the present work to exhibit high external quantum efficiencies. In these devices, a ligand replacement technique was employed to activate PbSe QDs, and ZnO nanoparticles were used for the electron transport layer. The emission wavelength of this solution processed device is QD size tunable over a broad spectral range, and an LED efficiency of 0.73% was measured at 1412 nm. Higher efficiencies at longer wavelengths are also inferred from spectral characterization. PMID- 22922395 TI - Effect of tree size and competition on tension wood production over time in beech plantations and assessing relative gravitropic response with a biomechanical model. AB - PREMISE OF THE STUDY: Gravitropic movements are unexpected mechanical processes that could disturb tree design allometries derived from the physics of nonliving bodies. We investigated whether the scaling law of gravitropic performance (power of -2 of stem diameter) derived from integrative biomechanical modeling is disturbed by ontogeny or environment, then discuss the silvicultural and dendroecological consequences. METHODS: In a beech (Fagus sylvatica) plantation, four plots with different initial planting densities evolved without any intervention for 26 yr. Regular tree inventories and a silvicultural model were used to monitor competition over time in each plot. The radial production of tension wood was quantified using a cross-section of the stems at 1.30-m height, and an integrative biomechanical model computed the tree gravitropic performance over time. KEY RESULTS: All trees developed tension wood over the whole period, with higher amounts at the youngest age, resulting in theoretical lean corrections of ca. 20-30 degrees on the first 4 m of the stem over the whole period. The scaling law of gravitropic performance is slightly larger than the power of -2 of stem diameter. CONCLUSIONS: Gravitropic performance in forest ecosystems is mainly limited by size (diameter). Ontogenic acclimation of tension wood formation allows the youngest trees to be more reactive. No additional effect of spacing was found. However, silviculture influences size and, therefore, tree reactivity at a given age. Such results will be helpful for dendroecological approaches that use wood as a marker of environmental disturbances or a trait linked to plant strategies. PMID- 22922396 TI - The evolutionary potential of Baker's weediness traits in the common morning glory, Ipomoea purpurea (Convolvulaceae). AB - PREMISE OF THE STUDY: Many reports have cited Baker's list of weediness traits, or those that exemplify the "ideal" weed, yet few have considered the evolutionary potential of such traits as a group. Thus, it is unknown whether constraints on the evolution of increased weediness, such as a lack of genetic variation or genetic correlations between the traits, are present. Ipomoea purpurea, the common morning glory, is a problematic weed that exhibits many of Baker's ideal weed traits. METHODS: We used progeny from a half/full-sib breeding design in a series of three greenhouse experiments to assess the presence of genetic variation, narrow sense heritabilities, and genetic correlations in Baker's growth, competition, and fitness "weediness" traits in two populations of I. purpurea. KEY RESULTS: We uncovered genetic variation underlying reproductive fitness traits and competitive ability in at least one population, but no evidence of genetic variation underlying growth rate in either population. Genetic correlations between many of the weediness characters differed significantly from zero; however, their direction and/or magnitude differed between populations. CONCLUSIONS: We found that increased weediness in the common morning glory is more likely to occur through selection on reproductive output and competitive ability rather than through selection on growth rate. Assessing Baker's traits in a quantitative genetics framework can provide a solid perspective on their evolutionary potential and a unique framework within which to determine how weeds will respond to different environmental stresses and/or scenarios of global climate change. PMID- 22922397 TI - Antarctic glossopterid diversity on a local scale: the presence of multiple megasporophyll genera, Upper Permian, Mt. Achernar, Transantarctic Mountains, Antarctica. AB - PREMISE OF THE STUDY: The glossopterids are a group of plants that thrived during a time of global warming similar to what is happening on the Earth today as well as the transition from archaic plant groups to the ancestors of modern groups. The diversity of the glossopterid clade is based on the megasporangiate structures assigned to the group, because the vegetative and pollen-bearing structures vary little. The presence of numerous reproductive genera from a single Upper Permian locality in the central Transantarctic Mountains provides important data on local glossopterid diversity in Antarctica. METHODS: Impression/compression fossils were imaged with a Leica 5000C digital camera on a dissecting microscope or a Fujifilm FinePix S1pro digital camera. KEY RESULTS: Two megasporangiate taxa are described: Scutum leiophyllum, which represents the first confirmed record of the genus in Antarctica, and Lidgettoniopsis ramulus, a new morphology consisting of a pinnate structure with oppositely attached megasporophylls. Plumsteadia ovata specimens indicate that this genus can be larger than previously recorded and illustrate the vegetative surface with a distinct midrib. CONCLUSIONS: The presence of a laminar, multiovulate structure and a pinnate structure at the same site indicates that local-level glossopterid diversity in Antarctica is greater than previously hypothesized. The discovery of a new megasporophyll morphology in Antarctica (confirming the presence of three distinctive morphologies on the continent) shows that Antarctic glossopterid heterogeneity is on a par with other Gondwanan continents. The diversity of the Antarctic landscape reveals that high polar latitudes can sustain a diverse ecosystem during times of global warming. PMID- 22922398 TI - Clinal variation in stomatal characteristics of an Arctic sedge, Eriophorum vaginatum (Cyperaceae). AB - PREMISE OF THE STUDY: In a large reciprocal transplant experiment, Eriophorum vaginatum tussocks transplanted along a latitudinal gradient in Alaska's interior exhibited genetic differentiation and phenotypic plasticity for vegetative traits. Using the same tussocks 30 yr later, we used estimates of growing season temperature at each site to ask whether there was a climatic cline for stomatal density, size, and conductance. METHODS: We created impressions of the abaxial leaf surfaces of the transplanted individuals for viewing under a microscope and measured stomatal density (SD) and length (SL) for 224 individuals. We used SD and SL to estimate stomatal conductance (C). Separate one-way analyses of variance were performed to quantify the effect of population genetic differences and latitudinal environmental variation on stomatal characteristics. KEY RESULTS: Our data suggest that stomatal size was influenced by both genetics and environment and that plasticity for stomatal density produced highest densities at the coolest sites. Stomatal conductance increased with decreasing temperature of site from which the populations originated. CONCLUSIONS: Our results demonstrate a cline in stomatal conductance in E. vaginatum, with some ability of populations to plastically produce an appropriate phenotypic response in a new environment. Because the species is a dominant species in many arctic plant communities, its ability to produce an appropriate stomatal phenotype and to optimize water use efficiency by decreasing stomatal conductance in warmer environments could affect both community composition and total primary productivity in future, warmer climates. PMID- 22922399 TI - Leaf traits in parental and hybrid species of Sorbus (Rosaceae). AB - PREMISE OF THE STUDY: Knowledge of functional leaf traits can provide important insights into the processes structuring plant communities. In the genus Sorbus, the generation of taxonomic novelty through reticulate evolution that gives rise to new microspecies is believed to be driven primarily by a series of interspecific hybridizations among closely related taxa. We tested hypotheses for dispersion of intermediacy across the leaf traits in Sorbus hybrids and for trait linkages with leaf area and specific leaf area. METHODS: Here, we measured and compared the whole complex of growth, vascular, and ecophysiological leaf traits among parental (Sorbus aria, Sorbus aucuparia, Sorbus chamaemespilus) and natural hybrid (Sorbus montisalpae, Sorbus zuzanae) species growing under field conditions. A recently developed atomic force microscopy technique, PeakForce quantitative nanomechanical mapping, was used to characterize the topography of cell wall surfaces of tracheary elements and to map the reduced Young's modulus of elasticity. KEY RESULTS: Intermediacy was associated predominantly with leaf growth traits, whereas vascular and ecophysiological traits were mainly parental like and transgressive phenotypes. Larger-leaf species tended to have lower modulus of elasticity values for midrib tracheary element cell walls. Leaves with a biomass investment related to a higher specific leaf area had a lower density. Leaf area- and length-normalized theoretical hydraulic conductivity was related to leaf thickness. CONCLUSIONS: For the whole complex of examined leaf traits, hybrid microspecies were mosaics of parental-like, intermediate, and transgressive phenotypes. The high proportion of transgressive character expressions found in Sorbus hybrids implies that generation of extreme traits through transgressive segregation played a key role in the speciation process. PMID- 22922400 TI - Microsatellite markers for Hylocomium splendens (Hylocomiaceae). AB - PREMISE OF THE STUDY: The perennial feather moss Hylocomium splendens is one of the most widely distributed and common bryophytes in the Northern Hemisphere and has, because of its capacity to grow under a wide range of environmental conditions, been used as a biomonitor for atmospheric metal deposition in Europe. METHODS AND RESULTS: We present a multiplex approach for the analysis of 14 microsatellite markers tested on 194 H. splendens gametophytes. Ten of the markers are developed recently, and are presented for the first time in this paper, whereas four were previously developed but have not been used for population genetic investigations. CONCLUSIONS: The microsatellite markers reported here will provide a powerful tool for further research on population genetic structure in H. splendens. PMID- 22922401 TI - Securing dual ipsilateral leads through a single burr hole in deep brain stimulation surgery: technical note. AB - Deep brain stimulation (DBS) surgery typically involves placement of a single lead through a burr hole, either unilaterally or bilaterally. Rare indications, however, call for placement of 2 ipsilateral leads. To date, there have been no technical descriptions of how best to secure dual ipsilateral leads to the skull. We describe a method of placing and securing 2 ipsilateral DBS leads through a single burr hole using standard cranial plating equipment and a simple modification to a burr hole-mounted anchoring ring. This method has been used safely in 6 patients without detectable displacement of the first lead during implantation of the second lead. PMID- 22922402 TI - Streptomyces competition and co-evolution in relation to plant disease suppression. AB - High densities of antagonistic Streptomyces are associated with plant disease suppression in many soils. Here we review use of inoculation and organic matter amendments for enriching antagonistic Streptomyces populations to reduce plant disease and note that effective and consistent disease suppression in response to management has been elusive. We argue that shifting the focus of research from short-term disease suppression to the population ecology and evolutionary biology of antagonistic Streptomyces in soil will enhance prospects for effective management. A framework is presented for considering the impacts of short- and long-term management on competitive and coevolutionary dynamics among Streptomyces populations in relation to disease suppression. PMID- 22922403 TI - Sacral neuromodulation and intravesical botulinum toxin for refractory overactive bladder. AB - PURPOSE OF REVIEW: To provide an overview of sacral neuromodulation (SNM) and intravesical botulinum toxin (BTX) injections in the treatment of refractory overactive bladder (OAB) and urge urinary incontinence. RECENT FINDINGS: SNM has been a successful treatment option for OAB for over a decade with efficacy rates reported between 50 and 90%. Recently, intravesical BTX has been studied as a less invasive but more transient option with similar efficacy rates. Side-effect profiles differ greatly between the treatments, with elevated postvoid residuals and urinary tract infections most commonly occurring after botulinum injection and pain or device revision or removal occurring with SNM. Recent studies have tried to elucidate the optimal dosing regimen for BTX and patient variables predicting success for both therapies in order to improve outcomes while reducing adverse events. SUMMARY: Both intravesical BTX and SNM have been shown to be effective treatment options for OAB. Further research is needed to determine equivalence or if one therapy is superior and to identify the ideal patient population for each therapy. PMID- 22922404 TI - Evidence for ligand-specific conformations of the histamine H(2)-receptor in human eosinophils and neutrophils. AB - The histamine H(2)-receptor (H(2)R) couples to G(S)-proteins and induces adenylyl cyclase-mediated cAMP accumulation. In human neutrophils and eosinophils, the H(2)R reduces chemotactic peptide-stimulated superoxide anion (O(2)(-)) formation. However, pharmacological characterization of the H(2)R in these cells is far from being complete. The aim of this study was to provide a comprehensive profiling of the H(2)R in neutrophils and eosinophils. Histamine inhibited O(2)( ) formation in human neutrophils more effectively than in eosinophils. H(2)R agonists mimicked the effects of histamine and H(2)R antagonists blocked the effects of histamine. We noticed multiple discrepancies in the potencies and efficacies of H(2)R agonists with respect to cAMP accumulation and inhibition of O(2)(-) formation in both cell types. There were also differences in the antagonist profiles between cAMP accumulation and inhibition of O(2)(-) formation in neutrophils. Moreover, the pharmacological profile of the recombinant H(2)R did not match the H(2)R profile in native cells. The H(2)R sequence identified in human neutrophils corresponds to the published H(2)R sequence, excluding the exclusive expression of a new H(2)R isoform as explanation for the differences. Very likely, the differences between ligands are explained by the existence of ligand-specific receptor conformations with unique affinities, potencies and efficacies. Thus, our data provide evidence for the notion that the concept of ligand-specific receptor conformations can be extended from recombinant systems to native cells. PMID- 22922405 TI - Repair of supracondylar humerus fractures in children: does pin spread matter? AB - Supracondylar humerus fractures occur frequently in children and can be repaired by the lateral or crossed pinning technique, although the importance of pin divergence is unknown. A surgeon's experience using the crossed (N=46) and lateral (N=57) pinning technique was reviewed to determine whether the pin-spread ratio (PSR), the distance between the pins at fracture level divided by the fracture width, was associated with fixation loss. No association existed between the PSR and change in Baumann's angle for fractures repaired by lateral pinning, although one existed for type III fractures repaired with crossed pinning. The PSRs employed in pediatric supracondylar humerus repair appear sufficient for fixation. PMID- 22922406 TI - Longitudinal follow-up of nutritional status and its influencing factors in adults undergoing allogeneic hematopoietic cell transplantation. AB - There are few longitudinal data on nutritional status and body composition of patients undergoing allogeneic hematopoietic cell transplantation (alloHCT). We assessed nutritional status of 105 patients before alloHCT and its course during the early post-transplant period to day +30 and day +100 via weight history, body mass index (BMI) normalized for gender and age, Subjective Global Assessment, phase angle normalized for gender, age, and BMI, and fat-free and body fat masses. Furthermore, we present a multivariate regression model investigating the impact of factors on body weight. At admission, 23.8% reported significant weight losses (>5%) in the previous 6 months, and we noted 31.5% with abnormal age- and sex-adjusted BMI values (?10th, ?90th percentiles). BMI decreased significantly (P<0.0001) in both periods by 11% in total, meaning a weight loss of 8.6+/-5.7 kg. Simultaneously, the patients experienced significant losses (P<0.0001) of both fat-free and body fat masses. Multivariate regression model revealed clinically relevant acute GVHD (parameter estimate 1.43; P=0.02) and moderate/severe anorexia (parameter estimate 1.07; P=0.058) as independent factors influencing early weight loss. In conclusion, our results show a significant deterioration in nutritional status during the early post-transplant period. Predominant alloHCT-associated complications such as anorexia and acute GVHD became evident as significant factors influencing nutritional status. PMID- 22922407 TI - Extracorporeal photopheresis in 62 patients with acute and chronic GVHD: results of treatment with the COBE Spectra System. AB - In this retrospective analysis, 30 patients with acute GVHD (aGVHD) and 32 patients with chronic GVHD (cGVHD) treated with extracorporeal photopheresis (ECP) performed by the COBE Spectra System were evaluated. After 3 months of ECP treatment, a CR and PR were observed in 9 (30%) and 6 (20%) patients with aGVHD and in 2 (6%) and 12 (38%) patients with cGVHD. In 16 (53%) patients with aGVHD and 9 (28%) with cGVHD ECP treatment was already stopped after 3 months. One (3%) patient with aGVHD and 7 (22%) patients with cGVHD received new additional immunosuppressive therapy started during the first 3 months of ECP treatment and were classified as 'nonresponder' with regard to ECP. Of these patients a PR was achieved in one patient with aGVHD and in three patients with cGVHD. Steroids could be tapered by ?50 in 83% of patients with aGVHD and in 29% of patients with cGVHD after 3 months of ECP treatment. Patients with aGVHD achieving a CR or PR showed a significant improved OS after allo-SCT (P=0.019). ECP is associated with significant response rates and successful reduction of steroids in patients with GVHD. PMID- 22922408 TI - The impact of sickle cell disease on exercise capacity in children. AB - BACKGROUND: Little is known about pulmonary vascular complications in children with sickle cell disease (SCD). We hypothesized that transfer factor (diffusing capacity of the lung for carbon monoxide [D(LCO)] ) may be used as a surrogate for the size of the pulmonary vascular bed and that pulmonary vascular abnormalities in children with SCD may limit exercise capacity. METHODS: Fifty stable patients with SCD aged 10 to 18 years and 50 healthy control subjects matched for race and age were recruited. Incremental ergometer cardiopulmonary exercise testing was performed using respiratory mass spectrometry for exhaled gas analysis. A rebreathing maneuver was used to measure functional residual capacity, effective pulmonary blood fl ow (Qpeff), and D(LCO), and helium dilution was used to calculate minute ventilation, oxygen consumption, and CO 2 production. RESULTS: In the 89 evaluable subjects, there were no ventilatory differences between SCD and control subjects. Qpeff was consistently 15% to 20% greater in subjects with SCD than control subjects at all stages, but D(LCO) corrected for both surface area and hemoglobin was only about 7% to 10% greater in subjects with SCD at all stages. As a result, the D(LCO)/Qpeff ratio was considerably lower in SCD at all stages. Arteriovenous oxygen content difference was about one-third less in SCD at all stages. CONCLUSIONS: Contrary to our hypothesis, failure to maintain a sufficient Qpeff to compensate for anemia led to exercise limitation. The ratio of pulmonary capillary blood volume to fl ow is reduced throughout, implying subtle pulmonary vascular disease; however, this was not a factor limiting exercise. PMID- 22922409 TI - Anti-inflammatory activity of IgG1 mediated by Fc galactosylation and association of FcgammaRIIB and dectin-1. AB - Complement is an ancient danger-sensing system that contributes to host defense, immune surveillance and homeostasis. C5a and its G protein-coupled receptor mediate many of the proinflammatory properties of complement. Despite the key role of C5a in allergic asthma, autoimmune arthritis, sepsis and cancer, knowledge about its regulation is limited. Here we demonstrate that IgG1 immune complexes (ICs), the inhibitory IgG receptor FcgammaRIIB and the C-type lectin like receptor dectin-1 suppress C5a receptor (C5aR) functions. IgG1 ICs promote the association of FcgammaRIIB with dectin-1, resulting in phosphorylation of Src homology 2 domain-containing inositol phosphatase (SHIP) downstream of FcgammaRIIB and spleen tyrosine kinase downstream of dectin-1. This pathway blocks C5aR-mediated ERK1/2 phosphorylation, C5a effector functions in vitro and C5a-dependent inflammatory responses in vivo, including peritonitis and skin blisters in experimental epidermolysis bullosa acquisita. Notably, high galactosylation of IgG N-glycans is crucial for this inhibitory property of IgG1 ICs, as it promotes the association between FcgammaRIIB and dectin-1. Thus, galactosylated IgG1 and FcgammaRIIB exert anti-inflammatory properties beyond their impact on activating FcgammaRs. PMID- 22922410 TI - Infection-induced NETosis is a dynamic process involving neutrophil multitasking in vivo. AB - Neutrophil extracellular traps (NETs) are released as neutrophils die in vitro in a process requiring hours, leaving a temporal gap that invasive microbes may exploit. Neutrophils capable of migration and phagocytosis while undergoing NETosis have not been documented. During Gram-positive skin infections, we directly visualized live polymorphonuclear cells (PMNs) in vivo rapidly releasing NETs, which prevented systemic bacterial dissemination. NETosis occurred during crawling, thereby casting large areas of NETs. NET-releasing PMNs developed diffuse decondensed nuclei, ultimately becoming devoid of DNA. Cells with abnormal nuclei showed unusual crawling behavior highlighted by erratic pseudopods and hyperpolarization consistent with the nucleus being a fulcrum for crawling. A requirement for both Toll-like receptor 2 and complement-mediated opsonization tightly regulated NET release. Additionally, live human PMNs injected into mouse skin developed decondensed nuclei and formed NETS in vivo, and intact anuclear neutrophils were abundant in Gram-positive human abscesses. Therefore early in infection NETosis involves neutrophils that do not undergo lysis and retain the ability to multitask. PMID- 22922411 TI - EPHA4 is a disease modifier of amyotrophic lateral sclerosis in animal models and in humans. AB - Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease affecting motor neurons. Disease onset and progression are variable, with survival ranging from months to decades. Factors underlying this variability may represent targets for therapeutic intervention. Here, we have screened a zebrafish model of ALS and identified Epha4, a receptor in the ephrin axonal repellent system, as a modifier of the disease phenotype in fish, rodents and humans. Genetic as well as pharmacological inhibition of Epha4 signaling rescues the mutant SOD1 phenotype in zebrafish and increases survival in mouse and rat models of ALS. Motor neurons that are most vulnerable to degeneration in ALS express higher levels of Epha4, and neuromuscular re-innervation by axotomized motor neurons is inhibited by the presence of Epha4. In humans with ALS, EPHA4 expression inversely correlates with disease onset and survival, and loss-of function mutations in EPHA4 are associated with long survival. Furthermore, we found that knockdown of Epha4 also rescues the axonopathy induced by expression of mutant TAR DNA-binding protein 43 (TDP-43), another protein causing familial ALS, and the axonopathy induced by knockdown of survival of motor neuron 1, a model for spinomuscular atrophy. This suggests that Epha4 generically modulates the vulnerability of (motor) neurons to axonal degeneration and may represent a new target for therapeutic intervention. PMID- 22922412 TI - Direct regulation of blood pressure by smooth muscle cell mineralocorticoid receptors. AB - Hypertension is a cardiovascular risk factor present in over two-thirds of people over age 60 in North America; elevated blood pressure correlates with increased risk of heart attack, stroke and progression to heart and kidney failure. Current therapies are insufficient to control blood pressure in almost half of these patients. The mineralocorticoid receptor (MR), acting in the kidney, is known to regulate blood pressure through aldosterone binding and stimulation of sodium retention. However, recent studies support the concept that the MR also has extrarenal actions and that defects in sodium handling alone do not fully explain the development of hypertension and associated cardiovascular mortality. We and others have identified functional MR in human vascular smooth muscle cells (SMCs), suggesting that vascular MR might directly regulate blood pressure. Here we show that mice with SMC-specific deficiency of the MR have decreased blood pressure as they age without defects in renal sodium handling or vascular structure. Aged mice lacking MR in SMCs (SMC-MR) have reduced vascular myogenic tone, agonist-dependent contraction and expression and activity of L-type calcium channels. Moreover, SMC-MR contributes to angiotensin II-induced vascular oxidative stress, vascular contraction and hypertension. This study identifies a new role for vascular MR in blood pressure control and in vascular aging and supports the emerging hypothesis that vascular tone contributes directly to systemic blood pressure. PMID- 22922413 TI - 2012 focused update of the ESC Guidelines for the management of atrial fibrillation: an update of the 2010 ESC Guidelines for the management of atrial fibrillation. Developed with the special contribution of the European Heart Rhythm Association. PMID- 22922414 TI - Third universal definition of myocardial infarction. PMID- 22922415 TI - Guidelines on the management of valvular heart disease (version 2012). PMID- 22922417 TI - Euthyroid submedian free T4 and subclinical hypothyroidism may have a detrimental clinical effect in Down syndrome. AB - BACKGROUND: Aberrant thyroid function is highly prevalent in Down syndrome (DS). We aimed to find whether subclinical hypothyroidism (SCH) or low-normal free T4 (FT4) are associated with a detrimental clinical outcome in untreated DS patients. METHODS: 157 patients assessed at Hadassah Down Syndrome Center between 2004 and 2010 by comprehensive clinical evaluation and tests for hemoglobin, FT4 and thyroid-stimulating hormone (TSH) were subdivided into subgroups including: clinical hypothyroidism, SCH, euthyroid submedian or supramedian FT4, and alternatively for euthyroidism and TSH levels (submedian or supramedian TSH). RESULTS: Hypothyroidism was found in 21.7% and SCH in another 14.9% of the patients. Moderate/severe hypotonia were more frequent among SCH patients compared to euthyroid patients (52.6 vs. 16.4%, p = 0.002). Patient's hemoglobin levels were lower in the euthyroid submedian FT4 group compared to the euthyroid supramedian FT4 group (10.9 vs. 0% below the normal range, p = 0.001). Interestingly, FT4 levels correlated negatively with increasing age among euthyroid DS patients (Pearson's correlation coefficient = -0.324, p = 0.009). CONCLUSION: SCH and euthyroid submedian FT4 may have significant clinical sequelae, such as hypotonia and anemia. Interventional studies with L-thyroxine replacement may be indicated in these subpopulations. Our finding that FT4 levels decrease with age in DS (contrasting the general population trend) may indicate redefining the normal FT4 levels range in DS. PMID- 22922418 TI - Orphan kidney diseases. AB - Rare kidney diseases are a unique subset of renal disorders that are often termed 'orphan' as a result of a multitude of reasons: the small number of patients with the consequent lack of well-defined natural history and course of many of these diseases, limited awareness among the medical community, and finally the significant cost of developing novel therapeutics which makes many of these diseases unattractive targets for the pharmaceutical industry. Nevertheless, in the last decade the study and clinical management of rare kidney disease patients has been the focus of many investigative efforts. In recent years we have witnessed an enormous expansion in our knowledge of the genetic nature of a number of rare kidney diseases. Moreover, the investigation of the role of genetic disruption aiming at elucidating the pathogenesis of different and complex renal diseases has helped not only in understanding the disease states, but has also given us fundamental insights into a number of kidney developmental and physiological functions. This article will give an overview of orphan renal diseases with particular emphasis on monogenic kidney diseases. It will also focus on the classification of these diseases while highlighting a prominent example in each category. PMID- 22922416 TI - ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation. PMID- 22922419 TI - Development of fully amorphous dispersions of a low T(g) drug via co-spray drying with hydrophilic polymers. AB - The aim of the study was to prepare molecular dispersions of a physically highly unstable amorphous drug, paracetamol (acetaminophen with a T(g) of ca. 25 degrees C) via co-spray drying with a variety of polymers. Solid dispersions at a range of drug loadings (10-90%w/w) using hydroxypropyl methylcellulose/acetate succinate (HPMC/HPMC AS), polyvinylpyrrolidone (PVP) and copovidone were produced and characterised by modulated temperature differential scanning calorimetry (MTDSC), thermogravimetric analysis (TGA), X-ray powder diffraction (XRPD), Fourier transform infrared spectroscopy (FTIR) and scanning electron microscopy (SEM). PVP-based polymers showed a greater tendency than the HPMC-based group to generate temperature-stable dispersions. In particular, copovidone (Plasdone(r) S 630) was found to be the most effective of the polymers studied and could formulate molecular dispersions at drug loadings up to and including 40%w/w. However, no evidence for direct drug-polymer interactions was found for such systems as a possible stabilising mechanism. The expected relationship of a higher T(g) of the polymer leading to greater stabilisation was not observed, while there was an inverse relationship between viscosity grade and amorphous phase generation. The study has therefore shown that temperature-stable amorphous dispersions of a low T(g) drug may be prepared by co-spray drying, particularly using PVP-based polymers. PMID- 22922420 TI - Towards development of a survival prediction tool for pediatric head injury. AB - BACKGROUND: The ability to provide an accurate prognosis for children with traumatic brain injury (TBI) would be useful for the children's families and the caregivers. In this study we examined whether an appropriate mathematical model can predict survival in this patient population. METHODS: Data from the Children's Hospital of Eastern Ontario (CHEO) TBI registry was analyzed. First, a series of univariate logistic regressions was performed to ascertain the significance of individual predictors, such as age, maximum Glasgow Coma Scale (GCS) score, maximum head injury Abbreviated Injury Scores (AIS) and the Injury Severity Score (ISS). Second, a multinomial logistic regression was fitted using only individually significant predictors and inmodel predictor significance, and interactions were tested. Only two significant predictors were kept in the final model. This final model was subsequently used to predict survival for each individual patient using the n-1 training set (i.e. Lachenbruch's leave-one-out method). The receiver operating characteristics (ROC) method was used to ascertain specificity-sensitivity trade-offs at different probability cut-offs in order to predict survival. RESULTS: Only the maximum GCS and head injury AIS remained significant, both individually and in the polynomial logistic regression. Empiric ROC curve analyses from leave-one-out survival predictions showed statistical significance (area under the curve = 0.87, Z = 6.8, p < 0.001). Only 12% of cases were misclassified using the 'best' cut-off. CONCLUSION: An outcome predictive model for pediatric TBI can be devised using an appropriate mathematical model. It may help to estimate expected outcomes in pediatric TBI more objectively. PMID- 22922421 TI - Large granular lymphocytic leukemia: a treatable form of refractory celiac disease. AB - Large granular lymphocyte leukemia (LGL) is characterized by clonal expansion of CD3+ T cells or CD3(-) natural killer cells and frequently is associated with autoimmune diseases. We describe 2 patients with celiac disease who no longer responded to gluten-free diets after they developed T-cell LGL, with intestinal localization of malignant lymphocytes. Flow cytometry phenotyping of isolated intestinal intraepithelial and lamina propria cells eliminated type II refractory celiac disease, identifying large-sized CD8(+)CD57(+) T cells. Treatment with a combination of cyclosporine and methotrexate restored the patients' sensitivity to gluten-free diets. LGL therefore might be a cause of refractory celiac disease that is sensitive to immunosuppressive therapy. PMID- 22922422 TI - Redundant sources of Wnt regulate intestinal stem cells and promote formation of Paneth cells. AB - BACKGROUND & AIMS: Wnt signaling regulates multiple aspects of intestinal physiology, including stem cell maintenance. Paneth cells support stem cells by secreting Wnt, but little is known about the exact sources and primary functions of individual Wnt family members. METHODS: We analyzed intestinal tissues and cultured epithelial cells from adult mice with conditional deletion of Wnt3 (Vil CreERT2;Wnt3fl/fl mice). We also analyzed intestinal tissues and cells from Atoh1 mutant mice, which lack secretory cells. RESULTS: Unexpectedly, Wnt3 was dispensable for maintenance of intestinal stem cells in mice, indicating a redundancy of Wnt signals. By contrast, cultured crypt organoids required Paneth cell-derived Wnt3. Addition of exogenous Wnt, or coculture with mesenchymal cells, restored growth of Vil-CreERT2;Wnt3fl/fl crypt organoids. Intestinal organoids from Atoh1 mutant mice did not grow or form Paneth cells; addition of Wnt3 allowed growth in the absence of Paneth cells. Wnt signaling had a synergistic effect with the Lgr4/5 ligand R-spondin to induce formation of Paneth cells. Mosaic expression of Wnt3 in organoids using a retroviral vector promoted differentiation of Paneth cells in a cell-autonomous manner. CONCLUSIONS: Wnt is part of a signaling loop that affects homeostasis of intestinal stem and Paneth cells in mice. Wnt3 signaling is required for growth and development of organoid cultures, whereas nonepithelial Wnt signals could provide a secondary physiological source of Wnt. PMID- 22922423 TI - Glucocorticoids promote hepatic cholestasis in mice by inhibiting the transcriptional activity of the farnesoid X receptor. AB - BACKGROUND & AIMS: Glucocorticoids have potent anti-inflammatory effects, but also can cause insulin resistance, osteoporosis, and muscle wasting, preventing their long-term use. Glucocorticoids also have been associated with the development of hepatic cholestasis and gallstone disease, but little is known about their pathogenic mechanisms. METHODS: We analyzed levels of bile acids (BAs) and glucocorticoids in serum samples from patients with Cushing disease and obese individuals (body mass index, >30). C57BL/6 mice were injected with dexamethasone and db/db obese mice were injected with glucocorticoid receptor (GR) antagonists or small hairpin RNAs. We analyzed farnesoid X receptor (FXR) signaling in HepG2 cells and cells from mice using immunoprecipitation, luciferase reporter, and glutathione-s-transferase and chromatin immunoprecipitation assays. We analyzed BA metabolism in FXR-/- mice and mice with reduced levels of the transcription factor C-terminal binding protein (CtBP). RESULTS: Serum levels of BAs were higher in patients with Cushing disease or obesity than in individuals with normal levels of glucocorticoids. Administration of dexamethasone promoted cholestasis and overproduction of BAs in C57BL/6 mice, but not in FXR-/- mice. GR antagonists, or injection of an adenoviral small hairpin RNA against GR, reduced features of hepatic cholestasis in db/db mice. The GR interacted with FXR to reduce its transcriptional activity by recruiting CtBP co-repressor complexes. Mice with reduced levels of CtBP were resistant to induction of hepatic cholestasis by dexamethasone. CONCLUSIONS: Glucocorticoids promote hepatic cholestasis in mice by recruiting CtBP co repressor complexes to FXR and thereby blocking the transcriptional activity. PMID- 22922424 TI - Sorafenib down-regulates expression of HTATIP2 to promote invasiveness and metastasis of orthotopic hepatocellular carcinoma tumors in mice. AB - BACKGROUND & AIMS: Antiangiogenic agents can sometimes promote tumor invasiveness and metastasis, but little is known about the effects of the antiangiogenic drug sorafenib on progression of hepatocellular carcinoma (HCC). METHODS: Sorafenib was administered orally (30 mg . kg(-1) . day(-1)) to mice with orthotopic tumors grown from HCC-LM3, SMMC7721, or HepG2 cells. We analyzed survival times of mice, along with tumor growth, metastasis within liver and to lung, and induction of the epithelial-mesenchymal transition. Polymerase chain reaction arrays were used to determine the effects of sorafenib on gene expression patterns in HCC cells. We analyzed regulation of HIV-1 Tat interactive protein 2 (HTATIP2) by sorafenib and compared levels of this protein in tumor samples from 75 patients with HCC (21 who received sorafenib after resection and 54 who did not). RESULTS: Sorafenib promoted invasiveness and the metastatic potential of orthotopic tumors grown from SMMC7721 and HCC-LM3 cells but not from HepG2 cells. In gene expression analysis, HTATIP2 was down-regulated by sorafenib. HCC-LM3 cells that expressed small hairpin RNAs against HTATIP2 (knockdown) formed less invasive tumors in mice following administration of sorafenib than HCC-LM3 without HTATIP2 knockdown. Alternatively, HepG2 cells that expressed transgenic HTATIP2 formed more invasive tumors in mice following administration of sorafenib. Sorafenib induced the epithelial-mesenchymal transition in HCC cell lines, which was associated with expression of HTATIP2. Sorafenib regulated expression of HTATIP2 via Jun-activated kinase (JAK) and signal transducer and activator of transcription (STAT)3 signaling. Sorafenib therapy prolonged recurrence-free survival in patients who expressed lower levels of HTATIP2 compared with higher levels. CONCLUSIONS: Sorafenib promotes invasiveness and the metastatic potential of orthotopic tumors from HCC cells in mice, down-regulating expression of HTATIP2 via JAK-STAT3 signaling. PMID- 22922425 TI - NF-kappaB essential modifier is required for hepatocyte proliferation and the oval cell reaction after partial hepatectomy in mice. AB - BACKGROUND & AIMS: The transcription factor nuclear factor kappaB (NF-kappaB) is activated by the IkappaB kinase complex. The regulatory subunit of this complex, NF-kappaB essential modifier (NEMO or IKBKG), is a tumor suppressor. Hepatocyte specific deletion of NEMO induces chronic liver inflammation that leads to apoptosis, oxidative stress, development of nonalcoholic steatohepatitis, and hepatocarcinogenesis. METHODS: We performed partial hepatectomies in mice with hepatocyte-specific disruption of NEMO (Nemo(Deltahepa)). Some mice were fed a diet that contained the antioxidant butylated hydroxyanisole (BHA), and others were given daily intraperitoneal injections of the oxidant phenetyl isothiocyanate (PEITC). RESULTS: Nemo(Deltahepa) mice had impaired liver regeneration after partial hepatectomy and 50% mortality, indicating that NEMO is required for the regenerative response. Liver cells of the mice had a strong oxidative stress response; these cells down-regulated the NF-kappaB-dependent antioxidant response and reduced levels of proteins that repair DNA double-strand breaks. However, the impairments to hepatocyte proliferation were compensated by a response of oval cells in Nemo(Deltahepa) mice. Oval cells expressed low levels of albumin and thereby expressed normal levels of NEMO. Repopulation of the liver with oval cells that expressed NEMO reversed liver damage in Nemo(Deltahepa) mice. Interestingly, these mice still developed hepatocellular carcinomas 6 months after partial hepatectomy, whereas Nemo(Deltahepa) mice fed the BHA diet were protected from carcinogenesis. CONCLUSIONS: In livers of mice, expression of NEMO and activation of NF-kappaB are required for hepatocyte proliferation and liver regeneration. These mechanisms require control of oxidative stress and DNA integrity. PMID- 22922426 TI - Radioecological assessment and remediation planning at the former uranium milling facilities at the Pridnieprovsky Chemical Plant in Ukraine. AB - A four year investigation of the largest uranium production legacy site in Ukraine (Pridneprovsky Chemical Plant) has been carried out, including: gamma dose mapping; indoor and outdoor (222)Rn concentrations; evaluation of tailings sites; as well as preliminary dose calculations for personnel working at the industrial site. This paper provides basic information on remediation planning, on decontamination of the former uranium extraction facilities, and the needs for proper management of the uranium residue in compliance with the best international practice. PMID- 22922427 TI - Outcomes of mid-trimester emergency cerclage in twin pregnancies. AB - INTRODUCTION: Placement of emergency cerclage at mid-trimester is controversial. At present, clinical trials comparing outcomes of mid-trimester cerclage to bed rest in twin pregnancies are lacking. Our aim was to examine the efficacy, safety and outcomes of mid-trimester cerclage in patients carrying twin gestations. MATERIAL AND METHODS: We retrospectively studied the outcomes of 14 patients carrying twin gestations with significant cervical dynamics who underwent cerclage. Outcomes of patients with cervical effacement only and patients with bulging membranes through the external os were examined. The interval between cerclage and delivery and the complication rates were calculated. RESULTS: The average time interval between cerclage placement and delivery was 71.1 days overall. Patients with cervical shortening or effacement only (n = 10) gave birth an average of 80.2 days after the procedure, while 4 patients with bulging membranes gave birth an average of 48.5 days after cerclage placement. The overall procedure failure rate, defined as delivery before 28 completed weeks, was 14.2%. DISCUSSION: Patients carrying twin gestations with advanced cervical changes might benefit from therapeutic cerclage. Further studies are required to demonstrate whether there is a difference compared to bed rest alone. PMID- 22922428 TI - PLGA microspheres encapsulating siRNA anti-TNFalpha: efficient RNAi-mediated treatment of arthritic joints. AB - The aim of this study was to investigate potentialities of poly(dl-lactide-co glycolide) (PLGA) microspheres for the delivery of small interfering RNAs (siRNAs) against tumor necrosis factor alpha (TNF-alpha) to achieve prolonged and efficient inhibition of TNF-alpha for the treatment of rheumatoid arthritis (RA). PLGA microspheres were prepared by a modified multiple emulsion-solvent evaporation method. The formulations were characterized in terms of morphology, mean diameter and siRNAs distribution, encapsulation efficiency, and in vitro release kinetics. The efficiency of this system was then evaluated both in vitro and in vivo using the murine monocytic cell line J774 and a pre-clinical model of RA, respectively. siRNA-encapsulating PLGA microspheres were characterized by a high encapsulation efficiency and a slow and prolonged anti-TNF-alpha siRNAs. Our results provide evidence that, upon intra-articular administration, PLGA microspheres slowly releasing siRNAs effectively inhibited the expression of TNF alpha in arthritic joints. Our system might represent an alternative strategy for the design of novel anti-rheumatic therapies based on the use of RNA interference in RA. PMID- 22922429 TI - Salivary progesterone is associated with reduced coherence of attentional, cognitive, and motivational systems. AB - The present study tested whether the hypothesis that high levels of progesterone (P) have a decoupling effect on the function of the brain hemispheres (Hausmann & Gunturkun, 2000) also extends to attentional functions, referential connections between verbal and nonverbal representations and the degree to which implicit motivational needs match a person's explicit goal commitments. Participants (28 women on oral contraceptives, 14 naturally cycling women, 50 men) completed the Lateralized Attention Network Task (Greene et al., 2008), a measure of the alerting, orienting, and conflict-resolution functions of attention for each hemisphere; a measure of referential competence (i.e., the ability to quickly name nonverbal information); a measure of the implicit motives power, achievement, and affiliation; and a content-matched personal goal inventory. In addition, they provided a saliva sample that was assayed for P and cortisol (C). Higher levels of P were associated with lower interhemispheric correlations for alerting and orienting, but with a higher correlation of conflict-resolution performance. Higher P was also associated with longer interhemispheric transfer time, lower congruence between implicit motives and explicit goal commitments and, after controlling for C, with lower referential competence. These results suggest that (a) P is associated with the degree to which attentional functions are correlated between hemispheres, although in a different direction for more posterior (alerting and orienting: decoupling) than for more anterior functions (conflict resolution: coupling), (b) that high P is associated with other indicators of reduced functional coherence between cognitive systems (longer interhemispheric transfer time, lower referential competence), and (c) that high P is also associated with low coherence between implicit and explicit motivational systems. PMID- 22922430 TI - Lifetime earnings for physicians across specialties. AB - BACKGROUND: Earlier studies estimated annual income differences across specialties, but lifetime income may be more relevant given physicians' long-term commitments to specialties. METHODS: Annual income and work hours data were collected from 6381 physicians in the nationally representative 2004-2005 Community Tracking Study. Data regarding years of residency were collected from AMA FREIDA. Present value models were constructed assuming 3% discount rates. Estimates were adjusted for demographic and market covariates. Sensitivity analyses included 4 alternative models involving work hours, retirement, exogenous variables, and 1% discount rate. Estimates were generated for 4 broad specialty categories (Primary Care, Surgery, Internal Medicine and Pediatric Subspecialties, and Other), and for 41 specific specialties. RESULTS: The estimates of lifetime earnings for the broad categories of Surgery, Internal Medicine and Pediatric Subspecialties, and Other specialties were $1,587,722, $1,099,655, and $761,402 more than for Primary Care. For the 41 specific specialties, the top 3 (with family medicine as reference) were neurological surgery ($2,880,601), medical oncology ($2,772,665), and radiation oncology ($2,659,657). The estimates from models with varying rates of retirement and including only exogenous variables were similar to those in the preferred model. The 1% discount model generated estimates that were roughly 150% larger than the 3% model. CONCLUSIONS: There was considerable variation in the lifetime earnings across physician specialties. After accounting for varying residency years and discounting future earnings, primary care specialties earned roughly $1-3 million less than other specialties. Earnings' differences across specialties may undermine health reform efforts to control costs and ensure adequate numbers of primary care physicians. PMID- 22922431 TI - Initial validation of a self-report measure of the extent of and reasons for medication nonadherence. AB - BACKGROUND: Self-report measures of medication nonadherence confound the extent of and reasons for medication nonadherence. Each construct is assessed with a different type of psychometric model, which dictates how to establish reliability and validity. OBJECTIVES: To evaluate the psychometric properties of a self report measure of medication nonadherence that assesses separately the extent of nonadherence and reasons for nonadherence. RESEARCH DESIGN: Cross-sectional survey involving the new measure and comparison measures to establish convergent, discriminant, and predictive validity. The new measure was readministered 2-21 days later. SUBJECTS: A total of 202 veterans with treated hypertension were recruited from the Durham Veterans Affairs Medical Center. MEASURES: A new self report measure assessed the extent of nonadherence and reasons for nonadherence. Comparison measures included self-reported medication self-efficacy, beliefs about medications, impression management, conscientiousness, habit strength, and an existing nonadherence measure. RESULTS: Three items assessing the extent of nonadherence produced reliable scores for this sample, alpha = 0.84 (95% confidence interval, 0.80-0.87). Correlations with comparison measures provided evidence of convergent and discriminant validity. Correlations with systolic ( r = 0.27, P < 0.0001) and diastolic (r = 0.27, P < 0.0001) blood pressure provided evidence of predictive validity. Reasons for nonadherence were assessed with 21 independent items. Intraclass correlations were 0.58 for the extent score and ranged from 0.07 to 0.64 for the reasons. CONCLUSIONS: The dual conceptualization of medication nonadherence allowed a stronger evaluation of the reliability and validity than was previously possible with measures that confounded these 2 constructs. Measurement of self-reported nonadherence consistent with psychometric principles will enable reliable, valid evaluation of interventions to reduce nonadherence. PMID- 22922432 TI - Assessing health care use and cost consequences of a new screening modality: the case of digital mammography. AB - BACKGROUND: Full-field digital mammography (FFDM) has largely replaced screen film mammography (SFM) for breast cancer screening, but how this affects downstream breast-related use and costs is unknown. OBJECTIVES: To compare breast related health care use and costs among Medicare beneficiaries undergoing SFM versus FFDM from 1999 to 2005. DESIGN: Retrospective cohort study. SUBJECTS: Medicare-enrolled women aged 66 and older with mammograms in Breast Cancer Surveillance Consortium registries. MEASURES: Subsequent follow-up with additional imaging or breast biopsy within 12 months was ascertained through Medicare claims. Associated mean costs were estimated by screening modality and year, adjusting for confounding factors, and clustering within mammography facilities using Generalized Estimating Equations. RESULTS: Among 138,199 women, 332,324 SFM and 22,407 FFDM mammograms were analyzed. Approximately 6.5% of SFM and 9.0% of FFDM had positive findings. In 2001, subsequent imaging was higher among FFDM versus SFM (127.5 vs. 97.4 follow-up mammography claims per 1000 index mammograms), whereas subsequent biopsy was lower among FFDM versus SFM (19.2 vs. 24.9 per 1000 index mammograms) with differences decreasing over time. From 2001 to 2004, mammography subsequent to FFDM had higher mean costs than SFM ($82.60 vs. $64.31 in 2001). The only cost differences between SFM and FFDM for ultrasound or biopsy were in 2001. CONCLUSIONS: Subsequent breast-related health care use differed early in FFDM introduction, but diminished over time with differences attributable to higher recall rates for additional imaging and lower rates of biopsy in those undergoing FFDM versus SFM. Remaining cost differences are because of higher reimbursement rates for FFDM versus SFM. PMID- 22922433 TI - Distinguishing screening from diagnostic mammograms using Medicare claims data. AB - BACKGROUND: Medicare claims data may be a fruitful data source for research or quality measurement in mammography. However, it is uncertain whether claims data can accurately distinguish screening from diagnostic mammograms, particularly when claims are not linked with cancer registry data. OBJECTIVES: To validate claims-based algorithms that can identify screening mammograms with high positive predictive value (PPV) in claims data with and without cancer registry linkage. RESEARCH DESIGN: Development of claims-derived algorithms using classification and regression tree analyses within a random half-sample of bilateral mammogram claims with validation in the remaining half-sample. SUBJECTS: Female fee-for service Medicare enrollees aged 66 years and older, who underwent bilateral mammography from 1999 to 2005 within Breast Cancer Surveillance Consortium (BCSC) registries in 4 states (CA, NC, NH, and VT), enabling linkage of claims and BCSC mammography data (N=383,730 mammograms obtained from 146,346 women). MEASURES: Sensitivity, specificity, and PPV of algorithmic designation of a "screening" purpose of the mammogram using a BCSC-derived reference standard. RESULTS: In claims data without cancer registry linkage, a 3-step claims-derived algorithm identified screening mammograms with 97.1% sensitivity, 69.4% specificity, and a PPV of 94.9%. In claims that are linked to cancer registry data, a similar 3-step algorithm had higher sensitivity (99.7%), similar specificity (62.7%), and higher PPV (97.4%). CONCLUSIONS: Simple algorithms can identify Medicare claims for screening mammography with high predictive values in Medicare claims alone and in claims linked with cancer registry data. PMID- 22922434 TI - The use of patient-reported outcomes (PRO) within comparative effectiveness research: implications for clinical practice and health care policy. AB - BACKGROUND: The goal of comparative effectiveness research (CER) is to explain the differential benefits and harms of alternate methods to prevent, diagnose, treat, and monitor a clinical condition or to improve the delivery of care. To inform decision making, information from the patient's perspective that reflects outcomes that patients care about are needed and can be collected rigorously using appropriate patient-reported outcomes (PRO). It can be challenging to select the most appropriate PRO measure given the proliferation of such questionnaires over the past 20 years. OBJECTIVE: In this paper, we discuss the value of PROs within CER, types of measures that are likely to be useful in the CER context, PRO instrument selection, and key challenges associated with using PROs in CER. METHODS: We delineate important considerations for defining the CER context, selecting the appropriate measures, and for the analysis and interpretation of PRO data. Emerging changes that may facilitate CER using PROs as an outcome are also reviewed including implementation of electronic and personal health records, hospital and population-based registries, and the use of PROs in national monitoring initiatives. The potential benefits of linking the information derived from PRO endpoints in CER to decision making is also reviewed. CONCLUSIONS: The recommendations presented for incorporating PROs in CER are intended to provide a guide to researchers, clinicians, and policy makers to ensure that information derived from PROs is applicable and interpretable for a given CER context. In turn, CER will provide information that is necessary for clinicians, patients, and families to make informed care decisions. PMID- 22922435 TI - Novel health economic evaluation of a vaccination strategy to prevent HPV-related diseases: the BEST study. AB - BACKGROUND: The development of human papillomavirus (HPV)-related diseases is not understood perfectly and uncertainties associated with commonly utilized probabilistic models must be considered. The study assessed the cost effectiveness of a quadrivalent-based multicohort HPV vaccination strategy within a Bayesian framework. METHODS: A full Bayesian multicohort Markov model was used, in which all unknown quantities were associated with suitable probability distributions reflecting the state of currently available knowledge. These distributions were informed by observed data or expert opinion. The model cycle lasted 1 year, whereas the follow-up time horizon was 90 years. Precancerous cervical lesions, cervical cancers, and anogenital warts were considered as outcomes. RESULTS: The base case scenario (2 cohorts of girls aged 12 and 15 y) and other multicohort vaccination strategies (additional cohorts aged 18 and 25 y) were cost-effective, with a discounted cost per quality-adjusted life-year gained that corresponded to ?12,013, ?13,232, and ?15,890 for vaccination programs based on 2, 3, and 4 cohorts, respectively. With multicohort vaccination strategies, the reduction in the number of HPV-related events occurred earlier (range, 3.8-6.4 y) when compared with a single cohort. The analysis of the expected value of information showed that the results of the model were subject to limited uncertainty (cost per patient = ?12.6). CONCLUSIONS: This methodological approach is designed to incorporate the uncertainty associated with HPV vaccination. Modeling the cost-effectiveness of a multicohort vaccination program with Bayesian statistics confirmed the value for money of quadrivalent-based HPV vaccination. The expected value of information gave the most appropriate and feasible representation of the true value of this program. PMID- 22922436 TI - Improvements in Medicare Part D risk adjustment: beneficiary access and payment accuracy. AB - INTRODUCTION: The continued success of the Medicare Part D program is contingent on appropriate Medicare payment adjustments for the projected drug costs of Part D plan enrollees. This article describes a major revision of these "risk adjustments," intended to more accurately match payments to costs, especially for high-cost, disadvantaged populations. METHODS: For the first time actual Part D data are used to calibrate risk adjustment. The sample is Medicare beneficiaries with fee-for-service enrollment in 2007 and Part D standalone prescription drug plan enrollment in 2008 (N = 14,224,301). Part D plan liability expenditures are predicted using demographic and diagnostic factors in a weighted least squares regression. Models for Medicare subpopulations are analyzed. The predictive accuracy of risk adjustment models is evaluated using R and predictive ratio statistics. RESULTS: Based on differences in both mean expenditures and incremental expenditures by diagnosis, separate Part D risk adjustment models are calibrated for 5 Medicare subpopulations: aged not low income; aged low income; nonaged not low income; nonaged low income; and institutionalized. The variation in plan liability drug expenditures (R) explained by these models ranges from 13% to 29%. The 5 separate models accurately predict mean plan liability expenditures ranging from $967 to $1762 across subpopulations and account for differences in incremental disease coefficients by subpopulation. CONCLUSIONS: The refined Part D risk adjustment model represents a significant improvement in the accuracy and fairness of payment to Part D plans. The new model provides greater incentives for drug plans to compete for low-income and institutionalized enrollees. PMID- 22922437 TI - Gamma knife stereotactic radiosurgery for radiation-induced meningiomas. AB - BACKGROUND: Radiation-induced meningiomas present a unique clinical dilemma given the fact that patients with these tumors have often received a prior full course of radiotherapy. As such, traditional radiotherapy is limited by lifetime tissue tolerances to radiation, leaving surgery and radiosurgery as attractive treatment options. OBJECTIVES: To ascertain the safety and efficacy of Gamma Knife radiosurgery as a treatment for radiation-induced meningiomas. METHODS: A retrospective chart review was conducted to identify patients who received Gamma Knife radiosurgery for a meningioma and met the criteria for this being a radiation-induced tumor. Serial imaging was used to determine the outcome of treatment and clinical notes used to assess for toxicity. RESULTS: We present our series of 12 patients with radiation-induced meningiomas treated with Gamma Knife stereotactic radiosurgery over a 12-year period at our institution. With a median follow-up of 35 months, local control was 100%. Two patients experienced distant brain failure (>2 cm from previous radiosurgical volume). Two patients experienced posttreatment toxicity related to treatment-related edema. A review of data collected from the scientific literature suggests that tumor volume predicts for treatment failure of radiosurgery. CONCLUSIONS: Gamma Knife radiosurgery is both a safe and effective treatment for radiation-induced meningiomas. PMID- 22922438 TI - D-dimer in preeclampsia: systematic review and meta-analysis. AB - Preeclampsia is a multifactorial disease characterized by high blood pressure and proteinuria after the 20th week of pregnancy. Preeclampsia is associated with microvasculature fibrin deposition and maternal organ dysfunction. D-dimer (D-Di) has been used as a marker of production/degradation of fibrin in vivo. D-Di has emerged as a useful diagnostic tool for thrombotic conditions because its plasma concentration has a high negative predictive value for venous thromboembolism. The aim of this study was to evaluate publications that assessed plasma D-Di in preeclampsia and normotensive pregnant subjects to define its diagnostic value. A total of 194 publications were identified. Following the exclusion process, seven studies were in accordance with the pre-defined eligibility criteria. This systematic review was performed with methodologic accuracy, including a careful definition of preeclampsia and a high sensitivity literature search strategy. Quality of the included studies was assessed in accordance with widely accepted literature recommendations. Our meta-analysis indicates that increased plasma D Di is associated with preeclampsia in the third trimester of gestation vs normotensive pregnant subjects. These preliminary findings in this select group of patients clearly highlight the need for additional comprehensive studies throughout pregnancy, including the establishment of an appropriate cut-off, in order to fully elucidate the diagnostic/prognostic role of D-Di in preeclampsia. PMID- 22922439 TI - Reply: To PMID 22314824. PMID- 22922440 TI - Detecting and exploiting etiologic heterogeneity in epidemiologic studies. AB - Contemporary searches for new risk factors frequently involve genome-wide explorations of very large numbers of candidate risk variants. Given that diseases can often be classified into subtypes that possess evidence of etiologic heterogeneity, the question arises as to whether or not a search for new risk factors would be improved by looking separately within subtypes. Etiologic risk heterogeneity inevitably increases the signal in at least one of the subtypes, but this advantage may be offset by smaller sample sizes and the increased chances of false discovery. In this article, the authors show that only a relatively modest degree of etiologic heterogeneity is necessary for the subtyping strategies to have improved statistical power. In practice, effective exploitation of etiologic heterogeneity requires strong evidence that the subtypes selected are likely to exhibit substantial heterogeneity. Further, defining the subtypes that demonstrate the most heterogeneous profiles is important for optimizing the search for new risk factors. The concepts are illustrated by using data from a breast cancer study in which results are available separately for estrogen receptor-positive (ER+) and -negative (ER-) tumors. PMID- 22922441 TI - SAHA, an HDAC inhibitor, synergizes with tacrolimus to prevent murine cardiac allograft rejection. AB - Suberoylanilide hydroxamic acid (SAHA), as a histone deacetylase (HDAC) inhibitor (HDACi), was recently found to exhibit an immunosuppressive effect. However, whether SAHA can synergize with calcineurin inhibitors (CNIs) to inhibit allograft rejection and its underlying mechanism remain elusive. In this study, we demonstrated the synergistic effects of SAHA and non-therapeutic dose of tacrolimus (FK506) in prolonging the allograft survival in a murine cardiac transplant model. Concomitant intragraft examination revealed that allografts from SAHA-treated recipients showed significantly lower levels of IL-17 expression, and no discernable difference for IL-17 expressions was detected between SAHA- and SAHA/FK506-treated allograft as compared with allografts from FK506-treated animals. In contrast, administration of FK506 significantly suppressed interferon (IFN)-gamma but increased IL-10 expression as compared with that of SAHA-treated animals, and this effect was independent of SAHA. Interestingly, SAHA synergizes with FK506 to promote Foxp3 and CTLA4 expression. In vitro, SAHA reduced the proportion of Th17 cells in isolated CD4+ T-cell population and decreased expressions of IL-17A, IL-17F, STAT3 and RORgammat in these cells. Moreover, SAHA enhances suppressive function of regulatory T (Treg) cells by upregulating the expression of CTLA-4 without affecting T effector cell proliferation, and increased the proportion of Treg by selectively promoting apoptosis of T effector cells. Therefore, SAHA, a HDACi, may be a promising immunosuppressive agent with potential benefit in conjunction with CNI drugs. PMID- 22922442 TI - Soluble ST2 protein inhibits LPS stimulation on monocyte-derived dendritic cells. AB - ST2 protein is a soluble splicing variant of ST2L protein, which is the receptor for interleukin-33 (IL-33). Previously, we reported that soluble ST2 suppressed the signal transduction of lipopolysaccharide (LPS) and cytokine production in monocytic cells. To investigate whether or not this inhibitory effect occurs in dendritic cells, which are the key players in innate and adaptive immunity, human monocyte-derived dendritic cells were pre-treated with soluble ST2 protein before LPS stimulation. Although soluble ST2 did not attenuate the LPS-induced maturation of dendritic cells, pre-treatment with soluble ST2 suppressed cytokine production and inhibited LPS signaling. Moreover, the proliferation of naive T cells was inhibited significantly by soluble ST2 pre-treatment. IL-33 had little effect on the cytokine production of immature monocyte-derived dendritic cells. Furthermore, soluble ST2 protein was internalized into dendritic cells, suggesting that soluble ST2 protein acts by a noncanonical mechanism other than the sequestration of IL-33. PMID- 22922443 TI - Site-controlled growth of InP/GaInP quantum dots on GaAs substrates. AB - A technology platform for the epitaxial growth of site-controlled InP quantum dots (QDs) on GaAs substrates is presented. Nanoholes are patterned in a GaInP layer on a GaAs substrate by electron beam lithography and dry chemical etching, serving as QD nucleation centers. The effects of a thermal treatment on the structured surfaces for deoxidation are investigated in detail. By regrowth on these surfaces, accurate QD positioning is obtained for square array arrangements with lattice periods of 1.25 MUm along with a high suppression of interstitial island formation. The optical properties of these red-emitting QDs (lambda ~ 670 nm) are investigated by means of ensemble- and micro-photoluminescence spectroscopy at cryogenic temperatures. PMID- 22922444 TI - Frequency of mediastinal lymphadenopathy in patients with idiopathic pulmonary arterial hypertension. AB - OBJECTIVE: The objective of this study was to assess the frequency of mediastinal lymphadenopathy in patients with idiopathic pulmonary arterial hypertension (IPAH) and describe the correlative clinical features. METHODS: We conducted a retrospective review of patients with IPAH who underwent right-sided heart catheterization (RHC) and chest CT scan within 3 months of each other. Patients were from a single tertiary institution. CT scans were reviewed for the presence of mediastinal lymphadenopathy (MLAD) with correlating demographic and clinical data, including lymph node size and location, right atrial pressure (RAP), mean pulmonary arterial pressure (mPAP), and the presence of pleural and pericardial effusion. RESULTS: The study population included 85 patients with a mean age of 48 17.3 years; 70 (82%) were women. Fifteen patients (18%) had MLAD on chest CT scan. The mean short-axis diameter of the largest lymph node in these patients was 13.6 mm (range, 11-20 mm). The enlarged lymph nodes were located predominantly in the lower paratracheal and subcarinal stations. There was no association of MLAD with age, sex, RAP, or mPAP. MLAD was associated with presence of pleural effusion ( P , .02) but not pericardial effusion. Mean left ventricular ejection fraction for those with lymphadenopathy was 63% (range, 45% 76%). CONCLUSIONS: MLAD without other identifiable causes is seen in approximately one in fi ve patients with IPAH and is associated with pleural effusion but not mPAP, RAP, or left ventricular function. PMID- 22922445 TI - Slow early graft function: a neglected entity after renal transplantation. AB - BACKGROUND: After renal transplantation, early graft function (EGF) can be divided into delayed graft function (DGF), slow graft function (SGF) and immediate graft function (IGF). DGF is well documented. However, when evaluating the long-term significance of early function, the literature shows conflicting definitions and inconsistent results. In addition, SGF, a new entity separate to DGF and IGF, is a recent and poorly understood development. AIM: To investigate the risk factors for and the impact of poor EGF (PEGF) on long-term outcome. METHODS: This retrospective study reviewed the records of local adult patients who underwent renal transplantation at the Groote Schuur Hospital (Cape Town, South Africa) between 2004 and 2008. EGF was divided according to day 5 serum creatinine into IGF (serum creatinine <150 umol/l), SGF (serum creatinine >150 but <450 umol/l) and DGF (serum creatinine >450 umol/l or dialysis in the first week). DGF and SGF together comprised PEGF, with IGF alone representing good EGF (GEGF). RESULTS: A total of 121 patients (77 men, 44 women; mean age 39 years, range 14-67) were included in the study. Eighteen were excluded due to nephrectomy (n = 8), death (n = 6) or loss to follow-up (n = 4) within the first year. Analysis of cadaveric donors showed no significant risk factors for PEGF with the exception of cold ischaemic time, which differed significantly between the GEGF and PEGF groups, with means of 12 and 16 h, respectively (p = 0.013). Considering both living and cadaveric grafts, the 1-year estimated glomerular filtration rate (eGFR) was significantly different between IGF and DGF (p = 0.038) as well as between IGF and SGF (p = 0.028), with no significant difference between SGF and DGF (p > 0.05). A comparison of the PEGF and GEGF groups yielded significantly different 1-year eGFR values (60 and 50 ml/min, respectively; p = 0.07), with PEGF also associated with a longer hospital stay (20 vs. 14 days; p = 0.00005). Acute rejection was independently associated with a lower 1-year eGFR (p = 0.028), but in the absence of rejection, GEGF and PEGF remained significantly different with regards to 1-year eGFR (p = 0.024). CONCLUSIONS: SGF is not related to IGF but rather to DGF and should thus be regarded as a form of PEGF as opposed to GEGF. PEGF has a worse long-term outcome, and this indicates the need for increased efforts in its prevention and greater attention to its management. PMID- 22922446 TI - Mitochondria-associated ER membranes in Alzheimer disease. AB - Alzheimer disease (AD) is associated with the accumulation in the brain of extracellular neuritic plaques composed mainly of beta-amyloid (Abeta) and of intracellular neurofibrillary tangles composed of hyperphosphorylated forms of the microtubule-associated protein tau. It is also associated with other features that have received less attention, including aberrant phospholipid, cholesterol, and calcium metabolism, and altered mitochondrial function and dynamics. The underlying mechanism(s) that might explain these observations are currently unknown. We recently showed that presenilin-1 (PS1), presenilin-2 (PS2), and gamma-secretase activity, which processes the amyloid precursor protein (APP) to generate Abeta, are located predominantly in a specialized subcompartment of the endoplasmic reticulum (ER) that is physically and biochemically connected to mitochondria, called mitochondria-associated ER membranes (MAM). MAM is an intracellular lipid raft-like structure intimately involved in cholesterol and phospholipid lipid metabolism, in calcium homeostasis, and in mitochondrial function and dynamics. The coincidence of the functions associated with MAM with the symptomatology of AD led us to speculate that presenilins play a role in maintaining MAM function. We found that, consistent with this supposition, both MAM function and ER-mitochondrial connectivity are increased significantly in AD, which may help explain many of the biochemical and morphological features of the disease. Based on these findings, we propose that AD is fundamentally a disorder of ER-mitochondrial communication (the "MAM hypothesis"). This article is part of a Special Issue entitled 'Mitochondrial function and dysfunction in neurodegeneration'. PMID- 22922447 TI - Analysis of the absence of the detrusor muscle in initial transurethral resected specimens and the presence of residual tumor tissue. AB - OBJECTIVE: To investigate the relationship between surgeon's experience, tumor characteristics, absent detrusor muscle (DM) tissue in resected specimens, and residual tumor after an initial transurethral resection. PATIENTS AND METHODS: We conducted an analysis of 216 patients from two centers over a 3-year period. Patients with primary bladder tumors that were judged to have been completely resected were recruited. The data included tumor characteristics, surgeon category, and DM status. Logistic regression multivariate analyses were conducted. RESULTS: Large tumors, lateral/dome/anterior wall tumors, and surgery performed by junior surgeons were independently associated with absent DM. Large tumors, dome/anterior wall tumors, T1 and absent DM were independently associated with residual disease. The absence and presence of the DM were associated with residual tumor rates of 51.8 and 20.9%, respectively (OR 15.537). Resection by senior surgeons was associated with the presence of DM and clean resection (OR 0.274 and 0.141, respectively). CONCLUSIONS: Absent DM and residual tumor were more likely to occur in cases involving large tumors that were located in the lateral/dome/anterior wall, especially when the surgery was performed by a junior surgeon. Absent DM appears to be a surrogate marker for residual disease. PMID- 22922448 TI - Macroporous nanowire nanoelectronic scaffolds for synthetic tissues. AB - The development of three-dimensional (3D) synthetic biomaterials as structural and bioactive scaffolds is central to fields ranging from cellular biophysics to regenerative medicine. As of yet, these scaffolds cannot electrically probe the physicochemical and biological microenvironments throughout their 3D and macroporous interior, although this capability could have a marked impact in both electronics and biomaterials. Here, we address this challenge using macroporous, flexible and free-standing nanowire nanoelectronic scaffolds (nanoES), and their hybrids with synthetic or natural biomaterials. 3D macroporous nanoES mimic the structure of natural tissue scaffolds, and they were formed by self-organization of coplanar reticular networks with built-in strain and by manipulation of 2D mesh matrices. NanoES exhibited robust electronic properties and have been used alone or combined with other biomaterials as biocompatible extracellular scaffolds for 3D culture of neurons, cardiomyocytes and smooth muscle cells. Furthermore, we show the integrated sensory capability of the nanoES by real-time monitoring of the local electrical activity within 3D nanoES/cardiomyocyte constructs, the response of 3D-nanoES-based neural and cardiac tissue models to drugs, and distinct pH changes inside and outside tubular vascular smooth muscle constructs. PMID- 22922449 TI - Do all patients with prosthetic valve endocarditis need surgery? AB - A best evidence topic in cardiothoracic surgery was written according to a structured protocol. The question addressed was 'do all patients with prosthetic valve endocarditis need surgery?' Seventeen papers were found using the reported search that represented the best evidence to answer the clinical question. The authors, journal, date and country of publication, patient group studied, study type, relevant outcomes and results of these papers are tabulated. These studies compared the outcome and survival between surgically and non-surgically treated patients with prosthetic valve endocarditis. Of these studies, two were prospective observational studies and the rest were retrospective studies. The results of most of these papers were in accordance with the guidelines of the American College of Cardiology and American Heart association. These studies showed that unless a patient is not a surgical candidate, an operation is the treatment of choice in prosthetic valve endocarditis. Surgery should be performed as soon as possible, particularly in haemodynamically unstable patients and those who develop complications such as heart failure, valvular dysfunction, regurgitation/obstruction, dehiscence and annular abscess. In addition to the above indications and cardiac/valvularrelated complications of prosthetic valve endocarditis, infection with Staphylococcus aureus plays an important role in the outcome, and the presence of this micro-organism should be considered an urgent surgical indication in the treatment of prosthetic valve endocarditis. Surgery should be performed before the development of any cerebral or other complications. In contrast, in stable patients with other micro-organisms, particularly those with organisms sensitive to antibiotic treatment who have no structural valvular damage or cardiac complications, surgery can be postponed. The option of surgical intervention can also be revisited if there is a change in response to the treatment. This option is reserved for selected patients only and we conclude that as soon as the diagnosis of prosthetic valve endocarditis is made, cardiac surgeons should be involved. PMID- 22922451 TI - Pharmacokinetic analysis of multi PEG-theophylline conjugates. AB - In the attempt of prolonging the effect of drugs, a new branched, high-molecular weight multimeric poly(ethylene glycol) (MultiPEG), synthesized with a simple assembling procedure that devised the introduction of functional groups with divergent and selective reactivity, was employed as drug carrier. In particular, the attention was focused on the study of theophylline (THEO) and THEO-MultiPEG conjugates pharmacokinetic after oral administration in rabbit. Pharmacokinetic behavior was studied according to an ad hoc developed mathematical model accounting for THEO-MultiPEG in vivo absorption and decomposition into drug (THEO) and carrier (MultiPEG). The branched high-molecular weight MultiPEG proved to be a reliable drug delivery system able to prolong theophylline staying in the blood after oral administration of a THEO-MultiPEG solution. The analysis of experimental data by means of the developed mathematical model revealed that the prolongation of THEO effect was essentially due to the low THEO-MultiPEG permeability in comparison to that of pure THEO. PMID- 22922450 TI - Malignant primary cardiac tumours. AB - OBJECTIVES: Management of malignant tumours of the heart remains a poorly investigated clinical area due to the scarcity of presentations. The purpose of this series and review is to present an outline of the management emphasized by our personal experience in a regional cardiothoracic centre. METHODS: We reviewed all cases presenting with primary cardiac tumours in our institution within the last 10 years, looking at presentation, management and outcomes. RESULTS: Of these, the records of 3 patients, who attended the Royal Victoria Hospital in Belfast and were treated for a cardiac sarcoma, were fully evaluated. A review of current literature was conducted through a search of Pubmed and Medline databases. A review of the presentation of these patients and the generally accepted management deterioration of patients diagnosed with cardiac sarcoma is discussed. CONCLUSIONS: With reference to our case series, we want to draw attention to the rapid deteriation of these patients following presentation. PMID- 22922452 TI - Safety of pacemakers and defibrillators in electromagnetic navigation bronchoscopy. AB - BACKGROUND: Electromagnetic Navigation Bronchoscopy (ENB) (InReach iLogic system; superDimension Inc) is a relatively new discipline, with promising diagnostic and therapeutic applications in patients with lung lesions. Navigation is performed in a magnetic field and, therefore, has been considered relatively contraindicated in patients with pacemakers and automated implantable cardioverter-defibrillators (AICDs). Potential risks include altering the function and shutting off the device, device damage, lead displacement, and potential overheating. Over the past decade, there has been extensive literature about the safety of pacemakers in either the 1.5-T or 3-T magnetic fields used in current MRI scanners. Although the magnetic field used in ENB is significantly weaker, 0.0001 T or approximately equal to the earth's gravity, its safety in patients with pacemakers is yet to be elucidated. We present our initial experience with ENB in patients with cardiac implanted electrical devices. METHODS: Twenty-four procedures in 24 patients with lung lesions and permanent pacemakers were performed. A cardiac electrophysiologist and programmer were present during the procedure. At baseline, the pacers were interrogated, and ECG was recorded. Continuous cardiac monitoring was performed during the procedure, and at the end, the pacer settings and function were reinterrogated to check for any changes. RESULTS: The procedures were all successfully concluded. None of the patients suffered any arrhythmias or disruption to their pacemakers' function. CONCLUSION: ENB appears to be safe when performed in patients with pacemakers and AICDs. Larger multicenter studies are needed to prove the final safety in this patient population. PMID- 22922453 TI - Association between the polymorphism A/G at position 49 of exon 1 of the CTLA-4 gene and antithyroid antibody production in children with Hashimoto's thyroiditis. AB - CTLA-4 gene is considered to be one of the strongest factors determining the predisposition to antithyroid antibody (Ab) production. The aim of the study was to evaluate the association of the polymorphism A/G of exon 1 of CTLA-4 gene and antithyroid Ab level in children with Hashimoto's thyroiditis (HT). MATERIAL AND METHODS: 45 children with HT (aged 14.9 +/- 2, range 8.1-7.9) and 55 healthy controls (aged 14.8 +/- 2.34, range 8.0-17.4) were enrolled. Controls were euthyroid and free from any autoimmune disease. CTLA-4 gene (+49)A/G polymorphism was evaluated by a single-strand conformation polymorphism method and restriction fragment-length polymorphism. RESULTS: The frequency of GG genotype in HT children was significantly higher than in controls: 31 vs. 14.5% respectively (p < 0.04, OR = 2.65, CI = 0.99-7.06). Anti-Tg Ab titers were higher in patients homozygous for G allele than with AA genotype. The GG genotype seemed to be protective from hypothyroidism at the moment of HT diagnosis, but this observation was not statistically confirmed. CONCLUSIONS: Our study provides the evidence supporting the association between CTLA-4 gene (+49)A/G polymorphism and the susceptibility to HT in Polish children and confirms the existence of a link between (+49)A/G polymorphism and anti-Tg Ab level. PMID- 22922454 TI - Electron beam induced chemical dry etching and imaging in gaseous NH3 environments. AB - We report the use of ammonia (NH(3)) vapor as a new precursor for nanoscale electron beam induced etching (EBIE) of carbon, and an efficient imaging medium for environmental scanning electron microscopy (ESEM). Etching is demonstrated using amorphous carbonaceous nanowires grown by electron beam induced deposition (EBID). It is ascribed to carbon volatilization by hydrogen radicals generated by electron dissociation of NH(3) adsorbates. The volatilization process is also effective at preventing the buildup of residual hydrocarbon impurities that often compromise EBIE, EBID and electron imaging. We also show that ammonia is a more efficient electron imaging medium than H(2)O, which up to now has been the most commonly used ESEM imaging gas. PMID- 22922455 TI - Morphology changes in human lung epithelial cells after exposure to diesel exhaust micron sub particles (PM1.0) and pollen allergens. AB - In the recent literature there has been an increased interest in the effects of particulate matter on the respiratory tract. The objective of this study was to use an in vitro model of type II lung epithelium (A549) to evaluate the cell ability to take up sub-micron PM(1.0) particles (PM(1.0)), Parietaria officinalis (ALL), and PM(1.0) + ALL together. Morphological analysis performed by Transmission Electron Microscope (TEM) showed that PM and ALL interacted with the cell surface, then penetrating into the cytoplasm. Each single treatment was able to point out a specific change in the morphology. The cells treated appear healthy and not apoptotic. The main effect was the increase of: multilamellar bodies, lysosomal enzymes, microvilli, and presence of vesicle/vacuoles containing particles. These observations demonstrate morphological and functional alterations related to the PM(1.0) and P. officinalis and confirm the induction of the inflammatory response in lung cells exposed to the inhalable particles. PMID- 22922456 TI - Temperature dependence of ofloxacin fluorescence quenching and complexation by Cu(II). AB - The coexistence of heavy metals and antibiotics is common in the environment, and their interactions may mutually alter their environmental behaviors and risks. This study investigated ofloxacin (OFL)-Cu(II) interaction using fluorescence quenching experiments. The possible artifacts were excluded and OFL quenching was attributed to static quenching as suggested by the linear Stern-Volmer plot and decreased quenching with increased temperature. The OFL-Cu(II) interaction was quantitatively described using a stoichiometry equation. The calculation suggested that OFL-Cu(II) association was the mixture of 1:1 and 1:2 complexes. The negative DeltaG values and the negative DeltaH values suggested that the complexation is a spontaneous and exothermic process. Cation-pi binding and electrostatic interaction were excluded and the complexation of Cu(II) with OFL ketonic and carboxyl groups was proposed through UV-visible spectrum characterization, pH dependent complexation, and thermodynamic analysis. PMID- 22922457 TI - Chemical coagulation-based processes for trace organic contaminant removal: current state and future potential. AB - Trace organic contaminants have become an increasing cause of concern for governments and water authorities as they attempt to respond to the potential challenges posed by climate change by implementing sustainable water cycle management practices. The augmentation of potable water supplies through indirect potable water reuse is one such method currently being employed. Given the uncertainty surrounding the potential human health impacts of prolonged ingestion of trace organic contaminants, it is vital that effective and sustainable treatment methods are utilized. The purpose of this article is to provide a comprehensive literature review of the performance of the chemical coagulation process in removing trace organic contaminants from water. This study evaluated the removal data collated from recent research relating to various trace organic contaminants during the coagulation process. It was observed that there is limited research data relating to the removal of trace organic contaminants using coagulation. The findings of this study suggest that there is a gap in the current research investigating the potential of new types of coagulants and exploring coagulation-based hybrid processes to remove trace organic contaminants from water. The data analysed in this study regarding removal efficiency suggests that, even for the significantly hydrophobic compounds, hydrophobicity is not the sole factor governing removal of trace organic contaminants by coagulation. This has important implications in that the usual practice of screening coagulants based on turbidity (suspended solid) removal proves inadequate in the case of trace organic contaminant removal. PMID- 22922458 TI - Characterization of the sterol carrier protein-x/sterol carrier protein-2 gene in the cotton bollworm, Helicoverpa armigera. AB - Cholesterol is a membrane component and the precursor of ecdysteroids in insects, but insects cannot synthesize cholesterol de novo. Therefore, cholesterol uptake and transportation during the feeding larval stages are critical processes in insects. The sterol carrier protein-2 domain (SCP-2) in sterol carrier proteins-x (SCP-x) has been speculated to be involved in intracellular cholesterol transfer and metabolism in vertebrates. However, a direct association between SCP-x gene expression, cholesterol absorption and development in lepidopteran insects is poorly understood. We identified the Helicoverpa armigera sterol carrier protein x/2 (HaSCP-x/2) gene from the larval midgut cDNAs. The HaSCP-x/2 gene is well conserved during evolution and relatively divergent in heterogenetic species. Transcripts of HaSCP-x/2 were detected by qRT-PCR at the highest level in the midgut of H. armigera during the larval stages. Expression knockdown of HaSCP-x/2 transcripts via dsRNA interference resulted in delayed larval development and decreased adult fecundity. Sterol carrier protein-2 inhibitors were lethal to young larvae and decreased fertility in adults emerged from treated elder larvae in H. armigera. The results taken together suggest that HaSCPx/2 gene is important for normal development and fertility in H. armigera. PMID- 22922460 TI - Improved dexterity after chronic electrical stimulation of the motor cortex for central pain: a special relevance for thalamic syndrome. AB - OBJECTIVES: To demonstrate that motor cortex stimulation (MCS) could improve motor function in patients with neuropathic pain. METHODS: In this prospective clinical study of 38 patients referred for MCS as treatment for their neuropathic pain, we collected any declaration of improvement in motor performance that could be attributed to MCS. RESULTS: Ten patients (26%) declared a benefit in their motor function. Eight presented objective evidence of recovered dexterity for rapid alternating movements. A minor proportion had improvement in dystonic posture (n = 2), but none had detectable increased motor strength or tonus changes. Overall, 73% of the patients with limb ataxia declared a benefit after MCS. In 6 out of 10 patients (60%), the anatomic lesion responsible for pain was restricted to the lateral aspect of the thalamus. All of them had either clinical or electrophysiological evidence of lemniscal dysfunction (proprioceptive ataxia). No correlation was found between the scores of pain relief and the modification of motor status. The correlation between thalamic lesions and benefits in motor performance was significant (Fisher's exact test, two-tailed, p = 0.0017). CONCLUSIONS: Up to 26% of patients estimated that MCS improved their motor outcome through recovered dexterity and in cases of lateral thalamic lesions. PMID- 22922461 TI - Intraventricular meningioma: case report and literature review. AB - In this article we describe the clinical course of a child with an intraventricular meningioma and review the relevant literature. A 7-year-old girl with a several-month history of headaches had a CT scan that demonstrated a large, enhancing, intraventricular tumor. The tumor was completely excised via a superior parietal approach. Pathological examination revealed a pleomorphic meningioma. Postoperative scans demonstrated no residual tumor. Pediatric intraventricular tumors are rare. The surgical objective is complete resection, which appears to be associated with excellent outcomes. PMID- 22922462 TI - Optimal cellular preservation for high dimensional flow cytometric analysis of multicentre trials. AB - High dimensional flow cytometry is best served by centralized facilities. However, the difficulties around sample processing, storage and shipment make large scale international studies impractical. We therefore sought to identify optimized fixation procedures which fully leverage the analytical capability of high dimensional flow cytometry without the need for complex cell processing or a sustained cold chain. Whole blood staining procedure was employed to investigate the applicability of fixatives including Cyto-Chex(r) Blood Collection tube (Streck), Transfix(r) (Cytomark), 1% and 4% paraformaldehyde to centralized analysis of field trial samples. Samples were subjected to environmental conditions which mimic field studies, without refrigerated shipment and analyzed across 10 days, based on cell count and marker expression. This study showed that Cyto-Chex(r) demonstrated the least variability in absolute cell count relative to samples analyzed directly from donors in the absence of fixation. Transfix(r) was better at preserving the marker expression among all fixatives. However, Transfix(r) caused marked increased cell membrane permeabilization and was detrimental to intracellular marker identification. Paraformaldehyde fixation, at either 1% or 4% concentrations, was unfavorable for cell preservation under the conditions tested and thus not recommended. Using these data, we have created an online interactive tool which enables researchers to evaluate the impact of different fixatives on their panel of interest. In this study, we have identified Cyto-Chex(r) as the optimal cellular preservative for high dimensional flow cytometry in large scale studies for shipped whole blood samples, even in the absence of a sustained cold chain. PMID- 22922463 TI - End-binding protein 1 controls signal propagation from the T cell receptor. AB - The role of microtubules (MTs) in the control and dynamics of the immune synapse (IS) remains unresolved. Here, we show that T cell activation requires the growth of MTs mediated by the plus-end specific protein end-binding 1 (EB1). A direct interaction of the T cell receptor (TCR) complex with EB1 provides the molecular basis for EB1 activity promoting TCR encounter with signalling vesicles at the IS. EB1 knockdown alters TCR dynamics at the IS and prevents propagation of the TCR activation signal to LAT, thus inhibiting activation of PLCgamma1 and its localization to the IS. These results identify a role for EB1 interaction with the TCR in controlling TCR sorting and its connection with the LAT/PLCgamma1 signalosome. PMID- 22922464 TI - Bromodomain-dependent stage-specific male genome programming by Brdt. AB - Male germ cell differentiation is a highly regulated multistep process initiated by the commitment of progenitor cells into meiosis and characterized by major chromatin reorganizations in haploid spermatids. We report here that a single member of the double bromodomain BET factors, Brdt, is a master regulator of both meiotic divisions and post-meiotic genome repackaging. Upon its activation at the onset of meiosis, Brdt drives and determines the developmental timing of a testis specific gene expression program. In meiotic and post-meiotic cells, Brdt initiates a genuine histone acetylation-guided programming of the genome by activating essential genes and repressing a 'progenitor cells' gene expression program. At post-meiotic stages, a global chromatin hyperacetylation gives the signal for Brdt's first bromodomain to direct the genome-wide replacement of histones by transition proteins. Brdt is therefore a unique and essential regulator of male germ cell differentiation, which, by using various domains in a developmentally controlled manner, first drives a specific spermatogenic gene expression program, and later controls the tight packaging of the male genome. PMID- 22922466 TI - The prognostic impact of the anatomical sites in the 'head and neck melanoma': scalp versus face and neck. AB - Cutaneous melanoma is a malignant neoplasia with several demographic and histopathological prognostic factors. Many studies stress that the head and neck region has a worse prognosis compared with other localizations, but the reasons for this worse prognosis are unclear. Therefore, the aim of our study is to analyse the poor prognosis of head and neck melanoma (HNM) with respect to the other anatomical sites, considering the face and neck (F&N) and the scalp separately. We carried out a retrospective analysis of 757 melanoma patients. In particular, we studied the prognostic impact of different melanoma skin localizations (head and neck, trunk, upper extremities and lower extremities). Afterwards, we divided HNM into two subgroups, F&N and scalp, to evaluate their impact in the HNM prognosis. Data showed a significantly lower 5-year overall survival probability for HNM (78.9 versus 93.1% for other body sites; P=0.05). Moreover, on analysing the two anatomical areas considered among HNM, we observed a 5-year overall survival of 81.8% for F&N and 66.7% for scalp. HNM has different and worse prognostic features with respect to other sites, but this trend is not only because of scalp melanoma but is also determined by F&N melanoma, which we believe to be underestimated until now. PMID- 22922467 TI - Additional support for the existence of skin conductance responses at unconditioned stimulus omission. AB - The existence of a skin conductance response to an expected but omitted aversive stimulus has recently been challenged. To counter this claim, we provide a review of the literature and a temporal analysis of two independent skin conductance data sets during aversive conditioning and extinction that demonstrates a consistent and reproducible skin conductance response at omission of an anticipated aversive stimulus. The validity of this so-called unconditioned stimulus (US) omission response is relevant for skin conductance modeling in the context of neuroimaging and more generally for conditioning theory. PMID- 22922465 TI - An atlas of Hfq-bound transcripts reveals 3' UTRs as a genomic reservoir of regulatory small RNAs. AB - The small RNAs associated with the protein Hfq constitute one of the largest classes of post-transcriptional regulators known to date. Most previously investigated members of this class are encoded by conserved free-standing genes. Here, deep sequencing of Hfq-bound transcripts from multiple stages of growth of Salmonella typhimurium revealed a plethora of new small RNA species from within mRNA loci, including DapZ, which overlaps with the 3' region of the biosynthetic gene, dapB. Synthesis of the DapZ small RNA is independent of DapB protein synthesis, and is controlled by HilD, the master regulator of Salmonella invasion genes. DapZ carries a short G/U-rich domain similar to that of the globally acting GcvB small RNA, and uses GcvB-like seed pairing to repress translation of the major ABC transporters, DppA and OppA. This exemplifies double functional output from an mRNA locus by the production of both a protein and an Hfq dependent trans-acting RNA. Our atlas of Hfq targets suggests that the 3' regions of mRNA genes constitute a rich reservoir that provides the Hfq network with new regulatory small RNAs. PMID- 22922468 TI - Task-related component analysis for functional neuroimaging and application to near-infrared spectroscopy data. AB - Reproducibility of experimental results lies at the heart of scientific disciplines. Here we propose a signal processing method that extracts task related components by maximizing the reproducibility during task periods from neuroimaging data. Unlike hypothesis-driven methods such as general linear models, no specific time courses are presumed, and unlike data-driven approaches such as independent component analysis, no arbitrary interpretation of components is needed. Task-related components are constructed by a linear, weighted sum of multiple time courses, and its weights are optimized so as to maximize inter block correlations (CorrMax) or covariances (CovMax). Our analysis method is referred to as task-related component analysis (TRCA). The covariance maximization is formulated as a Rayleigh-Ritz eigenvalue problem, and corresponding eigenvectors give candidates of task-related components. In addition, a systematic statistical test based on eigenvalues is proposed, so task related and -unrelated components are classified objectively and automatically. The proposed test of statistical significance is found to be independent of the degree of autocorrelation in data if the task duration is sufficiently longer than the temporal scale of autocorrelation, so TRCA can be applied to data with autocorrelation without any modification. We demonstrate that simple extensions of TRCA can provide most distinctive signals for two tasks and can integrate multiple modalities of information to remove task-unrelated artifacts. TRCA was successfully applied to synthetic data as well as near-infrared spectroscopy (NIRS) data of finger tapping. There were two statistically significant task related components; one was a hemodynamic response, and another was a piece-wise linear time course. In summary, we conclude that TRCA has a wide range of applications in multi-channel biophysical and behavioral measurements. PMID- 22922469 TI - Oxidative-nitrosative stress and systemic vascular function in highlanders with and without exaggerated hypoxemia. AB - BACKGROUND: Acute exposure to high altitude stimulates free radical formation in lowlanders, yet whether this persists during chronic exposure in healthy, well adapted and maladapted highlanders suffering from chronic mountain sickness (CMS) remains to be established. METHODS: Oxidative-nitrosative stress (as determined by the presence of the biomarkers ascorbate radical [A *- ], via electron paramagnetic resonance spectroscopy, and nitrite [NO 2 2 ], via ozone-based chemiluminescence) was assessed in venous blood of 25 male highlanders in Bolivia living at 3,600 m with CMS (n 5 13, CMS 1 ) and without CMS (n 5 12, CMS 2 ). Twelve age- and activity-matched, healthy, male lowlanders were examined at sea level and during acute hypoxia. We also measured fl ow-mediated dilatation (FMD), arterial stiffness defined by augmentation index normalized for a heart rate of 75 beats/min (AIx-75), and carotid intima-media thickness (IMT). RESULTS: Compared with normoxic lowlanders, oxidative-nitrosative stress was moderately increased in the CMS 2 group ( P , .05), as indicated by elevated A *- (3,191 457 arbitrary units [AU] vs 2,640 445 AU) and lower NO 2 2 (206 55 nM vs 420 128 nM), whereas vascular function remained preserved. This was comparable to that observed during acute hypoxia in lowlanders in whom vascular dysfunction is typically observed. In contrast, this response was markedly exaggerated in CMS 1 group (A *- , 3,765 429 AU; NO 2 2 , 148 50 nM) compared with both the CMS 2 group and lowlanders ( P , .05). This was associated with systemic vascular dysfunction as indicated by lower ( P , .05 vs CMS 2 ) FMD (4.2% 0.7% vs 7.6% 1.7%) and increased AIx-75 (23% 8% vs 12% 7%) and carotid IMT (714 127 m M vs 588 94 m M). CONCLUSIONS: Healthy highlanders display a moderate, sustained elevation in oxidative-nitrosative stress that, unlike the equivalent increase evoked by acute hypoxia in healthy lowlanders, failed to affect vascular function. Its more marked elevation in patients with CMS may contribute to systemic vascular dysfunction. PMID- 22922470 TI - High-precision thickness regulation of graphene layers with low energy helium plasma implantation. AB - In this paper we present a novel method of regulation to obtain graphene layers with homogeneous thickness by means of helium plasma implantation. The obtained graphene layers show neither large deep pits nor loss of lateral dimension. The etching rate can be precisely controlled (one to six atomic layers min(-1) or higher) and it remains consistent regardless of the thickness of the multilayer graphene. This approach is compatible with traditional complementary metal-oxide semiconductor fabrication technologies and has great potential to modulate the performance of graphene for device applications. PMID- 22922471 TI - Circulating urine phthalates are not associated with a decline in cognition in adults and the elderly: NHANES, 1999-2002. PMID- 22922473 TI - Effect of photodynamic antimicrobial chemotherapy on in vitro and in situ biofilms. AB - AIM: The effect of photodynamic antimicrobial chemotherapy (PACT) on oral biofilms was evaluated. METHODS: Biofilms formed in vitro were treated with sensitizer (S) and/or light (L) in the test (S+L+) and control (S-L-, S+L-, S-L+) groups. Additionally, 21 volunteers wore intraoral devices and the biofilms formed on each side of the device were referred to as S+L+ or S-L- groups. RESULTS: Significant decreases in the viability of in vitro biofilms were observed after PACT. PACT was ineffective in inhibiting multi-species biofilms formed in situ. CONCLUSION: PACT was effective on in vitro biofilms and was ineffective on in situ biofilms. PMID- 22922472 TI - Quantifying interactions of beta-synuclein and gamma-synuclein with model membranes. AB - The synucleins are a family of proteins involved in numerous neurodegenerative pathologies [alpha-synuclein and beta-synuclein (betaS)], as well as in various types of cancers [gamma-synuclein (gammaS)]. While the connection between alpha synuclein and Parkinson's disease is well established, recent evidence links point mutants of betaS to dementia with Lewy bodies. Overexpression of gammaS has been associated with enhanced metastasis and cancer drug resistance. Despite their prevalence in such a variety of diseases, the native functions of the synucleins remain unclear. They have a lipid-binding motif in their N-terminal region, which suggests interactions with biological membranes in vivo. In this study, we used fluorescence correlation spectroscopy to monitor the binding properties of betaS and gammaS to model membranes and to determine the free energy of the interactions. Our results show that the interactions are most strongly affected by the presence of both anionic lipids and bilayer curvature, while membrane fluidity plays a very minor role. Quantifying the lipid-binding properties of betaS and gammaS provides additional insights into the underlying factors governing the protein-membrane interactions. Such insights not only are relevant to the native functions of these proteins but also highlight their contributions to pathological conditions that are either mediated or characterized by perturbations of these interactions. PMID- 22922474 TI - Long-term outcome of anterior thalamic nucleus stimulation for intractable epilepsy. AB - BACKGROUND: Many patients with epilepsy have persistent seizures despite treatment with maximal antiepileptic drug therapy and are not candidates for resective brain surgery. OBJECTIVES: We investigated the effectiveness of seizure reduction after anterior thalamic nucleus (ATN) stimulation in patients with intractable epilepsy undergoing deep brain stimulation (DBS) of the thalamus. METHODS: Patients included in this study had poorly controlled seizures, despite anticonvulsant medication, and were not candidates for surgical resection of an identifiable seizure focus. Fifteen patients with medically refractory epilepsy underwent the placement of bilateral DBS electrodes in the anterior thalamus. The seizure frequency was monitored and compared with the preimplantation baseline. RESULTS: The treatment demonstrated a statistically significant decrease in the seizure frequency, with a mean reduction of 70.4% (mean follow-up, 27 months). Two of the patients had a remarkable reduction of seizure frequency. CONCLUSION: It seems to be important that the short-term outcome of ATN DBS reflects the long term outcome directly. The correlation between the seizure type, characteristics and anticonvulsant effects of ATN DBS did not exhibit significance because of the small number of cases. Therefore, a longer-term follow-up with a larger group of patients is required to fully evaluate the safety and effectiveness of this treatment modality. PMID- 22922475 TI - Evaluating learning curves for intubation in a simulator setting: a prospective observational cumulative sum analysis. PMID- 22922476 TI - A xenon recirculating ventilator for the newborn piglet: developing clinical applications of xenon for neonates. AB - CONTEXT: The clinical applications of xenon for the neonate include both anaesthesia and neuroprotection. However, due to the limited natural availability of xenon, special equipment is required to administer and recapture the gas to develop xenon as a therapeutic agent. OBJECTIVE: In order to test the xenon recirculating ventilator for the application of neuroprotection in a preclinical trial, our primary objective was to test the efficiency, reliability and safety of administering 50% xenon for 24 h in hypoxic ischaemic piglets. DESIGN: A prospective observational study. SETTING: Institute for Women's Health, University College London, January 2008 to March 2008. ANIMALS: Four anaesthetised male piglets, less than 24 h old, underwent a global hypoxic ischaemic insult for approximately 25 min prior to switching to the xenon recirculating ventilator. INTERVENTION: Between 2 and 26 h after hypoxic ischaemia, anaesthetised piglets were administered a mixture of 50% xenon, air, oxygen and isoflurane. MAIN OUTCOME MEASURES: The primary outcome measure was blood gas PaCO2 (kPa) and secondary outcome measure was xenon gas use (l h), over the 24-h duration of xenon administration. RESULTS: The xenon recirculating ventilator provided effective ventilation, automated control of xenon/air gas mixtures, and stable blood gas PaCO2 (4.5 to 6.3 kPa) for 24 h of ventilation with the xenon recirculating ventilator. Total xenon use was minimal at approximately 0.6 l h at a cost of approximately &OV0556;8 h. Additional features included an isoflurane scavenger and bellows height alarm. CONCLUSION: Stable gas delivery to a piglet with minimal xenon loss and analogue circuitry made the xenon recirculating ventilator easy to use and it could be modified for other large animals and noble gas mixtures. The technologies, safety and efficiency of xenon delivery in this preclinical system have been taken forward in the development of neonatal ventilators for clinical use in phase II clinical trials for xenon-augmented hypothermia and for xenon anaesthesia. PMID- 22922477 TI - Transcranial Doppler sonography as a potential screening tool for preanaesthetic evaluation: a prospective observational study. AB - CONTEXT: Intraoperative cervical spine rotation may compromise cerebral blood flow in susceptible individuals by distortion of cervical arteries. OBJECTIVE: To investigate the effect of five cervical spine positions on cerebral blood flow in the middle cerebral artery. DESIGN: Prospective observational study. SETTING: University hospital. PATIENTS: Fifty-six male and 24 female patients scheduled for general anaesthesia for routine surgery. Exclusion criteria were cranial spine pathology and cerebral vascular disease. INTERVENTIONS: Maximum rotation of the head to the left and right side with and without hyperextension, and hyperextension in the neutral position. MAIN OUTCOME MEASURES: Change of mean blood flow velocity in the middle cerebral artery measured by transcranial Doppler sonography. RESULTS: Age had a significant effect on mean blood flow velocity in the left middle cerebral artery in the neutral position (P = 0.047). There was a significant difference in mean blood flow velocity in the left middle cerebral artery between patients younger than 40 years and patients older than 59 years [61.2 (16.6) ml min(-1) vs. 47.7 (16.2) ml min(-1); P = 0.015]. There was a significant effect of head position on mean blood flow velocity in both the left and in the right middle cerebral arteries (P = 0.039 left, P = 0.025 right). Twenty patients had a decrease of more than 20% from their baseline mean blood flow velocity. CONCLUSION: Neck rotation and/or extension resulted in a significant change of blood flow in the middle cerebral artery. PMID- 22922478 TI - Inhibition of human neutrophil elastase by ergosterol derivatives from the mycelium of Phellinus linteus. PMID- 22922479 TI - Thoughts and facts about antibiotics: Where we are now and where we are heading. PMID- 22922480 TI - Cerebrospinal fluid beta-Amyloid turnover in the mouse, dog, monkey and human evaluated by systematic quantitative analyses. AB - BACKGROUND: Reducing brain beta-amyloid (Abeta) via inhibition of beta-secretase, or inhibition/modulation of gamma-secretase, has been widely pursued as a potential disease-modifying treatment for Alzheimer's disease. Compounds that act through these mechanisms have been screened and characterized with Abeta lowering in the brain and/or cerebrospinal fluid (CSF) as the primary pharmacological end point. Interpretation and translation of the pharmacokinetic (PK)/pharmacodynamic (PD) relationship for these compounds is complicated by the relatively slow Abeta turnover process in these compartments. OBJECTIVE: To understand Abeta turnover kinetics in preclinical species and humans. METHODS: We collected CSF Abeta dynamic data after beta- or gamma-secretase inhibitor treatment from in-house experiments and the public domain, and analyzed the data using PK/PD modeling to obtain CSF Abeta turnover rates (kout) in the mouse, dog, monkey and human. RESULTS: The kout for CSF Abeta40 follows allometry (kout = 0.395 * body weight( 0.351)). The kout for CSF Abeta40 is approximately 2-fold higher than the turnover of CSF in rodents, but in higher species, the two are comparable. CONCLUSION: The turnover of CSF Abeta40 was systematically examined, for the first time, in multiple species through quantitative modeling of multiple data sets. Our result suggests that the clearance mechanisms for CSF Abeta in rodents may be different from those in the higher species. The understanding of Abeta turnover has considerable implications for the discovery and development of Abeta lowering therapeutics, as illustrated from the perspectives of preclinical PK/PD characterization and preclinical-to-clinical translation. PMID- 22922481 TI - Contribution of SDF-1alpha/CXCR4 signaling to brain development and glioma progression. AB - The SDF-1alpha/CXCR4 signaling maintains central nervous system homeostasis through the interaction with the neurotransmitter and neuropeptide systems, the neuroendocrine systems. Recently, the SDF-1alpha/CXCR4 signaling has been reported to present nonrandom distribution in brain development and glioma progression, which exerts differential regulations on the assembly, differentiation, and function of neural precursors, neurons, glial cells, as well as glioma cells. In the present review, we highlight current knowledge about multiple molecular signaling pathways associated with the SDF-1alpha/CXCR4 signaling in glioma. Not only is the expression of CXCR4 a key determinant of glioma progression, but SDF-1alpha is essential for site-specific invasive or metastatic processes. SDF-1alpha is the switch of the SDF-1alpha/CXCR4 signaling from the endocrine loop to the autocrine and/or local paracrine loop in glioma progression and brain development. Studies of SDF-1alpha/CXCR4 signaling in the field of brain development may provide valuable tactics for glioma treatment. PMID- 22922482 TI - Prion protein mPrP[F175A](121-231): structure and stability in solution. AB - The three-dimensional structures of prion proteins (PrPs) in the cellular form (PrP(C)) include a stacking interaction between the aromatic rings of the residues Y169 and F175, where F175 is conserved in all but two so far analyzed mammalian PrP sequences and where Y169 is strictly conserved. To investigate the structural role of F175, we characterized the variant mouse prion protein mPrP[F175A](121-231). The NMR solution structure represents a typical PrP(C) fold, and it contains a 3(10)-helical beta2-alpha2 loop conformation, which is well defined because all amide group signals in this loop are observed at 20 degrees C. With this "rigid-loop PrP(C)" behavior, mPrP[F175A](121-231) differs from the previously studied mPrP[Y169A](121-231), which contains a type I beta turn beta2-alpha2 loop structure. When compared to other rigid-loop variants of mPrP(121-231), mPrP[F175A](121-231) is unique in that the thermal unfolding temperature is lowered by 8 degrees C. These observations enable further refined dissection of the effects of different single-residue exchanges on the PrP(C) conformation and their implications for the PrP(C) physiological function. PMID- 22922483 TI - Synergistic binding of the phosphorylated S233- and S259-binding sites of C-RAF to one 14-3-3zeta dimer. AB - C-RAF kinase is a central component of the Ras-RAF-MEK (mitogen-activated protein kinase/extracellular signal-regulated kinase)-ERK (extracellular signal-regulated kinase) pathway, which has been shown to be activated in 30% of human tumors. 14 3-3 proteins inactivate C-RAF by binding to the two N-terminal phosphorylation dependent binding sites surrounding S233 and S259. 14-3-3 proteins can bind two target sequences located on one polypeptide chain simultaneously, thereby increasing binding affinity compared to single-site binding and possibly allowing regulated 14-3-3 binding through gatekeeper phosphorylation. To date, it was unclear whether 14-3-3 proteins can bind the two N-terminal phosphorylation dependent binding sites of C-RAF simultaneously. Fluorescence polarization using phosphorylated peptides demonstrated that S233 is the low-affinity and S259 is the high-affinity binding site, while simultaneous engagement of both sites by 14 3-3zeta enhances affinity compared to single-site binding. Determination of a 1:1 stoichiometry for the di-phosphorylated peptide binding to one 14-3-3zeta dimer with isothermal titration calorimetry was supported by the crystal structure of the 14-3-3zeta/C-RAFpS233,pS259 complex. Cellular localization studies validate the significance of these sites for cytoplasmic retention of C-RAF, suggesting an extended mechanism of RAF regulation by 14-3-3 proteins. PMID- 22922485 TI - Tandem adaptation with a common design in Escherichia coli chemotaxis. AB - We analyze a model for motor-level adaptation in Escherichia coli based upon the premise that clockwise (CW) and counter-clockwise (CCW) states have different preferred numbers of FliM subunits. We show that this model provides a simple mechanism for the recently observed motor-level adaptation, and it also explains the long-lasting puzzle on the thresholds observed when tethered cells are used to monitor responses to temporal ramps. We note that the motor-level adaptation has the same negative-feedback network design as the upstream receptor-level adaptation, and the tandem architecture of one control circuit followed by the other mitigates the effects of cell-to-cell variation and broadens the range of stimuli over which cells optimally respond. PMID- 22922486 TI - Lead-free KNbO3 ferroelectric nanorod based flexible nanogenerators and capacitors. AB - In spite of high piezoelectricity, only a few one-dimensional ferroelectric nano materials with perovskite structure have been used for piezoelectric nanogenerator applications. In this paper, we report high output electrical signals, i.e. an open-circuit voltage of 3.2 V and a closed-circuit current of 67.5 nA (current density 9.3 nA cm(-2)) at 0.38% strain and 15.2% s(-1) strain rate, using randomly aligned lead-free KNbO(3) ferroelectric nanorods (~1 MUm length) with piezoelectric coefficient (d(33) ~ 55 pm V (-1)). A flexible piezoelectric nanogenerator is mainly composed of KNbO(3)-poly(dimethylsiloxane) (PDMS) composite sandwiched by Au/Cr-coated polymer substrates. We deposit a thin poly(methyl methacrylate) (PMMA) layer between the KNbO(3)-PDMS composite and the Au/Cr electrode to completely prevent dielectric breakdown during electrical poling and to significantly reduce leakage current during excessive straining. The flexible KNbO(3)-PDMS composite device shows a nearly frequency-independent dielectric constant (~3.2) and low dielectric loss (<0.006) for the frequency range of 10(2)-10(5) Hz. These results imply that short and randomly aligned ferroelectric nanorods can be used for a flexible high output nanogenerator as well as high-k capacitor applications by performing electrical poling and further optimizing the device structure. PMID- 22922484 TI - Membrane binding and self-association of the epsin N-terminal homology domain. AB - Epsin possesses a conserved epsin N-terminal homology (ENTH) domain that acts as a phosphatidylinositol 4,5-bisphosphate-lipid-targeting and membrane-curvature generating element. Upon binding phosphatidylinositol 4,5-bisphosphate, the N terminal helix (H(0)) of the ENTH domain becomes structured and aids in the aggregation of ENTH domains, which results in extensive membrane remodeling. In this article, atomistic and coarse-grained (CG) molecular dynamics (MD) simulations are used to investigate the structure and the stability of ENTH domain aggregates on lipid bilayers. EPR experiments are also reported for systems composed of different ENTH-bound membrane morphologies, including membrane vesicles as well as preformed membrane tubules. The EPR data are used to help develop a molecular model of ENTH domain aggregates on preformed lipid tubules that are then studied by CG MD simulation. The combined computational and experimental approach suggests that ENTH domains exist predominantly as monomers on vesiculated structures, while ENTH domains self-associate into dimeric structures and even higher-order oligomers on the membrane tubes. The results emphasize that the arrangement of ENTH domain aggregates depends strongly on whether the local membrane curvature is isotropic or anisotropic. The molecular mechanism of ENTH-domain-induced membrane vesiculation and tubulation and the implications of the epsin's role in clathrin-mediated endocytosis resulting from the interplay between ENTH domain membrane binding and ENTH domain self association are also discussed. PMID- 22922487 TI - Pancreatic stone protein predicts positive sputum bacteriology in exacerbations of COPD. AB - BACKGROUND: Pancreatic stone protein/regenerating protein (PSP/reg) serum levels are supposed to be increased in bacterial inflammation. PSP/reg levels also might be useful, therefore, as a predictor of bacterial infection in COPD. METHODS: Two hundred consecutive patients presenting to the ED due to acute exacerbation of COPD were prospectively assessed. Patients were evaluated based on clinical, laboratory, and lung functional parameters at admission (exacerbation) and after short-term follow-up (14-21 days). PSP/reg serum values were measured by a newly developed enzyme-linked immunosorbent assay. RESULTS: PSP/reg levels were elevated in subjects with COPD exacerbation (23.8 ng/mL; 95% CI, 17.1-32.7) when compared with those with stable disease (19.1 ng/mL; 95% CI, 14.1-30.4; P 5 .03) and healthy control subjects (14.0 ng/mL; 95% CI , 12.0-19.0; P , .01). Higher PSP/reg values were observed in exacerbations with positive sputum bacteriology compared with those with negative sputum bacteriology (26.1 ng/mL [95% CI, 19.2 38.1] vs 20.8 ng/mL [95% CI , 15.6-27.2]; P , .01). Multivariate regression analysis revealed PSP/reg level as an independent predictor of positive sputum bacteriology. A combination of a PSP/reg cutoff value of . 33.9 ng/mL and presence of discolored sputum had a specificity of 97% to identify patients with pathogenic bacteria on sputum culture. In contrast, PSP/reg levels , 18.4 ng/mL and nonpurulent sputum ruled out positive bacterial sputum culture (sensitivity, 92%). In survival analysis, high PSP/reg levels at hospital admission were associated with increased 2-year mortality. CONCLUSIONS: Serum PSP/reg level might represent a promising new biomarker to identify bacterial etiology of COPD exacerbation. PMID- 22922488 TI - Neurocysticercosis in nonendemic countries: time for a reappraisal. PMID- 22922489 TI - Evaluation of long-term outcomes, cytogenetic and molecular responses with imatinib mesylate in early and late chronic-phase chronic myeloid leukemia: a report from a single institute. AB - Here we compare the management and survival outcomes of chronic myeloid leukemia (CML) patients who had early or late imatinib mesylate (IM) therapy. The cytogenetic and molecular responses of 189 CML patients were analyzed. Of this group, 121 patients were classified as the early chronic phase (ECP) group and started IM within 12 months of diagnosis. The other 68 patients were classified as the late chronic phase (LCP) group who had been treated with interferon (IFN) alpha-2 and crossed over to IM more than 12 months after diagnosis. The overall rates of complete cytogenetic response (CCyR) and major molecular response (MMR) at last follow-up were 83.6 and 78.1% in the ECP and LCP groups, respectively. The CCyR rates were 89.3 (for ECP patients) versus 73.5% (for LCP patients; p < 0.0001). At last follow-up, 82.4% ECP and 64.2% LCP patients had achieved an MMR (p < 0.0001). No significant differences were noted between the two groups with regard to survival outcomes. Our experience reveals that IM is an effective rescue therapy in most CML LCP patients who are intolerant or in whom IFN-alpha therapy fails. Such therapeutic options should be considered in LCP patients, particularly in countries where IM may not be available. PMID- 22922490 TI - Maternal deprivation induces deficits in temporal memory and cognitive flexibility and exaggerates synaptic plasticity in the rat medial prefrontal cortex. AB - Early life adverse events can lead to structural and functional impairments in the prefrontal cortex (PFC). Here, we investigated whether maternal deprivation (MD) alters PFC-dependent executive functions, neurons and astrocytes number and synaptic plasticity in adult male Long-Evans rats. The deprivation protocol consisted of a daily separation of newborn Long-Evans pups from their mothers and littermates 3h/day postnatal day 1-14. Cognitive performances were assessed in adulthood using the temporal order memory task (TMT) and the attentional set shifting task (ASST) that principally implicates the PFC and the Morris water maze task (WMT) that does not essentially rely on the PFC. The neurons and astrocytes of the prelimbic (PrL) area of the medial PFC (mPFC) were immunolabelled respectively with anti-NeuN and anti-GFAP antibodies and quantified by stereology. The field potentials evoked by electrical stimulation of ventral hippocampus (ventral HPC) were recorded in vivo in the PrL area. In adulthood, MD produced cognitive deficits in two PFC-dependent tasks, the TMT and ASST, but not in the WMT. In parallel, MD induced in the prelimbic area of the medial PFC an upregulation of long-term potentiation (LTP), without any change in the number of neurons and astrocytes. We provide evidence that MD leads in adults to an alteration of the cognitive abilities dependent on the PFC, and to an exaggerated synaptic plasticity in this region. We suggest that this latter phenomenon may contribute to the impairments in the cognitive tasks. PMID- 22922492 TI - Bone mineral density of the trapezium in osteoarthritic trapeziometacarpal joints. AB - The aim of this study was to test the precision and reliability of measurements of the bone mineral density (BMD) of the trapezium in patients with osteoarthritic trapeziometacarpal joints using dual-energy X-ray absorptiometry scans and to assess whether there is an acceptable correlation between the BMD of the trapezium and that of the distal radius, for which normative data exist. We included 66 patients (52 women, 14 men) diagnosed with Eaton-Glickel stage II-IV osteoarthritis and a mean age of 59 years (range 40-77) in a prospective study. We found good intra- and inter-observer agreement of BMD measurements. Reliability was also good in repeated measurements. There was an indication of an increase in BMD with progression in the Eaton-Glickel stage. There was only a moderate correlation between the BMD of the trapezium and that of the radius. PMID- 22922491 TI - Weight change after globus pallidus internus or subthalamic nucleus deep brain stimulation in Parkinson's disease and dystonia. AB - BACKGROUND: Weight gain has been described in Parkinson's disease (PD) patients after subthalamic nucleus (STN) deep brain stimulation (DBS). OBJECTIVES: We examined change in weight following DBS in both PD and dystonia patients to further investigate the role of disease and brain target (STN or globus pallidus internus, GPi) specificity. METHODS: Data was retrospectively collected on 61 PD DBS patients (STN n = 31 or GPi n = 30) and on 36 dystonia DBS patients (STN n = 9 and GPi n = 27) before and after surgery. Annual change in body mass index (BMI) was evaluated with nonparametric tests between groups and multiple quantile regression. RESULTS: PD patients treated with STN DBS had a small increase in median BMI while those with GPi had a small decrease in BMI. Dystonia patients treated with STN DBS had a greater increase in BMI per year compared to those treated with GPi DBS. Multivariable regression analyses for each disease showed little difference between targets in weight gain in those with PD, but STN target was strongly associated with weight gain in dystonia patients (STN vs. GPi, +7.99 kg, p = 0.012). CONCLUSIONS: Our results support previous reports of weight gain after DBS in PD. This is the first report to suggest a target-specific increase in weight following STN DBS in dystonia patients. PMID- 22922493 TI - Costal osteochondral grafting as a treatment method for avascular necrosis of the ring finger metacarpal: a case report. PMID- 22922494 TI - Cognitive support for a better handoff: does it improve the quality of medical communication at shift change in an emergency department? AB - AIM: To improve the communication during shift handover in an emergency department. METHODS: We observed the handover process and analysed the discourse between physicians at shift change first, and then we created two cognitive tools and tested their clinical impact on the field. We used different measures to evaluate this impact on the health care process including the frequency and type of information content communicated between physicians, duration of the handoff, physician self-evaluation of the quality of the handoff and a posthandover study of patient handling. RESULTS: Our results showed that the patient's medical history, significant test results, recommendations (treatment plan) and patient follow-up were communicated to a greater extent when the tools are used. We also found that physicians spent more time at the bedside and less time consulting medical records using these tools. CONCLUSION: The present study showed how in depth observations and analyses of real work processes can be used to better support the quality of patient care. PMID- 22922495 TI - Acquiring basic life support skills in a self-learning station: video alone is not enough. AB - OBJECTIVES: To develop a self-learning station combining a video with computer exercises to learn cardiopulmonary resuscitation (CPR) to novices, and to assess the efficacy of these two components on CPR acquisition. METHODS: One hundred and twenty-five pharmacy students were trained using learning-while-watching video instructions followed by exercises with voice feedback. The proportion of students with adequate CPR skills (>= 70% compressions with depth >= 50 mm, >= 70% compressions with complete release <5 mm, a compression rate between 100 and 120/min, >= 70% ventilations with a volume between 400 and 1000 ml) was measured at baseline, after video training and after subsequent voice-feedback training. RESULTS: Complete datasets were obtained for 104 students. After video training, the 70% cut-off for compression depth was achieved in 29/104 students, for complete release in 75/104, for ventilation volume in 44/104. Mean compression rate 100-120/min was adequate in 77/104 students. Compared with baseline results, only rate (29/104 vs. 77/104) and ventilation volume (6/104 vs. 44/104) improved. After subsequent training with voice feedback the proportions were: compression depth 88/104, compression rate 77/104, ventilation volume 74/104 and complete release 90/104. Compared with the skill level after video training only compression rate did not further improve. A score combining the three compression skills resulted in the following success rates: 6/104 (baseline), 15/104 (after the video), 59/104 (after voice feedback). CONCLUSION: Although in a self learning station video training can introduce CPR skills to novices, additional voice-feedback exercises were needed to achieve acceptable CPR quality. PMID- 22922496 TI - AEE788 potentiates celecoxib-induced growth inhibition and apoptosis in human colon cancer cells. AB - AIMS: Combinatorial therapies that target multiple signaling pathways may provide improved therapeutic responses over monotherapies. In the present study, we evaluated the effect of celecoxib and AEE788 alone and in combination on cell proliferation, invasion, migration, angiogenesis, morphological changes, actin filament organization and apoptosis induction in the human colon cancer cell lines. MAIN METHODS: Effect of celecoxib and AEE788 alone and in combination on colon cancer cell lines was evaluated by cell proliferation assay, morphological analysis, cell cycle analysis, scratch-wound healing and chorioallantoic membrane assays, zymography, nuclear fragmentation and western blot analyses. KEY FINDINGS: Either drug alone or in combination inhibited human colonic adenocarcinoma cell lines HCT 15 and HT 29 in a dose-dependent manner. Microscopic analysis revealed inhibition of cell membrane extensions, cell shrinkage, and disorganization of actin filaments. Additionally, either drug alone or in combination inhibited HCT 15 migration, invasion and angiogenesis by suppressing matrix metalloproteinase-2 and -9 activities. Increased reactive oxygen generation, loss of mitochondrial membrane potential, cleavage of PARP, caspase-3 activation and DNA ladder formation characterized the induction of apoptosis by celecoxib and/or AEE788 treatment. Either drug individually induced apoptosis via down-regulation of the anti-apoptotic proteins Bcl(2) and Bcl-x(L), and up-regulation of pro-apoptotic protein Bax, cleavage of PARP, activation of caspase-3 and inhibition of vascular endothelial growth factor receptor signaling pathways. SIGNIFICANCE: Results indicate that AEE788 potentiates celecoxib mediated inhibition of proliferation and angiogenesis in HCT 15 colon cancer cells and may prove useful for developing a combinatorial therapy for colon cancer. PMID- 22922497 TI - The mechanisms and possible sites of acetylcholine release during chick primary sensory neuron differentiation. AB - AIMS: In this study, we evaluated the ability of differentiating embryonic chick DRG neurons to release and respond to acetylcholine (ACh). In particular, we investigated the neuronal soma and neurites as sites of ACh release, as well as the mechanism(s) underlying this release. MAIN METHODS: ACh release from DRG explants in the Campenot chambers was measured by a chemiluminescent assay. Real time PCR analysis was used to evaluate the expression of ChAT, VAChT, mediatophore and muscarinic receptor subtypes in DRGs at different developmental stages. KEY FINDINGS: We found that ACh is released both within the central and lateral compartments of the Campenot chambers, indicating that ACh might be released from both the neuronal soma and fibers. Moreover, we observed that the expression of the ChAT and mediatophore increases during sensory neuron differentiation and during the post-hatching period, whereas VAChT expression decreases throughout development. Lastly, the kinetics of the m2 and m3 transcripts appeared to change differentially compared to the m4 transcript during the same developmental period. SIGNIFICANCE: The data obtained demonstrate that the DRG sensory neurons are able to release ACh and to respond to ACh stimulation. ACh is released both by the soma and neurite compartments. The contribution of the mediatophore to ACh release appears to be more significant than that of VAChT, suggesting that the non-vesicular release of ACh might represent the preferential mechanism of ACh release in DRG neurons and possibly in non-cholinergic systems. PMID- 22922499 TI - Electrowetting on dielectric experiments using graphene. AB - We report electrowetting on dielectric (EWOD) experiments using graphene; a transparent, flexible and stretchable nanomaterial. Graphene sheets were synthesized by chemical vapor deposition, and transferred to various substrates (including glass slides and PET films). Reversible contact angle changes were observed on the Teflon-coated graphene electrode with both AC and DC voltages. Nyquist plots of the EWOD reveal that the graphene electrode has higher capacitive impedance than gold electrodes under otherwise identical conditions, suggesting a lower density of pin-holes and defects in the Teflon/graphene electrode than in the Teflon/gold electrode. Furthermore, we have observed reduced electrolysis of the electrolyte and smaller leakage current in the dielectric layer (Teflon) on graphene electrodes than on Au electrodes at the same Teflon thickness and applied voltage. We expect that the improved EWOD properties using graphene as an electrode material will open the door to various applications, including flexible displays and droplet manipulation in three dimensional microfluidics. PMID- 22922498 TI - Effects of synthetic cathinones contained in "bath salts" on motor behavior and a functional observational battery in mice. AB - Synthetic stimulants commonly sold as "bath salts" are an emerging abuse problem in the U.S. Users have shown paranoia, delusions, and self-injury. Previously published in vivo research has been limited to only two components of bath salts (mephedrone and methylone). The purpose of the present study was to evaluate in vivo effects of several synthetic cathinones found in bath salts and to compare them to those of cocaine (COC) and methamphetamine (METH). Acute effects of methylenedioxyphyrovalerone (MDPV), mephedrone, methylone, methedrone, 3 fluoromethcathinone (3-FMC), 4-fluoromethcathinone (4-FMC), COC, and METH were examined in male ICR mice on locomotor activity, rotorod, and a functional observational battery (FOB). All drugs increased locomotor activity, with different compounds showing different potencies and time courses in locomotor activity. 3-FMC and methylone decreased performance on the rotorod. The FOB showed that in addition to typical stimulant induced effects, some synthetic cathinones produced ataxia, convulsions, and increased exploration. These results suggest that individual synthetic cathinones differ in their profile of effects, and differ from known stimulants of abuse. Effects of 3-FMC, 4-FMC, and methedrone indicate these synthetic cathinones share major pharmacological properties with the ones that have been banned (mephedrone, MDPV, methylone), suggesting that they may be just as harmful. PMID- 22922500 TI - Evaluation of headspace equilibration methods for quantifying greenhouse gases in groundwater. AB - The objective of the study was to evaluate the different headspace equilibration methods for the quantification of dissolved greenhouse gases in groundwater. Groundwater samples were collected from wells with contrasting hydrogeochemical properties and degassed using the headspace equilibration method. One hundred samples from each well were randomly selected, treatments were applied and headspace gases analysed by gas chromatography. Headspace equilibration treatments varied helium (He):water ratio, shaking time and standing time. Mean groundwater N(2)O, CO(2) and CH(4) concentrations were 0.024 mg N L(-1), 13.71 mg C L(-1) and 1.63 MUg C L(-1), respectively. All treatments were found to significantly influence dissolved gas concentrations. Considerable differences in the optimal He:water ratio and standing time were observed between the three gases. For N(2)O, CO(2) and CH(4) the optimum operating points for He:water ratio was 4.4:1, 3:1 and 3.4:1; shaking time was 13, 12 and 13 min; and standing time was 63, 17 and 108 min, respectively. The headspace equilibration method needs to be harmonised to ensure comparability between studies. The experiment reveals that He:water ratio 3:1 and shaking time 13 min give better estimation of dissolved gases than any lower or higher ratios and shaking times. The standing time 63, 17 and 108 min should be applied for N(2)O, CO(2) and CH(4), respectively. PMID- 22922502 TI - In recovery from schizophrenia: regaining social cover - a phenomenological investigation. AB - We offer here a framework for the understanding of being in recovery from schizophrenia as an interpersonal process. We draw upon in-depth phenomenological descriptions of the fundamental changes taking place in an individual's mental life when they are suffering from schizophrenia. There is a loss of commonsensical habituality and interpersonal capabilities, usually most prominently expressed as an impaired intersubjective resonance. People with schizophrenia cannot as easily automatically and coherently display their own emotion via their facial expressions or perceive those of others, as do 'normal' people. This implies that interpersonal resonance between interacting individuals is not automatic, as is often taken for granted. The need to actively rebuild interpersonal resonance also holds true for the interacting 'normal' person, but would be an unfamiliar and unexpected task. These difficulties in empathizing provoke a mismatch in interpersonal resonance, often leading to the intuition that the person having schizophrenia lacks (explicit) self-awareness. We conclude that there is a mismatch in the form and scope of the social cover extended to the social role opportunities available in trans-Atlantic cultural settings for people with schizophrenia. Typically, these social roles imply that people with schizophrenia are unaware of themselves; however, while they often lack insight or may not consider their symptoms as signs of a mental disorder, they are usually not 'confused' or 'distracted' in the sense of no longer being aware of themselves. We discuss various options for adequate social cover achievable for people with schizophrenia, demonstrating their impact on the recovery process. PMID- 22922501 TI - Site-specific genome editing in Plasmodium falciparum using engineered zinc finger nucleases. AB - Malaria afflicts over 200 million people worldwide, and its most lethal etiologic agent, Plasmodium falciparum, is evolving to resist even the latest-generation therapeutics. Efficient tools for genome-directed investigations of P. falciparum induced pathogenesis, including drug-resistance mechanisms, are clearly required. Here we report rapid and targeted genetic engineering of this parasite using zinc finger nucleases (ZFNs) that produce a double-strand break in a user-defined locus and trigger homology-directed repair. Targeting an integrated egfp locus, we obtained gene-deletion parasites with unprecedented speed (2 weeks), both with and without direct selection. ZFNs engineered against the parasite gene pfcrt, responsible for escape under chloroquine treatment, rapidly produced parasites that carried either an allelic replacement or a panel of specified point mutations. This method will enable a diverse array of genome-editing approaches to interrogate this human pathogen. PMID- 22922503 TI - Predicting survival of patients with amyotrophic lateral sclerosis at presentation: a 15-year experience. AB - OBJECTIVE: To describe the clinical features at first evaluation that best predict survival of the amyotrophic lateral sclerosis (ALS) population from the Salpetriere Hospital between 1995 and 2009. METHODS: Data are collected and entered into a clinical database from all patients seen at the Paris ALS Center. Variables analyzed were demographic and baseline information, strength testing (manual muscle testing; 1995-2009), the revised ALS Functional Rating Scale (ALSFRS-R; 2002-2009) and survival status. The chi(2) test and ANOVA assessed differences in variables by region and across time period. Univariate and multivariate Cox proportional hazards models determined which variables best predicted survival. Flexible modeling of continuous predictors (splines) assessed trends in survival for different variables. RESULTS: 3,885 patients with ALS were seen in 1995-2009, of whom 2,037 had ALSFRS-R scores. Age, weight, strength, and site of onset varied by region of residence. The proportion of patients living outside Paris, the time to first visit, patient age, and motor function differed across time periods. In Cox models, site of onset, time to first visit greater than 18 months, strength and the year of visit after 2006 predicted survival (all p values <0.0001). Compared to patients first seen between 1999 and 2002, the hazard ratio of death was 1.04 (95% CI = 0.95-1.14) for 2003-2006, and 0.76 (95% CI = 0.66-0.87) after 2006, while adjusting for other predictors of survival. The use of noninvasive ventilation increased during 2004-2008 from 16 to 51% of patients. CONCLUSIONS: Older age, bulbar onset, shorter delay to first visit and poor motor function at first visit predicted shorter survival rates in this large center-based sample from France, showing marked consistency across time and region of residence. Survival improved after 2006, concurrent with increasing rates of noninvasive ventilation use. Clinicopathologic correlation could better define subgroups, but identification of etiologies may be needed to elucidate individual forms of ALS with unique survival patterns. PMID- 22922504 TI - High resting heart rate predicts mortality, disability, and cognitive decline in patients after ischaemic stroke: time for additional selective I(f) channel inhibitor trials? PMID- 22922505 TI - Women and men with stable coronary artery disease have similar clinical outcomes: insights from the international prospective CLARIFY registry. AB - AIMS: Men and women differ in terms of presentation and management in coronary artery disease (CAD). Whether these differences translate into different clinical outcomes in stable CAD is unclear. We analysed data from the international prospective CLARIFY registry to compare cardiovascular clinical outcomes in men and women with stable CAD. METHODS AND RESULTS: We analysed 1-year outcomes in 30 977 outpatients with stable CAD [23 975 (77.4%) men; 7002 (22.6%) women]. Women were older than men, more likely to have hypertension and diabetes, and less likely to exercise or smoke. They had more frequent angina, but were less likely to have undergone diagnostic non-invasive testing or coronary angiography. Women received less optimized treatment for stable CAD. One-year outcomes were similar for men and women for the composite of cardiovascular death, non-fatal myocardial infarction, or stroke [adjusted rates 1.7 vs. 1.8%, respectively, odds ratio (OR) 0.93, 95% confidence interval (CI) 0.75-1.15]; all-cause death (adjusted 1.5 vs. 1.6%, OR: 0.91, 95% CI: 0.72-1.13); fatal or non-fatal myocardial infarction (adjusted 1.0 vs. 0.9%, OR: 0.81, 95 CI: 0.60-1.08); and cardiovascular death or non-fatal myocardial infarction (adjusted 1.4 vs. 1.4%, OR: 0.89, 95% CI: 0.70 1.12). Fewer women underwent revascularization (2.6 vs. 2.2%, OR: 0.77, 95% CI: 0.64-0.93), although appropriateness was not analysed. CONCLUSION: The risk profiles of women and men with stable CAD differ substantially. However, 1-year outcomes were similar. Fewer women underwent revascularization. Further research is needed to better understand gender determinants of outcome and devise strategies to minimize bias in the management and treatment of women. PMID- 22922506 TI - Stable or not, woman or man: is there a difference? PMID- 22922507 TI - Impact of resting heart rate on mortality, disability and cognitive decline in patients after ischaemic stroke. AB - AIMS: Recurrent stroke is a frequent and disabling event. A high heart rate is associated with cardiovascular outcomes. We investigated the effects of the resting heart rate on cardiovascular and neurological outcomes after recurrent stroke in the high-risk population of the PRoFESS study. METHODS AND RESULTS: A total of 20,165 patients after ischaemic stroke (mean age 66.1, SD 8.6 years) assigned to the treatment arms of the PRoFESS trial were pooled divided by quintiles of the baseline heart rate and analysed according to cardiovascular and functional outcomes after stroke: recurrent stroke and major cardiovascular outcomes such as stroke, myocardial infarction, and worsening or new-onset heart failure as well as death from cardiovascular and non-cardiovascular causes. Pre defined endpoints were disability after a recurrent stroke, assessed with the modified Rankin scale (mRS) and the Barthel index at 3 months, and cognitive function, assessed with the Mini-Mental State Examination (MMSE) score at 4 weeks after randomization and at the penultimate visit. Patients in the two highest quintiles of heart rate (77-82 and >82 b.p.m.) were at a higher risk for total death [hazard ratio (HR) 1.42, 95% CI 1.19-1.69 and HR 1.74, 95% CI 1.48-2.06, P < 0.0001] compared with the lowest quintile. Similar results were observed for vascular death [71-<=76 b.p.m., HR 1.39 (1.11-1.74), P < 0.0001] and non-vascular death [from >82 b.p.m., HR 1.66 (1.29-2.13), P = 0.0016]. Myocardial infarction (P = 0.7084) and recurrent stroke (P = 0.1379) were not significantly associated with the baseline heart rate. Hazard ratios were adjusted to multiple confounders including the baseline blood pressure. In the group of patients with a recurrent stroke, an association of a lower heart rate to better outcomes was measured with the Barthel index across all heart rate groups. In addition, there was a significant association of the baseline heart rate to the occurrence of significant cognitive decline according to an MMSE score <=24 points at 1 month and at the penultimate visit or a decline of >=2 points between these two time periods. Better independence score at a low heart rate were observed. CONCLUSION: The heart rate is a risk indicator for mortality in patients with stroke and, importantly, a low heart rate is associated with a better functional outcome and less cognitive decline after an ischaemic stroke. TRIAL REGISTRATION: ClinicalTrials.gov, number NTC00153062. PMID- 22922508 TI - The effect of varying concentrations of fluoridated milk on enamel remineralisation in vitro. AB - The aim of this in vitro single blind study was to investigate the dose response of fluoride in milk on enamel demineralisation and remineralisation under pH cycling using transverse microradiography (TMR). Enamel slabs (n = 11) with caries-like lesions were exposed to milk containing 6 different fluoride concentrations (0, 0.25, 0.5, 1.0, 5.0 and 10.0 ppm F). On each of the 14 days of the cycling period the lesions were exposed to five 2-minute periods of cariogenic challenge (1.5 mM CaCl2, 0.9 mM KH2PO4 and 50 mM acetic acid at pH 5.0) and two 5-min periods in milk plus 10 min in a milk/saliva (1:3) slurry. The slabs were stored at 37 degrees C in artificial saliva throughout the cycling period and demineralisation and remineralisation was assessed by TMR using dedicated image software. Remineralisation (DeltaZ) was observed in all fluoride groups in contrast to demineralisation in the non-fluoride control. Remineralisation was significant (p < 0.05) for all concentrations above 1.0 ppm F. The results showed that fluoride concentration in milk exhibited a clear dose dependency and that the presence of fluoride even at low concentrations promoted remineralisation in this pH-cycling model. PMID- 22922509 TI - Resolution of an immunodiagnostic dilemma: heavy chain chimeric antibodies for species in which plasmocytomas are unknown. AB - The immunoglobulin (Ig) genes of many vertebrates have been characterized but IgG subclasses, IgD and IgE proteins are only available for three species in which plasmacytomas occur. This creates a major problem in the production and specificity verification of diagnostic anti-Ig reagents for the vast majority of mammals. We describe a novel solution using the swine system with its eleven different variants of IgG. It involves the in vitro synthesis of chimeric porcine camelid heavy chain antibodies (HCAbs) that do not require light chains and therefore only a single transfection vector. The expressed chimeric HCAbs are comprised of the camelid VHH domain encoding specificity for lysozyme and the hinge, CH2 and CH3 domains of the various porcine IgGs. These HCAb retain their antigenic integrity and their ability to recognize lysozyme. The engineered specificity assures that these HCAb can be immobilized in native configuration when used for testing the specificity of anti-swine IgG antibodies. Comparative data to illustrate the importance of this point are provided. These are now available for use in hybridoma selection and as reference standards for evaluating the specificity of currently available anti-swine IgG antibodies. PMID- 22922510 TI - Depression and heavy bleeding during the menopausal transition: adjusting our gaze. PMID- 22922511 TI - Preclinical evidence supporting a beneficial role for vitamin D and its cognate receptor in cardiovascular health. PMID- 22922512 TI - Hard stuff for the bones. PMID- 22922513 TI - Fat, fit, or famished? No clear answers from the Women's Health Initiative about diet and dieting for longstanding hot flashes. PMID- 22922515 TI - Deleterious effects of smoking on well-being, the effect on age at natural menopause (ANM). PMID- 22922514 TI - Moderate alcohol intake lowers biochemical markers of bone turnover in postmenopausal women. AB - OBJECTIVE: Epidemiological studies indicate that higher bone mass is associated with moderate alcohol consumption in postmenopausal women. However, the underlying cellular mechanisms responsible for the putative beneficial effects of alcohol on bone are unknown. Excessive bone turnover, combined with an imbalance whereby bone resorption exceeds bone formation, is the principal cause of postmenopausal bone loss. This study investigated the hypothesis that moderate alcohol intake attenuates bone turnover after menopause. METHODS: Bone mineral density was determined by dual-energy x-ray absorptiometry in 40 healthy postmenopausal women (mean +/- SE age, 56.3 +/- 0.5 y) who consumed alcohol at 19 +/- 1 g/day. Serum levels of the bone formation marker osteocalcin and the resorption marker C-terminal telopeptide (CTx) were measured by immunoassay at baseline (day 0) and after alcohol withdrawal for 14 days. Participants then consumed alcohol and were assayed on the following morning. RESULTS: Bone mineral density at the trochanter and total hip were positively correlated to the level of alcohol consumption. Serum osteocalcin and CTx increased after abstinence (4.1 +/- 1.6%, P = 0.01 and 5.8 +/- 2.6%, P = 0.02 compared with baseline, respectively). Osteocalcin and CTx decreased after alcohol readministration, compared with the previous day (-3.4 +/- 1.4%, P = 0.01 and -3.5 +/- 2.1%, P = 0.05, respectively), to values that did not differ from baseline (P > 0.05). CONCLUSIONS: Abstinence from alcohol results in increased markers of bone turnover, whereas resumption of alcohol reduces bone turnover markers. These results suggest a cellular mechanism for the increased bone density observed in postmenopausal moderate alcohol consumers. Specifically, the inhibitory effect of alcohol on bone turnover attenuates the detrimental skeletal consequences of excessive bone turnover associated with menopause. PMID- 22922517 TI - Barriers to optimal palliative care of lung transplant candidates. AB - BACKGROUND: The provision of effective palliative care is of great importance to patients awaiting lung transplantation. Although the prospect of lung transplantation provides hope to patients and their families, these patients are usually very symptomatic from their underlying disease. METHODS: An e-mail questionnaire was sent to members of the American College of Chest Physicians' Transplant NetWork and the Pulmonary Council of the International Society for Heart and Lung Transplantation (ISHLT). The survey included questions about barriers to providing palliative care, the availability of palliative care services, and recommended strategies to improve palliative care for lung transplant candidates. RESULTS: The 158 respondents represented approximately 65% of transplant programs in the ISHLT registry. Respondents were in practice a mean of 11.3 (+/- 9) years, 70% were pulmonologists, 17% were surgeons, and 13% were other care providers. Barriers were classified into domains including patient factors, family factors, physician factors, and institutional/transplant program/lung allocation system factors. Significant patient/family barriers included unrealistic patient/family expectations about survival, unwillingness to plan end-of-life care, concerns about abandonment or inappropriate care after enrollment in a palliative care program, and family disagreements about care goals. For institutional/program/allocation system barriers, only the requirement for weight loss or gain to meet program-specific BMI requirements was identified. Significant physician barriers included competing time demands and the seemingly contradictory goals of transplant vs palliative care. Strategies recommended to improve palliative care included routine advance care planning for patients awaiting transplantation, access to palliative care specialists, training of transplant physicians in symptom management, and regular meetings among transplant physicians, nurses, patients, and families. CONCLUSIONS: Physicians providing care to lung transplant candidates reported considerable barriers to the delivery and acceptance of palliative care and identified specific strategies to improve palliative care for lung transplant candidates. PMID- 22922518 TI - Nine-year risk of depression diagnosis increases with increasing self-reported concussions in retired professional football players. AB - BACKGROUND: Concussions may accelerate the progression to long-term mental health outcomes such as depression in athletes. PURPOSE: To prospectively determine the effects of recurrent concussions on the clinical diagnosis of depression in a group of retired football players. STUDY DESIGN: Cohort study; Level of evidence, 2. METHODS: Members of the National Football League Retired Players Association responded to a baseline General Health Survey (GHS) in 2001. They also completed a follow-up survey in 2010. Both surveys asked about demographic information, number of concussions sustained during their professional football career, physical/mental health, and prevalence of diagnosed medical conditions. A physical component summary (Short Form 36 Measurement Model for Functional Assessment of Health and Well-Being [SF-36 PCS]) was calculated from responses for physical health. The main exposure, the history of concussions during the professional playing career (self-report recalled in 2010), was stratified into 5 categories: 0 (referent), 1 to 2, 3 to 4, 5 to 9, and 10+ concussions. The main outcome was a clinical diagnosis of depression between the baseline and follow-up GHS. Classic tabular methods computed crude risk ratios. Binomial regression with a Poisson residual and robust variance estimation to stabilize the fitting algorithm estimated adjusted risk ratios. chi(2) analyses identified associations and trends between concussion history and the 9-year risk of a depression diagnosis. RESULTS: Of the 1044 respondents with complete data from the baseline and follow-up GHS, 106 (10.2%) reported being clinically diagnosed as depressed between the baseline and follow-up GHS. Approximately 65% of all respondents self reported sustaining at least 1 concussion during their professional careers. The 9-year risk of a depression diagnosis increased with an increasing number of self reported concussions, ranging from 3.0% in the "no concussions" group to 26.8% in the "10+" group (linear trend: P < .001). A strong dose-response relationship was observed even after controlling for confounders (years retired from professional football and 2001 SF-36 PCS). Retired athletes with a depression diagnosis also had a lower SF-36 PCS before diagnosis. The association between concussions and depression was independent of the relationship between decreased physical health and depression. CONCLUSION: Professional football players self-reporting concussions are at greater risk for having depressive episodes later in life compared with those retired players self-reporting no concussions. PMID- 22922519 TI - Anteroposterior thickening of the femoral neck with aging decreases the "offset" in men. AB - BACKGROUND: The contour of the femoral head-neck junction has been shown to have an effect on femoroacetabular impingement (FAI), which can lead to early osteoarthritis of the hip. This study uses computed tomography (CT) to investigate changes in the femoral head, femoral neck, and joint space with aging. HYPOTHESIS: The ratio of the diameter of the femoral head to the diameter of the femoral neck would decrease with increasing age, thus diminishing the "offset" of the femoral neck and being a possible mechanism for cam-type FAI and resultant osteoarthritis. STUDY DESIGN: Cross-sectional study; Level of evidence, 3. METHODS: There were 20 male and 20 female patients from each decade, aged 20 to 80 years, who received pelvic and abdominal CT scans. In the axial plane, the femoral head and neck were measured from anterior to posterior, and the joint space was measured anteromedially. The ratio of the diameter of the femoral head to the diameter of the femoral neck was calculated, and patients with radiographic signs of osteoarthritis were noted. Regression analysis was performed to examine the significance of the relationships between these variables, age, and osteoarthritis. RESULTS: Male and female patients showed significant increases in femoral head diameter and femoral neck diameter as well as decreases in joint space width with increasing age. Male patients showed a decrease in the femoral head-neck ratio (relative neck thickening) of 0.0053 per year (P < .0001) or an average 18% decrease from age 20 to 80 years, while female patients did not show a significant relationship (P = .29). Male patients with signs of osteoarthritis had a smaller femoral head-neck ratio (P < .0001) than those without, while female patients did not (P = .25). Male and female patients with signs of osteoarthritis had a larger femoral head and femoral neck and a more narrow joint space width than those without. CONCLUSION: Our results suggest that, as men age, they develop a relatively thicker femoral neck that could result in increasing cam impingement, which contributes to the known higher prevalence of osteoarthritis in men. This does not seem to be the case in women, as their femoral neck does not appear to grow as quickly. PMID- 22922520 TI - Return to high school- and college-level football after anterior cruciate ligament reconstruction: a Multicenter Orthopaedic Outcomes Network (MOON) cohort study. AB - BACKGROUND: There is a relative paucity of data regarding the effect of anterior cruciate ligament (ACL) reconstruction on the ability of American high school and collegiate football players to return to play at the same level of competition as before their injury or to progress to play at the next level of competition. PURPOSE: (1) To identify the percentage of high school and collegiate American football players who successfully returned to play at their previous level of competition, (2) to investigate self-reported performance for those players able to return to play or reason(s) for not returning to play, and (3) to elucidate risk factors responsible for players not being able to return to play or not returning to the same level of performance. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: This study was a retrospective analysis of prospective patients taken from the Multicenter Orthopaedic Outcomes Network (MOON) cohort who identified football as their primary or secondary sport. Identified patients were then questioned in a structured interview regarding their ACL injury, participation in football before their injury, and factors associated with returning to play. Data were analyzed for player position, concurrent meniscal/ligamentous/chondral injury, surgical technique and graft used for ACL reconstruction, and issues pertaining to timing and ability to return to play. RESULTS: One hundred forty-seven players (including 68 high school and 26 collegiate) met our criteria and were contacted from the 2002 and 2003 MOON cohorts. Return to play rates for all high school and collegiate athletes were similar (63% and 69%, respectively). Based on player perception, 43% of the players were able to return to play at the same self-described performance level. Approximately 27% felt they did not perform at a level attained before their ACL tear, and 30% were unable to return to play at all. Although two thirds of players reported some "other interest" contributing to their decision not to return, at both levels of competition, fear of reinjury or further damage was cited by approximately 50% of the players who did not return to play. Analysis of patient-reported outcome scores at a minimum of 2 years after surgery between patients who returned to play and those who did not demonstrated clinically and statistically significant differences in the International Knee Documentation Committee form, Marx Activity Scale, and Knee injury and Osteoarthritis Outcome Score knee-related quality of life subscale in the collegiate players. Similar clinical differences were not statistically significant in the high school students. Player position did not have a statistically significant effect on the ability to return to play for high school players, and 41% of "skilled" position players and 50% of "nonskilled" position players were able to return to play at the same performance level. CONCLUSION: Return to play percentages for amateur American football players after ACL reconstruction are not as high as would be expected. While technical aspects of ACL reconstruction and the ensuing rehabilitation have been studied extensively, the psychological factors (primarily a fear of reinjury) influencing the ability to return to play after ACL surgery may be underestimated as a critical factor responsible for athletes not returning to play at any level of competition. PMID- 22922521 TI - Clinical and radiological outcomes 5 years after matrix-induced autologous chondrocyte implantation in patients with symptomatic, traumatic chondral defects. AB - BACKGROUND: To date, few studies have been published reporting the 5-year follow up of clinical and radiological outcomes for chondral defects treated with matrix induced autologous chondrocyte implantation (MACI). HYPOTHESIS: A significant improvement in clinical and radiological outcomes after treatment of symptomatic, traumatic chondral defects of the knee with the MACI implant will be maintained up to 5 years after surgery. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: A prospective evaluation of the MACI procedure was performed in 21 patients with chondral defects of the knee. After the MACI procedure, patients were clinically assessed with the Knee injury and Osteoarthritis Outcome Score (KOOS), the Tegner-Lysholm score, the International Knee Documentation Committee (IKDC) Subjective Knee Form, and the modified Cincinnati score at years 1, 2, and 5. The quality of repair tissue was assessed by magnetic resonance imaging using the magnetic resonance observation of cartilage repair tissue (MOCART) score at months 3 and 6 and years 1, 2, and 5. RESULTS: Significant improvements (P < .05) were observed for all 5 KOOS subcategories at year 1 and were maintained through year 5 in 90.5% of patients (19/21). Treatment failure occurred in only 9.5% of patients (2/21). Significant improvements (P < .05) from baseline to year 5 were also observed for the IKDC score (30.1 to 74.3), the modified Cincinnati score (38.1 to 79.6), and the Tegner-Lysholm activity score (1.8 to 4.3). Similarly, the MOCART score significantly improved (P < .001) from baseline to year 5 (52.9 to 75.8). After 5 years, complete filling (83%) and integration (82%) of the graft were seen in the majority of patients. Signs of subchondral bone edema were still present in 47% of patients at 5 years. No product-specific adverse events were reported over the 5-year follow-up period. CONCLUSION: Patients treated with a MACI implant demonstrated significant clinical improvement and good quality repair tissue 5 years after surgery. The MACI procedure was shown to be a safe and effective treatment for symptomatic, traumatic chondral knee defects in this study. PMID- 22922524 TI - Risks and biases in case-control studies of iatrogenic Creutzfeldt-Jakob disease. PMID- 22922523 TI - Timeline, epidemiology, and risk factors for bacterial, fungal, and viral infections in children and adolescents after allogeneic hematopoietic stem cell transplantation. AB - Advances made in the field of hematopoietic stem cell transplantations (HSCT) over the past 20 years may have had an impact on the distribution of posttransplantation infections. We sought to retrospectively analyze the epidemiology and risk factors for bacterial, fungal, and viral infections in children after allogeneic HSCT in a cohort of 759 children who underwent allogeneic HSCT in a single institution between 1990 and 2009. The association between infections and risk factors of interest at 0 to 30 days, 31 to 100 days, and 101 days to 2 years posttransplantation was evaluated using logistic regression. Difference among the subtypes within each category was studied. There were 243 matched-related donors, 239 matched-unrelated donors (MUDs), and 176 haploidentical donor transplantations. Era of transplantation (0-30 days), peripheral blood stem cell product, acute graft-versus-host disease (aGVHD; 31 100 days), and chronic GVHD (cGVHD; 101-730 days) were associated with higher risk for bacterial infections at the respective time periods. Patients with aGVHD (31-100 days), cGVHD, and older age (101-730 days) were at higher risk for fungal infections. Cytomegalovirus (CMV) donor/recipient (D/R) serostatus (0-100 days), era of transplantation, MUD HSCT (31-100 days), and cGVHD (101-730 days), influenced viral infections. Gram-positive outnumbered gram-negative bacterial infections; aspergillosis and candidemia were equally prevalent in all time periods. Haploidentical donor HSCT was not associated with an increased risk of infections. There seems to be a continuum in the timeline of infections posttransplantation, with bacterial, fungal, and viral infections prevalent in all time periods, particularly late after the transplantation, the risk affected by GVHD, CMV, D/R status, product type, older age, and use of unrelated donors. PMID- 22922522 TI - Fifty years of melphalan use in hematopoietic stem cell transplantation. AB - Melphalan remains the most widely used agent in preparative regimens for hematopoietic stem cell transplantation (SCT). From its initial discovery more than 50 years ago, it has been gradually incorporated in the conditioning regimens for both autologous and allogeneic transplantations because of its myeloablative properties and broad antitumor effects as a DNA alkylating agent. Melphalan remains the mainstay conditioning for multiple myeloma and lymphomas, and it has been used successfully in preparative regimens of a variety of other hematological and nonhematological malignancies. The addition of newer agents to conditioning, such as bortezomib or lenalidomide for myeloma or clofarabine for myeloid malignancies, may improve antitumor effects for transplantation, whereas melphalan in combination with alemtuzumab may represent a backbone for future cellular therapy because of reliable engraftment and low toxicity profile. This review summarizes the development and the current use of this remarkable drug in hematopoietic SCT. PMID- 22922525 TI - The influence of risky and conservative mental sets on cerebral activations of cognitive control. AB - Mental set is known to influence cognitive functioning. Risk-seeking and risk aversive mental sets alter cerebral responses to conflicting events. Here, building on our previous imaging work of the stop signal task, we introduced a "reward uncertainty" condition to elicit changes in participants' mental sets and examined how individual differences altered the neural responses to salient events. Approximately half of 27 adult participants - the Conservatives - became more risk-aversive in the "reward" as compared to the "standard" condition, by slowing down in go reaction time. We hypothesized that stop errors were more salient for these participants, as compared to the other subjects - the Riskys - who speeded up in go reaction time in the reward as compared to standard condition. With statistical parametric mapping, we showed greater activation of the retrosplenial cortex, somatosensory cortex, pre-supplementary motor area, and thalamus during stop error, in contrast to stop success trials, in the Conservatives as compared to Riskys. These results provided evidence that mental set influences cerebral activations during stop signal performance and extended the potential utility of the stop signal task in elucidating the contextual effects on cognitive control. PMID- 22922526 TI - Partner influence and in-phase versus anti-phase physiological linkage in romantic couples. AB - Between-partner physiological linkage can be in-phase (changes in unison), or anti-phase (changes in opposite directions). In the context of conversation we predicted that in-phase linkage would occur when partners exert strong influence on each other; anti-phase linkage would occur due to the behavioral coordination of turn taking. To test this, blood pressure, inter-beat interval, and skin conductance were recorded from 44 heterosexual couples while they discussed how they influence each other's health-related behaviors. Partner influence was assessed in two ways: 1) partners' global perceptions of how they try to influence each other's health; and 2) behavioral manifestations of influence, specifically demand-withdraw behavior. As predicted, both measures of partner influence moderated physiological linkage of blood pressure such that at low levels of influence linkage was "anti-phase" and at high levels linkage was "in phase." Several alternative hypotheses were ruled out; the effects were not due to relationship conflict, emotional experience, or simply the pattern of blood pressure over time. These results suggest that partner influence may be driving physiological linkage, which may be one avenue through which partners can affect each other's health. PMID- 22922527 TI - Cost-effectiveness analysis of preventing mother-to-child transmission of hepatitis B by injecting hepatitis B immune globulin. AB - OBJECTIVE: Hepatitis B immune globulin (HBIG) injection during pregnancy and/or after birth is an intervention for preventing mother-to-child transmission of the hepatitis B (HB) virus. However, varying cost-effectiveness ratios among various HBIG therapies remain unclear. This study explored these differences in cost effectiveness ratios. METHODS: Four districts in Wuhan, China, were selected for the current study using stratified random sampling. Pregnant women who were positive for HB surface antigen (HBsAg) and who received prenatal care in district-level maternal and child health hospitals were interviewed. The mothers and their children underwent follow-up visits from the time of pregnancy until the children were six-and-a-half months old. RESULTS: A total of 324 cases completed the follow-up visits on a voluntary basis. Among the 324 HBsAg-positive pregnant women investigated, 60.49% (196/324) were injected with HBIG at different trimesters. A total of 249 neonates (76.85%) received an HBIG injection within 24 h after birth. The HBsAg-positive rate in infants was 5.56% (18/324). The HBIG-injected mother and infant group had the lowest chronic infection rate among children [odds ratio=0.14, 95% confidence interval (CI) 0.02-0.90, P=0.039]. The HBIG-injected infant group exhibited the lowest HBsAb-positive rate (odds ratio=0.07, 95% CI 0.02-0.23). The cost per averted disability-adjusted life years was lowest in the infant group: USD 118.61 (95% CI 105.23-131.99). CONCLUSION: These results indicate that active and passive immunizations (HBIG and HB vaccine) entail the lowest cost in the prevention of chronic HB infection in infants. However, this programme has the lowest HBsAb-positive rate, which possibly prevents children from self-acquiring antibodies. PMID- 22922528 TI - An acquired defect associated with abnormal signaling of the platelet collagen receptor glycoprotein VI. AB - INTRODUCTION: Ligands acting at the platelet collagen receptor, glycoprotein (GP)VI, induce intracellular FcRgamma/Syk-dependent signaling pathways and Syk dependent or Syk-independent generation of intracellular reactive oxygen species (ROS). Additional signaling-dependent or signaling-independent pathways lead to metalloproteinase-mediated shedding of GPVI. AIM: Analysis of platelet GPVI expression and signaling in a patient with a collagen-selective defect associated with myelodysplastic syndrome (MDS) uniquely demonstrates divergent pathways leading to ROS generation and Syk phosphorylation in human platelets. METHODS: Surface expression of GPVI and ligand-induced ROS generation was quantitated by flow cytometry. GPVI shedding and Syk phosphorylation were analyzed by Western blot. RESULTS: Despite platelet count/size and GPVI surface expression within normal ranges, platelet-rich plasma showed no aggregation in response to collagen or GPVI-selective agonist collagen-related peptide, but aggregated in response to other agonists, consistent with dysfunctional GPVI signaling. We observed rapid GPVI-dependent Syk-independent ROS generation and disulfide-dependent GPVI homodimerization, but not Syk-dependent ROS or ligand-induced shedding. Temporal analysis showed a gradual decline in platelet count and the appearance of ligand induced phosphorylation of an ~40-kDa Syk fragment. CONCLUSIONS: These studies show that GPVI ligation in platelets induces intracellular ROS production independent of either Syk activation or divergent pathways leading to platelet aggregation or ectodomain shedding. PMID- 22922529 TI - Assessment of lower-voltage TEM performance using 3D Fourier transform of through focus series. AB - We assess the imaging performance of a transmission electron microscopy (TEM) system operated at a relatively low acceleration voltage using the three dimensional (3D) Fourier transform of through-focus images. Although a single diffractogram and the Thon diagram cannot distinguish between the linear and non linear TEM imaging terms, the 3D Fourier transform allows us to evaluate linear imaging terms, resulting in a conclusive assessment of TEM performance. Using this method, information transfer up to 98 pm is demonstrated for an 80 kV TEM system equipped with a spherical aberration corrector and a monochromator. We also revisit the Young fringe method in the light of the 3D Fourier transform, and have found a considerable amount of non-linear terms in Young fringes at 80 kV even from a typical standard specimen, such as an amorphous Ge thin film. PMID- 22922530 TI - Age-specific trends in black-white disparities in cervical cancer incidence in the United States: 1975-2009. AB - BACKGROUND: Although overall cervical cancer incidence rates have decreased in both black and white women in the U.S. since the mid 1950s due to widespread screening, rates continue to be higher among blacks than among whites. However, whether this pattern differs by age is unknown. METHODS: Cervical cancer cases (1975-2009, N=36,503) were obtained from nine Surveillance, Epidemiology, and End Results (SEER) Program registries. Age-standardized incidence rates for white and black women were calculated from 1975-1979 through 2005-2009 by age group (<50, 50-64, and >=65 years). Rate ratios (RRs) and 95% confidence intervals (CIs) evaluated differences in rates for blacks vs. whites by age group and stage at diagnosis during 1975-1979 and 2005-2009. RESULTS: Among women aged <50 years, the black-to-white disparity RR decreased from nearly two-fold (RR, 1.9; 95% CI, 1.7-2.1) during 1975-1979 to unity during 2005-2009 (RR, 0.9; 95% CI, 0.8-1.0). In contrast, rates remained significantly elevated for blacks vs. whites aged 50 64 years (RR, 2.4; 95% CI, 2.1-2.7 and 1.7; 95% CI, 1.5-2.0), and for those aged >=65 years (RR, 3.3; 95% CI, 2.9-3.8 and 2.2; 95% CI, 1.9-2.7) during both time periods, although the disparities decreased over time. Similar disparities persisted for older black women with cervical cancer of all stages. CONCLUSION: Disparities in cervical cancer incidence rates were eliminated for younger blacks vs. whites but persisted for blacks aged 50 years and older. Additional strategies are needed to increase follow-up and treatment of precancerous lesions among middle-aged and older black women. PMID- 22922531 TI - A phase II evaluation of aflibercept in the treatment of recurrent or persistent endometrial cancer: a Gynecologic Oncology Group study. AB - OBJECTIVES: Aflibercept targets vascular endothelial growth factor and placental growth factor. We evaluated activity and toxicity of aflibercept in recurrent/persistent endometrial cancer patients. Biomarkers and association with clinical characteristics and outcome were explored. METHODS: Eligible patients had measurable disease; 1-2 prior cytotoxic regimens; performance status 0-2. Aflibercept 4 mg/kg IV q14 days (28-day cycles) was administered until disease progression or prohibitive toxicity. Primary endpoints were the proportion of patients with progression-free survival at 6 months (PFS6) and tumor response rate. A flexible two-stage group sequential design to detect 20% increases in the proportion of patients responding or enduring PFS6 with 90% power (alpha=10%) was employed. RESULTS: Forty-nine patients were enrolled; five were excluded: wrong primary (2), second primary (1), wrong cell type (1); and never treated (1). Median age was 64 (range 48-83). Eighteen patients (41%) had two prior regimens; 27 (61%) had prior radiation. The PFS6 rate was 41%; three patients (7%, 90% CI: 2-17) had partial response. Of note, 10 patients (23%) met the PFS6 endpoint without starting a subsequent therapy; the remaining eight patients discontinued therapy for toxicity and started another therapy before 6 months elapsed. Median PFS and overall survival were 2.9 months and 14.6 months, respectively. Significant grade 3/4 toxicities were: cardiovascular (23%/5%), constitutional (7%/0), hemorrhage (2%/5%), metabolic (7%/2%), and pain (18%/0). Two treatment related deaths were recorded: GI perforation (1), and arterial rupture (1). FGF1 expression was associated with response. CONCLUSIONS: Aflibercept met pretrial activity parameters, but was associated with significant toxicity at this dose and schedule in this population. PMID- 22922532 TI - Electrochemical impedance spectroscopy characterization of mercaptopropionic acid capped ZnS nanocrystal based bioelectrode for the detection of the cardiac biomarker--myoglobin. AB - 3-Mercaptopropionic acid (MPA) capped ZnS nanocrystals (ZnS(MPA)) are covalently attached to a self assembled monolayer (SAM) of 3-aminopropyltriethoxysilane (APTES) on an indium-tin-oxide (ITO) coated glass plate. The protein antibody, anti-myoglobin (Ab-Mb), is covalently linked to free carboxyl groups present on ZnS(MPA) nanocrystals via carbodiimide coupling reaction to form a bioelectrode (Ab-Mb(BSA)/ZnS(MPA)/APTES/ITO-glass). This bioelectrode has been characterized using atomic force microscopy (AFM), contact angle measurements, cyclic voltammetry and electrochemical impedance spectroscopy (EIS). The optimal equivalent circuit model that matches the impedimetric responses of the bioelectrode describes three distinct regions: the electrolyte solution resistance (R(s)), the double layer capacitance (C(dl)) and the specific charge transfer resistance (R(et)). The EIS measurements revealed that the R(et) increases considerably with no significant change in C(dl) after immunoreaction with protein specific antigen myoglobin, Ag-Mb, so that the prepared bioelectrode can be used for the detection of Ag-Mb. The bioelectrode exhibits an electrochemical impedance response to Ag-Mb, in a linear range from 10ng to 1MUgmL(-1) phosphate buffer solution (pH 7.4) with a R(et) sensitivity of 117.36Omegacm(2) per decade. PMID- 22922533 TI - Xenorhabdus ishibashii sp. nov., isolated from the entomopathogenic nematode Steinernema aciari. AB - Gram-negative bacteria of the genus Xenorhabdus exhibit a mutualistic association with steinernematid entomopathogenic nematodes and a pathogenic relationship with insects. Here we describe two isolates of the entomopathogenic nematode Steinernema aciari collected from China and Japan. 16S rRNA gene sequence similarity and phylogenetic analysis indicated that the isolates obtained from S. aciari belonged to the genus Xenorhabdus. Multilocus sequence analysis based on five universal protein-coding gene sequences revealed that the isolates were closely related to Xenorhabdus ehlersii DSM 16337(T) and Xenorhabdus griffiniae ID10(T) but that they exhibited <97 % sequence similarity with these reference strains, which indicated that the isolates were distinct from previously described species. Based on these genetic differences and several differential phenotypic traits, we propose that the isolates represent a novel species of the genus Xenorhabdus, for which we propose the name Xenorhabdus ishibashii sp. nov. The type strain is GDh7(T) ( = DSM 22670(T) = CGMCC 1.9166(T)). PMID- 22922534 TI - Aureimonas jatrophae sp. nov. and Aureimonas phyllosphaerae sp. nov., leaf associated bacteria isolated from Jatropha curcas L. AB - Four orange-pigmented isolates, L7-456, L7-484(T), L9-479 and L9-753(T), originating from surface-sterilized leaf tissues of Jatropha curcas L. cultivars were characterized using a polyphasic taxonomic approach. Phylogenetic analyses based on 16S rRNA gene sequences indicated that all four isolates belong to the genus Aureimonas. In these analyses, strain L7-484(T) appeared to be most closely related to Aureimonas ureilytica 5715S-12(T) (95.7 % sequence identity). The 16S rRNA gene sequences of strains L7-456, L9-479 and L9-753(T) were found to be identical and also shared the highest similarity with A. ureilytica 5715S-12(T) (97.5 %). Both L7-484(T) and L9-753(T) contained Q-10 and Q-9 as predominant ubiquinones and diphosphatidylglycerol, phosphatidylglycerol, phosphatidylcholine, phosphatidylmonomethylethanolamine, phosphatidylethanolamine, phosphatidyldimethylethanolamine, sulfoquinovosyldiacylglycerol and an aminophospholipid as the major polar lipids. C18 : 1omega7c and C16 : 0 were the major fatty acids. Similar to other species in the genus Aureimonas, hydroxylated fatty acids (e.g. C18 : 1 2-OH) and cyclic fatty acids (C19 : 0 cyclo omega8c) were also present. The DNA G+C contents of L7 484(T) and L9-753(T) were 66.1 and 69.4 mol%, respectively. Strains L7-484(T) and L9-753(T) exhibited less than 40 % DNA-DNA hybridization both between themselves and to A. ureilytica KACC 11607(T). Our results support the proposal that strain L7-484(T) represents a novel species within the genus Aureimonas, for which the name Aureimonas jatrophae sp. nov. is proposed, and that strains L9-753(T), L7 456 ( = KACC 16229 = DSM 25023) and L9-479 ( = KACC 16228 = DSM 25024) represent a second novel species within the genus, for which the name Aureimonas phyllosphaerae sp. nov. is proposed. The type strains of Aureimonas jatrophae sp. nov. and Aureimonas phyllosphaerae sp. nov. are respectively L7-484(T) ( = KACC 16230(T) = DSM 25025(T)) and L9-753(T) ( = KACC 16231(T) = DSM 25026(T)). PMID- 22922535 TI - Characterization of strains of Weissella fabalis sp. nov. and Fructobacillus tropaeoli from spontaneous cocoa bean fermentations. AB - Six facultatively anaerobic, non-motile lactic acid bacteria were isolated from spontaneous cocoa bean fermentations carried out in Brazil, Ecuador and Malaysia. Phylogenetic analysis revealed that one of these strains, designated M75(T), isolated from a Brazilian cocoa bean fermentation, had the highest 16S rRNA gene sequence similarity towards Weissella fabaria LMG 24289(T) (97.7%), W. ghanensis LMG 24286(T) (93.3%) and W. beninensis LMG 25373(T) (93.4%). The remaining lactic acid bacteria isolates, represented by strain M622, showed the highest 16S rRNA gene sequence similarity towards the type strain of Fructobacillus tropaeoli (99.9%), a recently described species isolated from a flower in South Africa. pheS gene sequence analysis indicated that the former strain represented a novel species, whereas pheS, rpoA and atpA gene sequence analysis indicated that the remaining five strains belonged to F. tropaeoli; these results were confirmed by DNA-DNA hybridization experiments towards their respective nearest phylogenetic neighbours. Additionally, matrix-assisted laser desorption/ionization time-of flight mass spectrometry proved successful for the identification of species of the genera Weissella and Fructobacillus and for the recognition of the novel species. We propose to classify strain M75(T) ( = LMG 26217(T) = CCUG 61472(T)) as the type strain of the novel species Weissella fabalis sp. nov. PMID- 22922536 TI - Streptomyces chlorus sp. nov. and Streptomyces viridis sp. nov., isolated from soil. AB - Two actinomycete strains, BK125(T) and BK199(T), isolated from a hay meadow soil sample were investigated to determine their taxonomic position using a polyphasic approach. The isolates produced greenish-yellow and light green aerial mycelium on oatmeal agar, respectively. They contained anteiso-C15 : 0, iso-C15 : 0 and C16 : 0 as the major fatty acids, and MK-9 (H6) and MK-9 (H8) as the predominant isoprenoid quinones. Phylogenetic analysis of the 16S rRNA gene sequences showed that the isolates formed distinct phyletic lines towards the periphery of the Streptomyces prasinus subclade. Analysis of DNA-DNA relatedness between the two isolates showed that they belonged to different genomic species. The organisms were also distinguished from one another and from type strains of species classified in the S. prasinus subclade using a combination of genotypic and phenotypic properties. On the basis of these data, it is proposed that the isolates be assigned to the genus Streptomyces as Streptomyces chlorus sp. nov. and Streptomyces viridis sp. nov. with isolates BK125(T) ( = KACC 20902(T) = CGMCC 4.5798(T)) and BK199(T) ( = KACC 21003(T) = CGMCC 4.6824(T)) as the respective type strains. PMID- 22922537 TI - Transfer of Bacillus schlegelii to a novel genus and proposal of Hydrogenibacillus schlegelii gen. nov., comb. nov. AB - Analysis of the 16S rRNA gene sequences of species currently assigned to the genus Bacillus has shown an extensive intrageneric phylogenetic heterogeneity. The 16S rRNA gene sequence of Bacillus schlegelii ATCC 43741(T) shows only 82.2 85.9% sequence similarity to type strains of other members of the genus Bacillus and <88.5 % sequence similarity to recognised species of the most closely related genera, Calditerricola (88.4-88.5 %), Planifilum (87.3-87.8 %) and Caldalkalibacillus (87.2-87.9%). Furthermore, B. schlegelii ATCC 43741(T) could not be assigned to an existing family by phylogenetic analysis. The predominant menaquinone was MK-7. The major polar lipids were diphosphatidylglycerol, phosphatidylglycerol, one unidentified phospholipid and two unidentified glycolipids. The major fatty acids were iso-C16 : 0, C16 : 0, iso-C17 : 0 and anteiso-C17 : 0. Both the polar lipid profile and the fatty acid composition clearly distinguished B. schlegelii DSM 2000(T) from the type species of the genus Bacillus, Bacillus subtilis. Hence, there is no evidence for a clear phenotypic grouping of this organism into the genus Bacillus nor to the genera Calditerricola, Caldalkalibacillus or Planifilum. A proposal is made to transfer Bacillus schlegelii to a novel genus and species, Hydrogenibacillus schlegelii gen. nov., comb. nov., and to emend the species description. The type strain of the type species is DSM 2000(T) ( = ATCC 43741(T) = CCUG 26017(T) = CIP 106933(T)). PMID- 22922538 TI - Optimization of process parameters of polymer solution mediated growth of calcium carbonate nanoparticles. AB - With the advent of nanotechnology, many methods of synthesis of nanoparticles have come into practice and the 'polymer mediated growth' technique is among them. In this route, ions of one of the reactants are allowed to diffuse from an external solution into a polymer matrix where the other reactant is complexed and bound. The exact role of ionic diffusion in the formation of nanoparticles was investigated in the current study by studying the patterns of kinetics of nanoparticle formation using UV vis spectroscopy. Typically, calcium carbonate nanoparticles were formed by the aforementioned technique using polyethylene glycol solution. The particle size was calculated using Scherrer's formula on x ray diffraction plots and was reconfirmed with field emission scanning electron microscope and transmission electron microscope images. Energy-dispersive x-ray analysis was used to study the composition and purity of the nanoparticles formed. The reactant to polymer ratio, reaction temperature and molecular weight of polyethylene glycol affected the size of the particles formed. Through this knowledge we optimized these parameters to obtain particles as small as 20 nm and confirmed that this technique can be used to control the size of nanoparticles. PMID- 22922539 TI - Structural analysis of strained quantum dots using nuclear magnetic resonance. AB - Strained semiconductor nanostructures can be used to make single-photon sources, detectors and photovoltaic devices, and could potentially be used to create quantum logic devices. The development of such applications requires techniques capable of nanoscale structural analysis, but the microscopy methods typically used to analyse these materials are destructive. NMR techniques can provide non invasive structural analysis, but have been restricted to strain-free semiconductor nanostructures because of the significant strain-induced quadrupole broadening of the NMR spectra. Here, we show that optically detected NMR spectroscopy can be used to analyse individual strained quantum dots. Our approach uses continuous-wave broadband radiofrequency excitation with a specially designed spectral pattern and can probe individual strained nanostructures containing only 1 * 10(5) quadrupole nuclear spins. With this technique, we are able to measure the strain distribution and chemical composition of quantum dots in the volume occupied by the single confined electron. The approach could also be used to address problems in quantum information processing such as the precise control of nuclear spins in the presence of strong quadrupole effects. PMID- 22922540 TI - Imaging the electrocatalytic activity of single nanoparticles. AB - The electrocatalytic properties of nanoparticles depend on their size, shape and composition. These properties are typically probed by measuring the total electrocatalytic reaction current of a large number of nanoparticles, but this approach is time-consuming and can only measure the average catalytic activity of the nanoparticles under study. However, the identification of new catalysts requires the ability to rapidly measure the properties of nanoparticles synthesized under various conditions and, ideally, to measure the electrocatalytic activity of individual nanoparticles. Here, we show that a plasmonic-based electrochemical current-imaging technique can simultaneously image and quantify the electrocatalytic reactions of an array of 1.6 * 10(5) platinum nanoparticles printed on an electrode surface, which could facilitate high-throughput screening of the catalytic activities of nanoparticles. We also show that the approach can be used to image the electrocatalytic reaction current and measure the cyclic voltammograms of single nanoparticles. PMID- 22922541 TI - Single-protein nanomechanical mass spectrometry in real time. AB - Nanoelectromechanical systems (NEMS) resonators can detect mass with exceptional sensitivity. Previously, mass spectra from several hundred adsorption events were assembled in NEMS-based mass spectrometry using statistical analysis. Here, we report the first realization of single-molecule NEMS-based mass spectrometry in real time. As each molecule in the sample adsorbs on the resonator, its mass and position of adsorption are determined by continuously tracking two driven vibrational modes of the device. We demonstrate the potential of multimode NEMS based mass spectrometry by analysing IgM antibody complexes in real time. NEMS based mass spectrometry is a unique and promising new form of mass spectrometry: it can resolve neutral species, provide a resolving power that increases markedly for very large masses, and allow the acquisition of spectra, molecule-by molecule, in real time. PMID- 22922542 TI - X-ray microtomography study to validate the efficacies of caries removal in primary molars by hand excavation and chemo-mechanical technique. AB - BACKGROUND/AIMS: Mechanical removal of carious dentine based on perceived hardness is subjective and tends to be excessively destructive; chemo-mechanical techniques have been proposed as being more objective and conservative. The aims of the present study are to use X-ray microtomography (XMT/micro-CT) to determine the three-dimensional mineral concentration distribution in sound, carious and excavated dentine using hand excavation (HE) and a chemo-mechanical, Carisolv (CS), removal technique for primary molars, and to compare the volume of sound dentine removed in order to validate the efficacies of these two techniques. METHODS: Twenty-one primary molars with open carious cavities were hemisected. The carious tissue in one half was then removed by HE and the other by CS. XMT scans were taken before and after caries removal. After alignment, subtracted XMT images from the two scans revealing the tissues removed were generated, from which mineral distributions were determined, and volumes of sound dentine removed by each technique were calculated. RESULTS: It was found that the sound dentine removed by HE and CS techniques accounted for 4.0 and 2.1% of total tissues removed, respectively. The mean cut-off linear attenuation coefficients at 40 keV to which HE and CS excavated to were 1.27 and 1.09 cm(-1), respectively. The corresponding Knoop hardness number for the cut-off for CS was 25 kg . mm(-2). CONCLUSION: It is concluded that using XMT, CS is validated to be more conservative than HE and preserves a layer of partially demineralised dentine with a mineral concentration > 0.97 g . cm(-3). PMID- 22922543 TI - Implementation and development of an automated, ultra-high-capacity, acoustic, flexible dispensing platform for assay-ready plate delivery. AB - Compound management faces the daily challenge of providing high-quality samples to drug discovery. The advent of new screening technologies has seen demand for liquid samples move toward nanoliter ranges, dispensed by contactless acoustic droplet ejection. Within AstraZeneca, a totally integrated assay-ready plate production platform has been created to fully exploit the advantages of this technology. This enables compound management to efficiently deliver large throughputs demanded by high-throughput screening while maintaining regular delivery of smaller numbers of compounds in varying plate formats for cellular or biochemical concentration-response curves in support of hit and lead optimization (structure-activity relationship screening). The automation solution, CODA, has the capability to deliver compounds on demand for single- and multiple concentration ranges, in batch sizes ranging from 1 sample to 2 million samples, integrating seamlessly into local compound and test management systems. The software handles compound orders intelligently, grouping test requests together dependent on output plate type and serial dilution ranges so that source compound vessels are shared among numerous tests, ensuring conservation of sample, reduced labware and costs, and efficiency of work cell logistics. We describe the development of CODA to address the customer demand, challenges experienced, learning made, and subsequent enhancements. PMID- 22922545 TI - Ischemic stroke on awakening: patients' characteristics, outcomes and potential for reperfusion therapy. AB - BACKGROUND: Reports on differences between patients with and without wake-up stroke are inconsistent. We studied the proportion, characteristics, and outcomes of wake-up ischemic stroke (IS) and estimated the number of potential candidates for reperfusion therapy in a national registry of hospitalized patients. METHODS: IS patients in all three National Acute Stroke ISraeli (NASIS) registry periods (2004, 2007, and 2010; 2 months each) were included. In-hospital neurological complications, poor functional outcome (death, modified Rankin scale >= 2, or discharge to a nursing home), and in-hospital mortality were the study outcomes. Risks of poor outcomes were estimated with logistic regression analysis. RESULTS: Wake-up IS was reported for 820/4,408 (18.6%) patients. Baseline characteristics were similar for patients with and without wake-up IS. ORs (95% CIs) for wake-up compared to non-wake-up IS were 1.2 (0.9-1.6) for neurological complications, 0.8 (0.7-0.98) for poor functional outcome, and 0.8 (0.5-1.2) for death. According to an estimated 20-40% prevalence of penumbra, wake-up stroke patients could add 3.7 7.4% to the number of patients potentially eligible for reperfusion therapy. CONCLUSIONS: Stroke on awakening is present in almost one fifth of IS patients. Characteristics and stroke outcomes are similar for patients with and without wake-up IS. Confirmation of a valid approach for the detection of wake-up stroke patients who can potentially benefit from reperfusion therapy is essential. PMID- 22922544 TI - Ageing and oxytocin: a call for extending human oxytocin research to ageing populations--a mini-review. AB - Interest in oxytocin has increased rapidly over the last decades. Consequently, quite a number of studies have addressed the influence of oxytocin on social stress, perception, cognition, and decision making in healthy adults as well as in clinical samples characterized by some form of social disturbance. Surprisingly little research on oxytocin has focused on ageing populations. This is particularly striking in two areas of study: the role of oxytocin in grandparents' behavior toward and bonding with their grandchildren and the effects of oxytocin on the neurocognitive processing of socioemotional stimuli. The current mini-review offers an overview of the literature on the involvement of oxytocin in parental behavior and neurocognitive functioning, and discusses the relevance of these findings to ageing individuals. As the literature shows that oxytocin is profoundly involved in parenting and in bonding throughout life, it is highly likely that oxytocin plays a role in grandparenting and bonding between grandparents and grandchildren as well. However, results obtained with younger adults may not be directly applicable to older individuals in yet another type of relationship. The possibility that age-related changes occur in the oxytocin system (which is at present unclear) must be taken into account. In addition, ageing impairs neurocognitive processes that are profoundly affected by oxytocin (including some aspects of memory and emotion recognition) and is associated with alterations in both structure and function of the amygdala, which is prominently involved in mediating effects of oxytocin. Research investigating the ageing oxytonergic system and studies focusing on the involvement of oxytocin in socioemotional neurocognitive processes and social behavior in elderly individuals, including grandparents, are therefore urgently needed. PMID- 22922547 TI - Pattern of injuries to neck structures in hanging-an autopsy study. AB - One hundred eighty-nine cases of known dead bodies brought for medicolegal autopsy with alleged history of hanging were studied at the Department of Forensic Medicine, State Medico Legal Institute, Government Medical College, Thiruvananthapuram, Kerala, India. All the findings noticed during detailed external examination and flap dissection of the neck were analyzed with special emphasis on correlation between the external and internal injuries on neck.There was a preponderance of males in the study group (70.9%), majority of them being middle-aged (64.9%). Among females, the major group was composed of adolescents and young adults (72.8%). Easily available materials were used as ligature materials. Soft materials such as saree, shawl, lungie, and so on were used as ligature by 47% of victims and hard materials such as coir rope, plastic rope, telephone cable, and so on were used by 29% of victims. Oblique ligature mark was noted in 94.2% of cases. The ligature mark was noncontinuous in 78% of cases. Horizontal ligature marks were noted in cases of partial hanging.Rupture of muscle fibers at the lower attachment of sternomastoid was seen in 19.6%, and carotid intimal tear was seen in 1.1% of cases. Fracture of hyoid bone at their greater horns was seen in 2.7% and thyroid cartilage in 5.3% of cases. Vertebral fracture and dislocation were noted between third and fourth cervical vertebrae in 1.6% of cases. Neck skeleton injuries were noted in persons older than 38 years. PMID- 22922548 TI - Re: article "angiocentric systemic granulomatosis" American Journal of Forensic Medicine and Pathology, June 2010. PMID- 22922549 TI - Nails in the brain. PMID- 22922550 TI - Estimation of the postmortem interval by analyzing potassium in the vitreous humor: could repetitive sampling enhance accuracy? AB - The relationship between the postmortem interval and the potassium concentration in the vitreous humor has been described by different authors. A limitation of most previous studies might be that all of the vitreous humor has been extracted in 1 sample from different subjects and that the sample was therefore inhomogeneous. In 32 traumatic deaths with known postmortem intervals, small quantities of vitreous humor have been sampled repetitively in 3-hour interval. The bodies were stored at 20 degrees C. The average concentrations of potassium in relation to the postmortem interval were 6.11 to 14.46 mmol/L. An equation that allows accurate prediction of the postmortem interval was established: postmortem interval (h) = 2.749 * [K] - 11.978. PMID- 22922551 TI - Multivisceral sarcoidosis: an unexpected finding in a water-related death. AB - Upon encountering a body submerged within or in close association with a watery environment, the temptation by the first responder may be to surmise that the death is probably an accidental drowning of some sort. The challenge, however, is to quickly move beyond such temptation, maintaining an open mind to other possibilities. Unearthing the circumstances surrounding a water-related death requires the collaborative efforts of groups of trained professionals including law enforcement officers, medicolegal death scene investigators, forensic scientists, and forensic pathologists. The forensic pathologist has the ultimate responsibility for the interpretation of all results arising from comprehensive autopsy and toxicological and other ancillary examinations within the context of all available investigative information, for the most accurate determination of cause and manner of death.A water-related death is presented in which investigation into the circumstances surrounding the death and ultimately comprehensive postmortem analysis lead to the discovery of multiorgan sarcoidosis and lack of supportive evidence of drowning. This in turn facilitated the proper classification of the manner of death as natural. PMID- 22922552 TI - Three nonlethal ligature strangulations filmed by an autoerotic practitioner: comparison of early agonal responses in strangulation by ligature, hanging, and manual strangulation. AB - Despite great advances in forensic sciences in the last decades, our knowledge of the pathophysiology of ligature strangulation is still largely based on old writings from the 19th and beginning of the 20th century. The study of filmed hangings by the Working Group on Human Asphyxia has contributed to a better understanding of the agonal responses to strangulation by hanging, and judo related studies have given some insight into the pathophysiology of manual strangulation, but the pathophysiology of ligature strangulation has remained largely unexplored so far. Three nonlethal strangulations filmed by an autoerotic practitioner are here presented. In these 3 ligature strangulations, the 35-year old man is sitting on a chair. A pair of pajama pants is rolled once around his neck, with the extremities of the pants falling down on each side of his chest. The man is pulling the extremities of the pants with both hands to apply compression on his neck. After losing consciousness, he ceases to pull on the ligature, and the pants slowly loosen around the neck. A few seconds later, he regains consciousness and gets up from the chair. In the 3 nonlethal ligature strangulations presented in this study, the loss of consciousness occurred in 11 seconds. The loss of consciousness was closely followed by the onset of convulsions (7-11 seconds). These results are compared with the early agonal responses documented in filmed hangings and judo studies. PMID- 22922553 TI - Homicidal deaths in the Western suburbs of Paris: a 15-year-study. AB - The aim of our study was to analyze the homicide pattern in the Western suburbs of Paris and its evolution between 1994 and 2008. All autopsy reports regarding homicides from the period January 1, 1994, to December 31, 2008, were retrospectively reviewed. Five hundred eleven homicide cases were selected of 4842 autopsy cases. The following data were recorded: assailants and victims characteristics, crime scene location, homicide motive, cause of death, and victim's postmortem toxicological results. Homicide rate steadily declined over the period at the exception of the number of homicide-suicide per year, which remained constant. Homicide victims remained unidentified after medicolegal investigations in 2% of the cases. Child and elder homicide cases represented, respectively, 10.7% and 8.2% of the cases. Offenders were male in 88% of the cases. Male and female assailants showed distinct homicide patterns: females were involved more frequently in familial quarrel and child abuse. They never killed a stranger and committed homicide exclusively in a private place with a predominance of sharp weapons. Males, in contrast, assaulted almost equally a stranger or an acquaintance, often in a public place with a predominance of firearm. Victim knew the assailant(s) in 57% of the cases. Homicides mostly took place at the residence of the assailant or the victim. Homicide motive was clearly determined in 71% of the cases. Argument was the most common motive in 44% of the cases. Sexual assault was rarely found (10 cases). Gunshot wounds were the most common cause of death (37%), followed by stab wounds (27%), blunt trauma (19%), and asphyxia (13%). A decrease of gunshot wounds as a cause of death was found over the studied period. Alcohol was the most common toxic detected in blood of the victim, in 48.5% of the cases when toxicological results were available. Blood alcohol concentration ranged from 1 to 500 mg/dL with a mean value of 150 mg/dL. PMID- 22922546 TI - Phylogenetic and population genetic analyses of Phaeosphaeria nodorum and its close relatives indicate cryptic species and an origin in the Fertile Crescent. AB - The origin of the fungal wheat pathogen Phaeosphaeria nodorum remains unclear despite earlier intensive global population genetic and phylogeographical studies. We sequenced 1683 bp distributed across three loci in 355 globally distributed Phaeosphaeria isolates, including 74 collected in Iran near the center of origin of wheat. We identified nine phylogenetically distinct clades, including two previously unknown species tentatively named P1 and P2 collected in Iran. Coalescent analysis indicates that P1 and P2 are sister species of P. nodorum and the other Phaeosphaeria species identified in our analysis. Two species, P. nodorum and P. avenaria f. sp. tritici 1 (Pat1), comprised ~85% of the sampled isolates, making them the dominant wheat-infecting pathogens within the species complex. We designed a PCR-RFLP assay to distinguish P. nodorum from Pat1. Approximately 4% of P. nodorum and Pat1 isolates showed evidence of hybridization. Measures of private allelic richness at SSR and sequence loci suggest that the center of origin of P. nodorum coincides with its host in the Fertile Crescent. We hypothesize that the origin of this species complex is also in the Fertile Crescent, with four species out of nine found exclusively in the Iranian collections. PMID- 22922555 TI - Long-term surgical outcome of mitral valve repair in infants and children with Shone's anomaly. AB - OBJECTIVES: Having assembled information on a large series of patients with Shone's anomaly with the longest follow-up, we studied the operative results and long-term outcome of mitral valve (MV) repair techniques performed to correct the left ventricular inflow tract lesions of this congenital anomaly. METHODS: Between 1986 and 2011, 45 infants and children [mean age 5.16 +/- 5.0 (median 3.9; range 2 months to 16.8 years] underwent surgical correction of Shone's anomaly. Left ventricular outflow tract obstructive lesions consisted of coarctation of the aorta, found in 89%, subaortic stenosis due to fibromuscular hypertrophy in 71% and subvalvular membrane in 51%. Left ventricular inflow tract obstructions concentrated on the mitral valve included mitral ring in all cases and the gamut of small and narrowed mitral orifice, commissural fusion, dysplastic or thickened leaflets, shortened and fused chordae, fibrous obliteration of interchordal spaces, underdeveloped papillary muscles, parachute valve, and supravalvular mitral ring-all contributing to mitral stenosis. RESULTS: MV repair was performed using commissurotomy, division of chordae tendinae, papillary muscle splitting and fenestration, and resection of mitral ring, applied according to the presenting morphology in patients with either previously-corrected or concomitant correction of the left-sided obstructive lesions. Postoperative echocardiography showed absence of MV stenosis and immediate improvement of symptoms, except in a 3-month-old infant who died 18 days postoperatively due to myocardial failure. During the 23-year follow-up, 23 patients underwent repeat MV repair and one underwent MV replacement after failed attempts at repair. Mean duration of follow-up was 17.5 +/- 1.5 years (range 6.4 22.7 years). Freedom from reoperation was 97.6 +/- 2.4%, 89.3 +/- 5.1%, 77.1 +/- 7.2%, 72.0 +/- 8.3% and 52.8 +/- 11.8%, at 30 days, 1, 5, 10 and 15 years postoperatively, respectively Cumulative survival rate was 97.6 +/- 2.4%, 92.3 +/ 4.3%, 83.8 +/- 6.1%, 75.7 +/- 7.8% and 70.3 +/- 8.9%, at 30 days, 1, 5, 10 and 15 years postoperatively, respectively. Mortality unrelated to valve repair accounted for nine deaths (20%). Age at operation, severity of mitral abnormalities and concomitant left ventricular outflow tract lesions proved to be independent risk factors for reoperation and mortality (P < 0.05). CONCLUSIONS: Long-term functional outcome of mitral valve repair in children with Shone's anomaly is satisfactory. Repeat MV repair and/or replacement may be deemed necessary during the course of follow-up. PMID- 22922554 TI - Benefits of intensive treadmill exercise training on cardiorespiratory function and quality of life in patients with pulmonary hypertension. AB - BACKGROUND: Pulmonary hypertension (PH) restricts the ability to engage in physical activity and decreases longevity. We examined the impact of aerobic exercise training on function and quality of life in patients with World Health Organization group 1 PH. METHODS: Patients were randomized to a 10-week education only (EDU) or education/exercise combined (EXE) group. The exercise program consisted of 24-30 sessions of treadmill walking for 30-45 min per session at 70% to 80% of heart rate reserve. Outcome variables included changes in 6-min walk test (6MWT) distance, time to exercise intolerance, peak work rate (WR) from a cardiopulmonary treadmill test, and quality-of-life measures, including the Short Form Health Survey, version 2 (SF-36v2) and Cambridge Pulmonary Hypertension Outcome Review (CAMPHOR). RESULTS: Data are presented as mean SD. Twenty-three women (age, 54 11 years; BMI, 31 7 kg/m 2 ) were randomized to the EDU (n 5 13) or EXE (n 5 10) groups. Following 10 weeks of intervention, patients in the EXE group demonstrated an improvement in 6MWT distance (56 45 m; P 5 .002), increased time to exercise intolerance (1.9 1.3 min; P 5 .001), and peak WR (26 23 W; P 5 .004). Additionally, the EXE group scored significantly ( P , .050) better on six of the eight scales on SF-36v2, and fi ve of the six scales on CAMPHOR. In contrast, no significant improvement was observed for any of the outcome measures following EDU. No adverse events were noted in either group. CONCLUSION: Ten weeks of brisk treadmill walking improved 6MWT distance, cardiorespiratory function, and patient-reported quality of life in female patients with group 1 PH. PMID- 22922556 TI - Evidences for intertypic and intratypic recombinant events in EV71 of hand, foot and mouth disease during an epidemic in Hubei Province, China, 2011. AB - Humane enterovirus 71 (HEV 71) is a common contagious agent of hand, foot and mouth disease (HFMD) which is normally mild but can caused deaths and severe neurological complications. In April 2011, an unpredicted HFMD outbreak in Xiangyang City of Hubei Province in China resulted in a high aggregation of HFMD cases including fatal cases and many severe cases. In this study, 71 clinical specimens were collected according to the different symptoms and RNA extraction and RT-PCR amplification were performed immediately. Laboratory testing and genetic analyses were used to identify the casual pathogen of this outbreak. HEV71 was confirmed as the etiological pathogen of the outbreak. Similarity and phylogenetic analyses of the VP1 gene of HEV71 from Xiangyang showed that they belong to C4a cluster of the C4 subgenotype. Intertypic recombinant events were found in the 3D region between the Xiangyang HEV71 strains and Coxsackievirus A16 (CV-A16). Intratypic recombination was found in the 3D region between two same subgenotypic Xiangyang HEV71 strains in this outbreak. It is suggested that these recombination events played important roles in the emergence of the various HEV 71 subgenotypes and different type of recombination of HEV71 might exist in one outbreak which might be the reason for the different virulent HEV71 strains in an outbreak. PMID- 22922557 TI - Acute stress reactions and associated factors in the help-seekers after the L'Aquila earthquake. AB - BACKGROUND: The assessment of acute stress reactions and psychiatric symptomatology shortly after the occurrence of a traumatic catastrophic event, like an earthquake, is essential for implementing relief activities and for the identification of the long-term aftermath. The aim of our study was to assess the psychological distress and the occurrence of acute stress disorder (ASD) among individuals seeking help at the General Hospital Psychiatric Unit at San Salvatore Hospital following the earthquake at L'Aquila. Factors (sociodemographic, coping strategies, event-related and postevent variables) associated with the acute stress reactions were also assessed. METHODS: For the first 4 weeks following the earthquake, 122 help-seekers were assessed with a checklist of traumatic-event-related variables. Measurement instruments included the Stanford Acute Stress Reaction Questionnaire (SASRQ) for the detection of ASD according to DSM-IV criteria, the 12-item General Health Questionnaire (GHQ-12) for assessing psychological distress, and the Brief Cope questionnaire for assessing coping strategies. RESULTS: Despite the high level of psychological distress (GHQ-12 >=20, cut-off value) found in 65.6% of the subjects, only 6 subjects (4.9%) could be considered affected by 'full' ASD, whereas 48 subjects (39.3%) could be considered affected by 'partial' ASD, which is defined as showing at least one symptom on each DSM-IV criterion as evidenced by scoring higher than 3 on each SASRQ scale. The strongest predictor of traumatic stress reactions among all the predictor variables included in our study was having been trapped/injured under rubble during the earthquake, and among earthquake stressors (explaining 20% of variance in our model), a weaker predictor was the loss of personal privacy because of home displacement. In our model, more variance (39%) was explained when individual psychopathological variables and coping styles were also included as predictors. Showing coping strategies as exhibiting 'behavioural disengagement' or 'requesting emotional support from others' were found to increase the likelihood of a positive estimate of being an 'ASD case', while the adoption of an 'acceptance' coping style seemed to reduce the likelihood of the positive estimate of being an 'ASD case'. CONCLUSIONS: This study underlines the importance of identifying ASD subsyndromal cases and taking appropriate intervention/prevention measures that focus on giving psychological support to individuals trapped/injured under rubble, showing a low acceptance of reality. A relevant underestimated source of distress was the dislocation in large accommodation settings (such as large tent camps) in which individuals lack privacy. PMID- 22922558 TI - A single-day paradigm of self-regulated human cocaine administration. AB - Prior work by our group has shown the feasibility, safety, and validity of a multi-day, multi-dose paradigm of self-regulated cocaine administration in humans. The current work sought to consolidate these methods in a single-day design focused on reducing logistical complexity, decreasing research burden to human subjects, and increasing suitability for medication development designs. METHODS: Eleven experienced cocaine users participated in a 6-hour, single-day design, consisting of one safety/eligibility and three experimental cocaine periods (during which subjects were allowed to self-administer 8, 16, and 32 mg/70 kg cocaine doses under a fixed-ratio 1:5 minute timeout schedule). Changes in cocaine-induced cardiovascular response, self-administration behavior, and subjective effects were assessed. RESULTS: Procedures were well tolerated by participants, and no significant adverse events were noted. Significant (p < 0.05), changes in measures of cocaine self-administration (e.g., responses, infusions, interinfusion intervals, consumption, and plasma levels), cardiovascular response (HR), and subjective effects ("high") were observed. In contrast, cocaine-induced increases in other vital signs (e.g., SBP, DBP) and subjective effect measures (e.g., paranoia) did not differ between doses. CONCLUSIONS: These data support the safety, tolerability and validity of our single-day design. Depending on the application, such methods may afford advantages for assessing the self-regulation of cocaine administration behavior in humans (e.g., including medication development designs). PMID- 22922559 TI - Facultative to strict anaerobes ratio in the preterm infant microbiota: a target for intervention? AB - During recent years there has been an increasing interest on the development of strategies for modulating the process of microbiota establishment in preterm infants. For successfully developing of such strategies, a detailed knowledge of the microbiota establishment process in these infants is needed. In a previous study we evidenced clear alterations in the process of microbiota establishment in preterm newborns when compared with a control group of full-term breast-fed infants. Here we have analyzed these data more in depth, corroborating a reduced proportion of strict anaerobes with respect to facultatives in the fecal microbiota of preterm infants. The potential benefits, as well as the side effects, of strategies aimed at counterbalancing this alteration in the facultative to strict anaerobes ratio are discussed in this addendum. PMID- 22922560 TI - Mechanism of co-nanoprecipitation of organic actives and block copolymers in a microfluidic environment. AB - Microreactors have been shown to be a powerful tool for the production of nanoparticles (NPs); however, there is still a lack of understanding of the role that the microfluidic environment plays in directing the nanoprecipitation process. Here we investigate the mechanism of nanoprecipitation of block copolymer stabilized organic NPs using a microfluidic-based reactor in combination with computational fluid dynamics (CFD) modelling of the microfluidic implementation. The latter also accounts for the complex interplay between molecular and hydrodynamic phenomena during the nanoprecipitation process, in order to understand the hydrodynamics and its influence on the NP formation process. It is demonstrated that the competitive reactions result in the formation of two types of NPs, i.e., either with or without loading organic actives. The obtained results are interpreted by taking into consideration a new parameter representing the mismatching between the aggregations of the polymers and actives, which plays a decisive role in determining the size and polydispersity of the prepared hybrid NPs. These results expand the current understanding of the co-nanoprecipitation mechanism of active and block copolymer stabilizer, and on the role exerted by the microfluidic environment, giving information that could be translated to the emerging fields of microfluidic formation of NPs and nanomedicine. PMID- 22922561 TI - Formation of the death domain complex between FADD and RIP1 proteins in vitro. AB - Fas-associated death domain (FADD) protein is an adapter molecule that bridges the interactions between membrane death receptors and initiator caspases. The death receptors contain an intracellular death domain (DD) which is essential to the transduction of the apoptotic signal. The kinase receptor-interacting protein 1 (RIP1) is crucial to programmed necrosis. The cell type interplay between FADD and RIP1, which mediates both necrosis and NF-kappaB activation, has been evaluated in other studies, but the mechanism of the interaction of the FADD and RIP1 proteins remain poorly understood. Here, we provided evidence indicating that the DD of human FADD binds to the DD of RIP1 in vitro. We developed a molecular docking model using homology modeling based on the structures of FADD and RIP1. In addition, we found that two structure-based mutants (G109A and R114A) of the FADD DD were able to bind to the RIP1 DD, and two mutations (Q169A and N171A) of FADD DD and four mutations (G595, K596, E620, and D622) of RIP1 DD disrupted the FADD-RIP1 interaction. Six mutations (Q169A, N171A, G595, K596, E620, and D622) lowered the stability of the FADD-RIP1 complex and induced aggregation that structurally destabilized the complex, thus disrupting the interaction. PMID- 22922562 TI - Diagnostic accuracy of fractional flow reserve from anatomic CT angiography. AB - CONTEXT: Coronary computed tomographic (CT) angiography is a noninvasive anatomic test for diagnosis of coronary stenosis that does not determine whether a stenosis causes ischemia. In contrast, fractional flow reserve (FFR) is a physiologic measure of coronary stenosis expressing the amount of coronary flow still attainable despite the presence of a stenosis, but it requires an invasive procedure. Noninvasive FFR computed from CT (FFR(CT)) is a novel method for determining the physiologic significance of coronary artery disease (CAD), but its ability to identify ischemia has not been adequately examined to date. OBJECTIVE: To assess the diagnostic performance of FFR(CT) plus CT for diagnosis of hemodynamically significant coronary stenosis. DESIGN, SETTING, AND PATIENTS: Multicenter diagnostic performance study involving 252 stable patients with suspected or known CAD from 17 centers in 5 countries who underwent CT, invasive coronary angiography (ICA), FFR, and FFR(CT) between October 2010 and October 2011. Computed tomography, ICA, FFR, and FFR(CT) were interpreted in blinded fashion by independent core laboratories. Accuracy of FFR(CT) plus CT for diagnosis of ischemia was compared with an invasive FFR reference standard. Ischemia was defined by an FFR or FFR(CT) of 0.80 or less, while anatomically obstructive CAD was defined by a stenosis of 50% or larger on CT and ICA. MAIN OUTCOME MEASURES: The primary study outcome assessed whether FFR(CT) plus CT could improve the per-patient diagnostic accuracy such that the lower boundary of the 1-sided 95% confidence interval of this estimate exceeded 70%. RESULTS: Among study participants, 137 (54.4%) had an abnormal FFR determined by ICA. On a per patient basis, diagnostic accuracy, sensitivity, specificity, positive predictive value, and negative predictive value of FFR(CT) plus CT were 73% (95% CI, 67% 78%), 90% (95% CI, 84%-95%), 54% (95% CI, 46%-83%), 67% (95% CI, 60%-74%), and 84% (95% CI, 74%-90%), respectively. Compared with obstructive CAD diagnosed by CT alone (area under the receiver operating characteristic curve [AUC], 0.68; 95% CI, 0.62-0.74), FFR(CT) was associated with improved discrimination (AUC, 0.81; 95% CI, 0.75-0.86; P < .001). CONCLUSION: Although the study did not achieve its prespecified primary outcome goal for the level of per-patient diagnostic accuracy, use of noninvasive FFR(CT) plus CT among stable patients with suspected or known CAD was associated with improved diagnostic accuracy and discrimination vs CT alone for the diagnosis of hemodynamically significant CAD when FFR determined at the time of ICA was the reference standard. PMID- 22922563 TI - Comparing hippocampal atrophy in Alzheimer's dementia and dementia with lewy bodies. AB - BACKGROUND/AIMS: Dementia with Lewy bodies (DLB) and Alzheimer's disease (AD) are the two most common neurodegenerative dementias. During the early stages, clinical distinction between them is often challenging. Our objective is to compare hippocampal atrophy patterns in mild AD and mild DLB. We hypothesized that DLB subjects have milder hippocampal atrophy relative to AD subjects. METHODS: We analyzed the T1-weighted magnetic resonance imaging data from 113 subjects: 55 AD, 16 DLB and 42 cognitively normal elderly (normal controls, NC). Using the hippocampal radial distance technique and multiple linear regression, we analyzed the effect of clinical diagnosis on hippocampal radial distance, while adjusting for gender and age. Three-dimensional statistical maps were adjusted for multiple comparisons using permutation-based statistics with a threshold of p < 0.01. RESULTS: Compared to NC, AD exhibited significantly greater atrophy in the cornu ammonis (CA)1, CA2-3 and subicular regions bilaterally while DLB showed left-predominant atrophy in the CA1 region and subiculum. Compared directly, AD and DLB did not reveal statistically significant differences. CONCLUSION: Hippocampal atrophy, while present in mildly impaired DLB subjects, is less severe than atrophy seen in mildly impaired AD subjects, when compared to NC. Both groups show predominant atrophy of the CA1 subfield and subiculum. PMID- 22922565 TI - Can we extend thrombolytic treatment for wake-up stroke?. PMID- 22922566 TI - Unusual aortic valve anomaly in the fetus: a case report. AB - Aortic valve anomalies in fetal life usually concern aortic valve stenosis, in severe forms associated to left ventricular impairment - endocardial fibroelastosis and mitral valve insufficiency. Isolated aortic regurgitation in utero is infrequent and is usually considered to be due to a rare anomaly: aorto left ventricular tunnel. We describe an unusual case of fetal aortic valve anomaly with severe dysplasia, with a marked regurgitant flow through the aortic valve, passing in a retrograde way from the duct, associated with a marked left ventricular endocardial fibroelastosis and dysfunction, resulting in the fatal outcome of the case. PMID- 22922564 TI - Efficacy of mycophenolate mofetil in adolescent patients with lupus nephritis: evidence from a two-phase, prospective randomized trial. AB - The safety and efficacy of mycophenolate mofetil (MMF) were evaluated in adolescent patients with systemic lupus erythematosus and active or active/chronic class III-V lupus nephritis. During the 24-week induction phase, patients were randomized to oral MMF (target dose 3.0 g/day) or intravenous cyclophosphamide (IVC) (0.5-1.0 g/m(2)/month), plus prednisone. Response was defined as a decrease in 24-hour urine protein:creatinine ratio (P:Cr) to < 3 in patients with baseline nephrotic range proteinuria, or by >= 50% if subnephrotic baseline proteinuria, and stabilization (+/- 25%) or improvement in serum creatinine. In the 36-month maintenance phase, induction therapy responders were randomized 1:1 to MMF (1.0 g twice daily) or oral azathioprine (AZA) (2 mg/kg/day), plus prednisone. In the induction phase, 10 patients received MMF and 14 received IVC; 15 (62.5%) achieved treatment response (MMF, 7 (70%); IVC, 8/15 (57.1%); p = 0.53, odds ratio (95% confidence interval) 2.0 (0.2, 15.5)). There was a non-statistically significant difference in maintenance of response to MMF (7/8; 87.5%) versus AZA (3/8; 37.5%). Seven patients withdrew (MMF, 2; AZA, 5). During both phases, rates of serious adverse events were similar in both arms. During both phases treatment response with MMF was as effective as the comparator. PMID- 22922567 TI - 450K-array analysis of chronic lymphocytic leukemia cells reveals global DNA methylation to be relatively stable over time and similar in resting and proliferative compartments. AB - In chronic lymphocytic leukemia (CLL), the microenvironment influences gene expression patterns; however, knowledge is limited regarding the extent to which methylation changes with time and exposure to specific microenvironments. Using high-resolution 450K arrays, we provide the most comprehensive DNA methylation study of CLL to date, analyzing paired diagnostic/follow-up samples from IGHV mutated/untreated and IGHV-unmutated/treated patients (n=36) and patient-matched peripheral blood and lymph node samples (n=20). On an unprecedented scale, we revealed 2239 differentially methylated CpG sites between IGHV-mutated and unmutated patients, with the majority of sites positioned outside annotated CpG islands. Intriguingly, CLL prognostic genes (for example, CLLU1, LPL, ZAP70 and NOTCH1), epigenetic regulator (for example, HDAC9, HDAC4 and DNMT3B), B-cell signaling (for example, IBTK) and numerous TGF-beta and NF-kappaB/TNF pathway genes were alternatively methylated between subgroups. Contrary, DNA methylation over time was deemed rather stable with few recurrent changes noted within subgroups. Although a larger number of non-recurrent changes were identified among IGHV-unmutated relative to mutated cases over time, these equated to a low global change. Similarly, few changes were identified between compartment cases. Altogether, we reveal CLL subgroups to display unique methylation profiles and unveil methylation as relatively stable over time and similar within different CLL compartments, implying aberrant methylation as an early leukemogenic event. PMID- 22922568 TI - Are ARID5B and IKZF1 polymorphisms also associated with childhood acute myeloblastic leukemia: the ESCALE study (SFCE)? PMID- 22922569 TI - Focus. PMID- 22922570 TI - Micropatterned stretching system for the investigation of mechanical tension on neural stem cells behavior. AB - In this study, we developed a feasible and reliable stretching platform combined with photolithography and microfluidic techniques to investigate the effect of directional tensile force and guiding microchannel on neural stem cell (NSC) behavior. Different stretching modes and culture conditions were conducted to investigate the mechanoresponse of NSCs on micropatterned substrate and to verify the effects of tension on NSCs maturation, axon sprouting, neurite outgrowth and orientation. From the results, we found that neurite extension and axon elongation were significantly enhanced and neurites were more directional orientated to parallel direction as stretching was experienced. The mechanical tension apparently influenced NSCs differentiation toward neuronal cells under stretching condition. The neuronal maturity also showed a significant difference when compared with parallel and vertical micropatterned channels. It is suggested that mechanical tension not only can guide neurites orientation and direction, but also promote their elongation length and trigger neural stem cells differentiation into mature neuronal cells. FROM THE CLINICAL EDITOR: This group of investigators report the development of a feasible and reliable stretching platform combined with photolithography and microfluidic techniques to investigate the effects of directional tensile force and guiding microchannel on neural stem cell behavior. They demonstrate that neurite extension and axon elongation could be significantly enhanced, and neuronal maturity can also be improved. PMID- 22922571 TI - Nanoassemblies from homostructured polypeptides as efficient nanoplatforms for oral drug delivery. AB - The assembly of homostructured polypeptides bearing various side groups into well defined nanostructures was presented, with their size and topology mainly dominated by the chemical structure and molecular weight of peptides. Pharmacokinetic and pharmacodynamic studies based on rat models suggested these newly constructed nanoassemblies with low cytotoxicity may function as novel nanoplatforms to efficiently and safely deliver therapeutics to achieve better efficacy but lower side effects. Other applications in biomedical fields, such as biotechnology, medical imaging, and tissue engineering, may also be expected. FROM THE CLINICAL EDITOR: This research team investigated the assembly of homostructured polypeptides bearing various side groups into well-defined nanostructures, and demonstrated low cytotoxicity in rat disease models, suggesting that these novel nanoplatforms may safely and efficiently deliver therapeutics with low side effects. PMID- 22922572 TI - Heat shock protein 70 gene polymorphisms in sudden sensorineural hearing loss. AB - BACKGROUND: Heat shock proteins protect cells and tissues against different types of damage. Previous studies have revealed that the serum level of heat shock protein 70 (HSP70) increases in sudden sensorineural hearing loss (SSNHL) patients. We hypothesized that genetic variants of the HSP70 gene are associated with susceptibility to SSNHL. METHODS: We conducted a case-control study with 160 SSNHL cases and 178 controls. Three tagging single nucleotide polymorphisms (SNPs) were selected. The genotypes were determined using TaqMan technology. Hardy-Weinberg equilibrium was tested for each SNP, and genetic effects were evaluated according to three inheritance modes. A haplotype analysis was also performed. RESULTS: All three SNPs were in Hardy-Weinberg equilibrium. The CT genotype of rs2075800 exhibited an adjusted odds ratio of 0.59 (95% confidence interval 0.37-0.94; p = 0.027). The T allele of SNP rs2075800 was associated with SSNHL under the dominant model (p = 0.019; odds ratio 0.59). Haplotype analysis of the three SNPs demonstrated that the haplotype TGC (rs2075800/rs1043618/rs2763979) was statistically significant (p = 0.0137). CONCLUSIONS: These results suggest that HSP70 gene polymorphisms influence the susceptibility to the development of SSNHL in the Taiwanese population. PMID- 22922573 TI - The synergistic effects of low-dose irinotecan and TRAIL on TRAIL-resistant HT-29 colon carcinoma in vitro and in vivo. AB - Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a member of the tumor necrosis factor superfamily that induces apoptosis in a broad range of human cancer cell lines while sparing most normal cell types. However, many tumors remain resistant to treatment with TRAIL. In this study, we investigated the synergistic effects of low-dose irinotecan (CPT-11) and TRAIL on TRAIL resistant HT-29 colon carcinoma cells and explored potential mechanisms of apoptosis. Cell viability was analyzed by sulforhodamine B (SRB) assay and apoptosis was evaluated by flow cytometry and DNA ladder assay. The mRNA expression of TRAIL receptors death receptor 4 (DR4) and DR5 were determined by reverse transcription polymerase chain reaction (RT-PCR). The changes of Bax and caspase-9 in protein levels were also detected by western blotting. Tumor growth curves were depicted and tumor inhibitive rates were calculated. Our results showed that the antitumor effect of TRAIL could be enhanced significantly by low dose CPT-11 on TRAIL-resistant HT-29 cells both in vitro and in vivo. The synergistic apoptotic effect of CPT-11 and TRAIL was proposed to be mediated by upregulating DR5 mRNA expression and increasing expression of Bax and caspase-9 proteins. The data suggest that the combination of TRAIL with low-dose CPT-11 could be an effective therapeutic approach for HT-29 colon carcinoma. PMID- 22922574 TI - Fcgamma receptor polymorphisms do not predict response to intravenous immunoglobulin in myasthenia gravis. AB - We studied 63 patients with myasthenia gravis (MG) requiring treatment with intravenous immunoglobulin, to determine if polymorphisms within the FCgammaR2A (rs1801274), FCgammaR2B (rs1050501), FCgammaR3A (rs396991), and FCgammaR3B (NA1/NA2) genes are correlated with response to treatment. There was no significant difference in any of the polymorphisms studied between responders and nonresponders. Patients with the FCgammaR2B-232I/I polymorphism had higher disease severity measured by the quatitative myasthenia gravis score (QMGS). There was no difference in the distribution of the FCgammaR2B-232 polymorphisms between the patients and 90 healthy controls. The finding of greater disease severity in patients with the FCgammaR2B-232I/I polymorphism requires confirmation in a larger population of patients with myasthenia gravis. PMID- 22922575 TI - Facial onset sensorimotor neuronopathy syndrome: a case series. AB - OBJECTIVE: Facial onset sensorimotor neuronopathy (FOSMN) is a recently described neurological syndrome characterized by slow onset of facial sensory abnormalities and subsequent development of motor deficits. Except for 1 patient, FOSMN has so far been identified only in men. METHODS: We describe a case series of 3 women with FOSMN. We report their clinical, laboratory, and neurophysiological findings. RESULTS: The age of onset ranged from 39 to 72 years (mean, 60 years) with presentation 4-7 years after symptom onset. The first symptom was slowly progressive facial numbness, which was followed years later by dysphagia and impaired corneal reflexes. Dysarthria occurred in 2 patients, and mild arm weakness was noted in 2. Muscle stretch reflexes were increased in 1 patient, and in another case, arm sensation was reduced. Laboratory studies were unremarkable, and magnetic resonance imaging of the brain in 3 patients and of the cervical spine in 2 patients was normal. Nerve conduction studies showed reduced leg compound muscle action potential amplitudes in 1 patient and asymmetrically reduced arm sensory nerve action potentials in another case. In 2 patients, electromyography showed widespread active denervation in arm muscles in conjunction with the involvement of leg muscles in 1 case and the tongue in the other patient. We identified chronic neurogenic motor unit action potentials in the genioglossus muscle of all 3 cases while facial EMG performed in case 3 showed similar findings. Blink reflexes were abnormal in all patients. We treated 1 patient with high-dose intravenous methylprednisolone followed by intravenous immunoglobulin without any improvement, and she required percutaneous endoscopic gastrostomy (PEG) tube placement. CONCLUSIONS: This is the first case series describing 3 women with the FOSMN syndrome. We expand phenotype of FOSMN to include upper motor neuron signs and normal arm sensory nerve action potentials. PMID- 22922576 TI - Copper levels in patients with celiac neuropathy. AB - OBJECTIVE: Neurological complications of celiac disease (CD) include neuropathy, myeloneuropathy, and cerebellar degeneration. The cause of neuropathy in patients with CD is not known. Prior publications describe copper deficiency in CD patients with myeloneuropathy and neuropathy and posit that hypocupremia is the cause of these neurological conditions. However, based on our clinical experience, we hypothesized that CD patients with polyneuropathy are not deficient in copper. METHODS: Patients who met diagnostic criteria for CD and peripheral neuropathy were included. We reviewed the patient's records, including assessment of serum copper level and other clinical parameters. RESULTS: Eighteen patients met inclusion criteria. Sixteen patients (89%) had normal copper levels, 2 had mild hypercupremia, and none had low copper levels. Of the 18 patients, 4 (22%) had large fiber neuropathy and 14 (78%) had a small fiber neuropathy. CONCLUSIONS: No patient in this study showed hypocupremia. We are unable to demonstrate a relationship between our CD patients with Peripheral Neuropathy and copper deficiency. PMID- 22922577 TI - Isolated mononeuropathy multiplex--a rare manifestation of intravascular large B cell lymphoma. AB - Intravascular large B-cell lymphoma, also known as angiotrophic large cell lymphoma, is a rare disorder where neoplastic lymphoid cells proliferate within the walls of small- to medium-sized blood vessels. Peripheral neuropathy and other neurological manifestations, including stroke and dementia, are common, but cases of isolated multiple mononeuropathies in the absence of systemic symptoms are distinctly rare. We present an unusual case of biopsy-proved angiotrophic large cell lymphoma presenting exclusively with multiple mononeuropathies. PMID- 22922578 TI - Focal hypokalemic paralysis: report of 2 cases and review of the literature. AB - Hypokalemia is one of the most frequent electrolytic disturbances encountered in clinical practice. It usually presents with symmetrical generalized muscle weakness and, on occasions, with arrhythmias. There are scarce reports of cases presenting with asymmetric or focal weakness in the literature and no systematic reviews on the subject. Therefore, our aim is to describe 2 cases of hypokalemic paralysis that presented as monoparesis and to review the literature on focal hypokalemic paralysis. Hypokalemic paralysis is usually reversible. However, it can be fatal if the diagnosis and treatment are delayed. It is important to take into account this presentation because failure to recognize it could lead to misdiagnosis, delaying the adequate treatment. PMID- 22922579 TI - Malignant peripheral nerve sheath tumor: the utility of fascicular biopsy and teased fiber studies. AB - We present the case of a 67-year-old man with a malignant peripheral nerve sheath tumor (MPNST) affecting the brachial plexus. He presented with progressive right upper extremity paresthesias, numbness, weakness, and severe pain. Nerve conduction studies/electromyography demonstrated a right lower and middle trunk predominant brachial plexopathy. Three-tesla magnetic resonance imaging of the brachial plexus showed a soft tissue mass with central necrosis and cystic changes and irregular contrast enhancement. Positron emission tomography showed increased fluorodeoxyglucose uptake within the mass. Targeted fascicular nerve biopsy revealed hypercellular tumor, featuring atypical cells with mitotic figures and limited immunoreactivity for S-100 protein. The findings were those of an MPNST. The effects on the variably involved fascicles were also seen in teased fiber preparations, paraffin sections, and through immunohistochemistry. This case illustrates the presentation of this rare type of tumor, and characteristic neuroimaging and pathologic features of MPNSTs. PMID- 22922580 TI - Orthostatic intolerance in multifocal acquired demyelinating sensory and motor neuropathy. AB - We report a patient with orthostatic intolerance and syncope as a major clinical manifestation of an acquired multifocal neuropathy with the clinical, electrodiagnostic, and cerebrospinal fluid features of multifocal acquired demyelinating sensory and motor neuropathy or the Lewis-Sumner syndrome. Immunomodulatory therapy led to clinical remission of both somatic and autonomic signs and symptoms. We are unaware of a previous description of symptomatic dysautonomia in this disorder. PMID- 22922581 TI - Role of activity-dependent conduction block in the diagnosis of primary demyelinating polyneuropathy. AB - Motor conduction block is one of the well-known neurophysiologic features of primary demyelinating polyneuropathy. In contrast, activity-dependent conduction block (motor conduction block after brief maximum voluntary contraction) is a "rare" neurophysiologic finding in primary demyelinating polyneuropathy. We are reporting the first known case of multifocal acquired demyelinating sensory and motor polyneuropathy with a well-documented activity-dependent conduction block of the ulnar nerve at the forearm segment that transformed into a typical motor response with abnormal temporal dispersion. PMID- 22922582 TI - Piriformis syndrome surgery causing severe sciatic nerve injury. AB - Piriformis syndrome is a controversial entrapment neuropathy in which the sciatic nerve is thought to be compressed by the piriformis muscle. Two patients developed severe left sciatic neuropathy after piriformis muscle release. One had a total sciatic nerve lesion, whereas the second had a predominantly high common peroneal nerve lesion. Follow-up studies showed reinnervation of the hamstrings only. We conclude that piriformis muscle surgery may be hazardous and result in devastating sciatic nerve injury. PMID- 22922583 TI - Sheet fitting palsy. AB - A 73-year-old woman developed an acute thrombosis of a persistent median artery following a Sisyphean struggle with a poorly fitted bedsheet. Ultrasound was able to diagnose the problem in a case where precise localization by electrodiagnostic testing was difficult. PMID- 22922585 TI - Consistent neurodegeneration and its association with clinical progression in Huntington's disease: a coordinate-based meta-analysis. AB - BACKGROUND: The neuropathological hallmark of Huntington's disease (HD) is progressive striatal loss starting several years prior to clinical onset. In the past decade, whole-brain magnetic resonance imaging (MRI) studies have provided accumulating evidence for widely distributed cortical and subcortical atrophy in the early course of the disease. OBJECTIVE: In order to synthesize current morphometric MRI findings and to investigate the impact of clinical and genetic features on structural changes, we performed a coordinate-based meta-analysis of voxel-based morphometry (VBM) studies in HD. METHODS: Twenty HD samples derived from 17 studies were integrated in the analysis comparing a total of 685 HD mutation carriers [345 presymptomatic (pre-HD) and 340 symptomatic (symp-HD) subjects] and 507 controls. Convergent findings across studies were delineated using the anatomical likelihood estimation approach. Effects of genetic and clinical parameters on the likelihood of observing VBM findings were calculated by means of correlation analyses. RESULTS: Pre-HD studies featured convergent evidence for neurodegeneration in the basal ganglia, amygdala, thalamus, insula and occipital regions. In symp-HD, cerebral atrophy was more pronounced and spread to cortical regions (i.e., inferior frontal, premotor, sensorimotor, midcingulate, frontoparietal and temporoparietal cortices). Higher cytosine adenosine-guanosine repeats were associated with striatal degeneration, while parameters of disease progression and motor impairment additionally correlated with cortical atrophy, especially in sensorimotor areas. CONCLUSION: This first quantitative meta-analysis in HD demonstrates the extent of striatal atrophy and further consistent extrastriatal degeneration before clinical conversion. Sensorimotor areas seem to be core regions affected in symp-HD and, along with widespread cortical atrophy, may account for the clinical heterogeneity in HD. PMID- 22922586 TI - Profiling and functional classification of esterases in olive (Olea europaea) pollen during germination. AB - BACKGROUND AND AIMS: A pollen grain contains a number of esterases, many of which are released upon contact with the stigma surface. However, the identity and function of most of these esterases remain unknown. In this work, esterases from olive pollen during its germination were identifided and functionally characterized. METHODS: The esterolytic capacity of olive (Olea europaea) pollen was examined using in vitro and in-gel enzymatic assays with different enzyme substrates. The functional analysis of pollen esterases was achieved by inhibition assays by using specific inhibitors. The cellular localization of esterase activities was performed using histochemical methods. KEY RESULTS: Olive pollen showed high levels of non-specific esterase activity, which remained steady after hydration and germination. Up to 20 esterolytic bands were identified on polyacrylamide gels. All the inhibitors decreased pollen germinability, but only diisopropyl fluorophosphate (DIFP) hampered pollen tube growth. Non-specific esterase activity is localized on the surface of oil bodies (OBs) and small vesicles, in the pollen intine and in the callose layer of the pollen tube wall. Acetylcholinesterase (AChE) activity was mostly observed in the apertures, exine and pollen coat, and attached to the pollen tube wall surface and to small cytoplasmic vesicles. CONCLUSIONS: In this work, for the first time a systematic functional characterization of esterase enzymes in pollen from a plant species with wet stigma has been carried out. Olive pollen esterases belong to four different functional groups: carboxylesterases, acetylesterases, AChEs and lipases. The cellular localization of esterase activity indicates that the intine is a putative storage site for esterolytic enzymes in olive pollen. Based on inhibition assays and cellular localization of enzymatic activities, it can be concluded that these enzymes are likely to be involved in pollen germination, and pollen tube growth and penetration of the stigma. PMID- 22922587 TI - Cytotype diversity in the Sorbus complex (Rosaceae) in Britain: sorting out the puzzle. AB - BACKGROUND AND AIMS: Large-scale ploidy surveys using flow cytometry have become an essential tool to study plant genome dynamics and to gain insight into the mechanisms and genetic barriers framing ploidy diversity. As an ideal complement to traditional techniques such as chromosome counting, the analysis of cytotype diversity in plant systems such as Sorbus provides primary investigation into the potential patterns and evolutionary implications of hybrid speciation. METHODS: Ploidy was assessed by means of relative nuclear DNA content using propidium iodide flow cytometry in 474 Sorbus samples collected from 65 populations in southern Wales and South-West England. Statistical tests were applied to evaluate the utility of this technique to confidently discriminate ploidy in the genus. KEY RESULTS: Flow cytometric profiles revealed the presence of four cytotypes (2x, 3x, 4x and 5x), confirming in many cases chromosome counts previously reported and demonstrating cytotype heterogeneity within specific Sorbus aggregates. Diploid cytotypes were restricted to the potential parental species and homoploid hybrids. Most of the samples processed were polyploid. The occurrence of the pentaploid cytotype had previously only been reported from a single specimen; it is now confirmed for two taxa occurring at different sites. CONCLUSIONS: Flow cytometry results obtained have proved useful in shedding light on the taxonomy of several controversial taxa and in confirming the presence of cytoypes which occur at very low frequencies. Notably, the coexistence of several cytotypes in Sorbus populations has probably been facilitated by the overlapping distribution of many of the species studied, which might also explain the high incidence of potential hybrid apomictic polyploids. These results will provide a solid baseline for molecular research aiming to better understand the genetic pathways controlling the formation and establishment of polyploid Sorbus. PMID- 22922588 TI - Chicken IL-17F: identification and comparative expression analysis in Eimeria infected chickens. AB - Interleukin-17F (IL-17F) is a proinflammatory cytokine, which plays an important role in gut homeostasis. A full-length chicken IL-17F (chIL-17F) cDNA with a 510 bp coding region was identified from ConA-activated chicken splenic lymphocytes. ChIL-17F shares 53% amino acid sequence identity with the previously described chicken IL-17 (chIL-17A) and 38-43% with mammalian homologues. The locus harboring chIL-17 and chIL-17F displayed inverted order compared to those of mammals. ChIL-17F transcript expression was high in lymphoblast cell line CU205 and at moderate levels in small and large intestines and liver. ChIL-17F and chIL 17 expression profiles were examined by quantitative real-time RT-PCR in mitogen stimulated splenic lymphocytes and intestinal areas affected by Eimeria maxima and Eimeria tenella infections. Expression levels of chIL-17F, like chIL-17, were elevated in mitogen-activated splenic lymphocytes. ChIL-17F, but not chIL-17, expression was upregulated in intestinal tissues affected by E. maxima and E. tenella infections. Recombinant chIL-17F biological activities were similar to that of chIL-17 in primary chicken embryonic fibroblasts. These results suggest that chIL-17F is a unique member of the IL-17 family of cytokines. PMID- 22922589 TI - Chicken CD56 defines NK cell subsets in embryonic spleen and lung. AB - NK cells have been widely investigated in various mammalian species, but their characterization in non-mammalian vertebrates has been hampered by the lack of appropriate markers. Here, we tested the suitability of a novel anti-chicken CD56 mab as a marker on NK cells. The entire CD56 extracellular domain was cloned into a vector providing a FLAG epitope as well as the CD8 transmembrane and CD3zeta cytoplasmic domain. This construct was used to stably transfect the chicken 2D8 B cell line as monitored by anti-FLAG staining. BALB/c mice were repeatedly immunized with this cell line before generation of hybridomas and screening of supernatants on the transfected cell line versus untransfected cells. The 4B5 hybridoma was further selected due to its reactivity with transfected cells only. Staining of various cell preparations isolated from blood, spleen, embryonic spleen, lung and intestine revealed a CD56 positive subpopulation in lung and embryonic spleen, whereas no reactivity could be observed with other cells. In two colour immunofluorescence, some of the CD56(+) lung cells coexpressed CD8, while they were largely negative for the markers 28-4 and 20E5. CD8 expression was also observed for a subset of CD56(+) embryonic splenocytes and 28-4 was found to be coexpressed on about half of the CD56(+) embryonic splenocytes. CD56 is therefore expressed on a subset of chicken NK cells predominantly found in embryonic spleen and lung. PMID- 22922590 TI - Detecting obstructive coronary disease with CT angiography and noninvasive fractional flow reserve. PMID- 22922591 TI - Pharmacokinetics and pharmacodynamics of CHF5074 after short-term administration in healthy subjects. AB - CHF5074 has been shown to inhibit brain beta-amyloid deposition and attenuate memory deficits in different transgenic mice models of Alzheimer disease. We evaluated the safety, pharmacokinetics, and pharmacodynamics of 3 ascending dose regimens of CHF5074 (200, 400, and 600 mg/d for 14 d) in a double-blind, placebo controlled, parallel group study involving 48 healthy subjects. Plasma, urine, and cerebrospinal fluid (CSF) samples were collected for measuring drug and main metabolite concentrations and potential biomarkers of pharmacodynamic activity (beta-amyloid1-40, beta-amyloid1-42, soluble CD40 ligand, and tumor necrosis factor-alpha). All subjects completed the study, and no serious or severe adverse events were reported. The maximum tolerated dose was close to 600 mg/d with mild diarrhea being the most frequent adverse event at this dose. CHF5074 reached peak plasma levels 2 to 3 hours after drug administration and then was slowly eliminated (t(1/2z)=30 h) in the urine as glucoronide. Systemic exposure to the drug appeared to be dose-proportional with a 2-fold accumulation ratio at steady state. Metabolite plasma levels peaked at 4 to 5 hours and accounted for about 25% of the parent compound. Drug levels in the CSF were dose-proportional. The drug dose-dependently lowered the levels of the soluble CD40 ligand, a marker of microglia activation, in both plasma and CSF samples. PMID- 22922592 TI - Diagnostic accuracy of statistical pattern recognition of electroencephalogram registration in evaluation of cognitive impairment and dementia. AB - BACKGROUND: There is still a need for simple, noninvasive, and inexpensive methods to diagnose the causes of cognitive impairment and dementia. In this study, contemporary statistical methods were used to classify the clinical cases of cognitive impairment based on electroencephalograms (EEG). METHODS: An EEG database was established from seven different groups of subjects with cognitive impairment and dementia as well as healthy controls. A classifier was created for each possible pair of groups using statistical pattern recognition (SPR). RESULTS: A good-to-excellent separation was found when differentiating cases of degenerative disorders from controls, vascular disorders, and depression but this was less so when the likelihood of comorbidity was high. CONCLUSIONS: Using EEG with SPR seems to be a reliable method for diagnosing the causes of cognitive impairment and dementia, but comorbidity must be taken into account. PMID- 22922593 TI - Size-tunable Au nanoparticles on MoS2(0001). AB - Ultra-fine Au nanoparticles (NPs) show great application potential in catalysis. Size-tunable Au NPs have been fabricated on MoS(2) covered with monolayer 3,4,5,10-perylene tetracarboxylic dianhydride (PTCDA), and the morphological evolution as a function of Au deposition amount was investigated using scanning tunneling microscopy (STM). The PTCDA molecules act as a surfactant to stabilize ultra-fine Au NPs. Molecular scale STM images show that on MoS(2) the Au NPs with PTCDA molecules on top can be formed with height and lateral size down to 1.3 nm and 3.5 nm, respectively. By controlling the deposition amount and annealing temperature, the size of Au NPs can be tuned. After annealing at 270 degrees C to remove PTCDA, Au NPs with a linear size <=5 nm can be obtained on MoS(2)(0001), facilitating the characterization of their intrinsic physical and chemical properties using various analytical techniques. In addition, photoemission spectroscopy data reveal charge transfer from Au NPs to PTCDA, indicating that the NPs possess more reactive chemical properties than bulk Au. PMID- 22922594 TI - Statins and risk of diabetes mellitus. PMID- 22922596 TI - Stent choice and the hidden consequences of cost savings. AB - Amin and colleagues have attempted to estimate the cost savings to the US health care system if drug-eluting coronary stents were more selectively used in patients at low risk of restenosis. Their results and conclusions raise statistical, societal, and ethical issues that need to be considered before this approach should be widely embraced. PMID- 22922595 TI - The role of nutrition and body composition in peripheral arterial disease. AB - Peripheral arterial disease (PAD) has not been as extensively investigated as other cardiovascular diseases. However, the available data suggest that nutrition based treatment strategies have the potential to reduce the cost-economic burden of PAD substantially. Abdominal obesity is associated with PAD and prospective and cross-sectional studies have shown that a low dietary intake of folate and reduced synthesis of vitamin D are associated with an increased risk of PAD and severe walking impairment in patients who have the disease. However, dietary patterns that are associated with decreased cardiovascular risk might protect against PAD. A small number of clinical trials have provided evidence that increased intakes of niacin and insoluble fiber might be associated with decreased levels of LDL cholesterol and thrombogenic biomarkers, as well as increased serum levels of HDL cholesterol in patients with PAD. However, little evidence that antioxidants, vitamins B(6) and B(12), or essential fatty acid supplements improve clinical outcomes in these patients exists. Overall, data on the effects of nutrition, body composition, and nutritional supplementation on the risk, progression, and prognosis of PAD are scarce. Further research into these areas is required to allow the development of evidence-based nutritional guidelines for the prevention and treatment of the disease. PMID- 22922598 TI - Trial of VADs in children with HF. PMID- 22922599 TI - Upregulation of the beta-form of 14-3-3 protein in telencephalon of goldfish (Carassius auratus): its possible role in spatial learning. AB - In the present study, we observed variations in the expression pattern of proteins isolated from the telencephalon of goldfish (Carassius auratus). The expression of a 28 kDa protein was elevated in the individuals trained in a spatial task when compared with the untrained individuals. The ~28 kDa protein was analyzed using liquid chromatography and mass spectrometry; further, the data were analyzed using the MASCOT search engine. The analysis showed that the ~28 kDa protein is a beta form of 14-3-3 protein with 35.1% identity. In addition, the semiquantitative PCR confirmed the variation in the expression of 14-3-3 between the trained and the untrained groups. Subsequently, we examined the effect of upregulation of 14-3-3 (beta) in the neurotransmitters; that is, serotonin (5-hydroxytryptamine, 5-HT) and dopamine (DA). Notably, the level of 5 HT and DA was found to be significantly elevated in the telencephalon of individuals trained in the spatial task than in the untrained individuals. Our results suggest that the spatial learning increases the expression of 14-3-3 (beta), which in turn leads to an increase in the level of 5-HT and DA. The upregulated 5-HT and DA may facilitate synapse formation during spatial learning in a novel environment. PMID- 22922600 TI - Amphetamine stimulates Wnt3 increases in rat nucleus accumbens. AB - Dopaminergic neurotransmission is thought to be involved in reward-related incentive learning and addictive behaviour. Amphetamine will alter glycogen synthase kinase-3beta (GSK-3beta) activity by increasing dopamine transporter efflux rates. We investigated the hypothesis that Wnt signalling will be altered in rat nucleus accumbens within 15 min of injection of amphetamine compared with saline. We isolated RNA from the nucleus accumbens and used reverse transcriptase PCR to screen for altered Wnt expression. We found that amphetamine had no effect on Wnt5a or Wnt7a expression but increased Wnt3. We then measured protein expression of Wnt3, phosphorylated lipoprotein-related peptide 6, GSK-3beta phosphorylated at serine-9 and tyrosine-216 and total beta-catenin. We found that amphetamine increased Wnt3 protein expression, increased pLRP6 (threonine-1572) levels, increased beta-catenin levels, increased GSK-3beta phosphorylation at serine-9, consistent with inhibition of GSK-3beta activity, and diminished GSK 3beta phosphorylation at tyrosine-216. Our data support the hypothesis that proximate Wnt signalling is rapidly activated by amphetamine in the adult rat nucleus accumbens. PMID- 22922601 TI - Event-related potential P2 correlates of implicit aesthetic experience. AB - Using event-related potential measures, the present study investigated the affective responses to aesthetic experience. To differentiate the objective aesthetic value from subjective aesthetic evaluation, an amended oddball task was used in which pendant pictures were presented as frequent nontarget stimuli, whereas the landscape pictures were presented as a rare target. The pendant pictures were chosen from the largest online store in China and divided into beautiful and less beautiful conditions by the sales ranking. A positive component, P2, was recorded for each condition on the participants' frontal, central and parietal scalp areas. Less beautiful pendants elicited greater amplitudes of P2 than the beautiful ones. This indicates that emotion arousal seems to occur at the early stage of processing of aesthetics and can be detected by the P2 component, implying that the event-related potential methodology may be a more sensitive measure of the beauty-related attention bias. From the perspective of artwork design and marketing, our finding also shows that P2 can potentially be used as a reference measure in consumer aesthetic experience. PMID- 22922597 TI - Third universal definition of myocardial infarction. PMID- 22922602 TI - Mortality of harmful drinkers increased after reduction of alcohol prices in northern Finland: a 10-year follow-up of head trauma subjects. AB - OBJECTIVE: Alcohol-related mortality may be influenced by the level of alcohol consumption. We investigated the effect of alcohol price reduction on mortality in a cohort of 827 subjects with head injury. METHODS: We used the Finnish National Hospital Discharge Register to identify all diagnoses recorded during hospital and health center visits for survivors of the index injury during a follow-up of 10 years. Mortality data were gathered from death records obtained from the Official Cause-of-Death Statistics. Cox proportional hazards model was used to identify independent predictors for death. Kaplan-Meier survival curves were used to characterize the effect of alcohol price reduction on mortality of harmful and non-harmful drinkers. RESULTS: Alcohol-related deaths increased after the reduction of alcohol prices on March 1, 2004. Subjects recorded as harmful drinkers during the follow-up period were significantly (p < 0.001) more likely than others to die after the price reduction. Older age (HR 1.06, 95% CI 1.05 1.07), moderate-to-severe brain injury (HR 2.39, 95% CI 1.59-3.60) and harmful drinking recorded after the index trauma (HR 2.59, 95% CI 1.62-4.62) were significant (p < 0.001) predictors for death. CONCLUSION: We conclude that a political decision to lower the price of alcohol may cause a significant increase in the death rate of harmful drinkers. PMID- 22922603 TI - The effect of American Society of Anesthesiology scores on percutaneous nephrolithotomy outcomes. AB - INTRODUCTION: To evaluate the effect of American Society of Anesthesiology (ASA) scores on percutaneous nephrolithotomy (PNL) outcomes. MATERIALS AND METHODS: The records of 186 consecutive patients undergoing PNL procedures from 2006 to 2011 at a single institution were evaluated. Patients were divided into a low-risk group with a preoperative ASA of I or II and a high-risk group with ASA of III or IV. Postoperative complications were classified according to the modified Clavien classification system. RESULTS AND CONCLUSIONS: There were 140 cases in the low risk and 46 cases in the high-risk groups. The mean operative time was 72 min (40 120 min) and 86 min (55-125 min) and the complication rates were 17.8 and 19.5% for the low- and high-risk groups, respectively. The average duration of nephrostomy tube drainage was 3.3 +/- 1 and 4.2 +/- 1.5 days for the low- and high-risk groups, respectively. Stone-free rates were 85 and 82% for the low- and high-risk groups, respectively. PNL can be safely performed in the ASA high-risk patient population. PMID- 22922604 TI - Beverages containing soluble fiber, caffeine, and green tea catechins suppress hunger and lead to less energy consumption at the next meal. AB - Previous research has shown that beverages containing soluble fibers can decrease energy intake at the next meal among normal weight participants. Caffeine and green tea catechins have separately been associated with increased satiety. The present study examined the satiating power of a beverage containing soluble fiber as well as a beverage containing the same fiber, caffeine and green tea catechins. These two test beverages were evaluated in comparison to an equal calorie control beverage as well as a no-beverage control condition. All beverage preloads were presented three times for a total of 0.28-0.35MJ and 0-30g fiber. Dependent measures were appetite ratings and calorie intake at a test meal. The no-beverage condition was associated with the highest ratings for hunger and the lowest ratings for fullness when compared to the other three beverage conditions. Of the three beverage conditions, the beverage containing the fiber, green tea catechins, and caffeine created the lowest hunger and the highest fullness ratings. That condition was also associated with the lowest energy intake at the next meal. The present findings indicate that the beverage containing caffeine and green tea catechins in combination with soluble fiber decrease appetite and energy intake relative to a beverage with equal caloric content. PMID- 22922605 TI - Isoform-specific alanine aminotransferase measurement can distinguish hepatic from extrahepatic injury in humans. AB - Serum alanine aminotransferase (ALT) is used as a clinical marker to detect hepatic damage and hepatoxicity. Two isoforms of ALT have been identified, ALT1 and ALT2, which have identical enzymatic capacities and are detected simultaneously in human serum/plasma using classical clinical chemical assays. Differences exist in the expression patterns of the ALT1 and ALT2 proteins in different organs which suggest that changes in the proportion of ALT1 and ALT2 in plasma may arise and reflect damage to different human organs. However, this has not been previously studied due to the lack of a selective methodology that can quantify both ALT1 and ALT2 isoforms in the total ALT activity normally measured in clinical samples. To the best of our knowledge, our current study reveals for the first time, that under 3 different conditions of liver damage (non-alcoholic fatty liver disease, hepatitis C and during liver surgery) the leakage of ALT1 activity into plasma greatly exceeds that of ALT2, and that the measurement of ALT1 during liver damage is equal to the measurement of total ALT activity. By contrast, during skeletal muscle injury, induced in volunteers by physical exertion, the leakage of ALT2 exceeds that of ALT1 and the proportion of circulating ALT isoforms changes accordingly. The ALT isoform changes occurring in plasma reflect previously demonstrated relative contents of ALT1 and ALT2 activities in human liver and skeletal muscle. These data suggest that assessing the percentage contribution of ALT1 and ALT2 activities to total ALT activity in plasma may distinguish hepatic from extrahepatic injury using the same standard analytical platform. PMID- 22922606 TI - Long-term follow-up of implanted children with cytomegalovirus-related deafness. AB - OBJECTIVE: To evaluate, with a long-term follow-up, the speech perception and language development in children with cytomegalovirus (CMV)-related deafness after cochlear implantation. STUDY DESIGN: A retrospective study on CMV-related profound deafness and cochlear implantation was performed from 1995 to 2010. Six children with an average follow-up of 10 years were included in this research. Medical history, imaging, cognitive delay, speech perception and production data were reviewed. RESULTS: Two of the 6 patients developed a functional language with the use of phrases and word sequences based on morphological and syntactic rules; the others demonstrated the development of a preverbal or transitional language with the use of single words only. CONCLUSION: Patients with CMV-related deafness benefit from cochlear implantation; however, the expectations of the parents must be evaluated in a series of counseling efforts prior to the surgery. PMID- 22922607 TI - Novel mutation in ARX associated with early hand preference and a mild phenotype. AB - The authors report detailed clinical and developmental assessment of 3 brothers who were found to carry a novel mutation in the ARX gene associated with a relatively mild phenotype of static global developmental delay and early hand preference. The decision of when to initiate specialized genetic testing for patients with apparently isolated developmental delay remains controversial, and this report of 3 brothers who presented with early hand preference and transient contralateral weakness may assist clinicians in prioritizing investigations in patients with a similar presentation. PMID- 22922608 TI - 15q11.2 proximal imbalances associated with a diverse array of neuropsychiatric disorders and mild dysmorphic features. AB - Deletion within the proximal region of chromosome 15q11.2 between breakpoints 1 and 2 (BP1-BP2) has been proposed to be a risk factor for intellectual disability, seizure, and schizophrenia. However, the clinical significance of its reciprocal duplication is not clearly defined yet. We evaluated 1654 consecutive pediatric patients with various neurological disorders by high-resolution microarray-based comparative genomic hybridization. We identified 21 patients carrying 15q11.2 BP1-BP2 deletion and 12 patients carrying 15q11.2 BP1-BP2 duplication in this cohort, which represent 1.27% (21/1,654) and 0.7% (12/1,654) of the patients analyzed, respectively. Approximately 87.5% of the patients carrying the deletion and 80% of the patients carrying the duplication have developmental delay or intellectual disability. Other recurrent clinical features in these patients include mild dysmorphic features, autistic spectrum disorders, and epilepsy. Our observations provide further evidence in favor of a strong association of 15q11.2 BP1-BP2 deletion with a variety of neuropsychiatric disorders. The diversity of clinical findings in these patients expands the phe notypic spectrum of individuals carrying the deletion. In addition, possible etiological effects of 15q11.2 BP1-BP2 duplication in neuropsychiatric disorders are proposed. PMID- 22922609 TI - beta-adrenergic signaling regulates evolutionarily derived sleep loss in the Mexican cavefish. AB - Sleep is a fundamental behavior exhibited almost universally throughout the animal kingdom. The required amount and circadian timing of sleep differs greatly between species in accordance with habitats and evolutionary history. The Mexican blind cavefish, Astyanax mexicanus, is a model organism for the study of adaptive morphological and behavioral traits. In addition to loss of eyes and pigmentation, cave populations of A. mexicanus exhibit evolutionarily derived sleep loss and increased vibration attraction behavior, presumably to cope with a nutrient-poor environment. Understanding the neural mechanisms of evolutionarily derived sleep loss in this system may reveal critical insights into the regulation of sleep in vertebrates. Here we report that blockade of beta adrenergic receptors with propranolol rescues the decreased-sleep phenotype of cavefish. This effect was not seen with alpha-adrenergic antagonists. Treatment with selective beta1-, beta2-, and beta3-antagonists revealed that the increased sleep observed with propranolol could partially be explained via the beta1 adrenergic system. Morphological analysis of catecholamine circuitry revealed conservation of gross catecholaminergic neuroanatomy between surface and cave morphs. Taken together, these findings suggest that evolutionarily derived changes in adrenergic signaling underlie the reduced sleep of cave populations. PMID- 22922610 TI - Hypocapnia during hypoxic exercise and its impact on cerebral oxygenation, ventilation and maximal whole body O2 uptake. AB - With hypoxic exposure ventilation is elevated through the hypoxic ventilatory response. We tested the hypothesis that the resulting hypocapnia reduces maximal exercise capacity by decreasing (i) cerebral blood flow and oxygenation and (ii) the ventilatory drive. Eight subjects performed two incremental exercise tests at 3454 m altitude in a blinded manner. In one trial end-tidal [Formula: see text] was clamped to 40 mmHg by CO(2)-supplementation. Mean blood flow velocity in the middle cerebral artery (MCAv(mean)) was determined by trans-cranial Doppler sonography and cerebral oxygenation by near infra-red spectroscopy. Without CO(2) supplementation, [Formula: see text] decreased to 30 +/- 3 mmHg (P<0.0001 vs isocapnic trial). Although CO(2)-supplementation increased MCAv(mean) by 17 +/- 14% (P<0.0001) and attenuated the decrease in cerebral oxygenation (-4.7 +/- 0.9% vs -5.4 +/- 0.9%; P=0.002) this did not affect maximal O(2)-uptake. Clamping [Formula: see text] increased ventilation during submaximal but not during maximal exercise (P=0.99). We conclude that although hypocapnia promotes a decrease in MCAv(mean) and cerebral oxygenation, this does not limit maximal O(2) uptake. Furthermore, hypocapnia does not restrict ventilation during maximal hypoxic exercise. PMID- 22922611 TI - Shoulder sonography: why we do it. PMID- 22922612 TI - Sonographically guided hand kneading and compression for treatment of femoral artery pseudoaneurysms. AB - OBJECTIVES: The purpose of this study was to evaluate the effectiveness of sonographically guided hand kneading and compression for the treatment of femoral artery pseudoaneurysms after percutaneous intervention. METHODS: Twenty-four patients who had post-percutaneous intervention femoral artery pseudoaneurysms treated with sonographically guided compression from 2001 to 2004 and 2008 to 2009 were compared with 25 patients who had postintervention pseudoaneurysms treated with sonographically guided hand kneading and compression from 2005 to 2009. RESULTS: All 25 patients (100%) treated with 1-stage sonographically guided hand kneading and compression had pseudoaneurysm occlusion; the median treatment time was 10 minutes. Twenty-two of the 24 patients (91.7%) treated with conventional sonographically guided compression had pseudoaneurysm occlusion. One stage compression was successful in 10 patients; 9 and 3 patients had pseudoaneurysm occlusion after 2 and 3 compression treatments, respectively. Two other patients who underwent compression treatment 3 and 4 times did not have pseudoaneurysm occlusion and required surgery. The median treatment time for sonographically guided compression was 30 minutes. The treatment time was significantly shorter for the hand-kneading and compression technique (P < .001), and significantly fewer procedures were needed (P < .001). CONCLUSIONS: Sonographically guided hand kneading and compression is as effective as sonographically guided compression alone for pseudoaneurysm occlusion after femoral artery percutaneous intervention and requires significantly less time to perform. PMID- 22922613 TI - Sonographically guided percutaneous needle release of the carpal tunnel for treatment of carpal tunnel syndrome: preliminary report. AB - OBJECTIVES: The purpose of this study was to evaluate the effectiveness of a novel treatment procedure, sonographically guided percutaneous needle release of the carpal tunnel, for individuals with carpal tunnel syndrome. METHODS: Seventeen patients (89% female; mean age, 62 years; SD, 13.6 years) with a clinical diagnosis of carpal tunnel syndrome who had undergone a sonographically guided percutaneous needle release of the carpal tunnel at least 6 months before follow-up evaluation were retrospectively reviewed. At the follow-up evaluation, to ascertain previous and current symptoms as well as functional impairment, the patients filled out a hand diagram and a questionnaire. In addition, medical records were reviewed, and patients were queried regarding complications such as infection or nerve damage. Median nerve sonographic measurements and a physical evaluation were performed on a subset of 13 patients who came to the office for evaluation. RESULTS: Postprocedure sonography showed that patients had a significantly smaller (P = .03) cross-sectional area of the median nerve compared to pretreatment values. In addition, patients had significantly fewer symptoms (P < .0001), less functional impairment (P = .0002), and an improved hand diagram score (P < .0001). Postprocedure patients had grip strength that was 12 lb below average (~1 SD below) compared to grip strength norms. However, most patients (84.6%) had negative clinical diagnostic test results for carpal tunnel syndrome, and 86% said they were satisfied with the procedure. There were no procedure related infections or nerve injuries. CONCLUSIONS: Of the patients with carpal tunnel syndrome who agreed to participate in this study, most had favorable symptomatic and functional outcomes. Sonographically guided percutaneous needle release of the carpal tunnel may be an alternative option to traditional surgical treatment of carpal tunnel syndrome. PMID- 22922614 TI - Sonographic measurement of diuretic-induced renal length changes: are they correlated with renal function? AB - OBJECTIVES: The purposes of this study were to prospectively identify diuretic induced renal length changes and to determine whether the percentages of the renal length changes allow estimation of the differential renal function. METHODS: Twenty-three children (14 boys and 9 girls; mean age, 7.83 years) who were undergoing technetium Tc 99m diethylenetriamine pentaacetic acid or technetium Tc 99m mercaptoacetyltriglycine diuretic renography were included in this study. Renal lengths were measured by sonography just before and 15 to 20 minutes after diuretic injection. The Spearman test was used to assess the correlation between renal length increases due to diuretic injection and the differential renal function. RESULTS: The mean renal lengths +/- SD measured before and after diuretic administration were 91.52 +/- 20.87 and 95.38 +/- 21.46 mm, respectively. The increase in renal length after diuretic administration was statistically significant (P < .001). There was a positive correlation between the renal length change and functional status (P = .006). CONCLUSIONS: Renal length may change after diuretic injection according to the functional status, and the sonographic measurements of these changes may be used as an alternative to other imaging methods in estimation of renal function. PMID- 22922615 TI - Use of emergency ultrasound in United States pediatric emergency medicine fellowship programs in 2011. AB - OBJECTIVES: The purpose of this study was to evaluate the use of and training in emergency ultrasound (US) in pediatric emergency departments (EDs) with pediatric emergency medicine (EM) fellowship programs. We hypothesized that emergency US use and pediatric EM fellow training have become widespread and that more structured training is being offered. METHODS: A survey instrument was sent via e mail to all 69 United States pediatric EM fellowship directors or associate directors in the spring of 2011. We used descriptive summary statistics and chi(2) tests to determine characteristics associated with having a formal emergency US training program for pediatric EM fellows. RESULTS: The survey response rate was 87% (60 of 69). Among responding programs, 40 (67%) resided within a children's hospital (versus general ED). Fifty-one (85%) were designated level 1 pediatric trauma centers. Fifty-seven programs (95%) endorsed the use of emergency US in their EDs. Fifty-three (88%) provided at least some emergency US training to fellows, and 42 (70%) offered a structured emergency US rotation. Training has existed for a median of 3 years (interquartile range, 2-4 years). Twenty-eight programs (67%) with emergency US rotations provided fellow training in the both a general ED as well as a pediatric ED. There were no hospital or program level factors statistically associated with having a formal training program for pediatric EM fellows. CONCLUSIONS: As of 2011, nearly all pediatric EDs with pediatric EM fellowship programs use emergency US. Pediatric EM fellowship programs provide emergency US training to their fellows, with a structured rotation being offered by most of these programs. PMID- 22922616 TI - Dynamic anatomic relationship of the esophagus and trachea on sonography: implications for endotracheal tube confirmation in children. AB - OBJECTIVES: Sonographic visualization of an empty esophagus to confirm endotracheal tube placement during intubation may be more reliable than identifying an endotracheal tube within the trachea. Our objective was to determine the frequency in which the normal empty esophagus can be identified at or below the level of the cricoid ring in children. METHODS: A prospective cohort of children and young adults presenting to the emergency department were examined by sonography to determine the dynamic anatomic relationship of the trachea and esophagus at or below the level of the cricoid ring. For children with the esophagus behind or partially behind the trachea, cricoid pressure was applied using a linear array transducer to visualize the presence of lateral sliding of the esophagus from behind the trachea. RESULTS: A total of 55 patients 21 years or younger were examined; 51% (28) were male. Sixty-two percent (34) had esophagi positioned partially to the left of the cricoid ring, 20% (11) completely to the left of the cricoid ring, 16% (9) behind the cricoid ring, and 2% (1) partially to the right of the cricoid ring. When cricoid pressure was applied using the ultrasound transducer, the esophagus was visualized lateral to the trachea in all patients (54 to the left and 1 to the right; n = 55 of 55; 95% confidence interval, 94%-100%). CONCLUSIONS: With cricoid pressure applied using a linear transducer, the esophagus was visualized lateral to the trachea in all children and young adults. Visualizing an empty esophagus by point-of-care sonography may be feasible to confirm endotracheal tube placement by a process of elimination. PMID- 22922617 TI - Use of sonography for evaluation of the cervical and thoracic esophagus in children. AB - OBJECTIVES: The purpose of this study was to determine the normal sonographic appearance of the cervical and thoracic esophagus and to provide corresponding measurements in healthy children. METHODS: In this prospective study, 93 children (51 girls and 42 boys) 1 to 15 years of age were examined sonographically. With the patient in a supine position for evaluation of the cervical esophagus, the ultrasound transducer was placed on both sides of the trachea. To evaluate the thoracic esophagus, the hands were raised over the head, and the ultrasound transducer was placed along the left side of the sternum. The length of the cervical esophagus was measured longitudinally, and the anteroposterior and transverse diameters of the cervical and thoracic esophagus were measured transversely, as was the thickness of the cervical esophageal wall. RESULTS: The cervical esophagus was identified in all of the children, whereas the thoracic esophagus was shown in 41 (44%) of the 93 participants. The length of the cervical esophagus and anteroposterior and transverse diameters of the cervical and thoracic esophagus increased with age. The mean thickness of the cervical esophagus was 2.8 mm at all ages. The cervical esophageal wall appeared as 5 layers on the sonograms, and the lumen was distinct. CONCLUSIONS: Evaluation of the cervical esophagus was readily achievable with sonography in children, whereas visualization of the thoracic esophagus was difficult because of the deep location, small size, and influence of bones and gas in the lungs. Conventional sonography can be easily used in the evaluation of cervical esophageal diseases in children. PMID- 22922618 TI - Doppler middle cerebral artery peak systolic velocity for diagnosis of neonatal anemia. AB - OBJECTIVES: The peak systolic velocity (PSV) of the middle cerebral artery was found to be predictive of fetal anemia and is routinely applied in the treatment of such fetuses. Our objective was to determine whether a correlation exists between the PSV in the neonatal middle cerebral artery and hemoglobin levels for possible future implementation in clinical practice. METHODS: A prospective study on 151 neonates was conducted, examining their middle cerebral artery PSV concomitantly with their hemoglobin level during the first 36 hours after delivery. The study population included 122 normocythemic, 24 anemic, and 5 polycythemic neonates. An analysis of variance between normocythemic, anemic, and polycythemic neonates was performed, and a regression analysis of the PSV versus hemoglobin levels was conducted. RESULTS: The normocythemic neonates had a mean middle cerebral artery PSV +/- SD of 41.3 +/- 11.4 cm/s, whereas the anemic neonates had a significantly higher PSV (63.8 +/- 28.5 cm/s), and the polycythemic neonates had a significantly lower PSV (26.8 +/- 7.4 cm/s; P < .001). A statistically significant correlation was found between hemoglobin levels and the middle cerebral artery PSV (P < .01). CONCLUSIONS: Neonatal anemia and polycythemia can be rapidly diagnosed at the bedside by examining the middle cerebral artery PSV. This technique can be used as an ancillary measure to promptly diagnose acute neonatal blood volume changes for an immediate intervention. PMID- 22922619 TI - Imaging of sound speed using reflection ultrasound tomography. AB - OBJECTIVES: The goal of this work was to obtain and evaluate measurements of tissue sound speed in the breast, particularly dense breasts, using backscatter ultrasound tomography. METHODS: An automated volumetric breast ultrasound scanner was constructed for imaging the prone patient. A 5- to 7-MHz linear array transducer acquired 17,920 radiofrequency pulse echo A-lines from the breast, and a back-wall reflector rotated over 360 degrees in 25 seconds. Sound speed images used reflector echoes that after preprocessing were uploaded into a graphics processing unit for filtered back-projection reconstruction. A velocimeter also was constructed to measure the sound speed and attenuation for comparison to scanner performance. Measurements were made using the following: (1) deionized water from 22 degrees C to 90 degrees C; (2) various fluids with sound speeds from 1240 to 1904 m/s; (3) acrylamide gel test objects with features from 1 to 15 mm in diameter; and (4) healthy volunteers. RESULTS: The mean error +/- SD between sound speed reference and image data was -0.48% +/- 9.1%, and the error between reference and velocimeter measurements was -1.78% +/- 6.50%. Sound speed image and velocimeter measurements showed a difference of 0.10% +/- 4.04%. Temperature data showed a difference between theory and imaging performance of 0.28% +/- 0.22%. Images of polyacrylamide test objects showed detectability of an approximately 1% sound speed difference in a 2.4-mm cylindrical inclusion with a contrast to noise ratio of 7.9 dB. CONCLUSIONS: An automated breast scanner offers the potential to make consistent automated tomographic images of breast backscatter, sound speed, and attenuation, potentially improving diagnosis, particularly in dense breasts. PMID- 22922620 TI - Sonoelastographic characteristics of abscess induration associated with therapy failure. AB - OBJECTIVES: Sonoelastography can visualize components of skin and soft tissue abscesses, including the abscess cavity and surrounding induration, related to the patient's response to the infection. We speculate that characteristics of the induration surrounding an abscess may predict which abscesses will eventually fail therapy. METHODS: We conducted a prospective trial of patients with a suspected skin abscess requiring surgical drainage who were enrolled from the emergency department of an urban tertiary care center. In this pilot study, all patients underwent incision and drainage for the suspected abscesses. Abscesses (n = 56) were imaged in orthogonal planes (long-axis and transverse to the body part) using B-mode sonography and elastography before incision and drainage. Telephone follow-up using a standardized questionnaire was performed 7 to 10 days after the initial drainage procedure to determine therapy failure. Physicians blinded to patient outcome analyzed the sonograms for predetermined image characteristics of the abscess induration. RESULTS: All patients underwent incision and drainage, but 16.1% of patients failed therapy. Asymmetry of the surrounding induration was associated with therapy failure. A higher percentage of patients who failed therapy had asymmetry (66%; 95% confidence interval, 35.1% 88.3%) versus those who were successfully treated (12.8%; 95% confidence interval, 5.6%-25.6%; P = .003). In all patients, the mean volumes +/- SD of the abscess cavity and induration were 2.2 +/- 3.7 and 19.9 +/- 24.7 cm, respectively, with a mean volume ratio (induration to abscess cavity) of 31.9 to 1. CONCLUSIONS: We describe sonographic characteristics of the abscess induration imaged with sonoelastography that are associated with therapy failure. We found that patients with asymmetric induration visualized with sonoelastography have higher rates of therapy failure. PMID- 22922621 TI - Reproducibility of quantitative assessment of altered hepatic hemodynamics with dynamic contrast-enhanced ultrasound. AB - OBJECTIVES: The aim of this clinical study was to evaluate the reproducibility of quantitative assessment of altered hepatic hemodynamics with dynamic contrast enhanced ultrasound. METHODS: Fifteen patients with colorectal liver metastases and 5 volunteers were studied. The hepatic artery proper and the portal vein were imaged simultaneously with dynamic contrast-enhanced ultrasound. The examination was repeated with 2 different contrast bolus volumes (1.2 and 2.4 mL), and time intensity curves were formed from dynamic contrast-enhanced ultrasound image loops. The rise time, peak intensity, and wash-in slope were derived from hepatic artery and portal vein time-intensity curves. Inter-reader, intra-reader, and inter-scan agreement was assessed by 2 independent readers. Quantitative (intraclass correlation coefficients and coefficients of variation [CVs]) and qualitative (Landis and Koch classification) analyses were performed. RESULTS: Intra-reader and inter-reader agreement was "almost perfect" for the hepatic artery (CV, 10%-15% and 8%-9%, respectively), portal vein (CV, 5%-8% and 6%-12%), and hepatic artery/portal vein ratio (CV, 8%-14% and 10%-15%) measurements of 3 all studied parameters. In contrast, inter-scan agreement was only "slight" to "moderate" (CV, 25%-27%) and "fair" to "moderate" (CV, 19%-24%) for rise time and peak intensity measurements in the hepatic artery and portal vein, respectively. CONCLUSIONS: Quantitative assessment of altered hepatic hemodynamics with dynamic contrast-enhanced ultrasound is reproducible provided that measurements in the hepatic artery are normalized by those in the portal vein. PMID- 22922622 TI - Value of the echocardiographic suprasternal view for diagnosis of patent ductus arteriosus subtypes. AB - OBJECTIVES: The purpose of this study was to explore the value of the transthoracic echocardiographic suprasternal view in the diagnosis of patent ductus arteriosus subtypes. METHODS: Sixty-five patients with a patent ductus arteriosus were examined using transthoracic echocardiographic suprasternal and parasternal views before ductus arteriosus closure. Diameters of the aortic and pulmonary sides of the ductus arteriosus were measured, and subtype diagnoses were made. The results were compared with those from digital subtraction angiography. RESULTS: The mean diameters +/- SD of the aortic side of the ductus arteriosus were 8.31 +/- 2.76, 10.87 +/- 3.26, and 11.15 +/- 3.29 for the parasternal view, the suprasternal view, and digital subtraction angiography, respectively, whereas the diameters of the pulmonary side were 5.69 +/- 2.82, 5.75 +/- 2.63, and 6.09 +/- 2.78 mm. Of the 65 cases, 12, 19, and 19 were the funnel-type patent ductus arteriosus as evaluated with the parasternal view, the suprasternal view, and digital subtraction angiography. Detection on the parasternal view was lower than that on the suprasternal view (chi(2) = 5.14; P < .025). CONCLUSIONS: The diameter of the aortic side of a patent ductus arteriosus can be accurately detected on the superasternal view, which would be helpful for diagnosis of patent ductus arteriosus subtypes. PMID- 22922623 TI - Carotid artery stiffness in patients with neurally mediated syncope. AB - OBJECTIVES: Neurally mediated syncope is defined as a transient loss of blood flow to the brain, resulting in vasodilatation, bradycardia, or both. The pathophysiologic mechanisms of neurally mediated syncope are not clear. In this study, we investigated carotid artery elasticity parameters in patients with neurally mediated syncope. METHODS: The study was conducted on 41 patients who were examined by the tilt table test. Group 1 constituted of 21 patients who had a positive response to the tilt table test. Clinical and hemodynamic parameters were compared with patients in a negative tilt table test group (group 2). The systolic and diastolic diameters of the carotid arteries, carotid distensibility, carotid strain, carotid stiffness index, and carotid elastic modulus of the left carotid arteries were calculated by a high-resolution ultrasound device. RESULTS: No differences in hemodynamic variables or clinical parameters were detected between the groups. Carotid distensibility (mean +/- SD, 1.6 +/- 0.6 versus 2.2 +/- 0.8 cm(2) * dyne(-1) * 10(-6); P = .044) and strain (6.8% +/- 1.7% versus 8.2% +/- 1.9%; P = .026) were lower in group 1 than in group 2. The carotid elastic modulus (0.88 +/- 0.33 versus 0.74 +/- 0.25 cm(2) * dyne(-1) * 10(-6); P = .002) and stiffness index (6.7 +/- 0.4 versus 6.2 +/- 0.5; P = .038) were higher in group 1. CONCLUSIONS: In this study, we concluded that elastic properties of the carotid artery are impaired in patients with neurally mediated syncope. This finding suggests that impaired carotid arterial elasticity may be a factor in the pathophysiologic mechanisms of neurally mediated syncope. PMID- 22922624 TI - Reduced difference in left ventricular mass at end diastole and peak systole is a predictor of major stenosis of the left coronary artery territory. AB - OBJECTIVES: To evaluate the feasibility of using the difference in left ventricular (LV) mass at end diastole and peak systole as determined by area length calculation methods to detect major stenosis of the left coronary artery territory by 2-dimensional echocardiography. METHODS: The LV mass at end diastole, LV mass at peak systole, and LV mass difference between end diastole and peak systole were measured and compared between 39 healthy participants and 40 patients with coronary artery disease (CAD) referred for coronary angiography. The mass difference was compared to the mean percent stenosis diameter by linear correlation analysis, and its performance in discrimination between the patients with CAD and the healthy participants was analyzed. RESULTS: Compared to the healthy participants, the patients with CAD had significantly higher LV mass at peak systole (mean +/- SD, 101.97 +/- 30.34 versus 89.87 +/- 28.71 g; P< .05) and a lower mass difference between end diastole and peak systole (21.36 +/- 17.55 versus 40.12 +/- 14.37 g; P < .01). The mass difference correlated significantly with the mean percent stenosis diameter (r = -0.71; P < .001) in patients with CAD . With the use of the mass difference as the criterion to distinguish patients with CAD from healthy participants, the area under the receiver operating characteristic curve was 0.81 (P < .05). The sensitivity, specificity, and accuracy for the prediction of major stenosis (>70%) of the left coronary artery were 82.35%, 70.37%, and 75% respectively for a mass difference of less than 30.2 g. CONCLUSIONS: The LV mass difference between end diastole and peak systole can effectively reflect the diameter changes of the left coronary artery, and a reduced mass difference is a sensitive and specific predictor of major stenosis of the left coronary artery territory. PMID- 22922625 TI - First-trimester assessment of the fetal palate: a novel application of the Volume NT algorithm. AB - We describe a new technique that can facilitate the first-trimester examination of the fetal palate using the Volume NT algorithm (Samsung Medison, Seoul, Korea), a program that automatically detects the exact midsagittal plane of the head and is primarily designed for semiautomatic measurement of the nuchal translucency thickness. Three-dimensional (3D) data sets from the fetal face were captured with Volume NT and subsequently reformatted with the Oblique View software to obtain orthogonal views of the primary and secondary palate in coronal and axial planes, respectively. By testing this method in selected 3D data sets obtained retrospectively (n = 12) and prospectively (n = 28), we were able to extract clinically acceptable views of the fetal palate in all cases. This preliminary report shows that with this new 3D automation development, early evaluation of the fetal palate is feasible and reproducible and could be easily incorporated into the first-trimester sonographic protocol once its ability to detect abnormal cases is demonstrated. PMID- 22922626 TI - Cesarean scar pregnancy: sonographic and magnetic resonance imaging findings, complications, and treatment. AB - A cesarean scar (ectopic) pregnancy occurs when a pregnancy implants on a cesarean scar. This condition is an uncommon but potentially devastating occurrence. The incidence is increasing as cesarean deliveries become more common. Early recognition of the salient sonographic findings is critical because a delay can lead to increased maternal morbidity and mortality. Magnetic resonance imaging is a valuable troubleshooting tool when sonography is equivocal or inconclusive before therapy or intervention. Early diagnosis by sonography directs therapy and improves outcomes by allowing preservation of the uterus and future fertility. We review the imaging features, differential diagnosis, complications, and treatment of cesarean scar pregnancies in the first trimester. PMID- 22922627 TI - Sonography of orthopedic hardware impingement of the extremities. AB - The purpose of this pictorial essay is to describe the sonographic appearance of orthopedic hardware impingement of the extremities. Sonography is not limited by metallic artifacts, can show the orthopedic hardware, and can be used to assess damage of adjacent soft tissues, including tendons, synovial bursas, muscles, nerves, and vessels. Its dynamic capabilities permit assessment of orthopedic hardware impingement present only in certain joint positions, during muscle contractions, and during tendon movements. Local pain elicited with application of pressure from the transducer confirms the diagnosis. Sonographically guided injections of steroid-anesthetic mixtures have both diagnostic and therapeutic effects. PMID- 22922628 TI - A rare demonstration of the filarial dance sign in the upper limb lymphatic vessels mimicking deep venous thrombosis. PMID- 22922629 TI - Large ovarian calcifications from an unresorbed corpus albicans. PMID- 22922630 TI - Bedside sonographic diagnosis of tracheal stenosis. PMID- 22922631 TI - Speed of sound correction and quality control. PMID- 22922632 TI - AIUM practice guideline for the performance of a musculoskeletal ultrasound examination. PMID- 22922633 TI - AIUM practice guideline for the performance of a transcranial Doppler ultrasound examination for adults and children. PMID- 22922634 TI - Risk factors and pathogenic significance of bacteremic pneumonia in adult patients with community-acquired pneumococcal pneumonia. AB - OBJECTIVE: This study was performed to identify risk factors for the development of bacteremic pneumonia and to evaluate the impact of bacteremia on the outcome of pneumococcal pneumonia. METHODS: Using a database from a surveillance study of community-acquired pneumococcal pneumonia, we compared data of the bacteremic group with that of the non-bacteremic group. RESULTS: Among 981 adult patients with pneumococcal pneumonia, 114 (11.6%) patients who had documented pneumococcal bacteremia were classified into the bacteremic group. In a multivariable analysis, use of immunosuppressant drugs, younger age (<65 years), and DM were independent risk factors associated with the development of bacteremic pneumonia among patients with pneumococcal pneumonia (all P < 0.05). The mortality rate was significantly higher in the bacteremic group than in the non-bacteremic group (28.6% vs. 8.5%; P < 0.001). The multivariable analysis revealed that concomitant bacteremia was one of the significant risk factors associated with mortality (OR, 2.57; 95% CI, 1.24-5.29), along with cerebrovascular disease and presentation with septic shock (all P < 0.05). CONCLUSIONS: Bacteremia was a common finding in pneumococcal pneumonia and was associated with a higher mortality rate. Several clinical variables may be useful for predicting bacteremic pneumonia among patients with pneumococcal pneumonia. PMID- 22922635 TI - A mixed-methods study of the quality of care provided to patients boarding in the emergency department: comparing emergency department and inpatient responsibility models. AB - Concern exists regarding care patients receive while boarding (staying in the emergency department [ED] after a decision to admit has been made). This exploratory study compares care for such ED patients under "Inpatient Responsibility" (IPR) and "ED Responsibility" (EDR) models using mixed methods. The authors abstracted quantitative data from 1,431 patient charts for ED patients admitted to two academic hospitals in 2004-2005 and interviewed 10 providers for qualitative data. The authors compared delays using logistic regression and used provider interviews to explore reasons for quantitative findings. EDR patients had more delays to receiving home medications over the first 26 hours of admission but fewer while boarding; EDR patients had fewer delayed cardiac enzymes checks. Interviews revealed that culture, resource prioritization, and systems issues made care for boarded patients challenging. A theoretically better responsibility model may not deliver better care to boarded patients because of cultural, resource prioritization, and systems issues. PMID- 22922636 TI - Public health insurance eligibility and labor force participation of low-income childless adults. AB - The Affordable Care Act aims to substantially increase public health insurance eligibility among low-income childless adults. The literature suggests that public health insurance may have important implications for labor market participation. With data from the March supplement to the Current Population Survey, difference-in-difference multivariable regression modeling is used to examine the association between state-level public health insurance expansions and the likelihood of full-time employment, part-time employment, and not working among eligible childless adults. Results indicate that public health insurance eligibility is associated with a 2.2 percentage point decrease in full-time employment, a 0.8 percentage point increase in the likelihood of part-time employment, and a 1.4 percentage point increase in the likelihood of not working. These associations were greatest among those with worse health and those aged from 50 to 64 years. This analysis provides important insights into the potential labor market repercussions of health insurance expansions under the Affordable Care Act. PMID- 22922637 TI - Estimating evapotranspiration and drought stress with ground-based thermal remote sensing in agriculture: a review. AB - As evaporation of water is an energy-demanding process, increasing evapotranspiration rates decrease the surface temperature (Ts) of leaves and plants. Based on this principle, ground-based thermal remote sensing has become one of the most important methods for estimating evapotranspiration and drought stress and for irrigation. This paper reviews its application in agriculture. The review consists of four parts. First, the basics of thermal remote sensing are briefly reviewed. Second, the theoretical relation between Ts and the sensible and latent heat flux is elaborated. A modelling approach was used to evaluate the effect of weather conditions and leaf or vegetation properties on leaf and canopy temperature. Ts increases with increasing air temperature and incoming radiation and with decreasing wind speed and relative humidity. At the leaf level, the leaf angle and leaf dimension have a large influence on Ts; at the vegetation level, Ts is strongly impacted by the roughness length; hence, by canopy height and structure. In the third part, an overview of the different ground-based thermal remote sensing techniques and approaches used to estimate drought stress or evapotranspiration in agriculture is provided. Among other methods, stress time, stress degree day, crop water stress index (CWSI), and stomatal conductance index are discussed. The theoretical models are used to evaluate the performance and sensitivity of the most important methods, corroborating the literature data. In the fourth and final part, a critical view on the future and remaining challenges of ground-based thermal remote sensing is presented. PMID- 22922638 TI - Evolution, function, and regulation of genomic imprinting in plant seed development. AB - Genomic imprinting is an epigenetic phenomenon whereby genetically identical alleles are differentially expressed dependent on their parent-of-origin. Genomic imprinting has independently evolved in flowering plants and mammals. In both organism classes, imprinting occurs in embryo-nourishing tissues, the placenta and the endosperm, respectively, and it has been proposed that imprinted genes regulate the transfer of nutrients to the developing progeny. Many imprinted genes are located in the vicinity of DNA-methylated transposon or repeat sequences, implying that transposon insertions are associated with the evolution of imprinted loci. The antagonistic action of DNA methylation and Polycomb group mediated histone methylation seems important for the regulation of many imprinted plant genes, whereby the position of such epigenetic modifications can determine whether a gene will be mainly expressed from either the maternally or paternally inherited alleles. Furthermore, long non-coding RNAs seem to play an as yet underappreciated role for the regulation of imprinted plant genes. Imprinted expression of a number of genes is conserved between monocots and dicots, suggesting that long-term selection can maintain imprinted expression at some loci. PMID- 22922639 TI - Transgenic Arabidopsis thaliana expressing a barley UDP-glucosyltransferase exhibit resistance to the mycotoxin deoxynivalenol. AB - Fusarium head blight (FHB), caused by Fusarium graminearum, is a devastating disease of small grain cereal crops. FHB causes yield reductions and contamination of grain with trichothecene mycotoxins such as deoxynivalenol (DON). DON inhibits protein synthesis in eukaryotic cells and acts as a virulence factor during fungal pathogenesis, therefore resistance to DON is considered an important component of resistance against FHB. One mechanism of resistance to DON is conversion of DON to DON-3-O-glucoside (D3G). Previous studies showed that expression of the UDP-glucosyltransferase genes HvUGT13248 from barley and AtUGt73C5 (DOGT1) from Arabidopsis thaliana conferred DON resistance to yeast. Over-expression of AtUGt73C5 in Arabidopsis led to increased DON resistance of seedlings but also to dwarfing of transgenic plants due to the formation of brassinosteroid-glucosides. The objectives of this study were to develop transgenic Arabidopsis expressing HvUGT13248, to test for phenotypic changes in growth habit, and the response to DON. Transgenic lines that constitutively expressed the epitope-tagged HvUGT13248 protein exhibited increased resistance to DON in a seed germination assay and converted DON to D3G to a higher extent than the untransformed wild-type. By contrast to the over-expression of DOGT1 in Arabidopsis, which conjugated the brassinosteriod castasterone with a glucoside group resulting in a dwarf phenotype, expression of the barley HvUGT13248 gene did not lead to drastic morphological changes. Consistent with this observation, no castasterone-glucoside formation was detectable in yeast expressing the barley HvUGT13248 gene. This barley UGT is therefore a promising candidate for transgenic approaches aiming to increase DON and Fusarium resistance of crop plants without undesired collateral effects. PMID- 22922642 TI - JAMA patient page. West Nile virus. PMID- 22922641 TI - Low cerebrospinal fluid sulfatide predicts progression of white matter lesions: The LADIS study. AB - BACKGROUND/AIMS: Demyelination and axonal degeneration are the hallmarks of established white matter lesions (WML). The neurochemistry of ongoing WML is only partially known. We explored cerebrospinal fluid (CSF) substances as markers of brain tissue damage in relation to progression of WML rated on magnetic resonance imaging. METHODS: CSF from elderly individuals with WML was analyzed for amyloid markers, total tau, hyperphosphorylated tau, neurofilament protein light subunit, sulfatide and CSF/serum-albumin ratio. After 3 years, a follow-up magnetic resonance imaging was performed. Progression of WML was rated using the Rotterdam Progression Scale (RPS). RESULTS: 37 subjects (age 73.6 +/- 4.6 years) were included. Subjects with more pronounced progression (RPS > 2; n = 15) had lower mean sulfatide concentration at baseline as compared to subjects with no or minimal progression (RPS 0-2; n = 22) according to univariate analyses (p = 0.009). Sulfatide was the only biomarker that predicted the RPS score according to regression analysis, explaining 18.9% of the total variance (r = 0.38, p = 0.015). CONCLUSION: The correlation of CSF sulfatide levels and RPS scores may reflect a remyelination response to the demyelination process associated with WML. Furthermore, the results strengthen the notion that WML pathology is different from that of Alzheimer's disease. PMID- 22922640 TI - Antisense reductions in the PsbO protein of photosystem II leads to decreased quantum yield but similar maximal photosynthetic rates. AB - Photosystem (PS) II is the multisubunit complex which uses light energy to split water, providing the reducing equivalents needed for photosynthesis. The complex is susceptible to damage from environmental stresses such as excess excitation energy and high temperature. This research investigated the in vivo photosynthetic consequences of impairments to PSII in Arabidopsis thaliana (ecotype Columbia) expressing an antisense construct to the PsbO proteins of PSII. Transgenic lines were obtained with between 25 and 60% of wild-type (WT) total PsbO protein content, with the PsbO1 isoform being more strongly reduced than PsbO2. These changes coincided with a decrease in functional PSII content. Low PsbO (less than 50% WT) plants grew more slowly and had lower chlorophyll content per leaf area. There was no change in content per unit area of cytochrome b6f, ATP synthase, or Rubisco, whereas PSI decreased in proportion to the reduction in chlorophyll content. The irradiance response of photosynthetic oxygen evolution showed that low PsbO plants had a reduced quantum yield, but matched the oxygen evolution rates of WT plants at saturating irradiance. It is suggested that these plants had a smaller pool of PSII centres, which are inefficiently connected to antenna pigments resulting in reduced photochemical efficiency. PMID- 22922643 TI - Solid state simulation of tetramer form of 5-aminoorotic acid: the vibrational spectra and molecular structure study by using MP2 and DFT calculations. AB - The Raman and IR spectra of the biomolecule 5-aminoorotic acid in the solid state were simulated by a dimer and tetramer forms, with the special interest in the interactions that involve the NH and NH(2) groups. The unit cell expected in the crystal was simulated as a tetramer form by density functional calculations. They were performed to clarify wavenumber assignments of the experimentally observed bands in the spectra. Correlations with the molecule of uracil were made, and accurate scaling procedures deduced by us were employed in the calculated wavenumbers of 5-aminoorotic acid. Good reproduction of the experimental wavenumbers is obtained and the % error is very small in the majority of cases. This fact confirms our simplified solid state model. The scaling leads to a reassignment of the IR and Raman experimental bands. The NBO atomic charges and several thermodynamic parameters were also calculated. PMID- 22922644 TI - Lubrication mechanisms of hollow-core inorganic fullerene-like nanoparticles: coupling experimental and computational works. AB - Inorganic fullerene-like (IF) nanoparticles made of metal dichalcogenides have previously been recognized to be good friction modifiers and anti-wear additives under boundary lubrication conditions. The tribological performance of these particles appears to be a result of their size, structure and morphology, along with the test conditions. However, the very small scale of the IF nanoparticles makes distinguishing the properties which affect the lubrication mechanism exceedingly difficult. In this work, a high resolution transmission electron microscope equipped with a nanoindentation holder is used to manipulate individual hollow IF-WS(2) nanoparticles and to investigate their responses to compression. Additional atomistic molecular dynamics (MD) simulations of similarly structured, individual hollow IF-MoS(2) nanoparticles are performed for compression studies between molybdenum surfaces on their major and minor axis diameters. MD simulations of these structures allows for characterization of the influence of structural orientation on the mechanical behavior and nano-sheet exfoliation of hollow-core IF nanoparticles. The experimental and theoretical results for these similar nanoparticles are qualitatively compared. PMID- 22922645 TI - RhoA/Rho kinase signaling regulates transforming growth factor-beta1-induced chondrogenesis and actin organization of synovium-derived mesenchymal stem cells through interaction with the Smad pathway. AB - Recent studies have suggested that synovium-derived mesenchymal stem cells (SMSCs) may be promising candidates for tissue engineering and play an important role in cartilage regeneration. However, the mechanisms of SMSC chondrogenesis remain to be identified and characterized. The aim of this study was to evaluate the activation of the RhoA/Rho kinase (ROCK) pathway, as well as the manner by which it may contribute to chondrogenesis and the actin cytoskeletal organization of rat temporomandibular SMSCs in response to transforming growth factor-beta1 (TGF-beta1). Primary isolated SMSCs were treated with TGF-beta1, and their actin organization was examined by fluorescein isothiocyanate-phalloidin staining. The specific biochemical inhibitors, C3 transferase, Y27632 and SB431542, were employed to evaluate the function of RhoA/ROCK and Smads. The effect of C3 transferase and Y27632 on the gene expression of chondrocyte-specific markers was evaluated by quantitative real-time polymerase chain reaction. To examine the effect of Y27632 on Smad2/3 phosphorylation induced by TGF-beta1, western blot analysis was also performed. The stimulation of TGF-beta1 in SMSCs resulted in the activation of the RhoA/ROCK pathway and concomitantly induced cytoskeletal reorganization, which was specifically blocked by C3 transferase and Y27632. The TGF-beta-induced gene expression of Sox9, type I collagen, type II collagen and aggrecan was also inhibited by both C3 transferase and Y27632, at different levels. Y27632 treatment reduced the phosphorylation of Smad2/3 in a concentration-dependent manner. These results demonstrate the RhoA/ROCK activation regulates chondrocyte-specific gene transcription and cytoskeletal organization induced by TGF-beta1 by interacting with the Smad pathway. This may have significant implications for the successful utilization of SMSCs as a cell source for articular cartilage tissue engineering. PMID- 22922646 TI - Activity in motor-sensory projections reveals distributed coding in somatosensation. AB - Cortical-feedback projections to primary sensory areas terminate most heavily in layer 1 (L1) of the neocortex, where they make synapses with tuft dendrites of pyramidal neurons. L1 input is thought to provide 'contextual' information, but the signals transmitted by L1 feedback remain uncharacterized. In the rodent somatosensory system, the spatially diffuse feedback projection from vibrissal motor cortex (vM1) to vibrissal somatosensory cortex (vS1, also known as the barrel cortex) may allow whisker touch to be interpreted in the context of whisker position to compute object location. When mice palpate objects with their whiskers to localize object features, whisker touch excites vS1 and later vM1 in a somatotopic manner. Here we use axonal calcium imaging to track activity in vM1 ->vS1 afferents in L1 of the barrel cortex while mice performed whisker-dependent object localization. Spatially intermingled individual axons represent whisker movements, touch and other behavioural features. In a subpopulation of axons, activity depends on object location and persists for seconds after touch. Neurons in the barrel cortex thus have information to integrate movements and touches of multiple whiskers over time, key components of object identification and navigation by active touch. PMID- 22922647 TI - RPN-6 determines C. elegans longevity under proteotoxic stress conditions. AB - Organisms that protect their germ-cell lineages from damage often do so at considerable cost: limited metabolic resources become partitioned away from maintenance of the soma, leaving the ageing somatic tissues to navigate survival amid an environment containing damaged and poorly functioning proteins. Historically, experimental paradigms that limit reproductive investment result in lifespan extension. We proposed that germline-deficient animals might exhibit heightened protection from proteotoxic stressors in somatic tissues. We find that the forced re-investment of resources from the germ line to the soma in Caenorhabditis elegans results in elevated somatic proteasome activity, clearance of damaged proteins and increased longevity. This activity is associated with increased expression of rpn-6, a subunit of the 19S proteasome, by the FOXO transcription factor DAF-16. Ectopic expression of rpn-6 is sufficient to confer proteotoxic stress resistance and extend lifespan, indicating that rpn-6 is a candidate to correct deficiencies in age-related protein homeostasis disorders. PMID- 22922648 TI - Genotoxic consequences of endogenous aldehydes on mouse haematopoietic stem cell function. AB - Haematopoietic stem cells (HSCs) regenerate blood cells throughout the lifespan of an organism. With age, the functional quality of HSCs declines, partly owing to the accumulation of damaged DNA. However, the factors that damage DNA and the protective mechanisms that operate in these cells are poorly understood. We have recently shown that the Fanconi anaemia DNA-repair pathway counteracts the genotoxic effects of reactive aldehydes. Mice with combined inactivation of aldehyde catabolism (through Aldh2 knockout) and the Fanconi anaemia DNA-repair pathway (Fancd2 knockout) display developmental defects, a predisposition to leukaemia, and are susceptible to the toxic effects of ethanol-an exogenous source of acetaldehyde. Here we report that aged Aldh2(-/-) Fancd2(-/-) mutant mice that do not develop leukaemia spontaneously develop aplastic anaemia, with the concomitant accumulation of damaged DNA within the haematopoietic stem and progenitor cell (HSPC) pool. Unexpectedly, we find that only HSPCs, and not more mature blood precursors, require Aldh2 for protection against acetaldehyde toxicity. Additionally, the aldehyde-oxidizing activity of HSPCs, as measured by Aldefluor stain, is due to Aldh2 and correlates with this protection. Finally, there is more than a 600-fold reduction in the HSC pool of mice deficient in both Fanconi anaemia pathway-mediated DNA repair and acetaldehyde detoxification. Therefore, the emergence of bone marrow failure in Fanconi anaemia is probably due to aldehyde-mediated genotoxicity restricted to the HSPC pool. These findings identify a new link between endogenous reactive metabolites and DNA damage in HSCs, and define the protective mechanisms that counteract this threat. PMID- 22922649 TI - Structure of the haptoglobin-haemoglobin complex. AB - Red cell haemoglobin is the fundamental oxygen-transporting molecule in blood, but also a potentially tissue-damaging compound owing to its highly reactive haem groups. During intravascular haemolysis, such as in malaria and haemoglobinopathies, haemoglobin is released into the plasma, where it is captured by the protective acute-phase protein haptoglobin. This leads to formation of the haptoglobin-haemoglobin complex, which represents a virtually irreversible non-covalent protein-protein interaction. Here we present the crystal structure of the dimeric porcine haptoglobin-haemoglobin complex determined at 2.9 A resolution. This structure reveals that haptoglobin molecules dimerize through an unexpected beta-strand swap between two complement control protein (CCP) domains, defining a new fusion CCP domain structure. The haptoglobin serine protease domain forms extensive interactions with both the alpha- and beta-subunits of haemoglobin, explaining the tight binding between haptoglobin and haemoglobin. The haemoglobin-interacting region in the alphabeta dimer is highly overlapping with the interface between the two alphabeta dimers that constitute the native haemoglobin tetramer. Several haemoglobin residues prone to oxidative modification after exposure to haem-induced reactive oxygen species are buried in the haptoglobin-haemoglobin interface, thus showing a direct protective role of haptoglobin. The haptoglobin loop previously shown to be essential for binding of haptoglobin-haemoglobin to the macrophage scavenger receptor CD163 (ref. 3) protrudes from the surface of the distal end of the complex, adjacent to the associated haemoglobin alpha-subunit. Small-angle X-ray scattering measurements of human haptoglobin-haemoglobin bound to the ligand binding fragment of CD163 confirm receptor binding in this area, and show that the rigid dimeric complex can bind two receptors. Such receptor cross-linkage may facilitate scavenging and explain the increased functional affinity of multimeric haptoglobin-haemoglobin for CD163 (ref. 4). PMID- 22922653 TI - Aging and implantable hearing solutions. Abstracts from the Cochlear Science and Research Seminar. Paris, France. March 19-20, 2012. PMID- 22922651 TI - Development of a novel primer combination to detect pathogenic Leptospira by loop mediated isothermal amplification. AB - Loop-mediated isothermal amplification (LAMP) has been used for the detection of leptospiral 16S rDNA. Here we report the development of the LAMP method for leptospiral 16S rDNA detection which can be interpreted easily within 90 min by visualizing the fluorescence of calcein. The lower limit of detection (LLOD) is 10-100 copies. PMID- 22922650 TI - Paramutation in Drosophila linked to emergence of a piRNA-producing locus. AB - A paramutation is an epigenetic interaction between two alleles of a locus, through which one allele induces a heritable modification in the other allele without modifying the DNA sequence. The paramutated allele itself becomes paramutagenic, that is, capable of epigenetically converting a new paramutable allele. Here we describe a case of paramutation in animals showing long-term transmission over generations. We previously characterized a homology-dependent silencing mechanism referred to as the trans-silencing effect (TSE), involved in P-transposable-element repression in the germ line. We now show that clusters of P-element-derived transgenes that induce strong TSE can convert other homologous transgene clusters incapable of TSE into strong silencers, which transmit the acquired silencing capacity through 50 generations. The paramutation occurs without any need for chromosome pairing between the paramutagenic and the paramutated loci, and is mediated by maternal inheritance of cytoplasm carrying Piwi-interacting RNAs (piRNAs) homologous to the transgenes. The repression capacity of the paramutated locus is abolished by a loss-of-function mutation of the aubergine gene involved in piRNA biogenesis, but not by a loss-of-function mutation of the Dicer-2 gene involved in siRNA production. The paramutated cluster, previously producing barely detectable levels of piRNAs, is converted into a stable, strong piRNA-producing locus by the paramutation and becomes fully paramutagenic itself. Our work provides a genetic model for the emergence of piRNA loci, as well as for RNA-mediated trans-generational repression of transposable elements. PMID- 22922654 TI - Implications of estimates of residential organophosphate exposure from dialkylphosphates (DAPs) and their relevance to risk. AB - Recent epidemiological studies have claimed to associate a variety of toxicological effects of organophosphorus insecticides (OPs) and residential OP exposure based on the dialkyl phosphates (DAPs; metabolic and environmental breakdown products of OPs) levels in the urine of pregnant females. A key premise in those epidemiology studies was that the level of urinary DAPs was directly related to the level of parent OP exposure. Specific chemical biomarkers and DAPs representing absorbed dose of OPs are invaluable to reconstruct human exposures in prospective occupational studies and even in non-occupational studies when exposure to a specific OP can be described. However, measurement of those detoxification products in urine without specific knowledge of insecticide exposure is insufficient to establish OP insecticide exposure. DAPs have high oral bioavailability and are ubiquitously present in produce at concentrations several-fold greater than parent OPs. Studies relying on DAPs as an indicator of OP exposure that lack credible information on proximate OP exposure are simply measuring DAP exposure and misattributing OP exposure. PMID- 22922655 TI - Colchicine protects against hyperoxic lung injury in neonatal rats. AB - BACKGROUND: Bronchopulmonary dysplasia (BPD) is characterized by inflammation, fibrosis and mucosal necrosis, which leads to emphysematous coalescence of alveoli. OBJECTIVE: We tested whether prophylaxis with colchicine , an anti inflammatory, antioxidant and antifibrotic drug, would decrease the severity of lung injury in an animal model of BPD. METHODS: Twenty-five rat pups were divided into three groups: control (n = 8), hyperoxia (n = 7), and hyperoxia + colchicine (n = 10). The hyperoxia groups were exposed to >95% oxygen from day 1 to 10 of life. On day 10, the animals were sacrificed and the lungs were processed for histology and biochemical analysis. Lung morphology was assessed by the mean linear intercept (MLI), a measure of alveolar size. The degree of lung inflammation and antioxidant capacity were assessed by quantifying lung homogenate tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta), malondialdehyde (MDA), superoxide dismutase (SOD) and glutathione peroxidase (GSH Px) levels. RESULTS: Colchicine significantly decreased lung damage as determined by the MLI in the hyperoxia groups (p < 0.01). The median level of lung MDA was significantly higher in the hyperoxia group compared with the control group (p < 0.05) and the colchicine-treated group (p < 0.05). Lung homogenate SOD and GSH-Px activities in the colchicine-treated group were significantly higher than in the hyperoxia group (p < 0.05). Furthermore, colchicine-treated pups had lower lung homogenate TNF-alpha and IL-1beta levels compared with the hyperoxia group (p < 0.05). CONCLUSIONS: Colchicine has favorable effects on alveolarization as well as inflammation and oxidative stress markers in an animal model of BPD. PMID- 22922656 TI - Impact of sinus surgery on pseudomonal airway colonization, bronchiolitis obliterans syndrome and survival in cystic fibrosis lung transplant recipients. AB - BACKGROUND: Lung transplantation (LTx) is a therapy for patients with cystic fibrosis (CF) end-stage lung disease. Pseudomonal airway colonization (PAC) is common in CF. OBJECTIVES: We investigated the influence of post-transplant sinus surgery and daily nasal douching on PAC after LTx and the influence of PAC on survival and bronchiolitis obliterans syndrome (BOS). METHODS: CF patients transplanted at our centre were included (November 1992 to December 2009). Clinical data, including microbiological data before and after LTx were collected. Survival and BOS following LTx were compared for CF recipients with and without PAC by Kaplan-Meier statistics and Cox regression analysis. RESULTS: Ninety-four CF patients were transplanted, of whom 82 (87%) underwent sinus surgery after transplantation, and 65% of 66 patients with pre-transplant PAC had persistent PAC after transplantation. Upper and lower PAC is related. Patients without PAC after transplantation had a significantly better survival rate, and BOS was less frequent with a later onset. PAC was the only significant parameter for the development of BOS stage 2 in the multivariate analysis for cytomegalovirus infection, acute rejection and PAC. CONCLUSIONS: Sinus surgery and daily nasal douching reduced PAC in LTx recipients. Absence of post transplant PAC had a positive impact on post-transplant survival and the development of BOS. PMID- 22922657 TI - Homeostasis of cerebrospinal fluid has a role in early brain development. AB - Embryonic cerebrospinal fluid (E-CSF) is a protein-containing fluid present in brain cavities that plays key roles in neuronal development and function. From the beginning of primary brain neurogenesis, E-CSF composition and homeostasis are precisely tuned by a transient blood-CSF barrier function, which controls protein transport and their relative concentration of within-brain cavities. One of the proteins found in E-CSF is ovalbumin, which is postulated to play a role in nutrition. Here, we address the question of whether neuroepithelial progenitor cells in developing chick embryos use ovalbumin as a highly specific nutritional source of amino acids or alternatively whether they use other amino acid sources, despite the fact that they cannot be transported from blood serum to brain cavities under physiological conditions. Although ovalbumin was not found to be a key protein required for neurogenesis and cell survival, our observations reinforce the crucial role of the embryonic blood-CSF barrier, as its precise regulation of protein transport and E-CSF homeostasis ensures the maximum efficiency of neural development. PMID- 22922658 TI - Short amyloid-beta immunogens with spacer-enhanced immunogenicity without junctional epitopes for Alzheimer's disease immunotherapy. AB - Induction of an immune response to amyloid-beta (Abeta) protein is effective in treating animal models of Alzheimer's disease. The Abeta1-15 sequence contains the antibody epitope(s), but lacks the T-cell reactive sites of full-length Abeta1-42. We tested two alternative peptide immunogens encompassing either a tandem repeat of GPGPG-linked Abeta1-15 sequences (2Abeta15-linker) or a tandem repeat Abeta1-15 without the spacer sequence (2Abeta15). Titers of the immunized sera were measured by indirect ELISA. We analyzed the production of interferon gamma and interleukin-4 cytokine by lymphocytes and CD4 T-cells using ELISPOT and FACS assays; we then measured CD4 T-cell proliferation using a CFSE-based lymphoproliferation assay. Immunization with 2Abeta15-linker resulted in a high anti-Abeta titer of the noninflammatory T-helper 2 isotype, a lack of lymphocyte proliferation against the spacer part peptide. We observed much lower titers against the Abeta protein after immunization with 2Abeta15. Restimulation of lymphocytes with the corresponding immunogens resulted in proliferative responses, which showed that the sequential arrangement of the epitopes created junctional epitopes. The disruption of junctional epitopes through the introduction of a GPGPG spacer restored the immunogenicity against all the epitopes. Our novel immunogen with spacer may be a safer alternative to a peptide based vaccine. PMID- 22922659 TI - Crystal structure of the C-terminal domain of Mu phage central spike and functions of bound calcium ion. AB - Bacteriophage Mu, which has a contractile tail, is one of the most famous genus of Myoviridae. It has a wide host range and is thought to contribute to horizontal gene transfer. The Myoviridae infection process is initiated by adhesion to the host surface. The phage then penetrates the host cell membrane using its tail to inject its genetic material into the host. In this penetration process, Myoviridae phages are proposed to puncture the membrane of the host cell using a central spike located beneath its baseplate. The central spike of the Mu phage is thought to be composed of gene 45 product (gp45), which has a significant sequence homology with the central spike of P2 phage (gpV). We determined the crystal structure of shortened Mu gp45Delta1-91 (Arg92-Gln197) at 1.5A resolution and showed that Mu gp45 is a needlelike structure that punctures the membrane. The apex of Mu gp45 and that of P2 gpV contained iron, chloride, and calcium ions. Although the C-terminal domain of Mu gp45 was sufficient for binding to the E. coli membrane, a mutant D188A, in which the Asp amino acid residue that coordinates the calcium ion was replaced by Ala, did not exhibit a propensity to bind to the membrane. Therefore, we concluded that calcium ion played an important role in interaction with the host cell membrane. PMID- 22922660 TI - Bipolar affective disorder and early dementia onset in a male patient with SHANK3 deletion. AB - The SHANK3 protein is a scaffold protein known to stabilize metabotropic glutamate receptor mGluR5 in the post-synaptic membrane of neurons. It is associated with genetic vulnerability in autism and schizophrenia. Here we report the case of an 18 year-old male patient who displayed psychiatric features of bipolar affective disorder associated with early setting of dementia. This mental status is related to sporadic occurrence of SHANK3 gene complex multiple deletions. A low beta amyloid protein rate (479 mg/L) found in cerebrospinal fluid suggests a possible link between SHANK3 deletion syndrome-associated regression and dementia of Alzheimers's type. In addition, we propose an overview of the phenotype related to SHANK3 deletion. PMID- 22922661 TI - Intranasal insulin modulates intrinsic reward and prefrontal circuitry of the human brain in lean women. AB - AIM: There is accumulating evidence that food consumption is controlled by a wide range of brain circuits outside of the homeostatic system. Activation in these brain circuits may override the homeostatic system and also contribute to the enormous increase of obesity. However, little is known about the influence of hormonal signals on the brain's non-homeostatic system. Thus, selective insulin action in the brain was investigated by using intranasal application. METHODS: We performed 'resting-state' functional magnetic resonance imaging in 17 healthy lean female subjects to assess intrinsic brain activity by fractional amplitude of low-frequency fluctuations (fALFF) before, 30 and 90 min after application of intranasal insulin. RESULTS: Here, we showed that insulin modulates intrinsic brain activity in the hypothalamus and orbitofrontal cortex. Furthermore, we could show that the prefrontal and anterior cingulate cortex response to insulin is associated with body mass index. CONCLUSION: This demonstrates that hormonal signals as insulin may reduce food intake by modifying the reward and prefrontal circuitry of the human brain, thereby potentially decreasing the rewarding properties of food. Due to the alarming increase in obesity worldwide, it is of great importance to identify neural mechanisms of interaction between the homeostatic and non-homeostatic system to generate new targets for obesity therapy. PMID- 22922662 TI - Trabeculectomy with or without anterior chamber maintainer and adjustable sutures. AB - PURPOSE: To assess the long-term outcomes of trabeculectomy using an anterior chamber maintainer and a combination of adjustable and releasable sutures compared with trabeculectomy using a viscoelastic and solely releasable sutures. METHODS: In a prospective, randomized, single-center study, 2 different trabeculectomy techniques were compared. One eye of each patient was randomly assigned to trabeculectomy with an anterior chamber maintainer and a combination of 2 adjustable and 2 releasable flap sutures (technique 1), whereas the other eye had trabeculectomy with viscoelastic and 2 releasable flap sutures (technique 2). The postoperative management was comparable in both groups except for the manipulation of the adjustable sutures. The main outcome measures were the postoperative intraocular pressure (IOP), the frequency of early postoperative complications and interventions, and the number of glaucoma medications. RESULTS: Thirty-two patients were included and had a follow-up of at least 18 months. The preoperative and postoperative IOP at 18 months was 22.1+/-8 and 13.3+/-2 mm Hg in the group using technique 1 and 22.7+/-7 and 13.3+/-3 mm Hg in the group using technique 2, respectively (mean+/-SD; P=0.18 for IOP reduction between both techniques). Early postoperative complications and interventions were infrequent and comparable in both techniques. The reduction in number of medications was not significantly different between the 2 groups (mean+/-SD from 2.4+/-1.0 to 0.4+/ 0.8 in the group using technique 1 and from 2.3+/-1.0 to 0.2+/-0.5 in the group using technique 2; P=0.50). CONCLUSIONS: There is no significant difference in IOP reduction, in frequency of postoperative complications and interventions, or in reduction of medications between the 2 techniques. PMID- 22922663 TI - Incidence of deepening of the upper eyelid sulcus after topical use of travoprost ophthalmic solution in Japanese. AB - PURPOSE: To investigate the incidence of deepening of the upper eyelid sulcus (DUES) with topical use of travoprost in Japanese glaucoma patients. PATIENTS AND METHODS: This prospective study enrolled 32 primary open-angle glaucoma Japanese patients who had been treated topically with travoprost unilaterally for 6 months at baseline, and started treatment in both eyes. The patients were observed during outpatient visits at 2, 4, and 6 months. At every visit, the photographs of both eyes and forehead were displayed randomly and the presence of DUES was diagnosed when 3 examiners unanimously rated the case as positive. The patients were also asked if they noticed any subjective symptom of DUES. Sex, refraction, and intraocular pressure (IOP) were evaluated as potential risk factors. RESULTS: DUES was identified objectively in 34% (11/32) of the patients after 2 months of treatment, and in 53% (17/32) after 4 and 6 months of treatment. The incidence was significantly higher in older patients (P<0.05), but not related to sex, refraction, pretreatment and posttreatment IOP, and IOP reduction. Finally, 41% (7/17) of patients with objectively diagnosed DUES noticed the presence of DUES by themselves. No patient dropped out of the study because of DUES. CONCLUSIONS: DUES is a common side effect of topical travoprost treatment in Japanese glaucoma patients. PMID- 22922664 TI - Minimally invasive external mini-glaucoma shunt implantation without conjunctival dissection. AB - The current method for implantation of the Ex-PRESS Glaucoma Filtration Device requires a conjunctival peritomy and shunt insertion under the guarded protection of a scleral flap. This technique requires suture closure of the flap and conjunctiva. A new minimally invasive technique for Ex-PRESS shunt implantation allows for insertion through a scleral tunnel originating from a grooved clear corneal incision. This new method avoids the need for conjunctival dissection and closure and offers the advantages of eliminating conjunctival wound leaks while maintaining the protection of a partial thickness scleral covering. This new technique may offer a faster safer means for shunt implantation with the potential for less conjunctival scarring. PMID- 22922665 TI - Ocular pulse amplitude in patients with descemet stripping endothelial keratoplasty. AB - PURPOSE: To study the relationship of ocular pulse amplitude (OPA) and intraocular pressure (IOP) in eyes that have undergone successful Descemet stripping endothelial keratoplasty (DSEK). PATIENTS AND METHODS: Fifty eyes of 38 patients with successful DSEK at a single tertiary referral center were followed up for at least 3 months. At the time of the study all patients were carefully examined to rule out any clinically detectable corneal edema. IOP was measured by Goldmann applanation tonometry (GAT), pneumotonometry (PT), and dynamic contour tonometry (DCT). IOP, OPA, and quality measurements were recorded. Central corneal thickness (CCT) was measured by ultrasonic pachymetry. RESULTS: Mean IOP was 15.9+/-4.9 mm Hg by GAT, 20.3+/-4.6 mm Hg by PT, and 19.8+/-4.4 mm Hg by DCT. Mean OPA was 2.53+/-1.24 mm Hg. OPA was correlated with GAT (r=0.357, P=0.011) and PT (r=0.316, P=0.026). The correlation of OPA and DCT approached significance (r=0.270, P=0.058). Mean CCT was 701+/-65 um (range, 529 to 928 um). OPA was not associated with CCT (r=0.238, P=0.096). CONCLUSIONS: In eyes with DSEK, our results showed that OPA was similar to that reported in normal eyes. Comparable with results in normal eyes, OPA was not associated with CCT but was associated with increasing IOP in DSEK eyes. PMID- 22922666 TI - Detection of early glaucomatous progression with different parameters of the RTVue optical coherence tomograph. AB - PURPOSE: To investigate the ability of different parameters of the RTVue-100 Fourier-domain optical coherence tomograph (RTVue-OCT) to detect early glaucomatous progression. METHODS: One eye of 17 healthy and 51 perimetric glaucoma patients was imaged prospectively at 6-month intervals for 1.5 to 3 years. Progression was determined by Octopus normal G2 visual field progression criteria. RESULTS: Ten of the 51 glaucoma eyes progressed based on visual field criteria. Median visual field mean defect change was -0.300 dB/y for the controls, -0.120 dB/y for all glaucoma eyes (P=0.461 vs. controls), and 1.231 dB/y for the 10 functionally progressing glaucoma eyes (P<0.001 vs. controls). Ganglion cell complex (GCC), focal loss volume, and GCC global loss volume showed significantly faster rate of progression in the glaucoma group than in controls (P=0.004 and P=0.001, respectively). No optic nerve head, retinal nerve fiber layer thickness, and average GCC parameter separated the rate of progression between the groups. CONCLUSIONS: Early structural progression of glaucoma may be better detected with pattern-based GCC parameters of the RTVue-OCT than with the optic nerve head, retinal nerve fiber layer thickness or average GCC parameters of the same instrument. PMID- 22922667 TI - The evaluation of neutrophil-lymphocyte ratio in Alzheimer's disease. AB - BACKGROUND/AIM: There is growing consensus in the literature that inflammation plays a significant role in the pathophysiology of Alzheimer's disease (AD). The blood neutrophil-lymphocyte ratio (NLR) is a new, inexpensive and easily applicable marker of inflammation. The aim of this study was to investigate the association between NLR, as an inflammatory biomarker, and AD. METHODS: 241 AD patients and 175 patients with normal cognitive function were evaluated in this study. RESULTS: The mean +/- SD NLR of AD patients was significantly higher than that of patients with normal cognitive function (3.21 +/- 1.35 vs. 2.07 +/- 0.74, p < 0.001, respectively). Receiver operating characteristic curve analysis suggested that the optimum NLR cutoff point for AD was 2.48 with 69.29% sensitivity, 79.43% specificity, 82.30% positive predictive values and 65.30% negative predictive values. Logistic regression analysis showed that elevated NLR (OR: 4.774, 95% CI: 2.821-8.076, p < 0.001) was an independent variable for predicting AD. CONCLUSION: Elderly people with AD have higher NLR than healthy controls. Elevated NLR levels are usually considered as an inflammatory marker. The results of this study suggested that inflammation plays a role in the pathogenesis of AD. PMID- 22922668 TI - Accurate and precise calibration of AFM cantilever spring constants using laser Doppler vibrometry. AB - Accurate cantilever spring constants are important in atomic force microscopy both in control of sensitive imaging and to provide correct nanomechanical property measurements. Conventional atomic force microscope (AFM) spring constant calibration techniques are usually performed in an AFM. They rely on significant handling and often require touching the cantilever probe tip to a surface to calibrate the optical lever sensitivity of the configuration. This can damage the tip. The thermal calibration technique developed for laser Doppler vibrometry (LDV) can be used to calibrate cantilevers without handling or touching the tip to a surface. Both flexural and torsional spring constants can be measured. Using both Euler-Bernoulli modeling and an SI traceable electrostatic force balance technique as a comparison we demonstrate that the LDV thermal technique is capable of providing rapid calibrations with a combination of ease, accuracy and precision beyond anything previously available. PMID- 22922669 TI - Combination therapy targeting Raf-1 and MEK causes apoptosis of HCT116 colon cancer cells. AB - Members of the Ras protooncogene family are mutated in approximately 75% of colon cancers. The Raf kinases (Raf-1, b-Raf and a-Raf) directly interact with Ras and serve as mediators of mitogenic signals. Expression of the constitutively active alleles of Raf or Ras gene families results in oncogenesis in a number of model systems. Previous studies emphasized the importance of Raf-1 and b-Raf in preventing apoptosis in addition to their roles in cell growth. In the present study, we examined whether inhibition of the Raf-1 or b-Raf kinase decreases cell growth and increases apoptosis in colon cancer cells. c-Raf and b-Raf were depleted in colon cancer cell lines, such as HCT116, HT29 and Colo205, containing Ras or b-Raf mutations by RNA interference (RNAi). The results showed that colon cancer cells with activating Ras mutations undergo apoptosis following Raf-1 inhibition, as determined by cell cycle analysis and the release of cytochrome c. Moreover, in b-Raf mutant colon cancers, the inhibition of b-Raf as compared to Raf-1 is crucial for cancer cell death. There is increasing evidence for both MEK independent Raf signaling and Raf-independent MEK signaling. Thus, we investigated whether targeting multiple points of the mitogen-activated protein kinase (MAPK) pathway with a MEK inhibitor and Raf RNAi increases cancer cell death. The results showed that combination therapy, inhibiting Raf and MEK kinases simultaneously, increased apoptosis in colon cancer cells. Taken together, our data demonstrate that combination therapy targeting the MAPK pathway at two distinct points, Raf kinase and MEK, has greater efficacy in increasing cancer cell death and is likely to improve therapeutic outcomes for patients. PMID- 22922670 TI - Contribution of endothelial progenitor cells to neovascularization (Review). AB - Endothelial progenitor cells (EPCs) are a cell population mobilized from bone marrow into the peripheral circulation and recruited into sites of vessel injury to participate in blood vessel formation in both physiological and pathological conditions. Due to the lack of unique surface markers and different isolation methods, EPCs represent heterogeneous cell populations including cells of myeloid or endothelial origin. Evidence suggests that EPCs play a critical role in postnatal blood vessel formation and vascular homeostasis and provide a promising therapy for vascular disease. However, the mechanisms by which EPCs participate in new vessel formation are still incompletely understood. We review the process of EPCs in neovascularization including EPC mobilization, migration, adhesion and effect on new vessel formation, in an attempt to better understand the underlying mechanisms and to provide potential effective management for the treatment of patients with vascular disease. PMID- 22922671 TI - The 32nd Annual Meeting of the J.B. Johnston Club for Evolutionary Neuroscience and the 24th Annual Karger Workshop in Evolutionary Neuroscience. PMID- 22922672 TI - Directed differentiation of human pluripotent stem cells into mature airway epithelia expressing functional CFTR protein. AB - Cystic fibrosis (CF) is a fatal genetic disease caused by mutations in the CFTR (cystic fibrosis transmembrane conductance regulator) gene, which regulates chloride and water transport across all epithelia and affects multiple organs, including the lungs. Here we report an in vitro directed differentiation protocol for generating functional CFTR-expressing airway epithelia from human embryonic stem cells. Carefully timed treatment by exogenous growth factors that mimic endoderm developmental pathways in vivo followed by air-liquid interface culture results in maturation of patches of tight junction-coupled differentiated airway epithelial cells that demonstrate active CFTR transport function. As a proof of concept, treatment of CF patient induced pluripotent stem cell-derived epithelial cells with a small-molecule compound to correct for the common CF processing mutation resulted in enhanced plasma membrane localization of mature CFTR protein. Our study provides a method for generating patient-specific airway epithelial cells for disease modeling and in vitro drug testing. PMID- 22922674 TI - Engineering phosphorus metabolism in plants to produce a dual fertilization and weed control system. AB - High crop yields depend on the continuous input of orthophosphate (PO(4)(-3)) based fertilizers and herbicides. Two major challenges for agriculture are that phosphorus is a nonrenewable resource and that weeds have developed broad herbicide resistance. One strategy to overcome both problems is to engineer plants to outcompete weeds and microorganisms for limiting resources, thereby reducing the requirement for both fertilizers and herbicides. Plants and most microorganisms are unable to metabolize phosphite (PO(3)(-3)), so we developed a dual fertilization and weed control system by generating transgenic plants that can use phosphite as a sole phosphorus source. Under greenhouse conditions, these transgenic plants require 30-50% less phosphorus input when fertilized with phosphite to achieve similar productivity to that obtained by the same plants using orthophosphate fertilizer and, when in competition with weeds, accumulate 2 10 times greater biomass than when fertilized with orthophosphate. PMID- 22922673 TI - Polyethyleneimine is a potent mucosal adjuvant for viral glycoprotein antigens. AB - Protection against mucosally transmitted infections probably requires immunity at the site of pathogen entry, yet there are no mucosal adjuvant formulations licensed for human use. Polyethyleneimine (PEI) represents a family of organic polycations used as nucleic acid transfection reagents in vitro and DNA vaccine delivery vehicles in vivo. Here we show that diverse PEI forms have potent mucosal adjuvant activity for viral subunit glycoprotein antigens. A single intranasal administration of influenza hemagglutinin or herpes simplex virus type 2 (HSV-2) glycoprotein D with PEI elicited robust antibody-mediated protection from an otherwise lethal infection, and was superior to existing experimental mucosal adjuvants. PEI formed nanoscale complexes with antigen, which were taken up by antigen-presenting cells in vitro and in vivo, promoted dendritic cell trafficking to draining lymph nodes and induced non-proinflammatory cytokine responses. PEI adjuvanticity required release of host double-stranded DNA that triggered Irf3-dependent signaling. PEI therefore merits further investigation as a mucosal adjuvant for human use. PMID- 22922675 TI - Intake of own mother's milk during the first days of life is associated with decreased morbidity and mortality in very low birth weight infants during the first 60 days of life. AB - BACKGROUND: The incidence of necrotizing enterocolitis (NEC) and possibly also of sepsis is lower in preterm infants fed their own mother's milk (hereafter 'mother's milk') compared with formula-fed infants. It is unclear whether this is caused by the protective properties of breast milk or by the absence of cow's milk. Especially in early life, mother's milk is often unavailable to preterm infants, while minimal enteral nutrition is initiated immediately. OBJECTIVES: To determine whether there is an association between intake of mother's milk during the first days of life and the combined outcome of sepsis, NEC and death over a prolonged period. METHODS: Retrospective study in infants with a birth weight <1,500 g. Intake of mother's milk and formula during the first 10 days of life was recorded. The occurrence of sepsis, NEC and death was registered during the first 60 days. Data were analysed using Cox regression analysis, taking confounders into account. RESULTS: In total, 349 infants were included. Intake of mother's milk during the first 5 days of life was associated with a lower incidence of NEC, sepsis and/or death during the first 60 days of life (hazard ratio (HR) in the category 0.01-50% intake of mother's milk: 0.49, 95% confidence interval (CI) 0.28, 0.87; HR in the category 50.01-100% intake of mother's milk: 0.50, 95% CI 0.31, 0.83, both compared to no mother's milk). During days 6-10, the protective effect was only present if >50% of the total intake was mother's milk (HR = 0.37, 95% CI 0.22, 0.65). CONCLUSION: The type of enteral nutrition during the first 10 days of life is associated with the risk of NEC, sepsis and/or death during the first 60 days of life. PMID- 22922676 TI - Angioarchitecture determines obliteration rate after radiosurgery in brain arteriovenous malformations. AB - BACKGROUND: Radiosurgery as a potential treatment modality for brain arteriovenous malformations (AVM) has 60% to 90% obliteration rates. OBJECTIVE: To test whether AVM angioarchitecture determines obliteration rate after radiosurgery. METHODS: This study was a retrospective analysis of 139 patients with AVM who underwent radiosurgery. Multiple angioarchitectural characteristics were reviewed on conventional angiogram on the day of radiosurgery: enlargement of feeding arteries, flow-related or intranidal aneurysms, perinidal angiogenesis, arteriovenous transit time, nidus type, venous ectasia, focal pouches, venous rerouting, and presence of a pseudophlebitic pattern. The radiation plan was reviewed for nidus volume and eloquence of AVM location. A chart review was performed to determine clinical presentation and previous treatment. Outcome was dichotomized into complete/incomplete obliteration, and various statistics were performed, examining whether outcome status was associated with the investigated factors. RESULTS: Marginal dose ranged from 15 to 25 Gy (mean, 18.8 Gy), with lower doses prescribed in eloquent locations. Sizes of AVMs ranged from 0.08 to 21 cm (mean, 3.78 +/- 4.19 cm). Complete AVM obliteration was achieved in 92 patients (66%) and was related to these independent factors: noneloquent location (odds ratio [OR], 3.20), size (OR, 0.88), low flow (OR, 3.47), no or mild arterial enlargement (OR, 3.32), and absence of perinidal angiogenesis (OR, 2.61). Concerning the 3 last angioarchitectural characteristics, if no or only a single factor was present in an individual patient (n = 92 patients), obliteration was observed in 74 (80%); if 2 or 3 factors were present (n = 47), obliteration was observed in 18 patients (38%; OR, 6.62). CONCLUSION: Angioarchitectural factors that indicate high flow are associated with a lower rate of AVM obliteration after radiosurgery. PMID- 22922677 TI - Are we underestimating the burden of traumatic brain injury? Surveillance of severe traumatic brain injury using centers for disease control International classification of disease, ninth revision, clinical modification, traumatic brain injury codes. AB - BACKGROUND: The epidemiology of traumatic brain injury (TBI) is often studied through the use of International classification of disease, ninth revision, clinical modification (ICD-9-CM), diagnosis codes from the Centers for Disease Control and Prevention TBI Surveillance System. Recent studies suggest that these codes may underestimate the burden of TBI because of inaccuracies and low sensitivity. OBJECTIVE: To determine the sensitivity and specificity of ICD-9-CM codes in a severe TBI population. METHODS: We retrospectively reviewed medical records of all hospital admissions including computed tomography of the head at a single center to identify severe blunt TBI patients, their injuries, and the neurosurgical procedures performed. We calculated sensitivity and specificity by comparing ICD-9-CM diagnosis and procedure codes assigned by hospital coders with medical records, the gold standard. RESULTS: In 2008, there were 148 qualifying admissions. These codes were 89% sensitive for the presence of any severe TBI. However, one-fifth of these cases were identified only with a code defining a nonspecific head injury. Next, we studied types of TBI by categories defined by the Centers for Disease Control and Prevention (morbidity groups) and by ICD-9-CM codes for types of injury (any skull fracture, intracranial contusion, intracranial hemorrhage, concussion/loss of consciousness) and found widely varying sensitivity and specificity for both. In general, these codes had higher specificity than sensitivity. Both sensitivity and specificity were > 80% for only 2 categories: any skull fracture and intracranial hemorrhage. In contrast, we found high sensitivity and specificity for neurosurgical procedures (97% and 94%). CONCLUSION: ICD-9-CM codes were sensitive for the presence of any severe TBI, but further classification of specific types of TBI was limited by variable sensitivity/specificity. Use of these codes should be supplemented by other methodology. PMID- 22922678 TI - Hemodynamic characteristics at the rupture site of cerebral aneurysms: a case study. AB - BACKGROUND AND IMPORTANCE: Hemodynamics play an important role in the mechanisms of aneurysm formation, growth, and rupture. However, little is known about the hemodynamics of rupture sites. CLINICAL PRESENTATION: We incidentally acquired 3 dimensional images before and at the moment of rebleeding of a cerebral aneurysm in a patient. Comparison of these 2 images enabled precise identification of the rupture site. On the basis of computational fluid dynamics simulation, we propose that there are characteristic hemodynamic parameters of the rupture site in cerebral aneurysms. We evaluated flow velocity, wall shear stress (WSS), pressure, and the oscillatory shear index to determine characteristic parameters at the rupture site. Among the hemodynamic parameters in the cardiac cycle, the rupture site was most markedly distinguished by a combination of low WSS at end diastole and high pressure at peak systole. The flow patterns around the rupture site uniquely changed in the cardiac cycle. The rupture site was an impingement zone at peak systole. Flow separation at the rupture site was observed at end diastole. CONCLUSION: In this case, a region with low WSS at end diastole and high pressure at peak systole was at the rupture site. A possible mechanism of rupture in this particular aneurysm is that low WSS at end diastole caused degeneration and thinning of the aneurysm wall and that high pressure at peak systole (impingement zone) resulted in rupture of the thinning wall. PMID- 22922679 TI - Controlling urban epidemics of West Nile virus infection. PMID- 22922680 TI - Erosive pustular dermatosis of the scalp-like eruption due to gefitinib: case report and review of the literature of alopecia associated with EGFR inhibitors. AB - A 69-year-old Japanese woman with multiple brain metastases secondary to non small-cell lung cancer was treated with radiosurgery, and subsequently started oral gefitinib. Three years later, she presented with erythematous erosive alopecia with pustules on the scalp. A biopsy specimen showed a dense perifollicular infiltration composed of lymphocytes, neutrophils and abundant plasma cells. Methicillin-resistant Staphylococcus aureus was cultured from the lesions; however, treatment with antibiotics was not effective. We diagnosed an eruption resembling erosive pustular dermatosis of the scalp. Although oral steroids did not improve the lesions, the pustules and erythema of the scalp rapidly improved within a few weeks after discontinuation of gefitinib. There have been only 11 case reports of alopecia associated with epidermal growth factor receptor (EGFR) inhibitors including our case. It is noteworthy that all cases were female, and most cases involved the parietal scalp. Moreover, the reduction or discontinuation of the EGFR inhibitors was needed in all cases with erythematous alopecia, which remained as scarring alopecia. PMID- 22922681 TI - Establishment of a human lung cancer cell line with high metastatic potential to multiple organs: gene expression associated with metastatic potential in human lung cancer. AB - Convenient and reliable multiple organ metastasis model systems might contribute to understanding the mechanism(s) of metastasis of lung cancer, which may lead to overcoming metastasis and improvement in the treatment outcome of lung cancer. We isolated a highly metastatic subline, PC14HM, from the human pulmonary adenocarcinoma cell line, PC14, using an in vivo selection method. The expression of 34,580 genes was compared between PC14HM and parental PC14 by cDNA microarray analysis. Among the differentially expressed genes, expression of four genes in human lung cancer tissues and adjacent normal lung tissues were compared using real-time reverse transcription polymerase chain reaction. Although BALB/c nude mice inoculated with parental PC14 cells had few metastases, almost all mice inoculated with PC14HM cells developed metastases in multiple organs, including the lung, bone and adrenal gland, the same progression seen in human lung cancer. cDNA microarray analysis revealed that 981 genes were differentially (more than 3 fold) expressed between the two cell lines. Functional classification revealed that many of those genes were associated with cell growth, cell communication, development and transcription. Expression of three upregulated genes (HRB-2, HS3ST3A1 and RAB7) was higher in human cancer tissue compared to normal lung tissue, while expression of EDG1, which was downregulated, was lower in the cancer tissue compared to the normal lung. These results suggest that the newly established PC14HM cell line may provide a mouse model of widespread metastasis of lung cancer. This model system may provide insights into the key genetic determinants of widespread metastasis of lung cancer. PMID- 22922682 TI - Pharmacokinetic interaction studies of co-administration of ticagrelor and atorvastatin or simvastatin in healthy volunteers. AB - PURPOSE: Interactions between ticagrelor and atorvastatin or simvastatin were investigated in two-way crossover studies. METHODS: Both studies were open-label for statin; the atorvastatin study was placebo-controlled for ticagrelor. For atorvastatin, volunteers (n = 24) received ticagrelor (loading dose 270 mg; 90 mg twice daily, 7 days) or placebo, plus atorvastatin calcium (80 mg; day 5). For simvastatin, volunteers (n = 24) received simvastatin 80 mg, or ticagrelor (loading dose 270 mg; 180 mg twice daily, 7 days) plus simvastatin (80 mg; day 5). In each study, volunteers received the alternate treatment after washout (>= 7 days). RESULTS: Ticagrelor increased mean atorvastatin maximum plasma concentration (C(max)) and area under the plasma concentration-time curve from zero to infinity (AUC) by 23 % and 36 %, respectively. Simvastatin C(max) and AUC were increased by 81 % and 56 % with ticagrelor. Ticagrelor also increased C(max) and AUC of analysed atorvastatin metabolites by 13-55 % and 32-67 %, respectively, and simvastatin acid by 64 % and 52 %, respectively. Co administration of ticagrelor with each statin was well tolerated. CONCLUSIONS: Exposure to ticagrelor and its active metabolite, AR-C124910XX, was generally unchanged by a single dose of either statin, except for a minor increase in ticagrelor C(max) in the presence of simvastatin. Effects of ticagrelor on atorvastatin pharmacokinetics were modest and unlikely clinically relevant, while with simvastatin, changes were slightly larger, and simvastatin doses >40 mg with ticagrelor should be avoided. PMID- 22922683 TI - Different patterns in use of antibiotics for lower urinary tract infection in institutionalized and home-dwelling elderly: a register-based study. AB - PURPOSE: We compared the quality and pattern of use of antibiotics to treat urinary tract infection (UTI) between institutionalized and home-dwelling elderly. METHODS: We analyzed the quality of use of UTI antibiotics in Swedish people aged >= 65 years at 30 September 2008 (1,260,843 home-dwelling and 86,721 institutionalized elderly). Data regarding drug use, age and sex were retrieved from the Swedish Prescribed Drug Register and information about type of housing from the Social Services Register. In women, we assessed: (1) the proportion who use quinolones (should be as low as possible); (2) the proportion treated with the recommended drugs (pivmecillinam, nitrofurantoin, or trimethoprim) (proportions should be about 40 %, 40 % and 15-20 %, respectively); In men, we assessed: (1) the proportion who used quinolones or trimethoprim (should be as high as possible). RESULTS: The 1-day point prevalence for antibiotic use for UTI was 1.6 % among institutionalized and 0.9 % among home-dwelling elderly. Of these, about 15 % of institutionalized and 19 % of home-dwelling women used quinolones. The proportion of women treated with the recommended drugs pivmecillinam, nitrofurantoin or trimethoprim was 29 %, 27 % and 45 % in institutions and 40 %, 28 % and 34 % for home-dwellers. In men treated with antibiotics for UTI, quinolones or trimethoprim were used by about 76 % in institutions and 85 % in home-dwellers. CONCLUSIONS: Our results indicate that recommendations for UTI treatment with antibiotics are not adequately followed. The high use of trimethoprim amongst institutionalized women and the low use of quinolones or trimethoprim among institutionalized men need further investigation. PMID- 22922684 TI - The cyclooxygenase-2 inhibitor NS-398 inhibits proliferation and induces apoptosis in human osteosarcoma cells via downregulation of the survivin pathway. AB - Cyclooxygenase-2 (COX-2) is frequently overexpressed in human malignancies and plays a crucial role in tumorigenesis and cancer progression. The present study aimed to investigate the expression and clinical significance of COX-2 and survivin (SUV) in human osteosarcomas (OS), and explore the effects and molecular mechanisms of a selective COX-2 inhibitor NS-398 and SUV on tumor proliferation and apoptosis. Fifty cases of human OS and osteochondromas (OC) were collected. The expression of COX-2 and SUV was assessed using immunohistochemical assays in biopsy samples. MG-63 human OS cells were treated with different concentrations of NS-398, used to investigate their effects on cell proliferation and apoptosis. The recombinant small hairpin RNA adenovirus vector rAd5-SUV was constructed, and the effects and molecular mechanisms of knockdown of SUV on proliferation and apoptosis were evaluated in MG-63 cells. A subcutaneous xenograft tumor model was established, validating the effects of rAd5-SUV on tumor growth in vivo. Based on the results, the expression of COX-2 and SUV in OS showed a higher strong reactivity rate compared with OC (73.3 vs. 25.0%, P=0.001; 63.3 vs. 30.0%, P=0.02), but it did not correlate with the clinicopathological characteristics of OS. NS-398 inhibited proliferation, induced apoptosis and decreased the mRNA expression of COX-2 and SUV in MG-63 cells. Furthermore, adenovirus-mediated knockdown of SUV inhibited proliferation, induced apoptosis, reduced the expression of proliferating cell nuclear antigen (PCNA), increased the expression of caspase-3 (CAS-3) and slowed the growth of xenograft tumors in MG-63 cells. Taken together, the expression of COX-2 and SUV is closely correlated with human OS, and inhibition of COX-2 or knockdown of SUV suppresses tumor proliferation and induces apoptosis, suggesting that COX-2 may be involved in OS cell proliferation and apoptosis through SUV-mediated regulation of PCNA and CAS-3 expression, and provides a potential therapeutic strategy for the treatment of cancer. PMID- 22922686 TI - Hair today... PMID- 22922685 TI - The logic of inhibitory connectivity in the neocortex. AB - Although inhibition plays a major role in the function of the mammalian neocortex, the circuit connectivity of GABAergic interneurons has remained poorly understood. The authors review recent studies of the connections made to and from interneurons, highlighting the overarching principle of a high density of unspecific connections in inhibitory connectivity. Whereas specificity remains in the subcellular targeting of excitatory neurons by interneurons, the general strategy appears to be for interneurons to provide a global "blanket of inhibition" to nearby neurons. In the review, the authors highlight the fact that the function of interneurons, which remains elusive, will be informed by understanding the structure of their connectivity as well as the dynamics of inhibitory synaptic connections. In a last section, the authors describe briefly the link between dense inhibitory networks and different interneuron functions described in the neocortex. PMID- 22922687 TI - A power and data link for a wireless-implanted neural recording system. AB - A wireless cortical neural recording system with a miniature-implanted package is needed in a variety of neuroscience and biomedical applications. Toward that end, we have developed a transcutaneous two-way communication and power system for wireless neural recording. Wireless powering and forward data transmission (into the body) at 1.25 Mbps is achieved using a frequency-shift keying modulated class E converter. The reverse telemetry (out of the body) carrier frequency is generated using an integer-N phase-locked loop, providing the necessary wideband data link to support simultaneous reverse telemetry from multiple implanted devices on separate channels. Each channel is designed to support reverse telemetry with a data rate in excess of 3 Mbps, which is sufficient for our goal of streaming 16 channels of raw neural data. We plan to incorporate this implantable power and telemetry system in a 1-cm diameter single-site cortical neural recording implant. PMID- 22922688 TI - Massively parallel energy space exploration for uncluttered visualization of vascular structures. AB - Images captured using computed tomography and magnetic resonance angiography are used in the examination of the abdominal aorta and its branches. The examination of all clinically relevant branches simultaneously in a single 2-D image without any misleading overlaps facilitates the diagnosis of vascular abnormalities. This problem is called uncluttered single-image visualization (USIV). We can solve the USIV problem by assigning energy-based scores to visualization candidates and then finding the candidate that optimizes the score; this approach is similar to the manner in which the protein side-chain placement problem has been solved. To obtain near-optimum images, we need to explore the energy space extensively, which is often time consuming. This paper describes a method for exploring the energy space in a massively parallel fashion using graphics processing units. According to our experiments, in which we used 30 images obtained from five patients, the proposed method can reduce the total visualization time substantially. We believe that the proposed method can make a significant contribution to the effective visualization of abdominal vascular structures and precise diagnosis of related abnormalities. PMID- 22922689 TI - Segmentation of the common carotid intima-media complex in ultrasound images using active contours. AB - The segmentation of the intima-media complex (IMC) of the common carotid artery (CCA) wall is important for the evaluation of the intima media thickness (IMT) on B-mode ultrasound (US) images. The IMT is considered an important marker in the evaluation of the risk for the development of atherosclerosis. The fully automated segmentation algorithm presented in this article is based on active contours and active contours without edges and incorporates anatomical information to achieve accurate segmentation. The level set formulation by Chan and Vese using random initialization provides a segmentation of the CCA US images into different distinct regions, one of which corresponds to the carotid wall region below the lumen and includes the far wall IMC. The segmented regions are used to automatically achieve image normalization, which is followed by speckle removal. The resulting smoothed lumen-intima boundary combined with anatomical information provide an excellent initialization for parametric active contours that provide the final IMC segmentation. The algorithm is extensively evaluated on 100 different cases with ground truth (GT) segmentation available from two expert clinicians. The GT mean IMT value is 0.6679 mm +/ - 0.1350 mm and the corresponding automatically segmented (AS) mean IMT value is 0.6054 mm +/ - 0.1464 mm. The mean absolute difference between the GT IMT and the IMT evaluated from from the AS region is 0.095 mm +/ - 0.0615 mm. The polyline distance is 0.096 mm +/ - 0.034 mm while the Hausdorff distance is 0.176 mm +/ - 0.047 mm. The algorithm compares favorably to both automatic and semiautomatic methods presented in the literature. PMID- 22922690 TI - An implantable, batteryless, and wireless capsule with integrated impedance and pH sensors for gastroesophageal reflux monitoring. AB - In this study, a device for gastroesophageal reflux disease (GERD) monitoring has been prototyped. The system consists of an implantable, batteryless and wireless transponder with integrated impedance and pH sensors; and a wearable, external reader that wirelessly powers up the transponder and interprets the transponded radio-frequency signals. The transponder implant with the total size of 0.4 cm * 0.8 cm * 3.8 cm harvests radio frequency energy to operate dual-sensor and load modulation circuitry. The external reader can store the data in a memory card and/or send it to a base station wirelessly, which is optional in the case of multiple-patient monitoring in a hospital or conducting large-scale freely behaving animal experiments. Tests were carried out to verify the signal transduction reliability in different situations for antenna locations and orientation. In vitro, experiments were conducted in a mannequin model by positioning the sensor capsule inside the wall of a tube mimicking the esophagus. Different liquids with known pH values were flushed through the tube creating reflux episodes and wireless signals were recorded. Live pigs under anesthesia were used for the animal models with the transponder implant attached on the esophageal wall. The reflux episodes were created while the sensor data were recorded wirelessly. The data were compared with those recorded independently by a clinically used wireless pH sensor capsule placed next to our implant transponder. The results showed that our transponder detected every episode in both acid and nonacid nature, while the commercial pH sensor missed events that had similar, repeated pH values, and failed to detect pH values higher than 10. Our batteryless transponder does not require a battery thus allowing longer diagnosis and prognosis periods to monitor drug efficacy, as well as providing accurate assessment of GERD symptoms. PMID- 22922691 TI - Retention of features on a mapped Drosophila brain surface using a Bezier-tube based surface model averaging technique. AB - Model averaging is a widely used technique in biomedical applications. Two established model averaging methods, iterative shape averaging (ISA) method and virtual insect brain (VIB) method, have been applied to several organisms to generate average representations of their brain surfaces. However, without sufficient samples, some features of the average Drosophila brain surface obtained using the above methods may disappear or become distorted. To overcome this problem, we propose a Bezier-tube-based surface model averaging strategy. The proposed method first compensates for disparities in position, orientation, and dimension of input surfaces, and then evaluates the average surface by performing shape-based interpolation. Structural features with larger individual disparities are simplified with half-ellipse-shaped Bezier tubes, and are unified according to these tubes to avoid distortion during the averaging process. Experimental results show that the average model yielded by our method could preserve fine features and avoid structural distortions even if only a limit amount of input samples are used. Finally, we qualitatively compare our results with those obtained by ISA and VIB methods by measuring the surface-to-surface distances between input surfaces and the averaged ones. The comparisons show that the proposed method could generate a more representative average surface than both ISA and VIB methods. PMID- 22922692 TI - Automatic pre- to intra-operative CT registration for image-guided cochlear implant surgery. AB - Percutaneous cochlear implantation (PCI) is a minimally-invasive image-guided cochlear implant approach, where access to the cochlea is achieved by drilling a linear channel from the skull surface to the cochlea. The PCI approach requires pre- and intra-operative planning. Computation of a safe linear drilling trajectory is performed in a preoperative CT. This trajectory is mapped to intraoperative space using the transformation matrix that registers the pre- and intra-operative CTs. However, the difference in orientation between the pre- and intra-operative CTs is too extreme to be recovered by standard, gradient descent based registration methods. Thus far, the registration has been initialized manually by an expert. In this paper, we present a method that aligns the scans completely automatically. We compared the performance of the automatic approach to the registration approach when an expert does the manual initialization on 11 pairs of scans. There is a maximum difference of 0.18 mm between the entry and target points of the trajectory mapped with expert initialization and the automatic registration method. This suggests that the automatic registration method is accurate enough to be used in a PCI surgery. PMID- 22922693 TI - Single-port video-assisted thoracoscopic anatomic segmentectomy and right upper lobectomy. AB - Video-assisted thoracoscopic surgery (VATS) segmentectomies are usually more complex procedures than lobectomies. With the gained experience in the field of thoracoscopic surgery, many thoracic surgery departments have progressively adopted this technique to preserve lung parenchyma, especially in cases of metastasis or benign conditions. The majority of surgeons use three incisions but the procedure can be performed by only one port. We report the first anatomic segmentectomy performed by uniportal VATS with no rib spreading. PMID- 22922694 TI - EuroSCORE II and the art and science of risk modelling. PMID- 22922695 TI - The role of intercostal nerve preservation in pain control after thoracotomy. AB - OBJECTIVES: Pain control after thoracotomy is an important issue that affects the outcome in thoracic surgery. Intercostal nerve preservation (ICNP) has increased interest in the outcomes of conventional thoracotomy. The current study critically evaluates the role of preservation of the intercostal nerve in early and late pain control and its benefit in patients undergoing thoracotomy. METHODS: Data obtained prospectively between January 2006 and December 2010 by a study colleague at our division of General Thoracic Surgery were retrospectively analysed. There were 491 patients who underwent thoracotomy. Eighty-one patients were excluded from the study due to incompatible data. Patients were divided into two groups according to the intercostal nerve state: Group I consisted of patients with ICNP and Group II consisted of patients with intercostal nerve sacrifice. RESULTS: Group I consisted of 288 patients [206 male (71%), P < 0.001, mean age 66 years]. Group II consisted of 122 patients [79 male (64%), P = 0.001, mean age 66 years]. There was less use of opiate in Group I (P = 0.019). Early mobilization of the patients was significantly higher in Group I (P = 0.031). The rate of pneumonia and re-admission to the intensive care unit was higher in Group II (P = 0.017 and 0.023, respectively). The rate of pain-free patients at discharge was significantly higher in Group I (P = 0.028). A 2-week follow-up after hospital discharge showed parasternal hypoesthesia to be more in Group II (P = 0.034). Significant patient contentment in Group I was noticed (P = 0.014). Chronic post-thoracotomy pain (CPTP) was higher in Group II (P = 0.016). CONCLUSIONS: ICNP without harvesting an intercostal muscle flap achieves excellent outcomes in controlling acute post-thoracotomy pain and CPTP. ICNP is an effective, simple method to perform, and it should be considered as standard in performing thoracotomy. PMID- 22922696 TI - Short- and long-term outcomes in octogenarians after coronary artery bypass surgery. AB - OBJECTIVES: Coronary artery surgery in octogenarians is carried out with an increasing frequency. We tried to determine short- and long-term outcomes and quality of life after coronary artery surgery in this patient group. METHODS: From 3312 patients undergoing isolated coronary artery bypass graft (CABG) surgery in two centres in the years 2004-06, 240 (7.2%) were older than 80 years (mean age 82.3 years, 57.1% male). The octogenarians were analysed regarding perioperative major adverse cardiac and cerebrovascular events (MACCE), late mortality and health-related quality of life (SF-12 questionnaire) and compared with 376 younger patients (mean age 66.8 years, 61.4% male) using propensity score matching. The mean follow-up time of 30-day survivors was 53 months, and follow-up completeness was 97.1%. RESULTS: The octogenarians' 30-day mortality rate was 6.8% (vs 1.6% in the younger group). In the multivariate analysis, age was a risk factor for early death [odds ratio (OR) 4.28, 95% confidence interval (CI): 1.59-11.53] and perioperative MACCE (OR 2.78, 95% CI:1.44-5.37). One-year and 3-year survivals were 94.5 and 81.4% in the octogenarians and 98 and 91.3% in the younger group. Four years after surgery, 95.2% of the octogenarians lived alone, with a partner or with relatives, and only 4.0% required permanent nursing care. 83.9% of the octogenarians would recommend surgery to their friends and relatives for relief of symptoms. CONCLUSIONS: Octogenarians can undergo CABG surgery with an acceptable risk of early death. Though late mortality is high, late quality of life is comparable with that of younger patients. PMID- 22922697 TI - Pulmonary venous aneurysm mimicking a right infrahilar tumour. PMID- 22922699 TI - Effect of iron restriction on renal damage and mineralocorticoid receptor signaling in a rat model of chronic kidney disease. AB - OBJECTIVE: Iron is associated with the pathogenesis of chronic kidney disease (CKD). Activation of mineralocorticoid receptor signaling is implicated in CKD; however, a link between iron and mineralocorticoid receptor signaling in CKD remains unknown. We have previously shown that long-term dietary iron restriction leads to increased sodium and decreased potassium excretions in the rat urine. Herein, we investigated the effect of iron restriction on renal damage and mineralocorticoid receptor signaling in a rat model of CKD. METHODS: CKD was induced by 5/6 nephrectomy in Sprague-Dawley rats. CKD rats were divided into untreated and dietary iron-restricted groups. RESULTS: CKD rats exhibited proteinuria, glomerulosclerosis, tubulointerstitinal damage, and podocyte injury. In contrast, these changes were attenuated by 16 weeks of iron-restricted diet. Consistent with these findings, iron restriction suppressed increased gene expression of collagen type III, transforming growth factor-beta, CD68, and tumor necrosis factor-alpha in the CKD kidney. Importantly, increased expression of nuclear mineralocorticoid receptor and SGK1, a key downstream effector of mineralocorticoid receptor signaling, in the CKD kidney was markedly attenuated by iron restriction. Of interest, expression of cellular iron transport proteins, transferrin receptor 1, and divalent metal transporter 1 was increased in the CKD renal tubules, along with increased iron accumulation, superoxide production, and urinary iron excretion. CKD rats also developed hypertension, although iron restriction suppressed the development of hypertension. CONCLUSION: Taken together, these data uncover a novel effect of iron restriction on renal damage and hypertension through the inhibition of renal mineralocorticoid receptor signaling. PMID- 22922698 TI - Guidelines on the management of valvular heart disease (version 2012): the Joint Task Force on the Management of Valvular Heart Disease of the European Society of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery (EACTS). PMID- 22922700 TI - Association between hypertension and musculoskeletal complaints: a population based study. AB - OBJECTIVE: To investigate the association between hypertension and musculoskeletal complaints among men and women selected by a population-based sample. METHODS: A cross-sectional study, with participants selected using a multistage sampling procedure and interviewed at home, was conducted to investigate the association between hypertension and musculoskeletal complaints. Hypertension was defined by the average of four measurements of blood pressure (BP) at least 140/90 mmHg or use of BP-lowering drugs. Musculoskeletal complaints in the 3 months before the interview were investigated by a structured questionnaire. RESULTS: Among 1858 participants, 58% were women, 64% were 18-49 years old, and 45% had up to 8 years of education. The prevalence of musculoskeletal complaint was 33% [95% confidence interval (CI) 30-36] and of hypertension was 34% (95% CI 32-37). Men and women with hypertension had higher prevalence of musculoskeletal complaint, which was no longer significant in women after adjustment for age, educational level, skin color, BMI, physical inactivity, diabetes mellitus, alcohol consumption, smoking and history of cardiovascular disease. Hypertensive men with uncontrolled hypertension using BP agents had higher prevalence of musculoskeletal complaint (adjusted risk ratio = 1.78; 95% CI 1.11-2.86). CONCLUSIONS: Chronic musculoskeletal complaints are more frequent in men with uncontrolled hypertension under drug treatment. The absence of association in women and in hypertensive men not taking BP drugs suggest that hypertension is not a risk or protection against musculoskeletal complaints. PMID- 22922701 TI - Monochorionic triplets complicated by fetofetal transfusion syndrome: a case series and review of the literature. AB - OBJECTIVE: To compare perinatal outcome in monochorionic (MC) triplets with twin to-twin transfusion syndrome (TTTS) versus dichorionic (DC) triplets with TTTS. STUDY DESIGN: Retrospective analysis of all triplets with TTTS treated at our center and all cases reported in the literature between 1990 and 2010. Survival and gestational age at birth of MC and DC triplets were compared and stratified by type of intervention. We excluded triplets with one or more fetal deaths <16 weeks' gestation and those with one or more fetuses with congenital anomalies. RESULTS: MC triplets were affected by TTTS in a total of 27 cases, and overall survival was 51% (38/75 fetuses) compared to 105 DC triplets with a survival of 76% (220/291 fetuses) (p < 0.05). Mean gestational age at birth in MC triplets was 28 weeks, compared to 31 weeks in DC triplets (p < 0.05). Perinatal survival of at least one fetus in MC triplet and DC triplet pregnancies was 70% (19/27) and 91% (96/105) (p < 0.05). In DC triplets, survival after laser therapy was significantly improved compared to expectant management, amniodrainage or selective feticide (p < 0.05). CONCLUSION: MC triplets with TTTS are at a considerably higher risk for perinatal mortality and preterm birth than DC triplets. The optimal strategy to manage MC triplets with TTTS, including the role of selective feticide and laser therapy of all anastomoses, is still to be established. PMID- 22922702 TI - Protective effect of 7-difluoromethoxy-5,4'-Di-hydroxyl isoflavone against the damage induced by glutamate in PC12 cells. AB - 7-difluoromethoxy-5,4'-Di-hydroxyl isoflavone (dFGEN), prepared by the difluoromethylation of genistein, is an active chemical entity. In this study, our main purpose was to investigate whether dFGEN had an effect on glutamate induced apoptosis in cultured PC12 cells. The PC12 cells were treated with different glutamate concentrations for 24 h in vitro. The PC12 cells impaired by glutamate were used as the cell model of excitability. Cells were incubated for 30 min with genistein, dFGEN, vitamin E, and exposed to 10 mM glutamate for 24 h. Cell morphology was observed by light microscopy. The growth and proliferation of PC12 cells were detected by 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) assay. Cell apoptosis was determined by flow cytome-try (FCM) with propidium iodide (PI) staining. The activity of lactate dehydrogenase (LDH), superoxide dismutase (SOD) and the content of malondialdelyde (MDA) were measured by kits, respectively. Acridine orange (AO) staining was used to detect characteristics of cell apoptosis. When PC12 cells were incubated with glutamate for 24 h, cells appeared to have significant changes in shape. The cellular viability was reduced and the apoptotic rate was increased. The levels of LDH and the content of MDA were increased. The activity of SOD was decreased. After PC12 cells were pretreated with dFGEN, dFGEN significantly improved cell morphology, cell growth and proliferation, suppressed apoptosis of cells, reduced the release of LDH, improving SOD activity and decreased MDA content in a concentration dependent manner. AO staining displayed that apoptosis was decreased. These results suggested that dFGEN has a protective effect against glutamate-induced damage in PC12 cells. dFGEN seemed to have a better protective effect than the lead compound genistein in a concentration-dependent manner. The mechanism of protective effect of dFGEN may be mainly related to its antioxidative activity. PMID- 22922703 TI - Prospective evaluation of behavioral scales in the behavioral variant of frontotemporal dementia. AB - BACKGROUND: The Neuropsychiatric Inventory (NPI) and the Frontal Behavioral Inventory (FBI) are widely used in patients with the behavioral variant of frontotemporal dementia (bvFTD). Yet, few data are available on the long-term relevance of these scales. MATERIAL AND METHODS: Based on a bvFTD population that participated in the Memantine Clinical Trial (NCT00200538), we studied the evolution and correlation between scores obtained on behavioral scales (NPI and FBI), cognitive scales [Mini-Mental State Examination (MMSE) and Mattis Dementia Rating Scale (MDRS)] and a burden scale [Zarit Burden Inventory (ZBI)]. The assessments were performed at 1 year in 41 patients and at 2 years in 23 patients who agreed to participate in this open-label study. RESULTS: The 2-year scores obtained on the FBI were significantly higher than the scores at inclusion while those obtained on the NPI did not change. There were significant correlations between the FBI, and the MDRS and MMSE, especially regarding the negative items. The ZBI correlated with behavioral scales at all stages for positive items. CONCLUSIONS: This study based on a large population shows that the FBI is a better tool than the NPI for the long-term assessment of bvFTD patients. Moreover, the FBI allows a distinction to be made between behavioral disturbances that involve cognitive functions from those which have an important impact on caregiver burden. PMID- 22922704 TI - Gold nanoparticles reduced in situ and dispersed in polymer thin films: optical and thermal properties. AB - Optical and thermal activity of plasmon-active nanoparticles in transparent dielectric media is of growing interest in thermal therapies, photovoltaics and optoelectronic components in which localized surface plasmon resonance (LSPR) could play a significant role. This work compares a new method to embed gold nanoparticles (AuNPs) in dense, composite films with an extension of a previously introduced method. Microscopic and spectroscopic properties of the two films are related to thermal behavior induced via laser excitation of LSPR at 532 nm in the optically transparent dielectric. Gold nanoparticles were incorporated into effectively nonporous 680 MUm thick polydimethylsiloxane (PDMS) films by (1) direct addition of organic-coated 16 nm nanoparticles; and (2) reduction of hydrogen tetrachloroaurate (TCA) into AuNPs. Power loss at LSPR excitation frequency and steady-state temperature maxima at 100 mW continuous laser irradiation showed corresponding increases with respect to the mass of gold introduced into the PDMS films by either method. Measured rates of temperature increase were higher for organic-coated NP, but higher gold content was achieved by reducing TCA, which resulted in larger overall temperature changes in reduced AuNP films. PMID- 22922705 TI - Therapist effects in the therapeutic alliance-outcome relationship: a restricted maximum likelihood meta-analysis. AB - OBJECTIVE: Although the relationship between the therapeutic alliance and outcome has been supported consistently across several studies and meta-analyses, there is less known about how the patient and therapist contribute to this relationship. The purpose of this present meta-analysis was to (1) test for therapist effects in the alliance-outcome correlation and (2) extend the findings of previous research by examining several potential confounds/covariates of this relationship. METHOD: A random effects analysis examined several moderators of the alliance-outcome correlation. These included (a) patient-therapist ratio (patient N divided by therapist N), (b) alliance and outcome rater (patient, therapist, and observer), (c) alliance measure, (d) research design and (e) DSM IV Axis II diagnosis. RESULTS: The patient-therapist ratio (PTR) was a significant moderator of the alliance-outcome correlation. Controlling for several potential confounds in a multi-predictor meta-regression, including rater of alliance, research design, percentage of patient Axis II diagnoses, rater of outcome and alliance measure, PTR remained a significant moderator of the alliance-outcome correlation. CONCLUSION: Corroborating previous research, therapist variability in the alliance appears to be more important than patient variability for improved patient outcomes. This relationship remains significant even when simultaneously controlling for several potential covariates of this relationship. PMID- 22922706 TI - Schmallenberg virus antibodies in bovine and ovine fetuses. PMID- 22922707 TI - Retrospective study of the prevalence of postanaesthetic hypothermia in dogs. AB - The anaesthetic records of 1525 dogs were examined to determine the prevalence of postanaesthetic hypothermia, its clinical predictors and consequences. Temperature was recorded throughout the anaesthesia. At the end of the procedure, details coded in were: hyperthermia (>39.50 degrees C), normothermia (38.50 degrees C-39.50 degrees C), slight (38.49 degrees C-36.50 degrees C), moderate (36.49 degrees C-34.00 degrees C) and severe hypothermia (<34.00 degrees C). Statistical analysis consisted of multiple regression to identify the factors that are associated with the temperature at the end of the procedure. Before premedication, the temperature was 38.7 +/- 0.6 degrees C (mean +/- sd). At 60, 120 and 180 minutes from induction, the temperature was 36.7 +/- 1.3 degrees C, 36.1 +/- 1.4 degrees C and 35.8 +/- 1.5 degrees C, respectively. The prevalence of hypothermia was: slight, 51.5 per cent (95 per cent CI 49.0 to 54.0 per cent); moderate, 29.3 per cent (27.1-31.7 per cent) and severe: 2.8% (2.0-3.7%). The variables that associated with a decrease in the temperature recorded at the end of the anaesthesia were: duration of the preanesthetic time, duration of the anaesthesia, physical condition (ASA III and ASA IV dogs showed lower temperatures than ASA I dogs), the reason for anaesthesia (anaesthesia for diagnostic procedures or thoracic surgery reduce the temperature when compared with minor procedures), and the recumbency during the procedure (sternal and dorsal recumbencies showed lower temperatures than lateral recumbency). The temperature before premedication and the body surface (BS) were associated with a higher temperature at the end of the anaesthesia, and would be considered as protective factors. PMID- 22922708 TI - Crystallisation pattern of vestibular mucus and its relation to vestibular electrical resistance in cycling sow. AB - Changes in the genital mucus around the oestrus are used by different diagnostic methods to determine optimal fertilisation time. In the current study, the authors evaluated the different arborisation patterns found in vestibular mucus, and also established its relationship with vestibular resistance changes during oestrus. Thirty multiparous sows were checked by transrectal ultrasonography to determine ovulation time every 12 hours. Vestibular resistance was measured with a commercial resistance probe, and vestibular mucus ferning was also evaluated every 12 hours during the oestrus. Significant changes (P < 0.05) in vestibular resistance were detected, registering high variation among individuals. Maximum resistance data was reached between 12 and 24 hours after ovulation time in 83 per cent of the sows. Crystallisation samples were classified into three different patterns according to the fern-like crystal degree. Arborisation peak occurred from 48 to 36 hours before the moment of ovulation, when vestibular resistance values increased gradually. In the optimal insemination moment, vestibular resistance increased significantly (P < 0.05) and vestibular mucus showed a low crystallisation pattern (P < 0.05). Combining several methods to measure genital mucus changes may predict the ovulation time and the best insemination moment. PMID- 22922709 TI - Peritoneal dialysis as compared with hemodialysis is associated with higher overhydration but non-inferior blood pressure control and heart function. AB - BACKGROUND/AIMS: Fluid overload is an important factor causing cardiovascular complications in dialysis patients. We compared fluid status, blood pressure (BP) and heart function between peritoneal dialysis (PD) patients and hemodialysis (HD) patients. METHODS: We recruited 94 PD and 75 HD patients in our hospital. Fluid status was assessed by bioimpedance spectroscopy. Home BP was recorded. Use of antihypertensives was retrieved by chart review. In each group, 39 patients received echocardiographic examinations. RESULTS: PD patients' fluid status was similar to that of predialysis HD patients. PD patients had lower systolic BP. E/E' and left ventricular mass index (LVMI) showed no significant intergroup difference. In multiple linear regression analyses, overhydration (OH)/extracellular water ratio >0.15 was associated with higher systolic BP, E/E' and LVMI. CONCLUSIONS: While PD was associated with higher OH but non-inferior BP control and heart function, OH was indeed related to poor BP control, diastolic dysfunction and left ventricular hypertrophy. PMID- 22922710 TI - Suppression of lymphangiogenesis in human lymphatic endothelial cells by simultaneously blocking VEGF-C and VEGF-D/VEGFR-3 with norcantharidin. AB - Lymph node metastasis of tumors is a crucial early step in the metastatic process. Tumor lymphangiogenesis plays an important role in promoting tumor metastasis to regional lymph nodes. Norcantharidin (NCTD) has been reported to possess potent anti-angiogenesis and antitumor properties in several cell lines and xenograft tumor models. However, its role in tumor-associated lymphangiogenesis and lymphatic metastasis remains unclear. Here, we investigated the effect of NCTD on proliferation, apoptosis, migration, invasion and the lymphatic tube formation, lymphangiogenesis, of human lymphatic endothelial cells (HLECs) in vitro by MTT, proliferation assay, Hoechst staining and flow cytometry, scraping line method, Matrigel invasion assay, inverted or fluorescence microscope and transmission electron microscope. Moreover, the underlying mechanisms, such as VEGF-C, VEGF-D, VEGFR-3 at protein and mRNA levels in lymphangiogenesis using 3-dimensional (3-D) culture of HLECs were measured by immunohistochemistry, western blotting and real-time polymerase chain reaction (RT-PCR). It was shown that NCTD inhibited proliferation, migration, invasion and lymphatic tube formation (forming-lymphatic and/or formed-lymphatic) of HLECs, induced HLEC apoptosis (all P<0.01) significantly, in a dose- and time-dependent manner (IC50 6.8 ug/ml); and downregulated the expression of VEGF-C, VEGF-D and VEGFR-3 at protein or/and mRNA levels (P<0.01) in HLEC lymphatic tube formation. Thus, we identified for the first time that NCTD inhibited HLEC lymphangiogenesis by simultaneously blocking VEGF-C and VEGF-D/VEGFR-3 in vitro. The present findings may be of importance to explore the therapeutical target or strategy of NCTD for tumor lymphangiogenesis and lymphatic metastasis. PMID- 22922711 TI - Shape-based regularization of electron tomographic reconstruction. AB - We introduce a tomographic reconstruction method implemented using a shape-based regularization technique. Spatial models of known features in the structure being reconstructed are integrated into the reconstruction process as regularizers. Our regularization scheme is driven locally through shape information obtained from segmentation and compared with a known spatial model. We demonstrated our method on tomography data from digital phantoms, simulated data, and experimental electron tomography (ET) data of virus complexes. Our reconstruction showed reduced blurring and an improvement in the resolution of the reconstructed volume was also measured. This method also produced improved demarcation of spike boundaries in viral membranes when compared with popular techniques like weighted back projection and the algebraic reconstruction technique. Improved ET reconstructions will provide better structure elucidation and improved feature visualization, which can aid in solving key biological issues. Our method can also be generalized to other tomographic modalities. PMID- 22922714 TI - A child with undiagnosed ADHD. PMID- 22922712 TI - CDKL5 ensures excitatory synapse stability by reinforcing NGL-1-PSD95 interaction in the postsynaptic compartment and is impaired in patient iPSC-derived neurons. AB - Mutations of the cyclin-dependent kinase-like 5 (CDKL5) and netrin-G1 (NTNG1) genes cause a severe neurodevelopmental disorder with clinical features that are closely related to Rett syndrome, including intellectual disability, early-onset intractable epilepsy and autism. We report here that CDKL5 is localized at excitatory synapses and contributes to correct dendritic spine structure and synapse activity. To exert this role, CDKL5 binds and phosphorylates the cell adhesion molecule NGL-1. This phosphorylation event ensures a stable association between NGL-1 and PSD95. Accordingly, phospho-mutant NGL-1 is unable to induce synaptic contacts whereas its phospho-mimetic form binds PSD95 more efficiently and partially rescues the CDKL5-specific spine defects. Interestingly, similarly to rodent neurons, iPSC-derived neurons from patients with CDKL5 mutations exhibit aberrant dendritic spines, thus suggesting a common function of CDKL5 in mice and humans. PMID- 22922715 TI - Hypertension in the acutely ill neurologic patient. PMID- 22922713 TI - The BBSome controls IFT assembly and turnaround in cilia. AB - The bidirectional movement of intraflagellar transport (IFT) particles, which are composed of motors, IFT-A and IFT-B subcomplexes, and cargoes, is required for the biogenesis and signalling of cilia(1,2). A successful IFT cycle depends on the proper assembly of the massive IFT particle at the ciliary base and its turnaround from anterograde to retrograde transport at the ciliary tip. However, how IFT assembly and turnaround are regulated in vivo remains elusive. From a whole-genome mutagenesis screen in Caenorhabditis elegans, we identified two hypomorphic mutations in dyf-2 and bbs-1 as the only mutants showing normal anterograde IFT transport but defective IFT turnaround at the ciliary tip. Further analyses revealed that the BBSome (refs 3, 4), a group of conserved proteins affected in human Bardet-Biedl syndrome(5) (BBS), assembles IFT complexes at the ciliary base, then binds to the anterograde IFT particle in a DYF-2- (an orthologue of human WDR19) and BBS-1-dependent manner, and lastly reaches the ciliary tip to regulate proper IFT recycling. Our results identify the BBSome as the key player regulating IFT assembly and turnaround in cilia. PMID- 22922716 TI - Voraxaze treats toxic methotrexate levels. PMID- 22922717 TI - Rheumatoid arthritis in the older adult patient. PMID- 22922721 TI - Disordered eating in adolescent females with T1DM. AB - Disordered eating behaviors are common in the adolescent population. These behaviors are especially dangerous for young females with type 1 diabetes due to frequent alterations in insulin levels. This article provides an overview of disordered eating in adolescent females with type 1 diabetes, including prevalence and morbidity, insulin omission and associated health outcomes, risk factors, and suggestions for screening and prevention. PMID- 22922722 TI - Sexually transmitted infection updates: recommendations from the CDC. AB - The CDC's latest sexually transmitted infection recommendations offer the most current diagnostic and treatment recommendations, including medication changes for drug-resistant disease and expanded sexual health histories as primary prevention of disease transmission. PMID- 22922723 TI - U-500 concentrated regular insulin: practical application in the outpatient setting. AB - Administering large insulin doses to patients with severely insulin-resistant diabetes is often ineffective, expensive, and painful. U-500 regular insulin is absorbed better, less painful, and more cost-effective due to the reduced volume. This article describes the most recent guidelines for U-500 insulin in the clinical setting. PMID- 22922725 TI - CPAP of 4 cm H(2)O Has no short-term benefit at term in infants with BPD. AB - BACKGROUND: Lung development and function is compromised at term in infants with bronchopulmonary dysplasia (BPD), characterized by reduced functional residual capacity (FRC) and impaired gas-mixing efficiency in distal airways. OBJECTIVE: To determine whether continuous positive airway pressure (CPAP) improves FRC, ventilation, distal airway function, and gas exchange in spontaneously breathing infants with BPD. DESIGN/METHODS: Twenty-one infants with BPD (median birth weight 0.72 kg (range 0.50-1.27) and median gestational age 26 weeks (range 23 28)) were studied before and after CPAP of 4 cm H(2)O was applied by a facemask system. A multiple-breath nitrogen washout method was used to assess FRC, ventilation, and gas-mixing efficiency. Moment analysis and lung clearance index was calculated from the nitrogen-decay curve for assessment of gas-mixing efficiency. Transcutaneous (Tc) PO(2)/PCO(2) was monitored during stable infant conditions before each washout test. RESULTS: When CPAP was raised from 0 to 4 cm H(2)O, FRC increased significantly together with a significant increase in moment ratios (M(1)/M(0) and M(2)/M(0)). Tc PO(2) decreased significantly and the breathing pattern changed, with significantly reduced respiratory rate, minute ventilation, and alveolar ventilation. There was also an increase in tidal volume and dead space. CONCLUSIONS: CPAP of 4 cm H(2)O applied with a facemask at term to infants with BPD did not improve ventilation, gas-mixing efficiency in distal airways, or oxygenation despite an increase in FRC. We speculate that instead of promoting recruitment of unventilated lung volumes, increasing the end-expiratory pressure in infants with BPD may lead to an overexpansion of already ventilated parts of the lung, causing further compromise of lung function. PMID- 22922726 TI - LLSURE: local linear SURE-based edge-preserving image filtering. AB - In this paper, we propose a novel approach for performing high-quality edge preserving image filtering. Based on a local linear model and using the principle of Stein's unbiased risk estimate as an estimator for the mean squared error from the noisy image only, we derive a simple explicit image filter which can filter out noise while preserving edges and fine-scale details. Moreover, this filter has a fast and exact linear-time algorithm whose computational complexity is independent of the filtering kernel size; thus, it can be applied to real time image processing tasks. The experimental results demonstrate the effectiveness of the new filter for various computer vision applications, including noise reduction, detail smoothing and enhancement, high dynamic range compression, and flash/no-flash denoising. PMID- 22922727 TI - (n, k, p)-Gray code for image systems. AB - This paper introduces a new parametric n-ary Gray code, the (n, k, p)-Gray code, which includes several commonly used codes such as the binary-reflected, ternary, and (n, k)-Gray codes. The new (n, k, p)-Gray code has potential applications in digital communications and signal/image processing systems. This paper focuses on three illustrative applications of the (n, k, p)-Gray code, namely, image bit plane decomposition, image denoising, and encryption. The computer simulations demonstrate that the (n, k, p)-Gray code shows better performance than other traditional Gray codes for these applications in image systems. PMID- 22922728 TI - Irregular breathing classification from multiple patient datasets using neural networks. AB - Complicated breathing behaviors including uncertain and irregular patterns can affect the accuracy of predicting respiratory motion for precise radiation dose delivery [3-6, 25, 36]. So far investigations on irregular breathing patterns have been limited to respiratory monitoring of only extreme inspiration and expiration [37]. Using breathing traces acquired on a Cyberknife treatment facility, we retrospectively categorized breathing data into several classes based on the extracted feature metrics derived from breathing data of multiple patients. The novelty of this paper is that the classifier using neural networks can provide clinical merit for the statistical quantitative modeling of irregular breathing motion based on a regular ratio representing how many regular/irregular patterns exist within an observation period. We propose a new approach to detect irregular breathing patterns using neural networks, where the reconstruction error can be used to build the distribution model for each breathing class. The proposed irregular breathing classification used a regular ratio to decide whether or not the current breathing patterns were regular. The sensitivity, specificity, and receiver operating characteristic (ROC) curve of the proposed irregular breathing pattern detector was analyzed. The experimental results of 448 patients breathing patterns validated the proposed irregular breathing classifier. PMID- 22922729 TI - A resource-efficient planning for pressure ulcer prevention. AB - Pressure ulcer is a critical problem for bed-ridden and wheelchair-bound patients, diabetics, and the elderly. Patients need to be regularly repositioned to prevent excessive pressure on a single area of body, which can lead to ulcers. Pressure ulcers are extremely costly to treat and may lead to several other health problems, including death. The current standard for prevention is to reposition at-risk patients every two hours. Even if it is done properly, a fixed schedule is not sufficient to prevent all ulcers. Moreover, it may result in nurses being overworked by turning some patients too frequently. In this paper, we present an algorithm for finding a nurse-effort optimal repositioning schedule that prevents pressure ulcer formation for a finite planning horizon. Our proposed algorithm uses data from a commercial pressure mat assembled on the beds surface and provides a sequence of next positions and the time of repositioning for each patient. PMID- 22922730 TI - A posture recognition based fall detection system for monitoring an elderly person in a smart home environment. AB - We propose a novel computer vision based fall detection system for monitoring an elderly person in a home care application. Background subtraction is applied to extract the foreground human body and the result is improved by using certain post-processing. Information from ellipse fitting and a projection histogram along the axes of the ellipse are used as the features for distinguishing different postures of the human. These features are then fed into a directed acyclic graph support vector machine (DAGSVM) for posture classification, the result of which is then combined with derived floor information to detect a fall. From a dataset of 15 people, we show that our fall detection system can achieve a high fall detection rate (97.08%) and a very low false detection rate (0.8%) in a simulated home environment. PMID- 22922731 TI - Curcumin inhibits HCV replication by induction of heme oxygenase-1 and suppression of AKT. AB - Although hepatitis C virus (HCV) affects approximately 130-170 million people worldwide, no vaccines are available. HCV is an important cause of chronic hepatitis, cirrhosis and hepatocellular carcinoma, leading to the need for liver transplantation. In this study, curcumin, a constituent used in traditional Chinese medicine, has been evaluated for its anti-HCV activity and mechanism, using a human hepatoma cell line containing the HCV genotype 1b subgenomic replicon. Below the concentration of 20% cytotoxicity, curcumin dose-dependently inhibited HCV replication by luciferase reporter gene assay, HCV RNA detection and HCV protein analysis. Under the same conditions, curcumin also dose dependently induced heme oxygenase-1 with the highest induction at 24 h. Hemin, a heme oxygenase-1 inducer, also inhibited HCV protein expression in a dose dependent manner. The knockdown of heme oxygenase-1 partially reversed the curcumin-inhibited HCV protein expression. In addition to the heme oxygenase-1 induction, signaling molecule activities of AKT, extracellular signal-regulated kinases (ERK) and nuclear factor-kappaB (NF-kappaB) were inhibited by curcumin. Using specific inhibitors of PI3K-AKT, MEK-ERK and NF-kappaB, the results suggested that only PI3K-AKT inhibition is positively involved in curcumin inhibited HCV replication. Inhibition of ERK and NF-kappaB was likely to promote HCV protein expression. In summary, curcumin inhibited HCV replication by heme oxygenase-1 induction and AKT pathway inhibition. Although curcumin also inhibits ERK and NF-kappaB activities, it slightly increased the HCV protein expression. This result may provide information when curcumin is used as an adjuvant in anti HCV therapy. PMID- 22922732 TI - Genomic insights from the oleaginous model alga Nannochloropsis gaditana. AB - Nannochloropsis species have emerged as leading phototrophic microorganisms for the production of biofuels. Several isolates produce large quantities of triacylglycerols, grow rapidly, and can be cultivated at industrial scales. Recently, the mitochondrial, plastid and nuclear genomes of Nannochloropsis gaditana were sequenced. Genomic interrogation revealed several key features that likely facilitate the oleaginous phenotype observed in Nannochloropsis, including an over-representation of genes involved in lipid biosynthesis. Here we present additional analyses on gene orientation, vitamin B12 requiring enzymes, the acetyl-CoA metabolic node, and codon usage in N. gaditana. Nuclear genome transformation methods are established with exogenous DNA integration occurring via either random incorporation or by homologous recombination, making Nannochloropsis amenable to both forward and reverse genetic engineering. Completion of a draft genomic sequence, establishment of transformation techniques, and robust outdoor growth properties have positioned Nannochloropsis as a new model alga with significant potential for further development into an integrated photons-to-fuel production platform. PMID- 22922734 TI - Construction of a penoid after penectomy using a transpositioned testicle. AB - Total penectomy results in a disfiguring anatomic situation which may have a devastating effect on the patient's psychologic health. Here we report our experience with construction of a penoid by covering a transpositioned testicle with remaining penile skin after radical penectomy in 2 patients with malignant underlying disease. PMID- 22922733 TI - Relationship between the expression of Rab family GTPases and neuropeptide hormones in the brain of Bombyx mori. AB - Rab proteins are small GTPases that play essential roles in vesicle transport. In this study, we examined the expression of Rab proteins and neuropeptide hormones in the brain of the silkworm, Bombyx mori. We produced antibodies against B. mori Rab1 and Rab14 in rabbits. Immunoblotting of samples of brain tissue from B. mori revealed a single band for each antibody. Rab1 and Rab14 immunohistochemical labeling in the brain of B. mori was restricted to neurons of the pars intercerebralis and dorsolateral protocerebrum. Rab1, Rab7 and Rab14 co-localized with bombyxin. Rab1 and Rab7 co-localized with eclosion hormone. Rab1 co localized with prothoracicotropic hormone. These results suggest that Rab1, Rab7 and Rab14 may be involved in neuropeptide transport in the brain of B. mori. This is the first report on the specificity of Rab proteins for the secretion of different neuropeptides in insects. PMID- 22922735 TI - Computer-aided evaluation of the anatomical accuracy of hybrid SPECT/spiral-CT imaging of lesions localized in the neck and upper abdomen. AB - OBJECTIVE: The purpose of this study was to investigate the anatomical accuracy of hardware-based single-photon emission computed tomography/computed tomography (SPECT/CT) registration in the upper abdomen and neck. METHODS: The database consisted of 90 patients referred for SPECT/CT for diagnostic workup of either thyroid/parathyroid disease (n=46) or abdominal neuroendocrine tumours (n=44). In the first group, 99mTc-MIBI was used as the tracer and in the second 123I metaiodobenzylguanidine (n=13), 111In-octreotide (n=28) or 99mTc-octreotide (n=3). For predefined structures represented by both modalities, the distances between the centres of gravity of their CT and SPECT representation were determined in a semiautomated manner. In cervical data sets, this analysis was performed for the submandibular salivary glands (n=92) and in abdominal data sets for 69 neoplastic foci. RESULTS: The mean distances were 5.7 +/- 2.0 mm (range: 1.84-9.67 mm) in the neck and 6.8 +/- 3.3 mm (range: 1.4-19.7 mm) in the abdomen. In 42 out of 92 of the cervical and 40 out of 69 of the abdominal data sets at least one of the X-direction-determined, Y-direction-determined, and Z-direction determined distances was greater than the SPECT pixel width of 4.6 mm. CONCLUSION: The anatomical accuracy of hardware-based SPECT/CT fusion depends also on the region of the body studied. For example, in the neck and upper abdomen the accuracy is lower than in the lower lumbar spine. In clinical routine, SPECT/CT data sets acquired for the neck and upper abdomen should be regularly checked and corrected for SPECT/CT misalignment. This is, in particular, important when CT-based corrections of SPECT involving pixelwise data integration such as for attenuation correction are made. PMID- 22922736 TI - Decrease in incidence of bronchopulmonary dysplasia with erythropoietin administration in preterm infants: a retrospective study. AB - BACKGROUND: Despite advances in clinical care, the incidence of bronchopulmonary dysplasia (BPD) remains high in premature infants. Erythropoietin (EPO) is used for the treatment of anemia of prematurity (AOP) to decrease blood transfusion needs. EPO has been shown to mobilize circulating endothelial progenitor cells and to enhance lung repair in animal models. OBJECTIVE: To determine whether EPO treatment for AOP was associated with a reduced incidence of BPD in premature infants. METHODS: This retrospective study was performed on all live-born neonates with birth weights from 500 to 1,500 g and gestational age (GA) from 22 to 32 weeks admitted from 1994 to 2002. Infants who received EPO and those who did not receive EPO were compared for incidence of BPD and other morbidities. RESULTS: Of 478 patients, 297 received EPO before 36 weeks' postmenstrual age (group 1) and 181 did not receive EPO (group 2). Group 1 was of similar birth weight but lower GA than group 2. The incidence of BPD was lower in group 1 than group 2 (26 vs. 36%, p = 0.03); after adjusting for significant risk factors, the adjusted odds ratio for BPD was 0.50 (95% CI 0.32, 0.79), p = 0.0028. The BPD rate was much lower when EPO was initiated before 4 weeks of age (16%) as compared to later initiation (44%). CONCLUSIONS: This study shows an association between EPO treatment and reduced incidence of BPD in preterm infants, particularly when EPO treatment was initiated within the first 4 weeks of life. PMID- 22922737 TI - Aquaporin-4 upregulated expression in glioma tissue is a reaction to glioma associated edema induced by vascular endothelial growth factor. AB - Glioma-associated edema contributes significantly to morbidity and death in patients with glioma. It has been suggested that vascular endothelial growth factor (VEGF) and aquaporin-4 (AQP4) play important roles in glioma-associated edema. However, the effect of VEGF on AQP4 expression is not clear. In this study, AQP4 expression was assayed in cultured glioma cells that express different amounts of VEGF, and AQP4 expression, vessel permeability and water content were assayed in glioma xenografts that express different amounts of VEGF. No difference in AQP4 expression was found between glioma cells expressing different VEGF amounts in vitro. However, AQP4 expression was increased in glioma tissue with increased VEGF, vessel permeability and water content. In conclusion, VEGF does not directly affect AQP-4 expression. The redistribution of AQP4 in glioblastoma cells is a reaction to vasogenic edema induced by VEGF for the purpose of facilitating reabsorption of excess fluid. The pattern of AQP4 expression in glioma provides new insights into the molecular changes occurring in glioma-associated edema and may help plan future therapeutic strategies. PMID- 22922738 TI - Impact of rapamycin on peritoneal fibrosis and transport function. AB - OBJECTIVES: To observe the impact of rapamycin on peritoneal fibrosis and peritoneal transport function in a rat model of peritoneal fibrosis. METHODS: A total of 40 male SD rats were randomly divided into five groups, with 8 rats in each group. Group N was the normal control. In group NS, the rats were injected daily with 20 ml of saline intraperitoneally. In groups GLU, L-RAPA and H-RAPA, rats were injected daily with 20 ml of 4.25% peritoneal dialysis solution intraperitoneally, together with 150 ug of lipopolysaccharide on days 1, 3, 5 and 7. Rapamycin was administered to groups L-RAPA (250 ug/day) and H-RAPA (500 ug/day) intragastrically. On days 21 and 35, 4 rats from each group were selected to evaluate their peritoneal transport function (ultrafiltration volume, D(2)/D(0) ratio). The parietal peritoneal membrane from the rats was used for pathological study. Light microscopy (HE staining and VG staining) was used to assess the morphological changes. The expression levels of Col I, alpha-SMA, TGF beta(1), Reca and Ki67 in the parietal peritoneal membrane were observed by immunohistochemistry. RESULTS: The ultrafiltration volume and D(2)/D(0) ratio decreased in group GLU compared with group N on day 21 (p < 0.05) and further decreased on day 35 (p < 0.01), whereas such a significant change was not observed in group L-RAPA or H-RAPA. Furthermore, severe loss of the peritoneal mesothelial cells, exposure of the collagen matrix under the mesothelial cells, and infiltration of fibroblasts and various inflammatory cells were detected in group GLU on days 21 and 35. The thickness of the submesothelial compact zone significantly increased in group GLU compared with group N (p < 0.01). However, in groups L-RAPA and H-RAPA, the morphological changes were clearly alleviated, and the submesothelial compact zone was thinner than in group GLU (p < 0.01). The expression levels of Col I, alpha-SMA, TGF-beta(1), Ki67 and Reca in the peritoneal membrane were significantly increased in group GLU compared with group N on days 21 and 35 (p < 0.01), whereas these changes were significantly attenuated in groups L-RAPA and H-RAPA compared with group GLU (p < 0.01). CONCLUSIONS: Rapamycin had an obvious effect in inhibiting peritoneal fibrosis and improving peritoneal membrane transport function. PMID- 22922739 TI - Chronic treatment with ginsenoside Rg3 induces Akt-dependent senescence in human glioma cells. AB - Therapy-induced senescence, an irreversible growth arrest, in cancer cells is regarded as a novel functional target that may improve cancer therapy. 20(S) ginsenoside Rg3 [20(S)-Rg3], a chemical component extracted from Panax ginseng, has recently emerged as an effective anticancer medicine with evident antitumor effects and no observed toxic adverse reactions. We report here that chronic treatment with 20(S)-Rg3 in a sub-lethal concentration induced senescence-like growth arrest in human glioma cells. Glioma cells treated with 20(S)-Rg3 showed high expression of senescence-associated beta-galactosidase, followed by upregulation of the CDK inhibitors p21 and p16. Moreover, reactive oxygen species (ROS) generation markedly increased in 20(S)-Rg3-treated cells compared with control cells. Consistently, co-incubation with the antioxidant N-acetyl cysteine interfered with 20(S)-Rg3-induced senescence in glioma cells. In addition, 20(S) Rg3-induced-activation of Akt was associated with increased ROS levels, and depletion of Akt partially prevented 20(S)-Rg3-induced ROS generation and senescence induction in glioma cells. Furthermore, 20(S)-Rg3-induced senescence was partially rescued when the p53/p21 pathway was inactivated. Our data indicate that 20(S)-Rg3 induces senescence-like growth arrest in human glioma cancer through the Akt and p53/p21-dependent signaling pathways. This is the first report of a pro-senescent effect of 20(S)-Rg3 in cancer cells. PMID- 22922740 TI - Enhanced membrane-type 1 matrix metalloproteinase expression by hyaluronan oligosaccharides in breast cancer cells facilitates CD44 cleavage and tumor cell migration. AB - Hyaluronan (HA), a component of the extracellular matrix, plays an important role in cell-cell adhesion and cell migration. Membrane type 1-matrix metalloproteinase (MT1-MMP) is often expressed in invasive cancer cells. CD44, a transmembrane receptor for HA, is implicated in various adhesion-dependent cellular processes including cell migration, tumor cell metastasis and invasion. Previous studies have shown that CD44 is highly expressed in cancer cells and may be proteolytically cleaved at the ectodomain by MT1-MMP; this process of inducing CD44 cleavage plays a critical role in cancer cell migration. We hypothesized that HA modulates MT1-MMP expression to facilitate breast cancer cell migration. Flow cytometry, real-time PCR, western blotting and immunofluorescence staining were used to quantify HA-induced MT1-MMP expression in breast cancer cells. In order to validate the relevance of cell migration and HA-induced MT1-MMP, we analyzed the cell migration via matrigel-coated transwell. We found that after HA oligosaccharide (6.5 kDA) stimulation, MT1-MMP expression in the membrane of breast cancer cells was increased. In response to HA oligosaccharide stimulation, significant upregulation of MT1-MMP mRNA occurred. Our data also provide evidence that HA oligosaccharide enhances MT1-MMP; the elevated expression of MT1-MMP confers enhanced CD44 cleavage and cell migration. In conclusion, we have identified a new function of HA in the induction of MT1-MMP expression in breast cancer cell lines and CD44 cleavage to increase cell migration during the invasion process. The HA oligosaccharide-induced MT1-MMP expression in breast cancer cells may be a critical step in the formation of metastatic colonies. PMID- 22922741 TI - Applicability of the CANTAB-PAL computerized memory test in identifying amnestic mild cognitive impairment and Alzheimer's disease. AB - AIM: To compare the diagnostic accuracy of a computerized test, the CANTAB paired associate learning (PAL) to that of an established and validated noncomputerized test, the CERAD Wordlist Learning task in differentiating between normal aging, aMCI and AD in a cross-sectional design. METHODS: 58 participants were assessed (19 with mild probable AD, 17 aMCI, 22 healthy controls). RESULTS: The variables found to best discriminate between the three groups were the CANTAB PAL total errors adjusted (p < 0.0001, 81.0% of the cases correctly classified), and CERAD Wordlist Learning Delayed Recall (p < 0.0001, 77.6% of the cases correctly classified). Using both PAL total errors adjusted and Wordlist Learning Delayed Recall, 84.5% of the cases were correctly classified. DISCUSSION: The results suggest that the CANTAB could be used for screening of AD-typical memory impairment. PMID- 22922742 TI - Telomere length regulates TERRA levels through increased trimethylation of telomeric H3K9 and HP1alpha. AB - Gene silencing by the repressive telomeric chromatin environment, referred to as telomere position effect (TPE), has been well characterized in yeast and depends on telomere length. However, proof of its existence at native human chromosome ends has remained elusive, mainly owing to the paucity of genes near telomeres. The discovery of TERRAs, the telomeric noncoding RNAs transcribed from subtelomeric promoters, paved the way to probing for telomere-length impact on physiological TPE. Using cell lines of various origins, we show that telomere elongation consistently represses TERRA expression. Repression is mediated by increased trimethylated H3K9 density at telomeres and by heterochromatin protein HP1alpha, with no detectable spreading of the marks beyond the telomeric tract, restricting human TPE to telomere transcription. Our data further support the existence of a negative-feedback mechanism in which longer TERRA molecules repress their own transcription upon telomere elongation. PMID- 22922743 TI - Chromatin remodelers Isw1 and Chd1 maintain chromatin structure during transcription by preventing histone exchange. AB - Set2-mediated methylation of histone H3 Lys36 (H3K36) is a mark associated with the coding sequences of actively transcribed genes, but it has a negative role during transcription elongation. It prevents trans-histone exchange over coding regions and signals for histone deacetylation in the wake of RNA polymerase II (RNAPII) passage. We have found that in Saccharomyces cerevisiae the Isw1b chromatin-remodeling complex is specifically recruited to open reading frames (ORFs) by H3K36 methylation through the PWWP domain of its Ioc4 subunit in vivo and in vitro. Isw1b acts in conjunction with Chd1 to regulate chromatin structure by preventing trans-histone exchange from taking place over coding regions. In this way, Isw1b and Chd1 are important in maintaining chromatin integrity during transcription elongation by RNAPII. PMID- 22922745 TI - Change is good. PMID- 22922744 TI - Osmotic and desiccation tolerance in Escherichia coli O157:H7 requires rpoS (sigma(38)). AB - The contribution of RecA, Dps, and RpoS to survival of Escherichia coli O157:H7 during desiccation and osmotic stress was determined in Luria-Bertani broth with 12 % NaCl (LB-12) at 30 and 37 degrees C, on filter disks at 23 and 30 degrees C, and in sterile bovine feces at 30 degrees C. RecA did not significantly contribute to survival in any condition or temperature. The contribution of Dps to survival was only significant in LB-12 at 37 degrees C. RpoS was necessary for survival during desiccation and osmotic stress, and survival of the RpoS mutant was significantly less than the parent in all conditions and temperatures. The RpoS mutant survived up to 21 days in bovine feces, <4 days on filter disks, and >8 and <4 days in LB-12 at 30 and 37 degrees C, respectively. The parent, DeltarecA, dps, and dps/DeltarecA mutant strains survived >8 days in LB-12, >28 days on filter disks, and >28 days in bovine feces. Increased incubation temperatures were associated with decreased survival. E. coli O157:H7 can persist in desiccating and osmotically challenging environments, especially sterile feces, for an extended period time. PMID- 22922746 TI - Meaningful use: intersections with evidence-based practice and outcomes. AB - In this department, Drs Newhouse and Wilson highlight hot topics in nursing outcomes, research, and evidence-based practice relevant to the nurse administrator. Content includes evidence-based projects and decision making, locating measurement tools for quality improvement and safety projects, using outcome measures to evaluate quality, practice implications of administrative research, and exemplars of projects that demonstrate innovative approaches to organizational problems. In this article, the authors describe the implications of meaningful use implementation to evidence-based practice and outcome measurement and discuss issues facing nurse executives in planning for these changes. PMID- 22922747 TI - Stakeholder analysis and mapping as targeted communication strategy. AB - This department highlights change management strategies that may be successful in strategically planning and executing organizational change initiatives. With the goal of presenting practical approaches helpful to nurse leaders advancing organizational change, content includes evidence-based projects, tools, and resources that mobilize and sustain organizational change initiatives. In this article, the author highlights the importance of stakeholder theory and discusses how to apply the theory to conduct a stakeholder analysis. This article also provides an explanation of how to use related stakeholder mapping techniques with targeted communication strategies. PMID- 22922748 TI - Implementing Institute of Medicine Future of Nursing recommendations: a model for transforming nurse practitioner privileges. AB - The Institute of Medicine Future of Nursing report created a sense of urgency to remove barriers preventing advanced practice RNs from practicing to their full scope of practice. With the chief nursing officer as catalyst for change, this article describes a collaborative model and process that resulted in expanded clinical privileges for nurse practitioners in an integrated healthcare system. PMID- 22922749 TI - Guidelines for successful self-scheduling on nursing units. AB - Self-scheduling programs are an increasingly popular strategy utilized by employers to address the individual and organizational challenges resulting from employee work-life imbalance among the nursing workforce. Certain key components will ensure buy-in and support from staff when self-scheduling programs are developed. PMID- 22922750 TI - The state of evidence-based practice in US nurses: critical implications for nurse leaders and educators. AB - This descriptive survey assessed the perception of evidence-based practice (EBP) among nurses in the United States. Although evidence-based healthcare results in improved patient outcomes and reduced costs, nurses do not consistently implement evidence-based best practices. A descriptive survey was conducted with a random sample of 1015 RNs who are members of the American Nurses Association. Although nurses believe in evidence-based care, barriers remain prevalent, including resistance from colleagues, nurse leaders, and managers. Differences existed in responses of nurses from Magnet(r) versus non-Magnet institutions as well as nurses with master's versus nonmaster's degrees. Nurse leaders and educators must provide learning opportunities regarding EBP and facilitate supportive cultures to achieve the Institute of Medicine's 2020 goal that 90% of clinical decisions be evidence-based. PMID- 22922751 TI - The influence of interpersonal relationships on nurse managers' work engagement and proactive work behavior. AB - OBJECTIVE: This study tested the effects of interpersonal relationships on nurse managers' work engagement and proactive work behavior. BACKGROUND: An engaged workforce may help healthcare organizations improve performance. In healthcare, nurse managers are responsible for creating motivating work environments. They also need to be engaged, yet little is known about what influences nurse managers' performance. METHODS: A self-administered electronic survey was used to collect data from 323 nurse managers working in acute care hospitals. Instruments included the Relational Coordination Scale, Utrecht Work Engagement Scale, and Proactive Work Behavior Scale. RESULTS: Interpersonal relationships with nurse administrators were most predictive of nurse managers' work engagement. Interpersonal relationships with physicians were most predictive of nurse managers' proactive work behavior. CONCLUSION: Organizational cultures that foster quality interpersonal relationships will support the job performance of nurse managers. PMID- 22922752 TI - Techniques to improve patient safety in hospitals: what nurse administrators need to know. AB - Nurse administrators are challenged to determine the best use of limited resources to support organizational patient safety improvement efforts. This article reviews the literature on techniques to reduce errors and improve patient safety in hospitals with a focus on team training initiatives. Implications for nurse administrators are discussed. PMID- 22922753 TI - Impact of the unit-based patient safety officer. AB - One organization assessed the association between increased caregiver hours per patient-day and a reduction in inpatient falls by adding a new role for a patient safety officer. Although the role was statistically significant in reducing patient falls by 50% on the intervention unit, fall reductions were not statistically significant when compared with the control unit. PMID- 22922754 TI - Changing nursing practice: letting go of the nursing history on admission. AB - In this project, 2 performance improvement (PI) methodologies were used to evaluate the process of nursing admission and history collection. Nurses have a responsibility to methodically assess bedside care, ensuring that practice changes do not merely add on to an often inefficient workload but add value. This article illustrates the use of PI to modify the initial nursing inpatient admission assessment process. PMID- 22922755 TI - Extending the continuum of care in congestive heart failure: an interactive technology self-management solution. AB - OBJECTIVE: The goal of this study was to determine if an interactive voice response system (IVRS) with daily self-management and clinical monitoring messages would be well accepted by patients and reduce 30-day congestive heart failure (CHF) readmissions. BACKGROUND: Patient adherence to a treatment regimen contributes to successful management following discharge for CHF. Cost-effective, scalable technology solutions can be useful tools in reducing readmissions. METHODS: Sixty inpatients with a primary diagnosis of CHF were provided voice messages delivered via an Mp3 player. Following discharge, patients received daily IVRS messages with self-management tips based on self-reporting of symptoms. RESULTS: Greater than a 50% reduction in the 30-day readmission rate was realized for intervention patients. CONCLUSIONS: An IVRS self-management support system can be an effective technology to reduce CHF readmissions. PMID- 22922756 TI - Optical emission of InAs nanowires. AB - Wurtzite InAs nanowire samples grown by chemical beam epitaxy have been analyzed by photoluminescence spectroscopy. The nanowires exhibit two main optical emission bands at low temperatures. They are attributed to the recombination of carriers in quantum well structures, formed by zincblende-wurtzite alternating layers, and to the donor-acceptor pair. The blue-shift observed in the former emission band when the excitation power is increased is in good agreement with the type-II band alignment between the wurtzite and zincblende sections predicted by previous theoretical works. When increasing the temperature and the excitation power successively, an additional band attributed to the band-to-band recombination from wurtzite InAs appears. We estimated a lower bound for the wurtzite band gap energy of approximately 0.46 eV at low temperature. PMID- 22922757 TI - Pyruvate kinase M2 activators promote tetramer formation and suppress tumorigenesis. AB - Cancer cells engage in a metabolic program to enhance biosynthesis and support cell proliferation. The regulatory properties of pyruvate kinase M2 (PKM2) influence altered glucose metabolism in cancer. The interaction of PKM2 with phosphotyrosine-containing proteins inhibits enzyme activity and increases the availability of glycolytic metabolites to support cell proliferation. This suggests that high pyruvate kinase activity may suppress tumor growth. We show that expression of PKM1, the pyruvate kinase isoform with high constitutive activity, or exposure to published small-molecule PKM2 activators inhibits the growth of xenograft tumors. Structural studies reveal that small-molecule activators bind PKM2 at the subunit interaction interface, a site that is distinct from that of the endogenous activator fructose-1,6-bisphosphate (FBP). However, unlike FBP, binding of activators to PKM2 promotes a constitutively active enzyme state that is resistant to inhibition by tyrosine-phosphorylated proteins. These data support the notion that small-molecule activation of PKM2 can interfere with anabolic metabolism. PMID- 22922758 TI - Ceramide targets autophagosomes to mitochondria and induces lethal mitophagy. AB - Mechanisms by which autophagy promotes cell survival or death are unclear. We provide evidence that C(18)-pyridinium ceramide treatment or endogenous C(18) ceramide generation by ceramide synthase 1 (CerS1) expression mediates autophagic cell death, independent of apoptosis in human cancer cells. C(18)-ceramide induced lethal autophagy was regulated via microtubule-associated protein 1 light chain 3 beta-lipidation, forming LC3B-II, and selective targeting of mitochondria by LC3B-II-containing autophagolysosomes (mitophagy) through direct interaction between ceramide and LC3B-II upon Drp1-dependent mitochondrial fission, leading to inhibition of mitochondrial function and oxygen consumption. Accordingly, expression of mutant LC3B with impaired ceramide binding, as predicted by molecular modeling, prevented CerS1-mediated mitochondrial targeting, recovering oxygen consumption. Moreover, knockdown of CerS1 abrogated sodium selenite induced mitophagy, and stable LC3B knockdown protected against CerS1- and C(18) ceramide-dependent mitophagy and blocked tumor suppression in vivo. Thus, these data suggest a new receptor function of ceramide for anchoring LC3B-II autophagolysosomes to mitochondrial membranes, defining a key mechanism for the induction of lethal mitophagy. PMID- 22922759 TI - PDGF-AA and bFGF mediate B104CM-induced proliferation of oligodendrocyte precursor cells. AB - The conditioned medium from B104 neuroblastoma cells (B104CM) induces proliferation of omicronligodendrocyte precursor cells (OPCs) in vitro, which indicates that certain factors contained within B104CM give instructional signals that direct the proliferation of OPCs. However, the OPC-proliferative factors present in B104CM have yet to be identified. Platelet-derived growth factor AA (PDGF-AA), basic fibroblast growth factor (bFGF) and insulin-like growth factor-1 (IGF-1) have been reported to act as potent mitogens for OPC proliferation. This raises the possibility that B104CM induces proliferation of OPCs through secretion of PDGF-AA, bFGF and/or IGF-1. In the present study, we detected the expression and levels of PDGF-AA, bFGF and IGF-1 in B104 cells and B104CM, and observed the expression of their receptors in OPCs. The results indicated that these growth factors were expressed in B104 cells and B104CM. All 3 receptors, PDGFR, FGFR2 and IGF-1R, were also detected in OPCs. Furthermore, B104CM stimulated OPC proliferation could be markedly decreased by both AG1295 (an inhibitor of PDGFR) and PD173074 (an inhibitor of FGFR). However, the inhibition of IGF-1R with AG1204 did not affect the proliferation of OPCs. Our study suggests that the PDGF-AA and bFGF in B104CM are 2 key factors that stimulate OPC proliferation. PMID- 22922760 TI - Hormone, relationships of parathyroid gamma counts, and adenoma mass in minimally invasive parathyroidectomy. AB - OBJECTIVE: To better understand relationships of parathyroid hormone (PTH) production, adenoma gamma counts, and adenoma mass in patients undergoing minimally radioguided invasive parathyroidectomy for primary hyperparathyroidism from single-gland disease. STUDY DESIGN: A prospective review of 104 patients operated on by a single surgeon. SETTING: University tertiary hospital. SUBJECTS: Adults who have primary hyperparathyroidism due to a single gland. RESULTS: There were 23 men and 81 women with an average age of 63 years. The mean (SD) adenoma mass was 0.78 (0.69) g (median, 0.57 g). The mean (SD) percent of background for the adenoma was 120.2 (90.5). Preoperative PTH and percent of background gamma count of the adenoma showed a likely correlation with a Spearman rho value of 0.2039 and a P value of .037. There were significant correlations between both percent of background of the adenoma and adenoma mass (Spearman rho = 0.4991 and P < .0001). Preoperative PTH and adenoma mass also showed a significant positive correlation (Spearman rho = 0.308 and P = .002). CONCLUSION: There exist correlations between gland mass, radioactivity, and PTH level. Adenoma radiation counts do not appear to be a proxy for changes in PTH levels measured during surgery as has been reported. Intraoperative PTH has been shown by others not to be necessary when doing radioguided parathyroid surgery if the Norman rule is observed. However, a radioguided technique and intraoperative PTH can provide complementary information in making an assessment of completion of parathyroid procedures. PMID- 22922761 TI - Microbial factories under control: auto-regulatory control through engineered stress-induced feedback. AB - Severely stressed, with their resources depleted, and their cellular machinery working beyond capacity, the host cells that are used for heterologous protein production have no option but to activate their stress response pathways in order to mitigate the accumulating effects of expressing a foreign, possibly toxic, protein at vast quantities. The result is lower protein yield and quality, with many products being misfolded or part of inclusion bodies that need further processing. Recently, new techniques aim to shift the control of protein production from humans to cells and empower the latter to regulate the production process, thus leading to increased protein quality. Herein we provide a perspective on how integrative synthetic biology can be applied to traditional biotechnological applications with potentially transformative results. PMID- 22922762 TI - ERG is specifically associated with ETS-2 and ETV-4, but not with ETS-1, in prostate cancer. AB - The erythroblast transformation-specific (ETS) family of transcription factors plays important roles in both physiological and pathological conditions. Even though many studies have focused on single ETS factors within a single tissue and within the context of specific promoters, the functional impact of multiple ETS members present within a specific cell type has not yet been investigated, especially in prostate cancer (PCa). As the most prominent gene rearrangement in PCa leads to the overexpression of the ETS-related gene (ERG), the aim of this study was to investigate whether ERG is part of a complex integrated transcriptional network that involves other ETS factors. More specifically, as the ETS family consists of 27 members, we focused our efforts initially on investigating whether ERG is associated with the three family members, ETS-1, ETS 2 and ETS variant gene-4 (ETV-4), in PCa as a proof of principle. Using western blot analysis, we show that ERG, ETS-1, ETS-2 and ETV-4 are expressed in PC3 cell nuclear extracts and in protein lysates prepared from human PCa prostatectomy specimens. Immunoprecipitations using an anti-ERG antibody were used with PC3 cell nuclear extracts as well as with a pooled protein lysate sample prepared from the PCa tissue samples of five patients. Importantly, our results revealed that ERG is specifically associated with ETS-2 and ETV-4, but not with ETS-1, in PC3 cell nuclear extracts and PCa tissue protein lysates. Our findings strongly support the notion that ERG is part of a complex integrated transcriptional network that involves other ETS factors, which are likely to cooperate or influence the activity of ERG in PCa. The functional impact of multiple ETS factors being associated with ERG in PCa requires further study, as it may provide insights into the mechanism by which ERG exerts its influence in PCa and may subsequently contribute to our understanding of the molecular basis of PCa. PMID- 22922763 TI - Drug allergy: causes and desensitization. AB - Allergic drug reactions occur when a drug, usually a low molecular weight molecule, has the ability to stimulate an immune response. This can be done in one of two ways. The first is by binding covalently to a self-protein, to produce a haptenated molecule that can be processed and presented to the adaptive immune system to induce an immune response. Sometimes the drug itself cannot do this but a reactive breakdown product of the drug is able to bind covalently to the requisite self-protein or peptide. The second way in which drugs can stimulate an immune response is by binding non-covalently to antigen presenting or antigen recognition molecules such as the major histocompatibility complex (MHC) or the T cell receptor. This is known as the p-I or pharmacological interaction hypothesis. The drug binding in this situation is reversible and stimulation of the response may occur on first exposure, not requiring previous sensitization. There is probably a dependence on the presence of certain MHC alleles and T cell receptor structures for this type of reaction to occur. PMID- 22922764 TI - A multiagent filovirus DNA vaccine delivered by intramuscular electroporation completely protects mice from ebola and Marburg virus challenge. AB - We evaluated the immunogenicity and protective efficacy of DNA vaccines expressing the codon-optimized envelope glycoprotein genes of Zaire ebolavirus, Sudan ebolavirus, and Marburg marburgvirus (Musoke and Ravn). Intramuscular or intradermal delivery of the vaccines in BALB/c mice was performed using the TriGridTM electroporation device. Mice that received DNA vaccines against the individual viruses developed robust glycoprotein-specific antibody titers as determined by ELISA and survived lethal viral challenge with no display of clinical signs of infection. Survival curve analysis revealed there was a statistically significant increase in survival compared to the control groups for both the Ebola and Ravn virus challenges. These data suggest that further analysis of the immune responses generated in the mice and additional protection studies in nonhuman primates are warranted. PMID- 22922765 TI - Development of a multicomponent Staphylococcus aureus vaccine designed to counter multiple bacterial virulence factors. AB - Staphylococcus aureus is a major cause of healthcare-associated infections and is responsible for a substantial burden of disease in hospitalized patients. Despite increasingly rigorous infection control guidelines, the prevalence and corresponding negative impact of S. aureus infections remain considerable. Difficulties in controlling S. aureus infections as well as the associated treatment costs are exacerbated by increasing rates of resistance to available antibiotics. Despite ongoing efforts over the past 20 years, no licensed S. aureus vaccine is currently available. However, learning from past clinical failures of vaccine candidates and a better understanding of the immunopathology of S. aureus colonization and infection have aided in the design of new vaccine candidates based on multiple important bacterial pathogenesis mechanisms. This review outlines important considerations in designing a vaccine for the prevention of S. aureus disease in healthcare settings. PMID- 22922766 TI - Preclinical evaluation of the immunogenicity and safety of plasmid DNA-based prophylactic vaccines for human cytomegalovirus. AB - Human cytomegalovirus (CMV) establishes a lifelong persistent infection characterized by periods of latency and sporadic viral replication and is a major infectious cause of birth defects following congenital infection. Currently, no licensed vaccine is available that would prevent CMV infection. In an effort to develop a prophylactic CMV vaccine, the effects of different formulations, immunization routes and delivery devices on the immunogenicity of plasmid DNA (pDNA)-based vaccines were evaluated in rabbits and mice. Compared with PBS- and poloxamer-based formulations, significantly higher antibody responses were obtained with pDNA formulated with Vaxfectin ((r)) , a cationic lipid-based adjuvant. With low vaccine doses, the intradermal (ID) route resulted in higher antibody responses than obtained when the same dose was administered intramuscularly (IM). Since the IM route allowed injection of larger volumes and higher doses than could be administered at a single ID site, better antibody responses were obtained using the IM route. The needle-free injection system Biojector ((r)) 2000 and electroporation devices enhanced antibody responses only marginally compared with responses obtained with Vaxfectin ((r)) -formulated pDNA injected IM with a needle. A single-vial Vaxfectin ((r)) formulation was developed in a dosage form ready for use after thawing at room temperature. Finally, in a GLP-compliant repeat-dose toxicology study conducted in rabbits, single-vial Vaxfectin ((r)) -formulated vaccines, containing pDNA and Vaxfectin ((r)) up to 4.5 mg and 2 mg/injection, respectively, showed a favorable safety profile and were judged as well-tolerated. The results support further development of a Vaxfectin ((r)) -formulated pDNA vaccine to target congenital CMV infection. PMID- 22922767 TI - Immunogenicity and immune modulatory effects of in silico predicted L. donovani candidate peptide vaccines. AB - Visceral leishmaniasis (VL) is a serious parasitic disease for which control measures are limited and drug resistance is increasing. First and second generation vaccine candidates have not been successful. The goal of the present study was to select possibly immunogenic L. donovani donovani GP63 peptides using immunoinformatics tools and to test their immunogenicity in vitro. The amino acid sequence of L. donovani donovani GP63 [GenBank accession: ACT31401] was screened using the EpiMatrix algorithm for putative T cell epitopes that would bind to the most common HLA class II alleles (DRB1*1101 and DRB1*0804) among at-risk populations. Four T cell epitopes were selected from nine potential candidates. Stimulation of whole blood from healthy volunteers using the peptides separately produced mean IFN-gamma and IL-4 levels that were not significantly different from negative controls, while the pooled peptides produced a moderate IFN-gamma increase in some volunteers. However, mean IL-10 levels were significantly reduced for all individuals compared with controls. The immunogenicity of these epitopes may be harnessed most effectively in a vaccine delivered in combination with immune-modulating adjuvants. PMID- 22922768 TI - Prevention of infection in immunosuppressive patients with autoimmune nephrosis by using an immunostimulating bacterial lysate Broncho-vaxom. AB - The utilization of immunosuppressive agents presents patients with autoimmune nephrosis at a high risk of infection. The present trial was to investigate the efficacy and safety of Broncho-Vaxom on preventing infection in immunosuppressive patients with autoimmune nephrosis. METHODS: 40 patients with autoimmune nephrosis were randomly divided into two groups. The control group (20 cases) routinely received corticosteroid and (or) immunosuppressive therapy, while the treatment group (20 cases) received a capsule containing 7 mg Broncho-Vaxom daily for the first 10 d of each month for 3 consecutive months on the basis of conventional corticosteroid and (or) immunosuppressive therapy. The condition of infection and blood lymphocyte were assessed. RESULTS: 4 patients in the treatment group and 5 patients in the control group were lost during the follow up period. 25% of patients in the treatment group and 40% of patients in the control group suffered infection. There was no difference in the incidence of infection between the two groups (p > 0.05), while Broncho-Vaxom treated patients suffered a shorter infection period and of which fewer patients need to receive antibiotics therapy (p < 0.05). After the treatment with Broncho-Vaxom, the total number of blood T lymphocyte, proportion of CD4 (+) T lymphocyte, CD4 (+) /CD8 (+) reduced less and the serum IgG rose more obviously (p < 0.05), but the blood lymphocyte, B lymphocyte, CD8 (+) T lymphocyte, IgA and IgM have no differences between the two groups (p > 0.05). CONCLUSION: Broncho-Vaxom might be a good choice for preventing the respiratory infection in nephrosis, especially in the patients under the therapy of immunosuppressive agents. PMID- 22922769 TI - Universal fungal vaccines: could there be light at the end of the tunnel? AB - The complex nature of fungal pathogens, the intricate host-pathogen relationship and the health status of subjects in need of antifungal vaccination continue to hamper efforts to develop fungal vaccines for clinical use. That said, the rise of the universal vaccine concept is hoped to revive fungal vaccine research by expanding the pool of vaccine candidates worthy of clinical evaluation. It can do so through antigenic commonality-based screening for vaccine candidates from a wide range of pathogens and by reassessing the sizable collection of already available experimental and approved vaccines. Development of experimental vaccines protective against multiple fungal pathogens is evidence of the utility of this concept in fungal vaccine research. However, universal fungal vaccines are not without difficulties; for instance, development of vaccines with differential effectiveness is an issue that should be addressed. Additionally, rationalizing the development of universal fungal vaccines on health or economic basis could be contentious. Herein, universal fungal vaccines are discussed in terms of their potential usefulness and possible drawbacks. PMID- 22922770 TI - A one-item workability measure mediates work demands, individual resources and health in the prediction of sickness absence. AB - OBJECTIVES: The study tested the hypothesis that a one-item workability measure represented an assessment of the fit between resources (the individuals' physical and mental health and functioning) and workplace demands and that this resource/demand fit was a mediator in the prediction of sickness absence. We also estimated the relative importance of health and work environment for workability and sickness absence. METHODS: Baseline data were collected within a Danish work and health survey (3,214 men and 3,529 women) and followed up in a register of sickness absence. Probit regression analysis with workability as mediator was performed for a binary outcome of sickness absence. The predictors in the analysis were as follows: age, social class, physical health, mental health, number of diagnoses, ergonomic exposures, occupational noise, exposure to risks, social support from supervisor, job control and quantitative demands. RESULTS: High age, poor health and ergonomic exposures were associated with low workability and mediated by workability to sickness absence for both genders. Low social class and low quantitative demands were associated with low workability and mediated to sickness absence among men. The mediated part was from 11 to 63 % of the total effect for the significant predictors. CONCLUSION: Workability mediated health, age, social class and ergonomic exposures in the prediction of sickness absence. The health predictors had the highest association with both workability and sickness absence; physical work environment was higher associated with the outcomes than psychosocial work environment. However, the explanatory value of the predictors for the variance in the model was low. PMID- 22922771 TI - Lower pole midsize (1-2 cm) calyceal stones: outcome analysis of 56 cases. AB - OBJECTIVES: To compare efficacy of shockwave lithotripsy (SWL) with percutaneous nephrolithotomy (PNL) and retrograde ureterorenoscopy (RUR) in the management of midsize (1-2 cm) lower calyceal stones and the impact of lower pole (LP) anatomy on lithotripsy results. PATIENTS AND METHODS: Between 2007 and 2011, 56 patients with lower calyceal stones 1-2 cm were indicated for intervention. 24 patients were treated with SWL, 19 with PNL, and 13 with RUR. RESULTS: Mean age at surgery was 53, 45 and 47 years for SWL, PNL and RUR, respectively. Mean stone size was 15.6 +/- 4.3, 17.3 +/- 3.3 and 14.5 +/- 3.2 mm, respectively. The stone-free rate was 62.5, 89.4 and 74.6%, respectively (p > 0.05). The mean time of procedures was 48.3 +/- 16 min compared to 63 +/- 32 and 76 +/- 34 min in PNL and RUR, respectively (p > 0.05). In the SWL group there was a significant difference in LP anatomical measurements between the stone-free group and residual stone group. CONCLUSION: SWL is an effective treatment modality for patients with favorable LP calyceal anatomy. PNL and RUR with laser lithotripsy are effective therapeutic alternative options in midsize (1-2 cm) lower calyceal stones. This study may be limited by its retrospective nature and modest sample size, but it is enhanced by comparing three different treatment modalities. PMID- 22922772 TI - Phylogenetic diversity of nitrogen fixation genes in the intestinal tract of Reticulitermes chinensis Snyder. AB - Wood-feeding termites live on cellulolytic materials that typically lack of nitrogen sources. It was reported that symbiotic microbes play important roles in the maintenance of a normal nitrogen contents in termite by different metabolisms including nitrogen fixation. In this study, the diversity of nitrogen-fixing organisms in the symbiotic intestinal microflora of Reticulitermes chinensis Snyder was investigated with culture independent method. Fragments of the nifH genes, which encode dinitrogenase reductase, were directly amplified from the DNA of the mixed microbial population in the termite gut with four sets of primers corresponding to the conserved regions of the genes. Clones were randomly selected and analyzed by RFLP. Sequence analysis revealed that a large number of nifH sequences retrieved from the termite gut were most closely related to strict anaerobic bacteria such as clostridia and spirochetes, some of the others were affiliated with proteobacteria, bacteroides, or methanogenic archaea. The results showed that there was a remarkable diversity of nitrogenase genes in the gut of Reticulitermes chinensis Snyder. PMID- 22922773 TI - Production of antifungal chitinase by Aspergillus niger LOCK 62 and its potential role in the biological control. AB - Aspergillus niger LOCK 62 produces an antifungal chitinase. Different sources of chitin in the medium were used to test the production of the chitinase. Chitinase production was most effective when colloidal chitin and shrimp shell were used as substrates. The optimum incubation period for chitinase production by Aspergillus niger LOCK 62 was 6 days. The chitinase was purified from the culture medium by fractionation with ammonium sulfate and affinity chromatography. The molecular mass of the purified enzyme was 43 kDa. The highest activity was obtained at 40 degrees C for both crude and purified enzymes. The crude chitinase activity was stable during 180 min incubation at 40 degrees C, but purified chitinase lost about 25 % of its activity under these conditions. Optimal pH for chitinase activity was pH 6-6.5. The activity of crude and purified enzyme was stabilized by Mg(2+) and Ca(2+) ions, but inhibited by Hg(2+) and Pb(2+) ions. Chitinase isolated from Aspergillus niger LOCK 62 inhibited the growth of the fungal phytopathogens: Fusarium culmorum, Fusarium solani and Rhizoctonia solani. The growth of Botrytis cinerea, Alternaria alternata, and Fusarium oxysporum was not affected. PMID- 22922775 TI - Evaluation of adrenal reserve in children with acute lymphocytic leukemia treated with prednisone or dexamethasone. AB - BACKGROUND/AIMS: The purpose of this study was to compare adrenal gland reserve in acute lymphocytic leukemia (ALL) patients 8 weeks after treatment with either prednisone (PRED) or dexamethasone (DEX) during the induction phase of therapy. METHODS: A double-blind comparative study of patients treated with PRED and DEX was performed. Sixteen patients received PRED (40 mg/m(2)/day) and 13 patients received DEX (6 mg/m(2)/day), both for 28 days. A low-dose adrenocorticotropic hormone test (1.0 ug/m(2), IV) was performed before and weekly for 8 weeks after abrupt cessation of glucocorticoid therapy. Sixteen children without ALL were used as controls to determine the cutoff peak cortisol level (14.2 ug/dl). RESULTS: Both groups (PRED and DEX) displayed similar mean peak cortisol levels before treatment and during the 8 weeks of evaluation (p = 0.652). No relationship was observed between the incidence of infection/stress and peak cortisol level within each group, nor was there a difference in the frequency of infection/stress between groups (p = 0.359). Although the patients presented variations in peak cortisol during the study period, no signs or symptoms of adrenal insufficiency were observed. CONCLUSION: Patients who received PRED or DEX for 4 weeks showed similar adrenal reserves and infection rates for 8 weeks after abruptly stopping glucocorticoid therapy, suggesting that DEX, which is a better antileukemic drug than PRED, has similar adrenal suppression and recovery rates. PMID- 22922776 TI - Network for development of electroporation-based technologies and treatments: COST TD1104. AB - Exposure of biological cells to a sufficiently strong external electric field results in increased permeability of cell membranes, referred to as "electroporation." Since all types of cells (animal, plant and microorganism) can be effectively electroporated, electroporation is considered to be a universal method and a platform technology. Electroporation has become a widely used technology applicable to, e.g., cancer treatment, gene transfection, food and biomass processing and microbial inactivation. However, despite significant progress in electroporation-based applications, there is a lack of coordination and interdisciplinary exchange of knowledge between researchers from different scientific domains. Thus, critical mass for new major breakthroughs is missing. This is why we decided to establish cooperation between research groups working in different fields of electroporation. Cooperation in Science and Technology (COST), which funds networking and capacity-building activities, presents a perfect framework for such scientific cooperation. This COST action aims at (1) providing necessary steps toward EU cooperation of science and technology to foster basic understanding of electroporation; (2) improving communication between research groups, resulting in streamlining European research and development activities; and (3) enabling development of new and further development of existing electroporation-based applications by integrating multidisciplinary research teams, as well as providing comprehensive training for early-stage researchers. Results of this COST action will provide multiple societal, scientific and technological benefits from improving existing electroporation-based applications to adding new ones in the fields of medicine, biotechnology and environmental preservation. PMID- 22922774 TI - Trends in morbidity and mortality among very-low-birth-weight infants from 2003 to 2008 in Japan. AB - BACKGROUND: Although medical care for very-low-birth-weight (VLBW) infants has improved over time, it is unclear how this has affected mortality and morbidity. To characterize these trends, a network database was analyzed. METHODS: This is a cohort study of VLBW infants born from 2003 through 2008. RESULTS: Over the 6-y period, 19,344 infants were registered and analyzed. Crude mortality rates among the infants at discharge decreased significantly (from 10.8 to 8.7%) during the study period. The greatest improvement in mortality was observed among infants with birth weights between 501 and 750 g (25.6-17.7 %). The odds ratio (OR) of mortality over year adjusted for potential confounders by a logistic regression model was 0.94 (95% confidence interval 0.92-0.97). Significant increases were observed in some morbidities, including symptomatic patent ductus arteriosus with an OR of 1.11 (1.09-1.13); late-onset adrenal insufficiency, 1.21 (1.17-1.26); and necrotizing enterocolitis/intestinal perforation, 1.10 (1.01-1.12). However, the severe form of intraventricular hemorrhage, with an OR of 0.98 (0.92-0.99), decreased significantly. Risk-adjusted trends in other morbidities showed no significant change. CONCLUSION: Mortality of VLBW infants decreased significantly over the 6-y study period. Decreasing morbidity is essential for further improvement in the outcomes in VLBW infants. PMID- 22922777 TI - The impact of parental myopia on myopia in Chinese children: population-based evidence. AB - PURPOSE: To determine the relationship between myopia in parents and their children in a sample of urban Chinese children. METHODS: Random sampling was used to identify a population-based sample of 4364 children aged 5 to 15 years from Guangzhou. Children had a comprehensive ocular examination including cycloplegic (1% cyclopentolate) refraction (ARK-30; Nidek Corp.). Data on parental myopia, education levels, incomes and occupations, and children's near-work activities were collected by questionnaire. Myopia in the children was defined as a spherical equivalent refraction of <=-0.5 diopter. RESULTS: The prevalence of myopia was significantly higher in the children than in their parents (78.4% in 15-year-old children, compared with 19.8% in the parents, p < 0.001). The prevalence of myopia was 88.9% in children with one parent myopic, 83.3% in those with two parents myopic, and 68.2% in those without myopic parents, compared with 85.3% in those with tertiary-educated parents, 73.3% in those with secondary educated parents, and 60.0% in those with less educated parents. Parental income and occupation had weaker associations with childhood myopia. In multiple regression analysis, only parental myopia remained significantly associated with myopia in the children. The observed additional risk among those with more myopic parents could not be attributed to reported near-work activities in children. CONCLUSIONS: A high percentage of children in Guangzhou become myopic by the age of 15, irrespective of the myopic status of their parents. There is, however, an additional risk of myopia in children with myopic parents, which may have a genetic basis, but further analysis of the impact of possible environmental confounders is required. PMID- 22922778 TI - Lid margins: sensitivity, staining, meibomian gland dysfunction, and symptoms. AB - PURPOSE: Ocular surface sensitivity plays a role in dry eye and ocular comfort through its probable influence on the neural feedback loop that regulates tear secretion, but little is known specifically about the role of lid or lid margin sensitivity in ocular surface health. The aim of this study was to characterize the eyelid margin and explore the relationships between lid margin sensitivity and staining, meibomian gland dysfunction, tear osmolarity, and ocular symptoms. A secondary aim was to look for differences and associations between lower- and upper-lid characteristics. METHODS: Pilot study involving 27 healthy subjects (7 men, 20 women; mean age: 31 +/- 14 years). Measurements included ocular symptoms (Ocular Surface Disease Index, Dry Eye Questionnaire), tear osmolarity, lid margin staining (fluorescein and lissamine green), meibomian gland dysfunction, and mechanical sensitivity of lower and upper lids. RESULTS: Lower-lid margins were more sensitive (45.0 +/- 13.2 vs. 40.0 +/- 14.7 mm; p = 0.02) and displayed more staining (1.5 +/- 1.0 vs. 0.2 +/- 0.6, p < 0.001), but less evidence of meibomian gland dysfunction (2.0 +/- 2.8 vs. 7.3 +/- 6.2, p < 0.001), than upper lid margins. Lid margin staining was more frequent in lower than upper lids (78% vs. 15% of subjects). Tear osmolarity correlated with upper-lid staining (r = 0.41, p = 0.04) and lower-lid sensitivity (r = 0.46, p = 0.02). Lid sensitivity was also inversely correlated with meibomian gland dysfunction at the lower lid (r = -0.51, p = 0.01). Surprisingly, there were no associations between symptoms and lid staining. CONCLUSIONS: Our study highlighted clear clinical differences between the lower and upper lids and demonstrated, for the first time, significant relationships between tear osmolarity and lid characteristics, including lid sensitivity. PMID- 22922779 TI - The effect of phenylephrine on the ciliary muscle and accommodation. AB - PURPOSE: To objectively measure changes in the human ciliary muscle dimensions in vivo after instillation of topical phenylephrine, a mydriatic and vasodilating agent. METHODS: A cross-sectional study of 25 healthy young adults was conducted. Measurements of pupil size, accommodation, and ciliary muscle thickness were made both before and 30 min after instillation of 1% proparacaine and 2.5% phenylephrine. Accommodation was measured in three ways: subjectively using a push-up technique and Royal Air Force (RAF) rule, and objectively using both the Grand Seiko autorefractor and PowerRefractor. Images of the temporal ciliary muscle were acquired using the Visante Anterior Segment Optical Coherence Tomographer (OCT). Ciliary muscle images were objectively analyzed using a computer-based segmentation technique. RESULTS: Amplitude of accommodation using the push-up test was reduced by about 1 D with phenylephrine (p < 0.001). Phenylephrine did not change the accommodative response to a 4 D Badal target as measured by either autorefraction or photorefraction (p > 0.30). There was statistically significant thickening of the anterior region and thinning of the posterior region of the ciliary muscle with accommodation (p < 0.001, all locations). Phenylephrine did not affect either baseline ciliary muscle thickness or the accommodative contraction of the muscle (p > 0.09). CONCLUSIONS: Low-dose phenylephrine does not affect ciliary muscle dimensions, ciliary muscle contractility, or accommodative response to a 4 D near target. PMID- 22922780 TI - Volume perimetry: measurement in depth of visual field loss. AB - PURPOSE: Volume scotomas are three-dimensional regions of space that are not visible to the observer. Volume perimetry maps volume scotomas. Volume scotomas predicted from combining monocular visual fields assume known fixation locus (mainly foveal). However, fixation loci are not always known, especially with central field loss (CFL). Here we demonstrate methods for measuring and calculating volume scotomas and discuss their practical implications. METHODS: Three patients (bitemporal hemianopia, binasal scotoma, and CFL) were evaluated. Slices through the volume scotomas were measured at three distances: at the plane of fixation, at a plane anterior to fixation (representing anterior volume perimetry), and at a plane posterior to fixation (representing posterior volume perimetry). For anterior volume perimetry, patients fixated on a screen 100 cm away through a beamsplitter that reflected the perimetric stimulus (at 50 cm). For posterior volume perimetry, patients fixated on a near target (50 cm), while perimetric stimuli were presented on a screen 150 cm beyond fixation. At the plane of fixation, monocular visual fields under binocular viewing conditions were measured using a computerized dichoptic perimeter. RESULTS: Posterior and anterior volume scotomas were documented in patients with bitemporal hemianopia and binasal scotomas, respectively. The CFL patient demonstrated both anterior and posterior volume scotomas. Scotoma magnitude was considered to determine its effect on visual function. CONCLUSIONS: Direct measurement of volume scotomas can be performed. Anterior and posterior volume visual fields can vary substantially from conventional binocular perimetry measured at the fixation plane, revealing blind areas not otherwise identified. These volume scotomas are likely to impair functional vision such as driving (for bitemporal hemianopes) and near work with small hand tools (for binasal scotomas). Patients with CFL will have impaired functional vision for both distance and near tasks. Consideration of volume scotomas can help provide more effective vision rehabilitation and counseling. PMID- 22922782 TI - Humans can learn new information during sleep. AB - During sleep, humans can strengthen previously acquired memories, but whether they can acquire entirely new information remains unknown. The nonverbal nature of the olfactory sniff response, in which pleasant odors drive stronger sniffs and unpleasant odors drive weaker sniffs, allowed us to test learning in humans during sleep. Using partial-reinforcement trace conditioning, we paired pleasant and unpleasant odors with different tones during sleep and then measured the sniff response to tones alone during the same nights' sleep and during ensuing wake. We found that sleeping subjects learned novel associations between tones and odors such that they then sniffed in response to tones alone. Moreover, these newly learned tone-induced sniffs differed according to the odor pleasantness that was previously associated with the tone during sleep. This acquired behavior persisted throughout the night and into ensuing wake, without later awareness of the learning process. Thus, humans learned new information during sleep. PMID- 22922781 TI - Symptoms in children with convergence insufficiency: before and after treatment. AB - PURPOSE: To investigate symptom patterns and evaluate the relationship between patient characteristics and symptom severity before and after treatment for symptomatic children with convergence insufficiency (CI). METHODS: In a randomized clinical trial, the convergence insufficiency symptom survey was administered pre- and posttreatment to 221 children aged 9 to <18 years with symptomatic CI. Frequency of symptom type was determined at baseline, mean change in performance-related vs. eye-related symptoms for treatment responders was compared, and the relationship between patient characteristics and symptom severity at baseline for the entire cohort and after treatment for those who responded to treatment was determined. RESULTS: At baseline, the score for performance-related symptoms was greater than that for eye-related symptoms (mean response of 2.3 vs. 1.8, p < 0.001) regardless of age, sex, race/ethnicity, or presence of parent-reported Attention Deficit Hyperactivity Disorder (ADHD). Symptom severity increased with age for both the overall and eye-related subscale scores (p = 0.048, p = 0.022, respectively). Children with parent-reported ADHD were more symptomatic (p = 0.005) than those without parent-reported ADHD because of a higher performance-related score (p < 0.001). A significant and equal improvement (p < 0.01) for the performance- and eye-related symptoms was found in treatment responders. Girls had significantly lower performance-related symptoms than boys (p = 0.014), and black children reported less eye-related symptoms than white children (p = 0.022). Children without parent-reported ADHD had significantly less symptoms overall and less eye-related symptoms than children with parent-reported ADHD (p = 0.019, p = 0.011, respectively). CONCLUSIONS: Because of a high frequency of both performance- and eye-related symptoms, clinicians should perform a targeted history that addresses both types of symptoms to help identify children with symptomatic CI. Future study regarding the relationship of CI and symptoms and their potential influence on ADHD, reading performance, and attention is warranted. PMID- 22922783 TI - Positive modulation of a Cys-loop acetylcholine receptor by an auxiliary transmembrane subunit. AB - Auxiliary subunits regulate the trafficking, localization or gating kinetics of voltage- and ligand-gated ion channels by associating tightly and specifically with pore-forming subunits. However, no auxiliary subunits have been identified for members of the Cys-loop receptor superfamily. Here we identify MOLO-1, a positive regulator of levamisole-sensitive acetylcholine receptors (L-AChRs) at the Caenorhabditis elegans neuromuscular junction. MOLO-1 is a one-pass transmembrane protein that contains a single extracellular globular domain-the TPM domain, found in bacteria, plants and invertebrates, including nonvertebrate chordates. Loss of MOLO-1 impairs locomotion and renders worms resistant to the anthelmintic drug levamisole. In molo-1 mutants, L-AChR-dependent synaptic transmission is reduced by half, while the number and localization of receptors at synapses remain unchanged. In a heterologous expression system, MOLO-1 physically interacts with L-AChRs and directly enhances channel gating without affecting unitary conductance. The identification of MOLO-1 expands the mechanisms for generating functional and pharmacological diversity in the Cys loop superfamily. PMID- 22922784 TI - Lipidomics identifies cardiolipin oxidation as a mitochondrial target for redox therapy of brain injury. AB - The brain contains a highly diversified complement of molecular species of a mitochondria-specific phospholipid, cardiolipin, which, because of its polyunsaturation, can readily undergo oxygenation. Using global lipidomics analysis in experimental traumatic brain injury (TBI), we found that TBI was accompanied by oxidative consumption of polyunsaturated cardiolipin and the accumulation of more than 150 new oxygenated molecular species of cardiolipin. RNAi-based manipulations of cardiolipin synthase and cardiolipin levels conferred resistance to mechanical stretch, an in vitro model of traumatic neuronal injury, in primary rat cortical neurons. By applying a brain-permeable mitochondria targeted electron scavenger, we prevented cardiolipin oxidation in the brain, achieved a substantial reduction in neuronal death both in vitro and in vivo, and markedly reduced behavioral deficits and cortical lesion volume. We conclude that cardiolipin oxygenation generates neuronal death signals and that prevention of it by mitochondria-targeted small molecule inhibitors represents a new target for neuro-drug discovery. PMID- 22922785 TI - Low prefrontal PSA-NCAM confers risk for alcoholism-related behavior. AB - The factors underlying vulnerability to alcoholism are largely unknown. We identified in rodents an innate endophenotype predicting individual risk for alcohol-related behaviors that was associated with decreased expression of the neuroplasticity-related polysialylated neural cell adhesion molecule (PSA-NCAM). Depletion of PSA-NCAM in the ventromedial prefrontal cortex was sufficient to render mice unable to extinguish alcohol seeking, indicating a causal role of naturally occurring variation. These data suggest a mechanism of aberrant prefrontal neuroplasticity that underlies enhanced propensity for inflexible addiction-related behavior. PMID- 22922786 TI - Orchestrated experience-driven Arc responses are disrupted in a mouse model of Alzheimer's disease. AB - Experience-induced expression of immediate-early gene Arc (also known as Arg3.1) is known to be important for consolidation of memory. Using in vivo longitudinal multiphoton imaging, we found orchestrated activity-dependent expression of Arc in the mouse extrastriate visual cortex in response to a structured visual stimulation. In wild-type mice, the amplitude of the Arc response in individual neurons strongly predicted the probability of reactivation by a subsequent presentation of the same stimulus. In a mouse model of Alzheimer's disease, this association was markedly disrupted in the cortex, specifically near senile plaques. Neurons in the vicinity of plaques were less likely to respond, but, paradoxically, there were stronger responses in those few neurons around plaques that did respond. To the extent that the orchestrated pattern of Arc expression reflects nervous system responses to and physiological consolidation of behavioral experience, the disruption in Arc patterns reveals plaque-associated interference with neural network integration. PMID- 22922787 TI - Catechol-O-methyltransferase genetic variant associated with the risk of Alzheimer's disease in a Brazilian population. AB - The aim of the present study was to examine the association between polymorphism in the catechol-O-methyltransferase(COMT) gene and Alzheimer's disease (AD) in a Brazilian population. The case-control method was used to study the association between AD and genetic variants of COMT. Six tag single-nucleotide polymorphisms(SNPs) in the COMT gene were genotyped by RT-PCR. Our findings showed that the 6 tag SNPs analyzed in this study were not associated with AD at the allele and genotype levels in comparison with the control group. No statistical difference was found between groups with and without behavioral and psychological symptoms of dementia (BPSD). Our results do not support the hypothesis that the polymorphisms of the COMT gene may be associated with susceptibility to AD with and without BPSD. PMID- 22922788 TI - Inhibition of lung cancer cells growth, motility and induction of apoptosis by Klotho, a novel secreted Wnt antagonist, in a dose-dependent manner. AB - Klotho (KL) is a transmembrane protein that can be shed, and act as a circulating hormone and modulate several signaling pathways. There also exists a splice variant of Klotho mRNA, which encodes a putative secreted protein (Klotho-S, KL S) in both human and mouse. The potential anti-senescence gene Klotho has been recently found to participate in the progression of several different human cancers. In the current study, we undertook to study the expression and activity of Klotho in lung cancer cell line A549. Klotho expression was studied by using RT-PCR and western blotting. Effects of Klotho on cell growth and motility were assessed using MTT and scratch motility assay, and the apoptosis was assessed by TUNEL. Wnt signaling pathway activity was measured by western blotting. We established that the Klotho was endogenous expressed in A549 cells, but the expression level is lower compared with normal lung tissues. The overexpression of KL or KL-S could inhibit the cell proliferation, motility, and induce apoptosis in a dose-dependent manner. Also, we report KL could inhibit activation of Wnt -TCF/beta-catenin signaling pathway, and it is involved in KL-induced growth inhibition. These studies indicate Klotho works as a potential tumor suppressor in lung cancer, and suggest that the Klotho tumor suppressive activities could be mediated through its KL-S isoform. These results suggest the use of Klotho or KL-S as potential strategy for the development of novel therapeutic interventions for lung cancers. PMID- 22922790 TI - Heart rate variability in peritoneal dialysis patients: what is the role of residual renal function?. AB - BACKGROUND: The relationship between heart rate variability (HRV) and residual renal function (RRF) has not been elucidated previously. METHODS: In this cross sectional study, HRV was evaluated in 71 peritoneal dialysis patients. Patients were divided into RRF decline group, RRF stable group and anuric group. RESULTS: RRF was negatively correlated with SDNN (r = -0.284, p = 0.017), TP (r = -0.247, p = 0.039), and HF (r = -0.238, p = 0.047). Significant sympathetic nerve activation was found in the RRF decline group (significantly lower SDNN, SDSD, RMSSD, pNN50, LF, HF, TP and higher LF/HF ratio) as compared to the RRF stable and anuric groups. Besides, significantly parasympathetic activation was found in the anuric group (the lowest LF/HF ratio as compared to the other groups (both p < 0.05). Multivariate stepwise regression analysis showed that the status of RRF was an independent factor associated with HRV parameters. CONCLUSION: This study showed autonomic nervous function in peritoneal dialysis patients was associated with a different status of RRF. PMID- 22922789 TI - The inhibitory effect of MSCs expressing TRAIL as a cellular delivery vehicle in combination with cisplatin on hepatocellular carcinoma. AB - Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has been demonstrated to induce cell apoptosis in many types of tumors, while many hepatocellular carcinoma (HCC) cells display high resistance to TRAIL. Another outstanding limitation of TRAIL is the short half-life in vivo. Stem cell-based therapies provide a promising approach for the treatment of many types of tumors because of the ability of tropism. Therefore, as a new therapeutic strategy, the combination of chemotherapeutic agents and TRAIL gene modified MSCs (TRAIL-MSCs) would improve the therapeutic efficacy of HCC in vivo. This is the first time to show the potential of combination of chemotherapeutic agents and MSCs as a gene vector in the therapy of HCC. PMID- 22922791 TI - Excessive heat and respiratory hospitalizations in New York State: estimating current and future public health burden related to climate change. AB - BACKGROUND: Although many climate-sensitive environmental exposures are related to mortality and morbidity, there is a paucity of estimates of the public health burden attributable to climate change. OBJECTIVE: We estimated the excess current and future public health impacts related to respiratory hospitalizations attributable to extreme heat in summer in New York State (NYS) overall, its geographic regions, and across different demographic strata. METHODS: On the basis of threshold temperature and percent risk changes identified from our study in NYS, we estimated recent and future attributable risks related to extreme heat due to climate change using the global climate model with various climate scenarios. We estimated effects of extreme high apparent temperature in summer on respiratory admissions, days hospitalized, direct hospitalization costs, and lost productivity from days hospitalized after adjusting for inflation. RESULTS: The estimated respiratory disease burden attributable to extreme heat at baseline (1991-2004) in NYS was 100 hospital admissions, US$644,069 in direct hospitalization costs, and 616 days of hospitalization per year. Projections for 2080-2099 based on three different climate scenarios ranged from 206-607 excess hospital admissions, US$26-$76 million in hospitalization costs, and 1,299-3,744 days of hospitalization per year. Estimated impacts varied by geographic region and population demographics. CONCLUSIONS: We estimated that excess respiratory admissions in NYS due to excessive heat would be 2 to 6 times higher in 2080-2099 than in 1991-2004. When combined with other heat-associated diseases and mortality, the potential public health burden associated with global warming could be substantial. PMID- 22922792 TI - Fragments of SLIT3 inhibit cellular migration. AB - The repellent factor family of Slit molecules has been described as having a repulsive function in the developing nervous system on growing axons expressing the Roundabout (Robo) receptors. Recent studies determined the effects of Slit molecules on the migratory and invasive potential of several types of tumor cells but also on synovial fibroblasts (SFs) derived from rheumatoid arthritis (RA) patients. To optimize a potential therapeutic application we aimed at generatingfragments of Slit3 showing the same functional ability as the full length molecule but having the advantage of a smaller size. Recombinant Slit3 proteins were expressed and analyzed by western blotting. Their activity was defined by functional assays such as migration assays with RASF and melanoma cells. Recombinant Slit3 containing only leucine rich repeat domain 2 (D2), the domain important for Robo binding and the minimal functional unit D2 dNC were both able to inhibit migration of RASFs as effectively as Slit3 with all 4 repeats. Collectively, our data showed that the ability of Slit3 to reduce the migratory activity of synovial cells from patients with RA and melanoma cells can be mimicked by small protein fragments derived from Slit3. Slit3 fragments may be helpful in therapeutic attempts; however, further studies are necessary in order to elucidate their activity in vivo. PMID- 22922793 TI - Celebrating Ruby: 40 years of NAS->SNANSC->SNACC->SNACC. AB - The 40-year history of the Society of Neurosurgical Anesthesia and Critical Care (SNACC) is reviewed. Annual meetings have been a focus for reporting scientific advances and providing education to those attending. The society has undergone significant maturation dealing with transitions in leadership and dealing with an existential threat and undergoing name changes reflecting growth and maturation in its mission. SNACC has collaborated with several other professional societies, most notable being the American Society of Anesthesiologists (ASA), in which SNACC members have advocated for neuroscience in the ASA's educational and scientific activities, with several SNACC members being recognized through several major ASA awards and presentations. SNACC has been a strong advocate for educational advances, most recently addressing issues in neuroanesthesia fellowship accreditation and possibly certification. SNACC's initial North American focus has grown such that SNACC is now an international society dedicated to the advancement of neuroanesthesia, neurocritical care, neuromonitoring, and neuroscience. PMID- 22922794 TI - The prognostic value of KRAS mutations in patients with colorectal cancer. AB - Our aim was to evaluate the KRAS genotypes of Japanese colorectal cancer (CRC) patients and to assess the effect of these genotypes on clinical outcome. A total of 99 patients with stage I-IV CRC who underwent resection were prospectively studied for KRAS mutations by direct sequencing. KRAS mutations were found in 37 (37.4%) of 99 patients. Of these, 11.1% were the KRAS p.G13D mutation and the remaining 26.2% were other KRAS mutations. The cumulative 5-year survival rates for patients with wild-type KRAS, KRAS 12 and KRAS p.G13D mutations were 81.4, 61.4 and 42.0%, respectively (P=0.0397). The KRAS genotype had no effect on stage IV patient prognosis without anti-epithelial growth factor receptor (EGFR) antibody therapy. However, in stage I-III patients significant or trends in prognostic factors for disease-free survival (DFS) were pathological T stage, lymphatic vessel involvement and KRAS p.G13D. Multivariate analysis identified T4 pathological stage (P=0.0076) and the KRAS p.G13D mutation (P=0.0499) as the most significant independent prognostic factors associated with DFS. In Japanese CRC patients KRAS p.G13D had prognostic impact on DFS in stage I-III disease, while the prognosis of stage IV patients without anti-EGFR antibody therapy was unaffected by KRAS status. PMID- 22922796 TI - The absence of A-to-I editing in the anticodon of plant cytoplasmic tRNA (Arg) ACG demands a relaxation of the wobble decoding rules. AB - It is a prevalent concept that, in line with the Wobble Hypothesis, those tRNAs having an adenosine in the first position of the anticodon become modified to an inosine at this position. Sequencing the cDNA derived from the gene coding for cytoplasmic tRNA (Arg) ACG from several higher plants as well as mass spectrometric analysis of the isoacceptor has revealed that for this kingdom an unmodified A in the wobble position of the anticodon is the rule rather than the exception. In vitro translation shows that in the plant system the absence of inosine in the wobble position of tRNA (Arg) does not prevent decoding. This isoacceptor belongs to the class of tRNA that is imported from the cytoplasm into the mitochondria of higher plants. Previous studies on the mitochondrial tRNA pool have demonstrated the existence of tRNA (Arg) ICG in this organelle. In moss the mitochondrial encoded distinct tRNA (Arg) ACG isoacceptor possesses the I34 modification. The implication is that for mitochondrial protein biosynthesis A-to I editing is necessary and occurs by a mitochondrion-specific deaminase after import of the unmodified nuclear encoded tRNA (Arg) ACG. PMID- 22922797 TI - miR-3928 activates ATR pathway by targeting Dicer. AB - Alterations in microRNA (miRNA) expression have been observed in cells subjected to exogenous stresses, implying that miRNAs play an important role in cellular stress response; however, the underlying mechanism is still largely unknown. In the present study, we found that miR-3928 was implicated in cellular response to ionizing radiation. After exposed to X-rays, miR-3928 expression increased in 1.5 h and then decreased, meanwhile Dicer, a key component in the miRNA processing machinery, increased gradually. An oscillation was observed in the expression of both mature miR-3928 and Dicer mRNA from 2 h to 3.5 h in irradiated cells. Then, we verified that miR-3928 directly bound to the 3'-untranslated region of Dicer mRNA. Consequently, Dicer expression was suppressed and the maturation of other miRNAs including miR-185, miR-300, and miR-663, was inhibited. Overexpression of miR-3928 induced DNA damage, activated ATR, and phosphorylated Chk1 accompanied by G1 arrest. Taken together, these findings replenished ATR/Chk1 pathway by revealing a novel miRNA regulatory network in response to exogenous stress, in which miR-3928 plays an important role in regulating the expression of Dicer. PMID- 22922795 TI - DExD/H-box RNA helicases in ribosome biogenesis. AB - Ribosome synthesis requires a multitude of cofactors, among them DExD/H-box RNA helicases. Bacterial RNA helicases involved in ribosome assembly are not essential, while eukaryotes strictly require multiple DExD/H-box proteins that are involved in the much more complex ribosome biogenesis pathway. Here, RNA helicases are thought to act in structural remodeling of the RNPs including the modulation of protein binding, and they are required for allowing access or the release of specific snoRNPs from pre-ribosomes. Interestingly, helicase action is modulated by specific cofactors that can regulate recruitment and enzymatic activity. This review summarizes the current knowledge and focuses on recent findings and open questions on RNA helicase function and regulation in ribosome synthesis. PMID- 22922798 TI - IDH1 mutation of gliomas with long-term survival analysis. AB - A recurrent mutation affecting codon 132 of the isocitrate dehydrogenase 1 (IDH1) gene has been found in ~5% of primary glioblastomas (GBMs), but in >70% of secondary GBMs or oligodendroglial and astrocytic tumors. We investigated IDH1 mutations in a series of 134 brain tumors to determine the prevalence and prognostic impact of IDH1 mutations. We also examined the correlations among histology, p53 and PTEN immunoexpression, MGMT methylation status, 1p 19q co deletion and EGFR gene amplification. The 134 brain tumors included 41 low-grade oligodendrogliomas (LOs), 47 anaplastic oligodendrogliomas (AOs) and 46 primary GBMs. Data showed that 53.7% (72/134) of cases showed mutations affecting codon 132 of IDH1, including 73.2% of LOs, 82.9% of AOs and three primary GBMs (6.5%). All IDH1 mutations were Arg132His. In a survival analysis, patients with IDH1 mutations had better survival compared to those with wild-type IDH1 (p<0.05) in LOs and AOs, but not in primary GBMs (p=0.587). In addition, in patients with both IDH1 mutation and MGMT methylation, p53 overexpression was a significant poor prognostic factor both in LOs and AOs. However, IDH1 mutation was not correlated with common genetic profiles that affect patient prognosis, including MGMT methylation, 1p 19q co-deletion, PTEN loss and EGFR amplification in LOs, AOs and GBMs. From our results, IDH1 mutation was an independent positive prognostic factor in LOs and AOs, especially in the absence of p53 overexpression. PMID- 22922799 TI - Engineered domain-based assays to identify individual antibodies in oligoclonal combinations targeting the same protein. AB - Quantitation of individual monoclonal antibodies (mAbs) within a combined antibody drug product is required for preclinical and clinical drug development. We have developed two antitoxins, XOMA 3B and XOMA 3E, each consisting of three mAbs that neutralize type B and type E botulinum neurotoxin (BoNT/B and BoNT/E) to treat serotype B and E botulism. To develop mAb-specific binding assays for each antitoxin, we mapped the epitopes of the six mAbs. Each mAb bound an epitope on either the BoNT light chain (LC) or translocation domain (H(N)). Epitope mapping data were used to design LC-H(N) domains with orthogonal mutations to make them specific for only one mAb in either XOMA 3B or XOMA 3E. Mutant LC-H(N) domains were cloned, expressed, and purified from Escherichia coli. Each mAb bound only to its specific domain with affinity comparable to the binding to holotoxin. Further engineering of domains allowed construction of enzyme-linked immunosorbent assays (ELISAs) that could characterize the integrity, binding affinity, and identity of each of the six mAbs in XOMA 3B and 3E without interference from the three BoNT/A mAbs in XOMA 3AB. Such antigen engineering is a general method allowing quantitation and characterization of individual mAbs in a mAb cocktail that bind the same protein. PMID- 22922800 TI - miR-183 inhibits the metastasis of osteosarcoma via downregulation of the expression of Ezrin in F5M2 cells. AB - Osteosarcoma is the most common primary malignancy of bone in teenagers and approximately 30% of patients develop lung metastasis, which is the leading cause of mortality. Recent studies suggest that the Ezrin protein is correlated with the metastatic potential of several malignant tumors. In our study, ectopic overexpression of miR-183 repressed the expression levels of Ezrin and significantly inhibited the motility and invasion of osteosarcoma cells. This suggests that miR-183 may possibly play a tumor suppressor role in the metastasis of osteosarcoma by downregulating Ezrin expression levels. These findings show that through inhibition of Ezrin expression levels, miR-183 is significantly involved in cell migration and invasion of osteosarcoma. PMID- 22922801 TI - Is hybrid surgery of the cervical spine a good balance between fusion and arthroplasty? Pilot results from a single surgeon series. AB - PURPOSE: Few studies have investigated the role of hybrid surgery (HS) that incorporates anterior cervical discectomy and fusion (ACDF) and artificial disc replacement (ADR) techniques. To our knowledge, this is the first study that provides a direct comparison of all three groups in terms of intra-operative parameters and outcomes with a minimum follow-up of 2 years. METHODS: Seven consecutive patients who underwent HS were matched with another seven patients who underwent ACDF and ADR based on levels of surgery. Prospective data on demographics, pre-operative and post-operative assessments, complications and functional scores (VAS, NDI, EQ-5D health score and index) were analysed using Mann-Whitney U test. Type I error was set at 5 %. RESULTS: Duration of surgery was significantly shorter for ACDF at 135 min (p = 0.025) compared with HS and ADR. ACDF also had greater blood loss when compared with ADR (p < 0.036). ADR has the shortest duration of hospitalization followed by HS and ACDF (p < 0.031). The HS group returned to work fastest (54 days) when compared with both ACDF (107 days) and ADR (73 days) with statistical significance seen between HS and ACDF (p = 0.035). Cervical range of motion (ROM) and functional scores did not show any significant differences. CONCLUSION: HS is comparable to ACDF and ADR in terms of safety and feasibility. Findings of shorter in-hospital stay and earlier return to work in HS group may be further explored in large, randomised controlled trials. PMID- 22922802 TI - Posterior instrumentation, anterior column reconstruction with single posterior approach for treatment of pyogenic osteomyelitis of thoracic and lumbar spine. AB - PURPOSE: Surgical treatment of thoracolumbar osteomyelitis consists of radical debridement, reconstruction of anterior column either with or without posterior stabilization. The objective of present study is to evaluate a case series of patients with osteomyelitis of thoracic and lumbar spine treated by single, posterior approach with posterior instrumentation and anterior column reconstruction. METHODS: Seventeen patients underwent clinical and radiological evaluation pre and postoperatively with latest follow-up at 19 months (8-56 months) after surgery. Parameters assessed were site of infection, causative organism, angle of deformity, blood loss, duration of surgery, ICU stay, deformity correction, time to solid bony fusion, ambulatory status, neurologic status (ASIA impairment scale), and functional outcome (Kirkaldy-Willis criteria). RESULTS: Mean operating time was 207 min and average blood loss 1,150 ml. Patients spent 2 (1-4) days in ICU and were able to walk unaided 1.6 (1-2) days after surgery. Infection receded in all 17 patients postoperatively. Solid bony fusion occurred in 15 out of 17 patients (88 %) on average 6.3 months after surgery. Functional outcome was assessed as excellent or good in 82 % of cases. Average deformity correction was 8 (1-18) degrees, with loss of correction of 4 (0-19) degrees at final follow-up. CONCLUSIONS: Single, posterior approach addressing both columns poses safe alternative in treatment of pyogenic vertebral osteomyelitis of thoracic and lumbar spine. It proved to be less invasive resulting in faster postoperative recovery. PMID- 22922803 TI - Circulating hormone and cytokine response to low-load resistance training with blood flow restriction in older men. AB - It has been suggested that circulating hormones and cytokines are important in the adaptive response to low-load resistance training (LLRT) with blood flow restriction (BFR); however, their response following this type of training in older men is unclear. Seven healthy older men (age 71.0 +/- 6.5 year, height 1.77 +/- 0.05 m, body mass 80.0 +/- 7.5 kg; mean +/- SD) performed five sets of unilateral LLRT knee extensions (20 % 1-RM) of both limbs, with or without BFR in a counterbalanced order. For the BFR condition, a pressure cuff was applied on the upper thigh and inflated to ~110 mmHg. Venous blood samples were taken at rest and 30-, 60- and 120-min post-exercise and measured for plasma concentrations of growth hormone (GH), insulin-like growth factor 1 (IGF-1), vascular endothelial growth factor (VEGF), cortisol and interleukin-6 (IL-6). GH increased (P < 0.05) from rest to 30-min post-exercise and was greater (P < 0.05) during LLRT with BFR than without. VEGF was significantly (P < 0.05) elevated from resting levels at 30-, 60- and 120-min post-exercise following LLRT with BFR with no change seen following LLRT without BFR. IL-6 increased (P < 0.05) from 30 to 60-min post-exercise and remained elevated at 120-min post-exercise in both conditions. Cortisol and IGF-1 were unaffected following exercise. In conclusion, a single bout of LLRT with BFR increases the circulating concentrations of GH and VEGF in older men and may explain the skeletal muscle and peripheral vascular adaptations observed following training with BFR. PMID- 22922805 TI - AKT serine/threonine protein kinase modulates bufalin-triggered intrinsic pathway of apoptosis in CAL 27 human oral cancer cells. AB - Bufalin has been reported to induce apoptosis in a variety of cancers but little is demonstrated in oral squamous cell carcinoma (OSCC) cells. The present study investigated the inhibition of proliferation, cell cycle arrest and apoptotic effects of bufalin in CAL 27 human oral cancer cells. Bufalin inhibited the growth of CAL 27 cells in a concentration-dependent manner and an IC50 value of bufalin was about 125 nM for 24 h treatment using the MTT assay. Moreover, the cell cycle distribution was arrested at the G0/G1 phase in CAL 27 cells after bufalin exposure. Upon bufalin stimulation, the expression of Bcl-2 was significantly decreased while that of cytochrome c, Apaf-1 and AIF was increased compared to the control group by western blot analysis. An increase in the expression of the active form of caspases was found in bufalin-treated cells, and the caspase activities were also elevated. Bufalin-triggered apoptosis was blocked by specific inhibitors of caspase-9 (z-LEHD-fmk) and caspase-3 (z-DEVD fmk), respectively. In contrast, CAL 27 cells overexpressing constitutively active AKT (CAL 27/CA-AKT) were exposed to bufalin at different concentrations, and cell growth remained unchanged. Bufalin exhibited minimal apoptotic effects on CAL 27/CA-AKT cells. Taken together, bufalin induced G0/G1 phase arrest and provoked the intrinsic apoptotic pathway via AKT activation in CAL 27 cells. Our data suggest that bufalin could be potentially efficacious in the treatment of oral cancer in the future. PMID- 22922806 TI - Growth hormone-releasing effects of whole body vibration alone or combined with squatting plus external load in severely obese female subjects. AB - BACKGROUND: Whole body vibration (WBV) has been reported to exert growth hormone(GH)-releasing effects in healthy subjects. Despite the potential of WBV to positively affect body composition changes via lipolytic effects, few studies have been performed in obese subjects to date. METHODS: This study evaluated the acute effects of WBV alone or in combination with squatting plus external load (WBV+S) on serum GH levels and blood lactate concentrations in 7 severely obese women (age 22 +/- 5 years; BMI 39.9 +/- 2.9 kg/m2). RESULTS: WBV and WBV+S determined a significant GH increase (mean GH peaks 5.1 +/- 1.9 ng/ml, p < 0.001 vs. basal, and 6.5 +/- 3.7 ng/ml, p < 0.001 vs. basal, respectively), GH peaks occurring immediately after both exercise sessions. No significant differences were observed between GH peaks and GH net incremental area under the curve (nAUC) after both conditions (p = 0.39 and p = 0.53, respectively), the whole pattern of GH responsiveness being comparable among all the subjects. Lactate concentrations increased after both conditions (mean lactate peaks 2.0 +/- 0.5 mmol/l, p < 0.05 vs. basal, and 4.5 +/- 2.0 mmol/l, p < 0.001 vs. basal, respectively). The lactate response was significantly higher after WBV+S than after WBV (p < 0.05). Baseline GH and GH peak values positively correlated to baseline lactate and lactate peak concentrations in both conditions (R(2) = 0.64, p < 0.001, and R2 = 0.52, p < 0.05, respectively). CONCLUSIONS: WBV alone stimulates GH release and lactate production in severely obese female subjects, with no additive effect when combined with squatting plus external load. Further additional studies are required to verify the chronic effects of WBV exercise on the GH/IGF-1 system, which could represent a potentially effective approach for weight management in obese subjects. PMID- 22922807 TI - Fyn gene polymorphisms contribute to both trait and state anxieties in healthy Chinese-Han individuals. PMID- 22922808 TI - Organosilane functionalization of halloysite nanotubes for enhanced loading and controlled release. AB - The surfaces of naturally occurring halloysite nanotubes were functionalized with gamma-aminopropyltriethoxysilane (APTES), which was found to have a substantial effect on the loading and subsequent release of a model dye molecule. APTES was mostly anchored at the internal lumen surface of halloysite through covalent grafting, forming a functionalized surface covered by aminopropyl groups. The dye loading of the functionalized halloysite was 32% greater than that of the unmodified sample, and the release from the functionalized halloysite was dramatically prolonged as compared to that from the unmodified one. Dye release was prolonged at low pH and the release at pH 3.5 was approximately three times slower than that at pH 10.0. These results demonstrate that organosilane functionalization makes pH an external trigger for controlling the loading of guest on halloysite and the subsequent controlled release. PMID- 22922809 TI - Anaplastic ganglioglioma: a very rare intramedullary spinal cord tumor. AB - Gangliogliomas (GGs) are a small subset of intramedullary spinal cord tumors in children. The anaplastic variant (WHO grade III) appears to be an extreme rarity. A literature research revealed only 15 case reports of intramedullary anaplastic GGs (aGGs) and only 4 pediatric patients. The course of an 18-month-old boy with sudden onset of paraparesis is presented. Spinal MRI revealed a contrast enhancing intramedullary tumor ranging from T6 to T12. The patient underwent a standard laminectomy/laminoplasty and gross total resection of the lesion. His neurological status remained unchanged postoperatively and he recovered very well during outpatient neurorehabilitation. Neuropathologic examination revealed an aGG of WHO grade III. Because of the high-grade histology, adjuvant radiotherapy and chemotherapy with temozolomide were administered. The patient subsequently recovered to a normal functional status. Clinical and radiographic progression free survival is now 4 years. Based on an extensive literature review, this is only the fifth pediatric patient with a primary intramedullary aGG and the second with documented progression-free survival of over 4 years. Another 4 primary intramedullary aGGs in adults and 7 patients with spinal dissemination from a cerebral aGG or malignant transformation of a low-grade GG have been reported. In comparison to the published case reports, which often indicate significant neurological dysfunction and rather short survival, the neurological recovery in this patient was favorable, and the oncologic outcome even more so. This is an argument for the use of the aggressive treatment regimen of complete resection followed by radio- and chemotherapy applied here. PMID- 22922810 TI - Prostate-specific antigen kinetics after I125-brachytherapy for prostate adenocarcinoma. AB - PURPOSE: To investigate a potential correlation between the achievement of a cut off of nadir PSA (nPSA) after brachytherapy (BRT) with biochemical Disease-Free Survival (bDFS) and to define the rate of post-BRT PSA bounces. METHODS: Retrospective analysis was carried out in 105 consecutive patients affected with early-stage prostate adenocarcinoma who underwent (125)I BRT. Only patients with a minimum follow-up >=24 months were included. Biochemical DFS was chosen as primary endpoint. RESULTS: At a median follow-up of 51.2 months, 3- and 5-year bDFS were 96.8 and 91.2%, respectively. Median time to biochemical failure (BF) was 54 months. By Kaplan-Meier analysis, patients achieving nPSA <= 0.35 ng/mL had significantly higher bDFS (3- and 5-year bDFS: 100 and 98.5 % vs. 83.3 and 66.7 %, respectively; p = 0.001). Bounce PSA occurred in 28.6% of patients, at a median time of 21.5 months. No BFs were observed in the bounce group. Achieving a nPSA <= 0.35 ng/mL was the only factor independently associated with long-term bDFS on both univariate (p = 0.000) and multivariate analysis (HR 3.82; p = 0.003). CONCLUSIONS: Patients attaining a nPSA <= 0.35 ng/mL are significantly more likely to experience long-term freedom-from-biochemical failure. Bounce PSA occurs in approximately 30% of patients. Time to onset of PSA increase seems the most reliable feature to distinguish bounce from failure. Tailored follow-up strategies are needed for patients at higher risk of recurrence, and caution is advised in interpreting an early increase in PSA levels in the first 24-30 months after BRT. PMID- 22922811 TI - Delusional misidentification syndromes in obsessive-compulsive disorder. AB - Delusional misidentification syndromes (DMS) have been rarely reported in patients with conditions other than schizophrenia-related disorders, diffuse brain disease (dementia) and focal neurological illness. In this report, we describe DMS (i.e. Capgras and Fregoli syndromes) in two patients with severe and treatment resistant obsessive-compulsive disorder (OCD), one with paranoid personality disorder (PPD) and the other with a pervasive developmental disorder (PDD) not otherwise specified. While our findings highlight an interesting phenomenon (the occurrence of DMS in OCD), it is presently unclear whether this association is rare or underreported. Misidentification syndromes might be the ultimate result of a combination of obsessive fears and preexisting cognitive bias/deficits, such as mistrustfulness (in PPD) or poor theory of mind (in PDD). PMID- 22922812 TI - Age and physical health as predictors of family contact among adults with severe psychiatric illness. AB - We assessed the association of frequency of family contact with age and physical health for a sample of adults with severe psychiatric illness (N = 171). This cross-sectional, observational study measured frequency of face-to-face and telephone contact with family members; satisfaction with family relations; and severity of participants' chronic or permanent physical health conditions. In this sample of adults with severe psychiatric illness, having a physical health condition and advancing age correlated negatively with frequency of face-to-face contact with family members. However, a hierarchical regression analysis controlling for residence in a family member's home, and participants' ratings of satisfaction with family relations, showed that the combination of being older and having more severe health conditions was associated with a more frequent rate of family contact than would be expected based on age or physical health considered alone. Because almost all older participants in this heterogeneous sample had serious physical health conditions, as well as frequent telephone and face-to-face contact with their family members, we recommend the recruitment of family members as collaborators in illness management interventions for aging and mid-life adults with psychiatric illness. PMID- 22922813 TI - Supplementary ultrafiltration may improve inflammation and cardiac dysfunction in patients with high interdialytic weight gain. AB - BACKGROUND/AIMS: We tested the hypothesis that adding an ultrafiltration session per week may improve brain natriuretic peptide (BNP) and C-reactive protein (CRP) levels and left ventricular function in hypervolemic hemodialysis patients. METHODS: Twenty-six patients (18 male, 8 female; mean age 57.2 +/- 12.7 years) who had high BNP and CRP levels and interdialytic weight gain (IDWG) were recruited for the study. Patients were randomly allocated to one of two groups, namely the supplementary ultrafiltration (sUF) group (n = 13), who had additional ultrafiltrations for 8 weeks, and the regular hemodialysis (rHD) group (n = 13), who continued regular dialysis treatments. RESULTS: There were significant decreases in mean CRP and BNP levels and mean arterial blood pressure and significant improvements in left ventricular function in the sUF group, with no changes in the rHD group. Higher IDWG was observed in the rHD group compared to the sUF group after 8 weeks. CONCLUSION: sUF may be effective in reducing inflammatory burden and improving cardiac function. PMID- 22922814 TI - Chromosomal localization of ribosomal and telomeric DNA provides new insights on the evolution of gomphocerinae grasshoppers. AB - Chromosome location of ribosomal DNA (rDNA) and telomeric repeats was analysed in mitotic chromosomes of 15 species of Gomphocerinae grasshoppers belonging to the tribes Arcypterini, Gomphocerini, Stenobothrini, and Chrysochraontini. Two types of rDNA distribution were found in the Gomphocerini tribe. Type 1, found in 9 species, was characterized by the presence of rDNA in the short arm of the long biarmed chromosomes 2 and 3 and, in some species, also in the X chromosome. Type 2 was found only in Aeropus sibiricus and Stauroderus scalaris and consisted in the presence of pericentromeric rDNA blocks in all chromosomes. A comparison of rDNA distribution in Gomphocerini species with 2n ? = 23, 2n ? = 21, and 2n ? = 17 suggested the possible involvement of chromosome 6 in the ancestral karyotype (2n ? = 23) in 1 of the 3 centric fusions that decreased the chromosome number in these species. In the tribe Stenobothrini, Stenobothrus eurasius carried a single rDNA cluster in the X chromosome, likewise 2 Spanish species previously analysed, but Omocestus viridulus unusually showed a single rDNA cluster in the longest autosome. Telomeric repeats were located primarily on the ends of chromosome arms. In 2 species, however, we observed the presence of interstitial clusters outside telomeric regions. The first one, Aeropus sibiricus, exhibited a polymorphic interstitial site of telomeric repeats in chromosome 6 as a consequence of a paracentric inversion. Most remarkably, Chorthippus jacobsoni showed the presence of telomeric repeats in the pericentric regions of the 3 biarmed chromosome pairs originated by centric fusion, thus suggesting that these rearrangements were not of the Robertsonian type but true centric fusion with a probable generation of dicentric chromosomes. PMID- 22922815 TI - Molecular and cellular mechanisms of Mycobacterium avium-induced thymic atrophy. AB - Thymic atrophy has been described as a consequence of infection by several pathogens and shown to be induced through diverse mechanisms. Using the mouse model of Mycobacterium avium infection, we show in this study that the production of NO from IFN-gamma-activated macrophages plays a major role in mycobacterial infection-induced thymic atrophy. Our results show that disseminated infection with a highly virulent strain of M. avium, but not with a low-virulence strain, led to a progressive thymic atrophy. Thymic involution was prevented in genetically manipulated mice unable to produce IFN-gamma or the inducible NO synthase. In addition, mice with a selective impairment of IFN-gamma signaling in macrophages were similarly protected from infection-induced thymic atrophy. A slight increase in the concentration of corticosterone was found in mice infected with the highly virulent strain, and thymocytes presented an increased susceptibility to dexamethasone-induced death during disseminated infection. The administration of an antagonist of glucocorticoid receptors partially reverted the infection-induced thymic atrophy. We observed a reduction in all thymocyte populations analyzed, including the earliest thymic precursors, suggesting a defect during thymic colonization by T cell precursors and/or during the differentiation of these cells in the bone marrow in addition to local demise of thymic cells. Our data suggest a complex picture underlying thymic atrophy during infection by M. avium with the participation of locally produced NO, endogenous corticosteroid activity, and reduced bone marrow seeding. PMID- 22922816 TI - The molecular signature of tissue resident memory CD8 T cells isolated from the brain. AB - Tissue resident memory (Trm) CD8 T cells represent a newly described memory T cell population. We have previously characterized a population of Trm cells that persists within the brain after acute virus infection. Although capable of providing marked protection against a subsequent local challenge, brain Trm cells do not undergo recall expansion after dissociation from the tissue. Furthermore, these Trm cells do not depend on the same survival factors as the circulating memory T cell pool as assessed either in vivo or in vitro. To gain greater insight into this population of cells, we compared the gene expression profiles of Trm cells isolated from the brain with those of circulating memory T cells isolated from the spleen after an acute virus infection. Trm cells displayed altered expression of genes involved in chemotaxis, expressed a distinct set of transcription factors, and overexpressed several inhibitory receptors. Cumulatively, these data indicate that Trm cells are a distinct memory T cell population disconnected from the circulating memory T cell pool and display a unique molecular signature that likely results in optimal survival and function within their local environment. PMID- 22922817 TI - Overall neutralization of complement factor H by autoantibodies in the acute phase of the autoimmune form of atypical hemolytic uremic syndrome. AB - Complement is a major innate immune surveillance system. One of its most important regulators is the plasma protein factor H (FH). FH inactivation by mutations or by autoantibodies is associated with a thrombotic microangiopathy disease, atypical hemolytic uremic syndrome. In this study, we report the characterization of blood samples from 19 anti-FH Ab-positive atypical hemolytic uremic syndrome patients collected at the acute phase of the disease. Analyses of the functional consequences and epitope mapping, using both fluid phase and solid phase approaches, were performed. The anti-FH Abs perturbed FH-mediated cell protection (100%), inhibited FH interaction with C3 (46%), and caused C3 consumption (47%). The Abs were directed against multiple FH epitopes located at the N and C termini. In all tested patients, high titers of FH-containing circulating immune complexes were detected. The circulating immune complex titers correlated with the disease stage better than did the Ab titers. Our results show that anti-FH autoantibodies induce neutralization of FH at acute phase of the disease, leading to an overall impairment of several functions of FH, extending the role of autoantibodies beyond the impairment of the direct cell surface protection. PMID- 22922819 TI - Publishing in Biomedical journals - Following rules to publication. PMID- 22922818 TI - Inducible IL-33 expression by mast cells is regulated by a calcium-dependent pathway. AB - IL-33 is an IL-1 family cytokine that displays dual functions: a cytokine via its receptor, T1/ST2, or a chromatin-binding factor within the nucleus. Functionally, it promotes Th2-associated immunity by enhancing the activation and survival of several cell types. However, the pathways regulating IL-33 expression are still unclear. Although several cells display constitutive expression of IL-33, we showed previously that mast cells expressed low levels of IL-33 constitutively but that IL-33 was induced upon IgE-mediated activation. This was mediated via a calcium-dependent mechanism. In this study, we define the pathway through which this inducible IL-33 is regulated. Importantly, this pathway does not alter expression in cells with high constitutive IL-33 expression, such as epithelial cells or fibroblasts. Our data show that, upstream of calcium, inhibition of PI3K and Sphk activity decreases inducible IL-33 expression to IgE/Ag activation. Additionally, expression of Sphk1 short hairpin RNA prevents upregulation of IL 33 expression. Downstream of calcium, NFAT activity is necessary and sufficient for inducible IL-33 expression. We also demonstrate calcium-dependent transcription from two regions of the IL-33 gene that contain putative NFAT binding sites, one upstream of exon 1 and one upstream of the start site. Interestingly, we show that blocking other calcium pathways, including inositol triphosphate receptor, or NF-kappaB inhibits IgE-driven IL-1beta, another IL-1 family cytokine, but it has no influence on inducible IL-33 expression. In summary, our data demonstrate cell-specific differences in the regulation of IL 33 expression and define a pathway critical for the expression of inducible IL-33 by mast cells upon their activation. PMID- 22922820 TI - Air pollution exposure and markers of placental growth and function: the generation R study. AB - BACKGROUND: Air pollution exposure during pregnancy might affect placental growth and function, perhaps leading to pregnancy complications. OBJECTIVE: We prospectively evaluated the associations of maternal air pollution exposure with markers of placental growth and function among 7,801 pregnant women in the Netherlands. METHODS: We estimated levels of particulate matter <= 10 um in aerodynamic diameter (PM10) and nitrogen dioxide (NO2) at the home address for different periods during pregnancy using dispersion modeling techniques. Pro- and anti-angiogenic factors [placental growth factor (PlGF) and soluble fms-like tyrosine kinase 1 (sFlt-1), respectively] were measured in first- and second trimester maternal blood and in fetal cord blood samples at delivery. Pulsatility index of the uterine and umbilical arteries was measured by Doppler ultrasound in second and third trimester, and notching was assessed in third trimester. Placenta weight and birth weight were obtained from medical records. RESULTS: Higher PM10 and NO2 exposure levels were associated with lower second-trimester maternal sFlt-1 and PlGF levels. PM10 and NO2 exposures averaged over total pregnancy were associated with higher sFlt-1 and lower PlGF levels in fetal cord blood, consistent with an anti-angiogenic state. PM10 and NO2 exposures were not consistently associated with second- or third-trimester placental resistance indices. NO2 exposure was associated with third-trimester notching (odds ratio 1.33; 95% CI: 0.99, 1.78 per 10-ug/m3 increase in the prior 2 months). PM10 and NO2 exposures were associated with lower placenta weight (-11.8 g; 95% CI: -20.9, -2.7, and -10.7 g; 95% CI: -19.0, -2.4, respectively, per 10-ug/m3 increase in the prior 2 months), but not with placenta to birth weight ratio. CONCLUSIONS: Our results suggest that maternal air pollution exposure may influence markers of placental growth and function. Future studies are needed to confirm these findings and explore the maternal and fetal consequences. PMID- 22922821 TI - Neuropsychiatric symptoms and global functional impairment along the Alzheimer's continuum. AB - BACKGROUND/AIMS: Neuropsychiatric symptoms in Alzheimer's disease (AD) are highly prevalent. We sought to determine whether neuropsychiatric symptoms were related to global functional impairment at baseline and over a 3-year period in older normal control (NC), mild cognitive impairment (MCI) and mild AD dementia subjects. METHODS: Eight hundred and twelve subjects (229 NC, 395 MCI, 188 AD) from the Alzheimer's Disease Neuroimaging Initiative study underwent cognitive and behavioral assessments over 3 years. RESULTS: Greater hallucinations, anxiety and apathy were associated with greater global functional impairment at baseline, while the presence of hallucinations and apathy at baseline was associated with greater global functional impairment over time across all subjects. The following neuropsychiatric symptoms were not significantly associated with global functioning: delusions, agitation, depression, euphoria, disinhibition, irritability, aberrant motor behaviors, sleep and appetite. CONCLUSIONS: These results suggest that increased baseline hallucinations, apathy and anxiety are associated with current and future disease progression in AD. PMID- 22922822 TI - Pannexin 1 ohnologs in the teleost lineage. AB - Advances in genomic analysis indicate that the early chordate lineage underwent two whole-genome duplication events in fairly rapid succession around 400-600 million years ago, and that a third duplication event punctuated the radiation of ray-finned fishes (teleosts) around 320-350 million years ago. Connexin ohnologs have been disproportionately well maintained in the teleost genome following this third event, implying that gap junction proteins are amenable to neofunctionalization. A second family of gap junction-like proteins, the pannexins, is also present in chordates, but expansion of this family following the teleost whole-genome duplication has not been addressed in the literature. In the current study we report that ohnologs of panx1 are expressed by zebrafish, and orthologs of these two genes can be found in various other teleost species. The genomic locality of each gene is described, along with sequence alignments that reveal conservation of classic pannexin-specific features/motifs. The transcripts were then cloned from cDNA for in vitro analysis, and both are shown to traffic to the plasma membrane when exogenously expressed. Furthermore, electrophysiological recordings show differences in the biophysical properties between the channels formed by these two proteins. Our results indicate that both copies of the ancestral teleost panx1 gene were conserved following the last whole-genome duplication event and, following conventional zebrafish nomenclature, should now be referred to as panx1a and panx1b. PMID- 22922823 TI - Constraint-induced movement therapy combined with conventional neurorehabilitation techniques in chronic stroke patients with plegic hands: a case series. AB - OBJECTIVE: To determine whether the combination of Constraint-Induced Movement Therapy (CIMT) and conventional rehabilitation techniques can produce meaningful motor improvement in chronic stroke patients with initially fisted hands. DESIGN: Case series. SETTING: University hospital outpatient laboratory. PARTICIPANTS: Consecutive sample (N=6) >1 year poststroke with plegic hands. INTERVENTIONS: Treatment consisted of an initial period of 3 weeks (phase A) when adaptive equipment in the home, orthotics, and splints were employed to improve ability to engage in activities of daily living. This was continued in phase B, when CIMT and selected neurodevelopmental treatment techniques were added. MAIN OUTCOME MEASURES: Motor Activity Log (MAL), accelerometry, Fugl-Meyer Motor Assessment (F M). RESULTS: Patients exhibited a large improvement in spontaneous real-world use of the more-affected arm (mean lower-functioning MAL change=1.3+/-0.4 points; P<.001; d'=3.0) and a similar pattern of increase in an objective measure of real world more-affected arm movement (mean change in ratio of more- to less-affected arm accelerometer recordings=0.12+/-0.1 points; P=.016; d'=1.2). A large improvement in motor status was also recorded (mean F-M change=5.3+/-3.3 points; P=.005; d'=1.6). CONCLUSIONS: The findings of this pilot study suggest that stroke patients with plegic hands can benefit from CIMT combined with some conventional rehabilitation techniques, even long after brain injury. More research is warranted. PMID- 22922824 TI - Single impact cartilage trauma and TNF-alpha: interactive effects do not increase early cell death and indicate the need for bi-/multidirectional therapeutic approaches. AB - Blunt trauma of articular cartilage, often resulting from accidents or sports injuries, is associated with local inflammatory reactions and represents a major risk factor for development of post-traumatic osteoarthritis. TNF-alpha is increased in synovial fluid early after trauma, potentiates injury-induced proteoglycan degradation and may act proapoptotic under permissive conditions. We asked whether TNF-alpha also influences chondrocyte death, gene expression of catabolic and anabolic markers and the release of proinflammatory mediators in the early post-traumatic phase. Interactive effects of a defined single impact trauma (0.59 J) and TNF-alpha (100 ng/ml) on human early-stage osteoarthritic cartilage were investigated in vitro over 24 h. Exposure of traumatized cartilage to TNF-alpha did not increase chondrocyte death. IL-6-synthesis was augmented by trauma, TNF-alpha and combined treatment. The impact increased the release of PGE2 and PGD2 in the presence and absence of TNF-alpha to a similar extent while TNF-alpha alone showed no effect. In contrast, NOS2A-expression and nitric oxide (NO)-release were not affected by trauma but significantly increased by TNF alpha. Expression of OPG and RANKL was not affected by TNF-alpha but modulated by trauma. TNF-alpha with and without trauma significantly induced MMP1 gene expression. These results indicate that TNF-alpha does not potentiate early cell death in early-stage osteoarthritic cartilage after blunt injury. However, trauma and TNF-alpha showed independent and interactive effects concerning prostaglandin and NO release. TNF-alpha probably contributes to cartilage degradation after trauma by an early induction of MMP1 gene expression. Our study confirms that an anti-TNF-alpha therapy may have inhibitory effects on catabolic and, partly, on inflammatory processes after a single impact trauma. As TNF-alpha does not contribute to the loss of chondrocytes in the initial post-traumatic phase, a combination with pharmaco-therapeutic strategies reducing early cell death could be reasonable. PMID- 22922825 TI - The future of school nursing: banishing band-AIDS to improve public health outcomes. AB - This article provides analysis and commentary on the cultural roots that promote the provision of minor first aid in schools by school nurses. Using the Institute of Medicine's Future of Nursing report as a lens, this article illustrates how the focus on provision of first aid by school nurses dilutes larger public health contributions that school nurses could make if they were able to work to the full extent of their education, training and licensure. The article concludes with recommendations designed to support fuller use of nurses' scope of practice in schools. PMID- 22922826 TI - Increased expression of heat shock protein 90 under chemical hypoxic conditions protects cardiomyocytes against injury induced by serum and glucose deprivation. AB - Heat shock proteins (HSPs) are critical for adaptation to hypoxia and/or ischemia. Previously, we demonstrated that cobalt chloride (CoCl2), a well-known hypoxia mimetic agent, is an inducer of HSP90. In the present study, we tested the hypothesis that CoCl2-induced upregulation of HSP90 is able to provide cardioprotection in serum and glucose-deprived H9c2 cardiomyocytes (H9c2 cells). Cell viability was detected using a CCK-8 assay, while HSP90 expression was detected via western blotting. The findings of this study showed that serum and glucose deprivation (SGD) induced significant cytotoxicity, overproduction of reactive oxygen species (ROS) and a loss of mitochondrial membrane potential (MMP) in H9c2 cells. In addition, SGD downregulated the expression of HSP90 in a time-dependent manner. The selective inhibitor of HSP90 17-allylamino-17 demethoxygeldanamycin (17-AAG) aggravated SGD-induced cytotoxicity. CoCl2 at 100 uM time-dependently enhanced the expression of HSP90. Treatment with CoCl2 from 50 to 200 uM significantly attenuated cytotoxicity and the downregulation of HSP90 expression induced by SGD for 24 h, respectively. Notably, pretreatment of H9c2 cells with 17-AAG at 2 uM for 60 min before exposure to both CoCl2 (100 uM) and SGD significantly blocked the CoCl2-induced cardioprotective effect, demonstrated by decreased cell viability and MMP loss, as well as increased ROS generation. Taken together, these results suggest that HSP90 may be one of the endogenous defensive mechanisms for resisting ischemia-like injury in H9c2 cells, and that HSP90 plays an important role in chemical hypoxia-induced cardioprotection against SGD-induced injury by its antioxidation and preservation of mitochondrial function. PMID- 22922827 TI - miR-15a and miR-16-1 downregulate CCND1 and induce apoptosis and cell cycle arrest in osteosarcoma. AB - Osteosarcoma, the most common primary tumor of the bones, causes many deaths due to its rapid proliferation and drug resistance. Recent studies have shown that cyclin D1 plays a key regulatory role during cell proliferation, and non-coding microRNAs (miRNAs) act as crucial modulators of cyclin D1 (CCND1). The aim of the current study was to determine the role of miRNAs in controlling CCND1 expression and inducing cell apoptosis. CCND1 has been found to be a target of miR-15a and miR-16-1 through analysis of complementary sequences between microRNAs and CCND1 mRNA. The upregulation of miR-15a and miR-16-1 in the cell line SOSP-9607 induces apoptosis and cell cycle arrest. Osteosarcoma cells transfected with miR-15a and miR-16-1 show slower proliferation curves. Moreover, the transcription of CCND1 is suppressed by miR-15a and miR-16-1 via direct binding to the CCND1 3' untranslated region (3'-UTR). The data presented here demonstrate that the CCND1 contributes to osteosarcoma cell proliferation, suggesting that repression of CCND1 by miR-15a and miR-16-1 could be used for osteosarcoma therapy. PMID- 22922828 TI - Effects on costs of frontline diagnostic evaluation in patients suspected of angina: coronary computed tomography angiography vs. conventional ischaemia testing. AB - AIMS: The aim of this study was to investigate in patients with stable angina the effects on costs of frontline diagnostics by exercise-stress testing (ex-test) vs. coronary computed tomography angiography (CTA). METHODS AND RESULTS: In two coronary units at Lillebaelt Hospital, Denmark, 498 patients were identified in whom either ex-test (n = 247) or CTA (n = 251) were applied as the frontline diagnostic strategy in symptomatic patients with a low-intermediate pre-test probability of coronary artery disease (CAD). During 12 months of follow-up, death, myocardial infarction and costs associated with downstream diagnostic utilization (DTU), treatment, ambulatory visits, and hospitalizations were registered. There was no difference between cohorts in demographic characteristics or the pre-test probability of significant CAD. The mean (SD) age was 56 (11) years; 52% were men; and 96% were at low-intermediate pre-test probability of CAD. All serious cardiac events (n = 3) during follow-up occurred in patients with a negative ex-test result. Mean costs per patient associated with DTU, ambulatory visits, and cardiovascular medication were significantly higher in the ex-test than in the CTA group. The mean (SD) total costs per patient at the end of the follow-up were 14% lower in the CTA group than in the ex-test group, ? 1510 (3474) vs. ?1777 (3746) (P = 0.03). CONCLUSION: Diagnostic assessment of symptomatic patients with a low-intermediate probability of CAD by CTA incurred lower costs when compared with the ex-test. These findings need confirmation in future prospective trials. PMID- 22922829 TI - Single coronary artery from the right sinus of valsalva: an unusual variant of a rare condition. PMID- 22922830 TI - Polymorphisms in base excision repair genes and thyroid cancer risk. AB - Thyroid cancer (TC) is the most frequent endocrine malignancy, accounting however for only 1-2% of all human cancers, and the best-established risk factor for TC is radiation exposure, particularly during childhood. Since the BER pathway seems to play an important role in the repair of DNA damage induced by IR and other genotoxicants, we carried out a hospital-based case-control study in order to evaluate the potential modifying role of 6 BER polymorphisms on the individual susceptibility to non-familial TC in 109 TC patients receiving iodine-131, and 217 controls matched for age (+/- 2 years), gender and ethnicity. Our results do not reveal a significant involvement of XRCC1 Arg194Trp and Arg399Gln, OGG1 Ser326Cys, APEX1 Asp148Glu, MUTYH Gln335His and PARP1 Val762Ala polymorphisms on the individual susceptibility towards TC, mostly in agreement with the limited available evidence. By histological stratification analysis, we observed that the association between the presence of heterozygosity in the MUTYH Gln335His polymorphism and TC risk almost reached significance for the papillary subtype of TC. This was the first time that the putative association between this polymorphism and TC susceptibility was evaluated. However, since the sample size was modest, the possibility of a type I error should not be excluded and this result should, therefore, be interpreted with caution. More in depth studies involving larger populations should be pursued in order to further clarify the potential usefulness of the MUTYH Gln335His genotype as a predictive biomarker of susceptibility to TC and the role of the remaining BER polymorphisms on TC susceptibility. PMID- 22922831 TI - Optimising the sampling effort in riparian surveys. AB - Riparian condition is commonly measured as part of stream health monitoring programs as riparian vegetation provides an intricate linkage between the terrestrial and aquatic ecosystems. Field surveys of a riparian zone provide comprehensive riparian attribute data but can be considerably intensive and onerous on resources and workers. Our objective was to assess the impact of reducing the sampling effort on the variation in key riparian health indicators. Subsequently, we developed a non-parametric approach to calculate an information retained (IR) statistic for comparing several constrained systematic sampling schemes to the original survey. The IR statistic is used to select a scheme that reduces the time taken to undertake riparian surveys (and thus potentially the costs) whilst maximising the IR from the original survey. Approximate bootstrap confidence intervals were calculated to improve the inferential capability of the IR statistic. The approach is demonstrated using riparian vegetation indicators collected as part of an aquatic ecosystem health monitoring program in Queensland, Australia. Of the nine alternative sampling designs considered, the sampling design that reduced the sampling intensity per site by sixfold without significantly comprising the quality of the IR, results in halving the time taken to complete a riparian survey at a site. This approach could also be applied to reducing sampling effort involved in monitoring other ecosystem health indicators, where an intensive systematic sampling scheme was initially employed. PMID- 22922832 TI - Notch1 activation contributes to tumor cell growth and proliferation in human hepatocellular carcinoma HepG2 and SMMC7721 cells. AB - Notch signaling controls cellular differentiation and proliferation. Recent studies have shown that Notch signaling plays an important role in the carcinogenesis and progression of a growing number of malignant tumors. We investigated the effect of Notch1 activation on human hepatocellular carcinoma (HCC). In five human HCC cell lines, it was found that SMMC7721 had relatively high while HepG2 relatively low expression of Notch1 and the activity of Notch signaling. Notch1 activation by transfection of active intracellular region of Notch1 (ICN1) into HCC HepG2 cells enhanced cell growth and proliferation, including in vitro single cell colony formation, anchorage-independent proliferation, and in vivo tumorigenicity. Notch1 activation also promoted HepG2 cell cycle progression. Suppression of Notch1 activation by RNAi of Notch1 or by gamma-secretase inhibitor (GSI) in HCC SMMC7721 cells decreased cell growth capability and blocked cell cycle progression. Moreover, it was found that suppression of Notch1 activation induced SMMC7721 cell apoptosis, as demonstrated by apoptosis assays. These findings indicate that Notch1 activation promotes human HCC cell growth and proliferation, which may contribute to the progression of this type of malignant carcinoma. PMID- 22922833 TI - Challenges in acute ischemic stroke clinical trials. AB - There have been only 3 positive Phase III randomized clinical trials in acute ischemic stroke, all reperfusion therapies (NINDS; PROACT II; ECASS III). The only approved acute stroke therapy is <3-hour IV tPA. Although numerous compounds have shown benefit in animal models of brain infarction, there has never been a positive Phase III randomized clinical trial of a neuroprotectant in acute ischemic stroke. There are many challenges to acute stroke clinical trials but chief among these are the very short therapeutic window ("time is brain") and the issue of stroke heterogeneity. Stroke is a syndrome and only a very small percentage of all stroke patients present to hospitals in time to consider reperfusion therapy. Many drugs have been rushed to trial prematurely based on inadequate preclinical testing. Many trials have been seriously underpowered due to overly optimistic treatment expectations and the risk of brain hemorrhage has precluded aggressive multimodal treatment strategies. Rather than simply relying on a clock, new imaging methods are being developed to identify patients with "tissue at risk" and "salvageable brain" regardless of time of stroke onset. The 7 STAIR conferences have been convened to address these and other challenges to acute ischemic stroke trial design and completion. PMID- 22922834 TI - Lobar emphysema with pneumothorax in an adult: report of a case. AB - A 31-year-old woman was transferred to our hospital for treatment of a right pneumothorax. She had presented initially with moderate dyspnea and coughing at a local clinic, where a chest radiograph showed a collapsed right lung. Chest computed tomography showed overinflation of the middle lobe and a large bulla. We diagnosed congenital lobar emphysema of the middle lobe with pneumothorax and performed middle lobectomy by video-assisted thoracic surgery via four ports (5 12 mm in size). The patient had an uneventful postoperative course and was discharged from hospital 5 days after surgery. PMID- 22922835 TI - Adult with primary hyperoxaluria type 1 regrets not receiving preemptive liver transplantation during childhood: report of a case. AB - A 32-year-old male was suspected to have primary hyperoxaluria type 1 (PH1) and eventually underwent liver transplantation (LT). He was diagnosed with nephrolithiasis at 9 years of age. Right heminephrectomy was performed for a staghorn calculus. He underwent urethrotomy for urinary retention at 12 years of age. Percutaneous nephrolithotomy was performed for nephrolithiasis when he was 16 years of age. He underwent frequent extracorporeal shock wave lithotripsy for recurrent nephrolithiasis from 18 to 24 years of age. PH1 was suspected at 32 years of age, and pharmacological therapy was also initiated. He developed renal failure at 36 years of age, which was treated with intensive hemodialysis. A definitive diagnosis of PH1 was made based on a liver needle biopsy 1 month later. He received a living-donor LT at 38 years of age, and a living-donor kidney transplant from the same donor 8 months later. Though he made a good recovery, an early diagnosis and preemptive LT are important for PH1 patients. PMID- 22922836 TI - Is the threshold for postoperative prosthesis-patient mismatch the same for all prostheses? AB - PURPOSE: The effective orifice area index (EOAI) is used to define the prosthesis patient mismatch (PPM) after aortic valve replacement (AVR). However, few studies have so far evaluated whether the cutoff value for PPM varies across prostheses. This study assessed the hemodynamics in patients given a mechanical valve and then re-evaluated the validity of the commonly accepted threshold. METHODS: The subjects included 329 patients that underwent AVR with a St. Jude Medical Regent valve. The transvalvular pressure gradient and EOAI were determined echocardiographically, and the commonly accepted threshold was analyzed in relation to survival. RESULTS: The mechanical valves very often yielded a postoperative transvalvular pressure gradient >10 mmHg, and thus, clinically significant residual pressure, regardless of the EOAI. The slope of the curve describing the relationship between the transvalvular pressure gradient and EOAI was gentler than that reported for bioprosthetic valves, for which the pressure gradient rises sharply at EOAI <0.85 cm(2)/m(2). The commonly defined PPM did not affect the long-term survival or regression of the left ventricular mass index. CONCLUSIONS: The relationship between the transvalvular pressure gradient and the EOAI in patients given a mechanical prosthesis differed from the reference standard. These data suggest the need to reconsider the appropriate cutoff value for PPM in relation to different prostheses. PMID- 22922837 TI - Characterization and quantification of phenolic compounds in four tomato (Lycopersicon esculentum L.) farmers' varieties in northeastern Portugal homegardens. AB - Tomato (Lycopersicon esculentum L.) is one of the most widely consumed fresh and processed vegetables in the world, and contains bioactive key components. Phenolic compounds are one of those components and, according to the present study, farmers' varieties of tomato cultivated in homegardens from the northeastern Portuguese region are a source of phenolic compounds, mainly phenolic acid derivatives. Using HPLC-DAD-ESI/MS, it was concluded that a cis p coumaric acid derivative was the most abundant compound in yellow (Amarelo) and round (Batateiro) tomato varieties, while 4-O-caffeolyquinic acid was the most abundant in long (Comprido) and heart (Coracao) varieties. The most abundant flavonoid was quercetin pentosylrutinoside in the four tomato varieties. Yellow tomato presented the highest levels of phenolic compounds (54.23 MUg/g fw), including phenolic acids (43.30 MUg/g fw) and flavonoids (10.93 MUg/g fw). The phenolic compounds profile obtained for the studied varieties is different from other tomato varieties available in different countries, which is certainly related to genetic features, cultivation conditions, and handling and storage methods associated to each sample. PMID- 22922838 TI - Comparison of learning and memory of Apis cerana and Apis mellifera. AB - The honeybee is an excellent model organism for research on learning and memory among invertebrates. Learning and memory in honeybees has intrigued neuroscientists and entomologists in the last few decades, but attention has focused almost solely on the Western honeybee, Apis mellifera. In contrast, there have been few studies on learning and memory in the Eastern honeybee, Apis cerana. Here we report comparative behavioral data of color and grating learning and memory for A. cerana and A. mellifera in China, gathered using a Y-maze apparatus. We show for the first time that the learning and memory performance of A. cerana is significantly better on both color and grating patterns than that of A. mellifera. This study provides the first evidence of a learning and memory difference between A. cerana and A. mellifera under controlled conditions, and it is an important basis for the further study of the mechanism of learning and memory in honeybees. PMID- 22922839 TI - Evaluation of sexual function in sexually active women 1 year after transvaginal NOTES: a prospective cohort study of 106 patients. AB - PURPOSE: The primary objective of this prospective cohort study was to investigate sexual function, quality of life and patient satisfaction in sexually active women 1 year after transvaginal hybrid natural orifice transluminal endoscopic surgery (NOTES). PATIENTS AND METHODS: This prospective single-centre cohort study included sexually active female patients after transvaginal hybrid NOTES cholecystectomy or anterior resection. Sexual life impairment and quality of life were assessed by the Gastrointestinal Quality of Life Index (GIQLI) prior and 1 year after surgery. Patient satisfaction was assessed as well as the sexual function 1 year postoperatively using the validated German version of the Female Sexual Function Index (FSFI-D). RESULTS: Between September 2008 and December 2009, 106 sexually active women after transvaginal hybrid NOTES cholecystectomy or anterior resection were identified. Sexual life significantly improved (GIQLI scores 3.2 +/- 1.0 preoperatively vs. 3.7 +/- 0.7 1 year postoperatively, P < 0.001), and painful sexual intercourse (3.3 +/- 1.0 vs. 3.6 +/- 0.7, P = 0.008) decreased post-surgery. The mean FSFI-D total score after transvaginal NOTES was 28.1 +/- 4.6, exceeding the cutoff for sexual dysfunction defined as 26. Four (4.5 %) out of 88 patients who answered this question were not satisfied with the transvaginal hybrid NOTES procedure. CONCLUSIONS: This prospective cohort study of female sexual function after transvaginal NOTES provides compelling evidence that the transvaginal access is safe and associated with high satisfaction rate. PMID- 22922840 TI - Surgery for Crohn's disease: new developments. AB - BACKGROUND/AIMS: Crohn's disease is a chronic relapsing inflammatory bowel disease requiring surgery in a large number of patients. This review describes new developments in surgical techniques for treating Crohn's disease. RESULTS: Single-incision laparoscopic surgery decreases abdominal wall trauma by reducing the number of abdominal incisions, possibly improving postoperative results in terms of pain and cosmetics. The resected specimen can be extracted through the single-incision site or the future stoma site. Another option is to use natural orifices for extraction (i.e. transcolonic/transanal), but actual benefits of these procedures have not yet been determined. In patients with extensive perianal disease or rectal involvement, transperineal completion proctectomy is often feasible, thereby avoiding relaparotomy. By using a close rectal intersphincteric resection, damage to the pelvic autonomic nerves is avoided. In addition, the risk of presacral abscess formation is reduced by leaving the mesorectal tissue behind. CONCLUSION: Minimally invasive surgery and associated techniques have become standard clinical practice in surgical treatment of patients with Crohn's disease. New developments aim at further reducing the hospital stay and morbidity, and improving the cosmetic outcomes. PMID- 22922841 TI - Evaluation of ultrasmall superparamagnetic iron oxide-enhanced MRI of carotid atherosclerosis to assess risk of cerebrovascular and cardiovascular events: follow-up of the ATHEROMA trial. PMID- 22922842 TI - Clonal dominance of CD133+ subset population as risk factor in tumor progression and disease recurrence of human cutaneous melanoma. AB - Chemotherapeutic refractoriness of advanced cutaneous melanoma may be linked with melanoma-initiating cells, also known as melanoma stem cells. This study aimed to determine relative risk of clonal dominance of the CD133+ phenotype in tissues from melanoma patients with different clinical outcomes that could be applied to early diagnosis, prognosis or disease monitoring. Significant overexpression of CD133 (p<0.02) was observed by immunohistochemical staining in tissues from patients with recurrent disease versus those without disease recurrence. Relative risk analysis between these two groups suggested that the patients with recurrence or metastatic lesion had a greater than 2-fold overexpression of CD133. In addition, immunodetectable CD133 corroborated with upregulation of CD133 RNA levels (14- to 30-fold) as assessed by quantitative real-time reverse transcription-PCR (qRT-PCR) comparison of melanoma cell lines derived from patients with poor clinical outcomes and short overall survival (<10 months), vs. those derived from patients with good clinical outcomes and longer overall survival (>24 months). Further, cells derived from patients, and MACS-sorted according to their CD133 status retained their CD133-positivity (>95%) or CD133 negativity (>95%) for more than 8 passages in culture. CD133+ cells could repopulate and form tumors (p<0.03) in athymic NCr-nu/nu mice within 8 weeks while no tumors were observed with CD133- phenotype (up to 200,000 cells). Taken together, the study demonstrates, for the first time, that there exists a clonal dominance of a CD133+ population within the hierarchy of cells in cutaneous tissues from patients that have undergone successive progressive stages of melanoma, from primary to metastatic lesions. CD133, thus, provides a predictive marker of disease as well as a potential therapeutic target of high-risk melanoma. PMID- 22922843 TI - Comparison of spectral-domain optical coherence tomography and Heidelberg retina tomograph III optic nerve head parameters in glaucoma. AB - BACKGROUND: To evaluate the agreement between the optic nerve head (ONH) measurements obtained by spectral-domain optical coherence tomography/scanning laser ophthalmoscope (SD-OCT/SLO) and the Heidelberg retinal tomograph III (HRT III), and to compare the ONH measurements of both devices in different glaucoma types. METHODS: In a prospective study, 30 patients with primary open-angle glaucoma (POAG) and 30 patients with pseudoexfoliation glaucoma (PXG) were enrolled. All patients underwent SD-OCT/SLO and HRT-III evaluation of the ONH during the same visit. Agreement between measurements of SD-OCT/SLO and HRT-III were evaluated by determination of intraclass correlation coeficients. In addition, mean ONH measurements obtained with both devices were compared between POAG and PXG patient groups. RESULTS: Mean SD-OCT/SLO measurements were greater than those of HRT-III, except for mean and maximum cup depth. Intraclass correlation coefficient values for disc area, rim area, cup area, cup/disc area ratio, mean cup depth and maximum cup depth were 0.367, 0.213, 0.632, 0.681, 0.775 and 0.661, respectively. No significant differences were found between ONH parameters of POAG and PXG patients as measured with both devices (p > 0.01). CONCLUSION: ONH measurements with SD-OCT/SLO and HRT-III did not show clinically acceptable agreement in glaucoma patients. This precludes interchangeable use of these measurements in clinical practice. PXG and POAG patient groups displayed similar ONH measurements with both devices. PMID- 22922844 TI - Anti-vascular endothelial growth factor therapy for myopic choroidal neovascularization: do we need more evidence? PMID- 22922845 TI - Polypoidal choroidal vasculopathy--an important diagnosis to make with therapeutic implications. PMID- 22922846 TI - Intravitreal ranibizumab versus bevacizumab for treatment of myopic choroidal neovascularization. AB - PURPOSE: To compare intravitreal bevacizumab (IVB) and intravitreal ranibizumab (IVR) in the treatment of subfoveal choroidal neovascularization associated with pathologic myopia. METHODS: Fifty-five patients fulfilling inclusion and exclusion criteria were randomized either to IVB or to IVR. After the first injection, re-treatments were performed on a pro re nata basis in monthly examinations over an 18-month follow-up. Primary outcome measures were the change in mean best-corrected visual acuity and the proportion of eyes improving in best corrected visual acuity by >1 and >3 lines at the 18-month examination. RESULTS: Forty-eight eyes received the treatment and were subsequently included in the analysis. At the 18-month examination, a significant improvement of 1.7 lines and 1.8 lines compared with baseline were noticed in the IVR and IVB subgroups, respectively. The difference in the final mean best-corrected visual acuity between the groups was not significant. A 3-line gain or higher was noted in 30% of eyes in the IVR subgroup and 44% of eyes in the IVB subgroup. Although both groups attained a significant improvement in central macular thickness, the IVR subgroup achieved a faster central macular thickness reduction. A significantly lower number of injections were administered in the IVR subgroup (2.5) compared with the IVB subgroup (4.7; P < 0.001). CONCLUSION: Intravitreal ranibizumab and IVB are effective in the treatment of subfoveal myopic choroidal neovascularization. Intravitreal ranibizumab achieved greater efficacy than IVB in terms of the mean number of injections administered. PMID- 22922847 TI - Optical coherence tomography in retinitis pigmentosa: reproducibility and capacity to detect macular and retinal nerve fiber layer thickness alterations. AB - PURPOSE: To evaluate the ability of time-domain and Fourier-domain optical coherence tomographies (OCTs) to detect macular and retinal nerve fiber layer atrophies in retinitis pigmentosa (RP). To test the intrasession reproducibility using three OCT instruments (Stratus, Cirrus, and Spectralis). METHODS: Eighty eyes of 80 subjects (40 RP patients and 40 healthy subjects) underwent a visual field examination, together with 3 macular scans and 3 optic disk evaluations by the same experienced examiner using 3 OCT instruments. Differences between healthy and RP eyes were compared. The relationship between measurements with each OCT instrument was evaluated. Repeatability was studied by intraclass correlation coefficients and coefficients of variation. RESULTS: Macular and retinal nerve fiber layer atrophies were detected in RP patients for all OCT parameters. Macular and retinal nerve fiber layer thicknesses, as determined by the different OCTs, were correlated but significantly different (P < 0.05). Reproducibility was moderately high using Stratus, good using Cirrus and Spectralis, and excellent using the Tru-track technology of Spectralis. In RP eyes, measurements showed higher variability compared with healthy eyes. CONCLUSION: Differences in thickness measurements existed between OCT instruments, despite there being a high degree of correlation. Fourier-domain OCT can be considered a valid and repeatability technique to detect retinal nerve fiber layer atrophy in RP patients. PMID- 22922848 TI - A novel technique for high-density silicone oil removal. PMID- 22922849 TI - A 23-gauge dual light probe for vitreoretinal surgery. PMID- 22922851 TI - Re: Dexamethasone intravitreal implant for treatment of diabetic macular edema in vitrectomized patients. PMID- 22922853 TI - Re: Single session of Pascal versus multiple sessions of conventional laser for panretinal photocoagulation in proliferative diabetic retinopathy: a comparative study. PMID- 22922855 TI - Association of serum LDL cholesterol level with periodontitis among patients visiting a tertiary-care hospital. AB - INTRODUCTION: High low-density lipoproteins (LDL) cholesterol is one of the major risk factors for cardiovascular disease. In recent years, some evidence has been presented that periodontitis, an infectious inflammatory condition of the periodontium, is associated with an increased risk of cardiovascular disease. To further elucidate this association, we have studied the levels of LDL cholesterol, a known risk marker for cardiovascular disease, in a periodontally diseased group. METHODS: The levels of serum LDL cholesterol in 47 subjects with mild to severe (clinical attachment loss equal to or greater than 1 mm) chronic generalized (at least 30% of teeth affected) periodontitis with the mean age of 42.21 +/- 1.46 years were measured and compared with those obtained from 42 age (39.83 +/- 0.94) and sex matched controls. Both groups were free from systemic illnesses. RESULTS: The mean serum LDL cholesterol in periodontitis patients was found to be significantly higher (P < 0.001) as compared to that of the controls. The mean clinical attachment loss was positively correlated with serum LDL cholesterol (P < 0.01) and gingival index (P<0.05). The frequency of persons with pathologic values of LDL cholesterol was significantly higher in periodontitis patients compared with that of the controls. CONCLUSIONS: These results showed that high serum LDL cholesterol may be associated with periodontitis in healthy people. However, it is unclear whether periodontitis causes an increase in the levels of serum LDL or an increased LDL is a risk factor for both periodontitis and cardiovascular disease. PMID- 22922856 TI - Efficacy of endovascular therapy for direct occlusion of intracranial aneurysms. AB - INTRODUCTION: Our purpose was to evaluate the effectiveness of endovascular therapy using detachable coils and balloons for the direct occlusion of intracranial aneurysms. METHODS: We retrospectively reviewed 563 patients undergoing digital subtraction angiography from January 2007 to July 2009. Two hundred and fifty patients with 323 embolized intracranial aneurysms were studied. RESULTS: Among 250 patients, 66 % were female and 34 % male, the age ranging from 19 - 83 years (mean 50.66 +/- 12.92). One hundred and seventy-seven had a single aneurysm while 73 showed multiple aneurysms. Seventeen (9.6 %) had giant aneurysms. Three hundred and eleven aneurysms were treated using detachable coils, and 12 giant aneurysms were embolized by detachable balloons for the parent vessel occlusion. Of 323 aneurysms treated via the endovascular approach, total occlusion was seen in 93 % of the aneurysms, near total occlusion in 5.2 % and incomplete embolization in 1.5 %. Among patients presenting with sub arachnoid hemorrhage, 62 improved to the Glasgow outcome score (GOS) of 5, 93 improved to GOS 4, 14 improved to GOS 3, 10 improved to GOS 2 at the time of discharge and 5 patients died. Angiographic follow-up was scheduled between 6 - 12 months post-embolization. The aneurysm recurred in 1.2 % and were re-embolized using additional coils. Statistically, Hunt and Hess Grade and GOS indicated clinical significance (P < 0.05). The patients, gender, clinical presentation and aneurysmal location did not show statistical significance (P > 0.05). CONCLUSIONS: Hunt and Hess VI and V are considered as poor clinical gradings in aneurysmal SAH. However, endovascular treatment has been established as an effective method to obliterate intracranial aneurysms allowing subsequent decrease in mortality and morbidity. PMID- 22922857 TI - Role of magnetic resonance imaging in evaluation of tubercular spondylitis: pattern of disease in 100 patients with review of literature. AB - INTRODUCTION: The purpose of this study is to evaluate the role of magnetic resonance imaging (MRI) in evaluation of tubercular spondylitis and to correlate imaging findings with clinical severity of the disease. METHODS: One hundred consecutive patients, who presented with features suggestive of spinal infections, were subjected to MRI examination. T1W and STIR images were obtained followed by T2W and post-contrast T1W images. Various imaging characteristics of spinal infections were noted and correlated with the clinical severity of the disease. RESULTS: Backache was the most common presenting symptom present in 86 %, while paraparesis was the most common sign seen in 62 %. The neurological status of the patients correlated well with MRI findings in the majority of the cases with an overall good correlation obtained in 96 % of cases. The majority of the vertebrae and intervertebral discs affected showed hypointensity or isointensity on T1W images and hyperintensity on T2W images. Epidural/dural disease was present in 74 % while 68 % of patients demonstrated decreased intervertebral disc height. Epidural extension and subligamentous spread was in 74 % and 90 % of patients respectively. CONCLUSIONS: MRI plays a vital role in early and accurate diagnosis of spinal infections. It is non-invasive and clearly demonstrates soft tissue anatomy and pathology which makes it superior to X-rays and Computed Tomography (CT). Imaging findings of tubercular spondylitis were also found to have a good correlation with the clinical status of the patients. Hence, it is of much help in the evaluation and assessment of patients presenting with features of spinal infections. PMID- 22922858 TI - Anatomical and visual outcome following macular hole surgery at a tertiary eye care centre in Nepal. AB - INTRODUCTION: Macular hole (MH) leading to central vision loss is common in the elderly. This study aimed to explore the anatomical and functional outcome of MH surgery at a tertiary eye care setting in Nepal. METHODS: This retrospective, interventional case series study included patients who had undergone MH treatment with pars plana vitrectomy, membrane peeling and perfluoropropane gas (C3F8) from 2007 January to 2010 August and had completed three months of follow up. The best corrected visual acuity (BCVA) and anatomical status of MH assessed with bio microscopy and optical coherence tomography (OCT) at six weeks, three months and at the last follow-up following surgery were recorded. RESULTS: A total of 36 cases with the age range of 11 - 73 years and the mean age of 53.2 years (19.3 S.D) were included in the study. The mean duration of decreased vision was 11.1 months (12.1 S.D). Idiopathic macular hole comprised of 31 cases (86.1 %) and traumatic of five cases (13.9 %). The mean follow-up period was 9.4 months. The MH closed in 27 cases (75 %) at six weeks and in 28 cases (77.8%) at three months and at the last follow-up. The vision had improved in 36 % of cases, with more than 2 lines in 27.8 %, and was stable in 27.7 % of cases during the the last follow-up. The anatomical success rate was higher in the idiopathic MH (80.65 %) than in the traumatic (60 %) and visual acuity improved in 45 % of cases in the idiopathic and 20 % in the traumatic cases. CONCLUSIONS: The overall anatomic success rate was 78 % and improvement in visual acuity was seen in one -third of cases. The success rate was higher among idiopathic MH than in traumatic. PMID- 22922859 TI - Risk of periodontal disease: is there a correlation with the type of antihypertensive medication? AB - INTRODUCTION: The purpose of this study was to evaluate the effects of long-term oral antihypertensive treatment using centrally acting sympatho-inhibitory drugs (clonidine) and beta-blockers (metoprolol) on capillary microcirculation in the labial and periodontal mucosa. METHODS: Sixty subjects were recruited for the study: 20 patients affected by hypertension in treatment with centrally-acting sympatho-inhibitory drugs (64.28 +/- 11.78 years); 20 patients in treatment with beta-blockers (62.03 +/- 9.84 years) and 20 healthy subjects (62.06 +/- 6.72 years). We use the videocapillaroscopic technique to evaluate in vivo the microcirculation of the labial mucosa corresponding to the lower lip and of the periodontal mucosa corresponding to the central superior incisor. RESULTS: Capillaroscopy revealed a significant increase in the length, diameter, tortuousity and density (P <0.05) of capillaries in patients affected by hypertension in treatment with centrally acting sympatho-inhibitory drugs, while beta-blockers had a lower effect on the labial and periodontal microcirculation compared to the healthy population. CONCLUSIONS: The capillaroscopic has revealed substantial modifications of the oral microcirculatory pattern in hypertensive patients in treatment with centrally-acting sympatho-inhibitory drugs than with beta-blockers. PMID- 22922860 TI - Efficacy of IV iron compared to oral iron for increment of haemoglobin level in anemic chronic kidney disease patients on erythropoietin therapy. AB - INTRODUCTION: Anemia is the most common finding in chronic kidney disease patients. Iron supplements are commonly prescribed for these patients with or without erythropoietin therapy by means of oral and intravenous iron. Both oral and intravenous irons have their own advantage and disadvantage, and the efficacy is also different. The objective of the study is to analyze the efficacy of oral and intravenous iron in chronic kidney disease patients on erythropoietin therapy, an erythropoiesis stimulating agents for increment of haemoglobin. METHODS: This is a prospective study comparing intravenous iron to oral iron in chronic kidney disease patients who underwent maintenance hemodialysis at different centers and visited Kathmandu Medical College Teaching Hospital from April 2010 to April 2011. Patients having a haemoglobin level of < 11 g/dl, transferrin saturation (TSAT) < 25%, ferritin < 300ng/ml and who were on erythropoietin therapy were allocated alternately into two groups to receive oral iron (iron fumarate) or IV iron (iv sucrose). Haemoglobin was measured after 30 days of therapy. RESULTS: A significant increase in haemoglobin levels was observed in both groups. But the mean haemoglobin increment was more in the IV iron group than in the oral iron group. Sixty percent 60% of patients in the IV iron group had an increase in the haemoglobin level of more than 1gm/dl while only 20% of the oral iron group had this increase. CONCLUSIONS: Intravenous iron therapy is more effective in raising the hemoglobin level in hemodialysis dependent chronic kidney disease patients. PMID- 22922861 TI - Lemierre's syndrome in a patient with severe lupus nephritis. AB - Lemierre's syndrome is a rare septic thrombophlebitis of the internal jugular vein with frequent metastatic complications following an acute oropharyngeal infection. Immunocompromised patients are at higher risk of developing this syndrome owing to the decreased host response and increased risk of oropharyngeal sepsis. We herein report a 24-year-old woman with severe lupus nephritis on immunosuppressive therapy, who developed Lemierre's syndrome following a pharyngeal infection despite an adequate and timely antibiotic therapy. We hereby draw an attention to the importance of accurate and timely diagnosis and appropriate management of Lemierre's syndrome in immunocompromised patients so as to achieve a successful prognosis for this deadly infection. PMID- 22922862 TI - Subcutaneous emphysema in pregnancy. AB - Spontaneous pneumomediastinum and subcutaneous emphysema are rare complications of labor, especially in the late pregnancy period, but they are usually self limiting. Management includes avoidance of exacerbative factors and close observation with supportive treatment. A 19-year-old primi gravida at 36 weeks pregnancy presented with swelling over the right side of the face, neck and chest. Her general examination was normal. Systemic examination revealed swelling with palpatory crepitation over the right side of chest, neck and face, and other examination findings were normal. Chest X-ray revealed subcutaneous emphysema without pneumothorax. The patient left hospital against medical advice. PMID- 22922863 TI - Interrelationship between diabetes and periodontitis: a review. AB - Evidence for the link between periodontal disease and several systemic diseases is growing rapidly. Diabetes mellitus is a systemic disease with several major complications affecting both the quality and length of life causing morbidity and mortality. Periodontitis, one of these complications, is a chronic infection associated with substantial morbidity in the form of tooth loss and that affects the quality of life directly. The association between diabetes and inflammatory periodontal disease has been studied extensively. The relationship between these two conditions appears bidirectional. The presence of one condition tends to promote the other and the meticulous management of either may assist treatment of the other. It also provides a perfect example of a cyclical association, whereby a systemic disease predisposes the individual to oral infections, and once the oral infection is established, it exacerbates the systemic disease. This review focuses to explain the interrelationship between the two based on information in the literature and the potential common immunoregulatory connections involved, exploring the mechanisms through which periodontal infection can contribute to the low-grade general inflammation associated with diabetes. PMID- 22922864 TI - Tertiary eye care centre model for development of paediatric cataract surgery services in developing countries. AB - It is estimated that every minute a child becomes bilaterally blind in developing nations. Paediatric cataract blindness presents an enormous problem to developing countries in terms of the human social burden, economic loss, and morbidity. The management of the paediatric cataract is lens aspiration with intra ocular lens implantation with anterior vitrectomy. The surgery should be performed by paediatric ophthalmologist in tertiary eye care centres. Facilities of general anaesthesia should be available in these centres and the operating theatres should be well-equipped with vitrectomy machine, biometry and portable keratometer. PMID- 22922865 TI - Oral health and general health connections - an emerging challenge. PMID- 22922866 TI - Is general anaesthesia preferable to conscious sedation in the treatment of acute ischaemic stroke with intra-arterial mechanical thrombectomy? A review of the literature. AB - INTRODUCTION: Intra-arterial mechanical thrombectomy (IAMT) is an endovascular technique that allows for the acute retrieval of intravascular thrombi and is increasingly being used for the treatment of acute ischaemic stroke (AIS). There are currently two anaesthetic options during IAMT: general anaesthesia (GA) and conscious sedation (CS). The decision to use GA versus CS is the source of controversy, as it requires careful balance between patient pain, movement and airway protection whilst minimising time delay and haemodynamic fluctuations. This review examines and summarises the evidence for the use of GA versus CS in the treatment of AIS by IAMT. METHODS: Studies were identified using systematic bibliographic searches. The five applicable studies were analysed with reference to overall outcomes and the key parameters that govern the decision to use GA or CS. The key parameters included the impact of GA and CS on pain, complication rates, time delays, airway protection and haemodynamic stability. RESULTS: Several retrospective analyses have shown that the use of GA is associated with adverse outcomes. CONCLUSION: Intra-arterial mechanical thrombectomy under general anaesthesia is associated with poor outcomes in observational studies. It is reasonable to offer conscious sedation as the preferred option where adverse patient factors such as agitation are lacking. PMID- 22922867 TI - Sensory neuronopathy involves the spinal cord and brachial plexus: a quantitative study employing multiple-echo data image combination (MEDIC) and turbo inversion recovery magnitude (TIRM). AB - INTRODUCTION: Sensory neuronopathy (SNN) is a distinctive subtype of peripheral neuropathies, specifically targeting dorsal root ganglion (DRG). We utilized MRI to demonstrate the imaging characteristics of DRG, spinal cord (SC), and brachial plexus at C7 level in SNN. METHODS: We attempted multiple-echo data image combination (MEDIC) and turbo inversion recovery magnitude (TIRM) methods in nine patients with sensory neuronopathy and compared with those in 16 disease controls and 20 healthy volunteers. All participants underwent MRI for the measurement of DRG, posterior column (PC), lateral column, and spinal cord area (SCA) at C7 level. DRG diameters were obtained through its largest cross section, standardized by dividing sagittal diameter of mid-C7 vertebral canal. We also made comparisons of standardized anteroposterior diameter (APD) and left-right diameters of SC and PC in these groups. Signal intensity and diameter of C7 spinal nerve were assessed on TIRM. RESULTS: Compared to control groups, signal intensities of DRG and PC were higher in SNN patients when using MEDIC, but the standardized diameters were shorter in either DRG or PC. Abnormal PC signal intensities were identified in eight out of nine SNN patients (89 %) with MEDIC and five out of nine (56 %) with T2-weighted images. SCA, assessed with MEDIC, was smaller in SNN patients than in the other groups, with significant reduction of its standardized APD. C7 nerve root diameters, assessed with TIRM, were decreased in SNN patients. CONCLUSION: MEDIC and TIRM sequences demonstrate increased signal intensities and decreased area of DRG and PC, and decreased diameter of nerve roots in patients with SNN, which can play a significant role in early diagnosis. PMID- 22922869 TI - GFP/HPV-16E6 fusion protein induces apoptosis in MCF-7 and 293T cells using a transient expression system. AB - Since mucosal high-risk human papillomavirus (HPV) E6 can target and degrade the tumor suppressor p53, it is recognized as a major causative agent of cervical cancer. However, to date the distribution of high-risk HPV-E6 protein remains elusive. Thus, in the present study we used a mammalian green fluorescent protein (GFP) expression system to express a GFP/HPV-16E6 fusion protein (GFP-16E6) in wild-type (wt) p53 cells, such as MCF-7 and 293T cells to investigate the trafficking and localization of E6 and p53. Following transfection, we observed that the overexpressed GFP-16E6 was a nuclear protein, and that endogenous wt p53 localized to the nucleus together with GFP-16E6. Strikingly, p53 levels were not decreased but increased in 24 h transfected with pGFP-16E6. Furthermore, we observed significant apoptosis induced by GFP-16E6, which proved to be dependent on p53 expression. PMID- 22922868 TI - How do 'housekeeping' genes control organogenesis?--Unexpected new findings on the role of housekeeping genes in cell and organ differentiation. AB - In recent years, an increasing number of mutations in what would appear to be 'housekeeping genes' have been identified as having unexpectedly specific defects in multicellular organogenesis. This is also the case for organogenesis in seed plants. Although it is not surprising that loss-of-function mutations in 'housekeeping' genes result in lethality or growth retardation, it is surprising when (1) the mutant phenotype results from the loss of function of a 'housekeeping' gene and (2) the mutant phenotype is specific. In this review, by defining housekeeping genes as those encoding proteins that work in basic metabolic and cellular functions, we discuss unexpected links between housekeeping genes and specific developmental processes. In a surprising number of cases housekeeping genes coding for enzymes or proteins with functions in basic cellular processes such as transcription, post-transcriptional modification, and translation affect plant development. PMID- 22922870 TI - Gastrodin inhibits cell proliferation in vascular smooth muscle cells and attenuates neointima formation in vivo. AB - Vascular smooth muscle cell (VSMC) proliferation plays a critical role in the development of vascular diseases. In the present study, we tested the efficacy and the mechanisms of action of gastrodin, a bioactive component of the Chinese herb Gastrodia elata Bl, in relation to platelet-derived growth factor-BB (PDGF BB)-dependent cell proliferation and neointima formation after acute vascular injury. Cell experiments were performed with VSMCs isolated from rat aortas. WST and BrdU incorporation assays were used to evaluate VSMC proliferation. Eight week-old C57BL/6 mice were used for the animal experiments. Gastrodin (150 mg/kg/day) was administered in the animal chow for 14 days, and the mice were subjected to wire injury of the left carotid artery. Our data demonstrated that gastrodin attenuated the VSMC proliferation induced by PDGF-BB, as assessed by WST assay and BrdU incorporation. Gastrodin influenced the S-phase entry of VSMCs and stabilised p27Kip1 expression. In addition, pre-incubation with sinomenine prior to PDGF-BB stimulation led to increased smooth muscle-specific gene expression, thereby inhibiting VSMC dedifferentiation. Gastrodin treatment also reduced the intimal area and the number of PCNA-positive cells. Furthermore, PDGF BB-induced phosphorylation of ERK1/2, p38 MAPK, Akt and GSK3beta was suppressed by gastrodin. Our results suggest that gastrodin can inhibit VSMC proliferation and attenuate neointimal hyperplasia in response to vascular injury. Furthermore, the ERK1/2, p38 MAPK and Akt/GSK3beta signalling pathways were found to be involved in the effects of gastrodin. PMID- 22922871 TI - Exome sequencing of hepatitis B virus-associated hepatocellular carcinoma. AB - Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide and shows a propensity to metastasize and infiltrate adjacent and more distant tissues. HCC is associated with multiple risk factors, including hepatitis B virus (HBV) infection, which is especially prevalent in China. Here, we used exome sequencing to identify somatic mutations in ten HBV-positive individuals with HCC with portal vein tumor thromboses (PVTTs), intrahepatic metastases. Both C:G>A:T and T:A>A:T transversions were frequently found among the 331 non-silent mutations. Notably, ARID1A, which encodes a component of the SWI/SNF chromatin remodeling complex, was mutated in 14 of 110 (13%) HBV-associated HCC specimens. We used RNA interference to assess the roles of 91 of the confirmed mutated genes in cellular survival. The results suggest that seven of these genes, including VCAM1 and CDK14, may confer growth and infiltration capacity to HCC cells. This study provides a view of the landscape of somatic mutations that may be implicated in advanced HCC. PMID- 22922872 TI - A low-frequency variant at 8q24.21 is strongly associated with risk of oligodendroglial tumors and astrocytomas with IDH1 or IDH2 mutation. AB - Variants at 8q24.21 have been shown to be associated with glioma development. By means of tag SNP genotyping and imputation, pooled next-generation sequencing using long-range PCR and subsequent validation SNP genotyping, we identified seven low-frequency SNPs at 8q24.21 that were strongly associated with glioma risk (P=1*10(-25) to 1*10(-14)). The most strongly associated SNP, rs55705857, remained highly significant after individual adjustment for the other top six SNPs and two previously published SNPs. After stratifying by histological and tumor genetic subtype, the most significant associations of rs55705857 were with oligodendroglial tumors and gliomas with mutant IDH1 or IDH2 (odds ratio (OR)=5.1, P=1.1*10(-31) and OR=4.8, P=6.6*10(-22), respectively). Strong associations were observed for astrocytomas with mutated IDH1 or IDH2 (grades 2 4) (OR=5.16-6.66, P=4.7*10(-12) to 2.2*10(-8)) but not for astrocytomas with wild type IDH1 and IDH2 (smallest P=0.26). The conserved sequence block that includes rs55705857 is consistently modeled as a microRNA. PMID- 22922873 TI - A direct characterization of human mutation based on microsatellites. AB - Mutations are the raw material of evolution but have been difficult to study directly. We report the largest study of new mutations to date, comprising 2,058 germline changes discovered by analyzing 85,289 Icelanders at 2,477 microsatellites. The paternal-to-maternal mutation rate ratio is 3.3, and the rate in fathers doubles from age 20 to 58, whereas there is no association with age in mothers. Longer microsatellite alleles are more mutagenic and tend to decrease in length, whereas the opposite is seen for shorter alleles. We use these empirical observations to build a model that we apply to individuals for whom we have both genome sequence and microsatellite data, allowing us to estimate key parameters of evolution without calibration to the fossil record. We infer that the sequence mutation rate is 1.4-2.3*10(-8) mutations per base pair per generation (90% credible interval) and that human-chimpanzee speciation occurred 3.7-6.6 million years ago. PMID- 22922874 TI - Mutations in ABCD4 cause a new inborn error of vitamin B12 metabolism. AB - Inherited disorders of vitamin B12 (cobalamin) have provided important clues to how this vitamin, which is essential for hematological and neurological function, is transported and metabolized. We describe a new disease that results in failure to release vitamin B12 from lysosomes, which mimics the cblF defect caused by LMBRD1 mutations. Using microcell-mediated chromosome transfer and exome sequencing, we identified causal mutations in ABCD4, a gene that codes for an ABC transporter, which was previously thought to have peroxisomal localization and function. Our results show that ABCD4 colocalizes with the lysosomal proteins LAMP1 and LMBD1, the latter of which is deficient in the cblF defect. Furthermore, we show that mutations altering the putative ATPase domain of ABCD4 affect its function, suggesting that the ATPase activity of ABCD4 may be involved in intracellular processing of vitamin B12. PMID- 22922876 TI - The draft genome of a diploid cotton Gossypium raimondii. AB - We have sequenced and assembled a draft genome of G. raimondii, whose progenitor is the putative contributor of the D subgenome to the economically important fiber-producing cotton species Gossypium hirsutum and Gossypium barbadense. Over 73% of the assembled sequences were anchored on 13 G. raimondii chromosomes. The genome contains 40,976 protein-coding genes, with 92.2% of these further confirmed by transcriptome data. Evidence of the hexaploidization event shared by the eudicots as well as of a cotton-specific whole-genome duplication approximately 13-20 million years ago was observed. We identified 2,355 syntenic blocks in the G. raimondii genome, and we found that approximately 40% of the paralogous genes were present in more than 1 block, which suggests that this genome has undergone substantial chromosome rearrangement during its evolution. Cotton, and probably Theobroma cacao, are the only sequenced plant species that possess an authentic CDN1 gene family for gossypol biosynthesis, as revealed by phylogenetic analysis. PMID- 22922877 TI - Transition to adult care for youth with type 1 diabetes. AB - Emerging adults with type 1 diabetes are at risk for poor glycemic control, gaps in medical care, and adverse health outcomes. With the increasing incidence in type 1 diabetes in the pediatric population, there will be an increase in the numbers of teens and young adults transferring their care from pediatric providers to adult diabetes services in the future. In recent years, the topic of transitioning pediatric patients with type 1 diabetes to adult diabetes care has been discussed at length in the literature and there have been many observational studies. However, there are few interventional studies and, to date, no randomized clinical trials. This paper discusses the rationale for studying this important area. We review both observational and interventional literature over the past several years, with a focus on new research. In addition, important areas for future research are outlined. PMID- 22922878 TI - Response of ATPases in the osmoregulatory tissues of freshwater fish Oreochromis niloticus exposed to copper in increased salinity. AB - An increase in salinity of freshwater can affect the physiology and metal uptake in fish. In the present study, Nile tilapia Oreochromis niloticus were exposed to copper (1.0 mg/l) in increased salinities (2, 4, and 8 ppt) for 0, 1, 3, 7, and 14 days. Following the exposures, the activities of Na(+)/K(+)-ATPase, Mg(2+) ATPase, and Ca(2+)-ATPase were measured in the gill, kidney, and intestine to evaluate the changes in osmoregulation of fish. Results showed that increases in salinity and Cu exposure of fish significantly altered the ATPase activities depending on the tissue type, salinity increase, and exposure durations. Salinity alone exposures increased Na(+)/K(+)-ATPase activity and decreased Ca(2+)-ATPase activity. Na(+)/K(+)-ATPase activity decreased following Cu exposure in 2 and 4 ppt salinities, though the activity increased in 8 ppt salinity. Ca(2+)-ATPase activity decreased in the gill and intestine in all salinities, while the activity mostly increased in the kidney. However, there were great variations in Mg(2+)-ATPase activity following exposure to salinity alone and salinity+Cu combination. Cu accumulated in the gill and intestine following 14 days exposure and accumulation was negatively correlated with salinity increase. Data indicated that ATPases were highly sensitive to increases in salinity and Cu and might be a useful biomarker in ecotoxicological studies. However, data from salinity increased freshwaters should carefully be handled to see a clear picture on the effects of metals, as salinity affects both metal speciation and fish osmoregulation. PMID- 22922875 TI - Genome-wide association analyses identify three new susceptibility loci for primary angle closure glaucoma. AB - Primary angle closure glaucoma (PACG) is a major cause of blindness worldwide. We conducted a genome-wide association study including 1,854 PACG cases and 9,608 controls across 5 sample collections in Asia. Replication experiments were conducted in 1,917 PACG cases and 8,943 controls collected from a further 6 sample collections. We report significant associations at three new loci: rs11024102 in PLEKHA7 (per-allele odds ratio (OR)=1.22; P=5.33*10(-12)), rs3753841 in COL11A1 (per-allele OR=1.20; P=9.22*10(-10)) and rs1015213 located between PCMTD1 and ST18 on chromosome 8q (per-allele OR=1.50; P=3.29*10(-9)). Our findings, accumulated across these independent worldwide collections, suggest possible mechanisms explaining the pathogenesis of PACG. PMID- 22922879 TI - The novel Solanum tuberosum calcium dependent protein kinase, StCDPK3, is expressed in actively growing organs. AB - Calcium-dependent protein kinases (CDPKs) are key components of calcium regulated signaling cascades in plants. In this work, isoform StCDPK3 from Solanum tuberosum was studied and fully described. StCDPK3 encodes a 63 kDa protein with an N-terminal variable domain (NTV), rich in prolines and glutamines, which presents myristoylation and palmitoylation consensus sites and a PEST sequence indicative of rapid protein degradation. StCDPK3 gene (circa 11 kb) is localized in chromosome 3, shares the eight exons and seven introns structure with other isoforms from subgroup IIa and contains an additional intron in the 5'UTR region. StCDPK3 expression is ubiquitous being transcripts more abundant in early elongating stolons (ES), leaves and roots, however isoform specific antibodies only detected the protein in leaf particulate extracts. The recombinant 6xHis StCDPK3 is an active kinase that differs in its kinetic parameters and calcium requirements from StCDPK1 and 2 isoforms. In vitro, StCDPK3 undergoes autophosphorylation regardless of the addition of calcium. The StCDPK3 promoter region (circa 1,800 bp) was subcloned by genome walking and fused to GUS. Light and ABRE responsive elements were identified in the promoter region as well as elements associated to expression in roots. StCDPK3 expression was enhanced by ABA while GA decreased it. Potato transgenic lines harboring StCDPK3 promoter?GUS construct were generated by Agrobacterium tumefaciens mediated plant transformation. Promoter activity was detected in leaves, root tips and branching points, early ES, tuber eyes and developing sprouts indicating that StCDPK3 is expressed in actively growing organs. PMID- 22922880 TI - Thaxtomin A-deficient endophytic Streptomyces sp. enhances plant disease resistance to pathogenic Streptomyces scabies. AB - Each plant species in nature harbors endophytes, a community of microbes living within host plants without causing any disease symptom. However, the exploitation of endophyte-based phytoprotectants is hampered by the paucity of mechanistic understandings of endophyte-plant interaction. We here reported two endophytic Streptomyces isolates IFB-A02 and IFB-A03 recovered from a stress-tolerant dicotyledonous plant Artemisia annua L. After the determination of their non pathogenicity at the genomic level and from the toxin (thaxtomin A, TXT) level, the endophytism of both isolates was supported by their successful colonization in planta. Of the two endophytes, IFB-A03 was further studied for the mechanism of endophyte-conferred phytoprotection owing to its plant growth promotion in model eudicot Arabidopsis thaliana. Using the endophyte-Arabidopsis co cultivation system into which pathogenic Streptomyces scabies was introduced, we demonstrated that IFB-A03 pre-inoculation could activate the salicylic acid (SA) mediated plant defense responses upon pathogen challenge. Moreover, IFB-A03 was shown to partially rescue the defense deficiency in eds5 (enhanced disease susceptibility 5) Arabidopsis mutants, putatively acting at the upstream of SA accumulation in the defense signaling pathway associated with the systemic acquired resistance (SAR). These data suggest that endophytic Streptomyces sp. IFB-A03 could be a promising candidate for biocontrol agents against S. scabies- a causative pathogen of common scab diseases prevailing in agronomic systems. PMID- 22922881 TI - Nutritional yield: a proposed index for fresh food improvement illustrated with leafy vegetable data. AB - Consumer interest in food products, including fresh vegetables, with health promoting properties is rising. In fresh vegetables, these properties include vitamins, minerals, dietary fiber, and secondary compounds, which collectively impart a large portion of the dietary, nutritional or health value associated with vegetable intake. Many, including farmers, aim to increase the health promoting properties of fresh vegetables on the whole but they face at least three obstacles. First, describing crop composition in terms of its nutrition based impact on human health is complex and there are few, if any, accepted processes and associated metrics for assessing and managing vegetable composition on-farm, at the origin of supply. Second, data suggest that primary and secondary metabolism can be 'in conflict' when establishing the abundance versus composition of a crop. Third, fresh vegetable farmers are rarely compensated for the phytochemical composition of their product. The development and implementation of a fresh vegetable 'nutritional yield' index could be instrumental in overcoming these obstacles. Nutritional yield is a function of crop biomass and tissue levels of health-related metabolites, including bioavailable antioxidant potential. Data from a multi-factor study of leaf lettuce primary and secondary metabolism and the literature suggest that antioxidant yield is sensitive to genetic and environmental production factors, and that changes in crop production and valuation will be required for fresh vegetable production systems to become more focused and purposeful instruments of public health. PMID- 22922882 TI - Conservative treatment for isolated superior mesenteric artery dissection. AB - PURPOSE: The treatment guidelines for isolated superior mesenteric artery (SMA) dissection have not been established. We assessed 14 cases of SMA dissection and reviewed the literature on this entity. METHODS: The subjects were 11 men and 3 women (average age 64 years), with SMA dissection diagnosed by computed tomography (CT) scan or digital subtraction angiography, between 2001 and 2009, at our institution. Eight patients presented with symptoms such as abdominal pain, but SMA dissection was diagnosed incidentally during investigations of another illness in six patients. Thirteen patients were treated conservatively with anticoagulation and/or antiplatelet drugs, but one underwent exploratory laparotomy. The median follow-up period was 22 months. RESULT: The symptoms did not worsen, and ultimately resolved in the eight patients who had symptoms. Isolated dissection improved dramatically in two of the six patients with obstruction of the false lumen and was not seen on computed tomography (CT) scans 1 and 3 months after its onset. CONCLUSION: We recommend conservative treatment as the first choice for isolated SMA dissection, even if the patient has abdominal pain and tenderness, given that there are no signs of peritonitis. PMID- 22922883 TI - Association of autotaxin and lysophosphatidic acid receptor 3 with aggressiveness of human breast carcinoma. AB - In vitro and in vivo experimental studies have demonstrated the role of lysophosphatidic acid (LPA) signaling in tumor proliferation, invasiveness, and metastasis. Among LPA receptors, the overexpression of LPA receptor 3 (LPAR3) in transgenic mice has resulted in the highest rate of breast cancer metastasis. Our goal is to evaluate the LPA-producing enzyme autotaxin and LPAR3 as potential therapeutic targets in breast cancer patients. The expression of autotaxin and LPAR3 was examined by immunohistochemical analysis of 87 invasive human breast carcinomas. Carcinomas were more frequently positive for autotaxin and LPAR3 (24.4 and 43 %, respectively) compared to adjacent normal breast tissue (6.1 and 2.9 %, respectively). Increased stromal autotaxin expression was found in 16.3 % of the tumors. LPAR3 overexpression was associated with less differentiated tumors, human epidermal growth factor receptor 2 expression, and absence of progesterone receptors. The luminal type A carcinomas showed the lowest frequency of autotaxin and LPAR3 expression. Strong desmoplastic stromal reaction was more frequent among the carcinomas with autotaxin-positive tumor cells or autotaxin positive stroma. Patients with carcinomas overexpressing LPAR3 in epithelial cells or autotaxin in stromal cells were more likely to have larger tumors, nodal involvement, and higher stage disease. Autotaxin overexpression in tumor cells also correlated with tumor size and clinical stage. Our data indicate that the increased expression of LPAR3 and autotaxin in human breast cancer is associated with tumor aggressiveness. They also suggest that LPA mediates tumor metastatic ability and peritumoral desmoplastic reaction through autocrine-paracrine mechanisms. A substantial portion of breast cancer patients might benefit from autotoxin/LPA receptor-targeted therapies. PMID- 22922884 TI - PRKAR1A overexpression is associated with increased ECPKA autoantibody in liver fluke-associated cholangiocarcinoma: application for assessment of the risk group. AB - Cholangiocarcinoma (CCA) associated with Opisthorchis viverrini (Ov) chronic infection is the most frequent primary liver cancer in Thailand, and current approaches to early diagnosis and curative treatments are largely disappointing. We hypothesize a role for protein kinase A (PKA) in Ov-induced CCA. First, we studied the PKA isozyme switching in the liver from the hamster CCA model using quantitative (q) PCR, in situ hybridization, and immunohistochemical and western blot analysis. Second, the presence of extracellular PKA (ECPKA) in CCA cell lines and their conditioned media was demonstrated by western blot and PKA activity assay. Third, we determined the association between PRKAR1A expression and serum ECPKA autoantibody in patients with CCA by ELISA. We demonstrated that an increased PRKAR1A expression is restricted to the biliary cells starting from week 1, with remarkable up-regulation when CCA has completely developed by week 24. The switching of the PKA regulatory subunit isoforms from PRKAR2B/PKAII to PRKAR1A/PKAI is significantly associated with cholangiocyte proliferation. Further, we observed that human CCA cell lines express PRKAR1A but not PRKAR2B and excrete ECPKA. Finally, ECPKA autoantibodies are detected in serum of patients with CCA, adenocarcinoma, and Ov infection with periductal fibrosis, but not from Ov-infected subjects without periductal fibrosis lesion and healthy controls. We conclude that PKA isozyme switching and the PRKAR1A/PKAI pathway might contribute to the induction of cholangiocyte transformation and proliferation in Ov-induced CCA. Overexpression of PRKAR1A leads to secretion of ECPKA which is associated with serum autoantibody that may constitute a biomarker for human CCA genesis. PMID- 22922886 TI - Delayed surgery for rectal cancer patients receiving neoadjuvant chemoradiotherapy: a promising method in its infancy. AB - BACKGROUND: Neoadjuvant chemoradiotherapy (nCRT) is used to downstage locally advanced rectal cancer before surgery. Accumulating data suggest that tumor response to nCRT is time dependent. A delay between nCRT and surgery may increase the proportion of patients that achieve a favorable response. However, delayed surgery beyond 6-8 weeks may increase the technical difficulty, and the risks of surgical complications and recurrence or metastasis. This article briefly reviews the relevant literature to evaluate the efficiency and safety of delayed surgery. METHODS: Two non-cohort studies and 10 cohort studies were reviewed. The results were analyzed and the limitations discussed. RESULTS: Although debatable, the findings of the included studies are promising. Delayed surgery may increase the proportion of favorable tumor response without compromising prognosis. However, most of the studies were retrospective, which introduces bias into the evaluation. CONCLUSION: Delayed surgery is potentially useful, but this needs to be verified by further well-designed prospective trials. PMID- 22922885 TI - Therapeutic antitumor efficacy of anti-epidermal growth factor receptor antibody, cetuximab, against malignant pleural mesothelioma. AB - Epidermal growth factor receptor (EGFR) is commonly overexpressed in malignant pleural mesothelioma (MPM). Cetuximab is a chimeric mouse-human antibody targeted against EGFR and induces potent antibody-dependent cellular cytotoxicity (ADCC). The action of cetuximab against MPM cells has not been well studied. Therefore, in this study, we investigated the antitumor activity of cetuximab against MPM cell lines, particularly with respect to ADCC activity in vitro and in vivo. EGFR expression of MPM cells was measured by a quantitative flow cytometric analysis and immunohistochemistry. The effect of cetuximab on growth inhibition was assessed using a modified MTT assay. The ADCC activity was measured by a 4-h 51Cr release assay using fresh or IL-2-activated peripheral blood mononuclear cells. In vivo antitumor activity of cetuximab was evaluated using an orthotopic implantation mouse model. Cetuximab-mediated ADCC activity against MPM cells was observed at low concentration (0.25 mg/ml) and was enhanced by IL-2, whereas no direct effect on growth inhibition was detected. A logarithmic correlation was observed between the number of EGFRs on MPM cells and ADCC activity. Low EGFR expression on the MPM cells, which was weakly detectable by immunohistochemistry, was sufficient for maximum ADCC activity. In the mouse model, cetuximab treatment with or without IL-2 significantly inhibited intrathoracic tumor growth and prolonged their survival. Our study shows that cetuximab has potent anti-MPM activity both in vitro and in vivo, mainly through the immunologic mechanism of ADCC. Cetuximab has the potential to be used as a novel therapy for MPM patients. PMID- 22922887 TI - Prognostic significance of neuronal marker expression in glioblastomas. AB - PURPOSE: Glioblastomas are the most malignant tumors of central nervous system neoplasms and are well known for their biological heterogeneity. Contrary to the putative hypothesis of purely glial differentiation in glioblastomas, they often demonstrate immunopositivity for neuronal markers. However, the significance of their neuronal marker expression is still controversial. To evaluate the prognostic implication of neuronal expression in glioblastoma, this study investigated the expression of neuronal markers in a large series of glioblastoma patients in terms of patient survival rate. METHODS: Expression of synaptophysin, neurofilament protein, and NeuN was explored using immunohistochemistry in 88 cases of glioblastoma. Clinicopathological variables as well as patients' survival data were compared according to the immunopositivity of cases. RESULTS: Sixty-one of the 88 tumors (69.3 %) were positive for at least one neuronal marker. Synaptophysin positivity was observed in 43 cases (48.9 %). Neurofilament protein and NeuN were positive in 38 (43.2 %) and 42 cases (47.7 %), respectively. There was no statistically significant difference in overall survival and progression-free survival in association with neuronal marker expression. However, gross total removal or combined radiotherapy and chemotherapy significantly prolonged survival (P=0.041 and 0.044). Cox's proportional hazard model revealed that NeuN expression was the independent prognostic factors in progression-free survival (P=0.012). CONCLUSIONS: Although the correlation of neuronal marker expression and clinical outcome in glioblastoma is of considerable interest, the presented data support the limited prognostic value of neuronal marker expression in glioblastoma. PMID- 22922888 TI - The role of the EQ-5D in the economic evaluation of dermatological conditions and therapies. AB - Economic evaluation is an increasingly important aspect of assessment of the burden of skin diseases. Although dermatology data were not used in its development, the use of the EQ-5D questionnaire has been encouraged by the requirement of health technology assessment agencies for utility comparisons informing reimbursement decisions. The aim of this review was to examine the use of the EQ-5D in dermatology and to consider its future role in the economic evaluation of skin diseases. Published studies reporting the use of the EQ-5D in the economic analysis of skin diseases were carefully examined. Nineteen articles and 1 abstract published between 2003 and 2011 were identified, in which cost-of illness, cost-effectiveness and cost-utility analyses were described. The EQ-5D is not a dermatology-specific measure, and it is not yet clear whether it is the most appropriate measure to support economic evaluation in the context of dermatology. PMID- 22922889 TI - The role of Glycyrrhizin, an inhibitor of HMGB1 protein, in anticancer therapy. AB - Certain anticancer drugs, such as the peptide CAMEL (aa sequence KWKLFKKIGAULKVL) induce necrotic type of cell death. During this process, a protein termed high mobility group box 1 (HMGB1) is released from cell nucleus into cytoplasm and then into extracellular milieu. Outside of cells, it becomes a proinflammatory cytokine. Its effects range from stimulation of cancer as well as endothelial cell proliferation, to activation of angiogenesis, cell motility and induction of inflammatory conditions. Release of HMGB1 cytokine during the course of anticancer therapy has negative effects upon the therapy itself, since it leads to tumor relapse. We assumed that the inhibition of HMGB1 activity may be conducive towards better therapeutic results in case of drugs inducing necrotic cell death. In this context we studied glycyrrhizin (GR), a triterpenoid saponin glycoside of glycyrrhizic acid and a well-known inhibitor of HMGB1. We have shown that GR inhibits proliferation and migration of cells stimulated by HMGB1 cytokine, as well as HMGB1-induced formation of blood vessels and reduces inflammatory condition (lowering tumor necrosis factor alpha levels). GR-mediated inhibition of HMGB1 activity (CAMEL-induced release) impedes, in turn, tumor regrowth in mice. As expected, inhibited tumor regrowth is linked to diminished tumor levels of the released HMGB1 and reduced inflammatory condition. To conclude, the use of GR significantly improved anticancer effectiveness of the CAMEL peptide. PMID- 22922890 TI - A comparative study of breast-specific gamma imaging with the conventional imaging modality in breast cancer patients with dense breasts. AB - OBJECTIVE: The aim of this study was to evaluate the value of breast-specific gamma imaging (BSGI) as compared with mammography (MMG) and ultrasonography (US). METHODS: This study retrospectively enrolled 121 women with breast cancer (45.0 +/- 8.1 years) and dense breasts (breast density >50 %). All patients underwent preoperative BSGI, MMG, and US, and the results were correlated with the biopsy results. RESULTS: In the 121 patients, 153 breast lesions were malignant tumors and 75 lesions were diagnosed as benign tumors. The sensitivity and specificity of BSGI were 92.2 and 89.3 %, while the values of MMG and US were 53.6 and 94.7 and 91.5 and 53.3 %, respectively (p < 0.0001 and p < 0.0004). In breast lesions <=1 cm, the sensitivity and specificity of BSGI were 80.6 and 91.5 %, which were different from MMG and US, respectively (p < 0.0001 and p < 0.0003). Of 28 patients with 59 multiplicities, BSGI and US found 49 lesions and 51 lesions correctly. However, MMG detected only 26 lesions as malignancies. CONCLUSION: Given the results of this study, women with dense breasts are not evaluated with MMG at all and went straight to US or MRI in order to minimize radiation exposure. Due to the high false-positive rate of these modalities, BSGI could then be utilized if the US or MRI are positive. PMID- 22922891 TI - Scheuermann kyphosis in nonhuman primates. AB - STUDY DESIGN: A cadaveric survey of the thoracic spines of extant species of nonbipedal primates for the presence of Scheuermann kyphosis. OBJECTIVE: To determine the presence and prevalence of Scheuermann kyphosis in quadrupedal species of the closest living relatives to humans to demonstrate that bipedalism is not an absolute requirement for the development of Scheuermann kyphosis. SUMMARY OF BACKGROUND DATA: The etiology of Scheuermann kyphosis remains poorly understood. Biomechanical factors associated with upright posture are thought to play a role in the development of the disorder. To date, Scheuermann kyphosis has been described only in humans and extinct species of bipedal hominids. METHODS: Thoracic vertebrae from 92 specimens of Pan troglodytes (chimpanzee) and 105 specimens of Gorilla gorilla (gorilla) from the Hamann-Todd Osteological Collection at the Cleveland Museum of Natural History were examined for Scheuermann kyphosis on the basis of Sorenson criteria and the presence of anterior vertebral body extensions and for the presence of Schmorl nodes. RESULTS: Two specimens of P. troglodytes (2.2%) were found to have anatomic features consistent with Scheuermann kyphosis including vertebral body wedging greater than 5 degrees at 3 or more adjacent levels and the presence of anterior vertebral body extensions. One of the affected specimens (50%) demonstrated the presence of Schmorl nodes whereas 2 of the unaffected specimens (2.2%) had Schmorl nodes. None of the specimens of G. gorilla (0%) were found to have anterior vertebral body extensions characteristic of Scheuermann kyphosis or Schmorl nodes. CONCLUSION: Thoracic kyphotic deformity consistent with Scheuermann kyphosis exists in quadrupedal nonhuman primates. Bipedalism is not a strict requirement for the development of Scheuermann kyphosis, and the evolutionary origins of the disease predate the vertebral adaptations of bipedal locomotion. PMID- 22922892 TI - Analysis of cardiopulmonary bypass status in China: eight-year development trends. AB - OBJECTIVE: To study the development of cardiopulmonary bypass (CPB) in the past 8 years and to come up with predictions and recommendations for the future in China. METHODS: Domestic hospitals performing cardiovascular operations were supplied with questionnaires, annually (between 2003 and 2008), upon the number of on-pump and off-pump cardiovascular operations, oxygenators of different types and the number of extracorporeal membrane oxygenation (ECMO). All the hospitals in this study were divided into 8 grades, according to the number of cardiovascular operations. The market share of hospitals in each grade was analyzed. RESULTS: The total anumber of cardiovascular operations was 170,547 in 2010, of which 136,753 were performed under CPB. The ratio of imported membrane oxygenators increased from 43.22% in 2003 to 59.75% in 2010, while bubble oxygenator composition decreased from 43.78% in 2003 to 14.59% in 2010. Forty four hospitals carried out 206 cases of ECMO in 2010. There were 32 hospitals that performed cardiovascular operations of over 1,000 cases and their market share was 43%. There were 255 hospitals that performed cardiovascular operations in less than 50 cases and their market share was only 3%. CONCLUSIONS: CPB in China has gone through a rapid development in the past eight years. Medical resources for CPB should be concentrated and systematic training regulations should be established in the future. PMID- 22922893 TI - Inhibition of the AKT/mTOR and erbB pathways by gefitinib, perifosine and analogs of gonadotropin-releasing hormone I and II to overcome tamoxifen resistance in breast cancer cells. AB - Endocrine resistance in breast cancer remains a major clinical problem and is caused by crosstalk mechanisms of growth factor receptor cascades, such as the erbB and PI3K/AKT pathways. The possibilities a single breast cancer cell has to achieve resistance are manifold. We developed a model of 4-hydroxy-tamoxifen (OHT)-resistant human breast cancer cell lines and compared their different expression patterns, activation of growth factor receptor pathways and compared cells by genomic hybridization (CGH). We also tested a panel of selective inhibitors of the erbB and AKT/mTOR pathways to overcome OHT resistance. OHT resistant MCF-7-TR and T47D-TR cells showed increased expression of HER2 and activation of AKT. T47D-TR cells showed EGFR expression and activated MAPK (ERK 1/2), whereas in resistant MCF-7-TR cells activated AKT was due to loss of CTMP expression. CGH analyses revealed remarkable aberrations in resistant sublines, which were predominantly depletions. Gefitinib inhibited erbB signalling and restored OHT sensitivity in T47D-TR cells. The AKT inhibitor perifosine restored OHT sensitivity in MCF-7-TR cells. All cell lines showed expression of receptors for gonadotropin-releasing hormone (GnRH) I and II, and analogs of GnRH-I/II restored OHT sensitivity in both resistant cell lines by inhibition of erbB and AKT signalling. In conclusion, mechanisms to escape endocrine treatment in breast cancer share similarities in expression profiling but are based on substantially different genetic aberrations. Evaluation of activated mediators of growth factor receptor cascades is helpful to predict response to specific inhibitors. Expression of GnRH-I/II receptors provides multi-targeting treatment strategies. PMID- 22922894 TI - Association of cardiovascular risk factors in hypertensive subjects with metabolic syndrome defined by three different definitions. AB - INTRODUCTION: Different authorities have put forward their criteria to define metabolic syndrome (MetS). The aim of this study was to find the prevalence of MetS in hypertensive individuals by the available three different definitions from National Cholesterol Education Program (NCEP), International diabetes Federation (IDF) and WHO and their association with other cardiac risk factors. METHODS: After anthropometric measurements fasting blood was analyzed for glucose, lipids, high sensitivity C-reactive protein (hsCRP) and anti-oxidized LDL antibody in 150 hypertensive individuals. A ten-year coronary heart disease risk was predicted using the Framingham risk score (FRS). RESULTS: The prevalence of MetS was 54.7 % by NCEP, 42.0 % by IDF) and 18.7 % by WHO. As many as 63.4 % had MetS by any definition, while only 9.4 % fulfilled all the criteria of the three definitions. The association of cardiac risk factors also varied according to the definition used. hsCRP was significantly elevated in MetS compared to non MetS. Body mass index, waist circumference and HDL-C were associated in MetS defined by NCEP and IDF. FRS was higher in MetS defined by Adult Treatment Panel and WHO definitions. An increase in urine albumin and a decrease in eGFR were associated with MetS individuals defined by WHO only. CONCLUSION: There is a wide variation in the prevalence of MetS and associated cardiac risk factors according to three different definitions used. The different cardiac risk factors among MetS also vary with the definitions used. However, hsCRP and emerging risk factor are significantly elevated in hypertensive individuals with MetS as defined by all definitions. PMID- 22922895 TI - Diagnostic accuracy of computed tomogram in the evaluation of a neck mass. AB - OBJECTIVE: The concept of dividing extracranial head and neck into different spaces is a notion that dates back to the 1800s. Various studies have led to detailed description of the soft tissue spaces that are contained within the fascial layers. This study was carried out to determine the accuracy of computed tomogram (CT) in differentiating malignant from benign lesions in the neck, to study the spatial distribution of different types of histological groups in the neck and the prevalence of malignant versus benign diseases involving the neck. METHODS: This was a hospital-based, prospective study conducted in the department of Radiodiagnosis, Kasturba Medical college, Mangalore, from 2005-2008. A hundred consecutive patients referred for CT scan examination presenting with complaints related to involvement of neck spaces or presence of palpable neck masses were enrolled in this study. The details of all the cases regarding their radiological findings and histopathology were reviewed. RESULTS: Of the 100 patients studied, 53 % had malignant lesions, out of which 43 % were squamous cell carcinoma and 4 % were metastatic lymph nodal involvement. Twenty percent of the lesions were of an infective origin while 23 % were benign and congenital cystic lesions. CONCLUSION: CT scan as an imaging modality has the ability to evaluate the malignant and benign tumors of the neck. Considering histopathology as the gold standard, the sensitivity of CT in detecting malignant/benign lesions was 96.5 % with a specificity of 100 %. The positive predictive value was 100 % and the negative predictive value 95.2 %. PMID- 22922896 TI - Combined treatment of alendronate and low-intensity pulsed ultrasound (LIPUS) increases bone mineral density at the cancellous bone osteotomy site in aged rats: a preliminary study. AB - INTRODUCTION: During fracture healing, alendronate encourages callus volume by inhibiting bone resorption, whereas low-intensity pulsed ultrasound (LIPUS) enhances bone regeneration by promoting an anabolic response. METHODS: In the present study, 9-month-old Sprague-Dawley rats, with a unilateral proximal tibial osteotomy, were treated with alendronate (daily, 1 ug/kg) plus sham-LIPUS (n = 14), saline plus LIPUS (20 min/day) (n = 18), alendronate plus LIPUS (n = 16), or saline plus sham-LIPUS as a control (n = 13) for 4 weeks. The rats were then examined for changes in bone mineral density (BMD) during metaphyseal bone repair. RESULTS: The combined therapy significantly increased BMD at the osteotomy site at 4 weeks (p < 0.001) compared with the control, without affecting the contralateral, non-osteotomized tibia. Both alendronate and LIPUS alone also exerted a positive, albeit less, effect on BMD in the affected limb (p < 0.001 and p = 0.006, respectively). CONCLUSION: Alendronate and LIPUS cooperate to enhance BMD during metaphyseal bone healing. PMID- 22922897 TI - Prevalence of dental caries in 5 - 6 years and 12 - 13 years age group of school children of Kathmandu valley. AB - INTRODUCTION: Dental caries is one of the most common conditions affecting the general health of children. The present study was carried out among school children of Kathmandu valley to determine the prevalence of dental caries in two age groups. METHODS: The study was conducted from December 2007 to May 2008. The age of the school children of the study was divided into two group: 5 - 6 years and 12 - 13 years. A stratified cluster sampling with proportional allocation was used while grouping the subjects. The dental status examination was done with the help of trained dentists. Decayed, missed and filled teeth index and decayed, missed and filled surfaces index (dmft for primary dentition and DMFT for permanent dentition) were used as the standard tools for the determination of prevalence. RESULTS: A total of 638 students (325 of age group 12 - 13 years and 313 of age group 5 - 6 years) from 30 different schools of the Kathmandu valley were included in the study. The caries status was found higher in the age group of 5 - 6 years than in the 12 - 13 years and it was found to be statistically significant (p < 0.001). The dmfs and caries percentage of the age group 5 - 6 years and the DMFS and caries percent of the 12 - 13 years was found to be 3.79, 69 % and 1.6, 53.23 % respectively. The dmft/dmfs value was found to be significant according to the districts in the 5 - 6 years age group whereas the DMFS was found statistically significant among the sexes of the 12 - 13 years age group. CONCLUSION: The caries percentage was found to be above the recommended level of the World Health Organization. However, the DMFS and DMFT values were within the WHO level. PMID- 22922898 TI - Ocular morbidity among children attending government and private schools of Kathmandu valley. AB - INTRODUCTION: Children from the developing world are more prone to going blind from avoidable and preventable causes. In Nepal, children in private schools are reported to have a higher ocular morbidity than those in government schools, with myopia being the major cause of the morbidity. This study was designed to evaluate ocular morbidity in students from both types of school. METHOD: This was a cross-sectional, comparative study among students from government and private schools of Kathmandu. Eye examination was carried out evaluating visual acuity, color vision, refractive status, binocular vision status, and anterior and posterior segment findings. RESULTS: A total of 4,228 students from government and private schools were evaluated. The prevalence of ocular morbidity was 19.56 % with refractive error (11.9 %) being the major cause of the morbidity, followed by strabismus and infective disorders. No significant difference in the prevalence of ocular morbidity and refractive status was found in the students from government and private schools. CONCLUSION: A significant number of children of school-going age have ocular morbidity with no significant difference in the prevalence in the students from government and private schools. Research exploring the effect of various risk factors in the progression of myopia would be helpful to investigate the refractive status in children from these different types of schools. PMID- 22922899 TI - Early development of reflux esophagitis after successful Helicobacter pylori eradication in superficial gastritis. AB - The relationship between gastroesophageal reflux disease (GERD) and Helicobacter pylori (H. pylori) eradication is still debated. Recently, we had a patient of GERD who had developed it shortly after H. pylori eradication therapy. A 72-year old man was diagnosed by endoscopy as suffering from severe superficial gastritis in the stomach body. A rapid urease test showed H. pylori infection. He was then started on proton pump inhibitor (PPI) based therapy for two weeks eradicating H.pylori. After completion of H. pylori eradication, he complained of a heart burn sensation. Follow-up endoscopy showed reflux esophagitis, of grade B according to the Los Angeles classification. Since the patient had developed GERD after completion of the triple therapy, their suggests that H. pylori eradication must have triggered the development of de novo GERD after a short period of time. PMID- 22922900 TI - Intraventricular Taenia solium neurocysticercosis: a report of three cases. AB - Neurocysticercosis (NCC), caused by the pork tapeworm Taenia solium, is reported to be a common condition in Nepal. So far imaging diagnosis was mainstay of the diagnosis. In this paper, we report three patients presenting with neurological symptoms due to intraventricular NCC. We have diagnosed the causative agent as T. solium on molecular basis. Further research is warranted to assess the actual health impact of T. solium in Nepal. PMID- 22922901 TI - Late complication due to placenta increta left in situ and management options. AB - With the rising incidence of caesarean sections, the number of cases of placenta praevia and morbidly adherent placenta is increasing. Antenatal diagnosis and management in a tertiary care centre helps to reduce maternal and neonatal morbidity and mortality. We present a patient in whom the antenatal diagnosis of morbidly adherent placenta was missed due to late booking. In spite of the conservative approach at the time of caesarean section in the secondary care hospital, the patient presented with delayed complications and a total hysterectomy was performed. PMID- 22922902 TI - Non-communicating rudimentary uterine horn pregnancy. AB - Pregnancy in a non-communicating rudimentary horn is an extremely rare form of ectopic gestation. The rudimentary horn may or may not communicate with the uterine cavity with the majority of cases being non-communicating. The patient exhibits features of acute abdomen and carries a high risk of maternal death. Even modern scans remain elusive whereas laparatomy remains the confirmatory procedure for the diagnosis. Because of the varied muscular constitution in the thickness and distensibility of the wall of the rudimentary horn, pregnancy is accommodated for a variable period of gestation. Here, we report three cases of pregnancy in a non-communicating rudimentary horn of the uterus in different periods of gestation, their outcome and a review of the available literature. PMID- 22922903 TI - Dengue: an emerging disease in Nepal. AB - Dengue is an acute infectious disease caused by dengue viruses and transmitted by the Aedes species of mosquito. The rapid global spread of the dengue virus into new areas has begun to attract more research attention. A series of dengue fever outbreaks in several districts of Nepal has been recently observed. The evidence of all four serotypes (DEN - 1 - 4) could be a consequence of a sudden resurgence of a more severe dengue disease in Nepal. Health care providers need to become familiar with the disease to prevent or control the possibility of future outbreaks. The clinical features, diagnosis, treatment, epidemiological patterns and challenges of dengue virus infection in Nepal will be discussed here. PMID- 22922904 TI - Natural orifice transluminal endoscopic surgery (NOTES): an emerging technique in surgery. AB - Natural orifice transluminal endoscopic surgery (NOTES), which utilises natural anatomical passages for gaining access to the intra-abdominal organs for surgical interventions, that result in scarless surgery, is a recent advancement in the specialty of minimally invasive surgery and has gained significant momentum, It has been postulated as a promising alternative to laparoscopic surgery in the field of minimal invasive surgery. Significant advantages over conventional open surgery, such as less postoperative pain, a shorter hospital stay, early return to activity, avoidance of wound-related complications and better cosmesis have been demonstrated. This article provides an update in the development, principles, practice and future applications of NOTES. PMID- 22922905 TI - Reaching the unreached: a model for sustainable community development through information and communication technology. AB - Telemedicine, which is defined as 'the practice of healthcare using interactive audio, visual and data communications and includes healthcare delivery, diagnosis, consultation and treatment as well as education and transfer of medical data', has been gaining popularity in the health services sector. Dermatology as a specialty is particularly suitable for telemedicine and more so in geographic regions with scarcity of qualified manpower, where it has greatly facilitated the outreach of specialist care delivery. However, the cost of telemedicine technology is a significant hurdle which makes the sustainability of such services challenging. Maximum utilization of such technology by active participation of well motivated beneficiary communities and bringing innovative strategies for its use will be crucial in sustaining such services in rural communities. PMID- 22922906 TI - Violence in health sectors of Nepal. PMID- 22922907 TI - A comparative study of the shell matrix protein aspein in pterioid bivalves. AB - Aspein is one of the unusually acidic shell matrix proteins originally identified from the pearl oyster Pinctada fucata. Aspein is thought to play important roles in the shell formation, especially in calcite precipitation in the prismatic layer. In this study, we identified Aspein homologs from three closely related pterioid species: Pinctada maxima, Isognomon perna, and Pteria penguin. Our immunoassays showed that they are present in the calcitic prismatic layer but not in the aragonitic nacreous layer of the shells. Sequence comparison showed that the Ser-Glu-Pro and the Asp-Ala repeat motifs are conserved among these Aspein homologs, indicating that they are functionally important. All Aspein homologs examined share the Asp-rich D-domain, suggesting that this domain might have a very important function in calcium carbonate formation. However, sequence analyses showed a significantly high level of variation in the arrangement of Asp in the D-domain even among very closely related species. This observation suggests that specific arrangements of Asp are not required for the functions of the D-domain. PMID- 22922909 TI - Atypical transformation in sacral drop metastasis from posterior fossa choroid plexus papilloma. AB - Choroid plexus papillomas (CPP) are rare tumours and spinal metastases of CPP are even less common. We report a 50-year-old woman with spinal drop metastases at Th9 and S1-2 6 years after total resection of a posterior fossa CPP. The metastasis at S1-2 was resected and histological examination showed transformation to an atypical CPP. Atypical transformation in a metastasis years after resection of a benign posterior fossa CPP has been described once. We would like to advocate craniospinal MRI at the time of initial diagnosis as well as periodic follow-up after total and subtotal resection of a posterior fossa CPP in adults at least once in 1 or 2 years, depending on the histological grading of the primary CPP. In our case report, this could have resulted in earlier diagnosis of the locoregional recurrence or of the spinal drop metastasis. PMID- 22922908 TI - Large scale of human duplicate genes divergence. AB - Proteome complexity increases in the evolution mostly by means of gene duplication followed by divergence. In this genome-scale study of human genome I show that density distribution of duplicate gene pairs along the axis of protein divergence between pair members forms two main peaks with a small peak and plateau before the first main peak. This picture indicates the existence of three evolutionary stages of duplicate gene evolution. The analysis of various functional parameters (gene expression level and breadth, transcription factor targets, protein interaction networks) suggests that subfunctionalization (partition of function) is a predominant mode of divergence in the first main peak, whereas neofunctionalization (acquiring of novel functions) prevails in the second main peak. The young duplicate pairs show a much higher expression level compared with singleton genes and more diverged duplicates, which indicates that requirement for high gene dosage is important for retention of duplicates just after the duplication event. Thus, a prevailing route of duplicate evolution seems to be the high gene dosage-subfunctionalization-neofunctionalization. This adaptationist model suggests that an organism is evolving in the direction of its most intensively used functions. PMID- 22922910 TI - Congenital skull indentation: a case report and review of the literature. AB - Congenital depressions of the skull are rare in Western countries. The majority relate to obstetric trauma at delivery. We present a case of a congenital depression of a neonate's skull not relating to obstetric trauma. The child had an ovoid indentation behind the right coronal suture in the temperoparietal region. This skull depression was thought to relate to the position of her right hand in utero. We report her management, neuro-imaging and outcome on follow-up. A literature review is given in brief. PMID- 22922911 TI - An unusual case of POEMS syndrome. AB - We report a 48-year-old man, a farmer, presenting with chronic sensori-motor polyneuropathy. Electrophysiology revealed demyelinating type of neuropathy. Immunoelectrophoresis for monoclonal protein was negative; however, plasmacytoma was discovered on spine imaging. After receiving radiotherapy and chemotherapy over past 9 months there has been a considerable improvement in patient's disability. This case highlights the role of skeletal survey in evaluation of chronic demyelinating neuropathy. PMID- 22922912 TI - Skeletal metastases from renal cell carcinoma: diagnostic uncertainty with molecular imaging. PMID- 22922913 TI - Evaluation of electrical aversion therapy for inappropriate sexual behaviour after traumatic brain injury: a single case experimental design study. AB - Inappropriate sexual behaviour after acquired brain injury is a severe complication. Evidence for effective treatment is not available. Electrical aversion therapy (EAT) is a behavioural therapeutic option used in persons with intellectual disabilities, which might be suitable for brain-injured individuals for whom other therapies are not effective. The effect of EAT in brain injury has not been investigated previously. A single case experimental design was used. In an ABBA (baseline-treatment-treatment-withdrawal) design the frequency of the target behaviour (ie, inappropriate sexual behaviour) in a 40-year-old man was measured daily. A total of 551 measurements were recorded. A significant reduction of the target behaviour was seen after the first treatment phase (baseline 12.18 (2.59) vs 3.15 (3.19) mean target behaviours daily); this reduction remained stable over time. We conclude that EAT was effective in this patient with inappropriate sexual behaviour due to severe brain injury. EAT can therefore be considered in therapy resistant inappropriate sexual behaviour in brain-injured patients. PMID- 22922914 TI - Life-threatening complications following multidose methotrexate for medical management of ectopic pregnancy. AB - A 25-year-old primigravida was diagnosed to be suffering from unruptured ectopic pregnancy. The serum beta-human chorionic gonadotropin levels were 2851 mIU/l and the ectopic gestational sac was 2.7*2.7 cm without any fetal pole. It was decided to manage her by expectant therapy. But she received medical therapy with multidose methotrexate because of misinterpretation of expectant therapy as medical therapy. She suffered from methotrexate toxicity, which manifested as high-grade fever, vomiting, melena, oral ulcerations, pneumonitis, subconjunctival haemorrhages and skin pigmentation. She developed severe third space fluid collection and shock, which was mistaken for rupture ectopic gestation. Her haematological picture showed severe neutropaenia and thrombocytopaenia which confirmed the clinical picture to be due to methotrexate toxicity. She also developed septicaemia and candidal infection secondary to immunosuppression. She was managed in intensive care unit with ventilatory support, high-dose leucovorin and injection filgastrim. She responded well to the therapy with dramatic recovery in 4 days. PMID- 22922915 TI - Perforation of the right ventricle during cardiac resynchronisation therapy upgrade not related to a coexisting persistent left superior vena cava. AB - Right ventricle (RV) perforation is a complication that may arise during device implants. We present the case of a patient undergoing cardiac resynchronisation therapy upgrade that was complicated with an RV perforation. The lead was successfully repositioned with a good final outcome. Despite being uncommon, persistence of the left superior vena cava is the most frequent venous cardiac anomaly and may pose challenges during the implant procedure, namely when the right superior vena cava (RSVC) is absent. Still, in this patient it was not related to the event, as the leads were advanced through the RSVC. PMID- 22922916 TI - Somatoform abdominal pain in surgery: is SD worthy of surgical attention? Case reports and literature review. AB - Somatoform disorders (SD) or medically unexplained physical symptoms (MUPS) are a group of disorders that represent a group of symptoms that cannot be explained by an organic or physical pathology. These disorders are widely prevalent, and, if unrecognised, SD may lead medical professionals to embark on tests or procedures which may inflict unnecessary iatrogenic complications. Despite the high prevalence, they are only poorly included in medical training curricula, at both undergraduate and postgraduate levels. In this article, we review the literature and present two cases. The first one presented with a recurrent acute abdomen had an unnecessary CT abdomen. The second case had laparoscopy for acute right-sided abdominal pain which turned out to be normal, and was readmitted again after a short period with acute urine retention which resolved spontaneously following discussion with the patient and family. Both cases were referred for psychiatric assessment and their family doctors were informed. PMID- 22922917 TI - Initial expression of the Papillon-Lefevre syndrome in consanguine family. AB - A rare case of Papillon-Lefevre syndrome is discussed with clinicoradiological presentation. The purpose of the case report is to make the medical community aware of this rare syndrome and its association with consanguinity. Papillon Lefevre syndrome is an extremely rare genodermatosis of autosomal-recessive inheritance which usually manifests itself between the ages of 6 months to 4 years characterised by diffuse palmoplanter hyperkeratosis (keratoderma), and rapidly progressive and devastating periodontitis, affecting the primary as well as permanent dentition. Papillon-Lefevre syndrome results from a combination of host and bacterial factors, including recessive gene, consanguinity, specific periodontal pathogens and lack of thorough oral hygiene. The present case report describes Papillon-Lefevre syndrome and its association with consanguinity in a 3 year-old girl. PMID- 22922918 TI - Fetal Ebstein's anomaly. PMID- 22922919 TI - Infected complex odontoma: an unusual presentation. AB - Odontomas represent a hamartomatous malformation. They are usually asymptomatic and are diagnosed on routine radiological examination .The eruption and infection of odontoma are uncommon. Till now, only 20 cases of erupted odontoma are reported in the literature. We report an unusual case of infected complex odontoma with eruption of odontoma in the oral cavity and perforation of the cheeks with a tooth impacted upon which makes the presentation unusual that has not been reported earlier. The dentist should be familiar with common and unusual appearance of odontoma for proper diagnosis and management. PMID- 22922920 TI - Kawasaki disease: always straight to the heart? AB - Kawasaki disease is an important differential diagnosis when evaluating prolonged fever in childhood. Although the aetiology of this vasculitic disease process remains obscure, prompt recognition and treatment significantly reduces vascular complications such as coronary artery aneurysms. Patients presenting with atypical or incomplete diagnostic features remain a challenge. Here the authors describe the atypical features of Kawasaki disease that led to profound acute hearing loss in a 6-year-old boy with complex congenital heart disease. Coronary changes were not seen on early follow-up, but the patient required bilateral hearing aids. Considering Kawasaki disease early, even in the possibly confusing context of complex congenital heart disease and atypical symptomatology, is crucial to avoid long-term sequelae. PMID- 22922921 TI - Bowel injury after a routine change of suprapubic catheter. PMID- 22922922 TI - Hypothyroid myopathy mimicking postpolio syndrome. AB - Hypothyroidism can have diverse neurological manifestations. Myopathy may rarely be the sole manifestation of autoimmune thyroiditis. We hereby report an atypical manifestation of severe hypothyroidism in a middle-aged woman with childhood onset of paralytic polio involving her right leg presenting with a recent onset of increased weakness in the right leg mimicking postpolio syndrome. PMID- 22922923 TI - An abdominal mass in a 4-year-old child. AB - The author describes a 4-year-old boy who presented to the accident and emergency department after a mass in his abdominal wall had been rapidly enlarging for at least a week. There was a delay in management due to difficulty reaching the diagnosis. Once obtained, a CT scan revealed the true diagnosis; an infected intramuscular haematoma arising from the right abdominal oblique muscles. This was large enough to displace the right lobe of the liver medially. The patient was treated with surgical drainage and intravenous antibiotics. PMID- 22922924 TI - Salicylate toxicity from ingestion of traditional massage oil. AB - A 16-month-old child developed a brief generalised tonic-clonic fitting episode and vomiting at home, after accidental ingestion of traditional massage oil. As the patient presented with clinical features of salicylate toxicity, appropriate management was instituted. He was admitted to the intensive care unit for multiorgan support. The child was discharged well 1 week after the incident. Methyl-salicylate is a common component of massage oils which are used for topical treatment of joint and muscular pains. However, these massage oils may be toxic when taken orally. Early recognition of the salicylate toxicity is very important in producing a good patient outcome. PMID- 22922925 TI - Endomyocardial fibrosis causing stroke in a young man. AB - An Indian man in his late 30s presented with ischaemic stroke and eosinophilia of 711/mm(3). ECG showed first-degree heart block with ST depression and symmetrical T-wave inversions in the chest leads. Subsequently, the patient was further evaluated by echocardiography and cardiac MRI which identified the presence of endomyocardial fibrosis in the heart. PMID- 22922926 TI - Skin lesion in axilla: an unusual presentation of invasive lobular carcinoma of breast. AB - Invasive lobular carcinoma (ILC) of breast is known to present with atypical clinical findings in the breast, making it difficult to diagnose. It is also known to have unusual sites of metastases arising de novo or in patients treated for known ILC. Skin lesion in axilla could be a cutaneous metastasis from ILC or ILC in ectopic breast tissue (EBT). We present two cases with skin lesion in axillas which after excision were surprisingly reported as ILC. On further investigations these were found to be primary in EBT. Though such cases are reported, carcinoma arising from EBT is a very rare presentation and one should be aware of this, when dealing with a skin lesion. PMID- 22922927 TI - Purple glove syndrome: a dreadful complication of intravenous phenytoin administration. AB - Purple glove syndrome is an uncommon but dreaded complication of intravenous phenytoin administration characterised by pain, oedema and purple-blue discolouration of the limb distal to the site of injection. We describe a 37-year old gentleman having the characteristic purple glove appearance after phenytoin loading, and discuss the salient features of this syndrome highlighting the pathophysiological and preventive aspects. PMID- 22922928 TI - The process of recovery of a schizoaffectively disordered mind: a psychoanalytic theory of the functional psychoses, the psychodynamic pentapointed cognitive construct theory. AB - A schizoaffectively disordered young woman made a small study of her mind while she was in psychoanalytic psychotherapy so that she might understand herself better. She worked closely with her psychoanalyst, and with the researcher who wrote up her case. She had a very difficult time for 30 years, but by the end of that time emerged completely recovered and with a great zest for life. This paper provides rare positive/constructive data about the processes involved in a case of schizoaffective disorder that involved manic as well as depressive and schizophrenic symptoms, and also the patient's stages of recovery. It demonstrates how psychiatric and psychoanalytic principles are inextricably linked together both in understanding this patient's ordeals and in her successful treatment, and suggests the clinical potential for theoretical and practical engagement between psychiatry and psychoanalysis. PMID- 22922929 TI - A fateful kiss: the use of CT coronary angiogram in the diagnosis of non-cardiac chest pathology. AB - A 34-year-old dental nurse presented with a 2-day history of retrosternal chest pain that was constant and 'burning' in nature. She was otherwise fit and well, no significant prior medical history and no ischaemic heart disease risk factors. Clinical examination was entirely normal apart from pyrexia of 38.3 degrees C. Admission ECG showed ST depression in the inferior and anterolateral leads suggestive of myocardial ischaemia, consequently a CT coronary angiogram (CTCA) was performed. This showed normal coronary arteries, incidental distal oesophageal thickening was seen. Further history taking revealed that her youngest daughter had recently suffered from cold sores. The patient went on to have a diagnostic procedure, an oesophagogastroduodenoscopy. Biopsies confirmed acute oesophagitis with features suggestive of herpes virus infection. The patient responded promptly to oral acyclovir. This case highlights the value of CT coronary angiogram in identifying non-cardiac pathology in patients with a low pretest probability of coronary artery disease. PMID- 22922930 TI - Hypoxic cardiac arrest in pregnancy due to pulmonary haemorrhage. AB - A 23-year-old woman developed massive pulmonary haemorrhage in the 19th week of pregnancy. Essential invasive ventilation was seriously impaired by the mechanical properties of the blood-filled lungs. Consecutive severe respiratory failure (pO(2) 10 mm Hg, pCO(2) 320 mm Hg, pH 6.73) induced a cardiac arrest. Bronchoscopy could not identify the source of bleeding. During 45 min of cardiopulmonary resuscitation, veno-venous extracorporeal membrane oxygenation (ECMO) was installed. Subsequently, neither a high-resolution CT (HRCT) scan nor pulmonary angiography could identify the origin of the haemorrhage. Finally, the excessive pulmonary bleeding was controlled by placing an endobronchial blocker in the middle lobe bronchus. However, pulmonary haemorrhage reoccurred and this time HRCT revealed an isolated bronchiectasis in the middle lobe. Based on this finding, surgical lobectomy was performed. The patient recovered fully without any neurological sequelae. A solitary bronchiectasis has not previously been described as a cause of massive pulmonary haemorrhage in pregnancy. PMID- 22922931 TI - Flail tricuspid valve secondary to blunt chest trauma. AB - A 78-year-old man admitted with complaints of breathlessness of 1 year and typical chest pain of 2 months duration. He had a blunt chest trauma 7 years back. Transthoracic echocardiography revealed severe tricuspid regurgitation due to a flail anterior leaflet of the tricuspid valve. It also revealed global left ventricular dysfunction. Flail tricuspid valve causing severe regurgitation is usually due to mechanical trauma. Since it is well tolerated for years, the diagnosis may be delayed or missed entirely. Echocardiography has allowed easier diagnosis of this condition resulting in earlier and, hence, more effective treatment. PMID- 22922932 TI - Persistently elevated alkaline phosphatase. AB - A 32-year-old overweight asymptomatic man was found to have a persistently raised serum alkaline phosphatase at 250-300 U/l (normal range <130). Other liver function tests were unremarkable apart from an initial marginally elevated alanine transaminase, which normalised with weight reduction. Abdominal imaging revealed a fatty liver but an extensive serological search for significant hepatobiliary disease was negative. Subsequent isoenzyme electrophoresis revealed normal liver and bone fractions of alkaline phosphatase but a grossly elevated intestinal fraction. Elevated intestinal fraction of alkaline phosphatase should be considered in the investigation of unexplained alkaline phosphatase, particularly when the usual associated hepatobiliary and bony pathologies are not present. Although an elevated intestinal fraction of alkaline phosphatase can be linked to significant gastrointestinal pathology, this case report highlights that it can be a benign biochemical finding. PMID- 22922933 TI - Septic arthritis of the pubic symphysis from Pseudomonas aeruginosa: reconsidering traditional risk factors and symptoms in the elderly patient. AB - A high-functioning 82-year-old man presented with lower lumbar pain and pubic tenderness. On admission he was afebrile with a normal white count. A grossly elevated C reactive protein was noted. CT scan of the pelvis showed a fluid collection anterior to the pubic symphysis and to the right of the midline measuring 2.0 * 2.2 cm. Pseudomonas aeruginosa was cultured from the fluid collection. The patient had no history of intravenous drug use, pelvic surgeries, malignancies or trauma. We report what we believe is the first documented case of P aeruginosa infection of the pubic symphysis in an elderly patient that did not have any of the traditional risk factors associated with neither P aeruginosa septic arthritis nor infections of the pubic symphysis. Instead, we propose that phimosis with chronic infection of the foreskin and balanitis may have led to septic arthritis. PMID- 22922934 TI - Pyogenic flexor tenosynovitis leading to an amputation. AB - Flexor tenosynovitis is an aggressive closed-space infection of the digital flexor tendon sheaths of the hand. We present a case of pyogenic flexor tenosynovitis in an immunocompromised patient and discuss the importance of early diagnosis and referral to a specialist hand surgery unit. A 61-year-old man visited his general practitioner because of swelling and tenderness of his left index finger. The patient was discharged on oral antibiotics but returned 4 days after because of deterioration of his symptoms and was referred to a plastic surgery unit. A diagnosis of flexor tenosynovitis was made and the patient required multiple debridements in theatre, resulting in the amputation of the infected finger. Pyogenic flexor tenosynovitis is a relatively common but often misdiagnosed hand infection. Patients with suspected flexor tenosynovitis should be referred and treated early to avoid significant morbidity, especially when risk factors for poor prognosis are present. PMID- 22922935 TI - Fresh frozen plasma in the treatment of ACE inhibitor-induced angioedema. AB - Angioedema secondary to the use of ACE-inhibitors is well recognised, with a high rate of airway intervention required. Several treatments have been described, but little evidence exists for any of them. We describe the successful use of fresh frozen plasma in two cases. PMID- 22922936 TI - Bifid mandibular condyle: CT and MRI appearance. AB - Bifid mandibular condyle (BMC) is a rare asymptomatic morphological alteration with no predilection for age group or gender. Its morphology varies from a shallow groove to two condylar heads with separate necks, oriented mediolaterally or anteroposteriorly. This report describes an unusual case of bilateral mediolateral bifid condyle in a 24-year-old female patient with the main complaint of mouth-opening limitation. MRI and CT findings revealed bilateral bifid condyle. PMID- 22922938 TI - Anti-adipogenic effects of 1,25-dihydroxyvitamin D3 are mediated by the maintenance of the wingless-type MMTV integration site/beta-catenin pathway. AB - 1,25-dihydroxyvitamin D3 (1,25(OH)2D3), the active metabolite of vitamin D, was found to have anti-adipogenic activity, however, its mechanism of action has not been fully elucidated. In this study, 3T3-L1 preadipocytes were differentiated in the presence and absence of 1,25(OH)2D3, and the expression of the genes and proteins of the wingless-type MMTV integration site (WNT)/beta-catenin pathway were analyzed. While the expression of the members of the WNT/beta-catenin pathway were significantly downregulated during the adipogenesis of untreated 3T3 L1 cells, 1,25(OH)2D3 treatment was found to maintain the WNT/beta-catenin pathway. Among the members of the WNT/beta-catenin pathway, the levels of WNT10B and disheveled (DVL)2 as well as the phosphorylation of glycogen synthase kinase (GSK)3beta were maintained by 1,25(OH)2D3 treatment. The levels of nuclear beta catenin, which were downregulated during adipogenesis, were also maintained by 1,25(OH)2D3 treatment. The results of this study suggested that the anti adipogenic effect of 1,25(OH)2D3 was mediated by the maintenance of the WNT/beta catenin pathway, which was normally downregulated during adipogenesis. PMID- 22922937 TI - Sulforaphane synergistically enhances the cytotoxicity of arsenic trioxide in multiple myeloma cells via stress-mediated pathways. AB - Persistent paraprotein production in plasma cells necessitates a highly developed rough endoplasmic reticulum (ER) that is unusually susceptible to perturbations in protein synthesis. This biology is believed to account for the exquisite sensitivity of multiple myeloma (MM) to the proteasomal inhibitor bortezomib (BTZ). Despite remarkable response rates to BTZ in MM, BTZ carries the potential for serious side-effects and development of resistance. We, therefore, sought to identify therapeutic combinations that effectively disrupt proteostasis in order to provide new potential treatments for MM. We found that sulforaphane, a dietary isothiocyanate found in cruciferous vegetables, inhibits TNFalpha-induced Ikappabeta proteasomal degradation in a manner similar to BTZ. Like BTZ, sulforaphane synergistically enhances the cytotoxicity of arsenic trioxide (ATO), an agent with clinical activity in MM. ATO and sulforaphane co-treatment augmented apoptotic induction as demonstrated by cleavage of caspase-3, -4 and PARP. The enhanced apoptotic response was dependent upon production of reactive oxygen species (ROS) as demonstrated by glutathione depletion and partial inhibition of the apoptotic cascade after pretreatment with the radical scavenger N-acetyl-cysteine (NAC). Combination treatment resulted in enhanced ER stress signaling and activation of the unfolded protein response (UPR), indicative of perturbation of proteostasis. Specifically, combination treatment caused elevated expression of the molecular chaperone HSP90 (heat shock protein 90) along with increased PERK (protein kinase RNA-like endoplasmic reticulum kinase) and eIF2alpha phosphorylation and XBP1 (X-box binding protein 1) splicing, key indicators of UPR activation. Moreover, increased splicing of XBP1 was apparent upon combination treatment compared to treatment with either agent alone. Sulforaphane in combination with ATO effectively disrupts protein homeostasis through ROS generation and induction of ER stress to culminate in inhibition of protein secretion and apoptotic induction in MM. Our results suggest that sulforaphane deserves further investigation in combination with ATO in the treatment of MM. PMID- 22922939 TI - Diverse correlation patterns between microRNAs and their targets during tomato fruit development indicates different modes of microRNA actions. AB - MicroRNAs negatively regulate the accumulation of mRNAs therefore when they are expressed in the same cells their expression profiles show an inverse correlation. We previously described one positively correlated miRNA/target pair, but it is not known how widespread this phenomenon is. Here, we investigated the correlation between the expression profiles of differentially expressed miRNAs and their targets during tomato fruit development using deep sequencing, Northern blot and RT-qPCR. We found an equal number of positively and negatively correlated miRNA/target pairs indicating that positive correlation is more frequent than previously thought. We also found that the correlation between microRNA and target expression profiles can vary between mRNAs belonging to the same gene family and even for the same target mRNA at different developmental stages. Since microRNAs always negatively regulate their targets, the high number of positively correlated microRNA/target pairs suggests that mutual exclusion could be as widespread as temporal regulation. The change of correlation during development suggests that the type of regulatory circuit directed by a microRNA can change over time and can be different for individual gene family members. Our results also highlight potential problems for expression profiling-based microRNA target identification/validation. PMID- 22922940 TI - Novel conserved segments are associated with differential expression patterns for Pinaceae dehydrins. AB - Dehydrins are thought to play an essential role in the response, acclimation and tolerance to different abiotic stresses, such as cold and drought. These proteins have been classified into five groups according to the presence of conserved and repeated motifs in their amino acid sequence. Due to their putative functions in the response to stress, dehydrins have been often used as candidate genes in studies on population variability and local adaptation to environmental conditions. However, little is still known regarding the differential role played by such groups or the mechanism underlying their function. Based on the sequences corresponding to dehydrins available in public databases we have isolated eight different dehydrins from cDNA of Pinus pinaster. We have obtained also their genomic sequences and identified their intron/exon structure. Quantitative RT-PCR analysis of their expression pattern in needles, stems and roots during a severe and prolonged drought stress, similar to the ones trees must face in nature, is also reported. Additionally, we have identified two amino acid motifs highly conserved and repeated in Pinaceae dehydrins and absent in angiosperms, presumably related to the divergent expression profiles observed. PMID- 22922941 TI - Testing for associations between candidate genes for circadian rhythms and individual variation in sleep behaviour in blue tits. AB - The regulation of sleep in animals is controlled by environmental factors, homeostatic mechanisms and endogenous circadian oscillators. The molecular mechanisms underlying such circadian oscillators have been described in detail and a variety of genes that are components of these molecular clocks have been reported. In addition to inter-specific variation in the temporal organization of sleep, there is significant intra-specific variation in different organisms. From numerous studies in humans it is known that polymorphisms in the regulatory clock genes are causing such variation but knowledge about associations between naturally occurring polymorphisms and sleep patterns in wild animals is scarce. In this study, we investigated the phenotypic sleep correlates of eleven previously described polymorphisms in seven candidate genes within a free-living blue tit Cyanistes caeruleus population. We detected associations between four single nucleotide polymorphisms and three of the nine tested sleep parameters representing temporal organization. Awakening time was associated with polymorphisms in AANAT and PERIOD2, morning latency with a polymorphism in CKIepsilon and the duration of the longest sleep bout with a second polymorphism in AANAT. However, by a permutation procedure we showed that the number of significant results and the most significant association has a study-wide likelihood of 46.7 and 5.9 % respectively. Further replication studies are needed to evaluate the potential associations. PMID- 22922942 TI - Arabinose is metabolized via a phosphoketolase pathway in Clostridium acetobutylicum ATCC 824. AB - In this report, a novel zymogram assay and coupled phosphoketolase assay were employed to demonstrate that Clostridium acetobutylicum gene CAC1343 encodes a bi functional xylulose-5-P/fructose-6-P phosphoketolase (XFP). The specific activity of purified recombinant XFP was 6.9 U/mg on xylulose-5-P and 21 U/mg on fructose 6-P, while the specific activity of XFP in concentrated C. acetobutylicum whole cell extract was 0.094 and 0.52 U/mg, respectively. Analysis of crude cell extracts indicated that XFP activity was present in cells grown on arabinose but not glucose and quantitative PCR was used to show that CAC1343 mRNA expression was induced 185-fold during growth on arabinose when compared to growth on glucose. HPLC analysis of metabolites revealed that during growth on xylose and glucose more butyrate than acetate was formed with final acetate:butyrate ratios of 0.72 and 0.83, respectively. Growth on arabinose caused a metabolic shift to more oxidized products with a final acetate:butyrate ratio of 1.95. The shift towards more oxidized products is consistent with the presence of an XFP, suggesting that arabinose is metabolized via a phosphoketolase pathway while xylose is probably metabolized via the pentose phosphate pathway. PMID- 22922943 TI - Upregulation and inhibition of the nuclear translocation of Oct4 during multistep gastric carcinogenesis. AB - Gastric cancer is the fourth most commonly diagnosed malignancy and the second leading cause of cancer-related mortality worldwide. Recent research suggests that tissue stem cells and the self renewal transcription factor, octamer-binding transcription factor 4 (Oct4), could be involved in the development of certain tumors. The aim of this study was to investigate the expression pattern of Oct4 in normal human stomach and during multistep gastric carcinogenesis. Pyloric antral mucosal tissues were obtained from consenting individuals undergoing endoscopy (due to upper gastrointestinal symptoms) and gastrectomy (due to pyloric antral adenocarcinoma). Some tissue samples were processed to assemble an array of tissue sections representing multistep carcinogenesis and probed using anti-Oct4 antibodies and lectins specific for alpha-L-fucose or N-acetyl-D glucosamine. Some tissue samples were processed for subcellular fractionation and western blot analysis using the same antibodies. The results revealed that Oct4 expressing cells were found in the proliferative cell compartment of the pit gland units of microscopically normal gastric mucosal biopsies. Mucosal tissues with evidence of severe gastritis, metaplastic/dysplastic transformation and gastric cancer showed a significant increase in the expression of Oct4 (the labeled area increased from 2% in the control to 6 and 16% in the gastritis and cancerous tissues, respectively), suggesting a role for Oct4 in the early stages of cancer development. Furthermore, the data revealed an alteration in the subcellular distribution of Oct4, possibly due to the inhibition of cytoplasm-to nucleus translocation during carcinogenesis. In conclusion, this study demonstrates an alteration in the expression pattern and nuclear translocation of Oct4 during gastric carcinogenesis and may be helpful in designing new modalities for the early detection and/or therapy of gastric cancer. PMID- 22922944 TI - Balloon dilatation of benign rectal anastomotic strictures -- a review. AB - BACKGROUND: The occurrence of anastomotic stricture at the level of the rectum gives rise to three broad therapeutic options, namely major pelvic and abdominal revisional surgery, faecal diversion (stoma), or local revision by transanal approaches (including endoscopic and fluoroscopic). This article updates the current evidence and focuses on the results of the balloon dilatation technique. METHODS: A Medline search was carried out using the search terms (dilatation OR dilatation) AND (stricture OR strictures OR stenosis OR stenotic) AND (rectum OR rectal). In an effort to lessen publication bias, articles included at least 10 patients who were consecutively referred for treatment. RESULTS/CONCLUSION: This review would suggest that probably relatively short strictures have been chosen for balloon dilatation and that the results have had a very low major morbidity (0.45%) and mortality (0%) rate. PMID- 22922946 TI - Eagle syndrome, a rare cause of glossodynia. PMID- 22922945 TI - Recent advances (2011-2012) in technology-delivered interventions for people living with HIV. AB - Technology is rapidly advancing and becoming a cost effective option for intervention delivery particularly for isolated and hard to reach populations, such as people living with HIV/AIDS. A systematic review was conducted to identify recent technology based interventions for people living with HIV. The review yielded 12 studies that were grouped by the health behavior that it addressed and then the type of technology utilized. The majority of studies reviewed focused on medication adherence and used several different technologies to deliver the intervention including SMS/text messaging, cell phones and computers. This review identified several gaps in the literature particularly the lack of technology-based interventions focusing on engagement and retention to care as well as sexual risk reduction. Suggestions for future research based on these findings are provided. PMID- 22922947 TI - Comparison of in-hospital morbidity and mortality in HIV-infected and uninfected children after surgery. AB - PURPOSE: Increasingly HIV-infected children can be expected to require surgery. The aim of this study was to compare the outcome of HIV-infected and HIV unexposed children undergoing surgery. PATIENTS AND METHODS: A prospective study of children less than or equal to 60 months admitted to a tertiary pediatric surgical service from July 2004 to July 2008. Children underwent age-definitive HIV testing and were followed up postoperatively for complications, length of stay and mortality. RESULTS: Three hundred and twenty-seven children were enrolled: 82 (23 %) HIV-infected and 245 (67 %) were HIV-unexposed. Eighty-four (26 %) children were malnourished, which was higher in the HIV-infected group [41 (50.0 %) vs. 43 (17.5 %), relative risk (RR) 2.9; 95 % confidence interval (CI) 2.0-4.1; p < 0.0001]. Three hundred and twenty-eight surgical procedures were performed. A similar number of major [28 (34.2 %) vs. 64 (26.1 %); p = 0.2] and emergency procedures [37 (45.1 %) vs. 95 (38.8 %); p = 0.34] were performed in each group. HIV-infected children had a higher rate of contamination at surgery [40 (48.7 %) vs. 49 (20 %); RR 2.43 (CI 1.7-3.4); p < 0.0001]. There were more complications in the HIV-infected group [34 (41.5 %) vs. 14 (5.7 %); RR 7.3 (CI 4.1-12.8); p < 0.0001]. The most common complications were surgical site complications 30 (55 %), followed by postoperative infections, 19 (34 %). Infections with drug-resistant organisms occurred more commonly in HIV-infected children [11/19 (58 %) vs. 2/13 (15 %); RR 3.8 (CI 1.3-14.2); p = 0.02]. The median length of hospital stay was longer in the HIV-infected group [4 (IQR 2-14) vs. 2 (IQR 1-4) days; p = 0.0001]. There was a higher mortality amongst the HIV infected group [6 (7.3 %) vs. 0 (0 %); p < 0.0001]. CONCLUSION: HIV-infected children have a higher rate of postoperative complications and mortality compared with HIV-unexposed children. PMID- 22922948 TI - Primary splenic angiosarcoma in a 2.5-year-old boy with hepatic metastasis. AB - Primary splenic angiosarcoma in children is extremely rare and has a very poor prognosis. We reported a 2.5-year-old boy who had this rare entity and hepatic metastasis. The patient presented with left upper quadrant abdominal mass and anemia. The patient received multidisciplinary treatment and died 32 months after splenectomy. PMID- 22922949 TI - Right atrial lipomatous hypertrophy resection and reconstruction using autologus pericardium. AB - We report a case of lipomatous hypertrophy, which is a relatively uncommon entity. The patient presented with premature atrial conduction and echocardiography showed a large intracardiac mass in the right atrium. He underwent successful resection of the mass with septal reconstruction using autologous pericardium. Pathological examination revealed benign fatty infiltration suggestive of benign lipomatous hypertrophy. PMID- 22922950 TI - Ultrasound-guided infraclavicular axillary vein puncture is effective to avoid pinch-off syndrome: a long-term follow-up study. AB - PURPOSE: Pinch-off syndrome (POS) is a serious complication encountered during the long-term management of totally implantable access ports (TIAPs). The aim of this study was to examine the effect of ultrasound-guided infraclavicular axillary vein puncture to avoid POS in patients with long-term use of a TIAP. METHODS: This was a retrospective review of 207 consecutive TIAPs: one hundred devices implanted using an anatomical landmark technique were used as historical controls (Landmark group), while 107 devices were implanted using an ultrasound (US)-guided puncture method (US group). The pinch-off grade (POG) was determined using chest X-ray findings following the definition of Hinke, and the progression of POG during the follow-up period of the Landmark and US groups was compared. RESULTS: Sixteen cases in the Landmark group were POG-1 and 3 were POG-2, while all cases in the US group were POG-0 at the time of venipuncture (p < 0.001). Eleven patients in the Landmark group showed some degree of progression of the POG during the follow-up period. In contrast, there were no cases showing progression of the POG in the US group (p = 0.002). CONCLUSIONS: US-guided infraclavicular axillary vein puncture was found to effectively make it possible to avoid POS for the long-term management of TIAPs, as well as at the time of implantation. PMID- 22922951 TI - Leiomyosarcoma arising from the inferior mesenteric vein draining in the splenomesenteric angle with a tumour thrombus at the splenomesenteric confluence: a case report and review of the literature. PMID- 22922952 TI - Multilevel socioeconomic effects on quality of life in adolescent and young adult survivors of leukemia and lymphoma. AB - PURPOSE: Cancer registry survival analyses have shown that adolescent and young adult patients with low socioeconomic status (SES) have reduced survival compared to those with higher SES. The objective of this study was to determine whether neighborhood- (nSES) and/or individual-level SES (iSES) also predicted current quality of life in adolescent and young adult survivors. METHODS: The Socioeconomics and Quality of Life study surveyed adolescent and young adult survivors of leukemia and lymphoma at least one year post-diagnosis using population-based ascertainment. Factor analysis was used to create a multidimensional age-relevant iSES score and compared with a preexisting census block-group derived nSES score. Four quality of life domains were assessed: physical health, psychological and emotional well-being, social relationships, and life skills. Nested multivariable linear regression models were run to test the associations between both SES measures and quality of life and to compare the explanatory power of nSES and iSES. RESULTS: Data from 110 individuals aged 16-40 were included in the final analysis. After adjustment for sociodemographic confounders, low nSES was associated only with poorer physical health, whereas low iSES was related to poorer quality of life in all four domains with iSES accounting for an additional 14, 12, 25, and 10 % of the variance, respectively. CONCLUSIONS: Measures of SES at the individual as compared to the neighborhood level may be stronger indicators of outcomes in adolescents and young adults, which has important implications for SES measurement in the context of cancer surveillance. PMID- 22922954 TI - The Alberta Diabetes and Physical Activity Trial (ADAPT): a randomized trial evaluating theory-based interventions to increase physical activity in adults with type 2 diabetes. AB - BACKGROUND: Physical activity (PA) is associated with reduced morbidity and mortality in individuals with type 2 diabetes mellitus (T2DM); however, most T2DM adults are insufficiently active. PURPOSE: To explore the effectiveness of two innovative/theoretically based behavioral-change strategies to increase PA and reduce hemoglobin A1c (A1c) in T2DM adults. METHODS: Participants (n = 287) were randomly assigned to a control group or an intervention group (i.e., print-based materials/pedometer group or print-based materials/pedometer plus telephone counseling group). Changes in PA and A1c and other clinical measures were examined by Linear Mixed Model analyses over 18 months, along with moderating effects for gender and age. RESULTS: PA and A1c levels did not significantly change in intervention groups. Step counts significantly increased in the print based materials and pedometer plus telephone counseling group, for women. CONCLUSIONS: No significant effects were found for PA or A1c levels for T2DM adults. The multi-component strategy including telephone counseling may have potential for women. The trial was registered on ClinicalTrials.gov identifier: NCT00221234. PMID- 22922953 TI - Recombinant human beta 2-defensin fusion proteins as a tool to investigate defensin structure and function in small human intestinal tissue samples. AB - OBJECTIVE: Effects of immune cells on the beta 2 (beta2)-defensin (HBD2) expression and its antibacterial activity in the intestinal mucosa of patients with inflammatory bowel diseases remains unclear. The small size of these proteins presents a major challenge in localizing antibacterial activities in human intestinal tissue. In this study, we evaluated the detection limits at mRNA and protein level by approaching HBD2 from small tissue samples. METHODS: HT-29 colonic epithelial cells were incubated with proinflammatory cytokines before HBD2 mRNA was investigated by quantitative polymerase chain reaction. The HBD2 protein was assessed by Western blot analysis using HBD2 fused with enhanced green fluorescent protein (HBD2-EGFP). Purified HBD2 fused with the glutathione-S transferase (GST-HBD2) was used to detect antibacterial activity in a densitometric assay. RESULTS: Interleukin (IL)-1beta induced HBD2 mRNA in HT-29 cells; however, tumor necrosis factor-alpha, IL-6 and IL-17 did not. The Western blot had a sensitivity of 1.5 pmol to detect recombinant HBD2, but did not detect HBD2 in either human intestinal or IL-1beta-treated HT-29 cells. HBD2-EGFP was detected by HBD2-specific Western blot within cell lysates and culture supernants of transfected HT-29 and primary cells. In nanomolar ranges, GST-HBD2 reduced bacterial growth. The HBD2 bioactivity depended on solution conditions, but not on the size of the fusion partner. CONCLUSION: The established fusion proteins provide excellent tools to evaluate expression patterns and antibacterial effects of HBD2 in human intestinal tissue samples. PMID- 22922956 TI - Renal cell carcinoma presenting as a stress cardiomyopathy. PMID- 22922955 TI - Body mass index and the prevalence, severity, and risk of coronary artery disease: an international multicentre study of 13,874 patients. AB - AIMS: Obesity is associated with the presence of coronary artery disease (CAD) risk factors and cardiovascular events. We examined the relationship between body mass index (BMI) and the presence, extent, severity, and risk of CAD in patients referred for coronary computed tomographic angiography (CCTA). METHODS AND RESULTS: We evaluated 13,874 patients from a prospective, international, multicentre registry of individuals without known CAD undergoing CCTA. We compared risk factors, CAD findings, and risk of all-cause mortality and non fatal myocardial infarction (MI) amongst individuals with underweight (18.5-20.0 kg/m(2)), normal (20.1-24.9 kg/m(2)), overweight (25-29.9 kg/m(2)), and obese (>=30 kg/m(2)) BMI. The mean follow-up was 2.4 +/- 1.2 years with 143 deaths and 193 MIs. Among underweight, normal weight, overweight, and obese individuals, there was increasing prevalence of diabetes (7 vs.10% vs. 12 vs. 19%), hypertension (37 vs. 40% vs. 46 vs. 59%), and hyperlipidaemia (48 vs. 52% vs. 56 vs. 56%; P < 0.001 for trend). After multivariable adjustment, BMI was positively associated with the prevalence of any CAD [odds ratio (OR) 1.25 per +5 kg/m(2), 95% confidence interval (CI): 1.20-1.30, P < 0.001] and obstructive (>=50% stenosis) CAD (OR: 1.13 per +5 kg/m(2), 95% CI: 1.08-1.19, P < 0.001); a higher BMI was also associated with an increased number of segments with plaque (+0.26 segments per +5 kg/m(2), 95% CI: 0.22-0.30, P < 0.001). Larger BMI categories were associated with an increase in all-cause mortality (P = 0.004), but no difference in non-fatal MI. After multivariable adjustment, a higher BMI was independently associated with increased risk of MI (hazards ratio: 1.28 per +5 kg/m(2), 95% CI: 1.12-1.45, P < 0.001). CONCLUSIONS: Amongst patients with suspected CAD referred for CCTA, individuals with increased BMI have greater prevalence, extent, and severity of CAD that is not fully explained by the presence of traditional risk factors. A higher BMI is independently associated with increased risk of intermediate-term risk of myocardial infarction. PMID- 22922957 TI - Extracellular acidification activates cAMP responsive element binding protein via Na+/H+ exchanger isoform 1-mediated Ca2+ oscillation in central nervous system pericytes. AB - OBJECTIVE: We have previously shown that Na(+)/H(+) exchanger isoform 1 (NHE1) plays an important role in Ca(2+) signaling and cell proliferation in human central nervous system (CNS) pericytes. The aims of the present study were to elucidate how NHE1-induced Ca(2+) signaling during acidosis is transformed into cellular responses in CNS pericytes. METHODS AND RESULTS: Human CNS pericytes were cultured, and the activation of cAMP responsive element-binding protein (CREB) was evaluated by Western blotting analysis, immunofluorescence, and luciferase assays. In human CNS pericytes, low extracellular Na(+) or low pH generated Ca(2+) oscillation and subsequently phosphorylated Ca(2+)/calmodulin dependent kinase II (CaMKII) and CREB in a time-dependent manner. Focal cerebral ischemia was applied using photothrombotic distal middle cerebral artery occlusion in mice, and the phosphorylation of CREB and the production of interleukin-6 were observed in pericytes migrating into the peri-infarct penumbra during the early phase after ischemic insult. CONCLUSIONS: Our results indicate that extracellular acidosis induces Ca(2+) oscillation via NHE1, leading to Ca(2+)/CaMKII-dependent CREB activation in human CNS pericytes. Acidosis may upregulate a variety of proteins, such as interleukin-6, through the NHE1 Ca2+/CaMKII-CREB pathway in brain pericytes and may thus modulate brain ischemic insult. PMID- 22922958 TI - Decreased Krev interaction-trapped 1 expression leads to increased vascular permeability and modifies inflammatory responses in vivo. AB - OBJECTIVE: The regulation of vascular permeability, leukocyte trafficking, and the integrity of endothelial cell-cell contacts are closely linked by a complex mechanism of interregulation. Here, we investigate the role of Krev interaction trapped 1 (KRIT1), an adherens junction accessory protein required for cell-cell junction stability, in regulating these vascular functions. METHODS AND RESULTS: Krit1(+/-) mice exhibited an enhanced edematous response to the complex inflammatory stimuli found in the passive K/BxN model of inflammatory arthritis and the murine air pouch model, yet leukocyte infiltration was unchanged. Correspondingly, reduced KRIT1 expression increased baseline arteriole and venule permeability 2-fold over that of wild-type littermates, as measured by intravital microscopy of the intact cremaster muscle vascular network, but this increase was not accompanied by increased leukocyte extravasation or activation. Direct stimulation with tumor necrosis factor-alpha induced increased permeability in wild-type mice, but surprisingly no increase over baseline levels was observed in Krit1(+/-) mice, despite extensive leukocyte activation. Finally, adoptive transfer of Krit1(+/-) bone marrow failed to increase permeability in wild-type mice. However, reduced expression of KRIT1 in the hematopoietic lineage dampened the differences observed in baseline permeability. CONCLUSIONS: Taken together, our data indicate an integral role for KRIT1 in microvessel homeostasis and the vascular response to inflammation. PMID- 22922959 TI - Intermedin: a novel regulator for vascular remodeling and tumor vessel normalization by regulating vascular endothelial-cadherin and extracellular signal-regulated kinase. AB - OBJECTIVE: Intermedin (IMD), a member of calcitonin family, was suggested to play a role in angiogenesis and cancer. The aim of this study was to investigate the role of IMD in the angiogenic process and the underlying mechanism, and the possibility for it to be used as a target for angiogenesis-based anticancer therapies. METHODS AND RESULTS: Using in vivo and in vitro 3-dimensional angiogenic models, we found that IMD induced a well-ordered vasculature with hierarchical structure and had a synergistic effect with vascular endothelial growth factor. Using RNA interference, real-time polymerase chain reaction, and Western blot analysis, we found that IMD alleviated the undesirable effects of vascular endothelial growth factor by restricting the excessive vessel sprouting and uneven lumen formation through the regulation of vascular endothelial cadherin and identified its receptor on the endothelial cells. Both mitogen activated protein kinase/extracellular signal-regulated kinase and phosphoinositide 3-kinase/Akt activation were involved in the effects. Furthermore, using experimental tumor models, we demonstrated that IMD was involved in tumor angiogenesis, and the blockade of IMD severely impaired blood supply and eventually inhibited tumor growth. CONCLUSIONS: We demonstrated that IMD played a critical role in the vascular remodeling process and tumor angiogenesis and may serve as a novel target for the development of angiogenesis based anticancer therapies. PMID- 22922960 TI - Facio-genital dysplasia-5 regulates matrix adhesion and survival of human endothelial cells. AB - OBJECTIVE: The function of the endothelial cell (EC)-enriched Rho family guanine nucleotide exchange factor, facio-genital dysplasia-5 (FGD5), is poorly understood. We sought to determine whether FGD5 regulates endothelial cytoskeletal reorganization and angiogenesis. METHODS AND RESULTS: We observed that FGD5 is expressed in primary human EC isolated from sites across the vasculature. Inhibition of FGD5 expression using RNA interference decreased the protein by ~70%. In 3-dimensional vascular endothelial growth factor-stimulated angiogenesis in vitro, FGD5-deficient endothelial sprout protrusion was markedly blunted versus nonsilenced controls. FGD5 knockdown impaired adhesion to fibronectin and collagen IV and remodeling of matrix adhesion complexes. Similarly, monolayer electric impedance was decreased, and impedance increased at a slower rate after seeding FGD5-deficient cells versus controls, reflecting decreased EC spreading. Further, FGD5 plays a role in cell survival, because expression of cleaved caspase-3 was increased in FGD5-deficient EC after loss of cell-matrix contacts, and proapoptotic tumor necrosis factor-alpha stimulation elicited EC with subdiploid DNA content among FGD5-deficient EC. Mechanistically, the phosphatidylinositol 3-kinase/Akt pathway that regulates both adhesive and survival signal transduction pathways requires FGD5. Vascular endothelial growth factor-stimulated Akt phosphorylation and downstream forkhead box protein-O1 inactivation is inhibited by FGD5 loss. CONCLUSIONS: FGD5 regulates endothelial adhesion, survival, and angiogenesis by modulating phosphatidylinositol 3-kinase signaling. PMID- 22922961 TI - Simultaneous exposure of sites in von Willebrand factor for glycoprotein Ib binding and ADAMTS13 cleavage: studies with ristocetin. AB - OBJECTIVE: Platelet-bound von Willebrand factor (VWF) was recently demonstrated to be a better substrate for ADAMTS13, suggesting that 1 conformational change exposes both the glycoprotein Ibalpha binding site in the A1 domain and the ADAMTS13 cleavage site in the A2 domain. Because ristocetin induces VWF to bind glycoprotein Ibalpha in the absence of shear stress, we evaluated whether it could also enhance ADAMTS13 proteolysis of VWF. METHODS AND RESULTS: We used several VWF sources: plasma, purified plasma VWF, recombinant VWF fragments encompassing A1A2A3, A1A2, and 2 A2 domains, 1 containing a ristocetin-binding site (Asp1459-His1472) and the other lacking it. Ristocetin accelerated ADAMTS13 cleavage of multimeric VWF and of each of the recombinant VWF fragments except for the A2 domain lacking the ristocetin-binding site. We also examined the effect of ristocetin on the conformation of the A2 domain by assessing its effect on the susceptibility of Met1606 at the ADAMTS13 cleavage site to be oxidized by hypochlorous acid. Ristocetin markedly enhanced oxidation of Met1606 and Met1521 of the A2 domain. CONCLUSIONS: These data indicate that exposure of the sites for glycoprotein Ibalpha and ADAMTS13 are coupled, explaining why platelet-bound VWF is a better ADAMTS13 substrate and why enhanced proteolysis is often observed in type 2B von Willebrand disease. PMID- 22922962 TI - Novel role of proline-rich nonreceptor tyrosine kinase 2 in vascular wall remodeling after balloon injury. AB - OBJECTIVE: To investigate the role of Pyk2, a proline-rich nonreceptor tyrosine kinase, in G protein-coupled receptor agonist, thrombin-induced human aortic smooth muscle cell growth and migration, and injury-induced vascular wall remodeling. METHODS AND RESULTS: Thrombin, a G protein-coupled receptor agonist, activated Pyk2 in a time-dependent manner and inhibition of its stimulation attenuated thrombin-induced human aortic smooth muscle cell migration and proliferation. Thrombin also activated Grb2-associated binder protein 1, p115 Rho guanine nucleotide exchange factor, Rac1, RhoA, and p21-activated kinase 1 (Pak1) and interference with stimulation of these molecules attenuated thrombin-induced human aortic smooth muscle cell migration and proliferation. In addition, adenovirus-mediated expression of dominant negative Pyk2 inhibited thrombin induced Grb2-associated binder protein 1, p115 rho guanine nucleotide exchange factor, Rac1, RhoA and Pak1 stimulation. Balloon injury also caused activation of Pyk2, Grb2-associated binder protein 1, p115 rho guanine nucleotide exchange factor, Rac1, RhoA, and Pak1 in the carotid artery of rat, and these responses were sensitive to inhibition by the dominant negative Pyk2. Furthermore, inhibition of Pyk2 activation resulted in reduced recruitment of smooth muscle cells onto the luminal surface and their proliferation in the intimal region leading to suppression of neointima formation. CONCLUSIONS: Together, these results demonstrate for the first time that Pyk2 plays a crucial role in G protein-coupled receptor agonist thrombin-induced human aortic smooth muscle cell growth and migration, as well as balloon injury-induced neointima formation. PMID- 22922964 TI - Glioblastoma cell line-derived spheres in serum-containing medium versus serum free medium: a comparison of cancer stem cell properties. AB - In addition to the primary culturing of cancer stem cells (CSCs) from tumor tissues, CSCs are found in established tumor cell lines. However, it is unclear how culture conditions affect CSC enrichment. Additionally, the differentiation potential of cell line-derived CSCs has not been well studied. In our study, the glioblastoma cell lines LN229, T98G, U251n and U87, were cultured as spheres in serum-containing medium (serum spheres) or serum-free medium (serum-free spheres). We found that LN229 and U251n cells expressed multiple stem cell markers such as Nestin, Sox2, Musashi-1 and CD44, and their serum spheres expressed even higher levels of Nestin, Sox2 and Musashi-1 compared to monolayer cells and serum-free spheres. LN229 and U251n cells showed higher migration and colony formation potential compared to T98G and U87 cells, which did not express Nestin, Sox2 and Musashi-1. Serum spheres of LN229 and U251n cells also exhibited higher resistance to temozolomide compared to serum-free spheres. All tumor cell lines showed neuronal differentiation (Tuj-1 positive). Only U251n serum spheres exhibited both astrocytic (GFAP-positive) and neuronal differentiation. We conclude that sphere culture in serum-containing medium provides the most efficient enrichment of cancer stem cells. U251n cells are distinguished from other tumor cells due to their potential for multilineage differentiation. PMID- 22922963 TI - The induction of yes-associated protein expression after arterial injury is crucial for smooth muscle phenotypic modulation and neointima formation. AB - OBJECTIVE: Abnormal proliferation and migration of vascular smooth muscle cells (SMCs) are the key events in the progression of neointima formation in response to vascular injury. The goal of this study is to investigate the functional role of a potent oncogene yes-associated protein (YAP) in SM phenotypic modulation in vitro and in vivo. METHODS AND RESULTS: In vitro cell culture and in vivo in both mouse and rat arterial injury models YAP expression is significantly induced and correlated with the vascular SMC synthetic phenotype. Overexpression of YAP promotes SMC migration and proliferation while attenuating SM contractile gene expression. Conversely, knocking down endogenous YAP in SMCs upregulates SM gene expression but attenuates SMC proliferation and migration. Consistent with this, knocking down YAP expression in a rat carotid balloon injury model and genetic deletion of YAP, specifically, in vascular SMCs in mouse after carotid artery ligation injury attenuates injury-induced SM phenotypic switch and neointima formation. CONCLUSIONS: YAP plays a novel integrative role in SM phenotypic modulation by inhibiting SM-specific gene expression while promoting SM proliferation and migration in vitro and in vivo. Blocking the induction of YAP would be a potential therapeutic approach for ameliorating vascular occlusive diseases. PMID- 22922966 TI - A comparison of the effect of convection against diffusion in hemodynamics and cytokines clearance in an experimental model of septic shock. AB - BACKGROUND: Replacement therapies based on the use of convection have value for the removal of inflammatory mediators. Such therapies have been proposed for the management of septic shock, but diffusion has not proved useful in this scenario, unless high-flow membranes are used. The exact role of diffusion in these cases remains to be clarified because continuous replacement therapies are usually delivered with low-flow membranes and mixed convection-diffusion modalities. However, studies specifically addressing this problem have not been performed. Our aim was to define the efficacy of hemofiltration (convection) and hemodialysis (diffusion) in cytokine clearance and hemodynamic improvement in an experimental model of septic shock. METHODS: Shock was induced in 15 beagle dogs (weight 10-15 kg) by infusion of 1 mg/kg of ultrapure Escherichia coli lipopolysaccharide diluted in 20 mL saline for 10 minutes. Five animals were followed without interventions (controls), five animals were treated with convection (100 mL kg h) for 6 hours, and five animals were treated with diffusion (100 mL kg h) for 6 hours. RESULTS: All subjects in the control group died during the study, whereas all treated subjects survived. Mean arterial pressure, cardiac output, systolic variability volume, systemic vascular resistances, dPMax, and pulmonary compliance improved in treated subjects. However, the differences in mean arterial pressure and cardiac output were significant only in the convection group and not in the diffusion-treated group.Tumor necrosis factor alpha rose equally in all groups and decreased only in treated subjects. Interleukin 6 rose in the three groups but decreased only in the convection group and remained unchanged in the control and diffusion groups. CONCLUSION: Convection and diffusion improved survival and hemodynamic parameters in a septic shock model. Improvement was more pronounced with convection, a difference that may be explained by convective clearance of cytokines. PMID- 22922965 TI - Molecular imaging and therapeutic efficacy of 188Re-(DXR)-liposome-BBN in AR42J pancreatic tumor-bearing mice. AB - Liposomes are good candidates as drug carriers and have been widely investigated in drug delivery systems. In this study, a new combination of bimodal 188Re-(DXR) liposome-BBN radiochemotherapeutics was designed and studied for treating solid pancreatic tumor by intravenous administration. The in vivo nuclear microSPECT/CT imaging of tumor targeting, prolonged survival time and therapeutic efficacy were evaluated in AR42J malignant pancreatic solid tumor-bearing nude mice. MicroSPECT/CT imaging of 188Re-liposome-BBN pointed to significant targeting in tumors at 24 h after intravenous injection (SUV=2.13 +/- 0.98). Co-injection of a blocking dose of cold BBN (4 mg/kg) inhibited the accumulation of 188Re-liposome BBN in tumors (SUV=1.82 +/- 0.31). For therapeutic efficacy, inhibition of tumor growth in mice treated with 188Re-DXR-liposome-BBN was precisely controlled [mean growth inhibition rate (MGI) = 0.092] and had longer survival time [life-span (LS) = 86.96%] than those treated with anticancer drug 188Re-liposome-BBN (MGI = 0.130; LS = 75%), Lipo-Dox-BBN (MGI = 0.666; LS = 3.61%) and untreated control mice. An additive tumor regression effect was observed (CI 0.946) for co-delivery of 188Re-DXR-liposome-BBN radiochemotherapeutics. These results point to the potential benefit of the 188Re-(DXR)-liposome-BBN radiochemotherapeutics for adjuvant cancer treatment with applications in oncology. PMID- 22922967 TI - Derivation of a clinical risk score for traumatic orbital fracture. AB - BACKGROUND: Given that orbital fractures are found in only one of every eight patients receiving computed tomography for acute orbital trauma, we sought to prospectively identify clinical predictors of orbital fracture that may obviate the need for exposing low-risk patients to ionizing radiation. METHODS: Prospective cohort study conducted from July 2007 through October 2009 at two urban emergency departments. Consecutive patients undergoing computed tomography for acute blunt orbital trauma were evaluated on 15 clinical findings before imaging. The primary outcome of interest was presence of any acute orbital fracture. The secondary outcome was a fracture requiring emergent operative intervention. Multivariable logistic regression analysis with multiple imputation was used to derive a predictive risk score. RESULTS: A total of 2,262 patients with acute orbital trauma were enrolled. Median age was 38 years with male predominance (68.3%). Acute orbital fractures were found in 360 patients (15.9%). The derived risk score included orbital rim tenderness, periorbital emphysema, subconjunctival hemorrhage, pain with extraocular movement, impaired extraocular movement, and epistaxis. Across 10 multiply imputed data sets, a mean of 660 patients (29.2%) lacked all six equally weighted predictors, of which 6.3% (95% confidence interval, 4.3-8.2) experienced an acute orbital fracture and only 0.5% (95% confidence interval, 0.0-1.0) required emergent operative intervention. CONCLUSION: Six clinical predictors identify patients with blunt orbital trauma at increased risk for acute orbital fracture. A risk score of 0 identifies patients at very low risk for emergent operative intervention. Multicenter studies are needed to validate these findings and derive a clinical decision instrument to reduce orbital imaging without compromising patient safety. LEVEL OF EVIDENCE: Diagnostic study, level II. PMID- 22922968 TI - Physiopathology of anemia and transfusion thresholds in isolated head injury. AB - BACKGROUND: Blood transfusion strategies among patients with critical illness use a restrictive hemoglobin threshold. However, among patients with head injury, no outcome differences have been shown between either liberal or restrictive strategies. Several studies and literature reviews suggest that anemia is associated with markers of tissue ischemia. The paucity of prospective data confuses the association between surrogates of tissue ischemia and neurological outcome. METHODS: A narrative review of transfusion practices among patients in the acute phase of head injury was performed using PubMed, MEDLINE, EMBASE, Cochrane, and WEB of Science databases. A total of 104 articles were reviewed. RESULTS: There are few data to guide clinical practice. Clinicians use blood hemoglobin concentrations to trigger transfusion. Markers of potential cerebral injury are not in regular use despite experimental and observational data rising from histologic examination, microdialysis, oximetry, and flow-based multimonitoring systems recommending their use to titrate blood transfusion in neurotrauma. CONCLUSION: The generalization of transfusion triggers is common practice. Evidence-based approaches to transfusions strategies in head injury are lacking and not based on an understanding of cerebral physiopathology. PMID- 22922969 TI - Institutional and provider factors impeding access to trauma center care: an analysis of transfer practices in a regional trauma system. AB - BACKGROUND: More than a third of patients with severe injury who receive initial care at nontrauma centers (NTCs) are not transferred to trauma center care. In those who are transferred, significant delays have been described. The availability of specialists, imaging modalities, or critical care resources might significantly affect transfer practices. METHODS: We undertook a population-based retrospective cohort study of adult patients with severe injury who were transported from the scene to an NTC. NTCs were characterized based on the availability of general and orthopedic surgeons, computed tomographic scanners, intensive care units, and emergency department staffing. NTCs that had all of the resources were characterized as resource rich, while those with none were characterized as resource limited. We evaluated the relationships between NTC resources and the likelihood and timeliness of interfacility transfer through the use of hierarchical regression modeling. RESULTS: We identified 15,906 patients with severe injury across 192 NTCs (22% were resource limited, 57% were resource intermediate, and 21% were resource rich). Patients at resource rich centers, as compared with those at resource limited centers, were less likely to be transferred (27% vs. 50%, p < 0.001). This association persisted after adjustment for confounders (odds ratio, 0.66; 95% confidence interval, 0.47-0.92). Among patients who were transferred, median emergency department length of stay (ED LOS) was 3.5 hours (interquartile range, 1.7-4.6 hours). However, ED-LOS varied significantly because resource rich centers had a greater proportion of patients experiencing prolonged ED-LOS when compared with resource limited centers (31% vs. 15%, p < 0.001). This association also persisted on multivariable analysis (odds ratio, 2.02; 95% confidence interval, 1.19-3.43). CONCLUSION: Severely injured patients who received initial care in resource rich NTCs were less likely to be transferred to a trauma center compared with resource limited NTCs. Significant delays in the transfer process were identified. However, patients transferred from resource rich centers were more likely to experience prolonged ED-LOS compared with resource limited NTCs. LEVEL OF EVIDENCE: Epidemiologic study, level II. PMID- 22922970 TI - Age should be considered in the decision making of prophylactic splenic angioembolization in nonoperative management of blunt splenic trauma: a study of 208 consecutive civilian trauma patients. AB - BACKGROUND: A strategy of prophylactic splenic angioembolization using observation failure risk (OFR) computed tomographic (CT) scan criteria has been proposed recently. The main aim of the present study was to evaluate the relevance of the criteria in terms of delayed splenic rupture in patients with blunt splenic injury. METHODS: All patients with blunt splenic injuries admitted consecutively between January 2005 and January 2010 to our institution were included. Clinical, CT scan, and angiographic data, initial management, and outcome were noted. Patients managed expectantly were classified according to OFR CT scan criteria (high OFR was defined by at least one of the following CT scan signs: blush, pseudoaneurysm, Organ Injury Scale [OIS] grade III with a large hemoperitoneum, and OIS grade IV or 5). Initial management success was especially studied. RESULTS: Among the 208 patients included, 161 (77%) were treated by observation (35 OIS grade I, 64 OIS grade II, 33 OIS grade III, 18 OIS grade IV, and 11 OIS grade V) and 129 (80%) were men, with a mean (SD) age of 36.1 (18.7) years and a mean (SD) Injury Severity Score of 20.8 (15.4). Forty-nine patients (30%) had high OFR CT scan criteria. Thirteen patients (8%) experienced observation failure. High OFR CT scan criteria (odds ratio, 11; 95% confidence interval, 2.5-47.5) and patients 50 years and older (odds ratio, 33.9; 95% confidence interval, 6.2-185.5) were independent factors related to observation failure. The positive predictive value of OFR CT scan criteria for observation failure was 18%, and the negative predictive value was 96%. The corresponding values were 67% and 90%, respectively, in patients 50 years and older and 3% and 99%, respectively, in patients younger than 50 years. CONCLUSION: OFR CT scan criteria lack specificity to predict observation failure, mainly in patients younger than 50 years. Age should be considered when identifying patients requiring prophylactic splenic angioembolization. LEVEL OF EVIDENCE: Diagnostic study, level III. PMID- 22922971 TI - Posttraumatic pulmonary pseudocyst: computed tomography findings and management in 33 patients. AB - BACKGROUND: Posttraumatic pulmonary pseudocyst (PPP) is a complication of blunt chest trauma and poorly documented. A retrospective review of PPPs observed during the past 6 years in our hospitals is presented in this report. METHODS: We retrospectively studied the serial chest computed tomographic scans and clinical data of 33 consecutive patients with PPPs. RESULTS: Fifty-three PPPs from 33 patients were found. Thirty-six PPPs were located in the subpleural pulmonary parenchyma, whereas others were located in the pulmonary parenchyma near other harder structures. Follow-up examinations demonstrated that air-filled cavities and air-fluid cavities could turn into pulmonary hematomas and eventually resolved without specific treatment. The PPPs were resolved in 11 to 82 days. The resolving time of air-fluid cavity (mean, 47.5 days) was significantly longer than the resolving time of air-filled cavity (mean, 16.3 days; p = 0.001). Three patients died of acute respiratory distress syndrome or head trauma. No patient died of PPP. Twelve patients with serious pneumothorax, hemothorax, or both were cured with surgical hemostasis and/or drainage. Eighteen patients resolved without specific treatment. CONCLUSION: Computed tomography increased the frequency of PPP diagnosis and accurately demonstrated the characteristics of the lesions. Air-filled pseudocysts resolved more quickly than those containing fluid. The outcome of PPPs can be favorable without specific treatment. PPP does not require follow-up CT scan or intervention in the absence of complications. LEVEL OF EVIDENCE: Prognostic/epidemiologic study, level V. PMID- 22922972 TI - Postoperative computed tomography after surgery for head trauma. AB - BACKGROUND: It is well known that intracranial lesions, which are already diagnosed on preoperative computed tomography, often expand after surgery, and the risk factors have been investigated. On the other hand, we have experienced cases in which new lesions, which were not detected on preoperative computed tomography, were found on postoperative computed tomography. However, little is known about the factors associated with such new postoperative lesions. Here, we investigated the predictive factors of new findings (NFs) on computed tomography early after surgery. METHODS: We conducted a retrospective registry-based review of 186 consecutive patients who underwent surgery for traumatic brain injury and investigated the prognostic factors of NFs on computed tomography early after surgery. RESULTS: Mean age was 51 years, and 67.2% were males among the 186 patients. NFs on postoperative computed tomography were observed in 29 patients (15.6%). A univariate analysis showed that Glasgow Coma Scale (GCS) score of 8 or less (p < 0.001), subdural hematoma as the primary indication for surgery (p = 0.012), midline shift (p < 0.001), absence of basal cistern (p < 0.001), and decompressive craniectomy and craniotomy as the surgical procedures (p < 0.001, p = 0.004, respectively) were significantly associated with NFs on postoperative computed tomography. A logistic regression analysis demonstrated that decompressive craniectomy as the surgical procedure (p = 0.001; odds ratio [OR], 8.1; 95% confidence interval [CI], 2.23-28.82), GCS score of 8 or less (p = 0.019; OR, 3.4; 95% CI, 1.23-9.52), and absence of basal cistern (p = 0.023; OR, 3.5; 95% CI, 1.19-10.35) were significant factors. CONCLUSION: Early postoperative computed tomography after surgery for head trauma seems to be warranted in patients presenting with the indicated predictive factors of NFs. LEVEL OF EVIDENCE: Prognostic/therapeutic study, level III. PMID- 22922973 TI - Failure rate and complications of angiography and embolization for abdominal and pelvic trauma. AB - BACKGROUND: Angiography and embolization have become the treatment of choice after abdominal trauma or pelvic injury in hemodynamically stable patients with a suspicion of internal hemorrhage (contrast extravasation, pseudo-aneurysm, or a vessel cutoff diagnosed on computed tomographic scanning). Some studies, however, report a high incidence of rebleeding (failure) or complications. The aim of this study was to evaluate the failure rate and the complications in trauma patients undergoing such procedures. METHODS: All consecutive patients (n = 97) admitted to our Level I trauma center between January 2002 and December 2008 in whom angiography with or without embolization was performed were analyzed. Complications were classified as organ specific, puncture site related, and systemic. Additional interventions, required to treat complications, were documented. RESULTS: The overall failure rate was 12%. Overall, 48 complications were documented in 28 patients. Organ-specific complications were observed in 18 patients (19%), especially abscess formation and infarction of the liver. Puncture site-related complications occurred in three patients. The incidence of contrast-induced nephropathy was 24%. Three patients developed renal failure. Nine of the 15 patients with rebleeding could be managed with reembolization or operative packing, resulting in an organ salvage rate of 93%. Most (83%) of the organ-specific complications and all of the puncture site-related complications could be managed conservatively or with percutaneous treatment. CONCLUSION: In the present study, the failure rate and incidence of organ-specific and procedure related complications were low and often could be managed with nonoperative minimally invasive interventions. Trauma patients undergoing angiography have a high chance (24%) of developing contrast-induced nephropathy and should therefore receive optimal prophylactic measures to avoid this complication. LEVEL OF EVIDENCE: Therapeutic study, level IV; prognostic/epidemiologic study, level III. PMID- 22922974 TI - Oxidative stress caused by a low concentration of hydrogen peroxide induces senescence-like changes in mouse gingival fibroblasts. AB - Periodontal tissue deteriorates under persistent oxidative stress induced by inflammatory reactions in the microflora of the oral cavity. This study aimed to evaluate the cellular properties of mouse gingival fibroblasts (MGFs) in the presence of oxidative stress. MGFs from 10-, 30- and 52-week-old mice were used to evaluate the changes in the cellular properties with aging. The study investigated the effects of oxidative stress on the cellular properties of MGFs from 10-week-old mice. The expression of p53, p21 and murine double minute 2 (Mdm2) in the MGFs in response to oxidative stress was also examined. By day 8, the number of MGFs increased in culture. However, the increase was markedly lower in MGFs derived from aged mice. Oxidative stress due to hydrogen peroxide (H2O2) induced morphological changes characterized by a round shape with enlarged nuclei and expanded cytoplasm. The cell number of MGFs was decreased subsequent to treatment with 50 uM or a higher concentration of H2O2. MGFs treated with H2O2 at 20 uM showed a similar cell growth curve as the one seen in 52-week-old mice. Phosphorylated p53 protein was increased in MGFs subsequent to treatment with 20 uM H2O2, along with an upregulated transcription of p21 and Mdm2 mRNAs. These results suggest that treatment with a lower concentration of H2O2 in MGFs induces cell cycle arrest, resulting in stress-induced premature senescence, possibly correlated with the development of periodontal diseases. PMID- 22922975 TI - Strategies for the profiling, characterisation and detailed structural analysis of N-linked oligosaccharides. AB - Many post-translational modifications, including glycosylation, are pivotal for the structural integrity, location and functional activity of glycoproteins. Sub populations of proteins that are relocated or functionally changed by such modifications can change resting proteins into active ones, mediating specific effector functions, as in the case of monoclonal antibodies. To ensure safe and efficacious drugs it is essential to employ appropriate robust, quantitative analytical strategies that can (i) perform detailed glycan structural analysis, (ii) characterise specific subsets of glycans to assess known critical features of therapeutic activities (iii) rapidly profile glycan pools for at-line monitoring or high level batch to batch screening. Here we focus on these aspects of glycan analysis, showing how state-of-the-art technologies are required at all stages during the production of recombinant glycotherapeutics. These data can provide insights into processing pathways and suggest markers for intervention at critical control points in bioprocessing and also critical decision points in disease and drug monitoring in patients. Importantly, these tools are now enabling the first glycome/genome studies in large populations, allowing the integration of glycomics into other 'omics platforms in a systems biology context. PMID- 22922976 TI - Synthesis and Structure-Activity Relationships of Pyridoxal-6-arylazo-5' phosphate and Phosphonate Derivatives as P2 Receptor Antagonists. AB - Novel analogs of the P2 receptor antagonist pyridoxal-5'-phosphate-6-phenylazo 2',4'-disulfonate (PPADS) were synthesized. Modifications were made through functional group substitution on the sulfophenyl ring and at the phosphate moiety through the inclusion of phosphonates, demonstrating that a phosphate linkage is not required for P2 receptor antagonism. Substituted 6-phenylazo and 6 naphthylazo derivatives were also evaluated. Among the 6-phenylazo derivatives, 5'-methyl, ethyl, propyl, vinyl, and allyl phosphonates were included. The compounds were tested as antagonists at turkey erythrocyte and guinea-pig taenia coli P2Y(1) receptors, in guinea-pig vas deferens and bladder P2X(1) receptors, and in ion flux experiments by using recombinant rat P2X(2) receptors expressed in Xenopus oocytes. Competitive binding assay at human P2X(1) receptors in differentiated HL-60 cell membranes was carried out by using [(35)S]ATP-gamma-S. A 2'-chloro-5'-sulfo analog of PPADS (C(14)H(12)O(9)N(3)ClPSNa), a vinyl phosphonate derivative (C(15)H(12)O(11)N(3)PS(2)Na(3)), and a naphthylazo derivative (C(18)H(14)O(12)N(3)PS(2)Na(2)), were particularly potent in binding to human P2X(1) receptors. The potencies of phosphate derivatives at P2Y(1) receptors were generally similar to PPADS itself, except for the p carboxyphenylazo phosphate derivative C(15)H(13)O(8)N(3)PNa and its m-chloro analog C(15)H(12)O(8)N(3)ClPNa, which were selective for P2X vs. P2Y(1) receptors. C(15)H(12)O(8)N(3)ClPNa was very potent at rat P2X(2) receptors with an IC(50) value of 0.82 MUM. Among the phosphonate derivatives, [4-formyl-3 hydroxy-2-methyl-6-(2-chloro-5-sulfonylphenylazo)-pyrid-5-yl]methylphosphonic acid (C(14)H(12)-O(8)N(3)ClPSNa) showed high potency at P2Y(1) receptors with an IC(50) of 7.23 MUM. The corresponding 2,5-disulfonylphenyl derivative was nearly inactive at turkey erythrocyte P2Y(1) receptors, whereas at recombinant P2X(2) receptors had an IC(50) value of 1.1 MUM. An ethyl phosphonate derivative (C(15)H(15)O(11)N(3)PS(2)Na(3)), whereas inactive at turkey erythrocyte P2Y(1) receptors, was particularly potent at recombinant P2X(2) receptors. PMID- 22922977 TI - Cauda equina tumor surgery: how I do it. AB - BACKGROUND: Tumors of the cauda equina usually require surgery due to their impingement on neighboring nerve roots, often resulting in pain and neurological deficits. METHOD: The Authors first give a brief introduction on cauda equina tumors, followed by a description of the surgical anatomy, and then develop the microsurgical technique. In particular, tricks to avoid complications are presented, underlining the importance of intraoperative neuromonitoring. CONCLUSION: Both microsurgical technique and neuromonitoring are important in cauda equina tumor surgery, the goal of which is to achieve complete resection while at the same time preserving neurological function. PMID- 22922978 TI - Allergy to implants in lumbar screw fixation mimics postsurgical wound infection. PMID- 22922979 TI - Fully endoscopic endonasal anterior C1 arch reconstruction as a function preserving surgical option for unstable atlas fractures. PMID- 22922980 TI - Quality of life in nonfunctioning pituitary macroadenoma patients before and after surgical treatment. AB - BACKGROUND: Nonfunctioning pituitary macroadenoma (NFMA) is a benign neoplasm that causes visual function disturbances and headaches and can be treated by transsphenoidal surgery (TSS). It is unclear how quality of life (QOL) changes with surgery and which QOL factors are affected by treatment. METHODS: The aim is to assess the temporal transition of QOL in NFMA patients undergoing TSS and to identify influential factors. The QOL of NFMA patients who underwent endoscopic TSS was investigated with the short-form 36 (SF-36) health survey questionnaire, general health questionnaire 30 (GHQ30), and numerical rating scale (NRS) of pain at the following three time points: immediately before, 1 month after, and 6 months after surgery. RESULTS: Twenty-four of 30 patients had visual deterioration. The SF-36 baseline value of visual function-impaired NFMA patients was lower than that of the normal population. SF-36 results showed that physical summary scores decreased at 1 month after the operation, but recovered up to the normal population level by 6 months. Mental summary scores generally increased at 1 month after surgery and remained stable until 6 months later. The GHQ30 results were similar to the SF-36 mental summary scores. The strongest factor related to the QOL was visual function. The amount of pain and the necessity of hormonal replacement were also influencing factors. CONCLUSIONS: The QOL of NFMA patients is affected both physically and mentally by surgical treatment and symptoms. This QOL assessment is important for planning treatment strategies. PMID- 22922981 TI - Transphenoidal surgery without steroid replacement in patients with morning serum cortisol below 9 MUg/dl (250 Nmol/l). AB - BACKGROUND: Adrenal insufficiency is a feared complication in patients undergoing transphenoidal surgery (TSS). Using the insulin tolerance test (ITT) for the preoperative assessment of hypothalamic-pituitary-adrenal (HPA) status is less than ideal, and the morning serum cortisol (MSC) is often used as a proxy for ITT. However, neither the ITT nor the MSC level has been validated to indicate HPA sufficiency compared to a physiological gold standard such as patients' ability to withstand transphenoidal surgery. OBJECTIVE: To evaluate the intraoperative and postoperative course of nine patients with non-ACTH-secreting pituitary adenomas who did not receive intraoperative cortisol replacement despite having a preoperative MSC below 9 MUg/dl (250 nmol/l) and to compare this with a set of patients with a preoperative MSC greater than 14.5 MUg/dl (400 nmol/l) and another set of patients with MSC below 9 MUg/dl (250 nmol/l) who received intraoperative cortisol administration. METHODS: Preoperative and day 1 and day 2 postoperative MSC, intraoperative anesthetic record, vital signs, fluid balance, medications, and complications were recorded. RESULTS: None of the patients experienced the full syndrome of adrenal insufficiency. One patient with a preoperative MSC <9 MUg/dl (250 mol/l) had isolated postoperative fatigue and required cortisol replacement. No patient suffered any life-threatening complications. There were no differences among the three groups in their intraoperative or postoperative courses when compared for intraoperative hypotension, acute blood pressure drop, and administration of vasopressors. CONCLUSION: This study suggests that TSS can be performed safely in patients with preoperative MSC less than 9 MUg/dl (250 nmol/l) in closely monitored settings without intraoperative cortisol administration. Further studies are warranted. PMID- 22922982 TI - Radiosensitizing effects of arsenic trioxide on MCF-7 human breast cancer cells exposed to 89 strontium chloride. AB - The aim of this study was to investigate the radiosensitizing effects of arsenic trioxide (As2O3) on MCF-7 human breast cancer cells irradiated with 89 strontium chloride (89SrCl2). The 50% inhibitory concentration (IC50) was calculated from results of an MTT assay. The concentration of As2O3 less than 20% IC50 was selected for subsequent experiments. Cells were treated with As2O3 and 89SrCl2. Morphological changes of cells were observed under an inverted microscope. The radiosensitivity enhancing ratio (SER) was computed based on a clone formation assay. Cell cycle distribution and apoptosis were measured by flow cytometry (FCM). Expression of Bcl-2 and Bax at both the mRNA and protein levels was assessed by RT-PCR and western blotting. The IC50 of As2O3 at 24 h was 11.7 uM. Doses of As2O3 (1 and 2 uM) were used in combination treatments and SER values were 1.25 and 1.79, respectively. As2O3 significantly suppressed cell growth, caused G2/M arrest, enhanced cell death and apoptosis induced by 89SrCl2 and decreased expression of the Bcl-2 gene. Since expression of Bax was unchanged following treatment, As2O3 effectively reduced the Bcl-2/Bax ratio. As2O3 (1-2 uM) enhances the cytotoxic effects of 89SrCl2 on the MCF-7 human breast cancer cell line by inducing G2 phase delay and promoting apoptosis through the reduction of the Bcl-2/Bax ratio. PMID- 22922983 TI - Disaster hypertension: experience from the great East Japan earthquake of 2011. AB - After a major disaster, such as the East Japan Earthquake with ensuing tsunami and nuclear accident in March 2011, there is typically a spike in cardiovascular disease onset due to increased blood pressure and hypercoagulability. The risk of cardiovascular disease after an earthquake can be reduced by understanding the characteristics of these risks and taking appropriate preventive and remedial measures. During the East Japan Earthquake disaster, Disaster Cardiovascular Prevention (DCAP) Risk Scores (0-6 points; goal <=4 points)/Prevention Scores (0 8 points; goal >= 6 points) were used to identify patients at risk at shelters and then safeguard their living conditions, chiefly by monitoring blood pressure and offering appropriate lifestyle guidance as well as treatment. By quickly reducing elevated blood pressures and then assuring stable control we could prevent the mortality and morbidity associated with disaster hypertension. This paper reviews the disaster-related mechanisms that induce cardiovascular disease and introduces the DCAP system and four typical cases in which it intervened. PMID- 22922984 TI - Association between polymorphisms of the E-selectin gene, hepatitis B virus DNA copies and preS1 antigen in patients with chronic hepatitis B infection. AB - The aim of this study was to investigate the relationship between E-selectin +G98T, +A561C polymorphisms and the levels of hepatitis B virus (HBV) DNA and preS1 antigen (preS1Ag) in patients with chronic hepatitis B (CHB) infection. Polymorphisms of the E-selectin gene in 150 CHB patients and 150 healthy controls of two different nationalities were detected using polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP). Real-time quantitative PCR was used to detect the levels of HBV DNA. preS1Ag and five items of hepatitis B were detected by enzyme-linked immunosorbent assay. Two genotypes, GG (94%, 96%) and GT (6%, 4%) of the E-selectin +G98T polymorphism, and AA (78.67%, 80.67%) and AC (21.33%, 19.33%) of the +A561C polymorphism, were found in these patients. There were also significant differences in the two nationalities in the genotypic frequencies in +A561C polymorphisms between patients and healthy subjects (chi2=5.489, chi2=5.653; P<0.05). In the patients studied, the relative risk of suffering from CHB in genotype AC was 2.122 and 2.313-fold higher for the two nationalities, respectively, than that of the AA genotype (OR=2.122, 95% CI 1.121 4.019; OR=2.313, 95% CI 1.002-5.360). There was also significant over representation in the C allele frequency between the two groups (chi2=5.000, chi2=5.30; P<0.05), and the levels of HBV DNA and preS1Ag in the AC genotype patients were higher than those in the AA genotype (P<0.01 and P<0.05). E selectin +A561C and +G98T polymorphisms were present in the populations studied. Therefore, there is a correlation between E-selectin +A561C polymorphisms and CHB. Allele C may be one of the predisposing factors, and mutation of this locus may impact the virus copy number. PMID- 22922985 TI - Prevalence of restless legs syndrome in a Georgian primary healthcare setting: a pilot study. AB - BACKGROUND: The prevalence of restless legs syndrome (RLS) is approximately 10% in Western Europe, but unknown in Georgia. This pilot study aimed to assess RLS prevalence in a focused Georgian population. METHODS: An RLS epidemiological questionnaire [Allen et al.: Sleep Med 2003;4:101-119] was filled out by patients in five primary healthcare centers in two Georgian cities between March and September 2006. Additionally, questions related to RLS symptom onset, family history, treatment, sleep disturbance and history of iron deficiency were included. RLS diagnosis was based on an expert interview and an epidemiological questionnaire for RLS. RESULTS: The total number of respondents was 115 (75% women/25% men); mean age was 47 years (range 18-85). Thirteen subjects (11.3%) reported RLS symptoms (9 women/4 men); mean age was 52 years (range 32-83). Eleven (85%) had a positive family history of RLS. All subjects had sleep disturbance and none had a history of known iron deficiency. CONCLUSION: The prevalence of RLS in a focused Georgian population is in line with other RLS epidemiologic studies performed in clinical settings. However, the prevalence rate of RLS in a studied group might not be representative for the general Georgian population. Further population-based epidemiological studies are required. PMID- 22922986 TI - Flow control in our vessels: vascular valves make sure there is no way back. AB - The efficient transport of blood and lymph relies on competent intraluminal valves that ensure unidirectional fluid flow through the vessels. In the lymphatic vessels, lack of luminal valves causes reflux of lymph and can lead to lymphedema, while dysfunction of venous valves is associated with venous hypertension, varicose veins, and thrombosis that can lead to edema and ulcerations. Despite their clinical importance, the mechanisms that regulate valve formation are poorly understood and have only recently begun to be characterized. Here, we discuss new findings regarding the development of venous and lymphatic valves that indicate the involvement of common molecular mechanisms in regulating valve formation in different vascular beds. PMID- 22922988 TI - Transurethral cystolithotripsy with a novel special endoscope. AB - To evaluate the safety and efficiency of the Aihua (AH)-1 stone removal system (SRS) to treat bladder stones. Thirty five patients with of bladder stones >2 cm and with benign prostatic hyperplasia were treated by transurethral cystolithotripsy with the SRS and TURP. The results in these patients were compared with 14 patients treated with current devices. In the SRS group, 26 patients had a single stone. Average stone size was 3.34 +/- 1.03 cm, total operating time was 55.12 +/- 19.95 min, and stone removal time was 23.30 +/- 17.08 min. In the control group, 12 patients had a single stone. The average stone size was 2.46 +/- 0.45 cm (larger stone size in SRS group, P < 0.05), total operating time was 79.85 +/- 24.63 min (shorter operating time in SRS group, P < 0.05) and stone removal time was 43.28 +/- 24.18 min the control group (shorter removal time in SRS group, P < 0.05). Mean stone size was 2.37 +/- 1.18 cm and mean time to remove one stone was 12.57 +/- 12.99 min in the SRS group. Mean stone size was 2.40 +/- 0.48 cm (no significant difference between groups, P > 0.05) and mean time to remove one stone was 33.23 +/- 25.26 min in the control group (shorter time in the SRA group, P < 0.001). No significant complication was found in the SRS group. This study suggests that multiple functions of SRS can be expected in transurethral cystolithotripsy. It can be used to fix stones during lithotripsy, and automatically collect stones and extract more stones through the sheath at one time during lithoextraction, which can reduce surgical time and damage to the bladder and urethra. This surgical procedure appears to be safe and efficient, and operating indications for transurethral cystolithotripsy could be expanded with this surgical procedure. PMID- 22922987 TI - MicroRNA-mediated gene regulations in human sarcomas. AB - Sarcomas are a heterogeneous group of tumors with mesenchymal origins. Sarcomas are broadly classified into bone and soft tissue sarcomas with over 50 subtypes. Despite recent advances in sarcoma classification and treatment strategies, the prognosis of some aggressive sarcoma types remains poor due to treatment infectiveness and development of drug resistance. A better understanding of sarcoma pathobiology will significantly increase the potential for the development of therapeutics and treatment strategies. Recently, expressions of microRNAs (miRNA), a class of small non-coding RNAs, have been found to be deregulated in many sarcomas and are implicated in sarcoma pathobiology. Comprehensive understanding of gene regulatory networks mediated by miRNAs in each sarcoma type and the conservation of some shared/conserved miRNA-gene networks could be potentially investigated in the prevention, diagnosis, prognosis and as multi-modal treatment options in these cancers. In this review, we will discuss the current knowledge of miRNA-gene regulatory networks in various sarcoma types and give a perspective of the complex multilayer miRNA mediated gene regulation in sarcomas. PMID- 22922989 TI - Epidermal growth factor induces bladder cancer cell proliferation through activation of the androgen receptor. AB - Androgen receptor (AR) signals have been suggested to contribute to bladder tumorigenesis and cancer progression. Activation of epidermal growth factor receptor (EGFR) also leads to stimulation of bladder tumor growth. However, crosstalk between AR and EGFR pathways in bladder cancer remains uncharacterized. We have recently shown that androgens activate the EGFR pathway in bladder cancer cells. The purpose of this study was to investigate the effects of EGF on AR activity in bladder cancer. EGF increased AR transcriptional activity by 1.2-, 1.9- and 2.0-fold in UMUC3, 5637-AR and J82-AR cell lines, respectively, over mock treatment and a specific EGFR inhibitor, PD168393, antagonized the EGF effect. Combined treatment of EGF and dihydrotestosterone (DHT) further induced AR transactivation while an AR antagonist, hydroxyflutamide (HF), abolished the effect of not only DHT but also EGF. In growth assays, EGF alone/DHT alone/EGF+DHT increased cell numbers by 16/12/19%, 6/14/18% and 30/12/38% in UMUC3-control-shRNA, 5637-AR and J82-AR, respectively, whereas the effects of EGF were marginal or less significant in UMUC3-AR-shRNA (8%) or AR-negative 5637-V (<1%) and J82-V (17%) cells. HF treatment at least partially counteracted the EGF effect on the growth of AR-positive cells. Western blotting demonstrated that EGF, especially in the presence of DHT, upregulated the expression of the p160 coactivator TIF2 and HF again blocked this stimulation. Co-immunoprecipitation revealed the association between AR and estrogen receptor (ER)-beta or Src in UMUC3 cells and stronger associations with EGF treatment, implying the involvement of the AR/ER/Src complex in EGF-increased AR transactivation and cell growth. Current results, thus, suggest that EGF promotes bladder cancer cell proliferation via modulation of AR signals. Taken together with our previous findings, crosstalk between EGFR and AR pathways can play an important role in the progression of bladder cancer. PMID- 22922991 TI - Active route learning in virtual environments: disentangling movement control from intention, instruction specificity, and navigation control. AB - Active navigation research examines how physiological and psychological involvement in navigation benefits spatial learning. However, existing conceptualizations of active navigation comprise separable, distinct factors. This research disentangles the contributions of movement control (i.e., self contained vs. observed movement) as a central factor from learning intention (Experiment 1), instruction specificity and instruction control (Experiment 2), as well as navigation control (Experiment 3) to spatial learning in virtual environments. We tested the effects of these factors on landmark recognition (landmark knowledge), tour-integration and route navigation (route knowledge). Our findings suggest that movement control leads to robust advantages in landmark knowledge as compared to observed movement. Advantages in route knowledge do not depend on learning intention, but on the need to elaborate spatial information. Whenever the necessary level of elaboration is assured for observed movement, too, the development of route knowledge is not inferior to that for self contained movement. PMID- 22922990 TI - Biotransformation of benzonitrile herbicides via the nitrile hydratase-amidase pathway in rhodococci. AB - The aim of this work was to determine the ability of rhodococci to transform 3,5 dichloro-4-hydroxybenzonitrile (chloroxynil), 3,5-dibromo-4-hydroxybenzonitrile (bromoxynil), 3,5-diiodo-4-hydroxybenzonitrile (ioxynil) and 2,6 dichlorobenzonitrile (dichlobenil); to identify the products and determine their acute toxicities. Rhodococcus erythropolis A4 and Rhodococcus rhodochrous PA-34 converted benzonitrile herbicides into amides, but only the former strain was able to hydrolyze 2,6-dichlorobenzamide into 2,6-dichlorobenzoic acid, and produced also more of the carboxylic acids from the other herbicides compared to strain PA-34. Transformation of nitriles into amides decreased acute toxicities for chloroxynil and dichlobenil, but increased them for bromoxynil and ioxynil. The amides inhibited root growth in Lactuca sativa less than the nitriles but more than the acids. The conversion of the nitrile group may be the first step in the mineralization of benzonitrile herbicides but cannot be itself considered to be a detoxification. PMID- 22922992 TI - Sage weed (Salvia plebeia) extract antagonizes foam cell formation and promotes cholesterol efflux in murine macrophages. AB - Lipid-laden peripheral tissue cells release cholesterol to an extracellular acceptor such as high-density lipoprotein (HDL). Foam cells are formed at the first stage of atherosclerosis development. This study investigated whether sage weed (Salvia plebeia) extract (SWE) influences cholesterol handling of J774A1 murine macrophages. A murine macrophage cell line, J774A1, was used in this study. Oxidized low-density lipoproteins (LDL) treatment was used for foam cell formation, which was confirmed using Oil red O staining. The oxidized LDL uptake and cholesterol efflux from lipid-laden foam cell-associated proteins were detected by western blot analysis. Also, transcriptional levels of these associated genes were examined using reverse transcription-PCR. Also, cholesterol efflux was measured using NBD-cholesterol efflux assay. Non-toxic SWE at >=10 ug/ml attenuated scavenger receptor (SR)-B1 expression of macrophages induced by oxidized LDL for 6 h, which was achieved at its transcriptional levels. Consistently, SWE suppressed oxidized LDL-stimulated cellular lipid accumulation and foam cell formation due to downregulated SR-B1. SWE upregulated the protein expression and mRNA levels of ATP-binding cassette transporter A1 (ABCA1) and ATP binding cassette transporter G1 (ABCG1) in lipid-laden foam cells, both responsible for cholesterol efflux. In addition, SWE promoted apolipoprotein E (apoE) secretion from oxidized LDL-induced foam cells. Cholesterol efflux was enhanced by >=10 ug/ml SWE most likely through the induction of ABCA1 and ABCG1 and the secretion of apoE. Although 10 uM homoplantaginin, a compound mainly present in sage weeds, did not influence cellular expression of ABCA1 and ABCG1, it suppressed oxidized LDL-enhanced SR-B1 induction and foam cell formation. These results demonstrate that SWE antagonized oxidized LDL uptake and promoted cholesterol efflux in lipid-laden macrophages. Therefore, SWE may serve as a protective therapeutic agent against the development of atherosclerosis. PMID- 22922993 TI - Artemisinin suppresses sympathetic hyperinnervation following myocardial infarction via anti-inflammatory effects. AB - Inflammation plays an important role in sympathetic remodeling after myocardial infarction (MI), and the inhibition of inflammation has therapeutic benefits that could alleviate the progression of sympathetic remodeling. Recent studies have indicated that the antimalarial agent artemisinin has the ability to inhibit inflammation. In this study, the inhibitory effects of artemisinin on the production of proinflammatory mediators and the number of macrophages were investigated 4 weeks after MI. Our results show that artemisinin significantly inhibited IL-1beta and TNF-alpha protein expression and the infiltration of macrophages. Artemisinin significantly decreased the protein expression of NGF, GAP43, and TH compared with the control group, which was related to sympathetic nerve remodeling. Interestingly, a clear positive correlation was observed between the expression of NGF and GAP43 in our study, and a similar correlation was revealed between NGF and TH. In addition, the densities of both GAP-43- and TH-immunoreactive nerves in the peri-infarct zone were significantly attenuated by artemisinin treatment. Our results suggest that artemisinin is able to inhibit sympathetic remodeling after MI, possibly through an anti-inflammatory effect. The data provide direct evidence of the potential application of artemisinin for the treatment of sympathetic remodeling after MI. PMID- 22922994 TI - Comparative study of three angiotensin II type 1 receptor antagonists in preventing liver fibrosis in diabetic rats: stereology, histopathology, and electron microscopy. AB - The presence of liver disease in patients with progressively worsening insulin resistance may not be recognized until patients develop manifestations of the metabolic syndrome such as diabetes, hypertension, hyperlipidemia, and vascular disease. It was aimed to investigate whether three angiotensin II type 1 receptor antagonists (ARBs) (olmesartan, losartan, and valsartan) had preventive effect against hepatic fibrosis and this was a common characteristic among ARBs. In current study, 25 adult male rats were used and divided into five groups: the non diabetic healthy group, alloxan induced diabetic (AID) control group, AID losartan group, AID valsartan group and AID olmesartan group. According to numerical density of hepatocytes, significant difference was found between the non-diabetic healthy group and diabetic control group. All treatments groups were significant when compared to diabetic control group. In diabetic control group it was examined swelling, irregular cristae arrangement in some of mitochondria. It was also determined mitochondria membrane degeneration in some areas of section profiles. In diabetic rats treated with losartan group, there were necrotic hepatocytes. In diabetic rats treated with valsartan group, predominantly, findings were similar to losartan group. In diabetic rats treated with olmesertan group, plates of hepatocytes were quite regular. There were hardly necrotic cells. Not only other organelles such as RER, SER and lysosom but also mitochondrial structures had normal appearance. In the diabetic control group electron microscopy revealed edema in both the cytoplasm and perinuclear area and the nuclear membranes appeared damaged. In conclusion, it was established that the most protective ARB the liver in diabetic rats was olmesartan, followed by losartan. PMID- 22922996 TI - Interleukin-17, produced by lymphocytes, promotes tumor growth and angiogenesis in a mouse model of breast cancer. AB - Previous studies have suggested that interleukin-17 (IL-17), an inflammatory cytokine expressed predominantly by Th17 cells, is highly expressed in tumor tissue and may help tumors to evade immune surveillance. In this study, the significance of IL-17 expression in the tumors of murine models of breast cancer was explored. BALB/c mice were injected with MA782/5S28102 or 4T1 breast cancer cell lines to establish breast tumors. The expression of IL-17 in tumor tissue was detected by western blotting 1 and 4 weeks later, which revealed that it increased with tumor progression (P<0.05). Additionally, tumor cells and tumor infiltrating lymphocytes were isolated from tumor tissues and cultured for 5 days with stimulation by phorbol-12-myristate-13-acetate (PMA), anti-CD3 antibody and anti-CD28 antibody. Culture media from stimulated tumor cells or tumor infiltrating lymphocytes were harvested and their concentrations of IL-17 were tested by ELISA. Tumor cells secreted low levels of IL-17 into the media; however, lymphocytes from tumor tissues secreted high levels of IL-17, with 4T1 tumors secreting higher levels of IL-17 than MA782 tumors (P<0.05). To evaluate the effect of IL-17 on the proliferation of tumor cells, 4T1 cells were cultured in the presence or absence of recombinant IL-17 and cell numbers were counted on day 5 of culturing. Ectopic IL-17 did not promote the proliferation of tumor cells in vitro. To further understand the effect of IL-17 expression within tumors, 4T1 tumor-bearing mice were injected with recombinant IL-17 or saline via the tail vein. Tumor size was measured up to 21 days following the initial infusion of IL-17. IL-17 infusion resulted in an increased tumor volume and microvascular density (as measured by the immunohistochemical detection of CD34 expression in microvessels; P<0.05). Therefore, IL-17 expression within tumor tissues appears to originate from tumor-infiltrating lymphocytes and is likely to promote tumor growth by enhancing angiogenesis. PMID- 22922995 TI - STAT3 signal transduction through interleukin-22 in oral squamous cell carcinoma. AB - Interleukin (IL)-22 is a member of the IL-10 family. Its main targets are epithelial cells, not immune cells. We examined IL-22 signal transduction in oral squamous cell carcinoma (OSCC) cells. Immunohistochemical staining revealed that IL-22R was expressed more highly in OSCC compared to normal regions. An IL-22R signal was also observed in metastatic OSCC cells in the lymph node. RT-PCR showed that the human OSCC cell lines MISK81-5, HSC-3, HSC-4, SAS and SQUU-B expressed IL-22 receptor chains. Immunoblotting showed that IL-22 induced a transient tyrosine phosphorylation of STAT3 (pY705-STAT3) in MISK81-5 cells. The change in the serine phosphorylation of STAT3 was subtle during the examination periods. Simultaneously, pY705-STAT3 activation in HSC-3 cells was undetectable after IL-22 stimulation. Immunocytochemistry demonstrated that IL-22 induced the translocation of phosphorylated STAT3 into the nucleus of MISK81-5 cells. IL-22 temporarily upregulated the expression of anti-apoptotic and mitogenic genes such as Bcl-x, survivin and c-Myc, as well as SOCS3. IL-22 transiently activated ERK1/2 and induced a delayed phosphorylation of p38 MAP kinase, but negligibly involved the activation of NF-kappaB in MISK81-5 cells. MISK81-5 and SQUU-B cells treated with IL-22 showed mild cellular proliferation. MISK81-5, HSC-4 and SAS cells treated with IL-22 downregulated the keratinocyte differentiation-related genes compared with unstimulated cells. Conversely, STAT3 suppression by STAT3 siRNA strongly disrupted the downregulation of these genes by IL-22, but it did not significantly affect the activation of ERK1/2 by IL-22. The OSCC cells used in this study upregulated the expression of SERPINB3/4 (SCCA1/2), well-known SCC markers, following treatment with IL-22. These results indicate that IL-22 differentially activates the STAT3 signaling system depending on the type of OSCC. IL-22 may therefore play a role in tumor growth, cell differentiation and progression through STAT3-dependent and -independent pathways. PMID- 22922997 TI - Hand Hygiene: State-of-the-Art Review With Emphasis on New Technologies and Mechanisms of Surveillance. AB - Hand hygiene (HH) is an important measure in infection prevention to decrease transmission of microbial pathogens; however, HH compliance by health-care workers (HCWs) remains suboptimal. One of the principal recommendations of current guidelines is that waterless, alcohol-based hand rubs are the preferred method for HH in most situations, due to the superior efficacy of these agents in rapidly reducing bacterial counts on hands and their ease of use. Improving HH compliance is a good quality indicator for hospital patient safety programs. Observers can follow HCWs to perform direct HH observations; however, HCWs may be prompted to clean their hands when observers are nearby, which does not represent real-world conditions. Moreover, having observers walk into patient rooms violates patient privacy and is time consuming. HH strategies using indirect metrics for surveillance (e.g., measuring the volume of HH products consumed) and the use of new technologies (e.g., electronic dispenser counters, radiofrequency, alcohol sensors, and video recording) will also be discussed. PMID- 22922999 TI - [Economization of long-term care in Great Britain, Sweden and Germany]. AB - This article deals with long-term care policies in three different welfare and long-term care regimes. Despite of divergent regime assignments-Great Britain: liberal welfare state und means-tested long-term care regime, Sweden: social democratic welfare state and social services long-term care regime, and Germany: conservative-corporatist welfare state and subsidiarity long-term care regime-all three countries restructured their long-term care policies during the 1990s in the context of neoliberal economization and marketization. All countries introduced efficiency-oriented measures, foster competition between different social service providers, and increase choices of people in need of elderly care. By analyzing the regulation of long-term care policies since the National Health Service and Community Care Act (1990) in Great Britain, the Adel reform (1992) in Sweden, and the introduction of the long-term care insurance (1994) in Germany, it can be shown that specific, national pathways, which due to the divergence of regimes and the specific long-term care problems within a country, have evolved. PMID- 22922998 TI - What is measured with verbal fluency tests in Parkinson's disease patients at different stages of the disease? AB - Verbal fluency tests (VFT) are often used to assess executive functioning in Parkinson's disease (PD). Various cognitive functions may, however, impair performance on VFT. Furthermore, since PD is a progressive neurodegenerative disease, it is also not clear whether deficits on VFT reflect impairments in the same cognitive functions throughout the different disease stages. This study will investigate what is measured with VFT in PD, in particular at different disease stages. Eighty-eight PD patients and 65 healthy participants, matched for age, gender, and education, were included. All were assessed with semantic and phonemic VFT and tests assessing executive functions, memory, and psychomotor speed. Mild and moderate PD patients did not differ in the number of words generated on both VFT. However, mild and moderate PD patients differed significantly with regard to the size of the largest cluster and the number of intra-dimensional shifts on phonemic VFT. Furthermore, at the mild disease stages, psychomotor speed predicted the performance on both VFT; whereas at the moderate stages of the disease, cognitive flexibility and psychomotor speed predicted the performance on both VFT. In conclusion, different cognitive functions underlie the performances of PD patients at different stages of the disease on semantic and phonemic VFT. Impairments in VFT, therefore, do not necessarily represent a specific deficit of executive functioning in patients with PD but should rather be interpreted in the context of disease severity and dysfunctions in other domains of cognition. PMID- 22923000 TI - Could spindle cell lung carcinoma be considered and treated as sarcoma, according to its clinical course, morphology, immunophenotype and genetic finding? AB - The actual nature of spindle cell carcinoma has been debated extensively because of its rarity. It carries a poor prognosis, even when early-stage disease is diagnosed and resected. In view of the rarity and the significance of the histological diagnosis, we report a patient with rapidly progressing spindle cell lung carcinoma with soft tissue metastasis. Diagnosis was confirmed by immunohistochemistry finding. Analysis of the TP53 gene mutations by polymerase chain reaction and DNA sequencing revealed insertion of single thymine resulting in frameshift mutation in the exon 8. Prognosis of spindle cell lung carcinoma might be determined by the sarcoma component of the tumor and, based on that, we wonder if this type of lung carcinoma could be followed-up and treated by strategies for soft tissue sarcomas, because of its rapid, sarcomatous type of growth, beside the properly lung carcinoma oncological treatment. PMID- 22923004 TI - [Not Available]. PMID- 22923003 TI - Immunomodulatory and anti-inflammatory effect of p-coumaric acid, a common dietary polyphenol on experimental inflammation in rats. AB - In this study, p-coumaric acid was evaluated for its immunomodulatory and anti inflammatory properties in vivo. The immunomodulatory effect of p-coumaric acid (100 mg/kg body weight) was assessed by evaluating its effect on cell-mediated immune responses (delayed type hypersensitivity reaction), serum immunoglobulin levels, and macrophage phagocytic index in rats. The anti-inflammatory effects of p-coumaric acid (100 mg/kg body weight) were investigated by examining its effect on expression of tumor necrosis factor (TNF-alpha) in synovial tissue by immunofluorescence confocal microscopy and circulating immune complexes in serum of adjuvant-induced arthritic rats. The increased cell-mediated immune responses and macrophage phagocytic index observed in control rats were significantly reduced (p < 0.05) upon treatment with p-coumaric acid implying its immunosuppressive property, whereas serum immunoglobulin levels were found to be increased in p-coumaric acid treated control rats. p-coumaric acid also showed significant (p < 0.05) anti-inflammatory effects in adjuvant-induced arthritic rats by effecting a decrease in the expression of inflammatory mediator TNF-alpha and circulating immune complexes. Indomethacin was used as a reference drug for anti-inflammatory studies. Thus, our results show that p-coumaric acid could be considered a potential immunosuppressive agent in treating autoimmune inflammatory diseases like rheumatoid arthritis. PMID- 22923002 TI - Adenosine A2A receptor and TNF-alpha regulate the circadian machinery of the human monocytic THP-1 cells. AB - Morning stiffness and increased symptoms of inflammatory arthritis are among the most common manifestations of rheumatoid arthritis (RA). Tumor necrosis alpha (TNF-alpha), an important mediator of inflammation in RA, regulates the circadian expression of clock proteins, and adenosine A(2A) receptors (A(2A)R) mediate many of the anti-inflammatory and antirheumatic actions of methotrexate, the cornerstone drug in the treatment of RA. We found that A(2A)R activation and TNF alpha activated the clock core loop of the human monocytic THP-1 cell line. We further observed that interleukin (IL)-10, but not IL-12, mRNA expression fluctuates in a circadian fashion and that TNF-alpha and A(2A)R stimulation combined increased IL-10 expression. Interestingly, TNF-alpha, but not CGS21680, dramatically inhibited IL-12 mRNA expression. The demonstration that A(2A)R and TNF-alpha regulate the intrinsic circadian clock in immune cells provides an explanation for both the pathologic changes in circadian rhythms in RA and for the adverse circadian effects of methotrexate, such as fatigue. PMID- 22923001 TI - Strategies for the treatment of restless legs syndrome. AB - Restless legs syndrome (RLS) is a common neurological disorder of unknown etiology that is managed by therapy directed at relieving its symptoms. Treatment of patients with milder symptoms that occur intermittently may be treated with nonpharmacological therapy but when not successful, drug therapy should be chosen based on the timing of the symptoms and the needs of the patient. Patients with moderate to severe RLS typically require daily medication to control their symptoms. Although the dopamine agonists, ropinirole and pramipexole have been the drugs of choice for patients with moderate to severe RLS, drug emergent problems like augmentation may limit their use for long term therapy. Keeping the dopamine agonist dose as low as possible, using longer acting dopamine agonists such as the rotigotine patch and maintaining a high serum ferritin level may help prevent the development of augmentation. The alpha2delta anticonvulsants may now also be considered as drugs of choice for moderate to severe RLS patients. Opioids should be considered for RLS patients, especially for those who have failed other therapies since they are very effective for severe cases. When monitored appropriately, they can be very safe and durable for long term therapy. They should also be strongly considered for treating patients with augmentation as they are very effective for relieving the worsening symptoms that occur when decreasing or eliminating dopamine agonists. PMID- 22923005 TI - Serious aortic complications in a patient with Turner syndrome. AB - An asymptomatic young woman was discovered to have life-threatening aneurysms and dissection of the thoracic aorta during routine evaluation in a Turner syndrome (TS) study. The presence of a heart murmur and hypertension had led to diagnosis and surgical repair of an atrial septal defect at age 5 and of aortic coarctation at age 12. The diagnosis of TS was made at 16 years of age due to short stature and delayed pubertal development. She was treated with growth hormone from age 16 to 18 and with atenolol, thyroid hormone, and estrogen. She discontinued her medications and was lost to medical follow-up at age 20. Upon presenting here at age 26, she reported a very active lifestyle, including vigorous exercise and an acting career, with no symptoms of chest or back pain or shortness of breath. Cardiovascular imaging revealed aortic regurgitation, an unsuspected dissection of a severely dilated ascending aorta, and a large descending aortic aneurysm. She required surgical replacement of her aortic valve and ascending aorta, followed by endovascular repair of the descending aortic aneurysm. This patient illustrates the importance of considering the diagnosis of TS in girls with congenital aortic defects and the absolute necessity for close, expert follow-up of these patients who are at high risk for complications after surgical repair due to an underlying aortopathy, hypertension, and metabolic disorders. This patient also emphasizes the need to publicize and follow screening guidelines as there is an increasing number of patients with congenital defects who need transition to adult care. PMID- 22923006 TI - Hazardous alcohol levels in adolescents are underestimated by barkeepers and security personnel. AB - Drunkenness among adolescents represents a significant problem and is associated with adverse consequences. A Licensing Act, which prohibits the dispensing of alcoholic beverages to visibly intoxicated individuals, was introduced in Germany to curb excessive drinking. The objective of the study was to explore whether it is possible for barkeepers and security personnel to correctly estimate the alcohol level (AL) of adolescents merely based on their outer appearance and self report. In a commercial dance club, 89 adolescents reported their past and current alcohol consumption and estimated their own AL. Their breath alcohol level was measured with a breathalyzer. The sample was divided into "moderate drinkers" and "binge drinkers." Barkeepers and security personnel spoke to and examined the adolescents in order to estimate the adolescents' AL. Professional staff underestimated the ALs of adolescents in 60.7 % of all cases. Estimates of the personnel showed greater deviations from the measured AL of the adolescents as compared to estimates of the adolescents themselves, especially in the group of binge drinkers (t = 2.764; p = 0.009). CONCLUSION: It seems that adolescents suffer less from observable effects of alcohol, such as sedation or impairment of motor function. Consequently, we do not recommend the application of the Licensing Act to adolescents, but suggest its replacement by other restrictions and prevention measures. PMID- 22923007 TI - Correlation of von Willebrand factor gene polymorphism and coronary heart disease. AB - To characterize von Willebrand factor (vWF) gene polymorphisms at site A1381T and the correlation of plasma vWF levels with coronary heart disease, the vWF genotypes at site A1381T were analyzed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) in patients diagnosed with coronary heart disease and normal controls (n=110 per group), and plasma vWF levels were measured by enzyme-linked immunosorbent assay. The results showed that the plasma vWF levels were higher in the experimental group than in the control group and had no association with gender (t=11.69, p<0.05). In the experimental group, the plasma vWF levels were higher in the patients with the AG genotype than in those with the GG genotype (p<0.05). In the control group, the plasma vWF levels of the subjects with blood type O were significantly lower than those of the individuals with other blood types (p<0.05). In the experimental group, all blood types had significantly higher plasma vWF levels than the control group and the difference was significant among different blood types (p<0.05). In summary, vWF gene polymorphisms at site A1381T were not associated with coronary heart disease, but plasma vWF levels were influenced by vWF gene polymorphisms at site A1381T, blood type and coronary heart disease. PMID- 22923008 TI - Whitefly-mediated transmission of cotton leaf curl Multan betasatellite: evidence for betasatellite encapsidation in coat protein of helper begomoviruses. AB - Cotton leaf curl Multan betasatellite (CLCuMB) is responsible for symptom expression of a devastating disease of cotton in the Indian subcontinent. CLCuMB depends on helper virus replication-associated protein for its replication and on viral coat protein (CP) for its encapsidation. However, no direct evidence of encapsidation of CLCuMB in viral CP has been available. In the present study, non viruliferous whiteflies were placed on tomato plants that had been agroinoculated with infectious clones of an Iranian isolate of tomato yellow leaf curl virus (TYLCV-[Ab]) and CLCuMB for an acquisition access period of 72 h and then transferred to healthy tomato seedlings at the 3- to 4-leaf stage. Typical symptoms of TYLCV-[Ab] appeared on inoculated seedlings 30-45 days post inoculation. The presence of TYLCV-[Ab] and CLCuMB DNAs in symptomatic test plants and viruliferous whiteflies was confirmed by PCR analysis using specific primers and DIG Southern blotting. Furthermore, the possibility of CLCuMB DNA encapsidation in TYLCV-[Ab] CP within infected plants was examined by immunocapture PCR. The results showed that CLCuMB DNA was encapsidated in TYLCV [Ab] CP. Whitefly-mediated transmission of CLCuMB in the presence of helper virus is additional evidence for encapsidation of CLCuMB by TYLCV-[Ab] CP. PMID- 22923009 TI - Comparison between proximal thoracic vascular measurements obtained by contrast enhanced magnetic resonance angiography and by transthoracic echocardiography in infants and children with congenital heart disease. AB - Accurate assessment of the proximal thoracic vasculature in infants and children with congenital heart disease (CHD) is vital for deciding the appropriate surgical or interventional procedure and predicting outcomes. This information usually is obtained by transthoracic echocardiography (TTE). Contrast-enhanced magnetic resonance angiography (CE-MRA) frequently is used to obtain diagnostic data when the image quality by TTE is limited. Calculation of z-scores for measurements obtained by CE-MRA in this population currently is not possible due to the lack of normative data. A reasonable agreement between vessel dimensions by CE-MRA and TTE will allow the use of TTE-based z-scores on measurements from CE-MRA. This study examines the accuracy and agreement of proximal thoracic vascular measurements obtained by CE-MRA versus TTE. Infants and children younger than 3 years with CHD who had a CE-MRA between August 2006 and May 2011 were retrospectively identified. Main and branch pulmonary arteries, ascending aorta, distal transverse arch, and aortic isthmus were measured from CE-MRA and TTE in analogous imaging planes and locations by two investigators blinded to each other. The study enrolled 35 subjects with CHD. The median age was 129 days (range, 0-1077 days), and the median weight was 5.8 kg (range, 2.16-17 kg). The median interval between the two imaging methods was 9 days (range, 0-60 days). Data analysis was performed with 129 of the 210 possible paired measurements. The remaining 81 paired measurements could not be performed due to inaccurate visualization of vessel borders or an unavailable imaging plane from TTE, CE-MRA, or both. The range of vessel sizes measured from 2.8 to 23.4 mm. There was excellent correlation between CE-MRA and TTE (r = 0.94, p < 0.001). The mean difference between the measurements was -0.1 +/- 1.2 mm, and the limits of agreement were -2.5 to 2.3 mm. Proximal thoracic vascular measurements obtained by CE-MRA and TTE in infants and children with CHD have a strong correlation. The agreement between these two imaging methods is adequate. Until normative data for vessel size measurements obtained from CE-MRA are available for this population, TTE-based z-scores can be applied to the measurements obtained by CE-MRA. PMID- 22923010 TI - Atrioventricular septal defect prognosis for patients with Down syndrome. PMID- 22923011 TI - Effect of rosemary polyphenols on human colon cancer cells: transcriptomic profiling and functional enrichment analysis. AB - In this work, the effect of rosemary extracts rich on polyphenols obtained using pressurized fluids was investigated on the gene expression of human SW480 and HT29 colon cancer cells. The application of transcriptomic profiling and functional enrichment analysis was done via two computational approaches, Ingenuity Pathway Analysis and Gene Set Enrichment Analysis. These two approaches were used for functional enrichment analysis as a previous step for a reliable interpretation of the data obtained from microarray analysis. Reverse transcription quantitative-PCR was used to confirm relative changes in mRNA levels of selected genes from microarrays. The selection of genes was based on their expression change, adjusted p value, and known biological function. According to genome-wide transcriptomics analysis, rosemary polyphenols altered the expression of ~4 % of the genes covered by the Affymetrix Human Gene 1.0ST chip in both colon cancer cells. However, only ~18 % of the differentially expressed genes were common to both cell lines, indicating markedly different expression profiles in response to the treatment. Differences in induction of G2/M arrest observed by rosemary polyphenols in the two colon adenocarcinoma cell lines suggest that the extract may be differentially effective against tumors with specific mutational pattern. From our results, it is also concluded that rosemary polyphenols induced a low degree of apoptosis indicating that other multiple signaling pathways may contribute to colon cancer cell death. PMID- 22923012 TI - Antiproliferative and apoptotic effect of epigallocatechin-3-gallate on Ishikawa cells is accompanied by sex steroid receptor downregulation. AB - Endometrial cancer is a significant malignancy in developed countries. Unopposed estrogen stimulation is considered as an important risk factor for endometrial cancer. Epigallocathechin-3-gallate (EGCG), biological active component of green tea, inhibits cancer cell proliferation. However, it is unknown whether EGCG has anticancer effects on endometrial cancer and what the molecular mechanism(s) are. We investigated the anticancer effects of EGCG on a human endometrial adenocarcinoma cell line (Ishikawa cells) with or without 17beta-estradiol (E2) treatment. Cell proliferation assay was performed using 3-(4,5-dimethylthiaxol-2 yi)-2,5-diphenyltetraxolium bromide (MTT). The cell cycle was determined by flow cytometry and real-time analysis of cyclin and cdk genes. The apoptosis was measured by Annexin V-PI staining and real-time analysis of bcl-2, Bax and caspase genes. The MAPK signal, Akt and caspase-3 were determined by immunoblotting. Decreased estrogen and progesterone receptor expression was observed in EGCG-treated Ishikawa cells, and decreased MAPK signals and phospho Akt were observed as well. EGCG caused the arrest of cells in the G0/G1 phase of the cell cycle. This compound interfered with Akt activation and MAPK signals, and increased apoptosis signals leading to a controlled caspases, Bcl-2, Bax genes and protein expression. Taken together, EGCG inhibits cell proliferation and induces apoptosis through Akt and MAPK signals. These findings suggest that EGCG may exert growth-inhibitory and apoptosis-inducing effects on endometrial cancer cells, accompanied by decreased estrogen and progesterone receptor. EGCG may have future clinical implications with respect to the development of novel approaches as an adjuvant therapy in endometrial cancer. PMID- 22923013 TI - Simultaneous knockdown of APRIL via multiple shRNAs reduces the malignancy of SW480 cells. AB - A proliferation-inducing ligand (APRIL) is a key factor involved in the tumor development and progression in some tumor tissues and cells. Its overexpression and as gene target in SW480 colon carcinoma cells was confirmed in our previous study. To seek a more potent way to treat colon carcinoma using a gene therapy method, herein, we constructed a multiple short hairpin RNA (shRNA) expression vector containing four shRNAs against the APRIL gene in SW480 cells. APRIL expression levels and cell biological behavior were detected after transfection with different kinds of vectors. As expected, we found that our multiple shRNA vector produced a more significant knockdown effect of APRIL than the vectors containing only one APRIL shRNA. Furthermore, our findings indicate that silencing APRIL expression in SW480 cells decreased their malignancy by reducing proliferation, invasion and adhesion, as well as inducing apoptosis. Based on our findings, vectors containing multiple shRNAs to silence the expression of APRIL may be exploited as a novel therapeutic strategy for tumors. PMID- 22923014 TI - Selective deletion of the internal lysine residue from the peptide sequence by collisional activation. AB - The gas-phase peptide ion fragmentation chemistry is always the center of attraction in proteomics to analyze the amino acid sequence of peptides and proteins. In this work, we describe the formation of an anomalous fragment ion, which corresponds to the selective deletion of the internal lysine residue from a series of lysine containing peptides upon collisional activation in the ion trap. We detected several water-loss fragment ions and the maximum number of water molecules lost from a particular fragment ion was equal to the number of lysine residues in that fragment. As a consequence of this water-loss phenomenon, internal lysine residues were found to be deleted from the peptide ion. The N,N dimethylation of all the amine functional groups of the peptide stopped the internal lysine deletion reaction, but selective N-terminal alpha-amino acetylation had no effect on this process indicating involvement of the side chains of the lysine residues. The detailed mechanism of the lysine deletion was investigated by multistage CID of the modified and unmodified peptides, by isotope labeling and by energy resolved CID studies. The results suggest that the lysine deletion might occur through a unimolecular multistep mechanism involving a seven-membered cyclic imine intermediate formed by the loss of water from a lysine residue in the protonated peptide. This intermediate subsequently undergoes degradation reaction to deplete the interior imine ring from the peptide backbone leading to the deletion of an internal lysine residue. PMID- 22923015 TI - Application of probe electrospray ionization mass spectrometry (PESI-MS) to clinical diagnosis: solvent effect on lipid analysis. AB - We have examined several combinations of solvents with the aim of optimizing the ionization conditions for molecular diagnosis of malignant tumours by PESI-MS. Although the best conditions may depend on the actual species in the sample, the optimal conditions for renal cell carcinoma (RCC) were achieved by using alcohols. PESI-MS successfully delineated the differential expression of phospholipids (PCs) and triacylglycerols (TAGs) in noncancerous and RCC tissues by using these solvent systems. This study paves the way for the application of PESI-MS in medical samples. PMID- 22923016 TI - Association of anorexia with sarcopenia in a community-dwelling elderly population: results from the ilSIRENTE study. AB - OBJECTIVE: There is increasing evidence that anorexia of aging can cause physical and mental impairment. The aim of the present study was to evaluate the relationship between anorexia and sarcopenia in elderly persons aged 80 years or older. METHODS: Data are from the baseline evaluation of 354 subjects enrolled in the ilSIRENTE study. The ilSIRENTE study is a prospective cohort study performed in the mountain community living in the Sirente geographic area (L'Aquila, Abruzzo) in Central Italy. We defined anorexia as the presence of loss of appetite and/or lower food intake. According to the European Working Group on Sarcopenia in Older People (EWGSOP) criteria, diagnosis of sarcopenia required the documentation of low muscle mass plus the documentation of either low muscle strength or low physical performance. The relationship between anorexia and sarcopenia was estimated by deriving odds ratios from the multiple logistic regression models considering sarcopenia as the dependent variable. RESULTS: Nearly 21 % of the study sample showed symptoms of anorexia. Using the EWGSOP suggested algorithm, 103 subjects (29.1 %) with sarcopenia were identified. Thirty-four (46.6 %) participants were affected by sarcopenia among subjects with anorexia compared to 69 subjects [24.6 %] without anorexia (p < 0.001). After adjusting for potential confounders including age, gender, functional and cognitive impairment, physical activity, urinary incontinence, comorbidity, congestive heart failure, COPD, depression, anti-cholinergic drugs, and TNF-alpha plasmatic levels, participants with anorexia had a higher risk of sarcopenia compared with non-anorexic subjects (HR 1.88, 95 % CI 1.01-3.51). CONCLUSIONS: Anorexia is common among community-dwelling older subjects in Italy. Our results suggest that among old-old subjects, anorexia is independently associated with sarcopenia. PMID- 22923017 TI - Krill oil versus fish oil in modulation of inflammation and lipid metabolism in mice transgenic for TNF-alpha. AB - PURPOSE: Biological effects of marine oils, fish oil (FO) and krill oil (KO), are mostly attributed to the high content of n-3 polyunsaturated fatty acids (n-3 PUFAs), predominantly eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). The study was aimed to investigate the influence of FO and KO on lipid homeostasis and inflammation in an animal model of persistent low-grade exposure to human tumor necrosis factor alpha (hTNF-alpha) and to evaluate whether these effects depend on the structural forms of EPA and DHA [triacylglycerols (TAG) vs. phospholipids]. METHODS: Male C57BL/6 hTNF-alpha mice were fed for 6 weeks a high fat control diet (24.50 % total fats, w/w) or high-fat diets containing either FO or KO at similar doses of n-3 PUFAs (EPA: 5.23 vs. 5.39 wt%, DHA: 2.82 vs. 2.36 wt% of total fatty acids). RESULTS: We found that KO, containing bioactive n-3 PUFAs in the form of phospholipids, was capable of modulating lipid metabolism by lowering plasma levels of TAG and cholesterol and stimulating the mitochondrial and peroxisomal fatty acid beta-oxidation, as well as improving the overall carnitine turnover. Though the administration of FO was not as effective as KO in the lowering of plasma TAG, FO significantly improved the levels of all cholesterol classes in plasma. Except from the increase in the levels of IL-17 in FO-fed mice and a trend to decrease in MCP-1 levels in KO-fed animals, the levels of pro-inflammatory cytokines were not substantially different between treatment groups. CONCLUSION: Our findings demonstrate that FO and KO are comparable dietary sources of n-3 PUFAs. However, when quantitatively similar doses of n-3 PUFAs are administered, KO seems to have a greater potential to promote lipid catabolism. The effect of dietary oils on the levels of inflammatory markers in hTNF-alpha transgenic mice fed a high-fat diet needs further investigations. PMID- 22923018 TI - Abandoning "TAP" as treatment of metastatic endometrial cancer: a serious example of the consequences resulting from the failure to adequately define the question being addressed in a phase 3 trial. PMID- 22923019 TI - Association analysis of single-nucleotide polymorphisms of USP24 and USP40 with Parkinson's disease in the Han Chinese population. AB - BACKGROUND: The ubiquitin-proteasomal pathway has been found to be involved in the etiology of Parkinson's disease (PD). Numerous single-nucleotide polymorphisms (SNPs) in both USP24 and USP40 genes have been linked to increased risks of late-onset PD, but the association has not been confirmed in the residents of mainland China, especially the Han population. METHODS: We included 378 unrelated Han Chinese PD patients from south west China and 274 unrelated Han Chinese healthy controls from the same region. Multiple SNPs, including rs13312, rs1165226, rs487230, and rs287235 of USP24 and rs1048603 of USP40, were genotyped using Sequenom iPLEX Assay technology. RESULTS: No significant differences in the genotype frequencies and minor allele frequency of all SNPs were observed between the PD and control groups, between the early-onset PD and control groups, between the late-onset PD and control groups, and between the early-onset PD and late onset PD groups. CONCLUSION: The present study is the first to report a lack of association between SNPs of USP24 and USP40 and PD in Han Chinese patients. Other association studies with larger numbers of participants are necessary to confirm the present findings. PMID- 22923020 TI - Quantitative accuracy of attenuation correction in the Philips Ingenuity TF whole body PET/MR system: a direct comparison with transmission-based attenuation correction. AB - OBJECTIVE: Evaluation of the quantitative accuracy of MR-based attenuation correction (MRAC) in the Philips Ingenuity TF whole-body PET/MR. MATERIALS AND METHODS: In 13 patients, PET emission data from the PET/MR were reconstructed using two different methods for attenuation correction. In the first reconstruction, the vendor-provided standard MRAC was used. In the second reconstruction, a coregistered transmission-based attenuation map from a second immediately preceding investigation with a stand-alone Siemens ECAT EXACT HR(+) PET scanner was used (TRAC). The two attenuation maps were compared regarding occurrence of segmentation artifacts in the MRAC procedure. Standard uptake values (SUVs) of multiple VOIs (liver, cerebellum, hot focal structures at various locations in the trunk) were compared between both reconstructed data sets. Furthermore, a voxel-wise intensity correlation analysis of both data sets in the lung and trunk was performed. RESULTS: VOI averaged SUV differences between MRAC and TRAC were as follows (relative differences, mean +/- standard deviation): (+12 +/- 6) % cerebellum, (-4 +/- 9) % liver, (-2 +/- 11) % hot focal structures. The fitted slopes of the voxel-wise correlations in the lung and trunk were 0.87 +/- 0.17 and 0.95 +/- 0.10 with averaged adjusted R (2) values of 0.96 and 0.98, respectively. These figures include two instances with partially erroneous lung segmentation due to artifacts in the underlying MR images. CONCLUSION: The MR-based attenuation correction implemented on the Philips Ingenuity PET/MR provides reasonable quantitative accuracy. On average, deviations from TRAC-based results are small (on the order of 10% or below) across the trunk, but due to interindividual variability of the segmentation quality, deviations of more than 20% can occur. Future improvement of the segmentation quality would help to increase the quantitation accuracy further and to reduce the inter-subject variability. PMID- 22923021 TI - Novel BRCA1 and BRCA2 pathogenic mutations in Slovene hereditary breast and ovarian cancer families. AB - The estimated proportion of hereditary breast and ovarian cancers among all breast and ovarian cancer cases is 5-10%. According to the literature, inherited mutations in the BRCA1 and BRCA2 tumour-suppressor genes, account for the majority of hereditary breast and ovarian cancer cases. The aim of this report is to present novel mutations that have not yet been described in the literature and pathogenic BRCA1 and BRCA2 mutations which have been detected in HBOC families for the first time in the last three years. In the period between January 2009 and December 2011, 559 individuals from 379 families affected with breast and/or ovarian cancer were screened for mutations in the BRCA1 and BRCA2 genes. Three novel mutations were detected: one in BRCA1 - c.1193C>A (p.Ser398*) and two in BRCA2 - c.5101C>T (p.Gln1701*) and c.5433_5436delGGAA (p.Glu1811Aspfs*3). These novel mutations are located in the exons 11 of BRCA1 or BRCA2 and encode truncated proteins. Two of them are nonsense while one is a frameshift mutation. Also, 11 previously known pathogenic mutations were detected for the first time in the HBOC families studied here (three in BRCA1 and eight in BRCA2). All, except one cause premature formation of stop codons leading to truncation of the respective BRCA1 or BRCA2 proteins. PMID- 22923022 TI - The dynamics of angiogenic factors and their soluble receptors in relation to organ dysfunction in disseminated intravascular coagulation associated with sepsis. AB - We prospectively studied (1) the relationships between angiogenic factors, their soluble receptors and organ dysfunction and (2) the effects of disseminated intravascular coagulation (DIC)-induced platelet consumption, thrombin generation, and tissue hypoxia on the expression of the factors and receptors. Fifty patients with sepsis were classified into two subgroups: 37 patients with DIC and 13 patients without DIC. DIC patients showed higher Sequential Organ Failure Assessment (SOFA) scores, the prevalence of multiple organ dysfunction syndrome (MODS) and more increased soluble fibrin and lactate levels. We observed lower levels of vascular endothelial growth factor (VEGF), soluble VEGF receptor 2 (sVEGFR2), angiopoietin 1 (Ang1) and Ang1/Ang2, and higher sVEGFR1 and Ang2 levels in DIC patients, but not significant differences in soluble Tie2 expression during the study period. The levels of VEGF, sVEGFR1, and Ang2 in DIC patients correlated with the SOFA scores. Clear differences were observed in the levels of Ang2 in the DIC patients between survivors and nonsurvivors and between those with and without MODS. The area under receiver operating characteristic curves for predicting death and MODS by Ang2 were 0.710 and 0.784, respectively. The VEGF levels showed a marked correlation with the platelet counts. Soluble fibrin and lactate levels independently predicted increases in the levels of VEGF, sVEGFR1, and Ang2 in DIC patients. In conclusion, VEGF, sVEGFR1, Ang2, and Ang1/Ang2, especially Ang2, may have roles in the development of MODS in sepsis associated with DIC, and VEGF, sVEGFR1, and Ang2 serum levels correlated with the extent of DIC-induced platelet consumption, thrombin generation, and blood lactate levels. PMID- 22923023 TI - Intranidal signal distribution in post-contrast time-of-flight MRA is associated with rupture risk factors in arteriovenous malformations. AB - PURPOSE: To evaluate if arteriovenous malformations (AVMs) that are associated with a high rupture risk (HRR) are represented by different intranidal Time-of Flight (TOF) magnetic resonance angiography intensity distributions compared to those with presumably low rupture risk (LRR). METHODS: Fifty post-contrast TOF datasets of patients with an AVM were analyzed in this study. The patients were classified to the HRR group in case of a deep location, presence of exclusive deep venous drainage, previous hemorrhagic event or a combination thereof. For each TOF dataset, the AVM nidus was semi-automatically delineated and used for histogram extraction. Each histogram was analyzed by calculating the skewness, kurtosis, mean and median intensity and full-width-half-maximum. Statistical analysis was performed using parameter-wise two-sided t-tests of the parameters between the two groups. RESULTS: Based on morphological analysis, 21 patients were classified to the HRR and 29 patients to the LRR group. Statistical analysis revealed that TOF intensity distributions of HRR AVMs exhibit a significant higher skewness (p=0.0005) parameter compared to LRR AVMs. Contrary to these findings, no significant differences were found for the other parameters evaluated. CONCLUSION: Intranidal flow heterogeneity, for example, caused by turbulent flow conditions, may play an important role for risk of a hemorrhage. An analysis of post-contrast TOF intensities within the nidus of an AVM may offer simple and valuable information for clinical risk estimation of AVMs and needs to be tested prospectively. PMID- 22923024 TI - Pharmacodynamic effects of EV-077: results of an in vitro pilot investigation in healthy volunteers. PMID- 22923025 TI - Fine-mapping of IL16 gene and prostate cancer risk in African Americans. AB - BACKGROUND: Prostate cancer is the most common type of cancer among men in the United States, and its incidence and mortality rates are disproportionate among ethnic groups. Although genome-wide association studies of European descents have identified candidate loci associated with prostate cancer risk, including a variant in IL16, replication studies in African Americans (AA) have been inconsistent. Here we explore single-nucleotide polymorphism (SNP) variation in IL16 in AAs and test for association with prostate cancer. METHODS: Association tests were conducted for 2,257 genotyped and imputed SNPs spanning IL16 in 605 AA prostate cancer cases and controls from Washington, D.C. Eleven of them were also genotyped in a replication population of 1,093 AAs from Chicago. We tested for allelic association adjusting for age, global and local West African ancestry. RESULTS: Analyses of genotyped and imputed SNPs revealed that a cluster of IL16 SNPs were significantly associated with prostate cancer risk. The strongest association was found at rs7175701 (P = 9.8 * 10(-8)). In the Chicago population, another SNP (rs11556218) was associated with prostate cancer risk (P = 0.01). In the pooled analysis, we identified three independent loci within IL16 that were associated with prostate cancer risk. SNP expression quantitative trait loci analyses revealed that rs7175701 is predicted to influence the expression of IL16 and other cancer-related genes. CONCLUSION: Our study provides evidence that IL16 polymorphisms play a role in prostate cancer susceptibility among AAs. IMPACT: Our findings are significant given that there has been limited focus on the role of IL16 genetic polymorphisms on prostate cancer risk in AAs. PMID- 22923027 TI - Association study of dimethylarginine dimethylaminohydrolase 2 gene polymorphisms and coronary heart disease. AB - While a number of genetic and environmental risk factors for coronary heart disease (CHD) have been identified, the list of potential risk factors remains long. One candidate is dimethylarginine dimethylaminohydrolase (DDAH2), which is known to be polymorphic in humans. The gene product indirectly increases the endogenous production of nitric oxide, an anti-atherogenic molecule. Therefore, alterations in DDAH2 activity may indirectly result in an increased risk of CHD. We studied allele and genotype distributions for two polymorphic loci of DDAH2, rs805305 and rs2272592, in 180 patients with CHD and 180 healthy controls. Disease history and other clinical data were recorded. Polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) was used to determine the genotype at rs805305, and ligase detection reaction (LDR) was used to determine the genotype at rs2272592. Systolic blood pressure and blood triglyceride and glucose levels were higher, and history of hypertension, diabetes, smoking and alcohol use was more common in the patients with CHD (P<0.05). However, the genotype and allele frequencies at the two polymorphic loci of DDAH2 were not statistically different between the two groups. Therefore, no association was observed between the DDAH2 polymorphisms at rs805305 and rs2272592 and CHD. PMID- 22923026 TI - Evaluating genetic risk for prostate cancer among Japanese and Latinos. AB - BACKGROUND: There have been few genome-wide association studies (GWAS) of prostate cancer among diverse populations. To search for novel prostate cancer risk variants, we conducted GWAS of prostate cancer in Japanese and Latinos. In addition, we tested prostate cancer risk variants and developed genetic risk models of prostate cancer for Japanese and Latinos. METHODS: Our first-stage GWAS of prostate cancer included Japanese (cases/controls = 1,033/1,042) and Latino (cases/controls = 1,043/1,057) from the Multiethnic Cohort (MEC). Significant associations from stage I (P < 1.0 * 10(-4)) were examined in silico in GWAS of prostate cancer (stage II) in Japanese (cases/controls = 1,583/3,386) and Europeans (cases/controls = 1,854/1,894). RESULTS: No novel stage I single nucleotide polymorphism (SNP) outside of known risk regions reached genome-wide significance. For Japanese, in stage I, the most notable putative novel association was seen with 10 SNPs (P <= 8.0 * 10(-6)) at chromosome 2q33; however, this was not replicated in stage II. For Latinos, the most significant association was observed with rs17023900 at the known 3p12 risk locus (stage I: OR = 1.45; P = 7.01 * 10(-5) and stage II: OR = 1.58; P = 3.05 * 10(-7)). The majority of the established risk variants for prostate cancer, 79% and 88%, were positively associated with prostate cancer in Japanese and Latinos (stage I), respectively. The cumulative effects of these variants significantly influence prostate cancer risk (OR per allele = 1.10; P = 2.71 * 10(-25) and OR = 1.07; P = 1.02 * 10(-16) for Japanese and Latinos, respectively). CONCLUSION AND IMPACT: Our GWAS of prostate cancer did not identify novel genome-wide significant variants. However, our findings show that established risk variants for prostate cancer significantly contribute to risk among Japanese and Latinos. PMID- 22923028 TI - The role of menstrual cycle phase and anxiety sensitivity in catastrophic misinterpretation of physical symptoms during a CO(2) challenge. AB - The current study examined the interactive effects of anxiety sensitivity (AS; fear of anxiety and anxiety-related sensations) and menstrual cycle phase (premenstrual phase vs. follicular phase) on panic-relevant responding (i.e., cognitive and physical panic symptoms, subjective anxiety, and skin conductance level). Women completed a baseline session and underwent a 3-min 10 % CO(2) enriched air biological challenge paradigm during her premenstrual and follicular menstrual cycle phases. Participants were 55 women with no current or past history of panic disorder recruited from the general community (M (age) = 26.18, SD = 8.9) who completed the biological challenge during both the premenstrual and follicular cycle phases. Results revealed that women higher on AS demonstrated increased cognitive panic symptoms in response to the challenge during the premenstrual phase as compared to the follicular phase, and as compared to women lower on AS assessed in either cycle phase. However, the interaction of AS and menstrual cycle phase did not significantly predict physical panic attack symptoms, subjective ratings of anxiety, or skin conductance level in response to the challenge. Results are discussed in the context of premenstrual exacerbations of cognitive, as opposed to physical, panic attack symptoms for high AS women, and the clinical implications of these findings. PMID- 22923029 TI - Atherosclerosis causing recurrent catastrophic aortopulmonary shunt dehiscence in a patient with Alagille syndrome. AB - Alagille syndrome (ALGS) is an autosomal dominant disorder associated with cholestatic liver disease, pulmonary valvar stenosis or atresia, vasculopathy, and renal disease. Although the liver and cardiac manifestations contribute to overall morbidity and mortality during their life span, these patients also carry a burden of important but often underappreciated vascular abnormalities. This report describes a 3 year-old girl with Alagille syndrome, hepatic cholestasis, systemic hypertension, hypercholesterolemia, hypertriglyceridemia, and tetralogy of Fallot, pulmonary atresia, and major aortopulmonary collaterals (TOF/PA/MAPCAs). She presented for bilateral pulmonary artery plasty and central shunt upsizing. She then experienced three shunt dehiscence episodes, necessitating emergent intervention. Autopsy showed diffuse atherosclerosis and significant atherosclerotic plaque at the site of shunt dehiscence. This is the first reported case of ALGS with TOF/PA/MAPCAs and catastrophic shunt dehiscence due to significant generalized vasculopathy caused by dyslipidemia and atherosclerosis. Dyslipidemia, a known comorbidity in ALGS, is one of few modifiable risk factors that should be screened for and treated, particularly before cardiac surgery. PMID- 22923030 TI - Prospective assessment of novice learners in a simulation-based extracorporeal membrane oxygenation (ECMO) education program. AB - This study aimed to assess the impact of integrating a simulation-based education module into an extracorporeal membrane oxygenation (ECMO) curriculum on novice learners and to test the duration of time that skills obtained during this training exercise were retained. The authors hypothesized that multidisciplinary, simulation-based ECMO training would improve comfort and confidence levels among participants. An ECMO training curriculum was developed that incorporated in situ simulation modules to train multidisciplinary health care professionals involved in the management of patients receiving ECMO in the pediatric cardiac intensive care unit (PCICU). During the simulation, a team was assembled similar to the one that would staff the PCICU during a routine workday. Pre- and postparticipation questionnaires were used to determine the effects on the knowledge, ability, and confidence level of the participants. The participants were required to repeat the simulation test within 6-8 months. The study enrolled 26 providers (10 fellow physicians, 12 nurses and nurse practitioners, 4 respiratory therapists). All except one had no previous training in the management of ECMO. Of the 26 participants, 24 passed the initial written and practical tests. One participant failed the written test, whereas another failed the practical test. All the responding participants scored the didactic and scenarios education as useful, at 4 or higher (5 = very useful), in improving their perception of their overall knowledge and their ability to perform the required critical performance criteria on simulated ECMO. The 20 participants who appeared for the 6 month follow-up visit to assess maintenance of competency skills demonstrated success with simulated ECMO emergencies. All four questionnaires were completed by 18 participants. Simulation-based training is an effective method of improving knowledge, ability, and confidence levels among novice ECMO specialists and physician trainees. Further research is needed to assess real-time demonstration of skills retention during ECMO emergencies. PMID- 22923032 TI - Tobacco control: reflections on our mistakes and those who made them. PMID- 22923031 TI - Downregulation of matrix metalloproteinase-9 mRNA by valproic acid plays a role in inhibiting the shedding of MHC class I-related molecules A and B on the surface of human osteosarcoma cells. AB - Valproic acid, a histone deacetylase inhibitor, increases the expression of cell surface MHC class I-related chain molecules (MICs) A and B (MICA and B) in osteosarcoma cells and decreases their secretion of soluble MICA and MICB, which are produced by the proteolytic cleavage of cell surface MICs. Osteosarcoma cells have been reported to produce high levels of matrix metalloproteinase (MMP)-2 and -9. In this study, we investigated the involvement of MMP-2 and -9 in the inhibitory action of valproic acid (VPA) on the proteolytic cleavage of cell surface MICs using the U-2 OS and SaOS-2 osteosarcoma cell lines. VPA caused a marked decrease in the expression of MMP-9 mRNA in the U-2 OS and SaOS-2 cells and in the expression of MMP-2 mRNA in the U-2 OS cells, but only a slight decrease in the expression of MMP-2 mRNA in the SaOS-2 cells. The transfection of small interfering RNA (siRNA) for MMP-9 decreased the secretion of soluble MICA and MICB by both U-2 OS and SaOS-2 cells, but that of siRNA for MMP-2 did not. The present study therefore demonstrates that the downregulation of MMP-9 mRNA by VPA plays a role in the inhibitory action of VPA on the secretion of soluble MICA and MICB in osteosarcoma cells. PMID- 22923033 TI - Induction of LGR5 by H2O2 treatment is associated with cell proliferation via the JNK signaling pathway in colon cancer cells. AB - Recently, the leucine-rich repeat G protein-coupled receptor 5 (LGR5/GPR49) was identified as a potential marker of intestinal stem cells in human. The LGR5 is known as a Wnt signaling target gene, and its expression pattern is related with beta-catenin mutation. H2O2 is a member of reactive oxygen species (ROS) and regulates metabolism, aging, apoptosis and the intensity of growth factor signaling. In addition, it acts as a negative or positive regulator of Wnt signaling. However, the effect of H2O2 on Wnt signaling and its target gene LGR5 is not clear. In this study, we investigated the effects of ROS on cancer stem cells, in colorectal cancer cells. Colorectal cancer cells were treated with exogenous H2O2, after which cellular responses and the expression of LGR5 were examined. In SNU-C2A cells, proliferation increased following treatment with 50 300 uM of H2O2, whereas cell viability significantly decreased after treatment with 600-900 uM of H2O2. Expression of heme oxygenase (HO)-1 and jun, which aid in the reduction of oxidative stress, were induced in the low dose H2O2-treated SNU-C2A cells. The LGR5 expression level was significantly increased following 50 300 uM H2O2 treatment; in addition, beta-catenin was increased in H2O2-treated colon cancer cells. However, the increased beta-catenin was detected not in the nucleus but in the cytoplasm, which means that beta-catenin was stabilized in the cytoplasm and not translocated into the nucleus where it could function as a transcription factor for the expression of LGR5. In addition, there was no direct interaction between LGR5 and beta-catenin. In this study, we found that LGR5 expression increased when cancer cells were treated with a low dose of H2O2. Our results indicate that the LGR5 increase resulted via activation of the JNK signaling pathway. The induction of LGR5 expression influenced cell proliferation in colorectal cancer cells. PMID- 22923034 TI - Colorectal cancer cells Caco-2 and HCT116 resist epigenetic effects of isothiocyanates and selenium in vitro. AB - PURPOSE: It is relatively unknown how different dietary components, in partnership, regulate gene expression linked to colon pathology. It has been suggested that the combination of various bioactive components present in a plant based diet is crucial for their potential anticancer activities. This study employed a combinatorial chemopreventive strategy to investigate the impact of selenium and/or isothiocyanates on DNA methylation processes in colorectal carcinoma cell lines. METHODS: To gain insights into the epigenetic-mediated changes in gene expression in response to these dietary constituents cultured Caco-2 and HCT116 cells were exposed for up to 12 days to different concentrations of selenium methylselenocysteine and selenite (ranging from 0.2 to 5 MUM) either alone or in combination with sulforaphane and iberin (ranging from 6 to 8 MUM), and changes to gene-specific (p16(INK4A) and ESR1), global (LINE-1) methylation and DNMT expression were quantified using real-time PCR-based assays. RESULTS: No effects on the methylation of CpG islands in ESR1, p16(INK4A) or of LINE-1, a marker of global genomic methylation, were observed after exposure of Caco-2 and HCT116 cells to selenium or isothiocyanates. Only transient changes in DNMT mRNA expression, which occurred mostly in the treatment groups containing isothiocyanates, were observed, and these occurred only for specific DNMT transcripts and did not lead to the modification of the aberrant methylation status present in these cells. CONCLUSION: These data suggest that treatment for colon cancer cells with selenium and/or isothiocyanates, either individually or in combination does not impact abnormal methylation patterns of key genes involved in the complex multistep process of colon carcinogenesis in vitro. PMID- 22923035 TI - Modulation of the nuclear factor-kappa B (NF-kappaB) signalling pathway by glutamine in peritoneal macrophages of a murine model of protein malnutrition. AB - BACKGROUND AND AIMS: Protein malnutrition affects resistance to infection by impairing the inflammatory response, modifying the function of effector cells, such as macrophages. Recent studies have revealed that glutamine-a non-essential amino acid, which could become conditionally essential in some situations like trauma, infection, post-surgery and sepsis-is able to modulate the synthesis of cytokines. The aim of this study was to evaluate the effect of glutamine on the expression of proteins involved in the nuclear factor-kappa B (NF-kappaB) signalling pathway of peritoneal macrophages from malnourished mice. METHODS: Two month-old male Balb/c mice were submitted to protein-energy malnutrition (n = 10) with a low-protein diet containing 2 % protein, whereas control mice (n = 10) were fed a 12 % protein-containing diet. The haemogram and analysis of plasma glutamine and corticosterone were evaluated. Peritoneal macrophages were pre treated in vitro with glutamine (0, 0.6, 2 and 10 mmol/L) for 24 h and then stimulated with 1.25 MUg LPS for 30 min, and the synthesis of TNF-alpha and IL 1alpha and the expression of proteins related to the NF-kappaB pathway were evaluated. RESULTS: Malnourished animals had anaemia, leucopoenia, lower plasma glutamine and increased corticosterone levels. TNF-alpha production of macrophages stimulated with LPS was significantly lower in cells from malnourished animals when cultivated in supraphysiological (2 and 10 mmol/L) concentrations of glutamine. Further, glutamine has a dose-dependent effect on the activation of macrophages, in both groups, when stimulated with LPS, inducing a decrease in TNF-alpha and IL-1alpha production and negatively modulating the NF kappaB signalling pathway. CONCLUSIONS: These data lead us to infer that the protein malnutrition state interferes with the activation of macrophages and that higher glutamine concentrations, in vitro, have the capacity to act negatively in the NF-kappaB signalling pathway. PMID- 22923036 TI - Intact risk-based decision making in rats with prefrontal or accumbens dopamine depletion. AB - The medial prefrontal cortex (mPFC) and the core region of the nucleus accumbens (AcbC) are key regions of a neural system that subserves risk-based decision making. Here, we examined whether dopamine (DA) signals conveyed to the mPFC and AcbC are critical for risk-based decision making. Rats with 6-hydroxydopamine or vehicle infusions into the mPFC or AcbC were examined in an instrumental task demanding probabilistic choice. In each session, probabilities of reward delivery after pressing one of two available levers were signaled in advance in forced trials followed by choice trials that assessed the animal's preference. The probabilities of reward delivery associated with the large/risky lever declined systematically across four consecutive blocks but were kept constant within four subsequent daily sessions of a particular block. Thus, in a given session, rats need to assess the current value associated with the large/risky versus small/certain lever and adapt their lever preference accordingly. Results demonstrate that the assessment of within-session reward probabilities and probability discounting across blocks were not altered in rats with mPFC and AcbC DA depletions, relative to sham controls. These findings suggest that the capacity to evaluate the magnitude and likelihood of rewards associated with alternative courses of action seems not to rely on intact DA transmission in the mPFC or AcbC. PMID- 22923037 TI - Brief report: effects of tact training on emergent intraverbal vocal responses in adolescents with autism. AB - The present study evaluated the emergence of intraverbal responses following tact training with three adolescents diagnosed with autism spectrum disorders. Participants were taught to tact the name of a cartoon character (e.g., "What is the name of this monster?" ["Simon"]) and that character's preferred food (e.g., "What food does this monster eat?" ["Chips"]). Following tact training, test probes revealed the emergence of untrained vocal intraverbals. Specifically, in the absence of pictures, participants stated the name of the character when given the food preference (e.g., "Which monster eats chips?"), and stated the food when given the character name (e.g., "What food does Simon eat?"). The findings are discussed with reference to the growing literature on verbal behavior and derived relational responding. PMID- 22923038 TI - Fascination and isolation: a grounded theory exploration of unusual sensory experiences in adults with Asperger syndrome. AB - Unusual sensory experiences are commonly seen in people with Asperger syndrome (AS). They correlate with functional impairments and cause distress. The current study investigates how these experiences have affected nine adults with AS's lives, as well as the coping strategies utilised. Semi-structured interviews were conducted using Instant Messaging software. Data were analysed using Grounded Theory. A number of inter-related categories and focused codes were identified. The categories included heightened senses, sensory stress, the stress avalanche, moderating factors, coping strategies, other people, self-acceptance, fascination, and isolation. A model was constructed as to how these categories and codes interact. How these findings link with previous research into autism spectrum disorders is discussed. Implications for services and future research are also made. PMID- 22923039 TI - [Anxiety and depression in cancer patients during the course of radiotherapy treatment]. AB - BACKGROUND: Undergoing radiotherapy is often associated with severe impairment of quality of life in cancer patients. Especially psychosocial aspects like anxiety and depression play a major role. The aim of this study was to closely analyze anxiety and depression during the course of radiotherapy treatment. METHODS: A total of 60 patients, who received radiotherapy because of a tumor disease between June 2005 and April 2006, were included in the prospective study; 57 (95%) patients were primarily treated with radiotherapy. In 72% of the cases the intention to treat was curable, in 18% palliative. Anxiety and depression (HADS D) were assessed at three points in time: before (A) and after (B) radiotherapy treatment (RT), and 6 weeks after finishing RT at the follow-up appointment (C). RESULTS: Before therapy (A), 41% of the treated patients showed positive or marginally positive symptoms of anxiety and 33% symptoms of depression. The symptoms of anxiety significantly decreased during the course of therapy. The proportion of patients with a positive score of anxiety dropped from 16% at the beginning of RT (A) to 9% after the RT (B; p = 0.04). In addition, there was an increase in the number of patients who scored negatively with regard to anxiety from 59% (A) to 72% (B; p = 0.04). With regard to the median score of anxiety, no statistically significant change (p > 0.05) was observed during therapy, while for depression, the number of positively tested patients also decreased significantly during the course of therapy from the beginning of RT (A, 14%) to the first follow-up appointment (C, 9%; p = 0.02). Furthermore, the number of negatively tested patients rose by 8% (p = 0.02). During the whole course of the study, the median score of depression decreased from 6 (A) to 5 points (C; p = 0.01). CONCLUSION: More than one third of the treated patients suffered from positive or marginally positive symptoms of anxiety and depression. This present study showed a decrease of anxiety and depression symptoms during the course of radiotherapy. PMID- 22923040 TI - A live weight-heart girth relationship for accurate dosing of east African shorthorn zebu cattle. AB - The accurate estimation of livestock weights is important for many aspects of livestock management including nutrition, production and appropriate dosing of pharmaceuticals. Subtherapeutic dosing has been shown to accelerate pathogen resistance which can have subsequent widespread impacts. There are a number of published models for the prediction of live weight from morphometric measurements of cattle, but many of these models use measurements difficult to gather and include complicated age, size and gender stratification. In this paper, we use data from the Infectious Diseases of East Africa calf cohort study and additional data collected at local markets in western Kenya to develop a simple model based on heart girth circumference to predict live weight of east African shorthorn zebu (SHZ) cattle. SHZ cattle are widespread throughout eastern and southern Africa and are economically important multipurpose animals. We demonstrate model accuracy by splitting the data into training and validation subsets and comparing fitted and predicted values. The final model is weight(0.262) = 0.95 + 0.022 * girth which has an R (2) value of 0.98 and 95 % prediction intervals that fall within the +/- 20 % body weight error band regarded as acceptable when dosing livestock. This model provides a highly reliable and accurate method for predicting weights of SHZ cattle using a single heart girth measurement which can be easily obtained with a tape measure in the field setting. PMID- 22923041 TI - Long-term culture in vitro impairs the immunosuppressive activity of mesenchymal stem cells on T cells. AB - Improved knowledge of the immunological properties of mesenchymal stem cells (MSCs) creates a potential cell-mediated immunotherapeutic approach for arthritic diseases. The low frequency of MSCs necessitates their in vitro expansion prior to clinical use. As sequential passage has been used as the most popular strategy for expansion of MSCs, the effect of long-term culture on the immunological properties of MSCs is not clear. In this study, we observed that the morphology of MSCs showed the typical characteristics of the Hayflick model of cellular aging during sequential expansion. The growth kinetics of MSCs decreased while the number of MSCs staining positive for SA beta-gal (senescence marker) increased in long-term culture. Although long-term culture exerts less of an effect on the immunophenotype of MSCs, the immunosuppressive effects of MSCs on the allogeneic T-cell proliferation, activation-antigen expression (CD69 and CD25) and cytokine production (IFN-gamma, TNF-alpha, IL-10) were significantly impaired following stimulation with phytohemagglutinin (PHA). PMID- 22923042 TI - How to put things together. AB - Instructions for putting things together or understanding how things work are notoriously frustrating. Performance relies on constructing mental models of the object and the actions of the object from text or diagrams or both. Here, we show that instructions can be improved by turning users into designers and deriving design principles from their designs. People first assembled an object and then crafted assembly instructions, using text alone or text and diagrams. Some were required to be brief and to include only the most essential information. Users' instructions had a narrative structure with an introduction, a middle, and an end. The essential middle described or depicted the step-by-step sequence of actions on parts. Diagrams were regarded as fundamental, and redundancy of depictions and descriptions desirable. These design principles have wide applicability to many kinds of explanations. PMID- 22923043 TI - Enhancing the mental representations of space used by blind pedestrians, based on an image schemata model. AB - The configuration of mental representation of space plays a major role in successful navigational activities. Therefore, navigational assistance for pedestrians who are blind should help them to better configure their mental representation of the environment. In this paper, we propose and exploit a computational model for the mental representation of urban areas as an aid to orientation and navigation for visually impaired pedestrians. Our model uses image schemata to capture the spatial semantics and configural elements of urban space necessary for this purpose. These image schemata are schematic structures that are continually requested by individuals in their perception, bodily movement and interaction with surrounding objects. Our proposed model also incorporates a hierarchical structure to provide different levels of detail tied to appropriate spatial perspectives at each scale. We presume that such computational model will help us to develop an appropriate structure of spatial data used to assist the target population. At the end of the paper, we illustrate the utility of our configural model by developing a typical scenario for the navigation of a blind pedestrian in an urban area. PMID- 22923044 TI - The three clades of the telomere-associated TLO gene family of Candida albicans have different splicing, localization, and expression features. AB - Candida albicans grows within a wide range of host niches, and this adaptability enhances its success as a commensal and as a pathogen. The telomere-associated TLO gene family underwent a recent expansion from one or two copies in other CUG clade members to 14 expressed copies in C. albicans. This correlates with increased virulence and clinical prevalence relative to those of other Candida clade species. The 14 expressed TLO gene family members have a conserved Med2 domain at the N terminus, suggesting a role in general transcription. The C terminal half is more divergent, distinguishing three clades: clade alpha and clade beta have no introns and encode proteins that localize primarily to the nucleus; clade gamma sometimes undergoes splicing, and the gene products localize within the mitochondria as well as the nuclei. Additionally, TLOalpha genes are generally expressed at much higher levels than are TLOgamma genes. We propose that expansion of the TLO gene family and the predicted role of Tlo proteins in transcription regulation provide C. albicans with the ability to adapt rapidly to the broad range of different environmental niches within the human host. PMID- 22923045 TI - The "finger," a unique multicellular morphology of Candida albicans induced by CO2 and dependent upon the Ras1-cyclic AMP pathway. AB - Most experiments exploring the basic biology of pathogenic microbes are performed in vitro under conditions that do not usually mimic those of their host niche. Hence, developmental programs initiated by specific host cues may be missed in vitro. We have tested the effects of growing low-density agar cultures of the yeast pathogen Candida albicans in concentrations of CO(2) found in the gastrointestinal tract. It is demonstrated that in physiological concentrations of CO(2) at 37 degrees C, yeast cells form a heretofore undescribed multicellular "finger" morphology distinct from a previously described stalk-like structure induced by high doses of UV irradiation that kills more than 99.99% of cells. The finger extends aerially, is uniform in diameter, and is visible to the naked eye, attaining lengths of 3 mm. It is composed of a basal yeast cell monolayer adhering to a semispherical crater formed in the agar and connected to a basal bulb of yeast cells at a fragile interface. The bulb extends into the long shaft. We propose that a single, centrally located hypha extending the length of the shaft forms buds at compartment junctions that serve as the source of the yeast cells in the shaft. A mutational analysis reveals finger formation is dependent upon the pathway Ras1->Cdc35->cyclic AMP (cAMP) (PDE2-|)->Tpk2->Tec1. Because of the mechanically fragile interface and the compactness of bulb and shaft, we suggest that the finger may function as a multicellular dispersal mechanism produced in host niches containing high levels of CO(2). PMID- 22923046 TI - Dynamics and innovations within oomycete genomes: insights into biology, pathology, and evolution. AB - The eukaryotic microbes known as oomycetes are common inhabitants of terrestrial and aquatic environments and include saprophytes and pathogens. Lifestyles of the pathogens extend from biotrophy to necrotrophy, obligate to facultative pathogenesis, and narrow to broad host ranges on plants or animals. Sequencing of several pathogens has revealed striking variation in genome size and content, a plastic set of genes related to pathogenesis, and adaptations associated with obligate biotrophy. Features of genome evolution include repeat-driven expansions, deletions, gene fusions, and horizontal gene transfer in a landscape organized into gene-dense and gene-sparse sectors and influenced by transposable elements. Gene expression profiles are also highly dynamic throughout oomycete life cycles, with transcriptional polymorphisms as well as differences in protein sequence contributing to variation. The genome projects have set the foundation for functional studies and should spur the sequencing of additional species, including more diverse pathogens and nonpathogens. PMID- 22923047 TI - Functional and physical interactions among Saccharomyces cerevisiae alpha-factor receptors. AB - The alpha-factor receptor Ste2p is a G protein-coupled receptor (GPCR) expressed on the surface of MATa haploid cells of the yeast Saccharomyces cerevisiae. Binding of alpha-factor to Ste2p results in activation of a heterotrimeric G protein and of the pheromone response pathway. Functional interactions between alpha-factor receptors, such as dominant-negative effects and recessive behavior of constitutive and hypersensitive mutant receptors, have been reported previously. We show here that dominant-negative effects of mutant receptors persist over a wide range of ratios of the abundances of G protein to receptor and that such effects are not blocked by covalent fusion of G protein alpha subunits to normal receptors. In addition, we detected dominant effects of mutant C-terminally truncated receptors, which had not been previously reported to act in a dominant manner. Furthermore, coexpression of C-terminally truncated receptors with constitutively active mutant receptors results in enhancement of constitutive signaling. Together with previous evidence for oligomerization of Ste2p receptors, these results are consistent with the idea that functional interactions between coexpressed receptors arise from physical interactions between them rather than from competition for limiting downstream components, such as G proteins. PMID- 22923048 TI - Gain-of-function mutations in UPC2 are a frequent cause of ERG11 upregulation in azole-resistant clinical isolates of Candida albicans. AB - In Candida albicans, Upc2 is a zinc-cluster transcription factor that targets genes, including those of the ergosterol biosynthesis pathway. To date, three documented UPC2 gain-of-function (GOF) mutations have been recovered from fluconazole-resistant clinical isolates that contribute to an increase in ERG11 expression and decreased fluconazole susceptibility. In a group of 63 isolates with reduced susceptibility to fluconazole, we found that 47 overexpressed ERG11 by at least 2-fold over the average expression levels in 3 unrelated fluconazole susceptible strains. Of those 47 isolates, 29 contained a mutation in UPC2, whereas the remaining 18 isolates did not. Among the isolates containing mutations in UPC2, we recovered eight distinct mutations resulting in putative single amino acid substitutions: G648D, G648S, A643T, A643V, Y642F, G304R, A646V, and W478C. Seven of these resulted in increased ERG11 expression, increased cellular ergosterol, and decreased susceptibility to fluconazole compared to the results for the wild-type strain. Genome-wide transcriptional analysis was performed for the four strongest Upc2 amino acid substitutions (A643V, G648D, G648S, and Y642F). Genes commonly upregulated by all four mutations included those involved in ergosterol biosynthesis, in oxidoreductase activity, the major facilitator efflux pump encoded by the MDR1 gene, and the uncharacterized ATP binding cassette transporter CDR11. These findings demonstrate that gain-of function mutations in UPC2 are more prevalent among clinical isolates than previously thought and make a significant contribution to azole antifungal resistance, but the findings do not account for ERG11 overexpression in all such isolates of C. albicans. PMID- 22923049 TI - Electroconvulsive therapy in adolescents with intellectual disability and severe self-injurious behavior and aggression: a retrospective study. AB - Efficacious intervention for severe, treatment-refractory self-injurious behavior and aggression (SIB/AGG) in children and adolescents with intellectual disability and concomitant psychiatric disorders remains a complex and urgent issue. The aim of this study is to assess the efficacy of electroconvulsive therapy (ECT) on severe and treatment-resistant SIB/AGG in young people with intellectual disability and current psychiatric disorder. We reviewed the charts of all patients (N = 4) who received ECT in the context of SIB/AGG with resistance to behavioral interventions, milieu therapy and pharmacotherapy from 2007 to 2011. We scored the daily rate of SIB/AGG per patient for each hospital day. Inter rater reliability was good (intraclass correlations = 0.91). We used a mixed generalized linear model to assess whether the following explanatory variables (time, ECT) influenced the course of SIB/AGG over time, the dependant variable. The sample included two girls and two boys. The mean age at admission was 13.8 years old [range 12-14]. The patients had on average 19 ECT sessions [range 16 26] and one patient received maintenance ECT. There was no effect of time before and after ECT start. ECT was associated with a significant decrease in SIB/AGG scores (p < 0.001): mean aggression score post-ECT was half the pre-ECT value. ECT appears beneficial in severe, treatment-resistant SHBA in adolescents with intellectual disability. PMID- 22923050 TI - The exon 29 c.3535A>T in the alpha-2-macroglobulin gene causing aberrant splice variants is associated with mastitis in dairy cattle. AB - Alpha-2-macroglobulin (A2M) binds proteases, thereby acting as defense barriers against pathogens in the plasma and tissues of vertebrates and invertebrates. Quantitative real-time polymerase chain reaction (PCR) and the isobaric tags for relative and absolute quantitation method were used to determine the expression levels of A2M mRNA and proteins in mastitis-infected mammary tissues. A2M mRNA and protein expression were significantly higher in mastitis-infected mammary tissues than those in healthy tissues. We also identified 23 novel A2M splice variants in the bovine mammary tissues using reverse transcription PCR combined with clone sequencing. These splice variants predominantly affected the bait region, the inhibitory region, and the thioester region of the protein, which have the functional key roles in inhibiting the proteases of pathogens. Genomic sequencing analysis revealed a nonsynonymous c.3535A>T single-nucleotide polymorphism (SNP) in exon 29, which is located within a putative exonic splice enhancer and may be the reason why the A2M gene produces the aberrant splice variant A2M-AS4. Our findings suggest that the A2M gene can play its role by alternative splicing mechanism and it may be of significance against mastitis. This study provides clues to better understand the function of the bovine A2M gene and the effects of the exonic SNP on the production of aberrant splice variants. PMID- 22923051 TI - The impact of HLA-C matching depends on the C1/C2 KIR ligand status in unrelated hematopoietic stem cell transplantation. AB - It was previously shown that chronic myeloid leukemia (CML) patients transplanted with peripheral blood progenitor cells (PBPC) from HLA-C allele-matched donors had better clinical outcome when lacking the HLA-C-encoded KIR epitope C2. We investigated whether this holds true in other diseases and in HLA-C allele mismatched patients. Twenty-four myelodysplastic syndrome (MDS), 39 acute myeloid leukemia (AML)/CML, and 34 acute lymphoblastic leukemia/non-Hodgkin lymphoma patients received unrelated unmanipulated PBPC. HLA matching was analyzed retrospectively (including DNA-based direct sequencing of HLA-C). Only in AML/CML, the C2 ligand was associated with impaired overall survival (OS, p < 0.05). We next calculated the impact of donor/recipient HLA-C allele matching within the C1 and C2 groups. Surprisingly, AML/CML and MDS patients with C2 ligands profited from HLA-C allele mismatching (OS, p < 0.01), whereas in the C1 group, allele matching was beneficial (p < 0.05). HLA-C allele mismatching in the C2 KIR ligand group was associated with lower TRM (OR 0.48, p < 0.009) and lower relapse rate (OR 2.7 p < 0.1) when compared to allele-matched C2 patients. Thus, patients could be assigned to a low- and a high-risk group according to their C1/C2 ligand status and the HLA-C allele matching degree. These data suggest that four-digit allele matching of HLA-C has differential effects dependent on the presence of C1 and C2 KIR epitopes in the patient. PMID- 22923052 TI - Inhibition of hedgehog signaling depresses self-renewal of pancreatic cancer stem cells and reverses chemoresistance. AB - Pancreatic cancer stem cells play a crucial role in tumorigenesis and chemoresistance. The Hedgehog signaling pathway is a key regulator in pancreatic tumorigenesis and drug resistance. To identify pancreatic cancer stem cells, tumorspheres derived from the PANC-1 pancreatic cancer cell line were cultured under a floating-culture system. PANC-1 tumorspheres possessed properties of self renewal, differentiation, higher tumorigenesis and chemoresistance. It was observed that Hedgehog pathway is active in PANC-1 tumorspheres as shown by expression of hedgehog components Smo, Gil 1 and Gli 2, detected by quantitative RT-PCR and western blotting. After cyclopamine-mediated blockade of hedgehog, a decrease in proliferation of PANC-1 tumorspheres and G0/G1 transition were observed, as well as a decreased expression of Bmi-1 in PANC-1 tumorspheres. Cyclopamine reversed chemoresistance to gemcitabine, resulting in decreased expression of ABCG2 in PANC-1 tumorspheres. Taken together, our data indicate that PANC-1 tumorspheres have 'stemness' potential, and hedgehog signaling pathway plays an important role in the regulation of self-renewal and reversal of chemoresistance in cancer stem cells in pancreatic adenocarcinoma. PMID- 22923053 TI - What is the role of sedating antidepressants, antipsychotics, and anticonvulsants in the management of insomnia? AB - Psychiatric medications such as antidepressants, antipsychotics, and anticonvulsants are commonly prescribed by physicians for the off-label use of improving sleep. Reasons for preferential prescription of these medications over FDA-approved insomnia drugs may include a desire to treat concurrent sleep problems and psychiatric illness with a single medication, and/or an attempt to avoid hypnotic drugs due to their publicized side effects. However, there have been few large studies demonstrating the efficacy and safety of most off-label medications prescribed to treat insomnia. In addition, many of these medications have significant known side effect profiles themselves. Here we review the pertinent research studies published in recent years on antidepressant, antipsychotic, and anticonvulsant medications frequently prescribed for sleep difficulties. Although there have been few large-scale studies for most of these medications, some may be appropriate in the treatment of sleep issues in specific well-defined populations. PMID- 22923057 TI - Comparison of cellular lethality in DNA repair-proficient or -deficient cell lines resulting from exposure to 70 MeV/n protons or 290 MeV/n carbon ions. AB - Charged particle therapy utilizing protons or carbon ions has been rapidly intensifying over recent years. The present study was designed to jointly investigate these two charged particle treatment modalities with respect to modeled anatomical depth-dependent dose and linear energy transfer (LET) deliveries to cells with either normal or compromised DNA repair phenotypes. We compared cellular lethality in response to dose, LET and Bragg peak location for accelerated protons and carbon ions at 70 and 290 MeV/n, respectively. A novel experimental live cell irradiation OptiCellTM in vitro culture system using three different Chinese hamster ovary (CHO) cells as a mammalian model was conducted. A wild-type DNA repair-competent CHO cell line (CHO 10B2) was compared to two other CHO cell lines (51D1 and xrs5), each genetically deficient with respect to one of the two major DNA repair pathways (homologous recombination and non-homologous end joining pathways, respectively) following genotoxic insults. We found that wild-type and homologous recombination-deficient (Rad51D) cellular lethality was dependent on both the dose and LET of the carbon ions, whereas it was only dependent on dose for protons. The non-homologous end joining deficient cell line (Ku80 mutant) showed nearly identical dose-response profiles for both carbon ions and protons. Our results show that the increasingly used modality of carbon ions as charged particle therapy is advantageous to protons in a radiotherapeutic context, primarily for tumor cells proficient in non-homologous end joining DNA repair where cellular lethality is dependent not only on the dose as in the case of more common photon therapeutic modalities, but more importantly on the carbon ion LETs. Genetic characterization of patient tumors would be key to individualize and optimize the selection of radiation modality, clinical outcome and treatment cost. PMID- 22923054 TI - A genome-wide association study of breast cancer in women of African ancestry. AB - Genome-wide association studies (GWAS) in diverse populations are needed to reveal variants that are more common and/or limited to defined populations. We conducted a GWAS of breast cancer in women of African ancestry, with genotyping of >1,000,000 SNPs in 3,153 African American cases and 2,831 controls, and replication testing of the top 66 associations in an additional 3,607 breast cancer cases and 11,330 controls of African ancestry. Two of the 66 SNPs replicated (p < 0.05) in stage 2, which reached statistical significance levels of 10(-6) and 10(-5) in the stage 1 and 2 combined analysis (rs4322600 at chromosome 14q31: OR = 1.18, p = 4.3 * 10(-6); rs10510333 at chromosome 3p26: OR = 1.15, p = 1.5 * 10(-5)). These suggestive risk loci have not been identified in previous GWAS in other populations and will need to be examined in additional samples. Identification of novel risk variants for breast cancer in women of African ancestry will demand testing of a substantially larger set of markers from stage 1 in a larger replication sample. PMID- 22923055 TI - The success of pharmacogenomics in moving genetic association studies from bench to bedside: study design and implementation of precision medicine in the post GWAS era. AB - Pharmacogenomics is emerging as a popular type of study for human genetics in recent years. This is primarily due to the many success stories and high potential for translation to clinical practice. In this review, the strengths and limitations of pharmacogenomics are discussed as well as the primary epidemiologic, clinical trial, and in vitro study designs implemented. A brief discussion of molecular and analytic approaches will be reviewed. Finally, several examples of bench-to-bedside clinical implementations of pharmacogenetic traits will be described. Pharmacogenomics continues to grow in popularity because of the important genetic associations identified that drive the possibility of precision medicine. PMID- 22923058 TI - Prostaglandin E1 facilitates inotropic effects of 5-HT4 serotonin receptors and beta-adrenoceptors in failing human heart. AB - Prostaglandins have displayed both beneficial and detrimental effects in clinical studies in patients with severe heart failure. Prostaglandins are known to increase cardiac output, but the mechanism is not clarified. Here, we tested the hypothesis that prostaglandins can increase contractility in human heart by amplifying cAMP-dependent inotropic responses. Contractility was measured ex vivo in isolated left ventricular strips and phosphodiesterase (PDE) and adenylyl cyclase (AC) activity was measured in homogenates or membranes from failing human left ventricles. PGE(1) (1 uM) alone did not modify contractility, but given prior, amplified maximal serotonin (5-HT)-evoked (10 uM) contractile responses mediated by 5-HT(4) receptors several fold (24 +/- 7 % with PGE(1) vs. 3 +/- 2 % above basal with 5-HT alone). The 5-HT(4)-mediated inotropic response was amplified by the PDE3 inhibitor cilostamide and further amplified in combination with PGE(1) (26 +/- 6 vs. 56 +/- 12 % above basal). PGE(1) reduced the time to reach 90 % of both the maximal 5-HT- and isoproterenol-evoked inotropic response compared to 5-HT or isoproterenol alone. PGE(1) did not modify PDE activity in the homogenate, either alone or when given simultaneously with PDE3 and/or PDE4 inhibitors. Neither 5-HT- nor isoproterenol-stimulated AC activity was significantly amplified by PGE(1). Sensitivity of ventricular strips to Ca(2+) was not enhanced in the presence of PGE(1). Our results show that PGE(1) can enhance cAMP-mediated responses in failing human left ventricle, through a mechanism independent of PDE inhibition, amplification of AC activity or increasing sensitivity to calcium. This effect of PGE(1) possibly contributes to the increase of cardiac output, independent of decreased afterload, observed after prostaglandin administration in humans. PMID- 22923059 TI - Investigation of equine influenza virus in two geographical regions of Pakistan. AB - PURPOSE: The present study was an attempt to elucidate the seroprevalence of equine influenza virus (H3N8) in two geographically distinct regions of Pakistan where vaccination is not routinely practiced. METHODS: A total number of 315 animals of family Equidae were included in the survey. Blood samples and nasal swabs were collected from the same animal and analyzed through ELISA and Hemagglutination Inhibition. RESULTS: The seroprevalence for EIV was 10 and 8.39 in districts under study. Out of 29 ELISA positive sera, 7 (24.1 %) showed antibodies against H1 and 22 (75.9 %) showed against H3 of influenza strains. Specie-wise antibody titer against H1 was 7.5 and 9.0 for horses and donkeys, respectively, while mules were negative. Similarly, antibody titer against H3 was 7.12, 6.9, and 6.0 for horses, donkeys, and mules, respectively. No strain was isolated from the nasal swabs despite very high antibody titers of H1 and H3 in the sera of the same animals. CONCLUSIONS: Influenza viruses are circulating in equine species and continuous surveillance is needed to keep check on any future outbreak. PMID- 22923060 TI - Drug screening study using glioma stem-like cells. AB - Glioma is one of the most common malignant tumors affecting the central nervous system. We screened active drugs from 12 classes to provide experimental data for the study of human glioma. Serum-free suspension clone formation was used to induce the formation of glioma stem-like cells (GSLCs) from U251 cells. We screened active drugs from 12 classes and observed their effects on the number of tumor balls. The results revealed that serum-free suspension clone formation successfully induced the formation of GSLCs. Six active drugs [curcumin, chrysin, apigenin, luteolin, casticin and 8-bromo-7-methoxychrysin (BrMChR)] were identified by MTT assay. The drugs that affected the number of tumor balls were curcumin, luteolin, casticin and BrMChR (all P<0.05). The GSLCs were obtained by serum-free clone suspension formation and exhibited the features of cancer stem cells. PMID- 22923061 TI - Hemodynamically motivated choice of patch angioplasty for the performance of carotid endarterectomy. AB - Patch angioplasty is the most common technique used for the performance of carotid endarterectomy. A large number of materials are available, but little is known to aid the surgeon in choosing a patch while caring for a patient with carotid disease. The objective of this study was to investigate biomechanics of the carotid artery (CA) repaired with patch angioplasty, study the influence of patch width and location of closure on hemodynamics, and to select the optimal patch material from those commonly used. For this purpose, a mathematical model was built that accounts for fluid-structure interaction, three-dimensional arterial geometry, non-linear anisotropic mechanical properties, non-Newtonian flow and in vivo boundary conditions. This model was used to study disease related mechanical factors in the arterial wall and blood flow for different types of patch angioplasty. Analysis indicated that patch closures performed with autologous vein and bovine pericardium were hemodynamically superior to carotid endarterectomy with synthetic patch angioplasty (polytetrafluoroethylene, Dacron) in terms of restenosis potential. Width of the patch and location of arteriotomy were found to be of paramount importance, with narrow patches being superior to wide patches, and anterior arteriotomy being superior to the lateral arteriotomy. These data can aid vascular surgeons in their selection of patch angioplasty technique and material for the care of patients undergoing open CA repair. PMID- 22923063 TI - Multilevel examination of diabetes in modernising China: what elements of urbanisation are most associated with diabetes? AB - AIMS/HYPOTHESIS: The purpose of this study was to examine the association between urbanisation-related factors and diabetes prevalence in China. METHODS: Anthropometry, fasting blood glucose (FBG) and community-level data were collected for 7,741 adults (18-90 years) across 217 communities and nine provinces in the 2009 China Health and Nutrition Survey to examine diabetes (FBG >=7.0 mmol/l or doctor diagnosis). Sex-stratified multilevel models, clustered at the community and province levels and controlling for individual-level age and household income were used to examine the association between diabetes and: (1) a multicomponent urbanisation measure reflecting overall modernisation and (2) 12 separate components of urbanisation (e.g., population density, employment, markets, infrastructure and social factors). RESULTS: Prevalent diabetes was higher in more-urbanised (men 12%; women 9%) vs less-urbanised (men 6%; women 5%) areas. In sex-stratified multilevel models adjusting for residential community and province, age and household income, there was a twofold higher diabetes prevalence in urban vs rural areas (men OR 2.02, 95% CI 1.47, 2.78; women, OR 1.94, 95% CI 1.35, 2.79). All urbanisation components were positively associated with diabetes, with variation across components (e.g. men, economic and income diversity, OR 1.42, 95% CI 1.20, 1.66; women, transportation infrastructure, OR 1.18, 95% CI 1.06, 1.32). Community-level variation in diabetes was comparatively greater for women (intraclass correlation [ICC] 0.03-0.05) vs men (ICC <=0.01); province-level variation was greater for men (men 0.03-0.04; women 0.02). CONCLUSIONS/INTERPRETATION: Diabetes prevention and treatment efforts are needed particularly in urbanised areas of China. Community economic factors, modern markets, communications and transportation infrastructure might present opportunities for such efforts. PMID- 22923064 TI - HbA1c variability is associated with microalbuminuria development in type 2 diabetes: a 7-year prospective cohort study. AB - AIMS/HYPOTHESIS: HbA(1c) variability has been shown to be an independent risk factor for nephropathy in patients with type 1 diabetes. In this study, we aimed to explore the association between HbA(1c) variability and microalbuminuria development in patients with type 2 diabetes. We also intended to test the applicability of serially measured HbA(1c) over 2 years for this risk assessment. METHODS: Between 2003 and 2005, we recruited 821 middle-aged normoalbuminuric individuals with type 2 diabetes and followed them through to the end of 2010. The average follow-up time was 6.2 years. We defined microalbuminuria as a urine albumin to creatinine ratio of 30 mg/g (3.4 mg/mmol) or higher. HbA(1c) variability was calculated by the SD of serially measured HbA(1c). The Cox proportional hazards model was used to evaluate the association between HbA(1c) SD quartile and development of microalbuminuria. RESULTS: The incidence of microalbuminuria for the overall population was 58.4, 58.6, 60.8 and 91.9 per 1,000 person-years for Q1- to Q4-adjusted HbA(1c) SD, respectively (p for trend = 0.042). Compared with patients in Q1, those in Q4 were about 37% more likely to develop microalbuminuria. The HR derived from a series of 2 year HbA(1c) measurements was similar to that from data collection for longer than 4 years. CONCLUSIONS/INTERPRETATION: In addition to mean HbA(1c) values, HbA(1c) variability, even measured as early as 2 years, is independently associated with the development of microalbuminuria in patients with type 2 diabetes. PMID- 22923065 TI - Predictors and moderators of outcome in child and adolescent anxiety and depression: a systematic review of psychological treatment studies. AB - The aim of this literature review was to examine pre-treatment child and adolescent characteristics as predictors and moderators of outcome in psychotherapy treatment trials of anxiety and depressive disorders. A literature search was conducted using several databases and resulted in 45 published studies (32 anxiety studies and 13 depression studies) meeting predefined methodological criteria. Ten client demographic (age, gender, ethnicity, IQ) and clinical factors (duration, type of diagnosis, pre-treatment severity, comorbidity) were examined across studies. The majority of findings showed non-significant associations between demographic factors (gender and age) with treatment outcome for both the anxiety and the depression treatment trials. Some important differences between the results of the anxiety and depression treatment trials were found. The majority of findings for the anxiety studies suggest that there are no demographic or clinical factors that predict or moderate treatment outcome. For the depression studies, however, the findings suggest that baseline symptom severity and comorbid anxiety may impact on treatment response. Overall, existing studies of pre-treatment patient variables as predictors and moderators of anxiety and depression treatment outcome provide little consistent knowledge concerning for what type of patients and under what conditions treatments work. Suggestions for future research are discussed. PMID- 22923066 TI - Head circumference and height abnormalities in autism revisited: the role of pre- and perinatal risk factors. AB - Pre/perinatal risk factors and body growth abnormalities have been studied frequently as early risk markers in autism spectrum disorder (ASD), yet their interrelatedness in ASD has received very little research attention. This is surprising, given that pre/perinatal risk factors can have a substantial impact on growth trajectories in the first years of life. We aimed to determine which pre/perinatal factors were more prevalent in ASD children and if these factors differentially influenced body growth in ASD and control children. A total of 96 ASD and 163 control children matched for gender participated. Data of growth of head size and body length during the first 13 months of life were collected. Data on pre/perinatal risk factors were retrospectively collected through standardized questionnaires. Results indicated that after matching for SES, prematurity/low birth weight and being first born were more prevalent in the ASD versus the control group. In addition, with increasing age children with ASD tended to have a proportionally smaller head circumference compared to their height. However, the effect of prematurity/low birth weight on head growth corrected for height was significantly different in ASD and control children: premature/low birth weight control children showed a disproportionate larger head circumference in relation to height during their first year of life, whereas this effect was absent in premature/low birth weight ASD children. This may suggest that the etiology of abnormal growth is potentially different in ASD and control children: where abnormal growth in control children is related to suboptimal conditions in the uterus, abnormal growth in ASD may be more strongly related to the causal factors that also increase the risk for ASD. However, prospective studies measuring growth and ASD characteristics in both premature/low birth weight and a terme children are necessary to support this conclusion. PMID- 22923067 TI - Enhanced chemical and biological activities of a newly biosynthesized eugenol glycoconjugate, eugenol alpha-D-glucopyranoside. AB - Eugenol, the essential component (over 90 %) of clove oil from Eugenia caryophyllata Thunb. (Myrtaceae), is a phenolic compound well known for its versatile pharmacological actions, including analgesic, local anesthetic, anti inflammatory, antimicrobial, antitumor, and hair-growing effects. However, the application of eugenol is greatly limited mainly because of its unwanted physicochemical properties, such as low solubility, liability to sublimation, and pungent odor. Since glycosylation has been suggested to improve the physicochemical and biological properties of the parental compound, we have previously developed a novel and efficient way to biosynthesize highly purified eugenol alpha-D-glucopyranoside (alpha-EG). In light of the widely acknowledged importance of pure eugenol and the potential superiority of the glycosylation, it is crucial to further explore and compare the physicochemical and biological properties of these two phenolic compounds. In this study, we demonstrate that glucosylation is a promising method for modification of phenolic compound, and that alpha-EG is superior over its parent eugenol, in all of the tested aspects, including physicochemical properties, antioxidation activity, and antimicrobial and antitumor activities. These results strongly suggest that alpha-EG, as a novel prodrug, may serve as a useful probe and potential therapeutic drug in both fundamental research and clinical application in the coming future. PMID- 22923068 TI - Antibacterial activity and dual mechanisms of peptide analog derived from cell penetrating peptide against Salmonella typhimurium and Streptococcus pyogenes. AB - A number of research have proven that antimicrobial peptides are of greatest potential as a new class of antibiotics. Antimicrobial peptides and cell penetrating peptides share some similar structure characteristics. In our study, a new peptide analog, APP (GLARALTRLLRQLTRQLTRA) from the cell-penetrating peptide ppTG20 (GLFRALLRLLRSLWRLLLRA), was identified simultaneously with the antibacterial mechanism of APP against Salmonella typhimurium and Streptococcus pyogenes. APP displayed potent antibacterial activity against Gram-negative and Gram-positive strains. The minimum inhibitory concentration was in the range of 2 to 4 MUM. APP displayed higher cell selectivity (about 42-fold increase) as compared to the parent peptide for it decreased hemolytic activity and increased antimicrobial activity. The calcein leakage from egg yolk L-alpha phosphatidylcholine (EYPC)/egg yolk L-alpha-phosphatidyl-DL-glycerol and EYPC/cholesterol vesicles demonstrated that APP exhibited high selectivity. The antibacterial mechanism analysis indicated that APP induced membrane permeabilization in a kinetic manner for membrane lesions allowing O-nitrophenyl beta-D-galactoside uptake into cells and potassium release from APP-treated cells. Flow cytometry analysis demonstrated that APP induced bacterial live cell membrane damage. Circular dichroism, fluorescence spectra, and gel retardation analysis confirmed that APP interacted with DNA and intercalated into the DNA base pairs after penetrating the cell membrane. Cell cycle assay showed that APP affected DNA synthesis in the cell. Our results suggested that peptides derived from the cell-penetrating peptide have the potential for antimicrobial agent development, and APP exerts its antibacterial activity by damaging bacterial cell membranes and binding to bacterial DNA to inhibit cellular functions, ultimately leading to cell death. PMID- 22923069 TI - Acetylcholine for male LUTS. AB - In this review, we present the evidence on the safety and efficacy of anticholinergic therapy for men with lower urinary tract symptoms (LUTS) secondary to benign prostatic hyperplasia (BPH) and emphasize the data published over the past year. This review discusses two classes of medications whose mechanism of action attenuates the effect of acetylcholine on the LUT: anticholinergics and botulinum toxin. We review the randomized controlled trials that investigate the efficacy and side effects of anticholinergics when used in men with LUTS secondary to BPH. We emphasize new studies and developments that have been made in the past year. PMID- 22923070 TI - In vivo real-time imaging of chemotherapy response on the liver metastatic tumor microenvironment using multiphoton microscopy. AB - In vivo real-time visualization of chemotherapy response at the cellular level provides us with direct evidence of what happens on the tumor microenvironment of metastatic organs. We imaged the response of metastatic tumor cells and host stromal cells to chemotherapeutics on liver metastatic xenografts in living mice using intravital two-photon laser scanning microscopy (TPLSM). Red fluorescent protein-expressing human colorectal cancer cells (HT29) was inoculated to the spleen of green fluorescent protein-expressing nude mice. 5-Fluorouracil or irinotecan was intraperitoneally administered after the formation of macroscopic liver metastases. Intravital TPLSM was performed at multiple time-points for time series imaging of liver metastatic xenografts in the same mice. Under the 1st TPLSM, HT29 cells were visualized in hepatic sinusoids at the single cell level. Liver metastatic nodules consisting of viable cancer cells and surrounding stroma with tumor vessels were visualized under the 2nd TPLSM. After chemotherapy, tumor cell fragmentation, condensation, swelling and intracellular vacuoles were observed under the 3rd TPLSM. There was no obvious morphological difference in tumor response between these chemotherapeutics. Time-series intravital TPLSM imaging on the metastatic tumor xenografts may be useful for screening and evaluating new chemotherapeutics with less interindividual variability. PMID- 22923071 TI - Clinical significance of LGR5 and CD44 expression in locally advanced rectal cancer after preoperative chemoradiotherapy. AB - LGR5, known as a target of Wnt signaling, has been reported as an intestinal stem cell marker. Recent reports showed that LGR5 was associated with carcinogenesis and tumor invasion in colorectal cancer. CD44 is a ubiquitously expressed cell adhesion molecule and also a potential cell surface marker on colon cancer stem cells. Both LGR5 and CD44 have been also reported to be Wnt signal targets. The aim of this study was to investigate the association of these markers with clinical outcome in rectal cancer after preoperative chemoradiotherapy (CRT). A total of 52 rectal cancer specimens were obtained from patients who underwent preoperative CRT. We performed transcriptional and immunohistochemical analyses, and retrospectively studied the association of LGR5 and CD44 expression levels with clinical outcomes. For CD44, its expression in cancer stroma was also evaluated. The levels of cancer LGR5 and CD44 gene expression were significantly and positively correlated. LGR5 gene expression level in cancer and positivity of CD44 gene expression in cancer stroma were significantly correlated with disease recurrence. Elevated cancer LGR5 gene expression and positive CD44 gene expression in cancer stroma were significantly associated with poor recurrence free and overall survival. Multivariate analysis indicated that positivity of stromal CD44 gene expression was an independent prognostic factor for the recurrence and overall survival of patients with rectal cancer after preoperative CRT. In conclusion, LGR5 and CD44 expression may be coordinately associated with tumor relapse in locally advanced rectal cancer after preoperative CRT. PMID- 22923072 TI - Evaluation of long-term outcomes of pasteurized autografts in limb salvage surgeries for bone and soft tissue sarcomas. AB - BACKGROUND: Pasteurized autografts used in limb salvage operations for malignant musculoskeletal tumors have several advantages, including reduced disease transmission, economic efficiency, accessibility, and anatomical conformation. However, their use has been associated with bone absorption, fracture, and pseudarthrosis. Few studies exist which have assessed the long-term outcomes of pasteurized autografts. The purpose of this study was to investigate the clinical outcomes of patients treated with pasteurized autografts and to compare these outcomes across various graft types. METHODS: A retrospective analysis of 46 patients treated with pasteurized autografts between 1992 and 2010 was conducted. The analysis included 22 intercalary bone grafts, 17 inlay grafts, 4 composite grafts, and 3 osteochondral grafts, with the mean follow-up period of 8.7 years (2-17 years). RESULTS: The 10-year survival rate of the 46 pasteurized autograft cases analyzed was 93.5 %, and the average bone union time between host and pasteurized autogenous bone was 9.5 months. Infections were identified in 6 (13 %) patients, fractures in 7 (15 %) patients, non-union in 8 (17 %) patients, and bone absorption in 6 (13 %) patients. Inlay grafts were completely incorporated with the host bone at the follow-up period. Combination with a vascularized fibular graft significantly reduced the risk of non-union and bone absorption (p < 0.05 and p < 0.01, respectively), with an average functional score of 23.1/30 (83.8 %). CONCLUSION: Our findings show that pasteurized bone grafts in combination with vascularized fibular grafts have improved outcomes and potential clinical indications. PMID- 22923073 TI - Developmental aspects of mood disorders. AB - Rates of depression double in the transition to adolescence. Symptoms of depression in adolescence also predict adult mood disorders. From a preventative perspective, research into the risk factors for adolescent depression is critical. Simultaneously, there is also growing interest in understanding why adolescence reflects a particularly critical period for the onset of early mood symptoms. Here, we review (a) the role of social, genetic, neural and cognitive factors in explaining individual differences in the propensity to develop symptoms in adolescence, and (b) whether changes in these factors may explain why adolescence is a particularly sensitive period for the onset of depressive symptoms. Finally, we speculate on whether novel social stressors interact with 'genetic innovation' to produce changes in brain circuitry structure and function and associated changes in emotion regulation abilities and social understanding to increase emergence of symptoms in adolescence. PMID- 22923074 TI - Classification of depressive disorders. AB - The classification of depression is well established in major diagnostic systems and operational definitions now make the diagnosis of depression reasonably reliable. However, classification and diagnosis continue to be based on clinical presentation and course and are not currently informed by aetiological or pathophysiological considerations. It is still unclear, for example, whether or not categories such as melancholic depression represent distinct subforms of illness or whether a dimensional classification based on severity can capture clinical presentation adequately and more economically. Despite these caveats, there is some evidence that distinctions between various subforms of depression can predict treatment response and this can be useful for clinical practice as well as guiding research strategies. PMID- 22923075 TI - Quality of life monitoring in ambulatory heart failure patients: temporal changes and prognostic value. AB - AIMS: Heart failure (HF) is a chronic condition that typically affects a patient's quality of life (QoL). Little is known about long-term QoL monitoring in HF. This study aimed to evaluate the temporal changes and prognostic value of QoL assessment in a real-life cohort of HF patients. METHODS AND RESULTS: The Minnesota Living with Heart Failure Questionnaire was used to monitor QoL at baseline and at 1, 3, and 5 years for 1151 consecutive patients {71.7% men, median age 69 years [25th-75th percentiles (P(25)-P(75)) 59-76]} in an HF unit. Follow-up for prognosis assessment was extended to 6 years. The number of answered questionnaires was 1151 at baseline, 746 at 1 year, 268 at 3 years, and 240 at 5 years. QoL scores showed a steep decrease (indicating QoL improvement) during the first year [29 (P(25)-P(75) 16-43) at baseline vs. 15 (P(25)-P(75) 8 27) at 1 year, P < 0.001], which was tempered, yet significant up to 5 years [12 (P(25)-P(75) 7-23) at 3 years vs. 10 (P(25)-P(75) 5-21) at 5 years, P = 0.012]. We recorded 457 deaths during follow-up. In a comprehensive multivariable Cox regression analysis, baseline QoL remained a significant prognosticator during follow-up [hazard ratio (HR)(Cox) for death 1.012, 95% confidence interval 1.006 1.018, P < 0.001]. QoL monitoring showed that a score increase >=10% between consecutive assessments stratified high-risk patients within the next 12 months (P = 0.008). CONCLUSION: Both baseline and follow-up QoL monitoring were useful for patient risk stratification in a real-life HF cohort. Worse QoL may warn of a worse prognosis. Widespread QoL monitoring in routine clinical practice is recommended. PMID- 22923076 TI - Stochastic and deterministic processes together determine alpine meadow plant community composition on the Tibetan Plateau. AB - To predict the consequences of environmental change on the structure and composition of communities, it is necessary to also understand the regional drivers underlying the structuring of these communities. Here, we have taken a hypothesis-based approach to test the relative importance of niche versus neutral processes using niche overlap, species traits and population asynchrony in two crossed treatments of fertilization and grazing in an alpine meadow community. Our results suggested that the observed species biomass overlap was not significantly different between treatments of grazing, grazing * fertilization and grazer exclusion. In contrast, the species biomass overlap was higher than expected in fertilization treatments when grazers were excluded. On the one hand, we found no relationship between species traits and relative abundance in grazing, grazing * fertilization and grazer-exclusion treatments; on the other hand, mechanistic trait-based theory could be used to predict species relative abundance patterns in fertilization treatments when grazers were excluded. From grazing to fertilization, when grazers were excluded, there was a slight increase in species synchrony, which indicated that the complementary dynamic of species gradually changed from complete independence into synchronously fluctuating with increasing fertilization. Based on the above results, we concluded that stochastic and deterministic processes formed ends of a continuum from grazing to fertilization when grazers were excluded in an alpine meadow plant community, and the importance of niche differences between species in structuring grassland communities increased with increasing fertilization and decreased with grazing. PMID- 22923078 TI - Warning on blackleg incidence in Scotland. PMID- 22923077 TI - Action on antimicrobial resistance highlighted in VMD's annual review. PMID- 22923079 TI - RCVS clarifies legal position on disbudding goats. PMID- 22923080 TI - New sentencing guidelines for dangerous dog offences. PMID- 22923082 TI - International disease monitoring, April to June 2012. PMID- 22923083 TI - Is obesity a problem in pet rabbits? PMID- 22923084 TI - Systemic coronavirus-associated disease resembling feline infectious peritonitis in ferrets in the UK. PMID- 22923085 TI - Schmallenberg virus: lessons from related viruses. PMID- 22923086 TI - Efficient visual object and word recognition relies on high spatial frequency coding in the left posterior fusiform gyrus: evidence from a case-series of patients with ventral occipito-temporal cortex damage. AB - Recent visual neuroscience investigations suggest that ventral occipito-temporal cortex is retinotopically organized, with high acuity foveal input projecting primarily to the posterior fusiform gyrus (pFG), making this region crucial for coding high spatial frequency information. Because high spatial frequencies are critical for fine-grained visual discrimination, we hypothesized that damage to the left pFG should have an adverse effect not only on efficient reading, as observed in pure alexia, but also on the processing of complex non-orthographic visual stimuli. Consistent with this hypothesis, we obtained evidence that a large case series (n = 20) of patients with lesions centered on left pFG: 1) Exhibited reduced sensitivity to high spatial frequencies; 2) demonstrated prolonged response latencies both in reading (pure alexia) and object naming; and 3) were especially sensitive to visual complexity and similarity when discriminating between novel visual patterns. These results suggest that the patients' dual reading and non-orthographic recognition impairments have a common underlying mechanism and reflect the loss of high spatial frequency visual information normally coded in the left pFG. PMID- 22923087 TI - Mapping region-specific longitudinal cortical surface expansion from birth to 2 years of age. AB - The human cerebral cortex develops rapidly and dynamically in the first 2 years of life. It has been shown that cortical surface expansion from term infant to adult is highly nonuniform in a cross-sectional study. However, little is known about the longitudinal cortical surface expansion during early postnatal stages. In this article, we generate the first longitudinal surface-based atlases of human cortical structures at 0, 1, and 2 years of age from 73 healthy subjects. On the basis of the surface-based atlases, we study the longitudinal cortical surface expansion in the first 2 years of life and find that cortical surface expansion is age related and region specific. In the first year, cortical surface expands dramatically, with an average expansion of 1.80 times. In particular, regions of superior and medial temporal, superior parietal, medial orbitofrontal, lateral anterior prefrontal, occipital cortices, and postcentral gyrus expand relatively larger than other regions. In the second year, cortical surface still expands substantially, with an average expansion of 1.20 times. In particular, regions of superior and middle frontal, orbitofrontal, inferior temporal, inferior parietal, and superior parietal cortices expand relatively larger than other regions. These region-specific patterns of cortical surface expansion are related to cognitive and functional development at these stages. PMID- 22923088 TI - The doublesex homolog Dmrt5 is required for the development of the caudomedial cerebral cortex in mammals. AB - Regional patterning of the cerebral cortex is initiated by morphogens secreted by patterning centers that establish graded expression of transcription factors within cortical progenitors. Here, we show that Dmrt5 is expressed in cortical progenitors in a high-caudomedial to low-rostrolateral gradient. In its absence, the cortex is strongly reduced and exhibits severe abnormalities, including agenesis of the hippocampus and choroid plexus and defects in commissural and thalamocortical tracts. Loss of Dmrt5 results in decreased Wnt and Bmp in one of the major telencephalic patterning centers, the dorsomedial telencephalon, and in a reduction of Cajal-Retzius cells. Expression of the dorsal midline signaling center-dependent transcription factors is downregulated, including Emx2, which promotes caudomedial fates, while the rostral determinant Pax6, which is inhibited by midline signals, is upregulated. Consistently, Dmrt5(-/-) brains exhibit patterning defects with a dramatic reduction of the caudomedial cortex. Dmrt5 is increased upon the activation of Wnt signaling and downregulated in Gli3(xt/xt) mutants. We conclude that Dmrt5 is a novel Wnt-dependent transcription factor required for early cortical development and that it may regulate initial cortical patterning by promoting dorsal midline signaling center formation and thereby helping to establish the graded expression of the other transcription regulators of cortical identity. PMID- 22923089 TI - Dynamic equilibrium of Marek's disease genomes during in vitro serial passage. AB - Attenuation of Gallid herpesvirus-2 (GaHV-2), the causative agent of Marek's disease, can occur through serial passage of a virulent field isolate in avian embryo fibroblasts. In order to gain a better understanding of the genes involved in attenuation and associate observed changes in phenotype with specific genetic variations, the genomic DNA sequence of a single GaHV-2 virulent strain (648A) was determined at defined passage intervals. Biological characterization of these "interval-isolates" in chickens previously indicated that the ability to induce transient paralysis was lost by passages 40 and the ability to induce persistent neurological disease was lost after passage 80, coincident with the loss of neoplastic lesion formation. Deep sequencing of the interval-isolates allowed for a detailed cataloguing of the mutations that exist within a single passage population and the frequency with which a given mutation occurs across passages. Gross genetic alterations were identified in both novel and well-characterized genes and cis-acting regions involved in replication and cleavage/packaging. Deletions in genes encoding the virulence factors vLipase, vIL8, and RLORF4, as well as a deletion in the promoter of ICP4, appeared between passages 61 and 101. Three mutations in the virus-encoded telomerase which predominated in late passages were also identified. Overall, the frequency of mutations fluctuated greatly during serial passage and few genetic changes were absolute. This indicates that serial passage of GaHV-2 results in the generation of a collection of genomes with limited sequence heterogeneity. PMID- 22923090 TI - Phylogenetic analysis of the bovine parainfluenza virus type 3 from cattle herds revealing the existence of a genotype A strain in China. AB - In 2009, a bovine parainfluenza virus (BPIV3), named as NM09, was isolated using MDBK cell culture from the nasal swabs of normal cattle in China. The NM09 isolate was characterized by RT-PCR and nucleotide sequence analysis. Its complete genome was 15,456 nucleotides in length. Similar to other sequenced PIV strains, the NM09 virus consisted of six non-overlapping genes, which were predicted to encode nine proteins with conserved and complementary 3' leader and 5' trailer regions, conserved gene starts, gene stops, and trinucleotide intergenic sequences. Nucleotide phylogenetic analysis of matrix and hemagglutinin-neuraminidase gene demonstrated that this NM09 isolate belonged to BPIV3 genotype A instead of the previously reported BPIV3 genotype C in China. It is implicated that the different genotypes A and C might coexist infection for a long time in China. PMID- 22923091 TI - Icariin inhibits corticosterone-induced apoptosis in hypothalamic neurons via the PI3-K/Akt signaling pathway. AB - Excessive corticosterone (CORT) is acknowledged to induce neuronal damage in a number of regions of the brain, particularly the hippocampus, the main area implicated in depression. However, little research has been conducted on alterations to hypothalamic neurons in depression and the cellular and molecular basis for these changes. In the present study, we aimed to determine whether CORT causes apoptosis in primary cultured hypothalamic neurons, and to investigate the protective effects of icariin, an active natural ingredient from the Chinese plant, Epimedium sagittatum Maxim. Our study demonstrates that exposure of hypothalamic neurons to CORT causes a significant loss in viability, a significant decrease in mitochondrial membrane potential, an increase in caspase 3 activity, an elevation in intracellular reactive oxygen species elevation and decreased superoxide dismutase activity. However, pretreatment of cells with icariin prior to CORT exposure was identified to noticeably suppress these CORT induced events. Furthermore, icariin may prevent CORT-induced cell death via activation of the PI3-K/Akt pathway. In conclusion, icariin is able to prevent CORT-induced hypothalamic cell apoptosis via activation of the PI3-K/Akt pathway. PMID- 22923094 TI - 'Omics investigations of HIV and SIV pathogenesis and innate immunity. AB - In the 30 years since the advent of the AIDS epidemic, the biomedical community has put forward a battery of molecular therapies that are based on the accumulated knowledge of a limited number of viral targets. Despite these accomplishments, the community still confronts unanswered foundational questions about HIV infection. What are the cellular or biomolecular processes behind HIV pathogenesis? Can we elucidate the characteristics that distinguish those individuals who are naturally resistant to either infection or disease progression? The discovery of simian immunodeficiency viruses (SIVs) and the ensuing development of in vivo, nonhuman primate (NHP) infection models was a tremendous advance, especially in abetting the exploration of vaccine strategies. And while there have been numerous NHP infection models and vaccine trials performed, fundamental questions remain regarding host-virus interactions and immune correlates of protection. These issues are, perhaps, most starkly illustrated with the appreciation that many species of African nonhuman primates are naturally infected with strains of SIV that do not cause any appreciable disease while replicating to viral loads that match or exceed those seen with pathogenic SIV infections in Asian species of nonhuman primates. The last decade has seen the establishment of high-throughput molecular profiling tools, such as microarrays for transcriptomics, SNP arrays for genome features, and LC-MS techniques for proteins or metabolites. These provide the capacity to interrogate a biological model at a comprehensive, systems level, in contrast to historical approaches that characterized a few genes or proteins in an experiment. These methods have already had revolutionary impacts in understanding human diseases originating within the host genome such as genetic disorders and cancer, and the methods are finding increasing application in the context of infectious disease. We will provide a review of the use of such 'omics investigations as applied to understanding of HIV pathogenesis and innate immunity, drawing from our own research as well as the literature examples that utilized in vitro cell-based models or studies in nonhuman primates. We will also discuss the potential for systems biology to help guide strategies for HIV vaccines that offer significant protection by either preventing acquisition or strongly suppressing viral replication levels post-infection. PMID- 22923095 TI - Effects of Lactobacillus salivarius, Lactobacillus reuteri, and Pediococcus acidilactici on the nematode Caenorhabditis elegans include possible antitumor activity. AB - This study examined the effects of three lactic acid bacteria (LAB) strains on the nematode Caenorhabditis elegans. Lactobacillus salivarius, Lactobacillus reuteri, and Pediococcus acidilactici were found to inhibit the development and growth of the worm. Compared to Escherichia coli used as the control, L. reuteri and P. acidilactici reduced the lifespan of wild-type and short-lived daf-16 worms. On the contrary, L. salivarius extended the lifespan of daf-16 worms when used live, but reduced it as UV-killed bacteria. The three LAB induced the expression of genes involved in pathogen response and inhibited the growth of tumor-like germ cells, without affecting DAF16 localization or increasing corpse cells. Our results suggest the possible use of C. elegans as a model for studying the antitumor attributes of LAB. The negative effects of these LAB strains on the nematode also indicate their potential use against parasitic nematodes. PMID- 22923096 TI - Conversion of CO2 into biomass by microalgae: how realistic a contribution may it be to significant CO2 removal? AB - Microalgae have been proposed as a CO(2) removal option to contribute to climate change avoidance and problems coming from the use of fossil fuels. However, even though microalgae can be used to fix CO(2) from air or flue gases, they do not permit long-term CO(2) storage because they are easily decomposed. On the other hand, microalgae can contribute to an enhancement in human sustainability by producing biofuels as an alternative to fossil fuels in addition to the production of other useful chemicals and commodities. Moreover, microalgae can contribute to enhancing the sustainability of waste treatment processes, reducing the energy consumed, and improving the recycling of nutrients contained within them. This paper reviews the potential contribution of these processes and the existing knowledge in these areas. PMID- 22923097 TI - Management of tachyarrhythmias in children. AB - OPINION STATEMENT: Management of tachycardia in children depends on the accurate characterization of the origin and mechanism of the rhythm, which can usually be achieved using noninvasive tests such as an electrocardiogram, Holter or cardiac event monitoring. Supraventricular tachycardia (SVT), the most common tachyarrhythmia in children, is most often due to an accessory pathway or dual AV nodal pathways. Adenosine and vagal maneuvers are useful to diagnose and terminate an acute event. Long-term management options include prophylactic drug therapy (aimed at suppressing the tachyarrhythmia) and catheter ablation. Ablation for SVT is highly successful with a low complication rate, and is first line therapy in older patients. Ventricular arrhythmias are fortunately uncommon in children with normal hearts, and are seen primarily in the setting of abnormal myocardium and inherited ion channel defects. Management options for ventricular rhythms include drugs, catheter ablation and implantable cardioverter defibrillators (ICDs). ICDs are indicated in patients with a risk of sudden death due to an arrhythmia. PMID- 22923098 TI - Treatment of obstructive sleep apnea in patients with cardiac arrhythmias. AB - OPINION STATEMENT: Obstructive sleep apnea (OSA) is the most common form of sleep disordered breathing that is prevalent in the population and frequently under diagnosed. Usually presenting with respiratory symptoms, the most significant consequences of OSA are cardiovascular, including arrhythmias. The pathophysiology of OSA through multiple mechanisms may promote bradyarrhythmias, atrial fibrillation, premature ventricular complexes, ventricular arrhythmias, and sudden death. These mechanisms may acutely trigger nocturnal arrhythmias and may chronically affect electrical and structural myocardial changes, causing arrhythmias. Numerous epidemiological data have identified an increased risk for atrial fibrillation, ventricular fibrillation and sudden death in subjects with OSA. Diagnosis of OSA should be considered in patients with arrhythmias. However, not all patients with arrhythmias need to undergo formal testing for sleep apnea. Patients who are observed to have nocturnal arrhythmias should be considered for evaluation for possible OSA. Also, if the arrhythmia is refractory to standard therapy and if other clinical indicators of OSA are also present, there should be a low threshold for pursuing the diagnosis of sleep apnea. The principal therapy for OSA is continuous positive airway pressure (CPAP). Currently, there are limited data to support the efficacy of CPAP for arrhythmia prevention or treatment. Randomized trials are necessary to determine the efficacy of OSA treatment on arrhythmia prevention. PMID- 22923100 TI - Rising to the challenge: cross-cultural adaptation and psychometric evaluation of the adapted German version of the Jefferson Scale of Physician Empathy for Students (JSPE-S). AB - Assessment of students' attitudes towards physicians' empathy is essential in medical education and in practice because empathy is vital in physician-patient communication. To cross-culturally adapt the Jefferson Scale of Physician Empathy (S-version, JSPE-S) into a German version, examine its psychometric properties in comparison to the original US version (psychometric equivalence), and to compare the level of attitude towards empathy to the original US version and to other cultural adaptations. The German version was administered to the 2010 2nd year medical students cohort at the Medical University of Vienna, Austria (n = 516). Item-total score correlations were all positive. Reliability was high (Cronbach's alpha = .82); a 6-7 weeks test-retest correlation for a subsample was .45. In an explanatory factor analysis, a four-factor solution emerged and is akin to published results of the original JSPE-S. This study provides an example of successful cross-cultural adaptation of an assessment instrument. The German adaptation of the JSPE at hand will pave the way for future international research regarding the concept of empathy and its outcomes. PMID- 22923099 TI - Update on the use and outcomes of implantable cardioverter defibrillators in pediatric patients. AB - OPINION STATEMENT: The vast majority of implantable cardioverter defibrillators (ICDs) continue to be implanted in the adult population. Accordingly, manufacturers develop devices and leads primarily for the adult population. Whilst the number of ICDs implanted in children is small in comparison, the potential benefits are large to this group. It is a common frustration among pediatric cardiologists whom implant devices that impressive technological developments continue to be developed for the adult population; as the population of children with ICDs is small, robust clinical studies often lag behind. By necessity, pediatric cardiologists and cardiothoracic surgeons have developed innovative techniques utilizing adult components in unusual configurations for children with complex congenital heart disease. As in the adult population, inappropriate shocks are one of the most limiting and concerning complications in the use of ICDs. Unfortunately, as will be discussed below, children are at increased risk of inappropriate shocks when compared with adults. The true impact of inappropriate shocks is increasingly being realized, and much of the focus in management of children with ICDs surrounds the prevention of inappropriate shocks. PMID- 22923101 TI - Cell migration: regulation of cytoskeleton by Rap1 in Dictyostelium discoideum. AB - Cell movement involves a coordinated regulation of the cytoskeleton, F-actin mediated protrusions at the front and myosin-mediated contraction of the posterior of a cell. The small GTPase Rap1 functions as a key regulator in the spatial and temporal control of cytoskeleton reorganization for cell migration. This review outlines the establishment of cell polarity by differential localizations of the cytoskeleton and discusses the spatial and temporal regulation of cytoskeleton reorganization via the Rap1 signaling pathway during chemotaxis with a focus on recent advances in the study of chemotaxis using a simple eukaryotic model organism, Dictyostelium discoideum. PMID- 22923102 TI - Flavobacterium cheonhonense sp. nov., isolated from a freshwater reservoir. AB - A novel bacterium, designated strain ARSA-15(T), was isolated from a freshwater sample collected from the Cheonho reservoir, Cheonan, Republic of Korea. The isolate was deep-yellow pigment, Gram-negative, rod-shaped, non-motile, and catalase- and oxidase-positive. Phylogenetic analysis based on 16S rRNA gene sequences showed that the isolate belongs to the genus Flavobacterium, and shared less than 97% sequence similarity with recognized Flavobacterium species. The novel species was able to grow at 10-37 degrees C, pH 6.5-10.0, and in 0-0.5% (w/v) NaCl concentrations. Chemotaxonomically, iso-C(15:1), iso-C(15:0), and iso C(16:0) were observed to be the predominant cellular fatty acid, and menaquinone 6 (MK-6) was the predominant respiratory quinone. The major polar lipid patterns of strain ARSA-19(T) was phosphatidylethanolamine, unknown aminolipid (AL1 and AL2), and unidentified polar lipids (L1, L2, and L3). The genomic DNA G+C content of the isolate was 39.2 mol%. On the basis of polyphasic approach, strain ARSA 15(T) represents a novel species of the genus Flavobacterium, for which the name Flavobacterium cheonhonense sp. nov. is proposed. The type strain is ARSA-15(T) (=KACC 14967(T) =KCTC 23180(T) =JCM 17064(T)). PMID- 22923103 TI - Parallel gene loss and acquisition among strains of different Brucella species and biovars. AB - The genus Brucella is divided into six species; of these, B. melitensis and B. abortus are pathogenic to humans, and B. ovis and B. neotomae are nonpathogenic to humans. The definition of gene loss and acquisition is essential for understanding Brucella's ecology, evolutionary history, and host relationships. A DNA microarray containing unique genes of B. melitensis Type strain 16MT and B. abortus 9-941 was constructed and used to determine the gene contents of the representative strains of Brucella. Phylogenetic relationships were inferred from sequences of housekeeping genes. Gene loss and acquisition of different Brucella species were inferred. A total of 214 genes were found to be differentially distributed, and 173 of them were clustered into 15 genomic islands (GIs). Evidence of horizontal gene transfer was observed for 10 GIs. Phylogenetic analysis indicated that the 19 strains formed five clades, and some of the GIs had been lost or acquired independently among the different lineages. The derivation of Brucella lineages is concomitant with the parallel loss or acquisition of GIs, indicating a complex interaction between various Brucella species and hosts. PMID- 22923104 TI - Thionine increases electricity generation from microbial fuel cell using Saccharomyces cerevisiae and exoelectrogenic mixed culture. AB - Microbial fuel cells (MFCs) have been shown to be capable of clean energy production through the oxidation of biodegradable organic waste using various bacterial species as biocatalysts. In this study we found Saccharomyces cerevisiae, previously known electrochemcially inactive or less active species, can be acclimated with an electron mediator thionine for electrogenic biofilm formation in MFC, and electricity production is improved with facilitation of electron transfer. Power generation of MFC was also significantly increased by thionine with both aerated and non-aerated cathode. With electrochemically active biofilm enriched with swine wastewater, MFC power increased more significantly by addition of thionine. The optimum mediator concentration was 500 mM of thionine with S. cerevisae in MFC with the maximum voltage and current generation in the microbial fuel cell were 420 mV and 700 mA/m(2), respectively. Cyclic voltametry shows that thionine improves oxidizing and reducing capability in both pure culture and acclimated biofilm as compared to non-mediated cell. The results obtained indicated that thionine has great potential to enhance power generation from unmediated yeast or electrochemically active biofilm in MFC. PMID- 22923105 TI - Enhancement of anti-candidal activity of endophytic fungus Phomopsis sp. ED2, isolated from Orthosiphon stamineus Benth, by incorporation of host plant extract in culture medium. AB - This study examined the effect of host extract in the culture medium on anti candidal activity of Phomopsis sp. ED2, previously isolated from the medicinal herb Orthosiphon stamineus Benth. Interestingly, upon addition of aqueous host extract to the culture medium, the ethyl acetate extract prepared from fermentative broth exhibited moderate anti-candidal activity in a disc diffusion assay. The minimal inhibitory concentration of this extract was 62.5 MUg/ml and it only exhibited fungistatic activity against C. albicans. In the time-kill study, a 50% growth reduction of C. albicans was observed at 31.4 h for extract from the culture incorporating host extract. In the bioautography assay, only one single spot (Rf 0.59) developed from the extract exhibited anti-candidal activity. A spot with the a similar Rf was not detected for the crude extract from YES broth without host extract. This indicated that the terpenoid anti candidal compound was only produced when the host extract was introduced into the medium. The study concluded that the incorporation of aqueous extract of the host plant into the culture medium significantly enhanced the anti-candidal activity of Phomopsis sp. ED2. PMID- 22923106 TI - Copper as an antimicrobial agent against opportunistic pathogenic and multidrug resistant Enterobacter bacteria. AB - Infections by Enterobacter species are common and are multidrug resistant. The use of bactericidal surface materials such as copper has lately gained attention as an effective antimicrobial agent due to its deadly effects on bacteria, yeast, and viruses. The aim of the current study was to assess the antibacterial activity of copper surfaces against Enterobacter species. The antibacterial activity of copper surfaces was tested by overlying 5*10(6) CFU/ml suspensions of representative Enterobacter strains and comparing bacterial survival counts on copper surfaces at room temperature. Iron, stainless steel, and polyvinylchloride (PVC) were used as controls. The mechanisms responsible for bacterial killing on copper surfaces were investigated by a mutagenicity assay of the D-cycloserin (cyclA gene), single cell gel electrophoresis, a staining technique, and inductively coupled plasma mass spectroscopy. Copper yielded a significant decrease in the viable bacterial counts at 2 h exposure and a highly significant decrease at 4 h. Loss of cell integrity and a significantly higher influx of copper into bacterial cells exposed to copper surfaces, as compared to those exposed to the controls, were documented. There was no increase in mutation rate and DNA damage indicating that copper contributes to bacterial killing by adversely affecting cellular structure without directly targeting the genomic DNA. These findings suggest that copper's antibacterial activity against Enterobacter species could be utilized in health care facilities and in food processing plants to reduce the bioburden, which would increase protection for susceptible members of the community. PMID- 22923107 TI - Involvement of alternative oxidase in the regulation of growth, development, and resistance to oxidative stress of Sclerotinia sclerotiorum. AB - Sclerotinia sclerotiorum is a cosmopolitan, filamentous, fungal pathogen that can cause serious disease in many kinds of crops. Alternative oxidase is the terminal oxidase of the alternative mitochondrial respiratory pathway in fungi and higher plants. We report the presence of this alternative pathway respiration and demonstrate its expression in two isolates of S. sclerotiorum under unstressed, normal culture conditions. Application of salicylhydroxamic acid, a specific inhibitor of alternative oxidase, severely inhibited the mycelial growth of S. sclerotiorum both on potato dextrose agar plates and in liquid culture media. Inhibition of alternative oxidase could influence the growth pattern of S. sclerotiorum, as salicylhydroxamic acid treatment induced obvious aerial mycelia growing on potato dextrose agar plates. Under the treatment with salicylhydroxamic acid, S. sclerotiorum formed sclerotia much more slowly than the control. Treatment with hydrogen peroxide in millimolar concentrations greatly decreased the growth rate of mycelia and delayed the formation of sclerotia in both tested S. sclerotiorum isolates. As well, this treatment obviously increased their alternative pathway respiration and the levels of both mRNA and protein of the alternative oxidase. These results indicate that alternative oxidase is involved in the regulation of growth, development, and resistance to oxidative stress of S. sclerotiorum. PMID- 22923108 TI - Screening for probiotic properties of strains isolated from feces of various human groups. AB - The present study searched for potential probiotic strains from various human fecal samples. A total of 67 aerobic and 38 anaerobic strains were isolated from 5 different categories of human feces. Systematic procedures were used to evaluate the probiotic properties of the isolated strains. These showed about 75 97% survivability in acidic and bile salt environments. Adhesion to intestinal cell line Caco-2 was also high. The isolates exhibited hydrophobic properties in hexadecane. The culture supernatants of these strains showed antagonistic effects against pathogens. The isolates were resistant to a simulated gastrointestinal environment in vitro. Of the 4 best isolates, MAbB4 (Staphylococcus succinus) and FIdM3 (Enterococcus fecium), were promising candidates for a potential probiotic. S. succinus was found to be a probiotic strain, which is the second such species reported to date in this particular genus. A substantial zone of inhibition was found against Salmonella spp., which adds further support to the suggestion that the probiotic strain could help prevent intestinal infection. This study suggested that the human flora itself is a potential source of probiotics. PMID- 22923109 TI - Lactobacillus delbrueckii ssp. lactis R4 prevents Salmonella typhimurium SL1344 induced damage to tight junctions and adherens junctions. AB - Cell junctions are the gatekeepers of the paracellular route and defend the mucosal barrier. Several enteropathogenic bacteria can invade intestinal epithelial cells by targeting and damaging cell junctions. It is not well understood how Salmonella typhimurium is able to overcome the intestinal barrier and gain access to the circulation, nor is it understood how Lactobacillus prevents the invasion of S. typhimurium. Therefore, we sought to determine whether infection with S. typhimurium SL1344 could regulate the molecular composition of cell junctions and whether Lactobacillus delbrueckii ssp. lactis R4 could affect this modification. Our data demonstrated that infection of Caco-2 cells with S. typhimurium over 2 h resulted in a redistribution of claudin-1, ZO 1, occluding, and E-cadherin. Western blot analysis of epithelial cell lysates demonstrated that S. typhimurium could decrease the expression of cell junction proteins. However, L. delbrueckii ssp. lactis R4 ameliorated this destruction and induced increased expression of ZO-1, occludin, and E-cadherin relative to the levels in the control group. The results of these experiments implied that S. typhimurium may facilitate its uptake and distribution within the host by regulating the molecular composition of cell junctions. Furthermore, Lactobacillus may prevent the adhesion and invasion of pathogenic bacteria by maintaining cell junctions and the mucosal barrier. PMID- 22923110 TI - The role of a dark septate endophytic fungus, Veronaeopsis simplex Y34, in Fusarium disease suppression in Chinese cabbage. AB - The soil-inhabiting fungal pathogen Fusarium oxysporum has been an increasing threat to Chinese cabbage (Brassica campestris L.). A dark septate endophytic fungus, Veronaeopsis simplex Y34, isolated from Yaku Island, Japan, was evaluated in vitro for the ability to suppress Fusarium disease. Seedlings grown in the presence of the endophyte showed a 71% reduction in Fusarium wilt disease and still had good growth. The disease control was achieved through a synergetic effect involving a mechanical resistance created by a dense network of V. simplex Y34 hyphae, which colonized the host root, and siderophore production acting indirectly to induce a resistance mechanism in the plant. Changes in the relative abundance of the fungal communities in the soil as determined by fluorescently labelled T-RFs (terminal restriction fragments), appeared 3 weeks after application of the fungus. Results showed the dominance of V. simplex Y34, which became established in the rhizosphere and out-competed F. oxysporum. PMID- 22923111 TI - cDNA cloning of Korean human norovirus and nucleotidylylation of VPg by norovirus RNA-dependent RNA polymerase. AB - Norovirus, a member of the Caliciviridae family, is a major causative agent of gastroenteritis worldwide. The cDNA of the entire genome of human norovirus (HuNV) was cloned using the RNA extracted from the stool sample of a Korean patient. The RNA genome consists of 7,559 nucleotides, carries 3 open reading frames (ORFs), 5 and 3 noncoding regions, and a poly(A) tail at the 3 end. Phylogenic analysis of the nucleotide sequence indicated that it belongs to GII.4, the most dominant genogroup. To analyze RNA synthesis and nucleotidylylation of VPg by RNA-dependent RNA polymerase (RdRp), recombinant RdRp and VPg were expressed in Escherichia coli as His-tagged forms. The HuNV RdRp exhibited template and divalent cation-dependent RNA synthesis in vitro. The HuNV RdRp nucleotidylylated HuNV VPg but not murine norovirus (MNV) VPg, whereas MNV RdRp nucleotidylylated both MNV and HuNV VPg more efficiently than HuNV RdRp. PMID- 22923112 TI - Structural and functional importance of outer membrane proteins in Vibrio cholerae flagellum. AB - Vibrio cholerae has a sheath-covered monotrichous flagellum that is known to contribute to virulence. Although the structural organization of the V. cholerae flagellum has been extensively studied, the involvement of outer membrane proteins as integral components in the flagellum still remains elusive. Here we show that flagella produced by V. cholerae O1 El Tor strain C6706 were two times thicker than those from two other Gram-negative bacteria. A C6706 mutant strain (SSY11) devoid of two outer membrane proteins (OMPs), OmpU and OmpT, produced thinner flagella. SSY11 showed significant defects in the flagella-mediated motility as compared to its parental strain. Moreover, increased shedding of the flagella-associated proteins was observed in the culture supernatant of SSY11. This finding was also supported by the observation that culture supernatants of the SSY11 strain induced the production of a significantly higher level of IL-8 in human colon carcinoma HT29 and alveolar epithelial A549 cells than those of the wild-type C6706 strain. These results further suggest a definite role of these two OMPs in providing the structural integrity of the V. cholerae flagellum as part of the surrounding sheath. PMID- 22923113 TI - Novel Bifidobacterium promoters selected through microarray analysis lead to constitutive high-level gene expression. AB - For the development of a food-grade expression system for Bifidobacterium, a strong promoter leading to high-level expression of cloned gene is a prerequisite. For this purpose, a promoter screening host-vector system for Bifidobacterium has been established using beta-glucosidase from Bifidobacterium lactis as a reporter and Bifidobacterium bifidum BGN4 as a host, which is beta glucosidase negative strain. Seven putative promoters showing constitutive high level expression were selected through microarray analysis based on the genome sequence of B. bifidum BGN4. They were cloned into upstream of beta-glucosidase gene and transformed into Escherichia coli DH5alpha and B. bifidum BGN4. Promoter activities were analyzed both in E. coli and B. bifidum BGN4 by measuring beta glucosidase activity. beta-Glucosidase activities in all of the transformants showed growth-associated characteristics. Among them, P919 was the strongest in B. bifidum BGN4 and showed maximum activity at 18 h, while P895 was the strongest in E. coli DH5alpha at 7 h. This study shows that novel strong promoters such as P919 can be used for high-level expression of foreign genes in Bifidobacterium and will be useful for the construction of an efficient food-grade expression system. PMID- 22923114 TI - Phospholipase A2 inhibitors in bacterial culture broth enhance pathogenicity of a fungus Nomuraea rileyi. AB - An entomopathogenic fungus, Nomuraea rileyi, was isolated and its identity was confirmed by its internal transcribed spacer DNA sequence. The isolated N. rileyi exhibited a specific pathogenicity to lepidopteran species. This study was focused on enhancing the fungal pathogenicity by using immunosuppressive agents. In response to infection of N. rileyi, Spodoptera exigua larvae significantly induced catalytic activity of phospholipase A(2) (PLA(2)) in three immune associated tissues, namely hemocytes, fat body, and hemolymph plasma. Furthermore, the infected S. exigua larvae induced transcription of several antimicrobial peptide (AMP) genes. Two entomopathogenic bacteria, Xenorhabdus nematophila (Xn) and Photorhabdus temperata subsp. temperata (Ptt), possessed specific PLA(2)-inhibitory activities and their culture broths significantly inhibited the enzyme activities in hemocytes, fat body, and plasma of S. exigua. In addition, the bacterial metabolites inhibited transcription of AMP genes in S. exigua that would normally respond to the immune challenge by N. rileyi. The immunosuppressive effect of Xn or Ptt bacterial broth resulted in significant enhancement of the fungal pathogenicity against late instar larvae of S. exigua and Plutella xylostella. The effect of such a mixture was confirmed by field assay against two lepidopteran species. These results suggest that the bacterial and fungal mixture can be applied to develop a novel biopesticide to control lepidopteran species. PMID- 22923115 TI - Screening, purification, and characterization of an extracellular prolyl oligopeptidase from Coprinopsis clastophylla. AB - Culture filtrates of 22 mushrooms were screened for extracellular prolyl oligopeptidase activity. Four strains with relatively high enzyme activity were all from inky cap mushrooms. The production of Coprinopsis clastophylla prolyl oligopeptidase was associated with the growth of the fungus and the enzyme was not released by cell lysis. The enzyme was purified 285-fold to a specific activity of 52.05 U/mg. It was purified to a single band on a native polyacrylamide gel. However, the enzyme separated into three bands on a sodium dodecyl sulfate-polyacrylamide gel with mobility corresponding to molecular weights of approximately 84, 60, and 26 kDa. The results of tandem mass spectrometric analysis revealed that the 60 kDa protein was likely a degradation product of the 84 kDa protein. The isoelectric point of the purified enzyme was 5.2. The purified enzyme had an optimal pH and temperature of 8.0 and 37 degrees C, respectively. Diisopropyl fluorophosphate (DFP), p-chloromercuribenzoaic acid (PCMB), Hg(2+), and Cu(2+) strongly inhibited C. clastophylla prolyl oligopeptidase. This enzyme is a serine peptidase and one or more cysteine residues of the enzyme are close to the active site. PMID- 22923116 TI - Pedobacter jeongneungensis sp. nov., isolated from forest soil. AB - Strain BH45(T) was isolated from forest soil of Mt. Bukhan in Jeongneung, Seoul, Korea. The Gram-staining-negative strain BH45(T) grows at 4-30 degrees C (optimum of 25-30 degrees C) and between pH 5-8 (optimum of pH 6-8). Its major cellular fatty acids are C(18:3) omega6c (6,9,12) and C(10:0). The G+C content of genomic DNA was 40.2 mol%. The major respiratory quinone system in strain BH45(T) is menaquinone-7. Phylogenetic analysis based on 16S rRNA gene sequences indicates that strain BH45(T) is closely related to the genus Pedobacter. Sequence similarities with P. terrae KCTC 12762(T), P. suwonensis KACC 11317(T), P. soli KACC 14939(T), P. alluvionis DSM 19624(T), P. roseus KCCM 42272(T), P. yonginense KCTC 22721(T) were 97.5, 97.1, 97.0, 97.0, 97.0, and 96.0%, respectively. DNA-DNA hybridization results distinguish strain BH45(T) from two Pedobacter species with high 16S rRNA gene sequence similarities. According to the phenotypic and molecular data, the strain BH45(T) clearly represents a novel species within the genus Pedobacter; thus, the name Pedobacter jeongneungensis sp. nov. is proposed for this strain. The type strain is BH45(T) (=KACC 15514(T) =JCM 17626(T)). PMID- 22923117 TI - Probing the ArcA regulon in the rumen bacterium Mannheimia succiniciproducens by genome-wide expression profiling. AB - In this study, the putative target genes of the Arc two-component system of the rumen bacterium Mannheimia succiniciproducens were determined by analyzing the transcriptome of the ArcA overexpression strain and by the in silico scanning of the entire genome sequence with the position weight matrix of the ArcA binding sequence developed for Escherichia coli. The majority of 79 repressed genes were involved in energy metabolism and carbohydrate transport and metabolism, while the majority of 82 induced genes were involved in hypothetical or unknown functions. Our results suggest that the Arc system in M. succiniciproducens has a specific function that differs from that in E. coli. PMID- 22923119 TI - Fosmid cloning, nucleotide sequence, and characterization of a beta-lactamase gene from subsurface isolates. AB - A beta-lactamase gene was isolated for the first time from a terrestrial subsurface environment using a combined cultivation and direct cloning strategy. The gene, discovered from 24 m below land surface in Hawaii, was most similar to the penicillinase from Bacillus licheniformis. The resistance gene was confirmed via subcloning and its minimum inhibitory concentration values were measured against several test beta-lactam antibiotics. This study extends the knowledge on resistance to antimicrobials, which may help the efforts to minimize their future threat. PMID- 22923118 TI - Homoserinimonas aerilata gen. nov., sp. nov., a novel member of the family Microbacteriaceae isolated from an air sample in Korea. AB - A bacterial strain isolated from an air sample, strain 5317J-19(T), was characterized. The isolate was an aerobic, motile, Gram-positive rod. The organism was able to grow between 4 and 35 degrees C and between pH 6 and 9. The predominant fatty acids were anteiso-C(15:0) and iso-C(16:0). The major respiratory menaquinones were MK-12 and MK-11, and the minor ones were MK13, MK 10, and MK-9. Genomic DNA G+C content was 66 mol%. The diagnostic diamino acid of the peptidoglycan is presumably D-Orn. The peptidoglycan is supposed to be B2beta type. The 16S rRNA gene sequence analysis indicated that this isolate belongs to the family Microbacteriaceae and had the highest sequence similarities with Salinibacterium xinjiangense 0543(T) (97.6%), Salinibacterium amurskyense KMM 3673(T) (97.2%), and Leifsonia bigeumensis MSL-27(T) (97.2%). Phylogenetic analysis and phenotypic characteristics support the proposal of a new genus and a novel species, with the name Homoserinimonas aerilata gen. nov., sp. nov. The type strain of Homoserinimonas aerilata is 5317J-19(T) (=KACC 15522(T) =NBRC 108729(T)). PMID- 22923120 TI - Evaluation of a fosmid-clone-based microarray for comparative analysis of swine fecal metagenomes. AB - Glass slide arrayed with fosmid clone DNAs generated from swine feces as probes were fabricated and used as a metagenome microarray (MGA). MGA appeared to be specific to their corresponding target genomic fragments. The detection limit was 10 ng of genomic DNA (ca. 10(6) bacterial cells) in the presence of 1000 ng of background DNA. Linear relationships between the signal intensity and the target DNA (20-100 ng) were observed (r ( 2 )=0.98). Application of MGA to the comparison of swine fecal metagenomes suggested that the microbial community composition of swine intestine could be dependent on the health state of swine. PMID- 22923121 TI - The activity of phosphoinositide-specific phospholipase C is required for vegetative growth and cell wall regeneration in Coprinopsis cinerea. AB - Three isotypes of phosphoinositide-specific phospholipase C designated CcPLC1, CcPLC2, and CcPLC3 were identified in Coprinopsis cinerea, through a search of the genome sequence database. The functional role of the PI-PLCs were studied by using U73122, which specifically inhibits the activity of PI-PLC. The specificity of the inhibitor effect was confirmed by using an inactive structural analog U73433. The inhibition of PI-PLCs activity resulted in severely retarded germination of basidiospores and oidia, reduced hyphal growth, knobbly hyphal tips with many irregular side branches, and aberrant (branch-like structure) clamp cells. Furthermore, U73122 definitely inhibited cell wall formation. Here we report that PI-PLCs play important roles in various aspects of C. cinerea biology. PMID- 22923122 TI - Biosynthetic pathway for poly(3-hydroxypropionate) in recombinant Escherichia coli. AB - Poly(3-hydroxypropionate) (P3HP) is a biodegradable and biocompatible thermoplastic. In this study, we engineered a P3HP biosynthetic pathway in recombinant Escherichia coli. The genes for malonyl-CoA reductase (mcr, from Chloroflexus aurantiacus), propionyl-CoA synthetase (prpE, from E. coli), and polyhydroxyalkanoate synthase (phaC1, from Ralstonia eutropha) were cloned and expressed in E. coli. The E. coli genes accABCD encoding acetyl-CoA carboxylase were used to channel the carbon into the P3HP pathway. Using glucose as a sole carbon source, the cell yield and P3HP content were 1.32 g/L and 0.98% (wt/wt [cell dry weight]), respectively. Although the yield is relatively low, our study shows the feasibility of engineering a P3HP biosynthetic pathway using a structurally unrelated carbon source in bacteria. PMID- 22923124 TI - Identification of the Vibrio vulnificus htpG gene and its influence on cold shock recovery. AB - An htpG gene encoding the heat shock protein HtpG was identified and cloned from Vibrio vulnificus. The deduced amino acid sequence of HtpG from V. vulnificus exhibited 71 and 85% identity to those reported from Escherichia coli and V. cholera, respectively. Functions of HtpG were assessed by the construction of an isogenic mutant whose htpG gene was deleted and by evaluating its phenotype changes during and after cold shock. The results demonstrated that recovery of the wild type from cold shock was significantly faster (p<0.05) than that of the htpG mutant, and indicated that the chaperone protein HtpG contributes to cold shock recovery, rather than cold shock tolerance, of V. vulnificus. PMID- 22923123 TI - Biological and genetic properties of SA14-14-2, a live-attenuated Japanese encephalitis vaccine that is currently available for humans. AB - Japanese encephalitis virus (JEV), a mosquito-borne flavivirus, is a major cause of acute encephalitis, a disease of significance for global public health. In the absence of antiviral therapy to treat JEV infection, vaccination is the most effective method of preventing the disease. In JE-endemic areas, the most widely used vaccine to date is SA(14)-14-2, a live-attenuated virus derived from its virulent parent SA(14). In this study, we describe the biological properties of SA(14)-14-2, both in vitro and in vivo, and report the genetic characteristics of its genomic RNA. In BHK-21 (hamster kidney) cells, SA(14)-14-2 displayed a slight delay in plaque formation and growth kinetics when compared to a virulent JEV strain, CNU/LP2, with no decrease in maximum virus production. The delay in viral growth was also observed in two other cell lines, SH-SY5Y (human neuroblastoma) and C6/36 (mosquito larva), which are potentially relevant to JEV pathogenesis and transmission. In 3-week-old ICR mice, SA(14)-14-2 did not cause any symptoms or death after either intracerebral or peripheral inoculation with a maximum dose of up to 1.5*10(3) plaque-forming units (PFU) per mouse. The SA(14)-14-2 genome consisted of 10977 nucleotides, one nucleotide longer than all the previously reported genomes of SA(14)-14-2, SA(14) and two other SA(14)-derived attenuated viruses. This difference was due to an insertion of one G nucleotide at position 10701 in the 3 noncoding region. Also, we noted a significant number of nucleotide and/or amino acid substitutions throughout the genome of SA(14)-14-2, except for the prM protein-coding region, that differed from SA(14) and/or the other two attenuated viruses. Our results, together with others', provide a foundation not only for the study of JEV virulence but also for the development of new and improved vaccines for JEV. PMID- 22923125 TI - Aspergillus cibarius sp. nov., from traditional meju in Korea. AB - Aspergillus cibarius sp. nov. isolated from meju, a brick of dried fermented soybeans in Korea, is described. The species was also found from black bean, bread and salami in the Netherlands. It is characterized by abundant yellow to reddish brown ascomata and small lenticular ascospores (4.5-5.5 MUm) with a wide furrow, low equatorial crests and tuberculate or reticulate convex surface. The species was resolved as phylogenetically distinct from the other reported Aspergillus species with an Eurotium teleomorph based on multilocus sequence typing using partial fragments of the beta-tubulin, calmodulin, ITS and RNA polymerase II genes. PMID- 22923129 TI - Aesthetic outcome as a goal using pectoral muscle-strip in recurrent subareolar abscess of the breast and for double subdermal flap in modelling of the inverted nipple. PMID- 22923130 TI - Response to inhibition of smoothened in diverse epithelial cancer cells that lack smoothened or patched 1 mutations. AB - Hedgehog (HH) pathway Smoothened (Smo) inhibitors are active against Gorlin syndrome-associated basal cell carcinoma (BCC) and medulloblastoma where Patched (Ptch) mutations occur. We interrogated 705 epithelial cancer cell lines for growth response to the Smo inhibitor cyclopamine and for expressed HH pathway regulated species in a linked genetic database. Ptch and Smo mutations that respectively conferred Smo inhibitor response or resistance were undetected. Previous studies revealed HH pathway activation in lung cancers. Therefore, findings were validated using lung cancer cell lines, transgenic and transplantable murine lung cancer models, and human normal-malignant lung tissue arrays in addition to testing other Smo inhibitors. Cyclopamine sensitivity most significantly correlated with high cyclin E (P=0.000009) and low insulin-like growth factor binding protein 6 (IGFBP6) (P=0.000004) levels. Gli family members were associated with response. Cyclopamine resistance occurred with high GILZ (P=0.002) expression. Newer Smo inhibitors exhibited a pattern of sensitivity similar to cyclopamine. Gain of cyclin E or loss of IGFBP6 in lung cancer cells significantly increased Smo inhibitor response. Cyclin E-driven transgenic lung cancers expressed a gene profile implicating HH pathway activation. Cyclopamine treatment significantly reduced proliferation of murine and human lung cancers. Smo inhibition reduced lung cancer formation in a syngeneic mouse model. In human normal-malignant lung tissue arrays cyclin E, IGFBP6, Gli1 and GILZ were each differentially expressed. Together, these findings indicate that Smo inhibitors should be considered in cancers beyond those with activating HH pathway mutations. This includes tumors that express genes indicating basal HH pathway activation. PMID- 22923132 TI - Role of epigenetics in human aging and longevity: genome-wide DNA methylation profile in centenarians and centenarians' offspring. AB - The role of epigenetics in the modulation of longevity has not been studied in humans. To this aim, (1) we evaluated the DNA methylation from peripheral leukocytes of 21 female centenarians, their 21 female offspring, 21 offspring of both non-long-lived parents, and 21 young women through ELISA assay, pyrosequencing analysis of Alu sequences, and quantification of methylation in CpG repeats outside CpG islands; (2) we compared the DNA methylation profiles of these populations through Infinium array for genome-wide CpG methylation analysis. We observed an age-related decrease in global DNA methylation and a delay of this process in centenarians' offspring. Interestingly, literature data suggest a link between the loss of DNA methylation observed during aging and the development of age-associated diseases. Genome-wide methylation analysis evidenced DNA methylation profiles specific for aging and longevity: (1) aging associated DNA hypermethylation occurs predominantly in genes involved in the development of anatomical structures, organs, and multicellular organisms and in the regulation of transcription; (2) genes involved in nucleotide biosynthesis, metabolism, and control of signal transmission are differently methylated between centenarians' offspring and offspring of both non-long-lived parents, hypothesizing a role for these genes in human longevity. Our results suggest that a better preservation of DNA methylation status, a slower cell growing/metabolism, and a better control in signal transmission through epigenetic mechanisms may be involved in the process of human longevity. These data fit well with the observations related to the beneficial effects of mild hypothyroidism and insulin-like growth factor I system impairment on the modulation of human lifespan. PMID- 22923133 TI - A universal primer multiplex PCR method for typing of toxinogenic Pseudomonas aeruginosa. AB - Pseudomonas aeruginosa is a well-known opportunistic pathogen that can cause acute nosocomial necrotizing pneumonia and genetic disorder cystic fibrosis of lung patients. Pathogenic interactions between P. aeruginosa and hosts are often guided by the secreted virulence determinants that interact with specific host targets. Exotoxin A, pyocyanin, elastase, and type III secretion system are the most significant virulence determinants and cause great concern. However, P. aeruginosa in various environments has high genotypic diversity, leading to deficiency of exotoxin genes for some P. aeruginosa strains. In current study, a universal primer-multiplex PCR method (UP-MPCR) was employed for the detection of five significant enterotoxin genes (toxA, phzM, lasB, ExoU, and ExoS) and one internal control gene ecfX in P. aeruginosa. Owing to the application of universal primer (UP), different targeted products have identical amplified efficiency and the sensitivity of multiplex PCR is improved. In addition, the complexity of multiplex PCR system is reduced and the compatibility of primers in a reaction is greatly increased. This UP-MPCR method can detect the presence of five P. aeruginosa enterotoxin genes in a single assay more rapidly and sensitively than conventional methods. In 214 drinking water and environmental isolates, the ExoU, ExoS, phzM, toxA, and lasB genes were detected in 20 (9 %), 180 (84 %), 179 (84 %), 196 (92 %), and 171 (80 %) isolates, respectively. PMID- 22923134 TI - Insight into substituent effects in Cal-B catalyzed transesterification by combining experimental and theoretical approaches. AB - Candida antarctica lipase B (Cal-B) is one of the most recognized biocatalysts because of its high degree of selectivity in a broad range of synthetic applications of industrial importance. Herein, the substituent effects involved in transesterification catalyzed by Cal-B are explored in detail using a combination of experimental analysis and theoretical modeling. The transesterification ability of Cal-B was experimentally determined with 22 vinyl ester analogs and ribavirin as substrates and, on this basis, a series of quantitative structure-activity relationship (QSAR) models are developed using various structural parameters characterizing the variation in substituent groups of the substrate molecules. The resulting models exhibit a good stability and predictive power, from which five most important properties are highlighted and engaged to ascertain the structural basis and reaction mechanism underlying the transesterification. From the modeling analysis it is seen that the size, geometry, and charge distributions of substrate exert a significant effect on reaction yield, where, the size of the substituent group was the most significant impact factor on the reaction yield, the charge distribution was the second, and then the topological structure of the substrate. PMID- 22923135 TI - Downregulation of indoleamine-2,3-dioxygenase in cervical cancer cells suppresses tumor growth by promoting natural killer cell accumulation. AB - This study examined the role of the immunosuppressive enzyme indoleamine-2,3 dioxygenase (IDO) in cervical cancer progression and the possible use of this enzyme for cervical cancer therapy. We analyzed IDO protein expression in 9 cervical cancer cell lines (SKG-I, -II, -IIIa, -IIIb, SiHa, CaSki, BOKU, HCS-2 and ME-180) stimulated with interferon-gamma. IDO expression was observed in all cell lines except for SKG-IIIb. We transfected the human cervical cancer cell line CaSki that constitutively expresses IDO with a short hairpin RNA vector targeting IDO, and established an IDO-downregulated cell line to determine whether inhibition of IDO mediates cervical cancer progression. IDO downregulation suppressed tumor growth in vivo, without influencing cancer cell growth in vitro. Moreover, IDO downregulation enhanced the sensitivity of cervical cancer cells to natural killer (NK) cells in vitro and promoted NK cell accumulation in the tumor stroma in vivo. These findings indicate that downregulation of IDO controls cervical cancer progression by activating NK cells, suggesting IDO as a potential therapy for cervical cancer. PMID- 22923136 TI - Potential molecular approaches for the early diagnosis of lung cancer (review). AB - Lung cancer is the leading cause of mortality from cancer among men and women worldwide. More individuals die each year of lung cancer than of colon, breast and prostate cancer combined. Despite new diagnostic techniques, the overall 5 year survival rate remains at approximately 15% and the majority of patients still present with advanced disease. Therefore, lung cancer is the most lethal cancer at present. Diagnosing and treating cancer at its early stages, ideally during the precancerous stages, could increase the 5-year survival rate by 3-4 fold, with the possibility of cure. To date, no screening method has been shown to decrease the disease-specific mortality rate. This review describes issues related to early lung cancer screening and their rationale, the management of primary cancers detected by screening and the different approaches that have been tested for cancer screening; these include imaging techniques, bronchoscopies and molecular screening, such as analysis of epigenomics using different noninvasive or invasive sources, such as blood, sputum, bronchoscopic samples and exhaled breath. PMID- 22923137 TI - Effects of bioreactor hydrodynamics on the physiology of Streptomyces. AB - Streptomyces are filamentous bacteria which are widely used industrially for the production of therapeutic biomolecules, especially antibiotics. Bioreactor operating conditions may impact the physiological response of Streptomyces especially agitation and aeration as they influence hydromechanical stress, oxygen and nutrient transfer. The understanding of the coupling between physiological response and bioreactor hydrodynamics lies on a simultaneous description of the flow and transfers encountered by the bacteria and of the microbial response in terms of growth, consumption, morphology, production or intracellular signals. This article reviews the experimental and numerical works dedicated to the study of the coupling between bioreactor hydrodynamics and antibiotics producing Streptomyces. In a first part, the description of hydrodynamics used in these works is presented and then the main relations used. In a second part, the assumptions made in these works are discussed and put into emphasize. Lastly, the various Streptomyces physiological responses observed are detailed and compared. PMID- 22923138 TI - Accelerating animal cell growth in perfusion mode by multivariable control: simulation studies. AB - This study considers the problem of manipulating in an optimal way the perfusion and bleed flow rates of a continuous culture of hybridoma cells, so as to achieve a fast transient start-up and reject potential disturbances. The proposed solution makes use of an analysis of the properties of the steady state solutions of the nonlinear dynamic model of the cell culture, and in particular the relationship between the two main limiting substrates, glucose and glutamine. The solution is implemented using extended prediction self-adaptive control. Simulation results demonstrate the approach potentiality. PMID- 22923139 TI - Mercury concentrations in muscle and liver tissue of fish from marshes along the Magdalena River, Colombia. AB - The present research determined the total mercury concentrations in muscle and liver tissue in fish collected from the Magdalena River watershed. A total of 378 muscle samples and 102 liver samples were included in the analysis. The highest mean mercury level in muscle tissue was found in the noncarnivore, Pimelodus blochii. However, as a group, carnivores had significantly higher (p < 0.05) mercury levels in their muscle tissue than noncarnivores. A significant correlation (p < 0.05) was obtained between fish mass and mercury concentrations in muscle or liver in four species. No differences were observed in total mercury concentration based either on species or gender. PMID- 22923140 TI - Growth study and hydrocarbonoclastic potential of microorganisms isolated from aviation fuel spill site in Ibeno, Nigeria. AB - The growth study and hydrocarbonoclastic potential of microorganisms isolated from aviation fuel spill sites at Inua-eyet Ikot in Ibeno, Nigeria were examined using standard microbiological methods. The results of the analysis revealed that the viable plate count of microorganisms in the polluted soil ranged from 2.2 +/- 0.04 * 10(3) to 3.4 +/- 0.14 * 10(6) cfu/g for bacteria and 1.4 +/- 0.5 * 10(2) to 2.3 +/- 0.4 * 10(4) cfu/g for fungi while count of biodegraders ranged from 1.2 +/- 0.4 * 10(3) to 2.1 +/- 0.8 * 10(5) cfu/g. A total of 11 microbial isolates comprising of Micrococcus, Klebsiella, Flavobacterium, Bacillus, Pseudomonas, Candida, Aspergillus, Cladosporium, Penicillium, Saccharomyces and Fusarium were characterized. The ability of the selected isolates to utilize the pollutant (aviation fuel) as their sole source of carbon and energy was examined and noticed to vary in growth profiles between the isolates. The results of their degradability after 28 days of incubation shows that species of Cladosporium, Pseudomonas, Candida, Bacillus, Micrococcus and Penicillium were the most efficient Aviation fuel degraders with percentage weight loss of 86.2, 78.4, 78, 56, 53 and 50.6 respectively. Flavobacterium, Saccharomyces and Aspergillus exhibited moderate growth with percentage weight loss of 48, 45.8 and 43.4 respectively while Klebsiella and Fusarium species showed minimal growth with percentage weight loss of 20 and 18.5 respectively. The results imply that the most efficient biodegraders like Cladosporium, Pseudomonas, Candida, Bacillus and Microoccus could tolerate and remove aviation fuel from the environment. PMID- 22923141 TI - Therapy for sleep hypoventilation and central apnea syndromes. AB - OPINION STATEMENT: * Primary Central Sleep Apnea (CSA): We would recommend a trial of Positive Airway Pressure (PAP), acetazolamide, or zolpidem based on thorough consideration of risks and benefits and incorporation of patient preferences.* Central Sleep Apnea Due to Cheyne-Stokes Breathing Pattern in Congestive Heart Failure (CSR-CHF): We would recommend PAP devices such as continuous positive airway pressure (CPAP) or adaptive servo-ventilation (ASV) to normalize sleep-disordered breathing after optimizing treatment of heart failure. Oxygen may also be an effective therapy. Acetazolamide and theophylline may be considered if PAP or oxygen is not effective.* Central Sleep Apnea due to High Altitude Periodic Breathing: We would recommend descent from altitude or supplemental oxygen. Acetazolamide may be used when descent or oxygen are not feasible, or in preparation for ascent to high altitude. Slow ascent may be preventative.* Central Sleep Apnea due to Drug or Substance: If discontinuation or reduction of opiate dose is not feasible or effective, we would recommend a trial of CPAP, and if not successful, treatment with ASV. If ASV is ineffective or if nocturnal hypercapnia develops, bilevel positive airway pressure spontaneous timed mode (BPAP-ST) is recommended.* Obesity hypoventilation syndrome: We would recommend an initial CPAP trial. If hypoxia or hypercapnia persists on CPAP, BPAP, BPAP-ST or average volume assured pressure support (AVAPSTM) is recommended. Tracheostomy with nocturnal ventilation should be considered when the above measures are not effective. Weight loss may be curative.* Neuromuscular or chest wall disease: We would recommend early implementation of BPAP-ST based on thorough consideration of risks and benefits and patient preferences. AVAPSTM may also be considered. We recommend close follow up due to disease progression. PMID- 22923142 TI - 2,3-Hexanediols as sex attractants and a female-produced sex pheromone for cerambycid beetles in the prionine genus Tragosoma. AB - Recent work suggests that closely related cerambycid species often share pheromone components, or even produce pheromone blends of identical composition. However, little is known of the pheromones of species in the subfamily Prioninae. During field bioassays in California, males of three species in the prionine genus Tragosoma were attracted to 2,3-hexanediols, common components of male produced aggregation pheromones of beetles in the subfamily Cerambycinae. We report here that the female-produced sex pheromone of Tragosoma depsarium "sp. nov. Laplante" is (2R,3R)-2,3-hexanediol, and provide evidence from field bioassays and electroantennography that the female-produced pheromone of both Tragosoma pilosicorne Casey and T. depsarium "harrisi" LeConte may be (2S,3R)-2,3 hexanediol. Sexual dimorphism in the sculpting of the prothorax suggests that the pheromone glands are located in the prothorax of females. This is the second sex attractant pheromone structure identified from the subfamily Prioninae, and our results provide further evidence of pheromonal parsimony within the Cerambycidae, in this case extending across both subfamily and gender lines. PMID- 22923143 TI - Juvenile prey induce antipredator behaviour in adult predators. AB - It is generally assumed that the choice of oviposition sites in arthropods is affected by the presence of food for the offspring on the one hand and by predation risk on the other hand. But where should females oviposit when the food itself poses a predation risk for their offspring? Here, we address this question by studying the oviposition behaviour of the predatory mite Amblyseius swirskii in reaction to the presence of its counterattacking prey, the western flower thrips Frankliniella occidentalis. We offered the mites a choice between two potential oviposition sites, one with and one without food. We used two types of food: thrips larvae, which are predators of eggs of predatory mite but are consumed by older predator stages, and pollen, a food source that poses no risk to the predators. With pollen as food, the predators preferred ovipositing on the site with food. This might facilitate the foraging for food by the immature offspring that will emerge from the eggs. With thrips as food, female predators preferred ovipositing on the site without thrips. Predators that oviposited more on the site with thrips larvae killed more thrips larvae than females that oviposited on the site without food, but this did not result in higher oviposition. This suggests that the females killed thrips to protect their offspring. Our results show that predators display complex anti-predator behaviour in response to the presence of counter-attacking prey. PMID- 22923144 TI - Transcriptome sequencing and annotation of the predatory mite Metaseiulus occidentalis (Acari: Phytoseiidae): a cautionary tale about possible contamination by prey sequences. AB - Next-generation sequencing was applied to the transcriptome of the phytoseiid Metaseiulus occidentalis to characterize gene expression in all life stages reared under different conditions to optimize the recovery of as many genes as possible. One production and one titration run produced a total of 862,069 reads (average size: 314.87 bp), which generated 255.6 Mbp of sequences on the GS-FLX Titanium sequencing platform. After removal of putative prey sequences 850,543 reads were used in NewBler and PTA assemblies to produce 74,172 non-redundant sequences, including 30,691 contigs and 43,481 singlets with 11,994 contigs consisting of more than 500 bp and 37,278 sequences >300 bp, constituting 48.7 % of all sequences. There were 25,888 hits with the NCBI non-redundant database and 15,376 unique transcripts. There were 26,225 hits with the Ixodes scapularis genome and 6,634 unique transcripts. There were 22,225 hits with the RefSeq of Homo sapiens with 6,465 unique transcripts, and 23,656 hits with the RefSeq of Drosophila melanogaster with 9,216 unique transcripts. Selected ESTs corresponding to genes of interest were analyzed including those related to transposable elements, GPCRs, Sox transcription factors, diapause and foraging behavior, and pesticide resistances. Novel and important genes appear to have been discovered that provide insight into the evolution, biology, and physiology of this important predator of pest mites in agriculture and will be useful in analyzing complete genome sequences of this natural enemy. PMID- 22923146 TI - Responses to sulfated steroids of female mouse vomeronasal sensory neurons. AB - The rodent vomeronasal organ plays an important role in many social behaviors. Using the calcium imaging technique with the dye fluo-4 we measured intracellular calcium concentration changes induced by the application of sulfated steroids to neurons isolated from the vomeronasal organ of female mice. We found that a mix of 10 sulfated steroids from the androgen, estrogen, pregnanolone, and glucocorticoid families induced a calcium response in 71% of neurons. Moreover, 31% of the neurons responded to a mix composed of 3 glucocorticoid-derived compounds, and 28% responded to a mix composed of 3 pregnanolone-derived compounds. Immunohistochemistry showed that neurons responding to sulfated steroids expressed phosphodiesterase 4A, a marker specific for apical neurons expressing V1R receptors. None of the neuron that responded to 1 mix responded also to the other, indicating a specificity of the responses. Some neurons responded to more than 1 individual component of the glucocorticoid-derived mix tested at high concentration, suggesting that these neurons are broadly tuned, although they still displayed strong specificity, remaining unresponsive to high concentrations of the ineffective compounds. PMID- 22923145 TI - 2012 focused update of the ESC Guidelines for the management of atrial fibrillation: an update of the 2010 ESC Guidelines for the management of atrial fibrillation--developed with the special contribution of the European Heart Rhythm Association. PMID- 22923148 TI - Differential sensitivity to paclitaxel-induced apoptosis and growth suppression in paclitaxel-resistant cell lines established from HEC-1 human endometrial adenocarcinoma cells. AB - To investigate acquired paclitaxel (PTX) resistance in cancer cells, we established five monoclonal PTX-resistant cell lines from HEC-1 human endometrial adenocarcinoma cells by means of long-term PTX-exposed cultures and limiting dilution cultures. The established PTX-resistant subclones showed apparent resistance to PTX-induced DNA fragmentation but not to PTX-induced growth suppression. None of the five PTX-resistant subclones showed apparent resistance to other anticancer drugs such as cisplatin, etoposide, 5-fluorouracil, pirarubicin-HCl, 4-hydroxy-cyclophosphamide or mitomycin C. Semiquantitative flow cytometric analysis revealed no apparent differential expression of 17 molecules that were previously reported to regulate apoptosis or drug resistance, between the five PTX-resistant subclones and the parent cells. Karyotyping analysis revealed common changes in chromosomes 4 and 18 in the five PTX-resistant subclones but not in the HEC-1 parent cells. These results indicate that PTX induced growth suppression is regulated by different mechanisms from those involved in PTX-induced apoptosis. It was concluded that these established PTX resistant subclones can be useful models in studies related to the prevention or treatment of recurrent cancers after PTX chemotherapy. PMID- 22923147 TI - Low-titer anti-GAD-antibody-positive cerebellar ataxia. AB - The majority of cases of anti-glutamic acid decarboxylase (GAD)-antibody-positive cerebellar ataxia are reported to have high levels of anti-GAD antibody, and the diagnostic value of low titers of anti-GAD antibody in a patient with cerebellar ataxia is still unknown. The purpose of this study was to verify the characteristics of low-titer-anti-GAD-antibody-positive cerebellar ataxia patients and the diagnostic value of low titers of anti-GAD antibody in patients with cerebellar ataxia. The subjects were six patients positive for low-titer GAD antibody (<100 U/mL). We examined them with MRI, including voxel-based morphometry, and with single-photon emission computed tomography and monitored the GAD antibody index in the cerebrospinal fluid. The levels of antineuronal, antigliadin, anti-SS-A, antithyroid antibodies, and of vitamins E, B1, and B12 were determined. Thoracic and abdominal CT scans were performed to exclude a paraneoplastic origin. We treated three patients with immunotherapy. All cases showed cortical cerebellar atrophy. The GAD antibody index in three of the five patients reviewed was >1.0. Two of the six patients were thyroid antibody positive, and one was both antinuclear- and anti-SS-A antibody-positive. After the administration of immunotherapy to three patients, two showed clear effectiveness, and one, transient effectiveness. Effectiveness was greatest in the two patients with familial occurrence of the disease. In cerebellar ataxia, regardless of family history or isolated illness, it is critical to measure the GAD antibody level, and, even with a low titer level, if the result is positive, immunotherapy should be considered. PMID- 22923149 TI - New insights in acute kidney failure in the critically ill. AB - The term acute kidney injury (AKI) has been recently coined by a large panel of international experts in place of the former expression "acute renal failure". This change has been motivated by a double intention: first it served to definitely find a conventional definition for acute changes of renal function, previously lacking in the medical community. In fact, any attempt to compare scientific papers and different centres experiences on AKI was essentially impossible. The second aim was to remark that this syndrome is characterised by a spectrum of progressive damage, from mild creatinine increase to renal injury to a more severe form, failure: this important concept should increase clinicians awareness to every form of renal dysfunction, even milder ones, in order to improve epidemiologic analyses, potentially preventing eventual AKI progression and finally helping standardisation of medical and supportive therapy. This review will describe such "new era" of critical care nephrology by presenting current literature (and its many controversies) about AKI diagnosis, physiopathology and management. PMID- 22923150 TI - A comparative study of luteal estradiol pre-treatment in GnRH antagonist protocols and in micro dose flare protocols for poor-responding patients. AB - PURPOSE: This study aims to verify if luteal estradiol pre-treatment improves IVF/ICSI outcomes in a GnRH antagonist protocol as compared with a micro dose GnRH agonist protocol in poor-responding patients. METHODS: A total of 116 IVF/ICSI cycles were included in this prospective randomized single blind clinical trial. The selected women were randomly assigned to receive an estradiol pre-treatment in a GnRH antagonist protocol (daily oral Estradiol Valerate 4 mg preceding the IVF cycle from the 21st day until the first day of the next cycle) or in oral contraceptive pill micro dose GnRH agonist protocol. RESULTS: The patients in the luteal estradiol protocol required more days of stimulation (10.9 +/- 1.6 vs. 10.2 +/- 1.8) and a greater gonadotropin requirement (3,247.8 +/- 634.6 vs. 2,994.8 +/- 611 IU), yet similar numbers of oocytes were retrieved and fertilized. There was no significant difference between the two groups in terms of the implantation rates (9.8 vs. 7.9 %) and the clinical pregnancy rates per transfer (16.3 vs. 15.6 %). CONCLUSION: This study demonstrates that the use of estradiol during a preceding luteal phase in a GnRH antagonist protocol can provide similar IVF outcomes when compared to a micro dose GnRH agonist protocol. PMID- 22923152 TI - Measurement of pelvic motion is a prerequisite for accurate estimation of hip joint work in maximum height squat jumping. AB - In experiments investigating vertical squat jumping, the HAT segment is typically defined as a line drawn from the hip to some point proximally on the upper body (eg, the neck, the acromion), and the hip joint as the angle between this line and the upper legs (thetaUL-HAT). In reality, the hip joint is the angle between the pelvis and the upper legs (thetaUL-pelvis). This study aimed to estimate to what extent hip joint definition affects hip joint work in maximal squat jumping. Moreover, the initial pelvic tilt was manipulated to maximize the difference in hip joint work as a function of hip joint definition. Twenty-two male athletes performed maximum effort squat jumps in three different initial pelvic tilt conditions: backward (pelvisB), neutral (pelvisN), and forward (pelvisF). Hip joint work was calculated by integrating the hip net joint torque with respect to thetaUL-HAT (WUL-HAT) or with respect to thetaUL-pelvis (WUL-pelvis). thetaUL-HAT was greater than thetaUL-pelvis in all conditions. WUL-HAT overestimated WULpelvis by 33%, 39%, and 49% in conditions pelvisF, pelvisN, and pelvisB, respectively. It was concluded that thetaUL-pelvis should be measured when the mechanical output of hip extensor muscles is estimated. PMID- 22923153 TI - Single port totally extraperitoneal (STEP) hernia repair: improving the benefits of one-day surgery setting. PMID- 22923151 TI - Neuroinflammation, neuroautoimmunity, and the co-morbidities of complex regional pain syndrome. AB - Complex Regional Pain Syndrome (CRPS) is associated with non-dermatomal patterns of pain, unusual movement disorders, and somatovisceral dysfunctions. These symptoms are viewed by some neurologists and psychiatrists as being psychogenic in origin. Recent evidence, however, suggests that an autoimmune attack on self antigens found in the peripheral and central nervous system may underlie a number of CRPS symptoms. From both animal and human studies, evidence is accumulating that neuroinflammation can spread, either anterograde or retrograde, via axonal projections in the CNS, thereby establishing neuroinflammatory tracks and secondary neuroinflammatory foci within the neuraxis. These findings suggest that neuroinflammatory lesions, as well as their associated functional consequences, should be evaluated during the differential diagnosis of non-dermatomal pain presentations, atypical movement disorders, as well as other "medically unexplained symptoms", which are often attributed to psychogenic illness. PMID- 22923154 TI - Hexane extracts of garlic cloves induce apoptosis through the generation of reactive oxygen species in Hep3B human hepatocarcinoma cells. AB - Garlic (Allium sativum) compounds have recently received increasing attention due to their cancer chemopreventive properties, and their anticancer activities are extensively reported in many cancer cell lines. However, the anticancer activity and the signaling pathway associated with the induction of apoptosis by extracts of garlic cloves have not been elucidated. In this study, we examined the effects of hexane extracts of garlic cloves (HEGCs) on reactive oxygen species (ROS) production and the association of these effects with apoptotic cell death, using a Hep3B human hepatocarcinoma cell line in vitro. The results demonstrated that HEGCs mediate ROS production, and that this mediation is followed by a collapse of mitochondrial membrane potential (MMP, DeltaPsim), the downregulation of anti apoptotic Bcl-2 and Bcl-xL and the activation of caspase-9 and -3. HEGCs also promoted the activation of caspase-8 and the downregulation of Bid, a BH3-only pro-apoptotic member of the Bcl-2. However, the apoptotic phenomena displayed by HEGCs were significantly diminished by the presence of z-VAD-fmk (non-selective caspase inhibitor). Moreover, N-acetyl-L-cysteine (NAC), a widely used ROS scavenger, effectively blocked the HEGC-induced apoptotic effects via the inhibition of ROS production and MMP collapse. These observations clearly indicate that HEGC-induced ROS are key mediators of MMP collapse, which leads to the induction of apoptosis, followed by caspase activation. PMID- 22923155 TI - The effect of vascular endothelial growth factor C expression in tumor-associated macrophages on lymphangiogenesis and lymphatic metastasis in breast cancer. AB - The aim of this study was to investigate the effect of vascular endothelial growth factor-C (VEGF-C) expression in tumor-associated macrophages (TAMs) on lymphatic microvessel density (LMVD) and lymphatic endothelial cell proliferation (LECP) and to determine the role of VEGF-C expression in lymphangiogenesis in patients with breast cancer. Breast cancer tissue specimens confirmed by pathological analysis were obtained from 75 patients. Samples were observed by microscopy analysis after immunohistochemical double-staining. The total number of TAMs and the number of VEGF-C-positive TAMs were determined. LMVD and LECP were calculated for the intratumoral and peritumoral areas. Correlation analysis was performed among these indexes, lymph vessel invasion (LVI) and lymph node metastasis in the peritumoral regions. Immunohistochemical double-staining demonstrated that VEGF-C was markedly expressed in TAMs. The number of TAMs, LMVD and LECP in the peritumoral areas was significantly higher than that in the intratumoral areas (P<0.001). We observed positive correlations between the following parameters: the number of TAMs and the peritumoral LMVD (P<0.001), the percentage of TAMs expressing VEGF-C and the peritumoral LMVD (P<0.001), the number of TAMs and the peritumoral LECP (P<0.001), and the percentage of TAMs expressing VEGF-C and the peritumoral LECP (P<0.001). Furthermore, the total number of TAMs and VEGF-C-positive TAMs, LMVD and LECP in cases with lymph node metastasis or LVI were significantly higher compared to those in cases without lymph node metastasis or LVI (P<0.01 or P<0.05). Our findings suggest that TAMs play a critical role in tumor-induced lymphangiogenesis through upregulating VEGF C, which may contribute to lymphatic invasion in breast cancer. PMID- 22923156 TI - Assessment of the diagnostic value of dual-energy CT and MRI in the detection of iatrogenically induced injuries of anterior cruciate ligament in a porcine model. AB - INTRODUCTION: Magnetic resonance imaging (MRI) is the standard of reference for the non-invasive evaluation of ligament injuries of the knee. The development of dual-energy CT (DE-CT) made it possible to differentiate between tissues of different density by two simultaneous CT measurements with different tube voltages. This approach enables DE-CT to discriminate ligament structures without intra-articular contrast media injection. The aims of this study were on the one hand to determine the delineation of the anterior cruciate ligament (ACL) and on the other hand to assess the diagnostic value of DE-CT and MRI in the detection of iatrogenically induced injury of the ACL in a porcine knee joint model. MATERIALS AND METHODS: Twenty porcine hind legs, which were placed in a preformed cast in order to achieve a standardized position, were scanned using DE-CT. Thereafter, a 1.5-T MRI using a standard protocol was performed. The imaging procedures were repeated with the same parameters after inducing defined lesions (total or partial incision) on the ACL arthroscopically. After post-processing, two radiologists and two orthopedic surgeons first analyzed the delineation of the ACL and then, using a consensus approach, the iatrogenically induced lesions. The result of the arthrotomy was defined as the standard of reference. RESULTS: The ACL could be visualized both on DE-CT and MRI in 100% of the cases. As for the MRI, the sensitivity and specificity of detecting the cruciate ligament lesion respectively compared with the defined arthrotomy was 66.7% and 78.6% for intact cruciate ligaments, 100% and 75% in the case of a complete lesion, 33.3% and 78.6% for lesions of the anteromedial bundle, and 0% and 100% for lesions of the posterolateral bundle. In comparison, DE-CT demonstrated a sensitivity and specificity of 66.7% and 71.4% in the case of intact cruciate ligaments, 75% and 68.8% in the case of completely discontinued ACLs, 0% and 92.9% in the case of lesions of the anteromedial bundle, and 25% and 87.5% in the case of lesions of the posterolateral bundle. CONCLUSIONS: The present ex vivo experiment shows that both study modalities (DE-CT and MRI) are equal with regard to the delineation of the ACL, while MRI achieved higher sensitivity and specificity regarding iatrogenically induced complete ACL lesions. DE-CT could be a possible alternative to MRI for certain indications in the diagnosis of a knee ligament injury. PMID- 22923157 TI - Autophagy modulators sensitize prostate epithelial cancer cell lines to TNF-alpha dependent apoptosis. AB - TNF-alpha levels in prostate cancer correlate with the extent of disease and are significantly elevated in the metastatic stage. TNF receptor superfamily controls two distinct signalling cascades, leading to opposite effects, i.e. apoptosis and survival; in prostate cancer TNF-alpha-mediated signalling induces cell survival and resistance to therapy. The apoptosis of prostate epithelial cancer cells LNCaP and PC3 was investigated upon treatment with the autophagy inhibitor 3 methyladenine and the autophagy inducer rapamycin, in combination with TNF-alpha. Cells were exposed to these molecules for 18, 24 and 48 h. Autophagy was assessed via LC3 Western blot analysis; propidium iodide and TUNEL stainings followed by flow cytometry or caspase-8 and caspase-3 activation assays were performed to evaluate apoptosis. TNF-alpha-induced apoptosis was potentiated by 3 methyladenine in the androgen-responsive LNCaP cells, whereas no effect was observed in the androgen-insensitive PC3 cells. Interestingly such pro-apoptosis effect in LNCaP cells was associated with reduced c-Flip levels through proteasomal degradation via increased reactive oxygen species production and p38 activation; such c-Flip reduction was reversed in the presence of either the proteasome inhibitor MG132 or the reactive oxygen species scavenger N-acetyl cysteine. Conversely in PC3 but not in LNCaP cells, rapamycin stimulated TNF alpha-dependent apoptosis; such effect was associated with reduced c-Flip promoter activity and FoxO3a activation. We conclude that TNF-alpha-induced apoptosis may be potentiated, in prostate cancer epithelial cells, through autophagy modulators. Increased sensitivity to TNF-alpha-dependent apoptosis correlates with reduced c-Flip levels which are consequent to a post transcriptional and a transcriptional mechanism in LNCaP and PC3 cells respectively. PMID- 22923158 TI - Is pain and dissatisfaction after TKA related to early-grade preoperative osteoarthritis? AB - BACKGROUND: There is growing evidence to suggest many patients experience pain and dissatisfaction after TKA. The relationship between preoperative osteoarthritis (OA) severity and postoperative pain and dissatisfaction after TKA has not been established. QUESTIONS/PURPOSES: We explored the relationship between early-grade preoperative OA with pain and dissatisfaction after TKA by (1) determining the incidence of early-grade preoperative OA in painful TKAs with no other identifiable abnormality; and (2) comparing this incidence with the incidence of early-grade OA in three other cohorts of patients undergoing TKA. METHODS: We evaluated all (n = 49) painful TKAs in a 1-year period that had no evidence of loosening, instability, malalignment, infection, or extensor mechanism dysfunction and classified the degree of preoperative OA according to the scale of Kellgren and Lawrence. For comparison, we identified three other cohorts of TKAs from the same center and classified their preoperative grade of OA: Group B (n = 100) was a consecutive series of primary TKAs performed for OA during the same year; Group C (n = 80) were asymptomatic TKAs from 1 to 4 years postoperatively; and Group D (n = 80) were TKAs with some degree of pain at 1 to 4 years postoperatively. RESULTS: Patients in Group A had a higher incidence of early-grade OA is preoperatively (49%) compared with any of the comparison groups: Group B, 5%; Group C, 6%; and Group D, 10%. CONCLUSIONS: A high percentage of patients referred for unexplained pain after TKA had early-grade osteoarthritis preoperatively. Patients undergoing TKA for less than Grade 3 or 4 OA should be informed that they may be at higher risk for persistent pain and dissatisfaction. PMID- 22923159 TI - [Therapy strategies for the septic spine: state of the art]. PMID- 22923160 TI - [Gold standard for implant selection in operative therapy of spondylitis/spondylodiscitis]. AB - The operative therapy management of vertebral osteomyelitis including debridement and stabilization is well established. Autologous bone is the preferred graft material but is limited due to availability, failure of consolidation in large defects and donor morbidity. Titanium mesh cages are alternatively equally well evaluated and other materials are also mentioned. Immobilization of affected segments is the fundamental requirement for healing of osteomyelitis. The operative therapy of choice is meticulous debridement and internal stabilization of the defect. Autologous bone seems to provide the best conditions to bridge and consolidate defects. Bone marrow aspirate, reaming irrigator aspiration (RIA) and bone marrow protein (BMP) in combination with cages have the same qualities considering bone healing but they are not yet sufficiently evaluated for management of vertebral osteomyelitis. Autologous bone graft remains the gold standard, nevertheless, its disadvantages point out the need for alternative grafts. Titanium is well proven to provide stability but bone substitutes are not sufficiently evaluated but seem to be promising. PMID- 22923161 TI - Effects on lipid profile of dipeptidyl peptidase 4 inhibitors, pioglitazone, acarbose, and sulfonylureas: meta-analysis of placebo-controlled trials. AB - INTRODUCTION: Lipid profile is an important determinant of cardiovascular risk in type 2 diabetes. It is well known that patients with type 2 diabetes are more likely to be dyslipidemic than the general population. Given the observed connection between glucose and lipid metabolism in patients with type 2 diabetes, it is conceivable that different glucose-lowering agents can have a varying impact on the lipid profile. When metformin monotherapy fails, other drugs can be added to achieve sufficient glycemic control. Available oral agents include pioglitazone, acarbose, dipeptidyl peptidase 4 (DPP-4) inhibitors, and insulin secretagogs. The present meta-analysis was designed to assess the effect of DPP-4 inhibitors, pioglitazone, insulin secretagogs, and acarbose on blood lipids when compared to placebo. METHODS: An extensive search (any date up to November 1, 2011) was performed for all trials performed on the following classes of drugs: gliptin, insulin secretagogs, pioglitazone, and acarbose. The following endpoints were considered: endpoint total, high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C) and triglycerides. RESULTS: The difference in mean total cholesterol values at endpoint versus baseline was significantly higher in patients on pioglitazone, sulfonylureas, and DPP-4 inhibitor treatment (but not on acarbose) than those on placebo, demonstrating that treatment with these drugs (except acarbose) is associated with a significant reduction in total cholesterol. With respect to triglycerides, a significant reduction could be observed with acarbose, pioglitazone, and DPP-4 inhibitors, but not with sulfonylureas. HDL-C appeared to be increased by treatment with acarbose and pioglitazone, and decreased by sulfonylureas. CONCLUSION: The present meta-analysis shows that available glucose-lowering drugs may have varying effects on the lipid profile. DPP-4 inhibitors, acarbose, and pioglitazone seem to have a more favorable effect on the lipid profile than sulfonylureas. PMID- 22923162 TI - SWAAT study: extracorporeal shock wave therapy and arginine supplementation and other nutraceuticals for insertional Achilles tendinopathy. AB - INTRODUCTION: Extracorporeal shockwave therapy (ESWT) produces good results in the treatment of insertional Achilles tendinopathy. The efficacy of combined administration of dietary supplements with ESWT has not yet been studied. METHODS: In this prospective, randomized clinical trial, Shock Waves therapy and Arginine for Achilles Tendinopathy (SWAAT), subjects affected by insertional Achilles tendinopathy were enrolled. Between January and October 2011, all participants underwent three sessions of ESWT. In addition, the patients in the experimental group received a daily dietary supplement containing arginine, Vinitrox (Bio Serae Laboratories SAS, Bram, France), collagen, methyl-sulfonyl methane, vitamin C, and bromelain, while the control group patients received placebo. RESULTS: There was no statistically significant difference in the visual analog scale (VAS) score between the two groups at 2 months (3.9 vs. 5.1; P=0.07), whereas at 6 months the value was significantly lower in the experimental group (2.0 vs. 2.9; P=0.04). The difference in the Ankle-Hindfoot Scale score at 2 and 6 months of follow-up (FU) was significantly in favor of the experimental group (2 months: 85.4 vs. 72.1; P=0.0035; 6 months: 92.4 vs. 76.5; P=0.0002). The Roles and Maudsley score also showed a statistically significant difference between the two groups in favor of the experimental arm as regards patient satisfaction (at 2 months: 1.7 vs. 2.8; P<0.0001; at 6 months: 1.5 vs. 2.3; P<0.001). There was a statistically significant reduction in tissue oximetry values compared to baseline in both treatment groups at 2 and 6 months of FU. Comparing the groups, only at the last FU, at 6 months, was a significantly lower oximetry value observed in the experimental group versus controls (60.2 vs. 66.0; P=0.007). CONCLUSION: On the basis of the results obtained in this study, the authors conclude that in the treatment of insertional Achilles tendinopathy, ESWT induces a hemodynamic re-equilibrium with an amelioration in tendon trophism [corrected]. The addition of specific dietary supplements could improve the therapeutic response. PMID- 22923163 TI - KP-CoT-23 (CCDC83) is a novel immunogenic cancer/testis antigen in colon cancer. AB - Cancer/testis (CT) antigens are considered target molecules for cancer immunotherapy. To identify novel CT antigens, immunoscreening of a testicular cDNA library was performed using serum obtained from a colon cancer patient who was immunized with a new dendritic cell vaccine. We isolated 64 positive cDNA clones comprised of 40 different genes, designated KP-CoT-1 through KP-CoT-40. Three of these putative antigens, including KP-CoT-23 (CCDC83), had testis specific expression profiles in the Unigene database. RT-PCR analysis showed that the expression of 2 KP-Cot-23 variants was restricted to the testis in normal adult tissues. In addition, KP-CoT-23 variants were frequently expressed in a variety of tumors and cancer cell lines, including colon cancer. A serological western blot assay showed IgG antibodies to the KP-CoT-23 protein in 26 of 37 colon cancer patients and in 4 of 21 healthy patients. These data suggest that KP CoT-23 is a novel CT antigen that may be useful for the diagnosis and immunotherapy of cancer. PMID- 22923164 TI - The EHRA White Book. PMID- 22923165 TI - Resistance to targeted therapies in pancreatic neuroendocrine tumors (PNETs): molecular basis, preclinical data, and counteracting strategies. AB - Management of advanced pancreatic neuroendocrine tumors (PNETs) is challenging. Chemotherapy has remained for decades the only validated therapeutic option, with debated efficacy. Recently, data from two large placebo-controlled phase III trials have demonstrated that targeted therapies directed against receptor of vascular endothelial growth factor (sunitinib) and mammalian target of rapamycin (mTOR) (everolimus) produced clinically significant improvement in patients with advanced PNETs, resulting in a doubling of progression free survival and leading to their FDA approval. However, as more patients have been treated following the approval of those drugs, reports of early progression, and tumor regrowth following initial responses strongly suggested that primary and acquired resistances may limit the efficacy of targeted therapies in PNETs. In this review, we aim to summarize the current knowledge about primary and acquired resistance to targeted therapies, i.e., antiangiogenic agents and mTOR inhibitors, using data available from preclinical and clinical studies in various malignancies. Herein, we also describe how these general mechanisms of resistance may emerge in PNETs in patients treated with sunitinib and everolimus. Overcoming such resistances is likely to be the next challenge for clinicians in advanced PNETs management, warranting seeking for new anticancer strategies. PMID- 22923166 TI - Place of surgical resection in the treatment strategy of gastrointestinal neuroendocrine tumors. AB - Neuroendocrine tumors (NET) are usually slow-growing neoplasms carrying an overall favorable prognosis. Surgery, from resection to transplantation, remains the only potential curative option for these patients, and should always be considered. Nevertheless, because of very few randomized controlled trials available, the optimal treatment for these patients remains controversial, especially regarding the place of surgery. We herein discuss the place of surgical resection in the treatment strategy in neuroendocrine tumors of the digestive tract. PMID- 22923167 TI - Mini-invasive lateral oropharyngectomy for T3-T4a oropharyngeal cancer. AB - Mandibular swing is the approach of choice for resection of advanced oropharyngeal carcinomas without bone involvement. This approach requires a mandibulotomy, which is associated with complications. A prospective outcome analysis was performed for 21 patients operated without mandibulotomy for T3-T4a oropharyngeal carcinoma. Tumour size was categorized as T3 in 14 patients (66.7 %) and as T4a (33.3 %) in 7 patients. Twelve patients were N0 (57.1 %), 2 (9.5 %) were N1, and 7 (33.3 %) were N2. Surgical margins were negative in 18 cases (85.7 %), positive in 1 (4.8 %), and close in 2 (9.5 %). Average hospital stay was 14.5 days (range 10-22). Adjuvant treatment (radiotherapy or concurrent chemoradiotherapy) was administered to all but three patients previously irradiated. In all cases radiotherapy started within 42 days of surgery. The 3 year overall survival was 85.7 %, and relapse-free survival was 71.4 %. Oropharyngectomy without mandibulotomy has the same indications as mandibular swing. It provides good access to achieve satisfactory clearance of tumours, sparing patients the morbidity associated with mandibulotomy. PMID- 22923169 TI - Survey of blood pump diaphragm damage in the NIPRO-ventricular assist device. AB - We surveyed the incidence of blood pump diaphragm damage (rupture or crack) in the NIPRO-ventricular assist device (VAD). In the cases in which rupture or suspected blood pump crack was detected, we disassembled the pumps to visually check the condition of the diaphragm after replacement or use. Of 366 blood pumps surveyed, diaphragm damage was observed in 2.7 %. The duration of use of the blood pumps with diaphragm damage was significantly longer than that of pumps without damage. The incidence of diaphragm damage increased with longer duration of use. On the basis of these findings, blood pump diaphragm damage in the NIPRO VAD may be associated with duration of use. However, some blood pumps were used for prolonged periods without diaphragm damage. All blood pumps with damage had a crack in the diaphragm on the air chamber side near the diaphragm-housing (D-H) junction. Cracks were not found in any specific part of the diaphragm. In blood pumps with diaphragm rupture, the crack had a through-hole reaching the blood contacting surface. Although we were unable to identify the causes of the cracks, it is suggested that when a crack appears in the diaphragm it will gradually expand and eventually lead to rupture. If a crack is detected in a blood pump, we advocate replacing the pump before it grows. When the NIPRO-VAD is used, it is necessary to keep in mind that blood pump diaphragm damage may occur. PMID- 22923170 TI - Endoscopic biliary recanalization with a needle-knife in post liver-transplant complete anastomotic stricture. PMID- 22923168 TI - The effect of retinyl palmitate on healing of benign vocal fold lesions. AB - The leading cause of vocal fold lesions such as nodules and polyps is phonotrauma, which causes microhematoma formation in the vocal fold cover that can initiate an inflammatory process. Vitamin A (Vit A) is essential for immunity, cellular differentiation and maintenance of respiratory epithelium. The aim of this study is to investigate the effect of Vit A (retinyl palmitate) on healing of vocal fold lesions, including vocal polyps and nodules. Eighteen patients with vocal fold lesions were included in the study. Of the patients, 13 had vocal polyps and 5 had vocal nodules. Patients received 90,000 IU oral Vit A in palmitate form daily for 2 months. In addition to Vit A treatment, only vocal hygiene recommendations were given to the patients, without any other medication or specific voice therapy. Pre- and post-treatment acoustic analysis [jitter % (jitt %), shimmer % (shim %), normalized noise energy (NNE), maximum phonation time (MPT), etc.] were performed. Lesion dimensions and stroboscopic findings were evaluated. Voice handicap index (VHI) was applied. Statistical analysis was performed between pre- and post-treatment measurements. Of the 18 patients, 8 had immature lesions (6 polyp-like lesions and 2 immature nodules) and 10 had mature lesion (7 polyps and 3 nodules). None of the patients showed complete healing. Partial response was seen in four patients with immature lesions. There were minimal changes in lesion dimensions, but this difference did not reach statistical significance. MPT of patients with immature lesions were close to significance level but overall MPT revealed no significant improvement (p = 0.051). Jitt %, shim % and NNE did not change significantly. In this study, the only statistically significant finding was VHI of the patients with immature lesions. Three of the patients complained of weight gain. Our data showed that Vit A at a given level of dose and duration seems to be ineffective in the treatment of benign vocal fold lesions. On the other hand, whether Vit A is effective on mature and immature lesions of vocal folds at higher doses and/or longer duration of treatment or not requires further studies. PMID- 22923171 TI - Suppression of tunicamycin-induced CD44v6 ectodomain shedding and apoptosis is correlated with temporal expression patterns of active ADAM10, MMP-9 and MMP-13 proteins in Caki-2 renal carcinoma cells. AB - CD44v6 has been shown to coordinate the activation of anti-apoptotic molecules as well as resistance to apoptosis. Here, we investigated CD44v6 ectodomain shedding in Caki-2 human renal carcinoma cells as well as its underlying mechanisms. Exposure of cells to tunicamycin (TM)-induced apoptosis was accompanied by cleavage of caspase-3, PARP-1 and CD44v6 ectodomain. TM-induced apoptosis was also closely associated with endoplasmic reticulum (ER) stress, as shown by increased expression of GRP-78 and CHOP proteins. Furthermore, induction of matrix metallo-proteinase (MMP)-13, MMP-9 and ADAM10 expression was highly stimulated by tunicamycin in a time- and dose-dependent manner. TM-induced PARP-1 cleavage was significantly inhibited by treatment with GM6001 (a broad spectrum MMP inhibitor), MMP-9/-13 inhibitor and GI254023X (specific ADAM10 inhibitor). In addition, inhibition of all examined MMPs resulted in reversal of TM-induced apoptosis as well as increased cell viability. When considering the functional implications of MMP-9 and ADAM10, it is likely that active MMP-9 and ADAM10 help regulate the cellular levels of CD44v6 through cleavage of CD44v6 ectodomain during TM-induced apoptosis of Caki-2 cells. Collectively, these findings suggest that multiple TM-induced MMPs may cooperate to induce apoptosis. PMID- 22923172 TI - Pre-embolization evaluation of high-flow priapism: magnetic resonance angiography of the penis. AB - PURPOSE: High-flow priapism is often a sequela of perineal trauma resulting in an arteriocavernosal fistula (ACF) between a cavernosal artery and lacunar spaces of the penis. We report our experience utilizing magnetic resonance angiography (MRA) in addition to color Doppler Sonography (CDS) in the workup and treatment planning of 4 patients with high-flow priapism. METHODS: All patients had suspected high-flow priapism diagnosed by clinical exam and CDS and underwent MRA of the penis prior to sub-selective arterial embolization (SSAE) of the feeding vessel(s). RESULTS: While CDS is valuable in diagnosing and lateralizing high flow priapism, it does not provide clear anatomic delineation of the number and origin of feeding vessels. MRA provided demonstration of the fistula, demonstrated bilateral ACF supply in 2 patients, and afforded three-dimensional display of the feeding vessels which facilitated pre-embolization planning. CONCLUSIONS: In all four cases, MRA was an effective tool for displaying arterial and venous anatomy, localizing the ACF, and planning subsequent SSAE. MRA influenced management in two out of 4 patients by demonstrating bilateral feeding vessels to their ACFs that required bilateral SSAE. PMID- 22923173 TI - Cross-linking of structural proteins in ageing skin: an in situ assay for the detection of amine oxidase activity. AB - With increasing age, dynamic tissues such as lungs, blood vessels and skin lose their ability to both deform and recoil, culminating in tissue stiffening. This loss of tissue elasticity, which profoundly impacts tissue function and thus morbidity, may be due not only to changes in the relative abundance of key extracellular matrix proteins within tissues but also to their accumulation of post-translational modifications. Whilst to date attention has focussed primarily on the age-related non-enzymatic formation of advanced glycation end products, the accumulation of pathological enzyme-mediated cross-links may also lead to age related tissue stiffening. The lysyl oxidase (LOX) family of enzymes are constitutively expressed in adult tissues and are known to drive the catalysis of cross-links in both fibrillar collagens and elastin. Although immunochemical approaches are commonly used to localise the inactive pro-enzyme of LOX, and biochemical methods are employed to quantify activity in homogenised tissue, they do not allow for the in situ localisation of the enzyme. Thus, we have developed a novel assay to both detect and localise LOX enzyme activity in situ. LOX family members are amine oxidases and this assay uses the principle that an amine substrate in the presence of this class of enzyme will be oxidised to an aldehyde and hydrogen peroxide (H2O2). In turn, H2O2, when combined with luminol and horseradish peroxidase, will produce a light-emitting reaction that can be detected by film autoradiography. The development of a technique to localise specific amine oxidase activity in tissue sections may provide crucial additional information on the exact role played by this class of enzymes in mediating age related tissue stiffening. PMID- 22923174 TI - Differential expression of aging biomarkers at different life stages of the annual fish Nothobranchius guentheri. AB - Short-lived vertebrates such as annual fishes serve as model organisms for gaining insights into the mechanisms of aging, but the study on the changes in age-related markers during the normal aging of the annual fish Nothobranchius guentheri, one of the earliest fish models for aging research, remains open. This study was undertaken to examine the changes in the expression of age-related markers at the different developmental stages of N. guentheri, and to evaluate its suitability as a model organism for aging studies. Here we clearly demonstrated that the expression of senescence-associated beta-galactosidase and accumulation of lipofuscin increased with age. Similarly, the protein oxidation and lipid peroxidation also increased with age. By contrast, the activities of catalase, glutathione peroxidase and superoxide dismutase decreased with age, while the activity of telomerase showed no apparent change with age. Taken together, these data suggest that the annual fish N. guentheri can be a suitable model for aging studies. It also provides a set of biomarkers that can be used to trace the process of normal tissue aging in N. guentheri. PMID- 22923176 TI - WITHDRAWN: The Development of a Custom Built Portable Impact Testing Device for Assessing the Cushioning Properties of Athletic Socks. AB - Ahead of Print article withdrawn by publisher. PMID- 22923175 TI - Dietary supplementation with bovine lactoferrampin-lactoferricin produced by Pichia pastoris fed-batch fermentation affects intestinal microflora in weaned piglets. AB - This work is aimed at investigating the effects of recombinant bovine lactoferrampin-lactoferricin (LFA-LFC) instead of chlortetracycline on intestinal microflora in weaned piglets. The high cost of peptide production from either native digestion or chemical synthesis limits the clinical application of antimicrobial peptides. The expression of recombinant peptides in yeast may be an effective alternative. In the current study, recombinant LFA-LFC was produced via fed-batch fermentation in recombinant strain Pichia pastoris (KM71) XS10. Uniform design U6(6(4)) was used to optimize the fermentation conditions. The target peptide purified via cation-exchange and size-exclusion chromatography was added into the dietary of weaned piglets. After 21 days, the Lactobacilli, Bifidobacteria, and Enterobacteria in the chyme of the gut were quantified using real-time polymerase chain reaction. The results showed that approximately 82 mg of LFA-LFC was secreted into 1 L of medium under optimized conditions. Moreover, purified peptide showed strong antimicrobial activities against all the tested microorganisms. Compared with the control group, the LFA-LFC group increased the amount of Lactobacilli and Bifidobacteria (P<0.05) in the chyme of the stomach, duodenum, jejunum, ileum, colon, and caecum. These results show that dietary supplementation with LFA-LFC can affect intestinal microflora in weaned piglets. PMID- 22923177 TI - Osthole suppresses migration and invasion of A549 human lung cancer cells through inhibition of matrix metalloproteinase-2 and matrix metallopeptidase-9 in vitro. AB - Osthole, a natural compound, may be extracted from Cnidium monnieri and other medicinal plants. Previous studies have shown that osthole has anticancer effects in various human cancer cell lines. There is, however, no available information concerning the effects of osthole on the migration and invasion of human lung cancer cells. In the current study, we used Transwell assays to demonstrate that osthole inhibited the migration and invasion of A549 human lung cancer cells. Western blot analysis revealed that osthole reduced the levels of matrix metalloproteinase-2 (MMP-2) and matrix metallopeptidase-9 (MMP-9) in the A549 human lung cancer cells. Our findings indicate that osthole may have a novel function as an inhibitor of the metastasis of human lung cancer. PMID- 22923178 TI - A safety analysis of oral prednisone as a pretreatment for rituximab in rheumatoid arthritis. AB - The administration of 100 mg of methylprednisolone intravenously (IV) 1/2 h prior to rituximab decreases the incidence of acute infusion reactions (AIRs). However, this pretreatment adds considerable time and conveys potential risk. We performed an open-label prospective assessment of oral prednisone as a pretreatment to rituximab. This was a 26-week open-label trial of 40 mg of oral prednisone given 1/2 h prior to rituximab as a prophylaxis against AIRs in patients with rheumatoid arthritis (RA). The primary endpoint was AIRs in the first 24 h after their initial infusion. Secondary endpoints include AIRs during the 24 h following their second infusion and any adverse events experienced during the 26 week study; efficacy measures were also followed as secondary endpoints. Sixty four subjects were screened, and 50 subjects qualified. Fourteen out of the 50 (28 %) subjects had AIRs within 24 h of their first infusion. There were four AIRs (8.3 %) within 24 h of their second infusion. One of day 0 AIRs required drug discontinuation (wheezing/bronchospasm). Forty out of 50 (80 %) subjects experienced an adverse event during the 26 weeks. There were three SAEs deemed not to be study-drug related. The DAS28 and HAQ-DI all improved significantly at weeks 8, 16, and 26 compared to baseline. Historical controls demonstrate that 27 % of RA subjects experience AIRs with their first rituximab infusion. Our data suggest a smaller dose of oral prednisone is an effective alternative to IV methylprednisolone as a pretreatment for rituximab in patients with RA. PMID- 22923179 TI - Shrinking lung syndrome masked by pleuropericarditis: a case report and review of the literature. AB - The purpose of this article is to present an unusual case of shrinking lung syndrome (SLS) masked by pleuropericarditis with a review of the literature. We report a case of SLS in a 44-year-old woman in which the diagnosis was initially confounded by concurrent pleuropericarditis. The English medical literature was comprehensively reviewed for SLS for its presentation, clinical findings, diagnosis, treatment, with specific focus on its pathogenesis. SLS is a rare respiratory complication associated with systemic lupus erythematosus (SLE). The main manifestation of the disease is unexplained dyspnea, chest pain, and orthopnea. Lung volume reduction without parenchymal abnormalities along with restrictive ventilatory defect on pulmonary function test (PFT) is the hallmarks of this condition. Pathogenesis, treatment, and prognosis of SLS are not well described due to the small number of reported cases. The diagnosis of SLS in our patient was made based on imaging, PFT, and the exclusion of other respiratory diseases associated with SLE. Treatment with corticosteroid and intravenous cyclophosphamide was initiated due to simultaneously diagnosed renal involvement. Our case demonstrates the salient features of SLS. It emphasizes that although SLS is a rare disease limited to small subset of patients with SLE, it should be considered in patients with SLE with unexplained dyspnea. Moreover, symptoms of pleuropericarditis can mask and delay the diagnosis of SLS. Prompt diagnosis and treatment can lead to a decrease in morbidity and stabilization of pulmonary function test abnormalities. PMID- 22923180 TI - Characteristics and outcome of Goodpasture's disease in children. AB - Antiglomerular basement membrane antibody disease (aGD) remains a very uncommon entity in the pediatric population, characterized by pulmonary hemorrhage, glomerulonephritis, and antibodies against the glomerular basement membrane. We herein describe the case of a 14-year-old girl with primary pulmonary symptoms diagnosed with aGD. Furthermore, we review 23 cases described in English literature over a 25-year period. Our case is the fourth child that presented with only pulmonary symptoms and no or minimal renal involvement. Based on the 23 cases, we present data on demographics and clinical symptoms, diagnostic tools, and prognosis. aGD presents in children with a male/female ratio of 1:2. Most children (91 %) survive, but in many cases renal disease progresses to end stage, requiring maintenance therapy on dialysis and some undergo kidney transplantation. However, no case was identified with signs of relapse after remission. aGD should be considered in the differential diagnosis of diffuse lung hemorrhage despite the lack of renal abnormalities. Antiglomerular basement membrane antibody testing can be of great value in confirming the diagnosis. PMID- 22923182 TI - Subsequent entry biologics/biosimilars: a viewpoint from Canada. AB - We have reviewed the issues surrounding the advent of biosimilars in the rheumatoid arthritis biologic field. Our proposals emphasize the need to focus primarily on patient safety and to assess the outcomes of therapy both in the short and longer term. PMID- 22923181 TI - Febrile conditions in rheumatology. AB - Fever is not the most frequent symptom in rheumatology; however, its occurrence always draws attention to a severe underlying pathologic process. The rheumatologic assessment of febrile patients usually takes place for three reasons: the patient's fever is associated with known rheumatic disease or musculoskeletal symptoms, or rheumatologic cause is suggested as the underlying cause of fever of unknown origin. The primary task of the rheumatologist is to rule out infections and autoimmune processes. In addition to the musculoskeletal and accompanying symptoms, the information about the course of fever and the observation of the continuity or periodicity of fever provide help to establish the diagnosis. A summarising discourse about this issue is rarely published in this speciality; therefore, we found it important to provide an overview of rheumatological diseases accompanied by fever. PMID- 22923183 TI - Short-term therapeutic effects of transcatheter arterial chemoembolization using miriplatin-lipiodol suspension for hepatocellular carcinoma. AB - PURPOSE: To retrospectively investigate the short-term therapeutic effects and adverse effects associated with the use of miriplatin-lipiodol suspension for transcatheter arterial chemoembolization (TACE) in patients with hepatocellular carcinoma (HCC), using TACE with cisplatin-lipiodol suspension as the historical control. MATERIALS AND METHODS: The study was conducted on 48 and 50 consecutive patients with HCC who underwent TACE with miriplatin-lipiodol suspension and cisplatin-lipiodol suspension, respectively. Therapeutic effect was evaluated by mRECIST. Adverse effects were graded by CTCAE, version 4.0. The therapeutic and adverse effects were compared using Fisher's exact test and multivariate logistic regression. RESULTS: Complete remission, partial response, stable disease and progressive disease were observed in 37.5, 18.8, 33.3 and 10.4 % of patients in the miriplatin group, with the corresponding percentages being 54.0, 32.0, 14.0 and 0.0 %, respectively, in the cisplatin group. The short-term therapeutic effects were statistically significantly worse in the miriplatin group than in the cisplatin group, even after adjustment for tumor size and Child-Pugh class. The rates of nausea and serum creatinine elevation were statistically significantly lower in the miriplatin group (p < 0.05). CONCLUSION: TACE using miriplatin-lipiodol suspension yielded worse short-term responses than cisplatin lipiodol suspension; however, the rates of adverse events were significantly lower in the miriplatin group. PMID- 22923184 TI - Ectopic pituitary adenoma with empty sella in the setting of MEN-1 syndrome: detection with 68Ga-DOTANOC PET/CT. AB - Patients with multiple endocrine neoplasia type-1 syndromes are known to have neuroendocrine tumors (NETs) involving the pituitary and gastroenteropancreatic region, in addition to the presence of parathyroid abnormalities. In rare instances adenomas in the ectopic pituitary gland have been reported. As pituitary gland and pituitary adenomas are known to express SSTRs, somatostatin receptor scintigraphy can be used for imaging. Somatostatin receptor-based PET/CT imaging using 68Ga-DOTANOC has become a popular noninvasive imaging modality for evaluation of patients with NETs. The application of 68Ga-DOTANOC PET/CT can be extended to multiple endocrine neoplasia type 1 patients, as is evident from this case study. PMID- 22923185 TI - Clinical applications of high-resolution ocular magnetic resonance imaging. AB - Magnetic resonance imaging (MRI) using fast sequences with subjects staring at a target can provide motion-free ocular images, and small receiver surface coils make it possible to produce ocular images with high spatial resolution. MRI using half-Fourier single-shot rapid acquisition with a relaxation enhancement sequence as a fast T2-weighted imaging yields useful images for the morphologic diagnosis of ocular diseases, and MRI using a fast spoiled gradient-recalled-echo sequence as a T1-weighted imaging yields additional information by the administration of gadolinium-based contrast material for assessing the vascularity of intraocular tumors. These ocular imaging techniques are useful for the evaluation of patients with angle closure glaucoma, congenital abnormality of ocular globes, intraocular tumors and several types of detachments, as well as patients after ocular surgery. In this pictorial essay, we demonstrate the clinical applications of fast high-resolution ocular MRI with fixation of the subjects' visual foci. PMID- 22923186 TI - Anatomy of the levator claviculae, with an overview and a literature survey. AB - We report here an anatomical study of the levator claviculae discovered during an anatomical dissection course for medical students. The muscle was identified on the left side, and followed a typical topography to previous detections, originating from the transverse process of the fourth cervical vertebra and attaching to the upper facet of the middle part of the clavicle. Innervation to this muscle came from both the third and fourth rami of the cervical spinal nerves. Blood supply to the muscle could not be identified clearly. In this report, we undertook a comprehensive literature survey of this muscle dating back ca. 170 years, and attempted to ascertain the phylogenic and ontogenetic explanations for the development of this muscle. PMID- 22923187 TI - Translocator protein (18 kDa) (TSPO) as a therapeutic target for anxiety and neurologic disorders. AB - The translocator protein (18 kD) (TSPO) plays a crucial role for the synthesis of neurosteroids by promoting the transport of cholesterol to the inner mitochondrial membrane, which is the rate-limiting step in neurosteroidogenesis. Neurosteroids are allosteric modulators of GABA(A) receptor function, which plays an important role in the pathophysiology of anxiety disorders. The TSPO ligand XBD173 enhances GABAergic neurotransmission by promoting neurosteroidogenesis without direct effects at the GABA(A) receptor. In humans, XBD173 shows potent antipanic efficacy without sedation and withdrawal after 7 days of treatment. XBD173 therefore appears to be a promising compound for rapid anxiolytic efficacy with a favorable side-effect profile. Furthermore, TSPO ligands show neuroprotective and antiinflammatory effects in experimental models of peripheral neuropathies and traumatic brain injury. These compounds might therefore also be valuable for the treatment of neurologic diseases with inflammation-related pathophysiology. PMID- 22923188 TI - Blood test for schizophrenia. AB - Schizophrenia is a complex disease with mostly unknown aetiology. Rapid development of molecular profiling technologies in recent years has facilitated identification of physiological processes associated with schizophrenia. In particular, changes have been found in the blood of schizophrenia patients, and this offers an accessible and efficient alternative to brain samples for research purposes. Here, we review the metabolic, immune and hormonal imbalances characterised in subgroups of schizophrenia patients and discuss potential applications in differential diagnosis, prognosis and early intervention. We also describe development of the first validated biological blood test for diagnosis of schizophrenia, and the challenges involved after introduction of this into clinical practice. Moreover, we discuss possibilities for further research on biomarkers for diagnostic applications in schizophrenia. Promising research avenues include extension to functional analysis of blood cells and applications in prediction of drug response and novel drug discovery. PMID- 22923189 TI - Schizophrenia: from risk genes to outcome and comorbidity. PMID- 22923190 TI - DNA methylation at promoter regions of interleukin 1B, interleukin 6, and interleukin 8 in non-small cell lung cancer. AB - Epidemiologic and experimental evidences support the concept that inflammation promotes the development and progression of cancers. Interleukins (ILs) regulate the expression of several molecules and signaling pathways involved in inflammation. High expression of some ILs in the tumor microenvironment has been associated with a more virulent tumor phenotype. To examine the role of IL-1beta, IL-6, and IL-8 in non-small cell lung cancer, we measured mRNA levels and promoter DNA methylation in a panel of cultured human lung cells (n = 23) and in matched pair lung tumor versus adjacent non-tumorous tissues (n = 24). We found that lung cancer cells or tissues had significantly different DNA methylation and mRNA levels than normal human bronchial epithelial cells or adjacent non-tumorous tissues, respectively. High DNA methylation of ILs promoters in lung cancer cells or tissues was associated with low mRNA levels. We found an inverse correlation between DNA methylation of IL1B, IL6, and IL8 gene promoters and their corresponding mRNA levels, such inverse correlation was more significant for IL1B (i.e., all cancer cell lines used in this study had a hypermethylated IL1B promoter which was associated with silencing of the gene). Our results underline for the first time the role of epigenetic modifications in the regulation of the expression of key cytokines involved in the inflammatory response during lung cancer development. PMID- 22923192 TI - Inhibitor of apoptosis protein (IAP) antagonists demonstrate divergent immunomodulatory properties in human immune subsets with implications for combination therapy. AB - Inhibitor of apoptosis proteins (IAPs) are critical in regulating apoptosis resistance in cancer. Antagonists of IAPs, such as LCL161, are in clinical development and show promise as anti-cancer agents for solid and hematological cancers, with preliminary data suggesting they may act as immunomodulators. IAP antagonists hypersensitize tumor cells to TNF-alpha-mediated apoptosis, an effect that may work in synergy with that of cancer vaccines. This study aimed to further investigate the immunomodulatory properties of LCL161 on human immune subsets. T lymphocytes treated with LCL161 demonstrated significantly enhanced cytokine secretion upon activation, with little effect on CD4 and CD8 T-cell survival or proliferation. LCL161 treatment of peripheral blood mononuclear cells significantly enhanced priming of naive T cells with synthetic peptides in vitro. Myeloid dendritic cells underwent phenotypic maturation upon IAP antagonism and demonstrated a reduced capacity to cross-present a tumor antigen-based vaccine. These effects are potentially mediated through an observed activation of the canonical and non-canonical NF-kappaB pathways, following IAP antagonism with a resulting upregulation of anti-apoptotic molecules. In conclusion, this study demonstrated the immunomodulatory properties of antagonists at physiologically relevant concentrations and indicates their combination with immunotherapy requires further investigation. PMID- 22923193 TI - Direct serum and tissue assay for EGFR mutation in non-small cell lung cancer by high-resolution melting analysis. AB - Biological therapy with epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) have noted promising outcomes for patients with non-small cell lung carcinoma (NSCLC), especially those with mutated EGFR. Tissue EGFR gene mutation testing can predict the benefit of taking a first-line EGFR-TKI, thus, allowing the physician to prescribe the most suitable therapy. Unfortunately, most lung cancer patients, especially NSCLC patients present with advanced disease that is surgically unresectable. The goal of this study was to develop high-resolution melting (HRM) assays to detect EGFR mutations in exons 18 to 21, compare their sensitivity and concordance to direct sequencing, and evaluate the feasibility and reliability of serum as a tissue alternate for routine EGFR mutation screening. EGFR mutations of 126 Formalin-Fixed Paraffin-Embedded (FFPE), 47 fresh frozen tissues and from 47 matched pre-operation serum specimens of NSCLC patients were screened by the HRM assays. EGFR mutations by HRM were confirmed through sequencing. We found 78 EGFR mutations in 70 FFPE tissues, 25 EGFR mutations in 24 fresh frozen tissues, with a mutation rate of 55.56% (70/126) and 51.06% (24/47), respectively. Most mutations were correctly identified by sequencing. EGFR mutations were detected in 22 serum samples from 24 tissue EGFR mutation-positive patients. The concordance rate between serum and tissue in EGFR mutation screening was 91.67%. We conclude that the HRM assay can provide convincing and valuable results both for serum and tissues samples, thus, it is suitable for routine serum EGFR mutation screening for NSCLC patients, especially those surgically unresectable. PMID- 22923191 TI - Endotoxin induces proliferation of NSCLC in vitro and in vivo: role of COX-2 and EGFR activation. AB - Lung cancer is frequently complicated by pulmonary infections which may impair prognosis of this disease. Therefore, we investigated the effect of bacterial lipopolysaccharides (LPS) on tumor proliferation in vitro in the non-small cell lung cancer (NSCLC) cell line A549, ex vivo in a tissue culture model using human NSCLC specimens and in vivo in the A549 adenocarcinoma mouse model. LPS induced a time- and dose-dependent increase in proliferation of A549 cells as quantified by MTS activity and cell counting. In parallel, an increased expression of the proliferation marker Ki-67 and cyclooxygenase (COX)-2 was detected both in A549 cells and in ex vivo human NSCLC tissue. Large amounts of COX-2-derived prostaglandin (PG)E(2) were secreted from LPS-stimulated A549 cells. Pharmacological interventions revealed that the proliferative effect of LPS was dependent on CD14 and Toll-like receptor (TLR)4. Moreover, blocking of the epidermal growth factor receptor (EGFR) also decreased LPS-induced proliferation of A549 cells. Inhibition of COX-2 activity in A549 cells severely attenuated both PGE(2) release and proliferation in response to LPS. Synthesis of PGE(2) was also reduced by inhibiting CD14, TLR4 and EGFR in A549 cells. The proliferative effect of LPS on A549 cells could be reproduced in the A549 adenocarcinoma mouse model with enhancement of tumor growth and Ki-67 expression in implanted tumors. In summary, LPS induces proliferation of NSCLC cells in vitro, ex vivo in human NSCLC specimen and in vivo in a mouse model of NSCLC. Pulmonary infection may thus directly induce tumor progression in NSCLC. PMID- 22923194 TI - Additive effect of single amino acid replacements on the kinetic stability of beta-glucosidase B. AB - Previously, we applied in vitro evolution to generate the thermoresistant triple mutant H62R/N223Y/M319I of beta-glucosidase B (BglB) from Paenibacillus polymyxa. In order to dissect the energetic contributions to protein stabilization achieved by these mutations, we measured the kinetic constants of the heat denaturation of wild type BglB, the triple mutant and the three single mutants (H62R, N223Y, M319I) by circular dichroism at various temperatures. Our results show that all four mutants delayed the denaturation process. Based on the Transition State theory, the increase of the activation barrier for the thermal denaturation of the triple mutant (DeltaDeltaG ( N->TS )) is equivalent to that produced by the sum of the contributions from the three single mutants, whose C ( beta ) s are located at least 18 A apart. This analysis provides a formal demonstration of the generally accepted idea that protein thermal stability can be increased through sequential addition of individual mutations. Each of the mutations described here contribute in part to the overall effect, which in this case affects the unfolding barrier. PMID- 22923195 TI - Anxiolytic properties of Valeriana officinalis in the zebrafish: a possible role for metabotropic glutamate receptors. AB - Valerian extract is used in complementary and alternative medicine for its anxiolytic and sedative properties. Our previous research demonstrated valerian interactions with glutamate receptors. The purpose of this study was to determine if valerian anxiolytic properties are mediated by metabotropic glutamate receptors (mGluR) such as mGluR (1/5) (mGluR I) and mGluR (2/3) (mGluR II). Adult wild-type zebrafish (Danio rerio) prefer the black compartment and avoid the white compartment in the dark/light preference task. Zebrafish exposed to 1 mg/mL of valerian extract or 0.00117 mg/mL valerenic acid increased their residence time in the white side by 84.61 +/- 6.55 % and 58.30 +/- 8.97 %, respectively. LAP3 (mGluR I antagonist) and EGLU (mGluR II antagonist) significantly inhibited the effects of valerian and valerenic acid. These results demonstrated that valerian and valerenic acid have anxiolytic properties in the zebrafish. Moreover, the selective interaction of valerian with mGluR I and II represent an alternative explanation for the anxiolytic properties of this plant and support the role of mGluR in anxiety. PMID- 22923196 TI - New steroidal saponins and sterol glycosides from Paris polyphylla var. yunnanensis. AB - Four new steroidal saponins, pariposides A-D (1-4), and two new sterol glycosides, pariposides E-F (5-6), along with eight known steroidal saponins (7 14), two known sterol glycosides (15-16), and two known ecdysteroids (17-18), were isolated from the roots of Paris polyphylla var. yunnanensis. Among them, compounds 1-4 are the first spirostanol saponins with a peroxy group located between C-5 and C-8 of the aglycone. Their structures were determined by detailed spectroscopic analyses and chemical methods. All the isolated compounds were evaluated for their in vitro cytotoxicities against human nasopharyngeal carcinoma epithelial (CNE) cells, and steroidal saponins 7, 11, 13, and 14 showed a potent antiproliferative effect on CNE cells with IC50 values of 9.2, 4.7, 11.1, and 2.7 uM, respectively. PMID- 22923197 TI - Activation of antioxidant response element in mouse primary cortical cultures with sesquiterpene lactones isolated from Tanacetum parthenium. AB - Tanacetum parthenium produces biologically active sesquiterpene lactones (SL). Nuclear factor E2-related factor 2 (Nrf2) is a transcription factor known to activate a series of genes termed the antioxidant response element (ARE). Activation of Nrf2/ARE may be useful for the treatment of neurodegenerative disease. In this study we isolated 11 SL from T. parthenium with centrifugal partition chromatography and semipreparative HPLC. Compounds were screened in vitro for their ability to activate the ARE on primary mouse cortical cultures as well as for their toxicity towards the cultures. All SL containing the alpha methylene-gamma-lactone moiety were able to activate the ARE and cause cellular toxicity. The structure-activity relationship among the SL isolated indicates that the guaianolides were more active and when lacking the endoperoxide functionality less toxic then the germacranolides. PMID- 22923198 TI - Quantitative determination of phenolic compounds in lotus (Nelumbo nucifera) leaves by capillary zone electrophoresis. AB - The traditional use of lotus leaves as an anti-inflammatory remedy is associated with the occurrence of phenolic compounds. In this study the first CE method for the analysis of all major phenolic constituents in Nelumbo nucifera leaves is presented. It permits the separation of nine relevant markers in less than 10 min. The optimized procedure was fully validated and then used to analyze diverse samples collected in Vietnam. They revealed significant qualitative and quantitative differences depending on growing area and season. Yet, in all of them, quercetin-3-O-beta-D-glucuronide, hyperoside, and isoquercitrin were the most dominant flavonoids. PMID- 22923199 TI - The in vitro protective effects of curcumin and demethoxycurcumin in Curcuma longa extract on advanced glycation end products-induced mesangial cell apoptosis and oxidative stress. AB - Curcuma longa L. (CLL), a traditional herbal medicine, has been widely used for the prevention of diabetic vascular complications in recent years. However, the protective effects of curcuminoids in CLL on the AGEs-induced damage to mesangial cell are not fully understood. In this present study, dihydroethidium, superoxide dismutase kit, malondialdehyde kit, and acridine orange/ethidium bromide staining methods were used to evaluate the activities of curcumin and demethoxycurcumin (10(-11)-10(-9) M) on AGEs-induced oxidative stress and apoptosis, which were associated with the damage to mesangial cell. The results showed that these two compounds could significantly restore advanced glycation end products (AGEs) induced apoptosis to normal levels (IC50 = 3.874 * 10(-11) M for curcumin and IC50 = 6.085 * 10(-11) M for demethoxycurcumin) and reduce remarkably reactive oxygen species generation in mesangial cell. Furthermore, curcumin and demethoxycurcumin dramatically elevated AGEs-decreased superoxide dismutase activity while significantly reducing AGEs-increased malondialdehyde content in cell culture supernatant. Our results suggest that both curcumin and demethoxycurcumin have a significant protective potential to the prevention of diabetic nephropathy. PMID- 22923200 TI - Adrenomedullin is involved in the progression of colonic adenocarcinoma. AB - Adrenomedullin (ADM), initially identified in human pheochromocytoma, participates in a wide range of physiological and pathological processes, including vasorelaxation, angiogenesis and apoptosis. Recent studies have reported that ADM protected tumor cells against apoptotic cell death via the upregulation of Bcl-2 or the activation of the phosphatidylinositol 3-kinase/Akt pathway. Several studies have also provided evidence that ADM is involved in tumor initiation and progression. However, this has not been shown in gastrointestinal tumors. To investigate the role of ADM in gastrointestinal tumor progression, we determined the expression levels of ADM in 72 cases of stomach cancer and 84 cases of colon cancer and determined whether there was an association between the ADM expression levels and pathological parameters or clinical survival rates. We found that the expression levels of ADM were significantly higher in colon cancers than in matching normal mucosal tissues. In addition, the expression levels of ADM in colon cancers were correlated with cancer stage and clinical survival rate. However, we did not find any significant correlations between ADM expression levels and clinical or pathological parameters in stomach cancers. Taken together, our data strongly suggest that ADM is involved in the progression of colon cancer. PMID- 22923201 TI - Changes in expression of human serine protease HtrA1, HtrA2 and HtrA3 genes in benign and malignant thyroid tumors. AB - Human HtrA proteins are serine proteases involved in essential physiological processes. HtrA1 and HtrA3 function as tumor suppressors and inhibitors of the TGF-beta signaling pathway. HtrA2 regulates mitochondrial homeostasis and plays a pivotal role in the induction of apoptosis. The aim of the study was to determine whether the HtrA proteins are involved in thyroid carcinogenesis. We used the immunoblotting technique to estimate protein levels of HtrA1, HtrA2, long and short variants of HtrA3 (HtrA3-L and HtrA3-S) and TGF-beta1 in tissues of benign and malignant thyroid lesions, and control groups. We found that the levels of HtrA2 and HtrA3-S were higher in thyroid malignant tumors compared to normal tissues and benign tumors. The HtrA3-L level was increased in malignant tumor tissues compared to benign tumor tissues and control tissues from patients with benign lesions, and elevated in normal tissues from patients with thyroid carcinoma compared to normal tissues from patients with benign lesions. We also compared levels of HtrA proteins in follicular thyroid carcinoma (FTC) and papillary thyroid carcinoma (PTC) and found that these types of carcinoma differed in the expression of HtrA3-S and HtrA1. These results indicate the implication of HtrA proteins in thyroid carcinogenesis suggest that HtrA3 variants may play different roles in cancer development, and that the increased HtrA3-L levels in thyroid tissue could be correlated with the development of malignant lesions. The TGF-beta1 levels in tumor tissues were not significantly altered compared to control tissues. PMID- 22923202 TI - Rhabdomyolysis and acute kidney injury in two children: questions. PMID- 22923204 TI - Renal function and injury in infants and young children with congenital heart disease. AB - BACKGROUND: The aim of this study was to investigate renal function and injury in infants and young children with congenital heart disease (CHD). METHODS: We prospectively enrolled 58 CHD children aged <=3 years and 20 age-matched controls and divided these into four groups: Group I, acyanotic CHD (n = 24); Group II, cyanotic CHD with arterial oxygen saturation of >75 % (n = 20); Group III, cyanotic CHD with arterial oxygen saturation of <=75 % (n = 14); Group IV, normal controls (n = 20). Urinary levels of microalbumin (MA), N-acetyl-beta-D glucosaminidase (NAG), and alpha1-microglobulin (alpha1-MG) corrected by creatinine (UCr) were compared. RESULTS: Children with CHD had elevated urinary alpha1-MG/UCr levels, with Group III children having the highest level. Groups I and III children had higher urinary NAG/UCr levels than those of Groups II and IV. Urinary MA/UCr levels in the three patient groups were comparable and significantly higher than that in the control group. A alpha1-MG * 100/ (alpha1 MG + MA) of <15 %, indicative of glomerular damage, was present in two patients in Group I and one in Group III, but none in Group II. CONCLUSIONS: Tubular injury can occur in CHD patients during infancy and early childhood. Among our patient cohort, it was most prominent in children with severe cyanosis. Glomerular injury was detected in some individuals with advanced heart failure or severe cyanosis. PMID- 22923206 TI - Spatiotemporal neural interactions underlying continuous drawing movements as revealed by magnetoencephalography. AB - Continuous and sequential movements are controlled by widely distributed brain regions. A series of studies have contributed to understanding the functional role of these regions in a variety of visuomotor tasks. However, little is known about the neural interactions underpinning continuous movements. In the current study, we examine the spatiotemporal neural interactions underlying continuous drawing movements and the association of them with behavioral components. We conducted an experiment in which subjects copied a pentagon continuously for ~45 s using an XY joystick, while neuromagnetic fluxes were recorded from their head using a 248-sensor whole-head magnetoencephalography (MEG) device. Each sensor time series was rendered stationary and non-autocorrelated by applying an autoregressive integrated moving average model and taking the residuals. We used the directional variability of the movement as a behavioral measure of the controls generated. The main objective of this study was to assess the relation between neural interactions and the variability of movement direction. That is, we divided the continuous recordings into consecutive periods (i.e., time-bins) of 51 steps duration and computed the pairwise cross-correlations between the prewhitened time series in each time-bin. The circular standard deviation of the movement direction within each time-bin provides an estimate of the directional variability of the 51-ms trajectory segment. We looked at the association between neural interactions and variability of movement direction, separately for each pair of sensors, by running a cross-correlation analysis between the strength of the MEG pairwise cross-correlations and the circular standard deviations. We identified two types of neuronal networks: in one, the neural interactions are correlated with the directional variability of the movement at negative time-lags (feedforward), and in the other, the neural interactions are correlated with the directional variability of the movement at positive time-lags (feedback). Sensors associated mostly with feedforward processes are distributed in the left hemisphere and the right occipital-temporal junction, whereas sensors related to feedback processes are distributed in the right hemisphere and the left cerebellar hemisphere. These results are in line with findings from a series of previous studies showing that specific brain regions are involved in feedforward and feedback control processes to plan, perform, and correct movements. Additionally, we looked at whether changes in movement direction modulate the neural interactions. Interestingly, we found a preponderance of sensors associated with changes in movement direction over the right hemisphere ipsilateral to the moving hand. These sensors exhibit stronger coupling with the rest of the sensors for trajectory segments with high rather than low directional movement variability. We interpret these results as evidence that ipsilateral cortical regions are recruited for continuous movements when the curvature of the trajectory increases. To the best of our knowledge, this is the first study that shows how neural interactions are associated with a behavioral control parameter in continuous and sequential movements. PMID- 22923207 TI - Balancing bistable perception during self-motion. AB - In two experiments we investigated whether bistable visual perception is influenced by passive own body displacements due to vestibular stimulation. For this we passively rotated our participants around the vertical (yaw) axis while observing different rotating bistable stimuli (bodily or non-bodily) with different ambiguous motion directions. Based on previous work on multimodal effects on bistable perception, we hypothesized that vestibular stimulation should alter bistable perception and that the effects should differ for bodily versus non-bodily stimuli. In the first experiment, it was found that the rotation bias (i.e., the difference between the percentage of time that a CW or CCW rotation was perceived) was selectively modulated by vestibular stimulation: the perceived duration of the bodily stimuli was longer for the rotation direction congruent with the subject's own body rotation, whereas the opposite was true for the non-bodily stimulus (Necker cube). The results found in the second experiment extend the findings from the first experiment and show that these vestibular effects on bistable perception only occur when the axis of rotation of the bodily stimulus matches the axis of passive own body rotation. These findings indicate that the effect of vestibular stimulation on the rotation bias depends on the stimulus that is presented and the rotation axis of the stimulus. Although most studies on vestibular processing have traditionally focused on multisensory signal integration for posture, balance, and heading direction, the present data show that vestibular self-motion influences the perception of bistable bodily stimuli revealing the importance of vestibular mechanisms for visual consciousness. PMID- 22923205 TI - The effect of occupational lead exposure on blood levels of zinc, iron, copper, selenium and related proteins. AB - The study objective was to evaluate the effect of occupational lead exposure on blood concentrations of zinc, iron, copper, selenium and proteins related to them, such as transferrin, caeruloplasmin and haptoglobin. The examined group consisted of 192 healthy male employees of zinc-lead works. By the degree of lead exposure, the exposed group was subdivided into three subgroups. The control group was composed of 73 healthy male administrative workers. The markers of lead exposure (blood levels of lead and zinc protoporphyrin) were significantly elevated in the exposed group compared with the control group. Additionally, concentrations of copper and caeruloplasmin were raised. The significant increase in haptoglobin level was observed only in the low exposure group. Selenium levels were significantly decreased, whereas iron, zinc and transferrin levels were unchanged in the exposed group compared with the control group. There were positive correlations between the lead toxicity parameters and the copper and caeruloplasmin levels. In conclusion, the effect of occupational exposure to lead on the metabolism of trace metals appears to be limited. However, significant associations between lead exposure and levels of copper and selenium were shown. Changed levels of positive acute-phase proteins, such as caeruloplasmin and haptoglobin, were also observed. PMID- 22923208 TI - Two-dimensional static manipulation tasks: does force coordination depend on change of the tangential force direction? AB - Coordination of the grip force (GF) with a tangential force (TF, often referred to as load force) exerted along a certain line in space (i.e., one-dimensional tasks) during object manipulation has proved both to be high and based on feed forward neural control mechanisms. However, GF-TF coordination deteriorates when the TF of one-dimensional task consecutively switches its direction (bidirectional task). In the present study, we aimed to explore GF-TF coordination in the generally neglected multi-dimensional manipulations. We hypothesized that the coordination would depend on the number of unidirectional and bidirectional orthogonal components of a two-dimensional TF exertion. Fourteen subjects traced various circular TF patterns and their orthogonal diameters shown on a computer screen by exerting a static TF. As expected, the unidirectional tasks revealed higher GF-TF coordination than the bidirectional ones (e.g., higher GF-TF correlations and GF gains, and lower GF/TF ratio). Regarding the circular tasks, most of the data were in line with the hypothesis revealing higher coordination associated with higher number of unidirectional components. Of particular importance could be that the circular tasks also revealed prominent time lags of GF with respect to TF, suggesting involvement of feedback mechanisms. We conclude that the force coordination in bidirectional static manipulations could be affected by changes in TF direction along either of its orthogonal components. The time lags observed from the circular tasks could be a consequence of the activity of sensory afferents, rather than of the visual feedback provided or the task complexity. PMID- 22923209 TI - Links between multisensory processing and autism. AB - Autism spectrum disorder is typically associated with social deficits and is often specifically linked to difficulty with processing faces and other socially relevant stimuli. Emerging research has suggested that children with autism might also have deficits in basic perceptual abilities including multisensory processing (e.g., simultaneously processing visual and auditory inputs). The current study examined the relationship between multisensory temporal processing (assessed via a simultaneity judgment task wherein participants were to report whether a visual stimulus and an auditory stimulus occurred at the same time or at different times) and self-reported symptoms of autism (assessed via the Autism Spectrum Quotient questionnaire). Data from over 100 healthy adults revealed a relationship between these two factors as multisensory timing perception correlated with symptoms of autism. Specifically, a stronger bias to perceive auditory stimuli occurring before visual stimuli as simultaneous was associated with greater levels of autistic symptoms. Additional data and analyses confirm that this relationship is specific to multisensory processing and symptoms of autism. These results provide insight into the nature of multisensory processing while also revealing a continuum over which perceptual abilities correlate with symptoms of autism and that this continuum is not just specific to clinical populations but is present within the general population. PMID- 22923210 TI - Influence of hepatic parenchymal histology on outcome following right hepatic trisectionectomy. AB - BACKGROUND: Histological abnormalities in the non-tumour-bearing liver (NTBL) may influence outcome following hepatectomy. Effects will be most pertinent following right trisectionectomy but have yet to be specifically examined in this context. This study aimed to investigate the influence of perioperative factors, including NTBL histology, on outcome following right trisectionectomy. METHODS: Pathological review of the NTBL of 103 consecutive patients undergoing right trisectionectomy between January 2003 and December 2009 was performed using established criteria for steatosis, non-alcoholic steatohepatitis (NASH), sinusoidal injury (SI), fibrosis and cholestasis. Perioperative and pathological factors were correlated with post-operative outcome (morbidity, major morbidity, hepatic insufficiency and mortality). RESULTS: Morbidity, hepatic insufficiency and major morbidity occurred in 37.9 %, 14.6 % and 22.3 % of cases, respectively. Ninety-day mortality rate was 5.8 %. NASH (P = 0.007) and perioperative blood transfusion (P = 0.001) were independently associated with hepatic insufficiency following trisectionectomy. NASH (P = 0.028), perioperative transfusion (P = 0.016), diabetes mellitus (P = 0.047) and coronary artery disease (P = 0.036) were independently associated with major morbidity. Steatosis, SI, fibrosis and cholestasis in the NTBL demonstrated no association with any adverse outcome. CONCLUSION: NASH, but not steatosis or SI, is associated with adverse outcome following right trisectionectomy and caution must be exerted when considering major hepatectomy in patients with NASH. PMID- 22923211 TI - Enhancement of a small bowel obstruction model using the gastrografin(r) challenge test. AB - BACKGROUND: Based on a previous published data on small bowel obstruction (SBO), a management model for predicting the need for exploration has been adopted in our institution. In our model, patients presenting with three criteria-the history of obstipation, the presence of mesenteric edema, and the lack of small bowel fecalization on computed tomography (CT)-undergo exploration. Patients with two or less features were managed nonoperatively. An alternative tool for predicting need for operative intervention is Gastrografin (GG) challenge test. HYPOTHESIS: We hypothesized that the GG challenge test, when used in combination with our prior model, will decrease the rate of explorations in patients not meeting the criteria for immediate operation. METHODS: An approval from IRB was obtained to review patients admitted with a diagnosis of SBO from November 2010 to September 2011. All patients presenting with signs of ischemia, patients with all three model criteria defined previously, and those who had an abdominal operation within 6 weeks of diagnosis were excluded. All patients had an abdominal/pelvic CT and GG challenge at the time of diagnosis. Patients were compared to historic controls managed without the GG challenge (from July to December 2009). Successful GG challenge was defined as the presence of contrast in the colon after a follow-up film or a bowel movement. Data were presented as medians or percentages; significance was considered at p < 0.05. RESULTS: One hundred and twenty-five patients with a diagnosis of small bowel obstruction were identified wherein 47 % were males. Fifty-three received a GG challenge (study), and 72 did not have a GG challenge (historic). There was no difference in age (70 vs 65 years), history of prior SBO (51 vs 49 %), history of diabetes mellitus (21 vs 18 %), history of malignancy (32 vs 39 %), or cardiac disease (30 vs 39 %). Both groups had similar number of previous abdominal operations (two vs two). The presence of mesenteric edema (68 vs 75 %), the lack of small bowel fecalization (47 vs 46 %), and a history of obstipation (25 vs 24 %) were similar in both groups. Patients in the study group had a lesser rate of abdominal exploration (25 vs 42 %, p = 0.05) and fewer complications (13 vs 31 %, p = 0.02) compared to the historic control group. There was equivalent incidence of ischemic bowel (4 vs 7 %), duration of hospital stay (4 vs 7 days), duration from admission to operation (2 vs 3 days), and mortality (8 vs 6 %); 44 patients had a successful GG challenge with nine failures. There was a greater rate of exploration in patients with a failed challenge compared to those with a successful challenge (89 vs 11 %, p < 0.01). CONCLUSION: The use of the GG challenge enhanced the SBO prediction model by decreasing the need for exploration in patients not meeting the criteria for immediate operation. Patients who failed the GG challenge test were much more likely to undergo an exploration. PMID- 22923213 TI - Gorillas' use of the escape response in object choice memory tests. AB - The ability to monitor and control one's own cognitive states, metacognition, is crucial for effective learning and problem solving. Although the literature on animal metacognition has grown considerably during last 15 years, there have been few studies examining whether great apes share such introspective abilities with humans. Here, we tested whether four gorillas could meet two criteria of animal metacognition, the increase in escape responses as a function of task difficulty and the chosen-forced performance advantage. During testing, the subjects participated in a series of object choice memory tests in which a preferable reward (two grapes) was placed under one of two or three blue cups. The apes were required to correctly select the baited blue cup in this primary test. Importantly, the subjects also had an escape response (a yellow cup), where they could obtain a secure but smaller reward (one grape) without taking the memory test. Although the gorillas received a relatively small number of trials and thus experienced little training, three gorillas significantly declined the memory tests more often in difficult trials (e.g., when the location of the preferred reward conflicted with side bias) than in easy trials (e.g., when there was no such conflict). Moreover, even when objective cues were eliminated that corresponded to task difficulty, one of the successful gorillas showed evidence suggestive of improved memory performance with the help of escape response by selectively avoiding trials in which he would be likely to err before the memory test actually proceeded. Together, these findings demonstrate that at least some gorillas may be able to make optimal choices on the basis of their own memory trace strength about the location of the preferred reward. PMID- 22923215 TI - Fabrication of channeled scaffolds with ordered array of micro-pores through microsphere leaching and indirect Rapid Prototyping technique. AB - Advanced scaffold fabrication techniques such as Rapid Prototyping (RP) are generally recognized to be advantageous over conventional fabrication methods in terms architectural control and reproducibility. Yet, most RP techniques tend to suffer from resolution limitations which result in scaffolds with uncontrollable, random-size pores and low porosity, albeit having interconnected channels which is characteristically present in most RP scaffolds. With the increasing number of studies demonstrating the profound influences of scaffold pore architecture on cell behavior and overall tissue growth, a scaffold fabrication method with sufficient architectural control becomes imperative. The present study demonstrates the use of RP fabrication techniques to create scaffolds having interconnected channels as well as controllable micro-size pores. Adopted from the concepts of porogen leaching and indirect RP techniques, the proposed fabrication method uses monodisperse microspheres to create an ordered, hexagonal closed packed (HCP) array of micro-pores that surrounds the existing channels of the RP scaffold. The pore structure of the scaffold is shaped using a single sacrificial construct which comprises the microspheres and a dissolvable RP mold that were sintered together. As such, the size of pores as well as the channel configuration of the scaffold can be tailored based on the design of the RP mold and the size of microspheres used. The fabrication method developed in this work can be a promising alternative way of preparing scaffolds with customized pore structures that may be required for specific studies concerning cell-scaffold interactions. PMID- 22923216 TI - Death due to crush injuries in a compactor truck: vitality assessment by immunohistochemistry. AB - We present a case in which the timing of injuries was requested to determine whether the death of a man found in a landfill was due to homicide or accident. The use of immunohistochemistry to detect P-selectin and E-selectin on endothelial cells of vessels in damaged skin samples, and compare them with intact skin samples, as well as the presence of lung adipose embolism provide information on the timing of the injury, thereby helping substantially to identify the dynamics of death. PMID- 22923217 TI - The stability of literacy-related cognitive contributions to Chinese character naming and reading fluency. AB - The present study examined the developmental issue of cognitive factors that explain Chinese literacy. Phonological awareness, rapid automatized naming, short term memory, orthographic awareness and morphological awareness and two literacy tasks (character naming and reading fluency) were administered to 408 second graders, 428 fourth-graders and 496 six-graders. Results from linear regression analysis and path analysis model showed that the five reading-related cognitive constructs explained unique variances in character naming. Second, character naming is primary for reading fluency after controlling other cognitive constructs; third, the relation between the cognitive factors and literacy changes significantly as a function of reading skills. Results give a clear direction to understanding Chinese reading development. PMID- 22923218 TI - Chemokine receptor 7 via proline-rich tyrosine kinase-2 upregulates the chemotaxis and migration ability of squamous cell carcinoma of the head and neck. AB - Aberrant regulation in the chemotaxis and migration ability of cancer cells is closely associated with their metastatic activity. The chemokine receptor 7 (CCR7) has recently been shown to play an important role in regional lymph node metastasis of squamous cell carcinoma of the head and neck (SCCHN). In this study, we examined the role of proline-rich tyrosine kinase-2 (Pyk2) in CCR7 induced chemotaxis and migration ability of metastatic SCCHN cells. We showed that Pyk2 is overexpressed in squamous cell carcinoma of the head and neck. We also found that CCR7 induced Pyk2 and cofilin activation. Inhibition of Pyk2 activity using a pharmacological inhibitor, Tyrphostin A9, significantly attenuated CCR7-induced Pyk2 tyrosine phosphorylation, activation of cofilin and sequentially abolished F-actin rearrangment, diminished the chemotaxis and migration ability of SCCHN cells. In summary, our data suggest that CCR7 via Pyk2 and cofilin regulates the chemotaxis and migration ability of metastatic SCCHN cells. PMID- 22923219 TI - Expression of BMP2, TLR3, TLR4 and COX2 in colorectal polyps, adenoma and adenocarcinoma. AB - The initiation and development of colorectal cancer is closely associated with the malignant transformation of colorectal polyps. The aim of this study was to analyze the expression of the bone morphogenetic protein-2 (BMP2), toll-like receptor 3 (TLR3), TLR4 and cyclooxygenase-2 (COX2) proteins in colorectal polyps, adenoma and adenocarcinoma. An immunohistochemical streptavidin peroxidase (SP) method was used to examine the expression of MBP2, TLR4, TLR3 and COX2 in 20 colorectal juvenile polyps and 15 colorectal polyps of hamartomatous polyposis obtained from children, and 20 colorectal adenomas and 20 colorectal adenocarcinomas obtained from adults. A comparison of the expression levels of TLR3 among the groups revealed a gradual downward trend from the colorectal juvenile polyp group to the colorectal hamartomatous polyposis, adenoma and adenocarcinoma groups, respectively. The expression level of TLR3 was significantly lower in the colorectal adenocarcinoma group (p<0.05). The expression levels of TLR3, TLR4 and BMP2 were significantly different among the colorectal juvenile polyp, hamartomatous polyposis, adenoma and adenocarcinoma groups. These three protein molecules may be significant in the development and malignant transformation of colorectal polyps. PMID- 22923220 TI - Analysis of cytotoxic T lymphocyte antigen-4 (CTLA-4) promoter -318C/T and +49A/G gene polymorphisms in Turkish patients with familial Mediterranean fever. AB - Either the role of the adaptive immune system or the interaction between innate and adaptive immune systems in familial Mediterranean fever (FMF) is not clear so far. So, we planned to search for the interaction between the innate and adaptive immune systems in the pathogenesis of FMF by investigating polymorphism for CTLA 4 gene, which plays a role in controlling antigen presentation to T cells. We also aimed to investigate whether there is an association between -318C/T and +49A/G polymorphisms in the CTLA-4 gene and the main clinical features of the disease. 75 FMF patients and 179 controls were studied. Polymorphism was detected by the PCR-RFLP technique. The CT genotype and T allele frequencies of the 318C/T polymorphism and the haplotype frequency for the -318T/+49A in the CTLA-4 gene were higher in the FMF (21.3, 21.3, and 10.7 %) when compared with the controls (10.6, 10.6, and 5.3 %; P = 0.029, 0.044, and 0.029). However, these differences did not reach a statistically significant level after the Bonferroni correction. A significant linkage disequilibrium was found between the -318C/T and +49A/G polymorphisms in the CTLA-4 gene (D' = 0.997, r(2) = 0.027, P = 0.0002). Genotype and carrier frequencies of the CTLA-4 gene +49A/G polymorphism were not significantly different between FMF patients and healthy controls. No association was found between the studied polymorphisms and the main clinical features of the disease. Our findings suggest that although not statistically significant, higher frequencies of CTLA-4 gene -318CT genotype, T allele, and 318T/+49A haplotype in FMF patients may be related to the non-autoimmune pathogenesis of FMF. PMID- 22923221 TI - [Mucocele after rectum extirpation - a rarity]. PMID- 22923222 TI - Breast microcalcifications as type descriptors to stratify risk of malignancy: a systematic review and meta-analysis of 10665 cases with special focus on round/punctate microcalcifications. AB - PURPOSE: To use a systematic review and meta-analysis to determine the predictive value of five suspicious type descriptors of microcalcifications, with special focus on round/punctate microcalcifications because of controversy. MATERIALS AND METHODS: We performed a literature search using three databases and one search engine. We screened citations for malignancy rates of type descriptors. We regarded malignancy rates below 2% (BI-RADS 3) and above 95% (BI-RADS 5) as clinically significant threshold values for suspicion (BI-RADS 4). RESULTS: Forty studies from 14 countries with a total of 10,665 microcalcification lesions were included. The pooled malignancy rates were: coarse heterogeneous, 13% (95% confidence interval (95%-CI): 7 - 20%); amorphous or indistinct, 27% (95%-CI: 21 33%); pleomorphic, 50% (95%-CI: 43-58%); linear, 78% (95%-CI: 68 - 86%). The pooled malignancy rate of all round/punctate microcalcifications was 9% (95%-CI: 6-13%), for the subgroup follow-up it was 0,5% (95%-CI: 0.08-2.57%), and with histological verification it was 14% (95%-CI: 11-19%). Woman selection and consideration of additional suspicious image findings were reasons for between study heterogeneity. Addition of ACR distribution descriptors diversified risk stratification, but did not alter BI-RADS assessment category. CONCLUSION: All suspicious type descriptors including round/punctate microcalcifications as well as combinations of type with suspicious distribution descriptors fell into BI RADS assessment category 4. Exclusion of suspicious adjunct factors can direct clustered, round/punctate microcalcifications to a lower BI-RADS assessment category. PMID- 22923223 TI - Reproducibility and sensitivity of detecting brain activity by simultaneous electroencephalography and near-infrared spectroscopy. AB - The aims were (1) to determine the sensitivity and reproducibility to detect the hemodynamic responses and optical neuronal signals to brain stimulation by near infrared spectroscopy (NIRS) and evoked potentials by electroencephalography (EEG) and (2) to test the effect of novel filters on the signal-to-noise ratio. This was achieved by simultaneous NIRS and EEG measurements in 15 healthy adults during visual stimulation. Each subject was measured three times on three different days. The sensitivity of NIRS to detect hemodynamic responses was 55.2 % with novel filtering and 40 % without. The reproducibility in single subjects was low. For the EEG, the sensitivity was 86.4 % and the reproducibility 57.1 %. An optical neuronal signal was not detected, although novel filtering considerably reduced noise. PMID- 22923224 TI - The effect of removing visual information on reach control in young children. AB - Visual information about the hand, the reach space, and a target can all contribute to the control of a reaching movement. When visual information is removed, both feedforward mechanisms (involved in planning the movement) and feedback mechanisms (involved in correcting errors) may be affected. This study looks at how 4- to 5-year-old children use visual information to guide reaching movements. Children reached for a toy object in four conditions--in the light, in the dark while the toy was glowing, and in complete darkness after a 0-s delay and a 4-s delay. When a reach in the glowing condition was compared with a reach in the light, reaches were more curved, had a longer duration, and earlier time to-peak-velocity than a reach in the light but the number of grasping responses were comparable to in the light condition. When a reach in the two dark conditions (0- and 4-s) was compared with a reach in the light, the number of grasping responses decreased and 14 and 31 % of reaches resulted in a miss, that is, no contact was made with the object. While we did not find any significant kinematic differences between the 0- and 4-s dark conditions, there was a significantly larger number of misses in the 4-s dark condition, suggesting that memory of target position may decay over time. Overall, removing vision of the hand and reach space in the glowing condition appears to affect the planning of a reach (as vision of the hand was not available at reach initiation) and feedback control, while removing vision of the object in the dark conditions has an effect on endpoint response as we found that children experience difficulty retrieving the object in the dark. While young children demonstrate more adult-like reach control (i.e., relatively longer deceleration time, increased reach duration) under reduced feedback conditions, they have difficulty retrieving the object in the dark, particularly after a 4-s delay, and it is possible that mechanisms guiding predictive control and visual memory are still developing. PMID- 22923225 TI - Signal detection theory and vestibular perception: II. Fitting perceptual thresholds as a function of frequency. AB - Vestibular perceptual thresholds are defined by a dynamic sensory system. To capture these dynamics, thresholds were previously fit as a function of frequency. In this paper, we compare fits using two published models with two new models. Furthermore, a new fitting method that utilizes vestibular perceptual dynamics is developed to improve fit quality and overcome problems associated with the conventional approach. Combinations of the four models and two fitting methods are tested using both simulated data and previously published experimental data. Simulations reveal that the conventional approach underestimates thresholds when the number of trials at each frequency is limited (circa 50); this underestimation is reduced fivefold by the new fitting method that simultaneously utilizes data across frequencies. The new fitting method also scored best for goodness of fit for both the simulations and experimental data. In fact, the new approach of fitting simultaneously across frequencies proved more accurate, more precise, more robust, and more efficient than the conventional approach of fitting the responses at each frequency individually and then fitting these threshold data across frequency. The revised fit of published yaw rotation threshold data shows that these are best fit by a first-order high pass filter having a plateau of 0.5 degrees /s (roughly a factor of 4 higher than the motion platform vibration) at frequencies above the cutoff frequency of 0.26 Hz, which is well above the cutoff frequency of the semicircular canals (circa 0.03 Hz). This dynamic analysis suggests the contributions of a velocity leakage mechanism to human yaw rotation thresholds. PMID- 22923226 TI - The social and economic influences on medication use and misuse. PMID- 22923227 TI - Current management of the mangled upper extremity. AB - Mangled describes an injury caused by cutting, tearing, or crushing, which leads to the limb becoming unrecognizable; in essence, there are two treatment options for mangled upper extremities, amputation and salvage reconstruction. With advances in our understanding of human physiology and basic science, and with the development of new fixation devices, modern microsurgical techniques and the possibility of different types of bony and soft tissue reconstruction, the clinical and functional outcomes are often good, and certainly preferable to those of contemporary prosthetics. Early or even immediate (emergency) complete upper extremity reconstruction appears to give better results than delayed or late reconstruction and should be the treatment of choice where possible. Before any reconstruction is attempted, injuries to other organs must be excluded. Each step in the assessment and treatment of a mangled extremity is of utmost importance. These include radical tissue debridement, prophylactic antibiotics, copious irrigation with a lavage system, stable bone fixation, revascularization, nerve repair, and soft tissue coverage. Well-planned and early rehabilitation leads to a better functional outcome. Despite the use of scoring systems to help guide decisions and predict outcomes, the decision to reconstruct or to amputate still ultimately lies with the surgical judgment and experience of the treating surgeon. PMID- 22923228 TI - Implantable electrophysiologic cardiac device infections: a risk factor analysis. AB - The risk of cardiac device infection (CDI) is rising significantly, with several risk factors identified. The purpose of this study is to determine the rate of CDI at our center and to assess the associated risk factors, in order to define appropriate measures to prevent this complication. We retrospectively reviewed all cases of patients with CDI at St. George Hospital between February 1999 and July 2010. Each case was matched with three controls. We performed a descriptive and bivariate analysis to identify significant risk factors. Eighteen case patients and 54 control subjects met the inclusion criteria. An organism was recovered in 58 % of the cases. Significant risk factors included previous history of CDI (p < 0.001), recent manipulation (p < 0.001), trauma to the site of implant (p = 0.003), having a dual chamber/dual lead pacemaker (p = 0.002), and development of post-procedural hematoma (p = 0.012). Our findings complement the results of previous studies. We recommend a pre-procedural risk assessment and a thorough post-implantation follow-up to prevent the development of infective complications. PMID- 22923229 TI - A delivery system of linezolid to enhance the MRSA osteomyelitis prognosis: in vivo experimental assessment. AB - Staphylococcus aureus, a major responsible microorganism of osteomyelitis, represents a challenge to treat because of the poor penetration of antibiotics in bone and increasing minimum inhibitory concentrations (MICs) to glycopeptides. The calcium-deficient apatites (CDA), closer to the biological components found in bone and other calcified tissues, have osteoconductive properties. So, to process severe osseous infections, CDA can be used to deliver in the infectious site antibiotics like linezolid. The acute experimental osteomyelitis due to methicillin-resistant Staphylococcus aureus (MRSA) was induced in rabbit's femurs and surgery mimicking human procedures was performed at day three after inoculation. Animals were randomly assigned to treatment groups: L((IV)) [4-day linezolid IV infusion, human-equivalent dose of 10 mg/kg/12 h], L((CDA50%)) (100 mg CDA with linezolid 500 MUg/mg) and L((CDA50%)) + L((IV)). Surviving bacteria were counted in bone marrow (BM) and bone (Bo) at day 3 (before treatment), day 7 (4-day treatment) or day 17 (14-day treatment). L(iv) was effective after a 4-day treatment with a log(10)CFU/g decrease of -2.63 +/- 1.92 and -2.17 +/- 1.58 in bone marrow and bone, respectively. CDA loaded with linezolid enhance the efficacy of the IV linezolid regimen by more than one log(10)CFU/g. PMID- 22923230 TI - Inhibition of augmented muscle vasoconstrictor drive following asphyxic apnoea in awake human subjects is not affected by relief of chemical drive. AB - Progressive asphyxia, produced by a prolonged voluntary breath hold (end expiratory apnoea), evokes large bursts of muscle sympathetic nerve activity (MSNA). These bursts increase in amplitude until the asphyxic break point is reached, at which point the bursts are inhibited. We tested the hypothesis that lung inflation, rather than relief from hypoxia and hypercapnia, is responsible for the inhibition of MSNA. Multiunit MSNA was recorded from motor fascicles of the common peroneal nerve in 11 subjects. Following a period of quiet breathing, subjects were instructed to behave as follows: (i) to hold their breath in expiration for as long as they could (mean duration 32.3 +/- 1.9 s); (ii) to take a single breath of room air, 100% N(2) or 10% CO(2) + 90% N(2) at the asphyxic break point; (iii) to exhale and continue the apnoea until the next break point; and then (iv) to resume breathing. All subjects reported relief during inhalation of any gas, and could continue holding their breath for a further 30.7 +/- 2.8 s with room air, 18.6 +/- 1.7 s with N(2) and 11.8 +/- 1.8 s with 10% CO(2) + 90% N(2). Despite the exaggerated chemoreceptor drive in the latter two conditions (hence the significantly shorter latencies to the subsequent asphyxic break point), the inhibition still occurred; moreover, there was no significant difference in duration of the inhibition of MSNA following the single breath of room air (7.6 +/- 0.7 s), N(2) (6.2 +/- 0.6 s) or 10% CO(2) + 90% N(2) (5.5 +/- 0.4 s). Following the resumption of breathing, however, the duration of MSNA inhibition (11.0 +/- 1.0 s) was significantly longer than that following a single breath. To investigate the involvement of chemoreceptors in the respiratory modulation of MSNA further, the same gases were used during an inspiratory capacity apnoea, which causes a brief inhibition of MSNA during the inflation phase and a sustained increase during the hold phase. The duration of the apnoea was shortest after a breath of 10% O(2) + 90% N(2), but the latency until the bursts resumed after the inspiratory breath hold were similar for all gases, which suggests that there is no chemoreceptor involvement during the sympathetic silence seen during the inflation phase of inspiratory-capacity apnoeas. We conclude that neither peripheral nor central chemoreceptors are responsible for the inhibition of muscle vasoconstrictor drive following an end-expiratory apnoea or an end-inspiratory apnoea. Rather, we suggest that the inhibition is evoked by stretch receptors in the lungs and/or chest wall, which may also contribute to the longer inhibition associated with the hyperventilation following the subsequent resumption of rhythmic breathing. PMID- 22923231 TI - Genetic downregulation of receptor-interacting protein 140 uncovers the central role of Akt signalling in the regulation of fatty acid oxidation in skeletal muscle cells. AB - The role of the nuclear co-repressor receptor-interacting protein 140 (RIP140) in metabolic regulation, gene and protein expression and insulin signalling in skeletal muscle cells remains to be delineated. To study this question, L6 myotubes were treated with or without an RNA interference oligonucleotide sequence to downregulate RIP140 expression and incubated with or without insulin (1 MUM). Downregulation of RIP140 increased (P < 0.05) basal palmitate uptake (by 20%) and decreased (P < 0.05) basal palmitate oxidation (by 38%). In control small interfering RNA-treated cells, insulin increased (P < 0.05) glucose (by 31%) and palmitate uptake (by 20%) and decreased (P < 0.05) palmitate oxidation (by 35%). However, in RIP140 small interfering RNA-treated cells, insulin did not affect (P > 0.05) palmitate uptake and increased (P < 0.05) palmitate oxidation (by 79%). In insulin-mediated conditions, downregulation of RIP140 decreased (P < 0.05) Akt(Ser473) and atypical protein kinase C-zeta(Thr403/410) phosphorylation. As expected, downregulation of RIP140 was accompanied by an increase (P < 0.05) in cytochrome c oxidase subunit 4 isoform 1 and peroxisome proliferator-activated receptor receptor gamma coactivator-1alpha mRNA content. Downregulation of RIP140 increased (P < 0.05) fatty acid transport protein 1 mRNA content and carnitine palmitoyltransferase 1b protein content and decreased (P < 0.05) medium chain acyl-CoA dehydrogenase mRNA content in basal conditions. In insulin-mediated conditions, downregulation of RIP140 increased (P < 0.05) carnitine palmitoyltransferase 1b, fatty acid transport protein 1 and fibroblast growth factor 21 mRNA content and decreased (P < 0.05) medium chain acyl-CoA dehydrogenase mRNA content and plasma membrane fatty acid translocase/cluster of differentiation 36 protein content. Our data show that, in skeletal muscle cells, RIP140 expression significantly impacts palmitate uptake and oxidation and that alterations in gene expression and Akt-atypical protein kinaseC-zeta signalling can partly explain these changes. PMID- 22923232 TI - Altering the rest interval during high-intensity interval training does not affect muscle or performance adaptations. AB - It has been hypothesized that exercise-induced changes in metabolites and ions are crucial in the adaptation of contracting muscle. We tested this hypothesis by comparing adaptations to two different interval-training protocols (differing only in the rest duration between intervals), which provoked different perturbations in muscle metabolites and acid-base status. Prior to and immediately after training, 12 women performed the following tests: (1) a graded exercise test to determine peak oxygen uptake (V(O2)); (2) a high-intensity exercise bout (followed 60 s later by a repeated-sprint-ability test; and (3) a repeat of the high-intensity exercise bout alone with muscle biopsies pre exercise, immediately postexercise and after 60 s of recovery. Subjects performed 5 weeks (3 days per week) of training, with either a short (1 min; HIT-1) or a long rest period (3 min; HIT-3) between intervals; training intensity and volume were matched. Muscle [H(+)] (155 +/- 15 versus 125 +/- 8 nmol l(-1); P < 0.05) and muscle lactate content (84.2 +/- 7.9 versus 46.9 +/- 3.1 mmol (g wet weight)( 1)) were both higher after HIT-1, while muscle phosphocreatine (PCr) content (52.8 +/- 8.3 versus 63.4 +/- 9.8 mmol (g wet weight)(-1)) was lower. There were no significant differences between the two groups regarding the increases in , repeated-sprint performance or muscle Na(+),K(+)-ATPase content. Following training, both groups had a significant decrease in postexercise muscle [H(+)] and lactate content, but not postexercise ATP or PCr. Postexercise PCr resynthesis increased following both training methods. In conclusion, intense interval training results in marked improvements in muscle Na(+),K(+)-ATPase content, PCr resynthesis and . However, manipulation of the rest period during intense interval training did not affect these changes. PMID- 22923234 TI - Complacency is the enemy of innovation. PMID- 22923235 TI - Conclusions based on in vitro GME studies using different oxygenator blood flow limitations. PMID- 22923236 TI - Enhanced chemosensitization in multidrug-resistant human breast cancer cells by inhibition of IL-6 and IL-8 production. AB - Drug resistance remains a major hurdle to successful cancer treatment. Many mechanisms such as overexpression of multidrug-resistance related proteins, increased drug metabolism, decreased apoptosis, and impairment of signal transduction pathway can contribute multidrug resistance (MDR). Recent studies strongly suggest a close link between cytokines and drug resistance. To identify new targets involved in drug resistance, we established a multidrug-resistant human breast cancer cell line MCF-7/R and examined the cytokine profile using cytokine antibody array technology. Among 120 cytokines/chemokines screened, IL 6, IL-8, and 13 other proteins were found to be markedly increased in drug resistant MCF-7/R cell line as compared to sensitive MCF-7/S cell line, while 7 proteins were specifically reduced in drug-resistant MCF-7/R cells. Neutralizing antibodies against IL-6 and IL-8 partially reversed the drug resistance of MCF 7/R to paclitaxel and doxorubicin, while a neutralizing antibody against MCP-1 had no significant effect. Inhibition of endogenous IL-6 or IL-8 by siRNA technology significantly enhanced drug sensitivity of MCF-7/R cells. Furthermore, overexpression of IL-6 or IL-8 expression by transfection increased the ADM resistance in MCF-7/S cells. Our data suggest that increased expression levels of IL-6 and IL-8 may contribute to MDR in human breast cancer cells. PMID- 22923237 TI - Preoperative breast MRI in early-stage breast cancer. AB - Rapid uptake of new imaging technology is a major contributor to rising healthcare costs. Preoperative breast magnetic resonance imaging (MRI) for patients with early-stage breast cancer has dramatically increased in use without the evidence of improved outcomes compared to standard assessment and is associated with higher rates of mastectomy. A decision analytic model was developed to evaluate the impact of adding breast MRI to the preoperative evaluation of women with early-stage breast cancer who were candidates for breast conserving therapy on patient outcomes measured in quality-adjusted life years (QALYs). Model inputs, including survival, recurrence rates, and health utilities, were obtained from a comprehensive literature review. One-way sensitivity analyses were performed to estimate threshold values for key parameters at which adding MRI would become the optimal imaging strategy over standard assessment. Preoperative MRI resulted in 17.77 QALYs compared to 17.86 QALYs with standard assessment, a decrease of 0.09 QALYs or 34 days. In sensitivity analyses, standard assessment was associated with better patient outcomes than preoperative breast MRI across all plausible probabilities for mastectomy, local recurrence, and health utilities. For routine preoperative breast MRI to become the optimal strategy, the conversion rate to mastectomy after preoperative MRI would need to be <1 % (versus the range of 3.6-33 % reported in the literature). Routine preoperative breast MRI appears to confer no advantage over the standard diagnostic evaluations for early-stage breast cancer and may lead to worse patient outcomes. PMID- 22923239 TI - Reassessment of individual dosimetry of long-lived alpha radionuclides of uranium miners through experimental determination of urinary excretion of uranium. AB - Urinary excretion of uranium of 40 uranium miners was determined by the high resolution inductively coupled mass spectrometry method. The concentration of uranium in the urine of the miners was converted to daily excretion of (238)U either under the assumption that the daily urinary excretion is 1.6 l or daily urinary excretion of creatinine is 1.7 g and compared with the excretion of (238)U calculated with a biokinetic model. Input data to the excretion model were derived from personal three- component ALGADE dosemeters, using the component for the estimation of inhalation of long-lived alpha radionuclides. Experimentally found contents of uranium in the urine of uranium miners are generally lower than the modelled ones, which means that the dosimetric approach is conservative. The uncertainty of inhalation intakes, derived from the measurements of filters from personal dosemeters, and the uncertainty of the concentration of uranium in the urine are discussed. PMID- 22923238 TI - Treatment patterns and clinical outcomes in elderly patients with HER2-positive metastatic breast cancer from the registHER observational study. AB - Limited data exist regarding treatment patterns and outcomes in elderly patients with HER2-positive metastatic breast cancer (MBC). registHER is an observational study of patients (N = 1,001) with HER2-positive MBC diagnosed within 6 months of enrollment and followed until death, disenrollment, or June 2009 (median follow up 27 months). Outcomes were analyzed by age at MBC diagnosis: younger (<65 years), older (65-74 years), elderly (>=75 years). For progression-free survival (PFS) and overall survival (OS) analyses of first-line trastuzumab versus nontrastuzumab, older and elderly patients were combined. Cox regression analyses were adjusted for baseline characteristics and treatments. Estrogen receptor/progesterone receptor status was similar across age groups. Underlying cardiovascular disease was most common in elderly patients. In patients receiving trastuzumab-based first-line treatment, elderly patients were less likely to receive chemotherapy. In trastuzumab-treated patients, incidence of left ventricular dysfunction (LVD) and congestive heart failure (CHF) (grades >= 3) were highest in elderly patients (LVD: elderly 4.8 %, younger 2.8 %, older 1.5 %; CHF: elderly 3.2 %, younger 1.9 %, older 1.5 %). Unadjusted median PFS (months) was significantly higher in patients treated with first-line trastuzumab than those who were not (<65 years: 11.0 vs. 3.4, respectively; >=65 years: 11.7 vs. 4.8, respectively). In patients <65 years, unadjusted median OS (months) was significantly higher in trastuzumab-treated patients; in patients >=65 years, median OS was similar (<65 years: 40.4 vs. 25.9; >=65 years: 31.2 vs. 28.5). In multivariate analyses, first-line trastuzumab use was associated with significant improvement in PFS across age. For OS, significant improvement was observed for patients <65 years and nonsignificant improvement for patients >=65 years. Elderly patients with HER2-positive MBC had higher rates of underlying cardiovascular disease than their younger counterparts and received less aggressive treatment, including less first-line trastuzumab. These real-world data suggest improved PFS across all age groups and similar trends for OS. PMID- 22923240 TI - Determination of the minimum measurement time for estimating long-term mean radon concentration. AB - Radon measurements, as do any measurements, include errors in their readings. The relative values of such errors depend principally on the measurement methods used, the radon concentration to be measured and the duration of the measurements. Typical exposure times for radon surveys using passive detectors [nuclear track detectors, activated charcoal, electrostatic (E-perm), etc.)] may extend from a few days to months, whereas, in the case of screening methods utilising active radon monitors (AlphaGUARD, RAD7, EQF, etc.), the measurements may be completed quickly within a few hours to a few days. Thus, the latter may have relatively large error values, which affect the measurement accuracy significantly compared with the former measurements made over long time periods. The method presented in this paper examines the uncertainty of a short-term radon measurement as an estimate of the long-term mean and suggests a minimum measurement time to achieve a given margin of uncertainty of that estimate. PMID- 22923241 TI - Measurement of radon/thoron exhalation rates and gamma-ray dose rate in granite areas in Japan. AB - Radon and thoron exhalation rates and gamma-ray dose rate in different places in Hiroshima Prefecture were measured. Exhalation rates were measured using an accumulation chamber method. The radon exhalation rate was found to vary from 3 to 37 mBq m(-2) s(-1), while the thoron exhalation rate ranged from 40 to 3330 mBq m(-2) s(-1). The highest radon exhalation rate (37 mBq m(-2) s(-1)) and gamma ray dose rate (92 nGy h(-1)) were found in the same city (Kure City). In Kure City, indoor radon and thoron concentrations were previously measured at nine selected houses using a radon-thoron discriminative detector (Raduet). The indoor radon concentrations varied from 16 to 78 Bq m(-3), which was higher than the average value in Japan (15.5 Bq m(-3)). The indoor thoron concentration ranged from ND (not detected: below a detection limit of approximately 10 Bq m(-3)) to 314 Bq m(-3). The results suggest that radon exhalation rate from the ground is an influential factor for indoor radon concentration. PMID- 22923243 TI - Radiation-responsive transcriptome analysis in human lymphoid cells. AB - Ionising radiation (IR) causes DNA (deoxyribonucleic acid) injury and activates intracellular signal pathways including the regulation of DNA repair and cell cycle. However, the further knowledge of molecular events involved in radiation exposure is essential to more comprehensively understand the effects of irradiation. Therefore, the gene expressions of mRNA (messenger ribonucleic acid) by X-ray irradiation in human B lymphoblast cell line (IM-9) using a microarray were investigated. The mRNA expressions of 65 genes were shown to be up-regulated at >2.0-fold in irradiated cells (4 Gy) when compared with non-irradiated cells (0 Gy) by microarray analysis. Among 65 genes, a large number of genes were up regulated with an X-ray dose-dependent change. These results indicate that the up regulation of their mRNAs is the effects of irradiation and may be due to biological dosimetric markers for the evaluation of radiation exposure in the future. PMID- 22923242 TI - Dose point kernel simulation for monoenergetic electrons and radionuclides using Monte Carlo techniques. AB - Monte Carlo (MC) simulation has been commonly used in the dose evaluation of radiation accidents and for medical purposes. The accuracy of simulated results is affected by the particle-tracking algorithm, cross-sectional database, random number generator and statistical error. The differences among MC simulation software packages must be validated. This study simulated the dose point kernel (DPK) and the cellular S-values of monoenergetic electrons ranging from 0.01 to 2 MeV and the radionuclides of (90)Y, (177)Lu and (103 m)Rh, using Fluktuierende Kaskade (FLUKA) and MC N-Particle Transport Code Version 5 (MCNP5). A 6-MUm radius cell model consisting of the cell surface, cytoplasm and cell nucleus was constructed for cellular S-value calculation. The mean absolute percentage errors (MAPEs) of the scaled DPKs, simulated using FLUKA and MCNP5, were 7.92, 9.64, 4.62, 3.71 and 3.84 % for 0.01, 0.1, 0.5, 1 and 2 MeV, respectively. For the three radionuclides, the MAPEs of the scaled DPKs were within 5 %. The maximum deviations of S(N<-N), S(N<-Cy) and S(N<-CS) for the electron energy larger than 10 keV were 6.63, 6.77 and 5.24 %, respectively. The deviations for the self absorbed S-values and cross-dose S-values of the three radionuclides were within 4 %. On the basis of the results of this study, it was concluded that the simulation results are consistent between FLUKA and MCNP5. However, there is a minor inconsistency for low energy range. The DPK and the cellular S-value should be used as the quality assurance tools before the MC simulation results are adopted as the gold standard. PMID- 22923244 TI - Realising the European Network of Biodosimetry (RENEB). AB - In Europe, a network for biological dosimetry has been created to strengthen the emergency preparedness and response capabilities in case of a large-scale nuclear accident or radiological emergency. Through the RENEB (Realising the European Network of Biodosimetry) project, 23 experienced laboratories from 16 European countries will establish a sustainable network for rapid, comprehensive and standardised biodosimetry provision that would be urgently required in an emergency situation on European ground. The foundation of the network is formed by five main pillars: (1) the ad hoc operational basis, (2) a basis of future developments, (3) an effective quality-management system, (4) arrangements to guarantee long-term sustainability and (5) awareness of the existence of RENEB. RENEB will thus provide a mechanism for quick, efficient and reliable support within the European radiation emergency management. The scientific basis of RENEB will concurrently contribute to increased safety in the field of radiation protection. PMID- 22923245 TI - Diurnal and seasonal variations of concentration and size distribution of nano aerosols (10-1100 nm) enclosing radon decay products in the Postojna Cave, Slovenia. AB - At the lowest point along the tourist route in the Postojna Cave, the activity concentration of radon ((222)Rn) short-lived decay products and number concentration and size distribution of background aerosol particles in the size range of 10-1100 nm were measured. In the warm yearly season, aerosol concentration was low (52 cm(-3)) with 21 % particles smaller than 50 nm, while in the cold season, it was higher (1238 cm(-3)) with 8 % of <50 nm particles. Radon activity concentrations were 4489 and 1108 Bq m(-3), and fractions of unattached radon decay products were 0.62 and 0.13, respectively. PMID- 22923246 TI - Distribution of naturally occurring radioactivity and 137Cs in the marine sediment of Farasan Island, southern Red Sea, Saudi Arabia. AB - The present work is a part of a project dedicated to measure the marine radioactivity near the Saudi Arabian coasts of the Red Sea and Arabian Gulf for establishing a marine radioactivity database, which includes necessary information on the background levels of both naturally occurring and man-made radionuclides in the marine environment. Farasan Islands is a group of 84 islands (archipelago), under the administration of the Kingdom of Saudi Arabia, in the Red Sea with its main island of Farasan, which is 50 km off the coast of Jazan City. The levels of natural radioactivity of (238)U, (235)U, (226)Ra, (232)Th and (40)K and man-made radionuclides such as (137)Cs in the grab sediment and water samples around Farasan Island have been measured using gamma-ray spectroscopy. The average activity concentrations of (238)U, (235)U, (226)Ra, (232)Th, (40)K and (137)Cs in the sediment samples were found to be 35.46, 1.75, 3.31, 0.92, 34.34 and 0.14 Bq kg(-1), respectively. PMID- 22923247 TI - An optimal measuring timetable for thoron measurements by using Lucas scintillation cell. AB - Up to now, several different timetables have been proposed for thoron ((220)Rn) measurements by using the Lucas scintillation cell. In this study, based on the measuring principle, the uncertainty of the measurements was theoretically studied by using a self-developed simulation program. The results showed that a measuring timetable of 1-min consecutive counting lasted for 10 times was an optimal routine for (220)Rn measurements. Compared with the previously proposed timetables, the new measuring timetable could reduce the uncertainty of (220)Rn measurements by >19 %. PMID- 22923248 TI - Cytogenetic dose-response in vitro for biological dosimetry after exposure to high doses of gamma-rays. AB - The dose response for dicentrics plus centric rings and total unstable chromosome type aberrations was studied in the first mitoses of cultured human peripheral blood lymphocytes irradiated in vitro to doses of ~2, 4, 6, 8, 10, 16 and 20 Gy of acute (60)So gamma-rays. A dose-dependent increase of aberration yield was accompanied by a tendency to the underdispersion of dicentrics and centric rings among cells distributions compared with Poisson statistics at doses >=6 Gy. The formal fitting of the data to a linear-quadratic model resulted in an equation with the linear and quadratic coefficients ranged 0.098-0.129*cell(-1)*Gy(-1) and 0.039-0.034*cell(-1)*Gy(-2), respectively, depending on the fitting method. The actual radiation-induced aberration yield was markedly lower than expected from a calibration curve, generated earlier within a lower dose range. Interlaboratory variations in reported dicentric yields induced by medium-to-high radiation doses in vitro are discussed. PMID- 22923249 TI - The level and distribution of 220Rn concentration in soil-gas in Guangdong Province, China. AB - In order to understand the level and distribution of (220)Rn concentrations in soil-gas in the high-radiation-background area, an (220)Rn survey was carried out for the first time using a RAD7 portable radon monitor at 67 locations covering a total area of 1800 km(2) in the South of China. (220)Rn concentrations were significantly different from that in the surface areas covered by the weathered granite of Yanshan Period or Quaternary sediments. The (220)Rn concentrations varied between 6.65 and 461 kBq m(-3) and the averages were 294.42 +/- 81.36 and 23.30 +/- 25.84 kBq m(-3) for weathered granite products and sediments, respectively. A high positive correlation between (220)Rn concentrations and (232)Th activity concentrations was found. (220)Rn concentrations had no statistically significant variations from depths of 20-140 cm with an interval of 20 cm. It is worth paying attention to the problem of such a high soil (220)Rn concentration in Zhuhai City and Zhongshan City. PMID- 22923250 TI - Field tests using radioactive matter 2. AB - Results of field tests with explosive dispersal of a radioactive substance (RaS) are presented. The paper deals with tests exploiting artificial obstacles as a continuation and expansion of the tests used in this study performed in free area described previously. The essential goal of the tests was to estimate the distribution of the released RaS in the case of intentional abuse of radioactive sources and to get a set of data applicable to testing physical or mathematical models of propagation. Effects of different geometrical and meteorological conditions on the distribution of dispersed RaS were studied via the assessment of dose rate, surface and volume activities, aerosol mass and activity aerodynamic diameters. The principal results can be summarised as follows: the prevalent proportion of the activity of the radionuclide dispersed by an explosion (born by the blast wave and by air convection) is transferred to the detection system/collecting pads essentially within the first minute. Enhanced aerosol mass concentrations were also detected within the same period. The RaS carried by the blast wave passed through the polygon (50 m) within <1 s. An expected crucial impact of meteorological conditions at the moment of the explosion and shortly after was proved by the tests. PMID- 22923251 TI - Uranium and thorium leached from uranium mill tailing of Guangdong Province, China and its implication for radiological risk. AB - The paper focused on the leaching behaviour of uranium (U) and thorium (Th) from uranium mill tailing collected from the Uranium Mill Plant in Northern Guangdong Province, China. Distilled water (pH 6) and sulphuric acid solution (pH 4 and 3) were used as solvent for the leaching over 22 weeks. It was found that the cumulative leach fraction from the mill tailing was 0.1, 0.1 and 0.7 % for U release, and overall 0.01 % for Th release, using distilled water, sulphuric acid solution of pH 4 and pH 3 as leaching agents, respectively. The results indicate that (1) the release of U and Th in uranium mill tailing is a slow and long-term process; (2) surface dissolution is the main mechanism for the release of U and Th when sulphuric acid solution of pH 3 is employed as the leaching agent; (3) both U and Th are released by diffusion when using sulphuric acid solution of pH 4 as the leaching agent and (4) U is released by surface dissolution, while Th is released by diffusion when using distilled water as the leaching agent. The implication for radiological risk in the real environment was also discussed. PMID- 22923252 TI - Dose-dependent and gender-related radiation-induced transcription alterations of Gadd45a and Ier5 inhuman lymphocytes exposed to gamma ray emitted by (60)Co. AB - Growth arrest DNA damage-inducible 45a gene (Gadd45a) and immediate early response gene 5 (Ier5) have been emphasised as ideal radiation biomarkers in several reports. However, some aspects of radiation-induced transcriptional alterations of these genes are unknown. In this study, gender-dependency and dose dependency as two factors that may affect radiation-induced transcription of Gadd45a and Ier5 genes were investigated. Human lymphocyte cells from six healthy voluntary blood donors (three women and three men) were irradiated in vitro with doses of 0.5-4.0 Gy from a (60)Co source and RNA isolated 4 h later using the High Pure RNA Isolation Kit. Dose and gender dependency of radiation-induced transcriptional alterations of Gadd45a and Ier5 genes were studied by quantitative real-time polymerase chain reaction. The results showed that as a whole, Gadd45a and Ier5 gave responses to gamma rays, while the responses were independent of radiation doses. Therefore, regardless of radiation dose, Gadd45a and Ier5 can be considered potential radiation biomarkers. Besides, although radiation-induced transcriptional alterations of Gadd45a in female and male lymphocyte samples were insignificant at 0.5 Gy, at other doses, their quantities in female samples were at a significantly higher level than in male samples. Radiation-induced transcription of Ier5 of females samples had a reduction in comparison with male samples at 1 and 2 Gy, but at doses of 0.5 and 4 Gy, females were significantly more susceptible to radiation-induced transcriptional alteration of Ier5. PMID- 22923253 TI - Efficiency of whole-body counter for various body size calculated by MCNP5 software. AB - The efficiency of a whole-body counter for (137)Cs and (40)K was calculated using the MCNP5 code. The ORNL phantoms of a human body of different body sizes were applied in a sitting position in front of a detector. The aim was to investigate the dependence of efficiency on the body size (age) and the detector position with respect to the body and to estimate the accuracy of real measurements. The calculation work presented here is related to the NaI detector, which is available in the Serbian Whole-body Counter facility in Vinca Institute. PMID- 22923254 TI - Effects of air exchange property of passive-type radon-thoron discriminative detectors on performance of radon and thoron measurements. AB - Pairs of diffusion chambers with different air exchange rates are used in a large scale survey to determine radon and thoron, separately. When they are enclosed in radon-proof bags for keeping after the exposure, since radon does not escape out immediately from the low-diffusion chamber, it leads to further exposure in the bags and disturbs the estimation of radon and thoron concentrations. In this study, the effects of the different air exchange properties of the radon-thoron discriminative detectors with CR-39 chips on the estimations of radon and thoron concentrations were investigated. The commercially available and frequently used detectors, Raduet, are examined in this study. The result shows that radon escapes out in 10 h. When degassing is not enough after the exposure in a calibration experiment or high-background radiation area, the residual radon causes the overestimation of the radon concentration and increase in the uncertainty in the thoron concentration, i.e. a low-performance quality of radon and thoron measurements. PMID- 22923255 TI - Attempted validation of ICRP 30 and ICRP 66 respiratory models. AB - The validation of human biological models for inhaled radionuclides is nearly impossible. Requirements for validation are: (1) the measurement of the relevant human tissue data and (2) valid exposure measurements over the interval known to apply to tissue uptake. Two lung models, ICRP 30(1) and ICRP 66(2), are widely used to estimate lung doses following acute occupational or environmental exposure. Both ICRP 30 and 66 lung models are structured to estimate acute rather than chronic exposure. Two sets of human tissue measurements are available: (210)Po accumulated in tissue from inhaled cigarettes and ingested in diet and airborne global fallout (239,240)Pu accumulated in the lungs from inhalation. The human tissue measurements include pulmonary and bronchial tissue in smokers, ex smokers and non-smokers analysed radiochemically for (210)Po, and pulmonary, bronchial and lymph nodes analysed for (239,240)Pu in lung tissue collected by the New York City Medical Examiner from 1972 to 1974. Both ICRP 30 and 66 models were included in a programme to accommodate chronic uptake. Neither lung model accurately described the estimated tissue concentrations but was within a factor of 2 from measurements. ICRP 66 was the exception and consistently overestimated the bronchial concentrations probably because of its assumption of an overly long 23-d clearance half-time in the bronchi and bronchioles. PMID- 22923256 TI - DT-13 suppresses MDA-MB-435 cell adhesion and invasion by inhibiting MMP-2/9 via the p38 MAPK pathway. AB - Previous research has shown that the Dwarf lilyturf tuber has antitumor effects. The antitumor ability of DT-13, a saponin monomer isolated from the roots of the Dwarf lilyturf tuber, is discussed in this study. The results showed that DT-13 inhibited the proliferation, adhesion and invasion of MDA-MB-435 cells. DT-13 decreased the excretion and expression of MMP-2/9. Furthermore, DT-13 inhibited the phosphorylation of p38 in MDA-MB-435 cells. In conclusion, the results suggest that DT-13 possesses anticancer and antimetastatic properties by inhibiting the invasion of cancer cells. PMID- 22923257 TI - Parkinson's disease-like midbrain hyperechogenicity is frequent in amyotrophic lateral sclerosis. AB - Clinical and neuroimaging data suggest impairment of the nigrostriatal system in amyotrophic lateral sclerosis (ALS). We thus hypothesized whether Parkinson's disease (PD)-like midbrain sonography findings are also present in ALS. Eighty six patients with the diagnosis of possible or definite ALS according to revised El Escorial criteria were examined by transcranial B-mode sonography compared to 76 age- and gender-matched controls and 33 PD patients. Hyperechogenic areas of the midbrain representing the substantia nigra were measured planimetrically using standard protocols. In subjects with sufficient temporal acoustic bone windows, mean midbrain hyperechogenic areas were significantly higher in ALS (0.251 +/- 0.104 cm(2)) and PD patients (0.286 +/- 0.078 cm(2)) compared to controls (0.091 +/- 0.054 cm(2)) with no significant difference between ALS and PD patients (one-way ANOVA: F value = 94.3; P < 0.0001). Sixty-seven percent (95 % CI 57-78 %) of ALS patients and 84 % (95 % CI 71-97 %) of PD patients displayed abnormal midbrain hyperechogenic areas (P = 0.383 for group comparison, chi(2) test). No correlations of hyperechogenic area sizes in ALS patients were found in regard to age, gender, ALS subtype (bulbar versus spinal form) or ALS-FRS-R score. In summary, we observed hyperechogenicity of the substantia nigra in patients with sporadic ALS with a frequency similar to that in PD and higher than in all other movement disorders. These findings are important for the diagnosis and differential diagnosis of PD and ALS alike. PMID- 22923258 TI - Effects of pretreatment with a small dose of dexmedetomidine on sufentanil induced cough during anesthetic induction. AB - PURPOSE: We aimed to investigate the effects of pretreatment with a small dose of dexmedetomidine on the cough caused by sufentanil during anesthetic induction. METHODS: Two hundred and forty patients undergoing elective gynecological surgery under general anesthesia were randomly allocated to 4 groups (n = 60, each group). Dexmedetomidine 0, 0.1, 0.25, and 0.5 MUg/kg was administered in 5 min to groups I, II, III, and IV, respectively, followed by the induction of general anesthesia with intravenous propofol, at a target concentration of 5 MUg/ml, and sufentanil 0.5 MUg/kg. The incidences and severity of cough that occurred within 1 min after the injection of sufentanil were recorded, and the incidences of cardiovascular adverse events that occurred between the administration of the dexmedetomidine infusion and 1 min after tracheal intubation were recorded. RESULTS: The incidences of cough in group II, group III, and group IV were lower than that in group I (6.7, 5.0, and 6.7 vs. 26.7 %, P < 0.01), while there were no significant differences between group II, group III, and group IV. The incidences of severe sinus bradycardia in group III and group IV were higher than that in group I (18.3 and 23.3 vs. 0.0 %, P < 0.01), while there was no significant difference between group I and group II. There was no significant difference in the incidence of low blood pressure among the four groups. CONCLUSION: Dexmedetomidine at 0.10, 0.25, and 0.50 MUg/kg significantly reduced the incidence of sufentanil-induced cough during anesthetic induction, with the effect being most marked for 0.10 MUg/kg dexmedetomidine. PMID- 22923259 TI - Can high-resolution ultrasound avoid the sentinel lymph-node biopsy procedure in the staging process of patients with stage I-II cutaneous melanoma? AB - PURPOSE: The objective of our study was to define the diagnostic accuracy of high resolution ultrasound (US) in detecting nodal involvement before sentinel lymph node biopsy (SLNB) in patients with cutaneous melanoma, to define the sonographic criteria used to assess nodal metastases, and to establish if high-resolution US can directly select patients to radical lymphadenectomy, sparing selective lymphadenectomy. MATERIALS AND METHODS: 623 patients underwent high-resolution US of the regional lymph nodes, 24 hours prior being submitted to the sentinel lymph node biopsy procedure. The US findings were compared with histological findings. RESULTS: In 14.7 % out of 122 excised lymph nodes, high-resolution US showed sonographic features consistent with malignant involvement before the surgical step. US scan sensitivity and specificity were 15 and 100 %, respectively, since positive and negative predictive values were 100 and 87 % respectively. CONCLUSION: US is an effective modality in the presurgical detection of subclinical deposits within sentinel lymph nodes. However, preoperative staging work-up with high-resolution US cannot substitute the SLNB, mainly because of low sensitivity due to missing many micrometastases. PMID- 22923260 TI - Contrast-enhanced ultrasound for the monitoring of the efficacy of intra articular glucocorticosteroids in 2 patients with inflammatory knee joint synovitis. PMID- 22923261 TI - Diagnosis of acute cortical necrosis in renal transplantation by contrast enhanced ultrasound: a preliminary experience. AB - PURPOSE: To evaluate the use of contrast-enhanced ultrasound (CEUS) for diagnosis of cortical necrosis in renal allografts. MATERIALS AND METHODS: We reviewed the medical records and imaging studies of five patients who underwent emergency transplantectomy and a histological diagnosis of cortical necrosis in the period between May 2009 and May 2011. US examinations included initially B-mode and color Doppler and then contrast-enhanced ultrasound with low mechanical index after injection of 2.4 ml of a second generation echo-signal enhancer. Renal transplant vascularization was evaluated during a period of 4 minutes including arterial, corticomedullary and nephrographic phases. Radiologic-pathologic correlation was obtained after transplantectomy in all cases. RESULTS: Five patients with an age range between 30 and 48 years. Post-transplant color Doppler ultrasound showed decreased renal parenchymal vascularization and difficulty to find the spectral waveforms with resistive indexes greater than 0.7 in 4 of 5 patients. CEUS showed enhancement of the main arteries, followed by the enhancement of medullary pyramids, but with an unenhanced peripheral cortical continuous band viewed in all phases, a similar finding to the peripheral rim sign, pathognomonic of cortical necrosis on CT or MRI. The pathologic assessment showed violet kidneys macroscopically with hemorrhagic foci in the outer cortical that drew a well-defined band, findings agreed with CEUS findings. CONCLUSION: CEUS can show the typical peripheral rim sign in cases of cortical necrosis allowing a reliable and fast diagnosis of this condition and it could obviate further imaging studies or biopsy, allowing an earlier decision of nephrectomy. PMID- 22923262 TI - Anaphylactic shock induced by sulphur hexafluoride in an individual with no history of heart disease: case report and literature review. PMID- 22923263 TI - Mitochondrial involvement in sensory neuronal cell death and survival. AB - Peripheral nerve injuries (PNI) are continuing to be an ever-growing socio economic burden affecting mainly the young working population and the current clinical treatments to PNI provide a poor clinical outcome involving significant loss of sensation. Thus, our understanding of the underlying factors responsible for the extensive loss of the sensory cutaneous subpopulation in the dorsal root ganglia (DRG) that occurs following injury needs to be improved. The current investigations focus in identifying visual cues of mitochondria-related apoptotic events in the various subpopulations of sensory cutaneous neurons. Sensory neuronal subpopulations were identified using FastBlue retrograde labelling following axotomy. Specialised fluorogenic probes, MitoTracker Red and MitoTracker Orange, were employed to visualise the dynamic changes of the mitochondrial population of neurons. The results reveal a fragmented mitochondrial network in sural neurons following apoptosis, whereas a fused elongated mitochondrial population is present in sensory proprioceptive muscle neurons following tibial axotomy. We also demonstrate the neuroprotective properties of NAC and ALCAR therapy in vitro. The dynamic mitochondrial network breaks down following oxidative exposure to hydrogen peroxide (H(2)O(2)), but reinitiates fusion after NAC and ALCAR therapy. In conclusion, this study provides both qualitative and quantitative evidence of the susceptibility of sensory cutaneous sub-population in apoptosis and of the neuroprotective effects of NAC and ALCAR treatment on H(2)O(2)-challenged neurons. PMID- 22923264 TI - Interhemispheric inhibition in human wrist muscles. AB - The interhemispheric interactions between homologous wrist extensor and flexor muscles representations in the right and left primary cortex (M1) were studied using a paired-pulse transcranial magnetic stimulation in healthy subjects. The magnitude of interhemispheric inhibition (IHI) was studied in 9 right-handed subjects at short (10 ms, SIHI) and long (40 ms, LIHI) interstimulus intervals between the magnetic conditioning (CS) and test stimulus in the motor dominant to non-dominant cortex and vice versa, while the right or left hand was at rest or performing a unimanual sustained tonic contraction (holding a pen with the hand contralateral to the CS). A bidirectional powerful interhemispheric inhibition could be elicited at the short and long IHI phases (SIHI and LIHI) in wrist extensor and flexor muscles in most of the subjects at rest. SIHI but not LIHI was significantly bidirectionally reduced during unimanual contraction of the hand contralateral to the CS stimulation in comparison with rest. The amount of IHI after the stimulation of the "non-dominant" right hemisphere was not reduced in comparison with IHI after stimulation of the "dominant" left hemisphere whatever the active or resting condition. IHI directed to the wrist muscles had a similar level than IHI directed to digit muscles (FDI) at rest. Our data indicate that contralateral wrist muscles activity evokes a global, bidirectional reduction in IHI which was more pronounced for SIHI. These results provide additional evidence that changes in interhemispheric interactions between the M1s are involved in the control of unimanual movements including suppression of unwanted motor activity in the opposite limb during unilateral movements. PMID- 22923265 TI - Lipid-rich ("clear cell") neuroendocrine tumors of the pancreas in MEN I patients. AB - The presence of "clear" or lipid-rich cells within pancreatic neuroendocrine tumors is thought to be pathognomonic of von Hippel-Lindau (VHL) disease, especially in the context of multiple tumors. However, we encountered the presence of lipid-rich cells in six of 16 patients (eight microadenomas/adenomas) who had multiple endocrine neoplasia type I (MEN I). Three of the lesions (two microadenomas and one adenoma) were composed entirely of lipid-rich cells while the remaining five lesions had a component of lipid-rich cells. All lesions containing lipid-rich cells were negative for alpha-inhibin, but positive for chromogranin and synaptophysin. In addition, four of the eight lesions were glucagon positive. None of the patients had clinical symptoms related to hormone production. We suggest that lipid-rich cells are not reflexly indicative of VHL, and that they may be encountered in a proportion of cases of MEN I either focally or constituting the entire neuroendocrine lesion. PMID- 22923266 TI - The distribution of human papillomavirus in tissues from patients with head and neck squamous cell carcinoma. AB - Several types of HPVs have been shown to be associated with the development of malignant cancers in various head and neck tumors. More information on the HPV prevalence in patients with head and neck squamous cell carcinomas (SCCs) need to be obtained. In this study, formalin-fixed and paraffin-embedded tissues of 93 pathologically diagnosed head and neck SCC patients were collected from Peking University Cancer Hospital. HPV DNA sequences in tumor tissues were screened by a commercial Luminex technique for HPVs and HPV-specific PCR assays. Presence of HPV16/18 oncoprotein in tumor tissues was assessed by immunohistochemistry (IHC) with HPV16/18 E6-specific antibodies. Of the 93 patients, 16 (17.2%) cases were found to be HPV DNA-positive, including 7 HPV18-positive, 8 HPV16-positive and 1 HPV52-positive. IHC assays demonstrated that 31.2% (29/93) tested sections showed positive signals in the tumor cells. The total positive rate of HPV genome and its encoding products in the tested samples was 44.1% (41/93). Further analyses revealed that HPV infections in head and neck SCCs were significantly related with the tumor anatomic sites, showing decreasing tendency from outside (lip cancer) to inside (laryngeal cancer), but had no correlation with pathological, clinical grades and age of the patients. In all, HPV infections are commonly identified in the tumor tissues of patients with head and neck SCCs, in which HPV16 and 18 are the most prevalent HPV genotypes. Direct detection of high-risk HPV oncoprotein by IHC may be a good tool for classifying a tumor as truly HPV associated. PMID- 22923267 TI - The Locking Compression Paediatric Hip Plate: technical guide and critical analysis. AB - PURPOSE: Osteotomies of the proximal femur and stable fixation of displaced femoral neck fractures are demanding operations. An LCP Paediatric Hip Plate was developed to make these operations safer and less demanding. The article focuses on the surgical technique and critically analyses the device. METHODS: Between 2006 and 2008, 30 hips in 22 patients underwent surgery. Patients' demographics, perioperative details, postoperative outcome and complications were retrospectively collected and analysed. RESULTS: Patients' diagnoses included persistent congenital hip dysplasia (n = 4), neuropathic hip dysplasia (n = 9), idiopathic ante/retroversion (n = 8), femoral neck fracture (n = 3), Perthes' disease (n = 2), deformity after slipped capital femoral epiphysis (SCFE), congenital femoral neck pseudarthrosis, deformity after pelvic tumour resection and malunion following proximal femoral fracture (one each). In 21 of 22 patients, the postoperative radiographs showed corrections as planned. Two cases had to be revised for screw loosening. Intraoperative handling using the plate was excellent in all cases. CONCLUSIONS: In our case series of 30 hip operations, the LCP Paediatric Hip Plate was shown to be safe and applicable in the clinical setting with excellent results and a low complication rate. We consider that the LCP Paediatric Hip Plate is a valuable device for correction of pathological conditions of the proximal femur and for fixation of displaced femoral neck fractures in children. Larger studies should be carried out to better quantify the risk of clinically relevant complications. PMID- 22923268 TI - Construction of an isokinetic eccentric cycle ergometer for research and training. AB - Eccentric cycling serves a useful exercise modality in clinical, research, and sport training settings. However, several constraints can make it difficult to use commercially available eccentric cycle ergometers. In this technical note, we describe the process by which we built an isokinetic eccentric cycle ergometer using exercise equipment modified with commonly available industrial parts. Specifically, we started with a used recumbent cycle ergometer and removed all the original parts leaving only the frame and seat. A 2.2 kW electric motor was attached to a transmission system that was then joined with the ergometer. The motor was controlled using a variable frequency drive, which allowed for control of a wide range of pedaling rates. The ergometer was also equipped with a power measurement device that quantified work, power, and pedaling rate and provided feedback to the individual performing the exercise. With these parts along with some custom fabrication, we were able to construct an isokinetic eccentric cycle ergometer suitable for research and training. This paper offers a guide for those individuals who plan to use eccentric cycle ergometry as an exercise modality and wish to construct their own ergometer. PMID- 22923269 TI - Laser and LED phototherapies on angiogenesis. AB - Angiogenesis is a key process for wound healing. There are few reports of LED phototherapy on angiogenesis, mainly in vivo. The aim of the present investigation was to evaluate histologically the angiogenesis on dorsal cutaneous wounds treated with laser (660 and 790 nm) or LEDs (700, 530, and 460 nm) in a rodent model. Twenty-four young adult male Wistar rats weighting between 200 and 250 g were used on the present study. Under general anesthesia, one excisional wound was created on the dorsum of each animal that were then randomly distributed into six groups with four animals each: G0-control; G1-laser lambda660 nm (60 mW, phi ~2 mm, 10 J/cm(2)); G2-laser lambda790 nm (50 mW, phi ~2 mm, 10 J/cm(2)); G3-LED lambda700 +/- 20 nm (15 mW, phi ~16 mm, 10 J/cm(2)); G4 LED lambda530 +/- 20 nm (8 mW, phi ~16 mm, 10 J/cm(2)); G5-LED lambda460 +/- 20 nm (22 mW, phi ~16 mm, 10 J/cm(2)). Irradiation started immediately after surgery and was repeated every other day for 7 days. Animal death occurred at the eighth day after surgery. The specimens were removed, routinely processed to wax, cut and stained with HE. Angiogenesis was scored by blood vessel counting in the wounded area. Quantitative results showed that green LED (lambda530 +/- 20 nm), red LED (lambda700 +/- 20 nm), lambda790 nm laser and lambda660 nm laser caused significant increased angiogenesis when compared to the control group. It is concluded that both laser and LED light are capable of stimulating angiogenesis in vivo on cutaneous wounds and that coherence was not decisive on the outcome of the treatment. PMID- 22923270 TI - Extracardiac neural remodeling in humans with cardiomyopathy. AB - BACKGROUND: Intramyocardial nerve sprouting after myocardial infarction is associated with ventricular arrhythmias. Whether human stellate ganglia remodel in association with cardiac pathology is unknown. The purpose of this study was to determine whether cardiac pathology is associated with remodeling of the stellate ganglia in humans. METHODS AND RESULTS: Left stellate ganglia were collected from patients undergoing sympathetic denervation for intractable ventricular arrhythmias and from cadavers, along with intact hearts. Clinical data on patients and cadaveric subjects were reviewed. We classified ganglia from normal, scarred, and nonischemic cardiomyopathic hearts without scar as NL (n=3), SCAR (n=24), and NICM (n=7), respectively. Within left stellate ganglia, neuronal size, density, fibrosis, synaptic density, and nerve sprouting were determined. Nerve density and sprouting were also quantified in cadaveric hearts. Mean neuronal size in normal, scarred, and nonischemic cardiomyopathic hearts without scar groups were 320 +/- 4 MUm(2), 372 +/- 10 MUm(2), and 435 +/- 10 MUm(2) (P=0.002), respectively. No significant differences in neuronal density and fibrosis were present between the groups. Synaptic density in ganglia from SCAR and NICM groups were 57.8 +/- 11.2 MUm(2)/mm(2) (P=0.084) and 44.5 +/- 7.9 MUm(2)/mm(2) (P=0.039), respectively, compared with the normal group, 17.8 +/- 7 MUm(2)/mm(2) (overall P=0.162). There were no significant differences in left stellate ganglia nerve sprouting or myocardial nerve density between the groups. CONCLUSIONS: Neuronal hypertrophy within left stellate ganglia is associated with chronic cardiomyopathy in humans. Ganglionic and myocardial nerve sprouting and nerve density were not significantly different. These changes may be related to increased cardiac sympathetic signaling and ventricular arrhythmias. Further studies are needed to determine the electrophysiological consequences of extracardiac neuronal remodeling in humans. PMID- 22923271 TI - Trends in Fidelis lead survival: transition from an exponential to linear pattern of lead failure over time. AB - BACKGROUND: The Sprint Fidelis implantable cardioverter-defibrillator lead was recalled in 2007 because of an levated risk of lead fracture. Several studies have demonstrated an accelerating risk of lead failure over time. We sought to identify predictors and characterize trends of Fidelis lead failure. METHODS AND RESULTS: We evaluated 604 Fidelis leads with >= 90 days of follow-up implanted at our institution. Fidelis lead survival was analyzed by the Kaplan-Meier method. Analysis of log-log plots of cumulative hazard plots was performed to assess changes in lead failure rate over time. During follow-up of 3.3 +/- 1.7 years, 51 (8.4%) Fidelis lead failures were identified. The 3-year and 5-year Fidelis lead survival rates were 93.5% and 85.3%, respectively. Female sex was the only significant predictor of lead failure (heart rate, 2.1; 95% CI, 1.1-3.9; P<0.0001). The rate of lead failure initially increased exponentially with a power of 2.3 (95% CI, 2.22-2.43; P<0.0001). However, log-log analysis of cumulative hazard for leads functioning at 2 and 4 years revealed a stable rate of failure of 4.5%/year. Mathematical modeling of the Fidelis lead failure demonstrated a transition from an exponential to linear pattern of lead failure at 2.9 years. CONCLUSIONS: After 3 years, failure rates of Fidelis leads stabilize but at a significantly elevated rate. Female sex is associated with a doubling of the risk of Fidelis lead failure. These findings have implications for Fidelis lead management decisions that are based on the prediction of lead failure risk. PMID- 22923272 TI - Inverse solution mapping of epicardial potentials: quantitative comparison with epicardial contact mapping. AB - BACKGROUND: Catheter ablation of ventricular tachycardia (VT) is still one of the most challenging procedures in cardiac electrophysiology, limited, in part, by unmappable arrhythmias that are nonsustained or poorly tolerated. Calculation of the inverse solution from body surface potential mapping (sometimes known as ECG imaging) has shown tremendous promise and can rapidly map these arrhythmias, but we lack quantitative assessment of its accuracy in humans. We compared inverse solution mapping with computed tomography-registered electroanatomic epicardial contact catheter mapping to study the resolution of this technique, the influence of myocardial scar, and the ability to map VT. METHODS AND RESULTS: For 4 patients undergoing epicardial catheter mapping and ablation of VT, 120-lead body surface potential mappings were obtained during implantable defibrillator pacing, catheter pacing from 79 epicardial sites, and induced VT. Inverse epicardial electrograms computed using individualized torso/epicardial surface geometries extracted from computed tomography images were compared with registered electroanatomic contact maps. The distance between estimated and actual epicardial pacing sites was 13 +/- 9 mm over normal myocardium with no stimulus QRS delay but increased significantly over scar (P=0.013) or was close to scar (P=0.014). Contact maps during right ventricular pacing correlated closely to inverse solution isochrones. Maps of inverse epicardial potentials during 6 different induced VTs indicated areas of earliest activation, which correlated closely with clinically identified VT exit sites for 2 epicardial VTs. CONCLUSIONS: Inverse solution maps can identify sites of epicardial pacing with good accuracy, which diminishes over myocardial scar or over slowly conducting tissue. This approach can also identify epicardial VT exit sites and ventricular activation sequences. PMID- 22923273 TI - Docosahexaenoic acid, but not eicosapentaenoic acid, supplementation reduces vulnerability to atrial fibrillation. AB - BACKGROUND: The potential health benefits of omega-3 polyunsaturated fatty acids (PUFAs) usually are studied using a combination of docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA). This combination reduces vulnerability to experimentally induced atrial fibrillation (AF). It is unknown whether EPA and DHA have differential effects when taken alone. Using a model of pacing-induced atrial hemodynamic overload, we investigated the individual effects of EPA and DHA on vulnerability to AF and atrial remodeling. METHODS AND RESULTS: Thirty four dogs were randomized into 3 groups, all of which underwent simultaneous atrial and ventricular pacing at 220 beats per minute for 14 days. One group received purified DHA (~1 g/d) orally for 21 days beginning 7 days before pacing began. Similarly, 1 group received ~1 g/d purified EPA. In a third (control) group (No-PUFAs), 8 dogs received ~1 g/d olive oil, and 12 were unsupplemented. Electrophysiological and echocardiographic measurements were taken at baseline and 21 days. Atrial tissue samples were collected at 21 days for histological and molecular analyses. Persistent AF inducibility was significantly reduced by DHA compared with No-PUFAs median [25-75 percentiles], 0% [0%-3%] for DHA versus 3.1% [2.2%-11%] for No-PUFAs; P=0.007) but not by EPA (3.4% [1.9%-8.9%]). DHA also reduced atrial fibrosis compared with No-PUFAs (11 +/- 6% versus 20 +/- 4%, respectively; P<0.05), whereas EPA did not (15 +/- 5%; P>0.05). CONCLUSIONS: DHA is more effective than EPA in attenuating AF vulnerability and atrial remodeling in structural remodeling-induced AF. PMID- 22923274 TI - Shock efficacy of subcutaneous implantable cardioverter-defibrillator for prevention of sudden cardiac death: initial multicenter experience. AB - BACKGROUND: Recently, subcutaneous implantable cardioverter-defibrillator (S-ICD) has become available. The aim of our study was to assess the efficacy of S-ICD in a clinical setting. METHODS AND RESULTS: Between June 2010 and July 2011, 40 consecutive patients (42 +/- 15 years; body mass index, 27 +/- 6 kg/m(2); left ventricular ejection fraction, 47 +/- 15%; 28 men) received an S-ICD for primary (n=17) or secondary prevention (n=23 [58%]) at 3 institutions in Germany. Intraoperative defibrillation efficacy testing failed in 1 patient with severely reduced left ventricular ejection fraction; testing was effective in all other patients. All episodes stored in the S-ICD were analyzed for appropriate and inappropriate detection, as well as effective shock delivery to convert ventricular tachyarrhythmia into sinus rhythm. During a median follow-up of 229 (interquartile range, 116-305) days, 4 patients experienced 21 episodes, with correct detection of ventricular tachyarrhythmia and subsequent shock therapy. A total of 28 shocks were delivered in these 4 patients. Mixed logistic regression modeling revealed a shock efficacy of 96.4% (95% CI, 12.8%-100%). The efficacy of first shocks, however, was only 57.9% (95% CI, 35.6%-77.4%). Four episodes were incorrectly classified as ventricular tachyarrhythmia, which led to inappropriate shock delivery in 2 patients. CONCLUSIONS: Ineffective shock delivery may occur in patients with S-ICD, even after successful intraoperative testing. Multicenter trials are required with close monitoring of safety and efficacy end points to identify patients who may be at risk for shock failure. PMID- 22923275 TI - Assessing the risk of bleeding in patients with atrial fibrillation: the Loire Valley Atrial Fibrillation project. AB - BACKGROUND: Management decisions for thromboprophylaxis in atrial fibrillation need to balance the risk of stroke against serious hemorrhage. The objective of the present analysis is to compare the Hypertension, Abnormal renal/liver function, Stroke, Bleeding history or predisposition, Labile international normalized ratio, Elderly (>65 years), Drugs/alcohol concomitantly (HAS-BLED) score against other older bleeding risk scores and the new Anticoagulation and Risk Factors in Atrial Fibrillation score in an atrial fibrillation cohort. METHODS AND RESULTS: Patients diagnosed with nonvalvular atrial fibrillation in a 4-hospital institution between 2000 and 2010 were identified. Independent risk factors of bleeding were investigated using Cox regression. The predictive value of several bleeding risk schema was assessed using the c-statistic and net reclassification improvement. Oral anticoagulation use was highest in moderate risk patients (59.8%) but only slightly more than high-risk (50.1%) and low-risk (46.4%) patients. Those at higher bleeding risk (HAS-BLED >= 3) were also at highest risk of stroke/thromboembolism or stroke/thromboembolism/death, as well as bleeding and all-cause mortality. On multivariable analysis, independent predictors of bleeding were age >= 75 years and age >= 65 years, alcohol excess, anemia, and heart failure. All risk scores had only modest predictive ability for bleeding, whether on vitamin K antagonist or not (c-statistic ~0.6). When the HAS BLED score was compared with other bleeding risk scores, the net reclassification improvement was significantly improved against all other scores tested. CONCLUSIONS: Current oral anticoagulation prescribing patterns would suggest that bleeding risk estimation by clinicians is poor and that oral anticoagulation prescribing does not reflect bleeding risk per se. The HAS-BLED score performs well in relation to predicting bleeding events compared with older bleeding scores and the Anticoagulation and Risk Factors in Atrial Fibrillation score, with significantly improved reclassification using HAS-BLED compared with all other bleeding risk scores tested. PMID- 22923276 TI - Spectrum of pancreatitis in children and adolescents. AB - BACKGROUND: Very little is known about the early stages of tropical chronic pancreatitis except that many patients give history of childhood abdominal pain. AIM: To examine whether tropical chronic pancreatitis may initially present clinically as recurrent acute pancreatitis. METHODS: Children and adolescents with acute, recurrent acute and chronic pancreatitis were prospectively followed up from 2003 to 2010. Seventy-three consecutive patients were analyzed for progression from acute to recurrent and recurrent acute to chronic pancreatitis. RESULTS: Of the 36 acute, 28 were recurrent acute pancreatitis patients. Similarly of the 37 chronic pancreatitis patients 27 were de novo and 10 had progressed to chronicity from recurrent acute. The mean age of patients was not significantly different between the different groups. Majority of patients in all groups were of idiopathic etiology. The progression of recurrent acute to chronic took 1 to 5 years. Minimum number of episodes of acute pancreatitis before progression to chronicity was 2 and minimum period was 1 year. In 11 of the 27 de novo chronic pancreatitis patients, the age of first pain and diagnosis were identical, in the remaining 16, there were varying intervals between the first pain and diagnosis (1-12 years). DISCUSSION: There was a continuum of acute pancreatitis to recurrent acute pancreatitis, some of the recurrent acute pancreatitis patients further progressed to chronic. CONCLUSION: In some instances tropical chronic pancreatitis may initially present clinically as recurrent acute pancreatitis. PMID- 22923277 TI - T cell lymphoma--presentation as cecal gangrene. PMID- 22923279 TI - Evaluation of a community pharmacy delivered oral contraception service. AB - INTRODUCTION: In the UK half of all pregnancies are unplanned and half of teenage pregnancies terminated. Southwark and Lambeth have the highest teenage conception rates in London. In 2009, many teenage pregnancies in Southwark led to terminations. A contraception service was established where qualified pharmacists supplied oral contraception (OC) using a patient group direction (PGD). This service evaluation aimed to assess this service delivered in five community pharmacies. METHODS: Monthly data were submitted by each pharmacy to the Primary Care Trust on consultations, pills supplied, initial or subsequent supply and client referral. For specified periods consultation time was collected and a clinical notes audit undertaken. Client satisfaction was determined using a structured questionnaire returned to the pharmacy. Mystery shoppers were employed to assess the service. RESULTS: A total of 741 consultations were undertaken by seven pharmacists at five community pharmacies (October 2009-June 2011) with many (45.5%) occurring following emergency contraception supply. The mean consultation time was 19 minutes . Combined OC was most commonly supplied with nearly half (46.1%) of initial supplies to first-time pill users. Most consultations (92.2%) were with women aged under 30 years, with 22.5% aged under 20. Most consultations were with black or black British clients. Of the 99 women who completed the satisfaction questionnaires, most clients were very satisfied or satisfied with the service and felt comfortable talking to the pharmacist about contraception. CONCLUSIONS: Trained pharmacists were clinically competent and provided OC in community pharmacy according to a PGD. This service was accessed by the target population; young women using emergency hormonal contraception who had not previously used OC. Clients were largely very satisfied with the service. PMID- 22923278 TI - Oxidative stress and antioxidant capacity in patients with chronic pancreatitis with and without diabetes mellitus. AB - AIM: To determine oxidant stress and antioxidant capacity in chronic pancreatitis (CP) patients with and without diabetes mellitus. METHODS: This study is a secondary data analysis of our earlier study on 127 (male = 86) patients with CP, grouped as those with diabetes (case; n = 23) and those without diabetes (control). Markers of antioxidant status included vitamins A and E, total antioxidant capacity (TAC; measured as ferric-reducing ability of plasma [FRAP]), and total glutathione (T-GSH). Markers for oxidative stress included lipid peroxidation, measured as thiobarbituric acid reactive substances (TBARS) and serum superoxide dismutase (s-SOD). RESULTS: Patients with diabetes were older (mean [SD] age 36.4 [9.7] vs. 29.3 [10.0] years; p = 0.032), had longer duration of CP [4 (0.3-21) vs. 3 (0.3-24) years; p = 0.07), and had a lower TAC (269.8 [92.4] vs. 355.5 [128.6] MUmoles Fe(+2) liberated; p = 0.003) compared to those without diabetes. In multiple logistic regression analysis taking all exploratory variables, FRAP (<270 MUmoles Fe(+2) liberated) was associated with diabetes independent of duration of CP, age of patients, and TBARS levels. However, oxidative stress levels were not different between diabetic and nondiabetic patients. CONCLUSIONS: Diabetes was found to be associated with longer duration of CP and with low antioxidant capacity. Further studies will be needed to evaluate a causal association. PMID- 22923280 TI - Image quality of adaptive iterative dose reduction 3D of coronary CT angiography of 640-slice CT: comparison with filtered back-projection. AB - To assess the image quality of coronary CT angiography (CCTA) of 640-slice CT reconstructed by Adaptive Iterative Dose Reduction (AIDR) three-dimensional (3D) in comparison with the conventional filtered back-projection (FBP). CCTA images of 51 patients were scanned at the lowest tube voltage possible on condition that the built-in automatic exposure control system could suggest the optimal tube current. They were, then, reconstructed with FBP and AIDR 3D (standard). Objective measurements including CT density, noise, signal-to-noise ratio (SNR), and contrast-to-noise ratio (CNR) were performed. Subjective assessment was done by two radiologists, using a 5-point scale (0:nondiagnostic-4:excellent) based on the 15-coronary segment model which was grouped into three parts as the proximal, mid, and distal segmental classes. Radiation dose was also measured. AIDR images showed lower noise than FBP images (45.0 +/- 9.4 vs. 73.4 +/- 14.6 HU, p < 0.001) without any significant difference in CT density (665.5 +/- 131.7 vs. 668 +/- 136.3 HU, p = 0.8). Both SNR (15.0 +/- 2.1 vs. 9.2 +/- 1.7) and CNR (16.8 +/- 2.3 vs. 10.4 +/- 1.8) were significantly higher for AIDR than FBP (p < 0.001). Total subjective image quality score was also significantly improved in AIDR compared with FBP (3.1 +/- 0.6 vs. 1.6 +/- 0.4, p < 0.001), with better interpretability of the mid and distal segmental classes (100 vs. 95 % for the mid, p < 0.001; 100 vs. 90 % for the distal, p < 0.001). Mean effective radiation dose was 2.0 +/- 1.0 mSv. The AIDR 3D reconstruction algorithm reduced image noise by 39 % compared with the FBP without affecting CT density, thus improving SNR and CNR for CCTA. Its advantages in interpretability were also confirmed by subjective evaluation by experts. PMID- 22923281 TI - Aortic dilatation and calcification in asymptomatic patients with bicuspid aortic valve: analysis in a Korean health screening population. AB - Entire anatomic area involved in the bicuspid aortic valve (BAV) disease has not been studied well, especially in Asian populations. We investigated prevalence and vascular characteristics of the BAV disease in a Korean population. In a health screening program from 2005 through 2010, 38 BAV patients (BAV group, 0.16 %, 35 males) were isolated among a total of 23,291 persons based on echocardiography. Each BAV patient was matched with three TAV patients (TAV group, n = 114) of the same age, gender, BSA, and hypertension. Using echocardiography and low-dose chest CT scan, diameters of the aortic root to proximal descending aorta (pDA) and pulmonary artery (PA), morphologic types of BAV, and calcification in the aortic root were evaluated in both groups. Diameters of the sinotubular junction and ascending aorta in BAV group were larger than in TAV group (29 +/- 7 vs. 27 +/- 3 mm, p = 0.046; 42 +/- 7 vs. 34 +/ 4 mm, p < 0.001, respectively). Diameters of the annulus, sinus of Valsalva, aortic arch, pDA, and PA were not different between two groups. Calcification in the aortic root was approximately seven times more common in BAV group (p < 0.001). Diameters of the aortic root were larger in the R-L type (n = 24) than in the R-N type (n = 11). Prevalence of BAV in a Korean population appears lower than in Western populations. Within the entire anatomic boundaries of BAV, the ascending aorta was predominantly dilated in BAV patients. The R-L type showed more dilatation than the R-N type, not in the ascending aorta but in the aortic root. PMID- 22923283 TI - Building leadership skills and promoting workforce development: evaluation data collected from public health professionals in the field of maternal and child health. AB - Professional development, including training and leadership skill building, is important for maternal and child health (MCH) epidemiologists. Current workforce development and training opportunities vary, but lack an emphasis on linking leadership competencies with MCH epidemiology. This paper describes efforts at the annual MCH Epidemiology Conference (the "Conference") to promote leadership activities and workforce development, and recommendations to enhance professional development. An evaluation of attendee opinions on Conference workforce development activities was conducted during the 2009 and 2010 Conferences (70 and 66 % response rates, respectively). Frequencies and percentages were calculated overall and by attendee profession. Qualitative responses to questions regarding workforce and professional development were classified by theme in 2009, and a categorical question was developed for the 2010 evaluation. A combined 38 % of Conference attendees in 2009 and 2010 were MCH epidemiologists and 62 % were other MCH professionals. Attendees recommended more support and access to training, mentoring, and resources including job opportunities. Continuing education (41 %), special knowledge and skills-building training (51 %), and development of online resources for training (57 %) were highly recommended by attendees. Career (47 %) and leadership (49 %) mentoring by senior-level professionals in the field were also highly recommended. Promotion of leadership can be achieved by integrating the concept of leadership into the Conference itself; by publishing and disseminating MCH epidemiologic research in scientific, program, and policy settings; and by communicating the importance of epidemiologic findings to stakeholders and other non-scientific audiences. PMID- 22923284 TI - Medical and sociodemographic risk factors for preterm birth in a French Caribbean population of African descent. AB - There appears to be an incompressible high rate of preterm births among populations of African origin irrespective of their geographic location. The objective of this study was to assess the risk factors for preterm birth in a French Caribbean population of African descent, offered medical care comparable to that on the French mainland, but presenting a higher rate of preterm birth. The study was based on a birth cohort at maternity hospitals in Guadeloupe (French West Indies) including 911 singleton pregnancies enrolled during their third trimester check-up visits. Associations between risk factors and the risk of preterm delivery (spontaneous and induced) were assessed using a multivariate Cox model. In addition, prevalences of sociodemographic and medical factors in Guadeloupe were compared with those on the French mainland. 144 women (15.8 %) delivered preterm, medically induced in 52 %. Women delivering preterm were more often over 35 years old (37 %), single (54 %), and had higher prevalence of prior preterm birth (20 %), prior miscarriage (37 %), lupus (3 %), asthma (14 %), gestational hypertension (26 %), gestational diabetes (13 %) and urinary tract infection (24 %) than women with term births. In the whole cohort, these risk factors were also more frequent than in mainland France. Our results suggest highly prevalent medical risk factors for preterm births in Guadeloupe. This observation combined with specific social risk factors (older maternal age, single living) less frequent on the French mainland probably explains a large part of a higher prevalence of preterm births in this population despite similar medical provision. PMID- 22923282 TI - Two-year outcome of photodynamic therapy combined with intravitreal injection of bevacizumab and triamcinolone acetonide for polypoidal choroidal vasculopathy. AB - PURPOSE: To compare the 2-year results after photodynamic therapy (PDT) alone and PDT combined with intravitreal injections of bevacizumab and triamcinolone acetonide (triple therapy) for polypoidal choroidal vasculopathy (PCV). METHODS: We retrospectively reviewed the medical records of 40 consecutive patients (40 eyes) with subfoveal PCV. Of these 40 eyes, 16 were treated with PDT alone and 24 were treated with triple therapy. RESULTS: The change in visual acuity in the triple therapy group was significantly better than that in the PDT group (P < 0.001). At 24 months, improvement in visual acuity was seen in only two eyes (12.5 %) of the PDT group, while it was seen in ten eyes (41.7 %) of the triple therapy group. Retreatment was given to 12 eyes (75.0 %) in the PDT group and to nine eyes (37.5 %) in the triple therapy group, although the retreatment-free period was significantly longer in the triple therapy group than in the PDT group (P < 0.001). Post-treatment vitreous hemorrhage was seen in only two eyes (12.5 %), all of which were in the PDT group. CONCLUSION: Compared with PDT alone, triple therapy appears to reduce the postoperative hemorrhagic complications and recurrences of PCV and to improve the 2-year visual outcomes of PCV. PMID- 22923285 TI - Incidence of and risk factors for postoperative nausea and vomiting at a Japanese Cancer Center: first large-scale study in Japan. AB - PURPOSE: The first purpose of this study was to determine the incidence of postoperative nausea and/or vomiting (PONV) 0-48 h after anesthesia at a Japanese cancer center. The second purpose of this study was to collect information on PONV risk factors, independently, in the categories of patient-related, anesthesia-related, and surgery-related factors. METHODS: The frequency of nausea and vomiting was prospectively investigated from 0 to 48 h after anesthesia in 1645 patients (11-94 years of age) at a single medical institution. The occurrence of nausea and vomiting and the use of antiemetics were recorded up to 48 h after anesthesia. Patient-related, anesthesia-related, and surgery-related factors were also recorded and submitted to multiple logistic regression analysis to determine the relationship of these factors to nausea and vomiting. RESULTS: The incidences of nausea and vomiting from 0 to 24 h after anesthesia were 40 and 22 %, respectively. The incidences 24-48 h after anesthesia were 10 and 3 %, respectively. Female sex, previous history of PONV, prolonged anesthesia, and remifentanil use during surgery were identified as risk factors for both nausea and vomiting. The use of a volatile anesthetic, use of fentanyl during surgery, postoperative use of opioids, nonsmoking status, and drinking alcohol on 4 or fewer days per week were identified as risk factors for nausea alone. CONCLUSION: The incidence of and risk factors for PONV at a Japanese cancer center according to this study are comparable to those reported elsewhere. PMID- 22923286 TI - The group discussion effect: integrative processes and suggestions for implementation. AB - One of the most consistent findings in experimental social dilemmas research is the positive effect group discussion has on cooperative behavior. At a time when cooperation and consensus is critical to tackle global problems, ranging from debt to deforestation, understanding the dynamics of group discussion is a pressing need. Unfortunately, research investigating the underlying processes and implementation of the effect has been inconclusive. The authors present a critical review of existing explanations and integrate these perspectives into a single process model of group discussion, providing a more complete theoretical picture of how interrelated factors combine to facilitate discussion-induced cooperation. On the basis of this theoretical analysis, they consider complimentary approaches to the indirect and feasible implementation of group discussion. They argue that such strategies may overcome the barriers to direct discussion observed across a range of groups and organizations. PMID- 22923287 TI - Epigallocatechin gallate sensitizes CAL-27 human oral squamous cell carcinoma cells to the anti-metastatic effects of gefitinib (Iressa) via synergistic suppression of epidermal growth factor receptor and matrix metalloproteinase-2. AB - Human head and neck squamous cell carcinoma (HNSCC) is a major cause of cancer related death during the last decade due to its related metastasis and poor treatment outcomes. Gefitinib (Iressa), a tyrosine kinase inhibitor has been reported to reduce the metastatic abilities of oral cancer. Previous studies have shown that epigallocatechin gallate (EGCG), a green tea polyphenol, possesses cancer chemopreventive and anticancer activity. However, the mechanisms involved in the suppression of invasion and metastasis of human oral cancer cells following co-incubation with gefitinib and EGCG remain poorly understood. In the present study, we attempted to investigate the synergistic effects of a combined treatment of gefitinib and EGCG in CAL-27 cells in vitro and to elucidate the underlying molecular mechanisms associated with the supression of cell migration and invasion. In the present study, we found that the individual treatments or the combined treatment of gefitinib and EGCG synergistically inhibited the invasion and migration of CAL-27 cells using Transwell invasion and wound-healing scratch assays, respectively. Similarly, gefitinib in combination with EGCG synergistically attenuated enzymatic activity and the protein expression of MMP-2 in CAL-27 cells. Furthermore, individual or combined treatment with EGCG and gefitinib suppressed the protein expression of p-EGFR and the phosphorylated protein levels of ERK, JNK, p38 and AKT and displayed inhibitory effects on metastatic ability of CAL-27 cells. Combined effects of EGCG and gefitinib altered anti-metastatic actions for related gene expression were observed using DNA microarray analysis. Importantly, EGCG sensitizes CAL-27 cells to gefitinib suppressed phosphorylation of epidermal growth factor receptor (EGFR in vitro. Taken together, our results suggest that the synergistic suppression of the metastatic ability of CAL-27 cells after EGCG and gefitinib individual or combined treatment are mediated through mitogen-activated protein kinase (MAPK) signaling. Our novel findings provide potential insights into the mechanism involved with synergistic responses of gefitinib and EGCG against the progression of oral cancer. PMID- 22923288 TI - Estimation of the risk of secondary cancer in the thyroid gland and the breast outside the treated volume in patients undergoing brain, mediastinum and breast radiotherapy. AB - The purpose of this study was to measure the peripheral dose which is the absorbed dose in organs located outside the treatment volume such as the thyroid gland and the breast in patients undergoing radiotherapy, utilising the MOSFET dosemeters, as well as to estimate the probability of secondary cancer. The thyroid gland doses, expressed as a percentage of the prescribed dose (%TD), were measured to be 2.0+/-0.3 %, in whole brain irradiation, 10.0+/-8.0 % in mediastinum treatment and 8.0+/-2.0 and 2.0+/-0.8 % in breast treatment, with and without the supraclavicular irradiation, respectively, with a corresponding risk of 0.2, 2.0, 1.0 and 0.3 %. The dose to the breast was 7.0+/-2.0 %, in the mediastinum treatment, and 4.0+/-1.0 and 2.0+/-0.8 %, in the breast treatment, with and without supraclavicular irradiation, respectively, with a corresponding risk of 4.0, 2.0 and 1.0 %. Although the results indicate that the risk is not negligible, its significance should be considered in conjunction with the existing pathology and age of the patients. PMID- 22923289 TI - Skeletal effects of vitamin D supplementation in postmenopausal black women. AB - Black women have lower serum 25-hydroxyvitamin D (25[OH]D) levels and higher parathyroid hormone (PTH) levels than white peers but lower bone turnover, suggesting skeletal resistance to PTH. Our objective was to determine if vitamin D supplementation (1,000 IU/day) would prevent bone loss and whether vitamin D receptor (VDR) polymorphisms modify the response. We performed a 2-year randomized, controlled, double-blind study of 1,000 IU vitamin D(3) vs. placebo in postmenopausal black women with serum 25(OH)D levels <20 ng/mL (n = 103). Measurements of 25(OH)D, PTH, and bone turnover were evaluated at baseline and 3, 6, 12, 18, and 24 months. DNA was extracted from peripheral blood leukocytes, and genotyping was conducted using standard techniques. Spine and hip bone mineral density (BMD) was measured at baseline and every 6 months. Serum 25(OH)D increased 11 ng/mL with vitamin D supplementation (p < 0.001), with no change in the placebo group. Vitamin D supplementation produced a significant decline in PTH at 3 months only, with no differences in bone turnover between placebo and vitamin D at any time point. Two-year changes in BMD were not significantly different between placebo- and vitamin D-treated black women at any skeletal site. Despite similar elevations in 25(OH)D, femoral neck BMD was only responsive to vitamin D supplementation in FF subjects (n = 47), not Ff/ff subjects (n = 31). Vitamin D supplementation does not appear to influence bone loss in black women. However, in the FF polymorphism of the VDR gene group, vitamin D supplementation may retard the higher rate of bone loss. PMID- 22923290 TI - Positive-unlabeled learning for disease gene identification. AB - BACKGROUND: Identifying disease genes from human genome is an important but challenging task in biomedical research. Machine learning methods can be applied to discover new disease genes based on the known ones. Existing machine learning methods typically use the known disease genes as the positive training set P and the unknown genes as the negative training set N (non-disease gene set does not exist) to build classifiers to identify new disease genes from the unknown genes. However, such kind of classifiers is actually built from a noisy negative set N as there can be unknown disease genes in N itself. As a result, the classifiers do not perform as well as they could be. RESULT: Instead of treating the unknown genes as negative examples in N, we treat them as an unlabeled set U. We design a novel positive-unlabeled (PU) learning algorithm PUDI (PU learning for disease gene identification) to build a classifier using P and U. We first partition U into four sets, namely, reliable negative set RN, likely positive set LP, likely negative set LN and weak negative set WN. The weighted support vector machines are then used to build a multi-level classifier based on the four training sets and positive training set P to identify disease genes. Our experimental results demonstrate that our proposed PUDI algorithm outperformed the existing methods significantly. CONCLUSION: The proposed PUDI algorithm is able to identify disease genes more accurately by treating the unknown data more appropriately as unlabeled set U instead of negative set N. Given that many machine learning problems in biomedical research do involve positive and unlabeled data instead of negative data, it is possible that the machine learning methods for these problems can be further improved by adopting PU learning methods, as we have done here for disease gene identification. AVAILABILITY AND IMPLEMENTATION: The executable program and data are available at http://www1.i2r.a star.edu.sg/~xlli/PUDI/PUDI.html. PMID- 22923291 TI - EFICAz2.5: application of a high-precision enzyme function predictor to 396 proteomes. AB - High-quality enzyme function annotation is essential for understanding the biochemistry, metabolism and disease processes of organisms. Previously, we developed a multi-component high-precision enzyme function predictor, EFICAz(2) (enzyme function inference by a combined approach). Here, we present an updated improved version, EFICAz(2.5), that is trained on a significantly larger data set of enzyme sequences and PROSITE patterns. We also present the results of the application of EFICAz(2.5) to the enzyme reannotation of 396 genomes cataloged in the ENSEMBL database. AVAILABILITY: The EFICAz(2.5) server and database is freely available with a use-friendly interface at http://cssb.biology.gatech.edu/EFICAz2.5. PMID- 22923292 TI - Static network structure can be used to model the phenotypic effects of perturbations in regulatory networks. AB - MOTIVATION: Biological processes are dynamic, whereas the networks that depict them are typically static. Quantitative modeling using differential equations or logic-based functions can offer quantitative predictions of the behavior of biological systems, but they require detailed experimental characterization of interaction kinetics, which is typically unavailable. To determine to what extent complex biological processes can be modeled and analyzed using only the static structure of the network (i.e. the direction and sign of the edges), we attempt to predict the phenotypic effect of perturbations in biological networks from the static network structure. RESULTS: We analyzed three networks from different sources: The EGFR/MAPK and PI3K/AKT network from a detailed experimental study, the TNF regulatory network from the STRING database and a large network of all NCI-curated pathways from the Protein Interaction Database. Altogether, we predicted the effect of 39 perturbations (e.g. by one or two drugs) on 433 target proteins/genes. In up to 82% of the cases, an algorithm that used only the static structure of the network correctly predicted whether any given protein/gene is upregulated or downregulated as a result of perturbations of other proteins/genes. CONCLUSION: While quantitative modeling requires detailed experimental data and heavy computations, which limit its scalability for large networks, a wiring-based approach can use available data from pathway and interaction databases and may be scalable. These results lay the foundations for a large-scale approach of predicting phenotypes based on the schematic structure of networks. PMID- 22923293 TI - TRFolder-W: a web server for telomerase RNA structure prediction in yeast genomes. AB - TRFolder-W is a web server capable of predicting core structures of telomerase RNA (TR) in yeast genomes. TRFolder is a command-line Python toolkit for TR specific structure prediction. We developed a web-version built on the django web framework, leveraging the work done previously, to include enhancements to increase flexibility of usage. To date, there are five core sub-structures commonly found in TR of fungal species, which are the template region, downstream pseudoknot, boundary element, core-closing stem and triple helix. The aim of TRFolder-W is to use the five core structures as fundamental units to predict potential TR genes for yeast, and to provide a user-friendly interface. Moreover, the application of TRFolder-W can be extended to predict the characteristic structure on species other than fungal species. AVAILABILITY: The web server TRFolder-W is available at http://rna-informatics.uga.edu/?f=software&p=TRFolder w. PMID- 22923294 TI - The GlycomeAtlas tool for visualizing and querying glycome data. AB - MOTIVATION: The development of glycomics technologies in recent years has produced a sufficient amount of data to begin analyzing the glycan structures present in various organisms and tissues. In particular, glycan profiling using mass spectrometry (MS) and tandem MS has generated a large amount of data that are waiting to be analyzed. The Consortium for Functional Glycomics (CFG) has provided a web resource for obtaining such glycan profiling data easily. Although an interactive spectrum viewer is provided on the website as a Java applet, it is not necessarily easy to search for particular glycans or to find commonalities between different tissues in a single organism, for example. Therefore, to allow users to better take advantage of the valuable glycome data that can be obtained from mass spectra and other leading technologies, we have developed a tool called Glycome Atlas which is pre-loaded with the data from the CFG and is also able to visualize local glycan profiling data for human and mouse. RESULTS: We have developed a tool to allow users to visualize and perform queries of glycome data. This tool, called GlycomeAtlas, is pre-loaded with glycome data as provided by the CFG. Moreover, users can load their own local glycome data into this tool to visualize and perform queries on their own data. AVAILABILITY: This tool is available at the following URL: http://www.rings.t.soka.ac.jp/GlycomeAtlas/GUI.html. PMID- 22923295 TI - RazerS 3: faster, fully sensitive read mapping. AB - MOTIVATION: During the past years, next-generation sequencing has become a key technology for many applications in the biomedical sciences. Throughput continues to increase and new protocols provide longer reads than currently available. In almost all applications, read mapping is a first step. Hence, it is crucial to have algorithms and implementations that perform fast, with high sensitivity, and are able to deal with long reads and a large absolute number of insertions and deletions. RESULTS: RazerS is a read mapping program with adjustable sensitivity based on counting q-grams. In this work, we propose the successor RazerS 3, which now supports shared-memory parallelism, an additional seed-based filter with adjustable sensitivity, a much faster, banded version of the Myers' bit-vector algorithm for verification, memory-saving measures and support for the SAM output format. This leads to a much improved performance for mapping reads, in particular, long reads with many errors. We extensively compare RazerS 3 with other popular read mappers and show that its results are often superior to them in terms of sensitivity while exhibiting practical and often competitive run times. In addition, RazerS 3 works without a pre-computed index. AVAILABILITY AND IMPLEMENTATION: Source code and binaries are freely available for download at http://www.seqan.de/projects/razers. RazerS 3 is implemented in C++ and OpenMP under a GPL license using the SeqAn library and supports Linux, Mac OS X and Windows. PMID- 22923296 TI - HiTC: exploration of high-throughput 'C' experiments. AB - SUMMARY: The R/Bioconductor package HiTC facilitates the exploration of high throughput 3C-based data. It allows users to import and export 'C' data, to transform, normalize, annotate and visualize interaction maps. The package operates within the Bioconductor framework and thus offers new opportunities for future development in this field. AVAILABILITY AND IMPLEMENTATION: The R package HiTC is available from the Bioconductor website. A detailed vignette provides additional documentation and help for using the package. PMID- 22923297 TI - Information-theoretic analysis and prediction of protein atomic burials: on the search for an informational intermediate between sequence and structure. AB - MOTIVATION: It has been recently suggested that atomic burials, as expressed by molecular central distances, contain sufficient information to determine the tertiary structure of small globular proteins. A possible approach to structural determination from sequence could therefore involve a sequence-to-burial intermediate prediction step whose accuracy, however, is theoretically limited by the mutual information between these two variables. We use a non-redundant set of globular protein structures to estimate the mutual information between local amino acid sequence and atomic burials. Discretizing central distances of or atoms in equiprobable burial levels, we estimate relevant mutual information measures that are compared with actual predictions obtained from a Naive Bayesian Classifier (NBC) and a Hidden Markov Model (HMM). RESULTS: Mutual information density for 20 amino acids and two or three burial levels were estimated to be roughly 15% of the unconditional burial entropy density. Lower estimates for the mutual information between local amino acid sequence and burial of a single residue indicated an increase in mutual information with the number of burial levels up to at least five or six levels. Prediction schemes were found to efficiently extract the available burial information from local sequence. Lower estimates for the mutual information involving single burials are consistently approached by predictions from the NBC and actually surpassed by predictions from the HMM. Near-optimal prediction for the HMM is indicated by the agreement between its density of prediction information and the corresponding density of mutual information between input and output representations. AVAILABILITY: The dataset of protein structures and the prediction implementations are available at http://www.btc.unb.br/ (in 'Software'). PMID- 22923298 TI - MEGA-CC: computing core of molecular evolutionary genetics analysis program for automated and iterative data analysis. AB - There is a growing need in the research community to apply the molecular evolutionary genetics analysis (MEGA) software tool for batch processing a large number of datasets and to integrate it into analysis workflows. Therefore, we now make available the computing core of the MEGA software as a stand-alone executable (MEGA-CC), along with an analysis prototyper (MEGA-Proto). MEGA-CC provides users with access to all the computational analyses available through MEGA's graphical user interface version. This includes methods for multiple sequence alignment, substitution model selection, evolutionary distance estimation, phylogeny inference, substitution rate and pattern estimation, tests of natural selection and ancestral sequence inference. Additionally, we have upgraded the source code for phylogenetic analysis using the maximum likelihood methods for parallel execution on multiple processors and cores. Here, we describe MEGA-CC and outline the steps for using MEGA-CC in tandem with MEGA Proto for iterative and automated data analysis. AVAILABILITY: http://www.megasoftware.net/. PMID- 22923299 TI - GFOLD: a generalized fold change for ranking differentially expressed genes from RNA-seq data. AB - MOTIVATION: RNA-seq has been widely used in transcriptome analysis to effectively measure gene expression levels. Although sequencing costs are rapidly decreasing, almost 70% of all the human RNA-seq samples in the gene expression omnibus do not have biological replicates and more unreplicated RNA-seq data were published than replicated RNA-seq data in 2011. Despite the large amount of single replicate studies, there is currently no satisfactory method for detecting differentially expressed genes when only a single biological replicate is available. RESULTS: We present the GFOLD (generalized fold change) algorithm to produce biologically meaningful rankings of differentially expressed genes from RNA-seq data. GFOLD assigns reliable statistics for expression changes based on the posterior distribution of log fold change. In this way, GFOLD overcomes the shortcomings of P-value and fold change calculated by existing RNA-seq analysis methods and gives more stable and biological meaningful gene rankings when only a single biological replicate is available. AVAILABILITY: The open source C/C++ program is available at http://www.tongji.edu.cn/~zhanglab/GFOLD/index.html PMID- 22923301 TI - Bayesian inference of signaling network topology in a cancer cell line. AB - MOTIVATION: Protein signaling networks play a key role in cellular function, and their dysregulation is central to many diseases, including cancer. To shed light on signaling network topology in specific contexts, such as cancer, requires interrogation of multiple proteins through time and statistical approaches to make inferences regarding network structure. RESULTS: In this study, we use dynamic Bayesian networks to make inferences regarding network structure and thereby generate testable hypotheses. We incorporate existing biology using informative network priors, weighted objectively by an empirical Bayes approach, and exploit a connection between variable selection and network inference to enable exact calculation of posterior probabilities of interest. The approach is computationally efficient and essentially free of user-set tuning parameters. Results on data where the true, underlying network is known place the approach favorably relative to existing approaches. We apply these methods to reverse phase protein array time-course data from a breast cancer cell line (MDA-MB-468) to predict signaling links that we independently validate using targeted inhibition. The methods proposed offer a general approach by which to elucidate molecular networks specific to biological context, including, but not limited to, human cancers. AVAILABILITY: http://mukherjeelab.nki.nl/DBN (code and data). PMID- 22923300 TI - RIsearch: fast RNA-RNA interaction search using a simplified nearest-neighbor energy model. AB - MOTIVATION: Regulatory, non-coding RNAs often function by forming a duplex with other RNAs. It is therefore of interest to predict putative RNA-RNA duplexes in silico on a genome-wide scale. Current computational methods for predicting these interactions range from fast complementary-based searches to those that take intramolecular binding into account. Together these methods constitute a trade off between speed and accuracy, while leaving room for improvement within the context of genome-wide screens. A fast pre-filtering of putative duplexes would therefore be desirable. RESULTS: We present RIsearch, an implementation of a simplified Turner energy model for fast computation of hybridization, which significantly reduces runtime while maintaining accuracy. Its time complexity for sequences of lengths m and n is with a much smaller pre-factor than other tools. We show that this energy model is an accurate approximation of the full energy model for near-complementary RNA-RNA duplexes. RIsearch uses a Smith-Waterman like algorithm using a dinucleotide scoring matrix which approximates the Turner nearest-neighbor energies. We show in benchmarks that we achieve a speed improvement of at least 2.4* compared with RNAplex, the currently fastest method for searching near-complementary regions. RIsearch shows a prediction accuracy similar to RNAplex on two datasets of known bacterial short RNA (sRNA)-messenger RNA (mRNA) and eukaryotic microRNA (miRNA)-mRNA interactions. Using RIsearch as a pre-filter in genome-wide screens reduces the number of binding site candidates reported by miRNA target prediction programs, such as TargetScanS and miRanda, by up to 70%. Likewise, substantial filtering was performed on bacterial RNA-RNA interaction data. AVAILABILITY: The source code for RIsearch is available at: http://rth.dk/resources/risearch. PMID- 22923302 TI - HSPIR: a manually annotated heat shock protein information resource. AB - SUMMARY: Heat shock protein information resource (HSPIR) is a concerted database of six major heat shock proteins (HSPs), namely, Hsp70, Hsp40, Hsp60, Hsp90, Hsp100 and small HSP. The HSPs are essential for the survival of all living organisms, as they protect the conformations of proteins on exposure to various stress conditions. They are a highly conserved group of proteins involved in diverse physiological functions, including de novo folding, disaggregation and protein trafficking. Moreover, their critical role in the control of disease progression made them a prime target of research. Presently, limited information is available on HSPs in reference to their identification and structural classification across genera. To that extent, HSPIR provides manually curated information on sequence, structure, classification, ontology, domain organization, localization and possible biological functions extracted from UniProt, GenBank, Protein Data Bank and the literature. The database offers interactive search with incorporated tools, which enhances the analysis. HSPIR is a reliable resource for researchers exploring structure, function and evolution of HSPs. AVAILABILITY: http://pdslab.biochem.iisc.ernet.in/hspir/ PMID- 22923303 TI - COMPADRE: an R and web resource for pathway activity analysis by component decompositions. AB - The analysis of biological networks has become essential to study functional genomic data. Compadre is a tool to estimate pathway/gene sets activity indexes using sub-matrix decompositions for biological networks analyses. The Compadre pipeline also includes one of the direct uses of activity indexes to detect altered gene sets. For this, the gene expression sub-matrix of a gene set is decomposed into components, which are used to test differences between groups of samples. This procedure is performed with and without differentially expressed genes to decrease false calls. During this process, Compadre also performs an over-representation test. Compadre already implements four decomposition methods [principal component analysis (PCA), Isomaps, independent component analysis (ICA) and non-negative matrix factorization (NMF)], six statistical tests (t- and f-test, SAM, Kruskal-Wallis, Welch and Brown-Forsythe), several gene sets (KEGG, BioCarta, Reactome, GO and MsigDB) and can be easily expanded. Our simulation results shown in Supplementary Information suggest that Compadre detects more pathways than over-representation tools like David, Babelomics and Webgestalt and less false positives than PLAGE. The output is composed of results from decomposition and over-representation analyses providing a more complete biological picture. Examples provided in Supplementary Information show the utility, versatility and simplicity of Compadre for analyses of biological networks. AVAILABILITY AND IMPLEMENTATION: Compadre is freely available at http://bioinformatica.mty.itesm.mx:8080/compadre. The R package is also available at https://sourceforge.net/p/compadre. PMID- 22923304 TI - Qualitative translation of relations from BioPAX to SBML qual. AB - MOTIVATION: The biological pathway exchange language (BioPAX) and the systems biology markup language (SBML) belong to the most popular modeling and data exchange languages in systems biology. The focus of SBML is quantitative modeling and dynamic simulation of models, whereas the BioPAX specification concentrates mainly on visualization and qualitative analysis of pathway maps. BioPAX describes reactions and relations. In contrast, SBML core exclusively describes quantitative processes such as reactions. With the SBML qualitative models extension (qual), it has recently also become possible to describe relations in SBML. Before the development of SBML qual, relations could not be properly translated into SBML. Until now, there exists no BioPAX to SBML converter that is fully capable of translating both reactions and relations. RESULTS: The entire nature pathway interaction database has been converted from BioPAX (Level 2 and Level 3) into SBML (Level 3 Version 1) including both reactions and relations by using the new qual extension package. Additionally, we present the new webtool BioPAX2SBML for further BioPAX to SBML conversions. Compared with previous conversion tools, BioPAX2SBML is more comprehensive, more robust and more exact. AVAILABILITY: BioPAX2SBML is freely available at http://webservices.cs.uni tuebingen.de/ and the complete collection of the PID models is available at http://www.cogsys.cs.uni-tuebingen.de/downloads/Qualitative-Models/. PMID- 22923305 TI - Optimal timepoint sampling in high-throughput gene expression experiments. AB - MOTIVATION: Determining the best sampling rates (which maximize information yield and minimize cost) for time-series high-throughput gene expression experiments is a challenging optimization problem. Although existing approaches provide insight into the design of optimal sampling rates, our ability to utilize existing differential gene expression data to discover optimal timepoints is compelling. RESULTS: We present a new data-integrative model, Optimal Timepoint Selection (OTS), to address the sampling rate problem. Three experiments were run on two different datasets in order to test the performance of OTS, including iterative online and a top-up sampling approaches. In all of the experiments, OTS outperformed the best existing timepoint selection approaches, suggesting that it can optimize the distribution of a limited number of timepoints, potentially leading to better biological insights about the resulting gene expression patterns. AVAILABILITY: OTS is available at www.msu.edu/~jinchen/OTS. PMID- 22923306 TI - Exploring spatial patterns of gene expression from fruit fly embryogenesis on the iPhone. AB - Mobile technologies provide unique opportunities for ubiquitous distribution of scientific information through user-friendly interfaces. Therefore, we have developed a new FlyExpress mobile application that makes available a growing collection (>100 000) of standardized in situ hybridization images containing spatial patterns of gene expression from Drosophila melanogaster (fruit fly) embryogenesis. Using this application, scientists can visualize and compare expression patterns of >4000 developmentally relevant genes. The FlyExpress app displays the expression patterns of the selected gene for different visual projections (e.g. lateral) and displays them according to their developmental stages, which shows a gene's progression of spatial expression over developmental time. Ultimately, we envision the use of FlyExpress app in the laboratory where scientists may wish to immediately conduct a visual comparison of a known expression pattern with the one observed on the bench top or to display expression patterns of interest during scientific discussions at large. AVAILABILITY: Search "FlyExpress" on the Apple iTunes store. PMID- 22923307 TI - FacPad: Bayesian sparse factor modeling for the inference of pathways responsive to drug treatment. AB - MOTIVATION: It is well recognized that the effects of drugs are far beyond targeting individual proteins, but rather influencing the complex interactions among many relevant biological pathways. Genome-wide expression profiling before and after drug treatment has become a powerful approach for capturing a global snapshot of cellular response to drugs, as well as to understand drugs' mechanism of action. Therefore, it is of great interest to analyze this type of transcriptomic profiling data for the identification of pathways responsive to different drugs. However, few computational tools exist for this task. RESULTS: We have developed FacPad, a Bayesian sparse factor model, for the inference of pathways responsive to drug treatments. This model represents biological pathways as latent factors and aims to describe the variation among drug-induced gene expression alternations in terms of a much smaller number of latent factors. We applied this model to the Connectivity Map data set (build 02) and demonstrated that FacPad is able to identify many drug-pathway associations, some of which have been validated in the literature. Although this method was originally designed for the analysis of drug-induced transcriptional alternation data, it can be naturally applied to many other settings beyond polypharmacology. AVAILABILITY AND IMPLEMENTATION: The R package 'FacPad' is publically available at: http://cran.open-source-solution.org/web/packages/FacPad/. PMID- 22923308 TI - Medial compressible forefoot sole elements reduce ankle inversion in lateral SSC jumps. AB - Sideward movements are associated with high incidences of lateral ankle sprains. Special shoe constructions might be able to reduce these injuries during lateral movements. The purpose of this study was to investigate whether medial compressible forefoot sole elements can reduce ankle inversion in a reactive lateral movement, and to evaluate those elements' influence on neuromuscular and mechanical adjustments in lower extremities. Foot placement and frontal plane ankle joint kinematics and kinetics were analyzed by 3-dimensional motion analysis. Electromyographic data of triceps surae, peroneus longus, and tibialis anterior were collected. This modified shoe reduced ankle inversion in comparison with a shoe with a standard sole construction. No differences in ankle inversion moments were found. With the modified shoe, foot placement occurred more internally rotated, and muscle activity of the lateral shank muscles was reduced. Hence, lateral ankle joint stability during reactive sideward movements can be improved by these compressible elements, and therefore lower lateral shank muscle activity is required. As those elements limit inversion, the strategy to control inversion angles via a high external foot rotation does not need to be used. PMID- 22923309 TI - Hypogonadotropic hypogonadism in morbidly obese males is reversed after bariatric surgery. AB - BACKGROUND: The effect of weight loss by bariatric surgery on gonadal hormones in morbidly obese males is not entirely known. The main objective of the study was to analyze gonadal hormonal changes after weight loss. METHODS: An observational study was conducted before and after 12 months of weight loss at a clinical research center. Thirty-three men [age 40.5 +/- 9.9, body mass index (BMI) 50.3 +/- 6.1 kg/m(2)] undergoing bariatric surgery were included. The main outcome measures were as follows: changes in total (TT) and free testosterone (FT), estradiol (E2), sex hormone binding globulin (SHBG), luteinizing hormone (LH), follicle-stimulating hormone (FSH), anti-Mullerian hormone (AMH), inhibin B, and prolactin (PRL). RESULTS: Baseline prevalence of hypogonadism (defined by TT < 300 ng/dl or FT < 65 pg/ml) was 78.8 and 51.5%, respectively. Hypogonadal patients were older and showed inhibin B and AMH significantly lower than those with normal TT. BMI correlated negatively with TT, LH, and SHBG. Regression analyses showed a significant and independent association of hypogonadism with age (OR = 1.2, p = 0.01), BMI (OR = 1.3, p = 0.03), and AMH (OR = 0.4, p = 0.03) after adjustments. After 1 year, percentage of weight loss (%WL) was 18.8 +/- 5.2%, and there was a significant increase of TT, FT, SHBG, and FSH and a decrease of E2 and PRL. Prevalence of persistent hypogonadism after surgery was 6% (low TT) and 15% (low FT). %WL was significantly associated with percent changes in SHBG (r = -0.4, p = 0.04), inhibin B (r = -0.4, p = 0.03), and AMH (r = -0.4, p = 0.01). Age and %WL were the only significant and independent parameters associated with %TT change. CONCLUSIONS: Obesity-associated hypogonadism is very prevalent in males with morbid obesity and is mostly reversed after sustained weight loss by bariatric surgery. PMID- 22923310 TI - Plastic surgery after gastric bypass improves long-term quality of life. AB - BACKGROUND: Excess skin after massive weight loss impairs patient's health related quality of life (HRQoL). Therefore, body-contouring surgeries can be proposed. However, few data exist concerning the effect of body contouring after bariatric surgery on HRQoL, including control group with a long-term follow-up. METHODS: In a prospective study, 98 consecutive patients who had body contouring after gastric bypass for obesity (BMI > 40) were included (group A). A matched control-group containing 102 patients who had only gastric bypass was selected (group B). HRQoL was measured by Moorehead-Ardelt questionnaire before (group A1) and after (A2) body contouring, and at different time points for group B until 8 years post-gastric bypass. To evaluate the effect of body contouring by two parallel methods, HRQoL was compared between groups A1 and A2, and between A2 and B. RESULTS: We found that body contouring procedures improved significantly patients' HRQoL, in comparison to those who had only gastric bypass. Of the patients who had body contouring (group A2), 57 % evaluated their HRQoL "much better" in comparison to only 22 % of patients before body contouring (group A1) or those who never had body contouring (group B) (p < 0.001). The improvement was significant in all sub-domains of HRQoL: self-esteem, social life, work ability, sexual activity and physical activity (p < 0.001), and remained stable over time. CONCLUSIONS: Our study confirms the important role of plastic surgery in treatment of patients after massive weight loss. We demonstrated that body contouring, despite important scars, significantly improves satisfaction and HRQoL of patients after gastric bypass. Therefore, the treatment of morbid obesity should not be deemed achieved unless plastic surgery has been considered. PMID- 22923311 TI - Bariatric Outcomes Longitudinal Database (BOLD) suggests excess weight loss and excess BMI loss to be inappropriate outcome measures, demonstrating better alternatives. AB - Excess weight loss (%EWL) results show significant variation by initial body mass index (BMI): the heavier the patient, the lower the result. It is unclear whether this effect originates from the arithmetic construction of this outcome measure or from any true difference in bariatric impact on heavier and lighter patients. Outcome measures generating inappropriate variation would actually be unsuited for bariatric reports with possible implications on existing bariatric evidence. Nadir weight loss results after laparoscopic gastric bypass in 7,212 women from the Bariatric Outcomes Longitudinal Database (BOLD) are calculated for %EWL and 26 different relative measures using the formula 100% * (initial BMI - nadir BMI)/(initial BMI - a), with reference point 0 <= a <= 25. Variations by initial BMI and deviations in results using each relative measure are compared. Mean initial BMI, 47.5 kg/m(2). Mean nadir BMI, 28.9 kg/m(2). Mean nadir results of the lighter (A) and heavier (B) halves (2* n=3, 606) by reference point, a=25 (excess BMI loss (%EBMIL)), 95.3% (A)-77.2% (B); a=ideal weight (%EWL), 81.7% (A) 70.4% (B); a=10, 49.6% (A)-49.7% (B); a=0 (total weight loss (%TWL)), 37.7% (A) 40.2% (B). Variation by initial BMI is significant using all relative measures, except those with a = 9 (p = 0.396) and a = 10 (p = 0.504). The smallest variation coefficient is 21.5% at 8 <= a <= 14. Gastric bypass works equally effective for all female patients, reducing the part of body mass above 10 kg/m(2) by an average of 49.6%, regardless of their initial BMI. In contrast, %EWL and %EBMIL generate variation by initial BMI, providing lighter patients inappropriately with better results, potentially interfering with the significance of bariatric evidence. These two most widespread used outcome measures in bariatric surgery are therefore actually unsuited for comparing patients or groups. This BOLD data makes a strong argument for abandoning %EWL and %EBMIL altogether and reporting bariatric relative outcome as %TWL only. PMID- 22923312 TI - Outcomes of laparoscopic Roux-en-Y gastric bypass versus laparoscopic adjustable gastric banding in adolescents. AB - BACKGROUND: The goal of this study is to compare the outcomes of laparoscopic adjustable gastric banding (LAGB) and laparoscopic Roux-en-Y gastric bypass (LRYGB) in obese adolescents. METHODS: We performed a retrospective review of all adolescents between the ages of 15 and 19 who underwent LAGB or LRYGB at our university affiliated Bariatric Center of Excellence from 2002 to 2011. Postsurgical weight loss at 1, 3, 6, 12, 18, and 24 months was noted and expressed as percentage of excess weight loss (% EWL). RESULTS: Thirty-two patients underwent LRYGB and 23 underwent LAGB. The LAGB group was younger (18.6 +/- 0.6 versus 17.2 +/- 1.5) than the LRYGB group. Other preoperative demographic factors including body mass index, gender, ethnicity, and comorbidities were similar between the two groups. The average % EWL was superior in the LRYGB group compared to the LAGB group at all time points studied (p < 0.05), although at 2 year follow-up, only 16% (5/32) LRYGB and 30% (7/23) LAGB patients were available for follow-up. Three patients with type II diabetes mellitus underwent LRYGB and all experienced remission of their diabetes. The number of complications requiring interventions was similar between the two groups. CONCLUSIONS: In our study, adolescents undergoing LRYGB achieved superior weight loss compared to LAGB in the short-term follow-up. The complication rate for LAGB was similar compared to LRYGB. More studies are needed to monitor the long-term effects of these operations on adolescents before definitive recommendations can be made. PMID- 22923313 TI - Improvement in cardiovascular indices after Roux-en-Y gastric bypass or sleeve gastrectomy for morbid obesity. AB - BACKGROUND: Morbidly obese patients display cardiac abnormalities which are partially reversed after weight loss. The aim of the present study was to assess the potential difference in cardiovascular disease indices between patients who underwent either gastric bypass surgery or sleeve gastrectomy. METHODS: Thirty seven morbidly obese patients who underwent either Roux-en-Y gastric bypass (RYGB) (n = 14) or SG (n = 23) were examined before, 3 and 6 months after surgery. Indices of cardiac autonomic nervous system activity were evaluated, namely baroreflex sensitivity (BRS) and heart rate variability (HRV). A complete echocardiographic study was performed in a subgroup of 17 patients (RYGB 8, SG 9) preoperatively and 6 months after surgery, evaluating epicardial fat thickness, aortic distensibility, left ventricular (LV) Tei index, left atrium diameter, ejection fraction, and LV mass. RESULTS: All subjects experienced significant (p < 0.001) and similar weight loss independently of the type of operation. BRS and HRV indices improved significantly and to the same degree after surgery in both groups. In the echocardiographic study, all parameters improved significantly at 6 months in comparison with the baseline values. In addition, the RYGB group displayed significantly greater reduction in epicardial fat thickness (p = 0.007) and also tended to have a better LV performance as expressed by the lower values of the Tei index (p = 0.06) compared to the SG group 6 months after surgery. CONCLUSIONS: Both RYGB and SG exert comparable effects on weight loss and improvement of cardiovascular parameters. RYGB displays a more beneficial influence on epicardial fat thickness and left ventricular performance than SG. PMID- 22923314 TI - Dysphagia and spontaneous esophageal perforation in sarcoidosis. PMID- 22923315 TI - Lubiprostone targets prostanoid signaling and promotes ion transporter trafficking, mucus exocytosis, and contractility. AB - BACKGROUND AND AIM: Lubiprostone is a chloride channel activator in clinical use for the treatment of chronic constipation, but the mechanisms of action of the drug are poorly understood. The aim of this study was to determine whether lubiprostone exerts secretory effects in the intestine by membrane trafficking of ion transporters and associated machinery. METHODS: Immunolabeling and quantitative fluorescence intensity were used to examine lubiprostone-induced trafficking of the cystic fibrosis transmembrane conductance regulator (CFTR), sodium/potassium-coupled chloride co-transporter 1 (NKCC1), electrogenic sodium/bicarbonate co-transporter 1 (NBCe1), down-regulated in adenoma (DRA), putative anion transporter 1 (PAT1), sodium/proton exchanger 3 (NHE3), Ca(2+) activated chloride channel 2 (ClC-2) serotonin and its transporter SERT, E prostanoid receptors EP4 and EP1, sodium/potassium ATPase (Na-K-ATPase) and protein kinase A (PKA). The effects of lubiprostone on mucus exocytosis in rat intestine and human rectosigmoid explants were also examined. RESULTS: Lubiprostone induced contraction of villi and proximal colonic plicae and membrane trafficking of transporters that was more pronounced in villus/surface cells compared to the crypt. Membrane trafficking was determined by: (1) increased membrane labeling for CFTR, PAT1, NKCC1, and NBCe1 and decreased membrane labeling for NHE3, DRA and ClC-2; (2) increased serotonin, SERT, EP4, EP1 and PKA labeling in enterochromaffin cells; (3) increased SERT, EP4, EP1, PKA and Na-K-ATPase in enterocytes; and (4) increased mucus exocytosis in goblet cells. CONCLUSION: These data suggest that lubiprostone can target serotonergic, EP4/PKA and EP1 signaling in surface/villus regions; stimulate membrane trafficking of CFTR/NBCe1/NKCC1 in villus epithelia and PAT1/NBCe1/NKCC1 in colonic surface epithelia; suppress NHE3/DRA trafficking and fluid absorption; and enhance mucus-mobilization and mucosal contractility. PMID- 22923317 TI - Delayed visual maturation in otherwise normal infants. AB - BACKGROUND: Children may present in early infancy for evaluation of decreased visual responsiveness. Most such infants have systemic or ocular abnormalities that explain their poor fixation and tracking. Some infants, however, have no other medical or ocular problems. This study evaluated prognostic factors in this latter group of otherwise normal infants with decreased visual responsiveness. METHODS: This was a retrospective cohort study in which medical records of infants evaluated for decreased visual responsiveness were reviewed to identify children who had no history of premature birth or systemic problems associated with developmental delay. Examination findings that were predicted to indicate a good prognosis included: the presence of some reaction to light, normal pupil responses, no nystagmus, and no structural ocular abnormalities. Follow-up information was obtained from office visits and telephone interviews. Main outcome measures were visual acuity and developmental status. RESULTS: Thirty-two children met the criteria noted above. Six were excluded due to lack of follow up. Four were normal by the time of their initial examination. Follow-up for the remaining patients ranged from 3 months to 11 years (mean 2.94 years). One patient developed strabismus and required surgery. The remaining patients all had normal vision and development. CONCLUSIONS: Otherwise normal infants who present for evaluation of decreased visual responsiveness have a good prognosis if they have some reaction to light, normal pupil responses, absence of nystagmus, and no structural ocular abnormalities. The developmental prognosis for these infants appears to be good. Additional testing at the time of initial evaluation is not indicated. PMID- 22923316 TI - The impact of family history on the risk of colorectal neoplasia: don't change the guidelines just yet! PMID- 22923318 TI - Salvage pancreaticogastrostomy for pancreatic fistulae after pancreaticoduodenectomy. AB - Pancreatic anastomotic dehiscence after pancreaticoduodenectomy (PD) remains a common problem. Although the management of this condition is mostly conservative, some patients require surgical intervention. This study reviews our experience with surgical intervention in this clinical setting. All patients who underwent PD by the author between 1999 and 2011 were reviewed. The causes for reoperation and mortality after PD were evaluated. The nature of the operative intervention and outcome in those who underwent reoperation for postoperative pancreatic fistula were analyzed. Reoperation was necessary in a total of 36/208 patients in this series and the overall mortality for the entire series was 6.25 % (13/208). Twelve of these 36 reoperations in 208 patients were for treatment of pancreatic anastomotic dehiscence after PD. Five (42 %) patients reoperated for anastomotic dehiscence died, including four of six patients that underwent surgical drainage of percutaneously inaccessible collections and one of two patients that underwent completion pancreatectomy. None of those who underwent salvage pancreaticogastrostomy (PG) died, nor did they require additional interventions prior to discharge from hospital. In our experience, salvage PG was an effective and organ function preserving technique to manage pancreatic anastomotic dehiscence after PD. PMID- 22923319 TI - Open access upper gastrointestinal endoscopy: a 2-year experience from 2001 to 2003. AB - BACKGROUND: The role of open access endoscopy in detecting serious diseases like malignancy and peptic ulcers is debated. We participated in an open access endoscopy service and this study details our experience. METHODS: The Cancer Society of Kashmir provided an open access upper gastrointestinal (GI) endoscopy service in Kashmir between 2001 and 2003. The records of patients who underwent endoscopy were analyzed. RESULTS: A total of 1,000 endoscopies were performed over a two-year period (average >40 endoscopies per month). Two-thirds of endoscopies were normal. Gastric (n = 30) and esophageal (n = 42) tumors were seen in 7.2 % of patients. The other common abnormality detected was peptic ulcer. No complications were reported during or immediately after the procedure. CONCLUSION: Open access upper GI endoscopy is a viable service option that can become more widely available. PMID- 22923321 TI - Baseline survey of health prophylaxis and management practices on Swiss dairy farms. AB - Health prophylaxis management practices have acquired a major role in the success of dairy herd health programs, however, little is known about the scope and level of implementation on Swiss dairy farms. The main objective of this study was therefore to provide a general overview of the most important preventive measures which are currently being used on these farms. In March 2011, an online survey with 75 questions was sent to 2'285 randomly selected Swiss dairy farmers. Response rate by question ranged from 35 to 53 %. Within this study, answers were compared between dairy farms with a tie-stall (n = 739) and farms with a free stall (n = 458). Homeopathic treatments were used by 51 % of the dairy farmers and antibiotic dry cow treatments by 94 %. Farmers with a tie-stall tended to carry out more prophylactic treatments against external parasites, vaccinated their cows more frequently against Clostridium chauvoei and Moraxella bovis, and carried out claw trimming more frequently than dairy farmers with a free-stall. A higher proportion of dairy farmers with a free-stall had a written feeding plan, carried out regular feed analysis, wore an apron and rubber gloves during milking, and carried out post milking teat disinfection more frequently than dairy farmers with a tie-stall. The data collected in this survey could assist in improving future dairy health communication campaigns in Switzerland. PMID- 22923322 TI - Treatment of cows with milk fever using intravenous and oral calcium and phosphorus. AB - Fifteen cows with milk fever were treated with 500ml of 40 % calcium borogluconate (group A) administered intravenously. Fifteen other cows with milk fever received the same treatment, supplemented with 500ml of 10 % sodium phosphate administered intravenously, and 80g calcium as calcium lactate and 70g inorganic phosphorus as sodium phosphate administered orally in drinking water. The cows were monitored and blood samples collected for 3 days to measure the concentrations of total and ionized calcium, inorganic phosphorus and magnesium and the activity of creatine kinase. The two groups did not differ significantly with respect to the course of the disease. In each group 14 cows were cured. A rapid and significant increase in serum calcium concentration from the hypo- to the hypercalcaemic range occurred in both groups within 10min of the start of treatment, followed by a slow and steady decrease to the hypocalcaemic range. Calcium lactate did not prevent the calcium concentration from returning to the hypocalcaemic range, and the calcium profiles of the two groups did not differ significantly. As expected, treatment had little effect on the concentration of inorganic phosphorus in group A. In group B, treatment caused a rapid increase in the concentration of inorganic phosphorus to a maximum 20min after the start of treatment. This was followed by a slow decrease in the phosphorus concentration to the normophosphataemic range. Our findings confirmed that combined intravenous and oral administration of sodium phosphate in cows with periparturient paresis attributable to hypocalcaemia and hypophosphataemia results in a rapid and sustained increase in serum phosphorus, but not in serum calcium concentration. This modified therapy did not improve the success rate of milk fever treatment and further studies are needed to improve treatment of periparturient paresis. PMID- 22923320 TI - In vitro molecular characterization of RNA-proteins interactions during initiation of translation of a wild-type and a mutant Coxsackievirus B3 RNAs. AB - Translation initiation of Coxsackievirus B3 (CVB3) RNA is directed by an internal ribosome entry site (IRES) within the 5' untranslated region. Host cell factors involved in this process include some canonical translation factors and additional RNA-binding proteins. We have, previously, described that the Sabin3 like mutation (U475 -> C) introduced in CVB3 genome led to a defective mutant with a serious reduction in translation efficiency. With the aim to identify proteins interacting with CVB3 wild-type and Sabin3-like IRESes and to study interactions between HeLa cell or BHK-21 protein extracts and CVB3 RNAs, UV-cross linking assays were performed. We have observed a number of proteins that specifically interact with both RNAs. In particular, molecular weights of five of these proteins resemble to those of the eukaryotic translation initiation factors 4G, 3b, 4B, and PTB. According to cross-linking patterns obtained, we have demonstrated a better affinity of CVB3 RNA binding to BHK-21 proteins and a reduced interaction of the mutant RNA with almost cellular polypeptides compared to the wild-type IRES. On the basis of phylogeny of some initiation factors and on the knowledge of the initiation of translation process, we focused on the interaction of both IRESes with eIF3, p100 (eIF4G), and 40S ribosomal subunit by filter-binding assays. We have demonstrated a better affinity of binding to the wild-type CVB3 IRES. Thus, the reduction efficiency of the mutant RNA to bind to cellular proteins involved in the translation initiation could be the reason behind inefficient IRES function. PMID- 22923323 TI - Gammaglobulin and selenium status in healthy neonatal dairy calves in Switzerland. AB - Serum samples from 142 calves and their dams were analyzed for gammaglobulins (gammaG, calves) and selenium concentrations (Se, calves and dams). A questionnaire provided information about birth and colostrum management. The calves and their dams were distributed into two groups according the calves' gammaG concentration (< 10 and >= 10 g/L), Se concentrations were compared between groups. The correlation between gammaG and Se concentrations in the calves and their dams was analyzed. Risk factors for failure of passive transfer and Se deficiency were assessed based on the questionnaire. The gammaG concentration of 42.9 % of the calves was < 10 g/L (median: 10.9). Calves showed significantly higher gammaG values after optimized colostrum administration than calves with suboptimal colostrum administration (p < 0.004). The median Se concentration was 26.8 and 36.5 ug/L for the calves and dams, respectively. A high correlation was observed between the Se concentration of the dam and her calf (r = 0.72, p < 0.001). The calves' Se and gammaG concentrations were not significantly correlated. These results demonstrate that further efforts toward better information of farmers regarding colostrum management and Se supply are warranted. PMID- 22923324 TI - [Atrial rupture and pericardial effusion as a complication of chronic mitral valve endocardiosis]. AB - A 9-year-old Labrador mixed breed dog, known to suffer from heart disease, was presented. It had recently collapsed on the street. Based on clinical findings and ultrasonography the tentative diagnosis of an atrial rupture with bleeding into the pericardial sac, resulting into a cardiac tamponade, was made. The dog's state of health improved under treatment, including infusion, sedation and analgesia. Therefore pericardiocentesis was unnecessary. The dog was released from hospital the next evening and the medical therapy of its heart disease was continued. The animal died 85 days later. PMID- 22923328 TI - Upper gastrointestinal tract transit times of tablet and drinkable solution formulations of alendronate: a bioequivalence and a quantitative, randomized study using video deglutition. AB - The bioequivalence and upper digestive tract transit time of a drinkable solution of 70 mg/100 mL alendronate was compared to reference tablets. A randomized, single- dose, two-way crossover study of the rate of urinary recovery of alendronate during 36 h (AE((0-36 h))) by HPLC, in 104 healthy young male volunteers, showed that AE((0-36 h)) and the maximum excretion rate (R (max)) were within the accepted range of bioequivalence 81.8-105.7 and 81.7-106.2, respectively. To characterize the oesophageal passage time of the two alendronate formulations, we performed a randomized, controlled study, in 24 healthy men and women (mean 52 years old), who took the formulations standing or lying down, by an X-ray video deglutition system. When taken in the standing position, both formulations had equal mean transit times from mouth to stomach and tablet disintegration but data dispersion was significantly smaller with the liquid form. When taken in lying position, drinkable alendronate had shorter and less variable median transit times compared to the tablets. These results show that the drinkable alendronate formulation is bioequivalent to the tablets and may be advantageous in patients in whom the transit or disintegration of the tablets is impaired. PMID- 22923330 TI - Endovascular treatment of totally occluded superior mesenteric artery by retrograde crossing via the Villemin arcade. AB - Chronic mesenteric ischemia (CMI) is a rare disorder that is commonly caused by progressive atherosclerotic stenosis or occlusion of one or more mesenteric arteries. Endovascular treatment for symptomatic CMI represents a viable option, especially in high-operative risk patients. We report a case of acute symptomatic CMI with chronic totally occlusion of the superior mesenteric artery (SMA) associated with significant stenosis of celiac trunk (CT) and inferior mesenteric artery (IMA) that underwent endovascular treatment of all the three mesenteric arteries: stenting of CT and IMA stenosis, and recanalization of the SMA occlusion by retrograde crossing via the Villemin arcade. PMID- 22923329 TI - AS30D model of hepatocellular carcinoma: tumorigenicity and preliminary characterization by imaging, histopathology, and immunohistochemistry. AB - PURPOSE: This study was designed to determine the tumorigenicity of the AS30D HCC cell line following orthotopic injection into rat liver and preliminarily characterize the tumor model by both magnetic resonance imaging (MRI) and ultrasound (US) as well as histopathology and immunohistochemistry. MATERIALS: AS30D cell line in vitro proliferation was assessed by using MTT assay. Female rats (N = 5) underwent injection of the AS30D cell line into one site in the liver. Rats subsequently underwent MR imaging at days 7 and 14 to assess tumor establishment and volume. One rat underwent US of the liver at day 7. Rats were euthanized at day 7 or 14 and livers were subjected to gross, histopathologic (H&E), and immunohistochemical (CD31) analysis to assess for tumor growth and neovascularization. RESULTS: AS30D cell line demonstrated an in vitro doubling time of 33.2 +/- 5.3 h. MR imaging demonstrated hyperintense T2-weighted and hypointense T1-weighted lesions with tumor induction in five of five and three of three sites at days 7 and 14, respectively. The mean (SD) tumor volume was 126.1 +/- 36.2 mm(3) at day 7 (N = 5). US of the liver demonstrated a well circumscribed, hypoechoic mass and comparison of tumor dimensions agreed well with MRI. Analysis of H&E- and CD31-stained sections demonstrated moderate-high grade epithelial tumors with minimal tumor necrosis and evidence of diffuse intratumoral and peritumoral neovascularization by day 7. CONCLUSIONS: AS30D HCC cell line is tumorigenic following orthotopic injection into rat liver and can be used to generate an early vascularizing, slower-growing rat HCC tumor model. PMID- 22923331 TI - Paying the price for an incentive: an exploratory study of smokers' reasons for failing to complete an incentive based smoking cessation scheme. AB - OBJECTIVES: In 2009, one Scottish region launched a smoking cessation programme offering a weekly financial incentive of L12.50 over a 12-week period. However, a significant proportion of registered participants dropped out of the programme, some even failing to collect the financial reward they were owed. We explore reasons for disengagement and failure to re-engage within this group. METHOD: Individuals (n = 14) were interviewed in depth. Transcripts from recorded interviews formed the dataset and were analysed using the "Framework" method. RESULTS: Incentives appeared to introduce a potential change/reversal in the felt contractual relationship between service provider and client: the client was now the provider and being paid to quit. This led to an increased sense of obligation towards the service, and enhanced feelings of failure, guilt and shame post relapse, and reluctance to continue engagement or re-engagement. Other service factors promoting disengagement included issues of practical delivery through location, timing, administrative burden and incentive preference. CONCLUSION: The future design of incentive-based schemes should be cognisant of the potential impact on the client-professional relationship. Increasing the value of the incentive may overcome clients' antipathy towards bureaucracy and monitoring, but may simultaneously exacerbate the sense of failure and resultant stigma associated with relapse. It may be more cost-effective to reduce barriers/costs such as inconvenience, lack of privacy, timing and embarrassment of association of attendance at the pharmacy with methadone use. Alternatively, risks may be managed by reframing weekly rewards as three separate month-long stages, increasing a sense of achievement that a particular stage has been achieved before any relapse. PMID- 22923332 TI - Pain inhibition by blocking leukocytic and neuronal opioid peptidases in peripheral inflamed tissue. AB - Inflammatory pain can be controlled by endogenous opioid peptides. Here we blocked the degradation of opioids in peripheral injured tissue to locally augment this physiological system. In rats with hindpaw inflammation, inhibitors of aminopeptidase N (APN; bestatin) or neutral endopeptidase (NEP; thiorphan), and a dual inhibitor, NH(2)-CH-Ph-P(O)(OH)CH(2)-CH-CH(2)Ph(p-Ph)-CONH-CH-CH(3) COOH (P8B), were applied to injured paws. Combined bestatin (1.25-5 mg)/thiorphan (0.2-0.8 mg) or P8B (0.0625-1 mg) alone elevated mechanical nociceptive thresholds to 307 and 227% of vehicle-treated controls, respectively. This analgesia was abolished by antibodies to methionine-enkephalin, leucine enkephalin, and dynorphin A 1-17, by peripherally restricted and by selective MU , delta-, and kappa-opioid receptor antagonists. Flow cytometry and photospectrometry revealed expression and metabolic activity of APN and NEP on macrophages, granulocytes, and sciatic nerves from inflamed tissue. Radioimmunoassays showed that inhibition of leukocytic APN and NEP by bestatin (5 500 MUM)/thiorphan (1-100 MUM) combinations or by P8B (1-100 MUM) prevented the degradation of enkephalins. Blockade of neuronal peptidases by bestatin (0.5-10 mM)/thiorphan (0.1-5 mM) or by P8B (0.1-10 mM) additionally hindered dynorphin A 1-17 catabolism. Thus, leukocytes and peripheral nerves are important sources of APN and NEP in inflamed tissue, and their blockade promotes peripheral opioid analgesia. PMID- 22923334 TI - Average torsion axis location of athletic movements: subject specific or movement specific? AB - Foot torsion angles have previously been studied for different athletic movements. Sport shoes often contain a torsion element even though the location of the rotation axis of the foot is unknown. Therefore, the purpose of this study was to quantify the torsion axis location and determine if the location is influenced by the movement or the subject. The torsion axis location was calculated using a modified finite helical axis approach, which allowed the calculation of the rotation axis between the forefoot and the rearfoot without the influence of forefoot flexion. The torsion axis location during the lateral jab was 9.72 mm below and 26.96 mm lateral to a marker located at the posterior, central heel, whereas the shuffle cut resulted in an axis location of 9.59 mm below and 26.19 mm lateral to the reference marker. There was no significant difference for the average axis location between movements. There was, however, a significant difference for the location between subjects, indicating a subject specificity of the torsion axis. The results of the current study are the first to quantify the torsion axis location of the human foot during athletic movements. PMID- 22923333 TI - Molecular architecture of the MHC I peptide-loading complex: one tapasin molecule is essential and sufficient for antigen processing. AB - The loading of antigen-derived peptides onto MHC class I molecules for presentation to cytotoxic T cells is a key process in adaptive immune defense. Loading of MHC I is achieved by a sophisticated machinery, the peptide-loading complex (PLC), which is organized around the transporter associated with antigen processing (TAP) with the help of several auxiliary proteins. As an essential adapter protein recruiting MHC I molecules to TAP, tapasin catalyzes peptide loading of MHC I. However, the exact stoichiometry and basic molecular architecture of TAP and tapasin within the PLC remains elusive. Here, we demonstrate that two tapasin molecules are assembled in the PLC, with one tapasin bound to each TAP subunit. However, one tapasin molecule bound either to TAP1 or TAP2 is sufficient for efficient MHC I antigen presentation. By specifically blocking the interaction between tapasin-MHC I complexes and the translocation complex TAP, the MHC I surface expression is impaired to the same extent as with soluble tapasin. Thus, the proximity of the peptide supplier TAP to the acceptor MHC I is crucial for antigen processing. In summary, the human PLC consists maximally of 2* tapasin-ERp57/MHC I per TAP complex, but one tapasin-ERp57/MHC I in the PLC is essential and sufficient for antigen processing. PMID- 22923335 TI - Donor diabetes mellitus is an independent risk factor for graft loss in HCV positive but not HCV negative liver transplant recipients. AB - BACKGROUND AND AIMS: Graft survival in HCV (hepatitis C virus) infected recipients is worse than those transplanted for other liver diseases. We studied whether several donor cardiovascular risk factors (including advanced age, smoking, hypertension, and diabetes mellitus) contribute to worse outcomes for HCV positive and HCV negative liver transplant recipients. METHODS: We obtained data from the United Network for Organ Sharing on all adult liver transplants performed in the United States between January 1, 1998 and December 31, 2003. In total, 27,033 transplant cases were evaluated. Independent predictors of graft survival were determined using Cox proportional hazards regression analysis after controlling for factors previously found to be associated with differences in transplant outcomes. RESULTS: Donor diabetes was a strong independent risk factor for graft failure [hazard ratio (HR) = 1.20, p = 0.006] only in HCV positive recipients. Neither donor smoking status nor hypertension predicted graft loss in either cohort. Consistent with previous studies, advanced donor age, donation after cardiac death, height, and African American donor all predicted graft loss amongst both cohorts. CONCLUSION: Accounting for donor diabetes in relation to recipient HCV status in the selection of liver recipients may result in improved graft survival. PMID- 22923336 TI - Dietary patterns and self-reported associations of diet with symptoms of inflammatory bowel disease. AB - BACKGROUND: There are insufficient data to make firm dietary recommendations for patients with inflammatory bowel disease (IBD). Yet patients frequently report that specific food items influence their symptoms. In this study, we describe patients' perceptions about the benefits and harms of selected foods and patients' dietary patterns. METHODS: CCFA Partners is an ongoing internet-based cohort study of patients with IBD. We used a semi-quantitative food frequency questionnaire to measure dietary consumption patterns and open-ended questions to elicit responses from patients about food items they believe ameliorate or exacerbate IBD. We categorized patients into four mutually exclusive disease categories: CD without an ostomy or pouch (CD), UC without an ostomy or pouch (UC), CD with an ostomy (CD-ostomy), and UC with a pouch (UC-pouch). RESULTS: Yogurt, rice, and bananas were more frequently reported to improve symptoms whereas non-leafy vegetables, spicy foods, fruit, nuts, leafy vegetables, fried foods, milk, red meat, soda, popcorn, dairy, alcohol, high-fiber foods, corn, fatty foods, seeds, coffee, and beans were more frequently reported to worsen symptoms. Compared to CD patients, CD-ostomy patients reported significantly greater consumption of cheese (odds ratio [OR] 1.56, 95 % CI 1.03-2.36), sweetened beverages (OR 2.14, 95 % CI 1.02-1.03), milk (OR 1.84, 95 % CI 1.35 2.52), pizza (OR 1.57, 95 % CI 1.12-2.20), and processed meats (OR 1.40; 95 % CI 1.04-1.89). CONCLUSIONS: Patients identified foods that they believe worsen symptoms and restricted their diet. Patients with ostomies ate a more liberal diet. Prospective studies are needed to determine whether diet influences disease course. PMID- 22923337 TI - Distinct attention networks for feature enhancement and suppression in vision. AB - Attention biases sensory processing toward neurons containing information about behaviorally relevant events. These attentional biases apparently reflect the combined influence of feature enhancement and suppression. We examined the separate influence of enhancement and suppression in visual processing by determining whether responses to an unattended flicker were modulated when the flicker features matched target features at the attended location, competed with those features, or were neutral. We found that suppression primarily modulated parietal networks with a preferred frequency in the lower alpha band (f2=8 Hz), and enhancement primarily influenced parietal networks with a preferred frequency in the upper alpha band (f2=12 Hz). These responses were coupled with perception, with large responses to the unattended flicker leading to subsequently detected targets when the target features matched the flicker features (i.e., during enhancement). Our results suggest that enhancement and suppression are two distinct processes that work together to shape visual perception. PMID- 22923338 TI - Nonword-repetition ability does not appear to be a causal influence on children's vocabulary development. AB - In the study reported here, we assessed the theory that vocabulary learning in children depends critically on the capacity of a "phonological loop" that is indexed by nonword-repetition ability. A 3-year longitudinal study of 219 children assessed nonword-repetition ability and vocabulary knowledge at yearly intervals between the ages of 4 and 7 years. There was a considerable degree of longitudinal stability in children's vocabulary and nonword-repetition skills, but there was no evidence of any influence of nonword-repetition ability on later vocabulary knowledge. These results seriously call into question the claim that vocabulary learning in children is constrained by nonword-repetition ability, and they cast doubt on the broader theory that the phonological loop functions as a language-learning device. PMID- 22923339 TI - Ghrelin level and weight loss after laparoscopic sleeve gastrectomy and gastric mini-bypass for Prader-Willi syndrome in Chinese. AB - Prader-Willi syndrome (PWS) is a chromosomal disorder characterized by the presence of hyperghrelinemia, hyperphagia, and obesity. The optimal treatment for PWS patient remains controversial. Here, we present our experience of treating PWS with laparoscopic mini-gastric bypass (LMGBP) and laparoscopic sleeve gastrectomy (LSG). Three patients with genetic diagnosis of PWS and body mass index (BMI) greater than 40 kg/m(2) were referred for bariatric surgery. All of them had completed 2-year postoperative follow-up. Body weight, BMI, and ghrelin levels were recorded before and after surgery. They were two females and one male. Their age ranged from 15 to 23 years old, and the mean BMI was 46.7 kg/m(2) (range 44-50). Two patients underwent LSG and one patient underwent LMGBP. After a median follow-up of 33 months (range 24-36 months), mean weight loss and percentage of excessive weight loss at 2 years were 32.5 kg (24.9-38.3 kg) and 63.2 % (range 50.5-86.2 %), respectively. The mean fasting active ghrelin level decreased from 1,134.2 pg/ml preoperatively to 519.8 pg/ml 1 year after surgery. No major complication was observed. Iron deficiency anemia was observed in the patient who underwent LMGBP. Significant reduction of body weight and level of serum ghrelin can be achieved with minimal morbidity by LSG or LMGBP in patients with PWS. PMID- 22923341 TI - Reasons for loss of cardiac resynchronization therapy pacing: insights from 32 844 patients. AB - BACKGROUND: The efficacy of cardiac resynchronization therapy (CRT) is associated with the amount of CRT pacing delivered. The specific causes of CRT pacing loss and their relative frequencies remain poorly defined. METHODS AND RESULTS: CRT patients who transmitted device data from 2006 to 2011 were screened for inclusion. Device diagnostics were analyzed using an automated algorithm to categorize CRT loss into 10 different causes. The algorithm was validated against manual adjudications using a portion of the entire cohort. There were 80 768 patients analyzed with a median time of 594 (interquartile range, 294-1003) days from implant to time of analysis. In this cohort, 40.7% of patients had <98% pacing, and 11.5% of patients had <90% pacing. For patients with <98% pacing, device diagnostics explained 55.8% of pacing loss: 30.6% atrial tachycardia/atrial fibrillation; 16.6% premature ventricular contractions; and 8.6% captured as episodes with at least 10 consecutive beats of CRT loss (ventricular sensing episodes). Inappropriately programmed sensed and paced atrioventricular (AV) intervals (SAV/PAV) accounted for 34.5% of all ventricular sensing episodes. As the severity of CRT loss increased, the contribution of atrial tachycardia/atrial fibrillation and SAV/PAV to the loss increased. Atrial tachycardia/atrial fibrillation accounted for >50% and premature ventricular contractions accounted for <10% of CRT loss in those with <90% CRT pacing. CONCLUSIONS: CRT pacing <98% was observed in 40.7% of patients. Among those with suboptimal pacing, atrial tachycardia/atrial fibrillation was the most common reason for CRT pacing loss. Inappropriately programmed SAV/PAV intervals was the most common reason for episodes of sustained loss of CRT pacing. This information can help in defining more effective treatments to improve CRT delivery. PMID- 22923340 TI - What are gastric banding patients eating one year post-surgery? AB - BACKGROUND: There is a paucity of evidence-based dietary management guidelines for patients post-laparoscopic adjustable gastric banding, including no consensus recommendations for macronutrient intake. We examined the macronutrient intake across a multi-centre cohort of post-bariatric surgery patients and compared these intakes to post-bariatric surgery and population-based dietary guidelines. METHODS: Two hundred and fifteen patients from three bariatric surgery centres in Melbourne, Australia were invited to complete a validated Food Frequency Questionnaire 12 months post-operatively. RESULTS: Energy intakes of the 52 participants ranged from 1,140 to 13,200 kJ/day, with an average of 4,890 kJ/day (+/-2,360 kJ/day). Many patients did not meet minimum population recommendations for macronutrients. The average fibre intake was only 14 g/day (compared to the recommendations of 25 g for women and 30 g for men). The average diet 1 year post operatively was 36% total fat compared to the recommendations of 20-25%, with 14% of intake from saturated fat. CONCLUSIONS: Patients' dietary intakes vary significantly 1 year post-laparoscopic adjustable band surgery, with many patients not meeting recommendations. These results suggest that patients decrease their total energy intake; however, eating habits may not improve as they consume a diet high in saturated fat. It is recommended that all patients receive dietary education about diet quality post-laparoscopic adjustable gastric band surgery to assist them in improving their diet quality as well as quantity for optimal health and weight loss. Specific international guidelines for nutrient intakes for people undergoing bariatric surgery are needed. PMID- 22923342 TI - Role for MicroRNA-21 in atrial profibrillatory fibrotic remodeling associated with experimental postinfarction heart failure. AB - BACKGROUND: Atrial tissue fibrosis is often an important component of the atrial fibrillation (AF) substrate. Small noncoding microRNAs are important mediators in many cardiac remodeling paradigms. MicroRNA-21 (miR-21) has been suggested to be important in ventricular fibrotic remodeling by downregulating Sprouty-1, a protein that suppresses fibroblast proliferation. The present study examined the potential role of miR-21 in the atrial AF substrate resulting from experimental heart failure after myocardial infarction (MI). METHODS AND RESULTS: Large MIs (based on echocardiographic left ventricular wall motion score index) were created by left anterior descending coronary artery ligation in rats. Changes induced by MI versus sham controls were first characterized with echocardiography, histology, biochemistry, and in vivo electrophysiology. Additional MI rats were then randomized to receive anti-miR-21 (KD21) or scrambled control sequence (Scr21) injections into the left atrial myocardium. Progressive left ventricular enlargement, hypocontractility, left atrial dilation, fibrosis, refractoriness prolongation, and AF promotion occurred in MI rats versus sham controls. Atrial tissues of MI rats showed upregulation of miR 21, along with dysregulation of the target genes Sprouty-1, collagen-1, and collagen-3. KD21 treatment reduced atrial miR-21 expression levels in MI rats to values in sham rats, decreased AF duration from 417 (69-1595; median [Q1-Q3]) seconds to 3 (2-16) seconds (8 weeks after MI; P<0.05), and reduced atrial fibrous tissue content from 14.4 +/- 1.8% (mean +/- SEM) to 4.9 +/- 1.2% (8 weeks after MI; P<0.05) versus Scr21 controls. CONCLUSIONS: MI-induced heart failure leads to AF-promoting atrial remodeling in rats. Atrial miR-21 knockdown suppresses atrial fibrosis and AF promotion, implicating miR-21 as an important signaling molecule for the AF substrate and pointing to miR-21 as a potential target for molecular interventions designed to prevent AF. PMID- 22923343 TI - [When some Flaviviruses are throwing our certainties]. AB - During the past two decades, a number of mosquito-borne flaviviruses, mainly of African origin, have invaded new geographical areas where they have never been active. This was the case for the Japanese encephalitis virus which reached the northeastern part of Australia (1995) and, above all, for the West Nile virus which, since 1999, entirely colonized the American continent. Then, the Usutu virus invaded a large part of the Western Europe (2001) while the Zika virus caused a large epidemic in an island of Micronesia (2007). Finally, in 2010, the Tembusu virus devastated many duck farms in China while the Bagaza virus, after having provoked human encephalitis in India, reached the southern part of Spain. In the affected areas, new pathogenic outcomes were observed in humans and animals while new vertebrate hosts and mosquito species were infected. Moreover, unusual ways of contamination were described. The origins of this unprecedented evolution remain to be clarified. PMID- 22923346 TI - Molecular chaperones, alpha-synuclein, and neurodegeneration. AB - Parkinson's disease (PD) is a devastating neurological condition that affects about 1 % of people older than 65 years of age. In PD, dopaminergic neurons in the mid-brain slowly accumulate cytoplasmic inclusions (Lewy bodies, LBs) of the protein alpha-synuclein (alpha-syn) and then gradually lose function and die off. Cell death is thought to be causally linked to the aggregation/fibrillization of alpha-syn. This review focuses on new findings about the structure of alpha-syn, about how alpha-syn cooperates with Hsp70 and Hsp40 chaperones to promote neurotransmitter release, and about cell-to-cell transfer of pathogenic forms of alpha-syn and how Hsp70 might protect against this disease process. PMID- 22923348 TI - The neuroprotective effect of overexpression of calbindin-D(28k) in an animal model of Parkinson's disease. AB - Overexpression of calbindin-D(28k) (CaBP-28 k) induces neurite outgrowth in dopaminergic neuronal cells and could provide some protection to dopaminergic neurons against the pathological process in Parkinson's disease. Transgenic mice CaBP-28 k overexpression and the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mouse models were generated, and the effect of midbrain dopamine neurons in ethology was also assessed. Tyrosine hydroxylase (TH)-immunoreactive neurons were counted, and the concentration of total protein and dopamine (DA) of striatum corpora was measured in four animal models. Results showed that the positive TH cells, content of DA, and ability of ethology in MPTP-induced transgenic mice were significantly higher than that in MPTP-induced wild-type mice. The findings demonstrate that overexpression of CaBP-28 k could provide protection for DA neurons from neurodegeneration. It would provide a potential strategy in the treatment of Parkinson's diseases. PMID- 22923347 TI - alpha-Synuclein posttranslational modification and alternative splicing as a trigger for neurodegeneration. AB - Lewy body diseases include Parkinson disease and dementia with Lewy bodies and are characterized by the widespread distribution of Lewy bodies in virtually every brain area. The main component of Lewy bodies is alpha-synuclein (AS). Accumulating evidence suggests that AS oligomerization and aggregation are strongly associated with the pathogenesis of Lewy body diseases. AS is a small soluble protein with aggregation-prone properties under certain conditions. These properties are enhanced by posttranslational modifications such as phosphorylation, ubiquitination, nitration, and truncation. Accordingly, Lewy bodies contain abundant phosphorylated, nitrated, and monoubiquitinated AS. However, alternative splicing of the AS gene is also known to modify AS aggregation propensities. Splicing gives rise to four related forms of the protein, the main transcript and those that lack exon 4, exon 6, or both. Since AS structure and properties have been extensively studied, it is possible to predict the consequences of the splicing out of the two aforesaid exons. The present review discusses the latest insights on the mechanisms of AS posttranslational modifications and intends to depict their role in the pathogenesis of Lewy body diseases. The implications of deregulated alternative splicing are examined as well, and a hypothesis for the development of the pure form of dementia with Lewy bodies is proposed. PMID- 22923349 TI - Magnetic resonance microscopy for assessment of morphological changes in hydrating hydroxypropylmethyl cellulose matrix tablets in situ. AB - PURPOSE: To resolve contradictions found in morphology of hydrating hydroxypropylmethyl cellulose (HPMC) matrix as studied using Magnetic Resonance Imaging (MRI) techniques. Until now, two approaches were used in the literature: either two or three regions that differ in physicochemical properties were identified. METHODS: Multiparametric, spatially and temporally resolved T(2) MR relaxometry in situ was applied to study the hydration progress in HPMC matrix tablets using a 11.7 T MRI system. Two spin-echo based pulse sequences-one of them designed to specifically study short T(2) signals-were used. RESULTS: Two components in the T(2) decay envelope were estimated and spatial distributions of their parameters, i.e. amplitudes and T(2) values, were obtained. Based on the data, five different regions and their temporal evolution were identified: dry glassy, hydrated solid like, two interface layers and gel layer. The regions were found to be separated by four evolving fronts identified as penetration, full hydration, total gelification and apparent erosion. CONCLUSIONS: The MRI results showed morphological details of the hydrating HPMC matrices matching compound theoretical models. The proposed method will allow for adequate evaluation of controlled release polymeric matrix systems loaded with drug substances of different solubility. PMID- 22923350 TI - Effect of vehicles on the maximum transepidermal flux of similar size phenolic compounds. AB - PURPOSE: In principle, maximum transepidermal fluxes of solutes should be similar for different vehicles, except when the solute or vehicle modifies the skin. Here we estimated maximum flux, stratum corneum solubility, diffusivity and permeability coefficient for a range of similarly sized phenolic compounds with varying lipophilicity from polar and lipophilic vehicles. METHODS: Maximum flux and other skin transport parameters through human epidermis were obtained from lipophilic vehicles (mineral oil (MO) and isopropyl myristate (IPM)) and compared with values from water and propylene glycol (PG)-water solutions. Solvent uptake and changes in stratum corneum infrared spectroscopy and multiphoton microscopy imaging were also investigated. RESULTS: Maximum fluxes for MO and water were similar but IPM has a higher value for more polar phenols due to a higher diffusivity and PG-water had a higher flux due to higher solubility in the stratum corneum. Whereas maximum flux for various phenols was directly related to solubility in the stratum corneum independent of vehicle, increasing phenol lipophilicity increased and decreased permeability coefficient for aqueous solvents and lipophilic solvents, respectively. CONCLUSION: The maximum fluxes for phenols with a similar molecular size and varying lipophilicity were comparable between water and MO vehicles but higher for IPM and PG-water mixtures. PMID- 22923353 TI - Influence of surface on impact shock experienced during a fencing lunge. AB - The purpose of this study was to investigate the effect of sports surface on the magnitude of impact shock experienced during a lunge movement. Thirteen experienced, competitive fencers (age 32.4 +/- 4.6 years; height 178.4 +/- 7.2 cm; mass 74.4 +/- 9.1 kg) performed 10 lunges on four different surfaces: concrete with an overlaid vinyl layer (COVL), wooden sprung court surface (WSCS), metallic carpet fencing piste overlaid on the WSCS, and aluminum fencing piste overlaid on the WSCS. An accelerometer measured accelerations along the longitudinal axis of the tibia at 1000 Hz. The results identified a significantly (P < .05) larger impact shock magnitude was experienced during a lunge on the COVL (14.88 +/- 8.45 g) compared with the WSCS (11.61 +/- 7.30 g), WSCS with metallic carpet piste (11.14 +/- 6.38 g) and WSCS with aluminum piste (11.95 +/- 7.21 g). Furthermore, the two types of piste used had no significant effect the impact shock magnitude measured when overlaid on the WSCS compared with the WSCS on its own. The results of this investigation suggest that occurrences of injuries related to increased levels of impact shock may be reduced through the utilization of a WSCS as opposed to a COVL surface during fencing participation. PMID- 22923352 TI - Electrospun formulations containing crystalline active pharmaceutical ingredients. AB - PURPOSE: To investigate the use of electrospinning for forming solid dispersions containing crystalline active pharmaceutical ingredients (API) and understand the relevant properties of the resulting materials. METHOD: Free surface electrospinning was used to prepare nanofiber mats of poly(vinyl pyrrolidone) (PVP) and crystalline albendazole (ABZ) or famotidine (FAM) from a suspension of the drug crystals in a polymer solution. SEM and DSC were used to characterize the dispersion, XRD was used to determine the crystalline polymorph, and dissolution studies were performed to determine the influence of the preparation method on the dissolution rate. RESULTS: The electrospun fibers contained 31 wt% ABZ and 26 wt% FAM for the 1:2 ABZ:PVP and 1:2 FAM:PVP formulations, respectively, and both APIs retained their crystalline polymorphs throughout processing. The crystals had an average size of about 10 MUm and were well dispersed throughout the fibers, resulting in a higher dissolution rate for electrospun tablets than for powder tablets. CONCLUSIONS: Previously used to produce amorphous formulations, electrospinning has now been demonstrated to be a viable option for producing fibers containing crystalline API. Due to the dispersion of the crystals in the polymer, tablets made from the fiber mats may also exhibit improved dissolution properties over traditional powder compression. PMID- 22923354 TI - [Acute occlusions of cerebral arterial vessels - intravenous versus intraarterial thrombolysis]. AB - In selected stroke patients intravenous thrombolysis and/or endovascular therapies lead to a significant reduction of long term disabilities. In case of no contraindications, patients with acute ischemic stroke, which arrive within the time window on the emergency unit, should receive thrombolysis consequently and current data indicate that patients with a severe acute ischemic stroke and a proximal cerebral arterial vessel occlusion (i. e. main stem of the arteria cerebri media, posterior, maybe also anterior, arteria carotis interna and basilaris) should preferentially be treated endovascularly, patients with a peripheral cerebral arterial vessel occlusion (i. e. main branch of the arteria cerebri media, anterior and posterior) and mild symptoms with intravenous thrombolysis. PMID- 22923355 TI - [The new anticoagulants - their role in secondary prevention of thromboembolism after stroke]. AB - For many decades Vitamin K antagonists were the standard orally given medication for primary and secondary prevention of thromboembolism in patients with atrial fibrillation and stroke. Three compounds, dabigatran, rivaroxaban, and apixaban, are now challenging this well established prescription, as they showed similar effect in preventing thromboembolism with a lower bleeding rate in recently published well designed, controlled randomised, non-inferiority trials. Their advantages of each are to have a fixed dosage, no need to monitor coagulation factors, and fewer interactions with food and other drug intake. The therapeutic effect is estimated overall similar between the three compounds. Who is a candidate for one of the new drugs: Patients with atrial fibrillation and the clear indication to get a future oral anticoagulation are potential candidates to receive one of the new drugs. Further this may be patients where the treatment with Vit K antagonists was difficult to optimise, patients who are not willing to have blood controls done regularly or where blood controls are difficult to obtain. This will also be an option in patients who had a stroke due to atrial fibrillation and had no history of cerebral bleeding. Who should not receive the new anticoagulants: patients who present stable blood coagulation values in the treatment range and no complications should not be merged to the new drugs. Patients with severe renal insufficiency or receiving a medication that interacts with the new drugs (e. g. ketoconazole) or with synthetic heart valves will not be candidates to receive the new drugs. PMID- 22923356 TI - [Endovascular treatment for carotid artery stenosis]. AB - About 10 - 15% of all ischaemic strokes are caused by focal atherosclerosis and consecutive narrowing (stenosis) of the internal carotid artery (ICA). Carotid endarterectomy (CEA) - the standard treatment for carotid stenosis - substantially reduces the risk of recurrent stroke among patients who have had ischaemic symptoms such as stroke or transient ischaemic attack attributable to the stenosis. To a smaller extent, CEA also reduces the risk of first stroke in patients with hitherto asymptomatic carotid stenosis. Endovascular treatment techniques, including balloon angioplasty in the initial years and more recently, carotid artery stenting (CAS), have been developed as an alternative to CEA for treating carotid stenosis without necessitating surgery. The present review compares risks and benefits between CAS and CEA summarising the existing evidence derived from randomised controlled trials. Among patients with symptomatic carotid stenosis, CEA is associated with a lower risk of peri-procedural stroke or death than CAS. CAS reduces the risk of peri-procedural myocardial infarction, cranial nerve palsy and access site haematoma compared with CEA. The excess peri procedural stroke risk associated with CAS appears to be limited to patients older than 70 years while in younger patients, CAS is as safe as CEA. Both treatments are equally effective in preventing recurrent stroke in the first few years following treatment. However, recurrent stenosis appears to be more common after CAS, and longer-term follow-up of ongoing trials should be awaited to investigate whether restenosis might be associated with recurrent stroke. The best treatment approach for patients with asymptomatic carotid stenosis remains to be determined in ongoing clinical trials. PMID- 22923357 TI - [Arterial-ischaemic stroke in childhood]. AB - The risk to have a stroke during childhood is at least as frequent as to suffer from a brain tumour. Unlike adults, in whom ischaemic strokes overweigh haemorrhagic strokes, ischaemic and haemorrhagic strokes are equally frequent in children, occurring with an incidence of 2 - 3/100'000 children/year. Even though the clinical presentation of arterial-ischaemic stroke in children (pedAIS) is similar to adults, time to diagnosis is longer. The delay to diagnosis is mainly explained by the low index of suspicion of both the general population and the medical personnel, a broad range of differential diagnoses, and the fact that diagnostic imaging in children often requires sedation, which is not always readily available. PedAIS is a multiple risk problem, usually occurring due to a combination of risk factors, such as infectious diseases, dehydration, trauma or an underlying condition such as congenital heart disease. Still little is known about the appropriate management of pedAIS. Supportive measures are considered to be the mainstay of therapy. The use of antithrombotic medication depends on pedAIS aetiology. In an ongoing multicenter trial, the safety and effectiveness of thrombolysis are currently being investigated. PedAIS carries an important mortality and morbidity, with neurological and neuropsychological deficits persisting in two thirds of the affected children. PMID- 22923351 TI - Inhibition of cholesterol absorption: targeting the intestine. AB - Atherosclerosis, the gradual formation of a lipid-rich plaque in the arterial wall is the primary cause of Coronary Artery Disease (CAD), the leading cause of mortality worldwide. Hypercholesterolemia, elevated circulating cholesterol, was identified as a key risk factor for CAD in epidemiological studies. Since the approval of Mevacor in 1987, the primary therapeutic intervention for hypercholesterolemia has been statins, drugs that inhibit the biosynthesis of cholesterol. With improved understanding of the risks associated with elevated cholesterol levels, health agencies are recommending reductions in cholesterol that are not achievable in every patient with statins alone, underlying the need for improved combination therapies. The whole body cholesterol pool is derived from two sources, biosynthesis and diet. Although statins are effective at reducing the biosynthesis of cholesterol, they do not inhibit the absorption of cholesterol, making this an attractive target for adjunct therapies. This report summarizes the efforts to target the gastrointestinal absorption of cholesterol, with emphasis on specifically targeting the gastrointestinal tract to avoid the off-target effects sometimes associated with systemic exposure. PMID- 22923358 TI - [Neuroradiological focus on stroke imaging]. AB - Stroke is heterogenous in its symptoms, which are also caused by various pathologies. Clinically the causing mechanism (bleeding or ischemia) of a new onset of neurological deficits can not reliably be distinguished. However, ischemia is four times more frequent than a bleeding causing neurological symptoms. Modern imaging technologies (computed assisted tomography or magnetic resonace imaging) and interventional techniques are a mainstay in diagnostics and management of acute onset of neurological symptoms. They can reliably distinguish between bleeding and stroke, especially taking newest technologies, such as perfusion studies and angiographies, into account. Neuroradiology with its interventional options has nowadays furthermore become an important tool in strokes and offers a local maneuver to retrieve the clotting pathology and even opens the therapeutic window for a delayed start of the therapy since symptom's onset beyong the conventional 4.5 hours window. Also risks of a therapy and which therapy option should be used can immediately be assessed. PMID- 22923359 TI - [Stroke unit - the requirements for optimal treatment of acute stroke]. AB - Organised care of stroke patients is based on scientific evidence from randomized controlled trials,clinical practice guidelines, and expert consensus. Important features include emergency room facility, the presence of a dedicated stroke unit ward, and a multi-professional team approach. In adherence to diagnostic and therapeutic time-windows, intravenous thrombolytic therapy, periods of automated monitoring, access to decompressive craniectomy and intraarterial thrombolysis or clot removal, early swallowing diagnostics and therapy, early mobilization and rehabilitation are warranted. Further supported discharge and basic aftercare with treatment of risk factors and post-stroke prevention are consequently applied. The main components of the necessary infrastructure, technical equipment, diagnostic pathways, therapeutic interventions, nursing care and multi professional rehabilitation are to be organised and planned for each institution, who aims to treat stroke patients. This also covers the hospital environment and interactions between the stroke unit and other departments. Quality indicators are also required. PMID- 22923361 TI - Malpractice claims regarding calls to Swedish telephone advice nursing: what went wrong and why? AB - We analysed the characteristics of all malpractice claims arising out of telephone calls to Swedish Healthcare Direct (SHD) during 2003-2010 (n = 33). The National Board of Health and Welfare's (NBHW) investigations describing the causes of the malpractice claims and the healthcare providers' reported measures were analysed using Qualitative Content Analysis. The original telephone calls themselves, which had been recorded, were analysed using the Roter Interaction Analysis System (RIAS). Among the 33 cases, 13 patients died and 12 were admitted to intensive care. Failure to listen to the caller (n = 12) was the most common reason for malpractice claims, and work-group discussion (n = 13) was the most common measure taken to prevent future re-occurrence. Male patients (n = 19) were in the majority, and females (n = 24) were the most common callers. The most common symptoms were abdominal (n = 11) and chest pain (n = 6). Telenurses followed up on caller understanding in six calls, and mainly used closed-ended questions. Despite the severity of these malpractice claims, the measures taken mainly addressed active failure, rather than the latent conditions. Third-party communication should be regarded as a risk. When callers make repeated contacts, telenurses need to re-evaluate their need for care. PMID- 22923360 TI - Detailed functional and structural characterization of a macular lesion in a rhesus macaque. AB - PURPOSE: Animal models are powerful tools to broaden our understanding of disease mechanisms and to develop future treatment strategies. Here we present detailed structural and functional findings of a rhesus macaque suffering from a naturally occurring bilateral macular dystrophy (BMD), partial optic atrophy and corresponding reduction of central V1 signals in visual fMRI experiments when compared to data in a healthy macaque (CTRL) of similar age. METHODS: Retinal imaging included infrared and autofluorescence recordings, fluorescein and indocyanine green angiography and spectral domain optical coherence tomography (OCT) on the Spectralis HRA + OCT platform. Electroretinography included multifocal and Ganzfeld-ERG recordings. Animals were killed and eyes analyzed by immunohistochemistry. RESULTS: Angiography showed reduced macular vascularization with significantly larger foveal avascular zones (FAZ) in the affected animal (FAZBMD = 8.85 mm(2) vs. FAZCTRL = 0.32 mm(2)). OCT showed bilateral thinning of the macula within the FAZ (total retinal thickness, TRTBMD = 174 +/- 9 um) and partial optic nerve atrophy when compared to control (TRTCTRL = 303 +/- 45 um). Segmentation analysis revealed that inner retinal layers were primarily affected (inner retinal thickness, IRTBMD = 33 +/- 9 um vs. IRTCTRL = 143 +/- 45 um), while the outer retina essentially maintained its thickness (ORTBMD = 141 +/- 7 um vs. ORTCTRL = 160 +/- 11 um). Altered macular morphology corresponded to a preferential reduction of central signals in the multifocal electroretinography and to a specific attenuation of cone-derived responses in the Ganzfeld electroretinography, while rod function remained normal. CONCLUSION: We provided detailed characterization of a primate macular disorder. This study aims to stimulate awareness and further investigation in primates with macular disorders eventually leading to the identification of a primate animal model and facilitating the preclinical development of therapeutic strategies. PMID- 22923362 TI - From impending toxic megacolon to multiple organ failure in severe ulcerative colitis. PMID- 22923363 TI - [Profile of Buruli ulcer treated at the National Reference Centre of Togo: a study of 119 cases]. AB - The purpose of this study was to describe the epidemiological, clinical, therapeutic profile and the outcome of Buruli ulcer (BU) in the National Reference Center for Buruli ulcer treatment (NRCBUT) in Togo. It was a retrospective and descriptive study of records of patients treated for BU in the NRCBUT between June 2007 and December 2010. During the study period, 119 patients (56.3% males) were treated in the NRCBUT for BU. The median age of patients was 14 years. The proportion of children (< 15 years) was 56.3%. On admission, 85 patients were at ulcer stage and 34 patients at the pre-ulcer stage. BU wounds were mainly located on lower limbs (50.4%), followed by upper limbs (32.6%) and trunk (13.3%). The location of the wounds on the lower limbs were more frequent in patients older than 15 years (P < 0.001), while those on the upper limbs (P = 0.002) and trunk (P = 0.03) were more frequent in patients aged less than 15 years. All patients had received medical treatment which was based on rifampicin streptomycin combination for eight weeks. This treatment was coupled to surgery in 30 cases. The outcome was punctuated by complications in 7 patients, limb amputation in 3 patients, and sequels in 10 patients. This study confirmed that the BU is the prerogative of young subjects and the exposed areas in the skin facilitates transmission. Apart from these classic features, some unique aspects including the age-dependent distribution are related to the pathogenesis of this disease. PMID- 22923364 TI - Abstracts of the 2012 International Conference of Neurological Disorder, from Molecular Neurobiology to Clinical Therapy. September 26-29, 2012. Wuhan China. PMID- 22923365 TI - Integrating molecular mechanisms with synaptic plasticity in neurological disease. PMID- 22923366 TI - Dyrk1A, a serine/threonine kinase, is involved in ERK and Akt activation in the brain of hyperhomocysteinemic mice. AB - Hyperhomocysteinemia due to cystathionine beta synthase (CBS) deficiency is associated with diverse brain disease. Whereas the biological actions linking hyperhomocysteinemia to the cognitive dysfunction are not well understood, we tried to establish relationships between hyperhomocysteinemia and alterations of signaling pathways. In the brain of CBS-deficient mice, a murine model of hyperhomocysteinemia, we previously found an activation of extracellular signal regulated kinase (ERK) pathway and an increase of Dyrk1A, a serine/threonine kinase involved in diverse functions ranging from development and growth to apoptosis. We then investigated the relationship between Dyrk1A and the signaling pathways initiated by receptor tyrosine kinases (RTK), the ERK and PI3K/Akt pathways. We found a significant increase of phospho-ERK, phospho-MEK, and phospho-Akt in the brain of CBS-deficient and Dyrk1a-overexpressing mice. This increase was abolished when CBS-deficient and Dyrk1A-transgenic mice were treated with harmine, an inhibitor of Dyrk1A kinase activity, which emphasizes the role of Dyrk1A activity on ERK and Akt activation. Sprouty 2 protein level, a negative feedback loop modulator that limits the intensity and duration of RTK activation, is decreased in the brain of CBS-deficient mice, but not in the brain of Dyrk1A transgenic mice. Furthermore, a reduced Dyrk1A and Grb2 binding on sprouty 2 and an increased interaction of Dyrk1A with Grb2 were found in the brain of Dyrk1A transgenic mice. The consequence of Dyrk1A overexpression on RTK activation seems to be a decreased interaction of sprouty 2/Grb2. These observations demonstrate ERK and Akt activation induced by Dyrk1A in the brain of hyperhomocysteinemic mice and open new perspectives to understand the basis of the cognitive defects in hyperhomocysteinemia. PMID- 22923367 TI - Recent advances in alpha-synuclein functions, advanced glycation, and toxicity: implications for Parkinson's disease. AB - The toxicity of alpha-synuclein in the neuropathology of Parkinson's disease which includes its hallmark aggregation has been studied scrupulously in the last decade. Although little is known regarding the normal functions of alpha synuclein, its association with membrane phospholipids suggests its potential role in signaling pathways. Following extensive evidences for its nuclear localization, we and others recently demonstrated DNA binding activity of alpha synuclein that modulates its conformation as well as aggregation properties. Furthermore, we also underscored the similarities among various amyloidogenic proteins involved in neurodegenerative diseases including amyloid beta peptides and tau. Our more recent studies show that alpha-synuclein is glycated and glycosylated both in vitro and in neurons, significantly affecting its folding, oligomeric, and DNA binding properties. Glycated alpha-synuclein causes increased genome damage both via its direct interaction with DNA and by increased generation of reactive oxygen species as glycation byproduct. In this review, we discuss the mechanisms of glycation and other posttranslational modifications of alpha-synuclein, including phosphorylation and nitration, and their role in neuronal death in Parkinson's disease. PMID- 22923369 TI - Scapula kinematics differ by body mass index. AB - The biomechanical changes due to increased arm mass in individuals with high body mass index (BMI) may lead to altered scapular motions at the shoulder joint. Scapula kinematic alterations are often associated with shoulder pain and pathology, and if present in overweight or obese individuals could impact shoulder health. The purpose of this study was to examine if scapula biomechanics differ between groups separated by BMI. Three-dimensional scapula kinematic data during arm elevation were collected on 41 subjects, and then compared between higher BMI (BMI >= 27; n = 10) and lower BMI (BMI <= 23; n = 10) individuals, both with and without holding a 1.36 kg (3 lb) weight. Data were analyzed with a mixed-model ANOVA with Group and Elevation Angle the between- and within-subject factors, respectively. The higher BMI group had significantly greater scapula upward rotation than the lower BMI group at 120 degrees for both the unweighted and weighted tasks. Individuals with higher BMI in this study had altered scapulothoracic movement, which may be a strategy to better manage increased arm mass. With increased scapula upward rotation also reported in groups with rotator cuff tears, this study supports the potential link between high BMI, kinematics, and rotator cuff pathology. PMID- 22923368 TI - Implementing a clinical pharmacy survey of adverse drug events in a French emergency department. AB - BACKGROUND: The prevalence of adverse drug events (ADEs) occurring in the ambulatory setting is high, requiring the development of a coherent and comprehensive patient-safety policy framework. Former experiences demonstrated that emergency department (ED) surveillance can help characterise the burden of outpatient ADEs. We developed a clinical pharmacy programme called the clinical pharmacy survey of adverse drug events (CPSA) to support interventions and research projects in the area of ADE prevention and management. OBJECTIVE: To design a survey to identify and describe ADEs in patients visiting the medical ED of our tertiary care hospital. We report the results of the first 2 years of CPSA implementation and an assessment of its performance. SETTING: The medical ED of a French 3,000-bed tertiary care hospital. METHOD: Between January 2008 and December 2009, adult patients visiting our medical ED were included during randomised time slots. Data were collected by pharmacy students. ADEs were documented by a trained physician pharmacist team using the chart review method. MAIN OUTCOME MEASURE: The primary outcome was the number of patients visiting our ED with an ADE. The CPSA attributes were assessed on the basis of the Centers for Disease Control and Prevention's 2001 updated guidelines for evaluating public health surveillance systems. RESULTS: Of the 1,035 included patients, 201 experienced an ADE at the ED visit (19.4 %; 95 % confidence interval 15.8-23.0 %). Forty-seven ADEs (23.4 %) were unrelated to the patient's chief complaint. An ADE was the leading cause of 154 in the 1,035 admissions (14.9 %). The assessment of our method on the basis of the Centers for Disease Control and Prevention guidelines showed good performances in terms of data quality, stability, flexibility, timeliness, and acceptability, but not in terms of simplicity and representativeness. The profile of patients with an ADE at admission and detected ADEs did not significantly differ between years 2008 and 2009. CONCLUSION: Our experience demonstrates that clinical pharmacists can successfully implement a survey process of ADEs in an ED over time. Our method seems basic enough to suit most health care facilities with pharmacy students. PMID- 22923370 TI - Synthesis and characterization of novel n-9 fatty acid conjugates possessing antineoplastic properties. AB - The present study enumerates the synthesis, spectroscopic characterization, and evaluation of anticancer potential of esters of two n-9 fatty acids viz., oleic acid (OLA) and ricinoleic acid (RCA) with 2,4- or 2,6-diisopropylphenol. The synthesis strategy involved esterification of the hydroxyl group of diisopropylphenol (propofol) to the terminal carboxyl group of n-9 fatty acid. The synthesized propofol-n-9 conjugates having greater lipophilic character were tested initially for cytotoxicity in-vitro. The conjugates showed specific growth inhibition of cancer cell lines whereas no effect was observed in normal cells. In general, pronounced growth inhibition was found against the human skin malignant melanoma cell line (SK-MEL-1). The anticancer potential was also determined by testing the effect of these conjugates on cell migration, cell adhesion and induction of apoptosis in SK-MEL-1 cancer cells. Propofol-OLA conjugates significantly induced apoptosis in contrast to propofol-RCA conjugates which showed only weak signals for cytochrome c. Conclusively, the synthesized novel ester conjugates showed considerable moderation of anti-tumor activity. This preliminary study places in-house synthesized conjugates into the new class of anticancer agents that possess selectivity toward cancer cells over normal cells. PMID- 22923372 TI - Nematodes as bioindicators of soil degradation due to heavy metals. AB - The effect of distance from a heavy metal pollution source on the soil nematode community was investigated on four sampling sites along an 4 km transect originating at the Kovohuty a.s. Krompachy (pollution source). The soil nematode communities were exposed to heavy metal influence directly and through soil properties changes. We quantified the relative effects of total and mobile fraction of metals (As, Cd, Cr, Cu, Pb, and Zn) on soil ecosystem using the nematode community structure (trophic and c-p groups,) and ecological indices (Richness of genera, H', MI2-5, etc.). Pollution effects on the community structure of soil free living nematodes was found to be the highest near the pollution source, with relatively low population density and domination of insensitive taxa. A decrease in heavy metals contents along the transect was linked with an increase in complexity of nematode community. The majority of used indices (MI2-5, SI, H') negatively correlated (P < 0.05 or P < 0.01) with heavy metals content and were sensitive to soil ecosystem disturbance. Contamination by heavy metals has negatively affected the soil environment, which resulted in nematode community structure and ecological indices changes. Results showed that the free-living nematodes are useful tools for bioindication of contamination and could be used as an alternative to the common approaches based on chemical methods. PMID- 22923373 TI - The Khan Academy: a great opportunity for cancer education. PMID- 22923371 TI - Dietary trans-fatty acid induced NASH is normalized following loss of trans-fatty acids from hepatic lipid pools. AB - Previous experiments in mice showed that dietary trans-fats could play a role in non-alcoholic steatohepatitis (NASH) yet little is known about the accumulation trans-fats in hepatic lipid pools in relationship to liver injury. NASH is also associated with obesity yet improves with only modest weight loss. To distinguish the role of obesity versus sustained consumption of a trans-fat containing diet in causing NASH, mice with obesity and NASH induced by consuming a high trans-fat diet for 16 weeks were subsequently fed standard chow or maintained on trans-fat chow for another 8 weeks. The accumulation, partitioning and loss of trans-fats in the major hepatic lipid pools during and after trans-fat consumption were determined. Obese mice switched to standard chow remained obese but steatohepatitis improved. trans-fats were differentially incorporated into the major hepatic lipid pools and the loss of trans-fats after crossover to control chow was greatest in the cholesteryl ester pool. In summary, dietary changes can improve the biochemical and histopathological changes of NASH despite persistent obesity in mice. Analysis of hepatic lipids confirmed that dietary trans-fats accumulate in the major lipid pools and are released differentially with diet normalization. The substantial loss of trans-fats from the cholesteryl ester pool in parallel with improvement in NASH suggests that this pool of trans-fats could play a role in the pathogenesis of NASH. PMID- 22923374 TI - The effect of fastball backspin rate on baseball hitting accuracy. AB - The effectiveness of fastballs of equivalent speed can differ; for example, one element of this difference could be due to the effect of rate and orientation of ball spin on launched ball trajectory. In the present experiment, baseball batters' accuracy in hitting fastballs with different backspin rates at a constant ball velocity of 36 m/s was examined. Thirteen skilled baseball players (professionals, semiprofessionals, and college varsity players) participated in the study. The movements of bat and ball were recorded using two synchronized high-speed video cameras. The Pearson product-moment correlation coefficient (r) was calculated and used to analyze the relationship between ball backspin rate and the vertical distance between ball center and sweet spot at the moment of ball-bat impact. Ball backspin rate was positively correlated with increases in the distance from the optimal contact point of the swung bat (sweet spot) to the actual point of contact (r = .38, P < .001). Batters were most effective at the usual backspin rate for the ball velocity used. The decrease in accuracy of the batter's swing that was observed when the fastball's backspin deviated from the usual rate likely occurred because experienced batters predict ball trajectory from perceived ball speed. PMID- 22923375 TI - Distribution of metals (Fe, Mn, Zn, Cu) in fish tissues in two lakes of different trophy in Northwestern Poland. AB - This study presents concentrations of iron, manganese, zinc, and copper in selected tissues of two fish species: pike (Esox lucius L.) and bream (Abramis brama L.) living in lakes Insko and Wisola, Northwestern Poland. The lakes differ in their trophic status. The effect of gender and environmental conditions on metals accumulation was also investigated. Metal analyses were performed using inductively coupled plasma atomic emission spectroscopy. Considering all studied fish species and tissues, the average metal concentrations (micrograms per gram wet weight) in both lakes occurred in the following ranges: Fe 0.8-240.6, Mn 0.2 8.4, Zn 3.0-185.9, and Cu 0.14-7.76. The lowest levels of the studied metals were always detected in the muscles. The spleen, kidneys, and liver were found to accumulate the highest amounts of Fe. In the case of the other metals, the highest levels were found, as follows: Mn in skin, gills, and gonads, Zn in digestive tract and gills, Cu in liver. Heavy metal content in fish gonads was observed to be sex dependent. PMID- 22923376 TI - Distribution coefficients (K(d)) of stable iodine in estuarine and coastal regions, Japan, and their relationship to salinity and organic carbon in sediments. AB - The sediment-water distribution coefficient, (K(d)), is one of the most important parameters in radionuclide assessment models. In this study, we determined K ds of stable iodine (I) in estuarine and coastal regions. We studied 16 estuarine and coastal regions of Japan and obtained I data on water and sediments. Data on salinity, pH, dissolved organic carbon and dissolved oxygen in water, and organic carbon (OC) in sediments were also obtained as estuarine variables. Determined (K(d))S of I in the Sagami River estuary decreased along the salinity gradient (salinity range, 0.1-33.8), indicating that salinity is one of the important factors controlling the (K(d)) values; however, when the (K(d)) values were compared among all the estuaries, the difference between minimum and maximum (K(d)) values varied by about two orders of magnitude in a narrow salinity range of 30.0-34.4. A significant correlation between (K(d)) value and OC content in sediments was observed in all the stations with a salinity of >= 30 except for stations in the Ishikari and Onga River estuaries. The exceptions are probably due to different sources of the sediments, which are explained by the results of relatively low I/OC ratios in sediments in those two estuaries, compared to the other estuaries. Thus, OC in sediments as well as salinity may be responsible for the variation of (K(d))S of I in the estuarine and coastal regions. PMID- 22923377 TI - Monitoring the drastic growth of ship breaking yards in Sitakunda: a threat to the coastal environment of Bangladesh. AB - The vast coastal and marine resources that occur along the southern edge of Bangladesh make it one of the most productive areas of the world. However, due to growing anthropogenic impacts, this area is under considerable environmental pressure from both physical and chemical stress factors. Ship breaking, or the dismantling and demolition of out-of-service ocean-going vessels, has become increasingly common in many coastal areas. To investigate the extent of ship breaking activities in Bangladesh along the Sitakunda coast, various spatial and non-spatial data were obtained, including remote sensing imagery, statistical records and published reports. Impacts to coastal and marine life were documented. Available data show that ship breaking activities cause significant physical disturbance and release toxic materials into the environment, resulting in adverse effects to numerous marine taxonomic groups such as fish, mammals, birds, reptiles, plants, phytoplankton, zooplankton and benthic invertebrates. Landsat imagery illustrates that the negatively impacted coastal area has grown 308.7 % from 367 ha in 1989 to 1,133 ha in 2010. Physicochemical and biological properties of coastal soil and water indicate substantially elevated pollution that poses a risk of local, regional and even global contamination through sea water and atmospheric transport. While damage to the coastal environment of Bangladesh is a recognized hazard that must be addressed, the economic benefits of ship breaking through job creation and fulfilling the domestic demand for recycled steel must be considered. Rather than an outright ban on beach breaking of ships, the enterprise must be recognized as a true and influential industry that should be held responsible for developing an economically viable and environmentally proactive growth strategy. Evolution of the industry toward a sustainable system can be aided through reasonable and enforceable legislative and judicial action that takes a balanced approach, but does not diminish the value of coastal conservation. PMID- 22923378 TI - Evolutionary analysis of heterochromatin protein compatibility by interspecies complementation in Saccharomyces. AB - The genetic bases for species-specific traits are widely sought, but reliable experimental methods with which to identify functionally divergent genes are lacking. In the Saccharomyces genus, interspecies complementation tests can be used to evaluate functional conservation and divergence of biological pathways or networks. Silent information regulator (SIR) proteins in S. bayanus provide an ideal test case for this approach because they show remarkable divergence in sequence and paralog number from those found in the closely related S. cerevisiae. We identified genes required for silencing in S. bayanus using a genetic screen for silencing-defective mutants. Complementation tests in interspecies hybrids identified an evolutionarily conserved Sir-protein-based silencing machinery, as defined by two interspecies complementation groups (SIR2 and SIR3). However, recessive mutations in S. bayanus SIR4 isolated from this screen could not be complemented by S. cerevisiae SIR4, revealing species specific functional divergence in the Sir4 protein despite conservation of the overall function of the Sir2/3/4 complex. A cladistic complementation series localized the occurrence of functional changes in SIR4 to the S. cerevisiae and S. paradoxus branches of the Saccharomyces phylogeny. Most of this functional divergence mapped to sequence changes in the Sir4 PAD. Finally, a hemizygosity modifier screen in the interspecies hybrids identified additional genes involved in S. bayanus silencing. Thus, interspecies complementation tests can be used to identify (1) mutations in genetically underexplored organisms, (2) loci that have functionally diverged between species, and (3) evolutionary events of functional consequence within a genus. PMID- 22923379 TI - Rapid profiling of disease alleles using a tunable reporter of protein misfolding. AB - Many human diseases are caused by genetic mutations that decrease protein stability. Such mutations may not specifically affect an active site, but can alter protein folding, abundance, or localization. Here we describe a high throughput cell-based stability assay, IDESA (intra-DHFR enzyme stability assay), where stability is coupled to cell proliferation in the model yeast, Saccharomyces cerevisiae. The assay requires no prior knowledge of a protein's structure or activity, allowing the assessment of stability of proteins that have unknown or difficult to characterize activities, and we demonstrate use with a range of disease-relevant targets, including human alanine:glyoxylate aminotransferase (AGT), superoxide dismutase (SOD-1), DJ-1, p53, and SMN1. The assay can be carried out on hundreds of disease alleles in parallel or used to identify stabilizing small molecules (pharmacological chaperones) for unstable alleles. As demonstration of the general utility of this assay, we analyze stability of disease alleles of AGT, deficiency of which results in the kidney stone disease, primary hyperoxaluria type I, identifying mutations that specifically affect the protein-active site chemistry. PMID- 22923380 TI - Restoration of topoisomerase 2 function by complementation of defective monomers in Drosophila. AB - Type II topoisomerases are essential ATP-dependent homodimeric enzymes required for transcription, replication, and chromosome segregation. These proteins alter DNA topology by generating transient enzyme-linked double-strand breaks for passage of one DNA strand through another. The central role of type II topoisomerases in DNA metabolism has made these enzymes targets for anticancer drugs. Here, we describe a genetic screen that generated novel alleles of Drosophila Topoisomerase 2 (Top2). Fifteen alleles were obtained, resulting from nonsense and missense mutations. Among these, 14 demonstrated recessive lethality, with one displaying temperature-sensitive lethality. Several newly generated missense alleles carry amino acid substitutions in conserved residues within the ATPase, Topoisomerase/Primase, and Winged helix domains, including four that encode proteins with alterations in residues associated with resistance to cancer chemotherapeutics. Animals lacking zygotic Top2 function can survive to pupation and display reduced cell division and altered polytene chromosome structure. Inter se crosses between six strains carrying Top2 missense alleles generated morphologically normal trans-heterozygous adults, which showed delayed development and were female sterile. Complementation occurred between alleles encoding Top2 proteins with amino acid substitutions in the same functional domain and between alleles encoding proteins with substitutions in different functional domains. Two complementing alleles encode proteins with amino acid substitutions associated with drug resistance. These observations suggest that dimerization of mutant Top2 monomers can restore enzymatic function. Our studies establish the first series of Top2 alleles in a multicellular organism. Future analyses of these alleles will enhance our knowledge about the contributions made by type II topoisomerases to development. PMID- 22923382 TI - Physician behaviors surrounding the implementation of decision and communication AIDS in a breast cancer clinic: a qualitative analysis of staff intern perceptions. AB - The aim of this paper is to examine how physician behavior facilitated or impeded our implementation of decision and communication aids in a breast cancer clinic. Staff interns provided decision and communication aids to patients and wrote up case notes for each patient they served. We used grounded theory to code our staff interns' case notes. We then identified barriers and facilitators to our program's implementation from each category we generated in the coding. Facilitators included physicians reading patient questions and then bringing the staff interns to the consultation. Barriers included physicians forgetting to bring the staff interns to the appointments and discouraging interns from speaking during the consultation. Physicians vary in their cooperation with our program. Our next steps will be to inquire directly with physicians about how to adapt our program design. We will also seek to position the staff interns as mentees to increase physician commitment to our program. PMID- 22923383 TI - "Balint group" meetings for oncology residents as a tool to improve therapeutic communication skills and reduce burnout level. AB - Medical training, particularly residency, may pose many challenges and may lead to burnout. Oncology training may be more stressful, given the prolonged exposure to death and dying. Balint group is an intervention method common in medical training, aimed at improving communication skills and strengthening doctor patient relationships. We arranged for our oncology residents, guided by a senior oncologist and a clinical psychologist, to meet monthly for a discussion of personal cases from the residents' experiences. At the beginning of the year, higher measures in two burnout parameters were found in junior residents compared to senior residents. At the end of the year, the gap in Maslach Burnout Inventory scores between junior and senior residents had decreased, while burnout level decreased slightly during the year in junior residents. It was felt that participation in a Balint group could improve communication abilities of residents and contribute to their feelings of self-accomplishment as doctors. PMID- 22923381 TI - The endosomal protein-sorting receptor sortilin has a role in trafficking alpha-1 antitrypsin. AB - Up to 1 in 3000 individuals in the United States have alpha-1 antitrypsin deficiency, and the most common cause of this disease is homozygosity for the antitrypsin-Z variant (ATZ). ATZ is inefficiently secreted, resulting in protein deficiency in the lungs and toxic polymer accumulation in the liver. However, only a subset of patients suffer from liver disease, suggesting that genetic factors predispose individuals to liver disease. To identify candidate factors, we developed a yeast ATZ expression system that recapitulates key features of the disease-causing protein. We then adapted this system to screen the yeast deletion mutant collection to identify conserved genes that affect ATZ secretion and thus may modify the risk for developing liver disease. The results of the screen and associated assays indicate that ATZ is degraded in the vacuole after being routed from the Golgi. In fact, one of the strongest hits from our screen was Vps10, which can serve as a receptor for the delivery of aberrant proteins to the vacuole. Because genome-wide association studies implicate the human Vps10 homolog, sortilin, in cardiovascular disease, and because hepatic cell lines that stably express wild-type or mutant sortilin were recently established, we examined whether ATZ levels and secretion are affected by sortilin. As hypothesized, sortilin function impacts the levels of secreted ATZ in mammalian cells. This study represents the first genome-wide screen for factors that modulate ATZ secretion and has led to the identification of a gene that may modify disease severity or presentation in individuals with ATZ-associated liver disease. PMID- 22923384 TI - Achilles tendon mechanical properties after both prolonged continuous running and prolonged intermittent shuttle running in cricket batting. AB - Effects of prolonged running on Achilles tendon properties were assessed after a 60 min treadmill run and 140 min intermittent shuttle running (simulated cricket batting innings). Before and after exercise, 11 participants performed ramp-up plantar flexions to maximum-voluntary-contraction before gradual relaxation. Muscle-tendon-junction displacement was measured with ultrasonography. Tendon force was estimated using dynamometry and a musculoskeletal model. Gradients of the ramp-up force-displacement curves fitted between 0-40% and 50-90% of the preexercise maximal force determined stiffness in the low- and high-force-range, respectively. Hysteresis was determined using the ramp-up and relaxation force displacement curves and elastic energy storage from the area under the ramp-up curve. In simulated batting, correlations between tendon properties and shuttle times were also assessed. After both protocols, Achilles tendon force decreased (4% to 5%, P < .050), but there were no changes in stiffness, hysteresis, or elastic energy. In simulated batting, Achilles tendon force and stiffness were both correlated to mean turn and mean sprint times (r = -0.719 to -0.830, P < .050). Neither protocol resulted in fatigue-related changes in tendon properties, but higher tendon stiffness and plantar flexion force were related to faster turn and sprint times, possibly by improving force transmission and control of movement when decelerating and accelerating. PMID- 22923386 TI - Posttraumatic stress disorder patients' experiences of hope. AB - In this qualitative study we examined the experience and perception of hope of 10 Israeli soldiers with chronic posttraumatic stress disorder (PTSD), with the goal of achieving an understanding of the manners in which hope intertwines with trauma. The results indicate that hope is an integrative, changing, multidimensional phenomenon which plays a unique role in the individual's life. Viewing hope as a crucial aspect of human life was further evident when participants referred to the traumatic event. Hope and trauma are interconnected phenomena. The form of hope a person possesses thus shapes the manner in which the traumatic event is perceived, whereas the trauma clearly reshapes the individual's form of hope. We discuss practical implications for treatment of chronic PTSD, based on the important role of hope at times of trauma, as well as on the interrelation between hope and trauma. PMID- 22923385 TI - Patient perceptions of the path to osteoporosis care following a fragility fracture. AB - Coordinator-based osteoporosis (OP) screening programs for fragility-fracture patients in orthopedic environments improve rates of OP testing and care, but there are still gaps in care. The purpose of this study was to understand the process by which patients decided whether to proceed with OP testing or care within these programs. Twenty-four fragility-fracture patients in the OP screening program at a large, urban, university hospital in Canada participated in one of five focus groups. Focus group transcripts were sorted and coded. Links between themes were developed to generate a description of the process leading to successful initiation of OP care after a fragility fracture. To initiate OP testing and care, patients had to both comprehend the link between their fragility fracture and OP, and make an action-oriented appraisal of what action to take. Several modifiable facilitators and barriers influenced the process between screening and undergoing OP testing and initiating treatment. PMID- 22923387 TI - Mexican immigrants' and Mexican Americans' perceptions of hypertension. AB - Although the rate of hypertension (HTN) is no higher for Mexican-origin clients than for non-Hispanic Whites, their rate of blood pressure (BP) control is lower. To effectively assist clients with their BP, health care providers must first understand barriers and facilitators to BP control from the clients' perspectives. The purpose of this study was to describe the experience of living with HTN for Mexican immigrants and Mexican Americans. A phenomenological method was appropriate to describe their lived experience. We conducted one-time interviews with 26 adults who self-identified as Mexican-origin. Some participants did not know what caused HTN and others believed in causes they could control. Many believed HTN was of short duration. Some participants forgot to take medication or were not able to afford it. Mexican-origin clients need more assistance with BP control, and need it in both English and Spanish. PMID- 22923388 TI - Patient centered, nurse averse? Nurses' care experiences in a 21st-century hospital. AB - Implementations of patient centeredness can vary tremendously across settings, yet we know little about how clinicians experience local interpretations of patient centeredness. In this article, we investigate nurses' experiences in a hospital designed to be patient centered in its emphasis on patient amenities and customer service. This environment altered nurses' articulation work by shifting the visibility of a number of nursing tasks; customer service tasks became more visible whereas many medical and caring tasks were obscured. We found that these changes in nursing work challenged nurses' professional roles, and the informants reported that the changes disrupted their relationships with patients and with one another. This implementation of patient centeredness resulted in a view of nursing that conflicted with many nurses' implicit and explicit understanding of their work. Our findings suggest that the adoption of some versions of patient centeredness might obscure substantial and substantive nursing work and might undermine nurses' concepts of caregiving. PMID- 22923389 TI - CIP2A is overexpressed in human ovarian cancer and regulates cell proliferation and apoptosis. AB - CIP2A is a recently characterized oncoprotein which involves in the progression of several human malignancies. This study aimed to investigate its clinical significance and biological function in ovarian cancer. CIP2A expression was analyzed in 152 archived ovarian cancer specimens using immunohistochemistry. One hundred cases (65.79 %) showed CIP2A overexpression, including 63 of 92 serous carcinomas (68.48 %), 21 of 33 endometrioid carcinomas (63.64 %), 12 of 23 mucinous carcinomas (52.17 %), and 4 of 4 clear cell carcinomas (100 %). There is no significant difference of CIP2A expression between serous tumors and all other morphologies combined. CIP2A overexpression positively correlated with advanced FIGO stage (p = 0.0336) and tumor grade (p = 0.0213). siRNA knockdown was performed in A2780 and SKOV3 cell lines. MTT, colony formation assay, and flow cytometry were carried out to assess the role of CIP2A in proliferation, cell cycle, and apoptosis. CIP2A depletion in ovarian cancer cell lines inhibited proliferation, blocked cell cycle progression, and increased paclitaxel-induced apoptosis. Furthermore, CIP2A depletion downregulated cyclin D1, c-myc, phospho Rb, Bcl-2, and phospho-AKT expression. These results validate the role of CIP2A as a clinically relevant oncoprotein and establish CIP2A as a promising therapeutic target of ovarian cancer. PMID- 22923390 TI - Gait mechanics are different between healthy controls and patients with multiple sclerosis. AB - Multiple sclerosis (MS) causes severe gait problems in relatively young individuals, yet there have been limited studies to quantitatively identify the specific gait parameters that are affected. The purpose of this study was to define any differences in biomechanical gait parameters between patients with MS and healthy controls. A total of 31 MS patients and 31 healthy controls were evaluated: joint torques and joint powers were calculated at the ankle, knee, and hip during the stance phase of gait. The self-selected walking velocity was used as a covariate in the analysis to ensure that group differences were not due to differences in walking velocity between the MS and healthy control groups. Reduced angular range, less joint torque, and reduced joint power were seen in patients with MS. We also found significant correlations between biomechanical gait parameters and EDSS score, which provides a clinical rating of disease severity. Our findings provide a quantitative assessment of the gait mechanics employed in patients with MS. The altered lower extremity mechanics observed in patients with MS reflect both a neurological and strength deficit compared with healthy controls during walking. PMID- 22923391 TI - Next-generation sequencing of microbial communities in the Athabasca River and its tributaries in relation to oil sands mining activities. AB - The Athabasca oil sands deposit is the largest reservoir of crude bitumen in the world. Recently, the soaring demand for oil and the availability of modern bitumen extraction technology have heightened exploitation of this reservoir and the potential unintended consequences of pollution in the Athabasca River. The main objective of the present study was to evaluate the potential impacts of oil sands mining on neighboring aquatic microbial community structure. Microbial communities were sampled from sediments in the Athabasca River and its tributaries as well as in oil sands tailings ponds. Bacterial and archaeal 16S rRNA genes were amplified and sequenced using next-generation sequencing technology (454 and Ion Torrent). Sediments were also analyzed for a variety of chemical and physical characteristics. Microbial communities in the fine tailings of the tailings ponds were strikingly distinct from those in the Athabasca River and tributary sediments. Microbial communities in sediments taken close to tailings ponds were more similar to those in the fine tailings of the tailings ponds than to the ones from sediments further away. Additionally, bacterial diversity was significantly lower in tailings pond sediments. Several taxonomic groups of Bacteria and Archaea showed significant correlations with the concentrations of different contaminants, highlighting their potential as bioindicators. We also extensively validated Ion Torrent sequencing in the context of environmental studies by comparing Ion Torrent and 454 data sets and by analyzing control samples. PMID- 22923393 TI - Unveiling the expression characteristics of IspC, a cell wall-associated peptidoglycan hydrolase in Listeria monocytogenes, during growth under stress conditions. AB - Listeria monocytogenes serotype 4b is a food-borne pathogen of public health concern, since it accounts for approximately 40% of human listeriosis cases. We have recently identified IspC, a surface-localized peptidoglycan hydrolase, as the antigen recognized by a number of monoclonal antibodies (MAbs) produced against a serotype 4b strain for diagnostic applications. To determine whether IspC, which is well conserved among various serotype 4b strains, is a useful diagnostic marker in antibody-based methods, we assessed the expression of IspC in L. monocytogenes cultured under normal and stress conditions. A functional promoter directing the transcription of the ispC gene was identified upstream of the ispC open reading frame by constructing a promoterless lacZ gene fusion with the putative ispC promoter region and by 5' rapid amplification of cDNA ends analysis. Using both the lacZ reporter gene system and immunofluorescent staining with an IspC-specific MAb, we provide evidence that IspC is expressed on the cell surface in all growth conditions tested (temperature, osmotic stress, pH, ethanol, oxidative stress, anaerobic conditions, carbon source, and type of growth media) that allow for cellular division, although the level of ispC gene expression varies. These results demonstrated the usefulness of IspC as an excellent diagnostic marker for the serotype 4b strains and imply that IspC, in conjunction with specific MAbs, can be targeted for detection and isolation of L. monocytogenes serotype 4b strains directly from food, environmental, and clinical samples with minimal or no need for culture enrichment. PMID- 22923394 TI - Prevalence and population structure of Vibrio vulnificus on fishes from the northern Gulf of Mexico. AB - The prevalence of Vibrio vulnificus on the external surfaces of fish from the northern Gulf of Mexico was determined in this study. A collection of 242 fish comprising 28 species was analyzed during the course of 12 sampling trips over a 16-month period. The prevalence of V. vulnificus was 37% but increased up to 69% in summer. A positive correlation was found between the percentages of V. vulnificus-positive fish and water temperatures, while salinity and V. vulnificus positive fish prevalence were inversely correlated. A general lineal model (percent V. vulnificus-positive fish = 0.5930 - 0.02818 * salinity + 0.01406 * water temperature) was applied to best fit the data. Analysis of the population structure was carried out using 244 isolates recovered from fish. Ascription to 16S rRNA gene types indicated that 157 isolates were type A (62%), 72 (29%) were type B, and 22 (9%) were type AB. The percentage of type B isolates, considered to have greater virulence potential, was higher than that previously reported in oyster samples from the northern Gulf of Mexico. Amplified fragment length polymorphism (AFLP) was used to resolve the genetic diversity within the species. One hundred twenty-one unique AFLP profiles were found among all analyzed isolates, resulting in a calculated Simpson's index of diversity of 0.991. AFLP profiles were not grouped on the basis of collection date, fish species, temperature, or salinity, but isolates were clustered into two main groups that correlated precisely with 16S rRNA gene type. The population of V. vulnificus associated with fishes from the northern Gulf of Mexico is heterogeneous and includes strains of great virulence potential. PMID- 22923395 TI - Degradation of the twin-arginine translocation substrate YwbN by extracytoplasmic proteases of Bacillus subtilis. AB - Bacterial twin-arginine translocases can export fully folded proteins from the cytoplasm. Such proteins are usually resistant to proteolysis. Here we show that multiple extracellular proteases degrade the B. subtilis Tat substrate YwbN. This suggests either that secreted YwbN is not fully folded or that folded YwbN exposes protease cleavage sites. PMID- 22923396 TI - Genomic and transcriptomic studies of an RDX (hexahydro-1,3,5-trinitro-1,3,5 triazine)-degrading actinobacterium. AB - Whole-genome sequencing, transcriptomic analyses, and metabolic reconstruction were used to investigate Gordonia sp. strain KTR9's ability to catabolize a range of compounds, including explosives and steroids. Aspects of this mycolic acid containing actinobacterium's catabolic potential were experimentally verified and compared with those of rhodococci and mycobacteria. PMID- 22923392 TI - Changes in the gut microbiome of the sea lamprey during metamorphosis. AB - Vertebrate metamorphosis is often marked by dramatic morphological and physiological changes of the alimentary tract, along with major shifts in diet following development from larva to adult. Little is known about how these developmental changes impact the gut microbiome of the host organism. The metamorphosis of the sea lamprey (Petromyzon marinus) from a sedentary filter feeding larva to a free-swimming sanguivorous parasite is characterized by major physiological and morphological changes to all organ systems. The transformation of the alimentary canal includes closure of the larval esophagus and the physical isolation of the pharynx from the remainder of the gut, which results in a nonfeeding period that can last up to 8 months. To determine how the gut microbiome is affected by metamorphosis, the microbial communities of feeding and nonfeeding larval and parasitic sea lamprey were surveyed using both culture dependent and -independent methods. Our results show that the gut of the filter feeding larva contains a greater diversity of bacteria than that of the blood feeding parasite, with the parasite gut being dominated by Aeromonas and, to a lesser extent, Citrobacter and Shewanella. Phylogenetic analysis of the culturable Aeromonas from both the larval and parasitic gut revealed that at least five distinct species were represented. Phenotypic characterization of these isolates revealed that over half were capable of sheep red blood cell hemolysis, but all were capable of trout red blood cell hemolysis. This suggests that the enrichment of Aeromonas that accompanies metamorphosis is likely related to the sanguivorous lifestyle of the parasitic sea lamprey. PMID- 22923397 TI - Bioaugmentation of syntrophic acetate-oxidizing culture in biogas reactors exposed to increasing levels of ammonia. AB - The importance of syntrophic acetate oxidation for process stability in methanogenic systems operating at high ammonia concentrations has previously been emphasized. In this study we investigated bioaugmentation of syntrophic acetate oxidizing (SAO) cultures as a possible method for decreasing the adaptation period of biogas reactors operating at gradually increased ammonia concentrations (1.5 to 11 g NH(4)(+)-N/liter). Whole stillage and cattle manure were codigested semicontinuously for about 460 days in four mesophilic anaerobic laboratory-scale reactors, and a fixed volume of SAO culture was added daily to two of the reactors. Reactor performance was evaluated in terms of biogas productivity, methane content, pH, alkalinity, and volatile fatty acid (VFA) content. The decomposition pathway of acetate was analyzed by isotopic tracer experiments, and population dynamics were monitored by quantitative PCR analyses. A shift in dominance from aceticlastic methanogenesis to SAO occurred simultaneously in all reactors, indicating no influence by bioaugmentation on the prevailing pathway. Higher abundances of Clostridium ultunense and Tepidanaerobacter acetatoxydans were associated with bioaugmentation, but no influence on Syntrophaceticus schinkii or the methanogenic population was distinguished. Overloading or accumulation of VFA did not cause notable dynamic effects on the population. Instead, the ammonia concentration had a substantial impact on the abundance level of the microorganisms surveyed. The addition of SAO culture did not affect process performance or stability against ammonia inhibition, and all four reactors deteriorated at high ammonia concentrations. Consequently, these findings further demonstrate the strong influence of ammonia on the methane producing consortia and on the representative methanization pathway in mesophilic biogas reactors. PMID- 22923398 TI - Genetic linkage of soil carbon pools and microbial functions in subtropical freshwater wetlands in response to experimental warming. AB - Rising climate temperatures in the future are predicted to accelerate the microbial decomposition of soil organic matter. A field microcosm experiment was carried out to examine the impact of soil warming in freshwater wetlands on different organic carbon (C) pools and associated microbial functional responses. GeoChip 4.0, a functional gene microarray, was used to determine microbial gene diversity and functional potential for C degradation. Experimental warming significantly increased soil pore water dissolved organic C and phosphorus (P) concentrations, leading to a higher potential for C emission and P export. Such losses of total organic C stored in soil could be traced back to the decomposition of recalcitrant organic C. Warming preferentially stimulated genes for degrading recalcitrant C over labile C. This was especially true for genes encoding cellobiase and mnp for cellulose and lignin degradation, respectively. We confirmed this with warming-enhanced polyphenol oxidase and peroxidase activities for recalcitrant C acquisition and greater increases in recalcitrant C use efficiency than in labile C use efficiency (average percentage increases of 48% versus 28%, respectively). The relative abundance of lignin-degrading genes increased by 15% under warming; meanwhile, soil fungi, as the primary decomposers of lignin, were greater in abundance by 27%. This work suggests that future warming may enhance the potential for accelerated fungal decomposition of lignin like compounds, leading to greater microbially mediated C losses than previously estimated in freshwater wetlands. PMID- 22923399 TI - Interspecies electron transfer via hydrogen and formate rather than direct electrical connections in cocultures of Pelobacter carbinolicus and Geobacter sulfurreducens. AB - Direct interspecies electron transfer (DIET) is an alternative to interspecies H(2)/formate transfer as a mechanism for microbial species to cooperatively exchange electrons during syntrophic metabolism. To understand what specific properties contribute to DIET, studies were conducted with Pelobacter carbinolicus, a close relative of Geobacter metallireducens, which is capable of DIET. P. carbinolicus grew in coculture with Geobacter sulfurreducens with ethanol as the electron donor and fumarate as the electron acceptor, conditions under which G. sulfurreducens formed direct electrical connections with G. metallireducens. In contrast to the cell aggregation associated with DIET, P. carbinolicus and G. sulfurreducens did not aggregate. Attempts to initiate cocultures with a genetically modified strain of G. sulfurreducens incapable of both H(2) and formate utilization were unsuccessful, whereas cocultures readily grew with mutant strains capable of formate but not H(2) uptake or vice versa. The hydrogenase mutant of G. sulfurreducens compensated, in cocultures, with significantly increased formate dehydrogenase gene expression. In contrast, the transcript abundance of a hydrogenase gene was comparable in cocultures with that for the formate dehydrogenase mutant of G. sulfurreducens or the wild type, suggesting that H(2) was the primary electron carrier in the wild-type cocultures. Cocultures were also initiated with strains of G. sulfurreducens that could not produce pili or OmcS, two essential components for DIET. The finding that P. carbinolicus exchanged electrons with G. sulfurreducens via interspecies transfer of H(2)/formate rather than DIET demonstrates that not all microorganisms that can grow syntrophically are capable of DIET and that closely related microorganisms may use significantly different strategies for interspecies electron exchange. PMID- 22923401 TI - Enzymatic glycosylation of nonbenzoquinone geldanamycin analogs via Bacillus UDP glycosyltransferase. AB - Geldanamycin (GM) is a naturally occurring anticancer agent isolated from several strains of Streptomyces hygroscopicus. However, its potential clinical utility is compromised by its severe toxicity and poor water solubility. For this reason, considerable efforts are under way to make new derivatives that have both good clinical efficacy and high water solubility. On the other hand, glycosylation is often a step that improves the water solubility and/or biological activity in many natural products of biosynthesis. Here, we report the facile production of glucose-conjugated nonbenzoquinone GM analogs using the Bacillus UDP glycosyltransferase BL-C. Five aglycon substrates containing nonbenzoquinone aromatic rings were chosen to validate the in vitro glycosylation reaction. Putative glucoside compounds were determined through the presence of a product peak(s) and were also verified using LC/MS analyses. Further, the chemical structures of new glucoside compounds 6 and 7 were elucidated using spectroscopy data. These glucoside compounds showed a dramatic improvement in water solubility compared with that of the original aglycon, nonbenzoquinone GM. PMID- 22923400 TI - Diversity, physiology, and niche differentiation of ammonia-oxidizing archaea. AB - Nitrification, the aerobic oxidation of ammonia to nitrate via nitrite, has been suggested to have been a central part of the global biogeochemical nitrogen cycle since the oxygenation of Earth. The cultivation of several ammonia-oxidizing archaea (AOA) as well as the discovery that archaeal ammonia monooxygenase (amo) like gene sequences are nearly ubiquitously distributed in the environment and outnumber their bacterial counterparts in many habitats fundamentally revised our understanding of nitrification. Surprising insights into the physiological distinctiveness of AOA are mirrored by the recognition of the phylogenetic uniqueness of these microbes, which fall within a novel archaeal phylum now known as Thaumarchaeota. The relative importance of AOA in nitrification, compared to ammonia-oxidizing bacteria (AOB), is still under debate. This minireview provides a synopsis of our current knowledge of the diversity and physiology of AOA, the factors controlling their ecology, and their role in carbon cycling as well as their potential involvement in the production of the greenhouse gas nitrous oxide. It emphasizes the importance of activity-based analyses in AOA studies and formulates priorities for future research. PMID- 22923402 TI - Evidence of in vivo prophage induction during Clostridium difficile infection. AB - Prophages contribute to the evolution and virulence of most bacterial pathogens, but their role in Clostridium difficile is unclear. Here we describe the isolation of four Myoviridae phages, PhiMMP01, PhiMMP02, PhiMMP03, and PhiMMP04, that were recovered as free viral particles in the filter-sterilized stool supernatants of patients suffering from C. difficile infection (CDI). Furthermore, identical prophages were found in the chromosomes of C. difficile isolated from the corresponding fecal samples. We therefore provide, for the first time, evidence of in vivo prophage induction during CDI. We completely sequenced the genomes of PhiMMP02 and PhiMMP04, and bioinformatics analyses did not reveal the presence of virulence factors but underlined the unique character of PhiMMP04. We also studied the mobility of PhiMMP02 and PhiMMP04 prophages in vitro. Both prophages were spontaneously induced, with 4 to 5 log PFU/ml detected in the culture supernatants of the corresponding lysogens. When lysogens were grown in the presence of subinhibitory concentrations of ciprofloxacin, moxifloxacin, levofloxacin, or mitomycin C, the phage titers further increased, reaching 8 to 9 log PFU/ml in the case of PhiMMP04. In summary, our study highlights the extensive genetic diversity and mobility of C. difficile prophages. Moreover, antibiotics known to represent risk factors for CDI, such as quinolones, can stimulate prophage mobility in vitro and probably in vivo as well, which underscores their potential impact on phage-mediated horizontal gene transfer events and the evolution of C. difficile. PMID- 22923403 TI - Identification of Cj1051c as a major determinant for the restriction barrier of Campylobacter jejuni strain NCTC11168. AB - Campylobacter jejuni is a leading cause of human diarrheal illness in the world, and research on it has benefitted greatly by the completion of several genome sequences and the development of molecular biology tools. However, many hurdles remain for a full understanding of this unique bacterial pathogen. One of the most commonly used strains for genetic work with C. jejuni is NCTC11168. While this strain is readily transformable with DNA for genomic recombination, transformation with plasmids is problematic. In this study, we have identified a determinant of this to be cj1051c, predicted to encode a restriction-modification type IIG enzyme. Knockout mutagenesis of this gene resulted in a strain with a 1,000-fold-enhanced transformation efficiency with a plasmid purified from a C. jejuni host. Additionally, this mutation conferred the ability to be transformed by plasmids isolated from an Escherichia coli host. Sequence analysis suggested a high level of variability of the specificity domain between strains and that this gene may be subject to phase variation. We provide evidence that cj1051c is active in NCTC11168 and behaves as expected for a type IIG enzyme. The identification of this determinant provides a greater understanding of the molecular biology of C. jejuni as well as a tool for plasmid work with strain NCTC11168. PMID- 22923404 TI - Contribution of spores to the ability of Clostridium difficile to adhere to surfaces. AB - Clostridium difficile is the commonest cause of hospital-acquired infection in the United Kingdom. We characterized the abilities of 21 clinical isolates to form spores; to adhere to inorganic and organic surfaces, including stainless steel and human adenocarcinoma cells; and to germinate. The composition of culture media had a significant effect on spore formation, as significantly more spores were produced in brain heart infusion broth (Student's t test; P = 0.018). The spore surface relative hydrophobicity (RH) varied markedly (14 to 77%) and was correlated with the ability to adhere to stainless steel. We observed no correlation between the ribotype and the ability to adhere to steel. When the binding of hydrophobic (DS1813; ribotype 027; RH, 77%) and hydrophilic (DS1748; ribotype 002; RH, 14%) spores to human gut epithelial cells at different stages of cell development was examined, DS1813 spores adhered more strongly, suggesting the presence of surface properties that aid attachment to human cells. Electron microscopy studies revealed the presence of an exosporium surrounding DS1813 spores that was absent from spores of DS1748. Finally, the ability of spores to germinate was found to be strain and medium dependent. While the significance of these findings to the disease process has yet to be determined, this study has highlighted the importance of analyzing multiple isolates when attempting to characterize the behavior of a bacterial species. PMID- 22923405 TI - Escherichia coli Nissle 1917 targets and restrains mouse B16 melanoma and 4T1 breast tumors through expression of azurin protein. AB - Many studies have demonstrated that intravenously administered bacteria can target and proliferate in solid tumors and then quickly be released from other organs. Here, we employed the tumor-targeting property of Escherichia coli Nissle 1917 to inhibit mouse B16 melanoma and 4T1 breast tumors through the expression of azurin protein. For this purpose, recombinant azurin-expressing E. coli Nissle 1917 was developed. The levels of in vitro and in vivo azurin secretion in the engineered bacterium were determined by immunochemistry. Our results demonstrated that B16 melanoma and orthotopic 4T1 breast tumor growth were remarkably restrained and pulmonary metastasis was prevented in immunocompetent mice. It is worth noting that this therapeutic effect partially resulted from the antitumor activity of neutrophils and lymphocytes due to inflammatory responses caused by bacterial infections. No toxicity was observed in the animal during the experiments. This study indicates that E. coli Nissle 1917 could be a potential carrier to deliver antitumor drugs effectively for cancer therapy. PMID- 22923406 TI - RcsB contributes to the distinct stress fitness among Escherichia coli O157:H7 curli variants of the 1993 hamburger-associated outbreak strains. AB - Curli are adhesive fimbriae of Enterobactericaeae and are involved in surface attachment, cell aggregation, and biofilm formation. We reported previously that curli-producing (C(+)) variants of E. coli O157:H7 (EcO157) were much more acid sensitive than their corresponding curli-deficient (C(-)) variants; however, this difference was not linked to the curli fimbriae per se. Here, we investigated the underlying molecular basis of this phenotypic divergence. We identified large deletions in the rcsB gene of C(+) variants isolated from the 1993 U.S. hamburger associated outbreak strains. rcsB encodes the response regulator of the RcsCDB two-component signal transduction system, which regulates curli biogenesis negatively but acid resistance positively. Further comparison of stress fitness revealed that C(+) variants were also significantly more sensitive to heat shock but were resistant to osmotic stress and oxidative damage, similar to C(-) variants. Transcriptomics analysis uncovered a large number of differentially expressed genes between the curli variants, characterized by enhanced expression in C(+) variants of genes related to biofilm formation, virulence, catabolic activity, and nutrient uptake but marked decreases in transcription of genes related to various types of stress resistance. Supplying C(+) variants with a functional rcsB restored resistance to heat shock and acid challenge in cells but blocked curli production, confirming that inactivation of RcsB in C(+) variants was the basis of fitness segregation within the EcO157 population. This study provides an example of how genome instability of EcO157 promotes intrapopulation diversification, generating subpopulations carrying an array of distinct phenotypes that may confer the pathogen with survival advantages in diverse environments. PMID- 22923407 TI - High-salinity growth conditions promote Tat-independent secretion of Tat substrates in Bacillus subtilis. AB - The Gram-positive bacterium Bacillus subtilis contains two Tat translocases, which can facilitate transport of folded proteins across the plasma membrane. Previous research has shown that Tat-dependent protein secretion in B. subtilis is a highly selective process and that heterologous proteins, such as the green fluorescent protein (GFP), are poor Tat substrates in this organism. Nevertheless, when expressed in Escherichia coli, both B. subtilis Tat translocases facilitated exclusively Tat-dependent export of folded GFP when the twin-arginine (RR) signal peptides of the E. coli AmiA, DmsA, or MdoD proteins were attached. Therefore, the present studies were aimed at determining whether the same RR signal peptide-GFP precursors would also be exported Tat dependently in B. subtilis. In addition, we investigated the secretion of GFP fused to the full-length YwbN protein, a strict Tat substrate in B. subtilis. Several investigated GFP fusion proteins were indeed secreted in B. subtilis, but this secretion was shown to be completely Tat independent. At high-salinity growth conditions, the Tat-independent secretion of GFP as directed by the RR signal peptides from the E. coli AmiA, DmsA, or MdoD proteins was significantly enhanced, and this effect was strongest in strains lacking the TatAy-TatCy translocase. This implies that high environmental salinity has a negative influence on the avoidance of Tat-independent secretion of AmiA-GFP, DmsA-GFP, and MdoD-GFP. We conclude that as-yet-unidentified control mechanisms reject the investigated GFP fusion proteins for translocation by the B. subtilis Tat machinery and, at the same time, set limits to their Tat-independent secretion, presumably via the Sec pathway. PMID- 22923408 TI - Molecular characterization of fluoroquinolone-resistant Aeromonas spp. isolated from imported shrimp. AB - Sixty-three nalidixic acid-resistant Aeromonas sp. isolates were obtained from imported shrimp. Phylogenetic analysis of gyrB sequences indicated that 18 were A. enteropelogenes, 26 were A. caviae, and 19 were A. sobria. Double missense mutations in the quinolone resistance-determining region (QRDR) of gyrA at codon 83 (Ser->Val/Ile) and codon 92 (Leu->Met) coupled with a point mutation of parC at codon 80 (Ser->Ile/Phe) conferred high levels of quinolone resistance in the isolates. A majority of A. enteropelogenes and A. caviae strains harbored toxin genes, whereas only a few A. sobria strains harbored these genes. The fluoroquinolone-resistant Aeromonas spp. exhibited higher cytotoxicity than fluoroquinolone-sensitive, virulent Aeromonas spp. to rat epithelial cells. PMID- 22923409 TI - Survival and germination of Bacillus cereus spores without outgrowth or enterotoxin production during in vitro simulation of gastrointestinal transit. AB - To study the gastrointestinal survival and enterotoxin production of the food borne pathogen Bacillus cereus, an in vitro simulation experiment was developed to mimic gastrointestinal passage in 5 phases: (i) the mouth, (ii) the stomach, with gradual pH decrease and fractional emptying, (iii) the duodenum, with high concentrations of bile and digestive enzymes, (iv) dialysis to ensure bile reabsorption, and (v) the ileum, with competing human intestinal bacteria. Four different B. cereus strains were cultivated and sporulated in mashed potato medium to obtain an inoculum of 7.0 log spores/ml. The spores showed survival and germination during the in vitro simulation of gastrointestinal passage, but vegetative outgrowth of the spores was suppressed by the intestinal bacteria during the final ileum phase. No bacterial proliferation or enterotoxin production was observed, despite the high inoculum levels. Little strain variability was observed: except for the psychrotrophic food isolate, the spores of all strains survived well throughout the gastrointestinal passage. The in vitro simulation experiments investigated the survival and enterotoxin production of B. cereus in the gastrointestinal lumen. The results obtained support the hypothesis that localized interaction of B. cereus with the host's epithelium is required for diarrheal food poisoning. PMID- 22923410 TI - Detection of botulinum neurotoxin serotype A, B, and F proteolytic activity in complex matrices with picomolar to femtomolar sensitivity. AB - Rapid, high-throughput assays that detect and quantify botulinum neurotoxin (BoNT) activity in diverse matrices are required for environmental, clinical, pharmaceutical, and food testing. The current standard, the mouse bioassay, is sensitive but is low in throughput and precision. In this study, we present three biochemical assays for the detection and quantification of BoNT serotype A, B, and F proteolytic activities in complex matrices that offer picomolar to femtomolar sensitivity with small assay volumes and total assay times of less than 24 h. These assays consist of magnetic beads conjugated with BoNT serotype specific antibodies that are used to purify BoNT from complex matrices before the quantification of bound BoNT proteolytic activity using the previously described BoTest reporter substrates. The matrices tested include human serum, whole milk, carrot juice, and baby food, as well as buffers containing common pharmaceutical excipients. The limits of detection were below 1 pM for BoNT/A and BoNT/F and below 10 pM for BoNT/B in most tested matrices using 200-MUl samples and as low as 10 fM for BoNT/A with an increased sample volume. Together, these data describe rapid, robust, and high-throughput assays for BoNT detection that are compatible with a wide range of matrices. PMID- 22923411 TI - Functional analysis of family GH36 alpha-galactosidases from Ruminococcus gnavus E1: insights into the metabolism of a plant oligosaccharide by a human gut symbiont. AB - Ruminococcus gnavus belongs to the 57 most common species present in 90% of individuals. Previously, we identified an alpha-galactosidase (Aga1) belonging to glycoside hydrolase (GH) family 36 from R. gnavus E1 (M. Aguilera, H. Rakotoarivonina, A. Brutus, T. Giardina, G. Simon, and M. Fons, Res. Microbiol. 163:14-21, 2012). Here, we identified a novel GH36-encoding gene from the same strain and termed it aga2. Although aga1 showed a very simple genetic organization, aga2 is part of an operon of unique structure, including genes putatively encoding a regulator, a GH13, two phosphotransferase system (PTS) sequences, and a GH32, probably involved in extracellular and intracellular sucrose assimilation. The 727-amino-acid (aa) deduced Aga2 protein shares approximately 45% identity with Aga1. Both Aga1 and Aga2 expressed in Escherichia coli showed strict specificity for alpha-linked galactose. Both enzymes were active on natural substrates such as melibiose, raffinose, and stachyose. Aga1 and Aga2 occurred as homotetramers in solution, as shown by analytical ultracentrifugation. Modeling of Aga1 and Aga2 identified key amino acids which may be involved in substrate specificity and stabilization of the alpha-linked galactoside substrates within the active site. Furthermore, Aga1 and Aga2 were both able to perform transglycosylation reactions with alpha-(1,6) regioselectivity, leading to the formation of product structures up to [Hex](12) and [Hex](8), respectively. We suggest that Aga1 and Aga2 play essential roles in the metabolism of dietary oligosaccharides and could be used for the design of galacto-oligosaccharide (GOS) prebiotics, known to selectively modulate the beneficial gut microbiota. PMID- 22923412 TI - Versatility in corrinoid salvaging and remodeling pathways supports corrinoid dependent metabolism in Dehalococcoides mccartyi. AB - Corrinoids are cobalt-containing molecules that function as enzyme cofactors in a wide variety of organisms but are produced solely by a subset of prokaryotes. Specific corrinoids are identified by the structure of their axial ligands. The lower axial ligand of a corrinoid can be a benzimidazole, purine, or phenolic compound. Though it is known that many organisms obtain corrinoids from the environment, the variety of corrinoids that can serve as cofactors for any one organism is largely unstudied. Here, we examine the range of corrinoids that function as cofactors for corrinoid-dependent metabolism in Dehalococcoides mccartyi strain 195. Dehalococcoides bacteria play an important role in the bioremediation of chlorinated solvents in the environment because of their unique ability to convert the common groundwater contaminants perchloroethene and trichloroethene to the innocuous end product ethene. All isolated D. mccartyi strains require exogenous corrinoids such as vitamin B(12) for growth. However, like many other corrinoid-dependent bacteria, none of the well-characterized D. mccartyi strains has been shown to be capable of synthesizing corrinoids de novo. In this study, we investigate the ability of D. mccartyi strain 195 to use specific corrinoids, as well as its ability to modify imported corrinoids to a functional form. We show that strain 195 can use only specific corrinoids containing benzimidazole lower ligands but is capable of remodeling other corrinoids by lower ligand replacement when provided a functional benzimidazole base. This study of corrinoid utilization and modification by D. mccartyi provides insight into the array of strategies that microorganisms employ in acquiring essential nutrients from the environment. PMID- 22923413 TI - Peptide-guided surface-enhanced Raman scattering probes for localized cell composition analysis. AB - The ability to control the localization of surface-enhanced Raman scattering (SERS) nanoparticle probes in bacterial cells is critical to the development of analytical techniques that can nondestructively determine cell composition and phenotype. Here, selective localization of SERS probes was achieved at the outer bacterial membrane by using silver nanoparticles functionalized with synthetic hydrophobic peptides. PMID- 22923414 TI - Iterative combinatorial mutagenesis as an effective strategy for generation of deacetoxycephalosporin C synthase with improved activity toward penicillin G. AB - An iterative combinatorial mutagenesis (ICM) strategy was used to engineer deacetoxycephalosporin C synthase of Streptomyces clavuligerus (scDAOCS) for improved activity toward penicillin G. Seven mutational sites were repeatedly combined onto a starter mutant (C155Y Y184H V275I C281Y) of scDAOCS. Eleven improved combinatorial mutants were identified from 24 mutants in four rounds of ICM. PMID- 22923416 TI - A biomechanical study of side steps at different distances. AB - Lateral quickness is a crucial component of many sports. However, biomechanical factors that contribute to quickness in lateral movements have not been understood well. Thus, the purpose of this study was to quantify 3-dimensional kinetics of hip, knee, and ankle joints in side steps to understand the function of lower extremity muscle groups. Side steps at nine different distances were performed by nine male subjects. Kinematic and ground reaction force data were recorded, and net joint torque and work were calculated by a standard inverse- dynamics method. Extension torques and work done at hip, knee, and ankle joints contributed substantially to the changes in side step distances. On the other hand, hip abduction work was not as sensitive to the changes in the side step distances. The main roles of hip abduction torque and work were to accelerate the center of mass laterally in the earlier phase of the movement and to keep the trunk upright, but not to generate large power for propulsion. PMID- 22923415 TI - Heat resistance and salt hypersensitivity in Lactococcus lactis due to spontaneous mutation of llmg_1816 (gdpP) induced by high-temperature growth. AB - During construction of several gene deletion mutants in Lactococcus lactis MG1363 which involved a high-temperature (37.5 degrees C) incubation step, additional spontaneous mutations were observed which resulted in stable heat resistance and in some cases salt-hypersensitive phenotypes. Whole-genome sequencing of one strain which was both heat resistant and salt hypersensitive, followed by PCR and sequencing of four other mutants which shared these phenotypes, revealed independent mutations in llmg_1816 in all cases. This gene encodes a membrane bound stress signaling protein of the GdpP family, members of which exhibit cyclic dimeric AMP (c-di-AMP)-specific phosphodiesterase activity. Mutations were predicted to lead to single amino acid substitutions or protein truncations. An independent llmg_1816 mutant (Delta1816), created using a suicide vector, also displayed heat resistance and salt hypersensitivity phenotypes which could be restored to wild-type levels following plasmid excision. L. lactis Delta1816 also displayed improved growth in response to sublethal concentrations of penicillin G. High-temperature incubation of a wild-type industrial L. lactis strain also resulted in spontaneous mutation of llmg_1816 and heat-resistant and salt hypersensitive phenotypes, suggesting that this is not a strain-specific phenomenon and that it is independent of a plasmid integration event. Acidification of milk by the llmg_1816-altered strain was inhibited by lower salt concentrations than the parent strain. This study demonstrates that spontaneous mutations can occur during high-temperature growth of L. lactis and that inactivation of llmg_1816 leads to temperature resistance and salt hypersensitivity. PMID- 22923417 TI - Chronic hypoxia impairs cytochrome oxidase activity via oxidative stress in selected fetal Guinea pig organs. AB - We hypothesized that chronic hypoxia disrupts mitochondrial function via oxidative stress in fetal organs. Pregnant guinea pig sows were exposed to either normoxia or hypoxia (10.5% O2, 14 days) in the presence or absence of the antioxidant, N-acetylcysteine (NAC). Near-term anesthetized fetuses were delivered via hysterotomy, and fetal livers, hearts, lungs, and forebrains harvested. We quantified the effects of chronic hypoxia on cytochrome oxidase (CCO) activity and 2 factors known to regulate CCO activity: malondialdehyde (MDA) and CCO subunit 4 (COX4). Hypoxia increased the MDA levels in fetal liver, heart, and lung with a corresponding reduction in CCO activity, prevented by prenatal NAC. The COX4 expression paralleled CCO activity in fetal liver and lung, but was unaltered in fetal hearts due to hypoxia. Hypoxia reduced the brain COX4 expression despite having no effect on CCO activity. This study identifies the mitochondrion as an important target site in tissue-specific oxidative stress for the induction of fetal hypoxic injury. PMID- 22923418 TI - Spongious hypertrophic cardiomyopathy in patients with mutations in the four-and a-half LIM domain 1 gene. AB - BACKGROUND: X-linked myopathy with postural muscle atrophy is a novel X-linked myopathy caused by mutations in the four-and-a-half LIM domain 1 gene (FHL1). Cardiac involvement was suspected in initial publications. We now systematically analyzed the association of the FHL1 genotype with the cardiac phenotype to establish a potential cardiac involvement in the disease. METHODS AND RESULTS: Seventeen male patients and 23 female mutation carriers were compared with healthy controls. Every patient underwent a comprehensive clinical and cardiovascular workup. ECG abnormalities occurred frequently in affected males and were less frequent in heterozygous females. Both male and female mutation carriers had increased myocardial mass (affected males=115.1+/-25.3 g/m(2); heterozygous females=95.1+/-19.6 g/m(2); controls=89.0+/-15.6 g/m(2) and 72.6+/ 12.6 g/m(2); respectively) with increased wall thickness (typically midventricular and apical segments) mainly in affected males. Longitudinal systolic function was reduced in affected males (radial systolic strain: affected males=24.6+/-11.8%; male controls=43.2+/-14.8%; P=0.002). Diastolic dysfunction occurred in both affected males and heterozygous females. Cardiac MRI revealed a morphological hallmark of X-linked myopathy with postural muscle atrophy; a characteristic spongious structure and replacement fibrosis indicated by late enhancement could be detected in most affected males. X-linked myopathy with postural muscle atrophy was associated with reduced exercise capacity in affected males but not in heterozygous female mutation carriers. CONCLUSIONS: X-linked myopathy with postural muscle atrophy patients consistently showed electrical, functional, and characteristic morphological cardiac abnormalities that translate into reduced exercise capacity. Reduced systolic and diastolic function is associated with a novel type of spongious hypertrophic cardiomyopathy. An unexpected finding was that some cardiac abnormalities were also present in heterozygous female mutation carriers. PMID- 22923419 TI - Exome sequencing identifies 2 rare variants for low high-density lipoprotein cholesterol in an extended family. AB - BACKGROUND: Exome sequencing is a recently implemented method to discover rare mutations for Mendelian disorders. Less is known about its feasibility to identify genes for complex traits. We used exome sequencing to search for rare variants responsible for a complex trait, low levels of serum high-density lipoprotein cholesterol (HDL-C). METHODS AND RESULTS: We conducted exome sequencing in a large French-Canadian family with 75 subjects available for study, of which 27 had HDL-C values less than the fifth age-sex-specific population percentile. We captured ~50 Mb of exonic and transcribed sequences of 3 closely related family members with HDL-C levels less than the fifth age-sex percentile and sequenced the captured DNA. Approximately 82,000 variants were detected in each individual, of which 41 rare nonsynonymous variants were shared by the sequenced affected individuals after filtering steps. Two rare nonsynonymous variants in the ATP-binding cassette, subfamily A (ABC1), member 1 (ABCA1), and lipoprotein lipase genes predicted to be damaging were investigated for cosegregation with the low HDL-C trait in the entire extended family. The carriers of either variant had low HDL-C levels, and the individuals carrying both variants had the lowest HDL-C values. Interestingly, the ABCA1 variant exhibited a sex effect which was first functionally identified, and, subsequently, statistically demonstrated using additional French-Canadian families with ABCA1 mutations. CONCLUSIONS: This complex combination of 2 rare variants causing low HDL-C in the extended family would not have been identified using traditional linkage analysis, emphasizing the need for exome sequencing of complex lipid traits in unexplained familial cases. PMID- 22923420 TI - Pooled DNA resequencing of 68 myocardial infarction candidate genes in French canadians. AB - BACKGROUND: Familial history is a strong risk factor for coronary artery disease (CAD), especially for early-onset myocardial infarction (MI). Several genes and chromosomal regions have been implicated in the genetic cause of coronary artery disease/MI, mostly through the discovery of familial mutations implicated in hyper-/hypocholesterolemia by linkage studies and single nucleotide polymorphisms by genome-wide association studies. Except for a few examples (eg, PCSK9), the role of low-frequency genetic variation (minor allele frequency [MAF]) ~0.1%-5% on MI/coronary artery disease predisposition has not been extensively investigated. METHODS AND RESULTS: We selected 68 candidate genes and sequenced their exons (394 kb) in 500 early-onset MI cases and 500 matched controls, all of French-Canadian ancestry, using solution-based capture in pools of nonindexed DNA samples. In these regions, we identified 1852 single nucleotide variants (695 novel) and captured 85% of the variants with MAF>=1% found by the 1000 Genomes Project in Europe-ancestry individuals. Using gene-based association testing, we prioritized for follow-up 29 low-frequency variants in 8 genes and attempted to genotype them for replication in 1594 MI cases and 2988 controls from 2 French Canadian panels. Our pilot association analysis of low-frequency variants in 68 candidate genes did not identify genes with large effect on MI risk in French Canadians. CONCLUSIONS: We have optimized a strategy, applicable to all complex diseases and traits, to discover efficiently and cost-effectively DNA sequence variants in large populations. Resequencing endeavors to find low-frequency variants implicated in common human diseases are likely to require very large sample size. PMID- 22923421 TI - BMPR2 mutations influence phenotype more obviously in male patients with pulmonary arterial hypertension. AB - BACKGROUND: BMPR2 mutations predispose to idiopathic and heritable pulmonary arterial hypertension (IPAH and HPAH). The influence of BMPR2 mutations on clinical outcome is not concordant in different ethnic groups. Although the BMPR2 mutation spectrum and mutation rate in Chinese PAH patients has been reported previously, the influence of genotype on phenotype and whether this influence is associated with sex have not been investigated. METHODS AND RESULTS: We analyzed data from 305 PAH patients considered as either idiopathic or heritable who underwent genetic counseling in Shanghai Pulmonary Hospital. The clinical, functional, and hemodynamic characteristics of BMPR2 mutation carriers and noncarriers were compared. The more severe hemodynamic compromise at diagnosis in BMPR2 mutation carriers versus noncarriers is concordant with other ethnic groups. In the Chinese PAH cohort, BMPR2 mutations were associated with a higher risk of mortality after adjustment for age and sex (hazard ratio, 1.971; 95% confidence interval, 1.121-3.466; P=0.018). The overall survival difference between mutation carriers and noncarriers was more obvious in male patients, which was reflected by a higher mortality risk of male mutation carriers than that of male noncarriers after adjustment for age at diagnosis (hazard ratio, 3.702; 95% confidence interval, 1.416-9.679; P=0.008). In females, this trend did not reach statistical significance. CONCLUSIONS: BMPR2 mutations influence phenotype more obviously in male PAH patients. The pathogenesis of female PAH patients is more complicated, and the influence of BMPR2 mutations may be modified by other unknown factors, making disparities in the prognosis between female mutation carriers and noncarriers less evident. PMID- 22923422 TI - Diagnostic and prognostic performance of myeloperoxidase plasma levels compared with sensitive troponins in patients admitted with acute onset chest pain. AB - BACKGROUND: Activation of leukocytes with release of myeloperoxidase (MPO) has been linked to acute coronary disease. To date, studies investigating the diagnostic and prognostic performance of circulating MPO in patients with chest pain (CP) are mainly retrospective, of low size, and lack a cut-off value for MPO. Herein, we prospectively assess the diagnostic and prognostic properties of MPO compared with sensitive troponin I (sTNI) in patients admitted to the emergency room with CP. METHODS AND RESULTS: One thousand, eight hundred and eighteen consecutive patients (mean age, 61.4+/-13.5 years; 33.6% female) admitted for CP underwent determination of MPO, sTnI, and B-natriuretic peptide plasma levels at admission and 3 hours and 6 hours thereafter. A cut-off for MPO was defined in 5000 population-based subjects. Baseline MPO levels were elevated in patients with acute myocardial infarction compared with patients with noncoronary CP. For all time-points accuracy of MPO was inferior to sTNI for predicting AMI. The sensitivity of MPO to diagnose AMI at presentation was 73.5% compared with 90.7% for sTNI, and the specificity of MPO was 45.5% as opposed to 90.2%. B-natriuretic peptide levels also failed to demonstrate independent diagnostic information. Both MPO and B-natriuretic peptide were predictive for increased risk of adverse events at 30 days and 6 months, whereas their predictive value was weakened after covariate adjustment. CONCLUSIONS: The data demonstrate that MPO and B-natriuretic peptide fail to provide incremental information for patients with acute onset CP when added to sensitive troponin. However, there is a potential value for both biomarkers as prognostic markers. PMID- 22923423 TI - The interday reliability of ankle, knee, leg, and vertical musculoskeletal stiffness during hopping and overground running. AB - A number of methods are used to measure lower extremity musculoskeletal stiffness, but there is a paucity of research examining the reliability of these techniques. Therefore, we investigated the reliability of vertical, leg, knee, and ankle stiffness during overground running and hopping in 20 active men. Participants were required to run on a 10 m overground runway at 3.83 m/s (actual; 3.35 +/- 0.12 m/s) and to hop in place at 2.2 Hz (actual; 2.37 +/- 0.03 Hz), and at a self-selected frequency (actual; 2.05 +/- 0.12 Hz) and at 2.2 Hz (actual; 2.39 +/- 0.04 Hz). Reliability was determined using the intraclass correlation coefficient, coefficient of variation, mean differences, and Cohen's effect sizes. There was good reliability for vertical stiffness, moderate reliability for leg stiffness, and poor reliability for knee and ankle stiffness during the running task. Similar results were observed during the 2.2 Hz hopping tasks, with good reliability displayed for vertical stiffness and poor reliability for ankle and knee stiffness. In conclusion, our results suggest that vertical stiffness is a reliable measure when running at 3.83 m/s and hopping at 2.2 Hz. PMID- 22923424 TI - The effect of foot progression angle on knee joint compression force during walking. AB - It is unclear how rotations of the lower limb affect the knee joint compression forces during walking. Increases in the frontal plane knee moment have been reported when walking with internally rotated feet and a decrease when walking with externally rotated feet. The aim of this study was to investigate the knee joint compressive forces during walking with internal, external and normal foot rotation and to determine if the frontal plane knee joint moment is an adequate surrogate for the compression forces in the medial and lateral knee joint compartments under such gait modifications. Ten healthy males walked at a fixed speed of 4.5 km/h under three conditions: Normal walking, internally rotated and externally rotated. All gait trials were recorded by six infrared cameras. Net joint moments were calculated by 3D inverse dynamics. The results revealed that the medial knee joint compartment compression force increased during external foot rotation and the lateral knee joint compartment compression force increased during internal foot rotation. The increases in joint loads may be a result of increased knee flexion angles. Further, these data suggest that the frontal plane knee joint moment is not a valid surrogate measure for knee joint compression forces but rather indicates the medial- to-lateral load distribution. PMID- 22923425 TI - Single and multiple microphone noise reduction strategies in cochlear implants. AB - To restore hearing sensation, cochlear implants deliver electrical pulses to the auditory nerve by relying on sophisticated signal processing algorithms that convert acoustic inputs to electrical stimuli. Although individuals fitted with cochlear implants perform well in quiet, in the presence of background noise, the speech intelligibility of cochlear implant listeners is more susceptible to background noise than that of normal hearing listeners. Traditionally, to increase performance in noise, single-microphone noise reduction strategies have been used. More recently, a number of approaches have suggested that speech intelligibility in noise can be improved further by making use of two or more microphones, instead. Processing strategies based on multiple microphones can better exploit the spatial diversity of speech and noise because such strategies rely mostly on spatial information about the relative position of competing sound sources. In this article, we identify and elucidate the most significant theoretical aspects that underpin single- and multi-microphone noise reduction strategies for cochlear implants. More analytically, we focus on strategies of both types that have been shown to be promising for use in current-generation implant devices. We present data from past and more recent studies, and furthermore we outline the direction that future research in the area of noise reduction for cochlear implants could follow. PMID- 22923426 TI - Role of BMPR2 alternative splicing in heritable pulmonary arterial hypertension penetrance. AB - BACKGROUND: Bone morphogenic protein receptor 2 (BMPR2) gene mutations are the most common cause of heritable pulmonary arterial hypertension. However, only 20% of mutation carriers get clinical disease. Here, we explored the hypothesis that this reduced penetrance is due in part to an alteration in BMPR2 alternative splicing. METHODS AND RESULTS: Our data showed that BMPR2 has multiple alternative spliced variants. Two of these, isoform-A (full length) and isoform-B (missing exon 12), were expressed in all tissues analyzed. Analysis of cultured lymphocytes of 47 BMPR2 mutation-positive heritable pulmonary arterial hypertension patients and 35 BMPR2 mutation-positive unaffected carriers showed that patients had higher levels of isoform-B compared with isoform-A (B/A ratio) than carriers (P=0.002). Furthermore, compared with cells with a low B/A ratio, cells with a high B/A ratio had lower levels of unphosphorylated cofilin after BMP stimulation. Analysis of exon 12 sequences identified an exonic splice enhancer that binds serine arginine splicing factor 2 (SRSF2). Because SRSF2 promotes exon inclusion, reduced SRSF2 expression would mean that exon 12 would not be included in final BMPR2 mRNA (thus promoting increased isoform-B formation). Western blot analysis showed that SRSF2 expression was lower in cells from patients compared with cells from carriers and that siRNA-mediated knockdown of SRSF2 in pulmonary microvascular endothelial cells resulted in elevated levels of isoform-B compared with isoform-A, ie, an elevated B/A ratio. CONCLUSIONS: Alterations in BMPR2 isoform ratios may provide an explanation of the reduced penetrance among BMPR2 mutation carriers. This ratio is controlled by an exonic splice enhancer in exon 12 and its associated splicing factor, SRSF2. PMID- 22923427 TI - Numerical simulation of two-phase flow around flatwater competition kayak design evolution models. AB - The aim of the current study was to analyze the hydrodynamics of three kayaks: 97 kg-class, single-rower, flatwater sports competition, full-scale design evolution models (Nelo K1 Vanquish LI, LII, and LIII) of M.A.R. Kayaks Lda., Portugal, which are among the fastest frontline kayaks. The effect of kayak design transformation on kayak hydrodynamics performance was studied by the application of computational fluid dynamics (CFD). The steady-state CFD simulations where performed by application of the k-omega turbulent model and the volume-of-fluid method to obtain two-phase flow around the kayaks. The numerical result of viscous, pressure drag, and coefficients along with wave drag at individual average race velocities was obtained. At an average velocity of 4.5 m/s, the reduction in drag was 29.4% for the design change from LI to LII and 15.4% for the change from LII to LIII, thus demonstrating and reaffirming a progressive evolution in design. In addition, the knowledge of drag hydrodynamics presented in the current study facilitates the estimation of the paddling effort required from the athlete during progression at different race velocities. This study finds an application during selection and training, where a coach can select the kayak with better hydrodynamics. PMID- 22923428 TI - Force-generation capacity of single vastus lateralis muscle fibers and physical function decline with age in African green vervet monkeys. AB - Previous studies on the contractile properties of human myofibrils reported increase, decrease, or no change with aging, perhaps due to the differences in physical activity, diet, and other factors. This study examined physical performance and contractile characteristics of myofibrils of vastus lateralis (VL) muscle in young adult and old African green vervet monkeys. Animals were offered the same diet and lived in the same enclosures during development, so we were able to examine skeletal muscle function in vivo and in vitro with fewer potential confounding factors than are typical in human research studies. Fiber atrophy alone did not account for the age-related differences in specific force and maximal power output. Regression modeling used to identify factors contributing to lower fiber force revealed that age is the strongest predictor. Our results support a detrimental effect of aging on the intrinsic force and power generation of myofilament lattice and physical performance in vervet monkeys. PMID- 22923430 TI - Gait speed as a measure in geriatric assessment in clinical settings: a systematic review. AB - BACKGROUND: Gait speed is a quick, inexpensive, reliable measure of functional capacity with well-documented predictive value for major health-related outcomes. Numerous epidemiological studies have documented gait speed in healthy, community dwelling older people. The purpose of this study is to undertake a systematic review and meta-analysis of gait speed in a specific group with mobility limitations-geriatric patients in clinical settings. METHODS: Relevant databases were searched systematically for original research articles published in February 2011 measuring gait speed in persons aged 70 or older in hospital inpatient or outpatients settings. Meta-analysis determined gait speed data for each setting adjusting for covariates. RESULTS: The review included 48 studies providing data from 7,000 participants. Across the hospital settings, the gait speed estimate for usual pace was 0.58 m/s (95% confidence interval [CI]: 0.49-0.67) and for maximal pace was 0.89 m/s (95% CI: 0.75-1.02). These estimates were based on most recent year of publication (2011) and median percentage of female participants (63%). Gait speed at usual pace in acute care settings was 0.46 m/s (95% CI: 0.34 0.57), which was significantly slower than the gait speed of 0.74 m/s (95% CI: 0.65-0.83) recorded in outpatient settings. CONCLUSIONS: Gait speed is an important measure in comprehensive geriatric assessment. The consolidation of data from multiple studies reported in this meta-analysis highlights the mobility limitations experienced by older people in clinical settings and the need for ongoing rehabilitation to attain levels sufficient for reintegration in the community. PMID- 22923429 TI - Pathogenesis of age-related bone loss in humans. AB - BACKGROUND: Although data from rodent systems are extremely useful in providing insights into possible mechanisms of age-related bone loss, concepts evolving from animal models need to ultimately be tested in humans. METHODS: This review provides an update on mechanisms of age-related bone loss in humans based on the author's knowledge of the field and focused literature reviews. RESULTS: Novel imaging, experimental models, biomarkers, and analytic techniques applied directly to human studies are providing new insights into the patterns of bone mass acquisition and loss as well as the role of sex steroids, in particular estrogen, on bone metabolism and bone loss with aging in women and men. These studies have identified the onset of trabecular bone loss at multiple sites that begins in young adulthood and remains unexplained, at least based on current paradigms of the mechanisms of bone loss. In addition, estrogen appears to be a major regulator of bone metabolism not only in women but also in men. Studies assessing mechanisms of estrogen action on bone in humans have identified effects of estrogen on RANKL expression by several different cell types in the bone microenvironment, a role for TNF-alpha and IL-1beta in mediating effects of estrogen deficiency on bone, and possible regulation of the Wnt inhibitor, sclerostin, by estrogen. CONCLUSIONS: There have been considerable advances in our understanding of age-related bone loss in humans. However, there are also significant gaps in knowledge, particularly in defining cell autonomous changes in bone in human studies to test or validate concepts emerging from studies in rodents. Decision Editor: Luigi Ferrucci, MD, PhD. PMID- 22923431 TI - Loss of renal function in the elderly Italians: a physiologic or pathologic process? AB - BACKGROUND: Nowadays it seems that chronic kidney disease (CKD) is outbreaking, mostly in the elderly participants. The aim of this study was to assess the progression of CKD in different ages. METHODS: We conducted a monocentric, retrospective, observational study enrolling 116 patients afferent to our outpatient clinic. INCLUSION CRITERIA: age >18 years, follow-up >=5 years, estimated glomerular filtration rate (eGFR) <60mL/min/1.73 m(2), and/or diagnosed renal disease and/or presence of renal damage. Patients were divided into four groups according to their age: 25-55 years (n = 27), 56-65 (25), 66-75 (42), and 76-87 (22). eGFR was calculated using the modification of diet in renal disease and the CKD-epidemiology collaboration formulas. RESULTS: Younger patients had a significantly longer follow-up and less comorbidities, evaluated by the cumulative illness rating scale score, compared with the other groups. There was no difference between creatinine at baseline and at the end-of-follow-up period among the groups. Even though renal function significantly decreased in all groups, we noticed a slower progression as the age increased, and the difference between basal and end-of-follow-up eGFR was minimal in the group of patients aged 76-87 years. Analyzing the eGFR of every ambulatory control plotted against the year of follow-up, we showed a more rapid loss of filtrate in the younger group. Instead, loss of renal function decreased as the age of patients increased. CONCLUSIONS: This study demonstrates that, in elderly Italian participants, progression of CKD occurs more slowly than in younger patients. This implies that we may probably face an epidemic of CKD but that most of elderly patients diagnosed with CKD may not evolve to end-stage renal disease and require renal replacement therapy. PMID- 22923432 TI - Third universal definition of myocardial infarction. PMID- 22923433 TI - Genome sequencing identifies a basis for everolimus sensitivity. AB - Cancer drugs often induce dramatic responses in a small minority of patients. We used whole-genome sequencing to investigate the genetic basis of a durable remission of metastatic bladder cancer in a patient treated with everolimus, a drug that inhibits the mTOR (mammalian target of rapamycin) signaling pathway. Among the somatic mutations was a loss-of-function mutation in TSC1 (tuberous sclerosis complex 1), a regulator of mTOR pathway activation. Targeted sequencing revealed TSC1 mutations in about 8% of 109 additional bladder cancers examined, and TSC1 mutation correlated with everolimus sensitivity. These results demonstrate the feasibility of using whole-genome sequencing in the clinical setting to identify previously occult biomarkers of drug sensitivity that can aid in the identification of patients most likely to respond to targeted anticancer drugs. PMID- 22923434 TI - Acute gastrointestinal infection induces long-lived microbiota-specific T cell responses. AB - The mammalian gastrointestinal tract contains a large and diverse population of commensal bacteria and is also one of the primary sites of exposure to pathogens. How the immune system perceives commensals in the context of mucosal infection is unclear. Here, we show that during a gastrointestinal infection, tolerance to commensals is lost, and microbiota-specific T cells are activated and differentiate to inflammatory effector cells. Furthermore, these T cells go on to form memory cells that are phenotypically and functionally consistent with pathogen-specific T cells. Our results suggest that during a gastrointestinal infection, the immune response to commensals parallels the immune response against pathogenic microbes and that adaptive responses against commensals are an integral component of mucosal immunity. PMID- 22923435 TI - Molecular mechanics of cardiac myosin-binding protein C in native thick filaments. AB - The heart's pumping capacity results from highly regulated interactions of actomyosin molecular motors. Mutations in the gene for a potential regulator of these motors, cardiac myosin-binding protein C (cMyBP-C), cause hypertrophic cardiomyopathy. However, cMyBP-C's ability to modulate cardiac contractility is not well understood. Using single-particle fluorescence imaging techniques, transgenic protein expression, proteomics, and modeling, we found that cMyBP-C slowed actomyosin motion generation in native cardiac thick filaments. This mechanical effect was localized to where cMyBP-C resides within the thick filament (i.e., the C-zones) and was modulated by phosphorylation and site specific proteolytic degradation. These results provide molecular insight into why cMyBP-C should be considered a member of a tripartite complex with actin and myosin that allows fine tuning of cardiac muscle contraction. PMID- 22923436 TI - Synthesis and characterization of a rhodium(I) sigma-alkane complex in the solid state. AB - Transition metal-alkane complexes-termed sigma-complexes because the alkane donates electron density to the metal from a sigma-symmetry carbon-hydrogen (C-H) orbital-are key intermediates in catalytic C-H activation processes, yet these complexes remain tantalizingly elusive to characterization in the solid state by single-crystal x-ray diffraction techniques. Here, we report an approach to the synthesis and characterization of transition metal-alkane complexes in the solid state by a simple gas-solid reaction to produce an alkane sigma-complex directly. This strategy enables the structural determination, by x-ray diffraction, of an alkane (norbornane) sigma-bound to a d(8)-rhodium(I) metal center, in which the chelating alkane ligand is coordinated to the pseudosquare planar metal center through two sigma-C-H bonds. PMID- 22923437 TI - Cold-inducible RNA-binding protein modulates circadian gene expression posttranscriptionally. AB - In mammalian tissues, circadian gene expression can be driven by local oscillators or systemic signals controlled by the master pacemaker in the suprachiasmatic nucleus. We show that simulated body temperature cycles, but not peripheral oscillators, controlled the rhythmic expression of cold-inducible RNA binding protein (CIRP) in cultured fibroblasts. In turn, loss-of-function experiments indicated that CIRP was required for high-amplitude circadian gene expression. The transcriptome-wide identification of CIRP-bound RNAs by a biotin streptavidin-based cross-linking and immunoprecipitation (CLIP) procedure revealed several transcripts encoding circadian oscillator proteins, including CLOCK. Moreover, CLOCK accumulation was strongly reduced in CIRP-depleted fibroblasts. Because ectopic expression of CLOCK improved circadian gene expression in these cells, we surmise that CIRP confers robustness to circadian oscillators through regulation of CLOCK expression. PMID- 22923438 TI - Adhesion functions in cell sorting by mechanically coupling the cortices of adhering cells. AB - Differential cell adhesion and cortex tension are thought to drive cell sorting by controlling cell-cell contact formation. Here, we show that cell adhesion and cortex tension have different mechanical functions in controlling progenitor cell cell contact formation and sorting during zebrafish gastrulation. Cortex tension controls cell-cell contact expansion by modulating interfacial tension at the contact. By contrast, adhesion has little direct function in contact expansion, but instead is needed to mechanically couple the cortices of adhering cells at their contacts, allowing cortex tension to control contact expansion. The coupling function of adhesion is mediated by E-cadherin and limited by the mechanical anchoring of E-cadherin to the cortex. Thus, cell adhesion provides the mechanical scaffold for cell cortex tension to drive cell sorting during gastrulation. PMID- 22923439 TI - Why is it possible to enhance moral status and why doing so is wrong? AB - This paper presents arguments for two claims. First, post-persons, beings with a moral status superior to that of mere persons, are possible. Second, it would be bad to create such beings. Actions that risk bringing them into existence should be avoided. According to Allen Buchanan, it is possible to enhance moral status up to the level of personhood. But attempts to improve status beyond that fail for want of a target - there is no category of moral status superior to that of personhood. Buchanan presents personhood as a threshold. He allows that persons may succeed in enhancing their cognitive and physical powers but insists that they cannot enhance their moral status. I argue that it is an implication of accounts that make a cognitive capacity, or collection of such capacities, constitutive of moral status, that those who do not satisfy the criteria for a given status find these criteria impossible to adequately describe. This obstacle notwithstanding, I offer an inductive argument for the existence of moral statuses superior to personhood, moral statuses that are necessarily beyond human expressive powers. The second part of this paper presents an argument that it is wrong to risk producing beings with moral status higher than persons. We should look upon moral status enhancement as creating especially morally needy beings. We are subject to no obligation to create them in the first place. We avoid creating their needs by avoiding creating them. PMID- 22923440 TI - Application of a medicolegal approach in clinical stalemates. PMID- 22923442 TI - Single amino acid exchange in bacteriophage HK620 tailspike protein results in thousand-fold increase of its oligosaccharide affinity. AB - Bacteriophage HK620 recognizes and cleaves the O-antigen polysaccharide of Escherichia coli serogroup O18A1 with its tailspike protein (TSP). HK620TSP binds hexasaccharide fragments with low affinity, but single amino acid exchanges generated a set of high-affinity mutants with submicromolar dissociation constants. Isothermal titration calorimetry showed that only small amounts of heat were released upon complex formation via a large number of direct and solvent-mediated hydrogen bonds between carbohydrate and protein. At room temperature, association was both enthalpy- and entropy-driven emphasizing major solvent rearrangements upon complex formation. Crystal structure analysis showed identical protein and sugar conformers in the TSP complexes regardless of their hexasaccharide affinity. Only in one case, a TSP mutant bound a different hexasaccharide conformer. The extended sugar binding site could be dissected in two regions: first, a hydrophobic pocket at the reducing end with minor affinity contributions. Access to this site could be blocked by a single aspartate to asparagine exchange without major loss in hexasaccharide affinity. Second, a region where the specific exchange of glutamate for glutamine created a site for an additional water molecule. Side-chain rearrangements upon sugar binding led to desolvation and additional hydrogen bonding which define this region of the binding site as the high-affinity scaffold. PMID- 22923441 TI - Accumulation of glycolipids and other non-phosphorous lipids in Agrobacterium tumefaciens grown under phosphate deprivation. AB - Phosphate deficiency is characteristic for many natural habitats, resulting in different physiological responses in plants and bacteria including the replacement of phospholipids by glycolipids and other phosphorous-free lipids. The plant pathogenic bacterium Agrobacterium tumefaciens, which is free of glycolipids under full nutrition, harbors an open reading frame (ORF) coding for a processive glycosyltransferase (named as Pgt). This glycosyltransferase was previously shown to synthesize glucosylgalactosyldiacylglycerol (GGD) and digalactosyldiacylglycerol (DGD) after heterologous expression. The native function of this enzyme and the conditions for its activation remained unknown. We show here that Pgt is active under phosphate deprivation synthesizing GGD and DGD in Agrobacterium. A corresponding deletion mutant (Deltapgt) is free of these two glycolipids. Glycolipid accumulation is mainly regulated by substrate (diacylglycerol) availability. Diacylglycerol and the total fatty acid pool are characterized by an altered acyl composition in dependence of the phosphate status with a strong decrease of 18:1 and concomitant increase of 19:0 cyclo during phosphate deprivation. Furthermore, Agrobacterium accumulates two additional unknown glycolipids and diacylglycerol trimethylhomoserine (DGTS) during phosphate deprivation. Accumulation of all these lipids is accompanied by a reduction in phospholipids from 75 to 45% in the wild type. A further non phosphorous lipid, ornithine lipid, was not increased but its degree of hydroxylation was elevated under phosphate deprivation. The lack of GGD and DGD in the Deltapgt mutant has no effect on growth and virulence of Agrobacterium, suggesting that these two lipids are functionally replaced by DGTS and the two unknown glycolipids under phosphate deprivation. PMID- 22923443 TI - Negligence and the communication of neonatal genetic information to parents. AB - It is inevitable that neonatal genetic information will be communicated to parents and a potential for psychiatric injury exists where the communication is negligent. An important question in this regard is whether a health-care provider may owe a duty of care to parents when communicating accurate genetic information, or whether the courts might treat it as merely the receipt of distressing news, which hitherto attracts no liability in English Tort Law. The important role of genetic counselling in this context will likely be determinative in deciding whether communicating accurate genetic information is actionable because it arguably distinguishes the parent-physician relationship from that of messenger-recipient. If communication is accepted as being something more than the receipt of distressing news and is capable of causing 'shock', then parents will need to establish themselves as either primary or secondary victims if claims are to be reconciled with the Alcock paradigm. Claims by parents as secondary victims will be unlikely to succeed because the neonate does not fulfil the role of primary victim, although parents may be owed a duty as elevated primary victims as a result of the lack of an immediate victim. Elevating claimants to primary victim status is not without criticism and may serve to further complicate a difficult area of tort law. Alternatively, it may be open to parents to demonstrate that a duty exists subsequent to an assumption of responsibility, as the provision of genetic counselling during and after neonatal screening is indicative of health-care providers assuming responsibility for the parents' mental health. If parents are able to establish that a duty of care exists, then success of their claims will be determined by reference to breach and causation. The potential difficulties and solutions, particularly with regard to causation, are also briefly considered. It is suggested that breach will likely be determined by reference to a responsible body of medical opinion, while it is proposed that the courts adopt a material increase analysis when assessing causation. PMID- 22923444 TI - Modulation of neural plasticity as a basis for stroke rehabilitation. PMID- 22923445 TI - Nonadditive neuroprotection with early glutamate receptor blockade and delayed hypothermia after asphyxia in preterm fetal sheep. AB - BACKGROUND AND PURPOSE: Hypothermia induced after perinatal hypoxia-ischemia is partially protective. This study examined whether early treatment with the noncompetitive N-methyl-d-aspartate receptor antagonist, dizocilpine, can augment neuroprotection with delayed hypothermia after severe asphyxia in preterm fetal sheep at 0.7 weeks gestation (equivalent to 28-32 weeks in humans). METHODS: Fifty minutes after umbilical cord occlusion for 25 minutes, fetuses were randomized to either dizocilpine (2 mg/kg estimated fetal weight intravenously, then 0.07 mg/kg/h for 4 hours) and then after 5.5 hours to whole-body cooling to 3 degrees C below baseline, or sham cooling, until 72 hours, and euthanized 7 days after umbilical cord occlusion. RESULTS: Delayed hypothermia was associated with improved neuronal survival (P<0.02) and reduced microglia (P=0.004) and caspase-3-positive cells (P<0.01) compared with umbilical cord occlusion. Dizocilpine was associated with reduced microglia (P<0.05) but no effect on caspase-3 induction and improved survival only in CA1/2 (P<0.05) with no apparent additive effect with delayed hypothermia. CONCLUSIONS: Early N-methyl-d-aspartate blockade and a clinical regime of delayed whole-body hypothermia provide nonadditive neuroprotection in the preterm brain. PMID- 22923446 TI - Increased cerebral arterial pulsatility in patients with leukoaraiosis: arterial stiffness enhances transmission of aortic pulsatility. AB - BACKGROUND AND PURPOSE: Arterial stiffening reduces damping of the arterial waveform and hence increases pulsatility of cerebral blood flow, potentially damaging small vessels. In the absence of previous studies in patients with recent transient ischemic attack or stroke, we determined the associations between leukoaraiosis and aortic and middle cerebral artery stiffness and pulsatility. METHODS: Patients were recruited from the Oxford Vascular Study within 6 weeks of a transient ischemic attack or minor stroke. Leukoaraiosis was categorized on MRI by 2 independent observers with the Fazekas and age-related white matter change scales. Middle cerebral artery (MCA) stiffness (transit time) and pulsatility (Gosling's index: MCA-PI) were measured with transcranial ultrasound and aortic pulse wave velocity and aortic systolic, diastolic, and pulse pressure with applanation tonometry (Sphygmocor). RESULTS: In 100 patients, MCA-PI was significantly greater in patients with leukoaraiosis (0.91 versus 0.73, P<0.0001). Severity of leukoaraiosis was associated with MCA-PI and aortic pulse wave velocity (Fazekas: chi(2)=0.39, MCA-PI P=0.01, aortic pulse wave velocity P=0.06; age-related white matter change: chi(2)=0.38, MCA-PI P=0.015; aortic pulse wave velocity P=0.026) for periventricular and deep white matter lesions independent of aortic systolic blood pressure, diastolic blood pressure, and pulse pressure and MCA transit time with MCA-PI independent of age. In a multivariate model (r(2)=0.68, P<0.0001), MCA-PI was independently associated with aortic pulse wave velocity (P=0.016) and aortic pulse pressure (P<0.0001) and inversely associated with aortic diastolic blood pressure (P<0.0001) and MCA transit time (P=0.001). CONCLUSIONS: MCA pulsatility was the strongest physiological correlate of leukoaraiosis, independent of age, and was dependent on aortic diastolic blood pressure and pulse pressure and aortic and MCA stiffness, supporting the hypothesis that large artery stiffening results in increased arterial pulsatility with transmission to the cerebral small vessels resulting in leukoaraiosis. PMID- 22923447 TI - Clinical and histological significance of gadolinium enhancement in carotid atherosclerotic plaque. AB - BACKGROUND AND PURPOSE: Although the ability of MRI to investigate carotid plaque composition is well established, the mechanism and the significance of plaque gadolinium (Gd) enhancement remain unknown. We evaluated clinical and histological significance of Gd enhancement of carotid plaque in patients undergoing endarterectomy for carotid stenosis. METHODS: Sixty-nine patients scheduled for a carotid endarterectomy prospectively underwent a 3-T MRI. Carotid plaque enhancement was assessed on T1-weighted images performed before and 5 minutes after Gd injection. Enhancement was recorded according to its localization. Histological analysis was performed of the entire plaque and of the area with matched contrast enhancement on MR images. RESULTS: Gd enhancement was observed in 59% patients. Three types of carotid plaques were identified depending on enhancement location (shoulder region, shoulder and fibrous cap, and central in the plaque). Fibrous cap rupture, intraplaque hemorrhage, and plaque Gd enhancement was significantly more frequent in symptomatic than in asymptomatic patients (P=0.043, P<0.0001, and P=0.034, respectively). After histological analysis, Gd enhancement was significantly associated with vulnerable plaque (American Heart Association VI, P=0.006), neovascularization (P<0.0001), macrophages (P=0.030), and loose fibrosis (P<0.0001). Prevalence of neovessels, macrophages, and loose fibrosis in the area of Gd enhancement was 97%, 87%, and 80%, respectively, and was different depending on the enhancement location in the plaque. Fibrous cap status and composition were different depending on the type of plaque. CONCLUSIONS: Gd enhancement of carotid plaque is associated with vulnerable plaque phenotypes and related to an inflammatory process. PMID- 22923448 TI - Cerebral hemodynamic reserve and vascular remodeling in C57/BL6 mice are influenced by age. AB - BACKGROUND AND PURPOSE: Age is the most important risk factor for ischemic stroke. Recent experiments evidenced an age-associated rarefaction of the native collateral vasculature. The purpose of this study was to assess in what way age and arteriogenesis influence cortical perfusion and recovery of hemodynamic impairment in aged and young C57/BL6 mice. METHODS: After model establishment of chronic cerebral hypoperfusion in the C57/BL6 strain, sustained hemodynamic impairment was induced by permanent unilateral internal carotid artery occlusion in animals aged 4 to 6 weeks, 12 weeks, and 18 months. Functional and morphological outcome was assessed by laser speckle imaging before and during acetazolamide challenge on Days 0, 3, 7, and 14 and latex/carbon black angiography and immunohistochemistry on Day 21. RESULTS: Although internal carotid artery occlusion did not result in a reduction of baseline perfusion, it led to significant hemodynamic impairment in all age groups. Furthermore, baseline perfusion in sham and cerebrovascular reactivity after internal carotid artery occlusion were significantly lower in animals aged 18 months (468+/-57 Flux; 20.8%+/-17%) compared with mice aged 4 to 6 weeks (568+/-120 Flux; 30.3%+/ 17%) and 12 weeks (591+/-72 Flux; 34.2%+/-12%) from the beginning until Day 7 of the monitoring period. Functional outcome was in line with a 27% reduction of native leptomeningeal anastomoses in aged mice and only limited collateral outgrowth compared with young animals. Strikingly, all age groups reached spontaneous functional compensation by Day 14. CONCLUSIONS: Next to limited collateral remodeling, our results suggest that a hampered cerebrovascular response with age could intensify the risk for hemodynamic stroke in the elderly. PMID- 22923451 TI - Health activism. PMID- 22923449 TI - Phase I study of vorinostat in combination with temozolomide in patients with high-grade gliomas: North American Brain Tumor Consortium Study 04-03. AB - PURPOSE: A phase I, dose-finding study of vorinostat in combination with temozolomide (TMZ) was conducted to determine the maximum tolerated dose (MTD), safety, and pharmacokinetics in patients with high-grade glioma (HGG). EXPERIMENTAL DESIGN: This phase I, dose-finding, investigational study was conducted in two parts. Part 1 was a dose-escalation study of vorinostat in combination with TMZ 150 mg/m(2)/day for 5 days every 28 days. Part 2 was a dose escalation study of vorinostat in combination with TMZ 150 mg/m(2)/day for 5 days of the first cycle and 200 mg/m(2)/day for 5 days of the subsequent 28-day cycles. RESULTS: In part 1, the MTD of vorinostat administered on days 1 to 7 and 15 to 21 of every 28-day cycle, in combination with TMZ, was 500 mg daily. Dose limiting toxicities (DLT) included grade 3 anorexia, grade 3 ALT, and grade 5 hemorrhage in the setting of grade 4 thrombocytopenia. In part 2, the MTD of vorinostat on days 1 to 7 and 15 to 21 of every 28-day cycle, combined with TMZ, was 400 mg daily. No DLTs were encountered, but vorinostat dosing could not be escalated further due to thrombocytopenia. The most common serious adverse events were fatigue, lymphopenia, thrombocytopenia, and thromboembolic events. There were no apparent pharmacokinetic interactions between vorinostat and TMZ. Vorinostat treatment resulted in hyperacetylation of histones H3 and H4 in peripheral mononuclear cells. CONCLUSION: Vorinostat in combination with temozolomide is well tolerated in patients with HGG. A phase I/II trial of vorinostat with radiotherapy and concomitant TMZ in newly diagnosed glioblastoma is underway. PMID- 22923450 TI - Arylsulfonamide KCN1 inhibits in vivo glioma growth and interferes with HIF signaling by disrupting HIF-1alpha interaction with cofactors p300/CBP. AB - PURPOSE: The hypoxia-inducible factor-1 (HIF-1) plays a critical role in tumor adaptation to hypoxia, and its elevated expression correlates with poor prognosis and treatment failure in patients with cancer. In this study, we determined whether 3,4-dimethoxy-N-[(2,2-dimethyl-2H-chromen-6-yl)methyl]-N phenylbenzenesulfonamide, KCN1, the lead inhibitor in a novel class of arylsulfonamide inhibitors of the HIF-1 pathway, had antitumorigenic properties in vivo and further defined its mechanism of action. EXPERIMENTAL DESIGN: We studied the inhibitory effect of systemic KCN1 delivery on the growth of human brain tumors in mice. To define mechanisms of KCN1 anti-HIF activities, we examined its influence on the assembly of a functional HIF-1alpha/HIF-1beta/p300 transcription complex. RESULTS: KCN1 specifically inhibited HIF reporter gene activity in several glioma cell lines at the nanomolar level. KCN1 also downregulated transcription of endogenous HIF-1 target genes, such as VEGF, Glut 1, and carbonic anhydrase 9, in a hypoxia-responsive element (HRE)-dependent manner. KCN1 potently inhibited the growth of subcutaneous malignant glioma tumor xenografts with minimal adverse effects on the host. It also induced a temporary survival benefit in an intracranial model of glioma but had no effect in a model of melanoma metastasis to the brain. Mechanistically, KCN1 did not downregulate the levels of HIF-1alpha or other components of the HIF transcriptional complex; rather, it antagonized hypoxia-inducible transcription by disrupting the interaction of HIF-1alpha with transcriptional coactivators p300/CBP. CONCLUSIONS: Our results suggest that the new HIF pathway inhibitor KCN1 has antitumor activity in mouse models, supporting its further translation for the treatment of human tumors displaying hypoxia or HIF overexpression. PMID- 22923452 TI - Mediator probe PCR: a novel approach for detection of real-time PCR based on label-free primary probes and standardized secondary universal fluorogenic reporters. AB - BACKGROUND: The majority of established techniques for monitoring real-time PCR amplification involve individual target-specific fluorogenic probes. For analysis of numerous different targets the synthesis of these probes contributes to the overall cost during assay development. Sequence-dependent universal detection techniques overcome this drawback but are prone to detection of unspecific amplification products. We developed the mediator probe PCR as a solution to these problems. METHODS: A set of label-free sequence-specific primary probes (mediator probes), each comprising a target-specific region and a standardized mediator tag, is cleaved upon annealing to its target sequence by the polymerases' 5' nuclease activity. Release of a mediator triggers signal generation by cleavage of a complementary fluorogenic reporter probe. RESULTS: Real-time PCR amplification of human papillomavirus 18 (HPV18), Staphylococcus aureus, Escherichia coli, and Homo sapiens DNA dilution series showed exceptional linearity when detected either by novel mediator probes (r(2) = 0.991-0.999) or state-of-the-art hydrolysis probes (TaqMan probes) (r(2) = 0.975-0.993). For amplification of HPV18 DNA the limits of detection were 78.3 and 85.1 copies per 10-MUL reaction when analyzed with the mediator probe and hydrolysis probe, respectively. Duplex amplification of HPV18 target DNA and internal standard had no effects on back calculation of target copy numbers when quantified with either the mediator probe PCR (r(2) = 0.998) or the hydrolysis probe PCR (r(2) = 0.988). CONCLUSIONS: The mediator probe PCR has equal performance to hydrolysis probe PCR and has reduced costs because of the use of universal fluorogenic reporters. PMID- 22923454 TI - Establishing a standard of care for small bowel adenocarcinomas: challenges and lessons learned. PMID- 22923453 TI - Differences in the therapeutic approach to colorectal cancer in young and elderly patients. AB - PURPOSE: To analyze differences in the therapeutic approach to and tumor-related mortality of young and elderly colorectal cancer (CRC) patients. PATIENTS AND METHODS: This was a descriptive study of a retrospective cohort, based on administrative databases, of all patients with CRC diagnosed or treated in our institution. We extracted data on sociodemographic characteristics, comorbidity, type of cancer, type of treatment received, survival time, and cause of death. We compared differences between a young group (YG) (age <75 years) and an older group (OG) (age >=75 years) and assessed the variables associated with receiving different therapeutic options (multivariate analysis) and with survival time (Cox proportional hazards models). RESULTS: The study included 503 patients (YG, 320; OG, 183), with mean ages of 63.1 years in the YG and 81.8 years in the OG. No differences were observed between the groups in degree of differentiation, extension, tumor stage, or comorbidity. After adjustment for gender, comorbidity, and tumor localization and extension, YG patients were more likely than OG patients to receive surgery, radiotherapy, and chemotherapy and less likely to receive palliative care. After a median follow-up of 36.5 months, YG patients had a longer tumor-specific survival time than OG patients (36.41 months vs 26.05 months). After further adjustment, the YG had a lower tumor-specific mortality risk (hazard ratio, 0.66) than the OG. CONCLUSION: In comparison with younger patients, elderly CRC patients are undertreated, mainly because of their age and not because of their tumor type or comorbidity. Elderly patients have a significantly shorter tumor-specific survival time, partially because of this undertreatment. PMID- 22923455 TI - Improved gap size estimation for scaffolding algorithms. AB - MOTIVATION: One of the important steps of genome assembly is scaffolding, in which contigs are linked using information from read-pairs. Scaffolding provides estimates about the order, relative orientation and distance between contigs. We have found that contig distance estimates are generally strongly biased and based on false assumptions. Since erroneous distance estimates can mislead in subsequent analysis, it is important to provide unbiased estimation of contig distance. RESULTS: In this article, we show that state-of-the-art programs for scaffolding are using an incorrect model of gap size estimation. We discuss why current maximum likelihood estimators are biased and describe what different cases of bias we are facing. Furthermore, we provide a model for the distribution of reads that span a gap and derive the maximum likelihood equation for the gap length. We motivate why this estimate is sound and show empirically that it outperforms gap estimators in popular scaffolding programs. Our results have consequences both for scaffolding software, structural variation detection and for library insert-size estimation as is commonly performed by read aligners. AVAILABILITY: A reference implementation is provided at https://github.com/SciLifeLab/gapest. SUPPLEMENTARY INFORMATION: Supplementary data are availible at Bioinformatics online. PMID- 22923456 TI - Long-term visual outcomes following lens-sparing vitrectomy for retinopathy of prematurity. AB - AIM: To describe the long-term outcomes of lens-sparing vitrectomy (LSV) for retinopathy of prematurity (ROP). METHODS: Single-centre retrospective case series of eyes that underwent LSV for ROP between 1998 and 2005 and had a follow up of at least 5 years. The primary outcome was the mean visual acuity, and secondary outcomes were the proportion of eyes without functional vision, proportion of eyes with anatomic success, proportion of Stage 4A eyes with vision better than 20/400, proportion of Stage 4B eyes with vision better than 20/800. RESULTS: Thirty-seven eyes of 30 patients (mean age at last follow-up: 7.1 years) were included in the study, while an additional 23 patients had been lost to follow-up and were not included in the study. Of eyes that underwent LSV for Stage 4A or 4B: 63% had measurable visual acuity (mean logMAR 0.92 for Stage 4A, 1.63 for Stage 4B), 19% had form vision, but neurological comorbidities precluded visual acuity measurement, and the remaining 18% had light perception or no light perception. CONCLUSIONS: While most eyes that underwent LSV for Stage 4A or 4B ROP maintain useful vision with long-term follow-up, approximately one-fifth of eyes had no functional vision, and in a further fifth, vision could not be measured due to severe neurological impairment. PMID- 22923459 TI - BCG protects against tuberculosis irrespective of HIV status: a matched case control study in Mwanza, Tanzania. AB - While BCG vaccine protects against severe tuberculosis (TB) in children, its effect against adult TB is questionable. Furthermore, it is not known if HIV co infection modifies the effect of BCG. Among 352 pairs of Tanzanian TB cases and matched controls, the BCG scar was associated with a reduced risk of TB (OR 0.3, 95% CI 0.2 to 0.7, p=0.005), irrespective of HIV status (interaction, p=0.623). BCG vaccination considerably reduced the risk of TB, both among individuals with and without HIV infection. PMID- 22923461 TI - An historical ophthalmic study of Jane Austen. AB - Today, no other classic novelist has the popularity or power of Jane Austen, and in 2013 the world will celebrate 200 years of her comic masterpiece Pride and Prejudice. Her millions of fans have an abiding fascination with all aspects of her life, including her health and the cause of her death. This historical ophthalmic study of Jane Austen, based on very incomplete medical bibliographic data, finds that she had a mild ocular surface disorder from age 23. This disorder did not significantly impact on her visual performance for writing. There are many references to eyes in her novels, but Jane's eyes and those of her characters cannot contribute further to the debate around the cause of her death at age 41. PMID- 22923457 TI - BCG-specific IgG-secreting peripheral plasmablasts as a potential biomarker of active tuberculosis in HIV negative and HIV positive patients. AB - BACKGROUND: Diagnosis of active tuberculosis (TB) among sputum-negative cases, patients with HIV infection and extra-pulmonary TB is difficult. In this study, assessment of BCG-specific IgG-secreting peripheral plasmablasts, was used to identify active TB in these high-risk groups. METHODS: Peripheral blood mononuclear cells were isolated from patients with TB and controls and cultured in vitro using an assay called Antibodies in Lymphocyte Supernatant, which measures spontaneous IgG antibody release from migratory plasmablasts. A BCG specific ELISA and flow cytometry were used to quantify in vivo activated plasmablasts in blood samples from Ethiopian subjects who were HIV negative or HIV positive. Patients diagnosed with different clinical forms of sputum-negative active TB or other diseases (n=96) were compared with asymptomatic individuals including latent TB and non-TB controls (n=85). Immunodiagnosis of TB also included the tuberculin skin test and the interferon (IFN)-gamma release assay, QuantiFERON. RESULTS: This study demonstrated that circulating IgG+ plasmablasts and spontaneous secretion of BCG-specific IgG antibodies were significantly higher in patients with active TB compared with latent TB cases and non-TB controls. BCG-specific IgG titres were particularly high among patients coinfected with TB and HIV with CD4 T-cell counts <200 cells/ml who produced low levels of Mycobacterium tuberculosis-specific IFNgamma in vitro. CONCLUSIONS: These results suggest that BCG-specific IgG-secreting peripheral plasmablasts could be successfully used as a host-specific biomarker to improve diagnosis of active TB, particularly in people who are HIV positive, and facilitate administration of effective treatment to patients. Elevated IgG responses were associated with impaired peripheral T-cell responses, including reduced T-cell numbers and low M tuberculosis-specific IFNgamma production. PMID- 22923462 TI - Injury trend analysis from the US Open Tennis Championships between 1994 and 2009. AB - OBJECTIVE: Injuries can be a debilitating aspect of professional tennis. Injury rates and trends at the US Open Tennis Championships over multiple years are unknown. The purpose of this study was to examine injury trends in professional tennis players competing in a major professional tennis tournament between 1994 and 2009. METHODS: From 1994 to 2009, injury data from the US Open Tennis Championships were recorded. Injuries were classified by location and type using terminology derived from a consensus statement developed specifically for tennis. Injury rates were determined based on the exposure of an athlete to a match event, and were calculated as the ratio of injuries per 1000 match exposures (MEs). RESULTS: There was a statistically significant fluctuation in injuries across the timeframe analysed (p<0.05). There were 76.2+/-19.6 total injuries and 43.8+/-11.8 acute injuries per year seeking medical assistance. Muscle or tendon injuries were the most common type of acute injury. The rate of lower limb injuries was significantly higher than upper limb and trunk injuries (p<0.01). The ankle, followed by the wrist, knee, foot/toe and shoulder/clavicle were the most common injury sites. CONCLUSIONS: Acute injuries occurred more frequently than gradual-onset injuries, and most common injury types were similar to previously examined populations. However, there were differences in injury location trends compared to previous research, suggesting that further research in this elite-level population is warranted. PMID- 22923464 TI - Influence of admixture and paleolithic range contractions on current European diversity gradients. AB - Cavalli-Sforza and Edwards (Analysis of human evolution. 1963. In: Geerts SJ, editor. Genetics today: Proceedings of the 11th International Congress of Genetics, The Hague, The Netherlands. New York: Pergamon. p. 923-993.) initiated the representation of genetic relationships among human populations with principal component (PC) analysis (PCA). Their study revealed the presence of a southeast-northwest (SE-NW) gradient of genetic variation in current European populations, which was interpreted as the result of the demic diffusion of early neolithic farmers during their expansion from the near east. However, this interpretation has been questioned, as PCA gradients can occur even when there is no expansion and because the first PC axis is often orthogonal to the expansion axis. Here, we revisit PCA patterns obtained under realistic scenarios of the settlement of Europe, focusing on the effects of various levels of admixture between paleolithic and neolithic populations, and of range contractions during the last glacial maximum (LGM). Using extensive simulations, we find that the first PC (PC1) gradients are orthogonal to the expansion axis, but only when the expansion is recent (neolithic). More ancient (paleolithic) expansions alter the orientation of the PC1 gradient due to a spatial homogenization of genetic diversity over time, and to the exact location of LGM refugia from which re expansions proceeded. Overall we find that PC1 gradients consistently follow an SE-NW orientation if there is a large paleolithic contribution to the current European gene pool, and if the main refuge area during the last ice age was in the Iberian Peninsula. Our study suggests that an SE-NW PC1 gradient is compatible with little genetic impact of neolithic populations on the current European gene pool, and that range contractions have affected observed genetic patterns. PMID- 22923463 TI - Evolution of flux control in the glucosinolate pathway in Arabidopsis thaliana. AB - Network characteristics of biochemical pathways are believed to influence the rate of evolutionary change in constituent enzymes. One characteristic that may affect rate heterogeneity is control of the amount of product produced by a biochemical pathway or flux control. In particular, theoretical analyses suggest that adaptive substitutions should be concentrated in the enzyme(s) that exert the greatest control over flux. Although a handful of studies have found a correlation between position in a pathway and evolutionary rate, these investigations have not examined the relationship between evolutionary rate and flux control. Given that genes with greater control will experience stronger selection and that the probability of fixation is proportional to the selective advantage, we ask the following: 1) do upstream enzymes have majority flux control, 2) do enzymes with majority flux control accumulate adaptive substitutions, and 3) are upstream enzymes under higher selective constraint? First, by perturbing the enzymes in the aliphatic glucosinolate pathway in Arabidopsis thaliana with gene insertion lines, we show that flux control is focused in the first enzyme in the pathway. Next, by analyzing several sequence signatures of selection, we also show that this enzyme is the only one in the pathway that shows convincing evidence of selection. Our results support the hypothesis that natural selection preferentially acts on enzymes with high flux control. PMID- 22923465 TI - The diversity of class II transposable elements in mammalian genomes has arisen from ancestral phylogenetic splits during ancient waves of proliferation through the genome. AB - DNA transposons make up 3% of the human genome, approximately the same percentage as genes. However, because of their inactivity, they are often ignored in favor of the more abundant, active, retroelements. Despite this relative ignominy, there are a number of interesting questions to be asked of these transposon families. One particular question relates to the timing of proliferation and inactivation of elements in a family. Does an ongoing process of turnover occur, or is the process more akin to a life cycle for the family, with elements proliferating rapidly before deactivation at a later date? We answer this question by tracing back to the most recent common ancestor (MRCA) of each modern transposon family, using two different methods. The first method identifies the MRCA of the species in which a family of transposon fossils can still be found, which we assume will have existed soon after the true origin date of the transposon family. The second method uses molecular dating techniques to predict the age of the MRCA element from which all elements found in a modern genome are descended. Independent data from five pairs of species are used in the molecular dating analysis: human-chimpanzee, human-orangutan, dog-panda, dog-cat, and cow pig. Orthologous pairs of elements from host species pairs are included, and the divergence dates of these species are used to constrain the analysis. We discover that, in general, the times to element common ancestry for a given family are the same for the different species pairs, suggesting that there has been no order specific process of turnover. Furthermore, for most families, the ages of the common ancestor of the host species and of that of the elements are similar, suggesting a life cycle model for the proliferation of transposons. Where these two ages differ, in families found only in Primates and Rodentia, for example, we find that the host species date is later than that of the common ancestor of the elements, implying that there may be large deletions of elements from host species, examples of which were found in their ancestors. PMID- 22923466 TI - Alveolate mitochondrial metabolic evolution: dinoflagellates force reassessment of the role of parasitism as a driver of change in apicomplexans. AB - Mitochondrial metabolism is central to the supply of ATP and numerous essential metabolites in most eukaryotic cells. Across eukaryotic diversity, however, there is evidence of much adaptation of the function of this organelle according to specific metabolic requirements and/or demands imposed by different environmental niches. This includes substantial loss or retailoring of mitochondrial function in many parasitic groups that occupy potentially nutrient-rich environments in their metazoan hosts. Infrakingdom Alveolata comprises a well-supported alliance of three disparate eukaryotic phyla-dinoflagellates, apicomplexans, and ciliates. These major taxa represent diverse lifestyles of free-living phototrophs, parasites, and predators and offer fertile territory for exploring character evolution in mitochondria. The mitochondria of apicomplexan parasites provide much evidence of loss or change of function from analysis of mitochondrial protein genes. Much less, however, is known of mitochondrial function in their closest relatives, the dinoflagellate algae. In this study, we have developed new models of mitochondrial metabolism in dinoflagellates based on gene predictions and stable isotope labeling experiments. These data show that many changes in mitochondrial gene content previously only known from apicomplexans are found in dinoflagellates also. For example, loss of the pyruvate dehydrogenase complex and changes in tricarboxylic acid (TCA) cycle enzyme complement are shared by both groups and, therefore, represent ancestral character states. Significantly, we show that these changes do not result in loss of typical TCA cycle activity fueled by pyruvate. Thus, dinoflagellate data show that many changes in alveolate mitochondrial metabolism are independent of the major lifestyle changes seen in these lineages and provide a revised view of mitochondria character evolution during evolution of parasitism in apicomplexans. PMID- 22923467 TI - The timing of pigmentation lightening in Europeans. AB - The inverse correlation between skin pigmentation and latitude observed in human populations is thought to have been shaped by selective pressures favoring lighter skin to facilitate vitamin D synthesis in regions far from the equator. Several candidate genes for skin pigmentation have been shown to exhibit patterns of polymorphism that overlap the geospatial variation in skin color. However, little work has focused on estimating the time frame over which skin pigmentation has changed and on the intensity of selection acting on different pigmentation genes. To provide a temporal framework for the evolution of lighter pigmentation, we used forward Monte Carlo simulations coupled with a rejection sampling algorithm to estimate the time of onset of selective sweeps and selection coefficients at four genes associated with this trait in Europeans: KITLG, TYRP1, SLC24A5, and SLC45A2. Using compound haplotype systems consisting of rapidly evolving microsatellites linked to one single-nucleotide polymorphism in each gene, we estimate that the onset of the sweep shared by Europeans and East Asians at KITLG occurred approximately 30,000 years ago, after the out-of-Africa migration, whereas the selective sweeps for the European-specific alleles at TYRP1, SLC24A5, and SLC45A2 started much later, within the last 11,000-19,000 years, well after the first migrations of modern humans into Europe. We suggest that these patterns were influenced by recent increases in size of human populations, which favored the accumulation of advantageous variants at different loci. PMID- 22923468 TI - Contribution of common genetic variation to the risk of type 2 diabetes in the Mexican Mestizo population. AB - Several studies have identified nearly 40 different type 2 diabetes susceptibility loci, mainly in European populations, but few of them have been evaluated in the Mexican population. The aim of this study was to examine the extent to which 24 common genetic variants previously associated with type 2 diabetes are associated in Mexican Mestizos. Twenty-four single nucleotide polymorphisms (SNPs) in or near genes (KCNJ11, PPARG, TCF7L2, SLC30A8, HHEX, CDKN2A/2B, CDKAL1, IGF2BP2, ARHGEF11, JAZF1, CDC123/CAMK1D, FTO, TSPAN8/LGR5, KCNQ1, THADA, ADAMTS9, NOTCH2, NXPH1, RORA, UBQLNL, and RALGPS2) were genotyped in Mexican Mestizos. A case-control association study comprising 1,027 type 2 diabetic individuals and 990 control individuals was conducted. To account for population stratification, a panel of 104 ancestry-informative markers was analyzed. Association to type 2 diabetes was found for rs13266634 (SLC30A8), rs7923837 (HHEX), rs10811661 (CDKN2A/2B), rs4402960 (IGF2BP2), rs12779790 (CDC123/CAMK1D), and rs2237892 (KCNQ1). In addition, rs7754840 (CDKAL1) was associated in the nonobese type 2 diabetic subgroup, and for rs7903146 (TCF7L2), association was observed for early-onset type 2 diabetes. Lack of association for the rest of the variants may have resulted from insufficient power to detect smaller allele effects. PMID- 22923469 TI - A theranostic small interfering RNA nanoprobe protects pancreatic islet grafts from adoptively transferred immune rejection. AB - Islet transplantation has recently emerged as an acceptable clinical modality for restoring normoglycemia in patients with type 1 diabetes mellitus (T1DM). The long-term survival and function of islet grafts is compromised by immune rejection-related factors. Downregulation of factors that mediate immune rejection using RNA interference holds promise for improving islet graft resistance to damaging factors after transplantation. Here, we used a dual purpose therapy/imaging small interfering (si)RNA magnetic nanoparticle (MN) probe that targets beta(2) microglobulin (B2M), a key component of the major histocompatibility class I complex (MHC I). In addition to serving as a siRNA carrier, this MN-siB2M probe enables monitoring of graft persistence noninvasively using magnetic resonance imaging (MRI). Human islets labeled with these MNs before transplantation into B2M (null) NOD/scid mice showed significantly improved preservation of graft volume starting at 2 weeks, as determined by longitudinal MRI in an adoptive transfer model (P < 0.05). Furthermore, animals transplanted with MN-siB2M-labeled islets demonstrated a significant delay of up to 23.8 +/- 4.8 days in diabetes onset after the adoptive transfer of T cells relative to 6.5 +/- 4.5 days in controls. This study demonstrated that our approach could protect pancreatic islet grafts from immune rejection and could potentially be applied to allotransplantation and prevention of the autoimmune recurrence of T1DM in islet transplantation or endogenous islets. PMID- 22923470 TI - Plasma levels of fetuin-A and hepatic enzymes and risk of type 2 diabetes in women in the U.S. AB - Fetuin-A interferes with insulin action in animal studies, but data on fetuin-A and diabetes risk in humans are sparse and the role of nonalcoholic fatty liver disease in this association is unknown. From 2000 to 2006, we prospectively identified 470 matched incident diabetes case-control pairs in the Nurses' Health Study, for whom levels of plasma fetuin-A, alanine transaminase (ALT), and gamma glutamyltranspeptidase (GGT) were measured. After multivariate adjustment for covariates, including ALT and GGT, the odds ratio (OR) (95% CI) comparing extreme fetuin-A quintiles was 1.81 (1.07-3.06) (P for trend = 0.009). A mediational analysis showed that this positive association was largely (79.9%) explained by fasting insulin and hemoglobin A(1c) levels; after further adjustment of these factors, the OR (95% CI) comparing extreme quintiles was attenuated to 1.09 (0.56 2.10) (P for trend = 0.42). In addition, liver enzymes did not modify this association (P for interaction = 0.91 for ALT and 0.58 for GGT). When results from this study were pooled with those in three prior prospective investigations of the same association, a consistent, positive association was observed between high fetuin-A levels and diabetes risk: the relative risk (95% CI) comparing high versus low fetuin-A levels was 1.69 (1.39-2.05) (P for heterogeneity = 0.45). These findings suggest that plasma fetuin-A levels were independently associated with higher risk of developing type 2 diabetes. PMID- 22923471 TI - A new role for lipocalin prostaglandin d synthase in the regulation of brown adipose tissue substrate utilization. AB - In this study, we define a new role for lipocalin prostaglandin D synthase (L PGDS) in the control of metabolic fuel utilization by brown adipose tissue (BAT). We demonstrate that L-PGDS expression in BAT is positively correlated with BAT activity, upregulated by peroxisome proliferator-activated receptor gamma coactivator 1alpha or 1beta and repressed by receptor-interacting protein 140. Under cold-acclimated conditions, mice lacking L-PGDS had elevated reliance on carbohydrate to provide fuel for thermogenesis and had increased expression of genes regulating glycolysis and de novo lipogenesis in BAT. These transcriptional differences were associated with increased lipid content in BAT and a BAT lipid composition enriched with de novo synthesized lipids. Consistent with the concept that lack of L-PGDS increases glucose utilization, mice lacking L-PGDS had improved glucose tolerance after high-fat feeding. The improved glucose tolerance appeared to be independent of changes in insulin sensitivity, as insulin levels during the glucose tolerance test and insulin, leptin, and adiponectin levels were unchanged. Moreover, L-PGDS knockout mice exhibited increased expression of genes involved in thermogenesis and increased norepinephrine-stimulated glucose uptake to BAT, suggesting that sympathetically mediated changes in glucose uptake may have improved glucose tolerance. Taken together, these results suggest that L PGDS plays an important role in the regulation of glucose utilization in vivo. PMID- 22923472 TI - Intravenous niacin acutely improves the efficiency of dietary fat storage in lean and obese humans. AB - Spillover of fatty acids released by lipoprotein lipase hydrolysis of meal triglycerides may be a major contributor to the free fatty acid (FFA) pool. We studied lean (n = 6) and overweight and obese (n = 5) subjects during continuous feeding on two occasions: during intravenous infusion of niacin (2.8 mg/min) and saline. After establishment of steady-state chylomicronemia and suppression of adipose tissue lipolysis with a liquid meal, spillover was measured with infusions of [U-(13)C]oleate and [(3)H]triolein. Total FFA concentrations were lower during niacin infusion in both lean (50 +/- 4 vs. 102 +/- 7 MUmol/L; P < 0.002) and obese (75 +/- 6 vs. 143 +/- 13 MUmol/L; P < 0.01) subjects. Oleate appearance was lower during niacin infusion than during saline infusion in both lean (21 +/- 2 vs. 32 +/- 5 MUmol/min; P = 0.07) and obese subjects (25 +/- 3 vs. 46 +/- 8 MUmol/min; P < 0.02). Spillover was lower during niacin infusion than during saline infusion in lean (21 +/- 4 vs. 29 +/- 3%) and obese (21 +/- 2 vs. 29 +/- 5%) subjects (P < 0.03 for both). In summary, during meal absorption, niacin produces additional suppression of lipolysis and a reduction in fractional spillover compared with saline in both normal and obese subjects. Infusion of intravenous niacin provides a model for acutely improving dietary fat storage, perhaps by suppressing lipolysis in visceral adipose tissue. PMID- 22923473 TI - Liver glycogen loading dampens glycogen synthesis seen in response to either hyperinsulinemia or intraportal glucose infusion. AB - The purpose of this study was to determine the effect of liver glycogen loading on net hepatic glycogen synthesis during hyperinsulinemia or hepatic portal vein glucose infusion in vivo. Liver glycogen levels were supercompensated (SCGly) in two groups (using intraportal fructose infusion) but not in two others (Gly) during hyperglycemic-normoinsulinemia. Following a 2-h control period during which fructose infusion was stopped, there was a 2-h experimental period in which the response to hyperglycemia plus either 4* basal insulin (INS) or portal vein glucose infusion (PoG) was measured. Increased hepatic glycogen reduced the percent of glucose taken up by the liver that was deposited in glycogen (74 +/- 3 vs. 53 +/- 5% in Gly+INS and SCGly+INS, respectively, and 72 +/- 3 vs. 50 +/- 6% in Gly+PoG and SCGly+PoG, respectively). The reduction in liver glycogen synthesis in SCGly+INS was accompanied by a decrease in both insulin signaling and an increase in AMPK activation, whereas only the latter was observed in SCGly+PoG. These data indicate that liver glycogen loading impairs glycogen synthesis regardless of the signal used to stimulate it. PMID- 22923474 TI - Disruption of growth factor receptor-binding protein 10 in the pancreas enhances beta-cell proliferation and protects mice from streptozotocin-induced beta-cell apoptosis. AB - Defects in insulin secretion and reduction in beta-cell mass are associated with type 2 diabetes in humans, and understanding the basis for these dysfunctions may reveal strategies for diabetes therapy. In this study, we show that pancreas specific knockout of growth factor receptor-binding protein 10 (Grb10), which is highly expressed in pancreas and islets, leads to elevated insulin/IGF-1 signaling in islets, enhanced beta-cell mass and insulin content, and increased insulin secretion in mice. Pancreas-specific disruption of Grb10 expression also improved glucose tolerance in mice fed with a high-fat diet and protected mice from streptozotocin-induced beta-cell apoptosis and body weight loss. Our study has identified Grb10 as an important regulator of beta-cell proliferation and demonstrated that reducing the expression level of Grb10 could provide a novel means to increase beta-cell mass and reduce beta-cell apoptosis. This is critical for effective therapeutic treatment of both type 1 and 2 diabetes. PMID- 22923475 TI - Marrow-derived cells regulate the development of early diabetic retinopathy and tactile allodynia in mice. AB - The hypothesis that marrow-derived cells, and specifically proinflammatory proteins in those cells, play a critical role in the development of diabetes induced retinopathy and tactile allodynia was investigated. Abnormalities characteristic of the early stages of retinopathy and allodynia were measured in chimeric mice lacking inducible nitric oxide synthase (iNOS) or poly(ADP-ribosyl) polymerase (PARP1) in only their marrow-derived cells. Diabetes-induced capillary degeneration, proinflammatory changes, and superoxide production in the retina and allodynia were inhibited in diabetic animals in which iNOS or PARP1 was deleted from bone marrow cells only. Of the various marrow cells, neutrophils (and monocytes) play a major role in retinopathy development, because retinal capillary degeneration likewise was significantly inhibited in diabetic mice lacking the receptor for granulocyte colony-stimulating factor in their marrow derived cells. Immunodepletion of neutrophils or monocytes inhibited the endothelial death otherwise observed when coculturing leukocytes from wild-type diabetic animals with retinal endothelium. iNOS and PARP1 are known to play a role in inflammatory processes, and we conclude that proinflammatory processes within marrow-derived cells play a central role in the development of diabetes complications in the retina and nerve. PMID- 22923477 TI - A cross-country study of cigarette prices and affordability: evidence from the Global Adult Tobacco Survey. AB - OBJECTIVE: To describe the characteristics of two primary determinants of cigarette consumption: cigarette affordability and the range of prices paid for cigarettes (and bidis, where applicable) in a set of 15 countries. From this cross-country comparison, identify places where opportunities may exist for reducing consumption through tax adjustments. DATA: Self-response data from 45,838 smokers from 15 countries, obtained from the Global Adult Tobacco Survey (GATS) 2008-2011. DESIGN: Using self-response data on individual cigarette expenditure and consumption, we construct a measure of the average cigarette price smokers pay for manufactured cigarettes (and bidis, where applicable) in 15 countries. We use these prices to evaluate cigarette affordability and the range of prices available in each country. These survey-derived measures of cigarette price and affordability are uniquely suited for cross-country comparison because they represent each country's distinctive mix of individual consumption characteristics such as brand choice, intensity of consumption, and purchasing behavior. RESULTS: In this sample of countries, cigarettes are most affordable in Russia, which has the most room for tobacco tax increase. Affordability is also relatively high in Brazil and China for cigarettes, and in India and Bangladesh for bidis. Although the affordability of cigarettes in India is relatively low, the range of cigarette prices paid is relatively high, providing additional evidence to support the call for simplifying the existing tax structure and reducing the width of price options. China has both high affordability and wide price ranges, suggesting multiple opportunities for reducing consumption through tax adjustments. PMID- 22923476 TI - C-peptide prevents hyperglycemia-induced endothelial apoptosis through inhibition of reactive oxygen species-mediated transglutaminase 2 activation. AB - C-peptide is a bioactive peptide with a potentially protective role in diabetes complications; however, its molecular mechanism of protection against cardiovascular damage caused by hyperglycemia-induced apoptosis remains unclear. We investigated the protective mechanism of C-peptide against hyperglycemia induced apoptosis using human umbilical vein endothelial cells and streptozotocin diabetic mice. High glucose (33 mmol/L) induced apoptotic cell death in endothelial cells via sequential elevation of intracellular Ca(2+) and reactive oxygen species (ROS) as well as subsequent activation of transglutaminase 2 (TG2). C-peptide (1 nmol/L) prevented endothelial cell death by inhibiting protein kinase C- and NADPH oxidase-dependent intracellular ROS generation and by abolishing high glucose-induced TG2 activation, without affecting intracellular Ca(2+) levels. Consistently, in the aorta of streptozotocin diabetic mice, hyperglycemia stimulated transamidating activity and endothelial cell apoptosis that was inhibited by C-peptide replacement therapy (35 pmol/min/kg) using osmotic pumps (control and diabetes, n = 8; diabetes + C-peptide, n = 7). In addition, C-peptide prevented hyperglycemia-induced activation of transamidation activity and apoptosis in the heart and renal cortex of streptozotocin diabetic mice. Thus, C-peptide protects endothelial cells from hyperglycemia-induced apoptotic cell death by inhibiting intracellular ROS-mediated activation of TG2. Furthermore, TG2 may be a promising avenue of therapeutic investigation to treat diabetic vasculopathies. PMID- 22923478 TI - Cigarette prices, cigarette expenditure and smoking-induced deprivation: findings from the International Tobacco Control Mexico survey. AB - AIM: Mexico implemented annual tax increases between 2009 and 2011. We examined among current smokers the association of price paid per cigarette and daily cigarette expenditure with smoking-induced deprivation (SID) and whether the association of price or expenditure with SID varies by income. METHODS: We used data (n=2410) from three waves of the International Tobacco Control Mexico survey (ie, 2008, 2010, 2011) and employed logistic regression to estimate the association of price paid per cigarette and daily cigarette expenditure with the probability of SID ('In the last 6 months, have you spent money on cigarettes that you knew would be better spent on household essentials like food?'). RESULTS: Price paid per cigarette increased from Mex$1.24 in 2008, to Mex$1.36 in 2010, to Mex$1.64 in 2011. Daily cigarette expenditure increased from Mex$6.9, to Mex$7.6 and to Mex$8.4 in the 3 years. There was no evidence of an association between price and SID. However, higher expenditure was associated with a higher probability of SID. There was no evidence that the association of price or expenditure with SID varied by income. CONCLUSION: Tax increases in Mexico have resulted in smokers paying more and spending more for their cigarettes. Those with higher cigarette expenditure experience more SID, with no evidence that poorer smokers are more affected. PMID- 22923479 TI - Contents and price of vendor assembled paan quid with tobacco in five London localities: a cross-sectional study. AB - BACKGROUND: Little is known of paan quid with tobacco (PQT), a hand-made mixture of smokeless tobacco, areca nut, lime and flavourings in a betel leaf, despite its wide use in south Asian communities. This study has explored the price, tobacco types, brands and ingredient weights in vendor assembled PQT in London (England). METHODS: This cross-sectional study identified 31 commercial outlets selling PQT. Outlet staff were invited to assemble PQT for purchase. Individual ingredients were identified and weighed using a calibrated scale. Free nicotine availability was assessed in the laboratory. The data were analysed using frequencies, means, t test and Pearson correlations. Significance was set at p<0.05. RESULTS: 73 samples were assembled and purchased. Mean total PQT weight was 10.06 g (95% CI 9.26 to 10.86). Mean price was L1.43 (range L0.50-3.50), which varied by location (p=0.001). The most common smokeless tobacco type was zarda (64.4%). Mean tobacco weight was 0.65 g (95% CI 0.56 to 0.76) and the mean lime weight was 0.58 g (95% CI 0.41 to 0.75). While other ingredients did not vary, tobacco and lime mean weights varied by location (p=0.01). Tobacco and lime weights correlated positively (r=0.427, p=0.01). The pH of the tobacco and lime mix varied between 12.2 and 12.5, indicating 99% free nicotine availability. CONCLUSIONS: Vendor assembled PQT shares similar ingredients but varies by assembly locality, price and tobacco and lime weights. Tobacco and lime weights were balanced to ensure optimal free nicotine availability and dependency potential. PMID- 22923480 TI - Tobacco dependence curricula in Middle Eastern and North African medical education. PMID- 22923481 TI - Nearly 85% of tobacco smoke is invisible--a confirmation of previous claims. PMID- 22923482 TI - Can we improve adherence to guidelines for the treatment of lower urinary tract infection? A simple, multifaceted intervention in out-of-hours services. AB - OBJECTIVES: To improve antimicrobial prescribing behaviour of general practitioners in large-scale out-of-hours services for uncomplicated lower urinary tract infection (LUTI) in females aged 20-80 years, which is regarded as one of the most prevalent bacterial infections in primary care. METHODS: A quasi experimental design was used in two regional large-scale out-of-hours services. A simple, multifaceted intervention was offered in a 16 week period in one region (the intervention region). During the two washout periods, at 5 and 17 months, we observed diagnoses and prescriptions. The main outcome measure was the share of appropriate and inappropriate prescriptions. RESULTS: The proportion of patients with LUTI ranged from 1.0% to 2.1%. The relative proportion of appropriate prescriptions in the intervention region increased from 26.9% to 69.4%, but decreased afterwards to 40.8%. CONCLUSIONS: A simple, multifaceted intervention for treatment of LUTI during out-of-hours care may improve the quality of antimicrobial prescribing, although the improvement may not be sustained in the longer term. PMID- 22923483 TI - Once- versus twice-daily lopinavir/ritonavir tablets in virologically suppressed, HIV-infected, treatment-experienced children: comparative pharmacokinetics and virological outcome after switching to once-daily lopinavir/ritonavir. AB - OBJECTIVES: Data on lopinavir/ritonavir tablets administered once daily in children are limited. We compared the pharmacokinetics (PK) of lopinavir/ritonavir twice daily versus once daily in virologically suppressed, HIV-infected children, and assessed the virological outcome, at 48 weeks, in children receiving the regimen of lopinavir/ritonavir once daily. PATIENTS AND METHODS: HIV-infected children receiving a twice-daily lopinavir/ritonavir-based regimen and with an HIV-1 RNA viral load (VL) <40 copies/mL for at least 3 months were enrolled. Intensive steady-state 12 h blood sampling for PK assessment was performed at enrolment. Immediately afterwards, the lopinavir/ritonavir dose was changed to once daily with the equivalent daily dose, and intensive steady-state 24 h blood sampling was repeated 2 weeks later. If the lopinavir C(trough) was <1.0 MUg/mL, the lopinavir/ritonavir dose was increased by 20%-30% and C(trough) measurement repeated. CD4 cell counts and VL were determined at baseline and at 12, 24 and 48 weeks. RESULTS: Twelve children were enrolled. The median age was 13.1 years. Lopinavir AUC(0-24) following twice-daily and once-daily dosing was 169.7 (124.0-200.8) and 167.1 (95.1-228.1) MUg . h/mL, respectively. Seven children, including all six concomitantly receiving efavirenz, had a C(trough) <1.0 MUg/mL with once-daily lopinavir/ritonavir dosing, and four of seven children had a C(trough) <1.0 MUg/mL after dose adjustment. All children maintained virological suppression throughout the 48 week period. CONCLUSIONS: Lopinavir/ritonavir-based once-daily regimens could simplify therapy in children/adolescents with virological control, but a lower lopinavir C(trough) was evident. Further efficacy studies of lopinavir/ritonavir once daily in children are necessary before routinely recommending this dosing strategy. PMID- 22923484 TI - Phase II feasibility trial of adjuvant chemoradiotherapy with 3-weekly cisplatin for Japanese patients with post-operative high-risk squamous cell carcinoma of the head and neck. AB - OBJECTIVE: The current standard of care for post-operative high-risk squamous cell carcinoma of the head and neck is concurrent chemoradiotherapy with a 3 weekly cycle of cisplatin (3W-CDDP/RT). In previous pivotal trials, the complete delivery rate of three cycles of cisplatin and radiation therapy was only ~60%. Here, we evaluated the feasibility and safety of 3W-CDDP/RT in a Japanese population. METHODS: The study enrolled post-operative high-risk squamous cell carcinoma of the head and neck patients. High-risk factors were a microscopically incomplete resection, extracapsular extension and two or more lymph node metastases. Subjects received three cycles of cisplatin at a dose of 100 mg/m(2) concomitant with radiation therapy (66 Gy/33 Fr). RESULTS: From August 2006 to May 2009, 25 eligible subjects were accrued, including 13 males, with a median age of 59 years, Eastern Cooperative Oncology Group performance status 0/1 (18/7), Stage III/IVA/IVB/recurrent (1/18/1/5) and oral cavity/oropharynx/hypopharynx/larynx (17/4/3/1). Protocol completion rate was 80%. The lower limit of the one-sided 90% confidence interval was 66%, which met the predefined statistical criteria. Grade 3/4 acute and late toxicities were almost identical to those in previous pivotal trials. No treatment-related deaths were observed. With a median follow-up of 39 months, 14 have had progression and 10 have died. Estimated 3-year locoregional control rate, relapse-free survival and overall survival were 74, 43 and 60%, respectively. On univariate analysis, oral cavity cancer and a cumulative cisplatin dose below 240 mg/m(2) appeared to be poor prognostic factors. CONCLUSIONS: This is the first Phase II feasibility trial of adjuvant chemoradiotherapy with 3-weekly cisplatin for post-operative high-risk squamous cell carcinoma of the head and neck in a Japanese population. This treatment was feasible and the safety profile was identical to those in pivotal Phase III trials. PMID- 22923486 TI - Platelets: key players in vascular inflammation. AB - Platelets play a crucial role in the physiology of the primary hemostasis and in the pathophysiological activity of arterial thrombosis, provide rapid protection against bleeding, and catalyze the formation of stable blood clots via the coagulation cascade. Over the past years, it has become clear that platelets are important, not only in hemostasis and thrombosis but also in inflammation and in distinct aspects of atherosclerosis. Nowadays, platelets are known to have a large variety of functions. Platelets are able to interact with a large variety of cell types, such as leukocytes, endothelial cells, and SMCs, and these interactions have been implicated in the pathophysiology of vascular inflammation. In addition, platelets carry a highly inflammatory payload and are able to transport, synthesize, and deposit cytokines, chemokines, and lipid mediators, thereby initiating and propagating atherosclerotic disease. In this review, the current state of the art of the proinflammatory functions in the context of atherosclerotic cardiovascular disease will be outlined. PMID- 22923485 TI - Threonine 2609 phosphorylation of the DNA-dependent protein kinase is a critical prerequisite for epidermal growth factor receptor-mediated radiation resistance. AB - The EGF receptor (EGFR) contributes to tumor radioresistance, in part, through interactions with the catalytic subunit of DNA-dependent protein kinase (DNA PKc), a key enzyme in the nonhomologous end joining DNA repair pathway. We previously showed that EGFR-DNA-PKcs interactions are significantly compromised in the context of activating mutations in EGFR in non-small cell lung carcinoma (NSCLC) and human bronchial epithelial cells. Here, we investigate the reciprocal relationship between phosphorylation status of DNA-PKcs and EGFR-mediated radiation response. The data reveal that both the kinase activity of DNA-PKcs and radiation-induced phosphorylation of DNA-PKcs by the ataxia telangiectasia mutated (ATM) kinase are critical prerequisites for EGFR-mediated radioresponse. Alanine substitutions at seven key serine/threonine residues in DNA-PKcs or inhibition of DNA-PKcs by NU7441 completely abrogated EGFR-mediated radioresponse and blocked EGFR binding. ATM deficiency or ATM inhibition with KU55933 produced a similar effect. Importantly, alanine substitution at an ATM-dependent DNA-PKcs phosphorylation site, T2609, was sufficient to block binding or radioresponse of EGFR. However, mutation of a DNA-PKcs autophosphorylation site, S2056 had no such effect indicating that DNA-PKcs autophosphorylation is not necessary for EGFR mediated radioresponse. Our data reveal that in both NSCLCs and human bronchial epithelial cells, activating mutations in EGFR specifically abolished the DNA PKcs phosphorylation at T2609, but not S2056. Our study underscores the critical importance of a reciprocal relationship between DNA-PKcs phosphorylation and EGFR mediated radiation response and elucidates mechanisms underlying mutant EGFR associated radiosensitivity in NSCLCs. PMID- 22923487 TI - The molecular connections between the cannabinoid system and endometriosis. AB - The endocannabinoid system consists of an array of endogenously produced bioactive lipids that activate cannabinoid 1 (CB1) and 2 (CB2) receptors. Alterations of this system have been described in almost every category of disease. These changes can be protective or maladaptive, making the endocannabinoid network an attractive therapeutic target. Little is known about the potential role of endocannabinoids in endometriosis development although this is a topic worthy of further investigation since endocannabinoid modulators have recently been shown to affect specific mechanisms critical to endometriosis establishment and maintenance. A literature review was herein performed with the aim of defining the regulation and function of the endocannabinoid signaling in in vitro and animal models of endometriosis. The components of the endocannabinoid system, CB1 and CB2 receptors and the enzymes N acylphosphatidylethanolamine-phospholipase D and fatty acid amide hydrolase are differentially regulated throughout the menstrual cycle in the endometrium and are expressed in deep endometriotic nodules and in sensory and sympathetic neurons innervating the lesions. Selective cannabinoid receptor agonists, such as WIN 55212-2, appear to have a favorable action in limiting cell proliferation and in controlling pain symptoms. Conversely, endometrial cell migration tends to be stimulated by receptor agonists. The phosphatidylinositol 3-kinase/Akt and extracellular signal-regulated kinase 1/2 pathways seem to be involved in these processes. However, the underlying mechanisms of action are only just beginning to unfold. Given the complexity of the system, further studies are needed to clarify whether the endocannabinoid system might represent a promising target for endometriosis. PMID- 22923488 TI - Specific genes are selectively expressed between cumulus and granulosa cells from individual human pre-ovulatory follicles. AB - During folliculogenesis, the granulosa cells differentiate into two cell types: cumulus cells (CCs) and mural granulosa cells (MGCs). The objective of the study was to generate and compare the transcriptomes of MGCs and CCs from the pre ovulatory follicle to characterize the detailed profile of the two cell populations shortly before ovulation. Twenty-one IVF/ICSI patients undergoing controlled ovarian stimulation (COS) donated CCs and MGCs from individual follicles containing metaphase II oocytes. Cells were prepared immediately after recovery and mRNA was isolated for whole-genome gene expression analysis and reverse transcriptase-polymerase chain reactions. Paired (within the individual follicle) comparisons between the CC and MGC expression profiles were performed and corrected for multiple comparisons. A total of 1562 genes were differentially expressed by >2-fold (P < 0.01) in the two cell types. Of these, 156 genes were >8-fold changed and represented specialized cellular functional categories such as inflammatory response, extracellular matrix and cell-cell communication, whereas the 1406 genes were 2-8-fold changed and represented functional categories such as proliferation and lipid metabolism. Transcripts not previously linked to the follicle were found to be differentially expressed between CCs and MGCs, suggesting specialized function in these compartments, e.g. pepsinogen A was selectively expressed in MGCs, whereas ryanodine receptor-2 (RYR2) was selectively expressed in CCs. Positive correlations were present between expression levels of RYR2 and the amphiregulin and gap-junction proteins. In conclusion, the transcriptomes of corresponding CCs and MGCs from individual pre ovulatory follicles clearly revealed two distinct cell types. New as well as known genes representing specific cell functions close to ovulation were highlighted. PMID- 22923489 TI - 2012 Global Summit on Regulatory Science (GSRS-2012)--modernizing toxicology. AB - Regulatory science encompasses the tools, models, techniques, and studies needed to assess and evaluate product safety, efficacy, quality, and performance. Several recent publications have emphasized the role of regulatory science in improving global health, supporting economic development and fostering innovation. As for other scientific disciplines, research in regulatory science is the critical element underpinning the development and advancement of regulatory science as a modern scientific discipline. As a regulatory agency in the 21st century, the Food and Drug Administration (FDA) has an international component that underpins its domestic mission; foods, drugs, and devices are developed and imported to the United States from across the world. The Global Summit on Regulatory Science, an international conference for discussing innovative technologies, approaches, and partnerships that enhance the translation of basic science into regulatory applications, is providing leadership for the advancement of regulatory sciences within the global context. Held annually, this international conference provides a platform where regulators, policy makers, and bench scientists from various countries can exchange views on how to develop, apply, and implement innovative methodologies into regulatory assessments in their respective countries, as well as developing a harmonized strategy to improve global public health through global collaboration. PMID- 22923490 TI - Efficient monitoring of in vivo pig-a gene mutation and chromosomal damage: summary of 7 published studies and results from 11 new reference compounds. AB - The ability to effectively monitor gene mutation and micronucleated reticulocyte (MN-RET) frequency in short-term and repeated dosing schedules was investigated using the recently developed flow cytometric Pig-a mutation assay and flow cytometric micronucleus analysis. Eight reference genotoxicants and three presumed nongenotoxic compounds were studied: chlorambucil, melphalan, thiotepa, cyclophosphamide, azathioprine, 2-acetylaminofluorene, hydroxyurea, methyl methanesulfonate, o-anthranilic acid, sulfisoxazole, and sodium chloride. These experiments extend previously published results with seven other chemicals. Male Sprague Dawley rats were treated via gavage for 3 or 28 consecutive days with several dose levels of each chemical up to the maximum tolerated dose. Blood samples were collected at several time points up to day 45 and were analyzed for Pig-a mutation with a dual-labeling method that facilitates mutant cell frequency measurements in both total erythrocytes and the reticulocyte subpopulation. An immunomagnetic separation technique was used to increase the efficiency of scoring mutant cells. Blood samples collected on day 4, and day 29 for the 28-day study, were evaluated for MN-RET frequency. The three nongenotoxicants did not induce Pig-a or MN-RET responses. All genotoxicants except hydroxyurea increased the frequency of Pig-a mutant reticulocytes and erythrocytes. Significant increases in MN-RET frequency were observed for each of the genotoxicants at both time points. Whereas the highest Pig-a responses tended to occur in the 28-day studies, when total dose was greatest, the highest induction of MN-RET was observed in the 3-day studies, when dose per day was greatest. There was no clear relationship between the maximal Pig-a response of a given chemical and its corresponding maximal MN-RET response, despite the fact that both endpoints were determined in the same cell lineage. Taken with other previously published results, these data demonstrate the value of integrating Pig-a and micronucleus endpoints into in vivo toxicology studies, thereby providing information about mutagenesis and chromosomal damage in the same animals from which toxicity, toxicokinetics, and metabolism data are obtained. PMID- 22923491 TI - Diuron-induced rat bladder epithelial cytotoxicity. AB - Diuron, a substituted urea herbicide, is carcinogenic to the rat urinary bladder at high dietary levels (2500 ppm). To further elucidate the mode of action, this study aimed to determine the time course and sequence of bladder cytotoxic and proliferative changes induced by diuron treatment of male Wistar rats. Rats were randomized into two groups (control and 2500 ppm diuron) and treated for 28 days. Ten rats from each group were terminated on each of study days 1, 3, 7, or 28. Scanning electron micro scopy (SEM) showed urothelial cell swelling beginning on day 1, and by day 28, showed extensive necrosis, exfoliation and piling up of cells suggestive of hyperplasia. No difference in the bromo deoxyuridine labeling index was detected. In a second experiment, rats were randomized into control and diuron-treated groups and treated for 7 days or 8 weeks. After 7 days, transmission electron microscopy showed cell degenerative changes and distention of the cytoplasm, organelles, and nuclei characteristic of cytolysis. This resulted in protrusion of the superficial cells into the lumen, corresponding to the cell swelling observed previously by SEM. After 8 weeks, bladders in the diuron-treated group showed an increased incidence of simple hyperplasia by light microscopy (6/10, p < 0.05) compared with controls (0/10) and a significantly different SEM classification. In summary, our results support the hypothesis that urothelial cytotoxicity followed by regenerative cell proliferation are the sequential key events that occur with high-dose diuron exposure in rats. PMID- 22923492 TI - Amino acid sequence of the ligand-binding domain of the aryl hydrocarbon receptor 1 predicts sensitivity of wild birds to effects of dioxin-like compounds. AB - The sensitivity of avian species to the toxic effects of dioxin-like compounds (DLCs) varies up to 1000-fold among species, and this variability has been associated with interspecies differences in aryl hydrocarbon receptor 1 ligand binding domain (AHR1 LBD) sequence. We previously showed that LD(50) values, based on in ovo exposures to DLCs, were significantly correlated with in vitro EC(50) values obtained with a luciferase reporter gene (LRG) assay that measures AHR1-mediated induction of cytochrome P4501A in COS-7 cells transfected with avian AHR1 constructs. Those findings suggest that the AHR1 LBD sequence and the LRG assay can be used to predict avian species sensitivity to DLCs. In the present study, the AHR1 LBD sequences of 86 avian species were studied, and differences at amino acid sites 256, 257, 297, 324, 337, and 380 were identified. Site-directed mutagenesis, the LRG assay, and homology modeling highlighted the importance of each amino acid site in AHR1 sensitivity to 2,3,7,8 tetrachlorodibenzo-p-dioxin and other DLCs. The results of the study revealed that (1) only amino acids at sites 324 and 380 affect the sensitivity of AHR1 expression constructs of the 86 avian species to DLCs and (2) in vitro luciferase activity of AHR1 constructs containing only the LBD of the species of interest is significantly correlated (r (2) = 0.93, p < 0.0001) with in ovo toxicity data for those species. These results indicate promise for the use of AHR1 LBD amino acid sequences independently, or combined with the LRG assay, to predict avian species sensitivity to DLCs. PMID- 22923493 TI - HLA-DP genetic variation, proxies for early life immune modulation and childhood acute lymphoblastic leukemia risk. AB - The human leukocyte antigen (HLA) genes are candidate genetic susceptibility loci for childhood acute lymphoblastic leukemia (ALL). We examined the effect of HLA DP genetic variation on risk and evaluated its potential interaction with 4 proxies for early immune modulation, including measures of infectious exposures in infancy (presence of older siblings, daycare attendance, ear infections) and breastfeeding. A total of 585 ALL cases and 848 controls were genotyped at the HLA-DPA1 and DPB1 loci. Because of potential heterogeneity in effect by race/ethnicity, we included only non-Hispanic white (47%) and Hispanic (53%) children and considered these 2 groups separately in the analysis. Logistic regression analyses showed an increased risk of ALL associated with HLA DPB1*01:01 (odds ratio [OR] = 1.43, 95% CI, 1.01-2.04) with no heterogeneity by Hispanic ethnicity (P = .969). Analyses of DPB1 supertypes showed a marked childhood ALL association with DP1, particularly for high-hyperdiploid ALL (OR = 1.83; 95% CI, 1.20-2.78). Evidence of interaction was found between DP1 and older sibling (P = .036), and between DP1 and breastfeeding (P = .094), with both showing statistically significant DP1 associations within the lower exposure categories only. These findings support an immune mechanism in the etiology of childhood ALL involving the HLA-DPB1 gene in the context of an insufficiently modulated immune system. PMID- 22923494 TI - Chromatin accessibility, p300, and histone acetylation define PML-RARalpha and AML1-ETO binding sites in acute myeloid leukemia. AB - Chromatin accessibility plays a key role in regulating cell type specific gene expression during hematopoiesis but has also been suggested to be aberrantly regulated during leukemogenesis. To understand the leukemogenic chromatin signature, we analyzed acute promyelocytic leukemia, a subtype of leukemia characterized by the expression of RARalpha-fusion proteins, such as PML RARalpha. We used nuclease accessibility sequencing in cell lines as well as patient blasts to identify accessible DNA elements and identified > 100 000 accessible regions in each case. Using ChIP-seq, we identified H2A.Z as a histone modification generally associated with these accessible regions, whereas unsupervised clustering analysis of other chromatin features, including DNA methylation, H2A.Zac, H3ac, H3K9me3, H3K27me3, and the regulatory factor p300, distinguished 6 distinct clusters of accessible sites, each with a characteristic functional makeup. Of these, PML-RARalpha binding was found specifically at accessible chromatin regions characterized by p300 binding and hypoacetylated histones. Identifying regions with a similar epigenetic make up in t(8;21) acute myeloid leukemia (AML) cells, another subtype of AMLs, revealed that these regions are occupied by the oncofusion protein AML1-ETO. Together, our results suggest that oncofusion proteins localize to accessible regions and that chromatin accessibility together with p300 binding and histone acetylation characterize AML1-ETO and PML-RARalpha binding sites. PMID- 22923496 TI - Sickle cell pain: a critical reappraisal. AB - Sickle cell pain includes 3 types: acute recurrent painful crises, chronic pain syndromes, and neuropathic pain. The acute painful crisis is the hallmark of the disease and the most common cause of hospitalization and treatment in the emergency department. It evolves through 4 phases: prodromal, initial, established, and resolving. Each acute painful episode is associated with inflammation that worsens with recurrent episodes, often culminating in serious complications and organ damage, such as acute chest syndrome, multiorgan failure, and sudden death. Three pathophysiologic events operate in unison during the prodromal phase of the crisis: vaso-occlusion, inflammation, and nociception. Aborting the acute painful episode at the prodromal phase could potentially prevent or minimize tissue damage. Our hypothesis is that managing these events with hydration, anti-inflammatory drugs, aggressive analgesia, and possibly vasodilators could abort the crisis and prevent or minimize further damage. Chronic pain syndromes are associated with or accompany avascular necrosis and leg ulcers. Neuropathic pain is not well studied in patients with sickle cell disease but has been modeled in the transgenic sickle mouse. Management of sickle cell pain should be based on its own pathophysiologic mechanisms rather than borrowing guidelines from other nonsickle pain syndromes. PMID- 22923497 TI - On the value of portfolio diversity in heart, lung, and blood research. PMID- 22923495 TI - PSTPIP2 deficiency in mice causes osteopenia and increased differentiation of multipotent myeloid precursors into osteoclasts. AB - Missense mutations that reduce or abrogate myeloid cell expression of the F-BAR domain protein, proline serine threonine phosphatase-interacting protein 2 (PSTPIP2), lead to autoinflammatory disease involving extramedullary hematopoiesis, skin and bone lesions. However, little is known about how PSTPIP2 regulates osteoclast development. Here we examined how PSTPIP2 deficiency causes osteopenia and bone lesions, using the mouse PSTPIP2 mutations, cmo, which fails to express PSTPIP2 and Lupo, in which PSTPIP2 is dysfunctional. In both models, serum levels of the pro-osteoclastogenic factor, MIP-1alpha, were elevated and CSF-1 receptor (CSF-1R)-dependent production of MIP-1alpha by macrophages was increased. Treatment of cmo mice with a dual specificity CSF-1R and c-Kit inhibitor, PLX3397, decreased circulating MIP-1alpha and ameliorated the extramedullary hematopoiesis, inflammation, and osteopenia, demonstrating that aberrant myelopoiesis drives disease. Purified osteoclast precursors from PSTPIP2 deficient mice exhibit increased osteoclastogenesis in vitro and were used to probe the structural requirements for PSTPIP2 suppression of osteoclast development. PSTPIP2 tyrosine phosphorylation and a functional F-BAR domain were essential for PSTPIP2 inhibition of TRAP expression and osteoclast precursor fusion, whereas interaction with PEST-type phosphatases was only required for suppression of TRAP expression. Thus, PSTPIP2 acts as a negative feedback regulator of CSF-1R signaling to suppress inflammation and osteoclastogenesis. PMID- 22923498 TI - Reduced DEAF1 function during type 1 diabetes inhibits translation in lymph node stromal cells by suppressing Eif4g3. AB - The transcriptional regulator deformed epidermal autoregulatory factor 1 (DEAF1) has been suggested to play a role in maintaining peripheral tolerance by controlling the transcription of peripheral tissue antigen genes in lymph node stromal cells (LNSCs). Here, we demonstrate that DEAF1 also regulates the translation of genes in LNSCs by controlling the transcription of the poorly characterized eukaryotic translation initiation factor 4 gamma 3 (Eif4g3) that encodes eIF4GII. Eif4g3 gene expression was reduced in the pancreatic lymph nodes of Deaf1-KO mice, non-obese diabetic mice, and type 1 diabetes patients, where functional Deaf1 is absent or diminished. Silencing of Deaf1 reduced Eif4g3 expression, but increased the expression of Caspase 3, a serine protease that degrades eIF4GII. Polysome profiling showed that reduced Eif4g3 expression in LNSCs resulted in the diminished translation of various genes, including Anpep, the gene for aminopeptidase N, an enzyme involved in fine-tuning antigen presentation on major histocompatibility complex (MHC) class II. Together these findings suggest that reduced DEAF1 function, and subsequent loss of Eif4g3 transcription may affect peripheral tissue antigen (PTA) expression in LNSCs and contribute to the pathology of T1D. PMID- 22923499 TI - Activation of the ATM-Snail pathway promotes breast cancer metastasis. AB - The DNA damage response (DDR) is critical for the maintenance of genetic stability and serves as an anti-cancer barrier during early tumorigenesis. However, the role of the DDR in tumor progression and metastasis is less known. Here, we demonstrate that the ATM kinase, one of the critical DDR elements, is hyperactive in late stage breast tumor tissues with lymph-node metastasis and this hyperactivity correlates with elevated expression of the epithelial mesenchymal transition marker, Snail. At the molecular level, we demonstrate that ATM regulates Snail stabilization by phosphorylation on Serine-100. Using mass spectrometry, we identified HSP90 as a critical binding protein of Snail in response to DNA damage. HSP90 binds to and stabilizes phosphorylated Snail. We further provide in vitro and in vivo evidence that activation of ATM-mediated Snail phosphorylation promotes tumor invasion and metastasis. Finally, we demonstrate that Snail Serine-100 phosphorylation is elevated in breast cancer tissues with lymph-node metastasis, indicating clinical significance of the ATM Snail pathway. Together, our findings provide strong evidence that the ATM-Snail pathway promotes tumor metastasis, highlighting a previously undescribed role of the DDR in tumor invasion and metastasis. PMID- 22923500 TI - Locating a plausible binding site for an open-channel blocker, GlyH-101, in the pore of the cystic fibrosis transmembrane conductance regulator. AB - High-throughput screening has led to the identification of small-molecule blockers of the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel, but the structural basis of blocker binding remains to be defined. We developed molecular models of the CFTR channel on the basis of homology to the bacterial transporter Sav1866, which could permit blocker binding to be analyzed in silico. The models accurately predicted the existence of a narrow region in the pore that is a likely candidate for the binding site of an open-channel pore blocker such as N-(2-naphthalenyl)-[(3,5-dibromo-2,4 dihydroxyphenyl)methylene]glycine hydrazide (GlyH-101), which is thought to act by entering the channel from the extracellular side. As a more-stringent test of predictions of the CFTR pore model, we applied induced-fit, virtual, ligand docking techniques to identify potential binding sites for GlyH-101 within the CFTR pore. The highest-scoring docked position was near two pore-lining residues, Phe337 and Thr338, and the rates of reactions of anionic, thiol-directed reagents with cysteines substituted at these positions were slowed in the presence of the blocker, consistent with the predicted repulsive effect of the net negative charge on GlyH-101. When a bulky phenylalanine that forms part of the predicted binding pocket (Phe342) was replaced with alanine, the apparent affinity of the blocker was increased ~200-fold. A molecular mechanics-generalized Born/surface area analysis of GlyH-101 binding predicted that substitution of Phe342 with alanine would substantially increase blocker affinity, primarily because of decreased intramolecular strain within the blocker-protein complex. This study suggests that GlyH-101 blocks the CFTR channel by binding within the pore bottleneck. PMID- 22923501 TI - Resveratrol sensitizes acute myelogenous leukemia cells to histone deacetylase inhibitors through reactive oxygen species-mediated activation of the extrinsic apoptotic pathway. AB - Histone deacetylase inhibitors (HDACIs) activate the prosurvival nuclear factor kappaB (NF-kappaB) pathway by hyperacetylating RelA/p65, whereas the chemopreventive agent resveratrol inhibits NF-kappaB by activating the class III histone deacetylase Sirt1. Interactions between resveratrol and pan-HDACIs (vorinostat and panobinostat) were examined in human acute myelogenous leukemia (AML) cells. Pharmacologically achievable resveratrol concentrations (25-50 MUM) synergistically potentiated HDACI lethality in AML cell lines and primary AML blasts. Resveratrol antagonized RelA acetylation and NF-kappaB activation in HDACI-treated cells. However, short hairpin RNA Sirt1 knockdown failed to modify HDACI sensitivity, which suggests that factors other than or in addition to Sirt1 activation contribute to resveratrol/HDACI interactions. These interactions were associated with death receptor 5 (DR5) up-regulation and caspase-8 activation, whereas cells expressing dominant-negative caspase-8 were substantially protected from resveratrol/HDACI treatment, which suggests a significant functional role for the extrinsic apoptotic pathway in lethality. Exposure to resveratrol with HDACI induced sustained reactive oxygen species (ROS) generation, which was accompanied by increased levels of DNA double-strand breaks, as reflected in gammaH2A.X and comet assays. The free radical scavenger Mn(III)tetrakis(4-benzoic acid)porphyrin chloride blocked ROS generation, DR5 up-regulation, caspase-8 activation, DNA damage, and apoptosis, which indicates a primary role for oxidative injury in lethality. Analyses of cell-cycle progression and 5-ethynyl 2'-deoxyuridine incorporation through flow cytometry revealed that resveratrol induced S-phase accumulation; this effect was abrogated by HDACI coadministration, which suggests that cells undergoing DNA synthesis may be particularly vulnerable to HDACI lethality. Collectively, these findings indicate that resveratrol interacts synergistically with HDACIs in AML cells through multiple ROS-dependent actions, including death receptor up-regulation, extrinsic apoptotic pathway activation, and DNA damage induction. They also raise the possibility that S-phase cells may be particularly susceptible to these actions. PMID- 22923502 TI - Stroke volume-to-wall stress ratio as a load-adjusted and stiffness-adjusted indicator of ventricular systolic performance in chronic loading. AB - Load-adjusted measures of left ventricle (LV) systolic performance are limited by dependence on LV stiffness and afterload. To our knowledge, no stiffness-adjusted and afterload-adjusted indicator was tested in models of pressure (POH) and volume overload hypertrophy (VOH). We hypothesized that wall stress reflects changes in loading, incorporating chamber stiffness and afterload; therefore, stroke volume-to-wall stress ratio more accurately reflects systolic performance. We used rat models of POH (ascending aortic banding) and VOH (aorto-cava shunt). Animals underwent echocardiography and pressure-volume analysis at baseline and dobutamine challenge. We achieved extreme bidirectional alterations in LV systolic performance, end-systolic elastance (Ees), passive stiffness, and arterial elastance (Ea). In POH with LV dilatation and failure, some load independent indicators of systolic performance remained elevated compared with controls, while some others failed to decrease with wide variability. In VOH, most, but not all indicators, including LV ejection fraction, were significantly reduced compared with controls, despite hyperdynamic circulation, lack of heart failure, and preserved contractile reserve. We related systolic performance to Ees adjusted for Ea and LV passive stiffness in multivariate models. Calculated residual Ees was not reduced in POH with heart failure and was reduced in VOH, while it positively correlated to dobutamine dose. Conversely, stroke volume-to wall stress ratio was normal in compensated POH, markedly decreased in POH with heart failure, and, in contrast with LV ejection fraction, normal in VOH. Our results support stroke volume-to-wall stress ratio as a load-adjusted and stiffness-adjusted indicator of systolic function in models of POH and VOH. PMID- 22923504 TI - Comparison of hyperthermic hyperventilation during passive heating and prolonged light and moderate exercise in the heat. AB - Elevation of core temperature leads to increases in ventilation in both resting subjects and those engaged in prolonged exercise. We compared the characteristics of the hyperthermic hyperventilation elicited during passive heating at rest and during prolonged moderate and light exercise. Twelve healthy men performed three trials: a rest trial in which subjects were passively heated using hot-water immersion (41 degrees C) and a water-perfused suit and two exercise trials in which subjects exercised at 25% (light) or 50% (moderate) of peak oxygen uptake in the heat (37 degrees C and 50% relative humidity) after first using water immersion (18 degrees C) to reduce resting esophageal temperature (T(es)). This protocol enabled detection of a T(es) threshold for hyperventilation during the exercise. When minute ventilation (Ve) was expressed as a function of T(es), 9 of the 12 subjects showed T(es) thresholds for hyperventilation in all trials. The T(es) thresholds for increases in Ve during light and moderate exercise (37.1 +/- 0.4 and 36.9 +/- 0.4 degrees C) were both significantly lower than during rest (38.3 +/- 0.6 degrees C), but the T(es) thresholds did not differ between the two exercise intensities. The sensitivity of Ve to increasing T(es) (slope of the T(es)-Ve relation) above the threshold was significantly lower during moderate exercise (8.7 +/- 3.5 l . min(-1) . degrees C(-1)) than during rest (32.5 +/- 24.2 l . min(-1) . degrees C(-1)), but the sensitivity did not differ between light (10.4 +/- 13.0 l . min(-1) . degrees C(-1)) and moderate exercise. These results suggest the core temperature threshold for hyperthermic hyperventilation and the hyperventilatory response to increasing core temperature in passively heated subjects differs from that in exercising subjects, irrespective of whether the exercise is moderate or light. PMID- 22923503 TI - Effects of aging, TNF-alpha, and exercise training on angiotensin II-induced vasoconstriction of rat skeletal muscle arterioles. AB - Skeletal muscle vascular resistance during physical exertion is higher with old age. The purpose of this study was to determine whether 1) aging enhances angiotensin II (ANG II)-induced vasoconstriction; 2) the proinflammatory cytokine tumor necrosis factor (TNF)-alpha contributes to alterations in ANG II-mediated vasoconstriction with aging; 3) exercise training attenuates putative age associated increases in ANG II-mediated vasoconstriction; and 4) the mechanism(s) through which aging and exercise training alters ANG II-induced vasoconstriction in skeletal muscle arterioles. Male Fischer 344 rats were assigned to four groups: young sedentary (4 mo), old sedentary (24 mo), young trained, and old trained. In a separate group of young sedentary and old sedentary animals, a TNF type 1 receptor inhibitor was administered subcutaneously for 10 wk. First-order arterioles were isolated from soleus and gastrocnemius muscles for in vitro experimentation. Old age augmented ANG II-induced vasoconstriction in both soleus (young: 27 +/- 3%; old: 38 +/- 4%) and gastrocnemius (young: 42 +/- 6%; old: 64 +/- 9%) muscle arterioles; this augmented vasoconstriction was abolished with the removal of the endothelium, N(G)-nitro-l-arginine methyl ester, and chronic inhibition of TNF-alpha. In addition, exercise training ameliorated the age induced increase in ANG II vasoconstriction. These findings demonstrate that old age enhances and exercise training diminishes ANG II-induced vasoconstrictor responses in skeletal muscle arterioles through an endothelium-dependent nitric oxide synthase signaling pathway. In addition, the enhancement of ANG II vasoconstriction with old age appears to be related to a proinflammatory state. PMID- 22923505 TI - Mitochondrial ROS and muscle glucose uptake during exercise in transgenic mice. PMID- 22923506 TI - 55th Bowditch Lecture: Effects of chronic hypoxia on the pulmonary circulation: role of HIF-1. AB - When exposed to chronic hypoxia (CH), the pulmonary circulation responds with enhanced contraction and vascular remodeling, resulting in elevated pulmonary arterial pressures. Our work has identified CH-induced alterations in the expression and activity of several ion channels and transporters in pulmonary vascular smooth muscle that contribute to the development of hypoxic pulmonary hypertension and uncovered a critical role for the transcription factor hypoxia inducible factor-1 (HIF-1) in mediating these responses. Current work is focused on the regulation of HIF in the chronically hypoxic lung and evaluation of the potential for pharmacological inhibitors of HIF to prevent, reverse, or slow the progression of pulmonary hypertension. PMID- 22923507 TI - Cardiac structural and hemodynamic changes associated with physiological heart hypertrophy of pregnancy are reversed postpartum. AB - Pregnancy is associated with ventricular hypertrophy and volume overload. Here we investigated whether late pregnancy is associated with cardiac structural and hemodynamic changes, and if these changes are reversed postpartum. Female mice (C57BL/6) were used in nonpregnant diestrus (NP), late-pregnant (LP), or 7-day postpartum (PP7) stages. Echocardiography and cardiac catheterization were performed to monitor cardiac hemodynamics. Transcript expression of proangiogenic vascular endothelial growth factor, cardiac fetal gene osteopontin, cardiac extracellular matrix-degrading enzymes matrix metalloproteinase-2, and a disintegrin and metalloproteinase-15 and -17 were assessed by RT-PCR. Masson trichrome staining for cardiac fibrosis and endothelial marker CD31 immunostaining for angiogenesis were performed. Heart hypertrophy in LP was fully reversed in PP7 (heart weight: NP = 114 +/- 4 mg; LP = 147 +/- 2 mg; PP7 = 117 +/ 8 mg, P < 0.05 for LP vs. PP7). LP had elevated left ventricular (LV) pressure (119 +/- 5 mmHg in LP vs. 92 +/- 7 mmHg in NP, P < 0.05) that was restored at PP7 (95 +/- 8 mmHg, P < 0.001 vs. LP). LP had increased LV contractility (maximal rate of increase of LV pressure = 6,664 +/- 297 mmHg/s in LP vs. 4,294 +/- 568 mmHg/s in NP, P < 0.01) that was restored at PP7 (5,313 +/- 636 mmHg/s, P < 0.05 vs. LP). LV ejection fraction was reduced in LP (LP = 58 +/- 1% vs. NP = 70 +/- 4%, P < 0.001) and was already restored at PP1 (77 +/- 2%, P < 0.001 vs. LP). Myocardial angiogenesis was significantly increased in LP (capillary density = 1.25 +/- 0.02 vs. 0.95 +/- 0.01 capillaries/myocyte in NP, P < 0.001) and was fully restored in PP7 (0.98 +/- 0.01, P < 0.001 vs. LP). Vascular endothelial growth factor was upregulated in LP (LP = 1.4 +/- 0.1 vs. NP = 1 +/- 0.1, normalized to NP, P < 0.001) and was restored in PP7 (PP7 = 0.83 +/- 0.1, P < 0.001 vs. LP). There was no increase in cardiac fibrosis in LP. Matrix metalloproteinase-2 transcript levels were downregulated in LP (LP = 0.47 +/- 0.03 vs. NP = 1 +/- 0.01, normalized to NP, P < 0.001) and was restored at PP7 (0.70 +/- 0.1, P < 0.001 vs. LP). In conclusion, pregnancy-induced heart hypertrophy is associated with transient cardiac dysfunction, increased cardiac angiogenesis, lack of fibrosis, and decreased expression of remodeling enzymes that are reversed postpartum. PMID- 22923508 TI - Functional adaptations in the skeletal muscle microvasculature to endurance and interval sprint training in the type 2 diabetic OLETF rat. AB - Prevention and treatment of type 2 diabetes includes recommendation to perform aerobic exercise, but evidence indicates that high-intensity exercise training may confer greater benefit. Unique motor recruitment patterns during exercise elicit spatially focused increases in blood flow and subsequent adaptations. Therefore, using 20-wk-old Otsuka Long Evans Tokushima fatty (OLETF) rats with advanced insulin resistance, we examined whether 12 wk of exercise protocols that elicit different motor unit recruitment patterns, endurance exercise (EndEx), and interval sprint training (IST) induce spatially differential effects on endothelial-dependent dilation to acetylcholine (ACh; 1 nM-100 MUM) and vasoreactivity to insulin (1-1,000 MUIU/ml) in isolated, pressurized skeletal muscle resistance arterioles. Compared with sedentary OLETF rats, EndEx enhanced sensitivity to ACh in second-order arterioles perfusing the "red" (G2A-R) and "white" (G2A-W) portions of the gastrocnemius (EC(50): +36.0 and +31.7%, respectively), whereas IST only increased sensitivity to ACh in the G2A-R (+35.5%). Significant heterogeneity in the vasomotor response to insulin was observed between EndEx and IST as mean endothelin-1 contribution in EndEx was 27.3 +/- 7.6 and 25.9 +/- 11.0% lower in the G2A-R and G2A-W, respectively. These microvascular effects of exercise were observed in conjunction with training related improvements in glycemic control (HbA1c: 6.84 +/- 0.23, 5.39 +/- 0.06, and 5.30 +/- 0.14% in sedentary, EndEx, and IST, respectively). In summary, this study provides novel evidence that treatment of advanced insulin resistance in the OLETF rat with exercise paradigms that elicit diverse motor recruitment patterns produce differential adaptive responses in endothelial-dependent dilation and in the complex vascular actions of insulin. PMID- 22923509 TI - Neuromuscular factors influencing the maximum stretch limit of the human plantar flexors. AB - Maximum joint range of motion is an important parameter influencing functional performance and musculoskeletal injury risk. Nonetheless, a complete description of the muscle architectural and tendon changes that occur during stretch and the factors influencing maximum range of motion is lacking. We measured muscle-tendon elongation and fascicle lengthening and rotation sonographically during maximal plantar flexor stretches in 21 healthy men. Electromyogram (EMG) recordings were obtained synchronously with ultrasound and joint moment data, and H-reflex measurements were made with the ankle at neutral (0 degrees ) and dorsiflexed (50% maximal passive joint moment) positions; the maximum H amplitude (normalized to maximum M-wave amplitude; M(max)) and H-amplitude elicited at a stimulation intensity that evoked 10% M(max) were obtained. Maximal stretch was accomplished through significant muscle (14.9%; 30 mm) and tendon lengthening (8.4%; 22 mm). There were similar relative changes in fascicle length and angle, but planimetric modeling indicated that the contribution of fascicle rotation to muscle lengthening was small (<4 mm). Subjects with a greater range of motion showed less resistance to stretch and a greater passive joint moment at stretch termination than less flexible subjects (i.e., greater stretch tolerance). Also, greater fascicle rotation accompanied muscle elongation (9.7 vs. 5.9%) and there was a greater tendon length at stretch termination in more flexible subjects. Finally, a moderate correlation between the angle of EMG onset and maximum range of motion was obtained (r = 0.60, P < 0.05), despite there being no difference in H-reflex magnitudes between the groups. Thus clear differences in the neuromuscular responses to stretch were observed between "flexible" and "inflexible" subjects. PMID- 22923511 TI - Re: Hepatocellular carcinoma and other liver diseases among Greenlanders chronically infected with hepatitis B virus: a population-based study. PMID- 22923512 TI - Re: A DNA repair pathway-focused score for prediction of outcomes in ovarian cancer treated with platinum-based chemotherapy. PMID- 22923510 TI - Identification of molecular pathway aberrations in uterine serous carcinoma by genome-wide analyses. AB - BACKGROUND: Uterine cancer is the fourth most common malignancy in women, and uterine serous carcinoma is the most aggressive subtype. However, the molecular pathogenesis of uterine serous carcinoma is largely unknown. We analyzed the genomes of uterine serous carcinoma samples to better understand the molecular genetic characteristics of this cancer. METHODS: Whole-exome sequencing was performed on 10 uterine serous carcinomas and the matched normal blood or tissue samples. Somatically acquired sequence mutations were further verified by Sanger sequencing. The most frequent molecular genetic changes were further validated by Sanger sequencing in 66 additional uterine serous carcinomas and in nine serous endometrial intraepithelial carcinomas (the preinvasive precursor of uterine serous carcinoma) that were isolated by laser capture microdissection. In addition, gene copy number was characterized by single-nucleotide polymorphism (SNP) arrays in 23 uterine serous carcinomas, including 10 that were subjected to whole-exome sequencing. RESULTS: We found frequent somatic mutations in TP53 (81.6%), PIK3CA (23.7%), FBXW7 (19.7%), and PPP2R1A (18.4%) among the 76 uterine serous carcinomas examined. All nine serous carcinomas that had an associated serous endometrial intraepithelial carcinoma had concordant PIK3CA, PPP2R1A, and TP53 mutation status between uterine serous carcinoma and the concurrent serous endometrial intraepithelial carcinoma component. DNA copy number analysis revealed frequent genomic amplification of the CCNE1 locus (which encodes cyclin E, a known substrate of FBXW7) and deletion of the FBXW7 locus. Among 23 uterine serous carcinomas that were subjected to SNP array analysis, seven tumors with FBXW7 mutations (four tumors with point mutations, three tumors with hemizygous deletions) did not have CCNE1 amplification, and 13 (57%) tumors had either a molecular genetic alteration in FBXW7 or CCNE1 amplification. Nearly half of these uterine serous carcinomas (48%) harbored PIK3CA mutation and/or PIK3CA amplification. CONCLUSION: Molecular genetic aberrations involving the p53, cyclin E-FBXW7, and PI3K pathways represent major mechanisms in the development of uterine serous carcinoma. PMID- 22923513 TI - 7 T MRI reveals diffuse iron deposition in putamen and caudate nucleus in CADASIL. AB - OBJECTIVE: Diffuse iron deposition in the brain is commonly found in older people. One of the possible mechanisms that contribute to this iron deposition is cerebral small vessel disease. The aim of this study is to quantify diffuse iron deposition in patients with the hereditary small vessel disease cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). METHODS: 25 NOTCH3 mutation carriers and 18 healthy controls were examined using high-resolution T2*-weighted imaging on a 7 T whole body MRI scanner. Susceptibility-weighted MRI scans were analysed for areas of signal loss and increased phase shift. Phase shift measurements in deep grey nuclei, cortex and subcortical white matter were compared between mutation carriers and controls. For confirmation, ex vivo brain specimens from another three patients with CADASIL were analysed for iron deposition using ex vivo MRI combined with iron histochemistry. RESULTS: In vivo MRI showed areas of decreased signal intensity and increased phase shift in mutation carriers. Compared with healthy controls, mutation carriers had significantly higher phase shift in the putamen (p=0.0002) and caudate nucleus (p=0.006). Ex vivo MRI showed decreased signal intensity in the putamen and caudate nucleus in all specimens. Histochemistry confirmed the presence of iron deposition in these nuclei. CONCLUSIONS: This study demonstrates increased diffuse iron accumulation in the putamen and caudate nucleus in patients with the small vessel disease CADASIL. This supports the hypothesis that small vessel disease contributes to the process of increased iron accumulation in the general population. PMID- 22923514 TI - How reliable is repeated testing for hemispatial neglect? Implications for clinical follow-up and treatment trials. PMID- 22923515 TI - Impact commentaries. Sensory nerve action potentials in patients with peripheral lesions. PMID- 22923516 TI - Genome-wide analysis reveals distinct patterns of epigenetic features in long non coding RNA loci. AB - A major fraction of the transcriptome of higher organisms comprised an extensive repertoire of long non-coding RNA (lncRNA) which express in a cell type and development stage-specific manner. While lncRNAs are a proven component of epigenetic gene expression modulation, epigenetic regulation of lncRNA itself remains poorly understood. Here we have analysed pan-genomic DNA methylation and histone modification marks (H3K4me3, H3K9me3, H3K27me3 and H3K36me3) associated with transcription start site (TSS) of lncRNA in four different cell types and three different tissue types representing various cellular stages. We observe that histone marks associated with active transcription H3K4me3 and H3K36me3 along with the repressive histone mark H3K27me3 have similar distribution pattern around TSS irrespective of cell types. Also, the density of these marks correlates well with expression of protein-coding and lncRNA genes. In contrast, the lncRNA genes harbour higher methylation density around TSS than protein coding genes regardless of their expression status. Furthermore, we found that DNA methylation along with the other repressive histone mark H3K9me3 does not seem to play a role in lncRNA expression. Thus, our observation suggests that epigenetic regulation of lncRNA shares common features with mRNA except the role of DNA methylation which is markedly dissimilar. PMID- 22923517 TI - Structural basis for the substrate recognition and catalysis of peptidyl-tRNA hydrolase. AB - Peptidyl-tRNA hydrolase (Pth) cleaves the ester bond between the peptide and the tRNA of peptidyl-tRNA molecules, which are produced by aborted translation, to recycle tRNA for further rounds of protein synthesis. Pth is ubiquitous in nature, and its enzymatic activity is essential for bacterial viability. We have determined the crystal structure of Escherichia coli Pth in complex with the tRNA CCA-acceptor-TPsiC domain, the enzyme-binding region of the tRNA moiety of the substrate, at 2.4 A resolution. In combination with site-directed mutagenesis studies, the structure identified the amino acid residues involved in tRNA recognition. The structure also revealed that Pth interacts with the tRNA moiety through the backbone phosphates and riboses, and no base-specific interactions were observed, except for the interaction with the highly conserved base G53. This feature enables Pth to accept the diverse sequences of the elongator-tRNAs as substrate components. Furthermore, we propose an authentic Pth:peptidyl-tRNA complex model and a detailed mechanism for the hydrolysis reaction, based on the present crystal structure and the previous studies' results. PMID- 22923518 TI - Identification of a two-layer regulatory network of proliferation-related microRNAs in hepatoma cells. AB - To elucidate how microRNA (miRNA)-regulated networks contribute to the uncontrolled growth of hepatoma cells (HCCs), we identified several proliferation related miRNAs by comparing miRNA expression patterns in clinical HCC samples and growth-arrested HepG2 cells. To explore the molecular functions targeted by these miRNAs, we classified genes differentially expressed in clinical HCC samples into six functional clusters based on their functional similarity. Using target enrichment analysis, we discovered that targets of three proliferation-related miRNAs-miR-101, miR-199a-3p and miR-139-5p-were significantly enriched in the 'transcription regulation' functional cluster. An interactome network consisting of these three miRNAs and genes in the 'transcriptional control' cluster revealed that all three miRNAs were highly connected hubs in the network. All three miRNA centered subnetworks displayed characteristics of a two-layer regulatory architecture, with transcription factors and epigenetic modulators as the first neighbors and genes involved in cell-cycle progression as second neighbors. The overexpression of miR-101 in HepG2 cells reduced the expression of transcription regulators and genes in cell-cycle progression and suppressed the proliferation and colony formation of HepG2 cells. This study not only provides direct experimental data to support the 'miRNA-centered two-layer regulatory network' model, but our results also suggest that such a combinatorial network model may be widely used by miRNAs to regulate critical biological processes. PMID- 22923519 TI - Bacterial topoisomerase I and topoisomerase III relax supercoiled DNA via distinct pathways. AB - Escherichia coli topoisomerases I and III (Topo I and Topo III) relax negatively supercoiled DNA and also catenate/decatenate DNA molecules containing single stranded DNA regions. Although these enzymes share the same mechanism of action and have similar structures, they participate in different cellular processes. In bulk experiments Topo I is more efficient at DNA relaxation, whereas Topo III is more efficient at catenation/decatenation, probably reflecting their differing cellular roles. To examine the differences in the mechanism of these two related type IA topoisomerases, single-molecule relaxation studies were conducted on several DNA substrates: negatively supercoiled DNA, positively supercoiled DNA with a mismatch and positively supercoiled DNA with a bulge. The experiments show differences in the way the two proteins work at the single-molecule level, while also recovering observations from the bulk experiments. Overall, Topo III relaxes DNA efficiently in fast processive runs, but with long pauses before relaxation runs, whereas Topo I relaxes DNA in slow processive runs but with short pauses before runs. The combination of these properties results in Topo I having an overall faster total relaxation rate, even though the relaxation rate during a run for Topo III is much faster. PMID- 22923520 TI - Recognition of the 70S ribosome and polysome by the RNA degradosome in Escherichia coli. AB - The RNA degradosome is a multi-enzyme assembly that contributes to key processes of RNA metabolism, and it engages numerous partners in serving its varied functional roles. Small domains within the assembly recognize collectively a diverse range of macromolecules, including the core protein components, the cytoplasmic lipid membrane, mRNAs, non-coding regulatory RNAs and precursors of structured RNAs. We present evidence that the degradosome can form a stable complex with the 70S ribosome and polysomes, and we demonstrate the proximity in vivo of ribosomal proteins and the scaffold of the degradosome, RNase E. The principal interactions are mapped to two, independent, RNA-binding domains from RNase E. RhlB, the RNA helicase component of the degradosome, also contributes to ribosome binding, and this is favoured through an activating interaction with RNase E. The catalytic activity of RNase E for processing 9S RNA (the ribosomal 5S RNA precursor) is repressed in the presence of the ribosome, whereas there is little affect on the cleavage of single-stranded substrates mediated by non coding RNA, suggestings that the enzyme retains capacity to cleave unstructured substrates when associated with the ribosome. We propose that polysomes may act as antennae that enhance the rates of capture of the limited number of degradosomes, so that they become recruited to sites of active translation to act on mRNAs as they become exposed or tagged for degradation. PMID- 22923521 TI - Targeted manipulation of heterochromatin rescues MeCP2 Rett mutants and re establishes higher order chromatin organization. AB - Heterochromatic regions represent a significant portion of the mammalian genome and have been implied in several important cellular processes, including cell division and genomic stability. However, its composition and dynamics remain largely unknown. To better understand how heterochromatin functions and how it is organized within the context of the cell nucleus, we have developed molecular tools allowing the targeting of virtually any nuclear factor specifically to heterochromatic regions and, thereby, the manipulation, also in a temporally controlled manner, of its composition. To validate our approach, we have ectopically targeted MeCP2 chromatin binding deficient Rett mutants to constitutive heterochromatic regions and analyze its functional consequences. We could show that, once bound to their endogenous target regions, their ability to re-organize higher order chromatin structure is restored. Furthermore, a temporally controlled targeting strategy allowed us to monitor MeCP2-mediated chromatin rearrangements in vivo and to visualize large-scale chromatin movements over several micrometers, as well as heterochromatic foci fusion events. This novel strategy enables specific tethering of any protein to heterochromatin and lays the ground for controlled manipulation of its composition and organization. PMID- 22923522 TI - Repeat or not repeat?--Statistical validation of tandem repeat prediction in genomic sequences. AB - Tandem repeats (TRs) represent one of the most prevalent features of genomic sequences. Due to their abundance and functional significance, a plethora of detection tools has been devised over the last two decades. Despite the longstanding interest, TR detection is still not resolved. Our large-scale tests reveal that current detectors produce different, often nonoverlapping inferences, reflecting characteristics of the underlying algorithms rather than the true distribution of TRs in genomic data. Our simulations show that the power of detecting TRs depends on the degree of their divergence, and repeat characteristics such as the length of the minimal repeat unit and their number in tandem. To reconcile the diverse predictions of current algorithms, we propose and evaluate several statistical criteria for measuring the quality of predicted repeat units. In particular, we propose a model-based phylogenetic classifier, entailing a maximum-likelihood estimation of the repeat divergence. Applied in conjunction with the state of the art detectors, our statistical classification scheme for inferred repeats allows to filter out false-positive predictions. Since different algorithms appear to specialize at predicting TRs with certain properties, we advise applying multiple detectors with subsequent filtering to obtain the most complete set of genuine repeats. PMID- 22923523 TI - Dynamic regulation of HIV-1 mRNA populations analyzed by single-molecule enrichment and long-read sequencing. AB - Alternative RNA splicing greatly expands the repertoire of proteins encoded by genomes. Next-generation sequencing (NGS) is attractive for studying alternative splicing because of the efficiency and low cost per base, but short reads typical of NGS only report mRNA fragments containing one or few splice junctions. Here, we used single-molecule amplification and long-read sequencing to study the HIV-1 provirus, which is only 9700 bp in length, but encodes nine major proteins via alternative splicing. Our data showed that the clinical isolate HIV-1(89.6) produces at least 109 different spliced RNAs, including a previously unappreciated ~1 kb class of messages, two of which encode new proteins. HIV-1 message populations differed between cell types, longitudinally during infection, and among T cells from different human donors. These findings open a new window on a little studied aspect of HIV-1 replication, suggest therapeutic opportunities and provide advanced tools for the study of alternative splicing. PMID- 22923524 TI - Improved predictions of transcription factor binding sites using physicochemical features of DNA. AB - Typical approaches for predicting transcription factor binding sites (TFBSs) involve use of a position-specific weight matrix (PWM) to statistically characterize the sequences of the known sites. Recently, an alternative physicochemical approach, called SiteSleuth, was proposed. In this approach, a linear support vector machine (SVM) classifier is trained to distinguish TFBSs from background sequences based on local chemical and structural features of DNA. SiteSleuth appears to generally perform better than PWM-based methods. Here, we improve the SiteSleuth approach by considering both new physicochemical features and algorithmic modifications. New features are derived from Gibbs energies of amino acid-DNA interactions and hydroxyl radical cleavage profiles of DNA. Algorithmic modifications consist of inclusion of a feature selection step, use of a nonlinear kernel in the SVM classifier, and use of a consensus-based post processing step for predictions. We also considered SVM classification based on letter features alone to distinguish performance gains from use of SVM-based models versus use of physicochemical features. The accuracy of each of the variant methods considered was assessed by cross validation using data available in the RegulonDB database for 54 Escherichia coli TFs, as well as by experimental validation using published ChIP-chip data available for Fis and Lrp. PMID- 22923525 TI - Detection of alternative lengthening of telomeres by telomere quantitative PCR. AB - Alternative lengthening of telomeres (ALT) is one of the two known telomere length maintenance mechanisms that are essential for the unlimited proliferation potential of cancer cells. Existing methods for detecting ALT in tumors require substantial amounts of tumor material and are labor intensive, making it difficult to study prevalence and prognostic significance of ALT in large tumor cohorts. Here, we present a novel strategy utilizing telomere quantitative PCR to diagnose ALT. The protocol is more rapid than conventional methods and scrutinizes two distinct characteristics of ALT cells concurrently: long telomeres and the presence of C-circles (partially double-stranded circles of telomeric C-strand DNA). Requiring only 30 ng of genomic DNA, this protocol will facilitate large-scale studies of ALT in tumors and can be readily adopted by clinical laboratories. PMID- 22923527 TI - Good reason to test for vitamin D deficiency. PMID- 22923526 TI - Crystal structure of RlmM, the 2'O-ribose methyltransferase for C2498 of Escherichia coli 23S rRNA. AB - RlmM (YgdE) catalyzes the S-adenosyl methionine (AdoMet)-dependent 2'O methylation of C2498 in 23S ribosomal RNA (rRNA) of Escherichia coli. Previous experiments have shown that RlmM is active on 23S rRNA from an RlmM knockout strain but not on mature 50S subunits from the same strain. Here, we demonstrate RlmM methyltransferase (MTase) activity on in vitro transcribed 23S rRNA and its domain V. We have solved crystal structures of E. coli RlmM at 1.9 A resolution and of an RlmM-AdoMet complex at 2.6 A resolution. RlmM consists of an N-terminal THUMP domain and a C-terminal catalytic Rossmann-like fold MTase domain in a novel arrangement. The catalytic domain of RlmM is closely related to YiiB, TlyA and fibrillarins, with the second K of the catalytic tetrad KDKE shifted by two residues at the C-terminal end of a beta strand compared with most 2'O MTases. The AdoMet-binding site is open and shallow, suggesting that RNA substrate binding may be required to form a conformation needed for catalysis. A continuous surface of conserved positive charge indicates that RlmM uses one side of the two domains and the inter-domain linker to recognize its RNA substrate. PMID- 22923528 TI - Being aware of opposite dangers. PMID- 22923529 TI - Yes, let's take down the BMJ pay wall. PMID- 22923530 TI - Deaths associated with new designer drug 5-IT. PMID- 22923531 TI - Pathologists and coroners must work together on retaining tissue at necropsy. PMID- 22923532 TI - Escherichia coli O157 causes blood stained nappies. PMID- 22923533 TI - What should doctors do about fasting during Ramadan? PMID- 22923534 TI - Early management of acutely ill ward patients. PMID- 22923535 TI - Hypovitaminosis D and disease: consequence rather than cause? PMID- 22923536 TI - Vitamin D: don't forget mental health. PMID- 22923537 TI - No incentives for new NHS commissioners to act for children. PMID- 22923538 TI - Potential sources of overdiagnosis in histopathology. PMID- 22923539 TI - Transfer of high cost drugs to NICE risks fragmentation of care of rare diseases. PMID- 22923540 TI - The V word: selling genital hygiene products to women. PMID- 22923541 TI - Donation must be a gift. PMID- 22923542 TI - Consolidate the donor register with unambiguous affirmation from next of kin. PMID- 22923543 TI - The ups and downs of dialysate calcium concentration in haemodialysis patients. PMID- 22923544 TI - What can the dialysis physician learn from kinetic modelling beyond Kt/V(urea)? PMID- 22923546 TI - Socio-economic status and incidence of renal replacement therapy: a registry study of Australian patients. AB - BACKGROUND: Socio-economic disadvantage has been linked to higher incidence of end-stage kidney disease in developed countries. Associations between socio economic status (SES) and incidence of renal replacement therapy (RRT) have not been explored for different kidney diseases, genders or age groups in a country with universal access to healthcare. METHODS: We investigated the incidence of non-indigenous patients commencing RRT in Australia in 2000-09, using the Australia and New Zealand Dialysis and Transplant (ANZDATA) Registry. Patient postcodes were grouped into deciles using a standard SES index. We analysed incidence by five groups of kidney diseases, age groups, gender and geographic remoteness. RESULTS: Incidence of RRT decreased with increasing area advantage. Differences were most evident for the most disadvantaged areas [markedly increased burden; incident rate ratio (IRR) 1.27; 95% confidence interval (CI) 1.18-1.38] and most advantaged decile (decreased burden, IRR 0.76; 95% CI 0.72 0.81), compared with decile 5. Patients with diabetic nephropathy showed the greatest disparities: residents of the most disadvantaged decile were 2.38 (95% CI 2.09-2.71) times more at risk than the most advantaged decile. Congenital and genetic kidney diseases showed lesser gradients-the most disadvantaged decile was 1.28 times (95% CI 0.98-1.68) more at risk. SES was not associated with incidence for patients older than 69 years. DISCUSSION: These SES gradients existed, despite all Australians having access to healthcare. Diseases associated with lifestyle show the greatest gradients with SES. PMID- 22923548 TI - A new dawn for science in Africa. PMID- 22923545 TI - Chronic renovascular hypertension is associated with elevated levels of neutrophil gelatinase-associated lipocalin. AB - BACKGROUND: Renovascular hypertension (RVH) is characterized by chronic inflammation of the stenotic kidney and progressive renal dysfunction. Neutrophil gelatinase-associated lipocalin (NGAL), an acute phase protein induced in inflammatory conditions and ischemia, is a novel biomarker for acute kidney injury. We hypothesized that chronic RVH would be associated with increased renal and circulating NGAL levels. METHODS: We prospectively measured renal vein and inferior vena cava (IVC) levels of NGAL and inflammatory cytokines in essential hypertensive (EH) and RVH patients, during constant sodium intake and anti hypertensive regimens, and compared them with systemic levels in age-matched normotensive subjects (n = 22 each). In addition, we measured urinary NGAL and kidney injury molecule (KIM)-1 in all patients. RESULTS: Blood pressure, serum creatinine, estimated glomerular filtration rate (eGFR), lipid panels and medications were similar in RVH and EH. Systemic, stenotic and contralateral renal vein levels of NGAL were all similarly elevated in RVH versus normal hypertension and EH (P < 0.05), as were renal vein levels of inflammatory markers like tumor necrosis factor-alpha. Furthermore, renal vein NGAL levels inversely correlated with eGFR, and directly with renal vein (but not systemic) levels of inflammatory markers. Urinary levels of NGAL and KIM-1 were elevated in both EH and RVH, as were systemic levels of C-reactive protein. CONCLUSIONS: Chronic RVH is associated with elevated NGAL levels, likely due to ongoing kidney and systemic inflammation and ischemia. These findings may also imply the occurrence of the inflammation process in chronic RVH, which might contribute to the poorer outcomes of RVH compared with EH patients. PMID- 22923553 TI - Astronomy. Panel says NSF should shutter six U.S. instruments. PMID- 22923554 TI - China. Dinosaur kingpin opens fossil bonanza to science. PMID- 22923555 TI - Linguistics. New method puts elusive Indo-European homeland in Anatolia. PMID- 22923556 TI - Infectious disease. Calling all baby boomers: get your hepatitis C test. PMID- 22923557 TI - Ecology and evolution. The great guppy experiment. PMID- 22923559 TI - Archaeology. Economic crisis forces Spanish archaeology to rethink its roots. PMID- 22923558 TI - Ecology and evolution. Eco-evo effects up and down the food chain. PMID- 22923560 TI - Personalized medicine: temper expectations. PMID- 22923564 TI - Water management. Water security: research challenges and opportunities. PMID- 22923565 TI - Astronomy. Probing black hole gravity. PMID- 22923566 TI - Climate change. A long view on climate sensitivity. PMID- 22923567 TI - Molecular biology. How to read the chromatin past. PMID- 22923568 TI - Materials science. Retaining the nano in nanocrystalline alloys. PMID- 22923569 TI - Cell biology. The unusual case of Porcupine. PMID- 22923570 TI - Biochemistry. Walking on solid ground. PMID- 22923571 TI - Cancer. Glycosylation to adapt to stress. PMID- 22923572 TI - Luminous supernovae. AB - Supernovae, the luminous explosions of stars, have been observed since antiquity. However, various examples of superluminous supernovae (SLSNe; luminosities >7 * 10(43) ergs per second) have only recently been documented. From the accumulated evidence, SLSNe can be classified as radioactively powered (SLSN-R), hydrogen rich (SLSN-II), and hydrogen-poor (SLSN-I, the most luminous class). The SLSN-II and SLSN-I classes are more common, whereas the SLSN-R class is better understood. The physical origins of the extreme luminosity emitted by SLSNe are a focus of current research. PMID- 22923573 TI - Gamma-ray bursts. AB - Gamma-ray bursts (GRBs) are bright flashes of gamma rays coming from the cosmos. They occur roughly once per day, typically last for tens of seconds, and are the most luminous events in the universe. More than three decades after their discovery, and after pioneering advances from space and ground experiments, they still remain mysterious. The launch of the Swift and Fermi satellites in 2004 and 2008 brought in a trove of qualitatively new data. In this Review, we survey the interplay between these recent observations and the theoretical models of the prompt GRB emission and the subsequent afterglow. PMID- 22923575 TI - PTF 11kx: a type Ia supernova with a symbiotic nova progenitor. AB - There is a consensus that type Ia supernovae (SNe Ia) arise from the thermonuclear explosion of white dwarf stars that accrete matter from a binary companion. However, direct observation of SN Ia progenitors is lacking, and the precise nature of the binary companion remains uncertain. A temporal series of high-resolution optical spectra of the SN Ia PTF 11kx reveals a complex circumstellar environment that provides an unprecedentedly detailed view of the progenitor system. Multiple shells of circumstellar material are detected, and the SN ejecta are seen to interact with circumstellar material starting 59 days after the explosion. These features are best described by a symbiotic nova progenitor, similar to RS Ophiuchi. PMID- 22923574 TI - A periciliary brush promotes the lung health by separating the mucus layer from airway epithelia. AB - Mucus clearance is the primary defense mechanism that protects airways from inhaled infectious and toxic agents. In the current gel-on-liquid mucus clearance model, a mucus gel is propelled on top of a "watery" periciliary layer surrounding the cilia. However, this model fails to explain the formation of a distinct mucus layer in health or why mucus clearance fails in disease. We propose a gel-on-brush model in which the periciliary layer is occupied by membrane-spanning mucins and mucopolysaccharides densely tethered to the airway surface. This brush prevents mucus penetration into the periciliary space and causes mucus to form a distinct layer. The relative osmotic moduli of the mucus and periciliary brush layers explain both the stability of mucus clearance in health and its failure in airway disease. PMID- 22923576 TI - Absorption features in the x-ray spectrum of an ordinary radio pulsar. AB - The vast majority of known nonaccreting neutron stars (NSs) are rotation-powered radio and/or gamma-ray pulsars. So far, their multiwavelength spectra have all been described satisfactorily by thermal and nonthermal continuum models, with no spectral lines. Spectral features have, however, been found in a handful of exotic NSs and were thought to be a manifestation of their unique traits. Here, we report the detection of absorption features in the x-ray spectrum of an ordinary rotation-powered radio pulsar, J1740+1000. Our findings bridge the gap between the spectra of pulsars and other, more exotic, NSs, suggesting that the features are more common in the NS spectra than they have been thought so far. PMID- 22923577 TI - Design of stable nanocrystalline alloys. AB - Nanostructured metals are generally unstable; their grains grow rapidly even at low temperatures, rendering them difficult to process and often unsuitable for usage. Alloying has been found to improve stability, but only in a few empirically discovered systems. We have developed a theoretical framework with which stable nanostructured alloys can be designed. A nanostructure stability map based on a thermodynamic model is applied to design stable nanostructured tungsten alloys. We identify a candidate alloy, W-Ti, and demonstrate substantially enhanced stability for the high-temperature, long-duration conditions amenable to powder-route production of bulk nanostructured tungsten. This nanostructured alloy adopts a heterogeneous chemical distribution that is anticipated by the present theoretical framework but unexpected on the basis of conventional bulk thermodynamics. PMID- 22923578 TI - Stepwise evolution of spherical seeds into 20-fold twinned icosahedra. AB - Understanding the factors that influence the growth and final shape of noble metal nanostructures is important for controlling their properties. However, relative to their single-crystalline counterparts, the growth of nanoparticles that contain twin defects can be difficult to control because multiple competitive growth pathways can yield such structures. We used spherical, cubic, and octahedral single-crystalline gold nanoparticles as dual electron microscopy labels and plasmonic seeds to track the growth of multiply twinned silver nanostructures. As the bimetallic nanostructures grew, they successively developed twin planes to ultimately form multiply twinned nanoparticles from single-crystalline seeds. Collectively, these data demonstrate how a series of nanoparticles of different shapes and internal crystal structures are interrelated and develop from one another. PMID- 22923579 TI - Mapping the origins and expansion of the Indo-European language family. AB - There are two competing hypotheses for the origin of the Indo-European language family. The conventional view places the homeland in the Pontic steppes about 6000 years ago. An alternative hypothesis claims that the languages spread from Anatolia with the expansion of farming 8000 to 9500 years ago. We used Bayesian phylogeographic approaches, together with basic vocabulary data from 103 ancient and contemporary Indo-European languages, to explicitly model the expansion of the family and test these hypotheses. We found decisive support for an Anatolian origin over a steppe origin. Both the inferred timing and root location of the Indo-European language trees fit with an agricultural expansion from Anatolia beginning 8000 to 9500 years ago. These results highlight the critical role that phylogeographic inference can play in resolving debates about human prehistory. PMID- 22923580 TI - Assembly of an evolutionarily new pathway for alpha-pyrone biosynthesis in Arabidopsis. AB - Plants possess arrays of functionally diverse specialized metabolites, many of which are distributed taxonomically. Here, we describe the evolution of a class of substituted alpha-pyrone metabolites in Arabidopsis, which we have named arabidopyrones. The biosynthesis of arabidopyrones requires a cytochrome P450 enzyme (CYP84A4) to generate the catechol-substituted substrate for an extradiol ring-cleavage dioxygenase (AtLigB). Unlike other ring-cleavage-derived plant metabolites made from tyrosine, arabidopyrones are instead derived from phenylalanine through the early steps of phenylpropanoid metabolism. Whereas CYP84A4, an Arabidopsis-specific paralog of the lignin-biosynthetic enzyme CYP84A1, has neofunctionalized relative to its ancestor, AtLigB homologs are widespread among land plants and many bacteria. This study exemplifies the rapid evolution of a biochemical pathway formed by the addition of a new biological activity into an existing metabolic infrastructure. PMID- 22923581 TI - Cis-acting transcriptional repression establishes a sharp boundary in chordate embryos. AB - The function of bone morphogenetic protein (BMP) signaling in dorsoventral (DV) patterning of animal embryos is conserved among Bilateria. In vertebrates, the BMP ligand antidorsalizing morphogenetic protein (Admp) is expressed dorsally and moves to the opposite side to specify the ventral fate. Here, we show that Pinhead is an antagonist specific for Admp with a role in establishing the DV axis of the trunk epidermis in embryos of the ascidian Ciona intestinalis. Pinhead and Admp exist in tandem in the genomes of various animals from arthropods to vertebrates. This genomic configuration is important for mutually exclusive expression of these genes, because Pinhead transcription directly disturbs the action of the Admp enhancer. Our data suggest that this dual negative regulatory mechanism is widely conserved in animals. PMID- 22923582 TI - Dense chromatin activates Polycomb repressive complex 2 to regulate H3 lysine 27 methylation. AB - Polycomb repressive complex 2 (PRC2)-mediated histone H3 lysine 27 (H3K27) methylation is vital for Polycomb gene silencing, a classic epigenetic phenomenon that maintains transcriptional silencing throughout cell divisions. We report that PRC2 activity is regulated by the density of its substrate nucleosome arrays. Neighboring nucleosomes activate the PRC2 complex with a fragment of their H3 histones (Ala(31) to Arg(42)). We also identified mutations on PRC2 subunit Su(z)12, which impair its binding and response to the activating peptide and its ability in establishing H3K27 trimethylation levels in vivo. In mouse embryonic stem cells, local chromatin compaction occurs before the formation of trimethylated H3K27 upon transcription cessation of the retinoic acid-regulated gene CYP26a1. We propose that PRC2 can sense the chromatin environment to exert its role in the maintenance of transcriptional states. PMID- 22923584 TI - A window on the psychiatric mind. PMID- 22923583 TI - Phosphofructokinase 1 glycosylation regulates cell growth and metabolism. AB - Cancer cells must satisfy the metabolic demands of rapid cell growth within a continually changing microenvironment. We demonstrated that the dynamic posttranslational modification of proteins by O-linked beta-N-acetylglucosamine (O-GlcNAcylation) is a key metabolic regulator of glucose metabolism. O GlcNAcylation was induced at serine 529 of phosphofructokinase 1 (PFK1) in response to hypoxia. Glycosylation inhibited PFK1 activity and redirected glucose flux through the pentose phosphate pathway, thereby conferring a selective growth advantage on cancer cells. Blocking glycosylation of PFK1 at serine 529 reduced cancer cell proliferation in vitro and impaired tumor formation in vivo. These studies reveal a previously uncharacterized mechanism for the regulation of metabolic pathways in cancer and a possible target for therapeutic intervention. PMID- 22923585 TI - South London Healthcare Trust may be run by the private sector or broken up. PMID- 22923586 TI - G20 pathologist is struck off. PMID- 22923587 TI - PAS domain residues and prosthetic group involved in BdlA-dependent dispersion response by Pseudomonas aeruginosa biofilms. AB - Biofilm dispersion by Pseudomonas aeruginosa in response to environmental cues is dependent on the cytoplasmic BdlA protein harboring two sensory PAS domains and a chemoreceptor domain, TarH. The closest known and previously characterized BdlA homolog is the flavin adenine dinucleotide (FAD)-binding Aer, the redox potential sensor and aerotaxis transducer in Escherichia coli. Here, we made use of alanine replacement mutagenesis of the BdlA PAS domain residues previously demonstrated to be essential for aerotaxis in Aer to determine whether BdlA is a potential sensory protein. Five substitutions (D14A, N23A, W60A, I109A, and W182A) resulted in a null phenotype for dispersion. One protein, the BdlA protein with the G31A mutation (BdlA-G31A), transmitted a constant signal-on bias as it rendered P. aeruginosa biofilms hyperdispersive. The hyperdispersive phenotype correlated with increased interaction of BdlA-G31A with the phosphodiesterase DipA under biofilm growth conditions, resulting in increased phosphodiesterase activity and reduced biofilm biomass accumulation. We furthermore demonstrate that BdlA is a heme-binding protein. None of the BdlA protein variants analyzed led to a loss of the heme prosthetic group. The N-terminal PASa domain was identified as the heme binding domain of BdlA, with BdlA-dependent nutrient-induced dispersion requiring the PASa domain. The findings suggest that BdlA plays a role in intracellular sensing of dispersion-inducing conditions and together with DipA forms a regulatory network that modulates an intracellular cyclic d-GMP (c-di-GMP) pool to enable dispersion. PMID- 22923588 TI - Characterization of axial and proximal histidine mutations of the decaheme cytochrome MtrA from Shewanella sp. strain ANA-3 and implications for the electron transport system. AB - Extracellular respiration of solid-phase electron acceptors in some microorganisms requires a complex chain of multiheme c-type cytochromes that span the inner and outer membranes. In Shewanella species, MtrA, an ~35-kDa periplasmic decaheme c-type cytochrome, is an essential component for extracellular respiration of iron(III). The exact mechanism of electron transport has not yet been resolved, but the arrangement of the polypeptide chain may have a strong influence on the capability of the MtrA cytochrome to transport electrons. The iron hemes of MtrA are bound to its polypeptide chain via proximal (CXXCH) and distal histidine residues. In this study, we show the effects of mutating histidine residues of MtrA to arginine on protein expression and extracellular respiration using Shewanella sp. strain ANA-3 as a model organism. Individual mutations to six out of nine proximal histidines in CXXCH of MtrA led to decreased protein expression. However, distal histidine mutations resulted in various degrees of protein expression. In addition, the effects of histidine mutations on extracellular respiration were tested using ferrihydrite and current production in microbial fuel cells. These results show that proximal histidine mutants were unable to reduce ferrihydrite. Mutations to the distal histidine residues resulted in various degrees of ferrihydrite reduction. These findings indicate that mutations to the proximal histidine residues affect MtrA expression, leading to loss of extracellular respiration ability. In contrast, mutations to the distal histidine residues are less detrimental to protein expression, and extracellular respiration can proceed. PMID- 22923589 TI - Characterization of novel phages isolated in coagulase-negative staphylococci reveals evolutionary relationships with Staphylococcus aureus phages. AB - Despite increasing interest in coagulase-negative staphylococci (CoNS), little information is available about their bacteriophages. We isolated and sequenced three novel temperate Siphoviridae phages (StB12, StB27, and StB20) from the CoNS Staphylococcus hominis and S. capitis species. The genome sizes are around 40 kb, and open reading frames (ORFs) are arranged in functional modules encoding lysogeny, DNA metabolism, morphology, and cell lysis. Bioinformatics analysis allowed us to assign a potential function to half of the predicted proteins. Structural elements were further identified by proteomic analysis of phage particles, and DNA-packaging mechanisms were determined. Interestingly, the three phages show identical integration sites within their host genomes. In addition to this experimental characterization, we propose a novel classification based on the analysis of 85 phage and prophage genomes, including 15 originating from CoNS. Our analysis established 9 distinct clusters and revealed close relationships between S. aureus and CoNS phages. Genes involved in DNA metabolism and lysis and potentially in phage-host interaction appear to be widespread, while structural genes tend to be cluster specific. Our findings support the notion of a possible reciprocal exchange of genes between phages originating from S. aureus and CoNS, which may be of crucial importance for pathogenesis in staphylococci. PMID- 22923590 TI - Dynamics of the SetCD-regulated integration and excision of genomic islands mobilized by integrating conjugative elements of the SXT/R391 family. AB - Mobilizable genomic islands (MGIs) are small genomic islands that are mobilizable by SXT/R391 integrating conjugative elements (ICEs) due to similar origins of transfer. Their site-specific integration and excision are catalyzed by the integrase that they encode, but their conjugative transfer entirely depends upon the conjugative machinery of SXT/R391 ICEs. In this study, we report the mechanisms that control the excision and integration processes of MGIs. We found that while the MGI-encoded integrase Int(MGI) is sufficient to promote MGI integration, efficient excision from the host chromosome requires the combined action of Int(MGI) and of a novel recombination directionality factor, RdfM. We determined that the genes encoding these proteins are activated by SetCD, the main transcriptional activators of SXT/R391 ICEs. Although they share the same regulators, we found that unlike rdfM, int(MGI) has a basal level of expression in the absence of SetCD. These findings explain how an MGI can integrate into the chromosome of a new host in the absence of a coresident ICE and shed new light on the cross talk that can occur between mobilizable and mobilizing elements that mobilize them, helping us to understand part of the rules that dictate horizontal transfer mechanisms. PMID- 22923591 TI - Whole surface image of Mycoplasma mobile, suggested by protein identification and immunofluorescence microscopy. AB - Mycoplasma mobile, a freshwater fish pathogen featured with robust gliding motility, binds to the surface of the gill, where it then colonizes. Here, to obtain a whole image of its cell surface, we identified the proteins exposed on the surface using the following methods. (i) The cell surface was labeled with sulfosuccinimidyl-6-(biotinamido) hexanoate and recovered by an avidin column. (ii) The cells were subjected to phase partitioning using Triton X-114, and the hydrophobic proteins were recovered. (iii) The membrane fraction was analyzed by two-dimensional gel electrophoresis. These recovered proteins were subjected to peptide mass fingerprinting, and a final list of 36 expressed surface proteins was established. The ratio of identified proteins to whole surface proteins was estimated through two-dimensional gel electrophoresis of the membrane fraction. The localization of three newly found proteins, Mvsps C, E, and F, has been clarified by immunofluorescence microscopy. Integrating all information, a whole image of the cell surface showed that the proteins for gliding that were localized at the base of the protrusion of flask-shaped M. mobile account for more than 12% of all surface proteins and that Mvsps, surface variants that were localized at both parts other than the neck, account for 49% of all surface proteins. PMID- 22923592 TI - Three mutations in Escherichia coli that generate transformable functional flagella. AB - Hydrodynamics predicts that swimming bacteria generate a propulsion force when a helical flagellum rotates because rotating helices necessarily translate at a low Reynolds number. It is generally believed that the flagella of motile bacteria are semirigid helices with a fixed pitch determined by hydrodynamic principles. Here, we report the characterization of three mutations in laboratory strains of Escherichia coli that produce different steady-state flagella without losing cell motility. E. coli flagella rotate counterclockwise during forward swimming, and the normal form of the flagella is a left-handed helix. A single amino acid exchange A45G and a double mutation of A48S and S110A change the resting flagella to right-handed helices. The stationary flagella of the triple mutant were often straight or slightly curved at neutral pH. Deprotonation facilitates the helix formation of it. The helical and curved flagella can be transformed to the normal form by torsion upon rotation and thus propel the cell. These mutations arose in the long-term laboratory cultivation. However, flagella are under strong selection pressure as extracellular appendages, and similar transformable flagella would be common in natural environments. PMID- 22923593 TI - Functional characterization of the RNA chaperone Hfq in the opportunistic human pathogen Stenotrophomonas maltophilia. AB - Hfq is an RNA-binding protein known to regulate a variety of cellular processes by interacting with small RNAs (sRNAs) and mRNAs in prokaryotes. Stenotrophomonas maltophilia is an important opportunistic pathogen affecting primarily hospitalized and immunocompromised hosts. We constructed an hfq deletion mutant (Deltahfq) of S. maltophilia and compared the behaviors of wild-type and Deltahfq S. maltophilia cells in a variety of assays. This revealed that S. maltophilia Hfq plays a role in biofilm formation and cell motility, as well as susceptibility to antimicrobial agents. Moreover, Hfq is crucial for adhesion to bronchial epithelial cells and is required for the replication of S. maltophilia in macrophages. Differential RNA sequencing analysis (dRNA-seq) of RNA isolated from S. maltophilia wild-type and Deltahfq strains showed that Hfq regulates the expression of genes encoding flagellar and fimbrial components, transmembrane proteins, and enzymes involved in different metabolic pathways. Moreover, we analyzed the expression of several sRNAs identified by dRNA-seq in wild-type and Deltahfq S. maltophilia cells grown in different conditions on Northern blots. The accumulation of two sRNAs was strongly reduced in the absence of Hfq. Furthermore, based on our dRNA-seq analysis we provide a genome-wide map of transcriptional start sites in S. maltophilia. PMID- 22923594 TI - Burkholderia xenovorans RcoM(Bx)-1, a transcriptional regulator system for sensing low and persistent levels of carbon monoxide. AB - The single-component RcoM transcription factor couples an N-terminally bound heme cofactor with a C-terminal "LytTR" DNA-binding domain. Here the RcoM(Bx)-1 protein from Burkholderia xenovorans LB400 was heterologously expressed and then purified in a form with minimal bound CO (~10%) and was found to stably bind this effector with a nanomolar affinity. DNase I protection assays demonstrated that the CO-associated form binds with a micromolar affinity to two ~60-bp DNA regions, each comprised of a novel set of three direct-repeat binding sites spaced 21 bp apart on center. Binding to each region was independent, while binding to the triplet binding sites within a region was cooperative, depended upon spacing and sequence, and was marked by phased DNase I hyperactivity and protection patterns consistent with considerable changes in the DNA conformation of the nucleoprotein complex. Each protected binding site spanned a conserved motif (5'-TTnnnG-3') that was present, in triplicate, in putative RcoM-binding regions of more than a dozen organisms. In vivo screens confirmed the functional importance of the conserved "TTnnnG" motif residues and their triplet arrangement and were also used to determine an improved binding motif [5' CnnC(C/A)(G/A)TTCAnG-3'] that more closely corresponds to canonical LytTR domain/DNA-binding sites. A low-affinity but CO-dependent binding of RcoM(Bx)-1 to a variety of DNA probes was demonstrated in vitro. We posit that for the RcoM(Bx)-1 protein, the high CO affinity combined with multiple low-affinity DNA binding events constitutes a transcriptional "accumulating switch" that senses low but persistent CO levels. PMID- 22923595 TI - Two systems for conditional gene expression in Myxococcus xanthus inducible by isopropyl-beta-D-thiogalactopyranoside or vanillate. AB - Conditional expression of a gene is a powerful tool to study its function and is typically achieved by placing the gene under the control of an inducible promoter. There is, however, a dearth of such inducible systems in Myxococcus xanthus, a well-studied prokaryotic model for multicellular development, cell differentiation, motility, and light response and a promising source of secondary metabolites. The few available systems have limitations, and exogenously based ones are unavailable. Here, we describe two new, versatile inducible systems for conditional expression of genes in M. xanthus. One employs isopropyl-beta-d thiogalactopyranoside (IPTG) as an inducer and is inspired by those successfully applied in some other bacteria. The other requires vanillate as an inducer and is based on the system developed originally for Caulobacter crescentus and recently adapted for mammalian cells. Both systems are robust, with essentially no expression in the absence of an inducer. Depending on the inducer and the amounts added, expression levels can be modulated such that either system can conditionally express genes, including ones that are essential and are required at high levels such as ftsZ. The two systems operate during vegetative growth as well as during M. xanthus development. Moreover, they can be used to simultaneously induce expression of distinct genes within the same cell. The conditional expression systems we describe substantially expand the genetic tool kit available for studying M. xanthus gene function and cellular biology. PMID- 22923596 TI - Glucose transport in Escherichia coli mutant strains with defects in sugar transport systems. AB - In Escherichia coli, several systems are known to transport glucose into the cytoplasm. The main glucose uptake system under batch conditions is the glucose phosphoenolpyruvate:carbohydrate phosphotransferase system (glucose PTS), but the mannose PTS and the galactose and maltose transporters also can translocate glucose. Mutant strains which lack the enzyme IIBC (EIIBC) protein of the glucose PTS have been investigated previously because their lower rate of acetate formation offers advantages in industrial applications. Nevertheless, a systematic study to analyze the impact of the different glucose uptake systems has not been undertaken. Specifically, how the bacteria cope with the deletion of the major glucose uptake system and which alternative transporters react to compensate for this deficit have not been studied in detail. Therefore, a series of mutant strains were analyzed in aerobic and anaerobic batch cultures, as well as glucose-limited continuous cultivations. Deletion of EIIBC disturbs glucose transport severely in batch cultures; cyclic AMP (cAMP)-cAMP receptor protein (CRP) levels rise, and induction of the mgl operon occurs. Nevertheless, Mgl activity is not essential for growth of these mutants, since deletion of this transporter did not affect the growth rate; the activities of the remaining transporters seem to be sufficient. Under conditions of glucose limitation, mgl is upregulated 23-fold compared to levels for growth under glucose excess. Despite the strong induction of mgl upon glucose limitation, deletion of this transport system did not lead to further changes. Although the galactose transporters are often regarded as important for glucose uptake at micromolar concentrations, the glucose as well as mannose PTS might be sufficient for growth at this relatively low dilution rate. PMID- 22923597 TI - An extracelluar protease, SepM, generates functional competence-stimulating peptide in Streptococcus mutans UA159. AB - Cell-cell communication in Gram-positive bacteria often depends on the production of extracellular peptides. The cariogenic bacterium Streptococcus mutans employs so-called competence-stimulating peptide (CSP) to stimulate mutacin (bacteriocin) production and competence development through the activation of the ComDE two component pathway. In S. mutans, CSP is secreted as a 21-residue peptide; however, mass spectrometric analysis of culture supernatant indicates the presence of an 18-residue proteolytically cleaved species. In this study, using a transposon mutagenesis screening, we identified a cell surface protease that is involved in the processing of 21-residue CSP to generate the 18-residue CSP. We named this protease SepM for streptococcal extracellular protease required for mutacin production. We showed that the truncated 18-residue peptide is the biologically active form and that the specific postexport cleavage is a prerequisite to activate the ComDE two-component signal transduction pathway. We also showed that the CSP and the mutacins are exported outside the cell by the same ABC transporter, NlmTE. Our study further confirmed that the ComDE two component system is absolutely necessary for mutacin production in S. mutans. PMID- 22923598 TI - Localization of poly(3-hydroxybutyrate) (PHB) granule-associated proteins during PHB granule formation and identification of two new phasins, PhaP6 and PhaP7, in Ralstonia eutropha H16. AB - Poly(3-hydroxybutyrate) (PHB) granules are covered by a surface layer consisting of mainly phasins and other PHB granule-associated proteins (PGAPs). Phasins are small amphiphilic proteins that determine the number and size of accumulated PHB granules. Five phasin proteins (PhaP1 to PhaP5) are known for Ralstonia eutropha. In this study, we identified three additional potential phasin genes (H16_B1988, H16_B2296, and H16_B2326) by inspection of the R. eutropha genome for sequences with "phasin 2 motifs." To determine whether the corresponding proteins represent true PGAPs, fusions with eYFP (enhanced yellow fluorescent protein) were constructed. Similar fusions of eYFP with PhaP1 to PhaP5 as well as fusions with PHB synthase (PhaC1), an inactive PhaC1 variant (PhaC1-C319A), and PhaC2 were also made. All fusions were investigated in wild-type and PHB-negative backgrounds. Colocalization with PHB granules was found for all PhaC variants and for PhaP1 to PhaP5. Additionally, eYFP fusions with H16_B1988 and H16_B2326 colocalized with PHB. Fusions of H16_B2296 with eYFP, however, did not colocalize with PHB granules but did colocalize with the nucleoid region. Notably, all fusions (except H16_B2296) were soluble in a DeltaphaC1 strain. These data confirm that H16_B1988 and H16_B2326 but not H16_B2296 encode true PGAPs, for which we propose the designation PhaP6 (H16_B1988) and PhaP7 (H16_B2326). When localization of phasins was investigated at different stages of PHB accumulation, fusions of PhaP6 and PhaP7 were soluble in the first 3 h under PHB-permissive conditions, although PHB granules appeared after 10 min. At later time points, the fusions colocalized with PHB. Remarkably, PHB granules of strains expressing eYFP fusions with PhaP5, PhaP6, or PhaP7 localized predominantly near the cell poles or in the area of future septum formation. This phenomenon was not observed for the other PGAPs (PhaP1 to PhaP4, PhaC1, PhaC1-C319A, and PhaC2) and indicated that some phasins can have additional functions. A chromosomal deletion of phaP6 or phaP7 had no visible effect on formation of PHB granules. PMID- 22923599 TI - The locus of enterocyte effacement type III secretion specificity switch: the devil's in the data for a common mechanism. PMID- 22923601 TI - Workplace exposure to secondhand smoke among non-smoking hospitality employees. AB - INTRODUCTION: This article examines salivary cotinine concentrations to characterize secondhand smoke (SHS) exposure among non-smoking hospitality employees (bar and casino employees and musicians who perform in bars) who are exposed to SHS in the workplace. METHODS: A pre-post test study design was implemented to assess SHS exposure in the workplace. The convenience sample of 41 non-smoking hospitality employees included 10 controls (non-smoking hospitality employees not exposed to SHS in the workplace). RESULTS: The findings demonstrate that post-shift saliva cotinine levels of hospitality employees who are exposed to SHS in the workplace are significantly higher than controls who work in smoke free venues. Findings also suggested a statistically significant increase between pre- and post-shift saliva cotinine levels of hospitality employees who are exposed in the workplace. No statistically significant difference was noted across labor categories, suggesting that all exposed employees are at increased risk. CONCLUSION: The study results indicate that non-smoking hospitality employees exposed to SHS in the workplace have significantly higher cotinine concentration levels compared with their counterparts who work in smoke-free venues. Findings from other studies suggest that these increased cotinine levels are harmful to health. Given the potential impact on the health of exposed employees, this study further supports the efforts of tobacco prevention and control programs in advocating for comprehensive smoke-free air policies to protect bar and casino employees. PMID- 22923600 TI - Role of EscP (Orf16) in injectisome biogenesis and regulation of type III protein secretion in enteropathogenic Escherichia coli. AB - Enteropathogenic Escherichia coli employs a type III secretion system (T3SS) to translocate virulence effector proteins directly into enterocyte host cells, leading to diarrheal disease. The T3SS is encoded within the chromosomal locus of enterocyte effacement (LEE). The function of some of the LEE-encoded proteins remains unknown. Here we investigated the role of the Orf16 protein in T3SS biogenesis and function. An orf16 deletion mutant showed translocator and effector protein secretion profiles different from those of wild-type cells. The orf16 null strain produced T3S structures with abnormally long needles and filaments that caused weak hemolysis of red blood cells. Furthermore, the number of fully assembled T3SSs was also reduced in the orf16 mutant, indicating that Orf16, though not essential, is required for efficient T3SS assembly. Analysis of protein secretion revealed that Orf16 is a T3SS-secreted substrate and regulates the secretion of the inner rod component EscI. Both pulldown and yeast two-hybrid assays showed that Orf16 interacts with the C-terminal domain of an inner membrane component of the secretion apparatus, EscU; the inner rod protein EscI; the needle protein EscF; and the multieffector chaperone CesT. These results suggest that Orf16 regulates needle length and, along with EscU, participates in a substrate specificity switch from early substrates to translocators. Taken together, our results suggest that Orf16 acts as a molecular measuring device in a way similar to that of members of the Yersinia YscP and flagellar FliK protein family. Therefore, we propose that this protein be renamed EscP. PMID- 22923602 TI - Nornicotine nitrosation in saliva and its relation to endogenous synthesis of N' nitrosonornicotine in humans. AB - INTRODUCTION: We recently reported that certain amounts of the carcinogen N' nitrosonornicotine (NNN) can be formed endogenously from nicotine and/or nornicotine in some users of oral nicotine replacement therapy products. Although the acidic environment of the stomach creates the most favorable conditions for nitrosation, this reaction could also occur in the oral cavity in the presence of bacteria that catalyze nitrosation at neutral pH. METHODS: To test the hypothesis that endogenous formation of NNN could occur in the oral cavity, we investigated nitrosation of nicotine and nornicotine in human saliva. To specifically identify NNN as derived from precursors added to saliva, we incubated saliva samples with [pyridine-D(4)]nicotine and [pyridine-D(4)]nornicotine, with and without the addition of nitrite, and subsequently analyzed [pyridine-D(4)]NNN by liquid chromatography-tandem mass spectrometry. RESULTS: Consistent with kinetic studies on nicotine and nornicotine nitrosation, incubation of saliva with [pyridine D(4)]nornicotine alone produced detectable amounts of [pyridine-D(4)]NNN, whereas only traces of [pyridine-D(4)]NNN were found in samples incubated with [pyridine D(4)]nicotine and sodium nitrite. Incubation of saliva samples from 10 nonsmoking volunteers with [pyridine-D(4)]nornicotine resulted in the formation of [pyridine D(4)]NNN in 8 samples, with yields ranging from 0.003% to 0.051% of the added alkaloid. CONCLUSION: Our results demonstrate that NNN can be formed from nornicotine in human saliva without deliberate addition of any other substance. Therefore, nornicotine, as present in tobacco or in nicotine replacement products, is a carcinogen precursor. PMID- 22923603 TI - Cigarette smoking and correlates among ultra-orthodox Jewish males. AB - INTRODUCTION: Ultra-orthodox Jews compose a segregated group that struggles to preserve its centuries-old way of life by strictly adhering to the Jewish religious law in every aspect of life. Their health habits were infrequently studied to date. We sought to determine the smoking prevalence and to find its significant correlates in the ultra-orthodox Jewish population of Israel. METHODS: The study was conducted in a cross-sectional design of men as smoking prevalence among ultra-religious women was found to be negligible in previous studies. Following a random ultra-orthodox households sampling and a phone survey, a total of 782 adult men were recruited. RESULTS: The age-adjusted smoking prevalence was 12.8% (95% confidence interval [CI] = 10.3%-15.3%). The multivariate model demonstrated that being single (odds ratio [OR] = 5.83; 95% CI = 2.44-13.98), being of Israeli (OR = 2.10; 95% CI = 1.18-3.71), or North African/Asian origin (OR = 2.92; 95% CI = 1.55-5.53) was positively correlated with smoking while being a full-time Yeshiva student (OR = 0.51; 95% CI = 0.30 0.85) was negatively correlated with smoking. CONCLUSION: The Israeli ultra orthodox Jewish men have very low prevalence of smoking when compared with the general population. The study contributes to a better understanding of habitual smoking correlates in ultra-religious minorities. PMID- 22923604 TI - A store cohort study of compliance with a point-of-sale cigarette display ban in Melbourne, Australia. AB - INTRODUCTION: This study aimed to evaluate compliance with legislation which restricted cigarette displays in retail outlets, and to assess prevalence of pro- and anti-tobacco elements in stores pre- and post-legislation. METHODS Three audits of 302 stores in Melbourne, Australia by trained observers who gathered information on point-of-sale tobacco displays 2-3 months before and 3-4 and 11-12 months after the enactment of new restrictions. RESULTS: Between the first and second audits, nine stores stopped selling tobacco and three stores had either shut down or were closed for renovations. Of the remaining 290 stores, 94.1% observed the full ban on cigarette package visibility, while new restrictions on price board size and new requirements for graphic health warnings were followed in 85.9% and 67.2% of stores, respectively. Between the second and third audits, another seven stores ended tobacco sales and two stores closed. In Audit 3, 89.7% of the remaining 281 stores complied with price board restrictions, and 82.2% of stores followed requirements for graphic health warnings. Overall, the prevalence of anti-tobacco signage increased and pro-tobacco features decreased between audits for every store type and neighborhood socio-economic status. CONCLUSIONS: Tobacco retailers were almost universally compliant with placing cigarettes out of sight and a substantial majority were compliant with regulations on price board size and display of graphic health warnings, demonstrating that such legislation can be implemented successfully. PMID- 22923605 TI - Socioeconomic circumstances, health behaviours and functional limitations in older persons in four Central and Eastern European populations. AB - OBJECTIVES: to investigate functional limitations and their association with socioeconomic factors in four Central and Eastern European populations. METHODS: a cross-sectional study of random population samples in Novosibirsk (Russia), Krakow (Poland), Kaunas (Lithuania) and six Czech towns participating in the HAPIEE study. Functional limitations (classified into tertiles of the SF-36 physical functioning subscale), socioeconomic circumstances and health behaviours were available for 34,431 subjects aged 45-69 years. RESULTS: the proportion of subjects in the worst tertile of the functional limitations score (<=80% of the maximum score) ranged from 21% of the men in Kaunas to 48% in Krakow women. In multivariate ordered logistic regression, functional limitations were strongly inversely associated with education and positively with material deprivation and with being economically inactive. Functional limitations were more common in male smokers and less common in alcohol drinkers. Socioeconomic characteristics explained some of the differences in functional limitations between populations. Health behaviours explained some of the differences between social groups in both genders and between populations in women. CONCLUSION: unexpectedly, functional limitations were not most common in the sample from Russia, the country with the highest mortality rates. All socioeconomic measures were strongly associated with functional limitations and made some contribution towards explaining differences in limitations between populations. PMID- 22923606 TI - Adult macronutrient intake and physical capability in the MRC National Survey of Health and Development. AB - BACKGROUND: poor physical capability is associated with higher subsequent risk of disability and mortality in older people. Energy and macronutrient intakes may play a role in the maintenance of physical capability. This analysis aimed to examine the role of intakes of energy and the macronutrients, protein, carbohydrate and fat in early and mid-adulthood on objective measures of physical capability in later adulthood in the MRC National Survey of Health and Development (1946 British birth cohort). METHODS: adult diet assessed by a 5-day diary at 36 years (1982) and 43 years (1989). Physical capability was assessed at 53 years. Objective measures were height, weight and three measures of physical capability: grip strength, standing balance time and chair rises. RESULTS: using multiple linear regression analysis, modest positive associations were found between energy intake at 36 and 43 years and grip strength at 53 years. Results for macronutrients were mixed although there was some indication of relationships of protein intake with grip strength and standing balance time. CONCLUSIONS: higher energy intake in midlife may play a role in the prevention of muscle weakness in later life. Higher protein intakes may also be related to physical capability but further research is needed. PMID- 22923607 TI - Inferior physical performance tests in 10,998 men in the MrOS study is associated with recurrent falls. AB - BACKGROUND: recurrent fallers are at especially high risk for injuries. OBJECTIVE: to study whether tests of physical performance are associated with recurrent falls. SUBJECTS: a total of 10,998 men aged 65 years or above. METHODS: questionnaires evaluated falls sustained 12 months preceding testing of grip strength, timed stand, 6-m walk and 20-cm narrow walk test. Means with 95% confidence interval (95% CI) are reported. P < 0.01 is a statistically significant difference. RESULTS: in comparison to both occasional fallers and non fallers, recurrent fallers performed more poorly on all the physical ability tests (all P < 0.001). A score below -2 standard deviations (SDs) in the right hand grip strength test was associated with an odds ratio of 2.4 (95% CI 1.7, 3.4) for having had recurrent falls compared with having had no fall and of 2.0 (95% CI 1.3, 3.4) for having had recurrent falls compared with having had an occasional fall. CONCLUSION: low performance in physical ability tests are in elderly men associated with recurrent falls. PMID- 22923608 TI - Cognitive screening in the acute stroke setting. AB - BACKGROUND: current literature suggests that two-thirds of patients will have cognitive impairment at 3 months post-stroke. Post-stroke cognitive impairment is associated with impaired function and increased mortality. UK guidelines recommend all patients with stroke have a cognitive assessment within 6 weeks. There is no 'gold standard' cognitive screening tool. The Montreal cognitive assessment (MoCA) is more sensitive than the Mini-Mental State Examination (MMSE) in mild cognitive impairment and for cognitive impairment in the non-acute post stroke setting and in a Chinese-speaking acute stroke setting. METHODS: a convenience sample of 50 patients, admitted with stroke or transient ischaemic attack (TIA), were screened within 14 days, using the MoCA and the MMSE. RESULTS: the mean MoCA was 21.80 versus a mean MMSE of 26.98; 70% were impaired on the MoCA (cut-off <26) versus 26% on MMSE (cut-off <27). The MoCA could be completed in <10 min in 90% of cases. CONCLUSION: the MoCA is easy and quick to use in the acute stroke setting. Further work is required to determine whether a low score on the MoCA in the acute stroke setting will predict the cognitive and functional status and to explore what the best cut-off should be in an acute post-stroke setting. PMID- 22923609 TI - Meprinalpha transactivates the epidermal growth factor receptor (EGFR) via ligand shedding, thereby enhancing colorectal cancer cell proliferation and migration. AB - Meprinalpha, an astacin-type metalloprotease is overexpressed in colorectal cancer cells and is secreted in a non-polarized fashion, leading to the accumulation of meprinalpha in the tumor stroma. The transition from normal colonocytes to colorectal cancer correlates with increased meprinalpha activity at primary tumor sites. A role for meprinalpha in invasion and metastatic dissemination is supported by its pro-angiogenic and pro-migratory activity. In the present study, we provide evidence for a meprinalpha-mediated transactivation of the EGFR signaling pathway and suggest that this mechanism is involved in colorectal cancer progression. Using alkaline phosphatase-tagged EGFR ligands and an ELISA assay, we demonstrate that meprinalpha is capable of shedding epidermal growth factor (EGF) and transforming growth factor-alpha (TGFalpha) from the plasma membrane. Shedding was abrogated using actinonin, an inhibitor for meprinalpha. The physiological effects of meprinalpha-mediated shedding of EGF and TGFalpha were investigated with human colorectal adenocarcinoma cells (Caco 2). Proteolytically active meprinalpha leads to an increase in EGFR and ERK1/2 phosphorylation and subsequently enhances cell proliferation and migration. In conclusion, the implication of meprinalpha in the EGFR/MAPK signaling pathway indicates a role of meprinalpha in colorectal cancer progression. PMID- 22923610 TI - Human vitamin K epoxide reductase and its bacterial homologue have different membrane topologies and reaction mechanisms. AB - Vitamin K epoxide reductase (VKOR) is essential for the production of reduced vitamin K that is required for modification of vitamin K-dependent proteins. Three- and four-transmembrane domain (TMD) topology models have been proposed for VKOR. They are based on in vitro glycosylation mapping of the human enzyme and the crystal structure of a bacterial (Synechococcus) homologue, respectively. These two models place the functionally disputed conserved loop cysteines, Cys-43 and Cys-51, on different sides of the endoplasmic reticulum (ER) membrane. In this study, we fused green fluorescent protein to the N or C terminus of human VKOR, expressed these fusions in HEK293 cells, and examined their topologies by fluorescence protease protection assays. Our results show that the N terminus of VKOR resides in the ER lumen, whereas its C terminus is in the cytoplasm. Selective modification of cysteines by polyethylene glycol maleimide confirms the cytoplasmic location of the conserved loop cysteines. Both results support a three-TMD model of VKOR. Interestingly, human VKOR can be changed to a four-TMD molecule by mutating the charged residues flanking the first TMD. Cell-based activity assays show that this four-TMD molecule is fully active. Furthermore, the conserved loop cysteines, which are essential for intramolecular electron transfer in the bacterial VKOR homologue, are not required for human VKOR whether they are located in the cytoplasm (three-TMD molecule) or the ER lumen (four-TMD molecule). Our results confirm that human VKOR is a three-TMD protein. Moreover, the conserved loop cysteines apparently play different roles in human VKOR and in its bacterial homologues. PMID- 22923611 TI - New insights into the mechanism of initial transcription: the T7 RNA polymerase mutant P266L transitions to elongation at longer RNA lengths than wild type. AB - RNA polymerases undergo substantial structural and functional changes in transitioning from sequence-specific initial transcription to stable and relatively sequence-independent elongation. Initially, transcribing complexes are characteristically unstable, yielding short abortive products on the path to elongation. However, protein mutations have been isolated in RNA polymerases that dramatically reduce abortive instability. Understanding these mutations is essential to understanding the energetics of initial transcription and promoter clearance. We demonstrate here that the P266L point mutation in T7 RNA polymerase, which shows dramatically reduced abortive cycling, also transitions to elongation later, i.e. at longer lengths of RNA. These two properties of the mutant are not necessarily coupled, but rather we propose that they both derive from a weakening of the barrier to RNA-DNA hybrid-driven rotation of the promoter binding N-terminal platform, a motion necessary to achieve programmatically timed release of promoter contacts in the transition to elongation. Parallels in the multisubunit RNA polymerases are discussed. PMID- 22923612 TI - Characterization of the DNA-binding properties of the Mohawk homeobox transcription factor. AB - The homeobox transcription factor Mohawk (Mkx) is a potent transcriptional repressor expressed in the embryonic precursors of skeletal muscle, cartilage, and bone. MKX has recently been shown to be a critical regulator of musculoskeletal tissue differentiation and gene expression; however, the genetic pathways through which MKX functions and its DNA-binding properties are currently unknown. Using a modified bacterial one-hybrid site selection assay, we determined the core DNA-recognition motif of the mouse monomeric Mkx homeodomain to be A-C-A. Using cell-based assays, we have identified a minimal Mkx-responsive element (MRE) located within the Mkx promoter, which is composed of a highly conserved inverted repeat of the core Mkx recognition motif. Using the minimal MRE sequence, we have further identified conserved MREs within the locus of Sox6, a transcription factor that represses slow fiber gene expression during skeletal muscle differentiation. Real-time PCR and immunostaining of in vitro differentiated muscle satellite cells isolated from Mkx-null mice revealed an increase in the expression of Sox6 and down-regulation of slow fiber structural genes. Together, these data identify the unique DNA-recognition properties of MKX and reveal a novel role for Mkx in promoting slow fiber type specification during skeletal muscle differentiation. PMID- 22923613 TI - Role of cysteine residues in heme binding to human heme oxygenase-2 elucidated by two-dimensional NMR spectroscopy. AB - Human heme oxygenases 1 and 2 (HO-1 and HO-2) degrade heme in the presence of oxygen and NADPH-cytochrome P450 reductase, producing ferrous iron, CO, and biliverdin. HO-1 is an inducible enzyme, but HO-2 is constitutively expressed in selected tissues and is involved in signaling and regulatory processes. HO-2 has three cysteine residues that have been proposed to modulate the affinity for heme, whereas HO-1 has none. Here we use site-specific mutagenesis and two dimensional NMR of l-[3-(13)C]cysteine-labeled proteins to determine the redox state of the individual cysteines in HO-2 and assess their roles in binding of heme. The results indicate that in the apoprotein, Cys(282) and Cys(265) are in the oxidized state, probably in an intramolecular disulfide bond. The addition of a reducing agent converts them to the reduced, free thiol state. Two-dimensional NMR of site-specific mutants reveals that the redox state of Cys(265) and Cys(282) varies with the presence or absence of other Cys residues, indicating that the microenvironments of the Cys residues are mutually interdependent. Cys(265) appears to be in a relatively hydrophilic, oxidizable environment compared with Cys(127) and Cys(282). Chemical shift data indicate that none of the cysteines stably coordinates to the heme iron atom. In the oxidized state of the apoprotein, heme is bound 2.5-fold more tightly than in the reduced state. This small difference in heme affinity between the oxidized and reduced states of the protein is much less than previously reported, suggesting that it is not a significant factor in the physiological regulation of cellular heme levels. PMID- 22923614 TI - Francisella DnaK inhibits tissue-nonspecific alkaline phosphatase. AB - Following pulmonary infection with Francisella tularensis, we observed an unexpected but significant reduction of alkaline phosphatase, an enzyme normally up-regulated following inflammation. However, no reduction was observed in mice infected with a closely related gram-negative pneumonic organism (Klebsiella pneumoniae) suggesting the inhibition may be Francisella-specific. In similar fashion to in vivo observations, addition of Francisella lysate to exogenous alkaline phosphatase (tissue-nonspecific isozyme) was inhibitory. Partial purification and subsequent proteomic analysis indicated the inhibitory factor to be the heat shock protein DnaK. Incubation with increasing amounts of anti-DnaK antibody reduced the inhibitory effect in a dose-dependent manner. Furthermore, DnaK contains an adenosine triphosphate binding domain at its N terminus, and addition of adenosine triphosphate enhances dissociation of DnaK with its target protein, e.g. alkaline phosphatase. Addition of adenosine triphosphate resulted in decreased DnaK co-immunoprecipitated with alkaline phosphatase as well as reduction of Francisella-mediated alkaline phosphatase inhibition further supporting the binding of Francisella DnaK to alkaline phosphatase. Release of DnaK via secretion and/or bacterial cell lysis into the extracellular milieu and inhibition of plasma alkaline phosphatase could promote an orchestrated, inflammatory response advantageous to Francisella. PMID- 22923615 TI - Olfactomedin 1 interacts with the Nogo A receptor complex to regulate axon growth. AB - Olfm1, a secreted highly conserved glycoprotein, is detected in peripheral and central nervous tissues and participates in neural progenitor maintenance, cell death in brain, and optic nerve arborization. In this study, we identified Olfm1 as a molecule promoting axon growth through interaction with the Nogo A receptor (NgR1) complex. Olfm1 is coexpressed with NgR1 in dorsal root ganglia and retinal ganglion cells in embryonic and postnatal mice. Olfm1 specifically binds to NgR1, as judged by alkaline phosphatase assay and coimmunoprecipitation. The addition of Olfm1 inhibited the growth cone collapse of dorsal root ganglia neurons induced by myelin-associated inhibitors, indicating that Olfm1 attenuates the NgR1 receptor functions. Olfm1 caused the inhibition of NgR1 signaling by interfering with interaction between NgR1 and its coreceptors p75NTR or LINGO-1. In zebrafish, inhibition of optic nerve extension by olfm1 morpholino oligonucleotides was partially rescued by dominant negative ngr1 or lingo-1. These data introduce Olfm1 as a novel NgR1 ligand that may modulate the functions of the NgR1 complex in axonal growth. PMID- 22923616 TI - Structure/function relationships of adipose phospholipase A2 containing a cys-his his catalytic triad. AB - Adipose phospholipase A(2) (AdPLA or Group XVI PLA(2)) plays an important role in the onset of obesity by suppressing adipose tissue lipolysis. As a consequence, AdPLA-deficient mice are resistant to obesity induced by a high fat diet or leptin deficiency. It has been proposed that AdPLA mediates its antilipolytic effects by catalyzing the release of arachidonic acid. Based on sequence homology, AdPLA is part of a small family of acyltransferases and phospholipases related to lecithin:retinol acyltransferase (LRAT). To better understand the enzymatic mechanism of AdPLA and LRAT-related proteins, we solved the crystal structure of AdPLA. Our model indicates that AdPLA bears structural similarity to proteins from the NlpC/P60 family of cysteine proteases, having its secondary structure elements configured in a circular permutation of the classic papain fold. Using both structural and biochemical evidence, we demonstrate that the enzymatic activity of AdPLA is mediated by a distinctive Cys-His-His catalytic triad and that the C-terminal transmembrane domain of AdPLA is required for the interfacial catalysis. Analysis of the enzymatic activity of AdPLA toward synthetic and natural substrates indicates that AdPLA displays PLA(1) in addition to PLA(2) activity. Thus, our results provide insight into the enzymatic mechanism and biochemical properties of AdPLA and LRAT-related proteins and lead us to propose an alternate mechanism for AdPLA in promoting adipose tissue lipolysis that is not contingent on the release of arachidonic acid and that is compatible with its combined PLA(1)/A(2) activity. PMID- 22923617 TI - NAD(P)H cytochrome b5 oxidoreductase deficiency in Leishmania major results in impaired linoleate synthesis followed by increased oxidative stress and cell death. AB - NAD(P)H cytochrome b(5) oxidoreductase (Ncb5or), comprising cytochrome b(5) and cytochrome b(5) reductase domains, is widely distributed in eukaryotic organisms. Although Ncb5or plays a crucial role in lipid metabolism of mice, so far no Ncb5or gene has been reported in the unicellular parasitic protozoa Leishmania species. We have cloned, expressed, and characterized Ncb5or gene from Leishmania major. Steady state catalysis and spectral studies show that NADH can quickly reduce the ferric state of the enzyme to the ferrous state and is able to donate an electron(s) to external acceptors. To elucidate its exact physiological role in Leishmania, we attempted to create NAD(P)H cytochrome b(5) oxidoreductase from L. major (LmNcb5or) knock-out mutants by targeted gene replacement technique. A free fatty acid profile in knock-out (KO) cells reveals marked deficiency in linoleate and linolenate when compared with wild type (WT) or overexpressing cells. KO culture has a higher percentage of dead cells compared with both WT and overexpressing cells. Increased O(2) uptake, uncoupling and ATP synthesis, and loss of mitochondrial membrane potential are evident in KO cells. Flow cytometric analysis reveals the presence of a higher concentration of intracellular H(2)O(2), indicative of increased oxidative stress in parasites lacking LmNcb5or. Cell death is significantly reduced when the KO cells are pretreated with BSA bound linoleate. Real time PCR studies demonstrate a higher Delta12 desaturase, superoxide dismutase, and glyceraldehyde 3-phosphate dehydrogenase (GAPDH) mRNA with a concomitant fall in Delta9 desaturase mRNA expression in LmNcb5or null cell line. Together these findings suggest that decreased linoleate synthesis, and increased oxidative stress and apoptosis are the major consequences of LmNcb5or deficiency in Leishmania. PMID- 22923618 TI - Effects of neuronal nitric oxide synthase inhibition on microvascular and contractile function in skeletal muscle of aged rats. AB - Advanced age is associated with derangements in skeletal muscle microvascular function during the transition from rest to contractions. We tested the hypothesis that, contrary to what was reported previously in young rats, selective neuronal nitric oxide (NO) synthase (nNOS) inhibition would result in attenuated or absent alterations in skeletal muscle microvascular oxygenation (Po(2)(mv)), which reflects the matching between muscle O(2) delivery and utilization, following the onset of contractions in old rats. Spinotrapezius muscle blood flow (radiolabeled microspheres), Po(2)(mv) (phosphorescence quenching), O(2) utilization (Vo(2); Fick calculation), and submaximal force production were measured at rest and following the onset of contractions in anesthetized old male Fischer 344 * Brown Norway rats (27 to 28 mo) pre- and postselective nNOS inhibition (2.1 MUmol/kg S-methyl-l-thiocitrulline; SMTC). At rest, SMTC had no effects on muscle blood flow (P > 0.05) but reduced Vo(2) by ~23% (P < 0.05), which elevated basal Po(2)(mv) by ~18% (P < 0.05). During contractions, steady-state muscle blood flow, Vo(2), Po(2)(mv), and force production were not altered after SMTC (P > 0.05 for all). The overall Po(2)(mv) dynamics following onset of contractions was also unaffected by SMTC (mean response time: pre, 19.7 +/- 1.5; and post, 20.0 +/- 2.0 s; P > 0.05). These results indicate that the locus of nNOS-derived NO control in skeletal muscle depends on age and metabolic rate (i.e., rest vs. contractions). Alterations in nNOS-mediated regulation of contracting skeletal muscle microvascular function with aging may contribute to poor exercise capacity in this population. PMID- 22923619 TI - Cyclin D2 rescues size and function of GATA4 haplo-insufficient hearts. AB - Transcription factor GATA4 is a key regulator of cardiomyocyte growth, and differentiation and 50% reduction in GATA4 levels results in hypoplastic hearts. Search for GATA4 targets/effectors revealed cyclin D(2) (CD2), a member of the D type cyclins (D(1), D(2), and D(3)) that play a vital role in cell growth and differentiation as a direct transcriptional target and a mediator of GATA4 growth in postnatal cardiomyocytes. GATA4 associates with the CD2 promoter in cardiomyocytes and is sufficient to induce endogenous CD2 transcription and to dose-dependently activate the CD2 promoter in heterologous cells. Cardiomyocyte specific overexpression of CD2 results in enhanced postnatal cardiac growth because of increased cardiomyocyte proliferation. When these transgenic mice are crossed with Gata4 heterozygote mice, they rescue the hypoplastic cardiac phenotype of Gata4(+/-) mice and enhance cardiomyocyte survival and heart function. The data uncover a role for CD2 in the postnatal heart as an effector of GATA4 in myocyte growth and survival. The finding that postnatal upregulation of a cell-cycle gene in GATA4 haplo-insufficient hearts may be protective opens new avenues for maintaining or restoring cardiac function in GATA4-dependent cardiac disease. PMID- 22923620 TI - Autoregulation and mechanotransduction control the arteriolar response to small changes in hematocrit. AB - Here, we present an analytic model of arteriolar mechanics that accounts for key autoregulation mechanisms, including the myogenic response and the vasodilatory effects of nitric oxide (NO) in the vasculature. It couples the fluid mechanics of blood flow in arterioles with solid mechanics of the vessel wall and includes the effects of wall shear stress- and stretch-induced endothelial NO production. The model can be used to describe the regulation of blood flow and NO transport under small changes in hematocrit and to analyze the regulatory response of arterioles to small changes in hematocrit. Our analysis revealed that the experimentally observed paradoxical increase in cardiac output with small increases in hematocrit results from the combination of increased NO production and the effects of a strong myogenic response modulated by elevated levels of WSS. Our findings support the hypothesis that vascular resistance varies inversely with blood viscosity for small changes in hematocrit in a healthy circulation that responds to shear stress stimuli. They also suggest beneficial effects independent of changes in O(2) carrying capacity associated with the postsurgical transfusion of one or two units of blood. PMID- 22923621 TI - Treatment with N-acetyl-seryl-aspartyl-lysyl-proline prevents experimental autoimmune myocarditis in rats. AB - Myocarditis is commonly associated with cardiotropic infections and has been linked to development of autoimmunity. N-acetyl-seryl-aspartyl-lysyl-proline (Ac SDKP) is a naturally occurring tetrapeptide that prevents inflammation and fibrosis in hypertension and other cardiovascular diseases; however, its effect on autoimmune-mediated cardiac diseases remains unknown. We studied the effects of Ac-SDKP in experimental autoimmune myocarditis (EAM), a model of T cell mediated autoimmune disease. This study was conducted to test the hypothesis that Ac-SDKP prevents autoimmune myocardial injury by modulating the immune responses. Lewis rats were immunized with porcine cardiac myosin and treated with Ac-SDKP or vehicle. In EAM, Ac-SDKP prevented both systolic and diastolic cardiac dysfunction, remodeling as shown by hypertrophy and fibrosis, and cell-mediated immune responses without affecting myosin-specific autoantibodies or antigen specific T cell responses. In addition, Ac-SDKP reduced cardiac infiltration by macrophages, dendritic cells, and T cells, pro-inflammatory cytokines [interleukin (IL)-1alpha, tumor necrosis factor-alpha, IL-2, IL-17] and chemokines (cytokine-induced neutrophil chemoattractant-1, interferon-gamma induced protein 10), cell adhesion molecules (intercellular adhesion molecule-1, L-selectin), and matrix metalloproteinases (MMP). Ac-SDKP prevents autoimmune cardiac dysfunction and remodeling without reducing the production of autoantibodies or T cell responses to cardiac myosin. The protective effects of Ac-SDKP in autoimmune myocardial injury are most likely mediated by inhibition of 1) innate and adaptive immune cell infiltration and 2) expression of proinflammatory mediators such as cytokines, chemokines, adhesion molecules, and MMPs. PMID- 22923622 TI - Relevance of anxiety in clinical practice of Guillain-Barre syndrome: a cohort study. AB - OBJECTIVES: Illness is often associated with anxiety, but few data exist about the prognostic significance of this phenomenon. To address this issue, we assessed whether patient anxiety is associated with subsequent need for intubation in Guillain-Barre syndrome (GBS). DESIGN: Incident case-cohort study. SETTING: Acute secondary care in a teaching hospital (France) from 2006 to 2010. PARTICIPANTS: 110 adult GBS patients. Either language barrier or cognitive decline that precluded understanding was considered as exclusion criteria. PRIMARY OUTCOME: Acute respiratory failure. INTERVENTIONS: At admission, anxiety and clinical factors (including known predictors of respiratory failure: delay between GBS onset and admission, inability to lift head, vital capacity (VC)) were assessed and related to subsequent need for mechanical ventilation (MV). Anxiety was assessed using a Visual Analogical Scale (VAS), the State Anxiety Inventory form Y1 (STAI-Y1) score and a novel-specific questionnaire, evaluating fears potentially triggered by GBS. Patients were asked to choose which they found most stressful from weakness, pain, breathlessness and uncertainty. RESULTS: 23 (22%) were subsequently ventilated. Mean STAI-Y1 was 47.2 (range 22 77) and anxiety VAS 5.2 (range 0-10). STAI was above 60/80 in 22 (21%) patients and anxiety VAS above 7/10 in 28 (27%) patients. Fear of remaining paralysed, uncertainty as to how the disease would progress and fear of intubation were the most stressful. Factors significantly associated with anxiety were weakness and bulbar dysfunction. STAI-Y1 was higher and uncertainty more frequent in subsequently ventilated patients, who had shorter onset-admission delay and greater weakness but not a lower VC. Uncertainty was independently associated with subsequent MV. CONCLUSIONS: Early management of patients with GBS should evaluate anxiety and assess its causes both to adjust psychological support and to anticipate subsequent deterioration. PMID- 22923623 TI - Adverse drug reaction-related admissions in paediatrics, a prospective single centre study. AB - OBJECTIVE: To investigate the incidence and characteristics of hospital admissions related to adverse drug events in the paediatric setting. DESIGN: Prospective single-centre study. SETTING: A secondary and tertiary paediatric care centre. PARTICIPANTS: A total of 683 acutely admitted patients, aged 0-18 year. All acutely admitted patients, using medication before admission, were prospectively screened for possible Adverse Drug Reactions (ADR)-related admission with a trigger list. Included cases were analysed with the Naranjo score for the assessment of causality. MAIN OUTCOME MEASURES: This research explored the incidence of ADR-related admissions and investigated the relation between ADR and the licensing status of the medicines, as well as the severity and potential to prevent the ADRs. RESULTS: A total of 683 patients were admitted acutely during the study period, 47 of them were exposed to cancer chemotherapy. Fifteen patients not exposed to chemotherapy (2.4%) were admitted due to an ADR. Five of these 15 ADRs (33%) were caused by unlicensed or off-label used drugs. Thirty-two patients exposed to chemotherapy (68.1%) were admitted due to an ADR; 27 of these (84%) were caused by unlicensed or off-label used drugs. CONCLUSIONS: In conclusion, this study shows that ADR-related hospital admissions occur more frequently in the paediatric population compared with adults, and more frequently in patients exposed to cancer chemotherapy. No relation was found between the unlicensed and off-label used drugs and the incidence of ADRs. PMID- 22923624 TI - A model for scale up of family health innovations in low-income and middle-income settings: a mixed methods study. AB - BACKGROUND: Many family health innovations that have been shown to be both efficacious and cost-effective fail to scale up for widespread use particularly in low-income and middle-income countries (LMIC). Although individual cases of successful scale-up, in which widespread take up occurs, have been described, we lack an integrated and practical model of scale-up that may be applicable to a wide range of public health innovations in LMIC. OBJECTIVE: To develop an integrated and practical model of scale-up that synthesises experiences of family health programmes in LMICs. DATA SOURCES: We conducted a mixed methods study that included in-depth interviews with 33 key informants and a systematic review of peer-reviewed and grey literature from 11 electronic databases and 20 global health agency web sites. STUDY ELIGIBILITY CRITERIA, PARTICIPANTS AND INTERVENTIONS: We included key informants and studies that reported on the scale up of several family health innovations including Depo-Provera as an example of a product innovation, exclusive breastfeeding as an example of a health behaviour innovation, community health workers (CHWs) as an example of an organisational innovation and social marketing as an example of a business model innovation. Key informants were drawn from non-governmental, government and international organisations using snowball sampling. An article was excluded if the article: did not meet the study's definition of the innovation; did not address dissemination, diffusion, scale up or sustainability of the innovation; did not address low-income or middle-income countries; was superficial in its discussion and/or did not provide empirical evidence about scale-up of the innovation; was not available online in full text; or was not available in English, French, Spanish or Portuguese, resulting in a final sample of 41 peer-reviewed articles and 30 grey literature sources. STUDY APPRAISAL AND SYNTHESIS METHODS: We used the constant comparative method of qualitative data analysis to extract recurrent themes from the interviews, and we integrated these themes with findings from the literature review to generate the proposed model of scale-up. For the systematic review, screening was conducted independently by two team members to ensure consistent application of the predetermined exclusion criteria. Data extraction from the final sample of peer-reviewed and grey literature was conducted independently by two team members using a pre-established data extraction form to list the enabling factors and barriers to dissemination, diffusion, scale up and sustainability. RESULTS: The resulting model-the AIDED model-includes five non linear, interrelated components: (1) assess the landscape, (2) innovate to fit user receptivity, (3) develop support, (4) engage user groups and (5) devolve efforts for spreading innovation. Our findings suggest that successful scale-up occurs within a complex adaptive system, characterised by interdependent parts, multiple feedback loops and several potential paths to achieve intended outcomes. Failure to scale up may be attributable to insufficient assessment of user groups in context, lack of fit of the innovation with user receptivity, inability to address resistance from stakeholders and inadequate engagement with user groups. LIMITATIONS: The inductive approach used to construct the AIDED model did not allow for simultaneous empirical testing of the model. Furthermore, the literature may have publication bias in which negative studies are under represented, although we did find examples of unsuccessful scale-up. Last, the AIDED model did not address long-term, sustained use of innovations that are successfully scaled up, which would require longer-term follow-up than is common in the literature. CONCLUSIONS AND IMPLICATIONS OF KEY FINDINGS: Flexible strategies of assessment, innovation, development, engagement and devolution are required to enable effective change in the use of family health innovations in LMIC. PMID- 22923625 TI - Reporting of lifetime fractures: methodological considerations and results from the Thai Cohort Study. AB - OBJECTIVES: To provide estimates of fracture incidence among young adults in Thailand. DESIGN: Cross-sectional analysis of a large national cohort. SETTING: Thailand. PARTICIPANTS: A total of 60 569 study participants residing nationwide responded to the 2009 follow-up survey; 55% were women and median age was 34 years (range 19-92). OUTCOME MEASURES: Self-reported lifetime fractures, along with age at fracture. Fracture incidence rates per person-year were then compared using lifetime fracture reports, and again selecting only fractures reported for the last year. Incidence rates were compared by age and sex. RESULTS: 18 010 lifetime fractures were reported; 11 645(65%) by men. Lifetime fracture prevalence was 30% for men and 15% for women. Lifetime incidence per 10 000 person-years was 83; analysing only fractures from the last year yielded a corresponding incidence rate of 187. For ages 21-30, fractures per 10 000 person years were more common among men than women (283 (95% CI 244 to 326) and 150 (130 to 173), respectively); with increasing age, rates decreased among men and increased among women (for ages 51-60, 97 (58 to 151) and 286 (189 to 417), respectively). CONCLUSIONS: Large-scale surveys provide a feasible method for establishing relative fracture incidence among informative subgroups in a population. Limiting analyses to fractures reported to have occurred recently minimises bias due to poor recall. The pattern of self-reported fracture incidence among Thais aged 20-60 was similar to that reported for Western countries: high falling rates in young men and high rising rates in older women. PMID- 22923626 TI - Analysing falls in coronary heart disease mortality in the West Bank between 1998 and 2009. AB - OBJECTIVES: To analyse coronary heart disease (CHD) mortality and risk factor trends in the West Bank, occupied Palestinian territory between 1998 and 2009. DESIGN: Modelling study using CHD IMPACT model. SETTING: The West Bank, occupied Palestinian territory. PARTICIPANTS: Data on populations, mortality, patient groups and numbers, treatments and cardiovascular risk factor trends were obtained from national and local surveys, routine national and WHO statistics, and critically appraised. Data were then integrated and analysed using a previously validated CHD model. PRIMARY AND SECONDARY OUTCOME MEASURES: CHD deaths prevented or postponed are the main outcome. RESULTS: CHD death rates fell by 20% in the West Bank, between 1998 and 2009. Smoking prevalence was initially high in men, 51%, but decreased to 42%. Population blood pressure levels and total cholesterol levels also decreased. Conversely, body mass index rose by 1-2 kg/m(2) and diabetes increased by 2-8%. Population modelling suggested that more than two-thirds of the mortality fall was attributable to decreases in major risk factors, mainly total cholesterol, blood pressure and smoking. Approximately one third of the CHD mortality decreases were attributable to treatments, particularly for secondary prevention and heart failure. However, the contributions from statins, surgery and angioplasty were consistently small. CONCLUSIONS: CHD mortality fell by 20% between 1998 and 2009 in the West Bank. More than two-third of this fall was due to decreases in major risk factors, particularly total cholesterol and blood pressure. Our results clearly indicate that risk factor reductions in the general population compared save substantially more lives to specific treatments for individual patients. This emphasizes the importance of population-wide primary prevention strategies. PMID- 22923627 TI - 'It's on my iPhone': attitudes to the use of mobile computing devices in medical education, a mixed-methods study. AB - OBJECTIVE: The last decade has seen the introduction of new technology which has transformed many aspects of our culture, commerce, communication and education. This study examined how medical teachers and learners are using mobile computing devices such as the iPhone in medical education and practice, and how they envision them being used in the future. DESIGN: Semistructured interviews were conducted with medical students, residents and faculty to examine participants' attitudes about the current and future use of mobile computing devices in medical education and practice. A thematic approach was used to summarise ideas and concepts expressed, and to develop an online survey. A mixed methods approach was used to integrate qualitative and quantitative findings. SETTING AND PARTICIPANTS: Medical students, residents and faculty at a large Canadian medical school in 2011. RESULTS: Interviews were conducted with 18 participants (10 students, 7 residents and 1 faculty member). Only 213 participants responded to the online survey (76 students, 65 residents and 41 faculty members). Over 85% of participants reported using a mobile-computing device. The main uses described for mobile devices related to information management, communication and time management. Advantages identified were portability, flexibility, access to multimedia and the ability to look up information quickly. Challenges identified included: superficial learning, not understanding how to find good learning resources, distraction, inappropriate use and concerns about access and privacy. Both medical students and physicians expressed the view that the use of these devices in medical education and practice will increase in the future. CONCLUSIONS: This new technology offers the potential to enhance learning and patient care, but also has potential problems associated with its use. It is important for leadership in medical schools and healthcare organisations to set the agenda in this rapidly developing area to maximise the benefits of this powerful new technology while avoiding unintended consequences. PMID- 22923628 TI - Seasonality, incidence and prognosis in atrial fibrillation and stroke in Denmark and New Zealand. AB - OBJECTIVES: There are relatively few large studies of seasonal variation in the occurrence of stroke in patients with atrial fibrillation (AF). We investigated the seasonal variation in incidence rates of hospitalisation with stroke in patients from Denmark and New Zealand. DESIGN: Cohort study. SETTING: Nationwide hospital discharge data from Denmark and New Zealand. PARTICIPANTS: 243 381 (median age 75) subjects having a first-time hospitalisation with AF in Denmark and 51 480 (median age 76) subjects in New Zealand constituted the study population. Subjects with previous hospitalisation with stroke were excluded. PRIMARY AND SECONDARY EFFECT MEASURES: Peak-to-trough ratio of the seasonal variation in incidence rates of stroke in AF patients adjusted for an overall trend was primary effect measure and was assessed using a log-linear Poisson regression model. Secondary effect measures were incidence rate ratios of AF and 30-day case fatality for stroke patients. RESULTS: Incidence rates of AF per 1000 person-years in Denmark increased by 5.4% (95% CI 5.3% to 5.7%) for patients aged <65 and 5% (95% CI 4.9% to 5.1%) for patients aged >=65, whereas the increase was 0.2% (95% CI -0.2% to 0.6%) for patients aged <65 and 2.6% (95% CI 2.4% to 2.8%) for patients aged >=65 in New Zealand. In Denmark 36 088 subjects were hospitalised with stroke, and 7518 subjects in New Zealand, both showing peaks during winter with peak-to-trough ratios of 1.22 and 1.27, respectively and a decreasing trend. The 30-day case fatality risk for stroke patients having AF is now (2000-2008) about 20% in both countries. CONCLUSIONS: Although incidence rates of hospitalisation with stroke in patients with AF have decreased in recent years, stroke remains a common AF complication with a high case fatality risk. The marked winter peak in incidence rates of hospitalisation with stroke in AF patients suggests that there are opportunities to reduce this complication. Further studies are necessary to identify how to optimise treatment of AF and prevention of stroke. PMID- 22923629 TI - Prevalence, awareness, treatment and control of hypertension in a self-selected sub-Saharan African urban population: a cross-sectional study. AB - OBJECTIVES: Hypertension has been established as a major public health problem in Africa, but its specific contributions to disease burden are still incompletely understood. We report the prevalence and determinants of hypertension, detection, treatment and control rates among adults in major cities in Cameroon. DESIGN: Cross-sectional study. SETTINGS: Community-based multicentre study in major cities in Cameroon. PARTICIPANTS: Participants were self-selected urban dwellers from the Center, Littoral, North-West and West Regions, who attended on 17 May 2011 a screening campaign advertised through mass media. PRIMARY AND SECONDARY OUTCOMES MEASURES: Hypertension defined as systolic (and/or diastolic) blood pressure (BP)>= 140 (90) mm Hg, or ongoing BP-lowering medications. RESULTS: In all, 2120 participants (1003 women) were included. Among them, 1007 (prevalence rate 47.5%) had hypertension, including 319 (awareness rate 31.7%) who were aware of their status. The prevalence of hypertension increased with age overall and by sex and region. Among aware hypertensive participants, 191 (treatment rate 59.9%) were on regular BP-lowering medication, and among those treated, 47 (controlled rate 24.6%) were at target BP levels (ie, systolic (and diastolic) BP<140 (90) mm Hg). In multivariable logistic regression analysis, male gender, advanced age, parental history of hypertension, diabetes mellitus, elevated waist and elevated body mass index (BMI) were the significant predictors of hypertension. Likewise, male gender, high BMI and physical inactivity were associated with poor control. CONCLUSIONS: High prevalence of hypertension with low awareness, treatment and control were found in this urban population; these findings are significant and alarming with consideration to the various improvements in the access to healthcare and the continuing efforts to educate communities over the last few decades. PMID- 22923630 TI - Equal cancer treatment regardless of education level and family support? A qualitative study of oncologists' decision-making. AB - OBJECTIVE: Treatment gradients by socioeconomic status have been observed within cancer care in several countries. The objective of this study was to explore whether patients' educational level and social network influence oncologists' clinical decision-making. DESIGN: Semi-structured interviews on factors considered when deciding on treatment for cancer patients. Interviews were transcribed and analysed using inductive qualitative content analysis. SETTING: Oncologists in Swedish university- and non-university hospitals were interviewed in their respective places of work. PARTICIPANTS: Twenty Swedish clinical oncologists selected through maximum-variation sampling. PRIMARY AND SECONDARY OUTCOME MEASURES: Elements which influence oncologists' decision-making process were explored with focus on educational level and patients' social support systems. RESULTS: Oncologists consciously used less combination chemotherapy for patients living alone, fearing treatment toxicity. Highly educated patients were considered as well-read, demanding and sometimes difficult to reason with. Patients with higher education, those very keen to have treatment and persuasive relatives were considered as challenges for the oncologist. Having large groups of relatives in a room made doctors feel outnumbered. A desire to please patients and relatives was posed as the main reason for giving in to patients' demands, even when this resulted in treatment with limited efficacy. CONCLUSIONS: Oncologists tailor treatment for patients living alone to avoid harmful side effects. Many find patients' demands difficult to handle and this may result in strong socioeconomic groups being over-treated. PMID- 22923631 TI - Do omega-3 or other fatty acids influence the development of 'growing pains'? A prebirth cohort study. AB - OBJECTIVES: To assess whether the prevalence of growing pains varies with indicators of fatty acid exposure. Growing pains (limb pains of no obvious explanation) have been shown to be strongly linked to a family history of arthritis, and are thought to predict an increased risk of the development of arthritis in adulthood. Much has been made of the possibility of fatty acids, particularly the omega-3 fatty acids, playing a preventive role in the development of arthritis, but little research has been undertaken to determine whether such fatty acids might reduce the risk of growing pains. We aimed to assess whether the prevalence of growing pains varies with indicators of fatty acid exposures. DESIGN: Case-control study nested within a prospective longitudinal cohort comparing prenatal and postnatal diet, blood measures and variants in fatty acid desaturase (FADS) genes that influence the metabolism of fatty acids. Statistical analysis took account of factors such as gender, smoke exposure, maternal age and education, social class and parity. SETTING: Avon Longitudinal Study of Parents & Children. PARTICIPANTS: All children born between 1 April 1991 and 31 December 1992 (approximately14 000) within the Avon area (only that part of Avon under the South-West Regional Health Authority). This project compared 1676 children who reported 'growing pains' at age 8 with 6155 with no such pain. PRIMARY OUTCOME: Reported limb pains of no apparent origin. RESULTS: There was no indication that the affected children had diets that differed with regard to omega-3, plasma levels of fatty acids, or the FADS genetic variants. We also assessed fetal and infant exposure but neither maternal prenatal blood levels nor maternal dietary intake, or duration of breast feeding showed any significant relationships even after adjustment for confounders. CONCLUSIONS: Thus, there is no evidence that omega-3 fatty acid status protects against the development of growing pains in childhood. PMID- 22923632 TI - The role of hypoxic-inducible factor (HIF1alpha) and aldolaseC protein in endometrial carcinogenesis: a retrospective study of 279 patients. AB - OBJECTIVES: Hypoxia-inducible factor (HIF1alpha) plays an integral role in response to hypoxia, controlling dozens of target genes including aldolaseC (ALDC), an important enzyme in the glycolytic pathway. It also induces angiogenesis, allowing survival and proliferation of cancer cells. The aims of our study were to evaluate the expressions of HIF1alpha and ALDC in patients with endometrial cancer (EC) and define their association with disease outcome and to determine the existence of an association between HIF1alpha and ALDC proteins. DESIGN: This is a population-based retrospective cohort study using the gynaecological-oncology database. The authors identified all women with EC with adequate follow-up. Immunohistochemistry using antibodies to ALDC and HIF1alpha was performed on paraffin-embedded tissue from 279 patients. To test the association between ALDC /HIF1alpha protein using immunohistochemistry (IHC) (positive and negative) and the clinical parameters, Fisher's exact test was performed for categorical parameters and the logistic regression model was used for continuous ones. Pearson correlation was used to check the association of IHC between ALDC and HIF1alpha. SETTING: Academic referral centre. PARTICIPANTS: Women with EC from 2000 to 2010 obtained from the gynaecological-oncology database. OUTCOME MEASURES: The disease outcome is defined by alive with no evidence of disease versus all other outcomes. RESULTS: ALDC and HIF1alpha were overexpressed in the vast majority of EC cases (78% and 76%, respectively). There was a strong positive association between HIF1alpha and ALDC (p=0.0017). There was a significant association between ALDC and depth of myometrial invasion (p=0.0438), and between HIF1alpha and tumour grade (p=0.0231) and tumour subtype (p=0.018). However, there was no association between neither ALDC nor HIF1alpha and disease status. CONCLUSIONS: ALDC and HIF1alpha play an important role in endometrial carcinogenesis. Their expression by the majority of EC makes inhibition of HIF1alpha a very attractive therapeutic option for treating patients with EC and we suggest that it will be prospectively validated in future studies. PMID- 22923633 TI - Myocardial performance assessment in neonates by one-segment strain and strain rate analysis by tissue Doppler - a quality improvement cohort study. AB - OBJECTIVES: To investigate one-segment strain and strain rate indices as measures of myocardial performance in asphyxiated term neonates. DESIGN: Quality improvement cohort study. SETTING: Newborns admitted to a neonatal intensive care unit at a Norwegian University Hospital for perinatal asphyxia and non asphyxiated newborn recruited from the maternity ward at the same hospital. PARTICIPANTS: Twenty asphyxiated and 48 non-asphyxiated term neonates. PRIMARY OUTCOME MEASURE: Strain and strain rate indices and repeatability measures. One segment longitudinal strain and strain rate by tissue Doppler were assessed on days 1, 2 and 3 of life in nine heart walls. Repeatability was compared against measurements from two-segment analyses previously performed in the same images. RESULTS: The 95% limits of agreement were significantly better for the one segment than two-segment repeatability analyses, the inter-rater peak systolic strain (PSS) was (-3.1, 3.3) vs (-11.4, 18.3)%, the inter-rater peak systolic strain rate (PSSR) was (-0.38, 0.40) vs (-0.79, 1.15)/s, the intra-rater PSS was (-2.5, 2.6) vs (-8.0, 9.8)% and the intra-rater PSSR was (-0.23, 0.25) vs (-0.75, 0.80)/s (p<0.05). The myocardial performance was lower in the asphyxiated neonates (indices closer to zero) than in the non-asphyxiated neonates, PSS was 17.8 (0.6) (mean (SEM)) vs -21.2 (0.3)%, PSSR -1.43 (0.08) vs -1.61 (0.03)/s, early diastolic strain rate 1.72 (0.11) vs 2.00 (0.11)/s and strain rate during the atrial systole 1.92 (0.17) vs 2.27 (0.10)/s (p<0.05), despite no difference in fractional shortening (29.0 (0.5) vs 29.1 (1.0)%) (p>0.05). CONCLUSIONS: One segment strain and strain rate assessed the reduced myocardial performance in asphyxiated neonates with significantly improved reproducibility as compared with two-segment analysis and was therefore more feasible than two-segment analyses for assessment of myocardial performance after perinatal asphyxia. PMID- 22923635 TI - Ultrasound-guided infraclavicular axillary vein cannulation: a useful alternative to the internal jugular vein. AB - BACKGROUND: Ultrasound (US) guidance reduces complications and increases accuracy during internal jugular vein (IJV) cannulation. The subclavian vein (SCV) is popular but is less amenable to US guidance. The axillary vein (AxV), a direct continuation of the SCV, is an alternative, but to date, experience with US is limited to small case series. METHODS: Retrospective procedural data were collected on 2586 sequential patients referred for insertion of tunnelled central venous access at a UK tertiary centre from 2004 to 2011. RESULTS: A total of 99.8% of patients tolerated the procedure with local anaesthesia +/- sedation; six patients had general anaesthesia. Twenty-six (1%) patients had uncorrected coagulopathy or thrombocytopenia. A total of 2572 (99.5%) of patients were cannulated successfully: right AxV 1644 cases, left AxV 279, right IJV 547, left IJV 89, other techniques 13, and 14 (0.5%) cases failed. The initial site chosen was successful in 96%. In patients who previously underwent long-term cannulation, 93.3% of lines were sited easily. Forty-eight (1.9%) procedural complications occurred. CONCLUSIONS: In this large analysis of US-guided central venous access in a complex patient group, the majority of patients were cannulated successfully and safely. The subset of patients undergoing AxV cannulation demonstrated a low rate of complications. The AxV route of access appears to be a safe and effective alternative to the IJV. PMID- 22923634 TI - Spectral and spatial shifts of post-ictal slow waves in temporal lobe seizures. AB - Temporal lobe seizures have a significant chance to induce impairment of normal brain functions. Even after the termination of ictal discharges, during the post ictal period, loss of consciousness, decreased responsiveness or other cognitive dysfunctions can persist. Previous studies have found various anatomical and functional abnormalities accompanying temporal lobe seizures, including an abnormal elevation of cortical slow waves. Intracranial electroencephalography studies have shown a prominent increase of lower frequency components during and following seizures that impair (complex partial seizures) but not those that preserve (simple partial seizures) normal consciousness and responsiveness. However, due to the limited spatial coverage of intracranial electroencephalography, the investigation of cortical slow waves cannot be easily extended to the whole brain. In this study, we used scalp electroencephalography to study the spectral features and spatial distribution of post-ictal slow waves with comprehensive spatial coverage. We studied simple partial, complex partial and secondarily generalized seizures in 28 patients with temporal lobe seizures. We used dense-array electroencephalography and source imaging to reconstruct the post-ictal slow-wave distribution. In the studied cohort, we found that a 'global' spectral power shift to lower frequencies accompanied the increased severity of seizures. The delta spectral power relative to higher frequency bands was highest for secondarily generalized seizures, followed by complex partial seizures and lastly simple partial seizures. In addition to this 'global' spectral shift, we found a 'regional' spatial shift in slow-wave activity. Secondarily generalized seizures and complex partial seizures exhibited increased slow waves distributed to frontal areas with spread to contralateral temporal and parietal regions than in simple partial seizures. These results revealed that a widespread cortical network including temporal and fronto-parietal cortex is involved in abnormal slow-wave activity following temporal lobe seizures. The differential spectral and spatial shifts of post-ictal electroencephalography activity in simple partial, complex partial and secondarily generalized seizures suggest a possible connection between cortical slow waves and behavioural and cognitive changes in a human epilepsy model. PMID- 22923636 TI - Long-term effect of epidural injection with sustained-release lidocaine particles in a rat model of postoperative pain. AB - BACKGROUND: Single applications of sustained-release local anaesthetics may provide prolonged pain relief without requiring indwelling catheters, but have not yet been investigated for epidural postoperative pain management. We synthesized injectable sustained-release lidocaine particles (SRLPs) from biodegradable polymers and examined their effect in a rat model of postoperative pain. METHODS: Two types of polylactic acid particles, SRLP-10 and SRLP-25, containing 10% or 25% lidocaine, respectively, were generated and the lidocaine release was evaluated in vitro for 14 days. The SRLPs were then injected epidurally in the male Sprague-Dawley rats immediately before they received a hindpaw incision (the postoperative pain model), and hindpaw hypersensitivity was evaluated with the von Frey test. Motor paralysis and coordination were also assessed using a paralysis score and rota-rod test. Neurotoxicity and inflammation of the spinal cord, cauda equina, and tissue surrounding the injection site were histologically evaluated. RESULTS: In vitro, SRLP-10 and SRLP 25 released lidocaine over 7 and 3 days, respectively. The in vivo injection of SRLP-10 (80 mg) produced anti-hypersensitivity with no evidence of motor paralysis for 7 days after the paw incision, and SRLP-25 (60 mg) inhibited postoperative hypersensitivity for 7 days. Temporary motor paralysis (15 min) was observed after the injection of SRLP-25 (even with 40 mg). Foreign body reactions were observed around the SRLP injection site at 1 and 4 weeks after injection. No histopathological changes were observed at 1 or 4 weeks. CONCLUSIONS: The epidural injection of SRLPs produced prolonged anti-hypersensitivity in a rat model of postoperative pain with no major complications. PMID- 22923638 TI - Expanding the pleiotropic effects of statins: attenuation of air pollution induced inflammatory response. PMID- 22923637 TI - Oxygen dose responsiveness of human fetal airway smooth muscle cells. AB - Maintenance of blood oxygen saturation dictates supplemental oxygen administration to premature infants, but hyperoxia predisposes survivors to respiratory diseases such as asthma. Although much research has focused on oxygen effects on alveoli in the setting of bronchopulmonary dysplasia, the mechanisms by which oxygen affects airway structure or function relevant to asthma are still under investigation. We used isolated human fetal airway smooth muscle (fASM) cells from 18-20 postconceptual age lungs (canalicular stage) to examine oxygen effects on intracellular Ca(2+) ([Ca(2+)](i)) and cellular proliferation. fASM cells expressed substantial smooth muscle actin and myosin and several Ca(2+) regulatory proteins but not fibroblast or epithelial markers, profiles qualitatively comparable to adult human ASM. Fluorescence Ca(2+) imaging showed robust [Ca(2+)](i) responses to 1 MUM acetylcholine (ACh) and 10 MUM histamine (albeit smaller and slower than adult ASM), partly sensitive to zero extracellular Ca(2+). Compared with adult, fASM showed greater baseline proliferation. Based on this validation, we assessed fASM responses to 10% hypoxia through 90% hyperoxia and found enhanced proliferation at <60% oxygen but increased apoptosis at >60%, effects accompanied by appropriate changes in proliferative vs. apoptotic markers and enhanced mitochondrial fission at >60% oxygen. [Ca(2+)](i) responses to ACh were enhanced for <60% but blunted at >60% oxygen. These results suggest that hyperoxia has dose-dependent effects on structure and function of developing ASM, which could have consequences for airway diseases of childhood. Thus detrimental effects on ASM should be an additional consideration in assessing risks of supplemental oxygen in prematurity. PMID- 22923639 TI - Sequential expression of IGF-IB followed by active TGF-beta1 induces synergistic pulmonary fibroproliferation in vivo. AB - Pulmonary fibrosis, the end stage of a variety of fibroproliferative lung diseases, is usually induced after repetitive or chronic lung injury or inflammation. The mechanisms of fibroproliferation are poorly understood. Insulin like growth factor-I (IGF-I) is significantly elevated in patients with pulmonary fibrosis and fibroproliferative acute respiratory distress syndrome. However, we showed that IGF-I overexpression alone in wild-type mouse lungs does not cause fibroproliferation. We therefore questioned whether IGF-I, acting together with active TGF-beta1, a known profibrotic cytokine, enhances pulmonary fibroproliferation caused by active TGF-beta1. A unique sequential adenoviral transgene mouse model was used expressing AdEmpty/AdTGF-beta1 or AdhIGF-IB/AdTGF beta1 transgenes. IGF-IB plus active TGF-beta1 transgene expression synergistically increased collagen deposition in the lung parenchyma compared with active TGF-beta1 expression alone. The enhanced fibrosis was accompanied by an increased recruitment of macrophages and lymphocytes into the bronchoalveolar lavage fluid (BALF) and inflammatory cells in the lungs. alpha-Smooth muscle actin expression, a marker of myofibroblast proliferation and differentiation, was also increased. Finally, fibroblasts exposed ex vivo to BALF isolated from AdhIGF-IB/AdTGF-beta1-transduced mice showed synergistic collagen induction compared with BALF from AdEmpty/AdTGF-beta1-transduced mice. This study provides the first direct evidence that IGF-I is able to synergistically enhance pulmonary fibroproliferation in cooperation with TGF-beta1. PMID- 22923640 TI - TSC2 modulates cell adhesion and migration via integrin-alpha1beta1. AB - Recent evidence suggests that the rare and progressive lung disease lymphangioleiomyomatosis (LAM) is metastatic in nature. Dysfunction of the tumor suppressor genes tuberous sclerosis complex (TSC), in particular mutational inactivation of TSC2, enhances both cell proliferation and migration. Although substantial progress has been made in understanding the role of TSC2 in abnormal LAM cell proliferation and its pharmacological targeting, the mechanisms underlying the enhanced migratory capacity in LAM are not well understood. In this study, we examined the role of TSC2 in cell attachment, spreading, and migration, processes that contribute to the metastatic phenotype. Here we show that loss of TSC2 increased both the attachment and spreading of mouse embryonic fibroblasts to the extracellular matrix proteins collagen type I and fibronectin and that reexpression of TSC2 reduced these effects. Integrin-alpha1beta1 modulated cell migration with the beta1-subunit involved in cell attachment and spreading as shown by using functional blocking antibodies. Loss of TSC2 increased integrin-alpha1 expression, and inhibition of this integrin subunit reduced cell migration. The enhanced attachment and spreading were independent of the intracellular signaling pathways mammalian target of rapamycin complex 1 and Rho-associated kinase, as pharmacological inhibition with rapamycin or Y27632, respectively, was without effect. Together, these data demonstrate that TSC2 controls cell migration, attachment, and spreading through the alpha1beta1 integrin receptor and thus suggest a potential therapeutic target for the treatment of increased cell invasiveness in LAM. PMID- 22923641 TI - The ly-6 protein, lynx1, is an endogenous inhibitor of nicotinic signaling in airway epithelium. AB - Our laboratory has previously reported that bronchial epithelial cells (BEC) express a regulatory cascade of classic neurotransmitters and receptors that communicate in an almost neuronal-like manner to achieve physiological regulation. In this paper we show that the similarity between neurotransmitter signaling in neurons and BEC extends to the level of transmitter receptor allosteric modulators. Lynx1 is a member of the ly-6/three-finger superfamily of proteins, many of which modulate receptor signaling activity. Lynx1 specifically has been shown to modulate nicotinic acetylcholine receptor (nAChR) function in neurons by altering receptor sensitivity and desensitization. We now report that lynx1 forms a complex with alpha7 nAChR in BEC and serves to negatively regulate alpha7 downstream signaling events. Treatment of primary cultures of BEC with nicotine increased levels of nAChR subunits and that increase was potentiated by lynx1 knockdown. Lynx1 knockdown also potentiated the nicotine-induced increase in GABA(A) receptors (GABA(A)R) and MUC5AC mRNA expression, and that effect was blocked by alpha7 antagonists and alpha7 knockdown. In parallel with the increases in nAChR, GABA(A)R, and mucin mRNA levels, lynx1 knockdown also increased levels of p-Src. Consistent with this, inhibition of Src signaling blocked the ability of the lynx1 knockdown to increase basal and nicotine stimulated GABA(A)R and mucin mRNA expression. Thus lynx1 appears to act as a negative modulator of alpha7 nAChR-induced events by inhibiting Src activation. This suggests that lynx1 agonists or mimetics are a potentially important therapeutic target to develop new therapies for smoking-related diseases characterized by increased mucin expression. PMID- 22923643 TI - Intranasal priming of newborn mice with microbial extracts increases opsonic factors and mature CD11c+ cells in the airway. AB - Nasal exposure to the mixture of microbial extracts (MME) after ablactation enhanced airway resistance of newborn mice to Streptococcus pneumoniae (J Physiol Lung Cell Mol Physiol 298: L67, 2010). The present study was addressed to elucidate effective factors responsible for the enhanced innate resistance in the airway of MME-exposed newborn mice. MME exposure significantly increased the amount of pulmonary surfactants (SP-A and SP-D) in the airway. Bronchoalveolar lavage fluid of the exposed mice exhibited greater levels of opsonic activity, thereby enhancing the phagocytic and intracellular killing activities of alveolar macrophages (MO) against S. pneumoniae. The exposure itself did not increase a complement component C3 and mannan-binding lectin-A (MBL-A) in the airway, whereas intratracheal infection with S. pneumoniae increased the quantity of SP A, SP-D, C3, and MBL-A in the exposed mice to a significant extent compared with control mice. The exposure enhanced the expression of the class A scavenger MO receptor with collagenous structure on alveolar MO and also increased the frequency of major histocompatibility complex II+ CD11c+ cells in the lung; the cells were able to produce IL-10 and transforming growth factor-beta in vitro. These results suggest that microbial exposure early in life increases the amounts of SP-A and SP-D and the number of scavenger MO and also promotes maturation of CD11c+ cells in the airway of newborn mice, which may be involved in airway resistance to S. pneumoniae. PMID- 22923642 TI - Caveolin-1 knockout mice exhibit airway hyperreactivity. AB - Caveolae are flask-shaped plasma membrane invaginations expressing the scaffolding caveolin proteins. Although caveolins have been found in endothelium and epithelium (where they regulate nitric oxide synthase activity), their role in smooth muscle is still under investigation. We and others have previously shown that caveolae of human airway smooth muscle (ASM), which express caveolin 1, contain Ca(2+) and force regulatory proteins and are involved in mediating the effects of inflammatory cytokines such as TNF-alpha on intracellular Ca(2+) concentration responses to agonist. Accordingly, we tested the hypothesis that in vivo, absence of caveolin-1 leads to reduced airway hyperresponsiveness, using a knockout (KO) (Cav1 KO) mouse and an ovalbumin-sensitized/challenged (OVA) model of allergic airway hyperresponsiveness. Surprisingly, airway responsiveness to methacholine, tested by use of a FlexiVent system, was increased in Cav1 KO control (CTL) as well as KO OVA mice, which could not be explained by a blunted immune response to OVA. In ASM of wild-type (WT) OVA mice, expression of caveolin 1, the caveolar adapter proteins cavins 1-3, and caveolae-associated Ca(2+) and force regulatory proteins such as Orai1 and RhoA were all increased, effects absent in Cav1 KO CTL and OVA mice. However, as with WT OVA, both CTL and OVA Cav1 KO airways showed signs of enhanced remodeling, with high expression of proliferation markers and increased collagen. Separately, epithelial cells from airways of all three groups displayed lower endothelial but higher inducible nitric oxide synthase and arginase expression. Arginase activity was also increased in these three groups, and the inhibitor nor-NOHA (N-omega-nor-l arginine) enhanced sensitivity of isolated tracheal rings to ACh, especially in Cav1 KO mice. On the basis of these data disproving our original hypothesis, we conclude that caveolin-1 has complex effects on ASM vs. epithelium, resulting in airway hyperreactivity in vivo mediated by altered airway remodeling and bronchodilation. PMID- 22923644 TI - Serotonin passes through myoendothelial gap junctions to promote pulmonary arterial smooth muscle cell differentiation. AB - Myoendothelial gap junctional signaling mediates pulmonary arterial endothelial cell (PAEC)-induced activation of latent TGF-beta and differentiation of cocultured pulmonary arterial smooth muscle cells (PASMCs), but the nature of the signal passing from PAECs to PASMCs through the gap junctions is unknown. Because PAECs but not PASMCs synthesize serotonin, and serotonin can pass through gap junctions, we hypothesized that the monoamine is the intercellular signal. We aimed to determine whether PAEC-derived serotonin mediates PAEC-induced myoendothelial gap junction-dependent activation of TGF-beta signaling and differentiation of PASMCs. Rat PAECs and PASMCs were monocultured or cocultured with (touch) or without (no-touch) direct cell-cell contact. In all cases, tryptophan hydroxylase 1 (Tph1) transcripts were expressed predominantly in PAECs. Serotonin was detected by immunostaining in both PAECs and PASMCs in PAEC/PASMC touch coculture but was not found in PASMCs in either PAEC/PASMC no touch coculture or in PASMC/PASMC touch coculture. Furthermore, inhibition of gap junctions but not of the serotonin transporter in PAEC/PASMC touch coculture prevented serotonin transfer from PAECs to PASMCs. Inhibition of serotonin synthesis pharmacologically or by small interfering RNAs to Tph1 in PAECs inhibited the PAEC-induced activation of TGF-beta signaling and differentiation of PASMCs. We concluded that serotonin synthesized by PAECs is transferred through myoendothelial gap junctions into PASMCs, where it activates TGF-beta signaling and induces a more differentiated phenotype. This finding suggests a novel role of gap junction-mediated intercellular serotonin signaling in regulation of PASMC phenotype. PMID- 22923645 TI - Why Do SGLT2 inhibitors inhibit only 30-50% of renal glucose reabsorption in humans? AB - Sodium glucose cotransporter 2 (SGLT2) inhibition is a novel and promising treatment for diabetes under late-stage clinical development. It generally is accepted that SGLT2 mediates 90% of renal glucose reabsorption. However, SGLT2 inhibitors in clinical development inhibit only 30-50% of the filtered glucose load. Why are they unable to inhibit 90% of glucose reabsorption in humans? We will try to provide an explanation to this puzzle in this perspective analysis of the unique pharmacokinetic and pharmacodynamic profiles of SGLT2 inhibitors in clinical trials and examine possible mechanisms and molecular properties that may be responsible. PMID- 22923646 TI - Immunotherapy in type 1 diabetes: a shorter but more winding road? PMID- 22923648 TI - Is endogenous GLP-1 the only important enhancer of glucose-induced insulin secretion in type 2 diabetes? PMID- 22923647 TI - Energizing the mind and body. PMID- 22923649 TI - The artificial pancreas. PMID- 22923650 TI - Endothelial insulin and IGF-1 receptors: when yes means NO. PMID- 22923651 TI - Loss of pulsatile insulin secretion: a factor in the pathogenesis of type 2 diabetes? PMID- 22923652 TI - An inhibitor of phospholipase A2 group IIA modulates adipocyte signaling and protects against diet-induced metabolic syndrome in rats. AB - Obesity, type 2 diabetes, and cardiovascular disease correlate with infiltration to adipose tissue of different immune cells, with uncertain influences on metabolism. Rats were fed a diet high in carbohydrates and saturated fats to develop diet-induced obesity over 16 weeks. This nutritional overload caused overexpression and secretion of phospholipase A(2) group IIA (pla2g2a) from immune cells in adipose tissue rather than adipocytes, whereas expression of adipose-specific phospholipase A(2) (pla2g16) was unchanged. These immune cells produce prostaglandin E(2) (PGE(2)), which influences adipocyte signaling. We found that a selective inhibitor of human pla2g2a (5-(4-benzyloxyphenyl)-(4S) (phenyl-heptanoylamino)-pentanoic acid [KH064]) attenuated secretion of PGE(2) from human immune cells stimulated with the fatty acid, palmitic acid, or with lipopolysaccharide. Oral administration of KH064 (5 mg/kg/day) to rats fed the high-carbohydrate, high-fat diet prevented the overexpression of pla2g2a and the increased macrophage infiltration and elevated PGE(2) concentrations in adipose tissue. The treatment also attenuated visceral adiposity and reversed most characteristics of metabolic syndrome, producing marked improvements in insulin sensitivity, glucose intolerance, and cardiovascular abnormalities. We suggest that pla2g2a may have a causal relationship with chronic adiposity and metabolic syndrome and that its inhibition in vivo may be a valuable new approach to treat obesity, type 2 diabetes, and metabolic dysfunction in humans. PMID- 22923655 TI - Comment on: Gogebakan et al. Glucose-dependent insulinotropic polypeptide reduces fat-specific expression and activity of 11beta-hydroxysteroid dehydrogenase type 1 and inhibits release of free fatty acids. Diabetes 2012;61:292-300. PMID- 22923656 TI - Comment on: Turban et al. Optimal elevation of beta-cell 11beta-hydroxysteroid dehydrogenase type 1 is a compensatory mechanism that prevents high-fat diet induced beta-cell failure. Diabetes 2012;61:642-652. PMID- 22923658 TI - Response to comment on: Marquez et al. Low-frequency variants in HMGA1 are not associated with type 2 diabetes risk. Diabetes 2012;61:524-530. PMID- 22923659 TI - Human rhinovirus species and season of infection determine illness severity. AB - RATIONALE: Human rhinoviruses (HRVs) consist of approximately 160 types that cause a wide range of clinical outcomes, including asymptomatic infections, common colds, and severe lower respiratory illnesses. OBJECTIVES: To identify factors that influence the severity of HRV illnesses. METHODS: HRV species and types were determined in 1,445 nasal lavages that were prospectively collected from 209 infants participating in a birth cohort who had at least one HRV infection. Questionnaires were used during each illness to identify moderate to severe illnesses (MSI). MEASUREMENTS AND MAIN RESULTS: Altogether, 670 HRV infections were identified, and 519 of them were solitary infections (only one HRV type). These 519 viruses belonged to 93 different types of three species: 49 A, 9 B, and 35 C types. HRV-A (odds ratio, 8.2) and HRV-C (odds ratio, 7.6) were more likely to cause MSI compared with HRV-B. In addition, HRV infections were 5- to 10-fold more likely to cause MSI in the winter months (P < 0.0001) compared with summer, in contrast to peak seasonal prevalence in spring and fall. When significant differences in host susceptibility to MSI (P = 0.004) were considered, strain-specific rates of HRV MSI ranged from less than 1% to more than 20%. CONCLUSIONS: Factors related to HRV species and type, season, and host susceptibility determine the risk of more severe HRV illness in infancy. These findings suggest that anti-HRV strategies should focus on HRV-A and -C species and identify the need for additional studies to determine mechanisms for seasonal increases of HRV severity, independent of viral prevalence, in cold weather months. PMID- 22923660 TI - Children's urinary phthalate metabolites and fractional exhaled nitric oxide in an urban cohort. AB - RATIONALE: Phthalates are used widely in consumer products. Exposure to several phthalates has been associated with respiratory symptoms and decreased lung function. Associations between children's phthalate exposures and fractional exhaled nitric oxide (Fe(NO)), a biomarker of airway inflammation, have not been examined. OBJECTIVES: We hypothesized that urinary concentrations of four phthalate metabolites would be positively associated with Fe(NO) and that these associations would be stronger among children with seroatopy or wheeze. METHODS: In an urban ongoing birth cohort, 244 children had phthalate metabolites determined in urine collected on the same day as Fe(NO) measurement. Repeated sampling gathered 313 observations between ages 4.9 and 9.1 years. Seroatopy was assessed by specific IgE. Wheeze in the past year was assessed by validated questionnaire. Regression models used generalized estimating equations. MEASUREMENTS AND MAIN RESULTS: Log-unit increases in urinary concentrations of metabolites of diethyl phthalate (DEP) and butylbenzyl phthalate (BBzP) were associated with a 6.6% (95% confidence interval [CI] 0.5-13.1%) and 8.7% (95% CI, 1.9-16.0%) increase in Fe(NO), respectively, adjusting for other phthalate metabolites and potential covariates/confounders. There was no association between concentrations of metabolites of di(2-ethylhexyl) phthalate or di-n-butyl phthalate and Fe(NO). There was no significant interaction by seroatopy. The BBzP metabolite association was significantly stronger among children who wheeze (P = 0.016). CONCLUSIONS: Independent associations between exposures to DEP and BBzP and Fe(NO) in a cohort of inner-city children were observed. These results suggest that these two ubiquitous phthalates, previously shown to have substantial contributions from inhalation, are positively associated with airway inflammation in children. PMID- 22923661 TI - Longitudinal analysis casts doubt on the presence of genetic anticipation in heritable pulmonary arterial hypertension. AB - RATIONALE: Analysis of the age of onset in heritable pulmonary arterial hypertension (HPAH) has led to the hypothesis that genetic anticipation causes younger age of onset and death in subsequent generations. With accrual of pedigree data over multiple decades, we retested this hypothesis using analyses that eliminate the truncation of data that exists with shorter duration of follow up. OBJECTIVES: To analyze the pedigrees of families with mutations in bone morphogenetic protein receptor type 2 (BMPR2), afflicted in two or more generations with HPAH, eliminating time truncation bias by including families for whom we have at least 57 years of data. METHODS: We analyzed 355 individuals with BMPR2 mutations from 53 families in the Vanderbilt Pulmonary Hypertension Registry. We compared age at diagnosis or death in affected individuals (n = 249) by generation within families with multigenerational disease. We performed linear mixed effects models and we limited time-truncation bias by restricting date of birth to before 1955. This allowed for 57 years of follow-up (1955-2012) for mutation carriers to develop disease. We also conducted Kaplan-Meier analysis to include currently unaffected mutation carriers (n = 106). MEASUREMENTS AND MAIN RESULTS: Differences in age at diagnosis by generation were found in a biased analysis that included all birth years to the present, but this finding was eliminated when the 57-year observation limit was imposed. By Kaplan-Meier analysis, inclusion of currently unaffected mutation carriers strengthens the observation that bias of ascertainment exists when recent generations are included. CONCLUSIONS: Genetic anticipation is likely an artifact of incomplete time of observation of kindreds with HPAH due to BMPR2 mutations. PMID- 22923662 TI - Efficacy of antibiotic therapy for acute exacerbations of mild to moderate chronic obstructive pulmonary disease. AB - RATIONALE: Antimicrobial therapy remains a controversial issue in nonsevere exacerbations of chronic obstructive pulmonary disease (COPD). OBJECTIVES: To evaluate the efficacy of antibiotic therapy in moderate exacerbations of mild-to moderate COPD. METHODS: This study involved a multicenter, parallel, double blind, placebo-controlled, randomized clinical trial. Patients aged 40 years or older, smokers, or ex-smokers of 10 pack-years or more with spirometrically confirmed mild-to-moderate COPD (FEV(1) > 50% predicted and FEV(1)/FVC ratio < 0.7) and diagnosed with an exacerbation were enrolled in the study. The patients were randomized to receive amoxicillin/clavulanate 500/125 mg three times a day or placebo three times a day for 8 days. MEASUREMENTS AND MAIN RESULTS: The primary outcome measure was clinical cure at end of therapy visit (EOT) at Days 9 to 11. A total of 310 subjects fulfilled all the criteria for efficacy analysis. A total of 117 patients with amoxicillin/clavulanate (74.1%) and 91 with placebo (59.9%) were considered cured at EOT (difference, 14.2%; 95% confidence interval, 3.7-24.3). The median time to the next exacerbation was significantly longer in patients receiving antibiotic compared with placebo (233 d [interquartile range, 110-365] compared with 160 d [interquartile range, 66-365]; P < 0.05). The best C reactive protein serum cut-off for predicting clinical failure with placebo was 40 mg/L, with an area under the curve of 0.732 (95% confidence interval, 0.614 0.851). CONCLUSIONS: Treatment of ambulatory exacerbations of mild-to-moderate COPD with amoxicillin/clavulanate is more effective and significantly prolongs the time to the next exacerbation compared with placebo. PMID- 22923664 TI - Alterations in gastrointestinal, endocrine, and metabolic processes after bariatric Roux-en-Y gastric bypass surgery. AB - OBJECTIVE: Obesity leads to severe long-term complications and reduced life expectancy. Roux-en-Y gastric bypass (RYGB) surgery induces excessive and continuous weight loss in (morbid) obesity, although it causes several abnormal anatomical and physiological conditions. RESEARCH DESIGN AND METHODS: To distinctively unveil effects of RYGB surgery on beta-cell function and glucose turnover in skeletal muscle, liver, and gut, nondiabetic, morbidly obese patients were studied before (pre-OP, five female/one male, BMI: 49 +/- 3 kg/m(2), 43 +/- 2 years of age) and 7 +/- 1 months after (post-OP, BMI: 37 +/- 3 kg/m(2)) RYGB surgery, compared with matching obese (CON(ob), five female/one male, BMI: 34 +/- 1 kg/m(2), 48 +/- 3 years of age) and lean controls (CON(lean), five female/one male, BMI: 22 +/- 0 kg/m(2), 42 +/- 2 years of age). Oral glucose tolerance tests (OGTTs), hyperinsulinemic-isoglycemic clamp tests, and mechanistic mathematical modeling allowed determination of whole-body insulin sensitivity (M/I), OGTT and clamp test beta-cell function, and gastrointestinal glucose absorption. RESULTS: Post-OP lost (P < 0.0001) 35 +/- 3 kg body weight. M/I increased after RYGB, becoming comparable to CON(ob), but remaining markedly lower than CON(lean) (P < 0.05). M/I tightly correlated (tau = -0.611, P < 0.0001) with fat mass. During OGTT, post-OP showed >=15% reduced plasma glucose from 120 to 180 min (<=4.5 mmol/L), and 29-fold elevated active glucagon-like peptide-1 (GLP-1) dynamic areas under the curve, which tightly correlated (r = 0.837, P < 0.001) with 84% increased beta-cell secretion. Insulinogenic index (0-30 min) in post-OP was >=29% greater (P < 0.04). At fasting, post-OP showed approximately halved insulin secretion (P < 0.05 vs. pre-OP). Insulin-stimulated insulin secretion in post-OP was 52% higher than before surgery, but 1-2 pmol/min(2) lower than in CON(ob)/CON(lean) (P < 0.05). Gastrointestinal glucose absorption was comparable in pre-OP and post-OP, but 9-26% lower from 40 to 90 min in post-OP than in CON(ob)/CON(lean) (P < 0.04). CONCLUSIONS: RYGB surgery leads to decreased plasma glucose concentrations in the third OGTT hour and exaggerated beta-cell function, for which increased GLP-1 release seems responsible, whereas gastrointestinal glucose absorption remains unchanged but lower than in matching controls. PMID- 22923663 TI - Lactic acid is elevated in idiopathic pulmonary fibrosis and induces myofibroblast differentiation via pH-dependent activation of transforming growth factor-beta. AB - RATIONALE: Idiopathic pulmonary fibrosis (IPF) is a complex disease for which the pathogenesis is poorly understood. In this study, we identified lactic acid as a metabolite that is elevated in the lung tissue of patients with IPF. OBJECTIVES: This study examines the effect of lactic acid on myofibroblast differentiation and pulmonary fibrosis. METHODS: We used metabolomic analysis to examine cellular metabolism in lung tissue from patients with IPF and determined the effects of lactic acid and lactate dehydrogenase-5 (LDH5) overexpression on myofibroblast differentiation and transforming growth factor (TGF)-beta activation in vitro. MEASUREMENTS AND MAIN RESULTS: Lactic acid concentrations from healthy and IPF lung tissue were determined by nuclear magnetic resonance spectroscopy; alpha smooth muscle actin, calponin, and LDH5 expression were assessed by Western blot of cell culture lysates. Lactic acid and LDH5 were significantly elevated in IPF lung tissue compared with controls. Physiologic concentrations of lactic acid induced myofibroblast differentiation via activation of TGF-beta. TGF-beta induced expression of LDH5 via hypoxia-inducible factor 1alpha (HIF1alpha). Importantly, overexpression of both HIF1alpha and LDH5 in human lung fibroblasts induced myofibroblast differentiation and synergized with low-dose TGF-beta to induce differentiation. Furthermore, inhibition of both HIF1alpha and LDH5 inhibited TGF-beta-induced myofibroblast differentiation. CONCLUSIONS: We have identified the metabolite lactic acid as an important mediator of myofibroblast differentiation via a pH-dependent activation of TGF-beta. We propose that the metabolic milieu of the lung, and potentially other tissues, is an important driving force behind myofibroblast differentiation and potentially the initiation and progression of fibrotic disorders. PMID- 22923665 TI - Birth weight, genetic susceptibility, and adulthood risk of type 2 diabetes. AB - OBJECTIVE: Both stressful intrauterine milieus and genetic susceptibility have been linked to later-life diabetes risk. The current study aims to examine the interaction between low birth weight, a surrogate measure of stressful intrauterine milieus, and genetic susceptibility in relation to risk of type 2 diabetes in adulthood. RESEARCH DESIGN AND METHODS: The analysis included two independent, nested case-control studies of 2,591 type 2 diabetic case subjects and 3,052 healthy control subjects. We developed two genotype scores: an obesity genotype score based on 32 BMI-predisposing variants and a diabetes genotype score based on 35 diabetes-predisposing variants. RESULTS: Obesity genotype scores showed a stronger association with type 2 diabetes risk in individuals with low birth weight. In low-birth weight individuals, the multivariable adjusted odds ratio (OR) was 2.55 (95% CI 1.34-4.84) by comparing extreme quartiles of the obesity genotype score, while the OR was 1.27 (1.04-1.55) among individuals with birth weight >2.5 kg (P for interaction = 0.017). We did not observe significant interaction between diabetes genotype scores and birth weight with regard to risk of type 2 diabetes. In a comparison of extreme quartiles of the diabetes gene score, the multivariable-adjusted OR was 3.80 (1.76-8.24) among individuals with low birth weight and 2.27 (1.82-2.83) among those with high birth weight (P for interaction = 0.16). CONCLUSIONS: Our data suggest that low birth weight and genetic susceptibility to obesity may synergistically affect adulthood risk of type 2 diabetes. PMID- 22923666 TI - Blood glucose control in type 1 diabetes with a bihormonal bionic endocrine pancreas. AB - OBJECTIVE: To test whether safe and effective glycemic control could be achieved in type 1 diabetes using a bihormonal bionic endocrine pancreas driven by a continuous glucose monitor in experiments lasting more than two days and including six high-carbohydrate meals and exercise as challenges to glycemic control. RESEARCH DESIGN AND METHODS: Six subjects with type 1 diabetes and no endogenous insulin secretion participated in two 51-h experiments. Blood glucose was managed with a bionic endocrine pancreas controlling subcutaneous delivery of insulin and glucagon with insulin pumps. A partial meal-priming bolus of insulin (0.035 units/kg/meal, then 0.05 units/kg/meal in repeat experiments) was administered at the beginning of each meal (on average 78 +/- 12 g of carbohydrates per meal were consumed). Plasma glucose (PG) control was evaluated with a reference quality measurement on venous blood every 15 min. RESULTS: The overall mean PG was 158 mg/dL, with 68% of PG values in the range of 70-180 mg/dL. There were no significant differences in mean PG between larger and smaller meal-priming bolus experiments. Hypoglycemia (PG <70 mg/dL) was rare, with eight incidents during 576 h of closed-loop control (0.7% of total time). During 192 h of nighttime control, mean PG was 123 mg/dL, with 93% of PG values in the range of 70-180 mg/dL and only one episode of mild hypoglycemia (minimum PG 62 mg/dL). CONCLUSIONS: A bihormonal bionic endocrine pancreas achieved excellent glycemic control with minimal hypoglycemia over the course of two days of continuous use despite high-carbohydrate meals and exercise. A trial testing a wearable version of the system under free-living conditions is justified. PMID- 22923667 TI - Transthyretin predicts cardiovascular outcome in hemodialysis patients with type 2 diabetes. AB - OBJECTIVE: BMI and albumin are commonly accepted parameters to recognize wasting in dialysis patients and are powerful predictors of morbidity and mortality. However, both parameters reveal limitations and may not cover the entire range of patients with wasting. The visceral protein transthyretin (TTR) may be helpful in overcoming the diagnostic and prognostic gap. Therefore, the aim of this study was to assess the association of TTR with morbidity and mortality in hemodialysis patients. RESEARCH DESIGN AND METHODS: The TTR concentration was determined in plasma samples of 1,177 hemodialysis patients with type 2 diabetes. Cox regression analyses were used to determine hazard ratios (HRs) for the risk of cardiovascular end points (CVEs) and mortality according to quartiles of TTR concentration for the total study cohort and the subgroups BMI >=23 kg/m(2), albumin concentration >=3.8 g/dL, and a combination of both. RESULTS: A low TTR concentration was associated with an increased risk for CVE for the total study cohort (HR 1.65 [95% CI 1.27-2.14]), patients with BMI >=23 kg/m(2) (1.70 [1.22 2.37]), albumin >=3.8 g/dL (1.68 [1.17-2.42]), and the combination of both (1.69 [1.13-2.53]). Additionally, a low TTR concentration predicted mortality for the total study cohort (1.79 [1.43-2.24]) and patients with BMI >=23 kg/m(2) (1.46 [1.09-1.95]). CONCLUSIONS: The current study demonstrated that TTR is a useful predictor for cardiovascular outcome and mortality in diabetic hemodialysis patients. TTR was particularly useful in patients who were not identified to be at risk by BMI or albumin status. PMID- 22923668 TI - Impaired glucose tolerance and obesity as effect modifiers of ethnic disparities of the progression to diabetes: the San Antonio Heart Study. AB - OBJECTIVE: The Diabetes Prevention Program (DPP) reported no racial/ethnic differences in the incidence of diabetes in individuals with impaired glucose tolerance (IGT). Therefore, it has been hypothesized that factors associated with racial/ethnic disparities act prior to the development of IGT. Because impaired fasting glucose (IFG) and obesity were also very prevalent in the DPP, we examined IGT, IFG, and obesity as effect modifiers of ethnic disparities in the San Antonio Heart Study. RESEARCH DESIGN AND METHODS: Participants were 3,015 Mexican Americans and non-Hispanic whites aged 25-64 years. The median follow-up period was 7.8 years. IGT, IFG, and diabetes were defined by the 2003 American Diabetes Association criteria, and obesity was defined as BMI >=30 kg/m(2). RESULTS: Mexican Americans had an excess risk of incident IGT (odds ratio 1.48 [95% CI 1.16-1.89]) and incident IFG (1.71 [1.31-2.23]) compared with non Hispanic whites. Mexican Americans also had a higher incidence of diabetes among individuals who had normal 2-h glucose (2.20 [1.48-3.29]) and IGT (1.72 [1.08 2.74]) at baseline. There was an interaction of obesity on the relationship between ethnicity and progression to IGT or diabetes (P = 0.034), with Mexican Americans having a greater risk among the nonobese (1.73 [1.36-2.21]) and a comparable risk among the obese (1.08 [0.75-1.56]). CONCLUSIONS: Ethnic differences can be detected at both the early and later stages of the diabetes disease process. However, non-Hispanic whites lose much of the ethnic advantage once they have developed obesity. PMID- 22923669 TI - Effects of cardiovascular disease risk communication for patients with type 2 diabetes on risk perception in a randomized controlled trial: the @RISK study. AB - OBJECTIVE: Patients with type 2 diabetes mellitus (T2DM) underestimate their risk of developing severe complications, and they do not always understand the risk communication by their caregivers. The aim of this study was to investigate the effects of an intervention focused on the communication of the absolute 10-year risk of developing cardiovascular disease (CVD) in patients with T2DM. RESEARCH DESIGN AND METHODS: A randomized controlled trial was performed in T2DM patients newly referred to the Diabetes Care System (DCS) West-Friesland, a managed-care system in the Netherlands. The intervention group (n = 131) received a six-step CVD risk communication. Control subjects (n = 130) received standard managed care. The primary outcome measure was appropriateness of risk perception (difference between actual CVD risk calculated by the UK Prospective Diabetes Study risk engine and risk perception). Secondary outcome measures were illness perceptions, attitude and intention to change behavior, satisfaction with the communication, and anxiety and worry about CVD risk. Patients completed questionnaires at baseline, at 2 weeks (immediately after the intervention), and at 12 weeks. RESULTS: Appropriateness of risk perception improved between the intervention and control groups at 2 weeks. This effect disappeared at 12 weeks. No effects were found on illness perceptions, attitude and intention to change behavior, or anxiety and worry about CVD risk. Patients in the intervention group were significantly more satisfied with the communication. CONCLUSIONS: This risk communication method improved patients' risk perception at 2 weeks but not at 12 weeks. Negative effects were not found, as patients did not become anxious or worried after the CVD risk communication. PMID- 22923670 TI - The use of metformin and the incidence of lung cancer in patients with type 2 diabetes. AB - OBJECTIVE: Observational studies have associated metformin use with a decreased risk of lung cancer incidence in patients with type 2 diabetes, but the studies had important methodological shortcomings. The objective of this study was to determine whether metformin use is associated with a decreased risk of lung cancer in patients with type 2 diabetes, while avoiding previous biases. RESEARCH DESIGN AND METHODS: Using the U.K. General Practice Research Database, we assembled a cohort of patients newly treated with oral hypoglycemic agents (OHAs) between 1988 and 2009. A nested case-control analysis was conducted, where case subjects with lung cancer occurring during follow-up were matched with up to 10 control subjects for age, sex, calendar time, and duration of follow-up. Conditional logistic regression was used to estimate adjusted rate ratios of lung cancer associated with ever use of metformin, along with measures of duration and cumulative dose. Models were adjusted for potential confounders, which included smoking. RESULTS: The cohort included 115,923 new users of OHAs, with 1,061 patients diagnosed with lung cancer during follow-up (rate 2.0/1,000 person years). Metformin use was not associated with a decreased rate of lung cancer (rate ratio 0.94 [95% CI 0.76-1.17]). No dose-response was observed by number of prescriptions received, cumulative duration of use, and dose. CONCLUSIONS: Metformin use is not associated with a decreased risk of lung cancer in patients with type 2 diabetes. The decreased risk reported in other observational studies is likely due to bias from methodological shortcomings. Nonetheless, greater consideration should be given to clarify inconsistencies between experimental models and population studies. PMID- 22923671 TI - Serum cathepsin S is associated with decreased insulin sensitivity and the development of type 2 diabetes in a community-based cohort of elderly men. AB - OBJECTIVE: To investigate associations between serum cathepsin S, impaired insulin sensitivity, defective insulin secretion, and diabetes risk in a community-based sample of elderly men without diabetes. RESEARCH DESIGN AND METHODS: Serum cathepsin S, insulin sensitivity (euglycemic-hyperinsulinemic clamp), and insulin secretion (early insulin response during an oral glucose tolerance test) were measured in 905 participants of the Uppsala Longitudinal Study of Adult Men (mean age, 71 years). Thirty participants developed diabetes during 6 years of follow-up. RESULTS: After adjustment for age, anthropometric variables, and inflammatory markers, higher cathepsin S was associated with decreased insulin sensitivity (regression coefficient per SD increase -0.09 [95% CI -0.14 to -0.04], P = 0.001), but no association with early insulin response was found. Moreover, higher cathepsin S was associated with a higher risk for developing diabetes (odds ratio per SD increase 1.48 [1.08-2.01], P = 0.01). CONCLUSIONS: Cathepsin S activity appears to be involved in the early dysregulation of glucose and insulin metabolism. PMID- 22923672 TI - Commentaries and letters to the editor of the plant cell. PMID- 22923673 TI - The shoot apical meristem regulatory peptide CLV3 does not activate innate immunity. AB - The Arabidopsis thaliana leucine-rich repeat receptor kinase FLAGELLIN SENSING2 (FLS2) is required for the recognition of bacterial flagellin in innate immunity. Recently, FLS2 was proposed to act as a multispecific receptor recognizing unrelated exogenous and endogenous peptide ligands, including CLAVATA3 (CLV3), a key regulator of shoot meristem stem cell production. Here, we report experimental evidence demonstrating that FLS2 does not recognize CLV3 and that the shoot apical meristem is immune to bacteria independently of CLV3 perception. PMID- 22923674 TI - Contamination risks in work with synthetic peptides: flg22 as an example of a pirate in commercial peptide preparations. AB - The pattern recognition receptor FLAGELLIN SENSING2 (FLS2) renders plant cells responsive to subnanomolar concentrations of flg22, the active epitope of bacterial flagellin. We recently observed that a preparation of the peptide IDL1, a signal known to regulate abscission processes via the receptor kinases HAESA and HAESA-like2, apparently triggered Arabidopsis thaliana cells in an FLS2 dependent manner. However, closer investigation revealed that this activity was due to contamination by a flg22-type peptide, and newly synthesized IDL1 peptide was completely inactive in FLS2 signaling. This raised alert over contamination events occurring in the process of synthesis or handling of peptides. Two recent reports have suggested that FLS2 has further specificities for structurally unrelated peptides derived from CLV3 and from Ax21. We thus scrutinized these peptides for activity in Arabidopsis cells as well. While responding to <1 nM flg22, Arabidopsis cells proved blind even to 100 MUM concentrations of CLV3p and axY(s)22. Our results confirm the exquisite sensitivity and selectivity of FLS2 for flg22. They also show that inadvertent contaminations with flg22-type peptides do occur and can be detected even in trace amounts by FLS2. PMID- 22923675 TI - FLS2-mediated responses to Ax21-derived peptides: response to the Mueller et al. commentary. PMID- 22923676 TI - Complexity in differential peptide-receptor signaling: response to Segonzac et Al. and Mueller et Al. commentaries. PMID- 22923677 TI - The GSK3-type kinase ASKalpha targets glucose-6-phosphate dehydrogenase to mediate oxidative stress responses in Arabidopsis. PMID- 22923678 TI - Putative glycosyltransferases and other plant Golgi apparatus proteins are revealed by LOPIT proteomics. AB - The Golgi apparatus is the central organelle in the secretory pathway and plays key roles in glycosylation, protein sorting, and secretion in plants. Enzymes involved in the biosynthesis of complex polysaccharides, glycoproteins, and glycolipids are located in this organelle, but the majority of them remain uncharacterized. Here, we studied the Arabidopsis (Arabidopsis thaliana) membrane proteome with a focus on the Golgi apparatus using localization of organelle proteins by isotope tagging. By applying multivariate data analysis to a combined data set of two new and two previously published localization of organelle proteins by isotope tagging experiments, we identified the subcellular localization of 1,110 proteins with high confidence. These include 197 Golgi apparatus proteins, 79 of which have not been localized previously by a high confidence method, as well as the localization of 304 endoplasmic reticulum and 208 plasma membrane proteins. Comparison of the hydrophobic domains of the localized proteins showed that the single-span transmembrane domains have unique properties in each organelle. Many of the novel Golgi-localized proteins belong to uncharacterized protein families. Structure-based homology analysis identified 12 putative Golgi glycosyltransferase (GT) families that have no functionally characterized members and, therefore, are not yet assigned to a Carbohydrate Active Enzymes database GT family. The substantial numbers of these putative GTs lead us to estimate that the true number of plant Golgi GTs might be one-third above those currently annotated. Other newly identified proteins are likely to be involved in the transport and interconversion of nucleotide sugar substrates as well as polysaccharide and protein modification. PMID- 22923679 TI - A set of regioselective O-methyltransferases gives rise to the complex pattern of methoxylated flavones in sweet basil. AB - Polymethoxylated flavonoids occur in a number of plant families, including the Lamiaceae. To date, the metabolic pathways giving rise to the diversity of these compounds have not been studied. Analysis of our expressed sequence tag database for four sweet basil (Ocimum basilicum) lines afforded identification of candidate flavonoid O-methyltransferase genes. Recombinant proteins displayed distinct substrate preferences and product specificities that can account for all detected 7-/6-/4'-methylated, 8-unsubstituted flavones. Their biochemical specialization revealed only certain metabolic routes to be highly favorable and therefore likely in vivo. Flavonoid O-methyltransferases catalyzing 4'- and 6-O methylations shared high identity (approximately 90%), indicating that subtle sequence changes led to functional differentiation. Structure homology modeling suggested the involvement of several amino acid residues in defining the proteins' stringent regioselectivities. The roles of these individual residues were confirmed by site-directed mutagenesis, revealing two discrete mechanisms as a basis for the switch between 6- and 4'-O-methylation of two different substrates. These findings delineate major pathways in a large segment of the flavone metabolic network and provide a foundation for its further elucidation. PMID- 22923680 TI - The grapevine root-specific aquaporin VvPIP2;4N controls root hydraulic conductance and leaf gas exchange under well-watered conditions but not under water stress. AB - We functionally characterized the grape (Vitis vinifera) VvPIP2;4N (for Plasma membrane Intrinsic Protein) aquaporin gene. Expression of VvPIP2;4N in Xenopus laevis oocytes increased their swelling rate 54-fold. Northern blot and quantitative reverse transcription-polymerase chain reaction analyses showed that VvPIP2;4N is the most expressed PIP2 gene in root. In situ hybridization confirmed root localization in the cortical parenchyma and close to the endodermis. We then constitutively overexpressed VvPIP2;4N in grape 'Brachetto', and in the resulting transgenic plants we analyzed (1) the expression of endogenous and transgenic VvPIP2;4N and of four other aquaporins, (2) whole plant, root, and leaf ecophysiological parameters, and (3) leaf abscisic acid content. Expression of transgenic VvPIP2;4N inhibited neither the expression of the endogenous gene nor that of other PIP aquaporins in both root and leaf. Under well-watered conditions, transgenic plants showed higher stomatal conductance, gas exchange, and shoot growth. The expression level of VvPIP2;4N (endogenous + transgene) was inversely correlated to root hydraulic resistance. The leaf component of total plant hydraulic resistance was low and unaffected by overexpression of VvPIP2;4N. Upon water stress, the overexpression of VvPIP2;4N induced a surge in leaf abscisic acid content and a decrease in stomatal conductance and leaf gas exchange. Our results show that aquaporin-mediated modifications of root hydraulics play a substantial role in the regulation of water flow in well-watered grapevine plants, while they have a minor role upon drought, probably because other signals, such as abscisic acid, take over the control of water flow. PMID- 22923681 TI - Gestational diabetes mellitus: primum non nocere. PMID- 22923682 TI - Severe hypoglycemia predicts mortality in diabetes. PMID- 22923685 TI - Characteristics and outcomes of subjects with diabetic foot ulceration. PMID- 22923683 TI - Ethnic differences in weight loss and diabetes remission after bariatric surgery: a meta-analysis. AB - OBJECTIVE: It has been postulated that the effectiveness of bariatric surgery varies between ethnic groups. However, data regarding this topic are inconclusive, as most studies included few patients from minority groups. We conducted a meta-analysis to determine the difference in percentage of excess weight loss (%EWL) 1-2 years after bariatric surgery in people of African and Caucasian descent. We also studied differences in diabetes mellitus (DM) remission. RESEARCH DESIGN AND METHODS: We performed a MEDLINE and EMBASE search for studies reporting %EWL and/or DM remission after bariatric surgery and including both African Americans and Caucasians. The 613 publications obtained were reviewed. We included 14 studies (1,087 African Americans and 2,714 Caucasians); all provided data on %EWL and 3 on DM remission. We extracted surgery type, %EWL, and DM remission 1-2 years after surgery. After analyzing %EWL for any surgery type, we performed subanalyses for malabsorptive and restrictive surgery. RESULTS: The overall absolute mean %EWL difference between African Americans and Caucasians was -8.36% (95% CI -10.79 to -5.93) significantly in favor of Caucasians. Results were similar for malabsorptive ( 8.39% [-11.38 to -5.40]) and restrictive (-8.46% [-12.95 to -3.97]) surgery. The remission of DM was somewhat more frequent in African American patients than in Caucasian patients (1.41 [0.56-3.52]). However, this was not statistically significant. CONCLUSIONS: In %EWL terms, bariatric surgery is more effective in Caucasians than in African Americans, regardless of procedure type. Further studies are needed to investigate the exact mechanisms behind these disparities and to determine whether ethnic differences exist in the remission of comorbidities after bariatric surgery. PMID- 22923686 TI - Quality of diabetes care in Italy: information from a large population-based multiregional observatory (ARNO diabetes). PMID- 22923687 TI - Pilot studies of wearable outpatient artificial pancreas in type 1 diabetes. PMID- 22923688 TI - Comment on: Jeffery et al. Age before stage: insulin resistance rises before the onset of puberty: a 9-year longitudinal study (EarlyBird 26). Diabetes care 2012;35:536-541. PMID- 22923690 TI - Cytochrome P450 3A5 plays a prominent role in the oxidative metabolism of the anti-human immunodeficiency virus drug maraviroc. AB - Maraviroc is an anti-human immunodeficiency virus drug that acts by blocking viral entry into target cells. With use of ultra-performance liquid chromatography-mass spectrometry several monooxygenated, dioxygenated, and glucuronidated metabolites of maraviroc were identified both in vitro and in vivo. Characterization of the enzymes involved in the production of these metabolites determined that cytochrome P450 3A5 was the principal enzyme responsible for the formation of an abundant metabolite of maraviroc that resulted from oxygenation of the dichlorocyclohexane ring. For the formation of this metabolite, the V(max) values for CYP3A4 and CYP3A5 were 0.04 and 0.93 pmol . min-1 . pmol P450-1, and the K(m) values were 11.1 and 48.9 MUM, respectively. Furthermore, human liver microsomes isolated from donors homozygous for the loss of-function CYP3A5*3 allele exhibited a 79% decrease in formation of this metabolite compared with those homozygous for the wild-type CYP3A5*1 allele. To probe which divergent residues between CYP3A4 and CYP3A5 might play a role in the differential activities of these enzymes toward maraviroc, mutations were introduced into both enzymes and metabolism of maraviroc was measured. A CYP3A5 L57F mutant exhibited a 61% decrease in the formation of this metabolite, whereas formation by a CYP3A4 F57L mutant was increased by 337% compared with that of the wild type. Taken together, these data provide novel insights into the biotransformation of maraviroc as well as the potential role of CYP3A4 and CYP3A5 divergent residues in the enzymatic activities of these two highly homologous enzymes. PMID- 22923691 TI - ECM microenvironment regulates collective migration and local dissemination in normal and malignant mammary epithelium. AB - Breast cancer progression involves genetic changes and changes in the extracellular matrix (ECM). To test the importance of the ECM in tumor cell dissemination, we cultured epithelium from primary human breast carcinomas in different ECM gels. We used basement membrane gels to model the normal microenvironment and collagen I to model the stromal ECM. In basement membrane gels, malignant epithelium either was indolent or grew collectively, without protrusions. In collagen I, epithelium from the same tumor invaded with protrusions and disseminated cells. Importantly, collagen I induced a similar initial response of protrusions and dissemination in both normal and malignant mammary epithelium. However, dissemination of normal cells into collagen I was transient and ceased as laminin 111 localized to the basal surface, whereas dissemination of carcinoma cells was sustained throughout culture, and laminin 111 was not detected. Despite the large impact of ECM on migration strategy, transcriptome analysis of our 3D cultures revealed few ECM-dependent changes in RNA expression. However, we observed many differences between normal and malignant epithelium, including reduced expression of cell-adhesion genes in tumors. Therefore, we tested whether deletion of an adhesion gene could induce sustained dissemination of nontransformed cells into collagen I. We found that deletion of P-cadherin was sufficient for sustained dissemination, but exclusively into collagen I. Our data reveal that metastatic tumors preferentially disseminate in specific ECM microenvironments. Furthermore, these data suggest that breaks in the basement membrane could induce invasion and dissemination via the resulting direct contact between cancer cells and collagen I. PMID- 22923692 TI - Brain conditioning is instrumental for successful microglia reconstitution following hematopoietic stem cell transplantation. AB - The recent hypothesis that postnatal microglia are maintained independently of circulating monocytes by local precursors that colonize the brain before birth has relevant implications for the treatment of various neurological diseases, including lysosomal storage disorders (LSDs), for which hematopoietic cell transplantation (HCT) is applied to repopulate the recipient myeloid compartment, including microglia, with cells expressing the defective functional hydrolase. By studying wild-type and LSD mice at diverse time-points after HCT, we showed the occurrence of a short-term wave of brain infiltration by a fraction of the transplanted hematopoietic progenitors, independently from the administration of a preparatory regimen and from the presence of a disease state in the brain. However, only the use of a conditioning regimen capable of ablating functionally defined brain-resident myeloid precursors allowed turnover of microglia with the donor, mediated by local proliferation of early immigrants rather than entrance of mature cells from the circulation. PMID- 22923693 TI - Collective many-body van der Waals interactions in molecular systems. AB - Van der Waals (vdW) interactions are ubiquitous in molecules and condensed matter, and play a crucial role in determining the structure, stability, and function for a wide variety of systems. The accurate prediction of these interactions from first principles is a substantial challenge because they are inherently quantum mechanical phenomena that arise from correlations between many electrons within a given molecular system. We introduce an efficient method that accurately describes the nonadditive many-body vdW energy contributions arising from interactions that cannot be modeled by an effective pairwise approach, and demonstrate that such contributions can significantly exceed the energy of thermal fluctuations--a critical accuracy threshold highly coveted during molecular simulations--in the prediction of several relevant properties. Cases studied include the binding affinity of ellipticine, a DNA-intercalating anticancer agent, the relative energetics between the A- and B-conformations of DNA, and the thermodynamic stability among competing paracetamol molecular crystal polymorphs. Our findings suggest that inclusion of the many-body vdW energy is essential for achieving chemical accuracy and therefore must be accounted for in molecular simulations. PMID- 22923695 TI - On the mechanism of CD47 targeting in cancer. PMID- 22923694 TI - Transgenerational epigenetic effects of the Apobec1 cytidine deaminase deficiency on testicular germ cell tumor susceptibility and embryonic viability. AB - Environmental agents and genetic variants can induce heritable epigenetic changes that affect phenotypic variation and disease risk in many species. These transgenerational effects challenge conventional understanding about the modes and mechanisms of inheritance, but their molecular basis is poorly understood. The Deadend1 (Dnd1) gene enhances susceptibility to testicular germ cell tumors (TGCTs) in mice, in part by interacting epigenetically with other TGCT modifier genes in previous generations. Sequence homology to A1cf, the RNA-binding subunit of the ApoB editing complex, raises the possibility that the function of Dnd1 is related to Apobec1 activity as a cytidine deaminase. We conducted a series of experiments with a genetically engineered deficiency of Apobec1 on the TGCT susceptible 129/Sv inbred background to determine whether dosage of Apobec1 modifies susceptibility, either alone or in combination with Dnd1, and either in a conventional or a transgenerational manner. In the paternal germ-lineage, Apobec1 deficiency significantly increased susceptibility among heterozygous but not wild-type male offspring, without subsequent transgenerational effects, showing that increased TGCT risk resulting from partial loss of Apobec1 function is inherited in a conventional manner. By contrast, partial deficiency in the maternal germ-lineage led to suppression of TGCTs in both partially and fully deficient males and significantly reduced TGCT risk in a transgenerational manner among wild-type offspring. These heritable epigenetic changes persisted for multiple generations and were fully reversed after consecutive crosses through the alternative germ-lineage. These results suggest that Apobec1 plays a central role in controlling TGCT susceptibility in both a conventional and a transgenerational manner. PMID- 22923696 TI - Inhibitory signaling through signal regulatory protein-alpha is not sufficient to explain the antitumor activities of CD47 antibodies. PMID- 22923697 TI - Deciphering the genome of polyphosphate accumulating actinobacterium Microlunatus phosphovorus. AB - Polyphosphate accumulating organisms (PAOs) belong mostly to Proteobacteria and Actinobacteria and are quite divergent. Under aerobic conditions, they accumulate intracellular polyphosphate (polyP), while they typically synthesize polyhydroxyalkanoates (PHAs) under anaerobic conditions. Many ecological, physiological, and genomic analyses have been performed with proteobacterial PAOs, but few with actinobacterial PAOs. In this study, the whole genome sequence of an actinobacterial PAO, Microlunatus phosphovorus NM-1(T) (NBRC 101784(T)), was determined. The number of genes for polyP metabolism was greater in M. phosphovorus than in other actinobacteria; it possesses genes for four polyP kinases (ppks), two polyP-dependent glucokinases (ppgks), and three phosphate transporters (pits). In contrast, it harbours only a single ppx gene for exopolyphosphatase, although two copies of ppx are generally present in other actinobacteria. Furthermore, M. phosphovorus lacks the phaABC genes for PHA synthesis and the actP gene encoding an acetate/H(+) symporter, both of which play crucial roles in anaerobic PHA accumulation in proteobacterial PAOs. Thus, while the general features of M. phosphovorus regarding aerobic polyP accumulation are similar to those of proteobacterial PAOs, its anaerobic polyP use and PHA synthesis appear to be different. PMID- 22923698 TI - Mental stress-induced ischemia in patients with coronary artery disease: echocardiographic characteristics and relation to exercise-induced ischemia. AB - OBJECTIVE: The aims of this study were to investigate the incidence and parameters associated with myocardial ischemia during mental stress (MS) as measured by echocardiography and to evaluate the relation between MS-induced and exercise-induced myocardial ischemia. METHODS: Study participants were 79 patients (63 men; mean [M] [standard deviation {SD}] age = 52 [8] years) with angiographically confirmed coronary artery disease and previous positive exercise test result. The MS protocol consisted of mental arithmetic and anger recall task. The patients performed a treadmill exercise test 15 to 20 minutes after the MS task. Data of post-MS exercise were compared with previous exercise stress test results. RESULTS: The frequency of echocardiographic abnormalities was 35% in response to the mental arithmetic task, compared with 61% with anger recall and 96% with exercise (p < .001, exercise versus MS). Electrocardiogram abnormalities and chest pain were substantially less common during MS than were echocardiographic abnormalities. Independent predictors of MS-induced myocardial ischemia were: wall motion score index at rest (p = .02), peak systolic blood pressure (p = .005), and increase in rate-pressure product (p = .004) during MS. The duration of exercise stress test was significantly shorter (p < .001) when MS preceded the exercise and in the case of earlier exercise (M [SD] = 4.4 [1.9] versus 6.7 [2.2] minutes for patients positive on MS and 5.7 [1.9] versus 8.0 [2.3] minutes for patients negative on MS). CONCLUSIONS: Echocardiography can be successfully used to document myocardial ischemia induced by MS. MS-induced ischemia was associated with an increase in hemodynamic parameters during MS and worse function of the left ventricle. MS may shorten the duration of subsequent exercise stress testing and can potentiate exercise-induced ischemia in susceptible patients with coronary artery disease. PMID- 22923699 TI - Neuroinflammation and depression: the role of indoleamine 2,3-dioxygenase (IDO) as a molecular pathway. PMID- 22923700 TI - Differential predictive value of depressive versus anxiety symptoms in the prediction of 8-year mortality after acute coronary syndrome. AB - OBJECTIVE: Both depression and anxiety have been associated with poor prognosis in patients with acute coronary syndrome (ACS). However, certain symptoms and how they are measured may be more important than others. We investigated three different scales to determine their predictive validity. METHODS: Patients with ACS (N = 598) completed either the Hospital Anxiety and Depression Scales (HADS A, HADS-D; n = 316) or the Beck Depression Inventory-Fast Screen (n = 282). Their all-cause mortality status was assessed at 8 years. RESULTS: During follow-up, 20% (121/598) of participants died. Cox proportional hazards modeling showed that the HADS-D was predictive of mortality (hazard ratio [HR] = 1.11, 95% confidence interval [CI] = 1.04-1.19), and this association remained significant after adjustment for major clinical/demographic factors, whereas the HADS-A (HR = 0.96, 95% CI = 0.85-1.09) and the Beck Depression Inventory-Fast Screen (HR = 0.99, 95% CI = 0.91-1.08) were not. The following depression items from the HADS-D predicted mortality: "I still enjoy the things I used to enjoy" (HR = 1.38, 95% CI = 1.05-1.82), "I can laugh and see the funny side of things" (HR = 1.48, 95% CI = 1.11-1.96), "I feel as if I am slowed down" (HR = 1.66, 95% CI = 1.24-2.22), and "I look forward with enjoyment to things" (HR = 1.36, 95% CI = 1.08-1.72). CONCLUSIONS: Depressive symptoms related to lack of enjoyment or pleasure and physical or cognitive slowing, as measured by the HADS-D, predicted all-cause mortality at 8 years ACS patients, whereas other depressive and anxiety symptoms did not. Whether symptoms of distress predict prognosis in ACS seems to be dependent on the measures and items used. PMID- 22923701 TI - Impact of HIV antiretroviral therapy on depression and mental health among clients with HIV in Uganda. AB - OBJECTIVE: With wide-reaching harmful effects of depression, and the absence of psychiatric treatment in most HIV care programs in sub-Saharan Africa, we examined the effects of antiretroviral therapy (ART) on depression and other mental health indicators. METHODS: 602 patients (302 non-ART, 300 ART) were followed for the first 12 months of HIV care in Uganda, with assessments at entry into care and Months 6 and 12. Mental health was assessed with measures of depression, hopelessness, and internalized HIV stigma; physical health functioning was assessed as an explanatory variable. RESULTS: Thirteen percent had clinical depression, 57% had elevated depressive symptoms, and CD4 cell count was negatively correlated with measures of depression at baseline. Significant reductions in elevated depressive symptoms (time: odds ratio [95% confidence interval] = 0.53 [0.43-0.64]) and hopelessness (time: beta = -0.12, p < .001) were observed in both the ART and non-ART groups, but the drop in depression was greater among ART patients in intention-to-treat multivariate analysis (ART * time: p < .001). When added to the regression models, change in physical health functioning predicted positive longitudinal change on measures of depression, hopelessness, and internalized stigma (all p values < .001), yet ART status remained a significant independent predictor of each (ART * time: p values ranged from < .05 to < .001). Most mental health benefits of ART were experienced in the first 6 months of care. CONCLUSIONS: These findings demonstrate the mental health benefits of HIV care and ART. However, in some people, mental health problems persist once physical health is stabilized, in which case mental health treatment may be needed. PMID- 22923702 TI - Obesity is associated with structural and functional brain abnormalities: where do we go from here? PMID- 22923703 TI - Evaluation of carotid plaque neovascularization using contrast ultrasound. AB - Contrast-enhanced ultrasound (CEUS) is increasingly used to improve visualization of carotid arteries. However, its reproducibility and utility for clinical research are not well established. The aim of the present study was to assess reproducibility of detection of carotid artery wall neovascularization using CEUS. Complete sequenced CEUS images from 10 individuals were analyzed for the presence of carotid arterial wall neovascularization. The images were acquired using Philips CompactXtreme CX50 ultrasound unit with an L12-3 probe and Bracco SonoVue contrast agent. The carotid wall neovascularization was graded by 2 independent observers with inter-/intraobserver agreement (kappa) calculated. Interobserver kappa values for intraplaque neovascularization (mean [95% confidence interval]) were 0.67 (0.40-0.94) for the left side. Interobserver kappa values for intraplaque neovascularization were 0.65 (0.38-0.92). No study related complications were observed. The CEUS method although semiquantitative shows moderate-to-strong intra- and interagreement for the results and can be used for clinical research purpose. PMID- 22923704 TI - Long-term coffee consumption associated with reduced risk of total and cause specific mortality. PMID- 22923705 TI - Dietary interventions more effective than physical activity or mixed interventions for weight management during pregnancy. PMID- 22923706 TI - Mammography screening in Norway caused substantial overdiagnosis and did not reduce late-stage breast cancers. PMID- 22923707 TI - Bariatric intervention effective at reversing Type 2 diabetes. PMID- 22923708 TI - Medical apps for smartphones: lack of evidence undermines quality and safety. AB - Increasing numbers of healthcare professionals are using smartphones and their associated applications (apps) in daily clinical care. While these medical apps hold great potential for improving clinical practice, little is known about the possible dangers associated with their use. Breaches of patient confidentiality, conflicts of interests and malfunctioning clinical decision-making apps could all negatively impact on patient care. We propose several strategies to enhance the development of evidence-based medical apps while retaining their open nature. The increasing use of medical apps calls for broader discussion across medicine's organising and accrediting bodies. The field of medical apps is currently one of the most dynamic in medicine, with real potential to change the way evidence based healthcare is delivered in the future. Establishing appropriate regulatory procedures will enable this potential to be fulfilled, while at all times ensuring the safety of the patient. PMID- 22923709 TI - Mental health community support needs don't stop at 65. PMID- 22923710 TI - A biobehavioral approach to understanding obesity and the development of obesogenic illnesses among Latino immigrants in the United States. AB - The prevalence of obesity and obesity-related illnesses is higher among Hispanics (Latinos) than other racial and ethnic groups, and rates increase exponentially with the number of years living in the United States. Mounting evidence suggests that the origins of many chronic illnesses among disadvantaged minority groups may lie with cumulative exposure to chronic psychological and physiological stressors through the biobehavioral process of allostatic load (AL). Among immigrant Latinos, acculturation stress may contribute to an increase in AL and thus may be an independent risk factor for the development of obesity and obesogenic illnesses. The purpose of this theoretical article is to present a proposed model of the effects of acculturation stress on AL and obesity among Latino immigrants. Such a model can be useful to guide intervention efforts to decrease obesity among immigrant Latinos by adding education, skill building, and social integration strategies to healthy eating and physical activity to reduce the deleterious impact of acculturation stress. PMID- 22923711 TI - Cognitive bias modification training in adolescents reduces anxiety to a psychological challenge. AB - Many anxiety disorders begin in adolescence. Early interventions that target adolescent anxiety may prevent later disabling consequences. Previous studies show that cognitive bias modification training can generate positive interpretative styles of ambiguous information in adolescents but effects on anxious mood reduction are less clear. Adult studies suggest more consistent training effects on mood when assessed in response to a psychological challenge. Here, we assess whether positive training reduces adolescent anxious responses to a laboratory stressor. A total of 40 adolescents were randomly assigned to positive or negative computerised training. During training, ambiguous scenarios were resolved positively or negatively. After training, adolescents completed a test of interpretation bias and a difficult mental arithmetic task while believing that they were being videotaped for teaching purposes. First, positively-trained adolescents endorsed more positive and fewer negative interpretations of new ambiguous situations than negatively-trained adolescents. Second, positively-trained adolescents also showed attenuated anxiety levels after but not before the challenge. Induced positive interpretations via computerised cognitive training may modify anxious responsivity. Although there are some caveats to these data, in general they justify extensions of computerised training to adolescents with clinical anxiety, to reduce anxious responsivity. PMID- 22923712 TI - Sodium MR imaging of the lumbar intervertebral disk at 7 T: correlation with T2 mapping and modified Pfirrmann score at 3 T--preliminary results. AB - PURPOSE: To compare sodium imaging of lumbar intervertebral disks in asymptomatic volunteers at 7-T magnetic resonance (MR) imaging with quantitative T2 mapping and morphologic scoring at 3 T. MATERIALS AND METHODS: Following ethical board approval and informed consent, the L2-3 to L5-S1 disks were examined in 10 asymptomatic volunteers (nine men, one woman; mean age, 30 years; range, 23-43 years). At 7 T, normalized sodium signal-to-noise ratios were calculated, by using region-of-interest analysis. At 3 T, T2 mapping was performed with a multiecho spin-echo sequence (repetition time msec/echo times msec, 1500/24, 36, 48, 60, 72, 84, 96, 108, 120, 132, 144, 156). T2 values were calculated over the nucleus, with a pixelwise, monoexponential nonnegative least-squares-fit analysis. Morphologic grading according to a modified Pfirrmann score was assessed independently by three experienced musculoskeletal radiologists, and Pearson correlation analysis of the covariates was performed. RESULTS: The mean normalized sodium signal intensity was 275.5+/-115.4 (standard deviation). The T2 mapping showed a mean value of 89.8 msec+/-19.34. The median modified Pfirrmann score was 2b (90% had score<=3c). The Pearson correlation coefficient showed a cubic function between sodium imaging and the modified Pfirrmann score, a moderate inverse correlation between T2 mapping and the modified Pfirrmann score (r=-0.62), and no correlation between sodium imaging and T2 mapping (r=0.06). CONCLUSION: The results suggest that MR imaging of the intervertebral disk, using sodium imaging and T2 mapping, can help characterize different component changes and that both of these methods are to some degree related to the Pfirrmann score. PMID- 22923713 TI - Obstruction at middle hepatic venous tributaries in modified right lobe grafts after living-donor liver Transplantation: diagnosis with contrast-enhanced US. AB - PURPOSE: To investigate the ability of contrast material-enhanced ultrasonography (US) to help diagnose obstruction of middle hepatic venous (MHV) tributaries soon after living-donor liver transplantation with modified right lobe grafts. MATERIALS AND METHODS: The institutional review board approved the study and waived requirement for informed consent. Sixty-five consecutive patients (48 men, 17 women; mean age, 52.8 years; range, 33-69 years) who underwent living-donor liver transplantation with modified right lobe grafts between February and May 2009 were included. All patients underwent contrast-enhanced US and Doppler US on postoperative day 1 and underwent computed tomography (CT) within 7 days after US. At contrast-enhanced US, parenchymal enhancement patterns in the territory of each MHV tributary during arterial and portal venous phases were evaluated. With use of most frequent enhancement patterns in patients with obstruction at MHV tributaries as a criterion, diagnostic performance of contrast-enhanced US was compared with that of Doppler US for diagnosis of obstruction at MHV tributaries; CT was the reference standard. Generalized estimating equations were used to adjust for data clustering. RESULTS: Of 148 MHV tributaries in 65 patients, 36 (24.3%) in 31 patients were diagnosed as obstructed at CT. With arterial high echogenicity or portal low echogenicity used as a criterion for hepatic venous obstruction, contrast-enhanced US had sensitivity, specificity, and accuracy of 91% (33 of 36), 97% (109 of 112), and 95% (142 of 148), respectively, whereas Doppler US had values of 83% (30 of 36), 86% (97 of 112), and 85% (127 of 148), respectively. Contrast-enhanced US was significantly more specific and accurate than Doppler US for diagnosis of obstruction at MHV tributaries (P=.024 and .01, respectively). Arterial high echogenicity was noted only in the hepatic venous obstruction group. CONCLUSION: Contrast-enhanced US can help accurately assess hepatic venous obstruction at MHV tributaries after living-donor liver transplantation with a modified right lobe graft. Contrast-enhanced US was significantly more specific than Doppler US, with arterial hyperenhancement in the affected area being specific to hepatic venous obstruction. PMID- 22923714 TI - Nephrogenic systemic fibrosis and class labeling of gadolinium-based contrast agents by the Food and Drug Administration. AB - In 2007, the Food and Drug Administration requested that manufacturers of all approved gadolinium-based contrast agents (GBCAs), drugs widely used in magnetic resonance imaging, use nearly identical text in their product labeling to describe the risk of nephrogenic systemic fibrosis (NSF). Accumulating information about NSF risks led to revision of the labeling text for all of these drugs in 2010. The present report summarizes the basis and purpose of this class labeling approach and describes some of the related challenges, given the evolutionary nature of the NSF risk evidence. The class-labeling approach for presentation of product risk is designed to decrease the occurrence of NSF and to enhance the safe use of GBCAs in radiologic practice. PMID- 22923715 TI - Prediction of subacute infarct size in acute middle cerebral artery stroke: comparison of perfusion-weighted imaging and apparent diffusion coefficient maps. AB - PURPOSE: To compare perfusion-weighted (PW) imaging and apparent diffusion coefficient (ADC) maps in prediction of infarct size and growth in patients with acute middle cerebral artery infarct. MATERIALS AND METHODS: This study was approved by the local institutional review board. Written informed consent was obtained from all 80 patients. Subsequent infarct volume and growth on follow-up magnetic resonance (MR) images obtained within 6 days were compared with the predictions based on PW images by using a time-to-peak threshold greater than 4 seconds and ADC maps obtained less than 12 hours after middle cerebral artery infarct. ADC- and PW imaging-predicted infarct growth areas and infarct volumes were correlated with subsequent infarct growth and follow-up diffusion-weighted (DW) imaging volumes. The impact of MR imaging time delay on the correlation coefficient between the predicted and subsequent infarct volumes and individual predictions of infarct growth by using receiver operating characteristic curves were assessed. RESULTS: The infarct volume measurements were highly reproducible (concordance correlation coefficient [CCC] of 0.965 and 95% confidence interval [CI]: 0.949, 0.976 for acute DW imaging; CCC of 0.995 and 95% CI: 0.993, 0.997 for subacute DW imaging). The subsequent infarct volume correlated (P<.0001) with ADC- (rho=0.853) and PW imaging- (rho=0.669) predicted volumes. The correlation was higher for ADC-predicted volume than for PW imaging-predicted volume (P<.005), but not when the analysis was restricted to patients without recanalization (P=.07). The infarct growth correlated (P<.0001) with PW imaging DW imaging mismatch (rho=0.470) and ADC-DW imaging mismatch (rho=0.438), without significant differences between both methods (P=.71). The correlations were similar among time delays with ADC-predicted volumes but decreased with PW imaging-based volumes beyond the therapeutic window. Accuracies of ADC- and PW imaging-based predictions of infarct growth in an individual prediction were similar (area under the receiver operating characteristic curve [AUC] of 0.698 and 95% CI: 0.585, 0.796 vs AUC of 0.749 and 95% CI: 0.640, 0.839; P=.48). CONCLUSION: The ADC-based method was as accurate as the PW imaging-based method for evaluating infarct growth and size in the subacute phase. PMID- 22923716 TI - Diagnostic performance of a dedicated 1.5-T breast MR imaging system. AB - PURPOSE: To assess diagnostic performance of dedicated breast magnetic resonance (MR) imaging at breast imaging centers by using a dedicated 1.5-T breast MR system that used high-spatial-resolution, high-contrast-resolution spiral trajectory acquisitions. MATERIALS AND METHODS: The study was institutional review board approved and HIPAA compliant, with waiver of informed consent. Diagnostic performance was retrospectively assessed for 934 consecutive screening (n=347) and diagnostic (n=587) examinations performed from April 2006 to December 2007 in women aged 25-89 years old from four sites for which dedicated breast MR imaging reports and ground truth (biopsy for cancer cases, 1-year follow-up with negative results for cases with negative findings) were available. The sensitivity, specificity, and receiver operating characteristic (ROC) for breast MR imaging were determined. RESULTS: The sensitivity and specificity for the dedicated breast MR imaging system were 92% (92 of 100) and 88.8% (741 of 834). For all cases, the negative predictive value (NPV) was 98.9% (741 of 749). The NPV for screening cases was 100% (326 of 326). The area under the ROC curve was 0.942. Of the 93 cases with false-positive findings seen at dedicated breast MR imaging, 25 (27%) were high-risk histologic findings for which excision is often recommended. The false-positive rate was 93 of 834 (11.2%) for all cases, but only 16 of 326 (4.9%) for the screening cohort. CONCLUSION: High accuracy was achieved by using dedicated breast MR imaging. PMID- 22923717 TI - Evaluation of valvular insufficiency and shunts with parallel-imaging compressed sensing 4D phase-contrast MR imaging with stereoscopic 3D velocity-fusion volume rendered visualization. AB - PURPOSE: To assess the potential of compressed-sensing parallel-imaging four dimensional (4D) phase-contrast magnetic resonance (MR) imaging and specialized imaging software in the evaluation of valvular insufficiency and intracardiac shunts in patients with congenital heart disease. MATERIALS AND METHODS: Institutional review board approval was obtained for this HIPAA-compliant study. Thirty-four consecutive retrospectively identified patients in whom a compressed sensing parallel-imaging 4D phase-contrast sequence was performed as part of routine clinical cardiac MR imaging between March 2010 and August 2011 and who had undergone echocardiography were included. Multiplanar, volume-rendered, and stereoscopic three-dimensional velocity-fusion visualization algorithms were developed and implemented in Java and OpenGL. Two radiologists independently reviewed 4D phase-contrast studies for each of 34 patients (mean age, 6 years; age range, 10 months to 21 years) and tabulated visible shunts and valvular regurgitation. These results were compared with color Doppler echocardiographic and cardiac MR imaging reports, which were generated without 4D phase-contrast visualization. Cohen kappa statistics were computed to assess interobserver agreement and agreement with echocardiographic results. RESULTS: The 4D phase contrast acquisitions were performed, on average, in less than 10 minutes. Among 123 valves seen in 34 4D phase-contrast studies, 29 regurgitant valves were identified, with good agreement between observers (k=0.85). There was also good agreement with the presence of at least mild regurgitation at echocardiography (observer 1, kappa=0.76; observer 2, kappa=0.77) with high sensitivity (observer 1, 75%; observer 2, 82%) and specificity (observer 1, 97%; observer 2, 95%) relative to the reference standard. Eight intracardiac shunts were identified, four of which were not visible with conventional cardiac MR imaging but were detected with echocardiography. No intracardiac shunts were found with echocardiography alone. CONCLUSION: With velocity-fusion visualization, the compressed-sensing parallel-imaging 4D phase-contrast sequence can augment conventional cardiac MR imaging by improving sensitivity for and depiction of hemodynamically significant shunts and valvular regurgitation. PMID- 22923718 TI - Effect of multipeak spectral modeling of fat for liver iron and fat quantification: correlation of biopsy with MR imaging results. AB - PURPOSE: To investigate the effect of the multipeak spectral modeling of fat on R2* values as measures of liver iron and on the quantification of liver fat fraction, with biopsy as the reference standard. MATERIALS AND METHODS: Institutional review board approval and informed consent were obtained. Patients with liver disease (n = 95; 50 men, 45 women; mean age, 57.2 years+/-14.1 [standard deviation]) underwent a nontargeted liver biopsy, and 97 biopsy samples were reviewed for steatosis and iron grades. MR imaging at 1.5 T was performed 24 72 hours after biopsy by using a three-echo three-dimensional gradient-echo sequence for water and fat separation. Data were reconstructed off-line, correcting for T1 and T2* effects. Fat fraction and R2* maps (1/T2*) were reconstructed and differences in R2* and steatosis grades with and without multipeak modeling of fat were tested by using the Kruskal-Wallis test. Spearman rank correlation coefficient was used to assess fat fractions and steatosis grades. Linear regression analysis was performed to compare the fat fraction for both models. RESULTS: Mean steatosis grade at biopsy ranged from 0% to 95%. Biopsy specimens in 26 of 97 patients (27%) showed liver iron (15 mild, six moderate, and five severe). In all 71 samples without iron, a strong increase in the apparent R2* was observed with increasing steatosis grade when single-peak modeling of fat was used (P=.001). When multipeak modeling was used, there were no differences in the apparent R2* as a function of steatosis grading (P=.645), and R2* values agreed closely with those reported in the literature. Good correlation between fat fraction and steatosis grade was observed (rS=0.85) both without and with spectral modeling. CONCLUSION: In the presence of fat, multipeak spectral modeling of fat improves the agreement between R2* and liver iron. Single-peak modeling of fat leads to underestimation of liver fat. PMID- 22923720 TI - Reduction of metal artifacts in patients with total hip arthroplasty with slice encoding metal artifact correction and view-angle tilting MR imaging. AB - PURPOSE: To compare the new "warp" sequence (slice-encoding metal artifact correction [SEMAC], view-angle tilting [VAT], and increased bandwidth) for the reduction of both through-plane and in-plane magnetic resonance (MR) artifacts with current optimized MR sequences in patients with total hip arthroplasty (THA). MATERIALS AND METHODS: The institutional review board issued a waiver for this study. Forty patients with THA were prospectively included. SEMAC, VAT, and increased bandwidth were applied by using the warp turbo-spin-echo sequence at 1.5 T. Coronal short tau inversion-recovery (STIR)-warp and transverse T1 weighted warp (hereafter, T1-warp) images, as well as standard coronal STIR and transverse T1-weighted sequence images optimized with high bandwidth (STIR-hiBW and T1-hiBW), were acquired. Fifteen additional patients were examined to compare the T1-warp and T1-hiBW sequence with an identical matrix size. Signal void was quantified. Qualitative criteria (distinction of anatomic structures, blurring, and noise) were assessed on a five-point scale (1, no artifacts; 5, not visible due to severe artifacts) by two readers. Abnormal imaging findings were recorded. Quantitative data were analyzed with a t test and qualitative data with a Wilcoxon signed rank test. RESULTS: Signal void around the acetabular component was smaller for STIR-warp than STIR-hiBW images (21.6 cm2 vs 42.4 cm2; P=.0001), and for T1-warp than T1-hiBW images (17.6 cm2 vs 20.2 cm2; P=.0001). Anatomic distinction was better on STIR-warp compared with STIR-hiBW images (1.9-2.8 vs 3.6-4.6; P=.0001), and on T1-warp compared with T1-hiBW images (1.3-2.8 vs 1.8 3.2; P<.002). Distortion, blurring, and noise were lower with warp sequences than with the standard sequences (P=.0001). Almost half of the abnormal imaging findings were missed on STIR-hiBW compared with STIR-warp images (55 vs 105 findings; P=.0001), while T1-hiBW was similar to T1-warp imaging (50 vs 55 findings; P=.06). CONCLUSION: STIR-warp and T1-warp sequences were significantly better according to quantitative and qualitative image criteria, but a clinically relevant artifact reduction was only present for STIR images. PMID- 22923719 TI - Use of MR cell tracking to evaluate targeting of glial precursor cells to inflammatory tissue by exploiting the very late antigen-4 docking receptor. AB - PURPOSE: To determine if glial precursor cells can be targeted to inflamed brain through overexpression of very late antigen-4 (VLA-4) and whether this docking process can be monitored with magnetic resonance (MR) cell tracking after intraarterial injection. MATERIALS AND METHODS: All experimental procedures were performed between August 2010 and February 2012 and were approved by the institutional animal care and use committee. Human glial precursor cells (hGPs) were transfected with VLA-4 and labeled with superparamagnetic iron oxide that contained rhodamine. A microfluidic adhesion assay was used for assessing VLA-4 receptor-mediated cell docking in vitro. A rat model of global lipopolysaccharide (LPS)-mediated brain inflammation was used to induce global vascular cell adhesion molecule-1 (VCAM-1) expression. hGPs were infused into the carotid artery in four animal cohorts (consisting of three rats each): rats that received VLA-4-naive hGPs but did not receive LPS, rats that received VLA-4-expressing hGPs but not LPS, rats that received VLA-4-naive hGPs and LPS, and rats that received VLA-4-expressing hGPs and LPS. MR imaging was performed at 9.4 T before and 1, 10, 20, and 30 minutes after injection. Brain tissue was processed for histologic examination. Quantification of low-signal-intensity pixels was performed with pixel-by-pixel analysis for MR images obtained before and after cell injection. RESULTS: With use of the microfluidic adhesion assay, cell binding to activated brain endothelium significantly increased compared with VLA 4-naive control cells (71.5 cells per field of view+/-11.7 vs 36.4 cells per field of view+/-3.3, respectively; P<.05). Real-time quantitative in vivo MR cell tracking revealed that VLA-4-expressing cells docked exclusively within the vascular bed of the ipsilateral carotid artery and that VLA-4-expressing cells exhibited significantly enhanced homing as compared with VLA-4-naive cells (1448 significant pixels+/-366.5 vs 113.3 significant pixels+/-19.88, respectively; P<.05). Furthermore, MR cell tracking was crucial for correct cell delivery and proper ligation of specific arteries. CONCLUSION: Targeted intraarterial delivery and homing of VLA-4-expressing hGPs to inflamed endothelium is feasible and can be monitored in real time by using MR imaging in a quantitative, dynamic manner. PMID- 22923721 TI - MR-guided freehand biopsy of breast lesions in a 1.0-T open MR imager with a near real-time interactive platform: preliminary experience. AB - PURPOSE: To identify the most appropriate magnetic resonance (MR) sequence for breast biopsy with regard to lesion visibility and artifact size and to assess feasibility and safety of this approach in a clinical setting. MATERIALS AND METHODS: MR-guided interventions were performed in an open 1.0-T MR imager between November 2009 and January 2011. The prospective clinical study was approved by the institutional review board. Written informed consent was obtained. Four different fast dynamic sequences (balanced steady-state free precession, T1-weighted turbo gradient-echo, T1-weighted turbo spin-echo [SE], and T2-weighted single-shot SE sequences) were evaluated for artifact size of biopsy needle and in vivo for lesion visibility. In vivo breast biopsies were performed with the freehand technique and without immobilization or a positioning device by using an interactive MR mode that allowed continuous imaging in two orthogonal planes for guidance. RESULTS: On the basis of good lesion detection in combination with small artifact size, T1-weighted SE imaging was used for biopsy. A total of 75 biopsies were performed successfully in 69 patients (mean age, 53 years; age range, 35-78 years) (mean lesion size, 7.1 mm; range, 4-15 mm). The interactive MR platform enabled immediate localization and correction of intended needle trajectory. Average time for freehand biopsy was 12 minutes (range, 8-23 minutes). No major complications were recorded. CONCLUSION: MR-guided freehand biopsy of breast lesions with the near-real-time interactive MR platform in an open 1.0-T MR imager is safe and feasible in a clinical setting. The method simplifies work flow and intervention performance. PMID- 22923722 TI - Interpatient variation in normal peripheral zone apparent diffusion coefficient: effect on the prediction of prostate cancer aggressiveness. AB - PURPOSE: To determine the interpatient variability of prostate peripheral zone (PZ) apparent diffusion coefficient (ADC) and its effect on the assessment of prostate cancer aggressiveness. MATERIALS AND METHODS: The requirement for institutional review board approval was waived. Intra- and interpatient variation of PZ ADCs was determined by means of repeated measurements of normal ADCs at three magnetic resonance (MR) examinations in a retrospective cohort of 10 consecutive patients who had high prostate-specific antigen levels and negative findings at transrectal ultrasonographically-guided biopsy. In these patients, no signs of PZ cancer were found at all three MR imaging sessions. The effect of interpatient variation on the assessment of prostate cancer aggressiveness was examined in a second retrospective cohort of 51 patients with PZ prostate cancer. Whole-mount step-section pathologic evaluation served as reference standard for placement of regions of interest on tumors and normal PZ. Repeated-measures analysis of variance was used to determine the significance of the interpatient variations in ADCs. Linear logistic regression was used to assess whether incorporating normal PZ ADCs improves the prediction of cancer aggressiveness. RESULTS: Analysis of variance revealed that interpatient variability (1.2-2.0*10( 3) mm2/sec) was significantly larger than measurement variability (0.068*10(-3) mm2/sec+/-0.027 [standard deviation]) (P=.0058). Stand-alone tumor ADCs showed an area under the receiver operating characteristic curve (AUC) of 0.91 for discriminating low-grade versus high-grade tumors. Incorporating normal PZ ADC significantly improved the AUC to 0.96 (P=.0401). CONCLUSION: PZ ADCs show significant interpatient variation, which has a substantial effect on the prediction of prostate cancer aggressiveness. Correcting this effect results in a significant increase in diagnostic accuracy. PMID- 22923723 TI - The role of methionine sulfoxide reductase in redox signaling. PMID- 22923724 TI - The role of presentation method and depth singletons in visual search for objects moving in depth. AB - Are objects moving in depth searched for efficiently? Previous studies have reported conflicting results, with some finding efficient search for only approaching motion (Franconeri & Simons, 2003), and others reporting that both approaching and receding motion are found more efficiently than static targets (Skarratt, Cole, & Gellatly, 2009). This may be due to presentation protocol differences and a confounding variable. We systematically tested the effect of the motion-in-depth presentation method and the effect of a confounding unique depth singleton on search performance. Simulating motion in depth using size scaling, changing binocular disparity, or a calibrated combination of these two depth cues, we found that search performance was affected by presentation method and that a combination of size scaling and changing disparity gives rise to the most compelling motion-in-depth perception. Exploiting this finding in Experiment 2, we found that removing the depth singleton does not affect motion-in-depth search performance. Overall, we found that search is more efficient for targets moving in depth than static targets. Approaching and receding motion had an equal advantage over static targets in target selection, shown through shallower search slopes. However, approaching motion had lower intercepts, consistent with an advantage over receding motion in later stages of processing associated with target identification and response. PMID- 22923725 TI - To bind or not to bind: addressing the question of object representation in visual short-term memory. AB - Visual short-term memory (VSTM) is a capacity limited resource, which is consistently estimated to hold about four visual items at a time. There is, however, debate in the literature about what constitutes an "item" and how resources are allocated within VSTM. Some research suggests information is stored in VSTM as discrete objects; however, there is also evidence suggesting that within-object features alter VSTM performance. The present study addresses the question of whether VSTM load effects reflect the number of discrete objects and/or the number of within-object features. An electrophysiological correlate of VSTM--the contralateral delay activity (CDA)--was measured while participants performed a lateralized change-detection task, in which to-be-remembered items varied in the number of features and locations. Each trial contained either a solitary simple feature (shape, color, or orientation) or one of two multifeature arrays: three features presented at three separate locations or three features bound at one location. While presenting multiple features--regardless of whether they are at discrete locations or bound within a single object--resulted in greater CDA amplitude relative to a solitary feature, there was a dissociation in the distribution of activity between the two multifeature conditions, such that the CDA at site P1/P2 was sensitive to the number of discrete objects, while activity at P7/P8 was most enhanced when multiple features were bound in one object. The findings demonstrate the inhomogeneity of the CDA and suggest this electrophysiological marker may reflect both discrete object individuation/separation and flexible feature-feature binding in VSTM. PMID- 22923727 TI - Stimulus-salience and the time-course of saccade trajectory deviations. AB - The deviation of a saccade trajectory is a measure of the oculomotor competition evoked by a distractor. The aim of the present study was to investigate the impact of stimulus-salience on the time-course of saccade trajectory deviations to get a better insight into how stimulus-salience influences oculomotor competition over time. Two experiments were performed in which participants were required to make a vertical saccade to a target presented in an array of nontarget line elements and one additional distractor. The distractor varied in salience, where salience was defined by an orientation contrast relative to the surrounding nontargets. In Experiment 2, target-distractor similarity was additionally manipulated. In both Experiments 1 and 2, the results revealed that the eyes deviated towards the irrelevant distractor and did so more when the distractor was salient compared to when it was not salient. Critically, salience influenced performance only when people were fast to elicit an eye movement and had no effect when saccade latencies were long. Target-distractor similarity did not influence this pattern. These results show that the impact of salience in the visual system is transient. PMID- 22923726 TI - Perceptual consequences of feature-based attentional enhancement and suppression. AB - Feature-based attention has been shown to enhance the responses of neurons tuned to an attended feature while simultaneously suppressing responses of neurons tuned to unattended features. However, the influence of these suppressive neuronal-level modulations on perception is not well understood. Here, we investigated the perceptual consequences of feature-based attention by having subjects judge which of four random dot patterns (RDPs) contained a motion signal (Experiment 1) or which of four RDPs contained the most salient nonrandom motion signal (Experiment 2). Subjects viewed pre-cues which validly, invalidly, or neutrally cued the direction of the target RDP. Behavioral data were fit using the linear ballistic accumulator (LBA) model; the model design that best described the data revealed that the rate of sensory evidence accumulation (drift rate) was highest on valid trials and systematically decreased until the cued direction and the target direction were orthogonal. These results demonstrate behavioral correlates of both feature-based attentional enhancement and suppression. PMID- 22923728 TI - Clinician-trialist rounds: 11. When your grant gets turned down--part 1: remorse, anger, and reconciliation. PMID- 22923732 TI - The functional roles of S1P in immunity. AB - The lipid mediator sphingosine-1-phosphate (S1P) is generated within cells from sphingosine by two sphingosine kinases (SPHK1 and SPHK2). Intracellularly synthesized S1P is released into the extracellular fluid by S1P transporters, including SPNS2. Released S1P binds specifically to the G protein-coupled S1P receptors (S1PR1/S1P(1)-S1PR5/S1P(5)), which activate a diverse range of downstream signalling pathways. Recent studies have proposed that one of the central physiological functions of intercellular S1P signalling is in lymphocyte trafficking in vivo because genetic disruption of SPHK1/2, SPNS2 or S1PR1/S1P(1) in mice induces a lymphopenia phenotype. In this review, we discuss the current understanding of intercellular S1P signalling in the context of immunity. PMID- 22923731 TI - Matrix control of transforming growth factor-beta function. AB - The cytokine transforming growth factor-beta (TGF-beta) has multiple effects in both physiological and pathological conditions. TGF-beta is secreted as part of a tripartite complex from which it must be released in order to bind to its receptor. Sequestration of latent TGF-beta in the extracellular matrix (ECM) is crucial for proper mobilization of the latent cytokine and its activation. However, contrary to expectation, loss-of-function mutations in genes encoding certain matrix proteins that bind TGF-beta yield elevated, rather than decreased, TGF-beta levels, posing a 'TGF-beta paradox.' In this review, we discuss recent findings concerning the relationship of TGF-beta, ECM molecules, and latent TGF beta activation and propose a model to resolve the 'TGF-beta paradox.' PMID- 22923733 TI - Mediator lipidomics in acute inflammation and resolution. AB - Acute inflammation is an indispensable host response to foreign challenges or tissue injury. In healthy conditions, inflammatory processes are self-limiting and self-resolving, suggesting the existence of endogenous mechanisms for the control of inflammation and resolution. A comprehensive understanding of the cellular and molecular events of a well-orchestrated inflammatory response is required, and recent studies have uncovered the roles of endogenous lipid mediators derived from polyunsaturated fatty acids (i.e. lipoxins, resolvins, protectins) in controlling the resolution of inflammation. This review presents recent advances in understanding the formation and action of these mediators, especially focusing on the LC-MS/MS-based lipidomics approach and the emerging roles of eosinophils and eosinophil-derived lipid mediators in controlling acute inflammation and resolution. PMID- 22923734 TI - Stable complex formation between serine protease inhibitor and zymogen: coagulation factor X cleaves the Arg393-Ser394 bond in a reactive centre loop of antithrombin in the presence of heparin. AB - Antithrombin (AT) inhibits several blood coagulation proteases, including activated factor X (FXa), by forming stable complexes with these proteases. Herein, we demonstrate that AT forms a stable complex with zymogen factor X (FX). Sodium dodecyl sulphate-polyacrylamide gel electrophoresis (SDS-PAGE) and size exclusion chromatography analyses showed that AT and FX formed an SDS-stable complex, which is distinct in apparent molecular mass from an FXa-AT complex, in the presence of heparin. Amino-terminal sequence analysis of the complex following SDS-PAGE under reducing conditions provided clear evidence that AT forms this complex with the heavy chain of FX, because two sequences, HGSPVDI (residues 1-7 of AT) and SVAQATS (residues 1-7 of the heavy chain of FX), were identified. Furthermore, sequence SLNPNRV, which corresponds to residues 394-400 of AT, was identified in the non-reduced FX-AT complex, indicating that FX cleaved the Arg393-Ser394 bond in a reactive centre loop of AT. Unfractionated heparin induced FX-AT complex formation more effectively than low-molecular weight heparin or AT-binding pentasaccharide, and appeared to promote complex formation mainly via a template effect. These data suggest that AT is capable of forming a stable complex with zymogen FX by acting as an inhibitor in the presence of heparin. PMID- 22923735 TI - sigma-1 receptor at the mitochondrial-associated endoplasmic reticulum membrane is responsible for mitochondrial metabolic regulation. AB - The mitochondria-associated endoplasmic reticulum (ER) membrane (MAM) is a small section of the outer mitochondrial membrane tethered to the ER by lipid and protein filaments. One such MAM protein is the sigma-1 receptor, which contributes to multiple signaling pathways. We found that short interfering RNA mediated knockdown of sigma-1 reduced pregnenolone synthesis by 95% without affecting expression of the inner mitochondrial membrane resident enzyme, 3-beta hydroxysteroid dehydrogenase 2. To explore the underlying mechanism of this effect, we generated a series of sigma-receptor ligands: 5,6-dimethoxy-3-methyl-N phenyl-N-(3-(piperidin-1-yl)propyl)benzofuran-2-carboxamide (KSCM-1), 3-methyl-N phenyl-N-(3-(piperidin-1-yl)propyl)benzofuran-2-carboxamide (KSCM-5), and 6 methoxy-3-methyl-N-phenyl-N-(3-(piperidin-1-yl) propyl)benzofuran-2-carboxamide (KSCM-11) specifically bound to sigma-1 in the nanomolar range, whereas KSCM-5 and KSCM-11 also bound to sigma-2. Treatment of cells with the KSCM ligands led to decreased cell viability, with KSCM-5 having the most potent effect followed by KSCM-11. KSCM-1 increased sigma-1 expression by 4-fold and progesterone synthesis, whereas the other compounds decreased progesterone synthesis. These differences probably are caused by ligand molecular structure. For example, KSCM 1 has two methoxy substituents at C-5 and C-6 of the benzofuran ring, whereas KSCM-11 has one at C-6. KSCM ligands or sigma-1 knockdown did not alter the expression of ER resident enzymes that synthesize steroids. However, coimmunoprecipitation of the sigma-1 receptor pulled down voltage-dependent anion channel 2 (VDAC2), whose expression was enhanced by KSCM-1. VDAC2 plays a key role in cholesterol transport into the mitochondria, suggesting that the sigma-1 receptor at the MAM coordinates with steroidogenic acute regulatory protein for cholesterol trafficking into the mitochondria for metabolic regulation. PMID- 22923737 TI - GS-6201, a selective blocker of the A2B adenosine receptor, attenuates cardiac remodeling after acute myocardial infarction in the mouse. AB - Adenosine (Ado) is released in response to tissue injury, promotes hyperemia, and modulates inflammation. The proinflammatory effects of Ado, which are mediated by the A(2B) Ado receptor (AdoR), may exacerbate tissue damage. We hypothesized that selective blockade of the A(2B) AdoR with 3-ethyl-1-propyl-8-(1-(3 trifluoromethylbenzyl)-1H-pyrazol-4-yl)-3,7-dihydropurine-2,6-dione (GS-6201) during acute myocardial infarction (AMI) would reduce adverse cardiac remodeling. Male ICR mice underwent coronary artery ligation or sham surgery (n = 10-12 per group). The selective A(2B) AdoR antagonist GS-6201 (4 mg/kg) was given intraperitoneally twice daily starting immediately after surgery and continuing for 14 days. Transthoracic echocardiography was performed before surgery and after 7, 14, and 28 days. A subgroup of mice was killed 72 h after surgery, and the activity of caspase-1, a key proinflammatory mediator, was measured in the cardiac tissue. All sham-operated mice were alive at 4 weeks, whereas 50% of vehicle-treated mice and 75% of GS-6201-treated mice were alive at 4 weeks after surgery. Compared with vehicle, treatment with GS-6201 prevented caspase-1 activation in the heart at 72 h after AMI (P < 0.001) and significantly limited the increase in left ventricular (LV) end-diastolic diameter by 40% (P < 0.001), the decrease in LV ejection fraction by 18% (P < 0.01) and the changes in the myocardial performance index by 88% (P < 0.001) at 28 days after AMI. Selective blockade of A(2B) AdoR with GS-6201 reduces caspase-1 activity in the heart and leads to a more favorable cardiac remodeling after AMI in the mouse. PMID- 22923736 TI - Natriuretic peptide-induced catecholamine release from cardiac sympathetic neurons: inhibition by histamine H3 and H4 receptor activation. AB - We reported previously that natriuretic peptides, including brain natriuretic peptide (BNP), promote norepinephrine release from cardiac sympathetic nerves and dopamine release from differentiated pheochromocytoma PC12 cells. These proexocytotic effects are mediated by an increase in intracellular calcium secondary to cAMP/protein kinase A (PKA) activation caused by a protein kinase G (PKG)-mediated inhibition of phosphodiesterase type 3 (PDE3). The purpose of the present study was to search for novel means to prevent the proadrenergic effects of natriuretic peptides. For this, we focused our attention on neuronal inhibitory Galpha(i/o)-coupled histamine H(3) and H(4) receptors. Our findings show that activation of neuronal H(3) and H(4) receptors inhibits the release of catecholamines elicited by BNP in cardiac synaptosomes and differentiated PC12 cells. This effect results from a decrease in intracellular Ca(2+) due to reduced intracellular cAMP/PKA activity, caused by H(3) and H(4) receptor-mediated PKG inhibition and consequent PDE3-induced increase in cAMP metabolism. Indeed, selective H(3) and H(4) receptor agonists each synergized with a PKG inhibitor and a PDE3 activator in attenuating BNP-induced norepinephrine release from cardiac sympathetic nerve endings. This indicates that PKG inhibition and PDE3 stimulation are pivotal for the H(3) and H(4) receptor-mediated attenuation of BNP-induced catecholamine release. Cardiac sympathetic overstimulation is characteristic of advanced heart failure, which was recently found not to be improved by the administration of recombinant BNP (nesiritide), despite the predicated beneficial effects of natriuretic peptides. Because excessive catecholamine release is likely to offset the desirable effects of natriuretic peptides, our findings suggest novel means to alleviate their adverse effects and improve their therapeutic potential. PMID- 22923738 TI - Lighting up by EMARS. AB - Transmembrane proteins on the cell surface dynamically move in the sea of phospholipids. During the process of cell adhesion, migration and proliferation, physical interactions of transmembrane proteins such as integrins and receptor tyrosine kinases (RTKs) on the cell surface constantly vary. The enzyme-mediated activation of radical source (EMARS) reaction, a newly developed biochemical labelling method for cell surface molecules clustering in living cells, is a powerful tool for capturing new partners even if they only transiently cluster with the interesting target molecules during a biological process such as cell adhesion, migration, invasion or proliferation. The EMARS reaction was applied for investigating new partner RTKs to an adhesion molecule integrin beta1, resulting in the identification of ErbB4. This study further reveals that the association of integrin beta1 and ErbB4 occurs in a spatiotemporally regulated manner at an early phase within 2 h of seeding cells and that this induced activation of ErbB4 tyrosine kinase, which is required for integrin-dependent cell migration (Yamashita, R., Kotani, N., Ishiura, Y., Higahsiyama, S., and Honke, K. Spatiotemporally-regulated interaction between b1 integrin and ErbB4 that is involved in fibronectin-dependent cell migration. J Biochem 2011;149:347 355). The EMARS reaction is also currently lighting up intriguing new partners of target therapeutic molecules. PMID- 22923739 TI - Single-molecule imaging with a tagged ribosome to explore trans-translation. AB - Single-molecule imaging is a powerful technique to visualize molecular interactions and movements. Translation is one of the most interesting targets for researchers with the molecular-imaging skills, since mRNA, tRNA and translation factors interact with or move inside or on the ribosome in an ordered manner. Trans-translation is a bacterial quality control system to rescue the ribosomes stalled at the 3' end of the mRNA, and this phenomenon is recapitulated in vitro with defined factors including two trans-translation-specific entities tmRNA and SmpB. Zhou et al. (Single molecule imaging of the trans-translation entry process via anchoring of the tagged ribosome. J Biochem 2011;149:609-618.) successfully visualized the interaction of the tmRNA-SmpB complex with the ribosome by immobilizing the ribosome on the quartz surface with the HaloTag technology. This ribosome-anchoring system may be useful for the imaging analysis of other processes of translation. PMID- 22923740 TI - Depletion of glutamine enhances sodium butyrate-induced erythroid differentiation of K562 cells. AB - Human erytholeukemia K562 cells are induced to differentiate along the erythroid lineage by a variety of chemical compounds, including hemin, sodium butyrate and 1-beta-d-arabinofuranosylcytosine. We have investigated the induction of erythroid differentiation of K562 cells by glutamine depletion. When K562 cells were cultured in glutamine-minus medium, the induction of hemoglobin synthesis, accompanied by those of heme-biosynthetic enzymes and erythroid transcriptional factors, was observed. This induction was dependent on the temporally marked decrease of intracellular level of glutathione, followed by the marked activation of p38MAPK and SAPK/JNK, but not ERK. Under glutamine-deficient conditions, the treatment of K562 cells with sodium butyrate resulted in the marked enhancement of the induction of heme biosynthesis. Glutamine depletion also accelerated the expressions of erythroid-related factors including alpha-globin and heme biosynthetic enzymes, GATA-1 and NF-E2, in sodium butyrate-induced K562 cells. The transcriptional activity of beta-globin gene promoter-reporter was markedly enhanced by these treatments, indicating that glutamine deficiency in combination with sodium butyrate treatment gives high efficiency of chemical-induced differentiation in the hematopoiesis process. PMID- 22923741 TI - Impaired dimer assembly and decreased stability of naturally recurring R260C mutant A subunit for coagulation factor XIII. AB - Factor XIII (FXIII) consists of catalytic A subunits (FXIII-A) and carrier B subunits. Congenital FXIII deficiency is a severe bleeding disorder. We previously identified an R260C missense mutation and an exon-IV deletion in Japanese patients' F13A genes. To characterize the molecular basis of this disease, we expressed a wild-type and the mutant FXIII-A in yeast cells for detailed investigation, by taking advantage of yeast's ability for mass protein production. The mutant proteins were expressed less efficiently than the wild type and considerably aggregated; even their non-aggregated forms became aggregated with time. Ultra-centrifugation and gel-filtration analyses revealed that the mutants were of extremely high-molecular weight, and that the wild-type formed a dimer. Notably, a part of the R260C mutant was found in monomer form. This was consistent with the prediction by molecular modelling that the mutant molecule would lose the electrostatic interaction between the two monomers, leading to their inability to form a dimer. The mutants lost enzymatic activity. The mutants were only partially converted by thrombin to the cleaved form. The wild-type was fully converted and activated. These mutants might have significantly altered conformations, resulting in their aggregation in vitro, and may ultimately lead to FXIII deficiency in vivo as well. PMID- 22923742 TI - Maintenance of the secondary structure of horse cytochrome c during the conversion process of monomers to oligomers by addition of ethanol. AB - We have previously shown that polymerization of cytochrome c (cyt c) occurs by successively domain swapping its C-terminal alpha-helix in the presence of ethanol. However, the factors that govern the conversion process of monomers to domain-swapped oligomers remain unknown. We found that oligomeric cyt c is produced in the presence of ethanol and the oligomers precipitate due to low solubility. The optical absorption spectra revealed that in the presence of 30 40% ethanol, the Met-heme coordination in cyt c is dissociated. However, according to circular dichroism and small-angle X-ray scattering measurements, the alpha-helical structure of cyt c is maintained in solution with a little perturbation and the radius of gyration increases slightly but without dissociation of the C-terminal alpha-helix from the rest of the protein by the addition of ethanol. Solid-state nuclear magnetic resonance spectra showed that oligomeric cyt c in the precipitate also retains most of its alpha-helical structure. In the transmission electron microscopic image of the precipitate obtained by the addition of ethanol to cyt c, spherical particles with diameters of about 3 nm were detected. These results indicate that oligomeric cyt c forms through a state with the Met80 region locally unfolded, while maintaining the secondary structure, possibly an open monomer. PMID- 22923743 TI - Inhibition of acetyltransferase alters different histone modifications: probed by small molecule inhibitor plumbagin. AB - Histone modifications; acetylation, methylation (both Lysine and Arginine) etc., at different positions regulates the chromatin fluidity and function in a combinatorial manner, which could be referred as an epigenetic language. In the context of transcription, histone acetylation, methylation and phosphorylation at specific sites, especially at the N-terminal tails of histones play very important roles in activation and/or repression. While acetylation of histones is generally important for transcriptional activation, methylation and phosphorylation could also be involved in repression, depending on the context. Here, we have investigated the crosstalk of histone modifications on a gross scale over histone H3, using a small molecule inhibitor of lysine acetyltransferase KAT3B/p300, Plumbagin, to analyze the histone modification profile upon inhibition of acetylation. In addition to the inhibition of acetylation, there was a concomitant decrease of transcriptional activation mark, H3 lysine 4 trimethylation (H3K4me3) in the cellular context. The histone H3 Serine 10 Phosphorylation (H3S10p) also decreased upon inhibition of acetylation. However, there were no changes observed with transcriptional repressive marks like H3 Lysine 9 di/trimethylation (H3K9me2/me3) suggesting that transcriptional activation marks were selectively targeted. These data suggest that Plumbagin induces a distinct modification profile involving transcriptional activation marks H3K4me3 and H3S10 phosphorylation in the context of histone acetylation brought about by KAT3B/ p300. PMID- 22923744 TI - Feasibility evaluation of a new irradiation technique: three-dimensional unicursal irradiation with the Vero4DRT (MHI-TM2000). AB - The Vero4DRT (MHI-TM2000) is a newly designed unique image-guided radiotherapy system consisting of an O-ring gantry. This system can realize a new irradiation technique in which both the gantry head and O-ring continuously and simultaneously rotate around the inner circumference of the O-ring and the vertical axis of the O-ring, respectively, during irradiation. This technique creates three-dimensional (3D) rotational dynamic conformal arc irradiation, which we term '3D unicursal irradiation'. The aim of this study was to present the concept and to estimate feasibility and potential advantages of the new irradiation technique. Collision maps were developed for the technique and a 3D unicursal plan was experimentally created in reference to the collision map for a pancreatic cancer case. Thereafter, dosimetric comparisons among the 3D unicursal, a two-dimensionally rotational dynamic conformal arc irradiation (2D DCART), and an intensity-modulated radiation therapy (IMRT) plan were conducted. Dose volume data of the 3D unicursal plan were comparable or improved compared to those of the 2D-DCART and IMRT plans with respect to both the target and the organs at risk. The expected monitor unit (MU) number for the 3D unicursal plan was only 7% higher and 22.1% lower than the MUs for the 2D-DCART plan and IMRT plan, respectively. It is expected that the 3D unicursal irradiation technique has potential advantages in both treatment time and dose distribution, which should be validated under various conditions with a future version of the Vero4DRT fully implemented the function. PMID- 22923745 TI - Mechanism of enhancement of radiation-induced cytotoxicity by sorafenib in colorectal cancer. AB - Sorafenib, an orally available multikinase inhibitor, combined with radiation has shown potential as an anticancer treatment in an in vitro and in vivo colon cancer model. In this study, we investigated the mechanism of enhancement of radiation-induced cytotoxicity by sorafenib in colorectal cancer. The effects of sorafenib on radiation-induced cytotoxicity of DLD-1 and HT-29 were evaluated via clonogenic assay. The impact of sorafenib on radiation-induced cell cycle kinetics and on apoptosis was analyzed using flow cytometry. Cyclin B1 was examined by western blot. As a measure of DNA damage after treatment, gamma-H2AX foci and nuclear fragmentation were determined as a function of time after irradiation plus sorafenib combination. Tumor growth delay was used to evaluate the effects of sorafenib on in vivo radiation-induced cytotoxicity. Exposure of each cell line to sorafenib combined with irradiation resulted in an increased radiation-induced cytotoxicity with dose enhancement factors at a surviving fraction of 0.37 ranging from 1.13 to 1.76. Sorafenib strengthened radiation induced accumulation of tumor cells in the G2-M phase with attenuated expression of cyclin B1, but had no effect on radiation-induced apoptosis. Exposure to sorafenib and radiation resulted in a greater number of remaining gamma-H2AX foci and fragmented nuclei than radiation alone. In vivo tumor xenograft study confirmed that administration of sorafenib results in significant tumor growth inhibition when combined with radiation. These results indicate that sorafenib enhances radiation-induced cytotoxicity in colorectal cancer and suggest that the mechanism is associated with delaying repair of radiation-induced DNA damage and down-regulation of cyclin B1. PMID- 22923746 TI - Relieved residual damage in the hematopoietic system of mice rescued by radiation induced adaptive response (Yonezawa Effect). AB - Existence of adaptive response (AR) was previously demonstrated in C57BL/6J mice. Irradiations were performed by delivering a priming low dose of X-rays (0.50 Gy) in combination with a challenge high dose of accelerated carbon or neon ion particles. AR was characterized by significantly decreased mortality in the 30 day survival test. This mouse AR model ('Yonezawa Effect') was originally established by using X-rays as both the priming and challenge irradiations. The underlying mechanism was due to radio-resistance occurring in blood-forming tissues. In this study, we verified the existence of AR and further investigated residual damage in the hematopoietic system in surviving animals. Results showed that the priming low dose of X-rays could relieve the detrimental effects on the hematopoietic system. We observed both an improvement in the blood platelet count and the ratio of polychromatic erythrocytes (PCEs) to the sum of PCEs and normochromatic erythrocytes (NCEs) and a marked reduction of the incidences of micronucleated PCEs and micronucleated NCEs. These findings suggest that the priming low dose of low linear energy transfer (LET) X-rays induced a protective effect on the hematopoietic system, which may play an important role in both rescue from acute lethal damage (mouse killing) and prevention of late detrimental consequences (residual anhematopoiesis and delayed genotoxic effects) caused by exposure to a high challenge dose from low-LET (X-ray) or high-LET (carbon and neon ion) irradiations. These findings provide new knowledge of the characterization of the Yonezawa Effect by providing new insight into the mechanistic study of AR in vivo. PMID- 22923747 TI - Alternating chemoradiotherapy in patients with nasopharyngeal cancer: prognostic factors and proposal for individualization of therapy. AB - The purpose of this study is to assess the efficacy of alternating chemoradiation in patients with nasopharyngeal cancer. From 1990-2006, 100 patients with nasopharyngeal cancer were treated with alternating chemoradiation at the Aichi Cancer Center. Of these, 4, 2, 23, 34, 13 and 23 patients were staged as I, IIA, IIB, III, IVA and IVB, respectively. The median radiation doses for primary tumors and metastatic lymph nodes were 66.6 Gy (range, 50.4-80.2 Gy) and 66 Gy (range, 40.4-82.2 Gy), respectively. A total of 82 patients received chemotherapy with both cisplatin and 5-fluorouracil (5-FU), while 14 patients received nedaplatin (CDGP) and 5-FU. With a median follow-up of 65.9 months, the 5-year rates of overall survival (OAS) and progression-free survival (PFS) were 78.1% and 68.3%, respectively. On multivariate analysis (MVA), elderly age, N3, and WHO type I histology proved to be significantly unfavorable prognostic factors of OAS. As for PFS, there were T4, N3, and WHO type I histology in MVA. Acute toxicities of hematologic and mucositis/dermatitis >= Grade 3 were relatively high (32%); however, they were well-managed. Late toxicities of >= Grade 3 were three (3%) mandibular osteomyelitis and one (1%) lethal mucosal bleeding. Results for alternating chemoradiation for nasopharyngeal carcinoma are promising. In order to improve outcomes, usage of intensity-modulated radiation therapy and application of active anticancer agents are hopeful treatments, especially for groups with poor prognosis factors with WHO type I histopathology, T4 and/or N3 disease. PMID- 22923748 TI - Clinical results of stereotactic body radiotherapy for Stage I small-cell lung cancer: a single institutional experience. AB - The purpose of this study was to evaluate the treatment outcomes of stereotactic body radiotherapy (SBRT) for Stage I small-cell lung cancer (SCLC). From April 2003 to September 2009, a total of eight patients with Stage I SCLC were treated with SBRT in our institution. In all patients, the lung tumors were proven as SCLC pathologically. The patients' ages were 58-84 years (median: 74). The T stage of the primary tumor was T1a in two, T1b in two and T2a in four patients. Six of the patients were inoperable because of poor cardiac and/or pulmonary function, and two patients refused surgery. SBRT was given using 7-8 non-coplanar beams with 48 Gy in four fractions. Six of the eight patients received 3-4 cycles of chemotherapy using carboplatin (CBDCA) + etoposide (VP-16) or cisplatin (CDDP) + irinotecan (CPT-11). The follow-up period for all patients was 6-60 months (median: 32). Six patients were still alive without any recurrence. One patient died from this disease and one died from another disease. The overall and disease specific survival rate at three years was 72% and 86%, respectively. There were no patients with local progression of the lesion targeted by SBRT. Only one patient had nodal recurrence in the mediastinum at 12 months after treatment. The progression-free survival rate was 71%. No Grade 2 or higher SBRT-related toxicities were observed. SBRT plus chemotherapy could be an alternative to surgery with chemotherapy for inoperable patients with Stage I small-cell lung cancer. However, further investigation is needed using a large series of patients. PMID- 22923749 TI - Measuring fatigue in SSc: a comparison of the Short Form-36 Vitality subscale and Functional Assessment of Chronic Illness Therapy-Fatigue scale. AB - OBJECTIVE: Fatigue is a common and important problem in SSc. No studies, however, have compared the properties of fatigue measures in SSc. The objective of this study was to compare the performances of the Short Form-36 (SF-36) Vitality subscale and Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT) in SSc. METHODS: Cross-sectional, multi-centre study of Canadian Scleroderma Research Group Registry patients. The associations of the two instruments with other patient-reported outcome measures, as well as physician- and patient-rated disease variables were compared. Item response theory models were used to compare the degree to which items and the total scores of each measure effectively covered the full spectrum of fatigue levels. RESULTS: There were 348 patients (297 women, 85%) in the study. The instruments correlated at r = 0.65 with each other. The FACIT tended to correlate slightly higher than the SF-36 Vitality subscale with physician- and patient-rated disease variables and patient-reported physical function and disability, whereas the SF-36 Vitality subscale correlated minimally higher with mental health measures. The FACIT had markedly better discrimination across the range of fatigue, particularly at average to high fatigue levels, whereas the SF-36 Vitality subscale discriminated well only among patients in the low to average range. CONCLUSION: The FACIT discriminates better than the SF-36 Vitality subscale at average to high ranges of fatigue, which is common in SSc, suggesting that it is preferred for measuring fatigue in SSc. PMID- 22923750 TI - Primary anti-phospholipid syndrome: any role for serum complement levels in predicting pregnancy complications? AB - OBJECTIVE: To evaluate the association between serum complement levels (C3 and C4) and obstetric complications. METHODS: Fifty-seven pregnancies in primary APS (PAPS) patients were compared with 49 pregnancies in patients with UCTD and SS. A group of 175 healthy pregnant women were studied to calculate a normality range for C3 and C4 during pregnancy. Such a range was applied to define hypocomplementaemia in PAPS and UCTD/SS. RESULTS: Both groups of patients (PAPS and UCTD/SS) showed significantly lower levels of C3 and C4 in each trimester as compared with healthy women; conversely, no significant difference was found between PAPS and UCTD/SS. Comparing PAPS pregnancies with and without complications, no difference was found in the prevalence of low C3 or low C4. CONCLUSION: No association was found between hypocomplementaemia and obstetric complications in PAPS. However, both cases of pre-eclampsia were characterized by low C3 throughout pregnancy. There is evidence that the complement system is a contributor to the mechanisms of aPL-mediated damage, but its predictive role on the final pregnancy outcome does not seem to be of major impact. PMID- 22923751 TI - Foot kinematics in people with medial compartment knee osteoarthritis. AB - OBJECTIVES: Foot orthoses are commonly used in the management of knee OA, although the relationship between foot function and knee OA is still unclear. The purpose of the study was to examine foot function during walking in people with and without medial compartment knee OA. METHODS: Motion of the tibia, rearfoot and forefoot in 32 patients with medial compartment knee OA and 28 age-matched control subjects was investigated. Multivariate analysis was used to compare the groups. RESULTS: The knee OA group contacted the ground with a more everted rearfoot, demonstrated greater peak rearfoot eversion and exhibited reduced rearfoot frontal plane range of motion and reduced rearfoot peak inversion. The tibia was more internally rotated and laterally tilted throughout the gait cycle, with reduced peak external rotation. CONCLUSION: People with medial compartment knee OA exhibit altered foot kinematics during gait that are indicative of a less mobile, more everted foot type. The presence and degree of tibial malalignment and the available rearfoot range of motion during walking may affect individual responses to load-altering interventions, such as foot orthoses and footwear modifications. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry, www.anzctr.org.au/, ACTRN12608000116325. PMID- 22923752 TI - Use of adalimumab in refractory non-infectious childhood chronic uveitis: efficacy in ocular disease--a case cohort interventional study. AB - OBJECTIVE: To assess the use of adalimumab in the treatment of refractory non infectious childhood chronic uveitis. METHODS: A case cohort interventional study was performed on patients with uveitis, who were treated with adalimumab after failure of treatment with a combination of corticosteroids and another immunosuppressant drug. Main outcome measures were (i) stability of vision, (ii) stability of inflammation and (iii) reduction of immunosuppressive load. Adverse events and reasons for stopping adalimumab were noted. RESULTS: Seventeen patients from a single regional centre were included in the study. Nine patients had previously received an anti-TNF agent, and because of inefficacy, all were changed to adalimumab. At 12 months, fewer patients had visual acuity worse than LogMAR 0.4 (18% vs 32% at baseline). Using standardized uveitis nomenclature criteria, at 3 months, 50% of the patients eyes (n = 32) had improved, 16% had stable inflammation and 3% had worsened, whereas 31% were maintained with no anterior chamber cells. Six patients required courses of oral steroids for uveitis. Seven patients received intra- or periocular injections of steroids. Adalimumab treatment was interrupted in one patient because of varicella zoster infection. It was stopped in three patients. Seven (41%) patients reported injection site reactions. CONCLUSION: In this group of children with refractory uveitis, use of adalimumab was associated with improvement in visual acuity and improving or stable ocular inflammation. However, it did not completely obviate the need for systemic or periocular steroid treatment. Prospective randomized controlled trials are required to help determine which subset of patients may benefit from adalimumab and the duration of treatment. PMID- 22923753 TI - Efficacy and safety of certolizumab pegol in a broad population of patients with active rheumatoid arthritis: results from the REALISTIC phase IIIb study. AB - OBJECTIVE: To investigate the efficacy and safety of certolizumab pegol (CZP) in a broad population of patients with active RA. METHODS: In this 12-week, double blind period of the phase IIIb trial, RA patients with inadequate response to at least one DMARD were randomized 4:1 to CZP (400 mg at weeks 0, 2 and 4, followed by 200 mg every 2 weeks) or placebo (every 2 weeks) plus current therapy stratified by previous TNF inhibitor use, concomitant methotrexate use and disease duration (<2 vs >=2 years). The primary outcome was ACR20 response rate at week 12. RESULTS: Of 1063 patients (CZP = 851; placebo = 212), 37.6% had previous TNF inhibitor use. Baseline mean HAQ Disability Index (HAQ-DI) and DAS 28-joint assessment-ESR [DAS28(ESR)] values were 1.5 and 6.4 in the CZP group, and 1.6 and 6.4 in the placebo group, respectively. The primary endpoint was significant (week 12 ACR20, CZP vs placebo: 51.1 vs 25.9%; P < 0.001); differences were noted at week 2 (31.8 vs 8.5%; P < 0.001). HAQ-DI and DAS28(ESR) change from baseline and ACR50 were significant from week 2. Week 12 ACR20 responses were similar across CZP patient subgroups regardless of concomitant DMARD use at baseline. Adverse and serious adverse events were comparable between CZP and placebo, with no new safety signals. CONCLUSION: CZP was associated with rapid and consistent clinical responses and improved physical function in a diverse group of RA patients, irrespective of concomitant or previous therapy. TRIAL REGISTRATION: ClinicalTrials.gov, http://clinicaltrials.gov/, NCT00717236. PMID- 22923754 TI - Increase in ventricular-arterial stiffness in patients with psoriatic arthritis. AB - OBJECTIVES: Ventricular and arterial stiffness is an accepted cause of myocardial diastolic dysfunction. The aim of this study is to determine whether there is increased ventricular and arterial stiffness in patients with PsA and any relationship with disease-related risk factors. METHODS: Seventy-three patients with PsA were divided into two subgroups based on the absence or presence of hypertension and/or left ventricular (LV) hypertrophy. Fifty healthy controls were enrolled for comparison. All participants underwent non-invasive assessments including conventional echocardiography with tissue Doppler imaging and pulse wave analysis. Ventricular stiffness was measured by ventricular end-systolic and diastolic elastance, whereas arterial stiffness was measured by total arterial compliance and aortic augmentation index. RESULTS: There was significantly increased ventricular and arterial stiffness in patients with PsA (P < 0.001), even in those without hypertension and/or LV hypertrophy. Based on the cut-off points derived from the controls, 38.4% of PsA patients had increased LV stiffness including 31.5% in diastole and 17.8% in systole, and 15.1% had increased arterial stiffness. Multivariable logistic regression analysis showed that long PsA disease duration (>10 years) (odds ratio = 6.55, P = 0.001) was an independent risk factor for increased LV diastolic elastance after adjusting for age, gender and hypertension. CONCLUSION: Patients with PsA may have increased ventricular and arterial stiffness even without evidence of LV remodelling, and those with long disease duration may be at a higher risk. Therefore, prolonged inflammatory burden may be an important cause of early cardiovascular disease in patients with PsA. PMID- 22923755 TI - Disease impact of hand OA compared with hip, knee and generalized disease in specialist rheumatology health care. AB - OBJECTIVE: To describe and compare disease impact in patients with hand OA with those with hip, knee and generalized disease. METHODS: Patients with OA referred to a specialized rheumatology clinic (408 patients, 86% women) were included in a cross-sectional study. They were examined by a rheumatologist and classified into primary hand, hip, knee and/or generalized (more than two joint localizations) OA. Patient-reported disease impact was collected on numeric rating scales (pain, fatigue), Hopkins Symptom Checklist-25 (emotional distress), Western Ontario and McMaster and Australian/Canadian Hand OA indexes (disease-specific functioning), Short Form 36 (generic health-related quality of life) and a comorbidity checklist. RESULTS: Considerable disease impact was detected across all localizations: patients scored >5 on pain (range 0-10), had on average two comorbidities and scored >1.5 on emotional distress (Hopkins Symptom Checklist 25, range 1-4). Patients with hand OA scored poor on disease-specific functioning of the lower extremities, and patients with lower extremity OA also scored poor on disease-specific hand functioning. Patients with hand OA scored better on pain (P = 0.001, one-way analyses of variance) and the Short Form 36 Health Survey physical component (P < 0.001), whereas no major differences were observed for the mental component (P = 0.07). CONCLUSION: OA patients referred to specialist care reported considerable levels of disease impact across localizations. Regardless of functional impairments related to the primary OA localization, patients generally reported high levels of impaired disease-specific functioning at other sites. In the management of OA clinicians should also consider functioning in joint sites other than the primary OA localization. Trial registration. Current controlled trials, www.controlled-trials.com, ISRCTN25778426. PMID- 22923756 TI - Significance of serum uric acid levels on the risk of all-cause and cardiovascular mortality. AB - OBJECTIVE: To assess the associations between serum uric acid (SUA) level and mortality. METHODS: The study included 354 110 subjects without a history of gout and whose SUA levels were tested at Chang Gung Memorial Hospital in Taiwan. Cox regression models were used to estimate hazard ratios and 95% CIs for mortality in six predefined SUA strata (<=0.17, 0.18-0.29, 0.30-0.41, 0.42-0.53, 0.54-0.65 and >=0.66 mmol/l), after adjusting for age, sex, SUA stratum, estimated glomerular filtration rate, fasting glucose, total cholesterol and history of hypertension, diabetes mellitus, coronary heart disease, stroke, heart failure or chronic kidney disease. RESULTS: There were 33 562 all-cause deaths during the study period. Crude all-cause mortality rates across the SUA strata were 52.5, 19.7, 17.4, 20.0, 28.0 and 41.1 deaths per 1000 person-years. Using the stratum 3 of SUA as a reference, the age- and sex-adjusted hazard ratios (95% CIs) across SUA strata were 2.79 (2.62, 2.96), 1.32 (1.28, 1.36), 1.00, 1.10 (1.07, 1.14), 1.42 (1.37, 1.48) and 2.12 (2.01, 2.23) for all-cause mortality; 2.24 (1.93, 2.59), 1.18 (1.10, 1.27), 1.00, 1.21 (1.14, 1.29), 1.74 (1.60, 1.88) and 2.53 (2.28, 2.81) for cardiovascular mortality and 3.41 (3.11, 3.73), 1.48 (1.42, 1.55), 1.00, 0.88 (0.84, 0.92), 0.91 (0.85, 0.98) and 1.23 (1.11, 1.36) for cancer-related mortality. CONCLUSION: Individuals with SUA levels at either extremes are at higher risk for all-cause and cardiovascular mortality. SUA levels of 0.30-0.41 mmol/l were associated with the lowest mortality rate and should be regarded as optimal. PMID- 22923757 TI - ANCA vasculitis: to lump or split? Why we should study MPA and GPA separately. PMID- 22923758 TI - Attenuation of nephritis in lupus-prone mice by thalidomide. AB - OBJECTIVES: Thalidomide has various effects, such as immune modulation, anti angiogenicity, anti-inflammation and anti-proliferation. Moreover, thalidomide modulates the activity of NF-kappaB, which can up-regulate the expression of downstream genes involved in the pathophysiology of LN. Here we investigated the efficacy of thalidomide monotherapy or thalidomide plus prednisolone (PL) on nephritis in NZB/WF1 mice at different doses and compared both with a combination therapy of MMF plus PL. METHODS: Forty-three female NZB/WF1 mice were divided into eight groups (untreated; 1.7, 5 or 10 mg/kg of thalidomide alone; 1.7, 5 or 10 mg/kg of thalidomide plus 1.5 mg/kg of PL and 33.3 mg/kg of MMF plus PL). Proteinuria and histological damage were evaluated. Immune complex deposition and nuclear translocation of NF-kappaB in kidney tissues were assessed by immunofluorescence staining. Serum concentrations of anti-dsDNA and IgG subclasses were also measured. RESULTS: In comparison with untreated mice, mice treated with 10 mg/kg of thalidomide monotherapy showed a significant decrease in proteinuria and significantly lower glomerular and tubular damage scores, comparable to 5 or 10 mg/kg of thalidomide plus PL or MMF plus PL. Also, treatment with 10 mg/kg of thalidomide significantly decreased immune complex accumulation, reduced the serum concentration of anti-dsDNA, IgG2a and IgG2b and inhibited nuclear translocation of NF-kappaB in kidney tissues, comparable to standard therapy for LN. CONCLUSION: These data suggest that thalidomide might play an anti-inflammatory role in the pathophysiology of LN, and it could serve as a complementary therapy to standard induction regimens for refractory LN. PMID- 22923759 TI - Obstructive sleep apnoea in relation to rheumatic disease. AB - Sleep problems are common concerns in rheumatology patients and have been independently linked to increased pain perception and fatigue severity. Evidence supports an increased prevalence of primary sleep disorders, including sleep apnoea, in some rheumatic disease populations, particularly RA. Obstructive sleep apnoea is a significant public health concern and contributes to increased cardiovascular morbidity and mortality. Patients with obstructive sleep apnoea have also been found to have elevations in circulating acute-phase markers and pro-inflammatory cytokines. Co-existence of sleep apnoea in rheumatic disease patients may influence the severity of reported symptoms of pain and fatigue, accelerate the risk of cardiovascular events and possibly influence levels of circulating inflammatory markers and mediators. In this article we review the risk factors, prevalence and impact of sleep apnoea from a rheumatological perspective. Additionally, we recommend considering sleep apnoea screening in patients with rheumatic disease and, when appropriate, referral to a specialized sleep disorders clinic. PMID- 22923760 TI - Generalized joint hypermobility in professional dancers: a sign of talent or vulnerability? AB - OBJECTIVE: To study the impact of generalized joint hypermobility (GJH) in professional dancers on physical fitness, musculoskeletal complaints and psychological distress. METHODS: Thirty-six professional dancers were recruited and compared with control subjects (mean age 20.1, range 17-27). Height, weight, Beighton score, physical fitness (walking distance, muscle strength, estimated VO2max), musculoskeletal complaints (pain, fatigue) and psychological distress (anxiety, depression) were measured. RESULTS: Univariate analysis revealed, in between-group analysis, that dancers (with and without GJH) had higher physical fitness [the six-minute walk test (6MWT): DeltaD = +8.4%, P = 0.001; VO2max: DeltaD = +12.8%, P = 0.01], fatigue (checklist individual strength: DeltaD = +80.3%, P < 0.0001) and greater psychological distress (Hospital Anxiety and Depression Scale: DeltaD = +115.0%, P < 0.0001). When comparing dancers and control subjects with GJH to those without GJH, lower levels of physical fitness (muscle strength: DeltaD = -11.3%, P < 0.0001; 6MWT: DeltaD = -9.9%, P < 0.0001), more fatigue (checklist individual strength: DeltaD = +84.4%, P < 0.0001) and greater psychological distress (Hospital Anxiety and Depression Scale: DeltaD = +79.6%, P < 0.0001) were observed in subjects with GJH. Multivariate analysis showed that dancers have higher levels of physical fitness (6MWT, P = 0.001; VO2max, P = 0.020); however, when taking GJH into account, this advantage disappeared, indicating lower levels of physical fitness in comparison with control subjects (6MWT, P = 0.001; muscle strength, P < 0.0001; VO2max, P = 0.040). Dancers experienced more fatigue (P = 0.001) and psychological distress (P < 0.0001). This was associated with even more fatigue (P = 0.010) and psychological distress (P = 0.040) when GJH was present. CONCLUSION: Dancers with GJH seem more vulnerable to musculoskeletal and psychological complaints. In addition, GJH was also associated with lower physical fitness, despite training. Caregivers for professional dancers should monitor closely the physical capabilities and the amount of psychological strain. PMID- 22923761 TI - Successful alpha1-antitrypsin replacement therapy in a patient with alpha1 antitrypsin deficiency and granulomatosis with polyangiitis. PMID- 22923762 TI - A systematic review of evidence for the effectiveness of practitioner-based complementary and alternative therapies in the management of rheumatic diseases: osteoarthritis. AB - OBJECTIVE: To critically review the evidence on the efficacy and effectiveness of practitioner-based complementary therapies for patients with osteoarthritis. We excluded t'ai chi and acupuncture, which have been the subject of recent reviews. METHODS: Randomized controlled trials, published in English up to May 2011, were identified using systematic searches of bibliographic databases and searching of reference lists. Information was extracted on outcomes, statistical significance in comparison with alternative treatments and reported side effects. The methodological quality of the identified studies was determined using the Jadad scoring system. Outcomes considered were pain and patient global assessment. RESULTS: In all, 16 eligible trials were identified covering 12 therapies. Overall, there was no good evidence of the effectiveness of any of the therapies in relation to pain or global health improvement/quality of life because most therapies only had a single randomized controlled trial. Where positive results were reported, they were often comparing an active intervention with no intervention. Therapies with multiple trials either provided null (biofeedback) or inconsistent results (magnet therapy), or the trials available scored poorly for quality (chiropractic). There were few adverse events reported in the trials. CONCLUSION: There is not sufficient evidence to recommend any of the practitioner based complementary therapies considered here for the management of OA, but neither is there sufficient evidence to conclude that they are not effective or efficacious. PMID- 22923763 TI - Acro-osteolysis in systemic sclerosis is associated with digital ischaemia and severe calcinosis. AB - OBJECTIVES: Acro-osteolysis (bony resorption of the terminal digital tufts) is a well-recognized, but under-researched, manifestation of SSc. Our aim was to investigate the hypothesis that acro-osteolysis is associated with (i) the severity of digital ischaemia and (ii) the presence of calcinosis. METHODS: This was a retrospective study of 101 patients with SSc in whom hand radiographs taken between 2001 and May 2008 were available for review. These radiographs were graded for severity of acro-osteolysis on a 0-4-point scale for each finger (0 = normal bone structure, 4 = severe pencilling of the terminal phalanges). From these scores, patients were subdivided into the following two groups: normal/minimal acro-osteolysis and moderate/severe acro-osteolysis. The presence or absence of calcinosis (mild, moderate or severe) was also documented. RESULTS: Of the 101 patients, 68 were grouped as normal/minimal acro-osteolysis and 33 as moderate/severe acro-osteolysis. Forty-five had severe digital ischaemia: 25 (76%) of the patients with moderate/severe acro-osteolysis compared with 20 (29%) of those with normal/minimal acro-osteolysis (multifactorial analysis: P < 0.001). Patients with moderate/severe acro-osteolysis were more likely to have severe calcinosis (33% vs 13%), but this was not statistically significant after adjustment for potential confounders. CONCLUSION: Acro-osteolysis was strongly associated with severe digital ischaemia. The potential association with severe calcinosis merits further study. Prospective studies are required to investigate acro-osteolysis as a marker of digital vascular disease progression and of treatment response. PMID- 22923764 TI - Fatal acute monocytic leukaemia with t(6;11) (q27;q23) translocation and KRAS mutation. PMID- 22923765 TI - Elevated, combined serum free light chain levels and increased mortality: a 5 year follow-up, UK study. AB - AIMS: Abnormal serum free light chain (FLC) ratios are diagnostically important in almost all plasma cell disorders. However, absolute increases in polyclonal FLC levels are often discarded as inconsequential. Here we report an association between increased combined polyclonal FLC (cFLC: FLCkappa plus FLClambda) concentrations and mortality. METHODS: 723 patients sent for 30 routine haematological assessments were enrolled. Patients with a confirmed monoclonal gammopathy were removed. The remaining 527 patients were followed up for up to 4.5 years. Statistical analysis was performed using SPSS (V.19). RESULTS: During follow-up, there were 99 deaths (18.8%). Kaplan-Meier survival analysis revealed 29% of these deaths occurred within the first 100 days (N=29). Multivariate analysis identified only cFLC >65 mg/l, albumin <33 g/l and estimated glomerular filtration rate <30 ml/min/1.73 m(2) to be independently associated with mortality within 100 days and 4.5 years with, cFLC having the highest HR of 7.1. A simple risk stratification model based only on albumin and cFLC identified 86% mortality within 100 days and 62% over 4.5 years. CONCLUSIONS: Elevated cFLC is significantly associated with increased mortality and with albumin can be used to identify patients at risk of mortality at 4.5 years with high-risk patients detected within 100 days. PMID- 22923766 TI - Recurrent axillary lymphadenopathy with benign squamous epithelial inclusions in a female with no breast pathology. PMID- 22923767 TI - Air proteins control differential TRAMP substrate specificity for nuclear RNA surveillance. AB - RNA surveillance systems function at critical steps during the formation and function of RNA molecules in all organisms. The RNA exosome plays a central role in RNA surveillance by processing and degrading RNA molecules in the nucleus and cytoplasm of eukaryotic cells. The exosome functions as a complex of proteins composed of a nine-member core and two ribonucleases. The identity of the molecular determinants of exosome RNA substrate specificity remains an important unsolved aspect of RNA surveillance. In the nucleus of Saccharomyces cerevisiae, TRAMP complexes recognize and polyadenylate RNAs, which enhances RNA degradation by the exosome and may contribute to its specificity. TRAMPs contain either of two putative RNA-binding factors called Air proteins. Previous studies suggested that these proteins function interchangeably in targeting the poly(A)-polymerase activity of TRAMPs to RNAs. Experiments reported here show that the Air proteins govern separable functions. Phenotypic analysis and RNA deep-sequencing results from air mutants reveal specific requirements for each Air protein in the regulation of the levels of noncoding and coding RNAs. Loss of these regulatory functions results in specific metabolic and plasmid inheritance defects. These findings reveal differential functions for Air proteins in RNA metabolism and indicate that they control the substrate specificity of the RNA exosome. PMID- 22923768 TI - Mechanism of the AAA+ ATPases pontin and reptin in the biogenesis of H/ACA RNPs. AB - The AAA+ ATPases pontin and reptin function in a staggering array of cellular processes including chromatin remodeling, transcriptional regulation, DNA damage repair, and assembly of macromolecular complexes, such as RNA polymerase II and small nucleolar (sno) RNPs. However, the molecular mechanism for all of these AAA+ ATPase associated activities is unknown. Here we document that, during the biogenesis of H/ACA RNPs (including telomerase), the assembly factor SHQ1 holds the pseudouridine synthase NAP57/dyskerin in a viselike grip, and that pontin and reptin (as components of the R2TP complex) are required to pry NAP57 from SHQ1. Significantly, the NAP57 domain captured by SHQ1 harbors most mutations underlying X-linked dyskeratosis congenita (X-DC) implicating the interface between the two proteins as a target of this bone marrow failure syndrome. Homing in on the essential first steps of H/ACA RNP biogenesis, our findings provide the first insight into the mechanism of action of pontin and reptin in the assembly of macromolecular complexes. PMID- 22923769 TI - Dynamic relations between fast-food restaurant and body weight status: a longitudinal and multilevel analysis of Chinese adults. AB - BACKGROUND: Mixed findings have been reported on the association between Western fast-food restaurants and body weight status. Results vary across study contexts and are sensitive to the samples, measures and methods used. Most studies have failed to examine the temporally dynamic associations between community exposure to fast-food restaurants and weight changes. METHODS: Bayesian hierarchical regressions are used to model changes in body mass index, waist-to-height ratio (WHtR) and waist-to-hip ratio (WHpR) as a function of changes in Western fast food restaurants in 216 communities for more than 9000 Chinese adults followed up multiple times between 2000 and 2009. RESULTS: Number of Western fast-food restaurants is positively associated with subsequent increases in WHtR and WHpR among rural population. More fast-food restaurants are positively associated with a future increase in WHpR for urban women. Increased availability of fast food between two waves is related to increased WHtR for urban men over the same period. A past increase in number of fast-food restaurants is associated with subsequent increases in WHtR and WHpR for rural population. CONCLUSIONS: The associations between community exposure to Western fast food and weight changes are temporally dynamic rather than static. Improved measures of exposure to community environment are needed to achieve more precise estimates and better understanding of these relationships. In light of the findings in this study and China's rapid economic growth, further investigation and increased public health monitoring is warranted since Western fast food is likely to be more accessible and affordable in the near future. PMID- 22923770 TI - Is the human sex ratio at birth a sentinel health indicator that is associated with HIV/AIDS and tuberculosis prevalences in the 21st century? AB - BACKGROUND: A reduction in sex ratio at live birth has been proposed as a sentinel health indicator that can be used to monitor the health of populations. OBJECTIVE: To test the hypothesis that a lower sex ratio is associated with adverse national population health using the prevalences of HIV and tuberculosis as measures of societal well-being. METHODS: An ecological study design using routinely collected data and adjusting for potential confounding factors. RESULTS: The mean global sex ratio was 1.05. There was marked heterogeneity in the sex ratio between different global regions (p<0.0001). Those regions with the highest prevalences of HIV infection had lower sex ratios, with the value for the highest quartile being 0.022 (95% CIs CI 0.013 to 0.031) lower than the lowest quartile. Similarly, those areas with the highest quartile of tuberculosis infection had a sex ratio of 0.016 (95% CI 0.004 to 0.028) lower than those in the lowest quartile. Similar results were observed in a subgroup analysis limited to countries from the African continent. CONCLUSIONS: The data are consistent with the hypothesis that a reduced sex ratio at live birth is a potential sentinel health indicator of lower population health. However, these data do not demonstrate either a casual relationship or reveal any biological mechanisms that may account for these observations. PMID- 22923771 TI - Using communication theory for health promotion: practical guidance on message design and strategy. AB - According to the U.S. Department of Health and Human Services, health communication is "the study and use of communication strategies to inform and influence individual and community decisions that enhance health." The purpose of this article is to look at how health educators can use communication theory to create messages that are innovative, relatable, and motivating to intended audiences. Three specific communication theories are presented, along with examples of how they have been successfully used in behavior change initiatives. These three theories are offered in an effort to stimulate further investigation into how theory supports the creation of targeted, tailored, and effective communication strategies. PMID- 22923772 TI - Professional development through planning for and/or participating in an accreditation/approval review. AB - The quality of delivery of health education services is connected to landmark events in the history of health education. Quality assurance is one type of professional development in which practicing health education specialists engage. This article presents the steps of an accreditation/approval process, brief overviews of the major accreditation/approval systems, and the opportunities within the accreditation/approval process for professional development. PMID- 22923774 TI - What is hidden in my data? Practical strategies to reveal Yule-Simpson's paradox and strengthen research quality in health education research. AB - Yule-Simpson's paradox (YSP) often occurs when statistical data are aggregated from multiple groups, research sites, or time points. If YSP-type effects go unrecognized, health educators risk yielding erroneous and spurious findings or misinterpreting study data. These paradoxical effects may be avoided if health researchers carefully consider strategies to avoid YSP at the onset of and throughout research studies. This article presents strategies to reduce or avoid YSP-type effects across multiple stages of the research process. A practical checklist is also provided to minimize the likelihood YSP will go unnoticed in research studies. PMID- 22923775 TI - Criminal prosecution of suicide attempt survivors in Ghana. AB - Recently, there have been calls for the decriminalization (or depenalization) of nonfatal suicidal behavior (attempted suicide) in Ghana, India, Uganda, and other societies that currently criminalize nonfatal suicidal behavior. Despite this, there is a dearth of systematic studies that examine the extent, nature, and characteristics of attempted suicide prosecutions in countries that currently criminalize nonfatal suicidal behavior. The current study, therefore, explores the phenomenon of criminal prosecution and punishment for suicide attempters in Ghana, one among several countries where nonfatal suicidal behavior is a crime. Drawing from data extracted from local Ghanaian print and electronic news media articles, the study examines the sociodemographic characteristics of suicide attempt survivors, the patterns of nonfatal suicidal behavior, as well as the criminal justice outcomes of the criminal prosecutions. The findings indicate that the majority of defendants pled guilty to or were found guilty of the charge and sentenced to penalties ranging from monetary fines to incarceration. The results are discussed with regard to their implications for reducing nonfatal suicidal behavior in Ghana. PMID- 22923776 TI - The scream. PMID- 22923777 TI - Reliability and effectiveness of GEWF solution in the identification of lymph nodes in specimens of colorectal carcinoma. AB - Lymph node status is pivotal in the staging process of cancer. With regards to colorectal cancer, lymph node retrieval is always laborious. Sometimes, it is also a challenge to recover a minimum of 12 lymph nodes from the pericolorectal tissue. Among many proposed adjunctive solutions, GEWF solution (glacial acetic acid, ethanol, distilled water, and formaldehyde) has been introduced recently and suggested to be superior. To further evaluate its efficiency, the pericolorectal tissue, which has been reexamined extensively in the conventional condition, was refixed into GEWF solution in this study. More lymph nodes were found in 75% (n = 6) of the 8 experimental cases, and 50% (n = 4) of them had 12 or more yielded lymph nodes eventually. In addition, no adverse influences on the expressions of immunohistochemical and special stains were seen. These data support the reliability and effectiveness of GEWF solution in improvement of lymph node yield. PMID- 22923778 TI - Minute type I gastric carcinoid with regional lymph node metastasis. AB - Type I gastric carcinoids are indolent lesions that only rarely metastasize. Until now, lymph node metastasis had only being observed in large (>=10 mm) and usually invasive lesions (deep submucosa or beyond). This study reports a diminutive (8 mm) gastric carcinoid, limited to the superficial layer of the submucosa (sm1), with no angiovascular invasion, but with a high Ki-67 index (7%) and an involved perigastric lymph node. The aggressive behavior of this lesion ends the previous believe that small and superficial type I gastric carcinoids do not metastasize. This case also indicates that better parameters are necessary to evaluate the malignant potential of these lesions and presents a further support to the value of 2010 World Health Organization classification of gastrointestinal neuroendocrine tumors. PMID- 22923779 TI - Sinonasal teratocarcinosarcoma: a clinical and pathological analysis. AB - The goal of this study was to assess the pathological and differential diagnoses of sinonasal teratocarcinosarcoma (SNTCS) in order to ultimately improve the diagnosis and treatment of this rare disease. Data from 2 cases of sinonasal teratocarcinosarcoma from the Wuxi People's Hospital (China) were analyzed. The clinical presentation for these patients consisted of nasal obstruction, epistaxis, and headache. On further physical examination, the presence of a polypoid mass was identified and, despite surgery and radiotherapy, both cases experienced recurrence. Histologically, the tumors showed a heterogeneous mixture of components from the 3 germ layers, primitive neuroepithelial elements, diagnostic immature squamous cell nests (clear cell nests), and various epithelial and mesenchymal components. Staining of the different germ layers corresponded with the appropriate immune markers. In case 1, the postradiotherapy resection specimen was completely dominated by a mature teratoma, with a complete absence of the corresponding adenocarcinoma and fibrosarcoma components. To date, this is the first study describing this composition within an SNTCS recurrent tumor. In summary, SNTCS is a rare tumor characterized by the presence of benign and malignant epithelial, mesenchymal, and dysembryomal components. Owing to its heterogeneous histologic appearance, adequate sampling and recognition of all SNTCS components are needed for future diagnosis. Currently, surgical removal, postoperative radiotherapy, and a histology-specific multidrug chemotherapy appear to be the best therapeutic approach. Future individualized therapy may also hold promise. PMID- 22923780 TI - The relationships between sensory modulation and sleep among adolescents with ADHD. AB - OBJECTIVE: The purpose of this study was to investigate the effect of sensory modulation and sleeping among 30 adolescents diagnosed with ADHD, compared with 28 adolescents without ADHD. METHOD: Two questionnaires were completed by parents to assess the participants' level of ADHD symptoms. Two other questionnaires were completed by the participants assessing difficulties in sensory modulation and sleep. RESULTS: The ADHD group had more sensory difficulties in Activity Level, Hearing, and Low Registration, and more difficulties in the Sleep Behavior variables. Higher correlations between the sensory variables and the sleep measures were found in the ADHD group as compared with the non-ADHD group. Significant differences between correlations were found between three sleep measures and four sensory variables. CONCLUSION: The discussion is devoted to an assessment of the relationships between the measures, with the conclusion that among adolescents with ADHD, it is important to assess and treat possible sensory and sleep difficulties. PMID- 22923781 TI - How Informative Is the CANTAB to Assess Executive Functioning in Children With ADHD? A Controlled Study. AB - OBJECTIVE: The authors examined the utility of the computerized Cambridge Neuropsychological Test Automated Battery (CANTAB) to evaluate executive functioning deficits in children with ADHD. METHOD: Participants were unmedicated children and adolescents with (n = 107) and without (n = 45) Diagnostic and Statistical Manual of Mental Disorders (4th ed.) ADHD. The authors administered the CANTAB Eclipse battery, which comprises specific tasks shown to be deficient in individuals with ADHD. RESULTS: With the exception of the affective go/no-go total omissions, ADHD participants were significantly more impaired on all other subtests of the CANTAB in comparison with controls. Effect sizes for individual CANTAB tests were largely in the medium range with the largest effect sizes seen in spatial working memory total and between errors. CONCLUSION: These CANTAB results are highly congruent with those reported in studies using traditional neuropsychological testing batteries, supporting the utility of the CANTAB to assess neuropsychological deficits in children with ADHD in clinical and research settings. PMID- 22923782 TI - Hoarding in Children With ADHD. AB - OBJECTIVE: Although evidence suggests that hoarding may be associated with symptoms of ADHD, no study has examined this relationship in children. METHOD: Participants included 99 youth diagnosed with ADHD (and a parent) seen in a general outpatient psychiatry clinic. Children completed the Obsessive-Compulsive Inventory-Child Version, the Revised Child Anxiety and Depression Scale, and the Rosenberg Self-Esteem Scale. Parents completed the Children's Saving Inventory and Vanderbilt ADHD Diagnostic Rating Scale-Parent Version. RESULTS: Inattentive and hyperactive/impulsive symptoms were the only indicator that differentiated those with and without clinically significant hoarding. Symptoms of ADHD, but not nonhoarding obsessive-compulsive symptoms, significantly predicted hoarding. Inattention and hyperactivity/impulsivity were uniquely associated with individual hoarding features. Hoarding symptoms mediated the relationship between ADHD and oppositionality. CONCLUSION: These findings contribute to the growing literature about the association between hoarding and ADHD. PMID- 22923783 TI - Evolution of the Study of Methylphenidate and Its Actions on the Adult Versus Juvenile Brain. AB - OBJECTIVE: Methylphenidate (MPH) is the most often prescribed medication for treatment of ADHD. However, many of its specific cellular and molecular mechanisms of action, as well as developmental consequences of treatment, are largely unknown. This review provides an overview of current understanding of MPH efficacy, safety, and dosage in adult and pediatric ADHD patients, as well as adult animal studies and pioneering studies in juvenile animals treated with MPH. METHOD: A thorough review of the current literature on MPH efficacy and safety in children, adults, and animal models was included. Results of studies were compared and contrasted. RESULTS: While MPH is currently considered safe, there is a lack of knowledge of potential developmental consequences of early treatment, as well as differences in drug actions in the developing versus mature brain system. CONCLUSION: This review emphasizes the need for further research into the age-dependent activities and potency of MPH, and a need for tighter control and clinical relevance in future studies. PMID- 22923784 TI - Translation of a tumor microenvironment mimicking 3D tumor growth co-culture assay platform to high-content screening. AB - For drug discovery, cell-based assays are becoming increasingly complex to mimic more realistically the nature of biological processes and their diversifications in diseases. Multicellular co-cultures embedded in a three-dimensional (3D) matrix have been explored in oncology to more closely approximate the physiology of the human tumor microenvironment. High-content analysis is the ideal technology to characterize these complex biological systems, although running such complex assays at higher throughput is a major endeavor. Here, we report on adapting a 3D tumor co-culture growth assay to automated microscopy, and we compare various imaging platforms (confocal vs. nonconfocal) with correlating automated image analysis solutions to identify optimal conditions and settings for future larger scaled screening campaigns. The optimized protocol has been validated in repeated runs where established anticancer drugs have been evaluated for performance in this innovative assay. PMID- 22923785 TI - A selective ATP-binding cassette subfamily G member 2 efflux inhibitor revealed via high-throughput flow cytometry. AB - Chemotherapeutics tumor resistance is a principal reason for treatment failure, and clinical and experimental data indicate that multidrug transporters such as ATP-binding cassette (ABC) B1 and ABCG2 play a leading role by preventing cytotoxic intracellular drug concentrations. Functional efflux inhibition of existing chemotherapeutics by these pumps continues to present a promising approach for treatment. A contributing factor to the failure of existing inhibitors in clinical applications is limited understanding of specific substrate/inhibitor/pump interactions. We have identified selective efflux inhibitors by profiling multiple ABC transporters against a library of small molecules to find molecular probes to further explore such interactions. In our primary screening protocol using JC-1 as a dual-pump fluorescent reporter substrate, we identified a piperazine-substituted pyrazolo[1,5-a]pyrimidine substructure with promise for selective efflux inhibition. As a result of a focused structure-activity relationship (SAR)-driven chemistry effort, we describe compound 1 (CID44640177), an efflux inhibitor with selectivity toward ABCG2 over ABCB1. Compound 1 is also shown to potentiate the activity of mitoxantrone in vitro as well as preliminarily in vivo in an ABCG2-overexpressing tumor model. At least two analogues significantly reduce tumor size in combination with the chemotherapeutic topotecan. To our knowledge, low nanomolar chemoreversal activity coupled with direct evidence of efflux inhibition for ABCG2 is unprecedented. PMID- 22923786 TI - Evaluation of cholesterol reduction activity of methyl-beta-cyclodextrin using differentiated human neurons and astrocytes. AB - Recent advances in stem cell technology have enabled large-scale production of human cells such as cardiomyocytes, hepatocytes, and neurons for evaluation of pharmacologic effect and toxicity of drug candidates. The assessment of compound efficacy and toxicity using human cells should lower the high clinical attrition rates of drug candidates by reducing the impact of species differences on drug efficacy and toxicity from animal studies. Methyl-beta-cyclodextrin (MBCD) has been shown to reduce lysosomal cholesterol accumulation in skin fibroblasts derived from patients with Niemann Pick type C disease and in the NPC1-/- mouse model. However, the compound has never been tested in human differentiated neurons. We have determined the cholesterol reduction effect of MBCD in neurons differentiated from human neural stem cells (NSCs) and commercially available astrocytes. The use of NSCs for producing differentiated neurons in large quantities can significantly reduce the production time and enhance the reproducibility of screening results. The EC(50) values of MBCD on cholesterol reduction in human neurons and astrocytes were 66.9 and 110.7 uM, respectively. The results indicate that human neurons differentiated from the NSCs and human astrocytes are useful tools for evaluating pharmacologic activity and toxicity of drug candidates to predict their clinical efficacy. PMID- 22923787 TI - High-throughput FRET assay yields allosteric SERCA activators. AB - Using fluorescence resonance energy transfer (FRET), we performed a high throughput screen (HTS) in a reconstituted membrane system, seeking compounds that reverse inhibition of sarcoplasmic reticulum Ca-ATPase (SERCA) by its cardiac regulator, phospholamban (PLB). Such compounds have long been sought to correct aberrant Ca(2+) regulation in heart failure. Donor-SERCA was reconstituted in phospholipid membranes with or without acceptor-PLB, and FRET was measured in a steady-state fluorescence microplate reader. A 20 000-compound library was tested in duplicate. Compounds that decreased FRET by more than three standard deviations were considered hits. From 43 hits (0.2%), 31 (72%) were found to be false-positives upon more thorough FRET testing. The remaining 12 hits were tested in assays of Ca-ATPase activity, and six of these activated SERCA significantly, by as much as 60%, and several also enhanced cardiomyocyte contractility. These compounds directly activated SERCA from heart and other tissues. These results validate our FRET approach and set the stage for medicinal chemistry and preclinical testing. We were concerned about the high rate of false positives, resulting from the low precision of steady-state fluorescence. Preliminary studies with a novel fluorescence lifetime plate reader show 20-fold higher precision. This instrument can dramatically increase the quality of future HTS. PMID- 22923788 TI - Use of escin as a perforating agent on the IonWorks quattro automated electrophysiology platform. AB - The automated electrophysiology platform IonWorks has facilitated the medium throughput study of ion channel biology and pharmacology. Electrical and chemical access to the cell is by perforated patch, afforded by amphotericin. Permeation of the amphotericin pore is limited to monovalent cations. We describe here the use of the saponin escin as an alternative perforating agent. With respect to the number and robustness of seals formed across a variety of cell and ion channel types, the performance of escin is equal to that of amphotericin. Escin also permits the permeation of larger molecules through its pore. These include nucleotides, important intracellular modulators of ion channel activity that can be used to prevent ion channel rundown of, for instance, Ca(V)1.2. Furthermore, pharmacologic agents such as QX314 can also permeate and be used for mechanistic studies. Escin, in combination with IonWorks, increases the scope of ion channel screening and can facilitate the assay of previously difficult-to-assay targets. PMID- 22923789 TI - A high-throughput screen for Wnt/beta-catenin signaling pathway modulators in human iPSC-derived neural progenitors. AB - Wnt/beta-catenin signaling has emerged as a central player in pathways implicated in the pathophysiology and treatment of neuropsychiatric disorders. To identify potential novel therapeutics for these disorders, high-throughput screening (HTS) assays reporting on Wnt/beta-catenin signaling in disease-relevant contexts are needed. The use of human patient-derived induced pluripotent stem cell (iPSC) models provides ideal disease-relevant context if these stem cell cultures can be adapted for HTS-compatible formats. Here, we describe a sensitive, HTS-compatible Wnt/beta-catenin signaling reporter system generated in homogeneous, expandable neural progenitor cells (NPCs) derived from human iPSCs. We validated this system by demonstrating dose-responsive stimulation by several known Wnt/beta-catenin signaling pathway modulators, including Wnt3a, a glycogen synthase kinase-3 (GSK3) inhibitor, and the bipolar disorder therapeutic lithium. These responses were robust and reproducible over time across many repeated assays. We then conducted a screen of ~1500 compounds from a library of Food and Drug Administration-approved drugs and known bioactives and confirmed the HTS hits, revealing multiple chemical and biological classes of novel small-molecule probes of Wnt/beta-catenin signaling. Generating these type of pathway-selective, cell based phenotypic assays in human iPSC-derived neural cells will advance the field of human experimental neurobiology toward the goal of identifying and validating targets for neuropsychiatric disorders. PMID- 22923790 TI - Characterizing human ion channels in induced pluripotent stem cell-derived neurons. AB - Neurons derived from human-induced pluripotent stem cells were characterized using manual and automated patch-clamp recordings. These cells expressed voltage gated Na(+) (Na(v)), Ca(2+) (Ca(v)), and K(+) (K(v)) channels as expected from excitable cells. The Na(v) current was TTX sensitive, IC(50) = 12 +/- 6 nM (n = 5). About 50% of the Ca(v) current was blocked by 10 uM of the L-type channel blocker nifedipine. Two populations of the K(v) channel were present in different proportions: an inactivating (A-type) and a noninactivating type. The A-type current was sensitive to 4-AP and TEA (IC(50) = 163 +/- 93 uM; n = 3). Application of gamma-aminobutyric acid (GABA) activated a current sensitive to the GABA(A) receptor antagonist bicuculline, IC(50) = 632 +/- 149 nM (n = 5). In both devices, comparable action potentials were generated in the current clamp. With unbiased, automated patch clamp, about 40% of the cells expressed Na(v) currents, whereas visual guidance in manual patch clamp provided almost a 100% success rate of patching "excitable cells." These results show high potential for pluripotent stem cell-derived neurons as a useful model for drug discovery, in combination with automated patch-clamp recordings for high-throughput and high quality drug assessments at human neuronal ion channels in their correct cellular background. PMID- 22923791 TI - Entire genomic sequence of novel canine papillomavirus type 13. AB - Papillomaviruses are associated with benign and malignant neoplasias of the skin and mucous membranes. The sequence of a novel canine papillomavirus was determined from DNA detected in the oral cavity of a dog. The sequence of the novel virus canine papillomavirus type 13 (CPV13) shares the highest levels of similarity with the Tau papillomaviruses CPV2 and CPV7. PMID- 22923792 TI - Complete genome sequence of two coxsackievirus A1 strains that were cytotoxic to human rhabdomyosarcoma cells. AB - Coxsackievirus A1 (CVA1) belongs to human enterovirus species C within the family Picornaviridae, order Picornavirales. Two Chinese CVA1 isolates, HT THLH02F/XJ/CHN/2011 and KS-ZPH01F/XJ/CHN/2011, were isolated from stool specimens of two healthy children in the Xinjiang Uygur autonomous region of China. They were found to elicit cytopathic effects in a human rhabdomyosarcoma cell line, and complete genome sequences of these two CVA1 isolates revealed that natural intertypic recombination events occurred between CVA1 and CVA22. PMID- 22923793 TI - Biology of a novel mycobacteriophage, SWU1, isolated from Chinese soil as revealed by genomic characteristics. AB - Mycobacteriophage SWU1 is a newly isolated phage from a soil sample collected at Gongping village, Pingchang County, Sichuan Province, China, using Mycobacterium smegmatis mc(2)155 as a host. Plaques of SWU1 appear as a unique bull's-eye on an M. smegmatis lawn. In this paper, we report the complete genome sequence of SWU1 and some major findings from the analysis result. PMID- 22923794 TI - Complete genome of Staphylococcus aureus phage SA11. AB - A novel lytic bacteriophage, SA11, infecting Staphylococcus aureus was isolated, and the whole genome was sequenced. It belongs to the siphoviridae based on electron microscopic observation. It has a linear double-stranded DNA genome of 136,326 bp. Genomic analysis showed that it is distantly related to Staphylococcus phages A5W, K, ISP, Sb-1, and G1. PMID- 22923795 TI - Complete genome sequence of a bovine viral diarrhea virus 2 from commercial fetal bovine serum. AB - We isolated a bovine viral diarrhea virus (BVDV) from commercial fetal bovine serum and designated it HLJ-10. The complete genome is 12,284 nucleotides (nt); the open reading frame is 11,694 nt, coding 3,898 amino acids. Phylogenetic analysis indicated that this strain belongs to BVDV group 2. PMID- 22923796 TI - Complete genome sequence of Caulobacter crescentus bacteriophage phiCbK. AB - phiCbK is a B3 morphotype bacteriophage of the Siphoviridae family that infects Caulobacter crescentus, the preeminent model system for bacterial cell cycle studies. The last 4 decades of research with phiCbK as a genetic and cytological tool to study the biology of the host warrant an investigation of the phage genome composition. Herein, we report the complete genome sequence of phiCbK and highlight unusual features that emerged from its annotation. The complete genome analysis of the phiCbK phage provides new insight into its characteristics and potential interactions with its Caulobacter crescentus host, setting the stage for future functional studies with phiCbK. PMID- 22923797 TI - Genome sequence of an unusual human G10P[8] rotavirus detected in Vietnam. AB - A rare human G10P[8] rotavirus with a reassortment between bovine and human viruses was detected from a patient with acute gastroenteritis in Vietnam. Genetic analysis using complete coding sequences of all segments showed a genomic constellation of this virus of G10-P[8]-I1-R1-C1-M1-A1-N1-T1-E1-H1. Its VP7 region was genetically related to that of a bovine rotavirus derived from Australia (strain VICG10.01), whereas all other genes were identical to those of a human rotavirus derived from Australia (strain Victoria/CK00047). These results indicate a possibility that the reassortment of the rotavirus was caused by immune escape in Australia and the rotavirus was carried to Vietnam. Additionally, this finding will help further understanding the evolution of rotaviruses circulating in Vietnam. PMID- 22923798 TI - Complete genome sequence of an avian-origin H3N2 canine influenza A virus isolated in farmed dogs in southern China. AB - We report here the complete genomic sequence of an avian-origin H3N2 canine influenza A virus containing multiple mutations in farmed dogs in southern China. Phylogenetic analyses of the sequences of all eight viral RNA segments demonstrated that these are wholly avian influenza viruses of the Asia lineage. To our knowledge, this is the first report of interspecies transmission of an avian H3N2 influenza virus to domestic farm dogs under natural conditions in Southern China. The amino acid information provided herein suggests that continued study is required to determine if this virus could be established in the farm dog population and pose potential threats to public health. PMID- 22923799 TI - Genome sequence of the broad-host-range Pseudomonas phage Phi-S1. AB - The broad-host-range lytic Pseudomonas phage Phi-S1 possess a 40,192 bp double stranded DNA (dsDNA) genome of 47 open reading frames (ORFs) and belongs to the family Podoviridae, subfamily Autographivirinae, genus T7likevirus. PMID- 22923800 TI - Complete genome sequence of a novel H9N2 subtype influenza virus FJG9 strain in China reveals a natural reassortant event. AB - A/chicken/FJ/G9/09 (FJ/G9) is an H9N2 subtype avian influenza virus (H9N2 AIV) strain causing high morbidity that was isolated from broilers in Fujian Province of China in 2009. FJ/G9 has been used as the vaccine strain against H9N2 AIV infection in Fujian Province of China. Here, we report the complete genome sequence of FJ/G9 with natural six-way reassortment, which is the most complex genotype strain in China and even in the world so far. The present findings will aid in understanding the complexity and diversity of H9N2 subtype avian influenza virus. PMID- 22923801 TI - Complete genome sequence of Ikoma lyssavirus. AB - Lyssaviruses (family Rhabdoviridae) constitute one of the most important groups of viral zoonoses globally. All lyssaviruses cause the disease rabies, an acute progressive encephalitis for which, once symptoms occur, there is no effective cure. Currently available vaccines are highly protective against the predominantly circulating lyssavirus species. Using next-generation sequencing technologies, we have obtained the whole-genome sequence for a novel lyssavirus, Ikoma lyssavirus (IKOV), isolated from an African civet in Tanzania displaying clinical signs of rabies. Genetically, this virus is the most divergent within the genus Lyssavirus. Characterization of the genome will help to improve our understanding of lyssavirus diversity and enable investigation into vaccine induced immunity and protection. PMID- 22923802 TI - Complete genome of Pseudomonas aeruginosa phage PA26. AB - PA26, a novel lytic bacteriophage infecting Pseudomonas aeruginosa, was isolated, and the whole genome was sequenced. It was found to belong to the myoviridae by an electron microscopic observation. It had a linear double-stranded DNA genome of 72,321 bp. Genomic analysis showed that it resembled another Pseudomonas phage, LIT1. PMID- 22923803 TI - Genome sequence of a Bombyx mori nucleopolyhedrovirus strain with cubic occlusion bodies. AB - Bombyx mori nucleopolyhedrovirus (BmNPV) is a typical species of Baculoviridae. The complete genome sequence of a BmNPV strain with cubic occlusion bodies is reported here. The genome of this strain consists of 127,465 nucleotides with a G+C content of 40.36% and is 97.3% and 97.5% identical to those of BmNPV strain T3 and Bombyx mandarina NPV S1, respectively. Despite the abnormal polyhedra it forms, the polyhedrin gene of the BmNPV cubic strain is 100% identical to those of the other two strains. Baculovirus repeated ORFs and homologous repeat regions cause the major differences in genome size of these BmNPV isolates. PMID- 22923804 TI - Escherichia coli O157:H7 typing phage V7 is a T4-like virus. AB - The complete genome sequence of the Escherichia coli O157:H7 typing phage V7 was determined. Its double-stranded DNA genome is 166,452 bp long, encoding 273 proteins and including 11 tRNAs. This virus belongs to the genus T4-like viruses within the subfamily Tevenvirinae, family Myoviridae. PMID- 22923805 TI - Complete genome sequence of a novel duck hepatitis A virus discovered in southern China. AB - We report here the complete genomic sequence of a novel duck hepatitis A virus (DHAV) isolated from mixed infections with DHAV type 1 (DHAV-1) and DHAV-3 in ducklings in Southern China. The whole nucleotide sequence had the highest homology with the sequence of DHAV-3 (GenBank accession number DQ812093) (96.2%). To our knowledge, this is the first report of gene rearrangement between DHAV-1 and DHAV-3, and it will help to understand the epidemiology and molecular characteristics of duck hepatitis A virus in Southern China. PMID- 22923806 TI - Complete genome sequence of a novel porcine epidemic diarrhea virus in south China. AB - Since early 2010, outbreaks of porcine epidemic diarrhea (PED) have been observed frequently in immunized swine herds in southern China. The suckling piglets are particularly susceptible to porcine epidemic diarrhea virus (PEDV), with a high mortality rate (90%). Recently, a virulent PEDV strain, GD-A, was isolated from an immunized-swine breeding farm in Guangdong, China. This report describes the complete genome sequence of GD-A, and the data will provide important insights into the variation of PEDV field isolates in southern China. PMID- 22923807 TI - Complete genome analysis of porcine enterovirus B isolated in Korea. AB - The complete genome sequence of porcine enterovirus B (PEV-B) from a Korean isolate was analyzed. The genome size was 7,393 bp. Previously, full genome sequences of PEV-B had been reported from the United Kingdom, Hungary, and China. The Korean PEV-B isolate presented polyprotein gene nucleotide sequence similarities of 77.9, 73.7, 78.9, and 80.3%, respectively, to PEV-B UKG/410/73, LP54, PEV15, and Chinese strains (Ch-ah-f1). PMID- 22923808 TI - Complete genome of the human norovirus GIV.1 strain Lake Macquarie virus. AB - Norovirus is an important human pathogen that is now recognized as the leading cause of acute gastroenteritis globally. Six viral genogroups have been described, although only genogroups GI, GII, and GIV are known to infect humans, with the GII viruses most commonly identified in both outbreak and sporadic settings. In contrast, infections by GIV viruses are rarely reported, and their overall prevalence in the community is unknown. Here, we report the complete genome sequence of the human GIV.1 strain Lake Macquarie virus, which caused two linked outbreaks of acute gastroenteritis in aged-care facilities in the Hunter region of New South Wales, Australia. The Lake Macquarie virus genome was 7,527 nucleotides (nt) in length and shared highest identity (70%) with the recently completed feline GIV.2 virus genome. PMID- 22923809 TI - Complete genome sequence of Salmonella bacteriophage SS3e. AB - A Salmonella lytic bacteriophage, SS3e, was isolated, and its genome was sequenced completely. This phage is able to lyse not only various Salmonella serovars but also Escherichia coli, Shigella sonnei, Enterobacter cloacae, and Serratia marcescens, indicating a broad host specificity. Genomic sequence analysis of SS3e revealed a linear double-stranded DNA sequence of 40,793 bp harboring 58 open reading frames, which is highly similar to Salmonella phages SETP13 and MB78. PMID- 22923810 TI - Complete genome sequence analysis of a reference strain of bluetongue virus serotype 16. AB - The entire genome of the reference strain of bluetongue virus (BTV) serotype 16 (strain RSArrrr/16) was sequenced (a total of 23,518 base pairs). The virus was obtained from the Orbivirus Reference Collection (ORC) at IAH, Pirbright, United Kingdom. The virus strain, which was previously provided by the Onderstepoort Veterinary Research Institute in South Africa, was originally isolated from the Indian subcontinent (Hazara, West Pakistan) in 1960. Previous phylogenetic comparisons show that BTV RNA sequences cluster according to the geographic origins of the virus isolate/lineage, identifying distinct BTV topotypes. Sequence comparisons of segments Seg-1 to Seg-10 show that RSArrrr/16 belongs to the major eastern topotype of BTV (BTV-16e) and can be regarded as a reference strain of BTV-16e for phylogenetic and molecular epidemiology studies. All 10 genome segments of RSArrrr/16 group closely with the vaccine strain of BTV-16 (RSAvvvv/16) that was derived from it, as well as those recently published for a Chinese isolate of BTV-16 (>99% nucleotide identity), suggesting a very recent common ancestry for all three viruses. PMID- 22923811 TI - Complete genomic sequence of goose-origin reovirus from China. AB - We report the full-genome sequence of a goose-origin reovirus (GRV) strain 03G from Zhejiang Province, China. This is the first report of the complete genomic sequence (segments 1 to 10) of GRV. Phylogenetic analyses of the sequence suggest that GRV 03G represents a new species distinct from other established species within the avian reovirus (ARV) group of orthoreoviruses. PMID- 22923812 TI - Nuclear export signal and immunodominant CD8+ T cell epitope in influenza A virus matrix protein 1. PMID- 22923814 TI - Phosphoproteome of Pristionchus pacificus provides insights into architecture of signaling networks in nematode models. AB - Pristionchus pacificus is a nematode that is increasingly used as a model organism in evolutionary biology. The genome of P. pacificus differs markedly from that of C. elegans, with a high number of orphan genes that are restricted to P. pacificus and have no homologs in other species. To gain insight into the architecture of signal transduction networks in model nematodes, we performed a large-scale qualitative phosphoproteome analysis of P. pacificus. Using two-stage enrichment of phosphopeptides from a digest of P. pacificus proteins and their subsequent analysis via high accuracy MS, we detected and localized 6,809 phosphorylation events on 2,508 proteins. We compared the detected P. pacificus phosphoproteome to the recently published phosphoproteome of C. elegans. The overall numbers and functional classes of phosphoproteins were similar between the two organisms. Interestingly, the products of orphan genes were significantly underrepresented among the detected P. pacificus phosphoproteins. We defined the theoretical kinome of P. pacificus and compared it to that of C. elegans. While tyrosine kinases were slightly underrepresented in the kinome of P. pacificus, all major classes of kinases were present in both organisms. Application of our kinome annotation to a recent transcriptomic study of dauer and mixed stage populations showed that Ser/Thr and Tyr kinases show similar expression levels in P. pacificus but not in C. elegans. This study presents the first systematic comparison of phosphoproteomes and kinomes of two model nematodes and, as such, will be a useful resource for comparative studies of their signal transduction networks. PMID- 22923815 TI - The Effect of Temperature and Moisture Content of Stored Rapeseed on the Phytosterol Degradation Rate. AB - The effect of temperature (25 or 35 degrees C) and moisture content (10, 12.5, 15.5 %) on rapeseed phytosterol degradation was examined for 18 days. Statistical analysis showed that temperature, moisture and time of storage have a significant effect on phytosterol degradation. After 18 days of seed storage at a temperature of 25 and 30 degrees C losses of these compounds amounted to 11 and 13 % in seeds with moisture contents of 10, 12 and 16 % in seeds with a moisture content of 12.5 %, while they were 24 and 58 % in seeds with a moisture content of 15.5 %. Among all the identified sterols the greatest degradation rate was observed for stigmasterol and brassicasterol. Losses of stigmasterol and brassicasterol during storage of seeds with a 12.5 % moisture content at a temperature of 30 degrees C were 17 and 28 %, respectively, while in seeds with a moisture content of 15.5 % these losses increased to 73 and 63 %. PMID- 22923816 TI - Degradation of Phytosterols During Near-Ambient Drying of Rapeseeds in a Thick Immobile Layer. AB - The effect of the drying method applied and subsequent rapeseed storage on changes in phytosterols was determined. After harvest, rapeseeds were dried by the near-ambient method in a thick immobile layer of 2 m and using air heated to a temperature of 60, 80 and 100 degrees C. Analyses of phytosterol contents were performed immediately after drying and after 6 and 12 months of storage at a temperature of 10 +/- 2 degrees C. Results showed a significant effect of drying conditions, cultivar-specific differences and storage time on the contents of phytosterols. Near-ambient drying of seeds resulted in a reduction in total sterol contents by 6-20 %, while for drying with hot air it was by 14-40 %. The level of sterols decreased by 13-18 % after a 1 year storage of seeds dried by the near-ambient methods. A reduction in 12-22 % in sterols for seeds dried by high temperature occurred after 1 year of storage. PMID- 22923817 TI - Pharmacological thromboprophylaxis and epidural anaesthesia. PMID- 22923818 TI - Internet resources for the anaesthesiologist. AB - There is considerable useful information about anaesthesia available on the World Wide Web. However, at present, it is very incomplete and scattered around many sites. Many anaesthetists find it difficult to get the right information they need because of the sheer volume of information available on the internet. This article starts with the basics of the Internet, how to utilize the search engine at the maximum and presents a comprehensive list of important websites. These important websites, which are felt to offer high educational value for the anaesthesiologists, have been selected from an extensive search on the Internet. Top-rated anaesthesia websites, web blogs, forums, societies, e-books, e-journals and educational resources are elaborately discussed with relevant URLs. PMID- 22923819 TI - Free radical scavengers in anaesthesiology and critical care. AB - Free radicals are highly reactive and unstable compounds. These highly reactive molecules cause oxidative damage to cellular components such as DNA, proteins and lipids. They play central role in the mechanism of cell injury and cell death. Free radical scavengers either prevent these reactive species from being formed, or remove them before they can damage vital components of the cell. Oxidative stress defines an imbalance in production of oxidizing chemical species and their effective removal by protective antioxidants and scavenger enzymes. Evidence of massive oxidative stress is well established in critical illnesses characterized by tissue ischaemia-reperfusion injury and by an intense systemic inflammatory response such as during sepsis and acute respiratory distress syndrome, acute lung injury. Several clinical trials have been performed in order to reduce oxidative stress by supplementation of antioxidants alone or in combination with standard therapies. Antioxidant supplementation at an early stage of illness may lead to improved therapies in the treatment of critically ill patients. Several intravenous anaesthetic drugs act as reactive oxygen species scavengers. Anaesthetic preconditioning is of particular interest to anaesthesiologist, in which lasting protection of myocardium is elicited by brief exposure to a inhalational anaesthetic agent. These anasthetics may also mediate protective effects in other organs, such as the brain and kidney It is important for the anaesthesiologist to understand the mechanism of damage caused by free radicals and how free radical scavengers work so that this knowledge can be applied to varied pathological conditions. The topic was hand searched in text books and electronically searched from PubMed and Google scholar using text words. PMID- 22923820 TI - Appropriateness of perioperative blood transfusion in patients undergoing cancer surgery: A prospective single-centre study. AB - BACKGROUND: Allogenic blood transfusion is associated with several potential complications, especially in patients with cancer. The objective of this prospective single-centre study was to identify the rates of perioperative blood transfusion and overtransfusion in a tertiary-level cancer hospital. METHODS: Between March and May 2008, we studied all adult patients undergoing elective major cancer surgery under anaesthesia and recorded intra- and immediate post operative (within 24 h) blood transfusions and post-operative investigations. Overtransfusion was defined as post-transfusion haemoglobin (Hb) exceeding 10 g/dL. RESULTS: One hundred and eighty-six of 1175 (16%) patients received perioperative blood transfusion. The main trigger for intraoperative transfusion was blood loss exceeding the patient's maximum allowable blood loss (92, 49%). Ninety-five (51%) transfused patients had post-transfusion Hb more than 10 g/dL. The rate of overtransfusion was not higher in patients who received single-unit transfusions. CONCLUSION: The perioperative transfusion rate in patients undergoing cancer surgery was 16%. More than half of these patients were overtransfused. Following this audit, point-of-care facilities for intraoperative haemoglobin measurement have been introduced. PMID- 22923821 TI - Closed loop anaesthesia at high altitude (3505 m above sea level): Performance characteristics of an indigenously developed closed loop anaesthesia delivery system. AB - BACKGROUND: Closed loop anaesthesia delivery systems (CLADSs) are a recent advancement in accurate titration of anaesthetic drugs. They have been shown to be superior in maintaining adequate depth of anaesthesia with few fluctuations as compared with target-controlled infusion or manual titration of drug delivery. METHODS: Twenty patients scheduled to undergo general abdominal or orthopaedic procedures under general anaesthesia at Leh (3505 m above sea level) were recruited as subjects. Anaesthesia was delivered by a patented closed loop system that uses the Bispectral Index (BISTM) as a feedback parameter to titrate the rate of propofol infusion. All vital parameters, drug infusion rate and the BISTM values were continuously recorded and stored online by the system. The data generated was analysed for the adequacy of anaesthetic depth, haemodynamic stability and post-operative recovery parameters. RESULTS: The CLADS was able to maintain a BISTM within +/-10 of the target of 50 for 85.0+/-7.8% of the time. Haemodynamics were appropriately maintained (heart rate and mean arterial blood pressure were within 25% of baseline values for 91.2+/-2.2% and 94.1+/-3% of the total anaesthesia time, respectively). Subjects were awake within a median of 3 min from cessation of drug infusion and achieved fitness to recovery room discharge within a median of 15 min. There were no adverse events or report of awareness under anaesthesia. CONCLUSIONS: The study demonstrates the safety of our CLADS at high altitude. It seeks to extend the use of our system in challenging anaesthesia environments. The system performance was also adequate and no adverse events were recorded. PMID- 22923822 TI - Comparison of dexmedetomidine and clonidine (alpha2 agonist drugs) as an adjuvant to local anaesthesia in supraclavicular brachial plexus block: A randomised double-blind prospective study. AB - BACKGROUND AND OBJECTIVES: Alpha-2 agonists are mixed with local anaesthetic agents to extend the duration of spinal, extradural and peripheral nerve blocks. We compared clonidine and dexmedetomidine as an adjuvant to local anaesthetic agent in supraclavicular brachial plexus block with respect to onset and duration of sensory and motor block and duration of analgesia. METHODS: Sixty ASA I and II patients scheduled for elective upper limb surgeries under supraclavicular brachial plexus block were divided into two equal groups in a randomized, double blinded fashion. Group C received clonidine 1 MUg/kg and Group D received dexmedetomidine 1 MUg/kg added to bupivacaine 0.25% (35 cc). Onset and recovery time of sensory and motor block, duration of analgesia and quality of block were studied in both the groups. RESULTS: Duration of sensory block and motor block was 227.00+/-48.36 and 292.67+/-59.13 min, respectively, in group C, while it was 413.97+/-87.13 and 472.24+/-90.06 min, respectively, in group D. There was no statistically significant difference in onset of sensory and motor block between the two groups. The duration of analgesia (time to requirement of rescue analgesia) in group D was 456+/-97 min, while in group C, it was 289+/-62 min. Statistically, this difference was significant (P=0.001). The number of patients achieving grade IV quality (excellent) of block was higher in group D (80%) as compared with group C (40%) (P<0.05). CONCLUSION: Dexmedetomidine when added to local anaesthetic in supraclavicular brachial plexus block enhanced the duration of sensory and motor block and also the duration of analgesia. The time for rescue analgesia was prolonged in patients receiving dexmedetomidine. It also enhanced the quality of block as compared with clonidine. PMID- 22923823 TI - Correlation between spinous process dimensions and ease of spinal anaesthesia. AB - BACKGROUND: Neuraxial anaesthesia, despite being a common technique, may pose some technical challenges leading to complications such as post-dural puncture headache, trauma to neural structures and neuraxial haematoma. We hypothesised that the interspinous gap (ISG) and the spinous process width (SPW) could be used as objective measures to predict ease of access to the neuraxial space. METHODS: Two hundred and two consecutive patients scheduled to have spinal anaesthesia for various surgical procedures were enrolled prospectively after institutional approval. Following proper positioning for the neuraxial blockade, the ISG and SPW at the intended level were measured with calipers. The number of attempts, and redirections at the selected spinal level, and the number of levels required for successful needle placement were also recorded. RESULTS: Group-wise analysis of the data into patients requiring >1 attempt, >1 level and >=3 redirections showed that the single independent predictor of a difficult neuraxial block was the ISG. Twenty-three percent of the patients required more than one attempt, with a mean gap of 6.35 (+/-1.2) mm, in contrast to 8.15 (+/-2.4) mm in those with a single attempt (P=0.000). In addition, 16% of the patients needed more than one level, with a mean gap of 6.03 (+/-2.01) mm in contrast to 8.07 (+/ 2.37) mm for a single level (P=0.000). CONCLUSIONS: The single independent predictor of ease or difficulty during spinal anaesthesia was the ISG (P=0.000). PMID- 22923824 TI - Validation of the unassisted, gum-elastic bougie-guided, laryngeal mask airway ProSealTM placement technique in anaesthetized patients. AB - AIMS: The laryngeal mask airway-ProSealTM can be inserted digitally, by introducer tool, or by railroading it over a bougie placed first in the patient's oesophagus, which is highly successful, but as originally described, requires an assistant. An unassisted bougie-guided placement technique has also been described, but no data on its effectiveness have been reported. METHODS: We reviewed data collected during a randomized, controlled trial comparing the air Q((r)) Intubating Laryngeal Airway and LMA-ProsealTM, in which all LMA-ProsealTM devices were inserted using the unassisted (one-operator), bougie-guided placement technique. RESULTS: Forty-eight devices were placed. All devices were placed successfully. Successful placement was achieved in 47 (98%) patients on first attempt and in one (2%) patient on the third attempt. Mean (SD) time required for insertion establishing ventilation was 28 (11) s. Mean (SD) airway seal pressure was 30 (6) cmH(2)O. Gross blood was found on four (8%) devices upon removal, but no oropharyngeal injuries were noted on oral exam in the recovery unit prior to discharge. The most common complaints in recovery and 24 h post operatively were sore throat [discharge: mild = 18/48 (38%); 24 h: mild = 9/38 (19%), moderate = 1/38 (3%)] and pain on swallowing [discharge: mild = 7/48 (15%); 24 h: mild = 2/38 (6%)]. CONCLUSIONS: Our data confirm that in experienced hands, bougie-guided placement of the LMA-ProsealTM without the aid of an assistant can be accomplished quickly and successfully without affecting the expected clinical performance of the device. PMID- 22923825 TI - Straight versus flex back: Does it matter in spinal anaesthesia? AB - PURPOSE: It is sometimes difficult for our patients to acquire recommended flexion of their back to perform subarachnoid block upon them. The aim of this study was to find out the degree of procedural success and patient preference when subarachnoid blocks were performed on patients with suboptimal flexion of the back. METHODS: Subarachnoid blocks were performed on 160 adult patients from both sexes without any spinal deformity. Procedures were performed with patients in the lateral or seated position with the back either straight or flexed. This approach divided the study population into 4 equal groups: Lateral with back straight (LS) or flexed (LF) and seated with back straight (SS) or flexed (SF). The primary endpoint was correct needle placement. Numbers of attempts, needle redirections and patients' preferred posture were determined to compare the outcome in different groups. RESULTS: For both positions, the overall success rates were 95% and 100% in patients who had straight or flexed back, respectively (P=0.81). In the lateral position, significantly more patients of the LF group (40) than those of the LS group (32) had successful placement of spinal needle at first attempt (P=0.03). Altogether, 34 and 21 patients in the SS and SF groups, respectively, required cephalad redirections of the needle (P=0.003). Most patients preferred the straight back position (69.7-88%). CONCLUSION: With a higher preference by patients for the straight back posture, the overall success rate of correct spinal needle placement was comparable among the groups who had their back placed in a straight or in a flexed posture for subarachnoid block. PMID- 22923826 TI - Effect of pre-operative rectal diclofenac suppository on post-operative analgesic requirement in cleft palate repair: A randomised clinical trial. AB - BACKGROUND: Opioid analgesics used for analgesia are associated with sedation, respiratory depression and post-operative nausea and vomiting. Non-steroidal anti inflammatory drugs such as diclofenac are a safe and effective alternative with opioid-sparing effect. OBJECTIVE: To evaluate the effectiveness of pre-operative rectal diclofenac suppository (1 mg/kg) in cleft palate repair for post-operative analgesia and reduction in post-operative opioid requirements. STUDY DESIGN: A randomized clinical trial. METHODS: After obtaining approval from the institutional ethical committee, 60 children were allocated by a computer generated randomisation into two groups of 30 each; group D (Diclofenac group) and group C (Conventional group). Children in group D and group C were similar in all aspects except for the fact that group D children received 1 mg/kg diclofenac suppository after induction. Pain was evaluated using modification of the objective pain scale by Hannallah and colleagues for 6 h post-operatively by an anaesthesiology resident or nursing staff who was blinded to the group. If the pain score was more than 3, rescue analgesic I.V. fentanyl 0.5 MUgm/kg was administered. The pain scores at different intervals, number of doses and quantity of rescue analgesic required were noted. RESULTS: We observed that pre operative rectal diclofenac provided effective analgesia in the immediate post operative period, as evidenced by reduced pain scores and reduced opioid requirement (P=0.00002). There was no evidence of any increased perioperative bleeding in the diclofenac group. CONCLUSION: Pre-operative rectal diclofenac reduces opioid consumption and provides good post-operative analgesia. PMID- 22923827 TI - Comparative study of ultrasound-guided continuous femoral nerve blockade with continuous epidural analgesia for pain relief following total knee replacement. AB - BACKGROUND: Regional analgesia is widely used for total knee replacement surgeries (TKR) as it has lesser side-effects and better analgesic efficacy when compared with traditional oral analgesics. Peripheral nerve blockade has also been utilized, including continuous infusion techniques. With the use of ultrasound, the needle and catheter placement can be done accurately under real time guidance. This may prove a more suitable approach compared with the epidural technique. AIMS: Post-operative analgesia in TKR patients was compared between continuous epidural analgesia (CEA) and continuous femoral block (CFB) techniques. VAS scores and use of rescue analgesic were used as parameters. Secondary aims included comparison of rehabilitation scores and side-effects in the form hypotension, vomiting, itching and urinary retention. SETTINGS AND DESIGN: Randomised, controlled, non-blinded study done in a tertiary care private hospital. METHODS: Forty-two patients fulfilling the study criteria were randomised into the CEA and CFB groups. In total, four patients: three in the CFB group and one in the CEA group, were excluded because of catheter migration. STATISTICAL ANALYSIS: Mean VAS score at 6, 6-24, 24-48 and 48-72 h were considered. Significance was assessed at the 5% level. RESULTS AND CONCLUSION: VAS scores were significantly high (P=0.001) in the femoral group at 6 h, after which there was a declining trend, and scores were essentially similar from 24 h. Common side-effects were more common in the CEA group. Our study shows that CFB gives equivalent analgesia compared with CEA in TKR patients with clinically meaningful decrease in side-effects. PMID- 22923828 TI - A comparison between volume-controlled ventilation and pressure-controlled ventilation in providing better oxygenation in obese patients undergoing laparoscopic cholecystectomy. AB - BACKGROUND: The maintenance of oxygenation is a commonly encountered problem in obese patients undergoing laparoscopic cholecystectomy. There is no specific guideline on the ventilation modes for this group of patients. Although several studies have been performed to determine the optimal ventilatory settings in these patients, the answer is yet to be found. The aim of this study was to evaluate the efficacy of pressure-controlled ventilation (PCV) in comparison with volume-controlled ventilation (VCV) for maintaining oxygenation during laparoscopic cholecystectomy in obese patients. METHODS: One hundred and two adult patients of ASA physical status I and II, Body Mass Index of 30-40 kg/m(2), scheduled for laparoscopic cholecystectomy were included in this prospective randomized open-label parallel group study. To start with, all patients received VCV. Fifteen minutes after creation of pneumoperitoneum, they were randomized to receive either VCV (Group V) or PCV (Group P). The ventilatory parameters were adjusted accordingly to maintain the end-tidal CO(2) between 35 and 40 mmHg. Respiratory rate, tidal volume, minute ventilation and peak airway pressure were noted. Arterial blood gas analyses were done 15 min after creation of pneumoperitoneum and at 20-min intervals thereafter till the end of the surgery. All data were analysed statistically. RESULTS: Patients in Group P showed a statistically significant (P < 0.05) higher level of PaO(2) and lower value of PAO(2)-PaO(2) than those in Group V. CONCLUSION: PCV is a more effective mode of ventilation in comparison with VCV regarding oxygenation in obese patients undergoing laparoscopic cholecystectomy. PMID- 22923829 TI - Anaesthetic significance and management of a child with neonatal purpura fulminans. AB - Protein C deficiency is a rare autosomal-dominant disorder of varying severity. Patients with homozygous and compound heterozygous protein C deficiency present with neonatal purpura fulminans (NPF). Other presentations usually include disseminated intravascular coagulation and venous thromboembolism. This disorder usually poses a unique anaesthetic challenge to the anaesthesiologist, requiring special precautions to prevent various intra- and post-operative complications. We hereby report the successful anaesthetic management of a 1-month-old infant who presented with NPF. PMID- 22923830 TI - "Dry tap" during spinal anaesthesia turns out to be epidural abscess. AB - We report a case of "dry tap" during spinal anaesthesia in a patient posted for incision and drainage of lower limb with cellulitis. When the patient was being given sub-arachnoid block (SAB) for regional anaesthesia, it turned out to be a case of pyogenic ilio-psoas abscess extended up to the paravertebral and epidural spaces. The causative organism was Staphylococcus aureus. This is probably the first case reported when epidural abscess is diagnosed during SAB. PMID- 22923831 TI - Anaesthesia for a patient with Eisenmenger's syndrome undergoing caesarean section. AB - Eisenmenger's syndrome is a cyanotic congenital heart disease that includes pulmonary hypertension with reversed or bidirectional shunt associated with septal defects or patent ductus arteriosus. The decreased systemic vascular resistance associated with pregnancy increases the degree of right to left shunting, thereby carrying substantial risk to both the mother and the foetus. The maternal mortality rate of pregnancy in the presence of Eisenmenger's syndrome is reported to be as high as 30-70%. We present a case of a 22-year-old primigravida with Eisenmenger's syndrome who gave birth at 37 weeks of gestation via caesarean section to a live female baby under general anaesthesia. On the third post-operative day, the patient developed tachycardia, tachypnoea, hypotension and decrease in oxygen saturation despite supplemental oxygen, clinically suspected pulmonary thromboembolism. We describe the anaesthetic management for caesarean section and its complications in a patient with Eisenmenger's syndrome. Although pregnancy should be discouraged in women with Eisenmenger's syndrome, it can be successful. PMID- 22923832 TI - The challenging aspects and successful anaesthetic management in a case of situs inversus totalis. AB - Situs inversus totalis is a rare condition with a predicted incidence of one in 10,000 among the general population, the aetiologic factors for which are still not completely understood. In a patient with situs inversus totalis, not just the diagnosis of any acute abdomen pathology is difficult due to distorted anatomy and transposition of thoraco abdominal viscera but equally challenging is the anaesthetic management during the respective surgical procedure. We are reporting a patient who had situs inversus totalis and was operated for open cholecystectomy. The present case report lays an emphasis on the potential difficulties during anaesthetic management and its various implications. PMID- 22923833 TI - Nerve stimulator-guided thoracic paravertebral block for gynecomastia surgery. AB - Thoracic paravertebral block (TPVB) is gaining popularity for female breast surgeries due to various advantages like less nausea and vomiting and better post operative pain relief, which helps in early ambulation and discharge from the hospital. Use of nerve stimulator during this block has further enhanced its success and safety profile. Male breast surgery is usually done either under general anaesthesia or local infiltrative anaesthesia combining with intravenous sedation. We postulated that the advantages of TPVB could be helpful for early mobilization and discharge of minor breast surgery in male patients. However, to our knowledge, there is no such report suggestive of TPVB for exclusive male breast surgery. We used nerve stimulator-guided TPVB for gynecomastia surgery in two patients where general anaesthesia was not feasible. Both patients had successful block and showed good post-operative recovery and were discharged on the same day. They had long post-operative pain relief without any block-related complication. A case report of two such cases of gynecomastia surgery (male breast surgery) done under TPVB is presented. PMID- 22923834 TI - Rare iatrogenic airway foreign body: The rivet from the fulcrum of the McCoy laryngoscope blade. PMID- 22923835 TI - Anaesthetic management of a case of Sturge-Webers syndrome. PMID- 22923836 TI - Asystole following craniotomy closure: Yet another complication of negative pressure suctioning of subgaleal drain. PMID- 22923837 TI - An unusual complication of caudal anaesthesia. PMID- 22923838 TI - Stellate ganglion block as a limb salvaging technique. PMID- 22923839 TI - Comment on "Applicability of different scoring systems in outcome prediction of patients with mixed drug poisoning-induced coma". PMID- 22923840 TI - Management of a case of accidental intrathecal administration of meglumine diatrizoate. PMID- 22923841 TI - Management of hypertrophic obstructive cardiomyopathy in prone position. PMID- 22923842 TI - Intra-operative endotracheal tube damage: Anaesthetic challenges. PMID- 22923843 TI - Severe haemodynamic disturbances following normal saline irrigation in cerebro pontine tumour surgery. PMID- 22923844 TI - Anaphylaxis to vecuronium: A rare event. PMID- 22923846 TI - A peculiar complication during trachea-oesophageal fistula repair in a neonate. PMID- 22923845 TI - Treatment of post-operative orchialgia with therapeutic unilateral penile and spermatic cord block. PMID- 22923847 TI - Do we need prolonged local anaesthesia for cataract surgery by phacoemulsification? PMID- 22923848 TI - Haemodynamic and intraocular pressure changes during peribulbar anaesthesia with ropivacaine and clonidine in phacoemulsification cataract surgery. PMID- 22923849 TI - Tranexamic acid in total knee replacement surgeries: Some concerns. PMID- 22923850 TI - A Ruthenium-Catalyzed Coupling of Alkynes with 1,3-Diketones. AB - Ruthenium(III) chloride hydrate is a convenient catalyst for the addition of active methylene compounds to aryl alkynes. These reactions are rapid, operationally simple, and high yielding in cases. Most significantly, no precautions are required to exclude air or water from the reactions. All reagents are commercially available at reasonable prices, and the reactions can be conducted in disposable glassware with minimal solvent. PMID- 22923851 TI - Synthesis of Tetrazolo-Fused Benzodiazepines and Benzodiazepinones by a Two-Step Protocol Using an Ugi-Azide Reaction for Initial Diversity Generation. AB - A two-step strategy for the synthesis of arrays of tricyclic tetrazolo-fused benzodiazepines and benzodiazepinones has been investigated. The protocol uses ortho-N-Boc phenylisocyanides and phenylglyoxaldehydes or ethyl glyoxylate in the 4-component Ugi-Azide reaction to afford MCR (Multi Component Reactions) derived adducts equipped with the desired diversity inputs. A subsequent acidic treatment (TFA/DCE) allows a simultaneous deprotection-cyclization leading to the final products. PMID- 22923852 TI - How Adaptive Learning Affects Evolution: Reviewing Theory on the Baldwin Effect. AB - We review models of the Baldwin effect, i.e., the hypothesis that adaptive learning (i.e., learning to improve fitness) accelerates genetic evolution of the phenotype. Numerous theoretical studies scrutinized the hypothesis that a non evolving ability of adaptive learning accelerates evolution of genetically determined behavior. However, their results are conflicting in that some studies predict an accelerating effect of learning on evolution, whereas others show a decelerating effect. We begin by describing the arguments underlying the hypothesis on the Baldwin effect and identify the core argument: adaptive learning influences the rate of evolution because it changes relative fitness of phenotypes. Then we analyze the theoretical studies of the Baldwin effect with respect to their model of adaptive learning and discuss how their contrasting results can be explained from differences in (1) the ways in which the effect of adaptive learning on the phenotype is modeled, (2) the assumptions underlying the function used to quantify fitness and (3) the time scale at which the evolutionary rate is measured. We finish by reviewing the specific assumptions used by the theoretical studies of the Baldwin effect and discuss the evolutionary implications for cases where these assumptions do not hold. PMID- 22923853 TI - Orangutan Instrumental Gesture-Calls: Reconciling Acoustic and Gestural Speech Evolution Models. PMID- 22923854 TI - Adaptive Programming Improves Outcomes in Drug Court: An Experimental Trial. AB - Prior studies in Drug Courts reported improved outcomes when participants were matched to schedules of judicial status hearings based on their criminological risk level. The current experiment determined whether incremental efficacy could be gained by periodically adjusting the schedule of status hearings and clinical case-management sessions in response to participants' ensuing performance in the program. The adjustments were made pursuant to a priori criteria specified in an adaptive algorithm. Results confirmed that participants in the full adaptive condition (n = 62) were more than twice as likely as those assigned to baseline matching only (n = 63) to be drug-abstinent during the first 18 weeks of the program; however, graduation rates and the average time to case resolution were not significantly different. The positive effects of the adaptive program appear to have stemmed from holding noncompliant participants more accountable for meeting their attendance obligations in the program. Directions for future research and practice implications are discussed. PMID- 22923855 TI - The Dynamics of Self-Esteem in Cognitive Therapy for Avoidant and Obsessive Compulsive Personality Disorders: An Adaptive Role of Self-Esteem Variability? AB - Self-esteem variability is often associated with poor functioning. However, in disorders with entrenched negative views of self and in a context designed to challenge those views, variable self-esteem might represent a marker of change. We examined self-esteem variability in a sample of 27 patients with Avoidant and Obsessive-Compulsive Personality Disorders who received Cognitive Therapy (CT). A therapy coding system was used to rate patients' positive and negative views of self expressed in the first ten sessions of a 52-week treatment. Ratings of negative (reverse scored) and positive view of self were summed to create a composite score for each session. Self-esteem variability was calculated as the standard deviation of self-esteem scores across sessions. More self-esteem variability predicted more improvement in personality disorder and depression symptoms at the end of treatment, beyond baseline and average self-esteem. Early variability in self-esteem, in this population and context, appeared to be a marker of therapeutic change. PMID- 22923856 TI - Coherence and Coreference Revisited. AB - For more than three decades, research into the psycholinguistics of pronoun interpretation has argued that hearers use various interpretation 'preferences' or 'strategies' that are associated with specific linguistic properties of antecedent expressions. This focus is a departure from the type of approach outlined in Hobbs (1979), who argues that the mechanisms supporting pronoun interpretation are driven predominantly by semantics, world knowledge and inference, with particular attention to how these are used to establish the coherence of a discourse. On the basis of three new experimental studies, we evaluate a coherence-driven analysis with respect to four previously proposed interpretation biases-based on grammatical role parallelism, thematic roles, implicit causality, and subjecthood-and argue that the coherence-driven analysis can explain the underlying source of the biases and predict in what contexts evidence for each will surface. The results further suggest that pronoun interpretation is incrementally influenced by probabilistic expectations that hearers have regarding what coherence relations are likely to ensue, together with their expectations about what entities will be mentioned next, which, crucially, are conditioned on those coherence relations. PMID- 22923857 TI - Will They Stay? Foreign-Born Out-Migration from New U.S. Destinations. AB - Immigrants living in new destinations in 1995 were 2.5 times more likely to have migrated to another labor market by 2000 as immigrants living in traditional places. The researchers look at two competing explanations for immigrants' differential internal migration patterns, namely that immigrants prefer areas with relatively large nativity concentrations which provide them with social support versus immigrants are target earners who prefer robust labor markets with strong employment growth and high wages. Utilizing confidential Census data for 1990 and 2000, the authors develop new destination classifications for 741 labor markets that take into account the differential growth and composition characteristics of 24 Asian, Latin American and Caribbean immigrant groups living in those markets. The empirical analysis of labor market out-migration indicates that immigrants do not see internal migration as an either/or choice between economics and social support but prefer residence places that allow them to maximize both conditions. PMID- 22923858 TI - End-of-semester syndrome: How situational regulatory fit affects test performance over an academic semester. AB - Psychology researchers often avoid running participants from subject pools at the end of the semester because they are "unmotivated". We suggest that the end of the semester induces a situational prevention focus (i.e., sensitive to losses) unlike the beginning of the semester, which may induce a situational promotion focus (i.e., sensitive to gains). In two experiments, we presented participants with math problems at the beginning or end of an academic semester. End-of semester participants performed better minimizing losses as compared to maximizing gains, while the opposite was true for beginning-of-semester participants. PMID- 22923859 TI - A Review on the Taxonomy, Ethnobotany, Chemistry and Pharmacology of Oroxylum indicum Vent. AB - Oroxylum indicum Vent. (O. indicum) is a tree commonly called Indian trumpet tree found in tropical countries, such as India, Japan, China, Sri Lanka, Malaysia. The chemical constituents obtained from different parts of plant include baicalein-7-O-diglucoside (Oroxylin B), baicalein-7-O-glucoside, chrysin, apegenin, prunetin, sitosterol, oroxindin, biochanin-A, ellagic acid, baicalein and its 6- and 7-glucuronides, scutellarein, tetuin, antraquinone and aloe emodin. Various parts of the plant are used in Ayurveda and folk medicine for the treatment of different ailments such as cancer, diarrhea, fever, ulcer and jaundice. Recent in vivo and in vitro studies have indicated its antiinflammatory, antiulcer, hepatoprotective, anticancer, antioxidant, photocytotoxic, antiproliferative, antiarthritic, antimicrobial, antimutagenic and immunostimulant properties. Exhaustive literature survey reveals that there are some activities which are still not proven scientifically. This article is an attempt to compile an up-to-date and comprehensive review on O. indicum covering its traditional and folk medicinal uses, phytochemistry and pharmacology. PMID- 22923860 TI - Formulation design and optimization of fast dissolving clonazepam tablets by sublimation method. AB - Fast dissolving tablets of clonazepam were prepared by sublimation method with a view to enhance patient compliance. A 3(2) full factorial design was applied to investigate the combined effect of two formulation variables: amount of croscarmellose sodium and camphor. Croscarmellose sodium (2-8% w/w) was used as superdisintegrant and camphor (20-40% w/w) was used as subliming agent, to increase the porosity of the tablets, since it helps water to penetrate into the tablets, along with directly compressible mannitol to enhance mouth feel. The tablets were evaluated for hardness, friability, thickness, drug content uniformity, in vitro dispersion time, wetting time and water absorption ratio. Based on in vitro dispersion time (approximately 11 s); the formulation containing 5% w/w croscarmellose sodium and 40% w/w camphor was found to be promising and tested for in vitro drug release pattern (in pH 6.8 phosphate buffer). Short-term stability (at 40 degrees /75% relative humidity for 3 mo) and drug-excipient interaction. Surface response plots are presented to graphically represent the effect of independent variables on the in vitro dispersion time. The validity of the generated mathematical model was tested by preparing two extra-design checkpoints. The optimized tablet formulation was compared with conventional commercial tablet formulation for drug release profiles. This formulation showed nearly nine-fold faster drug release (t(50%) 1.8 min) compared to the conventional commercial tablet formulation (t(50%) 16.4 min). Short-term stability studies on the formulation indicated that there are no significant changes in drug content and in vitro dispersion time (P<0.05). PMID- 22923861 TI - Brain targeted transcranial administration of diazepam and shortening of sleep latency in healthy human volunteers. AB - Application of medicated oils on scalp had been practiced for centuries in the Ayurvedic system of medicine in diseases associated with the central nervous system. It is possible that the effectiveness of the therapy may be a result of targeted delivery of active compounds to the brain transcranially. Evidence also comes from two previous studies with positive results on brain targeted transcranial delivery of methadone base and diazepam on rat models. Possibility of transcranial drug delivery was investigated in healthy human volunteers using electroencephalography techniques by assessing the ability of transcranially administered diazepam in bringing about beta activity in the electroencephalographic wave patterns and shortening of the sleep latency period. Non polar drug molecules dissolved in a non-aqueous sesame oil based vehicle is a significant feature in the transcranial dosage design. The study was under taken in two phases. In the Phase-I study scalp application of a single dose of 2 mg/3 ml of the oil was employed and in the Phase-II study repeat application of three doses 24 h apart were employed. Sleep latency changes were monitored with Multiple Sleep Latency Tests with 5 naps employing the standard electroencephalography, electroocculography and electromyography electrodes. Sleep onset was identified with the first epoch of any sleep stage non rapid eye movement 1, 2, 3, 4 or rapid eye movement using electroencephalography, electroocculography and electromyography criteria. In both phases of the study there was significant reduction in the sleep latencies. It was much more pronounced in the Phase-II study. None of the subjects however displayed beta activity in the electroencephalography. Sleep latency reduction following scalp application in both the phases are suggestive of transcranial migration of diazepam molecules to the receptor sites of the nerve tissue of the brain eliciting its pharmacological effect of sedation. Transcranial brain targeted dosage design is therefore feasible. PMID- 22923862 TI - Ionotropically Gelled Novel Hydrogel Beads: Preparation, Characterization and In vitro Evaluation. AB - Prolonged release drug delivery system of stavudine was made by ionotropic gelation and polyelectrolyte complexation technique. Cross-linking reinforced chitosan-gellan complex beads were prepared by gelation of anionic gellan gum, the primary polymer, with oppositely charged counter ion to form beads which were further complexed with chitosan as a polyelectrolyte. The effect of this polymer on release profile of drug was studied. Beads without chitosan complexation were also made. The reaction of chitosan-gellan complex dominates the formation of skin layer on the surface of beads. Stavudine an antiretroviral drug was selected as novel drug for the experiment. The final formulations were subjected to in vitro evaluation and several characterization studies. Batches with gellan gum shows Higuchi model, while chitosan-gellan shows zero order release. All the batches with copolymer showed sustained the drug release more than 12 h, whereas with gellan gum alone showed up to 10 h. Batches with chitosan showed maximum drug encapsulation efficiency. PMID- 22923863 TI - Two Formulations of Venlafaxine are Bioequivalent when Administered as Open Capsule Mixed with Applesauce to Healthy Subjects. AB - Venlafaxine is a unique antidepressant approved for treatment of various depressive disorders. A single dose, cross-over bioequivalence study was performed with two different formulations of venlafaxine 150 mg extended-release capsules in which the contents of capsule were mixed with applesauce and administered to healthy subjects under fed condition. A total of 24 healthy adult male subjects participated in this randomized, single-dose, non-blinded, two-way crossover study conducted at a single centre and 23 subjects completed the study as per the study protocol. After an overnight fast of 10 h, a high-fat and high calorie breakfast was served 30 min before dosing. The subjects then received a single dose of either formulation administered with apple sauce followed by 240 ml of water as per randomized schedule in each period separated by a washout period of 7 days. A series of blood samples were collected upto 72 h for estimation of venlafaxine and its active metabolite, O-desmethylvenlafaxine. The quantification of venlafaxine and O-desmethylvenlafaxine was done by LC-MS/MS method and pharmacokinetic and statistical analysis by WinNonlin((r)) 5.2 and SAS((r)) 9.1.3. The results of the study demonstrated bioequivalence of two formulations as the 90% confidence interval for the intra-individual mean ratio of log-transformed C(max), AUC(0-t) and AUC(0-inf) of the test to the reference formulation were found within the defined bioequivalence range of 80.00%-125.00%. Both the formulations were well tolerated. This alternative mode of administration may provide benefits to patients who have difficulty in swallowing the capsule as a whole. PMID- 22923864 TI - Improvement of solubility and dissolution properties of clotrimazole by solid dispersions and inclusion complexes. AB - Solid dispersions of a slightly water-soluble drug, clotrimazole, were prepared in different weight ratios using polyethyleneglycol 4000 and different molecular weight polyvinyl pyrrolidones as carriers. Moreover, binary and ternary beta cyclodextrin complexes were prepared in different molar ratios. Both solid dispersions and beta-cyclodextrin complexes were prepared by solvent evaporation technique. A phase solubility method was used to evaluate the effect of the tested carriers on the aqueous solubility of clotrimazole. The dissolution of all the preparations was tested using the USP paddle method. The selected solid dispersions and inclusion complexes were characterized by differential scanning calorimetry and X-ray powder diffractometry studies, and results clarified the role of the tested carriers in decreasing the crystallinity of clotrimazole and complexing abilities. Based on physical characters and in vitro drug release pattern, polyvinylpyrrolidone solid dispersions (1:1 weight ratio) and ternary cyclodextrin complexes (clotrimazole-beta-cyclodextrin complexes with either polymer, 1:1 molar ratio) were selected as ideal batches for suppositories. Suppocire AM/50 mg carbopol 940, was chosen as a suppository base and the suppositories were prepared by molding technique. The prepared suppositories were characterized for weight variation, softening time and drug content. All these properties were found to be ideal. The in vitro drug release pattern was determined in citrate buffer (pH 4.5) containing 1% sodium lauryl sulfate. The in vitro release of clotrimazole from its solid dispersions and inclusion complexes incorporated suppositories was markedly improved when compared to the intact drug incorporated suppositories. Polyvinyl pyrrolidone solid dispersions incorporated suppositories were found to possess excellent antifungal activity. PMID- 22923865 TI - Development and validation of new discriminative dissolution method for carvedilol tablets. AB - The objective of the present study was to develop and validate a discriminative dissolution method for evaluation of carvedilol tablets. Different conditions such as type of dissolution medium, volume of dissolution medium and rotation speed of paddle were evaluated. The best in vitro dissolution profile was obtained using Apparatus II (paddle), 50 rpm, 900 ml of pH 6.8 phosphate buffer as dissolution medium. The drug release was evaluated by high-performance liquid chromatographic method. The dissolution method was validated according to current ICH and FDA guidelines using parameters such as the specificity, accuracy, precision and stability were evaluated and obtained results were within the acceptable range. The comparison of the obtained dissolution profiles of three different products were investigated using ANOVA-based, model-dependent and model independent methods, results showed that there is significant difference between the products. The dissolution test developed and validated was adequate for its higher discriminative capacity in differentiating the release characteristics of the products tested and could be applied for development and quality control of carvedilol tablets. PMID- 22923866 TI - Effects of D-003 on Lipopolysaccharides-induced Osteonecrosis in Rabbits. AB - D-003, a mixture of high molecular weight acids, inhibits cholesterol synthesis prior to mevalonate and prevents osteoporosis induced by ovariectomy in rats, and both osteoporosis and osteonecrosis induced by corticoids in rats. The aim of this study was to investigate effects of D-003 on lipopolysaccharides-induced osteonecrosis in rabbits. Animals were randomized into 5 groups: a sham and four groups injected with lipopolysaccharides: one treated orally with vehicle and three with D-003 (5, 25 and 200 mg/kg, respectively) during four weeks. We assessed the effects of treatments on the incidence of osteonecrosis (number of animals with osteonecrosis lesions/animals per group), the mean numbers and areas of osteonecrosis per animal and on the mean sizes of the bone marrow fat cells. The incidence of osteonecrosis in the groups of D-003 25 and 200 mg/kg was significantly lower than in the positive controls. The reduction of osteonecrosis increased with the doses, but significant dose-dependence relationship was not achieved. D-003 significantly and dose-dependently decreased the number of osteonecrosis lesions per animal as compared to the positive controls. Likewise, the mean osteonecrosis areas in the proximal femoral and humeral bones were significantly decreased by D-003. The injection of lipopolysaccharides significantly increased the average size of bone marrow fat cells as compared to the negative controls, and such increase was significantly and markedly reduced with D-003. It is concluded that D-003 reduced the incidence, number and percent areas of osteonecrosis lesions, and the size of bone marrow fat cells, a marker of adipogenesis, in rabbits with lipopolysaccharides-induced ostenonecrosis. PMID- 22923867 TI - Formulation and development of metered dose inhalations of salbutamol in solution form. AB - In the present study attempts were made to prepare metered dose inhalation of salbutamol in solution form and compared it with the marketed metered dose inhalation in suspension form. Solution form of the drug was found better than marketed suspension formulation with respect to homogeneity and content uniformity. Propellant blend P-11 and P-12 in the proportion 30:70 was selected as it gave optimum vapour pressure. Surfactant oleic acid in concentration 10 mg per can was selected as it gave best results with clarity, spray pattern, vapour pressure, content per spray and rate of evaporation. Ethyl alcohol 2 ml per can was used as a cosolvent to give a clear solution, optimum vapour pressure, maximum content per spray and fair rate of evaporation. The selected formulation was subjected to the physico-chemical evaluation tests as per the standard pharmacopoeial procedures and the characteristics of the formulations were further compared with a conventional marketed formulation. In vitro study reveled the net respirable fraction was better than marketed preparation. PMID- 22923868 TI - A biochemical study on the gastroprotective effect of andrographolide in rats induced with gastric ulcer. AB - The major objective of the study was to evaluate the gastroprotective property of andrographolide, a chief component of the leaves of Andrographis paniculata in terms of the ulcer preventive effect in rats. An acute toxicity test was conducted with different concentrations of andrographolide to determine the LD(50) value. The dose responsive study was conducted in rats pretreated with andrographolide (1, 3 and 5 mg/kg) for a period of 30 days, prior to ulcer induction by administering ethanol, aspirin or by pyloric ligation. The ulcer protective efficacy was tested by determining the ulcer score, pH, pepsin, titrable acidity, gastric mucin, lipid peroxides, reduced glutathione, and enzymatic antioxidants superoxide dismutase, catalase and glutathione peroxidase in gastric tissue. The activities of H(+)-K(+) ATPase and myeloperoxidase were also determined in gastric tissue. The LD(50) value was found to be 48 mg/kg b. wt and the effective dose was found to be 3 mg/kg. We have observed a significant reduction in the ulcer score in rats pretreated with 3 mg of andrographolide/kg body weight. A favourable increase in the pH and decrease in titrable acidity were observed in the gastric fluid of rats pretreated with the test drug. The gastric tissue H(+)-K(+) ATPase and myeloperoxidase activities were elevated in ulcer-induced animals. The elevation in the enzyme activity was significantly minimized in the andrographolide received animals. The antioxidants and mucin levels were significantly maintained in the gastric tissue of drug-pretreated animals. Andrographolide did not produce any toxic effects in normal rats. This study reveals that the ulcer preventive efficacy of andrographolide may probably due to its antioxidant, cytoprotective and antiacid secretory effects. PMID- 22923869 TI - Development and validation of liquid chromatography-mass spectrometry method for the estimation of rifampicin in plasma. AB - A selective, rapid and sensitive liquid chromatography-mass spectrometry method was developed for the quantitative estimation of rifampicin in plasma. With phenacetin as internal standard, sample pretreatment involved a one-step extraction with ethyl acetate from plasma. The sample was analyzed using methanol: 2mM ammonium acetate: 80:20 v/v as mobile phase. Chromatographic separation was achieved on a BDS Hypersil Gold C(18) column which was followed by detection with mass spectrometry. Linear calibration curves were obtained in the concentration range of 5.021-1008.315 ng/ml. The inter- and intra-day accuracy values were below 15% at all quality control levels. Percent recoveries for rifampicin at high, middle and low quality control samples was obtained 55.15, 48.65 and 49.62%, respectively and for internal standard was 60.22%. Rifampicin was found stable through all validation parameters. Developed method was found to be simple, precise, accurate and rapid for estimation of rifampicin in plasma. Thus, the method can be employed for routine pharmacokinetic and bioequivalence studies. PMID- 22923870 TI - A Validated HPLC Method for Zanamivir and its Application to In vitro Permeability Study in Caco-2 Culture Model. AB - A simple HPLC method was developed and validated for the quantification of zanamivir in permeability studies using Caco-2 cell culture model. Chromatographic resolution was achieved using 98% (v/v) ultrapure water and 2% (v/v) acetonitrile as mobile phase with flow rate of 0.5 ml/min on a BDS Hypersil Cyano column (length 250 mm; internal diameter 4.6 mm; particle size 5 MUm) and UV detection at 230 nm. The method was linear for the quantification of zanamivir at concentration ranging from 0.1-10 MUg/ml with coefficient of determination greater than 0.999. The recovery of zanamivir was in the range of 99.76-105.08%. The relative standard deviations of the within-day precision and between-day precision were lower than 10.32 and 14.33%, respectively. The permeability of zanamivir was independent of the transport direction and zanamivir concentrations, indicating a passive transport of zanamivir across Caco-2 cells. With the absence of Ca(2+) in transport medium, the permeability values of zanamivir increased 56.21 and 57.20 fold in the directions of apical to basolateral and basolateral to apical, respectively. On the basis of these results, zanamivir was found to be predominantly transported across Caco-2 monolayers via the passive paracellular pathway. PMID- 22923871 TI - Development and Validation of a UV Spectrophotometric Method for the Simultaneous Estimation of Eprosartan Mesylate and Hydrochlorothiazide in Bulk and Formulations. AB - A simple, efficient, precise and accurate absorbance ratio method have been developed for the estimation of eprosartan mesylate and hydrochlorothiazide in pure and in fixed dose combination. In this method, UV spectra of eprosartan mesylate and hydrochlorothiazide were overlayed which involves the formation of Q absorbance equation at 249.1 nm (isobestic point) and 274.5 nm, the max of hydrochlorothiazide. Both the drugs obeyed Beers law in the concentration range of 6-36 MUg/ml and 1-10 MUg/ml for eprosartan mesylate and hydrochlorothiazide, respectively. The accuracy of the method was determined by recovery studies and was found to be in the range of 102.29-103.10% and 99.52-101.60% for eprosartan mesylate and hydrochlorothiazide, respectively. The method was validated as per ICH guidelines and statistically. The method showed good reproducibility and recovery with % RSD less than 2. The method was found to be simple, economic, accurate and reproducible and can be used for routine analysis of eprosartan mesylate and hydrochlorothiazide in pure and in fixed dose combinations. PMID- 22923872 TI - Antiulcer Activity of Hydroalchol Extract of Momordica dioica roxb. Fruit. AB - The present study was carried out to evaluate antiulcer activity of hydroalcohol extract of Momordica dioica Roxb. fruit. Momordica dioica Roxb. fruit extract (100, 200 and 400 mg/kg body weight) was administered orally, twice daily for 5 days for prevention from ethanol, cold-restraint stress and pylorus ligation induced ulcers. Estimation of H(+)-K(+) ATPase activity and gastric wall mucous were performed in ethanol-induced ulcer model, antioxidant enzyme activities was carried out in cold-restraint stress-induced ulcer model, and various gastric secretion parameters like volume of gastric juice, acid output, and pH value were estimated in pylorus ligation-induced ulcer model. A significant reduction in lesion index was observed in ulcer-induced animals pre treated with extract at different doses when compared with ulcerated rats in all models. A significant decrease occurred in the level of H(+)-K(+) ATPase, volume of gastric juice, and acid output. Gastric wall mucus and pH were increased significantly. These showed dose-dependent action of extract. LPO and antioxidant enzyme levels of SOD were decreased, but CAT enzyme showed significant increase. Thus the results indicate that the Momordica dioica extract possess antiulcerogenic effect, that attributable to augmentation of gastric defense mechanisms. PMID- 22923873 TI - Development and Validation of a RP-HPLC Method for Estimation of Prulifloxacin in Tablet Dosage Form. AB - A simple, precise, rapid, accurate and economic reverse phase high performance liquid chromatographic method has been developed for the estimation of prulifloxacin in tablet dosage form. The separation was achieved by using octadecylsilane column (C(18)) and KH(2)PO(4) buffer: acetonitrile adjusted to pH 7.3 with triethyl amine in proportion of 10:90 v/v as mobile phase, at a flow rate of 1.0 ml/min. The detection was carried out at 278 nm. The retention time of prulifloxacin was found to be 2.4 min. The limit of detection and limit of quantitation were found to be 0.14 MUg/ml and 0.42 MUg/ml respectively. The accuracy and reliability of the proposed method was ascertained by evaluating various validation parameters like linearity, precision, accuracy and specificity according to ICH guidelines. The proposed method provides an accurate and precise quality control tool for routine analysis of prulifloxacin in tablet dosage form. PMID- 22923874 TI - Spectrophotometric Determination of Poorly Water Soluble Drug Rosiglitazone Using Hydrotropic Solubilization technique. AB - In the present investigation, hydrotropic solution of urea was employed as a solubilizing agent for spectrophotometric determination of poorly water-soluble drug rosiglitazone maleate. In solubility determination study, it was found that there was more than 14-folds enhancement in solubility of rosiglitazone maleate in a 6M solution of urea. Rosiglitazone maleate obeys Beer's law in concentration range of 5-300 MUg/ml. Linearity of rosiglitazone maleate was found in the range of 80-120% of the label claim. The proposed method has been applied successfully to the analysis of the cited drug in pharmaceutical formulations with good accuracy and precision. The method herein described is new, simple, eco-friendly, economic, and accurate and can be utilized in routine analysis of rosiglitazone maleate in bulk drug and tablet dosage form. PMID- 22923875 TI - Simultaneous voltammetric determination of nitazoxanide and ofloxacin in pharmaceutical formulation. AB - A simple, sensitive and highly selective electrochemical method was developed for the simultaneous determination of nitazoxanide and ofloxacin in aqueous media (Britton-Robinson buffer, pH-8.36) on a hanging mercury drop electrode (HMDE) using differential pulse polarography (DPP). Using DPP a separation of about 936 mV between the peak oxidation potentials of nitazoxanide and ofloxacin present in binary mixtures was obtained. The quantification limits for the simultaneous determination of nitazoxanide and ofloxacin were 0.083 MUg/ml and 0.208 MUg/ml, respectively. The proposed method was successfully applied for the simultaneous determination of nitazoxanide and ofloxacin in bulk drug and pharmaceutical tablet formulation. PMID- 22923876 TI - Synthesis and Antimicrobial Activity of Some New 2-(3-(4-Aryl)-1-phenyl-1H pyrazol-4-yl) Chroman-4-ones. AB - Seven new 2-(3-(4-aryl)-1-phenyl-1H-pyrazol-4-yl) chroman-4-ones (4a-4g) have been synthesized by cyclization of 2-hydroxychalcone analogues of pyrazole 3a-3g using conc. HCl in acetic acid. The structures of the compounds 4a-4g were established by the combined use of (1)HNMR, IR and mass spectra. All the seven compounds were tested in vitro for their antibacterial activity against two Gram positive bacteria namely Staphylococcus aureus and Bacillus subtilis and two Gram negative bacteria Escherichia coli and Pseudomonas aeruginosa. The compounds 4b, 4c, 4e, 4f, 4g have displayed good antibacterial activity when compared with commercially available antibiotic, ciprofloxacin. These compounds also were screened for their antifungal activity against two ear pathogenic fungi, namely Aspergillus Niger and A. flavus. The compounds 4a, 4c, 4d, 4g exhibited good antifungal activity when compared with commercially available antifungal, fluconazole. PMID- 22923877 TI - Out-patients Prescriptions are Safe from Drug Interactions or Not: A Pilot Study Report. AB - The objective of the research work was to analysis the out patients drug interactions and alerts the healthcare professionals to prevent the future complications. The study was done in three pharmacies within a 200 meters distance of each other. The doctors involved were made aware of the study but data were collected without their knowledge. All prescriptions presented to the three pharmacies were analyzed during the five-month study period. A total of 500 prescriptions were analyzed and 64 drug-drug interactions were detected giving a drug-drug interaction rate of 12.8 percent but 436 (87.2%) prescriptions are free from drug interactions. Moderate drug interactions were found in 10.2%, Severe were 2.6% and contraindicated were 0% and also disease wise drug interaction analysis were carried out during the study results, more number of drug interactions reported in central nerves system followed by diabetes mellitus. Outpatient visits resulted in minimal numbers of clinically important drug-drug interactions, these interactions can have significant implications due to medication-related morbidity and mortality. Pharmacists can play a critical role in managing the medication therapy of patients at risk for clinically important drug-drug interactions. PMID- 22923878 TI - Synthesis and Pharmacological Activities of Some New 5-Substituted-2-mercapto 1,3,4-oxadiazoles. AB - In this study, various 5-beta-[(N-benzenesulphony/tosyl)-4-(un) substituted anilino]ethyl-2-mercapto-1,3,4-oxadiazole (4a-f), with sulphonamide moiety at the side chain have been synthesised. The structures of the newly synthesised compounds have been established on the basis of their spectral data and elemental analysis. All the compounds were screened for antimicrobial activities against Escherichia coli, Bacillus cirroflagellosus, Aspergillus niger. Colletotrichum capsici and antituberclosis activity against Mycobacterium tuberculosis H37Rv strain. Only two compounds 4b (73%) and 4e (54%), have shown moderate antituberculosis activity. All the compounds have shown moderate antiinflamatory activity and least ulcerogenecity. Most of the compounds have shown significant analgesic activity (64.20-120.72%) in comparison with the standard, Aspirin (49.39%) In the MES method, however only compound 4a, exhibited a protection of 33.33%, and others failed to protect. PMID- 22923879 TI - AphasiaBank: Methods for Studying Discourse. AB - BACKGROUND: AphasiaBank is a computerized database of interviews between persons with aphasia (PWAs) and clinicians. By February 2011, the database had grown to include 145 PWAs and 126 controls from 12 sites across the United States. The data and related analysis programs are available free over the web. AIMS: The overall goal of AphasiaBank is the construction of a system for accumulating and sharing data on language usage by PWAs. To achieve this goal, we have developed a standard elicitation protocol and systematic automatic and manual methods for transcription, coding, and analysis. METHODS #ENTITYSTARTX00026; PROCEDURES: We present sample analyses of transcripts from the retelling of the Cinderella story. These analyses illustrate the application of our methods for the study of phonological, lexical, semantic, morphological, syntactic, temporal, prosodic, gestural, and discourse features. MAIN CONTRIBUTION: AphasiaBank will allow researchers access to a large, shared database that can facilitate hypothesis testing and increase methodological replicability, precision, and transparency. CONCLUSIONS: AphasiaBank will provide researchers with an important new tool in the study of aphasia. PMID- 22923880 TI - Cats of the Pharaohs: Genetic Comparison of Egyptian Cat Mummies to their Feline Contemporaries. AB - The ancient Egyptians mummified an abundance of cats during the Late Period (664 332 BC). The overlapping morphology and sizes of developing wildcats and domestic cats confounds the identity of mummified cat species. Genetic analyses should support mummy identification and was conducted on two long bones and a mandible of three cats that were mummified by the ancient Egyptians. The mummy DNA was extracted in a dedicated ancient DNA laboratory at the University of California - Davis, then directly sequencing between 246 and 402 bp of the mtDNA control region from each bone. When compared to a dataset of wildcats (Felis silvestris silvestris, F. s. tristrami, and F. chaus) as well as a previously published worldwide dataset of modern domestic cat samples, including Egypt, the DNA evidence suggests the three mummies represent common contemporary domestic cat mitotypes prevalent in modern Egypt and the Middle East. Divergence estimates date the origin of the mummies' mitotypes to between two and 7.5 thousand years prior to their mummification, likely prior to or during Egyptian Predyanstic and Early Dynastic Periods. These data are the first genetic evidence supporting that the ancient Egyptians used domesticated cats, F. s. catus, for votive mummies, and likely implies cats were domesticated prior to extensive mummification of cats. PMID- 22923881 TI - The simple view of second language reading throughout the primary grades. AB - In the Simple View of Reading proposed by Hoover and Gough (1990), reading comprehension is conceived as the product of word decoding and listening comprehension. It is claimed that listening comprehension or the linguistic processes involved in the comprehension of oral language strongly constrain the process of reading comprehension. In several studies, evidence for this theoretical framework has been provided for first language learners. In the present study, an attempt was made to find empirical evidence for the same view underlying second language reading. Therefore, the word decoding and listening comprehension skills of samples of 1,293 first language (L1) learners and 394 second language (L2) learners of Dutch were related to their reading comprehension abilities throughout the primary grades. It was found that the levels of word decoding were more or less equal in the two groups of learners, whereas the L2 learners stayed behind their first L1 peers in both listening, and reading comprehension. The relationships between word decoding, listening comprehension and reading comprehension turned out to be highly comparable. A longitudinal analysis of data showed the Simple View of Reading to be equally valid for L1 and L2 learners. With progression of grade, the impact of word decoding on reading comprehension decreased, whereas the impact of listening comprehension showed an increase to the same extent in the two groups of learners. However, the reciprocity of the relationship between listening comprehension and reading comprehension tended to be less prominent in the group of L2 learners. PMID- 22923882 TI - High Resolution Non-contact Fluorescence Based Temperature Sensor for Neonatal Care. AB - To date, thermistors are used to continuously monitor the body temperature of newborn babies in the neonatal intensive care unit. The thermistor probe is attached to the body with a strong adhesive tape to ensure that the probe stays in place. However, these strong adhesives are shown to increase microbial growth and cause serious skin injuries via epidermal stripping. The latter compromises the skin's ability to serve as a protective barrier leading to increase in water loss and further microbial infections. In this article a new approach is introduced that eliminates the need for an adhesive. Instead, two kinds of fluorophores are entrapped in a skin friendly chitosan gel that can be easily wiped on and off of the skin, and has antimicrobial properties as well. A CCD camera is used to detect the temperature dependent fluorescence of the fluorophore, tris(1,10-phenthroline)ruthenium(II) while 8-aminopyrene-1,3,6 trisulfonic acid serves as the reference. This temperature sensor was found to have a resolution of at least 0.13 degrees C. PMID- 22923883 TI - Walking with the new JOMFP. PMID- 22923884 TI - Collagen in histologic stages of oral submucous fibrosis: A polarizing microscopic study. AB - BACKGROUND: Oral submucous fibrosis (OSF) is a precancerous condition in which there is excessive deposition of collagen in connective tissue. The purpose of present study was to compare changes in birefringence of collagen fibers in histopathological stages of OSF. MATERIALS AND METHODS: Collagen in connective tissue of 91 cases of OSF was studied by staining 5 MUm thick sections with picrosirius red. The polarization colors of thin (0.8 MUm or less) and thick (1.6 2 MUm) collagen fibers were recorded. RESULTS: The birefringence of thin collagen fibers showed no difference in both histopathological connective tissue stages and degrees of epithelial dysplasia. The polarization colors of thick collagen fibers showed a gradual change from predominantly yellow-orange to greenish yellow in advancing connective tissue stages and degrees of epithelial dysplasia. CONCLUSION: The results of present study show a significant change in birefringence of collagen between connective tissue stages and between mild, moderate to severe degree of epithelial dysplasia. This change in birefringence colors and arrangement of collagen fibers may give an implication of impending neoplastic change in OSF. PMID- 22923885 TI - Cysts of the oro-facial region: A Nigerian experience. AB - AIM: Though many studies have examined cysts of the jaws, most of them focused on a group of cysts and only few have examined cysts based on a particular classification. The aim of this study is to review cysts of the oro-facial region seen at a tertiary health centre in Ibadan and to categorize these cases based on Lucas, Killey and Kay and WHO classifications. MATERIALS AND METHODS: All histologically diagnosed oro-facial cysts were retrieved from the oral pathology archives. Information concerning cyst type, topography, age at time of diagnosis and gender of patients was gathered. Data obtained was analyzed with the SPSS 18.0.1 version software. RESULTS: A total of 92 histologically diagnosed oro facial cysts comprising 60 (65.2%) males and 32 (34.8%) females were seen. The age range was 4 to 73 years with a mean age of 27.99 +/- 15.26 years. The peak incidence was in the third decade. The mandible/ maxilla ratio was 1.5:1. Apical periodontal was the most common type of cyst accounting for 50% (n = 46) of total cysts observed. Using the WHO classification, cysts of the soft tissues of head, face and neck were overwhelmingly more common in males than females with a ratio of 14:3, while non-epithelial cysts occurred at a 3:1 male/female ratio. CONCLUSION: This study showed similar findings in regard to type, site and age incidence of oro-facial cysts compared to previous studies and also showed that the WHO classification protocol was the most comprehensive classification method for oro-facial cysts. PMID- 22923886 TI - Expression of p53 and Cyclin D1 in oral squamous cell carcinoma and normal mucosa: An Immunohistochemical study. AB - AIM: To assess p53 and Cyclin D1 expression using Immunohistochemistry in normal mucosa and oral squamous cell carcinoma. MATERIALS AND METHODS: Twenty cases of Oral squamous cell carcinoma (OSCC) and 10 normal mucosa were used and the primary antibodies used were p53 (DAKO-DO7) and Cyclin D1 Mouse Anti human Cyclin D1 (DCS-6) 1: 100 dilution. STATISTICAL ANALYSIS: Labelling index was calculated and mean LI and SD were calculated, using Descriptive Statistics and t-test was used to compare mean LI between antibodies used in OSCC. Percentage positivity was done by Chi-Square test. Comparison of LI between p53 and Cyclin D1 was studied using t test. RESULTS: p53 was positive in 30% and Cyclin D1 in40% of normal cases and 65% and 95% of OSCC were positive for p53 and Cyclin D1 respectively. Mean LI of p53 and Cyclin D1 were found to be statistically significant between the normal mucosa and OSCC. The correlation of mean LI of p53 and Cyclin D1 in OSCC was found to be statistically significant. LI of p53 was found to be higher than Cyclin D1 in OSCC. CONCLUSION: In the present study, increased p53 and Cyclin D1 expression were seen in OSCC when compared to the normal mucosa and a positive correlation was seen between increased p53 and Cyclin D1 expression in OSCC. PMID- 22923887 TI - Salivary copper and zinc levels in oral pre-malignant and malignant lesions. AB - Recent technological advances have made saliva as a tool for diagnosis of many things; among them are hormone imbalances, liver function, immunodeficiency and even cancer. AIM: The present study was done to evaluate the levels of copper and zinc and copper/zinc ratio in saliva of premalignant and malignant lesions of oral cavity, because of the anatomical proximity of the saliva to both premalignant and malignant oral neoplasms. MATERIALS AND METHODS: The levels of copper and zinc were estimated in the saliva of 5 patients with oral submucous fibrosis, 5 patients with oral leukoplakia, 5 patients with oral lichen planus and 10 patients with oral squamous cell carcinoma of oral cavity using inductively coupled mass spectrometry (ICP- MS). The values were compared with 6 normal age and sex matched control subjects. RESULTS: There was significant difference of the mean salivary copper and zinc levels of premalignant and malignant lesions when compared to the normal controls. In oral cancer patients there was significant difference in the copper levels according the histodifferentiaton in squamous cell carcinoma. Within the premalignant group the copper levels were more in the oral sub mucous fibrosis when compared to the leukoplakia and lichen planus. Copper zinc ratio decreased in premalignant and malignant group when compared to the normal group. CONCLUSIONS: Saliva may be used as a potential diagnostic tool, which can be efficiently employed to evaluate the copper and zinc levels in pre malignant and malignant lesions of oral cavity. Key words: Copper, inductively couples mass spectrometry, leukoplakia, lichen planus, oral squamous cell carcinoma, oral submucous fibrosis, saliva, zinc. PMID- 22923888 TI - Expression of epithelial growth factor receptor in oral epithelial dysplastic lesions. AB - AIM: The aim of the study was to assess the expression of epithelial growth factor receptor (EGFR) in normal oral mucosa and varying grades of oral epithelial dysplasia (OED) and to correlate these findings, with clinicopathologic features and findings on routine hematoxylin and eosin-stained (H and E) sections. MATERIALS AND METHODS: Twenty-nine formalin-fixed, paraffin embedded blocks of various grades of OED and 10 normal mucosa were stained with routine H and E and immunostained with EGFR by avidin-biotin method. RESULTS: The results showed a significant increase in the staining reactions in varying grades of dysplasia as compared with normal mucosa. CONCLUSION: EGFR can be considered as an early marker of a cell proliferation and maturation as well as early marker of epithelial dysplasia and onset of cancer in oral dysplasia. However, further studies with a larger sample size and continuous followup is suggested to determine its role and significance precisely. PMID- 22923889 TI - Altered expression of HSP70 in oral lichen planus. AB - BACKGROUND: Oral lichen planus (OLP), a well-known mucocutaneous lesion has been the center of debate regarding its obscure etiopathogenesis. Recent highlight has been placed on the role of autoimmunity and a sect of constitutional molecules, the native chaperones HSP70, proposed to be important in the onset and progress of disease. AIM: To substantiate a potential role of HSP70 in the pathogenesis of oral lichen planus. SETTINGS AND DESIGN: The study involved immunohistochemical (IHC) analyses in a laboratory under monitored conditions. It was a retrospective study on clinically and histopathologically confirmed specimens. MATERIALS AND METHODS: 30 samples of confirmed cases of OLP were selected and grouped on the basis of the thickness of the epithelial layer into atrophic, normal (classical) and acanthotic. An immunohistochemical analysis of the expression of HSP70 protein was done, followed by a quantitative and qualitative analysis of the stained layers. STATISTICAL ANALYSES: A Z test was performed to estimate the difference observed between two sample proportions. The statistics was given at 1% level of significance i.e. P<0.01. RESULTS: An increased expression of HSP70 was noted in the basal and suprabasal cells of the epithelium of OLP. A higher count and intensity of HSP70 expression was seen in the basal layer of the epithelium. Greater expression was noted in the epithelium of the atrophic group. CONCLUSION: The expression pattern of HSP70 positively implicates it in the pathogenesis of OLP. PMID- 22923890 TI - Oral manifestations of human immunodeficiency virus in children: An institutional study at highly active antiretroviral therapy centre in India. AB - CONTEXT: More than 1000 children are newly infected with Human immunodefi ciency virus (HIV) every day, and of these more than half will die as a result of AIDS due to lack of access to HIV treatment. HIV disease varies considerably in children. Among those infected prenatally, some experience few or no symptoms for years, whereas in others the disease progresses rapidly. The risk factors that influence the development of such oral manifestations include, low CD4+ T cell count, xerostomia and lack of highly active antiretroviral therapy (HAART). AIMS: To identify the oral manifestations of HIV in children receiving HAART. MATERIALS AND METHODS: The study comprised 95 children receiving HAART. 95 HIV +ve children not receiving HAART and 95 HIV -ve children were also included for comparing the manifestations of HIV. STATISTICAL ANALYSIS USED: Statistical analysis was done using Fisher's Chi-square test. Probability value (P value) was obtained for the three groups. RESULTS: The manifestations of HIV that were observed in children receiving HAART include dental caries (26%), periodontal diseases (23%), candidiasis (19%), hyperpigmentation (17%), ulcerative stomatitis (9%) and one case of mucocele. These manifestations were compared with HIV +ve children not receiving HAART and HIV -ve children to find manifestations with statistical significance. CONCLUSIONS: We conclude that HAART had increased the disease-free states in HIV +ve children on HAART promising them better life span. The incidence of oral lesions can further come down with adequate oral hygiene measures in HIV-infected children. PMID- 22923891 TI - Detection of human herpes viruses in patients with chronic and aggressive periodontitis and relationship between viruses and clinical parameters. AB - BACKGROUND AND AIMS: Recent microbiological researches have revealed the possible role of human cytomegalovirus (HCMV), Epstein barr virus (EBV), and herpes simplex virus (HSV-1 and HSV-2) in the etiopathogenesis of periodontal diseases. The present pilot study has been undertaken to detect the presence of these viruses in chronic periodontitis, aggressive periodontitis, and healthy individuals and to determine the relationship between these viruses and the clinical parameters. MATERIALS AND METHODS: A total of 10 patients belonging to the age group of 18 to 55 years were included. The patients were randomly assigned into periodontally healthy (sulcus depth <= 3 mm), chronic periodontitis, and aggressive periodontitis with pockets measuring >=6 mm. Seventy-five subgingival plaque samples (25 samples from each group) were collected and subjected to multiplex polymerase chain reaction for the detection of presence of HCMV, EBV, HSV-1, and HSV-2. The results were analyzed using one way ANOVA for multiple group comparisons followed by Student's t-test for pair wise comparisons. Categorical data was analyzed by Fisher's exact test. RESULTS: HSV-1 was detected in 76% (P<0.001) of sites with chronic periodontitis and 80% (P<0.001) sites with aggressive periodontitis. EBV was detected in 32% (P<0.05) of sites with chronic periodontitis and aggressive periodontitis. The probing pocket depth and clinical attachment level was statistically significant in HSV-1 detected sites compared with undetected sites in aggressive periodontitis patients CONCLUSION: Among these viruses HSV-1 and EBV were found to be significantly associated with destructive periodontal disease, including chronic and aggressive periodontitis. Further, HSV-1 was found to be associated with severity and progression of destructive periodontal disease. PMID- 22923892 TI - Bisphosphonate induced osteonecrosis of jaw in breast cancer patients: A systematic review. AB - BACKGROUND: Bisphosphonate therapy is widely used for the treatment of bone metastasis in breast cancer patients. AIM: The aim of this study is to estimate the overall prevalence of bisphosphonate induced osteonecrosis of jaw (BONJ) in breast cancer patients with bone metastasis. MATERIALS AND METHODS: A literature review was conducted to search and evaluate all the articles that contained original data on the prevalence of BONJ in breast cancer patients from the year 2003-2009. Pubmed search terms used were bisphosphonate, osteonecrosis, breast cancer and jaw. Eleven publications that fulfilled the inclusion criteria were chosen for the study. Case reports and reviews were excluded from the analysis based on assessing the title and abstract. RESULTS: Of the 2490 breast cancer patients, 69 developed BONJ with the overall prevalence rate of 2.8%. All the patients with BONJ had received zoledronate or pamidronate, either alone or in combinations. CONCLUSION: BONJ is a significant complication occurring in 2.8% of the breast cancer patients receiving bisphosphonates for metastatic bone disease. It is very important to identify the trigger factors associated with BONJ and also to establish guidelines for the prevention and effective treatment of this condition. PMID- 22923893 TI - Oral manifestations in hypertensive patients: A clinical study. AB - AIM: The aim of this work was to determine the frequency and nature of oral manifestations in a hypertensive patient. MATERIALS AND METHODS: The study sample consisted of 465 known hypertensive patients, between the age group of 20-80 years of which 250 patients were males and 215 were females. 105 were between the age group of 1-40 years, 136 in 41-50 years, 110 in 51-60 years, and 114 in 60 and above year of age. Data were statistically analyzed Student's t-test. RESULTS: 79.14% of the patients presented with Russell's periodontal index score ranging from 2- 4.9 which suggested an established periodontal lesion. The risk factors for old men and women to develop hypertension were 90%, among those who survived to ages 65 to 89 years. CONCLUSION: The frequency of potential oral manifestations in patients with hypertension was significantly high, thus showing an association of gingival and periodontal pathology in hypertensive patients. PMID- 22923894 TI - Evaluation and comparison of decalcification agents on the human teeth. AB - CONTEXT: In routine histopathology, decalcification of bone and teeth is often an essential and important step during tissue processing. Various decalcifying agents have been used in the past. The rate of decalcification and the effect of decalcifying agents on the tissue and its staining characteristics are two important parameters which influence the selection of decalcifying solutions. Though some agents remove the calcium ions completely and rapidly, they adversely affect the staining characteristics and may also damage the organic components. There have been very few studies which have systematically evaluated the efficacy of these agents in decalcifying dental hard tissues. AIMS: The present study was done to evaluate the rate of decalcification of six different decalcifying agents and also their effect on staining characteristics on dental hard tissues. MATERIALS AND METHODS: Six decalcifying agents namely, neutral ethylene diamine tetra acetic acid (EDTA) decalcifying solution, 5% nitric acid, Perenyi's fluid, formalin-nitric acid, 5% trichloracetic acid, and 10% formic acid were used to decalcify 24 natural teeth (four in each solution). The endpoint of decalcification was evaluated by radiographic and chemical methods. The decalcified teeth were then routinely processed, sectioned, and stained with hematoxylin and eosin stains. RESULTS: Neutral EDTA was the most considerate to the soft and hard tissues and 5% nitric acid was the least considerate to the tooth structure. CONCLUSIONS: Neutral EDTA, though being the slowest decalcifying agent among the six agents used in the study, gave excellent results for soft tissue integrity, and best quality of both soft-tissue and hard-tissue stainings. PMID- 22923895 TI - Etiopathogenesis of orofacial clefting revisited. AB - The cleft anomaly may be more ancient than the man himself. It is one of the most common developmental malformations reported in the literature. There are number of intriguing theories regarding its etiopathogenesis, each of which has some evidence in its favor. This review highlights all the genetic and environmental etiologic factors and focuses on its pathogenesis. PMID- 22923896 TI - Osteosarcoma of jaws. AB - Tumors of jaw bones are among the most uncommon of all types of neoplasms. Osteosarcoma of jaw bones represents a distinct group of lesions from the conventional type commonly occurring in long bones. Nonetheless, our present knowledge of the tumor allows us to affirm that its clinical behavior and pathologic features differ markedly from those of its homolog in the long bones. The maxillary tumors show predilection for posterior portion of the alveolar process and the antrum, whereas the body is most commonly involved in the mandible followed, by angle, symphysis, and ascending ramus. We have reviewed around 300 cases of osteosarcoma of varied racial origin from PubMed indexed journals spanning from 1967 to 2010 and present their etiology, pathogenesis, features and treatment modalities. PMID- 22923897 TI - Pathophysiology of Langerhans cells. AB - Langerhans cells (LCs) were first described by Paul Langerhans, in 1868, as dendritically shaped cells, which were located in the squamous epithelia of epidermis. Later on, these cells were identified in all stratified squamous epithelium of mammals. Dendritic cells (DCs) play an important role in local defense mechanisms in the epithelium. LCs are situated usually in the suprabasal layer of stratified squamous epithelia of oral mucosa and epidermis of skin. They constitute 3% of the cell population in epidermis. LCs are thought to act as antigen presenting cells (APCs) during initiation of immune responses. With the help of APCs, the lymphocytes are able to recognize and respond to specific microbes. In this paper we have reviewed the origin, distribution, demonstration and mechanism of action of LCs and their role in different pathological conditions. PMID- 22923898 TI - Laugier-Hunziker syndrome. AB - Laugier-Hunziker syndrome is a rare acquired disorder characterized by diffuse hyperpigmentation of the oral mucosa and longitudinal melanonychia in adults. They appear as macular lesions less than 5 mm in diameter. Laugier-Hunziker syndrome is considered to be a benign disease with no systemic manifestation or malignant potential. Therefore, it is important to rule out other mucocutaneous pigmentary disorders that do require medical management. Prompt clinical recognition also averts the need for excessive and invasive procedures and treatments. In India, the reported cases of this syndrome are very few. We provide a review of literature on Laugier-Hunziker syndrome with its differential diagnosis. PMID- 22923899 TI - Toluidine blue: A review of its chemistry and clinical utility. AB - Toluidine blue is a basic thiazine metachromatic dye with high affinity for acidic tissue components, thereby staining tissues rich in DNA and RNA. It has found wide applications both as vital staining in living tissues and as a special stain owing to its metachromatic property. Toluidine blue has been used in vivo to identify dysplasia and carcinoma of the oral cavity. Use of toluidine blue in tissue sections is done with the aim to highlight components, such as mast cells granules, mucins, and cartilage. This article provides an overview on chemistry, technique, and the various applications of toluidine blue. PMID- 22923901 TI - Dens invaginatus (Type III B). AB - Dens invaginatus or 'dens in dente' is a developmental malformation of the tooth resulting from infolding of the dental papilla before calcification. This article presents a case of dens invaginatus occurring in maxillary right lateral incisor of a 45-year-old male patient. The patient presented with pain and clinically missing maxillary right canine. The tooth was found to be non-vital. Radiographic examination revealed the tooth-in-tooth appearance of lateral incisor with a dilated pulp chamber. The crown of impacted canine was found within the pulp chamber of lateral incisor. Owing to this unique clinical presentation, both the lateral incisor and the impacted canine were extracted. Histopathologic examination confirmed the diagnosis of Dens invaginatus Type III B. A brief review on etiopathogenesis, radiographic features and treatment of dens invaginatus has also been included. PMID- 22923900 TI - The use of salivary cytokines as a screening tool for oral squamous cell carcinoma : A review of the literature. AB - Oral squamous cell carcinoma (OSCC) is the most common type of head and neck cancer. The 5-year survival rate has remained below 50% over the last two decades, and new tools for early diagnosis are needed. Saliva has been used for diagnosis of several systemic diseases, and its use for diagnosis of OSCC has been sought extensively. Among the many salivary analytes for diagnosis of OSCC, accumulating evidences indicate the possibility of using salivary cytokines. Overproduction of proinflammatory, proangiogenic cytokines by OSCC cells has been reported, and their role in tumor progression and angiogenesis is well established. However, many inflammatory conditions and immunological diseases could affect the levels of cytokines in serum and saliva. This article has reviewed publications in this matter, and some strengths and weaknesses have been pointed out. Conclusively, large-scale investigations are required for validation of the use of salivary cytokines for diagnosis of OSCC, with consideration to the influential role of periodontal inflammation in their levels. PMID- 22923902 TI - Syndontia with talon cusp. AB - Teeth are specialized structural components of the craniofacial skeleton. Developmental defects occur either alone or in combination with other birth defects. Macrodontia of anterior teeth may occur as an isolated condition or as a result of fusion or gemination and can occur in the primary or permanent dentition. Fusion is more commonly seen in the anterior maxillary region. This case presentation reports a case of fusion of a supplemental tooth to one in the normal series in conjunction with a talon cusp. This condition is extremely rare and has been reported at fourth occasion in the literature. The etiology, prevalence, clinical features, and management of the aforementioned anomalies have been reviewed in detail. Early diagnosis of this condition is important because it may cause clinical problems, such as esthetic concerns and tooth crowding. PMID- 22923903 TI - Adenoid ameloblastoma with dentinoid. AB - Ameloblastomas seldom cause diagnostic difficulties due to classic histopathological presentations. Adenoid ameloblastoma is a rare variant in this category which can cause problem in diagnosis due to the presence of areas resembling adenomatoid odontogenic tumor (AOT) and occurrence of varying degrees of dentinoid formation. In this article, we report a case of adenoid ameloblastoma with dentinoid, which was diagnosed accurately after the third recurrence. To the best of our knowledge, so far, only 13 cases have been reported of tumors that histologically show features of amelobalstoma and AOT with hard tissue formation. The recurrences were due to under diagnosis of the lesion followed by a conservative treatment. PMID- 22923904 TI - Collagenous fibroma (desmoplastic fibroblastoma) of the oral cavity. AB - Collagenous fibroma (desmoplastic fibroblastoma) is a distinctive yet uncommon fibrous soft tissue tumor. These tumors are rather nondescript in their morphological appearance and have been diagnosed as fibromas or some other benign mesenchymal lesions for years. The most common sites are the upper extremities, followed by the lower extremities. Rare lesions arise in the head and neck region. We report a rare case in the oral cavity and present its unique histopathological features (central fat entrapment) besides others, and diffusely strong vimentin immunopositivity. PMID- 22923905 TI - Parosteal osteochondrolipoma of the mandible. AB - Osteochondrolipoma is a rare benign soft tissue neoplasm. It is occasionally considered to be a variant of adipose tissue neoplasm 'lipoma' showing multiple differentiation pathways of pluripotent stem cells. As with the lipomas they can be seen at any location and show cartilagenous and osteoid differentiation when located parosteally. We present a case of osteochondrolipoma located at the symphysis of the mandible. To our knowledge, this is the first reported case of an oral osteochondrolipoma associated with parosteal localization. PMID- 22923906 TI - Intraosseous angiolipoma of the mandible. AB - Lipoma is a common soft-tissue tumor. There are only very few reported cases of intraosseous lipoma of the jaws in the literature. Intraosseous angiolipomas are even rarer. The exact nature of these lesions is debatable, but it is widely accepted that they represent true benign tumors. These are slow-growing tumor consisting of a mass of mature fat cells. When the vascular component within these tumors is a prominent feature, they are considered to be angiolipomas. The cause of these lesions is uncertain. Clinically, intraosseous lipoma may be asymptomatic, may cause swelling, or may show neurologic signs such as hypesthesia or paresthesia, as was manifested in this case. Radiographically, the lesion usually appears as a well-circumscribed radiolucency. The diagnosis of intraosseous lipoma of the mandible may be a challenge, due to its rarity and clinical similarity with many other radiolucent jaw lesions; therefore, the histopathological examination is always required. Here, we report a case of intraosseous angiolipoma of mandible in a 21-year-old female patient. PMID- 22923907 TI - Pseudovascular adenoid squamous cell carcinoma of oral cavity: A mimicker of angiosarcoma. AB - Pseudovascular adenoid squamous cell carcinoma (PASCC) is an uncommon histological variant of squamous cell carcinoma that can mimic vascular neoplasms, particularly angiosarcoma, in its morphologic characteristics. PASCC has been reported in the head and neck, as well as in the other organs such as the breast, lungs, urinary bladder, vulva, and uterine cervix. Only two cases of PASCC arising from the upper aerodigestive tract have been reported so far. We report a case of PASCC of oral cavity in a 40-year-old man, which mimicked an angiosarcoma initially. Immunohistochemical analysis led to a conclusive diagnosis of PASCC. PMID- 22923908 TI - Inverted papilloma of the palate with malignant transformation. AB - The inverted papilloma is a unilateral sinonasal benign tumor which is characterized by aggressive local invasion, high recurrence rate, and transformation into malignancy. The etiology of inverted papilloma is still unknown. Possible causes include allergy, chronic sinusitis, occupational exposure to dusts and aerosols, tobacco, and viral infections. Treatment is complete surgical excision and close postoperative follow-up is necessary. Here we report a case of inverted papilloma arising from the hard palate with malignant transformation in a 41-year-old female. Clinical and histological features and treatment are discussed with the review of literature. PMID- 22923909 TI - Intraosseous schwannoma of the mandible. AB - Schwannomas (neurilemmomas) are slow-growing, benign neoplasms derived from schwann cells, the sheath cells that cover myelinated nerve fibers. These tumors most commonly arise in the soft tissues of the head and neck, as well as on the flexor surfaces of the upper and lower extremities. Intraoral lesions are uncommon, however, and intraosseous schwannomas are even rarer. In the Mayo Clinic series of 11,087 primary bone tumors, 14 cases of intraosseous schwannoma were identified, accounting for less than 1% of these benign primary bone tumors. The most common site of occurrence is the mandible, a characteristic traditionally attributed to the long intraosseous path of the inferior alveolar nerve. In this article, we describe an additional case occurring in the mandible of a 15-year-old boy. PMID- 22923910 TI - Invasive aspergillosis in an immunocompetent host. AB - Aspergillosis is a common opportunistic fungal infection affecting the nose and paranasal sinuses. The disease presents in various forms ranging from non invasive to invasive, destructive and allergic types. We report here a rare case of invasive aspergillosis in an immunocompetent host with the literature review. PMID- 22923911 TI - Clinicoradiologic perspective of a severe case of polyostotic fibrous dysplasia. AB - Fibrous dysplasia (FD) of bone is a congenital non-heritable disorder that was first reliably reported by von Recklinghausen, when he described patients with pathologic condition of bone characterized by deformity and fibrotic changes that he termed as osteitis fibrosa generalisata. FD may involve one bone (monostotic) or multiple bones (polyostotic) and occurs throughout the skeleton with predilection for long bones, ribs, and cranio-facial bones. Seventy percent of the lesions are monostotic and asymptomatic, and identified incidentally. The polyostotic form of disease is often deforming and devastating, with multiple skeletal complications like repeated fractures, limb length discrepancies, and bone pains. The bone lesion of unknown origin is characterized by slow progressive replacement of normal bone by abnormal proliferative, isomorphic fibrous tissue. This case report documents a 40-year-old male with severe polyostotic FD that involved most of the skeleton, including long bones of all extremities, pelvis, facial bones, and skull base. Initial evaluation consisted of physical examination, plain radiographs, which was followed by computed tomography scan, Single-photon emission computed tomography scan, and biochemical and hematological examination. This paper stresses on the clinical implications and management of this rare debilitating disease. PMID- 22923912 TI - Undifferentiated pleomorphic sarcoma. PMID- 22923913 TI - Mucormycosis in an immunocompetent patient. PMID- 22923914 TI - Molecular species identification of Candida from blood samples of intensive care unit patients by polymerase chain reaction - restricted fragment length polymorphism. AB - INTRODUCTION: Candida spp is an emerging cause of blood stream infections worldwide. Delay in speciation of Candida isolates by conventional methods and resistance to antifungal drugs (especially fluconazole, amphotericin B, etc.) in various Candida species are some of the factors responsible for the increase in morbidity and mortality due to candidemia. So, the rapid detection and identification of Candida isolates from blood is very important for the proper management of patients having candidemia. MATERIALS AND METHODS: In this study, we have used polymerase chain reaction (PCR) - restriction fragment length polymorphism (RFLP) as a method for the speciation of Candida isolates from blood samples of intensive care unit (ICU) patients. PCR was used to amplify the ITS-1 and ITS-2 regions of Candida spp using universal primers ITS-1 and ITS-4. The amplified product was digested using Msp I restriction enzyme by RFLP. RESULTS AND DISCUSSION: The method PCR-RFLP helped in identifying five medically important Candida spp (C. tropicalis, C. albicans, C. parapsilosis, C. krusei and C. glabrata) from blood. This method is rapid, reliable, easy and cost-effective and can be used in routine laboratory diagnostics for the rapid identification of Candida isolates from blood. CONCLUSION: PCR-RFLP is an easy, rapid and highly valuable tool which can be used in routine diagnostic laboratories to speciate Candida isolates obtained from blood. This rapid method of speciation will help clinicians to decide on empirical therapy in candidemia cases before antifungal susceptibility results are available. PMID- 22923915 TI - Mean platelet volume in Type 2 diabetes mellitus. AB - CONTEXT: Diabetes mellitus is a global pandemic. The increased platelet activity may play a role in the development of vascular complications of this metabolic disorder. The mean platelet volume (MPV) is an indicator of the average size and activity of platelets. Larger platelets are younger and exhibit more activity. AIMS: to determine the MPV in diabetics compared to nondiabetics, to see if there is a difference in MPV between diabetics with and without vascular complications, and to determine the correlation of MPV with fasting blood glucose, glycosylated hemoglobin (HbA1c), body-mass index, and duration of diabetes in the diabetic patients. MATERIALS AND METHODS: platelet counts and MPV were measured in 300 Type 2 diabetic patients and 300 nondiabetic subjects using an automated blood cell counter. The blood glucose levels and HbA1c levels were also measured. Statistical evaluation was performed by SPSS using Student's t test and Pearson correlation tests. RESULTS: the mean platelet counts and MPV were higher in diabetics compared to the nondiabetic subjects [277.46 +/- 81 X 109/l vs. 269.79 +/- 78 X 109/l (P= 0.256)], 8.29 +/- 0.74 fl versus 7.47 +/- 0.73 fl (P= 0.001), respectively. MPV showed a strong positive correlation with fasting blood glucose, postprandial glucose and HbA1C levels (P=0.001). CONCLUSIONS: our results showed significantly higher MPV in diabetic patients than in the nondiabetic subjects. This indicates that elevated MPV could be either the cause for or due to the effect of the vascular complications. Hence, platelets may play a role and MPV can be used as a simple parameter to assess the vascular events in diabetes. PMID- 22923916 TI - Laboratory evaluation of three regimens of treatment of chronic hepatitis B: tenofovir, entecavir and combination of lamivudine and adefovir. AB - BACKGROUND: Chronic hepatitis B is a disease of concern due to its life threatening complications like cirrhosis, and hepatocellular carcinoma (HCC) in 20-40% of patients. There are about 400 million people affected worldwide with HBV, and over 300,000 die every year from HBV-related diseases. Oral antivirals like lamivudine, adefovir, entecavir, and tenofovir are commonly used to treat chronic hepatitis B. In this study, we tried to evaluate the comparative efficacy of these drugs alone and in combination. MATERIALS AND METHODS: Chronic hepatitis B patients with HBV-DNA more than 104Copies/mL irrespective of their HBeAg status (n=60) were enrolled in a prospective study. 21, 20, and 19 patients were treated with lamivudine (100 mg/day) plus adefovir (10 mg/day) combination entecavir monotherapy (0.5 mg/day) and tenofovir monotherapy (300 mg/day), respectively and were followed up for 24 weeks with their virological, serological, and biochemical markers measured at 12 and 24 weeks. RESULTS: After 24 weeks of treatment, there was no significant difference between the 3 groups in suppressing HBV-DNA to undetectable levels. The median decrease in HBV-DNA levels from baseline was better with tenofovir and entecavir monotherapies than lamivudine and adefovir combination, which was statistically significant. There was no significant difference between the 3 groups in HBsAg and HBeAg seroconversion and normalization of biochemical parameters. CONCLUSION: Entecavir and tenofovir monotherapy were found to be more effective than lamivudine plus adefovir combination in reducing the HBV-DNA levels. However, lamivudine plus adefovir combination was not too inferior, especially when cost of treatment was taken into consideration. PMID- 22923917 TI - Effect of exercise therapy on lipid parameters in patients with end-stage renal disease on hemodialysis. AB - BACKGROUND: Dyslipidemia has been established as a well-known traditional risk factor for cardiovascular disease in chronic kidney disease patients. AIM: This study investigated the impact of Hatha yoga exercise on lipid parameters in patients with end-stage renal disease (ESRD) on hemodialysis. MATERIALS AND METHODS: This prospective randomized study consisted of 33 ESRD patients in the Hatha yoga exercise group that was matched with 35 ESRD patients in the control group. Serum total cholesterol, triglycerides, low-density lipoprotein (LDL) cholesterol, and high-density lipoprotein (HDL)-cholesterol were determined at baseline (0 month) and after 4 months. RESULTS: Comparing values after 4 months versus baseline in the prehemodialysis Hatha yoga exercise group, there was found a significant decrease in total cholesterol from 5.126 +/- 0.092 mmol/l to 4.891 +/- 0.072 mmol/l (-4.58%; P = 0.0001), triglycerides from 2.699 +/- 0.078 mmol/l to 2.530 +/- 0.063 mmol/l (-6.26%; P = 0.0001), LDL-cholesterol from 2.729 +/- 0.083 mmol/l to 2.420 +/- 0.066 mmol/l (-11.32%; P = 0.0001), and total cholesterol/HDL-cholesterol ratio from 5.593 +/- 0.119 mmol/l to 4.907 +/- 0.116 mmol/l (-12.26%; P = 0.047). For patients in the Hatha yoga exercise group, 51.5% had normal total cholesterol at 0 month while 70.0% had normal total cholesterol (P < 0.05) after 4 four months and 54.5% of patients had normal LDL-cholesterol at 0 month while 84.9% had normal LDL-cholesterol after 4 months (P < 0.05). CONCLUSION: These findings suggest that Hatha yoga exercise has preventive and beneficial effects and may be a safe therapeutic modality in ESRD patients. PMID- 22923918 TI - Prevalence and characterization of diarrheagenic Escherichia coli isolated from adults and children in Mangalore, India. AB - BACKGROUND: Diarrheal diseases are a major cause of morbidity and mortality in resource-limited countries. Among the bacterial pathogens, diarrheagenic E. coli (DEC) are most frequently implicated in cases of epidemic and endemic diarrhea worldwide. The objective of this study was to determine the prevalence of DEC in stool specimens from patients with acute diarrhea using polymerase chain reaction (PCR). MATERIALS AND METHODS: Escherichia coli stool samples were collected from 115 hospitalized children and adults with acute diarrhea in Mangalore, a coastal city, in southern India. PCR amplification of eae, bfp, stx, ehx genes were used for detection of enteropathogenic (EPEC) and shigatoxigenic E. coli (STEC), lt and st genes were used for enterotoxigenic E. coli (ETEC) and astA gene for enteroaggregative E. coli (EAEC). RESULTS: During the 24 month study period, of the 115 stool samples, DEC type was detected in 20 (17.4%) using the PCR method. The most prevalent DEC was atypical EPEC accounting for 12 (10.4%) cases followed by 4 cases of EAEC (3.4%) and 4 of STEC (3.4%). No ETEC strains were isolated from any of the examined stool samples. CONCLUSION: This study suggests that the atypical EPEC are the newly emerging group among DEC stains in Southern India. Further studies are needed to evaluate the epidemiology and virulence properties of atypical EPEC strains. PMID- 22923919 TI - Rapid identification of yeast isolates from clinical specimens in critically ill trauma ICU patients. AB - PURPOSE: The purpose was to evaluate the performance of a commercially available chromogenic Candida speciation media and the Vitek 2 ID system for the identification of medically important yeasts and yeast-like organisms in a routine clinical microbiology laboratory. MATERIALS AND METHODS: A total of 429 non duplicate, consecutive yeast strains were included during the 3.5-year study period. The performance of the Vitek 2 ID system and a chromogenic agar medium was evaluated against the gold standard conventional phenotypic and biochemical identification method for speciation of yeast isolates from trauma patients. RESULTS: Candida tropicalis (64%) was the most common Candida species, followed by Candida albicans (14%), Candida rugosa (7%), and Candida parapsilosis (6.5%). Of the 429 isolates, 183 could be identified to species level by all the three methods. Agreement between the chromogenic agar method and conventional methods was 80% for Candida tropicalis, 100% for Candida rugosa, 89% for Candida albicans, and 77% for Candida parapsilosis. Vitek 2 had lower sensitivity, with agreement of 49% for Candida tropicalis, 100% for Candida rugosa, 39% for Candida albicans, and 31% for Candida parapsilosis. CONCLUSION: Thus, in long-term ICU patients, an increasing trend of isolating nonalbicans Candida spp. continues. The chromogenic agar medium is a convenient and economic method to identify commonly isolated species in busy clinical microbiology laboratories. PMID- 22923920 TI - Closed pleural biopsy is still useful in the evaluation of malignant pleural effusion. AB - BACKGROUND: Pleural fluid cytology for malignant cells is the easiest way to diagnose malignant pleural effusion with good sensitivity and specificity. With the introduction of medical thoracoscopy, the use of closed pleural biopsy for the diagnosis of cytology negative malignant pleural effusion is gradually decreasing. However use of thoracoscopy is limited due to its high cost and procedure related complications. AIMS: The aim was to assess the usefulness of closed pleural biopsy in the diagnosis of malignant pleural effusion. MATERIALS AND METHODS: Sixty-six patients of pleural effusion associated with malignancy were selected from the patients admitted in the chest ward of a tertiary care hospital over a period of 1 year. Pleural fluid aspiration for cytology and closed pleural biopsy were done in all the patients. RESULTS: Out of 66 patients, 46 (69%) patients showed malignant cells in pleural fluid cytology examination. Cytology was positive in 35 (52%), 10 (15%), and 1 (1.5%) patients in the first, second, and third samples respectively. Closed pleural biopsy was positive in 32 (48%) patients. Among them, 22 also had positive cytology. Additional 10 cytology negative patients were diagnosed by pleural biopsy. Cytology-histology concordance was seen in 12 patients. Definite histological diagnosis could be achieved in five patients with indeterminate cytology. Pleural biopsy was not associated with any major postoperative complication. CONCLUSION: Closed pleural biopsy can improve the diagnostic ability in cytology negative malignant pleural effusion. Closed pleural biopsy has still a place in evaluation of malignant pleural effusion especially in a resource-limited country like India. PMID- 22923922 TI - Ophthalmomyiasis externa caused by Oestrus ovis. AB - A 50-year-old male presented with foreign body sensation, pain, and redness in left eye. Slit-lamp biomicroscopy revealed tiny larvae crawling around the conjunctival sac. The larvae, numbering 13, were mechanically removed under topical anesthesia and identified under light microscope as first-stage larvae of Oestrus ovis causing ophthalmomyiasis externa. PMID- 22923921 TI - Prevalence and risk factors of Metallo beta-lactamase producing Pseudomonas aeruginosa and Acinetobacter species in burns and surgical wards in a tertiary care hospital. AB - INTRODUCTION: The production of Metallo-beta-lactamases (MBLs) is one of the resistance mechanisms of Pseudomonas aeruginosa and Acinetobacter species. There is not much Indian data on the prevalence of MBLs in burns and surgical wards. MATERIALS AND METHODS: A total of 145 non-duplicate isolates of carbapenem resistant Pseudomonas aeruginosa and Acinetobacter species, isolated from pus/wound swabs and endotracheal secretions from burns and surgical wards, were tested for MBL production by modified ethylene diamine tetra acetic acid (EDTA) disc synergy and double disc synergy tests. RESULTS: Prevalence of MBLs was 26.9% by both the above tests. All MBL-positive isolates were multidrug resistant. Only 6.06% (2/33) P.aeruginosa and 16.67% (1/06) Acinetobacter species were susceptible to piperacillin-tazobactam and netilmycin, respectively. These patients had multiple risk factors like >8 days hospital stay, catheterization, IV lines, previous antibiotic use, mechanical ventilation, etc. Graft application and surgical intervention were significant risk factors in MBL-positive patients. Overall mortality in MBL-positive patients was 34.21%. CONCLUSION: Emergence of MBL-producing Pseudomonas aeruginosa and Acinetobacter species in this hospital is alarming, which reflect excessive use of carbapenems and at the same time, pose a therapeutic challenge to clinicians as well as to microbiologists. Therefore, a strict antibiotic policy and implementation of proper infection control practices will go a long way to prevent further spread of MBLs. Detection of MBLs should also become mandatory in all hospitals. PMID- 22923923 TI - A case of Empyema thoracic due to Salmonella typhi in 18-month-old child: an unusual cause. AB - We herein report an 18-months-old child who presented with high-grade fever, cough, and breathlessness along with tachypnoea and diminished air entry on the left side of the chest, in which a diagnosis of left-sided pleural effusion was made. Salmonella typhi was isolated from the pleural tap culture. The patient had uneventful recovery with appropriate antibiotic therapy. Empyema thoracic as a complication is extremely rare in the absence of an underlying co-morbid illness, is even more uncommon in a child, and is even rarer to find with Salmonella typhi species. After reviewing the available literature we could find only five cases of empyema thoracic due to Salmonella typhi in children with the age range of 9 13 years. We are reporting this case as the youngest child reported with this complication. PMID- 22923924 TI - Primary pulmonary sporotrichosis in a sub-Himalayan patient. AB - Primary pulmonary sporotrichosis, a rare fungal disease was found in chronic alcoholic farmer from the sub-Himalayan region, an endemic mycoses area. Primary pulmonary sporotrichosis is a hidden entity, at times mimicking tuberculosis, and often under or lately diagnosed due to lack of awareness. We should consider the possibility of pulmonary sporotrichosis in patients with chronic cough and cavitary parenchymal disease, particularly in chronic alcoholics, gardeners, and forest workers. Sputum culture for fungus as a part of diagnostic studies is needed especially in endemic mycoses areas for early detection and management of such fungal diseases. PMID- 22923925 TI - Squamous predominant teratoid Wilms' tumor. AB - Teratoid Wilms tumor is an unusual histological variant of nephroblastoma with predominant heterologous component. Frequently present components include adipose tissue, glial tissue, muscle, cartilage or bone. The presence of squamous epithelial component on the other hand is rarely reported. We describe a case of unilateral teratoid Wilms' tumor in a 2-year-old boy with lung metastasis. In this case, tumor showed the familiar triphasic histologic pattern of nephroblastoma along with extensive squamous epithelial component. PMID- 22923926 TI - Cutaneous clear cell sarcoma: a rare aggressive tumor with potential diagnostic challenge. AB - Clear cell sarcoma is a deep-seated, exceedingly rare aggressive tumor, typically involving the tendons and aponeuroses with melanocytic differentiation and a distinct genetic background. A primary dermal location is rarer. It exhibits histological, immunohistochemical, and ultrastructural similarities with the more common primary (or metastatic) malignant melanoma causing major diagnostic confusion. We describe a case of primary cutaneous clear cell sarcoma arising in the right lower extremity of a 40-year-old male patient. PMID- 22923927 TI - Case of lingual cysticercosis and review of literature. AB - A 30-year-old female presented with a painless solitary swelling at right lateral border of tongue of 2-month duration. Fine-needle aspiration cytology was nonconclusive. Excision biopsy was done. Histopathology revealed cysticercosis cellulosae and parasite visualized in the slide with tongue muscles. Lingual cysticercosis is rare and therefore its literature is reviewed and discussed. PMID- 22923928 TI - Florid erythrophagocytosis on the peripheral smear. AB - Erythrophagocytosis is a relatively rare observation on blood smears. It has been reported in auto immune hemolytic anemias and sporadically in few other conditions. Here, we report a case of florid erythrophagocytosis with severe anemia following a viral infection in an 18-year-old girl. Her complete blood count (CBC) revealed hemoglobin of 3.6 gm/dl and a hematocrit of 10%. The peripheral smear showed erythrophagocytosis by neutrophils and rosetting of erythrocytes around neutrophils. The direct Coombs test and direct Donath- Landsteiner tests were positive. PMID- 22923929 TI - Primary papillary adenocarcinoma of the fallopian tube with ovarian metastasis. PMID- 22923930 TI - Congenital ovarian cyst: a report of two cases. PMID- 22923931 TI - Shigella Flexneri bacteremia in adult. PMID- 22923932 TI - Molecular epidemiology of Methicillin-resistant Staphylococcus aureus in children: comparison between cystic fibrosis and non-cystic fibrosis isolates. PMID- 22923933 TI - Preface to the Journal of Cardiovascular Disease Research, third issue 2012. PMID- 22923935 TI - Impact of urbanization and gender on frequency of metabolic syndrome among native Abuja settlers in Nigeria. AB - BACKGROUND: Metabolic syndrome (MetS) is an important cause of morbidity and mortality. Nigeria is currently undergoing rapid epidemiological transition. The objective was to study whether urbanization is associated with increased prevalence of MetS between native rural Abuja settlers and genetically related urban dwellers. MATERIALS AND METHODS: It was a cross-sectional study. Three hundred and forty-two urban native Abuja settlers and 325 rural dwellers were used for the study. Fasting blood lipid, glucose, waist circumference, blood pressure, and body mass index were determined. MetS was defined according to three standard criteria. SPSS 16.0 was used for statistical analysis. P<0.05 was used as statistically significant. RESULTS: Obesity, hypertriglyceridemia, and hypertension were commoner among urban dwellers than rural dwellers. MetS was associated more with the female gender. Urbanization significantly increases the frequency of MetS using the three standard definitions. The prevalence of MetS using International Diabetes Federation, World Health Organization, and National Cholesterol Education Program Adult Treatment Panel III among rural versus urban dwellers were 7.7% vs. 14.9%, P<0.05; 0% vs. 0.9%, P>0.05; and 3.7% vs. 13.7%, P<0.05, respectively. CONCLUSION: This study shows that MetS is a major health condition among rural and urban Nigerians and that urbanization significantly increases the prevalence of MetS. This can be explained on the basis of higher prevalence of dyslipidemia, obesity, and hypertension in urban setting, possibly as a result of stress, diet, and reduction in physical activity. Effective preventive strategy is therefore required to stem the increased risk associated with urbanization to reduce the cardiovascular risk associated with MetS among Nigerians. PMID- 22923936 TI - ABO-Rh blood groups distribution in cardiac syndrome X patients. AB - BACKGROUND: Data on frequency distribution of ABO-Rh blood groups in cardiac syndrome X (CSX) patients are not available. We aimed to investigate the distribution of ABO-Rh blood groups in these patients. MATERIALS AND METHODS: A total of 247 CSX patients' records were reviewed in a cross-sectional study from 2006 to 2010. One hundred forty six patients (59.1%) were female, and the mean patient age was 52 +/- 11 years. The frequency of ABO-Rh blood groups was compared to the frequency of these blood groups in the West-Azerbaijan province, Iran; general population. RESULTS: Blood groups distribution among CSX patients showed phenotypes A, B, AB, O and Rh negative as 33.1%, 21.9%, 9.3%, 35.8%, and 7.9%, respectively. According to our results, there were no differences in ABO-Rh blood groups distribution between CSX patients and normal population. CONCLUSION: These data suggest that ABO-Rh blood groups might be unassociated with CSX. PMID- 22923934 TI - Aged garlic extract and coenzyme Q10 have favorable effect on inflammatory markers and coronary atherosclerosis progression: A randomized clinical trial. AB - BACKGROUND: Aged garlic extract (AGE) and coenzyme Q10 (CoQ10) have been shown to affect multiple cardiovascular risk factors. The current study evaluates the effect of AGE combined with CoQ10 on inflammatory markers and progression of coronary atherosclerosis compared with placebo. METHODS AND RESULTS: In this placebo-controlled, double-blind, randomized trial, 65 intermediate risk firefighters (age 55 +/- 6 years) were treated with a placebo capsule or a capsule containing AGE and CoQ10 (AGE+CoQ10, 1200 and 120 mg, respectively) daily for 1 year. All participants underwent coronary artery calcium (CAC) scanning and C-reactive protein (CRP) at baseline and at 12 months. At 1 year, mean CAC progression was significantly lower in AGE+CoQ10 (32 +/- 6 vs. 58 +/- 8, P = 0.01) than placebo. Similarly, CRP were significantly decreased in AGE+CoQ10 compared with placebo (-0.12 +/- 0.24 vs. 0.91 +/- 0.56 mg/L, P < 0.05). After adjustment for age, gender, conventional cardiac risk factors, and statin therapy, AGE+CoQ10 was associated with 3.99 fold (95% 1.3-12.2, P = 0.01) lack of CAC progression compared with the placebo. CONCLUSION: AGE+CoQ10 are associated with beneficial effects on inflammatory markers and reduced progression of coronary atherosclerosis. PMID- 22923937 TI - Hemodynamic effect of atrioventricular and interventricular dyssynchrony in patients with biventricular pacing: Implications for the pacemaker syndrome. AB - BACKGROUND/OBJECTIVES: Pacemaker syndrome was mainly described as the sequel of atrioventricular (AV) dyssynchrony. The role of interventricular (VV) dyssynchrony has not been studied yet. The aims of this study were to noninvasively assess the hemodynamic effects of different ventricular pacing sites with and without AV and VV dyssynchrony and to observe the patients for clinical symptoms of the pacemaker syndrome during the AV sequential and ventricular-only pacing modes. MATERIALS AND METHODS: Between March 2009 and February 2010, 40 patients (28 men; mean age, 61 +/- 15 years) with biventricular (BiV) device were enrolled. Mean systolic and diastolic blood pressures (BP) of 5 beats were measured 5 minutes after each mode change using fingertip plethysmography. The patients were also observed for the occurrence of symptoms suggestive of the pacemaker syndrome, including dyspnea, palpitations, dizziness, presyncope, and syncope. RESULTS: There was no difference in mean systolic BP among different ventricular-only pacing modes (all P = NS). However, mean systolic BP was significantly higher in AV sequential biventricular pacing (DDD BiV) compared with ventricular-only pacing modes (all P<0.05). In addition, there was no difference in terms of pacemaker syndrome-related symptoms following mode change from DDD-BiV to DDD-RV or DDD-LV (all P>0.05). CONCLUSIONS: The present study showed that the non-AV sequential BiV and LV pacing may have no significant benefit compared with RV pacing in terms of systolic blood pressure. However, there was marked hemodynamic improvement following mode change to AV sequential BiV pacing. This study may have important implications for pathogenesis of pacemaker syndrome. PMID- 22923938 TI - Prevalence and risk factors for metabolic syndrome in Asian Indians: A community study from urban Eastern India. AB - OBJECTIVES: To determine the prevalence of metabolic syndrome and to identify predictors for the same, specific to an underdeveloped urban locale of Eastern India. MATERIALS AND METHODS: STUDY DESIGN: Population-based cross-sectional study, with multistage random sampling technique. SETTING: Urban city-dwellers in Orissa one of the poorest states of Eastern India bordering a prosperous state of Andhra Pradesh of Southern India. PARTICIPANTS: 1178 adults of age 20-80 years randomly selected from 37 electoral wards of the urban city. Definition of Metabolic Syndrome: We followed a unified definition of the metabolic syndrome by joint interim statement of five major scientific organizations - the International Diabetes Federation, the National Heart, Lung, and Blood Institute, the American Heart Association, the World Heart Federation, the International Atherosclerosis Society, and the International Association of the Study of Obesity. Individuals who meet at least three of five clinical criteria of abdominal obesity, hypertriglyceredimia, low HDL, hypertension, and hyperglycemia are diagnosed as having the condition; presence of none of these criteria is mandatory. Explicit cut points are defined for all criteria, except elevated waist circumference, which must rely on population and country-specific definitions. MAIN OUTCOME MEASURE: Prevalence and significant predictors of metabolic syndrome. STATISTICAL ANALYSIS: Both descriptive and multivariable logistic regression analyses. RESULTS: Age-standardized prevalence rates of metabolic syndrome were 33.5% overall, 24.9 % in males and 42.3% in females. Older age, female gender, general obesity, inadequate fruit intake, hypercholesterolemia, and middle-to-high socioeconomic status significantly contributed to increased risk of metabolic syndrome. CONCLUSION: Metabolic syndrome is a significant public health problem even in one of the poorest states of India that needs to be tackled with proven strategies. PMID- 22923939 TI - Behavioral risk factors of coronary artery disease: A paired matched case control study. AB - BACKGROUND: Cardiovascular diseases are becoming the major cause of morbidity and mortality in most of the developing countries including India. Various behavioral risk factors are the major risk factors for coronary artery disease. Present study was carried out to study the role of various behavioral risk factors in the occurrence of coronary artery disease. MATERIALS AND METHODS: Present study was a hospital-based paired-matched case-control study, carried out at civil hospital, Ahmedabad. A total of 135 newly-diagnosed cases of coronary artery disease and 135 controls were studied after taking an informed written consent. Data was analyzed by using Epi-info version 3.5.1 computer package, Chi -square test, Z test and Odds ratio was calculated. RESULTS: Among the total 135 cases, 70.4% were male and 29.6% were female, most of the cases (40%) belong to the age group of 51-60 years. Smokers, smokeless tobacco users, and alcoholic were significantly higher among the cases as compared to controls. Significant association was also observed between current smokers, smokeless tobacco users, and coronary artery disease. Dose-response relationship was observed between the frequency of smoking per day and coronary artery disease (OR = 3.72). Significant association was also observed between obesity, physical inactivity, and coronary artery disease. Salt and oil intake per day were significantly higher among the cases as compared to controls. CONCLUSION: Modifiable and preventable behavioral risk factors are major etiology behind the occurrence of coronary artery disease, which highlights the need of appropriate control strategies and measures. PMID- 22923940 TI - Screening for risk of cardiovascular disease among officer grade bank employees of Gulbarga city. AB - CONTEXT: The risk of cardiovascular disease was assessed among officer grade bank employees of Gulbarga city, as they face a large of amount of work related stress. AIMS: (1) To assess the risk of cardiovascular disease among the study group. (2) To propose a similar population based heart disease screening strategy for other groups. SETTINGS AND DESIGN: Out of the 242 officers in 26 banks in Gulbarga city (nationalized and private), 59 officers were willing to be a part of the study. This population was initially screened by a self-assessment scale, consisting of 10 questions relating to past history, family history, and lifestyle practices. Scoring system was used for the analysis. MATERIALS AND METHODS: The initial part of this cross-sectional study was conducted during April 2006. Forty nine officers who scored >=3 were recruited for preliminary assessment, which consists of physical examination, Electrocardiogram (ECG) and some invasive investigations (fasting blood sugar and cholesterol). Those found at further risk, were recruited for detailed assessment. 15 officers who qualified were screened for specific cardiac markers using advanced investigations Lipoprotein (Lp) a, homocysteine, C reactive protein (CRP), lipid profile measurements, Treadmill test (TMT) / Echocardiogram (ECHO), and Glucose tolerance test (GTT). All the five officers who were found at the highest level of risk were referred to the tertiary health care centre. STATISTICAL ANALYSIS: Microsoft excel was used to compute the frequencies and percentages. RESULTS: Among the 59 employees examined in the study, 49 were found to be at risk for cardiovascular diseases (comprising ~83% of the assessed population) and thus qualified to the second round of assessment. Only 31 officers underwent the second round of assessment, out of whom 15 (48.4%) were found to be at higher risk and thus were subjected to the third round. Only five officers (of the 15) underwent the third round of assessment and all were found to be utmost at risk for CVDs and were duly referred to a tertiary health care centre. CONCLUSIONS: The study shows the application of a risk assessment model, towards predicting the risk for cardiovascular diseases among a group of high risk population. Similar models could be used for the risk assessment of other population groups. PMID- 22923941 TI - Reverse Wenckebach "pseudo-supernormal" conduction or paroxysmal atrioventricular block. AB - Paroxysmal atrioventricular-block is a poorly-recognized cause of atrioventricular conduction abnormality leading to syncope and can be fatal. Here we report a case of paroxysmal atrioventricular-block presenting as syncope treated effectively with pacemaker implantation and review the current literature on prevalence, known mechanisms and treatment for it. Importantly we provide the diagnostically important differentiating points between vagally mediated block and paroxysmal atrioventricular-block as well as the highlight the vastly varying prognosis between the two. PMID- 22923942 TI - Acute thrombosis of mechanical bi-leaflet aortic valve prosthesis. AB - Thrombosis of mechanical aortic valve prosthesis is a rare but life-threatening complication. In most reported cases, inadequate anticoagulation or cessation of anticoagulation is the cause of prosthesis thrombosis. The case of a 70-year-old male patient hospitalized for severe dyspnoea is presented. Although the patient was under continuous anticoagulation, thrombosis of the 16 years previously implanted mechanical 31-sized aortic valve prosthesis was diagnosed. Emergency surgery was performed and postoperative course was uneventful. Patients with large size prostheses should have closer anticoagulation monitoring, even after many years of event-free postimplant course. PMID- 22923943 TI - Various coronary artery complications of Kawasaki disease: Series of 5 cases and review of literature. AB - Kawasaki disease is a generalized systemic vasculitis of unknown etiology involving medium and small size blood vessels throughout the body, virtually always involving the coronaries. In many part of this world, it is more common than rheumatic fever and viral myocarditis. Here, we are reporting 5 cases with history suggestive of Kawasaki disease in the early life, presenting with different coronary artery abnormalities. One of the patients had left main coronary artery cut-off, and the remaining 4 had some form of coronary artery aneurysms. 3 patients were given medical management, 1 patient had coronary bypass grafting, and the remaining 1 was planned for surgical correction. All the patients were stable on subsequent follow-ups. PMID- 22923945 TI - Kawasaki's disease: An unusual presentation. AB - Atypical presentations of Kawasaki's disease have been described in the form of intestinal pseudo-obstruction, tonsillitis, hemorrhagic serous effusions, thrombocytopenia, and non-fulfillment of all criteria for diagnosis of Kawasaki's disease. However, presentation of Kawasaki's disease with shock and need for ionotropic support have been rarely described. We present a 4-year-old girl with Kawasaki's disease who presented with anasarca, oliguria, shock, and presence of dilated coronary arteries within 5 days of fever and responded to intravenous immunoglobulin (IVIG) and inotropic support. PMID- 22923946 TI - A case of double right coronary artery with bifurcation stenosis in association with complete heart block. AB - Congenital coronary artery anomalies are present at birth, but most anomalies are discovered as incidental findings during coronary angiography or at autopsy. Double right coronary artery (RCA) is a rare coronary anomaly. Double RCA with bifurcation stenosis in association with degenerative complete heart block (CHB) have never been reported in literature to the best of our knowledge. We therefore report an interesting case of a patient with double RCA and degenerative CHB. PMID- 22923944 TI - Pulmonary endarteritis, cerebral abscesses, and a single ventricle: An uncommon combination. AB - Endocarditis of the right side of the heart is otherwise uncommon in children. Pulmonary endarteritis as a complication of congenital heart disease is even rarer. Herein, we report the case of pulmonary endarteritis with a 7 mm *5 mm vegetation, involving the main pulmonary artery in a 4-year-old male child, with cyanosis and a 1-week history of fever and rapidly-progressive hemiparesis. A full segmental echocardiography demonstrated a double inlet left ventricle with left-sided subaortic hypoplastic right ventricle (Van Praagh's A-III type - Single Ventricle). Additionally, CT scan of the brain revealed bilateral cerebral abscesses. To the best of our knowledge, the occurrence of pulmonary endarteritis and cerebral abscesses in a case of single ventricle is hitherto unreported. This article underlines the importance of heightened clinical awareness and meticulous echocardiography in cases of congenital heart disease so that relatively rare complications may not be missed. PMID- 22923947 TI - Slow ventricular response atrial fibrillation related to mad honey poisoning. AB - Mad honey poisoning which is induced by Grayanotoxin (Andromedotoxin), is also known to have adverse effects in the cardiovascular system leading to different clinical entities. This toxin is produced by a member of the Rhododendron genus of plants of two R. Luteum and R. Panticum. In this article, we presented a case of slow ventricular response atrial fibrillation complaints with nausea, vomiting, dizziness and chest pain about an hour after eating honey produced in the Black Sea Region. PMID- 22923948 TI - Rare variant of mixed total anomalous pulmonary venous connection. AB - Mixed variety of Total anomalous pulmonary venous connection is a rare congenital heart disorder with a wide variation of pulmonary venous anatomy and their drainage. Present article depicts "3+1" variant of mixed TAPVC treated by rechannelizing all pulmonary veins to left atrium using a Polytetrafleuroethylene patch. PMID- 22923950 TI - Vitex negundo inhibits cyclooxygenase-2 inflammatory cytokine-mediated inflammation on carrageenan-induced rat hind paw edema. AB - BACKGROUND: Vitex negundo L. (Verbenaceae) is a hardy plant widely distributed in the Indian subcontinent and used for treatment of a wide spectrum of health disorders in traditional and folk medicine, some of which have been experimentally validated. In present study, we aimed to investigate the anti inflammatory effects of V. negundo in carrageenan-induced paw edema in rats, and to investigate the probable mechanism of anti-inflammatory action. MATERIALS AND METHODS: Paw edema was produced by injecting 1% solution of carrageenan, and the paw volume was measured before and after carrageenan injection up to 5 h. V. negundo leaf oil was extracted using a Clevenger apparatus and administered by a trans-dermal route to Wistar rats and the percentage of inhibition of inflammation was observed using a Plethysmometer by comparing a compound aerosol based formulation with 1 mg diclofinac diethylamine BP and 7 mg methyl salicylate IP/kg body weight served as a standard drug whereas paraffin oil served as the placebo group. After withdrawing of blood, serum was separated and cyclooxygenase (COX)-1 and COX-2 inhibitory activities were measured by the enzyme immuno assay (EIA) method by using a COX inhibitor screening assay kit. RESULTS AND DISCUSSION: V. negundo leaf oil significantly (P < 0.05) reduced the carrageenan induced paw edema as compared to the placebo group (paraffin oil) and 1 mg diclofinac diethylamine BP and 7 mg methyl salicylate IP showed the maximum inhibition of paw edema as compared to the V. negundo leaf oil treated group and the control group. Also in the present study V. negundo leaf oil showed significantly (P < 0.05) inhibits COX-1 pathways rather than COX-2 pathways as compared to the V. negundo leaf oil treated group. CONCLUSION: It is suggested that the V. negundo leaf oil is a potent anti-inflammatory agent and acts via inhibition of COX-2 without much interfering COX-1 pathways. PMID- 22923949 TI - Sub-acute effect of N(G)-nitro-l-arginine methyl-ester (L-NAME) on biochemical indices in rats: Protective effects of Kolaviron and extract of Curcuma longa L. AB - BACKGROUND: Kolaviron (KV) (biflavonoid from Garcinia kola) and extract of Curcuma longa (CL) are frequently used in folk medicine for treatment of hypertension. One of their mechanisms of action is to enhance antioxidant properties in animals. N(G)- nitro- l- arginine methyl- ester (L- NAME) is L- arginine analogue, which by binding to Nitric Oxide Synthase (NOS) may induce hypertension partly due to increase in tissues oxidative stress. OBJECTIVES: To investigate the effect of L- NAME on some biochemical indices and the possible protective effect of KV or CL. MATERIALS AND METHODS: Four groups consisting of 6 rats each were used. One group served as control, second group received L- NAME (40 mg/kg/day). Third and fourth groups were treated with KV and CL, respectively and also received L- NAME. KV and CL were given at a dose of 200 mg/kg/day. RESULTS: L- NAME caused a significant (P <0.05) increase in the levels of serum urea, creatine kinase and alanine aminotransferase relative to controls. L- NAME treated rats had markedly decreased hepatic catalase (CAT), superoxide dismutase (SOD), glutathione- S- transferase (GST) and reduced glutathione (GSH) levels. Precisely, L- NAME decreased CAT, SOD, GST and GSH by 48, 52, 76 and 40%, respectively. L- NAME intoxication significantly decreased (P <0.05) renal GSH and SOD levels. Also, L- NAME caused a significant (P <0.05) induction of lipid peroxidation (LPO) in the animals. Administration of KV or CL with L- NAME caused significant (P <0.05) inhibition of LPO and augments tissue antioxidant indices. CONCLUSION: These results confirm the adverse effect of L- NAME on biochemical indices and, the ability of kolaviron or Curcuma longa to ameliorate the alterations. PMID- 22923952 TI - A validated UV-HPLC method for determination of chlorogenic acid in Lepidogrammitis drymoglossoides (Baker) Ching, Polypodiaceae. AB - BACKGROUND: Lepidogrammitis drymoglossoides (Baker) Ching (L. drymoglossoides), a member of the Polypodiaceae family, was used in the treatment of numerous diseases. However, none of the potential ingredients and the quality control methods concerning this plant medicine was pronounced. OBJECTIVE: To identify chlorogenic acid (CGA) from L. drymoglossoides and develop a high performance liquid chromatography (HPLC) assay of CGA. MATERIALS AND METHODS: UV, TLC, and HPLC were utilized to identify the phytochemicals of L. drymoglossoides and determine the CGA content, respectively. The HPLC conditions were as following: a Phenomenex Luna C18 (2) (250 * 4.6 mm i.d.; 5 MUm particle size; 100 A pore size) column; the mobile phase of the mixture of acetonitrile and 0.5% aqueous phosphoric acid (11.5:88.5 v/v); the flow rate of 1.0 mL/min and determination wavelength of 327 nm. RESULTS: The proposed HPLC method has been developed and validated. The calibration curve was y = 28328x + 16610 (R(2) = 0.9997). The intra-day and inter-day precision and intermediate precision were validated with the RSD less than 5%. The mean recovery rate of the method ranged from 95% to 104%, with the RSD less than 5%. The LOD and LQD values were 0.049 and 0.132 mg/L, respectively. The content of CGA in L. drymoglossoides approximately reached 0.24% (v/v) by the proposed extraction and determination methods. CONCLUSION: The assay method was simple, convenient, and accurate to the quantification of CGA and can be used for the quality control of the herb. PMID- 22923951 TI - Active spermatogenesis induced by a reiterated administration of Globularia alypum L. aqueous leaf extract. AB - BACKGROUND: Globularia alypum L. (Globulariaceae) is a shrub growing in the Mediterranean basin and known to be used as a popular medicine for its several pharmacological properties against rheumatism, gout, typhoid, intermittent fever, and diabetes. MATERIALS AND METHODS: The acute and chronic toxicities of a G. alypum L. aqueous leaf extract were studied in animals. Acute toxicity was performed in male and female mice whereas chronic toxicity was realized in male and female rats that orally received the drug at the doses of 300 and 600 mg/kg/24 h for 30 days. RESULTS: Acute toxicity showed that the extract, administered by the oral route, does not induce any mortality even for a dose of 10,000 mg/kg. Administered by the intra-peritoneal route to female and male mice, the LD(50) of the extract was found to be of 2750 and 2550 mg/kg, respectively. A chronic toxicity study showed that, compared to the control groups that only received the vehicle (water), the drugs affects weight growth (effects more pronounced in female than in male rats), some organs weight after autopsy, hematological and biochemical parameters and histology of some principal organs (lungs: histological grades I to II pulmonary hypertension (PHT), respiratory distress syndrome (ARDS), and lymphoid hyperplasia; esophagus: thinning down of esophageal wall, atrophic muscular coat). The most important finding of the study was the recorded active spermatogenesis induced by the reiterated administrations of the drug that was confirmed by reducing the administered dose and the period of treatment (100 mg/kg/24 h for 15 days). CONCLUSION: It is suggested that the G. alypum L. leaf extract contains active substances with androgenic properties that could be used in human therapy. PMID- 22923953 TI - Co-administration of sodium arsenite and ethanol: Protection by aqueous extract of Aframomum longiscapum seeds. AB - BACKGROUND: Human exposure to arsenicals, its toxicity, subsequent adverse effects on health has been widely reported and implicated in the etiology of several cancers. OBJECTIVES: We investigated the effect of Aframomum longiscapum (AL) extracts on sodium arsenite (SA) and ethanol (EtOH)-induced toxicities in rats. MATERIALS AND METHODS: Male rats were fed SA, EtOH, and SA + EtOH, with or without AL for 5 weeks. Hepatic transaminases were assessed in serum, micronucleated polychromatic erythrocytes (mPCEs) from bone marrow, liver histopathology, and semen quality from caudal epididymis were assessed, respectively, and data were represented as mean +/- SD, analyzed by ANOVA. RESULTS: SA, SA + EtOH, and AL alone induced mPCEs formation in rat bone marrow (P < 0.05). A decrease (P < 0.05) in mPCEs in AL + SA + EtOH-treated rats compared with SA, and SA + EtOH was observed. SA and EtOH treatment increased serum hepatic transaminases (P < 0.05) relative to control, while AL treatment resulted in a decrease (P < 0.05). AL, SA, and SA + EtOH treatment decreased sperm count and motility (P < 0.05) with no effect on viability compared with control. Semen morphological abnormalities showed no difference (P > 0.05) across the treated groups. Hepatic histopathology indicated mild mononuclear cellular infiltration in the control group. Necrotic hepatocyte were observed in SA, SA + EtOH treated groups, with no visible lesions seen in the AL treated group. Mild hepatocyte congestion of the portal vessels was observed in AL + SA + EtOH treated groups. CONCLUSION: The AL extract exhibited anticlastogenic and hepatoprotective potentials, reduced sperm count, motility, with no effect on viability and morphology. Our findings suggest that AL may mitigate the effect of arsenicals-induced clastogenicity implicated in chemical carcinogenesis. PMID- 22923954 TI - Chemical composition, antibacterial and antifungal activities of essential oil from Cordia verbenacea DC leaves. AB - BACKGROUND: Cordia verbenacea is a Brazilian coastal shrub popularly known as "erva baleeira". The essential oil from fresh leaves was obtained by hydrodistillation and analyzed by CG/MS. The main components were identified as beta-caryophyllene (25.4%), bicyclogermacrene (11.3%), delta-cadinene (9.%) and alpha-pinene (9.5%). In this study, the antimicrobial activity of Cordia verbenacea was evaluated. MATERIALS AND METHODS: The minimal inhibitory concentration (MIC) of the essential oil was obtained using the broth microdilution assay (from 512 to 8 MUg/ml). RESULTS: The results showed that the essential oil presented fungistatic activity against Candida albicans and Candida krusei and antibacterial activity against Gram-positive strains (Staphylococcus aureus and Bacillus cereus) and against multiresistant Gram-negative (Escherichia coli 27), in all tests the MIC was 64 MUg/ml. When the essential oil was associated to aminoglycosides (subinhibitory concentrations, MIC/8), a synergic and antagonic activity was verified. The synergic effect was observed to the amikacin association (MIC reduction from 256 mlto 64 MUg/ml) in all strains tested. CONCLUSION: The essential oil of Cordia verbenacea influences the activity of antibiotics and may be used as an adjuvant in antibiotic therapy against respiratory tract bacterial pathogens. PMID- 22923955 TI - Allelopathic effect of Ashwagandha against the germination and radicle growth of Cicer arietinum and Triticum aestivum. AB - BACKGROUND: Ashwagandha (Withania somnifera) is an important medicinal plant in Indian traditional system of medicine and traditionally has been used for several medicinal purposes in the Indian subcontinent. OBJECTIVE: The present study was aimed at the evaluation of allelopathic effect of hydroalcoholic extract of ashwagandha against germination and radicle growth of Cicer arietinum and Triticum aestivum seeds. MATERIALS AND METHODS: The extract at different concentrations was incubated in controlled conditions with the surface sterilized seeds of C. arietinum and T. aestivum and observed periodically for seed germination and radicle growth to assess the allelopathic behavior. RESULTS: The extract mainly at higher concentrations demonstrated promising allelopathic potential by significantly affecting seed germination and radicle elongation of both C. arietinum and T. aestivum in a concentration dependent manner. T. aestivum was found to be more sensitive than C. arietinum. CONCLUSION: The present study demonstrated remarkable allelopathic potential of ashwagandha against the test seeds. The effect was plausibly due to the alkaloid and withanolide contents of ashwagandha. PMID- 22923956 TI - Acute toxicity impacts of Euphorbia hirta L extract on behavior, organs body weight index and histopathology of organs of the mice and Artemia salina. AB - BACKGROUND: The methanol extract of Euphorbia hirta L (Euphorbiaceae), which is used in traditional medicines, was tested for in vivo toxicity. MATERIALS AND METHODS: In vivo brine shrimp lethality assay and oral acute toxicity study at single high dose of 5000 mg/kg and observation for 14 days in mice were used to study the toxic effect of E. hirta. RESULTS: Brine shrimp lethality assay was used to calculate the median lethal concentration (LC(50)) of E. hirta (for leaves, stems, flowers and roots) methanolic extracts at concentrations from 100 to 0.07 mg/ml. The LC(50) values of 1.589, 1.420, 0.206 and 0.0827 mg/ml were obtained for stems, leaves, flowers and roots, respectively. Potassium dichromate (the positive control) had LC(50) value of 0.00758 mg/ml. The acute oral toxicity study of the leaf extract resulted in one third mortality and mild behavioral changes among the treated mice. No significant statistical differences found between body weight, relative (%) and absolute (g) organ weights of treated and untreated groups (P> 0.05). Gross and microscopic examination of the vital organ tissues revealed no differences between control and treated mice. All the tissues appeared normal. CONCLUSIONS: E. hirta leaves methanol extract has exhibited mild toxic effects in mice. PMID- 22923957 TI - The effects of aqueous extract of Cleistanthus collinus (Roxb.) (Euphorbiaceae) leaves on rat blood pressure. PMID- 22923958 TI - Locust bean gum: Exploring its potential for biopharmaceutical applications. AB - Polysaccharides have been finding, in the last decades, very interesting and useful applications in the biomedical and, specifically, in the biopharmaceutical field. Locust bean gum is a polysaccharide belonging to the group of galactomannans, being extracted from the seeds of the carob tree (Ceratonia siliqua). This polymer displays a number of appealing characteristics for biopharmaceutical applications, among which its high gelling capacity should be highlighted. In this review, we describe critical aspects of locust bean gum, contributing for its role in biopharmaceutical applications. Physicochemical properties, as well as strong and effective synergies with other biomaterials are described. The potential for in vivo biodegradation is explored and the specific biopharmaceutical applications are discussed. PMID- 22923959 TI - Nanotechnology in cosmetics: Opportunities and challenges. AB - Nanotechnology is the science of manipulating atoms and molecules in the nanoscale - 80,000 times smaller than the width of a human hair. The world market for products that contain nanomaterials is expected to reach $2.6 trillion by 2015. The use of nanotechnology has stretched across various streams of science, from electronics to medicine and has now found applications in the field of cosmetics by taking the name of nanocosmetics. This widespread influence of nanotechnology in the cosmetic industries is due to the enhanced properties attained by the particles at the nano level including color, transparency, solubility etc. The different types of nanomaterials employed in cosmetics include nanosomes, liposomes, fullerenes, solid lipid nanoparticles etc. Recently, concerns over the safety of such nanocosmetics are raised and have forced the cosmetic industries to limit the use of nanotechnology in cosmetics and for enforcing laws to undergo a full-fledged safety assessment before they enter into the market. In this review, emphasis is made on the types of nanomaterials used in cosmetics by the various cosmetic brands, the potential risks caused by them both to human life and also to the environment and what all regulations have been undertaken or can be taken to overcome them. PMID- 22923960 TI - Recent advances in gene therapy for thalassemia. AB - Thalassemias are genetically transmitted disorders. Depending upon whether the genetic defects or deletion lies in transmission of alpha or beta globin chain gene, thalassemias are classified into alpha and beta-thalassemias. Thus, thalassemias could be cured by introducing or correcting a gene into the hematopoietic compartment or a single stem cell. Initial attempts at gene transfer have proved unsuccessful due to limitations of available gene transfer vectors. The present review described the newer approaches to overcome these limitations, includes the introduction of lentiviral vectors. New approaches have also focused on targeting the specific mutation in the globin genes, correcting the DNA sequence or manipulating the development in DNA translocation and splicing to restore globin chain synthesis. This review mainly discusses the gene therapy strategies for the thalassemias, including the use of lentiviral vectors, generation of induced pluripotent stem (iPS) cells, gene targeting, splice switching and stop codon readthrough. PMID- 22923961 TI - Medicine utilization review at a university teaching hospital in New Delhi. AB - OBJECTIVE: A prospective medicine usage evaluation based on prescription monitoring was conducted in the medicine OPD of our university teaching hospital to know prescribing trends of different categories of medicines. MATERIALS AND METHODS: A total of 600 patients were included in the study comprising of 339 (56.5%) males and 261 (43.5%) females. The data were recorded within the OPD by a registered pharmacist on a medicine usage evaluation form, approved by The University Institutional Review Board (IRB). RESULTS: A total of 2365 medicines were prescribed to 600 patients during the 3 months study period. The mean number of medicines per prescription were found to be 3.94. Medicines were most frequently prescribed as solid dosage forms (85.62%), especially tablets (70.82%), and liquid formulations (14.12%). Oral route (96.17%) was the most preferred mode of administration, followed by topical (2.11%) and parenteral (1.60%) routes. Combination therapy (94.33%) was more prevalent than monotherapy (5.66%). An overwhelming tendency for prescribing medicines by brand names (99%) was observed by the physicians. The most frequently prescribed class of medicines were antimicrobials > analgesics > cardiovascular > gastrointestinal agents. The most prescribed individual medicines among various therapeutic classes included isoniazid (antimicrobial), amlodipine (cardiovascular), metformin (hypoglycemic), cetirizine (antiallergic), rabeprazole (GI medicine), atorvastatin (hypolipidemic), dextromethorphan (respiratory medicine), alprazolam (sedative hypnotic), paracetamol (analgesic). CONCLUSIONS: There is a considerable scope of improvement in the existing prescribing practice, especially prescribing by generic names, needs to be encouraged and a hospital formulary has to be developed for the purpose. The number of medicines to be included per prescription should be judged rationally and polypharmacy ought to be curbed. Use of antimicrobial also needs to be rationalized as over usage of antibiotics may lead to the problems such as medicine resistance and noncompliance. PMID- 22923962 TI - Carcinogenic effects of N-nitroso-3-(substituted phenylimino)-indolin-2-one derivatives. AB - AIM: A novel series of N-nitroso-3-(substituted phenylimino)-indolin-2-one 3a-h was synthesized and tested for carcinogenic effects. MATERIALS AND METHODS: The synthesized pyrazole derivatives' chemical structures were proved by means of their infra red (IR), proton nuclear magnetic resonance ((1)H-NMR), and mass,and confirmed by elemental analyses. The carcinogenic activity was assessed by 3 (4,5dimethyl thiazole-2yl)-2,5-diphenyltetrazoliumbromide (MTT) cell-viability assay. RESULTS: The results show that most of the synthesized compounds exhibit significant carcinogenic activities. Among the synthesized compounds, N-nitroso-3 (2,4-dinitrophenylimino)-indolin-2-one 3h exhibited the most potent carcinogenic activity. CONCLUSION: The structure-activity relationship (SAR) studies show that the nature as well as the position of the amine are important for deciding the activity profile of the indolin-2-one derivatives, which reiterates the need for further experimental investigations. PMID- 22923963 TI - Effect of hydroalcoholic extract of Hypericum perforatum on selected traditional and novel biochemical factors of cardiovascular diseases and atherosclerotic lesions in hypercholesterolemic rabbits: A comparison between the extract and lovastatin. AB - CONTEXT: Evidence suggests that diets with high contents of cholesterol will increase serum lipoproteins and apolipoproteins, thereby increase risk of atherosclerosis. According to literature, some plants show hypolipidemic, hypocholestrolemic, and antiatherosclerotic activities. AIMS: In this study, antiatherosclerotic effect of Hypericum perforatum hydroalcoholic extract on hypercholesterolemic rabbits was compared with that of lovastatin. MATERIALS AND METHODS: Twenty five mature male New Zealand rabbits were randomly divided into five groups of five and were fed for 60 days as follows: Standard diet (GroupI), standard diet and hydroalcoholic extract of Hypericum perforatum (150 mg/kg daily)(GroupII), standard diet, hydroalcoholic extract of Hypericum perforatum (150 mg/ kg daily) and cholesterol (1% of food content) (Group III), standard diet and cholesterol (1% of food content)(GroupIV), and finally standard diet, lovastatin (10 mg/kg), and cholesterol (1% of foodcontent) (GroupV). RESULTS: Hypericum perforatum extract significantly decreased the levels of apolipoprotein B(apoB), apolipoprotein B/apolipoprotein A (apoB/apoA), triglyceride, cholesterol, low density lipoprotein cholesterol, oxidized LDL, malondialdehyde, and C-reactive protein (CRP) as well as atherosclerosis index, and increased high density lipoprotein and apoA in rabbits of Group III compared to the rabbits of Group IV. The effect of Hypericum perforatum extract in decreasing the level of some biochemical factors like apoB, apoB/apoA, and CRP was meaningfully more than that of lovastatin. Histopathological findings confirmed that hydroalcoholic extract of Hypericum perforatum restricted the atherosclerotic lesions. CONCLUSIONS: This study indicates that hydroalcoholic extract of Hypericum perforatum possesses hypolipidemic and anti-atherosclerotic effects and could be beneficial in the management of hyperlipidemia and atherosclerosis. PMID- 22923965 TI - Antimicrobial resistance of Staphylococcus aureus strains from patients with urinary tract infections in Yenagoa, Nigeria. AB - CONTEXT: Antimicrobial resistance in Staphylococcus aureus infections is a global public health problem resulting in very limited treatment options. This study determined the antimicrobial resistance pattern of S. aureus strains from urinary tract infections (UTIs) to commonly used antimicrobial agents. MATERIALS AND METHODS: Midstream urine specimens of UTIs symptomatic patients from public and private health institutions in Yenagoa, Nigeria were collected, cultured, and screened for common pathogens using standard microbiological protocols. The antimicrobial susceptibility of identified S. aureus strains was evaluated using disc diffusion and agar dilution techniques. RESULTS: A total of 46 (33.6%) S. aureus strains were identified from 137 growths of the 200 urine specimens. All the S. aureus isolates were methicillin resistant; they exhibited total resistance to ampicillin, 97.8% to tetracycline, 80.4% to chloramphenicol and co trimoxazole, 73.9% to gentamicin, 69.6% to augmentin and vancomycin, 54.3% to cefuroxime, 39.1% to nitrofurantoin, 34.8% to ofloxacin, and 32.6% to ciprofloxacin. The isolates were commonly resistant to 7 (77.8%) of the nine classes of antimicrobial agents used in this study and 45 (97.8%) of all the isolates were multi-resistant. CONCLUSION: The faster rate at which this pathogen is developing resistance to nitrofurantoin and fluoroquinolones is reducing their usefulness in the empiric treatment of uncomplicated UTIs. Thus, the need to adopt new strategies in the control of antibiotic resistance in this country cannot be overemphasized. PMID- 22923964 TI - The effects of Nigella sativa hydro-alcoholic extract and thymoquinone on lipopolysaccharide - induced depression like behavior in rats. AB - BACKGROUND: Neuroimmune factors have been proposed as contributors to the pathogenesis of depression. Beside other therapeutic effects including neuroprotective, antioxidant, anticonvulsant and analgesic effects, Nigella sativa and its main ingredient, thymoquinone (TQ), have been shown to have anti inflammatory effects. In the present study, the effects of Nigella sativa hydro alcoholic extract and thymoquinone was investigated on lipopolysaccharide- induced depression like behavior in rats. MATERIALS AND METHODS: 50 male Wistar rats were divided into 5 groups: Group 1 (control group) received saline instead of NS extract, thymoquinone or lipopolysaccharide. The animals in group 2 (lipopolysaccharide (LPS)) were treated by saline instead of NS extract and were injected LPS (100MUg/kg, ip) 2 hours before conducting each forced swimming test. Groups 3 (LPS + NS 200) and 4 (LPS + NS 400) were treated by 200 and 400 mg/kg of NS (ip), respectively, from the day before starting the experiments and before each forced swimming test. These animals were also injected LPS 2hours before conducting each swimming test. The animals in group 5 received TQ instead of NS extract. Forced swimming test was performed 3 times for all groups (in alternative days), and immobility time was recorded. Finally, the animals were placed in an open- field apparatus, and the crossing number on peripheral and central areas was observed. RESULTS: The immobility time in the LPS group was higher than that in the control group in all 3 times (P<0.001). The animals in LPS + NS 200, LPS + NS 400 and LPS + TQ had lower immobility times in comparison with LPS groups (P<0.01, and P<0.01). In the open- field test, the crossing number of peripheral in the LPS group was higher than that of the control one (P<0.01) while the animals of LPS + NS 200, LPS + NS 400 and LPS + TQ groups had lower crossing number of peripheral compared with the LPS group (P <0.05, and P<0.001). Furthermore, in the LPS group, the central crossing number was lower than that of the control group (P<0.01). In the animals treated by NS or TQ, the central crossing number was higher than that of the LPS group (P<0.05, and P<0.001). CONCLUSIONS: The results of the present study showed that hydro alcoholic extract of Nigella sativa can prevent LPS-induced depression like behavior in rats. These results support the traditional belief on the beneficial effects of Nigella sativa in the nervous system. Moreover, further investigations are required in order to better understand this protective effect. PMID- 22923966 TI - Hepatoprotective potential of ether insoluble phenolic components of n-butanol fraction (EPC-BF) of flaxseed against CCl(4) -induced liver damage in rats. AB - OBJECTIVE: to investigate the hepatoprotective potential of ether insoluble phenolic components of n-butanol fraction (EPC-BF) of flaxseed against CCl(4) induced liver damage in rats. MATERIALS AND METHODS: Hepatotoxicity was induced to Wistar rats by administration of 0.2% CCl(4) in olive oil (8 mL/kg, i.p.) on the seventh day of treatment. Hepatoprotective potential of EPC-BF at doses, 250 and 500 mg/kg, p.o. was assessed through biochemical and histological parameters. RESULTS: EPC-BF and silymarin pretreated animal groups showed significantly decreased activities of Aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), and level of total bilirubin, elevated by CCl(4) intoxication. Hepatic lipid peroxidation elevated by CCl(4) intoxication were also found to be alleviated at almost normal level in the EPC BF and silymarin pretreated groups. Histological studies supported the biochemical findings and treatment of EPC-BF at doses 250 and 500 mg/kg, p.o. was found to be effective in restoring CCl(4) -induced hepatic damage. However, EPC BF did not show dose-dependent hepatoprotective potential. EPC-BF depicted maximum protection against CCl(4) -induced hepatic damage at lower dose 250 mg/kg than higher dose (500 mg/ kg). CONCLUSION: EPC-BF possesses the significant hepatoprotective activity against CCl(4) induced liver damage, which could be mediated through increase in antioxidant defenses. PMID- 22923967 TI - A novel chiral GC/MS method for the analysis of fluoxetine and norfluoxetine enantiomers in biological fluids. AB - AIMS: A novel robust chiral gas chromatographic/mass spectrometric (GC/MS) method for the separation and measurement of fluoxetine and norfluoxetine enantiomers in urine and plasma was developed. MATERIALS AND METHODS: The drug was extracted from the samples by a liquid-liquid technique, using chloroform, and the enantiomers were separated and measured on a chiral gas chromatographic column (HYDRODEX beta-6TBDM((r)), 0.25 MUm * 0.25 mm * 50 m). GC/MS instrumentation was used for the acquisition of data in the electron impact selective-ion monitoring mode. RESULTS: The ions chosen were of a mass-to-charge ratio (m/z) exactly equal to 44 units, in order to measure fluoxetine enantiomers, 134 units in order to measure norfluoxetine enantiomers, and 58 units in order to measure diphenhydramine, the internal standard. The method was found to be linear and reproducible in the 50-500 ng/mL concentration range for both urine samples and plasma samples and for both fluoxetine and norfluoxetine, with correlation coefficients ranging between 0.994 and 0.997. CONCLUSIONS: This methodology has an enormous potential for application in pharmacokinetic studies of the enantiomers of fluoxetine. PMID- 22923968 TI - Synthesis and biological evaluation of Schiff bases and azetidinones of 1 naphthol. AB - INTRODUCTION: Schiff bases and azetidinones form an important structural class possessing wide spectrum of biological activities that include antibacterial and antifungal activity. A series of Schiff's bases N'-(substituted benzylidene)-2 (naphthalen-1-yloxy) acetohydrazides (3a-f) and azetidinones N-[3-chloro-2-oxo-4 (substituted phenyl)-azetidin-1-yl]-2-(naphthalen-1-yloxy) acetamides (4a-b) were synthesized and tested for antimicrobial activity. MATERIALS AND METHODS: The chemical structures of synthesized compounds were elucidated on the basis of IR and 1H NMR spectroscopy. The synthesized compounds were screened for antibacterial activity against E. coli (ESS 2231) and B. subtilis (MTCC 441). The compounds were also tested for antifungal activity against A. niger (NCIM 618) and C. albicans (NCIM 3557) by the cup diffusion method. RESULTS AND DISCUSSION: The in vitro antimicrobial activity results showed that the N-[3-chloro-2-oxo-4 (4-substitutedphenyl)-azetidin-1-yl]-2-(naphthalen-1-yloxy) acetamides (4a-b) exhibited better antibacterial activity than the synthesized N'-(substituted benzylidene)-2-(naphthalen-1-yloxy)-acetohydrazides (3a-f). Compound (4b) displayed potent antibacterial activity against the B. subtilis and E. coli (MIC values of 16-64 MUg/mL). The antifungal activity of the synthesized compounds (3a f and 4a-b) against the A. niger and C. albicans was relatively weak, most of the compounds showed poor activities (MIC >128MUg/mL). CONCLUSION: The antibacterial activity of the synthesized compounds was moderate to low and antifungal activity was relatively weak. Therefore, a further study with this class of compounds is necessary to elucidate the mechanism and structure activity relationship. PMID- 22923969 TI - Amla as an antihyperglycemic and hepato-renal protective agent in fluoride induced toxicity. AB - Purpose of the study was to examine the antihyperglycemic and hepato-renal protective effects of Emblica officinalis (Eo) fruit as a food supplement in fluoride induced toxicity. Eo fruit powder was incorporated into the diet (2.5, 5 and 10 gm %) of fluoride exposed animals for a duration of 30 days. Fluoride exposure caused significant elevation in plasma glucose, serum glutamate oxaloacetate transaminase (SGOT), serum glutamate pyruvate transaminase (SGPT), acid phosphatase (ACP), alkaline phosphatase (ALP) activities, hepatic glucose-6 phosphatase (G-6-Pase) and decreased hepatic glycogen content, hexokinase activity and antioxidant profiles (hepatic and renal). An inclusion of Eo fruit powder significantly reduced plasma glucose levels, SGOT, SGPT, ACP and ALP activities, hepatic G-6-Pase activity and increased hepatic glycogen content and hexokinase activity. Hepatic and renal antioxidant status of fluoride exposed animals improved upon feeding Eo fruit powder. We, therefore, conclude that E. officinalis fruit could be useful in regulating hyperglycemia and enhances antioxidant status of fluoride exposed animals. PMID- 22923970 TI - HCG: Yet another fraudulence. PMID- 22923971 TI - Farewell from the chief editors. PMID- 22923972 TI - Burning mouth syndrome at menopause: Elusive etiology. PMID- 22923973 TI - Effect of menopause on women's periodontium. AB - Steroid sex hormones have a significant effect on different organ systems. As far as gingiva is concerned, they can influence the cellular proliferation, differentiation and growth of keratinocytes and fibroblasts. Estrogen is mainly responsible for alterations in blood vessels and progesterone stimulates the production of inflammatory mediators. In addition, some micro-organisms found in the human mouth synthesize enzymes needed for steroid synthesis and catabolism. In women, during puberty, ovulation, pregnancy, and menopause, there is an increase in the production of sex steroid hormones which results in increased gingival inflammation, characterized by gingival enlargement, increased gingival bleeding, and cervicular fluid flow and microbial changes. PMID- 22923974 TI - Various treatment options for benign prostatic hyperplasia: A current update. AB - In benign prostatic hyperplasia (BPH) there will be a sudden impact on overall quality of life of patient. This disease occurs normally at the age of 40 or above and also is associated with sexual dysfunction. Thus, there is a need of update on current medications of this disease. The presented review provides information on medications available for BPH. Phytotherapies with some improvements in BPH are also included. Relevant articles were identified through a search of the English-language literature indexed on MEDLINE, PUBMED, Sciencedirect and the proceedings of scientific meetings. The search terms were BPH, medications for BPH, drugs for BPH, combination therapies for BPH, Phytotherapies for BPH, Ayurveda and BPH, BPH treatments in Ayurveda. Medications including watchful waitings, Alpha one adrenoreceptor blockers, 5-alpha reductase inhibitors, combination therapies including tamsulosin-dutasteride, doxazosin finasteride, terazosin-finasteride, tolterodine-tamsulosin and rofecoxib finasteride were found. Herbal remedies such as Cernilton, Saxifraga stolonifera, Zi-Shen Pill (ZSP), Orbignya speciosa, Phellodendron amurense, Ganoderma lucidum, Serenoa Repens, pumpkin extract and Lepidium meyenii (Red Maca) have some improvements on BPH are included. Other than these discussions on Ayurvedic medications, TURP and minimally invasive therapies (MITs) are also included. Recent advancements in terms of newly synthesized molecules are also discussed. Specific alpha one adrenoreceptor blockers such as tamsulosin and alfuzosin will remain preferred choice of urologists for symptom relief. Medications with combination therapies are still needs more investigation to establish as preference in initial stage for fast symptom relief reduced prostate growth and obviously reduce need for BPH-related surgery. Due to lack of proper evidence Phytotherapies are not gaining much advantage. MITs and TURP are expensive and are rarely supported by healthcare systems. PMID- 22923975 TI - Efficacy of levonorgestrel releasing intrauterine system for the treatment of menorrhagia due to benign uterine lesions in perimenopausal women. AB - AIMS: To evaluate the efficacy of levonorgestrel-releasing intrauterine system (LNG-IUS, Mirena, Bayer Healthcare) in the treatment of menorrhagia caused by benign lesions of the uterus in perimenopausal women. SETTINGS AND DESIGN: A prospective observational study was conducted to study the efficacy of levonorgestrel intrauterine device in the treatment of menorrhagia due to benign lesions of the uterus in perimenopausal women. MATERIALS AND METHODS: Forty women with menorrhagia, due to benign conditions like idiopathic menorrhagia, fibroid (not more than 12 weeks size) or adenomyosis, attending our out-patient department were included in the study. All the women underwent a PAP smear, transvaginal sonography and endometrial biopsy. Endometrial carcinoma and cervical carcinoma were excluded. LNG-IUS was inserted in the postmenstrual phase. Blood loss was assessed by pictorial blood loss assessment chart (PBAC). They were followed up after 3 months, 6 months, and after 1 year. RESULTS: Majority of the women had menstrual spotting for 3-4 months followed by infrequent menstruation, scanty menstruation or amenorrhoea. LNG-IUS was removed because of continued bleeding in two cases and was removed because of displacement in one case. It was expelled spontaneously in four cases. Thirty three women continued to use LNG-IUS. CONCLUSION: LNG-IUS is a safe and effective option for women with menorrhagia due to benign lesions of the uterus in perimenopausal women. PMID- 22923976 TI - Menopause versus aging: The predictor of obesity and metabolic aberrations among menopausal women of Karnataka, South India. AB - CONTEXT: Increased incidences of cardiovascular disorder and metabolic syndrome particularly after menopause have raised curiosity for the underlying factors. However, it is still a debate whether age or menopausal transition is a greater contributor. AIMS: To elucidate the inter-relationships of age, menopause, and associated obesity and to assess their independent effects on aggravation of cardio metabolic risk factors in postmenopausal women. SETTINGS AND DESIGN: Four hundred two women aged between 30 and 75 years were recruited in a cross sectional study from Southern India. Three hundred sixteen participants exempting exclusion criteria, comprising of 169 premenopausal and 147 postmenopausal women were finally included. MATERIALS AND METHODS: Anthropometric measurements such as weight, height, waist circumference (WC), hip circumference (HC), fat percentage, basal metabolic rate (BMR), and blood pressure were taken. Fasting plasma glucose, postprandial glucose, glycated hemoglobin (HbA1c), lipid profile, and C reactive protein (CRP) were also measured. STATISTICAL ANALYSIS USED: Independent t-test, Analysis of covariates (ANCOVA), Pearson's correlation coefficients and multiple stepwise linear regression model analysis were done. RESULTS: A significant increase in physical and metabolic factors was observed in postmenopausal women compared to premenopausal women except WC and HbA1c. Contrastingly, high-density lipoprotein cholesterol (HDL) levels and BMR were significantly decreased. After adjusting for BMI and age, the significant differences in the variables through the menopausal transition persisted, including an increase in WC. Significant correlation was observed between age and measures of general obesity such as BMI (P < 0.05) and fat percentage (P < 0.001) but not with central obesity indices. Menopausal status and WC exerted an independent effect on most of the metabolic risk factors (P < 0.001 or P < 0.01). Fat percentage was the predicting variable for CRP, HbA1c, diastolic blood pressure (P < 0.001), and HDL (P < 0.01). But Age showed independent effect only on HbA1c. CONCLUSIONS: Menopausal transition brings about anomalies in total body composition characterized by an increased body fat mass and central adiposity. This creates a compatible atmosphere for abnormal metabolism and aggravated cardio metabolic risk factors. Thus, menopausal status and associated obesity is the major predictor of metabolic aberrations over age in menopausal women. PMID- 22923977 TI - A study of predictors of anxiety and depression among stroke patient-caregivers. AB - CONTEXT: Caregivers play an important role in supporting people with illness either acute or chronic. It is important to explore caregiver's emotional turmoil as it helps in exploring their burden which can have impact on the patient's illness and functioning apart from their own. AIMS: The current study aimed at assessing the predictors of anxiety and depression among caregivers of patients with stroke. SETTINGS AND DESIGN: Seventy-five consecutive patient-caregiver dyads were recruited in the study. MATERIALS AND METHODS: Patients and caregivers were assessed using a semi-structured proforma for the sociodemographic details. Subsequently these dyads were assessed for anxiety and depression levels using the Hospital Anxiety and Depression Scale. STATISTICAL ANALYSIS USED: Chi-square tests (for categorical variables) were used to find difference between the patients and the caregivers on different variables. Additionally Cramer's V-test and phi test were used for 2*4 contingency tables. Linear regression model was used. RESULTS: Linear regression revealed that anxiety level in caregivers was predicted by the sex of care giver. CONCLUSIONS: Caring for the patients with stroke presents increased burden to the care givers which manifests as increased rate of anxiety and depression among them. It is important to assess the care givers along with the patients for emergence of these negative affective states. One needs to be extra cautious if the patient happens to be the primary earning member of the family. PMID- 22923978 TI - Assessment of anxiety and depression in patients with burning mouth syndrome: A clinical trial. AB - INTRODUCTION: Burning mouth syndrome is a chronic pain syndrome primarily affecting elderly women with hormonal changes or psychological disorders. It is multifactorial in origin, often idiopathic and its etiopathogenesis, majorly being neuropathic, largely remains enigmatic. AIM: To determine the prevalence of burning mouth symptom, in elderly women and evaluate local and systemic causes responsible for burning sensation. MATERIALS AND METHODS: 100 elderly postmenopausal women were included in the study out of which 56 had a chief complaint of burning sensation. These patients were evaluated for the levels of anxiety and depression by means of questionnaire. The severity of burning and the response to the treatment was assessed with a five point Visual Analog Scale. The results were analyzed using "Chi-square test". RESULTS: There was statistically significant increase in the levels of anxiety and depression in the study group. CONCLUSION: The present study clearly indicates that most of the patients had moderate to severe levels of depression, which suggests that anxiety and depression are constant features in postmenopausal female patients. PMID- 22923979 TI - Posthysterectomy fallopian tube prolapse. AB - Fallopian tube prolapse into the vaginal vault is a rare complication after hysterectomy with adnexal preservation. It can occur following vaginal and abdominal hysterectomy, and rarely following interposition and colpotomy. Histopathology is the only means of definitive diagnosis. Prevention of tubal prolapse can be achieved by suturing the adnexae high in the pelvis at abdominal hysterectomy, and the incidence decreases if the pelvic peritoneum is closed properly. PMID- 22923980 TI - Giant adrenal myelolipoma with hemorrhage masquerading as retroperitoneal sarcoma. AB - Adrenal myelolipomas are functionally inactive, rare adrenal tumors which are usually small in size and are discovered incidentally. Giant symptomatic myelolipomas have rarely been reported in medical literature. Here, we describe the case of a 40-year-old female patient who presented to the surgical outpatient department with left flank pain. An ultrasonogram of the abdomen suggested a large retroperitoneal tumor which was then surgically resected. Histopathological examination of the resected specimen revealed a giant adrenal myelolipoma with intratumoral hemorrhage. The patient was relieved of symptoms and was free of any complaints in follow-up. PMID- 22923981 TI - Modified shoe for adjusting hard stuffy and smelly sole: An uncommon accompaniment of hypothyroidism. AB - Disorders of smell and taste are both neglected as well as underreported problems of hypothyroidism. A 35-year-old male presented with intolerance to cold, dryness of skin, and swelling of both feet and some foul smelling odor from his feet. When we examined his feet we found that instead of wearing his shoes properly he had just slipped his feet inside the shoe so that the odor from his feet is not smelled by us. Although this symptom was largely ignored by many doctors, the literature mentions that patients of hypothyroidism may perceive dysosmia (distortion of smell) and hyposmia (elevated threshold for detection of smell). PMID- 22923982 TI - Aggressive angiomyxoma of the vulva. AB - Aggressive angiomyxoma is a rare, benign neoplasm occurring in 3(rd) to 5(th) decade of life that can be mistaken both clinically and on microscopy for several other conditions, it should be included as a differential diagnosis for any vaginal mass. These lesions have a predilection for female pelvic soft tissues, slow in growth, and are characterized histologically by a predominantly myxoid stroma and an abundance of thin and thick walled vascular channels. This is a deep soft tissue tumor, which as the name suggests, may have a locally aggressive course. Most tumors occur in women and are large, usually greater than 10 cm, slowly growing, and painless. Standard of care treatment for angiomyxoma has been surgery. Some authors believe that it is the only possible treatment, but surgery is often radical and can be mutilating, with massive blood loss. PMID- 22923983 TI - Peeping thread from a laparotomy scar: Misery of an old man. AB - Despite availability of modern methods of various surgical techniques for treating complicated patients, there are still some unreported incidents in day to day practice where simple surgical procedure ends up in unwanted complications. This may be attributed sometimes to the negligence of treating doctors and sometime to the patient himself. We present here one such case where unnecessary morbidity added to the patient after surgery. PMID- 22923984 TI - Comment on "Glutathione peroxidase activity in obese and nonobese diabetic patients and role of hyperglycemia in oxidative stress". PMID- 22923985 TI - RECIPROCAL RELATION BETWEEN POPULATION AND ENVIRONMENT: INNOVATIONS ON FLORA DATA COLLECTION. AB - In recent years, social and natural scientists have gained interest in understanding reciprocal relations between human populations and the environment. Research methods have been developed for investigating the secrets of interations of human and environment. This paper describes the flora data collection methods used in a longitudinal research project "Reciprocal Relation Between Population and the Environment" and highlights how the research sites were selected, how the research plots were designed in each site and how the qualitative and quantitative data of flora found in each research plot were recorded. This paper also discusses how the flora data can be linked with sociodemographic data and how the data can be used to unfold the effect of human activities on flora diversity and/or the effect of flora on the life of the human population in the study area. PMID- 22923986 TI - Development of terbinafine solid lipid nanoparticles as a topical delivery system. AB - To resolve problems of long treatment durations and frequent administration of the antifungal agent terbinafine (TB), solid lipid nanoparticles (SLNs) with the ability to load lipophilic drugs and nanosize were developed. The SLNs were manufactured by a microemulsion technique in which glyceryl monostearate (GMS), glyceryl behenate (Compritol((r)) 888; Gattefosse), and glyceryl palmitostearate (Precirol((r)) ATO 5; Gattefosse) were used as the solid lipid phases, Tween((r)) and Cremophor((r)) series as the surfactants, and propylene glycol as the cosurfactant to construct ternary phase diagrams. The skin of nude mice was used as a barrier membrane, and penetration levels of TB of the designed formulations and a commercial product, Lamisil((r)) OnceTM (Novartis Pharmaceuticals), in the stratum corneum (SC), viable epidermis, and dermis were measured; particle sizes were determined as an indicator of stability. The optimal SLN system contained a <5% lipid phase and >50% water phase. The addition of ethanol or etchants had no significant effect on enhancing the amount of TB that penetrated the skin layers, but it was enhanced by increasing the percentage of the lipid phase. Furthermore, the combination of GMS and Compritol((r)) 888 was able to increase the stable amount of TB that penetrated all skin layers. For the ACP1-GM1 (4% lipid phase; Compritol((r)) 888: GMS of 1:1) formulation, the amount of TB that penetrated the SC was similar to that of Lamisil((r)) OnceTM, whereas the amount of TB of the dermis was higher than that of Lamisil((r)) OnceTM at 12 hours, and it was almost the same as that of Lamisil((r)) OnceTM at 24 hours. It was concluded that the application of ACP1-GM1 for 12 hours might have an efficacy comparable to that of Lamisil((r)) OnceTM for 24 hours, which would resolve the practical problem of the longer administration period that is necessary for Lamisil((r)) OnceTM. PMID- 22923987 TI - Effects of pH-sensitive chain length on release of doxorubicin from mPEG-b-PH-b PLLA nanoparticles. AB - BACKGROUND: Two methoxyl poly(ethylene glycol)-poly(L-histidine)-poly(L-lactide) (mPEG-PH-PLLA) triblock copolymers with different poly(L-histidine) chain lengths were synthesized. The morphology and biocompatibility of these self-assembled nanoparticles was investigated. METHODS: Doxorubicin, an antitumor drug, was trapped in the nanoparticles to explore their drug-release behavior. The drug loaded nanoparticles were incubated with HepG2 cells to evaluate their antitumor efficacy in vitro. The effects of poly(L-histidine) chain length on the properties, drug-release behavior, and antitumor efficiency of the nanoparticles were investigated. RESULTS: The nanoparticles were pH-sensitive. The mean diameters of the two types of mPEG-PH- PLLA nanoparticle were less than 200 nm when the pH values were 5.0 and 7.4. The nanoparticles were nontoxic to NIH 3T3 fibroblasts and HepG2 cells. The release of doxorubicin at pH 5.0 was much faster than that at pH 7.4. The release rate of mPEG(45)-PH(15)-PLLA(82) nanoparticles was much faster than that of mPEG(45)-PH(30)-PLLA(82) nanoparticles at pH 5.0. CONCLUSION: The inhibition effect of mPEG(45)-PH(15)-PLLA(82) nanoparticles on the growth of HepG2 cells was greater than that of mPEG(45)-PH(30)-PLLA(82) nanoparticles when the concentration of encapsulated doxorubicin was less than 15 MUg/mL. PMID- 22923988 TI - Peptide ligand and PEG-mediated long-circulating liposome targeted to FGFR overexpressing tumor in vivo. AB - BACKGROUND AND METHODS: Paclitaxel, a widely used antitumor agent, has limited clinical application due to its hydrophobicity and systemic toxicity. To achieve sustained and targeted delivery of paclitaxel to tumor sites, liposomes composed of egg phosphatidylcholine, cholesterol, and distearolyphosphatidyl ethanolamine N-poly(ethylene glycol) (PEG(2000)) were prepared by a lipid film method. In addition, the liposomes also contained truncated fibroblast growth factor fragment-PEG-cholesterol as a ligand targeting the tumor marker fibroblast growth factor receptor. Physicochemical characteristics, such as particle size, zeta potential, entrapment efficiency, and release profiles were investigated. Pharmacokinetics and biodistribution were evaluated in C57BL/6 J mice bearing B16 melanoma after intravenous injection of paclitaxel formulated in Cremophor EL (free paclitaxel), conventional liposomes (CL-PTX), or in targeted PEGylated liposomes (TL-PTX). RESULTS: Compared with CL-PTX and free paclitaxel, TL-PTX prolonged the half-life of paclitaxel by 2.01-fold and 3.40-fold, respectively, in plasma and improved the AUC(0->t) values of paclitaxel by 1.56-fold and 2.31 fold, respectively, in blood. Biodistribution studies showed high accumulation of TL-PTX in tumor tissue and organs containing the mononuclear phagocyte system (liver and spleen), but a considerable decrease in other organs (heart, lung, and kidney) compared with CL-PTX and free paclitaxel. CONCLUSION: The truncated fibroblast growth factor fragment-conjugated PEGylated liposome has promising potential as a long-circulating and tumor-targeting carrier system. PMID- 22923989 TI - Carbon nanotube interaction with extracellular matrix proteins producing scaffolds for tissue engineering. AB - In recent years, significant progress has been made in organ transplantation, surgical reconstruction, and the use of artificial prostheses to treat the loss or failure of an organ or bone tissue. In recent years, considerable attention has been given to carbon nanotubes and collagen composite materials and their applications in the field of tissue engineering due to their minimal foreign-body reactions, an intrinsic antibacterial nature, biocompatibility, biodegradability, and the ability to be molded into various geometries and forms such as porous structures, suitable for cell ingrowth, proliferation, and differentiation. Recently, grafted collagen and some other natural and synthetic polymers with carbon nanotubes have been incorporated to increase the mechanical strength of these composites. Carbon nanotube composites are thus emerging as potential materials for artificial bone and bone regeneration in tissue engineering. PMID- 22923991 TI - Intracellular CXCR4+ cell targeting with T22-empowered protein-only nanoparticles. AB - BACKGROUND: Cell-targeting peptides or proteins are appealing tools in nanomedicine and innovative medicines because they increase the local drug concentration and reduce potential side effects. CXC chemokine receptor 4 (CXCR4) is a cell surface marker associated with several severe human pathologies, including colorectal cancer, for which intracellular targeting agents are currently missing. RESULTS: Four different peptides that bind CXCR4 were tested for their ability to internalize a green fluorescent protein-based reporter nanoparticle into CXCR4+ cells. Among them, only the 18 mer peptide T22, an engineered segment derivative of polyphemusin II from the horseshoe crab, efficiently penetrated target cells via a rapid, receptor-specific endosomal route. This resulted in accumulation of the reporter nanoparticle in a fully fluorescent and stable form in the perinuclear region of the target cells, without toxicity either in cell culture or in an in vivo model of metastatic colorectal cancer. CONCLUSION: Given the urgent demand for targeting agents in the research, diagnosis, and treatment of CXCR4-linked diseases, including colorectal cancer and human immunodeficiency virus infection, T22 appears to be a promising tag for the intracellular delivery of protein drugs, nanoparticles, and imaging agents. PMID- 22923993 TI - Sustained-release G-CSF microspheres using a novel solid-in-oil-in-oil-in-water emulsion method. AB - BACKGROUND: The main treatments for cancers are still chemotherapy and radiotherapy for intermediate-stage cancer and terminal cancer. However, the therapeutic methods often result in a decreased neutrophilic granulocyte count and other side effects. In this study, in order to improve the neutrophilic granulocyte levels in the blood after radiotherapy and chemotherapy, we developed a sustained-release granulocyte colony-stimulating factor (G-CSF) microsphere formulation using a novel solid-in-oil-in-oil-in-water (S/O/O/W) emulsification method. METHODS: G-CSF was loaded into dextran nanoparticles by freezing-induced phase separation, and then the G-CSF-loaded nanoparticles were encapsulated into sustained-release poly(lactic-co- glycolic acid) microspheres using S/O/O/W emulsification. The control microspheres were also prepared through W/O/W emulsification. The performance of the two microsphere formulations was investigated both in vitro and in vivo. RESULTS: The microspheres for the controlled release of G-CSF in a zero-order or near-zero-order pattern were provided for 2 weeks. The in vitro cumulative G-CSF release kept over 90% of its bioactivity, which was proved by a NFS-60 cell line growth assay. The microspheres of the control group fabricated by W/O/W emulsification maintained less then half of its bioactivity. The in vivo efficacy of microspheres made using the S/O/O/W method was higher than those using the W/O/W method. CONCLUSION: These results suggested that the microspheres prepared by the S/O/O/W method had increased neutrophil activity compared to those prepared by W/O/W. PMID- 22923994 TI - Diabetes mellitus and comorbid depression: improvement of both diseases with milnacipran. A replication study (results of the Austrian Major Depression Diabetes Mellitus study group). AB - Comorbid depression is common in patients with type 2 diabetes mellitus and is associated with greater mortality risk and a higher incidence of diabetic complications and decreased quality of life. In an earlier pilot study, we found that treatment with the serotonin norepinephrine reuptake inhibitor antidepressant, milnacipran, significantly improved metabolic parameters in diabetic patients with comorbid depression who had an antidepressant response. We sought to replicate these results in a larger cohort (n = 135). Patients received milnacipran and metformin for 6 months and metabolic parameters and depressive symptoms were measured at baseline and after 3 and 6 months. At the end of the study, 72.6% of patients had an antidepressant response (>=50% reduction of baseline Beck Depression Inventory score). Overall, there was significant improvement in the metabolic and anthropometric parameters measured. The number of patients with glycated hemoglobin > 8% (>63.9 mmol/mol), an indicator of poor metabolic control requiring intensive therapeutic intervention, decreased from 31.9% at baseline to 11.9% during the study. As found in the pilot study, levels of total cholesterol and triglycerides were only significantly decreased in antidepressant responders. Body weight was significantly reduced in both responders and nonresponders but the effect size was significantly greater in the responder group. In contrast to the pilot study, fasting blood glucose and glycated hemoglobin were significantly decreased to a similar extent in both antidepressant-responders and nonresponders. The present study thus replicates some of the original findings. The main difference between the present and the pilot study is that in the larger cohort significant reductions in fasting blood glucose and glycated hemoglobin were found in all patients irrespective of whether or not they responded to antidepressant treatment. The present data underline the importance of diagnosis and treatment of comorbid depression in patients with type 2 diabetes mellitus with milnacipran. PMID- 22923992 TI - Nanoparticles and their potential for application in bone. AB - Biomaterials are commonly applied in regenerative therapy and tissue engineering in bone, and have been substantially refined in recent years. Thereby, research approaches focus more and more on nanoparticles, which have great potential for a variety of applications. Generally, nanoparticles interact distinctively with bone cells and tissue, depending on their composition, size, and shape. Therefore, detailed analyses of nanoparticle effects on cellular functions have been performed to select the most suitable candidates for supporting bone regeneration. This review will highlight potential nanoparticle applications in bone, focusing on cell labeling as well as drug and gene delivery. Labeling, eg, of mesenchymal stem cells, which display exceptional regenerative potential, makes monitoring and evaluation of cell therapy approaches possible. By including bioactive molecules in nanoparticles, locally and temporally controlled support of tissue regeneration is feasible, eg, to directly influence osteoblast differentiation or excessive osteoclast behavior. In addition, the delivery of genetic material with nanoparticulate carriers offers the possibility of overcoming certain disadvantages of standard protein delivery approaches, such as aggregation in the bloodstream during systemic therapy. Moreover, nanoparticles are already clinically applied in cancer treatment. Thus, corresponding efforts could lead to new therapeutic strategies to improve bone regeneration or to treat bone disorders. PMID- 22923995 TI - Helicobacter pylori infection is identified as a cardiovascular risk factor in Central Africans. AB - BACKGROUND: Helicobacter pylori is now incriminated in the pathogenesis of atherosclerosis. OBJECTIVE: To examine the importance of H. pylori infection as a cardiovascular disease (CVD) risk factor. METHODS: Two hundred five patients (128 with H. pylori infection [HP-seropositive] and 77 without) had a baseline assessment for other potential CVD risk factors and were followed prospectively for 10 years (1999-2008). They were assessed on a monthly basis for the outcomes of carotid plaque, angina pectoris, myocardial infarction, and stroke. In the HP seropositive group, male sex and quartile 4 for IgG anti-H. pylori antibodies (anti-HP Ab) were correlated with traditional CVD risk factors, stroke, myocardial infarction, and angina pectoris. RESULTS: At the baseline assessment, the levels of carotid intima-media thickness, blood fibrinogen, total cholesterol, fasting plasma glucose, and uric acid were higher in H. pylori infected patients than in the uninfected group. Serum HDL-cholesterol was significantly lower in the HP-seropositive group. Men had higher levels of IgG anti-HP Ab, waist circumference, blood pressure, uric acid, and total cholesterol than women. Within the HP-seropositive group, individuals in quartile 4 for IgG anti-HP Ab had higher rates of elevated fibrinogen, diabetes mellitus, low high density lipoprotein cholesterol, arterial hypertension, and high total cholesterol than those in quartile 1. After adjusting for traditional CVD risk factors, H. pylori infection was the only independent predictor of incident carotid plaque (multivariate odds ratio [OR] = 2.3, 95% confidence interval [CI]: 1.2-7.2; P < 0.0001) and incident acute stroke (multivariate OR = 3.6, 95% CI: 1.4-8.2; P < 0.0001). Within the HP-seropositive group and after adjusting for traditional CVD risk factors, male sex was the only independent predictor of incident angina pectoris (multivariate OR = 3.5, 95% CI: 1.6-16; P < 0.0001), incident acute stroke (multivariate OR = 3.2, 95% CI: 1.4-28; P < 0.0001), and acute myocardial infarction (multivariate OR = 7.2, 95% CI: 3.1-18; P < 0.0001). CONCLUSION: Our study provides evidence for an association among known CVD risk factors, carotid plaque, stroke, and H. pylori infection. Among infected individuals, there is a significant association among severity of HP seropositivity, male sex, and CVD. The eradication of H. pylori infection may therefore reduce the emerging burden of CVD in Africa. PMID- 22923996 TI - Sinusitis and chronic cough in children. AB - BACKGROUND: Chronic cough in children is a common problem, and sinusitis is a common etiology. The diagnosis of sinusitis is often clinical, but confirmation is thought to require a CT scan due to the difficulty of interpreting a Water's view sinus X-ray. OBJECTIVES: The purposes of the study were (1) to examine the frequency of an abnormal sinus X-ray in children with a chronic cough of more than 4 weeks duration; (2) to compare the interpretation of the sinus film between allergy/pulmonary clinicians and radiologists; and (3) to correlate symptoms with X-ray results. METHODS: A chart review of 2- to 18-year-old patients with coughing exceeding 4 weeks was performed. Data was collected for patients who had received a Water's view sinus film as part of their evaluation. Exam, X-ray results, and clinical outcomes were categorized and statistical analyses performed. RESULTS: A total of 86 patients were included. Clinicians found that 65% of the children had positive Water's view films, compared with the radiologist's reading of 62% (non significant). Significant associations between post-tussive emesis (P = 0.01) and purulence (P = 0.03) were noted with a positive film. Positive sinus X-ray was highly associated with all findings except wheeze when present together (P < 0.001). CONCLUSION: Sinus abnormalities on X-ray are associated with prolonged cough in 65% of children. The Water's view sinus film is a clinically useful screening tool for clinicians in the workup of chronic cough. Certain physical findings and clinical complaints, when present concurrently, correlate with the X-ray results. PMID- 22923997 TI - Long-term use of doxycycline can improve chronic asthma and possibly remodeling: the result of a pilot observation. AB - Progressive loss of lung function and reversibility characterize chronic asthma. The conventional therapy is targeted to control the disease without targeting the loss of lung function or reversibility. In a prospective real-world observation of long-term use of add-on doxycycline as a matrix-metalloproteinase inhibitor, we documented significant improvement in lung function with possible reversal of remodeling. BACKGROUND: Chronic asthma shows progressive decline in lung function with reduction or even loss of reversibility secondary to remodeling. A set of endopeptidase enzymes known as matrix metalloproteinases are intimately related to the pathogenesis of asthma and remodeling. The inhibition of matrix metalloproteinases is recognized as a prospective way of treating asthma and its corresponding structural remodeling. METHODS: In a randomized, prospective, real world study, we have observed the change in lung function (spirometry) with an add-on of long-term doxycycline to standard asthma therapy as per the Global Initiative for Asthma guidelines in a small asthmatic population. The change in terms of forced expiratory volume (FEV(1)), forced vital capacity (FVC), percent of FEV(1) (FEV(1)%), and forced expiratory flow (FEF(25-75)) were noted following variable duration of doxycycline therapy. RESULTS: There has been a global improvement in all the parameters in all the six patients suggesting improvement in obstruction, and reduction in air trapping following a treatment of add-on doxycycline for a mean duration of 162.83 +/- 83.07 days. Of the changes seen, the post bronchodilator FEV(1), the FVC, and the FEF(25-75) showed significant improvements with the P-value set at 0.004, 0.054, and 0.031, respectively. There was also evidence of the reversal of remodeling from the improvement in the FEV(1)/FVC ratio. Moreover there was a greater than expected improvement of pre bronchodilator FEV(1) after treatment that far surpassed the initial post bronchodialator FEV(1) value. Even after such a change, there were presences of some reversibility suggesting room for further improvement. CONCLUSION: The results suggest significant improvements in the obstructive parameters used to evaluate asthma, with possible reversal of remodeling evident in chronic asthmatics when treated with doxycycline in addition to standard therapies. This observation needs further scientific validation. PMID- 22923998 TI - Targeting the kidney and glucose excretion with dapagliflozin: preclinical and clinical evidence for SGLT2 inhibition as a new option for treatment of type 2 diabetes mellitus. AB - Sodium-glucose cotransporter-2 (SGLT2) inhibitors are a novel class of glucuretic, antihyperglycemic drugs that target the process of renal glucose reabsorption and induce glucuresis independently of insulin secretion or action. In patients with type 2 diabetes mellitus, SGLT2 inhibitors have been found to consistently reduce measures of hyperglycemia, including hemoglobin A1c, fasting plasma glucose, and postprandial glucose, throughout the continuum of disease. By inducing the renal excretion of glucose and its associated calories, SGLT2 inhibitors reduce weight and have the potential to be disease modifying by addressing the caloric excess that is believed to be one of the root causes of type 2 diabetes mellitus. Additional benefits, including the possibility for combination with insulin-dependent antihyperglycemic drugs, a low potential for hypoglycemia, and the ability to reduce blood pressure, were anticipated from the novel mechanism of action and have been demonstrated in clinical studies. Mechanism-related risks include an increased incidence of urinary tract and genital infections and the possibility of over-diuresis in volume-sensitive patients. Taken together, the results of Phase III clinical studies generally point to a positive benefit-risk ratio across the continuum of diabetes patients. To date, data on dapagliflozin, a selective SGLT2 inhibitor in development, demonstrate that the kidney is an efficacious and safe target for therapy, and that SGLT2 inhibition may have benefits for patients with type 2 diabetes mellitus beyond glycemic control. PMID- 22923999 TI - Glucose estimation in the salivary secretion of diabetes mellitus patients. AB - AIM: Saliva is one of the most abundant secretions in the human body and its collection is easy and noninvasive. The aim of this study was to find a medium that can be used to diagnose and monitor diabetes. In this, saliva could play a major role. To substantiate the role of saliva as a diagnostic tool, we compared saliva samples with blood glucose and glycated hemoglobin (HbA(1c)) in healthy and diabetic subjects. MATERIALS AND METHODS: Included in the study were 106 patients, newly diagnosed with type 2 diabetes mellitus and 15 healthy control subjects. The patients and control subjects were asked to come to the clinic in the morning, after an 8-hour fast. At that time, 5 mL of venous blood was collected, 2 mL of which was collected in an ethylenediaminetetraacetic acid (EDTA)-containing blood collection tube and sent for HbA(1c) estimation. Unstimulated saliva was collected from both groups as well. The saliva and sera from the blood samples were subjected to glucose estimation. RESULTS: The correlation coefficient between serum glucose and salivary glucose in the control group was calculated and the r value was found to be 0.5216, which was statistically significant (P < 0.05). The correlation coefficient between serum glucose and salivary glucose in the patient group was also calculated and the r value was found to be 0.7686, which was highly significant (P < 0.01). Finally, the correlation coefficient between HbA(1c) level and salivary glucose in the patient group was calculated and the r value was found to be 0.5662, which was also highly significant (P < 0.01). PMID- 22924000 TI - Pilot study on the additive effects of berberine and oral type 2 diabetes agents for patients with suboptimal glycemic control. AB - BACKGROUND: Suboptimal glycemic control is a common situation in diabetes, regardless of the wide range of drugs available to reach glycemic targets. Basic research in diabetes is endeavoring to identify new actives working as insulin savers, use of which could delay the introduction of injectable insulin or reduce the insulin dose needed. Commonly available as a nutraceutical, berberine is a potential candidate. METHODS AND RESULTS: Because its low oral bioavailability can be overcome by P-glycoprotein inhibitors like herbal polyphenols, we have tested the nutraceutical combination of Berberis aristata extract and Silybum marianum extract (Berberol((r))) in type 2 diabetes in terms of its additive effect when combined with a conventional oral regimen for patients with suboptimal glycemic control. After 90 days of treatment, the nutraceutical association had a positive effect on glycemic and lipid parameters, significantly reducing glycosylated hemoglobin, basal insulin, homeostatic model assessment of insulin resistance, total and low-density lipoprotein cholesterol, and triglycerides. A relevant effect was also observed in terms of liver function by measuring aspartate transaminase and alanine transaminase. The product had a good safety profile, with distinctive gastrointestinal side effects likely due to its acarbose-like action. CONCLUSION: Although further studies should be carried out to confirm our data, Berberol could be considered a good candidate as an adjunctive treatment option in diabetes, especially in patients with suboptimal glycemic control. PMID- 22924001 TI - Prediction of insulin resistance with anthropometric measures: lessons from a large adolescent population. AB - OBJECTIVE: The aim of this study was to describe the minimum number of anthropometric measures that will optimally predict insulin resistance (IR) and to characterize the utility of these measures among obese and nonobese adolescents. RESEARCH DESIGN AND METHODS: SIX ANTHROPOMETRIC MEASURES (SELECTED FROM THREE CATEGORIES: central adiposity, weight, and body composition) were measured from 1298 adolescents attending two New York City public high schools. Body composition was determined by bioelectric impedance analysis (BIA). The homeostatic model assessment of IR (HOMA-IR), based on fasting glucose and insulin concentrations, was used to estimate IR. Stepwise linear regression analyses were performed to predict HOMA-IR based on the six selected measures, while controlling for age. RESULTS: The stepwise regression retained both waist circumference (WC) and percentage of body fat (BF%). Notably, BMI was not retained. WC was a stronger predictor of HOMA-IR than BMI was. A regression model using solely WC performed best among the obese II group, while a model using solely BF% performed best among the lean group. Receiver operator characteristic curves showed the WC and BF% model to be more sensitive in detecting IR than BMI, but with less specificity. CONCLUSION: WC combined with BF% was the best predictor of HOMA-IR. This finding can be attributed partly to the ability of BF% to model HOMA-IR among leaner participants and to the ability of WC to model HOMA IR among participants who are more obese. BMI was comparatively weak in predicting IR, suggesting that assessments that are more comprehensive and include body composition analysis could increase detection of IR during adolescence, especially among those who are lean, yet insulin-resistant. PMID- 22924002 TI - Six-minute walk test in non-insulin-dependent diabetes mellitus patients living in Northwest Africa. AB - INTRODUCTION: International recommendations of the exploration of non-insulin dependent diabetes mellitus (NIDDM) are focused on deficiency and not incapacity. AIMS: (1) To estimate the incapacity of NIDDM patients through the 6-minute walk test (6MWT) data. (2) To determine their 6-minute walk distance (6MWD) influencing factors (3) To compare data of NIDDM patient group (PG; n = 100) with those of two control groups (CG): CG1 (n = 174, healthy nonobese and nonsmoker); CG2 (n = 55, obese nondiabetic free from comorbidities). POPULATION AND METHODS: The anthropometric, socioeconomic, clinical, metabolic, and 6MWT data of 100 NIDDM patients (45 females) were collected. RESULTS: Total sample means +/- standard deviation of age, weight, and height were 54 +/- 8 years, 81 +/- 14 kg, and 1.64 +/- 0.09 m. (1) Measured 6MWD (566 +/- 81 m) was significantly lower than the theoretical 6MWD (90% +/- 12%). The profile of the PG carrying the 6MWT, was as follows: 23% had an abnormal 6MWD; at the end of the 6MWT, 21% and 12% had, respectively, a low heart rate and a high dyspnea (>5/10), and 4% had desaturation during the walk. The estimated "cardiorespiratory and muscular chain" age (68 +/- 16 years) was significantly higher than the chronological age. (2) The factors that significantly influenced the 6MWD (r(2) = 0.58) are included in the following equation: 6MWD (m) = -73.94 * gender (0, male; 1, female) - 3.25 * age (years) + 7.33 * leisure activity score - 35.57 * obesity (0, no; 1, yes) + 32.86 * socioeconomic level (0, low; 1, high) - 27.67 * cigarette use (0, no; 1, yes) + 8.89 * resting oxyhemoglobin saturation - 105.48. (3) Compared to the CGs, the PG had a significantly (P < 0.05) lower 6MWD (100%+9% and 100%+8%, respectively, for the CG1 and CG2). CONCLUSION: NIDDM seems to accelerate the decline of the submaximal aerobic capacity evaluated through the 6MWD. PMID- 22924004 TI - Reduction in urinary albumin excretion with a moderate low-carbohydrate diet in patients with type 2 diabetes: a 12-month intervention. AB - INTRODUCTION: Urinary albumin excretion (UAE) is a marker of the early phase of diabetic nephropathy. Although a low-carbohydrate diet (LCD) has been shown to effectively improve glycemic control in patients with type 2 diabetes (T2DM), its effects on UAE remain unknown. PATIENTS AND METHODS: A total of 124 patients (mean age +/- standard deviation, 61.6 +/- 9.2 years) with T2DM were instructed to consume a moderate LCD (1734 +/- 416 kcal/d; % carbohydrate:fat:protein = 38:37:19) for 12 months. We measured the levels of UAE, hemoglobin A(1c), fasting plasma glucose, fasting serum insulin (IRI), and the serum lipid profiles in the patients and recorded their dosages of antidiabetic drugs during this 12-month period. RESULTS: Of the 124 patients, 68 were normoalbuminuric, 50 were microalbuminuric, and six were macroalbuminuric at baseline. The patients had relatively good compliance with the moderate LCD diet. After 12 months, the mean levels of hemoglobin A(1c), fasting plasma glucose, IRI, homeostasis model assessment-estimated insulin resistance, and the body mass index of all participants significantly decreased (P = 0.003 for IRI and P < 0.001 for the other parameters). Among the microalbuminuric patients (n = 50), remission to normoalbuminuria was frequently achieved (52%) and the geometric mean UAE significantly decreased by 53% (95% confidence interval: 43, 62) over 12 months (P < 0.001). After patients taking an angiotensin 2 receptor blocker were excluded, the UAE significantly decreased by 41% (n = 26, 95% confidence interval: 25, 54; P < 0.001). Moreover, the reduction in UAE was significantly and positively correlated with a reduction in homeostasis model assessment estimated insulin resistance levels (r(s) = 0.308; P = 0.031). CONCLUSION: A moderate LCD (38% carbohydrate diet) achieved a remarkable reduction in UAE over 12 months in microalbuminuric patients with T2DM. PMID- 22924005 TI - Pharmacological approaches to the management of type 2 diabetes in fasting adults during Ramadan. PMID- 22924006 TI - Placental-mediated increased cytokine response to lipopolysaccharides: a potential mechanism for enhanced inflammation susceptibility of the preterm fetus. AB - BACKGROUND: Cerebral palsy is a nonprogressive motor impairment syndrome that has no effective cure. The etiology of most cases of cerebral palsy remains unknown; however, recent epidemiologic data have demonstrated an association between fetal neurologic injury and infection/inflammation. Maternal infection/inflammation may be associated with the induction of placental cytokines that could result in increased fetal proinflammatory cytokine exposure, and development of neonatal neurologic injury. Therefore, we sought to explore the mechanism by which maternal infection may produce a placental inflammatory response. We specifically examined rat placental cytokine production and activation of the Toll-like receptor 4 (TLR4) pathway in response to lipopolysaccharide exposure at preterm and near-term gestational ages. METHODS: Preterm (e16) or near-term (e20) placental explants from pregnant rats were treated with 0, 1, or 10 MUg/mL lipopolysaccharide. Explant integrity was assessed by lactate dehydrogenase assay. Interleukin-6 and tumor necrosis alpha levels were determined using enzyme linked immunosorbent assay kits. TLR4 and phosphorylated nuclear factor kappa light chain enhancer of activated B cells (NFkappaB) protein expression levels were determined by Western blot analysis. RESULTS: At both e16 and e20, lactate dehydrogenase levels were unchanged by treatment with lipopolysaccharide. After exposure to lipopolysaccharide, the release of interleukin-6 and tumor necrosis alpha from e16 placental explants increased by 4-fold and 8-9-fold, respectively (P < 0.05 versus vehicle). Conversely, interleukin-6 release from e20 explants was not significantly different compared with vehicle, and tumor necrosis alpha release was only 2-fold higher (P < 0.05 versus vehicle) following exposure to lipopolysaccharide. Phosphorylated NFkappaB protein expression was significantly increased in the nuclear fraction from placental explants exposed to lipopolysaccharide at both e16 and e20, although TLR4 protein expression was unaffected. CONCLUSION: Lipopolysaccharide induces higher interleukin-6 and tumor necrosis alpha expression at e16 versus e20, suggesting that preterm placentas may have a greater placental cytokine response to lipopolysaccharide infection. Furthermore, increased phosphorylated NFkappaB indicates that placental cytokine induction may occur by activation of the TLR4 pathway. PMID- 22924008 TI - The spectrum of medical errors: when patients sue. AB - Inarguably medical errors constitute a serious, dangerous, and expensive problem for the twenty-first-century US health care system. This review examines the incidence, nature, and complexity of alleged medical negligence and medical malpractice. The authors hope this will constitute a road map to medical providers so that they can better understand the present climate and hopefully avoid the "Scylla and Charybdis" of medical errors and medical malpractice. Despite some documented success in reducing medical errors, adverse events and medical errors continue to represent an indelible stain upon the practice, reputation, and success of the US health care industry. In that regard, what may be required to successfully attack the unacceptably high severity and volume of medical errors is a locally directed and organized initiative sponsored by individual health care organizations that is coordinated, supported, and guided by state and federal governmental and nongovernmental agencies. PMID- 22924007 TI - Epidemiology, clinical, immune, and molecular profiles of microsporidiosis and cryptosporidiosis among HIV/AIDS patients. AB - BACKGROUND: The objective of this study was to determine the prevalence of intestinal parasites, with special emphasis on microsporidia and Cryptosporidium, as well as their association with human immunodeficiency virus (HIV) symptoms, risk factors, and other digestive parasites. We also wish to determine the molecular biology definitions of the species and genotypes of microsporidia and Cryptosporidium in HIV patients. METHODS: In this cross-sectional study, carried out in Kinshasa, Democratic Republic of the Congo, stool samples were collected from 242 HIV patients (87 men and 155 women) with referred symptoms and risk factors for opportunistic intestinal parasites. The analysis of feces specimen were performed using Ziehl-Neelsen stainings, real-time polymerase chain reaction (PCR), immunofluorescence indirect monoclonal antibody, nested PCR-restriction fragment length polymorphism, and PCR amplification and sequencing. Odds ratio (OR) and 95% confidence intervals were used to quantify the risk. RESULTS: Of the 242 HIV patients, 7.8%, 0.4%, 5.4%, 0.4%, 2%, 10.6%, and 2.8% had Enterocytozoon bieneusi, Encephalitozoon intestinalis, Cryptosporidium spp., Isospora belli, pathogenic intestinal protozoa, nonpathogenic intestinal protozoa, and helminths, respectively. We found five genotypes of E. bieneusi: two older, NIA1 and D, and three new, KIN1, KIN2, and KIN3. Only 0.4% and 1.6% had Cryptosporidium parvum and Cryptosporidium hominis, respectively. Of the patients, 36.4%, 34.3%, 31%, and 39% had asthenia, diarrhea, a CD4 count of <100 cells/mm(3), and no antiretroviral therapy (ART), respectively. The majority of those with opportunistic intestinal parasites and C. hominis, and all with C. parvum and new E. bieneusi genotypes, had diarrhea, low CD4+ counts of <100 cells/mm(3), and no ART. There was a significant association between Entamoeba coli, Kaposi sarcoma, herpes zoster, chronic diarrhea, and asthenia, and the presence of 28 cases with opportunistic intestinal parasites. Rural areas, public toilets, and exposure to farm pigs were the univariate risk factors present in the 28 cases with opportunistic intestinal parasites. In logistic regression analysis, a CD4 count of <100 cells/mm(3) (OR = 4.60; 95% CI 1.70-12.20; P = 0.002), no ART (OR = 5.00; 95% CI 1.90-13.20; P < 0.001), and exposure to surface water (OR = 2.90; 95% CI 1.01-8.40; P = 0.048) were identified as the significant and independent determinants for the presence of opportunistic intestinal parasites. CONCLUSION: E. bieneusi and Cryptosporidium are becoming more prevalent in Kinshasa, Congo. Based on the findings, we recommend epidemiology surveillance and prevention by means of hygiene, the emphasis of sensitive PCR methods, and treating opportunistic intestinal parasites that may be acquired through fecal-oral transmission, surface water, normal immunity, rural area-based person-person and animal-human infection, and transmission of HIV. Therapy, including ART and treatment with fumagillin, is needed. PMID- 22924009 TI - A 61-year-old man presented with myopathy, neuropathy, and inflammatory dermatitis responsive to chronic lymphocytic leukemia treatment. AB - The prevalence of paraneoplastic neurologic syndrome in cancer is 0.01%. Neurological syndromes can be seen in chronic lymphocytic leukemia (CLL) and mostly present as either leukemic infiltration of the central nervous system (CNS) or progressive multifocal leukoencephalopathy. To our knowledge, this is the first reported case of combined sensory-motor neuropathy, myopathy, and dermatitis in a patient with CLL. CASE PRESENTATION: A 61-year-old African American man presented with acute dysphagia, rapidly progressive proximal limb girdle weakness, and dermatitis. He had a white blood cell (WBC) count of 14,600/mm(3), hemoglobin of 11.4 mg/dL, and a platelet count of 165,000/mm(3). Lymphocytes comprised 15% of the total WBC with an absolute lymphocyte count of 2100/mm(3). Metabolic profile was unremarkable except for a serum creatine phosphokinase (CPK) level of 1056 mg/dL. Serum protein electrophoresis, serologic studies for autoimmune, genetic diseases, and paraneoplastic syndromes were all negative. Electrodiagnostic studies revealed sensorimotor neuropathy with mixed axonal and demyelinating features. Muscle biopsy revealed discrete areas of interstitial fibrosis juxtaposed to areas of intact muscle without any inflammation. At that point, a bone marrow biopsy was done because of anemia and slightly elevated mean corpuscular volume of 103. Bone marrow biopsy revealed minimal involvement with CD5/CD19-positive CLL. Flow cytometry demonstrated monoclonal CD5/CD19/CD20/CD23-positive cells, with dim kappa expression, and negative FMC-7 and CD3. This case doesn't meet the criteria for CLL/small lymphocytic lymphoma. However, considering the possibility of paraneoplastic phenomenon for his symptoms, it was decided to start the patient on CLL-directed therapy with Rituximab and Cyclophosphamide. After only two cycles, the patient experienced a dramatic improvement in his muscle strength with disappearance of the rash. CONCLUSION: This case highlights a unique clinical picture of inflammatory dermatitis with electromyography and biopsy findings suggestive of myopathy and combined sensorimotor neuropathy with response to CLL-directed therapy. Also the symptoms started before peripheral lymphocytosis which masked the diagnosis for over a year. PMID- 22924003 TI - Microvesicles/exosomes as potential novel biomarkers of metabolic diseases. AB - Biomarkers are of tremendous importance for the prediction, diagnosis, and observation of the therapeutic success of common complex multifactorial metabolic diseases, such as type II diabetes and obesity. However, the predictive power of the traditional biomarkers used (eg, plasma metabolites and cytokines, body parameters) is apparently not sufficient for reliable monitoring of stage dependent pathogenesis starting with the healthy state via its initiation and development to the established disease and further progression to late clinical outcomes. Moreover, the elucidation of putative considerable differences in the underlying pathogenetic pathways (eg, related to cellular/tissue origin, epigenetic and environmental effects) within the patient population and, consequently, the differentiation between individual options for disease prevention and therapy - hallmarks of personalized medicine - plays only a minor role in the traditional biomarker concept of metabolic diseases. In contrast, multidimensional and interdependent patterns of genetic, epigenetic, and phenotypic markers presumably will add a novel quality to predictive values, provided they can be followed routinely along the complete individual disease pathway with sufficient precision. These requirements may be fulfilled by small membrane vesicles, which are so-called exosomes and microvesicles (EMVs) that are released via two distinct molecular mechanisms from a wide variety of tissue and blood cells into the circulation in response to normal and stress/pathogenic conditions and are equipped with a multitude of transmembrane, soluble and glycosylphosphatidylinositol-anchored proteins, mRNAs, and microRNAs. Based on the currently available data, EMVs seem to reflect the diverse functional and dysfunctional states of the releasing cells and tissues along the complete individual pathogenetic pathways underlying metabolic diseases. A critical step in further validation of EMVs as biomarkers will rely on the identification of unequivocal correlations between critical disease states and specific EMV signatures, which in future may be determined in rapid and convenient fashion using nanoparticle-driven biosensors. PMID- 22924010 TI - Assessment of electrocardiography, echocardiography, and heart rate variability in dynamic and static type athletes. AB - BACKGROUND: Over the last two decades, morphological cardiac changes induced by athletic conditioning have been of great interest. Therefore, several studies have been orchestrated to delineate electrocardiography (ECG), echocardiography, and heart rate variability (HRV) findings in athletes. PURPOSE: To assess the ECG, echocardiography, and HRV in a group of dynamic and static type athletes. METHODS: Fifty professional athletes (20 static and 30 dynamic exercise athletes) and 50 healthy nonathletes (control group) were recruited. Standard 12-lead ECG and transthoracic echocardiography was performed on all athletes and the control group. Through echocardiography, variables including left ventricular (LV) end diastolic/systolic diameter, LV mass, and left atrial volume index were measured. In addition, both the athletes and the control group underwent ECG Holter monitoring for 15 minutes and several parameters related to HRV (time and frequency domain) were recorded. RESULTS: The most common ECG abnormalities among the athletes were sinus bradycardia and incomplete right bundle branch block. LV end-diastolic diameter and left atrial volume index were significantly greater in the dynamic athletes (P < 0.001). LV end-systolic diameter was significantly lower in the static group (P < 0.001). LV mass of the dynamic and static athletes was significantly greater than that of the controls (P < 0.001). Among the ECG Holter monitoring findings, the dynamic athletes had lower systolic blood pressure than the controls (P = 0.01). Heart rate was lowest in the control group (P < 0.001). CONCLUSION: The most common ECG abnormalities among adolescent Iranian athletes were sinus bradycardia and incomplete right bundle branch block. Static exercise seemed to reduce LV end-systolic diameter, while dynamic exercise resulted in increased LV end-diastolic diameter and left atrial volume index. Additionally, Iranian athletes showed no differences in HRV parameters, excluding heart rate and systolic blood pressure, compared with the nonathletes. PMID- 22924011 TI - Myocardial infarction in a patient with left ventricular noncompaction: a case report. AB - We describe a 73-year-old male patient with left ventricular noncompaction (LVNC) who was diagnosed with acute myocardial infarction (MI), three-vessel coronary artery disease, a fresh intraventricular thrombus, and mitral regurgitation. He was treated with full anticoagulant therapy, coronary artery bypass grafting, and mitral valve repair. This case adds to a small but growing literature showing association between LVNC and MI and/or coronary artery disease. We suggest that patients with LVNC could be considered at heightened risk for MI, and the two conditions might have a common genetic underpinning in some cases. PMID- 22924012 TI - Identification of atrophy of the subgenual anterior cingulate cortex, in particular the subcallosal area, as an effective auxiliary means of diagnosis for major depressive disorder. AB - BACKGROUND: Despite being a very common psychiatric disorder, physicians often have difficulty making a diagnosis of major depressive disorder (MDD) because, without established diagnostic criteria, they have to depend on interviews with patients and observation to assess psychiatric symptoms. However, previous researchers have reported that magnetic resonance imaging (MRI) scans identify morphological changes in the brains of patients with MDD, which inspired us to hypothesize that assessment of local changes in the brain using voxel-based morphometry would serve as an auxiliary diagnostic method for MDD. Therefore, we focused on the VSRAD((r)) plus (voxel-based specific regional analysis system for Alzheimer's disease), a diagnostic support system for use in early Alzheimer's disease, which allowed us to identify regional atrophy in the brain easily based on images obtained from MRI scans. METHODS: The subjects were 75 patients with MDD, 15 with bipolar disorder, and 30 healthy subjects, aged 54-82 years. First, 1.5 T MRI equipment was used to scan three-dimensional T(1)-weighted images for the individual subjects, and the imaged data were analyzed by VSRAD advance (voxel-based morphometric software developed for diagnosis of early Alzheimer's disease). The efficacy of the equipment for diagnosis of MDD was evaluated based on the distribution of atrophy in the subgenual anterior cingulate cortex (sACC) on the z-score map obtained. RESULTS: No significant difference in atrophy was noted between the left and right sACCs. The VSRAD advance used in the present study was more effective than the VSRAD plus for diagnosis of MDD, with a sensitivity of 90.7%, specificity of 86.7%, accuracy of 89.5%, a positive predictive value of 94.4%, and a negative predictive value of 78.8%. In particular, atrophy was observed in the subcallosal area of the sACC. CONCLUSION: The identification of atrophy in the sACC, in particular of the subcallosal area, with the use of updated voxel-based morphometric software proved to be effective as an auxiliary diagnostic method for MDD. PMID- 22924013 TI - Clinical differences between influenza A (H1N1) virus and respiratory infection between the two waves in 2009 and 2010. AB - BACKGROUND: The purpose of the present retrospective study was to examine the clinical differences between patients hospitalized with H1N1 virus and those hospitalized with nonvirus respiratory tract infection in 2009 and 2010. METHODS: Adult patient data were collected from three tertiary hospital centers. Real-time reverse transcriptase polymerase chain reaction testing was used to confirm the diagnosis. We included 106 H1N1-positive patients (52 from 2009 and 54 from 2010). These data were compared with those from 108 patients with H1N1-negative respiratory tract infection (51 patients from 2009 and 57 from 2010). RESULTS: In 2009, the mean age was 36.4 years for H1N1-positive patients versus 46.4 years for H1N1-negative patients, and mean body mass index (BMI) was 26.4 kg/m(2) patients and 28.1 kg/m(2), respectively. In 2009, seven patients required intubation, six of whom were H1N1-positive. In 2010, the mean age was 43.8 years for H1N1-positive patients versus 60.2 years for H1N1-negative patients, and mean BMI was 32.3 kg/m(2) and 26.9 kg/m(2), respectively. In 2010, six patients required intubation, three of whom were H1N1-positive. Abnormal chest x-ray findings were found significantly more frequently in H1N1-negative patients than in H1N1-positive patients. CONCLUSION: In comparison with 2009, H1N1-positive patients in 2010 were older, were more likely to be obese, and had more severe clinical and laboratory perturbations. However, this did not affect their outcomes. H1N1-negative patients were older in comparison with those who were H1N1-positive, and had more severe clinical and laboratory perturbations. PMID- 22924014 TI - Mechanisms of Biliary Damage. AB - Bile duct damage is present in virtually all cholangiopathies, which share the biliary epithelial cells (i.e. cholangiocytes) as a common pathogenic target. Cholangiocyte cell death largely occurs through the process of apoptosis. In this review, we will summarize the mechanisms through which biliary damage occurs in a variety of animal and in vitro models, such as extrahepatic cholestasis induced by bile duct ligation (BDL), cytotoxin- and hepatotoxin-induced liver injury, and biliary atresia. Although we have increased our knowledge of the factors that regulate cholangiocyte cell death mechanisms during cholangiopathies, especially in experimental models, there is still a lack of effective treatment modalities for these biliary disorders. However, future studies will hopefully provide for new therapeutic modalities for the prevention or restoration of biliary mass and function lost during the progression of cholangiopathies. PMID- 22924015 TI - Influence of provider experience on antiretroviral adherence and viral suppression. AB - BACKGROUND AND AIM: Early in the combination antiretroviral therapy (cART) era, provider experience (as measured by panel size) was associated with improved outcomes. We explored that association and other characteristics of provider experience. METHODS: We performed a retrospective cohort analysis in Kaiser Permanente California (an integrated health care system in the United States), examining all human immunodeficiency virus seropositive (HIV+) patients initiating a first cART regimen (antiretroviral therapy [ART]-naive, N = 7071) or initiating a second or later cART regimen (ART-experienced, N = 3730) from 1996 2006. We measured ART adherence through 12 months (pharmacy fill and refill records) and determined HIV viral load levels below limits of quantification at 12 months. Provider experience, updated annually, was measured as (1) HIV panel size (0-10 patients as reference strata), (2) years treating HIV (less than 1 year as reference), and (3) specialty ( noninfectious disease specialty, non-HIV expert as reference). We assessed associations by utilizing mixed modeling analyses (clustered by provider and medical center), controlling for patient age, sex, race/ethnicity, HIV risk behavior, hepatitis C coinfection, ART regimen class, and calendar year. RESULTS: Among the ART-experienced, improved adherence was associated with greater years experience (mean increase 3.1% 2-5 years experience; 3.7% 5-10 years; 2.7% 11-20 years; P = 0.07, categorical). In adjusted analyses, viral suppression among ART-naive was positively associated with panel size (odds ratio 26-50 patients: 1.31, P = 0.03, categorical), but negatively associated with years experience (18% less for greater than 100 patients; P = 0.003). No provider characteristic was significantly associated with improved adherence among ART-naive or odds of maximal viral suppression among ART-experienced in adjusted analysis. CONCLUSIONS: Except for panel size and years experience among ART-naive, provider characteristics did not significantly influence ART adherence or likelihood of viral suppression. PMID- 22924016 TI - Desmoid fibromatosis in pediatric patients: management based on a retrospective analysis of 59 patients and a review of the literature. AB - Background. Only limited data are available concerning desmoid tumor in children. Methods. Fifty-nine children and adolescents with desmoid tumor treated in 2 French cancer centers with a very long followup were retrospectively reviewed. Results. Median age was 6 years (range, 0-15). Tumors mainly involved the limbs (42%). Five cases occurred in a context of genetic disorder. Surgery was first line treatment in 80% of cases. Resection was microscopically complete in 3 patients (pts), with a microscopic residue in 19 pts and a macroscopic residue in 35 cases. Various adjuvant therapies were used. Overall response to all systemic therapies was 33%. Thirty-eight patients developed one or more recurrences or progressions. After a median followup of 8.5 years, 34 patients were alive in complete remission (CR), including 16 first CR. Seven patients died, 6 from refractory disease and 1 from colorectal carcinoma in a genetic context. Ten-year progression-free survival (PFS) and overall survival were 31% and 88%, respectively. In univariate analysis, age less than 10 years and head-neck site were favorable prognostic factors for PFS. Conclusions. When surgery is required, surgical margins must be negative. Low-dose chemotherapy can be proposed as adjuvant therapy. Prospective trials must be developed to evaluate long-term response and side effects. PMID- 22924017 TI - Quantitative trait locus analysis and construction of consensus genetic map for drought tolerance traits based on three recombinant inbred line populations in cultivated groundnut (Arachis hypogaea L.). AB - Groundnut (Arachis hypogaea L.) is an important food and cash crop grown mainly in semi-arid tropics (SAT) regions of the world where drought is the major constraint on productivity. With the aim of understanding the genetic basis and identification of quantitative trait loci (QTL) for drought tolerance, two new recombinant inbred line (RIL) mapping populations, namely ICGS 76 * CSMG 84-1 (RIL-2) and ICGS 44 * ICGS 76 (RIL-3), were used. After screening of 3,215 simple sequence repeat (SSR) markers on the parental genotypes of these populations, two new genetic maps were developed with 119 (RIL-2) and 82 (RIL-3) SSR loci. Together with these maps and the reference map with 191 SSR loci based on TAG 24 * ICGV 86031 (RIL-1), a consensus map was constructed with 293 SSR loci distributed over 20 linkage groups, spanning 2,840.8 cM. As all these three populations segregate for drought-tolerance-related traits, a comprehensive QTL analysis identified 153 main effect QTL (M-QTL) and 25 epistatic QTL (E-QTL) for drought-tolerance-related traits. Localization of these QTL on the consensus map provided 16 genomic regions that contained 125 QTL. A few key genomic regions were selected on the basis of the QTL identified in each region, and their expected role in drought adaptation is also discussed. Given that no major QTL for drought adaptation were identified, novel breeding approaches such as marker assisted recurrent selection (MARS) and genomic selection (GS) approaches are likely to be the preferred approaches for introgression of a larger number of QTL in order to breed drought-tolerant groundnut genotypes. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s11032-011-9660-0) contains supplementary material, which is available to authorized users. PMID- 22924018 TI - Quantitative trait locus analysis and construction of consensus genetic map for foliar disease resistance based on two recombinant inbred line populations in cultivated groundnut (Arachis hypogaea L.). AB - Late leaf spot (LLS) and rust have the greatest impact on yield losses worldwide in groundnut (Arachis hypogaea L.). With the objective of identifying tightly linked markers to these diseases, a total of 3,097 simple sequence repeats (SSRs) were screened on the parents of two recombinant inbred line (RIL) populations, namely TAG 24 * GPBD 4 (RIL-4) and TG 26 * GPBD 4 (RIL-5), and segregation data were obtained for 209 marker loci for each of the mapping populations. Linkage map analysis of the 209 loci resulted in the mapping of 188 and 181 loci in RIL-4 and RIL-5 respectively. Using 143 markers common to the two maps, a consensus map with 225 SSR loci and total map distance of 1,152.9 cM was developed. Comprehensive quantitative trait locus (QTL) analysis detected a total of 28 QTL for LLS and 15 QTL for rust. A major QTL for LLS, namely QTL(LLS)01 (GM1573/GM1009-pPGPseq8D09), with 10.27-62.34% phenotypic variance explained (PVE) was detected in all the six environments in the RIL-4 population. In the case of rust resistance, in addition to marker IPAHM103 identified earlier, four new markers (GM2009, GM1536, GM2301 and GM2079) showed significant association with the major QTL (82.96% PVE). Localization of 42 QTL for LLS and rust on the consensus map identified two candidate genomic regions conferring resistance to LLS and rust. One region present on linkage group AhXV contained three QTL each for LLS (up to 67.98% PVE) and rust (up to 82.96% PVE). The second candidate genomic region contained the major QTL with up to 62.34% PVE for LLS. Molecular markers associated with the major QTL for resistance to LLS and rust can be deployed in molecular breeding for developing groundnut varieties with enhanced resistance to foliar diseases. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s11032-011-9661-z) contains supplementary material, which is available to authorized users. PMID- 22924019 TI - Exploring the genetic diversity of Ethiopian grass pea (Lathyrus sativus L.) using EST-SSR markers. AB - Expressed sequence tags (ESTs) in public databases and cross-species transferable markers are considered to be a cost-effective means for developing sequence-based markers for less-studied species. In this study, EST-simple sequence repeat (SSR) markers developed from Lathyrus sativus L. EST sequences and cross-transferable EST-SSRs derived from Medicago truncatula L. were utilized to investigate the genetic diversity among grass pea populations from Ethiopia. A total of 45 alleles were detected using eleven EST-SSRs with an average of four alleles per locus. The average polymorphism information content for all primers was 0.416. The average gene diversity was 0.477, ranging from 0.205 for marker Ls942 to 0.804 for MtBA32F05. F(ST) values estimated by analysis of molecular variance were 0.01, 0.15, and 0.84 for among regions, among accessions and within accessions respectively, indicating that most of the variation (84%) resides within accessions. Model-based cluster analysis grouped the accessions into three clusters, grouping accessions irrespective of their collection regions. Among the regions, high levels of diversity were observed in Gojam, Gonder, Shewa and Welo regions, with Gonder region showing a higher number of different alleles. From breeding and conservation aspects, conducting a close study on a specific population would be advisable for genetic improvement in the crop, and it would be appropriate if future collection and conservation plans give due attention to under-represented regions. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s11032-011-9662-y) contains supplementary material, which is available to authorized users. PMID- 22924020 TI - Genetic characterization of a reciprocal translocation present in a widely grown barley variety. AB - Artificially induced translocation stocks have been used to physically map the barley genome; however, natural translocations are extremely uncommon in cultivated genotypes. Albacete is a barley variety widely grown in recent decades in Spain and carrying a reciprocal translocation which obviously does not affect its agronomical fitness. This translocation has been characterized by a combination of cytological and molecular genetic approaches. Firstly, recombination frequencies between markers on chromosomes 1H and 3H were estimated to determine the boundaries of the reciprocal interchange. Secondly, 1H-3H wheat barley telosome addition lines were used to assign selected markers to chromosome arms. Thirdly, fluorescence in situ hybridization (FISH) with rDNA probes (5S and 18S-5.8S-26S) and microsatellite probes [(ACT)(5), (AAG)(5) and (CAG)(5)] was used to determine the locations of the translocation breakpoints more precisely. Fourthly, fine-mapping of the regions around the translocation breakpoints was used to increase the marker density for comparative genomics. The results obtained in this study indicate that the translocation is quite large with breakpoints located on the long arms of chromosomes 1H and 3H, between the pericentromeric (AAG)(5) bands and above the (ACT)(5) interstitial distal bands, resulting in the reciprocal translocation 1HS.1HL-3HL and 3HS.3HL-1HL. The gene content around the translocation breakpoints could be inferred from syntenic relationships observed among different species from the grass family Poaceae (rice, Sorghum and Brachypodium) and was estimated at approximately 1,100 and 710 gene models for 1H and 3H, respectively. Duplicated segments between chromosomes Os01 and Os05 in rice derived from ancestral duplications within the grass family overlap with the translocation breakpoints on chromosomes 1H and 3H in the barley variety Albacete. PMID- 22924021 TI - DNA sequence polymorphism of the Rhg4 candidate gene conferring resistance to soybean cyst nematode in Chinese domesticated and wild soybeans. AB - Rhg4 is one of the major resistant genes conferring resistance to soybean cyst nematode races 1, 3 and 4. In order to better understand its sequence diversity among different Chinese soybean populations and the impact of human activities on it, we designed 5 primer sets based on its sequence deposited in Genbank (Genbank accession No. AF506518) to obtain the Rhg4 sequence from 104 Chinese cultivated and wild soybean genotypes, and then analyzed the DNA sequence polymorphism in different Chinese soybean populations. The alignment of Rhg4 sequence included 5,216 nucleotide base pairs. A total of 67 single nucleotide polymorphisms (SNPs) including 59 single base changes and 8 DNA insertion-deletions (InDels) were identified with a SNP frequency of 1/78. Except for a 14-base InDel, there were 29 SNPs in coding regions, and among them, 13 were non-synonymous (9 in functional domains with 1 in a leucine-rich repeats region, 2 in a transmembrane region and 6 in a Ser/Thr kinase domain). The probability of substitution at each site was not the same, there were two hot spots, one was in the 5'-untranslated region between positions 124 and 804, and the other was in the region between positions 2520 and 3733. Sequence diversity analysis among 104 soybean genotypes showed pi = 0.00102 and theta = 0.00218 for Rhg4. A domestication bottleneck was found because of lower sequence diversity and 58% unique SNPs loss in landraces compared with Glycine soja. Intensive selection increased the sequence diversity of cultivars, which had higher diversity and more unique SNPs than landraces. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s11032-012-9703-1) contains supplementary material, which is available to authorized users. PMID- 22924022 TI - Composition tunable cobalt-nickel and cobalt-iron alloy nanoparticles below 10 nm synthesized using acetonated cobalt carbonyl. AB - A general organometallic route has been developed to synthesize Co(x)Ni(1-x) and Co(x)Fe(1-x) alloy nanoparticles with a fully tunable composition and a size of 4 10 nm with high yield. In contrast to previously reported synthesis methods using dicobalt octacarbonyl (Co(2)(CO)(8)), here the cobalt-cobalt bond in the carbonyl complex is first broken with anhydrous acetone. The acetonated compound, in the presence of iron carbonyl or nickel acetylacetonate, is necessary to obtain small composition tunable alloys. This new route and insights will provide guidelines for the wet-chemical synthesis of yet unmade bimetallic alloy nanoparticles. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s11051-012-0991-5) contains supplementary material, which is available to authorized users. PMID- 22924023 TI - Neonatal Informatics: Transforming Neonatal Care Through Translational Bioinformatics. AB - The future of neonatal informatics will be driven by the availability of increasingly vast amounts of clinical and genetic data. The field of translational bioinformatics is concerned with linking and learning from these data and applying new findings to clinical care to transform the data into proactive, predictive, preventive, and participatory health. As a result of advances in translational informatics, the care of neonates will become more data driven, evidence based, and personalized. PMID- 22924024 TI - Predictive models of gene regulation from high-throughput epigenomics data. AB - The epigenetic regulation of gene expression involves multiple factors. The synergistic or antagonistic action of these factors has suggested the existence of an epigenetic code for gene regulation. Highthroughput sequencing (HTS) provides an opportunity to explore this code and to build quantitative models of gene regulation based on epigenetic differences between specific cellular conditions. We describe a new computational framework that facilitates the systematic integration of HTS epigenetic data. Our method relates epigenetic signals to expression by comparing two conditions. We show its effectiveness by building a model that predicts with high accuracy significant expression differences between two cell lines, using epigenetic data from the ENCODE project. Our analyses provide evidence for a degenerate epigenetic code, which involves multiple genic regions. In particular, signal changes at the 1st exon, 1st intron, and downstream of the polyadenylation site are found to associate strongly with expression regulation. Our analyses also show a different epigenetic code for intron-less and intron-containing genes. Our work provides a general methodology to do integrative analysis of epigenetic differences between cellular conditions that can be applied to other studies, like cell differentiation or carcinogenesis. PMID- 22924025 TI - Comparative Analysis of SWIRM Domain-Containing Proteins in Plants. AB - Chromatin-remodeling complexes affect gene expression by using the energy of ATP hydrolysis to locally disrupt or alter the association of histones with DNA. SWIRM (Swi3p, Rsc8p, and Moira) domain is an alpha-helical domain of about 85 residues in chromosomal proteins. SWIRM domain-containing proteins make up large multisubunit complexes by interacting with other chromatin modification factors and may have an important function in plants. However, little is known about SWIRM domain-containing proteins in plants. In this study, 67 SWIRM domain containing proteins from 6 plant species were identified and analyzed. Plant SWIRM domain proteins can be divided into three distinct types: Swi-type, LSD1 type, and Ada2-type. Generally, the SWIRM domain forms a helix-turn-helix motif commonly found in DNA-binding proteins. The genes encoding SWIRM domain proteins in Oryza sativa are widely expressed, especially in pistils. In addition, OsCHB701 and OsHDMA701 were downregulated by cold stress, whereas OsHDMA701 and OsHDMA702 were significantly induced by heat stress. These observations indicate that SWIRM domain proteins may play an essential role in plant development and plant responses to environmental stress. PMID- 22924026 TI - Interactome of Radiation-Induced microRNA-Predicted Target Genes. AB - The microRNAs (miRNAs) function as global negative regulators of gene expression and have been associated with a multitude of biological processes. The dysfunction of the microRNAome has been linked to various diseases including cancer. Our laboratory recently reported modulation in the expression of miRNA in a variety of cell types exposed to ionizing radiation (IR). To further understand miRNA role in IR-induced stress pathways, we catalogued a set of common miRNAs modulated in various irradiated cell lines and generated a list of predicted target genes. Using advanced bioinformatics tools we identified cellular pathways where miRNA predicted target genes function. The miRNA-targeted genes were found to play key roles in previously identified IR stress pathways such as cell cycle, p53 pathway, TGF-beta pathway, ubiquitin-mediated proteolysis, focal adhesion pathway, MAPK signaling, thyroid cancer pathway, adherens junction, insulin signaling pathway, oocyte meiosis, regulation of actin cytoskeleton, and renal cell carcinoma pathway. Interestingly, we were able to identify novel targeted pathways that have not been identified in cellular radiation response, such as aldosterone-regulated sodium reabsorption, long-term potentiation, and neutrotrophin signaling pathways. Our analysis indicates that the miRNA interactome in irradiated cells provides a platform for comprehensive modeling of the cellular stress response to IR exposure. PMID- 22924030 TI - Reinstitution of mechanical ventilation within 14 days as a poor predictor in prolonged mechanical ventilation patients following successful weaning. AB - Although many parameters were investigated about weaning and mortality in critical patients in intensive units, no studies have yet investigated predictors in prolonged mechanical ventilation (PMV) patients following successful weaning. A cohort of 142 consecutive PMV patients with successful weaning in our respiratory care center was enrolled in this study. Successful weaning is defined as a patient having smooth respiration for more than 5 days after weaning. The results showed as follows: twenty-seven patients (19%) had the reinstitution within 14 days, and 115 patients (81%) had the reinstitution beyond 14 days. Renal disease RIFLE-LE was associated with the reinstitution within 14 days (P = 0.006). One year mortality rates showed significant difference between the two groups (85.2% in the reinstitution within 14 days group versus 53.1% in the reinstitution beyond 14 days; P < 0.001). Kaplan-Meier analysis showed that age >=70 years (P = 0.04), ESRD (P = 0.02), and the reinstitution within 14 days (P < 0.001) were associated with one-year mortality. Cox proportional hazards regression model showed that only the reinstitution within 14 days was the independent predictor for mortality (P < 0.001). In conclusion, the reinstitution within 14 days was a poor predictor for PMV patients after successful weaning. PMID- 22924032 TI - Dietary available phosphorus affected growth performance, body composition, and hepatic antioxidant property of juvenile yellow catfish Pelteobagrus fulvidraco. AB - An 8-week feeding trial was carried out with juvenile yellow catfish to study the effects of dietary available phosphorus (P) on growth performance, body composition, and hepatic antioxidant property. Six pellet diets were formulated to contain graded available P levels at 0.33, 0.56, 0.81, 1.15, 1.31, and 1.57% of dry matter, respectively. Triplicate tanks with each tank containing 60 juveniles (3.09 +/- 0.03 g) were fed one of the six experimental diets for 8 weeks. Specific growth rate, feeding rate, and protein efficiency ratio were significantly higher at 0.81% dietary available P. Efficiency of P utilization distinctly decreased with increasing P level. Body lipid content significantly decreased while body ash and feces P content significantly increased with increasing P level. Quadratic regression analysis indicated that vertebrae P content was maximized at 1.21% dietary available P. Fish fed 1.57% dietary available P had highest activity of hepatic superoxide dismutase and catalase and malonaldehyde content. In conclusion, decreasing dietary available P increased P utilization efficiency and body lipid content while decreased vertebrae P content. Juvenile yellow catfish were subjected to oxidative damage under the condition of high dietary P content (1.57%), and the damage could not be eradicated by their own antioxidant defense system. PMID- 22924031 TI - Expression of the type VI secretion system 1 component Hcp1 is indirectly repressed by OpaR in Vibrio parahaemolyticus. AB - The type VI secretion system (T6SS) is bacterial protein injection machinery with roles in virulence, symbiosis, interbacterial interaction, antipathogenesis, and environmental stress responses. There are two T6SS loci, T6SS1 and T6SS2, in the two chromosomes of Vibrio parahaemolyticus, respectively. This work disclosed that the master quorum sensing (QS) regulator OpaR repressed the transcription of hcp1 encoding the structural component Hcp1 of T6SS1 in V. parahaemolyticus, indicating that QS had a negative regulatory action on T6SS1. A single sigma(54) dependent promoter was transcribed for hcp1 in V. parahaemolyticus, and its activity was repressed by the OpaR regulator. Since the OpaR protein could not bind to the upstream region of hcp1, OpaR would repress the transcription of hcp1 in an indirect manner. PMID- 22924033 TI - Elastic Network Models are Robust to Variations in Formalism. AB - Understanding the functions of biomolecules requires insight not only from structures, but from dynamics as well. Often, the most interesting processes occur on time scales too slow for exploration by conventional molecular dynamics (MD) simulations. For this reason, alternative computational methods such as elastic network models (ENMs) have become increasingly popular. These simple, coarse-grained models represent molecules as beads connected by harmonic springs; the system's motions are solved analytically by normal mode analysis. In the past few years, many different formalisms for performing ENM calculations have emerged, and several have been optimized using all-atom MD simulations. In contrast to other studies, we have compared the various formalisms in a systematic, quantitative way. In this study, we optimize many ENM functional forms using a uniform dataset containing only long (> 1 MUs) all-atom MD simulations. Our results show that all models once optimized produce spring constants for immediate neighboring residues that are orders of magnitude stiffer than more distal contacts. In addition, the statistical significance of ENM performance varied with model resolution. We also show that fitting long trajectories does not improve ENM performance due to a problem inherent in all network models tested: they underestimate the relative importance of the most concerted motions. Finally, we characterize ENMs' resilience by tessellating the parameter space to show that broad ranges of parameters produce similar quality predictions. Taken together our data reveals that choice of spring function and parameters are not vital to performance of a network model and that simple parameters can by derived "by hand" when no data is available for fitting, thus illustrating the robustness of these models. PMID- 22924034 TI - Anti-hyperglycaemic and lipid lowering potential of Adenanthera pavonina Linn. in streptozotocin induced diabetic rats. AB - In India, Adenanthera pavonina is traditionally used in the treatment of diabetes mellitus and lipid disorders. In the present study, the antihyperglycaemic and lipid lowering effect of Adenanthera pavonina seed aqueous extract (APSAE) was evaluated using streptozotocin induced diabetes in rats. Streptozotocin was given at the dose of 55 mg/kg, i.p. After induction of diabetes, APSAE was administered for 30 days p. o. and simultaneously different biochemical parameters like plasma glucose, HbA1c, serum triglyceride, cholesterol, LDL-cholesterol and HDL cholesterol were estimated. Diabetic control showed significant increase (P < 0.01) in plasma glucose, serum triglyceride, cholesterol, LDL-cholesterol and significant decrease (P < 0.01) in serum HDL-cholesterol and HbA1c. Treatment with APSAE showed significant reduction (P < 0.01) in plasma glucose when compared with diabetic control. The elevated levels of serum triglyceride and cholesterol levels were significantly reduced (P < 0.01) by APSAE. APSAE treatment for 30 days showed significant decrease in serum LDL-cholesterol (P < 0.01) and significant increase in serum HDL cholesterol level (P < 0.01). Moreover, diabetic control there was significant decrease in HbA1c which was significantly increased (P < 0.05) by treatment with APSAE. Hence, from the result obtained in the present study it can be confirmed that Adenanthera pavonina has the potential to treat diabetes condition and associated lipid disorders. PMID- 22924035 TI - A comparative study of human thermal face recognition based on Haar wavelet transform and local binary pattern. AB - Thermal infrared (IR) images focus on changes of temperature distribution on facial muscles and blood vessels. These temperature changes can be regarded as texture features of images. A comparative study of face two recognition methods working in thermal spectrum is carried out in this paper. In the first approach, the training images and the test images are processed with Haar wavelet transform and the LL band and the average of LH/HL/HH bands subimages are created for each face image. Then a total confidence matrix is formed for each face image by taking a weighted sum of the corresponding pixel values of the LL band and average band. For LBP feature extraction, each of the face images in training and test datasets is divided into 161 numbers of subimages, each of size 8 * 8 pixels. For each such subimages, LBP features are extracted which are concatenated in manner. PCA is performed separately on the individual feature set for dimensionality reduction. Finally, two different classifiers namely multilayer feed forward neural network and minimum distance classifier are used to classify face images. The experiments have been performed on the database created at our own laboratory and Terravic Facial IR Database. PMID- 22924036 TI - Detection of fractal behavior in temporal series of synaptic quantal release events: a feasibility study. AB - Since the pioneering work of Fatt and Katz at the neuromuscular junction (NMJ), spontaneous synaptic release (minis), that is, the quantal discharge of neurotransmitter molecules which occurs in the absence of action potentials, has been unanimously considered a memoryless random Poisson process where each quantum is discharged with a very low release probability independently from other quanta. When this model was thoroughly tested, for both population and single-synapse recordings, some clear evidence in favor of a more complex scenario emerged. This included short- and long-range correlation in mini occurrences and divergence from mono-exponential inter-mini-interval distributions, both unexpected for a homogeneous Poisson process, that is, with a rate parameter that does not change over time. Since we are interested in accurately quantifying the fractal exponent alpha of the spontaneous neurotransmitter release process at central synaptic sites, this work was aimed at evaluating the sensitivity of the most established methods available, such as the periodogram, the Allan, factor and the detrended fluctuation analysis. For this analysis we matched spontaneous release series recorded at individual hippocampal synapses (single-synapse recordings) to generate large collections of simulated quantal events by means of a custom algorithm combining Monte Carlo sampling methods with spectral methods for the generation of 1/f series. These tests were performed by varying separately: (i) the fractal exponent alpha of the rate driving the release process; (ii) the distribution of intervals between successive releases, mimicking those encountered in single-synapse experimental series; (iii) the number of samples. The aims were to provide a methodological framework for approaching the fractal analysis of single-unit spontaneous release series recorded at central synapses. PMID- 22924037 TI - Effectiveness of onion extract gel on surgical scars in asians. AB - Background. Onion extracts have been shown in vitro to accelerate wound healing. Results from clinical studies on surgical scars in Caucasians were disappointing. The aim of this study is to evaluate the effectiveness of onion extract gel in improving the cosmetic and symptoms of surgical scars in Asians. Patients/Methods. Twenty Asians who had new Pfannenstiel's cesarean section scars were recruited in this prospective double-blinded, split-scar study. Each side was randomly assigned treatment with onion extract gel or placebo at 7 days after surgery. The product was applied three times daily for 12 weeks. Subjects were evaluated at baseline and 4th and 12th weeks. Scar redness was assessed by calorimeter, scar height and pliability were assessed by blinded investigators, and scar symptoms and overall cosmetic improvement were assessed by subjects. Results. Sixteen subjects completed the study. A statistically significant difference between two sides of scar in terms of scar height and scar symptoms was found. There was no statistically significant difference in scar redness, scar pliability, and overall cosmetic appearance between two sides. Conclusions. The early use of topical 12% onion extract gel on Pfannenstiel's cesarean section scar in Asians resulted in the improvement of scar height and scar symptoms. PMID- 22924038 TI - Muscle invasive bladder cancer: from diagnosis to survivorship. AB - Bladder cancer is the fifth most commonly diagnosed cancer and the most expensive adult cancer in average healthcare costs incurred per patient in the USA. However, little is known about factors influencing patients' treatment decisions, quality of life, and responses to treatment impairments. The main focus of this paper is to better understand the impact of muscle invasive bladder cancer on patient quality of life and its added implications for primary caregivers and healthcare providers. In this paper, we discuss treatment options, side effects, and challenges that patients and family caregivers face in different phases along the disease trajectory and further identify crucial areas of needed research. PMID- 22924039 TI - Significance of the intraoperative methylene blue test for postoperative evaluation of the vesicourethral anastomosis. AB - We prospectively investigated whether routine evaluation of the vesicourethral anastomosis (VUA) after radical prostatectomy can be waived. Primary integrity of the VUA was analysed by an intraoperative methylene-blue test (IMBT) and postoperatively by conventional cystography. Data on the IMBT, contrast extravasation and prostate volume as well as pad usage were collected prospectively. Significantly more patients with a primary watertight anastomosis demonstrated by the MBT had no leakage in the postoperative cystography (P < 0.001). In a multivariate logistic regression with adjustment for prostate size and surgeon, the positive correlation between IMBT and postoperative cystography remained statistically significant (P = 0.001). The IMBT is easy to perform, inexpensive, and timesaving. With it postoperative evaluation of VUA for integrity can be waived in a significant number of patients. Following our algorithm, the Foley can be removed without further testing of the VUA, whenever the IMBT detected no leakage. PMID- 22924040 TI - The influence of pharmacological preconditioning with sevoflurane on incidence of early allograft dysfunction in liver transplant recipients. AB - Background. Pharmacological preconditioning is one of the tools used to diminish preservation injury. We investigated the influence of sevoflurane preconditioning of liver grafts on postoperative graft function. Methods. Consecutive 60 deceased brain donors were randomized into sevoflurane group or control group. In sevoflurane group donors were treated with endexpiratory 2,0 volume% of sevoflurane during procurement. Primary endpoint was postoperative liver injury. Secondary endpoint was incidence of early allograft dysfunction (EAD). Results. The groups were not different in median DRI, donor age, graft steatosis, and MELD score. Peak AST and ALT levels were lower in sevoflurane group than in control group: 792 and 1861 (P = 0, 038) for AST and 606 and 1191 for ALT (P = 0, 117). Incidence of EAD was 16,7% in sevoflurane group and 50% in control group (Fisher test, P = 0, 013). In subgroups without steatosis preconditioning with sevoflurane did not have influence on incidence of EAD. In subgroups with mild and moderate steatosis incidence of EAD was lower in recipients of liver grafts treated with sevoflurane. Conclusions. Preconditioning with sevoflurane during organ procurement improves graft function by lowering incidence of early allograft dysfunction, particularly in recipients of steatotic liver grafts. PMID- 22924029 TI - Beyond the definitions of the phenotypic complications of sickle cell disease: an update on management. AB - The sickle hemoglobin is an abnormal hemoglobin due to point mutation (GAG -> GTG) in exon 1 of the beta globin gene resulting in the substitution of glutamic acid by valine at position 6 of the beta globin polypeptide chain. Although the molecular lesion is a single-point mutation, the sickle gene is pleiotropic in nature causing multiple phenotypic expressions that constitute the various complications of sickle cell disease in general and sickle cell anemia in particular. The disease itself is chronic in nature but many of its complications are acute such as the recurrent acute painful crises (its hallmark), acute chest syndrome, and priapism. These complications vary considerably among patients, in the same patient with time, among countries and with age and sex. To date, there is no well-established consensus among providers on the management of the complications of sickle cell disease due in part to lack of evidence and in part to differences in the experience of providers. It is the aim of this paper to review available current approaches to manage the major complications of sickle cell disease. We hope that this will establish another preliminary forum among providers that may eventually lead the way to better outcomes. PMID- 22924041 TI - Hantavirus regulation of type I interferon responses. AB - Hantaviruses primarily infect human endothelial cells (ECs) and cause two highly lethal human diseases. Early addition of Type I interferon (IFN) to ECs blocks hantavirus replication and thus for hantaviruses to be pathogenic they need to prevent early interferon induction. PHV replication is blocked in human ECs, but not inhibited in IFN deficient VeroE6 cells and consistent with this, infecting ECs with PHV results in the early induction of IFNbeta and an array of interferon stimulated genes (ISGs). In contrast, ANDV, HTNV, NY-1V and TULV hantaviruses, inhibit early ISG induction and successfully replicate within human ECs. Hantavirus inhibition of IFN responses has been attributed to several viral proteins including regulation by the Gn proteins cytoplasmic tail (Gn-T). The Gn T interferes with the formation of STING-TBK1-TRAF3 complexes required for IRF3 activation and IFN induction, while the PHV Gn-T fails to alter this complex or regulate IFN induction. These findings indicate that interfering with early IFN induction is necessary for hantaviruses to replicate in human ECs, and suggest that additional determinants are required for hantaviruses to be pathogenic. The mechanism by which Gn-Ts disrupt IFN signaling is likely to reveal potential therapeutic interventions and suggest protein targets for attenuating hantaviruses. PMID- 22924042 TI - Inhibition of Indoleamine-2,3-dioxygenase (IDO) in Glioblastoma Cells by Oncolytic Herpes Simplex Virus. AB - Successful oncolytic virus treatment of malignant glioblastoma multiforme depends on widespread tumor-specific lytic virus replication and escape from mitigating innate immune responses to infection. Here we characterize a new HSV vector, JD0G, that is deleted for ICP0 and the joint sequences separating the unique long and short elements of the viral genome. We observed that JD0G replication was enhanced in certain glioblastoma cell lines compared to HEL cells, suggesting that a vector backbone deleted for ICP0 may be useful for treatment of glioblastoma. The innate immune response to virus infection can potentially impede oncolytic vector replication in human tumors. Indoleamine-2,3-dioxygenase (IDO) is expressed in response to interferon gamma (IFNgamma) and has been linked to both antiviral functions and to the immune escape of tumor cells. We observed that IFNgamma treatment of human glioblastoma cells induced the expression of IDO and that this expression was quelled by infection with both wild-type and JD0G viruses. The role of IDO in inhibiting virus replication and the connection of this protein to the escape of tumor cells from immune surveillance suggest that IDO downregulation by HSV infection may enhance the oncolytic activity of vectors such as JD0G. PMID- 22924043 TI - Ureteroscopy-Assisted Retrograde Nephrostomy (UARN) after Anatrophic Nephrolithotomy. AB - Introduction. Open surgical anatrophic nephrolithotomy (ANL) had been the standard treatment for large renal calculi prior to the development of endoscopic devices and endoscopic techniques. A previous report described the efficacy of ureteroscopy-assisted retrograde nephrostomy (UARN) and presented a case of renal calculi successfully treated with UARN during percutaneous nephrolithotomy (PCNL) in a patient after ANL. Case Presentation. A 61-year-old male with left renal calculi was referred for further treatment. The patient was placed under general and epidural anesthesia, in a Galdakao-modified Valdivia position. A flexible ureteroscope (URS) was inserted, and a Lawson retrograde nephrostomy puncture wire was advanced into the flexible URS. The puncture wire then followed the route from the renal pelvis to the exit skin. Calculus fragmentation was undertaken using a pneumatic lithotripter. Conclusions. UARN for PCNL was therefore found to be a safe, effective, and appropriate treatment for a patient presenting with renal calculi after undergoing ANL. PMID- 22924044 TI - Ectopic Axillary Breast during Systemic Lupus. AB - Many breast changes may occur in systemic lupus erythematosus. We report a 41 year-old woman with lupus who presented three years after the onset of lupus an ectopic mammary gland confirmed by histological study. PMID- 22924045 TI - Successful remove of a metal axletree causing penile strangulation in a 19-year old male by degloving operation. AB - Penile strangulation caused by foreign bodies mostly occurs in adolescents and adult males. When it happens, foreign bodies are often not easy to be removed. Penile strangulation is a rarely described urological emergency, especially in the adolescent population. This paper demonstrates the successful removal of a metal axletree causing penile strangulation in a 19-year-old male with the help of degloving operation. PMID- 22924046 TI - Central Nervous System Strongyloidiasis and Cryptococcosis in an HIV-Infected Patient Starting Antiretroviral Therapy. AB - We report a case of Strongyloides stercoralis hyperinfection syndrome with central nervous system involvement, in a patient with late human immunodeficiency virus (HIV) infection starting antiretroviral therapy, in whom Strongyloides stercoralis larvae and Cryptococcus neoformans were isolated antemortem from cerebrospinal fluid. Our patient was not from an endemic region for the parasite, so strongyloidiasis was not originally suspected. For this reason, we conclude that Strongyloides stercoralis infection should be suspected in HIV-infected patients starting antiretroviral therapy in order to avoid potential fatal outcomes. PMID- 22924047 TI - Endoscopic aspects of gastric syphilis. AB - Introduction. Considered as a rare event, gastric syphilis (GS) is reported as an organic form of involvement. Low incidence of GS emphasizes the importance of histopathological analysis. Objective. We aim to characterize GS endoscopic aspects in an immunocompetent patient. Case Report. A 23-year-old man presented with epigastric pain associated with nausea, anorexia, generalized malaise and 11 kg weight loss that started 1 month prior to his clinical consultation. Physical examination was normal except for mild abdominal tenderness in epigastrium. Endoscopy observed diminished gastric expandability and diffuse mucosal lesions, from cardia to pylorus. Gastric mucosa was thickened, friable, with nodular aspect, and associated with ulcers lesions. Gastric biopsies were performed, and histopathological analysis resulted in dense inflammatory infiltration rich in plasmocytes. Syphilis serologies were positive for VDRL and Treponema pallidum reagents. Immunohistochemical tests were positive for Treponema pallidum and CD138. The patient was treated with penicillin, leading to resolution of his clinical complaints and endoscopic findings. Conclusion. Diagnosis suspicion of GS is important in view of its nonspecific presentation. Patients with gastric symptoms that mimic neoplastic disease should be investigated thoroughly based on the fact that clinical, endoscopic, and histological findings can easily be mistaken for lymphoma or plastic linitis. PMID- 22924048 TI - Successful treatment of hemifacial myokymia and dystonia associated to linear scleroderma "en coup de sabre" with repeated botox injections. AB - Linear scleroderma "en coup de sabre" (LSCS) is a form of localized scleroderma presents as band-like sclerotic lesions of the frontoparietal area. It has been reported in association with diverse neurological manifestations like seizures, migraine, neuromyotonia, dystonia and abnormalities in MRI and CT studies as cerebral atrophy, white matter lesions, intraparenchymal calcification, meningeocortical alterations, and skull atrophy. We describe a patient with LSCS associated with two abnormal movements: permanent myokimia of right masseter muscle and recurrent spasmodic retraction of right cigomatic and depressor labii inferioris muscles. He was initially treated with methotrexate and steroids without response, so later on he underwent repeated Botox injections with remarkable improvement. PMID- 22924049 TI - Massive levemir (long-acting) insulin overdose: case report. AB - A 52-year-old insulin-dependant diabetic man presented to the Emergency Department 2 hours after a deliberate massive overdose of 2100 units of long acting Levemir insulin and a large quantity of whisky. On initial assessment, his GCS was 3/15 and his capillary blood sugar was 2.6 mmol/L. The patient was given a 50 ml bolus of 50% dextrose, followed by intravenous infusions of both 5% and 10% dextrose. Despite the continuous infusions, he experienced 4 symptomatic hypoglycaemic episodes in the first 12 hours after admission. These were managed with oral glucose, IM glucagon, and further dextrose boluses. Blood electrolytes and pH were monitored throughout. Insulin overdoses are relatively common and often occur with an excess of other drugs or alcohol which can enhance its action. Overdoses can result in persistent hypoglycaemia, liver enzyme derangement, electrolyte abnormalities, and neurological damage. Overall mortality is 2.7% with prognosis poorest in patients who are admitted with decreased Glasgow Coma scale (GCS) 12 hours after overdose. PMID- 22924050 TI - Lymphangitic pulmonary metastases in castrate-resistant prostate adenocarcinoma. AB - A 63-year-old man with castrate-resistant metastatic prostate adenocarcinoma with known osseous and pelvic nodal involvement presented with progressive dyspnea for one week. Complete cardiopulmonary evaluation revealed a restrictive lung defect that could not be attributed to any of his previous therapies. On presentation, physical examination revealed coarse breath sounds diffusely with hypoxemia. Computed tomography of the chest showed severe bilateral airspace opacities and ground-glass appearance most consistent with interstitial pneumonitis. The patient was intubated due to progressive hypoxemia and worsening respiratory status despite empiric antibiotics and high dose steroids. Subsequent emergent bronchoscopy with transbronchial biopsies revealed atypical intralymphatic cells that stained positively for prostate-specific antigen and prostatic-specific acid phosphatase, confirming the diagnosis of intralymphatic pulmonary metastasis from prostate adenocarcinoma. Lymphangitic pulmonary metastasis from prostate adenocarcinoma is exceedingly rare, with few reported cases that are biopsy proven. Herein, we describe a rare case of biopsy-proven lymphangitic pulmonary metastasis in the setting of castrate-resistant prostate adenocarcinoma and provide a comprehensive literature review. PMID- 22924052 TI - Mechanistic study on the antidepressant-like effect of danggui-shaoyao-san, a chinese herbal formula. AB - Danggui-Shaoyao-San (DSS), a famous Chinese herbal formula, has been widely used in the treatment of various diseases. Previous studies have shown that DSS produces antidepressant-like effect in rodents. This study aims to investigate the mechanism(s) underlying the antidepressant-like action of DDS. The results showed that DSS treatment significantly antagonized reserpine-induced ptosis in mice. In addition, DSS treatment significantly increased sucrose consumption in chronic unpredictable stress- (CUS-) treated mice. DSS treatment also markedly attenuated CUS-induced decreases in noradrenaline and dopamine concentrations in mouse brain. Furthermore, DSS treatment significantly reversed CUS-induced increase in serum malondialdehyde (MDA) content and decrease in serum superoxide dismutase (SOD) activity in mice. The results suggest that the antidepressant like activity of DSS is probably mediated by the modulation of central monoamine neurotransmitter systems and the reduction of oxidative stress. PMID- 22924051 TI - Lessons from cancer immunoediting in cutaneous melanoma. AB - We will revisit the dual role of the immune system in controlling and enabling tumor progression, known as cancer immunoediting. We will go through the different phases of this phenomenon, exposing the most relevant evidences obtained from experimental models and human clinical data, with special focus on Cutaneous Melanoma, an immunogenic tumor per excellence. We will describe the different immunotherapeutic strategies employed and consider current models accounting for tumor heterogeneity. And finally, we will propose a rational discussion of the progress made and the future challenges in the therapeutics of Cutaneous Melanoma, taking into consideration that tumor evolution is the resulting from a continuous feedback between tumor cells and their environment, and that different combinatorial therapeutic approaches can be implemented according to the tumor stage. PMID- 22924053 TI - In vitro schistosomicidal activity of some brazilian cerrado species and their isolated compounds. AB - Miconia langsdorffii Cogn. (Melastomataceae), Roupala montana Aubl. (Proteaceae), Struthanthus syringifolius (Mart.) (Loranthaceae), and Schefflera vinosa (Cham. & Schltdl.) Frodin (Araliaceae) are plant species from the Brazilian Cerrado whose schistosomicidal potential has not yet been described. The crude extracts, fractions, the triterpenes betulin, oleanolic acid, ursolic acid and the flavonoids quercetin 3-O-beta-D-rhamnoside, quercetin 3-O-beta-D-glucoside, quercetin 3-O-beta-D-glucopyranosyl-(1-2)-alpha-L-rhamnopyranoside and isorhamnetin 3-O-beta-D-glucopyranosyl-(1-2)-alpha-L-rhamnopyranoside were evaluated in vitro against Schistosoma mansoni adult worms and the bioactive n hexane fractions of the mentioned species were also analyzed by GC-MS. Betulin was able to cause worm death percentage values of 25% after 120 h (at 100 MUM), and 25% and 50% after 24 and 120 h (at 200 MUM), respectively; besides the flavonoid quercetin 3-O-beta-D-rhamnoside promoted 25% of death of the parasites at 100 MUM. Farther the flavonoids quercetin 3-O-beta-D-glucoside and quercetin 3 O-beta-D-rhamnoside at 100 MUM exhibited significantly reduction in motor activity, 75% and 87.5%, respectively. Biological results indicated that crude extracts of R. montana, S. vinosa, and M. langsdorffii and some n-hexane and EtOAc fractions of this species were able to induce worm death to some extent. The results suggest that lupane-type triterpenes and flavonoid monoglycosides should be considered for further antiparasites studies. PMID- 22924054 TI - In vitro and in vivo toxicity of garcinia or hydroxycitric Acid: a review. AB - Obesity is one of the pandemic chronic diseases commonly associated with health disorders such as heart attack, high blood pressure, diabetes or even cancer. Among the current natural products for obesity and weight control, Garcinia or more specifically hydroxycitric acid (HCA) extracted from Garcinia has been widely used. The evaluation of the potential toxicity of weight control supplement is of the utmost importance as it requires long term continuous consumption in order to maintain its effects. Majority of reports demonstrated the efficacy of Garcinia/HCA without any toxicity found. However, a few clinical toxicity reports on weight-loss diet supplements of which some were combinations that included Garcinia/HCA as an active ingredient showed potential toxicity towards spermatogenesis. Nonetheless, it cannot be concluded that Garcinia/HCA is unsafe. Those products which have been reported to possess adverse effects are either polyherbal or multi-component in nature. To date, there is no case study or report showing the direct adverse effect of HCA. The structure, mechanism of action, long history of the use of Garcinia/HCA and comprehensive scientific evidence had shown "no observed adverse effect level (NOAEL)" at levels up to 2800 mg/day, suggesting its safety for use. PMID- 22924055 TI - The Study on the Agreement between Automatic Tongue Diagnosis System and Traditional Chinese Medicine Practitioners. AB - Tongue diagnosis is an important practice in traditional Chinese medicine (TCM) for diagnosing diseases before determining proper means of treatments. Traditionally, it depends solely on personal knowledge and experience of the practitioner, thereby being criticized as lacking of objectivity. Currently, no research regarding intra- and inter-agreements of automatic tongue diagnosis system (ATDS) and TCM doctors has been conducted. In this study, the ATDS is developed to extract a variety of tongue features and provide practitioners with objective information to assist diagnoses. To evaluate the ATDS clinical stability, 2 sets of tongue images taken 1 hour apart from 20 patients with possible variations in lighting and extruding tongue, are employed to investigate intra-agreement of the ATDS, intra-agreement of the TCM doctors, and the inter agreement between the ATDS and TCM doctors. The ATDS is shown to be more consistent with significantly higher intra-agreement than the TCM doctors (kappa value: 0.93 +/- 0.06 versus 0.64 +/- 0.13) with P < 0.001 (Student's t-test). Inter-agreements between the ATDS and TCM doctors, as well as among the TCM doctors are both moderate. The high agreement of the ATDS can provide objective and reliable tongue features to facilitate doctor in making effective observation and diagnosis of specific diseases. PMID- 22924056 TI - The Effects of Cosmos caudatus on Structural Bone Histomorphometry in Ovariectomized Rats. AB - Osteoporosis is considered a serious debilitating disease. Cosmos caudatus (ulam raja), a plant containing antioxidant compounds and minerals, may be used to treat and prevent osteoporosis. This study determines the effectiveness of C. caudatus as bone protective agent in postmenopausal osteoporosis rat model. Thirty-two female rats, aged 3 months old, were divided into 4 groups. Group one was sham operated (sham) while group two was ovariectomized. These two groups were given ionized water by forced feeding. Groups three and four were ovariectomized and given calcium 1% ad libitum and force-fed with C. caudatus at the dose of 500 mg/kg, respectively. Treatments were given six days per week for a period of eight weeks. Body weight was monitored every week and structural bone histomorphometry analyses of the femur bones were performed. Ovariectomy decreased trabecular bone volume (BV/TV), decreased trabecular number (Tb.N), and increased trabecular separation (Tb.Sp). Both calcium 1% and 500 mg/kg C. caudatus reversed the above structural bone histomorphometric parameters to normal level. C. caudatus shows better effect compared to calcium 1% on trabecular number (Tb.N) and trabecular separation (Tb.Sp). Therefore, Cosmos caudatus 500 mg/kg has the potential to act as the therapeutic agent to restore bone damage in postmenopausal women. PMID- 22924057 TI - Combined Effects of Eurycoma longifolia and Testosterone on Androgen-Deficient Osteoporosis in a Male Rat Model. AB - Androgen-deficient osteoporosis in men is treated with testosterone therapy, which is associated with side effects. Eurycoma longifolia (EL) is known to possess androgenic properties and has been reported to protect bone from androgen deficient osteoporosis in experimental animal models. The present study aimed to determine the effectiveness of combination therapy of EL and testosterone (T) in treating androgen-deficient osteoporosis. Forty male Sprague-Dawley rats were divided into: sham-operated (SHAM), orchidectomized-control (ORX), orchidectomized with testosterone (ORX + T), orchidectomized with EL (ORX + EL), and orchidectomized with combined T and EL therapy (ORX + T + EL). EL was administered via oral gavages daily at the dose of 15 mg/kg. T was injected intramuscularly at 8 mg/kg and 4 mg/kg for the ORX + T and ORX + T + EL groups, respectively. Following 6 weeks of treatment, the osteocalcin levels of ORX + T and ORX + T + EL groups were significantly lower than the SHAM group (P < 0.05). The posttreatment CTX levels of ORX + T and ORX + T + EL groups were significantly lower than their pretreatment levels (P < 0.05). Biomechanically, the strain parameter of the ORX + T + EL group was significantly higher than the ORX group (P < 0.05). Thus, the combination therapy of EL and low-dose T has potential for treatment of androgen-deficient osteoporosis. The lower T dose is beneficial in reducing the sideeffects of testosterone therapy. PMID- 22924058 TI - An epidemiological model of Rift Valley fever with spatial dynamics. AB - As a category A agent in the Center for Disease Control bioterrorism list, Rift Valley fever (RVF) is considered a major threat to the United States (USA). Should the pathogen be intentionally or unintentionally introduced to the continental USA, there is tremendous potential for economic damages due to loss of livestock, trade restrictions, and subsequent food supply chain disruptions. We have incorporated the effects of space into a mathematical model of RVF in order to study the dynamics of the pathogen spread as affected by the movement of humans, livestock, and mosquitoes. The model accounts for the horizontal transmission of Rift Valley fever virus (RVFV) between two mosquito and one livestock species, and mother-to-offspring transmission of virus in one of the mosquito species. Space effects are introduced by dividing geographic space into smaller patches and considering the patch-to-patch movement of species. For each patch, a system of ordinary differential equations models fractions of populations susceptible to, incubating, infectious with, or immune to RVFV. The main contribution of this work is a methodology for analyzing the likelihood of pathogen establishment should an introduction occur into an area devoid of RVF. Examples are provided for general and specific cases to illustrate the methodology. PMID- 22924059 TI - A novel weighted support vector machine based on particle swarm optimization for gene selection and tumor classification. AB - We develop a detection model based on support vector machines (SVMs) and particle swarm optimization (PSO) for gene selection and tumor classification problems. The proposed model consists of two stages: first, the well-known minimum redundancy-maximum relevance (mRMR) method is applied to preselect genes that have the highest relevance with the target class and are maximally dissimilar to each other. Then, PSO is proposed to form a novel weighted SVM (WSVM) to classify samples. In this WSVM, PSO not only discards redundant genes, but also especially takes into account the degree of importance of each gene and assigns diverse weights to the different genes. We also use PSO to find appropriate kernel parameters since the choice of gene weights influences the optimal kernel parameters and vice versa. Experimental results show that the proposed mRMR-PSO WSVM model achieves highest classification accuracy on two popular leukemia and colon gene expression datasets obtained from DNA microarrays. Therefore, we can conclude that our proposed method is very promising compared to the previously reported results. PMID- 22924060 TI - An automated optimal engagement and attention detection system using electrocardiogram. AB - This research proposes to develop a monitoring system which uses Electrocardiograph (ECG) as a fundamental physiological signal, to analyze and predict the presence or lack of cognitive attention in individuals during a task execution. The primary focus of this study is to identify the correlation between fluctuating level of attention and its implications on the cardiac rhythm recorded in the ECG. Furthermore, Electroencephalograph (EEG) signals are also analyzed and classified for use as a benchmark for comparison with ECG analysis. Several advanced signal processing techniques have been implemented and investigated to derive multiple clandestine and informative features from both these physiological signals. Decomposition and feature extraction are done using Stockwell-transform for the ECG signal, while Discrete Wavelet Transform (DWT) is used for EEG. These features are then applied to various machine-learning algorithms to produce classification models that are capable of differentiating between the cases of a person being attentive and a person not being attentive. The presented results show that detection and classification of cognitive attention using ECG are fairly comparable to EEG. PMID- 22924061 TI - Atomic radiations in the decay of medical radioisotopes: a physics perspective. AB - Auger electrons emitted in nuclear decay offer a unique tool to treat cancer cells at the scale of a DNA molecule. Over the last forty years many aspects of this promising research goal have been explored, however it is still not in the phase of serious clinical trials. In this paper, we review the physical processes of Auger emission in nuclear decay and present a new model being developed to evaluate the energy spectrum of Auger electrons, and hence overcome the limitations of existing computations. PMID- 22924062 TI - Machine learning approach to extract diagnostic and prognostic thresholds: application in prognosis of cardiovascular mortality. AB - Machine learning has become a powerful tool for analysing medical domains, assessing the importance of clinical parameters, and extracting medical knowledge for outcomes research. In this paper, we present a machine learning method for extracting diagnostic and prognostic thresholds, based on a symbolic classification algorithm called REMED. We evaluated the performance of our method by determining new prognostic thresholds for well-known and potential cardiovascular risk factors that are used to support medical decisions in the prognosis of fatal cardiovascular diseases. Our approach predicted 36% of cardiovascular deaths with 80% specificity and 75% general accuracy. The new method provides an innovative approach that might be useful to support decisions about medical diagnoses and prognoses. PMID- 22924063 TI - A technique for in vitro fit assessment of multi-unit screw-retained implant restorations: Application of a triple-scan protocol. AB - Recent advances in industrial non-contact scanners offer unprecedented opportunities for quality assessment of dental restorations. The majority of investigations published to date are limited to local two-dimensional results. A triple-scan protocol for virtual fit assessment of multi-unit screw-retained implant restorations is presented in this technical report. The advantages for application in biomechanical research include detailed three-dimensional information on internal component congruence in implant superstructures to be used in mathematical models. PMID- 22924064 TI - Finite element analysis of adhesive endo-crowns of molars at different height levels of buccally applied load. AB - This study aimed to evaluate the biomechanical behaviour of adhesive endo-crowns and the influence of their design on the restoration prognosis when four loading positions are applied from the restoration-tooth junction. Two three-dimensional finite element models for the lower first molar were developed: endo-crown as a monobloc and endo-crown of a primary abutment and a full crown. Four crown loading positions were considered: 5, 6, 7 and 8 mm. A force of 1400 N was applied buccally on the middle of the mesiodistal width. No differences were observed for the two endo-crowns concerning restoration displacement and the distribution of equivalent von Mises stress and total equivalent strain. Shifting the position of the applied load to 8 mm resulted in an increase in the displacement from 25 to 42 um and an increase of equivalent von Mises stress concentration at the tooth. The height of load application on the restoration has a significant role in the prognosis of endo-crowns. PMID- 22924065 TI - Alveolar ridge resorption after tooth extraction: A consequence of a fundamental principle of bone physiology. AB - It is well established that tooth extraction is followed by a reduction of the buccolingual as well as the apicocoronal dimension of the alveolar ridge. Different measures have been taken to avoid this bone modelling process, such as immediate implant placement and bone grafting, but in most cases with disappointing results. One fundamental principle of bone physiology is the adaptation of bone mass and bone structure to the levels and frequencies of strain. In the present article, it is shown that the reduction of the alveolar ridge dimensions after tooth extraction is a natural consequence of this physiological principle. PMID- 22924066 TI - Sleep medicine: Present and future. PMID- 22924067 TI - Role of ATP binding and hydrolysis in the gating of the cystic fibrosis transmembrane conductance regulator. AB - The CFTR gene is unique within the ATP-binding cassette (ABC) protein family, predominantly of transporters, by coding a chloride channel. The gating mechanism of ABC proteins has been characterized by the ATP Switch model in terms cycles of dimer formation and dissociation linked to ATP binding and hydrolysis, respectively. It would be of interest to assess the extent that Cystic Fibrosis Transmembrane Conductance Regulator (CFTR), a functional channel, fits the ATP Switch model for ABC transporters. Additional transporter mechanisms, namely those of Pgp and HlyB, are discussed for perspective. Literature search of databases selected key references in comparing and contrasting the gating mechanism. CFTR is a functional chloride channel facilitating transmembrane anion flow down electrochemical gradients. A dysfunctional CFTR protein results in cystic fibrosis, a fatal pleiotropic disease currently managed symptomatically. Understanding the gating mechanism will help target drug development aimed at alleviating and curing the disease. PMID- 22924068 TI - Predicting tobacco use among high school students by using the global youth tobacco survey in Riyadh, Saudi Arabia. AB - OBJECTIVE: To identify the predictors that lead to cigarette smoking among high school students by utilizing the global youth tobacco survey in Riyadh, Kingdom of Saudi Arabia (KSA). METHODS: A cross-sectional study was conducted among high school students (grades 10-12) in Riyadh, KSA, between April 24, 2010, and June 16, 2010. RESULTS: The response rate of the students was 92.17%. The percentage of high school students who had previously smoked cigarettes, even just 1-2 puffs, was 43.3% overall. This behavior was more common among male students (56.4%) than females (31.3%). The prevalence of students who reported that they are currently smoking at least one cigarette in the past 30 days was 19.5% (31.3% and 8.9% for males and females, respectively). "Ever smoked" status was associated with male gender (OR = 2.88, confidence interval [CI]: 2.28-3.63), parent smoking (OR = 1.70, CI: 1.25-2.30) or other member of the household smoking (OR = 2.11, CI: 1.59-2.81) who smoked, closest friends who smoked (OR = 8.17, CI: 5.56-12.00), and lack of refusal to sell cigarettes (OR = 5.68, CI: 2.09-15.48). CONCLUSION: Several predictors of cigarette smoking among high school students were identified. PMID- 22924069 TI - MMP1-1607(1G>2G) polymorphism and the risk of lung cancer in Lebanon. AB - CONTEXT: Matrix metalloproteinases (MMPs) are a family of enzymes that degrade various components of the extracellular matrix and are involved in the development and progression of cancer. Lung cancer is the most commonly diagnosed cancer in Lebanon. MMP1 is responsible for degrading stromal collagens, which enhance the ability of neoplastic cells to cross basal membrane of both the endothelium and the vascular endothelium. A recent meta-analysis has suggested that the MMP1-1607 2G allele may be associated with an increased risk for certain types of cancers. AIM: This study was undertaken to investigate the association between guanine insertion polymorphism in the MMP1 promoter and the susceptibility to lung cancer in the Lebanese population. SETTINGS AND DESIGN: This case-control study was conducted on 41 patients with lung cancer and 51 age matched healthy controls, recruited from different regions of Lebanon. METHODS: Cases were histologically confirmed lung cancer patients obtained from different hospitals in Lebanon. Controls were healthy unrelated individuals with no history of cancer or genetic diseases. All subjects were genotyped for MMP1 -1607(1G>2G) polymorphism using polymerase chain reaction-restriction fragment length polymorphism method (PCR-RFLP). RESULTS: No statistically significant differences were found when genotype and allele distribution of MMP1 -1607(1G>2G) polymorphism were compared between patients with lung cancer and controls [P= 0.6 by chi-squared test on a 3*2 contingency table; allelic P=0.61, OR (95% CI) = 1.18 (0.60-2.31)]. CONCLUSION: Our data shows that MMP1 promoter polymorphism is not associated with lung cancer susceptibility in the Lebanese population. PMID- 22924070 TI - Prevalence of short sleep duration and its association with obesity among adolescents 15- to 19-year olds: A cross-sectional study from three major cities in Saudi Arabia. AB - BACKGROUND: Adequate sleep has been considered important for the adolescent's health and well being. On the other hand, self-imposed sleep curtailment is now recognized as a potentially important and novel risk factor for obesity. The present study aimed to assess the prevalence of short sleep duration and its association with obesity among Saudi adolescents. METHODS: This is a school-based cross-sectional study with self-reported sleep questionnaires. It was conducted during the years 2009/2010 in three cities in Saudi Arabia; Al-Khobar, Jeddah, and Riyadh. Participants were 2868 secondary-school males (1379) and females (1389) aged 15 to 19 years, randomly selected using a multistage stratified sampling technique. Measurements included weight, height, waist circumference, BMI, and sleeping duration. Logistic regression analysis while adjusted for age, gender, and location was used to examine the associations between sleep duration and obesity measures. RESULTS: The mean (SD) of sleep duration was 7.2 (1.6) hours/day with no significant differences between males and females. About 31% of the participants obtain less than 7 hours of sleep per day, while approximately 50% of the sample gets less than 8 hours of daily sleep. Two-way ANCOVA results while controlling for the effect of age revealed a significant gender by school type interaction (P<0.001). In addition, adequate sleep duration increased the odds of having normal weight (adjusted odds ratios = 1.28, 95% CI = 1.08-1.50, P = 0.003). CONCLUSION: The present study observed a high prevalence of short sleep duration among Saudi adolescents 15- to 19-year olds and that short sleep duration was significantly associated with increased risk of overweight and obesity. Future interventions should investigate whether adopting a healthy lifestyle by adolescents with short sleep duration would improve their sleeping habits or not. PMID- 22924071 TI - Comparison of the effect of high-dose inhaled budesonide and fluticasone on adrenal function in patients with severe chronic obstructive pulmonary disease. AB - INTRODUCTION: Chronic obstructive pulmonary disease (COPD) is a leading cause of respiratory-related morbidity and mortality. Inhaled steroids are frequently used in patients with moderate to severe disease and may lead to adrenal suppression. OBJECTIVES: The aim of this study was to compare the effect of inhaled budesonide/formoterol with inhaled fluticasone/salmeterol in severe COPD. METHODS: It was a prospective open-label crossover study of 22 patients. Adrenal suppression was measured by overnight urinary cortisol/creatinine ratio. The measurements were taken while patients were on either combination for at least 4 weeks. RESULTS: A total of 12 patients completed the study. The mean age was 64 years (8 males, 4 females). The mean FEV1 was 1 L (range, 0.5-1.8). There was no significant difference in adrenal suppression measured by overnight urinary cortisol/creatinine ratio (budesonide 5.2 +/- 4.3, fluticasone 4.7 +/- 3.1; 95% CI -2.2 to 1.2; P = 0.52) and urinary cortisol concentration (budesonide 51 +/- 53, fluticasone 43 +/- 31 [nmol/l]; 95% CI -35 to 20; P = 0.56). CONCLUSION: Inhaled budesonide and fluticasone have no significantly different effect on adrenal function in moderate to severe COPD. The adverse event profile of high dose inhaled steroids should not influence the choice of medication. PMID- 22924072 TI - The use of thoracoscopy to enhance medical students' interest and understanding of thoracic anatomy. AB - AIM: To develop a video-based educational tool designed for teaching thoracic anatomy and to examine whether this tool would increase students' stimulation and motivation for learning anatomy. METHODS: Our video-based tool was developed by recording different thoracoscopic procedures focusing on intraoperative live thoracic anatomy. The tool was then integrated into a pre-existing program for first year medical students (n = 150), and included cadaver dissection of the thorax and review of clinical problem scenarios of the respiratory system. Students were guided through a viewing of the videotape that demonstrated live anatomy of the thorax (15 minutes) and then asked to complete a 5-point Likert type questionnaire assessing the video's usefulness. Apart from this, a small group of entirely different set of students was divided into two groups, one group to view the 15-minute video presentation of thoracoscopy and chest anatomy and the other group to attend a 15-minute lecture of chest anatomy using radiological images. Both groups took a 10-item pretest and post-test multiple choice questions examination to assess short-term knowledge gained. RESULTS: Of 150 medical students, 119 completed the questionnaires, 88.6% were satisfied with the thoracoscopic video as a teaching tool, 86.4% were satisfied with the quality of the images, 69.2% perceived it to be beneficial in learning anatomy, 96.2% increased their interest in learning anatomy, and 88.5% wanted this new teaching tool to be implemented to the curriculum. Majority (80.7%) of the students increased their interest in surgery as a future career. Post-test scores were significantly higher in the thoracoscopy group (P = 0.0175). CONCLUSION: Incorporating live surgery using thoracoscopic video presentation in the gross anatomy teaching curriculum had high acceptance and satisfaction scores from first year medical students. The video increased students' interest in learning, in clinically applying anatomic fact, and in surgery as a future career. PMID- 22924073 TI - Micrometastasis in non-small-cell lung cancer: Detection and staging. AB - BACKGROUND: The clinical relevance of bone marrow micrometastasis (BMM) in non small-cell lung cancer is undetermined, and the value of such analyses in advanced stage patients has not been clearly assessed previously. This study was conducted to estimate the accuracy of both polymerase chain reaction (PCR) and immunohistochemistry (IHC) in micrometastases detection and determine the best site for bone marrow biopsy in order to find micrometastasis. METHODS: This prospective cross-sectional study was performed in the Department of Thoracic Surgery, Alzahra University Hospital from September 2008 to June 2009. To evaluate the bone marrow, a 3-cm rib segment and an aspirated specimen from the iliac bone prior to tumor resection were taken. PCR and IHC were performed for each specimen to find micrometastasis. RESULTS: Of 41 patients, 14 (34%) were positive for BMM by PCR compared with two positive IHC (4.8%). All BMMs were diagnosed in rib segments, and iliac specimens were all free from metastatic lesion. Our data showed no significant association between variables such as age, sex, histology, tumor location, side of tumor, involved lobe, smoking, or weight loss and presence of BMM. CONCLUSION: PCR could use as a promising method for BMM detection. BMM in a sanctuary site (rib) is not associated with advanced stages of lung cancer. In addition, when predictor variables such as age, sex, histology, tumor location, smoking, or weight loss are analyzed, no correlation can be found between micrometastasis prevalence and any of those variables. PMID- 22924074 TI - Effect of drinking Arabian Qahwa on fractional exhaled nitric oxide levels in healthy nonsmoking Saudi adults. AB - OBJECTIVES: Fractional exhaled nitric oxide (FENO) is an emerging marker of inflammation in respiratory diseases. However, it is affected by a number of confounding factors. We aimed to study the effect of drinking Arabian Qahwa on FENO in non-smoking Saudi healthy adults. METHODS: We recruited 12 nonsmoker healthy male adults aged 36.6 +/- 2.7 (21-50) years. All subjects were free from acute respiratory infections or allergies and had normal ventilatory functions and serum IgE levels. At 8 am in the morning, their baseline values of FENO were recorded. They had not taken tea or coffee in the morning and had taken similar light breakfast. They were given three cups of Arabian Qahwa to drink and then after every 30 minutes, serial levels of FENO were recorded. RESULTS: Average FENO levels at baseline were 28.73 +/- 9.33 (mean +/- SD) parts per billion (ppb). The mean FENO levels started to decrease significantly after 30 minutes of drinking Arabian Qahwa (P=0.002). This decrease in FENO level was further observed till two hours after Qahwa drinking and then it started to increase in next 90 minutes but still was significantly lower than the baseline (P=0.002). The mean FENO level recorded after 4 hours was 27.22 +/- 10.22 (P=0.039). CONCLUSIONS: FENO levels were significantly lowered by intake of Arabian Qahwa and this effect remains for about 4 hours. Therefore, history of recent Qahwa intake and abstinence is essential before performance of FENO and its interpretation. PMID- 22924075 TI - Novel approach for the management of sub-massive pulmonary embolism. AB - BACKGROUND: Right ventricular (RV) dysfunction has been identified as a poor prognostic indicator in sub-massive pulmonary embolism (SPE). We hypothesized that using selective vasodilator agent is beneficial in improving RV function in patients with this condition. METHODS: We used inhaled prostacyclin analogue (Iloprost, Ventavis((r))) in five patients with SPE. Helical computerized tomography angiogram was confirmatory for pulmonary embolism and echocardiography was used to evaluate the RV status. All patients received inhaled Iloprost, 2.5 to 5 MUg every 4 hours for 3 weeks. RESULTS: Patients were prospectively followed for 3 months. They were assessed at baseline before starting Iloprost treatment and at 3 days, 3 weeks, and 3 months after treatment. All patients showed significant improvement in their functional class, Borg dyspnea score, NT pro-BNP level, and echocardiographic parameters. CONCLUSION: In SPE, directing therapy toward decreasing pulmonary vascular resistance improves the associated pulmonary hemodynamic compromise and improves RV function. PMID- 22924077 TI - Congenital pulmonary venolobar syndrome: Value of multidetector computed tomography in preoperative assessment. AB - A 6-month old baby referred to our department because of recurrent attacks of respiratory distress with chest infection. Chest radiology revealed reduction of the right hemithorax with mediastinal shift to the right. Multidetector computed tomography showed hypoplasia of the right lung and right pulmonary artery, systemic arterial supply to the lung from the abdominal aorta, and and absence of right venous drainage to the left atrium. This picture is consistent with congenital pulmonary venolobar syndrome. The patient underwent right pneumonectomy; the postoperative course was uneventful. PMID- 22924076 TI - An unusual interstitial lung disease. PMID- 22924078 TI - Pulmonary tumor thrombotic microangiopathy caused by gastric cancer. AB - Pulmonary tumor thrombotic microangiopathy (PTTM) is a fatal cancer-related pulmonary complication with rapidly progressing dyspnea, and occasionally induces sudden death. Here, we describe a postmortem-diagnosed PTTM case caused by gastric cancer, with the complaint of progressing dyspnea for 5 days.He did not have any abdominal symptoms or cancer history. PTTM should be considered in patients with rapidly worsening respiratory conditions, even if there is no cancer history. PMID- 22924079 TI - Palliative radiotherapy for superior vena caval obstruction by lung cancer: A major issue about timing and a minor issue about efficacy. PMID- 22924080 TI - Serum hepcidin and chronic obstructive pulmonary disease. PMID- 22924081 TI - Authors' reply. PMID- 22924082 TI - Effects of Fluid Shear Stress on a Distinct Population of Vascular Smooth Muscle Cells. AB - Vascular smooth muscle cells (SMCs) are a major cell type involved in vascular remodeling. The various developmental origins of SMCs such as neural crest and mesoderm result in heterogeneity of SMCs, which plays an important role in the development of vascular remodeling and diseases. Upon vascular injury, SMCs are exposed to blood flow and subjected to fluid shear stress. Previous studies have shown that fluid shear stress inhibits SMC proliferation. However, the effect of shear stress on the subpopulation of SMCs from specific developmental origin and vascular bed is not well understood. Here we investigated how shear stress regulates human aortic SMCs positive for neural crest markers. DNA microarray analysis showed that shear stress modulates the expression of genes involved in cell proliferation, matrix synthesis, cell signaling, transcription and cytoskeleton organization. Further studies demonstrated that shear stress induced SMC proliferation and cyclin D1, downregulated cell cycle inhibitor p21, and activated Akt pathway. Inhibition of PI-3 kinase blocked these shear stress induced changes. These results suggest that SMCs with neural crest characteristics may respond to shear stress in a different manner. This finding has significant implications in the remodeling and diseases of blood vessels. PMID- 22924083 TI - The Deformation Rate of Smooth Muscle Cells in Vessel Walls After Short-Duration Heating Dilatation in a Porcine Model Ex Vivo and In Vivo. AB - We have proposed a novel short-duration thermal angioplasty with uniform temperature distribution. Although the dilatation mechanism of our short-duration heating dilatation was reported in our previous study, the influences on smooth muscle cells (SMCs) are not sufficiently understood. We studied the influences on SMCs in terms of shape change and discussed the relationship between the SMCs' shape change and dilatation mechanism ex vivo and in vivo. We found that the SMCs were fixed in the stretched condition after our short-duration heating dilatation both ex vivo and in vivo. The deformation rate of SMCs' shape, measured by the cells' nuclei, was increased with rising balloon maximum temperature (T(balloon)), and the same tendency was observed for the arterial dilatation rate. We hypothesize that the SMCs were fixed in the stretched condition because the arterial dilatation with our short-duration heating dilatation was performed without any plastic deformations of the vessel wall, causing the vessel wall itself to be stretched. We also prospect that the reasons for the positive correlation between the deformation rate of SMCs' shape and T(balloon) are that (i) the area heated over 60 degrees C was expanded with rising T(balloon), and (ii) the arterial dilatation rate was also increased with rising T(balloon). PMID- 22924085 TI - Relationship Between Morbidly Obese Subjects' Attributions of Low General Well being, Expectations and Health-Related Quality of Life: Five-year Follow-up After Gastric Banding. AB - Low health-related quality of life among morbidly obese subjects is well-known. However, the relationship may not be simple. We aim to examine the association between pre-operative expectations and health-related quality of life and long term changes in health-related quality of life after gastric banding. The questionnaires were answered twice: before and five years after gastric banding. Short Form-36 assessed health-related quality of life. Obesity specific questions were used to assess the subjects' attribution of impairment to morbid obesity and their expectations to changes as a result of weight loss. The subjects attribute morbid obesity as a major reason for their impairments in state of health, physical activity, pain and work capacity. As a result of weight loss, the subjects expect improvements even within fields which they did not consider to be impaired due to morbid obesity. We found an inverse association between high expectations and mental component summary score at baseline. At follow-up having expectations fully fulfilled was associated with a higher mental component summary score than having expectations fulfilled only to a fair extension and not having expectations fulfilled. Physical component summary was statistically significant improved at follow-up Morbidly obese subjects' attributions of low general well-being combined with their expectations may be a central part of understanding the mechanisms involved in the association between morbid obesity and low health-related quality of life. Furthermore the impact of morbid obesity on health-related quality of life may be reduced if healthprofessionals bridge the gap between morbidly obese subjects' expectations and their experience. PMID- 22924084 TI - Meeting them where they are: Using the Internet to deliver behavioral medicine interventions for pain. AB - Pharmacological and interventional pain medicine treatments are emphasized in the routine treatment of chronic pain despite strong evidence for the efficacy and safety of behavioral approaches. Most medical professionals have not incorporated behavioral pain treatments into their practices. Internet-based interventions have the potential to increase clinical use of these treatments. We discuss the strengths and weaknesses of current Internet-based behavioral pain management interventions, focusing on three broad intervention categories: therapist-guided interventions, unguided (automated) interventions, and pain-relevant applications for mobile platforms. Examples of each category are discussed, revealing a high degree of variation in approaches, user interfaces, and components as well as variability in the degree to which these interventions have been subjected to empirical testing. Finally, we highlight key issues for research and clinical implementation, with the goal of advancing this field so that it can meet its potential to increase access to evidence-based behavioral medicine treatments for chronic pain. PMID- 22924086 TI - The Old-Age Healthy Dependency Ratio in Europe. AB - The aim of this study is to answer the question of whether improvements in the health of the elderly in European countries could compensate for population ageing on the supply side of the labour market. We propose a state-of-health specific (additive) decomposition of the old-age dependency ratio into an old-age healthy dependency ratio and an old-age unhealthy dependency ratio in order to participate in a discussion of the significance of changes in population health to compensate for the ageing of the labour force. Applying the proposed indicators to the Eurostat's population projection for the years 2010-2050, and assuming there will be equal improvements in life expectancy and healthy life expectancy at birth, we discuss various scenarios concerning future of the European labour force. While improvements in population health are anticipated during the years 2010-2050, the growth in the number of elderly people in Europe may be expected to lead to a rise in both healthy and unhealthy dependency ratios. The healthy dependency ratio is, however, projected to make up the greater part of the old-age dependency ratio. In the European countries in 2006, the value of the old-age dependency ratio was 25. But in the year 2050, with a positive migration balance over the years 2010-2050, there would be 18 elderly people in poor health plus 34 in good health per 100 people in the current working age range of 15-64. In the scenarios developed in this study, we demonstrate that improvements in health and progress in preventing disability will not, by themselves, compensate for the ageing of the workforce. However, coupled with a positive migration balance, at the level and with the age structure assumed in the Eurostat's population projections, these developments could ease the effect of population ageing on the supply side of the European labour market. PMID- 22924087 TI - Near-Infrared Fluorescence Imaging in Humans with Indocyanine Green: A Review and Update. AB - Near-infrared (NIR) fluorescence imaging clinical studies have been reported in the literature with six different devices that employ various doses of indocyanine green (ICG) as a non-specific contrast agent. To date, clinical applications range from (i) angiography, intraoperative assessment of vessel patency, and tumor/metastasis delineation following intravenous administration of ICG, and (ii) imaging lymphatic architecture and function following subcutaneous and intradermal ICG administration. In the latter case, NIR fluorescence imaging may enable new discoveries associated with lymphatic function due to (i) a unique niche that is not met by any other conventional imaging technology and (ii) its exquisite sensitivity enabling high spatial and temporal resolution. Herein, we (i) review the basics of clinical NIR fluorescence imaging, (ii) survey the literature on clinical application of investigational devices using ICG fluorescent contrast, (iii) provide an update of non-invasive dynamic lymphatic imaging conducted with our FDPM device, and finally, (iv) comment on the future NIR fluorescence imaging for non-invasive and intraoperative use given recent demonstrations showing capabilities for imaging following microdose administration of contrast agent. PMID- 22924088 TI - Presence of Striatal Amyloid Plaques in Parkinson's Disease Dementia Predicts Concomitant Alzheimer's Disease: Usefulness for Amyloid Imaging. AB - Dementia is a frequent complication of Parkinson's disease (PD). About half of PD dementia (PDD) is hypothesized to be due to progression of the underlying Lewy body pathology into limbic regions and the cerebral cortex while the other half is thought to be due to coexistent Alzheimer's disease. Clinically, however, these are indistinguishable. The spread of amyloid plaques to the striatum has been reported to be a sensitive and specific indicator of dementia due to Alzheimer's disease (AD). The purpose of the present study was to determine if the presence of striatal plaques might also be a useful indicator of the presence of diagnostic levels of AD pathology within PD subjects. We analyzed neuropathologically-confirmed cases of PD without dementia (PDND, N = 31), PDD without AD (PDD, N = 31) and PD with dementia meeting clinicopathological criteria for AD (PDAD, N =40). The minimum diagnostic criterion for AD was defined as including a clinical history of dementia, moderate or frequent CERAD cortical neuritic plaque density and Braak neurofibrillary stage III-VI. Striatal amyloid plaque densities were determined using Campbell-Switzer and Thioflavine S stains. Striatal plaque densities were significantly higher in PDAD compared to PDD (p<0.001). The presence of striatal plaques was approximately 80% sensitive and 80% specific for predicting AD. In comparison, the presence of cerebral cortex plaques alone was highly sensitive (100%) but had poor specificity (48% to 55%). The results suggest that striatal amyloid imaging may be clinically useful for making the distinction between PDD and PDAD. PMID- 22924089 TI - Inter-subject correlation in fMRI: method validation against stimulus-model based analysis. AB - Within functional magnetic resonance imaging (fMRI), the use of the traditional general linear model (GLM) based analysis methods is often restricted to strictly controlled research setups requiring a parametric activation model. Instead, Inter-Subject Correlation (ISC) method is based on voxel-wise correlation between the time series of the subjects, which makes it completely non-parametric and thus suitable for naturalistic stimulus paradigms such as movie watching. In this study, we compared an ISC based analysis results with those of a GLM based in five distinct controlled research setups. We used International Consortium for Brain Mapping functional reference battery (FRB) fMRI data available from the Laboratory of Neuro Imaging image data archive. The selected data included measurements from 37 right-handed subjects, who all had performed the same five tasks from FRB. The GLM was expected to locate activations accurately in FRB data and thus provide good grounds for investigating relationship between ISC and stimulus induced fMRI activation. The statistical maps of ISC and GLM were compared with two measures. The first measure was the Pearson's correlation between the non-thresholded ISC test-statistics and absolute values of the GLM Z statistics. The average correlation value over five tasks was 0.74. The second was the Dice index between the activation regions of the methods. The average Dice value over the tasks and three threshold levels was 0.73. The results of this study indicated how the data driven ISC analysis found the same foci as the model-based GLM analysis. The agreement of the results is highly interesting, because ISC is applicable in situations where GLM is not suitable, for example, when analyzing data from a naturalistic stimuli experiment. PMID- 22924090 TI - Wavelength Dependence of the Fluorescence Quenching Efficiency of Nearby Dyes by Gold Nanoclusters and Nanoparticles: The Roles of Spectral Overlap and Particle Size. AB - The efficiency of the glutathione monolayer-protected gold nanocluster (NC) Au(25) (1.2 nm metal core diameter (d)) in quenching the emission of dyes intercalated into DNA is compared to that of 2 and 4 nm gold nanoparticles (NPs). In all cases, the DNA/dye moieties and the gold particles are not covalently attached but rather form non-covalent ground state complexes. Under these conditions, steady-state measurements reveal that the quenching efficiency of Au(25) is a factor of 10 lower than that of plasmonic 4 nm gold NPs but comparable to that of 2 nm particles which do not show a distinct plasmon band. Nonetheless, significant emission quenching is observed even at very low (nM) concentrations of Au(25). The quenching efficiency of the 4 nm NPs is significantly higher for dyes emitting near the wavelength of the plasmon peak whereas that of the 2 nm gold NPs is well described by the nano-surface energy transfer (NSET) model proposed by the Strouse group (J. Am. Chem. Soc. 127, 3115 2005). Interestingly, for Au(25) the maximum quenching efficiency occurs for dyes emitting in the same wavelength range as that of the 2 and 4 nm NPs (490-560 nm), where it shows no discrete absorption features, rather than for wavelengths coincident with its HOMO-LUMO, intra-band or inter-band transitions. The fluorescence quenching properties of Au(25) NCs are therefore found to be distinct from those of larger NCs and NPs but do not appear to conform to theoretical predictions advanced thus far. PMID- 22924091 TI - Analysis of Cyclin D1 in Breast Cancer: A Call to Arms. AB - The oncogenic capabilities of the cell cycle protein cyclin D1 have long been established in a breast cancer setting. The CCND1 gene is amplified in up to 15 % of breast tumors, with overexpression of its corresponding protein found in up to 50 % of cases. While gene amplification is consistently associated with reduced patient survival times and treatment resistance, repeated attempts to clarify the prognostic and predictive impact of the cyclin D1 protein in breast cancer have yielded contrasting results. Here, we recommend that any examination of cyclin D1 in a patient cohort should begin by determining CCND1 copy number, with subsequent removal and separate analysis of amplified cases. Next, the remaining tumors should be examined for cyclin D1 protein expression in the context of well defined breast cancer subgroups. Only in this manner can the true clinical value of cyclin D1 be fully elucidated. PMID- 22924092 TI - Comparison of Random Periareolar Fine Needle Aspirate versus Ductal Lavage for Risk Assessment and Prevention of Breast Cancer. AB - Random periareolar fine needle aspiration (RPFNA) and ductal lavage (DL) are research techniques developed to (1) assess short-term breast cancer risk in asymptomatic women who are at increased risk for breast cancer and (2) track cytological response to risk reduction strategies. RPFNA and DL provide minimally invasive methods to repeatedly sample epithelial cells and research tools to investigate the biological origins of breast cancer in high-risk women. This review gives an overview of the strengths and limitations of both RPFNA and DL for risk assessment and breast cancer prevention in asymptomatic high-risk women. PMID- 22924093 TI - Attentional Control Buffers the Effect of Public Speaking Anxiety on Performance. AB - We explored dispositional differences in the ability to self-regulate attentional processes in the domain of public speaking. Participants first completed measures of speech anxiety and attentional control. In a second session, participants prepared and performed a short speech. Fear of public speaking negatively impacted performance only for those low in attentional control. Thus, attentional control appears to act as a buffer that facilitates successful self-regulation despite performance anxiety. PMID- 22924094 TI - Metabotropic glutamate receptor 5 negative allosteric modulators as novel tools for in vivo investigation. AB - Negative allosteric modulators (NAMs) of metabotropic glutamate receptor subtype 5 (mGluR5) have shown promising results in preclinical models for anxiety and drug abuse. Here we describe a series of aryl-substituted alkynyl analogues of the prototypic mGluR5 NAM 2-methyl-6-(phenylethynyl)pyridine (MPEP, 1). Displacement of [(3)H]1 binding in rat brain membranes showed that several of these novel compounds displayed high affinity binding (K(i) < 10 nM) for mGluR5, with up to a 24-fold increase in affinity over 1. Replacements of the 2-position Me on the pyridyl ring of 1 along with various 3'-CN, 5'-substitutions were generally well tolerated. All of the active analogues in this series had cLogP values in the 2-5 range and displayed inverse agonist characteristics in an ELISA based assay of G(q)alpha-mediated IP3 production. Compounds 7i and 7j produced in vivo effects in mouse models of anxiety-like behaviors more potently than 1 or 3 ((2-methyl-1,3-thiazol-4-yl)ethynyl)pyridine (MTEP, 2), supporting their utility as in vivo tools. PMID- 22924095 TI - In vitro evaluation of isolation possibility of stem cells from intra oral soft tissue and comparison of them with bone marrow stem cells. AB - OBJECTIVE: Stem cells are of great interest for regenerating disturbed tissues and organs. These cells are commonly isolated from the bone marrow, but there has been interest in other tissues in the recent years. In this study, we evaluated the possibility of isolation of stem cells from oral connective tissue and investigated their characteristics. MATERIALS AND METHODS: In this experimental study, sampling from the bone marrow and oral connective tissue of a beagle dog was performed under general anesthesia. Bone marrow stem cell isolation was performed according to the established protocols. The samples obtained from oral soft tissue were broken to small pieces and after adding collagenase I, the samples were incubated for 45 minutes in 37 degrees C. Other processes were similar to the processes which were carried out on bone marrow cells. Then cell properties were compared to evaluate if the cells from the connective tissue were stem cells. RESULTS: The cells from the bone marrow and connective tissue had the same morphology. The result of colony forming unit assay was relatively similar. Population doubling time was similar too. In addition, both cell groups differentiated to osteoblasts in osteogenic media. CONCLUSION: The cells isolated from the oral connective tissue had the characteristics of stem cells, including fibroblastoid morphology, self renewal properties, high proliferation rate and differentiation potential. PMID- 22924096 TI - Mutational Status of FGFR3 in Oral Squamous Cell Carcinoma. AB - OBJECTIVE: Head and neck squamous cell carcinoma, including oral squamous cell carcinoma (OSCC) is the sixth most common cancer in the human population. Despite significant efforts committed in treatment of OSCC the overall survival rate of OSCC has not improved significantly. Activating mutations in the fibroblast growth factor receptor 3 (FGFR3) genes are responsible for some human cancers, including bladder and cervical carcinoma. Despite a high frequency in some benign skin disorders, FGFR3 mutations have not been reported in cutaneous malignancies. Therefore, FGFR3 gene may play a role in epithelial biology and mutations of FGFR3 gene may contribute to the development of OSCC. MATERIALS AND METHODS: In this cross-sectional study, DNA was extracted and purified from snap frozen tissue biopsy sections of 20 OSCC cases. Exons 7 and 15 were amplified by polymerase chain reaction (PCR) and sequenced in both directions. RESULTS: In three cases silent mutations were identified in exon 7 (882 T to C) which may be introduced as Single Nucleotide Polymorphism (SNP) and no mutation was identified in exon 15. CONCLUSION: FGFR3 gene mutation in exon 7 and 15 has no significant role in the development and progression of OSCC. Analyzing other exons or considering other advanced gene mutation assessment techniques may clarify the role of this receptor mutation in OSCC pathogenesis. PMID- 22924097 TI - Effect of iron containing supplements on rats' dental caries progression. AB - OBJECTIVE: Iron deficiency is the most common form of malnutrition in developing countries. Iron containing supplements have been used effectively to solve this problem. In children, because of teeth staining after taking iron drops, parents have the idea that iron drops are the cause of tooth decay; therefore, they limit this vital supplement in their children's diet. Hereby, we evaluate the histologic effect of iron containing supplements on tooth caries in rice rats with cariogenic or non-cariogenic diet. MATERIALS AND METHODS: Twelve rats were selected and divided into four groups for this interventional experimental study. Four different types of dietary regimens were used for four months; group A, cariogenic diet with iron containing supplements; group B, cariogenic diet without iron containing supplements; group C, non-cariogenic diet with iron containing supplements; group D, non-cariogenic diet without iron containing supplements. After sacrificing the rats, 20-micron histological sections of their posterior teeth were prepared using the Ground Section method, then they were studied under polarized light microscopy. In order to compare the progression of caries in different samples, the depth of the lesions in the enamel was measured as three grades I, II and III. RESULTS: The mean grade value of A, B, C and D groups were 1.61, 2.61, 1.37 and 1.80, respectively. Statistical analysis revealed that significantly fewer caries were seen in the group which had received iron containing supplements and cariogenic diet compared with cariogenic diet without iron supplements (p<0.05). CONCLUSION: Ferrous sulfate reduces the progression of dental caries in the cariogenic dietary regimen. PMID- 22924098 TI - Comparison of Shear Bond Strength of Orthodontic Brackets Bonded to Enamel Prepared By Er:YAG Laser and Conventional Acid-Etching. AB - INTRODUCTION: The purpose of this study was to compare shear bond strength (SBS) of orthodontic brackets bonded to enamel prepared by Er:YAG laser with two different powers and conventional acid-etching. MATERIALS AND METHODS: Forty-five human premolars extracted for orthodontic purposes were randomly assigned to three groups based on conditioning method: Group 1- conventional etching with 37% phosphoric acid; Group 2- irradiation with Er:YAG laser at 1 W; and Group 3- irradiation with Er:YAG laser at 1.5 W. Metal brackets were bonded on prepared enamel using a light-cured composite. All groups were subjected to thermocycling process. Then, the specimens mounted in auto-cure acryle and shear bond strength were measured using a universal testing machine with a crosshead speed of 0.5 mm per second. After debonding, the amount of resin remaining on the teeth was determined using the adhesive remnant index (ARI) scored 1 to 5. One-way analysis of variance was used to compare shear bond strengths and the Kruskal-Wallis test was performed to evaluate differences in the ARI for different etching types. RESULTS: The mean and standard deviation of conventional acid-etch group, 1W laser group and 1.5W laser group was 3.82 +/- 1.16, 6.97 +/- 3.64 and 6.93 +/- 4.87, respectively. CONCLUSION: The mean SBS obtained with an Er:YAG laser operated at 1W or 1.5W is approximately similar to that of conventional etching. However, the high variability of values in bond strength of irradiated enamel should be considered to find the appropriate parameters for applying Er:YAG laser as a favorable alternative for surface conditioning. PMID- 22924099 TI - Evaluation of mandibular incisor extraction treatment outcome in patients with bolton discrepancy using peer assessment rating index. AB - OBJECTIVE: Mandibular incisor extraction in carefully selected cases as an alternative option to four bicuspid extraction or non extraction treatment has been advocated. The purpose of this study was to determine the degree of improvement in occlusion in patients with Bolton discrepancy treated by one lower incisor extraction using Peer Assessment Rating Index (PAR indexes). MATERIALS AND METHODS: Pre and post treatment dental casts of 14 patients treated with one lower incisor extraction were included in the study. Pre and post treatment dental casts were scored with PAR index. 70% reduction in PAR index was considered as high standard improvement. To test the hypothesis that the mean improvement in dental occlusion after one mandibular incisor extraction is at least 70%, one-tail one-sample student t-test was used. RESULTS: The mean improvement in dental occlusion in this group of patients was 78%. Fifty percent of the cases finished with a post treatment PAR score of 2. Spearman correlation coefficient was 0.763 (p<0.01), showing that more severe cases had greater post treatment PAR scores. CONCLUSION: Mandibular incisor extraction treatment may provide a high standard treatment outcome. PMID- 22924100 TI - Histologic Evaluation of Bone Healing Following Application of Anorganic Bovine Bone and beta-tricalcium Phosphate in Rabbit Calvaria. AB - OBJECTIVE: Both anorganic bovine bone (ABB) and beta-tricalcium phosphate (beta TCP) are used in clinical practice as bone substitute materials, but there is limited data comparing these two materials in standardized defects. The aim of this study was to histologically evaluate the effectiveness of ABB and beta-TCP in the healing of experimentally induced bone defects. MATERIALS AND METHODS: Eighteen bone defects were created on the calvaria of six rabbits. In each animal, one defect was left untreated and the other two were filled with ABB and beta-TCP. After one month, histological sections were prepared. Type and vitality of newly formed bone, percentage of new bone formation and residual material, thickness of trabeculae, inflammation and foreign body reaction were assessed. RESULTS: The newly formed osseous tissue was vital in all defects and consisted of woven and lamellar bone. Mean percentages of new bone formation were 30.83+/ 14.29%, 16.83+/-11.07% and 14.00+/-8.17% in beta-TCP, ABB and control groups, respectively and the mean percentages of residual biomaterial were 24.17+/-14.01% and 36.50+/-8.43% in beta-TCP and ABB groups, respectively. However, the differences were not statistically significant (all ps>0.05). Inflammatory infiltration was statistically higher in beta-TCP compared to the control group (p=0.025), but the difference was not significant between beta-TCP and ABB groups (p=0.083). Trabeculation thickness and foreign body reaction were not statistically different between beta-TCP and ABB groups. CONCLUSION: beta-TCP and ABB were not different with regard to the quantity and quality of newly formed osseous tissue. However, inflammatory infiltration was higher in sites filled with beta-TCP. PMID- 22924101 TI - Treatment of Mandibular Molar Class II Furcation Defects in Humans With Bovine Porous Bone Mineral in Combination With Plasma Rich in Growth Factors. AB - OBJECTIVE: The purpose of the present randomized clinical trial study was to compare the effectiveness of Bovine Porous Bone Mineral (BPBM) with and without Plasma Rich in Growth Factors (PRGF) in the treatment of mandibular Class II furcation defects. MATERIALS AND METHODS: In seven patients, nine pairs of symmetric buccal or lingual mandibular class II furcation defects were treated. In each patient, one defect received BPBM (control) and the other received BPBM/PRGF (test) by random assignment. Clinical measurements were made both at baseline and 6-month evaluation. RESULTS: Similar improvements were observed with both treatment modalities. Significant reductions were gained in the gingival index, probing depth and relative vertical clinical attachment level. Plaque index and gingival recession changes were not significant in both groups. The mean probing depth reductions were 2.67+/-0.87 mm for the control group and 3.22+/-1.56 mm for the test group (p<0.001). The mean relative vertical clinical attachment level gains were 1.57+/-0.96 mm (p<0.001) and 1.65+/-1.24 mm (p<0.004) in the control and test groups, respectively. In the test group, the relative horizontal clinical attachment level reduced from 5.87+/-0.96 mm to 4.58+/-1.02 mm (p<0.02). No significant differences were observed in all clinical parameters 6 months postoperatively between the two groups. CONCLUSION: The application of a combined technique using BPBM/PRGF, compared to the BPBM alone, resulted in greater healing, although not significant, in the treatment of mandibular class II furcation defects. PMID- 22924102 TI - Comparison of 1-periodontal indices and cultural porphyromonas gingivalis colony count in aggressive periodontitis patients treated by scaling and rootplanning with or without metronidazole gel. AB - OBJECTIVE: Systemic antibiotics and locally applied antimicrobial agents have been suggested to enhance clinical parameters. Patients exhibiting aggressive periodontitis in particular benefit from adjunctive antibiotic therapy. The purpose of this investigation was to evaluate the effect of local antibiotic therapy with metronidazole adjunctively to scaling and root planning (SRP) in the treatment of aggressive periodontitis. MATERIALS AND METHODS: Twenty patients diagnosed with aggressive periodontitis were placed in a spilt mouth design. Microbial specimens were taken from the deepest pocket of the teeth. The sites that had positive results of Porphyromonas gingivalis (P.g) were located randomly to receive SRP treatment in the control group and SRP plus metronidazole gel in the test group. Pocket probing depth (PPD), clinical attachment level (CAL) and bleeding on probing (BOP) parameters and numbers of P.g. colony were taken at baseline, 6 weeks and 12 weeks later. All data were collected and analyzed and tested by Wilcoxon and paired t test. RESULTS: The case group patients had significantly better results in BOP, PPD and the number of P.g colony count reduction in comparison with the control group (p<0.05). According to the measurements of CAL, the statistical difference was non significant (p>0.05). CONCLUSION: In non-surgical periodontal treatment of aggressive periodontits adjunctive metronidazole gel therapy has a better effect on the reduction of porphyromonas gingivalis content of pockets. PMID- 22924103 TI - Evaluation of the Effect of Plasma Rich in Growth Factors (PRGF) on Bone Regeneration. AB - OBJECTIVE: Reconstruction methods are an essential prerequisite for functional rehabilitation of the stomatognathic system. Plasma rich in growth factors (PRGF) offers a new and potentially useful adjunct to bone substitute materials in bone reconstructive surgery. This study was carried out to investigate the influence of PRGF and fibrin membrane on regeneration of bony defects with and without deproteinized bovine bone mineral (DBBM) on rabbit calvaria. MATERIALS AND METHODS: Twelve New Zealand white rabbits were included in this randomized, blinded, prospective study. Four equal 3.3*6.6 mm cranial bone defects were created and immediately grafted with DBBM, PRGF+DBBM, PRGF+fibrin membrane and no treatment as control. The defects were evaluated with histologic and histomorphometric analysis performed 4 and 8 weeks later. RESULTS: Adding PRGF to DBBM led to increased bone formation as compared with the control group in 4- and 8-week intervals. In DBBM and PRGF+fibrin membrane samples, no significant increase was seen compared to the control group. There was also a significant increase in the rate of biodegradation of DBBM particles with the addition of PRGF in the 8-week interval. Neither noticeable foreign body reaction nor any severe inflammation was seen in each of the specimens evaluated. CONCLUSION: Under the limitation of this study, adding PRGF to DBBM enhanced osteogenesis in rabbit calvarias. Applying autologous fibrin membrane in the defects was not helpful. PMID- 22924104 TI - Remineralization Effect of Topical NovaMin Versus Sodium Fluoride (1.1%) on Caries-Like Lesions in Permanent Teeth. AB - OBJECTIVE: NovaMin, a synthetic mineral composed of calcium, sodium, phosphorous and silica releases deposits of crystalline hydroxyl-carbonate apatite (HCA) structurally similar to tooth mineral composition. The aim of this investigation was to compare the potential remineralization effect of topical NovaMin and Sodium Fluoride gel on caries like lesions in permanent teeth. MATERIALS AND METHODS: A total of 60 sound human freshly extracted teeth were subjected to a pH cycling protocol. Specimens were randomly assigned to one of the two treatment groups with NovaMin contained dentifrice applied to group 1, while group 2 received a dentifrice containing 1.1% neutral Sodium Fluoride. Pastes were applied five times after the samples received a demineralization from an earlier cariogenic challenge. Specimens were then evaluated by a Surface Micro Hardness test (SMH, 25G, 5s). Post-treatment SMH measurements were conducted and Mann Whitney test was employed for statistical analysis. RESULTS: Mean post lesion SMH values were 221.99+/-26.27 and 224.50+/-28.64 for the first and second groups, respectively. Post treatment SMH values were 232.52+/-24.34 for NovaMin and 232.03 +/-24.46 for the fluoride group. Two way ANOVA test showed a highly significant difference between the two different treatment protocols (p<0.001). CONCLUSION: NovaMin dentifrice appears to have a greater effect on remineralization of carious-like lesions when compared to that of fluoride containing dentifrice in permanent teeth. PMID- 22924105 TI - Occlusal recording components for dental implant-supported prostheses. AB - In this article, three techniques for maxillo-mandibular relationship for Replace Select implants are described. The use of healing abutments, planning abutments, and Impression copings are presented, and the advantages and disadvantages are discussed. PMID- 22924106 TI - Unerupted primary molar teeth positioned inferior to the permanent premolar: a case report. AB - Primary tooth impaction is a rare finding during the development of primary dentition. Several factors contribute to the impaction of a deciduous tooth. This report describes the diagnosis and treatment of a 10-year-old boy who presented an impacted second primary mandibular molar. This tooth, located inferior to the second premolar together with an odontoma, was positioned superior to the premolar teeth. Treatment consisted of surgical removal of the impacted deciduous tooth and odontoma and placement of a passive lower lingual holding arch. Periodic examination was indicated for follow-up. Early intervention was recommended to manage orofacial disfigurement and to avoid consequent problems. PMID- 22924107 TI - Why the bigger live longer and travel farther: animals, vehicles, rivers and the winds. AB - Here we show that constructal-law physics unifies the design of animate and inanimate movement by requiring that larger bodies move farther, and their movement on the landscape last longer. The life span of mammals must scale as the body mass (M) raised to the power 1/4, and the distance traveled during the lifetime must increase with body size. The same size effect on life span and distance traveled holds for the other flows that move mass on earth: atmospheric and oceanic jets and plumes, river basins, animals and human operated vehicles. The physics is the same for all flow systems on the landscape: the scaling rules of "design" are expressions of the natural tendency of all flow systems to generate designs that facilitate flow access. This natural tendency is the constructal law of design and evolution in nature. Larger bodies are more efficient movers of mass on the landscape. PMID- 22924108 TI - Oxygen rocking aqueous batteries utilizing reversible topotactic oxygen insertion/extraction in iron-based perovskite oxides Ca(1-x)La(x)FeO(3-delta). AB - Developments of large-scale energy storages with not only low cost and high safety but also abundant metals are significantly demanded. While lithium ion batteries are the most successful method, they cannot satisfy all conditions. Here we show the principle of novel lithium-free secondary oxygen rocking aqueous batteries, in which oxygen shuttles between the cathode and anode composed of iron-based perovskite-related oxides Ca(0.5)La(0.5)FeO(z) (2.5 <= z <= 2.75 and 2.75 <= z <= 3.0). Compound Ca(0.5)La(0.5)FeO(z) can undergo two kinds of reduction and reoxidation of Fe(4+)/Fe(3+) and Fe(3+)/Fe(2+), that are accompanied by reversible and repeatable topotactic oxygen extraction and reinsertion during discharge and charge processes. PMID- 22924110 TI - Allelic imbalances in radiation-associated acute myeloid leukemia. AB - Acute myeloid leukemia (AML) can develop as a secondary malignancy following radiotherapy, but also following low-dose environmental or occupational radiation exposure. Therapy-related AML frequently carries deletions of chromosome 5q and/or 7, but for low-dose exposure associated AML this has not been described. For the present study we performed genome-wide screens for loss-of-heterozygosity (LOH) in a set of 19 AML cases that developed after radiation-exposure following the Chernobyl accident. Using Affymetrix SNP arrays we found large regions of LOH in 16 of the cases. Eight cases (42%) demonstrated LOH at 5q and/or 7, which is a known marker of complex karyotypic changes and poor prognosis. In accordance with literature data, the overall survival for these patients was significantly shorter as compared to patients without this alteration (P=0,014). We could show here for the first time that exposure to low-dose ionizing radiation induces AML with molecular alterations similar to those seen in therapy-related cases. PMID- 22924109 TI - Sex determination in beetles: production of all male progeny by parental RNAi knockdown of transformer. AB - Sex in insects is determined by a cascade of regulators ultimately controlling sex-specific splicing of a transcription factor, Doublesex (Dsx). We recently identified homolog of dsx in the red flour beetle, Tribolium castaneum (Tcdsx). Here, we report on the identification and characterization of a regulator of Tcdsx splicing in T. castaneum. Two male-specific and one female-specific isoforms of T. castaneum transformer (Tctra) were identified. RNA interference aided knockdown of Tctra in pupa or adults caused a change in sex from females to males by diverting the splicing of Tcdsx pre-mRNA to male-specific isoform. All the pupa and adults developed from Tctra dsRNA injected final instar larvae showed male-specific sexually dimorphic structures. Tctra parental RNAi caused an elimination of females from the progeny resulting in production of all male progeny. Transformer parental RNAi could be used to produce all male population for use in pest control though sterile male release methods. PMID- 22924111 TI - Management of Strategic and Operational Plans in Rescue Organizations to Maintain Preparedness against Disasters. PMID- 22924112 TI - The Relationship between Exposure to Pesticides and the Occurrence of Lymphoid Neoplasm. AB - BACKGROUND: The etiology of malignant lymphoma is still largely unknown. This study determines the relationship between exposure to pesticides and the occurrence of lymphoid neoplasms in Shiraz, Southern Iran. METHODS: Between 2007 and 2008, in a case control study conducted in Nemazee Hospital in Shiraz, Southern Iran, 200 subjects diagnosed with lymphoma according to the World Health Organization (WHO) classification were enrolled. Controls (n=200) were frequency matched to the cases by sex, age, and center. Subjects who were a farmer were compared with all other occupations. RESULTS: Out of the 200 cases that were diagnosed as lymphoid neoplasms, 100 were non-Hodgkin's lymphoma, 54 Hodgkin's lymphoma and 46 multiple myeloma. Seventy two percent of the NHL's were of the B cell type, 15% of the T-cell type and the rest were not classified. Furthermore, subjects exposed to pesticides were at an increased risk of non-Hodgkin lymphoma and MM, but not Hodgkin lymphoma. CONCLUSION: Risk of non-Hodgkin lymphoma and MM was highest for exposure to pesticides, among them, insecticide's risk was confirmed. PMID- 22924113 TI - Frequency and severity of obsessive-compulsive symptoms/disorders, violence and suicidal in schizophrenic patients. AB - BACKGROUND: This study determined the prevalence and severity of obsessive compulsive symptoms/disorder (OCS/OCD), aggression and suicidal in schizophrenic patients. Also we compared the prevalence and severity of aggression and suicidal in schizophrenic patients with and without OCS/OCD considering anxiety, depression and substance abuse as confounding factors. METHODS: During 2007 and 2008, 100 schizophrenic patients were evaluated with Yale-Brown Obsessive Compulsive Scale, Positive and Negative Syndrome Scale, Beck Depression Inventory, Spilberger State/Trait Anxiety Inventory, Beck Scale for suicide Ideation, and Overt Aggression Scale. RESULTS: OCS/OCD and suicidal attempts were seen in 33%, 10% and 12% of patients respectively. The most common form of aggression was against others (55%), and aggressive obsessions were seen in 10% of the patients. Comparing patients with and without OCS/OCD, there were no significant differences in the severity of schizophrenia, suicidal and overt aggression. The severity of overt aggression was related to the patients' age and education reversely. Also, there was a relationship between their suicidal thoughts and residence in the cities. CONCLUSIONS: High rate of aggressive obsessions and lack of relationship between severity of aggression and presence of OCD indicated that these patients did not act on these thoughts. The risk of suicide was more serious in patients living in the cities, and risk of violence was more serious in younger and less educated patients. PMID- 22924114 TI - The Association between Y Chromosome Microdeletion and Recurrent Pregnancy Loss. AB - BACKGROUND: To date, the role of male factor contributing in evaluation of spontaneous recurrent pregnancy loss (RPL) has been less investigated and there is discrepancy in the role of Y chromosome microdeltions in RPL. Therefore, the current study was designed to examine whether Y chromosome microdeletions were associated with RPL in an Iranian population. METHODS: One hundred men from couples, experiencing three or more RPLs, and one hundred normal men from couples with at least one child and no history of miscarriages as control group were included. Genomic DNA was extracted from peripheral blood and tested for Y chromosome microdeletions in AZFa, AZFb and AZFc regions using two multiplex PCR. RESULTS: None of the men in the case and control groups had any microdeletions in the AZFa, AZFb and AZFc regions. CONCLUSION: It seems that Y chromosome microdeletion is not associated with recurrent pregnancy loss, therefore performing this test in Iranian couples with RPL is not recommended. PMID- 22924115 TI - Psychometric properties of the persian version of the youth risk behavior survey questionnaire. AB - BACKGROUND: Adolescents may get involved in high-risk behaviors. Surveys are the primary, and sometimes the sole source of data collection for many high-risk health behaviours. We examined the reliability and validity of the psychometric properties of the self-administered Persian version of the 2009 Youth Risk Behavior Surveillance System (YRBSS) questionnaire. METHODS: In a methodological study in summer 2010, 100 Iranian adolescents aged 15-18 years were recruited through convenience sampling. The face and content validity were used for the questionnaire validity. In order to evaluate the questionnaire's reliability, the Intraclass Correlation Coefficient (ICC) and Cronbach's alpha were calculated for domains and 89 items. RESULTS: Among 89 items, the ICC values were below 0.4 (weak reliability) for 2 items (2.25%), 0.4-0.6 (moderate reliability) for 10 items (11.24%), 0.6-0.8 (good reliability) for 32 items (35.96%) and 0.8-1 (excellent reliability) for 45 items (50.56%). The prevalence of most high-risk behaviors was constant in the first and second survey. The value of Cronbach's alpha was 0.73 for intentional and unintentional injuries, 0.77 for tobacco use, 0.86 for alcohol and other drug use, and 0.79 for unsafe sexual behaviors. No domain had a mean ICC of below 0.6. Furthermore, 97.75% of the items had moderate to excellent reliability. Thus, the Persian YRBSS questionnaire had an acceptable reliability. CONCLUSION: Over the 2-week period, sexual behaviors were reported with less consistency compared to other behaviors. In any case, researchers must be aware of the limitation of the data collected through this questionnaire, particularly in comparison to the domain of sexual behaviors. Overall, 97.75% of the items had moderate to excellent reliability. Thus, the Persian YRBSS questionnaire had an acceptable reliability. PMID- 22924116 TI - Epidemiological Study of Youth Mental Health Using Strengths and Difficulties Questionnaire (SDQ). AB - BACKGROUND: Prevention and treatment of youths' mental disorders are important, not just for to diminish their present problems but to improve their functions in adulthood. This study was performed to evaluate the mental health status of 6-18 years old youths in a community-based sample using the strength and difficulties questionnaire (SDQ). METHODS: Parent of 2000 youths (6-18 years old) were selected from 250 clusters from different municipality areas of Isfahan, Iran and they responded to extended version of SDQ parent's form. The mean score in each subscale and prevalence of symptom and relation with some demographic features were determined. RESULTS: The total score of SDQ was 26%, means that 26% of youth had psychiatric problems. By determining the subscale score, it reveals that conduct disorder (34.7%) was the most common problem in youth followed by peer relationship problems (25.4%), emotional problems (24.5%), hyperactivity (23%) and impairment of prosocial behavior (5.7%). CONCLUSION: Our findings showed that mental health of youth population in Isfahan especially the conduct problem needs more attention. PMID- 22924117 TI - Contamination of a dental unit water line system by legionella pneumophila in the mashhad school of dentistry in 2009. AB - BACKGROUND: Dental unit waterline system is considered potential source for contamination with Legionella species. The aim of this study was to determine if contamination of a dental unit water line system by Legionella pneumophila serogroup1 in the Mashhad School of Dentistry occurred in 2009. METHODS: A total of 52 dental units were selected from all clinical departments of the Mashhad School of Dentistry. Samples of water were collected from outlets of water/air spray, high-speed dental hand pieces and water cup fillers. Samples were tested via the ELISA method. RESULTS: At the beginning of the work day, a total of 36.1 percent of dental units were contaminated by Legionella pneumophila serogroup 1. CONCLUSION: Infection control of the dental unit water line system regarding legionella in the Mashhad School of Dentistry is a challenge and engineering controls should be used in contaminated clinics. PMID- 22924118 TI - Ovarian Cyst Enlargement in a 14 Year Old Female with Persistent Ascities, Severe Hypothyroidism and Elevated Serum CA-125 Level. AB - A 14 year old female complained of abdominal pain and distention with vomiting. The physical exam showed thyroid enlargement and ascites. The imaging evaluation demonstrated a large ovarian cyst. Laboratory tests depicted hypothyroidism and marked elevation of Carbohydrate antigen 125 (CA-125) levels. As the bone age was 10 years, more retarded than the chronological age, Van Wyk and Grumbach syndrome was suspected. Treatment with thyroid hormone was initiated and the condition improved dramatically with disappearance of symptoms and signs 5 weeks later. PMID- 22924119 TI - The experiences of infertile women on assistant reproductive treatments: a phenomenological study. PMID- 22924120 TI - Leech bite: a rare cause of postmenopausal vaginal bleeding. PMID- 22924121 TI - Hemostatic Tampon to Reduce Bleeding following Tooth Extraction. PMID- 22924122 TI - Optical frequency domain imaging system and catheters for volumetric imaging of the human esophagus. AB - Barrett's esophagus (BE) is a metaplastic disorder that can undergo dysplastic progression, leading to esophageal adenocarcinoma. Upper endoscopy is the standard of care for screening for BE, but this technique has a relatively low diagnostic accuracy and high cost due to the requirement of conscious sedation. Optical frequency domain imaging (OFDI) is a high-speed imaging modality that generates cross-sectional images of tissues with a resolution of approximately 10MUm that is sufficient for detecting microscopic tissue architecture. In combination with a balloon-centering catheter, this method enables BE diagnosis over the entire distal esophagus. PMID- 22924123 TI - Improved Metabolic Control in Diabetes, HSP60, and Proinflammatory Mediators. AB - The diabetes-atherosclerosis relationship remains to be fully defined. Repeated prolonged hyperglycemia, increased ROS production and endothelial dysfunction are important factors. One theory is that increased blood levels of heat shock protein (HSP)60 are proinflammatory, through activation of innate immunity, and contribute to the progression of vascular disease. It was hypothesized that improvement of diabetes control in patients presenting with metabolic syndrome would lower HSP60, and anti-HSP60 antibody levels and decrease inflammatory markers. Paired sera of 17 Italian patients, before and after intensive treatment, were assayed for cytokines, HSP60 and anti-HSP60 antibodies. As expected, intensive treatment was associated with a decrease in HgbA1C (P < 0.001) and BMI (P < 0.001). After treatment, there was a significant decrease in IL-6 (P < 0.05). HSP60 levels were before treatment -6.9 + 1.9, after treatment 7.1 + 2.0 ng/mL (P = ns). Overall HSP60 concentrations were lower than published reports. Anti-HSP60 antibody titers were high and did not decrease with treatment. In conclusion, improvement of diabetic control did not alter HSP60 concentrations or antiHSP60 antibody titers, but led to a reduction of IL-6 levels. PMID- 22924124 TI - The Cancer-Associated Virus Landscape in HIV Patients with Oral Hairy Leukoplakia, Kaposi's Sarcoma, and Non-Hodgkin Lymphoma. AB - Although HIV-positive patients are at higher risk for developing a variety of infection-related cancers, the prevalence of infections with the seven known cancer-associated viruses has not been studied. Luciferase immunoprecipitation systems were used to evaluate antiviral antibodies in four 23-person groups: healthy blood donors and HIV-infected patients with oral hairy leukoplakia (OLP), Kaposi's sarcoma (KS), or non-Hodgkin lymphoma (NHL). Antibody profiling revealed that all HIV-positive individuals were strongly seropositive for anti-gp41 and antireverse transcriptase antibodies. However, anti-p24 HIV antibody levels were highly variable and some OLP and KS patients demonstrated weak or negative responses. Profiling two EBV antigens revealed no statistical difference in antibody levels among the three HIV-infected groups. A high frequency of KSHV infection was detected in HIV patients including 100% of KS, 78% of OLP, and 57% of NHL patients. Most HIV-infected subjects (84%) showed anti-HBV core antibodies, but only a few showed antibodies against HCV. MCV seropositivity was also common (94%) in the HIV-infected individuals and KS patients showed statistically higher antibody levels compared to the OLP and NHL patients. Overall, 68% of the HIV-infected patients showed seropositivity with at least four cancer-associated viruses. Antibody profiles against these and other infectious agents could be useful for enhancing the clinical management of HIV patients. PMID- 22924125 TI - Health-Related Quality of Life, Treatment Satisfaction, Adherence and Persistence in beta-Thalassemia and Myelodysplastic Syndrome Patients with Iron Overload Receiving Deferasirox: Results from the EPIC Clinical Trial. AB - Treatment of iron overload using deferoxamine (DFO) is associated with significant deficits in patients' health-related quality of life (HRQOL) and low treatment satisfaction. The current article presents patient-reported HRQOL, satisfaction, adherence, and persistence data from beta-thalassemia (n = 274) and myelodysplastic syndrome (MDS) patients (n = 168) patients participating in the Evaluation of Patients' Iron Chelation with Exjade (EPIC) study (NCT00171821); a large-scale 1-year, phase IIIb study investigating the efficacy and safety of the once-daily oral iron chelator, deferasirox. HRQOL and satisfaction, adherence, and persistence to iron chelation therapy (ICT) data were collected at baseline and end of study using the Medical Outcomes Short-Form 36-item Health Survey (SF 36v2) and the Satisfaction with ICT Questionnaire (SICT). Compared to age-matched norms, beta-thalassemia and MDS patients reported lower SF-36 domain scores at baseline. Low levels of treatment satisfaction, adherence, and persistence were also observed. HRQOL improved following treatment with deferasirox, particularly among beta-thalassemia patients. Furthermore, patients reported high levels of satisfaction with deferasirox at end of study and greater ICT adherence, and persistence. Findings suggest deferasirox improves HRQOL, treatment satisfaction, adherence, and persistence with ICT in beta-thalassemia and MDS patients. Improving such outcomes is an important long-term goal for patients with iron overload. PMID- 22924126 TI - An Epidemiological Study of Anemia and Renal Dysfunction in Patients Admitted to ICUs across the United States. AB - The aims of this study were to determine the associations between anemia of critical illness, erythropoietin stimulating agents (ESA), packed red blood cell transfusions and varying degrees of renal dysfunction with mortality, and ICU- and hospital length of stay (LOS). This was a cross-sectional retrospective study of 5,314 ICU patients from USA hospitals. Hospital, patient demographics, and clinical characteristics were collected. Predictors of mortality and hospital and ICU LOS were evaluated using multivariate logistic regression models. The mean ICU admission hemoglobin in this study was 9.4 g/dL. The prevalence of ESA use was 13% and was associated with declining renal function; 26% of the ICU patients in this study received transfusion. ESA utilization was associated with 28% longer hospital LOS (P < 0.001). ICU LOS was increased by up to 18% in patients with eGFR rates of <30 and 30-59 mL/min/1.73 m(2), respectively (P < 0.05) but not in those receiving dialysis. Mortality was significantly associated with renal dysfunction and dialysis with odds ratios of 1.94, 2.66 and 1.40 for the dialysis, and eGFR rates of <30 and 30-59 and mL/min/1.73 m(2), respectively (P < 0.05). These data provide a snapshot of anemia treatment practices and outcomes in USA ICU patients with varying degrees of renal dysfunction. PMID- 22924127 TI - Lung Function before and Two Days after Open-Heart Surgery. AB - Reduced lung volumes and atelectasis are common after open-heart surgery, and pronounced restrictive lung volume impairment has been found. The aim of this study was to investigate factors influencing lung volumes on the second postoperative day. Open-heart surgery patients (n = 107, 68 yrs, 80% male) performed spirometry both before surgery and on the second postoperative day. The factors influencing postoperative lung volumes and decrease in lung volumes were investigated with univariate and multivariate analyses. Associations between pain (measured by numeric rating scale) and decrease in postoperative lung volumes were calculated with Spearman rank correlation test. Lung volumes decreased by 50% and were less than 40% of the predictive values postoperatively. Patients with BMI >25 had lower postoperative inspiratory capacity (IC) (33 +/- 14% pred.) than normal-weight patients (39 +/- 15% pred.), (P = 0.04). More pain during mobilisation was associated with higher decreases in postoperative lung volumes (VC: r = 0.33, P = 0.001; FEV(1): r = 0.35, P <= 0.0001; IC: r = 0.25, P = 0.01). Patients with high BMI are a risk group for decreased postoperative lung volumes and should therefore receive extra attention during postoperative care. As pain is related to a larger decrease in postoperative lung volumes, optimal pain relief for the patients should be identified. PMID- 22924128 TI - The Association between Databases for Indexing Studies Intended for an Exercise Meta-Analysis of Arthritis Randomized Controlled Trials. AB - Objective. The purpose of this study was to determine the database indexing of randomized controlled trials (RCTs) for a meta-analysis addressing the effects of exercise on pain and physical function in adults with arthritis and other rheumatic diseases (AORD). Methods. The number, percentage, and 95% confidence intervals (CIs) for included articles at initial and follow-up periods were calculated from PubMed, EMBASE, CENTRAL, CINAHL, SPORTDiscus, and DAO databases. The number needed to review (NNR) was also calculated along with the number of articles retrieved by expert review. Cross-referencing from reviews and included articles also occurred. Results. Thirty-four of 36 articles (94.4%, 95% CI, 81.3 99.3) were located by database searching. PubMed and CENTRAL yielded 32 of 36 articles (88.9%, 73.9-96.9). Two articles not identified in any of the other databases were found in either CINAHL or SPORTDicsus. Two other articles were located by scanning the reference lists of review articles. The NNR ranged from 2 (CINAHL) to 118 (SPORTDiscus). More articles were identified in EMBASE at follow up (36%, 12.1-42.2 versus 86.1%, 70.5-95.3). Conclusions. Searching multiple databases and cross-referencing from reviews was important for identifying RCTs addressing the effects of exercise on pain and physical function in adults with AORD. PMID- 22924129 TI - Induction chemotherapy in locally advanced pharyngolaryngeal cancers with stridor: is it feasible and safe? AB - Background. The standard initial management of patients with locally advanced pharyngolaryngeal presenting with stridor is tracheostomy. Tracheostomy has been shown to negatively impact cancer-related outcomes. Methods. Retrospective analysis of prospectively collected data of 9 patients, who underwent induction chemotherapy with the aim of prevention of tracheostomy. Presenting features, time to resolution of stridor, and further management are reported. Results. Eight out of 9 patient received chemotherapy within 12 hours of presentation with stridor. There were 4 patients each with primary hypopharynx and larynx. The stage was IVA in 6 patients and IVB in 2 patients. In all patients receiving immediate chemotherapy, clinical stridor resolved within 48 hours. The radiological response rate was 62.5%. The median reduction in size of tumor was 37%. Conclusion. Immediate neoadjuvant chemotherapy is a feasible and safe option for patients presenting with early stridor and helps in resolution of stridor and avoiding tracheostomy. PMID- 22924133 TI - Unexpected High Sensory Blockade during Continuous Spinal Anesthesiology (CSA) in an Elderly Patient. AB - A 98-year-old woman presented for a hemiarthroplasty of the left hip. Because of her age and cardiac and pulmonary co-existing diseases we decided to provide adequate regional anesthesia by continuous spinal anesthesia. Fragmented doses of isobaric bupivacaine 0.5% were administered through a system consisting of a spinal catheter connected to an antimicrobial filter. After an uneventful surgical procedure, prior to removal of the catheter, this system was flushed with 10 mL of normal saline in order to try to prevent post-dural-puncture headache. After arrival at the postanesthesia care unit and fifteen minutes after removal of the catheter the patient suffered an unexpected high thoracic sensory blockade and hypotension requiring treatment. The continuous spinal anesthesia technique can be used in selected cases to be able to administer local anesthetic agents in a slow and controlled manner to reach the desired effect. The risk of post-dural-puncture headache using this technique in elderly patients is very low and therefore precludes the need to try to prevent it. We have described a potentially dangerous complication of flushing a bupivacaine-filled system into the spinal canal of an elderly patient resulting in an undesirable high sensory blockade. PMID- 22924132 TI - Role of p16(INK4A) in Replicative Senescence and DNA Damage-Induced Premature Senescence in p53-Deficient Human Cells. AB - The p16(INK4A) (hereafter p16) tumor suppressor is encoded by the INK4A/ARF locus which is among the most commonly dysregulated sequences in human cancer. By inhibiting cyclin-dependent kinases, p16 activates the G1-S checkpoint, and this response is often considered to be critical for establishing a senescence-like growth arrest. Not all studies support a universal role for p16 in senescence. Single-cell analysis of noncancerous human fibroblast cultures undergoing senescence as a function of culture age (replicative senescence) has revealed that p16 is not expressed in the majority (>90%) of cells that exhibit features of senescence (e.g., flattened and enlarged morphology coupled with senescence associated beta-galactosidase expression), ruling out a requirement for p16 in this process. In addition, ionizing radiation triggers premature senescence in human cancer cell lines that do not express p16. These observations are made with cells that express wild-type p53, a key mediator of the DNA damage response. In this paper, we examine the growing evidence suggesting a negative regulatory relationship between p16 and p53 and discuss recent reports that implicate a role for p16 in replicative senescence and ionizing radiation-induced premature senescence in human cells that lack wild-type p53 function. PMID- 22924134 TI - Intraoral Laser Welding (ILW) in Implant Prosthetic Dentistry: Case Report. AB - The aim of this clinical study was to describe the possibility of using the Nd:YAG laser device utilized in the dental offices to weld metals intraorally. The authors, before applying this technique "in vivo" on human subjects, tested the "in vitro" metal welding efficacy of dental Nd:YAG device firstly by interferometry, SEM, and EDS and subsequently by thermal camera and thermocouples in order to record temperature changes during the welding process on bovine jaws. Four implants were inserted in the edentulous maxillary arch of a 67 years old male patient. Immediately after that, a bar previously made by the dental technician was intraorally welded to the abutments by Nd:YAG laser (Fidelis Plus III, Fotona, Slovenia) with these parameters: 9.90 mJ, 1 Hz, 15 msec, 0.6 mm spot. Then the prosthesis was connected to the bar with four OT Caps. This clinical study, even if preliminary, suggests that laser welding technique may be intraorally used without side effects. PMID- 22924131 TI - Cardiomyopathy classification: ongoing debate in the genomics era. AB - Cardiomyopathies represent a group of diseases of the myocardium of the heart and include diseases both primarily of the cardiac muscle and systemic diseases leading to adverse effects on the heart muscle size, shape, and function. Traditionally cardiomyopathies were defined according to phenotypical appearance. Now, as our understanding of the pathophysiology of the different entities classified under each of the different phenotypes improves and our knowledge of the molecular and genetic basis for these entities progresses, the traditional classifications seem oversimplistic and do not reflect current understanding of this myriad of diseases and disease processes. Although our knowledge of the exact basis of many of the disease processes of cardiomyopathies is still in its infancy, it is important to have a classification system that has the ability to incorporate the coming tide of molecular and genetic information. This paper discusses how the traditional classification of cardiomyopathies based on morphology has evolved due to rapid advances in our understanding of the genetic and molecular basis for many of these clinical entities. PMID- 22924135 TI - Ameloblastic fibroodontoma of the mandible with normal karyotype in a pediatric patient. AB - Background. Ameloblastic fibroodontoma (AFO) is a rare mixed odontogenic tumor with epithelial and mesenchymal components. AFO presents as a painless swelling in the mandible or maxilla. Radiographs show a well-defined radiolucent area containing various amounts of radiopaque material of irregular size and form. The common treatment is enucleation. It is not an aggressive tumor but recurrence and malignant transformation are possible. Methods. An AFO of the mandible of a 3 year-old female is reported. Panoramic radiograph and CT scan revealed a unilocular lesion with radiopaque center and radiolucent margins. Enucleation was performed with a good outcome. Results. Histopathology was a classic AFO. The karyotype was normal. No recurrence was noted at 12 months. Conclusions. As it is a benign tumor with low recurrence rate, conservative surgery is the treatment of choice. As malignant transformation to ameloblastic fibrosarcoma or ameloblastic odontosarcoma is possible despite the normal karyotype, long-term followup is recommended. PMID- 22924136 TI - Dedifferentiated liposarcoma arising in an esophageal polyp: a case report. AB - Liposarcoma is one of the most common sarcomas in adults, but only rarely presents as an esophageal primary. There have been several reports of well differentiated liposarcoma (WDL) arising in the esophagus, but we present a case of dedifferentiated liposarcoma (DL) presenting as a large esophageal polyp. We believe this is the first reported case of DL of the esophagus with morphologic evidence of both well-differentiated and dedifferentiated components. The diagnosis was confirmed by demonstration of CPM gene amplification by fluorescence in situ hybridization (FISH). PMID- 22924137 TI - Congenital double pylorus. AB - The double pylorus is an uncommon finding and maybe congenital due to gastrointestinal duplication abnormality or more commonly secondary to peptic ulcer disease. The case we present is an elderly patient with mild dyspeptic symptoms who had an upper endoscopy as part of her investigative workup. The congenital double pylorus, being asymptomatic, may often go undetected. It is sometimes found incidentally on upper endoscopy, but needs no directed therapy. It is not associated with any specific complication. PMID- 22924138 TI - Beyond cat scratch disease: a case report of bartonella infection mimicking vasculitic disorder. AB - Cat scratch disease (CSD) is a bacterial disease caused by Bartonella henselae and it is mainly characterized by self-limiting lymphadenopathy in the draining site of a cat scratch or bite. We report a patient with history of fever, swelling lymph nodes, vasculitic-like skin lesions, and positivity of Bartonella serology initially considered as expression of a disimmune disease. PMID- 22924139 TI - Bacillus cereus Bloodstream Infection in a Preterm Neonate Complicated by Late Meningitis. AB - Central nervous system infections caused by Bacillus cereus have rarely been reported in infants. In this paper, the case of a 2-month-old low-birth-weight female who developed meningitis 45 days after resolution of a bloodstream infection (BSI) is described. The pulsed-field gel electrophoresis results revealed that the patterns of both B. cereus isolates responsible for the acute meningitis and for the prior bacteraemic episode were closely related. Although the source of the infection from within the patient was not clear, it is suggested that the B. cereus BSI developed in the neonate was complicated by acute meningitis. PMID- 22924140 TI - Staphylococcus epidermidis Urinary Tract Infection in an Infant. AB - We describe the case of a previously healthy 7-month-old male infant with urinary tract infection due to Staphylococcus epidermidis grown from two separate urine cultures. Further evaluation showed severe bilateral vesicoureteral reflux. Physicians should not assume that S. epidermidis is always a contaminant in urine cultures. PMID- 22924141 TI - Prenatal diagnosis of sacrococcygeal teratoma using two and three-dimensional ultrasonography. AB - Sacrococcygeal teratoma accounts for half of all fetal tumors, with a prevalence of 1 : 40,000 births. It is believed to originate from pluripotent cells in Hensen's nodule. Although most are benign, they are associated with high morbidity and mortality rates because the fetus develops congestive heart failure and hydrops. Factors leading to poor prognosis include solid components in the mass, and hydrops diagnosed before the 30th week. A case of prenatal sacrococcygeal teratoma diagnosed using B-mode and color Doppler two-dimensional ultrasonography (2DUS) is described, in which three-dimensional ultrasonography (3DUS) enabled characterization of the extent of fetal lesions and allowed the parents to understand the pathological condition better. A 20-year-old primigravida was referred with a solid mass diagnosed in the lumbosacral spine. Examinations performed at our institution revealed pregnancy of 23 weeks and 4 days, with a female fetus presenting a bulky solid mass with cystic components and calcifications, measuring 7.7 * 9.1 * 12.2 cm, starting from the sacral region, with internal flow seen on color Doppler. A new ultrasound confirmed fetal death at 25 weeks and 4 days. Postnatal findings confirmed the diagnosis of sacrococcygeal teratoma. 3DUS can be used in cases of sacrococcygeal teratoma to assess the development of tumor during the prenatal and to allow better understanding of this anomaly by the parents. PMID- 22924142 TI - Autoimmune progesterone dermatitis: a case report. AB - Background. Autoimmune progesterone dermatitis is a rare cyclic premenstrual allergic reaction to progesterone produced during the luteal phase of a woman's menstrual cycle. Patients present with a variety of conditions including erythema multiforme, eczema, urticaria, angioedema, and progesterone-induced anaphylaxis. Case. Thirty-eight-year-old woman G2P2002 presents with erythema multiforme and urticarial rash one week prior to her menses starting one year after menarche. She was treated with oral contraceptive pills and the symptoms resolved. Conclusion. This is a typical case of progesterone autoimmunity. The diagnosis is based on cyclic nature of the dermatitis. This differentiates the condition from other allergies or systemic diseases with skin manifestations. Inhibition of ovulation in such cases results in decrease in progesterone secretion and prevention of symptoms. PMID- 22924143 TI - Splenic hematoma mimicking angiosarcoma: a case report. AB - Introduction. Splenic hematomas usually occur after blunt abdominal trauma. Most of the subcapsular hematomas will be resolved and reabsorbed spontaneously. However in rare cases, some of them organize and form calcified splenic masses. Angiosarcoma is an uncommon primary tumor of the spleen. Splenic angiosarcoma behaves extremely aggressive and has poor prognosis. Case Presentation. We report a forty-nine-year-old white male with organized splenic hematoma due to traffic accident mimicking splenic angiosarcoma. Conclusion. Both angiosarcoma and splenic organized hematoma have nonspecific symptoms and clinical findings. Because of the risk of hemorrhage and rupture, fine-needle biopsy should not be preferred. In case of splenic masses, excision and spleen-conserving surgery or total splenectomy should be performed. PMID- 22924144 TI - Maxillary mucocele with orbital floor remodelling. AB - A 79-year-old man presents with signs of an orbital mass. A CT scan revealed a large maxillary mucocele eroding through the orbital floor. Surgical drainage of the mucocele and conservative postoperative care, returned all ophthalmic signs to normal and bony remodelling of the orbital floor was demonstrated. Maxillary mucoceles should be assessed by both ENT and Ophthalmic surgeons. Postoperative remodelling of the orbital floor can be illustrated with serial CT Scans. PMID- 22924145 TI - Early-onset chronic inflammatory disease associated with maternal microchimerism. AB - Maternal microchimerism (mMc) refers to the presence of a small population of cells originating from the mother. Whether mMc leads to autoimmune responses in children remains controversial. We describe here an 11-year-old boy with persistent fever and elevated levels of C-reactive protein from infancy onward. During infancy, the patient presented with high fever, skin rashes, and hepatic dysfunction. Careful examination including a liver biopsy failed to reveal the cause. At 4 years old, petechiae developed associated with thrombocytopenia and positive anti-dsDNA autoantibodies. Steroid pulse therapy was effective, but the effect of low-dose prednisone was insufficient. At age 9, an extensive differential diagnosis was considered especially for infantile onset autoinflammatory disorders but failed to make a definitive diagnosis. On admission, the patient exhibited short stature, hepatosplenomegaly, generalized superficial lymphadenopathy, and rashes. Laboratory findings revealed anemia, elevated levels of inflammation markers, and hypergammaglobulinemia. Serum complement levels were normal. Serum levels of IL-6 and B-cell activating factor were elevated. Viral infections were not identified. Although HLA typing revealed no noninherited maternal antigens in lymphocytes, female cells were demonstrated in the patient's skin and lymph nodes, suggesting that maternal microchimerism might be involved in the pathogenesis of fever without source in infants. PMID- 22924146 TI - Tuberculosis of the parotid gland. AB - Parotid gland involvement is extremely rare, even in countries in which tuberculosis is endemic. Clinically, it usually presents as a slow-growing mass indistinguishable from a malignancy. On imaging too, tuberculosis of the parotid may mimic neoplasm. The diagnosis of parotid tuberculosis needs a high degree of clinical suspicion. This paper highlights the clinical presentation, imaging findings, and importance of FNAC in diagnosis of this rare entity. PMID- 22924147 TI - Abdominoscrotal hydrocele with intestinal malrotation: a rare association. AB - Abdominoscrotal hydrocele is an uncommon clinical entity and so is intestinal malrotation. We report a case of 15 year old boy who presented with lump in abdomen previously diagnosed as mesenteric cyst on ultrasound. A multislice CT scan and repeat ultrasound not only diagnosed the case as abdominoscrotal hydrocele but also detected intestinal malrotation with positive whirl sign. This is the first reported case of abdominoscrotal hydrocele with intestinal malrotation. PMID- 22924148 TI - Recurrent bilateral breast abscesses after sternotomy. AB - Median sternotomy is the most commonly used incision in cardiothoracic procedures. Development of breast abscess after sternotomy is a very rare situation. We present a case of sternal wound infection with recurrent bilateral breast abscess after sternotomy. Our case is the first and only case in the literature due to the presence of sternal wound infection with recurrent bilateral breast abscess after sternotomy. PMID- 22924149 TI - Gastric schwannoma: a rare but important differential diagnosis of a gastric submucosal mass. AB - Schwannomas are generally slow growing asymptomatic neoplasms that rarely occur in the GI tract. However, if found, the most common site is the stomach. Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract, and 60-70% of them occur in the stomach. Owing to their typical presentation as submucosal neoplasms, gastric schwannomas and GISTs appear grossly similar. Accordingly, the differential diagnosis for a gastric submucosal mass should include gastric schwannomas. Furthermore, GI schwannomas are benign neoplasms with excellent prognosis after surgical resection, whereas 10-30% of GISTs have malignant behavior. Hence, it is important to distinguish gastric schwannomas from GISTs to make an accurate diagnosis to optimally guide treatment options. Nevertheless, owing to the paucity of gastric schwannomas, the index of suspicion for this diagnosis is low. We report a rare case of gastric schwannoma in 53-year-old woman who underwent laparoscopic partial gastrectomy under the suspicion of a GIST preoperatively but confirmed to have a gastric schwannoma postoperatively. This case underscores the importance of including gastric schwannomas in the differential diagnosis when preoperative imaging studies reveal a submucosal, exophytic gastric mass. For a gastric schwannoma, complete margin negative surgical resection is the curative treatment of choice. PMID- 22924150 TI - Postoperative aseptic intracranial granuloma: the possible influence of fluid hemostatics. AB - Background. Numerous reports have demonstrated how postoperative intracranial granulomas can often mimic neoplasm clinically, radiologically, and even macroscopically. Herein we present an unusual case of postsurgical intracranial aseptic granuloma secondary to a chronic inflammatory reaction without any identifiable retained foreign body. Case Description. A 71-year-old patient started complaining of severe headache seven months after surgical excision of WHO Grade I right frontal falx meningioma. CT and MRI scans disclosed a contrast enhanced lesion with diffuse mass effect in the previous surgical site. The lesion was resected; intraoperative finding and histological specimens led to the diagnosis of postoperative granuloma, likely expression of a glial reaction to the fluid absorbable hemostatics applied in the surgical site after meningioma excision. The possible granuloma-inducing materials and the timing of granuloma formation are discussed. Conclusion. A comprehensive analysis of clinical and neuroradiological data, as well as results of blood tests including positive and negative acute phase proteins, is mandatory to raise the suspicion of postoperative granuloma. The treatment options should be evaluated on a case-by case basis, with a conservative attitude being the one of choice only for patients without progressive neurological deficit. Alternatively, aggressive surgical treatment and histopathological examination should be advocated. PMID- 22924151 TI - Bilateral true giant aneurysm of the profunda femoral artery: case report and review of the literature. AB - We report a rare case of a bilateral true giant aneurysm of the profunda femoral artery aneurysms (PFAAs) in a 80-year-old man with a previous history of "open" abdominal aortic surgery and small bilateral popliteal artery aneurysm. In the English Literature only seven previously cases of true bilateral PFAAs are reported. Due to its location, this lesion may require surgical intervention and removal. The presentation, the diagnostic evaluation, and the surgical management of the aneurysm are discussed. PMID- 22924152 TI - Self-inflicted urethrovesical foreign bodies in children. AB - We present two cases of self-inflicted urethrovesical foreign body in children. Case 1 was a 6-year-old girl admitted with a history of self-introduction of a pin. The X-ray revealed the pin as 3.5 cm in length and in the bladder. The foreign body was removed endoscopically. Case 2 was a 13-year-old boy with a self introduced packing needle, 13 cm in length, partially in the urethra. The end and the tip of the needle passed through the urethra to the surrounding tissues. Foreign body removed via a little skin incision with endoscopic guidance. Foreign bodies are rarely found in the lower urinary tract of children. Definitive treatment is usually the endoscopic removal; however, sometimes surgical intervention may require. PMID- 22924153 TI - Urethral hairballs as a long-term complication of hypospadias repair: two case reports. AB - Many times hair-bearing urethral grafts have been used inadvertently in the treatment of hypospadias. This can be accompanied with numerous troublesome long term complications such as formation of stones, diverticula, and hairballs. We report two cases of men with a history of hypospadias repair being affected by such complications. We also discuss about their management and the effect of thioglycolic acid instillation to stop hair growth in the urethra mucosa in the second case. PMID- 22924154 TI - Recent Advances in Transition Metal-Catalyzed Glycosylation. AB - Having access to mild and operationally simple techniques for attaining carbohydrate targets will be necessary to facilitate advancement in biological, medicinal, and pharmacological research. Even with the abundance of elegant reports for generating glycosidic linkages, stereoselective construction of alpha and beta-oligosaccharides and glycoconjugates is by no means trivial. In an era where expanded awareness of the impact we are having on the environment drives the state-of-the-art, synthetic chemists are tasked with developing cleaner and more efficient reactions for achieving their transformations. This movement imparts the value that prevention of waste is always superior to its treatment or cleanup. This review will highlight recent advancement in this regard by examining strategies that employ transition metal catalysis in the synthesis of oligosaccharides and glycoconjugates. These methods are mild and effective for constructing glycosidic bonds with reduced levels of waste through utilization of sub-stoichiometric amounts of transition metals to promote the glycosylation. PMID- 22924155 TI - Controlling Nuclear Jaks and Stats for Specific Gene Activation by Ifn gamma and Other Cytokines: A Possible Steroid-like Connection. AB - The mechanism of specific gene activation by cytokines that use JAK/STAT signalling pathway is unknown. There are four different types of JAKs and seven different types of STATs. In the classical model of signaling, ligand interacts solely with the receptor extracellular domain, which triggers JAK activation at the receptor cytoplasmic domain. Activated STATs are then said to carry out nuclear events of specific gene activation, including associated epigenetic changes that cause heterochromatin destabilization. Ligand, receptor, and JAKs play no further role in the classical model. Given the limited number of STATs and the activation of the same STATs by cytokines with different functions, the mechanism of the specificity of their signalling is not obvious. Focusing on gamma interferon (IFNgamma), we have shown that ligand, receptor, and activated JAKs are involved in nuclear events that are associated with specific gene activation. In this model, receptor subunit IFNGR1 functions as a transcription/cotranscription factor and the JAKs are involved in key epigenetic events that are required for specific gene activation. The model has implications for gene activation in cancer as well as stem cell differentiation. PMID- 22924157 TI - Nutrition Labeling to Prevent Obesity: Reviewing the Evidence from Europe. AB - Overweight and obesity are major public health problems in the European Union (EU). Providing nutrition information on foods and menus is considered a relevant means to guide consumers toward more healthful food choices, in part characterized by adequate energy intakes to achieve and maintain a healthy body weight. Various formats of back-of-pack and front-of-pack nutrition labeling can currently be found across the EU, with varying levels of penetration. Experimental studies show that consumers are reasonably able to understand and use the different systems to identify more healthful food products from given choice sets. However, European studies assessing the impact of nutrition labeling on actual dietary intake are scarce, and no real-life evidence exists linking nutrition label use with measured changes in body weight. This review summarizes how European consumers respond to nutrition labels when shopping for food or eating out of home, considering evidence published between 2007 and mid-March 2012. PMID- 22924158 TI - Oncolytic virus-mediated tumor radiosensitization in mice through DNA-PKcs specific shRNA. AB - One of the key issues in cancer radiotherapy research is to sensitize tumor cells to the cell killing effects of ionizing radiation while leaving normal tissues intact. One potential approach to achieve this is through tumor-specific targeting of DNA repair genes. In this study, we engineered a replication deficient adenovirus encoding a mini shRNA gene targeted to the DNA-PKcs gene, which is involved in double strand break DNA repair, and evaluated its anti-tumor efficacy in combination with radiotherapy. Our shRNA-encoding adenovirus showed significant efficacy in down-regulating the levels of the DNA-PKcs protein that was accompanied by increased radiation sensitivity in the human HCT116 colon cancer cells. However, when delivered intratumorally to xenograft human tumors, minimal anti-tumor effects of the virus were seen either alone or in combination with radiation therapy, suggesting an inefficiency of the non-replicative adenovirus in delivering shRNA genes to the tumor mass. When a conditionally replicative adenovirus targeted to telomerase-positive tumor cells was used in conjunction with the DNA-PKcs-targeted shRNA-encoding non-replicative adenovirus, the efficiency of tumor-specific anti-DNA-PKcs shRNA gene expression was enhanced significantly. Most importantly, this enhanced shRNA expression led to significant anti-tumor efficacy of concurrently delivered radiation therapy. Our results suggest our shRNA-based DNA-PKcs- targeting approach in combination with tumor-targeting replicative adenovirus is a promising method to sensitize solid tumors to radiation therapy. PMID- 22924156 TI - Insights into Assessing the Genetics of Endometriosis. AB - Endometriosis is a complex disease arising from the interplay between multiple genetic and environmental factors. The genetic variants potentially underlying the hereditary component of endometriosis have been widely investigated through hypothesis-driven candidate gene studies, an approach that generally has proven to be inherently difficult and problematic for a number of reasons. Recently, through major collaborative efforts in the endometriosis research field, hypothesis-free genome-wide approaches have started to provide new insights into potential pathways leading to development of endometriosis, as well as highlighting the phenotypic heterogeneity of the condition. This review summarizes the most recent studies investigating the genetic variation contributing to endometriosis, with a particular focus on genome-wide approaches, and discusses promising future directions of genetic research. PMID- 22924159 TI - Common Pitfalls in Exposure and Response Prevention (EX/RP) for OCD. AB - Obsessive-compulsive disorder (OCD) is a highly debilitating disorder. Fortunately there are treatments that help the majority of OCD sufferers. The behavioral treatment with the most empirical support for its efficacy is exposure and response prevention (EX/RP). Over the years in our supervision meetings and in our clinical practice we have noted a number of relatively common therapist pitfalls that decrease the effectiveness of EX/RP. These pitfalls include not encouraging patients to approach the most distressing situations, doing imaginal exposure when in vivo is called for (and vice versa), encouraging distraction during exposure, providing reassurance, failing to address the core fear, ineffective handling of mental compulsions, and difficulty working with close others in the patient's life. In the current article we describe these common pitfalls and how to avoid them. PMID- 22924161 TI - Serum concentration of visfatin is decreased in patients with chronic heart failure. AB - BACKGROUND: There is an increasing interest in the role of adipocytokines in cardiovascular pathophysiology. AIM: The aim of the study was to compare visfatin levels, a novel adipokine, in patients with heart failure (HF) due to the left ventricular systolic dysfunction with those in age- and body mass index (BMI) - matched healthy controls in relation to the parameters of glucose metabolism and high sensitivity C-reactive protein (hsCRP) levels. MATERIAL/SUBJECTS AND METHODS: The study population consisted of 28 males with systolic HF referred for cardiopulmonary exercise testing, divided into two subgroups based on their NYHA class (HF patients NYHA(I+II), n=17, and HF patients NYHA(III+IV,) n=11), and 23 controls. The following indices were measured in a serum samples: visfatin, hsCRP, glucose and lipid metabolism parameters, and the insulin resistance index HOMA(IR) (homeostasis model assessment insulin resistance) was calculated. RESULTS: Concentrations of visfatin and high-density lipoprotein cholesterol (HDL cholesterol) in the HF subjects were significantly lower (p<=0.01) than in controls. The Kruskal-Wallis test showed significant differences between three groups (controls and both subgroups of heart failure patients) in mean levels of visfatin, hsCRP, glucose, HOMA(IR) and HDL-cholesterol. CONCLUSION: Serum visfatin concentrations in patients with systolic HF, particularly with more advanced NYHA classes, are significantly lower in comparison to healthy controls and are independent of age or anthropometric and metabolic parameters. PMID- 22924160 TI - Sustained virologic response and IL28B single-nucleotide polymorphisms in patients with chronic hepatitis C treated with pegylated interferon alfa and ribavirin. AB - INTRODUCTION: Hepatitis C virus (HCV) infection is a global health problem which can lead to liver cirrhosis or hepatocellular carcinoma in one-fifth of chronically infected patients. MATERIALS AND METHODS: The study group consisted of 123 patients: 90 with HCV mono- and 33 with HIV/HCV co-infection, who were treated with pegylated interferon alfa (Peg-IFN-alpha) and ribavirin. We analyzed selected pretreatment factors: age, sex, HIV/HCV co-infection, grade of inflammation, necrotic changes and fibrosis in histological analysis of liver bioptates, HCV viral load, HCV genotypes, and single nucleotide polymorphisms (SNPs) of IL28B and tried to find out which of them influence sustained virological response (SVR). The IL28B SNP C/T (rs12979860) was analyzed using Custom((r)) SNP Genotyping Assays (Applied Biosystems). RESULTS: Multivariate analysis demonstrated that after adjusting for the other variables three predictors independently influence SVR, namely genotype 3 of HCV, presence of the CC genotype and age >40 years (OR respectively 15.14, 3.62, and 0.36). HCV mono infected patients were infected with HCV genotype 3 or 4 less frequently (p=0.0001) compared to HIV/HCV co-infected individuals. In patients with HIV/HCV co-infection the CC variant occurred more frequently whereas CT was found less frequently (p=0.001, p=0.0146, respectively). In patients with HIV/HCV co infection, 3 and 4 genotype of HCV occurred more frequently compared to patients with HCV mono-infection (p=0.0001). CONCLUSIONS: These data suggest that age, HCV genotype and IL28B polymorphism are useful for prediction of the response to treatment with Peg-IFN-alpha and ribavirin. The more frequent occurrence of HCV genotypes 3 or 4 in patients with HIV/HCV co-infection could be associated with the route of transmission. PMID- 22924162 TI - Bacterial putative metacaspase structure from Geobacter sulfureducens as a template for homology modeling of type II Triticum aestivum metacaspase (TaeMCAII). AB - Metacaspases, cysteine proteases belonging to the peptidase C14 family, are suspected of being involved in the programmed cell death of plants, although their sequences and substrate specificity differ from those of animal caspases. At present, the knowledge on the metacaspase reaction mechanism is based only on biochemical data and homology models constructed on caspase templates. Here we propose a novel template for metacaspase modeling and demonstrate important advantages in comparison to the conventionally used caspase templates. We also point out the connection between plant and bacterial metacaspases, underlining the prokaryotic roots of Programmed Cell Death (PCD). PMID- 22924164 TI - Lipid-coated PLGA nanoparticles as robust siRNA delivery vehicles. PMID- 22924165 TI - Noninvasive real-time quantification of nanoparticles in vivo. PMID- 22924163 TI - Patent foramen ovale in severe obstructive sleep apnea: clinical features and effects of closure. AB - BACKGROUND: Patent foramen ovale (PFO) may contribute to nocturnal desaturation in patients with obstructive sleep apnea (OSA), and the effect of PFO closure in OSA is unknown. Our study tested the hypotheses that: (1) patients with severe OSA have a higher prevalence of PFO compared with healthy control subjects, (2) patients with severe OSA with clinically significant PFO experience more nocturnal desaturation than those without, and (3) PFO closure reduces nocturnal desaturation. METHODS: Patients with severe OSA and healthy control subjects underwent contrast transthoracic echocardiography and transcranial Doppler to detect PFO and determine shunt size. A subgroup of patients with OSA with large shunts underwent percutaneous PFO closure. Polysomnography was performed at baseline and 1, 6, and 12 months postclosure. RESULTS: One hundred patients with OSA (mean [SD] age, 52 [10] years; apnea-hypopnea index [AHI], 54 [18] events/h) and 50 control subjects (age, 52 [11] years; AHI, 2 [2] events/h) were studied. PFO prevalence was 43% in patients with OSA and 30% in control subjects ( P = .16). Large shunts were detected in 18% of patients with OSA and 6% of control subjects ( P = .049). Patients with OSA with clinically significant shunts had higher oxygen-desaturation index (ODI)/AHI ratios than patients without (ratio, 1.05 [0.27] vs 0.86 [0.26], P = .004). Six patients with OSA underwent PFO closure, which was not associated with a reduction in ODI (baseline, 48 [18]; 12 months, 51 [19] events/h; P = .92) or percentage of the night with arterial oxygen saturation , 90% (baseline, 23% [16%]; 12 months, 20% [22%]; P = .35). CONCLUSIONS: Patients with severe OSA have a higher prevalence of PFO with large shunts compared with control subjects. The ODI/AHI ratio is increased in patients with OSA with clinically significant shunts. PFO closure does not reduce nocturnal desaturation. PMID- 22924166 TI - A matter of the heart. PMID- 22924167 TI - Let's get the numbers! PMID- 22924168 TI - Phenazepam and cannabinomimetics sold as herbal highs in New Zealand. AB - A smokeable product called Kronic, is legally available, sold under five product names, and marketed in New Zealand as containing natural extracts. Two such products called Pineapple Express and Purple Haze were purchased from shops in Auckland city. They were investigated for the presence of synthetic drugs specifically synthesized for recreational purposes. The synthetic cannabinomimetics identified were JWH-018, JWH-073, JWH-122, JWH-250, and 1 pentyl-3-(4-methoxybenzoyl)indol. A compound not previously reported in such designer drug preparations 1-butyl-3-(4-methoxybenzoyl)indol was also seen. There was a marked variation in the content of these compounds within a named brand. The pharmaceutical benzodiazepine phenazepam (fenazepam) was identified as a constituent, along with certain cannabinominetics, in nearly all of the Kronic samples examined. Phenazepam has not previously been reported as a constituent of designer drug or herbal high products. The amount of phenazepam was approximately 1 mg per gram of Kronic leaf material. Use of these products could result in severe toxicity. PMID- 22924169 TI - Dexamethasone does not reduce pain or analgesic consumption after thyroid surgery; a prospective, randomized trial. AB - BACKGROUND: Post-operative analgesic effect of a perioperative fixed dose glucocorticoid has been demonstrated in studies on different surgical procedures. The aim of this study was to look for analgesic and opioid sparing effect after thyroid surgery with a weight-adjusted medium dose of dexamethasone compared with placebo or a higher dose. Further, to register other effects and side effects of dexamethasone in the 0-30 days postoperative period. METHODS: One hundred and twenty patients scheduled for thyroid surgery were randomly assigned to three groups receiving either dexamethasone 0.30 mg/kg, 0.15 mg/kg or placebo. Pain scores at rest and on coughing, post-operative nausea and vomiting (PONV), consumption of opioids and anti-emetics, appetite, sleep pattern, fatigue, mood, blood sugar, wound infection and dyspepsia were recorded. RESULTS: There was no effect of either dexamethasone doses on post-operative pain or rescue opioid consumption. PONV was lower in the dexamethasone groups 2-4 h post-operatively (P < 0.01). Blood sugar increased moderately from baseline in all groups, but significantly more in the dexamethasone groups (P < 0.01 at 2 h and P < 0.001 at 4 h). Minor improvement in appetite was shown with dexamethasone, along with a tendency towards less sleep and more fatigue in the 3-30 days period for the higher dose. No effect was demonstrated on other parameters. CONCLUSION: Dexamethasone had no analgesic or opioid sparing effect in our set-up after thyroid surgery. Dexamethasone reduced the incidence of PONV and led to a modest increase in blood sugar. A medium dose seems as effective as a higher dose. PMID- 22924170 TI - Every beginning calls an end. PMID- 22924171 TI - Managing dysmenorrhea in young women. AB - Primary dysmenorrhea is one of the most common health problems in women of reproductive age; however, it remains the most underdiagnosed gynecologic condition. This article will increase nurse practitioners' knowledge of primary dysmenorrhea, which is essential for diagnosing, providing evidence-based education and treatment, and enhancing patient quality of life. PMID- 22924172 TI - Unique doubly connected left ventricular diverticulum. AB - This case report describes a unique form of a left ventricular diverticulum in a 17-year-old patient.Echocardiography, angiography, and magnetic resonance imaging including virtual endoscopy complete a detailed picture of the size and texture of a diverticulum, as well as the localisation of the two connections into the left ventricle. PMID- 22924173 TI - Effects of dietary protein and amino acid levels on the expression of selected cationic amino acid transporters and serum amino acid concentration in growing pigs. AB - The absorption of lysine is facilitated by leucine, but there is no information regarding the effect of crude protein, lysine and leucine levels on the expression of cationic amino acid transporters in pigs. Therefore, an experiment was conducted with 20 pigs (14.9 +/- 0.62 kg initial body weight) to evaluate the effect of two protein levels, and the content of lysine, threonine, methionine and leucine in low crude protein diets on the expression of b(0,+) and CAT-1 mRNA in jejunum, Longissimus dorsi and Semitendinosus muscles and serum concentration of amino acids. Treatments were as follows: (i) wheat-soybean meal diet, 20% crude protein (Control); (ii) wheat diet deficient in lysine, threonine and methionine (Basal diet); (iii) Basal diet plus 0.70% L-lysine, 0.27% L-threonine, 0.10% DL-methionine (Diet LTM); (iv) Diet LTM plus 0.80% L-leucine (Diet LTM + Leu). Despite the Basal diet, all diets were formulated to meet the requirements of lysine, threonine and methionine; Diet LTM + Leu supplied 60% excess of leucine. The addition of lysine, threonine and methionine in Diet LTM increased the expression of b(0,+) in jejunum and CAT-1 in the Semitendinosus and Longissiums muscles and decreased CAT-1 in jejunum; the serum concentration of lysine was also increased (p < 0.01). Further addition of L-leucine (Diet LTM + Leu) decreased the b(0,+) expression in jejunum and CAT-1 in the Longissimus dorsi muscle (p < 0.05), increased the serum concentration ofleucine and arginine and decreased the concentration of isoleucine (p < 0.05). Pigs fed the Control diet expressed less b(0,+) in jejunum, and CAT-1 in the Semitendinosus and Longissiums muscles expressed more CAT-1 in jejunum (p < 0.05) and had lower serum concentration ofisoleucine, leucine and valine (p < 0.05), but higher lysine concentrations (p < 0.01) than those fed Diet LTM. These results indicated that both, the level and the source of dietary amino acids, affect the expression of cationic amino acid transporters in pigs fed wheat-based diets. PMID- 22924174 TI - Effect of dietary sunflower oil and coconut oil on adipose tissue gene expression, fatty acid composition and serum lipid profile of grower pigs. AB - The present study was conducted to assess whether the partial replacement of feed energy by vegetable oils containing high medium-chain saturated fatty acids (MCFA) and n-6 polyunsaturated fatty acids (PUFA) would modify lipogenic gene expression and other parameter of fat metabolism in pigs. Eighteen pigs (17-19 kg body weight) received one of three experimental diets for 60 days (six animals per group): (i) Control diet; (ii) a diet with sunflower oil (SO) or (iii) a diet with coconut oil (CO). In diets SO and CO, 10% of the feed energy was replaced by the respective oils. The experimental treatment did not influence the performance of the pigs. In blood serum, an increased content of total cholesterol was observed for SO and CO fed animals, whereas no significant changes for total triglycerides and different lipoprotein fractions were detected. The fatty acid composition of adipose tissue was significantly modified, with an increased content of MCFA and n-6 PUFA in CO and SO fed pigs, respectively. The gene expression for fatty acid synthase was decreased for SO and CO fed pigs; for stearoyl CoA desaturase and sterol regulatory element binding protein, a depression was observed in SO but not in CO fed pigs. The results of present study suggest that the type of dietary fat can modulate the adipose tissue gene expression and fatty acid composition differentially, with minimal effect on serum lipid profile. PMID- 22924175 TI - Nutritional value of 15 corn gluten meals for growing pigs: chemical composition, energy content and amino acid digestibility. AB - The objectives of this study were to determine the chemical composition, energy content and amino acid digestibility for corn gluten meals (CGM) and to develop prediction equations for estimating energy content and amino acid digestibility for growing pigs based on the chemical characteristics of these meals. The 15 CGM tested were obtained from seven Chinese companies. Experiment 1 was conducted to determine the digestible (DE) and metabolisable energy (ME) of the 15 CGM. The 18 growing barrows (38 +/- 4 kg) were assigned to three 6 x 6 Latin square designs. The 15 CGM test diets were formulated to contain 19.20% CGM, which replaced 20% of the energy supplied by corn and crystalline amino acid in the basal diet. Experiment 2 was conducted to determine the apparent (AID) and standardised (SID) ileal digestibility of the crude protein (CP) and amino acids in the 15 CGM using chromic oxide as an inert marker. The 18 growing barrows (25 +/- 2 kg) fitted with a simple T-cannula were assigned to three 6 x 6 Latin square designs. The 15 test diets contained 35% of one of the 15 CGM as the sole source of amino acids in the diet. The results showed a considerable variation in the chemical composition of CGM within and among plants. On dry matter basis, the DE and ME content of the CGM ranged from 18.8 to 21.0 MJ/kg and from 18.0 to 19.9 MJ/kg, respectively. There were no significant differences in the AID and SID for CP, arginine, lysine, glycine and proline among the 15 CGM, however, for all the other amino acids, significant differences were found for their AID and SID. With R2 values exceeding 0.50, the DE of CGM can be predicted accurately from CP and fibre content and ME from starch and fibre content. Suitable prediction equations for SID of methionine were also developed. PMID- 22924176 TI - Effect of niacin supplementation on rumen fermentation characteristics and nutrient flow at the duodenum in lactating dairy cows fed a diet with a negative rumen nitrogen balance. AB - The aim of the present experiment was to ascertain if a daily niacin supplementation of 6 g/cow to lactating dairy cow diets can compensate for the decrease in rumen microbial fermentation due to a negative rumen nitrogen balance (RNB). A total of nine ruminally and duodenally fistulated lactating multiparous German Holstein cows was used. The diets consisted of 10 kg dry matter (DM) maize silage and 7 kg DM concentrate and differed as follows: (i) Diet RNB- (n = 6) with energy and utilisable crude protein (CP) at the duodenum (uCP) according to the average requirement of the animals, but with a negative RNB (-0.41 g N/MJ metabolisable energy [ME]); (ii) Diet RNB0 (n = 7) with energy, uCP, and RNB (0.08 g N/MJ ME) according to the average requirement of the animals; and (iii) Diet NA (nicotinic acid; n = 5), which was the same diet as RNB-, but supplemented with 6 g niacin/d. The negative RNB affected the rumen fermentation pattern and reduced ammonia content in rumen fluid and the daily duodenal flows of microbial CP (MP) and uCP. Niacin supplementation increased the apparent ruminal digestibility of neutral detergent fibre. The efficiency of microbial protein synthesis per unit of rumen degradable CP was higher, whereby the amount of MP reaching the duodenum was unaffected by niacin supplementation. The number of protozoa in rumen fluid was higher in NA treatment. The results indicated a more efficient use of rumen degradable N due to changes in the microbial population in the rumen when niacin was supplemented to diets deficient in RNB for lactating dairy cows. PMID- 22924177 TI - Lucerne silage in high yielding dairy cows: effect of parity and analysis of reasons in mixed-parity group housing using random regression test-day models. AB - A study with high-yielding dairy cows was re-analysed in order to test the suitability of lucerne silage separately for primi- and multiparous cows as an alternative to grass silage in maize-based total mixed rations (TMR). Lactation curves were fitted using random regression test-day models for energy corrected milk (ECM) and dry matter intake (DMI) as well as for number and duration of feeder visits (NFV and DFV, respectively). Existing models for ECM and DMI were extended by animal-specific random effects, which were formulated in their dependency on days in milk. For NFV and DFV random regression models were applied for the very first time. The chosen approach of statistical analysis permitted comparisons of the lactation curves as well as of least square means for sub periods to answer nutritional questions. Whilst primiparous cows had generally lower DMI and ECM as compared to multiparous cows, only in primiparous cows a negative effect of lucerne TMR on ECM was observed, especially in early lactation. Nutritional factors should be rejected because of very similar ECM between the various TMR in multiparous cows. Traits of feeding behaviour indicated that particle size could contribute to the decreased ECM. Even more impact on the lower ECM should be addressed to domination behaviour of multiparous cows. The resulting restlessness of primiparous cows caused a reduced intake per minute spent at the feeder. Further studies should focus on optimising the proportion and chopping length of lucerne in the diet and to improve flock management to maximise feed intake of primiparous cows. Generally, statistical analysis of lactation data became a very complex issue. It seems inevitable that nutritionists and statisticians team up to address this problem. PMID- 22924178 TI - Effects of free air carbon dioxide enrichment and drought stress on the feed value of maize silage fed to sheep at different thermal regimes. AB - Information about the effects of rising atmospheric CO2 concentration and drought on the feed value of maize silage and interactions with the thermal environment during feeding is limited. A free air carbon dioxide enrichment facility was operated in a maize field to generate an elevated CO2 concentration of 550 ppm. Drought was induced by the exclusion of precipitation in one half of all experimental plots. Plants were harvested, chopped and ensiled. In a balance experiment on sheep, the nutrient digestibility was determined for three climatic treatments (temperate, temperature humidity index (THI) 57-63; mild heat, THI 68 71; severe heat, THI 75-80). The CO2 concentration and drought did not alter the crude nutrient content of silage dry matter (DM) or nutrient and organic matter (OM) digestibility. Drought increased the concentration of deoxynivalenol (DON, p < 0.001). The drought-associated increase of DON was reduced by CO2 enrichment (p = 0.003). The lowest digestibility of acid detergent fibre (p = 0.024) and neutral detergent fibre (p = 0.005) was observed during the coldest climate. OM digestibility increased during mild heat (p = 0.023). This study did not indicate considerable alterations of the feed value of maize silage due to increased atmospheric CO2 and drought. Enriched CO2 may decrease DON contaminations during drought. The thermal environment during the balance experiment did not interact with feeding maize silage grown under elevated CO2, but may affect cell wall and OM digestibility. PMID- 22924179 TI - Matariki--preparing for the next 50 years. PMID- 22924181 TI - Facing skin cancer surgery. Mohs surgery may be your best option for nonmelanoma skin cancers. PMID- 22924180 TI - Radiographic validation of manual functional analysis of temporomandibular joint osteoarthritis. AB - The finding of osteoarthritis of temporomandibular joint (TMJ) obtained by clinical diagnosis, i.e. manual functional analysis (MFA) and the finding obtained by magnetic resonance imaging (MRI) as the gold standard were compared in 30 patients (mean age 52.6) diagnosed with osteoarthritis, selected out of 140 consecutive patients diagnosed with a TMJ disorder by MRI. The clinical parameters were symptoms of pain in the TMJ region, crepitations, and absence of clicking, which was confirmed by manual examinations as part of MFA. A positive MRI finding included flattening, subchondral degenerative changes with or without intact cortical bone, osteophytes and subchondral degenerative cysts of joint surfaces. The validity of MFA for osteoarthritis was as follows: sensitivity 0.38, specificity 0.91, positive predictive value (PPV) 0.77 and negative predictive value (NPV) 0.65. MRI examination revealed disk displacement (DD) without reduction in 12 (40.00%) patients and DD with reduction in one (3.33%) patient. The finding of passive compressions for the osteoarthritis diagnosis depending on DD showed sensitivity of 0.29, specificity of 0.95, PPV 0.67 and NPV 0.78. Although MFA significantly improves validity of clinical diagnosis when differentiating a myogenic from TMJ disorder, clinical determination of osteoarthritis is not satisfactory. Nonspecific clinical signs and symptoms accompanied by predominant pain in the TMJ on dynamic but not on passive manual examinations cannot help differentiate DD from osteoarthritis. PMID- 22924182 TI - [Indoor air quality in school buildings: risk for respiratory and allergic diseases. Current situation in Italy and preventive strategies. First initiatives]. PMID- 22924183 TI - Early detection of colorectal cancer: on the M2PK test. PMID- 22924184 TI - Method for improving the resolution and accuracy against birefringence dispersion in distributed polarization cross-talk measurements. AB - We present a novel method for improving the spatial resolution and amplitude accuracy of distributed polarization cross-talk measurements in a polarization maintaining (PM) fiber against its birefringence dispersion. We show that the broadening of measured polarization cross-talk peaks caused by birefringence dispersion can be restored by simply multiplying the measurement data with a compensation function. The birefringence dispersion variable in the function can be obtained by finding the widths of measured cross-talk envelopes at known distances along the fiber. We demonstrate that this method can effectively improve spatial resolution and amplitude accuracy of the space-resolved polarization cross-talk measurements of long PM fibers. PMID- 22924185 TI - Scattering forces and electromagnetic momentum density in crossed circularly polarized standing waves. AB - We analyze the forces on a small dipolar particle and the electromagnetic momentum density in a configuration consisting in two perpendicular circularly polarized stationary waves. The field distribution shows regions in which the electric and magnetic fields are parallel corresponding to a null Poynting vector. Although the average value of the momentum density, proportional to the Poynting vector, is zero in these regions, there are scattering forces acting on small particles due to light's spin force. The total scattering force suggests a new definition of the average value of the momentum density for free propagating electromagnetic fields. PMID- 22924186 TI - [Notes on syrups and dry syrups of ambroxol hydrochloride and L-carbocysteine]. PMID- 22924187 TI - Healthcare sector reform and its influence on public hospitals in mainland China. AB - The government has launched the healthcare sector reform since the 1980s. From the beginning, the reform has been controversial. What is then the real purpose of the reform? Is it only to reduce the government's burden of health care or establish a just and effective healthcare system? Can healthcare be geared by the market or should the government play a guiding role in it? PMID- 22924188 TI - Medicine: business or profession? AB - As professionals, doctors have a contractual relationship with society that trains them and confers on them exclusive power to practice medical care. In the contract, power and responsibility should be balanced. When the power is conferred by society to a profession, the profession should take responsibility for society, including the provision of high quality services, and maintain high standard principled conduct and integrity. PMID- 22924189 TI - [The difficulty of applying the fundamental right to care for all within the French healthcare system: a major ethical and political challenge]. AB - The incidence of the reform is beginning to make itself felt and reveal a profound modification of the behaviour of health professionals in hospitals as well as of the financial structure of hospitals. PMID- 22924190 TI - Access to health care and social protection. AB - In France, the access to healthcare has been conceived as a social right and is mainly managed through the coverage of the population by the National Health Insurance, which is a part of the whole French social security scheme. This system was based on the so-called Bismarckian model, which implies that it requires full employment and solid family links, as the insured persons are the workers and their dependents. This paper examines the typical problems that this system has to face as far as the right to healthcare is concerned. First, it addresses the need to introduce some universal coverage programs, in order to integrate the excluded population. Then, it addresses the issue of financial sustainability as the structural weakness of the French system--in which healthcare is still mainly provided by private practice physicians and governed by the principle of freedom--leads to conceive and implement complex forms of regulations between the State, the Social security institutions and the healthcare providers. PMID- 22924191 TI - [Impact of the new system of resource allocation on French public healthcare establishments]. AB - The reform of the tarification according to activity is now in place with a "T2A" rate said to be 100%, ie the hospitals are paid based on the national tariffs for a stay in hospital. The reform will continue with a list of stays for which, each year, a single tariff between the public sector and the private sector is applied. This single tariff results from the "inter-sector tariff convergence" policy which is applied. PMID- 22924192 TI - [Bioethics committee in the university teaching hospital in Bordeaux]. AB - Set up in 2011, the ethics committee at the teaching hospital in Bordeaux, although it is now obsolete in its organisation because of the "standardisation" in early 2012 of regional ethics groups, was nevertheless an original structure which deserves to be analysed for several reasons. First of all, why have a hospital ethics committee? Then, to do what? Finally, it is interesting to give a few indications about the working of this committee. PMID- 22924193 TI - Undue game of baseline principles: the physician-patient relationship from a bioethical perspective. AB - This article is inspired by an accident in a hospital where a pregnant woman died on the operating table because her husband was unwilling to sign the operation consent form. What's lurking behind this tragedy is the crisis of faith between doctors and patients in China. The crisis is a product of the Marketization of the health care system, which generates an unequal relationship between doctors and patients. Such a relationship makes patients unable to actively protect their rights. From a bioethical perspective, health is a basic right for everyone. In order to improve the physician-patient relationship, health rights must be considered as a priority in policy making. Although the Chinese government has been trying to implement universal health coverage, a progress indeed, problems and difficulties still exist in equalizing status between patients and doctors and in rebuilding a benign physician-patient relationship. PMID- 22924194 TI - An analysis of the changing doctor-patient relationship in China. AB - As China is undergoing marketization and privatization, the doctor-patient relationship (DPR) is changing, posing numerous social problems such as a trust crisis. In this article, the authors look at the characteristics of the DPR, and then present an historical account of the changing features of the Chinese DPR. In the final section, they explain how Chinese traditional culture is important for rebuilding the DPR in reform-era China and make suggestions for its health care reform. PMID- 22924195 TI - [Ethics and medical genetics]. AB - Medical genetics may be distinguished from other medical specialities by its family dimension. Genetics raises many questions in the field of ethics concerning the potential applications in clinical medicine, in particular because of the technological evolution of human genetics in the medical field and the genetic research on the charting of the human genome. Human genetics involves filiation and questions the foundation of our society and the potential standardisation of human beings. The prescription of genetic tests is a tool for doctors but its use should be measured and carefully thought out according to the questions asked and the results expected. Examination of this issue within the context of the bioethics laws in France has made it possible to establish a framework for a certain number of practices so as to answer certain questions in human genetics. This article attempts to review the situation as it stands today with regard to the ethical issues raised by genetic tests, presymptomatic diagnosis, prenatal and pre-implantation diagnosis, and bio-collections. PMID- 22924196 TI - [Transcultural discussion in bioethics drawn from research experience in China: building up a theoretical and methodological framework for further research cooperation]. AB - My article discusses bioethics in transcultural context and builds on an experience of conducting research in China in partnership with Chinese scholars and institutions. Key points are about the creation of ethical committees and their prerogatives, the regulation of experimenting in human and animal, and of donating and transplanting organs. Ethical issues are approached according to an anthropological reading. Three transversal lines for further research are suggested: global/local ethical governance applied to research ethics; implications of transnationalizing and delocalizing research practices with regards to governance; theoretical positioning--conceptual pluralism versus pragmatic pluralism--following actual confrontation to transcultural variations in research ethics. Moreover, this work claims for conceptualizing and implementing an ethics in context while assessing intangible (non-relative) principles based on knowledge production and a global patrimony. PMID- 22924197 TI - [The research ethics committees: the French example of the Comites de Protection des Personnes]. AB - Succeeding to the CCPPRB as created by the statute of December 20, 1988, the CPP are the ethics committees foreseen by international texts dealing with research involving human beings. They were ruled by the statute of 9 August 9, 2004 and are partly modified by the last statute of March 5, 2012, settling a new classification of research, each category under a different set of rules. To solve difficulties arising from the number of committees (40), a new National Committee for research is created, working closely with the minister. Another purpose of the reform was to include the observational research to extend the area of research with opened access to international level for publications. PMID- 22924198 TI - The survey of clinical human experimentation research in ethical review of postgraduates students. AB - An anonymous questionnaire was used to investigate the status quo of ethics review of human subject experiments among postgraduate students in clinical practice with the main conclusions as follows: Human subject experiments make up a large ratio of clinical research; the construction of an ethics review has been initially formulated, but there exists a gap in ethics awareness between advisors and the postgraduates with the desperate need to receive ethics review. It is necessary to realize the importance of informed consent and to strengthen the strict supervision of placebo application. PMID- 22924199 TI - The impact of development of population-based study in the biomedical field on laws and regulations: a cross-strait experience on biobank development. AB - Together with the completion of the Human Genome Project, biomedical research has marched into the "Post-Genomic Era." In order to take advantage of this extracted gene related information extensively and precisely so as to realize man's biological phenomena as well as the mechanism of pathogenesis, consequentially, a large scale sample collection of different geological areas and/or ethnic groups becomes necessary for the future population based genetic research of a country and, in turn, the construction of population-based genetic database (Biobank). In recent years, both mainland China and Taiwan have not only made great progress in information and computation technologies, but have also gradually taken a close look into the quality of medicine delivery. Thus, it becomes unavoidable for both sides to create each one's population-based genetic databases (Biobank). Theoretically speaking, the Biobank development shall benefit the study on the correlation between genes and disease and also the solution for disease treatment as well. At the same time, medical diagnostic technology has also been significantly improved. It is believable that the population-based genetic database might be utilized to promote medical quality and to reduce the cost of public health delivery. Further; in the near future, it might become the "raw materials "for medical research application. However when taking promotion of public welfare as the premises for a Biobank development, the severe and multi challenge occurred against the traditional legal rules in terms of the privacy protection, public trust development, the compliance of informed consent principle, the implementation of benefit-sharing doctrine and the possible discrimination concern about the population/participants selection and some other ELSI issues. In this paper, the major legal issues encountered by the Biobank development will first be reviewed accompanied by the background information concerning the Biobank development scenario crossing the Taiwan Strait. Also, mainly following the realm of comparative policy or legal approaches, the paper learning from the fruits of this comparative study, tries to propose some recommendations for future legislative consideration by both mainland China and Taiwan. It's been this author's wish that, when establishing a large scale population based Biobank, the promotion of public trust shall be placed as the primary goal together with the emphasis on supporting publicity and transparency on the administrative practices, so as to encourage the public participation in observing the principle of altruism and, in turn, benefit the future biomedicine development. PMID- 22924200 TI - Biobanks for research. Ethical and legal aspects in human biological samples collections in France. AB - Because they gather huge quantities of human biological samples and information allowing for better understanding of diseases, biobanks appear as a very powerful tool for boosting both medical research and public health as a whole. Although France does not really appear as a leader in biobanking compared to China or UK, biobanks and other samples collections abound in our country and have then been regulated, even though french law does not use the term biobank as such. The present article gives an overview of the current legal framework and explores the remaining ethical and legal issues, concerning particularly the protection of donors, the sharing of biobanks content and the sharing of biobanks benefits. The article explains how these universal questions arise in this country and what answers (sometimes specific) they get or could get in the following years. PMID- 22924201 TI - A study of health beliefs and practices of the Yoruba. AB - The issue of how immigrant populations combine traditional and Western health beliefs and practices has not been given due attention. Hence, this qualitative research study of Yoruba immigrants, an ethnic group from south-western Nigeria, living in the mid-Atlantic region of the United States, sheds some light on the question of how best to provide culturally appropriate health care to Yoruba immigrant groups with differences in health beliefs and practices. The study found that there are three types of Yoruba immigrant groups: (1) those who use only Western medicine (though mostly for pragmatic reason); (2) those who combine traditional Yoruba and Western beliefs; and (3) those who combine Western medicine and Christian beliefs. PMID- 22924202 TI - Health and healing: traditional medicine and the Karen experience. AB - OBJECTIVE: To examine the beliefs, attitudes and health-seeking behavior surrounding the use of traditional medicine among the Karen (refugees from Burma). METHODS: Three focus groups and two key-informant interviews were conducted with the Karen along with observations by researchers. RESULTS: The Karen continue to use elements of their traditional healthcare system after resettling in the U.S. Accessibility and perceived efficacy of treatments influence their health-seeking behavior. The participants discussed beliefs about health and healing, spirituality, and their experience as refugees. Implications for improving the quality of healthcare for the Karen and recommendations for further research are discussed. PMID- 22924203 TI - Latino elders reframing familismo: implications for health and caregiving support. AB - Abstract: This study explores Latino elders' perceptions of familismo and the extent to which a familistic orientation translates into health support. Latinos have traditionally been portrayed as adhering to a familistic orientation with the presumption of duty and obligation to care or aging parents. Latino elders participated in focus groups that became the basis of this study. These elders shared ways they are reframing the familismo construct. Despite a greater need for support, elders reported infrequent contact with family. In the absence of family, family boundaries have been extended, so that others become "like family to me. The findings call into question the present state of familismo and the presumption that the Latino family is able to care for its own. PMID- 22924204 TI - Acculturation stress among Maya in the United States. AB - Abstract: As health care disparities become more evident in our multicultural nation, culture sensitive health research needs to be a priority in order for good health care to take place. This article will explore the literature related to acculturation stress and mental health disparities among the Mayan population. Literatures of similar but distinct groups are included due to the limited amount of research of the Mayan population. Using Leiniger's Transcultural nursing theory, these findings suggest that nurses have a large gap to fill to address the mental health disparities of specific cultural groups like the indigenous Maya, thereby satisfying their nursing obligations. PMID- 22924205 TI - Health promotion in nursing and cost-effectiveness. AB - Close examination of the different healthcare systems and the present economic crisis worldwide suggests that all health organizations should re-evaluate the concept of health promotion and its relationship to cost-effectiveness. When choosing the most efficient and cost-effective system, each nation's healthcare system must seriously start to implement strategies for the change. Health professions, including nursing, must change their vision of education both in academic and practice settings, to focus on health promotion and illness prevention. The key principle underlying this paper is to illustrate the importance of health promotion and cost-effectiveness being adopted by all health organizations worldwide, as well as to observe the experiences of selected counties in developing a health policy related to education in primary healthcare. The paper will include a plan adopted by the General Nursing Directorate (GND) in the Kingdom of Saudi Arabia (SA), which contains a health promotion policy for the nursing administrations in all governmental primary healthcare centers in Saudi Arabia. PMID- 22924206 TI - Healthy people, malaria and South Dakota. AB - The U.S. Department of Health and Human Services' Healthy People 2020 goals call for a reduction in the number of cases of malaria in the United States. Historically, South Dakota has had a low incidence of this infection, but a demographic shift has poised the state for a potential increase in the number of cases. The reasons for this are reviewed, and proactive steps that can be taken to avoid this rise are presented. PMID- 22924207 TI - Evaluating hip pain in children. AB - Hip pathology in the pediatric patient can be very challenging to diagnose, as there are many diagnoses that must be considered by the clinician. Categorizing children by age can aid in the process of making an early diagnosis, which is especially important when it comes to serious pediatric hip conditions such as septic arthritis, Legg-Calve-Perthes disease and slipped capital femoral epiphysis. PMID- 22924208 TI - Medical foods: glorified dietary supplements? PMID- 22924209 TI - The Supreme Court has ruled...now what? PMID- 22924210 TI - The never ending story of staffing. PMID- 22924211 TI - Nursing 2012. A historic collaboration to enhance the nursing profession. PMID- 22924212 TI - Nursing 2015's Yellow Team--Advancing the education of nurses in Ohio. PMID- 22924213 TI - Standards criteria for new health care facilities. PMID- 22924214 TI - Green team focuses in on professional boundaries and social networking. PMID- 22924215 TI - Excerpt from the Just Culture Toolkit. PMID- 22924216 TI - Be aware--protect yourself and your patients! PMID- 22924217 TI - Can I hire Kerr, Russell and Weber as my personal legal counsel? PMID- 22924218 TI - Leaves of absence: the definition of a 'reasonable accommodation'. PMID- 22924219 TI - Alcoholics Anonymous, Al-Anon and Alateen. PMID- 22924220 TI - Tips to better understand coordination of benefits. PMID- 22924221 TI - The dangers of micromanagement and the 'three freedoms'. PMID- 22924222 TI - Anna's story. PMID- 22924223 TI - It happened to me. PMID- 22924224 TI - My personal journey with Factor V Lieden thrombophilia. PMID- 22924225 TI - Management of oral anticoagulation in patients undergoing minor dental procedures. AB - Approximately 4.2 million patients in the United States are taking warfarin, making it the 11th most prescribed drug. Warfarin is primarily used for treatment of venous thromboembolic disease and stroke prevention in patients with atrial fibrillation and mechanical heart valves. Dentists frequently encounter anticoagulated patients and are faced with management decisions in these patients who require dental procedures. Observational studies suggest the risk of thrombosis if anticoagulation is suspended during dental procedures is higher than the risk of bleeding if anticoagulation is not suspended. Several groups now offer guidelines that recommend most minor dental procedures should be performed while on therapeutic warfarin. The recent approval of several new oral anticoagulants has introduced greater complexity to the management of the anticoagulated patient, and this narrative review will discuss current guidelines, the scientific underpinnings of the guidelines, and offer some practical suggestions for patients that are receiving the new agents. PMID- 22924226 TI - When your patient refuses. AB - Refusals of care are a fact of life in dentistry. Following the above risk management guidelines will not guarantee that you will never be sued for failure to properly inform the patient of the risks of refusing care. However, the adequate quantity and good quality of your documentation will greatly benefit your defense of any claim. PMID- 22924227 TI - What's the true value of your practice? It depends! PMID- 22924228 TI - Scholarly perspectives on obesity among black women. AB - There are a disproportionate number of Black women who are either overweight or obese. Health professionals who are overweight or obese were found to have less confidence in weight management practice. Studies show that overweight and obese nurses avoid the topic of obesity with their overweight and obese patients. This article describes the biological, psychological, social and cultural factors which may influence obesity in Black women. Specifically, this synthesis of the literature raises the question whether Black nurses with relevant health knowledge have different rates of obesity when compared to Black women that are not registered nurses. PMID- 22924229 TI - Correlates of physical activity and the theory of planned behavior between African American women who are physically active and those who are not. AB - Many people have positive intention to engage in physical activity but fail to act. In general, Physical activity (PA) levels among Americans are declining. However, when compared to all other racial groups, middle aged African American women (AAW) have the lowest rate of PA participation. The lack of physical activity has dire illness consequences for AAW Despite significant efforts to increase physical activity to levels that benefit health, the need to understand successful translation of intention to engage in physical activity, attitude, subjective norm, and perceived behavioral control is warranted in order to design theoretically derived culturally tailored interventions to increase physical activity participation among middle aged AAW. Moreover, there is a paucity of studies that use theoretical underpinnings to elucidate the differences between middle aged AAW who are physically active and those who are not physically active. Therefore, the Theory of Planned Behavior's (TPB) measuring the constructs of intention, subjective norm, attitude, and perceived behavioral control was used to guide the design of this study. One-hundred-fifty-three respondents completed the socio-demographic profile, a Theory of Planned Behavior Questionnaire (TPBQ), and the International Physical Activity Questionnaire (IPAQ). The Pearson's Product-Moment Correlation Coefficient indicated the highest correlation between intention and attitude r (137) = .740, p < .001. The correlation between intention and perceived behavior control was r (137) = .546, p < .001; intention and physical activity r (137) = .439, p < .001; attitude and perceived behavior control r (137) = .487, p < .001; and attitude and physical activity r (137) = .429, p < .001 demonstrated a moderately strong positive relationship. Subjective norm and perceived behavior control demonstrate the smallest correlational significance r (137) = .264, p <.001. Multiple regression analysis revealed attitude towards physical activity, and perceived behavior control for physical activity were statistically and clinically significant predictors of physical activity among the middle-aged African American women in this study. PMID- 22924231 TI - Student disruption in a global college classroom: multicultural issues as predisposing factors. AB - University and college faculty members may face inappropriate student behavior in a global classroom. This situation can complicate the maintenance of a positive effective learning environment. Student disruption is seen as disturbing behavior that interferes with the faculty member's academic or administrative ability to conduct class, or the ability of other students to profit from the class instruction. Disruptive behavior may threaten or endanger the physical or psychological health, safety or welfare of others. Various types of disruptive behavior and disrespect that university or college faculty are likely to experience include: grandstanding (use the classroom for themselves by monopolizing class discussion with no regard to relevancy to the discussion); prolonged chattering (small cliques of students who engage in private conversations or passing notes to each other); noisy electric devices (cell phones ringing in class, or students talking or text messaging during class time); leaving and entering class (frequently in the absence of notice to professor of illness or other extenuating circumstances); and disputing the professor's authority or expertise (students may be disappointed or unhappy over a grade and may debunk or devalue the professor's judgment, authority and expertise). This action may be in the form of comments in the class or memos to department chair or dean. Persistent speaking without permission and verbal or physical threats to faculty members or other students are also disruptive mannerisms. Working with a diverse student population can present unique challenges. Multicultural issues related to race, ethnicity, gender, physical, emotional or socioeconomic status and sexual orientation might require increased sensitivity, knowledge and self-exploration. PMID- 22924232 TI - Is it safe to drink? PMID- 22924230 TI - Influence of scary beliefs about the Tuskegee Syphilis Study on willingness to participate in research. AB - OBJECTIVES: To assess whether scary/alarming beliefs about details on the Tuskegee Syphilis Study (TSS) are associated with willingness and/or fear to participate in biomedical research. METHODS: Scary beliefs about TSS were examined for 565 Black and White adults who had heard of the TSS. Multivariate analyses by race were used to measure association. RESULTS: No association between scary beliefs and willingness or fear to participate in research was found (P > 0.05). CONCLUSIONS: These findings provide additional evidence that awareness or detailed knowledge about the TSS does not appear today to be a major factor influencing Blacks' willingness to participate in research. PMID- 22924233 TI - "What's the clicking sound?". PMID- 22924234 TI - Licorice extract a sweet way to control decay. PMID- 22924235 TI - Advanced fee dental practice. PMID- 22924236 TI - Meet your president--Dr. Bernie Dishler. PMID- 22924237 TI - After-birth abortion. PMID- 22924238 TI - Some comments on the paper 'After-birth abortion: why should the baby live'? PMID- 22924239 TI - Public distress as a moral consideration in after-birth abortion. PMID- 22924240 TI - Moral uncertainty and the moral status of early human life. PMID- 22924241 TI - 'After-birth abortion' and arguments from potential. PMID- 22924242 TI - The performativity of personhood. PMID- 22924243 TI - Why Kass and Callahan are wrong (but maybe a little right). PMID- 22924244 TI - Applying for ethical approval for a national multisite study: the challenges and barriers. PMID- 22924245 TI - Comparative analysis of accuracy of diagnosis of chronic periapical lesions made by clinical and histopatological examination. AB - INTRODUCTION: The preliminary diagnosis of chronic periapical lesions is made on the basis of clinical symptoms and radiographs, which is a reliable diagnostic tool, but it has only a subsidiary role since histopathological verification is essential for the definitive diagnosis. This study was aimed at diagnosing removed chronic periapical lesions and classifying them by size as well as at comparing the clinical diagnoses with histipathological results. MATERIAL AND METHODS: The study included 34 patients diagnosed with chronic periapical process by applying clinical examination and radiography. The removed chronic periapical lesions were processed according to classical histological technique and analyzed by hematoxylin and eosin staining protocol. RESULTS: According to histopathological analysis 53% of chronic periapical lesions were periapical granulomas and 47% were radicular cysts. The size of the lesions ranged from <9 mm (70% of lesions), 9 to 20 mm (18% of lesions) and >20 mm (12% of lesions).The histopathological examination revealed that clinical diagnosis was wrong in 26% of cases. CONCLUSION: A statistically significant difference between clinical and histopathological diagnosis has been found. The histopathological findings strongly suggest the necessity of complete curettage of lesions sizing >20 mm in order to prevent recurrences. PMID- 22924246 TI - [Occlusion of maxillary artery in treatment of trigeminal neuralgia]. AB - INTRODUCTION: This paper deals with a treating method of trigeminal neuralgia classified so far as idiopathic neuralgias and treated conservatively. The study was aimed at proving the compression of peripheral branches of N. trigeminus in those patients by vascular elements of A. maxillaris within the bone-ligament space of the scull and the face base. MATERIAL AND METHODS: The study sample consisted of 76 patients having trigeminal neuralgia. The compression was proved by clinical examination, by angiography and electrophysiological investigations. Endovascular occlusion of A. maxillaris is the original method and it was carried out in selected patients. RESULTS: This method was applied in 76 patients. Embolisation was done in 71 patients by using occlusion spiral and gelfoan was used in 3 patients. Externa carotid artery ligation was done in 2 cases. CONCLUSION: The effect of absolute improvement has been achieved and verified by electrophysiological method and subjective assessment of the patients. PMID- 22924247 TI - [Pilot programme--detection of colon tumour in subjects living in the district of northern Banat]. AB - INTRODUCTION: Tumours of the colon are among the leading neoplasms in the world as well as in Europe and our country both in the male and female population. The study was aimed at showing the incidence of colon tumour in a group of 300 subjects who had undergone total colonoscopy as well. MATERIAL AND METHODS: The endoscopic examinations were performed by the Fujinon video endoscopes. The faecal occult blood test was done by the original test 'ULTI Med Products Deutschland GmbH' The biopsy specimens were delivered to the Pathomorphological Service to be processed andstained by the method of Hematoksilin-eosin. RESULTS: A group of 300 subjects, consisting of 144 men (48%) and 156 women (52%) were examined. The indication for the lower endoscopy in 52 patients (17.33%) was manifest bleeding The faecal occult blood test was positive in 79 patients (26.33). The endoscopic examination verified 25 colon polyps (8.33%) and 14 malignant colon tumours (4.60%) in the examined group. The endoscopy was also performed in 48 patients who had been already operated for colon carcinoma (16%) and in 5 patients who had undergone endoscopic polypectomy (1.66%). Specificity, sensitivity and predictivity were calculated to be 55.8%, 63% and for positive finding 9.4% and for negative finding 95.8%, respectively, for the Haemoccult test as compared to the histological finding as a "gold standard" DISCUSSION: The obtained results were compared with the findings of other authors. CONCLUSION: Our opinion, formed according to the obtained results and findings of other authors, is that it is necessary to perform systematic examination of people over 45 years of age for early detection of colon tumour. PMID- 22924248 TI - [Effects of epidural analgesia using different concentrations of bupivacaine during combined general and epidural anesthesia]. AB - INTRODUCTION: Thoracic epidural analgesia, combined with general anesthesia, is an established anesthetic choice for abdominal aortic surgery. However, there are controversies about the level of anesthesia as well as the dose and concentration of the local anesthetic used. The aim of the study was to compare the effects of two different concentrations of epidural bupivacaine on sevoflurane requirements and hemodynamic parameters during aortic surgery under combined epidural/general anesthesia. METHODS AND MATERIAL: Sixty patients scheduled for abdominal aortic surgery were randomly divided into two groups according to the concentration of local anesthetic used for epidural anesthesia: group 1--low concentration--where 0.125% bupivacaine was used, and group 2--high concentration--where 0.5% bupivacaine was used at the beginning and then the concentration was reduced to 0.25%. Anesthesia was maintained with sevoflurane, the dose was adjusted to achieve the target entropy of 40-60. The measurements included the inspired sevoflurane concentrations, blood pressure, and heart rate at the beginning and every 5 min during the surgery. RESULTS: Both groups had similar heart rate and blood pressure, but the inspired sevoflurane concentration was significantly higher and more variable in patients where bupivacaine 0.125% was used. Vasopressors were used more often and in higher doses in the 0.5% bupivacaine group, and in the same group the blood loss and fluid requirements were reduced. CONCLUSION: When 0.5% bupivacaine is used in combined thoracic epidural/ general anesthesia for aortic surgery, the sevoflurane concentrations are lower and less variable. In addition, the blood loss and fluid requirements are reduced. PMID- 22924249 TI - [Prepuce in boys and adolescents: what when, and how?]. AB - INTRODUCTION: The prepuce envelops the glans as a variant of a mucocutaneous tissue presenting with a lot offunctions, the most important of them being to protect the infant's glans from feces and ammonia in diapers, to protect the glans from abrasions and trauma throughout life, and to provide sufficient skin in erection. Circumcision was recognized as a method of solving foreskin problems a long time before Christ. Practicing male circumcision in history was customary several thousand years ago and has spread worldwide. Today it depends on races, and it is often an initiation ceremony near the age of puberty. In everyday practice in pediatric urology outpatient department the foreskin problems have been noticed as a phimosis in 9.91% cases and prepuce adhesions in 3.98%. Congenital anomalies are present in different numbers. Other problems, such as paraphimosis, balanoposthitis, are recorded as accidental cases. Over-all prepuce pathology can be observed in 12%-25% of patients. The article presents a review of foreskin conditions, clinical manifestation, therapy and arguments for patient's benefits. CLINICAL PRESENTATION: The term phimnosis describes a foreskin that is unable to retract. It is necessary to distinguish normal anatomic situation in neonate and infantile period, when prepuce has not been separated yet from true pathologic phimosis due to fibrosis and sclerosis. Up to six years of age the tip of the prepuce is elastic and might be retracted by gentle manipulations. In cases when the foreskin is trapped behind the glans penis and cannot be pulled back to normal position, paraphimosis is present and can be treated as a medical emergency by manual manipulation, or by dorsal slit (incision). Many studies have demonstrated that frequency of urinary tract infection increases in uncircumcised males and that is a reason for routine circumcision. The others are against routine circumcision. The contraindications are newborns, especially prematurely born. and congenital penile anomalies. Condition in which the frenulunm of penis is short with consequent restriction of movement of the prepuce can be easily treated by frenulotomy. Hooded prepuce is a condition of incomplete circumferential formation of foreskin with a dorsal component present and ventral component absent. In cases without any penile anomalies this is only a cosmetically unattractive appearance and could be corrected by circumcision. Infection of the foreskin due to bacterial colonization could be both prevented and treated easily However, an infection due to peno-preputial incisions in adolescent age is serious and has to be cured promptly. CONCLUSION: As a part of external genitalia, the foreskin has a lot of functions. Despite its natural role many advocates routine circumcision due to problematic condition that can develop. Routine circumcision is not generally recommended. Improved education for physicians and parents with regard to the foreskin development and management is required. PMID- 22924250 TI - [Mechanisms of neurodegeneration in Alzheimer's disease]. AB - INTRODUCTION: Recent research into mechanisms of neurodegeneration in Alzheimer's disease has lead to a dramatic increase in our understanding of the mechanisms of cell death and neuroprotection. Alzheimer's disease is a complex disease with multiple etiological factors involved in disease pathogenesis. OXIDATIVE STRESS AND MITOCHONDRIAL DYSFUNCTION IN ALZHEIMER'S DISEASE: Amyloid-beta peptide toxicity is mediated at least in part by oxidative stress. Anmyloid-beta peptide directly generates reactive oxygen species in the presence of redox-active metal ions. In Alzheimer's disease, oxidative stress is present early in pathogenesis and contributes to disease pathogenesis. Unlike other organs, the brain is especially vulnerable to reactive oxygen species due to neurons having relatively low levels of endogenous antioxidants. Overly abundant oxygen radicals cause the destruction of cellular macromolecules and participate in signaling mechanisms that result in apoptotic cell death. MICROGLIAL ACTIVATION AND NICOTINAMIDE ADENINE DINUCLEOTIDE PHOSPHATE OXIDASE IN ALZHEIMER'S DISEASE: There is a wealth of evidence demonstrating that microglia, the resident innate immune cells in the brain, can become deleterious and damage neurons. Microglial activation causes neuron damage through the production of neurotoxic factors, such as reactive oxygen species and cytokines that are toxic to neurons. The neuron also has strong homeostatic mechanisms that can delay or prevent activation of apoptosis and necrosis. INSULIN RESISTANCE AND ALZHEIMER'S DISEASE: Insulin plays a role in Alzheimer's disease, as it is involved in the metabolism of beta-amyloid. Hyperinsulinemia and type-2 diabetes mellitus results in an increased risk of developing Alzheimer's disease, but its implications when the disease is already well established remain unknown. Treatment of central insulin resistance may be a promising avenue, not only in metabolic syndrom, but also in Alzheimer's disease. CONCLUSION: Increasing evidence suggests a role for oxidative stress, mitochondrial dysfunction, microglial activation and insulin resistance in pathogenesis of neurodegenerative diseases including Alzheimer's disease. PMID- 22924251 TI - Postoperative visual recovery following surgical treatment of suprasellar meningiomas. AB - INTRODUCTION: The purpose of this study was to investigate pre- and postoperative visual acuity in patients with meningioma in the area of optic chiasm. MATERIAL AND METHODS: This retrospective study included 43 patients with meningioma in the area of optic chiasm, who had been found to have impaired visual function according to anamnestic data and neuro-ophthalmologic examination which excluded the presence of any other eye diseases. The visual status was analyzed both preoperatively and postoperatively, i.e., 10 days, one month and six months after surgery. RESULTS: An improvement in visual acuity was recorded in 50% of the examined eyes (68.42% of patients), the most expressed changes being in terms of higher number of the eyes with normalized visual acuity and lower number of the eyes with severely reduced visual acuity after surgery. These changes were particularly prominent immediately after surgery, during the first ten days. CONCLUSION: The recovery of visual acuity after decompression in the area of optic chiasm is possible in cases where mechanical pressure on the nerve fibres and resulting fibre ischemia have not lasted long enough to lead to their irreversible damage. PMID- 22924252 TI - [Results of in vitro fertilization cycles at the Clinic for Gynecology and Obstetrics, Clinical Center of Nis]. AB - INTRODUCTION: Infertility affects 15-17% of reproductive age couples in our country. In vitro fertilization brought revolution in treatment of this problem, bringing hope to many couples around the world for more than 3 decades. The aim of this paper was to present results and experiences of implementation of this method of treatment at the Clinic of Gynecology and Obstetrics in Nis. MATERIAL AND METHODS: The study included the first 402 women who had undergone in vitro fertilization program at the Clinical Center of Nis. The data were statistically analyzed by basic descriptive methods. The main outcome measures were demographic features, cause of infertility, duration of stimulation, average gonadothropine consumption, number of oocytes per aspiration and embryos transferred, mode of conception as well as clinical pregnancy and aspiration rate. RESULTS: The two main factors were the male infertility and tubal factor inferitily, being 51.61% and 48.39%, respectively The classical method of in vitro fertilization constituted 72.40% of all cycles, while intra cytoplasmic sperm injection method was used in 27.60% of all cycles. The average number of embryos transferred was 2.75. The cycle cancellation rate was 15.05%. The clinical pregnancy rate per ermbryo transfer was 35.44%; while the live birth rate per embryo transfer was 26.53%. DISCUSSION AND CONCLUSION: Our success rates are comparable with those in other European countries, where for in vitro fertilization the clinical pregnancy rates per aspiration and per transfer were 29.0 and 32.4%, respectively in the observed period. For intra cytoplasmic sperm injection, the corresponding rates were 29.9 and 33.0%. The main difference from the European average was the average number of transferred embryos and lower percentage rate of intra cytoplasmic sperm injection as a method of conception. Results PMID- 22924253 TI - [Radiation-induced lung damage--etiopathogenesis, clinical features, imaging findings and treatment]. AB - INTRODUCTION: This review is related to the mechanism of development of radiation induced pneumonitis, its pathological, clinical and radiological features and therapy. The team treating cancer patients consists of radiation oncologists and oncologists, as well as general practitioners, pulmologists and radiologists for monitoring effects of therapy. Therefore, a different number of specialists should be familiar with the importance of diagnosis in order to avoid differential diagnostic error in relation to infection, relapse or metastasis, chemotherapeutic adverse effects. LUNG DAMAGE BY IONIZING RADIATION: Factors that influence the development of radiation pneumonitis are numerous: (1) the volume of irradiated parenchyma (2) the absorbed dose, (3) the number of fractions which divided the absorbed dose. (4) the size ofindividual doses per fraction, (5) radiation dose rate (the radiotherapy output device). Acute radioneumonitis is characterized by dyspnea, cough, and, rarely fever and chest pain. The timely treatment of the symptoms makes it easier for patients and reduces the likelihood of developing pulmonary fibrosis. DIAGNOSIS OF RADIATION PNEUMONITIS: There are no specific markers in serum or sputum that would definitely indicate the development of acute pneumnonitis. Changes in lung radiography and computed tomography may suggest its development; however, extra diagnostics information sometime needs to be obtained from magnetic resonance images and positron emission tomography to make diagnosis and choose the treatment. CONCLUSION: The longer survival results from new modalities of treatment applied in cancer patients, and the prevention of adverse effects of radiation therapy is getting more important since longlasting toxicity affects the life quality. PMID- 22924254 TI - Factors given by birth and oxygen therapy in relation to development of retinopathy of prematurity. AB - INTRODUCTION: Retinopathy of prematurity is a disease of the eye which affects the blood vessels of the retina and represents the most important cause of blindness and low vision in children worldwide. There are many risk factors given by birth and parameters of general health status that may influence this disease. The aim of this study was to investigate the significance of the factors given by birth and use of oxygen in relation to the development of premature retinopathy. MATERIAL AND METHODS: A two-year-long prospective study was done at the Institute for Child and Youth Health Care of Vojvodina. In this study the following parameters were examined: weight, gestational age as a factor given by birth and parameters of oxygenotherapy--the number of days on oxygenotherapy and the number of days of mechanical ventilation. The findings on the eye fundus were also taken into consideration. RESULTS: The test results suggest that the gestational age is the most important factor given by birth which determines the possibility of development of premature retinopathy. CONCLUSION: In fact, the most important risk factor for the development of premature retinopathy is premature birth. PMID- 22924255 TI - Treatment of pediatric patient with ruptured intracranial aneurysm--case report. AB - INTRODUCTION: Despite the contemporary diagnostics of intracranial aneurysms their treatment is still a great challenge. The decision when and if to apply a surgical or endovascular treatment of intracranial aneurysms should be made by a team of medical specialists which consists of a cerebrovascular neurosurgeon, neuro-radiologist and neuro-anesthesiologist. CASE REPORT: We report a case of a patient aged 16 who was admitted because of a sudden intensive headache followed by sickness, vomiting, and loss of consciousness. On admission the patient was conscious but sleepy. Glasgow Coma Scale score was 14 and the World Federation of Neurological Surgeons Scale grade was I. The computed tomography scan showed a massive subarachnoid haemorrhage. The computed tomography angiography and digital subtraction angiography revealed a ruptured saccular aneurysm in the left vertebral artery. An early treatment with the coiling of the lumen of the aneurysm was performed under general anaesthesia. On the tenth day the boy was discharged in good condition and without any neurological deficits. Six months after the intervention the patient was without symptoms and the control digital subtraction angiography showed the complete occlusion of the aneurysm. CONCLUSION: Intracranial aneurysms in children are more common in males and are predominantly localized in the posterior circulation. In addition, they are frequently of greater size and more complex architecture and they are associated with a lower incidence of clinically manifest vasospasm. According to previous experience, endovascular treatment of intracranial aneurysms in paediatric patients has proven to be a safe and efficient method with a small number of complications. PMID- 22924256 TI - [Polyostotic Paget's disease of bone: diagnostic dilemma in detection of bone metastases from prostate cancer]. AB - INTRODUCTION: Paget's disease of bone (osteitis deformans) is a rare metabolic disorder of bone remodeling with complex etiology. In the most cases, it is detected by coincidence, during nuclear medicine and radiological diagnostic procedures. Herein we report a case of advanced prostate cancer coexisting with asymptomatic Paget's disease. CASE REPORT: We present a 69-year-old patient, with biochemical recurrence two years after radical prostatectomy for localized prostate cancer and period of stable remission. During the evaluation of metastatic spread of prostate cancer, the bone scintigraphy with technetium diphosphonate showed diffuse areas of increased radiotracer uptake in the left leg long bones and focal changes in the axial part of the skeleton. Scintigraphic findings led to a differential diagnostic dilemma regarding etiology of bone changes, so it was supplemented by standard radiologic methods and laboratory evaluation of bone metabolism parameters. The existence of asymptomatic polyostotic Paget's disease and metastatic bone changes was found at the same time. CONCLUSION: Metastatic bone lesions, in this case from prostate cancer, and asymptomatic Paget's disease may closely resemble each other. They both need careful evaluation in order to determine the proper stages of malignant disease and selection of appropriate therapies for patients. PMID- 22924257 TI - [Massive hemorrhage of upper gastrointestinal tract caused by gastrointestinal stromal tumor of the stomach--case report]. AB - INTRODUCTION: Acute bleeding from the upper gastrointestinal system is a medical emergency which is followed by high mortality rate, ranging from 6 to 15% in spite of modern diagnostic methods and treatment. Bleeding from the upper gastrointestinal system may be caused by gastrointestinal stromal tumors of the stomach, which are mainly characterized by occult bleeding, while profuse bleeding rarely occurs accompanied by hemorrhagic shock. Gastrointestinal stromal tumors of stomach are the most common mesenchimal tumors of the gastrointestinal tract. CASE REPORT: In our study we showed a 60-year-old female patient with profuse bleeding from the stomach and the clinical picture of severe hemorrhagic shock, caused by gastrointestinal stromal tumor. An ovoid junction, raised towards the lumen, covered with ulcerated mucosa in several places and followed by massive arterial bleeding was found intraoperatively, after the performed gastrotomy. Histopathological examination with immunohistochemical analysis confirmed that this was a gastrointestinal stromal tumor of the stomach. DISCUSSION: Acute bleeding from the digestive system is a sudden and serious condition of the body. Urgent esophagogastroduodenoscopy is a sensitive and specific diagnostic and therapeutic method of choice. Massive bleeding from the upper gastrointestinal tract is very rarely caused by gastrointestinal stromal tumors, whose clinical picture is very heterogeneous and depends on tumor size and location. Abundant bleeding from the tumor is an indication for urgent surgical intervention. CONCLUSION: According to the literature massive hemorrhage of the upper digestive system can rarely be caused by gastrointestinal stromal tumor of the stomach. It is shown that abundant hemorrhage of the upper digestive tract can be caused with gastric gastrointestinal stromal tumor. Surgical resection is the main form of treatment of gastrointestinal stromal tumors of the digestive system and bleeding from these tumors caused by failure of endoscopic hemostasis. PMID- 22924258 TI - [Medicine in notafilia--part II]. AB - Only a few countries in the world have issued banknotes featuring portraits of doctors and health workers who have made their people and medicine world famous. The hereby presented banknotes are those issued in Germany featuring the portrait of Dr. Paul Ehrlich, a Nobel laureate; the Austrian banknotes with the portrait of a Nobel laureate Dr. Karl Landsteiner and of Dr. Sigmund Freud, the founder of modern psychoanalysis; the Greek one featuring the portrait of Georgios Nicholas Papanikolaou, who was a pioneer in early detection of pre-cancerous cervix lesions in women and who gave his name to the test "Papa test"; and, the one issued in Sweden featuring the portrait of Carl von Linnd, a court physician and the first President of the Royal Swedish Academy of Science. PMID- 22924259 TI - [The costs of urinary tract infection therapy with implementation of pharmacoeconomic guidelines at the Clinic for Infectious Diseases of the Clinical Center of Vojvodina]. AB - BACKGROUND/AIM: The Serbian health system does not have strict guidelines for the treatment of bacterial infections. The choice of treatment is empirical which is not necessarily the same compared to the treatment guidelines from countries with a developed pharmacotherapeutic practice. In this study we compared the difference between the current treatment and the treatment taking into account the latest pharmacotherapeutic and pharmacoeconomic guidelines in order to estimate clinical efficiency of antibacterial drugs that were given as a therapy of urinary tract infections and to evaluate pharmacoeconomic aspect of this therapy as well. METHODS: Our study included 100 patients that were randomly chosen and divided into 2 groups. The first group was treated in an ordinary way, while the second one was treated strictly in accordance with the guidelines (British National Formulary - BNF, and Senford Guide). In both groups of the patients we compared length of hospitalization, combination of the used antibiotics, progress as a whole in clinical picture, laboratory analyses and the price of the whole treatment. RESULTS: Analyzing these values independently and according to statistical tests we proved that there were no significant differences between two groups with regard to the progress in a clinical picture as a whole and the length of hospitalization. According to this analysis, however suggested treatment based on guidelines showed a saving of 34.48% in comparison with the usual system of therapy. CONCLUSION: Efficacy of current treatment of urinary tract infection and the treatment according to foreign guidelines is the same, but the costs of the treatment are lower if the guidelines of developed health care systems are applied. PMID- 22924260 TI - Clinical and functional evaluation of patients with acute low back pain and radiculopathy treated with different energy doses of low level laser therapy. AB - BACKGROUND/AIM: The main clinical phenomena in acute low back pain (LBP) with radiculopathy are pain and neurological disorders. Although some studies show that low level laser therapy (LLLT) has the ability to modulate inflammatory processes and relieve acute pain condition, the laser therapy dose protocol has not been yet completely established. The aim of this study was to investigate the effects of three different energy doses of LLLT in patients with acute LBP and radiculopathy. METHODS: The study included 66 patients with acute LBP and radiculopathy who had been randomly divided into three groups (22 patients each) received three different doses of LLLT. The patients were treated 5 times weekly, for a total of 10 treatments, with the following parameters: wave length 904 nm, frequency 3,000 Hz, average diode power 25 mW; energy dose of 0.1 J per point in the first group, 1 J per point in the second and 4 J per point in the third group; daily treatment time and accumulated energy were 16 s and 0.4 J in the first group, 160 s and 4J in the second group and 640 s and 16 J in the third group, respectively. The parameters of assessment before and after the therapy were: lumbar and leg pain measured by visual analogue scale (VAS), local and general functional changes (Schober test, manual muscle test, straight leg raise test and the modified North American Spine Society-Low Back Pain Outcome Instrument-NASS LBP). RESULTS: Highly significant improvements (p < 0.01) were noted in all the groups after LLLT with respect to all the investigated parameters. The VAS scores were significantly lower in all the groups without a difference between the groups (p > 0,05). Functional improvements were better in the third group treated with the dose of 4 J per point than in other two groups (p < 0.05). CONCLUSIONS: Three different energy doses of LLLT were equally effective in alleviating lumbar and leg pain without side effects, but the dose of 4 J per point seemed to be more effective in improving the activities of daily living and lumbar mobility. PMID- 22924261 TI - Treatment of Achilles tendon rupture using different methods. AB - BACKGROUND/AIM: Today there are controversies about searching for the ideal surgical method (conservatively with plaster cast, with open and percutaneous tenorrhaphy) for repairing a ruptured Achilles tendon. The aim of this study study was to examine the results of treating Achilles tendon ruptures in patients by using the following methods: percutaneous suturing, open surgery technique and non-surgical treatment by plaster cast immobilisation. METHODS: Forty two patients treated at our facility in the period August 2003 - September 2010 for Achilles tendon ruptures were included in the study. They were operated on by using different orthopedic procedures (percutaneous reconstruction of the Achilles tendon, open surgery, plaster cast only) and two anaesthesia technique (spinal aneasthesia and local infiltrational anaesthesia). The following parameters were monitored after interventions performed and compared: duration of hospital stay, postsurgical complications, incidence of the reruptures of the Achilles tendon and time for full leg functionality. RESULTS: The patients sustained their respective injuries in the following manner: 8 of them while pursuing sports activities, 24 while pursuing recreational activities, 4 at workplace, 4 while performing everyday activities, and 2 of the patients did not know how they had sustained their injuries. The average age of the patients was 40.5, with 37 (88%) men and 5 (12%) women. Surgeries were performed under spinal anaesthesia in 29 (69%) patients, and in 5 (12%) patients tenorrhaphy was performed under local anaesthesia. Anaesthesia was not used in 8 (19%) patients treated with plaster cast. We performed percutaneous reconstruction of the Achilles tendon in 19 (45%) patients. A total of 14 (33%) patients were treated under spinal anaesthesia, and 5 (11.90%) under local infiltrational anaesthesia with 2% xylocain. We treated 15 (36%) patients with open surgery. The patients treated conservatively stayed in hospital on average for up to 5 hours. Those who underwent an percutaneous surgery stayed 2 days and those who underwent an open surgery stayed 9 days. A total of 28 (66%) patients from the given series experienced no complications. The patients treated with open surgical reconstruction experienced skin complications ranging from inflammatory changes on the skin in 6 (14%) patients to dehiscence and skin necrosis in 3 (7%). The 5 (11.9%) patients whose ruptured Achilles tendon was treated percutaneously experienced temporary redness and delayed healing of the incision(s) longer than 5 mm. A total of 3 (7%) patients treated with open surgery and 1 (2%) patient treated with percutaneous tenorrhaphy had temporary peroneal nerve prolapses. A total of 7 (16.6%) patients had reruptures: 4 were treated with plaster cast, 2 underwent open surgery, and 1 was treated percutaneously. Out of the 8 patients who were treated with plaster cast, 4 sustained reruptures and 3 of the 4 had diabetes. CONCLUSION: Surgical treatment, percutaneous tenorrhaphy, performed in a small operating theatre under local anaesthesia, should be preferred in cases of fresh ruptures of the Achilles tendon. PMID- 22924262 TI - [Efficacy of Epley maneuver in treatment of benign paroxysmal positional vertigo of the posterior semicircular canal]. AB - BACKGROUND/AIM: Benign paroxysmal positional vertigo is one of the most frequent peripheral vestibular system disorders. The aim of this study was to examine the efficacy of the Epley maneuver in treating benign paroxysmal positional vertigo of the posterior semicircular canal (p-BPPV) and to discover possible causes of failure. METHODS: This prospective study included 75 patients. In all the cases medical history showed and the positioning Dix-Hallpike test confirmed the diagnosis of p-BPPV. We also performed clinical ENT examination, searching for spontaneous nystagmus, vestibulospinal tests, caloric test, and audiometry. All the patients were treated by the modified Epley canalith repositioning maneuver. The patients were followed up at the intervals of seven and, fourteen days, and one, tree, and six months and one year. The maneuver was repeated if vertigo and nystagmus on control positioning test persisted. The transition from positive into negative Dix Hallpike test after one or two Epley maneuver was considered as success in treatment. RESULTS: After the initial Epley maneuver the recovery rate was 90.7%, and after the second 96%. In three (4%) patients with secondary p BPPV, symptoms did not cease even after the second repositioning maneuver. The etiology of p-BPPV had a significant effect on the maneuver's success rate (p < 0.01), whereas duration of symptoms, age and gender had no effect (p > 0.05). After a successful treatment 11 (14.66%) patients had recurrent attack of BPPV during the first year. CONCLUSION: The Epley maneuver is very successful repositioning procedure in treating p-BPPV. The patients with idiopathic form p BPPV showed higher success rate with Epley maneuver than those with secondary p BPPV. PMID- 22924263 TI - [A comparative analysis of the influence of different types of Carbopol on the release rate of lithium-carbonate from matrix tablets]. AB - BACKGROUND/AIM: Hydrophilic matrix tablets represent the most commonly used oral dosage form. Carbomers used in the concentration of 10%-30% for preparation of matrix tablets, may significantly affect the profile of drug release due to the formation of hydrogel matrix tablets. The aim of this study was to compare the influence of different types of Carbopol (carbomers in the pharmacopoeia) on the release rate of lithium-carbonate and other pharmaceutical, technological, physical and chemical properties of the prepared formulations of matrix tablets. METHODS: Three different formulations of matrix tablets were made according to direct compression method. The tablets were of the following composition: carbomer, lactose monohydrate, magnesium-stearate, lithium-carbonate in the proportion 75:120: 5 : 300. The first formulation was made with Carbopol 971P NF, the second one with Carbopol 974 P NF and the third one with Carbopol 71G NF. The quantity of lithium-carbonate was determined according to the BP 2009, pharmaceutical and tecnological properties were examined in accordance with the regulations of Ph. Jug. V, whereas the release rate of lithium-carbonate from the formulations was examined by the application of dissolution test, prescribed in the monography 'Lithium Carbonate Extended-Release Tablets' in USP 26. RESULTS: The profile of lithium-carbonate release from matrix tablets with Carbopol 974P NF entirely complies with the regulations of USP 26, whereas the values obtained from the analysis of matrix tablets with Carbopol 971P NF and Carbopol 71G NF were considerably lower than the prescribed ones. In all the investigated formulations the content of the drug, mass variation and tablet hardness comply with the regulations set in pharmacopoeia. CONCLUSION: In the formulation of matrix tablets with lithium-carbonate, by the application of carbomers in the concentration of 15%, with Carbopol 974 P NF a favourable lithium-carbonate release profile was achieved, whereas in the formulations with Carbopol 971P NF and Carbopol 71G NF, the release rate was significantly lower than that given in the USP 26 monography. PMID- 22924264 TI - Asymmetries in numerical density of pyramidal neurons in the fifth layer of the human posterior parietal cortex. AB - BACKGROUND/AIM: Both superior parietal lobule (SPL) of dorsolateral hemispheric surface and precuneus (PEC) of medial surface are the parts of posterior parietal cortex. The aim of this study was to determine the numerical density (Nv) of pyramidal neurons in the layer V of SPL and PEC and their potential differences. METHODS: From 20 (40 hemispheres) formaline fixed human brains (both sexes; 27- 65 years) tissue blocks from SPL and PEC from the left and right hemisphere were used. According to their size the brains were divided into two groups, the group I with the larger left (15 brains) and the group II with the larger right hemisphere (5 brains). Serial Nissl sections (5 microm) of the left and right SPL and PEC were used for stereological estimation of Nv of the layer V pyramidal neurons. RESULTS: Nv of pyramidal neurons in the layer V in the left SPL of brains with larger left hemispheres was significantly higher than in the left SPL of brains with larger right hemisphere. Comparing sides in brains with larger left hemisphere, the left SPL had higher Nv than the right one, and then the left PEC, and the right SPL had significantly higher Nv than the right PEC. Comparing sides in brains with the larger right hemisphere, the left SPL had significantly higher Nv than left PEC, but the right SPL had significantly higher Nv than left SPL and the right PEC. CONCLUSION: Generally, there is an inverse relationship of Nv between the medial and lateral areas of the human posterior parietal cortex. The obtained values were different between the brains with larger left and right hemispheres, as well as between the SPL and PEC. In all the comparisons the left SPL had the highest values of Nv of pyramidal neurons in the layer V (4771.80 mm( 3)), except in brains with the larger right hemisphere. PMID- 22924265 TI - Diagnostical significance of dimethylarginine in the development of hepatorenal syndrome in patients with alcoholic liver cirrhosis. AB - BACKGROUND/AIM: Chronic consumption of alcohol during a longer period of time leads to the development of cirrhosis with the reduction in metabolic liver function and disorders in arginine metabolism. Hepatorenal syndrome (HRS) is the most severe complication of alcoholic liver cirrhosis. The aim of the study was to analyze disorders in arginine metabolism by monitoring concentrations of asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA) in patients with liver cirrhosis and HRS. METHODS: The study included three groups of subjects: a group of patients with cirrhosis and HRS (24 patients), a group of patients with cirrhosis without HRS (18 patients) and a control group composed of 42 healthy voluntary blood donors. Concentrations of ADMA, SDMA and L-arginine in plasma were measured in all groups using the high pressure liquid chromatography (HPLC) method. RESULTS: The concentration of SDMA was significantly higher in the patients with HRS compared to the patients without HRS and it was also higher than the values obtained from the healthy participants 1.76 +/- 0.3 micromol/L; 1.01 +/- 0.32 and 0.520 +/- 0.18 micromol/L, respectively; p < 0.01). The concentrations of ADMA were higher in the cirrhotic patients with HRS than in those without this serious complication of cirrhosis. The concentration of ADMA in all the examined cirrhotic patients was higher than those obtained from healthy volunteers (1.35 +/- 0.27 micromol/L, 1.05 +/- 0.35 micromol/L and 0.76 +/- 0.21 micromol/L, respectively). In the patients with terminal alcoholic liver cirrhosis, the concentrations of ADMA and SDMA correlated with the progress of cirrhosis as well as with the development of cirrhosis complications. In the patients with HRS there was a positive correlation between creatinine and SDMA in plasma (r2 0.0756,p < 0.001) which was not found between creatinine and ADMA. CONCLUSION: The obtained results demonstrate that the increase in SDMA concentration is proportionate to the progression of chronic damage of the liver and kidneys. Increased ADMA concentration can be a causative agent of renal insufficiency in patients with cirrhosis. PMID- 22924266 TI - [Responsibility of medical institutions for damages resulting from treatment]. PMID- 22924267 TI - Genetics of breast cancer: contribution of BRCA1/2 genes alterations to hereditary predisposition. PMID- 22924268 TI - Severe acute caffeine poisoning due to intradermal injections: mesotherapy hazard. AB - INTRODUCTION: Caffeine is indicated in the treatment of migraine headaches, as well as neonatal apnea and bradycardia syndrome. In mild poisoning, the most prevalent symptoms are nausea, vomiting, diarrhea, tremor, anxiety and headache. In more severe cases, symptoms consist of heart rythym abnormalities, myocardial infarction and seizures. Due to its common lipolytic effect, caffeine is used in mesotherapy, usually in combination with drugs of similar effect. We presented a patient with acute iatrogenic caffeine poisoning. CASE REPORT: A 51-year-old woman, with preexisting hypertension and hypertensive cardiomyopathy was subjected to cosmetic treatment in order to remove fat by intradermal caffeine injections. During the treatment the patient felt sickness, an urge to vomit, and a pronounced deterioration of general condition. Upon examination, the patient exhibited somnolence, hypotension and nonsustained ventricular tachycardia, which was sufficient enough evidence for further hospitalization. On admission to the intensive care unit the patient was anxious with increased heart rate, normotensive, with cold, damp skin, and visible traces of injection sites with surrounding hematomas on the anterior abdominal wall. Paroxysmal supraventricular tachycardia (PSVT) on electrocardiographic monitoring was found. The laboratory analysis determined a lowered potassium level of 2.1 mmol/L (normal range 3,5 - 5.2 mmol/L), and a toxicological analysis (liquid chromatography with ultraviolet detection) proved a toxic concentration of caffeine in plasma - 85.03 mg/L (toxic concentration over 25 mg/L). On application of intensive therapy, antiarrhythmics, and substitution of potassium, as well as both symptomatic and supportive therapy, there was a significant recovery. The patient was discharged without any sequele within four days. CONCLUSION: A presented rare iatrogenic acute caffeine poisoning occured due to massive absorption of caffeine from the subcutaneous adipose tissue into the circulation when injected directly into the tiny blood vessels, as evidenced by hematoma formation. Poisoning manifestations were registered in gastrointestinal, CNS (anxiety, somnolence) and cardiovascular (hypotension, ventricular tachycardia and nonsustained PSVT) system. In this era of mesotherapeutic treatment promotion, one should keep in mind toxic prevention, with application being carried out exclusively in a specialized institution. PMID- 22924269 TI - Successful resuscitation from two cardiac arrests in a female patient with critical aortic stenosis, severe mitral regurgitation and coronary artery disease. AB - INTRODUCTION: The incidence of sudden cardiac death in patients with severe symptomatic aortic stenosis is up to 34% and resuscitation is described as highly unsuccessful. CASE REPORT: A 72-year-old female patient with severe aortic stenosis combined with severe mitral regurgitation and three-vessel coronary artery disease was successfully resuscitated following two in-hospital cardiac arrests. The first cardiac arrest occurred immediately after intraarterial injection of low osmolar iodinated agent during coronary angiography. Angiography revealed 90% occlusion of the proximal left main coronary artery and circumflex branch. The second arrest followed induction of anesthesia. Following successful open-chest resuscitation, aortic valve replacement, mitral valvuloplasty and three-vessel aortocoronary bypass were performed. Postoperative pericardial tamponade required surgical revision. The patient recovered completely. CONCLUSION: Decision to start resuscitation may be justified in selected patients with critical aortic stenosis, even though cardiopulmonary resuscitation in such cases is generally considered futile. PMID- 22924270 TI - Rapunzel syndrome. AB - INTRODUCTION: Trichobezoars are foreign bodies in gastrointestinal tract, composed of hair. They occur mainly in children and adolescents suffering from trichotillophagia. They commonly occur in the stomach, but as they enlarge over time, they can extend through the pylorus into distal parts of the small intestine resembling a tail. This rare form of trichobezoar is named Rapunzel syndrome. CASE REPORT: We presented a 19-year-old female patient, who suffered from trichotillomania and trichotillophagia, which led to trichobezoar formation. Intra-abdominal tumour was suspected after initial clinical examination. Abdominal echosonography, endoscopy and abdominal computed tomography (CT scan) in the pre-operational period revealed trichobezoar formation. The patient was operated on and subjected to further psychiatric treatment. CONCLUSION: Trichobezoar should be differentially diagnostically taken into consideration in younger women with abdominal pain, nausea, vomiting, palpable abdominal mass and psychiatric disorders. Most trichobezoar cases require surgical treatment, whereas the patients need long-term psychiatric treatment and monitoring. PMID- 22924271 TI - Paraganglioma--a cause of hypertension in a young patient. AB - INTRODUCTION: Collections of neuroendocrine cells dispersed throughout the body are known as paraganglia and the tumor arising from these paraganglia are known as paragangliomas. Paragangliomas located along side the aorta are associated with the pheochromocytoma and they secrete and store catecholamines. CASE REPORT: We reported a 29-year-old woman with episodes of headache, palpitations, dizziness and sweats, associated with hypertension. Elevated urine catecholamines were consistent with pheochromocytoma. Nuclear magnetic resonance (NMR) was performed and the symptoms were caused by associated mediastinal and retroperitoneal paragangliomas. The tumors were surgically removed. In a 3-year follow-up period the patient had two recidivate lesions, one of them was surgically removed, and for the last one a 6-month follow-up was recommended, because urine cathecholamine level was not significantly elevated and blood pressure was normal. CONCLUSION: Clinical and imaging data of patients with extra adrenal paragangliomas are not specific. Many of them may be asymptomatic even when the lesion is large, but if tumor is functional, diagnosis may be easier. Patients should be initially evaluated by determining catecholamine level, followed by computerized tomography (CT) or NMR to locate the primary lesion. Since there are no definite microscopic criteria for the distinction between benign and malignant tumors, radical excision and prolonged follow-up is necessary. PMID- 22924272 TI - Mitral valve endocarditis during brucellosis relapse. AB - INTRODUCTION: Endocarditis is the most common cardiovascular manifestation of brucellosis with high mortality rate. Brucella is less accesable to antibiotic (but not for all) and relapse can occur after a various period of clinical latency. CASE REPORT: A 55-year-old farmer was diagnozed with acute systemic Brucella infection in May 2008 and treated with antibiotic therapy in regional hospital for two months and for three months after discharge. He began to feel myalgia, arthralgia, malaise, shortness of breath, abdominal pain, vomiting, diarrhoea and lost weight eight months after initial symptoms occured. Because symptoms progressed he was admitted to our hospital in February 2009. Based on a combination of epidemiological, clinical data (on admission he was catchetic, adynamic, dyspneic, hypotensive 80/50 mmHg, fever up to 39.5 degrees C), positive serological Wright test for brucellosis (1 : 5,120), and echocardiographic examination findings, the diagnosis of very severe relapse of brucellosis with mitral valve endocarditis, complicated with perforation of anterior mitral leaflet, severe mitral regurgitation and pulmonary hypertension was established. He was treated with a combined triple antibiotic therapy (vancomycin, ciprofloxacin and gentamicin, and swiched to regimen with doxycycline, gentamicin and imipenem, replacing gentamicin by rifampicin) for 4 weeks and for the next 2 weeks was receiving trimetoprime/sulfamethoxazole and rifampicin. The patients' condition was improved and he was operated. The diagnosis of infective endocarditis was confirmed intraoperatively. Mitral valve replacement was performed, and combined triple antibiotic treatment (amikacin + ciprofloxacin + cefazolin, for 2 weeks and cephazolin + doxycycline + rifampicin, for 2 weeks) was continued, following with two antibiotics (doxycycline + rifampicin) for 5 months. The patient completely recovered without any signs of infection 30 months postoperatively. CONCLUSION: A combined antibiotic therapy and surgery reduce complications and mortality associated with Brucella endocarditis and improve quality of patients' life. PMID- 22924273 TI - [Serbian physicians--writers of 19th century]. PMID- 22924274 TI - [Criminology and victimology of rape in context with war-like conflicts using the example of the former Yugoslavia and Rwanda]. AB - The topic of this article is sexual violence in context with war-like conflicts in the former Yugoslavia and Rwanda. The fundamental categories of sexual violence in war-like conflicts are described. The authors discuss the types of sexual violence as defined in the report of the UN Commission of Experts on the war-like conflicts in the former Yugoslavia. Four criminal trials were evaluated: three held before the International Criminal Tribunal for the Former Yugoslavia (ICTY) in The Hague/Netherlands and one before the International Criminal Tribunal for Rwanda (ICTR) in Arusha/Tansania. The defendants were found guilty of torture, crime against humanity and genocide. Potential procedures with respect to similar crimes in current or prospective conflicts are discussed. An alternative may be the assignment of medical personnel (for example of the German Federal Armed Forces). Finally, the post-war cooperation between the Institute of Legal Medicine at the University Medical Centre of Hamburg-Eppendorf as well as the medical and government institutions in Rwanda is presented, which has been going on since 2005. PMID- 22924275 TI - [Post-mortem examination prior to cremation--an instrument to verify the quality of medical post-mortems and uncover non-natural deaths?]. AB - The external post-mortem examination, its deficient quality and possible causes have been the subject of numerous political and professional discussions. The external post-mortem examination is the basis for the decision whether further criminal investigations are required to clarify the cause of death. It is thus an essential instrument to ensure legal certainty. Before cremation, a second external post-mortem examination is performed by a public medical officer to make sure that errors of the first post-mortem are corrected. In the present study, cases were retrospectively analyzed in which a forensic autopsy had been ordered on the basis of the results of the post-mortem examination performed before cremation. The entries on the death certificate regarding the manner and cause of death were compared with the autopsy results. Between 1998 and 2007, 387 autopsies were ordered after external examination before cremation. In 55 cases (14.2%), the autopsy revealed a non-natural death, although a natural death had been attested on the death certificate. In descending order, a wrong manner of death was attested by clinicians, general practitioners and emergency physicians. With regard to the place where the first external post-mortem had been performed the lowest error rate was seen in nursing homes. Concerning the cause of death, discrepancies between the first post-mortem and autopsy were found in 59.4% of the cases. In this respect, general practitioners and clinicians were ranking first, whereas in nursing homes the cause of death was wrongly assessed in over 70% of cases. At present, the medical post-mortem does not meet the required quality standards, especially with regard to legal certainty. Determination of the cause of death on the basis of the external post-mortem examination is a challenging task even for the experienced medical examiner. As to the categorization of the manner of death it has to be stated that non-natural deaths are often not recognized or that the possibility to certify a death as unclear is not sufficiently used. As a result, it seems important to demand intensive, qualified, additional training in external post-mortem examinations for physicians. PMID- 22924276 TI - [Fixation of cells for analysis by laser microdissection--comparative studies in forensic trace material]. AB - This paper is focused on the preparation of samples for laser microdissection (LM) in forensic casework. In forensic genetics, it is essential to preserve and separate cellular traces during sample preparation, as they are usually gathered in very small amounts and are often contaminated with undesired cells. This is made possible by laser microdissection, a technique developed to cut cells or tissue of a certain type from a microscopical specimen by UV laser and catapult them directly into a PCR reactor. This method minimizes the risk of getting inconclusive, mixed DNA profiles due to contamination by foreign DNA and also supplies information about the cellular origin of a DNA profile. A method for optimized fixation and staining of spermatozoa for laser microdissection was established. Four different fixation methods combined with two staining methods were tested on two different microscope slides. Moreover, the effect of a blocker pen to contain the specimen on the slide was investigated. PMID- 22924277 TI - [Differential diagnosis: blue gastric mucosa. Post-mortem staining of the gastric mucosa with methylene blue]. AB - An intense discoloration of the gastric mucosa or the gastrointestinal tract found at autopsy gives rise to the question of its cause. Such discolorations are mostly described in the context of intoxications. However, traditional foods and diagnostic procedures using indicator dyes can also lead to an unusual discoloration of the mucous membranes. The authors report on the autopsy findings in a man who died from a bleeding gastric ulcer and whose gastric mucosa showed intense blue discoloration. Experimental postmortem examinations (on stomachs) were performed with methylene blue, a dye used in gastroenterology, resulting in a blue discoloration resembling the appearance of the stomach in the autopsy case. Together with the outcome of the toxicological analyses, the experiments pointed to a diagnostic procedure using methylene blue (chromoendoscopy). PMID- 22924278 TI - [Morphology of low-velocity impact stains produced from single drops of blood]. AB - Systematic variation of blood droplet volume, the distance fallen and the surface (paper, wood, plastics, tiles) led to the conclusion that the size and the shape of the stains ("fingers", satellites) allowed to deduce the distance fallen but only if the actual surface structure was known. We found that detailed photography at the crime scene was necessary, yet experiments have to be performed due to the extreme influence of the actual surface texture on all characteristics (size, spines, peripheral spatter) of the blood stains. PMID- 22924279 TI - Adverse drug reactions associated with antiretroviral treatment among adult Ethiopian patients in a tertiary hospital. AB - BACKGROUND: Adverse drug reactions (ADRs) are frequently encountered among patients taking Antiretroviral Treatment (ART). The aim of this study was to describe the type and frequency of ADRs among adult Ethiopians on ART. OBJECTIVE: to describe the type and frequency of short term adverse drug reactions among adult Ethiopian patients on ART at Tikur Anbessa teaching Hospital in Addis Ababa, Ethiopia. METHODS: From October 2008 to December 2009, 228 HIV positive patients were enrolled to a tertiary teaching hospital in Addis Ababa. Patients were closely monitored for ADRs for a median observation period of 18 weeks (79 total person-years of observation). Time-dependent occurrence of clinical adverse effects and abnormal laboratory values as defined by the AIDS Clinical Trial Group were analyzed (41). RESULTS: A total of 392 ARV drug related ADRs occurred Mild GI disturbances (36.8%) and headache (35.9%) were the most frequently reported symptoms. Thirty (7.7%) of the ADRs were severe requiring change or interruption of therapy (19 hematological and 11 hepatotoxic). Severe hematological complications were anemia (4.8%), neutropenia (2.6%) and thrombocytopenia (0.9%). Anemia occurred earl), in the first 4 weeks of ART treatment. Hepatic toxicity was also seen early but continued throughout the observation period, decreasing over time. Other ADRs encountered were grade I/II toxicities of rash, peripheral neuropathy, and metabolic disturbances. CONCLUSION AND RECOMMENDATIONS: ADRs occurred frequently in patients receiving ART. Grade III/IV toxicity that required withholding or change of treatment occurred in nearly 10% of the patients. Regular clinical, and laboratory monitoring appropriate to centers with limited resources need to be devised to monitor toxicity of ART Patient education on the easily recognizable ADRs could also reduce severe drug toxicities. PMID- 22924280 TI - Factors associated with adherence to highly active antiretroviral therapy among children in two referral hospitals, northwest Ethiopia. AB - BACKGROUND: highly active antiretroviral therapy (HAART) results in improved survival, clinical, immunological and virological response for children. Adherence to HAART is one of the very important factors which determine treatment success and occurrence of viral resistance. The need for near perfect adherence to lifelong antiretroviral therapy (ART) during childhood is a major challenge in the administration of HAART to HIV infected children. OBJECTIVE: the study was aimed to determine the level of adherence and factors associated with adherence to HAART among children in Felege Hiwot and Gondar University referral hospitals. METHODS: institution based cross-sectional study was conducted on 204 children in the paediatric ART clinics of Gondar University and Felege Hiwot hospitals. Sample size was determined by single population proportion formula and all children on ART for > or = 1 month and coming to the clinic during the data collection period were studied Ethical clearance was obtained from the Institutional Review Board of the University of Gondar. Data were collected by four nurses from the caregivers and patient charts using a pretested and structured questionnaire after informed consent. Descriptive statistics were calculated to describe study population and medical characteristics of participants while binary and multiple logistic regression analyses were used to determine the effect of factors on the outcome variable. RESULTS: The study included 204 children (123 from Flege Hiwot and 81 from Gondar). One hundred and seven (52.4%) were males and 97(47.6%) were females. Majority (82.4%) of caregivers were females. Thirty days optimum (> or = 95%) adherence rate was 80.9% for children. Adherence counseling before initiation (OR=4.37, 95%CI 1.17 - 16.37), caregiver formal education, (OR=4.85, 95%CI 1.89 - 12.39) and caregiver's ability to identify ARV drug correctly (OR = 8.61, 95%CI 2.59-28.68) were positively associated while care giver substance use (OR=0.31, 95%CI 0.10 - 0.93) was negatively associated with adherence as compared to their counter parts. CONCLUSION: optimum adherence rate to HAART in the study population was lower than the recommended Adherence counseling, caregiver education, substance use by caregiver, identification of ARVs determined adherence to HAART of children. Adherence assessment and counseling efforts should be continually integrated with ART for children and their caregivers. PMID- 22924281 TI - Predictors of carer-burden in schizophrenia: a five-year follow-up study in Butajira, Ethiopia. AB - OBJECTIVE: We assessed carer-burden and its predictors in a traditional rural Ethiopian community in order to establish the longitudinal course of carer-burden and factors predicting changes. METHODS: Using a 5-year follow-up data from the ongoing Butajira outcome study on SMI, carer-burden was assessed annually with the Family Interview Schedule (FIS). Multilevel modeling was used to identify clinical predictors of severity and rate of change of burden. RESULTS: Scores in all domains of carer burden decreased over time, although the greatest reduction was seen in the first year. In a univariate analyses, longitudinal reduction in burden score was predicted by longer period in remission during follow-up, while negative and positive symptom severity scores predicted higher burden score. In the fully adjusted model, poor social support predicted higher burden score (beta=0.38, 95%CI 0.04, 0.72), and longer period in remission predicted lower level of carer-burden (beta = -0.49, 95%CI = -0.89, - 0.10). Reduction in positive symptoms was associated with the instantaneous rate of reduction of burden score (beta = -0.03, 95%CI - 0.05, -0.01). CONCLUSION: There is a significant reduction in carer-burden over the years in all burden domains. Providing accessible mental health care has the potential to alleviate carer burden, as positive symptoms are believed to be more amenable to intervention. The study also indicates that remission is associated with reduction in carer burden. PMID- 22924282 TI - Hospital acquired infections among surgical, gynaecology and obstetrics patients in Felege-Hiwot referral hospital, Bahir Dar, northwest Ethiopia. AB - BACKGROUND: Hospital-acquired infection is an important public health problem that contributes to significant morbidity and mortality worldwide. OBJECTIVE: The aim of this study was to assess the prevalence and risk factors of hospital acquired infections and the antibiotic susceptibility pattern of bacterial isolates in Felege-Hiwot referral hospital. METHODS: The study was conducted during April-August 2009. A total of 1383 patients admitted to Surgical and Gynecology/Obstetrics wards were followed throughout their stay in the hospital for development of infections. Data on sociodemographic, underlying diseases and risk factors were collected and analysed Laboratory investigations including culture, biochemical tests, Gram staining and antibacterial sensitivity tests using disc diffusion methods were done. RESULTS: Of the 1383 patients assessed 961 surgical, 333 obstetrics and 89 gynaecology patients assessed, 17.1% 21.0% and 13.5% developed infections, respectively. The over all incidence of hospital acquired infections was 246 (17.8%) with 251 (18.1%) episodes of bacterial infections. Urinary tract and surgical site infections were detected in 118 (48%) and 112 (45.6%) of the cases, respectively. Of the bacterial isolates, 132 (52.6%) were gram negative and 119 (47.4%) gram positive. Escherichia coli, Klebsiella pneumoniae, Psuedomonas aeruginosa, were the dominant gram negative isolates accounting for 49 (19.5%), 36 (14.3%) and 26 (10.4%), respectively. On the other hand, Staphylococcus aureus, coagulase negative staphylococci, and Enteroccocus species were isolated in 91 (36.3%), 18 (7.2%) and 10 (4.0%), respectively. Surgery, catheterization, underlying diseases, antibiotics prophylaxis and length of hospital stay were risk factors for infection (P<0.0001). Most, >80% of isolates showed high rate of resistance to ampicillin, chloramphenicol, and amoxacillin-clavulanic acid CONCLUSION: The incidence of surgical site infection in surgical and UTI in obstetrics patients was high. Escherichia coli from urinary tract infection and Staphylococcus aureus from surgical wounds were predominant isolates. The isolates showed high resistance to common antibiotics. PMID- 22924283 TI - Perforated peptic ulcer disease in Zewditu Hospital. AB - BACKGROUND: Peptic ulcer perforation is a serious complication of peptic ulcer disease with a significant morbidity and mortality. OBJECTIVE: To evaluate 76 patients operated for peptic ulcer perforation and analyse the associated factors in Zewditu Memorial Hospital, Addis Ababa from September 2006 to August 2008. PATIENTS AND METHODS: A retrospective analysis of medical records of 76 patients who were operated up on for perforated peptic ulcer over a two year period (2006 2008). RESULTS: The male to female ratio was 6.6:1 with a mean age being 31.5 years. The most common presenting symptom was abdominal pain in 76 (100%) patients. History of smoking and khat chewing was documented in 53/64 (82.8%) and 48/64 (75%) of the patients respectively. Twenty five per cent of the patients gave no history of previous peptic ulcer disease. Seventy patients (92.1%) presented after 48 hours of their illness. The mean hospital stay was 14.5 days. Leucocytosis was found in 31.6% of the cases. Sixty five (85.5%) patients had duodenal ulcer perforation. Postoperative complications occurred in 24 (31.6%) patients. Twelve (15.8%) patients died in the hospital. CONCLUSION: Early presentation of patients and change in life style may reduce morbidity and mortality in patients with peptic ulcer perforation. PMID- 22924284 TI - Normal liver size measurement in Ethiopian children below thirteen years of age, Black Lion Hospital, Addis Ababa, Ethiopia. AB - BACKGROUND: Ultrasound is an easy, safe and accurate imaging modality. It helps in safe evaluation of liver and measure the size to determine the normal value. Normal value for liver size by ultrasound has to be determined in different age group and its variation with sex, height and weight has to be seen to detect hepatomegally. Studies done on the normal size of the liver by ultrasound are limited in Ethiopian children. OBJECTIVE: To estimate normal range of liver size in children below 13 years of age and determine variation of liver size with age, sex, height and weight. MATERIAL AND METHODS: A cross-sectional study was done, among 384 children (236 males and 148 females) below 13 years of age. The study was done at Tikur Anbessa Specialized Teaching Hospital, Addis Ababa, Ethiopia. Age, sex, height and weight recorded, and liver size was measured along mid clavicular line and mid sternal line. Pearson's correlation coefficient and linear regression model were used to assess the relationship between age, sex height and weight and liver size. RESULT: The liver size increased progressively from birth to 13 years with accelerated growth in the first year. Mean (SD) of liver size on mid clavicular line were 9.46cm (1.77)and range was 8.6, and on mid sternal line Mean (SD) were 4.6 (1.14) and the range was 5.1. It had statistically significant correlation (p< 0.05) with age, height and weight, with strong correlation with height. But there were no significant difference in liver size seen between male and female. CONCLUSION: Our study demonstrated the normal range of liver size. It also showed the variation in liver size with age, sex, height and weight, with best correlation to height, but no variation in liver size between males and females. This study can be used as a background for further study of large population. PMID- 22924285 TI - Initial clinical experience of tube-shunt surgery in Ethiopian patients with refractory glaucoma. AB - BACKGROUND: In Ethiopia, it is not uncommon to encounter refractory glaucoma cases that could be managed with tube-shunt surgery. Tube-shunt implant surgery has been a standard procedure option and widely used for various forms of refractory glaucoma. OBJECTIVE: To described the initial experience and outcome of Ahmed Tube shunt implant for refractory adult Ethiopian glaucoma cases. METHODS: Retrospective review of consecutive adult patients with refractory glaucoma who underwent Ahmed glaucoma valve implant at the Department of ophthalmology, Menelik II Hospital, Addis Ababa between April 2009 and December 2010. MAIN OUTCOME MEASURED: intraocular pressure (IOP), visual acuity, use of supplemental medical therapy and surgical complications. Success was defined as IOP greater than 5 and less than 22 mmHg with at least 30% reduction in IOP from preoperative levels with and without supplemental glaucoma medications, no additional surgeries to lower the IOP and without visual loss of light perception from devastating postoperative complications. RESULTS: Thirteen eyes of 12 patients (10 men, 2 women; mean age 52.4 +/- 15. 7) who underwent glaucoma tube shunt drainage surgery with Ahmed-tube valve were included in this analysis. The mean preoperative IOP was 31.38 +/- 8.67 mmHg with 2.23 +/- 0.44 antiglaucoma medications. Postoperatively, the mean IOP reduced to 15.52 +/- 8.80 mmHg at 1 week, 14.77 +/- 6.39 mmHg at 1 month, 16.62 +/- 4.48 mmHg at 3 months, and 17.15 +/- 3.87 mmHg at 6 months. The reduction from the preoperative mean IOP at last follow up was 45.3% with 1.08 +/- 0.44 supplemental glaucoma medications. The success rate of IOP controlling according to the definition was 76.9%. The pressure remained below 18 mmHg with and without medication in 9/13 (69.2%) eyes, while three eyes required no medication at all till the last follow-up with sustained IOP < 15 mmHg. At the last follow-up the visual acuity reduced by > or = 2 lines in two eyes while one patient's vision worsened from counting finger of one meter to hand movement. Visual improvement of one and two lines documented in two eyes. Hypotony, Tube-corneal touch, acceleration of cataract, choroidal effusion, flat anterior chamber, visual reduction and tube exposure were the types of complications encountered in 6 eyes, while 3 eyes had more than one complication. CONCLUSIONS: The study has shown that tube-shunt implant to be effective in lowering intraocular pressure in refractory glaucoma cases. The few cases reported are indicators of the importance of the procedure in salvaging vision of patients with refractory glaucoma and the need of large scale prospective study in the country. PMID- 22924286 TI - Perspectives on optimization of vaccination and immunization of Ethiopian children/women: what should and can we further do? Why and how? AB - BACKGROUND: Vaccination and immunization of children and child-bearing women, in particular, is uniquely important public health intervention Ethiopia inclusive. In spite of the promising progresses, much is desired toward the ultimate optimization, effectiveness and protection. OBJECTIVES: This analytical discourse recourse piece of work aimed at flagging the optimization perspectives on the basis of readily available information. CONTEXT, MATERIALS AND METHODS: The study emerged consequent to the review and capacity enhancement workshop of experts on Reaching Every District (RED) strategy of the Eastern and Southern African countries which was hosted by the WHO Afro Country Support Team for Eastern and Southern Africa in Harare, Zimbabwe, 28 February, - 03, March 2012. The study, essentially, is a qualitative analytical review of the pertinent literature with a particular focus on Ethiopia. Both peer reviewed and published and gray (unpublished) pertinent literature were solicited and reviewed systematically. The analytical discourse focused on performance progresses, achievements, opportunities, gaps/shortcomings, challenges and threats and perspectives. Vaccination-immunization performance evidences which were consolidated by the WHO Afro Country Support Team served the starting point to the central analytical discussion. KEY FINDINGS AND REFLECTIONS: Without underestimating the progresses and successes registered thus far, however, there indeed are quite many areas that warrant further discourse and/or recourse in Ethiopia in particular. Compared with other member countries, the size of the unimmunized, reporting quality, fragileness of systems, weak capacity, resource limitation, and others in particular respect to Ethiopia deserve further concerted attention. Districts with under 80% DPT3 coverage were still too many for Ethiopia by 2010/11. Whilst the challenges appeared prevalent, but more so effective and maximal use of the readily available opportunities appeared even more crucial. CONCLUSIONS: Further and dynamic optimization is desired more than ever before. Presumably promising and realistic enough recommendation perspectives are duly highlighted. PMID- 22924287 TI - Adamantinoma of tibia in Ethiopia: the first bone transplant in Ethiopia. AB - Adamantinoma of long bones is an extremely rare tumor with no report, to authors' knowledge from neither Ethiopia nor Africa. We are reporting a 25 year old female college student with one and half years history of right mid leg pain and swelling with radiologically and histologically proven adamantinoma of right tibia. At CURE Hospital, she had undergone complete excision of the tumor with histologically documented clean margins. The limb was salvaged by reconstructing with a fresh frozen tibial allograft obtained from the USA and an interlocking intramedullary nail (SIGN nail). Such insertion and incorporation of huge allograft using SIGN nail and saving a limb is the first surgery in Ethiopia. The gradual incorporation of the allograft at different months during follow-up is elucidated with clinical signs of healing. CONCLUSION: At times, limb salvage surgery and technology should be offered to selected patients with a chosen type of bone tumor. PMID- 22924288 TI - Adult Langerhans cell histiocytosis in a middle aged Ethiopian woman. AB - Langerhans' cell histiocytosis represents a diverse group of rare disorders characterized by proliferation and infiltration of various organs by bone marrow derived abnormal Langerhans' cells. These diorders exhibit varied patterns of organ involvement, age distribution, prognosis and clinical manifestation. Here in we discuss an adult presentation of the disease in a 43 years old lady and summarize the latest recommendations regarding the classification, pathogenesis, work up and treatment of adult patients with these disorders. PMID- 22924289 TI - Squamous cell carcinoma of the esophagus presenting with features of intracranial space occupying lesion. AB - We are reporting on a rare case of a male patient with squamous cell carcinoma (SCC) of the esophagus presented itself clinically as a pure intracranial space occupying lesion with symptoms of abnormal body movement, hemiplegia and failure to communicate. PMID- 22924290 TI - Have BSN? Will hire. PMID- 22924291 TI - Nurses address staffing and other professional issues at ANS's national meeting. PMID- 22924292 TI - Affordable Care Act is still the law. PMID- 22924293 TI - Opportunities for APRNs through state health insurance exchanges. PMID- 22924295 TI - Participants at ANA conference learn strategies to help themselves and their patients. PMID- 22924294 TI - Asking questions, finding solutions. PMID- 22924296 TI - History of caesarean hysterectomy. AB - Caesarean hysterectomy evolved as a life-saving procedure following caesarean delivery. The concept underlying caesarean hysterectomy dates back to the mid 1700s and with a description of the procedure performed on laboratory animals. Eduardo Porro of Milan performed the first planned caesarean hysterectomy in which both the infant and the mother survived. He documented his operation in a paper published in 1876. Porro advocated hysterectomy combined with caesarean section to control post partum haemorrhage and to prevent infection. The maternal death rate following the operation remained high, but was substantly below the rate prior to the introduction of the procedure. The Porro procedure contributed to more favourable outcome for both the mother and the infant, having sterility and premature menopause as its side effects. Fortunately, the need for the procedure was soon minimised following the proposal to close the uterine incision with sutures. Although elective caesarean hysterectomy is still a controversial issue, there is no doubt that emergency post partum hysterectomy in case of massive obstetric haemorrhage is potentially life-saving. Over the past decades, the availability of potent uterotonics and broad-spectrum antibiotics, the development of embolisation techniques, and new methods of vessel ligation, have markedly reduced the need for caesarean hysterectomy, which, however, remains an important procedure in modern obstetric practice. PMID- 22924297 TI - [Friedrich von Esmarch--surgeon, one career]. AB - Friedrich von Esmarch was born in 1823 in Germany and he is one of the greatest surgeons of the Germany of that time. Fridrich von Esmarch introduced the Esmarch tourniquet, which enables operative field bloodless. This revolutionary innovation is still present in the orthopaedic surgery all around world, as well as for the first line hemostasis. Beside this, Esmarch also improves others fields of surgery: immobilizations, methods of antiseptic surgery, modified Esmarch mask for anesthesia. He joined few wars and had a rang surgeon-general. Although his experience was primary from the trauma, he also introduced the training courses of the First aid for the ordinary people, making medicine of that time more modern and efficient PMID- 22924298 TI - Radiofrequency ablation for Barrett's esophagus high-volume center initial results. AB - INTRODUCTION: Barrett's esophagus (BE) is a well established precursor of esophageal adenocarcinoma. Both, surveillance and therapeutic strategies have been proposed over the years. Recent deve-lopment of endoscopic radiofrequency ablation (RFA) brought new perspectives in the treatment of BE, with excellent initial results. METHODS: The study of 40 pts with macroscopically visible BE on endoscopy and biopsy proven goblet cells presence, was conducted from January 2010 until March 2012. In all pts a complete symptomatic, endoscopic and manometric evaluation was performed. Initially RFA HALO 90 and 360 were performed in 28 and 12 pts respectively. Repeated treatments were conducted in 7 pts. The overall number was 50, while the mean number of RFA procedures per patient was 1.25. RESULTS: The mean circumferential length and maximal extent of BE were 1.61 and 3.29 cm respectively. We did not encounter esophageal perforation or hemorrhage during the procedure. Complications were transient short-term retrosternal pain (23 pts) and dysphagia (11 pts). Three months after the RFA mean values of cumulative symptom and heartburn score dropped significantly (p < 0.05). Functional diagnostics did not disclose any statistically significant decrease of lower esophageal sphincter pressure or esophageal body contraction amplitudes. One year foIlow-up was obtained in 26 pts and revealed a complete macroscopically visible BE eradication. So far, in 19 pts a laparoscopic Nissen fundoplication was performed up to 3 months after complete RFA BE eradication. CONCLUSION: HALO RFA procedure is safe and very effective in the treatment of pts with BE, does not lead to esophageal function impairment, and produces no long term and serious side effects. PMID- 22924299 TI - Talar injuries--the orthopaedic challenge. AB - Injuries of the talus represents an important part of the foot and ankle trauma. Since talar bone connect the lower limb and foot, the sequelas of its trauma could have significant influence on the function of the whole lower limb and gait. The specific vascularization of the talus results in delayed union and even in the avascular necrosis. The diagnosis of the fractures of the talus can be made on the x-rays, but sometimes real picture of the fracture pattern can be seen only in the CT scans. Ocult fractures such as osteochondral fractures and avascular necrosis can be exactly detected on MRI in aim not to be overlookded as the ankle sprain diagnosis. The precise reduction and stable internal fixation is mandatory in the treatment to enable the anatomical position of the talonavicular, talocrural and subtalar joint and to make possible early motion and rehabilitation, without weight bearing. On the other hand, crushed fractures, open fractures and the Hawkins III-IV fractures with the dislocations of the talar body sometimes needs salvage procedures like Blair or tibio-talar or tibio calcaneal fusion. PMID- 22924300 TI - Influence of second or multiple tumours on the prognosis of patients with colorectal cancer. AB - BACKGROUND: Colorectal cancer is one of the most common forms of cancer in the Western world. A wide variety of prognostic factors for colorectal cancer have been identified. There is, however, a paucity of literature addressing the influence of multiple primary carcinomas on prognosis. We conducted the present study in order to investigate the influence of second or multiple primary tumours on the prognosis of colorectal cancer patients. PATIENTS AND METHODS: From 1992 to 2005, 1500 patients underwent surgery for colorectal cancer at the University Hospital of Luebeck. Of these, 276 patients (19%) had multiple primary malignant tumours. We performed statistical analyses only on patients who underwent surgery with curative intent in order to minimise additional prognostic factors. The patients were divided into groups according to the time of multiple primary tumour occurrence. Data were analysed for various variables. RESULTS: We did not detect any significant differences in survival either between the various groups or between patients with and without multiple primary tumours. CONCLUSION: The presence of multiple primary carcinomas is not an independent prognostic factor in patients with an index tumour of the colorectum. Multiple primary tumours are thus not necessarily associated with a poorer outcome and patients should receive curative intent surgery and appropriate follow-up care. PMID- 22924301 TI - Expression of neural cell adhesion molecule in renal cell carcinoma. AB - Neural cell adhesion molecule (NCAM) is important for cell migration and it could be expressed in some renal cell carcinoma (RCC). In recent decades, the incidence of RCC has been steadily rising by 2-4% each year. In this study NCAM expression and correlation with nuclear grade in different RCC were analyzed. We analyzed NCAM expression on 7 different RCC cell lines and 32 different RCC by immunohistochemistry, immunofluorescence, Western blot and FACS analysis. NCAM expression is detected in 6 cell lines and 16 RCC cases. NCAM-140 kDa isoform is expressed in different RCC and RCC cell lines. NCAM expression in non-invasive clear cell RCC is lower than in clear cell RCC with high nuclear grade. Expression of NCAM is not exclusive for specific RCC type, so NCAM can not be used as a specific diagnostic marker for RCC. NCAM expression is in correlation with nuclear grade in clear cell RCC, suggesting that NCAM expression is involved in aggressive behavior and metastatic potential in RCC. PMID- 22924302 TI - The results of treatment of primary brain tumors in children. AB - During the period of 2009-2011 in UCH in Belgrade, we treated 22 patients with brain tumors. Treatment included the diagnosis and therapy that included surgery and postoperative neuroradiological follow-up of all patients regardless of whether radiotherapy was conducted with or without chemotherapy. The most frequent were low grade astrocytomas and medulloblastomas. Patients with supratentorial localization of tumor had significantly smaller neurological sequelae compared with patients with infratentorial as well as patients diagnosed with low grade astrocytomas of any localization. From 10 patients with supratentorial localization, 7 of them had no neurological deficit, while from 11 patients with infratentorial localization, 3 of them were Without deficit. Patients with histological diagnosis of low grade astrocytoma of any localization had less neurological deficits compared with other tumors. From 7 low grade astrocytoma in 5 of them there was no neurological deficit, while only in one patient residual tumor was verified. In 7 patients the rest of the tumor was diagnosed, while in 14 patients no residual tumors was diagnosed during follow-up based on the MRI diagnosis. Surgery, postoperative radiotherapy and chemotherapy in some cases represent an effective therapeutic approach in the treatment of brain tumors in children. PMID- 22924303 TI - Malignant disease in renal transplant recipients--our experience. AB - Kidney transplantation is a treatment of choice for patient with end stage renal disease. Chronic renal failure is characterized with weak cellular and humoral immunity. In our paper we present our experience with presence of malignancy in renal transplant patients. Urology clinic in Belgrade transplanted 411 patients over the period of 16 years. Living donor transplantation was performed for 272 and cadaveric kidney transplant for 139 patients. In the postoperative follow up, malignancies were diagnosed in 7 of the transplanted patients. Three patients developed basal cell skin carcinoma, one was diagnosed with adenocarcinoma of the transplanted kidney, one developed transitional cell carcinoma of the bladder and testicular tumors were diagnosed in two patients. Postoperative immunosuppressive therapy usually double or triple when patients are in the immunological high risk group. Incidence of malignancy according to big health centers is around 1 in every 1000 transplanted patients. It is also noted the rise of incidence of malignancies in transplanted patient in over 50%. PMID- 22924304 TI - Tumors of the horseshoe kidney--characteristics and literature review. AB - The aim of this paper is to point out the significance of the rare urinary system anomaly such as horseshoe kidney. Tumors of the horseshoe kidney are rarely described as single cases in literature. Bilateral tumors of the horseshoe kidney can present a health and therapeutically challenge. In this paper we have analyzed characteristics of the horse shoe kidney tumors and their diagnostics. Primary means of the horseshoe kidney tumors treatment are surgical with different techniques depending on the size, presentation of the tumor and other indications. The review of the available literature is also included. PMID- 22924305 TI - Urinary PSA in monitoring of patients with prostate cancer. AB - OBJECTIVE: To estimate the value of urinary prostate specific antigen (uPSA) determination in the monitoring of prostate cancer (PCa) patients. MATERIAL AND METHODS: From January 2001 to December 2011, uPSA was determined in 397 patients. There were 265 patients with benign prostate, 19 with prostatitis and 113 with prostate cancer. Radical retropubic prostatectomy (RRP) was performed at 65 patients, while 48 patients had PCa received antiandrogen therapy. RESULTS: Average uPSA value in the patients with benign prostate hyperplasia (BPH) was 190.8 +/- 184.2 ng/mL. Average uPSA in the patients with PCa was 287.5 +/- 303.4 ng/ml and it was not significantly different from BPH group. The average uPSA in the prostatitis group was 113.1 +/- 148.5 ng/mL, and 16.4 +/- 36.7 ng/mL in the post RRP group. During antiandrogen therapy, uPSA and PSA correlated significantly (r = 0.49). CONCLUSION: The uPSA level reflects the response of normal prostatic and urethral secretory cells on total androgen activity. The uPSA level cannot distinguish the cases with BPH and cases with PCa. In addition, in the patients after RRP, uPSA reflects local urethral PSA production and has no role in the diagnosis of PCa recurrence. However, uPSA is better indicator of androgen suppression than testosterone (T), as it reflects the effect of suppression of all androgens, not only T. PMID- 22924306 TI - The effect of intraocular pressure on visual field after trabeculectomy in patients with primary open angle glaucoma. AB - PURPOSE: To compare the mean intraocular pressure (IOP), peak IOP and percentage reduction in IOP in the first five years following trabeculectomy between the patients with progressed visual field loss and the patients with stable visual fields. MATERIAL AND METHODS: Thirty-six eyes of 36 patients were followed for five years after their first trabeculectomy with tonometry and automated perimetry (Octopus 500EZ, program G1). The rate of change of the visual field was measured by linear regression analysis of the mean sensitivity value (dB) of each field test versus time (month). Based on the statistical significance of the slope of the regression line (Spearman p value of the correlation coefficient less than 0.05), patients were divided into two groups: with significant negative slope of the regression line (group with progressed visual field loss) and with non-significant slope of the regression line (group with stable visual field). The mean IOP values and percentage of IOP reduction at the end of each of the first five years after surgery were compared between the group with progressed field loss and group with stable fields by using Mann-Whitney U test. RESULTS: Patients with progressed visual field loss had higher mean IOP, higher peak IOP and less reduction in pressure after the operation than patients with stable visual field. The mean IOP at end of the two year postoperative period was significantly higher in patients with progressed visual field loss (21.98 +/- 3.38 mmHg) than in those with stable fields (17.48 +/- 4.80 mmHg). The mean percentage reduction in IOP at the end of two year postoperative period was significantly less in patients that showed progression of field loss (21.84%) than in those with stable fields (41.0%). CONCLUSION: Prognosis for further field loss seems to be better if postoperative pressure is at lower levels and greater percent reduction of IOP is obtained after surgery. The data that predict better prognosis is the mean postoperative IOP value of approximately 18 mmHg or less resulting from at least 35% of IOP reduction. PMID- 22924307 TI - Single-incision laparoscopic cholecystectomy--initial experience with different multichannel ports. AB - Single-incision laparoscopic cholecystectomy is a relatively new minimally invasive surgical technique in treatment of benign gallbladder diseases. It is considered a bridge technique between conventional laparoscopic cholecystectomy (LC) and NOTES. We are presenting our initial experiences in SILC (single incision laparoscopic cholecystectomy). Seventeen patients underwent SILC (11 women and 6 men) with an average age of 43 years. Mean BMI score was 29,4 kg/m2. The mean operative time was 93,5 minutes. There were conversions to conventional LC in two cases (11,6%). Average pain score measured on visual-analogue scale (VAS) 8 h after the operation was 2,00. All patients expressed satisfaction with achieved cosmetic effect. We conclude that SILC is safe and feasible procedure, with excellent cosmetic effect, but further prospective studies are required before SILC can be generally accepted. PMID- 22924308 TI - Knowledge and occupational exposure to blood and body fluids among health care workers and medical students. AB - INTRODUCTION: Health workers and medical students are at occupational risk of blood-borne diseases during the accidents, that is, via percutaneous injury or entry of blood or body fluids through the mucosa or injured skin. OBJECTIVE: to review and analyze the knowledge, attitudes and perception of risks of bloodborne diseases of the clinical course students and health workers as well as the frequency of accidents. MATERIAL AND METHODS: Cross-sectional study was carried out among the students of the Faculty of Medicine in Belgrade, and health workers of the Clinical Center of Serbia. The subjects responded anonymously to questionnaire specially designed for the study. RESULTS: Both students and health workers were aware, in a high percentage, of the fact that the risk of hepatitis B spread was about 30%. Significantly more students gave affirmative reply that blood as biological material was a potential hazard of HIV infection spread (p = 0.001), and significantly more students knew that HIV would not be spread by sweat (p = 0.001). Hepatitis B vacci-nation was administered only to 24.1% of students and 71.4% of health workers. About 10% of students and 65.5% of health workers experienced some accident. There was no significant difference of accidents bet-ween nurses/technicians and physicians (p > 0.05), as well as of accidents and a total length of service (p > 0.05). The majority of accidents occurred during the use of needle/sharp object (in 27.3% of students and 33.1% of health workers). About 40% of students and slightly over a half of the workers reported the accidents to appropriate authorities. Additional education in this field is considered necessary by 73% of students. CONCLUSION: During the studies and via continuous medical education it is necessary to upgrade the level of knowledge on prevention of accidents, what would, at least partially, influence their reduction. PMID- 22924309 TI - Radical retropubic prostatectomy--experience of two urological departments. AB - We have analyzed oncological and functional results of the patients who underwent radical retropubic prostatectomy for treatment of localized prostate cancer. MATERIAL AND METHODS: In the period of 4 years, from 2007. to 2011. on two analyzed urological departments there have been 32 patients who underwent surgical treatment for treatment of localized prostate carcinoma. All of the patients underwent radical retropubic prostatectomy. Patient age was in range from 57 to 70 years of age, with average value of 63 years of age. Gleason score values were: GS 8--2 patients, GS 7--6 patients, GS 6--10 patients, GS 5--9 patients, GS 3--4 patients GS 10--1 patient. Duration of the surgery was in the range of 55 to 95 minutes with the average blood loss between 220 and 640 ml. Fifty percent of the patients did not required blood transfusion. RESULTS: After radical retropubic prostatectomy all patients are continent. Average urinary catheter removal time was 12 days after surgery. Postoperative surgical wound healing was prolonged for 4 patients. One patient had stenosis of urethrovesical anastomosis with was resolved with urethral dilatation. Control PSA values for 29 patients tree months after surgery was under 0, 2 ng/ml. Three patients were diagnosed with local tumor recurrence who underwent radiotherapy and latter on with hormonal therapy protocol. All patients are alive. CONCLUSION: Results of surgical treatment of localized prostate carcinoma have shown that the radical retropubic prostatectomy is the safe method for treatment of the localized prostate cancer, with good oncological response and small amount of postoperative complications. PMID- 22924310 TI - Evaluation of comparative results of rehabilitation of patients with acromioclavicular dislocation of the third degree treated by surgical techniques by Phemister and Vukov. AB - INTRODUCTION: In terms of access to treatment of acromioclavicular joint injuries, there are many controversies, especially after the appearance of works that promote "neglecting of injury". GOAL: The aim of this paper is to give a comparative analysis of the results of rehabilitation of patients after acute injury of the acromioclavicular joint of the third degree, treated by two surgical techniques: by Phemister and Vukov. MATERIAL AND METHODS: In this study, we investigated a total of 60 operated patients: 30 patients were operated by Phemister techniq-ue, and 30 by Vukov technique. RESULTS: Postoperative follow-up lasted for one year. Between these two groups, the time when the rehabilitation process began is significantly different p < 0.01. With technique by Vukov, the rehabilitation begins on the first postoperative day and with technique by Phemister it begins later (after 7 weeks outpatient). With technique by Phemister, rehabilitation lasted on average 60 days, and with technique by Vukov on average 40 days. The duration of recovery is also significantly different p < 0.01, with technique by Vukov the duration time is shorter, and therefore the process of rehabilitation in days--is shorter than with the other technique. Both techniques gave good stability of the lateral end of clavicle. The difference was not statistically significant p > 0.05, which means that both techniques can be applied depending on the indication and the experience of the surgeon. PMID- 22924311 TI - "One step procedure" local anaesthesia for inguinal hernia repair in ambulatory surgery conditions--district general hospital experience. AB - Ambulatory surgery refers to hospitalization that does not exceed 24 hours, during which a surgical procedure is performed. Inguinal hernia repairs done under local anaesthesia on an outpatient basis are no longer performed exclusively in specialized hernia centers. They are becoming widely accepted by surgeons working in district hospitals, which was significantly contributed to by the publication of the EHS Guidelines on the Treatment of Inguinal Hernia. OBJECTIVE: The objective of this retrospective study is to show local anaesthesia practicability for inguinal hernia repairs through "one -step procedure", being a one-day procedure used in District General Hospital. METHODS: From January 2006 to June 2011, 460 elective surgery procedures were performed on 428 patients with inguinal hernia (396 with unilateral and 32 with bilateral inguinal hernia), using Lichtenstein technique, UHS/PHS, plug repair, and Shouldice technique. All the proceduress were performed under local anaesthesia by the same surgeon using "one-step procedure" in ambulatory surgery. The following anaesthetics were used: Lidocaine for intradermal and subcutaneous anaesthesia as well as Bupivacaine/Levobupivacaine for subfascial anaesthesia. RESULTS: From January 2006 to June 2011, 460 surgical procedures were performed on 428 patients with inguinal hernia (396 with unilateral and 32 with bilateral inguinal hernia). The mean age was 58.2 yrs (20-84). All the patients were in the ASA I-III group. In unilateral hernias, the mean operating time using Lichtenstein technique was 38mins (28-56), using PHS/UHS 28mins (22-40), with plug 33mins (27-39) and using Shouldice technique 43mins (32-53). In bilateral hernias, the mean operating time using Lichtenstein technique was 71mis (56-87), and using PHS /UHS 56mins (49 64). The mean hospital stay was 2.9hrs (2-6). The mean distance of residence from the hospital was 23km (1-150). During the course of the surgery, 15 patients (3.5%) had problems such as pain, bradycardia, hypotension, or perspiration. The complications during the mean follow-up of 31 months (1-60) was: 1.4% (6 patients)--a hematoma, 1.87% (8 patients)--seroma, 0.47% (2 patients)--wound infection, 0.23% (1 patient)--chronic pain, and 0.47% (2 patients)--recurrence. Revision due to active bleeding was conducted in two patients (0.47%), after using PHS and Lichtenstein techniques. These were the only patients who were rehospitalized due to complications. CONCLUSION: In hernia repairs on an outpatient basis, "one-step procedure" in local anaesthetic administration is reliable, easy, safe, effective, and the type of the surgical technique is not a determining factor. The success rate and treatment outcome depend on the surgical technique and the surgeon's experience in using local anaesthesia in ambulatory surgery. PMID- 22924312 TI - Rehabilitation of a patient after operationally treated idiopathic recurrent, posterior shoulder subluxation. AB - INTRODUCTION: involuntary, idiopathic, recurrent posterior shoulder subluxation is a rare entity. Subluxation of the shoulder joint occurs with every elevation movement of the hand with a certain level of pain. Active abduction and anteflexion are possible only to 90 degrees. Only surgical treatment produces results. GOAL: The goal is to show that timely commenced, continuously conducted rehabilitation of the shoulder after surgically repaired involuntary, idiopathic, recurrent posterior subluxation of the shoulder, leads to restitution of function. Case outline R.M. patient 24 years old, was admitted to the Institute for Orthopaedic Surgery and Traumatology, Clinical Center in Belgrade, for surgical treatment. Previously was treated conservatively. ROM (anteflexion 700 abduction 60 degrees) with persistant pain in shoulder. Rehabilitation started first postoperative day. RESULT: - 2.5 months post surgery- ROM (active movement) antetlexion 165 degrees, abduction 140 degrees, without pain and no tendency of posterior subluxation. - 3.5 months post surgery,full active movements were achieved, except external rotation of -20 degrees. - 5 months post surgery, the patient had full range of motion in all directions.The last control was performed one year after surgery. The patient has no symptoms, lives normal life and is engaged with sports. PMID- 22924313 TI - Unusual eye injuries. AB - PURPOSE: The analysis of ten unusual eye injuries, and the discussion of appropriate preventive measures. CASE OUTLINE: Ten patients hospitalized at the Clinic of Eye Diseases, Clinical Center of Serbia, Belgrade, in the period from January 2000. to December 2009. were presented. Following data were taken in account: sex and age of the patient, injured eye, the mechanism of injury, type of the injury, applied treatment and final visual acuity. The circumstances of the eye injuring of ten patients were described. The eye injuries in all cases occurred in a bizarre way and they were severe enough to require hospital admission. The surgery was necessary in seven patients. Three injured eyes resulted in blindness, and two additional had subnormal vision. CONCLUSION: In three quarters of discussed cases injuries can be avoided. It is necessary to implement protective measures constantly and consistently and to think about the possible consequences of certain activities. Particular attention should be paid on safety of children. The iatrogenic injuries require special consideration. PMID- 22924314 TI - Multiple port-site metastasis of incidental gallbladder carcinoma after laparoscopic cholecystectomy. AB - Laparoscopic cholecystectomy is a surgical procedure of choice for benign gallbladder diseases. In about 1-2% of cases histopathological examination demonstrate incidental gallbladder cancer (GBCA). We report a case of a 61 year old woman who developed port site metastases after laparoscopic cholecystectomy for adenocarcinoma of the gallbladder. Metastases appeared on all four port sites. Review of literature regarding incidental GBCA an port site metastases was also performed. We conclude that the retrieval bag should be routinely used in laparoscopic cholecystectomy; the procedure should be performed with minimal trauma; in cases of incidental GB carcinoma, full thickness excision of the abdominal wall of the port sites demands additional studies; additional liver bed excision and local lymphadenectomy for T1b carcinoma are yet to be considered. PMID- 22924315 TI - [Giant asymptomatic borderline ovarian tumor in a patient suffering from choledocholithiasis and cholangitis]. AB - Borderline tumors account for about 15% of all ovarian epithelial tumors and are usually diagnosed only when they reach a significant size causing abdominal pain or distension. Clinical, sonographic and Doppler examinations, as well as tumor marker levels cannot detect this type of ovarian tumor with certainty. The definitive diagnosis can only be established by a histopathological examination. We present a case of a 58-year-old patient operated on at our clinic for asymptomatic borderline ovarian tumor. Prior to admission, the patient underwent a medical check-up at the surgery department, where she was diagnosed with choledocholithiasis, and, consequently, the need for urgent surgical treatment for calculosis was excluded. In the presented case the ovarian tumor was revealed owing to the occurrence of choledocholithiasis and cholangitis. The choledocholithiasis and cholangitis, which contributed to the accurate diagnosis of the tumor, were at the same time some of the possible reasons for misleading diagnosis and therapy complications in our patient's case. PMID- 22924316 TI - Surgical management of stab injuries of the heart. AB - ITRODUCTION: Cardiac injuries today are not rare and they present a significant group of pathological cardiac diseases, with a large number of the injured (60 90%) dying before being transported to the hospital. CASE REPORT: A patient with a stab wound of the right chamber, upper abdomen and pelvis, in a state of hemorrhagic shock, was successfully managed after being reanimated. CONCLUSION: Good health service organization in the field and urgent transport of the injured should be obligatory in the management of heart trauma. PMID- 22924317 TI - [Adnexal torsion during puerperium as a complication of delayed surgical treatment of ovarian tumor in pregnancy]. AB - Ovarian tumors in pregnancy represent a significant issue both in terms of diagnostics and therapy. Increased use of the ultrasound in pregnancy in the last several decades has contributed to the rise in the number of diagnosed asymptomatic adnexal tumors with pregnant women. We present a case of a patient treated in our clinic for asymptomatic ovarian tumor, which was diagnosed in pregnancy. The patient underwent check-ups every four weeks, comprising clinical and sonographical examinations and relevant laboratory and tumor marker tests. The course of pregnancy was normal, with no detected tumor growth and with the tumor marker levels within the reference range. Following an uneventful delivery, she developed abdominal pains during the puerperium, and the adnexal torsion was diagnosed intraoperatively. The attitudes to treating of adnexal tumors in pregnancy are controversial, and there exist no defined treatment protocols. It is, therefore, necessary to make an individual evaluation of each case, and the relevant decisions should be made with the pregnant woman's informed consent. The adnexal torsion in the presented case can be explained by the size of the tumor as well as the progressive reduction of the size of the uterus due to the physical involution during puerperium. PMID- 22924318 TI - Accountable care: where will NPs & PAs fit in? PMID- 22924319 TI - Head lice. PMID- 22924320 TI - Concussion care. PMID- 22924321 TI - Beware the irritable bowel. PMID- 22924322 TI - Inpatient hyperglycemia. PMID- 22924323 TI - Development and investigation of a dual-pad in-channel referencing surface plasmon resonance sensor. AB - Herein, we describe the construction of a novel dual-pad referencing surface plasmon resonance (SPR) sensor utilizing electrolytic grafting of diazonium salts to individually functionalize two gold pads positioned in a single fluidic channel. Using a dove prism, a simple single axis optical train may be employed without compromising the analytical performance. Once functionalized, one pad is used as the analytical sensing pad for detection of molecular interactions while the other serves as the reference pad, compensating for background refractive index fluctuations. The reference pad effectively compensates bulk refractive index changes and temperature variations as well as other nonspecific effects. The sensor was applied to calibration of a pH-responsive polymer layer in the presence of bulk refractive index and temperature variations. Monitoring selective attachment of a protein is also demonstrated. To our knowledge, this is the first implementation of in-channel referencing SPR sensor utilizing diazonium salt-based surface chemistry. PMID- 22924324 TI - Measuring single-walled carbon nanotube length distributions from diffusional trajectories. AB - A new method is demonstrated for measuring the length distributions of dispersed single-walled carbon nanotube (SWCNT) samples by analyzing diffusional motions of many individual nanotubes in parallel. In this method, termed "length analysis by nanotube diffusion" (LAND), video sequences of near-IR fluorescence microscope images showing many semiconducting SWCNTs are recorded and processed by custom image analysis software. This processing locates the individual nanotubes, tracks their translational trajectories, computes the corresponding diffusion coefficients, and converts those values to nanotube lengths. The deduced length values are then compiled into a histogram of lengths present in the sample. By using specific excitation wavelengths and emission filters, this analysis is performed on selected (n,m) structural species. The new LAND method has been found to give distributions in very good agreement with those obtained by conventional AFM analysis of the same samples. Because it is fluorescence-based, LAND monitors only semiconducting, relatively pristine SWCNTs. However, it is less sensitive to artifacts from impurities and bundled nanotubes than AFM or light scattering methods. In addition, samples can be analyzed with less time and operator attention than by AFM. LAND is a promising alternative method for characterizing length distributions of SWCNTs in liquid suspension. PMID- 22924325 TI - Tricolor emission of a fluorescent heteroditopic ligand over a concentration gradient of zinc(II) ions. AB - The internal charge transfer (ICT) type fluoroionophore arylvinyl-bipy (bipy = 2,2'-bipyridyl) is covalently tethered to the spirolactam form of rhodamine to afford fluorescent heteroditopic ligand 4. Compound 4 can be excited in the visible region, the emission of which undergoes sequential bathochromic shifts over an increasing concentration gradient of Zn(ClO(4))(2) in acetonitrile. Coordination of Zn(2+) stabilizes the ICT excited state of the arylvinyl-bipy component of 4, leading to the first emission color shift from blue to green. At sufficiently high concentrations of Zn(ClO(4))(2), the nonfluorescent spirolactam component of 4 is transformed to the fluorescent rhodamine, which turns the emission color from green to orange via intramolecular fluorescence resonance energy transfer (FRET) from the Zn(2+)-bound arylvinyl-bipy fluorophore to rhodamine. While this work offers a new design of ratiometric chemosensors, in which sequential analyte-induced emission band shifts result in the sampling of multiple colors at different concentration ranges (i.e., from blue to green to orange as [Zn(2+)] increases in the current case), it also reveals the nuances of rhodamine spirolactam chemistry that have not been sufficiently addressed in the published literature. These issues include the ability of rhodamine spirolactam as a fluorescence quencher via electron transfer, and the slow kinetics of spirolactam ring-opening effected by Zn(2+) coordination under pH neutral aqueous conditions. PMID- 22924326 TI - Memory asymmetry of forward and backward associations in recognition tasks. AB - There is an intensive debate on whether memory for serial order is symmetric. The objective of this study was to explore whether associative asymmetry is modulated by memory task (recognition vs. cued recall). Participants were asked to memorize word triples (Experiments 1-2) or pairs (Experiments 3-6) during the study phase. They then recalled the word by a cue during a cued recall task (Experiments 1-4) and judged whether the presented 2 words were in the same or in a different order compared with the study phase during a recognition task (Experiments 1-6). To control for perceptual matching between the study and test phase, participants were presented with vertical test pairs when they made directional judgment in Experiment 5. In Experiment 6, participants also made associative recognition judgments for word pairs presented at the same or the reversed position. The results showed that forward associations were recalled at similar levels as backward associations and that the correlations between forward and backward associations were high in the cued recall tasks. On the other hand, the direction of forward associations was recognized more accurately (and more quickly) than backward associations, and their correlations were comparable to the control condition in the recognition tasks. This forward advantage was also obtained for the associative recognition task. Diminishing positional information did not change the pattern of associative asymmetry. These results suggest that associative asymmetry is modulated by cued recall and recognition manipulations and that direction as a constituent part of a memory trace can facilitate associative memory. PMID- 22924330 TI - Impaired memory for syntactical information in poor readers. AB - Syntactical knowledge is vital for the comprehension and production of any language and this knowledge has also been shown to aid short-term memory (Perham, Marsh & Jones, 2009). Given that people with dyslexia are known to have difficulties in processing long-term serial order information which can be argued to underpin the use of syntactical rules, the following study explored a larger population-those who were high or low in reading abilities-and their ability to recall six-item word lists in both syntactically congruent and syntactically incongruent orders. Analyses revealed that the low reading group showed a syntactical congruency effect, but the high reading group did not. Results are discussed in terms of language and short-term memory. PMID- 22924328 TI - Effects of different manual periodontal probes on periodontal measurements. AB - AIM: To quantify the digit preference effect for three manual periodontal probes and to calculate correction values to enable comparison of studies with equal recording protocols, but different periodontal probes. MATERIAL AND METHODS: A prospective in vivo crossover study was conducted with a six-sequence three period design. Six examiners assessed attachment loss (AL), probing pocket depth (PD) and gingiva height (GH) at four surfaces, full-mouth, in six generally healthy subjects using three manual probes: PCP11 (3-3-3-2 mm increments), PCP2 (2 mm increments), and PCPUNC15 (1 mm increments). RESULTS: Distributions of AL, PD and GH differed between probes (p < 0.001). Compared with PCPUNC15, periodontal measurements coinciding with probe markings of PCP11 and PCP2, respectively, were preferentially named by examiners. Digit preference was most pronounced for PD, but less for AL and GH. In multilevel models, PD differed significantly between all three probes (p < 0.05); probe- and examiner-related effects were also observed for AL and GH. Correction values for pairwise combinations of probes were determined. CONCLUSIONS: We provided empirical evidence and quantified the effect of probe type on periodontal measurements. Differences in probe type should be considered when comparing periodontal data within and between epidemiological studies and appropriate corrections, provided here, should be applied. PMID- 22924331 TI - Multi-tier mental health program for refugee youth. AB - OBJECTIVE: We sought to establish that refugee youths who receive a multi-tiered approach to services, Project SHIFA, would show high levels of engagement in treatment appropriate to their level of mental health distress, improvements in mental health symptoms, and a decrease in resource hardships. METHOD: Study participants were 30 Somali and Somali Bantu refugee youths in the English language learner classroom in a middle school in New England. Project SHIFA is a multi-tiered program including prevention and community resilience building for the community at large, school-based early intervention groups for at-risk students, and direct intervention using an established trauma model (trauma systems therapy) for those with significant psychological distress. Data were collected from students at time of enrollment, 6-month follow-up, and 12-month follow-up. Measures used were the War Trauma Screening Scale, Adolescent Post-War Adversities Scale-Somali version, UCLA PTSD Reaction Index for DSM-IV (Revision 1), and the Depression Self-Rating Scale. RESULTS: Students across all tiers of the program demonstrated improvements in mental health and resources. Resource hardships were significantly associated with symptoms of posttraumatic stress disorder over time, and the stabilization of resource hardships coincided with significant improvements in symptoms of depression and posttraumatic stress disorder for the top tier of participants. CONCLUSIONS: Project SHIFA is a promising model of treatment for young refugees. PMID- 22924333 TI - Further issues in determining the readability of self-report items: comment on McHugh and Behar (2009). AB - OBJECTIVE: Issues regarding the readability of self-report assessment instruments, methods for establishing the reading ability level of respondents, and guidelines for development of scales designed for marginal readers have been inconsistently addressed in the literature. A recent study by McHugh and Behar (2009) provided new findings relevant to these issues. McHugh and Behar calculated indices of readability separately for the instructions and the item sets of 105 self-report measures of anxiety and depression. Results revealed substantial variability in readability among the measures, with most measures being written at or above the mean reading grade level in the United States. These results were consistent with those reported previously by Schinka and Borum (1993, 1994) in analyses of the readability of commonly used self-report psychopathology and personality inventories. In their discussion, McHugh and Behar addressed implications of their findings for clinical assessment and for scale development. METHOD: I expand on their comments by addressing the failure to consider vocabulary difficulty, a major shortcoming of readability indices that examine only text complexity. I demonstrate how vocabulary difficulty influences readability and discuss additional considerations and possible solutions for addressing the gap between scale readability and the reading skill level of the self-report respondent. RESULTS AND CONCLUSION: The work of McHugh and Behar clearly demonstrates that the issues of reading ability that arise in collecting self-report data are neither simple nor straightforward. Comments are offered to focus attention on the problems identified by their work. These problems will require additional effort on the part of researchers and clinicians in order to obtain reliable, valid estimates of clinical status. PMID- 22924332 TI - Behavioral economic predictors of overweight children's weight loss. AB - OBJECTIVE: Our goal was to determine whether behavioral economic constructs including impulsivity (i.e., steep discounting of delayed food and monetary rewards), the relative reinforcing value of food (RRVfood), and environmental enrichment (i.e., the presence of alternatives to unhealthy foods in the home and neighborhood environments)-are significant pretreatment predictors of overweight children's weight loss within family-based treatment. METHOD: Overweight children (N = 241; ages 7-12 years; 63% female; 65% non-Hispanic White) enrolled in a 16 week family-based obesity treatment with at least one parent. At baseline, children completed a task to assess RRVfood and delay discounting measures of snack foods and money to assess impulsivity. Parents completed questionnaires to assess environmental enrichment. RESULTS: Children who found food highly reinforcing and steeply discounted future food rewards at baseline showed a blunted response to treatment compared with children without this combination of risk factors. High environmental enrichment was associated with treatment success only among children who did not find food highly reinforcing. Monetary discounting rate predicted weight loss, regardless of children's level of RRVfood. CONCLUSIONS: Investigation is warranted into novel approaches to obesity treatment that target underlying impulsivity and RRVfood. Enriching the environment with alternatives to unhealthy eating may facilitate weight loss, especially for children with low RRVfood. PMID- 22924334 TI - Addressing alcohol use and problems in mandated college students: a randomized clinical trial using stepped care. AB - OBJECTIVE: Over the past 2 decades, colleges and universities have seen a large increase in the number of students referred to the administration for alcohol policies violations. However, a substantial portion of mandated students may not require extensive treatment. Stepped care may maximize treatment efficiency and greatly reduce the demands on campus alcohol programs. METHOD: Participants in the study (N = 598) were college students mandated to attend an alcohol program following a campus-based alcohol citation. All participants received Step 1: a 15 min brief advice session that included the provision of a booklet containing advice to reduce drinking. Participants were assessed 6 weeks after receiving the brief advice, and those who continued to exhibit risky alcohol use (n = 405) were randomized to Step 2, a 60- to 90-min brief motivational intervention (n = 211), or an assessment-only control (n = 194). Follow-up assessments were conducted 3, 6, and 9 months after Step 2. RESULTS: Results indicated that the participants who received a brief motivational intervention showed a significantly reduced number of alcohol-related problems compared to those who received assessment only, despite no significant group differences in alcohol use. In addition, low risk drinkers (n = 102; who reported low alcohol use and related harms at 6-week follow-up and were not randomized to stepped care) showed a stable alcohol use pattern throughout the follow-up period, indicating they required no additional intervention. CONCLUSION: Stepped care is an efficient and cost-effective method to reduce harms associated with alcohol use by mandated students. PMID- 22924335 TI - Sperm cryopreservation in live-bearing Xiphophorus fishes: offspring production from Xiphophorus variatus and strategies for establishment of sperm repositories. AB - Cryopreservation of sperm from Xiphophorus fishes has produced live young in three species: X. hellerii, X. couchianus, and X. maculatus. In this study, the goal was to establish protocols for sperm cryopreservation and artificial insemination to produce live young in X. variatus, and to identify needs for repository development. The objectives were to: 1) collect basic biological characteristics of males; 2) cryopreserve sperm from X. variatus, 3) harvest live young from cryopreserved sperm, and 4) discuss the requirements for establishment of sperm repositories. The 35 males used in this study had a body weight of 0.298+/-0.096 g (mean+/-SD), body length of 2.5+/-0.2 cm, and testis weight of 6.4+/-3.4 mg. The sperm production per gram of testis was 2.33+/-1.32*10(9) cells. After freezing, the post-thaw motility decreased significantly to 37%+/ 17% (ranging from 5% to 70%) (p=0.000) from 57%+/-14% (40%-80%) of fresh sperm (N=20). Artificial insemination of post-thaw sperm produced confirmed offspring from females of X. hellerii and X. variatus. This research, taken together with previous studies, provides a foundation for development of strategies for sperm repositories of Xiphophorus fishes. This includes: 1) the need for breeding strategies for regeneration of target populations, 2) identification of minimum fertilization capacity of frozen samples, 3) identification of fish numbers necessary for sampling and their genetic relationships, 4) selection of packaging containers for labeling and biosecurity, 5) assurance of quality control and standardization of procedures, 6) information systems that can manage the data associated with cryopreserved samples, including the genetic data, 7) biological data of sampled fish, 8) inventory data associated with frozen samples, and 9) data linking germplasm samples with other related materials such as body tissues or cells saved for DNA and RNA analyses. PMID- 22924336 TI - Randomised clinical trial: low-volume bowel preparation for colonoscopy - a comparison between two different PEG-based formulations. AB - BACKGROUND: Low-volume bowel preparations with polyethylene glycol (PEG) have been shown to provide an equivalent cleansing with improved tolerability as compared with standard PEG bowel preparation for colonoscopy. A new iso-osmotic sulphate-free formulation of PEG-Citrate-Simethicone (PEG-CS) in combination with bisacodyl has been recently developed. AIM: To compare the quality of bowel cleansing with PEG-CS with bisacodyl vs. PEG-Ascorbate (PEG-ASC) in adult out patients undergoing colonoscopy. METHODS: Randomised, observer-blind, parallel group study in adult out-patients undergoing colonoscopy in five Italian centres. Both preparations were taken the evening before the procedure. Subjects were instructed to take 2-4 tablets of 5 mg bisacodyl at 16:00 hours and 2 L of PEG-CS at 20:00 hours or 2 L of PEG-ASC plus 1 L of additional water the day before colonoscopy. Bowel cleansing was evaluated according to the Boston Bowel Preparation Scale (>=6 scores were considered as 'clinical success'), and mucosal visibility according to a 3-point scale. Tolerability, acceptability and compliance were also evaluated. RESULTS: Four hundred and eight patients were randomly allocated to PEG-CS and bisacodyl (n = 204, male patient 48%, mean age 59.1 years) or PEG-ASC (n = 204, male patient 51%, age 59.4 years). In the planned per-protocol analysis, the rate of successful preparation was 79.1% following PEG-CS with bisacodyl, and 70% following PEG-ASC (P < 0.05). Mucosal visibility was evaluated as optimal in 56.1% in the PEG-CS and bisacodyl and 46.3% in the PEG-ASC group (P < 0.05). There were no serious adverse events (AE) in each of the two experimental groups. Two subjects in the PEG-ASC group discontinued the study because of AE. CONCLUSIONS: Polyethylene glycol-Citrate Simethicone in combination with bisacodyl was more effective for bowel cleansing than PEG-ASC for out-patient colonoscopy. Tolerability, safety, acceptability and compliance of the two low-volume bowel preparations were similar. PMID- 22924337 TI - Squamous cell carcinoma in a child with Clericuzio-type poikiloderma with neutropenia. PMID- 22924338 TI - Fatal ischemic enteritis with hemorrhage--a late complication of treated Wilms tumor. AB - A 35-year-old man with a history of childhood Wilms tumor successfully treated with radiotherapy, chemotherapy, and surgery, collapsed and died unexpectedly in hospital following admission for abdominal pain. At autopsy, there was ischemic necrosis of the small intestine with altered blood within the stomach and small intestine. Within the upper abdominal aorta, there was patchy confluent calcific atherosclerosis with extension into the proximal superior mesenteric artery which was occluded by thrombus. Death was attributed to ischemic enteritis of the small intestine caused by mesenteric artery thrombosis complicated by gastrointestinal hemorrhage with aspiration. Localization of atherosclerosis to the radiation field with no significant atherosclerosis elsewhere and the young age of the decedent were supportive of radiation-induced atherogenesis. Geographically, localized atherosclerosis at autopsy in a tumor survivor should raise the possibility of a treatment-related side effect that may directly contribute to death many years after the original therapeutic intervention. PMID- 22924339 TI - Redox-active scandium oxide cluster inside a fullerene cage: spectroscopic, voltammetric, electron spin resonance spectroelectrochemical, and extended density functional theory study of Sc4O2@C80 and its ion radicals. AB - The clusterfullerene Sc(4)O(2)@C(80) with a mixed redox state of scandium was found to be an exciting molecule for endohedral electrochemistry as demonstrated by means of an in situ electron spin resonance (ESR) spectroelectrochemical study of the spin density distribution in its electrochemically generated cation and anion radicals. The compound exhibits two reversible reduction and oxidation steps with a relatively small electrochemical gap of 1.10 V. The ESR spectra of the ion radicals have a rich hyperfine structure caused by two pairs of equivalent Sc atoms. The Sc-based hyperfine structure with large hyperfine coupling constants shows that both oxidation and reduction of Sc(4)O(2)@C(80) are in cavea redox processes, which is the subject of endohedral electrochemistry. The assignment of the experimentally determined a((45)Sc) values to the two types of Sc atoms in the Sc(4)O(2) cluster was accomplished by extended density functional theory and molecular dynamics simulations. Sc atoms adopting a divalent state in the neutral Sc(4)O(2)@C(80) exhibited an especially large coupling constant of 150.4 G in the cation radical, which is the record high a((45)Sc) value for Sc-based endohedral metallofullerenes. Such a high value is explained by the nature of the highest occupied molecular orbital (HOMO) localized on the six-atom Sc(4)O(2) cluster. This HOMO is a Sc-Sc bonding MO and hence has large contributions from the 4s atomic orbitals of Sc(II). We claim that ESR spectroelectrochemistry is an invaluable experimental tool in the studies of metal-metal bonding in endohedral metallofullerenes and in endohedral electrochemistry. PMID- 22924340 TI - Two new metabolites from a soil fungus Curvularia affinis strain HS-FG-196. AB - Two new metabolites, pyrenocine J (1) and pyrenochaetic acid D (2), together with two known metabolites, pyrenocine A (3) and pyrenochaetic acid A (4), were isolated from a soil fungus, Curvularia affinis strain HS-FG-196. Their structures were established by extensive spectroscopic analysis. Compound 1 showed cytotoxic activity against the human hepatic cancer cell line HepG2 with an IC(50) value of 28.5 MUg/ml. PMID- 22924341 TI - The mirror mechanism and its potential role in autism spectrum disorder. AB - The mirror mechanism allows the direct translation of a perceived (seen, felt, heard) action into the same motor representation of its related goal. This mechanism allows a direct comprehension of others' goals and motor intentions, enabling an embodied link between individuals. Because the mirror mechanism is a functional expression of the motor system, these findings suggest the relevance of the motor system to social cognition. It has been hypothesized that the impaired understanding of others' intentions, sensations, and emotions reported in autism spectrum disorder (ASD) could be linked to an alteration of the mirror mechanism in all of these domains. In this review, we address the theoretical issues underlying the social impairments in ASD and discuss them in relation to the cognitive role of the mirror mechanism. PMID- 22924342 TI - Potential use of selective and nonselective Pim kinase inhibitors for cancer therapy. PMID- 22924343 TI - Predicting dispersal distance in mammals: a trait-based approach. AB - Dispersal is one of the principal mechanisms influencing ecological and evolutionary processes but quantitative empirical data are unfortunately scarce. As dispersal is likely to influence population responses to climate change, whether by adaptation or by migration, there is an urgent need to obtain estimates of dispersal distance. Cross-species correlative approaches identifying predictors of dispersal distance can provide much-needed insights into this data scarce area. Here, we describe the compilation of a new data set of natal dispersal distances and use it to test life-history predictors of dispersal distance in mammals and examine the strength of the phylogenetic signal in dispersal distance. We find that both maximum and median dispersal distances have strong phylogenetic signals. No single model performs best in describing either maximum or median dispersal distances when phylogeny is taken into account but many models show high explanatory power, suggesting that dispersal distance per generation can be estimated for mammals with comparatively little data availability. Home range area, geographic range size and body mass are identified as the most important terms across models. Cross-validation of models supports the ability of these variables to predict dispersal distances, suggesting that models may be extended to species where dispersal distance is unknown. PMID- 22924344 TI - Outcome in 146 patients with paediatric acute myeloid leukaemia treated according to the AML99 protocol in the period 2003-06 from the Japan Association of Childhood Leukaemia Study. AB - The acute myeloid leukaemia (AML) 99 trial conducted previously in Japan for the treatment of de novo paediatric AML showed excellent results, with a 5-year overall survival (OS) and event-free survival (EFS) of 75.6% and 61.6%, respectively. To examine reproducibility of these results in another cohort, the outcome of 146 newly diagnosed AML paediatric patients prospectively registered in the Japan Association of Childhood Leukaemia Study (JACLS) from 2003 to 2006 was compared to that of 240 patients in the original AML 99 clinical trial. The 5 year EFS and OS achieved in the new cohort was 66.7 +/- 4.0% and 77.7 +/- 8.0% respectively, which were comparable to those obtained in the original AML 99 clinical trial, although less frequent core-binding factor (CBF) AML (29.5% vs. 37%) and an almost equal frequency of allogeneic haematopoietic stem cell transplantation (allo-HSCT) during first complete remission (16.5% vs. 19%) were observed. The 5-year EFS in patients with a normal karyotype (NK) (n = 35, 54.9 +/- 15.1%) was inferior in the present cohort when compared to the original AML99 trial. This study confirmed the excellent outcome of the original AML99 protocol. PMID- 22924345 TI - Expression and processing of an unusual tRNA gene cluster in the cyanobacterium Anabaena sp. PCC 7120. AB - Anabaena sp. PCC 7120 is a filamentous cyanobacterium that bears a cluster of 26 tRNA genes and pseudogenes in the delta plasmid. The sequences of these tRNAs suggest that they have been acquired by horizontal gene transfer from another organism. The cluster is transcribed as a single transcript that is quickly processed to individual tRNAs. RNase P and RNase Z, in vitro, are able to process precursors containing some of these tRNAs. Deletion of the cluster causes no obvious phenotype or effect on growth under diverse culture conditions, indicating that the tRNAs encoded in the cluster are not required for growth under laboratory conditions, although they are aminoacylated in vivo. We have studied a possible tRNA(Ser) [tRNA(Ser) GCU(2)] present in the cluster with a sequence that deviates from consensus. This tRNA is processed in vitro by RNase P at the expected position. In addition, this tRNA(Ser) GCU is specifically aminoacylated with serine by an Anabaena sp. PCC 7120 crude extract. These data indicate that tRNA(Ser) GCU(2) is fully functional, despite its unusual structure. Similar clusters are found in other three cyanobacteria whose genomes have been sequenced. PMID- 22924346 TI - The changing demographics of our journal. PMID- 22924347 TI - HIV and dentistry in Australia: clinical and legal issues impacting on dental care. AB - The number of people in Australia living with HIV is growing. This reflects a consistent rate of new HIV infections combined with an increased life expectancy of people with HIV. Dentists are ideally positioned to identify, manage and treat HIV-associated oral manifestations and have a responsibility to themselves and to their patients to be up-to-date with the evolving area of HIV and related issues. Those issues include medico-legal implications associated with HIV diagnosis and treatment. This article provides a review of the current clinical and medico legal aspects of HIV in Australia. The oral manifestations of HIV can be divided into five categories: microbiological infections (fungal, bacterial and viral); oral neoplasms; neurological conditions; other oral conditions that may be associated with HIV infection; and oral conditions associated with HIV treatment. Current treatment options in the scope of general dental practice are outlined. Medico-legal issues related to the management of patients with HIV are explored, including rights of the patient regarding disclosure of HIV status; an algorithm for the management of a patient with signs or symptoms indicating possible HIV infection, including referral pathways; and an algorithm for dealing with patient management and referral issues. PMID- 22924348 TI - Comparison of quantitative light-induced fluorescence, digital photography and transverse microradiography for quantification of enamel remineralization. AB - BACKGROUND: Quantitative light-induced fluorescence (QLF) and digital photography (DP) have been proposed as clinical methods for measuring changes in enamel mineral content. The aim of this study was to compare the ability of QLF and DP with the in vitro gold standard transverse microradiography (TMR) to measure the remineralization of enamel subsurface lesions. METHODS: Subsurface lesions were formed in enamel (n = 40) and exposed to remineralization solutions for 10 days. Changes were analysed by DP, QLF and TMR to determine percentage changes in luminescence (%L), fluorescence (%F) and mineral content (%R), respectively and correlation between these parameters determined. RESULTS: The correlations between TMR and QLF (r = 0.63), TMR and DP (r = 0.59), and DP and QLF (r = 0.64) were all moderate but statistically significant (p < 0.001). The variability in %L and, to a lesser extent, %F values significantly impacted on the potential role of DP and QLF as methods by which mineral content changes produced by remineralization treatments could be accurately measured. CONCLUSIONS: Both QLF and DP provided data that correlated moderately with TMR data. QLF images were easier to analyse, free of glare and had less variability compared with those produced using DP. PMID- 22924349 TI - Effect of halogen light irradiation on hydrogen peroxide bleaching: an in vitro study. AB - BACKGROUND: The aim of this study was to evaluate the effect of halogen light irradiation on hydrogen peroxide (HP) bleaching by assessing HP concentrations, tooth whitening efficacy, and temperature variations in bleaching agents and pulp chambers. METHODS: Sixteen premolars were randomly divided into two groups: Group BL (bleaching agent with halogen light irradiation for 3 * 10 minutes) and Group B (bleaching agent alone). HP concentrations were tested before and after treatment. CIE L*a*b* values of specimens were obtained using a spectrophotometer. Temperatures of bleaching gels and pulpal chambers were recorded by a digital multimeter with K-type thermocouple. Data were analysed using ANOVA and paired t-test. RESULTS: After treatment, HP concentration in group BL was slightly higher than that in group B. Paired t-tests revealed significant differences of DeltaE between groups BL and B in all time intervals except at day 35. The temperature rise of bleaching gels and pulpal chambers in group BL was significantly higher than that in group B. CONCLUSIONS: In-office bleaching was effective for tooth whitening. The involvement of halogen light was beneficial for the immediate whitening effect but had little impact on the long term whitening effect. PMID- 22924350 TI - Inflammatory and bone regulators expression in murine macrophages under exposure of commercial and experimental mineral trioxide aggregate. AB - BACKGROUND: Mineral trioxide aggregate (MTA) has been used in a variety of surgical and non-surgical endodontic applications. The aim of this study was to evaluate the gene expression and protein production of TNF-alpha, IL-1beta and IL 6, as well as the gene expression of RANKL and OPG using both commercial and experimental MTA in macrophage cell cultures. METHODS: Peritoneal macrophage cell culture was performed. Viability, gene expression of cytokines, RANKL and OPG, and protein levels in experimental- and commercial-grey MTA co-cultured with peritoneal macrophages was determined by tryptan blue, real time PCR and ELISA. RESULTS: The expression of TNF-alpha for both commercial and experimental MTA was higher, while the expression of IL-1beta and IL-6 was similar when compared to the negative control. At protein expression level, no differences were observed between the negative control and cements. RANKL did not show a significant improvement in gene expression when compared with the negative control, but OPG expression in cement samples was higher when compared to the negative control. CONCLUSIONS: This study suggests that commercial and experimental MTA promotes anti-inflammatory processes, as well as bone healing capacity. PMID- 22924351 TI - The relationship between bite force and oral sensation during biting in molars. AB - BACKGROUND: In prosthodontic treatment, the occlusal form should be designed such that bite force is applied at the position that has higher load-bearing capacity and is comfortable for the patient. The purpose of this study was to clarify the differences in bite force and occlusal sensation with different loading positions on the occlusal surface. METHODS: Twelve healthy subjects were recruited for this study. Bite force and occlusal sensation were measured at five loading points on the upper and lower left first molars. Occlusal sensation was evaluated using a Visual Analogue Scale (VAS). RESULTS: Bite forces on the lingual side of the upper first molar and the buccal side of the lower first molar were significantly higher and VAS scores were significantly lower, i.e. the subjects felt less discomfort during biting on the buccal side of the upper first molar and the lingual side of the lower first molar compared to the other side of each molar. CONCLUSIONS: Loading on the occlusal surfaces of the functional cusps of the upper and lower first molars produces more load-bearing capacity and is more comfortable than loading on the non-functional cusps. PMID- 22924352 TI - Immunoexpression of matrix metalloproteinases and their inhibitors in different areas of oral squamous cell carcinoma. AB - BACKGROUND: Several studies have shown the participation of MMPs in oral squamous cell carcinoma, the most frequent malignant neoplasm of the oral cavity. The expression of some MMPs correlates with a more aggressive biological behaviour. The objective of this study was to determine which MMPs and TIMPs were expressed in both neoplastic and peritumoural stromal cells in different histopathology areas. METHODS: Patients who underwent primary tumour neck dissection for oral squamous cell carcinoma were included. Immunoexpression of MMP-1, -2, -3, -7, -9, -11, -13, and TIMP-1 and -2 in different areas of pathologic specimens (in situ carcinoma, primary tumour, invasive front, distant invasion carcinoma, and lymph node metastasis) was evaluated. Enzyme expression on mucosa adjacent to tumour served as control. RESULTS: Thirty cases were included. Only 6 MMPs and 1 TIMP were expressed in the studied areas. Statistically significant differences in the number of cases with positive MMPs or TIMP expression, in both neoplastic and peritumoural cells, between control and the rest of the areas were observed. MMP 2 expression was constant in the areas with a more aggressive biological behaviour. CONCLUSIONS: MMP-2 expression may represent a dynamic interaction between host and tumour that favours the establishment of neoplastic cells at distant sites. PMID- 22924353 TI - Clinical evaluation of diamine silver fluoride/potassium iodide as a dentine desensitizing agent. A pilot study. AB - BACKGROUND: The aim of the present study was to compare the efficacy of an experimental diamine silver fluoride/potassium iodide product with an oxalic acid based preparation in reducing dentine hypersensitivity. METHODS: The study was conducted as a double-blind, randomized clinical trial. A total of 19 subjects with dentine hypersensitivity on both sides of their upper arch were selected. The most sensitive tooth in each quadrant was identified and received a cold stimulus. The response was recorded on a visual analogue scale (VAS). The tooth thus selected was treated with one of the treatment agents. One week later the level of dentine sensitivity was assessed. Participants were also asked for their subjective assessment of treatment effects. RESULTS: The mean difference between VAS at baseline and seven days for teeth treated with diamine silver fluoride/potassium iodide was greater than that for teeth treated with the oxalic acid-based preparation (p = 0.0134). The subjects' subjective assessment of changes in dentine hypersensitivity indicated that more obtained relief with the diamine silver fluoride/potassium iodide treatment (p = 0.0129). CONCLUSIONS: It was concluded that an experimental diamine silver fluoride/potassium iodide product has potential as a treatment for dentine hypersensitivity. PMID- 22924354 TI - Clinical and microbiologic effects of commercially available gel and powder containing Acacia arabica on gingivitis. AB - BACKGROUND: There is a need for an anti-plaque agent that can be used on a daily basis without the side effects of antibacterial chemicals such as chlorhexidine. The present study was designed to evaluate the clinical and microbiologic effects of commercially available gel and powder containing Acacia arabica in subjects with gingivitis. METHODS: One hundred and twenty subjects with chronic generalized gingivitis were selected and randomly divided into four groups: Group 1 - placebo group; Group 2 -Acacia arabica gel group; Group 3 -Acacia arabica powder group; and Group 4 - 1% chlorhexidine gel group. Microbial counts of plaque samples, the gingival index of Loe and Silness and the plaque index were evaluated at baseline, 6 weeks, 12 weeks and 24 weeks. Microbial counts of plaque samples were evaluated at all visits. RESULTS: Acacia arabica gel and powder showed significant clinical improvement in gingival and plaque index scores as compared to a placebo. This improvement was comparable to 1% chlorhexidine gel. The difference between gel and powder with regard to clinical and microbiological parameters was not found to be significant at any time interval. CONCLUSIONS: Both Acacia arabica gel and powder may be useful herbal formulations for chemical plaque control in subjects with gingivitis. PMID- 22924355 TI - Relationship between composite fracture toughness and bond strengths to enamel and dentine. AB - BACKGROUND: This study aimed to evaluate the association between the fracture toughness of two nanofilled-hybrid resin composites (Clearfil Majesty Esthetic [CME], Kuraray Medical, Japan; Estelite Sigma [ES], Tokuyama, Japan) and their bond strengths to enamel and dentine mediated by a self-etching primer system (Clearfil SE Bond [CSE]; Kuraray). METHODS: Twenty-four permanent human molars were sectioned into enamel and dentine specimens and finished with 600-grit silicon carbide paper, bonded with CSE and either CME or ES, for MU-shear bond strength (MUSBS) and MU-tensile bond strength (MUTBS). The specimens were tested until failure at a cross-head speed of 1 mm/min, failure loads recorded, bond strengths calculated and results analysed using independent samples t-tests. Eight single-notched bar-shaped specimens, 30 mm * 5.2 mm * 2.2 mm, were prepared for each resin composite and fracture toughness measured using four-point bending at a cross-head speed of 0.5 mm/min. Results were analysed using independent samples t-tests. RESULTS: For MUSBS and MUTBS, there was no significant difference between the resin composites for enamel or dentine. The fracture toughness of CME was significantly higher than that of ES. CONCLUSIONS: For both enamel and dentine, resin composite fracture toughness affected neither MUTBS nor MUSBS to enamel or dentine. PMID- 22924356 TI - A comparison of articaine 4% and lignocaine 2% in block and infiltration analgesia in children. AB - BACKGROUND: Articaine administered through buccal infiltration (BI) has been suggested as providing adequate posterior mandibular analgesia. This study compared the efficacy of articaine 4% with 1:100 000 adrenaline (test) and lignocaine 2% with 1:80 000 adrenaline (control), delivered either through an inferior alveolar nerve block (IANB) or BI for routine restorative procedures in mandibular posterior teeth among children. METHODS: Children enrolled within the Western Australian School Dental Service and in need of restorative care on contralateral mandibular posterior teeth were eligible. Consenting children were randomly allocated to test and control techniques, and to type of local anaesthetic. Using the faces pain scale, pain reports from analgesia administration and from dental treatment were elicited. Analgesia success and pain reports were compared by anaesthetic technique and type. RESULTS: Fifty seven children were recruited into the study; 29 allocated to IANB. Analgesia success for IANB 100%; BI 67%; p < 0.001. Analgesia success for BI with articaine 71%; lignocaine 64%, p > 0.05. Analgesia success was associated with fewer reports of painful dental treatment, p = 0.005. CONCLUSIONS: There was higher success and less painful treatment with IANB. There was no statistically significant difference in local analgesia success between articaine and lignocaine when delivered via BI. PMID- 22924357 TI - Effect of bonding application time on the microleakage of Class V sandwich restorations. AB - BACKGROUND: The aim of this study was to assess the effect of bonding application time on the microleakage of Class V sandwich restorations. METHODS: Eighty non carious third molars were randomly divided into 16 groups. Two Class V cavities were prepared on the buccal and lingual surfaces of teeth. Three groups were restored with Fuji II GIC and treated with a total-etch bonding system (Stea/SDI) immediately after insertion, at 7 minutes and 15 minutes after mixing the glass ionomer cements (GICs). Another three groups were restored with Riva Self Cure GIC and treated with the total-etch system identically. The other six groups were subjected to self-etching bonding (Frog/SDI) after GIC placement in an identical procedure. The remaining groups were made using light cure GICs (Fuji II or Riva Light Cure) in conjunction with the total-etch or self-etching systems. Cavities were then restored with composite (Valux plus, 3M/ESPE). Samples were subsequently immersed in 2% methylene blue solution for 48 hours and observed under a stereomicroscope after sectioning. Four-scale grading was used to assess microleakage in occlusal and gingival walls. Data were analysed using Kruskal Wallis and Mann-Whitney tests. RESULTS: The self-etching bonding system exhibited more microleakage in occlusal margins regardless of time. Over time, microleakage significantly decreased in gingival margins in all self-cure groups except for Riva Self Cure treated with the total-etch system (p < 0.05). CONCLUSIONS: Bonding application time had no effect on the microleakage of occlusal margins. However, maturation of GICs induced a decreased microleakage in gingival margins. PMID- 22924358 TI - Antibacterial efficacy of casein-derived peptides against Enterococcus faecalis. AB - BACKGROUND: The aim of this study was to test a casein peptide in its glycosylated form (kappa-casein glycopeptide, KCGP) and its non-glycosylated form (kappa-casein peptide, KCP) for antibacterial efficacy against Enterococcus faecalis in planktonic and biofilm cultures. METHODS: E. faecalis strain JKD 15036 was exposed to different concentrations of KCGP and KCP in a 96-well culture plate. The effect of the peptides on the growth of E. faecalis in planktonic culture was monitored by measuring optical density over 7 hours. Biofilm formation was measured after 24 hours using a crystal violet assay. All experiments were performed in triplicate. RESULTS: KCGP and KCP inhibited growth of E. faecalis in planktonic culture with no significant difference in activity between the peptides. KCGP at 0.16% w/v was significantly better at inhibiting E. faecalis biofilm formation than KCP at the same concentration and significantly better than NaOCl at 1.0% w/v. CONCLUSIONS: KCGP effectively inhibited E. faecalis biofilm formation and may have potential to augment the efficacy of traditional antiseptic agents. PMID- 22924359 TI - Comparative evaluation of different chelators in removal of calcium hydroxide preparations from root canals. AB - BACKGROUND: This study compared the efficacy of 10% citric acid, 17% EDTA and 7% maleic acid (MA) with ultrasonic agitation in the removal of calcium hydroxide (CH) from root canals. METHODS: Seventy maxillary anterior teeth were enlarged to F3 using protaper files. Teeth were then divided into two groups: A and B. Group A was filled with (CH + iodoform + silicone oil) mixture and group B with CH and propylene glycol (PG). Ten teeth were divided into positive and negative control groups. The volume of CH preparations was estimated using spiral CT. After seven days, teeth in groups A and B were further divided into three subgroups based on irrigants used and CH was retrieved along with ultrasonic agitation. Volume analysis was undertaken using spiral CT. Mean percentage of CH removed was analysed using one-way ANOVA followed by Tukey's Honestly Significant Difference test. RESULTS: All irrigants removed (CH + PG) completely without any difference between them (p = 0.17). Removal of (CH + iodoform + silicone oil) was significantly higher for MA and citric acid than EDTA (p < 0.001). There was no difference between MA and citric acid. CONCLUSIONS: Concentrations of 7% MA and 10% citric acid were found to be superior to 17% EDTA in the removal of (CH + iodoform + silicone oil). (CH + PG) preparation was completely removed by all the irrigants. PMID- 22924360 TI - Effect of storage media and time on the fracture toughness of resin-based luting cements. AB - BACKGROUND: Resin-based cements are brittle materials and the major shortcomings of these materials are manifested in their sensitivity to flaws and defects. Although various mechanical properties of resin luting cements have been described, few fracture toughness test data for resin-based luting cements using the short rod design have been published. METHODS: Specimens were prepared from five resin luting cements. For each material a total of 36 disc-shaped specimens were prepared using a custom-made mould. Specimens were randomly divided into six groups of six, immersed in two solutions: distilled water and 0.01 mol/L lactic acid at 37 degrees C for 24 hours, 1 month or 3 months. The specimens were loaded using a universal testing machine. The maximum load at specimen failure was recorded and the K(Ic) (MPa. M 0.5) was calculated. RESULTS: There was a relationship between material, storage solution and time (p < 0.05). Nexus 3 showed the highest K(Ic) followed by Panavia F, Calibra, Smart Cem2 and seT. CONCLUSIONS: The fracture toughness of the resin luting cements was affected by both time and storage solution. Comparable fracture toughness of conventional resin cement and self-adhesive resin cements was observed. PMID- 22924361 TI - Incidence of craniofacial pain of cardiac origin: results from a prospective multicentre study. AB - BACKGROUND: The aim of this study was to reveal the incidence and distribution pattern of craniofacial pain of cardiac origin. METHODS: We undertook a prospective study of 248 consecutive patients (aged 26 to 88 years) hospitalized with confirmed cardiac ischaemic periods. Digital OPG radiographs were obtained from all patients for radiographic examination of the jaws and dentition. Patients underwent clinical and radiographic examinations, and symptoms were evaluated in detail to determine the prevalence and distribution pattern of craniofacial pain of cardiac origin. RESULTS: Craniofacial pain was the sole symptom of cardiac ischaemia in 13 patients (5.2%); two developed acute myocardial infarction (AMI). Pain in the craniofacial region, chest, shoulders and arms was experienced by 72 patients. The most frequently affected region was the left mandible. In the absence of chest pain, patients most frequently experienced pain in craniofacial structures. Incidence of craniofacial pain was significantly higher in females than males (p = 0.024). CONCLUSIONS: Cardiac pain commonly radiates to the craniofacial structures. Pain of cardiac origin is usually described as pressure and/or a burning sensation that is provoked by physical activity and relieved by rest. Craniofacial pain of cardiac origin usually occurs bilaterally. Dental practitioners can play a crucial role in the diagnosis of craniofacial pain of cardiac origin. PMID- 22924362 TI - Erosive potential of sports beverages. AB - BACKGROUND: Dental erosion is an increasingly prevalent problem in Australia, with the consumption of sports beverages suggested as a risk factor. The aim of this study was to compare the erosive potential of Australian sports beverages. METHODS: Ten beverages were selected and analysed to determine their pH, titratable acidity and apparent degree of saturation with respect to apatite. The erosive potential of the beverages was measured by human enamel surface loss and surface softening following a 30-minute exposure. A taste testing panel was established to determine the palatability of the sports beverages. RESULTS: All sports beverages except Sukkie and Endura produced substantial surface loss and surface softening. Compared with the other sports beverages, Sukkie and Endura had a higher pH, lower titratable acidity and higher calcium content. However, Sukkie and Endura were deemed to be less palatable than the other more acidic sports beverages. CONCLUSIONS: The majority of the sports beverages tested produced dental erosion in this in vitro model. However, two new products Sukkie and Endura have lower erosive potential but also lower palatability. PMID- 22924363 TI - Effect of different orthodontic adhesive removal techniques on sound, demineralized and remineralized enamel. AB - BACKGROUND: The aim of this in vitro study was to determine the effect of four different orthodontic adhesive removal techniques on sound, demineralized and remineralized enamel. METHODS: Composite resin adhesive was bonded to 100 teeth which were divided into four groups with each comprising five sound teeth and 20 teeth with demineralized and remineralized lesions adjacent to the adhesive. Adhesive was removed with either: (1) slow speed bur (SS); (2) high speed bur (HS); (3) aluminium oxide disc (DC); or (4) ultrasonic scaler (US). Damage to the enamel was assessed using white light profilometry, digital photography and scanning electron microscopy. RESULTS: The least to greatest mean depth of damage with the four different adhesive removal techniques to sound enamel was DC = SS < US = HS and to demineralized and remineralized enamel were DC < HS < US = SS. Sound enamel experienced the least amount of damage. Remineralization prior to adhesive removal significantly reduced the amount of damage produced by all techniques compared with demineralized enamel. Discs were the least damaging to demineralized and remineralized enamel compared with the other removal techniques. CONCLUSIONS: When demineralization was present discs were found to be the least damaging adhesive removal technique and remineralization further reduced the amount of enamel damage. PMID- 22924364 TI - Areca nut chewing in an expatriate population in Sydney: report of two cases. AB - Areca nut (betel nut) consumption occurs in a variety of forms, either on its own or with the addition of a number of products. This habit is prevalent in the Indian Subcontinent and South-East Asia. Recent immigration statistics indicate that 30% of new arrivals in Australia are from these geographical regions and are known to perpetuate this custom long after migration. The objective of this paper is to highlight the variety of oral presentations that may occur as a result of areca nut consumption in these particular demographic subgroups. Dental practitioners must be familiar with the wide spectrum of oral lesions that may present in this setting. More significantly, they must be aware that some of these lesions possess the potential for malignant transformation and hence require more specific management. Best practice mandates that dental practitioners in a multicultural society must: (1) be capable of recognizing the expatriate populations in which this custom is widely practised; (2) incorporate this particular line of questioning into the routine risk factor analysis that is undertaken for every patient from these particular sub-populations; and (3) institute appropriate referral and follow-up of these lesions if required. PMID- 22924365 TI - Microvascular reconstruction of the mouth, face and jaws. Oromandibular reconstruction - free fibula flap. AB - Dental surgeons may encounter in their clinical practice patients who present with aggressive pathologies that require early diagnosis and prompt treatment. This action may limit the extent of tissue damage and, where relevant, improve survival outcome. Clinicians should therefore be aware of the range of resective, reconstructive and rehabilitative options that are available in the management of these patients. We present our experience with the free fibula flap used for oromandibular reconstruction; this was undertaken in 21 patients following resective surgery for malignant pathology, cytologically benign but biologically aggressive odontogenic pathology and radiation induced osteonecrosis. We also review the history, surgical anatomy, surgical assessment and potential complications that are relevant to the free fibula flap. PMID- 22924366 TI - The importance of a thorough medical and pharmacological history before dental implant placement. AB - The risk of osteonecrosis in patients treated with bisphosphonates is well known and guidelines intended to prevent this complication have been established and accepted. Bisphosphonate related osteonecrosis of the jaws (BRONJ) is a unique condition in which even past administration of medication may be of current and future relevance. We present a case of BRONJ in the maxilla after dental implant placement. The patient suffered from osteoporosis and had been treated with oral alendronate sodium in the past. However, the medication was stopped two years before implant placement, and the treating dentist was unaware of the patient's past bisphosphonate use. Prevention of BRONJ is based on identifying at-risk patients, and then avoiding or modifying dentoalveolar surgical procedures in these individuals. Nevertheless, there seems to be some difficulties identifying patients at risk. We present some of the challenges that impede thorough assessment of a patient's medical background (review of systems) in the dental office, and suggest possible solutions. PMID- 22924367 TI - Statistical learning in reading: variability in irrelevant letters helps children learn phonics skills. AB - Early reading abilities are widely considered to derive in part from statistical learning of regularities between letters and sounds. Although there is substantial evidence from laboratory work to support this, how it occurs in the classroom setting has not been extensively explored; there are few investigations of how statistics among letters and sounds influence how children actually learn to read or what principles of statistical learning may improve learning. We examined 2 conflicting principles that may apply to learning grapheme-phoneme correspondence (GPC) regularities for vowels: (a) variability in irrelevant units may help children derive invariant relationships and (b) similarity between words may force children to use a deeper analysis of lexical structure. We trained 224 first-grade students on a small set of GPC regularities for vowels, embedded in words with either high or low consonant similarity, and tested their generalization to novel tasks and words. Variability offered a consistent benefit over similarity for trained and new words in both trained and new tasks. PMID- 22924368 TI - Prevention of cardiovascular diseases in developing countries. PMID- 22924369 TI - Cardiovascular disease prevention using fixed dose pharmacotherapy in Iran: updated meta-analyses and mortality estimation. AB - BACKGROUND: Short term randomized trials have shown the effectiveness of a fixed dose combination therapy (known as Polypill) on reducing blood pressure and serum cholesterol but the impact of Polypill on cardiovascular disease risk or mortality has not yet been directly investigated. Previous studies combined the effects of each component assuming a multiplicative joint risk model that may have led to overestimating the combined effects. We conducted an updated meta analysis of randomized trials of anti-hypertensives, and aspirin. We used the estimated effect sizes applying a more conservative assumption to estimate the number of ischemic heart disease (IHD) and stroke deaths that could have been averted by Polypill in Iranians aged 55 years or older in 2006. METHODS: We searched Medline and reviewed previous meta-analyses to select randomized trials on Angiotensin Converting Enzyme-inhibitors, thiazides, aspirin, and statins. We used a random-effects model to pool relative risks for each component and estimated the joint relative risks using multiplicative and additive assumptions for 4 combinations of Polypill components. We used age- and cause-specific mortality, separately by gender, and estimated the number of preventable deaths from IHD and stroke. RESULTS: Under the additive joint RR assumption, the standard Polypill formulation was estimated to prevent 28500 (95% CI: 21700, 34100) IHD deaths and 12700 (95% CI: 8800, 15900) stroke deaths. Removing aspirin from the combination decreased preventable IHD deaths by 15% under the additive assumption (5600 deaths) and by 21% under the multiplicative assumption (6800 deaths) and reduced preventable stroke deaths under both additive and multiplicative assumptions by 3% (300 deaths). There was no significant difference between Polypill combinations with anti-hypertensive agents in full dose or half-dose. CONCLUSIONS: Polypill can prevent a large number of IHD and stroke deaths in Iran. The cost-effectiveness, feasibility, and acceptability of this prevention strategy remain to be investigated. PMID- 22924370 TI - Legume intake is inversely associated with metabolic syndrome in adults. AB - BACKGROUND: Studies on the association between legume intake and metabolic syndrome (MetS) are sparse. The objective of this study is to evaluate the association between legume intake, MetS, and its components. METHODS: This study was conducted on 80 subjects (48% female) with MetS as cases and 160 age and gender-matched healthy controls. Anthropometric measures, blood pressure, fasting blood glucose, and lipid profiles were evaluated by standard methods. Dietary data were collected using a food frequency questionnaire (FFQ) and legume intake was determined. MetS was defined according to the definition of the Adult Treatment Panel III. RESULTS: The mean (SD) intake of legumes was 1.4 (0.9) servings/week for cases and 2.3 (1.1) servings/week for control subjects (P < 0.05). After adjustment for potential confounders, decreases in mean systolic blood pressure, fasting blood glucose, and increase in HDL cholesterol levels were observed across increasing quartile categories of legume intake. After adjustments for life style and food groups, subjects in the highest quartile of legume intake had lower odds of having MetS compared with those in the lowest quartile [odds ratio (OR): 0.25; 95% CI: 0.11 - 0.64, P < 0.05], an association that weakened after adjustment for body mass index (BMI), but remained significant (OR: 0.28; 95% CI: 0.12 - 0.81, P < 0.05). CONCLUSIONS: Legume intake is inversely associated with the risk of having MetS and some of its components. PMID- 22924371 TI - Fish consumption in a sample of people in Bandar Abbas, Iran: application of the theory of planned behavior. AB - BACKGROUND: This study aimed to apply the conceptual framework of the theory of planned behavior (TPB) to explain fish consumption in a sample of people who lived in Bandar Abbass, Iran. We investigated the role of three traditional constructs of TPB that included attitude, social norms, and perceived behavioral control in an effort to characterize the intention to consume fish as well as the behavioral trends that characterize fish consumption. METHODS: Data were derived from a cross-sectional sample of 321 subjects. Alpha coefficient correlation and linear regression analysis were applied to test the relationships between constructs. The predictors of fish consumption frequency were also evaluated. RESULTS: Multiple regression analysis revealed that attitude, subjective norms, and perceived behavioral control significantly predicted intention to eat fish (R2 = 0.54, F = 128.4, P < 0.001). Multiple regression analysis for the intention to eat fish and perceived behavioral control revealed that both factors significantly predicted fish consumption frequency (R2 = 0.58, F = 223.1, P < 0.001). CONCLUSION: The results indicated that the models fit well with the data. Attitude, subjective norms, and perceived behavioral control all had significant positive impacts on behavioral intention. Moreover, both intention and perceived behavioral control could be used to predict the frequency of fish consumption. PMID- 22924372 TI - Effect of fish oil supplements on serum paraoxonase activity in female patients with rheumatoid arthritis: a double-blind randomized controlled trial. AB - BACKGROUND: This study was conducted to determine the effect of fish oil (FO) supplements on high density lipoprotein cholesterol (HDL-C), apolipoprotein-AI (Apo-AI), malondialdehyde (MDA), arylesterase (Aryl), and paraoxonase-1 (PON1) activity in female patients with rheumatoid arthritis (RA). METHODS: A total of 90 RA patients were randomly allocated into two groups that were treated with one FO pearl (1 gr) daily or placebo for three months in addition to conventional treatment. HDL-C, Apo-AI, and MDA levels as well as PON1 and Aryl activities were measured before and after treatment. Independent t-test was used to match basal parameters of case and control groups. Paired t-test was used to assess significance of the differences. Correlation was evaluated by Pearsons test and the statistical significance was set at P < 0.05. RESULTS: No significant differences were noted between FO and placebo patients with regards to age, disease duration, post-menopausal status, conventional therapy, body mass index (BMI), and numbers of swollen and tender joints at the beginning of the study. There were 83 patients who completed the three-month follow up. Serum levels of HDL-C (P = 0.018), Apo-AI (P = 0.165), Aryl (P = 0.026), and PON1 (P = 0.049) activity increased, whereas MDA levels decreased significantly with FO supplementation (P = 0.077). Significant correlations between increased PON1 activity and both HDL-C (P = 0.007, r = 0.419) and Apo-AI (P < 0.001, r = 0.742) concentrations as well as between HDL-C and Apo AI levels (P = 0.01, r = 0.403) were found. CONCLUSION: According to the results of this study, FO could increase serum HDL-C and PON1 levels and Aryl activity in female patients with RA. PMID- 22924373 TI - A comparative study of recombinant human basic fibroblast growth factor (bFGF) and erythropoietin (EPO) in prevention of skin flap ischemic necrosis in rats. AB - BACKGROUND: Impaired wound healing in ischemic tissues such as skin flaps resulting from inefficient perfusion is one major cause of complications in plastic surgery. In present experimental study, we investigated the effects of fibroblast growth factor-2 (FGF-2 or bFGF) and erythropoietin (EPO) in prevention of skin flap necrosis in rats. METHODS: 30 adult albino rats were randomized into 3 groups: in control group, normal saline solution; in EPO group, erythropoietin (100U/kg/day); and in FGF-2 group, fibroblast growth factor-2 (2.5ug/day) were injected subcutaneously in 3 daily consecutive doses in the designated flap areas before creating 4:1 random pattern skin flaps on the dorsum of animals. Areas of ischemic (SI) and necrotic (SN) zones were measured and compared in all groups one week after the flap creations. RESULTS: The necrotic zone (SN), as well as the ratio of the necrotic zone to the total discolored zone (SN/[SI+SN]) were substantially larger in the control group (41%+/-7%, 90%+/-6%) compared to the EPO (20%+/-2%, 42%+/-4%) and the FGF-2 (8%+/-2%, 19%+/-3%) groups (p<0.001). The differences in these values were also meaningful between the EPO and FGF-2 groups (p<0.001).Vascular density in ischemic area of the control group was less than those in the EPO and the FGF-2 groups; however, the differences were not statistically significant between any of the groups (p>0.05). CONCLUSIONS: Local administration of erythropoietin or fibroblast growth factor-2 in skin flaps could remarkably increase tissue viability and accelerate the wound healing process. However, the therapeutic effect of fibroblast growth factor-2 in preventing the necrotic event in ischemic zones of skin flaps is much more considerable than that of erythropoietin. PMID- 22924374 TI - Effect of intra-amygdala injection of lipopolysaccharide on kindling epileptogenesis in adult rats. AB - BACKGROUND: Contribution of neuroinflammation and epilepsy in the mature brain has elicited contradictory results with either excitatory or inhibitory effects. The amygdala is one of the main parts of the limbic system susceptible to insults that lead to neuroinflammation and epilepsy. This study evaluates the effect of chronic inflammation of the rat amygdala induced by lipopolysaccharide (LPS) on kindling epileptogenesis. METHODS: LPS (5ug/rat) was infused once daily into the basolateral amygdala (BLA) of adult rats. Daily electrical stimulation (150 - 300 uA, 100 Hz, monophasic square wave stimulus of 1 msec per wave, 2 sec duration) was delivered into BLA 30 min after LPS injections until the animals became fully kindled. RESULTS: LPS had no significant effect on the development of focal and generalized seizures. CONCLUSION: The type of neural system exposed to LPS and its specific electrophysiological properties seems to ascertain the final excitatory or inhibitory outcome. PMID- 22924375 TI - Associated factors with attention deficit hyperactivity disorder (ADHD): a case control study. AB - BACKGROUND: The current study attempted to investigate factors associated with attention deficit hyperactivity disorder (ADHD) in children without co morbidities. METHODS: In this case-control study, 164 ADHD children who attended the Child and Adolescent Psychiatric Clinics of Tabriz University of Medical Sciences, Iran were compared with 166 normal children selected in a random cluster method from primary and secondary schools. Clinical interviews based on DSM-IV-TR using K-SADS were used to diagnose ADHD cases and to select the control group. Participants were matched for age. We used chi-square and binary logistic regression for data analysis. RESULTS: Among the associated factors with ADHD were gender and maternal employment. Boys (OR 0.54; 95% confidence interval: 0.34 - 0.86) and those children with working mothers (OR 0.16: 95% confidence interval: 0.06 - 0.86) suffered more from ADHD. The birth season, family size, birth order, and parental kinship were not among risk factors for ADHD. CONCLUSION: The results of the study show that maternal employment and male gender are among the associated risk factors for ADHD. PMID- 22924376 TI - Identification of alpha-globin chain variants: a report from Iran. AB - BACKGROUND: This study was carried out to identify molecular and hematological features of alpha- globin chain variants and to evaluate their effects on the clinical and hematological characteristics in Iranian individuals suspected of having thalassemia trait. METHODS: Analysis of red blood cell indices, hemoglobin (Hb) analysis and genomic DNA isolation were carried out according to standard methods. For identifying the alpha-thalassemia (alpha-thal) genotype, investigation of common Mediterranean alpha-globin gene deletions (-alpha3.7, alpha4.2 -alpha20.5 and --MED) was performed by Gap-PCR. To characterize chain variants the entire alpha1 and alpha2 genes that spanned from the promoter region to the poly A tail were amplified and directly sequenced. RESULTS: In this study, 19 members of 17 unrelated families showed alpha-chain variants. Among these cases ten alpha-chain variantsthat included Hb Setif, Hb Constant Spring (Hb CS), Hb Handsworth, Hb Icaria, Hb Evanston, Hb Val de Marne, Hb Utrecht, Hb Savaria, Hb Adana, and Hb Dartmouth were identified. The hematological profile and molecular basis of these ten alpha-chain variants and the phenotypic consequences of their interactions were discussed. CONCLUSIONS: The knowledge of the spectrum of alpha-globin variants present in the Iranian population is essential for the molecular diagnosis and prevention of hemoglobinopathies. PMID- 22924377 TI - Surveillance of ventilator-associated pneumonia in a neonatal intensive care unit: characteristics, risk factors, and outcome. AB - BACKGROUND: This study determined the incidence, characteristics, risk factors, and outcomes of ventilator-associated pneumonia (VAP) in newborns hospitalized in a Neonatal Intensive Care Unit (NICU) in Tehran, Iran. METHODS: A prospective cohort study was carried out in the NICU of Mahdieh Hospital over a period of one year, from December 2008 to November 2009, on all neonates mechanically ventilated for more than 48 hours. VAP was diagnosed in accordance with the CDC definition of nosocomial pneumonias for patients younger than 12 months. Risk factors relevant to the development of VAP were studied. Multiple logistic and Cox regression analysis were performed to determine independent predictors for VAP and survival rate, respectively. RESULTS: There were 81 neonates enrolled. VAP occurred in 14 (17.3%), at a rate of 11.6/1000 days on the ventilator. Gram negative bacteria were the predominant etiologic agents. The most common bacterial isolates from the endotracheal aspirate were E. coli (21.4%), Klebsiella (21.4%), and Pseudomonas (14.1%). The only VAP predictor was sputum [odds ratio (OR) = 5.11, P = 0.02]. Mortality rate for VAP was 2/14 (14.3%). Duration of mechanical ventilation [hazard ratio (HR) = 0.96, P = 0.01], birth weight (HR = 0.81, P < 0.001), and purulent tracheal aspirate (HR = 0.25, P < 0.006) were independent predictors of overall survival. CONCLUSIONS: VAP occurs at a significant rate in mechanically ventilated newborns. Additional studies are needed to accurately determine the incidence and risk factors in order to develop effective preventive and therapeutic protocols. PMID- 22924378 TI - Association between the evidence of human papilloma virus infection in bladder transitional cell carcinoma in men and cervical dysplasia in their spouses. AB - BACKGROUND: Cervical cancer is one of the most common tumors in women. One of its risk factors is direct contact with viruses, in particular human papillomavirus (HPV). Recent studies have shown a prevalence of 2%-35% for HPV in cases with bladder cancer. In addition, some malignancies of the urogenital organs in males may promote the probability of cervical cancer in their spouses. In this study, the relationship between cervical dysplasia in women and evidence of HPV infection in tissue specimens obtained from their spouses' bladders has been investigated. METHODS: This cross-sectional study was conducted on 82 male patients with bladder tumors and their spouses between February 2004 and February 2007 in Tehran. We gathered data related to the histopathology of the transitional cell carcinoma (TCC) in men and Pap smear tests of their spouses. Tissue specimens of patients with bladder TCC were analyzed for HPV infection using polymerase chain reaction (PCR). HPV-positive specimens were tested for subtypes 16 and 18. RESULTS: In 24 (29.3%) men, bladder tumor samples were positive for HPV infection. Of these, we found HPV-18 infection in 9 (37.5%), while 3 (12.5%) were infected with HPV-16. In the spouses of those men with HPV infected bladder tumors, 4 (4.9%) cases had cellular dysplasia noted on their Pap smear tests. We found no dysplasia in those women whose husbands had bladder TCC, but no HPV infection (P = 0.006). CONCLUSION: It is possible to decrease the incidence of bladder TCC in men and cervical cancer in women through public education regarding the methods of transmission and avoidance of risky sexual behaviors. PMID- 22924379 TI - Effect modification in epidemiology and medicine. AB - Effect modification, also known as interaction or heterogeneity of effect, is an important concept in epidemiology. This article reviews the definition and types of effect modification, methods to detect effect modification, the reasons for observing effect modification in epidemiologic studies, the importance of choice of model in finding effect modifiers, and effect modifications that are important to public health. PMID- 22924380 TI - Isolated third nerve palsy from mild closed head trauma. AB - Head injury is a common occurrence in motor vehicle accidents. There are numerous causes for cranial nerve injury that include head trauma or other lesions. Few studies regarding cranial nerve injury following mild head trauma (GCS: 14 - 15) exist in the literature. The oculomotor nerve is a somatic and visceral motor nerve. When it is completely injured the result is ptosis, pupils that are non reactive to light and a lack of eye movement. We report the case of a completely isolated oculomotor nerve palsy associated with minor head injury. PMID- 22924381 TI - Photoclinic. PMID- 22924382 TI - The challenges of establishing an integrative medicine primary care clinic in Sydney, Australia. AB - BACKGROUND: In May 2006, a multidisciplinary community-based integrative medicine (IM) clinic was established in Sydney, Australia. It was designed to offer a wide range of IM services, for primary care and to serve as a referral center. OBJECTIVE: The aim of this study was to determine which factors were successful and which ones posed challenges for establishing this kind of clinic. METHOD: A study of the first 4 years of this primary care integrative medicine clinic was undertaken, using mixed methods--both qualitative and quantitative. RESULTS: Consistent with success factors identified in the literature, the clinic had an open-minded culture, credible supporters, suitable facilities, and clinically competent practitioners. Throughout the 4 years of its existence, the clinic strove to create an economically sustainable environment and to develop the service. As time progressed, it became evident that at least half of the practitioners needed to be biomedical doctors for the practice to remain viable. The challenges encountered were creating an economically sustainable clinic, managing high staff and practitioner turnover, finding the right balance between practitioners and services offered, developing an integrative medicine team, and building research capacity to evaluate the clinic and patient outcomes. CONCLUSIONS: Although many integrative medicine clinics fail to survive the first few years, after 4 years, this multidisciplinary primary care clinic had succeeded in establishing a viable health care service offering both integrative medicine and conventional, traditional, complementary, and alternative medicine. Finding the right mix of staff members and following up with evaluations to track progress are important. PMID- 22924383 TI - Evaluation of impact on health-related quality of life and cost effectiveness of Traditional Chinese Medicine: a systematic review of randomized clinical trials. AB - BACKGROUND: Traditional Chinese Medicine (TCM), an important part of health care in China and with increased popularity worldwide, has received extensive attention from governments at all levels. With the current emphasis on clinical efficacy and cost-effectiveness, TCM, as indeed do all other treatments, requires rigorous evidence to be considered in reimbursement decision-making. Nevertheless, despite the fact that TCM treatment has always been considered to possess the advantage of improving the health-related quality of life (HRQOL) of patients, there is a lack of systematic study about available evidence to assess the impact of TCM treatments on HRQOL of patients. OBJECTIVES: The current study aimed to perform a review of available literature to evaluate whether sufficient evidence existed to allow an assessment of the impact on HRQOL and cost effectiveness of TCM treatments. This information would support a recommendation for wider use of TCM in the clinical setting as well as its consideration for reimbursement. METHODS: A structured search was performed using data sources including MEDLINE,((r)) Cumulative Index for Allied Health and Nursing (CINAHL), PubMed, Cochrane database, EBSCO, SciSearch, Embase, and Google Scholar from 2000 to 2010. The search was supplemented with manual search after relevant articles were retrieved. RESULTS: After culling, a total 31 articles covering a range of TCM therapies applied to a variety of conditions were retrieved. The measurement tools used in these studies to assess impact in patient's HRQOL were mainly SF-36 based scales, but the results of HRQOL/patient preference studies were inconsistent and inconclusive. Of the 10 articles of cost-effectiveness evaluation of TCM treatments, the majority reported that TCM treatments resulted in better outcomes at a higher cost, but the incremental cost-effectiveness ratio was below the usually recommended thresholds. The overall results showed acupuncture and t'ai chi to be the most studied TCM-related therapies. CONCLUSIONS: The current review showed that there is a relative lack of cost effectiveness research in TCM. For those few empirical research available, the major emphasis is for acupuncture or t'ai chi showing the acceptance of these branches of TCM that are better understood by the scientific community. The current results also showed the need for studies with better designs and longer duration to ascertain the actual impact of TCM on patients' HRQOL as well as a need for a generic HRQOL instrument that is specific for TCM. PMID- 22924385 TI - Highly-precise measurements of ambient oxygen using near-infrared cavity-enhanced laser absorption spectrometry. AB - Highly precise measurements of ambient oxygen have been used to constrain the carbon budget, study photosynthesis, estimate marine productivity, and prescribe individual pollution events to their point of origin. These studies require analyzers that can measure ambient oxygen with ppm-level precision. In this work, we utilize near-infrared off-axis integrated cavity output spectroscopy (off-axis ICOS) to quantify ambient oxygen with a precision (1sigma, 100s) of +/-7 ppm. By periodically calibrating the instrument, the analyzer is capable of making oxygen measurements to better than +/-1 ppm (1sigma). The sensor is highly linear (R(2) > 0.9999) over a wide dynamic range (0-100% oxygen). The sensor was combined with a commercial CO(2)/CH(4)/H(2)O Analyzer, and used to make measurements of respiration and fossil fuel pollution events with oxidative ratios ranging from 1.15-1.60. Future improvements will increase the analyzer precision (1sigma, 100s) to better than +/-1.4 ppm, and decrease the periodic referencing interval to >1 h. By including an additional diode laser, the instrument can be extended to make simultaneous measurements of O(2), CO(2), and H(2)O to enable improved understanding of carbon dioxide production and loss. PMID- 22924384 TI - Arylnaphthalene lignan glycosides and other constituents from Phyllanthus reticulatus. AB - Two new arylnaphthalene lignan glycosides, named reticulatusides A (1) and B (2), together with eight known compounds were isolated from the 95% EtOH extract of the whole plant of Phyllanthus reticulatus. The structures of the new compounds were elucidated by spectroscopic methods. PMID- 22924386 TI - Evidence for the role of cognitive resources in flavour-flavour evaluative conditioning. AB - One way that dis/likes are formed is through evaluative conditioning (EC). In two experiments we investigated the role of cognitive resources in flavour-flavour conditioning. Both experiments employed an EC procedure in which three novel flavoured conditioned stimuli (CSs) were consumed. One was consumed with a pleasant unconditioned stimulus (US; CS+ sugar), one with an aversive US (CS+ saline), and a third with plain water (CS-). Half of participants in each experiment performed a cognitive load task during conditioning. We measured EC using self-reported measures of liking (Experiments 1 and 2) and an indirect measure of liking: drink pick-up latency (Experiment 2). In both experiments, differential EC was observed in the no cognitive load condition but not in the cognitive load condition. This pattern of results was observed in self-reported measures of liking as well as in the drink pick-up latency data. Results from both experiments show that EC occurs only when there are sufficient cognitive resources available. The fact that this was observed using both self-reported and indirect measures suggests that insufficient cognitive resources affect learning itself rather than merely obstructing reporting. PMID- 22924387 TI - The mitochondrial Amidoxime Reducing Component (mARC) is involved in detoxification of N-hydroxylated base analogues. AB - The "mitochondrial Amidoxime Reducing Component" (mARC) is the newly discovered fourth molybdenum enzyme in mammals. All hitherto analyzed mammals express two mARC proteins, referred to as mARC1 and mARC2. Together with their electron transport proteins cytochrome b(5) and NADH cytochrome b(5) reductase, they form a three-component enzyme system and catalyze the reduction of N-hydroxylated prodrugs. Here, we demonstrate the reductive detoxification of toxic and mutagenic N-hydroxylated nucleobases and their corresponding nucleosides by the mammalian mARC-containing enzyme system. The N-reductive activity was found in all tested tissues with the highest detectable conversion rates in liver, kidney, thyroid, and pancreas. According to the presumed localization, the N-reductive activity is most pronounced in enriched mitochondrial fractions. In vitro assays with the respective recombinant three-component enzyme system show that both mARC isoforms are able to reduce N-hydroxylated base analogues, with mARC1 representing the more efficient isoform. On the basis of the high specific activities with N-hydroxylated base analogues relative to other N-hydroxylated substrates, our data suggest that mARC proteins might be involved in protecting cellular DNA from misincorporation of toxic N-hydroxylated base analogues during replication by converting them to the correct purine or pyrimidine bases, respectively. PMID- 22924388 TI - Chiral interconversions of Pd and/or Au bis-metalated [32]octaphyrins(1,0,1,0,1,0,1,0) involving Huckel and Mobius macrocyclic topologies: a theoretical prediction. AB - Several Pd and/or Au bis-metalated [32]octaphyrins(1,0,1,0,1,0,1,0) were theoretically designed with rich conformations of Huckel or Mobius topology. The conformations and hence properties of macrocycles were tuned by twisting the active pyrrolic ring either clockwise (through multistep reactions with several Huckel and Mobius macrocyclic intermediates) or anticlockwise (via a direct Huckel-Huckel chiral interconversion). The encapsulated metal atoms, M(1), M(2) = Pd, Au, give different impacts on these two reaction processes. Facile occurrences of chiral interconversions between two enantiomers of bis-metalated octaphyrins were predicted with the largest activation barrier less than 40 kcal/mol. Some Au-coordinated octaphyrins (M(1) = Au) were demonstrated to be thermodynamically stable with large negative nucleus-independent chemical shift (NICS) values, which are comparable to those of the synthetic Pd-coordinated complexes. The free-base [32]octaphyrins(1,0,1,0,1,0,1,0) display the characteristic absorption spectra with distinct sharp Soret-like bands. After metalation, the Soret-like bands are red-shifted in different degrees along with the appearance of rather weak Q-like band. The heterometal-coordinated complexes (i.e., M(1) ? M(2)) show stronger and more splitting absorptions than the homometal-coordinated ones with M(1) = M(2). The hyperpolarizabilities sharply augment with the metalation in Huckel systems due to the destruction of the centrosymmetry and the increase in polarizability by coordinated metal atoms. PMID- 22924389 TI - Medical history of optic chiasm compression in patients with pituitary insufficiency affects skin temperature and its relation to sleep. AB - The hypothalamus is crucially involved in the circadian timing of the sleep-wake rhythm, yet also accommodates the most important thermoregulatory neuronal network. We have shown before that adults with pituitary insufficiency and history of chiasm compression due to a tumor with suprasellar extension fall asleep later and sleep shorter than those without such history and presumed hypothalamic involvement. To solidify the hypothesized link between vigilance and thermoregulation by the hypothalamus, we aimed to test the hypothesis that the presumed hypothalamic impairment in these patients also affects skin temperature and its association with sleep onset. In a case-control study of 50 patients (54.7 +/- 14.5 yrs of age, 30 males) with pituitary insufficiency, 33 of whom had a history of chiasm compression, ambulatory distal and proximal skin temperatures were assessed continuously for 24 h. Sleep parameters were assessed via questionnaire. Group differences in mean skin temperature, calculated over the wake and sleep periods separately, and group differences in the strength of association between pre-sleep skin temperature and sleep onset latency were compared. Results showed that patients with a medical history of chiasm compression had lower proximal skin temperature during the day (34.1 degrees C +/ .7 degrees C vs. 34.6 degrees C +/- .7 degrees C, p = .045). Additionally, the typical association between sleep onset latency and pre-sleep distal-to-proximal skin temperature gradient was absent in these patients (r = -.01, p = .96), whereas it was unimpaired in those without chiasm compression (r = -.61, p = .02). Thus, patients with history of chiasm compression show impaired skin temperature regulation in association with disturbed sleep. The findings support the hypothesis that a medical history of chiasm compression affects hypothalamic regulation of both vigilance and temperature, possibly by chronically affecting relevant nuclei, including the ventrolateral preoptic area and anterior hypothalamic preoptic area. PMID- 22924390 TI - Ocular actions of platelet-activating factor: clinical implications. AB - INTRODUCTION: To summarize the currently available evidence of platelet activating factor (PAF) implication in the pathogenesis of inflammatory ocular diseases. AREAS COVERED: PAF is a potent mediator of inflammation, implicated in the pathogenesis of chronic inflammatory disorders, allergic reactions, oncogenic transformation, wound repair and hypoxia-induced angiogenesis. It seems to be involved in the protection of ocular surface against various harmful agents through inflammatory processes, which can lead to chronic allergic reactions or even corneal neovascularization and haze, if they do not undergo regulation. Pathogenesis of uveitis, which is significant cause for the blurring of the visual system, has also been associated with PAF's activity. The hypoxia and the breakdown of the blood-retina barrier, observed in severe vascular retinal diseases, such as age-related macular degeneration and diabetic retinopathy, are associated with PAF ocular activity. EXPERT OPINION: Understanding the pathophysiology of vision threatening diseases could enhance clinical treatment and encourage experimental studies, which could be based on potential beneficial effects of new agents, such as PAF antagonists. PMID- 22924391 TI - Early cryptococcal meningitis following treatment with rituximab, fludarabine and cyclophosphamide in a patient with chronic lymphocytic leukemia. PMID- 22924392 TI - Comorbidity and metabolic context are crucial factors determining neurological sequelae of hypoglycaemia. AB - AIM: To determine risk factors for neurological sequelae following hypoglycemia. METHOD: We analysed the neurological outcome in 164 patients (mean age 10y 10mo, SD 5.9) following hypoglycemia due to three diseases with various metabolic contexts, different ages at onset, and combinations with comorbidity (fever/infection, hypoxia/ischemia): glycogen storage disease type I (GSDI) (21 patients, mean age at first hypoglycemic episode 3.8mo, SD 3.5); fatty acid beta oxidation defects (FAOD) (29 patients, mean age at first hypoglycemic episode 14.8mo, SD 12.6); and hyperinsulinism (HIns) (114 patients, mean age at first hypoglycemic episode 2.3mo, SD 4.7). RESULTS: Risk factors of poor neurological outcome were aetiology (p<0.006), comorbidity (p<0.001), and prolonged convulsions (p<0.001). Ordinal logistic regression showed that comorbidity (p<0.001) and status epilepticus (p=0.002) were the main determinants of sequelae. Asymptomatic hypoglycemia did not lead to sequelae, whatever the aetiology. Age was not correlated to sequelae, whatever the aetiology. The highest prevalence of hypoglycemic sequelae was found in FAOD and HIns combined with comorbidity, the lowest in GSDI (p<0.001) in which hypoglycemia is often asymptomatic, associated with increased plasma lactate, and rarely combined with comorbidity. INTERPRETATION: Hypoglycemia is severely deleterious for the brain in the context of fever/infection and/or hypoxia/ischemia, and status epilepticus. The metabolic context providing alternative fuels may improve neurological outcome. PMID- 22924393 TI - Synthesis and characterization of a novel prostate cancer-targeted phosphatidylinositol-3-kinase inhibitor prodrug. AB - The phosphatidylinositol-3-kinase/Akt (PI3K/Akt) pathway is constitutively activated in a substantial proportion of prostate tumors and is considered a key mechanism supporting progression toward an androgen-independent status, for which no effective therapy is available. Therefore, PI3K inhibitors, alone or in combination with other cytotoxic drugs, could potentially be used to treat cancer with a constitutive activated PI3K/Akt pathway. To selectively target advanced prostate tumors with a constitutive activated PI3K/Akt pathway, a prostate cancer specific PI3K inhibitor was generated by coupling the chemically modified form of the quercetin analogue LY294002 (HO-CH(2)-LY294002, compound 8) with the peptide Mu-LEHSSKLQL, in which the internal sequence HSSKLQ is a substrate for the prostate-specific antigen (PSA) protease. The result is a water-soluble and latent PI3K inhibitor prodrug (compound 11), its activation being dependent on PSA cleavage. Once activated, the L-O-CH(2)-LY294002 (compound 10) can specifically inhibit PI3K in PSA-secreting prostate cancer cells and induce apoptosis with a potency comparable to that of the original LY294002 compound. PMID- 22924394 TI - Scope and mechanistic analysis of the enantioselective synthesis of allenes by rhodium-catalyzed tandem ylide formation/[2,3]-sigmatropic rearrangement between donor/acceptor carbenoids and propargylic alcohols. AB - Rhodium-catalyzed reactions of tertiary propargylic alcohols with methyl aryl- and styryldiazoacetates result in tandem reactions, consisting of oxonium ylide formation followed by [2,3]-sigmatropic rearrangement. This process competes favorably with the standard O-H insertion reaction of carbenoids. The resulting allenes are produced with high enantioselectivity (88-98% ee) when the reaction is catalyzed by the dirhodium tetraprolinate complex, Rh(2)(S-DOSP)(4). Kinetic resolution is possible when racemic tertiary propargylic alcohols are used as substrates. Under the kinetic resolution conditions, the allenes are formed with good diastereoselectivity and enantioselectivity (up to 6.1:1 dr, 88-93% ee), and the unreacted alcohols are enantioenriched to 65-95% ee. Computational studies reveal that the high asymmetric induction is obtained via an organized transition state involving a two-point attachment: ylide formation between the alcohol oxygen and the carbenoid and hydrogen bonding of the alcohol to a carboxylate ligand. The 2,3-sigmatropic rearrangement proceeds through initial cleavage of the O-H bond to generate an intermediate with close-lying open-shell singlet, triplet, and closed-shell singlet electronic states. This intermediate would have significant diradical character, which is consistent with the observation that the 2,3-sigmatropic rearrangement is favored with donor/acceptor carbenoids and more highly functionalized propargylic alcohols. PMID- 22924396 TI - Measuring academic impact. PMID- 22924395 TI - In vitro and in vivo antimammary tumor activities and mechanisms of the apple total triterpenoids. AB - Consumption of apples has been linked to the prevention of various chronic diseases, including tumors and cardiovascular diseases. The apple total triterpenoid content (ATT) was extracted and concentrated from apple peels. The in vitro and in vivo antitumor activities, related antitumor mechanisms, were investigated. In vitro, ATT showed potent antiproliferative activities against human breast cancer (MCF-7, MDA-MB-231), human colon cancer (Caco-2), and human liver cancer (HepG2) cell lines. In vivo antitumor experiments showed that ATT could substantially reduce the occurrence and growth of mammary tumor with a good dose-dependent manner in a rat model. During the apoptosis in MDA-MB-231 cells induced by ATT, the caspase-independent pathway was involved in the process of apoptosis, and the mitochondrial transmembrane potential was markedly reduced. Also the PI3K/Akt/NF-kappaB pathway was activated. These results indicated that ATT-induced apoptosis of MDA-MB-231 cells may involve a mitochondrial-related pathway. PMID- 22924397 TI - Comment on "Upconversion and downconversion fluorescent graphene quantum dots: ultrasonic preparation and photocatalysis". PMID- 22924400 TI - Editorial: "Holy Grail" or "Siren's Song"? The dangers for the field of child psychology and psychiatry of over-focusing on the journal impact factor. PMID- 22924401 TI - Ion-brew: clarifying the influences on plant ionomes. PMID- 22924402 TI - Shaping the pathogen response by protein kinase triggered oxidative burst. PMID- 22924403 TI - The resilience and functional role of moss in boreal and arctic ecosystems. AB - Mosses in northern ecosystems are ubiquitous components of plant communities, and strongly influence nutrient, carbon and water cycling. We use literature review, synthesis and model simulations to explore the role of mosses in ecological stability and resilience. Moss community responses to disturbance showed all possible responses (increases, decreases, no change) within most disturbance categories. Simulations from two process-based models suggest that northern ecosystems would need to experience extreme perturbation before mosses were eliminated. But simulations with two other models suggest that loss of moss will reduce soil carbon accumulation primarily by influencing decomposition rates and soil nitrogen availability. It seems clear that mosses need to be incorporated into models as one or more plant functional types, but more empirical work is needed to determine how to best aggregate species. We highlight several issues that have not been adequately explored in moss communities, such as functional redundancy and singularity, relationships between response and effect traits, and parameter vs conceptual uncertainty in models. Mosses play an important role in several ecosystem processes that play out over centuries - permafrost formation and thaw, peat accumulation, development of microtopography - and there is a need for studies that increase our understanding of slow, long-term dynamical processes. PMID- 22924404 TI - Stoichiometric flexibility as a regulator of carbon and nutrient cycling in terrestrial ecosystems under change. AB - Ecosystems across the biosphere are subject to rapid changes in elemental balance and climatic regimes. A major force structuring ecological responses to these perturbations lies in the stoichiometric flexibility of systems - the ability to adjust their elemental balance whilst maintaining function. The potential for stoichiometric flexibility underscores the utility of the application of a framework highlighting the constraints and consequences of elemental mass balance and energy cycling in biological systems to address global change phenomena. Improvement in the modeling of ecological responses to disturbance requires the consideration of the stoichiometric flexibility of systems within and across relevant scales. Although a multitude of global change studies over various spatial and temporal scales exist, the explicit consideration of the role played by stoichiometric flexibility in linking micro-scale to macro-scale biogeochemical processes in terrestrial ecosystems remains relatively unexplored. Focusing on terrestrial systems under change, we discuss the mechanisms by which stoichiometric flexibility might be expressed and connected from organisms to ecosystems. We suggest that the transition from the expression of stoichiometric flexibility within individuals to the community and ecosystem scales is a key mechanism regulating the extent to which environmental perturbation may alter ecosystem carbon and nutrient cycling dynamics. PMID- 22924405 TI - Environmental and stoichiometric controls on microbial carbon-use efficiency in soils. AB - Carbon (C) metabolism is at the core of ecosystem function. Decomposers play a critical role in this metabolism as they drive soil C cycle by mineralizing organic matter to CO(2). Their growth depends on the carbon-use efficiency (CUE), defined as the ratio of growth over C uptake. By definition, high CUE promotes growth and possibly C stabilization in soils, while low CUE favors respiration. Despite the importance of this variable, flexibility in CUE for terrestrial decomposers is still poorly characterized and is not represented in most biogeochemical models. Here, we synthesize the theoretical and empirical basis of changes in CUE across aquatic and terrestrial ecosystems, highlighting common patterns and hypothesizing changes in CUE under future climates. Both theoretical considerations and empirical evidence from aquatic organisms indicate that CUE decreases as temperature increases and nutrient availability decreases. More limited evidence shows a similar sensitivity of CUE to temperature and nutrient availability in terrestrial decomposers. Increasing CUE with improved nutrient availability might explain observed declines in respiration from fertilized stands, while decreased CUE with increasing temperature and plant C : N ratios might decrease soil C storage. Current biogeochemical models could be improved by accounting for these CUE responses along environmental and stoichiometric gradients. PMID- 22924406 TI - A non-targeted metabolomics approach to quantifying differences in root storage between fast- and slow-growing plants. AB - Life history theory posits that slower-growing species should invest proportionally more resources to storage, structural (e.g. stems) or defence traits than fast-growing species. Previously, we showed that the slower-growing monocarpic plants had lower mortality rates and higher bolting probabilities after two defoliation events. Here, we consider a mechanistic explanation, that the slower-growing species invested relatively more resources to storage. We compared the relative levels of root storage compounds between eight monocarpic species using metabolomic profiling, and characterized plant growth using a size corrected estimate of relative growth rate (RGR). Growth rate was negatively correlated with the proportional allocation of root metabolites identified as sucrose, raffinose and stachyose and with amino acids known for their roles in nitrogen storage, particularly proline and arginine. The total amount and concentration of energy-corrected carbohydrates were also negatively correlated with RGR. Our results show for the first time that slower-growing species invest proportionally more of their total root metabolites in carbon- and nitrogen storage compounds. We conclude that the increased investment in these reserves is an important resource allocation strategy underlying the growth-survival trade off in plants. PMID- 22924407 TI - Fluorescence overlay antigen mapping using laser scanning confocal microscopy differentiates linear IgA bullous dermatosis from epidermolysis bullosa acquisita mediated by IgA. AB - BACKGROUND: Linear IgA bullous dermatosis (LABD) and epidermolysis bullosa acquisita (EBA) mediated by IgA antibodies belong to the group of autoimmune subepidermal bullous diseases mediated by IgA autoantibodies. Early and correct diagnosis is crucial because the management and prognosis of the diseases are different. OBJECTIVES: To determine whether fluorescence overlay antigen mapping using laser scanning confocal microscopy (FOAM-LSCM) is helpful in the differentiation between these diseases. METHODS: FOAM-LSCM and immunoblot studies were performed in 19 patients with disseminated tense blisters who presented with in vivo bound and circulating IgA antibasement membrane zone (BMZ) antibodies on immunofluorescence. RESULTS: Using FOAM-LSCM, in vivo bound IgA above type IV collagen, which is characteristic for LABD, was seen in 14 of the 19 cases, whereas five of the 19 cases had IgA deposits below type IV collagen, typical for EBA. Immunoblot studies showed that IgA antibodies in 11 of the 14 patients with deposits above type IV collagen reacted with different epitopes on BP180, mainly with LAD-1, which is a target antigen in LABD. Among the five patients with deposits below type IV collagen, one showed IgA antibodies to the 200-kDa laminin gamma-1 and one had antibodies to the 290-kDa type VII collagen, EBA antigen. Additionally, enzyme-linked immunosorbent assay with recombinant type VII collagen was positive in three of the five cases who presented with IgA deposits below type IV collagen on FOAM-LSCM. CONCLUSIONS: The results using FOAM-LSCM were consistent with those obtained on immunoblotting. FOAM-LSCM is useful in routine diagnostics in cases with undetectable circulating anti-BMZ antibodies, and can differentiate LABD from IgA-EBA, the former with in vivo bound IgA above type IV collagen and the latter with IgA deposits below type IV collagen. PMID- 22924408 TI - Novel traits of Trichoderma predicted through the analysis of its secretome. AB - Mycotrophic species of Trichoderma are among the most common fungi isolated from free soil, dead wood and as parasites on sporocarps of other fungi (mycoparasites). In addition, they undergo various other biotrophic associations ranging from rhizosphere colonization and endophytism up to facultative pathogenesis on such animals as roundworms and humans. Together with occurrence on a variety of less common substrata (marine invertebrates, artificial materials, indoor habitats), these lifestyles illustrate a wealthy opportunistic potential of the fungus. One tropical species, Trichoderma reesei, has become a prominent producer of cellulases and hemicellulases, whereas several other species are applied in agriculture for the biological control of phytopathogenic fungi. The sequencing of the complete genomes of the three species (T. reesei, T. virens, and T. atroviride) has led to a deepened understanding of Trichoderma lifestyle and its molecular physiology. In this review, we present the in silico predicted secretome of Trichoderma, and - in addition to the unique features of carbohydrate active enzymes - demonstrate the importance of such protein families as proteases, oxidative enzymes, and small cysteine-rich proteins, all of that received little attention in Trichoderma genetics so far. We also discuss the link between Trichoderma secretome and biology of the fungus. PMID- 22924410 TI - Emerging pathogens and their implications for the blood supply and transfusion transmitted infections. AB - The threat of infection by conventional transfusion-transmitted agents has been essentially eliminated from the blood supply in developed countries, thus focusing attention on the potential risk from emerging infections. Over recent years, actions have been taken to manage a number of such risks to blood safety. These illustrate the inherent variability of the agents concerned and of the measures needed to define and control the risk. PMID- 22924409 TI - A randomized trial of the safety, pharmacokinetics and pharmacodynamics of edoxaban, an oral factor Xa inhibitor, following a switch from warfarin. AB - AIMS: To evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of edoxaban, an oral direct factor Xa inhibitor, in healthy subjects switching from warfarin. METHODS: Seventy-two subjects were randomized to edoxaban 60 mg once daily (n = 48) or matching placebo (n = 24) for 5 days at 24 h after the last dose of warfarin treatment (INR 2.0 to 3.0). Safety/tolerability was the primary outcome measure. Pharmacokinetics, INR, aPTT, anti-FXa, thrombin generation and other coagulation assays were assessed. RESULTS: Seventy-two subjects were randomized and 64 subjects received at least one dose of edoxaban (n = 43) or placebo (n = 21) after achieving a target INR of 2.0 to 3.0 on warfarin treatment. Edoxaban 60 mg administered 24 h post-warfarin appeared to be safe and well tolerated. Adverse events were similar across treatments. For bleeding-related adverse events, eight subjects tested positive for faecal occult blood, five subjects during warfarin treatment and three subjects during edoxaban treatment. The mean (SD) baseline (post-dose of warfarin) INR was 2.31 (0.193) which increased to 3.84 (0.744) over 2 h during the edoxaban treatment (P < 0.0001 vs. placebo), returning to post-warfarin baseline within 12 h. A similar time course of effects for the other coagulation assays was observed in accordance with the drugs' mechanisms of action. CONCLUSION: In this study of healthy subjects, edoxaban administered 24 h after the last dose of warfarin was safe and well tolerated with transient increases across the various coagulation assays above post-warfarin baseline levels. PMID- 22924411 TI - SolTrack: an automatic video processing software for in situ interface tracking. AB - High-Resolution in situ observation of solidification experiments has become a powerful technique to improve the fundamental understanding of solidification processes of metals and alloys. In the present study, high-temperature laser scanning confocal microscopy (HTLSCM) was utilized to observe and capture in situ solidification and phase transformations of alloys for subsequent post processing and analysis. Until now, this analysis has been very time consuming as frame-by frame manual evaluation of propagating interfaces was used to determine the interface velocities. SolTrack has been developed using the commercial software package MATLAB and is designed to automatically detect, locate and track propagating interfaces during solidification and phase transformations as well as to calculate interfacial velocities. Different solidification phenomena have been recorded to demonstrate a wider spectrum of applications of this software. A validation, through comparison with manual evaluation, is included where the accuracy is shown to be very high. PMID- 22924412 TI - Comment on Some implications of the reported effects of Johrei on the viability and proliferation of cultured cancer cells in vitro. PMID- 22924413 TI - Epidemiology, quality, and reporting characteristics of systematic reviews of acupuncture interventions published in Chinese journals. AB - BACKGROUND: Systematic reviews (SRs) of acupuncture have become increasingly popular in China in recent years and have been published in large numbers. This review provides the first examination of epidemiological characteristics of these SRs as well as compliance with the PRISMA and AMSTAR guidelines. OBJECTIVES: The study objectives were to examine epidemiological and reporting characteristics as well as methodological quality of SRs of acupuncture published in Chinese journals. METHODS: Four (4) Chinese databases were searched (CBM, CSJD, CJFD, and Wanfang Database) for SRs of Traditional Chinese Medicine, from January 1978 through to December 2010. Data were extracted into Excel spreadsheets. The PRISMA and AMSTAR checklists were used to assess reporting characteristics and methodological quality, respectively. RESULTS: A total of 88 SRs were identified; none of the reviews had been updated. Less than one third (27.3%) were written by clinicians and one third (35.2%) were reported in specialty journals. The impact factor of 53.4% of the journals published was 0. Information retrieval was not comprehensive in more than half (59.1%) of the reviews. Less than half (36.4%) reported assessing for publication bias. Though 97.7% of the reviews used the term "systematic review" or "meta-analysis" in the title, no reviews reported a protocol and none were updated even after they had been published after 2 or more years. CONCLUSIONS: Although many SRs of acupuncture interventions have been published in Chinese journals, the reporting quality is troubling. Thus, the most urgent strategy is to focus on increasing the standard of SRs of acupuncture interventions, rather than continuing to publish them in great quantity. PMID- 22924414 TI - Acupuncture for shoulder pain after stroke: a systematic review. AB - OBJECTIVES: Shoulder pain, for which acupuncture has been used, is a common complication after a stroke that interferes with the function of the upper extremities. The aim of this systematic review is to summarize and evaluate the effects of acupuncture for shoulder pain after stroke. METHODS: Randomized controlled trials (RCTs) involving the effects of acupuncture for shoulder pain, published between January 1990 and August 2009, were obtained from the National Libraries of Medicine, MEDLINE((r)), CINAHL, AMED, Embase, Cochrane Controlled Trials Register 2009, Korean Medical Database (Korea Institute of Science Technology Information, DBPIA, KoreaMed, and Research Information Service System), and the Chinese Database (China Academic Journal). RESULTS: Among the 453 studies that were obtained (300 written in English, 137 in Chinese, and 16 in Korean), 7 studies met the inclusion criteria for this review. All of them were RCTs published in China and reported positive effects of the treatment. The quality of the studies was assessed by the Modified Jadad Scores (MJS) and the Cochrane Back Review Group Criteria List for Methodologic Quality Assessment of RCTs (CBRG); the studies scored between 2 and 3 points on MJS, and between 4 and 7 points on CBRG. CONCLUSIONS: It is concluded from this systematic review that acupuncture combined with exercise is effective for shoulder pain after stroke. It is recommended that future trials be carefully conducted on this topic. PMID- 22924415 TI - Integrating complementary medicine and supportive care: patients' perspectives toward complementary medicine and spirituality. AB - OBJECTIVES: The association of spirituality and complementary and alternative medicine (CAM) in oncology is unfolding as a research theme that may have practical implications in supportive care. The purpose of this study was to explore patients' perspectives regarding CAM and spirituality in order to address their needs in an integrative oncology program. METHODS: A 27-item questionnaire was developed that was administered by research assistants to a convenience sample of patients attending a community-based oncology service in northern Israel. RESULTS: Of the 509 respondents, 302 (67.4%) were undergoing active oncological treatment and 146 (32.6%) were doing follow-up surveillance. Current and/or previous year CAM use for oncology treatment was reported by 244 of 495 respondents (49%). A logistic regression model indicated that CAM use was associated with younger age, Jewish religion, and higher cancer-related spiritual quest [EXP(B)=2.102, 95% confidence interval for EXP(B) 1.236-3.575, p=0.006]. Compared with patients with lower spiritual quest, CAM users with higher spiritual quest expressed more expectations of CAM counseling in the following themes: improving daily functioning and coping with disease, lessening chemotherapy side-effects, and supporting the patient and family emotionally and spiritually. In addition, they expected their social worker to be more involved in building the CAM treatment plan compared to patients with average spiritual quest (35.3% versus 16.3%, p=0.038). CONCLUSIONS: Higher degree of spiritual quest is associated with increased CAM use, and higher expectations from CAM providers and social workers in the context of CAM integration within cancer care. PMID- 22924417 TI - Mechanistic insights into the antileukemic activity of hyperforin. AB - Hyperforin is a prenylated phloroglucinol present in the medicinal plant St John's wort (Hypericum perforatum). The compound has many biological properties, including antidepressant, anti-inflammatory, antibacterial and antitumor activities. This review focuses on the in vitro antileukemic effects of purified hyperforin and related mechanisms in chronic lymphoid leukemia (CLL) and acute myeloid leukemia (AML) - conditions that are known for their resistance to chemotherapy. Hyperforin induces apoptosis in both CLL and AML cells. In AML cell lines and primary AML cells, hyperforin directly inhibits the kinase activity of the serine/threonine protein kinase B/AKT1, leading to activation of the pro apoptotic Bcl-2 family protein Bad through its non-phosphorylation by AKT1. In primary CLL cells, hyperforin acts by stimulating the expression of the pro apoptotic Bcl-2 family member Noxa (possibly through the inhibition of proteasome activity). Other hyperforin targets include matrix metalloproteinase-2 in AML cells and vascular endothelial growth factor and matrix metalloproteinase-9 in CLL cells - two mediators of cell migration and angiogenesis. In summary, hyperforin targets molecules involved in signaling pathways that control leukemic cell proliferation, survival, apoptosis, migration and angiogenesis. Hyperforin also downregulates the expression of P-glycoprotein, a protein that is involved in the resistance of leukemia cells to chemotherapeutic agents. Lastly, native hyperforin and its stable derivatives show interesting in vivo properties in animal models. In view of their low toxicity, hyperforin and its derivatives are promising antileukemic agents and deserve further investigation in vivo. PMID- 22924418 TI - The changes of glucose and lipid metabolism in overweight middle-aged cynomolgus monkeys. AB - BACKGROUND: Excessive weight gain has been observed in middle-aged cynomolgus monkeys. This study was designed to investigate the metabolic characteristics in overweight monkeys. METHODS: A total of 26 cynomolgus monkeys were grouped based on gender and body weight. Overweight was operationally defined as body weight heavier than 9.6 kg in males and 7.5 kg in females. They were monitored for glucose and insulin in fasting state, serum parameters, and somatometric measurements. RESULTS: Higher measurements of weight, body mass index (BMI), waist, hip, and waist/hip ratio (WHR) were the somatometric characteristics of overweight monkeys. Abdominal fat deposition was more prominent in females. Elevated total cholesterol, HDL-C, LDL-C, and fasting glucose were observed in female overweight monkeys. Impaired insulin sensitivity occurred in overweight monkeys. CONCLUSIONS: Overweight could result in impaired insulin sensitivity. The metabolic changes were more prominent in female overweight monkeys. PMID- 22924419 TI - Phlebotomine sandflies and the spreading of leishmaniases and other diseases of public health concern. AB - Phlebotomine sandflies transmit pathogens that affect humans and animals worldwide. We review the roles of phlebotomines in the spreading of leishmaniases, sandfly fever, summer meningitis, vesicular stomatitis, Chandipura virus encephalitis and Carrion's disease. Among over 800 species of sandfly recorded, 98 are proven or suspected vectors of human leishmaniases; these include 42 Phlebotomus species in the Old World and 56 Lutzomyia species in the New World (all: Diptera: Psychodidae). Based on incrimination criteria, we provide an updated list of proven or suspected vector species by endemic country where data are available. Increases in sandfly diffusion and density resulting from increases in breeding sites and blood sources, and the interruption of vector control activities contribute to the spreading of leishmaniasis in the settings of human migration, deforestation, urbanization and conflict. In addition, climatic changes can be expected to affect the density and dispersion of sandflies. Phlebovirus infections and diseases are present in large areas of the Old World, especially in the Mediterranean subregion, in which virus diversity has proven to be higher than initially suspected. Vesiculovirus diseases are important to livestock and humans in the southeastern U.S.A. and Latin America, and represent emerging human threats in parts of India. Carrion's disease, formerly restricted to regions of elevated altitude in Peru, Ecuador and Colombia, has shown recent expansion to non-endemic areas of the Amazon basin. PMID- 22924421 TI - Always aware (Siempre pendiente): Latina mothers' parenting in high-risk neighborhoods. AB - Poor mothers contend with numerous economic and environmental stressors that may severely tax their resources for parenting. This study relied on qualitative interviews with 49 low-income Latina mothers to examine how parenting practices are used when facing neighborhood poverty and the threat of community violence. Several themes emerged in the interviews regarding mothers' approaches to parenting. First, Latina mothers in our sample relied on three strategies previously identified in the literature: (a) strict monitoring, (b) physical and/or social withdrawal from the neighborhood, and (c) engagement in positive, enriching activities for children. In concert with these strategies, these mothers also emphasized the importance of (d) establishing strong parent-child communication as essential to effective parenting in challenging environments. Furthermore, two overarching, culturally salient parental goals were identified: (a) fostering principles of educacion in their children and (b) maintaining astute parental awareness (estar pendiente) of children's physical as well as emotional states. Our findings illuminated culturally specific meanings that accompany parenting practices for low-income Latina mothers and underscored the importance of adapting culturally sensitive interventions for parents. PMID- 22924420 TI - Mini-review: the role of redox in Dopa-mediated marine adhesion. AB - 3, 4-Dihydroxyphenylanine (Dopa)-containing proteins are key to wet adhesion in mussels and possibly other sessile organisms also. However, Dopa-mediated adhesive bonding is a hard act to follow in that, at least in mussels, bonding depends on Dopa in both reduced and oxidized forms, for adhesion and cohesion, respectively. Given the vulnerability of Dopa to spontaneous oxidation, the most significant challenge to using it in practical adhesion is controlling Dopa redox in a temporally- and spatially defined manner. Mussels appear to achieve such control in their byssal attachment plaques, and factors involved in redox control can be measured with precision using redox probes such as the diphenylpicryl hydrazyl (DPPH) free radical. Understanding the specifics of natural redox control may provide fundamentally important insights for adhesive polymer engineering and antifouling strategies. PMID- 22924422 TI - Impact of posttraumatic stress disorder on the relationship quality and psychological distress of intimate partners: a meta-analytic review. AB - The authors conducted a meta-analysis of the literature on associations between trauma survivors' PTSD symptoms and the (a) relationship quality and (b) psychological distress of intimate partners. Results yielded a small combined effect size (r = -.24) for the association between PTSD and partners' perceived relationship quality. Gender and military status moderated this association with a larger effect size for female partners of male trauma survivors than for male partners of female trauma survivors and a larger effect size for military samples than for civilians. The effect size of the association between PTSD and partners' psychological distress was moderate in magnitude (r = .30). Analysis of hypothesized moderators indicated this association was stronger among military than civilian samples. The association was also stronger among samples of survivors who experienced traumatic events in the more distant past compared with those who experienced more recent events. Results support the systemic impact of one family member's PTSD symptoms and highlight areas for future research. PMID- 22924423 TI - Dyadic support in stepfamilies: buffering against depressive symptoms among more and less experienced stepparents. AB - Stepparenting is a common but stressful experience that has been linked to depressive symptoms. This study examines the associations among years of experience stepparenting, support, and validation from three sources-partner, the children's other biological parent (i.e., the spouse's ex-partner), and stepchildren-and depressive symptoms. Participants included 125 stepparents (84 female) recruited online. Using cross-sectional data, findings suggested that although support and validation from all three sources were associated with fewer depressive symptoms, when included in a single model, partner support emerged as the only significant predictor. Partner support was most associated with lower symptoms in the early years of stepparenting, highlighting the particular importance of partners' facilitation and support while the family is still adjusting to its new structure. PMID- 22924424 TI - Intergenerational transmission of attachment representations in the context of single parenthood in France. AB - Despite a dramatic increase of single parenthood during the past decades, parent child transmission of attachment has almost always been examined in intact families. A first objective of the current study was to examine child attachment in the context of single parenthood, both maternal and paternal. A second objective was to investigate intergenerational transmission of attachment in single parent-child dyads, compared with that observed in two-parent families. The samples consisted of 50 married couples and 43 single parents (22 mothers and 21 fathers), along with their 3- to 6-year-old children. Parental and child attachment representations were measured, respectively, with the Adult Attachment Interview and the Attachment Story Completion Task. Findings suggested that single parenthood per se was not linked to more insecure or disorganized child attachment representations. However, when the father was the sole caregiver, children exhibited more disorganized representations. Different patterns of mother-child associations were found according to family structure: associations were significant among married families but not among single-mother families. Results also replicated those of previous studies in finding a nonsignificant father-child association in two-parent families and a significant one in single father families, specifically with respect to hyperactivation. Further research is needed to clarify whether the differences found are attributable to different circumstances leading to single parenthood for men and women, or to parental gender itself. PMID- 22924425 TI - Purification implications on SERS activity of silica coated gold nanospheres. AB - Silica coated gold nanospheres are purified using traditional centrifugation steps and/or anion exchange chromatography and their resulting surface-enhanced Raman activities compared. Partially silica-coated gold nanostructures are retained on the column while fully coated nanostructures elute. As a result, SERS activity becomes less erratic and follows distance dependence models. This simple chromatographic step adds a quality control measure to nanoparticle preparation which could be extended to other solution-phase nanoparticles for more predictable function in future applications. PMID- 22924426 TI - Angular and linear spinal parameters associated with relaxed and erect postures in healthy subjects. AB - Spinal posture assessment is an essential component in physical evaluation. Establishing reproducible value of spinal curves is necessary for detecting postural changes. Therefore, the main objectives of this study were to assess the reproducibility of spinal curves in relaxed standing of healthy subjects and to explore the extent and pattern of change upon transition from relaxed to a fully erect posture. Thirty young women and men were measured twice over a 1 week interval for recording the cervical, thoracic, and lumbar curves values using an ultrasound-based system. Thereafter, additional 28 men and women extracted from the same reference group were assigned for a single measurement session, in which the same angular values were obtained in relaxed and fully erect standing postures, as well as stature using stadiometer. Excellent, good, and poor reproducibility indices, standard error of measurement (SEM), and smallest real difference (SRD), were noted for the thoracic (interclass correlation coefficient, ICC(3,3) = 0.95, SEM = 1.2 degrees , SRD = 3.3 degrees ), lumbar (ICC(3,3) = 0.85, SEM = 2.6 degrees , SRD = 7.2 degrees ), and cervical (ICC(3,3) = 0.68, SEM = 3.8 degrees , SRD = 10.5 degrees ) curves, respectively. Erecting from relaxed posture was associated with a significant (>SRD) thoracic angle difference of 7.2 degrees in men and 4.8 degrees in women which was expressed in a height increase of 1.3 cm in men and 0.8 cm in women. These changes were significantly larger in men in whom the angular and height differences were also significantly correlated (r = 0.7). Using this system, angular measurements are highly reproducible in the thoracic curvature in young healthy adults, leading to the use of the associated SRD as a criterion for thoracic postural flexibility. PMID- 22924427 TI - User perceptions of gaming interventions for improving upper extremity motor function in persons with chronic stroke. AB - Finding ways to engage patients with stroke in repetitive intervention protocols long-term is poorly understood, particularly from the patients' perspective. Limited information exists that combines clinical expertise as well as user feedback on improving gaming interaction. The purpose of this study was to utilize input from focus groups of gaming intervention users with chronic stroke to identify characteristics of gaming that influence user/patient engagement in the activity. Two focus groups (n = 10) were conducted with each group participant playing two different gaming systems. Following exposure to the two systems, guided group interview sessions occurred that consisted of open-ended questions encompassing areas of overall gaming system preference, aspects that were liked or disliked, background appearance, music options, feedback provided, as well as recommendations for change. Findings revealed that participants enjoyed playing the gaming systems. Three primary themes emerged differentiating the systems: (1) musical encouragement; (2) focus and attention; and (3) motivation provided by performance feedback. It was concluded that when selecting a gaming system for upper extremity rehabilitation, a clinician should select a system that provides user-relevant music options with a modifiable background appearance for progression from basic to more challenging, providing appropriate feedback in an effort to encompass to a variety of user performance levels. PMID- 22924428 TI - Kinesio tape management for superficial radial nerve entrapment: a case report. AB - This case report describes a 41-year-old female who presented with complaints of pain in the lower lateral one-third of the right radius extending into the first web space. Tinel's sign reproducing the patient's symptoms was elicited 8.2 cm above the radial styloid process. Physical diagnosis for superficial radial nerve entrapment was made based on a positive upper limb neural tension test 2a along with symptom reproduction during resisted isometrics to brachioradialis and wrist extensors. A potential first time successful conservative Kinesio tape (KT) management for entrapment of the superficial radial nerve is described in this report. An immediate improvement in grip strength and functional activities along with a reduction in pain and swelling was noted in this patient after the first treatment session, which was maintained at a 6 month follow-up. A model is proposed describing the mechanism by which KT application could be used to intervene for nerve entrapment interfaces. PMID- 22924429 TI - Regio- and chemoselective bromination of 2,3-diarylcyclopent-2-en-1-ones. AB - The bromination of 2,3-diarylcyclopent-2-en-1-ones under various conditions has been studied. It was found that depending on the brominating reagent and nature of solvent the bromine atom can be introduced at the 4- or 5-position of the ethene "bridge", as well as into the aryl moieties. Aryl group bromination is accomplished with such reagents as molecular bromine, N-bromosuccinimide, or tetrabutylammonium tribromide. 5-Bromocyclopentenones with very high efficiency can be obtained by the reaction with copper(II) bromide in methanol, while 4 bromoketones are prepared in n-propyl acetate. The developed methods can be highly useful for the synthesis of bromo-substituted 2-cyclopenten-1-ones and their close analogues, which are important synthons in organic synthesis and for the preparation of a variety of useful substances. PMID- 22924430 TI - Steroid receptor coactivator-3 as a potential molecular target for cancer therapy. AB - INTRODUCTION: Steroid receptor coactivator-3 (SRC-3), also called amplified-in breast cancer-1 (AIB1), is an oncogenic coactivator in endocrine and non endocrine cancers. Functional studies demonstrate SRC-3 promotes numerous aspects of cancer, through its capacity as a coactivator for nuclear hormone receptors and other transcription factors, and via its ability to control multiple growth pathways simultaneously. Targeting SRC-3 with specific inhibitors therefore holds future promise for clinical cancer therapy. AREAS COVERED: We discuss critical advances in understanding SRC-3 as a cancer mediator and prospective drug target. We review SRC-3 structure and function and its role in distinct aspects of cancer. In addition, we discuss SRC-3 regulation and degradation. Finally, we comment on a recently discovered SRC-3 small molecular inhibitor. EXPERT OPINION: Most targeted chemotherapeutic drugs block only a single cellular pathway. In response, cancers frequently acquire resistance by upregulating alternative pathways. SRC-3 coordinates multiple signaling networks, suggesting SRC-3 inhibition offers a promising therapeutic strategy. Development of an effective SRC-3 inhibitor faces critical challenges. Better understanding of SRC-3 function and interacting partners, in both the nucleus and cytosol, is required for optimized inhibitor development. Ultimately, blockade of SRC-3 oncogenic function may inhibit multiple cancer-related signaling pathways. PMID- 22924432 TI - Rational design of allosteric inhibitors and activators using the population shift model: in vitro validation and application to an artificial biosensor. AB - The population-shift mechanism can be used for rational re-engineering of structure-switching biosensors to enable their allosteric inhibition and activation. As a proof-of-principle example of this, we have introduced distal allosteric sites into molecular beacons, which are optical sensors for the detection of specific nucleic acid sequences. The binding of inhibitors and activators to these sites enabled the rational modulation of the sensor's target affinity-and thus its useful dynamic range-over 3 orders of magnitude. The convenience with which this was done suggests that the population-shift mechanism may prove to be a useful method by which allosteric regulation can be introduced into biosensors, "smart" biomaterials, and other artificial biotechnologies. PMID- 22924431 TI - Acceptability and potential effectiveness of a foot drop stimulator in children and adolescents with cerebral palsy. AB - AIM: Ankle-foot orthoses are the standard of care for foot drop in cerebral palsy (CP), but may overly constrain ankle movement and limit function in those with mild CP. Functional electrical stimulation (FES) may be a less restrictive and more effective alternative, but has rarely been used in CP. The primary objective of this study was to conduct the first trial in CP examining the acceptability and clinical effectiveness of a novel, commercially available device that delivers FES to stimulate ankle dorsiflexion. METHOD: Twenty-one individuals were enrolled (Gross Motor Function Classification System [GMFCS] levels I and II, mean age 13y 2mo). Gait analyses in FES and non-FES conditions were performed at two walking speeds over a 4 month period of device use. Measures included ankle kinematics and spatiotemporal variables. Differences between conditions were revealed using repeated measures multivariate analyses of variance. RESULTS: Nineteen individuals (nine females, 10 males; mean age 12y 11mo, range 7y 5mo to 19y 11mo; 11 at GMFCS level I, eight at level II) completed the FES intervention, with all but one choosing to continue using FES beyond that phase. Average daily use was 5.6 hours (SD 2.3). Improved dorsiflexion was observed during swing (mean and peak) and at foot-floor contact, with partial preservation of ankle plantarflexion at toe-off when using the FES at self-selected and fast walking speeds. Gait speed was unchanged. INTERPRETATION: This FES device was well accepted and effective for foot drop in those with mild gait impairments from CP. PMID- 22924433 TI - Correlation of the microculture-kinetic drug-induced apoptosis assay with patient outcomes in initial treatment of adult acute myelocytic leukemia. AB - Overall survival (OS) with acute myeloid leukemia (AML) remains poor. Determining prognostic factors will help in selecting patients for appropriate treatments. Our aim was to determine whether the level of drug-induced apoptosis (chemosensitivity) demonstrated by the microculture-kinetic drug-induced apoptosis (MiCK) assay significantly predicted outcomes after standard AML induction therapy. A total of 109 patients with untreated AML had blood and/or bone marrow aspirate samples analyzed for anthracycline-induced apoptosis using the MiCK assay. The amount of apoptosis observed over 48 h was determined and expressed as kinetic units of apoptosis (KU). Complete remission (CR) was significantly higher (72%) in patients with high idarubicin-induced apoptosis >3 KU compared to patients with apoptosis <= 3 KU (p = 0.01). Multivariate analysis showed the only significant variables to be idarubicin-induced apoptosis and karyotype. Median overall survival of patients with idarubicin-induced apoptosis >3 KU was 16.1 months compared to 4.5 months in patients with apoptosis <= 3 KU (p = 0.004). Multivariate analysis showed the only significant variable to be idarubicin-induced apoptosis. Chemotherapy-induced apoptosis measured by the MiCK assay demonstrated significant correlation with outcomes and appears predictive of complete remission and overall survival for patients receiving standard induction chemotherapy. PMID- 22924434 TI - Progress in the development and application of small molecule inhibitors of bromodomain-acetyl-lysine interactions. AB - Bromodomains, protein modules that recognize and bind to acetylated lysine, are emerging as important components of cellular machinery. These acetyl-lysine (KAc) "reader" domains are part of the write-read-erase concept that has been linked with the transfer of epigenetic information. By reading KAc marks on histones, bromodomains mediate protein-protein interactions between a diverse array of partners. There has been intense activity in developing potent and selective small molecule probes that disrupt the interaction between a given bromodomain and KAc. Rapid success has been achieved with the BET family of bromodomains, and a number of potent and selective probes have been reported. These compounds have enabled linking of the BET bromodomains with diseases, including cancer and inflammation, suggesting that bromodomains are druggable targets. Herein, we review the biology of the bromodomains and discuss the SAR for the existing small molecule probes. The biology that has been enabled by these compounds is summarized. PMID- 22924435 TI - High numbers of Staphylococcus aureus at three bathing beaches in South Florida. AB - While the value of Staphylococcus aureus as an indicator for non-enteric diseases is unclear, understanding its prevalence in recreational beaches would prove useful, given its pathogenic potential. Staphylococcus aureus levels were evaluated in sand and seawater at three beaches during one year. To elucidate possible S. aureus sources or colonization trends, distribution in sand was analyzed at Hollywood Beach. Staphylococcus aureus levels fluctuated throughout the study with highest average densities detected in dry sand (3.46 * 105 CFU/g, Hobie Beach), particularly at beaches with high human density. Patchy distribution marked hotspots of human use and/or possible bacterial re-growth. Data from a brief epidemiological survey indicated a very slight association between beach usage and skin conditions; suggesting high S. aureus levels in sand may not necessarily constitute major health risks. Because the possibility of disease transmission exists, particularly to children and immuno-compromised beach-goers, periodic surveying of highly frequented beaches seems warranted. PMID- 22924436 TI - Analysis of total contents of hydroxytyrosol and tyrosol in olive oils. AB - The most abundant phenolic compounds in olive oils are the phenethyl alcohols hydroxytyrosol and tyrosol. An optimized method to quantify the total concentration of these substances in olive oils has been described. It consists of the acid hydrolysis of the aglycons and the extraction of phenethyl alcohols with a 2 M HCl solution. Recovery of the phenethyl alcohols from oils was very high (<1% remained in the extracted oils), and the limits of quantification (LOQ) were 0.8 and 1.4 mg/kg for hydroxytyrosol and tyrosol, respectively. Precision values, both intraday and interday, remained below 3% for both compounds. The final optimized method allowed for the analysis of several types of commercial olive oils to evaluate their hydroxytyrosol and tyrosol contents. The results show that this method is simple, robust, and reliable for a routine analysis of the total concentration of these substances in olive oils. PMID- 22924437 TI - The interplay between expressed parental anxiety and infant behavioural inhibition predicts infant avoidance in a social referencing paradigm. AB - BACKGROUND: Anxiety aggregates in families. Environmental factors, such as modelling of anxious behaviours, are assumed to play a causal role in the development of child anxiety. We investigated the predictive value of paternal and maternal anxiety (lifetime anxiety disorders and expressed parental anxiety) on infants' fear and avoidance during encounters with social and nonsocial novel stimuli in a social referencing (SR) paradigm. METHODS: A total of 122 12-month old infants participated in this study separately with their fathers and mothers (parents with lifetime: social anxiety disorders [n=47], other types of anxiety disorders [n=33], comorbid social and other types of anxiety disorders [n=52] and without anxiety disorders [n=112]). Infants were confronted with a stranger and a mechanical dinosaur as novel stimuli in two SR situations. Infants' avoidance as well as fear and parents' expressed anxiety were observed. Infants' behavioural inhibition (BI) was separately observed in structured tasks. RESULTS: Parental lifetime anxiety disorders did not significantly predict infant fear or avoidance. Expressed parental anxiety interacted with BI to significantly predict infant avoidance, revealing a positive association between expressed parental anxiety and infant avoidance among infants with moderate-to-high BI. The association between infant avoidance and expressed parental anxiety was not significantly different for mothers and fathers, pointing to an equally important role of fathers at this young age. Infant fear was significantly predicted by infant BI, but not by expressed parental anxiety. CONCLUSIONS: Infants with a temperamental disposition for anxiety (BI) may learn from both paternal and maternal anxious signals and become avoidant towards novelty when their parents express anxiety. This link between expressed parental anxiety and infant avoidance for moderate-to-high BI children, that seems to hold across contexts and to be independent of lifetime parental anxiety disorders, may be a mechanism explaining early intergenerational transmission of anxiety. PMID- 22924438 TI - The tomato CAROTENOID CLEAVAGE DIOXYGENASE8 (SlCCD8) regulates rhizosphere signaling, plant architecture and affects reproductive development through strigolactone biosynthesis. AB - Strigolactones are plant hormones that regulate both above- and belowground plant architecture. Strigolactones were initially identified as rhizosphere signaling molecules. In the present work, the tomato (Solanum lycopersicum) CAROTENOID CLEAVAGE DIOXYGENASE 8 (SlCCD8) was cloned and its role in rhizosphere signaling and plant physiology assessed by generating knock-down lines. Transgenic SlCCD8 plants were generated by RNAi-mediated silencing. Lines with different levels of strigolactone reduction--confirmed by UPLC-MS/MS--were selected and their phenotypes investigated. Lines exhibiting reduced SlCCD8 levels displayed increased shoot branching, reduced plant height, increased number of nodes and excessive adventitious root development. In addition, these lines exhibited reproductive phenotypes such as smaller flowers, fruits, as well as fewer and smaller seeds per fruit. Furthermore, we show that strigolactone loading to the xylem sap is possibly restricted to orobanchol. Infestation by Phelipanche ramosa was reduced by 90% in lines with a relatively mild reduction in strigolactone biosynthesis and secretion while arbuscular mycorrhizal symbiosis, apical dominance and fruit yield were only mildly affected. This demonstrates that reduction of strigolactone biosynthesis could be a suitable tool in parasitic weed management. Furthermore, our results suggest that strigolactones are involved in even more physiological processes than so far assumed. PMID- 22924439 TI - Greetings from the new President of the Japanese Dermatological Association. PMID- 22924440 TI - Retraction. A sulfated proteoglycan as a novel ligand for CD44. PMID- 22924441 TI - Functional studies for the TRAF6 mutation associated with hypohidrotic ectodermal dysplasia. AB - BACKGROUND: Hypohidrotic ectodermal dysplasia (HED) is a rare condition characterized by hypotrichosis, hypohidrosis and hypodontia. A de novo heterozygous mutation in the tumour necrosis factor receptor-associated factor 6 gene (TRAF6) was recently identified in a patient with HED, while functional consequences resulting from the mutation remained unknown. OBJECTIVES: To determine the mechanism by which the TRAF6 mutation results in HED. METHODS: We performed coimmunoprecipitation (co-IP) studies to determine whether the mutation would affect the interaction of TRAF6 with transforming growth factor beta activated kinase 1 (TAK1), TAK1-binding protein 2 (TAB 2) and ectodysplasin-A receptor-associated death domain protein (EDARADD). We then performed co-IP and glutathione S-transferase-pulldown assays to determine the TRAF6 binding sequences in EDARADD. In addition, we analysed the effect of the mutant TRAF6 protein on the affinity between wild-type TRAF6 and EDARADD, as well as on EDARADD-mediated nuclear factor (NF)-kappaB activation. RESULTS: The mutant TRAF6 protein was capable of forming a complex with TAK1 and TAB 2 in a similar way to wild-type TRAF6. However, the mutant TRAF6 protein completely lost the affinity to EDARADD, while the wild-type TRAF6 bound to the N-terminal domain of EDARADD. Furthermore, the mutant TRAF6 inhibited the interaction between the wild-type TRAF6 and EDARADD, and also potentially reduced the EDARADD-mediated NF-kappaB activity. CONCLUSIONS: We conclude that the mutant TRAF6 protein shows a dominant negative effect against the wild-type TRAF6 protein, which is predicted to affect the EDARADD-mediated activation of NF-kappaB during the development of ectoderm derived organs, and to lead to the HED phenotype. PMID- 22924442 TI - Detection of tick-borne pathogens in ticks from migratory birds in the Baltic region of Russia. AB - We report the finding of tick-borne encephalitis (TBE)-virus in indigenous Ixodes ricinus (L.), 'Candidatus Neoehrlichia mikurensis' in exotic Ixodes frontalis (Panzer) and Rickettsia aeshlimannii in exotic Hyalomma marginatum Koch subadult ticks detached from 18.5% (107/577) infested migratory birds in the Baltic region of Russia. This is the first record of human pathogenic 'Candidatus N. mikurensis' in I. frontalis ticks. Moreover, seven other pathogens were identified in I. ricinus ticks. Spotted Fever Group rickettsiae were the predominant pathogen group and were detected only in nymphs. Future investigations are warranted to further characterize the role of birds in the epizootiology of tick-borne pathogens in this region. PMID- 22924443 TI - What determines skin sensitization potency-myths, maybes and realities. Part 1. The 500 molecular weight cut-off. AB - BACKGROUND: It is widely accepted that there is a molecular weight (MW) cut-off of 500, such that single chemicals with MWs higher than 500 cannot be skin sensitizers. If true, this could serve as a useful principle for designing non sensitizing chemicals. OBJECTIVES: To assess whether the 500 MW cut-off is a myth or a reality. METHODS: A database of 699 chemicals tested for skin sensitization in guinea pigs or mice was analysed to establish the number of tested chemicals with MW > 500, and to establish whether any of these were sensitizers. RESULTS: Only 13 (2%) of the 699 chemicals in the database have MW > 500. Of the 13 tested compounds with MW > 500 in the database, five are sensitizers and eight are non sensitizers. CONCLUSIONS: The 500 MW cut-off for skin sensitization is a myth, probably derived from the widespread misconception that ability to efficiently penetrate the stratum corneum is a key determinant of sensitization potency. The scarcity of sensitizers with MW > 500 simply reflects the general scarcity of chemicals with MW > 500. PMID- 22924444 TI - Possession attachment predicts cell phone use while driving. AB - OBJECTIVE: Distracted driving has become an important public health concern. However, little is known about the predictors of this health-risking behavior. One overlooked risk factor for distracted driving is the perceived attachment that one feels toward his or her phone. Prior research has suggested that individuals develop bonds toward objects, and qualitative research suggests that the bond between young drivers and their phones can be strong. It follows that individuals who perceive a strong attachment to their phone would be more likely to use it, even when driving. METHOD: In a nationally representative sample of young drivers (17-28 years), participants (n = 1,006) completed a survey about driving behaviors and phone use. Risk perception surrounding cell phone use while driving and perceived attachment to one's phone were assessed by administering factor-analytically derived scales that were created as part of a larger project. RESULTS: Attachment toward one's phone predicted the proportion of trips in which a participant reported using their cell phone while driving, beyond that accounted for by risk perception and overall phone use. Further, attachment predicted self-reported distracted driving behaviors, such as the use of social media while driving. CONCLUSIONS: Attachment to one's phone may be an important but overlooked risk factor for the engagement of potentially health-risking driving behaviors. Understanding that phone attachment may adversely affect driving behaviors has the potential to inform prevention and intervention efforts designed to reduce distracted driving behaviors, especially in young drivers. PMID- 22924445 TI - Predictors of growth and decline in leisure time physical activity from adolescence to adulthood. AB - OBJECTIVE: To study the predictors of change in leisure time physical activity (LTPA) from adolescence to young adulthood. METHOD: A nationally representative sample of 3,251 Norwegian students between 12 and 19 years of age were initially surveyed, and follow-up surveys were conducted three times over a 13-year period. The initial response rate was 97%, and retention rates for the three follow-up sessions were 92%, 84%, and 82%, respectively. Four groups of predictors were assessed: sociodemographics, such as gender, age, parental socioeconomic status, pubertal status, and grades; previous LTPA, such as the amount of LTPA and sports club membership; athletic self-concept and depressive symptoms; and other health behaviors, such as smoking, dieting, and body mass. Autoregressive cross-lagged analyses were supplemented with latent growth-curve analyses. RESULTS: Membership in a sports club and a positive athletic self-concept in adolescence predicted a high level of LTPA in adulthood, whereas smoking tobacco, high BMI, and depressive symptoms in adolescence predicted low levels of LTPA. CONCLUSIONS: Engaging adolescents in organized sports and enhancing adolescents' athletic self concept may increase the number of adults who are physically active. Preventive efforts to reduce tobacco consumption, obesity, and depression in adolescence may also contribute to an increase in adult LTPA. PMID- 22924446 TI - The role of dispositional factors in moderating message framing effects. AB - OBJECTIVE: Health messages can be framed in terms of the benefits of adopting a recommendation (gain frame) or the costs of not adopting a recommendation (loss frame). In recent years, research has demonstrated that the relative persuasiveness of gain and loss frames can depend on a variety of dispositional factors. This article synthesizes this growing literature to develop our understanding of the moderators of framing. METHOD: A systematic review of published literature on gain and loss framing was conducted. Articles were retrieved that tested the interaction between framing and moderators representing individual differences in how people are predisposed to think, feel, and behave. The significance and direction of framing main effects and interactions were noted and effect size data extracted where available. RESULTS: Forty-seven reports published between January 1990 and January 2012 were retrieved that reported on 50 unique experiments testing 23 different moderators. Significant interactions with typically small to medium simple main effect sizes were found in 37 of the 50 studies. Consistent interactions were found for factors such as ambivalence, approach-avoidance motivation, regulatory focus, need for cognition, and self-efficacy beliefs. Less consistent effects were found for perceived riskiness of activity, issue involvement, and perceived susceptibility/severity. CONCLUSION: The relative effectiveness of gain- or loss-framed messages can depend on the disposition of the message recipient. Tailoring the frame to the individual therefore has the potential to maximize message persuasiveness. PMID- 22924447 TI - Longitudinal relationships between fatigue and depression in cancer patients with depression and/or pain. AB - OBJECTIVE: Fatigue is one of the most common and debilitating symptoms reported by cancer patients, yet relatively little is understood about its etiology. Recently, as researchers have begun to focus attention on cancer-related fatigue (CRF), depression has emerged as its strongest correlate. Few longitudinal studies, however, have examined directionality of the relationship between the two symptoms. Our aim was to evaluate the directionality of the association between depression and CRF. METHOD: The study used a single-group cohort design of longitudinal data (N = 329) from a randomized controlled trial of an intervention for pain and depression in a heterogeneous sample of cancer patients. Participants met criteria for clinically significant pain and/or depression. Our hypothesis that depression would predict change in fatigue over 3 months was tested using latent variable cross-lagged panel analysis. RESULTS: Depressive symptoms and fatigue were strongly correlated in the sample (baseline correlation of latent variables = 0.71). Although the model showed good fit to the data, chi(2) (66, N = 329) = 88.16, p = .04, SRMR = 0.030, RMSEA = 0.032, and CFI = 1.00, neither structural path linking depression and fatigue was significant, suggesting neither symptom preceded and predicted the other. CONCLUSIONS: Our findings did not support hypotheses regarding the directionality of the relationship between depressive symptoms and fatigue. The clinical implication is that depression-specific treatments may not be sufficient to treat CRF and that instead, interventions specifically targeting fatigue are needed. PMID- 22924449 TI - Alcohol peer influence of participating in organized school activities: a network approach. AB - OBJECTIVE: This study compares the network influences on adolescent substance use from peers who coparticipated in school-sponsored organized activities (affiliation-based peer influence) with the influence both from their "nominated" friends (i.e., the adolescent named the alter as a friend), and only "reciprocated" friends (i.e., both adolescents mutually named each other as friends). The study also attempts to parse affiliation-based peer influence into the influence of both activity members who are also friends and those who are not, to address the potential confounding of these sources of peer influence. METHODS: The study data consisted of a nationally representative sample of 12,551 adolescents in Grades 7-12 within 106 schools from the Add Health data. Ordinal logistic regression was conducted to estimate the effects of affiliation-based and friends influence on alcohol use and drinking frequency. RESULTS: Peer influence via organized activities (sports or clubs) with drinkers and the influence of friends who drink had significant effects on adolescent drinking. Peer influence through club activities with drinkers had a stronger effect on any drinking behavior than through sports activities with drinkers. After decomposing peer influence through activities by friendship status, influence through sport activities had a significant effect on drinking only when coparticipant drinkers were also reciprocated friends (but not nominated friends), whereas influence through club activities had a significant effect on drinking, regardless of friendship reciprocation. CONCLUSIONS: The design and implementation of school based substance use prevention and treatment programs should consider the contextual effects of school-sponsored activities. PMID- 22924450 TI - Changes in psychological resources moderate the effect of socioeconomic status on distress symptoms: a 10-year follow-up among young adults. AB - OBJECTIVE: This study examined the impact of socioeconomic status (SES) on changes in psychological resources and whether these changes in turn moderate the effect of SES on distress symptoms in a prospective 10-year follow-up among young adults. METHOD: Subjects (N = 1239) were participants in two phases (1989, 22 years; 1999, 32 years) of a Finnish cohort study. The measurements were SES (basic education at 22 years, occupation at 32 years), distress symptoms (index of 17 somatic and mental complaints), and psychological resources (self-esteem, meaningfulness, locus of control). RESULTS: The results showed that lower SES is associated with poorer psychological resources both concurrently and prospectively. Lower SES at age 22 also predicted slower resource development, but only among females. In prospective analyses among both genders, changes in psychological resources moderated the effect of SES on distress symptoms: for those with losses in psychological resources, lower SES was associated with greater increases in distress between 22 and 32 years of age, whereas for those with stable or increasing resources, no effects of SES on distress were found. CONCLUSION: The results indicate that higher SES is associated with more favorable changes in psychological resources. In a longitudinal setting, SES differences in health seem to increase only when psychological resources decrease during the same period. The results emphasize the importance of dynamic conceptualizations of psychological resources in SES-health research. PMID- 22924448 TI - Depression is associated with reduced physical activity in persons with heart failure. AB - OBJECTIVE: Reduced physical activity is common in persons with heart failure (HF). However, studies of correlates and modifiers of physical activity in this population rarely employ objective measures. Motivational and mood related factors that may exacerbate inactivity in HF patients are also rarely investigated. In this study, we examined the relationship between physical activity as assessed by accelerometry, and depression in older adults with HF. METHODS: At baseline, older adults with HF (N = 96; 69.81 +/- 8.79) wore an accelerometer for seven days, and completed a brief fitness assessment, neuropsychological testing, and psychosocial measures including the Beck Depression Inventory-II (BDI-II). Medical and demographic history was obtained through record review and self-report. RESULTS: Accelerometer measures showed that HF patients averaged 587 minutes of sedentary time and just 0.31 minutes of vigorous activity per day. Lower daily step count was associated with poorer quality of life and reduced cognitive function. A multiple linear regression adjusting for important demographic and medical variables found that greater number of depressive symptoms on the BDI-II independently predicted lower physical activity levels. CONCLUSION: Consistent with past work, the current study found that low physical activity is common in older adults with HF. Depression is an independent predictor of physical activity in older adults with HF and reduced physical activity is associated with numerous adverse psychosocial outcomes. Future studies need to determine whether treatment of depression can boost physical activity and thus improve health outcomes in this population. PMID- 22924451 TI - Monitoring of exhaled carbon monoxide to promote preoperative smoking abstinence. AB - OBJECTIVE: Brief preoperative abstinence from cigarette smoking reduces risk for perioperative complications in surgical patients. This study tested the hypothesis that the efficacy of brief advice recommending abstinence the morning of surgery would be increased if patients were informed that exhaled carbon monoxide (CO) levels would be monitored to assess compliance. METHOD: Cigarette smokers scheduled for elective surgery were randomized to 2 groups. Subjects in both groups received brief advice (BA) recommending smoking abstinence on the morning of surgery. The CO-informed + BA group was also told that their smoking status would be checked before surgery using exhaled CO monitoring; the other group (BA only) was not. RESULTS: CO levels on the morning of surgery were not significantly different in the CO-informed + BA (n = 80) and BA-only groups (n = 84; M = 9.7, SD = 8.0, and M = 9.3, SD = 6.6 parts per million (ppm), respectively, p = .67). When the data from both groups were combined and compared with data from 506 additional surgical patients receiving only usual care, CO levels were significantly higher in those patients receiving usual care. CONCLUSIONS: Informing patients that their smoking status would be checked the morning of surgery by CO monitoring does not further increase the efficacy of BA to abstain the morning of surgery. PMID- 22924452 TI - How, when and why do young women use nutrition information on food labels? A qualitative analysis. AB - BACKGROUND: Nutrition information (NI) on food packaging offers a public health tool that could be used to promote informed consumer choice and aid consumption of a healthy diet. Research indicates that the use of NI can lead to reduced energy intake and lower BMI, but little evidence is available regarding how, when or why people use NI when making everyday food choices. METHODS: This qualitative study explored motivations and contexts surrounding the use of NI among 25 UK based female NI users aged 23-35 years, using semi-structured individual interviews. Verbatim transcripts were analysed using thematic analysis. RESULTS: Six themes were identified: (1) understanding and (2) functions of NI, (3) health versus appearance motives, NI use in (4) affective and (5) symbolic food episodes, and (6) competing point-of-purchase influences. Notable observations included a difficulty in understanding and converting NI into personally meaningful terms, and eschewal of NI in settings where food plays an affective or symbolic role (e.g. food consumption after a stressful day, buying food for a dinner party). CONCLUSIONS: We suggest evidence-based directions for future research and offer policy and practice recommendations, including the adoption of clear and consistent NI formats. PMID- 22924453 TI - Three-dimensional nanofabrication of polystyrene by focused ion beam. AB - Focused ion beam micromachining provides a maskless and resistless technique for prototyping of structures from thermoplastic polymers, an example being the production of polystyrene microcantilevers with potential applications as micro/nanoelectromechanical systems sensors and actuators. The applicability of FIB technology is, however, often restricted by the damage created by high energy gallium ion bombardment and local beam heating, which can affect the desired properties and limit the minimum achievable size of the fabricated structure. To investigate the ion-induced damage and determine the limitations of the technique for polymer nanofabrication, we have exposed thin polystyrene film to the ion beam at varying ion doses, ion energies and specimen temperatures. Ion doses ranging from 10(16) to 10(18) ions cm(-2) show significant gallium implantation, redeposition of sputtered material and chemical degradation in the polymer. Raman results show that the local heating in polymer during milling is severe at room temperature, damaging the aromatic carbon bonding (C = C) in particular. These observations are supported by the results of a beam heating model and Monte Carlo simulations. The chemical degradation caused by local beam heating is found to be significantly reduced by cooling the specimen to -25 degrees C during milling. This is consistent with observations that reversible and repeatable thermal actuation of a fabricated polystyrene-platinum microcantilever is only observed when the cantilever is prepared at low temperature milling. Using this cooling approach, polymer structures can be fabricated with dimensions as low as 200 nm and still retain a sufficient volume of material unaffected by the ion beam. PMID- 22924454 TI - Higher anticholinergic drug scale (ADS) scores are associated with peripheral but not cognitive markers of cholinergic blockade. Cross sectional data from 21 Norwegian nursing homes. AB - AIM: This study evaluated a presumed gradual decline in cognitive function in nursing home residents when the anticholinergic drug scale (ADS) score increased above 3. METHOD: The study population was recruited from 21 nursing homes in Norway. Criteria for inclusion were ADS score >= 3 and no severe dementia, defined as Clinical Dementia Rating (CDR) score < 3. Primary cognitive end points were CERAD 10-word lists for recall and Mini Mental State Examination (MMSE). Secondary end points were activity of daily living (ADL), mouth dryness and serum anticholinergic activity (SAA). The patients were stratified into subgroups according to ADS score, i.e. a reference group with score 3 and test groups with scores 4, 5 or >=6. End points were compared by analyses of covariance (ancova). RESULTS: Overall, 230 of the 1101 screened nursing home residents (21%) had an ADS score >=3. After exclusion 101 residents were recruited and among these, 87 managed to participate in the study. No significant differences were detected in cognitive function or ADL when ADS increased above 3 (P > 0.10), but in vivo (mouth dryness) and in vitro (SAA) measures of peripheral anticholinergic activity were significantly higher in patients with an ADS score >=6 (P < 0.01). CONCLUSION: The present study does not support a progressive decline in cognitive function with ADS score above 3. This might indicate that the ADS score model has limited potential to predict the clinical risk of central anticholinergic side effects in frail elderly patients receiving multiple anticholinergic drugs. PMID- 22924455 TI - Increased phospho-mTOR expression in megakaryocytic cells derived from CD34+ progenitors of essential thrombocythaemia and myelofibrosis patients. PMID- 22924456 TI - Polyethylene as a nonvolatile solid cosolvent phase for catalyst separation and recovery. AB - The studies described here show that a relatively low molecular weight, narrow polydispersity polyethylene (PE) wax (Polywax) can serve as a nontoxic and nonvolatile alternative to alkane solvents in monophasic catalytic organic reactions where catalysts and products are separated under biphasic conditions. In this application, a polymer that is a solid at room temperature substitutes for a conventional alkane solvent at ca. 80 degrees C. In addition to the advantages of being a nonvolatile, nontoxic, reusable solvent, this hydrocarbon polymer solvent, like heptane, can sequester nonpolar soluble polymer-bound catalysts after a reaction and separate them from products. The extent of this separation and its generality were studied using polyisobutylene (PIB)- and poly(4-dodecylstyrene)-bound dyes and PE-bound Pd allylic substitution catalysts, PIB-bound Pd cross-coupling catalysts, and PE- and PIB-bound metathesis catalysts. Catalytic reactions were effected using single-phase reaction mixtures containing Polywax with toluene, THF, or THF/DMF at ca. 80 degrees C. These solutions either separate into two liquid phases on addition of a perturbing agent or separate as a solid/liquid mixture on cooling. The hydrocarbon polymer bound dyes or catalysts either separate into the hot liquid Polywax phase or coprecipitate with Polywax and are subsequently isolated as a nonvolatile Polywax solid phase that contains the dye or the recyclable catalyst. PMID- 22924457 TI - Immunotherapy in allergies: an update. AB - The allergen specific immunotherapy is the administration, in IgE-mediated allergic patients, of a specific allergen in a gradually increased number to provide protection against allergic symptoms and inflammatory reaction. The current immunotherapeutic approaches occur by modulating the release of inflammatory mediators involved in allergic reaction and consequently the inhibition of allergic inflammatory process. Since 1997 several World Associations of Allergy, Asthma and Immunology, have reviewed this issue, seeking to establish standards for its use. Also many publications about the immunotherapy's efficacy, as well as, several guidelines on the use of immunotherapy in the treatment of allergic are available. This article will focus on the most current evidence about the immunotherapy in allergies regarding its mechanism of action, effectiveness and practical considerations. PMID- 22924458 TI - Theoretical approaches to estimating homolytic bond dissociation energies of organocopper and organosilver compounds. AB - Although organocopper and organosilver compounds are known to decompose by homolytic pathways among others, surprisingly little is known about their bond dissociation energies (BDEs). In order to address this deficiency, the performance of the DFT functionals BLYP, B3LYP, BP86, TPSSTPSS, BHandHLYP, M06L, M06, M06-2X, B97D, and PBEPBE, along with the double hybrids, mPW2-PLYP, B2-PLYP, and the ab initio methods, MP2 and CCSD(T), have been benchmarked against the thermochemistry for the M-C homolytic BDEs (D(0)) of Cu-CH(3) and Ag-CH(3), derived from guided ion beam experiments and CBS limit calculations (D(0)(Cu CH(3)) = 223 kJ.mol(-1); D(0)(Ag-CH(3)) = 169 kJ.mol(-1)). Of the tested methods, in terms of chemical accuracy, error margin, and computational expense, M06 and BLYP were found to perform best for homolytic dissociation of methylcopper and methylsilver, compared with the CBS limit gold standard. Thus the M06 functional was used to evaluate the M-C homolytic bond dissociation energies of Cu-R and Ag R, R = Et, Pr, iPr, tBu, allyl, CH(2)Ph, and Ph. It was found that D(0)(Ag-R) was always lower (~50 kJ.mol(-1)) than that of D(0)(Cu-R). The trends in BDE when changing the R ligand reflected the H-R bond energy trends for the alkyl ligands, while for R = allyl, CH(2)Ph, and Ph, some differences in bond energy trends arose. These trends in homolytic bond dissociation energy help rationalize the previously reported (Rijs, N. J.; O'Hair, R. A. J. Organometallics2010, 29, 2282 2291) fragmentation pathways of the organometallate anions, [CH(3)MR](-). PMID- 22924459 TI - Primary repair of giant hiatus hernia is satisfactory without mesh: early results of a method revisited. AB - Small numbers of hiatus hernias are very large, cause other nonreflux symptoms as well, and have an attached morbidity and mortality through strangulation. Patients are elderly and unfit, and surgery has been troubled by recurrence. Mesh repair has been advocated in an attempt to reduce a perceived high revision rate. We describe the early results of a "composite" form of laparoscopic repair where no mesh has been used, with excellent early results in levels of symptom control, morbidity, mortality, and recurrence, and discuss the value of mesh repair as a primary operation against the recently recognized severe complications secondary to mesh repair failure. The technique requires five-port laparoscopy, primary nonabsorbable diaphragmatic repair, and fixation of the cardioesophageal junction, within a fundoplication, to the posterior crural repair and median arcuate ligament. Thirty-eight patients with a mean age of 70 years operated on during 1 year had a recurrence of 6% but of minimal size by objective measure between 4 and 19 months of operation. Mesh repair in the literature is poorly supported, highly complicated, and by these figures not required. PMID- 22924460 TI - Inhibition of trace element release during Fe(II)-activated recrystallization of Al-, Cr-, and Sn-substituted goethite and hematite. AB - Aqueous Fe(II) reacts with Fe(III) oxides by coupled electron transfer and atom exchange (ETAE) resulting in mineral recrystallization, contaminant reduction, and trace element cycling. Previous studies of Fe(II)-Fe(III) ETAE have explored the reactivity of either pure iron oxide phases or those containing small quantities of soluble trace elements. Naturally occurring iron oxides, however, contain substantial quantities of insoluble impurities (e.g., Al) which are known to affect the chemical properties of such minerals. Here we explore the effect of Al(III), Cr(III), and Sn(IV) substitution (1-8 mol %) on trace element release from Ni(II)-substituted goethite and Zn(II)-substituted hematite during reaction with aqueous Fe(II). Fe(II)-activated trace element release is substantially inhibited from both minerals when an insoluble element is cosubstituted into the structure, and the total amount of release decreases exponentially with increasing cosubstituent. The limited changes in surface composition that occur following reaction with Fe(II) indicate that Al, Cr, and Sn do not exsolve from the structure and that Ni and Zn released to solution originate primarily from the bulk rather than the particle exterior (upper ~3 nm). Incorporation of Al into goethite substantially decreases the amount of iron atom exchange with aqueous Fe(II) and, consequently, the amount of Ni release from the structure. This implies that trace element release inhibition caused by substituting insoluble elements results from a decrease in the amount of mineral recrystallization. These results suggest that naturally occurring iron oxides containing insoluble elements are less susceptible to Fe(II)-activated recrystallization and exhibit a greater retention of trace elements and contaminants than pure mineral phases. PMID- 22924461 TI - Septo-optic dysplasia in childhood: the neurological, cognitive and neuro ophthalmological perspective. AB - AIM: We set out to describe 17 patients with septo-optic dysplasia (SOD), focusing on the little-explored neurological, cognitive, and neuro ophthalmological components. A further aim was to identify possible clinical correlations and phenotypic characteristics within the diagnostic spectrum. METHOD: We collected clinical-instrumental data (from the history, general and neurological examination, developmental assessment, and neuro-ophthalmological, neuroradiological, neurophysiological, and endocrinological evaluations) on nine males and eight females (mean age 34.4mo, SD 31.6; range 4mo-9y 6mo) diagnosed with SOD who were referred to our Centre of Child Neuro-ophthalmology between 1999 and 2010. RESULTS: We observed a heterogeneous clinical spectrum characterized by nervous system, visual, and endocrine dysfunctions; optic nerve involvement was present in all 17 children, midline brain defects in 14, and cortical developmental malformations in seven. Developmental/cognitive delay and relational and communication difficulties were observed in eight and seven children, respectively, and reduced visual acuity and oculomotor dysfunction were observed in all. Pituitary hormone deficiencies were present in nine children. INTERPRETATION: Nervous system involvement emerged as a key feature of SOD. As part of a holistic approach to the disease, particular attention should be paid to this aspect. The emergence of new clinical correlations and correlations between clinical features and three SOD subtypes opens the way for better clarification of this disease and, therefore, more targeted diagnosis, follow-up, and care of affected children. PMID- 22924463 TI - Towards an in vitro culture method for the rainbow trout pathogen Tetracapsuloides bryosalmonae. PMID- 22924462 TI - The effect of early deprivation on executive attention in middle childhood. AB - BACKGROUND: Children reared in deprived environments, such as institutions for the care of orphaned or abandoned children, are at increased risk for attention and behavior regulation difficulties. This study examined the neurobehavioral correlates of executive attention in post institutionalized (PI) children. METHODS: The performance and event-related potentials (ERPs) of 10- and 11-year old internationally adopted PI children on two executive attention tasks, go/no go and Flanker, were compared with two groups: children internationally adopted early from foster care (PF) and nonadopted children (NA). RESULTS: Behavioral measures suggested problems with sustained attention, with PIs performing more poorly on go trials and not on no-go trials of the go/no-go and made more errors on both congruent and incongruent trials on the Flanker. ERPs suggested differences in inhibitory control and error monitoring, as PIs had smaller N2 amplitude on go/no-go and smaller error-related negativity on Flanker. CONCLUSIONS: This pattern of results raises questions regarding the nature of attention difficulties for PI children. The behavioral errors are not specific to executive attention and instead likely reflect difficulties in overall sustained attention. The ERP results are consistent with neural activity related to deficits in inhibitory control (N2) and error monitoring (error-related negativity). Questions emerge regarding the similarity of attention regulatory difficulties in PIs to those experienced by non-PI children with ADHD. PMID- 22924464 TI - Clinical implementation of systematic medication reconciliation and review as part of the Lund Integrated Medicines Management model--impact on all-cause emergency department revisits. AB - WHAT IS KNOWN AND OBJECTIVE: Interventions involving medication reconciliation and review by clinical pharmacists can reduce drug-related problems and improve therapeutic outcomes. The objective of this study was to examine the impact of routine admission medication reconciliation and inpatient medication review on emergency department (ED) revisits after discharge. Secondary outcomes included the combined rate of post-discharge hospital revisits or death. METHODS: This prospective, controlled study included all patients hospitalized in three internal medicine wards in a university hospital, between 1 January 2006 and 31 May 2008. Medication reconciliation on admission and inpatient medication review, conducted by clinical pharmacists in a multiprofessional team, were implemented in these wards at different times during 2007 and 2008 (intervention periods). A discharge medication reconciliation was undertaken in all the study wards, during both control and intervention periods. Patients were included in the intervention group (n = 1216) if they attended a ward with medication reconciliation and review, whether they had received the intervention or not. Control patients (n = 2758) attended the wards before implementation of the intervention. RESULTS AND DISCUSSION: No impact of medication reconciliation and reviews on ED revisits [hazard ratio (HR), 0.95; 95% confidence interval (CI), 0.86-1.04]or event-free survival (HR, 0.96; 95% CI, 0.88-1.04) was demonstrated. In the intervention group, 594 patients (48.8%) visited the ED, compared with 1416 (51.3%) control patients. In total, 716 intervention (58.9%) and 1688 (61.2%) control patients experienced any event (ED visit, hospitalization or death). Because the time to a subsequent ED visit was longer for the control as well as the intervention groups in 2007 than in 2006 (P < 0.05), we re-examined this cohort of patients; the proportion of patients revisiting the ED was similar in both groups in 2007 (P = 0.608). WHAT IS NEW AND CONCLUSION: Routine implementation of medication reconciliation and reviews on admission and during the hospital stay did not appear to have any impact on ED revisits, re-hospitalizations or mortality over 6 month follow-up. PMID- 22924466 TI - Concurrence of bullous pemphigoid and herpetiform pemphigus with IgG antibodies to desmogleins 1/3 and desmocollins 1-3. PMID- 22924467 TI - (+)-Ascosalitoxin and vermelhotin, a calmodulin inhibitor, from an endophytic fungus isolated from Hintonia latiflora. AB - Chemical investigation of the endophytic MEXU 26343, isolated from the medicinal plant Hintonia latiflora, yielded the known polyketide vermelhotin (1) and a new salicylic aldehyde derivative, namely, 9S,11R-(+)-ascosalitoxin (2). The structure and absolute configuration of the new compound were established through extensive NMR spectroscopy and molecular modeling calculations at the DFT B3LYP/DGDZVP level, which included the comparison between theoretical and experimental optical rotation values. In addition, chemical transformations of 2 yielded suitable derivatives for NOESY and (1)H-(1)H NMR coupling constant analyses, which reinforce the stereochemical assignment. The potential affinity of 1 and 2 with (Ca(2+))(4)-hCaM in solution was measured using the fluorescent biosensor hCaM M124C-mBBr. The results showed that 1 bound to the protein with a dissociation constant (K(d)) of 0.25 +/- 0.04 MUM, close to that of chlorpromazine (K(d) = 0.64 +/- 0.03 MUM), a classical CaM inhibitor. The stoichiometry ratio of 1 to (Ca(2+))(4)-hCaM was 1:4, similar to other well-known CaM ligands. PMID- 22924468 TI - How factors present during the immediate interrogation situation produce short sighted confession decisions. AB - Suspects have a preexisting vulnerability to make short-sighted confession decisions, giving disproportionate weight to proximal, rather than distal, consequences. The findings of the current research provided evidence that this preexisting vulnerability is exacerbated by factors that are associated with the immediate interrogation situation. In Experiment 1 (N = 118), a lengthy interview exacerbated participants' tendency to temporally discount a distal consequence when deciding whether or not to admit to criminal and unethical behaviors. This effect was especially pronounced among less serious behaviors. In Experiment 2 (N = 177), participants' tendency to temporally discount a distal consequence when making admission decisions was exacerbated by the expectation of a lengthy interview; an effect that became stronger the longer the interview continued. These findings suggest that conditions of the immediate interrogation situation may capitalize on an already-present vulnerability among suspects to make short sighted confession decisions, thereby increasing the chances that even innocent suspects might confess. PMID- 22924465 TI - Targeting disease through novel pathways of apoptosis and autophagy. AB - INTRODUCTION: Apoptosis and autophagy impact cell death in multiple systems of the body. Development of new therapeutic strategies that target these processes must address their complex role during developmental cell growth as well as during the modulation of toxic cellular environments. AREAS COVERED: Novel signaling pathways involving Wnt1-inducible signaling pathway protein 1 (WISP1), phosphoinositide 3-kinase (PI3K), protein kinase B (Akt), beta-catenin and mammalian target of rapamycin (mTOR) govern apoptotic and autophagic pathways during oxidant stress that affect the course of a broad spectrum of disease entities including Alzheimer's disease, Parkinson's disease, myocardial injury, skeletal system trauma, immune system dysfunction and cancer progression. Implications of potential biological and clinical outcome for these signaling pathways are presented. EXPERT OPINION: The CCN family member WISP1 and its intimate relationship with canonical and non-canonical wingless signaling pathways of PI3K, Akt1, beta-catenin and mTOR offer an exciting approach for governing the pathways of apoptosis and autophagy especially in clinical disorders that are currently without effective treatments. Future studies that can elucidate the intricate role of these cytoprotective pathways during apoptosis and autophagy can further the successful translation and development of these cellular targets into robust and safe clinical therapeutic strategies. PMID- 22924469 TI - Modelling terrestrial nitrous oxide emissions and implications for climate feedback. AB - Ecosystem nitrous oxide (N2O) emissions respond to changes in climate and CO2 concentration as well as anthropogenic nitrogen (N) enhancements. Here, we aimed to quantify the responses of natural ecosystem N2O emissions to multiple environmental drivers using a process-based global vegetation model (DyN-LPJ). We checked that modelled annual N2O emissions from nonagricultural ecosystems could reproduce field measurements worldwide, and experimentally observed responses to step changes in environmental factors. We then simulated global N2O emissions throughout the 20th century and analysed the effects of environmental changes. The model reproduced well the global pattern of N2O emissions and the observed responses of N cycle components to changes in environmental factors. Simulated 20th century global decadal-average soil emissions were c. 8.2-9.5 Tg N yr(-1) (or 8.3-10.3 Tg N yr(-1) with N deposition). Warming and N deposition contributed 0.85+/-0.41 and 0.80+/-0.14 Tg N yr(-1), respectively, to an overall upward trend. Rising CO2 also contributed, in part, through a positive interaction with warming. The modelled temperature dependence of N2O emission (c. 1 Tg N yr(-1) K( 1)) implies a positive climate feedback which, over the lifetime of N2O (114 yr), could become as important as the climate-carbon cycle feedback caused by soil CO2 release. PMID- 22924470 TI - Direct synthesis of self-assembled ferrite/carbon hybrid nanosheets for high performance lithium-ion battery anodes. AB - Extensive applications of rechargeable lithium-ion batteries (LIBs) to various portable electronic devices and hybrid electric vehicles result in the increasing demand for the development of electrode materials with improved electrochemical performance including high energy, power density, and excellent cyclability, while maintaining low production cost. Here, we present a direct synthesis of ferrite/carbon hybrid nanosheets for high performance lithium-ion battery anodes. Uniform-sized ferrite nanocrystals and carbon materials were synthesized simultaneously through a single heating procedure using metal-oleate complex as the precursors for both ferrite and carbon. 2-D nanostructures were obtained by using sodium sulfate salt powder as a sacrificial template. The 2-D ferrite/carbon nanocomposites exhibited excellent cycling stability and rate performance derived from 2-D nanostructural characteristics. The synthetic procedure is simple, inexpensive, and scalable for mass production, and the highly ordered 2-D structure of these nanocomposites has great potential for many future applications. PMID- 22924471 TI - Incident diabetes and statins: the blemish of an undisputed heavy weight champion? PMID- 22924472 TI - The clinical value of sonourethrography after bipolar transurethral plasmakinetic prostatectomy. AB - The aim of this study was to assess the value of transrectal sonourethrography in the diagnosis of dysuria after bipolar transurethral plasmakinetic prostatectomy (TUPKP). Seventy-seven male patients with dysuria after TUPKP underwent transrectal sonourethrography. The clinical data were then compared with the surgical outcomes. The following pathologies were diagnosed: Bladder neck atresia (17/77), bladder orifice strictures (15/77), membranous urethral strictures (21/77), pars cavernosa urethral stricture (12/77), residual prostate gland (5/77), external urethral orifice stricture (2/77), calculi in the prostatic urethra (2/77), flap in the internal urethral orifice (2/77), and postoperative dysfunction of the bladder detrusor muscle (1/77). Transrectal sonourethrography is a reliable diagnostic method for numerous pathologies that occur in patients with dysuria after TUPKP and is a clinically useful tool. PMID- 22924473 TI - Design and optical trapping of a biocompatible propeller-like nanoscale hybrid. AB - Designing nanoscale objects with the potential to perform externally controlled motion in biological environments is one of the most sought-after objectives in nanotechnology. Different types of chemically and physically powered motors have been prepared at the macro- and microscale. However, the preparation of nanoscale objects with a complex morphology, and the potential for light-driven motion has remained elusive to date. Here, we go a step forward by designing a nanoscale hybrid with a propeller-resembling shape, which can be controlled by focused light under biological conditions. Our hybrid, hereafter "Au@DNA-origami", consists of a spherical gold nanoparticle with self-assembled, biocompatible, two dimensional (2D) DNA sheets on its surface. As a first step toward the potential utilization of these nanoscale objects as light-driven assemblies in biological environments, we show that they can be optically trapped, and hence translated and deposited on-demand, and that under realistic trapping conditions the thermally induced dehybridization of the DNA sheets can be avoided. PMID- 22924474 TI - An assessment of the compatibility of DSM-IV and proposed DSM-5 criteria in the diagnosis of cannabis use disorders. AB - The current study used an automated version of the substance use disorder diagnostic schedule-IV (SUDDS-IV) to assess DSM-IV (fourth edition of the Diagnostic and statistical manual of mental disorders) and two sets of proposed DSM-5 (fifth edition of the Diagnostic and statistical manual of mental disorders) cannabis use disorder criteria among adult prison inmates in the Minnesota Department of Corrections state prison system from 2000 to 2003. Initially proposed DSM-5 criteria had only two diagnostic designations (moderate and severe). A subsequent revision added a mild designation and required a greater number of positive findings for the severe diagnosis. The sample was composed of 7,672 (89.6% male) inmates. Inmates with no DSM-IV diagnoses and most who currently received a cannabis dependence diagnosis according to the DSM-IV guidelines will fit into corresponding DSM-5 categories (i.e., no diagnosis and severe cannabis use disorder, respectively). Some diagnostic criteria, in addition to those proposed for the DSM-5, emerged as cardinal indicators of moderate cannabis use disorder. The study's limitations are noted. PMID- 22924475 TI - beta-Lactoglobulin as a molecular carrier of linoleate: characterization and effects on intestinal epithelial cells in vitro. AB - The dairy protein beta-lactoglobulin (betalg) is known to bind hydrophobic ligands such as fatty acids. In the present work, we investigated the biological activity in vitro of linoleate once complexed to bovine betalg. Binding of linoleate (C18:2) to bovine betalg was achieved by heating at 60 degrees C for 30 min at pH 7.4, resulting in a linoleate/betalg molar binding stoichiometry of 1.1, 2.1, and 3.4. Two types of binding sites were determined by ITC titrations. Binding of linoleate induced the formation of covalent dimers and trimers of betalg. The LD(50) on Caco-2 cells after 24 h was 58 MUM linoleate. However, cell viability was unaffected when 200 MUM linoleate was presented to the Caco-2 cells as part of the betalg complex. The Caco-2 cells did not increase mRNA transcript levels of long chain fatty acid transport genes, FATP4 and FABPpm, or increase levels of the cAMP signal, in response to the presence of 50 MUM linoleate alone or as part of the betalg complex. Therefore, it is proposed that betalg can act as a molecular carrier and alter the bioaccessibility of linoleate/linoleic acid. PMID- 22924476 TI - Microtomographic quantification of hydraulic clay mineral displacement effects during a CO2 sequestration experiment with saline aquifer sandstone. AB - We combined a noninvasive tomographic imaging technique with an invasive open system core-flooding experiment and compared the results of the pre- and postflooded states of an experimental sandstone core sample from an ongoing field trial for carbon dioxide geosequestration. For the experiment, a rock core sample of 80 mL volume was taken from the 629 m Stuttgart Formation storage domain of a saline sandstone aquifer at the CCS research pilot plant Ketzin, Germany. Supercritical carbon dioxide and synthetical brine were injected under in situ reservoir p/T-conditions at an average flow rate of 0.1 mL/min for 256 h. X-ray computed microtomographic imaging was carried out before and after the core flooding experiment at a spatial voxel resolution of 27 MUm. No significant changes in microstructure were found at the tomographic imaging resolution including porosity and pore size distribution, except of an increase of depositional heterogeneous distribution of clay minerals in the pores. The digitized rock data were used as direct real microstructure input to the GeoDict software package, to simulate Navier-Stokes flow by a lattice Boltzmann equation solver. This procedure yielded 3D pressure and flow velocity fields, and revealed that the migration of clay particles decreased the permeability tensor probably due to clogging of pore openings. PMID- 22924477 TI - Detection of salmon pancreas disease virus in the faeces and mucus of Atlantic salmon, Salmo salar L., by real-time RT-PCR and cell culture following experimental challenge. PMID- 22924478 TI - Targeting PDGF pathway in pulmonary arterial hypertension. AB - INTRODUCTION: Pulmonary arterial hypertension (PAH) encompasses a rare potentially lethal group of diseases characterized by vasoconstriction, in situ thrombosis and vascular remodeling. Most of the existing therapies including endothelin receptor antagonists, prostacyclin and derivatives, or phsophodiesterase-5 inhibitors tackle mainly the endothelial dysfunction, leaving the remodeling suboptimally inhibited. This explains the disease progression that occurs even with combined therapies and the need for other therapies able to adequately inhibit the vascular remodeling. AREAS COVERED: Platelet-derived growth factor (PDGF) signaling pathway was demonstrated to be involved in the vascular remodeling in PAH, and therefore, it might be a desirable therapeutic target in this setting. This review discusses the pathogenic role of this pathway in PAH and its potential inhibitory approaches, focusing on imatinib as well as on the existing preclinical data on this compound. EXPERT OPINION: Preclinical studies demonstrated that PDGF inhibition with receptor antagonists such as imatinib reduces vascular remodeling. Therefore, PDGF might represent a plausible therapeutic target in this disease. However, compounds able to block this pathway via different mechanisms might also become potential PAH therapies. PMID- 22924479 TI - Observation of exceptionally low-lying pi-pi* excited states in oxidized forms of quadruple-decker phthalocyanine complexes. AB - Spectroscopic investigations have been performed for the oxidized forms of two quadruple-decker phthalocyanine complexes in order to clarify the electronic structures of multiply stacked pi-systems. Up to three-electron-oxidized species were isolated by using phenoxathiin hexachloroantimonate as the oxidant. As the oxidations proceed, the Q-bands in the visible region shift bathochromically along with the clear isosbestic points. The one- and three-electron-oxidized species exhibited typical pi-radical signals in the ESR spectra, while the neutral and two-electron oxidized species gave no indication of the presence of pi-radicals. The electronic transitions observed for the oxidized species reach even into the so-called fingerprint region in IR spectroscopy (~1000 cm(-1)). With the aid of theoretical calculations, these bands can be assigned to the pi pi* transitions. Our results provide new insights into pi-electronic systems having exceptionally small MO energy gaps. PMID- 22924480 TI - Mammalian multidrug resistance lipopentasaccharide inhibitors from Ipomoea alba seeds. AB - As part of an ongoing project to identify inhibitors of multidrug efflux pumps, three new resin glycosides, albinosides I-III (1-3), were isolated from a CHCl(3) soluble extract from the seeds of moon vine (Ipomoea alba). Their structures were established through NMR spectroscopy and mass spectrometry as partially acylated branched pentasaccharides derived from three new glycosidic acids, named albinosinic acids A-C (4-6). The same oligosaccharide core formed by two D quinovose, one D-glucose, and two L-rhamnose units was linked to either convolvulinolic or jalapinolic acid for 1 and 3, respectively. They were partially esterified with (2R,3R)-3-hydroxy-2-methylbutanoic, acetic, or 2-methyl 2-butenoic acid. Compound 2 has two D-quinovose and three L-rhamnose units, linked to convolvulinolic acid, and its esterifying residues were characterized as two units of 2-methyl-2-butenoic acid. The aglycone lactonization site was located at C-2 of the terminal rhamnose unit (Rha) for 1, at C-3 of the terminal rhamnose unit (Rha') for 2, and at C-3 of the second saccharide unit (Glc) for 3. Reversal of multidrug resistance by this class of plant metabolites was also evaluated in vinblastine-resistant human breast carcinoma cells (MCF-7/Vin). The noncytotoxic compound 3 exerted the strongest potentiation effect of vinblastine susceptibility to over 2140-fold, while a moderate activity was observed for 1 (3.1-fold) and 2 (2.6-fold) at a concentration of 25 MUg/mL. PMID- 22924481 TI - 'The chicken and egg thing': cognitive representations and self-management of multimorbidity in people with diabetes and depression. AB - OBJECTIVE: Diabetes with depression is common and can lead to poorer outcomes in both conditions. The existing literature has demonstrated that patients' single condition representations inform self-management, but less is known about the composition and impact of multimorbid representations. This study aimed to explore accounts of multimorbidity with a focus on the content of cognitive representations and reported management of diabetes and depression. DESIGN: Semi structured qualitative interviews were carried out with 17 people with diabetes and depression. Data were audio-taped, transcribed and analysed using an inductive thematic analysis and elements of grounded theory. RESULTS: The nature of multimorbid representations varied and some participants, in particular those who prioritised other conditions, described diabetes and depression as unrelated and managed each separately. Others saw interactions between conditions, often in terms of causation, and described how diabetes and depression management could be either integrated or conflicting. Problems taking multiple-medications were frequently described, but participants differed in the confidence with which they described representations of multimorbidity. CONCLUSION: People hold multimorbid representations that appear to impact on their preferred self-management. An awareness of patients' understanding of multimorbidity could have implications for the provision of care and intervention design in this population. PMID- 22924482 TI - The expression of dual-specificity phosphatase 1 mRNA is downregulated in lesional psoriatic skin. AB - BACKGROUND: The p38 mitogen-activated protein kinase (MAPK) plays an important role in inflammatory processes and displays increased activity in psoriasis. Dual specificity phosphatase 1 (DUSP1) is an important negative regulator of p38 MAPK activity. OBJECTIVES: To study mRNA expression of DUSP1 in normal human epidermal keratinocytes (NHEKs) stimulated with proinflammatory cytokines and to investigate DUSP1 in psoriatic skin. METHODS: NHEKs were cultured in vitro and punch biopsies were obtained from the skin of patients with psoriasis vulgaris and atopic dermatitis. mRNA expression was analysed by reverse transcription quantitative polymerase chain reaction (RT-qPCR). RESULTS: In NHEKs, interleukin (IL)-1beta induced DUSP1 mRNA expression in a rapid and time-dependent manner through the p38 MAPK/mitogen- and stress-activated kinase (MSK) signalling pathway. DUSP1 mRNA expression was demonstrated to be significantly downregulated in psoriatic skin lesions compared with paired samples of nonlesional psoriatic skin. This was in contrast to atopic dermatitis. The downregulation of DUSP1 mRNA in lesional psoriatic skin was not explained by the difference in the mRNA expression of the potential DUSP1 transcript stability-affecting proteins Hu antigen R or tristetraprolin. Furthermore, DUSP1 mRNA expression was shown not to increase during the early course of treatment with the antitumour necrosis factor alpha antibody adalimumab. CONCLUSIONS: In lesional psoriatic skin, the p38 MAPK negative feedback mechanism provided by DUSP1 seems to be inhibited. Downregulation of DUSP1 may contribute to the sustained inflammatory response seen in psoriasis. PMID- 22924483 TI - Novel monoclonal antibodies broadly reactive to human recombinant sapovirus-like particles. AB - Sapovirus (SaV), a member of the family Caliciviridae, is an important cause of acute epidemic gastroenteritis in humans. Human SaV is genetically and antigenically diverse and can be classified into four genogroups (GI, GII, GIV, and GV) and 16 genotypes (7 GI [GI.1-7], 7 GII, [GII.1-7], 1 GIV and 1 GV), based on capsid sequence similarities. Monoclonal antibodies (MAbs) are powerful tools for examining viruses and proteins. PAI myeloma cells were fused with spleen cells from mice immunized with a single type of recombinant human SaV virus-like particles (VLPs) (GI.1, GI.5, GI.6, GII.3, GIV, or GV). Sixty-five hybrid clones producing MAbs were obtained. Twenty-four MAbs were characterized by ELISA, according to their cross-reactivity to each VLP (GI.1, GI.5, GI.6, GII.2, GII.3, GII.4, GII.7, GIV, and GV). The MAbs were classified by this method into: (i) MAbs broadly cross-reactive to all GI, GII, GIV and GV strains; (ii) those reactive in a genogroup-specific; and (iii) those reactive in a genotype-specific manner. Further analysis of three broadly cross-reactive MAbs with a competitive ELISA demonstrated that at least two different common epitopes are located on the capsid protein of human SaVs in the four genogroups. The MAbs generated and characterized in this study will be useful tools for further study of the antigenic and structural topography of the human SaV virion and for developing new diagnostic assays for human SaV. PMID- 22924484 TI - Sex steroid hormone determination of the maternal brain: effects beyond reproduction. AB - Herein we discuss the effects of hormones on reproduction, but with a focus on the ripples that emanate from the main effects. That is, the role of hormones in reproductive events is both well-known and well accepted; less studied and understood are effects that appear to be ancillary to the primary objectives of the hormonal effects, which support, complement and extend their primary effects. We present evidence for how the hormonal stimulation of pregnancy constructs the maternal brain; makes it more efficient; enhances cognition; regulates stress responsiveness; modifies sensory systems (we discuss mainly olfaction); neurogenesis; and learning. Thus, steroid and other hormones and neuropeptides restructure the nervous system, particularly of females, to produce and regulate maternal behavior as well as behaviors and physiological systems that contribute to and support what is arguably the primary function of the hormones: survival and effective nurturance of the female's metabolic and genetic investment. PMID- 22924485 TI - Beyond the reproductive effect of sex steroids: their role during immunity to helminth parasite infections. AB - During the helminth infections, the immune system tends to be modulated by host's sex hormones. Actually, many studies show the reciprocal relationship between sex steroids, the immune system and the elimination or establishment of helminth parasites. Is well known that innate immune response determines the type of adaptive immune response, so the effects in the innate immune response by hormones may affect subsequent adaptive immunity. The sex steroids as estrogens, progesterone and testosterone regulate growth, differentiation, survival and function of many cell types that could be involved in process like homeostasis and immunity, but also have a direct effect on the helminthes, that may probably be mediated by specific receptors on these parasites. Sex steroids, parasites and immunity are closely connected, and their interconnection is involved in the maintenance of elimination or establishment of helminthes in an immunocompetent host. For that reason, understanding the action's mechanisms of sex steroids on immune cells and its direct effect on helminth parasites is important for further progress in the development of novel therapies for chronic helminth diseases associated to immune dysregulation. In this review, we will describe the effects of sex steroids on the immune response during helminth infections as well as the direct effect in these parasites, and the possible implications of these effects on the incidence of several helminth infections. PMID- 22924486 TI - Contingency in ecosystem but not plant community response to multiple global change factors. AB - Community and ecosystem responses to global environmental change are contingent on the magnitude of change and interacting global change factors. To reveal whether responses are also contingent on the magnitude of each interacting factor, multifactor, multilevel experiments are required, but are rarely conducted. We exposed model grassland ecosystems to six levels of atmospheric CO2 and six levels of nitrogen enrichment, applying the latter both chronically (simulating deposition) and acutely (simulating fertilization). The 66 treatments were maintained for 6 months under controlled growing conditions, with biomass harvested every 28 d and sorted to species. Aboveground plant productivity responses to CO2 were contingent on nitrogen amount, and the responses to nitrogen amount were dependent on whether applications were chronic or acute. Specifically, productivity responses to increasing CO2 concentrations were accentuated with higher nitrogen enrichments, and productivity was greater when higher nitrogen enrichments were applied acutely. Plant community composition was influenced only by nitrogen enrichment, where the co-dominant grass species with the greatest leaf trait plasticity increasingly dominated with higher nitrogen amounts. Community processes are considered to be unpredictable, but our data suggest that the prediction of the impacts of simultaneous global changes is more complex for ecosystem processes, given that their responses are contingent on the levels of interacting factors. PMID- 22924487 TI - An international pooled analysis for obtaining a benchmark dose for environmental lead exposure in children. AB - Lead is a recognized neurotoxicant, but estimating effects at the lowest measurable levels is difficult. An international pooled analysis of data from seven cohort studies reported an inverse and supra-linear relationship between blood lead concentrations and IQ scores in children. The lack of a clear threshold presents a challenge to the identification of an acceptable level of exposure. The benchmark dose (BMD) is defined as the dose that leads to a specific known loss. As an alternative to elusive thresholds, the BMD is being used increasingly by regulatory authorities. Using the pooled data, this article presents BMD results and applies different statistical techniques in the analysis of multistudy data. The calculations showed only a limited variation between studies in the steepness of the dose-response functions. BMD results were quite robust to modeling assumptions with the best fitting models yielding lower confidence limits (BMDLs) of about 0.1-1.0 MU g/dL for the dose leading to a loss of one IQ point. We conclude that current allowable blood lead concentrations need to be lowered and further prevention efforts are needed to protect children from lead toxicity. PMID- 22924489 TI - Anxiety in adolescents born preterm or with very low birthweight: a meta-analysis of case-control studies. AB - AIM: To determine if adolescents who are born very preterm (<32 wks; of gestation) and/or with very low birthweight (VLBW; <1500 g) have a higher risk of experiencing clinically significant anxiety problems. METHOD: We used a systematic review and meta-analysis. We searched the databases ISI Web of Knowledge, PubMed, PsycNET, Educational Resources Information Center (ERIC), Latin American and Caribbean Literature on the Health Sciences (LILACS), and Virtual Health Library (VHL) with equivalent search expressions (from the databases' inception to June 2011). Also, we screened reference lists of identified articles. We selected case-control studies of adolescents 11 to 20 years old who were very preterm/VLBW and had a matched reference group born at term with normal birthweight that reported a validated anxiety outcome measure. For data extraction, two authors independently reviewed titles, abstracts, and full articles identified through the searches. Subsequently two authors independently extracted data. RESULTS: We included six studies with 1519 adolescents (787 very preterm/VLBW, 732 comparisons). The general risk of developing clinically significant anxiety problems was nearly doubled (p<0.05) in the very preterm/VLBW population (OR 2.27, 95% confidence interval 1.15-4.47). The overall prevalences were 9.9% in the very preterm/VLBW group and 5.5% in the comparison group. INTERPRETATION: Those born very preterm/VLBW have an increased risk of developing clinically significant anxiety problems in adolescence. PMID- 22924488 TI - Predicted metabolic drug clearance with increasing adult age. AB - AIM: To determine the effect of increasing adult age on predicted metabolic drug clearance. METHOD: Predicted metabolic drug clearances (CLPT ) were determined using in vitro-in vivo extrapolation coupled with physiological-based pharmacokinetic modelling and simulation (IVIVE-PBPK) in Simcyp(r). Simulations were conducted using CYP-selective 'probe' drugs with subjects in 5 year age groups (20-25 to 90-95 years). CLPT values were compared with human pharmacokinetic data stratified according to age (young = 20-40 years and elderly = 65-85 years) and gender. Age-related changes in the physiological parameters used for IVIVE of CLPT were described. RESULTS: Predicted metabolic drug clearances decreased with increasing adult age to approximately 65-70 years: caffeine from 1.5 to 1.0 ml min(-1) kg(-1) (a 33% decrease), S-warfarin from 0.100 to 0.064 ml min(-1) kg(-1) (36%), S-mephenytoin from 4.1 to 2.5 ml min(-1) kg(-1) (39%), desipramine from 10.6 to 7.3 ml min(-1) kg(-1) (31%) and midazolam from 5.4 to 3.9 ml min(-1) kg(-1) (27%). Except for S-mephenytoin, predictions were within 3.5-fold of clearances from clinical studies when stratified by age and gender. A trend towards higher CLPT was observed in females, but this was only statistically significant in larger virtual trials. Physiological parameters that determine CLPT decreased with increasing adult age: mean microsomal protein g(-1) of liver, liver weight, hepatic blood flow and human serum albumin concentration. CONCLUSION: Decreased metabolic clearance in the elderly was predicted by Simcyp(r) and was generally consistent with limited clinical data for four out of five drugs studied and the broader literature for drugs metabolized by CYP enzymes. IVIVE-PBPK may be increasingly useful in predicting metabolic drug clearance in the elderly. PMID- 22924490 TI - The identification of vitamin E homologues in medicinal plant samples using ESI(+)-LC-MS3. AB - The aim of this study was to elucidate the presence of vitamin E homologues in medicinal plants. To identify various homologues in the matrix of medicinal plant samples, a method for simultaneous determination was developed using ESI(+)-LC MS3. A complete separation of each homologue was achieved within 20 min using a PFP column and an isocratic elution system of water/methanol (10:90, v/v) at a flow rate of 0.5 mL/min. The ESI-MS condition for each homologue was optimized, and the m/z value and the fragmentation pathway of each homologue were summarized. This LC-MS3 method made it possible to detect the homologues without the effect of matrix; therefore, high sensitive analysis was established, and then, the MS3 makes it possible to extract from plants with methanol only. The LC MS3 method was applied to identify the eight vitamin E homologues in 11 medicinal plants. PMID- 22924491 TI - Reusing steel and aluminum components at end of product life. AB - Reusing steel and aluminum components would reduce the need for new production, possibly creating significant savings in carbon emissions. Currently, there is no clearly defined set of strategies or barriers to enable assessment of appropriate component reuse; neither is it possible to predict future levels of reuse. This work presents a global assessment of the potential for reusing steel and aluminum components. A combination of top-down and bottom-up analyses is used to allocate the final destinations of current global steel and aluminum production to product types. A substantial catalogue has been compiled for these products characterizing key features of steel and aluminum components including design specifications, requirements in use, and current reuse patterns. To estimate the fraction of end-of-life metal components that could be reused for each product, the catalogue formed the basis of a set of semistructured interviews with industrial experts. The results suggest that approximately 30% of steel and aluminum used in current products could be reused. Barriers against reuse are examined, prompting recommendations for redesign that would facilitate future reuse. PMID- 22924492 TI - Processing pathway dependence of amorphous silica nanoparticle toxicity: colloidal vs pyrolytic. AB - We have developed structure/toxicity relationships for amorphous silica nanoparticles (NPs) synthesized through low-temperature colloidal (e.g., Stober silica) or high-temperature pyrolysis (e.g., fumed silica) routes. Through combined spectroscopic and physical analyses, we have determined the state of aggregation, hydroxyl concentration, relative proportion of strained and unstrained siloxane rings, and potential to generate hydroxyl radicals for Stober and fumed silica NPs with comparable primary particle sizes (16 nm in diameter). On the basis of erythrocyte hemolytic assays and assessment of the viability and ATP levels in epithelial and macrophage cells, we discovered for fumed silica an important toxicity relationship to postsynthesis thermal annealing or environmental exposure, whereas colloidal silicas were essentially nontoxic under identical treatment conditions. Specifically, we find for fumed silica a positive correlation of toxicity with hydroxyl concentration and its potential to generate reactive oxygen species (ROS) and cause red blood cell hemolysis. We propose fumed silica toxicity stems from its intrinsic population of strained three membered rings (3MRs) along with its chainlike aggregation and hydroxyl content. Hydrogen-bonding and electrostatic interactions of the silanol surfaces of fumed silica aggregates with the extracellular plasma membrane cause membrane perturbations sensed by the Nalp3 inflammasome, whose subsequent activation leads to secretion of the cytokine IL-1beta. Hydroxyl radicals generated by the strained 3MRs in fumed silica, but largely absent in colloidal silicas, may contribute to the inflammasome activation. Formation of colloidal silica into aggregates mimicking those of fumed silica had no effect on cell viability or hemolysis. This study emphasizes that not all amorphous silicas are created equal and that the unusual toxicity of fumed silica compared to that of colloidal silica derives from its framework and surface chemistry along with its fused chainlike morphology established by high-temperature synthesis (>1300 degrees C) and rapid thermal quenching. PMID- 22924493 TI - Viequeamide A, a cytotoxic member of the kulolide superfamily of cyclic depsipeptides from a marine button cyanobacterium. AB - The viequeamides, a family of 2,2-dimethyl-3-hydroxy-7-octynoic acid (Dhoya) containing cyclic depsipeptides, were isolated from a shallow subtidal collection of a "button" cyanobacterium (Rivularia sp.) from near the island of Vieques, Puerto Rico. Planar structures of the two major compounds, viequeamide A (1) and viequeamide B (2), were elucidated by 2D-NMR spectroscopy and mass spectrometry, whereas absolute configurations were determined by traditional hydrolysis, derivative formation, and chromatography in comparison with standards. In addition, a series of related minor metabolites, viequeamides C-F (3-6), were characterized by HRMS fragmentation methods. Viequeamide A was found to be highly toxic to H460 human lung cancer cells (IC(50) = 60 +/- 10 nM), whereas the mixture of B-F was inactive. From a broader perspective, the viequeamides help to define a "superfamily" of related cyanobacterial natural products, the first of which to be discovered was kulolide. Within the kulolide superfamily, a wide variation in biological properties is observed, and the reported producing strains are also highly divergent, giving rise to several intriguing questions about structure-activity relationships and the evolutionary origins of this metabolite class. PMID- 22924494 TI - Noninvasive prenatal diagnosis of Down syndrome in samples from Southwest Chinese gravidas using pregnant plasma placental RNA allelic ratio. AB - OBJECTIVE: The purpose of this research was to attempt a preliminary study of noninvasive prenatal diagnosis of Down syndrome in Southwest Chinese gravidas by using the plasma placental RNA allelic ratio. METHODS: The genotypes of the single-nucleotide polymorphisms (SNPs) located in the transcribed regions of the gene PLAC4 were detected in population samples collected in Southwest China by using polymerase chain reaction-restriction fragment length polymorphism, and SNPs with a higher heterozygosity were selected. Mass spectrometer analysis was adopted, and cases with the heterozygous SNPs on PLAC4 mRNA in maternal plasma were selected from 29 pregnancies with a euploid fetus and from 21 pregnancies with a trisomy-21 fetus, and then their RNA-SNP allelic ratios were further determined for noninvasive prenatal diagnosis of Down syndrome. RESULTS: Of all 50 singleton pregnancies, 37 gravidas were found with at least one heterozygous SNP on PLAC4 mRNA in maternal plasma. Among them, 13 pregnancies with a trisomy 21 fetus were detected by the analysis of the RNA-SNP allelic ratio. CONCLUSION: The plasma placental RNA allelic ratio can be used for noninvasive prenatal diagnosis of Down syndrome, if SNPs on PLAC4 mRNA in maternal plasma are heterozygous. PMID- 22924495 TI - Translation of a research-based genetic test on a rare syndrome into clinical service testing, with sotos syndrome as an example. AB - BACKGROUND AND AIMS: It is often the case that the genetic background of a rare disease has been solved, but the testing of a clinical patient can be performed only through research projects. Translating a research-based test into diagnostic service may also appear laborious and costly. Based on our molecular research of the genetics of Sotos syndrome, we developed a clinical laboratory test that is both effective and relatively inexpensive. METHODS AND RESULTS: Pilot testing was performed with samples of clinically diagnosed Sotos cases (n=13), and testing was continued with samples of patients who were suspected of having Sotos syndrome (n=161). The testing methods used were direct sequencing and multiplex ligation-dependent probe amplification. Sotos syndrome was a suitable example for test translation, because its genetic background was well established, and the demand for the test was expected to be fairly high. In the pilot phase, a mutation was detected in 12 out of 13 patients (92%), and in the second group, 49 out of 161 (30%) patients had a mutation in the NSD1 gene. CONCLUSIONS: In Sotos syndrome, detecting the mutation is valuable for the patient/family, while the value of a negative result is less clear and other differential diagnostic diagnoses should be considered. For successful translation of the research-based test into routine diagnostics, intense collaboration between clinicians, researchers, and diagnostic laboratory personnel is essential. PMID- 22924496 TI - Associations between TNFAIP3 gene polymorphisms and systemic lupus erythematosus: a meta-analysis. AB - OBJECTIVE: The aim of this study was to determine whether the tumor necrosis factor-alpha-inducible protein 3 (TNFAIP3) polymorphisms confer susceptibility to systemic lupus erythematosus (SLE) in ethnically different populations. METHODS: The authors conducted meta-analyses on associations between the TNFAIP3 polymorphisms and SLE susceptibility, using fixed and random effects models. RESULTS: A total of eight comparative studies were included in this meta analysis, which included four Asian, three European, and one African American population. Meta-analysis revealed that an association was found between the minor allele of rs2230926 and SLE in all subjects (odds ratio [OR] 1.848, 95% confidence interval [CI] 1.547-2.208, p<1.0*10(-9)). After stratification by ethnicity, the minor allele of rs2230926 was found to be significantly associated with SLE in Asians and Europeans (OR 1.821, 95% CI 1.495-2.219, p<1.0*10(-9); OR 2.251, 95% CI 1.830-2.768, p<1.0*10(-9)). In addition, a significant association was found between the minor allele of the rs5029939 polymorphism and the risk of developing SLE in all study subjects and Europeans (OR 1.804, 95% CI 1.255-2.592, p=0.001; OR 2.145, 95% CI 1.731-2.658, p<1.0*10(-9)). Furthermore, an association was found between the minor allele of rs3757173 and SLE in all study subjects (OR 1.540, 95% CI 1.017-2.331, p=0.041). However, no association was found between SLE susceptibility and rs6922466 (OR 0.953, 95% CI 0.812-1.120, p=0.561). CONCLUSIONS: This meta-analysis confirms that the TNFAIP3 polymorphisms are associated with SLE susceptibility in different ethnic groups, namely in Asians and Europeans. PMID- 22924497 TI - MTHFR polymorphic variant C677T is associated to vascular complications in sickle cell disease. AB - Vaso-occlusion is a determinant for most signs and symptoms of sickle-cell anemia (SCA). The mechanisms involved in the pathogenesis of vascular complications in SCA remain unclear. It is known that genetic polymorphisms associated with thrombophilia may be potential modifiers of clinical features of SCA. The genetic polymorphisms C677T and A1298C relating to the enzyme methylenetetrahydrofolate reductase (MTHFR), a clotting Factor V Leiden mutation (1691G->A substitution of Factor V Leiden), and the mutant prothrombin 20210A allele were analyzed in this study. The aim was to find possible correlations with vascular complications and thrombophilia markers in a group of SCA patients in Pernambuco, Brazil. The study included 277 SCA patients, divided into two groups: one consisting of 177 nonconsanguineous SCA patients who presented vascular manifestations of stroke, avascular necrosis, leg ulcers, priapism, and acute chest syndrome (group 1); and the other consisting of 100 SCA patients without any reported vascular complication (group 2). Molecular tests were done using either polymerase chain reaction (PCR) restriction fragment length polymorphism or allele-specific PCR techniques. Comparisons between the groups were made using the chi(2) test. The 677 CT and TT genotypes showed a significant risk of vascular complications (p=0.015). No significant associations between the groups were found when samples were analyzed for the MTHFR A1298C allele (p=0.913), Factor V G1691 (p=0.555), or prothrombin G20210A mutation (p=1.000). The polymorphism MTHFR C677T seemed to be possibly predictive for the development of some vascular complications in SCA patients among this population. PMID- 22924498 TI - Biofuels that cause land-use change may have much larger non-GHG air quality emissions than fossil fuels. AB - Although biofuels present an opportunity for renewable energy production, significant land-use change resulting from biofuels may contribute to negative environmental, economic, and social impacts. Here we examined non-GHG air pollution impacts from both indirect and direct land-use change caused by the anticipated expansion of Brazilian biofuels production. We synthesized information on fuel loading, combustion completeness, and emission factors, and developed a spatially explicit approach with uncertainty and sensitivity analyses to estimate air pollution emissions. The land-use change emissions, ranging from 6.7 to 26.4 Tg PM(2.5), were dominated by deforestation burning practices associated with indirect land-use change. We also found Brazilian sugar cane ethanol and soybean biodiesel including direct and indirect land-use change effects have much larger life-cycle emissions than conventional fossil fuels for six regulated air pollutants. The emissions magnitude and uncertainty decrease with longer life-cycle integration periods. Results are conditional to the single LUC scenario employed here. After LUC uncertainty, the largest source of uncertainty in LUC emissions stems from the combustion completeness during deforestation. While current biofuels cropland burning policies in Brazil seek to reduce life-cycle emissions, these policies do not address the large emissions caused by indirect land-use change. PMID- 22924499 TI - Reflectance confocal microscopy as a new tool in the in vivo evaluation of desquamative gingivitis: patterns in mucous membrane pemphigoid, pemphigus vulgaris and oral lichen planus. AB - BACKGROUND: Desquamative gingivitis refers to a clinical manifestation associated with several mucocutaneous disorders. The most common are mucous membrane pemphigoid, pemphigus vulgaris and lichen planus. Their specific diagnosis is better established by histopathological and immunofluorescence evaluation. OBJECTIVES: To examine cases of desquamative gingivitis using reflectance confocal microscopy (RCM) and compare the findings with those of normal gingiva. To compare RCM findings in desquamative gingivitis with conventional histopathology of the biopsied lesions, in order to establish criteria for this noninvasive diagnostic technique. METHODS: A total of 25 cases of suspected mucous membrane pemphigoid, pemphigus vulgaris and lichen planus were included. RCM was performed on the gingiva of a healthy person and on gingival lesions. All lesions were biopsied in order to perform a RCM-histopathological correlation. RESULTS: Reflectance confocal microscopy examination of the gingival lesions suspected to be mucous membrane pemphigoid revealed a separation at the level of the dermal-epidermal junction, filled with small, bright structures interpreted as blood cells. Histopathological and immunofluorescence findings confirmed the diagnosis. For pemphigus vulgaris, RCM features were intraepithelial clefts with round, detached cells interpreted as acantholytic keratinocytes, similar to the histopathological features. Hyperkeratosis and spongiosis associated with infiltration of inflammatory cells, seen as small, bright cells intermingling with the honeycomb keratinocyte epithelial structure, were seen in lichen planus. Mildly bright, round structures interpreted as necrotic keratinocytes and mildly bright, stellate structures, interpreted as melanophages, were also seen in the dermis. These features were present on histopathology, confirming the diagnosis of lichen planus. CONCLUSION: We propose that RCM is a useful tool to help distinguish between the three most common causes of desquamative gingivitis. PMID- 22924500 TI - Foreword: neurodegenerative diseases: challenges and opportunities. PMID- 22924501 TI - Modeling neurodegenerative diseases using stem cells: is it accelerating drug discovery? PMID- 22924502 TI - Targeting the cellular prion protein to treat neurodegeneration. PMID- 22924503 TI - Busy period for Bristol-Myers Squibb. PMID- 22924504 TI - The future of neurodegenerative diseases: emerging targets, treatments and technologies. PMID- 22924505 TI - Small-molecule Klotho enhancers as novel treatment of neurodegeneration. AB - The majority of neurodegenerative diseases have an important age component, and thus, understanding the molecular changes that occur during normal aging of the brain is of utmost relevance. In search for the basis of the age-related cognitive decline found in humans, monkeys and rodents, we study the rhesus monkey. Surprisingly, there is no loss of neurons in aged monkey brains. However, we reported white matter and myelin abnormalities in aged monkeys, similar to those observed in Alzheimer's disease and multiple sclerosis patients. In a microarray analysis comparing young and old monkey white matter, we discovered that Klotho is downregulated in the aged brain. We then asked whether there is a connection between the age-related cognitive decline, myelin abnormalities and Klotho downregulation. If such a connection is found, compounds that upregulate Klotho expression could become of therapeutic interest for the treatment of multiple sclerosis, and perhaps even Alzheimer's disease. PMID- 22924506 TI - An alternative approach to drug discovery for Alzheimer's disease dementia. AB - There are no drugs that halt the progression of any age-associated neurodegenerative disease. This may be due to the failure of drug developers to recognize that while there are mutations that predispose individuals to disease as they get older, the vast majority of neurodegenerative diseases arise from a confluence of multiple toxic insults. Thus, it is unlikely that the current single-target approach is going to yield useful drugs for these conditions. The identification of multi-target lead compounds is needed and their selection should be based upon a requirement for their efficacy in phenotypic screening assays that reflect the biology of the aging brain. This approach to neurodegenerative disease drug discovery is likely to produce safe and effective drugs. PMID- 22924507 TI - Glutamate transporter EAAT2: a new target for the treatment of neurodegenerative diseases. AB - Glutamate is the primary excitatory amino acid neurotransmitter in the CNS. The concentration of glutamate in the synaptic cleft is tightly controlled by interplay between glutamate release and glutamate clearance. Abnormal glutamate release and/or dysfunction of glutamate clearance can cause overstimulation of glutamate receptors and result in neuronal injury known as excitotoxicity. The glial glutamate transporter EAAT2 plays a major role in glutamate clearance. Dysfunction or reduced expression of EAAT2 has been documented in many neurodegenerative diseases. In addition, many studies in animal models of disease indicate that increased EAAT2 expression provides neuronal protection. Here, we summarize these studies and suggest that EAAT2 is a potential target for the prevention of excitotoxicity. EAAT2 can be upregulated by transcriptional or translational activation. We discuss current progress in the search for EAAT2 activators, which is a promising direction for the treatment of neurodegenerative diseases. PMID- 22924508 TI - Current understanding of LRRK2 in Parkinson's disease: biochemical and structural features and inhibitor design. AB - Since leucine-rich repeat kinase 2 (LRRK2) was linked to Parkinson's disease in 2004, kinase activity of LRRK2 has been believed to play a critical role in the pathogenesis of Parkinson's disease. As a result, identification of LRRK2 inhibitors has been a focus for drug discovery. However, most LRRK2 mutations do not simply increase kinase activity. In this review we summarize the potential mechanisms that regulate the kinase activity of LRRK2. We outline some currently available kinase inhibitors, including the identification of a DFG-out (type-II) inhibitor. Finally, we discuss the relationship of LRRK2 with tau and alpha synuclein. The fact that all three proteins are autophapgy-related provides a future strategy for the identification of LRRK2 physiological substrate(s). PMID- 22924510 TI - Therapeutic strategies for the treatment of spinal muscular atrophy. AB - Spinal muscular atrophy (SMA) is an inherited neurodegenerative disease that results in progressive dysfunction of motor neurons of the anterior horn of the spinal cord. SMA is caused by the loss of full-length protein expression from the survival of motor neuron 1 (SMN1) gene. The disease has a unique genetic profile as it is autosomal recessive for the loss of SMN1, but a nearly identical homolog, SMN2, acts as a disease modifier whose expression is inversely correlated to clinical severity. Targeted therapeutic approaches primarily focus on increasing the levels of full-length SMN protein, through either gene replacement or regulation of SMN2 expression. There is currently no US FDA approved treatment for SMA. This is an exciting time as multiple efforts from academic and industrial laboratories are reaching the preclinical and clinical testing stages. PMID- 22924514 TI - A HLA-A null allele (A*24:132N) with a stop codon in exon 3 generated by a point mutation. AB - Exons 1-8 of HLA-A*24:132N allele are identical to those of HLA-A*24:02:01:01, except for one nucleotide change at nt 746 in exon 3 from C to A. PMID- 22924511 TI - Natural products as a rich source of tau-targeting drugs for Alzheimer's disease. AB - Alzheimer's disease (AD) is a neurodegenerative disorder and the most common form of dementia, affecting more than 5.4 million people in the USA. Although the cause of AD is not well understood, the cholinergic, amyloid and tau hypotheses were proposed to explain its development. Drug discovery for AD based on the cholinergic and amyloid theories have not been effective. In this article we summarize tau-based natural products as AD therapeutics from a variety of biological sources, including the anti-amyloid agent curcumin, isolated from turmeric, the microtubule stabilizer paclitaxel, from the Pacific Yew Taxus brevifolia, and the Streptomyces-derived Hsp90 inhibitor, geldanamycin. The overlooked approach of clearing tau aggregation will most likely be the next objective for AD drug discovery. PMID- 22924515 TI - Evolution of innate and adaptive immune systems in jawless vertebrates. AB - Because jawless vertebrates are the most primitive vertebrates, they have been studied to gain understanding of the evolutionary processes that gave rise to the innate and adaptive immune systems in vertebrates. Jawless vertebrates have developed lymphocyte-like cells that morphologically resemble the T and B cells of jawed vertebrates, but they express variable lymphocyte receptors (VLRs) instead of the T and B cell receptors that specifically recognize antigens in jawed vertebrates. These VLRs act as antigen receptors, diversity being generated in their antigen-binding sites by assembly of highly diverse leucine-rich repeat modules. Therefore, jawless vertebrates have developed adaptive immune systems based on the VLRs. Although pattern recognition receptors, including Toll-like receptors (TLRs) and Rig-like receptors (RLRs), and their adaptor genes are conserved in jawless vertebrates, some transcription factor and inflammatory cytokine genes in the TLR and RLR pathways are not present. However, like jawed vertebrates, the initiation of adaptive immune responses in jawless vertebrates appears to require prior activation of the innate immune system. These observations imply that the innate immune systems of jawless vertebrates have a unique molecular basis that is distinct from that of jawed vertebrates. Altogether, although the molecular details of the innate and adaptive immune systems differ between jawless and jawed vertebrates, jawless vertebrates have developed versions of these immune systems that are similar to those of jawed vertebrates. PMID- 22924509 TI - Modulating macroautophagy: a neuronal perspective. AB - Over this past decade, macroautophagy has gained prominence in the field of adult onset neurodegeneration: from sporadic disorders such as Alzheimer's and Parkinson's disease, to genetic disorders such as Huntington's disease and frontotemporal dementia, the influence of this fundamental pathway has become an important topic of discussion. While there has been particular emphasis on the potential benefits of macroautophagy, there is growing literature that also suggests that macroautophagy contributes towards neurotoxicity. In this review, we discuss the molecular mechanism of macroautophagy and the currently available pharmacological tools, with special emphasis on mammalian macroautophagy in adult brain. Studies indicate that neuronal context strongly influences the role macroautophagy plays in maintaining cellular health, reflecting an ongoing need for better understanding of how macroautophagic regulation is achieved in the heavily differentiated and polarized neurons if we are to effectively manipulate it to treat neurodegenerative disease. PMID- 22924516 TI - Coming of leaf age: control of growth by hydraulics and metabolics during leaf ontogeny. AB - Leaf growth is the central process facilitating energy capture and plant performance. This is also one of the most sensitive processes to a wide range of abiotic stresses. Because hydraulics and metabolics are two major determinants of expansive growth (volumetric increase) and structural growth (dry matter increase), we review the interaction nodes between water and carbon. We detail the crosstalks between water and carbon transports, including the dual role of stomata and aquaporins in regulating water and carbon fluxes, the coupling between phloem and xylem, the interactions between leaf water relations and photosynthetic capacity, the links between Lockhart's hydromechanical model and carbon metabolism, and the central regulatory role of abscisic acid. Then, we argue that during leaf ontogeny, these interactions change dramatically because of uncoupled modifications between several anatomical and physiological features of the leaf. We conclude that the control of leaf growth switches from a metabolic to a hydromechanical limitation during the course of leaf ontogeny. Finally, we illustrate how taking leaf ontogeny into account provides insights into the mechanisms underlying leaf growth responses to abiotic stresses that affect water and carbon relations, such as elevated CO2, low light, high temperature and drought. PMID- 22924517 TI - Women's perception of postpartum pelvic floor dysfunction and their help-seeking behaviour: a qualitative interview study. AB - AIMS: To explore women's perception of postpartum pelvic floor dysfunction and their help-seeking behaviour. METHODS: We interviewed 26 patients from two family practitioners' populations in the Netherlands 1 month to 1 year after their vaginal delivery. The semi-structured interviews were independently encoded and analysed by three researchers according to a scoring list on determined topics. Three researchers independently coded themes discussed by the interviewees that matched main topics from the interview guide. In the case of encoding differences, the researchers deliberated on them until consensus was reached. FINDINGS: All women suffered from pelvic floor dysfunction such as urinary incontinence, pelvic floor pain, prolapse, haemorrhoids, anal fissure, constipation and dyspareunia. Midwives and gynaecologists did not prepare them for postpartum pelvic floor problems. The women did not expect the problems to be that severe. They hoped their problems would improve by themselves. The women talked to close initiates (female relatives and friends who had had deliveries themselves), who confirmed that the problems were an inevitable consequence of vaginal delivery and that there were no real treatment options. The women indicated they needed professional information about their pelvic floor problems but were ashamed to talk about them outside their inner circle. CONCLUSIONS: These women are uninformed about postpartum pelvic floor problems. They discuss their pelvic floor dysfunction with close initiates who feed their hope that the problems will resolve spontaneously. The women are not stimulated to seek professional help. However, the women do indicate they need professional information. They want to understand their problems and know how to deal with them. It is time for doctors and midwives to focus on the mother's health after delivery so that mothers will suffer less from pelvic floor problems, have more awareness of what they can do about them and call in medical aid. PMID- 22924518 TI - Effects of tacrolimus on an organotypic raft-culture model mimicking oral mucosa. AB - BACKGROUND: Tacrolimus ointment has shown efficacy in treating T-cell-mediated inflammatory oral mucosal diseases, including lichen planus. However, the safety of topical tacrolimus has been questioned, based on its possible association with malignant transformation. AIM: To evaluate the safety aspects of tacrolimus in a three-dimensional in vitro model of oral mucosa containing both multilayered epithelium and connective tissue (raft culture). METHODS: Raft cultures mimicking oral mucosa were topically exposed to tacrolimus, and the effects on cell proliferation and adhesion, epidermal growth factor receptors (EGFR, ERBB2, ERBB3, ERBB4), and apoptosis were evaluated with immunohistochemistry and terminal dUTP nick-end labelling, respectively. Results. The epithelium of the cultures was found to be slightly thinner, but no changes in cell proliferation or adhesion, apoptosis, or expression of epidermal growth factor receptors were detected. CONCLUSIONS: Our results suggest that short-term topical tacrolimus exposure of in vitro constructed oral mucosa does not induce changes in a number of factors known to be involved in malignant transformation. PMID- 22924519 TI - Ellagic acid and polyhydroxylated urolithins are potent catalytic inhibitors of human topoisomerase II: an in vitro study. AB - Ellagic acid (EA), a natural polyphenol abundant in fruits and common in our diet, is under intense investigation for its chemopreventive activity resulting from multiple effects. EA inhibits topoisomerase II, but the effects on the human enzyme of urolithins, its monolactone metabolites, are not known. Therefore, the action of several synthetic urolithins toward topoisomerases II was evaluated, showing that polyhydroxylated urolithins, EA, and EA-related compounds are potent inhibitors of the alpha and beta isoforms of human topoisomerase II at submicromolar concentrations. Competition tests demonstrate a dose-dependent relationship between ATP and the inhibition of the enzyme. Docking experiments show that the active compounds bind the ATP pocket of the human enzyme, thus supporting the hypothesis that EA and polyhydroxylated urolithins act as ATP competitive inhibitors of human topoisomerase II. PMID- 22924520 TI - MICA*066, a novel major histocompatibility complex class I-related chain A allele found by high-resolution HLA-matching tests for hematopoietic stem cell transplantation. AB - MICA*066, a novel MICA allele identified in HLA/MICA typing of a unrelated donor hematopoietic stem cell transplantation donor-patient pair. PMID- 22924521 TI - Co-carriage of qnrS1, floR, and bla(CTX-M-14) on a multidrug-resistant plasmid in Escherichia coli isolated from pigs. AB - Plasmid-mediated quinolone resistance (PMQR) determinants were widely distributed among Enterobacteriaceae. The objectives of the present study were to analyze PMQR-positive Escherichia coli isolates from pigs, and to investigate the association between these determinants and other resistant genes. A total of 129 porcine E. coli isolates were included in this study. The presence of PMQR, floR, bla(CTX-M-14), and bla(TEM-1) genes were detected by polymerase chain reaction (PCR) amplification and confirmed by subsequent sequencing. The PMQR-positive isolates were subjected to plasmid profiling, and transformation experiments were conducted to identify the quinolone resistance plasmids. The qnrS1 region of a quinolone resistance plasmid was cloned and sequenced. Among the 129 E. coli isolates, the positive rate for PMQR determinants was 42.6%, and the prevalence of qnr genes, aa(6')-Ib-cr, and qepA were 23.3%, 18.6%, and 0.8%, respectively. A qnrS1-carrying plasmid of 81 kb, named plasmid T078 (pT078), was detected from one multidrug-resistant isolate. Hybridization and PCR analysis confirmed that floR, bla(CTX-M-14), and bla(TEM-1) genes were also located on this plasmid. Sequence analysis identified the qnrS1 gene flanked by a truncated transposase gene. Moreover, complete tetracycline resistance genes tet(A) and tet(R) were found upstream of the qnrS1 gene, and floR gene was found downstream of the qnrS1 gene on the plasmid pT078. To our knowledge, this is the first study demonstrating the occurrence of qnrS1, floR, bla(CTX-M-14), bla(TEM-1), and tet(A) on one plasmid in E. coli isolated from food animals. PMID- 22924522 TI - Campylobacter coli isolates from Finnish farrowing farms using aminopenicillins: high prevalence of bla(OXA-61) and beta-lactamase production, but low MIC values. AB - Antimicrobial treatment of animals may select resistance in Campylobacter to antimicrobial agents belonging to several classes of compounds. We investigated the effect of widely used aminopenicillin therapy on the minimum inhibitory concentration (MIC) levels in porcine Campylobacter coli isolates and investigated the presence of a beta-lactamase gene and beta-lactamase production. Epidemiological cut-off values (ECOFFs) were applied to detect decreased susceptibility. Fifty-three isolates were obtained from aminopenicillin-treated (ampicillin or amoxicillin) sows and piglets during and up to 3 weeks post treatment. All isolates had ampicillin MICs below the ECOFF (<= 8 MUg/mL). An additional 63 isolates were sampled before treatment or from other untreated sows and piglets. Of these isolates, four had ampicillin MICs above the ECOFF. All ciprofloxacin MICs were below the ECOFF (<= 1 MUg/mL), except for three isolates from untreated sows and four isolates after aminopenicillin therapy. One isolate originating from an untreated sow had an erythromycin MIC above the ECOFF (> 16 MUg/mL). None of the isolates had MICs above the ECOFFs for two or three studied antimicrobials simultaneously. Of the 116 C. coli isolates, 90 (77.6%) isolates carried the bla(OXA-61) beta-lactamase gene, and 63 (70.0%) of those produced beta-lactamase. The isolates producing beta-lactamase had higher ampicillin MICs than those without the bla(OXA-61) gene and production of beta-lactamase. Proportion of the bla(OXA-61)-positive C. coli isolates was similar among untreated animals or during and after the treatment. In conclusion, C. coli isolates did not acquire high ampicillin MICs even though aminopenicillins were administered at therapeutic levels for several days. The bla(OXA-61) gene and production of beta-lactamase increased ampicillin MICs in C. coli, but the values remained mainly under the ECOFF. We also demonstrated that aminopenicillin therapy did not select simultaneously resistance to the major antimicrobials used in human therapy against campylobacteriosis (i.e., erythromycin and ciprofloxacin). PMID- 22924523 TI - Antiviral effects of black raspberry (Rubus coreanus) juice on foodborne viral surrogates. AB - Abstract Human noroviruses (HuNoVs) are the most frequent cause of foodborne viral gastroenteritis, causing approximately 90% of non-bacterial epidemic outbreaks around the world. Rubus coreanus is a species of black raspberry, rich in polyphenols, and known to exert anti-inflammatory, antibacterial, and antiviral activities. In the present study, the antiviral effects of R. coreanus juice (black raspberry [BRB] juice) on foodborne viral surrogates, murine norovirus-1 (MNV-1) and feline calicivirus-F9 (FCV-F9), were compared with those of cranberry juice, grape juice, and orange juice by plaque assays. Among the four juices tested, BRB juice was the most effective in reducing plaques formation of these viruses. Time-of-addition experiments were designed to determine the mechanism of action of BRB juice on MNV-1 and FCV-F9. The maximal antiviral effect of BRB juice against MNV-1 was observed when it was added to RAW 264.7 cells (mouse leukemic monocyte macrophage cell line) simultaneously with the virus. Pre-treatment of either Crandell Reese Feline Kidney cells or FCV-F9 with BRB juice exhibited significant antiviral activity. The inhibition of viral infection by BRB juice on MNV-1 and FCV-F9 probably occurs at the internalization of virions into the cell or the attachment of the viral surface protein to the cellular receptor. The polyphenol components in BRB (i.e., gallic acid and quercetin), however, did not show any activity against these viruses. Our data provide great promise for the utilization of BRB in the prevention of foodborne viral outbreaks. PMID- 22924524 TI - The British Medical Journal and prescribing of minocycline for acne. PMID- 22924525 TI - Pollutant emissions and energy efficiency under controlled conditions for household biomass cookstoves and implications for metrics useful in setting international test standards. AB - Realistic metrics and methods for testing household biomass cookstoves are required to develop standards needed by international policy makers, donors, and investors. Application of consistent test practices allows emissions and energy efficiency performance to be benchmarked and enables meaningful comparisons among traditional and advanced stove types. In this study, 22 cookstoves burning six fuel types (wood, charcoal, pellets, corn cobs, rice hulls, and plant oil) at two fuel moisture levels were examined under laboratory-controlled operating conditions as outlined in the Water Boiling Test (WBT) protocol, Version 4. Pollutant emissions (carbon dioxide, carbon monoxide, methane, total hydrocarbons, and ultrafine particles) were continuously monitored. Fine particle mass was measured gravimetrically for each WBT phase. Additional measurements included cookstove power, energy efficiency, and fuel use. Emission factors are given on the basis of fuel energy, cooking energy, fuel mass, time, and cooking task or activity. The lowest PM(2.5) emissions were 74 mg MJ(delivered)(-1) from a technologically advanced cookstove compared with 700-1400 mg MJ(delivered)(-1) from the base-case open 3-stone cookfire. The highest thermal efficiency was 53% compared with 14-15% for the 3-stone cookfire. Based on these laboratory controlled test results and observations, recommendations for developing potentially useful metrics for setting international standards are suggested. PMID- 22924526 TI - Genetic characterization of swine influenza viruses isolated in Japan between 2009 and 2012. AB - Eleven swine influenza viruses (SIVs) isolated from pigs in Japanese institutions between 2009 and 2012 were genetically characterized. Seven H1N1 were shown to have originated from A(H1N1)pdm09 viruses. Two H1N2 viruses contained H1 and N2 genes of Japanese H1N2 SIV origin together with internal genes of A(H1N1)pdm09 viruses. Two H3N2 viruses isolated during animal quarantine were identified as triple reassortant H3N2 viruses maintained among pigs in North America. This study shows that A(H1N1)pdm09 viruses and their reassortant strains are already present in domestic pigs in Japan and that novel SIVs are possibly being imported from abroad. PMID- 22924527 TI - Functional electrical stimulation in children and adolescents with cerebral palsy. PMID- 22924528 TI - Handling knowledge on osteoporosis--a qualitative study. AB - The aim of this qualitative study was to increase understanding of the importance of osteoporosis information and knowledge for patients' ways of handling osteoporosis in their everyday lives. Interviews were performed with 14 patients recruited from two English university hospitals and 12 patients from a Danish university hospital. Critical psychology was used as a theoretical framework for the data analysis, which aimed at shedding light on patients' ways of conducting everyday life with osteoporosis. The themes that emerged from the analysis showed that life conditions influenced the way in which risk, pain and osteoporosis were handled. Everyday life was also influenced by patients' attitude to treatment. The patients who were experiencing emotional difficulties in handling osteoporosis were not those suffering from severe osteoporosis and fractures. Approaches to living with knowledge of future fracture risk varied according to the individual patient's resourcefulness and experiences. PMID- 22924529 TI - Coexistence of insulin-derived amyloidosis and an overlying acanthosis nigricans like lesion at the site of insulin injection. AB - A 59-year-old patient with diabetes mellitus had been treated with human recombinant insulin for 4 years. He developed a solid mass on his left abdomen at the insulin injection site, which had an overlying pigmented verrucous plaque and keratinized papules, similar to acanthosis nigricans (AN). On histological examination, the mass was found to contain a deposit of amyloid in the dermis, with hyperkeratosis, papillomatosis and acanthosis in the epidermis. Using immunohistochemistry, the amyloid deposits were found to be positive for insulin. A few cases of localized insulin-derived amyloid deposits at injection sites have been reported previously, but none had significant epidermal changes. The coexistence of dermal insulin-derived amyloidosis and an overlying AN-like change, as found in our patient, has not been reported previously, to our knowledge. The presence of a tumour-like lesion at the injection site should be carefully examined, as injection of insulin into amyloid deposits can result in insulin resistance. PMID- 22924531 TI - Fast determination of adenosine 5'-triphosphate (ATP) and its catabolites in royal jelly using ultraperformance liquid chromatography. AB - To obtain insight into the metabolic regulation of adenosine 5'-triphosphate (ATP) in royal jelly and to determine whether ATP and its catabolites can be used as objective parameters to evaluate the freshness and quality of royal jelly (RJ), a rapid ultraperformance liquid chromatography (UPLC) method has been developed for feasible separation and quantitation of ATP and its catabolites in RJ, namely, adenosine 5'-diphosphate (ADP), adenosine 5'-monophosphate (AMP), inosine monophosphate (IMP), inosine (HxR), and hypoxanthine (Hx). The analytes in the sample were extracted using 5% precooled perchloric acid. Chromatographic separation was performed on a Waters Acquity UPLC system with a Waters BEH Shield RP18 column and gradient elution based on a mixture of two solvents: solvent A, 50 mM phosphate buffer (pH 6.5); and solvent B, acetonitrile. The recoveries were in the range of 86.0-102.3% with RSD of no more than 3.6%. The correlation coefficients of six analytes were high (r(2) >= 0.9988) and within the test ranges. The limits of detection and quantification for the investigated compounds were lower, at 0.36-0.68 and 1.22-2.30 mg/kg, respectively. The overall intra- and interday RSDs were no more than 1.8%. The developed method was successfully applied to the analysis of the analytes in samples. The results showed that ATP in RJ sequentially degrades to ADP, AMP, IMP, HxR, and Hx during storage. PMID- 22924530 TI - Indole derivative production by the root endophyte Piriformospora indica is not required for growth promotion but for biotrophic colonization of barley roots. AB - Beneficial effects elicited by the root endophyte Piriformospora indica are widely known, but the mechanism by which these are achieved is still unclear. It is proposed that phytohormones produced by the fungal symbiont play a crucial role in the interaction with the plant roots. Biochemical analyses of the underlying biosynthetic pathways for auxin production have shown that, on tryptophan feeding, P. indica can produce the phytohormones indole-3-acetic acid (IAA) and indole-3-lactate (ILA) through the intermediate indole-3-pyruvic acid (IPA). Time course transcriptional analyses after exposure to tryptophan designated the piTam1 gene as a key player. A green fluorescence protein (GFP) reporter study and transcriptional analysis of colonized barley roots showed that piTam1 is induced during the biotrophic phase. Piriformospora indica strains in which the piTam1 gene was silenced via an RNA interference (RNAi) approach were compromised in IAA and ILA production and displayed reduced colonization of barley (Hordeum vulgare) roots in the biotrophic phase, but the elicitation of growth promotion was not affected compared with the wild-type situation. Our results suggest that IAA is involved in the establishment of biotrophy in P. indica-barley symbiosis and might represent a compatibility factor in this system. PMID- 22924532 TI - Intratumoral dispersion, retention, systemic biodistribution, and clearance of a small-size tumor necrosis factor-alpha-expressing MIDGE vector after nonviral in vivo jet-injection gene transfer. AB - For nonviral applications of therapeutic DNA, highly efficient and safe vector systems are of crucial importance. In the majority of nonviral approaches plasmid vectors are in use. A novel minimalistic gene expression vector (MIDGE) has been developed to overcome the limitations of plasmid vectors. This small-size double stranded linear DNA vector has shown improved transgene expression. However, only limited knowledge on uptake, biodistribution, and clearance of this vector exists. In this study we investigated the intratumoral and systemic biodistribution, clearance, and expression kinetics of the tumor necrosis factor (TNF)-alpha-carrying MIDGE-CMVhTNF vector in NMRI-nu/nu mice with subcutaneously xenotransplanted human A375 melanoma. Biodistribution was analyzed by quantitative real-time PCR in tumors, blood, and organs 0 to 60 min and 3 to 48 hr after intratumoral jet-injection of 50 MUg of MIDGE-CMVhTNF. We examined TNF mRNA expression in tumor tissue and organs, using real-time RT-PCR and TNF specific ELISA. High levels of MIDGE DNA in the tumor tissue demonstrated efficient gene transfer of the small-size vector, resulting in inhomogeneous DNA dispersion and efficient transgene expression. Intratumoral jet-injection of the vector DNA was accompanied by leakage into the blood circuit and appearance in peripheral organs within 5 min to 6 hr. However, this did not lead to TNF-alpha expression and was followed by rapid vector clearance resulting in the disappearance of MIDGE DNA 24 hr after gene transfer. These data provide important new information for the kinetics of intratumoral and systemic biodistribution and rapid clearance of the jet-injected small-size MIDGE vector. PMID- 22924533 TI - Aquisiflavoside, a new nitric oxide production inhibitor from the leaves of Aquilaria sinensis. AB - A new flavonoid glycoside, named aquisiflavoside, was isolated from the leaves of Aquilaria sinensis (Lour.) Gilg, and its structure was elucidated by spectroscopic analyses. Aquisiflavoside was evaluated for the inhibition of nitric oxide (NO) production induced by lipopolysaccharide in macrophage cell line RAW 264.7 and exhibited a potent inhibitory activity against NO production in a dose-dependent manner with an IC(50) value of 34.95 MUM. PMID- 22924534 TI - Identification of a novel HLA-C*04 allele, HLA-C*04:107, in a Chinese individual. AB - The novel HLA-C*04:107 allele shows one nucleotide difference from C*04:03 in exon 2 at nucleotide position 341. PMID- 22924535 TI - Electrostatic separation for recycling conductors, semiconductors, and nonconductors from electronic waste. AB - Electrostatic separation has been widely used to separate conductors and nonconductors for recycling e-waste. However, the components of e-waste are complex, which can be classified as conductors, semiconductors, and nonconductors according to their conducting properties. In this work, we made a novel attempt to recover the mixtures containing conductors (copper), semiconductors (extrinsic silicon), and nonconductors (woven glass reinforced resin) by electrostatic separation. The results of binary mixtures separation show that the separation of conductor and nonconductor, semiconductor and nonconductor need a higher voltage level while the separation of conductor and semiconductor needs a higher roll speed. Furthermore, the semiconductor separation efficiency is more sensitive to the high voltage level and the roll speed than the conductor separation efficiency. An integrated process was proposed for the multiple mixtures separation. The separation efficiency of conductors and semiconductors can reach 82.5% and 88%, respectively. This study contributes to the efficient recycling of valuable resources from e-waste. PMID- 22924537 TI - Effects of green tea consumption on human fecal microbiota with special reference to Bifidobacterium species. AB - Green tea is one of the most popular beverages in the world. Its beneficial health effects and components have been extensively reviewed. However, little is known about the influence of green tea consumption on the human intestinal microbiota (HIM), which plays a crucial role in human health. Ten volunteers who did not usually consume green tea, drank it for 10 days and then stopped drinking it for 7 days. Their fecal samples were collected at three time points: before beginning the 10-day green-tea regime, at the conclusion of that 10 days, and 7 days after stopping the regime. Their fecal samples were analyzed by terminal restriction fragment length polymorphism with specific primer-restriction enzyme systems for HIM and by using a real-time PCR method for the Bifidobacterium species. Although the HIM of each subject was relatively stable, the proportion of Bifidobacterium species played an important role in the classification of their fecal microbiota. Although there were inter-individual differences in the Bifidobacterium species, an overall tendency for the proportion of bifidobacteria to increase because of green tea consumption was noted. However, little change was observed in the composition of Bifidobacterium species in each sample. This suggests that the change in proportion was induced, not by an inter-species transition, but by an intra-species increase and/or decrease. In conclusion, green tea consumption might act as a prebiotic and improve the colon environment by increasing the proportion of the Bifidobacterium species. PMID- 22924536 TI - ATP1A3 mutations in infants: a new rapid-onset dystonia-Parkinsonism phenotype characterized by motor delay and ataxia. AB - We report new clinical features of delayed motor development, hypotonia, and ataxia in two young children with mutations (R756H and D923N) in the ATP1A3 gene. In adults, mutations in ATP1A3 cause rapid-onset dystonia-Parkinsonism (RDP, DYT12) with abrupt onset of fixed dystonia. The parents and children were examined and videotaped, and samples were collected for mutation analysis. Case 1 presented with fluctuating spells of hypotonia, dysphagia, mutism, dystonia, and ataxia at 9 months. After three episodes of hypotonia, she developed ataxia, inability to speak or swallow, and eventual seizures. Case 2 presented with hypotonia at 14 months and pre-existing motor delay. At age 4 years, he had episodic slurred speech, followed by ataxia, drooling, and dysarthria. He remains mute. Both children had ATP1A3 gene mutations. To our knowledge, these are the earliest presentations of RDP, both with fluctuating features. Both children were initially misdiagnosed. RDP should be considered in children with discoordinated gait, and speech and swallowing difficulties. PMID- 22924538 TI - A case of palmoplantar lichen planus in a patient with congenital sensorineural deafness. AB - We report a case of palmoplantar lichen planus in a 7-year-old Japanese girl with congenital deafness, who presented with erythematous eruptions and hyperkeratosis, with peeling and fissures on her soles, palms and digits. On histological examination of a skin biopsy from the lesion on her wrist, lichen planus was identified. Using computed tomography of the inner ears, bilateral cochlear dysplasia was found. The patient's DNA was sequenced; no sequence variants were detected in the GJB2 gene encoding connexin-26, but she had a missense mutation in SLC26A4 (solute carrier family 26, member 4). Mutations in SLC26A4 are known causes of hearing loss, but this is a novel mutation, which has not been reported previously. In addition, there have been no reports of cutaneous symptoms in previously reported patients with mutations in SLC26A4. To our knowledge, therefore, this is the first report of palmoplantar lichen planus associated with sensorineural deafness accompanied by a mutation in the SLC26A4 gene. PMID- 22924539 TI - Anxiety and depression following pulmonary rehabilitation. AB - AIM: The aim of this study was to evaluate changes and predictive factors of anxiety and depression in patients with chronic obstructive pulmonary disease (COPD) before and up to 3 months after pulmonary rehabilitation (PR). METHODS: A single group longitudinal design of patients with COPD underwent a PR programme. The measurements took place at baseline (T1: N=100), immediately before (T2: N=66), immediately after (T3: N=54) and 3 months after (T4: N=43) the programme. The programme was a 6-week outpatient programme, including education, psychosocial support and training sessions. Anxiety and depression were measured by the Hospital Anxiety and Depression Scale, self-efficacy by the COPD self efficacy scale, lung function by spirometry and exercise capacity by incremental shuttle walking test. Mixed effect model analyses were used. RESULTS: Results showed a tendency of less anxiety and depression immediately after (T3) compared with immediately before (T2) the PR programme, but the changes were not significant. Results also showed that female reported significantly more anxiety than male (p=0.019), better exercise capacity predicted significantly less depression (p=0.049), and higher self-efficacy predicted both significantly less anxiety (p=0.001) and less depression (p=0.005). CONCLUSIONS: A tendency of less anxiety and depression during the PR programme was found, but the changes were not significant. Higher level of self-efficacy and better exercise capacity are suggested to relieve anxiety and depression. PMID- 22924540 TI - Skin cancer risks avoided by the Montreal Protocol--worldwide modeling integrating coupled climate-chemistry models with a risk model for UV. AB - The assessment model for ultraviolet radiation and risk "AMOUR" is applied to output from two chemistry-climate models (CCMs). Results from the UK Chemistry and Aerosols CCM are used to quantify the worldwide skin cancer risk avoided by the Montreal Protocol and its amendments: by the year 2030, two million cases of skin cancer have been prevented yearly, which is 14% fewer skin cancer cases per year. In the "World Avoided," excess skin cancer incidence will continue to grow dramatically after 2030. Results from the CCM E39C-A are used to estimate skin cancer risk that had already been inevitably committed once ozone depletion was recognized: excess incidence will peak mid 21st century and then recover or even super-recover at the end of the century. When compared with a "No Depletion" scenario, with ozone undepleted and cloud characteristics as in the 1960s throughout, excess incidence (extra yearly cases skin cancer per million people) of the "Full Compliance with Montreal Protocol" scenario is in the ranges: New Zealand: 100-150, Congo: -10-0, Patagonia: 20-50, Western Europe: 30-40, China: 90-120, South-West USA: 80-110, Mediterranean: 90-100 and North-East Australia: 170-200. This is up to 4% of total local incidence in the Full Compliance scenario in the peak year. PMID- 22924541 TI - Kinetic model for the formation of acrylamide during the finish-frying of commercial french fries. AB - Acrylamide is formed from reducing sugars and asparagine during the preparation of French fries. The commercial preparation of French fries is a multistage process involving the preparation of frozen, par-fried potato strips for distribution to catering outlets, where they are finish-fried. The initial blanching, treatment in glucose solution, and par-frying steps are crucial because they determine the levels of precursors present at the beginning of the finish-frying process. To minimize the quantities of acrylamide in cooked fries, it is important to understand the impact of each stage on the formation of acrylamide. Acrylamide, amino acids, sugars, moisture, fat, and color were monitored at time intervals during the frying of potato strips that had been dipped in various concentrations of glucose and fructose during a typical pretreatment. A mathematical model based on the fundamental chemical reaction pathways of the finish-frying was developed, incorporating moisture and temperature gradients in the fries. This showed the contribution of both glucose and fructose to the generation of acrylamide and accurately predicted the acrylamide content of the final fries. PMID- 22924542 TI - Exploring the plasma chemistry in microwave chemical vapor deposition of diamond from C/H/O gas mixtures. AB - Microwave (MW)-activated CH(4)/CO(2)/H(2) gas mixtures operating under conditions relevant to diamond chemical vapor deposition (i.e., X(C/Sigma) = X(elem)(C)/(X(elem)(C) + X(elem)(O)) ~ 0.5, H(2) mole fraction = 0.3, pressure, p = 150 Torr, and input power, P = 1 kW) have been explored in detail by a combination of spatially resolved absorption measurements (of CH, C(2)(a), and OH radicals and H(n = 2) atoms) within the hot plasma region and companion 2 dimensional modeling of the plasma. CO and H(2) are identified as the dominant species in the plasma core. The lower thermal conductivity of such a mixture (cf. the H(2)-rich plasmas used in most diamond chemical vapor deposition) accounts for the finding that CH(4)/CO(2)/H(2) plasmas can yield similar maximal gas temperatures and diamond growth rates at lower input powers than traditional CH(4)/H(2) plasmas. The plasma chemistry and composition is seen to switch upon changing from oxygen-rich (X(C/Sigma) < 0.5) to carbon-rich (X(C/Sigma) > 0.5) source gas mixtures and, by comparing CH(4)/CO(2)/H(2) (X(C/Sigma) = 0.5) and CO/H(2) plasmas, to be sensitive to the choice of source gas (by virtue of the different prevailing gas activation mechanisms), in contrast to C/H process gas mixtures. CH(3) radicals are identified as the most abundant C(1)H(x) [x = 0-3] species near the growing diamond surface within the process window for successful diamond growth (X(C/Sigma) ~ 0.5-0.54) identified by Bachmann et al. (Diamond Relat. Mater.1991, 1, 1). This, and the findings of similar maximal gas temperatures (T(gas) ~2800-3000 K) and H atom mole fractions (X(H)~5-10%) to those found in MW-activated C/H plasmas, points to the prevalence of similar CH(3) radical based diamond growth mechanisms in both C/H and C/H/O plasmas. PMID- 22924543 TI - New abietane norditerpenoid from Salvia miltiorrhiza with cytotoxic activities. AB - One new abietane-type norditerpenoid, named militibetin A (1), was isolated from the dry roots of Salvia miltiorrhiza, along with two known diterpenoids, yunnannin A (2) and ferruginol (3). Their structures were established by means of extensive spectroscopic analyses. In vitro, compounds 1-3 were found to show cytotoxicities against selected cancer cells, including P-388, HONE-1, and HT-29, and gave ED(50) values in the range of 2.9-5.4 MUg ml(- 1). PMID- 22924544 TI - Verapamil synergistically enhances cytotoxicity of bortezomib in mantle cell lymphoma via induction of reactive oxygen species production. PMID- 22924545 TI - Magnetic nanoscaled Fe3O4/CeO2 composite as an efficient Fenton-like heterogeneous catalyst for degradation of 4-chlorophenol. AB - Magnetic nanoscaled Fe(3)O(4)/CeO(2) composite was prepared by the impregnation method and characterized as a heterogeneous Fenton-like catalyst for 4 chlorophenol (4-CP) degradation. The catalytic activity was evaluated in view of the effects of various processes, pH value, catalyst addition, hydrogen peroxide (H(2)O(2)) concentration, and temperature, and the pseudo-first-order kinetic constant of 0.11 min(-1) was obtained for 4-CP degradation at 30 degrees C and pH 3.0 with 30 mM H(2)O(2), 2.0 g L(-1) Fe(3)O(4)/CeO(2), and 0.78 mM 4-CP. The high utilization efficiency of H(2)O(2), calculated as 79.2%, showed a promising application of the catalyst in the oxidative degradation of organic pollutants. The reusability of Fe(3)O(4)/CeO(2) composite was also investigated after six successive runs. On the basis of the results of metal leaching, the effects of radical scavengers, intermediates determination, and X-ray photoelectron spectroscopic (XPS) analysis, the dissolution of Fe(3)O(4) facilitated by CeO(2) played a significant role, and 4-CP was decomposed mainly by the attack of hydroxyl radicals (*OH), including surface-bound *OH(ads) generated by the reaction of Fe(2+) and Ce(3+) species with H(2)O(2) on the catalyst surface, and *OH(free) in the bulk solution mainly attributed to the leaching of Fe. PMID- 22924546 TI - Consecutive reaction mechanism for the formation of spore photoproduct in DNA photolesion. AB - We have explored the potential energy profiles of TpT dinucleotides toward formation of a DNA photolesion product, spore photoproduct (SP), along the S(0), S(1), and T(1) states, by means of density functional theory and time-dependent density functional theory. Together with the spin density analysis, the consecutive mechanism for the SP formation can be established. The detailed reaction pathways have been revealed. All the adiabatic reaction pathways proceeding though S(1), T(1), or S(0) alone are shown to be energetically infeasible, while the nonadiabatic pathway involving both the T(1) and S(0) states corresponds to the lowest-energy path and is the most favorable in energy. The nonadiabatic pathway is rate-limited by the step of the hydrogen atom transfer proceeding in the T(1) state with a barrier of 14.2 kcal mol(-1) (11.9 kcal mol(-1) in bulk solution), whereas the subsequent C5-CH(2) bond formation toward the final SP formation occurs readily in S(0) after intersystem crossing from T(1) to S(0) via the singlet-triplet interaction. The results provide a rationale for the experimentally observed kinetic isotope effect after deuterium substitution at the 3'-T methyl group of TpT. PMID- 22924547 TI - Suppressive effect of calcipotriol on the induction of matrix metalloproteinase (MMP)-9 and MMP-13 in a human squamous cell carcinoma cell line. AB - BACKGROUND: Vitamin D3 is a potent regulator of cell growth, differentiation and death, tumour invasion, and angiogenesis. Production of matrix metalloproteinase (MMP)-9 and MMP-13 by tumour cells may promote tumour growth, invasion and metastasis. AIM: To investigate whether calcipotriol could suppress the expression of MMP-9 and MMP-13 in a human squamous cell carcinoma (SCC) cell line (DJM cells), and to examine the mechanism of modulation of MMP-9 and MMP-13 by calcipotriol in DJM cells treated with tumour necrosis factor (TNF)-alpha. METHODS: Protein and mRNA levels of MMP-9 and MMP-13 were examined by ELISA and real-time PCR, respectively. Activation of signalling cascades was assessed using several inhibitors of signalling molecules and western blot analysis. RESULTS: Production of MMP-9 and MMP-13 markedly increased when the cells were treated with TNF-alpha. Calcipotriol suppressed the production of MMP-9 and MMP-13 mRNA and proteins significantly, in a dose-dependent manner. Induction of MMP-9 by TNF alpha was suppressed by an extracellular signal-regulated kinase (ERK) inhibitor but not by a p38 inhibitor, whereas induction of MMP-13 was inhibited by a p38 inhibitor but not by an ERK inhibitor. Calcipotriol inhibited the phosphorylation of both ERK and p38, as shown by western blotting. CONCLUSION: Calcipotriol reduces MMP-9 and MMP-13 production through inhibiting the phosphorylation of ERK and p38, respectively. PMID- 22924548 TI - CCR5 gene polymorphism is a genetic risk factor for radiographic severity of rheumatoid arthritis. AB - The chemokine receptor [C-C chemokine receptor 5 (CCR5)] is expressed on diverse immune effecter cells and has been implicated in the pathogenesis of rheumatoid arthritis (RA). This study sought to determine whether single-nucleotide polymorphisms (SNPs) in the CCR5 gene and their haplotypes were associated with susceptibility to and severity of RA. Three hundred fifty-seven patients with RA and 383 healthy unrelated controls were recruited. Using a pyrosequencing assay, we examined four polymorphisms -1118 CTAT(ins) (/del) (rs10577983), 303 A>G (rs1799987), 927 C>T (rs1800024), and 4838 G>T (rs1800874) of the CCR5 gene, which were distributed over the promoter region as well as the 5' and 3' untranslated regions. No significant difference in the genotype, allele, and haplotype frequencies of the four selected SNPs was observed between RA patients and controls. CCR5 polymorphisms of -1118 CTAT(del) (P = 0.012; corrected P = 0.048) and 303 A>G (P = 0.012; corrected P = 0.048) showed a significant association with radiographic severity in a recessive model, and, as a result of multivariate logistic regression analysis, were found to be an independent predictor of radiographic severity. When we separated the erosion score from the total Sharp score, the statistical significance of CCR5 polymorphisms showed an increase; -1118 CTAT(ins) (/del) (P = 0.007; corrected P = 0.028) and 303 A>G (P = 0.007; corrected P = 0.028). Neither SNPs nor haplotypes of the CCR5 gene showed a significant association with joint space narrowing score. These results indicate that genetic polymorphisms of CCR5 are an independent risk factor for radiographic severity denoted by modified Sharp score, particularly joint erosion in RA. PMID- 22924549 TI - Psychological distress and perceived support among Jordanian parents living with a child with cerebral palsy: a cross-sectional study. AB - BACKGROUND: Cerebral palsy, with a prevalence in Europe of 2-2.5 per 1000 live births, is the most common severe physical disability affecting children. While many parents have positive perceptions of their disabled children, caring for a child with disability can be exhausting and stressful, and social support is an important coping resource. There is little evidence about how having a child with cerebral palsy affects Jordanian parents. AIM: The purpose of this study was to provide insight into the psychological distress and perceived support among Jordanian parents living with a child with cerebral palsy. METHOD: In 2010, a cross-sectional, descriptive, correlational design was used with a nonprobability sample of 204 Jordanian parents. Both mothers and fathers, interviewed individually rather than in pairs, were recruited from health care centres that provided comprehensive care for children with cerebral palsy in Jordan and from designated schools for special education. The Gross Motor Function Classification System, the Perceived Stress Scale (PSS), the Beck Depression Inventory, the Strengths and Difficulties Questionnaire and the Multidimensional Scale of Perceived Social Support (MSPSS) were administered to parents. Descriptive statistical analysis was applied. Bivariate correlation analysis was undertaken to examine the relationship between variables. RESULTS: More than 60% of parents often felt nervous and stressed. The mean score on the PSS was 27.0 (SD=9.33), and the mean score on the MSPSS was 58.9 (SD=15.1). Severe disability in the child was associated with high mental distress in the parent and linked to low support from friends. There was a significant negative correlation between parental stress, depression and social support. Parents with the most psychological distress were the least well supported. CONCLUSION: This study has implications for health professionals in terms of developing strategies for reducing parental stress. There are implications for policy to provide support for parents and to develop family-centred services. The findings will inform an intervention study to investigate multi-professional support. PMID- 22924550 TI - Distribution of insulin receptor and insulin-like growth factor-1 receptor in the digital laminae of mixed-breed ponies: an immunohistochemical study. AB - REASONS FOR PERFORMING STUDY: Hyperinsulinaemia has been implicated in the pathogenesis of laminitis; however, laminar cell types responding to insulin remain poorly characterised. OBJECTIVES: To identify laminar cell types expressing insulin receptor (IRc) and/or insulin-like growth factor-1 receptor (IGF-1R); and to evaluate the effect of dietary nonstructural carbohydrate (NSC) on their expression. METHODS: Mixed-breed ponies (n = 22) received a conditioning hay chop diet (NSC ~6%); following acclimation, ponies were stratified into lean (n = 11, body condition score [BCS]<=4) or obese (n = 11, BCS >=7) groups and each group further stratified to remain on the low NSC diet (n = 5 each for obese and lean) or receive a high NSC diet (total diet ~42% NSC; n = 6 each for obese and lean) for 7 days. Laminar samples were collected at the end of the feeding protocol and stained immunohistochemically for IRc and IGF-1R. The number of IRc(+) cells was quantified; distribution of IGF-1R was qualitatively described. Laminar IRc content was assessed via immunoblotting. RESULTS: The number of IRc(+) cells was greater in the laminae of high NSC ponies than low NSC ponies (P = 0.001); there was a positive correlation between the change in serum insulin concentration and number of IRc(+) cells (r(2) = 0.74; P<0.0001). No epithelial IRc(+) cells were observed; IRc(+) cells were absent from the deep dermis. Analysis of serial sections identified IRc(+) cells as endothelial cells. The distribution of IGF-1R was more extensive than that of IRc, with signal in vascular elements, epithelial cells and fibroblasts. CONCLUSIONS: Increased dietary NSC results in increased laminar endothelial IRc expression. Laminar keratinocytes do not express IRc, suggesting that insulin signalling in laminar epithelial cells must be mediated through other receptors (such as IGF-1R). POTENTIAL RELEVANCE: Manipulation of signalling downstream of IRc and IGF-1R may aid in treatment and prevention of laminitis associated with hyperinsulinaemia. PMID- 22924551 TI - Modeling androgen receptor flexibility: a binding mode hypothesis of CYP17 inhibitors/antiandrogens for prostate cancer therapy. AB - Prostate Cancer (PCa), a leading cause of cancer death worldwide (www.cancer.gov), is a complex malignancy where a spectrum of targets leads to a diversity of PCa forms. A widely pursued therapeutic target is the Androgen Receptor (AR). As a Steroid Hormone Receptor, AR serves as activator of transcription upon binding to androgens and plays a central role in the development of PCa. AR is a structurally flexible protein, and conformational plasticity of residues in the binding-pocket is a key to its ability to accommodate ligands from various chemical classes. Besides direct modulation of AR activity by antagonists, inhibition of cytochrome CYP17 (17alpha hydroxylase/17,20-lyase), essential in androgen biosynthesis, has widely been considered an effective strategy against PCa. Interestingly, Handratta et al. (2005) discovered new, potent inhibitors of CYP17 (C-17 steroid derivatives) with pure AR antagonistic properties. Although the antiandrogenic activity of their lead compound (VN/124-1) has been experimentally proven both in vitro and in vivo, no structural data are currently available to elucidate the molecular determinants responsible for these desirable dual inhibitory properties. We implemented a Structure-based Drug Design (SBDD) approach to generate a valuable hypothesis as to the binding modes of steroidal CYP17 inhibitors/antiandrogens against the AR. To deal with the plasticity of residues buried in the Ligand Binding Domain (LBD), we developed a flexible-receptor Docking protocol based on Induced-Fit (IFD) methodology (www.schrodinger.com/). Our results constitute an ideal starting point for the rational design of next-generation analogues of CYP17 inhibitors/antiandrogens as well as an attractive tool to suggest novel chemical classes of AR antagonists. PMID- 22924553 TI - High-level ab initio predictions of the energetics of mCO2.(H2O)n (n = 1-3, m = 1 12) clusters. AB - Electronic structure calculations at the correlated molecular orbital theory and density functional theory levels have been used to generate a reliable set of clustering energies for up to three water molecules in carbon dioxide clusters up to n = 12. The structures and energetics are dominated by Lewis acid-base interactions with hydrogen-bonding interactions playing a lesser energetic role. The actual binding energies are somewhat larger than might be expected. The correlated molecular orbital MP2 method and density functional theory with the omegaB97X exchange-correlation functional provide good results for the energetics of the clusters, but the B3LYP and omegaB97X-D functionals do not. Seven CO(2) molecules form the first solvent shell about a single H(2)O with four CO(2) molecules interacting with the H(2)O via Lewis acid-base interactions, two CO(2) interacting with the H(2)O by hydrogen bonds, and the seventh CO(2) completing the shell. The Lewis acid-base and weak hydrogen bond interactions between the water molecules and the CO(2) molecules are strong enough to disrupt the trimer ring configuration for as few as seven CO(2) molecules. Calculated (13)C NMR chemical shifts for mCO(2).(H(2)O)(n) show little change with respect to the number of H(2)O or CO(2) molecules in the cluster. The O-H stretching frequencies do exhibit shifts that can provide information about the interactions between water and CO(2) molecules. PMID- 22924554 TI - G503 is obligatory for coupling of regulatory domains in NCX proteins. AB - In multidomain proteins, interdomain linkers allow an efficient transfer of regulatory information, although it is unclear how the information encoded in the linker structure coins dynamic coupling. Allosteric regulation of NCX proteins involves Ca(2+)-driven tethering of regulatory CBD1 and CBD2 (through a salt bridge network) accompanied by alignment of CBDs and Ca(2+) occlusion at the interface of the two CBDs. Here we investigated "alanine-walk" substitutions in the CBD1-CBD2 linker (501-HAGIFT-506) and found that among all linker residues, only G503 is obligatory for Ca(2+)-induced reorientations of CBDs and slow dissociation of occluded Ca(2+). Moreover, swapping between positions A502 and G503 in the CBD1-CBD2 linker results in a complete loss of slow dissociation of occluded Ca(2+), meaning that dynamic coupling of CBDs requires an exact pose of glycine at position 503. Therefore, accumulating data revealed that position 503 occupied by glycine is absolutely required for Ca(2+)-driven tethering of CBDs, which in turn limits the linker's flexibility and, thus, restricts CBD movements. Because G503 is extremely well conserved in eukaryotic NCX proteins, the information encoded in G503 is essential for dynamic coupling of the two-domain CBD tandem and, thus, for propagation of the allosteric signal. PMID- 22924552 TI - Immune-mediated beta-cell death in type 1 diabetes: lessons from human beta-cell lines. AB - Type 1 diabetes (T1D) is a chronic, multifactorial disorder that results from a contretemps of genetic and environmental factors. Autoimmune attack and functional inhibition of the insulin-producing beta cells in the pancreas lead to the inability of beta cells to metabolize glucose, and thus results the hallmark clinical symptom of diabetes: abnormally high blood glucose levels. Treatment and protection from T1D require a detailed knowledge of the molecular effectors and the mechanism(s) of cell death leading to beta-cell demise. Primary islets and surrogate beta cells have been utilized in vitro to investigate in isolation specific mechanisms associated with progression to T1D in vivo. This review focuses on the data obtained from these experiments. Studies using transformed beta cells of human sources are described. PMID- 22924555 TI - Total synthesis of epiberberine. AB - Epiberberine, a natural bioactive protoberberine alkaloid, was totally synthesized in short, convenient and low-cost, four-step reactions including cyclization, condensation, reduction, and ring-closing, with an overall yield of 26.1%. PMID- 22924556 TI - Increased risk of arterial thromboembolism after a prior episode of venous thromboembolism: results from the Prevention of REnal and Vascular ENd stage Disease (PREVEND) Study. AB - Large population-based studies are needed to establish the magnitude and duration of the recently suggested association between arterial and venous thromboembolism. In 1997-98, all inhabitants of Groningen, the Netherlands, aged 28-75 years (n = 85 421), were invited to participate in a study that followed and monitored responding subjects (n = 40 856) for venous and arterial thromboembolism until 2009. Thromboembolism was verified with national registries of hospital discharge diagnoses and death certificates, anticoagulation clinic and medical records. During a median follow-up of 10.7 years, 549 participants developed venous thromboembolism and 3283 developed arterial thromboembolism. Annual incidence of arterial thromboembolism after venous thromboembolism was 2.03% [95% confidence interval (CI), 1.48-2.71], compared to 0.87% (95% CI, 0.84 0.90) in subjects without venous thromboembolism. The hazard ratio (HR) of arterial thromboembolism after venous thromboembolism was 1.40 (95% CI, 1.04 1.88) after adjustment for age, sex and cardiovascular risk factors. This risk was highest during the first year after venous thromboembolism [annual incidence, 3.00% (95% CI, 1.64-5.04); adjusted HR, 2.01 (95% CI, 1.19-3.40)] and after an unprovoked event [annual incidence, 2.53% (95% CI, 1.68-3.66); adjusted HR, 1.62 (95% CI, 1.11-2.34)]. This study showed that subjects with venous thromboembolism are at increased risk for arterial thromboembolism, particularly in the first year after venous thromboembolism and after an unprovoked event. PMID- 22924557 TI - Mechanisms of membrane fouling control by integrated magnetic ion exchange and coagulation. AB - Colloidal natural organic matter (NOM) is an important foulant to low-pressure membranes (LPMs) employed in drinking water treatment. Removal of colloidal NOM by magnetic ion exchange (MIEX), coagulation, and integrated MIEX and coagulation was investigated in this study to determine the relationship between colloidal NOM removal and membrane fouling reduction. The results showed that coagulation did not selectively remove colloidal NOM and the optimal coagulant dose was primarily determined by the concentration of humic substances. Comparatively, MIEX pretreatment preferentially removed humic substances and reduced the coagulant dose needed for colloidal NOM removal as a result of coagulation stoichiometry. A matched-pair analysis showed that integrated MIEX and coagulation pretreatment at much lower coagulant doses was as effective as coagulation in reducing membrane fouling. It is concluded that integrated MIEX and coagulation is potentially a viable pretreatment approach to reduce membrane fouling and in general removal of colloidal NOM in feedwater is an effective approach for membrane fouling control and should be considered in the research, development, and application of novel LPM-based treatment processes. PMID- 22924558 TI - Pulsed-field gradient NMR measurements on hydrogels from phosphocholine. AB - Gels from diacylphosphatidylcholine in glycerol/butylene glycol mixtures were investigated by pulsed-field gradient NMR measurements. Previous measurements had shown that the gels are formed by networks from crystalline multilamellar vesicles (MLV). The obtained self-diffusion coefficients for water and butylene glycol molecules indicate that both molecules occur in two different environments, even at temperatures above the phase transition T(m) where the system is still in a liquid crystalline state. While the larger fraction of the molecules shows a free self-diffusion process like in a homogeneous phase, the smaller fraction seems to be encapsulated in closed domains and undergoes only hindered self-diffusion. It is concluded that the hindered diffusions are due to the solvent molecules trapped between the bilayers of the multilamellar vesicles, while the free diffusion is assigned to the solvent molecules outside of the MLV. Since the fraction of the entrapped molecules does not change during phase transition, we assume that the structure of the network in the samples remains the same when gelation occurs. The gelation process is simply due to the transformation of the vesicle bilayers from the liquid crystalline to the crystalline state. The permeability of the bilayer for the solvent molecules is drastically changed by this transition. The exchange of water molecules through the bilayers slows down significantly below T(m): while the average residence time of water molecules inside the vesicles is smaller than 50 ms in the liquid crystalline state, this value increases to more than 1 s for the gel state. In the case of pure butylene glycol, no vesicles are present, and it is likely that these gels are formed from crystalline fibers. PMID- 22924559 TI - Identification of a new HLA-G allele, HLA-G*01:18, in a Canadian Caucasian individual. AB - We identified a novel HLA-G allele with a protein-modifying mutation in a Canadian Caucasian Individual. PMID- 22924560 TI - The case for interprofessional education. PMID- 22924561 TI - In response to the published article "A syndemic model of substance abuse, intimate partner violence, HIV infection, and mental health among Hispanics". PMID- 22924562 TI - Parental perceptions of the neighborhood context and adolescent depression. AB - OBJECTIVE: To examine the associations between parental perceptions of the neighborhood context and adolescent depression including potential gender differences in outcomes. DESIGN AND SAMPLE: Descriptive correlational study. A total of 32,499 parents of adolescents aged 12-17 years. MEASURES: Descriptive and multivariate logistic and linear regression analyses of the 2007 National Survey of Children's Health. Neighborhood context was operationalized as physical disorder, social isolation, and lack of safety. Two depression outcomes (current depression diagnosis and current depression symptoms) were analyzed. RESULTS: Parental perceptions of neighborhood physical disorder were positively associated with adolescent depression diagnosis (AOR = 1.73, 95% CI = 1.07, 2.80) and an increase in depression symptoms (0.186, p < 0.001). In addition, parental perceptions of neighborhood social isolation (0.061, p < 0.001) and lack of safety (0.037, p < 0.01) were associated with adolescent depression symptoms, and the measures modestly attenuated the relationship between neighborhood physical disorder and adolescent depression symptoms (0.117, p < 0.05). No significant gender differences were found. CONCLUSIONS: Public health interventions to reduce neighborhood physical disorder, social isolation, and lack of safety should be considered in efforts to promote adolescent mental health. Further research exploring other mechanisms through which neighborhood physical disorder may contribute to adolescent depression also is needed, including potential gender differences. PMID- 22924563 TI - Patterns of coping with partner violence: experiences of refugee women in Jordan. AB - OBJECTIVE: The relationship between intimate partner violence (IPV) and women's use of negative and positive coping strategies was investigated. DESIGN AND SAMPLE: For this cross-sectional study, a convenience sample of 300 refugee women was recruited from health care centers in three cities in Jordan. Logistic regression adjusted to women's demographic characteristics was used. RESULTS: The study's results revealed that, compared to non victims, victimized women showed a lower tendency to receive psychological support from the family (adjusted OR = 0.53, 95% CI = 0.29-0.96), to smoke (adjusted OR = 0.28, 95% CI = 0.09-0.82), to use tranquilizers (adjusted OR = 0.014, 95% CI = 0.00-0.86), to think of suicide (adjusted OR = 0.04, 95% CI = 0.009-0.15), and to attempt suicidal actions (adjusted OR = 0.02, 95% CI = 0.002-0.19). CONCLUSIONS: The study indicated that women's lack of use of negative coping strategies (smoking, use of tranquilizers, suicidal thoughts, and suicidal actions) was promising. However, the lack of use of positive coping strategies (disclosure of abuse, psychological support from friends, and help from family/friends) was somewhat concerning. The role of health care professionals may be helpful in this context. Counseling and support to IPV victims via effective listening, nonjudgmental discussions, and provision of information can be offered by health professionals as part of the treatment in health care centers. PMID- 22924564 TI - Nurse home visitors' perspectives of mandatory reporting of children's exposure to intimate partner violence to child protection agencies. AB - OBJECTIVES: To examine nurse home visitors' perspectives of and intentions to report children's exposure to intimate partner violence (IPV) in the context of the home visitation setting. DESIGN AND SAMPLE: Cross-sectional study of 532 nurse home visitors in the Nurse-Family Partnership home visitation program. MEASURES: A web-based questionnaire assessing nurse home visitors' support for and attitudes toward mandatory reporting of children's exposure to IPV. Nurses' considerations of what levels of exposure constitute maltreatment and their intended reporting behaviors were also examined. RESULTS: Variability and uncertainty were observed in participants' attitudes as well as in their determinations as to which situations constitute child maltreatment. Most of the sample believed reporting exposure to IPV can help the battered woman (67%) and can protect children (92%), while 56% indicated that reporting can negatively affect the nurse-client relationship. Nurses were more likely to endorse reporting children's exposure to IPV when the child was at greatest risk for being physically injured as a result of IPV. CONCLUSIONS: Training about maltreatment reporting procedures in home visitation programs should focus on the interpretation of child maltreatment laws as well as collaborations with local child protection service agencies to determine if children's exposure to IPV is reportable. PMID- 22924565 TI - Baccalaureate nursing students' intention to choose a public health career. AB - OBJECTIVE(S): To determine nursing students' public health career intentions, and to determine recruitment strategies and other factors that influence students' public health career intentions. DESIGN AND SAMPLE: Descriptive, correlational design. 354 junior and senior baccalaureate nursing students. MEASURES: Students completed a researcher developed survey about choosing public health career intentions and recruitment incentives. RESULTS: Students indicated that they were likely or very likely to consider a career in public health immediately following graduation (21.1%), 1 year after graduation (26.4%) and more than 1 year after graduation (35%). Significant variables influencing career choice immediately following graduation were enrolling institution [t(3,340) = 2.66, p = .008] and traditional clinical site [t(3,340) = -2.306, p = .022]. One year after graduation, traditional public health clinical site [t(3,340) = -2.648, p = .008], and more than 1 year after graduation enrolling institution [t(4,339) = 2.364, p = .019] and gender [t(4,339) = 2.094, p = .037] were significant variables influencing career intentions. The top three recruitment strategies ranked by students were comparable wages, flexible scheduling, and tuition reimbursement. CONCLUSIONS: Identifying priority recruitment strategies for public health students will enhance the ability of public health leaders to recruit graduate registered nurses to public health. Faculty should continue to evaluate both clinical and classroom experiences to stimulate excitement and interest for public health as a career choice. PMID- 22924566 TI - Political astuteness of baccalaureate nursing students following an active learning experience in health policy. AB - OBJECTIVES: To describe changes in political astuteness after baccalaureate nursing student participation in a series of public policy learning activities. DESIGN AND SAMPLE: This one-group pretest/posttest design included 300 undergraduate nursing students enrolled in the public/community health nursing course. Data collection occurred each semester beginning spring 2008 and ending summer 2011. MEASURES: The Political Astuteness Inventory (PAI) was used to compare levels of political astuteness and to identify conceptual factors contributing to political involvement prior to and at the completion of the public policy learning activities. INTERVENTION: The public policy learning activities were a central clinical component of the senior level public/community health nursing course. These activities included information sessions at the State Department of Health and State House, a legislative assignment, and a public policy group project. RESULTS: After participating in the public policy learning activities, students' political astuteness mean scores significantly increased (p = .000). Participation in professional organizations and knowledge of the legislative and policy processes significantly predicted posttest political involvement (p = .000). CONCLUSION: The PAI was a useful outcome measure for the public policy activities. Active learning experiences in public policy can increase the knowledge and skills that future nurses need to influence public policy. PMID- 22924567 TI - Moving policies upstream to mitigate the social determinants of early childbearing. AB - The teen birth rate in the United States is one of the highest in the post industrialized world. International comparisons suggest that U.S. rates reflect high levels of social disadvantage and misguided policies that frame teen parenting as costly for mothers, children, and taxpayers. Studies that control for background factors that predispose teens to become parents highlight the social inequities that contribute to early childbearing and unfavorable maternal child outcomes, regardless of maternal age. After reviewing these studies, federal policies that target and scrutinize teenage and single mothers are described and critiqued for the ways they disregard the social determinants of early childbearing and further the marginalization and social exclusion of low income families. This review calls for public health nurses to challenge the ideological assumptions driving downstream policies and to advocate for comprehensive reforms that reduce the wide and growing inequities in education, income, and health among U.S. citizens. Building the public support and political will to move upstream will remain daunting in light of the pervasive stereotypes of teen parents and the ideological assumptions that early childbearing and poor maternal-child outcomes stem more from individual choices and lifestyles than from social inequities. PMID- 22924568 TI - The Worksite Heart Health Improvement Project (WHHIP): feasibility and efficacy. AB - OBJECTIVE: Test the feasibility and efficacy of the Worksite Heart Health Improvement Project (WHHIP). DESIGN: The WHHIP was a quasi-experimental 6-month pilot performed in 2 long-term care facilities. SAMPLE: Thirty-nine female minority nursing assistants participated in this study with a mean age of 42.39 (SD = 12.79) years. MEASUREMENTS: Measures were collected at baseline, 3, and 6 months and included blood pressure, lipid panel, body mass index, physical activity levels, diet behaviors, depressive symptoms, and self-efficacy outcomes. INTERVENTION: The 3-month WHHIP intervention included 3 components: environmental and policy assessment; education; and on-going motivation. The control site received education only. RESULTS: Subject participation averaged 47% and 58% in exercise and diet related activities, respectively. Generalized estimating equations showed the treatment group showed significant improvements in depressive symptoms (p = .012), systolic blood pressure (p = .028), total cholesterol (p = .002) and triglycerides (p = .011) over time. The treatment group also showed trends for improvement in diet behaviors (p = .069) and diastolic blood pressure (p = .073). CONCLUSIONS: This study provided feasibility evidence for the WHHIP and preliminary evidence that the WHHIP can improve heart healthy behaviors and subsequent outcomes among nursing assistants in long-term care settings. PMID- 22924569 TI - Challenges and strategies for research in prisons. AB - In this article, we discuss some of the challenges encountered while conducting research in two maximum security prisons and approaches we found helpful to facilitate the research process through the development of collaborative relationships, the establishment of prison contacts, and the implementation of rigorous research methods. As a result of our experiences, we have been successful at maintaining a high rate of inmate participation (>80%) and a well functioning multidisciplinary team. The approaches described may be useful to other investigators planning to conduct research in a challenging setting such as prisons. PMID- 22924570 TI - Field training for rural public health nurses. AB - With the expansion of public health nursing beyond cities into rural areas, leaders in nursing education early on recognized the need for additional training to prepare nurses for the rural experience. To this end, nursing faculty at Teachers College, Columbia University developed a pilot program designed to prepare nurses for work in rural areas. These leaders recognized the unique conditions confronting the rural public health nurse in her daily work, including distances to be covered, isolation, and the dearth of facilities for health work. The pilot program discussed in this reprint, published in The Public Health Nurse in 1925, describes the genesis of this project, and the collaborative relationship that was developed with Dutchess County, a rural county about 2 hours north of New York City, to provide practical experiences for students. The project included a series of lectures on rural health issues and rural nursing, as well as field work that included school nursing, and nursing care of special populations such as tuberculosis and maternal and child health, as well as experiences in population-based nursing akin to what we think of as community development today. PMID- 22924571 TI - Efficacy of IGF-based growth hormone (GH) dosing in nonGH-deficient (nonGHD) short stature children with low IGF-I is not related to basal IGF-I levels. AB - OBJECTIVE: Weight-based GH dosing is the standard for treating children with short stature. The current study validates the usefulness of IGF-based GH dosing for GH therapy in nonGH-deficient (nonGHD) children and its relationship with pretreatment serum IGF-I concentration. DESIGN AND PATIENTS: In this twelve month, open-label, randomized controlled study, 151 nonGHD (based on GH stimulation tests), prepubertal children with short stature and IGF-I levels <= 33rd percentile [-0.44 standard deviation score (SDS)] were randomly assigned to receive GH (dose based on IGF-I titration algorithm; n = 114) or to observation (n = 37). GH dose (initially 40 MUg/kg/d) was adjusted every 3 months to achieve an IGF-I SDS in the upper normal range (66-99 th percentile). MEASUREMENTS AND RESULTS: In treated children, mean height SDS (HSDS) increased from -2.5 at baseline to -1.7 at 12 months and mean IGF-I SDS increased from -1.7 to 0.1. These parameters remained unchanged in untreated children. There was no relationship between change in HSDS (DeltaHSDS) and degree of IGF-I deficiency at baseline. No safety problems were observed. Both groups had a similar advance in bone age. At the end of study, DeltaHSDS in treated children showed a positive correlation with IGF-I SDS, but not with GH dose [mean 59 MUg/kg/d (range 29 92)], basal IGF-I SDS or 1-month IGF parameters. CONCLUSIONS: In nonGHD subjects with short stature and serum IGF-I concentrations within and below the lower third of normal, adjusting GH dose to achieve an IGF-I level in the upper normal range resulted in a significant increase in HSDS, regardless of basal IGF-I levels. PMID- 22924573 TI - Computational studies on energetic properties of trinitro-substituted imidazole triazole and pyrazole-triazole derivatives. AB - Heats of formation (HOFs) for 24 designed compounds were obtained by using the density functional theory (DFT). Molecular structures were investigated at the B3PW91/6-31G(d,p) level, and isodesmic reactions were designed for calculating the gas phase heats of formation. The solid state heats of formation for designed compounds were calculated by the Politzer approach using heats of sublimation. All the designed compounds possess solid state heats of formation above 140 kJ/mol. The distance between nitro groups influences the steric and repulsive interactions. Detonation performances were evaluated by the Kamlet-Jacobs equations based on the predicted densities and solid state heats of formation, and susceptibility of decomposition was studied by the computations of bond dissociation energy (BDE). Further, the present study might provide useful information for the structure-property relationship, the laboratory synthesis of imidazole-triazole and pyrazole-triazole based nitro derivatives and the development of novel high energy materials (HEMs). PMID- 22924572 TI - Adipocyte chemerin release is induced by insulin without being translated to higher levels in vivo. AB - BACKGROUND: Chemerin is an adipokine that regulates insulin sensitivity and insulin secretion. Prolonged hyperinsulinaemia is associated with higher systemic chemerin, and insulin induces adipose tissue chemerin release. These findings led us to hypothesize that systemic chemerin may be associated with post-prandial glucose metabolism and/or may even be induced after oral glucose load. Therefore, the effect of insulin on adipocyte chemerin levels and systemic chemerin in mice was analysed. Further, systemic levels of chemerin after oral glucose load in nondiabetic individuals were studied. DESIGN AND METHODS: Chemerin levels were determined in adipocytes after short-term and long-term treatment with insulin. Effects of acute hyperinsulinaemia were studied in mice. Chemerin was measured during oral glucose tolerance test in 66 healthy, nondiabetic individuals stratified for established body mass index categories. RESULTS: Insulin induces chemerin release from adipocytes within 24 h, while cellular levels are not affected. Short-term hyperinsulinaemia also upregulates adipocyte chemerin in vitro but has no effect on adipose tissue and chemerin serum levels of mice. Systemic chemerin is higher in overweight/obese than normal-weight controls and positively correlates with total cholesterol. Chemerin is not associated with markers of insulin sensitivity like fasting glucose or insulin. Fasting chemerin levels are similar to concentrations measured 1 and 2 h after oral glucose uptake in overweight and obese donors. CONCLUSIONS: Post-prandial hyperinsulinaemia does not contribute to higher chemerin levels in nondiabetic individuals. PMID- 22924574 TI - Study on the anti-H1N1 virus effects of quercetin and oseltamivir and their mechanism related to TLR7 pathway. AB - The antivirus effect of quercetin and oseltamivir on the Toll-like receptor 7 (TLR7) signaling pathway was observed when dendritic cells and macrophages were infected with H1N1. Leukomonocytes were obtained from umbilical cord blood and harvested after stimulation by recombinant human Granulocyte-Macrophage Colony Stimulating Factor (rhGM-CSF) and recombinant human Interleukin 4 (rhIL-4). Virus infected cell model was established by human bronchial epithelial cells (16HBE) infected with H1N1. After immunological cells and virus-infected cells were co cultured, quercetin and oseltamivir were also added into the medium as a treatment intervention. Then the immunological cells were collected for Real Time PCR (RT-PCR) and Western blot to determine the expression levels of genes related to TLR7 pathway. Viral infection led to cell death and increased the gene expression levels of TLR7 signal pathway. Quercetin and oseltamivir increased cell viability and reduced the expression levels of TLR7 signal pathway. PMID- 22924575 TI - Shop 'till we drop: a historical and policy analysis of retail goods movement in the United States. AB - The movement of retail goods is central to modern economies and is a significant but understudied-fraction of our overall energy footprint. Thus, we propose a new category for energy analysis called Retail Goods Movement (RGM) that draws its boundaries around the portion of freight dedicated to retail goods and the portion of driving dedicated to shopping. Historically, the components of RGM have not enjoyed policy priority. However, the net payoff from energy research and policy directed at RGM may now be high enough relative to other options to deserve increased investment. We combine a quantitative decomposition of the dynamics of RGM energy use with a qualitative discussion of what trends could have contributed to them. The RGM sector's energy use grew from 1.3 EJ (2.8% U.S.) in 1969 to 7.0 EJ (6.6% U.S.) in 2009. The major drivers were increases in population, freight tonnage (before 1990), distance freighted per tonne and driven per shopping trip (after 1990), and weekly shopping trips per household (before 1995). RGM energy intensity increased per capita (180%), per constant dollar GDP (60%), and per retail expenditure (140%). Finally, we describe policy recommendations that could become the basis of a sound RGM resource plan. PMID- 22924576 TI - Time to abandon the self-medication hypothesis in patients with psychiatric disorders. AB - BACKGROUND: The Self-Medication Hypothesis (SMH) of addictive disorders as articulated by Edward Khantzian in his seminal 1985 paper postulates that individuals with psychiatric disorders use substances to relieve psychiatric symptoms and that this pattern of usage predisposes them to addiction. Khantzian's SMH also postulates that the preferred substance is not random, but is based on the unique pharmacological properties of the substance. For example, an individual with attention deficit disorder would prefer amphetamines to alcohol, due to its stimulating properties, whereas an individual with anxiety would prefer alcohol to amphetamines, due to its anxiolytic properties. Finally, Khantzian's SMH implies that treating the underlying psychiatric disorder will improve or resolve the problems of addiction. AIMS AND RESULTS: A review of the scientific literature demonstrates a striking lack of robust evidence in support of the SMH as put forth by Khantzian. CONCLUSIONS AND SCIENTIFIC SIGNIFICANCE: Nonetheless, the SMH has had a profound influence on medical and lay culture, as well as clinical care. Although originally formulated as a compassionate explanation for addiction in those with psychiatric disorders, the SMH does not provide, as originally intended, a "useful rationale" for guiding treatment and instead has led to under-recognition and under-treatment of substance use disorders. PMID- 22924577 TI - Ion pairing and dynamics of the ionic liquid 1-hexyl-3-methylimidazolium bis(irifluoromethylsulfonyl)amide ([C6mim][NTf2]) in the low dielectric solvent chloroform. AB - The structural and dynamic behavior of the ionic liquid 1-hexyl-3 methylimidazolium bis(trifluoromethylsulfonyl)amide ([C(6)mim][NTf(2)]) in chloroform has been studied by experimental measurements of (1)H and (19)F self diffusion coefficients, viscosity, and excess molar volume in the concentration range of 0.001-1.0 mol.kg(-1) and temperatures ranging from 15 to 45 degrees C. Within measurement uncertainty, the (1)H and (19)F self-diffusion coefficients are identical at the same experimental conditions of concentration and temperature, indicating that even to the lowest measured concentrations the cation and anion are not completely dissociated. The combined experimental data indicates a progression from ion pairing to aggregate formation as concentration increases where at concentrations near 0.1 mol.kg(-1) aggregate formation becomes dominant. Concurrently with the formation of the IL aggregates at higher concentrations, we also observe an apparent breakdown of the validity of the Stokes-Einstein equation, which we explain by translational motion to become dominated by individual ion pairs moving rapidly between IL aggregates. PMID- 22924578 TI - Are elevated androgens a cause of discordant pubertal development? Evidence from a case of adrenocortical carcinoma. PMID- 22924579 TI - A simple new non-invasive sweat indicator test for the diagnosis of diabetic neuropathy. AB - A simple non-invasive indicator test (Neuropad((r))) has been developed for the assessment of sweating and, hence, cholinergic innervation in the diabetic foot. The present review summarizes current knowledge on this diagnostic test. The diagnostic ability of this test is based on a colour change from blue to pink at 10 min, with excellent reproducibility, which lends itself to patient self examination. It has a high sensitivity (65.1-100%) and negative predictive value (63-100%), with moderate specificity (32-78.5%) and positive predictive value (23.3-93.2%) for the diagnosis of diabetic peripheral neuropathy. It also has moderate to high sensitivity (59.1-89%) and negative predictive value (64.7-91%), but low to moderate specificity (27-78%) and positive predictive value (24-48.6%) for the diagnosis of diabetic cardiac autonomic neuropathy. There are some data to suggest that Neuropad can detect early diabetic neuropathy, but this needs further evaluation. It remains to be established whether this test can predict foot ulceration and amputation, thereby contributing to the identification of high-risk patients. PMID- 22924580 TI - Therapeutic delivery of siRNA silencing HIF-1 alpha with micellar nanoparticles inhibits hypoxic tumor growth. AB - The particular characteristics of the tumor microenvironment have the potential to strongly promote tumor growth, metastasis and angiogenesis and induce drug resistance. Therefore, the development of effective, systemic therapeutic approaches specifically based on the tumor microenvironment is highly desirable. Hypoxia-inducible factor-1alpha (HIF-1alpha) is an attractive therapeutic target because it is a key transcription factor in tumor development and only accumulates in hypoxic tumors. We report here that a cationic mixed micellar nanoparticle (MNP) consisting of amphiphilic block copolymers poly(epsilon caprolactone)-block-poly(2-aminoethylethylene phosphate) (PCL(29)-b-PPEEA(21)) and poly(epsilon-caprolactone)-block-poly(ethylene glycol) (PCL(40)-b-PEG(45)) was a suitable carrier for HIF-1alpha siRNA to treat hypoxic tumors, which showed an average diameter of 58.0 +/- 3.4 nm. The complex MNP(siRNA), formed by the interaction of MNP and siRNA, was transfected into PC3 prostate cancer cells efficiently, while the inhibition of HIF-1alpha expression by MNP loaded with HIF 1alpha siRNA (MNP(siHIF)) blocked PC3 cell proliferation, suppressed cell migration and disturbed angiogenesis under in vitro hypoxic mimicking conditions. It was further demonstrated that systemic delivery of MNP(siHIF) effectively inhibited tumor growth in a PC3 prostate cancer xenograft murine model without activating innate immune responses. Moreover, delivery of MNP(siHIF) sensitized PC3 tumor cells to doxorubicin chemotherapy in vitro and in vivo by downregulating MDR1 gene expression which was induced by hypoxia. The underlying concept of use of MNP(siHIF) to block HIF-1alpha holds promise as an example of a clinical approach using specific siRNA therapy for cancer treatment aimed at the hypoxic tumor microenvironment. PMID- 22924581 TI - This is your journal. PMID- 22924582 TI - Risk stratification for Splenic Marginal Zone Lymphoma based on haemoglobin concentration, platelet count, high lactate dehydrogenase level and extrahilar lymphadenopathy: development and validation on 593 cases. AB - This international retrospective study of 593 Splenic Marginal Zone Lymphoma (SMZL) patients aimed to identify factors that determine treatment initiation and influence lymphoma-specific survival (LSS). Logistic regression was used to identify the factors associated with treatment. A Cox regression was used to analyse LSS in a derivation cohort of 366 patients. This produced a prognostic index (PI) and enabled the identification of three risk groups. The resulting stratification was validated in another cohort of 227 patients and compared with the Interguppo Italiano Linfomi (IIL) score in the group of 450 patients for whom all the required data were available using an extension of the net reclassification improvement. Haemoglobin concentration (Hb), extrahilar lymphadenopathy and hepatitis C virus status were associated with the initiation of treatment. Hb, platelet count, high lactate dehydrogenase level and extrahilar lymphadenopathy were independently associated with LSS. Three risk groups with significantly different five-year LSS (94%, 78% and 69%, respectively) were identified. This stratification (named HPLL on the basis of determinant factors) had a better discriminative power than the IIL score. This system is useful for stratifying SMZL patients into risk groups and may help in the selection of risk tailored treatment approaches. PMID- 22924583 TI - Volatile dimethyl polonium produced by aerobic marine microorganisms. AB - The production of volatile polonium (Po(v)), a naturally occurring radioactive element, by pure cultures of aerobic marine tellurite-resistant microorganisms was investigated. Rhodotorula mucilaginosa, a carotogenic yeast, and a Bacillus sp. strain, a Gram-positive bacterium, generated approximately one and 2 orders of magnitude, respectively, greater amounts of Po(v) compared to the other organisms tested. Gas chromatography-inductively coupled plasma-mass spectrometry (GC-ICP-MS) analysis identified dimethyl polonide (DMPo) as the predominant volatile Po compound in culture headspace of the yeast. This species assignment is based on the exact relation between GC retention times and boiling points of this and other Group VI B analogues (S, Se, and Te). The extent of the biotic Po(v) production correlates exponentially with elevated particulate Po (Po(p)): dissolved Po (Po(aq)) ratios in the cultures, consistent with efficient Po bioaccumulation. Further experimentation demonstrated that some abiotic Po(v) generation is possible. However, high-level Po(v) generation in these cultures is predominantly biotic. PMID- 22924584 TI - Two new compounds from the roots of Rhodiola crenulata. AB - Two new compounds, named (3R,5R,8R)-3-O-[alpha-l-arabinopyranosyl (1 -> 6)-beta-d glucopyranosyl]-5-hydroxymegastigma-6,7-dien-9-one (1) and (1R)-1-O-(beta-d glucopyranosyl)-phenylethylene glycol (2), were isolated from the extract of Rhodiola crenulata. Their structures were determined on the basis of various spectroscopic methods, including IR, HR-ESI-MS, 1D and 2D NMR, and chemical evidences. The cytotoxicity of these two compounds was evaluated by using MTT method. PMID- 22924585 TI - The relationship between wisdom and abstinence behaviors in women in recovery from substance abuse. AB - BACKGROUND AND AIMS: Wisdom is theorized to be an important construct in recovery from substance abuse. In order to explore the role of wisdom in substance abuse recovery behaviors, the present study had two goals. First, it sought to examine the factor structure of a wisdom scale, the Foundational Value Scale (FVS) in a community sample of women in recovery from substance abuse. Second, the study examined how wisdom predicted the women's beliefs about their ability to abstain from future substance use. METHODS: 116 women in recovery from substance abuse disorders were recruited from self-run recovery homes and a substance abuse recovery convention. RESULTS: Results from an exploratory factor analysis indicated that a modified version of the FVS has good internal consistency reliability and is composed of three wisdom-related dimensions. The three factors were then used to create a higher-order wisdom factor in a structural equation model (SEM) that was used to predict abstinence self-efficacy behaviors. Results from the SEM showed that the wisdom factor was predictive of greater abstinence self-efficacy behaviors. CONCLUSION: The FVS was found to be a reliable measure with women in recovery from substance abuse. In addition, wisdom predicted beliefs about self-efficacy such that those who reported higher levels of wisdom felt more confident in their abilities to abstain from alcohol. SCIENTIFIC SIGNIFICANCE: The results of this study indicate that wisdom is an important construct in the abstinence behaviors of women who are in recovery from substance abuse disorders. PMID- 22924586 TI - Electrolytic nature of aqueous sulfuric acid. 1. Activity. AB - According to the literature, when H(2)SO(4) dissolves in water, (1) it retains its molecular formula and tetrahedral structure of two O atoms and two OH groups bonded to a central S atom, and (2) it ionizes partially, as a 1-1 electrolyte, to H(+) (H(3)O(+)) and HSO(4)(-); the latter ion further dissociates at low concentrations (<0.1 M) to H(+) and SO(4)(2-). Using the Debye-Huckel (DH) limiting law at very low concentration, and the smaller-ion shell (SiS) model of strong electrolyte solutions-an extension of the DH model for ion size dissimilarity-up to moderate concentration, I examine the theory-experiment fit of the mean ionic activity coefficient (gamma(+/-)) of the acid as a function of concentration (at 0 to ~6 m) and of temperature (at 0-60 degrees C). The fit is impossible if H(2)SO(4) in water is assumed to be a 1-1 or 1-2 electrolyte, but is excellent when the acid is treated instead as a strong 1-3 electrolyte; that is, aqueous sulfuric acid behaves as a fully dissociated H(3)A acid. At 25 degrees C, the SiS best fit is achieved with the H(+) diameter being 1.16 A (as obtained for strong mineral 1-1 protonic acids) and with the A(3-) ionic diameter being 5.77 A. On the basis of the present study, H(2)SO(4) in water may be H(4)SO(5) (dubbed "sulfoxuric", or parasulfuric acid) completely ionized to 3H(+) and the ("bisulfoxate", or parabisulfate) anion HSO(5)(3-). The calculated standard potential of a newly proposed half-cell reaction, H(2) + HSO(5)(3-) <-> H(+) + SO(4)(2-) + H(2)O + 2e(-), at 25 degrees C, is -1.0933 V. PMID- 22924587 TI - Screening for depression and diabetes-related distress in a diabetes outpatient clinic. AB - AIMS: To investigate: (1) the willingness of patients with diabetes to participate in a screening programme; (2) the extent to which patients with diabetes who screen positive endorse need for psychosocial care; (3) the rate of referral to psychosocial care during screening vs. usual care. METHODS: Four hundred and ninety-nine patients with diabetes were invited to complete the Center for Epidemiologic Studies Depression and the Problem Areas in Diabetes questionnaires. Patients screening positive on either instrument were invited for an interview. One year after screening was withdrawn, rates of referral to psychosocial care were assessed from physician reports of patient referrals. RESULTS: In total, 349/499 (70%) patients with diabetes completed the questionnaire. Patients who did not take up the screening were younger, smoked more often and had higher HbA(1c) values. 'No-shows' for clinical appointments accounted for 74% of non-participation. Of the 104 (30% of 349) patients screening positive, 45 accepted an invitation for an interview. Finally, 36/104 (35%) would like a referral for psychological care. Seven per cent of patients were referred to psychological care during screening compared with 1% when screening was withdrawn. CONCLUSIONS: Results raise questions as to whether screening is the most efficient way to identify patients with psychological problems. Many patients did not take up the screening, especially those with low adherence to diabetes care in general. Furthermore, few patients screening positive wanted to be referred. Screening should be evaluated in the context of consideration of alternative ways to identify at-risk patients, including providing resources to deal with patients with already known adjustment and adherence problems. PMID- 22924588 TI - Identification, functional analysis, prevalence and treatment of monocarboxylate transporter 8 (MCT8) mutations in a cohort of adult patients with mental retardation. AB - OBJECTIVE: Monocarboxylate transporter 8 (MCT8) is an essential thyroid hormone (TH) transporter as humans with MCT8 mutations have severe neurological and endocrine abnormalities. The objectives are (i) to identify novel MCT8 mutations and (ii) to assess their functional relevance; (iii) to describe the effects of block-and-replace treatment in an MCT8 patient. DESIGN: The TOP-R study is a cross-sectional nation-wide multicentre study. PATIENTS: Subjects with unexplained mental retardation (MR) were screened for MCT8 mutations. RESULTS: We identified three mutations: p.F501del (previously described), p.L492P and p.T162T. The F501del and L492P mutants, but not the T162T mutant, showed diminished T3, T4 and rT3 transport in transfected cells. TH transport in T162T fibroblasts was also not affected. One patient was treated with block-and-replace therapy to normalize serum TH levels. The results indicated a slow onset of the decrease in serum T4 and T3 by successive treatment with methimazole and PTU, and eventually their complete normalization by administration of LT4 with PTU but not with methimazole. The frequency of MCT8 mutations in males with X-linked MR approximately 3.9%. CONCLUSIONS: We identified several MCT8 mutations in a cohort of subjects with unexplained MR. We demonstrated the pathogenicity of two missense mutations. The synonymous variant did not affect TH transport. Block-and replace therapy of one patient reversed the TH abnormalities. Our data suggest a decreased TH secretion rate and an increased T4 to T3 conversion by the type I deiodinase in patients with MCT8 mutations. Our study indicates that MCT8 mutations are a relatively frequent cause of X-linked MR. PMID- 22924590 TI - Algorithm for initial management of priapism in chronic myeloid leukaemia. PMID- 22924589 TI - Enhancing single-nanoparticle surface-chemistry by plasmonic overheating in an optical trap. AB - Surface-chemistry of individual, optically trapped plasmonic nanoparticles is modified and accelerated by plasmonic overheating. Depending on the optical trapping power, gold nanorods can exhibit red shifts of their plasmon resonance (i.e., increasing aspect ratio) under oxidative conditions. In contrast, in bulk exclusively blue shifts (decreasing aspect ratios) are observed. Supported by calculations, we explain this finding by local temperatures in the trap exceeding the boiling point of the solvent that cannot be achieved in bulk. PMID- 22924592 TI - Challenges in undertaking mosquito surveillance at UK seaports and airports to prevent the entry and establishment of invasive vector species. AB - Port health authorities have played an important role in the control of infectious diseases worldwide. The International Health Regulations (2005) further clarifies this role and provides a legal statutory instrument that aims to assist the international community to prevent and respond to global public health risks. Eleven UK sea and airports participated in a pilot, investigating the challenges ports could face in attempting to monitor for mosquitoes. The study also examined the types of habitat that could support mosquitoes. There is a concern that exotic vector species, such as Aedes albopictus, could invade and become established in the UK. Environments in and around the ports differed, and this was reflected in the species of mosquitoes caught. Ports used different methods to collect mosquitoes and developed a range of techniques for surveying, which suited the conditions at their port. This paper discusses the implications of invasive mosquito surveillance to UK port health authorities. PMID- 22924591 TI - AKAP-dependent sensitization of Ca(v) 3.2 channels via the EP(4) receptor/cAMP pathway mediates PGE(2) -induced mechanical hyperalgesia. AB - BACKGROUND AND PURPOSE: The Ca(v) 3.2 isoform of T-type Ca(2+) channels (T channels) is sensitized by hydrogen sulfide, a pro-nociceptive gasotransmitter, and also by PKA that mediates PGE(2) -induced hyperalgesia. Here we examined and analysed Ca(v) 3.2 sensitization via the PGE(2) /cAMP pathway in NG108-15 cells that express Ca(v) 3.2 and produce cAMP in response to PGE(2) , and its impact on mechanical nociceptive processing in rats. EXPERIMENTAL APPROACH: In NG108-15 cells and rat dorsal root ganglion (DRG) neurons, T-channel-dependent currents (T currents) were measured with the whole-cell patch-clamp technique. The molecular interaction of Ca(v) 3.2 with A-kinase anchoring protein 150 (AKAP150) and its phosphorylation were analysed by immunoprecipitation/immunoblotting in NG108-15 cells. Mechanical nociceptive threshold was determined by the paw pressure test in rats. KEY RESULTS: In NG108-15 cells and/or rat DRG neurons, dibutyryl cAMP (db-cAMP) or PGE(2) increased T currents, an effect blocked by AKAP St-Ht31 inhibitor peptide (AKAPI) or KT5720, a PKA inhibitor. The effect of PGE(2) was abolished by RQ-00015986-00, an EP(4) receptor antagonist. AKAP150 was co immunoprecipitated with Ca(v) 3.2, regardless of stimulation with db-cAMP, and Ca(v) 3.2 was phosphorylated by db-cAMP or PGE(2) . In rats, intraplantar (i.pl.) administration of db-cAMP or PGE(2) caused mechanical hyperalgesia, an effect suppressed by AKAPI, two distinct T-channel blockers, NNC 55-0396 and ethosuximide, or ZnCl(2) , known to inhibit Ca(v) 3.2 among T channels. Oral administration of RQ-00015986-00 suppressed the PGE(2) -induced mechanical hyperalgesia. CONCLUSION AND IMPLICATIONS: Our findings suggest that PGE(2) causes AKAP-dependent phosphorylation and sensitization of Ca(v) 3.2 through the EP(4) receptor/cAMP/PKA pathway, leading to mechanical hyperalgesia in rats. PMID- 22924593 TI - Wellbore-wall compression effects on monitored groundwater levels and qualities. AB - The effects of wellbore-wall compression from rough excavation on monitored groundwater levels and qualities under natural hydraulic gradient conditions were investigated in a shallow clayey Andisol aquifer. Nine wellbores reaching the underlying aquitard at about 2.6-m depth were constructed by dynamic cone penetrometry to mimic rough wellbore construction. Five of these were constructed under wet aquifer soil conditions and the remaining four under dry conditions. A 15-month period monitoring showed that the groundwater levels in the wellbores constructed under wet conditions responded significantly in retard of, and in narrower ranges than, those constructed under dry conditions. The wellbore-wall hydraulic conductivities at the former wellbores were calculated to be more than one to two orders of magnitude lower than those at the latter ones. Furthermore, remarkable nitrate removal attributable to the occurrence of a heterotrophic denitrification was observed in one of the former wellbores. In contrast, the groundwater levels and qualities in the latter wellbores appeared to be generally similar to those monitored in the conventional soil coring and augering-derived wellbores. Our results suggest that the wellbore-wall compression induced by rough excavation under wet and soft aquifer soil conditions leads to a substantial decrease in the wellbore-wall hydraulic conductivity, which in turn can lead to unreliable groundwater levels and qualities. This problem can occur in clayey Andisols whenever the aquifer soil is wet; however, the problem can be largely avoided by constructing the wellbore under dry and hard aquifer soil conditions. PMID- 22924594 TI - Construction of heterometallic clusters in a small peptide scaffold as [NiFe] hydrogenase models: development of a synthetic methodology. AB - [NiFe]-hydrogenases are enzymes that catalyze the reversible interconversion of protons and hydrogen at a heterobimetallic site containing Ni and Fe. This organometallic site has served as an inspiration for the synthesis of a number of biomimetic complexes, but, unfortunately, most close structural mimics have shown little to no reactivity with either of the substrates for hydrogenases. This suggests that interactions between the metallo-active site and the protein scaffold are crucial in tuning reactivity. As a first step toward development of peptide-based models, in this paper we demonstrate a synthetic strategy for construction of peptide coordinated, cysteinyl thiolate bridged Ni-M complexes in which M is a hetero-organometallic fragment. We utilize the seven amino acid peptide ACDLPCG as a scaffold for construction of these peptide-coordinated metallocenters. This peptide binds Ni in an N(2)S(2) environment consisting of the amino terminus, an amide nitrogen, and the two cysteinyl thiolates. We show that these thiolates serve as reactive sites for formation of heterometallic complexes in which they serve as bridging ligands. The method is general, and a number of heterometallic fragments including Ru(eta(6)-arene)(2+), M(CO)(4)(piperidine) for M = Mo and W, and Fe(2)(CO)(6) were successfully incorporated, and the resulting metallopeptides characterized via a range of spectroscopic techniques. This methodology serves as the first step to construction of hydrogenase peptidomimetics that incorporate defined outer coordination sphere interactions intended to tune reactivity. PMID- 22924595 TI - Electrolytic nature of aqueous sulfuric acid. 2. Acidity. AB - In part 1 of this study, I reported that the Debye-Huckel limiting law and the smaller-ion shell (SiS) model of strong electrolyte solutions fit nicely with the experimental mean ionic activity coefficient (gamma(+/-)) of aqueous sulfuric acid as a function of concentration and of temperature when the acid is assumed to be a strong 1-3 electrolyte. Here, I report that the SiS-derived activity coefficient of H(+), gamma(H(+)), of the 1-3 acid is comparable to that of aqueous HCl. This agrees with titration curves showing, as well-known, that sulfuric acid in water is parallel in strength to aqueous HCl. The calculated pH is in good accord with the Hammett acidity function, H(0), of aqueous sulfuric acid at low concentration, and differences between the two functions at high concentration are discussed and explained. This pH-H(0) relation is consistent with the literature showing that the H(0) of sulfuric acid (in the 1-9 M range) is similar to those of HCl and the other strong mineral monoprotic acids. The titration of aqueous sulfuric acid with NaOH does not agree with the known second dissociation constant of 0.010 23; rather, the constant is found to be ~0.32 and the acid behaves upon neutralization as a strong diprotic acid practically dissociating in one step. A plausible reaction pathway is offered to explain how the acid may transform, upon base neutralization, from a dissociated H(4)SO(5) (as 3H(+) and HSO(5)(3-)) to a dissociated H(2)SO(4) even though the equilibrium constant of the reaction H(+) + HSO(5)(3-) <-> SO(4)(2-) + H(2)O, at 25 degrees C, is 10(-37) (part 1). PMID- 22924596 TI - Development of a model system for the study of spoilage associated secondary cucumber fermentation during long-term storage. AB - Calcium chloride fermentations represent an alternative to reduce chloride concentrations in the wastewaters generated from commercial cucumber fermentations, currently performed in cover brine solutions containing 6% to 12% sodium chloride. However, preliminary attempts to commercially ferment the cucumbers in the presence of oxygen led to the development of a secondary cucumber fermentation or spoilage. The development of cucumber secondary fermentation has also been occasionally reported by processors using cover brine solutions containing sodium chloride. This study focused on the development of a model system to characterize CaCl(2) and NaCl secondary cucumber fermentations under conditions similar to those present on the commercial scale. Cucumber fruits mixed with cover brine solutions, containing 100 mM CaCl(2) or 1.03 M NaCl, and 25 mM acetic acid, were fermented in 2 L fermentation vessels subjected to air-purging at a rate of 5 mL/min. Microorganisms and selected biochemical changes detected in the experimental cucumber fermentations had been previously observed in commercial spoilage samples, suggesting the successful reproduction of the secondary fermentation in the laboratory. Experimental secondary fermentations were characterized by the rapid oxidation of the lactic acid produced during the primary fermentation, which, in turn, increased pH. Lactic acid disappearance seemed to be the result of yeast metabolism that also led to the chemical reduction of the environment to levels at which other bacteria could become established and produce butyric, propionic, and acetic acids. This model system will be applied for the identification of strategies to prevent the initiation of the cucumber secondary fermentation and reduce economic losses in the pickling industry. PRACTICAL APPLICATION: The study of secondary cucumber fermentation has represented a challenge for many years. The successful development of a model system for the study of this phenomenon in the laboratory is instrumental in furthering the study of the event and in optimizing the sodium chloride-free fermentation at the commercial scale. PMID- 22924597 TI - Association of 25-hydroxyvitamin D with type 2 diabetes among patients undergoing coronary angiography: cross-sectional findings from the LUdwigshafen Risk and Cardiovascular Health (LURIC) Study. AB - OBJECTIVE: Evidence suggests that vitamin D may protect against the onset of diabetes. However, the mechanisms underlying the role of vitamin D on glycaemic status are unclear and warrant further investigation. We sought to determine the relationship between serum 25-hydroxyvitamin D (25[OH]D) and glycaemic status among intermediate-to-high-risk patients scheduled for coronary angiography. METHODS: Participants were 3316 male and female patients (mean +/- SD age, 62.7 +/- 10.6 years). Four categories were formed according to serum 25[OH]D levels. The association between serum 25[OH]D and diabetes was assessed using multivariable logistic regression. RESULTS: Fasting and 2 h post-load glucose, HbA1c and the HOMA-IR indices diminished with increasing serum 25[OH]D levels (P < 0.001). However, no associations were observed between insulin, pro-insulin or C-peptide and serum 25[OH]D concentrations. The pro-inflammatory markers IL-6 and hs-CRP also decreased considerably with higher vitamin D levels (P < 0.001). After full adjustment, those with optimal serum 25[OH]D levels had a reduced odds for fasting diabetes (OR = 0.63; 95% CI, 0.46-0.86; Ptrend = 0.01), 2 h post-load diabetes (OR = 0.46; 95% CI, 0.29-0.74; Ptrend = 0.004), both fasting/2 h post load diabetes (OR = 0.61; 95% CI, 0.42-0.87; Ptrend = 0.001) and all of the combined hyperglycaemic states (OR = 0.68; 95% CI, 0.52-0.80; Ptrend = 0.01). CONCLUSIONS: Higher serum 25[OH]D levels were associated with better glycaemic status and lower inflammation. Should these observations be confirmed in future studies, vitamin D supplementation may prove a useful adjunct in attenuating the onset of diabetes. PMID- 22924598 TI - The ironic effect of significant results on the credibility of multiple-study articles. AB - Cohen (1962) pointed out the importance of statistical power for psychology as a science, but statistical power of studies has not increased, while the number of studies in a single article has increased. It has been overlooked that multiple studies with modest power have a high probability of producing nonsignificant results because power decreases as a function of the number of statistical tests that are being conducted (Maxwell, 2004). The discrepancy between the expected number of significant results and the actual number of significant results in multiple-study articles undermines the credibility of the reported results, and it is likely that questionable research practices have contributed to the reporting of too many significant results (Sterling, 1959). The problem of low power in multiple-study articles is illustrated using Bem's (2011) article on extrasensory perception and Gailliot et al.'s (2007) article on glucose and self regulation. I conclude with several recommendations that can increase the credibility of scientific evidence in psychological journals. One major recommendation is to pay more attention to the power of studies to produce positive results without the help of questionable research practices and to request that authors justify sample sizes with a priori predictions of effect sizes. It is also important to publish replication studies with nonsignificant results if these studies have high power to replicate a published finding. PMID- 22924599 TI - Asking sensitive questions: a statistical power analysis of randomized response models. AB - This article derives the power curves for a Wald test that can be applied to randomized response models when small prevalence rates must be assessed (e.g., detecting doping behavior among elite athletes). These curves enable the assessment of the statistical power that is associated with each model (e.g., Warner's model, crosswise model, unrelated question model, forced-choice models, item count model, cheater detection model). This power analysis can help in choosing the optimal model and sample size and in setting model parameters in survey studies. The general framework can be applied to all existing randomized response model versions. The Appendix of this article contains worked-out numerical examples to demonstrate the power analysis for each specific model. PMID- 22924600 TI - Investigating inter-individual differences in short-term intra-individual variability. AB - Intra-individual variability over a short period of time may contain important information about how individuals differ from each other. In this article we begin by discussing diverse indicators for quantifying intra-individual variability and indicate their advantages and disadvantages. Then we propose an alternative method that models inter-individual differences in intra-individual variability by separately considering both the amplitude of fluctuations and temporal dependency in the data. In the proposed model, temporal dependency and amplitude of fluctuations are both included as random effects. Parameter estimation is done with a multiple-step approach using maximum likelihood, or with a recommended 1-step approach using a Bayesian method. The similarities and differences between the proposed method and some existing methods are discussed and investigated using diary study data from older adults. The results from empirical data analysis revealed that temporal dependency and amplitude of fluctuations have different predictability of health outcomes and thus should be modeled and considered separately. PMID- 22924601 TI - A new prenylated aurone from Artocarpus altilis. AB - Phytochemical study of the methanol extract of Artocarpus altilis resulted in the isolation of a new prenylated aurone, artocarpaurone (1), together with eight known compounds including two prenylated chalcones (2 and 3), three prenylated flavanones (4-6), and three triterpenes (7-9). The structure of 1 was elucidated as 6-hydroxy-2-[8-hydroxy-2-methyl-2-(4-methyl-3-pentenyl)-2H-1-benzopyran-5 ylmethylene]-3(2H)-benzofuranone by spectroscopic methods including 1D and 2D NMR spectra and FT-ICR-MS. Compound 1 showed moderate nitric oxide radical scavenging activity, whereas 2 and 3 had moderate 2,2-diphenyl-1-picrylhydrazyl radical scavenging effect, compared with the positive control (+)-catechin. PMID- 22924602 TI - Prevalence of zinc transporter 8 antibodies in gestational diabetes mellitus. AB - AIMS: Gestational diabetes mellitus affects approximately 7% of all pregnant women. Some of these women develop autoantibodies that are generally characteristic of Type 1 diabetes. Autoantibodies targeting glutamic acid decarboxylase and tyrosine phosphatase-like protein are the most frequently reported. A recently identified autoantigen in Type 1 diabetes is zinc transporter 8. Some reports suggest that the frequency of zinc transporter 8 antibodies is as high as glutamic acid decarboxylase antibodies in Type 1 diabetes and thus a good diagnostic marker for autoimmune diabetes. There are currently no reports of zinc transporter 8 antibodies in gestational diabetes. The aim of this pilot study was to investigate the frequency of zinc transporter 8 antibodies in patients at clinical onset of gestational diabetes mellitus. METHODS: Subjects included in this pilot study were all diagnosed with gestational diabetes at Skane University Hospital, Lund, Sweden, 2009-2010 (n = 193). Sera samples were analysed for antibodies using a commercial enzyme-linked immunosorbent assay according to the manufacturers' instructions. RESULTS: We found that 19/193 patients with gestational diabetes, diagnosed in 2009-2010, were positive for at least one autoantibody. Glutamic acid decarboxylase was the most common single autoantibody (52.6%; 10/19), followed by zinc transporter 8 (21.1%; 4/19) and tyrosine phosphatase-like protein (15.8%; 3/19). Combinations of two or more antibodies were rare (10.5%; 2/19). CONCLUSIONS: In this study, we found that zinc transporter 8 added 2.1% (4/193) of autoantibody positivity in women with gestational diabetes who were negative for glutamic acid decarboxylase and tyrosine phosphatase-like protein antibodies. Glutamic acid decarboxylase was still the most prevalent autoantibody in gestational diabetes, but, as zinc transporter 8 was present even in the absence of glutamic acid decarboxylase, this autoantibody could be an important independent marker of autoimmunity in gestational diabetes. PMID- 22924603 TI - Colloidal semiconductor quantum dots with tunable surface composition. AB - Colloidal CdS quantum dots (QDs) were synthesized with tunable surface composition. Surface stoichiometry was controlled by applying reactive secondary phosphine sulfide precursors in a layer-by-layer approach. The surface composition was observed to greatly affect photoluminescence properties. Band edge emission was quenched in sulfur terminated CdS QDs and fully recovered when QDs were cadmium terminated. Calculations suggest that electronic states inside the band gap arising from surface sulfur atoms could trap charges, thus inhibiting radiative recombination and facilitating nonradiative relaxation. PMID- 22924604 TI - Total synthesis of natural enantiomers of heliespirones A and C via the diastereoselective intramolecular Hosomi-Sakurai reaction. AB - A full account of the development of a novel type of the intramolecular Hosomi Sakurai reactions of the substrates with a p-benzoquinone and an allylsilane moieties connected by an ether linkage is described. This transformation proceeds via an addition-elimination sequence and provides the products with two stereogenic centers through a 1,3(or 1,4)-asymmetric induction in good to excellent diastereoselectivities. A reasonable mechanistic possibility for the reaction, determination of the stereochemistry for the product, and scope and limitation of the transformation are also discussed. The methodology developed here can successfully be applied to the enantiocontrolled total synthesis of the natural enantiomers of (-)-heliespirone A and (+)-heliespirone C, which have been isolated from sunflower Helianthus annuus L. as allelochemicals. PMID- 22924605 TI - Accounting for aquifer heterogeneity from geological data to management tools. AB - A nested workflow of multiple-point geostatistics (MPG) and sequential Gaussian simulation (SGS) was tested on a study area of 6 km(2) located about 20 km northwest of Quebec City, Canada. In order to assess its geological and hydrogeological parameter heterogeneity and to provide tools to evaluate uncertainties in aquifer management, direct and indirect field measurements are used as inputs in the geostatistical simulations to reproduce large and small scale heterogeneities. To do so, the lithological information is first associated to equivalent hydrogeological facies (hydrofacies) according to hydraulic properties measured at several wells. Then, heterogeneous hydrofacies (HF) realizations are generated using a prior geological model as training image (TI) with the MPG algorithm. The hydraulic conductivity (K) heterogeneity modeling within each HF is finally computed using SGS algorithm. Different K models are integrated in a finite-element hydrogeological model to calculate multiple transport simulations. Different scenarios exhibit variations in mass transport path and dispersion associated with the large- and small-scale heterogeneity respectively. Three-dimensional maps showing the probability of overpassing different thresholds are presented as examples of management tools. PMID- 22924606 TI - The dynamic nature of type 1 cannabinoid receptor (CB(1) ) gene transcription. AB - The type 1 cannabinoid receptor (CB(1) ) is an integral component of the endocannabinoid system that modulates several functions in the CNS and periphery. The majority of our knowledge of the endocannabinoid system involves ligand receptor binding, mechanisms of signal transduction, and protein-protein interactions. In contrast, comparatively little is known about regulation of CB(1) gene expression. The levels and anatomical distribution of CB(1) mRNA and protein are developmental stage-specific and are dysregulated in several pathological conditions. Moreover, exposure to a variety of drugs, including cannabinoids themselves, alters CB(1) gene expression and mRNA levels. As such, alterations in CB(1) gene expression are likely to affect the optimal response to cannabinoid-based therapies, which are being developed to treat a growing number of conditions. Here, we will examine the regulation of CB(1) mRNA levels and the therapeutic potential inherent in manipulating expression of this gene. LINKED ARTICLES: This article is part of a themed section on Cannabinoids. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2012.167.issue-8. PMID- 22924608 TI - Richard Burnard Rodnight, 1921-2012. PMID- 22924609 TI - Synthesis and structure of bismuth(III)-containing noncentrosymmetric phosphates, Cs3KBi2M4(PO4)6Cl (M = Mn, Fe). Monoclinic (Cc) and tetragonal (P43) polymorphs templated by chlorine-centered Cl(Bi2Cs) acentric units. AB - Single crystals of three new noncentrosymmetric (NCS) phosphates, alpha (1) and beta (2) forms of Cs(3)KBi(2)Mn(4)(PO(4))(6)Cl and alpha Cs(3)KBi(2)Fe(4)(PO(4))(6)Cl (3), were grown in a reactive CsCl/KCl molten-salt media. Their structures were determined by single-crystal X-ray diffraction methods showing that the alpha form crystallizes in the space group Cc (No. 9), which is in one of the 10 NCS polar crystal classes, m (2/m) while the beta form crystallizes in P4(3) (No. 78) of another polar class, 4 (4/m). The unit cell parameters of the alpha form can be approximately correlated with that of the beta form via the 3 * 3 orientation matrix [0.5, 0.5, 0; -0.5, 0.5, 0; 0, 0, 2 sin beta]. The structures of these otherwise complicated phosphates exhibit two types of channels with circular and elliptical windows where the Cl-centered Cl(Bi(2)Cs) acentric unit is located. The neighboring acentric units are arranged in a parallel fashion in the alpha form, resulting in the monoclinic (Cc) lattice, but "antiparallel" in the beta form, thus giving the tetragonal (P4(3)) unit cell. 1-3 feature the compatible M-O-P unit that contains four crystallographically independent MO(x) (x = 4, 5) polyhedra, which are connected to the Cl(Bi(2)Cs) acentric unit through one short and one long M(II)...Cl bond. The compositions of 1 and 2 consist of three Mn(2+) (d(5)) and one Mn(3+) (d(4)) per formula unit and that of 3 has three Fe(2+) (d(6)) and one Fe(3+) (d(5)). Bond valence sums reveal that, in the alpha phase, the trivalent site adopts distorted tetrahedral M(1)(3+)O(4) coordination and, in the beta phase, distorted trigonal-bipyramidal M(4)(3+)O(5). Thus far, the iron phase has only been isolated in the alpha form presumably because of little extra stabilization energy gain if the Fe(2+) d(6) ion were to occupy the M(1)O(4) site. The possible origins pertaining to the structural differences in the alpha and beta forms are discussed. PMID- 22924607 TI - High dose vitamin D therapy for chronic pain in children and adolescents with sickle cell disease: results of a randomized double blind pilot study. AB - We report results of a pilot study of high-dose vitamin D in sickle cell disease (SCD). Subjects were given a 6-week course of oral high-dose cholecalciferol (4000-100 000 IU per week) or placebo and monitored prospectively for a period of six months. Vitamin D insufficiency and deficiency was present at baseline in 82.5% and 52.5% of subjects, respectively. Subjects who received high-dose vitamin D achieved higher serum 25-hydroxyvitamin D, experienced fewer pain days per week, and had higher physical activity quality-of-life scores. These findings suggest a potential benefit of vitamin D in reducing the number of pain days in SCD. Larger prospective studies with longer duration are needed to confirm these effects. PMID- 22924610 TI - A plasmonic Fano switch. AB - Plasmonic clusters can support Fano resonances, where the line shape characteristics are controlled by cluster geometry. Here we show that clusters with a hemicircular central disk surrounded by a circular ring of closely spaced, coupled nanodisks yield Fano-like and non-Fano-like spectra for orthogonal incident polarization orientations. When this structure is incorporated into an uniquely broadband, liquid crystal device geometry, the entire Fano resonance spectrum can be switched on and off in a voltage-dependent manner. A reversible transition between the Fano-like and non-Fano-like spectra is induced by relatively low (~6 V) applied voltages, resulting in a complete on/off switching of the transparency window. PMID- 22924611 TI - Response of rotation-translation blocked proteins using Langevin dynamics on a locally harmonic landscape. AB - Langevin dynamics is used to compute the time evolution of the nonequilibrium motion of the atomic coordinates of a protein in response to ligand dissociation. The protein potential energy surface (PES) is approximated by a harmonic basin about the minimum of the unliganded state. Upon ligand dissociation, the protein undergoes relaxation from the bound to the unbound state. A coarse graining scheme based on rotation translation blocks (RTB) is applied to the relaxation of the two domain iron transport protein, ferric binding protein. This scheme provides a natural and efficient way to freeze out the small amplitude, high frequency motions within each rigid fragment, thereby allowing for the number of dynamical degrees of freedom to be reduced. The results obtained from all flexible atom (constraint free) dynamics are compared to those obtained using RTB Langevin dynamics. To assess the impact of the assumed rigid fragment clustering on the temporal relaxation dynamics of the protein molecule, three distinct rigid block decompositions were generated and their responses compared. Each of the decompositions was a variant of the one-block-per-residue grouping, with their force and friction matrices being derived from their fully flexible counterpart. Monitoring the time evolution of the distance separating a selected pair of amino acids, the response curves of the blocked decompositions were similar in shape to each other and to the control system in which all atomic degrees of freedom are fully independent. The similar shape of the blocked responses showed that the variations in grouping had only a minor impact on the kinematics. Compared with the all atom responses, however, the blocked responses were faster as a result of the instantaneous transmission of force throughout each rigid block. This occurred because rigid blocking does not permit any intrablock deformation that could store or divert energy. It was found, however, that this accelerated response could be successfully corrected by scaling each eigenvalue in the appropriate propagation matrix by the least-squares fitted slope of the blocked vs nonblocked eigenvalue spectra. The RTB responses for each test system were dominated by small eigenvalue overdamped Langevin modes. The large eigenvalue members of each response dissipated within the first 5 ps, after which the long time response was dominated by a modest set of low energy, overdamped normal modes, that were characterized by highly cooperative, functionally relevant displacements. The response assuming that the system is in the overdamped limit was compared to the full phase space Langevin dynamics results. The responses after the first 5 ps were nearly identical, confirming that the inertial components were significant only in the initial stages of the relaxation. Since the propagator matrix in the overdamped formulation is real-symmetric and does not require the inertial component in the propagator, the computation time and memory footprint was reduced by 1 order of magnitude. PMID- 22924612 TI - Determination of Cd (II), Cu (II), and Pb (II) in some foods by FAAS after preconcentration on modified silica gels with thiourea. AB - This study describes preconcentration method for determination of Cd (II), Cu (II), and Pb (II) in some food samples. Silica gel was modified with thiourea and characterized by IR and C, H, N, S elemental analysis. Modified silica gel was used as a solid phase extraction for determination of Cd (II), Cu (II) and Pb (II) in tuna fish, biscuit, black tea, rice, kasar cheese, honey, tomato paste, and margarine samples. The analytical conditions including eluent type, pH of sample solutions, flow rates of sample and eluent solutions, etc. were optimized. The influence of the matrix ions on the involvement of the Cd (II), Cu (II), and Pb (II) were also studied. GBW 07605 tea standard reference material was used for validation of method. The method was successfully applied for the determination of Cd (II), Cu (II), and Pb (II) ions in food samples. The detection limits were in the range of 0.81 MUg/L, 0.38 MUg/L, and 0.57 MUg/L for cadmium, copper and lead, respectively. The relative standard deviations of the procedure were below 10%. The sorption capacities were found as 92 MUmol/L Cd (II), 286 MUmol/L Cu (II), and 121 MUmol/L Pb (II). PMID- 22924613 TI - Higher TSH level is a risk factor for differentiated thyroid cancer. AB - OBJECTIVES: Higher thyroid-stimulating hormone (TSH) levels are associated with differentiated thyroid cancers (DTC). To validate this association, we compared TSH levels obtained from euthyroid patients with DTC with TSH levels from controls in the general population. DESIGN AND PATIENTS: The case group included 1759 patients with DTC, who underwent thyroid surgery at Chonnam National University Hwasun Hospital. The control group (n = 1548), who had participated in the Thyroid Disease Prevalence Study were used as a healthy control group. The subjects were divided into four groups of similar size according to their TSH levels, with the first quartile used as a reference group. RESULTS: The mean TSH level of the case group was significantly higher than the mean TSH level of the control group (1.95 +/- 0.9 mIU/l vs 1.62 +/- 0.8 mIU/l, P < 0.001), and was associated with DTC risk. Multiple logistic regression, after controlling for age, gender and the presence of a family history of thyroid cancer, showed that the odds ratios and 95% confidence intervals for the second, third and fourth quartiles of TSH levels were 1.27 (1.03-1.57), 1.55 (1.25-1.92) and 2.21 (1.78 2.74) respectively. No significant differences were observed in mean TSH levels in patients with different tumour stages and tumour sizes. CONCLUSION: Having a high TSH level within the normal range is an independent risk factor for DTC, and may contribute to the initiation of thyroid carcinogenesis. TSH levels in patients with thyroid nodules may be used as diagnostic adjuncts for the identification of high-risk patients, who require further investigation and/or surgical intervention. PMID- 22924615 TI - A portable membrane contactor sampler for analysis of noble gases in groundwater. AB - To enable a wider use of dissolved noble gas concentrations and isotope ratios in groundwater studies, we have developed an efficient and portable sampling device using a commercially available membrane contactor. The device separates dissolved gases from a stream of water and collects them in a small copper tube (6 mm in diameter and 100 mm in length with two pinch-off clamps) for noble gas analysis by mass spectrometry. We have examined the performance of the sampler using a tank of homogeneous water prepared in the laboratory and by field testing. We find that our sampling device can extract heavier noble gases (Ar, Kr, and Xe) more efficiently than the lighter ones (He and Ne). An extraction time of about 60 min at a flow rate of 3 L/min is sufficient for all noble gases extracted in the sampler to attain equilibrium with the dissolved phase. The extracted gas sample did not indicate fractionation of helium ((3) He/(4) He) isotopes or other noble gas isotopes. Field performance of the sampling device was tested using a groundwater well in Vienna and results were in excellent agreement with those obtained from the conventional copper tube sampling method. PMID- 22924614 TI - Antiviral activity of retrocyclin RC-101, a candidate microbicide against cell associated HIV-1. AB - Microbicides have been evaluated mostly against cell-free HIV-1. Because semen contains both cell-free and cell-associated HIV-1, HIV-1 transmission could occur via either or both sources. Therefore, it is important to examine the antiviral activity of microbicides against cell-associated HIV-1. The cyclic antimicrobial peptide retrocyclin RC-101 has been shown previously to have antiviral activity against cell-free HIV-1, with no associated cellular toxicity. In this article we have examined the antiviral activity of RC-101 against cell-associated HIV-1. The results demonstrate potent antiviral activity of RC-101 against cell-cell HIV-1 transmission in both CD4-dependent and CD4-independent assays against CCR5- and CXCR4-tropic HIV-1, with no cellular toxicity. Furthermore, this antiviral activity was retained in the presence of human seminal plasma. The potent antiviral activity of RC-101 against cell-associated HIV-1 reported here, and the previously reported antiviral activity in cervical tissues, suggest that RC-101 is an excellent and promising microbicide candidate against HIV-1. PMID- 22924616 TI - Melatonin suppresses tumor progression by reducing angiogenesis stimulated by HIF 1 in a mouse tumor model. AB - The sustained expansion of a tumor mass requires new blood vessel formation to provide rapidly proliferating tumor cells with an adequate supply of oxygen and nutrients. Hypoxia-inducible factor-1 (HIF-1) plays an essential role in tumor angiogenesis and growth by regulating the transcription of genes in response to hypoxic stress. This study was designed to investigate the effects of melatonin on tumor growth and angiogenesis, as well as the mechanism underlying the antitumor activities of melatonin. In this study, we show that the administration of melatonin inhibits tumor growth and blocks tumor angiogenesis in mice. Moreover, melatonin diminished the expression of the HIF-1alpha protein within the tumor mass during tumorigenesis. Our findings suggest that melatonin is a promising anti-angiogenic therapeutic agent targeting HIF-1alpha in cancer. Considering that HIF-1alpha is overexpressed in a majority of human cancers, melatonin could offer a potent therapeutic agent for cancer. PMID- 22924617 TI - Quality of raw and smoked fillets from clinically healthy Atlantic salmon, Salmo salar L., following an outbreak of pancreas disease (PD). AB - Pancreas disease (PD) is a viral disease of farmed salmonid fish, which causes huge economic losses. Pathological changes in skeletal muscle, pancreas and heart are hallmarks of PD. Stakeholders in the fish-smoking industry have claimed that fillets from PD-affected Atlantic salmon, Salmo salar L., are of poor quality. We therefore examined harvest-ready, clinically healthy Atlantic salmon from a population of fish previously affected by PD. Histopathological changes in skeletal muscle tissues ranged from minor to severe. Fillet quality measurements showed that fish with severe skeletal muscle changes provided a paler raw fillet and a yellowish and harder cold-smoked fillet than normal. PD had no significant effect on fillet gaping, bacteriological quality or off-odour development during storage. An unexpected finding was a significant subendocardial fibrosis in 23% of the PD-affected fish. The latter may indicate susceptibility to stress-related heart failure. PMID- 22924618 TI - Effect of illegal substance use on cognitive function in individuals with a psychotic disorder: a review and meta-analysis. AB - OBJECTIVE: Impairment in cognitive function is a core feature of schizophrenia and other psychoses. Substance misuse is associated with impairment in cognitive function in the healthy population. Due to the high prevalence of substance misuse in those with a psychotic disorder, there is concern that a "double deficit" may result in this population. The aim of the current systematic review was to give an overview of the literature, to date, that has investigated the effect of illegal substance abuse or dependence on cognitive function in those with a psychotic disorder and to evaluate the differences and limitations in the methodologies used. METHOD: A systematic review and evaluation of the current literature comparing those with a diagnosis of a psychotic disorder with and without a history of substance abuse or dependence was conducted. A meta-analysis was also conducted to quantitatively assess the association between substance use and cognitive function in those with a psychotic disorder. RESULTS: The current literature investigating the impact of substance misuse on cognitive function in those with a psychotic disorder suffers from many methodological limitations. The results of the meta-analysis show that substance users performed significantly better than nonusers in the cognitive domains of attention and psychomotor speed and verbal memory, with no "double deficit" apparent. CONCLUSIONS: The results of this meta-analysis should be interpreted with caution, in light of the methodological difficulties reviewed. PMID- 22924619 TI - Persistent cortical deafness: a voxel-based morphometry and tractography study. AB - OBJECTIVE: In cortical deafness, no auditory signals can be perceived by the cortex despite normal peripheral hearing. Cortical deafness rarely persists, but generally evolves into other cortical auditory syndromes. In this report, we describe a patient showing a stable and persisting pattern of cortical deafness 16 months after two major ischemic strokes. METHODS: Voxel based morphometric evidence from high resolution three-dimensional MRI and data from tractography are reported for the first time, to our knowledge, in this syndrome in addition to behavioral and electrophysiological findings. RESULTS: The most remarkable findings came from the tractography data, where an asymmetric pattern was found showing severe damage of connections within the anterior right hemisphere, in regions subserving self-awareness. Frontal asymmetry, although detectable by the morphometric analysis, was less informative than that detected in the tractography data. CONCLUSION: The evidence from this case study suggests that damage to the neural systems involved in awareness may play an important role in the emergence of cortical deafness and its persistence. PMID- 22924621 TI - Influence of pH on sphingomyelin monolayer at air/aqueous solution interface. AB - The pH dependence of the interfacial tension is an important factor in the behavior of sphingomyelin (SM) monolayers. We developed a theoretical model to describe this dependence in which the interfacial tension and molecular area contributions of each sphingomyelin form were additive and dependent on pH. The interfacial tension values and the molecular areas values for the SMH(+) and SMOH(-) forms of sphingomyelin were calculated and the proposed model was experimentally verified. The theoretical predictions agreed with the experimental results for pH values ranging from 2 to 12. PMID- 22924620 TI - Effect of tissue specificity on the performance of extracellular matrix in improving endothelialization of cardiovascular implants. AB - Natural extracellular matrix (ECM) deposited in situ by cultured endothelial cells (ECs) has been proven effective in accelerating endothelialization of titanium (Ti) cardiovascular implants (CVIs) in our previous studies. In this study, the ECM deposited by smooth muscle cells (SMCs) was used in comparison to investigate the effects of tissue specificity of the ECM on the ability to accelerate endothelialization of CVIs. The results demonstrated that the ECM deposited by ECs and SMCs (EC-ECM, SMC-ECM, respectively) differed considerably in components and fibril morphology. Surface modification of Ti CVIs with both types of natural ECM was effective in improving their in vitro hemocompatibility and cytocompatibility simultaneously. However, the endothelialization of ECM modified Ti CVIs in a canine model demonstrated a high tissue specificity of the ECM. Although the ECM deposited by SMCs (SMC-ECM) induced fewer platelet adhesion and sustained better growth and viability of ECs in vitro, its performance in accelerating in vivo endothelialization of Ti CVIs was extremely poor. In contrast, the ECM deposited by ECs (EC-ECM) led to complete endothelium formation in vivo. PMID- 22924622 TI - Which is more enduring--FAME or COURAGE? PMID- 22924623 TI - Synthesis and antitumor activity evaluation of new asiatic acid derivatives. AB - Twelve novel asiatic acid (AA) derivatives were designed and synthesized. Their structures were confirmed using NMR, MS, and IR spectra. Their in vitro cytotoxicities on various cancer cell lines (HeLa, HepG2, BGC-823, and SKOV3) were evaluated by the 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide assay. Most of the derivatives were found to have stronger cell growth inhibitory activity than AA. Among them, compounds 5-8 and 11 with substituted amide group at C-28 exhibited more potent cytotoxicity than AA, Gefitinib, and etoposide (positive control). PMID- 22924624 TI - Changes in the sensory characteristics of mango cultivars during the production of mango puree and sorbet. AB - The effects of processing on the flavor and texture properties of 4 mango cultivars available in the U.S. were studied. Descriptive panelists evaluated fresh mango, mango puree, and mango sorbet prepared from each cultivar. Purees were made by pulverizing mango flesh, passing it through a china cap, and heating it to 85 degrees C for 15 s. To prepare the sorbets, purees were diluted with water (1:1), sucrose was added to increase the total soluble solids (TSS) to 32 +/- 2 degrees Brix, and bases were frozen in a batch-type ice cream freezer. Processing fresh mangoes into mango puree generally decreased fruity character and mango identity and led to the appearance of a cooked note. Many of the flavor distinctions among cultivars carried over from fresh to puree samples, but much of the texture variation was lost. Thermal processing had differing effects on the flavor of the cultivars, and therefore, results suggest that mango cultivars for purees should be selected based on properties after thermal treatment. Processing purees into sorbets minimized flavor variation among cultivars, although Tommy Atkins sorbet was relatively high in green and green-viney character and low in caramelized flavor compared to the other cultivars in sorbet. Based on the current study only very distinct flavor properties of mango cultivars may carry over to sorbets. PRACTICAL APPLICATION: Findings from the present study will help mango puree and sorbet manufacturers select appropriate cultivars for their products by understanding the transformation that mango undergoes as it is processed into mango puree and subsequently to mango sorbet. PMID- 22924625 TI - HLA-B*27:05-specific cytotoxic T lymphocyte epitopes in Indian HIV type 1C. AB - HLA-B*27:05 is one of the widely reported alleles associated with resistance to HIV, while HLA-A24, HLA-B7, HLA-B*07:02, HLA-B*35:01, HLA-B*53:01, and HLA-B40 are reported to be associated with susceptibility to HIV. Using a bioinformatics approach we attempted to predict potential HLA-B*27:05-specific HIV-1C epitopes that do not bind to susceptibility-associated HLA alleles based on our hypothesis that such epitopes have a greater probability of eliciting a protective immune response in the host. A consensus sequence was built for all proteins of Indian clade C virus. Epitopes specific to HLA-B*27:05 were predicted from the consensus sequence using two different bioinformatics methods to enhance the accuracy of the prediction. Epitopes that were also predicted to bind to any of the susceptibility-associated HLA alleles were excluded from the list. The short listed epitopes were modeled using MODPROPEP to refine the prediction. Fourteen peptides were identified as epitopes by both sequence-based methods and were found to interact strongly with HLA-B*27:05 by molecular modeling studies. Five of the 14 epitopes were previously reported as immunogenic by other researchers, while the remaining nine are novel. The 14 epitopes have been repeatedly identified by three different methods indicating their potential as useful candidates for an effective HIV vaccine. PMID- 22924626 TI - Deletion of glutamate dehydrogenase 1 (Glud1) in the central nervous system affects glutamate handling without altering synaptic transmission. AB - Glutamate dehydrogenase (GDH), encoded by GLUD1, participates in the breakdown and synthesis of glutamate, the main excitatory neurotransmitter. In the CNS, besides its primary signaling function, glutamate is also at the crossroad of metabolic and neurotransmitter pathways. Importance of brain GDH was questioned here by generation of CNS-specific GDH-null mice (CnsGlud1(-/-)); which were viable, fertile and without apparent behavioral problems. GDH immunoreactivity as well as enzymatic activity were absent in Cns-Glud1(-/-) brains. Immunohistochemical analyses on brain sections revealed that the pyramidal cells of control animals were positive for GDH, whereas the labeling was absent in hippocampal sections of Cns-Glud1(-/-) mice. Electrophysiological recordings showed that deletion of GDH within the CNS did not alter synaptic transmission in standard conditions. Cns-Glud1(-/-) mice exhibited deficient oxidative catabolism of glutamate in astrocytes, showing that GDH is required for Krebs cycle pathway. As revealed by NMR studies, brain glutamate levels remained unchanged, whereas glutamine levels were increased. This pattern was favored by up-regulation of astrocyte-type glutamate and glutamine transporters and of glutamine synthetase. Present data show that the lack of GDH in the CNS modifies the metabolic handling of glutamate without altering synaptic transmission. PMID- 22924627 TI - Plasmon transmutation: inducing new modes in nanoclusters by adding dielectric nanoparticles. AB - Planar clusters of coupled plasmonic nanoparticles support nanoscale electromagnetic "hot spots" and coherent effects, such as Fano resonances, with unique near and far field signatures, currently of prime interest for sensing applications. Here we show that plasmonic cluster properties can be substantially modified by the addition of individual, discrete dielectric nanoparticles at specific locations on the cluster, introducing new plasmon modes, or transmuting existing plasmon modes to new ones, in the resulting metallodielectric nanocomplex. Depositing a single carbon nanoparticle in the junction between a pair of adjacent nanodisks induces a metal-dielectric-metal quadrupolar plasmon mode. In a ten-membered cluster, placement of several carbon nanoparticles in junctions between multiple adjacent nanoparticles introduces a collective magnetic plasmon mode into the Fano dip, giving rise to an additional subradiant mode in the metallodielectric nanocluster response. These examples illustrate that adding dielectric nanoparticles to metallic nanoclusters expands the number and types of plasmon modes supported by these new mixed-media nanoscale assemblies. PMID- 22924628 TI - Acid-induced opening of [closo-B10H10]2- as a new route to 6-substituted nido B10H13 decaboranes and related carboranes. AB - Protonation of the polyhedral anion [closo-B(10)H(10)](2-) under superacidic conditions apparently generates an electrophilic intermediate, [B(10)H(13)](+), that forms 6-R-nido-B(10)H(13) (R = aryl, alkyl, triflate) derivatives by electrophilic aromatic substitution, C-H bond activation, or ion-pair collapse, respectively. The proposed mechanism of formation of the 6-R-nido-B(10)H(13) derivatives via the boranocation [B(10)H(13)](+) is discussed. The synthesis of carboranes, starting from 6-R-nido-B(10)H(13) decaboranes, and single-crystal X ray diffraction analyses of several 6-R-nido-B(10)H(13) decaboranes and carboranes are described. PMID- 22924629 TI - Synthesis of (4-hexyloxybenzoyl)butylsaure methyl amide/poly(3-hexylthiophene) heterojunction nanowire arrays. AB - Large-area P-N heterojunction organic semiconductor nanowire combined (4 hexyloxybenzoyl)butylsaure methyl amide (H-t-B) and Poly (3-hexylthiophene) (P3HT) were fabricated and the morphology and photoelectric properties were investigated by the growth of composition. The performance of light on/off switching of the H-t-B/P3HT heterojunction nanowire arrays was measured by the light irradiation on and off, the current in the devices showed two distinct states, the current was only 0.34 MUA in the dark, while the current can reach 1.37 MUA under the illumination of 45 mW/cm(2). The on/off switching ratio for the device of the heterojunction nanowire arrays is about 4.03. PMID- 22924630 TI - Intranasal co-delivery with the mouse zona pellucida 3 and GM-CSF expressing constructs enhances humoral immune responses and contraception in mice. AB - Granulocyte-monocyte colony-stimulating factor (GM-CSF) regulates the function of antigen-presenting cells (APCs) and has been broadly used as the adjuvant. Here, we tested whether intranasal delivery of GM-CSF can improve the contraception of mouse zona pellucida 3 (mZP3) DNA vaccine. Our results showed that co administration of GM-CSF and mZP3 DNA vaccine increased the levels of secretory IgA (sIgA) and IgG antibodies in vaginal washes and serum, respectively. Co administration enhanced Th2 responses through improving the maturation of dendritic cells. Importantly, GM-CSF significantly reduced the fertility rate and mean litter size induced by mZP3 DNA vaccine alone without interfering the normal follicular development. These data suggest that GM-CSF could be used as adjuvant to develop immunocontraceptive vaccine. PMID- 22924631 TI - Expectation-maximization algorithm for determining natural selection of Y-linked genes through two-sex branching processes. AB - A two-dimensional bisexual branching process has recently been presented for the analysis of the generation-to-generation evolution of the number of carriers of a Y-linked gene. In this model, preference of females for males with a specific genetic characteristic is assumed to be determined by an allele of the gene. It has been shown that the behavior of this kind of Y-linked gene is strongly related to the reproduction law of each genotype. In practice, the corresponding offspring distributions are usually unknown, and it is necessary to develop their estimation theory in order to determine the natural selection of the gene. Here we deal with the estimation problem for the offspring distribution of each genotype of a Y-linked gene when the only observable data are each generation's total numbers of males of each genotype and of females. We set out the problem in a non parametric framework and obtain the maximum likelihood estimators of the offspring distributions using an expectation-maximization algorithm. From these estimators, we also derive the estimators for the reproduction mean of each genotype and forecast the distribution of the future population sizes. Finally, we check the accuracy of the algorithm by means of a simulation study. PMID- 22924632 TI - Single-molecule force spectroscopic studies on intra- and intermolecular interactions of G-quadruplex aptamer with target Shp2 protein. AB - With widespread applications in biosensors, diagnostics, and therapeutics, much investigation has been made in the structure of the G-quadruplexes and mechanism of their interactions with protein targets. However, in view of AFM based single molecule force spectroscopic (SMFS) studies of G-quadruplex systems, only bimolecular approaches have been employed. In this article, we present an improved dual-labeling approach for surface immobilization of G-quadruplex DNA apatmers for investigation of intramolecular interaction from an integral unimolecular G-quadruplex system. The melting force of HJ24 G-quadruplex aptamer in the presence of K(+) has been successfully measured. It has been found that dynamic equilibrium exists between unfolding and folding structures of the HJ24 aptamer even in pure water. We also investigated the interactions between the HJ24 aptamer and its target protein (Shp2) under the same solution condition. The HJ24/Shp2 unbinding force in the absence of K(+), 42.0 pN, is about 50% smaller than that in the presence of K(+), 61.7 pN. The great reduction in force in the absence of K(+) suggests that the stability of G-quadruplex secondary structure is important for a stable HJ24/Shp2 binding. The methodology developed and demonstrated in this work is applicable for studying the stability of secondary structures of other unimolecular G-quadruplex aptamers and their interactions with target proteins. PMID- 22924633 TI - Amidourea-based hydrogen-bonded heteroduplexes: structure and assembling selectivity. AB - A new class of multiply hydrogen-bonded heteroduplexes from readily available amidourea derivatives was designed, and their structures and selective assembling behaviors were investigated. Amidourea derivative 3 could selectively assemble with 1 to form a stable heteroduplex via eight intermolecular bifurcated hydrogen bonds, but could not assemble with 2 at all, because of their unique structures and the spacing effect, although 1 and 2 possessed the same hydrogen-bonding sequence. The high stability and selectivity will make the amidourea-based hydrogen-bonded heteroduplexes be potentially applicable in the design of well defined supramolecular architectures and novel functional materials. PMID- 22924635 TI - Evidence for the presence of white spot syndrome virus (WSSV) and monodon baculovirus (MBV) in wild Penaeus monodon (Fabricius) broodstock, in the southeast coast of India. AB - A survey on the presence of the viruses of two economically significant diseases, white spot syndrome virus (WSSV) and monodon baculovirus (MBV) in wild-collected Penaeus monodon broodstock, was conducted during different seasons of the year in two major coastal areas of southeast India. The broodstock were collected along the coast of Tamil Nadu and Andhra Pradesh during summer, premonsoon, monsoon and post-monsoon seasons for three consecutive years. A total of 7905 samples were collected and subjected to MBV screening, and 6709 samples that were screened as MBV negative were diagnosed for WSSV. MBV was detected using rapid malachite green staining and WSSV by nested polymerase chain reaction. Prevalence data of the viruses were analysed using the EpiCalc 2000 program at 95% confidence interval. Samples collected from the Andhra Pradesh coast displayed a slightly higher prevalence of WSSV and MBV infection than those collected from Tamil Nadu, although this difference was not statistically significant (P > 005). In addition, it was found that the prevalence of both WSSV and MBV infections fluctuated according to season. Data on prevalence of these viruses in broodstock would be useful to develop strategies for shrimp health management along the southeast coast of India. PMID- 22924634 TI - Reperfusion-induced myocardial dysfunction is prevented by endogenous annexin-A1 and its N-terminal-derived peptide Ac-ANX-A1(2-26). AB - BACKGROUND AND PURPOSE: Annexin-A1 (ANX-A1) is an endogenous, glucocorticoid regulated anti-inflammatory protein. The N-terminal-derived peptide Ac-ANX-A1(2 26) preserves cardiomyocyte viability, but the impact of ANX-A1-peptides on cardiac contractility is unknown. We now test the hypothesis that ANX-A1 preserves post-ischaemic recovery of left ventricular (LV) function. EXPERIMENTAL APPROACH: Ac-ANX-A1(2-26) was administered on reperfusion, to adult rat cardiomyocytes as well as hearts isolated from rats, wild-type mice and mice deficient in endogenous ANX-A1 (ANX-A1(-/-)). Myocardial viability and recovery of LV function were determined. KEY RESULTS: Ischaemia-reperfusion markedly impaired both cardiomyocyte viability and recovery of LV function by 60%. Treatment with exogenous Ac-ANX-A1(2-26) at the onset of reperfusion prevented cardiomyocyte injury and significantly improved recovery of LV function, in both intact rat and wild-type mouse hearts. Ac-ANX-A1(2-26) cardioprotection was abolished by either formyl peptide receptor (FPR)-nonselective or FPR1-selective antagonists, Boc2 and cyclosporin H, but was relatively insensitive to the FPR2 selective antagonist QuinC7. ANX-A1-induced cardioprotection was associated with increased phosphorylation of the cell survival kinase Akt. ANX-A1(-/-) exaggerated impairment of post-ischaemic recovery of LV function, in addition to selective LV FPR1 down-regulation. CONCLUSIONS AND IMPLICATIONS: These data represent the first evidence that ANX-A1 affects myocardial function. Our findings suggest ANX-A1 is an endogenous regulator of post-ischaemic recovery of LV function. Furthermore, the ANX-A1-derived peptide Ac-ANX-A1(2-26) on reperfusion rescues LV function, probably via activation of FPR1. ANX-A1-based therapies may thus represent a novel clinical approach for the prevention and treatment of myocardial reperfusion injury. PMID- 22924636 TI - Safety and activity of a new intensive short-term chemoimmunotherapy in HIV positive patients with Burkitt lymphoma. PMID- 22924637 TI - Duration of breastfeeding and childhood obesity: a generalized propensity score approach. AB - OBJECTIVE: To estimate the effect of breastfeeding duration on childhood obesity. DATA SOURCE: The Child Development Supplement (CDS) of the Panel Study of Income Dynamics (PSID). The PSID provides extensive data on the income and well-being of a representative sample of U.S. families from 1968 to the present. The CDS collects information on the children in PSID families ranging from cognitive, behavioral, and health status to their family and neighborhood environment. The first two waves of the CDS were conducted in 1997 and 2002, respectively. The data provide information on 3,271 children and their mothers. STUDY DESIGN: We use the generalized propensity score to adjust for confounding based on continuous treatment, and the general additive model to analyze the adjusted association between treatment and the outcome conditional on the propensity score. The main outcome is the body mass index (BMI) directly assessed during the in-person interview in 2002. Covariates include family, maternal, and child characteristics, many of which were measured in the year the child was born. PRINCIPAL FINDINGS: After using propensity scores to adjust for confounding, the relationship between breastfeeding duration and childhood BMI is trivially small across a range of model specifications, and none of them is statistically significant except the unadjusted model. CONCLUSIONS: The causal link between duration of breastfeeding and childhood obesity has not been established. Any recommendation of promoting breastfeeding to reduce childhood obesity is premature. PMID- 22924639 TI - Modeling the self-assembly of peptide amphiphiles into fibers using coarse grained molecular dynamics. AB - We have studied the self-assembly of peptide amphiphiles (PAs) into a cylindrical micelle fiber starting from a homogeneous mixture of PAs in water using coarse grained molecular dynamics simulations. Nine independent 16 MUs runs all show spontaneous fiber formation in which the PA molecules first form spherical micelles, and then micelles form a three-dimensional network via van der Waals interactions. As the hydrophobic core belonging to the different micelles merge, the three-dimensional network disappears and a fiber having a diameter of ~80 A appears. In agreement with atomistic simulation results, water molecules are excluded from the hydrophobic core and penetrate to ~15 A away from the axis of fiber. About 66% of the surface of fiber is covered with the IKVAV epitope, and ~92% of the epitope is exposed to water molecules. PMID- 22924640 TI - Simplified procedure for encapsulating cytochrome c in silica aerogel nanoarchitectures while retaining gas-phase bioactivity. AB - Cytochrome c (cyt. c) has been encapsulated in silica sol-gels and processed to form bioaerogels with gas-phase activity for nitric oxide through a simplified synthetic procedure. Previous reports demonstrated a need to adsorb cyt. c to metal nanoparticles prior to silica sol-gel encapsulation and processing to form aerogels. We report that cyt. c can be encapsulated in aerogels without added nanoparticles and retain structural stability and gas-phase activity for nitric oxide. While the UV-visible Soret absorbance and nitric oxide response indicate that cyt. c encapsulated with nanoparticles in aerogels remains slightly more stable and functional than cyt. c encapsulated alone, these properties are not very different in the two types of aerogels. From UV-visible and Soret circular dichroism results, we infer that cyt. c encapsulated alone self-organizes to reduce contact with the silica gel in a way that may bear at least some resemblance to the way cyt. c self-organizes into superstructures of protein within aerogels when nanoparticles are present. Both the buffer concentration and the cyt. c concentration of solutions used to synthesize the bioaerogels affect the structural integrity of the protein encapsulated alone within the dried aerogels. Optimized bioaerogels are formed when cyt. c is encapsulated from 40 mM phosphate buffered solutions, and when the loaded cyt. c concentration in the aerogel is in the range of 5 to 15 MUM. Increased viability of cyt. c in aerogels is also observed when supercritical fluid used to produce aerogels is vented over relatively long times. PMID- 22924638 TI - Fractional flow reserve-guided PCI versus medical therapy in stable coronary disease. AB - BACKGROUND: The preferred initial treatment for patients with stable coronary artery disease is the best available medical therapy. We hypothesized that in patients with functionally significant stenoses, as determined by measurement of fractional flow reserve (FFR), percutaneous coronary intervention (PCI) plus the best available medical therapy would be superior to the best available medical therapy alone. METHODS: In patients with stable coronary artery disease for whom PCI was being considered, we assessed all stenoses by measuring FFR. Patients in whom at least one stenosis was functionally significant (FFR, <=0.80) were randomly assigned to FFR-guided PCI plus the best available medical therapy (PCI group) or the best available medical therapy alone (medical-therapy group). Patients in whom all stenoses had an FFR of more than 0.80 were entered into a registry and received the best available medical therapy. The primary end point was a composite of death, myocardial infarction, or urgent revascularization. RESULTS: Recruitment was halted prematurely after enrollment of 1220 patients (888 who underwent randomization and 332 enrolled in the registry) because of a significant between-group difference in the percentage of patients who had a primary end-point event: 4.3% in the PCI group and 12.7% in the medical-therapy group (hazard ratio with PCI, 0.32; 95% confidence interval [CI], 0.19 to 0.53; P<0.001). The difference was driven by a lower rate of urgent revascularization in the PCI group than in the medical-therapy group (1.6% vs. 11.1%; hazard ratio, 0.13; 95% CI, 0.06 to 0.30; P<0.001); in particular, in the PCI group, fewer urgent revascularizations were triggered by a myocardial infarction or evidence of ischemia on electrocardiography (hazard ratio, 0.13; 95% CI, 0.04 to 0.43; P<0.001). Among patients in the registry, 3.0% had a primary end-point event. CONCLUSIONS: In patients with stable coronary artery disease and functionally significant stenoses, FFR-guided PCI plus the best available medical therapy, as compared with the best available medical therapy alone, decreased the need for urgent revascularization. In patients without ischemia, the outcome appeared to be favorable with the best available medical therapy alone. (Funded by St. Jude Medical; ClinicalTrials.gov number, NCT01132495.). PMID- 22924641 TI - Pharmacological mechanisms involved in the antinociceptive effects of dexmedetomidine in mice. AB - Dexmedetomidine (DEX) is a alpha2 -adrenoceptor (alpha2 -AR) agonist used as an anesthetic adjuvant and as sedative in critical care settings. Typically, alpha2 AR agonists release nitric oxide (NO) and subsequently activate NO-GMPc pathway and have been implicated with antinociception. In this study, we investigate the pharmacological mechanisms involved in the antinociceptive effects of DEX, using an acetic acid-induced writhing assay in mice. Saline or DEX (1, 2, 5, or 10 MUg/kg) was intravenously injected 5 min before ip administration of acetic acid and the resulting abdominal constrictions were then counted for 10 min. To investigate the possible mechanisms related to antinociceptive effect of DEX (10 MUg/kg), the animals were also pretreated with one of the following drugs: 7 nitroindazole (7-NI; 30 mg/kg ip); 1H-[1,2,4] oxadiazole [4,3-a] quinoxaline-1 one (ODQ; 2.5 mg/kg, ip); yohimbine (YOH; 1 mg/kg, ip); atropine (ATRO; 2 mg/kg, ip); glibenclamide (GLIB; 1 mg/kg, i.p.) and naloxone (NAL; 0.2 mg/kg, ip). A rotarod and open-field performance test were performed with DEX at 10 MUg/kg dose. DEX demonstrated its potent antinociceptive effect in a dose-dependent manner. The pretreatment with 7-NI, ODQ, GLIB, ATRO, and YOH significantly reduced the antinociceptive affects of DEX. However, NAL showed no effecting DEX induced antinociception. The rotarod and open-field tests confirmed there is no detectable sedation or even significant motor impairment with DEX at 10 MUg/kg dose. Our results suggest that the alpha2 -AR and NO-GMPc pathways play important roles in the systemic antinociceptive effect of DEX in a murine model of inflammatory pain. Furthermore, the antinociceptive effect exerted by DEX appears to be dependent on KATP channels, independent of opioid receptor activity. PMID- 22924642 TI - Human embryonic stem cell-derived mesodermal progenitors display substantially increased tissue formation compared to human mesenchymal stem cells under dynamic culture conditions in a packed bed/column bioreactor. AB - Bone tissue engineering represents a promising strategy to obviate bone deficiencies, allowing the ex vivo construction of bone substitutes with unprecedented potential in the clinical practice. Considering that in the human body cells are constantly stimulated by chemical and mechanical stimuli, the use of bioreactor is emerging as an essential factor for providing the proper environment for the reproducible and large-scale production of the engineered substitutes. Human mesenchymal stem cells (hMSCs) are experimentally relevant cells but, regardless the encouraging results reported after culture under dynamic conditions in bioreactors, show important limitations for tissue engineering applications, especially considering their limited proliferative potential, loss of functionality following protracted expansion, and decline in cellular fitness associated with aging. On the other hand, we previously demonstrated that human embryonic stem cell-derived mesodermal progenitors (hES MPs) hold great potential to provide a homogenous and unlimited source of cells for bone engineering applications. Based on prior scientific evidence using different types of stem cells, in the present study we hypothesized that dynamic culture of hES-MPs in a packed bed/column bioreactor had the potential to affect proliferation, expression of genes involved in osteogenic differentiation, and matrix mineralization, therefore resulting in increased bone-like tissue formation. The reported findings suggest that hES-MPs constitute a suitable alternative cell source to hMSCs and hold great potential for the construction of bone substitutes for tissue engineering applications in clinical settings. PMID- 22924644 TI - A sol-gel process for fabrication of NiO/NiCo2O4/Co3O4 composite with improved electrochemical behavior for electrochemical capacitors. AB - Transition metal oxides possess multiple oxidation states that enable rich redox reactions for pseudo capacitanc. They have been investigated as promising electrode materials to achieve high energy density. In this study, NiO/NiCo(2)O(4)/Co(3)O(4) composite with high specific surface and mesoporous structure is fabricated by a sol-gel process then calcined at 250 degrees C. Benefits from the improved electron conductivity and effective mesoporous structure, the fabricated composite exhibits high specific capacitance (1717 F g( 1)), enhanced rate capability, and excellent electrochemical stability (94.9% retention after 1000 cycles). Interestingly, the specific capacitance of the composite is higher than that of NiO, NiCo(2)O(4), and Co(3)O(4), which indicates a synergistic effect of the composite on improvement of electrochemical performance. The findings demonstrate the importance and great potential of NiO/NiCo(2)O(4)/Co(3)O(4) composite in development of high-performance energy storage systems. PMID- 22924643 TI - Reduced basal transcriptional activity of central nervous system-derived HIV type 1 long terminal repeats. AB - New evidence indicates that astrocytes of the central nervous system (CNS) are extensively infected with human immunodeficiency virus type 1 (HIV-1) in vivo. Although no new virus is produced, this nonproductive or restricted infection contributes to the pathogenesis of HIV-associated dementia (HAD) and compromises virus eradication strategies. The HIV-1 long terminal repeat (LTR) plays a critical role in regulating virus production from infected cells. Here, we determined whether LTRs derived from CNS and non-CNS compartments are genetically and functionally distinct and contribute to the restricted nature of astrocyte infection. CNS- and/or non-CNS-derived LTRs (n=82) were cloned from primary HIV-1 viruses isolated from autopsy tissues of seven patients who died with HAD. Phylogenetic analysis showed interpatient and intrapatient clustering of LTR nucleotide sequences. Functional analysis showed reduced basal transcriptional activity of CNS-derived LTRs in both astrocytes and T cells compared to that of non-CNS-derived LTRs. However, LTRs were heterogeneous in their responsiveness to activation by Tat. Therefore, using a relatively large, independent panel of primary HIV-1 LTRs derived from clinically well-characterized subjects, we show that LTRs segregate CNS- from non-CNS-derived tissues both genetically and functionally. The reduced basal transcriptional activity of LTRs derived from the CNS may contribute to the restricted HIV-1 infection of astrocytes and latent infection within the CNS. These findings have significance for understanding the molecular basis of HIV-1 persistence within cellular reservoirs of the CNS that need to be considered for strategies aimed at eradicating HIV-1. PMID- 22924645 TI - Threshold detection of boar taint chemicals using parasitic wasps. AB - Surgical castration has been long used to prevent consumers from experiencing taint in meat from male pigs, which is a large problem in the pig husbandry industry. Due to obvious animal welfare issues, the EU now wants an alternative for castration, suggesting an urgent need for novel methods of boar taint detection. As boar taint is only a problem when taint chemicals exceed a well defined threshold, detection methods should be concentration-specific. The wasp, Microplitis croceipes' ability to learn and respond to particular concentrations of the boar taint compounds, skatole, androstenone, and indole was tested. Also tested was the wasps' ability to discriminate between known concentrations of indole, skatole, and androstenone in real boar fat samples at room temperature. Wasps were trained using associative learning by providing food-deprived wasps with sucrose-water in the presence of specific odor concentrations. Trained wasps' responses were tested to a range of concentrations of 3 compounds. Wasps showed unidirectional generalization of learned concentration responses, whereby the direction of concentration generalization was shown to be chemical-dependent. Through both positive (sucrose) and negative feeding experiences (water only) with varying compound concentrations, the wasps can also be conditioned to respond to concentrations exceeding a defined threshold, and they were successful in reporting low, medium, and high concentrations of indole, skatole, and androstenone in boar fat at room temperature. The need for threshold detection rather than simple detection of absence/presence applies to many food quality issues, including the detection of spoilage or pest damage in crops or stored foods. PRACTICAL APPLICATION: An inexpensive and reliable means of detecting boar tainted pork at slaughter to avoid tainted meat on the market and dissatisfied consumers. PMID- 22924646 TI - Gold nanoparticle-enabled real-time ligation chain reaction for ultrasensitive detection of DNA. AB - A simple and ultrasensitive colorimetric DNA assay based on the detection of the product of a ligation chain reaction (LCR) and the use of gold nanoparticles (AuNPs) as signal generators has been developed. During LCR, the AuNPs were ligated together, resulting in a distinct color change in real time after a sufficient number of thermal cycles. The cumulative nature of the protocol produced a detection limit of 20 aM with a selectivity factor of 10(3). PMID- 22924647 TI - Bimetallic ruthenium PNP pincer complex as a platform to model proposed intermediates in dinitrogen reduction to ammonia. AB - A series of ruthenium complexes was isolated and characterized in the course of reactions aimed at studying the reduction of hydrazine to ammonia in bimetallic systems. The diruthenium complex {[HPNPRu(N(2))](2)(MU-Cl)(2)}(BF(4))(2) (2) (HPNP = HN(CH(2)CH(2)P(i)Pr(2))(2)) reacted with 1 equiv of hydrazine to generate [(HPNPRu)(2)(MU(2)-H(2)NNH(2))(MU-Cl)(2)](BF(4))(2) (3) and with an excess of the reagent to form [HPNPRu(NH(3))(kappa(2)-N(2)H(4))](BF(4))Cl (5). When phenylhydrazine was added to 2, the diazene species [(HPNPRu)(2)(MU(2)-HNNPh)(MU Cl)(2)](BF(4))(2) (4) was obtained. Treatment of 2 with H(2) or CO yielded {[HPNPRu(H(2))](2)(MU-Cl)(2)}(BF(4))(2) (7) and [HPNPRuCl(CO)(2)]BF(4) (8), respectively. Abstraction of chloride using AgOSO(2)CF(3) or AgBPh(4) afforded the species [(HPNPRu)(2)(MU(2)-OSO(2)CF(3))(MU-Cl)(2)]OSO(2)CF(3) (9) and [(HPNPRu)(2)(MU-Cl)(3)]BPh(4) (10), respectively. Complex 3 reacted with HCl/H(2)O or HCl/Et(2)O to produce ammonia stoichiometrically; the complex catalytically disproportionates hydrazine to generate ammonia. PMID- 22924648 TI - Lipidome analysis in multiple sclerosis reveals protein lipoxidative damage as a potential pathogenic mechanism. AB - Metabolomic and lipidomic analyses have been used for the profiling of neurodegenerative processes, both in targeted and untargeted approaches. In this work we have applied these techniques to the study of CSF samples of multiple sclerosis (MS) patients (n = 9), compared with samples of non-MS individuals (n = 9) using mass-spectrometry. We have used western-blot and analyzed cell culture to confirm pathogenic pathways suggested by mass-spectrometric measurements. The results of the untargeted approach of metabolomics and lipidomics suggest the existence of several metabolites and lipids discriminating both populations. Applying targeted lipidomic analyses focused to a pathogenic pathway in MS, oxidative stress, reveal that the lipid peroxidation marker 8-iso-prostaglandin F2alpha is increased in CSF from MS patients. Furthermore, as lipid peroxidation exerts its pathogenical effects through protein modification, we studied the incidence of protein lipoxidation, revealing specific increases in carboxymethylated, neuroketal and malondialdehyde-mediated protein modifications in proteins of CSF from MS patients, despite the absence of their precursors glyoxal and methylglyoxal. Finally, we report that the level of neuroketal modified proteins correlated with a hitherto unknown increased amount of autoantibodies against lipid peroxidation-modified proteins in CSF, without compensation by signaling induced by lipid peroxidation via peroxisome proliferator-activated receptor gamma (PPARgamma). The results, despite the limitation of being obtained in a small population, strongly suggest that autoimmunity against in situ produced epitopes derived from lipid peroxidation can be a relevant pathogenic factor in MS. PMID- 22924649 TI - Microbial transformation of Norkurarinone by Cunninghamella blakesleana AS 3.970. AB - In this paper, microbial transformation of norkurarinone (1) by Cunninghamella blakesleana AS 3.970 was investigated and seven transformed products were isolated and characterized as kurarinone (2), 4",5"-dihydroxykurarinone (3), 6" hydroxyl-2'-methoxyl-norkurarinone 7-O-beta-d-glucoside (4), 6"-hydroxyl norkurarinone 4'-O-beta-d-glucoside (5), 4",5"-dihydroxynorkurarinone (6), 7 methoxyl-norkurarinone (7), and 7-methoxyl-4",5"-dihydroxynorkurarinone (8), respectively. Among them, 3-5 are new compounds, and the glycosylation reaction in microbial transformation process was reported rarely. In addition, the cytotoxicities of transformed products (1-8) were also investigated. PMID- 22924650 TI - An inverse electron demand Diels-Alder-based total synthesis of defucogilvocarcin V and some C-8 analogues. AB - A concise total synthesis of defucogilvocarcin V is reported. The key features of the approach are the formation of the C-ring using a vinylogous Knoevenagel/transesterification reaction and construction of the D-ring by way of an inverse electron demand Diels-Alder-driven domino reaction. The resulting C-8 ester functionality provides a handle for the synthesis of defucogilvocarcin V as well as some C-8 analogues from a common late-stage intermediate. PMID- 22924651 TI - Photoisomerization of trans-2-[4'-(dimethylamino)styryl]benzothiazole. AB - Photoreaction of trans-2-[4'-(dimethylamino)styryl]benzothiazole (t-DMASBT) under direct irradiation has been investigated in dioxane, chloroform, methanol and glycerol to understand the mechanism of photoisomerization. Contrary to an earlier report, isomerization takes place in all these solvents including glycerol. The results show that restriction on photoisomerization leads to the increase in fluorescence quantum yield in glycerol. The results are consistent with the theoretically simulated potential energy surface reported earlier using time-dependent density functional theory (TDDFT) calculations. DFT calculations on cis isomers under isolated condition have suggested that cis-B conformer is more stable than cis-A conformer due to hydrogen-bonding interaction. In the ground state, cis-DMASBT is predominantly present as cis-B. The fluorescence spectra of the irradiated t-DMASBT suggested that photoisomerization follows not the adiabatic path as proposed by Saha et al., but the nonadiabatic path. PMID- 22924652 TI - Antioxidant effects of selenium on lung injury in paraquat intoxicated rats. AB - CONTEXT: Paraquat (PQ) causes lethal intoxication by inducing oxidant injury to the lung. Selenium is a cofactor for glutathione peroxidase (GPx), which is one of the major endogenous antioxidant enzymes. OBJECTIVE: To determine whether selenium post-treatment activates GPx, decreases lung injury, and improves survival in PQ intoxicated rats. MATERIALS AND METHODS: Male Spraque-Dawley rats were categorized into three groups: sham (n = 6), PQ (n = 12), and PQ + Se (n = 12). In the PQ and PQ + Se groups, 50 mg/kg of PQ was administered intraperitoneally. After 10 minutes, 60 MUg/kg of Se (PQ + Se) or saline (PQ) was administered via the tail vein. Six rats per group were euthanized 6 hours or 24 hours later. Lung tissues were harvested for the measurement of GPx activity, reduced glutathione (GSH), glutathione disulfide (GSSG) and malondialdehyde (MDA) and for histological analysis. Using separated set of rats, survival of PQ (n = 10) and PQ + Se (n = 10) were observed for 72 hours. RESULTS: GPx activity in the PQ group at the 6-hour and 24-hour time points was lower than in the sham group (p < 0.006). GPx activity in the PQ + Se group at the 6-hour and 24-hour time points was higher than in the PQ group at the same time (p < 0.006). GPx activity in the PQ + Se group at 24 hours was higher than at 6-hour time point and also higher than in the sham group (p < 0.006). The GSH/GSSG ratio in the PQ + Se group at 24 hours was lower than that in the sham group (p < 0.006). MDA levels in the PQ group at 6 hours and 24 hours were higher than in the sham group (p < 0.006). MDA levels at 24 hours in the PQ + Se group was lower than in the PQ group (p < 0.006). Acute lung injury (ALI) scores in the PQ group at 6 hours and 24 hours were higher than in the sham group (p < 0.006). ALI scores at 24 hours in the PQ + Se group were lower than in the PQ group. Survival rates did not differ between PQ and PQ + Se (p = 0.869). CONCLUSION: Single dose of selenium post-treatment activates GPx and attenuates lipid peroxidation and lung injury early after paraquat intoxication, but does not improve 72 hours of survival. PMID- 22924653 TI - Effect of pirfenidone on pulmonary fibrosis due to paraquat poisoning in rats. AB - BACKGROUND: This study investigated the effectiveness of pirfenidone compared with antioxidants, in the prevention of pulmonary fibrosis and increasing the survival in acutely paraquat poisoned rats. METHODS: Five groups of ten rats were included in this study. Three groups were poisoned with intraperitoneal injection of 15 mg/kg paraquat. Among these poisoned groups, one group was treated with vitamin C (500 mg/kg, intraperitoneal), vitamin E (200 mg/kg, intraperitoneal) and N-acetylcysteine (250 mg/kg, intravenous); two others were treated with either normal saline or pirfenidone (200 mg/kg, intravenous); two groups were not poisoned and received normal saline or pirfenidone (200 mg/kg, intravenous). All injections except paraquat were repeated in four consecutive days. On the 15th day of study a semi-quantitative determination of lung fibrosis was done using Ashcroft staging criteria on the lung sections. RESULTS: Pirfenidone decreased paraquat induced lung fibrosis (p < 0.001) while antioxidants did not decrease the lung fibrosis (p = 0.413). Life expectancy decreased in paraquat + normal saline (11 days, 95% CI 7.94-14.05) and paraquat + antioxidant (11 days, 95% CI 7.77-14.23) groups. The increase in the survival of rats in paraquat/pirfenidone group was insignificant (13.4 days, 95% CI 11.13-15.67). CONCLUSION: This study showed that pirfenidone is able to decrease pulmonary fibrosis following paraquat poisoning in a rat model. PMID- 22924656 TI - Gentamicin in combination with ascorbic acid regulates the severity of Staphylococcus aureus infection-induced septic arthritis in mice. AB - To study the effects of gentamicin in combination with ascorbic acid on septic arthritis, mice were infected with Staphylococcus aureus (S. aureus) and treated with gentamicin, which was given at 5 mg/kg after 24 h of infection, followed by ascorbic acid, given at 20 mg/kg body weight after 2 h of gentamicin treatment. Mice were sacrificed at 3, 9, 15 days post-infection (dpi). Combined treatment of infected mice with gentamicin and ascorbic acid eradicated the bacteria from the blood, spleen and synovial tissue and showed a significant gross reduction in arthritis, reduced serum levels of tumour necrosis factor alpha (TNF-alpha) and interferon gamma (IFN-gamma). S. aureus-infected mice have demonstrated the disturbed antioxidant status measured in terms of cellular antioxidants like reduced glutathione and antioxidant enzymes such as superoxide dismutase (SOD) and catalase. The same were ameliorated when the animals were co-treated with gentamicin along with ascorbic acid. PMID- 22924655 TI - Isolated dorsal root ganglion neurones inhibit receptor-dependent adenylyl cyclase activity in associated glial cells. AB - BACKGROUND AND PURPOSE: Hyper-nociceptive PGE(2) EP(4) receptors and prostacyclin (IP) receptors are present in adult rat dorsal root ganglion (DRG) neurones and glial cells in culture. The present study has investigated the cell specific expression of two other G(s) -protein coupled hyper-nociceptive receptor systems: beta-adrenoceptors and calcitonin gene-related peptide (CGRP) receptors in isolated DRG cells and has examined the influence of neurone-glial cell interactions in regulating adenylyl cyclase (AC) activity. EXPERIMENTAL APPROACH: Agonist-stimulated AC activity was determined in mixed DRG cell cultures from adult rats and compared with activity in DRG neurone-enriched cell cultures and pure DRG glial cell cultures. KEY RESULTS: Pharmacological analysis showed the presence of G(s) -coupled beta(2) -adrenoceptors and CGRP receptors, but not beta(1) -adrenoceptors, in all three DRG cell preparations. Agonist-stimulated AC activity was weakest in DRG neurone-enriched cell cultures. DRG neurones inhibited IP receptor-stimulated glial cell AC activity by a process dependent on both cell-cell contact and neurone-derived soluble factors, but this is unlikely to involve purine or glutamine receptor activation. CONCLUSIONS AND IMPLICATIONS: G(s) -coupled hyper-nociceptive receptors are readily expressed on DRG glial cells in isolated cell cultures and the activity of CGRP, EP(4) and IP receptors, but not beta(2) -adrenoceptors, in glial cells is inhibited by DRG neurones. Studies using isolated DRG cells should be aware that hyper-nociceptive ligands may stimulate receptors on glial cells in addition to neurones, and that variable numbers of neurones and glial cells will influence absolute measures of AC activity and affect downstream functional responses. PMID- 22924657 TI - Construction, expression and characterization of 11 putative flagellar apparatus genes of Aeromonas hydrophila AL09-73. PMID- 22924658 TI - Stereotype threat among older employees: relationship with job attitudes and turnover intentions. AB - Stereotype threat, or the belief that one may be the target of demeaning stereotypes, leads to acute performance decrements and reduced psychological well being. The current research examined stereotype threat among older employees, a group that is the target of many negative stereotypes. Study 1 surveyed older workers in two different organizations regarding their experiences of stereotype threat, their job attitudes and work mental health, and their intentions to resign or retire. Across both samples, feelings of stereotype threat were related to more negative job attitudes and poorer work mental health. In turn, these negative job attitudes were associated with intentions to resign and (possibly) retire. In Study 2, younger and older employees were surveyed. The results indicated that only for older employees were feelings of stereotype threat negatively related to job attitudes, work mental health, and intentions to resign. The implications of these findings for understanding job attitudes and intentions among older workers are discussed. (PsycINFO Database Record (c) 2013 APA, all rights reserved). PMID- 22924659 TI - Naturalistic measures of prospective memory in amnestic mild cognitive impairment. AB - Several studies have now reported that individuals with amnestic mild cognitive impairment (aMCI) are impaired on laboratory-based measures of prospective memory (PM). However, the age-PM paradox has revealed that impairment observed in the laboratory does not necessarily reflect functioning in day-to-day life. The current study examined naturalistic measures of PM by comparing participants with aMCI to healthy older adults on experimenter-introduced PM tasks (Experiment 1) and on participants' own, self-generated PM tasks (Experiment 2). Individuals with aMCI were found to be globally impaired on each of the naturalistic measures of PM Strategy use was found to be a distinguishing feature between the two groups with healthy older adults using more written strategies, whereas individuals with aMCI relied more on another person providing a reminder. Also of note was that both groups only used strategies around half the time for their own PM tasks. Findings are discussed in terms of implications for interventions and the day-to-day functioning of individuals with aMCI, a population that is struggling to maintain independence in the community. PMID- 22924660 TI - The role of routine surveillance for silent central nervous system relapse in children with acute lymphoblastic leukaemia. PMID- 22924661 TI - A method for estimating cost savings for population health management programs. AB - OBJECTIVE: To develop a quasi-experimental method for estimating Population Health Management (PHM) program savings that mitigates common sources of confounding, supports regular updates for continued program monitoring, and estimates model precision. DATA SOURCES: Administrative, program, and claims records from January 2005 through June 2009. DATA COLLECTION/EXTRACTION METHODS: Data are aggregated by member and month. STUDY DESIGN: Study participants include chronically ill adult commercial health plan members. The intervention group consists of members currently enrolled in PHM, stratified by intensity level. Comparison groups include (1) members never enrolled, and (2) PHM participants not currently enrolled. Mixed model smoothing is employed to regress monthly medical costs on time (in months), a history of PHM enrollment, and monthly program enrollment by intensity level. Comparison group trends are used to estimate expected costs for intervention members. Savings are realized when PHM participants' costs are lower than expected. PRINCIPAL FINDINGS: This method mitigates many of the limitations faced using traditional pre-post models for estimating PHM savings in an observational setting, supports replication for ongoing monitoring, and performs basic statistical inference. CONCLUSION: This method provides payers with a confident basis for making investment decisions. PMID- 22924662 TI - Appropriate maternal weight gain in singleton and twin pregnancies: what is the evidence? AB - A review of the literature on maternal weight gain in singleton and twin pregnancies has identified two main messages. Firstly, that very little robust evidence exists on which to base advice to mothers about appropriate weight gain during pregnancy. Evidence that does exist has tended to be observational, or based on under-powered intervention studies and unable to provide definitive conclusions. Secondly, that although specific weight gains have been recommended by the Institute of Medicine (IOM) in the USA, many women who gained weight outside these guidelines apparently achieved successful pregnancy and birth outcomes, in part because there were numerous confounders. Crucially, resources need to be invested to address women's concerns with weight management, so that they can receive the necessary support from midwives and others who care for them. Currently, women tend to receive little advice on weight gain during pregnancy and it is vital they are made aware of the increased risks associated with obesity, and that opportunities to minimise complications should be available and accessible prior to and during pregnancy. Overall, these findings highlight the difficulties in drawing up recommendations for individual women, whether expecting twins or singletons, on the basis of studies of populations, and the distinct difference between the USA and the UK in how weight gain is rationalised. PMID- 22924663 TI - Local thermomechanical analysis of a microphase-separated thin lamellar PS-b-PEO film. AB - We use atomic force microscopy (AFM) and hot tip AFM (HT-AFM) to thermophysically characterize a 30 nm thick film of poly(styrene-block-ethylene oxide), PS-b-PEO, and to modify its lamellar patterns having spacing of 39 +/- 3 nm. AFM tip scans of the polymer film induce either abrasive surface patterns or nanoscale ripples, which depend upon the tip force, temperature, and number of scans. The evolution of the lamellar patterns is explained by the polymer film molecular structure and mode I crack propagation in the polymer combined with the stick-and-slip behavior of the AFM tip. The HT-AFM measurements at various tip-sample temperatures and scanning speeds yield several thermophysical quantities: the PEO melting temperature of 54 +/- 12 degrees C, the PS glass transition temperature of 54 +/ 12 degrees C, the PS-b-PEO specific heat of 3.6 +/- 2.7 J g(-1) K(-1), the PEO melting enthalpy of 111 +/- 88 J g(-1), and the free energy of Helmholtz for PEO unfolding (and melting) of 10(-20) J nm(-2). These quantities are obtained for PS b-PEO volumes of 30,000 nm(3), which correspond to 30 ag of the polymer. PMID- 22924664 TI - A discrimination task used as a novel method of testing decision-making behavior following traumatic brain injury. AB - Traumatic brain injury (TBI) results in a multitude of deficits following injury. Some of the most pervasive in humans are the changes that affect frontally mediated cognitive functioning, such as decision making. The assessment of decision-making behavior in rodents has been extensively tested in the field of the experimental analysis of behavior. However, due to the narrow therapeutic window following TBI, time-intensive operant paradigms are rarely incorporated into the battery of tests traditionally used, the majority of which assess motor and sensory functioning. The cognitive measures that are used are frequently limited to memory and do not account for changes in decision-making behavior. The purpose of the present study was to develop a simplified discrimination task that can assess deficits in decision-making behavior in rodents. For the task, rats were required to dig in cocoa-scented sand (versus unscented sand) for a reinforcer. Rats were given 12 sessions per day until a criterion level of 80% accuracy for 3 days straight was reached. Once the criterion was achieved, cortical contusion injuries were induced (frontal, parietal, or sham). Following a recovery period, the rats were re-tested on cocoa versus unscented sand. Upon reaching criterion, a reversal discrimination was evaluated in which the reinforcer was placed in unscented sand. Finally, a novel scent discrimination (basil versus coffee with basil reinforced), and a reversal (coffee) were evaluated. The results indicated that the Dig task is a simple experimental preparation that can be used to assess deficits in decision-making behavior following TBI. PMID- 22924665 TI - Comparing the predictive value of multiple cognitive, affective, and motor tasks after rodent traumatic brain injury. AB - Controlled cortical impact injury (CCI) is a widely-used, clinically-relevant model of traumatic brain injury (TBI). Although functional outcomes have been used for years in this model, little work has been done to compare the predictive value of various cognitive and sensorimotor assessment tests, singly or in combination. Such information would be particularly useful for assessing mechanisms of injury or therapeutic interventions. Following isoflurane anesthesia, C57BL/6 mice were subjected to sham, mild (5.0 m/sec), moderate (6.0 m/sec), or severe (7.5 m/sec) CCI. A battery of behavioral tests were evaluated and compared, including the standard Morris water maze (sMWM), reversal Morris water maze (rMWM), novel object recognition (NOR), passive avoidance (PA), tail suspension (TS), beam walk (BW), and open-field locomotor activity. The BW task, performed at post-injury days (PID) 0, 1, 3, 7, 14, 21, and 28, showed good discrimination as a function of injury severity. The sMWM and rMWM tests (PID 14 23), as well as NOR (PID 24 and 25), effectively discriminated spatial and novel object learning and memory across injury severity levels. Notably, the rMWM showed the greatest separation between mild and moderate/severe injury. PA (PID 27 and 28) and TS (PID 24) also reflected differences across injury levels, but to a lesser degree. We also compared individual functional measures with histological outcomes such as lesion volume and neuronal cell loss across anatomical regions. In addition, we created a novel composite behavioral score index from individual complementary behavioral scores, and it provided superior discrimination across injury severities compared to individual tests. In summary, this study demonstrates the feasibility of using a larger number of complementary functional outcome behavioral tests than those traditionally employed to follow post-traumatic recovery after TBI, and suggests that the composite score may be a helpful tool for screening new neuroprotective agents or for addressing injury mechanisms. PMID- 22924666 TI - Contribution of endothelial cells to human bone-derived cells expansion in coculture. AB - Creating a functional vascularized bone tissue remains one of the main goals of bone tissue engineering. Recently, a growing interest in the crosstalk between endothelial cells (EC) and osteoblasts (OB), the two main players in a new bone formation, has been observed. However, only a few reports have addressed a mutual influence of OB and EC on cell proliferation. Our study focuses on this issue by investigating cocultures of human bone-derived cells (HBDC) and human umbilical vein endothelial cells (HUVEC). Three various proportions of cells have been used that is, HBDC:HUVEC 1:1, 1:4, and 4:1 and the cocultures were investigated on day 1, 4, and 7, while HUVEC and HBDC monocultures served as reference. We have detected enhanced alkaline phosphatase (ALP) activity in a direct HBDC-HUVEC coculture. This effect was not observed when cells were separated by an insert, which is consistent with other reports on various OB-EC lineages. The appearance of gap-junctions in coculture was confirmed by a positive staining for connexin 43. The number of cells of both phenotypes has been determined by flow cytometry: CD-31-positive cells have been considered EC, while CD-31-negative have been counted as OB. We have observed an over 14-fold increase in OB number after a week in the 1:4 HBDC:HUVEC coculture as compared with less than fourfold in monoculture. The increase in HBDC number in 1:1 coculture has been less pronounced and has reached the value of about sevenfold. These results correspond well with the cell proliferation rate, which has been measured by 5-bromo-2' deoxyuridine incorporation. Moreover, at day 7 EC have been still present in the coculture, which is inconsistent with some other reports. Real-time polymerase chain reaction analysis has revealed the upregulation of ALP and collagen type I genes, but not osteocalcin gene, in all the cocultures grown without pro osteogenic additives. Our study indicates that HUVEC significantly promote HBDC expansion and upregulate collagen I gene expression in these cells. We believe that these findings have application potency in bone tissue engineering. PMID- 22924667 TI - An unusually coloured lesion on the thigh. PMID- 22924669 TI - Fabrication of macroporous polymeric membranes through binary convective deposition. AB - Binary convective deposition of silica/polystyrene under a number of different operating conditions is used to form nanoporous polymeric membranes with uniform and repeatable pore size throughout and across the membrane. One micrometer silica microspheres and 100 nm PS nanoparticles are codeposited from suspension under conditions where respective constituent fluxes are matched. Membrane thickness is controlled through single and consecutive monolayer and multilayer depositions. Consecutive monolayer depositions result in thin films with highest order and packing. Polymeric membranes were successfully fabricated from a continuous thin film by etching the SiO(2) microspheres with HF or KOH. Etching proceeds radially inward from the polymer-oxide interface suggesting that etchant/thin film interfacial energies help create the initial etching profile and drastically increase the overall etching rate. These membranes, of tunable pore size and functionality, will be ideal for targeted bioseparations specifically in the partition of pathogen particles out of blood suspensions. PMID- 22924668 TI - Stereoselective synthesis of acortatarins A and B. AB - Acortatarins A and B have been synthesized via stereoselective spirocyclizations of glycals. Mercury-mediated spirocyclization of a pyrrole monoalcohol side chain leads to acortatarin A. Glycal epoxidation and reductive spirocyclization of a pyrrole dialdehyde side chain leads to acortatarin B. Acid equilibration and crystallographic analysis indicate that acortatarin B is a contrathermodynamic spiroketal with distinct ring conformations compared to acortatarin A. PMID- 22924670 TI - Stereoselective arylation of substituted cyclopentenes by substrate-directable Heck-Matsuda reactions: a concise total synthesis of the sphingosine 1-phosphate receptor (S1P(1)) agonist VPC01091. AB - We describe herein an efficient and diastereoselective substrate-directable Heck Matsuda reaction with nonactivated five-membered olefins. The carbamate acts as the main directing group in the arylation process allowing the synthesis of several functionalized aryl cyclopentenes in good to excellent diastereoselectivities (>85:15) and in isolated yields ranging from 41 to 90%. No double bond isomerizations were observed in these Heck reactions, and the newly created benzylic centers were preserved in all cases examined. The substrate directable Heck arylation approach was successfully applied in a straightforward total synthesis of the sphingosine 1-phosphate receptor-subtype 1 (S1P(1)) agonist VPC01091 by a concise and practical route involving 5 steps in 40% overall yield. PMID- 22924671 TI - Early mitochondrial abnormalities in hippocampal neurons cultured from Fmr1 pre mutation mouse model. AB - Pre-mutation CGG repeat expansions (55-200 CGG repeats; pre-CGG) within the fragile-X mental retardation 1 (FMR1) gene cause fragile-X-associated tremor/ataxia syndrome in humans. Defects in neuronal morphology, early migration, and electrophysiological activity have been described despite appreciable expression of fragile-X mental retardation protein (FMRP) in a pre CGG knock-in (KI) mouse model. The triggers that initiate and promote pre-CGG neuronal dysfunction are not understood. The absence of FMRP in a Drosophila model of fragile-X syndrome was shown to increase axonal transport of mitochondria. In this study, we show that dissociated hippocampal neuronal culture from pre-CGG KI mice (average 170 CGG repeats) express 42.6% of the FMRP levels and 3.8-fold higher Fmr1 mRNA than that measured in wild-type neurons at 4 days in vitro. Pre-CGG hippocampal neurons show abnormalities in the number, mobility, and metabolic function of mitochondria at this early stage of differentiation. Pre-CGG hippocampal neurites contained significantly fewer mitochondria and greatly reduced mitochondria mobility. In addition, pre-CGG neurons had higher rates of basal oxygen consumption and proton leak. We conclude that deficits in mitochondrial trafficking and metabolic function occur despite the presence of appreciable FMRP expression and may contribute to the early pathophysiology in pre-CGG carriers and to the risk of developing clinical fragile-X-associated tremor/ataxia syndrome. PMID- 22924674 TI - Two new triterpene saponins from Gynostemma pentaphyllum. AB - Two new dammarane-type triterpene saponins, gypenbiosides A (1) and B (2), were isolated from the aerial parts of Gynostemma pentaphyllum (Thunb.) Makino. Their structural elucidations were accomplished mainly on the basis of the interrelation of spectroscopic methods, such as IR, HR-TOF-MS, and NMR. The cytotoxic activity was evaluated against one human cancer cell line HL-60 using 3 (4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. PMID- 22924672 TI - Sweeping away protein aggregation with entropic bristles: intrinsically disordered protein fusions enhance soluble expression. AB - Intrinsically disordered, highly charged protein sequences act as entropic bristles (EBs), which, when translationally fused to partner proteins, serve as effective solubilizers by creating both a large favorable surface area for water interactions and large excluded volumes around the partner. By extending away from the partner and sweeping out large molecules, EBs can allow the target protein to fold free from interference. Using both naturally occurring and artificial polypeptides, we demonstrate the successful implementation of intrinsically disordered fusions as protein solubilizers. The artificial fusions discussed herein have a low level of sequence complexity and a high net charge but are diversified by means of distinctive amino acid compositions and lengths. Using 6xHis fusions as controls, soluble protein expression enhancements from 65% (EB60A) to 100% (EB250) were observed for a 20-protein portfolio. Additionally, these EBs were able to more effectively solubilize targets compared to frequently used fusions such as maltose-binding protein, glutathione S-transferase, thioredoxin, and N utilization substance A. Finally, although these EBs possess very distinct physiochemical properties, they did not perturb the structure, conformational stability, or function of the green fluorescent protein or the glutathione S-transferase protein. This work thus illustrates the successful de novo design of intrinsically disordered fusions and presents a promising technology and complementary resource for researchers attempting to solubilize recalcitrant proteins. PMID- 22924675 TI - Putting their best foot forward: emotional disclosure on Facebook. AB - Facebook has become a widely used online self-representation and communication platform. In this research, we focus on emotional disclosure on Facebook. We conducted two studies, and results from both self-report and observer rating show that individuals are more likely to express positive relative to negative emotions and present better emotional well-being on Facebook than in real life. Our study is the first to demonstrate impression management on Facebook through emotional disclosure. We discuss important theoretical and practical implications of our study. PMID- 22924673 TI - Concentration dependence of vitamin C in combinations with vitamin E and zeaxanthin on light-induced toxicity to retinal pigment epithelial cells. AB - The purpose of this study was to determine the effects of increasing concentration of ascorbate alone and in combinations with alpha-tocopherol and zeaxanthin on phototoxicity to the retinal pigment epithelium. ARPE-19 cells were exposed to rose bengal and visible light in the presence and absence of antioxidants. Toxicity was quantified by an assay of cell-reductive activity. A 20 min exposure to visible light and photosensitizer decreased cell viability to ca 42%. Lipophilic antioxidants increased viabilities to ca 70%, 61% and 75% for alpha-tocopherol, zeaxanthin and their combination, respectively. Cell viabilities were ca 70%, 56% and 5% after exposures in the presence of 0.35, 0.7 and 1.4 mm ascorbate, respectively. A 45 min exposure increased cell death to ca 74% and >95% in the absence and presence of ascorbate, respectively. In the presence of ascorbate, zeaxanthin did not significantly affect phototoxicity. alpha-Tocopherol and its combination with zeaxanthin enhanced protective effects of ascorbate, but did not prevent from ascorbate-mediated deleterious effects. In conclusion, there is a narrow range of concentrations and exposure times where ascorbate exerts photoprotective effects, exceeding which leads to ascorbate mediated increase in photocytotoxicity. Vitamin E and its combination with zeaxanthin can enhance protective effects of ascorbate, but do not ameliorate its deleterious effects. PMID- 22924676 TI - Understanding key factors of users' intentions to repurchase and recommend digital items in social virtual worlds. AB - Given to the remarkable profitability of digital items in social virtual worlds (SVWs), such as SecondLife, Cyworld, and Habbo Hotel, it has become crucial to understand SVW users' postadoption behaviors toward digital items. This study develops a theoretical framework to examine key antecedents of users' intentions to repurchase and recommend digital items. Data collected from 256 users of digital items were empirically tested against the research model. The analysis results indicate that both user satisfaction and a perceived value play an important role in establishing users' postadoption intentions about digital items. Moreover, the results clearly show what roles perceived usefulness, perceived enjoyment, and perceived fee play in SVW environments. PMID- 22924677 TI - The serotonin receptor-antagonist ondansetron induces significant increases in the expression of interferon-gamma which correlate with antiproliferative properties in the acute lymphoblastic leukaemia cell line REH. PMID- 22924678 TI - Stoppers and non-starters of disease-modifying treatment in multiple sclerosis. AB - OBJECTIVES: To explore the frequency of non-starters and stoppers of disease modifying therapy (DMT) in a cohort of people recently diagnosed with multiple sclerosis (MS) and to identify reasons for non-starting or stopping DMT measured by demographic variables, social support [The Interpersonal Support Evaluation List (ISEL)] and disease-related stress [The Impact of Event Scale (IES)]. MATERIALS AND METHODS: A multicentre retrospective cohort study using postal surveys completed by people with MS was performed, comprising all patients diagnosed with MS during 2000-2007 at four university clinics in Norway. RESULTS: Of the 424 respondents, 180 (42%) were still using the first prescribed DMT, 83 (20%) were using DMT after switching DMT at least once, 53 (12.5%) had ended DMT, and 108 (25.5%) had never started DMT. The risk of non-starting DMT was associated with increasing age at diagnosis, the region, disease-related stress and avoidant trauma coping. The risk factors for stopping therapy after the first prescribed DMT were adverse events and high education. CONCLUSIONS: Disease related stress, avoidant trauma coping, age at diagnosis and education should be considered when motivating people with MS to use DMT. Hence, the challenges to starting and continuing treatment will probably also remain a problem with orally administered DMT. PMID- 22924679 TI - Abnormal NMDA receptor function exacerbates experimental autoimmune encephalomyelitis. AB - BACKGROUND AND PURPOSE: Glutamate transmission is dysregulated in both multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE), the animal model of MS. A characteristic of EAE is increased glutamate transmission associated with up-regulation of AMPA receptors. However, little is known about the role of NMDA receptors in the synaptic modifications induced by EAE. EXPERIMENTAL APPROACH: The contribution of NMDA receptors to the alterations of glutamate transmission and disease severity in EAE mice was assessed by means of neurophysiological, morphological, Western blot, metabolic and clinical score assessments. KEY RESULTS: In our EAE mice, there was an NMDA receptor-dependent increase of glutamate release, associated with marked activation of the astroglia. Presynaptic NMDA receptors became overactive during EAE, increasing synaptic glutamate release by a mechanism dependent on voltage-gated sodium channels. By means of NAD(P)H autofluorescence analysis, we also found that EAE has a glutamate and NMDA receptor-dependent dysfunction of mitochondrial activity, which is known to contribute to the neurodegenerative damage of MS and EAE. Furthermore, pharmacological blockade of NMDA receptors in vivo ameliorated both synaptic transmission defects and of the clinical disease course of EAE mice, while EAE induced in mice with a genetically enhanced NMDA receptor signalling had opposite effects. CONCLUSIONS AND IMPLICATIONS: Our data, showing both sensitization of NMDA receptors and their involvement in the progression of the EAE disease, supggest that pharmacological impairment of NMDA receptor signalling would be a component of a neuroprotection strategy in MS. PMID- 22924681 TI - The sweetness concentration-response of r,r-monatin, a naturally occurring high potency sweetener. AB - Monatin, known by the common and usual name arruva, is a zero-calorie, high potency sweetener naturally occurring in the plant Sclerochiton ilicifolius A.Meeuse. The sweetness concentration-response (C-R) behavior of the most potent isomer (R,R-) in room-temperature (21 degrees C) water was determined using two alternative forced choice discrimination tests with a minimum of 69 tasters. Results were processed by a method previously published to obtain isosweet concentrations of sucrose for 8 monatin concentrations up to 240 mg/L. These were used to construct a C-R plot. The equation for the resultant hyperbolic curve relating sucrose equivalent (SE,%) to monatin concentration ([monatin], mg/L) was SE = 26.7 *[monatin]/(69.6 +[monatin]). R,R-monatin has a potency above 3000 at 5% sucrose equivalent, making it one of the most potently sweet naturally occurring substances known. PRACTICAL APPLICATION: Monatin is a naturally occurring, zero-calorie, high-potency sweetener. We have measured the sweetness of monatin over a range of concentrations. This information will help developers of zero-, low- and reduced-calorie products formulate with monatin. PMID- 22924680 TI - Preclinical evaluation of HIV eradication strategies in the simian immunodeficiency virus-infected rhesus macaque: a pilot study testing inhibition of indoleamine 2,3-dioxygenase. AB - Even in the setting of maximally suppressive antiretroviral therapy (ART), HIV persists indefinitely. Several mechanisms might contribute to this persistence, including chronic inflammation and immune dysfunction. In this study, we have explored a preclinical model for the evaluation of potential interventions that might serve to eradicate or to minimize the level of persistent virus. Given data that metabolic products of the inducible enzyme indoleamine 2,3-dioxygeanse (IDO) might foster inflammation and viral persistence, chronically simian immunodeficiency virus (SIV)-infected, ART-treated rhesus macaques were treated with the IDO inhibitor 1-methyl tryptophan (1mT). Orally administered 1mT achieved targeted plasma levels, but did not impact tryptophan metabolism or decrease viral RNA or DNA in plasma or in intestinal tissues beyond levels achieved by ART alone. Animals treated with 1mT showed no difference in the levels of T cell activation or differentiation, or in the kinetics or magnitude of viral rebound following cessation of ART. Notwithstanding these negative results, our observations suggest that the chronically SIV-infected rhesus macaque on suppressive ART can serve as a tractable model in which to test and to prioritize the selection of other potential interventions designed to eradicate HIV in vivo. In addition, this model might be used to optimize the route and dose by which such interventions are administered and the methods by which their effects are monitored. PMID- 22924682 TI - Tracking the repertoire of human adult and neonatal T cells during ex vivo amplification. PMID- 22924683 TI - The structural and predictive properties of the Psychopathy Checklist--revised in Canadian aboriginal and non-aboriginal offenders. AB - We examined the structural and predictive properties of the Psychopathy Checklist Revised (PCL-R) in large samples of Canadian male Aboriginal and non-Aboriginal offenders. The PCL-R ratings were part of a risk assessment for criminal recidivism, with a mean follow-up of 26 months postrelease. Using multigroup confirmatory factor analysis, we were able to show that the PCL-R items were invariant across these 2 groups and that a 4-factor model fit the data well. Predictive accuracy analyses (receiver operator characteristic curves and Cohen's d) generated effect sizes that were medium in magnitude overall for the PCL-R total score in the prediction of violent, nonviolent, and general criminal recidivism (area under the curve=.63-.70, Cohen's d=.28-.42) for both ancestral groups. When disaggregated into its constituent factors, for both ancestral groups, the Lifestyle and Antisocial factors consistently and significantly predicted all recidivism outcomes, whereas the Interpersonal and Affective factors did not significantly predict any of the recidivism outcomes. Finally, structural equation modeling results with the total sample indicated that the PCL R factors were able to account for 32% of the variance in a latent recidivism factor. Implications regarding the latent structure of psychopathy and the clinical use of the instrument with Aboriginal and non-Aboriginal male offenders are discussed. PMID- 22924684 TI - Early impact of the Affordable Care Act on health insurance coverage of young adults. AB - RESEARCH OBJECTIVE: To evaluate one of the first implemented provisions of the Patient Protection and Affordable Care Act (ACA), which permits young adults up to age 26 to enroll as dependents on a parent's private health plan. Nearly one in-three young adults lacked coverage before the ACA. STUDY DESIGN, METHODS, AND DATA: Data from the Current Population Survey 2005-2011 are used to estimate linear probability models within a difference-in-differences framework to estimate how the ACA affected coverage of eligible young adults compared to slightly older adults. Multivariate models control for individual characteristics, economic trends, and prior state-dependent coverage laws. PRINCIPAL FINDINGS: This ACA provision led to a rapid and substantial increase in the share of young adults with dependent coverage and a reduction in their uninsured rate in the early months of implementation. Models accounting for prior state dependent expansions suggest greater policy impact in 2010 among young adults who were also eligible under a state law. CONCLUSIONS AND IMPLICATIONS: ACA-dependent coverage expansion represents a rare public policy success in the effort to cover the uninsured. Still, this policy may have later unintended consequences for premiums for alternative forms of coverage and employer-offered rates for young adult workers. PMID- 22924686 TI - Controllable synthesis of highly conductive polyaniline coated silica nanoparticles using self-stabilized dispersion polymerization. AB - Highly conductive silica/polyaniline (PANi) core/shell nanoparticles (NPs) were synthesized in various diameters (from 18 to 130 nm) using self-stabilized dispersion polymerization. The polymerization was carried out in an aqueous/organic liquid system at -30 degrees C. In this system, the organic phase plays a key role in directing para-direction oriented polymerization of the PANi on the surface of silica NPs. Because of its para-direction polymerized structure, the synthesized silica/PANi core/shell NPs exhibited enhanced electrical conductivity (25.6 S cm(-1)) compared with NPs (1.4 S cm(-1)) prepared by homogeneous polymerization. The conductivities and BET surface areas were 25.6 S cm(-1)/170 m(2) g(-1) (18 nm in diameter), 22.5 S cm(-1)/111 m(2) g(-1) (35 nm in diameter), 18.3 S cm(-1)/78 m(2) g(-1) (63 nm in diameter), and 16.4 S cm( 1)/53 m(2) g(-1) (130 nm in diameter). In this series, increased para-coupling along the polymer backbone was elucidated using several characterization techniques, including Fourier transform infrared (FTIR), X-ray diffraction (XRD), and nuclear magnetic resonance (NMR) spectroscopy. As-prepared silica/PANi core/shell NPs exhibited capacitance as high as 305 F g(-1). PMID- 22924687 TI - Bis(perfluoroalkyl) phosphino-oxazoline: a modular, stable, strongly pi-accepting ligand for asymmetric catalysis. AB - A new class of stable, strongly pi-accepting and modular bis(perfluoroalkyl) phosphine-oxazoline ligands (FOX) as CO mimics was prepared. It was demonstrated that these ligands, when coordinated to palladium catalysts, promote the asymmetric alkylation of monosubstituted allyl substrates with excellent regio- and enantioselectivity. Solid and solution structure analysis of the FOX-ligated Pd-allyl intermediate reveals that the combination of relative steric and strong trans influences presented by the P(CF(3))(2) moiety gave rise to the excellent selectivity. PMID- 22924688 TI - PI3Kdelta and PI3Kgamma as targets for autoimmune and inflammatory diseases. PMID- 22924689 TI - Is there still a role for psoralen ultraviolet A in the treatment of chronic hand eczema? PMID- 22924690 TI - Photodynamic effects of zinc(II) phthalocyanine-loaded polymeric micelles in human nasopharynx KB carcinoma cells. AB - A major difficulty in photodynamic therapy is the poor solubility of the photosensitizer (PS) under physiological conditions which correlates with low bioavailability. PS aggregation leads to a decrease in the photodynamic efficiency and a more limited activity in vitro and in vivo. To improve the aqueous solubility and reduce the aggregation of 2,9(10),16(17),23(24) tetrakis[(2-dimethylamino)ethylsulfanyl]phthal-ocyaninatozinc(II) (Pc9), the encapsulation into four poloxamine polymeric micelles (T304, T904, T1107 and T1307) displaying a broad spectrum of molecular weight and hydrophilic-lipophilic balance was investigated. The aqueous solubility of Pc9 was increased up to 30 times. Morphological evaluation showed the formation of Pc9-loaded spherical micelles in the nanosize range. UV/Vis and fluorescence studies indicated that Pc9 is less aggregated upon encapsulation in comparison with Pc9 in water-DMSO 2% and remained photostable. Pc9-loaded micelles generated singlet molecular oxygen in high yields. Photocytotoxicity assays using human nasopharynx KB carcinoma cells confirmed that the encapsulation of Pc9 in T1107 and T1307 increases its photocytotoxicity by 10 times in comparison with the free form in water-DMSO. In addition, Pc9 incorporated into cells was mainly localized in lysosomes. PMID- 22924691 TI - Expectations of benefit and tolerance to risk of individuals with spinal cord injury regarding potential participation in clinical trials. AB - We conducted a survey of individuals living with spinal cord injury (SCI) to determine their receptivity to participating in clinical trials of drug therapies or stem cell therapies, their anticipation of therapeutic benefits, and their tolerance to risk. A 46-item questionnaire was administered to individuals with cervical or thoracic SCI identified through a provincial database. The average age was 42 years and the individuals were, on average, 5.5 years post-injury. Receptivity to neuroprotective drug trials in the acute setting was very high, but somewhat less so for stem cell trials in the subacute or chronic (current) setting. With respect to expectation of functional benefit, approximately one third of the respondents indicated that they would want a 5-25% chance of achieving some functional recovery if enrolling in a stem cell therapy clinical trial in the current, chronic injury state. Whereas the majority typically would require the risk of spinal cord damage, cancer, infection, and nerve pain from invasive cell transplantation trials to be <=1%, 15-30% would participate regardless of the risk of these complications. The factors associated with this high risk tolerance were gender (males>females), age (elderly>young), and self reported knowledge of SCI research (greater knowledge>less knowledge). Injury severity or chronicity did not have a significant correlation with risk tolerance. Whereas previous studies have shown that the understanding of stem cell science is limited among individuals with SCI, here we show that many still have high hopes for the possibility of neurological benefit, are anxious to participate in invasive stem cell trials, and, in many cases, have high tolerance for risk in such trials. Taken together, the data underscore the need for careful communication with individuals with SCI to avoid unrealistic expectations and therapeutic misconception in experimental trials. PMID- 22924692 TI - Human adipose tissue-derived SSEA-4 subpopulation multi-differentiation potential towards the endothelial and osteogenic lineages. AB - Human adipose tissue has been recently recognized as a potential source of stem cells for regenerative medicine applications, including bone tissue engineering (TE). Despite the gathered knowledge regarding the differentiation potential of human adipose tissue-derived stem cells (hASCs), in what concerns the endothelial lineage many uncertainties are still present. The existence of a cell subpopulation within the human adipose tissue that expresses a SSEA-4 marker, usually associated to pluripotency, raises expectations on the differentiation capacity of these cells (SSEA-4(+)hASCs). In the present study, the endothelial and osteogenic differentiation potential of the SSEA-4(+)hASCs was analyzed, aiming at proposing a single-cell source/subpopulation for the development of vascularized bone TE constructs. SSEA-4(+)hASCs were isolated using immunomagnetic sorting and cultured either in alpha-MEM, in EGM-2 MV (endothelial growth medium), or in osteogenic medium. SSEA-4(+)hASCs cultured in EGM-2 MV formed endothelial cell-like colonies characterized by a cobblestone morphology and expression of CD31, CD34, CD105, and von Willebrand factor as determined by quantitative reverse transcriptase (RT)-polymerase chain reaction, immunofluorescence, and flow cytometry. The endothelial phenotype was also confirmed by their ability to incorporate acetylated low-density lipoprotein and to form capillary-like structures when seeded on Matrigel. SSEA-4(+)hASCs cultured in alpha-MEM displayed fibroblastic-like morphology and exhibited a mesenchymal surface marker profile (>90% CD90(+)/CD73(+)/CD105(+)). After culture in osteogenic conditions, an overexpression of osteogenic-related markers (osteopontin and osteocalcin) was observed both at molecular and protein levels. Matrix mineralization detected by Alizarin Red staining confirmed SSEA-4(+)hASCs osteogenic differentiation. Herein, we demonstrate that from a single-cell source, human adipose tissue, and by selecting the appropriate subpopulation it is possible to obtain microvascular-like endothelial cells and osteoblasts, the most relevant cell types for the creation of vascularized bone tissue-engineered constructs. PMID- 22924693 TI - Aggregation behavior of bovine kappa- and beta-casein studied with small angle neutron scattering, light scattering, and cryogenic transmission electron microscopy. AB - In the native bovine casein micelle the calcium sensitive caseins (alpha(S1)-, alpha(S2)- and beta-casein) sequester amorphous calcium phosphate in nanometer sized clusters, whereas the calcium-insensitive kappa-casein limits the growth of the micelle. In this paper, we further investigate the self-association of kappa- and beta-casein, which are two of the key proteins that control the substructure of the milk casein micelle, using neutron and light scattering techniques and cryogenic transmission electron microscopy. Results demonstrate that kappa-casein can, apart from the known self-assembly, form amyloid-like fibrils already at temperatures of 25 degrees C when subject to agitation. This extended aggregation behavior of kappa-casein is inhibited by beta-casein, as reported by others. These findings have implications for the structure and stability of casein micelles. The neutron scattering data was used to gain information on the self-assembly structure of kappa-casein. beta-Casein shows similar self association behavior as kappa-casein, but unlike kappa-casein, the self association exhibits temperature dependence within the studied temperatures (6 and 25 degrees C). Here, we will discuss our extended study of the known self assembly of casein in the context of the fibrillation of kappa-casein. PMID- 22924695 TI - Complex formation with the activator RACo affects the corrinoid structure of CoFeSP. AB - Activation of the corrinoid [Fe-S] protein (CoFeSP), involved in reductive CO(2) conversion, requires the reduction of the Co(II) center by the [Fe-S] protein RACo, which according to the reduction potentials of the two proteins would correspond to an uphill electron transfer. In our resonance Raman spectroscopic work, we demonstrate that, as a conformational gate for the corrinoid reduction, complex formation of Co(II)FeSP and RACo specifically alters the structure of the corrinoid cofactor by modifying the interactions of the Co(II) center with the axial ligand. On the basis of various deletion mutants, the potential interaction domains on the partner proteins can be predicted. PMID- 22924694 TI - Ethanol disrupts axon outgrowth stimulated by netrin-1, GDNF, and L1 by blocking their convergent activation of Src family kinase signaling. AB - Pre-natal alcohol exposure causes fetal alcohol spectrum disorders (FASD), the most common, preventable cause of developmental disability. The developing cerebellum is particularly vulnerable to the effects of ethanol. We reported that ethanol inhibits the stimulation of axon outgrowth in cerebellar granule neurons (CGN) by NAP, an active motif of activity-dependent neuroprotective protein (ADNP), by blocking NAP activation of Fyn kinase and its downstream signaling molecule, the scaffolding protein Cas. Here, we asked whether ethanol inhibits the stimulation of axon outgrowth by diverse axon guidance molecules through a common action on the Src family kinases (SFK). We first demonstrated that netrin 1, glial cell line-derived neurotrophic factor (GDNF), and neural cell adhesion molecule L1 stimulate axon outgrowth in CGNs by activating SFK, Cas, and extracellular signal-regulated kinase 1 and 2 (ERK1/2). The specific SFK inhibitor, PP2, blocked the stimulation of axon outgrowth and the activation of the SFK-Cas-ERK1/2 signaling pathway by each of these axon-guidance molecules. In contrast, brain-derived neurotrophic factor (BDNF) stimulated axon outgrowth and activated ERK1/2 without first activating SFK or Cas. Clinically relevant concentrations of ethanol inhibited axon outgrowth and the activation of the SFK Cas-ERK1/2 pathway by netrin-1, GDNF, and L1, but did not disrupt BDNF-induced axon outgrowth or ERK1/2 activation. These results indicate that SFK, but not ERK1/2, is a primary target for ethanol inhibition of axon outgrowth. The ability of ethanol to block the convergent activation of the SFK-Cas-ERK1/2 pathway by netrin-1, GDNF, L1, and ADNP could contribute significantly to the pathogenesis of FASD. PMID- 22924696 TI - Genetical analysis of all Danish patients diagnosed with chronic granulomatous disease. AB - Chronic granulomatous disease (CGD) is a rare inherited disorder of the innate immune system caused by a defect in NADPH oxidase, leaving the granulocytes unable to kill invading microorganisms. CGD is caused by mutation in one of the five components gp91phox, p22phox, p47phox, p67phox and p40phox, encoded by the X linked CYBB gene and the autosomal CYBA, NCF1, NCF2 and NCF4 genes respectively. We have collected samples from all Danish patients with known CGD followed in the clinic or newly diagnosed during a 5-year period, a cohort of 27 patients, and characterized them genetically. The cohort includes 10 male patients with X linked CGD and one female with extremely lyonized expression of a defective CYBB allele. Six patients had mutation in CYBA. Seven of 10 patients with a defect in NCF1 were homozygous for the common GT deletion, one was compound heterozygous for the GT deletion and a splice-site mutation, and two patients were homozygous for a nonsense mutation in exon 7. Three novel mutations were detected, a deletion of exon 6 in CYBA, a duplication of exon 8-13 in CYBB and a splice site mutation in intron 7 of NCF1. PMID- 22924697 TI - Interactions between the apolipoprotein a1/c3/a5 haplotypes and alcohol consumption on serum lipid levels. AB - BACKGROUND: The interactions between apolipoprotein (Apo) A1/C3/A5 haplotypes and alcohol consumption on serum lipid profiles have not been previously explored. The present study was undertaken to detect the polymorphisms of ApoA1 -75 bp G>A (rs1799837), ApoC3 3238C>G (rs5128), ApoA5 -1131T>C (rs662799), ApoA5 c.553G>T (rs2075291), and ApoA5 c.457G>A (rs3135507) and the interactions between their haplotypes and alcohol consumption on serum lipid levels. METHODS: Genotyping was performed in 1,030 unrelated subjects (516 nondrinkers and 514 drinkers) aged 15 to 89. The interactions between ApoA1/C3/A5 haplotypes and alcohol consumption on serum lipid levels were detected by factorial regression analysis after controlling for potential confounders. RESULTS: The frequencies of ApoC3 3238 CG/GG genotypes and ApoA1 -75 bp A allele in nondrinkers were higher in females than in males (p < 0.05). The frequencies of ApoC3 3238 CG/GG genotypes and G allele in drinkers were higher in females than in males (p < 0.05). The frequencies of ApoA1 -75 bp GA/AA genotypes and A allele in males were higher, and those of ApoC3 3238 CG/GG genotypes were lower in drinkers than in nondrinkers (p < 0.05 to 0.01). The frequency of ApoC3 3238 GG genotype in male drinkers was also higher in >=25 g/d than in <25 g/d subgroups (p < 0.05). There were 11 haplotypes with a frequency >1% in our study population. The haplotypes of G-G-T-C-G (in the order of c.553G>T, c.457G>A, -1131T>C, 3238C>G, and -75 bp G>A), G-G-T-C-A, and G-G-C-G-G were shown consistent interactions with alcohol consumption to increase serum total cholesterol, high-density lipoprotein cholesterol (HDL-C), and ApoA1 levels (p < 0.05 to 0.001). The interactions between G-G-T-G-G (HDL-C and ApoA1), G-G-C-C-A (ApoA1), G-A-T-C-G (triglyceride), G-G-T-C-G (ApoA1/ApoB ratio), and G-G-C-G-G (ApoB) haplotypes and alcohol consumption on serum lipid levels were also detected (p < 0.05 to 0.001); the levels of these serum lipid parameters were significantly higher in drinkers than in nondrinkers. CONCLUSIONS: The differences in serum lipid parameters between drinkers and nondrinkers might partly result from different interactions between the ApoA1/C3/A5 haplotypes and alcohol consumption. PMID- 22924698 TI - Phenylpropene diglycosides from the bark of Machilus wangchiana. AB - Five new phenylpropene diglycosides (1-5), together with three known analogs, have been isolated from an ethanol extract of the bark of Machilus wangchiana. Their structures were determined by spectroscopic and chemical methods. In the preliminary assay, compounds 2 and 5-8 reduced dl-galactosamine (GalN)-induced hepatocyte (WB-F344 cells) damage with 37-41% inhibitions at 10 MUM. PMID- 22924699 TI - DNA hypermethylation promotes the low expression of pro-apoptotic BCL2L11 associated with BCR-ABL1 fusion gene of chronic myeloid leukaemia. PMID- 22924701 TI - Nano-technology for targeted drug delivery to combat antibiotic resistance. AB - Several microbes have evolved clinically significant resistance against almost every available antibiotic. Yet the development of new classes of antibiotics has lagged far behind our growing need. Frequent and suboptimal use of antibiotics particularly in developing countries aggravated the problem by increasing the rate of resistance. Therefore, developing new and multidimensional strategies to combat microbial infections is warranted. These include i) modification of existing antibiotics, ii) searching new and novel antibiotics, iii) development and improvement of antibiotics carrier system to reduce amount and frequency of antibiotic doses, iv) development of targeted antibiotic delivery systems. Here, the authors discuss trends and development of nano-materials and alternative antimicrobials to solve the problem of antibiotic resistance. PMID- 22924700 TI - Spinal administration of the monoacylglycerol lipase inhibitor JZL184 produces robust inhibitory effects on nociceptive processing and the development of central sensitization in the rat. AB - BACKGROUND AND PURPOSE: The cannabinoid receptor-mediated analgesic effects of 2 arachidonoylglycerol (2-AG) are limited by monoacylglycerol lipase (MAGL). 4 nitrophenyl 4-[bis (1,3-benzodioxol-5-yl) (hydroxy) methyl] piperidine-1 carboxylate (JZL184) is a potent inhibitor of MAGL in the mouse, though potency is reportedly reduced in the rat. Here we have assessed the effects of spinal inhibition of MAGL with JZL184 on nociceptive processing in rats. EXPERIMENTAL APPROACH: In vivo spinal electrophysiological assays in anaesthetized rats were used to determine the effects of spinal administration of JZL184 on spinal nociceptive processing in the presence and absence of hindpaw inflammation. Contributions of CB(1) receptors to these effects was assessed with AM251. Inhibition of 2-oleoylglycerol hydrolytic activity and alterations of 2-AG in the spinal cord after JZL 184 were also assessed. KEY RESULTS: Spinal JZL184 dose dependently inhibited mechanically evoked responses of wide dynamic range (WDR) neurones in naive anaesthetized rats, in part via the CB(1) receptor. A single spinal administration of JZL184 abolished inflammation-induced expansion of the receptive fields of spinal WDR neurones. However, neither spinal nor systemic JZL184 altered levels of 2-AG, or 2-oleoylglycerol hydrolytic activity in the spinal cord, although JZL184 displayed robust inhibition of MAGL when incubated with spinal cord tissue in vitro. CONCLUSIONS AND IMPLICATIONS: JZL184 exerted robust anti-nociceptive effects at the level of the spinal cord in vivo and inhibited rat spinal cord MAGL activity in vitro. The discordance between in vivo and in vitro assays suggests that localized sites of action of JZL184 produce these profound functional inhibitory effects. LINKED ARTICLES: This article is part of a themed section on Cannabinoids. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2012.167.issue-8. PMID- 22924702 TI - An ecological momentary assessment analysis of prequit markers for smoking cessation failure. AB - This study aimed to identify correlates of smoking-cessation failure, a failure to establish abstinence during a quit-smoking attempt. Identifying risk factors for early failure could facilitate the development of tailored interventions to promote cessation. The current study used existing ecological momentary assessment (EMA) data to investigate the extent to which prequit craving, negative affect, and recent smoking were associated with cessation failure in 374 smokers (189, 50.5% female). Subjects were prompted to complete 4-7 real-time reports of craving, negative affect, and recent smoking daily in the four days prior to quitting. Multilevel models of craving and negative affect (mean level, growth, volatility, and association with smoking) were estimated. Results indicated that recent smoking was associated with significantly lower craving among smokers who failed to quit than those who achieved a full day of cessation, but this held only among smokers who reduced smoking by at least 10% in the days preceding the quit attempt. Smokers who failed to quit on the quit day also experienced slower increases in negative affect in the days preceding the quit attempt than did initial abstainers, but delayed quitters and delayed cessation failures did not differ in negative-affect trajectories. These results suggest that successful abstainers and cessation failures can be differentiated by specific dimensions of prequit craving and negative-affect experiences, but the effects hold only in certain circumstances. PMID- 22924703 TI - The effects of exercise on cocaine self-administration, food-maintained responding, and locomotor activity in female rats: importance of the temporal relationship between physical activity and initial drug exposure. AB - Previous studies have reported that exercise decreases cocaine self administration in rats with long-term access (8+ weeks) to activity wheels in the home cage. The purpose of this study was to (a) examine the importance of the temporal relationship between physical activity and initial drug exposure, (b) determine the effects of exercise on responding maintained by a nondrug reinforcer (i.e., food), and (c) investigate the effects of exercise on cocaine induced increases in locomotor activity. To this end, female rats were obtained at weaning and divided into 4 groups: (a) EXE-SED rats were housed in exercise cages for 6 weeks and then transferred to sedentary cages after the first day of behavioral testing; (b) SED-EXE rats were housed in sedentary cages for 6 weeks and then transferred to exercise cages after the first day of behavioral testing; (c) SED-SED rats remained in sedentary cages for the duration of the study; and (d) EXE-EXE rats remained in exercise cages for the duration of the study. Relative to the sedentary group (SED-SED), exercise reduced cocaine self administration in both groups with access to activity wheels after initial drug exposure (EXE-EXE, SED-EXE) but did not reduce cocaine self-administration in the group with access to activity wheels only before drug exposure (EXE-SED). Exercise also decreased the effects of cocaine on locomotor activity but did not reduce responding maintained by food. These data suggest that exercise may reduce cocaine use in drug-experienced individuals with no prior history of aerobic activity without decreasing other types of positively reinforced behaviors. PMID- 22924704 TI - AlOOH-reduced graphene oxide nanocomposites: one-pot hydrothermal synthesis and their enhanced electrochemical activity for heavy metal ions. AB - This work described the preparation, characterization, and electrochemical behavior toward heavy metal ions of the AlOOH-reduced graphene oxide nanocomposites. This new material was synthesized through a green one-pot hydrothermal method. The morphologic and structure of the nanocomposites were characterized using atomic force microscopy, X-ray diffraction, Raman spectroscopy, X-ray photoemission spectroscopy, Fourier transform-infrared spectroscopy, and transmission electron microscopy. Electrochemical properties were characterized by cyclic voltammetry and electrochemical impedance spectroscopy. The chemical and electrochemical parameters that have influence on deposition and stripping of metal ions, such as pH value, deposition potential, and deposition time, were also studied. Due to the strong affinity of AlOOH to heavy metal ions and the fast electron-transfer kinetics of graphene, the combination of solid-phase extraction and stripping voltammetric analysis allowed fast and sensitive determination of Cd(II) and Pb(II) in drinking water, making these new nanocomposites promising candidates for practical applications in the fields of detecting heavy metal ions. Most importantly, these new nanocomposites may possess many unknown properties waiting to be explored. PMID- 22924706 TI - Differential sensing of Zn(II) and Cu(II) via two independent mechanisms. AB - Selective reduction of an anthracenone-quinoline imine derivative, 2, using 1.0 equiv of NaBH(4) in 95% ethanol affords the corresponding anthracen-9-ol derivative, 3, as confirmed by (1)H NMR, (13)C NMR, ESI-MS, FTIR, and elemental analysis results. UV-vis and fluorescence data reveal dramatic spectroscopic changes in the presence of Zn(II) and Cu(II). Zinc(II) coordination induces a 1,5 prototropic shift resulting in anthracene fluorophore formation via an imine enamine tautomerization pathway. Copper(II) induces a colorimetric change from pale yellow to orange-red and results in imine hydrolysis in the presence of water. Spectroscopic investigations of metal ion response, selectivity, stoichiometry, and competition studies all suggest the proposed mechanisms. ESI MS analysis, FTIR, and single-crystal XRD further support the hydrolysis phenomenon. This is a rare case of a single sensor that can be used either as a chemosensor (reversibly in the case of Zn(II)) or as a chemodosimeter (irreversibly in the case of Cu(II)); however, the imine must contain a coordinating Lewis base, such as quinoline, to be active for Cu(II). PMID- 22924705 TI - Human phagosome processing of Mycobacterium tuberculosis antigens is modulated by interferon-gamma and interleukin-10. AB - Intracellular pathogens, such as Mycobacterium tuberculosis, reside in the phagosomes of macrophages where antigenic processing is initiated. Mycobacterial antigen-MHC class II complexes are formed within the phagosome and are then trafficked to the cell surface. Interferon-gamma (IFN-gamma) and interleukin-10 (IL-10) influence the outcome of M. tuberculosis infection; however, the role of these cytokines with regard to the formation of M. tuberculosis peptide-MHC-II complexes remains unknown. We analysed the kinetics and subcellular localization of M. tuberculosis peptide-MHC-II complexes in M. tuberculosis-infected human monocyte-derived macrophages (MDMs) using autologous M. tuberculosis-specific CD4(+) T cells. The MDMs were pre-treated with either IFN-gamma or IL-10 and infected with M. tuberculosis. Cells were mechanically homogenized, separated on Percoll density gradients and manually fractionated. The fractions were incubated with autologous M. tuberculosis -specific CD4(+) T cells. Our results demonstrated that in MDMs pre-treated with IFN-gamma, M. tuberculosis peptide-MHC II complexes were detected early mainly in the phagosomal fractions, whereas in the absence of IFN-gamma, the complexes were detected in the endosomal fractions. In MDMs pre-treated with IL-10, the M. tuberculosis peptide-MHC-II complexes were retained in the endosomal fractions, and these complexes were not detected in the plasma membrane fractions. The results of immunofluorescence microscopy demonstrated the presence of Ag85B associated with HLA-DR at the cell surface only in the IFN-gamma-treated MDMs, suggesting that IFN-gamma may accelerate M. tuberculosis antigen processing and presentation at the cell membrane, whereas IL 10 favours the trafficking of Ag85B to vesicles that do not contain LAMP-1. Therefore, IFN-gamma and IL-10 play a role in the formation and trafficking of M. tuberculosis peptide-MHC-II complexes. PMID- 22924707 TI - A multipathway coupled domino strategy: metal-free oxidative cyclization for one pot synthesis of 2-acylbenzothiazoles from multiform substrates. AB - A multipathway coupled domino strategy has been developed for the efficient synthesis of 2-acylbenzothiazoles from multiform substrates arylethenes, arylacetylenes, 2-hydroxy-aromatic ketones, and carbinols via four distinct pathways. Through a logical coupled oxidation/heterocyclization domino process, a variety of 2-acylbenzothiazoles were synthesized free of metal in one pot. PMID- 22924708 TI - Contrasting hypoxia tolerance and adaptation in Malus species is linked to differences in stomatal behavior and photosynthesis. AB - We examined the potential differences in tolerance to hypoxia by two species of apple rootstocks. Stomatal behavior and photosynthesis were compared between Malus sieversii and Malus hupehensis. Plants were hydroponically grown for 15 days in normoxic or hypoxic nutrient solutions. Those of M. sieversii showed much greater sensitivity, with exposure to hypoxia resulting in higher leaf concentrations of abscisic acid (ABA) that prompted stomatal closure. Compared with the control plants of that species, stomatal density was greater in both new and mature leaves under stress conditions. In contrast, stomatal density was significantly decreased in leaves from M. hupehensis, while stomatal length was unaffected. Under stress, the net photosynthetic rate, stomatal conductance and chlorophyll contents were markedly reduced in M. sieversii. The relatively hypoxia-tolerant genotype M. hupehensis, however, showed only minor changes in net photosynthesis or chlorophyll content, and only a slight decrease in stomatal conductance due to such treatment. Therefore, we conclude that the more tolerant M. hupehensis utilizes a better protective mechanism for retaining higher photosynthetic capacity than does the hypoxia-sensitive M. sieversii. Moreover, this contrast in tolerance and adaptation to stress is linked to differences in their stomatal behavior, photosynthetic capacity and possibly their patterns of native distribution. PMID- 22924709 TI - A girl with multiple asymptomatic pigmented macules and patches. PMID- 22924710 TI - Enterococcus faecalis: a biological marker predicting the emergence of necrotizing enterocolitis. PMID- 22924713 TI - Array-based comparative genomic hybridization-guided identification of reference genes for normalization of real-time quantitative polymerase chain reaction assay data for lymphomas, histiocytic sarcomas, and osteosarcomas of dogs. AB - OBJECTIVE: To identify suitable reference genes for normalization of real-time quantitative PCR (RT-qPCR) assay data for common tumors of dogs. SAMPLE: Malignant lymph node (n = 8), appendicular osteosarcoma (9), and histiocytic sarcoma (12) samples and control samples of various nonneoplastic canine tissues. PROCEDURES: Array-based comparative genomic hybridization (aCGH) data were used to guide selection of 9 candidate reference genes. Expression stability of candidate reference genes and 4 commonly used reference genes was determined for tumor samples with RT-qPCR assays and 3 software programs. RESULTS: LOC611555 was the candidate reference gene with the highest expression stability among the 3 tumor types. Of the commonly used reference genes, expression stability of HPRT was high in histiocytic sarcoma samples, and expression stability of Ubi and RPL32 was high in osteosarcoma samples. Some of the candidate reference genes had higher expression stability than did the commonly used reference genes. CONCLUSIONS AND CLINICAL RELEVANCE: Data for constitutively expressed genes with high expression stability are required for normalization of RT-qPCR assay results. Without such data, accurate quantification of gene expression in tumor tissue samples is difficult. Results of the present study indicated LOC611555 may be a useful RT-qPCR assay reference gene for multiple tissue types. Some commonly used reference genes may be suitable for normalization of gene expression data for tumors of dogs, such as lymphomas, osteosarcomas, or histiocytic sarcomas. PMID- 22924711 TI - Acetate reduces microglia inflammatory signaling in vitro. AB - Acetate supplementation increases brain acetyl-CoA and histone acetylation and reduces lipopolysaccharide (LPS)-induced neuroglial activation and interleukin (IL)-1beta expression in vivo. To determine how acetate imparts these properties, we tested the hypothesis that acetate metabolism reduces inflammatory signaling in microglia. To test this, we measured the effect acetate treatment had on cytokine expression, mitogen-activated protein kinase (MAPK) signaling, histone H3 at lysine 9 acetylation, and alterations of nuclear factor-kappa B (NF-kappaB) in primary and BV-2 cultured microglia. We found that treatment induced H3K9 hyperacetylation and reversed LPS-induced H3K9 hypoacetylation similar to that found in vivo. LPS also increased IL-1beta, IL-6, and tumor necrosis factor-alpha (TNF-alpha) mRNA and protein, whereas treatment returned the protein to control levels and only partially attenuated IL-6 mRNA. In contrast, treatment increased mRNA levels of transforming growth factor-beta1 (TGF-beta1) and both IL-4 mRNA and protein. LPS increased p38 MAPK and JNK phosphorylation at 4 and 2-4 h, respectively, whereas treatment reduced p38 MAPK and JNK phosphorylation only at 2 h. In addition, treatment reversed the LPS-induced elevation of NF-kappaB p65 protein and phosphorylation at serine 468 and induced acetylation at lysine 310. These data suggest that acetate metabolism reduces inflammatory signaling and alters histone and non-histone protein acetylation. PMID- 22924714 TI - Simplified procedure for the estimation of glomerular filtration rate following intravenous administration of iodixanol in cats. AB - OBJECTIVE: To compare the use of a single-sample method involving IV administration of iodixanol with a multisample method involving inulin for the estimation of glomerular filtration rate (GFR) in cats. ANIMALS: 24 cats, including 15 healthy cats and 9 cats with naturally occurring renal diseases. PROCEDURES: Each cat was coadministered iodixanol (a nonionic contrast medium; dose providing 40 mg of I/kg) and inulin (50 mg/kg), IV, and blood samples were collected 60, 90, and 120 minutes later. Serum iodixanol and inulin concentrations were determined by means of high-performance liquid chromatography and colorimetry, respectively. Serum urea nitrogen and creatinine concentrations were also measured. RESULTS: Analysis of the data from healthy cats and cats with naturally occurring renal diseases revealed an excellent correlation between GFR values estimated by the multisample and single-sample methods with iodixanol. Likewise, GFR values estimated from the single-sample method with iodixanol were closely correlated with those calculated from the multisample method with inulin. CONCLUSIONS AND CLINICAL RELEVANCE: For estimation of GFR in cats, use of a single-sample method with iodixanol, instead of a multisample procedure, may be an expedient tool in both clinical and research settings because of its benefits to patient well-being as a result of reduced stress associated with blood sample collection. PMID- 22924715 TI - Determination of the minimum anesthetic concentration of sevoflurane in thick billed parrots (Rhynchopsitta pachyrhyncha). AB - OBJECTIVE: To determine the minimum anesthetic concentration (MAC) of sevoflurane in thick-billed parrots (Rhynchopsitta pachyrhyncha) and compare MAC obtained via mechanical and electrical stimulation. ANIMALS: 15 healthy thick-billed parrots. PROCEDURES: Anesthesia was induced in each parrot by administration of sevoflurane in oxygen. An end-tidal sevoflurane concentration of 2.5% was established in the first bird. Fifteen minutes was allowed for equilibration. Then, 2 types of noxious stimulation (mechanical and electrical) were applied; stimuli were separated by 15 minutes. Responses to stimuli were graded as positive or negative. For a positive or negative response to a stimulus, the target end-tidal sevoflurane concentration of the subsequent bird was increased or decreased by 10%, respectively. The MAC was calculated as the mean end-tidal sevoflurane concentration during crossover events, defined as instances in which independent pairs of birds evaluated in succession had opposite responses. A quantal method was used to determine sevoflurane MAC. Physiologic variables and arterial blood gas values were also measured. RESULTS: Via quantal analysis, mean sevoflurane MAC in thick-billed parrots determined with mechanical stimulation was 2.35% (90% fiducial interval, 1.32% to 2.66%), which differed significantly from the mean sevoflurane MAC determined with electrical stimulation, which was 4.24% (90% fiducial interval, 3.61% to 8.71%). CONCLUSIONS AND CLINICAL RELEVANCE: Sevoflurane MAC in thick-billed parrots determined by mechanical stimulation was similar to values determined in chickens and mammals. Sevoflurane MAC determined by electrical stimulation was significantly higher, which suggested that the 2 types of stimulation did not induce similar results in thick billed parrots. PMID- 22924716 TI - Efficacy of concurrent epidural administration of neostigmine and lidocaine for perineal analgesia in geldings. AB - OBJECTIVE: To evaluate perineal analgesic effects of 3 doses of neostigmine coadministered epidurally with lidocaine to geldings. ANIMALS: 6 healthy geldings. PROCEDURES: A few days before each treatment, a catheter was inserted between the first and second coccygeal vertebrae via the caudal approach in each gelding; the catheter tip was threaded approximately 10 cm cranial into the midsacral region. Each horse received 4 epidural treatments: 2% lidocaine (0.2 mg/kg) alone and 3 doses of neostigmine (0.5, 1, or 2 MUg/kg) coadministered with that same dose of lidocaine. Horses were restrained in stocks in a standing position. Heart rate, blood pressure, respiratory rate, rectal temperature, intestinal motility, analgesia, behavior, and ataxia were determined before treatment (time 0; baseline); at 5, 10, 15, 30, 45, 60, 75, and 90 minutes; and every 30 minutes thereafter until the cessation of analgesia. RESULTS: All doses of neostigmine coadministered with lidocaine improved and extended the duration of analgesia in the perineal region of the geldings. Total duration of analgesia was not a dose-dependent effect (120, 150, and 150 minutes for 0.5, 1, and 2 MUg/kg, respectively). All treatments induced mild or moderate ataxia. Cardiovascular changes were within acceptable limits. CONCLUSIONS AND CLINICAL RELEVANCE: Administration of neostigmine (1 MUg/kg) combined with lidocaine (0.2 mg/kg) in the caudal epidural space induced analgesia for 2.5 hours with a low prevalence of adverse effects in standing conscious geldings. Epidural doses of neostigmine greater than these should be avoided because they may cause undesirable effects in geldings. PMID- 22924717 TI - Hemodynamic effects in dogs after intramuscular administration of a combination of dexmedetomidine-butorphanol-tiletamine-zolazepam or dexmedetomidine butorphanol-ketamine. AB - OBJECTIVE: To evaluate hemodynamic effects in dogs after IM administration of dexmedetomidine (7.5 MUg/kg, butorphanol (0.15 mg/kg), and tiletamine-zolazepam (3 mg/kg [DBTZ]) or dexmedetomidine (15 MUg/kg), butorphanol (0.3 mg/kg), and ketamine (3 mg/kg [DBK]). ANIMALS: 5 healthy adult mixed-breed dogs. PROCEDURES: Each dog received DBTZ and DBK in a randomized crossover study with a 48-hour interval between treatments. Anesthesia was induced and maintained with sevoflurane in 100% oxygen while instrumentation with Swan-Ganz and arterial catheters was performed. Following instrumentation, hemodynamic measurements were recorded at 3.54% (1.5 times the minimum alveolar concentration) sevoflurane; then sevoflurane administration was discontinued, and dogs were allowed to recover. Six hours after cessation of sevoflurane administration, baseline hemodynamic measurements were recorded, each dog was given an IM injection of DBTZ or DBK, and hemodynamic measurements were obtained at predetermined intervals for 70 minutes. RESULTS: DBTZ and DBK induced hypoventilation (Paco2, approx 60 to 70 mm Hg), respiratory acidosis (pH, approx 7.2), hypertension (mean arterial blood pressure, approx 115 to 174 mm Hg), increases in systemic vascular resistance, and reflex bradycardia. Cardiac output, oxygen delivery, and oxygen consumption following DBTZ or DBK administration were similar to those following sevoflurane administration to achieve a surgical plane of anesthesia. Blood l lactate concentrations remained within the reference range at all times for all protocols. CONCLUSIONS AND CLINICAL RELEVANCE: In healthy dogs, both DBTZ and DBK maintained oxygen delivery and oxygen consumption to tissues and blood lactate concentrations within the reference range. However, ventilation should be carefully monitored and assisted when necessary to prevent hypoventilation. PMID- 22924718 TI - Hind limb kinematics during therapeutic exercises in dogs with osteoarthritis of the hip joints. AB - OBJECTIVE: To assess joint kinematics in dogs with osteoarthritis of the hip joints during walking up an incline or down a decline and over low obstacles and to compare findings with data for nonlame dogs. ANIMALS: 10 dogs with osteoarthritis of the hip joints (mean +/- SD age, 6.95 +/- 3.17 years; mean body weight, 34.33 +/- 13.58 kg) and 8 nonlame dogs (3.4 +/- 2.0 years; 23.6 +/- 4.6 kg). PROCEDURES: Reflective markers located on the limbs and high-speed cameras were used to record joint kinematics during walking up an incline or down a decline and over low obstacles. Maximal flexion, extension, and range of motion of the hip joints were calculated. RESULTS: Osteoarthritis of the hip joints reduced extension of both hip joints and flexion of the contralateral hind limb, compared with flexion of the lame hind limb, during walking down a decline. Walking up an incline resulted in decreased extension of the stifle joint in both hind limbs of osteoarthritic dogs; extension was significantly decreased for the lame hind limb. During walking over low obstacles, maximal flexion of the stifle joint was increased significantly for the contralateral hind limb. Maximal flexion was increased in both tarsal joints. CONCLUSIONS AND CLINICAL RELEVANCE: Osteoarthritis of the hip joints led to complex changes in the gait of dogs, which involved more joints than the affected hip joint alone. Each exercise had specific effects on joint kinematics that must be considered when planning a rehabilitation program. PMID- 22924719 TI - Ultrasonography and noncontrast computed tomography of medial retropharyngeal lymph nodes in healthy cats. AB - OBJECTIVE: To determine various measurements of medial retropharyngeal lymph nodes (MRPLNs) in healthy cats via ultrasonography and CT. ANIMALS: 45 cats (age range, 2 to 8 years). PROCEDURES: Cats underwent CT of the head and ultrasonography of the cervical region. Various measurements of MRPLNs were obtained, and parenchymal heterogeneity, presence of a hilus, appearance of margins, and attenuation of MRPLNs were determined. RESULTS: Data for 7 cats were excluded because they did not meet inclusion criteria; data for 38 cats were evaluated. Measurements of left and right MRPLNs were not significantly different. Mean length * rostral height * rostral width dimensions of MRPLNs were 20.7 * 12.4 * 3.7 mm and 20.7 * 13.1 * 4.7 mm in ultrasonographic and CT images, respectively. Maximum MRPLN dimensions were approximately 32 * 20 * 7 mm. Mean attenuation of MRPLNs was 40.2 Hounsfield units. Parenchyma of MRPLNs was mildly (via CT) to moderately (via ultrasonography) heterogeneous. A hilus was identified in 95% (via ultrasonography) and 24% or 92% (via CT [depending on criteria used to define a hilus]) of MPRLNs. Lymph node margins were smooth in CT images and mildly irregular in ultrasonographic images. A negative linear correlation was detected between age of cat and MRPLN volume. CONCLUSIONS AND CLINICAL RELEVANCE: MRPLNs in cats were easily imaged via ultrasonography and CT. Left and right MRPLNs were symmetric, and MRPLNs were larger in young adult cats versus old cats. Data were intended to serve as references for evaluation of MRPLNs in healthy cats. PMID- 22924720 TI - Effects of intensified training and subsequent reduced training on glucose metabolism rate and peripheral insulin sensitivity in Standardbreds. AB - OBJECTIVE: To determine the influence of intensified training and subsequent reduced training on glucose metabolism rate and peripheral insulin sensitivity in horses and identify potential markers indicative of early overtraining. ANIMALS: 12 Standardbred geldings. PROCEDURES: Horses underwent 4 phases of treadmill based training. In phase 1, horses were habituated to the treadmill. In phase 2, endurance training was alternated with high-intensity exercise training. In phase 3, horses were divided into control and intensified training groups. In the intensified training group, training intensity, duration, and frequency were further increased via a protocol to induce overtraining; in the control group, these factors remained unaltered. In phase 4, training intensity was reduced. Standardized exercise tests were performed after each phase and hyperinsulinemic euglycemic clamp (HEC) tests were performed after phases 2, 3, and 4. RESULTS: 10 of 12 horses completed the study. Dissociation between mean glucose metabolism rate and mean glucose metabolism rate-to-plasma insulin concentration ratio (M:I) was evident in the intensified training group during steady state of HEC testing after phases 3 and 4. After phase 4, mean glucose metabolism rate was significantly decreased (from 31.1 +/- 6.8 MUmol/kg/min to 18.1 +/- 3.4 MUmol/kg/min), as was M:I (from 1.05 +/- 0.31 to 0.62 +/- 0.17) during steady state in the intensified training group, compared with phase 3 values for the same horses. CONCLUSIONS AND CLINICAL RELEVANCE: Dissociation between the glucose metabolism rate and M:I in horses that underwent intensified training may reflect non-insulin-dependent increases in glucose metabolism. PMID- 22924721 TI - Effects of continuous or intermittent lipopolysaccharide administration for 48 hours on the systemic inflammatory response in horses. AB - OBJECTIVE: To determine whether the method of lipopolysaccharide (LPS) administration (intermittent vs continuous) affects the magnitude and duration of the systemic inflammatory response in horses and whether prolonged (48 hours) endotoxemia induces laminitis. ANIMALS: 12 healthy adult horses (10 mares and 2 geldings). PROCEDURES: Horses were randomly assigned to receive LPS (total dose, 80 MUg; n = 4) or saline (0.9% NaCl) solution (80 mL/h; 4) via constant rate infusion or 8 bolus IV injections of LPS (10 MUg, q 6 h;4) during a 48-hour period. Physical examinations were performed every 4 hours, inflammatory cytokine gene expression was determined for blood samples obtained every 8 hours, and IV glucose tolerance tests were performed. RESULTS: All LPS-treated horses had signs of depression and mild colic; those signs abated as the study progressed. Administration of LPS increased expression of interleukin-1beta, interleukin-6, and interleukin-8, but results were not significantly different between LPS treatment groups. Cytokine expression was significantly higher on the first day versus the second day of LPS treatment. Interleukin-1beta expression was positively correlated with rectal temperature and expression of other cytokines. Glucose and insulin dynamics for both LPS groups combined did not differ significantly from those of the saline solution group. Signs of laminitis were not detected in any of the horses. CONCLUSIONS AND CLINICAL RELEVANCE: Horses developed LPS tolerance within approximately 24 hours after administration was started, and the method of LPS administration did not affect the magnitude or duration of systemic inflammation. Laminitis was not induced in horses. PMID- 22924722 TI - Perinuclear antineutrophil cytoplasmic autoantibodies in dogs infected with various vector-borne pathogens and in dogs with immune-mediated hemolytic anemia. AB - OBJECTIVE: To determine the prevalence of perinuclear antineutrophil cytoplasmic autoantibodies (pANCA) in dogs with confirmed or suspected immune-mediated hemolytic anemia (IMHA) or dogs infected with various vector-borne pathogens, including Rickettsia rickettsii, Bartonella henselae, Bartonella vinsonii subsp berkhoffii, Ehrlichia canis, Borrelia burgdorferi, and Leishmania infantum. ANIMALS: 55 dogs with confirmed or suspected IMHA, 140 dogs seroreactive for vector-borne pathogens, and 62 healthy dogs and dogs seronegative for vector borne pathogens. PROCEDURES: Samples were allocated to subgroups on the basis of the health status of the dogs and the degree of seroreactivity against various vector-borne pathogens. Serum samples were tested retrospectively via indirect immunofluorescence assay to determine pANCA status. RESULTS: 26 of 55 (47%) dogs with confirmed or suspected IMHA and 67 of 140 (48%) dogs seroreactive for vector borne pathogens had positive results when tested for pANCA. Serum samples with the highest antibody concentrations against L infantum antigen had the highest proportion (28/43 [65%]) that were positive for pANCA. One of 20 (5%) dogs seronegative for tick-borne pathogens and 8 of 22 (36%) dogs seronegative for L infantum had positive results for pANCA. One of 20 (5%) healthy dogs had serum antibodies against pANCA. CONCLUSIONS AND CLINICAL RELEVANCE: pANCA were detected in a high percentage of dogs with IMHA and vector-borne infectious diseases. Therefore, pANCA may be a relatively nonspecific marker for dogs with inflammatory bowel disease, although they could represent a biomarker for immune mediated diseases and infections. PMID- 22924723 TI - Effect of parenteral l-alanyl-l-glutamine administration on phagocytic responses of polymorphonuclear neutrophilic leukocytes in dogs undergoing high-dose methylprednisolone sodium succinate treatment. AB - OBJECTIVE: To determine whether parenteral l-alanyl-l-glutamine (Ala-Gln) administration modulated phagocytic responses of polymorphonuclear neutrophilic leukocytes (PMNs) from dogs undergoing high-dose methylprednisolone sodium succinate (MPSS) treatment. ANIMALS: 15 healthy Beagles. PROCEDURES: Dogs were randomly assigned to 3 treatment groups (n = 5/group): 38-hour IV infusion of saline (0.9% NaCl) solution (control group), saline solution with 8.5% amino acids (2.3 g/kg/d), or saline solution with 8.5% amino acids (1.8 g/kg/d) and 20% l-alanyl-l-glutamine (Ala-Gln; 0.5 g/kg/d). High-dose MPSS treatment was initiated at the same time that IV infusions began, such that a total dose of 85 mg of MPSS/kg was administered through multiple IV injections over a 26-hour period. The infusions were maintained until 12 hours after the last MPSS injection. Blood samples collected before MPSS injections began and 2, 12, and 24 hours after injections ceased were used to evaluate PMN function. RESULTS: MPSS injections resulted in an increase in the total number of circulating leukocytes and increases in neutrophil and monocyte counts but did not affect lymphocyte, eosinophil, or basophil counts. Lymphocyte counts in the Ala-Gln group were higher than in the control group 12 hours after MPSS injections finished. Relative to preinfusion values, phagocytic capacity, oxidative burst activity, and filamentous actin polymerization of PMNs were suppressed in all dogs except those that received Ala-Gln. CONCLUSIONS AND CLINICAL RELEVANCE: Parenteral Ala Gln administration in dogs resulted in an increase in PMN phagocytic responses that were suppressed by high-dose MPSS treatment. PMID- 22924724 TI - Expression of interleukin-1beta, interleukin-8, and interferon-gamma in blood samples obtained from healthy and sick neonatal foals. AB - OBJECTIVE: To evaluate and compare the gene expression of interleukin(IL)-1beta, IL-8, and interferon-gamma during the first 72 hours after birth in healthy foals and during the first 72 hours after hospitalization in sick neonatal foals and investigate correlations of clinicopathologic variables with cytokine expressions in healthy and sick neonatal foals. ANIMALS: 33 foals < 7 days old (10 healthy foals, 7 foals with sepsis, 6 foals with peripartum asphyxia syndrome, and 12 foals with other diseases [2 with failure of passive transfer of immunity only were not further evaluated]). PROCEDURES: A blood sample (15 mL) was collected from each foal immediately after birth or hospital admission (0 hours) and at 24 and 72 hours later. Clinicopathologic variables were evaluated, and cytokine gene expression in WBCs was measured with an absolute quantitative real-time reverse transcriptase PCR assay. RESULTS: At all time points, gene expression of interferon-gamma was low in all groups. No time-dependent changes in cytokine expressions were detected in healthy or sick foals. Foals with sepsis had significantly higher IL-1beta gene expression than did healthy foals, foals with peripartum asphyxia syndrome, or foals with other diseases. At 0 hours, IL-1beta expression was correlated with plasma fibrinogen concentration in healthy foals and with the neutrophil-to-lymphocyte ratio in foals with sepsis; IL-8 expression was correlated with monocyte count in foals with sepsis and with arterial pH, plasma fibrinogen concentration, and plasma lactate concentration in foals with peripartum asphyxia syndrome. CONCLUSIONS AND CLINICAL RELEVANCE: Data have suggested that evaluation of IL-1beta expression in sick neonatal foals could help identify those with sepsis. PMID- 22924725 TI - Effects of administration of two growth hormone-releasing hormone plasmids to gilts on sow and litter performance for the subsequent three gestations. AB - OBJECTIVE: To determine whether a novel optimized plasmid carrying the porcine growth hormone-releasing hormone (GHRH) wild-type cDNA administered at a lower dose was as effective at eliciting physiologic responses as a commercial GHRH plasmid approved for use in Australia. ANIMALS: 134 gilts. PROCEDURES: Estrus was synchronized and gilts were bred. Pregnant gilts were assigned to 2 treatment groups (40 gilts/group) or 1 untreated control group (24 gilts). Gilts in one of the treatment groups received the commercial GHRH plasmid, whereas gilts in the other treatment group received a novel optimized GHRH plasmid; both plasmids were administered IM in the right hind limb, which was followed by electroporation. Sow and litter performance were monitored for the 3 gestations after treatment. RESULTS: A significant increase in insulin-like growth factor-I concentrations, decrease in perinatal mortality rate, increase in the number of pigs born alive, and increase in the weight and number of pigs weaned were detected for both groups receiving the GHRH-expressing plasmids, compared with values for the control group. Additionally, there was a significant decrease in sow attrition in GHRH-treated females, compared with attrition in the control group, during the 3 gestations after treatment. CONCLUSIONS AND CLINICAL RELEVANCE: Both of the GHRH plasmids provided significant benefits for sow performance and baby pig survivability for pregnant and lactating sows and their offspring during the 3 gestations after treatment, compared with results for untreated control gilts. Use of a novel optimized plasmid reduced the effective plasmid dose in these large mammals. PMID- 22924726 TI - Evaluation of a diode laser for use in induction of tendinopathy in the superficial digital flexor tendon of horses. AB - OBJECTIVE: To evaluate use of a diode laser to induce tendinopathy in the superficial digital flexor tendon (SDFT) of horses. ANIMALS: 4 equine cadavers and 5 adult horses. PROCEDURES: Cadaveric SDFT samples were exposed to a diode laser at various energy settings to determine an appropriate energy for use in in vivo experiments; lesion size was assessed histologically. In vivo experiments involved laser energy induction of lesions in the SDFT (2 preliminary horses [0, 25, 75, and 87.5 J] and 3 study horses [0 and 125 J]) and assessment of lesions. Study duration was 21 days, and lesions were assessed clinically and via ultrasonography, MRI, and histologic evaluation. RESULTS: Lesion induction in cadaveric tissues resulted in a spherical cavitated core with surrounding tissue coagulation. Lesion size had a linear relationship (R2 = 0.9) with the energy administered. Size of in vivo lesions in preliminary horses indicated that larger lesions were required. In study horses, lesions induced with 125 J were ultrasonographically and histologically larger than were control lesions. At proximal and distal locations, pooled (preliminary and study horses) ultrasonographically assessed lesions were discrete and variable in size (mean +/ SEM lesion percentage for control lesions, 8.5 +/- 3%; for laser lesions, 12.2 +/- 1.7%). Ultrasonography and MRI measurements were associated (R2 > 0.84) with cross-sectional area measurements. CONCLUSIONS AND CLINICAL RELEVANCE: In vivo diode laser-induced lesions did not reflect cadaveric lesions in repeatable size. Further research is required before diode lasers can reliably be used for inducing tendinopathy. PMID- 22924727 TI - Evaluation of diode endoscopic cyclophotocoagulation in bovine cadaver eyes. AB - OBJECTIVE: To evaluate the anterior chamber approach and energy levels for endoscopic cyclophotocoagulation (ECPC) and assess ECPC-induced tissue damage in phakic eyes of bovine cadavers. SAMPLE: 12 bovine cadaver eyes. PROCEDURES: Angle of reach was measured in 6 eyes following placement of a curved endoscopic probe through multiple corneal incisions. In another 6 eyes, each ocular quadrant underwent ECPC at 1 of 3 energy levels (0.75, 0.90, and 1.05 J) or remained untreated. Visible effects on tissues (whitening and contraction of ciliary processes) were scored (scale of 0 [no effects] to 6 [severe effects]), and severity and extent of histologic damage to the pigmented and nonpigmented ciliary epithelium and fibromuscular stroma were each scored (scale of 0 [no effect] to 3 [severe effect]) and summed for each quadrant. Overall mean scores for 6 quadrants/treatment were calculated. RESULTS: Mean +/- SD combined angle of reach was 148 +/- 24 degrees (range, 123 +/- 23 degrees [ventromedial] to 174 +/- 11 degrees [dorsolateral]). At the 0.75-, 0.90-, and 1.05-J levels, mean visible tissue effect scores were 3.12 +/- 0.47, 3.86 +/- 0.35, and 4.68 +/- 0.58, respectively; mean histologic damage scores were 4.79 +/- 1.38 (mild damage), 6.82 +/- 1.47 (moderate damage), and 9.37 +/- 1.42 (severe damage), respectively. Occasional popping noises (venting of vaporized interstitial water) were heard at the 1.05-J level. CONCLUSIONS AND CLINICAL RELEVANCE: Multiple incisions were necessary to facilitate 360 degrees ECPC treatment in bovine eyes. For ECPC in vivo, the 0.75- and 0.90-J energy levels had the potential to effectively treat the ciliary epithelium. PMID- 22924728 TI - Pharmacokinetics of methylprednisolone acetate after intra-articular administration and subsequent suppression of endogenous hydrocortisone secretion in exercising horses. AB - OBJECTIVE: To determine the pharmacokinetics of methylprednisolone (MP) and the relationship between MP and hydrocortisone (HYD) concentrations in plasma and urine after intra-articular (IA) administration of 100 or 200 mg of MP acetate (MPA) to horses. ANIMALS: Five 3-year-old Thoroughbred mares. PROCEDURES: Horses exercised on a treadmill 3 times/wk during the study. Horses received 100 mg of MPA IA, then 8 weeks later received 200 mg of MPA IA. Plasma and urine samples were obtained at various times for 8 weeks after horses received each dose of MPA; concentrations of MP and HYD were determined. Pharmacokinetic pharmacodynamic estimates for noncompartmental and compartmental parameters were determined. RESULTS: Maximum concentration of MP in plasma was similar for each MPA dose; concentrations remained greater than the lower limit of quantitation for 18 and 7 days after IA administration of 200 and 100 mg of MPA, respectively. Maximum concentration and area under the observed concentration-time curve for MP in urine were significantly higher (approximately 10-and 17-fold, respectively) after administration of 200 versus 100 mg of MPA. Hydrocortisone concentration was below quantifiable limits for >= 48 hours in plasma and urine of all horses after administration of each MPA dose. CONCLUSIONS AND CLINICAL RELEVANCE: Pharmacokinetics of MP may differ among IA MPA dosing protocols, and MP may be detected in plasma and urine for a longer time than previously reported. This information may aid veterinarians treating sport horses. Further research is warranted to determine whether plasma HYD concentration can aid identification of horses that received exogenous glucocorticoids. PMID- 22924729 TI - Effects of the addition of endotoxin during perfusion of isolated forelimbs of equine cadavers. AB - OBJECTIVE: To examine the effect of endotoxins on metabolism and histopathologic changes of isolated perfused equine forelimbs. SAMPLE: Forelimbs (comprising the metacarpus and digit) were collected from cadavers of 12 healthy adult horses after slaughter at an abattoir (14 limbs; 1 forelimb of 10 horses and both forelimbs of 2 horses). PROCEDURES: Forelimbs were perfused for 10 hours with autologous blood, with and without the addition of endotoxin (80 ng of lipopolysaccharide [LPS]/L). Two limbs of the endotoxin exposure group and 2 nonperfused limbs were loaded to failure of the suspensory apparatus of the pedal bone to evaluate the effect of body weight. Metabolic and histologic variables were evaluated. RESULTS: Blood pressure increased during the first hour and did not differ between groups. Lactate dehydrogenase activity was similar in both groups and increased significantly during the 10-hour period; glucose consumption at 5 hours and lactate concentration at 8 hours were significantly higher in limbs exposed to endotoxin. The width of secondary epidermal lamellae was greater in LPS limbs. In the primary dermal lamellae of LPS limbs, there were significantly more vessels with an open lumen and aggregates of intravascular neutrophils. CONCLUSIONS AND CLINICAL RELEVANCE: In the blood-perfused isolated forelimbs of equine cadavers, exposure to LPS led to significant changes in the laminar tissue as well as to metabolic changes. Therefore, endotoxin should be considered as a causative factor for laminitis and not merely as a risk factor. PMID- 22924730 TI - Hemostatic response to surgical neutering via ovariectomy and ovariohysterectomy in dogs. AB - OBJECTIVE: To investigate the hemostatic response to surgery and compare the response for ovariohysterectomy with that for ovariectomy and to evaluate the usefulness of thromboelastography on plasma samples. ANIMALS: 42 female dogs. PROCEDURES: Dogs were assigned to undergo ovariohysterectomy or ovariectomy. Blood samples were collected immediately before and 1, 6, and 24 hours after surgery and stored at -80 degrees C for subsequent analysis. Plasma samples were subjected to thromboelastography after thawing. In addition, coagulation variables were measured, including concentrations of von Willebrand factor antigen, fibrinogen, antithrombin, and protein C; activity of factor VIII; activated partial thromboplastin time; prothrombin time; and thrombin time. The fibrinolytic response was assessed via concentrations of D-dimer, plasminogen, and alpha-2-antiplasmin (plasmin inhibitor). RESULTS: Substantial hemostatic and fibrinolytic activation was evident after surgery in both groups, as characterized by significantly increased global clot strength and an overall hypercoagulable state at 4 hours after surgery in addition to decreases in von Willebrand factor antigen and factor VIII concentrations and shortened prothrombin and thrombin times. The dogs also typically had activation of the fibrinolytic system, as evidenced by increased postoperative concentrations of D dimer, plasminogen, and plasmin inhibitor. Differences between the 2 groups could not be detected for any variables. CONCLUSIONS AND CLINICAL RELEVANCE: Elective surgery with limited tissue trauma induced hemostatic activation in dogs, which led to hypercoagulability after surgery. A difference between the ovariohysterectomy and ovariectomy groups was not detected. Thromboelastography can be used on plasma samples and may be useful for evaluating patterns over time. PMID- 22924731 TI - Neurotoxic effects of ivermectin administration in genetically engineered mice with targeted insertion of the mutated canine ABCB1 gene. AB - OBJECTIVE: To develop in genetically engineered mice an alternative screening method for evaluation of P-glycoprotein substrate toxicosis in ivermectin sensitive Collies. ANIMALS: 14 wild-type C57BL/6J mice (controls) and 21 genetically engineered mice in which the abcb1a and abcb1b genes were disrupted and the mutated canine ABCB1 gene was inserted. PROCEDURES: Mice were allocated to receive 10 mg of ivermectin/kg via SC injection (n = 30) or a vehicle-only formulation of propylene glycol and glycerol formal (5). Each was observed for clinical signs of toxic effects from 0 to 7 hours following drug administration. RESULTS: After ivermectin administration, considerable differences were observed in drug sensitivity between the 2 types of mice. The genetically engineered mice with the mutated canine ABCB1 gene had signs of severe sensitivity to ivermectin, characterized by progressive lethargy, ataxia, and tremors, whereas the wild-type control mice developed no remarkable effects related to the ivermectin. CONCLUSIONS AND CLINICAL RELEVANCE: The ivermectin sensitivity modeled in the transgenic mice closely resembled the lethargy, stupor, disorientation, and loss of coordination observed in ivermectin-sensitive Collies with the ABCB1-1Delta mutation. As such, the model has the potential to facilitate toxicity assessments of certain drugs for dogs that are P-glycoprotein substrates, and it may serve to reduce the use of dogs in avermectin derivative safety studies that are part of the new animal drug approval process. PMID- 22924732 TI - Renal effects of carprofen and etodolac in euvolemic and volume-depleted dogs. AB - OBJECTIVE: To determine the effects of carprofen and etodolac on renal function in euvolemic dogs and dogs with extracellular fluid volume depletion induced via administration of furosemide. ANIMALS: 12 female Beagles. PROCEDURES: Dogs received a placebo, furosemide, carprofen, etodolac, furosemide and carprofen, and furosemide and etodolac. The order in which dogs received treatments was determined via a randomization procedure. Values of urine specific gravity, various plasma biochemical variables, glomerular filtration rate (GFR [urinary clearance of creatinine]), and renal plasma flow (urinary clearance of para aminohippuric acid) were determined before and after 8 days of drug administration. A washout time of approximately 12 days was allowed between treatment periods. RESULTS: Administration of furosemide, furosemide and carprofen, and furosemide and etodolac caused changes in urine specific gravity and values of plasma biochemical variables. Administration of carprofen or etodolac alone did not have a significant effect on renal plasma flow or GFR. Concurrent administration of furosemide and carprofen or furosemide and etodolac caused a significant decrease in GFR. After 12-day washout periods, mean values of GFR were similar to values before drug administration for all treatments. CONCLUSIONS AND CLINICAL RELEVANCE: Results indicated GFR decreased after 8 days of concurrent administration of furosemide and carprofen or furosemide and etodolac to dogs. Administration of preferential cyclooxygenase-2 inhibitors to dogs with extracellular fluid volume depletion or to dogs treated with diuretics may transiently impair renal function. PMID- 22924733 TI - A retrospective population-based study of injury types among elderly in Taiwan. AB - The aim of the article was to investigate the injury types and medical utilisations among patients more than 65 years in Taiwan. The data used in this study were obtained from the years 1997 to 2008 of the National Health Insurance Research Database (NHIRD). The patients with the age of 65 years and older as well as with ICM-9-CM discharge injury principal diagnoses 800-959 were included in this study. SPSS 18.0 was used for data analysis. The results showed that there were 518,601 older adults hospitalised because of injuries in the period of study. The average age among them was 76.1 years old and 51.7% of them were females. The common causes of injury were falls and motor vehicle accident. The average number of operations that patients received was one, and the average length of stay was 9.1 days. The total medical expenditure was over NT$ 28.9 billion, and the average expenditure was NT$ 55,738. The factors associated with deaths were sex, ages, co-morbidity disease, level of care, number of operations, length of stay, expenditure of medical care, injury types and causes of injury. This study concludes that in order to decrease the incident of injuries in elder patients, the education of preventing falls and traffic safety should be promoted continuously among elders. PMID- 22924734 TI - Discovery of a novel class of exquisitely selective mesenchymal-epithelial transition factor (c-MET) protein kinase inhibitors and identification of the clinical candidate 2-(4-(1-(quinolin-6-ylmethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin 6-yl)-1H-pyrazol-1-yl)ethanol (PF-04217903) for the treatment of cancer. AB - The c-MET receptor tyrosine kinase is an attractive oncology target because of its critical role in human oncogenesis and tumor progression. An oxindole hydrazide hit 6 was identified during a c-MET HTS campaign and subsequently demonstrated to have an unusual degree of selectivity against a broad array of other kinases. The cocrystal structure of the related oxindole hydrazide c-MET inhibitor 10 with a nonphosphorylated c-MET kinase domain revealed a unique binding mode associated with the exquisite selectivity profile. The chemically labile oxindole hydrazide scaffold was replaced with a chemically and metabolically stable triazolopyrazine scaffold using structure based drug design. Medicinal chemistry lead optimization produced 2-(4-(1-(quinolin-6-ylmethyl)-1H [1,2,3]triazolo[4,5-b]pyrazin-6-yl)-1H-pyrazol-1-yl)ethanol (2, PF-04217903), an extremely potent and exquisitely selective c-MET inhibitor. 2 demonstrated effective tumor growth inhibition in c-MET dependent tumor models with good oral PK properties and an acceptable safety profile in preclinical studies. 2 progressed to clinical evaluation in a Phase I oncology setting. PMID- 22924735 TI - Mapping the mechanical properties of cholesterol-containing supported lipid bilayers with nanoscale spatial resolution. AB - It has been demonstrated that many biological processes are influenced by mechanical changes in membranes comprised of a variety of lipid components. As a result, the ability to map physicomechanical properties of surfaces with high temporal and spatial resolution is desirable. Tapping mode atomic force microscopy (AFM) has proven to be a useful technique for imaging biological surfaces due to its ability to operate in solution; however, access to information concerning the mechanical properties of these surfaces can also be obtained by reconstructing the time-resolved tip/sample force interactions during the imaging process. An advantage of such an approach is the direct correlation of topographical features with mechanical properties. Reconstruction of the tip/sample force is achievable by a technique called scanning probe acceleration microscopy (SPAM), which treats the cantilever as an accelerometer. The acceleration, which is directly related to the tip/sample force, of the cantilever is obtained by taking the second derivative of the cantilever deflection signal during a tapping mode AFM experiment in solution with standard cantilevers. Herein, we describe the applicability of SPAM to study mechanical properties of supported lipid bilayers with nanoscale spatial resolution via numerical simulations and experiment. The maximum and minimum tapping forces respond to changes in specific surface mechanical properties. Furthermore, we demonstrate how these changes can be used to map relative changes in the Young's modulus and adhesive properties of supported total brain lipid extract bilayers containing exogenous cholesterol. Finally, the ability of SPAM to distinguish nanoscale lipid raft domains based on changes in local mechanical properties is demonstrated. PMID- 22924736 TI - Natural antioxidants in purple sprouting broccoli under Mediterranean climate. AB - Broccoli, (Brassica oleracea var. Italica), is generally recognized as a nutritive food rich in natural antioxidants, including vitamins and phenolics compounds. Phytochemical composition of 3 different purple sprouting broccoli varieties according with their production cycle: EEP (Extra Early), EP (Early), and LP (Late) were determined. The 3 cultivars tested were grown under the same conditions in an experimental field (SE Spain) where they were not previously cultivated since these cultivars are typical of cold, Northern-European areas. EP variety showed greater growth according to the photosynthetic rate and C assimilation. However, it was not possible to obtain inflorescences for variety LP. The health-promoting compounds (vitamin C, phenolic compounds, and glucosinolates) were higher in purple broccolis than in traditionally grown green broccolis and showed differences according to the variety. With respect to the use of broccoli byproducts as source of antioxidants, any variety would be suitable although the leaves of EP variety seems the richest in total phenolic acids, whereas the amount of anthocyanins was higher in LP variety, followed by EP and EEP varieties. Under our experimental conditions, the levels of glucosinolates were higher in purple broccoli than in green cultivars and also higher than other purple broccolis grown under different climate conditions. Therefore, the results reported data for production of the EEP and EP varieties in the Mediterranean climate with potential to obtain vegetables with improved nutritional quality. PRACTICAL APPLICATION: The results of this study reported data of the health-promoting nutrients and natural antioxidants of EEP, EP, and LP purple sprouting broccoli varieties grown under the Mediterranean climate. The vitamin C, phenolic compounds, and glucosinolates in these purple varieties were higher than in traditionally grown green broccolis and other purple broccolis grown under different climate conditions. PMID- 22924737 TI - Prenatal diagnosis of X-linked chronic granulomatous disease by percutaneous umbilical blood sampling. AB - In this study, we investigated how to prenatally diagnose X-linked chronic granulomatous disease (X-CGD) effectively and accurately. Percutaneous umbilical blood sampling was conducted in the 22nd week of pregnancy. NADPH oxidase activity and gp91(phox) protein expression of neutrophils were analysed using flow cytometry. Direct sequencing was used to detect CYBB gene mutations. Umbilical blood was obtained from seven foetuses whose mothers were X-CGD carriers. Six foetuses, whose mothers needed prenatal diagnosis because of other diseases, were used as control. The neutrophils in all 13 foetuses showed lower hydrogen peroxide generation (stimulation index < 100) and gp91(phox) protein expression. Among the seven foetuses whose mothers were X-CGD carriers, four foetuses (Family 2, 4, 5 and 7) had CYBB gene mutations and showed very low hydrogen peroxide generation (stimulation index < 10) and no gp91(phox) expression. The other three foetuses (Family 1, 3 and 6) had no CYBB gene mutations and showed stimulation index of 20-50 and partial or normal gp91(phox) protein expression (no difference with controls). Two of the three mothers (Family 1 and 3) have delivered healthy infants with normal hydrogen peroxide generation and expression of gp91(phox) in neutrophils. Combined with direct sequencing, dihydrorhodamine oxidation analysis and gp91(phox) protein detection is an effective and accurate method for prenatal screening for X-CGD. PMID- 22924738 TI - Accuracy and reliability of fetal heart rate monitoring using maternal abdominal surface electrodes. AB - OBJECTIVE: Compare the accuracy and reliability of fetal heart rate identification from maternal abdominal fetal electrocardiogram signals (ECG) and Doppler ultrasound with a fetal scalp electrode. DESIGN: Prospective open method equivalence study. SETTING: Three urban teaching hospitals in the Northeast United States. SAMPLE: 75 women with normal pregnancies in labor at >37 weeks of gestation. METHODS: Three fetal heart rate detection methods were used simultaneously in 75 parturients. The fetal scalp electrode was the standard against which abdominal fetal ECG and ultrasound were judged. MAIN OUTCOME MEASURES: The positive percent agreement with the fetal scalp electrode indicated reliability. Bland-Altman analysis determined accuracy. The confusion rate indicated how frequently the devices tracked the maternal heart rate. RESULTS: Positive percent agreement was 81.7 and 73% for the abdominal fetal ECG and ultrasound, respectively (p = 0.002). The abdominal fetal ECG had a lower root mean square error than ultrasound (5.2 vs. 10.6 bpm, p < 0.001). The confusion rate for ultrasound was 20-fold higher than for abdominal ECG (8.9 vs. 0.4%, respectively, p < 0.001). CONCLUSION: Compared with the fetal scalp electrode, fetal heart rate detection using abdominal fetal ECG was more reliable and accurate than ultrasound, and abdominal fetal ECG was less likely than ultrasound to display the maternal heart rate in place of the fetal heart rate. PMID- 22924739 TI - Sustained remission of psoriasis vulgaris after allogeneic bone marrow transplantation. PMID- 22924740 TI - Two new sesquiterpene derivatives from Chinese eaglewood. AB - Two new sesquiterpene derivatives, (+)-8beta-hydroxy-longicamphenylone (1) and 11beta-hydroxy-13-isopropyl-dihydrodehydrocostus lactone (2), were isolated from Chinese eaglewood. Their structures were elucidated on the basis of spectroscopic analyses including HR-ESI-MS, (1)H and (13)C NMR, DEPT, (1)H-(1)H COSY, HSQC, HMBC, and NOE. The two compounds exhibited potent anti-depressant activity in vitro by inhibiting [(3)H]-5-HT reuptake in rat brain synaptosomes by 54.8% and 51.9%, respectively, at 10 MUM. PMID- 22924741 TI - betaig-h3 potentiates the profibrogenic effect of TGFbeta signaling on connective tissue progenitor cells through the negative regulation of master chondrogenic genes. AB - Tendons and cartilage are specialized forms of connective tissues originated from common progenitor cells. Initial stages of differentiation of these tissues are characterized by the formation of cell aggregates, which share many molecular markers. Once differentiated, these cells retain considerable plasticity, and chondral metaplasia of tendon and fibrous connective tissues and eventual ossification often accompany degenerative diseases in the adult musculoskeletal system. While this fact is of great relevance for regenerative medicine and aging biology, its molecular basis remains to be elucidated. Gene expression analysis in several physiological and experimental paradigms suggests that differentiation of tendon and cartilage is regulated by a balance in the expression of chondrogenic versus tenogenic genes in the connective tissue cell precursors. Transforming growth factor beta (TGFbeta) may function both as a profibrogenic or as a prochondrogenic factor for embryonic limb mesoderm and mesenchymal stem cell cultures, but mice that are null for TGFbeta 2 and 3 lack tendons. Here, we identify betaig-h3 as a factor downstream TGFbeta signaling regulated by Smad 2 and 3, which is highly expressed in the differentiating tendons and joint capsules. Furthermore, gain- and loss-of-function experiments using limb mesoderm micromass cultures show that betaig-h3 downregulates the expression of cartilage master genes, including Sox9, type II collagen, and Hif-1alpha. Positive regulation of Sox9 and type II Collagen observed in micromass cultures grown under hypoxic conditions is prevented by exogenous administration of betaIG-H3, and the antichondrogenic influence of betaIG-H3 is lost after Hif-1alpha silencing with shRNA. Collectively, our findings indicate that betaig-h3 promotes the fibrogenic influence of TGFbeta signaling, neutralizing the prochondrogenic influence of the hypoxic-inducible factor 1 activated by the hypoxic microenvironment characteristic of limb mesenchymal aggregates. PMID- 22924743 TI - Pyrene-functionalized nanoparticles: two independent sensors, the excimer and the monomer. AB - The high surface-to-volume ratio of nanoparticles has been used to obtain a high local concentration of pyrene units on their periphery, making the formation of both pyrene emissive species possible using amazingly small pyrene concentrations. The sensing properties of model pyrene-functionalized nanoparticles was investigated by using different nitroaromatic compounds [m nitroaniline and p-nitroaniline] and nitrobenzenes [nitrobenzene, p-nitrotoluene, 2,4-dinitrotoluene, and 2,6-dinitrotoluene]. The hybrid system acts as a dual fluorescence sensor, in which the decrease of the pyrene emission, induced by the quencher, is hardly reflected in the pyrene excimer emission. The encapsulation capacity of the NPs also plays a key role in their sensitivity to the analyte. PMID- 22924742 TI - Adolescent rearing conditions influence the relationship between initial anxiety like behavior and ethanol drinking in male Long Evans rats. AB - BACKGROUND: Rodent studies have demonstrated that adolescent social isolation results in many behavioral perturbations, including increases in anxiety-like behaviors. Socially isolated (SI) rats have also been shown to self-administer greater amounts ethanol (EtOH) in some, but not all, studies. Here, we tested whether juvenile social isolation increases EtOH drinking using an intermittent procedure that engenders relatively high intake in normally reared animals. We also compared the behavioral phenotype of rats reared under social isolation or group-housed conditions with adult rats housed under conditions commonly used in EtOH-drinking studies. METHODS: Male Long Evans rats were procured immediately postweaning and were group housed for 1 week. Subjects were then randomly divided into 2 groups: SI rats, housed individually for 6 weeks and group-housed (GH) rats (4/cage). A third group was procured as young adults and was housed individually upon arrival for 1 week (standard housing condition). Rats were then tested in a plus-maze and novelty assay, and then, all subjects were singly housed and EtOH drinking was assessed. RESULTS: SI rats displayed increased anxiety-like behaviors on the plus-maze, a greater locomotor response to a novel environment, and increased EtOH intake, relative to GH rats. Age-matched standard housed (STD) rats exhibited an anxiety-like behavioral profile on the plus-maze that was similar to SI, and not GH rats, and also drank EtOH at levels comparable with SI subjects. In addition, anxiety-like behavior on the plus-maze correlated with intermittent EtOH intake in SI and GH rats. CONCLUSIONS: These data further support the validity of the rodent juvenile social isolation model for studies directed at elucidating behavioral and neurobiological mechanisms linking anxiety and EtOH drinking. These findings further suggest that housing conditions commonly employed in rodent drinking studies may recapitulate the anxiety-like and EtOH-drinking phenotype engendered by a juvenile social isolation procedure. PMID- 22924745 TI - Recent advances in polymeric microspheres for parenteral drug delivery--part 2. AB - INTRODUCTION: Currently marketed microsphere products are manufactured with the use of organic solvents which have a negative impact on the environment and stability of biological molecules. With recent advances in fabrication technologies, solvent free methods have demonstrated potential for the preparation of microspheres. AREAS COVERED: New technical advances recently achieved in solvent based microsphere manufacturing processes have allowed for major improvement in product quality and properties. Novel solvent free fabrication methods combined with newly functionalized biodegradable polymers have been explored for their application in the preparation of microspheres containing biological molecules. EXPERT OPINION: Novel fabrication methods for microspheres have been recently reported but technical challenges and development risks remain high for scale up from bench to industrial commercialization. While the applications of microspheres for delivery of proteins, genes and vaccines have shown promise for clinical use, the approval of newly functionalized polymers as carriers may still face scrutiny on safety and biocompatibility, which can be key factors in securing the regulatory approval of the product. PMID- 22924744 TI - Synergistic interaction between PPAR ligands and salbutamol on human bronchial smooth muscle cell proliferation. AB - BACKGROUND AND PURPOSE: An important objective in asthma therapy is to prevent the accelerated growth of airway smooth muscle cells which leads to hyperplasia and bronchial hyperreactivity. We investigated the effect of combination of salbutamol and PPARgamma agonists on growth factor-stimulated human bronchial smooth muscle cell (BSMC) proliferation. EXPERIMENTAL APPROACH: Synergism was quantified by the combination index-isobologram method. Assays used here included analyses of growth inhibition, cell viability, DNA fragmentation, gene transcription, cell cycle and protein expression. KEY RESULTS: The PPARgamma gene was highly expressed in BSMC and the protein was identified in cell nuclei. Single-agent salbutamol or PPARgamma agonists prevented growth factor-induced human BSMC proliferation within a micromolar range of concentrations through their specific receptor subtypes. Sub-micromolar levels of combined salbutamol PPARgamma agonist inhibited growth by 50% at concentrations from ~2 to 12-fold lower than those required for each drug alone, without induction of apoptosis or necrosis. Combination treatments also promoted cell cycle arrest at the G1/S transition phase and inhibition of ERK phosphorylation. CONCLUSIONS AND IMPLICATIONS: The synergistic interaction between PPARgamma agonists and beta(2) adrenoceptor agonists on airway smooth muscle cell proliferation highlights the anti-remodelling potential of this combination in chronic lung diseases. PMID- 22924746 TI - Total syntheses of (+)-alopecuridine, (+)-sieboldine A, and (-)-lycojapodine A. AB - (+)-Alopecuridine, (+)-sieboldine A, and (-)-lycojapodine A, three structurally unique and related lycopodium alkaloids, have been synthesized in enantiomeric forms through an efficient strategy. The main synthetic approach for (+) alopecuridine features a semipinacol rearrangement of hydroxyl epoxide to construct the spiro 6,9-azacarbocycles with an all-carbon quaternary center and a late-stage SmI(2)-mediated intramolecular coupling to form the 5-membered ring. Subsequently, the biomimetic synthesis of (+)-sieboldine A and (-)-lycojapodine A was accomplished successfully through two different bioinspired oxidations after a wide search for the oxidation methods. As a result, (+)-sieboldine A was derived from (+)-alopecuridine through an N-oxidation/nitrone formation process and (-)-lycojapodine A through an interesting cyclic hemiketal formation/oxidative diol cleavage pathway. These results confirmed the biogenetic relationship among the three alkaloids. PMID- 22924747 TI - Proteomic analysis of S-nitrosylated proteins in potato plant. AB - Nitric oxide (NO) has various functions in physiological responses in plants, such as development, hormone signaling and defense. The mechanism of how NO regulates physiological responses has not been well understood. Protein S nitrosylation, a redox-related modification of cysteine thiol by NO, is known to be one of the important post-translational modifications to regulate activity and interactions of proteins. To elucidate NO function in plants, proteomic analysis of S-nitrosylated proteins in potato (Solanum tuberosum) was performed. Detection and functional analysis of internal S-nitrosylated proteins is technically demanding because of the instability and reversibility of the protein S nitrosylation. By using a modified biotin switch assay optimized for potato tissues, and nano liquid chromatography combined with mass spectrometry, approximately 80 S-nitrosylated candidate proteins were identified in S nitrosoglutathione-treated potato leaves and tuber extracts. Identified proteins included redox-related enzymes, defense-related proteins and metabolic enzymes. Some of identified proteins were synthesized in Escherichia coli, and S nitrosylation of recombinant proteins was confirmed in vitro. Dehydroascorbate reductase 1 (DHAR1, EC 1.8.5.1), one of the identified S-nitrosylated target proteins, showed glutathione-dependent dehydroascorbate-reducing activity. Either point mutation in a target cysteine of S-nitrosylation or treatment with an NO donor, S-nitroso-L-cysteine, significantly reduced the activity of DHAR1, indicating that DHAR1 is negatively regulated by S-nitrosylation of the cysteine residue essential for the enzymatic activity. These results show that the modified method developed in this study can be used to identify proteins regulated by S-nitrosylation in potato tissues. PMID- 22924748 TI - Brainstem auditory response findings in preterm infants after necrotizing enterocolitis. AB - AIM: To examine brainstem auditory function and detect any abnormality at term in preterm infants after neonatal necrotizing enterocolitis (NEC). METHODS: Brainstem auditory evoked response (BAER) was recorded at 21/sec and 60 dB nHL in 37 preterm infants who had NEC. The data obtained at term equivalent age were analyzed and compared with those in normal term infants. RESULTS: The threshold of BAER in infants after NEC, though slightly elevated, did not differ significantly from that in the controls. The latencies of waves I and III were slightly longer than in the controls, without any statistical significance. However, wave V latency was prolonged and differed significantly from the controls (p < 0.01). I-V interpeak interval was also prolonged (p < 0.05). The data point distribution of wave V latency and I-V interval was higher in the infants after NEC than in the controls. The amplitudes of BAER wave components in the infants after NEC did not differ significantly from those in the controls. CONCLUSION: Preterm infants after NEC have no major abnormality in peripheral auditory function. However, neural conduction in the brainstem auditory pathway is abnormal, suggesting that NEC adversely affects brainstem auditory conduction. PMID- 22924750 TI - Correcting the past: failures to replicate psi. AB - Across 7 experiments (N = 3,289), we replicate the procedure of Experiments 8 and 9 from Bem (2011), which had originally demonstrated retroactive facilitation of recall. We failed to replicate that finding. We further conduct a meta-analysis of all replication attempts of these experiments and find that the average effect size (d = 0.04) is no different from 0. We discuss some reasons for differences between the results in this article and those presented in Bem (2011). PMID- 22924751 TI - Direct carbo-acylation reactions of 2-arylpyridines with alpha-diketones via Pd catalyzed C-H activation and selective C(sp2)-C(sp2) cleavage. AB - An efficient carbo-acylation reaction of 2-arylpyridines with alpha-diketones via Pd-catalyzed C-H bond activation and C-C bond cleavage in the presence of TBHP was developed that generated aryl ketones in good yields. The highly selective formation of aryl ketones was observed when 2-arylpyridines reacted with aromatic/aliphatic alpha-diketones. PMID- 22924753 TI - Immune tolerance in haemophilia: the long journey to the fork in the road. AB - Antibody eradication is the ultimate goal of inhibitor management. The only clinically proven strategy for achieving antigen-specific tolerance to factor VIII is immune tolerance induction (ITI). Our knowledge about ITI in haemophilia A and B was, historically, derived from small cohort studies and retrospective national and international ITI registries. Practice is now further influenced by prospective cohort data, and the results of a single prospective randomized international ITI trial. However, due to the low incidence of inhibitors in haemophilia B, there are few comparable data from which to develop a useful evidence-based approach to the prevention and eradication of factor IX inhibitors. The lack of an effective strategy is particularly problematic given the morbidity associated with the unique occurrence of allergic and anaphylactic reactions that often herald factor IX antibody development and preclude effective eradication. This paper will discuss our current understanding of immune tolerance outcome and outcome predictors for haemophilia A and B; review the current consensus practice recommendations for ITI; and summarize the emerging body of immunological science relating to antibody formation and tolerance. It will conclude by suggesting how our knowledge might inform the future investigative priorities impacting the therapeutic and preventative tolerance strategies of tomorrow. PMID- 22924752 TI - Molecular determinants of A2AR-D2R allosterism: role of the intracellular loop 3 of the D2R. AB - In the CNS, an antagonistic interaction has been shown between adenosine A(2A) and dopamine D(2) receptors (A(2A)Rs and D(2)Rs) that may be relevant both in normal and pathological conditions (i.e., Parkinson's disease). Thus, the molecular determinants mediating this receptor-receptor interaction have recently been explored, as the fine tuning of this target (namely the A(2A)R/D(2)R oligomer) could possibly improve the treatment of certain CNS diseases. Here, we used a fluorescence resonance energy transfer-based approach to examine the allosteric modulation of the D(2)R within the A(2A)R/D(2)R oligomer and the dependence of this receptor-receptor interaction on two regions rich in positive charges on intracellular loop 3 of the D(2)R. Interestingly, we observed a negative allosteric effect of the D(2)R agonist quinpirole on A(2A)R ligand binding and activation. However, these allosteric effects were abolished upon mutation of specific arginine residues (217-222 and 267-269) on intracellular loop 3 of the D(2)R, thus demonstrating a major role of these positively charged residues in mediating the observed receptor-receptor interaction. Overall, these results provide structural insights to better understand the functioning of the A(2A)R/D(2)R oligomer in living cells. PMID- 22924754 TI - Idiopathic pure sudomotor failure and cholinergic urticaria in a patient after acute infectious mononucleosis infection. AB - Idiopathic pure sudomotor failure (IPSF) is a subgroup of acquired idiopathic generalized anhidrosis, which is characterized by early age of onset, acute or sudden onset, concomitant sharp pain or cholinergic urticaria over the entire body, absence of autonomic dysfunction other than generalized anhidrosis, raised serum IgE level, and marked response to steroid. The aetiology of IPSF is still not well understood, but is thought to be caused by interference in cholinergic transmission in the eccrine glands of skin. IPSF after viral infection has rarely been reported in the literature. We describe a patient who developed generalized anhidrosis and cholinergic urticaria accompanied by heat intolerance after infectious mononucleosis infection. This is the first such case, to our knowledge, and the patient was successfully treated with steroid pulse therapy. PMID- 22924755 TI - Same-day discharge after laparoscopic hysterectomy. AB - The benefits of laparoscopic hysterectomy are well documented and include less postoperative pain, shorter hospital stay and faster recovery. The objective of this study was to assess the feasibility of laparoscopic hysterectomy as an outpatient procedure. A total of 26 women regarded eligible for an accelerated approach were included. The mean duration of the operation was 40 min (range 23 60 min), with a blood loss of 50 mL (range 10-200 mL). Twenty-three left the hospital the same day (88%). One woman required overnight hospitalization because of a port hematoma, while two stayed for reasons unrelated to the surgery. Three other women were referred with minor problems to an urgent clinic appointment within the first month. Overall, the women were satisfied with the procedure, with a mean rating of 9 of 10 possible points. Thus, outpatient laparoscopic hysterectomy appeared to be safe and well accepted by selected patients. PMID- 22924756 TI - Whole mouth antimicrobial effects after oral hygiene: comparison of three dentifrice formulations. AB - AIMS: This study compared the antimicrobial effects of three commercial dentifrice formulations: sodium fluoride/triclosan/copolymer (TCN/C), stannous fluoride/sodium hexametaphosphate/zinc lactate (SnF(2)/SHMP) and sodium fluoride (NaF). MATERIALS AND METHODS: Thirty-five adults (15 men and 20 women; average age 33 years and pockets <5 mm) completed this double-blind, triple-crossover study. After washout, baseline samples from four sites, plaque, saliva, tongue and buccal mucosa, were collected and evaluated for six microbial types, anaerobes, Streptococci, Actinomyces, hydrogen-sulphide (H(2) S)-producing bacteria, Fusobacteria and Veillonella. A specific dentifrice was randomly assigned for twice-daily use for 13 days. On day 14, 12 h after brushing, samples were collected for microbiological evaluations. Alternate dentifrices followed this identical protocol. RESULTS: For all four oral sites and six organisms evaluated in each site, the TCN/C demonstrated significant reductions (49-83%) as compared with the other treatments (p < 0.01). The SnF(2)/SHMP group showed significant reductions of 14-43% for 14 of 24 outcomes as compared with the NaF group (p < 0.01), with no differences in 10 outcomes. CONCLUSIONS: The TCN/C dentifrice formulation consistently demonstrated significant reductions for a range of microorganisms in diverse oral sites in comparison with the NaF, or the SnF(2)/SHMP dentifrice formulations as seen 12 h after brushing. PMID- 22924758 TI - Balance and agility training does not always decrease lower limb injury risks: a cluster-randomised controlled trial. AB - The objective of this study was to examine the effects on lower limb injury rates of adding structured balance and agility exercises to the 80-day basic training programme of army recruits. A blocked (stratified), cluster-randomised controlled trial was employed, with one intervention group (IG) and one control group (CG), in which 732 male and 47 female army recruits from the Australian Army Recruit Training Centre participated through to analysis. The IG performed specified balance and agility exercises in addition to normal physical training. The incidence of lower limb injury during basic training was used to measure effect. Analysis, which adhered to recommendations for this type of trial, used a weighted paired t-test based on the empirical logistic transform of the crude event rates. The intervention had no statistically significant effect on lower limb injury incidence (RR = 1.25, 95% CI 0.97-1.53, 90% CI 1.04-1.47), on knee and ankle injury incidence (RR = 1.08, 95% CI 0.83-1.38), and on knee and ankle ligament injury incidence (RR = 0.98, 95% CI 0.64-1.47). We conclude that the intervention, implemented in this fashion, is possibly harmful, with our best estimate of effect being a 25% increase in lower limb injury incidence rates. This type of structured balance and agility training added to normal military recruit physical training did not significantly reduce lower limb, knee and ankle, or knee and ankle ligament injury rates. Caution needs to be used when adding elements to training programmes with the aim of reducing injury, as fatigue associated with the addition may actually raise injury risk. PMID- 22924757 TI - Structure-activity relationships in human Toll-like receptor 8-active 2,3-diamino furo[2,3-c]pyridines. AB - In our ongoing search toward identifying novel and synthetically simpler candidate vaccine adjuvants, we hypothesized that the imidazo[1,2-a]pyrazines, readily accessible via the Groebke-Blackburn-Bienayme multicomponent reaction, would possess sufficient structural similarity with TLR7/8-agonistic imidazoquinolines. With pyridoxal as the aldehyde component, furo[2,3 c]pyridines, rather than the expected imidazo[1,2-a]pyridines, were obtained, which were characterized by NMR spectroscopy and crystallography. Several analogues were found to activate TLR8-dependent NF-kappaB signaling. In a focused library of furo[2,3-c]pyridines, a distinct SAR was observed with varying substituents at C2. In human PBMCs, none of the furo[2,3-c]pyridines showed any proinflammatory cytokine induction but upregulated several chemokine ligand genes. In immunization studies in rabbits, the most active compound showed prominent adjuvantic effects. The complete lack of proinflammatory cytokine induction coupled with strong adjuvantic activity of the novel furo[2,3 c]pyridines render this hitherto unknown chemotype an attractive class of compounds which are expected to be devoid of local or systemic reactogenicity. PMID- 22924759 TI - Analysis of phenolic composition of Noble muscadine (Vitis rotundifolia) by HPLC MS and the relationship to its antioxidant capacity. AB - Phenolic compounds and anthocyanins in muscadines have attracted much attention due to their diverse biological activities. With bioassays of antioxidant activities in terms of total phenolic content (TPC), total anthocyanin content (TAC), total procyanidin content (TPA), oxygen radical absorbance capacity (ORAC), and ferric reducing antioxidant power (FRAP) of different parts of the Noble muscadine, the butanol (BuOH) extract of the muscadine skin showed the highest TPC (317.91 +/- 1.83 mg GAE/100 g FW), which might be ascribed to its high TAC of 227.06 +/- 1.29 mg/100 g fresh weight (FW). The ethyl acetate (EtOAc) extract of the muscadine seed contained the highest TPA (55.30 +/- 0.63 mg CE/100 g FW). Correlation analyses demonstrated a significant linear relationship of TPC and TAC compared to their ORAC and FRAP values within the range of R(2) from 0.9283 to 0.9936, which suggested that phenolics and anthocyanins in the extracts contributed significantly to their antioxidant potential. Nineteen individual phenolics and 5 anthocyanins were identified by HPLC-MS, which indicated different chemical profiles of anthocyanins and other phenolics in the muscadine extracts. PRACTICAL APPLICATION: The paper has provided rich information of bioactive phytochemical profiles in different solvent extracts and their correlation with the antioxidant activity in the muscadine that is a very special regional fruit in U.S. Its high content of phenolic compounds demonstrates that muscadine could be beneficial to human health. PMID- 22924760 TI - Template-assisted assembly of the functionalized cubic and spherical microparticles. AB - The patterned template-assisted assembly of the cubic microparticles driven by the competing capillary, Columbic, and van der Waals forces had been studied in comparison with the traditional spherical colloidal microparticles. We observed that the spherical and cubic microparticles assembled with different probability in the channels of the hydrophobic-hydrophilic patterned substrates due to differences in a balance of adhesive and capillary forces. In contrast to highly selective assembly of spherical microparticles, selective deposition of cubic microcrystals with channels is impeded by strong adhesive forces facilitated by large specific interfacial areas between cube facets and substrate. The modification of the patterned substrate by functionalized coatings with oppositely charged topmost layers significantly increases the probability (to 86%) of the cubic microparticles to assemble into chemically modified channels. The introduction of ultrathin LbL shells on cubic microparticles and functionalization of patterned substrates are critical for the directed colloidal assembly of anisotropic microparticles into ordered aggregates. PMID- 22924761 TI - Changes in traditional chronic disease risk factors over time and their relationship with leisure-time physical activity in people living with spinal cord injury. AB - This study examined whether levels of chronic disease risk factors change over time, and whether leisure-time physical activity (LTPA) can explain any of the variation in those risk factors that change, in a sample of community-dwelling people living with spinal cord injury (SCI) in or near Hamilton, Ontario, Canada. LTPA was measured using the Physical Activity Recall Assessment for People with SCI at baseline (n = 76 adults with chronic (>=1 year) paraplegia or tetraplegia), at 6 months (n = 71) and at 18 months (n = 63). Body mass index, waist circumference at the lowest rib (WC(lowest rib)) and iliac crest (WC(iliac crest)), fat mass, blood pressure, and biochemical data were collected at all 3 time points. Women's BMI was higher at baseline (least square means (LSM) = 26.2 +/- SE = 1.56 kg.m(-2), p = 0.0004) and 6 months (25.9 +/- 1.6, p = 0.0024) than at 18 months (22.1 +/- 1.72). Men's WC(lowest rib) increased from baseline (92.1 +/- 1.87 cm) to 18 months (93.6 +/- 1.87, p = 0.0253). Women who were active vs. inactive at baseline had a lower BMI at 6 months (23.1 +/- 2.91 vs. 29.7 +/- 2.52, p = 0.0957) and WC(iliac crest) at 6 months (82.8 +/- 6.59 vs. 97.7 +/- 5.10, p = 0.0818). Women who were active vs. inactive at 6 months had a lower WC(iliac crest) at 18 months (73.4 +/- 14.3 vs. 102.5 +/- 6.41, p = 0.0723). There was little change in traditional risk factors over 18 months. Future studies should extend beyond 18 months in a larger sample, and explore traditional vs. novel risk factors and onset of cardiovascular disease and diabetes in the SCI population. PMID- 22924762 TI - Experimental and clinical evidence for use of decellularized nerve allografts in peripheral nerve gap reconstruction. AB - Despite the inherent capability for axonal regeneration, recovery following severe peripheral nerve injury remains unpredictable and often very poor. Surgeons typically use autologous nerve grafts taken from the patient's own body to bridge long nerve gaps. However, the amount of suitable nerve available from a given patient is limited, and using autologous grafts leaves the patient with scars, numbness, and other forms of donor-site morbidity. Therefore, surgeons and engineers have sought off-the-shelf alternatives to the current practice of autologous nerve grafting. Decellularized nerve allografts have recently become available as an alternative to traditional nerve autografting. In this review, we provide a critical analysis comparing the advantages and limitations of the three major experimental models of decellularized nerve allografts: cold preserved, freeze-thawed, and chemical detergent based. Current tissue engineering-based techniques to optimize decellularized nerve allografts are discussed. We also evaluate studies that supplement decellularized nerve grafts with exogenous factors such as Schwann cells, stem cells, and growth factors to both support and enhance axonal regeneration through the decellularized allografts. In examining the advantages and disadvantages of the studies of decellularized allografts, we suggest that experimental methods, including the animal model, graft length, follow-up time, and outcome measures of regenerative progress and success be consolidated. Finally, all clinical studies in which decellularized nerve allografts have been used to bridge nerve gaps in patients are reviewed. PMID- 22924763 TI - Two new naphthalene derivatives from an endolichenic fungal strain Scopulariopsis sp. AB - Chemical investigation on an endolichenic fungal strain Scopulariopsis sp. led to the isolation of two new naphthalene derivatives, 1-(4'-hydroxy-3',5'-dimethoxy phenyl)-1,8-dimethoxynaphthalen-2(1H)-one (1) and 1,8-dimethoxynaphthalen-2-ol (2). Their structures were determined by spectroscopic techniques (UV, IR, MS, 1D, and 2D NMR). PMID- 22924765 TI - Sensitive refractive index detection using a broad-band optical ring resonator. AB - Broad-band operation is investigated as an alternative means of refractive index detection in an optical ring resonator. In this work, a liquid-core (LCORR, capillary-based) design is used. Optical ring resonators have been recently demonstrated for the detection of a wide variety of analytes, including DNA, viruses, proteins, chemical vapors, and pesticides. In the field of analytical chemistry, much of their value is in the ability to provide enhanced detection of surface analytes in small volumes. Conventional analysis methods that employ a single resonant wavelength and propagation mode are highly dependent on resonator quality. By utilizing the complex and variable response of a multiple-mode resonator and the simultaneous data of more than 40 resonance peaks, impressive results exceeding the single-mode prediction are produced from a very modest quality device. The presented methods also become attractive through the use of inexpensive LED light sources and common UV-vis spectrometers, as well as the ability to also take absorbance measurements without any physical configuration changes. Complex interference spectra are produced from the convolution of multiple wavelengths and modes. Two possible methods for analyzing this type of data are presented-one using Fourier transform deconvolution to extract resonance components from interference spectra, and another using chemometrics by constructing a partial least-squares model. Using isopropyl alcohol and water mixtures, detection limits are the order of 10(-6) RIU (refractive index units), comparable to existing ring resonators devices. To study surface detectability and biomolecule detection feasibility, surface adsorption of bovine serum albumin (BSA) is also analyzed. PMID- 22924764 TI - Array-based profiling of DNA methylation changes associated with alcohol dependence. AB - BACKGROUND: Epigenetic regulation through DNA methylation may influence vulnerability to numerous disorders, including alcohol dependence (AD). METHODS: Peripheral blood DNA methylation levels of 384 CpGs in the promoter regions of 82 candidate genes were examined in 285 African Americans (AAs; 141 AD cases and 144 controls) and 249 European Americans (EAs; 144 AD cases and 105 controls) using Illumina GoldenGate Methylation Array assays. Association of AD and DNA methylation changes was analyzed using multivariate analyses of covariance with frequency of intoxication, sex, age, and ancestry proportion as covariates. CpGs showing significant methylation alterations in AD cases were further examined in a replication sample (49 EA cases and 32 EA controls) using Sequenom's MassARRAY EpiTYPER technology. RESULTS: In AAs, 2 CpGs in 2 genes (GABRB3 and POMC) were hypermethylated in AD cases compared with controls (p <= 0.001). In EAs, 6 CpGs in 6 genes (HTR3A, NCAM1, DRD4, MBD3, HTR2B, and GRIN1) were hypermethylated in AD cases compared with controls (p <= 0.001); CpG cg08989585 in the HTR3A promoter region showed a significantly higher methylation level in EA cases than in EA controls after Bonferroni correction (p = 0.00007). Additionally, methylation levels of 6 CpGs (including cg08989585) in the HTR3A promoter region were analyzed in the replication sample. Although the 6 HTR3A promoter CpGs did not show significant methylation differences between EA cases and EA controls (p = 0.067 to 0.877), the methylation level of CpG cg08989585 was nonsignificantly higher in EA cases (26.9%) than in EA controls (18.6%; p = 0.139). CONCLUSIONS: The findings from this study suggest that DNA methylation profile appears to be associated with AD in a population-specific way and the predisposition to AD may result from a complex interplay of genetic variation and epigenetic modifications. PMID- 22924766 TI - DDQ-supported alkoxylation of 2-aza-21-carbaporphyrin and noncatalyzed transetherification of its 3,21-dialkoxy derivatives. AB - An oxidative addition of primary alkoxyls into two sites of N-confused porphyrin (NCP) has been accomplished by means of alcohols in the presence of a stoichiometric amount of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ). The resulting aromatic monocationic species 1-R(3) (R = Me, Et) were characterized by the NMR and, in the case of triethoxy-NCP, by monocrystal X-ray diffraction analysis. One alkoxy group is located in position 3, on the macrocycle's perimeter, while two -OR moieties are attached to the internal carbon (position 21) of the confused pyrrole. The 3-EtO-21-Cl-NCP 2, which is formed as a byproduct, was also structurally characterized by means of X-ray diffraction. Reduction of 3-RO-21-(RO)(2)-NCP with hydrazine hydrate gave selectively a neutral and intrinsically chiral 3,21-bis(alkoxy)NCP 3-R(2). Dealkylation of the externally bonded 3-OR fragment under basic conditions leading to a zwitterionic aromatic 3-oxo-species 4-R(2), which still possesses the internal ketal functionality, was established by the NMR and X-ray diffraction methods. An unprecedented transetherification for the internal alkoxyl of 3-R(2) can be achieved under very mild conditions and without catalyst. One of the alkoxyl exchange products, i.e., 3-ethoxy-21-methoxy-NCP, was characterized by the X-ray diffraction method. The substitution proceeds via an associative (S(N)2) mechanism resulting in an inversion of the chirality of 3-RR', which was shown by means of the NMR and chirooptical methods. PMID- 22924767 TI - Structure-activity relationship of a broad-spectrum insect odorant receptor agonist. AB - Agonism of insect odorant receptor (OR) cation channels may represent a new strategy for the manipulation of destructive insect olfactory-driven behaviors. We have explored the chemical space around VUAA1, the first in class agonist of the obligate OR co-receptor ion channel (Orco), and describe novel compound analogues with increased potency across insect taxa. Functional analyses reveal several of these VUAA1 structural analogues display significantly greater potency as compared to the activity of the previously described active compounds in mobility-based behavioral assays on mosquito larvae. PMID- 22924769 TI - Evaluation of in vivo behavior of controlled and pulsatile release pastilles using pharmacokinetic and gamma-scintigraphic techniques. AB - OBJECTIVE: To evaluate the in vivo behavior of controlled and pulsatile release pastilles for chronic treatment of asthma and chronic obstructive pulmonary disease (COPD) and for the chronotherapeutic management of nocturnal asthma, respectively. RESEARCH DESIGN & METHODS: The prepared immediate release and controlled release pastilles were subjected to in vivo pharmacokinetic studies in rats. Whereas, pulsatile release formulation was subjected to gamma-scintigraphic study in rats to study the gastrointestinal transit of the formulations and its results were correlated with the previous pharmacokinetic data. RESULTS: The in vivo pharmacokinetic study of controlled release pastille formulation showed significant decrease in C(max) with increase in t(max), which indicates that the effect of dosage form would last for longer duration. Thus, the prepared formulation can be useful for the chronic treatment of asthma and COPD. The gamma scintigraphic study and pharmacokinetic data indicated that the pastilles coated with the enteric coat and the additional floating coat were effective in significantly delaying the in vivo drug release (by 4-5 h) required for the chronotherapeutic treatment of nocturnal asthma. CONCLUSION: This study opens a new alternative to the conventional tablet or capsule dosage form for the development of both immediate and modified release drug delivery systems. PMID- 22924770 TI - Exploring the conceptual universe. AB - Humans can learn to organize many kinds of domains into categories, including real-world domains such as kinsfolk and synthetic domains such as sets of geometric figures that vary along several dimensions. Psychologists have studied many individual domains in detail, but there have been few attempts to characterize or explore the full space of possibilities. This article provides a formal characterization that takes objects, features, and relations as primitives and specifies conceptual domains by combining these primitives in different ways. Explaining how humans are able to learn concepts within all of these domains is a challenge for computational models, but I argue that this challenge can be met by models that rely on a compositional representation language such as predicate logic. The article presents such a model and demonstrates that it accounts well for human concept learning across 11 different domains. PMID- 22924768 TI - NF-kappaB-dependent IL-8 induction by prostaglandin E(2) receptors EP(1) and EP(4). AB - BACKGROUND AND PURPOSE: Recent studies suggested a role for PGE(2) in the expression of the chemokine IL-8. PGE(2) signals via four different GPCRs, EP(1) -EP(4) . The role of EP(1) and EP(4) receptors for IL-8 induction was studied in HEK293 cells, overexpressing EP(1) (HEK-EP(1) ), EP(4) (HEK-EP(4) ) or both receptors (HEK-EP(1) + EP(4) ). EXPERIMENTAL APPROACH: IL-8 mRNA and protein induction and IL-8 promoter and NF-kappaB activation were assessed in EP expressing HEK cells. KEY RESULTS: In HEK-EP(1) and HEK-EP(1) + EP(4) but not HEK or HEK-EP(4) cells, PGE(2) activated the IL-8 promoter and induced IL-8 mRNA and protein synthesis. Stimulation of HEK-EP(1) + EP(4) cells with an EP(1) -specific agonist activated IL-8 promoter and induced IL-8 mRNA and protein, whereas a specific EP(4) agonist neither activated the IL-8 promoter nor induced IL-8 mRNA and protein synthesis. Simultaneous stimulation of HEK- EP(1) + EP(4) cells with both agonists activated IL-8 promoter and induced IL-8 mRNA to the same extent as PGE(2) . In HEK-EP(1) + EP(4) cells, PGE(2) mediated IL-8 promoter activation and IL-8 mRNA induction were blunted by inhibition of IkappaB kinase. PGE(2) activated NF-kappaB in HEK-EP(1) , HEK EP(4) and HEK-EP(1) + EP(4) cells. In HEK-EP(1) + EP(4) cells, simultaneous activation of both receptors was needed for maximal PGE(2) -induced NF-kappaB activation. PGE(2) -stimulated NF-kappaB activation by EP(1) was blocked by inhibitors of PLC, calcium-signalling and Src-kinase, whereas that induced by EP(4) was only blunted by Src-kinase inhibition. CONCLUSIONS AND IMPLICATIONS: These findings suggest that PGE(2) -mediated NF-kappaB activation by simultaneous stimulation of EP(1) and EP(4) receptors induces maximal IL-8 promoter activation and IL-8 mRNA and protein induction. PMID- 22924772 TI - Lignification of cell walls of infected cells in Casuarina glauca nodules that depend on symplastic sugar supply is accompanied by reduction of plasmodesmata number and narrowing of plasmodesmata. AB - The oxygen protection system for the bacterial nitrogen-fixing enzyme complex nitrogenase in actinorhizal nodules of Casuarina glauca resembles that of legume nodules: infected cells contain large amounts of the oxygen-binding protein hemoglobin and are surrounded by an oxygen diffusion barrier. However, while in legume nodules infected cells are located in the central tissue, actinorhizal nodules are composed of modified lateral roots with infected cells in the expanded cortex. Since an oxygen diffusion barrier around the entire cortex would also block oxygen access to the central vascular system where it is required to provide energy for transport processes, here each individual infected cell is surrounded with an oxygen diffusion barrier. In order to assess the effect of these oxygen diffusion barriers on oxygen supply for energy production for transport processes, apoplastic and symplastic sugar transport pathways in C. glauca nodules were examined. The results support the idea that sugar transport to and within the nodule cortex relies to a large extent on the less energy demanding symplastic mechanism. This is in line with the assumption that oxygen access to the nodule vascular system is substantially restricted. In spite of this dependence on symplastic transport processes to supply sugars to infected cells, plasmodesmal connections between infected cells, and to a lesser degree with uninfected cells, were reduced during the differentiation of infected cells. PMID- 22924771 TI - Using CRANID to test the population affinity of known crania. AB - CRANID is a statistical program used to infer the source population of a cranium of unknown origin by comparing its cranial dimensions with a worldwide craniometric database. It has great potential for estimating ancestry in archaeological, forensic and repatriation cases. In this paper we test the validity of CRANID in classifying crania of known geographic origin. Twenty-three crania of known geographic origin but unknown sex were selected from the osteological collections of the University of Melbourne. Only 18 crania showed good statistical match with the CRANID database. Without considering accuracy of sex allocation, 11 crania were accurately classified into major geographic regions and nine were correctly classified to geographically closest available reference populations. Four of the five crania with poor statistical match were nonetheless correctly allocated to major geographical regions, although none was accurately assigned to geographically closest reference samples. We conclude that if sex allocations are overlooked, CRANID can accurately assign 39% of specimens to geographically closest matching reference samples and 48% to major geographic regions. Better source population representation may improve goodness of fit, but known sex-differentiated samples are needed to further test the utility of CRANID. PMID- 22924773 TI - Synthesis and structure of two new mycolactones isolated from M. ulcerans subsp. shinshuense. AB - Two new mycolactones, mycolactones S1 and S2, were isolated from culture agar of Mycobacterium ulcerans subsp. shinshuense. Their structures were established in a three-step procedure: (1) probable structures were speculated from MS analysis; (2) candidates were synthesized; (3) HPLC profiles were established for identification of the natural products. Newly isolated mycolactones correspond to the "oxidized forms" of mycolactone A/B, the causative toxin of Buruli ulcer, isolated from Mycobacterium ulcerans. PMID- 22924774 TI - Lung ultrasound for paediatric pneumonia diagnosis: internationally officialized in a near future? PMID- 22924775 TI - Safety and efficacy analysis of liposomal insulin-like growth factor-1 in a fluid gel formulation for hair-loss treatment in a hamster model. AB - Insulin-like growth factor (IGF)-1 has shown some interesting results in studies examining its use as a hair-loss treatment. IGF-1 works by regulating cellular proliferation and migration during the development of hair follicles. Hepatotoxicity and myelotoxicity were evaluated in hamsters (Mesocricetus auratus) after topical application of the liquid gel vehicle (placebo), 1% IGF-1 or 3% IGF-1. No significant difference in the levels of aspartate aminotransferase or alanine aminotransferase was found between the control and treated groups. ELISA did not shown any increase in the plasma level of IGF-1. A haematopoietic niche was found, but it was not associated with myelotoxicity. Efficacy was determined by dermatoscopy analysis of hair density and microscopy analysis of hair diameter, with hair found to be thicker and with more rapid growth in the 3% group than in either the 1% group or the control group. These results strongly suggest that liposomal IGF-1 in a liquid gel formulation is a safe and efficient treatment for hair loss. PMID- 22924776 TI - Correlation between salivary anti-HCV antibodies and HCV RNA in saliva and salivary glands of patients with chronic hepatitis C. AB - BACKGROUND: To investigate the correlation between anti-hepatitis C virus (HCV) antibodies in saliva and detection of HCV RNA in saliva and salivary glands of patients with chronic hepatitis C. METHODS: A total of 180 samples of saliva (131 non-stimulated and 49 stimulated) from 133 patients with chronic hepatitis C were tested by ELISA for presence of anti-HCV antibodies. Results were compared with the detection of HCV RNA in saliva and salivary glands samples. Pearson's chi squared and Fisher's exact tests were performed for statistical analysis. RESULTS: Anti-HCV antibodies could be detected in 47/180 (26.1%) saliva samples. In 11/47 (23.5%) of these, HCV RNA was also detected. From the 133/180 (73.9%) saliva samples with undetectable anti-HCV antibodies, 49/133 (36.8%) were positive for HCV RNA at least in one saliva sample. From the 64 patients from whom salivary gland samples were available, 17/64 (26.6%) had detectable anti-HCV antibodies in saliva, from which 2/17 (11.8%) also had HCV RNA in the salivary gland. From the 47/64 (73.4%) cases negative for anti-HCV antibodies in saliva, 10/47 (21.3%) were positive for HCV RNA in salivary gland. CONCLUSIONS: Taken together, our results suggest that there is no correlation between the presence of anti-HCV antibodies in saliva and the detection of HCV RNA in saliva and salivary glands in patients with chronic hepatitis C. Nevertheless, as there was a statistically significant difference between detection of anti-HCV antibodies and HCV RNA in stimulated saliva, our study points toward the need for new research on mechanisms of HCV shedding in saliva. PMID- 22924777 TI - DNA methylation analysis of ALOX12 and GSTM1 in acute myeloid leukaemia identifies prognostically significant groups. AB - To determine the role of DNA methylation in the progression of acute myeloid leukaemia (AML), we analysed the methylation status of ALOX12, GSTM1, HS3ST2 and FZD9 in 127 AML patients. Aberrant methylation of ALOX12 was associated with the subcategory AML with myelodysplasia-related changes (P = 0.0439) and specifically with megakaryocytic dysplasia (P = 0.0003). An association between HS3ST2 and AML patients with favourable cytogenetic risk was identified (P = 0.0469). In univariate and multivariate analysis, methylation of GSTM1 was associated with worse overall survival (OS) and disease-free survival (DFS), with hazard ratios of 2.57 and 1.86, respectively. Furthermore, the significance of methylation of GSTM1 in predicting poor prognosis was maintained within the subcategories of AML not otherwise specified (NOS), AML with intermediate cytogenetic risk and normal karyotype AML. Finally, patients with both GSTM1 and ALOX12 methylated, demonstrated worse outcomes when all AML patients were assessed (OS; P = 0.000411) as well as within AML NOS (DFS; P = 0.0023), AML with intermediate cytogenetic risk (OS; P = 0.0104) and normal karyotype AML (OS; P = 0.00636). This study implicates methylation of specific genes in the classification and prognostication of AML and suggests that the morphological feature of multilineage dysplasia may be a surrogate marker of gene methylation in at least a subset of AML cases. PMID- 22924778 TI - LTBP2 gene analysis in the GLC3C-linked family and 94 CYP1B1-negative cases with primary congenital glaucoma. AB - PURPOSE: Primary congenital glaucoma (isolated trabeculodysgensis, PCG) generally presents between birth and 3 years of age. Recently, mutations in Latent Transforming Growth Factor (TGF)-beta Binding Protein 2 (LTBP2) have been reported in several families that were diagnosed with PCG, who actually had a more complex ocular phenotype with ectopia lentis and Marfanoid features. We screened this gene for mutations in the original Turkish GLC3C-linked PCG family and in a group of CYP1B1-negative British PCG cases and their matched normal control subjects. METHODS: The 36-coding exons of the LTBP2 gene were sequenced in 94 familial or sporadic CYP1B1-negative PCG cases and 96 matched normal control subjects. RESULTS: No disease-causing mutations were identified in the original GLC3C-linked family. Screening of LTBP2 in 94 PCG and 96 control subjects identified three novel synonymous variations (L429L, P680P, S1031S) in 12 PCG and seven control subjects. A novel heterozygous missense mutation (R538W) was also identified in 1 of 90 PCG cases that is unlikely to be disease causative. CONCLUSIONS: LTBP2 mutations were not found in the Turkish GLC3C linked PCG family or in 94 British CYP1B1-negative PCG cases. Our data suggest that LTBP2 mutations are not a significant cause for isolated trabeculodysgenesis. PMID- 22924779 TI - Histopathologic changes in the extraocular muscle in centronuclear myopathy with a Dynamin 2 mutation. AB - BACKGROUND: Centronuclear myopathy (CNM) is a rare inherited neuromuscular disorder characterized by centrally placed nuclei in striated muscle. In this report, we describe the histological changes in the extraocular muscle (EOM) from a CNM patient with a mutation in Dynamic 2 (DNM2). MATERIALS AND METHODS: A 33 year-old Caucasian female presented with horizontal diplopia and left exotropia for 6 months prior to which she was asymptomatic. Her past medical history was significant for CNM, diagnosed based on a left quadriceps biopsy with onset of lower extremity weakness in her late 20s. She underwent a left medial rectus (LMR) resection and a left lateral rectus (LLR) recession. The resected muscle was analyzed using light and electron microscopy. Screening for mutations in the DNM2 gene was carried out and the detected mutation was confirmed by direct sequencing. Expression of the DNM2 protein was performed using immunohistochemistry (IHC). RESULTS: Pathology of the EOM revealed 17% centrally located muscle nuclei in contrast to 90% in the quadriceps, variable fiber size, normal ultrastructure of the EOM and normal distribution of DNM2 by IHC. Genetic analysis revealed a heterozygous R369W mutation in the DNM2 gene. CONCLUSION: The histological changes in the EOM in this CNM patient were mild, which reflected the mild alterations in function seen in this patient. The ophthalmologist seeing patients with new onset strabismus and a history of a myopathy should consider this entity in the differential diagnosis that could be confirmed by a muscle biopsy and mutational analysis. PMID- 22924780 TI - Ocular manifestations of the autoinflammatory syndromes. AB - The autoinflammatory syndromes are rare inherited disorders characterized by recurrent attacks of multi-system inflammation caused by genetic mutations that result in abnormal upregulation of key innate immune mediators. The term autoinflammatory syndromes includes a broad variety of disorders, including cryopyrin-associated periodic syndromes (CAPS) such as neonatal onset multisystem inflammatory disease (NOMID), familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), periodic fever syndromes, including familial Mediterranean fever (FMF), TNF receptor-1 associated periodic syndrome (TRAPS), and Blau syndrome. Ocular manifestations are frequent and diverse in affected patients, and visual impairment and blindness are not uncommon sequelae of chronic active disease. Novel therapeutic interventions targeting specific pathophysiologic mechanisms have been extremely promising in the treatment of these disorders. The purpose of this article is to provide a review of these disorders with a focus on pathogenesis, clinical manifestations, ophthalmologic involvement, and available treatment options. PMID- 22924782 TI - Buoyant droplets on functional fibers. AB - In the absence of gravity, the wetting of droplets on fibers is characterized by the competition between an axisymmetric barrel morphology engulfing the fiber and a symmetry-broken clamshell morphology with the droplet sitting on the side of the fiber. In the generic case of nonzero buoyancy the cylindrical symmetry of the barrel morphology is broken, yet barrels and clamshells can still be distinguished based on their different interfacial topologies being multiply and simply connected, respectively. Next to contact angle and droplet size the capillary length appears as a third parameter controlling the droplet morphology. For droplets of variable size, contact angle and buoyancy are independently varied in experiments by use of electrowetting and density mismatch. This approach--together with the complementary numerical calculations--provides new insights into the gradual shifts of the stability limits in the presence of an external volume force. Overall, the parameter space for stable clamshells is found to expand with increasing gravitational forces, gradually shrinking the regimes of stable barrels and bistability. In addition, a new stability limit is introduced for the clamshell morphology related to a partial detachment of the wetting liquid from the fiber, appearing toward higher droplet volumes. PMID- 22924783 TI - The clinical picture of juvenile parotitis in a prospective setup. AB - AIM: To characterize the features of juvenile parotitis in a prospective setup and epidemiology. METHODS: All children with parotitis admitted to Helsinki University Central Hospital 2005-2010 were recruited. Clinical characteristics, given treatment, outcome, blood leukocyte count, C-reactive protein, serum amylase and trypsinogen, SPINK-1 genotype and mumps antibodies were recorded. To map the epidemiology, a questionnaire was sent to 1000 randomly selected 13-year old children. RESULTS: The prospective study included 41 children (aged <= 17) with acute parotitis, all in good general condition. Serum amylase, but not trypsinogen, was elevated in majority of the cases (79%) and C-reactive protein in 68%. Eleven (27%) children had an elevated blood leukocyte count. None had acute mumps. Most children recovered well, 51% being treated symptomatically only. Seven children were treated on ward. Seventeen (46%) children had recurrent symptoms. One child (2.4%) had SPINK P55S mutation. According to the epidemiological questionnaire, 1.1% of the respondents (8/728, response rate 73%) reported a verified episode(s) of parotitis. CONCLUSION: Juvenile parotitis has a frequency close to 1%. In the majority, the general condition is good during the episode. Serum amylase serves as an additional marker for the disease. Parotitis has a tendency to recur in almost half of the cases. PMID- 22924784 TI - In situ generation of surface plasmon polaritons using a near-infrared laser diode. AB - We demonstrate a semiconductor laser-based approach which enables plasmonic active devices in the telecom wavelength range. We show that optimized laser structures based on tensile-strained InGaAlAs quantum wells-coupled to integrated metallic patternings-enable surface plasmon generation in an electrically driven compact device. Experimental evidence of surface plasmon generation is obtained with the slit-doublet experiment in the near-field, using near-field scanning optical microscopy measurements. PMID- 22924786 TI - Editorial Comment from Dr Stone to interpreting a rising prostate-specific antigen after brachytherapy for prostate cancer. PMID- 22924785 TI - Synthesis and structure-activity relationship investigation of adenosine containing inhibitors of histone methyltransferase DOT1L. AB - Histone3-lysine79 (H3K79) methyltransferase DOT1L has been found to be a drug target for acute leukemia with MLL (mixed lineage leukemia) gene translocations. A total of 55 adenosine-containing compounds were designed and synthesized, among which several potent DOT1L inhibitors were identified with K(i) values as low as 0.5 nM. These compounds also show high selectivity (>4500-fold) over three other histone methyltransferases. Structure-activity relationships (SAR) of these compounds for their inhibitory activities against DOT1L are discussed. Potent DOT1L inhibitors exhibit selective activity against the proliferation of MLL translocated leukemia cell lines MV4;11 and THP1 with EC(50) values of 4-11 MUM. Isothermal titration calorimetry studies showed that two representative inhibitors bind with a high affinity to the DOT1L:nucleosome complex and only compete with the enzyme cofactor SAM (S-adenosyl-L-methionine) but not the substrate nucleosome. PMID- 22924787 TI - Women with acute intermittent porphyria have a defect in 5alpha-steroid production during the menstrual cycle. AB - OBJECTIVE: To measure serum concentrations of progesterone, estradiol and 5alpha- and 5beta-reduced progesterone metabolites in the follicular and luteal phases of the menstrual cycle in women with latent acute intermittent porphyria and manifest acute intermittent porphyria in comparison with healthy control women. DESIGN: A descriptive study with repeated measurements during a complete, ovulatory menstrual cycle. SETTING: University hospital out-patient clinic. POPULATION: Thirty-two women with DNA-diagnosed acute intermittent porphyria and 20 healthy control women. METHODS: Blood samples for serum progesterone, estradiol, allopregnanolone and pregnanolone were drawn on predefined menstrual cycle days, twice in the follicular phase and three times in the luteal phase. Serum levels of estradiol and progesterone were analysed with commercial kits. Allopregnanolone and pregnanolone levels were analysed with radioimmunoassay following diethylether extraction and celite column chromatography. MAIN OUTCOME MEASURES: Changes in serum levels of progesterone, estradiol, allopregnanolone and pregnanolone throughout the menstrual cycle. RESULTS: Women with acute intermittent porphyria displayed lower serum concentrations of allopregnanolone in comparison with healthy control women, the difference being most prominent in the luteal phase (p < 0.001). Levels of pregnanolone did not differ significantly between groups. No significant difference was found between women with latent acute intermittent porphyria and manifest acute intermittent porphyria. CONCLUSIONS: Decreased levels of the 5alpha-reduced progesterone metabolite allopregnanolone were found in the menstrual cycle of women with acute intermittent porphyria. This has not been reported previously and could indicate a reduced 5alpha-reductase type 1 capacity in the ovary and liver among these women. PMID- 22924788 TI - Rejection thresholds in solid chocolate-flavored compound coating. AB - Classical detection thresholds do not predict liking, as they focus on the presence or absence of a sensation. Recently however, Prescott and colleagues described a new method, the rejection threshold, where a series of forced choice preference tasks are used to generate a dose-response function to determine hedonically acceptable concentrations. That is, how much is too much? To date, this approach has been used exclusively in liquid foods. Here, we determined group rejection thresholds in solid chocolate-flavored compound coating for bitterness. The influences of self-identified preferences for milk or dark chocolate, as well as eating style (chewers compared to melters) on rejection thresholds were investigated. Stimuli included milk chocolate-flavored compound coating spiked with increasing amounts of sucrose octaacetate, a bitter and generally recognized as safe additive. Paired preference tests (blank compared to spike) were used to determine the proportion of the group that preferred the blank. Across pairs, spiked samples were presented in ascending concentration. We were able to quantify and compare differences between 2 self-identified market segments. The rejection threshold for the dark chocolate preferring group was significantly higher than the milk chocolate preferring group (P= 0.01). Conversely, eating style did not affect group rejection thresholds (P= 0.14), although this may reflect the amount of chocolate given to participants. Additionally, there was no association between chocolate preference and eating style (P= 0.36). Present work supports the contention that this method can be used to examine preferences within specific market segments and potentially individual differences as they relate to ingestive behavior. PRACTICAL APPLICATION: This work makes use of the rejection threshold method to study market segmentation, extending its use to solid foods. We believe this method has broad applicability to the sensory specialist and product developer by providing a process to identify how much is too much when formulating products, even in the context of specific market segments. We illustrate this in solid chocolate flavored compound coating, identifying substantial differences in the amount of acceptable bitterness in those who prefer milk chocolate compared to dark chocolate. This method provides a direct means to answer the question of how much is too much. PMID- 22924789 TI - Transseptal left ventricular lead placement using snare technique. AB - BACKGROUND: Coronary sinus (CS) lead placement for cardiac resynchronization therapy has a failure rate of ~5-10%. Here we describe a way of implanting an endocardial left ventricular (LV) lead via a transseptal puncture (TSP), using a GooseNeck snare and active fixation lead. METHODS: Three male patients (67-83 years) with failed or extracted epicardial LV leads implanted via the CS had an endocardial LV lead implanted. TSP was performed via a femoral vein. The active fixation pacing lead was advanced to the right atrium from a subclavian vein. A GooseNeck snare was passed via the TSP sheath and used to grasp the tip of the pacing lead. The sheath, GooseNeck snare, and pacing lead tip were then passed to the left atrium by sliding the system up the TSP guidewire and across the interatrial septum before deflecting the lead to permit implantation in the left ventricle. RESULTS: Successful implantation was performed in all patients with an LV implant time of 25-55 minutes. CONCLUSION: The use of a GooseNeck snare via a deflectable transseptal sheath represents a reliable alternative method for endocardial LV lead placement in patients with failed CS LV lead implantation. PMID- 22924790 TI - A new triterpenoid and a new glycoside from Pilea cavaleriei. AB - A new triterpenoid, 11alpha,12alpha-epoxy-3beta-hydroxy-24-nor-olean-4(23)-en 28,13beta-olide (1), and a new glycoside, benzyl 2-O-beta-d-apiofuranosyl-(1 -> 2)-beta-d-glucopyranosyl benzoate (2), together with eight known triterpenoids (3 10), were isolated from Pilea cavaleriei subsp. cavaleriei. Their structures were established on the basis of spectroscopic analysis including HR-ESI-MS, 1D NMR, and 2D NMR techniques. All compounds showed no anti-hepatitis C virus activity. PMID- 22924791 TI - Sequential identification of model parameters by derivative double two dimensional correlation spectroscopy and calibration-free approach for chemical reaction systems. AB - A sequential identification approach by two-dimensional (2D) correlation analysis for the identification of a chemical reaction model, activation, and thermodynamic parameters is presented in this paper. The identification task is decomposed into a sequence of subproblems. The first step is the construction of a reaction model with the suggested information by model-free 2D correlation analysis using a novel technique called derivative double 2D correlation spectroscopy (DD2DCOS), which enables one to analyze intensities with nonlinear behavior and overlapped bands. The second step is a model-based 2D correlation analysis where the activation and thermodynamic parameters are estimated by an indirect implicit calibration or a calibration-free approach. In this way, a minimization process for the spectral information by sample-sample 2D correlation spectroscopy and kinetic hard modeling (using ordinary differential equations) of the chemical reaction model is carried out. The sequential identification by 2D correlation analysis is illustrated with reference to the isomeric structure of diphenylurethane synthesized from phenylisocyanate and phenol. The reaction was investigated by FT-IR spectroscopy. The activation and thermodynamic parameters of the isomeric structures of diphenylurethane linked through a hydrogen bonding equilibrium were studied by means of an integration of model-free and model-based 2D correlation analysis called a sequential identification approach. The study determined the enthalpy (DeltaH = 15.25 kJ/mol) and entropy (TDeltaS = 13.20 kJ/mol) of C?O...H hydrogen bonding of diphenylurethane through direct calculation from the differences in the kinetic parameters (deltaDelta(?)H, TdeltaDelta(?)S) at equilibrium in the chemical reaction system. PMID- 22924792 TI - Scaling up: examining the macroecology of ectomycorrhizal fungi. AB - Ectomycorrhizal (ECM) fungi play major ecological roles in temperate and tropical ecosystems. Although the richness of ECM fungal communities and the factors controlling their structure have been documented at local spatial scales, how they vary at larger spatial scales remains unclear. In this issue of Molecular Ecology, Tedersoo et al. (2012) present the results of a meta-analysis of ECM fungal community structure that sheds important new light on global-scale patterns. Using data from 69 study systems and 6021 fungal species, the researchers found that ECM fungal richness does not fit the classic latitudinal diversity gradient in which species richness peaks at lower latitudes. Instead, richness of ECM fungal communities has a unimodal relationship with latitude that peaks in temperate zones. Intriguingly, this conclusion suggests the mechanisms driving ECM fungal community richness may differ from those of many other organisms, including their plant hosts. Future research will be key to determine the robustness of this pattern and to examine the processes that generate and maintain global-scale gradients of ECM fungal richness. PMID- 22924793 TI - Popular misconceptions. PMID- 22924794 TI - Insect P450s: mounted for battle in their war against toxins. AB - Transcriptome profiling methods are rapidly changing the ways in which insect responses to the environment can be assessed. One article featured in this issue of Molecular Ecology utilizes global expression analysis to extend previous studies examining the basis of insecticide resistance in Helicoverpa species that are devastating crop pests worldwide. In this issue Tao et al. (2012) have used a wide spectrum of biochemical and molecular techniques to examine the extent to which naturally occurring plant compounds and one synthetic insecticide change transcriptome profiles of Helicoverpa armigera larvae (Fig. 1) to enhance their adaptation to plant toxins and insecticides in their diet and environment. With their data highlighting an array of P450 transcripts and a few esterase transcripts that are correlated with increased tolerance to the insecticide deltamethrin, these researchers provide the first comprehensive evaluation of cytochrome P450 monooxygenase (P450), glutathione S-transferase (GST) and esterase (Est) gene responses in a lepidopteran species repeatedly subjected to pyrethroid selection. Building on this information, these researchers venture into the realm of the biorational in showing that RNAi-mediated destruction of one prominent toxin-inducible P450 transcript can increase sensitivity to deltamethrin, thereby compromising larval growth in the presence of this insecticide. The fact that the resulting levels of deltamethrin tolerance in the RNAi-silenced larvae are not restored completely to the levels in larvae whose defences are not stimulated by consuming plant compounds provides further evidence that their adaptive strategies for survival in toxin-rich environments include many different P450, esterase and, possibly, other genes. Together, their data highlight the complexity of the defence systems evolving in lepidopterans and other insect pests. PMID- 22924795 TI - Each life stage matters: the importance of assessing the response to climate change over the complete life cycle in butterflies. AB - As ectothermic organisms, butterflies have widely been used as models to explore the predicted impacts of climate change. However, most studies explore only one life stage; to our best knowledge, none have integrated the impact of temperature on the vital rates of all life stages for a species of conservation concern. Besides, most population viability analysis models for butterflies are based on yearly population growth rate, precluding the implementation and assessment of important climate change scenarios, where climate change occurs mainly, or differently, during some seasons. Here, we used a combination of laboratory and field experiments to quantify the impact of temperature on all life stages of a vulnerable glacial relict butterfly. Next, we integrated these impacts into an overall population response using a deterministic periodic matrix model and explored the impact of several climate change scenarios. Temperature positively affected egg, pre-diapause larva and pupal survival, and the number of eggs laid by a female; only the survival of overwintering larva was negatively affected by an increase in temperature. Despite the positive impact of warming on many life stages, population viability was reduced under all scenarios, with predictions of much shorter times to extinction than under the baseline (current temperature situation) scenario. Indeed, model predictions were the most sensitive to changes in survival of overwintering larva, the only stage negatively affected by warming. A proper consideration of every stage of the life cycle is important when designing conservation guidelines in the light of climate change. This is in line with the resource-based habitat view, which explicitly refers to the habitat as a collection of resources needed for all life stages of the species. We, therefore, encourage adopting a resource-based habitat view for population viability analysis and development of conservation guidelines for butterflies, and more generally, other organisms. Life stages that are cryptic or difficult to study should not be forsaken as they may be key determinants in the overall response to climate change, as we found with overwintering Boloria eunomia larvae. PMID- 22924796 TI - Review of ticagrelor in the management of acute coronary syndromes. AB - INTRODUCTION: Ticagrelor, an oral P2Y(12) receptor antagonist used as part of dual antiplatelet therapy in the treatment of acute coronary syndromes (ACS), has many favorable characteristics when compared with the more frequently used P2Y(12) receptor antagonist clopidogrel. Ticagrelor binds reversibly, with a rapid onset and offset of action, and produces high levels of platelet inhibition without variation secondary to genetic polymorphism. Ticagrelor produces increased platelet inhibition and an overall reduction in adverse cardiac events compared with clopidogrel. Clinically relevant side effects include an increase in non-CABG-related bleeding events as well as off-target adverse effects including ventricular pauses and dyspnea. AREAS COVERED: This article details ticagrelor's pharmacokinetic and pharmacodynamic characteristics, development and chemical properties. The authors review relevant clinical trials looking at the efficiency and safety of ticagrelor focusing predominantly on the management of patients with ACS. Finally, the review article concludes with discussion of ticagrelor's current role and future integration into clinical practice. EXPERT OPINION: Ticagrelor is a promising P2Y(12) receptor antagonist with characteristics that offer advantages for patients beyond those currently demonstrated by other P2Y(12) receptor antagonists. The challenge for prescribers is to identify those most likely to benefit from ticagrelor treatment while minimizing unnecessary bleeding events for 'real-world' ACS patients. PMID- 22924798 TI - Dial in: fostering the use of telebehavioral health services in frontier Alaska. AB - Telehealth programs continue to develop rapidly in the United States, with video teleconferencing leading the way in rural areas. Unfortunately, organizational factors can limit the use of these innovative services. Researchers explored key factors that foster initial or renewed interest, continued extensive use, and adaptations to barriers in implementing Telebehavioral Health Services in rural Alaska. A total of 18 key informant interviews were conducted with direct care staff, administrative staff, and information technology professionals. Summative interview narratives were thematically coded by hand. Results indicate that direct care and administrative staff were found to be interested in the following benefits of telehealth services: increased care, decreased patient travel, decreased organizational costs, and meeting a perceived patient preference. The fulfillment of these interests, coordination, adequate staffing, accessibility of equipment, and clinician competency all contributed to the use of telehealth services. Numerous adaptations to barriers were found involving coordination, personal oversight, acceptance of limitations, education, staffing, billing for services, consultation, modifying referrals patterns, and creating treatment alternatives. Information technology professionals identified communication and assistance, testing connections, resolving initial issues, maintenance, and vision and control as vital factors. Findings may aid programs in dealing with pragmatic issues to maintain organizational readiness. PMID- 22924797 TI - Recommendations for the use of online social support for African American men. AB - African American men face greater psychosocial stressors than African American women and men of other racial and ethnic groups, which place them at higher risk for psychological distress. Yet, research suggests that African Americans are less likely to utilize professional mental health services because of their mistrust of the health care system and their need for more specialized and innovative services. Supplemental resources aimed at positive coping and social support for African American men may reduce the likelihood that they experience psychological distress, which could lead to more severe mental disorders. This article proposes the use of online social support for African American men who are in early, nonsevere stages of psychological distress. We examine the unique experiences of African American men, discuss distress among this underserved group, and finally, offer recommendations for achieving an online community for African American men. PMID- 22924799 TI - The relationship between burnout and coping in adult and young offender center correctional officers: an exploratory investigation. AB - High levels of occupational stress and burnout are costly for correctional services and their employees. Correctional officers report high levels of burnout, absenteeism, turnover, and poor physical health. The purpose of this study was to investigate the prevalence of burnout and the coping mechanisms used to buffer the effects of burnout within correctional centers. In the current study, 208 correctional officers from adult and young offender centers completed an online survey measuring burnout and coping strategies. Results from the Maslach Burnout Inventory-Human Services Survey (MBI-HSS) and the Brief Coping Orientation to Problems Experienced (COPE) Scale indicated that even though correctional center officers mostly used adaptive coping strategies, they still reported high levels of burnout. The results of this study suggest that there are variables other than coping strategies, such as gender and length of experience, that lead to the level of burnout as observed in correctional officers. PMID- 22924800 TI - Mental health needs of federal female offenders. AB - Mental health problems are increasingly being recognized as one of the greatest challenges faced by correctional systems in the effective management of their populations. Over the past decade, the number of federally sentenced female offenders in Canada presenting with mental health problems has risen significantly, from 13% in 1996/1997 to 29% in 2008/2009 (Correctional Service of Canada, 2009a). This research used the screener version of the Computerized Diagnostic Interview Schedule (C-DIS-IV; n = 88) to outline the mental health needs of federally sentenced females in Canada. Results provide evidence for extremely elevated rates for certain diagnoses and confirm substance dependence as a significant area of need in this sample. Moreover, alcohol dependence emerged as an area of particular concern for Aboriginal women. Furthermore, all individuals experiencing a lifetime substance dependence disorder have also suffered from an additional psychiatric diagnosis at some point in their lives; thereby highlighting the possible levels of concurrent disorders among this population. This research highlights the critical importance of comprehensive and ongoing mental health assessment, and treatment, for the successful management and reintegration of female offenders. PMID- 22924801 TI - Potential mediators between child abuse and both violence and victimization in juvenile offenders. AB - Juvenile offenders are at risk for involvement in both fighting behavior and peer victimization. Understanding the potential causal mechanisms leading to these outcomes is important to address the needs of this population. The present study tested four mediator models of violent perpetration and peer victimization in a sample of 112 incarcerated youth (68 males and 44 females). In the models, the relationship between child physical and emotional abuse and fighting and victimization was expected to be mediated by impulsiveness, depression, and drug use. Multiple mediator models were tested according to Preacher and Hayes (2008). Depression fully mediated the relation between child emotional abuse and victimization and partially mediated the relation between child physical abuse and victimization. Drug use fully mediated the relation between child emotional abuse and fighting. These results suggest that treatment of depressive symptoms and drug use among juvenile offenders with a history of child physical or emotional abuse may limit violent perpetration and peer victimization in this population. PMID- 22924802 TI - The U.S. Department of Veterans Affairs Veterans Justice programs and the sequential intercept model: case examples in national dissemination of intervention for justice-involved veterans. AB - Veterans are a significant subpopulation in criminal justice populations, comprising between 9% and 10% of arrestee, jail, prison, and community supervision populations. In order to address the needs of justice-involved veterans, the U.S. Department of Veterans Affairs (VA) Veterans Justice Programs (VJP) offer services to veterans at multiple points in their involvement in the criminal justice system. Within the context of the VA's national mandate to develop VJP, this article presents best practice case examples using the Sequential Intercept Model as the intervention frame, and discusses each in context of a community psychology framework for innovation dissemination. The case examples demonstrate how central program guidance is adapted locally to meet the national mandate using strategies that fit the local environment, illustrating the innovations in action orientation, boundary spanning, and flexibility of organizations. This review provides examples of creative reinvention that expand on the mandate and work to meet local needs. To optimize services to veterans released from custody or supervised in the community, future study of the implementation of this national mandate should examine all VJP sites to identify the full range of best practices in local program implementation. PMID- 22924803 TI - Intimate partner violence intervention for high-risk offenders. AB - This study is an evaluation of pre-postprogram change associated with the High Intensity Family Violence Prevention Program (HIFVPP) for incarcerated male offenders who are perpetrators of Intimate Partner Violence (IPV). The sample consists of 159 male offenders who participated in the HIFVPP while incarcerated. Participants were assessed pre-, mid-, and postprogram using an assessment battery consisting of self-report questionnaires and facilitator-rated evaluation scales. Results found uniform and significant (p < .001) improvement for pre- and postprogram change in the self-report questionnaires and in the facilitator ratings. A positive improvement in motivation, whether assessed by the participant or facilitator, was associated with improvement in program outcomes and significant within, between, and interaction effects were found when participant program performance over time was compared among grouped postprogram ratings of motivation. The implication for the efficacy of addressing offender motivation to change in IPV interventions is discussed. PMID- 22924804 TI - Childhood bullying and becoming a young father in a national cohort of Finnish boys. AB - Childhood bullying is known to be associated with various adverse psychosocial outcomes in later life. No studies exist on its association with becoming a young father. The study is based on a national cohort, which included 2,946 Finnish boys at baseline in 1989. Information on bullying was collected from children, their parents and their teachers. Follow-up data on becoming a father under the age of 22 were collected from a nationwide register. The follow-up sample included 2,721 boys. Bullying other children frequently was significantly associated with becoming a young father independently of being victimized, childhood psychiatric symptoms and parental educational level. Being a victim of bullying was not associated with becoming a young father when adjusted for possible confounders. When the co-occurrence of bullying and victimization was studied, it was found that being a bully-victim, but not a pure bully or a pure victim, is significantly associated with becoming a young father. This study adds to other studies, which have shown that the risk profile and relational patterns of bully-victims differ from those of other children, and it emphasizes the importance of including peer relationships when studying young fathers. PMID- 22924805 TI - Acute forearm compartment syndrome associated with dialysis access bleeding. PMID- 22924806 TI - Brown tumours in a renal transplant recipient. PMID- 22924807 TI - Glycated matrix up-regulates inflammatory signaling similarly to Porphyromonas gingivalis lipopolysaccharide. AB - BACKGROUND AND OBJECTIVE: Hyperglycemia and advanced glycation end-products (AGEs) have been hypothesized as the etiologic factors of diabetic periodontitis. The aim of this study was to clarify in greater detail the patterns of AGE mediated periodontal inflammation under various physiological conditions. MATERIAL AND METHODS: The deposition of AGEs and expression of the receptor for AGEs (RAGE) were identified by immunohistochemistry in Sprague-Dawley rats with experimentally induced periodontitis or diabetes. Human periodontal ligament cells (PDLCs) and mesenchymal stem cells (MSCs) were cultured under simulated conditions of hyperglycemia, Porphyromonas gingivalis lipopolysaccharide (LPS) stimulation and matrix glycation. Cell viability and expression of toll-like receptors (TLRs), Rage, an inflammatory signaling initiator (nuclear factor kappa light chain enhancer of activator beta cells), an oxidative stressor (heme oxygenase-1) and collagen synthesis (type I and type IV) genes were evaluated. RESULTS: The deposition of AGEs and the expression of Rage were evident in the inflamed periodontal tissues in all rats and appeared to be enhanced in rats with diabetes. Matrix glycation augmented cytotoxicity, up-regulated RAGE and TLRs in both PDLCs and MSCs, and significantly activated downstream inflammatory signaling in MSCs. Oxidative stress was significantly increased under matrix glycation in both PDLCs and MSCs and was significantly increased at a high glucose concentration in MSCs. A consistent decrease in expression of type I and type IV collagens was observed in MSCs, but a delayed reduction was noted in PDLCs. CONCLUSIONS: Matrix glycation modulated cell behavior to induce inflammation equivalent to that produced by incubation with P. gingivalis LPS. Periodontal inflammation also led to matrix glycation, thus demonstrating a definite interaction between diabetes and periodontitis. PMID- 22924809 TI - Screening for and management of high-grade cervical intraepithelial neoplasia in Bangladesh: a cross-sectional study comparing two protocols. AB - AIM: To evaluate the feasibility of the 'see and treat' protocol for the management of high-grade cervical intraepithelial neoplasia (CIN) at a colposcopy clinic in Bangladesh. MATERIAL AND METHODS: A cross-sectional and comparative study was carried out between two periods on 358 colposcopy-diagnosed high-grade CIN at the colposcopy clinic of Bangabandhu Sheikh Mujib Medical University (BSMMU). During the first period (January 2005 to June 2008), 181 colposcopy diagnosed high-grade CIN patients had cervical biopsy by punch biopsy forceps and histology-confirmed high-grade CIN were treated by loop electrosurgical excision procedure (LEEP). During the second period (July 2008 to December 2009), 177 colposcopy-diagnosed high-grade CIN were treated by LEEP at their first visit. RESULTS: During the first and second periods, 48 of 87 and 55 of 73 histology proven high-grade CIN cases, respectively, received treatment. Among the study population, 37.3% women who had normal or CIN-I in histology were treated unnecessarily in the second period. The compliance of treatment improved by 20% and failure to receive treatment fell by 20%; these changes were statistically significant (P=0.006). CONCLUSION: 'See and treat' protocol is a well-accepted, feasible and useful option for management of high-grade CIN in Bangladesh. It reduces the number of visits to the clinic and failure to receive treatment. PMID- 22924808 TI - Text-in-context: a method for extracting findings in mixed-methods mixed research synthesis studies. AB - AIM: Our purpose in this paper is to propose a new method for extracting findings from research reports included in mixed-methods mixed research synthesis studies. BACKGROUND: International initiatives in the domains of systematic review and evidence synthesis have been focused on broadening the conceptualization of evidence, increased methodological inclusiveness and the production of evidence syntheses that will be accessible to and usable by a wider range of consumers. Initiatives in the general mixed-methods research field have been focused on developing truly integrative approaches to data analysis and interpretation. DATA SOURCE: The data extraction challenges described here were encountered, and the method proposed for addressing these challenges was developed, in the first year of the ongoing (2011-2016) study: Mixed-Methods Synthesis of Research on Childhood Chronic Conditions and Family. DISCUSSION: To preserve the text-in context of findings in research reports, we describe a method whereby findings are transformed into portable statements that anchor results to relevant information about sample, source of information, time, comparative reference point, magnitude and significance and study-specific conceptions of phenomena. IMPLICATIONS FOR NURSING: The data extraction method featured here was developed specifically to accommodate mixed-methods mixed research synthesis studies conducted in nursing and other health sciences, but reviewers might find it useful in other kinds of research synthesis studies. CONCLUSION: This data extraction method itself constitutes a type of integration to preserve the methodological context of findings when statements are read individually and in comparison to each other. PMID- 22924810 TI - The role of specific cow's milk proteins in the etiology of recurrent aphthous ulcers. AB - BACKGROUND: Recurrent aphthous ulcerations (RAU), or recurrent aphthous stomatitis, is recognized as one of the most common oral mucosal diseases worldwide. It was noted some connection between immunity to cow's milk proteins (CMP) and oral diseases. The goal of this study was to determine the prevalence of the increased levels of serum antibodies to specific cow's milk proteins (SCMP), constituents of cheese or of whey, by enzyme-linked immunosorbent assay (ELISA) test, in subjects who have RAU. METHODS: Fifty subjects with RAU and 50 healthy people, as controls (C), were included in this research. Levels of serum IgA, IgG, and IgE antibodies to SCMP were determined by ELISA. The statistical analysis of data was performed by Wilcoxon rank sum test with continuity correction. RESULTS: The levels of serum anti-SCMP IgA, IgG, and IgE antibodies were significantly higher in subjects with RAU in comparison with controls (P < 0.005). CONCLUSIONS: These results indicate the strong association between high levels of serum anti-SCMP IgA, IgG, and IgE antibodies, especially to caseins: alpha-, beta-, and kappa-casein from cow's milk and clinical manifestations of RAU. Serum immunity to the whey proteins in subjects with RAU was not in so high percentage expressed. PMID- 22924811 TI - A proline-based phosphine template for Staudinger ligation. AB - A proline-based phosphine template enabling a rapid Staudinger ligation of azide containing substrates under mild conditions is reported. This reaction has a second-order rate constant of 1.12 M(-1) s(-1). It is expected that the proline based Staudinger ligation strategy will be a useful method for bioconjugation and proline based peptide coupling. PMID- 22924812 TI - Editorial Comment from Dr Satoh to interpreting a rising prostate-specific antigen after brachytherapy for prostate cancer. PMID- 22924813 TI - Chemically functionalized water-soluble single-walled carbon nanotubes modulate morpho-functional characteristics of astrocytes. AB - We report the use of chemically functionalized water-soluble single-walled carbon nanotubes (ws-SWCNTs) for the modulation of morpho-functional characteristics of astrocytes. When added to the culturing medium, ws-SWCNTs were able to make astrocytes larger and stellate/mature, changes associated with the increase in glial fibrillary acidic protein immunoreactivity. Thus, ws-SWCNTs could have more beneficial effects at the injury site than previously thought; by affecting astrocytes, they could provide for a more comprehensive re-establishment of the brain computational power. PMID- 22924814 TI - Layer-by-layer click deposition of functional polymer coatings for combating marine biofouling. AB - "Click" chemistry-enabled layer-by-layer (LBL) deposition of multilayer functional polymer coatings provides an alternative approach to combating biofouling. Fouling-resistant azido-functionalized poly(ethylene glycol) methyl ether methacrylate-based polymer chains (azido-poly(PEGMA)) and antimicrobial alkynyl-functionalized 2-(methacryloyloxy)ethyl trimethyl ammonium chloride-based polymer chains (alkynyl-poly(META)) were click-assembled layer-by-layer via alkyne-azide 1,3-dipolar cycloaddition. The polymer multilayer coatings are resistant to bacterial adhesion and are bactericidal to marine Gram-negative Pseudomonas sp. NCIMB 2021 bacteria. Settlement of barnacle ( Amphibalanus (= Balanus ) amphitrite ) cyprids is greatly reduced on the multilayer polymer functionalized substrates. As the number of the polymer layers increases, efficacy against bacterial fouling and settlement of barnacle cyprids increases. The LBL-functionalized surfaces exhibit low toxicity toward the barnacle cyprids and are stable upon prolonged exposure to seawater. LBL click deposition is thus an effective and potentially environmentally benign way to prepare antifouling coatings. PMID- 22924815 TI - Design and synthesis of beta-site amyloid precursor protein cleaving enzyme (BACE1) inhibitors with in vivo brain reduction of beta-amyloid peptides. AB - The evaluation of a series of aminoisoindoles as beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitors and the discovery of a clinical candidate drug for Alzheimer's disease, (S)-32 (AZD3839), are described. The improvement in permeability properties by the introduction of fluorine adjacent to the amidine moiety, resulting in in vivo brain reduction of Abeta40, is discussed. Due to the basic nature of these compounds, they displayed affinity for the human ether-a-go-go related gene (hERG) ion channel. Different ways to reduce hERG inhibition and increase hERG margins for this series are described, culminating in (S)-16 and (R)-41 showing large in vitro margins with BACE1 cell IC(50) values of 8.6 and 0.16 nM, respectively, and hERG IC(50) values of 16 and 2.8 MUM, respectively. Several compounds were advanced into pharmacodynamic studies and demonstrated significant reduction of beta-amyloid peptides in mouse brain following oral dosing. PMID- 22924816 TI - Differences in insulin resistance markers between children born small for gestational age or born preterm appropriate for gestational age. AB - AIM: To evaluate the impact of prenatal or postnatal compromised environment on glucose homoeostasis in children born preterm and appropriate for gestational age or small for gestational age (SGA) at term. METHOD: Seventy-seven children (median 9.9 years, range 8.5-10) born at Karolinska Hospital were allocated to three groups: 21 subjects born before 30 weeks of gestational age (preterm), 26 SGA at term and 30 at term with appropriate birth weight (control). Anthropometric measurements were taken, and fasting blood samples for haemoglobin A1c, glucose, insulin, IGFBP-1, IGF-1 and lipid profile were taken. Glucose, insulin and IGFBP-1 samples were taken at 0, 30 and 120 min during an oral glucose tolerance test (OGTT). RESULTS: Subjects born preterm or SGA were shorter and thinner compared with Controls. After adjustment for body mass index (BMI), the SGA group had higher basal insulin levels (p = 0.029), higher homoeostasis model assessment-insulin resistance (p = 0.012) and lower whole-body insulin sensitivity index (p = 0.007) than Controls. IGFBP-1 decrease during OGTT was attenuated in the Preterm group compared with the Control (p = 0.045) and SGA groups (p = 0.007). CONCLUSION: The higher fasting insulin level in the SGA children, adjusted for BMI, could indicate peripheral insulin resistance. Preterm born children had reduced suppression of IGFBP-1 during OGTT, suggesting hepatic insulin resistance. PMID- 22924817 TI - Effects of pressurization on some contamination flora in beef pate. AB - Pate meat is one of the food products at the top of the high-risk category since it is an undercooked product, which does not undergo any treatment to ensure its safety before consumption. In this study, pressurization, a nonthermal technology, was administered to the product to enhance its microbial safety for the 1st time. After being cooked, ground, and mixed with broth and spices, the pate meat was divided into 3 batches. Their additional fat contents were adjusted to 9.11%, 25.00%, and 35.00%, respectively. After the division of each batch again into 3 portions with different acidities (pH 5.65, 5.95, 6.40), they were contaminated with Escherichia coli American Type Culture Collection (ATCC) 11229 or Listeria monocytogenes ATCC 7644. Each batch was treated with 220 or 308 MPa at 21 or 43 degrees C for 5 or 15 min. Whereas the increase in pressure from 220 to 308 MPa enhanced the antimicrobial effect (P < 0.01), the increase in pH level and fat ratio decreased it. In the study, only the interaction between the fat ratio and acidity was found significantly important. The effect of temperature and time was not significant. The highest microbial inhibition with 1.65 log reduction was observed on E. coli when the pate meat with pH 5.65 and 9.11% fat was treated at 308 MPa at 43 degrees C for 5 min. The findings indicate the necessity of using higher pressure levels as >=308 MPa with higher acidity levels (pH <= 5.65) and lower fat contents (<=9.11%) to achieve a higher microbial quality in pate meat. PRACTICAL APPLICATION: Different combinations of pressure (308 and 220 MPa), additional fat (9.11, 25.00, or 35.00%), pH (5.65, 5.95, or 6.40), temperature (21 or 43 degrees C), time (5 or 15 min) on Listeria monocytogenes ATCC 7644 and Escherichia coli ATCC 11229 contamination flora were comparatively studied for the 1st time in pate meat. The findings are especially important for pate meat safety and industry since they indicate the necessity of using pressure levels as >=308 MPa with higher acidity levels (pH <= 5.65) and lower fat contents (<=9.11%) to achieve a higher microbial quality in pate meat, which is highly prone to microbial spoilage. PMID- 22924818 TI - Interfacial ion-transfer mechanism for the intense luminescence observed when opening self-seal envelopes. AB - The unusually intense luminescence (commonly called triboluminescence) observed when opening self-seal envelopes has been studied using spectroscopy. Emissions from gas-phase species due to electrical discharge were observed, which in the case of air consists of vibronic transitions of N(2)(C(3)Pi(u)-B(3)Pi(g)) in the ultraviolet (UV) region (280-400 nm). However, the major cause of the intense blue luminescence (around 435 nm) is attributed to optical brightening agents added to the white paper. The results suggest that the emission from the brightening agents may be caused by two mechanisms: (i) fluorescence due to excitation by the UV light from the gas discharge and (ii) nonoptically, by electron transfer. The electrical discharge results from contact electrification; we propose a mechanism for the charge transfer involving a net migration of hydroxide anions out of the paper into the wet latex-adhesive during drying. PMID- 22924819 TI - Dual-concentrate bicarbonate-based hemodialysis: know your buffers. PMID- 22924820 TI - A novel translocation t(11;13) (q21;q14.2) in a child with suprasellar primitive neuroectodermal tumor and retinoblastoma. AB - PURPOSE: To report on a novel translocation related to a suprasellar primitive neuroectodermal tumor (sPNET) and retinoblastoma. DESIGN: Case report. METHODS: A 6-year-old girl underwent genetic testing after developing unilateral retinoblastoma subsequent to treatment (surgery, chemotherapy, and stem-cell rescue) for a sPNET found at 1 year of age. RESULTS: Genetic testing found the girl's karyotype to be 46,XX,t(11;13)(q21;q14.2); a novel translocation not previously reported in patients with either retinoblastoma or sPNET. CONCLUSIONS: Our patient had a novel translocation affecting the retinoblastoma 1 (RB1) gene, 46,XX,t(11;13)(q21;q14.2) resulting in the late development of unilateral retinoblastoma. Although she only developed unilateral retinoblastoma, her central nervous system was affected at a very early age. How her complex mutation resulted in retinoblastoma and antecedent sPNET remains unknown. PMID- 22924821 TI - Newborns of mothers with intellectual disability have a higher risk of perinatal death and being small for gestational age. AB - OBJECTIVE: To study mode of birth, perinatal health and death in children born to mothers with intellectual disability (ID) in Sweden. DESIGN: Population-based register study. SETTING: National registers; the National Patient Register linked to the Medical Birth Register. SAMPLE: Children of first-time mothers with ID (n = 326; classified in the International Classification of Diseases 8-10) were identified and compared with 340 624 children of first-time mothers without ID or any other psychiatric diagnosis between 1999 and 2007. METHODS: Population-based data were extracted from the National Patient Register and the Medical Birth Register. MAIN OUTCOME MEASURES: Mode of birth, preterm birth, small for gestational age, Apgar score, stillbirth and perinatal death. RESULTS: Children born to mothers with ID were more often stillborn (1.2 vs. 0.3%) or died perinatally (1.8 vs. 0.4%) than children born to mothers without ID. They had a higher proportion of cesarean section birth (24.5 vs. 17.7%) and preterm birth (12.2 vs. 6.1%), were small for gestational age (8.4 vs. 3.1%) and had lower Apgar scores (<7 points at five minutes; 3.7 vs 1.5%) compared with children born to mothers without ID. Logistic regression adjusted for maternal characteristics confirmed an increased risk of small for gestational age (odds ratio 2.25), stillbirth (odds ratio 4.53) and perinatal death (odds ratio 4.25) in children born to mothers with ID. CONCLUSIONS: Unborn and newborn children of mothers with ID should be considered a risk group, and their mothers may need better individual-based care and support. PMID- 22924823 TI - The stepwise acquisition of fluconazole resistance mutations causes a gradual loss of fitness in Candida albicans. AB - The pathogenic yeast Candida albicans can develop resistance to the widely used antifungal agent fluconazole, which inhibits ergosterol biosynthesis. Resistance is often caused by gain-of-function mutations in the transcription factors Mrr1, Tac1 and Upc2, which result in constitutive overexpression of multidrug efflux pumps and ergosterol biosynthesis genes respectively. It is not known how the permanently changed gene expression program in resistant strains affects their fitness in the absence of drug selection pressure. We have systematically investigated the effects of activating mutations in Mrr1, Tac1 and Upc2, individually and in all possible combinations, on the degree of fluconazole resistance and on the fitness of C. albicans in an isogenic strain background. All combinations of different resistance mechanisms resulted in a stepwise increase in drug resistance, culminating in 500-fold increased fluconazole resistance in strains possessing mutations in the three transcription factors and an additional resistance mutation in the drug target enzyme Erg11. The acquisition of resistance mutations was associated with reduced fitness under non selective conditions in vitro as well as in vivo during colonization of a mammalian host. Therefore, without compensatory mutations, the inability to appropriately regulate gene expression results in a loss of competitive fitness of drug-resistant C. albicans strains. PMID- 22924822 TI - The protective role of the transmembrane thioredoxin-related protein TMX in inflammatory liver injury. AB - AIMS: Accumulating evidence indicates that oxidative stress is associated with inflammation, and the cellular redox status can determine the sensitivity and the final outcome in response to inflammatory stimuli. To control the redox balance, mammalian cells contain a variety of oxidoreductases belonging to the thioredoxin superfamily. The large number of these enzymes suggests a complex mechanism of redox regulation in mammals, but the precise function of each family member awaits further investigations. RESULTS: We generated mice deficient in transmembrane thioredoxin-related protein (TMX), a transmembrane oxidoreductase in the endoplasmic reticulum (ER). When exposed to lipopolysaccharide (LPS) and d (+)-galactosamine (GalN) to induce inflammatory liver injury, mutant mice were highly susceptible to the toxicants and developed severe liver damage. LPS induced production of inflammatory mediators was equivalent in both wild-type and TMX(-/-) mice, whereas neutralization of the proinflammatory cytokine tumor necrosis factor-alpha suppressed the toxic effects of LPS/GalN in the mutant mice. Liver transcriptional profiles revealed enhanced activation of the p53 signaling pathway in the TMX(-/-) mice after LPS/GalN treatment. Furthermore, TMX deficiency also caused increased sensitivity to thioacetamide, which exerts its hepatotoxicity through the generation of reactive oxygen species. INNOVATION: The present study is the first to address the role of the oxidoreductase TMX in inflammatory liver injury. The phenotype of mice deficient in TMX suggests a functional link between redox regulation in the ER and susceptibility to oxidative tissue damage. CONCLUSION: We conclude that TMX plays a major role in host defense under the type of inflammatory conditions associated with oxidative stress. PMID- 22924824 TI - Incidence of facial fractures in the Australian Football League. AB - BACKGROUND: The incidence of facial injuries within the Australian Football League (AFL) raises concern and can cause the temporary or permanent loss of function thereby threatening a player's earning potential and length of playing career. The purpose of this study was to identify all facial fractures occurring within the AFL over a 17-season period from 1992 to 2008. We aimed to detail injury trends and possible factors that correlate to a player's risk of sustaining a facial fracture. METHODS: A case review of the AFL's prospective injury records looking at facial fractures sustained by AFL players over a 17 year period was conducted. We analysed various parameters including frequency, distribution, player location, time of season, player recovery, fracture incidence per season and geographical location of facial fracture. RESULTS: In the recorded period, 175 total facial fractures were sustained by AFL players. A majority of fractures, 108 (62%), were sustained during season matches. Zygomaticomaxillary complex fractures (41%) and mandibular (37%) fractures were the most commonly recorded. Players missed 517 matches because of injury with an average of three matches per injury. CONCLUSIONS: The AFL is a high-impact, physically demanding competition resulting in significant numbers of facial fractures. There has been a trend of decreased incidence of facial fractures in the AFL from 2006 to 2008. This trend may be attributable to an AFL rule change, which occurred during the study period. Further injury recording could give a more accurate representation of the impact that future AFL rule changes have. PMID- 22924825 TI - Development of a method to measure DNA methylation levels by using methyl CpG binding protein and luciferase-fused zinc finger protein. AB - DNA methylation, which is an important epigenetic event for transcriptional regulation, is regarded as a biomarker for cancer. A rapid and sensitive method for measuring DNA methylation levels in target genomic regions may enable early diagnosis of cancer. To detect DNA methylation levels conveniently, we developed a detection system for DNA methylation, designated as methylated DNA precipitation combined luciferase-fused zinc finger assay (MELZA), which uses methyl CpG-binding domain (MBD) and luciferase-fused zinc finger protein. This system comprises the following 3 steps: (1) MBD-based methylated DNA precipitation, (2) PCR amplification of the target genomic region, and (3) detection of the PCR product quantity by using luciferase-fused zinc finger protein. Using this system, we have accurately measured methylation levels of the androgen receptor gene promoter region in LNCaP, PC3, Du145, and whole blood cells. This system does not require bisulfite treatment, and all the steps can be automated. Therefore, it might be useful for measuring DNA methylation levels in clinical cancer diagnoses. PMID- 22924826 TI - Gender differences in young children's temperament traits: comparisons across observational and parent-report methods. AB - Evidence supporting the continuity between child temperament and adult personality traits is accumulating. One important indicator of continuity is the presence of reliable gender differences in traits across the lifespan. A substantial literature demonstrates gender differences on certain adult personality traits and recent meta-analytic work on child samples suggests similar gender differences for some broad and narrow domains of temperament. However, most existing studies of children rely only on parent-report measures. The present study investigated gender differences in temperament traits assessed by laboratory observation, maternal-report, and paternal-report measures. Across three independent samples, behavioral observations, maternal-report, and paternal report measures of temperament were collected on 463 boys and 402 girls. Across all three methods, girls demonstrated higher positive affect and fear and lower activity level than boys. For laboratory measures, girls demonstrated higher levels of sociability and lower levels of overall negative emotionality (NE), sadness, anger and impulsivity than boys. However, girls demonstrated higher levels of overall NE and sadness than boys when measured by maternal reports. Finally, girls demonstrated lower levels of sociability based on paternal reports. Results are discussed in relation to past meta-analytic work and developmental implications of the findings. PMID- 22924827 TI - Asymmetrical generalization of conditioning and extinction from compound to element and element to compound. AB - Four appetitive conditioning experiments studied generalization between compound conditional stimuli (AB) and their elements (e.g., A or B). In Experiments 1 and 2, rats received conditioning with A and AB, and then extinction with either A or AB. During subsequent testing, there was more generalization of extinction (nonresponding) from the compound (AB) to the element (A) than from the element (A) to the compound (AB). This asymmetry was consistent with earlier results involving temporal discrimination learning in which short and long temporal intervals played the roles of A and AB. In Experiment 3, rats received conditioning with either A or AB, and then testing with A and AB. Consistent with elemental models of conditioning, there was more generalization of conditioned responding from A to AB than from AB to A. Experiment 4 found that these asymmetries in the generalization of extinction (Experiments 1 and 2) and conditioning (Experiment 3) both contribute to the feature-positive effect. Overall, the parallel between the current findings and previous results with temporal discrimination learning supports an associative analysis of interval timing. Implications for elemental and configural theories of conditioning and generalization are also discussed. PMID- 22924831 TI - Competitive adsorption of thiolated poly(ethylene glycol) and alkane-thiols on gold nanoparticles and its effect on cluster formation. AB - The surface concentration and conformation of thiol-terminated poly(ethylene glycol) (PEG) on gold nanoparticles are studied before and after coadsorption of alkane-thiols. Thermogravimetric analysis (TGA) indicates alkane-thiol ligands will competitively adsorb on gold surfaces of nanoparticles and that the extent of PEG-thiol replacement depends on the specific length of the alkane-thiol molecule. The conformation of the polymer is also affected by the length and packing density of the alkane-thiol. Dynamic light scattering (DLS) shows that the hydrodynamic size of coated particles has an intermediate maximum for the adsorption of octane-thiol, which also forms the most densely packed alkane-thiol monolayers. These two factors greatly impact the formation of clusters by nanoparticle surfactants. Small angle X-ray scattering (SAXS) shows that the largest clusters are formed when particles have a low PEG-thiol surface concentration and an extended PEG conformation. PMID- 22924828 TI - How to make a thyroid hypothyroid. PMID- 22924832 TI - Demonstration of defect-free and composition tunable GaxIn1-xSb nanowires. AB - The Ga(x)In(1-x)Sb ternary system has many interesting material properties, such as high carrier mobilities and a tunable range of bandgaps in the infrared. Here we present the first report on the growth and compositional control of Ga(x)In(1 x)Sb material grown in the form of nanowires from Au seeded nanoparticles by metalorganic vapor phase epitaxy. The composition of the grown Ga(x)In(1-x)Sb nanowires is precisely controlled by tuning the growth parameters where x varies from 1 to ~0.3. Interestingly, the growth rate of the Ga(x)In(1-x)Sb nanowires increases with diameter, which we model based on the Gibbs-Thomson effect. Nanowire morphology can be tuned from high to very low aspect ratios, with perfect zinc blende crystal structure regardless of composition. Finally, electrical characterization on nanowire material with a composition of Ga(0.6)In(0.4)Sb showed clear p-type behavior. PMID- 22924833 TI - Characterizing a novel strain of Bacillus amyloliquefaciens BAC03 for potential biological control application. AB - AIMS: To identify and characterize a bacterial strain BAC03, evaluate its biological control activity against potato common scab (Streptomyces spp.) and characterize an antimicrobial substance produced by BAC03. METHODS AND RESULTS: Bacterial strain BAC03, isolated from potato common scab suppressive soil, was identified as Bacillus amyloliquefaciens by analysing sequences of fragments of the recA, recN, cheA and gyrA genes. BAC03 displayed an antagonistic activity against Streptomyces spp. on agar plates using a co-culture method. In glasshouse assays, BAC03 applied in potting mix significantly reduced common scab severity (P < 0.05) and potentially increased the growth of potato plants (P < 0.05). An antimicrobial substance extracted from BAC03 by ammonium sulfate precipitation was identified as an LCI protein using liquid chromatography-mass spectrometry. The antimicrobial activity of either a BAC03 liquid culture or the ammonium sulfate precipitate fraction was stable under a wide range of temperatures, and pH levels, as well as following incubation with several chemicals, but was reduced by all proteinases tested. CONCLUSIONS: Bacillus amyloliquefaciens strain BAC03 displayed a strong antimicrobial activity, that is, the suppression of potato common scab, and may potentially enhance the plant growth. LCI protein is associated with some of the antimicrobial activity. SIGNIFICANCE AND IMPACT OF THE STUDY: Bacterial strain BAC03 has the potential to be developed as a commercial biological control agent for potato common scab. PMID- 22924834 TI - Eight-year experience of bloodless surgery at a tertiary care hospital in Korea. AB - BACKGROUND: The Soonchunhyang University Hospital Bloodless Center was established in 2000, and more than 2000 bloodless surgeries has been performed there since. This study was carried out to analyze the characteristics of patients who underwent bloodless surgery and the influences of postoperative lowest hemoglobin level (H(blow)) along with the lowest postoperative Hb/preoperative Hb ratio (H(blow/pre)) on successful completion of bloodless surgery. STUDY DESIGN AND METHODS: A total of 1407 patients were included. Patients were divided according to H(blow) into not more than 7 and more than 7 g/dL groups and compared regarding use of transfusion alternatives, coexisting risk factors, and mortality rate. They were also grouped as H(blow/pre) of not more than 0.5 or more than 0.5, and mortalities were compared between them. RESULTS: Jehovah's Witnesses comprised 1323 (94.0%) of the total population. The frequency of simultaneous use of erythropoietin and iron was significantly higher in H(blow) of not more than 7 group than in more than 7 g/dL group, as was the use of hemostatics. Among risk factors urging transfusion, the frequencies of cardiovascular disease and cerebrovascular accident were higher in H(blow) of not more than 7 than in the more than 7 g/dL group. Mortality rates in H(blow) of not more than 7 g/dL and H(blow/pre) of not more than 0.5 groups were significantly higher than those in H(blow) of more than 7 g/dL and H(blow/pre) of more than 0.5 groups, respectively. CONCLUSION: We have provided an effective bloodless surgery program for the past 10 years. A prospective multicenter study with other bloodless centers in Korea concerning mortality rates, actual operative blood loss, and postoperative complications in high-risk group of patients would be needed to establish evidence-based guidelines for bloodless surgery. PMID- 22924835 TI - Experience of social role strain in Korean women with type 2 diabetes. AB - AIM: To expand our understanding of the experience of social role strain in the context of diabetes care among middle-aged married Korean women with type 2 diabetes. BACKGROUND: Diabetes remains an international concern. There are special challenges experienced by middle-aged married women who may not prioritize self-care and disease management. These challenges may be heightened in certain cultures due to traditional female and family roles along with other social norms and values. DESIGN: Descriptive qualitative study. METHODS: This qualitative descriptive study involves in-depth interviews conducted between January-February 2007 with ten middle-aged married Korean women purposively selected to represent both higher and lower levels of role strain as measured by the measure of role gratification and strain instrument from the companion study, which was conducted simultaneously. FINDINGS: Korean women in this study reported 'resentment regarding previous role strain'. This psychosocial burden was heightened by a noted pattern of 'sacrificing self in favour of others', which complicated both their personal lives and their ability to take care of themselves physically. Added to this were feelings of guilt related to their diabetes and the requirements of day-to-day management expressed as, 'my diabetes makes me a liability'. CONCLUSION: The women's role-strain experience related to their diabetes was intertwined with their past and current daily life. Further explication and interventions to address and manage role strain could potentially improve women's disease management and overall quality of life. PMID- 22924836 TI - Freckles and solar lentigines have different risk factors in Caucasian women. AB - BACKGROUND: To date, few epidemiological data on the relationships between solar lentigines, freckles and behavioural and constitutional risk factors in Caucasian populations exist. OBJECTIVES: To investigate the potential impact of behavioural and phenotypic variables, as well as the MC1R genetic background, on the history of facial freckles and the severity of solar lentigines in Caucasian women. METHODS: The severity of solar lentigines was graded from facial digital images of 523 French middle-aged women by a dermatologist and summarized by a score afterwards. The history of facial freckles was assessed and the sun-exposure behaviour was characterized using a six-category typology. Risk factors including MC1R polymorphism were evaluated using logistic regression models. RESULTS: Two constitutive host factors were found to be independently associated with a history of facial freckles: frequent sunburns and the presence of diminished function variants of the MC1R gene. In addition to age, five factors were independently associated with solar lentigines: constitutive host factors (dark skin colour and tanning capacity), a history of freckles, sun-exposure behaviour and current intake of oral contraceptive or progestogen treatments. CONCLUSION: These results strengthen the hypothesis that solar lentigines are markers of photoaging, whereas freckles are mainly determined by genetic factors. The finding that hormonal treatment is associated with a higher risk for solar lentigines merits further investigations. PMID- 22924837 TI - Preschool children born moderately preterm have increased waist circumference at two years of age despite low body mass index. AB - AIM: To investigate the development of waist circumference (WC) in preschool children born preterm compared with a population-based reference. BACKGROUND: Children born preterm are reported to be insulin resistant, despite being lean during early childhood. We hypothesize that the mechanism is through increased visceral adiposity. METHODS: Data from 4446 preschool children (2169 girls/2277 boys) born in 2001-2006 from a population-based study were compared with longitudinal measurements of body mass index (BMI) and WC from a cohort of 152 children (64 girls/88 boys) born moderately preterm in 2002-2004 (gestational age, 32-37 weeks). RESULTS: In the preterm children, the mean WC was 2.8 cm larger compared with the reference group (p < 0.001) at 2 years of age but not at 5 years of age. There was no significant difference in the mean BMI at 2 years of age. The preterm group was significantly leaner at 5 years of age, with a mean BMI of 15.13 compared with 15.98 in the reference group (p < 0.001). CONCLUSION: Children born moderately preterm present as lean during early childhood but have an increased waist circumference in infancy, pointing towards a change in fat distribution with more abdominal fat. This may have implications for their metabolic status. PMID- 22924838 TI - Mitochondrial DNA (COI) analyses reveal that amphipod diversity is associated with environmental heterogeneity in deep-sea habitats. AB - The relationship between species diversity and environmental parameters is poorly understood for the mobile macrofauna of deep-sea habitats due to under-sampling and subsequent lack of accurate taxonomic information. To redress this, cytochrome oxidase c subunit I (COI) DNA sequences were used to estimate species diversity and to compare phoxocephalid amphipod assemblages among 20 stations encompassing a range of environmental conditions. Two regions, east (Chatham Rise) and west (Challenger Plateau) of New Zealand were sampled to depths of 200 1200 m with an epibenthic sled. Using a comparison among identified morphospecies, we found a clear gap in sequence divergences between 6% and 13% and used a 6% threshold to designate molecular operational taxonomic units (MOTUs), as a surrogate to putative species. DNA sequences (n = 297) revealed high total diversity (n = 49 MOTUs), as well as high beta diversity (28 MOTUs found at single location only). Novel phoxocephalid MOTUs were found at most stations, especially on Challenger Plateau and the flanks of Chatham Rise. Analyses of interstation assemblages revealed a major split between regions, indicating minimal overlap in taxon distributions. A cluster of highly similar stations was identified, broadly distributed over the crest of Chatham Rise, in association with elevated food availability, probably resulting from higher surface productivity and relatively shallow depth. Accordingly, multivariate analysis revealed a strong correlation between phoxocephalid assemblages and food supply. This study highlights the value of molecular approaches, in particular COI sequences, for quantifying and comparing diversity in under-sampled and/or under-studied taxa. PMID- 22924839 TI - Asymmetric transfer hydrogenation of ketimines using well-defined iron(II)-based precatalysts containing a PNNP ligand. AB - Well-defined iron(II)-based complexes containing PNNP ligands catalyze a highly enantioselective reduction of N-(diphenylphosphinoyl)- and N-(p-tolylsulphonyl) ketimines. Under mild conditions and low catalyst loading, the ketimines are successfully reduced to the corresponding amines in enantiomeric excess ranging from 94 to 99%. PMID- 22924840 TI - Management of sigmoid volvulus: is early surgery justifiable? AB - INTRODUCTION: Sigmoid volvulus typically occurs in older patients who have multiple co-morbidities. Therefore, often, a conservative approach to management is chosen. However, there is little data on long-term outcomes of this approach in Australasia. The aim of this study was to review the recurrence and mortality outcomes of patients admitted to Dunedin Hospital with sigmoid volvulus. METHODS: All cases of sigmoid volvulus admitted to the Department of General Surgery at Dunedin Hospital from January 1989 to January 2009 were identified using a prospective database, the Otago Clinical Audit. Mortality data was accessed from the National Births and Deaths Registry. RESULTS: Fifty-seven patients, median age of 68, were included in the study with 84 admissions for sigmoid volvulus. A total of 39 of the 57 patients ultimately had surgery, 26 on the index admission. Thirty-one patients (61%) treated conservatively at index admission had a recurrence at a median of 31 days. Forty-two per cent of the patients treated conservatively a second time suffered a further recurrence at a median of 144 days. There was no recurrence in patients who had surgery. There was no in hospital mortality reported in either group. There was one anastomotic leak in the surgical group. Minor complications included ileus, respiratory infections, urinary tract infection and a hernia. CONCLUSION: Early elective operation for cases of sigmoid volvulus is encouraged in patients without prohibitive co morbidities as this study shows a high recurrence rate in conservatively managed patients and a low morbidity and mortality in surgically managed patients. PMID- 22924841 TI - A novel surgical-prosthetic approach for soft tissue dehiscence coverage around single implant. AB - OBJECTIVES: The aim of the study was to evaluate soft-tissue coverage and patient aesthetic satisfaction of a novel surgical-prosthetic approach to soft tissue dehiscence (STD) around single endosseous implant. MATERIAL AND METHODS: Twenty patients with buccal soft tissues dehiscence around single implants in the aesthetic area were consecutively enrolled. Treatment consisted in: removal of the implant supported crown, reduction in the implant abutment, coronally advanced flap in combination with connective tissue graft (CTG) and final restoration. The unrestored contralateral tooth normally positioned without recession defect was used as a reference. The soft tissue coverage and patient satisfaction were evaluated 1 year after the final restoration. RESULTS: One-year mean STD coverage was 96.3%, and complete coverage was achieved in 75% of the treated sites. The increase (1.54 +/- 0.21 mm) in buccal soft tissue thickness (STT) at 1 year was significantly correlated with CTG thickness at time of the surgery. The mean difference between graft thickness and STT increase was 0.09 +/ 0.14 mm, corresponding to the 5.8% of the original graft thickness. The aesthetic analysis showed a significant improvement between the baseline (median, 3.8; 95% CI, 2-4) and the 1-year (median, 8.0; 95% CI, 8-10) visual analogue scale (VAS) scores. CONCLUSION: The results from the present study demonstrated that the proposed bilaminar technique was effective in the coverage of buccal STD around single dental implant and the suggested prosthetic-surgical approach was aesthetically successful. PMID- 22924842 TI - Kinetically controlled nanostructure formation in self-assembled globular protein polymer diblock copolymers. AB - Aqueous processing of globular protein-polymer diblock copolymers into solid state materials and subsequent solvent annealing enables kinetic and thermodynamic control of nanostructure formation to produce block copolymer morphologies that maintain a high degree of protein fold and function. When model diblock copolymers composed of mCherry-b-poly(N-isopropylacrylamide) are used, orthogonal control over solubility of the protein block through changes in pH and the polymer block through changes in temperature is demonstrated during casting and solvent annealing. Hexagonal cylinders, perforated lamellae, lamellae, or hexagonal and disordered micellar phases are observed, depending on the coil fraction of the block copolymer and the kinetic pathway used for self-assembly. Good solvents for the polymer block produce ordered structures reminiscent of coil-coil diblock copolymers, while an unfavorable solvent results in kinetically trapped micellar structures. Decreasing solvent quality for the protein improves long-range ordering, suggesting that the strength of protein interactions influences nanostructure formation. Subsequent solvent annealing results in evolution of the nanostructures, with the best ordering and the highest protein function observed when annealing in a good solvent for both blocks. While protein secondary structure was found to be almost entirely preserved for all processing pathways, UV-vis spectroscopy of solid-state films indicates that using a good solvent for the protein block enables up to 70% of the protein to be retained in its functional form. PMID- 22924843 TI - Malignant lymphoma of the spleen in Japan: a clinicopathological analysis of 115 cases. AB - Primary splenic lymphoma is rare, but malignant lymphoma often produces a lesion in the spleen as part of systemic disease. The frequency of splenic malignant lymphoma in Japan is unknown. We classified 184 specimens of the spleen according to the World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues, 4th edition (2008). Of the 184 specimens, 115 were determined to be lymphoid neoplasm (62.5%). The most common subtype of lymphoid neoplasm was diffuse large B-cell lymphoma (DLBCL) (46 cases), followed by splenic marginal zone lymphoma (SMZL) (28 cases), follicular lymphoma (11 cases), splenic B-cell lymphoma, unclassifiable (SBL-U) (6 cases) and peripheral T-cell lymphoma, not otherwise specified (4 cases). In the SBL-U subtype, 5 of 6 cases were splenic diffuse red pulp small B-cell lymphoma, and one case was the hairy cell leukemia variant. Analysis of clinical features revealed that patients with DLBCL had a higher age, high lactate dehydrogenase and tumor formation in the spleen. On the other hand, it was found that patients with SMZL had splenomegaly but no discrete tumor formation. Most of the patients with SBL-U presented with thrombocytopenia, bone marrow involvement, and advanced stage. Our study revealed the frequency and clinical features of splenic malignant lymphoma in Japan. PMID- 22924844 TI - Altered expression of microRNA miR-21, miR-155, and let-7a and their roles in pulmonary neuroendocrine tumors. AB - MicroRNA (miRNA) has a critical effect on tumorigenesis through post transcriptional modification and is considered to be potential biomarkers for cancer diagnosis and treatment monitoring. We evaluated the expression pattern of three selected miRNAs (miR-21, miR-155, and let-7a) to evaluate their potential roles by quantitative reverse transcription-polymerase chain reaction using formalin-fixed and paraffin-embedded tissues of 63 surgically resected pulmonary neuroendocrine (NE) tumors (19 typical carcinoids (TCs), 6 atypical carcinoids (ACs), 19 large cell NE carcinomas (LCNECs), and 19 small cell lung carcinomas (SCLCs). Control amplification for U6 small nuclear RNA (U6) was performed in all samples. Normalized Ct values were calculated (Ct(Experimental miRNA) -Ct(U6) ) for each case and recorded. The expression levels of miR-21 and miR-155 were significantly higher in high-grade NE carcinomas (LCNECs and SCLCs) than in carcinoid tumors (TCs and ACs) (each P < 0.001). The expression level of miR-21 in carcinoid tumors with lymph node metastasis was significantly higher than in carcinoid tumors without lymph node metastasis (P= 0.010). To the best of our knowledge, the present study is the first to examine the expression patterns of miR-21 and miR-155 as an adjunctive diagnostic tool or clinically relevant biomarkers for pulmonary NE tumors. PMID- 22924845 TI - Evaluation of immunohistochemical staining using whole-slide imaging for HER2 scoring of breast cancer in comparison with real glass slides. AB - Whole-slide imaging (WSI) has been used for education and histological image preservation, and several studies have also reported its validity for practical pathological diagnosis. However, such studies employed materials stained with hematoxylin-eosin (HE), and very few attempts have been made to use immunohistochemically stained materials for diagnostic purposes. In the present study, we investigated the availability of WSI diagnosis for immunohistochemically stained materials in place of routine glass slides. Thirty pathologists participated in a trial of HER2 expression diagnosis using WSI and compared the results with those obtained by light microscopy. The validity of WSI diagnosis (interobserver agreement) was rated as 'substantial' in comparison with glass slide diagnosis (kappa-value = 0.719). There was a tendency for observers to assign higher scores with WSI than with glass slides, probably because WSI requires slides to be scanned into a computer and observed via a monitor. Although we were able to demonstrate the potential utility of WSI for diagnosing immunostained materials, it must be borne in mind that there are some differences in visualization between WSI and glass slides. PMID- 22924846 TI - Early colorectal carcinomas: CD10 expression, mucin phenotype and submucosal invasion. AB - We analyzed 170 tumors (polypoid, 98; non-polypoid, 72) of early colorectal carcinoma with or without submucosal invasions (Tis and T1 of TNM classification) from 161 patients to evaluate correlations between clinicopathological factors and immunohistochemical expressions of CD10, MUC2, and MUC5AC. The coexistence of adenomatous components was significantly less common in non-polypoid carcinomas (4.2%) than in polypoid carcinomas (66.3%) (P < 0.0001). Non-polypoid carcinomas were smaller in size and tended to infiltrate into the submucosa with higher incidence of lymphatic and venous permeations. CD10 was more frequently expressed in non-polypoid carcinomas (70.8%) than in polypoid carcinomas (51.0%) (P= 0.01). Total carcinomas with high grade atypia showed higher incidence of CD10 expression (60.6%) than those with low grade atypia (28.9%) (P < 0.0001). Carcinomas with low grade atypia exhibited a higher incidence of MUC2 and MUC5AC expression (91.1% and 57.8%, respectively), when compared with carcinomas with high grade atypia (41.6% and 20.0%, respectively) (both, P < 0.0001). In submucosal invasive carcinomas with residual intramucosal carcinoma component (IMCC), CD10 expression in IMCC and submucosal invasive carcinoma component (SMCC) simultaneously exhibited identical positive or negative results, regardless of the polypoid or non-polypoid growth pattern. The CD10 expression may occur in the early stage of carcinogenesis within the mucosa, and these neoplasms may retain CD10 in SMCC, possibly resulting in more advanced stages of stromal invasion and distant metastases. In conclusion, our data suggest that the CD10 expression and mucin phenotypes may be potentially useful markers for estimating biological properties of early colorectal carcinomas. PMID- 22924847 TI - Clinicopathological study of Japanese patients with genetic iron overload syndromes. AB - In addition to hemochromatosis, aceruloplasminemia and ferroportin disease may be complicated by iron-induced multiple organ damage. Therefore, clinicopathological features should be evaluated in a wider range of genetic iron disorders. This study included 16 Japanese patients with genetic iron overload syndromes. The responsible genes were CP in four, HAMP in one, HJV in three, TFR2 in five, and SLC40A1 in three patients. No phenotype dissociation was observed in patients with the CP, TFR2, or HAMP genotypes. Two of the three patients with the HJV genotype displayed classic hemochromatosis instead of the juvenile type. Patients with the SLC40A1 genotype were affected by mild iron overload (ferroportin A) or severe iron overload (ferroportin B). Transferrin saturation was unusually low in aceruloplasminemia patients. All patients, except those with ferroportin disease, displayed low serum hepcidin-25 levels. Liver pathology showed phenotype-specific changes; isolated parenchymal iron loading in aceruloplasminemia, periportal fibrosis associated with heavy iron overload in both parenchymal and Kupffer cells of ferroportin B, and parenchyma-dominant iron-loading cirrhosis in hemochromatosis. In contrast, diabetes occurred in all phenotypes of aceruloplasminemia, hemochromatosis, and ferroportin disease B. In conclusion, clinicopathological features were partially characterized in Japanese patients with genetic iron overload syndromes. PMID- 22924848 TI - Involvement of extraneural tissues and upregulation of inducible nitric oxide synthase after experimental infection with rabies virus in BALB/c mice and LEW/SsN rats. AB - Rabies virus can cause fatal encephalomyelitis, but the involvement of extraneural organs has not been well characterized. In this study, we investigated the histopathological changes and the distribution of viral antigens in extraneural organs after pathogenic rabies virus infection in mouse and rat models. In histopathological examination, classical viral encephalitis and rabies specific Negri body were observed in the brain. In addition to the central nervous system (CNS), inflammatory responses were found in other organs, such as the heart, kidney, liver, and lung. Similarly, immunohistochemical staining and reverse transcription-polymerase chain reaction revealed the presence of rabies virus in the CNS and extraneural tissues. Moreover, macrophages, especially in the lung and heart, were involved in the infection. Transcriptional analyses of the expression of inducible nitric oxide synthase (iNOS) demonstrated that rabies virus potentiated the gene expression of iNOS in the brain, lung, and heart. The immunoreactive iNOS-positive macrophages were detected adjacent to the infection. These results suggest that macrophages are involved in the extraneural infection and the expression of iNOS in macrophages contributes to the formation of tissue inflammation. Our study indicates the involvement of extraneural organs following rabies virus infection, which may aggravate the progression of this deadly disease. PMID- 22924850 TI - A case of pulmonary papillary adenoma: possible relationship between tumor histogenesis/tumorigenesis and fibroblast growth factor receptor 2 IIIb. AB - Pulmonary papillary adenoma is a rare tumor. We analyzed a tumor which appeared in a 16-year-old Japanese woman. The tumor histologically showed papillary proliferation of one-layered tumor cells coating inflammatory fibrovascular cores. At the periphery of the tumor, the tumor cells grew in a lepidic fashion. The tumor cells were confirmed as type-II pneumocytes with electron-microscope. In this study, using immunohistochemistry, in situ hybridization and real-time reverse transcription polymerase chain reaction, we examined the expressions and quantities of fibroblast growth factor 10 (FGF10), keratinocyte growth factor (KGF) and fibroblast growth factor receptor 2 (FGFR2) IIIb, based on the extent of their abilities of proliferation and differentiation of type II pneumocytes. The tumor cells expressed FGFR 2 and produced 350 times more FGFR2IIIb messenger RNA (mRNA) than did the nontumorous lung. The quantity of KGF mRNA in the tumor tissue was twice that of the nontumorous lung. Moreover, there was dysregulation of FGFR2IIIb transcription in the tumor. According to these findings, we expect overexpression of FGFR2IIIb to play an important role in causing tumor. Because FGFR is suspected to be connected with lung carcinoma, we also treat similar tumorigenesis via FGFR as carcinoma; complete resection of adenoma might be indicated. PMID- 22924849 TI - Effects of intrapulmonary viral tropism and cytokine expression on the histological patterns of cytomegalovirus pneumonia. AB - Pulmonary cytomegalovirus (CMV) infection causes fatal CMV pneumonia (CMVp) in immunocompromised patients; however, the mechanisms underlying CMV-infection induced pulmonary lesion development remain largely unknown. We examined the relationship between CMVp patterns and intrapulmonary viral tropism, including expression of inflammatory cytokines and related molecules. Double immunohistochemistry of CMV antigen and cellular markers showed that epithelial tropism was associated with a diffuse alveolar damage (DAD) pattern (CMVp-DAD) while stromal tropism was associated with a predominantly interstitial inflammation/fibrosis (IIF) (CMVp-IIF) or a combination of DAD and IIF (CMVp complex). Transforming growth factor (TGF)-beta1 expression was relevant to CMV induced tissue injury, and its expression was higher in CMVp-complex and CMVp-IIF than in CMVp-DAD. Expression of integrin beta6 (ITGB6), an adhesion molecule and important activator of TGF-beta1 in interstitial pneumonia, was lost in CMV infected pneumocytes, especially CMVp-DAD, whereas CMV-negative pneumocytes in CMVp-complex and CMVp-IIF showed overexpression. Diffuse interleukin (IL)-8 up regulation and strong expression were present in both CMV-infected pneumocytes and stromal cells only in CMVp-IIF cases with marked interstitial neutrophilic infiltration. On the basis of viral tropism and the expression of TGF-beta1, ITGB6, and IL-8, we conclude that CMV-infected pulmonary cells play an important role in the development of diverse CMVp patterns. PMID- 22924851 TI - Prediction of aided and unaided audiograms using sound-field auditory steady state evoked responses. AB - OBJECTIVE: To assess sound field auditory thresholds of hearing-impaired adults by using auditory steady-state evoked responses (ASSRs). DESIGN: ASSRs were recorded to carrier frequencies of 500, 1000, 2000, and 4000 Hz, each uniquely modulated at a single frequency of 80-100 Hz. ASSR thresholds were compared to behavioral auditory thresholds. STUDY SAMPLE: Twenty adults (11 male, age 35.6 years) with moderate-severe sensorineural hearing loss who had used hearing aids, and 10 normal-hearing subjects (mean age 22.4 years). RESULTS: For most frequencies, behavioral sound-field thresholds were slightly lower than ASSR thresholds in both aided and unaided conditions, with a significant correlation between them. Differences between ASSR and behavioral thresholds ranged between 516 dB in the unaided and between 5-16 dB in the aided condition. The ASSR amplitude growth function to 2000 Hz was steeper in both the aided and unaided conditions than in the normal-hearing group. CONCLUSIONS: Sound-field ASSRs can predict behavioral auditory thresholds in both the unaided and aided condition, as well as behavioral functional gains. The ASSR growth function for 2000 Hz is suggested to reflect an underlying mechanism of intensity encoding common to abnormal loudness perception frequently reported in cases of cochlear hearing loss. PMID- 22924852 TI - Dynamic complex formation between HD-GYP, GGDEF and PilZ domain proteins regulates motility in Xanthomonas campestris. AB - RpfG is a member of a class of wide spread bacterial two-component regulators with an HD-GYP cyclic di-GMP phosphodiesterase domain. In the plant pathogen Xanthomonas campestris, RpfG together with the sensor kinase RpfC regulates multiple factors as a response to the cell-to-cell Diffusible Signalling Factor (DSF). A dynamic physical interaction of RpfG with two diguanylate cyclase (GGDEF) domain proteins controls motility. Here we show that, contrary to expectation, regulation of motility by the GGDEF domain proteins does not depend upon their cyclic di-GMP synthetic activity. Furthermore we show that the complex of RpfG and GGDEF domain proteins recruits a specific PilZ domain 'adaptor' protein, and this complex then interacts with the pilus motor proteins PilU and PiIT. The results support a model in which DSF signalling influences motility through the highly regulated dynamic interaction of proteins that affect pilus action. A specific motif that we identify to be required for HD-GYP domain interaction is conserved in a number of GGDEF domain proteins, suggesting that regulation via interdomain interactions is of broad relevance. PMID- 22924853 TI - Invariant principles of speech motor control that are not language-specific. AB - Bilingual speakers must learn to modify their speech motor control mechanism based on the linguistic parameters and rules specified by the target language. This study examines if there are aspects of speech motor control which remain invariant regardless of the first (L1) and second (L2) language targets. Based on the age of academic exposure and proficiency in L2, 21 Bengali-English bilingual participants were classified into high (n = 11) and low (n = 10) L2 (English) proficiency groups. Using the Optotrak 3020 motion sensitive camera system, the lips and jaw movements were recorded while participants produced Bengali (L1) and English (L2) sentences. Based on kinematic analyses of the lip and jaw movements, two different variability measures (i.e., lip aperture and lower lip/jaw complex) were computed for English and Bengali sentences. Analyses demonstrated that the two groups of bilingual speakers produced lip aperture complexes (a higher order synergy) that were more consistent in co-ordination than were the lower lip/jaw complexes (a lower order synergy). Similar findings were reported earlier in monolingual English speakers by Smith and Zelaznik. Thus, this hierarchical organization may be viewed as a fundamental principle of speech motor control, since it is maintained even in bilingual speakers. PMID- 22924854 TI - Isolation and identification of lactic acid bacteria from fermented red dragon fruit juices. AB - Red dragon fruit or red pitaya is rich in potassium, fiber, and antioxidants. Its nutritional properties and unique flesh color have made it an attractive raw material of various types of food products and beverages including fermented beverages or enzyme drinks. In this study, phenotypic and genotypic methods were used to confirm the identity of lactic acid bacteria (LAB) appeared in fermented red dragon fruit (Hylocereus polyrhizus) beverages. A total of 21 isolates of LAB were isolated and characterized. They belonged to the genus of Enterococcus based on their biochemical characteristics. The isolates can be clustered into two groups by using the randomly amplified polymorphic DNA method. Nucleotide sequencing and restriction fragment length polymorphism of the 16S rRNA region suggested that they were either Enterococcus faecalis or Enterococcus durans. PRACTICAL APPLICATION: Current research revealed the use of biochemical analyses and molecular approaches to identify the microbial population particularly lactic acid bacteria from fermented red dragon fruit juices. PMID- 22924855 TI - Occupational disability in bipolar disorder: analysis of predictors of being on severe disablement benefit (PREBIS study data). AB - OBJECTIVE: Patients diagnosed with bipolar disorder (BD) are reported to have significant work impairment during interepisode intervals. This study was carried out to assess potential predictors of occupational disability in a longitudinal follow-up of euthymic patients. METHOD: We included 327 euthymic patients diagnosed with BD type I or type II, 226 of whom were employed and 101 were receiving a severe disablement benefit (SDB). Sociodemographic data were studied and episode recurrence was assessed along a 1-year follow-up. Logistic regression analysis was applied to determine predictors of receiving SDB. Cox regression was built to study recurrences. RESULTS: Predictors of receiving SDB were: axis II comorbidity [Odds Ratio (OR) = 2.94, CI: 1.26-6.86, P = 0.013], number of manic episodes (OR = 1.21, CI: 1.10-1.34, P < 0.001), being without stable partner (OR = 2.44, CI: 1.34-4.44, P = 0.004) and older age (OR = 1.08, CI: 1.05-1.12, P < 0.001). Bipolar patients receiving SDB presented more episodic recurrences regardless of polarity than employed bipolar patients (P = 0.002). The time until recurrence in 25% of the bipolar patients receiving SDB was 6.08 months (CI: 4.44 11.77) being 13.08 months (CI: 9.60 to -) in the employed group. CONCLUSION: Occupational disability in bipolar patients is associated with axis II comorbidity, more previous manic episodes, not having a stable relationship, older age, and more recurrences at 1-year follow-up. PMID- 22924856 TI - Transversal Modulation Ion Mobility Spectrometry (TM-IMS), a new mobility filter overcoming turbulence related limitations. AB - The analysis of ions according to their mobility is a technique that is attracting increasing interest. The new technology presented here, which we have termed Transversal Modulation Ion Mobility Spectrometry (TM-IMS), utilizes only electric fields, operates at atmospheric pressure, produces a continuous output of mobility selected ions (according to their true mobility and not to nonlinear effects), and has a very accessible inlet and outlet. These features would make it an ideal choice for tandem IMS-MS analysis in combination with most commercial Atmospheric Pressure Interface MS (API-MS) systems. We modeled and evaluated two different TM-IMS configurations (TM-IMS, and multistage TM-IMS), and we concluded that the most promising configuration would be a two-stage TM-IMS. We developed and tested a TM-IMS, and the measured resolving power is R = 55. The TM-IMS behaves similarly to the planar Differential Mobility Analyzer, but the TM-IMS utilizes only electric fields, and no fragile flow with high Reynolds numbers is required. We tested the robustness of the TM-IMS, which proves to be a very robust and reliable analyzer: the required voltage accuracy is 5 V in 10 kV, and the mechanical precision is 1 mm in 5 cm. PMID- 22924857 TI - Wide dynamic range sensing with single quantum dot biosensors. AB - Single-particle analysis of biosensors that use charge transfer as the means for analyte-dependent signaling with semiconductor nanoparticles, or quantum dots, was examined. Single-particle analysis of biosensors that use energy transfer show analyte-dependent switching of nanoparticle emission from off to on. The charge-transfer-based biosensors reported here show constant emission, where the analyte (maltose) increases the emission intensity. By monitoring the same nanoparticles under various conditions, a single charge-transfer-based biosensor construct (one maltose binding protein, one protein attachment position for the reductant, one type of nanoparticle) showed a dynamic range for analyte (maltose) detection spanning from 100 pM to 10 MUM while the emission intensities increase from 25 to 175% at the single-particle level. Since these biosensors were immobilized, the correlation between the detected maltose concentration and the maltose-dependent emission intensity increase could be examined. Minimal correlation between maltose detection limits and emission increases was observed, suggesting a variety of reductant-nanoparticle surface interactions that control maltose-dependent emission intensity responses. Despite the heterogeneous responses, monitoring biosensor emission intensity over 5 min provided a quantifiable method to monitor maltose concentration. Immobilizing and tracking these biosensors with heterogeneous responses, however, expanded the analyte dependent emission intensity and the analyte dynamic range obtained from a single construct. Given the wide dynamic range and constant emission of charge-transfer based biosensors, applying these single molecule techniques could provide ultrasensitive, real-time detection of small molecules in living cells. PMID- 22924858 TI - Backloading in the sequential lineup prevents within-lineup criterion shifts that undermine eyewitness identification performance. AB - Although the sequential lineup has been proposed as a means of protecting innocent suspects from mistaken identification, little is known about the importance of various aspects of the procedure. One potentially important detail is that witnesses should not know how many people are in the lineup. This is sometimes achieved by backloading the lineup so that witnesses believe that the lineup includes more photographs than it actually does. This study aimed to investigate the effect of backloading on witness decision making. A large sample (N = 833) of community-dwelling adults viewed a live "culprit" and then saw a target-present or target-absent sequential lineup. All lineups included 6 individuals, but the participants were told that the lineup included 6 photographs (nonbackloaded condition) or that the lineup included 12 or 30 photographs (backloaded conditions). The suspect either appeared early (Position 2) or late (Position 6) in the lineup. Innocent suspects placed in Position 6 were chosen more frequently by participants in the nonbackloaded condition than in either backloaded condition. Additionally, when the lineup was not backloaded, foil identification rates increased from Positions 3 to 5, suggesting a gradually shifting response criterion. The results suggest that backloading encourages participants to adopt a more conservative response criterion, and it reduces or eliminates the tendency for the criterion to become more lenient over the course of the lineup. The results underscore the absolute importance of ensuring that witnesses who view sequential lineups are unaware of the number of individuals to be seen. PMID- 22924859 TI - Reproductive performance of Thoroughbred mares in the Waikato region of New Zealand: 2. Multivariable analyses and sources of variation at the mare, stallion and stud farm level. AB - AIM: The objective of this study was to utilise multivariable statistical methods appropriate for clustered data to identify mare-related explanatory variables that significantly affected the reproductive performance of Thoroughbred mares in the Waikato region of New Zealand. In addition, we aimed to determine the relative contribution of the mare, stallion and stud farm to reproductive performance. METHODS: A prospective cohort study was performed involving five stud farms in the Waikato region of New Zealand during three consecutive breeding seasons (2006-2008). A total of 1,482 individual mares contributed 2007 mare years and 3,402 oestrous cycles over the three breeding seasons. Reproductive performance was measured using three parameters; (a) first-cycle pregnancy rate (FCPR), (b) end-of-season pregnancy rate (SPR), and (c) the start-of-mating to conception interval. RESULTS: When controlled for the effects of serving stallion, stud farm and year of study the only significant mare-related variables included in the final models of FCPR, SPR and conception interval were the age of the mare and her reproductive status (classified as dry or foaling). Advancing mare age significantly reduced reproductive performance regardless of reproductive status and foaling mares had significantly poorer reproductive outcomes compared with dry mares when controlled for age. For each additional increase in year of age, the FCPR was reduced by a factor of 0.94 (95% CI=0.92 0.96) and the SPR was reduced by a factor of 0.91 (95% CI=0.88-0.93). Mares older than 14 years of age took longer to conceive after the start-of-mating compared with younger mares. The daily hazard of conception for mares 14 years and older was 0.64 (95% CI=0.47-0.83) times less than mares younger than 9 years of age. Determining the relative contribution of the mare, stallion and stud farm to the FCPR indicated that 95.9% of the variation was at the mare level, 4.1% was at the stallion level and 0% was at the stud farm level. For the SPR the variance components indicated that 92.5% of the variation was at the mare level, 6.7% was at the stallion level and 0.8% was at the stud farm level. CONCLUSIONS: The reproductive performance of Thoroughbred mares in the Waikato region of New Zealand is influenced by two main mare-related factors; the age of the mare and her reproductive status (dry or foaling). The majority of variation in reproductive performance was associated with mare-level factors and the contribution of the stallion and stud farm was relatively minor. PMID- 22924860 TI - Are there long-term effects of extracorporeal shockwave lithotripsy in paediatric patients? AB - WHAT'S KNOWN ON THE SUBJECT? AND WHAT DOES THE STUDY ADD?: Extracorporeal shockwave lithotripsy is effective for the treatment of paediatric renal stones with favourable short-term safety. Extracorporeal shockwave lithotripsy for treatment of paediatric renal stones is also safe for the kidney and the child on long-term follow-up. OBJECTIVE: To evaluate the long-term effects of extracoporeal shockwave lithotripsy (SWL) for treatment of renal stones in paediatric patients. PATIENTS AND METHODS: A database of paediatric patients who underwent SWL monotherapy for treatment of renal stones from September 1990 through to January 2009 was compiled. This study included only patients with follow-up for more than 2 years. The long-term effects of SWL were evaluated at the last follow-up with measurement of patients' arterial blood pressure, estimation of random blood sugar and urine analysis. The results of diastolic blood pressure were plotted against a standardized age reference curve. The treated kidney was examined by ultrasonography for measurement of renal length and detection of stones. The measured renal lengths were plotted against age calculated normal renal lengths in healthy individuals. RESULTS: The study included 70 patients (44 boys (63%) and 26 girls) with mean age at the time of SWL 6.5 +/- 3.6 years (range 1-14). The mean follow-up period was 5.2 +/- 3.6 years (range 2.1-17.5). The mean age at last follow-up was 11.7 +/- 5.3 years (range 4.4-27.5). No patients developed hypertension or diabetes. Only one treated kidney was smaller than one standard deviation of the calculated length. The cause of this was obstruction by a stone in the pelvic ureter 3 years after SWL. CONCLUSION: The long-term follow-up after SWL for treatment of renal stones in paediatric patients showed no effect on renal growth and no development of hypertension or diabetes. PMID- 22924861 TI - Electrochemical switching of conformation of random polyampholyte brushes grafted onto polypyrrole. AB - We demonstrate the possibilities for subtle control over redox-driven surface switching that could be obtained by altering the balance between hydrophobic, ionic, and dipolar components of polymer brushes that are grafted onto electrochemically active conducting polymers (ECP). We extend our previous work on the conformation switching of polyzwitterionic brushes grafted onto ECP to the case of ABC random polyampholyte brushes: here, a statistical near-neutral copolymer of methyl methacrylate (MMA), methacryloxyethyltrimethylammonium chloride (METAC), and 3-sulfopropyl methacrylate potassium salt (SPMA). The statistical polyampholyte differs from the polyzwitterion in that it is not strictly neutral and the charges do not have a defined spatial relationship to one another. The consequence is a significant change in the switching behavior that is also dependent on the salt concentration in the electrolyte. The results can be understood by reference to the theory of polyampholyte conformation in solution given by Higgs and Joanny modified to apply to a surface-bound brush. Three states of the polyampholyte brush are deduced from electrochemical impedance spectroscopy (EIS): collapsed, partially collapsed, and expanded. At low salt concentration, the behavior was the opposite of that of the polyzwitterion: the brush switched between partially collapsed with the ECP reduced and expanded with the ECP oxidized. With increase of salt concentration, the switch changed, to collapsed with the ECP oxidized and partially collapsed with ECP reduced. At still higher salt concentration, the switch changed back again, to partially collapsed with the ECP reduced and expanded with the ECP oxidized. Measurements of surface wetting under electrochemical control supported the interpretation. The behavior can be contrasted with that of zwitterionic brushes, which show a switch between collapsed with ECP oxidized and expanded with ECP reduced, independent of salt concentration over the same range (10(-3)-2 M NaCl) as that studied here, and that of zwitterionic-hydrophobic block copolymers where the switch is suppressed at low salt concentration. The results illustrate the significant range of behavior that can be engineered into these electrochemically switchable systems. PMID- 22924862 TI - The development of prosociality from adolescence to early adulthood: the role of effortful control. AB - OBJECTIVE: The present longitudinal study examined the development of self reported prosociality (i.e., the tendency to enact prosocial behaviors) from adolescence to early adulthood and its prediction from teacher-reported effortful control (i.e., dispositional regulation) at age 13. METHOD: Participants were 573 (276 girls) Italian adolescents aged approximately 13 (M = 12.98, SD = 0.80) at the first assessment and 21 (M = 21.23, SD = 0.67) at the last assessment. The study used three different cohorts recruited across ten years (from 1994 to 2004) from a larger longitudinal project with a multiple-cohort design. RESULTS: Latent growth curve modeling indicated that the overall level of prosociality declined until approximately age 17 with a subsequent slight rebound until age 21. Significant inter-individual variability in developmental trends of prosociality in males and females was observed. Youths' effortful control was related to a lesser decline of prosociality in adolescence. CONCLUSIONS: Being able to regulate one's own emotions and behaviors in early adolescence may not only affect the tendency to behave prosocially, but also counter the self-centered tendencies observed across this phase of development. PMID- 22924864 TI - Abstracts of the 30th World Congress of Endourology & SWL. September 4-8, 2012. Istanbul, Turkey. PMID- 22924863 TI - Correlation of photographic images from the Leeds revised acne grading system with a six-category global acne severity scale. AB - BACKGROUND: Few global acne grading systems include individualized assessments of chest and back as well as face. The Leeds revised acne grading system is based on photographic images while the Comprehensive Acne Severity Scale (CASS) is based on textual descriptions. There exists an unmet need for a global scale based on both text and photos. PURPOSE: Our objective was to evaluate the correspondence of severity grades from descriptive text (CASS grades) for each Leeds image. METHODS: Twenty-three dermatologists independently graded 56 photos of face, chest and back of varying acne severity using CASS. Photographs were randomly presented from the The Leeds revised acne grading system (n = 31) and from acne patients of the corresponding author (n = 25). For each Leeds photo, rater responses for CASS grades were transformed into median, coefficient of variation and percentiles. RESULTS: High rater agreement (>=75%) was observed for Leeds facial inflammatory 2 (CASS 3), 4 (CASS 4), 6 (CASS 4), 9-12 (all CASS 5); Leeds facial comedonal A (CASS 2); Leeds chest 7 and 8 (both CASS 5); and Leeds back 7 and 8 (both CASS 5). Lowest coefficients of variance were observed in Leeds facial inflammatory 4, 9, 10, 11; Leeds facial comedonal A; Leeds chest 7 and 8; and Leeds back 8. Conclusions Leeds photos, by inadequately portraying facial acne grades 1 (almost clear) and 2 (mild) and back and chest grades 1-4 (almost clear to severe), cannot accurately represent the spectrum of severity in a six category global acne scale. Accordingly, there is a current need for images that correspond to a categorical acne scale. PMID- 22924865 TI - Impact of professionalism in nursing on in-hospital bedside monitoring practice. AB - AIM: This article reports a study exploring nursing practice of monitoring in hospital patients including intra- and interprofessional communication and collaboration. BACKGROUND: Sub-optimal care in general in-hospital wards may lead to admission for intensive care, cardiac arrest, or sudden death. Reasons may include infrequent measurements of vital parameters, insufficient knowledge of their predictive values, and/or sub-optimal use of Medical Emergency Teams. This study was designed to improve understanding of nursing practice and to identify changes required to support nursing staff in improving standards of clinical monitoring practice and patient safety in general in-hospital wards. DESIGN: The study was designed as a qualitative descriptive clinical study, based on method triangulation including structured individual observations and semi-structured individual interviews. METHODS: In the spring of 2009, structured observations and semi-structured interviews of 13 nurses were carried out at a university hospital in Copenhagen, Denmark. The observational notes and interview transcriptions were analysed using content analysis. RESULTS: One theme (Professionalism influences nursing monitoring practice) and two sub-themes (Knowledge and skills and Involvement in clinical practice through reflections) were identified. Three categories (Decision-making, Sharing of knowledge, and Intra- and interprofessional interaction) were found to be associated with the theme, the sub-themes, and with each other. CONCLUSION: Clinical monitoring practice varies considerably between nurses with different individual levels of professionalism. Future initiatives to improve patient safety by further developing professionalism among nurses need to embrace individual and organizational attributes to strengthen their practice of in-hospital patient monitoring and management. PMID- 22924866 TI - Noncontact measurement of charge carrier lifetime and mobility in GaN nanowires. AB - The first noncontact photoconductivity measurements of gallium nitride nanowires (NWs) are presented, revealing a high crystallographic and optoelectronic quality achieved by use of catalyst-free molecular beam epitaxy. In comparison with bulk material, the NWs exhibit a long conductivity lifetime (>2 ns) and a high mobility (820 +/- 120 cm(2)/(V s)). This is due to the weak influence of surface traps with respect to other III-V semiconducting NWs and to the favorable crystalline structure of the NWs achieved via strain-relieved growth. PMID- 22924867 TI - Alterations in serum lipid profile patterns in oral lichen planus: a cross sectional study. AB - BACKGROUND: Oral lichen planus (OLP) is a chronic inflammatory disorder. Recently, a case-control study found that lichen planus was associated with dyslipidemia in a large series of patients. However, no data were presented about lipid values in patients and controls. OBJECTIVES: The aim of this study was to investigate the hypothetical association between OLP and dyslipidemia. MATERIALS AND METHODS: The study included a total of 400 patients (200 with OLP and 200 controls with other oral diseases) and investigated the prevalence of dyslipidemia. The variables analyzed were age, sex, tobacco and alcohol consumption, clinical form of OLP and lipid profiles. RESULTS: A 54% prevalence of dyslipidemia was found (58% among the OLP group and 50% in the control group). Statistically significant differences in high-density lipoprotein were found between OLP patients and the control group (p = 0.003). A logistic regression model for presence/absence of cardiovascular risk (Castelli's atherogenic index of >= 5.1 for men and >= 4.5 for women) found statistically significant differences for sex and tobacco consumption. CONCLUSIONS: The study found a higher atherogenic index amongst OLP patients. PMID- 22924868 TI - A direct blood polymerase chain reaction approach for the determination of GP.Mur (Mi.III) and other Hil+ Miltenberger glycophorin variants. AB - BACKGROUND: GP.Mur (Mi.III) is a glycophorin B-A-B hybrid sialoglycoprotein expressing several potent immunogens, including Mi(a), Mur, and Hil. GP.Mur is considered one of the most important red blood cell (RBC) phenotypes in blood banking in Southeast Asia. However, there are no antibodies commercially available for the screening of GP.Mur RBCs. STUDY DESIGN AND METHODS: To develop a direct blood polymerase chain reaction (PCR) approach for the screening of GP.Mur cells, we first confirmed the genomic sequence differences among four GP.Mur and three Mi(a-) samples by sequencing their GYP.Mur and GYPB genes. With these data, we designed PCR primers that best discriminate GYPB and GYP.Mur. Our primer design also allows the detection of other Hil+ glycophorin variants. We also constructed two plasmids--pGBi2i3 and pMiIIIi2i3--which serve as the negative and positive control DNA, respectively, for the PCR procedure. Additionally, we designed a control PCR to be run side by side with the typing PCR. RESULTS: Because of the high specificity of our primers, we found it unnecessary to extract DNA from blood samples for PCR. We have tested this PCR method on 379 fresh and frozen blood samples. The results were further validated by serology and DNA sequencing and were shown to be completely accurate in our hand. We also found that the rapid genotyping method--high-resolution melting- can be a timesaving alternative for DNA sequencing. CONCLUSION: This direct blood PCR approach for determination of GP.Mur and related Hil+ phenotypes is reliable and economical and is expected to be useful for blood banking in Southeast Asia. PMID- 22924869 TI - Low postnatal serum IGF-I levels are associated with bronchopulmonary dysplasia (BPD). AB - AIM: To characterize postnatal changes in serum insulin-like growth factor-1 (IGF I) in relation to development of bronchopulmonary dysplasia (BPD) in very preterm infants. METHODS: Longitudinal study of 108 infants with mean (SD) gestational age (GA) 27.2 (2.2) weeks. Weekly serum samples of IGF-I were analysed from birth until postmenstrual age (PMA) 36 weeks. Multivariate models were developed to identify independent predictors of BPD. RESULTS: Postnatal mean IGF-I levels at postnatal day (PND) 3-21 were lower in infants with BPD compared with infants with no BPD (16 vs. 26 MUg/L, p < 0.001). Longitudinal postnatal change in IGF-I levels (IGF-I regression coefficient (beta)), PNDs 3-21, was lower in infants with BPD compared with infants with no BPD (0.28 vs. 0.97, p = 0.002) and mean IGF-I during PMA 30-33 weeks was lower in infants with BPD as compared with infants without BPD (22 vs. 29 MUg/L, p < 0.001). In a binomial multiple regression model, lower GA, male gender and lower mean serum IGF-I levels during PND 3-21 were the most predictive risk factors associated with BPD (r(2) = 0.634, p < 0.001). CONCLUSION: Lower IGF-I concentrations during the first weeks after very preterm birth are associated with later development of BPD. PMID- 22924871 TI - Pathologies of the appendix: a 10-year review of 4670 appendicectomy specimens. AB - BACKGROUND: Debate surrounds the management of the macroscopically normal appendix. Current literature recommends its removal given the high incidence of microscopic appendicitis, and other unusual pathologies in the normal-looking appendix. Negative appendicectomies are reported on the decline with increased use of diagnostic radiological adjuncts. METHODS: This study analysed pathologies of the appendix over 10 years in the Pathology Department in Canberra. A positive appendicectomy was defined as acute appendicitis, faecoliths, worms, endometriosis or appendiceal tumours. We reviewed the positive appendicectomy rate over this time period. RESULTS: There were 4670 appendicectomy specimens in 2386 males (51.1%) and 2284 (49%) females. The incidence of acute appendicitis was 71.3% and the positive appendicectomy rate was 76.3%. There were significantly fewer negative appendicectomies in males (16.8%) compared with females (31.0%). There was no appreciable change in this trend over the study period. Of the positive appendicectomies, there were 129 (3.6%) faecoliths. Of these, only 39.5% had concomitant appendicitis. There were 44 (1.2%) specimens identified with worms. Of these, 40.9% had concomitant appendicitis. There were 14 cases of endometriosis of the appendix of which 36% had concomitant appendicitis. There were 58/3562 (1.6%) appendiceal tumours within the positive appendicectomy group the majority of which were carcinoid tumours (65.5%). CONCLUSION: There is a higher incidence of negative appendicectomies in women compared with men, which is similar to other published studies. Faecoliths and worms are a known cause of appendiceal colic and in our series were identified mostly in the absence of histological evidence of appendicitis. PMID- 22924870 TI - Genome-wide patterns of divergence and gene flow across a butterfly radiation. AB - The Heliconius butterflies are a diverse recent radiation comprising multiple levels of divergence with ongoing gene flow between species. The recently sequenced genome of Heliconius melpomene allowed us to investigate the genomic evolution of this group using dense RAD marker sequencing. Phylogenetic analysis of 54 individuals robustly supported reciprocal monophyly of H. melpomene and Heliconius cydno and refuted previous phylogenetic hypotheses that H. melpomene may be paraphylectic with respect to H. cydno. Heliconius timareta also formed a monophyletic clade closely related but distinct from H. cydno with Heliconius heurippa falling within this clade. We find evidence for genetic admixture between sympatric populations of the sister clades H. melpomene and H. cydno/timareta, particularly between H. cydno and H. melpomene from Central America and between H. timareta and H. melpomene from the eastern slopes of the Andes. Between races, divergence is primarily explained by isolation by distance and there is no detectable genetic population structure between parapatric races, suggesting that hybrid zones between races are not zones of secondary contact. Our results also support previous findings that colour pattern loci are shared between populations and species with similar colour pattern elements. Furthermore, this pattern is almost unique to these genomic regions, with only a very small number of other loci showing significant similarity between populations and species with similar colour patterns. PMID- 22924872 TI - Current trends in interprofessional education of health sciences students: a literature review. AB - There is a pressing need to redesign health professions education and integrate an interprofessional and systems approach into training. At the core of interprofessional education (IPE) are creating training synergies across healthcare professions and equipping learners with the collaborative skills required for today's complex healthcare environment. Educators are increasingly experimenting with new IPE models, but best practices for translating IPE into interprofessional practice and team-based care are not well defined. Our study explores current IPE models to identify emerging trends in strategies reported in published studies. We report key characteristics of 83 studies that report IPE activities between 2005 and 2010, including those utilizing qualitative, quantitative and mixed method research approaches. We found a wide array of IPE models and educational components. Although most studies reported outcomes in student learning about professional roles, team communication and general satisfaction with IPE activities, our review identified inconsistencies and shortcomings in how IPE activities are conceptualized, implemented, assessed and reported. Clearer specifications of minimal reporting requirements are useful for developing and testing IPE models that can inform and facilitate successful translation of IPE best practices into academic and clinical practice arenas. PMID- 22924874 TI - Hearing loss in Angolan children with sickle-cell disease. AB - BACKGROUND: Hearing loss and pneumococcal infections occur in children with sickle-cell disease (SCD). We assessed the prevalence of hearing loss and otological findings, especially otitis media, among children with SCD in Luanda, Angola. METHODS: We performed otorhinolaryngological examination, tympanometry and, at ages over 5 years, pure-tone audiometry, in 61 outpatients of the SCD clinic and 61 healthy controls in the Paediatric Hospital of Luanda. RESULTS: Bilateral hearing loss exceeding 25 dB occurred in nine (36%; median age 7.8 years) SCD children versus three (11%; P = 0.047) control children. The hearing loss in the SCD group was predominantly mild (26-40 dB), involved low- and speech range frequencies, and was sex independent. Acute otitis media occurred in two (3%) children with SCD versus four (6%; P = 0.68) control children, chronic otitis in zero versus two (3%; P = 0.50), and middle-ear effusion in one versus one (2%; P > 0.99). We found no significant differences in the otological profiles of the study groups. CONCLUSIONS: In sub-Saharan Africa, hearing screening of SCD children is a must at preschool age. The actual prevalence of otitis media and its role in the cause of hearing loss in children with SCD remain subjects for further research. PMID- 22924875 TI - Effects of minute misregistrations of prefabricated markers for image-guided dental implant surgery: an analytical evaluation. AB - OBJECTIVES: The goal of the present study was to develop a theoretical analysis of errors in implant position, which can occur owing to minute registration errors of a reference marker in a cone beam computed tomography volume when inserting an implant with a surgical stent. MATERIAL AND METHODS: A virtual dental-arch model was created using anatomic data derived from the literature. Basic trigonometry was used to compute effects of defined minute registration errors of only voxel size. The errors occurring at the implant's neck and apex both in horizontal as in vertical direction were computed for mean +/-95% confidence intervals of jaw width and length and typical implant lengths (8, 10 and 12 mm). RESULTS: Largest errors occur in vertical direction for larger voxel sizes and for greater arch dimensions. For a 10 mm implant in the frontal region, these can amount to a mean of 0.716 mm (range: 0.201-1.533 mm). Horizontal errors at the neck are negligible, with a mean overall deviation of 0.009 mm (range: 0.001-0.034 mm). Errors increase with distance to the registration marker and voxel size and are affected by implant length. CONCLUSION: Our study shows that minute and realistic errors occurring in the automated registration of a reference object have an impact on the implant's position and angulation. These errors occur in the fundamental initial step in the long planning chain; thus, they are critical and should be made aware to users of these systems. PMID- 22924876 TI - Creating 3D angiogenic growth factor gradients in fibrous constructs to guide fast angiogenesis. AB - Fast angiogenesis in 3D fibrous constructs that mimic the morphology of the extracellular matrix remains challenging due to limited porosity in the densely packed constructs. We investigated whether mimicking the in vivo chemotaxis microenvironment for native blood vessel formation would stimulate angiogenesis in the fibrous constructs. The chemotaxis microenvironment was created by introducing 3D angiogenic growth factor gradients into the constructs. We have developed a technique that can quickly fabricate (~40 min) such 3D gradients by simultaneously electrospinning polycaprolactone (PCL) fibers, encapsulating gradient amount of bFGF (stabilized by heparin) into poly(lactide-co-glycolide) (PLGA) microspheres, and electrospraying the microspheres into PCL fibers. Gradient formation was confirmed by fluorescence microscopy. Gradients with different steepnesses were obtained by modulating the initial concentration of the bFGF solution. All of the constructs were able to sustainedly release bioactive bFGF over a 28 day period. The release kinetics was dependent on the bFGF loading and steepness of the gradient. In vitro cell migration study demonstrated that bFGF gradients significantly increased the depth of cell migration. To assess the efficacy of bFGF gradients in inducing angiogenesis, we implanted constructs subcutaneously using mouse model. bFGF gradients significantly promoted cell penetration into the constructs. After 10 days of implantation, a high density of mature blood vessels (positive to both CD31 and alpha-SMA) were formed in the constructs. Vessel density was increased with the increase in steepness of the bFGF gradient. These gradient constructs may have potential to engineer vascularized tissues for various applications. PMID- 22924877 TI - Long-term survival of microscopic animals under desiccation is not so long. AB - More frequent events of drought are predicted to happen in the future, but our ability to predict the effect on the biota may be limited by our partial understanding of extremophiles. Among the few animals that are able to survive in the absence of water for long periods of time are rotifers, tardigrades, and nematodes. Here, we take advantage of lichen collections stored dry at ambient temperature and humidity for years in museums, and through statistical modeling we demonstrate that the survival rates over time do not differ among animal groups but are strongly influenced by the type of substrate (the different lichen species). Our results suggest that desiccated organisms are prone to irreversible damage to biological structures, independently of the different biochemical processes involved in desiccation tolerance by different animals. The influence of the environment overcomes any taxon-specific response to survive extreme droughts. The predicted ability to survive for up to 10 years while desiccated enables these organisms to achieve potential global distributions, endurance against parasites, and even survival when exposed to outer space. PMID- 22924878 TI - Unemployment, ethnicity and psychosis. AB - OBJECTIVE: This study describes the incidence of psychosis in unemployed people and determines whether unemployment has a greater impact on the development of psychosis amongst Black minority groups than White groups. METHOD: Patients with a first diagnosis of Research Diagnostic Criteria psychosis, in a defined area of London from 1998 to 2004, were identified. Crude and standardised incidence rates of psychosis amongst unemployed people for each ethnic group were calculated. Poisson regression modelling tested for interactions between unemployment and ethnicity. RESULTS: Hundred cases occurred amongst employed people and 78 cases occurred amongst the unemployed people. When standardised to the employed White population of the area, White unemployed people had a standardised incidence ratio (SIR) of 11.7 (95% CI 6.4-19.7), Black Caribbean people had a SIR of 60.1(95% CI 39.3-88) and Black African people had a SIR of 40.7 (95% CI 25.8 61.1). There was no interaction however between ethnicity and unemployment (Likelihood ratio test P = 0.54). CONCLUSION: Rates of psychosis are high amongst unemployed people in south London and extremely high amongst Black Caribbean and Black African unemployed people. There was no evidence however that the minority groups were particularly sensitive to the stresses, limitations or meaning of unemployment. PMID- 22924879 TI - Optofluidic surface enhanced Raman spectroscopy microsystem for sensitive and repeatable on-site detection of chemical contaminants. AB - We demonstrate highly sensitive detection of real-world food and water contaminants using a portable and automated optofluidic surface enhanced Raman spectroscopy (SERS) microsystem. The optofluidic SERS device utilizes a porous microfluidic matrix formed by packed silica microspheres to concentrate silver nanoparticles and adsorbed analyte molecules, resulting in greatly improved SERS detection performance. In addition, a passive micromixer that mixes silver nanoparticles into the sample solution is integrated into the device for improved automation. Furthermore, two optical fibers are integrated into the device and aligned to the detection volume to improve the automation as compared to confocal SERS, which requires focusing and alignment. The device exhibits up to 2 orders of magnitude improvement in SERS performance as compared to conventional microfluidic SERS in an open channel. Using the optofluidic SERS device, the food contaminant melamine was detected in low concentrations, with an estimated limit of detection (LOD) of 63 ppb, while the fungicide thiram was detected down to an estimated LOD of 50 ppt. In both cases, the reported results meet the U.S. federal requirements. Additionally, it is shown that the device continues to exhibit excellent performance even when mated to a commercially available portable spectrometer for the trace detection of thiram. This combination of the optofluidic SERS microsystem with a portable spectrometer will lead to highly sensitive and automated sensing systems for on-site detection of food and water contaminants in the field. PMID- 22924880 TI - Unzipping a functional microbial amyloid. AB - Bacterial and fungal species produce some of the best-characterized functional amyloids, that is, extracellular fibres that play key roles in mediating adhesion and biofilm formation. Yet, the molecular details underlying their mechanical strength remain poorly understood. Here, we use single-molecule atomic force microscopy to measure the mechanical properties of amyloids formed by Als cell adhesion proteins from the pathogen Candida albicans. We show that stretching Als proteins through their amyloid sequence yields characteristic force signatures corresponding to the mechanical unzipping of beta-sheet interactions formed between surface-arrayed Als proteins. The unzipping probability increases with contact time, reflecting the time necessary for optimal inter beta-strand associations. These results demonstrate that amyloid interactions provide cohesive strength to a major adhesion protein from a microbial pathogen, thereby strengthening cell adhesion. We suggest that such functional amyloids may represent a generic mechanism for providing mechanical strength to cell adhesion proteins. In nanotechnology, these single-molecule manipulation experiments provide new opportunities to understand the molecular mechanisms driving the cohesion of functional amyloid-based nanostructures. PMID- 22924882 TI - The role of first impression in operant learning. AB - We quantified the effect of first experience on behavior in operant learning and studied its underlying computational principles. To that goal, we analyzed more than 200,000 choices in a repeated-choice experiment. We found that the outcome of the first experience has a substantial and lasting effect on participants' subsequent behavior, which we term outcome primacy. We found that this outcome primacy can account for much of the underweighting of rare events, where participants apparently underestimate small probabilities. We modeled behavior in this task using a standard, model-free reinforcement learning algorithm. In this model, the values of the different actions are learned over time and are used to determine the next action according to a predefined action-selection rule. We used a novel nonparametric method to characterize this action-selection rule and showed that the substantial effect of first experience on behavior is consistent with the reinforcement learning model if we assume that the outcome of first experience resets the values of the experienced actions, but not if we assume arbitrary initial conditions. Moreover, the predictive power of our resetting model outperforms previously published models regarding the aggregate choice behavior. These findings suggest that first experience has a disproportionately large effect on subsequent actions, similar to primacy effects in other fields of cognitive psychology. The mechanism of resetting of the initial conditions that underlies outcome primacy may thus also account for other forms of primacy. PMID- 22924881 TI - Iron and pH-responsive FtrABCD ferrous iron utilization system of Bordetella species. AB - A putative operon encoding an uncharacterized ferrous iron transport (FtrABCD) system was previously identified in cDNA microarray studies. In growth studies using buffered medium at pH values ranging from pH 6.0 to 7.6, Bordetella pertussis and Bordetella bronchiseptica FtrABCD system mutants showed dramatic reductions in growth yields under iron-restricted conditions at pH 6.0, but had no growth defects at pH 7.6. Supplementation of culture medium with 2 mM ascorbate reductant was inhibitory to alcaligin siderophore-dependent growth at pH 7.6, but had a neglible effect on FtrABCD system-dependent iron assimilation at pH 6.0 consistent with its predicted specificity for ferrous iron. Unlike Bordetella siderophore-dependent and haem iron transport systems, and in agreement with its hypothesized role in transport of inorganic iron from periplasm to cytoplasm, FtrABCD system function did not require the TonB energy transduction complex. Gene fusion analysis revealed that ftrABCD promoter activity was maximal under iron-restricted growth conditions at acidic pH. The pH of human airway surface fluids ranges from pH 5.5 to 7.9, and the FtrABCD system may supply ferrous iron necessary for Bordetella growth in acidic host microenvironments in which siderophores are ineffective for iron retrieval. PMID- 22924883 TI - Performance-approach goals deplete working memory and impair cognitive performance. AB - Although longitudinal studies have consistently shown the positive impact of performance-approach goals (i.e., the desire to demonstrate one's abilities and outperform others) on academic success, they might allow some strategic behaviors such as cheating and surface studying, leaving open the question of the sheer impact of performance-approach goals on cognitive performance. We argued that the pressure to outperform others might generate outcome concerns and thus deplete working memory resources available for the activity, thereby hindering cognitive performance. Three studies carried out in a laboratory context confirmed this hypothesis. During a demanding cognitive task, performance-approach goal manipulation hampered performance (Experiment 1) by generating distractive concerns that drew on the limited verbal component of working memory (Experiment 2). Moreover, this interference was shown to be specifically due to the activation of performance-approach goal-related thoughts during the task solving (Experiment 3). Together, the present results highlight the distractive consequence of performance-approach goals on cognitive performance, suggesting that cognitive resource allocation is divided among the storage, processing, and retrieval of task-relevant information and the activation of normative goal attainment concerns. PMID- 22924884 TI - Predicting affective choice. AB - Affect is increasingly recognized as central to decision making. However, it is not clear whether affect can be used to predict choice. To address this issue, we conducted 4 studies designed to create and test a model that could predict choice from affect. In Study 1, we used an image rating task to develop a model that predicted approach-avoidance motivations. This model quantified the role of two basic dimensions of affect--valence and arousal--in determining choice. We then tested the predictive power of this model for two types of decisions involving images: preference based selections (Study 2) and risk-reward trade-offs (Study 3). In both cases, the model derived in Study 1 predicted choice and outperformed competing models drawn from well-established theoretical views. Finally, we showed that this model has ecological validity: It predicted choices between news articles on the basis of headlines (Study 4). These findings have implications for diverse fields, including neuroeconomics and judgment and decision making. PMID- 22924885 TI - Immune and acute phase response in pigs experimentally infected with H1N2 swine influenza virus. AB - Acute phase proteins (APPs) and immune responses in pigs after experimental infection with H1N2 swine influenza virus (SwH1N2) were studied. Eight piglets were infected intranasally with SwH1N2. Four served as controls. Antibodies against swine influenza virus (SIV)s were measured by hemagglutination inhibition assay. The proliferation assay was used to measure influenza-specific cell mediated response. Hematological parameters were measured on a hematology analyzer. C-reactive protein (CRP), haptoglobin (Hp), serum amyloid A (SAA) and pig major APP (Pig-MAP) concentrations in serum were measured using commercial ELISAs. Antibodies against SwH1N2 in the serum of infected pigs were detected from 7 dpi. SwH1N2-specific T-cell response was observed from 5 dpi. A significant drop in lymphocyte numbers and an increase in medium-sized cell (MID) counts with no accompanying leukopenia was observed in all infected pigs from 3 to 7 dpi. In infected pigs, concentrations of CRP, Hp and SAA increased significantly when the greatest amounts of virus were shed (from 1 to 3 dpi). The level of Pig-MAP remained unchanged during study. The significant positive correlation found between maximum concentrations of SAA in serum and lung scores, makes SAA a potentially useful indicator in experimental infection studies (e.g. vaccine efficiency investigations) or as a marker for disease severity, but to confirm this hypothesis more studies are needed. PMID- 22924886 TI - Comparative study of one-step nucleic acid amplification assay, frozen section, and touch imprint cytology for intraoperative assessment of breast sentinel lymph node in Chinese patients. AB - Conventional procedures for the intraoperative assessment of breast cancer sentinel lymph nodes (SLNs) are frozen section (FS) and touch imprint cytology (TIC). The one-step nucleic acid amplification (OSNA) assay is a novel molecular technique. The aim of this study was to evaluate the optimal approach by comparing OSNA assay, FS, and TIC. Five hundred and fifty-two consecutive patients were enroled from five study centers in China. The SLNs were cut into alternating 2 mm blocks. The odd blocks were tested by the OSNA assay intraoperatively, and the even ones were assessed by postoperative histology (four 4- to 6-MUm-thick sections were taken every 200 MUm per block). In addition, intraoperative histological assessments were carried out on the even blocks of 211 patients by FS and all blocks of 552 patients by TIC. Overall performance of the assay compared to postoperative histology was: accuracy 91.4%; sensitivity 83.7%; and specificity 92.9%. The sensitivity of the assay was higher than FS (211 patients, 77.6% vs 69.7%; not significant, P = 0.286) and was significantly higher than TIC (552 patients, 83.6% vs 76.2%; P = 0.044). When assessing nodes with micrometastases, the sensitivity of the assay was higher than FS (17 nodes, 47.1% vs 23.5%; not significant, P = 0.289) and was significantly higher than TIC (48 nodes, 62.5% vs 35.4%; P = 0.007). The study indicated that the OSNA assay is an accurate and rapid intraoperative assay for assessing breast SLNs and it can replace FS and TIC for application in general medical practice. The trial was registered as: OSNA assay China Registration Study. CLINICAL TRIAL REGISTRATION NUMBER: China Breast Cancer Clinical Study Group 001c. PMID- 22924887 TI - Cerebral hypoxia in a cat following pharyngoscopy involving use of a mouth gag. PMID- 22924888 TI - Pain in children and adolescents in primary care; chronic and recurrent pain is common. AB - AIM: The aim of this study was to describe a paediatric primary care pain sample and examine associations between pain, health-related quality of life and disability. METHODS: The study design is descriptive and cross-sectional. One hundred and fifty-four consecutive children and adolescents between the ages of 8 and 16 seeking care for a pain-related conditions participated in this study. Pain characteristics, health-related quality of life and disability were investigated. RESULTS: Eighty-seven per cent of participants had a pain duration of 3 months or more, and almost half of the group studied had a pain duration of >= 12 months. The disability levels in the study group as a whole were low, with a mean FDI of 10.4 (SD 7.6). However, 35% of the study group had moderate disability levels and reported a mean FDI of 18.7 (SD 4.8). Single pain location was reported in 42%, whereas 58% had two or more pain locations. The children with multiple pain locations reported lower health-related quality of life and higher disability than children with single pain location. CONCLUSION: Paediatric pain patients in primary care consist partly of patients only slightly influenced by pain and partly of patients for whom pain has a great impact on their lives. PMID- 22924889 TI - Experimental evidence for distinct costs of pathogenesis and immunity against a natural pathogen in a wild bird. AB - Protective immunity is expected to evolve when the costs of mounting an immune response are less than those of harbouring pathogens. Estimating the costs of immunity vs. pathogenesis in natural systems is challenging, however, because they are typically closely linked. Here we attempt to disentangle the relative cost of each using experimental infections in a natural host-parasite system in which hosts (house finches, Carpodacus mexicanus) differ in resistance to a bacterium (Mycoplasma gallisepticum, MG), depending on whether they originate from co-evolved or unexposed populations. Experimental infection with a 2007 strain of MG caused finches from co-evolved populations to lose significantly more mass relative to controls, than those from unexposed populations. In addition, infected co-evolved finches that lost the most mass harboured the least amounts of MG, whereas the reverse was true in finches from unexposed populations. Finally, within co-evolved populations, individuals that displayed transcriptional evidence of higher protective immune activity, as indicated by changes in the expression of candidate immune and immune-related genes in a direction consistent with increased resistance to MG, showed greater mass loss and lower MG load. Thus, mass loss appeared to reflect the costs of immunity vs. pathogenesis in co-evolved and unexposed populations, respectively. Our results suggest that resistance can evolve even when the short-term energetic costs of protective immunity exceed those of pathogenesis, providing the longer-term fitness costs of infection are sufficiently high. PMID- 22924890 TI - Engineered synthetic polymer nanoparticles as IgG affinity ligands. AB - A process for the preparation of an abiotic protein affinity ligand is described. The affinity ligand, a synthetic polymer hydrogel nanoparticle (NP), is formulated with functional groups complementary to the surface presentation of the target protein. An iterative process is used to improve affinity by optimizing the composition and proportion of functional monomers. Since the polymer NPs are formed by a kinetically driven process, the sequence of functional monomers in the polymer chain is not controlled; only the average composition can be adjusted by the stoichiometry of the monomers in the feed. To compensate for this the hydrogel NP is lightly cross-linked resulting in chain flexibility that takes place on a submillisecond time scale allowing the polymer to "map" onto a protein surface with complementary functionality. In this study, we report a lightly cross-linked (2%) N-isopropyl acrylamide (NIPAm) synthetic polymer NP (50-65 nm) incorporating hydrophobic and carboxylate groups that binds with high affinity to the Fc fragment of IgG. The affinity and amount of NP bound to IgG is pH dependent. The hydrogel NP inhibits protein A binding to the Fc domain at pH 5.5, but not at pH 7.3. A computational analysis was used to identify potential NP-protein interaction sites. Candidates include a NP binding domain that overlaps with the protein A-Fc binding domain at pH 5.5. The computational analysis supports the inhibition experimental results and is attributed to the difference in the charged state of histidine residues. Affinity of the NP (3.5-8.5 nM) to the Fc domain at pH 5.5 is comparable to protein A at pH 7. These results establish that engineered synthetic polymer NPs can be formulated with an intrinsic affinity to a specific domain of a large biomacromolecule. PMID- 22924891 TI - Outpatient health care utilization of suicide decedents in their last year of life. AB - The characteristics of health care utilization during the last year of life by Taiwanese who died by suicide were analyzed. The degree of health services utilization was evaluated by extracting the data of National Health Insurance (NHI) outpatient cohort records in 2006. A total of 4,406 fatal suicide cases were matched with the 17,587,901 subjects in the NHI beneficiary registry file. Rate of visit of the suicide decedents for all NHI outpatient services during their last year before death was 85%, and that for mental disorders service only was 30.2%. Average number of visits per person-year of the suicide decedents was 24.5 visits per year, two times higher than that of the survivors. The average numbers of visits (ANV) of male suicide decedents who used the mental disorders services was increased 6.8 times compared to that for all survivors. The increase in female decedents, in contrast, was 2.7 times. The increase in ANV for 15-24 age group was 14.6 times, significantly higher than that for the other age groups (<4 times). Effective prediction or prevention of potential suicides through increased awareness and surveillance of medical care resource utilization is possible, especially for male and young adult patients under mental disorder health care. PMID- 22924892 TI - Suicide and war: the mediating effects of negative mood, posttraumatic stress disorder symptoms, and social support among army National Guard soldiers. AB - The mediating effects of posttraumatic stress disorder (PTSD) symptoms, negative mood, and social support on the relationship of war experiences to suicidality were examined. The research literature suggested a sequence among study scales representing these constructs, which was then tested on survey data obtained from a sample of National Guard soldiers (N=4,546). Results from structural equation modeling suggested that war experiences may precipitate a sequence of psychological consequences leading to suicidality. However, suicidality may be an enduring behavioral health condition. War experiences showed no direct effects on postdeployment suicidality, rather its effect was indirect through PTSD symptoms and negative mood. War experiences were, however, predictive of PTSD symptoms, as would be expected. PSTD symptoms showed no direct effect on postdeployment suicidality, but showed indirect effects through negative mood. Results also suggested that suicidality is relatively persistent, at least during deployment and postdeployment. The percentage of those at risk for suicide was low both during and after deployment, with little association between suicidality and time since returning from deployment. Additionally, few soldiers were initially nonsuicidal and then reported such symptoms at postdeployment. Implications of relationships of both negative mood and combat trauma to suicidality are discussed, as well as possible mediating effects of both personal dispositions and social support on relationships of war experiences to PTSD, negative mood, and suicidality. PMID- 22924893 TI - Neonatal animal testing paradigms and their suitability for testing infant formula. AB - Due to the ever increasing number of substances added to infant formula, and the fact that the majority of data determining the safety of these substances has been derived from adult animals, a search of the available data was performed to determine if an appropriate neonatal model could be found that could be used for performing toxicological safety studies. This exercise utilized three different forms of media. The first informational source is from a publication from the Institute of Medicine (IOM) of the National Academies. The second form of informational data utilized was from simple YAHOO and Google Scholar searches on the internet. The third source of information was from the U.S. Food and Drug Administration (FDA), more specifically, the Center for Drug Evaluation and Review (CDER) preclinical guidance document. Following the examination of the above informational sources, it became apparent that neonatal rats and pigs have been the most utilized of the neonatal models. Following the evaluation of the papers, the experimental paradigm which appears to be the most appropriate for testing substances new to infant formula, and could be used as a pivotal study was the neonatal pig utilizing the automated feeding device called the Autosow. PMID- 22924894 TI - Directed assembly of Janus particles under high frequency ac-electric fields: effects of medium conductivity and colloidal surface chemistry. AB - The manipulation and assembly of polystyrene-based Janus particles of varied surface chemistry on one hemispherical particle surface under high frequency nonuniform ac-electric fields is examined experimentally by in situ microscopic observation. Strong effects of ac-field frequency, medium conductivity, and particle surface chemistry on the structure of Janus colloidal assembly are observed. At low medium conductivity, sigma(m) from 0.0007 S/m to 0.0153 S/m, pearl chains of Janus particles are observed over the ac-frequency range from 25 kHz to 20 MHz, indicating the dielectrophoresis (DEP)-directed assembly. In contrast, the chaining of Janus particles is disrupted in a certain frequency range at high sigma(m) from 0.0153 S/m to 0.116 S/m, suggesting the combining effects of both induced-charge electrophoresis (ICEP) and DEP. The critical transition frequency for the onset of the fractal aggregation at high sigma(m) from 0.0153 S/m to 0.116 S/m is experimentally determined, showing a good agreement with the theoretically predicted upper ICEP frequency limit. Additionally, it is demonstrated that by using zwitterionic Janus particles, the assembled structure of Janus particles under ac-fields can be modified by the chemical coatings on each hemispherical surface of Janus particles. PMID- 22924895 TI - Observation of surface plasmon polariton pumping of optical eigenmodes of gold decorated gallium nitride nanowires. AB - The photocurrent of individual gallium nitride (GaN) nanowires decorated with Au nanoparticles as function of the wavelength of light (405 nm (blue), 532 nm (green), and 632.8 nm (red)) and nanowire diameter (80 to 400 nm) is reported. The photocurrent scales with photon energy but oscillates with nanowire diameter. The oscillations are described in terms of the scattering of surface plasmon polaritons into allowed transverse magnetic electromagnetic modes of the nanowire that have maximum intensities in the undepleted region of the nanowire. These oscillations do not occur below a nanowire diameter of ~200 nm due to the depletion layer formed at the Au-GaN interface, which completely depletes the nanowire, that is, there is an insufficient density of carriers that can be excited into the conduction band. On the basis of estimations of the depletion depth and solutions of the Helmholtz equation, the maxima in the photocurrent for d > 200 nm are assigned to the two lowest azimuthally symmetric transverse magnetic eigenmodes: (m = 0, n = 1) and (m = 0, n = 2), which have maximum electric field intensities within the undepleted region of the GaN nanowire. The outcome of this work could have far reaching implications on the development of nanophotonics. PMID- 22924896 TI - Evaluation of completeness of suspected adverse drug reaction reports submitted to the mexican national pharmacovigilance centre: a cross-sectional period prevalence study. AB - BACKGROUND: The Mexican National Centre of Pharmacovigilance (CNFV) receives suspected adverse drug reaction (ADR) reports from the pharmaceutical industry, Federal States Centre of Pharmacovigilance (CEFV) and Healthcare Institution Centres of Pharmacovigilance (CIFV). The completeness of these suspected ADR reports is particularly important for the proper evaluation of drug safety. OBJECTIVE: The aim of the study was to evaluate the completeness of the information reported in a representative sample of suspected ADR reports submitted to the CNFV during 2007 and 2008, to evaluate the completeness of the suspected ADR reports submitted to the CNFV from different sources during these 2 years and to identify the therapeutic subgroups with the highest number of suspected ADR reports during the study years. METHODS: A cross-sectional period prevalence study was conducted at the CNFV. Only reports of suspected ADRs submitted by the CEFV, pharmaceutical industry and CIFV during 2007 and 2008 were included in the present study (reports related to vaccines were excluded). The sample sizes to be used for each year were determined using the formula for population rate at 95% significance level. The samples for each year were randomly selected from the reports related to synthetic drugs submitted that year. The suspected ADR reports were classified according to the standing Mexican Official Norm (Norma Oficial Mexicana [NOM]) guidelines, which were used to divide the reports into four categories (0, 1, 2 and 3) based on their completeness. The seriousness of the suspected ADRs reported was also evaluated; a suspected ADR was classified as 'non-serious' when signs and symptoms are likely to be tolerated, 'moderate' when ADR is not life threatening and needs pharmacological treatment, 'serious' when ADR is life threatening and leads to hospitalization and 'fatal' when ADR contributes directly or indirectly to the patient's death. RESULTS: A total sample size of 370 and 371 suspected ADR reports from 2007 and 2008, respectively, were examined. Our analysis revealed that the pharmaceutical industry sent the highest number of suspected ADR reports for both years (58% and 63%, respectively). Results of the information completeness analysis by using the NOM categories showed that, in both study years, among the total suspected ADR reports about 32% (119) and 40% (148), respectively, were categorized as grade 0 (information insufficient to generate risk signals). Analyses of the seriousness of all suspected ADR reports revealed that 2% of reports were classified as fatal each year, whereas 6% and 5% were classified as serious and 25% and 29% were classified as moderate in 2007 and 2008, respectively. The therapeutic subgroups, according to the Anatomical Therapeutic Chemical classification, with the highest frequencies of suspected ADR reports in both study years were sex hormones and modulators of the genital system, antibacterial for systemic use, antiepileptics and psychoanaleptics, and antihypertensives. CONCLUSIONS: The completeness of the information provided in the suspected ADR reports submitted during the sample study years was incomplete and, in general, did not fulfil the requirements established by the NOM guidelines. Among the pharmaceutical industry, CEFV and CIFV, the suspected ADR reports were mainly provided by the pharmaceutical industry. It is necessary to improve the pharmacovigilance system in Mexico to achieve a high level of completeness of suspected ADR reports that totally fulfil the standing regulations. PMID- 22924897 TI - Malolactic fermentation and secondary metabolite production by Oenoccocus oeni strains in low pH wines. AB - Different wine varieties, including some with low pH, were studied to determine the ability to grow and produce secondary metabolites of a previously selected autochthonous Oenococcus oeni strain (C22L9), compared with a commercial strain. Monitoring of malolactic fermentation (MLF) was carried out by microbiological and chemical analysis of wines. The concentration of some major volatile compounds and biogenic amines in wines before and after malolactic fermentation was also determined. The results showed major differences in MLF duration both between wines and strains, although the differences between strains were slight for most of the analyzed compounds. Statistically significant differences in citric acid degradation were found in all wine varieties and it was confirmed that O. oeni C22L9 is a poor degrader of citric acid; this means that MLF can be prolonged without the risk of producing high concentrations of diacetyl and acetoin. Sensory analysis of wines after MLF showed similar characteristics in wines from both strains. This study thus shows that O. oeni C22L9 possesses even better sensory and fermentation properties than the commercial strain and can be used in wines with different characteristics, which makes it highly valuable for industrial use. PRACTICAL APPLICATION: The increasingly use of grape varieties of low pH in winemaking and the higher alcohol content of wines, as a consequence of the climatic change, make interesting the study of the behavior during MLF of O. oeni strains in order to determine their ability to grow, when growth conditions are not optimal, and to produce secondary metabolites. A comparative study was conducted using an autochthonous O. oeni strain (C22L9) and a commercial O. oeni strain and 4 wine varieties. PMID- 22924898 TI - Role of glutamate metabolism in bacterial responses towards acid and other stresses. AB - Glutamate plays a central role in a wide range of metabolic processes in bacterial cells. This review focuses on the involvement of glutamate in bacterial stress responses. In particular, it reviews the role of glutamate metabolism in response against acid stress and other stresses. The glutamate decarboxylase (GAD) system has been implicated in acid tolerance in several bacterial genera. This system facilitates intracellular pH homoeostasis by consuming protons in a decarboxylation reaction that produces gamma-aminobutyrate (GABA) from glutamate. An antiporter system is usually present to couple the uptake of glutamate to the efflux of GABA. Recent insights into the functioning of this system will be discussed. Finally, the intracellular fate of GABA will also be discussed. Many bacteria are capable of metabolizing GABA to succinate via the GABA shunt pathway. The role and regulation of this pathway will be addressed in the review. PMID- 22924899 TI - High anti-HLA response in women exposed to intrauterine transfusions for severe alloimmune hemolytic disease is associated with mother-child HLA triplet mismatches, high anti-D titer, and new red blood cell antibody formation. AB - BACKGROUND: Women whose fetuses were treated with intrauterine transfusions (IUTs) for alloimmune hemolytic disease are high responders to red blood cell (RBC) antigens. We investigated the risk for HLA alloimmunization. STUDY DESIGN AND METHODS: Women and their children treated with IUT between 1987 and 2008 were included. Participants were HLA antigen typed and studied for the prevalence of HLA antibodies compared to age-matched parous nontransfused blood donors. Anti-D titer, the formation of new RBC antibodies after IUT, and the degree of fetomaternal HLA mismatches on HLA antibody formation and/or persistence were analyzed. RESULTS: A higher prevalence of HLA Class I antibodies was observed in these women compared to controls (41% vs. 23%). Both a higher anti-D titer (>8000) and formation of new RBC antibodies after IUT were associated with increased HLA immunization. HLA antibody formation was associated with the number of fetomaternal triplet epitope mismatches. Antigens within HLA-Bw4, HLA B35/51/52/53/18/78-complex and A1/A9, were higher and mismatches within HLA-C were less immunogenic than expected. HLA antibodies against the IUT-treated fetus were more persistent than other antibodies. CONCLUSION: Women whose fetuses were treated with IUT had a high risk of developing and maintain fetal-specific HLA Class I antibodies. Factors associated with increased HLA immunization were a higher amount of fetomaternal HLA triplet mismatches, higher anti-D titer, and additional RBC antibody formation. We presume that the induction of HLA Class I antibodies is the result of increased fetomaternal hemorrhage during IUT, eliciting antibodies in women with an increased susceptibility to alloimmunization. PMID- 22924900 TI - Is change bad? Personality change is associated with poorer psychological health and greater metabolic syndrome in midlife. AB - Personality change is emerging as an important predictor of health and well being. Extending previous research, we examined whether two types of personality change, directional and absolute, are associated with both subjective and objective indicators of health. Utilizing the longitudinal Midlife in the United States survey (MIDUS) data, we examined whether both types of change over 10 years were associated with psychological well-being, self-reported global health, and the presence of metabolic syndrome (MetS) components and diagnosis. Socially undesirable personality change (e.g., becoming less conscientious and more neurotic) and absolute personality change were independently associated with worse perceived health and well-being at Time 2. Notably, absolute personality change, regardless of the direction, was also associated with having a greater number of MetS components and a greater probability of diagnosis at Time 2. In sum, too much personality change may be bad for one's health: Socially undesirable and absolute personality change were both associated with worse psychological health and worse metabolic profiles over 10 years. These findings suggest that personality change may contribute to psychological and physical health, and provide initial insight into potential intermediate links between personality change and distal outcomes such as mortality. PMID- 22924901 TI - Healing of buccal dehiscence defects at implants installed immediately into extraction sockets - an experimental study in dogs. AB - AIM: To evaluate the influence of implant positioning into extraction sockets on bone formation at buccal alveolar dehiscence defects. MATERIAL AND METHODS: In six Labrador dogs the pulp tissue of the mesial roots of (4) P(4) was removed and the root canals were filled. Flaps were elevated bilaterally, the premolars hemi-sectioned and the distal roots removed. The implants were placed in contact with either the buccal (test site) or with the lingual (control site) bony wall of the extraction sockets. Healing abutments were affixed and triangular buccal bony dehiscence defects, about 2.7 mm deep and 3.5 mm wide, were then prepared. No regenerative procedures were done and a non-submerged healing was allowed. After 4 months of healing, block sections of the implant sites were obtained for histological processing and peri-implant tissue assessment. RESULTS: After 4 months of healing, the bony crest and the coronal border of osseointegration at the test sites were located 1.71 +/- 1.20 and 2.50 +/- 1.21 mm apically to the implant shoulder, respectively. At the control sites, the corresponding values were 0.68 +/- 0.63 and 1.69 +/- 0.99 mm, respectively. The differences between test and control reached statistical significance (P < 0.05). Residual marginal bone defects were found both at the test and control sites. A statistically significant difference between test and control sites was only found at the lingual aspects (depth 2.09 +/- 1.01 and 1.01 +/- 0.48 mm, respectively). Similar heights of the buccal biological width were observed at both sites (about 5.1 mm). CONCLUSIONS: The placement of implants in a lingual position of the extraction sockets allowed a higher degree of bone formation at buccal alveolar dehiscence defects compared with a buccal positioning. PMID- 22924902 TI - Nitric oxide in patients with schizophrenia: the relationship with the severity of illness and the antipsychotic treatment. AB - OBJECTIVES: Past studies regarding the relationship between nitric oxide and schizophrenia have reported controversial results. Consequently, the aims of this study are i) to analyze the differences in nitric oxide concentration between patients with schizophrenia and healthy controls, ii) to investigate the influence of antipsychotic treatment on nitric oxide, iii) to correlate nitric oxide concentration with severity of illness, and iv) to investigate the relationship between nitric oxide and any personality disorder. RESEARCH DESIGN AND METHODS: We recruited 24 patients and 24 controls; the sample was divided into three groups of 8 patients, each according to the pharmacological treatment (haloperidol, olanzapine, or risperidone). The severity of illness was assessed by PANSS and personality traits were evaluated by SCID II. A blood sample was taken to assess the plasma concentration of nitrites and nitrates. RESULTS: Patients presented higher nitrate levels than controls (p < 0.05); subjects under olanzapine reported lower nitrate levels than those treated with risperidone (p < 0.05) or haloperidol (p < 0.001). Nitrate levels were correlated with PANSS total score (rho = 0.748; p < 0.001), but not with SCID II scores. CONCLUSIONS: Despite the fact that this study found a correlation between PANSS score and nitrate levels, it is unclear whether nitric oxide is related to the severity of schizophrenia, because nitrate levels are also affected by antipsychotic treatment. PMID- 22924903 TI - Sex ratio and sexual dimorphism of three lice species with contrasting prevalence parasitizing the house sparrow. AB - Female-biased sex ratio is a common phenomenon in parasites; however, the cause and consequence of the skewed sex ratio is less well known. Here, we studied the difference in sex ratio, a possible mechanism responsible for the development of unbalanced proportion of sexes and its consequences on sexual size dimorphism, between 3 louse species parasitizing the house sparrow Passer domesticus. Philopterus fringillae was more prevalent than Sturnidoecus refractariolus and Brueelia cyclothorax. As expected, the most common species, which was probably least affected by isolation and, hence, inbreeding, was characterized by a balanced sex ratio, whereas the 2 other species with low prevalence were significantly more female biased than expected on the basis of the local mate competition hypothesis. Further, in support of this notion, we found that P. fringillae infrapopulation size significantly, and positively, correlated with the sex ratio. Finally, we found significant differences in sexual dimorphism among the 3 louse species and, as expected, the relative size of males was smallest in species with a more female-biased sex ratio. PMID- 22924905 TI - Seasonal influences on parasite community structure of Turdus rufiventris (Aves). AB - Seasonality has strong effects on natural systems by influencing resource availability, thereby interfering in plant-herbivore, prey-predator, and host parasite interactions. We compared the seasonal structure of the helminth community of rufous-bellied thrushes (Turdus rufiventris), assessed its correlation with environmental variables, and interpreted temporal patterns of parasite abundance in relation to their life cycles and likely changes in the availability of intermediate hosts and vectors. Fifteen helminth species were found in a sample of 151 thrushes collected on a seasonal basis over 3 yr. Infracommunity structure was affected by season and year. The ordination of component communities grouped fall and winter samples within a gradient of similarity that was correlated with average relative air humidity (RH) and average ambient temperature. RH (alone or in combination with temperature, rainfall, or both) was also found to be a good predictor of the abundance of 5 helminth species. PMID- 22924904 TI - Adult mosquitoes parasitized by larval water mites in Pennsylvania. AB - A survey of water mite larvae parasitizing adult mosquitoes was conducted throughout Pennsylvania. In total, 929,873 individuals and 46 species of mosquitoes were collected from 6,499 sites, and mites were examined from a subset of the parasitized mosquitoes. From 282 of the sites, 1,836 mosquitoes were parasitized by 4,769 mites, with a mean intensity of 2.6, ranging from 1 to 31. Twenty-one species of mosquitoes representing Aedes, Anopheles, Coquillettidia, Culex, Ochlerotatus, Orthopodomyia, and Psorophora were parasitized by 1 Parathyas sp., 7 Arrenurus spp., and 7 Arrenurus morphotypes. All mite species are documented from Pennsylvania for the first time. The largest numbers of hosts were Coquillettidia perturbans and Ochlerotatus trivittatus, and of parasites were Arrenurus danbyensis and Parathyas barbigera. Aedes spp., Ochlerotatus spp., and Psorophora ferox were mostly parasitized by P. barbigera, Anopheles spp. and Cq. perturbans mostly by Arrenurus spp., and Culex spp. by both P. barbigera and Arrenurus spp. Thirty-three different associations were observed, and 17 of these are new records. Parasitism of individual mosquitoes by more than 1 mite species was rare. Most P. barbigera individuals were attached on the pre-abdominal region of their hosts, and, when not in this position, they were attached anterior on the thorax, and less commonly on the cervix or abdomen. Most A. danbyensis and Arrenurus delawarensis individuals were attached to the cervix of Cq. perturbans. Arrenurus danbyensis on Cq. perturbans had mean and maximum intensities of 2.8 and 31, and showed a clear trend in attachment site distribution, with sequential progression from head to abdomen. PMID- 22924906 TI - Genetic polymorphism of 12S rRNA gene among Dermacentor reticulatus Fabricius ticks in the Chernobyl Nuclear Power Plant Exclusion Zone. AB - The molecular genetic variability of the 12S rRNA gene, on the basis of partial primary sequence and in silico-predicted secondary structures among Dermacentor reticulatus (Fabricius 1794) ticks, was studied in the Chernobyl Nuclear Power Plant (ChNPP) Exclusion Zone. In total, 20, 20, and 25 ethanol-preserved specimens, previously collected at 3 sites with 0.76, 1.91, and 4.5 millisievert (mSv)/hr ionizing radiation background, were examined. The primary sequence analysis generated 4 haplotypes defined by 3 polymorphic sites. The most common haplotype 1 was found in all 3 locations, representing 86.2% of all sampled individuals. Haplotype 4 (10.8%) was detected at the 1.91 and 4.50 mSv/hr sites. The unique haplotypes 2 (1.5%) and 3 (1.5%) were detected only at the 1.91 and 4.50 mSv/hr sites, respectively. The haplotype diversity, nucleotide diversity, and pairwise nucleotide differences for 2 tick populations at the 1.90 and 4.50 mSv/hr sites were 0.279, 0.00085, and 0.289, and 0.397, 0.00122, 0.413, respectively. No polymorphism was detected in ticks collected at the 0.76 mSv/hr site. The primary sequences of 12S rRNA were folded into the secondary structures and the free energy of haplotypes was calculated. The free energy at 37 C (DeltaG) of the nonmutant haplotype 1 and the mutant haplotypes 2, 3, and 4 were 45.79, -44.17, -39.56, and -45.79 kcal/mol, respectively. Considering the correlation between the structural profile similarity of 12S rRNA and point mutations, haplotypes 1 and 4 have similar secondary structure profiles and have received a 0.999219 similarity score in the cluster tree. The unique haplotypes 2 and 3 have differences in the secondary structure in comparison with haplotypes 1 and 4; the similarity scores were 0.914747 and 0.169431, respectively. Further studies using more genetic markers are warranted to ascertain the genetic variability and population genetic structure within D. reticulatus tick populations in the ChNPP Exclusion Zone and to resolve their vector capacity. PMID- 22924907 TI - Effects of age and breed on the prevalence of Neospora caninum in commercial dairy cattle from Pakistan. AB - Neospora caninum is a major cause of bovine abortion worldwide. A serological survey was carried out to determine the seroprevalence of exposure to N. caninum in dairy cattle based on age and breed from Punjab and Sindh provinces, Pakistan. Serum samples from 641 animals from 12 herds from Punjab (n = 7) and Sindh (n = 5) provinces were tested for antibodies against N. caninum using a commercially available competitive enzyme-linked immunosorbent assay. Positive reactions to N. caninum were seen in 277 (43%) of the 641 of the samples. Seropositive animals were present in all 12 herds. Animals over 2 yr of age (47%) and crossbreds (55%) were more likely to be seropositive than the other cattle examined. These results indicate that N. caninum infection is widespread among dairy cattle in Pakistan. PMID- 22924909 TI - A new species of Haemoproteus from a tortoise (Testudo graeca) in Turkey, with remarks on molecular phylogenetic and morphological analysis. AB - Haemoproteus anatolicum n. sp. was identified in the tortoise Testudo graeca. The new species is described based on the morphology of its blood stages and a segment of the mitochondrial cytochrome b gene, which can be used for molecular identification and diagnosis. Chelonian haemoproteids recorded in the past were defined solely on the basis of their morphological characteristics. The chelonian haemoproteid we describe as a new species has a close genetic relationship to lizard haemoproteids, i.e., Haemoproteus ptyodactylii and Haemoproteus kopki. The new species description provides significant new information for little-known chelonian haemoproteids. PMID- 22924908 TI - Molecular phylogeny and host specificity of the larval Eustrongylides (Nematoda: Dioctophmidae) from freshwater fish in China. AB - The nematodes Eustrongylides spp. collected from different fish species in China were examined for their intra- and interspecific evolutionary variations using the molecular markers mitochondrial cytochrome oxidase c subunit 1 (COI) gene and internal transcribed spacer (ITS) rDNA regions. The phylogenetic analysis indicated that Eustrongylides species are divided into 3 well-supported clades. The ITS divergence between the clades suggested that clades 2 and 3 might represent the same species, whereas clade 1 represent another cryptic species. The host specificity of these nematodes was analyzed according to prevalence data, host range, and phylogenetic information. Clade 1 was found in 4 fish species, i.e., Odontobutis obscurus, Silurus asotus, Culter mongolicus, and Acanthogobius flavimanus, but was predominant in the 2 perciform species, O. obscurus and A. flavimanus. Clade 2 was found in 3 fish species, Monopterus albus, Channa argus, and Channa asiatica, but was predominant in M. albus, reported to feed primarily on oligochaetes, the first intermediate host of Eustrongylides sp. Clade 3 was found in 9 species, but its low prevalence suggests accidental infection in all species. Although the larval nematode presented low host specificity, it exhibited some host preference. PMID- 22924910 TI - Morphological and molecular characterization of Ortleppascaris sp. larvae, parasites of the cane toad Rhinella marina from eastern Amazonia. AB - This study presents a new record for the occurrence of larval Ortleppascaris sp.(Sprent, 1978). The nematodes were collected from inside fibrous cysts found in the livers of cane toads, Rhinella marina (Linnaeus, 1758), captured in eastern Brazilian Amazonia. This is the first record of Ortleppascaris sp. larvae in both Brazil and this amphibian host, increasing its distribution in South America as well as expanding the number of helminths known to infect this toad. The detailed description of Ortleppascaris sp. provides new taxonomic data for these larvae, as well as sequences of the internal transcribed spacers and small subunit DNA segments, and the cytochrome oxidase I gene, which will, in time, contribute to a better understanding of the phylogeny of this group of parasites. PMID- 22924911 TI - Occurrence of antibodies to Toxoplasma gondii in mules and donkeys in the northeast of Brazil. AB - The aim of the present study was to investigate antibodies to Toxoplasma gondii in the serum of mules and donkeys bred in the northeast of Brazil. In total, 483 samples were used (395 mules and 88 donkeys) from 4 states (Pernambuco, Rio Grande do Norte, Paraiba, and Sergipe). The indirect immunofluorescence reaction (IFI) technique was used to investigate antibodies to T. gondii with a cut-off point of 64. Positive frequencies of 23.8% and 43.2% were recorded for mules and donkeys, respectively. The state of Pernambuco had the highest prevalence of positive samples (29%) with statistically significant differences for species (P < 0.001) and state (P = 0.048). This is the first study of antibodies to T. gondii in mules and donkeys in these 4 states of the northeastern region of Brazil and serves as a warning to health authorities regarding the risks of ingesting equine meat. PMID- 22924912 TI - Observations on questing activity of adult Ixodes brunneus Koch (Acari: Ixodidae) in Mississippi. AB - The tick Ixodes brunneus Koch is a rare species occurring primarily in North America, where it feeds on many species of passeriform birds. Virtually nothing is known about the questing activity of this tick, although adults often stand with their front legs straight up, suggesting that they quest from a horizontal position. The present study analyzed I. brunneus questing behavior based on field data from drag cloth collections in northern Mississippi, as well as observational laboratory data from 10 I. brunneus ticks released into an experimental "questing apparatus." Ten ticks of a related species, I. scapularis Say, were used for comparison, and there were 3 replications each trial. Eight I. brunneus adults were collected along a nature trail in a northern Mississippi park during 20 total swaths with a drag cloth over a 2-day period (each time 5 swaths in the middle of the trail, with little or no vegetation; and 5 swaths along the edge of the trail, with taller vegetation). All 8 ticks were collected in the middle of the trail in vegetation no taller than 40 mm. In the laboratory experiment, the majority (>70%) of ticks of both species made no attempt to climb the metal or wood artificial stems, but instead they crawled around on the substratum. In 8/30 instances, I. brunneus climbed metal artificial stems to various heights as opposed to 4/30 instances for I. scapularis . Sometimes, ticks of both species seemed to quest at the base of both types of artificial stems. The mean height for questing by I. scapularis on metal stems was 38.2 mm as opposed to 31.8 mm for I. brunneus. Although the mean height was slightly higher for I. scapularis compared with I. brunneus, there was no statistical difference in questing heights observed between the 2 species. Ixodes brunneus and I. scapularis climbed wooden artificial stems in only 2/30 instances for each tick species, again with no statistical difference in questing heights between species. The field observations suggest that I. brunneus quests at ground level; however, laboratory simulations revealed that although the average height climbed was below 40 mm, they sometimes climb artificial stems to greater heights (approximately 50 mm in 4 instances). PMID- 22924913 TI - Serological survey of dogs from Egypt for antibodies to Leishmania species. AB - Leishmaniasis is an insect-transmitted parasitic disease with a worldwide distribution. Leishmania spp. infections cause a broad spectrum of clinical signs, ranging from skin lesions to fatal visceral disease. Dogs are a major reservoir host for visceral leishmaniasis in humans. While the disease is endemic in the Middle East and North Africa, little is known concerning canine Leishmania spp. infections in Egypt. Accordingly, blood samples were collected from 50 stray dogs in Giza, Egypt. Canine sera were tested for antibodies to visceralizing Leishmania spp. by commercial immunochromatographic strip assays based on recombinant antigen K39. Antibodies to Leishmania spp. were found in 5 of 50 (10%) of dogs tested from Egypt. Results from this study indicate that stray dogs are exposed to visceralizing Leishmania species in Egypt. PMID- 22924914 TI - Ante-mortem diagnosis, diarrhea, oocyst shedding, treatment, isolation, and genetic typing of Toxoplasma gondii associated with clinical toxoplasmosis in a naturally infected cat. AB - Toxoplasma gondii infections are common in humans and other animals, but clinical disease is relatively rare. It is unknown whether the severity of toxoplasmosis in immunocompetent hosts is due to the parasite strain, host variability, or to other factors. Recently, attention has been focused on the genetic variability among T. gondii isolates from apparently healthy and sick hosts. Whether T. gondii genetic makeup plays a part in the pathogenesis of clinical feline toxoplasmosis is uncertain because little is known of genetic typing of strains associated with clinical feline toxoplasmosis. A 6-mo-old domestic male cat was hospitalized because of lethargy, anorexia, fever, and diarrhea. Numerous (6 million in 1 sample) T. gondii oocysts were found in feces of the cat and antibodies to T. gondii (titer 1:800) were found in its serum by the modified agglutination test. The cat was medicated orally with Clindamycin for 10 days; it became asymptomatic after 10 days and was discharged from the hospital. Viable T. gondii (designated TgCatUs9) was isolated from feces (oocysts) by bioassays in mice. Genetic typing using the DNA extracted from the brains of infected mice and 10 PCR-restriction fragment length polymorphism (RFLP) markers revealed Type II allele at the SAG1, SAG2, SAG3, BTUB, GRA6, c22-8, c29-2, and PK1 loci and Type I at the L358 and Apico loci; therefore, this isolate belongs to the ToxoDB PCR RFLP genotype no. 4, which is grouped into the Type 12 lineage that is dominant in wildlife from North America. To our knowledge, this is the first T. gondii isolate characterized genetically from a sick cat in the USA. PMID- 22924915 TI - Evidence for an amoeba-like infectious stage of Ichthyophonus sp. and description of a circulating blood stage: a probable mechanism for dispersal within the fish host. AB - Small amoeboid cells, believed to be the infectious stage of Ichthyophonus sp., were observed in the bolus (stomach contents) and tunica propria (stomach wall) of Pacific staghorn sculpins and rainbow trout shortly after they ingested Ichthyophonus sp.-infected tissues. By 24-48 hr post-exposure (PE) the parasite morphed from the classically reported multinucleate thick walled schizonts to 2 distinct cell types, i.e., a larger multinucleate amoeboid cell surrounded by a narrow translucent zone and a smaller spherical cell surrounded by a "halo" and resembling a small schizont. Both cell types also appeared in the tunica propria, indicating that they had recently penetrated the columnar epithelium of the stomach. No Ichthyophonus sp. pseudo-hyphae ("germination tubes") were observed in the bolus or penetrating the stomach wall. Simultaneously, Ichthyophonus sp. was isolated in vitro from aortic blood, which was consistently positive from 6 to 144 hr PE, then only intermittently for the next 4 wk. Small PAS-positive cells observed in blood cultures grew into colonies consisting of non-septate tubules (pseudo-hyphae) terminating in multinucleated knob-like apices similar to those seen in organ explant cultures. Organ explants were culture positive every day; however, typical Ichthyophonus sp. schizonts were not observed histologically until 20-25 days PE. From 20 to 60 days PE, schizont diameter increased from <= 25 MUm to >= 82 MUm. Based on the data presented herein, we are confident that we have resolved the life cycle of Ichthyophonus sp. within the piscivorous host. PMID- 22924916 TI - Mulinia lateralis (Mollusca: Bivalvia) die-off in South Carolina: discovery of a vector for two elasmobranch cestode species. AB - Unexplained and episodic die-offs of the dwarf surf clam, Mulinia lateralis , have been reported on the West Atlantic coast, with such an occurrence in South Carolina in June 2010. A sample of live clams from the 2010 South Carolina event was collected, and 200 clams were measured and necropsied. Two species of tapeworm larvae were observed. Plerocercoids (Duplicibothrium sp.) occupied the digestive gland ducts, and merocercoids (Rhodobothrium sp.) were found beneath the mantle. Specimens of both species were sequenced to obtain partial 28S rRNA gene sequences, and they were identified as the tetraphyllidean D. minutum and the rhinebothriidean R. paucitesticulare, based on an NCBI Standard Nucleotide BLAST search. Of the 200 clams, 2.1% were infected with merocercoids (mean intensity 1.3 +/- 0.2) and 75% with plerocercoids (mean intensity 4.3 +/- 3.7). Intensity of infection by plerocercoids increased significantly with individual shell length. The presence of plerocercoids was associated with enlargement of the digestive gland ducts, but no other pathology was observed. Because uninfected clams were abundant among the stranded molluscs, these parasites are not considered to be the causative agent of the die-off. This is a new host record for both elasmobranch tapeworms. PMID- 22924917 TI - Further observations on in vitro hybridization of hemosporidian parasites: patterns of ookinete development in Haemoproteus spp. AB - Increasingly frequent outbreaks of zoonotic infections call for studies of wildlife parasites to reach a better understanding of the mechanisms of host switch, leading to the evolution of new diseases. However, speciation processes have been insufficiently addressed in experimental parasitology studies, primarily due to difficulties in determining and measuring mate-recognition signals in parasites. We investigated patterns of sexual process and ookinete development in avian Haemoproteus (Parahaemoproteus) spp. (Haemosporida, Haemoproteidae) using in vitro experiments on between-lineage hybridization. Eleven mitochondrial cytochrome b (cyt b) lineages belonging to 9 species of hemoproteid were isolated from naturally infected passerine birds. The parasites were identified to species on the basis of morphology of their gametocytes and polymerase chain reaction amplification of segments of the cyt b gene. Sexual process and ookinete development were initiated in vitro by mixing blood containing mature gametocytes with a 3.7% solution of sodium citrate and exposing the mixture to air. Ookinetes of all lineages except Haemoproteus payevskyi (lineage hRW1) and Haemoproteus nucleocondensus (hGRW1) developed; the 2 latter species did not exflagellate. Between-lineage hybridization was initiated by mixing blood containing mature gametocytes of 2 different parasites; the following experiments were performed: (1) Haemoproteus pallidus (lineage hPFC1) * Haemoproteus minutus (lineage hTURDUS2); (2) H. pallidus (hPFC1) * Haemoproteus tartakovskyi (hSISKIN1); (3) Haemoproteus belopolskyi (hHIICT3) * Haemoproteus lanii (hRB1); (4) Haemoproteus balmorali (hSFC1) * H. pallidus (hPFC1); (5) H. belopolskyi (hHIICT1) * Haemoproteus parabelopolskyi (hSYBOR1); (6) H. tartakovskyi (hHAWF1) * H. tartakovskyi (hSISKIN1); (7) H. pallidus (hPFC1) * H. lanii (hRB1); (8) H. tartakovskyi (hHAWF1) * H. parabelopolskyi (hSYBOR1). We report 4 patterns of between-lineage interactions that seem to be common and might prevent mixing lineages during simultaneous sexual process in wildlife: (1) the blockage of ookinete development of both parasites; (2) the development of ookinetes of 1 parasite and blockage of ookinete development of the other; (3) selective within-lineage mating resulting in ookinete development of both parent species and absence of hybrid organisms; (4) absence of selective within-lineage mating resulting in presence of ookinetes of both parents and also development of hybrid organisms with unclear potential for further sporogony. The present study indicates directions for collection of source material in the investigation of mechanisms of reproductive isolation leading to speciation in these parasites. The next steps in these studies should be the development of nuclear markers for distinguishing hemosporidian hybrid organisms and the experimental observation of further development of hybrid ookinetes in vectors. PMID- 22924918 TI - Characterization and expression of the Schistosoma japonicum thioredoxin peroxidase-2 gene. AB - We analyzed proteins that were differentially expressed by 10-day-old schistosomula from 3 different hosts and determined that a functional thioredoxin peroxidase-2 gene has an important antioxidant role in Schistosoma japonicum , which we investigated further. A full-length cDNA encoding the S. japonicum thioredoxin peroxidase-2 (SjTPx-2) had an open reading frame of 681 bp that encoded 226 amino acids with a signal peptide of 24 amino acids. A cDNA encoding SjTPx-2 without the signal peptide sequence was isolated from 42-day-old schistosome cDNAs. Real-time quantitative RT-PCR analysis revealed that SjTPx-2 was upregulated in 7- and 13-day-old schistosomes, while the expression level in females was around 2-fold higher than that in male worms at 42 days. SjTPx was subcloned into pET28a(+) and expressed as both inclusion bodies and supernatant in Escherichia coli BL21 (DE3) cells. Western blotting showed that the recombinant SjTPx-2 (rSjTPx-2) was immunogenic. The purified recombinant protein could form disulfide-bonded dimers and it had peroxidase activity in vitro. An immunoprotection experiment in BALB/c mice showed that vaccination with recombinant SjTPx-2 could induce 31.2% and 34.0% reductions in the numbers of worms and eggs in the liver, respectively. This study suggests that SjTPx-2 may be an important antioxidative enzyme in scavenging ROS, and it may be a potential vaccine candidate or new drug target for schistosomiasis. PMID- 22924919 TI - Seroprevalence and factors associated with Toxoplasma gondii infection in domestic cats from urban areas in Latvia. AB - Felids are important in the epidemiology of Toxoplasma gondii infection because they are the only hosts that shed resistant oocysts in the environment. A total of 242 serum samples and 80 fecal samples from domestic cats in Latvia was tested for T. gondii infection. Serum samples were tested for T. gondii antibodies by an indirect in-house ELISA; antibodies were found in 125 (51.6%) of 242 cats; seroprevalence increased with age, indicating postnatal infection. Using multiple logistic regression analyses, age and outdoor access were found to be the most significant (F = 21.70, P < 0.05) factors associated with T. gondii infection in Latvia. Toxoplasma gondii -like oocysts were detected in 2 of the cats examined microscopically using the salt flotation method, but definitive diagnosis could not be made because a bioassay was not performed. PMID- 22924920 TI - Genetic diversity of Hepatozoon spp. in coyotes from the south-central United States. AB - To better define the strains and species of Hepatozoon that infect coyotes in the south-central United States, whole blood and muscle samples were collected from 44 coyotes from 6 locations in Oklahoma and Texas. Samples were evaluated by a nested polymerase chain reaction (PCR) using primers amplifying a variable region of the apicomplexan 18S rRNA gene as well as histopathology (muscle only) for presence of tissue cysts. Hepatozoon spp. infections were identified in 79.5% (35/44) of coyotes tested including 27 of 44 (61.4%) whole blood samples and 17 of 44 (38.6%) muscle samples tested by PCR and 23 of 44 (52.3%) muscle samples evaluated by histological examination. Analysis revealed 19 distinct sequences comprising 3 major clusters of Hepatozoon spp., i.e., 1 most closely related to Hepatozoon americanum, another most closely related to Hepatozoon canis , and the third an intermediate between the 2 groups. The diversity of Hepatozoon spp. in wild canids appears greater than previously recognized and warrants further investigation. PMID- 22924922 TI - Toxoplasma gondii presence in women with spontaneous abortion in Yucatan, Mexico. AB - The objective of this study was to estimate the seroprevalence of anti- Toxoplasma gondii antibodies and DNA of women with spontaneous abortions in 2 hospitals located in Yucatan, Mexico. Between June 2008 and May 2009, blood samples were taken from 100 women with spontaneous abortion attending the Ticul City Communitarian Hospital and the Merida Mother-Kid Hospital. The sera were tested for anti- T. gondii IgG and IgM antibodies. Blood samples (5 ml with anticlotting agent) were also used for polymerase chain reaction (PCR) assay, to detect T. gondii DNA. Forty-two of the 100 samples were negative. Of the positive samples (n = 58), 32 were positive to IgG, 2 to IgM, 5 to IgG and IgM, 6 to IgG and PCR, 1 to IgM and PCR, and 12 to IgG, IgM, and PCR. Accordingly, 55% of the women were seropositive to at least IgG, 20% to at least IgM, and 19% via PCR. Differences between hospitals were significant (P < 0.05) only for IgM. The risk of infection (IgM positive) was 2.85 (odds ratio [OR] 95%, confidence interval [CI]; 1.03-7.87) times greater in women patients at the Merida Mother-Kid Hospital, than those at the Ticul Communitarian Hospital. More studies are needed to evaluate the impact of this disease and to establish strategies to follow in order to reduce congenital toxoplasmosis in the populations at risk. PMID- 22924921 TI - Genetic diversity of ixodid ticks parasitizing eastern mouse and dwarf lemurs in Madagascar, with descriptions of the larva, nymph, and male of Ixodes lemuris (Acari: Ixodidae). AB - The ixodid ticks parasitizing small-bodied nocturnal mouse and dwarf lemurs (Primates, Cheirogaleidae) in Madagascar are poorly documented. At Tsinjoarivo, a high-altitude eastern rain forest, mouse and dwarf lemurs were parasitized by ixodid ticks. At Ranomafana, a montane southeastern rain forest, dwarf lemurs hosted a species of Ixodes, whereas mouse lemurs were parasitized by Haemaphysalis lemuris. Ixodes specimens represent all active stages, and females are morphologically consistent with previous descriptions of Ixodes lemuris females, the only described stage in the literature. Morphological comparisons and genetic analysis using fragments of COI gene confirm that all Ixodes ticks from Tsinjoarivo and Ranomafana forests belong to the same species, i.e., Ixodes lemuris. Thus, we are able to provide descriptions of the previously unknown larva, nymph, and male. Mouse lemurs at both locations were parasitized only by immature stages of I. lemuris (at Tsinjoarivo) or H. lemuris (at Ranomafana), whereas dwarf lemurs were parasitized by all stages of I. lemuris. We suggest that ecological and biogeographical conditions may affect the pattern of tick infestation at Tsinjoarivo and Ranomafana. Additional studies are necessary to understand the tick-host associations of small-bodied nocturnal lemurs. PMID- 22924924 TI - Molecular detection of Theileria spp. and Babesia spp. in sheep and ixodid ticks from the northeast of Iran. AB - Theilerioses and babesioses are important diseases in Iranian sheep. The present study was undertaken to identify and classify/specify Theileria spp. and Babesia spp. in sheep and vector ticks. Investigation was carried out from 2009 to 2011 in the Khorasan Razavi Province, Iran. In total, 302 sheep originating from 60 different flocks were clinically examined and their blood collected. In addition, from the same flocks, ixodid ticks were sampled. Stained blood smears were microscopically examined for the presence of Theileria and Babesia organisms, and a semi-nested PCR was used for subsequent molecular specification. From the ticks, salivary glands and uterus were isolated and subsequently analyzed by semi nested PCR. Piroplasm organisms were observed in 29% of the blood smears with low parasitemia, whereas 65% of the blood samples yielded positive PCR findings. The presence of Theileria ovis (55.6%), Theileria lestoquardi, and mixed infection with Theileria spp. and Babesia ovis were detected by semi-nested PCR in 0.3%, 5.6%, and 0.99%, respectively. In total, 429 ixodid ticks were collected from different areas of the province. The most prevalent ticks were Rhipicephalus turanicus (n = 376; 87.6% of the total), followed by Hyalomma marginatum turanicum (n = 30; 7.0%), Dermacentor raskemensis (n = 12; 2.8%), Hyalomma anatolicum anatolicum (n = 7; 1.6%), Dermacentor marginatus (n = 2; 0.5%), Rhipicephalus bursa (n = 1; 0.2%), and Haemaphysalis sp. (n = 1; 0.2%). Of the positive R. turanicus samples, 5 (5.7%) were infected with T. ovis and 2 (2.9%) with T. lestoquardi. Neither Babesia ovis nor Babesia motasi infection was detected in salivary glands or uterine samples of the ticks. The results also suggest that R. turanicus could be the vector responsible for transmission of the 2 Theileria species. PMID- 22924923 TI - Real-time PCR to quantify Leishmania donovani in hamsters. AB - Visceral leishmaniasis, a vector-borne disease caused by Leishmania donovani and Leishmania infantum , currently affects 12 million individuals in 88 countries. In the present study, a real-time PCR (rt-PCR) assay has been optimized and validated against 2 other routine methods, i.e., microscopy and limiting dilution culture assay, to estimate parasite load in the liver of infected Syrian hamsters (Mesocricetus auratus). A set of specific primers amplified a 116-bp target template of the kinetoplastid DNA of L. donovani in a SYBR(r) Green-based rt-PCR assay. To assess the methods, we tested 2 anti-leishmanial compounds belonging to the class of arylimidamides, DB745 (2,5-bis[2-ethoxy-4-(2 pyridylimino)aminophenyl]furan) and DB766 (2,5-bis[2-(2-propoxy)-4-(2 pyridylimino)aminophenyl]furan) for efficacy in vivo in Syrian hamsters infected with L. donovani promastigotes. Parasite load was quantified in liver by all 3 methods and was found comparable. Of the 3 methods, rt-PCR was the fastest and most convenient, sensitive, and reproducible method. PMID- 22924925 TI - First World War German soldier intestinal worms: an original study of a trench latrine in France. AB - For the first time in the study of ancient parasites, analyses were carried out on samples taken from a First World War settlement in France (Geispolsheim, region of Alsace). Microscopic examination of sediment samples revealed the presence of 3 common human parasites, i.e., Trichuris trichiura , Ascaris lumbricoides , and Taenia sp. A review of paleoparasitological studies in Europe shows that these 3 parasites have infected humanity for centuries. Despite this recurrence, literature shows that knowledge regarding many helminths was limited, and their life cycles were only relatively recently elucidated. Finally, the present study provides additional information about the health of the German soldiers and the sanitary conditions in the trenches during the first modern world conflict. PMID- 22924926 TI - Toxoplasma gondii seroprevalence in Mali. AB - The protozoan parasite Toxoplasma gondii is globally distributed, with considerable local variation in prevalence based on behavioral and environmental factors. To assess prevalence and estimate risk in Mali, we conducted a survey of 760 serum samples previously collected for malaria studies. A modified agglutination test detected antibodies in ~27% of the adult population, with no significant differences between men and women, or between urban and rural study sites. In the village of Kolle, seroprevalence rose from 0% in infants (<1 yr, but after weaning of maternal immunoglobulin G) to 0.8% (1-5 yr), 2.7% (6-10), 11.3% (11-15), and 26.8% (>15); differences between the <10-, 11-15-, and >15-yr age groups were highly significant (P <= 0.01). We also observed an increase in anti- T. gondii antibody titers with age. Modeling the observed age distribution suggests a seroconversion rate of ~1%/yr, indicating that congenital toxoplasmosis may be an under-appreciated public health concern in Mali. PMID- 22924927 TI - A new species of Homalometron (Digenea: Apocreadiidae) from fishes in the northern Gulf of Mexico. AB - Homalometron palmeri n. sp. is described and reported from the following fishes in the northern Gulf of Mexico: Micropogonias undulatus, Sciaenops ocellatus, Bairdiella chrysoura, Pogonias cromis, Fundulus grandis, Fundulus similis, and Eucinostomus argenteus. This species historically has been misidentified as Homalometron pallidum by some, and treated as Homalometron sp. by others. The new species differs from H. manteri by having a smaller body size, relatively longer postcecal space ranging from 7 to 15% of body length compared with 6-8%, body spines from 12 to 17 MUm long compared with 15-20 MUm, and an oral-to-ventral sucker width ratio of 1:1.2-1.3 compared with 1:1.3-1.5. Ribosomal DNA sequences from H. palmeri n. sp., H. pallidum, Homalometron manteri, and Homalometron pseudopallidum are compared and the new species is found to be most similar to H. manteri, a sympatric species. Comparison between 2 mitochondrial genes from H. palmeri n. sp. and H. manteri provided further evidence for their status as distinct species. Pairwise comparison of 503 aligned bases from ND1 gene revealed 33 variable sites (6.5%) between the 2 species. Pairwise comparison of 1,152 aligned bases from COI gene revealed 73 variable sites (6.3%) between the 2 species. Interspecific variability in mitochondrial sequences between the 2 species was 3-16 times greater than intraspecific variability in either species. PMID- 22924928 TI - Isolation of viable Toxoplasma gondii from tissues and feces of cats from Addis Ababa, Ethiopia. AB - Cats are important in the epidemiology of Toxoplasma gondii because they are the only hosts that excrete environmentally resistant oocysts in feces. In the present study, hearts, serum, and feces from 36 feral cats from Addis Ababa area, Ethiopia, were examined for T. gondii infection. Antibodies to T. gondii were determined with the modified agglutination test (MAT, cutoff 1:25); 33 cats were seropositive. Hearts of all 36 cats were homogenized, digested in pepsin, and bioassayed in mice. Feces were examined for T. gondii oocysts by bioassay in mice. Viable T. gondii was isolated from heart of 26 by bioassay in mice and from 25 seropositive and 1 seronegative cats. Toxoplasma gondii was isolated from feces (oocysts) by bioassay in mice. In total, viable T. gondii was isolated from 27 of the 36 cats, and these isolates were designated TgCatEt1 to TgCatEt27. The high prevalence of T. gondii oocysts in feces of 8 (19.4%) of 36 cats is of high epidemiologic significance. This is the first report of isolation of viable T. gondii from any host in Ethiopia. PMID- 22924929 TI - Two new Eimeria spp. (Apicomplexa: Eimeriidae) from the dusky rice rat, Melanomys caliginosus, Tome 1860, in Costa Rica. AB - We collected fecal samples from 9 dusky rice rats, Melanomys caliginosus (Rodentia, Cricetidae, Sigmodontinae), in a Biological Reserve in Costa Rica and found 8 (89%) to be infected with 2 Eimeria species which we describe here as new. Sporulated oocysts (n = 20) of the first, Eimeria melanomytis n. sp., are cylindroidal and measure 20.1 * 13.3 MUm (18-23 * 13-15); micropyle and oocyst residuum are both absent, but a bilobular polar granule is present. Its sporocysts are ovoidal, 10.5 * 7.4 MUm (10-13 * 6-8) with a small Stieda body, but both substieda and parastieda bodies are absent; a spheroidal sporocyst residuum is present, ~ 5 MUm wide. Sporulated oocysts (n = 20) of the second, Eimeria rebambensis n. sp., are subspheroidal, 21.2 * 17.0 MUm (19-23 * 14-18); micropyle and oocyst residuum are both absent, but with a polar granule ~ 2 MUm wide. Sporocysts are elongate-ovoidal, 12.4 * 7.0 MUm (11-14 * 6-9) with a distinct knob-like Stieda body, and a substieda body directly beneath it which is about twice as wide, but no parastieda body is present; the sporocyst residuum is an irregular mass composed of 8-10 globules scattered among the sporozoites, which are ~ 10 * 5 MUm, and have 1 refractile body at their wider end and a central nucleus. These are the first eimerians described from this rodent genus. PMID- 22924930 TI - Predicting what helminth parasites a fish species should have using Parasite Co occurrence Modeler (PaCo). AB - Fish pathologists are often interested in which parasites would likely be present in a particular host. Parasite Co-occurrence Modeler (PaCo) is a tool for identifying a list of parasites known from fish species that are similar ecologically, phylogenetically, and geographically to the host of interest. PaCo uses data from FishBase (maximum length, growth rate, life span, age at maturity, trophic level, phylogeny, and biogeography) to estimate compatibility between a target host and parasite species-genera from the major helminth groups (Acanthocephala, Cestoda, Monogenea, Nematoda, and Trematoda). Users can include any combination of host attributes in a model. These unique features make PaCo an innovative tool for addressing both theoretical and applied questions in parasitology. In addition to predicting the occurrence of parasites, PaCo can be used to investigate how host characteristics shape parasite communities. To test the performance of the PaCo algorithm, we created 12,400 parasite lists by applying any possible combination of model parameters (248) to 50 fish hosts. We then measured the relative importance of each parameter by assessing their frequency in the best models for each host. Host phylogeny and host geography were identified as the most important factors, with both present in 88% of the best models. Habitat (64%) was identified in more than half of the best models. Among ecological parameters, trophic level (41%) was the most relevant while life span (34%), growth rate (32%), maximum length (28%), and age at maturity (20%) were less commonly linked to best models. PaCo is free to use at www.purl.oclc.org/fishpest. PMID- 22924931 TI - Introduced bullfrogs and their parasites: Haematoloechus longiplexus (Trematoda) exploits diverse damselfly intermediate hosts on Vancouver Island. AB - The lung fluke, Haematoloechus longiplexus, is the most prevalent and abundant parasite of introduced bullfrogs on Vancouver Island, British Columbia, Canada. The ecological success of this trematode in invasive bullfrogs is related to the fluke's ability to utilize native intermediate hosts for transmission. The purpose of this study was to identify the odonate (dragonfly/damselfly) species involved in the transmission of H. longiplexus to the introduced bullfrog. The prevalences and mean intensities of 21 species of odonates (nymphs and adults) were examined for metacercariae infections. Haematoloechus longiplexus is a second intermediate host specialist, being found only in damselflies. Six damselfly species exhibiting the "climber" ecological habit were identified as second intermediate hosts of H. longiplexus. Enallagma carunculatum (prevalence = 75.0%, mean intensity = 17.2 +/- 10.8), Ischnura cervula (65.2%, 8.9 +/- 4.3), Ischnura perparva (45.5%, 15.4 +/- 10.3), and Enallagma boreale (40.7%, 4.8 +/- 7.8) were the most commonly infected damselfly species. Metacercariae were absent in damselflies collected from sites lacking bullfrogs. Haematoloechus longiplexus was likely introduced along with the bullfrog, and subsequently adapted to the physid snail and diverse damselfly intermediate hosts present in ponds on Vancouver Island. PMID- 22924932 TI - Giardia duodenalis assemblage-specific induction of apoptosis and tight junction disruption in human intestinal epithelial cells: effects of mixed infections. AB - In view of the interest in genotype-specific pathogenesis in Giardia duodenalis , the aim of the present study was to examine the effects of infection with different, or mixed, G. duodenalis assemblages on the integrity of human intestinal epithelia. To that end, human epithelial cells (HCT-8) were cultured and exposed to different G. duodenalis assemblages (A, B, and E) or a combination of these assemblages. Epithelial disruption and apoptosis were evaluated by fluorescent microscopy and apoptotic oligonucleosome quantification. The results indicate that infection with trophozoites disrupts epithelial tight junctions and induces varying degrees of enterocyte apoptosis, depending on the infecting assemblage. All disruptions were caspase-3 dependent and were more pronounced when caused by a non-host specific assemblage. Furthermore, infections by isolates in combination with isolates from another assemblage enhanced the epithelial disruption and apoptosis. Further studies in vitro and in vivo are required to confirm the mechanisms of enhanced pathogenicity of mixed or non-host specific (or both) G. duodenalis infections. Findings in the present study point to the potential pathogenic importance of intra-species polyparasitism in giardiasis. PMID- 22924933 TI - Efficient iron uptake via a reductive mechanism in procyclic Trypanosoma brucei. AB - The bloodstream form of Trypanosoma brucei acquires iron from transferrin by receptor-mediated endocytosis. However, it is unknown how procyclic forms that cannot bind transferrin acquire iron. Here, we show that the procyclic form of T. brucei efficiently takes up iron from ferric complexes via a reductive mechanism and that iron obtained using this mechanism is transported to, and used in, the mitochondria. The affinity of the transport system is comparable to that of Saccharomyces cerevisiae , with an apparent K(m) of 0.85 MUM. PMID- 22924934 TI - A new species of Biacantha (Nematoda: Molineidae), a parasite of the common vampire bat from the Yungas, Argentina. AB - A new species of Biacantha Wolfgang, 1954 (Nematoda: Molineidae), is described from the common vampire bat, Desmodus rotundus Geoffroy and St. Hilaire, 1810, from northwest Argentina. Biacantha normaliae n. sp. Oviedo, Ramallo, and Claps, is characterized by the disposition and number of ridges of the synlophe, the excretory pore located on a knob, 2 lateral processes on the tail of females, the male caudal bursa morphology, and lack of gubernaculum. This is the first species of nematode described in a vampire bat from Argentina. PMID- 22924935 TI - Sequence characterization of heat shock protein gene of Cyclospora cayetanensis isolates from Nepal, Mexico, and Peru. AB - We have described the development of a 2-step nested PCR protocol based on the characterization of the 70-kDa heat shock protein (HSP70) gene for rapid detection of the human-pathogenic Cyclospora cayetanensis parasite. We tested and validated these newly designed primer sets by PCR amplification followed by nucleotide sequencing of PCR-amplified HSP70 fragments belonging to 16 human C. cayetanensis isolates from 3 different endemic regions that include Nepal, Mexico, and Peru. No genetic polymorphism was observed among the isolates at the characterized regions of the HSP70 locus. This newly developed HSP70 gene-based nested PCR protocol provides another useful genetic marker for the rapid detection of C. cayetanensis in the future. PMID- 22924936 TI - Evaluation of methods for the isolation of high quality RNA from bovine and cervine hide biopsies. AB - Molecular investigations of the ruminant response to ectoparasites at the parasite-host interface are critically dependent upon the quality of RNA. The complexity of ruminant skin decreases the capacity to obtain high quality RNA from biopsy samples, which directly affects the reliability of data produced by gene expression experiments. Two methods for isolating total RNA from skin were compared and the use of 4M guanidinium isothiocyanate (GITC) during frozen storage of the specimens was evaluated. In addition, the best procedure for RNA isolation from bovine skin punch biopsies was also tested on white-tailed deer skin biopsies. Skin biopsy punches were collected and frozen prior to pulverization for RNA isolation. Total RNA quantity and integrity were determined by spectrophotometry and capillary electrophoresis technology, respectively. Significantly increased total RNA yield (P < 0.05) and higher integrity (P < 0.05) were obtained with a TRI Reagent(r) isolation method. Freezing and subsequent storage of bovine skin punch biopsies in 4 M GITC did not affect the amount or integrity of total RNA recovered by either RNA isolation method. However, quantity and integrity of total RNA extracted with the TRI Reagent method were again significantly higher than with the alternate technique, confirming it as the superior method. The TRI Reagent isolation method also yielded high quality total RNA from white-tailed deer skin punch biopsies, suggesting the usefulness of this method for obtaining RNA of a quality suitable for gene expression studies in other ruminant species. PMID- 22924938 TI - Novel antiviral therapeutics to control foot-and-mouth disease. AB - Foot-and-mouth disease virus (FMDV) causes a highly contagious disease of cloven hoofed animals. Vaccines require ~7 days to induce protection; thus, before this time, vaccinated animals are still susceptible to the disease. Our group has previously shown that swine inoculated with 1*10(11) focus forming units (FFU) of a replication-defective human adenovirus containing the gene for porcine interferon alpha (Adt-pIFN-alpha) are sterilely protected from FMDV serotypes A24, O1 Manisa, or Asia 1 when the animals are challenged 1 day postadministration, and protection can last for 3-5 days. Polyriboinosinic polyribocytidylic acid stabilized with poly-l-lysine and carboxymethyl cellulose (poly ICLC) is a synthetic double-stranded RNA that is a viral mimic and activates multiple innate immune pathways through interaction with toll-like receptor 3 and MDA-5. It is a potent inducer of IFNs. In this study, we initially examined the effect of poly IC and IFN-alpha on FMDV replication and gene induction in cell culture. Poly ICLC alone or combined with Adt-pIFN-alpha was then evaluated for its therapeutic efficacy in swine against intradermal challenge with FMDV A24, 1 day post-treatment. Groups of swine were subcutaneously inoculated either with poly ICLC alone (4 or 8 mg) or in combination with different doses of Adt-pIFN-alpha (2.5*10(9), 1*10(9), or 2.5*10(8) FFU). While different degrees of protection were achieved in all the treated animals, a dose of 8 mg of poly ICLC alone or combined with 1*10(9) FFU of Adt-pIFN-alpha was sufficient to sterilely protect swine when challenged 24 h later with FMDV A24. IFN-stimulated gene (ISG) expression in peripheral blood mononuclear cells at 1 day post-treatment was broader and higher in protected animals than in nonprotected animals. These data indicate that poly ICLC is a potent stimulator of IFN and ISGs in swine and at an adequate dose is sufficient to induce complete protection against FMD. PMID- 22924937 TI - Lateral cervical cysts: an Australian perspective. AB - BACKGROUND: Correctly identifying the aetiology of lateral cervical cysts poses a diagnostic challenge commonly encountered by head and neck surgeons. The aim of this study was to ascertain the effectiveness of current investigatory techniques used in the diagnosis of these masses. METHODS: A retrospective analysis of all patients presenting to a single Sydney Head and Neck Unit between 2000 and 2010 with the diagnosis of a lateral cervical cyst was performed. Patients with a clinically evident primary malignancy were excluded from the study. Results of their clinical assessment and any investigations performed were compared with pathology after surgical excision. RESULTS: Forty-seven patients met the inclusion criteria. Twelve of the 47 masses showed squamous cell carcinoma on histology post-operatively. The remainder of the masses (35 out of 47) were histologically diagnosed as branchial cleft cysts. Of the malignant tumours, 4 of 12 (33%) were correctly identified before cyst removal. Fine-needle aspiration (FNA) was performed in 37 of the 47 patients, with a sensitivity of 25% and a specificity of 96.6%. Notably, a false-positive result was obtained from FNA in a patient who had a final diagnosis of branchial cyst after modified radical neck dissection. The rate of malignancy in patients aged over 40 years (44%) was higher than that of the total group (25.5%) and significantly higher than that of patients aged below 40 years (0%). CONCLUSIONS: Current techniques in the investigation of cystic neck masses are suboptimal in their accuracy. Clinical evaluation and, in particular, thorough examination of the oropharynx directly and by fibre-optic nasendoscopy will often reveal the presence of a primary cancer when present. Care must always be taken in the evaluation of such lesions to maximize the likelihood of making the correct diagnosis. PMID- 22924940 TI - Gelation, phase behavior, and dynamics of beta-lactoglobulin amyloid fibrils at varying concentrations and ionic strengths. AB - We have investigated the thermodynamic and dynamic behavior of multistranded beta lactoglobulin protein fibrils in water, by combining static, dynamic, and depolarized dynamic light scattering (SLS, DLS, DDLS), small angle neutron scattering (SANS), rheology, and cryogenic transmission electron microscopy (cryo TEM). We focus on the region of the phase diagram at which ionic strength and concentration changes induce transitions in gelation and lyotropic liquid crystalline behavior. An increase in ionic strength, induced by NaCl salt, progressively causes the phase transitions from nematic (N) to gel (G) phases; a further increase causes the transition to a translucent phase and to a macroscopic phase separation, respectively. An increase in fibril concentration induces first a phase transition from an isotropic (I) to a nematic phase (N); a further increase induces the formation of a gel phase. The protein gel strength is investigated by rheology measurements. SANS and osmotic compressibility calculated by SLS measurements clearly capture the main features of the IN transition of beta-lactoglobulin protein fibrils. The form and structure factors measured by scattering experiments are analyzed by the polymer reference interaction site model (PRISM). Dynamics of the protein fibrils at different concentrations, measured by polarized and depolarized dynamic light scattering, show both individual and collective diffusion after the isotropic-nematic transition. Above this transition, cryo-TEM images further demonstrate the alignment of the protein fibrils, which is quantified by a 2D order parameter. This work discusses comprehensively, both experimentally and theoretically, the thermodynamics and dynamic features of beta-lactoglobulin amyloid fibrils in a vast region of the concentration-ionic strength phase diagram. PMID- 22924939 TI - Interleukin-6 promoter polymorphisms and susceptibility to atrial fibrillation in elderly Han Chinese patients with essential hypertension. AB - There is an accumulating body of evidence indicating a strong association between inflammation and the pathogenesis of atrial fibrillation (AF). Interleukin-6 (IL 6) is a pleiotropic cytokine, functions as a mediator of inflammatory response, and has both proinflammatory and anti-inflammatory properties. The aim of the present study was to investigate the association of the -634C/G polymorphism of the IL-6 gene with AF in elderly Han Chinese patients with essential hypertension (EH). A total of 169 elderly patients with EH were eligible for this study. Patients with AF (n=75) were allocated to the AF group, and 94 subjects without AF to the control group. The polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique was used to assess the genotype frequencies. The distribution of the IL-6 -634C/G genotypes (CC, CG, and GG) was 67.02%, 30.85%, and 2.13% in the controls, and 50.67%, 40.00%, and 9.33% in AF subjects, respectively (P=0.0312). The frequency of the G allele in the AF group was significantly higher than that in the control group (29.33% vs. 17.55%, P=0.0103). Compared with the CC and CG genotypes, the GG homozygote had a 4.7353 fold increased risk of AF [95% confidence interval (CI)=0.9537-23.5116, P=0.0382]. These findings suggest that the IL-6 -634C/G polymorphism is associated with AF, and the G allele has increased risk of AF in elderly Han Chinese patients with EH. PMID- 22924941 TI - Detection of pandemic influenza A (H1N1) 2009 virus RNA by real-time reverse transcription polymerase chain reaction. PMID- 22924942 TI - African American mothers: bringing the case for breastfeeding home. PMID- 22924943 TI - Using social media to promote and support breastfeeding. PMID- 22924944 TI - Health disparities: breastfeeding's role in closing the gap. PMID- 22924945 TI - Should people with normal vitamin D status receive ultraviolet treatment? PMID- 22924947 TI - Photodynamic therapy and immunosuppression. PMID- 22924946 TI - Are antimicrobial peptides new players in skin cancer development? PMID- 22924948 TI - Combining rexinoids with psoralen-ultraviolet A sheds light on the management of mycosis fungoides. PMID- 22924949 TI - Efficacy and safety of tofacitinib, an oral Janus kinase inhibitor, in the treatment of psoriasis: a Phase 2b randomized placebo-controlled dose-ranging study. AB - BACKGROUND: Tofacitinib is a novel, oral Janus kinase inhibitor under investigation as a potential treatment for plaque psoriasis. OBJECTIVES: This Phase 2b, 12-week, dose-ranging study (A3921047, NCT00678210) aimed to characterize the exposure-response, efficacy and safety of tofacitinib vs. placebo in patients with moderate-to-severe chronic plaque psoriasis. METHODS: One hundred and ninety-seven patients were randomized. The primary endpoint was the proportion of patients achieving a >= 75% reduction in the Psoriasis Area and Severity Index (PASI 75) score at week 12. RESULTS: At week 12, PASI 75 response rates were significantly higher for all tofacitinib twice-daily groups: 25.0% (2 mg; P < 0.001), 40.8% (5 mg; P < 0.0001) and 66.7% (15 mg; P < 0.0001), compared with placebo (2.0%). Significant increases in the proportion of PASI 75 responses were seen by week 4 and were maintained at week 12. Exposure-response over the 0 15 mg tofacitinib twice-daily dose range was successfully characterized. PASI 50, PASI 90 and Physician's Global Assessment response rates were also higher for tofacitinib vs. placebo. The most frequently reported adverse events (AEs) were infections and infestations: 22.4% (2 mg twice daily), 20.4% (5 mg twice daily), 36.7% (15 mg twice daily) and 32.0% (placebo). Discontinuations due to AEs were 6.0%, 2.0%, 4.1% and 6.1% of patients in the placebo, and 2, 5 and 15 mg twice daily tofacitinib groups, respectively. Dose-dependent increases from baseline in mean serum high-density lipoprotein, low-density lipoprotein and total cholesterol, and decreases in haemoglobin and neutrophils were observed. CONCLUSION: Short-term treatment with oral tofacitinib results in significant clinical improvement in patients with moderate-to-severe plaque psoriasis and is generally well tolerated. PMID- 22924950 TI - Efficacy and safety of bexarotene combined with psoralen-ultraviolet A (PUVA) compared with PUVA treatment alone in stage IB-IIA mycosis fungoides: final results from the EORTC Cutaneous Lymphoma Task Force phase III randomized clinical trial (NCT00056056). AB - BACKGROUND: Psoralen plus ultraviolet A (PUVA) is the standard treatment for early stages of mycosis fungoides. There have been no adequate randomized controlled trials with sufficient power comparing this modality with other therapies. OBJECTIVE: To assess disease response and to compare the response rates of patients treated with PUVA alone or PUVA and bexarotene. METHODS: EORTC 21011 (NCT 00056056) was a randomized phase III study comparing combined bexarotene (Targretin((r)) ) and PUVA vs. PUVA alone in patients with stage IB and IIA mycosis fungoides (MF). The primary endpoint was the overall response rate [complete clinical response (CCR) plus partial response (PR)]. RESULTS: The study was prematurely closed due to low accrual after 93 of 145 required patients (65%) were randomized. Of the 93 randomized patients, 87 started treatment, 41 received PUVA and 46 received PUVA + bexarotene. Total UVA doses received were 107 J cm(-2) (range 1.4-489.9) in the PUVA arm vs. 101.7 J cm(-2) (0.2-529.9) in the combination arm. The safety profile was acceptable with few grade 3-4 toxicities observed in either arm. More drop-outs due to toxicity were observed in the combination arm compared with the PUVA-alone arm. The best overall response (CCR + PR) rate was 71% for PUVA alone and 77% for the combination arm (P = 0.57). The median duration of response was 9.7 months for PUVA vs. 5.8 months for the combination arm (P = 0.33). CCR was seen in 25 patients of whom 10 received PUVA alone (CCR 22%) and 15 received combination therapy (CCR 31%) (P = 0.45). CCR was sustained in 25% of patients regardless of therapy. There was a trend towards fewer PUVA sessions needed to achieve CCR in the combination arm (median 22) compared with the PUVA arm (median 27.5) (P = 0.11). Similarly, a trend towards lower UVA dose required to achieve CCR in the combination arm (median 55.8 J cm(-2) ) compared with the PUVA arm alone (median 117.5 J cm(-2) ) (P = 0.5) was observed. CONCLUSIONS: No significant difference in response rate or response duration was observed in this study. However, there was a trend towards fewer PUVA sessions and lower UVA dose required to achieve CCR in the combination arm (PUVA + bexarotene) but this did not achieve statistical significance due to insufficient power. PMID- 22924951 TI - Dyslexia and fluency: parafoveal and foveal influences on rapid automatized naming. AB - The ability to coordinate serial processing of multiple items is crucial for fluent reading but is known to be impaired in dyslexia. To investigate this impairment, we manipulated the orthographic and phonological similarity of adjacent letters online as dyslexic and nondyslexic readers named letters in a serial naming (RAN) task. Eye movements and voice onsets were recorded. Letter arrays contained target item pairs in which the second letter was orthographically or phonologically similar to the first letter when viewed either parafoveally (Experiment 1a) or foveally (Experiment 1b). Relative to normal readers, dyslexic readers were more affected by orthographic confusability in Experiment 1a and phonological confusability in Experiment 1b. Normal readers were slower to process orthographically similar letters in Experiment 1b. Findings indicate that the phonological and orthographic processing problems of dyslexic readers manifest differently during parafoveal and foveal processing, with each contributing to slower RAN performance and impaired reading fluency. PMID- 22924952 TI - Perceiving and acting on complex affordances: how children and adults bicycle across two lanes of opposing traffic. AB - This investigation examined how children and adults negotiate a challenging perceptual-motor problem with significant real-world implications--bicycling across two lanes of opposing traffic. Twelve- and 14-year-olds and adults rode a bicycling simulator through an immersive virtual environment. Participants crossed intersections with continuous cross traffic coming from opposing directions. Opportunities for crossing were divided into aligned (far gap opens with or before near gap) and rolling (far gap opens after near gap) gap pairs. Children and adults preferred rolling to aligned gap pairs, though this preference was stronger for adults than for children. Crossing aligned versus rolling gap pairs produced substantial differences in direction of travel, speed of crossing, and timing of entry into the near and far lanes. For both aligned and rolling gap pairs, children demonstrated less skill than adults in coordinating self and object movement. These findings have implications for understanding perception-action-cognition links and for understanding risk factors underlying car-bicycle collisions. PMID- 22924953 TI - Long-term outcome of resective epilepsy surgery in Norwegian children. AB - AIM: The aim of this study was to evaluate the long-term results of resective surgery on children with difficult-to-treat epilepsy in Norway. METHODS: In the period 1995-2004, 64 surgical procedures (54 resections and 10 functional hemispherotomies) were performed in 54 children. The children's medical records were retrospectively reviewed at a minimum of 2 years after surgery. We sent a questionnaire regarding their epilepsy (seizures, usage of antiepileptic drugs) and general functioning (social situation, motor, language, cognition, behavioural or emotional problems, any remedial action) to the children/parents after a mean follow-up period of 7 years. RESULTS: 55.5% of the children were seizure-free. The success rate varied according to the type of surgery. Best results were found after functional hemispherotomies and temporal lobe resections, as nine of 10 (90%) and 10 of 19 (53%) of these patients, respectively, became seizure-free. In addition to a better seizure control, 71% of the children/parents reported of a better cognitive and psychosocial functioning. CONCLUSION: The results of epilepsy surgery in this paediatric cohort are very edifying, and it is our impression that this treatment option is underused in Norway. PMID- 22924954 TI - Altered leaf colour is associated with increased superoxide-scavenging activity in aureusidin-producing transgenic plants. AB - The health-promoting property of diets rich in fruits and vegetables is based, in part, on the additive and synergistic effects of multiple antioxidants. In an attempt to further enhance food quality, we introduced into crops the capability to synthesize a yellow antioxidant, aureusidin, that is normally produced only by some ornamental plants. For this purpose, the snapdragon (Antirrhinum majus) chalcone 4'-O-glucosyltransferase (Am4'CGT) and aureusidin synthase (AmAs1) genes, which catalyse the synthesis of aureusidin from chalcone, were expressed in tobacco (Nicotiana tabacum) and lettuce (Lactuca sativa) plants that displayed a functionally active chalcone/flavanone biosynthetic pathway. Leaves of the resulting transgenic plants developed a yellow hue and displayed higher superoxide dismutase (SOD) inhibiting and oxygen radical absorbance capacity (ORAC) activities than control leaves. Our results suggest that the nutritional qualities of leafy vegetables can be enhanced through the introduction of aurone biosynthetic pathways. PMID- 22924955 TI - Surface analysis of materials in aqueous solution by localized alternating current impedance measurements. AB - Differences in electrical conductivity provide a basis for identification of different components present at a material surface. Here it is demonstrated that this effect can be exploited for surface analysis of compound materials in solution by making localized alternating current impedance measurements. PMID- 22924956 TI - Accumulation of staphylococcal Panton-Valentine leukocidin in the detergent resistant membrane microdomains on the target cells is essential for its cytotoxicity. AB - The mechanisms for the cytotoxicity of staphylococcal Panton-Valentine leukocidin (PVL), a pore-forming toxin consisting of LukS-PV and LukF-PV, in human immune cells are still unclear. Because LukS-PV binds to ganglioside GM1, a constituent of detergent-resistant membrane microdomains (DRMs) of the plasma membrane, the role of DRMs in PVL cytotoxicity was examined in human polymorphonuclear neutrophils (PMNs), monocytes, HL-60 cells, and THP-1 cells. PVL binding capacities in HL-60 and THP-1 cells were higher than those in PMNs and monocytes; however, the PVL concentration to obtain more than 80% cell lysis in HL-60 cells was 10 times higher than that in PMNs and PVL even at such concentration induced < 10% cell lysis in THP-1 cells. After incubation of PMNs with LukS-PV, more than 90% of LukS-PV bound to the detergent-soluble membranes. Subsequent incubation with LukF-PV at 4 degrees C induced the accumulation of more than 70% of PVL components and 170- to 220-kDa complex formation in DRMs in an actin-independent manner. However, only 30% of PVL was found, and complex formation was under detectable level in DRMs in HL-60 cells. PVL did not accumulate in DRMs in THP-1 cells. Our observations strongly indicate that PVL accumulation in DRMs is essential for PVL cytotoxicity. PMID- 22924958 TI - Romidepsin (FK228) and its analogs directly inhibit phosphatidylinositol 3-kinase activity and potently induce apoptosis as histone deacetylase/phosphatidylinositol 3-kinase dual inhibitors. AB - Activation of phosphatidylinositol 3-kinase (PI3K) signaling is involved in carcinogenesis and cancer progression. The PI3K inhibitors are considered candidate drugs for cancer treatment. Here, we describe a drug screening system for novel PI3K inhibitors using Saccharomyces cerevisiae strains with deleterious mutations in the ATP-binding cassette transporter genes, because wild-type S. cerevisiae uses drug efflux pumps for reducing intracellular drug concentrations. By screening the chemical library of the Screening Committee of Anticancer Drugs, we identified the histone deacetylase (HDAC) inhibitor romidepsin (FK228) and its novel analogs. In vitro PI3K activity assays confirmed that these compounds directly inhibit PI3K activity at MUM-range concentrations. FK-A5 analog was the most potent inhibitor. Western blotting revealed that these compounds inhibit phosphorylation of protein kinase B and downstream signaling components. Molecular modeling of the PI3K-FK228 complex indicated that FK228 binds to the ATP-binding pocket of PI3K. At MUM-range concentrations, FK228 and FK-A5 show potent cytotoxicity, inducing apoptosis even in HDAC inhibitor-resistant cells. Furthermore, HDAC/PI3K dual inhibition by FK228 and FK-A5 at MUM-range concentrations potentiates the apoptosis induction, mimicking the effect of combining specific HDAC and PI3K inhibitors. In this study, we showed that FK228 and its analogs directly inhibit PI3K activity and induce apoptosis at MUM-range concentrations, similar to HDAC/PI3K dual inhibition. In future, optimizing the potency of FK228 and its analogs against PI3K may contribute to the development of novel HDAC/PI3K dual inhibitors for cancer treatment. PMID- 22924957 TI - Hfq-dependent, co-ordinate control of cyclic diguanylate synthesis and catabolism in the plague pathogen Yersinia pestis. AB - Yersinia pestis, the cause of the disease plague, forms biofilms to enhance flea to-mammal transmission. Biofilm formation is dependent on exopolysaccharide synthesis and is controlled by the intracellular levels of the second messenger molecule cyclic diguanylate (c-di-GMP), but the mechanisms by which Y. pestis regulates c-di-GMP synthesis and turnover are not fully understood. Here we show that the small RNA chaperone Hfq contributes to the regulation of c-di-GMP levels and biofilm formation by modulating the abundance of both the c-di-GMP phosphodiesterase HmsP and the diguanylate cyclase HmsT. To do so, Hfq co ordinately promotes hmsP mRNA accumulation while simultaneously decreasing the stability of the hmsT transcript. Hfq-dependent regulation of HmsP occurs at the transcriptional level while the regulation of HmsT is post-transcriptional and is localized to the 5' untranslated region/proximal coding sequence of the hmsT transcript. Decoupling HmsP from Hfq-based regulation is sufficient to overcome the effects of Deltahfq on c-di-GMP and biofilm formation. We propose that Y. pestis utilizes Hfq to link c-di-GMP levels to environmental conditions and that the disregulation of c-di-GMP turnover in the absence of Hfq may contribute to the severe attenuation of Y. pestis lacking this RNA chaperone in animal models of plague. PMID- 22924959 TI - Real-time fit of a respirator during simulated health care tasks. AB - Fit is an important but difficult-to-predict feature of respirator performance. This study examined a new approach to measuring respirator performance using two continuous direct-reading particle-counting instruments in a simulated health care workplace. A pilot test was conducted with eight experienced health care professionals who passed a traditional quantitative fit test before performing three randomized 10-min health care scenarios (patient assessment [PA], IV treatment [IV], and wound care [WC]). Two TSI Portacount Plus (Model 8020) with N95 Companion (Model 8095) instruments were used to continuously measure 1-sec ambient particle concentrations inside and outside the respirator facepiece. A simulated workplace protection factor (SWPF) was calculated by dividing outside by inside concentrations. Data were log transformed and examined using analysis of variance (ANOVA) between subjects, scenario types, and scenario order. The GM SWPF for the eight subjects, three scenarios per subject, ranged from 172 to 1073 (GSD 1.7 to 3.5) and was significantly different for each subject. A multi-way analysis of variance showed no difference between the three scenario types (PA, IV, WC). There were differences by the order in which scenarios were performed: the third scenario SWPF was significantly different and higher than that of the first and second scenarios. All subjects passed the initial quantitative fit test with a fit factor of at least 100. Five subjects had fit factors greater than 200 and GM scenario SWPFs greater than 400. Three participants with initial fit factors less than 200 had GM scenario SWPFs ranging from 132 to 326. This pilot test demonstrates that it is possible to evaluate instantaneous respirator fit using two quantitative fit test instruments in a simulated health care environment. Results suggest that an initial fit test may be predictive of fit during simulated tasks and that one scenario may be adequate for measuring a simulated workplace protection factor. [Supplementary materials are available for this article. Go to the publisher's online edition of Journal of Occupational and Environmental Hygiene for the following free supplemental resource: a video for subject D activities overlaid with simulated workplace protection factor data.]. PMID- 22924960 TI - Evaluation of the recognizing and responding to suicide risk training. AB - Changes in attitudes, confidence, and practice behaviors were assessed among 452 clinicians who completed the training, Recognizing and Responding to Suicide Risk, and who work with clients at risk for suicide. Data were collected at three time points. Scores on measures of attitudes toward suicide prevention and confidence to work with clients at risk for suicide improved over time. Clinical practice behaviors improved for assessing and formulating suicide risk, developing suicide prevention treatment plans, and responding to vignettes. Results suggest training can improve clinicians' attitudes toward suicide, confidence to work with clients at risk for suicide, and, most importantly, clinical practice skills. PMID- 22924961 TI - An electrically-driven GaAs nanowire surface plasmon source. AB - Over the past decade, the properties of plasmonic waveguides have extensively been studied as key elements in important applications that include biosensors, optical communication systems, quantum plasmonics, plasmonic logic, and quantum cascade lasers. Whereas their guiding properties are by now fairly well understood, practical implementation in chipscale systems is hampered by the lack of convenient electrical excitation schemes. Recently, a variety of surface plasmon lasers have been realized, but they have not yet been waveguide-coupled. Planar incoherent plasmonic sources have recently been coupled to plasmonic guides but routing of plasmonic signals requires coupling to linear waveguides. Here, we present an experimental demonstration of electrically driven GaAs nanowire light sources integrated with plasmonic nanostrip waveguides with a physical cross-section of 0.08lambda(2). The excitation and waveguiding of surface plasmon-polaritons (SPPs) is experimentally demonstrated and analyzed with the help of full-field electromagnetic simulations. Splitting and routing of the electrically generated SPP signals around 90 degrees bends are also shown. The realization of integrated plasmon sources greatly increases the applicability range of plasmonic waveguides and routing elements. PMID- 22924962 TI - Complete paternal uniparental isodisomy for Chromosome 2 revealed in a parentage testing case. AB - BACKGROUND: Uniparental disomy (UPD) is a rare cytogenetic event that has previously been reported mostly via genetic analysis of patients with phenotypes of recessive diseases. The incidence of UPD of any chromosome is estimated to be approximately1:3500 live births. CASE REPORT: In a case of disputed paternity involving a phenotypically normal male child, mother-child exclusions were observed at five short tandem repeat markers, which were all located on Chromosome 2. Ten additional dinucleotide repeat markers spanning both arms of Chromosome 2 were investigated. The results revealed that the child was homozygous for all markers tested with all alleles originating from a single paternal Chromosome 2, which was consistent with paternal UPD for Chromosome 2. CONCLUSION: This case and other previous reports demonstrate that UPD poses a high risk for false exclusion and incorrect expert opinion. Furthermore, this case highlights that a conclusion of exclusion of paternity or maternity should not be postulated if multiple genetic incompatibilities are located on the same chromosome because of the occurrence of UPD. PMID- 22924963 TI - One-point binding ligands for asymmetric gold catalysis: phosphoramidites with a TADDOL-related but acyclic backbone. AB - Readily available phosphoramidites incorporating TADDOL-related diols with an acyclic backbone turned out to be excellent ligands for asymmetric gold catalysis, allowing a number of mechanistically different transformations to be performed with good to outstanding enantioselectivities. This includes [2 + 2] and [4 + 2] cycloadditions of ene-allenes, cycloisomerizations of enynes, hydroarylation reactions with formation of indolines, as well as intramolecular hydroaminations and hydroalkoxylations of allenes. Their preparative relevance is underscored by an application to an efficient synthesis of the antidepressive drug candidate (-)-GSK 1360707. The distinctive design element of the new ligands is their acyclic dimethyl ether backbone in lieu of the (isopropylidene) acetal moiety characteristic for traditional TADDOL's. Crystallographic data in combination with computational studies allow the efficiency of the gold complexes endowed with such one-point binding ligands to be rationalized. PMID- 22924964 TI - Holland Sleep Disorders Questionnaire: a new sleep disorders questionnaire based on the International Classification of Sleep Disorders-2. AB - The primary objectives of this study were to construct a self-assessment questionnaire for sleep disorders based on the International Classification of Sleep Disorders-2, and to evaluate the questionnaire's psychometric properties with respect to its total score and the individual scores for each of the six sleep disorders. In total, 1269 patients, clinically diagnosed with a sleep disorder, and 412 subjects without sleep complaints were enrolled into this study. Principal components analysis confirmed that the Holland Sleep Disorders Questionnaire differentially represented the six symptom clusters associated with International Classification of Sleep Disorders-2 classifications. The Holland Sleep Disorders Questionnaire's total score distinguished patients with a clinically diagnosed sleep disorder from individuals without sleep complaints, with area under the receiver operating curve P(A) of 0.95. The internal reliability coefficient alpha was 0.90 and, applying the Youden criterion as cutoff score, the overall accuracy was 88% (kappa: 0.75). Subsequently, the six diagnostic groups of sleep-disordered patients could be differentiated reliably, with P(A) values ranging between 0.69 and 0.95, alpha coefficients ranging between 0.73 and 0.81 and an overall percentage of 85% correctly classified patients (kappa = 0.80), indicating a substantial to excellent agreement between the primary diagnoses and the Holland Sleep Disorders Questionnaire classifications. PMID- 22924965 TI - Temperature-dependent electrical properties of graphene inkjet-printed on flexible materials. AB - Graphene electrode was fabricated by inkjet printing, as a new means of directly writing and micropatterning the electrode onto flexible polymeric materials. Graphene oxide sheets were dispersed in water and subsequently reduced using an infrared heat lamp at a temperature of ~200 degrees C in 10 min. Spacing between adjacent ink droplets and the number of printing layers were used to tailor the electrode's electrical sheet resistance as low as 0.3 MOmega/? and optical transparency as high as 86%. The graphene electrode was found to be stable under mechanical flexing and behave as a negative temperature coefficient (NTC) material, exhibiting rapid electrical resistance decrease with temperature increase. Temperature sensitivity of the graphene electrode was similar to that of conventional NTC materials, but with faster response time by an order of magnitude. This finding suggests the potential use of the inkjet-printed graphene electrode as a writable, very thin, mechanically flexible, and transparent temperature sensor. PMID- 22924966 TI - Subinhibitory concentrations of antibiotics affect stress and virulence gene expression in Listeria monocytogenes and cause enhanced stress sensitivity but do not affect Caco-2 cell invasion. AB - AIMS: Antibiotics can act as signal molecules and affect bacterial gene expression, physiology and virulence. The purpose of this study was to determine whether subinhibitory antibiotic concentrations alter gene expression and physiology of Listeria monocytogenes. METHODS AND RESULTS: Using an agar-based screening assay with promoter fusions, 14 of 16 antibiotics induced or repressed expression of one or more stress and/or virulence genes. Despite ampicillin induced up-regulation of PinlA-lacZ expression, Caco-2 cell invasion was not affected. Subinhibitory concentrations of ampicillin and tetracycline caused up- and down-regulation of stress response genes, respectively, but both antibiotics caused increased sensitivity to acid stress. Six combinations of gene-antibiotic were quantified in broth cultures and five of the six resulted in the same expression pattern as the agar-based assay. CONCLUSIONS: Antibiotics affect virulence and/or stress gene expression; however, altered expression could not predict changes in phenotypic behaviour. Subinhibitory concentrations of antibiotics led to increased acid sensitivity, and we speculate that this is attributed to changes in cell envelope or reduced sigma(B) -dependent gene expression. SIGNIFICANCE AND IMPACT OF THE STUDY: Although subinhibitory concentrations of antibiotics affect gene expression in L. monocytogenes, the changes did not increase virulence but did enhance the acid sensitivity. PMID- 22924968 TI - The role of scripts in psychological maladjustment and psychotherapy. AB - This article considers the value of script theory for understanding psychological maladjustment and psychotherapy. Scripts are implicit expectations that individuals develop to understand and deal with emotionally significant life experiences. Script theory provides a way to understand the complex patterns of thinking, feeling, and behavior that characterize personal consistency, as well as a way to address personality development and change. As such it is a vital model for understanding both personality and clinical phenomena. The article begins by describing script theory and noting similar models in personality and clinical psychology. It then outlines both idiographic and nomothetic methods for assessing scripts and discusses the strengths and weaknesses of each. A survey of the author's program of research follows, using a nomothetic method to examine the role of interpersonal scripts in psychological maladjustment and psychotherapy. The article concludes by presenting a promising method for future research synthesizing idiographic and nomothetic approaches and raising important questions for future research on the role of scripts in psychological maladjustment and psychotherapy. PMID- 22924967 TI - The cost effectiveness of newer epilepsy treatments: a review of the literature on partial-onset seizures. AB - BACKGROUND AND OBJECTIVE: Epilepsy is one of the most common neurological disorders, affecting more than 3 million people in Europe. This paper reviews the published evidence regarding the cost effectiveness of second-generation antiepileptic drugs (AEDs). METHODS: A systematic literature search was performed, using the databases Academic Search Complete, Econlit, EMBASE and MEDLINE. Health economic evaluations of newer (second-generation) AEDs, published as full-length journal articles, were searched for. We focused on evaluations of newer AEDs as treatment for partial-onset seizures. 470 studies were initially identified and 19 were finally included. Information regarding (i) AEDs studied, (ii) cost effectiveness, and (iii) a variety of health economic modelling specifics was extracted from each study. Then, the included studies were summarized and a quality assessment was performed, according to the British Medical Journal's guidelines for economic studies. RESULTS: The results were as follows: (i) the cost per additional QALY for newer AEDs used as adjunctive treatment, compared with standard therapy, ranged between $US19 139 (levetiracetam) and $US57 210 (pregabalin) [year 2010 values]; no cost effectiveness evidence was identified for felbamate, eslicarbazepine, oxcarbazepine or tiagabine; and (ii) all studies met at least 60% of the British Medical Journal's guidelines criteria, and seven studies were found to satisfy more than 80% of the criteria. Guidelines criteria not met involve inadequate reporting of input data and modelling details, including validation and availability of models used for cost-effectiveness calculations. CONCLUSIONS: Although failure to meet good practice guidelines influences the reliability of the presented evidence adversely, a sufficient number of the included studies were found to comply enough with the guidelines in order for the qualitative content of the cost-effectiveness results - that some of the newer AEDs are cost effective - to be reliable. In fact, this conclusion is likely to be relatively robust, since the effect of improved seizure control on labour market performance was not included in the base-case results in any of the included studies and improved seizure control need only to have a moderate effect on sickness absenteeism in order for the corresponding treatment to be cost effective even when willingness to pay for an additional QALY is low. However, the cost effectiveness of newer AEDs has only been studied for a small number of settings, and hence future studies incorporating additional settings are needed. PMID- 22924969 TI - Composition of sugars, organic acids, and total phenolics in 25 wild or cultivated berry species. AB - Sugars, organic acids, and total phenolic content in fruit of 25 wild and cultivated berry species were identified and quantified with high-performance liquid chromatograph. The composition of sugars, organic acids, and total phenolic compounds in various species of Vaccinium, Rubus, Ribes, and Fragaria genus was evaluated. Additonally, total phenolics of less known berry species of the Morus, Amelanchier, Sorbus, Sambucus, Rosa, Lycium, Actinidia, and Aronia genus were determined in wild growing as well as in cultivated fruits. Significant differences in the concentration of sugars and organic acids were detected among the berry species. Glucose and fructose were the most abundant sugars in berry fruits and the major organic acids were malic and citric acid. However, in kiwi fruit, sucrose represented as much as 71.9% of total sugars. Sorbitol has been detected and quantified in chokeberry, rowanberry, and eastern shadbush fruit. The highest content of total analyzed sugars was determined in rowanberry fruit, followed by dog rose, eastern shadbush, hardy kiwifruit, American cranberry, chokeberry, and jostaberry fruit. Rowanberry stands out as the fruit with the highest content of total analyzed organic acids, followed by jostaberry, lingonberry, red gooseberry, hardy kiwifruit, and black currant. The berries of white gooseberry, black currant, red currant, and white currant had the lowest sugar/organic acid ratio and were thus perceptively the sourest species analyzed. On the other hand, the species with highest sugar/organic acid ratio were goji berry, eastern shadbush, black mulberry, and wild grown blackberry. The highest amounts of total phenols were quantified in chokeberry fruit. Wild strawberry, raspberry, and blackberry had 2- to 5-fold more total phenolics compared to cultivated plants. PRACTICAL APPLICATION: The fruit of analyzed berry species contained different levels of sugars, organic acids, and total phenolics. Moreover, it has been demonstrated that wild grown species generally contain more phenolics than cultivated ones. This information is interesting for nutritionists as well as berry growers and breeders who can promote the cultivation of species and new cultivars with higher phenolic content. PMID- 22924970 TI - Effect of platelet-rich plasma on bone healing of fresh frozen bone allograft in mandibular defects: a histomorphometric study in dogs. AB - OBJECTIVE: This study histologically analyzed the healing of fresh frozen bone allograft (FFBA) with or without platelet-rich plasma (PRP) in bony defects surgically created in the mandible of dogs. MATERIAL AND METHODS: Bilateral resection defects were surgically created on the inferior border of the mandible in 10 dogs. The defects were randomly divided into three groups: C (the defect was filled by blood clot only), FFBA (the defect was filled with particulate FFBA), and FFBA/PRP (the defect was filled with particulate FFBA combined with PRP). The animals were euthanized at 12 weeks post-surgery. Histomorphometric and histological analyses were performed. Data were statistically analyzed using Friedman test and Dunn test (P < 0.05). RESULTS: Group FFBA/PRP presented a statistically greater mineralized bone area and a smaller marrow bone area than Groups FFBA and C. CONCLUSIONS: The use of PRP improved the incorporation of FFBA, increasing the density of newly formed bone at 12 weeks post-surgery. PMID- 22924971 TI - Children's responses to cognitive challenge and links to self-reported rumination. AB - We tested the hypothesis that less effective responses during a cognitive challenge would relate to higher levels of self-reported rumination in children. The sample was 100 children (55 boys, 45 girls), aged 7 to 14 years. A portion (n=65) was at high risk for depression due to having a parent with a childhood onset mood disorder, and 35 were a low-risk comparison group. Using an impossible puzzle task, we assessed children's responses following failure across several domains: emotions (expressed anger, sadness, and negative self-statements), performance (being off-task, the time to solve subsequent puzzles, and the number solved), and physiology (heart rate, respiratory sinus arrhythmia). Results indicated that making negative self-blaming statements during the solvable puzzles and taking more time to solve the puzzles were associated with higher levels of self-reported rumination. Our findings advance the understanding of potential correlates of children's tendency to ruminate and may have implications for children's performance on cognitive tasks. PMID- 22924973 TI - Direct adhesive measurements between wood biopolymer model surfaces. AB - For the first time the dry adhesion was measured for an all-wood biopolymer system using Johnson-Kendall-Roberts (JKR) contact mechanics. The polydimethylsiloxane hemisphere was successfully surface-modified with a Cellulose I model surface using layer-by-layer assembly of nanofibrillated cellulose and polyethyleneimine. Flat surfaces of cellulose were equally prepared on silicon dioxide substrates, and model surfaces of glucomannan and lignin were prepared on silicon dioxide using spin-coating. The measured work of adhesion on loading and the adhesion hysteresis was found to be very similar between cellulose and all three wood polymers, suggesting that the interaction between these biopolymers do not differ greatly. Surface energy calculations from contact angle measurements indicated similar dispersive surface energy components for the model surfaces. The dispersive component was dominating the surface energy for all surfaces. The JKR work of adhesion was lower than that calculated from contact angle measurements, which partially can be ascribed to surface roughness of the model surfaces and overestimation of the surface energies from contact angle determinations. PMID- 22924972 TI - The C5a receptor antagonist PMX205 ameliorates experimentally induced colitis associated with increased IL-4 and IL-10. AB - BACKGROUND AND PURPOSE: Anti-complement therapies have not been advanced for treating the inflammatory bowel diseases (IBDs) despite a growing body of evidence that blocking C5a protects against induced colitis in rodents. The purpose of this study was to further build on this evidence by examining the efficacy, mechanism and specificity of a potent, non-competitive and orally active C5a receptor (CD88) antagonist, PMX205, in the dextran sulphate sodium (DSS) model of murine innate colitis. EXPERIMENTAL APPROACH: Mice with DSS added to their drinking water were orally administered 100 or 200 MUg day(-1) PMX205 in prophylactic and therapeutic regimens. Clinical illness, colon histology and local generation of inflammatory mediators were measured to evaluate the impact of PMX205 on disease. KEY RESULTS: PMX205 significantly prevented DSS-induced colon inflammation in both regimens, associated with lower pro-inflammatory cytokine production and nitrotyrosine staining in colon sections. Additionally, the levels of anti-inflammatory cytokines IL-4 and IL-10 were increased. PMX205 had no significant effect on C5a levels. The beneficial effect of PMX205 was seen in two strains of mice of differing sensitivities to DSS inflammation, but was inactive in mice lacking CD88. CONCLUSIONS AND IMPLICATIONS: Pharmacological inhibition of C5a activity by PMX205 is efficacious in preventing DSS-induced colitis, providing further evidence that targeting CD88 in IBD patients could be a valuable therapeutic option. PMID- 22924974 TI - RNAi suppression of lignin biosynthesis in sugarcane reduces recalcitrance for biofuel production from lignocellulosic biomass. AB - Sugarcane is a prime bioethanol feedstock. Currently, sugarcane ethanol is produced through fermentation of the sucrose, which can easily be extracted from stem internodes. Processes for production of biofuels from the abundant lignocellulosic sugarcane residues will boost the ethanol output from sugarcane per land area. However, unlocking the vast amount of chemical energy stored in plant cell walls remains expensive primarily because of the intrinsic recalcitrance of lignocellulosic biomass. We report here the successful reduction in lignification in sugarcane by RNA interference, despite the complex and highly polyploid genome of this interspecific hybrid. Down-regulation of the sugarcane caffeic acid O-methyltransferase (COMT) gene by 67% to 97% reduced the lignin content by 3.9% to 13.7%, respectively. The syringyl/guaiacyl ratio in the lignin was reduced from 1.47 in the wild type to values ranging between 1.27 and 0.79. The yields of directly fermentable glucose from lignocellulosic biomass increased up to 29% without pretreatment. After dilute acid pretreatment, the fermentable glucose yield increased up to 34%. These observations demonstrate that a moderate reduction in lignin (3.9% to 8.4%) can reduce the recalcitrance of sugarcane biomass without compromising plant performance under controlled environmental conditions. PMID- 22924975 TI - Performance of matrix-assisted laser desorption-time of flight mass spectrometry for identification of clinical yeast isolates. AB - Accurate and fast yeast identification is important when treating patients with invasive fungal disease as susceptibility to antifungal agents is highly species related. Matrix-assisted laser desorption-time of flight mass spectrometry (MALDI TOF-MS) provides a powerful tool with a clear potential to improve current diagnostic practice. Two MALDI-TOF-MS-systems (BioTyper/Bruker and Saramis/AXIMA) were evaluated using: (i) A collection of 102 archived, well characterised yeast isolates representing 14 different species and (ii) Prospectively collected isolates obtained from clinical samples at two participating laboratories. Of the 102 archived isolates, 81 (79%) and 92 (90%) were correctly identified by Saramis/AXIMA and BioTyper/Bruker respectively. Saramis/AXIMA was unable to separate Candida albicans, C. africana and C. dubliniensis in 13 of 32 isolates. After manual interpretation of the mass spectra output, all 13 isolates were correctly identified, resulting in an overall identification performance of 92%. No misidentifications occurred with the two systems. Of the routine isolates one laboratory identified 99/99 (100%) and 90/99 (91%) to species level by Saramis/Axima and conventional identification, respectively, whereas the other laboratory identified 83/98 (85%) to species level by both BioTyper/Bruker and conventional identification. Both MALDI-TOF-MS systems are fast, have built-in databases that cover the majority of clinically relevant Candida species, and have an accuracy that outperforms our conventional identification systems. PMID- 22924977 TI - Calling all pain patients: telehealth has arrived. PMID- 22924979 TI - Sialic acid utilization by the soil bacterium Corynebacterium glutamicum. AB - The ability to use the sialic acid, N-acetylneuraminic acid, Neu5Ac, as a nutrient has been characterized in a number of bacteria, most of which are human pathogens that encounter this molecule because of its presence on mucosal surfaces. The soil bacterium Corynebacterium glutamicum also has a full complement of genes for sialic acid catabolism, and we demonstrate that it can use Neu5Ac as a sole source of carbon and energy and isolate mutants with a much reduced growth lag on Neu5Ac. Disruption of the cg2937 gene, encoding a component of a predicted sialic acid-specific ABC transporter, results in a complete loss of growth of C. glutamicum on Neu5Ac and also a complete loss of [(14)C]-Neu5Ac uptake into cells. Uptake of [(14)C]-Neu5Ac is induced by pregrowth on Neu5Ac, but the additional presence of glucose prevents this induction. The demonstration that a member of the Actinobacteria can transport and catabolize Neu5Ac efficiently suggests that sialic acid metabolism has a physiological role in the soil environment. PMID- 22924980 TI - Silodosin : a new subtype selective alpha-1 antagonist for the treatment of lower urinary tract symptoms in patients with benign prostatic hyperplasia. AB - INTRODUCTION: Silodosin is a new uroselective alpha-blocker with high pharmacological selectivity for the (1A) adrenoceptor. It is an effective and well-tolerated treatment in men with lower urinary tract symptoms (LUTS), due to presumed bladder outlet obstruction secondary to benign prostatic hyperplasia (BPH). The efficacy of silodosin is at least equivalent to existing selective alpha-1 antagonists such as tamsulosin. A beneficial consequence of its high selectivity is improved cardiovascular safety and failure to interact with other therapies such as anti-hypertensives and phosphodiesterase type-5 inhibitors. AREAS COVERED: This paper discusses the mechanism of action, uroselectivity and clinical efficacy/tolerability of Silodosin. Additionally, drug interactions and urodynamic effects are reviewed with a focus on ejaculatory dysfunction. EXPERT OPINION: Silodosin is a rapidly efficacious and safe agent in the treatment of LUTS/BPH in men. A lack of clinically important cardiovascular side effects makes it of potential use in the elderly. There is a higher risk of ejaculatory dysfunction, which may lead to discontinuation in younger men. The availability of generic counterparts may make this compound less marketable in countries with social healthcare systems. PMID- 22924982 TI - Multivalent nanofibers of a controlled length: regulation of bacterial cell agglutination. AB - Control of the size and shape of molecular assemblies on the nanometer scale in aqueous solutions is very important for the regulation of biological functions. Among the well-defined supramolecular structures of organic amphiphiles, one dimensional nanofibers have attracted much attention because of their potential applications in biocompatible materials. Although much progress has been made in the field of self-assembled nanofibers, the ability to control the fiber length remains limited. The approach for control of the fiber length presented herein overcomes this limitation through the coassembly of amphiphilic rod-coil molecules in which the crystallinity of the aromatic segment can be regulated by pi-pi stacking interactions. The introduction of carbohydrate segments into the fiber exterior endows the nanofibers with the ability to adhere to bacterial cells. Notably, the fiber length systematically regulates the agglutination and proliferation of bacterial cells exposed to these fibers. PMID- 22924981 TI - Gene silencing by H-NS from distal DNA site. AB - In the modern concept of gene regulation, 'DNA looping' is the most common underlying mechanism in the interaction between RNA polymerase (RNAP) and transcription factors acting at a distance. This study demonstrates an additional mechanism by which DNA-bound proteins communicate with each other, by analysing the bacterial histone-like nucleoid-structuring protein (H-NS), a general transcriptional silencer. The LEE5 promoter (LEE5p) of enteropathogenic Escherichia coli was used as a model system to investigate the mechanism of H-NS mediated transcription repression. We found that H-NS represses LEE5p by binding to a cluster of A tracks upstream of -114, followed by spreading to a site at the promoter through the oligomerization of H-NS molecules. At the promoter, the H-NS makes a specific contact with the carboxy terminal domain of the alpha subunit of RNAP, which prevents the processing of RNAP-promoter complexes into initiation competent open promoter complexes, thereby regulating LEE5p from distance. PMID- 22924983 TI - The relationship between self-control deficits and hoarding: a multimethod investigation across three samples. AB - Self-control is the capacity to exert control over one's behavior and is necessary for directing personal behavior toward achieving goals. Self-control has been described as operating within a resource model, and a lack of self control has been posited as a process that may impact the development or maintenance of various forms of psychopathology. Hoarding disorder is one phenomenon wherein self-control may play a substantial role, and this investigation represents the first empirical evaluation of self-control in relation to hoarding symptoms. Across three independent studies, we found that lower levels of self-control were robustly linked to greater hoarding symptoms. Study 1 (N = 484) examined the strength of the relationship in a large nonclinical sample, and found that low levels of self-control were strongly associated with greater hoarding symptoms. This relationship remained significant despite controlling for covariates, including general depression and anxiety symptoms, specific anxiety symptomatology, and symptoms linked to impulse control deficits. These findings were replicated in Study 2 (N = 135), where we compared levels of self-control in individuals with clinical hoarding, obsessive compulsive disorder, social anxiety disorder, and generalized anxiety disorder. Study 3 (N = 102) was an experimental investigation that considered the impact of a self-control manipulation on a behavioral index of hoarding symptoms. We found that depleting self-control resources was associated with an increase in subsequent saving behaviors. The implications of self-control for hoarding are discussed from a vulnerability standpoint. PMID- 22924984 TI - The zebrafish as a model for paediatric diseases. AB - The rapid increase in information about genes and their associations with human diseases has highlighted the need for model organisms suitable for genetic manipulation and drug testing. The zebrafish is a valuable vertebrate animal model that offers many advantages, including the relative ease of husbandry and genetic manipulation and the capacity for high-throughput screens. In this review, we describe the zebrafish as a model for paediatric diseases, with particular emphasis on haematopoietic and infectious diseases. CONCLUSION: The zebrafish has become an established vertebrate model in which to elucidate the molecular mechanisms of various human diseases. PMID- 22924985 TI - Effects of covered solid sorbent tube sample holders on organic vapor measurements. AB - A study was conducted to examine whether there are significant differences between organic vapor concentrations measured using charcoal tubes with three different configurations: uncovered sample holder (open tube), SKC, and Buck brand covered sample holders. A fractional factorial experimental design was used with the following factors and levels: vapor (n-hexane vs. m-xylene), pump type (pulsating vs. continuous), exposure profile (variable vs. constant), flow rate (30 mL/min vs. 200 mL/min), duration (30 min vs. 80 min), and sample placement (mannequin vs. free hanging). Two of each sampler configuration (six total) were placed in an exposure chamber, and a dynamic test-atmosphere generation system was used to prepare atmospheres containing approximately 12-15 ppm n-hexane or m xylene with exposure profiles and sampling conducted according to a run sheet generated for the experimental design. A total of 24 runs were completed with six samplers per run, yielding 144 samples that were analyzed by gas chromatography/flame ionization detector. Concentration results for each pair of SKC and Buck covered sample holders were averaged and normalized by dividing by the average result for the open tube sampler from the same run to eliminate the effect of daily variation in chamber concentrations. The resulting ratio of covered sample tube holder and open tube concentrations was used as the response variable. Results of analysis of variance using the general linear model (MINITAB 16) identified statistically significant main effects and/or interactions for pump type, exposure profile, flow rate, and sample holder. However, the magnitude of the effects was generally less than 10%, and overall mean concentration ratios were 0.989 and 1.02 for the Buck and SKC sample holders, respectively. These results show good agreement between covered sample holder results and open tube measurements and demonstrate that exposure assessment errors resulting from the use of covered sorbent tube sample holders for organic vapor monitoring are relatively small (<10%) and not likely to be of practical importance. PMID- 22924986 TI - Dumbbell-like PtPd-Fe3O4 nanoparticles for enhanced electrochemical detection of H2O2. AB - Dumbbell-like Pt(x)Pd(100-x)-Fe(3)O(4) nanoparticles (NPs) were synthesized and studied for electrocatalytic reduction and sensing of H(2)O(2). In 0.1 M phosphate buffered saline (PBS) solution, the 4-10 nm Pt(x)Pd(100-x)-Fe(3)O(4) NPs showed the Pt/Pd composition-dependent catalysis with Pt(48)Pd(52)-Fe(3)O(4) NPs having the best activity. The Pt(48)Pd(52)-Fe(3)O(4) NPs were tested for H(2)O(2) detection, and their H(2)O(2) detection limit reached 5 nM, which was suitable for monitoring H(2)O(2) generated from Raw 264.7 cells. These dumbbell like PtPd-Fe(3)O(4) NPs are the most sensitive probe ever reported and can be used to achieve real-time quantitative detection of H(2)O(2) in biological environment for biological and biomedical applications. PMID- 22924987 TI - Reduction of the risk of transfusion-transmitted viral infection by nucleic acid amplification testing in the Western Cape of South Africa: a 5-year review. AB - BACKGROUND AND OBJECTIVES: In October 2005, individual donation nucleic acid amplification testing (ID-NAT) for HIV, HBV and HCV was introduced in the Western Cape Province of South Africa. After 5 years, the impact on HIV, HBV and HCV transmission risk was assessed. MATERIALS AND METHODS: A total of 649745 donations were tested by ID-NAT using the Ultrio assay on the Tigris instrument (Novartis Diagnostics) and for anti-HIV, HBsAg and anti-HCV (Abbott Prism). Initial reactive samples were repeated in duplicate. Discrepant repeat reactive samples were subjected to confirmatory assays. ID-NAT nonrepeat reactive donations were further screened for occult HBV infection (OBI) by anti-HBc assay. RESULTS: ID-NAT yielded 6 HIV-RNA-positive donations in the anti-HIV-negative window period (WP) but only 2 were p24 Ag nonreactive (1:325000). Mathematical modelling estimated a similar HIV transmission risk for lapsed and repeat donations, in the order of 3 per million. The WP risk for HBV was 13 per million. Eight acute (1:81000) and 13 chronic OBI yield cases (1:50000) were interdicted. There were significantly more anti-HBc-positive donors in the Ultrio initial reactive/nonrepeat reactive group (12%) than in an Ultrio nonreactive control group (6%). CONCLUSION: ID-NAT in the Western Cape Province of South Africa has contributed significantly to enhancing blood safety, particularly for HBV transmission risk and to a lesser extent for HIV. Anti-HBc testing of NAT nonrepeat reactive donations seems useful in identifying a subgroup of donors with OBI who may be at risk of transmitting HBV. PMID- 22924988 TI - Remote frozen section examination of breast sentinel lymph nodes by telepathology. AB - BACKGROUND: Intraoperative sentinel lymph node (SLN) examination during breast cancer surgery guides the need for immediate axillary clearance. This may be difficult to implement when surgery is performed distant to the centres where pathological examination is undertaken. We aimed to implement and validate a telepathology service for the remote examination of breast SLN by frozen section (FS). METHODS: We tested an Internet-based remote microscopy system to report intraoperative FS in real time from two district hospitals without on-site anatomical pathology services. RESULTS: FS was performed remotely on 52 patients. Seventeen out of 52 patients had metastases, of which there were six false negative diagnoses comprising four of micrometastatic disease and two of isolated tumour cells (ITCs). There were no false-negative diagnoses for macrometastatic disease and no false-positive diagnoses. As a control, we audited our experience with 239 consecutive SLN FS examined by on-site pathologists. Sixty out of 239 patients had metastases, of which there were 24 false-negative diagnoses comprising 12 cases of ITC, 5 of micrometastases and 7 of macrometastases. The accuracy of remote FS was equivalent to that of in-house FS (88.2% versus 89.9%). CONCLUSION: Remote FS for breast SLN is an accurate procedure ,which is not inferior to FS performed on site. PMID- 22924989 TI - In situ hybridization chain reaction amplification for universal and highly sensitive electrochemiluminescent detection of DNA. AB - In this work, we describe a new universal and highly sensitive strategy for electrochemiluminescent (ECL) detection of sequence specific DNA at the femtomolar level via in situ hybridization chain reaction (HCR) signal amplification. The DNA capture probes are self-assembled on a gold electrode. The presence of the target DNA and two hairpin helper DNAs leads to the formation of extended dsDNA polymers through HCR on the electrode surface. The in situ, HCR generated dsDNA polymers cause the intercalation of numerous ECL indicators (Ru(phen)(3)(2+)) into the dsDNA grooves, resulting in significantly amplified ECL signal output. The proposed strategy combines the amplification power of the DNA HCR and the inherent high sensitivity of the ECL technique and enables low femtomolar detection of sequence specific DNA. The developed strategy also shows high selectivity against single-base mismatch sequences, which makes our new universal and highly sensitive HCR-based method a useful addition to the amplified DNA detection arena. PMID- 22924990 TI - Controlling surface ligand density and core size of alkanethiolate-capped Pd nanoparticles and their effects on catalysis. AB - This article presents systematic investigations on the relationship between the catalytic property and the surface ligand density/core size of thiolate ligand capped Pd nanoparticles (PdNPs). The systematic variations in the two-phase synthesis of PdNPs generated from sodium S-dodecylthiosulfate were performed. The resulting PdNPs were characterized by transmission electron microscopy (TEM), thermogravimetric analysis (TGA), and (1)H NMR and UV-vis spectroscopy. The decrease in the molar equivalent of sodium S-dodecylthiosulfate (Bunte salts) resulted in the formation of nanoparticles with lower surface ligand density and larger particle core size. A decrease in the molar equivalent of tetra-n octylammonium bromide or an increase in reaction temperature generated nanoparticles with higher surface ligand density and smaller particle core size. As the molar equivalent of NaBH(4) decreased, the particle core size increased. The catalysis studies on various PdNPs with different surface ligand density and average core size showed a strong correlation between the PdNP composition and the turnover frequency (TOF) of the isomerization of allyl alcohol. Optimized "good" PdNPs with lower surface ligand coverage and larger core size catalyzed the isomerization of various allyl alcohols to carbonyl analogues with high activity and selectivity. PMID- 22924991 TI - High-dose calcium reduces early-onset hyperkalemia in extremely preterm neonates. AB - BACKGROUND: Early-onset hyperkalemia often occurs in extremely preterm infants during a few days after birth. While there are several treatments for hyperkalemia, calcium infusion to reduce plasma potassium concentrations remains controversial. The purpose of this study is to investigate whether a high dosage of calcium reduces early-onset hyperkalemia. METHODS: Extremely low-birthweight neonates born at 22-25 weeks' gestation were enrolled. We analyzed data using multivariate regression analysis and performed a retrospective cohort study with patients divided into two groups according to the dosage of calcium in their initial infusion. RESULTS: A total of 103 patients were eligible. Early-onset hyperkalemia was observed in 27 patients. The dosage of calcium gluconate during 24 h after birth was the only independent factor affecting early-onset hyperkalemia. The maximum plasma potassium concentration during 72 h after birth was negatively correlated with the dosage of calcium. High-dose calcium reduced occurrences of hyperkalemia and hypoglycemia caused by insulin infusion given for treatment of hyperkalemia, without increasing the risk of any other complications. CONCLUSIONS: Infusion of calcium gluconate may reduce early-onset hyperkalemia in a dose-dependent manner. PMID- 22924992 TI - Semaphorin 3C is involved in the progression of gastric cancer. AB - Malignant tumors are often associated with denervation, suggesting the functional implication of axonal guidance molecules in tumor growth. Here, we assessed the role of semaphorin 3C (sema3C) in the progression of gastric cancer. Immunohistochemistry of human samples revealed that sema3C was strongly expressed in neoplastic cells, especially at the invasion front. Stable transfection of target sequences of sema3C miRNA did not affect the in vitro proliferative activity of human gastric cancer AZ-521 cells. However, when the tumor growth was examined in vivo using an orthotopic model in nude mice, primary stomach tumors as well as metastatic liver tumors were significantly suppressed by sema3C silencing with the reduction of microvessel density. Immunostaining of primary tumor indicated the rate of Ki-67 positive carcinoma cells was decreased, whereas that of apoptotic cells was significantly increased in sema3C-silenced tumor. In addition, capillary-like tubular formation was reduced by the addition of culture media of sema3C miRNA cells compared with the media of control miRNA cells. Semaphorin 3C is positively expressed in gastric cancer cells and may be involved in tumor progression, presumably through the stimulation of angiogenesis. PMID- 22924993 TI - Production of secoisolariciresinol from defatted flaxseed by bacterial biotransformation. AB - AIMS: Secoisolariciresinol (SECO) is increasingly recognized for potential clinical application because of its preventive effects against breast and colon cancers, atherosclerosis and diabetes, and its production through biotransformation has been attempted. However, previously reported bacteria all required stringent anaerobic culture conditions, precluding large-scale production. Here, we report the isolation and characterization of bacteria that produce SECO under less stringent anaerobic culture conditions. METHODS AND RESULTS: Using defatted flaxseed as raw material, we isolated a facultative anaerobic bacterium from human faeces that hydrolysed secoisolariciresinol diglucoside-3-hydroxy-3-methyl glutaric acid (SDG-HMGA) oligomers in flaxseed to produce SECO. Both conventional assays and 16S rRNA gene sequence analysis demonstrated its close relatedness with Bacteroides uniformis. The transformation efficiency of SDG in defatted flaxseed to SECO was more than 80% by this bacterial strain. We investigated factors that might influence fermentation, such as redox potential and pH, for large-scale fermentation of defatted flaxseed to produce SECO. CONCLUSIONS: The method to produce SECO through biotransformation of defatted flaxseed with this bacterial strain is highly efficient and economic. SIGNIFICANCE AND IMPACT OF THE STUDY: This bacterial strain can transform SDG to SECO under less stringent anaerobic culture conditions, which will greatly facilitate industry-scale production of SECO. PMID- 22924994 TI - Clinical application of the five-factor model. AB - The Five-Factor Model (FFM) has become the predominant dimensional model of general personality structure. The purpose of this paper is to suggest a clinical application. A substantial body of research indicates that the personality disorders included within the American Psychiatric Association's (APA) Diagnostic and Statistical Manual of Mental Disorders (DSM) can be understood as extreme and/or maladaptive variants of the FFM (the acronym "DSM" refers to any particular edition of the APA DSM). In addition, the current proposal for the forthcoming fifth edition of the DSM (i.e., DSM-5) is shifting closely toward an FFM dimensional trait model of personality disorder. Advantages of this shifting conceptualization are discussed, including treatment planning. PMID- 22924995 TI - Hippocampal agenesis in an individual who engaged in violent criminal behaviors after discontinuing carbamazepine and paroxetine treatment. AB - Antidepressant discontinuation syndrome (ADS) occurs after abrupt discontinuation of an antidepressant medication. A 23-year-old man with right hippocampal agenesis demonstrated sexual crime (hypersexuality) since the age of eight and had been successfully treated with carbamazepine since the age of 13. He had required increased doses of paroxetine and carbamazepine owing to the development of an unstable affect after quitting his job. He abruptly stopped taking his medication for 3 days and his criminal behaviors re-emerged. We examined changes in brain structure and activity before and after medication cessation, using MRI and functional MRI (fMRI). The image of a girl in a swimsuit increased activity in the thalamus only after medication discontinuation. The alteration in thalamic activity might induce hypersexuality. We conclude that a primary hypersexuality had been suppressed with carbamazepine and paroxetine treatment, and the discontinuation of the medication caused the hypersexuality. PMID- 22924997 TI - Outcome and management of invasive candidiasis following oesophageal perforation. AB - The regular colonisation of the oesophagus with a Candida species can, after oesophageal perforation, result in a contamination of the mediastinum and the pleura with a Candida species. A patient cohort of 80 patients with oesophageal perforation between 1986 and 2010 was analysed retrospectively. The most common sources with positive results for Candida were mediastinal biopsies and broncho alveolar secretions. Candida species were detected in 30% of the patients. The mortality rate was 41% in patients with positive microbiology results for Candida, whereas it was 23% in the remaining patient cohort. This difference did not reach statistical significance (P = 0.124). Mortality associated with oesophageal perforation was attributed mainly to septic complications, such as mediastinitis and severe pneumonia. During the study period we observed a shift towards non-albicans species that were less susceptible or resistant to fluconazole. In selected patients with risk factors as immunosuppression, granulocytopenia and long-term intensive-care treatment together with the finding of Candida, an antimycotic therapy should be started. A surgical approach offers the possibility to obtain deep tissue biopsies. The antimycotic therapy should start with an echinocandin, as the resistance to fluconazole is growing and to cover non-albicans Candida species, too. PMID- 22924998 TI - Constitutive expression of a fungal glucuronoyl esterase in Arabidopsis reveals altered cell wall composition and structure. AB - A family 15 carbohydrate esterase (CE15) from the white-rot basidiomycete, Phanerochaete carnosa (PcGCE), was transformed into Arabidopsis thaliana Col-0 and was expressed from the constitutive cauliflower mosaic virus 35S promoter. Like other CE15 enzymes, PcGCE hydrolyzed methyl-4-O-methyl-d-glucopyranuronate and could target ester linkages that contribute to lignin-carbohydrate complexes that form in plant cell walls. Three independently transformed Arabidopsis lines were evaluated in terms of nine morphometric parameters, total sugar and lignin composition, cell wall anatomy, enzymatic saccharification and xylan extractability. The transgenic lines consistently displayed a leaf-yellowing phenotype, as well as reduced glucose and xylose content by as much as 30% and 35%, respectively. Histological analysis revealed 50% reduction in cell wall thickness in the interfascicular fibres of transgenic plants, and FT-IR microspectroscopy of interfascicular fibre walls indicated reduction in lignin cross-linking in plants overexpressing PcGCE. Notably, these characteristics could be correlated with improved xylose recovery in transgenic plants, up to 15%. The current analysis represents the first example whereby a fungal glucuronoyl esterase is expressed in Arabidopsis and shows that the promotion of glucuronoyl esterase activity in plants can alter the extent of intermolecular cross-linking within plant cell walls. PMID- 22924999 TI - A meta-analysis of the effectiveness of psychological interventions for adults with skin conditions. AB - Skin conditions can be associated with heightened levels of psychological morbidity, suggesting the need for psychological interventions. A number of specific interventions (such as habit reversal) have been developed. However, to date, there has not been a systematic review of the effectiveness of psychological interventions. We sought to systematically evaluate the effectiveness of psychological interventions designed to improve the severity of and adjustment to skin conditions in adults. Database, archival and citation searches were conducted. Studies were included if participants were allocated to either a psychological intervention (excluding educational interventions and complementary therapies) or a comparison condition, and if they measured outcomes relevant to the skin condition. Twenty-two studies met these inclusion criteria. Effect sizes for each intervention were computed and we also coded a number of potential moderators of intervention efficacy. Psychological interventions were found to have a medium-sized effect on skin conditions (g = 0.54). The type of skin condition, age of sample, nature of the intervention, time interval between the end of the intervention and follow-up, and type of outcome measure all moderated the effect of interventions on outcomes. For example, interventions had a medium effect on the severity of the condition (g = 0.40) and psychosocial outcomes (g = 0.53), and a medium-to-large effect on itch/scratch reactions (g = 0.67). Psychological interventions are beneficial for people with skin conditions. However, more research is needed to extend the variety and focus of the psychological interventions that are available. Studies are also needed to explore the longer-term benefits of such interventions. PMID- 22925000 TI - STRoke Adverse outcome is associated WIth NoSocomial Infections (STRAWINSKI): procalcitonin ultrasensitive-guided antibacterial therapy in severe ischaemic stroke patients - rationale and protocol for a randomized controlled trial. AB - RATIONALE: Stroke-associated pneumonia is one of the most common causes of poor outcome in stroke patients. Clinical signs and laboratory parameters of stroke associated infections are often inconclusive. Biomarkers may help to identify stroke patients at high risk for pneumonia and to guide physicians in an early antibiotic treatment, thereby improving stroke outcome. AIM: The aim of the present study is to investigate whether procalcitonin ultrasensitive-guided antibiotic treatment improves functional outcome after severe ischaemic stroke by early treatment of pneumonia. DESIGN: STRAWINSKI is an investigator-initiated, multicentre, randomized, controlled trial with blinded assessment of outcome comparing procalcitonin ultrasensitive-guided antibiotic treatment with standard care. STUDY: 200 patients with ischaemic stroke in the middle cerebral artery territory and a score >9 on the National Institutes of Health Stroke Scale will be included and randomly assigned to two groups. One group will receive procalcitonin-based antibiotic therapy guidance; the other group will receive standard stroke unit care. OUTCOMES: The primary endpoint is functional outcome at day 90 after stroke on the modified Rankin Scale, dichotomized as favourable (0-4) or unfavourable outcome (5-6). Secondary endpoints are time to first event of death, rehospitalization, or recurrent stroke; death rate, infection rate, and days with fever up to day 7; length of hospital stay and hospital discharge disposition; shift analysis of the modified Rankin Scale; Barthel Index and days alive and out of hospital at day 90; use of antibiotics until day 90; and modified Rankin Scale, Barthel Index, and infarct volume at day 180. PMID- 22925002 TI - Self-assembling nanoparticles for the release of bisphosphonates in the treatment of human cancers [WO2012042024]. AB - The focus of this patent was to manipulate the pharmacokinetic profile of an amino-bisphosphonate (zoledronic acid, ZOL) to make it desirable for anti-tumor uses. This patent disclosed a unique drug loading strategy that was inspired by gene delivery vehicles based on similar materials (calcium phosphate, CaP). The promise of this drug delivery system (DDS) lies not only in a 44% in vivo inhibition of tumor growth compared with free drug, but also in the low toxicity of the drug which guarantees a dosage regimen with higher doses and longer course of treatment. Also, the disclosed DDS has the potential to be further upgraded. In this patent evaluation, the state of the art in the field of CaP-based drug carrier and the novelty of this invention will be discussed. PMID- 22925001 TI - Small molecule glucokinase activators disturb lipid homeostasis and induce fatty liver in rodents: a warning for therapeutic applications in humans. AB - BACKGROUND AND PURPOSE: Small-molecule glucokinase activators (GKAs) are currently being investigated as therapeutic options for the treatment of type 2 diabetes (T2D). Because liver overexpression of glucokinase is thought to be associated with altered lipid profiles, this study aimed at assessing the potential lipogenic risks linked to oral GKA administration. EXPERIMENTAL APPROACH: Nine GKA candidates were qualified for their ability to activate recombinant glucokinase and to stimulate glycogen synthesis in rat hepatocytes and insulin secretion in rat INS-1E cells. In vivo activity was monitored by plasma glucose and HbA1c measurements after oral administration in rodents. Risk associated effects were assessed by measuring hepatic and plasma triglycerides and free fatty acids, as well as plasma aminotransferases, and alkaline phosphatase. KEY RESULTS: GKAs, while efficiently decreasing glycaemia in acute conditions and HbA1c levels after chronic administration in hyperglycemic db/db mice, were potent inducers of hepatic steatosis. This adverse outcome appeared as soon as 4 days after daily oral administration at pharmacological doses and was not transient. GKA treatment similarly increased hepatic triglycerides in diabetic and normoglycaemic rats, together with a pattern of metabolic phenotypes including different combinations of increased plasma triglycerides, free fatty acids, alanine and aspartyl aminotransferases, and alkaline phosphatase. GKAs belonging to three distinct structural families induced hepatic steatosis in db/db mice, arguing in favour of a target-mediated, rather than a chemical class mediated, effect. CONCLUSION AND IMPLICATIONS: Given the risks associated with fatty liver disease in the general population and furthermore in patients with T2D, these findings represent a serious warning for the use of GKAs in humans. LINKED ARTICLE: This article is commented on by Rees and Gloyn, pp. 335-338 of this issue. To view this commentary visit http://dx.doi.org/10.1111/j.1476 5381.2012.02201.x. PMID- 22925003 TI - Conservative perioperative anticoagulation management in patients with chronic venous thromboembolic disease: a cohort study. AB - BACKGROUND: Guidelines for perioperative warfarin management in patients with venous thromboembolic disease (VTE) are largely based on expert opinion. OBJECTIVES: To assess the effectiveness and safety of a conservative perioperative anticoagulation strategy in patients with VTE on chronic warfarin therapy. Our center uses a conservative bridging approach for chronic VTE patients consisting of withholding warfarin for 5 days preoperatively, with prophylactic low-molecular-weight heparin (LMWH) post-procedure only if patients are admitted to hospital. PATIENTS/METHODS: We performed a single-center retrospective cohort study. During the study period (1997-2011) there were 634 procedures in 416 patients that were reviewed for postoperative outcomes at 30 and 90 days. RESULTS: Of the 634 procedures, 156 procedures (24.6%) were completed as inpatients. Pre- and post-procedure LMWH bridging was used in 15 (2.4%) and 152 (24.0%) of all procedures, respectively. The 30-day VTE incidence was 0.32% (95% confidence interval [CI] 0.087-1.14), all non-fatal DVTs. The 30 day incidence of major and total bleeding events was 1.26% (95% CI 0.64-2.47) and 3.00% (95% CI 1.93-4.63), respectively. The all-cause mortality rate was 0.32% (95% CI 0.087-1.14) at 30 days; two patients died from arterial thrombosis events. CONCLUSIONS: A randomized controlled trial is needed to provide definitive conclusions but a conservative bridging approach appears promising. PMID- 22925004 TI - Gene expression profiling demonstrates differential expression of osteopontin in follicular thyroid carcinomas compared to normal thyroid tissue in dogs. AB - Follicular thyroid carcinoma (FTC) is an aggressive tumour in dogs with little known about its molecular pathogenesis. The overall goal of this study was to examine FTC and normal thyroid tissue gene expression. Microarray analysis was performed on a pilot group of five FTC-affected dogs and four healthy dogs, and then osteopontin validated with quantitative polymerase chain reaction (PCR) and immunohistochemistry (IHC) of thyroid tissue from non-invasive FTC, invasive FTC and healthy dogs. On microarray analysis, 489 transcripts were differentially expressed between FTC and normal thyroid: 242 transcripts were down-regulated and 247 were up-regulated. Osteopontin expression was markedly increased in tumour tissue compared to normal thyroid tissue. Quantitative PCR and IHC confirmed differential expression of osteopontin in both tumour types (invasive and non invasive) compared to normal thyroid tissue. There is justification for further investigation of osteopontin as a potential molecular marker for screening and monitoring of canine FTC. PMID- 22925005 TI - Ischemic postconditioning diminishes matrix metalloproteinase 9 expression and attenuates loss of the extracellular matrix proteins in rats following middle cerebral artery occlusion and reperfusion. AB - AIMS: Ischemic postconditioning (IPostC) has been proved to have neuroprotective effects for cerebral ischemia, but the underlying mechanism remains elusive. This study aimed at validating the neuroprotective effects of IPostC and investigating whether the neuroprotection of IPostC is associated with matrix metalloproteinase 9 (MMP9) and the extracellular matrix proteins, laminin and fibronectin, following cerebral ischemia/reperfusion in rats. METHODS: The rats in middle cerebral artery occlusion (MCAO) group underwent MCAO and reperfusion, and the animals in MCAO + IPostC group were treated by occluding bilateral common carotid arteries for 10 seconds and then reperfusing for 10 seconds for five episodes at the beginning of MCAO. Apoptosis was detected with terminal deoxynucleotidyl transferase dUTP nick end labeling staining. The expression of MMP9, laminin, and fibronectin was measured with immunofluorescence and enzyme-linked immunosorbent assay. RESULTS: IPostC reduced brain edema and infarct volume and improved the neurological function. Furthermore, IPostC decreased cell apoptosis compared with the MCAO group. Compared to the MCAO group, IPostC treatment reduced MMP9 expression. Moreover, the results showed that the expression of laminin and fibronectin significantly increased in the MCAO + IPostC group compared to the MCAO group. CONCLUSION: These findings indicated that diminishment of MMP9 expression and the attenuation of degradation of laminin and fibronectin may be involved in the protective mechanisms of postconditioning against cerebral ischemia/reperfusion injury. PMID- 22925006 TI - Buccal and lingual bone level alterations after immediate implantation of four implant surfaces: a study in dogs. AB - OBJECTIVES: Bone formation and maintenance around implants placed immediately after tooth extraction may be affected by implant surface treatment and compromise long-term esthetic results. This study morphometrically evaluated buccal bone loss and bone-to-implant contact (BIC) of four implant systems placed immediately after tooth extraction in a dog model. MATERIAL AND METHODS: The premolars of eight beagle dogs were bilaterally extracted with a full-thickness flap, and root-form dental implants were placed on the root extraction socket. Implants (n = 16 each) with different surface treatments were placed from sites 1 to 4 and alternated between animals to allow evaluation of the same number of implants at sites and evaluation time points. Implant surface treatments were as follows: anodized, discrete crystalline deposition, SLActive, and microblasted. The left and right side provided implants that stayed for 2 and 4 weeks, respectively. Submerged healing was allowed and bone-to-implant contact (BIC) and buccal bone loss were morphometrically measured. Linear mixed models (P < 0.05) were used to assess differences between groups, across time, and their interaction. RESULTS: Buccal bone loss was observed to approximately double between 2 and 4 weeks (P = 0.01). BIC also increased between 2 and 4 weeks, by 20 25% (P = 0.01). These changes were statistically similar for each surface. CONCLUSION: When placed immediately after tooth extraction, the evaluated histomorphometric parameters vary only with time. PMID- 22925007 TI - Increased T-cell stimulating activity by mutated SEC2 correlates with its improved antitumour potency. AB - AIMS: To investigate the improved antitumour activity of SAM-3 compared with recombinant staphylococcal enterotoxins C2 (rSEC2). METHODS AND RESULTS: Methylthiazol tetrazolium and flow cytometry assays showed that the antitumour activity of SAM-3 in vivo was improved because of enhanced T-cell stimulating potency, resulting in massive activation of T cells, particularly CD4(+) and CD8(+) T cells, and subsequent cytokine release. Quantitative real-time PCR assay showed that despite similar Vbeta specificities induced by rSEC2 and SAM-3, the quantities of activated T cells bearing specific Vbetain vitro were different. CONCLUSIONS: The results strongly suggested that the increased SAM-3-T-cell receptor (TCR) binding affinity contributed to massive T-cell activation and cytokine release, substantially amplifying antitumour immune response in vivo. SIGNIFICANCE AND IMPACT OF THE STUDY: This study provided evidence for the mechanism of SAM-3 antitumour activity improvement compared with rSEC2. Results indicated that SAM-3 could be used as a potent powerful candidate agent for tumour treatment in clinics. PMID- 22925008 TI - A record-linkage study of drug-related death and suicide after hospital discharge among drug-treatment clients in Scotland, 1996-2006. AB - AIMS: To investigate the relationship between time after hospital discharge and drug-related death (DRD) and suicide among drug users in Scotland, while controlling for potential confounders. DESIGN: Cohort study. SETTING AND PARTICIPANTS: The 69 457 individuals who registered for drug treatment in Scotland during 1 April 1996-31 March 2006. MEASUREMENTS: Time-at-risk was from the date of an individual's first attendance at drug treatment services after 1 April 1996 until the earlier date of death or end-of-study, 31 March 2006, and was categorized according to time since the most recent hospitalization, as during hospitalization, within 28 days, 29-90 days, 91 days to 1 year and >1 year since discharge from most recent hospital stay versus 'never admitted' (reference). FINDINGS: Time-periods soon after discharge were associated with increased risk of DRD. DRD rates per 1000 person-years were: 87 (95% CI: 72-103) during hospitalization, 21 (18-25) within 28 days, 12 (10-15) during 29-90 days and 8.5 (7.5-9.5) during 91 days to 1 year after discharge versus 4.2 (3.7-4.7) when >1 year after most recent hospitalization and 1.9 (1.7-2.1) for those never admitted. Adjusted hazard ratios by time since hospital discharge (versus never admitted) were: 9.6 (95% CI: 8-12) within 28 days, 5.6 (4.6-6.8) during days 29 90, thereafter 4.0 (3.5-4.7) and 2.3 (2.0-2.7) when >1 year. Non-drug-related suicides were less frequent than DRDs (269 versus 1383) but a similar risk pattern was observed. CONCLUSIONS: In people receiving treatment for drug dependence, discharge from a period of hospitalization marks the start of a period of heightened vulnerability to drug-related death. PMID- 22925009 TI - Dangerous liaisons: the predation risks of receiving social signals. AB - Individuals are at risk when communicating because conspicuous signals attract both conspecifics and eavesdropping predators. This predation cost of communicating has typically been attributed to signalling individuals because of their conspicuous role, and is a core concept within sexual selection and communication ecology. But, if predators are attracted to signals, then receivers, both intended or otherwise, may also find themselves at risk of predation. Here, we review the theoretical basis and empirical evidence that receiving also carries a risk of predation. We distinguish between the risks of receiving and responding to signals, and we argue that receivers of signals that are long lived, are highly predictable in time or place and/or cannot be received quickly are likely to be at greater risk of predation compared to receivers of signals without these properties. We review recent empirical evidence from a variety of taxa that supports the hypothesis that receivers (including heterospecific prey) are aware of these risks and that they modify their behaviour to balance the risks against the benefits of receiving under predation threat. We also discuss the wider implications of risky receiving for receiving and signalling behaviour in prey, as well as for the prey's predators. PMID- 22925010 TI - Integrating brain and behavior: evaluating adolescents' response to a cannabis intervention. AB - Client language (change talk [CT] and counterchange talk [CCT]) is gaining increasing support as an active ingredient of psychosocial interventions. Preliminary work with adults suggests that there may be a neural basis for this. With a diverse sample of adolescent cannabis users, we evaluated the influence of CT and CCT on blood oxygen level dependent (BOLD) response during an fMRI cannabis cue-exposure paradigm. We also investigated how BOLD activation related to treatment outcomes. Adolescent cannabis users (N = 43; 83.7% male; 53.5% Hispanic; M age = 16 years) were presented with CT and CCT derived from their prescan intervention session during the fMRI paradigm. Additionally, BOLD activation during CT (vs. CCT) was tested as a predictor of 1-month follow-up cannabis use behavior (frequency of cannabis use, cannabis problems, cannabis dependence). We observed a significant interaction, with greater activation during CT (vs. CCT) during the cannabis (but not control) cues in several areas key to self-referential processes (uncorrected p < 0.001; medial frontal gyrus, insula). Furthermore, BOLD activation during CT (vs. CCT) during cannabis (but not control) cues in areas that underlie introspection (posterior cingulate, precuneus) was significantly related to youths' 1-month follow-up cannabis use behavior (frequency of cannabis use, cannabis problems, cannabis dependence; uncorrected p < 0.001). These data indicate a unique interaction pattern, whereby CT (vs. CCT) during the cannabis (but not control) cues was associated with significantly greater activation in brain areas involved in introspection. Further, this activation was related to significantly better treatment outcomes for youth. PMID- 22925011 TI - Drinking motives and drinking behavior over time: a full cross-lagged panel study among adults. AB - Drinking motives are among the most proximal factors for drinking behavior and serve as a mechanism through which more distal factors are mediated. However, it is less clear whether drinking motives are precursors of drinking or, in contrast, shaped by previous drinking experiences (reciprocal effects), or both. Moreover, in adults it is unclear whether drinking motives, usually shaped in adolescence, influence each other over time. In this longitudinal study (N = 2440, 47% women, average age 53 years), drinking motives and drinking behavior (i.e., number of drinks on the heaviest drinking day and number of drinking days; both during the past week) were assessed at 2 time points, separated by 3 months. Full cross-lagged regression models revealed that drinking motives were positively associated with drinking behavior over time and that drinking motives are shaped by the number of drinking days (i.e., reciprocal effects). Furthermore, coping and enhancement motives, as well as social and conformity motives, positively reinforced each other. Moreover, social motives were positively associated with enhancement motives over time. In conclusion, drinking motives influence each other over a 3-month period in adulthood and predict drinking behavior over time, making them important candidates for prevention efforts. Drinking motives are likely to be modifiable and might be used to stimulate drinking decrease. PMID- 22925012 TI - The EAGR box structure: a motif involved in mycoplasma motility. AB - Mycoplasma genitalium is an emerging human pathogen with the smallest genome found among self-replicating organisms. M. genitalium presents a complex cytoskeleton with a differentiated protrusion known as the terminal organelle. This polar structure plays a central role in functions essential for the virulence of the microorganism, such as motility and cell-host adhesion. A well conserved Enriched in Aromatic and Glycine Residues motif, the EAGR box, is present in many of the proteins found in the terminal organelle. We determined the crystal structure of the globular domain from M. genitalium MG200 that contains an EAGR box. This structural information is the first at near atomic resolution for the components of the terminal organelle. The structure revealed a dimer stabilized by a compact hydrophobic core that extends throughout the dimer interface. Monomers present a new fold that contains an accurate intra-subunit symmetry relating two conspicuous hairpins. Some features, such as the domain plasticity and the presence and organization of the intra- and inter-subunit symmetry axes, support a role for the EAGR box in protein-protein interactions. Genetic, biochemical and microcinematography analyses of MG200 variants lacking the EAGR box containing domain confirm the relevant and specific association of this domain with cell motility. PMID- 22925013 TI - Aptamer-guided silver-gold bimetallic nanostructures with highly active surface enhanced Raman scattering for specific detection and near-infrared photothermal therapy of human breast cancer cells. AB - The aptamer (S2.2)-guided Ag-Au nanostructures (aptamer-Ag-Au) have been synthesized by photoreduction and validated by ultraviolet-visible light (UV-vis) spectra and transmission electron microscopy (TEM) images. Differential interference contrast (DIC), fluorescence, and TEM images, and surface-enhanced Raman scattering (SERS) spectra indicated that the aptamer-Ag-Au nanostructures can target the surface of human breast cancer cells (MCF-7) with high affinity and specificity. This targeting is completed via the specific interaction between S2.2 aptamer (a 25-base oligonucleotide) and MUC1 mucin (a large transmembrane glycoprotein, whose expression increased at least 10-fold at MCF-7 cells in primary and metastatic breast cancers). However, the nanostructures cannot target HepG2 (human liver cancer cells) or MCF-10A cells (human normal breast epithelial cells), because these cells are MUC1-negative expressed. Moreover, the synthesized nanostructures exhibited a high SERS activity. Based on these results, a new assay for specifically detecting MCF-7 cells has been proposed. This assay can also discriminate MCF-7 cells from MCF-10A cells and different cancer cell lines, such as HepG2 cells. In addition, the aptamer-Ag-Au nanostructures have a high capability of adsorpting near-infrared (NIR) irradiation and are able to perform photothermal therapy of MCF-7 cells at a very low irradiation power density (0.25 W/cm(2)) without destroying the healthy cells and the surrounding normal tissue. Therefore, the proposed assay is significant for the diagnosis of tumors in their nascent stage. The synthesized nanostructures could offer a protocol to specifically recognize and sensitively detect the cancer cells, and would have great potential for application in the photothermal therapy of the cancers. PMID- 22925014 TI - Bionic eyes: where are we and what does the future hold? PMID- 22925017 TI - Evaluation of chimeric yellow fever 17D/dengue viral replication in ticks. AB - Chimeric yellow fever 17D/DENV-1-4 viruses (CYD-1-4) have been developed as a tetravalent dengue vaccine candidate which is currently being evaluated in efficacy trials in Asia and America. While YF 17D and DENV are mosquito-borne flaviviruses, it has been shown that CYD-1-4 do not replicate after oral infection in mosquitoes and are not transmitted to new hosts. To further document the risk of environmental dissemination of these viruses, we evaluated the replication of CYD-1-4 in ticks, the vector of tick-borne encephalitis virus (TBEV), another member of the flavivirus family. Females of two hard tick species, Ixodes ricinus and Rhipicephalus appendiculatus, were inoculated intracoelomically with CYD-1-4 viruses and parent viruses (DENV-1-4 and YF 17D). Virus persistence and replication was assessed 2, 16, and 44 days post inoculation by plaque titration and qRT-PCR. CYD-1-4 viruses were detected in I. ricinus ticks at early time points post-inoculation, but with infectious titers at least 100-fold lower than those observed in TBEV-infected ticks. Unlike TBEV, complete viral clearance occurred by day 44 in most ticks except for CYD-2, which had a tendency to decline. In addition, while about 70% of TBEV-infected I. ricinus nymphs acquired infection by co-feeding with infected tick females on non viremic hosts, no co-feeding transmission of CYD-2 virus was detected. Based on these results, we conclude that the risk of dissemination of the candidate vaccine viruses by tick bite is highly unlikely. PMID- 22925016 TI - Rickettsia species in ticks removed from humans in Istanbul, Turkey. AB - A total of 167 ticks collected from humans in Istanbul (Turkey) in 2006 were screened for Rickettsia species, and nested PCRs targeting gltA and ompA rickettsial fragment genes were carried out. Rickettsia monacensis (51), R. aeschlimannii (8), R. conorii subsp. conorii (3), R. helvetica (2), R. raoultii (1), R. africae (1), R. felis (1), and other Rickettsia spp. (2), were detected. To our knowledge, these Rickettsia species (except R. conorii) had never been reported in ticks removed from humans in Turkey. The presence of R. africae also had not been previously described, either in Hyalomma ticks or in any European tick species. In addition, R. aeschlimannii and R. felis had not been found associated with Rhipicephalus bursa specimens. The presence of human pathogenic Rickettsia in ticks removed from humans provides information about the risk of tick-borne rickettsioses in Turkey. PMID- 22925018 TI - Detection of Chikungunya virus in wild populations of Aedes albopictus in Kerala State, India. AB - We detected Chikungunya virus (CHIKV) infection among wild populations of Aedes albopictus female specimens during the CHIKV outbreaks of 2009 and 2006 collected in different localities in Kerala State, India. The envelope 1 gene (E1) sequences of the virus isolate 2009 from the mosquito species showed close genetic relatedness (Kimura 2 Parameter genetic distance=0.0013) to CHIKV positive isolates from human serum samples from the same area. E1 gene sequences from Ae. albopictus, as well as from human isolates, had the crucial non synonymous C/T mutation at position 10670, leading to the A226V amino acid change. This natural inclination indicated the role of this mosquito species in the transmission of CHIKV during its recent outbreaks in Kerala State. PMID- 22925020 TI - Evaluation of the infectiousness to mice of soil contaminated with Yersinia pestis-infected blood. AB - Plague, an often-fatal zoonotic disease caused by Yersinia pestis, is characterized by epizootic and quiescent periods. How Y. pestis is maintained during inter-epizootic periods is poorly understood, but soil has been implicated as a potential reservoir. Although previous studies have suggested that Y. pestis is able to survive in soil for weeks or months, it is unclear whether or not it is infectious to susceptible hosts. Here we investigate the potential for Y. pestis to infect mice through close contact with contaminated soil under laboratory conditions. In an attempt to approximate the natural conditions under which animals would be exposed to Y. pestis-contaminated soil, mouse cages filled with soil from a plague-endemic region were held at temperature and humidity ranges observed in ground squirrel burrows. These laboratory "burrows" were contaminated with highly bacteremic blood (>10(8) cfu/mL) to simulate the introduction of infectious material from a dying animal during an epizootic. Outbred Swiss-Webster mice with scarified skin patches were held on contaminated soil for 10 days and monitored for signs of illness. Following exposure to contaminated soil, one animal of 104 became infected with Y. pestis. None of the remaining animals seroconverted following a 21-day holding period. Under our experimental conditions, which maximized the likelihood of contact between susceptible mice and contaminated soil, transmission efficiency from soil to mice was 0.96% (95% CI 0.17, 5.25%). This suggests that although transmission of Y. pestis from contaminated soils is possible, it is not likely a major transmission route under natural conditions. PMID- 22925019 TI - Nanospheres encapsulating anti-leishmanial drugs for their specific macrophage targeting, reduced toxicity, and deliberate intracellular release. AB - The current work focuses on the study of polymeric, biodegradable nanoparticles (NPs) for the encapsulation of doxorubicin and mitomycin C (anti-leishmanial drugs), and their efficient delivery to macrophages, the parasite's home. The biodegradable polymer methoxypoly-(ethylene glycol)-b-poly (lactic acid) (MPEG PLA) was used to prepare polymeric NPs encapsulating doxorubicin and mitomycin C. The morphology, mean diameter, and surface area of spherical NPs were determined by transmission electron microscopy (TEM), field emission scanning electron microscopy (FESEM), and BET surface area analysis. X-ray diffraction was performed to validate drug encapsulation. An in vitro release profile of the drugs suggested a fairly slow release. These polymeric NPs were efficiently capable of releasing drug inside macrophages at a slower pace than the free drug, which was monitored by epi-fluorescence microscopy. Encapsulation of doxorubicin and mitomycin C into NPs also decreases cellular toxicity in mouse macrophages (J774.1A). PMID- 22925021 TI - Seroprevalence of Crimean Congo hemorrhagic fever virus in Ijara District, Kenya. AB - Crimean-Congo hemorrhagic fever (CCHF) is a tick-borne viral disease mainly affecting pastoralists who come in contact with animals infested with Hyalomma ticks, which are the key vectors of CCHF virus (CCHFV). CCHFV has been detected among these ticks in parts of North Eastern Kenya. This study aimed to identify acute cases of CCHF, and to determine the extent of previous exposure to CCHFV in an outpatient population attending Sangailu and Ijara health centers, Ijara District, North Eastern Kenya, presenting with acute febrile illnesses. A total of 517 human serum samples were collected from these patients. The samples were screened for the presence of IgM and IgG antibodies to CCHF using CCCHF-IgG and IgM ELISA test kits. A multivariable logistic regression model was used to investigate the risk factors associated with evidence of exposure to CCHFV. A single patient tested positive for anti-CCHF IgM, while 96 were positive for anti CCHF IgG. The seroprevalence of CCHFV was 23% in Sangailu and 14% in Ijara. Most exposed persons were aged 40-49 years. The likelihood of exposure was highest among farmers (29%). Age, location, and contact with donkeys were significantly associated with exposure to CCHFV. Acute CCHFV infections could be occurring without being detected in this population. This study confirms human exposure to CCHF virus in Ijara District, Kenya, and identifies several significant risk factors associated with exposure to CCHFV. PMID- 22925022 TI - Freshwater clams as bioconcentrators of avian influenza virus in water. AB - We report experimental evidence for bioconcentration of a low-pathogenicity avian influenza virus (H6N8) in the tissue of freshwater clams. Our results support the concept that freshwater clams may provide an effective tool for use in the early detection of influenza A viruses in aquatic environments. PMID- 22925023 TI - Relationship between Crimean-Congo hemorrhagic fever virus strains circulating in Iran and Turkey: possibilities for transborder transmission. AB - Crimean-Congo hemorrhagic fever (CCHF) is an important zoonotic viral disease that is asymptomatic in infected livestock, but poses a serious threat to humans. The high fatality rate may be due to phylogenetic variations in the virus, transmission routes, and a lack of an efficient surveillance system for the disease. The geographical features of the eastern and southeastern borders of Turkey may facilitate transmission of viruses between countries of the region. Therefore in this study we focused on the genetic relationship between Turkish and Iranian CCHF viruses based on their S-segment sequences. The research was performed on a total of 104 blood samples from small ruminants reared in southwest Iran. The results of phylogenetic analysis showed that Iranian CCHF virus isolates were closely related to human-originating Turkish Group II viruses from a European lineage reported previously. PMID- 22925024 TI - Zoonotic vector-borne bacterial pathogens in California mountain lions (Puma concolor), 1987-2010. AB - Sera collected from 442 mountain lions in 48 California counties between the years of 1987 and 2010 were tested using immunofluorescence assays and agglutination tests for the presence of antibodies reactive to Yersinia pestis, Francisella tularensis, Bartonella henselae, Borrelia burgdorferi, and Anaplasma phagocytophilum antigens. Data were analyzed for spatial and temporal trends in seropositivity. Seroprevalences for B. burgdorferi (19.9%) and B. henselae (37.1%) were relatively high, with the highest exposure in the Central Coast region for B. henselae. B. henselae DNA amplified in mountain lion samples was genetically similar to human-derived Houston-1 and domestic cat-derived U4 B. henselae strains at the gltA and ftsZ loci. The statewide seroprevalences of Y. pestis (1.4%), F. tularensis (1.4%), and A. phagocytophilum (5.9%), were comparatively low. Sera from Y. pestis- and F. tularensis-seropositive mountain lions were primarily collected in the Eastern and Western Sierra Nevada, and samples reactive to Y. pestis antigen were collected exclusively from adult females. Adult age (>= 2 years) was a risk factor for B. burgdorferi exposure. Over 70% of tested animals were killed on depredation permits, and therefore were active near areas with livestock and human residential communities. Surveillance of mountain lions for these bacterial vector-borne and zoonotic agents may be informative to public health authorities, and the data are useful for detecting enzootic and peridomestic pathogen transmission patterns, particularly in combination with molecular characterization of the infecting organisms. PMID- 22925025 TI - Review of Crimean Congo hemorrhagic fever infection in Kosova in 2008 and 2009: prolonged viremias and virus detected in urine by PCR. AB - Crimean-Congo hemorrhagic fever (CCHF) is a virus transmitted predominantly by ticks. However, contact with infected body fluids or tissues can result in animal to-human or human-to-human transmission. Numbers of CCHF cases appear to be increasing, especially in Europe. We reviewed cases admitted to a tertiary referral unit in Kosova with suspected CCHF in 2008 and 2009, and looked at a smaller number of specimens which were sent to the Health Protection Agency, Porton Down, U.K., in further detail. The clinical features of cases admitted with suspected CCHF infection were assessed in more detail, and these are the focus of this article. Between 2008 and 2009, the numbers of patients admitted for suspected CCHF infection increased. Of the samples received in Porton Down, CCHF virus was detected in urine samples, and these patients were found to have prolonged viremia. The detection of CCHF in urine, as well as the prolonged viremias seen, are important for clinicians to know, as they may have public health implications with regard to the risk of infection, as well as provide insights into the biology and pathophysiology of infection. Further studies are required regarding the pathogenesis of this virus. PMID- 22925026 TI - The 31-kDa antigen of Angiostrongylus cantonensis comprises distinct antigenic glycoproteins. AB - Human angiostrongyliasis results from accidental infection with Angiostrongylus, an intra-arterial nematode. Angiostrongylus cantonensis infections result in eosinophilic meningitis, and A. costaricensis infections cause eosinophilic enteritis. Immunological methodologies are critical to the diagnosis of both infections, since these parasites cannot be isolated from fecal matter and are rarely found in cerebrospinal fluid samples. A. costaricensis and A. cantonensis share common antigenic epitopes which elicit antibodies that recognize proteins present in either species. Detection of antibodies to a 31-kDa A. cantonensis protein present in crude adult worm extracts is a sensitive and specific method for immunodiagnosis of cerebral angiostrongyliasis. The objective of the present work was to isolate and characterize the 31-kDa proteins using soluble protein extracts derived from adult female worms using both one- (1DE) and two dimensional (2DE) gel electrophoresis. Separated proteins were blotted onto nitrocellulose and probed using sera from infected and non-infected controls. The 31-kDa band present in 1DE gels and the 4 spots identified in 2DE gels were excised and analyzed by electrospray ionization mass spectrometry. Using the highest scores obtained following Mascot analysis, amino acid sequences were obtained that matched four unique proteins: tropomyosin, the 14-3-3 phosphoserine binding protein, a protein containing a nascent polypeptide-associated complex domain, and the putative epsilon subunit of coatomer protein complex isoform 2. Oxidative cleavage of diols using sodium m-periodate demonstrated that carbohydrate moieties are essential for the antigenicity of all four spots of the 31-kDa antigen. In this article we describe the identification of the 31-kDa antigen, and provide DNA sequencing of the targets. In conclusion, these data suggest that reactivity to the 31-kDa proteins may represent antibody recognition of more than one protein, and recombinant protein-based assays for cerebral angiostrongyliasis diagnosis may require eukaryotic expression systems to maintain antigenicity. PMID- 22925027 TI - Human papillomavirus infection and the risk of cervical cancer in Japan. AB - Infection with a high-risk human papillomavirus (HPV) is established as a major risk factor for cervical cancer. In Japan, eight HPV genotypes (16, 18, 31, 33, 35, 45, 52 and 58) confer a much higher risk of cervical cancer and its immediate premalignant lesions (cervical intraepithelial neoplasia grade 3 [CIN 3]) than do other high-risk and the low-risk HPV types. However, only a small fraction of infected women develop CIN 3 or invasive cervical cancer, suggesting the involvement of additional cofactors in cervical carcinogenesis. A multicenter prospective cohort study of Japanese women with low-grade cervical abnormalities has demonstrated that tobacco smoking is significantly associated with an increased risk of persistent low-grade cervical lesions, while the presence of human leukocyte antigen Class II DRB1*1302 protects against progression to CIN 3. Understanding the epidemiology of HPV infections and cervical cancer may improve prevention and lead to novel clinical management strategies for cervical precursor lesions. Viral and host factors that affect the risk of cervical cancer are discussed in this review. PMID- 22925028 TI - Aggregation behavior of pegylated bile acid derivatives. AB - Bile acids are amphiphilic endogenous steroids that act as anionic surfactants in the digestive tract and aggregate in aqueous solutions. Nonionic surfactants were synthesized by grafting poly(ethylene glycol) chains of various lengths (pegylation) to three bile acids (lithocholic, deoxycholic, and cholic acid) using anionic polymerization. The aggregation properties of the derivatives were studied with viscosity measurements and light scattering as well as with steady state and time-resolved fluorescence techniques, and the aggregates were visualized by transmission electron microscopy to elucidate the effect of pegylation on the aggregation process. The fluorescence results showed a good correlation with the capacity of the bile acid derivatives to solubilize a hydrophobic drug molecule. The solubilization of ibuprofen depends on the length and the number of grafted PEG chains, and the solubilization efficiency increases with fewer PEG chains on the bile acid. The results indicate their potential for use in the design of new bile acid-based drug-delivery systems. PMID- 22925030 TI - Forensic epidemiologic and biomechanical analysis of a pelvic cavity blowout injury associated with ejection from a personal watercraft (jet-ski). AB - Jet-propelled personal watercraft (PWC) or jet-skis have become increasingly popular. The means of propulsion of PWC, which is a jet of water forced out of small nozzle at the rear of the craft, combined with a high risk of falling off of the seat and into close proximity with the water jet stream, raise the potential for a unique type of injury mechanism. The most serious injuries associated with PWC falls are those that occur when the perineum passes in close proximity to the jet nozzle and the high-pressure water stream enters the vaginal or rectal orifice. We describe the forensic investigation into a case of an anovaginal "blowout" injury in a passenger who was ejected from the rear seat position of a PWC and subsequently suffered life-threatening injuries to the pelvic organs. The investigation included a biomechanical analysis of the injury mechanism, a summary of prior published reports of internal pelvic injuries resulting from PWC falls as well as other water sports and activities, and a comparison of the severity of the injuries resulting from differing mechanisms using the New Injury Severity Score (NISS). The mean (+/- standard deviation [SD]) NISS values for reported PWC injuries [not including the NISS of 38 in this case study] were 11.2 (+/- 9.5), while the mean value for reported water-skiing falls was half that of the PWC group at 5.6 (+/- 5.2). It was concluded that the analyzed injuries were unique to a PWC ejection versus other previously described non-PWC-associated water sport injuries. It is recommended that PWC manufacturers help consumers understand the potential risks to passengers with highly visible warnings and reduce injury risk with revised seat design, and/or passenger seat "deadman" switches. PMID- 22925029 TI - Factors influencing consumer adoption of USB-based Personal Health Records in Taiwan. AB - BACKGROUND: Usually patients receive healthcare services from multiple hospitals, and consequently their healthcare data are dispersed over many facilities' paper and electronic-based record systems. Therefore, many countries have encouraged the research on data interoperability, access, and patient authorization. This study is an important part of a national project to build an information exchange environment for cross-hospital digital medical records carried out by the Department of Health (DOH) of Taiwan in May 2008. The key objective of the core project is to set up a portable data exchange environment in order to enable people to maintain and own their essential health information.This study is aimed at exploring the factors influencing behavior and adoption of USB-based Personal Health Records (PHR) in Taiwan. METHODS: Quota sampling was used, and structured questionnaires were distributed to the outpatient department at ten medical centers which participated in the DOH project to establish the information exchange environment across hospitals. A total of 3000 questionnaires were distributed and 1549 responses were collected, out of those 1465 were valid, accumulating the response rate to 48.83%. RESULTS: 1025 out of 1465 respondents had expressed their willingness to apply for the USB-PHR. Detailed analysis of the data reflected that there was a remarkable difference in the "usage intention" between the PHR adopters and non-adopters (chi2 =182.4, p < 0.001). From the result of multivariate logistic regression analyses, we found the key factors affecting patients' adoption pattern were Usage Intention (OR, 9.43, 95%C.I., 5.87-15.16), Perceived Usefulness (OR, 1.60; 95%C.I., 1.11-2.29) and Subjective Norm (OR, 1.47; 95%C.I., 1.21-1.78). CONCLUSIONS: Higher Usage Intentions, Perceived Usefulness and Subjective Norm of patients were found to be the key factors influencing PHR adoption. Thus, we suggest that government and hospitals should promote the potential usefulness of PHR, and physicians should encourage patients' to adopt the PHR. PMID- 22925031 TI - High-density carbon nanotube buckypapers with superior transport and mechanical properties. AB - High-density buckypapers were obtained by using well-aligned carbon nanotube arrays. The density of the buckypapers was as high as 1.39 g cm(-3), which is close to the ultimate density of ideal buckypapers. Then we measured the transport and mechanical properties of the buckypapers. Our results demonstrated that its electrical and thermal conductivities could be almost linearly improved by increasing its density. In particular, its superior thermal conductivity is nearly twice that of common metals, which enables it a lightweight and more efficient heat-transfer materials. The Young's modulus of the buckypapers could reach a magnitude over 2 GPa, which is greatly improved compared with previous reported results. In view of this, our work provided a simple and convenient method to prepare high-density buckypapers with excellent transport and mechanical properties. PMID- 22925032 TI - Self-defining memories, scripts, and the life story: narrative identity in personality and psychotherapy. AB - An integrative model of narrative identity builds on a dual memory system that draws on episodic memory and a long-term self to generate autobiographical memories. Autobiographical memories related to critical goals in a lifetime period lead to life-story memories, which in turn become self-defining memories when linked to an individual's enduring concerns. Self-defining memories that share repetitive emotion-outcome sequences yield narrative scripts, abstracted templates that filter cognitive-affective processing. The life story is the individual's overarching narrative that provides unity and purpose over the life course. Healthy narrative identity combines memory specificity with adaptive meaning-making to achieve insight and well-being, as demonstrated through a literature review of personality and clinical research, as well as new findings from our own research program. A clinical case study drawing on this narrative identity model is also presented with implications for treatment and research. PMID- 22925033 TI - Lactobacillus pentosus var. plantarum C29 protects scopolamine-induced memory deficit in mice. AB - AIMS: In the preliminary study, kimchi, a traditional food fermented with Chinese cabbage, protected scopolamine-induced mouse memory deficit in passive avoidance test. Therefore, we screened protective ingredients, particularly lactic acid bacteria, from Chinese cabbage kimchi against scopolamine-induced memory deficit in mice. METHODS AND RESULTS: Lactic acid bacteria, isolated from Chinese cabbage kimchi, were identified by 16S rDNA sequence analysis, G+C content and cellular fatty acid composition and sugar fermentation test. Memory deficit was induced in mice by intraperitoneally injecting with scopolamine. Kimchi, particularly its supernatant, protected scopolamine-induced memory deficit in mice in passive avoidance test. Of kimchi ingredients, a lactic acid bacterium, strain C29, potently protected scopolamine-induced memory deficit in mice. C29 was a gram positive, catalase-negative, anaerobic and non-motile rod. Its pylogenetic property was near to Lactobacillus pentosus (99%) and Lact. plantarum (99%). However, C29 fermented inulin and L-rhamnose and grew in pH 3 and at 45 degrees C in contrast with Lact. pentosus and Lact. plantarum. Therefore, it named to be Lact pentosus var. plantarum C29. The strain C29 protected scopolamine-induced memory deficit in Y-maze and Morris water maze tests. Furthermore, C29 increased hippocampal BDNF and p-CREB expressions, which were reduced by scopolamine. CONCLUSION: Lactobacillus pentosus var. plantarum C29 may protect memory deficit by inducing BDNF and p-CREB expressions. SIGNIFICANCE AND IMPACT OF THE STUDY: Lactic acid bacteria, such as Lact pentosus var. plantarum C29, may prevent memory deficit and its contained fermented foods may be beneficial for dementia. PMID- 22925034 TI - Establishment of phosphatidylinositol 3-kinase inhibitor-resistant cancer cell lines and therapeutic strategies for overcoming the resistance. AB - Acquired resistance is a major obstacle for conventional cancer chemotherapy, and also for some of the targeted therapies approved to date. Long-term treatment using protein tyrosine kinase inhibitors (TKIs), such as gefitinib and imatinib, gives rise to resistant cancer cells carrying a drug-resistant gatekeeper mutation in the kinase domain of the respective target genes, EGFR and BCR-ABL. As for the phosphatidylinositol 3-kinase inhibitors (PI3Kis), little is known about their acquired resistance, although some are undergoing clinical trials. To address this issue, we exposed 11 human cancer cell lines to ZSTK474, a PI3Ki we developed previously, for a period of more than 1 year in vitro. Consequently, we established ZSTK474-resistant cells from four of the 11 cancer cell lines tested. The acquired resistance was not only to ZSTK474 but also to other PI3Kis. None of the PI3Ki-resistant cells, however, contained any mutation in the kinase domain of the PIK3CA gene. Instead, we found that insulin-like growth factor 1 receptor (IGF1R) was overexpressed in all four resistant cells. Interestingly, targeted knockdown of IGF1R expression using specific siRNAs or inhibition of IGF1R using IGF1R-TKIs reversed the acquired PI3Ki resistance. These results suggest that long-term treatment with PI3Kis may cause acquired resistance, and targeting IGF1R is a promising strategy to overcome the resistance. PMID- 22925035 TI - The effect of shift length on fatigue and cognitive performance in air medical providers. AB - OBJECTIVE: To employ a battery of previously validated surveys and neuropsychological tests to compare changes in fatigue and cognitive abilities of air medical providers after 12- and 24-hour shifts. METHODS: A convenience sample of 34 flight nurses and flight paramedics employed by one air medical service completed the Pittsburgh Sleep Quality Index (PSQI) and the Chalder Fatigue Questionnaire (CFQ) to determine fatigue before and after 12-hour (n = 16) and 24 hour (n = 19) shifts. A battery of neuropsychological tests, including the University of Southern California Repeatable Episodic Memory Test (USC-REMT), Paced Auditory Serial Addition Test (PASAT), Trail Making Test (TMT), and Stroop Color-Word Test were administered before and after the shift to measure changes in cognition. We compared the change in scores stratified by shift length using t tests, Wilcoxon signed-rank test, and Fisher's exact test. RESULTS: Participants in the 12- and 24-hour shift groups were aged 36 +/- 8 years (12-hour shifts) and 39 +/- 6 years (24-hour shifts) (mean +/- standard deviation) and were preponderantly male (62% 12-hour shifts; 63%, 24 hour shifts). The PSQI scores identified 50% of both 12-hour and 24-hour shift subjects as having poor sleep quality. Preshift fatigue was described as a median 2/10 (interquartile range [IQR] = 2-4) and fatigue declined by the end of the shift to a median 1/10 [IQR = 1-2], p = 0.006. Providers averaged 6.8 hours of sleep during 24-hour shifts and 1 hour of sleep during 12-hour shifts. Changes in cognitive scores did not differ between groups. CONCLUSIONS: This study identified no changes in cognitive performance following 12- and 24-hour shifts in air medical providers. This suggests that 24-hour shifts in an air medical service with low to moderate utilization do not have a detrimental effect on cognition as measured by this test battery, and are comparable to 12-hour shifts in terms of impact on cognitive function. PMID- 22925037 TI - Balancing speed and accuracy of polyclonal T cell activation: a role for extracellular feedback. AB - BACKGROUND: Extracellular feedback is an abundant module of intercellular communication networks, yet a detailed understanding of its role is still lacking. Here, we study interactions between polyclonal activated T cells that are mediated by IL-2 extracellular feedback as a model system. RESULTS: Using mathematical modeling we show that extracellular feedback can give rise to opposite outcomes: competition or cooperation between interacting T cells, depending on their relative levels of activation. Furthermore, the outcome of the interaction also depends on the relative timing of activation of the cells. A critical time window exists after which a cell that has been more strongly activated nevertheless cannot exclude an inferior competitor. CONCLUSIONS: In a number of experimental studies of polyclonal T-cell systems, outcomes ranging from cooperation to competition as well as time dependent competition were observed. Our model suggests that extracellular feedback can contribute to these observed behaviors as it translates quantitative differences in T cells' activation strength and in their relative activation time into qualitatively different outcomes. We propose extracellular feedback as a general mechanism that can balance speed and accuracy - choosing the most suitable responders out of a polyclonal population under the clock of an escalating threat. PMID- 22925036 TI - Safety and efficacy of low-dose fondaparinux (1.5 mg) for the prevention of venous thromboembolism in acutely ill medical patients with renal impairment: the FONDAIR study. AB - BACKGROUND: Renal impairment is common, affecting around 40% of acutely ill medical patients, and is associated with an increased risk of both venous thromboembolism (VTE) and bleeding. The clinical benefit of effective thromboprophylactic strategies may be outweighed in these patients by an excessive rate of hemorrhage. OBJECTIVE: To assess the safety and efficacy of lower prophylactic doses of fondaparinux in acutely ill medical patients with renal impairment. PATIENTS/METHODS: We carried out a multicenter, investigator initiated, prospective cohort study. Patients at risk of VTE with a creatinine clearance between 20 and 50 mL min(-1) were treated with fondaparinux 1.5 mg qd for a minimum of 6 to a maximum of 15 days. The primary outcome was the incidence of major bleeding; secondary outcomes were clinically relevant non-major bleeding (CRNMB) and symptomatic VTE. RESULTS: We enrolled 206 patients with a mean age of 82 years, mean creatinine clearance of 33 mL min(-1) , and a mean Charlson co morbidity index of 8.2. One patient had major bleeding (0.49%, 95% confidence interval [CI] 0.03-3.10), eight had CRNMB (3.88%, 95% CI 1.81-7.78) and three developed symptomatic VTE (1.46%, 0.38-4.55). Twenty-three patients (11.17%, 7.36 16.48) died. No independent predictors of bleeding were found at univariate analysis. CONCLUSIONS: The addition of moderate to severe renal impairment to patients with traditional risk factors for VTE identified a population of very elderly acutely ill medical patients potentially at high risk of both VTE and bleeding complications. The recently approved lower prophylactic dose of fondaparinux appears to be a safe and relatively effective strategy in these patients. PMID- 22925038 TI - Suppressed G-protein-coupled receptor kinase 2 activity protects female diabetic mouse aorta against endothelial dysfunction. AB - AIM: Pre-menopausal women have less cardiovascular disease and lower cardiovascular morbidity and mortality than men the same age. Previously, we noted in mice that G-protein-coupled receptor kinase 2 (GRK2) negatively regulates the Akt/eNOS pathway in male diabetic aortas and that endothelial function via the Akt/eNOS pathway is less affected in female diabetic aortas. The cellular mechanisms underlying these sex differences remain unclear. We aimed to investigate the ways in which GRK2 might modulate vascular functions in male and female diabetic mice (DM). METHODS: Vascular functions were examined in aortic rings. GRK2, beta-arrestin 2 and Akt/eNOS-signalling-pathway protein levels and activities were assayed by Western blotting. RESULTS: Phenylephrine-induced contraction was greater, while both clonidine-induced and insulin-induced relaxations were weaker (vs. male controls), in aortas from male type 2 DM, suggesting impairments of the Akt/eNOS pathway and alpha-adrenoceptor function. GRK2-inhibitor reversed only the impairment in Akt/eNOS-pathway-mediated relaxation in male DM. Increases in GRK2 activity, GRK2 expression in the membrane, plasma Ang II and systolic blood pressure were seen in male DM (vs. male controls) but not in female DM; these increases were attenuated by GRK2 inhibitor treatment. Repeatedly obtaining clonidine concentration-response curves led to reduced relaxation in male and in female DM aortas, indicating similar desensitization between female DM and male DM. This effect was reversed by GRK2 inhibitor in both sexes. CONCLUSION: GRK2 plays a key role in modulating the aortic vasodilator effect of clonidine by selectively affecting the Akt/eNOS pathway. This action of GRK2 is more powerful in male than in female DM. PMID- 22925039 TI - Irreversible electroporation of a liver metastasis. PMID- 22925040 TI - Influence of the cumulus and gonadotropins on the metabolic profile of porcine cumulus-oocyte complexes during in vitro maturation. AB - The aim of this work was to examine the influence of the cumulus and gonadotropins on the metabolic profile of porcine cumulus oocyte complexes (COCs) during in vitro maturation. Immature COCs were assigned to morphological classes A(1) (with a dense cumulus), A(2) (with a translucent cumulus), B(1) (with the corona radiata), B(2) (with only some remaining cumulus cells) and matured with or without gonadotropins. Glycolysis and ammonia production were higher in the A class COCs; gonadotropins increased both, especially in the A(1) COCs (p < 0.05). The A class COCs had the highest initial protein contents and at the end of in vitro maturation. Furthermore, hormonal stimulation induced a similar increase in protein contents of both A classes (p < 0.05). The neutral lipid content and reactive oxygen species (ROS) levels were similar in the immature oocytes of the COCs of all classes. A reduction was seen in both these variables when maturation proceeded either in the presence or absence of gonadotropins. The cumulus type surrounding the oocyte is related to the metabolism of carbohydrates and amino acids by the COC during in vitro maturation under gonadotropic stimulation. Oocyte lipolytic activity and ROS production appear to be independent of the surrounding cumulus and the presence of gonadotropins. PMID- 22925041 TI - Targeting IL-1 in depression. AB - INTRODUCTION: Depression is associated with inflammation, Th1 and Th17 responses, oxidative and nitrosative stress (O&NS), autoimmune responses against neoantigenic determinants, and neuroprogression (i.e., neurodegeneration, impaired plasticity and reduced neurogenesis). These pathways involve increased monocytic activation and interleukin-1 (IL-1) levels. AREAS COVERED: This review will highlight the putative role of IL-1 in depression and the potential use of IL-1 signaling blockade as a treatment of depression. Electronic databases, i.e., Scopus, PUBMED and Google Scholar were employed using keywords: depression, depressive-like, interleukin-1, and interleukin-1 receptor antagonist (IL-1RA). EXPERT OPINION: Ample studies show that depression is accompanied by increased levels of IL-1 and IL-1RA, which attenuates the pro-inflammatory activities of IL 1. In some, but not all studies, antidepressant treatment decreased IL-1beta levels. In translational models, IL-1beta administration elicits depressive-like behaviors, neuroinflammation and neuroprogression, whereas treatment with IL-1RA yields antidepressant-like effects and attenuates neuroprogression. Anakinra, an IL-1RA, targets not only IL-1 signaling, but also Th1, Th17, O&NS and neuroprogressive pathways and therefore may be advanced to clinical Phase-II trials in depression due to medical conditions associated with an elevated IL 1/IL-1RA ratio. PMID- 22925042 TI - Parent-child shared time from middle childhood to late adolescence: developmental course and adjustment correlates. AB - The development and adjustment correlates of parent-child social (parent, child, and others present) and dyadic time (only parent and child present) from age 8 to 18 were examined. Mothers, fathers, and firstborns and secondborns from 188 White families participated in both home and nightly phone interviews. Social time declined across adolescence, but dyadic time with mothers and fathers peaked in early and middle adolescence, respectively. In addition, secondborns' social time declined more slowly than firstborns', and gendered time use patterns were more pronounced in boys and in opposite-sex sibling dyads. Finally, youths who spent more dyadic time with their fathers, on average, had higher general self-worth, and changes in social time with fathers were positively linked to changes in social competence. PMID- 22925043 TI - Early weight control. PMID- 22925044 TI - Precision of host sanctions in the fig tree-fig wasp mutualism: consequences for uncooperative symbionts. AB - Host sanctions that reduce the relative fitness of uncooperative symbionts provide a mechanism that can limit cheating and thus stabilise mutualisms over evolutionary timescales. Sanctions have been demonstrated empirically in several mutualisms. However, if multiple individual symbionts interact with each host, the precision with which individual cheating symbionts are targeted by host sanctions is critical to their short- and long-term effectiveness. No previous empirical study has directly addressed this issue. Here, we report the precision of host sanctions in the mutualism between fig trees and their pollinating wasps. Using field experiments and molecular parentage analyses, we show that sanctions in Ficus nymphaeifolia act at the level of entire figs (syconia), not at the level of the individual flowers within. Such fig-level sanctions allow uncooperative wasps, which do not bring pollen, to avoid sanctions in figs to which other wasps bring pollen. We discuss the relevance of sanction precision to other mutualisms. PMID- 22925045 TI - Learner-controlled practice difficulty in the training of a complex task: cognitive and motivational mechanisms. AB - An inherent aspect of learner-controlled instructional environments is the ability of learners to affect the degree of difficulty faced during training. However, research has yet to examine how learner-controlled practice difficulty affects learning. Based on the notion of desirable difficulties (Bjork, 1994), this study examined the cognitive and motivational antecedents and outcomes of learner-controlled practice difficulty in relation to learning a complex task. Using a complex videogame involving both strong cognitive and psychomotor demands, 112 young adult males were given control over their practice difficulty, which was reflected in the complexity of the training task. Results show that general mental ability, prior experience, pre-training self-efficacy, and error encouragement were positively related to learner-controlled practice difficulty. In turn, practice difficulty was directly related to task knowledge and post training performance, and it was related to adaptive performance through the mediating influences of task knowledge and post-training performance. In general, this study supports the notion that training difficulty operationalized in terms of task complexity is positively related to both knowledge and performance outcomes. Results are discussed with respect to the need for more research examining how task complexity and other forms of difficulty could be leveraged to advance learner-controlled instructional practices. PMID- 22925046 TI - Web-based alcohol intervention for Maori university students: double-blind, multi site randomized controlled trial. AB - AIMS: Like many indigenous peoples, New Zealand Maori bear a heavy burden of alcohol-related harm relative to their non-indigenous compatriots, and disparities are greatest among young adults. We tested the effectiveness of web based alcohol screening and brief intervention (e-SBI) for reducing hazardous drinking among Maori university students. DESIGN: Parallel, double-blind, multi site, randomized controlled trial. SETTING: Seven of New Zealand's eight universities. PARTICIPANTS: In April 2010, we sent e-mail invitations to all 6697 17-24-year-old Maori students to complete a brief web questionnaire including the Alcohol Use Disorders Identification Test (AUDIT)-C, a screening tool for hazardous and harmful drinking. Those screening positive were computer randomized to: <10 minutes of web-based alcohol assessment and personalized feedback (intervention) or screening alone (control). MEASUREMENTS: We conducted a fully automated 5-month follow-up assessment with observers and participants blinded to study hypotheses, design and intervention delivery. Pre-determined primary outcomes were: (i) frequency of drinking, (ii) amount consumed per typical drinking occasion, (iii) overall volume of alcohol consumed and (iv) academic problems. FINDINGS: Of the participants, 1789 were hazardous or harmful drinkers (AUDIT-C >= 4) and were randomized: 850 to control, 939 to intervention. Follow up assessments were completed by 682 controls (80%) and 733 intervention group members (78%). Relative to controls, participants receiving intervention drank less often [RR = 0.89; 95% confidence interval (CI): 0.82-0.97], less per drinking occasion (RR = 0.92; 95% CI: 0.84-1.00), less overall (RR = 0.78; 95% CI: 0.69-0.89) and had fewer academic problems (RR = 0.81; 95% CI: 0.69-0.95). CONCLUSIONS: Web-based screening and brief intervention reduced hazardous and harmful drinking among non-help-seeking Maori students in a large-scale pragmatic trial. The study has wider implications for behavioural intervention in the important but neglected area of indigenous health. PMID- 22925047 TI - Importance of riboflavin kinase in the pathogenesis of stroke. AB - AIMS: To explore risk factors for stroke independent of hypertension and the relationship between riboflavin kinase (RFK) and stroke. METHODS: Gene expression profiling in the brains of spontaneously hypertensive rats (SHR) and stroke-prone spontaneously hypertensive rats (SHRSP) was comparatively analyzed by gene chips. The differentially expressed gene RFK was further verified by q-PCR and Western blot. The protective role of RFK-regulated flavins (including riboflavin, flavin mononucleotide, and flavin adenine dinucleotide) in stroke was observed in middle cerebral artery occlusion (MCAO) mice. Influence of flavins on apoptosis and death in oxygen and glucose deprivation (OGD)-treated neurons was examined by flow cytometry. Bax and Bcl-2 proteins were detected by Western blot. RESULTS: Of the 76 differentially expressed genes, 41 genes were upregulated, and 35 genes were downregulated in SHRSP as compared with SHR. RFK was significantly downregulated in SHRSP. Flavins markedly decreased infarct area in MCAO mice, inhibited apoptosis and death in OGD-treated neurons, and decreased Bax protein expression. CONCLUSIONS: Physiological downregulation of RFK may be a new potential risk factor for stroke, which probably affects the absorbance and utility of riboflavin and further destroys the protective effect of flavins on stroke. RFK might act as a therapeutic target for stroke. PMID- 22925048 TI - Influence of implant neck design and implant-abutment connection type on peri implant health. Radiological study. AB - OBJECTIVE: To carry out a comparative study of two implants with different neck features and prostheses platform connection (machined with external connection and rough-surfaced with switching platform) upon peri-implant marginal bone loss, before and after functional loading. MATERIAL AND METHODS: A randomized, prospective radiological study was made. Eighteen totally edentulous patients were selected. Subjects were divided into two groups according to the type of implant neck used: (a) Osseous((r)), with machined surface, without microthreads, external connection, and without platform switching; and (b) Inhex((r)), with treated surface, microthreads, internal connection, and platform switching. Mesial and distal marginal bone loss was measured. Implant success was assessed according to the criteria of Buser. Control timepoints were as follows: (a) at implant placement; (b) at prosthesis placement; (c) 6 months after loading; (d) 12 months after loading. RESULTS: Fifteen patients that received 120 dental implants were included: 47% Osseous((r)) group and 53% Inhex((r)) group. Global mean marginal bone loss with Osseous((r)) was 0.27 +/- 0.43 mm and 0.38 +/- 0.51 mm as determined 6 and 12 months after prosthetic loading, respectively, whereas in the case of Inhex((r)) was 0.07 +/- 0.13 and 0.12 +/- 0.17 mm. These differences were statistically significant (P = 0.047). Difference between Osseous((r)) and Inhex((r)) in maxilla (P = 0.272) and mandibular (P = 0.462) bone loss were not statistically significant. CONCLUSIONS: Bone loss after 6 and 12 months proved statistically significant between two groups, with comparatively greater loss in the case of Osseous((r)) implants vs. Inhex((r)) implants. Regardless the heterogeneity of the two groups (neck shape, microthreads, surface texture), the implant-abutment connection appears to be a significant factor on peri-implant crestal bone levels. Anyway, in both groups, the values obtained were within normal ranges described in the literature. PMID- 22925049 TI - A complex network of small non-coding RNAs regulate motility in Escherichia coli. AB - Small Hfq-dependent non-coding regulatory RNAs (sRNAs) that alter mRNA stability and expression by pairing with target mRNAs have increasingly been shown to be important in influencing the behaviour of bacteria. In Escherichia coli, flhD and flhC, which encode the master regulator of flagellar synthesis, are co transcribed from a promoter that is regulated by multiple transcription factors that respond to different environmental cues. Here, we show that the 5' untranslated region (5' UTR) of the flhDC mRNA also serves as a hub to integrate additional environmental cues into the decision to make flagella. Four sRNAs, ArcZ, OmrA, OmrB and OxyS, negatively regulated and one sRNA, McaS, positively regulated motility and flhDC expression by base-pairing with the 5' UTR of this mRNA. Another sRNA, MicA, positively regulated motility independent of regulation of flhDC. Furthermore, we demonstrate that the regulation of motility by the ArcB/A two component system is in part due to its regulation of ArcZ. flhDC is the first mRNA that has been shown to be both positively and negatively regulated by direct pairing to sRNAs. Moreover, both positive regulation by McaS and negative regulation by ArcZ require the same binding site in the flhDC mRNA. PMID- 22925050 TI - Sexualities and genders in an age of neoterrorism. PMID- 22925051 TI - Racialized masculinities and the new homonormativity in LOGO's Noah's Arc. AB - Examining the relationship between neoliberalism, race, and gender performance, this article provides an analysis of Noah's Arc, a popular LOGO television series in the United States. More specifically, it focuses on the intricate relationship between specific forms of racialized masculinities and the new homonormativity in this show. This article is divided into six sections. First, an overview of the LOGO series is provided. Next, gay, lesbian, and queer visibility in mainstream U.S. popular culture and the new homonormativity are examined. Third, the relationship between race and masculinity is discussed. Next, a close reading and analysis of the show is provided. Fifth, an exploration of how representations of Noah's Arc queers and "quares" Black masculinity in U.S. culture is undertaken. Finally, some concluding thoughts on representations of racialized masculinities and homonormativity in this popular television series are offered. PMID- 22925052 TI - For the love of love: neoliberal governmentality, neoliberal melancholy, critical intersectionality, and the advent of solidarity with the other Mormons. AB - This article performs critical intellectual labor for social and political change against neoliberalism in three ways. First, it explores and connects neoliberal governmentality and neoliberal melancholy, two anchor experiences in our twenty first century political quotidian. Second, it engages in the sense making of Proposition 8 (a California voter initiative to ban same-sex marriage, which was narrowly passed in 2008) as a case study of religious organizations (the Mormon Church and their religious allies) and their complicity with neoliberal states to foster subjection and subjectivation through critical intersectionality that goes beyond the identity trinity of race, class, and gender. Finally, the article suggests two technologies as a new hand to outplay the excess of neoliberalism for the triumph of our common humanity: 1) mourning over the devastation brought about by neoliberalism and 2) loving our love for those with whom we usually do not form affinity connections, such as the other Mormons, those who are othered because of their departure from church orthodoxy. PMID- 22925053 TI - "I thought this course was going to be streamlined!": the limits of normal and the possibilities of transgression. AB - This article offers an analysis of the parallels between neo-liberalism, epistemology, and pedagogy, specifically related to how neoliberal ideologies narrow the possibilities for considering transgressive sexualities. Lesbian, gay, bisexual, transgender, and queer (LGBTQ) education encourages educators to consider queer lives and communities, and can do so in ways that leave intact or challenge dominant norms. Neoliberalism, an economic expression of liberalism, rests on ideologies that support privatization and a diminished notion of the public good. These ideologies can become intertwined with epistemological expectations in the classroom. Related to queer theory and pedagogy, neoliberalism can profoundly narrow the possibilities for queer subjecthood. Epistemological neoliberalism, or structures of knowing that endorse an often falsely rendered normality, can be active in the classroom. This article explores two comments students offered in courses on gender and communication to explore the ways in which neoliberal ideologies bear on epistemological and pedagogical practices in ways that profoundly narrow conceptions of the social and constitutions of the subject, particularly related to transgressive sexualities and queer lives. PMID- 22925054 TI - Contesting neoliberalism through critical pedagogy, intersectional reflexivity, and personal narrative: queer tales of academia. AB - In this article, we use personal narrative to explore allies and alliance building between marginalized people working in and through higher education, with an eye toward interrogating the ways in which ideologies of neoliberalism work to maintain hierarchy through the legitimation of othering. Inspired by Conquergood (1985 ), who calls scholars to engage in intimate conversation rather than distanced observation, we offer our embodied experiences as a way to use the personal to reflect on the cultural, social, and political. Our narratives often recount being out of place, moments of incongruence, or our marked otherness. Through the sharing of these narratives, we will demonstrate the possibility for ally building based in affective connections forged through shared queer consciousness, paying particular attention to the ways in which neoliberal ideologies, such as individualism and postracism, may advance and impede such alliances. PMID- 22925055 TI - A critique of neoliberalism with fierceness: queer youth of color creating dialogues of resistance. AB - As a form of deregulated capitalism that has run amok, commodifying all that is in its path, and as a cultural means of commodifying Black and brown bodies, neoliberalism has taken a serious toll on the lives of working-class queer youth of color. Although it has hijacked spaces of cultural representation and material production, neoliberal capitalism is far from transparent. Through resistance, activism and performance queer youth of color have now started to shape a critique of oppressive structures, neoliberal policies, and pedagogical practices that are critical of their intersecting identities. This article examines neoliberalism's impact on education, focusing on educational policy and how these policies have affected queer youth of color in the urban centers of our major cities. This article also considers the contributions made by educators writing from the perspective of critical pedagogy in addressing the plight of queer youth of color in U.S. schools while employing the example of the dance group, Innovation, as way of addressing the havoc of neoliberalism in the lives of queer youth of color through performance and activism. This group has not only transformed notions of gender, race, class and sexuality that challenge major tenants of neoliberalism, but has also served as potent sites for the development of a critical pedagogy for working-class queer youth of color. Through sites of resistance rooted in progressive struggle, queer youth of color must be enabled by critical transformative intellectuals committed to encouraging youth to critically evaluate and challenge ideologies while displaying an allegiance to egalitarianism. PMID- 22925056 TI - Queering the politics of lambda picture book finalists: challenging creeping neoliberalism through curricular innovations. AB - In many instances, adults serve as gatekeepers for what books children are permitted to explore. Unfortunately, this means that most children have limited access to picture books with lesbian, gay, bisexual, transgender, and queer (LGBTQ) characters. In this article, we use queer pedagogy and observations about neoliberalism to provide a qualitative analysis of LGBTQ characters in picture books which were finalists for a Lambda Literary Award during 2000-2005. We examined the ways in which LGBTQ identities and relationships are negotiated and how sexual prejudice is treated. While it is improbable that the books we analyze would be embraced by proponents of neoliberalism, we also briefly consider some ways in which they may be inadvertently consistent with that perspective. The article closes with recommendations regarding discussion questions, additional readings, and educational activities aimed at guiding children, and adults, to appreciate a diversity of multidimensional identities and family structures, to develop strategies to respond constructively to emotional and physical violence, and to promote the public wellbeing. We hope that this analysis will lead to more frequent, productive, and expansive discussions of this literature among adults and children. PMID- 22925057 TI - Erotic pedagogies. AB - This article considers the role of Audre Lorde's notion of the erotic as transformative pedagogical practices that can empower teachers and students to passionate learning and community formation. I argue that the erotic has been contained within the private sphere under neoliberalism through its articulation to heterosexuality, Whiteness, and U.S. exceptionalism. Neoliberalism contains the transformative potential of queer, feminist, and antiracist movements through circumscribing the transformative power of the erotic. When the erotic appears within the realm of the public sphere, it is articulated through the pornographic as against the seemingly progressive agenda of neoliberalism-in order to contain its transformative effects. I then consider what it may look like, as well as what pitfalls we may face, if we engage in erotic pedagogy. I argue that the healing of the mind/body split goes beyond an intellectual exercise. Therein lies transformative power to heal both the political and the spiritual body. PMID- 22925058 TI - The sexual and racial contradictions of neoliberalism. PMID- 22925059 TI - Homonormativity: A metropolitan concept that denigrates "ordinary" gay lives. PMID- 22925060 TI - Aye, and neoliberalism. PMID- 22925061 TI - The rough trade of U.S. imperialism. PMID- 22925062 TI - Homosexuality, gender nonconformity, and the neoliberal state. PMID- 22925063 TI - In situ synthesis of photocatalytically active hybrids consisting of bacterial nanocellulose and anatase nanoparticles. AB - Bacterial nanocellulose (BNC) is an extraordinary biopolymer with a wide range of potential technical applications. The high specific surface area and the interconnected pore system of the nanofibrillar BNC network suggest applications as a carrier of catalysts. The present paper describes an in situ modification route for the preparation of a hybrid material consisting of BNC and photocatalytically active anatase (TiO(2)) nanoparticles (NPs). The influence of different NP concentrations on the BNC biosynthesis and the resulting supramolecular structure of the hybrids was investigated. It was found that the number of colony forming units (CFUs) and the consumption of glucose during biosynthesis remained unaffected compared to unmodified BNC. During the formation of the BNC network, the NPs were incorporated in the whole volume of the accruing hybrid. Their distribution within the hybrid material is affected by the anisotropic structure of BNC. The photocatalytic activity (PCA) of the BNC-TiO(2) hybrids was determined by methanol conversion (MC) under UV irradiation. These tests demonstrated that the NPs retained their PCA after incorporation into the BNC carrier structure. The PCA of the hybrid material depends on the amount of incorporated NPs. No alteration of the photocatalyst's efficiency was found during repeated PCA tests. In conclusion, the in situ integration of photocatalytically active NPs into BNC represents an attractive possibility to extend its fields of application to porous filtering media for drinking water purification and air cleaning. PMID- 22925064 TI - Characterization of the standard and recommended CODIS markers. AB - As U.S. courts grapple with constitutional challenges to DNA identification applications, judges are resting legal decisions on the fingerprint analogy, questioning whether the information from a DNA profile could, in light of scientific advances, reveal biomedically relevant information. While CODIS loci were selected largely because they lack phenotypic associations, how this criterion was assessed is unclear. To clarify their phenotypic relevance, we describe the standard and recommended CODIS markers within the context of what is known currently about the genome. We characterize the genomic regions and phenotypic associations of the 24 standard and suggested CODIS markers. None of the markers are within exons, although 12 are intragenic. No CODIS genotypes are associated with known phenotypes. This study provides clarification of the genomic significance of the key identification markers and supports--independent of the forensic scientific community--that the CODIS profiles provide identification but not sensitive or biomedically relevant information. PMID- 22925065 TI - Survival of silage lactic acid bacteria in the goat gastrointestinal tract as determined by denaturing gradient gel electrophoresis. AB - AIMS: To determine the survival rate of silage lactic acid bacteria (LAB) in the ruminant gastrointestinal tract. METHODS AND RESULTS: Wilted Italian ryegrass (Lolium multiflorum Lam.) silage (containing 1.9*10(6) CFU LAB g(-1)) was fed ad libitum to three goats equipped with rumen cannulae. Silage was given alone or with concentrates at a 1:1 ratio on a dry matter basis. Rumen fluid was then obtained 2, 4 and 8h after the morning feeding. Denaturing gradient gel electrophoresis was performed to compare LAB communities in silage, rumen fluid and faeces. The LAB detected in the wilted silage included Lactobacillus plantarum, Lactobacillus brevis, Lactobacillus murinus and Lactobacillus sakei. Bands indicative of Lact. murinus were detected in either the rumen fluid or faeces, whereas the bands indicative of Lact. plantarum, Lact. brevis and Lact. sakei were not. Although the rumen fluid LAB counts and volatile fatty acid concentrations were higher in goats fed silage plus concentrates compared with those fed silage alone, the LAB communities themselves remained unaffected. Sampling times and goat-to-goat variations did not affect the LAB communities found in the rumen fluid. CONCLUSION: LAB communities found in the gut are not remarkably affected by the consumption of silage LAB, even when the silage is accompanied by concentrates that facilitate gut fermentation. SIGNIFICANCE AND IMPACT OF THE STUDY: Although silage can improve probiotic function, it may be difficult for silage LAB to survive the digestive process in the ruminant gastrointestinal tract. PMID- 22925066 TI - Management of recurrent Paecilomyces lilacinus keratitis. AB - A 72-year-old man presented with Paecilomyces keratitis subsequent to immunosuppressive treatment. Despite medical therapy with voriconazole, perforation occurred requiring a tectonic keratoplasty of 10 mm. Despite oral, topical and intracameral voriconazole, there was recurrent stromal infiltration. A corneoscleral graft of 15 mm was undertaken. Two weeks later, hyphae were seen on the anterior lens capsule with hypopyon requiring phacoemulsification and anterior chamber washout. Six weeks later, there was evidence of endophthalmitis. Pars plana vitrectomy, capsulectomy and intravitreal injection of voriconazole were performed. Voriconazole treatment was continued for a further 10 months and then ceased. At 16 months following the last recurrence of Paecilomyces, there was no evidence of infection. After 20 months, the patient had a sutured intraocular lens with an artificial iris. Vision is 6/36 unaided and 6/24 pinhole. PMID- 22925067 TI - Light-activated porphyrin-based formulations to inactivate bacterial spores. AB - AIM: The objective of this study was to develop porphyrin-based formulations to inactivate Bacillus spores. We probed the effect of porphyrins alone and in combination with germinants against both Bacillus cereus and Bacillus anthracis spores in the presence of light. METHODS AND RESULTS: We tested the effect of two different porphyrins, amine-modified protoporphyrin IX (PPIX) and meso-tetra (N methyl-4-pyridyl) porphine tetra tosylate (TMP). Treatment with the porphyrins alone did not significantly influence spore viability. However, when spores were pretreated with a solution containing the germinants, l-alanine and inosine, the spore viability dropped by as much as 4.5 logs in the presence of light. The extent of inactivation depended on the germination conditions and the type of porphyrin used, with TMP being more effective. CONCLUSION: Porphyrins can be used effectively in combination with germinants to inactivate Bacillus spores. SIGNIFICANCE AND IMPACT OF THE STUDY: The results of this study provide evidence that porphyrins can be used to inactivate Bacillus spores in the presence of germinants and light irradiation. This finding may be general and may be extended to spores of other pathogens. PMID- 22925068 TI - Functional variant in methionine synthase reductase decreases the risk of Down syndrome in China. AB - AIM: Down syndrome (DS) is the most common genetic cause of human mental retardation and the genes involved in homocysteine/folate metabolism may play important roles in this condition. Methionine synthase reductase (MTRR) is one of the key regulatory enzymes involved in the metabolic pathway of homocysteine. We investigated whether the polymorphism C524T of the MTRR gene is associated with DS. METHOD: A total of 104 mothers of children born with DS and 184 healthy mothers were included. The polymorphisms were detected by polymerase chain reaction and restriction fragment length polymorphism analysis. Plasma folate and total plasma homocysteine (t-Hcy) concentrations were also measured. RESULTS: Significant differences in the distributions of C524T alleles were observed between case and control mothers; a decreased risk of DS was associated with the 524TT genotype (OR=0.34), CT+TT genotype (OR=0.60). The mean t-Hcy value in the case group was higher than the mean value in the control group. t-Hcy concentrations were lower in TT homozygote than CC homozygote among the cases but not among the controls. CONCLUSION: MTRR C524T polymorphism decreases the risk of DS in the Chinese population. PMID- 22925070 TI - It takes two: a longitudinal dyadic study on predictors of fertility outcomes. AB - OBJECTIVE: Although previous studies have found personality traits to be associated with reproductive behavior, it remains unclear whether there are dyadic associations between partners' personality and couples' decisional process to have children. The aim of the present study was to investigate the associations between partners' personality, parenthood expectations and intentions, and the couple's fertility outcomes one year later. METHOD: We used dyadic longitudinal data from 2,482 couples with a mean age of 32.7 years (SD = 5.9) participating in the Panel Analysis of Intimate Relationships and Family Dynamics (PAIRFAM). RESULTS: Self-esteem, shyness, and aggressiveness of both partners were related to one's own and one's partner's expectations about parenthood. These expectations were associated with one's own and one's partner's intentions to become a parent, which in turn predicted the couple's actual fertility outcomes. Personality traits of both partners were directly associated with the fertility outcome, with self-esteem of both partners and male aggressiveness predicting the couple's decision to have their first child. The effect of self-esteem on the decision to become a parent was mediated by the partner's intention. CONCLUSIONS: In sum, our findings stress the importance of psychological factors in fertility outcomes and emphasize the role of dyadic processes. PMID- 22925069 TI - Vagal sensory innervation of the gastric sling muscle and antral wall: implications for gastro-esophageal reflux disease? AB - BACKGROUND: The gastric sling muscle has not been investigated for possible sensory innervation, in spite of the key roles the structure plays in lower esophageal sphincter (LES) function and gastric physiology. Thus, the present experiment used tracing techniques to label vagal afferents and survey their projections in the lesser curvature. METHODS: Sprague-Dawley rats received injections of dextran biotin into the nodose ganglia. Fourteen days postinjection, animals were euthanized and their stomachs were processed to visualize the vagal afferent innervation. In different cases, neurons, muscle cells, or interstitial cells of Cajal (ICC) were counterstained. KEY RESULTS: The sling muscle is innervated throughout its length by vagal afferent intramuscular arrays (IMAs) associated with ICC. In addition, the distal antral attachment site of the sling muscle is innervated by a novel vagal afferent terminal specialization, an antral web ending. The muscle wall of the distal antrum is also innervated by conventional IMAs and intraganglionic laminar endings, the two types of mechanoreceptors found throughout stomach smooth muscle. CONCLUSIONS & INFERENCES: The innervation of sling muscle by IMAs, putative stretch receptors, suggests that sling sensory feedback may generate vago-vagal or other reflexes with vagal afferent limbs. The restricted distribution of afferent web endings near the antral attachments of sling fibers suggests the possibility of specialized mechanoreceptor functions linking antral and pyloric activity to the operation of the LES. Dysfunctional sling afferents could generate LES motor disturbances, or normative compensatory sensory feedback from the muscle could compromise therapies targeting only effectors. PMID- 22925071 TI - Subtilisin-like proprotein convertase paired basic amino acid-cleaving enzyme 4 is required for chondrogenic differentiation in ATDC5 cells. AB - Bone morphogenetic proteins (BMPs) have been implicated in the regulation of multiple stages of endochondral bone development. BMPs are synthesized as inactive precursors, and activated by removal of the propeptide. The subtilisin like proprotein convertase (SPC) family comprises seven members [furin/SPC1, PC2/SPC2, PC1/PC3/SPC3, paired basic amino acid-cleaving enzyme 4 (PACE4)/SPC4, PC4/SPC5, PC6/PC5/SPC6, and PC8/PC7/LPC/SPC7], and activates various signaling molecules, including BMPs. In this study, we analyzed the role of this family in chondrogenic differentiation by using the mouse embryonal carcinoma-derived clonal cell line ATDC5. Both SPC-specific inhibitors, decanoyl-Arg-Val-Lys-Arg chloromethylketone and alpha1-antitrypsin Portland variant, suppressed chondrogenic differentiation. RT-PCR analysis revealed that PACE4 mRNA levels increased markedly during chondrogenic differentiation, whereas furin expression remained unchanged. Knockdown of PACE4 expression significantly reduced chondrogenic differentiation. Furthermore, proBMP6, which shows an expression pattern similar to that of PACE4, was efficiently processed into its mature form by PACE4, whereas furin could not process proBMP6. These results suggest that PACE4 may regulate the rate of hypertrophic conversion of ATDC5 cells through activation of proBMP6. PMID- 22925073 TI - Metabolic effects of sulforaphane oral treatment in streptozotocin-diabetic rats. AB - Diabetes has reached epidemic levels in the whole world, and the use of bioactive compounds that may have the capacity to prevent and treat diabetes is of great interest. Sulforaphane (SFN) is a compound which is found in cruciferous vegetables and that acts as both a potent antioxidant and regulator of gene expression. The aim of this study was to evaluate the effect of SFN in diabetes induced by streptozotocin (STZ). Male Wistar rats were gavaged with water or 0.1, 0.25, or 0.5 mg/kg of SFN before an injection of STZ (80 mg/kg). Animals treated with SFN showed fasting glycemia, insulin sensitivity, and hepatic glycogen concentrations, similar to the control group (nondiabetic), and different from the diabetic group. Diabetic animals also presented elevated levels of serum triacylglycerols (TAG), urea, and creatinine, and all SFN doses were able to reverse these alterations. However, the same doses of SFN accentuated alterations in total cholesterol, alanine, and aspartate aminotransferase levels, and had no effect on hepatic TAG, HDL cholesterol, and uptake of 2-deoxy glucose in adipose tissue and soleum muscle. Based on the effects inferred by the present data, SFN presented some positive effects against diabetes induction, although the impairment of hepatic function and cholesterol levels were aggravated after treatment with the compound. PMID- 22925072 TI - Isothiocyanates ameliorate the symptom of heart dysfunction and mortality in a murine AIDS model by inhibiting apoptosis in the left ventricle. AB - Cardiac involvement has been reported in as many as 45-55% of patients with human immunodeficiency virus (HIV) infection and acquired immune deficiency syndrome (AIDS), and significant cardiac morbidity is reported in 6-7% of HIV patients. We investigated the inhibitory effects of isothiocyanates (ITCs) on heart dysfunction and mortality by regulating apoptosis in the left ventricle of the heart in a murine AIDS model. Mice were divided into six groups: an uninfected group, an untreated LP-BM5 retrovirus-infected group, and four LP-BM5 retrovirus infected groups treated with one of four ITCs (sulforaphane [SUL], indolo[3,2 b]carbazole, benzyl isothiocyanate [BITC], or phenethyl isothiocyanate [PEITC]). After 16 weeks, the median survival time of the LP-BM5 retrovirus-infected mice was 87 days, whereas that of the uninfected control group and all ITC treatment groups was over 112 days. SUL, PEITC, and BITC significantly inhibited apoptosis in the left ventricle by increasing the Bcl-2/Bax ratio compared with LP-BM5 infected mice. In addition, SUL and PEITC suppressed inducible nitric oxide synthase (iNOS) expression at both the mRNA and protein levels in the left ventricle of heart tissue infected with the LP-BM5 retrovirus by inactivating cytoplasmic nuclear factor kappaB (NF-kappaB). In conclusion, LP-BM5 retrovirus infection was related to survival of murine AIDS mice, and NF-kappaB-mediated iNOS expression may be an important mediator of left ventricle dysfunction of the heart. Furthermore, certain ITCs may have the potential to improve AIDS-related heart dysfunction due to their inhibition of apoptosis by decreasing iNOS and Bax expression through suppression of NF-kappaB. PMID- 22925074 TI - Evaluation of the efficacy of flaxseed meal and flaxseed extract in reducing menopausal symptoms. AB - The objective of this study was to evaluate the efficacy of flaxseed meal and flaxseed extract in reducing climacteric symptoms of menopausal women. Ninety menopausal women were randomly distributed into three study groups: group I received 1 g per day of flaxseed extract containing at least 100 mg of secoisolariciresinol diglucoside (SDG), group II received 90 g per day of flaxseed meal containing at least 270 mg of SDG, and group III received 1 g per day of collagen (placebo group). Subjects were assessed for menopausal symptoms by the Kupperman index at the beginning and at the end of the 6 months of treatment. Subjects were also assessed for endometrial thickness and vaginal cytology. The Kupperman index values at the beginning and end of the treatments were analyzed using the paired t-test. Both the flaxseed extract (P=.007) and the flaxseed meal (P=.005) were effective in reducing the menopausal symptoms when compared with the placebo control (P=.082). Alternatively, the changes in Kupperman index were also computed and submitted to analysis of variance. In this case, no significant differences were found (P=.084) although the data indicate a decreasing tendency for the Kupperman index by both the flaxseed extract and the flaxseed meal groups. Neither the flaxseed extract nor the flaxseed meal exerted clinically important estrogenic effects on the vaginal epithelium or endometrium as revealed by the absence of changes in the blood levels of follicle stimulating hormone and estradiol, as well as in the endometrial thickness, and vaginal epithelial maturation value. No serious adverse events related to the treatments were reported. Although the results of the present study do not allow an unequivocal conclusion about the action of flaxseed on the menopausal symptoms, they suggest that it could be premature to conclude that no such action exists. Clearly the matter still deserves further experimental attention. PMID- 22925077 TI - Premorbid warfarin use and lower D-dimer levels are associated with a spontaneous early improvement in an atrial fibrillation-related stroke. PMID- 22925075 TI - ROCKs as immunomodulators of stroke. AB - INTRODUCTION: Stroke is the third leading cause of death and a major cause of long-term disability in the adult population. Growing evidence suggests that inflammation may play an important role in the evolution of stroke. Because Rho associated coiled-coil containing kinases (ROCKs) are important mediators of inflammation, they may contribute to stroke and stroke recovery. AREAS COVERED: The pathophysiological role of ROCKs in mediating inflammation at different phases of stroke, and the therapeutic opportunities for stroke prevention and stroke treatment with ROCK inhibitors will be discussed. EXPERT OPINION: Inflammation is a double-edged sword during the evolution of stroke. Immunomodulation might provide a novel therapeutic approach for stroke prevention and stroke treatment. ROCK plays an important role in mediating the inflammatory response following vascular injury as well as platelet activation and thrombus formation. ROCK inhibitors have been shown to be beneficial in stroke prevention, acute neuroprotection and chronic stroke recovery by affecting inflammatory mediated platelet and endothelial function, smooth muscle contraction and neuronal regeneration. Thus, ROCK-mediated inflammation could be a potential therapeutic target for stroke prevention and stroke treatment. However, the mechanism by which ROCKs regulate the inflammatory response is unclear, and the role of the two ROCK isoforms in stroke and stroke recovery remains to be determined. PMID- 22925076 TI - Developmental dynamics of emotion and cognition processes in preschoolers. AB - Dynamic relations during the preschool years across processes of control and understanding in the domains of emotion and cognition were examined. Participants were 263 children (42% non-White) and their mothers who were seen first when the children were 3 years old and again when they were 4. Results indicated dynamic dependence among the processes studied. Specifically, change in cognitive processes of control and understanding were dependent upon initial levels of the other processes. Changes in emotion control and understanding were not predicted by earlier performance in the other processes. Findings are discussed with regard to the constructs of control and understanding and the developmental interrelations among emotion and cognitive processes. PMID- 22925078 TI - Fatal meningitis during pregnancy in the Netherlands: a nationwide confidential enquiry. AB - OBJECTIVE: To determine the incidence of maternal deaths attributable to meningitis in the Netherlands, and to assess clinical features and risk factors. DESIGN: Confidential enquiry into the causes of maternal deaths. SETTING: Nationwide in the Netherlands. POPULATION: A total of 4 784 408 live births. METHODS: Analysis of all maternal deaths due to meningitis in pregnancy and puerperium from 1983 up to and including 2007 reported to the Maternal Mortality Committee of the Dutch Society of Obstetrics and Gynaecology. MAIN OUTCOME MEASURES: Incidence, clinical features and risk factors. RESULTS: Fifteen maternal deaths occurred due to meningitis, representing 4.4% of all maternal deaths. Twelve women (80%) presented with meningitis during pregnancy, 8 (66%) of them in the third trimester. Presenting symptoms were altered mental status (11; 73%), fever (9; 60%), nuchal rigidity (5; 33%) and headache (13; 87%). Nine women (60%) had otolaryngological infection at presentation or in the previous days or weeks. Twelve women (80%) underwent radiological examination, of which 5 (33%) showed distinct abnormalities. Cerebrospinal fluid (CSF) examination showed infected CSF in 8 (53%) women. In ten women (67%) Streptococcus pneumoniae was isolated. Substandard care was identified in 4 (27%) women. CONCLUSION: Pregnant or puerperal women presenting with classical symptoms of meningitis, particularly those with a history of otolaryngological infection or headache, should undergo thorough investigation and radiological and CSF examinations. Early diagnosis and immediate antibiotic treatment are imperative because of rapid deterioration in pregnant women. In case of doubt, the threshold for antibiotic treatment should be low and close monitoring is warranted. PMID- 22925079 TI - P-glycoprotein and multidrug resistance-associated protein 2 are oppositely altered in brain of rats with thioacetamide-induced acute liver failure. AB - BACKGROUND: P-glycoprotein (P-GP) and multidrug resistance-associated protein 2 (MRP2) are involved in transport of many drugs across blood-brain barrier (BBB). The function and expression of P-GP and MRP2 may be modulated by different pathologies. Acute liver failure (ALF) was reported to impair BBB function, resulting in the increased BBB permeability. AIMS: We investigated whether ALF altered function and expression of P-GP and MRP2 in brain of thioacetamide induced ALF rats. METHODS: ALF was induced by intraperitoneal injection of thioacetamide (300 mg/kg) for 2 days with a 24-h interval. The rats were used for experiments at 6, 12 and 24 h after the second administration. P-GP and MRP2 function in brain were determined using the brain-to-plasma ratios of corresponding substrates (rhodamine 123 and vincristine for P-GP; sulfobromophthalein and dinitrophenyl-S-glutathione for MRP2). Evans blue was used for examining the BBB integrity. Western blot was accomplished to determine P-GP and MRP2 protein expression. RESULTS: The brain-to-plasma ratios of rhodamine 123 and vincristine were significantly increased in ALF-6 h rats and almost returned to normal levels in ALF-24 h rats, whereas those of sulfobromophthalein and dinitrophenyl-S-glutathione were decreased in all ALF rats. Western blot results showed that ALF decreased brain P-GP levels at 6 and 12 h, whereas increased MRP2 levels at 6, 12 and 24 h. No significant difference of Evans blue concentrations in brain was found among the four groups. CONCLUSIONS: Function and expression of P-GP and MRP2 in brain of thioacetamide induced ALF rats were oppositely altered. PMID- 22925080 TI - Unifying cornerstones of sexual selection: operational sex ratio, Bateman gradient and the scope for competitive investment. AB - What explains variation in the strength of sexual selection across species, populations or differences between the sexes? Here, we show that unifying two well-known lines of thinking provides the necessary conceptual framework to account for variation in sexual selection. The Bateman gradient and the operational sex ratio (OSR) are incomplete in complementary ways: the former describes the fitness gain per mating and the latter the potential difficulty of achieving it. We combine this insight with an analysis of the scope for sexually selected traits to spread despite naturally selected costs. We explain why the OSR sometimes does not affect the strength of sexual selection. An explanation of sexual selection becomes more logical when a long 'dry time' ('time out', recovery after mating due to e.g. parental care) is understood to reduce the expected time to the next mating when in the mating pool (i.e. available to mate again). This implies weaker selection to shorten the wait. An integrative view of sexual selection combines an understanding of the origin of OSR biases with how they are reflected in the Bateman gradient, and how this can produce selection for mate acquisition traits despite naturally selected costs. PMID- 22925082 TI - A 3-year-old boy with drug-resistant complex partial seizures. PMID- 22925081 TI - Dose-dependent effects of prefrontal dopamine on behavioral state in rats. AB - An inverted-U mechanism has been proposed to explain findings that both under- and overstimulation of dopamine (DA) receptors in medial prefrontal cortex (mPFC) result in working memory impairments. Dopamine release in the mPFC is also associated with the mediation of other behavioral processes such as affective regulation, reward, and nociception. The present studies investigated mPFC DA dose-dependent effects on the performance of tasks that tap these other processes, including delayed alternation in the T maze for working memory, a water maze task for escape, the elevated plus maze for anxiolytic/anxiogenic effects, place preference conditioning for reward effects, the tail flick test for nociception, and a measure of locomotor activity for general arousal. Injection of 5 MUg of DA improved working memory, was anxiolytic in the plus maze, and increased pain sensitivity, but did not have any effects on water maze escape, place preference or locomotor activity. Doses of 10 MUg and 20 MUg impaired working memory and substantially decreased pain sensitivity, but did not affect plus maze behavior or locomotor activity. The 20-MUg dose also enhanced water maze escape. Taken together, these findings suggest a profile of two distinct behavioral states induced by low or high levels of mPFC DA: a low level facilitates foraging functions such as working memory and exploratory behaviors, with increased pain sensitivity, while higher levels facilitate stress-related adaptations, such as escape from threat and reduced pain sensitivity. These findings are concordant with behavioral flexibility views of mPFC DA functions. PMID- 22925083 TI - 49-year-old transplant recipient with fever and altered mental status. PMID- 22925084 TI - A 71-year-old woman with PSP-like symptoms. PMID- 22925085 TI - Incidental neuropathological findings in a child with cervical meningoradiculocele. PMID- 22925086 TI - Lessons from the berlioz requiem. PMID- 22925087 TI - Change process during synchronised conversion to a once-monthly erythropoiesis stimulating agent (ESA) administration at a single satellite haemodialysis unit. AB - BACKGROUND: There are currently no published data on the impact of changes to practice caused by introducing coordinated once-monthly erythropoiesis stimulating agent (ESA) administration. OBJECTIVE: This study aimed to measure staff satisfaction during and after ESA synchronisation within a single satellite haemodialysis unit. DESIGN: A quantitative survey using a Likert scale was distributed to dialysis nurses pre-synchronisation and during follow-up at three and nine months post-synchronisation. Secondary outcomes included monitoring of haemoglobin (Hb) levels. RESULTS: A total of 19 respondents completed the surveys. By nine months post-synchronisation, most nurses responded that ESA synchronisation was not a time-consuming task, did not increase their workload, had saved them time and was simpler for the unit. Additionally, most nurses reported that they had coped well with the change and that they wanted ESA synchronisation to be permanently introduced. At 8 months post-synchronisation, 53.3% of patients had an Hb level > 11 g/dl and < 12 g/dl. CONCLUSION: Changes to practice resulting from ESA synchronisation did not appear to negatively impact nurse workplace satisfaction. PMID- 22925088 TI - Osteotome sinus floor elevation with and without grafting material in the severely atrophic maxilla. A 1-year prospective randomized controlled study. AB - OBJECTIVES: (1) To measure and compare endo-sinus bone levels around implants randomly placed with an osteotome sinus floor elevation (OSFE) procedure in grafted (control) and non-grafted (test) sinuses, (2) to evaluate the OSFE efficacy with short, tapered, and chemically modified hydrophilic surfaced implants in extremely atrophic maxillae, (3) to show that fused corticals may constitute a complication risk. MATERIAL AND METHODS: The TE((r)) SLActive 8 mm long implants (Straumann AG) were placed using an OSFE procedure in 4 mm or less of bone height. Healing time before prosthetic rehabilitation was 10 weeks. One year after implant placement, bone levels were measured on standardized periapical radiographs. RESULTS: Thirty-seven (17 tests, 20 controls) implants were placed in 12 patients with a mean maxillary residual bone height (RBH) of 2.4 +/- 0.9 mm. Before loading, two control implants failed (RBH 1.4 and 1.2 mm); two others rotated at loading (one test, RBH 0.9 mm; one control, RBH 1.5 mm) but were uneventfully loaded after three additional months of healing. These adverse events and complications occurred when implants were placed in merged corticals. Endo-sinus bone gain was 3.9 +/- 1.0 and 5.0 +/- 1.3 mm for the test and control groups (P = 0.003). The 1-year success rate was 100% and 90%, respectively (P = 0.49). CONCLUSION: Although more bone is gained when grafting material is used, this may not be required to promote endo-sinus bone gain. The OSFE procedure with or without grafting material could be efficient when the RBH is <= 4 mm. However, when both corticals merged, the risk of complication could increase. PMID- 22925089 TI - Application of Variable Life Adjusted Displays (VLAD) on Victorian Admitted Episodes Dataset (VAED). AB - BACKGROUND: The need to improve patient safety has been identified as a major priority for health reform in developed countries, including Australia. We investigated the implementation and appropriateness of Variable Life Adjusted Displays as a quality control procedure to monitor "in-control" versus "out-of control" processes in Victorian public hospitals. METHODS: Victorian Admitted Episode Data from Department of Human Services, Victoria for 2004-7 were used. The VLAD is a plot of a cumulative sum of the difference in expected outcome (range 0-1) and observed outcome (0 or 1) for sequential separations. Three outcomes were assessed: in-hospital mortality for acute myocardial infarction, stroke and heart failure. Logistic regression was used to obtain a realistic measure of expected mortality over the period 2004-5, adjusting for covariates and comorbidities, to estimate expected mortality risk for the separations between 2005-7. VLAD were plotted for the years 2005-7, by the 11 hospitals with the highest frequency of separations. Signalling limits for 30%, 50% and 75% risk decrease and risk increase were determined and plotted for each VLAD utilizing risk-adjusted cumulative sum techniques. This is a likelihood-ratio test statistic for signalling. If the VLAD signalled by intersecting with a limit, the limit was reset. RESULTS: The three logit models displayed reasonable fit to the observed data. There were n = 2999 separations in the AMI model, n = 3598 in the HF model and n = 1922 in the stroke model. The number of separations plotted by VLAD ranged from n = 126 to n = 648. No signals were observed in 64%, 55% and 18% of VLAD for AMI, HF and stroke respectively. For AMI and HF 9% of hospitals signalled at least once for each of 30%, 50% and 75% risk increase, whereas this was 45% for stroke. Hospitals signalling at least once for risk decrease ranged from 18% to 36% across the levels of risk and outcomes. No VLAD signalled for both risk decrease and increase. CONCLUSIONS: VLAD intersecting with limits to signal "out-of-control" states, may be an appropriate technique to help hospitals assess quality control. Preliminary work displays some between hospital differences. Relevant signals can be used to investigate why a system is potentially performing better than or worse than expected. Types and levels of investigation could depend on the type of signalling. Validation work, for example attempting to correlate signals with clinical notes, prior to VLAD distribution needs to be undertaken. PMID- 22925092 TI - An evidence-based approach to the 12-min consultation for a child with Down's syndrome. AB - BACKGROUND: Down's syndrome is the commonest genetic condition. ENT problems are common in these children and can affect their development and quality of life. METHOD: English literature review and experience of the senior author in managing ENT problems in children and adults with Down's syndrome. SEARCH STRATEGY: We carried out a Medline search on 31/03/2012 of English language publications using the following keywords: Down/Down's syndrome, hearing loss, ear infections, sleep apnoea, thyroid. RESULTS: The prevalence, presenting features and management of many common ENT conditions are significantly different in children who have Down's syndrome. This is particularly true of otitis media with effusion and sleep-disordered breathing. CONCLUSION: The outpatient consultation for a child with Down's syndrome should assess a range of specific ENT problems affecting this patient group including hearing issues, sleep-disordered breathing, recurrent upper respiratory tract infections, as well as other health conditions like hypothyroidism, atlantoaxial instability and cardiac issues, which can potentially affect the management of the patient. PMID- 22925094 TI - Superior semicircular canal syndrome should be searching for an alternative pathology. PMID- 22925095 TI - First year with WHO Surgical Safety Checklist in 7148 otorhinolaryngological operations: use and user attitudes. PMID- 22925096 TI - Effectiveness of chitosan-based packing in 35 patients with recalcitrant epistaxis in the context of coagulopathy. PMID- 22925097 TI - Severe benign hypopharynx/upper-oesophageal strictures: successful treatment with a novel interventional radiology technique in three patients. PMID- 22925098 TI - The paediatric voice clinic: our experience of 81 children referred over 28 months. PMID- 22925099 TI - Sphenopalatine, anterior ethmoid and internal maxillary artery intervention in the management of refractory epistaxis: their efficacy in 25 patients. PMID- 22925100 TI - Staging primary middle ear cholesteatoma with non-echoplanar (half-Fourier acquisition single-shot turbo-spin-echo) diffusion-weighted magnetic resonance imaging helps plan surgery in 22 patients: our experience. PMID- 22925102 TI - Re: An evidence-based review of the assessment and management of penetrating neck injuries. PMID- 22925103 TI - Re: Meniere's disease and driving. PMID- 22925104 TI - Immediate autologous fat graft augmentation rhinoplasty after removal of extruding or infected silicone implant. PMID- 22925105 TI - Structural confirmation of oligosaccharides newly isolated from sugar beet molasses. AB - BACKGROUND: Sugar beet molasses is a viscous by-product of the processing of sugar beets into sugar. The molasses is known to contain sucrose and raffinose, a typical trisaccharide, with a well-established structure. Although sugar beet molasses contains various other oligosaccharides as well, the structures of those oligosaccharides have not been examined in detail. The purpose of this study was isolation and structural confirmation of these other oligosaccharides found in sugar beet molasses. RESULTS: Four oligosaccharides were newly isolated from sugar beet molasses using high-performance liquid chromatography (HPLC) and carbon-Celite column chromatography. Structural confirmation of the saccharides was provided by methylation analysis, matrix-assisted laser desorption/ionaization time of flight mass spectrometry (MALDI-TOF-MS), and nuclear magnetic resonance (NMR) measurements. CONCLUSION: The following oligosaccharides were identified in sugar beet molasses: beta-D-galactopyranosyl (1- > 6)-beta-D-fructofuranosyl-(2 <-> 1)-alpha-D-glucopyranoside (named beta planteose), alpha-D-galactopyranosyl-(1- > 1)-beta-D-fructofuranosyl-(2 <-> 1) alpha-D-glucopyranoside (named1-planteose), alpha-D-glucopyranosyl-(1- > 6)-alpha D-glucopyranosyl-(1 <-> 2)-beta-D-fructofuranoside (theanderose), and beta-D glucopyranosyl-(1- > 3)-alpha-D-glucopyranosyl-(1 <-> 2)-beta-D-fructofuranoside (laminaribiofructose). 1-planteose and laminaribiofructose were isolated from natural sources for the first time. PMID- 22925106 TI - Somatostatin varicosities contain the vesicular GABA transporter and contact orexin neurons in the hypothalamus. AB - Somatostatin (SST) is a neuropeptide with known inhibitory actions in the hypothalamus, where it inhibits release of growth hormone-releasing hormone (GHRH), while also influencing the sleep-wake cycle. Here we investigated in the rat whether SST neurons might additionally release GABA (gamma-aminobutyric acid) or glutamate in different regions and whether they might contact orexin neurons that play an important role in the maintenance of wakefulness. In dual immunostained sections viewed by epifluorescence microscopy, we examined if SST varicosities were immunopositive for the vesicular transporter for GABA (VGAT) or glutamate (VGLUT2) in the posterolateral hypothalamus and neighboring arcuate nucleus and median eminence. Of the SST varicosities in the posterolateral hypothalamus, 18% were immunopositive for VGAT, whereas <= 1% were immunopositive for VGLUT2. In the arcuate and median eminence, 26 and 64% were VGAT+ and < 3% VGLUT2 + , respectively. In triple-immunostained sections viewed by epifluorescence and confocal microscopy, SST varicosities were seen in contact with orexin somata, and of these varicosities, a significant proportion (23%) contained VGAT along with synaptophysin, the presynaptic marker for small synaptic vesicles, and a similar proportion (25%) abutted puncta that were immunostained for gephyrin, the postsynaptic marker for GABAergic synapses. Our results indicate that a significant proportion of SST varicosities in the hypothalamus have the capacity to release GABA, to form inhibitory synapses upon orexin neurons, and accordingly through their peptide and/or amino acid, to inhibit orexin neurons, as well as GHRH neurons. Thus while regulating GHRH release, SST neurons could serve to attenuate arousal and permit progression through the sleep cycle. PMID- 22925107 TI - Reasons rural Laotians choose home deliveries over delivery at health facilities: a qualitative study. AB - BACKGROUND: Maternal mortality among poor rural women in the Lao People's Democratic Republic (Lao PDR) is among the highest in Southeast Asia, in part because only 15% give birth at health facilities. This study explored why women and their families prefer home deliveries to deliveries at health facilities. METHODS: A qualitative study was conducted from December 2008 to February 2009 in two provinces of Lao PDR. Data was collected through eight focus group discussions (FGD) as well as through in-depth interviews with 12 mothers who delivered at home during the last year, eight husbands and eight grandmothers, involving a total of 71 respondents. Content analysis was used to analyze the FGD and interview transcripts. RESULTS: Obstacles to giving birth at health facilities included: (1) Distance to the health facilities and difficulties and costs of getting there; (2) Attitudes, quality of care, and care practices at the health facilities, including a horizontal birth position, episiotomies, lack of privacy, and the presence of male staff; (3) The wish to have family members nearby and the need for women to be close to their other children and the housework; and (4) The wish to follow traditional birth practices such as giving birth in a squatting position and lying on a "hot bed" after delivery. The decision about where to give birth was commonly made by the woman's husband, mother, mother-in-law or other relatives in consultation with the woman herself. CONCLUSION: This study suggests that the preference in rural Laos for giving birth at home is due to convenience, cost, comfort and tradition. In order to assure safer births and reduce rural Lao PDR's high maternal mortality rate, health centers could consider accommodating the wishes and traditional practices of many rural Laotians: allowing family in the birthing rooms; allowing traditional practices; and improving attitudes among staff. Traditional birth attendants, women, and their families could be taught and encouraged to recognize the signs of at-risk pregnancies so as to be able to reach health facilities on time. PMID- 22925108 TI - PPARalpha as a therapeutic target in inflammation-associated diseases. AB - INTRODUCTION: The nuclear receptor peroxisome proliferator-activated receptor alpha (PPARalpha) plays a major regulatory function of genes involved in energy metabolism and is a therapeutic target for dyslipidemia. The last decade provided a constellation of findings demonstrating that PPARalpha behaves as a modulator of both acute and chronic inflammation. PPARalpha became a rational potential therapeutic target for the treatment of inflammatory disorders. AERAS COVERED: The ability of PPARalpha to control inflammatory signaling pathways via a diversity of molecular mechanisms is discussed. This review is especially focused on the global action of PPARalpha on inflammation in several tissues from data obtained in numerous cell types and in vivo models exposed to inflammatory stimuli. EXPERT OPINION: Available PPARalpha agonists currently used in clinic belong to the class of hypolipidemic drugs but were not expected and not designed to act as anti-inflammatory drugs. To date, accumulating preclinical suggest evidence promising benefits when considering PPARalpha as a drug target to treat inflammatory disorders. However, clinical studies are needed to validate this concept. Drug design should also be directed toward the elaboration of PPARalpha agonists more specifically active in the control inflammatory signaling. PMID- 22925109 TI - Total situs inversus found coincidentally following a firearm injury. AB - Situs inversus totalis is very rare and usually diagnosed coincidentally as it does not affect the patient's life. Being unaware of the patient's condition can lead to undesirable results from the surgeon and patient's point of view when an emergency and forensic surgical intervention is required. We present a case who was operated on urgently for a firearm injury after receiving a preoperative diagnosis of situs inversus totalis. In conclusion, situs inversus totalis can cause difficulties for surgeons in case of emergency surgery and is usually diagnosed coincidentally. There are a few cases of situs inversus with lung cancer in the literature but this is the first time a case with a firearm injury has been reported. PMID- 22925111 TI - Expression of endothelial nitric oxide synthase in the uterus of patients with leiomyoma or adenomyosis. AB - AIM: To confirm the difference in the expression of endothelial nitric oxide synthase in the normal endometrium and myometrium of women who have leiomyoma or adenomyosis compared with controls, and its correlation with the pathogenesis of menorrhagia or dysmenorrhea in patients with uterine leiomyoma. METHODS: Fifty one hysterectomized patients were divided into three groups: (i) patients with leiomyoma (n=24); (ii) those with adenomyosis (n = 19); and (iii) the control group (n=8). The expression of endothelial nitric oxide synthase was confirmed on immunohistochemistry and analyzed using an evaluation nomogram. RESULTS: The expression of endothelial nitric oxide synthase was significantly higher in the leiomyoma group and the adenomyosis group as compared with the control group. In the subgroup analysis of leiomyoma depending on symptoms (menorrhagia or dysmenorrhea or both), the expression of endothelial nitric oxide synthase was significantly higher in the symptomatic subgroup than the asymptomatic subgroup (endometrium P=0.0029, myometrium P=0.0276). CONCLUSIONS: Based on the findings that the expression of endothelial nitric oxide synthase was significantly higher in the uterus with leiomyoma or adenomyosis, it can therefore be inferred that nitric oxide might have a pathological effect on the uterus with the above diseases. In particular, it is also presumed that endothelial nitric oxide synthase is closely associated with menorrhagia and dysmenorrhea. PMID- 22925110 TI - A reproducible oral microcosm biofilm model for testing dental materials. AB - AIMS: Most studies of biofilm effects on dental materials use single-species biofilms, or consortia. Microcosm biofilms grown directly from saliva or plaque are much more diverse, but difficult to characterize. We used the Human Oral Microbial Identification Microarray (HOMIM) to validate a reproducible oral microcosm model. METHODS AND RESULTS: Saliva and dental plaque were collected from adults and children. Hydroxyapatite and dental composite discs were inoculated with either saliva or plaque, and microcosm biofilms were grown in a CDC biofilm reactor. In later experiments, the reactor was pulsed with sucrose. DNA from inoculums and microcosms was analysed by HOMIM for 272 species. Microcosms included about 60% of species from the original inoculum. Biofilms grown on hydroxyapatite and composites were extremely similar. Sucrose pulsing decreased diversity and pH, but increased the abundance of Streptococcus and Veillonella. Biofilms from the same donor, grown at different times, clustered together. CONCLUSIONS: This model produced reproducible microcosm biofilms that were representative of the oral microbiota. Sucrose induced changes associated with dental caries. SIGNIFICANCE AND IMPACT OF THE STUDY: This is the first use of HOMIM to validate an oral microcosm model that can be used to study the effects of complex biofilms on dental materials. PMID- 22925112 TI - The comparison of fluoroquinolones to nonfluoroquinolone antibacterial agents for the prevention of endophthalmitis in a rabbit model. AB - PURPOSE: Topical antibacterial agents, used as an off-label indication, are frequently administered pre- and postoperatively to prevent endophthalmitis. We compared topical treatment with fluoroquinolone (FQ) anti-infectives to non-FQ antibacterial agents to prevent Staphylococcus aureus endophthalmitis. We hypothesize that FQ anti-infectives are more effective than non-FQ antibacterial agents for preventing endophthalmitis. METHODS: Moxifloxacin 0.5%, ofloxacin 0.3%, gentamicin 0.3%, chloramphenicol 0.5%, polymyxin B/trimethoprim (10,000 units/mL/0.1%), povidone-iodine 5%, and saline were tested for topical treatment to prevent endophthalmitis. Topical treatment was applied every 15 min for 1 h (5 drops) to the left eye of 14 rabbits for each antibacterial agent and saline. After appropriate anesthesia, the anterior chambers were injected with 1*10(5) colony-forming units of a clinical endophthalmitis isolate of a S. aureus that was susceptible to all tested antibacterials. One drop was administered immediately and another 4 drops of topical treatment were applied over 24 h after injection. At 24 h postinjection, the eyes were graded for clinical signs of endophthalmitis (ocular discharge, conjunctivitis/scleral injection, limbal injection, hypopyon*, iritis*, anterior chamber cells*, anterior chamber flare*, corneal infiltration, and fibrin production*) using a severity scale (0-3). The indication of clinical endophthalmitis was a total score of >3.0 for the presentations marked with an asterisk. The data were analyzed using Fisher's Exact Randomization or Mann-Whitney nonparametric testing. RESULTS: Topical ofloxacin (14/14, 100% without endophthalmitis) and moxifloxacin (13/14, 93%) prevented the clinical presentation of endophthalmitis significantly more frequently (P=0.03, Fisher's Exact Test (FE)) than topical gentamicin (7/14, 50%), povidone iodine (4/14, 29%), chloramphenicol (0/14, 0%), polymyxin B/trimethoprim (0/14, 0%), and saline (0/14, 0%). The median total clinical scores for the ofloxacin (0.5) and moxifloxacin (0.8) groups were significantly (P=0.008, Mann-Whitney Test (MW)) lower than gentamicin (5.7), chloramphenicol (17.5), polymyxin B/trimethoprim (21.2), povidone-iodine (15.5), and saline (18.7). CONCLUSIONS: The FQs, ofloxacin and moxifloxacin, were more effective in preventing endophthalmitis than the non-FQ antibacterial agents in a rabbit S. aureus endophthalmitis model. The observed results are consistent with the hypothesis that FQs penetrate into the anterior chamber at more effective levels than many of the common non-FQ antibacterial agents. PMID- 22925113 TI - The efficacy of intravitreal bevacizumab for acute central serous chorioretinopathy. AB - PURPOSE: To investigate the efficacy of intravitreal bevacizumab injection in patients with acute central serous chorioretinopathy (CSCR). METHODS: Between 6 weeks and 3 months, 13 eyes of 22 patients with acute CSCR received an intravitreal bevacizumab injection (2 mg/0.08 mL), 9 eyes had no medical treatment as a control. At baseline and follow-up visits patients had best corrected visual acuity (BCVA), intraocular pressure assessment, dilated fundus examination, and spectral optical coherence tomography imaging. Outcome measures were the resolution of neurosensory detachment, improvement in visual acuity, and symptoms. RESULTS: All patients showed prompt improvements of visual acuity and symptoms until the 3rd month and recovered from neurosensory detachment gradually following treatment in the study group. The vision of control subjects recovered later and the regression of serous retinal detachments were fairly slow. The mean BCVA improved from 0.39+/-0.16 at first visit (at baseline) to 0.73+/-0.17 at the 6th month in the study group; and, from 0.25+/-0.17 at first visit (at baseline) to 0.67+/-0.13 at the 6th month in the control group that was statistically significant (P=0.0001; P=0.0001, respectively). Mean retinal thickness for the study group was decreased from 414.38+/-102.79 at first visit (at baseline) to 256.46+/-84.77 at the 3rd month and 198.30+/-29.81 at the 6th month (P=0.0001, P=0.0001); and that for the control group was decreased from 510.33+/-80.59 at first visit (at baseline) to 336.33+/-127.83 at the 3rd month and 205.66+/-19.65 at the 6th month (P=0.004, P=0.0001, respectively). One of the patients in the control group revealed recurrence at the 6th month and the patient was given intravitreal injection of bevacizumab. CONCLUSION: Intravitreal bevacizumab injection for acute CSCR can lead to remarkable improvements of visual acuity within 3 months follow-up compared with controls. These results demonstrated that intravitreal bevacizumab injection may be a promising option for selected patients in the treatment of acute CSCR. PMID- 22925114 TI - Colorectal distension-evoked potentials in awake rats: a novel method for studies of visceral sensitivity. AB - BACKGROUND: Quantification of the visceromotor response induced by colorectal distension (CRD) in rodents is commonly used for preclinical studies of visceral pain. The model is well established but does not fully assess the central response to stimulation. The aim of this study was to establish a novel model assessing cerebral evoked potentials (CEPs) in response to CRD in awake rats. METHODS: Epidural recording electrodes were chronically implanted in the skull of female Sprague-Dawley rats. Colorectal distension-induced CEPs were recorded using either rapid balloon distensions (100 ms, 20-80 mmHg) or electric stimulation (1 ms, 1-4 mA) using stimulation probes placed in the distal colon. KEY RESULTS: Colorectal distension-induced CEPs were separated in three partly temporally overlapping components consisting of five prominent peaks. Peak latencies at 80 mmHg were (P1, N1) 23 +/- 1 and 55 +/- 4 ms, (N2, P2a, P2b) 91 +/ 3, 143 +/- 5 and 174 +/- 3 ms, and (P3) 297 +/- 3 ms. Amplitudes and latencies were, except for the early component, intensity dependent. Intrarectal administration of lidocaine significantly reduced the amplitude of N2 (by 42 +/- 6%, P < 0.001) and P2 (by 34 +/- 6%, P < 0.001). Electrically induced CEPs were intensity dependent and had similar topography and latencies as the mechanical evoked potentials (P1: 26 +/- 2 ms; N1: 61 +/- 1 ms; P2: 84 +/- 6 ms; N2: 154 +/- 6 ms; P3: 326 +/- 10 ms), but there were large variations in amplitudes in between repeated electrical stimulations. CONCLUSIONS & INFERENCES: Colorectal distension-induced CEPs can be recorded reliably in awake rats and may serve as a surrogate marker of colonic sensation and be a useful parameter in studies of visceral sensitivity. PMID- 22925115 TI - Fibrinolytic activity in cerebrospinal fluid of dogs with different neurological disorders. AB - BACKGROUND: Fibrinolytic activity in cerebrospinal fluid (CSF) is activated in humans by different pathologic processes. OBJECTIVES: To investigate fibrinolytic activity in the CSF of dogs with neurological disorders by measuring CSF D-dimer concentrations. ANIMALS: One hundred and sixty-nine dogs with neurological disorders, 7 dogs with systemic inflammatory diseases without central nervous system involvement (SID), and 7 healthy Beagles were included in the study. Dogs with neurological disorders included 11 with steroid-responsive meningitis arteritis (SRMA), 37 with other inflammatory neurological diseases (INF), 38 with neoplasia affecting the central nervous system (NEO), 28 with spinal compressive disorders (SCC), 15 with idiopathic epilepsy (IE), and 40 with noninflammatory neurological disorders (NON-INF). METHODS: Prospective observational study. D dimers and C-reactive protein (CRP) were simultaneously measured in paired CSF and blood samples. RESULTS: D-dimers and CRP were detected in 79/183 (43%) and in 182/183 (99.5%) CSF samples, respectively. All dogs with IE, SID, and controls had undetectable concentrations of D-dimers in the CSF. CSF D-dimer concentrations were significantly (P < .001) higher in dogs with SRMA than in dogs with other diseases and controls. CSF CRP concentration in dogs with SRMA was significantly (P < .001) higher than in dogs of other groups and controls, except for the SID group. No correlation was found between blood and CSF D-dimer concentrations. CONCLUSIONS AND CLINICAL IMPORTANCE: Intrathecal fibrinolytic activity seems to be activated in some canine neurological disorders, and it is high in severe meningeal inflammatory diseases. CSF D-dimer concentrations may be considered a diagnostic marker for SRMA. PMID- 22925116 TI - Supramolecular immobilization of redox enzymes on cyclodextrin-coated magnetic nanoparticles for biosensing applications. AB - Mono-6-formyl-beta-cyclodextrin moieties were attached to (3 aminopropyl)triethoxysilane-coated superparamagnetic Fe(3)O(4) nanoparticles by reductive alkylation with NaBH(3)CN. The oligosaccharide-capped core-shell nanoparticles were employed as support for the supramolecular immobilization of two different adamantane-modified enzymes, tyrosinase and xanthine oxidase, through host-guest interactions. The enzyme-modified nanomaterial was further used to magnetically modify carbon paste electrodes for constructing amperometric biosensors toward cathecol and xanthine. The tyrosinase and xanthine oxidase based biosensors showed excellent electroanalytical behaviours, with linear ranges of 100 nM-12 MUM cathecol and 5.0-120 MUM xanthine, sensitivities of 12 mA/M and 130 mA/M, and low detection limits of 22 nM and 2.0 MUM, respectively. The supramolecular nature of the immobilization approach was confirmed by electroanalytical methods. PMID- 22925117 TI - A one-step process for oil-in-water-in-oil double emulsion formation using a single surfactant. AB - A one-step double emulsification protocol using one surfactant was developed for oil-in-water-in-oil (O(1)/W/O(2)) double emulsions. Two n-alkane oils and three different surfactants were studied, with focus placed on a formulation containing mineral oil, glycerol monoleate (GMO) and deionized water. Phenomenologically, double emulsion formation and stability originate from the combined actions of phase inversion and interfacial charging of the oil/water interface during high shear homogenization. Based on the extent of double emulsion formation and stability, a critical emulsification zone dependent on the weight ratios of GMO to water was identified. Within this critical zone, enhanced O(1)/W/O(2) emulsion formation occurred at higher pH and lower salt concentrations, demonstrating the key role of interfacial charging on double emulsification. Overall, this novel approach provides a novel platform for the development of double emulsions with simple compositions and processing requirements. PMID- 22925118 TI - Effects of tethering alkyl chains for amphiphilic ruthenium complex dyes on their adsorption to titanium oxide and photovoltaic properties. AB - Ruthenium (II) complex dye, Ru(4,4'-dicarboxyl-2,2'-bipyridine)(4-nonyl-2,2' bipyridine) (NCS)(2), (denoted as RuC9) tethering single alkyl chain was synthesized and well characterized. Its adsorption behavior onto the mesoporous TiO(2) and photovoltaic properties were compared with Z907 which has similar chemical structure but tethers two alkyl chains. RuC9 dyes tend to aggregate into vesicles in the acetonitrile/t-butanol co-solvent as a result of the amphiphilic structure, whereas Z907 dyes aggregate into lamellae. The dye-sensitized solar cell (DSSC) with RuC9 dye showed higher short-circuit photocurrent than that with Z907, attributing to its higher molar optical extinction coefficient and more adsorption amount onto the mesoporous TiO(2). However, the DSSC with Z907 dye has higher open-circuit photovoltage and power conversion efficiency, presumably due to the fact that Z907 with more alkyl chains formed a molecular layer with higher hydrophobicity. It reduced the charge recombination in the interface between the dye-sensitized mesoporous TiO(2) and electrolyte as verified by the electrochemical impedance spectroscopy and intensity modulated photocurrent and photovoltage spectroscopies. PMID- 22925119 TI - Conductivity in nonpolar media: experimental and numerical studies on sodium AOT hexadecane, lecithin-hexadecane and aluminum(III)-3,5-diisopropyl salicylate hexadecane systems. AB - The conductivity behavior of doped hydrocarbon systems is studied by applying impedance spectroscopy. In the case of 3,5-diisopropyl salicylato aluminum (III) the charge carriers are formed by dissociation of the compound and their concentration is proportional to the square root of the solute concentration. In hydrocarbon systems that consist of micelle forming compounds (sodium AOT/ lecithin) a linear dependence of charge carrier concentration on solute concentration is observed in the concentration regime where micelles are present. The conduction mechanisms are studied by numerical solution of a Poisson-Nernst Planck system that describes the charge transport. We follow two different approaches to extract the degree of micelle dissociation from the impedance data. Firstly, by computing the response of a linear approximation of the Poisson Nernst-Planck model, and secondly by computing the fully nonlinear response from direct numerical simulations using finite elements. For high and moderate frequencies both approaches agree very well with the experimental data. For small frequencies the response becomes nonlinear and the concept of impedance fails. Furthermore, the numerically computed values for the degree of dissociation are of the same order of magnitude as the values obtained with classical formulas, but still differ by a factor of about 1/3. The direct numerical simulation allows new insight into the conduction mechanisms for different frequency regimes. PMID- 22925120 TI - Preconcentration and selective extraction of chromium species in water samples using amino modified mesoporous silica. AB - Speciation and separation of chromium (VI) and chromium (III) from aqueous solutions were investigated using amino-propyl functionalised mesoporous silica (AP-MCM-41) as an adsorbent. The as-synthesised adsorbent was produced following a simple synthesis method at room temperature prior to template removal using microwave digestion. The maximum adsorption capacity at 111.1 mg/g was calculated according to the Langmuir isotherm model, suggesting a 1:1 monolayer adsorption mechanism. Moreover, AP is a simple chelate, yet it can extract Cr (VI) exclusively from solutions containing other mixed metal ions simply by tuning the solution pH. Recovery of Cr (VI) from loaded sorbents is equally easy to perform with 100% extraction efficiencies allowing reuse of the sorbent and recovery of Cr (VI) from aqueous solutions containing a complex mixture of ions. The material would find use in environmental remediation applications, as a selective adsorbent of Cr (VI) or even as a solid-phase extraction stationary phase to remove and pre-concentrate Cr (VI) from aqueous solutions; this study demonstrates enrichment factors of 100 although higher levels are also possible. PMID- 22925121 TI - One-pot, solvothermal synthesis of TiO2-graphene composite nanosheets. AB - In this article, we propose a facile one-pot solvothermal route for synthesizing TiO(2)-graphene composite nanosheets (TGCN). In the system, ethylene glycol not only as a reducing agent can convert graphene oxide to reduced graphene oxide nanosheets, but also is employed to control the hydrolysis and condensation rates of tetrabutoxytitanium. The obtained TGCN hybrid materials are characterized by atomic force microscopy, transmission electron microscopy, UV-vis spectroscopy, Raman spectroscopy, X-ray photo-electron spectroscopy, X-ray diffraction, and thermal gravimetric analysis. It is found that the quantity of H(2)O used in the reaction is the key to obtain high-quality product. The photocatalytic activities of the products are evaluated using the photocatalytic degradation of methylene blue (MB) as a probe reaction. The results showed that the obtained TGCN have an enhanced adsorption capacity and remarkable improvements in the photodegradation rate of MB under visible light compared to P25. PMID- 22925122 TI - Tracing the cascade of children's insecurity in the interparental relationship: the role of stage-salient tasks. AB - This study examined whether children's difficulties with stage-salient tasks served as an explanatory mechanism in the pathway between their insecurity in the interparental relationship and their disruptive behavior problems. Using a multimethod, multi-informant design, 201 two-year-old children and their mothers participated in 3 annual measurement occasions. Structural equation modeling analyses indicated that coder ratings of children's insecure responses to interparental conflict from a maternal interview predicted observer ratings of their difficulties with stage-salient tasks (i.e., emotion regulation, autonomy, resourceful problem solving) 1 year later after controlling for initial stage salient task performance. Stage-salient task difficulties, in turn, predicted experimenter reports of children's behavior problems 1 year later. Associations remained robust in the broader context of other pathways hypothesized in prevailing developmental cascade models. PMID- 22925124 TI - A toast to the International Association of Forensic Nurses in its 20th year! PMID- 22925123 TI - Stoking the drug target pipeline for human African trypanosomiasis. AB - Trypanosoma brucei is the causative agent of African sleeping sickness, putting at risk up to 50 million people in sub-Saharan Africa. Current drug therapies are limited by toxicity and difficult treatment regimes and as the development of vaccines remains unlikely, the identification of better drugs to control this deadly disease is needed. Strategies for the identification of new lead compounds include phenotypic screening or target-based approaches. Implementation of the latter has been hampered by the lack of defined targets that are both essential and druggable. In this issue of Molecular Microbiology, Jones et al. (2012) report on the characterization of T. brucei pyridoxal kinase (PdxK), an enzyme required for the salvage of vitamin B6, an essential enzymatic cofactor. Genetic knock-down and small molecule inhibitor studies were used to demonstrate that PdxK is essential for parasite growth both in vitro and in a mouse model, providing both genetic and chemical validation of the target. An enzyme assay compatible with high-throughput screening (HTS) was developed and the X-ray crystal structure solved, showing the potential for species selective inhibition. These studies add a greatly needed additional target into the drug discovery pipeline for this deadly parasitic infection. PMID- 22925125 TI - Pediatric sexual assault nurse examiner care: trace forensic evidence, ano genital injury, and judicial outcomes. AB - INTRODUCTION: Although pediatric sexual assault nurse examiners (P-SANEs) have been providing care for over two decades there remain major gaps in the literature describing the quality of P-SANE care and legal outcomes associated with their cases. The purpose of this study was to compare quality indicators of care in a pediatric emergency department (PED) before and after the implementation of a P-SANE program described in terms of trace forensic evidence yield, identification of perpetrator DNA, and judicial outcomes in pediatric acute sexual assault. METHOD: A retrospective review of medical and legal records of all patients presenting to the PED at Nationwide Children's Hospital with concerns of acute sexual abuse/assault requiring forensic evidence collection from 1/1/04 to 12/31/07 was conducted. FINDINGS: Detection and documentation of ano-genital injury, evaluation and documentation of pregnancy status, and testing for N. gonorrhea and C. trachomatis was significantly improved since implementation of the P-SANE Program compared to the historical control. DISCUSSION: The addition of a P-SANE to the emergency department (ED) provider team improved the quality of care to child/adolescent victims of acute sexual abuse/assault. PMID- 22925126 TI - Patterns of federal Internet offenders: a pilot study. AB - Internet-facilitated sexual offending is receiving increased forensic and clinical attention. Two issues confront this field. First, studies are equivocal as to whether (or not) the possession of Internet pornography can escalate to contact sexual offenses against a child, and second, federal judges have been questioning the length of sentences for users only of child pornography. The findings of this pilot study of 101 federal Internet offenders revealed over half of the men at the time of arrest were employed, educated, were in (or had been in) a relationship, had children, and did not have a prior criminal offense, suggesting a changing profile of a convicted sex offender. Forensic and psychiatric nurses who evaluate users of child pornography contraband need to be knowledgeable of Internet file transfer technology and the various types of contraband viewed specifically for the age of the preferred child, extreme acts to the child (e.g., bondage, S&M), and whether the user prefers images of adults with children or images of children only. PMID- 22925128 TI - Information sharing between the National Health Service and criminal justice system in the United Kingdom. AB - Offenders with mental health problems often have complex and interrelated needs which separately challenge the criminal justice system (CJS) and National Health Service (NHS) in the United Kingdom (U.K.). Consequently, interagency collaboration and timely information sharing are essential. This study focused on the sharing of information about people with mental health problems in contact with the CJS. Questionnaires were distributed to a range of health and criminal justice personnel. The results showed that there was a mismatch between what service user information criminal justice agencies felt they needed and what was routinely received. Prison Service staff received more information (between 15% and 37%) from health agencies than the police (between 6% and 22%). Health professionals received most of the information they needed from criminal justice agencies (between 55% and 85%). Sharing service user information was impeded by incompatible computer systems and restrictions due to data protection/confidentiality requirements. In the U.K., recent governmental publications have highlighted the importance of information sharing; however there remains a clear mismatch between what health related information about service users criminal justice agencies need, and what is actually received. Better guidance is required to encourage and empower people to share. PMID- 22925127 TI - The influence of emergency contraception on post-traumatic stress symptoms following sexual assault. AB - Conservative estimates indicate that 18-25% of women in the United States will be exposed to some form of sexual assault in their lifetime. A great number of these women will develop post-traumatic stress disorder (PTSD). The current study explores the relationship between emergency contraception (EC) administration and subsequent post-traumatic stress symptoms in female sexual assault (SA) survivors. In a study population of 111 participants, post-traumatic stress symptoms were assessed approximately six months after the SA. Women who were already taking hormonal contraception (HC) at the time of the SA and those who declined EC were compared to women who took either Ogestrel or Plan B following the SA. While the administration of traditional HC and both types of EC were associated with fewer intrusive symptoms, women who took Ogestrel reported significantly lower post-traumatic stress total symptom levels than did those who took Plan B or those who declined EC. The results suggest that the manipulation of sex hormone levels with HC and EC in the immediate aftermath of trauma may influence subsequent post-traumatic stress symptoms. The current results may be useful in guiding the choice of EC. PMID- 22925129 TI - A case report of gunshot terror attack in pregnancy: implications for forensic nursing. AB - We present a case report of a third trimester pregnant woman who endured a gunshot terror attack. We demonstrate the complexity involved in the treatment of mother-infant, and suggest implementing the role of forensic nurse in Israel as a way to enhance the treatment of trauma patients within the hospital setting. PMID- 22925130 TI - The contribution of personality and workplace characteristics in predicting turnover intention among sexual assault nurse examiners: a path analytic study. AB - The purpose of this study was to determine how personality characteristics, sense of organizational empowerment, and job satisfaction combine to predict turnover intention among a population of Sexual Assault Nurse Examiners (SANEs). Data were collected from 161 SANEs from 23 SANE organizations across the central and west United States through standardized tools and a demographic questionnaire. Both personality, namely agreeableness and workplace characteristics, particularly perceived empowerment and job satisfaction, combine to predict intention to leave the job of these sampled SANEs. One particularly curious finding was the positive prediction of agreeableness on turnover intention - that is, more agreeable people would be more likely to leave their jobs as SANEs. Professionals can gain insight from the path analysis results that show the need to address both personal and organizational factors in mitigating turnover intention among SANEs. This appears to be particularly true in providing a sense of empowerment and opportunity within the organization. PMID- 22925131 TI - Lys66 residue as a determinant of high mismatch extension and misinsertion rates of HIV-1 reverse transcriptase. AB - A major factor contributing to the high mutation rate of HIV-1 reverse transcriptase (RT) is its high propensity for misincorporation. Misincorporation requires both deoxyribonucleotide triphosphate (dNTP) misinsertion and the subsequent extension of the mismatched terminus thus formed. We hypothesized that Lys66 is a determinant of mismatch extension based on its position near the primer terminus. This hypothesis was tested by steady-state kinetic studies using wild-type HIV-1 RT and four Lys66 substitution mutants: Lys66Arg, Lys66Ala, Lys66Asn and Lys66Thr. The mismatch extension efficiency was reduced for all mutants, with Lys66Ala, Lys66Asn and Lys66Thr showing a four- to six-fold reduction compared with wild-type HIV-1 RT. Surprisingly, the nonconservative substitutions also led to large decreases in misinsertion efficiency, ranging from as low as three-fold to values much higher than 23-fold. Thus, the Lys66Arg mutant was akin to wild-type HIV-1 RT, whereas all nonconservative mutants displayed significantly decreased efficiency for both events. Our results suggest that Lys66, much like Lys65, is a determinant of both dNTP misinsertion and mismatch extension efficiency. While Lys65 is known to contact the gamma phosphate of incoming dNTP, the Lys66 side chain is in the vicinity of the primer terminus. However, our results suggest that both residues have a similar influence on dNTP misinsertion and mispair extension efficiencies of HIV-1 RT. When we tested the mutants for susceptibility to selected nucleoside analog and non-nucleoside analog drugs, similarly to Lys65Arg, the Lys66Ala and Lys66Asn mutants displayed mild resistance to the nucleoside analog drug 3'-azido-3' deoxythymidine-5'-triphosphate (AZTTP). PMID- 22925132 TI - Downregulation of FGL2/prothrombinase delays HCCLM6 xenograft tumour growth and decreases tumour angiogenesis. AB - BACKGROUND: Fibrinogen-like protein 2 (FGL2), which directly generates thrombin from prothrombin without activation of the conventional coagulation cascade, was shown to be overexpressed in various human malignant tumours. AIMS: Herein, we aimed to investigate its expression pattern, biological function and mechanism of action in hepatocellular carcinoma (HCC). METHODS: FGL2 expression and colocalization with fibrin was examined in 15 HCC tissues. FGL2 downregulation was performed by targeting microRNA in a HCCLM6 cell line in which FGL2 was highly expressed in xenografts of nude mice. The effects of FGL2 knockdown on tumour growth and angiogenesis were evaluated in vitro and in vivo. Cytometric bead arrays were employed to identify FGL2-regulated signalling pathways. RESULTS: FGL2 was overexpressed in HCC tissues and colocalized with fibrin deposition. Knockdown of FGL2 expression in HCCLM6 cells (hFGL2(low) HCCLM6) resulted in delayed xenografts tumour growth within an observation period of 42 days and decreased vascularization, which was accompanied by decreased phosphorylation of extracellular signal-regulated kinase (ERK) and c-Jun N terminal kinase (JNK). In vitro hFGL2(low) HCCLM6 cells exhibited decreased proliferation without significant induction of apoptosis. Overexpression of FGL2 in HCCLM6 cells or addition of recombinant hFGL2 protein induced phosphorylation of p38-MAPK and ERK1/2 involving protease-activated receptors (PARs).activation. CONCLUSIONS: FGL2 contributes to HCC tumour growth and angiogenesis in a thrombin dependent manner, and downregulation of its expression might be of therapeutic significance in HCC. PMID- 22925133 TI - Expansion of melanoma-specific T cells from lymph nodes of patients in stage III: implications for adoptive immunotherapy in treating cancer. AB - BACKGROUND: Adoptive immunotherapy for patients with metastatic melanoma has yielded encouraging results. However, methods of expanding melanoma-specific T cells from stage III are limited. The objective of this study was to determine whether melanoma-specific T cells could be generated from the melanoma-draining lymph nodes (MDLNs) of patients in stage III. METHODS: Patients in stage III who were undergoing completion lymphadenectomy were enrolled into a protocol approved by the institutional review board. MDLN cells were tested for ability to undergo cryopreservation, expand ex vivo in IL-2 or IL-2 and IL-7, and mediate melanoma specific antitumor responses in vitro. RESULTS: Cryopreservation produced no significant differences from fresh cultures in terms of cell growth and cellular phenotype. IL-2 and IL-2/IL-7 cultures resulted in similar growth rates, and functional studies revealed the presence of T cells that secreted interferon gamma in response to melanoma antigen peptides. Both IL-2- and IL-2/IL-7-cultured MDLN cells mediated significant apoptosis of human melanoma cell lines as compared to breast and brain tumor lines in vitro. Overall, there did not seem to be a benefit of adding IL-7. Both CD4+ and CD8+ T cells appear to mediate tumor cell apoptosis. CONCLUSION: This study demonstrates that melanoma antigen specific T cells can be generated from regional melanoma-draining lymph nodes and expanded ex vivo from patients with stage III disease. PMID- 22925134 TI - Outcomes and prognostic factors in nodular melanomas. AB - BACKGROUND: The nodular subtype of cutaneous melanoma has a more pronounced vertical phase and less of a radial growth phase compared with other histologic subtypes. This study was performed to determine prognostic factors and outcomes for nodular melanomas. METHODS: A post hoc analysis of a prospective clinical trial was performed in all patients with nodular histologic subtype. Univariate and multivariate analyses of factors associated with disease-free survival (DFS), overall survival (OS), and local and in-transit recurrence-free survival (LITRFS) were performed. Kaplan-Meier survival analyses were performed. RESULTS: There were 736 patients available for analysis, and 189 (25.7%) were sentinel lymph node (SLN) positive. Breslow thickness of >=2.3 mm, presence of ulceration, nonextremity tumor location, positive SLN, and non-SLN-positive status were independent risk factors for worse OS and DFS. Kaplan-Meier analysis demonstrated that ulceration predicted worse OS and DFS in all nodular melanoma patients, and in both SLN-positive and -negative subsets. The presence of ulceration and a positive SLN together predicted significantly worse DFS and OS. CONCLUSION: The most important risk factors that determine prognosis in nodular melanomas are SLN status and ulceration. The presence of both a positive SLN and ulceration significantly affect DFS and OS, and to a lesser degree LITRFS. PMID- 22925135 TI - Hypertensive disorders in pregnancy and fetal death at different gestational lengths: a population study of 2 121 371 pregnancies. AB - OBJECTIVE: To compare the proportion of offspring that was stillborn in pregnancies with pre-eclampsia, gestational hypertension or chronic hypertension with those in normotensive pregnancies. DESIGN: Register-based observational study. SETTING: The Medical Birth Registry of Norway. POPULATION: All singleton births after 20 completed weeks of gestation in Norway from 1967 to 2006 (n = 2 121 371). METHODS: The proportion of stillborn offspring was estimated in normotensive pregnancies, and in pregnancies with pre-eclampsia, gestational and chronic hypertension at different gestational lengths. In addition, changes in the proportions of stillborn offspring by maternal hypertensive disorder from 1967-1986 to 1987-2006 were estimated. MAIN OUTCOME MEASURES: Fetal death. RESULTS: The prevalence of hypertensive disorders in pregnancy was 4.7%. In total, 17 933 fetal deaths occurred and 9.2% of these were in hypertensive pregnancies. In normotensive pregnancies, 0.8% (16 290/2 022 400) experienced fetal death. This was true for 1.9% (1170/62 261) of the pregnancies with pre eclampsia, 1.2% (390/32 068) with gestational hypertension and 1.8% (83/4642) with chronic hypertension. There was a 44% overall reduction in fetal death rate from 1967-1986 to 1987-2006. The largest decline was in women with pre-eclampsia (80% reduction). In women with gestational hypertension and chronic hypertension, the overall reductions in fetal death rates were 49% and 57%, respectively, comparable with the 41% decline in normotensive pregnancies. CONCLUSIONS: In our nationwide study during 1967-2006, the risk of fetal death among women with hypertensive disorders in pregnancy has been greatly reduced, especially among pre-eclamptic women at term. The risk of fetal death among women with gestational or chronic hypertension has also decreased, but in a different manner. PMID- 22925137 TI - The validity of individual Rorschach variables: systematic reviews and meta analyses of the comprehensive system. AB - We systematically evaluated the peer-reviewed Rorschach validity literature for the 65 main variables in the popular Comprehensive System (CS). Across 53 meta analyses examining variables against externally assessed criteria (e.g., observer ratings, psychiatric diagnosis), the mean validity was r = .27 (k = 770) as compared to r = .08 (k = 386) across 42 meta-analyses examining variables against introspectively assessed criteria (e.g., self-report). Using Hemphill's (2003) data-driven guidelines for interpreting the magnitude of assessment effect sizes with only externally assessed criteria, we found 13 variables had excellent support (r >= .33, p < .001; [Symbol: see text] FSN > 50), 17 had good support (r >= .21, p < .05, FSN >= 10), 10 had modest support (p < .05 and either r >= .21, FSN < 10, or r = .15-.20, FSN >= 10), 13 had little (p < .05 and either r = < .15 or FSN < 10) or no support (p > .05), and 12 had no construct-relevant validity studies. The variables with the strongest support were largely those that assess cognitive and perceptual processes (e.g., Perceptual-Thinking Index, Synthesized Response); those with the least support tended to be very rare (e.g., Color Projection) or some of the more recently developed scales (e.g., Egocentricity Index, Isolation Index). Our findings are less positive, more nuanced, and more inclusive than those reported in the CS test manual. We discuss study limitations and the implications for research and clinical practice, including the importance of using different methods in order to improve our understanding of people. PMID- 22925136 TI - Biofilm shows spatially stratified metabolic responses to contaminant exposure. AB - Biofilms are core to a range of biological processes, including the bioremediation of environmental contaminants. Within a biofilm population, cells with diverse genotypes and phenotypes coexist, suggesting that distinct metabolic pathways may be expressed based on the local environmental conditions in a biofilm. However, metabolic responses to local environmental conditions in a metabolically active biofilm interacting with environmental contaminants have never been quantitatively elucidated. In this study, we monitored the spatiotemporal metabolic responses of metabolically active Shewanella oneidensis MR-1 biofilms to U(VI) (uranyl, UO(2)(2+)) and Cr(VI) (chromate, CrO(4) (2-)) using non-invasive nuclear magnetic resonance imaging (MRI) and spectroscopy (MRS) approaches to obtain insights into adaptation in biofilms during biofilm contaminant interactions. While overall biomass distribution was not significantly altered upon exposure to U(VI) or Cr(VI), MRI and spatial mapping of the diffusion revealed localized changes in the water diffusion coefficients in the biofilms, suggesting significant contaminant-induced changes in structural or hydrodynamic properties during bioremediation. Finally, we quantitatively demonstrated that the metabolic responses of biofilms to contaminant exposure are spatially stratified, implying that adaptation in biofilms is custom-developed based on local microenvironments. PMID- 22925138 TI - Reviewing employee turnover: focusing on proximal withdrawal states and an expanded criterion. AB - We reconceptualize employee turnover to promote researchers' understanding and prediction of why employees quit or stay in employing institutions. A literature review identifies shortcomings with prevailing turnover dimensions. In response, we expand the conceptual domain of the turnover criterion to include multiple types of turnover (notably, involuntary quits) and multiple types of staying. Guided by the premise that "everyone eventually leaves; no one stays with an organization forever," we also suggest considering where leavers end up-or post exit destinations, such as another job, full-time parenting, or educational pursuits. We propose "proximal withdrawal states" that motivate members to participate or withdraw from organizations as an expanded criterion. These motivational states precede turnover and are derived from 2 overarching dimensions: desired employment status (whether employees want to stay or leave) and perceived volitional control (whether quit or stay decisions are completely up to them or at least partially under external regulation). Crossing these dimensions yields 4 prime states: enthusiastic leavers and stayers and reluctant leavers and stayers. We further subdivide these mind-sets into subtypes by differentiating employer from other forms of external control (e.g., family). Focusing on more common subtypes, we explain how they arise from particular motivational forces and profile how they differ by attitudes, behaviors, and turnover speed and destinations. We further discuss ways to measure this expanded criterion and proximal states (and subtypes) and investigate the latter's profiled differences. Finally, we discuss scientific and practical implications and future research directions. PMID- 22925139 TI - Further clarifying proximal withdrawal states and the turnover criterion space: Comment on Hom, Mitchell, Lee, and Griffeth (2012). AB - In "Reviewing Employee Turnover: Focusing on Proximal Withdrawal States and an Expanded Criterion," Hom, Mitchell, Lee, and Griffeth (2012) brought together many of the most important content and process factors in the employee turnover literature. In this paper, I attempt to clarify the true contributions of this framework for the turnover area and at the same time explain why improved prediction is not among these contributions. I then enumerate 3 theoretically problematic aspects of the proposed framework, which limit its contribution. Finally, I suggest 3 directions that researchers should pursue in order to test and extend the framework. PMID- 22925140 TI - Sometimes pursuits don't pan out: anticipated destinations and other caveats: comment on Hom, Mitchell, Lee, and Griffeth (2012). AB - Hom, Mitchell, Lee, and Griffeth (2012) presented an extensive review of employee turnover research, reconceptualized the turnover criterion to include multiple destinations, and proposed to expand the predictor domain. They illuminated the multiple destinations employees pursue following turnover. By crossing desire to remain and volitional control dimensions, Hom et al. defined and described 4 withdrawal states (or predeparture mind-sets). This commentary begins by introducing the issue that people do not know precisely where they will turn over to until they have actually gone. This suggests that researchers should consider anticipated destinations when conducting research on withdrawal states. We note the limitations of measuring withdrawal states as taxonomic categories; instead, we advocate for measuring the underlying continuous dimensions of desire and control or the weight associated with the pressures to leave or stay. Finally, we highlight some temporal considerations, as withdrawal states are temporary and there is much to be learned from studying changes in such states. We conclude with some directions for future turnover research based on Hom et al.'s contribution. PMID- 22925141 TI - Further clarification on the Hom, Mitchell, Lee, and Griffeth (2012) model: Reply to Bergman, Payne, and Boswell (2012) and Maertz (2012). AB - In this article, we reply to Bergman, Payne, and Boswell (2012) and Maertz (2012), who commented on our reconceptualization of the employee turnover criterion and proximal withdrawal states (Hom, Mitchell, Lee, & Griffeth, 2012). We agree with some points (e.g., anticipated destinations) but take issue with others (e.g., turnover intentions as the criterion). Nonetheless, our aim is to clarify our integrative formulation about mindsets for organizational participation and withdrawal. In our view, the current process of "article commentaries-reply" advances our collective understanding of staying and leaving, which is of longstanding interest to scholars in industrial and organizational psychology, organizational behavior, and human resource management. PMID- 22925142 TI - Does religious belief promote prosociality? A critical examination. AB - Numerous authors have suggested that religious belief has a positive association, possibly causal, with prosocial behavior. This article critiques evidence regarding this "religious prosociality" hypothesis from several areas of the literature. The extant literature on religious prosociality is reviewed including domains of charity, volunteering, morality, personality, and well-being. The experimental and quasi-experimental literature regarding controlled prosocial interactions (e.g., sharing and generosity) is reviewed and contrasted with results from naturalistic studies. Conceptual problems in the interpretation of this literature include separating the effects of stereotypes and ingroup biases from impression formation as well as controlling for self-report biases in the measurement of religious prosociality. Many effects attributed to religious processes can be explained in terms of general nonreligious psychological effects. Methodological problems that limit the interpretation of religious prosociality studies include the use of inappropriate comparison groups and the presence of criterion contamination in measures yielding misleading conclusions. Specifically, it is common practice to compare high levels of religiosity with "low religiosity" (e.g., the absence of denominational membership, lack of church attendance, or the low importance of religion), which conflates indifferent or uncommitted believers with the completely nonreligious. Finally, aspects of religious stereotype endorsement and ingroup bias can contribute to nonprosocial effects. These factors necessitate a revision of the religious prosociality hypothesis and suggest that future research should incorporate more stringent controls in order to reach less ambiguous conclusions. PMID- 22925143 TI - Is religion not prosocial at all? Comment on Galen (2012). AB - Galen (2012), critically reviewing recent research on religion and prosociality, concludes that the religious prosociality hypothesis is a (congruence) fallacy. The observed effects are not real: They only reflect stereotypes and ingroup favoritism, are due to secular psychological effects, are inconsistent, and confound (e.g., by ignoring curvilinear relationships) those low in religiosity with nonbelievers. In this commentary, a distinction is first made between the already known limitations on the extent, context, and quality of the religion prosociality link and the novel, more radical argument of Galen denying the validity and the plausibility of such a link. Second, careful examination of relevant studies shows that religious prosociality is not reduced to social desirability in self-reports, is confirmed through ratings by peers who are blind with regard to the religious status of the target, and is expressed through real prosocial behavior in controlled experiments and life decisions with long-term effects. This behavior cannot be reduced to ingroup favoritism. Finally, Galen's opposition between religious versus "secular" psychological effects is criticized as psychologically problematic, and his insistence for examination of curvilinear relationships is relativized on the basis of research confirming the linear relationship. Alternative research questions for understanding prosociality of atheists are proposed. PMID- 22925144 TI - Reflections on religious belief and prosociality: Comment on Galen (2012). AB - Luke Galen (2012) offers a timely analysis of associations between religiosity and prosocial and antisocial attitudes and behaviors. After identifying 10 points of agreement, I raise 8 questions for further reflection and research: (1) Is ingroup giving and volunteerism not prosocial? (2) Are religion-related prosocial norms part of the religious factor? (3) Is social support also appropriately considered part of the religious factor? (4) Are self-report data from more and less religious people invalid? (5) How should we disentangle gender and religiosity? (6) How might we resolve "the religious engagement paradox"? (7) Does religion serve an adaptive, evolutionary function? And (8) Might research further explore religiosity, in its varieties, and prosociality? PMID- 22925145 TI - The complex and elusive nature of religious prosociality: reply to Myers (2012) and Saroglou (2012). AB - This reply explores issues raised in comments by Myers (2012) and Saroglou (2012) on Galen (2012) regarding whether religiosity has any influence on prosociality. Areas of contention include (a) the distinction between religious belief and other influences, mainly the socialization effects of group behavior; (b) whether behavior largely restricted to the ingroup is genuine prosociality; (c) methodological issues such as the validity of self-report and peer-reported data and effects of social desirability; (d) the often paradoxical relationships with different forms of religiosity; and (e) potential curvilinear effects. Recent work regarding these issues is highlighted, and future directions that may productively resolve these debates are suggested. PMID- 22925146 TI - Donors self-reported experiences of live kidney donation--a prospective study. AB - Many reports on living kidney donation describe rapid recovery. In our experience rehabilitation is rather slow. This study aimed to explore self-reported health status among living donors (LDs) three to four weeks and six months post-donation with a longitudinal design. In this study. LDs (n = 112) reported their physical and mental health by responding to a questionnaire before surgery, after three to four weeks and after six months. Points could range from 1 (normal) to 5 (severe trouble), total score 7-35. Age (n = 112) was 50 years (median) and 52% were females. Before surgery, the total score was 9 (7-21). After three to four weeks, the score was 15 (7-31), with a rise in all measured variables. Women noted higher score rises than men (p = 0.01). The majority showed complete recovery after six months. It is clear that professional nursing support in the recuperation period is needed. Nursing interventions should aim at preventing delay and setbacks in the donors' recovery process. PMID- 22925147 TI - Bacterial adhesion affinities of various implant abutment materials. AB - OBJECTIVES: To investigate bacterial adhesion to various abutment materials. MATERIAL AND METHODS: Thirty volunteers participated in this study. Resin splints were fabricated, and five types of disks were fabricated from pure titanium, gold platinum alloy, zirconia, alumina, and hydroxyapatite with uniform surface roughness and attached to the buccal surface of each splint. After 4 days of use by the subjects, the plaque accumulated on the disk surfaces was analyzed. The bacterial community structure was evaluated using 16S rRNA gene profiling with terminal restriction fragment length polymorphism analysis. The total bacterial count on each disk was estimated using quantitative polymerase chain reaction. RESULTS: Terminal restriction fragment length polymorphism profiles were more similar between tested materials than between subjects, suggesting that the bacterial community structures on the abutment material were influenced more by the individuals than by the type of material. However, the total number of bacteria attached to a disk was significantly different among five materials (P < 0.001, Brunner-Langer test for longitudinal data). Fewer bacteria were attached to the gold-platinum alloy than to the other materials. CONCLUSIONS: Gold platinum alloy appears to be useful material for abutments when considering the accumulation of plaque. However, alternative properties of the abutment material, such as effects on soft tissue healing, should also be taken into consideration when choosing an abutment material. PMID- 22925148 TI - Parental rearing and psychopathology in mothers of adolescents with and without borderline personality symptoms. AB - BACKGROUND: A combination of multiple factors, including a strong genetic predisposition and environmental factors, are considered to contribute to the developmental pathways to borderline personality disorder (BPD). However, these factors have mostly been investigated retrospectively, and hardly in adolescents. The current study focuses on maternal factors in BPD features in adolescence. METHODS: Actual parenting was investigated in a group of referred adolescents with BPD features (N = 101) and a healthy control group (N = 44). Self-reports of perceived concurrent parenting were completed by the adolescents. Questionnaires on parental psychopathology (both Axis I and Axis II disorders) were completed by their mothers. RESULTS: Adolescents reported significantly less emotional warmth, more rejection and more overprotection from their mothers in the BPD-group than in the control group. Mothers in the BPD group reported significantly more parenting stress compared to mothers in the control group. Also, these mothers showed significantly more general psychopathology and clusters C personality traits than mothers in the control group. Contrary to expectations, mothers of adolescents with BPD features reported the same level of cluster B personality traits, compared to mothers in the control group. Hierarchical logistic regression revealed that parental rearing styles (less emotional warmth, and more overprotection) and general psychopathology of the mother were the strongest factors differentiating between controls and adolescents with BPD symptoms. CONCLUSIONS: Adolescents with BPD features experience less emotional warmth and more overprotection from their mothers, while the mothers themselves report more symptoms of anxiety and depression. Addition of family interventions to treatment programs for adolescents might increase the effectiveness of such early interventions, and prevent the adverse outcome that is often seen in adult BPD patients. PMID- 22925151 TI - Risk of coronary artery disease is not linked to head and neck cancers: a population-based retrospective cohort study. AB - OBJECTIVES: To explore the possible association between the risk of coronary artery disease and head or neck cancer based on some possible shared risk factors and/or treatment-related complications. DESIGN AND SETTING: A population-based retrospective cohort study. PARTICIPANTS: All new 729 patients with head and neck cancer diagnosed between 2000 and 2003 were followed up till 2009, and the risk of subsequent coronary artery disease was calculated. For each patient, the risk was calculated in 4 age-and sex-matched population controls. Matching was not possible for factors including socio-economic group and smoking. MAIN OUTCOME MEASURES: Cox's proportional hazard regression analysis was conducted to estimate the relationship between head or neck cancer and risk of coronary artery disease. RESULTS: For patients with head or neck cancer, the overall risk for developing coronary artery disease was almost the same as that of the control group [adjusted hazard ratio (but without control for some lifestyle factors): 0.95; 95% confidence interval: 0.65-1.35]. Overall, we found no increased risk of coronary artery disease for patients with head or neck cancer when the data were categorised either by treatment methods or by cancer subsites. CONCLUSIONS: This population-based study indicated that patients with head or neck cancer were at no higher risk of developing coronary artery disease than was the general population over a 6- to 9-year period; however, we cannot exclude the risk over a longer period of time. PMID- 22925150 TI - Functional properties of dopamine neurons and co-expression of vasoactive intestinal polypeptide in the dorsal raphe nucleus and ventro-lateral periaqueductal grey. AB - The dorsal raphe nucleus (DRN) and ventrolateral periaqueductal grey (vlPAG) regions contain populations of dopamine neurons, often considered to be a dorsal caudal extension of the A10 group [mostly found in the ventral tegmental area (VTA)]. Recent studies suggest they are involved in promoting wakefulness and mediate some of the antinociceptive and rewarding properties of opiates. However, little is known about their electrophysiological properties. To address this, we used Pitx3-GFP and tyrosine hydroxylase (TH)-GFP mice to carry out targeted whole cell recordings from this population in acute brain slices. We found that DRN/vlPAG dopamine neurons have characteristics similar to most VTA dopamine neurons, but distinct from dorsal raphe serotonin neurons. They fire broad action potentials at a relatively slow, regular rate, exhibit a hyperpolarization activated inward current and delayed repolarization, and show spike-frequency adaptation in response to prolonged depolarization. In addition, they receive fast excitatory and inhibitory synaptic inputs. Moreover, we found co-expression of vasoactive intestinal polypeptide in small, periaqueductal dopamine neurons, but generally not in larger, more ventral dopamine neurons. PMID- 22925152 TI - Effects of androgen deprivation on brain function in prostate cancer patients - a prospective observational cohort analysis. AB - BACKGROUND: Despite a lack of consensus regarding effectiveness, androgen deprivation therapy (ADT) is a common treatment for non-metastatic, low-risk prostate cancer. To examine a particular clinical concern regarding the possible impact of ADT on cognition, the current study combined neuropsychological testing with functional magnetic resonance imaging (fMRI) to assess both brain activation during cognitive performance as well as the integrity of brain connectivity. METHODS: In a prospective observational cohort analysis of men with non metastatic prostate cancer at a Veterans Affairs medical center, patients receiving ADT were compared with patients not receiving ADT at baseline and at 6 months. Assessments included fMRI, the N-back task (for working memory), the stop signal task (for cognitive control), and a quality of life questionnaire. RESULTS: Among 36 patients enrolled (18 in each group), 30 completed study evaluations (15 in each group); 5 withdrew participation and 1 died. Results for the N-back task, stop-signal task, and quality of life were similar at 6 months vs. baseline in each group. In contrast, statistically significant associations were found between ADT use (vs. non use) and decreased medial prefrontal cortical activation during cognitive control, as well as decreased connectivity between the medial prefrontal cortex and other regions involved with cognitive control. CONCLUSIONS: Although ADT for 6 months did not affect selected tests of cognitive function, brain activations during cognitive control and functional brain connectivity were impaired on fMRI. The long-term clinical implications of these changes are not known and warrant future study. PMID- 22925153 TI - Effects of quillaja and yucca saponins on communities and select populations of rumen bacteria and archaea, and fermentation in vitro. AB - AIMS: The objective of this study was to comprehensively evaluate quillaja (QSP) and yucca saponin (YSP) products with respect to their effects on diversity of rumen bacteria and archaea, abundance of selected microbes, and feed degradability and fermentation. METHODS AND RESULTS: Both QSP and YSP at doses 0 0.6 g l(-1) tended to increase degradability of feed substrate in in vitro rumen cultures, but to different extents. Neither one of the saponins affected the concentrations of ammonia, total volatile fatty acids, or molar proportion of acetate. However, QSP increased molar proportion of propionate and decreased that of butyrate, whereas YSP tended to decrease that of butyrate. As determined by qPCR, QSP and YSP did not affect the abundance of total bacteria or Ruminococcus albus. The QSP did not affect the abundances of Fibrobacter succinogenes or genus Prevotella, but tended to decrease that of Ruminococcus flavefaciens, whereas YSP significantly increased the abundance of R. flavefaciens and Prevotella, and numerically increased that of F. succinogenes. Both saponins increased archaeal abundance, although to small magnitudes (0.3-0.4 log). The protozoal populations were decreased significantly by QSP, but not by YSP. Based on DGGE and T-RFLP analysis, both saponins altered the bacterial community and species organization, but less so the archaeal community. CONCLUSIONS: This study demonstrated that saponins, although not effective in mitigating methane emission, may improve feed utilization at low doses, and modulate ruminal microbial communities in a dose dependent manner. SIGNIFICANCE AND IMPACT OF THE STUDY: The results of this study suggest that saponins at low doses may directly stimulate the growth of some rumen bacteria including cellulolytic bacteria, thus improving digestibility of feeds, independent of their defaunation activity. In contrast, saponins at high doses modulate rumen fermentation characteristically similar to defaunation. PMID- 22925154 TI - Atypical adult onset complicated spastic paraparesis with thin corpus callosum in two patients carrying a novel FA2H mutation. PMID- 22925149 TI - A comprehensive and quantitative review of dark fermentative biohydrogen production. AB - Biohydrogen production (BHP) can be achieved by direct or indirect biophotolysis, photo-fermentation and dark fermentation, whereof only the latter does not require the input of light energy. Our motivation to compile this review was to quantify and comprehensively report strains and process performance of dark fermentative BHP. This review summarizes the work done on pure and defined co culture dark fermentative BHP since the year 1901. Qualitative growth characteristics and quantitative normalized results of H2 production for more than 2000 conditions are presented in a normalized and therefore comparable format to the scientific community.Statistically based evidence shows that thermophilic strains comprise high substrate conversion efficiency, but mesophilic strains achieve high volumetric productivity. Moreover, microbes of Thermoanaerobacterales (Family III) have to be preferred when aiming to achieve high substrate conversion efficiency in comparison to the families Clostridiaceae and Enterobacteriaceae. The limited number of results available on dark fermentative BHP from fed-batch cultivations indicates the yet underestimated potential of this bioprocessing application. A Design of Experiments strategy should be preferred for efficient bioprocess development and optimization of BHP aiming at improving medium, cultivation conditions and revealing inhibitory effects. This will enable comparing and optimizing strains and processes independent of initial conditions and scale. PMID- 22925155 TI - Immunohistochemical expression of the proliferative marker Ki67 in hydatidiform moles and its diagnostic value in the progression to gestational trophoblastic neoplasia. AB - AIM: Considering that Ki-67 is a proliferative marker in molar pregnancies and the possible progression of these kinds of pregnancies to gestational trophoblastic neoplasia (GTN), we decided to evaluate the rate of expression of this marker in patients with uneventful hydatidiform moles and GTN. Moreover, we determined the predictive value of this factor for the progression of molar pregnancies to GTN. METHODS: In two groups of patients, including 30 patients with uneventful molar pregnancies and 30 patients with GTN, an immunohistochemical staining technique using the Envision method was performed. To evaluate nuclear immunoreactivity of trophoblastic cells for Ki67 on paraffin sections obtained from molar pregnancy products, the percentage of the stained cells was used. Semi-quantitative evaluation was also performed. Data were analyzed using Mann-Whitney tests and receiver operating characteristic curve analysis. RESULTS: The expression of Ki67 in cytotrophoblastic and syncytiotrophoblastic cells of patients with GTN was significantly more than for patients with an uneventful molar pregnancy (P<0.05). We considered a 12.5% cut off value for Ki67 in cytotrophoblastic cells and a sensitivity of 90%, specificity 93%, positive predictive value of 93.1% and negative predictive value of 90.3% were obtained. Similarly, considering a cut-off value of 6% for Ki67 in syncytiotrophoblastic cells, results of 90% were obtained for all diagnostic indices. CONCLUSION: Our findings suggest that expression of the Ki67 oncogene in trophoblastic cells in patients with GTN are found far more frequently than in patients with an uneventful molar pregnancy, and demonstrate a high predictive value of progression to GTN. PMID- 22925157 TI - Conceptual models for integrating palliative care at cancer centers. AB - Palliative care programs are rapidly evolving in acute care facilities. Increased and earlier access has been advocated for patients with life-threatening illnesses. Existing programs would need major growth to accommodate the increased utilization. The objective of this review is to provide an update on the current structures, processes, and outcomes of the Supportive and Palliative Care Program at the University of Texas M.D. Anderson Cancer Center (UTMDACC), and to use the update as a platform to discuss the challenges and opportunities in integrating palliative and supportive services in a tertiary care cancer center. Our interprofessional program consists of a mobile consultation team, an acute palliative care unit, and an outpatient supportive care clinic. We will discuss various metrics including symptom outcomes, quality of end-of-life care, program growth, and financial issues. Despite the growing evidence to support early palliative care involvement, referral to palliative care remains heterogeneous and delayed. To address this issue, we will discuss various conceptual models and practical recommendations to optimize palliative care access. PMID- 22925156 TI - Effects of N-butylscopolammonium bromide on lung function in horses with recurrent airway obstruction. AB - BACKGROUND: Equine recurrent airway obstruction (RAO) is characterized by airway inflammation, bronchoconstriction, and increased mucus production in the airways. Anticholinergic drugs like atropine induce bronchodilatation and rapid improvement in lung function. N-butylscopolammonium bromide (NBB) is an anticholinergic drug used to relieve spasmodic colic in horses, but its effect on airway smooth muscle is unknown. OBJECTIVE: To evaluate the effect of NBB on clinical signs and lung function of RAO-affected horses. ANIMALS: Nine horses diagnosed with RAO. METHODS: Double-blind, placebo-controlled, randomized crossover trial. Horses were challenged with moldy hay until a maximum change in transpulmonary pressure (?P(L) (max) ) > 15 cm H(2) O was achieved. NBB (0.3 mg/kg) or placebo (0.9% saline) was administered IV. Clinical scores and lung function were recorded at baseline and then periodically after treatment administration. Horses were allowed a 6-week washout before administration of opposite treatments. RESULTS: Clinical score at 10 and 30 minutes (8.7 +/- 2.8 and 8.7 +/- 3.2, respectively) after NBB administration was significantly lower than baseline (10.8 +/- 2.4). NBB administration resulted in a significant decrease in ?P(L) (max) (baseline: 35.1 +/- 6.9 cm H(2) O) starting 2 minutes after administration (16.3 +/- 6.6 cmH(2) O) with a maximum decline observed at 10 minutes (13.5 +/- 7.1 cm H(2) O). ?P(L) (max) values between 60 and 120 minutes after NBB administration were not different from placebo. CONCLUSION AND CLINICAL IMPORTANCE: N-butylscopolammonium bromide is a potent bronchodilator, reaching maximum effect 10 minutes after intravenous administration. This effect dissipates within 1 hour of drug administration. PMID- 22925158 TI - Morphine and hydromorphone-induced hyperalgesia in a hospice patient. AB - Opioids including morphine and hydromorphone are widely used for control of moderate to severe pain and dyspnea in hospice and palliative care patients. Accumulation of the active morphine-3-glucuronide (M3G) and hydromorphone-3 glucuronide (H3G) metabolites is one proposed mechanism for the development of neuroexcitatory effects including allodynia and opioid-induced hyperalgesia (OIH). We report the case of a 43-year-old female hospice patient with metastatic non-small cell lung cancer who initially developed allodynia following morphine administration and again following administration of hydromorphone. The allodynia resolved both times following the discontinuation of the opioid and rotation to a different opioid regimen. Potential opioid-induced neuroexcitatory treatment options include opioid rotation to an agent with inactive metabolites, use of adjuvant pain medications for opioid-sparing effects, management of undesired symptoms (e.g., myoclonus), or increasing opioid clearance with intravenous (IV) fluids. Although the incidence is not well defined in the literature, hospice and palliative care clinicians should suspect OIH in patients with allodynia and/or hyperalgesia, especially when repeated dose escalations do not improve analgesia or pain escalates following opioid dose titration. PMID- 22925160 TI - BDNF-mediated migration of cardiac microvascular endothelial cells is impaired during ageing. AB - This study indicates that brain-derived neurotrophic factor (BDNF) can promote young cardiac microvascular endothelial cells (CMECs) to migrate via the activation of the BDNF-TrkB-FL-PI3K/Akt pathway, which may benefit angiogenesis after myocardial infarction (MI). However, the ageing of CMECs led to changes in the expression of receptor Trk isoforms in that among the three isoforms (TrkB FL, TrkB-T1 and TrkB-T2), only one of its truncated isoforms, TrkB-T1, continued to be expressed, which leads to the dysfunction of its ligand, a decrease in the migration of CMECs and increased injury in ageing hearts. This shift in receptor isoforms in aged CMECs, together with changes in the ageing microenvironment, might predispose ageing hearts to decreased angiogenic potential and increased cardiac pathology. PMID- 22925162 TI - Abstracts of the International Veterinary Emergency and Critical Care Symposium and the European Veterinary Emergency and Critical Care Society Annual Congress. September 8-12, 2012. San Antonio, Texas, USA. PMID- 22925161 TI - The nucleoid-associated protein Fis directly modulates the synthesis of cellulose, an essential component of pellicle-biofilms in the phytopathogenic bacterium Dickeya dadantii. AB - Bacteria use biofilm structures to colonize surfaces and to survive in hostile conditions, and numerous bacteria produce cellulose as a biofilm matrix polymer. Hence, expression of the bcs operon, responsible for cellulose biosynthesis, must be finely regulated in order to allow bacteria to adopt the proper surface associated behaviours. Here we show that in the phytopathogenic bacterium, Dickeya dadantii, production of cellulose is required for pellicle-biofilm formation and resistance to chlorine treatments. Expression of the bcs operon is growth phase-regulated and is stimulated in biofilms. Furthermore, we unexpectedly found that the nucleoid-associated protein and global regulator of virulence functions, Fis, directly represses bcs operon expression by interacting with an operator that is absent from the bcs operon of animal pathogenic bacteria and the plant pathogenic bacterium Pectobacterium. Moreover, production of cellulose enhances plant surface colonization by D. dadantii. Overall, these data suggest that cellulose production and biofilm formation may be important factors for surface colonization by D. dadantii and its subsequent survival in hostile environments. This report also presents a new example of how bacteria can modulate the action of a global regulator to co-ordinate basic metabolism, virulence and modifications of lifestyle. PMID- 22925163 TI - Subtype specificity interaction of bactridines with mammalian, insect and bacterial sodium channels under voltage clamp conditions. AB - The present work demonstrates that bactridines (Bacts) possess different selectivities for neuronal and muscular voltage-dependent sodium (Na(V) ) channels, with subtle differences on channel isoforms. Bacts 2, 3, 4, 5 and 6 (100 nm) reduced the peak current of several skeletal and neuronal channel isoforms selectively. Bacts 2 and 3 were more potent on Na(V) 1.4, Bacts 4 and 6 on Na(V) 1.3 and Bact 5 on Na(V) 1.7. Bactridines (except Bacts 1 and 5) caused a hyperpolarizing shift in the V(1/2) of activation and inactivation of Na(V) 1.3, Na(V) 1.4 and Na(V) 1.6. Voltage shifts of Boltzmann curves fitted to activation and inactivation occurred with a decrease in kappa. Since the slope is proportional to kappa = RT/zF, changes in kappa probably express changes in z, the valence, in a voltage-dependent manner. Changes in z may express toxin induced changes in the channel ionic environment, perhaps due to surface charges of the molecules. Bact 2 induced a Na(V) 1.2 voltage shift of the activation curves but no shift of the mutant Na(V) 1.2 IFM/QQQ; peak I(N) (a) was reduced in both channel forms, suggesting that channel blockage resulted from toxin binding to a site partially distinct from the alpha subunit binding site 4. Bactridines emerge as potential research tools to understand sodium channel isoform structure-function relationships and also as pharmacologically interesting peptides. PMID- 22925164 TI - Congenital lower urinary tract obstruction: a population-based epidemiological study. AB - OBJECTIVE: To determine the prevalence and outcome of lower urinary tract obstruction (LUTO), including the sensitivity of antenatal diagnosis. DESIGN: A retrospective population-based study. SETTING: Regional population-based congenital anomalies register (WMCAR). POPULATION: Fetuses affected by LUTO delivered between 1995 and 2007 to women resident in the West Midlands. METHODS: Cases were selected from the WMCAR using codes and keyword terms from the International Classification of Diseases, tenth revision (ICD10). Diagnoses were validated using additional data sets from Regional Fetal Medicine, Perinatal Pathology and Paediatric services. MAIN OUTCOME MEASURES: Rates of prevalence, prenatal diagnosis and mortality, with trends. RESULTS: There were 284 LUTO cases in 851 419 births during the study period, representing a total prevalence of 3.34 (2.95-3.72) per 10 000 births, and this prevalence did not change significantly over time. The prevalence of LUTO was significantly higher in Black and minority ethnic groups when compared with white Europeans (OR 2.38; 95% CI 1.87-3.03), and are associated with area-based deprivation measures (P < 0.01). Of all LUTO cases, 221 (77.8%) were isolated, and the remainder were associated with other structural or chromosomal anomalies. The most common subtype was posterior urethral valves (PUVs; n = 179, 63%). In total there were 211 (74.3%) cases of isolated, non-female, singleton fetuses that fitted the referral criteria for in utero vesico-amniotic shunting, giving a prevalence of 2.48 (2.14 2.81) per 10 000 live births. Within this group, the prenatal diagnosis rate was 46.9% (99/211). CONCLUSION: This is the largest population-based study of LUTO that has been performed to date, and provides accurate estimates for prevalence. The low prevalence and relatively low rate of antenatal detection limit the number of cases amenable to prenatal surgical intervention. PMID- 22925165 TI - Vacuolar respiration of nitrate coupled to energy conservation in filamentous Beggiatoaceae. AB - We show that the nitrate storing vacuole of the sulfide-oxidizing bacterium Candidatus Allobeggiatoa halophila has an electron transport chain (ETC), which generates a proton motive force (PMF) used for cellular energy conservation. Immunostaining by antibodies showed that cytochrome c oxidase, an ETC protein and a vacuolar ATPase are present in the vacuolar membrane and cytochrome c in the vacuolar lumen. The effect of different inhibitors on the vacuolar pH was studied by pH imaging. Inhibition of vacuolar ATPases and pyrophosphatases resulted in a pH decrease in the vacuole, showing that the proton gradient over the vacuolar membrane is used for ATP and pyrophosphate generation. Blockage of the ETC decreased the vacuolar PMF, indicating that the proton gradient is build up by an ETC. Furthermore, addition of nitrate resulted in an increase of the vacuolar PMF. Inhibition of nitrate reduction, led to a decreased PMF. Nitric oxide was detected in vacuoles of cells exposed to nitrate showing that nitrite, the product of nitrate reduction, is reduced inside the vacuole. These findings show consistently that nitrate respiration contributes to the high proton concentration within the vacuole and the PMF over the vacuolar membrane is actively used for energy conservation. PMID- 22925166 TI - Coaching communication issues with elite female athletes: two Norwegian case studies. AB - The aim of this study was to examine the careers of two successful female elite athletes who later stagnated, and to identify possible factors that might have led to their demotivation. Individual interviews and a focus group interview were conducted. Using a multidisciplinary approach, the stories of April and Hazel raised several issues related to coaching, coach education, and the development of female athletes. Their individual profiles revealed that their perception of the lack of long-term development was caused by coach miscommunication, having to cope with sudden fame, and injuries provoked by overtraining. The coach-athlete relationship was discussed with a focus on the inexperience of some coaches, the number of coaches the athletes had to deal with, sociolinguistic issues, and the differing criteria of success communicated. Finally, the importance of their national governing bodies to focus on knowledge transfer, the supervision of coaches, and the infrastructure to monitor athletes were discussed. PMID- 22925167 TI - Degeneration of the cerebellum in Huntington's disease (HD): possible relevance for the clinical picture and potential gateway to pathological mechanisms of the disease process. AB - Huntington's disease (HD) is a polyglutamine disease and characterized neuropathologically by degeneration of the striatum and select layers of the neo- and allocortex. In the present study, we performed a systematic investigation of the cerebellum in eight clinically diagnosed and genetically confirmed HD patients. The cerebellum of all HD patients showed a considerable atrophy, as well as a consistent loss of Purkinje cells and nerve cells of the fastigial, globose, emboliform and dentate nuclei. This pathology was obvious already in HD brains assigned Vonsattel grade 2 striatal atrophy and did not correlate with the extent and distribution of striatal atrophy. Therefore, our findings suggest (i) that the cerebellum degenerates early during HD and independently from the striatal atrophy and (ii) that the onset of the pathological process of HD is multifocal. Degeneration of the cerebellum might contribute significantly to poorly understood symptoms occurring in HD such as impaired rapid alternating movements and fine motor skills, dysarthria, ataxia and postural instability, gait and stance imbalance, broad-based gait and stance, while the morphological alterations (ie ballooned neurons, torpedo-like axonal inclusions) observed in the majority of surviving nerve cells may represent a gateway to the unknown mechanisms of the pathological process of HD. PMID- 22925168 TI - Editorial. Bats and zoonoses. PMID- 22925170 TI - Intrastriatal excitotoxic lesion or dopamine depletion of the neostriatum differentially impairs response execution in extrapersonal space. AB - Dysfunction of the neostriatum, a primary feature of several neurodegenerative disorders, including Parkinson's disease and Huntington's disease, has been found to result in impaired localisation of, and reaction to, contralateral stimuli. On the basis of previous findings, it is hypothesised that, with increasing eccentricity of the response option, striatal cell loss may impair response localisation at the furthest levels of eccentricity, whereas dopamine (DA) depletion may not impact adversely upon responses executed in this extrapersonal space. In order to elucidate more fully the function of the striatum, the present study examined the differential impact of unilateral DA depletion or excitoxic lesion on response execution in ipsilateral and contralateral space at up to four levels of eccentricity. The results confirmed that, after both types of striatal dysfunction, the sensory ability to detect stimuli remains intact, whereas the ability to direct responses in absolute contralateral space is impaired. Distinct differences in the profiles of impairment were, however, evident, with a marked increase in response omissions observed after DA depletion, which may reflect decreased motivational processing, and recovery of function observed in rats with excitotoxic lesions, which suggests the ability to re-learn. Furthermore, the data demonstrate that, after cell loss, responding in near contralateral space is controlled by competing striata, whereas responding in extrapersonal space relies on the contralateral hemisphere. These results have implications for understanding the role of the striatum in egocentrically defined response localisation, as well as for unravelling the behavioural impact of striatal cell loss or aberrant DA transmission observed in neurodegenerative diseases. PMID- 22925169 TI - Body composition, dietary composition, and components of metabolic syndrome in overweight and obese adults after a 12-week trial on dietary treatments focused on portion control, energy density, or glycemic index. AB - BACKGROUND: Given the rise in obesity and associated chronic diseases, it is critical to determine optimal weight management approaches that will also improve dietary composition and chronic disease risk factors. Few studies have examined all these weight, diet, and disease risk variables in subjects participating in recommended multi-disciplinary weight loss programs using different dietary strategies. METHODS: This study compared effects of three dietary approaches to weight loss on body composition, dietary composition and risk factors for metabolic syndrome (MetS). In a 12-week trial, sedentary but otherwise healthy overweight and obese adults (19 M & 138 F; 38.7+/-6.7 y; BMI 31.8+/-2.2) who were attending weekly group sessions for weight loss followed either portion control, low energy density, or low glycemic index diet plans. At baseline and 12 weeks, measures included anthropometrics, body composition, 3-day food diaries, blood pressure, total lipid profile, HOMA, C-reactive protein, and fasting blood glucose and insulin. Data were analyzed by repeated measures analysis of variance. RESULTS: All groups significantly reduced body weight and showed significant improvements in body composition (p<0.001), and components of metabolic syndrome (p<0.027 to 0.002), although HDL decreased (p<0.001). Dietary energy, %fat and %saturated fat decreased while protein intake increased significantly (p<0.001). There were no significant differences among the three groups in any variable related to body composition, dietary composition, or MetS components. CONCLUSION: Different dietary approaches based on portion control, low energy density, or low glycemic index produced similar, significant short term improvements in body composition, diet compositin, and MetS components in overweight and obese adults undergoing weekly weight loss meetings. This may allow for flexibility in options for dietary counseling based on patient preference. PMID- 22925171 TI - The study of etiological and demographic characteristics of neonatal mortality and morbidity - a consecutive case series study from Pakistan. AB - BACKGROUND: To determine the etiology, management, bacteriological spectrum and outcome of neonatal patients admitted in Civil Hospital Karachi (CHK) and to examine the factors associated with it. METHODS: This hospital based descriptive study of 1463 patients from both sexes who were admitted to Paediatric department, CHK from 1st January 2008 till 31st December 2010 with an established cause according to modified Wigglesworth classification and fulfilling other inclusion criteria were included in the study. Data regarding their demographic profile and potential risk factors was collected on a well structured proforma. Cases were followed until discharge or expiry. Data was analyzed using descriptive statistics. RESULTS: The male to female ratio in our study was 1.12:1. Seven hundred and thirty-four patients were delivered at home (50.2%) and 1010 were less than 7 days old (69%). Out of the total cohort of expired subjects, 89 participants (74.8%) were < 7 days of life. Mortality was more in neonates born at home in rural areas to illiterate mother; 74 patients (62.2%). Most of the deaths; 57 were in neonates suffering from specific infections (47.9%) followed by 38 deaths in immaturity group (31.9%) and 19 related to asphyxial conditions (15.9%). The most common isolates were Staphylococcus aureus (28.7%) followed by Klebsiella (24.8%) and Pseudomonas aeruginosa (16.6 ). One hundred and nineteen (8.13%) of the neonates died in our study group. CONCLUSIONS: These results suggest that neonates with illiterate mothers with high parity and below average socioeconomic level were more susceptible to mortality in the early neonatal period. Most of the cases of mortality were due to specific infections. PMID- 22925172 TI - Markers of systemic inflammation in horses with heaves. AB - BACKGROUND: Systemic inflammation in horses with heaves is poorly characterized. OBJECTIVES: To assess acute phase proteins (APP) and inflammatory cytokine profiles in serum of healthy horses and horses with heaves. ANIMALS: Six healthy horses and 6 heaves-affected horses belonging to the University of Montreal. METHODS: Prospective, observational study. Healthy and heaves-affected control horses were exposed to a 30-day natural challenge with hay and straw to induce clinical exacerbation of heaves. Serum samples were obtained by venipuncture before (T0) as well as after 7 (T7) and 30 days (T30) of stabling. Serum APP (haptoglobin, serum amyloid A protein [SAA] and C-reactive protein [CRP]) and cytokines (IL-2, IL-4, IFN-alpha, IL-10, IFN-gamma, and CCL-2) were measured using singleplex or multiplex ELISA. RESULTS: Serum haptoglobin concentrations were significantly higher in heaves-affected horses at all time points with no overlap with those of healthy controls. They were also significantly increased by antigen challenge in both controls (T7) and horses with heaves (T7 and T30). Serum SAA was detected more frequently in heaves-affected horses compared with healthy controls at T7. There was no difference in serum concentrations of CRP, IL-10, IFN-gamma, and CCL-2 between groups, whereas IL-2, IL-4, and IFN-alpha remained undetectable in all samples. CONCLUSIONS AND CLINICAL IMPORTANCE: In heaves, haptoglobin is a marker of both acute and chronic systemic inflammation, whereas high concentrations of SAA indicate acute inflammation. PMID- 22925174 TI - Evolution of brain gray matter loss in Huntington's disease: a meta-analysis. AB - BACKGROUND: Huntington's disease is characterized by neuronal loss throughout the disease course. Voxel-based morphometry studies have reported reductions in gray matter concentration (GMC) in many brain regions in patients with Huntington. The description of the time course of gray matter loss may help to identify some evolution markers. Here, we conducted a meta-analysis of voxel-based morphometry studies of Huntington's disease to describe the evolution of brain gray matter loss. METHODS: A systematic search led to the inclusion of 11 articles on Huntington's disease (297 patients and 205 controls). We extracted data from patients with preclinical Huntington, patients with clinical Huntington, and controls. Finally, anatomical likelihood estimation analyses were conducted to identify GMC changes between preclinical patients and controls, between clinical patients and controls, and between preclinical and clinical patients. RESULTS: Preclinical patients exhibited gray matter loss in the left basal ganglia and the prefrontal cortex. Clinical patients had bilateral gray matter loss in the basal ganglia, the prefrontal cortex, and the insula. The left striatum was smaller in clinical patients than in preclinical patients. CONCLUSIONS: Neurodegenerative processes associated with Huntington's disease, as assessed by GMC reduction, begin in the left hemisphere and extend to the contralateral hemisphere throughout the inexorable course of the disease. Changes in gray matter, especially the volumetric side ratio of the striatum, could represent a relevant biomarker for characterizing the different progression stages of the disease. PMID- 22925173 TI - Exenatide once weekly for the treatment of type 2 diabetes: effectiveness and tolerability in patient subpopulations. AB - OBJECTIVE: Patient numbers in individual diabetes trials are often too limited to assess the effect of a treatment by different patient characteristics, and meta analyses often do not include patient-level data. The purpose of this pooled analysis was to evaluate the efficacy and tolerability of exenatide once weekly (EQW) in patients with type 2 diabetes grouped into subpopulations by key demographic characteristics. METHODS: This post hoc analysis included data from patients who received EQW in seven randomised, controlled phase 3 trials that were 24-30 weeks in duration. Patients were classified into subpopulations on the basis of their baseline age (< 65 or >= 65 years), gender (male or female), race (White, Black, Asian, Hispanic), duration of diabetes (< 10 years, >= 10 years) and body mass index (BMI; < 25, >= 25 to < 30, >= 30 to < 35, >= 35 to < 40 or >= 40 kg/m(2)). RESULTS: A total of 1719 patients were included in this analysis of patient subpopulations. All subpopulations experienced significant improvements from baseline in haemoglobin A1C, fasting glucose and body weight. Most subpopulations experienced significant improvements in blood pressure and lipid parameters. Overall, the most common AEs were hypoglycaemia (16.4% overall; 2.3% in patients not on concomitant sulfonylurea), nausea (14.7%), diarrhoea (10.9%) and nasopharyngitis (7.2%). CONCLUSION: These results show that the treatment of type 2 diabetes with EQW for 24-30 weeks was associated with significant improvements in glycaemic control and body weight, irrespective of age, gender, race, duration of diabetes or BMI. The most common adverse events were gastrointestinal in nature. PMID- 22925177 TI - Distance between residence and the dialysis unit does not impact self-perceived outcomes in hemodialysis patients. AB - BACKGROUND: Patients have to travel long distances to undergo hemodialysis (HD) in some regions. We aimed to search for an association of the distance between patients' residence and the dialysis unit with quality of life, depression and coping among end-stage renal disease (ESRD) patients undergoing maintenance HD. METHODS: We studied 161 ESRD patients undergoing HD during April 2009. Quality of life, depression and coping were assessed by the SF-36, the 10-item CES-D and the Jalowiec Coping Scale, respectively. The sample was stratified in three groups: I patients residing in Sobral (where the dialysis unit is located); II-patients residing in towns up to 100 km from Sobral; and III-patients residing in towns distant greater than 100 km from Sobral. Analysis of variance was used to detect differences in quality of life and coping scores between the groups. Logistic regression was used to test distance as a predictor of depression. RESULTS: There were 47 (29.2%) patients residing in Sobral, 46 (28.6%) up to 100 km away and 68 (42.2%) greater than 100 km from Sobral. There were no differences related to quality of life and coping scores between the groups. Distance was not a predictor of depression. CONCLUSIONS: Social and cultural factors may explain the lack of differences. Studies from other regions are needed to clarify the distance effects on self-perceived outcomes among HD patients. PMID- 22925176 TI - Intravenous iron sucrose versus oral iron in treatment of iron deficiency anemia in pregnancy: a randomized clinical trial. AB - AIM: Iron deficiency is a leading cause of anemia in pregnancy. The present study aimed to compare the efficacy of oral and intravenous iron therapy in improving iron deficiency anemia in pregnancy and restoring iron stores, compare the obstetric outcome in the two groups and evaluate the safety of intravenous iron sucrose. MATERIAL AND METHODS: This was a prospective study, where 100 anemic antenatal women with hemoglobin 7-9 g/dL, mean corpuscular volume <85 fL and serum ferritin <15 ng/mL, were randomized into two groups. In group A (n=50), the women received 200 mg tablets of ferrous sulphate, each containing 60 mg elemental iron, three times a day for 4 weeks. In group B (n=50), iron sucrose was given in divided doses of 200 mg each on alternate days by slow intravenous infusion. Primary outcome measure was treatment efficacy, assessed by measurement of hemoglobin, red blood cell indices and reticulocytes on days 7, 14, 21, and 30 and at delivery, and of ferritin on day 30 and at delivery. Any side-effects of treatment and the neonatal outcome were studied as secondary outcome measures. RESULTS: There was a statistically significant difference in increase of hemoglobin levels (3.1g/dL in group A vs 5.1 g/dL in group B; P=0.002) and ferritin levels between the two groups on day 30 (P=0.005). The adverse effects from iron treatment were mild but more prominent in group A. Neonatal outcome was comparable in the two groups. CONCLUSION: Intravenous administration of iron sucrose is a safe treatment for correction of anemia in pregnancy, without serious side-effects. PMID- 22925178 TI - Heparin-grafted dialysis membrane allows minimal systemic anticoagulation in regular hemodialysis patients: a prospective proof-of-concept study. AB - This prospective, multicenter, proof-of-concept study aimed to evaluate the possibility to reduce the ordinary heparin dose and the systemic anti-Xa activity during hemodialysis (HD) sessions using a new heparin-grafted HD membrane. In 45 stable HD patients, the use of a heparin-grafted membrane with the ordinary heparin dose was followed by a stepwise weekly reduction of dose. Reduction was stopped when early signs of clotting (venous pressure, quality of rinse-back) occurred during two out of three weekly HD sessions. Heparin dose was decreased for 67% of patients resulting in the lowering of these patients' anti-Xa activity by 50%. Dose reductions were achieved with both types of heparin (low-molecular weight heparin: 64 +/- 14 to 35 +/- 12 IU/kg, P < 0.0001; unfractionated heparin: 82 +/- 18 to 46 +/- 13 IU/kg, P < 0.0001) resulting in a decrease of anti-Xa activity at dialysis session end (low-molecular-weight heparin: 0.51 +/- 0.25 to 0.25 +/- 0.11 IU/mL, P < 0.0001; unfractionated heparin: 0.28 +/- 0.23 to 0.13 +/ 0.07 IU/mL, P < 0.0001). Failure to further decrease heparin dose was related to signs of clotting in blood lines (57% of sessions), in dialyzer (9%), or both (34%). Significant reduction of heparin dose and anti-Xa activity at the end of HD sessions was possible in stable HD patients using heparin-grafted membrane. HD patients who require low anti-Xa activity at the end of HD sessions might benefit from a heparin-grafted membrane to reduce bleeding risk and other heparin adverse events. PMID- 22925179 TI - Corneal power estimation for intraocular lens power calculation after corneal laser refractive surgery in Chinese eyes. AB - PURPOSE: To develop and evaluate an algorithm for corneal power estimation in intraocular lens (IOL) power calculation after corneal laser refractive surgery in Chinese eyes. SETTING: Guangdong Eye Institute, Guangdong Academy of Medical Sciences, Guangzhou, China. DESIGN: Prospective comparative case series. METHODS: Corneal parameters in Chinese eyes and German eyes were measured using a rotating Scheimpflug camera. Corneal power was simplified as a corrective algorithm: K(C) = 1.114 * K(M) + K(2) (K(M) = measured K reading; K(2) = K(P) - K(A) * K(P) * CT/1.376; K(A) = anterior corneal power; K(P) = posterior corneal power; CCT = central corneal thickness). The variation and change in K(2) induced by refractive surgery were analyzed in Chinese eyes. The corrective algorithm was identified as K(C) = 1.114 * K(M) - 6.20. The method was evaluated in Chinese cataract cases after refractive surgery using the Haigis formula. RESULTS: No difference in anterior corneal radius (R(A)) or CCT between Chinese eyes and German eyes were found; however, the posterior corneal radius (R(P)), R(A)/R(P) ratio, keratometric index, and K(2) were different. The mean K(2) was -6.23 diopters (D) +/- 0.24 (SD) in Chinese eyes and -6.12 +/- 0.23 D in German eyes (P<.01). The mean change in K(2) induced by refractive surgery was -0.02 +/- 0.06 D. The median absolute prediction error in IOL power calculation was 0.43 D (range 0.01 to 1.80 D). CONCLUSION: The algorithm was a relatively reliable method in IOL power calculation after corneal refractive surgery in Chinese eyes. PMID- 22925180 TI - Adherence efforts go high-tech. PMID- 22925181 TI - Literature watch: Implications for transplantation. Mast cells: inflammatory, immunoregulatory or something in between? PMID- 22925182 TI - Reducing complications in pediatric liver transplantation: do we have the answer? PMID- 22925183 TI - Costimulation blockade-a double-edged sword? PMID- 22925184 TI - Perspectives on lung transplantation and donation-after-determination-of-cardiac death donors. PMID- 22925186 TI - Fever, hepatosplenomegaly and a skin nodule in a kidney-pancreas transplant recipient. PMID- 22925188 TI - Mediastinitis after coronary artery bypass grafting: the effect of vacuum assisted closure versus traditional closed drainage on survival and re-infection rate. AB - Mediastinitis is treated with either vacuum-assisted closure (VAC) or traditional closed drainage (TCD) with irrigation. The aim of the study was to determine the effect of the two treatments on mortality and re-infection rate in a source population, using 21 314 consecutive patients undergoing isolated coronary artery bypass grafting (CABG) from January 1997 to October 2010. Median observation time was 2.9 years in the VAC group and 8.0 years in the TCD group. The epidemiological design was of an exposed (VAC, n = 64) versus non-exposed (TCD, n = 66) cohort with two endpoints: (1) mortality and (2) failure of sternal wound healing or re-infection. The crude effect of treatment technique versus endpoint was estimated by univariate analysis. Stratification analysis by the Mantel Haenszel method was performed to quantify confounders and to pinpoint effect modifiers. Adjustment for confounders was performed using Cox regression analysis. Mediastinitis was diagnosed 6-105 (median 14) days after primary operation in the VAC group and 13 (5-29) days in the TCD group. There was no difference between groups in long-term survival. Failure of sternal wound healing or re-infection occurred less frequently in the VAC group (6%) than in the TCD group (21%; relative risk = 0.29, 95% CI = 0.06-0.88, P = 0.01). There are concerns for increase in right ventricle rupture in VAC compared with TCD. There was no difference in survival after VAC therapy and TCD therapy of post-CABG mediastinitis. Failure of sternal wound healing or re-infection was more common after TCD therapy. PMID- 22925189 TI - MicroRNA expression in ovarian carcinoma and its correlation with clinicopathological features. AB - BACKGROUND: MicroRNA (miRNA) expression is known to be deregulated in ovarian carcinomas. However, limited data is available about the miRNA expression pattern for the benign or borderline ovarian tumors as well as differential miRNA expression pattern associated with histological types, grades or clinical stages in ovarian carcinomas. We defined patterns of microRNA expression in tissues from normal, benign, borderline, and malignant ovarian tumors and explored the relationship between frequently deregulated miRNAs and clinicopathologic findings, response to therapy, survival, and association with Her-2/neu status in ovarian carcinomas. METHODS: We measured the expression of nine miRNAs (miR-181d, miR-30a-3p, miR-30c, miR-30d, miR-30e-3p, miR-368, miR-370, miR-493-5p, miR-532 5p) in 171 formalin-fixed, paraffin-embedded ovarian tissue blocks as well as six normal human ovarian surface epithelial (HOSE) cell lines using Taqman-based real time PCR assays. Her-2/neu overexpression was assessed in ovarian carcinomas (n = 109 cases) by immunohistochemistry analysis. RESULTS: Expression of four miRNAs (miR-30c, miR-30d, miR-30e-3p, miR-370) was significantly different between carcinomas and benign ovarian tissues as well as between carcinoma and borderline tissues. An additional three miRNAs (miR-181d, miR-30a-3p, miR-532-5p) were significantly different between borderline and carcinoma tissues. Expression of miR-532-5p was significantly lower in borderline than in benign tissues. Among ovarian carcinomas, expression of four miRNAs (miR-30a-3p, miR-30c, miR-30d, miR 30e-3p) was lowest in mucinous and highest in clear cell samples. Expression of miR-30a-3p was higher in well-differentiated compared to poorly differentiated tumors (P = 0.02), and expression of miR-370 was higher in stage I/II compared to stage III/IV samples (P = 0.03). In multivariate analyses, higher expression of miR-181d, miR-30c, miR-30d, and miR-30e-3p was associated with significantly better disease-free or overall survival. Finally, lower expression of miR-30c, miR-30d, miR-30e-3p and miR-532-5p was significantly associated with overexpression of Her-2/neu. CONCLUSIONS: Aberrant expression of miRNAs is common in ovarian tumor suggesting involvement of miRNA in ovarian tumorigenesis. They are associated with histology, clinical stage, survival and oncogene expression in ovarian carcinoma. PMID- 22925190 TI - Tagaturonate-fructuronate epimerase UxaE, a novel enzyme in the hexuronate catabolic network in Thermotoga maritima. AB - Thermotoga maritima is a marine hyperthermophilic microorganism that degrades a wide range of simple and complex carbohydrates including pectin and produces fermentative hydrogen at high yield. Galacturonate and glucuronate, two abundant hexuronic acids in pectin and xylan, respectively, are catabolized via committed metabolic pathways to supply carbon and energy for a variety of microorganisms. By a combination of bioinformatics and experimental techniques we identified a novel enzyme family (named UxaE) catalysing a previously unknown reaction in the hexuronic acid catabolic pathway, epimerization of tagaturonate to fructuronate. The enzymatic activity of the purified recombinant tagaturonate epimerase from T. maritima was directly confirmed and kinetically characterized. Its function was also confirmed by genetic complementation of the growth of the Escherichia coli uxaB knockout mutant strain on galacturonate. An inferred novel galacturonate to mannonate catabolic pathway in T. maritima was reconstituted in vitro using a mixture of recombinant purified enzymes UxaE, UxaC and UxuB. Members of the newly identified UxaE family were identified in ~50 phylogenetically diverse heterotrophic bacteria from aquatic and soil environments. The genomic context of respective genes and reconstruction of associated pathways suggest that UxaE enzymatic and biological function remains conserved in all of these species. PMID- 22925191 TI - Fatal cases of gestational trophoblastic neoplasia over four decades in the Netherlands: a retrospective cohort study. AB - OBJECTIVE: To describe fatal cases of gestational trophoblastic neoplasia (GTN) over four decades and evaluate whether treatment was given according to the protocol and reveal possible implications for future management. DESIGN: Retrospective cohort study. SETTING: The Netherlands. POPULATION: Women who died from GTN from 1971 to 2011. METHODS: Records from the Dutch Central Registry for Hydatidiform Moles and the Working Party on Trophoblastic Disease were used to identify fatal cases of GTN. MAIN OUTCOME MEASURES: Disease extent, risk classification, treatment regimens and cause of death. RESULTS: Twenty-six women died from GTN. In five cases GTN developed after a hydatidiform mole and in 19 cases following term pregnancy. Half of the women died between 1971 and 1980, when women were not yet classified as having low-risk or high-risk disease and were therefore not yet treated accordingly. A major decline in the number of deaths was seen after the first decade, with a further decrease from 1981 to 2011. Early death occurred in nine women. In four of these women, death was treatment-related. Women who died more than 4 weeks after the start of treatment mostly died from metastatic tumour (n = 14). CONCLUSIONS: The yearly number of women who died from GTN decreased considerably over the last four decades. Appropriate risk classification is essential to start optimal initial therapy and to prevent therapy resistance. Women with post-term choriocarcinoma represented a large proportion of the dead women and we propose that these women are considered as having high-risk disease. PMID- 22925192 TI - Influence of Stratum Corneum on the entire skin mechanical properties, as predicted by a computational skin model. AB - BACKGROUND/PURPOSE: Skin mechanical properties are globally well described. The aim of this paper is to evaluate, by means of a numerical model, the influence of Stratum Corneum (SC) on skin folding resulting from an in-plane compression. METHODS: A computational skin model was developed where skin is divided into three layers (SC, epidermis and upper dermis, and deep dermis) of different thicknesses and elastic moduli. Skin surface deformation, consecutive to the application of a given surface compression, was computed by minimizing the mechanical energy of the multi-layered tissue. Influence of SC thickness and elastic modulus on skin buckling is presented. RESULTS: Varying both SC thickness and elastic modulus has a marked influence on both wavelength and amplitude of the skin's surface folds. These two parameters display a logarithmic variation versus SC elastic modulus. CONCLUSION: Although representing about one hundredth of the total skin thickness, SC has a marked influence on the skin mechanical properties. PMID- 22925193 TI - Complement in pregnancy: a delicate balance. AB - The complement system is a key component of innate host defence that, under normal conditions, is responsible for the opsonization and destruction of potential pathogens. However, inappropriate or excessive activation of complement can have a detrimental effect on the host and has been implicated in the pathophysiology of numerous disease states. Recently, there has been increasing evidence for a role of the complement system and, in particular, the potent pro inflammatory anaphylatoxin complement component 5a (C5a) in both normal and complicated pregnancy. The following review describes the results of in vitro, animal, and human clinical studies investigating the role of the complement system in healthy pregnancy, recurrent miscarriage, preterm birth, and preeclampsia. PMID- 22925194 TI - No serologic evidence for zoonotic canine respiratory coronavirus infections among immunocompetent adults. AB - Zoonotic diseases continue to emerge and threaten both human and animal health. Overcrowded shelters and breeding kennels create the perfect environment for amplified infectious disease transmission among dogs and present a critical opportunity for zoonotic pathogens to emerge and infect people who work in close contact with dogs. Coronaviruses' widespread prevalence, extensive host range, various disease manifestations and increased frequency of recombination events all underline their potential for interspecies transmission (Methods Mol. Biol. 2008, 454, 43). The objectives of this study were to determine whether people with occupational contact with dogs were more likely to have antibodies against canine respiratory coronavirus (CRCoV) compared to persons with no dog exposure. A seroepidemiological cohort study was completed, for which 302 canine-exposed and 99 non-canine-exposed study subjects enrolled in the study by providing a serum sample and completing a self-administered questionnaire. A competitive enzyme-linked immunosorbent assay (ELISA) was developed to detect human antibodies against CRCoV while controlling for cross-reacting antibodies against the human coronavirus OC43. All study subjects were negative for antibodies against CRCoV by this competitive ELISA. This study supports the premise that humans are not at risk for CRCoV infections; however, infrequent cross-species transmission of CRCoV cannot be ruled out. PMID- 22925195 TI - Evaluation of Mindray BC-3600 hematology analyzer in a university hospital. AB - INTRODUCTION: The BC-3600 Auto Hematology Analyzer (hereinafter call BC-3600) is a quantitative, automated hematology analyzer and leukocyte differential counter for In Vitro Diagnostic Use in clinical laboratories. METHODS: The analyzer was evaluated and compared with the Mindray BC-3200 3-part differential (BC-3200) and Sysmex XE-2100 5-part differential (XE-2100) Hematology Analyzer in the hematology laboratory of a university hospital. The BC-3600 was evaluated according to guidelines published by Clinical and Laboratory Standards Institute (CLSI), the International Committee for Standardization in Hematology (ICSH), and Department of Food and Drug Administration (FDA). RESULTS: There were no background, minimal carryover (<0.5%), and excellent linearity for white blood cell (WBC), hemoglobin (Hb) level, red blood cell (RBC), and platelet (PLT) counts (r > 0.999). Precision was good at all levels for the routine cell blood count (CBC) parameters: CV% being <=2.0, except for platelet count (PLT) at the low level with CV% of <=5.0% and WBC at the low level with CV% of <3.0%. Correlation between the BC-3600 and BC-3200, XE-2100 were excellent (r > 0.99) for all major CBC parameters. CONCLUSION: It is concluded that the overall performance of the BC-3600 is excellent and compares well with that of BC-3200 and XE-2100. PMID- 22925196 TI - Proactive inhibitory control varies with task context. AB - The goal of executive control is to adjust our behaviour to the environment. It involves not only the continuous planning and adaptation of actions but also the inhibition of inappropriate movements. Recently, a proactive form of inhibitory control has been shown, demonstrating that actions can be withheld, in an uncertain environment, thanks to the proactive locking of the mechanism by which motor commands are triggered (e.g. while waiting at traffic lights in a dense pedestrian zone, one will refrain in anticipation of a brisk acceleration when the green light comes on). However, little is known about this executive function and it remains unclear whether the overall amount of inhibitory control can be modulated as a function of the context. Here, we show that the level of this control varies parametrically as a function of the exogenous and endogenous factors setting the task context. We also show that the level of implemented proactive inhibitory control is dynamically readjusted to match the implicit temporal structure of the environment. These observations are discussed in relation to possible underlying functional substrates and related neurological and psychiatric pathologies. PMID- 22925197 TI - The primary type of tremor in essential tremor is kinetic rather than postural: cross-sectional observation of tremor phenomenology in 369 cases. AB - BACKGROUND: Essential tremor (ET) is amongst the most commonly misdiagnosed neurological diseases. The current aim was to provide observational data on a basic characteristic of ET, namely, the relative severity of postural to kinetic tremor. METHODS: A total of 369 ET cases were enrolled in a cross-sectional study. Postural tremor scores (0-3) and kinetic tremor scores (0-3) were assigned during a standardized neurological examination. RESULTS: In the vast bulk of cases (~95%), kinetic tremor was more severe than postural tremor. In nearly one in-three cases (32.8%), the kinetic tremor score was >= 1 points higher than the postural tremor score. Conversely, in only a few cases (~5%) was postural tremor even marginally (<1 point) more severe than kinetic tremor, and in no case was the postural tremor score >= 1 point higher than the kinetic tremor score. At each postural tremor score, nearly all cases had that amount of kinetic tremor or more. CONCLUSION: The primary type of tremor in ET is kinetic rather than postural. Recognition of the simple, empirical features of tremor phenomenology has potential diagnostic value for practicing clinicians. PMID- 22925198 TI - Preventing relapse in recurrent depression using mindfulness-based cognitive therapy, antidepressant medication or the combination: trial design and protocol of the MOMENT study. AB - BACKGROUND: Depression is a common psychiatric disorder characterized by a high rate of relapse and recurrence. The most commonly used strategy to prevent relapse/recurrence is maintenance treatment with antidepressant medication (mADM). Recently, it has been shown that Mindfulness-Based Cognitive Therapy (MBCT) is at least as effective as mADM in reducing the relapse/recurrence risk. However, it is not yet known whether combination treatment of MBCT and mADM is more effective than either of these treatments alone. Given the fact that most patients have a preference for either mADM or for MBCT, the aim of the present study is to answer the following questions. First, what is the effectiveness of MBCT in addition to mADM? Second, how large is the risk of relapse/recurrence in patients withdrawing from mADM after participating in MBCT, compared to those who continue to use mADM after MBCT? METHODS/DESIGN: Two parallel-group, multi-center randomized controlled trials are conducted. Adult patients with a history of depression (3 or more episodes), currently either in full or partial remission and currently treated with mADM (6 months or longer) are recruited. In the first trial, we compare mADM on its own with mADM plus MBCT. In the second trial, we compare MBCT on its own, including tapering of mADM, with mADM plus MBCT. Follow up assessments are administered at 3-month intervals for 15 months. Primary outcome is relapse/recurrence. Secondary outcomes are time to, duration and severity of relapse/recurrence, quality of life, personality, several process variables, and incremental cost-effectiveness ratio. DISCUSSION: Taking into account patient preferences, this study will provide information about a) the clinical and cost-effectiveness of mADM only compared with mADM plus MBCT, in patients with a preference for mADM, and b) the clinical and cost-effectiveness of withdrawing from mADM after MBCT, compared with mADM plus MBCT, in patients with a preference for MBCT. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00928980. PMID- 22925199 TI - Ascorbic acid blocks hyperglycemic impairment of endothelial function in adolescents with type 1 diabetes. AB - OBJECTIVE: To determine whether acute ascorbic acid infusions alter the effect of hyperglycemia on endothelial function in adolescents with type 1 diabetes. RESEARCH DESIGN AND METHODS: The forearm blood flow (FBF) reactive hyperemic response to 5 min of upper arm occlusion was studied in eight adolescents with type 1 diabetes during euglycemic and hyperglycemic insulin clamp (40 mU/m2/min) with and without ascorbic acid infusion (3 mg/min). RESULTS: The ratio of post- to preocclusion FBF decreased during hyperglycemia without ascorbic acid (p = 0.013), but did not change during hyperglycemia with ascorbic acid. The changes during hyperglycemia were different between the two studies (p = 0.038). Similar results were found when the percent change in forearm vascular resistance following occlusion was assessed. CONCLUSIONS: These results indicate that antioxidant treatment with ascorbic acid blocks acute hyperglycemic impairment of endothelial function in adolescents with type 1 diabetes. PMID- 22925200 TI - A comparative review of vitamin E and associated equine disorders. AB - Vitamin E is a primary chain-breaking antioxidant that prevents cyclic propagation of lipid peroxidation. Across species, vitamin E is essential for normal neuromuscular function by acting as a potent antioxidant, as well as by modulating the expression of certain genes, inhibiting platelet aggregation and stabilizing plasma membranes. This review focuses on vitamin E structure, absorption, metabolism, current equine dietary recommendations, the interplay between antioxidants and exercise, a discussion of the necessity of vitamin E supplementation in the horse above the Nutritional Research Council (NRC) 2007 requirements, and a review of equine diseases that are associated with a vitamin E deficiency. Particular emphasis is placed on the proteins involved in vitamin E absorption, transport, and metabolism as potential candidates for vitamin E associated diseases across species. PMID- 22925201 TI - Surgical challenge: endoscopic repair of cerebrospinal fluid leak. AB - BACKGROUND: Cerebrospinal fluid leaks (CSF) result from an abnormal communication between the subarachnoid space and the extracranial space. Approximately 90% of CSF leak at the anterior skull base manifests as rhinorrhea and can become life threatening condition. Endoscopic sinus surgery (ESS) has become a common otolaryngologist procedure. The aim of this article is to consider our experience and to evaluate the outcomes in patients who underwent a purely endoscopic repair of CSF leaks of the anterior skull base. FINDINGS: Retrospective chart review was performed of all patients surgically treated for CSF leaks presenting to the Section of Nasal and Sinus Disorders at the Service of ENT-Head and Neck Surgery, University Hospital Complex of Santiago de Compostela (CHUS), between 2004 and 2010. A total of 30 patients who underwent repair CSF leak by ESS. The success rate was 93.4% at the first attempt; only two patients (6.6%) required a second surgical procedure, and none of it was necessary to use a craniotomy for closure. Follow-up periods ranged from 4 months to 6 years. CONCLUSION: Identifying the size, site, and etiology of the CSF leak remains the most important factor in the surgical success. It is generally accepted that the ESS have made procedures minimally invasive, and CSF leak is now one of its well-established indications with low morbidity and high success rate, with one restriction for fistulas of the posterior wall of the frontal sinus should be repaired in conjunction with open techniques. PMID- 22925202 TI - Natural history of primary precursor B lymphoblastic lymphoma of the ovary: report of a rare case. AB - The involvement of the ovaries in lymphomatous processes is a relatively rare phenomenon. Secondary involvement as a part of systemic disease is common as compared to de novo primary lymphoma. Mostly, primary ovarian lymphomas are diffuse large B cell type, whereas the precursor lymphoblastic lymphomas are extremely rare and only four cases have been reported previously. We herein describe a case of primary precursor B lymphoblastic lymphoma involving both ovaries in a 28-year-old woman which was detected incidentally and spread into the blood after 7 months; consequently she succumbed to the disease. PMID- 22925204 TI - Characterization of NF1 allele containing two nonsense mutations in exon 37 that segregates with neurofibromatosis type 1. AB - Neurofibromatosis type 1 (NF1) is a common autosomal dominant disease caused by mutations in the NF1 gene. The mutation rate of NF1 is one of the highest known for human genes and the mutational analysis has revealed a wide variety of changes, a significant proportion of which affect normal pre-mRNA splicing. Here, we describe two truncating mutations in exon 37 of NF1, the recurrent c.6792C>A and the novel c.6799C>T change, that occur in cis and segregate with NF1 in a large family. The double mutation induces defective splicing of exon 37 and thus, we performed quantitative comparisons of transcripts harboring single (c.6792C>G or c.6792C>A) and double (c.6792C>A and c.6799C>T) mutations to assess their effects on exon 37 splicing. Skipping of exon 37 was greater and there were fewer mutant full-length transcripts in samples with the double mutation than in those carrying single mutations. Thus, the combination of the c.6792C>A and c.6799C>T mutations augmented exon 37 skipping. These findings suggest that, in addition to the previously described exonic splicing enhancer in the c.6791_6795 region, c.6799 lies within an additional regulatory element that influences the splicing of exon 37. PMID- 22925203 TI - Inactivation of Pde8b enhances memory, motor performance, and protects against age-induced motor coordination decay. AB - Phosphodiesterases (PDEs) are critical regulatory enzymes in cyclic nucleotide signaling. PDEs have diverse expression patterns within the central nervous system (CNS), show differing affinities for cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP), and regulate a vast array of behaviors. Here, we investigated the expression profile of the PDE8 gene family members Pde8a and Pde8b in the mouse brain. We find that Pde8a expression is largely absent in the CNS; by contrast, Pde8b is expressed in select regions of the hippocampus, ventral striatum, and cerebellum. Behavioral analysis of mice with Pde8b gene inactivation (PDE8B KO) demonstrate an enhancement in contextual fear, spatial memory, performance in an appetitive instrumental conditioning task, motor-coordination, and have an attenuation of age-induced motor coordination decline. In addition to improvements observed in select behaviors, we find basal anxiety levels to be increased in PDE8B KO mice. These findings indicate that selective antagonism of PDE8B may be an attractive target for enhancement of cognitive and motor functions; however, possible alterations in affective state will need to be weighed against potential therapeutic value. PMID- 22925205 TI - Supercath Safety Clampcath buttonhole creation: complication of catheter breakage. AB - The creation of buttonhole tracks with Supercath Safety Clampcath is a novel and simple technique that allows dull fistula needle insertions with relative ease and diminished pain. As greater experience with this procedure develops, new issues arise for consideration. We report an unexpected complication of Supercath Safety Clampcath catheter breakage that may be due to physical distortions as a result of its location in the antecubital fossa just proximal to the elbow joint. We present a review of our experience and a framework for the safe ongoing use of this device for creation of buttonholes in fistula for hemodialysis. PMID- 22925206 TI - Inhaled methoxyflurane for pain and anxiety relief during burn wound care procedures: an Australian case series. AB - Pain is a common and significant feature of burn injury. The use of intravenous opioids forms the mainstay of procedural burn pain management, but in an outpatient setting, the demand for novel agents that do not require parenteral access, are easy to administer and have a rapid onset are urgently needed. One such agent is the inhaled anaesthetic agent, methoxyflurane (MF). The aim of this study was to conduct a pilot investigation into the clinical effectiveness of MF inhaler on pain and anxiety scores in patients undergoing burn wound care procedures in an outpatient setting. A prospective case series involved recruiting patients undergoing a burn wound care procedure in an ambulatory burn care setting. Pain and anxiety were assessed using numerical rating scales. Overall, median numerical pain rating score was significantly higher post dressing [pre-dressing: 2; interquartile range (IQR): 1-3 versus post-dressing: 3; IQR 1.5-4; P = 0.01], whereas median numerical anxiety score significantly reduced following the dressing (pre-dressing: 5; IQR 4-7 versus post-dressing: 2; IQR 1-2; P < 0.001). Our study suggests that there is a role for MF in the pain management armamentarium in those undergoing burn care procedures in the ambulatory care setting. However, there is an urgent need for larger case series and randomised controlled trials to determine its overall clinical effectiveness. PMID- 22925207 TI - The association between female genital mutilation and intimate partner violence. AB - OBJECTIVE: To determine whether female genital mutilation (FGM) is a risk factor for intimate partner violence (IPV) and its subtypes (physical, sexual and emotional). DESIGN: Population-based cross-sectional study. SETTING: The study used the 2006 Demographic and Health Survey (DHS) conducted in Mali. POPULATION: A total of 7875 women aged 15-49 years who responded to the domestic violence and female circumcision modules in the 2006 administration of the DHS in Mali. METHODS: Multivariable logistic regression was used to compute adjusted odds ratios (aOR) and 95% confidence intervals (CI) to measure risk for IPV. MAIN OUTCOME MEASURES: The outcomes of interest were IPV and its subtypes. RESULTS: Women with FGM were at heightened odds of IPV (aOR 2.71, 95% CI 2.17-3.38) and IPV subtypes: physical (aOR 2.85, 95% CI 2.22-3.66), sexual (aOR 3.24, 95% CI 1.80-5.82), and emotional (aOR 2.28, 95% CI 1.68-3.11). The odds of IPV increased with ascending FGM severity (P for trend <0.0001). The most elevated odds were observed among women with severe FGM, who were nearly nine times as likely to experience more than one IPV subtype (aOR 8.81, 95% CI 5.87-13.24). CONCLUSIONS: Study findings underscore the need for multi-tiered strategies, incorporating policy and education, to reduce FGM and IPV, potentially improving the holistic health and wellbeing of Malian women. PMID- 22925208 TI - Increased expression of kisspeptin and GnRH forms in the brain of scombroid fish during final ovarian maturation and ovulation. AB - BACKGROUND: Kisspeptins (Kiss) are prime players in the control of reproductive function through their regulation of gonadotropin-releasing hormone (GnRH) expression in the brain. The experimental scombroid fish, chub mackerel (Scomber japonicus) expresses two kiss (kiss1 and kiss2) and three gnrh (gnrh1, gnrh2, and gnrh3) forms in the brain. In the present study, we analyzed expression changes of kiss and gnrh mRNAs in the brain and corresponding GnRH peptides in the brain and pituitary during final ovarian maturation (FOM) and ovulation. METHODS: Female fish possessing late vitellogenic oocytes were injected with GnRH analogue to induce FOM and ovulation. Fish were observed for daily spawning activities and sampled one week post-injection at germinal vesicle migration (GVM), oocyte hydration, ovulation, and post-ovulatory time periods. Changes in relative mRNA levels of kiss and gnrh forms in the brain were determined using quantitative real-time PCR. Changes in GnRH peptides in the brain and pituitary were analyzed using time-resolved fluoroimmunoassay. RESULTS: Both kiss1 and kiss2 mRNA levels in the brain were low at late vitellogenic stage and increased significantly during the GVM period. However, kiss1 mRNA levels decreased during oocyte hydration before increasing again at ovulatory and post-ovulatory periods. In contrast, kiss2 mRNA levels decreased at ovulatory and post-ovulatory periods. Levels of gnrh1 mRNA in the brain increased only during post-ovulatory period. However, levels of gnrh2 and gnrh3 mRNAs were elevated during GVM and then, decreased during oocyte hydration before increasing again at ovulatory period. During post-ovulatory period, both gnrh2 and gnrh3 mRNA levels declined. Peptide levels of all three GnRH forms in the brain were elevated during GVM and oocyte hydration; their levels were significantly lower during late vitellogenic, ovulatory, and post-ovulatory periods. In contrast, pituitary GnRH peptide levels did not show any significant fluctuations, with the GnRH1 peptide levels being many-fold higher than the GnRH2 and GnRH3 forms. CONCLUSION: The results indicate increased expression of multiple Kiss and GnRH forms in the brain and suggest their possible involvement in the regulation of FOM and ovulation in captive female chub mackerel. PMID- 22925209 TI - Comparative proteomic analysis reveals insights into anoxic growth of Methyloversatilis universalis FAM5 on methanol and ethanol. AB - Methyloversatilis universalis FAM5 is a facultative methylotrophic bacterium that has been found in a variety of natural and engineered ecosystems. The goal of this study was to investigate M. universalis FAM5 responses to different electron/carbon donors, e.g. methanol or ethanol, during anoxic growth in chemostats with nitrate as the electron acceptor. During steady-state anoxic growth on either methanol or ethanol, over 90% of the influent nitrate was reduced primarily to nitrite. The cell yield on methanol was lower, possibly due to high energy requirements for C(1) assimilation. Label-free proteomics further revealed that methanol-grown cells displayed elevated concentrations of the enzymes involved in C(1) metabolism (H(4)MPT/H(4) F pathways, formate oxidation and serine cycle). In contrast, C(2) metabolism (glyoxylate shunt and tri carboxylic acid cycle) and polyhydroxy-beta-butyrate (PHB) synthesis related proteins were overrepresented during subsequent growth on ethanol. Notably, the expression of respiratory nitrate reductase was not affected by the carbon sources applied. Furthermore, the changes in the proteome upon switching back to methanol were mostly reversible. Therefore, M. universalis displays wide-ranging responses to adapt between growth on methanol and ethanol. Such metabolic versatility could be particularly useful in wastewater treatment systems, which need to switch between different electron donors, while still reliably meeting effluent nitrogen discharge goals. PMID- 22925210 TI - Methicillin-resistant Staphylococcus aureus (MRSA) ST398 in pig farms and multispecies farms. AB - During the last few years, methicillin-resistant Staphylococcus aureus (MRSA) ST398 has been isolated frequently from livestock, especially from pigs and to a lesser extent from cattle and poultry. To gain insight into the distribution of this bacterium in pig farms versus multispecies farms, 30 Belgian farms (10 pig, 10 pig/poultry and 10 pig/cattle farms) were screened for the presence of MRSA. On each farm, 10 nasal swabs were taken from pigs. When present, cattle (n=10) were sampled in the nares and poultry (n=10) in the nares, earlobes and cloaca. A selection of the obtained isolates were further characterized using multilocus sequence typing (MLST), spa typing, SCCmec typing, pulsed field gel electrophoresis (PFGE), multiple-locus variable-number tandem repeat analysis (MLVA) and antimicrobial susceptibility testing. On 26 of 30 farms, MRSA was isolated from pigs. Furthermore, MRSA was also isolated from poultry and cattle on one pig/poultry and five pig/cattle farms, respectively. All tested MRSA isolates belonged to ST398. Eight spa types (t011, t034, t567, t571, t1451, t2974, t3423 and t5943) were detected, among which t011 predominated. SCCmec cassettes type IVa and V were present in 20% and 72% of the isolates, respectively. When combining the results of the two remaining typing methods, PFGE and MLVA, eighteen genotypes were obtained of which one genotype predominated (56% of the positive farms). All MRSA isolates were resistant to tetracycline. Resistance to trimethoprim, aminoglycosides, macrolides, lincosamides, fluoroquinolones and chloramphenicol was also observed. In conclusion, there was no effect of the farm type on the MRSA status of the pigs. A statistically significant difference was observed when comparing the pig/poultry or the pig/cattle MRSA status on the multispecies farms. Additionally, a wide variety of MRSA ST398 strains was found within certain farms when combining different typing methods. PMID- 22925211 TI - Developmental neurotoxicity testing: scientific approaches towards the next generation to protect the developing nervous system of children. An overview of the Developmental Neurotoxicity Symposium in 2011. AB - The Developmental Neurotoxicology (DNT) Committee has been working to promote developmental neurotoxicology and related scientific areas of interest to integrate academic and regulatory sciences in this field since the Behavioral Teratology Meeting was established by the Japanese Teratology Society in 1982. The committee has led several large-scale collaborative studies to standardize existing methodologies and held symposiums and workshops periodically at the society's annual meetings. This overview provides a history of the DNT Committee, as well as a brief summary of the DNT Symposium in 2011. PMID- 22925212 TI - Developmental neurotoxicity guideline study: issues with methodology, evaluation and regulation. AB - Recently social concerns have been increasing about the effects of environmental factors on children's health, especially on their nervous systems. The U.S. Environmental Protection Agency (EPA) and the Organisation for Economic Co operation and Development (OECD) have published testing guidelines for developmental neurotoxicity (DNT). Approximately 110 guideline studies have been conducted to date. Importantly, information from these studies has provided data critical for regulatory decisions for a number of chemicals. However, the DNT guidelines do not always satisfy all stakeholders because of some uncertainties in their methodology, evaluation, and regulation. Methodological issues include incomplete harmonization between EPA and OECD guidelines, criticisms of the methodology for learning and memory testing, and unspecified positive control substances. Potential artifacts in morphometric neuropathological measures, criteria for observation measures, uncertainty of postnatal offspring exposure, especially in feeding studies, and extrapolation of data from rats to humans are major evaluation issues. In addition, there is some uncertainty in the use of an additional safety factor for susceptibility of infants and children. Moreover, the DNT guidelines have extensive time and cost requirements, use large numbers of animals, and there is a limited set of laboratories that can conduct the study. This paper reviews some of these issues and summarizes discussions from the symposium 'Developmental neurotoxicity testing: Scientific approaches towards the next generation to protecting the developing nervous system of children' held at the 2011 annual meeting of the Japanese Teratology Society. PMID- 22925213 TI - Current problems of in vivo developmental neurotoxicity tests and a new in vivo approach focusing on each step of the developing central nervous system. AB - Developmental neurotoxicity (DNT) tests usually focus on postnatal indicators, such as behavior and neuropathology, for the detection of chemically induced neurodevelopmental defects in the central nervous system (CNS). However, low reliability, especially low reproducibility, of behavioral results often causes concern among scientists and the scientific community in general. Guidance of neurohistopathological examination in the DNT guideline also has some shortcomings, especially relating to the methodological aspects. Ongoing international trends in DNT tests have shifted from the use of original in vivo animal (mammalian) studies to in vitro experiments using cell cultures and/or non mammalian species, such as fish. In vitro systems might initially be useful to screen test chemicals for their DNT potential. Although in vitro systems are employed as alternative approaches for DNT studies, the use of in vivo studies based on animal models remains an important factor when data are to be extrapolated to the human case. In this review, a new in vivo approach that focuses on histopathological observation of each developmental step of the CNS, such as proliferation of neural stem cells, migration of immature neurons, and formation of neural networks, using fetal and neonatal brains after chemical exposure is introduced, and some queries and arguments for current DNT experimental guidelines are discussed. PMID- 22925214 TI - Developmental neurotoxicity testing: a path forward. AB - Great progress has been made over the past 40 years in understanding the hazards of exposure to a small number of developmental neurotoxicants. Lead, polychlorinated biphenyls, and methylmercury are all good examples of science based approaches to characterizing the hazard to the developing nervous systems from environmental contaminants. However, very little effort has been spent to address the challenge of assessing the potential developmental neurotoxic hazard of the thousands of other chemicals in common commercial use. The extensive time, financial and animal resource requirements for current regulatory testing guideline methods make this an untenable solution to this challenge. A new testing paradigm is needed that uses time and cost-efficient methods to screen large numbers of chemicals for developmental neurotoxicity (DNT). In silico models are needed to provide rapid chemical structure-based screening. In vitro techniques are being developed to provide rapid and efficient testing in cell free and cell-based systems. In addition, the use of alternative species, such as zebrafish, will provide efficient models for testing the effects of chemicals in organisms with intact developing nervous systems. Finally, these methods and models need to be used in an integrated fashion to provide the data needs for hazard assessment in a manner that is problem-driven and cost-efficient. This paper summarizes discussions on these issues from the symposium 'Developmental neurotoxicity testing: Scientific approaches towards the next generation to protecting the developing nervous system of children' held at the 2011 annual meeting of the Japanese Teratology Society. PMID- 22925215 TI - Pluripotent stem cells are protected from cytomegalovirus infection at multiple points: implications of a new pathogenesis for congenital anomaly caused by cytomegalovirus. AB - In humans, the cytomegalovirus (CMV) is the most significant cause of intrauterine infections that cause congenital anomalies. Intrauterine infection with human CMV is thought to be responsible for a variety of abnormalities, including mental retardation, microcephaly, developmental delay, seizure disorders, and cerebral palsy, depending on the timing of the fetal infection, the infectious route, and the virulence of the virus. In addition to the adaptive immune system, the embryo has potential resistance to CMV during early embryogenesis. Embryonic stem (ES) cells are more resistant to CMV than most other cell types, although the mechanism responsible for this resistance is not well understood. ES cells allow approximately 20-fold less murine CMV (MCMV) DNA to enter the nucleus than mouse embryonic fibroblasts (MEFs), and this inhibition occurs in a multistep manner. In situ hybridization showed that ES cell nuclei had significantly less MCMV DNA than MEF nuclei. This finding appears to be supported by the fact that ES cells express less heparan sulfate, beta1-integrin, and vimentin and have fewer nuclear pores than differentiated cells such as MEF. This may reduce the ability of MCMV to attach to and enter the cellular membrane, translocate to the nucleus, and cross the nuclear membrane in pluripotent stem cells (ES-induced pluripotent stem cells). This finding may indicate a new pathogenesis for the congenital anomaly caused by CMV. PMID- 22925216 TI - Historical control data on prenatal developmental toxicity studies in rabbits. AB - Historical control data on rabbit prenatal developmental toxicity studies, performed between 1994-2010, were obtained from 20 laboratories, including 11 pharmaceutical and chemical companies and nine contract laboratories, in Japan. In this paper, data were incorporated from a laboratory if the information was based on 10 studies or more. Japanese White rabbits and New Zealand White rabbits were used for prenatal developmental toxicity studies. The data included maternal reproductive findings at terminal cesarean sections and fetal findings including spontaneous incidences of morphological alterations. No noticeable differences between strains or laboratories were observed in the maternal reproductive and fetal developmental data. The inter-laboratory variations in the incidences of fetal external, visceral, and skeletal alterations seem to be due to differences in the selection of observation parameters, observation criteria, and classification of the findings, and terminology of fetal alterations. PMID- 22925217 TI - Promotional effects of vasoactive intestinal peptide on the development of rodent Hertwig's epithelial root sheath. AB - Hertwig's epithelial root sheath (HERS), a bilayered epithelial cell sheath located at the cervical loop of the enamel organ in a developing tooth, is at the forefront of root formation. However, little is known about the exact mechanisms that regulate the development of HERS. The neuropeptide vasoactive intestinal peptide (VIP) is involved in the development of various tissues and cells. In this study, we investigated the roles of VIP in HERS development. VIP immunoreactive nerve fibers were found in the dental pulp and around the root apex of the tooth, while the expression of VIP receptor 1 (VPAC1) was observed in HERS. The expression level of VPAC1 correlated with the development of HERS and was elevated at postnatal days 14 and 21. Using ex vivo cultures of neonatal tooth germs, VIP enhanced the elongation and proliferation of HERS. In vitro, VIP also promoted the proliferation of cells from the HERS-derived cell line, HERS01a cells, and upregulated the mRNA expression of cytokeratin 14 and vimentin (typical molecular markers of HERS) in these cells. These results suggest that VIP may be an essential factor for HERS development. PMID- 22925218 TI - Development of cerebral sulci and gyri in ferrets (Mustela putorius). AB - The present study aimed to clarify sulcation and gyration patterns in the developing cerebrum of ferrets. While the brain weight and fronto-occipital length of the cerebral hemisphere reached a plateau by postnatal day (PD) 42, the cerebral width reached a plateau at the rostral region by PD 21, and subsequently at the caudal region by PD 42. The ferret cerebrum already showed a convoluted surface with indentations of coronal and rostral suprasylvian sulci on PD 4. The presylvian and cruciate sulci emerged by PD 10, resulting in convolutions of gyri in the rostral half of the cerebrum. The caudal half of the cerebrum was infolded by the emergence of the pseudosylvian sulcus and the rhinal fissure by PD 10, and the caudal suprasylvian and lateral sulci by PD 21. The emergence of those sulci allowed a gyration in the caudal half of the cerebrum. Sexual differences in sulcation were detected by a more distinct convolution of the visual cortex in males than in females on PD 90. Those results, therefore, suggest that the ferret cerebrum experiences cortical maturation with sulcation and gyration in a rostrocaudal gradient manner. The present paper provides neuroanatomic references for normal development of cerebral sulci and gyri in both sexes of ferrets. PMID- 22925219 TI - Duplication of the extrahepatic bile duct. AB - Duplication of the extrahepatic bile duct is an extremely rare anomaly. There are five types of this anomaly, with type V being the least common variant. Only two cases of type V (one each of type Va and type Vb) have been reported. Here we report the second case of type Va duplication of the common bile duct presenting with choledocholithiasis. The patient underwent open choledocholithotomy and T tube choledochostomy after failed endoscopic stone clearance. Duplication of the bile duct was detected on T-tube cholangiogram, which was confirmed by magnetic resonance cholangiopancreaticography (MRCP). No associated pancreaticobiliary maljunction was found on the imaging. PMID- 22925220 TI - Prenatal findings of omphalocele-exstrophy of the bladder-imperforate anus-spinal defects (OEIS) complex. AB - Omphalocele-exstrophy of the bladder (cloaca)-imperforate anus-spinal defects (OEIS) complex describes a rare grouping of more commonly occurring component malformations. We report two cases of OEIS complex diagnosed prenatally by ultrasound and magnetic resonance imaging (MRI). In both cases, OEIS complex was suspected by conventional sonography in the second trimester, and fetal MRI was performed at 27 and 32 weeks of gestation. Conventional sonography revealed low abdominal wall mass, spina bifida, absent bladder and ambiguous genitalia, but those findings were inconclusive. Using fetal MRI, we were able to detect omphalocele, imfraumbilical mass connected to gut tract, absent bladder, ambiguous external genitalia and spinal defect. Our findings suggest that fetal MRI is a useful tool for prenatal diagnosis of OEIS complex. MRI helps prenatal counseling and planning of postnatal early treatment strategy. PMID- 22925221 TI - Gastroschisis with ceco-appendicular agenesis: a novel presentation. AB - Gastroschisis is associated with intestinal atresia and malrotation. A few cases have been reported of appendicular agenesis associated with gastroschisis. No previous case has been reported of cecal agenesis with gastroschisis in the literature. As cecal agenesis is a very rare anomaly, its concomitant presentation with gastroschisis is extremely rare. We report a case of gastroschisis associated with ceco-appendicular agenesis. The possible embryological explanation for the presentation is discussed. PMID- 22925222 TI - Is the real in vivo nitric oxide concentration pico or nano molar? Influence of electrode size on unstirred layers and NO consumption. AB - OBJECTIVE: There is a debate if the [NO] required to influence vascular smooth muscle is below 50 nM or much higher. Electrodes with 30 MUm and larger diameter report [NO] below 50 nM, whereas those with diameters of <10-12 MUm report hundreds of nM. This study examined how size of electrodes influenced [NO] measurement due to NO consumption and unstirred layer issues. METHODS: Electrodes were 2 mm disk, 30 MUm * 2 mm carbon fiber, and single 7 MUm diameter carbon fiber within open tip microelectrode, and exposed 7 MUm carbon fiber of ~15 MUm to 2 mm length. RESULTS: All electrodes demonstrated linear calibrations with sufficient stirring. As stirring slowed, 30 MUm and 2 mm electrodes reported much lower [NO] due to unstirred layers and high NO consumption. The three 7 MUm microelectrodes had minor stirring issues. With limited stirring with NO present, 7 MUm open tip microelectrodes advanced toward 30 MUm and 2 mm electrodes experienced dramatically decreased current within 10-50 MUm of the larger electrodes due to high NO consumption. None of the 7 MUm microelectrodes interacted. CONCLUSIONS: The data indicate large electrodes underestimate [NO] due to excessive NO consumption under conditions where unstirred layers are unavoidable and true microelectrodes are required for valid measurements. PMID- 22925223 TI - Mu opioid receptor availability in people with psychiatric disorders who died by suicide: a case control study. AB - BACKGROUND: Mu opioid receptors have previously been shown to be altered in people with affective disorders who died as a result of suicide. We wished to determine whether these changes were more widespread and independent of psychiatric diagnoses. METHODS: Mu receptor levels were determined using [3 H]DAMGO binding in BA24 from 51 control subjects; 38 people with schizophrenia (12 suicides); 20 people with major depressive disorder (15 suicides); 13 people with bipolar disorder (5 suicides) and 9 people who had no history of psychiatric disorders but who died as a result of suicide. Mu receptor levels were further determined in BA9 and caudate-putamen from 38 people with schizophrenia and 20 control subjects using [3 H]DAMGO binding and, in all three regions, using Western blots. Data was analysed using one-way ANOVAs with Bonferroni's Multiple Comparison Test or, where data either didn't approximate to a binomial distribution or the sample size was too small to determine distribution, a Kruskal-Wallis test with Dunn's Multiple Comparison Test. RESULTS: [3 H]DAMGO binding density was lower in people who had died as a result of suicide (p<0.01). People with schizophrenia who had died as a result of suicide had lower binding than control subjects (p<0.001), whilst people with bipolar disorder (non- suicide) had higher levels of binding (p<0.05). [3 H]DAMGO binding densities, but not mu protein levels, were significantly decreased in BA9 from people with schizophrenia who died as a result of suicide (p<0.01). CONCLUSIONS: Overall these data suggest that mu opioid receptor availability is decreased in the brains of people with schizophrenia who died as a result of suicide, which would be consistent with increased levels of endogenous ligands occupying these receptors. PMID- 22925224 TI - Screening for bipolar disorder in adolescents with the mood disorder questionnaire-adolescent version (MDQ-A) and the child bipolar questionnaire (CBQ). AB - AIM: Screening instruments for bipolar disorders (BDs) in children and adolescents have been developed recently. The present study examined performances of the French versions of the mood disorder questionnaire-adolescent version (MDQ A) and child bipolar questionnaire (CBQ) in a sample of in- and outpatients. METHODS: Seventy-six adolescents (age 13-18) and parents first completed the MDQ A (adolescent and parent versions) and CBQ screening instruments. About 3 weeks later, they had a diagnostic interview with the Kiddie-schedule for affective disorders and schizophrenia-present and lifetime (K-SADS-PL), and the adolescent MDQ-A self-report was completed a second time. RESULTS: Eight of 76 patients (10.5%) met K-SADS-PL diagnostic criteria for BD. Test-retest reliability of the adolescent MDQ-A self-report was moderate (kappa = 0.66), whereas agreement between adolescent and parent reports was poor (kappa = 0.07). Sensitivity and specificity of the MDQ-A with respect to K-SADS-PL were 75.0% and 57.4% for the adolescent version, and 87.5% and 63.2% for the parent version. Corresponding figures were 50.0% and 73.5% for the CBQ. All three screening instruments had low positive predictive values (17.1% for the MDQ-A adolescent version; 21.9% for the MDQ-A parent version; 18.2% for the CBQ), whereas negative predictive values were higher than 90%. CONCLUSIONS: The present study points to modest performances of the MDQ-A and CBQ to detect BDs in adolescents, with diagnostic criteria for BD being unmet for a majority of patients who screened positive. PMID- 22925225 TI - Epidemiology of hyperglycemic hyperosmolar syndrome in children hospitalized in USA. AB - BACKGROUND: Previous studies of hyperglycemic hyperosmolar syndrome (HHS) in children are limited to case series or single-institution reviews, which describe HHS primarily in children with type 2 diabetes mellitus. OBJECTIVE: To estimate the incidence and describe the epidemiologic characteristics of HHS among children in USA. SUBJECTS: All discharges in the Kids' Inpatient Database - a triennial, nationwide, stratified probability sample of hospital discharges for years 1997-2009 - with age 0-18 yr and a diagnosis of HHS. METHODS: Using sample weights, we calculated the incidence and population rate of hospitalization with a diagnosis of HHS. RESULTS: Our sample included 1074 HHS hospitalizations; of these, 42.9% were 16-18 yr, 70.6% had type 1 diabetes (T1D), and 53.0% had major or extreme severity of illness. The median length of stay was 2.6 d, 2.7% of hospitalizations ended in death, and median hospital charge was $10 882. When comparing HHS hospitalizations by diabetes type, the proportion with T1D fell steadily with age, from 89.1% among children 0-9 yr, to 65.1% in 16-18 yr olds. Patients with T1D had a shorter length of stay by 0.9 d, and had a lower median charge by $5311. There was no difference in mortality by diabetes type. Population rates for HHS hospitalization rose 52.4% from 2.1 to 3.2 per 1 000 000 children from 1997 to 2009. CONCLUSION: Hospitalizations for a diagnosis of HHS have high morbidity and are increasing in incidence since 1997. In contrast to prior reports, we found a substantial percentage of HHS hospitalizations occurred among children with T1D. PMID- 22925226 TI - Levetiracetam in patients with central neuropathic post-stroke pain--a randomized, double-blind, placebo-controlled trial. AB - BACKGROUND AND PURPOSE: Central post-stroke pain (CPSP) is a severe chronic neuropathic pain condition defined as a spontaneous pain or allodynia corresponding to a vascular lesion. It usually evolves weeks after stroke, and can distinctively impair the quality of life. Treatment is complex and mostly unsatisfactory. We hypothesized that the anti-epileptic drug levetiracetam (LEV) improves CPSP compared with placebo. The purpose of this study was to examine the efficacy and tolerability of LEV in patients with CPSP. METHODS: In a double blind, placebo-controlled, crossover study design patients with CPSP lasting at least 3 months and a pain score >= 4 on the 11-point Likert scale were treated over two 8-week periods with a maximum dose up to 3000 mg LEV or placebo. Primary endpoint was a median pain lowering >= 2 in the final treatment week compared with the last baseline week. Secondary outcome measures comprised additional pain ratings, depression, sleep quality, quality of life and patients' global impression of change. RESULTS: Of 42 patients, 33 [61.5 years (40-76); 38% women] completed the study. Side effects and withdrawals were more frequent in the LEV (n = 5) group than in the placebo group (n = 1). Patients treated with LEV did not show any improvement of pain or changes in secondary outcome parameters compared with placebo. CONCLUSIONS: LEV is not effective in treatment for CPSP. The mode of action of LEV does not exert an analgesic effect in chronic CPSP. PMID- 22925227 TI - A sad but forgotten truth: the story of slow-moving solutes in fast hemodialysis. AB - When trying to optimize hemodialysis adequacy, it can be questioned whether one should focus on the dialyzer or on the patient. Another crucial question is whether the currently applied dialysis adequacy parameter, Kt/V(urea) , is a reliable marker. For the small and water-soluble solutes, recent advances in convective strategies and/or new dialyzer designs do not add much removal capacity. Depending on their specific kinetics, generally quite different from those of urea, small solute removal benefits from longer or more frequent dialysis. Clearance of beta-2-microglobulin (beta(2) M), a marker of middle molecule removal pattern, is improved with dialysis using more open and permselective membranes, as well as by using high convective volume strategies. Furthermore, longer and more frequent dialyses have highly favorable removal characteristics because they facilitate the retarded transport between plasmatic and extraplasmatic compartments over which these molecules are distributed. As beta(2) M may not be representative of other middle molecules, future kinetic analyses of alternative middle molecules will be of the utmost interest. Protein bound solute clearance is improved by convective techniques, but not by more open dialyzer pores. Knowledge of their kinetics should be helpful in interpreting the observation that frequent (but not longer) dialysis enhances protein-bound solute removal. Hence, further technical improvements in dialyzers will have only a minor impact on dialysis adequacy, as retarded solute movement in the patient plays a decisive role. As urea kinetics is not representative of the kinetics of protein-bound compounds, middle molecules, nor even of other small and water soluble solutes, it becomes self-evident that urea clearance is a poor predictor of many aspects of dialysis adequacy. PMID- 22925228 TI - Painful tongue ulcers. PMID- 22925229 TI - Radiodermatitis with signs of eccrine squamous syringometaplasia following a diagnostic procedure. PMID- 22925230 TI - Rapid phylogenetic and functional classification of short genomic fragments with signature peptides. AB - BACKGROUND: Classification is difficult for shotgun metagenomics data from environments such as soils, where the diversity of sequences is high and where reference sequences from close relatives may not exist. Approaches based on sequence-similarity scores must deal with the confounding effects that inheritance and functional pressures exert on the relation between scores and phylogenetic distance, while approaches based on sequence alignment and tree building are typically limited to a small fraction of gene families. We describe an approach based on finding one or more exact matches between a read and a precomputed set of peptide 10-mers. RESULTS: At even the largest phylogenetic distances, thousands of 10-mer peptide exact matches can be found between pairs of bacterial genomes. Genes that share one or more peptide 10-mers typically have high reciprocal BLAST scores. Among a set of 403 representative bacterial genomes, some 20 million 10-mer peptides were found to be shared. We assign each of these peptides as a signature of a particular node in a phylogenetic reference tree based on the RNA polymerase genes. We classify the phylogeny of a genomic fragment (e.g., read) at the most specific node on the reference tree that is consistent with the phylogeny of observed signature peptides it contains. Using both synthetic data from four newly-sequenced soil-bacterium genomes and ten real soil metagenomics data sets, we demonstrate a sensitivity and specificity comparable to that of the MEGAN metagenomics analysis package using BLASTX against the NR database. Phylogenetic and functional similarity metrics applied to real metagenomics data indicates a signal-to-noise ratio of approximately 400 for distinguishing among environments. Our method assigns ~6.6 Gbp/hr on a single CPU, compared with 25 kbp/hr for methods based on BLASTX against the NR database. CONCLUSIONS: Classification by exact matching against a precomputed list of signature peptides provides comparable results to existing techniques for reads longer than about 300 bp and does not degrade severely with shorter reads. Orders of magnitude faster than existing methods, the approach is suitable now for inclusion in analysis pipelines and appears to be extensible in several different directions. PMID- 22925231 TI - Evaluating single-incision slings in female stress urinary incontinence: the usefulness of the CONSORT statement criteria. AB - OBJECTIVE: To evaluate the usefulness and applicability of the Consolidated Standards of Reporting Trials (CONSORT) for journal articles reporting randomized, controlled trials evaluating single-incision slings in the treatment of female stress urinary incontinence. METHODS: Original articles reporting randomized, controlled trials assessing single-incision slings in the treatment of female stress urinary incontinence were searched for in the PubMed and Embase databases in 2011. Reporting quality was studied by 2 hospital pharmacists and 2 urologic surgeons. Primary outcome was the score out of 20 in the abstract CONSORT checklist. Secondary outcomes were the scores in the standard CONSORT checklist and the extension CONSORT additional items for trials assessing nonpharmacologic treatments. RESULTS: Among 135 articles retrieved, 8 met the inclusion criteria and were assessed. Abstract scores ranged from 4.7-14.1. Standard scores were >10.0 out of 20 for most articles; the extension scores did not exceed 5.0 out of 10. Four reported trials were not identified as randomized in the title. The interventions were incompletely reported. Four articles reported whether blinding was achieved but lack of blinding was never discussed as a potential source of bias. Few articles reported the operators and centers characteristics and their impact on statistical analysis. The combination of the 3 checklists was considered a useful guideline to enhance and assess the reporting quality of a surgical trial. CONCLUSION: Our results support the further use of CONSORT criteria as a basic standardized tool in all stages of clinical evaluation for any prosthetic device in female pelvic surgery. PMID- 22925232 TI - Colpocleisis for advanced pelvic organ prolapse. AB - OBJECTIVE: To characterize our experience with colpocleisis in a urologic setting because it has not been documented broadly in the urologic literature. METHODS: Retrospective review of demographics, urodynamics, presenting symptoms, complications, and outcomes for patients undergoing colpocleisis from 2001-2010 was performed. A questionnaire including the short forms of the Urinary Distress Inventory and Pelvic Organ Prolapse Distress Inventory (POPDI-6), and the Patient Global Impression of Improvement was sent to consenting patients. RESULTS: Fifty three patients were identified. Examinations were all POP-Q stage 3 or greater or Baden Walker grade 3 or higher; 73.6% underwent total colpocleisis and 26.4% Le Fort; 60.4% underwent concomitant sling. Complications included 1 patient requiring transfusion, 1 with pulmonary embolus, 1 needing clot evacuation, and 1 requiring intraoperative cystotomy repair. There was no postoperative de novo urgency, no recurrence of prolapse, and no chronic urinary retention. In patients not undergoing urethral sling, stress urinary incontinence persisted in 4 patients and occurred de novo in 1. Mean follow-up was 9.3 months. Twenty-two surveys were returned: 90.9% described their condition as much or very much better on Patient Global Impression of Improvement. The average POPDI-6 score was 9.1. Frequency and urgency were the most common complaints leading to bother on the UDI-6 (33.3%). Most of these responders had a preoperative urge component. CONCLUSION: In a selected patient population, colpocleisis is safe and efficacious. Persistent lower urinary tract symptoms comprise the highest frequency of complaints after colpocleisis, and this must be included in patient counseling. In an aging patient population with expected increase in demand for pelvic floor reconstruction, colpocleisis is a useful approach for the urologist. PMID- 22925233 TI - Impact of body mass index on perioperative morbidity, oncological, and functional outcomes after extraperitoneal laparoscopic radical prostatectomy. AB - OBJECTIVE: To evaluate the impact of obesity on the outcomes of laparoscopic radical prostatectomy. METHODS AND MATERIALS: In a prospective urologic cancer database, 765 patients underwent extraperitoneal laparoscopic radical prostatectomy for localized prostate cancer. The patients were categorized into 3 groups of body mass index (kg/m(2)): <25.0 (n = 276, 30%, "normal weight"), 25.0 to 30.0 (n = 365, 48%, "overweight") and >30.0 (n = 124, 16%, "obese"). We assessed the perioperative, oncological, and functional outcomes in this cohort of patients. Preoperative and postoperative evaluation of continence and erectile function were performed using validated questionnaires. RESULTS: Mean operative time was significantly longer in obese patients (P < .001) and blood loss was also more important (P < .01). The obese patients had the highest likelihood of having aggressive tumors: nonorgan confined prostate cancer (49%, P = .002) and Gleason score >= 7 (80%, P = .005). The obese group had the higher positive surgical margins rate (overall: 27%, P = .012; pT2: 20%, P = .02). With a mean follow-up of 38 months, obesity was not an independent predictive factor of biochemical recurrence. At the 12-month follow-up, 85%, 74%, and 72% of normal, overweight, and obese men, respectively, were continent (no pad) (P = .04). At the 12-month follow-up, 57%, 58%, and 40% of normal, overweight, and obese men, respectively, reported an erection sufficient for intercourse (P = .01). CONCLUSION: Laparoscopic radical prostatectomy is a safe and effective procedure in obese men with midterm cancer control. However, obese patients are at higher risk of aggressive disease. Recovery of continence and potency in these patients are significantly lower compared to nonobese men. PMID- 22925234 TI - Editorial comment. PMID- 22925236 TI - Feasibility of transrectal hybrid natural orifice transluminal endoscopic surgery (NOTES) nephrectomy in the cadaveric model. AB - OBJECTIVE: To examine feasibility of transrectal hybrid natural orifice transluminal endoscopic surgery (NOTES) nephrectomy in human cadavers in the evolution of this technique, as transrectal hybrid NOTES nephrectomy has been demonstrated in the porcine model. METHODS: Four hybrid transrectal NOTES nephrectomies were performed on 4 cadavers (3 female/1 male, 2 right/2 left). Pneumoperitoneum was created by periumbilical 12-mm trocar, through which a laparoscope was advanced to obtain intra-abdominal visualization. A 4-cm horizontal incision was made 2-cm above the dentate line and a submucosal tunnel was created in the posterior rectal wall/presacral space. A dual-channel gastroscope was advanced through the submucosal tunnel and retroperitoneum to the level of the kidney using air insufflation. A peritoneal window was created and renal mobilization was completed. A transumbilically applied laparoscopic 45-mm stapler was used to transect the ureter and renal hilum. A specimen entrapment bag was deployed transrectally for specimen extraction, followed by transrectal incision closure. RESULTS: Transrectal NOTES nephrectomy was successfully performed in all cases, with intact specimen extraction. Median weight was 77 kg (range 74-85 kg); median body mass index (BMI) was 30.1 kg/m(2) (range 25.6-31.2 kg/m(2)). Mean operative time was 175 minutes (range 150-210 minutes). Median transrectal access time was 36 minutes (range 24-47 minutes). Median dimensions of removed kidneys were length 11.2 cm (range 10-12 cm), width 5 cm (range 4.5-6 cm), and thickness 3.8 cm (range 3-4.5 cm). CONCLUSION: Transrectal hybrid NOTES nephrectomy in the cadaver model is feasible with intact specimen extraction and acceptable operative times. Preclinical survival studies are requisite to assess sterility and complications. This approach may be an alternative to transvaginal access. PMID- 22925238 TI - Editorial comment. PMID- 22925237 TI - Real-time robotic transrectal ultrasound navigation during robotic radical prostatectomy: initial clinical experience. AB - OBJECTIVE: To describe a novel robotic transrectal ultrasound platform for real time navigation during robot-assisted laparoscopic radical prostatectomy (RALP) and to report its early clinical application. METHODS: Five men undergoing RALPs at our Institution agreed to participate in this Institutional Review Board approved pilot study. All of them were eligible for a bilateral nerve sparing procedure. Before docking the da Vinci robot, a transrectal ultrasound tri-plane side-fire probe was placed. A modified ViKY Endoscope Holder was used during RALPs to move the probe thanks to a remote control placed under the console surgeon's control during RALPs. During each procedure, attempt was made to estimate prostate volume, define 12 reference points, and to precisely identify location of the neurovascular bundles using Doppler ultrasound. The TilePro was used during the procedures to allow real-time ultrasound imaging to guide robotic instruments during dissection. RESULTS: Median robotic transrectal ultrasound probe holder (R-TRUS) setup time was 11 minutes (interquartile range [IQR], 10 14). Prostate volume calculation, reference point definition, neurovascular bundle identification, and instrument tip visualization were successful in all men. In 1 patient with a large prostate (120 mL), R-TRUS was withdrawn during recto-prostatic dissection. There were no rectal injuries. CONCLUSION: R-TRUS during RALPs is feasible and safe. It allows real-time TRUS navigation and guidance. Further studies are needed to evaluate its impact on oncological and functional outcomes. PMID- 22925239 TI - Bladder wash cytology at diagnosis of Ta-T1 bladder cancer is predictive for recurrence and progression. AB - OBJECTIVE: To evaluate the effect of the bladder wash cytology finding at the primary diagnosis of Stage Ta-T1 urinary bladder cancer on recurrence and progression. METHODS: The clinical and pathologic characteristics of all patients with primary Stage Ta-T1 urinary bladder cancer were prospectively registered. The data were divided according to the bladder wash cytology results at diagnosis. Multivariate analyses were performed to determine the influence of bladder wash cytology on recurrence and progression. RESULTS: The analysis included 768 evaluable patients with a mean follow-up of 60 months. Recurrence was observed in 478 patients (62%) and progression in 71 (9%). High-grade malignant bladder wash cytology was predictive for recurrence and progression (P < .001 and P = .036, respectively). Other factors affecting recurrence were missing bladder wash cytology data, tumors size 16-30 mm and >30 mm, Stage T1 tumor category, and multiplicity (P = .008, P = .006, P < .001, P = .002, and P < .001, respectively). Progression was also associated with T1 tumor category, local recurrence, and primary concomitant carcinoma in situ (P < .001, P < .001, and P = .024, respectively). CONCLUSION: High-grade malignant bladder wash cytology at the primary diagnosis was predictive for recurrence and progression. This could be taken into account in designing future follow-up schedules. PMID- 22925240 TI - Risk of Gleason grade inaccuracies in prostate cancer patients eligible for active surveillance. AB - OBJECTIVE: To evaluate increases in Gleason grade because of sample bias after immediate rebiopsy or prostatectomy for patients considered active surveillance candidates by institutional protocol. METHODS: A contemporary medical literature search was performed using PubMed. Series were included if the patients had no more than Gleason 6 prostate cancer score on initial biopsy and underwent a prostatectomy or rebiopsy within 6 months. Patient sets using neoadjuvant hormonal therapy or focal prostate treatment were excluded. RESULTS: In patients who would have fallen into the D'Amico low-risk prostate cancer group, 42% were found to have an increase in the Gleason score: 32% resulting in grade >= 7 disease and 3% grade >= 8. For series that limited patients to the Epstein criteria, Gleason upgrades were 34%, 29%, and 2%, respectively. Of the 139 patients whose second tissue specimens were from a rebiopsy, 17% were found to have grade >= 7 disease, whereas only 1 patient had grade >= 8. There were no consistent multivariate analysis variables among the series to predict for an increase in Gleason score. CONCLUSION: More than one third of the patients were found to have been undergraded based on their initial prostate biopsy. Therefore, 1 biopsy alone may not be sufficient to offer active surveillance as an option. Further exploration is necessary to better ensure low-risk disease before active surveillance. PMID- 22925241 TI - International variation in artificial urinary sphincter use. AB - OBJECTIVE: To analyze international trends in artificial urinary sphincter (AUS) use, indications for placement, and application by gender. METHODS: We conducted a retrospective review of data derived from patient information forms sent to American Medical Systems. There were 86 140 unique cases from March 1975 through December 2008, including all indications. RESULTS: AUS use increased worldwide from 1975 (90 procedures) through 2008 (4818 procedures). In 2008, patients with postprostatectomy incontinence (PPI) accounted for 61% (2907/4751) of AUS use compared to 12% (8/66) in 1975. Artificial urinary sphincter annual implant rates in women were much lower than in men, decreasing from 298 procedures in 1990 to 67 in 2008. Artificial urinary sphincter implants in the United States for men alone accounted for the majority (62%, 2995/4818) of worldwide artificial urinary sphincter use in 2008. Conversely, artificial urinary sphincter use has recently started declining in other areas, including South America and Canada. Frequency of artificial urinary sphincter surgery varied dramatically from less than 0.01 per 100 000 population in Brazil to 0.99 in the United States. Of surgeons performing artificial urinary sphincter implants in 2008, case volumes in and outside of the United States were similarly low: 56% in the United States and 52% outside the United States performed only 1 artificial urinary sphincter implant, whereas 76% in the United States and 73% outside the United States did fewer than 3. CONCLUSION: Artificial urinary sphincter use has continued to increase internationally over the study period, especially for patients with PPI. However, artificial urinary sphincter use exhibits considerable regional variation, and most surgeons performed very low annual case volumes of implants. PMID- 22925242 TI - Editorial comment. PMID- 22925244 TI - Transabdominal ultrasound measurement of pelvic floor muscle mobility in men with and without chronic prostatitis/chronic pelvic pain syndrome. AB - OBJECTIVE: To investigate the pelvic floor muscle motion in men with and without chronic prostatitic/chronic pelvic pain syndrome using transabdominal ultrasound. No study has directly evaluated pelvic floor muscle mobility in individuals with and without chronic pelvic pain syndrome. METHODS: A convenience sample of 40 males participated in the study. Subjects were categorized into 2 groups: those with chronic pelvic pain syndrome (n = 20) and those without chronic pelvic pain syndrome (n = 20). The amount of bladder base movement on ultrasound (normalized to body mass index) was measured in all subjects and considered as an indicator of pelvic floor muscle mobility. RESULTS: Statistical analysis (independent t test) revealed significant difference in transabdominal ultrasound measurements for pelvic floor muscle function between the 2 groups (P = .03, 95% CI -0.26 to 0.01). CONCLUSION: The results of this study indicate that pelvic floor muscle mobility differs in the 2 groups. PMID- 22925245 TI - The predictive value of ischemia-modified albumin in long-term results of ischemia-reperfusion injury in an experimental testicular torsion model. AB - OBJECTIVE: To establish the value of ischemia-modified albumin levels in the determination of the long-term results of testicular torsion/detorsion-associated ischemia-reperfusion injury. METHODS: Eighteen mature male Wistar rats were divided randomly into 3 groups (n = 6 for each group): control, acute torsion/detorsion (T/D) group, and long-term T/D. In the control group, scrotal incision only was performed; in the acute T/D group, after 4 hours of torsion, detorsion was performed and maintained for 2 hours. Blood samples and testicular tissue samples were taken after 2 hours of detorsion. The same T/D procedures were performed in the long-term T/D group. The long-term T/D groups were kept alive for 2 months, and samples were taken at 2 months post procedure. Serum ischemia-modified albumin, serum and tissue malondialdehyde levels, and histopathological damage scores were measured. RESULTS: Serum ischemia-modified albumin levels were significantly higher compared with the control group, in the acute-term T/D (P = .004). This elevation remained pronounced in the long term compared with the control group and acute period (P = .008 and P = .017, respectively). There was a significant negative correlation between serum ischemia-modified albumin levels and histopathological injury score in both the torsioned and contralateral testes (r = -.929, P < .0001 and r = -.560, P = .02, respectively). CONCLUSION: Ischemia-modified albumin is a valuable parameter in terms of reflecting testis injury in testicular torsion in both the acute period and the long term. It therefore has the potential to be used as data with predictive value regarding patients' fertility capacities. PMID- 22925246 TI - Laparoendoscopic single-site transvesical ureteroneocystostomy for vesicoureteral reflux in an adult: a one-year follow-up. AB - INTRODUCTION: Various minimally invasive techniques have been developed to decrease morbidity related to laparoscopic port placement and to improve cosmetic results while maintaining the same standards and efficacy of surgical care. One such approach is laparoendoscopic single-site surgery. We describe our initial clinical experience of using this technique for transvesical ureteral reimplantation. TECHNICAL CONSIDERATIONS: The procedure was performed transvesically (percutaneous intraluminal approach) with a single-port device (3 channel) via a 1.5-cm incision made 2 cm above the pubic symphysis. A standard 10 mm laparoscope was used with either straight or articulating instruments. The ureter was dissected, shortened, passed through the submucosal tunnel, and fixed in place with a running absorbable V-Loc suture. The operative time was 250 minutes. No significant bleeding or other complications were observed. CONCLUSION: Although further development of the instruments and skills is needed laparoendoscopic single-site surgery transvesical reimplantation of the ureter appeared to be feasible and safe. Nevertheless, further experience and observations are necessary. PMID- 22925247 TI - Histotripsy of renal implanted VX-2 tumor in a rabbit model: investigation of metastases. AB - OBJECTIVE: To compare the number and density of lung metastases in histotripsy treated and control subjects. Histotripsy is a noninvasive, nonthermal, pulsed ultrasound technology that produces targeted mechanical tissue fractionation. Histotripsy ablation of renal implanted VX-2 tumor has been previously demonstrated; however, concerns have been raised that mechanical forces associated with histotripsy might result in unwanted metastatic dissemination of tumor. METHODS: VX-2 tumor was implanted into the left kidneys of New Zealand White rabbits. Twenty rabbits were treated with histotripsy on day 13; 8 were maintained as controls. All rabbits underwent left nephrectomy on day 14. Lungs were harvested and processed for histopathologic inspection on day 19. Whole mount coronal lung sections were examined to determine the number of metastases and metastatic density. RESULTS: Tumors grew after implantation in all 28 cases and were localized with ultrasound in 19 of 20 subjects before treatment. Histology confirmed fractionation of tumor in all treatment rabbits. The number of lung metastases (88.7 vs 72.5; P = .29) and the metastatic density (8.9 vs 7.0 mets/cm(2); P = .22) were not statistically different between treatment and control rabbits. CONCLUSION: Histotripsy of renal implanted VX-2 tumor in an in vivo rabbit model did not produce a statistically significant increase in number or density of lung metastasis. Data suggesting a trend toward increased metastases after histotripsy are overwhelmed by the high baseline rate of metastases in this aggressive tumor model. Further investigation using less aggressive tumor models is indicated to clarify this relationship. PMID- 22925249 TI - Re: Ozden E, Mercimek MN, Bostanci Y, et al.: long-term outcomes of percutaneous nephrolithotomy in patients with chronic kidney disease: a single-center experience. (Urology February 4, 2012 [Epub ahead of print]). PMID- 22925251 TI - Re: Sofer M et al.: noncontrast computed tomography after percutaneous nephrolithotomy: findings and clinical significance (Urology February 3, 2012 [Epub ahead of print]). PMID- 22925252 TI - Re: Rourke et al.: effect of wound closure on buccal mucosal graft harvest site morbidity: results of a randomized prospective trial (urology 2012;79:443-448). PMID- 22925254 TI - Re: Tan H et al.: use of ureteroscopy before and after expansion of lithotriptor ownership in Michigan (Urology 2011;78:1287-1291). PMID- 22925256 TI - Re: Humphreys et al.: natural orifice transluminal endoscopic radical prostatectomy: initial perioperative and pathologic results (urology 2011;78:1211 1218). PMID- 22925258 TI - Re: Xu Y: Doppler Ultrasound-guided Percutaneous Nephrolithotomy With Two-step Tract Dilation for Management of Complex Renal Stones (Urology February 24, 2012 [Epub ahead of print]). PMID- 22925260 TI - Re: Bozkurt et al.: relationship between mean platelet volume and varicocele: a preliminary study (Urology 2012:79:1048-1051). PMID- 22925262 TI - Laparoscopic ureteroureterostomy for the management of obstructive uropathy caused by congenital ureteric entrapment in the iliac bone. AB - A rare case of congenital entrapment of the left ureter in an iliac bone canal causing left side hydroureteronephrosis is reported. The patient represented a case of congenital ureteral entrapment in a reversed C-shaped iliac bone canal that was missed before his laparoscopy. The ureter also had a retro-iliac course. The patient was successfully managed by laparoscopic ureteroureterostomy. Interestingly, in our experience, laparoscopy provided a minimally invasive milieu for both diagnosis and correction of this rare cause of obstructive uropathy. PMID- 22925263 TI - Small intestinal ganglioneuromatosis in a dog. AB - A 9-year-old female neutered collie-cross dog was presented with a 2-month history of persistent diarrhoea, weight loss and intermittent vomiting. Abdominal ultrasonography revealed one loop of jejunum with a markedly thickened and multifocally hyperechoic wall, without loss of wall layering. Laparotomies were performed for biopsy and resection of affected intestine. Histopathological examination revealed small intestinal ganglioneuromatosis (GN). The dog recovered well from surgery and the diarrhoea resolved. Eleven months later the dog has gained weight and remains asymptomatic. This is the first report of small intestinal GN affecting a mature dog, in which pathology was localized to the mucosal lamina propria and surgical treatment resulted in a successful outcome. PMID- 22925264 TI - Nematode-associated intramural alimentary nodules in pumas are histologically similar to gastrointestinal eosinophilic sclerosing fibroplasia of domestic cats. AB - Intramural alimentary nodules in the gastric pylorus and proximal duodenum are a common finding in free-ranging pumas (Puma concolor) in North America, and are often associated with the presence of an indwelling nematode (most commonly Cylicospirura spp.). This study compares the histological, histochemical and immunohistochemical appearance of three proximal gastrointestinal nodules in pumas with four cases of eosinophilic sclerosing fibroplasia in domestic cats. Histologically, the pattern of inflammation and repair was strikingly similar, consisting of lamillated anastomosing trabeculae of dense sclerotic collagen with interspersed inflammatory cells and reactive fibroblasts. The stromal trabeculae were histologically reminiscent of osteoid and were uniformly positive for collagenous protein by Masson's trichrome stain and negative for mineralized osteoid deposits with Von Kossa's stain. Trabecular cells expressed osteonectin, but not osteocalcin immunohistochemically. Collectively, these findings are most consistent with a stroma comprised of dense collagenous trabeculae that resembles, but is distinct, from osteoid. Both the puma and domestic cat lesions demonstrated an eosinophilic inflammatory component; however, eosinophils were present in small numbers in the puma nodules relative to the nodules in domestic cats. These entities likely represent a unique and stereotypic gastrointestinal repair response of felids, given their similar histological, histochemical and immunohistochemical profiles. PMID- 22925265 TI - Complement factors are secreted in human follicular fluid by granulosa cells and are possible oocyte maturation factors. AB - AIMS: In this study, we identify components of the complement system present in human follicular fluid that affect oocyte development and maturation. MATERIAL AND METHODS: Using bottom-up liquid chromatography/mass spectrometry/mass spectrometry, we identified complement factors as consistently present in human follicular fluid from 15 different subjects. RESULTS: According to our gene-chip data, these complement factors are actively produced by granulosa cells. CONCLUSIONS: By applying the computational Ingenuity Pathway Analysis software and database we have identified complement pathways that play a role in oocyte maturation and follicular development. PMID- 22925266 TI - Effects of beryllium coating layer on performance of the ultrasonic waveguide sensor. AB - Under-sodium viewing is one of the critical technical issues and requirements for the in-service inspection of the sodium-cooled fast reactor (SFR) that is currently under development. The waveguide sensor that uses leaky A(0) mode Lamb waves has shown its potential for high-resolution viewing/scanning of the reactor core and in-vessel structures. However, a few problems arise under a liquid sodium environment due to high sound speed in liquid sodium and dispersion in the long waveguide plate, which simultaneously deteriorate the reconstructed C-scan images. This paper proposes coating the surface of the waveguide sensor plate with a thin layer of material that has a very high ultrasonic wave velocity. It is shown that this coating layer can largely reduce the size (width) and radiation angle of the acoustic beam from the waveguide sensor. This paper precisely analyzes the effects of coating parameters on the beam quality. The proposed idea is validated through ultrasonic experiments in which the radiation beam profiles and group velocities in waveguide sensors with different surface treatments are measured and compared. PMID- 22925267 TI - Circumferential phased array of shear-horizontal wave magnetostrictive patch transducers for pipe inspection. AB - Several investigations report effective uses of magnetostrictive patch transducers to generate and measure longitudinal and torsional guided waves in a pipe. They can be used to form a phased array for the circumferential inspection of pipes. Although there are circumferential phased arrays employing piezoelectric transducers or EMAT's, no magnetostrictive patch transducer based array system has been attempted. In this investigation, we aim to develop a circumferential phased magnetostrictive patch transducer (PMPT) array that can focus shear-horizontal waves at any target point on a cylindrical surface of a pipe. For the development, a specific configuration of a PMPT array employing six magnetostrictive patch transducers is proposed. A wave simulation model is also developed to determine time delays and amplitudes of signals generated by the transducers of the array. This model should be able to predict accurately the angular profiles of shear-horizontal waves generated by the transducers. For wave focusing, the time reversal idea will be utilized. The wave focusing ability of the developed PMPT array is tested with multiple-crack detection experiments. Imaging of localized surface inspection regions is also attempted by using wave signals measured by the developed PMPT array system. PMID- 22925268 TI - Anomalies of the anaerobic tricarboxylic acid cycle in Shewanella oneidensis revealed by Tn-seq. AB - The availability of increasingly inexpensive sequencing combined with an ever expanding molecular biology toolbox has transported classical bacterial genetics into the 21st century. Whole genome genetic fitness analysis using transposon mutagenesis combined with next-generation high-throughput sequencing (Tn-seq) promises to revolutionize systems level analysis of microbial metabolism. Tn-seq measures the frequency of actual members of a heterogeneous mutant pool undergoing purifying selection to determine the contribution of every non essential gene in the genome to the fitness of an organism under a given condition. Here we use Tn-seq to assess gene function in the Gram negative gamma proteobacterium Shewanella oneidensis strain MR-1. In addition to being a model environmental organism, there is considerable interest in using S. oneidensis as a platform organism for bioremediation and biotechnology, necessitating a complete understanding of the metabolic pathways that may be utilized. Our analysis reveals unique aspects of S. oneidensis metabolism overlooked by over 30 years of classical genetic and systems level analysis. We report the utilization of an alternative citrate synthase and describe a dynamic branching of the S. oneidensis anaerobic tricarboxylic acid cycle, unreported in any other organism, which may be a widespread strategy for microbes adept at dissipating reducing equivalents via anaerobic respiration. PMID- 22925269 TI - International Spine Intervention Society (ISIS) presidential address: 20th Annual Scientific Meeting. Wednesday, July 18, 2012. PMID- 22925270 TI - Abstracts of the American Academy for Cerebral Palsy and Developmental Medicine 66th Annual Meeting. September 12-15, 2012. Toronto, Canada. PMID- 22925271 TI - Characterization of a monoclonal antibody to Spiroplasma eriocheiris and identification of a motif expressed by the pathogen. AB - Tremor disease (TD) has been found to be a lethal epidemic in Chinese mitten crab during recent years. A new species of spiroplasma, Spiroplasma eriocheiris (S. eriocheiris), was identified as the pathogen causing TD. In order to acquire appropriate biological tools for characterizing this newly discovered pathogen, we developed a new S. eriocheiris specific monoclonal antibody (mAb) 6H7. The antibody showed high binding affinity to S. eriocheiris (K(a)=6.25*10(8) M(-1)) and it bound to the adhesin-like protein (ALP41) of S. eriocheiris in Western blot analysis. Screening of a commercially available 12-mer linear peptide library by using 6H7 as bait led to isolation of a consensus sequence (FQGINHYNQMER). The clone displaying this sequence exhibited a significant, dose dependent binding to 6H7 and inhibited the binding of S. eriocheiris to 6H7, suggesting a similar epitope between the sequence and S. eriocheiris. Homology searches and multiple sequence alignments indicated moderate homology between the consensus peptides and the ALP of S. eriocheiris. Thus, an internal image of 6H7 binding epitope might be buried in ALP41 of S. eriocheiris. In conclusion, 6H7 is a promising mAb to identify S. eriocheiris and the consensus sequence can be used in future research on the characterization of S. eriocheiris and its pathogenesis. PMID- 22925272 TI - Review of pathogenesis and diagnostic methods of immediate relevance for epidemiology and control of Salmonella Dublin in cattle. AB - Salmonella enterica subsp. enterica serovar Dublin (S. Dublin) receives increasing attention in cattle production. It is host-adapted to cattle, and leads to unacceptable levels of morbidity, mortality and production losses in both newly and persistently infected herds. Cattle health promoting institutions in several countries are currently constructing active surveillance programmes or voluntary certification programmes, and encourage control and eradication of S. Dublin infected cattle herds. There is a need to understand the underlying pathogenesis of the infection at both animal and herd level to design successful programmes. Furthermore, knowledge about and access to diagnostic tests for use in practice including information about test accuracy and interpretation of available diagnostic test methods are requested. The aim is to synthesise the abundant literature on elements of pathogenesis and diagnosis of immediate relevance for epidemiology and control of S. Dublin at animal and herd level. Relatively few in vivo studies on S. Dublin pathogenesis in cattle included more than a few animals and often showed varying result. It makes it difficult to draw conclusions about mechanisms that affect dissemination in cattle and that might be targets for control methods directed towards improving resistance against the bacteria, e.g. new vaccines. It is recommended to perform larger studies to elucidate dose-response relationships and age- and genetic effects of immunity. Furthermore, it is recommended to attempt to develop faster and more sensitive methods for detection of S. Dublin for diagnosis of infectious animals. PMID- 22925273 TI - Experienced stigma and self-stigma in Chinese patients with schizophrenia. AB - OBJECTIVE: To investigate experienced stigma and self-stigma in patients with schizophrenia in mainland China. METHODS: Ninety-five patients with schizophrenia, enrolled between January 2011 and March 2011, completed Chinese versions of two self-report questionnaires: the Internalized Stigma of Mental Illness (ISMI) scale and the Modified Consumer Experiences of Stigma Questionnaire (MCESQ). They also completed two other self-report questionnaires: the Social Support Rating Scale (SSRS) and the World Health Organization Quality of Life (WHOQOL-BREF) questionnaire. Patients were also assessed by a senior psychiatrist using the Scale for Assessment of Positive Symptoms (SAPS) and the Scale for Assessment of Negative Symptoms (SANS). All analyses were performed using SPSS 17.0 and included descriptive statistics, correlation analysis and multiple linear regression. RESULTS: On the ISMI, the percentage of participants who rated themselves above the mid-point of 2.5 (meaning high level of self stigma) on subscales and overall score was 44.2% (n=42) for alienation, 14.7% (n=14) for stereotype endorsement, 25.3% (n=24) for perceived discrimination, 32.6% (n=31) for social withdrawal and 20.0% (n=19) on the overall score. On the MCESQ, the percentage of participants who rated themselves above the mid-point of 3.0 on subscales and overall score was 24.2% (n=23) for stigma, 1.1% (n=1) for discrimination and 1.1% (n=1) on the overall score. Some socioeconomic variables, but not positive or negative symptoms, were related to the severity of psychiatric stigma. CONCLUSIONS: Results document the seriousness of experienced stigma and self-stigma in persons with schizophrenia. Strategies are needed to improve how governments and persons with schizophrenia cope with stigma. PMID- 22925274 TI - Circulating microRNA-126 in patients with coronary artery disease: correlation with LDL cholesterol. AB - BACKGROUND: Coronary artery disease (CAD) is a major problem worldwide. Atherosclerosis and thrombosis underlying CAD involve multiple cell types. New and useful diagnostic markers are required. MicroRNAs (miRNAs) are a class of noncoding RNAs that posttranscriptionally regulate the gene expressions involved in various cellular processes. Endothelial dysfunction is implicated in early processes of athero-thrombosis. Thus, it was hypothesized that the level of vascular endothelium-enriched miRNAs would be altered in plasma samples of CAD patients. METHODS: Vascular endothelium-enriched miRNA (miR-126) level was analyzed in plasma from 31 patients with CAD and 36 patients without CAD (qRT-PCR analysis). RESULTS: MiR-126 was not significantly down-regulated or up-regulated in CAD patients. Interestingly, the level of miR-126 was significantly decreased in patients with CAD and high low-density lipoprotein (LDL) cholesterol level. In contrast, the level of miR-126 was significantly increased when LDL cholesterol was high in patients who had risk factors for CAD but did not have angiographically significant CAD. CONCLUSION: MiR-126 was not significantly down regulated or up-regulated in CAD patients and was not suitable for discriminating CAD patients from patients without CAD. The oppositely-directed relationship between miR-126 and LDL cholesterol in patients with or without CAD may have significant implications for identifying a potential role of miR-126 in cholesterol metabolism. PMID- 22925275 TI - Electrospun chitosan/polyvinyl alcohol nanofibre mats for wound healing. AB - Chitosan (CS) aqueous salt blended with polyvinyl alcohol (PVA) nanofibre mats was prepared by electrospinning. CS was dissolved with hydroxybenzotriazole (HOBt), thiamine pyrophosphate (TPP) and ethylenediaminetetraacetic acid (EDTA) in distilled water without the use of toxic or hazardous solvents. The CS aqueous salts were blended with PVA at different weight ratios, and the effect of the solution ratios was investigated. The morphologies and mechanical and swelling properties of the generated fibres were analysed. Indirect cytotoxicity studies indicated that the CS/PVA nanofibre mats were non-toxic to normal human fibroblast cells. The CS-HOBt/PVA and CS-EDTA/PVA nanofibre mats demonstrated satisfactory antibacterial activity against both gram-positive and gram-negative bacteria, and an in vivo wound healing test showed that the CS-EDTA/PVA nanofibre mats performed better than gauze in decreasing acute wound size during the first week after tissue damage. In conclusion, the biodegradable, biocompatible and antibacterial CS-EDTA/PVA nanofibre mats have potential for use as wound dressing materials. PMID- 22925277 TI - Comparative efficacy of postpartum sterilisation with the titanium clip versus partial salpingectomy: a randomised controlled trial. AB - A multicentre trial was conducted to compare efficacy of postpartum sterilisation with clip and partial salpingectomy. Life-table estimates of pregnancy probabilities were compared through 2 years of follow up. A significantly different risk of pregnancy between the clip and partial salpingectomy groups was observed. Nine pregnancies were observed in the clip group versus two in the partial salpingectomy group. Cumulative probability of pregnancy through 2 years was 0.017 with the clip and 0.004 [correction added after online publication 25 September 2012; 0.044 has been replaced with 0.004] for partial salpingectomy (P < 0.04). Equivalent efficacy of the clip compared with partial salpingectomy has not been demonstrated in postpartum women. PMID- 22925276 TI - Modifying the role of serotonergic 5-HTTLPR and TPH2 variants on disulfiram treatment of cocaine addiction: a preliminary study. AB - Disulfiram is a cocaine pharmacotherapy that may act through increasing serotonin, benefiting patients with genetically low serotonin transporter levels (5-HTTLPR, S' allele carriers) and low serotonin synthesis (TPH2, A allele carriers). We stabilized 71 cocaine and opioid co-dependent patients on methadone for 2 weeks and randomized them into disulfiram and placebo groups for 10 weeks. We genotyped the SLC6A4 5-HTTLPR (rs4795541, rs25531) and TPH2 1125A>T (rs4290270) variants and evaluated their role in moderating disulfiram treatment for cocaine dependence. Cocaine-positive urines dropped from 78% to 54% for the disulfiram group and from 77% to 76% for the placebo group among the 5-HTTLPR S' allele carriers (F = 16.2; df = 1,301; P < 0.0001). TPH2 A allele carriers responded better to disulfiram than placebo (F = 16.0; df = 1,223; P < 0.0001). Patients with both an S' allele and a TPH2 A allele reduced cocaine urines from 71% to 53% on disulfiram and had no change on placebo (F = 21.6; df = 1,185; P < 0.00001). PMID- 22925279 TI - Prevalence and genotypic characterization of Clostridium difficile from ruminants in Switzerland. AB - Clostridium difficile is an emerging enteric pathogen of humans and animals with a known main reservoir in the intestinal tract of various warm-blooded animals. This study was carried out to evaluate the prevalence of C. difficile in 150 rectal swab samples collected from cattle and goats in Switzerland. The overall prevalence of C. difficile was 6.6%. The isolates belonged to the PCR ribotypes 033, 066, 070, 003, 001 and 137. In addition, the occurrence of C. difficile in faecal samples collected from farm ground was also evaluated and C. difficile was detected in 21% (7/30) of these samples. These isolates belonged to ribotypes 033, 066, 014 and 137. Several isolates pertained to ribotypes known to cause Clostridium difficile infections in humans. PMID- 22925280 TI - Endoscopic approach to pancreatic pseudocyst, abscess and necrosis: review on recent progress. AB - AIM: The aim of this study is to introduce recent progress in the treatment of pancreatic pseudocyst, abscess and necrosis using the endoscopic approach. METHODS: Studies on PubMed and MEDLINE from the last 30 years on progress in the management of the complications from severe pancreatitis were researched and reviewed. Herein, the indication for intervention, definition of fluid collection associated with acute pancreatitis and treatment modalities of these complications are summarized. RESULTS: Three types of management are employed for complications of severe pancreatitis: the endoscopic, surgical and percutaneous approaches. CONCLUSIONS: Over the years, as technical expertise has increased and instruments for endoscopy have improved, patients who had endoscopic surgery to address the complications of severe pancreatitis have had higher survival rates, lower mortality rates and lower complication rates than those having open debridement. However, traditional open abdominal surgery should be advocated when minimally invasive management fails or necrosis is extensive and extends diffusely to areas such as the paracolic gutter and the groin (i.e. locations not accessible by endoscopy). PMID- 22925281 TI - Efficacy of acetic acid-spraying method in diagnosing extension of Barrett's cancer under the squamous epithelium. AB - AIM: Endoscopic diagnosis of the lateral extension of Barrett's cancer under the squamous epithelium (BCUS) is sometimes difficult because the cancer is unobservable in the esophageal lumen. The aim of the present study was to clarify the endoscopic features of the extension of BCUS and verify the usefulness of the acetic acid-spraying method (AAS) for diagnosis. METHODS: A total of 25 patients with Barrett's cancer who had undergone endoscopic resection were included in this study. Histological examination of patients' resected specimens was performed to identify the presence of BCUS. Then, the endoscopic images of the BCUS cases were reviewed to summarize the findings and to evaluate the feasibility of diagnosing the extent of BCUS with each imaging technique. RESULTS: Of the 25 patients, 10 (40%) had BCUS. With white-light imaging, subtle reddish change was observed in the area of BCUS in 80% of the patients, and a flat elevated lesion was recognized in 30%. With narrow band imaging, slight brownish change was observed in the area of BCUS in 86% of the patients. Slight white changes were visualized in all cases with AAS. The extension of BCUS was correctly diagnosed by white-light imaging, narrow band imaging and AAS in 50%, 43% and 100% of the cases, respectively. Histology verified the opening of cancerous glands, which extended under the squamous epithelium, into the esophagus in the area showing slight white changes by AAS. CONCLUSION: AAS can be useful for diagnosing the extension of BCUS. PMID- 22925282 TI - Usefulness of clip traction in the early phase of esophageal endoscopic submucosal dissection. AB - BACKGROUND: The usefulness of clip traction in endoscopic submucosal dissection (ESD) for early esophageal carcinoma was investigated. METHODS: A total of 87 patients who underwent ESD for esophageal squamous cell carcinoma were included in the study. The hook knife method was used for ESD. Twenty patients underwent ESD without clip traction (non-clip group) and 67 underwent procedures in which clip traction was used (clip group). A clip with a string was attached to the oral edge of the lesion after mucosal incision in the clip group. RESULTS: ESD was successful in all cases. Wide exposure of the submucosal tissue below the lesion was obtained by applying tension to the clip traction. The duration of ESD was shorter in the clip group, and there was a significant difference in duration between the non-clip and clip groups. There were no complications of ESD in the clip group, but muscle layer injury occurred in three patients in the non-clip group. CONCLUSION: Clip traction shortens operating time and is safer in esophageal ESD. Clip traction is recommended as a useful auxiliary procedure. PMID- 22925283 TI - Clinical evaluation of hemorrhagic gastroduodenal ulcer in the elderly: is Helicobacter pylori infection a risk factor for hemorrhage? AB - AIM: In this study, the aim was to determine the demographic characteristics of elderly patients with gastroduodenal ulcer who had undergone endoscopic hemostasis by comparing them with younger patients. METHODS: A total of 353 patients with Forrest class I-IIa hemorrhagic gastroduodenal ulcer who underwent endoscopic hemostasis at our hospital between December 2004 and May 2010 were divided into two groups: one for those 75 years or older (old-old group; n = 71; age >=75 years) and one for those younger than 75 years (younger group; n = 282; age <75 years). Then, their demographic characteristics were compared. RESULTS: There were significantly more female patients, patients with underlying chronic renal failure and patients using non-steroidal anti-inflammatory drugs in the old old group than in the younger group. In addition, the prevalence of open-type atrophy in the background gastric mucosa was significantly higher in the old-old group. Although more than half the patients in each group were infected with Helicobacter pylori, the prevalence was significantly higher in the younger group. Of the patients who underwent endoscopic hemostasis only once, those in the old-old group constituted a significantly higher medical cost than those in the younger group. Comparison of deaths between the two groups revealed that the old-old patients were more likely to develop severe complications associated with hematemesis, such as aspiration pneumonia. CONCLUSIONS: The observed lower prevalence of Helicobacter pylori infection among the elderly patients compared to the younger patients with hemorrhagic gastroduodenal ulcer suggests that other factors, such as non-steroidal anti-inflammatory drugs use and chronic renal failure, predispose the elderly to hemorrhagic ulcer. PMID- 22925284 TI - Relationship between vomiting reflex during esophagogastroduodenoscopy and dyspepsia symptoms. AB - AIM: Although frequent vomiting reflexes during esophagogastroduodenoscopy (EGD) causes suffering in patients, very few studies have investigated the characteristics of subjects who frequently develop vomiting reflexes. This study examined the incidence of the vomiting reflex and related factors, especially upper gastrointestinal symptoms, among individuals undergoing transoral EGD. METHODS: Subjects included 488 consecutive adults (mean age, 56.1 +/- 8.9 years) who underwent transoral EGD for gastric cancer screening between February 2010 and March 2011. All procedures were performed by an endoscopist with 15 years of experience. Based on a questionnaire survey using the frequency scale for the symptoms of gastroesophageal reflux disease (FSSG), symptoms (dyspepsia and acid reflux symptoms) and the number of vomiting reflexes during EGD were recorded. RESULTS: Of the 488 subjects, 271 (56%) developed vomiting reflexes (mean, 4.2 times). This reflex-positive group was younger (54.3 +/- 9.5 years) than the reflex-negative group (58.3 +/- 7.7 years, P < 0.001). The number of subjects in the reflex-positive group with a high FSSG dyspepsia score (2.27 +/- 2.57 vs 1.23 +/- 1.84; P < 0.001), acid reflux symptom score (1.96 +/- 2.22 vs 1.34 +/- 2.14; P < 0.01) or an esophageal hiatal hernia (14.8% vs 4.6%; P < 0.001) was significantly higher than in the reflex-negative group. Multivariate analysis also showed a significant correlation between these four factors and the occurrence of vomiting reflexes. Using an FSSG dyspepsia score of 1 as the cut off offered 68% sensitivity and 57% specificity for predicting the occurrence of vomiting reflexes. CONCLUSION: Based on FSSG questionnaire responses on upper gastrointestinal symptoms, dyspepsia symptoms, in particular, are related to presence of vomiting reflexes during EGD. PMID- 22925285 TI - Clinical characterization of gastric lesions initially diagnosed as low-grade adenomas on forceps biopsy. AB - AIM: The aim of this study was to elucidate characteristics of gastric lesions that are initially diagnosed as low-grade adenomas and to establish appropriate treatment. METHODS: We retrospectively reviewed 231 lesions initially diagnosed as gastric adenomas. All forceps biopsy samples were histologically diagnosed as category 3 low-grade adenomas according to the revised Vienna Classification. All patients underwent endoscopic resection with endoscopic findings and post resection diagnoses evaluated subsequently. RESULTS: Sixty-three lesions were initially diagnosed as depressed adenomas, and 168 lesions were diagnosed as protruding adenomas. The depressed lesions were significantly smaller (11.6 +/- 5.0 mm) than the protruding lesions (17.0 +/- 10.8 mm) (P < 0.001). Diagnoses reclassified to category 4 mucosal high-grade neoplasia (i.e. high-grade adenoma, adenocarcinoma in adenoma and adenocarcinoma) were more frequent among depressed lesions (52.4%) than among protruding lesions (31.0%) (P = 0.004). Multivariate analysis of all 231 lesions showed that lesion size larger than 20 mm (P < 0.001) and depressed appearance (including central depression) (P < 0.001) were significant independent factors suggesting cancer. For the 168 protruding lesions, lesion size larger than 20 mm (P < 0.001) and central depression (P < 0.001) were significant independent factors suggesting cancer. For the 63 depressed lesions, lesion size larger than 15 mm (P = 0.016) and a moth-eaten appearance (P = 0.017) were significant independent factors in the pre-treatment diagnosis of cancer. CONCLUSIONS: Adenocarcinoma lesions were often found in depressed lesions and protruding lesions with central depression. Endoscopic resection for total biopsy is recommended, even if forceps biopsy indicates low grade adenoma, as pre-treatment biopsy may be inadequate for an accurate histological diagnosis. PMID- 22925286 TI - Influence of endoscopic submucosal dissection on serum levels of pepsinogens in patients with early gastric cancer. AB - BACKGROUND: The serum levels of pepsinogens (PG) have been considered to be a useful marker for assessing the risk of metachronous gastric cancer in patients who undergo endoscopic submucosal dissection. However, the influence of endoscopic submucosal dissection (ESD) on serum levels of PG has not yet been examined. The aim of this study was to examine whether the level of PG after ESD can be used to predict the risk of metachronous cancer. PATIENTS AND METHODS: The study included of 100 consecutive patients who underwent ESD for gastric cancer at Hirosaki University Hospital from September 2009 to February 2011. Serum levels of PG I and II on the day before and after ESD were compared. Stool antigen test was also performed to examine the presence of Helicobacter pylori infection. RESULTS: The mean serum level of PG I before and after ESD was 34.3 +/ 31.6 ng/mL and 70.5 +/- 100.0 ng/mL (P < 0.001), respectively. PG I/II ratio before and after ESD was 2.40 +/- 1.51 and 2.79 +/- 1.70 (P < 0.001). The serum level of PG I and the PG I/II ratio were significantly changed after ESD, regardless of the use of proton pump inhibitor, Helicobacter pylori infection or the location of the tumor. CONCLUSIONS: ESD treatment modulates the serum level of PG I and significantly increases the PG I/II ratio. Serum levels of PG should be measured before the ESD procedure is performed to predict the risk of developing metachronous gastric cancer after ESD. PMID- 22925287 TI - Flicking method: a novel colonoscope insertion method for surveillance colonoscopy in ulcerative colitis patients. AB - AIM: Periodic surveillance colonoscopy is required for patients with ulcerative colitis to detect colitis-associated dysplasia at an early stage. However, sometimes colonoscopy may damage the fragile mucosa of patients with ulcerative colitis. The aim of this study was to devise a new method of surveillance colonoscopy for patients with mild to moderate ulcerative colitis. METHODS: The 'flicking method' of colonoscope insertion was recently developed by our team. It is a completely novel method that involves using the elastic force of the colonoscope to introduce it into the deeper regions while using colon mucosa patterns as a guide. The subjects were 66 hospital outpatients with ulcerative colitis who underwent colonoscopies during a 2-year period, from April 2006 to March 2008, with both the conventional insertion method and the flicking method. RESULTS: Cecal intubation rate, insertion time, patient pain level, change in number of defecations pre- and post-colonoscopy, and change in severity pre- and post-colonoscopy were compared between the conventional and flicking methods. The flicking method was superior in all respects. CONCLUSIONS: The flicking method is a novel colonoscope insertion method that is regarded as particularly useful in cases when the intestinal mucosa is fragile, as is the case with ulcerative colitis patients. PMID- 22925289 TI - Number of aberrant crypt foci in the rectum is a useful surrogate marker of colorectal adenoma recurrence. AB - AIM: Endoscopic screening and removal of colorectal adenomas can reduce the incidence of colorectal cancer. However, given the possibility of adenoma recurrence, surveillance colonoscopy is currently recommended after the initial screening and removal of colorectal adenomas. Aberrant crypt foci (ACF) have been shown to serve as a reliable surrogate marker of colorectal carcinogenesis. In this study, the relationship between the number of ACF at the initial endoscopic polypectomy and the likelihood of colorectal adenoma recurrence after polypectomy were investigated. METHODS: High-magnification chromoscopic colonoscopy was performed in 82 subjects who underwent endoscopic polypectomy to identify ACF in the lower rectum. Surveillance colonoscopy was then performed 3 years after the baseline polypectomy at Yokohama City University Hospital. RESULTS: The number of ACF was greater in patients who showed adenoma recurrence (7.88 +/- 6.35) than in those who did not (2.19 +/- 2.95) (P < 0.001). Receiver-operating curve analysis showed that the number of ACF was a highly specific predictor of the risk of adenoma recurrence. CONCLUSIONS: This is the first study conducted to investigate the relationship between the number of ACF after endoscopic polypectomy and the likelihood of recurrence of colorectal adenomas. These results suggest that the number of ACF is a useful predictor of the likelihood of colorectal adenoma recurrence. PMID- 22925288 TI - Usefulness of sodium hyaluronate solution in colorectal endoscopic mucosal resection. AB - BACKGROUND: In endoscopic mucosal resection (EMR), it is essential to inject submucosal fluid to prevent complications and ensure safe and complete en bloc resection of tumors. Sodium hyaluronate (SH) solution, which is effective in forming and maintaining a mucosal lift and is innocuous to mucosal tissue, is considered a useful injection solution for endoscopic submucosal dissection, a procedure associated with a high risk of perforation. This study was undertaken to assess the usefulness of this solution in EMR. METHODS: Ninety-four patients with colorectal tumors of <=20 mm in diameter were enrolled for this study and randomized to a SH solution group (0.2% two-fold diluted MucoUp) or to a normal saline group (control). Ease of EMR was primarily assessed based on ease of submucosal injection, ease of snaring and injection time. RESULTS: SH solution was superior to normal saline for ease of submucosal injection (57 +/- 0.7 vs 50 +/- 0.7; P < 0.05), and it showed better results for ease of snaring with less variability (63 +/- 0.8 vs 51 +/- 1.0; P < 0.05). The mean injection time was similar between the two groups (3.0 +/- 9.0 s and 3.0 +/- 2.7 s, respectively). Post-procedural hemorrhage occurred in 7% patients (3/46) injected with SH solution and in 6% of patients (3/48) in the control group; there was no significant difference between the groups. CONCLUSIONS: Use of two-fold diluted MucoUp facilitated colorectal EMR. PMID- 22925290 TI - Factors affecting the diagnostic accuracy of endoscopic ultrasonography-guided fine-needle aspiration (EUS-FNA) for upper gastrointestinal submucosal or extraluminal solid mass lesions. AB - AIM: A number of potential variables are associated with the diagnostic accuracy of endoscopic ultrasonography-guided fine-needle aspiration (EUS-FNA). The aim of this study was to evaluate factors affecting the diagnostic accuracy of EUS-FNA for upper gastrointestinal submucosal or extraluminal solid lesions. METHODS: Patients with such lesions who underwent EUS-FNA between January 2009 and December 2010 were studied retrospectively. Needles of 22, 25 and 19 gauge were used. The associations between the EUS-FNA results and factors such as mass location, mass size, needle size, number of needle passes, combined histologic cytologic analysis and final diagnosis were analyzed. RESULTS: A total of 170 EUS FNA procedures were performed in 158 patients with upper gastrointestinal submucosal or extraluminal solid lesions. The overall accuracy of EUS-FNA was 86.5% (147/170). The diagnostic accuracy with three or more needle passes was higher than with less than 3.0 needle passes (90.0%, 108/120 vs 78.0%, 39/50; P < 0.05). Mass location, mass size, and final diagnosis were not associated with EUS FNA accuracy. Combined cytologic-histologic analysis had significantly higher diagnostic accuracy than either cytologic or histologic analysis alone (P < 0.001). In a subgroup of 90 patients, both 22 and 25 gauge needles were used for EUS-FNA. The overall diagnostic accuracy was similar for 25 gauge needles and 22 gauge needles (80.0% vs 78.9% P = 1.000) in this subgroup. CONCLUSION: Overall, 25 and 22 gauge needles have a similar diagnostic accuracy. Our results suggest that 3.0 or more needle passes and combined cytologic-histologic analysis enhance the diagnostic accuracy of EUS-FNA. PMID- 22925291 TI - The efficacy of transcatheter arterial embolization as the first-choice treatment after failure of endoscopic hemostasis and endoscopic treatment resistance factors. AB - AIM: The aim of this retrospective study was to evaluate the efficacy of transcatheter arterial embolization (TAE) as the first-choice treatment in patients with bleeding peptic ulcer after the failure of endoscopic hemostasis. An additional objective was to clarify endoscopic treatment resistance factors. METHODS: Between April 2004 and December 2010, 554 patients were admitted to Kasugai Municipal Hospital for necessary endoscopic hemostasis for bleeding gastric ulcer or duodenal ulcer. In the patients for whom endoscopic hemostasis failed, TAE was attempted. If TAE failed, the patients underwent surgery. The backgrounds of the patients in whom endoscopic treatment was successful and in whom it failed were compared. RESULTS: TAE was attempted in 15 patients (2.7%). In 12 (80.0%) of 15 patients, embolization with coils was successful. In one patient (6.7%), embolization was ineffective. This patient underwent emergent salvage surgery. In two (13.3%) of 15 patients, no extravasation was observed during arteriography. These patients were cured with medication. In two patients, ulcer perforation was observed during endoscopy after rebleeding. These patients underwent surgery. In total, 3 (0.5%) of 554 patients underwent surgery. No recurrent bleeding was observed after TAE. Hemoglobin level <8 g/dL at presentation (P = 0.02), Rockall score >=7 at presentation (P = 0.002), and Forrest class Ia/Ib at initial endoscopic hemostasis (P < 0.001) were found to be independent significant endoscopic treatment resistance factors. CONCLUSIONS: TAE is a safe and effective first-choice treatment for patients in whom endoscopic hemostasis has failed. PMID- 22925292 TI - Diagnostic usefulness of precise examinations with intraductal ultrasonography, peroral cholangioscopy and laparoscopy of immunoglobulin G4-related sclerosing cholangitis. AB - Herein, a case of immunoglobulin G4 (IgG4)-related sclerosing cholangitis is reported. IgG4 was diagnosed based on observations from peroral cholangioscopy and laparoscopy, and these methods are proposed for definitive and precise diagnosis of this disease. A 76-year-old male patient with inguinal Paget's disease had intrahepatic bile duct dilatations detected with computed tomography at his periodic check-up. Magnetic resonance cholangiography showed stenosis of the upper common bile duct and poststenotic dilatation of left intrahepatic bile ducts. The portal tract and bilateral intrahepatic bile ducts were surrounded by a low-density area, facing a tumor-like lesion at segment 2. Cytological examinations of the stenotic and dilated lesions revealed no cellular atypia. Histological examination of the tumor showed normal liver tissue with infiltration of lymphocytes, indicating an inflammatory pseudotumor. Peroral cholangioscopy excluded the possibility of biliary cancer and indicated that the stenotic legion was of submucosal, not mucosal, origin. Laparoscopic observations showed discoloration with wide yellowish-white lobular markings and wide depressed lesions at segments 2 and 7. Liver histology showed mild cholangitis with infiltration of IgG4-positive plasma cells around the bile ducts. Serum IgG4 levels were elevated. From these findings, the patient was diagnosed with IgG4 related sclerosing cholangitis. After treatment with prednisolone, blood liver enzymes and IgG4 rapidly normalized, bile duct dilatations improved, and the hepatic pseudotumor disappeared. The cholangitis did not recur. In this case, biliary cancer was ruled out by observation with peroral cholangioscopy, and the spread of cholangitis in the liver periphery was verified with laparoscopy; this information could not be obtained with other modalities. PMID- 22925293 TI - Synchronous presentation of acute pancreatitis and splenomegaly with intussusceptions in Peutz-Jeghers syndrome. AB - Peutz-Jeghers syndrome (PJS) is a rare, autosomal dominant inherited disorder characterized by gastrointestinal hamartomatous polyps and pigmented mucocutaneous lesions. Intussusceptions and gastrointestinal tract bleeding are frequent complications of PJS caused by larger polyps, but acute pancreatitis and splenomegaly are very rare. Previously, surgical intervention was the only curative modality despite the associated complications. In recent years, double balloon enteroscopy (DBE) has become the alternative method as the ideal treatment. We report the case of a 20-year-old woman diagnosed with PJS, as she suffered from 4-day nausea and vomiting with acute abdominal pain, and clinically manifested acute pancreatitis, splenomegaly and duodenojejunal intussusceptions secondary to a huge proximal jejunal polyp (10 cm * 2 cm). We removed the polyp via DBE and found that the acute pancreatitis, splenomegaly and duodenojejunal intussusceptions were simultaneously ameliorated 2 days after treatment. Currently, the patient has been symptom free for 3 months after polypectomy. Acute pancreatitis, splenomegaly and intussusceptions can synchronously occur in PJS patients, and polypectomy via DBE is the effective treatment alternative to surgical intervention for this disease, thereby obviating some complications associated with the latter. PMID- 22925294 TI - Gastrojejunal fistula caused by peptic ulcer disease. PMID- 22925295 TI - Rare complication following screening colonoscopy: ischemic colitis. PMID- 22925296 TI - Primary leiomyoma of the pancreas diagnosed by endoscopic ultrasound-guided fine needle aspiration. PMID- 22925297 TI - Impact of endoscopic submucosal dissection knife on risk of perforation with an animal model-monopolar needle knife and with a bipolar needle knife. PMID- 22925298 TI - Colonic involvement in Stevens-Johnson syndrome: a rare entity. PMID- 22925299 TI - Esophageal pseudodiverticulosis presenting with massive gastrointestinal bleed. PMID- 22925300 TI - Demonstration of retraction of the main papilla toward the biliary system in patients with primary sclerosing cholangitis with magnetic resonance cholangiopancreatography. PMID- 22925301 TI - Abdominal corset for colonoscopy. PMID- 22925302 TI - Infected mediastinal cyst following endoscopic ultrasonography-guided fine-needle aspiration with rupture into the esophagus. PMID- 22925303 TI - Verruciform xanthoma arising in the mid esophagus. PMID- 22925304 TI - Intestinal helminths detected in capsule endoscopy. PMID- 22925305 TI - Primary gastric follicular lymphoma manifesting as a submucosal tumor-like lesion. PMID- 22925306 TI - Endoscopic ultrasonography-guided transgastric drainage of infectious biloma following radiofrequency ablation for hepatocellular carcinoma. PMID- 22925307 TI - Right colon blanching: endoscopic epiphany for mesenteric ischemia. PMID- 22925308 TI - Papillitis at endoscopic retrograde cholangiopancreatography: what's the relevance? PMID- 22925309 TI - Internet addiction, reality substitution and longitudinal changes in psychotic like experiences in young adults. AB - AIM: Internet use has grown exponentially in the past decade, but there has been little systematic research to inform our understanding of how this phenomenon may relate to mental illness. Although several characteristics of individuals experiencing psychotic-like experiences (PLEs) may render this group particularly susceptible to problematic Internet use, to date there have been no studies examining Internet use in this group. Because the experience of PLEs is considered a risk "behaviour" for formal psychosis, it is crucial to understand how patterns of Internet use may be tied to the progression of illness. METHODS: A total of 170 young adults were followed for 2 months, and grouped into those showing a steady/improved course of PLEs (PLE-Improved/Constant) and those showing an exacerbation in PLEs (PLE-Increase). Internet addiction and a factor 'Reality Substitute' were examined within and between the two groups. RESULTS: Findings indicated that although both groups reported a similar level of Internet addiction and Reality Substitute at baseline, the PLE-Improved/Constant group showed longitudinal declines in both domains of problematic Internet usage whereas the PLE-Increase group's reported level remained constant. Further, there were moderate correlations between PLEs and domains of problematic Internet use, and the magnitude of association with Reality Substitute for the PLE-Increase group grew significantly over time. CONCLUSION: Taken together, results implicate a close link between continued problematic Internet use and the phenomena of PLEs. PMID- 22925310 TI - When female circumcision comes to the West: attitudes toward the practice among Somali Immigrants in Oslo. AB - BACKGROUND: Female circumcision (FC) has lifelong adverse social and health consequences for women, and its abolition will not only enhance the health of children and women, but also promote gender equality. Like many other Western countries, Norway hosts a large proportion of immigrants from FC-practicing countries, though primarily from Somalia, which is the country with the highest prevalence of FC in the world. A behavioral change by the practicing communities has the best chance to successfully and sustainably eliminate this practice. However, FC prevention programs require a behavioral surveillance that monitors the process of change, with this being the first quantitative study since the major migration of the Somali community to Norway began in 1991 to investigate whether or not Somali immigrants' attitudes toward the practice has improved in favor of its abandonment. METHODS: A cross-sectional study using a respondent driven sampling (RDS) was conducted in Oslo from April to June of 2011. A sample of 214 persons was interviewed, using structured questionnaires. RESULTS: The results show that 70% of Somalis in Oslo support the discontinuation of all forms of FC compared to 30% who support its continuation, with the latter group more likely to be people who lived in Norway <= 4 years. Of the 10 girls who came to Norway at the age of <= 7 years, only one was circumcised, though whether the circumcision occurred before or after the girl's arrival in Norway remains unclear. The perception that FC is required by religion was the sole factor to be significantly associated with an ongoing support of FC. CONCLUSION: The study reveals that Somalis in Oslo demonstrate a trend to abandon this practice over time. Nevertheless, the 30% of the people who still support its continuation, and who are primarily newly arrived immigrants, require a targeted intervention that is implemented in the early phase of the immigrants' arrival. PMID- 22925311 TI - Acanthamoeba feature a unique backpacking strategy to trap and feed on Listeria monocytogenes and other motile bacteria. AB - Despite its prominent role as an intracellular human pathogen, Listeria monocytogenes normally features a saprophytic lifestyle, and shares many environmental habitats with predatory protozoa. Earlier studies claimed that Acanthamoeba may act as environmental reservoirs for L. monocytogenes, whereas others failed to confirm this hypothesis. Our findings support the latter and provide clear evidence that L. monocytogenes is unable to persist in Acanthamoeba castellanii and A. polyphaga. Instead, external Listeria cells are rapidly immobilized on the surface of Acanthamoeba trophozoites, forming large aggregates of densely packed bacteria that we termed backpacks. While the assembly of backpacks is dependent on bacterial motility, flagellation alone is not sufficient. Electron micrographs showed that the aggregates are held together by filaments of likely amoebal origin. Time-lapse microscopy revealed that shortly after the bacteria are collected, the amoeba can change direction of movement, phagocytose the backpack and continue to repeat the process. The phenomenon was also observed with avirulent L. monocytogenes mutants, non-pathogenic Listeria, and other motile bacteria, indicating that formation of backpacks is not specific for L. monocytogenes, and independent of bacterial pathogenicity or virulence. Hence, backpacking appears to represent a unique and highly effective strategy of Acanthamoeba to trap and feed on motile bacteria. PMID- 22925312 TI - The incidence of type 1 diabetes in Republic of Srpska (Bosnia and Herzegovina) and Slovenia in the period 1998-2010. AB - OBJECTIVE: To establish and compare the incidence and trends of type 1 diabetes mellitus (T1DM) in Republic of Srpska and Slovenia in age group 0-18 yr from 1998 to 2010. METHODS: The subjects (413 newly diagnosed T1DM patients in the Republic of Srpska and 664 in Slovenia) were grouped into the age groups: 0-4, 5-9, 10-14, and 15-18 yr. Confidence intervals (CI) for crude incidence rates were estimated assuming numbers of cases were counts from the Poisson distribution. Gender and age-specific standardization was done according to the EURODIAB criteria. Statistical analysis used Poisson-regression models to analyze difference rate between countries and to investigate the incidence trend. RESULTS: Case ascertainment was estimated to be 99.95% for the Republic of Srpska and 100% for Slovenia by using the capture-recapture method. The standardized incidence of T1DM for age group 0-18 yr in the Republic of Srpska was 7.5/100 000/yr (95% CI: 6.8-8.3). For the same period and the same age group incidence in Slovenia was 12.5/100 000/yr (95% CI: 11.5-13.5). Annual increase in the incidence in the Republic of Srpska was 2.3% (95% CI: -0.3 to 5.0%), whereas in Slovenia 4.3% (95% CI: 2.2-6.5%). CONCLUSION: The incidence for age group 0-18 yr standardized to the world population is remarkably higher in Slovenia than in the Republic of Srpska. Further follow-up and investigations are needed to explain the high difference in incidence of T1DM between the two geographically related countries. PMID- 22925313 TI - Neoadjuvant chemoradiotherapy followed by esophagectomy does not increase morbidity in patients over 70. AB - Esophagectomy in elderly esophageal carcinoma patients is correlated with a high morbidity and even mortality. Studies on neoadjuvant chemoradiotherapy (NT) in elderly patients are scarce. The aim of this study was to evaluate the effect of advanced age in combination with NT in esophageal carcinoma patients who underwent an esophagectomy. Patients who underwent NT prior to esophagectomy between 1993 and 2010 were divided into three groups: <70, 70-74, and >=75 years. Toxicity of NT and postoperative morbidity were compared between groups. Primary endpoints were toxicity, complication rate, and survival. Two hundred thirteen patients underwent NT during the study period, 26 were aged 70-74 years, and 17 were >=70 years. Toxicity of NT was comparable for younger and elderly patients (46% vs. 54% vs. 47%, P = 0.263). Overall complications occurred in 62% of younger patients versus 73% and 71% among patients aged 70-74 years and >=75 years, respectively (P = 0.836). Cardiac complications occurred in 14% of younger patients versus 27% and 41% of elderly patients (P = 0.021). Three-year survival rates were 59% versus 44% versus 31% among patients aged <70, 70-74, and >=75 years, respectively (P = 0.237). Higher age (odds ratio 1.750, P < 0.001) was an independent risk factor for development of cardiac complications. Toxicity of NT and postoperative complications are comparable for patients aged <70, 70-74, and >=75 years, with the exception of cardiac complications. Therefore, we consider NT followed by esophagectomy in elderly patients a safe treatment modality in our center. PMID- 22925314 TI - Predictors of adherence to performance measures in patients with acute myocardial infarction. AB - BACKGROUND: There have been substantial improvements in the use of evidence based, guideline-recommended therapies for patients with acute myocardial infarction. Nevertheless, some gaps, disparities, and variations in use remain. To understand how such gaps in recommended care may be narrowed further, it may be useful to determine those factors associated with lessened adherence to guideline-based care. METHODS: The Get with the Guidelines-Coronary Artery Disease registry measured adherence with 6 performance measures (aspirin within 24 hours, discharge on aspirin and beta-blockers, patients with low ejection fraction discharged on angiotensin-converting enzyme inhibitor/angiotensin receptor blocker, smoking cessation counseling, use of lipid-lowering medications) in 148,654 patients with acute myocardial infarction between 2002 and 2009. Logistic multivariable regression models using generalized estimating equations were utilized to identify patient and hospital characteristics associated with adherence to each of 6 measures, and to a summary score of performance for all measures, in eligible patients. RESULTS: We identified 10 variables that were associated significantly with either greater adherence (hypertension, hyperlipidemia, hospital with full interventional capabilities, calendar year) or worse adherence (age, female sex, congestive heart failure, chronic renal insufficiency, atrial fibrillation, chronic dialysis) in at least 4 of the 6 treatment adherence models, as well as the summary score adherence model. Age, sex, and calendar year were significant in all models. CONCLUSIONS: Use of evidence-based acute myocardial infarction treatments remains less than ideal for certain high-risk populations. The close correlations among factors associated with underperformance highlights the potential for specifically targeting and tailoring quality improvement interventions. PMID- 22925316 TI - Long-term macrolide treatment of chronic inflammatory airway diseases: risks, benefits and future developments. AB - Macrolide antibiotics were discovered over 50 years ago and following their use as antimicrobials it became apparent that this group of antibiotics also possessed anti-inflammatory properties. Subsequent clinical trials showed benefits of macrolides as long-term adjuncts in the treatment of a spectrum of chronic inflammatory respiratory diseases, particularly diffuse panbronchiolitis, cystic fibrosis, post-transplant bronchiolitis obliterans and more recently chronic obstructive pulmonary disease (COPD). The evidence for efficacy of macrolides in the long-term treatment of chronic asthma and bronchiectasis is less well established. The mechanism(s) of action of macrolides in the treatment of these diseases remains unexplained, but may be due to their antibacterial and/or anti-inflammatory actions, which include reductions in interleukin-8 production, neutrophil migration and/or function. Macrolides have additional potentially beneficial properties including anti-viral actions and an ability to restore corticosteroid sensitivity. The increased prescribing of macrolides for long-term treatment could result in the development of microbial resistance and adverse drug effects. New macrolides have been developed which do not possess any antimicrobial activity and hence lack the ability to produce microbial resistance, but which still retain immunomodulatory effects. Potentially novel macrolides may overcome a significant barrier to the use of this type of drug for the long-term treatment of chronic inflammatory airway diseases. PMID- 22925318 TI - Bronchial inflammation and hyperresponsiveness in well controlled asthma. AB - BACKGROUND: Little research has been devoted to the characteristics of bronchial inflammation in patients with stable, well controlled asthma. OBJECTIVE: The aim of this study was to assess the degree and type of airway inflammation and to investigate the relationship between inflammation and bronchial hyperresponsiveness in patients with well controlled asthma. METHODS: A cross sectional study was conducted in 84 adult patients (43 men, mean age 43 years) with documented well controlled asthma. Induced sputum samples were obtained and cell types determined by differential cell count. Spirometry and methacholine challenge testing were performed. Asthma Control Questionnaire (ACQ) was used to assess symptoms. Patients were included if their ACQ score was < 0.75. RESULTS: A total of 59 patients had persistent bronchial inflammation: 28 cases were considered eosinophilic, 28 neutrophilic, and 3 mixed. Median (range) percentage of eosinophils was 4% (0-64) in patients testing positive to methacholine challenge (n = 66) and 1% (0-3) in those testing negative (n = 18) (P = 0.003). A positive correlation was found between eosinophil percentage and the methacholine dose/response ratio (r = 0.477, P = 0.0001). The geometric mean (95% CI) of the methacholine PC20 was 1.74 mg/mL (1.04-2.93) in patients with eosinophilic inflammation and 4.14 mg/mL (2.5-6.84) in those with neutrophilic inflammation (P = 0.03). CONCLUSIONS: Inflammation and bronchial hyperresponsiveness persist in most patients with well controlled asthma. CLINICAL RELEVANCE: The study demonstrates that eosinophilic or neutrophilic inflammation persisted in most well controlled asthma patients despite the fact that their condition was controlled and therefore, measurement of bronchial inflammation seems essential to achieve proper asthma control. PMID- 22925317 TI - Cysteinyl leukotriene receptors, old and new; implications for asthma. AB - The cysteinyl leukotrienes (cys-LTs) are three structurally similar, but functionally distinct lipid mediators of inflammation. The parent cys-LT, LTC(4) , is synthesized by and released from mast cells, eosinophils, basophils, and macrophages, and is converted to the potent constrictor LTD(4) and the stable metabolite, LTE(4) . While only two cys-LT-selective receptors (CysLTRs) have been identified, cloned, and characterized, studies dating back three decades predicted the existence of at least three functional CysLTRs, each with a characteristic physiological function in airways and other tissues. The recent demonstration that mice lacking both known CysLTRs exhibit full (and in some instances, augmented) physiological responses to cys-LTs verifies the existence of unidentified CysLTRs. Moreover, the ability to manipulate receptor expression in both whole animal and cellular systems reveals that the functions of CysLTRs are controlled at multiple levels, including receptor-receptor interactions. Finally, studies in transgenic mice have uncovered a potentially major role for cys-LTs in controlling the induction of Th(2) responses to common allergens. This review focuses on these recent findings and their potential clinical implications. PMID- 22925319 TI - Childhood wheezing phenotypes and FeNO in atopic children at age 8. AB - BACKGROUND: Fractional exhaled Nitric Oxide (FeNO) is a surrogate biomarker of the degree of eosinophilic airway inflammation. Using longitudinal latent class analysis, five wheezing phenotypes have been identified, characterized by different ages of onset and prognosis. OBJECTIVES: To assess FeNO measured at 4 and 8 years in children with different phenotypes of wheeze and atopy. METHODS: Children participated in the Prevention and Incidence of Asthma and Mite Allergy (PIAMA) study, a prospective birth cohort in the Netherlands. Respiratory health was assessed yearly by questionnaires until the age of 8 years; these data were used to identify five wheezing phenotypes. Associations between FeNO and wheezing phenotypes were investigated using weighted linear regression. RESULTS: Data on wheezing phenotypes and FeNO at 4 and 8 years were available in 588 and 973 children respectively. Compared with the phenotype of never and transient wheeze, FeNO at 4 years was higher in intermediate onset and persistent wheeze. FeNO at 8 years of age differed significantly between all phenotypes, with highest FeNO values for persistent, intermediate onset, and late onset wheeze. Rise in FeNO from 4 to 8 years in intermediate and late onset wheezers was significantly higher compared to FeNO rise in never and transient wheezers. Stratified analyses showed that the increase in FeNO in persistent, intermediate, and late onset wheeze was only present in children with allergic sensitization at 8 years. CONCLUSIONS AND CLINICAL RELEVANCE: The FeNO measured at 8 years was associated with specific wheezing phenotypes, only among atopic children. PMID- 22925320 TI - The LINA cohort: indoor chemical exposure, circulating eosinophil/basophil (Eo/B) progenitors and early life skin manifestations. AB - BACKGROUND: Hematopoietic progenitor cells, especially those committed to the Eo/B lineage, are known to contribute to allergic inflammation. OBJECTIVE: The aim of the present study was to investigate whether environmental factors are associated with changes in numbers of circulating Eo/B progenitors at 1 year of age. METHODS: Peripheral blood from 60 1-year-old children enrolled in the LINA (Lifestyle and environmental factors and their Influence on Newborns Allergy risk) birth cohort was assessed for Eo/B progenitor cells (Eo/B CFU) using standardized and validated methylcellulose assays. Frozen peripheral blood mononuclear cells (PBMC) were cultured in the presence of IL-3, IL-5 or GM-CSF, and Eo/B CFUs enumerated. Clinical outcomes and exposure to environmental tobacco smoke (ETS) were documented by standardized questionnaires, and indoor volatile organic compound (VOC) concentrations were assessed by passive sampling. RESULTS: Children with skin manifestations (atopic dermatitis or cradle cap) within the first year of life had higher numbers of circulating IL-3-, IL-5- or GM-CSF stimulated Eo/B CFUs (P < 0.05) at 1 year. In children with cradle cap, a positive correlation was found between Eo/B CFUs and exposure to ETS-related VOCs during pregnancy or at 1 year of age (P < 0.05). CONCLUSIONS AND CLINICAL RELEVANCE: This is the first demonstration that environmental exposures are positively associated with levels of circulating Eo/B progenitors. The recruitment and differentiation of Eo/B progenitors in response to environmental triggers may play a role in the development of skin manifestations during the first year of life. PMID- 22925321 TI - The majority of allergen-specific IgE in the blood of allergic patients does not originate from blood-derived B cells or plasma cells. AB - BACKGROUND: The production of allergen-specific IgE antibodies is a hallmark of IgE-mediated allergy but the contribution of blood cells to allergen-specific IgE production in allergic patients has not been studied in detail. OBJECTIVE: Aim of this study was the characterization of IgE-producing cells in the blood of allergic patients and the determination of the amount of IgE antibodies which are produced by these cells in relation to total amounts of circulating specific IgE. METHODS: Peripheral blood mononuclear cells (PBMCs) were isolated from allergic patients and cell populations were purified or depleted using magnetically labelled antibodies directed against specific cell surface markers (CD19, CD20, CD22, CD27, CD38, CD126, CD138, CD203c). Allergen-specific IgE was measured in serum samples and cell culture supernatants by quantitative ImmunoCAP measurements and by ELISA using purified recombinant allergens. IgE transcripts were detected using RT-PCR with primers specific for human IgE. RESULTS: We found that allergen-specific IgE levels in PBMC supernatants correlated strongly with specific serum IgE but represented less than 1% of circulating IgE. Depletion of basophils resulted in substantial reduction of allergen-specific IgE levels in PBMC culture supernatants suggesting that an important source of allergen specific IgE in PBMC supernatants could be IgE derived from the surface of basophils. Newly synthesized IgE was derived from CD138+ plasma cells, but not from B and B memory cells, and accounted for only approximately 0.2% of circulating IgE in blood. CONCLUSION AND CLINICAL RELEVANCE: Our finding that the majority of allergen-specific IgE in the peripheral blood is not derived from IgE secreting cells in the blood suggests local IgE production in tissues as a major source for allergen-specific IgE and possible target for therapeutic intervention. PMID- 22925322 TI - An alternative allergen:adjuvant formulation potentiates the immunogenicity and reduces allergenicity of a novel subcutaneous immunotherapy product for treatment of grass-pollen allergy. AB - BACKGROUND: Subcutaneous specific immunotherapy (SCIT) has proven sustained clinical efficacy against allergy. The recommended regimen for SCIT is a gradual updosing over a period of weeks. Commonly, in commercial products for SCIT, the specific allergen is formulated with an adjuvant, most often in the form of aluminium hydroxide (AlOH). It has been shown that allergen-specific IgG antibodies are induced as a result of successful SIT. OBJECTIVE: To investigate the possibility of optimizing the formulation of AlOH-based grass-pollen allergy vaccines for SCIT in a way that allows for shorter updosing regimens while maintaining the immunogenicity of the vaccine. METHODS: Mice were immunized with various concentrations of Phleum pratense (Phl p) allergen extract and AlOH or a fixed dilution of the maintenance doses of one conventional and one alternatively formulated vaccine. The kinetics of Phl p-specific IgG antibody responses in serum and spleen T cell responses were determined. Allergenicity, measured as the ability of the formulations to activate human basophils, was also determined. In addition, human T cell responses and the expression of dendritic cell surface markers after vaccine challenge in vitro were analysed. RESULTS: Specific IgG antibody responses were shown to depend on the AlOH concentration, but not on the allergen concentrations. The immunogenicity of the conventional formulation and the alternative formulation was shown to be similar with regard to the in vivo induced IgG and T cell responses. In contrast, the allergenicity of the alternative formulation was significantly reduced compared with the conventional formulation. CONCLUSION: The optimization of the formulation allows for administration of a lower dose of allergen while maintaining the immunogenicity of the product and at the same time reducing allergenicity. CLINICAL RELEVANCE: This study indicates that the optimization of the allergen and the adjuvant formulation could benefit the safety/efficacy profile and allow for shorter updosing. PMID- 22925323 TI - The impact of birth mode of delivery on childhood asthma and allergic diseases--a sibling study. AB - BACKGROUND: Caesarean section (CS) has been reported to increase the risk of asthma in offspring. This may be due to that infants delivered by CS are unexposed to vaginal flora, according to the 'hygiene hypothesis'. OBJECTIVE: Our aim was to investigate if CS increases risk of childhood asthma, and if the risk increase remains after adjustment for familial confounding using sibling design. METHODS: A register-based cohort study with 87 500 Swedish sibling pairs was undertaken. Asthma outcome variables were collected from national health registers as diagnosis or asthma medication (ICD-10 J45-J46; ATC code R03) during the 10th or 13th year of life (year of follow-up). Mode of delivery and confounders were retrieved from the Medical Birth Register. The data were analysed both as a cohort and with sibling control analysis which adjusts for unmeasured familial confounding. RESULTS: In the cohort analyses, there was an increased risk of asthma medication and asthma diagnosis during year of follow-up in children born with CS (adjusted ORs, 95% CI 1.13, 1.04-1.24 and 1.10, 1.03 1.18 respectively). When separating between emergency and elective CS the effect on asthma medication remained for emergency CS, but not for elective CS, while both groups had significant effects on asthma diagnosis compared with vaginal delivery. In sibling control analyses, the effect of elective CS on asthma disappeared, while similar but non-significant ORs of medication were obtained for emergency CS. CONCLUSIONS AND CLINICAL RELEVANCE: An increased risk of asthma medication in the group born by emergency CS, but not elective, suggests that there is no causal effect due to vaginal microflora. A more probable explanation should be sought in the indications for emergency CS. PMID- 22925324 TI - Pets at birth do not increase allergic disease in at-risk children. AB - BACKGROUND: The literature is contradictory concerning pet exposure and risk of allergic disease in childhood especially among those with a family history of allergy. OBJECTIVE: To investigate the relationship between cat and dog exposure at birth and allergic outcomes over the first 12 years in a birth cohort selected for familial allergy. METHODS: A prospective birth cohort of 620 infants with a family history of allergic diseases was recruited. Data on pet keeping, family demographics and cord blood samples were collected at birth. Information on childhood wheeze, eczema and hay fever was collected 18 times in the first 2 years, at 7 years and at 12 years. Skin prick tests were conducted at 2, 7 and 12 years, and in parents. Regression analyses were used to investigate the relevant associations while adjusting for potential confounders. RESULTS: Exposure to cats or dogs at birth showed a moderate reduction in risk of wheeze (aOR = 0.76; 95% CI 0.53, 1.09) and hay fever (aOR = 0.71; 0.49, 1.02) after 7 years of age. Protective effects were stronger in children of non-sensitized fathers (aOR wheeze 0.55; 0.31, 0.98; aOR hay fever 0.33; 0.15, 0.77 on exposure to cats alone, or cats or dogs at birth). Pet keeping was not related to cord blood IgE or sensitization from 2 to 12 years. CONCLUSIONS AND CLINICAL RELEVANCE: Pets at birth either decreased or had no effect on allergic disease up to age 12. We found no evidence that exposure to cats or dogs at birth increases the risk of allergic disease in high-risk children. PMID- 22925325 TI - Prenatal and postnatal probiotics reduces maternal but not childhood allergic diseases: a randomized, double-blind, placebo-controlled trial. AB - BACKGROUND: The prevalence of atopic diseases has increased rapidly in recent decades globally. The administration of probiotics to reduce gastrointestinal inflammation has been popular, but its role in the prevention or treatment of allergic disease remains controversial. This study evaluated the effectiveness of prenatal and postnatal probiotics in the prevention of early childhood and maternal allergic diseases. METHODS: In a prospective, double-blind, placebo controlled clinical trial, pregnant women with atopic diseases determined by history, total immunoglobulin (Ig)E > 100 kU/L, and/or positive specific IgE were assigned to receive either probiotics (Lactobacillus GG; ATCC 53103; 1 * 10(10) colony-forming units daily) or placebo from the second trimester of pregnancy. Both of clinical evaluation performed by questionnaires concerning any allergic symptoms and plasma total IgE, and allergen-specific IgE were obtained in high risk parents and children at 0, 6, 18, and 36 months of age. The primary and secondary outcomes were the point and cumulative prevalence of sensitization and developing of allergic diseases, and improvement of maternal allergic symptom score and plasma immune parameters before and after intervention, respectively. RESULTS: In total, 191 pregnant women (LGG group, n = 95; control group, n = 96) were enrolled. No significant effects of prenatal and postnatal probiotics supplementation on sensitization, development of allergic diseases, and maternal IgE levels between placebo and LGG groups. Symptoms of maternal allergic scores improved significantly in the LGG group (P = 0.002). Maternal allergic diseases improvement was more prominent in pregnant women with IgE > 100 kU/L (P = 0.01) and significantly associated with higher interleukin-12p70 levels (P = 0.013). CONCLUSIONS: LGG administration beginning at the second trimester of pregnancy reduced the severity of maternal allergic disease through increment of Th1 response, but not the incidence of childhood allergic sensitization or allergic diseases (ClinicalTrials.govnumber, IDNCT00325273). PMID- 22925326 TI - Targeting IL-23 by employing a p40 peptide-based vaccine ameliorates murine allergic skin and airway inflammation. AB - BACKGROUND: Studies have found that the IL-23/Th17 pathway plays an important role in the pathogenesis of atopic dermatitis (AD) and severe and steroid resistant asthma. Targeting IL-23/Th17 pathway with monoclonal antibodies (mAb) has been successful in the reduction of skin and airway inflammation in animal models. However, the mAb has a short half-life, requiring repeated administrations. For the long-term suppression of IL-23/Th17 pathway, we have previously developed an IL-23p40 peptide-based virus-like particle vaccine, which induces long-lasting autoantibodies to IL-23. OBJECTIVE: We sought to evaluate the effects of this IL-23p40 peptide-based vaccine on the down-regulation of allergic skin and airway inflammation in mice. METHODS: Mice were subcutaneously injected three times with the IL-23p40 vaccine, or the vaccine carrier protein or saline as controls. Two weeks later, mice were epicutaneously sensitized with ovalbumin four times at a 2-week interval. One week after the final sensitization, mice were nasally administrated with ovalbumin daily for 3 days. One day later, bronchoalveolar lavage fluids (BALF), sera, lung and skin tissues were obtained and analysed. RESULTS: Mice immunized with the vaccine produced high levels of IgG antibodies to IL-23, p40 and IL-12 that in vitro inhibited IL 23-dependent IL-17 production. The numbers of total cells, neutrophils, and eosinophils in BALF were significantly reduced in the vaccine group, compared with controls. The levels of IL-13, IL-5, IL-23 and, IL-17 in BALF and levels of serum ovalbumin-specific IgE, IgG1, and total IgE were also significantly decreased. Histological analysis showed less inflammation of the lung and skin tissues in the vaccine group, compared with controls. CONCLUSION AND CLINICAL RELEVANCE: Administration of an IL-23p40 peptide-based vaccine down-regulates allergic skin and airway inflammation, suggesting that this strategy may be a potential therapeutic approach in the treatment of AD and asthma. PMID- 22925327 TI - Serum IL-23: a surrogate biomarker for asthma? PMID- 22925331 TI - The AIDS epidemic in haemophilia patients II: pursuing absolute viral safety of clotting factor concentrates 1985-1988. PMID- 22925330 TI - Molecular markers associated with outcome and metastasis in human pancreatic cancer. AB - BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is a heterogeneous cancer in which differences in survival rates might be related to a variety in gene expression profiles. Although the molecular biology of PDAC begins to be revealed, genes or pathways that specifically drive tumour progression or metastasis are not well understood. METHODS: We performed microarray analyses on whole-tumour samples of 2 human PDAC subpopulations with similar clinicopathological features, but extremely distinct survival rates after potentially curative surgery, i.e. good outcome (OS and DFS > 50 months, n = 7) versus bad outcome (OS < 19 months and DFS < 7 months, n = 10). Additionally, liver- and peritoneal metastases were analysed and compared to primary cancer tissue (n = 11). RESULTS: The integrin and ephrin receptor families were upregulated in all PDAC samples, irrespective of outcome, supporting an important role of the interaction between pancreatic cancer cells and the surrounding desmoplastic reaction in tumorigenesis and cancer progression. Moreover, some components such as ITGB1 and EPHA2 were upregulated in PDAC samples with a poor outcome, Additionally, overexpression of the non-canonical Wnt/beta-catenin pathway and EMT genes in PDAC samples with bad versus good outcome suggests their contribution to the invasiveness of pancreatic cancer, with beta-catenin being also highly upregulated in metastatic tissue. CONCLUSIONS: Components of the integrin and ephrin pathways and EMT related genes, might serve as molecular markers in pancreatic cancer as their expression seems to be related with prognosis. PMID- 22925332 TI - Is it justifiable to transplant infected livers into haemophilia recipients? PMID- 22925334 TI - The helicase activity of DDX56 is required for its role in assembly of infectious West Nile virus particles. AB - Although flaviviruses encode their own helicases, evidence suggests that cellular helicases are also required for replication and/or assembly of these viruses. By and large, the mechanisms of action for viral and cellular helicases are not known. Moreover, in some cases, enzymatic activity is not even required for their roles in virus biology. Recently, we showed that expression of the host nucleolar helicase DDX56 is important for infectivity of West Nile virus (WNV) particles. In the present study, we demonstrate that the helicase activity of this enzyme is essential for its role in assembly of infectious WNV virions. Over-expression of the capsid-binding region of DDX56 also reduces infectivity of WNV suggesting that interaction of DDX56 and capsid protein is an important step in the virion assembly pathway. To our knowledge, this is the first study showing that enzymatic activity of a cellular helicase is critical for infectivity of flaviviruses. PMID- 22925335 TI - Malakal virus from Africa and Kimberley virus from Australia are geographic variants of a widely distributed ephemerovirus. AB - Kimberley virus (KIMV) is an arthropod-borne rhabdovirus that was isolated in 1973 and on several subsequent occasions from healthy cattle, mosquitoes (Culex annulirostris) and biting midges (Culicoides brevitarsis) in Australia. Malakal virus (MALV) is an antigenically related rhabdovirus isolated in 1963 from mosquitoes (Mansonia uniformis) in Sudan. We report here the complete genome sequences of KIMV (15442 nt) and MALV (15444 nt). The genomes have a similar organisation (3'-l-N-P-M-G-G(NS)-alpha1-alpha2-beta-gamma-L-t-5') to that of bovine ephemeral fever virus (BEFV). High levels of amino acid identity in each gene, similar gene expression profiles, clustering in phylogenetic analyses of the N, P, G and L proteins, and strong cross-neutralisation indicate that KIMV and MALV are geographic variants of the same ephemerovirus that, like BEFV, occurs in Africa, Asia and Australia. PMID- 22925336 TI - Association between hTERT activation by HPV E6 proteins and oncogenic risk. AB - Expression of activated telomerase and subversion of the p16/pRb pathway is sufficient and essential for the in vitro immortalization of primary keratinocytes. Most cancers-including cervical carcinoma-over-express hTERT, the catalytic domain of the telomerase complex. Only a limited set of viruses within the Alphapapillomavirus genus are oncogenic. The viral functions responsible for this distinction are not well understood. The human papillomavirus type 16 E6 protein activates the hTERT promoter. We used a luciferase-based assay to test the ability of 29 viral types, representing all current species within the Alphapapillomavirus genus, to activate the hTERT promoter. We show that oncogenic types specifically activate the hTERT promoter, while non-oncogenic types do not. Statistical analysis supports the notion that activation of the hTERT promoter is uniquely associated with oncogenic types, independent of evolutionary relationships. This finding begins to shed light on the viral phenotypes correlated with oncogenic potential. PMID- 22925338 TI - National workplace violence summit a success! PMID- 22925337 TI - Vironome of Kaposi sarcoma associated herpesvirus-inflammatory cytokine syndrome in an AIDS patient reveals co-infection of human herpesvirus 8 and human herpesvirus 6A. AB - KSHV inflammatory cytokine syndrome (KICS) is a newly described condition characterized by systemic illness as a result of systemic, lytic KSHV infection. We used Illumina sequencing to establish the DNA vironome of blood from such a patient. It identified concurrent high-level viremia of human herpesvirus (HHV) 8 and 6a. The HHV8 plasma viral load was 5,300,000 copies/ml, which is the highest reported to date; this despite less than five skin lesions and no HHV8 associated lymphoma. This is the first report of systemic HHV6a/KSHV co-infection in a patient. It is the first whole genome KSHV sequence to be determined directly from patient plasma rather than cultured or biopsied tumor material. This case supports KICS as a new clinical entity associated with KSHV. PMID- 22925339 TI - Dilemmas 2012. PMID- 22925340 TI - Measurement validity of pediatric ED rapid triage. PMID- 22925342 TI - Barriers to process improvement: punishing nurses. PMID- 22925343 TI - Reply to death notification. PMID- 22925344 TI - Emergency Nursing Resource: wound preparation. PMID- 22925345 TI - Emergency Nursing Resource: orthostatic vital signs. PMID- 22925347 TI - Tranexamic acid (TXA) use in trauma. PMID- 22925348 TI - Partial trisomy of the long arm of chromosome 1: prenatal diagnosis, clinical evaluation and cytogenetic findings. Case report and review of the literature. AB - Partial trisomy of the long arm of chromosome 1 is a relatively rare cytogenetic anomaly. Its phenotype has still not been completely defined, because of the cytogenetic heterogeneity of the cases so far described. We report a prenatal case of partial 1q trisomy associated with partial monosomy 4q, secondary to balanced maternal translocation t(1;4). The trisomic segment extended from 1q31.1 to qter and the monosomy 4q was from 4q35.2 to qter. The phenotypic anomalies found by post-mortem and autopsy examinations were compared with those of similar cases reported in the literature. We performed standard cytogenetics and fluorescence in situ hybridization. Cerebral ventriculomegaly, present in our case, seemed to be a constant feature in partial 1q trisomies, so this cerebral malformation could be considered as the main echographic marker for this chromosomal imbalance and trisomy 1q should be added to the list of chromosomal abnormalities associated with ventriculomegaly. PMID- 22925349 TI - Information about male chronic pelvic and urogenital pain on the Internet: an evaluation of Internet resources. AB - OBJECTIVE: The objective of this study was to describe and evaluate the Internet resources available to patients searching for information about chronic urogenital/pelvic pain. DESIGN: As far as possible, we applied systematic review methods to search, retrieve, sort, and critique Websites, using common search engines and terms in the English language. Evaluation from a patient viewpoint focused particularly on the quality of explanations for chronic urogenital/pelvic pain in men, and on the psychological content of the Websites. RESULTS: While the 23 Websites reviewed were generally accessible and open, authorial attribution was largely missing and the nomenclature were inconsistent and confusing. Explanations of chronic pain were diverse and often inaccurate or only partially accurate; none represented current neurophysiologic models of chronic pain. Eight described psychological aspects of pain, five in a simple way and three with more complexity, but only one approximated a contemporary biopsychosocial model. CONCLUSIONS: As in other areas of chronic pain, there is a wealth of information available online, but much is of poor quality, and taken together, is likely to confuse more than enlighten patients attempting to understand male urogenital/pelvic pain symptoms or supplement information from health care professionals. PMID- 22925350 TI - The role of impulsivity in the relationship between anxiety and suicidal ideation. AB - BACKGROUND: The purpose of the present study was to examine the degree to which trait and cognitive (looming cognitive style) measures of anxiety are associated with suicidal ideation (SI), as well as whether trait and cognitive (time misperception) measures of impulsivity moderate the association between these variables. METHODS: The sample included 100 undergraduate students (72% female) who completed the Spielberger State-Trait Anxiety Inventory, Looming Maladaptive Style Questionnaire, Barratt Impulsiveness Scale, Time Paradigm Version 1.0 Task, Beck Scale for Suicidal Ideation, and the Brief Symptom Inventory. RESULTS: Trait anxiety and looming cognitive style were found to be positively associated with SI. Further, both trait impulsivity and time misperception moderated the association between these variables and SI, but in a different manner. Consistent with study hypotheses, among those high in trait anxiety, greater overestimation of time was associated with a higher likelihood of SI. Contrary to study hypotheses, among those low in trait anxiety, high trait impulsivity was associated with a greater likelihood of SI. The same pattern of results was found when looming cognitive style served as the independent variable. LIMITATIONS: The use of a cross-sectional design limits the ability to determine the temporal relationship of the study variables. Further, the sample included predominantly Caucasian undergraduates and thus study results may not generalize to other populations. CONCLUSIONS: Clinically, results suggest that high trait anxiety, looming cognitive style, time misperception, and trait impulsivity may be important risk factors for SI among college students and thus should be assessed when students present for treatment. Treatments that focus on problem solving, cognitive restructuring, and affect regulation strategies may help decrease anxiety and impulsivity, which in turn may help reduce the likelihood of suicidal thoughts. PMID- 22925351 TI - Subthreshold symptoms and time to relapse/recurrence in a community cohort of bipolar disorder outpatients. AB - BACKGROUND: Researchers have previously found that persistent subthreshold symptoms increase the risk and shorten the time until an affective relapse in bipolar disorder (BD) patients. Research has mainly focused on patients from tertiary Care Centers in USA. We tested the hypothesis that even in a different setting, BD outpatients with subsyndromal affective symptoms would re.turn to a subsequent major affective episode significantly faster than completely asymptomatic at baseline. Secondarily, we analysed other variables related to time and risk to relapse. METHODS: A community cohort of BD outpatients from Madrid (Spain) followed-up in a systematic prospective follow-up protocol for up to five years were evaluated. Patients in clinical euthymia at baseline were included and evaluated quarterly. RESULTS: Initially, 225 patients were included in the survival analysis. Of them, according to predefined psychometric criteria, 163 were in euthymia (72.4%) and 62 (27.6%) suffered subsyndromal symptoms. Median follow-up was 157.6 weeks (95% CI, 78.14 to 111); 57.3% of patients experienced at least one affective episode during their follow-up. Median survival time to first affective episode was 109 weeks for patients in euthymia at baseline, versus 35 weeks for those with subsyndromal symptoms (p<0.0001). Psychosocial stress (p=0.003; HR 2.20; 95% CI 1.31-3.68) and the affective mood baseline state, subsyndromal vs. euthymic (p=0.046; HR 1.74; 95%CI 1.009-3.020), were related to time to first affective episode. LIMITATIONS: Naturalistic study, some of the data collected were necessarily retrospective. CONCLUSIONS: In Spanish non-tertiary psychiatric outpatients, subsyndromal BD symptoms and psychosocial stress at baseline predict earlier episode relapse/recurrence. PMID- 22925352 TI - Service user perspectives on psychosocial assessment following self-harm and its impact on further help-seeking: a qualitative study. AB - BACKGROUND: Psychosocial assessment is a central aspect of managing self-harm in hospitals, designed to encompass needs and risk, and to lead to further care. However, little is known about service user experiences of assessment, or what aspects of assessment service users value. The aim of this study was to explore service user experiences of assessment, and examine the short-term and longer term meanings of assessment for service users. METHOD: Interpretative phenomenological analysis was applied to 13 interviews with service users following hospital attendance, and seven follow-up interviews conducted 3 months later. RESULTS: Few participants had a clear understanding of assessment's purpose. Assessment had the potential to promote or challenge hope, dependent on whether it was experienced as accepting or critical. If follow-up care did not materialise, this reinforced hopelessness and promoted disengagement from services. LIMITATIONS: The study sample was small and the participants heterogeneous in terms of self-harm history, method and intent, which may limit the transferability of the findings to other settings. Only self-report data on clinical diagnosis were collected. CONCLUSIONS: This was the first study to utilise an in-depth qualitative approach to investigate service user experiences of assessment and follow-up. The findings suggest that re-conceptualising psychosocial assessment as primarily an opportunity to engage service users therapeutically may consequently affect how health services are perceived. In order to maintain benefits established during the hospital experience, follow-up needs to be timely and integrated with assessment. PMID- 22925353 TI - A genome-wide association study of seasonal pattern mania identifies NF1A as a possible susceptibility gene for bipolar disorder. AB - OBJECTIVE: The use of subphenotypes may be an effective approach for genetic studies of complex diseases. Manic episodes with a seasonal pattern may distinguish phenotypic subgroups of bipolar subjects that may also differ genetically. METHOD: We have performed a genome-wide association study using GAIN genotype data from the Bipolar Genome Study (BiGS) and bipolar subjects that were categorized as having either seasonal or non-seasonal patterned manic episodes. RESULTS: A bipolar case-only analysis identified three genomic regions that differed between seasonal and non-seasonal patterned manic episodes of bipolar subjects. The most significant association was for rs41350144, which lies within an intron of NF1A gene on 1p31 (P=3.08*10(-7), OR=2.27). Haplotype construction using flanking three SNPs (rs41453448, rs1125777, and rs12568010) spanning 7549bp showed a more significant association (P=2.12*10(-7), OR=0.4). CONCLUSIONS: These data suggest that genetic variants in the NF1A gene region may predispose to seasonal patterned of mania in bipolar disorder. PMID- 22925354 TI - A human experimental bone pain model. AB - The aim of this study was to develop a human experimental bone pain model. Fourteen healthy men were included in two study sessions. Pressure pain threshold (PPT) was estimated using probes of different sizes. Computer-controlled and hand held algometry were applied to the skin area covering right and left medial tibia before and after local anaesthesia (LA) of the skin and reproducibility was evaluated. Pain experience (McGill questionnaire) was compared between healthy volunteers and 12 patients with vertebral fractures. Computer-controlled algometer: No differences in PPT between study sessions for 6 and 8-mm probes (p = 0.43 and 0.32) were seen. There was a difference in PPT before and after LA for the 6-mm probe (p = 0.008), but not for the 8-mm probe (p = 0.26). Hand-held algometer: A difference in PPT between study sessions was observed for 4- and 8 mm probes (p = 0.03 and 0.007), but not for 2, 6 and 10-mm probes (p = 0.19, 0.05 and 0.25). No differences in PPT were seen before and after LA for 2, 4, 8 and 10 mm probes (p = 0.35, 0.15, 0.08 and 0.53), but LA significantly influenced PPT with the 6-mm probe (p = 0.01). Similar words were chosen in the McGill pain questionnaire by healthy volunteers and patients, qualitatively describing the deep pain sensation. The pain evoked by hand-held algometer and the 2-mm probe was not influenced by LA, and PPT was reproducible between sessions and is recommended for studies of experimentally evoked bone-associated pain. PMID- 22925355 TI - Assessment of sperm antigen specific T regulatory cells in women with recurrent miscarriage. AB - BACKGROUND AND AIMS: The prevalence of recurrent miscarriage (RM) is about 1-3% of women; the pathogenesis of RM is not fully understood yet. This study aims to assess the sperm antigen specific regulatory T cells (Treg) in women with RM. METHODS: A group of women with RM was recruited into this study. The sperm antigen was extracted from the semen samples of each woman's husband. The sperm antigen specific T cell response was assessed by flow cytometry. RESULTS: Low frequency of sperm specific Tregs and high frequency of T helper (Th)1 cells were detected in RM women as compared with women without RM. The sperm specific Tregs in RM women expressed less Ubc13. Knockdown of Ubc13 from Tregs converted the Tregs to effector T cells. CONCLUSIONS: Immune deregulation may play an important role in RM. PMID- 22925356 TI - A parent focused child obesity prevention intervention improves some mother obesity risk behaviors: the Melbourne inFANT program. AB - BACKGROUND: The diets, physical activity and sedentary behavior levels of both children and adults in Australia are suboptimal. The family environment, as the first ecological niche of children, exerts an important influence on the onset of children's habits. Parent modeling is one part of this environment and a logical focus for child obesity prevention initiatives. The focus on parent's own behaviors provides a potential opportunity to decrease obesity risk behaviors in parents as well. OBJECTIVE: To assess the effect of a parent-focused early childhood obesity prevention intervention on first-time mothers' diets, physical activity and TV viewing time. METHODS: The Melbourne InFANT Program is a cluster randomized controlled trial which involved 542 mothers over their newborn's first 18 months of life. The intervention focused on parenting skills and strategies, including parental modeling, and aimed to promote development of healthy child and parent behaviors from birth, including healthy diet, increased physical activity and reduced TV viewing time. Data regarding mothers' diet (food frequency questionnaire), physical activity and TV viewing times (self-reported questionnaire) were collected using validated tools at both baseline and post intervention. Four dietary patterns were derived at baseline using principal components analyses including frequencies of 55 food groups. Analysis of covariance was used to measure the impact of the intervention. RESULTS: The scores of both the "High-energy snack and processed foods" and the "High-fat foods" dietary patterns decreased more in the intervention group: -0.22 (-0.42; 0.02) and -0.25 (-0.50;-0.01), respectively. No other significant intervention vs. control effects were observed regarding total physical activity, TV viewing time, and the two other dietary patterns, i.e. "Fruits and vegetables" and "Cereals and sweet foods". CONCLUSIONS: These findings suggest that supporting first-time mothers to promote healthy lifestyle behaviors in their infants impacts maternal dietary intakes positively. Further research needs to assess ways in which we might further enhance those lifestyle behaviors not impacted by the InFANT intervention. PMID- 22925358 TI - Opportunistic filamentous mycoses: aspergillosis, mucormycosis, phaeohyphomycosis and hyalohyphomycosis. AB - Opportunistic filamentous mycoses are widely distributed all over the world. They are rarely observed in Europe but are common in developing countries. The most common are the aspergilloses (due to Aspergillus spp.) mostly in neutropenia and immunosuppression; the mucormycoses characterized by rapid progression in patients with diabetic ketoacidosis; the phaeohyphomycoses due to pigmented fungi causing either a mild superficial or a very serious deep disease and the hyalohyphomycoses due to hyaline filamentous fungi (Fusarium spp., Pseudallescheria spp., Scopulariopsis spp.). Cutaneous manifestations are usually secondary to dissemination from pulmonary or visceral disease; primary cases are less frequent and due to direct inoculation into the skin. We review epidemiological, clinical, diagnostic, and therapeutic data on the four most important opportunistic filamentous mycoses: aspergillosis, mucormycosis, phaeohyphomycosis and hyalohyphomycosis. PMID- 22925365 TI - Electrosurgical bipolar vessel sealing versus conventional clamping and suturing for vaginal hysterectomy: a randomised controlled trial. AB - OBJECTIVE: To compare the effects of electrical bipolar vessel sealing and conventional suturing on postoperative pain, recovery, costs and micturition symptoms in women undergoing vaginal hysterectomy. DESIGN: Randomised controlled trial. SETTING: Eight teaching hospitals in the Netherlands. POPULATION: One hundred women scheduled to undergo vaginal hysterectomy for benign conditions excluding pelvic organ prolapse. METHODS: Women were randomised to vessel sealing or conventional surgery. The quality of life related to pelvic floor function was assessed using validated questionnaires before surgery and 6 months after surgery. Pain scores and recovery were assessed using a diary, including daily visual analogue scale scores, starting from the day before surgery until 6 weeks after surgery. MAIN OUTCOME MEASURES: Visual analogue scale pain scores, surgery time, blood loss, complications, quality of life related to pelvic floor function and costs. RESULTS: The evening after surgery, women in the vessel-sealing group reported significantly less pain (5.7 versus 4.5 on a scale of 0-10, P = 0.03), but after that pain scores were similar. Operation duration was shorter for vessel sealing (60 versus 71 minutes, P = 0.05). Blood loss and hospital stay did not differ. We observed no major difference in costs between the two interventions (2903 versus 3102 ?, P = 0.26). Changes in micturition and defecation symptoms were not affected by the surgical technique used. CONCLUSION: Using vessel sealing during vaginal hysterectomy resulted in less pain on the first postoperative day, shorter operating time, similar morbidity and similar pelvic floor function. No major differences in costs were found between the two interventions. PMID- 22925366 TI - Frequency of eosinophilic esophagitis in patients with esophageal symptoms: a single-center Turkish experience. AB - Eosinophilic esophagitis (EoE) is a chronic, immune/antigen-mediated esophageal disease characterized with symptoms related to esophageal dysfunction and eosinophil-predominant inflammation. There has been a dramatic increase in the diagnosis of this disease in recent years. The primary objective of this study was to determine the frequency of EoE in adult patients who were evaluated by gastroenterologists in our clinic with esophageal symptoms. Between November 2010 and May 2011, 311 adult patients who were evaluated in our clinic with esophageal symptoms were enrolled prospectively. All patients underwent endoscopy and had biopsies taken. Gastroesophageal reflux disease was excluded by either proton pump inhibitory treatment or 24-hour ambulatory pH monitorization. The diagnosis was confirmed by one independent pathologist. Frequency of EoE in patients with esophageal symptoms was 2.6% (n = 8; four men and four women). Mean age at diagnosis was 40.2 +/- 8 years. Heartburn was the predominant symptom in patients (75% of the patients), and 87.5% (n = 7) of patients had more than one symptom at diagnosis. Nearly 38% of the patients (n = 3) had a history of allergic disease. Endoscopic findings were as follows: transient/fixed esophageal rings (25%), white exudates (25%), and normal appearance (50%). Median number of circulating eosinophils was 208 (93-659)/mm(3) . Median number of intraepithelial eosinophils in proximal-middle 1/3 part and distal 1/3 part of esophagus were 0 (0-50)/hpf and 37 (16-50)/hpf, respectively. In conclusion, EoE is not rare in Turkey, and it should be considered in the differential diagnosis of patients with esophageal symptoms. PMID- 22925367 TI - Polycystic ovary syndrome in adolescence: impaired glucose tolerance occurs across the spectrum of BMI. AB - CONTEXT: Polycystic ovary syndrome (PCOS) is a chronic condition with metabolic manifestations spanning the reproductive years. OBJECTIVE: We sought to examine glucose metabolism, irrespective of the presence of obesity in a cohort of adolescent girls with PCOS. DESIGN: One hundred adolescents were assessed for PCOS in a multi-specialty adolescent PCOS program. PCOS was diagnosed by Androgen Excess Society criteria. Oral glucose tolerance testing (OGTT), homeostatic model assessment of insulin resistance, and androgen and lipid profiles were performed for those meeting criteria. RESULTS: Sixty-six adolescents (mean age 15.8 +/- 0.2 yrs, range 13.0-18.6) had confirmed PCOS, and were eligible for inclusion in our analysis. Abnormal glucose metabolism was present in 12 of 66 (18.2%) subjects: 2 (3.0%) impaired fasting glucose, 10 (15.2%) impaired glucose tolerance (IGT), and 1 (1.5%) type 2 diabetes. IGT was the most common abnormality, occurring with equal frequency in obese (OB, mean body mass index (BMI) 36.9 +/- 0.8 kg/m(2) ) and non-obese (NOB, mean BMI 24.5 +/- 0.6 kg/m(2) ) adolescents (p = 0.3). In a subgroup analysis, NOB adolescents with IGT (NOB-IGT) had similar mean 2-h insulin, high density lipoprotein, C-reactive protein, and testosterone levels to the OB cohort despite marked differences in BMI (p < 0.001) and % body fat (p = 0.002). However, the NOB-IGT group had a lower mean fasting insulin level than the OB cohort (p = 0.04). CONCLUSION: Abnormal glucose metabolism is highly prevalent in adolescents with PCOS. In particular, IGT occurs across the spectrum of BMI. A screening OGTT should be considered for adolescents diagnosed with PCOS, independently of their BMI. PMID- 22925369 TI - The experience of puberty in Iranian adolescent girls: a qualitative content analysis. AB - BACKGROUND: Adolescence is an important stage in human life span. Physiologic changes associated with puberty manifest themselves in often complex and bizarre ways to which girls show different reactions. This study aims to explore to puberty experiences in adolescent girls who live in the city of Sari in Iran. METHODS: The present study is a qualitative study of content analysis. Sampling took place in the city of Sari, Iran and was objective focused in accordance with qualitative studies. Participants were 38 girls of 12-20 years old who had at least experienced 3 menstrual cycles. Data was collected by means of focus group and in-depth interviews. RESULTS: As follows, Seven main themes were extracted from the interviews are follows: Menarche as the most unpleasant event in puberty, getting nervous about and ashamed of bodily changes, psychological changes, discordance with parents, sexual orientation and the need for education on this issue, scholastic dysfunction and religious considerations. CONCLUSION: The results showed that for the majority of the participants puberty was an unpleasant experience. Most of them were in need of education on how to go about the issues surrounding puberty. The society, families and of course the adolescents themselves are responsible to work together in order to create an atmosphere in which correct information on puberty and the associated issues are readily accessible. PMID- 22925370 TI - Characterization of CDKN2A(p16) methylation and impact in colorectal cancer: systematic analysis using pyrosequencing. AB - BACKGROUND: The aim of this study is to analyse CDKN2A methylation using pyrosequencing on a large cohort of colorectal cancers and corresponding non neoplastic tissues. In a second step, the effect of methylation on clinical outcome is addressed. METHODS: Primary colorectal cancers and matched non neoplastic tissues from 432 patients underwent CDKN2A methylation analysis by pyrosequencing (PyroMarkQ96). Methylation was then related to clinical outcome, microsatellite instability (MSI), and BRAF and KRAS mutation. Different amplification conditions (35 to 50 PCR cycles) using a range of 0-100% methylated DNA were tested. RESULTS: Background methylation was at most 10% with >=35 PCR cycles. Correlation of observed and expected values was high, even at low methylation levels (0.02%, 0.6%, 2%). Accuracy of detection was optimal with 45 PCR cycles. Methylation in normal mucosa ranged from 0 to >90% in some cases. Based on the maximum value of 10% background, positivity was defined as a >=20% difference in methylation between tumor and normal tissue, which occurred in 87 cases. CDKN2A methylation positivity was associated with MSI (p = 0.025), BRAF mutation (p < 0.0001), higher tumor grade (p < 0.0001), mucinous histology (p = 0.0209) but not with KRAS mutation. CDKN2A methylation had an independent adverse effect (p = 0.0058) on prognosis. CONCLUSION: The non-negligible CDKN2A methylation of normal colorectal mucosa may confound the assessment of tumor specific hypermethylation, suggesting that corresponding non-neoplastic tissue should be used as a control. CDKN2A methylation is robustly detected by pyrosequencing, even at low levels, suggesting that this unfavorable prognostic biomarker warrants investigation in prospective studies. PMID- 22925371 TI - A review on the relationship between testosterone and life-course persistent antisocial behavior. AB - Life-course persistent antisocial behavior is 10 to 14 times more prevalent in males and it has been suggested that testosterone levels could account for this gender bias. Preliminary studies with measures of fetal testosterone find inconsistent associations with antisocial behavior, especially studies that use the 2D:4D ratio as a proxy for fetal testosterone. However, circulating testosterone consistently shows positive associations with antisocial behaviors throughout childhood, adolescence, and adulthood, particularly in males. It is suggested that high fetal/circulating testosterone interactively influence the maturation and functionality of mesolimbic dopaminergic circuitry, right orbitofrontal cortex, and cortico-subcortical connectivity, resulting in a strong reward motivation, low social sensitivity, and dampened regulation of strong motivational/emotional processes. The link between these testosterone induced endophenotypes and actual display of antisocial behavior is strongly modulated by different social (e.g., social rejection, low SES) and genetic (e.g., MAOA, 5HTT) risk factors that can disturb socio-, psycho-, and biological development and interact with testosterone in shaping behavior. When these additional risk factors are present, the testosterone induced endophenotypes may increase the risk for a chronic antisocial lifestyle. However, behavioral endophenotypes induced by testosterone can also predispose towards socially adaptive traits such as a strong achievement motivation, leadership, fair bargaining behaviors, and social assertiveness. These adaptive traits are more likely to emerge when the high testosterone individual has positive social experiences that promote prosocial behaviors such as strong and secure attachments with his caregivers, affiliation with prosocial peers, and sufficient socioeconomic resources. A theoretical model is presented, various hypotheses are examined, and future venues for research are discussed. PMID- 22925373 TI - Adolescent and caregiver perception of family functioning: relation to suicide ideation and attempts. AB - This study assessed the relationship between perceived family functioning and two indicators of suicidality in an adolescent sample. A total of 103 adolescents psychiatrically hospitalized for suicidal ideation and/or behavior completed a battery of self-report questionnaires assessing family functioning, negative affectivity, suicidal ideation in the past week assessed by Beck's Scale for Suicide Ideation (BSS; Beck et al., 1979), and past suicide attempts. Participants' primary caregivers also completed a questionnaire on family functioning. A paired samples t-test evaluated overall discrepancy between adolescent- and caregiver-reported family functioning. Linear and logistic regression models were used to evaluate the simple associations between perceived family functioning and suicidal indicators (BSS and previous attempt status), as well as the associations between perceived family functioning and suicidal indicators after controlling for negative affect. Results indicated that adolescents' ratings of family functioning were significantly worse than caregivers' ratings, and positively associated with BSS scores and a history of suicide attempt. When negative affect was controlled for, adolescent-reported family functioning was significantly associated with BSS, but only trended toward significance with attempt status. Findings suggest that adolescents' perceptions of family functioning may be a key contributing factor to suicidal ideation in adolescents with psychiatric disorders. PMID- 22925372 TI - Patterns of deficits in brain function in bipolar disorder and schizophrenia: a cluster analytic study. AB - Historically, bipolar disorder and schizophrenia have been considered distinct disorders with different etiologies. Growing evidence suggests that overlapping genetic influences contribute to risk for these disorders and that each disease is genetically heterogeneous. Using cluster analytic methods, we empirically identified homogeneous subgroups of patients, their relatives, and controls based on distinct neurophysiologic profiles. Seven phenotypes were collected from two independent cohorts at two institutions. K-means clustering was used to identify neurophysiologic profiles. In the analysis of all participants, three distinct profiles emerged: "globally impaired", "sensory processing", and "high cognitive". In a secondary analysis, restricted to patients only, we observed a similar clustering into three profiles. The neurophysiological profiles of the Schizophrenia (SZ) and Bipolar Disorder (BPD) patients did not support the Diagnostic and Statistical Manual of Mental Disorders (DSM) diagnostic distinction between these two disorders. Smokers in the globally impaired group smoked significantly more cigarettes than those in the sensory processing or high cognitive groups. Our results suggest that empirical analyses of neurophysiological phenotypes can identify potentially biologically relevant homogenous subgroups independent of diagnostic boundaries. We hypothesize that each neurophysiology subgroup may share similar genotypic profiles, which may increase statistical power to detect genetic risk factors. PMID- 22925374 TI - A prospective study of human papillomavirus (HPV) testing to resolve uncertainty in colposcopy. AB - OBJECTIVE: UK colposcopy services are seeing increased workloads, a large proportion of which are follow-up appointments. The English Cervical Screening Programme HPV Special Interest Group identified five subcategories of colposcopy clinic patients who often require prolonged follow-up regimes for low-grade abnormalities. Human papillomavirus (HPV) testing has a high negative predictive value, meaning that HPV-negative women are at very low risk of underlying disease. Our objectives were to quantify the number of HPV-negative women in each study subcategory and to evaluate the number who could potentially be discharged from colposcopy on the basis of their results. METHODS: Four colposcopy clinics prospectively identified women according to five categories over 12 months. All women underwent cytological testing and high-risk HPV (hrHPV) testing using the Hybrid Capture 2 test. Management outcomes and decisions based on a knowledge of the HPV status were recorded. RESULTS: Data available on 755 women showed that 422/755 (55.9%) and 260/755 (34.4%) had persistent cervical intraepithelial neoplasia grade 1 (CIN1) (Category 1) or a minor abnormality following treatment (Category 2), respectively. In Categories 1 and 2, 51.7% and 60.2%, respectively, were hrHPV negative. The rates with biopsies of CIN2 or worse (CIN2+) across the two categories were 3/355 (0.8%) and 21/291 (7.0%) for hrHPV-negative and hrHPV positive women, respectively. CONCLUSION: The incorporation of hrHPV testing within organized cervical screening programmes has been widely accepted. hrHPV testing for the clinical scenarios outlined in this study detects women who are hrHPV negative and therefore at low risk of underlying disease, potentially reducing anxiety and inconvenience for women and costs to colposcopy services. PMID- 22925375 TI - Chemerin is present in human cord blood and is positively correlated with birthweight. AB - OBJECTIVE: Chemerin, a novel adipokine, has been implicated in adipogenesis, inflammation, and metabolism. The aims of this study were to determine the presence of chemerin in cord blood and its association with birthweight. STUDY DESIGN: This cross-sectional study included the following: (1) twins with (n = 24) or without (n = 28) birthweight discordancy; and (2) singletons subclassified into small-for-gestational-age (SGA; n = 18); appropriate for gestational age (AGA; n = 33); and large-for-gestational-age (LGA; n = 8). Cord blood chemerin was determined. Parametric and nonparametric statistics were used for analysis. RESULTS: The results of the study included the following: (1) within the discordant twins group, the median chemerin concentration was significantly lower in the SGA group than in their cotwins; (2) within singletons, the median chemerin concentration was significantly higher in the LGA than the AGA newborns; and (3) the regression model revealed that chemerin was independently associated with birthweight. CONCLUSION: Cord blood chemerin is present in cord blood and its concentrations are positively correlated with birthweight. These novel findings support a role of adipokines in fetal growth. PMID- 22925376 TI - Arm reactions evoked by the initial exposure to a small balance perturbation: a pilot study. AB - Perturbation of whole-body stability often evokes rapid arm reactions. It has been suggested that the earliest arm activation is a generic (e.g. startle-like) response to which a later stabilizing (e.g. counterweight or reach-to-grasp) or impact-protection component can be appended. To examine whether the initial part of the reaction is generic, we examined arm reactions evoked by small balance perturbations in 12 healthy young adults while varying perturbation direction (rightward or forward platform translation) and environmental conditions (handrail present or absent). The perturbation magnitude was selected to be sufficiently small to obviate the need to use the arms for stabilization. To avoid adaptation or habituation, analysis focused on each subject's very first exposure to the perturbation. Most subjects exhibited active movement of both arms in reaction to the perturbation, but there was large (non-stereotypical) inter-subject variation in muscle-onset latency and arm kinematics. Furthermore, the velocity and direction of the initial arm movement were affected by perturbation direction, in a manner consistent with functional strategies (counterweight strategy in backward falls, hybrid counterweight/protective strategy in leftward falls). Although subjects never contacted the handrail, responses were slower when it was present. These results are not consistent with a generic stereotyped response, but suggest instead that even the earliest component of first-trial arm reactions was functionally modulated. PMID- 22925377 TI - ParI, an orphan ParA family protein from Pseudomonas putida KT2440-specific genomic island, interferes with the partition system of IncP-7 plasmids. AB - Pseudomonas putida KT2440 is an ideal soil bacterium for expanding the range of degradable compounds via the recruitment of various catabolic plasmids. In the course of our investigation of the host range of IncP-7 catabolic plasmids pCAR1, pDK1 and pWW53, we found that the IncP-7 miniplasmids composed of replication and partition loci were exceptionally unstable in KT2440, which is the authentic host of the archetypal IncP-9 plasmid pWW0. This study identified ParI, a homologue of ParA family of plasmid partitioning proteins encoded on the KT2440-specific cryptic genomic island, as a negative host factor for the maintenance of IncP-7 plasmids. The miniplasmids were destabilized by ectopic expression of ParI, and the loss rate correlated with the copy number of ParB binding sites in the centromeric parS region. Mutations in the conserved ATPase domains of ParI abolished destabilization of miniplasmids. Furthermore, ParI destabilized miniplasmid derivatives carrying the partition-deficient parA mutations but failed to impact the stability of miniplasmid derivatives with parB mutations in the putative arginine finger. Altogether, these results indicate that ParI interferes with the IncP-7 plasmid partition system. This study extends canonical partition-mediated incompatibility of plasmids beyond heterogeneous mobile genetic elements, namely incompatibility between plasmid and genomic island. PMID- 22925378 TI - ICRP publication 118: ICRP statement on tissue reactions and early and late effects of radiation in normal tissues and organs--threshold doses for tissue reactions in a radiation protection context. AB - This report provides a review of early and late effects of radiation in normal tissues and organs with respect to radiation protection. It was instigated following a recommendation in Publication 103 (ICRP, 2007), and it provides updated estimates of 'practical' threshold doses for tissue injury defined at the level of 1% incidence. Estimates are given for morbidity and mortality endpoints in all organ systems following acute, fractionated, or chronic exposure. The organ systems comprise the haematopoietic, immune, reproductive, circulatory, respiratory, musculoskeletal, endocrine, and nervous systems; the digestive and urinary tracts; the skin; and the eye. Particular attention is paid to circulatory disease and cataracts because of recent evidence of higher incidences of injury than expected after lower doses; hence, threshold doses appear to be lower than previously considered. This is largely because of the increasing incidences with increasing times after exposure. In the context of protection, it is the threshold doses for very long follow-up times that are the most relevant for workers and the public; for example, the atomic bomb survivors with 40 50years of follow-up. Radiotherapy data generally apply for shorter follow-up times because of competing causes of death in cancer patients, and hence the risks of radiation-induced circulatory disease at those earlier times are lower. A variety of biological response modifiers have been used to help reduce late reactions in many tissues. These include antioxidants, radical scavengers, inhibitors of apoptosis, anti-inflammatory drugs, angiotensin-converting enzyme inhibitors, growth factors, and cytokines. In many cases, these give dose modification factors of 1.1-1.2, and in a few cases 1.5-2, indicating the potential for increasing threshold doses in known exposure cases. In contrast, there are agents that enhance radiation responses, notably other cytotoxic agents such as antimetabolites, alkylating agents, anti-angiogenic drugs, and antibiotics, as well as genetic and comorbidity factors. Most tissues show a sparing effect of dose fractionation, so that total doses for a given endpoint are higher if the dose is fractionated rather than when given as a single dose. However, for reactions manifesting very late after low total doses, particularly for cataracts and circulatory disease, it appears that the rate of dose delivery does not modify the low incidence. This implies that the injury in these cases and at these low dose levels is caused by single-hit irreparable-type events. For these two tissues, a threshold dose of 0.5Gy is proposed herein for practical purposes, irrespective of the rate of dose delivery, and future studies may elucidate this judgement further. PMID- 22925379 TI - Internet-ordered viagra (sildenafil citrate) is rarely genuine. AB - INTRODUCTION: Counterfeit medication is a growing problem. This study assessed the requirement for prescription, cost, origin, and content of medications sold via the Internet and purporting to be the phosphodiesterase type 5 inhibitor Viagra (sildenafil citrate). METHODS: Pfizer monitored top search results for the query "buy Viagra" on the two leading Internet search engines in March 2011. Orders were placed from 22 unique Web sites claiming to sell Viagra manufactured by Pfizer. Tablets received were assessed for chemical composition. RESULTS: No Web site examined required a prescription for purchase or a health screening survey; 90% offered illegal "generic Viagra." Cost per tablet ranged from $3.28 $33.00. Shipment origins of purchases were Hong Kong (N = 11), the United States (N = 6), and the United Kingdom (N = 2) as well as Canada, China, and India (N = 1 each). Notably, the four Internet pharmacies claiming to be Canadian did not ship medication from a Canadian address. Of 22 sample tablets examined, 17 (77%) were counterfeit, 4 (18%) were authentic, and 1 (5%) was an illegal generic. Counterfeit tablets were analyzed for sildenafil citrate, the active pharmaceutical ingredient (API) of Viagra, and contents varied between 30% and 50% of the label claim. Counterfeits lacked product information leaflets, including appropriate safety warnings, and genuine Viagra formulations. CONCLUSION: Internet sites claiming to sell authentic Viagra shipped counterfeit medication 77% of the time; counterfeits usually came from non-U.S. addresses and had 30% to 50% of the labeled API claim. Caution is warranted when purchasing Viagra via the Internet. PMID- 22925380 TI - Does microalbuminuria at mid-pregnancy predict development of subsequent pre eclampsia? AB - AIM: The aim of this study was to evaluate microalbuminuria at mid-pregnancy, using the albumin-to-creatinine ratio (ACR), as a predictor of pre-eclampsia. MATERIAL AND METHODS: This prospective observational study was carried out on 144 normotensive women, aged<35 years, body mass index<25kg/m2, and live singleton pregnancy between 24 and 28 weeks. In all, the ACR was measured in spot random urine samples. Normoalbuminuria was an ACR of <30 mg/g, whereas microalbuminuria was an ACR of 30-299 mg/g creatinine. All were followed till delivery. Primary outcome was the development of pre-eclampsia. The secondary outcome measures were preterm births and neonatal birthweight. Statistical analysis was done with Fisher's exact and t-tests. RESULTS: Of all, 77.1% (111/144) had normoalbuminuria and 22.9% (33/144) had microalbuminuria. Of 33 microalbuminuric women, the mean blood pressure was significantly higher in those who subsequently developed pre eclampsia (P<0.001). The mean ACR (mg/g) in this cohort was 60.6+/-29.4. The mean ACR (mg/g) in women who subsequently developed pre-eclampsia was significantly higher than in women who remained normotensive (P=0.003). Of 33 microalbuminuric women, 12 (36.4%) developed pre-eclampsia, and eight (24.2%) had preterm births. The mean birthweight (kg+/-standard deviation) was significantly lower in the microalbuminuria group (2.45+/-0.6) as compared to the normoalbuminuria group (2.8+/-0.37), P<0.001. CONCLUSION: Microalbuminuria in mid-pregnancy may be a significant predictor of development of subsequent pre-eclampsia, preterm birth and low-birthweight babies. PMID- 22925381 TI - Informing the public health. AB - Why with an increase in the amount of health information, and ways of accessing it, so many people experience poor health? What is the role of health library and information professionals in improving public health? These questions are of great interest to me. There are many examples of initiatives, particularly in the public library sector, which address health issues, however they are often very local and best practice is not always shared. Clearly changing the health status of a population requires more than information, but information is clearly an essential component. If health information is to be effective in improving public health then we need to address health literacy, and this is where health library and information professionals can play a significant role. Through this journal and the other activities of the Health Libraries Group I hope we can share good practice and explore new ways that health library and information workers can improve the health of individuals and communities. PMID- 22925382 TI - Do quality improvement systems improve health library services? A systematic review. AB - BACKGROUND: A turbulent financial and political climate requires health libraries to be more accountable than ever. Quality improvement systems are widely considered a 'good thing to do', but do they produce useful outcomes that can demonstrate value? OBJECTIVES: To undertake a systematic review to identify which aspects of health libraries are being measured for quality, what tools are being used and what outcomes are reported following utilisation of quality improvement systems. RESULTS: Many health libraries utilise quality improvement systems without translating the data into service improvements. Included studies demonstrate that quality improvement systems produce valuable outcomes including a positive impact on strategic planning, promotion, new and improved services and staff development. No impact of quality improvement systems on library users or patients is reported in the literature. CONCLUSIONS: The literature in this area is sparse and requires updating. We recommend further primary research is conducted in health libraries focusing upon the outcomes of utilising quality improvement systems. An exploration of quality improvement systems in other library sectors may also provide valuable insight for health libraries. PMID- 22925383 TI - Content analysis as a means of exploring research opportunities from a conference programme. AB - BACKGROUND: Health librarians should keep up-to-date in a dynamic environment and accept the importance of continuing personal development (CPD) and growth in their critical reflection and creative thinking skills. They also need to acknowledge the potential value of research activity and the challenges of ongoing improvement and development. Conference programmes may prove a useful source of stimulation, especially if supplemented by creativity techniques, action research and the ideal of 'finding flow'. OBJECTIVES: The article analyses the themes and papers presented at the 10th International Conference on International Medical Librarianship (ICML) to identify opportunities for further research, literature reviews, assessment of practices and services, etc. METHODS: Content analysis approach to conference papers and suggestions for further action including supplementing with techniques of creativity and group input. RESULTS: A fairly extensive list of further actions (although not intended to be exhaustive) is suggested for the sixteen conference themes. Although subjective, the list might help to stimulate growth in research on health librarianship and demonstrate how one source of stimulation--conference programmes (regularly presented to medical library communities)--can be used. CONCLUSIONS: Content analysis has proven a constructive means of generating research questions from a conference programme. Content analysis and other methods aimed at stimulating creative and progressive thinking, including brainstorming, force field analysis, De Bono's 6 hats, creative swiping and creative visualisation, may prove equally useful and require further investigation. To ensure an ongoing cycle, these can be linked to action research. PMID- 22925384 TI - Medical literature searches: a comparison of PubMed and Google Scholar. AB - BACKGROUND: Medical literature searches provide critical information for clinicians. However, the best strategy for identifying relevant high-quality literature is unknown. OBJECTIVES: We compared search results using PubMed and Google Scholar on four clinical questions and analysed these results with respect to article relevance and quality. METHODS: Abstracts from the first 20 citations for each search were classified into three relevance categories. We used the weighted kappa statistic to analyse reviewer agreement and nonparametric rank tests to compare the number of citations for each article and the corresponding journals' impact factors. RESULTS: Reviewers ranked 67.6% of PubMed articles and 80% of Google Scholar articles as at least possibly relevant (P = 0.116) with high agreement (all kappa P-values < 0.01). Google Scholar articles had a higher median number of citations (34 vs. 1.5, P < 0.0001) and came from higher impact factor journals (5.17 vs. 3.55, P = 0.036). CONCLUSIONS: PubMed searches and Google Scholar searches often identify different articles. In this study, Google Scholar articles were more likely to be classified as relevant, had higher numbers of citations and were published in higher impact factor journals. The identification of frequently cited articles using Google Scholar for searches probably has value for initial literature searches. PMID- 22925385 TI - Using the results of a satisfaction survey to demonstrate the impact of a new library service model. AB - BACKGROUND: In 2005, the University of Calgary entered into a contract to provide library services to the staff and physicians of Alberta Health Services Calgary Zone (AHS CZ), creating the Health Information Network Calgary (HINC). OBJECTIVES: A user satisfaction survey was contractually required to determine whether the new library service model created through the agreement with the University of Calgary was successful. Our additional objective was to determine whether information and resources provided through the HINC were making an impact on patient care. METHODS: A user satisfaction survey of 18 questions was created in collaboration with AHS CZ contract partners and distributed using the snowball or convenience sample method. RESULTS: Six hundred and ninety-four surveys were returned. Of respondents, 75% use the HINC library services. More importantly, 43% of respondents indicated that search results provided by library staff had a direct impact on patient care decisions. CONCLUSIONS: Alberta Health Services Calgary Zone staff are satisfied with the new service delivery model, they are taking advantage of the services offered, and using library provided information to improve patient care. PMID- 22925386 TI - Health information support provided by professional associations in Canada. AB - BACKGROUND: Healthcare practitioners in Alberta and across Canada have varying levels of access to information resources depending on their institutional and professional affiliations, yet access to current health information is critical for all. OBJECTIVES: To determine what information resources and services are provided by Albertan and Canadian professional health associations to their members. METHODS: Representatives of professional colleges and associations were interviewed regarding information resources and services offered to members and perceptions of their members' information needs. RESULTS: National-level associations are more likely to provide resources than provincial ones. There is a clear distinction between colleges and associations in terms of information offered: colleges provide regulatory information, while associations are responsible for provision of clinical information resources. Only half of the associations interviewed provide members with access to licensed databases, with cost being a major barrier. CONCLUSIONS: There is considerable variation in the number of electronic resources and the levels of information support provided by professional health associations in Alberta and Canada. Access and usage vary among the health professions. National licensing of resources or creation of a portal linking to freely available alternatives are potential options for increasing access and awareness. PMID- 22925387 TI - Health information seeking in the information society. AB - This article is the second student contribution to the Dissertations into Practice feature. It reports on a study that investigated the everyday health information-seeking practices of a small group of the 'general public' and the implications for information-seeking theory and health information provision. The first student article, about the implementation of radio frequency identification (RFID) in a hospital library, was very different, and the two articles illustrate the broad spectrum of possible subjects for the Dissertations into Practice feature. This study was conducted in summer 2011 by Abir Mukherjee for his MSc dissertation in the Library and Information Sciences programme at City University London. Further information and copies of the full dissertation may be obtained from Abir Mukherjee or David Bawden. AM. PMID- 22925388 TI - International trends in health science librarianship: part 3--the Nordic countries. AB - This is the third in a series of articles exploring international trends in health science librarianship in the first decade of the 21st century. The invited authors carried out a survey of librarians in Sweden, Denmark, Norway and Finland to identify common developments in their countries. A focus on pedagogy was seen as the most important trend. Future issues will track trends in Southern Europe and Latin America. JM. PMID- 22925389 TI - Making evidence-based decisions when organising information retrieval training for nurses and head nurses. AB - Using the PICO (Problem, Intervention, Comparison, Outcome) framework, this feature presents a case study on the information skills strand of a continuing education programme delivered at Kuopio University Hospital in Finland for nurses and head nurses. H.S. PMID- 22925390 TI - BRAF mutations in thyroid tumors from an ethnically diverse group. AB - BACKGROUND: The molecular etiology of thyroid carcinoma (TC) and other thyroid diseases which may present malignant precursor lesions is not fully explored yet. The purpose of this study was to estimate frequency, type and clinicopathological value of BRAF exon 15 mutations in different types of cancerous and non-cancerous thyroid lesions originating in an ethnically diverse population. METHODS: BRAF exon 15 was sequenced in 381 cases of thyroid lesions including Hashimoto's thyroiditis, nodular goiters, hyperplastic nodules, follicular adenomas (FA), papillary TC (PTC), follicular variant PTC (FVPTC), microcarcinomas of PTC (micro PTC; tumor size <= 1 cm), follicular TC (FTC), and non-well differentiated TC (non-WDTC). RESULTS: We identified BRAF mutations in one of 69 FA, 72 of 115 (63%) PTC, seven of 42 (17%) FVPTC, 10 of 56 (18%) micro PTC, one of 17 (6%) FTC, and one of eight (13%) non-WDTC. Most of the cases showed the common V600E mutation. One case each of PTC, FVPTC, and FTC harbored a K601E mutation. A novel BRAF mutation was identified in a FA leading to deletion of threonine at codon 599 (p.T599del). A rare 3-base pair insertion was detected in a stage III PTC resulting in duplication of threonine at codon 599 (p.T599dup). Patients with PTC harboring no BRAF mutation (BRAFwt) were on average younger than those with a BRAF mutation (BRAFmut) in the PTC (36.6 years vs. 43.8 years). Older age (>= 45 years) in patients with PTC was significantly associated with tumor size >= 4 cm (P = 0.018), vessel invasion (P = 0.004), and distant metastasis (P = 0.001). Lymph node (LN) involvement in PTC significantly correlated with tumor size (P = 0.044), and vessel invasion (P = 0.013). Of notice, taken the whole TC group, family history of thyroid disease positively correlated with capsular invasion (P = 0.025). CONCLUSIONS: Older age is manifold associated with unfavorable tumor markers in our series. The K601E identified in a PTC, FVPTC, and FTC seems to be more distributed among different histological types of TC than previously thought. The T599del is a yet undescribed mutation and the rare T599dup has not been reported as a mutation in PTC so far. PMID- 22925391 TI - Childhood trauma and premorbid adjustment among individuals at clinical high risk for psychosis and normal control subjects. AB - AIM: Traumatic childhood experiences are associated with psychotic illness and are frequently reported in patients at clinical high risk (CHR) for psychosis. Moreover, deteriorating premorbid functioning from childhood, and through adolescence, is related to greater severity of overall symptomatology and poorer outcomes in patients with psychosis. We studied the prevalence of traumatic childhood experiences and premorbid adjustment and their association with each other in patients at CHR for psychosis and normal control subjects (NCSs). METHODS: A total of 20 CHR patients for psychosis and 30 NCSs aged 14 to 35 participated in the present study. The CHR patients were identified as prodromal to psychosis using the Structured Interview for Prodromal Syndromes/Scale of Prodromal Symptoms. Premorbid adjustment was assessed by using the premorbid adjustment scale (PAS), and self-reported childhood trauma was assessed with the Trauma and Distress Scale (TADS). RESULTS: In CHR patients, TADS and PAS scores were higher than in NCSs. In CHR patients, TADS correlated significantly with the PAS general section and observably, but not significantly, with adolescence and adulthood sections. CONCLUSION: CHR patients reported more childhood trauma experiences and poorer premorbid adjustment than NCSs. In CHR patients, traumatic childhood experiences are associated with poor general premorbid adjustment. PMID- 22925392 TI - Use of three-dimensional excitation and emission matrix fluorescence spectroscopy for predicting the disinfection by-product formation potential of reclaimed water. AB - This study was undertaken to demonstrate the feasibility of using three dimensional excitation-emission matrix (3DEEM) fluorescence spectroscopy for the determination of chlorination disinfection by-product (DBP) precursors and the disinfection by-product formation potential (DBPFP) of reclaimed water samples. Two major DBP precursors were examined in this study, including humic acid (HA) and fulvic acid (FA). The 3DEEM fluorescence results obtained from various reclaimed water samples indicated that the reclaimed water samples were rich in fulvic acid-like substances that were associated with two main peaks (Ex/Em = 235 245/420-440 nm, and Ex/Em = 330-340/410-430 nm) in the fluorescence spectrum. The results also illustrated that the wavelength location of peak fluorescence intensity of a reclaimed water sample was independent of the influent water quality and the wastewater treatment process used in the reclamation plant. As a result, the peak fluorescence intensity and the wavelength location of the peak were used to identify the species of DBP precursors and their concentrations in the reclaimed water sample. Four regression models were then developed to relate the peak fluorescence intensity of the water sample to its DBPFP, including the formation potential of trihalomethane (THMFP) and the formation potential of haloacetic acid (HAAFP). The regression models were verified using the measured DBPFP results of a series of reclaimed water samples. It was found that the regression modeling results matched the measured DBPFP values well, with prediction errors below 10%. Therefore, the use of 3DEEM fluorescence spectroscopy together with the developed regression models in this study can provide a reliable and rapid tool for monitoring the quality of reclaimed water. Using this method, water quality could be monitored online, without utilizing the lengthy conventional DBPFP measurement. PMID- 22925393 TI - Modification of low pressure membranes with carbon nanotube layers for fouling control. AB - Carbon nanotubes (CNTs) with different physiochemical properties were layered onto low pressure membranes and tested for antifouling properties using a natural surface water with high fouling potential. Membranes modified with the largest diameter pristine multi-walled CNTs (MWCNTs) were most effective in controlling membrane fouling, tripling the time it took for the membrane to become noticeably fouled at a CNT loading of 22 g/m(2). The differences in the structure of CNT layers were an important contributing factor for antifouling properties; scanning electron microscopy imaging showed that large diameter MWCNTs formed homogeneous porous layers across the membrane surface, while less effective, small diameter MWCNTs formed heterogeneous layers. Water quality analysis showed that CNT membranes constructed with larger diameter CNTs were more effective at removing larger organic macromolecules responsible for fouling from feedwater compared to membranes made with smaller diameter CNTs. This reduced the concentration of foulants reaching the PVDF membrane and thus helped reduce membrane fouling. Beneficial for application, increased loadings of CNTs onto the membrane surface increased resistance to fouling while only slightly reducing the clean water permeability of the modified membranes. Overall, CNT layered membranes were shown to highly resist membrane fouling with potential applications in sustainable water treatment. PMID- 22925394 TI - Medically-derived 131I in municipal sewage effluent. AB - This work presents (131)I (t(1/2) = 8.04 d) concentrations in sewage effluent from the Stony Brook Water Pollution Control Plant (WPCP), a small plant serving a regional thyroid cancer treatment facility in Stony Brook, NY, USA. The concentrations detected in sewage effluent ranged from 1.8 +/- 0.3 to 227 +/- 2 Bq L(-1). The primary source of (131)I is excreta from thyroid cancer inpatients treated at the Stony Brook University Medical Center. Based on several time series measurements following known inpatient treatments, the mean sewage half life (T(s)) of iodine is 3 d in this plant. The T(s), analogous to a radioactive half-life, describes the time it takes for half of a wastewater component to be removed from a WPCP. Flow recycling, or activated sludge, used to maintain bacterial populations necessary for sewage treatment causes iodine to remain in this plant far longer than its hydraulic retention time. The experimental results suggest that most (131)I entering the Stony Brook WPCP leaves in sewage effluent, not in sewage sludge. Patient treatments can result in continuous discharges of (131)I to surface waters where it can be used as a tracer of sewage-derived material and to understand the behavior of (131)I in aquatic environments. PMID- 22925395 TI - Problematising public and private work spaces: midwives' work in hospitals and in homes. AB - OBJECTIVES: as the boundaries between public and private spaces become increasingly fluid, interest is growing in exploring how those spaces are used as work environments, how professionals both construct and convey themselves in those spaces, and how the lines dividing spaces traditionally along public and private lines are blurred. This paper draws on literature from critical geography, organisational studies, and feminist sociology to interpret the work experiences of midwives in Ontario, Canada who provide maternity care both in hospitals and in clients' homes. DESIGN: qualitative design involving in-depth semi-structured interviews content coded thematically. SETTING: Ontario, Canada. PARTICIPANTS: community midwives who practice at home and in hospital. FINDINGS: the accounts of practicing midwives illustrate the ways in which hospital and home work spaces are sites of both compromise and resistance. With the intention of making birthing women feel more 'at home', midwives describe how they attempt to recreate the woman's home in the hospital. Similarly, midwives also reorient women's homes to a certain degree into a more standardised work space for home birth attendance. Many midwives also described how they like 'guests' in both settings. KEY CONCLUSIONS: there seems to be a conscious or unconscious convergence of midwifery work spaces to accommodate Ontario midwives' unique model of practice. IMPLICATIONS FOR PRACTICE: we link these findings of midwives' place of work on their experiences as workers to professional work experiences in both public and private spaces and offer suggestions for further exploration of the concept of professionals as guests in their places of work. PMID- 22925396 TI - The Canadian Birth Place Study: describing maternity practice and providers' exposure to home birth. AB - OBJECTIVES: (1) to describe educational, practice, and personal experiences related to home birth practice among Canadian obstetricians, family physicians, and registered midwives; (2) to identify barriers to provision of planned home birth services, and (3) to examine inter-professional differences in attitudes towards planned home birth. DESIGN: the first phase of a mixed-methods study, a quantitative survey, comprised of 38 items eliciting demographic, education and practice data, and 48 items about attitudes towards planned home birth, was distributed electronically to all registered midwives (N=759) and obstetricians who provide maternity care (N=800), and a random sample of family physicians (n=3,000). SETTING: Canada. This national investigation was funded by the Canadian Institutes for Health Research. PARTICIPANTS: Canadian registered midwives (n=451), obstetricians (n=245), and family physicians (n=139). FINDINGS: almost all registered midwives had extensive educational and practice experiences with planned home birth, and most obstetricians and family physicians had minimal exposure. Attitudes among midwives and physicians towards home birth safety and advisability were significantly different. Physicians believed that home births are less safe than hospital births, while midwives did not agree. Both groups believed that their views were evidence-based. Midwives were the most comfortable with including planned home birth as an option when discussing choice of birth place with pregnant women. Both midwives and physicians expressed discomfort with inter-professional consultation related to planned home births. In addition, both family physicians and obstetricians reported discomfort with discussing home birth with their patients. A significant proportion of family physicians and obstetricians would have liked to attend a home birth as part of their education. CONCLUSIONS: the amount and type of education and exposure to planned home birth practice among maternity care providers were associated with attitudes towards home birth, comfort with discussing birth place options with women, and beliefs about safety. Barriers to home birth practice across professions were both logistical and philosophical. IMPLICATIONS FOR PRACTICE: formal mechanisms for midwifery and medical education programs to increase exposure to the theory and practice of planned home birth may facilitate evidence based informed choice of birth place, and increase comfort with integration of care across birth settings. An increased focus among learners and clinicians on reliable methods for assessing the quality of the evidence about birth place and maternal-newborn outcomes may be beneficial. PMID- 22925397 TI - Comprehensive care of the patient with haemophilia and inhibitors undergoing surgery: practical aspects. AB - Congenital haemophilia is a rare and complex condition for which dedicated specialized and comprehensive care has produced measurable improvements in clinical outcomes and advances in patient management. Among these advances is the ability to safely perform surgery in patients with inhibitor antibodies to factors VIII and IX, in whom all but the most necessary of surgeries were once avoided due to the risk for uncontrollable bleeding due to ineffectiveness of replacement therapy. Nevertheless, surgery continues to pose a major challenge in this relatively rare group of patients because of significantly higher costs than in patients without inhibitors, as well as a high risk for bleeding and other complications. Because of the concentration of expertise and experience, it is recommended that any surgery in patients with haemophilia and inhibitors be planned in conjunction with a haemophilia treatment centre (HTC) and performed in a hospital that incorporates a HTC. Coordinated, standard pre-, intra- and postoperative assessments and planning are intended to optimize surgical outcome and utilization of resources, including costly factor concentrates and other haemostatic agents, while minimizing the risk for bleeding and other adverse consequences both during and after surgery. This article will review the special considerations for patients with inhibitors as they prepare for and move through surgery and recovery, with an emphasis on the roles and responsibilities of individual members of the multidisciplinary team in facilitating this process. PMID- 22925398 TI - Results of chemoradiotherapy for stage I esophageal cancer in medically inoperable patients compared with results in operable patients. AB - The purpose of the present study was to evaluate long-term results of chemoradiotherapy for clinical T1b-2N0M0 esophageal cancer and to compare outcomes for operable and inoperable patients. Patients with stage I esophageal cancer (Union for International Cancer Control [UICC] 2009), excluding patients with cT1a esophageal cancer, were studied. All patients had histologically proven squamous cell carcinoma. Operable patients received cisplatin and 5-fluorouracil with concurrent radiotherapy of 60 Gy including a 2-week break. Inoperable patients received nedaplatin and 5-fluorouracil with concurrent radiotherapy of 60-70 Gy without a pause. End-points were overall survival rate (OS), cause specific survival rate (CSS), progression-free survival rate (PFS), and locoregional control rate (LC). Thirty-seven operable patients and 30 medically inoperable patients were enrolled. There was a significant difference in only age between the operable group and inoperable group (P = 0.04). The median observation period was 67.9 months. In all patients, 5-year OS, CSS, PFS, and LC were 77.9%, 91.5%, 66.9%, and 80.8%, respectively. Comparison of the operable group and inoperable group showed that there was a significant difference in OS (5-year, 85.5% vs. 68.7%, P = 0.04), but there was no difference in CSS, PFS, or LC. Grade 3 or more late toxicity according to Common Terminology Criteria for Adverse Events v 3.0 was found in seven patients. Even in medically inoperable patients with stage I esophageal cancer, LC of more than 80% can be achieved with chemoradiotherapy. However, OS in medically inoperable patients is significantly worse than that in operable patients. PMID- 22925399 TI - Serotonin syndrome in a patient with chronic pain polypharmacy. PMID- 22925400 TI - [S1 guideline for the treatment of hidradenitis suppurativa / acne inversa * (number ICD-10 L73.2)]. PMID- 22925402 TI - Oviductal, endometrial and embryonic gene expression patterns as molecular clues for pregnancy establishment. AB - In higher animals, the beginning of new life and transfer of genetic material to the next generation occurs in the oviduct when two distinct gametes cells unite resulting in the formation of a zygote. The zygote then undergoes serial developmental processes in the oviduct and enters into the uterus where it faces challenges and scrutiny from the endometrial ecosystem. Thus, embryos that are able to establish an appropriate embryo-maternal dialogue are capable of developing to term whereas the incompetent ones can perish any time during the gestation period. Although several lines of evidences indicated that pregnancy loss is a multi-factorial phenomenon, the biochemical composition of the embryo and maternal environment are the main players to determine pregnancy outcome. Indeed, expression patterns of the genes are the driving forces that induce biochemical composition changes in embryo, oviduct and uterine environment. Thus, examining the molecular signals that are associated with oviductal or endometrial receptivity and embryo implantation is essential for establishing strategies to improve pregnancy success. Therefore, this review focuses on the contribution of oviduct and its transcriptome profile on early stage embryo development and the impact of endometrium and its transcriptome changes on peri and post embryo implantation. In addition, this paper integrates established facts about hormonal and molecular signatures associated with endometrial receptivity. Finally, the blastocyst and pre-conception endometrial gene expression profiles have been discussed in relation to the pregnancy outcome to highlight the potentials of blastocyst and pre-transfer endometrial transcriptome profile approach for selecting appropriate recipient and developmentally competent embryo. PMID- 22925403 TI - Type I diabetes among children and young adults: the role of country of birth, socioeconomic position and sex. AB - OBJECTIVE: To investigate associations between country of birth, parental country of birth, and education with respect to incidence rate and time trends of type 1 diabetes mellitus (T1DM) among children and young adults. METHODS: We followed a nation-wide cohort of 4 469 671 males and 4 231 680 females aged 0-30 years between 1969 and 2008. Incidence rate ratios (IRRs) with 95% confidence intervals (CIs) for T1DM were calculated using Poisson regression models. We further calculated age-standardized rates (ASRs) of T1DM, using the world population as standard. RESULTS: During the study period, the ASR of T1DM increased among children younger than 15 years, but not among young adults (15-30 years). Compared with Swedish-born children, male and female immigrant children had 44 and 42% lower IRR of TIDM, respectively. Among offspring to immigrants, corresponding decreases in IRRs were 27 and 24%, respectively. Compared with children to parents with high education, male children to parents with low education had a 10% decreased IRR of T1DM, while no effect was observed among females. The IRR of T1DM increased with increasing age and calendar time of follow-up in both sexes (p-for trend <0.0001). In young adults, the IRR among immigrants decreased by 32% in males and 22% in females, while corresponding reductions in IRRs were less in offspring to immigrants. CONCLUSIONS: We found a lower IRR of T1DM among offspring to immigrants, but especially among young immigrants compared with Sweden-born individuals. The findings show that environmental factors are important in the etiology of T1DM. PMID- 22925404 TI - Transmission rate and reproductive number of the H5N1 highly pathogenic avian influenza virus during the December 2005-July 2008 epidemic in Nigeria. AB - We quantified the between-village transmission rate, beta (the rate of transmission of H5N1 HPAI virus per effective contact), and the reproductive number, Re (the average number of outbreaks caused by one infectious village during its entire infectious period), of H5N1 highly pathogenic avian influenza (HPAI) virus in Nigeria using outbreak data collected between December 2005 and July 2008. We classified the outbreaks into two phases to assess the effectiveness of the control measures implemented. Phase 1 (December 2005-October 2006) represents the period when the Federal Government of Nigeria managed the HPAI surveillance and response measures, while Phase 2 (November 2006-July 2008) represents the time during which the Nigeria Avian Influenza Control and Human Pandemic Preparedness project (NAICP), funded by a World Bank credit of US$ 50 million, had taken over the management of most of the interventions. We used a total of 204 outbreaks from 176 villages that occurred in 78 local government areas of 25 states. The compartmental susceptible-infectious model was used as the analytical tool. Means and 95% percentile confidence intervals were obtained using bootstrapping techniques. The overall mean beta (assuming a duration of infectiousness, T, of 12 days) was 0.07/day (95% percentile confidence interval: 0.06-0.09). The first and second phases of the epidemic had comparable beta estimates of 0.06/day (0.04-0.09) and 0.08/day (0.06-0.10), respectively. The Re of the virus associated with these beta and T estimates was 0.9 (0.7-1.1); the first and second phases of the epidemic had Re of 0.84 (0.5-1.2) and 0.9 (0.6 1.2), respectively. We conclude that the intervention measures implemented in the second phase of the epidemic had comparable effects to those implemented during the first phase and that the Re of the epidemic was low, indicating that the Nigeria H5N1 HPAI epidemic was unstable. PMID- 22925405 TI - Aerobic capacity and disease activity in children, adolescents and young adults with juvenile idiopathic arthritis (JIA). AB - BACKGROUND: As patients with juvenile idiopathic arthritis (JIA) progress into adulthood, long-term outcome is determined by disease activity, physical and psychosocial development. Decreased aerobic capacity may play a critical role in health-related outcomes in JIA, since it has been linked with cardiovascular morbidity and mortality in late adulthood. The objectives of the current study are to examine the aerobic capacity and its relation to parameters of disease activity in children, adolescents and young adults with JIA. METHODS: Sixty-three patients with JIA (aged 10-27 years) were cross sectional studied regarding their aerobic capacity and correlations were made to demographic, disease-related variables, and medication utilization. in a cross-sectional study group of 63 patients of all subtypes. Patients were divided in three age groups, 10-13 years; 14-17 years and 18-27 years. RESULTS: Reduced aerobic capacity is found in clinical remission as well as active disease in all subtypes and all age groups. Aerobic capacity is more impaired in active disease shown by DAS 28, JADAS 27, ESR and serum thrombocyte counts. Lower haemoglobin has a negative impact. Long term used medication including methotrexate and corticosteroids didn't influence outcome. There is no association with current sports participation. CONCLUSION: Reduced aerobic capacity is present in children and adolescents with JIA, both in active disease and in patients with remission. Measures of aerobic capacity may serve as important outcome measure in JIA. PMID- 22925406 TI - Effect of intrathecal administration of E-series prostaglandin 1 receptor antagonist in a cyclophosphamide-induced cystitis rat model. AB - OBJECTIVES: To investigate the effect of intrathecal administration of E-series prostaglandin 1 antagonist in cyclophosphamide-induced murine cystitis. METHODS: Female Wistar rats were used for this experimental study. Intrathecal administration of E-series prostaglandin 1 antagonist (ONO-8711; 0.5, 5 and 50 ug) in sham controls and rats with cystitis induced by a single intraperitoneal injection of cyclophosphamide (300 mg/kg) was assessed by evaluating micturition pressure and intercontraction interval using a conscious-filling cystometry at 48 h after cyclophosphamide or saline injection. In both groups, prostaglandin E2 concentrations and the expression of E-series prostaglandin 1 receptor in the spinal cord were measured by enzyme-linked immunosorbent assay and reverse transcription polymerase chain reaction, respectively. RESULTS: Rats with cyclophosphamide-induced cystitis showed a shorter intercontraction interval compared with controls, where the cumulative intrathecal administration of ONO 8711 did not significantly change micturition pressure or intercontraction interval compared with the baseline. In rats with cyclophosphamide-induced cystitis, each dose of ONO-8711 significantly increased the intercontraction interval compared with the baseline (46% increase at 50 ug intrathecally). Polymerase chain reaction revealed the expression of E-series prostaglandin 1 receptor in the spinal cord of both sham and cyclophosphamide-induced cystitis rats. In rats with cyclophosphamide-induced cystitis, PGE2 concentration in the dorsal horn of the L5-6 spinal cord was significantly higher than that in controls (3.55 +/- 1.24 vs 0.99 +/- 0.06 pg/mg tissue). CONCLUSIONS: In rats with cyclophosphamide-induced cystitis, urinary frequency seems to be caused by prostaglandin E2 acting on E-series prostaglandin 1 receptor at the level of the spinal cord. Blockade of the spinal E-series prostaglandin 1 receptor by ONO-8711 might have a therapeutic potential in the control of interstitial cystitis/bladder pain syndrome. PMID- 22925407 TI - An evaluation of two large scale demand side financing programs for maternal health in India: the MATIND study protocol. AB - BACKGROUND: High maternal mortality in India is a serious public health challenge. Demand side financing interventions have emerged as a strategy to promote access to emergency obstetric care. Two such state run programs, Janani Suraksha Yojana (JSY)and Chiranjeevi Yojana (CY), were designed and implemented to reduce financial access barriers that preclude women from obtaining emergency obstetric care. JSY, a conditional cash transfer, awards money directly to a woman who delivers in a public health facility. This will be studied in Madhya Pradesh province. CY, a voucher based program, empanels private obstetricians in Gujarat province, who are reimbursed by the government to perform deliveries of socioeconomically disadvantaged women. The programs have been in operation for the last seven years. METHODS/DESIGNS: The study outlined in this protocol will assess and compare the influence of the two programs on various aspects of maternal health care including trends in program uptake, institutional delivery rates, maternal and neonatal outcomes, quality of care, experiences of service providers and users, and cost effectiveness. The study will collect primary data using a combination of qualitative and quantitative methods, including facility level questionnaires, observations, a population based survey, in-depth interviews, and focus group discussions. Primary data will be collected in three districts of each province. The research will take place at three levels: the state health departments, obstetric facilities in the districts and among recently delivered mothers in the community. DISCUSSION: The protocol is a comprehensive assessment of the performance and impact of the programs and an economic analysis. It will fill existing evidence gaps in the scientific literature including access and quality to services, utilization, coverage and impact. The implementation of the protocol will also generate evidence to facilitate decision making among policy makers and program managers who currently work with or are planning similar programs in different contexts. PMID- 22925408 TI - Unique spectrum of GJB2 mutations in Mexico. AB - OBJECTIVE: The aim of this study was to elucidate the involvement of mutations in three relatively common deafness genes in Mexican individuals with non-syndromic hearing loss. METHODS: We sequenced GJB2 for mutations, screened for two deletions involving GJB6, del(GJB6-D13S1830) and del(GJB6-D13S1854), and for the m.1555A>G mutation in the MTRNR1 gene in 76 (71 simplex and 5 multiplex) unrelated Mexican probands with prelingual non-syndromic hearing loss. Samples were obtained from the Department of Genetics at Instituto Nacional de Rehabilitacion in Mexico City. RESULTS: Eight previously reported pathogenic variants and two polymorphic variants in GJB2 were identified. The two screened GJB6 deletions and the m.1555A>G mutation were not detected. Eight cases (10.6%) were found to have bi-allelic mutations in GJB2 and six (7.9%) were found to have a monoallelic GJB2 mutation. Of the six monoallelic mutations, one (p.R184Q) was a previously reported autosomal dominant variant. The most frequent pathological allele detected in this population was the c.35delG mutation in the GJB2 gene. The p.V27I polymorphic variant was also detected, with an allele frequency of 0.24. All eight probands with GJB2 mutations had symmetric profound deafness, whereas patients without GJB2 mutations had moderate, severe or profound hearing loss. CONCLUSIONS: This study shows that GJB2 mutations are an important cause of prelingual deafness in the Mexican population. PMID- 22925409 TI - Access to care for children with symptoms of sleep disordered breathing. AB - OBJECTIVES: To determine if children with sleep disordered breathing who have Medicaid insurance encounter more difficulty accessing an otolaryngologist than those with private insurance. DESIGN: Retrospective study. SETTING: Urban tertiary care pediatric hospital. PATIENTS: Children referred for evaluation of sleep disordered breathing (SDB). INTERVENTION: Survey of patients' parents and guardians. MAIN OUTCOME MEASURE: Timely access to an otolaryngologist in their community. RESULTS: Ninety-seven patients were included. Fifty patients had private insurance, 47 had Medicaid. The mean age was 5 years for those with private insurance and 5.6 years for those with Medicaid (p=0.27). The symptoms of SDB in both groups were similar. It took an average of 1.97 weeks for the children in the private insurance group to get an appointment versus 10.8 weeks for those with Medicaid (p=0.002). The mean distance traveled by the children in the private insurance group was 9.86 miles compared to 18.05 miles for those with Medicaid (p=0.001). CONCLUSION: Children who were referred for evaluation of SDB were of similar age and had similar symptoms regardless of insurance type. Children with Medicaid wait longer and travel farther to see an otolaryngologist than children with private insurance. PMID- 22925410 TI - Opioid substitution therapy clients' preferences for targeted versus general primary health-care outlets. AB - INTRODUCTION AND AIMS: Opioid substitution therapy (OST) ideally constitutes a window of opportunity for the provision of essential primary health care (PHC) for OST clients. In the absence of such opportunities, however, OST clients access PHC from existing outlets, either general services or those targeted to specific groups. This study examined OST clients' current main source and preferred future outlets of PHC services and correlates of preferences. DESIGN AND METHODS: Anonymous interviews conducted with n = 257 clients of two public OST clinics in Sydney's inner-west. RESULTS: Overall, 61% (n = 158) of participants reported currently accessing PHC primarily from general outlets (general practitioners or medical centres: 51%, hospital/emergence departments: 10%) and the remainder (39%, n = 99) from outlets that target specific groups (e.g. Aboriginal Medical Services, OST prescriber/clinics, drug user-targeted PHCs). Twenty-two percent reported discomfort disclosing drug use to their current PHC providers. However, the majority were satisfied with the care they received and reported a preference to remain with their current PHC providers for a range of reasons, most commonly familiarity with and trust in staff (56%) and not feeling judged about their drug use (49%). Nevertheless, 28% reported that they would access PHC through their OST clinic if it were available. DISCUSSION AND CONCLUSIONS: PHC outlets that target specific groups appear to have an ongoing and important role in providing accessible health care to OST clients. PMID- 22925411 TI - The translational repressor Crc controls the Pseudomonas putida benzoate and alkane catabolic pathways using a multi-tier regulation strategy. AB - Metabolically versatile bacteria usually perceive aromatic compounds and hydrocarbons as non-preferred carbon sources, and their assimilation is inhibited if more preferable substrates are available. This is achieved via catabolite repression. In Pseudomonas putida, the expression of the genes allowing the assimilation of benzoate and n-alkanes is strongly inhibited by catabolite repression, a process controlled by the translational repressor Crc. Crc binds to and inhibits the translation of benR and alkS mRNAs, which encode the transcriptional activators that induce the expression of the benzoate and alkane degradation genes respectively. However, sequences similar to those recognized by Crc in benR and alkS mRNAs exist as well in the translation initiation regions of the mRNA of several structural genes of the benzoate and alkane pathways, which suggests that Crc may also regulate their translation. The present results show that some of these sites are functional, and that Crc inhibits the induction of both pathways by limiting not only the translation of their transcriptional activators, but also that of genes coding for the first enzyme in each pathway. Crc may also inhibit the translation of a gene involved in benzoate uptake. This multi-tier approach probably ensures the rapid regulation of pathway genes, minimizing the assimilation of non-preferred substrates when better options are available. A survey of possible Crc sites in the mRNAs of genes associated with other catabolic pathways suggested that targeting substrate uptake, pathway induction and/or pathway enzymes may be a common strategy to control the assimilation of non-preferred compounds. PMID- 22925412 TI - Prolonged ictal aphasia: a diagnosis to consider. AB - Aphasia is a common symptom encountered by clinical neurologists. It is usually caused by strokes or lesions involving language regions of the brain, yet prolonged aphasia is rarely the sole manifestation of a simple partial status epilepticus. We report six patients, who suffered from prolonged ictal aphasia. All but one patient had a structural lesion in the left hemisphere, only three suffered from clinical seizures during or shortly prior to the aphasic episode. All patients had ictal patterns on the electroencephalogram (EEG), four of whom had periodic lateralized epileptiform discharges, and five showed frequent recurrent electrographic seizures during the aphasic state. The aphasia lasted several days in all patients, and it resolved after administration of antiepileptic drug treatment. In conclusion, prolonged ictal aphasia is a rare but important treatable cause of aphasia. Surface EEG recordings should be obtained in all patients with unexplained prolonged aphasia to diagnose this rare but treatable entity. PMID- 22925413 TI - Efficacy of extracranial-intracranial revascularization for non-moyamoya steno occlusive cerebrovascular disease in a series of 66 patients. AB - Although there is uncertainty about whether extracranial-intracranial arterial bypass is useful for the treatment of steno-occlusive cerebrovascular disease in general, there is some argument for its continued use in particular patients. In the present study, we evaluated the efficacy of superficial temporal artery middle cerebral artery (STA-MCA) anastomosis combined with encephalo-duro-myo synangiosis (EDMS) in the treatment of non-moyamoya steno-occlusive cerebrovascular disease by retrospectively reviewing clinical and radiological data from 66 patients treated between January 2006 and April 2011. Forty-six double STA-MCA anastomoses and 20 single anastomoses were completed, and all remained patent in the perioperative phase, as confirmed by CT angiography. Postoperative CT perfusion imaging demonstrated immediate improvement in perfusion in the revascularized hemisphere. On discharge, 50 of the 66 patients (75.8%) had an improved National Institutes of Health Stroke Scale (NIHSS) score relative to preoperative values. After at least 6 months of follow-up, 54 (88.5%) patients had improved NIHSS scores relative to discharge values. CT perfusion imaging showed significant improvement compared to post-operative images. Follow up digital subtraction angiography confirmed that 95 of 96 (99%) anastomoses remained patent. There was no significant difference between the single and double bypasses in terms of either clinical or hemodynamic outcomes on the revascularized side. STA-MCA combined with EDMS was effective for the treatment of non-moyamoya steno-occlusive cerebrovascular disease with hemodynamic impairment. Hemodynamic evaluation before and after surgery may help identify patients in need of a bypass and may be useful for predicting outcome. PMID- 22925414 TI - Microsurgical clipping of an unruptured lenticulostriate aneurysm. AB - Aneurysms of the lenticulostriate artery have been associated with hypertension, vasculopathy, tumors, and arteriovenous malformations. Although several cases of microsurgical treatment of ruptured lenticulostriate artery aneurysms have been reported, to our knowledge there is no published case of microsurgical treatment of an unruptured lenticulostriate artery aneurysm. We report a 66-year-old woman with a history of moyamoya disease, previously treated with a right-sided middle cerebral artery-to-superficial temporal artery bypass who presented with an unruptured aneurysm of a lenticulostriate artery. We report successful microsurgical treatment of this rare lesion and discuss the rationale for our treatment strategy. PMID- 22925415 TI - Subacute combined degeneration of the spinal cord despite prophylactic vitamin B12 treatment. PMID- 22925416 TI - A retrospective review of acute encephalitis in adults in Auckland over a five year period (2005-2009). AB - We conducted a retrospective audit of the outcomes of patients 15 years of age and older from the greater Auckland region who had a diagnosis of encephalitis over a five-year period. Patients were identified via a database search of all patients who had a cerebrospinal fluid (CSF) viral polymerase chain reaction (PCR) panel requested between 2005 and 2009. All CSF viral PCR were performed at one laboratory. This test was used as a default marker for patients who may have had encephalitis. There were 37 patients who met our definition of encephalitis during the study. Their ages ranged from 15 to 88 years (median 51 years), and 59% were female. There was an admission rate of 7.4 admissions per year or an annual incidence of approximately 0.5 cases per 100,000. An infective cause was found in 10 patients (27%): varicella zoster in five patients (14%), herpes simplex in four (11%) and enterovirus in one patient (3%). An autoimmune paraneoplastic encephalitis was felt most likely in three patients (8%); a paraneoplastic antibody screen was performed in two of these three but was negative in both. The cause of encephalitis was not identified in the other 24 patients (65%). There were five deaths (in-hospital mortality rate 14%). Encephalitis is an uncommon but important disease, because of the significant mortality. The cause of encephalitis remained undetermined in two-thirds of patients. PMID- 22925417 TI - Lumbar plexus schwannoma causing recurrent syncope. AB - Retroperitoneal schwannomas are rare and present non-specifically. They usually manifest secondary to their compressive effects on adjacent structures. We describe a patient who presented with recurrent syncope resulting from a large retroperitoneal schwannoma stretching the inferior vena cava and compromising venous return. We also discuss the salient aspects of preoperative investigations leading to definitive diagnosis and surgery. PMID- 22925418 TI - Spectrum disorder of neuromyelitis optica in a patient presenting with intractable vomiting and hiccups, transverse myelitis and acute encephalopathy. AB - Optic neuropathy and transverse myelitis (TM) are common symptoms of multiple sclerosis (MS) but may also be seen in association with the antibody-mediated autoimmune disorder, neuromyelitis optica (NMO). We report a female patient presenting with intractable vomiting and hiccups and TM shortly followed by an acute encephalopathy, most likely due to NMO spectrum disorder. Serum and cerebrospinal fluid NMO antibodies were negative. Serial MRI abnormalities included longitudinally extensive TM of the cervical cord, focal T2-weighted hyperintensity of the area postrema and lesions in both thalami and the hypothalamus. Clinical and MRI involvement of these brain regions, which have high aquaporin expression, in conjunction with a spinal lesion extending over three vertebral segments strongly favoured a diagnosis of NMO. She required several courses of intravenous methylprednisolone and plasmapheresis before receiving intravenous rituximab therapy. NMO spectrum disorder should be considered in the differential diagnosis of atypical central nervous system presentations such as intractable vomiting and hiccups and acute encephalopathy. Recognition of this syndrome has significant implications as its treatment and prognosis differs from MS. PMID- 22925419 TI - Treatment of limbic encephalitis with anti-glioma-inactivated 1 (LGI1) antibodies. AB - We report a 72-year-old patient who developed acute limbic encephalitis initially considered of uncertain aetiology. Detailed information on clinical presentation, MRI appearance, antibody levels, cognitive impairment assessment, treatment and evolution of the patient is reported here. Since the early 2000s, many antibodies implied in central nervous system autoimmune disorders have been identified. Anti glioma-inactivated 1 (LGI1) antibodies have been recently identified as associated with limbic encephalitis, as was the case in our patient. PMID- 22925420 TI - Erectile function is improved in aged rats by PnTx2-6, a toxin from Phoneutria nigriventer spider venom. AB - INTRODUCTION: Age-associated erectile dysfunction (ED) involves a decrease in nitric oxide (NO) availability and impaired relaxation. PnTx2-6, a toxin from the Phoneutria nigriventer spider, has been demonstrated to improve erectile function via NO/cyclic guanosine monophosphate (cGMP) pathway. This spider's venom is characterized by several symptoms, including erection. PnTx2-6 has been implicated in this phenomenon. Animal venoms have been postulated as potential drugs to treat ED. AIM: PnTx2-6 toxin improves erectile function in aged rats via NO/cGMP. We investigated the effect of PnTx2-6 in the erectile function of aged rats. MAIN OUTCOME MEASURES: ED was evaluated through changes in intracavernosal pressure/mean arterial pressure ratio during electrical field stimulation (EFS) of the pelvic ganglion of aged and adult rats (70 vs. 14 weeks). In functional studies, EFS-induced relaxation of corpus cavernosum (CC) strips were performed with or without PnTx2-6 (10-8M). RESULTS: The decrease in erectile function associated with age was partially restored 15-20 minutes after injection of PnTx2 6 and further improved by sildenafil. PnTx2-6 enhanced EFS-induced relaxation, as well as cGMP levels in CC, from young and aged rats. Relaxation due to PnTx2-6 was further increased after 30 minutes incubation with Y-27632, a Rho-kinase inhibitor (10-6 M), in aging CC. Nitric oxide synthase (NOS) activity in aged and young cavernosal tissue was increased by incubation with PnTx2-6 (10 minutes). However, this toxin did not modify NOS expression. CONCLUSION: PnTx2-6 improves penile relaxation in aged rats, via increased NOS activity and NO release, resulting in enhanced cGMP levels. PMID- 22925421 TI - Preincisional infiltration and intraperitoneal instillation of levobupivacaine 0.25% for management of early postoperative pain following laparoscopic ovarian drilling. AB - AIM: To assess the effectiveness of combined preincisional local infiltration (at trocar sites) and intraperitoneal instillation of levobupivacaine 0.25% for the management of early postoperative pain following laparoscopic ovarian drilling. MATERIALS AND METHODS: This is a prospective randomized controlled observer blinded study. The study included 106 infertile patients with the diagnosis of polycystic ovary syndrome (PCOS) who were scheduled to undergo diagnostic laparoscopy and laparoscopic ovarian drilling (LOD) during the period from November 2009 to February 2012 at TAIBA Hospital in Kuwait. Patients were randomly allocated to two groups of 53 patients each. Group I comprised patients who received preincisional local infiltration and intraperitoneal instillation levobupivacaine 0.25%. Patients in group II received equal volumes of normal saline 0.9% (NS) at the same sites. The primary outcome measures were visual analog scale pain scores and postoperative analgesic consumption. RESULTS: Postoperative average VAS pain scores, i.m. pethidine consumption and i.v. paracetamol consumption during the first 24 h were highly significantly lower in the levobupivacaine group compared to the NS group (P<0.01). This technique was also associated with significantly higher overall patient satisfaction, shorter hospital stay and more rapid resumption of normal activity (P<0.01) without any significant adverse events. CONCLUSION: The combination of preincisional local infiltration and intraperitoneal instillation of levobupivacaine 0.25% was found to substantially reduce postoperative pain and the consumption of postoperative analgesics during the first 24 h; and shorten hospital stay and time to resume normal activities after LOD. It was also associated with a very high overall patient satisfaction without any significant adverse events. PMID- 22925422 TI - Evidence for iron-mediated anaerobic methane oxidation in a crude oil contaminated aquifer. AB - In a methanogenic crude oil contaminated aquifer near Bemidji, Minnesota, the decrease in dissolved CH(4) concentrations along the groundwater flow path, along with the positive shift in delta(13) C(CH) (4) and negative shift in delta(13) C(DIC) , is indicative of microbially mediated CH(4) oxidation. Calculations of electron acceptor transport across the water table, through diffusion, recharge, and the entrapment and release of gas bubbles, suggest that these processes can account for at most 15% of the observed total reduced carbon oxidation, including CH(4) . In the anaerobic plume, the characteristic Fe(III)-reducing genus Geobacter was the most abundant of the microbial groups tested, and depletion of labile sediment iron is observed over time, confirming that reduced carbon oxidation coupled to iron reduction is an important process. Electron mass balance calculations suggest that organic carbon sources in the aquifer, BTEX and non-volatile dissolved organic carbon, are insufficient to account for the loss in sediment Fe(III), implying that CH(4) oxidation may also be related to Fe(III) reduction. The results support a hypothesis of Fe(III)-mediated CH(4) oxidation in the contaminated aquifer. PMID- 22925423 TI - Stable expression of promyelocytic leukaemia (PML) protein in telomerase positive MCF7 cells results in alternative lengthening of telomeres phenotype. AB - BACKGROUND: Cancer cells can employ telomerase or the alternative lengthening of telomeres (ALT) pathway for telomere maintenance. Cancer cells that use the ALT pathway exhibit distinct phenotypes such as heterogeneous telomeres and specialised Promyelocytic leukaemia (PML) nuclear foci called APBs. In our study, we used wild-type PML and a PML mutant, in which the coiled-coil domain is deleted (PML C/C-), to investigate how these proteins can affect telomere maintenance pathways in cancer cells that use either the telomerase or ALT pathway. RESULTS: Stable over-expression of both types of PML does not affect the telomere maintenance in the ALT cells. We report novel observations in PML over expressed telomerase-positive MCF7 cells: 1) APBs are detected in telomerase positive MCF7 cells following over-expression of wild-type PML and 2) rapid telomere elongation is observed in MCF7 cells that stably express either wild type PML or PML C/C-. We also show that the telomerase activity in MCF7 cells can be affected depending on the type of PML protein over-expressed. CONCLUSION: Our data suggests that APBs might not be essential for the ALT pathway as MCF7 cells that do not contain APBs exhibit long telomeres. We propose that wild-type PML can either definitively dominate over telomerase or enhance the activity of telomerase, and PML C/C- can allow for the co-existence of both telomerase and ALT pathways. Our findings add another dimension in the study of telomere maintenance as the expression of PML alone (wild-type or otherwise) is able to change the dynamics of the telomerase pathway. PMID- 22925424 TI - Biodegradation of alkyl derivatives of aromatic hydrocarbons and cell surface properties of a strain of Pseudomonas stutzeri. AB - Pseudomonas stutzeri strain 9 was isolated from petroleum-contaminated soil. The main purpose of this study was to investigate how the long-term contact of this strain with diesel oil influences its surface and biodegradation properties. The experiments showed that the tested strain was able to degrade aromatic alkyl derivatives (butylbenzene, sec-butylbenzene, tert-butylbenzene and isobutylbenzene) and that the storage conditions had an influence on the cell surface properties. Also greater agglomeration of the cells was observed in the scanning electron microscope (SEM) micrographs and confirmed in particle size distribution results. The results also indicated that the addition of rhamnolipids to the hydrocarbons led to modification of the surface properties of P. stutzeri strain 9, which could be observed in the zeta potential and hydrophobicity values. PMID- 22925425 TI - Emissions of particulate-bound elements from biodiesel and ultra low sulfur diesel: size distribution and risk assessment. AB - Use of waste cooking oil derived biodiesel (WCOB) as an alternative fuel in diesel engines has increased significantly in recent years. The impact of WCOB on particulate emissions from diesel engines needs to be investigated thoroughly. This study was conducted to make a comparative evaluation and size-differentiated speciation of the particulate bound elements from ultra low sulfur diesel (ULSD) and WCOB and a blend of both of the fuels (B50). Particle mass and their elemental size distributions ranging from 0.01-5.6 MUm were measured. It was observed that more ultrafine particles (UFPs, <100 nm) were emitted when the engine was fueled with WCOB. Fifteen particulate-bound elements such as K, Al, Mg, Co, Cr, Cu, Fe, Mn, Cd, Ni, As, Ba, Pb, Zn and Sr were investigated and reported in this study. Potential health risk associated with these particulate bound elements upon inhalation was also evaluated based on dose-response assessments for both adults and children. The findings indicate that the exposure to PM of the B100 exhaust is relatively more hazardous and may pose adverse health effects compared to that of ULSD. Also, investigations on human health risk due to exposure to UFPs indicate that UFPs contribute a major fraction (>70%) of the total estimated health risk. PMID- 22925426 TI - Assessing the role of trichloroacetyl-containing compounds in the natural formation of chloroform using stable carbon isotopes analysis. AB - Chloroform (CHCl(3)) is an environmental contaminant widely distributed around world, as well as a natural compound formed in various aquatic and terrestrial environments. However, the chemical mechanisms leading to the natural formation of chloroform in soils are not completely understood. To assess the role of trichloroacetyl-containing compound (TCAc) in the natural formation of chloroform in forest soils, carbon stable isotope analyses of chloroform and TCAc in field samples and chlorination experiments were carried out. The isotope analysis of field samples have revealed that the delta(13)C value of natural chloroform (delta(13)C(mean)=-25.80/00) is in the same range as the natural organic matter (delta(13)C(mean)=-27.70/00), whereas trichloromethyl groups of TCAc are much more enriched in (13)C (delta(13)C(mean)=-9.80/00). A similar relationship was also observed for TCAc and chloroform produced by chlorination of natural organic matter with NaOCl. The strong depletion of (13)C in chloroform relative to TCAc can be explained by carbon isotope fractionation during TCAc hydrolysis. As shown using a mathematical model, when steady state between formation of TCAc and hydrolysis is reached, the isotope ratio of chloroform is expected to correspond to isotope composition of NOM while TCAc should be enriched in (13)C by about 18.30/00, which is in good agreement with field observations. Hence this study suggests that TCAc are likely precursors of chloroform and at the same time explains why natural chloroform has a similar isotope composition as NOM despite large carbon isotope fractionation during its release. PMID- 22925427 TI - Patient perspectives on dysphonia after thyroidectomy for thyroid cancer. AB - OBJECTIVES: To determine the frequency and consequences of patient-reported post thyroidectomy voice disorder (PTVD) after surgery for thyroid cancer. STUDY DESIGN: Retrospective review of data gathered from a survey. PARTICIPANTS: Members of the Thyroid Cancer Survivors' Association (ThyCa). METHODS: ThyCa members were asked about their thyroid disease and surgery, voice disturbance, impact on quality of life, treatment, and non-identifying demographics in a 36 item electronic questionnaire. Patients with preoperative voice disturbance or vocal fold immobility and those reporting postoperative vocal fold paralysis were excluded. RESULTS: A total of 4426 members responded (37% response rate), and PTVD was reported by 51.1% of responders. Most were temporary (85.9%), with a minority reporting permanent hoarseness. Rates of postoperative dysphonia were similar between the extent of surgery and histology. Patients with PTVD predominantly characterized their impairment as loss of loudness and an inability to shout or sing. Nearly a quarter of patients reporting PTVD identified detrimental impact to their professional or personal lives. Only 57 patients (3.4%) were offered voice therapy; however, more than two-thirds of them (73.7%) experienced at least partial improvement. CONCLUSIONS: We report the results of a large-scale patient survey to underscore the commonness of postoperative hoarseness and its impact on patients. LEVEL OF EVIDENCE: 4. PMID- 22925428 TI - Productivity cost calculations in health economic evaluations: correcting for compensation mechanisms and multiplier effects. AB - Productivity costs related to paid work are commonly calculated in economic evaluations of health technologies by multiplying the relevant number of work days lost with a wage rate estimate. It has been argued that actual productivity costs may either be lower or higher than current estimates due to compensation mechanisms and/or multiplier effects (related to team dependency and problems with finding good substitutes in cases of absenteeism). Empirical evidence on such mechanisms and their impact on productivity costs is scarce, however. This study aims to increase knowledge on how diminished productivity is compensated within firms. Moreover, it aims to explore how compensation and multiplier effects potentially affect productivity cost estimates. Absenteeism and compensation mechanisms were measured in a randomized trial among Dutch citizens examining the cost-effectiveness of reimbursement for smoking cessation treatment. Multiplier effects were extracted from published literature. Productivity costs were calculated applying the Friction Cost Approach. Regular estimates were subsequently adjusted for (i) compensation during regular working hours, (ii) job dependent multipliers and (iii) both compensation and multiplier effects. A total of 187 respondents included in the trial were useful for inclusion in this study, based on being in paid employment, having experienced absenteeism in the preceding six months and completing the questionnaire on absenteeism and compensation mechanisms. Over half of these respondents stated that their absenteeism was compensated during normal working hours by themselves or colleagues. Only counting productivity costs not compensated in regular working hours reduced the traditional estimate by 57%. Correcting for multiplier effects increased regular estimates by a quarter. Combining both impacts decreased traditional estimates by 29%. To conclude, large amounts of lost production are compensated in normal hours. Productivity costs estimates are strongly influenced by adjustment for compensation mechanisms and multiplier effects. The validity of such adjustments needs further examination, however. PMID- 22925429 TI - Childhood obesity and human capital accumulation. AB - The prevalence of childhood obesity has tripled in the United States over the last 25 years, and in addition to increased risks of many chronic diseases, obesity may also be linked to lower skill attainment, poor social competency, and poorer labor outcomes. Any causal links between obesity and human capital accumulation could have important consequences for both health and economic well being over the life course. We investigate the association of obesity and cognitive and non-cognitive outcomes among US children and adolescents aged 5 to 19 using the Child Development Supplement of the Panel Survey of Income Dynamics. We perform OLS and individual fixed effects regressions to address unobserved time invariant heterogeneity in the relationship between overweight/obesity and abilities. Results provide limited support for the hypothesis that obesity negatively affects non-cognitive but not cognitive outcomes and suggest that discrimination rather than a biological mechanism contributes to negative outcomes found in the literature on adults. PMID- 22925430 TI - New therapeutic targets for osteoporosis: beyond denosumab. AB - Treatments for osteoporosis over the last few decades have largely focused on antiresorptive agents that effectively prevent bone loss. Beginning with hormone therapy, a variety of new potent antiresorptive agents were developed, including oral and intravenous bisphosphonates, raloxifene and other selective estrogen receptor modulators, nasal spray calcitonin, and denosumab. Teriparatide and PTH 1-84 are the only approved anabolic agents to date that primarily build new bone density. A variety of new biologic agents that focus on molecular targets important for the stimulation of new bone formation are being developed. Cathepsin K inhibitors appear to have mixed antiresorptive and anabolic actions because they inhibit one of the major osteoclast digestive enzymes without suppressing bone formation, thereby leading to anabolic effects on bone. New biologic agents in clinical trials include anti-sclerostin and anti-dickkopf antibodies that stimulate the Wnt/beta-catenin pathway in osteoblasts, leading to new bone formation. These new agents will effectively stimulate new bone formation by different mechanisms, leading to improved bone mineral density and reduced fractures. PMID- 22925431 TI - The study of pathogen resistance and antimicrobial use in dementia: study design and methodology. AB - Advanced dementia is characterized by the onset of infections and antimicrobial use is extensive. The extent to which this antimicrobial use is appropriate and contributes to the emergence of antimicrobial resistant bacteria is not known. The object of this report is to present the methodology established in the Study of Pathogen Resistance and Exposure to Antimicrobials in Dementia (SPREAD), and describe how challenges specific to this research were met. SPREAD is an ongoing, federally funded, 5-year prospective cohort study initiated in September 2009. Subjects include nursing home residents with advanced dementia and their proxies recruited from 31 Boston-area facilities. The recruitment and data collection protocols are described. Characteristics of participant facilities are presented and compared to those nationwide. To date, 295 resident/proxy dyads have been recruited. Baseline and selected follow-up data demonstrate successful recruitment of subjects and repeated collection of complex data documenting infections, decision-making for these infections, and antimicrobial bacteria resistance among the residents. SPREAD integrates methods in dementia, palliative care and infectious diseases research. Its successful implementation further establishes the feasibility of conducting rigorous, multi-site NH research in advanced dementia, and the described methodology serves as a detailed reference for subsequent publications emanating from the study. PMID- 22925434 TI - Development of a single tube multiplex real-time PCR to detect the most clinically relevant Mucormycetes species. AB - Mucormycetes infections are very difficult to treat and a delay in diagnosis could be fatal for the outcome of the patient. A molecular diagnostic technique based on Real Time PCR was developed for the simultaneous detection of Rhizopus oryzae, Rhizopus microsporus and the genus Mucor spp. in both culture and clinical samples. The methodology used was Molecular beacon species-specific probes with an internal control. This multiplex real-time PCR (MRT-PCR) was tested in 22 cultured strains and 12 clinical samples from patients suffering from a proven mucormycosis. Results showed 100% specificity and a detection limit of 1 fg of DNA per microlitre of sample. The sensitivity was 100% for clinical cultured strains and for clinical samples containing species detected by the PCR assay. Other mucormycetes species were not detected in clinical samples. This technique can be useful for clinical diagnosis and further studies are warranted. PMID- 22925432 TI - Meeting the challenges of medical countermeasure development. AB - Despite substantial investments since the events of 2001, much work remains to prepare the nation for a chemical, biological, radiological or nuclear (CBRN) attack or to respond to an emerging infectious disease threat. Following a 2010 review of the US Public Health Emergency Medical Countermeasures Enterprise, FDA launched its Medical Countermeasures initiative (MCMi) to facilitate the development and availability of medical products to counter CBRN and emerging disease threats. As a regulatory agency, FDA has a unique and critical part to play in this national undertaking. Using a three-pillar approach, FDA is addressing key challenges associated with the regulatory review process for medical countermeasures; gaps in regulatory science for MCM development and evaluation; and issues related to the legal, regulatory and policy framework for an effective public health response. Filling the gaps in the MCM Enterprise is a huge national undertaking, requiring the collaboration of all stakeholders, including federal partners, current and prospective developers of medical countermeasures, relevant research organizations, and state and local responders. Especially critical to success are an appreciation of the long timelines, risks and high costs associated with developing medical countermeasures - and the systems to deliver them - and the requisite support of all stakeholders, including national leadership. PMID- 22925435 TI - Heterozygous 21-hydroxylasedeficiency as a cause of hyperandrogenism. PMID- 22925436 TI - Reliability and validity of individual and composite recall pain measures in patients with cancer. AB - OBJECTIVES: To evaluate and compare the validity and reliability of individual and composite recall pain intensity measures. DESIGN: Secondary analyses using data from a published 14-day open-label crossover clinical trial comparing two active treatments. SETTING: Multiple settings. PARTICIPANTS: Fifty-two adults with a history of chronic cancer pain. MEASURES: Recall ratings of least, worst, and average pain during the past 2 days; composite score representing recalled characteristic pain in the past 2 days; and daily diary ratings of pain intensity from which "actual" least, worst, and average pain scores were derived. RESULTS: Recall ratings of least and average pain, and a composite score representing recalled characteristic pain were accurate (differed no more than three points from "actual" scores on a 0-100 scale). Although the recall rating of worst pain significantly (P < 0.05) overestimated actual worst pain, the differences were minor (i.e., seven to eight points on a 0-100 scale). All of the recall measures demonstrated validity via their strong associations with the measures of actual pain intensity. The recall measures also demonstrated excellent test-retest stability, although the diary-derived measures tended to be more stable than the recall measures did. The composite measure of recalled characteristic pain demonstrated a high level of internal consistency (Cronbach's alpha = 0.90). CONCLUSIONS: Individual recall ratings and a composite score representing recalled characteristic pain intensity are reliable and valid measures of actual pain in patients with cancer. The findings support their use as outcome measures in clinical trials. PMID- 22925437 TI - HIV and infant feeding in Malawi: public health simplicity in complex social and cultural contexts. AB - BACKGROUND: The question of when and how to best wean infants born to mothers with HIV requires complex answers. There are clinical guidelines on best approaches but limitations persist when applying them in diverse low-income settings. In such settings, infant-feeding practices are not only dependent on individual women's choices but are also subject to social and cultural pressures. However, when developing infant-feeding policies little attention has been paid to these pressures, even though they may yield useful empirical knowledge on the various forces that shape the infant-feeding dilemmas confronting women with HIV. This study aimed to a) identify the infant-feeding challenges that women with HIV faced when they were advised to wean their children at an early age of six months and b) explore how the women adhered to their infant-feeding options while facing and managing these challenges. METHODS: This study was conducted between February 2008 and April 2009 at two public health facilities where services to prevent mother-to-child transmission of HIV were implemented. Repeated in-depth interviews were conducted with 20 HIV-positive women. Two of the 20 women were also chosen for case studies which included home visits. RESULTS: Several interdependent factors including the conflicting pressures of sexual morality and the demands of nurturing and motherhood, in conditions of abject poverty, impeded the participating women from following medical advice on infant feeding. If they adhered to the medical advice, the women would encounter difficulty maintaining their ascribed roles as respected wives, mothers and members of the society at large. The necessity of upholding their moral standing through continued breastfeeding, which signified HIV-negative status, put pressure on them to ignore the medical advice. CONCLUSIONS: The infant-feeding dilemmas for women with HIV are complex. The integration of public health efforts with context specific socio-cultural understanding is essential. The recent 2010 WHO guidelines offer a possible way of resolving these challenges. They recommend breastfeeding for one year with an adaptation to two years for Malawi. Efforts in the PMTCT programmes to supplement existing support systems, e.g. through the mothers-to-mothers (M2M) programme or consultation with expert mothers may also help women overcome these challenges. PMID- 22925438 TI - Incidence of type 1 and type 2 diabetes in youth in the U.S. Virgin Islands, 2001 2010. AB - OBJECTIVE: To report the annual incidence of type 1 and type 2 diabetes among youth and to describe characteristics of youth diagnosed with diabetes in the U.S. Virgin Islands (USVI). RESEARCH DESIGN AND METHODS: All residents <=19 years of age diagnosed with diabetes between January 2001 and December 2010 were identified from review of medical records of all hospitals and confirmed by physician query. RESULTS: A total of 82 eligible patients were identified and the registry ascertainment was estimated to be 98.7% complete. The overall age adjusted annual incidence rates (per 100, 000) of type 1 and type 2 diabetes for the study period were 15.3 (95% CI: 11.3-20.1) and 9.6 (95% CI: 6.8-13.5), respectively. The incidence of type 1 diabetes increased significantly over the study period, with an epidemic-like threefold increase occurring from 2005 (8.7/100, 000) to 2006 (26.4/100, 000; p = 0.05). The incidence of type 1 diabetes was highest in the 10-19 age group in girls (25.6/100, 000), but no age difference was seen in boys, resulting from the lack of a pubertal peak in non Hispanic Black boys. The incidence of type 2 diabetes rose significantly between 2001 (5.3/100, 000) and 2010 (12.5/100, 000; p = 0.03). CONCLUSIONS: The incidence of type 1 and type 2 diabetes in youth is increasing in the USVI, similar to global patterns. Further studies are needed to explore the missing pubertal rise in type 1 diabetes incidence in non-Hispanic Black boys and factors associated with the epidemic-like increases observed over the decade. PMID- 22925439 TI - Prevalence of classical swine fever virus in domestic pigs in South Korea: 1999 2011. AB - The major policy for eradication of classical swine fever (CSF) in South Korea has focused on the implementation of compulsory vaccination of the susceptible pig population. A vaccine strain of CSF virus, the LOM strain, is used to maintain high herd seroconversion, a practice complementary to the 'stamping-out policy' and restriction of animal movement during disease outbreaks. To survey for the prevalence of CSF in domestic pigs in South Korea over the past 13 years (1999-2011), we tested 4 193 782 and 1 162 645 samples for antibodies and antigens, respectively. Whereas seropositivity for CSF antibodies has been maintained at over 95% in the mainland, in Jeju Island, where no-vaccination has been administered since 1999, seroprevalence has been below 1% during the last 3 years of study (2009-2011). The highest number of outbreaks in South Korea occurred in 2002 and 2003; since then, outbreaks have decreased each year, with the last CSF outbreak recorded in 2009. No outbreaks have occurred during the past 3 years, and a high level of herd immunity has been maintained in the mainland pig population for 8 years; therefore, South Korea could now switch to a no-vaccination policy throughout the country. However, the constant threat of the re-emergence of the disease in the susceptible pig population should be the main consideration in planning and carrying out the last phase of the CSF eradication process. PMID- 22925440 TI - Hungarian "jailhouse rock": incidence and morbidity of Vaseline self-injection of the penis. AB - INTRODUCTION: Vaseline self-injection into the penis is currently a popular procedure in prisons. Since such injections are illegal, severe complications of the procedure can often remain hidden. AIM: To identify the incidence, motivation, and morbidity of Vaseline self-injection into the penis among inmates. METHODS: A total of 4,735 inmates at the largest Hungarian prisons were asked to complete a questionnaire relating to their sexual life, whether they had self-injected Vaseline into their penis, the motivation leading them to resort to Vaseline self-injection, any complications observed and the level of satisfaction attained. MAIN OUTCOME MEASURES: A 17-point questionnaire on the circumstances, motivations, and complications of Vaseline self-injection among prisoners. RESULTS: Of the 1,905 responders, 15.7% admitted Vaseline self-injection. Only around one-fifth of the Vaseline injected subjects had not been satisfied with the original size of their penis and their sexual life up to the time of the injection, a proportion similar to that among Vaseline nonusers. While the satisfaction with the sexual life became significantly worse after the Vaseline injection, the satisfaction with the penis size did not change and an erectile dysfunction developed de novo in 21.4% of cases. The most common motivation for self-injection was a recommendation by another inmate; it was rarely recommended by a sexual partner. Complications had developed among 25.4% of the Vaseline users and 50.3% of them were not satisfied with the result of the Vaseline injection. Of the Vaseline users, 22.4% regretted the self-injection, while the rate among those who had developed complications was 53%. CONCLUSIONS: The self injection of Vaseline into the penile skin proved to be somewhat of a trend among these inmates. The complications depended mainly on the amount of Vaseline injected, the poor hygienic circumstances, and the personal tolerability. Increased awareness is needed for the prevention of this social, psychological, and physical problem. PMID- 22925441 TI - A re-analysis of sex differences in landscape use in early hominins: a comment on Copeland and colleagues. PMID- 22925442 TI - Tamoxifen for the management of breast events induced by non-steroidal antiandrogens in patients with prostate cancer: a systematic review. AB - BACKGROUND: Tamoxifen has emerged as a potential management option for gynecomastia and breast pain due to non-steroidal antiandrogens, and it is considered an alternative to surgery or radiotherapy. The objective of this systematic review was to assess the benefits and harms of tamoxifen, in comparison to other treatment options, for either the prophylaxis or treatment of breast events induced by non-steroidal antiandrogens in prostate cancer patients. METHODS: We searched CENTRAL, MEDLINE, EMBASE, reference lists, the abstracts of three major conferences and three trial registers to identify ongoing randomized controlled trials (RCTs). Two authors independently screened the articles identified, assessed the trial quality and extracted data. The protocol was prospectively registered (CRD42011001320; http://www.crd.york.ac.uk/PROSPERO). RESULTS: Four studies were identified. Tamoxifen significantly reduced the risk of suffering from gynecomastia (risk ratio 9RR0 0.10, 95% CI 0.05 to 0.22) or breast pain (RR 0.06, 95% CI 0.02 to 0.17) at six months compared to untreated controls. Tamoxifen also showed a significant benefit for the prevention of gynecomastia (RR 0.22, 95% CI 0.08 to 0.58) and breast pain (RR 0.25, 95% CI 0.10 to 0.64) when compared to anastrozole after a median of 12 months. One study showed a significant benefit of tamoxifen for the prevention of gynecomastia (RR 0.24, 95% CI 0.09 to 0.65) and breast pain (RR 0.20, 95% CI 0.06 to 0.65) when compared with radiotherapy at six months. Radiotherapy increased the risk of suffering from nipple erythema and skin irritation, but there were no significant differences for any other adverse events (all P>0.05). CONCLUSIONS: The currently available evidence suggests good efficacy of tamoxifen for the prevention and treatment of breast events induced by non-steroidal antiandrogens. The impact of tamoxifen therapy on long-term adverse events, disease progression and survival remains unclear. Further large, well-designed RCTs, including long-term follow ups, are warranted. Also, the optimal dose needs to be clarified. PMID- 22925443 TI - CBCT-based predictability of attachment of the neurovascular bundle to the proximal segment of the mandible during sagittal split osteotomy. AB - Injury to the inferior alveolar nerve (IAN) during surgery is an important complication of bilateral sagittal split osteotomy. With cone beam computed tomography, the course of the nerve and its relationship to the surrounding structures can be assessed in three dimensions. This study aims to determine whether tomography can predict attachment of the neurovascular bundle to the proximal segment of the mandible during sagittal split osteotomy (SSO). Bilateral linear measurements were taken on cross-sectional tomography images. During osteotomy, it was noted for each patient whether the neurovascular bundle was attached to the proximal segment during the split. If attached, a bone-cutting instrument or a blunt instrument was needed to free the nerve. The nerve was attached at more than one-third of operation sites (170 sites). Of these, over 65% of attached nerves (108 sites) required a bone-cutting intervention to free them from the mandible. After correcting for confounding factors, the linear distances from the buccal cortical margin of the IAN canal to the inner and outer buccal cortical margins of the mandible were important predictors of whether the IAN will be attached to the proximal segment of the mandible during SSO. PMID- 22925444 TI - Genetic and immunological markers predict titanium implant failure: a retrospective study. AB - This study evaluates diagnostic markers to predict titanium implant failure. Retrospectively, implant outcome was scored in 109 subjects who had undergone titanium implant surgery, IL1A -889 C/T (rs1800587), IL1B +3954 C/T (rs1143634), IL1RN +2018 T/C (rs419598) and TNFA -308 G/A (rs1800629) genotyping, in vitro IL 1beta/TNF-alpha release assays and lymphocyte transformation tests during treatment. TNF-alpha and IL-1beta release on titanium stimulation were significantly higher among patients with implant loss (TNF-alpha: 256.89 pg/ml vs. 81.4 pg/ml; p<0.0001; IL-1beta: 159.96 pg/ml vs. 54.01 pg/ml; p<0.0001). The minor alleles of the studied polymorphisms showed increased prevalence in the implant failure group (IL1A: 61% vs. 42.6% in controls, IL1B: 53.7% vs. 39.7% in controls, TNFA: 46.3% vs. 30.9% in controls, IL1RN: 58.5% vs. 52.9% in controls). Increasing numbers of risk genotypes of the studied polymorphisms were associated with an increasing risk of implant loss, suggesting an additive effect. Multiple logistic regression analysis showed positive IL-1beta/TNF-alpha release assay scores (p<0.0001, OR=12.01) and number of risk genotypes (p<0.046, OR=1.57-6.01) being significantly and independently associated with titanium implant failure. IL-1/IL1RN/TNFA genotyping and cytokine release assay scores provide prognostic markers for titanium implant outcome and may present new tools for individual risk assessment. PMID- 22925445 TI - Robotic ultrasound probe for tumor identification in robotic partial nephrectomy: Initial series and outcomes. AB - OBJECTIVES: Accurate tumor identification during partial nephrectomy is essential for successful tumor control. Intraoperative laparoscopic ultrasonography is useful for tumor localization, but the ultrasound probe is controlled by the assistant rather than the surgeon. We evaluated our initial experience using a robotic ultrasound probe that is controlled by the console surgeon. METHODS: Partial nephrectomy was carried out in 22 consecutive patients between November 2010 and March 2011. A robotic ultrasound probe under console surgeon control was used in all the cases. All patients had at least 1 year follow up. RESULTS: Mean patient age was 59 years and mean tumor size was 2.7 cm. There were six hilar tumors (27%) and 21 (95%) endophytic tumors. Mean R.E.N.A.L. nephrometry score was 6.9 (range 6-9). Mean operative time was 205.7 min and mean warm ischemia time was 17.9 min (range 6-28 min). All patients had negative tumor margins and were free of disease recurrence at a mean follow up of 13 months. CONCLUSION: The use of a robotic ultrasound probe during partial nephrectomy allows the surgeon to optimize tumor identification with maximal autonomy, and to benefit from the precision and articulation of the robotic instrument during this key step of the partial nephrectomy procedure. PMID- 22925446 TI - Discovery of 6-[4-(6-nitroxyhexanoyl)piperazin-1-yl)]-9H-purine, as pharmacological post-conditioning agent. AB - Novel purine analogues bearing nitrate esters were designed and synthesized in an effort to develop compounds triggering endogenous cardioprotective mechanisms such as ischemic preconditioning (IPC) or postconditioning (PostC). The majority of the compounds reduced infarct size compared to the control group in anesthetized rabbits, whereas administration of the most active analogue 16 at a dose of 3.8 MUmol/kg resulted on a significant reduction of infarct size, compared to PostC group (13.4 +/- 1.9% vs 26.4 +/- 2.3%). These findings introduce a novel class of promising pharmacological compounds that could be used as mimics or enhancers of PostC. PMID- 22925447 TI - Structure-anti-leukemic activity relationship study of ortho-dihydroxycoumarins in U-937 cells: key role of the delta-lactone ring in determining differentiation inducing potency and selective pro-apoptotic action. AB - Previous studies indicated the need of at least one phenolic hydroxyl group in the coumarin core for induction of cytotoxicity in different cell lines. Herein, we present an exhaustive structure-activity relationship study including ortho dihydroxycoumarins (o-DHC) derivatives, cinnamic acid derivatives (as open-chain coumarin analogues) and 1,2-pyrones (representative of the delta-lactone ring of the coumarin core), carried out to further identify the structural features of o DHC required to induce leukemic cell differentiation and apoptosis in U-937 cells. Our results show for the first time that the delta-lactone ring positively influences the aforementioned biological effects, by conferring greater potency to compounds with an intact coumarin nucleus. Most tellingly, we reveal herein the crucial role of this molecular portion in determining the selective toxicity that o-DHC show for leukemic cells over normal blood cells. From a pharmacological perspective, our findings point out that o-DHC may be useful prototypes for the development of novel chemotherapeutic agents. PMID- 22925448 TI - Competitive antagonism of insect GABA receptors by iminopyridazine derivatives of GABA. AB - A series of 4-(6-imino-3-aryl/heteroarylpyridazin-1-yl)butanoic acids were synthesized and examined for antagonism of GABA receptors from three insect species. When tested against small brown planthopper GABA receptors, the 3,4 methylenedioxyphenyl and the 2-naphthyl analogues showed complete inhibition of GABA-induced fluorescence changes at 100 MUM in assays using a membrane potential probe. Against common cutworm GABA receptors, these analogues displayed approximately 86% and complete inhibition of GABA-induced fluorescence changes at 100 MUM, respectively. The 4-biphenyl and 4-phenoxyphenyl analogues showed moderate inhibition at 10 MUM in these receptors, although the inhibition at 100 MUM was not complete. Against American cockroach GABA receptors, the 4-biphenyl analogue exhibited the greatest inhibition (approximately 92%) of GABA-induced currents, when tested at 500 MUM using a patch-clamp technique. The second most active analogue was the 2-naphthyl analogue with approximately 85% inhibition. The 3-thienyl analogue demonstrated competitive inhibition of cockroach GABA receptors. Homology modeling and ligand docking studies predicted that hydrophobic 3-substituents could interact with an accessory binding site at the orthosteric binding site. PMID- 22925449 TI - Antibacterial activities of Groebke-Blackburn-Bienayme-derived imidazo[1,2 a]pyridin-3-amines. AB - We sought to explore the imidazo[1,2-a]pyridin-3-amines for TLR7 (or 8) modulatory activities. This chemotype, readily accessed via the Groebke-Blackburn Bienayme multi-component reaction, resulted in compounds that were TLR7/8 inactive, but exhibited bacteriostatic activity against Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA). To investigate the mechanism of antibacterial activity of this new chemotype, a resistant strain of S. aureus was generated by serially passaging the organism in escalating doses of the most active analogue. A comparison of minimum inhibitory concentrations (MICs) of known bacteriostatic agents in wild-type and resistant strains indicates a novel mechanism of action. Structure-activity relationship studies have led to the identification of positions on the scaffold for additional structural modifications that should allow for the introduction of probes designed to examine cognate binding partners and molecular targets, while not significantly compromising antibacterial potency. PMID- 22925450 TI - Synthesis and structure-activity relationship of a novel class of 15-membered macrolide antibiotics known as '11a-azalides'. AB - Macrolide antibiotics are widely prescribed for the treatment of respiratory tract infections; however, the increasing prevalence of macrolide-resistant pathogens is a public health concern. Therefore, the development of new macrolide scaffolds with activities against resistant pathogens is urgently needed. An efficient method for reconstructing the erythromycin A macrolactone skeleton has been established. Based on this methodology, novel 15-membered macrolides, known as '11a-azalides', with substituents at the C12, C13, or C4" positions were synthesized and their antibacterial activities were evaluated. These derivatives showed promising antibacterial activities against erythromycin-resistant Streptococcus pneumoniae. Among them, the C4" substituted derivatives had the most potent activity against erythromycin-resistant S. pneumoniae. PMID- 22925452 TI - Vaginal delivery following single incision sling (TVT-Secur) for female stress urinary incontinence. AB - In recent years, surgical treatment of stress urinary incontinence has become minimally invasive owing to the introduction of the transobturator route first and then single incision devices for positioning of mid-urethral slings. Although a number of case reports in the literature describe pregnancies successfully terminated both by vaginal delivery and cesarean section following mid-urethral sling positioning, there is still no definitive consensus on which is the preferred mode of delivery in these patients. We report a case of spontaneous vaginal delivery at term in a 41-year-old multiparous woman two years after the positioning of a single incision sling (TVT-Secur). The patient remained continent throughout the gestation and in the following 24 months. This case seems to further support the concept that sling procedures for stress urinary incontinence do not represent an absolute contraindication to spontaneous vaginal delivery, although the preferred mode of delivery must be assessed on an individual basis. PMID- 22925451 TI - Pediatric hydrocephalus outcomes: a review. AB - The outcome of pediatric hydrocephalus, including surgical complications, neurological sequelae and academic achievement, has been the matter of many studies. However, much uncertainty remains, regarding the very long-term and social outcome, and the determinants of complications and clinical outcome. In this paper, we review the different facets of outcome, including surgical outcome (shunt failure, infection and independence, and complications of endoscopy), clinical outcome (neurological, sensory, cognitive sequels, epilepsy), schooling and social integration. We then provide a brief review of the English-language literature and highlighting selected studies that provide information on the outcome and sequelae of pediatric hydrocephalus, and the impact of predictive variables on outcome. Mortality caused by hydrocephalus and its treatments is between 0 and 3%, depending on the duration of follow-up. Shunt event-free survival (EFS) is about 70% at one year and 40% at ten years. The EFS after endoscopic third ventriculostomy (ETV) appears better but likely benefits from selection bias and long-term figures are not available. Shunt infection affects between 5 and 8% of surgeries, and 15 to 30% of patients according to the duration of follow-up. Shunt independence can be achieved in 3 to 9% of patients, but the definition of this varies. Broad variations in the prevalence of cognitive sequelae, affecting 12 to 50% of children, and difficulties at school, affecting between 20 and 60%, attest of disparities among studies in their clinical evaluation. Epilepsy, affecting 6 to 30% of patients, has a serious impact on outcome. In adulthood, social integration is poor in a substantial number of patients but data are sparse. Few controlled prospective studies exist regarding hydrocephalus outcomes; in their absence, largely retrospective studies must be used to evaluate the long-term consequences of hydrocephalus and its treatments. This review aims to help to establish the current state of knowledge and to identify conflicting data and unanswered questions, in order to direct future studies. PMID- 22925453 TI - Inside the alkalinity engine: the role of electron donors in the organomineralization potential of sulfate-reducing bacteria. AB - Mineral precipitation in microbial mats may have been the key to their preservation as fossil stromatolites, potentially documenting evidence of the earliest life on Earth. Two factors that contribute to carbonate mineral precipitation are the saturation index (SI) and the presence of nucleation sites. Both of these can be influenced by micro-organisms, which can either alter SI through their metabolisms, or produce and consume organic substances such as extracellular polymeric substances (EPS) that can affect nucleation. It is the balance of individual metabolisms within the mat community that determines the pH and the dissolved inorganic carbon concentration, thereby potentially increasing the alkalinity and consequently the SI. Sulfate-reducing bacteria (SRB) are an important component of this 'alkalinity engine.' The activity of SRB often peaks in layers where CaCO(3) precipitates, and mineral precipitation has been demonstrated in SRB cultures; however, the effect of their metabolism on the alkalinity engine and actual contribution to mineral precipitation is the subject of controversy. Here, we show through culture experiments, theoretical calculations, and geochemical modeling studies that the pH, alkalinity, and organomineralization potential will vary depending on the type of electron donor. Specifically, hydrogen and formate can increase the pH, but electron donors like lactate and ethanol, and to a lesser extent glycolate, decrease the pH. The implication of this for the lithification of mats is that the combination of processes supplying electron donors and the utilization of these compounds by SRB may be critical to promoting mineral precipitation. PMID- 22925454 TI - Two serine phosphorylation sites in the C-terminus of Rad9 are critical for 9-1-1 binding to TopBP1 and activation of the DNA damage checkpoint response in HeLa cells. AB - A heteromeric proliferating cell nuclear antigen-like ring complex 9-1-1 is comprised of Rad9, Hus1 and Rad1. When assembled, 9-1-1 binds to TopBP1 and activates the ATR-Chk1 checkpoint pathway. This binding in vitro depends on the phosphorylation of Ser-341 and Ser-387 in Rad9 and is reduced to 70% and 20% by an alanine substitution for Ser-341 (S341A) and Ser-387 (S387A), respectively, and to background level by their simultaneous substitution (2A). Here, we show the importance of phosphorylation of these two serine residues in vivo. siRNA mediated knockdown of Rad9 in HeLa cells impaired UV-induced phosphorylation of checkpoint kinase, Chk1, and conferred hypersensitivity to UV irradiation and to methyl methane sulfonate or hydroxyurea treatments. Either siRNA-resistant wild type Rad9 (Rad9R(r)) or Rad9R(r) harboring the S341A substitution restored the phosphorylation of Chk1 and damage sensitivity, whereas Rad9R(r) harboring S387A or 2A did not. However, high expression of S387A restored Chk1 phosphorylation and partially suppressed the hypersensitivity. Thus, the affinity of Rad9 to TopBP1 correlates with the activation of the cellular DNA damage response and survival after DNA damage in HeLa cells, and phosphorylation of Ser-341 and Ser 387 of Rad9 is critical for full activation of the checkpoint response to DNA damage. PMID- 22925455 TI - CLE peptides in plants: proteolytic processing, structure-activity relationship, and ligand-receptor interaction. AB - Ligand-receptor signaling initiated by the CLAVATA3/ ENDOSPERM SURROUNDING REGION (CLE) family peptides is critical in regulating cell division and differentiation in meristematic tissues in plants. Biologically active CLE peptides are released from precursor proteins via proteolytic processing. The mature form of CLE ligands consists of 12-13 amino acids with several post-translational modifications. This review summarizes recent progress toward understanding the proteolytic activities that cleave precursor proteins to release CLE peptides, the molecular structure and function of mature CLE ligands, and interactions between CLE ligands and corresponding leucine-rich repeat (LRR) receptor-like kinases (RLKs). PMID- 22925456 TI - Clinical breakpoint changes and their impact on surveillance of antimicrobial resistance in Escherichia coli causing bacteraemia. AB - Dutch laboratories are currently changing their breakpoint criteria from mostly Clinical Laboratory and Standards Institute (CLSI) breakpoints to European Committee on Antimicrobial Susceptibility Testing (EUCAST) breakpoints. To evaluate the impact of these changes, we studied antimicrobial resistance trends of Escherichia coli in blood specimens from January 2008 to January 2012 using CLSI and EUCAST breakpoints and compared them with the antimicrobial susceptibility test (AST) interpretations reported by Dutch laboratories participating in the Infectious Disease Surveillance Information System for Antibiotic Resistance (ISIS-AR). ISIS-AR collects AST interpretations, including underlying minimal inhibitory concentrations (MICs) of routinely cultured bacterial species on a monthly basis from Dutch laboratories. MICs of Etests or automated systems were reinterpreted according to the CLSI 2009 and EUCAST 2010 guidelines. Trends in non-susceptibility (i.e. intermediate resistant and resistant) over time were analysed by the Cochran-Armitage test for trend. The effects of the change from CLSI to EUCAST breakpoints on non-susceptibility were small. There were no differences in non-susceptibility to amoxicillin, amoxicillin/clavulanic acid, cefuroxim, gentamicin and co-trimoxazol and only small differences (1-1.5%) for ciprofloxacin between AST interpretations by CLSI or EUCAST. However, for ceftazidime, and cefotaxime/ceftriaxone the proportion of non-susceptibility was substantially higher when EUCAST breakpoints were used (2 3%). The effects on time trends of the change in guidelines were limited, with only substantial differences for the oxymino-cephalosporins. Our study shows that the implementation of EUCAST breakpoints has a limited effect on the proportion of non-susceptible isolates and time trends in E. coli for most, but not all, antimicrobial agents. PMID- 22925457 TI - Defining mild, moderate, and severe pain in persons with multiple sclerosis. AB - OBJECTIVE: To identify empirically derived cutoffs for mild, moderate, and severe pain in persons with multiple sclerosis (MS). Design. Cross-sectional survey. SETTING: . Community-based survey. PARTICIPANTS: Convenience sample of 236 individuals with MS and pain. Intervention. Not applicable. MAIN OUTCOME MEASURES: Zero to 10 Numeric Rating Scale for pain severity (both average and worst pain) and Brief Pain Inventory for pain interference. RESULTS: The optimal classification scheme for average pain was 0-2 = mild, 3-5 = moderate, and 6-10 = severe. Alternatively, the optimal classification scheme for worst pain was 0-4 = mild, 5-7 = moderate, and 8-10 = severe. CONCLUSIONS: The present study furthers our ability to use empirically based cutoffs to inform the use of clinical guidelines for pain treatment as well as our understanding of the factors that might impact the cutoffs that are most appropriate for specific pain populations. The results of the present study also add to the existing literature by drawing similarities to studies of other populations, but also by highlighting that clear, between-condition differences may exist that warrant using different cutoffs for patients with different medical conditions. Specifically, the present study highlights that cutoffs may be lower for persons with MS than other populations of persons with pain. PMID- 22925459 TI - Abstracts of the Australasian Society of Clinical Immunology and Allergy (ASCIA) 23rd Annual Scientific Meeting. September 5-8, 2012. Wellington, New Zealand. PMID- 22925458 TI - Cross-cultural adaptation and validation of a Bengali version of the modified fibromyalgia impact questionnaire. AB - BACKGROUND: Currently, no validated instruments are available to measure the health status of Bangladeshi patients with fibromyalgia (FM). The aims of this study were to cross-culturally adapt the modified Fibromyalgia Impact Questionnaire (FIQ) into Bengali (B-FIQ) and to test its validity and reliability in Bangladeshi patients with FM. METHODS: The FIQ was translated following cross cultural adaptation guidelines and pretested in 30 female patients with FM. Next, the adapted B-FIQ was physician-administered to 102 consecutive female FM patients together with the Health Assessment Questionnaire (HAQ), selected subscales of the SF-36, and visual analog scales for current clinical symptoms. A tender point count (TPC) was performed by an experienced rheumatologist. Forty randomly selected patients completed the B-FIQ again after 7 days. Two control groups of 50 healthy people and 50 rheumatoid arthritis (RA) patients also completed the B-FIQ. RESULTS: For the final B-FIQ, five physical function sub items were replaced with culturally appropriate equivalents. Internal consistency was adequate for both the 11-item physical function subscale (alpha = 0.73) and the total scale (alpha = 0.83). With exception of the physical function subscale, expected correlations were generally observed between the B-FIQ items and selected subscales of the SF-36, HAQ, clinical symptoms, and TPC. The B-FIQ was able to discriminate between FM patients and healthy controls and between FM patients and RA patients. Test-retest reliability was adequate for the physical function subscale (r = 0.86) and individual items (r = 0.73-0.86), except anxiety (r = 0.27) and morning tiredness (r = 0.64). CONCLUSION: This study supports the reliability and validity of the B-FIQ as a measure of functional disability and health status in Bangladeshi women with FM. PMID- 22925460 TI - Ordovician ash geochemistry and the establishment of land plants. AB - The colonization of the terrestrial environment by land plants transformed the planetary surface and its biota, and shifted the balance of Earth's biomass from the subsurface towards the surface. However there was a long delay between the formation of palaeosols (soils) on the land surface and the key stage of plant colonization. The record of palaeosols, and their colonization by fungi and lichens extends well back into the Precambrian. While these early soils provided a potential substrate, they were generally leached of nutrients as part of the weathering process. In contrast, volcanic ash falls provide a geochemically favourable substrate that is both nutrient-rich and has high water retention, making them good hosts to land plants. An anomalously extensive system of volcanic arcs generated unprecedented volumes of lava and volcanic ash (tuff) during the Ordovician. The earliest, mid-Ordovician, records of plant spores coincide with these widespread volcanic deposits, suggesting the possibility of a genetic relationship. The ash constituted a global environment of nutrient-laden, water-saturated soil that could be exploited to maximum advantage by the evolving anchoring systems of land plants. The rapid and pervasive inoculation of modern volcanic ash by plant spores, and symbiotic nitrogen-fixing fungi, suggests that the Ordovician ash must have received a substantial load of the earliest spores and their chemistry favoured plant development. In particular, high phosphorus levels in ash were favourable to plant growth. This may have allowed photosynthesizers to diversify and enlarge, and transform the surface of the planet. PMID- 22925461 TI - Tunica albuginea underlap--a new modification of the Nesbit procedure: description of the technique and preliminary results. AB - INTRODUCTION: We describe a new surgical technique for the treatment of penile curvature that combines features of the Nesbit procedure with features of tunical plication. U-shaped flaps of tunica albuginea are freed from the corpus cavernosum. The flaps are brought under the remaining tunica albuginea and are fixated with single absorbable sutures. As the defects of the tunica are sealed tightly and with high tensile strength by double layers of tunica albuginea, correction of the abnormal curvature is achieved. AIM: To present our experience with a new surgical technique for the treatment of penile curvature. METHODS: Between 2008 and 2011, 50 patients underwent the underlap technique because of Peyronie's disease (37) or congenital penile deviation (13) in a single center. MAIN OUTCOME MEASURES: Preoperative and postoperative evaluation included the Erection Hardness Score (EHS) and the Symptom Score for Induratio penis plastica (IPP-SSC), a symptom score for penile deviation that was based on a consensus of regional andrologists. Clinical data concerning the early postoperative outcome were analyzed retrospectively using standardized items. RESULTS: Mean age +/- standard deviation was 59.7 +/- 8.4 years for patients with Peyronie's disease and 34.1 +/- 7.8 years for patients with congenital penile deviation. The mean follow-up period was 27 months. The major complication rate was 4%, overall satisfaction 86%. Intraoperative correction of the curvature was achieved in 100%, significant relapse occurred in 6%. The mean difference of preoperative and postoperative IPP-SSC was 8.1 (95% confidence interval [CI] 7.24 to 8.96). The mean difference of preoperative and postoperative EHC was -0.03 (95% CI -0.16 to 0.09). CONCLUSIONS: Preliminary results obtained with the underlap technique showed promising outcome with minimal morbidity. The new technique might have three main advantages: more flexible intraoperative correctability of the curvature, tighter sealing of the tunical defects, and greater tensile strength of the plications. PMID- 22925462 TI - Composition of the type VII secretion system membrane complex. AB - Pathogenic mycobacteria require type VII secretion (T7S) systems to transport virulence factors across their complex cell envelope. These bacteria have up to five of these systems, termed ESX-1 to ESX-5. Here, we show that ESX-5 of Mycobacterium tuberculosis mediates the secretion of EsxN, PPE and PE_PGRS proteins, indicating that ESX-5 is a major secretion pathway in this important pathogen. Using the ESX-5 system of Mycobacterium marinum and Mycobacterium bovis BCG as a model, we have purified and analysed the T7S membrane complex under native conditions. blue native-PAGE and immunoprecipitation experiments showed that the ESX-5 membrane complex of both species has a size of ~ 1500 kDa and is composed of four conserved membrane proteins, i.e. EccB(5) , EccC(5) , EccD(5) and EccE(5) . Subsequent limited proteolysis suggests that EccC(5) and EccE(5) mostly reside on the periphery of the complex. We also observed that EccC(5) and EccD(5) expression is essential for the formation of a stable membrane complex. These are the first data on a T7S membrane complex and, given the high conservation of its components, our data can likely be generalized to most mycobacterial T7S systems. PMID- 22925463 TI - The gap between clinical gaze and systematic assessment of movement disorders after stroke. AB - BACKGROUND: Movement disorders after stroke are still captured by clinical gaze and translated to ordinal scores of low resolution. There is a clear need for objective quantification, with outcome measures related to pathophysiological background. Neural and non-neural contributors to joint behavior should be separated using different measurement conditions (tasks) and standardized input signals (force, position and velocity). METHODS: We reviewed recent literature for the application of biomechanical and/or elektromyographical (EMG) outcome measures under various measurement conditions in clinical research. RESULTS: Since 2005, 36 articles described the use of biomechanical and/or EMG outcome measures to quantify post-stroke movement disorder. Nineteen of the articles strived to separate neural and non-neural components. Only 6 of the articles measured biomechanical and EMG outcome measures simultaneously, while applying active and passive tasks and multiple velocities. CONCLUSION: The distinction between neural and non-neural components to separately assess paresis, stiffness and muscle overactivity is not commonplace yet, while a large gap is to be bridged to attain reproducible and comparable results. Pathophysiologically clear concepts, substantiated with a comprehensive and concise measuring protocol will help professionals to identify and treat limiting factors in movement capabilities of post-stroke patients. PMID- 22925464 TI - Blood microRNA changes in depressed patients during antidepressant treatment. AB - MicroRNAs (miRNAs) are potent modulators of protein expression that play key roles in brain pathways regulating neurogenesis and synaptic plasticity. These small RNAs may be critical for the pathophysiology of mental disorders and may influence the effectiveness of psychotropic drugs. To investigate the possible involvement of miRNAs in the mechanism of action of antidepressants (AD), we conducted a whole-miRNome quantitative analysis with qRT-PCR of the changes in the blood of 10 depressed subjects after 12 weeks of treatment with escitalopram. Thirty miRNAs were differentially expressed after the AD treatment: 28 miRNAs were up-regulated, and 2 miRNAs were strongly down-regulated. miRNA target gene prediction and functional annotation analysis showed that there was a significant enrichment in several pathways associated with neuronal brain function (such as neuroactive ligand-receptor interaction, axon guidance, long-term potentiation and depression), supporting the hypothesis that the differentially regulated miRNAs may be involved in the AD mechanism. PMID- 22925465 TI - Induced pluripotent stem cell technology for disease modeling and drug screening with emphasis on lysosomal storage diseases. AB - The recent derivation of disease-specific induced pluripotent stem cells (iPSCs) from somatic cells of patients with familial and sporadic forms of diseases and the demonstration of their ability to give rise to disease-relevant cell types provide an excellent opportunity to gain further insights into the mechanisms responsible for the pathophysiology of these diseases and develop novel therapeutic drugs. Here, we review the recent advances in iPSC technology for modeling of various lysosomal storage diseases (LSDs) and discuss possible strategies through which LSD-iPSCs can be exploited to identify novel drugs and improve future clinical treatment of LSDs. PMID- 22925466 TI - Assessment of nostril symmetry after primary cleft rhinoplasty in patients with complete unilateral cleft lip and palate. AB - The aim of this study was to assess the nostril symmetry following primary cleft rhinoplasty done with either a dorsal onlay or columellar strut graft in patients with non-syndromic complete unilateral cleft lip and palate. In this retrospective study 30 consecutive patients treated with autogenous or alloplastic dorsal onlay grafts and 30 consecutive patients treated with autogenous or alloplastic columellar strut grafts for complete unilateral cleft nose reconstruction were analyzed for nasal symmetry. The autogenous grafts used were costo-chondral or septal cartilage and the alloplastic graft used was high density polyethylene (Medpore((r))). Assessment of the nostril symmetry was done using a two-dimensional nasal analysis 24-30 months postoperatively. Ratios between cleft and noncleft side nostril for three parameters were used to assess symmetry namely nostril width, nostril height and nostril gap area. None of the three parameters showed statistically significant changes. A satisfactory, though not statistically significant, difference in symmetrical outcome could be achieved in both the groups with the exception of nostril width symmetry in group treated with dorsal onlay graft. PMID- 22925467 TI - Quantitative capabilities of four state-of-the-art SPECT-CT cameras. AB - BACKGROUND: Four state-of-the-art single-photon emission computed tomography computed tomography (SPECT-CT) systems, namely Philips Brightview, General Electric Discovery NM/CT 670 and Infinia Hawkeye 4, and Siemens Symbia T6, were investigated in terms of accuracy of attenuation and scatter correction, contrast recovery for small hot and cold structures, and quantitative capabilities when using their dedicated three-dimensional iterative reconstruction with attenuation and scatter corrections and resolution recovery. METHODS: The National Electrical Manufacturers Association (NEMA) NU-2 1994 phantom with cold air, water, and Teflon inserts, and a homemade contrast phantom with hot and cold rods were filled with 99mTc and scanned. The acquisition parameters were chosen to provide adequate linear and angular sampling and high count statistics. The data were reconstructed using Philips Astonish, General Electric Evolution for Bone, or Siemens Flash3D, eight subsets, and a varying number of iterations. A procedure similar to the one used in positron emission tomography (PET) allowed us to obtain the factor to convert counts per pixel into activity per unit volume. RESULTS: Edge and oscillation artifacts were observed with all phantoms and all systems. At 30 iterations, the residual fraction in the inserts of the NEMA phantom fell below 3.5%. Contrast recovery increased with the number of iterations but became almost saturated at 24 iterations onwards. In the uniform part of the NEMA and contrast phantoms, a quantification error below 10% was achieved. CONCLUSIONS: In objects whose dimensions exceeded the SPECT spatial resolution by several times, quantification seemed to be feasible within 10% error limits. A partial volume effect correction strategy remains necessary for the smallest structures. The reconstruction artifacts nevertheless remain a handicap on the road towards accurate quantification in SPECT and should be the focus of further works in reconstruction tomography. PMID- 22925468 TI - Bilateral, multicenteric metanephric adenoma associated with Wilms' tumor in a child: a rare presentation with important diagnostic and therapeutic implications. AB - Metanephric adenoma is an uncommon benign renal tumor that occurs predominantly in adult females and rarely in children. On histomorphology it shows a resemblance to Wilms' tumor, nephrogenic rests and papillary renal cell carcinoma. Multifocality along with multicentricity has not been documented in English literature till date. From a diagnostic and therapeutic viewpoint, recognition of this entity is of the utmost importance, because it shows a favorable clinical outcome. We describe a rare case of bilateral, multicentric metanephric adenoma associated with triphasic Wilms' tumor (stage II) of the left kidney in a male child. PMID- 22925469 TI - A systematic review of risk factors during first year of life for early childhood caries. AB - BACKGROUND: Early childhood caries (ECC) describes dental caries affecting children aged 0-71 months. Current research suggests ECC has important aetiological bases during the first year of life. Gaps in knowledge about disease progression prevent the effective and early identification of 'at risk' children. AIM: To conduct a systematic review of research studies focusing on (a) acquisition and colonization of oral bacteria and ECC and (b) risk and/or protective factors in infants aged 0-12 months. DESIGN: Ovid Medline and Embase databases (1996-2011) were searched for RCT, longitudinal, cross-sectional and qualitative studies. Two investigators undertook a quality assessment for risk of bias. RESULTS: Inclusion criteria were met for (a) by four papers and for (b) by 13 papers; five papers were rated medium or high quality. Bacterial acquisition/colonization and modifying factor interrelationships were identified, but their role in the caries process was not clarified. Key risk indicators were infant feeding practices (nine papers), maternal circumstances and oral health (6) and infant-related oral health behaviours (4). CONCLUSION: This review confirmed that factors occurring during the first year of life affect ECC experience. Despite heterogeneity, findings indicated maternal factors influence bacterial acquisition, whereas colonization was mediated by oral health behaviours and practices and feeding habits. PMID- 22925470 TI - Avoiding early dialysis for severe fluid retention in heart failure. PMID- 22925471 TI - Fetal growth restriction and reversed middle cerebral artery end-diastolic flow with subchorionic placental lake. AB - Fetal growth restriction (FGR) is frequently associated with uteroplacental insufficiency. Placental lakes are avillous spaces filled with maternal venous blood that usually do not compromise the pregnancy outcome; however, a few reports describe FGR in association with placental lakes. Reversed middle cerebral artery (MCA) end-diastolic flow is a rare event and a potential indicator of poor fetal outcome due to placental insufficiency. We report a case of severe FGR associated with a huge subchorionic placental lake concomitant with reversed MCA end-diastolic flow. We also conducted a literature review. PMID- 22925472 TI - Epidemiology of malaria in the Papua New Guinean highlands. AB - OBJECTIVES: To conduct an in-depth investigation of the epidemiology of malaria in the Papua New Guinea (PNG) highlands and provide a basis for evidence-based planning and monitoring of intensified malaria control activities. METHODS: Between December 2000 and July 2005, 153 household-based, rapid malaria population surveys were conducted in 112 villages throughout the central PNG highlands. The presence of malaria infections was determined by light microscopy and risk factors assessed using a structured questionnaire.The combined dataset from all individually published surveys was reanalysed. RESULTS: The prevalence of malaria infections in the different surveys ranged from 0.0% to 41.8%(median 4.3%) in non-epidemic surveys and 6.6% to 63.2% (median 21.2%, P < 0.001) during epidemics. Plasmodium falciparum was the predominant infection below 1400 m and during epidemics, Plasmodium vivax at altitudes >1600 m. Outside epidemics, prevalence decreased significantly with altitude, was reduced in people using bed nets [odds ratio (OR) = 0.8, P < 0.001] but increased in those sleeping in garden houses (OR = 1.34, P < 0.001) and travelling to highly endemic lowlands (OR = 1.80, P < 0.001). Below 1400 m, malaria was a significant source of febrile illness. At higher altitudes, malaria was only a significant source of febrile illness during epidemic outbreaks, but asymptomatic malaria infections were common in non-epidemic times. CONCLUSIONS: Malaria is once again endemic throughout the PNG highlands in areas below 1400-1500 m of altitude with a significant risk of seasonal malaria outbreaks in most area between 1400-1650 m. Ongoing control efforts are likely to result in a substantial reduction in malaria transmission and may even result in local elimination of malaria in higher lying areas. PMID- 22925473 TI - The polymicrobial nature of biofilm infection. AB - The model of biofilm infection was first proposed over a decade ago. Recent scientific advances have added much to our understanding of biofilms, usually polymicrobial communities, which are commonly associated with chronic infection. Metagenomics has demonstrated that bacteria pursuing a biofilm strategy possess many mechanisms for encouraging diversity. By including multiple bacterial and/or fungal species in a single community, biofilms obtain numerous advantages, such as passive resistance, metabolic cooperation, byproduct influence, quorum sensing systems, an enlarged gene pool with more efficient DNA sharing, and many other synergies, which give them a competitive advantage. Routine clinical cultures are ill-suited for evaluating polymicrobial infections. DNA methods utilizing PCR methods, PCR/mass spectroscopy and sequencing have demonstrated their ability to identify microorganisms and quantitate their contribution to biofilms in clinical infections. A more robust model of biofilm infection along with more accurate diagnosis is rapidly translating into improved clinical outcomes. PMID- 22925476 TI - Misoprostol as a therapeutic option for trigeminal neuralgia in patients with multiple sclerosis. PMID- 22925477 TI - COMAP: a new computational interpretation of human movement planning level based on coordinated minimum angle jerk policies and six universal movement elements. AB - Flash and Hogan (1985) suggested that the CNS employs a minimum jerk strategy when planning any given movement. Later, Nakano et al. (1999) showed that minimum angle jerk predicts the actual arm trajectory curvature better than the minimum jerk model. Friedman and Flash (2009) confirmed this claim. Besides the behavioral support that we will discuss, we will show that this model allows simplicity in planning any given movement. In particular, we prove mathematically that each movement that satisfies the minimum joint angle jerk condition is reproducible by a linear combination of six functions. These functions are calculated independent of the type of the movement and are normalized in the time domain. Hence, we call these six universal functions the Movement Elements (ME). We also show that the kinematic information at the beginning and end of the movement determines the coefficients of the linear combination. On the other hand, in analyzing recorded data from sit-to-stand (STS) transfer, arm-reaching movement (ARM) and gait, we observed that minimum joint angle jerk condition is satisfied only during different successive phases of these movements and not for the entire movement. Driven by these observations, we assumed that any given ballistic movement may be decomposed into several successive phases without overlap, such that for each phase the minimum joint angle jerk condition is satisfied. At the boundaries of each phase the angular acceleration of each joint should obtain its extremum (zero third derivative). As a consequence, joint angles at each phase will be linear combinations of the introduced MEs. Coefficients of the linear combination at each phase are the values of the joint kinematics at the boundaries of that phase. Finally, we conclude that these observations may constitute the basis of a computational interpretation, put differently, of the strategy used by the Central Nervous System (CNS) for motor planning. We call this possible interpretation "Coordinated Minimum Angle jerk Policy" or COMAP. Based on this policy, the function of the CNS in generating the desired pattern of any given task (like STS, ARM or gait) can be described computationally using three factors: (1) the kinematics of the motor system at given body states, i.e., at certain movement events/instances, (2) the time length of each phase, and (3) the proposed MEs. From a computational point of view, this model significantly simplifies the processes of movement planning as well as feature abstraction for saving characterizing information of any given movement in memory. PMID- 22925479 TI - Abstracts of the 42nd Annual Scientific Meeting of the Australian and New Zealand Society of Nuclear Medicine (ANZSNM). April 28-30, 2012. Melbourne, Victoria, Australia. PMID- 22925478 TI - Phloem-mobile Aux/IAA transcripts target to the root tip and modify root architecture. AB - In plants, the phloem is the component of the vascular system that delivers nutrients and transmits signals from mature leaves to developing sink tissues. Recent studies have identified proteins, mRNA, and small RNA within the phloem sap of several plant species. It is now of considerable interest to elucidate the biological functions of these potential long-distance signal agents, to further our understanding of how plants coordinate their developmental programs at the whole-plant level. In this study, we developed a strategy for the functional analysis of phloem-mobile mRNA by focusing on IAA transcripts, whose mobility has previously been reported in melon (Cucumis melo cv. Hale's Best Jumbo). Indoleacetic acid (IAA) proteins are key transcriptional regulators of auxin signaling, and are involved in a broad range of developmental processes including root development. We used a combination of vasculature-enriched sampling and hetero-grafting techniques to identify IAA18 and IAA28 as phloem-mobile transcripts in the model plant Arabidopsis thaliana. Micro-grafting experiments were used to confirm that these IAA transcripts, which are generated in vascular tissues of mature leaves, are then transported into the root system where they negatively regulate lateral root formation. Based on these findings, we present a model in which auxin distribution, in combination with phloem-mobile Aux/IAA transcripts, can determine the sites of auxin action. PMID- 22925480 TI - Rheumatoid arthritis and the incidence of influenza and influenza-related complications: a retrospective cohort study. AB - BACKGROUND: Patients with rheumatoid arthritis (RA) are known to be at increased risk of infection, particularly if they are taking drugs with immunomodulatory effects. There is a need for more information on the risk of influenza in patients with RA. METHODS: A retrospective cohort study was carried out using data gathered from a large US commercial health insurance database (Thomson Reuters Medstat MarketScan) from 1 January 2000 to 31 December 2007. Patients were >=18 years of age, with at least two RA claims diagnoses. The database was scanned for incidence of seasonal influenza and its complications on or up to 30 days after an influenza diagnosis in RA patients and matched controls. Other factors accounted for included medical conditions, use of disease-modifying anti rheumatic drugs (DMARDs), use of biological agents, influenza vaccination and high- or low-dose corticosteroids. Incidence rate ratios (IRRs) were calculated for influenza and its complications in patients with RA. RESULTS: 46,030 patients with RA and a matching number of controls had a median age of 57 years. The incidence of influenza was higher in RA patients than in controls (409.33 vs 306.12 cases per 100,000 patient-years), and there was a 2.75-fold increase in incidence of complications in RA. Presence or absence of DMARDs or biologics had no significant effect. The adjusted IRR of influenza was statistically significant in patients aged 60-69 years, and especially among men. A significantly increased rate of influenza complications was observed in women and in both genders combined (but not in men only) when all age groups were combined. In general, the risk of influenza complications was similar in RA patients not receiving DMARDs or biologics to that in all RA patients. Pneumonia rates were significantly higher in women with RA. Rates of stroke/myocardial infarction (MI) were higher in men, although statistical significance was borderline. CONCLUSIONS: RA is associated with increased incidence of seasonal influenza and its complications. Gender- and age-specific subgroup data indicate that women generally have a greater rate of complications than men, but that men primarily have an increased rate of stroke and MI complications. Concomitant DMARD or biological use appears not to significantly affect the rate of influenza or its complications. PMID- 22925481 TI - Anorectic and bulimic patients suffer from relevant sexual dysfunctions. AB - INTRODUCTION: Sexual life is often impaired in anorexia nervosa (AN) and bulimia nervosa (BN), and few studies have evaluated the possible relationships between body image concerns, eating disorder psychopathology, and sexual functioning in these syndromes. AIM: To evaluate sexual functioning in AN patients, BN patients, and healthy controls, and to define the predictors of sexual dysfunction in the AN and BN groups. METHODS: Eighty-eight eating disorders patients (44 AN, 44 BN) referring to the Outpatient Clinic for Eating Disorders of the University of Florence, and 72 healthy females were evaluated. MAIN OUTCOME MEASURES: The subjects were studied by means of the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders IV, the Female Sexual Function Index (FSFI), the Eating Disorder Examination Questionnaire, the Emotional Eating Scale, the Beck Depression Inventory, the Spielberg's State Trait Anxiety Inventory, the Barratt Impulsiveness Scale, and the Symptom Checklist 90. RESULTS: AN restricting/type patients had lower FSFI total scores (median; quartiles: 4.8; 2.1-15.4), compared with AN binge/purging type (28.3; 20.6-30.7) and BN patients (20.1; 3.8-30.3). Multiple linear regression analysis showed that shape concern was associated with sexual dysfunction in AN restricting type patients (beta=-0.61, P<0.01), whereas emotional eating (beta= 0.42, P<0.01), and subjective binge eating (beta=-0.55, P<0.01) were significantly associated with FSFI scores in AN binge/purging type and BN patients. CONCLUSIONS: Considering the sample size, the present results must be considered as preliminary. Sexual dysfunction was found to be a relevant concern in both AN and BN patients and was associated with different pathological eating behaviors. Sexual functioning should be carefully investigated in eating disorders patients, and treatments focused on shape concern, emotional eating, and binge eating could improve the sexual life of AN and BN patients. PMID- 22925482 TI - Small interfering RNA-producing loci in the ancient parasitic eukaryote Trypanosoma brucei. AB - BACKGROUND: At the core of the RNA interference (RNAi) pathway in Trypanosoma brucei is a single Argonaute protein, TbAGO1, with an established role in controlling retroposon and repeat transcripts. Recent evidence from higher eukaryotes suggests that a variety of genomic sequences with the potential to produce double-stranded RNA are sources for small interfering RNAs (siRNAs). RESULTS: To test whether such endogenous siRNAs are present in T. brucei and to probe the individual role of the two Dicer-like enzymes, we affinity purified TbAGO1 from wild-type procyclic trypanosomes, as well as from cells deficient in the cytoplasmic (TbDCL1) or nuclear (TbDCL2) Dicer, and subjected the bound RNAs to Illumina high-throughput sequencing. In wild-type cells the majority of reads originated from two classes of retroposons. We also considerably expanded the repertoire of trypanosome siRNAs to encompass a family of 147-bp satellite-like repeats, many of the regions where RNA polymerase II transcription converges, large inverted repeats and two pseudogenes. Production of these newly described siRNAs is strictly dependent on the nuclear DCL2. Notably, our data indicate that putative centromeric regions, excluding the CIR147 repeats, are not a significant source for endogenous siRNAs. CONCLUSIONS: Our data suggest that endogenous RNAi targets may be as evolutionarily old as the mechanism itself. PMID- 22925483 TI - A review of environmental fate, body burdens, and human health risk assessment of PCDD/Fs at two typical electronic waste recycling sites in China. AB - This paper reviews the levels of polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs) in different environmental media, human body burdens and health risk assessment results at e-waste recycling sites in China. To provide an indication of the seriousness of the pollution levels in the e-waste recycling sites in China, the data are compared with guidelines and available existing data for other areas. The comparison clearly shows that PCDD/Fs derived from the recycling processes lead to serious pollution in different environmental compartments (such as air, soil, sediment, dust and biota) and heavy body burdens. Of all kinds of e-waste recycling operations, open burning of e-waste and acid leaching activities are identified as the major sources of PCDD/Fs. Deriving from the published data, the estimated total exposure doses via dietary intake, inhalation, soil/dust ingestion and dermal contact are calculated for adults, children and breast-fed infants living in two major e-waste processing locations in China. The values ranged from 5.59 to 105.16 pg WHO-TEQ/kg bw/day, exceeding the tolerable daily intakes recommended by the WHO (1-4 pg WHO-TEQ/kg bw/day). Dietary intake is the most important exposure route for infants, children and adults living in these sites, contributing 60-99% of the total intakes. Inhalation is the second major exposure route, accounted for 12-30% of the total exposure doses of children and adults. In order to protect the environment and human health, there is an urgent need to control and monitor the informal e-waste recycling operations. Knowledge gaps, such as comprehensive dietary exposure data, epidemiological and clinical studies, body burdens of infants and children, and kinetics about PCDD/Fs partitions among different human tissues should be addressed. PMID- 22925484 TI - Sensitivity analysis of ecosystem service valuation in a Mediterranean watershed. AB - The services of natural ecosystems are clearly very important to our societies. In the last years, efforts to conserve and value ecosystem services have been fomented. By way of illustration, the Natural Capital Project integrates ecosystem services into everyday decision making around the world. This project has developed InVEST (a system for Integrated Valuation of Ecosystem Services and Tradeoffs). The InVEST model is a spatially integrated modelling tool that allows us to predict changes in ecosystem services, biodiversity conservation and commodity production levels. Here, InVEST model is applied to a stakeholder defined scenario of land-use/land-cover change in a Mediterranean region basin (the Llobregat basin, Catalonia, Spain). Of all InVEST modules and sub-modules, only the behaviour of the water provisioning one is investigated in this article. The main novel aspect of this work is the sensitivity analysis (SA) carried out to the InVEST model in order to determine the variability of the model response when the values of three of its main coefficients: Z (seasonal precipitation distribution), prec (annual precipitation) and eto (annual evapotranspiration), change. The SA technique used here is a One-At-a-Time (OAT) screening method known as Morris method, applied over each one of the one hundred and fifty four sub-watersheds in which the Llobregat River basin is divided. As a result, this method provides three sensitivity indices for each one of the sub-watersheds under consideration, which are mapped to study how they are spatially distributed. From their analysis, the study shows that, in the case under consideration and between the limits considered for each factor, the effect of the Z coefficient on the model response is negligible, while the other two need to be accurately determined in order to obtain precise output variables. The results of this study will be applicable to the others watersheds assessed in the Consolider Scarce Project. PMID- 22925486 TI - [Esophageal toxicity of radiation therapy: clinical risk factors and management]. AB - Acute radiation-induced esophagitis includes all clinical symptoms (odynophagia, dysphagia) occurring within 90 days after thoracic irradiation start. Its severity can be graded using RTOG and CTCAE scales. The clinical risk factors are: age, female gender, initial performance status, pre-therapeutic body mass index, pre-therapeutic dysphagia, tumoral and nodal stage, delivered dose, accelerated hyperfractionned radiotherapy, concomitant association of chemotherapy to radiotherapy and response to the treatment. The dosimetric parameters predictive of esophagitis are: mean dose, V(20Gy), V(30Gy), V(40Gy), V(45Gy) and V(50Gy). Amifostine is the only drug to have a proven radioprotective efficacy (evidence level C, ESMO recommendation grade III). The medical management of esophagitis associates a diet excluding irritant food, medication against gastroesophageal reflux, analgesic treatment according to the WHO scale and management of dehydration and denutrition by enteral feeding. PMID- 22925485 TI - Isolation and mutation trend analysis of influenza A virus subtype H9N2 in Egypt. AB - BACKGROUND: Avian influenza virus H9N2 is a panzootic pathogen that affects poultry causing mild to moderate respiratory distress but has been associated with high morbidity and considerable mortality. Interspecies transmission of H9N2 from avian species to mammalian hosts does occur. The virus possesses human virus like receptor specificity and it can infect humans producing flu-like illness. METHODS: Recently, mild influenza like symptoms were detected in H5N1 vaccinated flocks. Influenza A subtype H9N2 was isolated from the infected flock. The virus evolution was investigated by sequencing the viral genes to screen the possible virus recombination. The viral amino acid sequences from the isolated H9N2 strains were compared to other related sequences from the flu data base that were used to assess the robustness of the mutation trend. Changes in the species associated amino acid residues or those that enabled virulence to mammals were allocated. RESULTS: Phylogenetic analyses of haemagglutinin and neuraminidase genes showed that the recently isolated Egyptian strain belonged to the H9N2 sub lineage that prevails in Israel. The six internal segments of the isolated virus were found to be derived from the same sub-lineage with no new evidence of reassortment. The results demonstrated conserved genetic and biological constitution of H9N2 viruses in the Middle East. The recently isolated H9N2 virus from chicken in Egypt possessed amino acids that could enable the virus to replicate in mammals and caused severe disease in domestic chickens. CONCLUSION: The study highlights the importance of continuous monitoring of the mutations evolved in avian influenza viruses and its impact on virulence to avian species in addition to its importance in the emergence of new strains with the capacity to be a pandemic candidate. PMID- 22925487 TI - [Intensity modulated radiotherapy for breast cancer]. AB - Intensity modulated radiotherapy (IMRT) is a technique allowing dose escalation and normal tissue sparing for various cancer types. For breast cancer, the main goals when using IMRT were to improve dose homogeneity within the breast and to enhance coverage of complex target volumes. Nonetheless, better heart and lung protections are achievable with IMRT as compared to standard irradiation for difficult cases. Three prospective randomized controlled trials of IMRT versus standard treatment showed that a better breast homogeneity can translate into better overall cosmetic results. Dosimetric and clinical studies seem to indicate a benefit of IMRT for lymph nodes irradiation, bilateral treatment, left breast and chest wall radiotherapy, or accelerated partial breast irradiation. The multiple technical IMRT solutions available tend to indicate a widespread use for breast irradiation. Nevertheless, indications for breast IMRT should be personalized and selected according to the expected benefit for each individual. PMID- 22925488 TI - [Organs at risk and target volumes: definition for conformal radiation therapy in breast cancer]. AB - Adjuvant radiotherapy is a standard component of breast cancer treatment. The addition of radiotherapy after breast conserving surgery has been shown to reduce local recurrence rate and improve long-term survival. Accurate delineation of target volumes and organs at risk is crucial to the quality of treatment planning and delivered accomplished with innovate technologies in radiation therapy. This allows the radiation beam to be shaped specifically to each individual patient's anatomy. Target volumes include the mammary gland and surgical bed in case of breast conserving surgery, the chest wall in case of mastectomy, and if indicated, regional lymph nodes (axillary, supra- and infraclavicular and internal mammary). Organs at risk include lungs, thyroid, brachial plexus, heart, spinal cord and oesophagus. The aim of this article is to encourage the use of conformal treatment and delineation of target volumes and organs at risk and to describe specifically the definition of these volumes. PMID- 22925489 TI - [Radiotherapy for breast cancer: which strategy in 2012?]. AB - Postoperative radiotherapy remains essential in breast cancer in 2012. After conserving surgery, it reduces local recurrence risks from 50 to 70%, both for ductal carcinoma in situ and invasive cancers. This was confirmed in several randomized trials and three meta-analyses. The boost increases local control in invasive cancers, but its role should be better defined in ductal carcinoma in situ. Among the latter, there is no clearly identified subgroup for which radiotherapy could be avoided. Local recurrence risk factors are now well identified both for ductal carcinoma in situ and invasive cancers, with an inclusion, for the latter, of new molecular subgroups. After mastectomy, radiotherapy reduces local recurrence rates from 60 to 70%, especially among patients with axillary nodal involvement, with, in parallel, a 7 to 9% increased survival rate. In order to reduce the waiting list and to avoid under treatment, especially in the elderly, several hypofractionated radiotherapy schemes have been developed for several years. Three randomized trials confirmed similar results to classical radiotherapy. For ten years, several techniques of partial breast irradiation have been developed, with various doses and treated volumes. The optimal indications should be defined according to the new international guidelines. PMID- 22925490 TI - Role of high dose rate brachytherapy in the treatment of prostate cancer. AB - High dose rate (HDR) brachytherapy in intermediate and high-risk prostate cancer patients has started in the late eighties in Europe and the United States, as a boost combined with external beam radiation therapy, as an attractive method for dose escalation. The results of the first dose-escalation study performed at William Beaumont Hospital has established the safety and efficacy of this combined treatment approach. Likewise, this landmark study enabled a paradigm shift in the radiobiology of prostate cancer, demonstrating that the alpha/beta of prostate cancer was much lower than previously believed to be and therefore the sensitivity of this tumor model to higher-than-conventional doses per fraction led to a dramatic increase of hypofractionated treatment regimens, the object of significant clinical research efforts, currently under way. The excellent toxicity profile and clinical outcome of HDR boost combined treatment prompted investigators to expand HDR brachytherapy indications to low/intermediate prostate cancer patients as the sole treatment modality. The results, toxicity and a brief review of the literature for both HDR boost and HDR monotherapy will be presented. PMID- 22925491 TI - [Late sequelae and cosmetic outcome after radiotherapy in breast conserving therapy]. AB - Radiotherapy after breast-conserving therapy for early breast cancer is reported to adversely affect the cosmetic outcome. The incidence of radiation-induced fibroatrophy is around 10% at 5 years. A better knowledge of its pathophysiology has revealed the essential role of activated fibroblasts and reactive oxygen species, mediated by TGF beta 1, allowing the development of antioxidant in the management of the established radiation-induced fibroatrophy. Cosmetic sequelae are evaluated with standardized scales, such as the LENT-SOMA and must be monitored during at least 5 years. The main factors determining the occurrence of sequelae are a large breast volume, dose heterogeneity and the use of tumour bed boost after whole-breast radiation therapy. Intensity modulated radiotherapy and partial breast irradiation position themselves as a good alternatives to reduce the incidence of late skin side effects. The use of predictive tests of intrinsic radiosensitivity might fit into the therapeutic strategy. PMID- 22925492 TI - [Is volumetric modulated arctherapy the final evolution of conformal radiotherapy?]. AB - Technology development in radiotherapy has improved significantly during the last decade. The rapid evolution of 3D radiotherapy to intensity-modulated radiotherapy was possible thanks to inverse planning systems. Intensity modulated radiotherapy improved in its turn by possibilities of volumetric irradiation during a single rotation, reducing therefore the overall treatment. This article presents the technical parameters of this volumetric irradiation technique and a review of miscellaneous clinical indications. PMID- 22925493 TI - [Continuing medical education in radiation oncology]. AB - In France, continuing medical education (CME) and professional practice evaluation (PPE) became mandatory by law in July 2009 for all health professionnals. Recently published decrees led to the creation of national specialty councils to implement this organizational device. For radiation oncology, this council includes the French Society for Radiation Oncology (SFRO), the National Radiation Oncology Syndicate (SNRO) and the Association for Continuing Medical Education in Radiation Oncology (AFCOR). The Radiation Oncology National Council will propose a set of programs including CME and PPE, professional thesaurus, labels for CME actions consistent with national requirements, and will organize expertise for public instances. AFCOR remains the primary for CME, but each practitioner can freely choose an organisation for CME, provided that it is certified by the independent scientific commission. The National Order for physicians is the control authority. Radiation oncology has already a strong tradition of independent CME that will continue through this major reform. PMID- 22925494 TI - Bandwidth in double cross-polarization MAS NMR spectroscopy. AB - The signal intensity in double cross-polarization (DCP) NMR experiments is critically dependent on the experimental parameters, which include the rf field strength, carrier frequency, and magic-angle spinning (MAS) frequency. In this systematic study, we have monitored {(1)H}/(31)P/(13)C DCP signals from monosaccharide alpha-D-[UL-(13)C(6)] galactopyranosyl 1-phosphate (GalP) at a MAS frequency of 13 kHz, at which only double quantum cross-polarization (CP) coherence transfer is allowed. To lessen the stringent requirements for these experimental parameters, we have implemented linear ramp pulse, adiabatic ramp shaped pulse, and block pulse during the period of (31)P/(13)C CP. We unravel the CP matching profiles with respect to these parameters by monitoring the (31)P/(13)C signal while varying the rf field strength and carrier frequency. For comparison, we extracted the selectivity bandwidth from the full width at half maximum (FWHM) of the matching profiles, in units of frequency (kHz), and found bandwidths of 1.1, 14, and 22 kHz for the matching profiles of the (13)C rf field strength and the (13)C and (31)P carrier frequencies, respectively, for a linear ramp pulse CP. These bandwidths are broader than the measured values in an adiabatic-shaped pulse CP (0.8, 10, and 12 kHz), as well as in block CP (0.3, 7, and 10 kHz) experiments. We demonstrate that the linear ramp pulse CP is superior to both block CP and adiabatic-shaped CP in lessening the stringent requirements of the aforementioned experimental settings for DCP experiments. PMID- 22925496 TI - Pneumocystis jirovecii pneumonia prophylaxis during temozolomide treatment for high-grade gliomas. AB - High-grade glioma patients receiving concomitant chemoradiotherapy with temozolomide 75mg/m(2) during six to seven weeks or dose-dense temozolomide regimens especially in combination with chronic use of corticosteroids have a high risk for developing Pneumocystis jirovecii pneumonia. In this review, we define risk groups and propose a guideline for prophylaxis using risk stratification. PMID- 22925495 TI - Gene functionalities and genome structure in Bathycoccus prasinos reflect cellular specializations at the base of the green lineage. AB - BACKGROUND: Bathycoccus prasinos is an extremely small cosmopolitan marine green alga whose cells are covered with intricate spider's web patterned scales that develop within the Golgi cisternae before their transport to the cell surface. The objective of this work is to sequence and analyze its genome, and to present a comparative analysis with other known genomes of the green lineage. RESEARCH: Its small genome of 15 Mb consists of 19 chromosomes and lacks transposons. Although 70% of all B. prasinos genes share similarities with other Viridiplantae genes, up to 428 genes were probably acquired by horizontal gene transfer, mainly from other eukaryotes. Two chromosomes, one big and one small, are atypical, an unusual synapomorphic feature within the Mamiellales. Genes on these atypical outlier chromosomes show lower GC content and a significant fraction of putative horizontal gene transfer genes. Whereas the small outlier chromosome lacks colinearity with other Mamiellales and contains many unknown genes without homologs in other species, the big outlier shows a higher intron content, increased expression levels and a unique clustering pattern of housekeeping functionalities. Four gene families are highly expanded in B. prasinos, including sialyltransferases, sialidases, ankyrin repeats and zinc ion-binding genes, and we hypothesize that these genes are associated with the process of scale biogenesis. CONCLUSION: The minimal genomes of the Mamiellophyceae provide a baseline for evolutionary and functional analyses of metabolic processes in green plants. PMID- 22925497 TI - The relation of vascular endothelial growth factor (VEGF) gene polymorphisms on VEGF levels and the risk of vasoocclusive crisis in sickle cell disease. AB - OBJECTIVE: The association of vascular endothelial growth factor (VEGFA) variants and VEGF secretion with sickle cell disease (SCD) vasoocclusive crisis (VOC) was investigated in 210 VOC patients and 114 pain-free control patients. METHODS: VEGFA -2578C/A (rs699947), -460T/C (rs833061), -1154G/A (rs15703060), -634G/C (rs2010963), 398G/A (rs833068), 497G/A (rs833070), -583T/C (rs3025020), and 936C/T (rs3025039) were carried out by real-time PCR. RESULTS: Higher frequency of rs2010963 C-allele, rs833068 A-allele, and rs3025020 C-allele and significant differences in rs2010963, rs833068, and rs3025020 genotype distribution were seen in VOC than steady-state patients. Increased VOC risk was seen with rs2010963 as heterozygous and more as homozygous, and in rs833068 and rs3025020 homozygous carriers. While there were no differences in VEGF levels between VOC and steady state controls, there was a progressive decline in serum VEGF in rs2010963 and rs833068 heterozygous and homozygous genotypes, but an opposite trend was seen in VOC patients. Haploview analysis revealed high LD between rs699947, rs833061, rs1570360, rs2010963, rs833068, and rs833070, but weak or no LD between rs3025020 and rs3025039 and other SNPs. Six-locus (rs699947/rs833061/rs1570360/rs2010963/rs833068/rs833070) VEGFA haplotype analysis identified haplotype 111111 to be negatively (OR = 0.68) and haplotype 111222 to be positively (OR = 1.89) associated with VOC. rs2010963, rs833068, and rs3025020 were correlated with VOC type, while rs3025020 was correlated with hospitalization, VOC treatment, and duration. CONCLUSION: Specific VEGFA variants contribute to the pathogenesis of SCD VOC. PMID- 22925498 TI - Intravesical hyaluronic acid for interstitial cystitis/painful bladder syndrome: a comparative randomized assessment of different regimens. AB - OBJECTIVES: To compare the clinical effectiveness of different regimens of intravesical hyaluronic acid instillation for patients with interstitial cystitis/painful bladder syndrome. METHODS: A total of 60 patients (age 16-77 years) diagnosed with interstitial cystitis/painful bladder syndrome were enrolled in this prospective, randomized study. A total of 30 patients were assigned to receive four weekly intravesical instillations of 40 mg of hyaluronic acid followed by five monthly instillations (hyaluronic acid-9 group). Another 30 patients received 12 intravesical instillations of 40 mg hyaluronic acid every 2 weeks (hyaluronic acid-12 group). Symptomatic changes after hyaluronic acid treatments were assessed using Interstitial Cystitis Symptom and Problem Indexes, pain visual analog scale, functional bladder capacity, frequency and nocturia in voiding diary, maximum flow rate, voided volume, postvoid residual volume, and Quality of Life Index at 1, 3 and 6 months. RESULTS: Of the 60 patients, 59 were evaluable at the end of the study. The Interstitial Cystitis Symptom Index, Interstitial Cystitis Problem Index and total score, pain visual analog scale, functional bladder capacity, maximum flow rate, and Quality of Life Index improved significantly after 6 months in both groups. The frequency and voided volume improved significantly only in the hyaluronic acid-12 group. However, patients with moderate and marked improvement were clinically similar in both groups. The measured variables did not differ between the two groups over the course of the study. CONCLUSION: No significant difference was noted in the therapeutic effect between two hyaluronic acid instillation regimens for treatment of interstitial cystitis/painful bladder syndrome patients. Both groups showed significant improvement in symptom scores and Quality of Life Index. PMID- 22925499 TI - Tissue engineered esophagus by mesenchymal stem cell seeding for esophageal repair in a canine model. AB - PURPOSE: Acellular porcine small intestinal submucosa (SIS) has been successfully used for esophagoplasty in dogs. However, this has not led to complete epithelialization and muscular regeneration. We undertook the present study to assess the effect of tissue-engineered esophagus generated by seeding bone marrow mesenchymal stem cells (BMSCs) onto an SIS scaffold (BMSCs-SIS) in a canine model. METHODS: We cultured, passaged, and measured autologous BMSCs and myoblasts with cell proliferation and immunohistochemical assays. We labeled the third passage of BMSCs with PKH-26, a fluorescent dye, before seeded it onto the SIS. We resected canine cervical esophagus to generate a defect 5 cm in length and 50% in circumference, which we repaired with BMSCs-SIS or SIS alone. RESULTS: Four weeks later, barium esophagram demonstrated that esophageal lumen surface of the patch graft was smoother in the BMSCs-SIS group compared with the SIS group. Histological examination suggested a strong similarity between BMSCs and esophageal myoblasts in terms of morphology and function. Although both BMSCs-SIS and SIS repaired the esophageal defects, we noted complete re-epithelialization with almost no inflammation only in the former group. By 12 wk after the surgery, we observed long bundles of skeletal muscles only in the BMSCs-SIS group, where the microvessel density was also much greater. CONCLUSIONS: Bone marrow mesenchymal stem cells on an SIS scaffold can promote re-epithelialization, revascularization, and muscular regeneration. This approach may provide an attractive option for esophageal regeneration. PMID- 22925500 TI - EGF signalling pathway regulates colon cancer stem cell proliferation and apoptosis. AB - OBJECTIVES: Cancer stem cells (CSCs) compose a subpopulation of cells within a tumour that can self-renew and proliferate. Growth factors such as epidermal growth factor (EGF) and basic fibroblast growth factor (b-FGF) promote cancer stem cell proliferation in many solid tumours. This study assesses whether EGF, bFGF and IGF signalling pathways are essential for colon CSC proliferation and self-renewal. MATERIAL AND METHODS: Colon CSCs were cultured in serum-free medium (SFM) with one of the following growth factors: EGF, bFGF or IGF. Characteristics of CSC gene expression were evaluated by real time PCR. Tumourigenicity of CSCs was determined using a xenograft model in vivo. Effects of EGF receptor inhibitors, Gefitinib and PD153035, on CSC proliferation, apoptosis and signalling were evaluated using fluorescence-activated cell sorting and western blotting. RESULTS: Colon cancer cell HCT116 transformed to CSCs in SFM. Compared to other growth factors, EGF was essential to support proliferation of CSCs that expressed higher levels of progenitor genes (Musashi-1, LGR5) and lower levels of differential genes (CK20). CSCs promoted more rapid tumour growth than regular cancer cells in xenografts. EGFR inhibitors suppressed proliferation and induced apoptosis of CSCs by inhibiting autophosphorylation of EGFR and downstream signalling proteins, such as Akt kinase, extracellular signal-regulated kinase 1/2 (ERK 1/2). CONCLUSIONS: This study indicates that EGF signalling was essential for formation and maintenance of colon CSCs. Inhibition of the EGF signalling pathway may provide a useful strategy for treatment of colon cancer. PMID- 22925501 TI - Korean mistletoe lectin regulates self-renewal of placenta-derived mesenchymal stem cells via autophagic mechanisms. AB - OBJECTIVES: The balance between survival and death is a key point for regulation of physiology of stem cells. Recently, applications of natural products to enhance efficiencies in culturing and differentiation of stem cells are increasing. Korean mistletoe lectin (Viscum album L. var. coloratum agglutinin, VCA) has been known to be toxic to some cancer cells, but it is still unclear whether VCA has a cytotoxic or indeed a proliferative effect on mesenchymal stem cells (MSCs). Here, we have compared effects of VCA in naive placenta-derived stem cells (PDSCs), immortalized PDSCs and cancer cells (HepG2), and analysed their mechanisms. MATERIALS AND METHODS: MTT assay was performed to analyse effects of VCA on naive PDSCs, immortalized PDSCs and HepG2. FACS, ROS, caspase-3 assay, western blotting and immunofluorescence were performed to detect signalling events involved in self-renewal of the above cell types. RESULTS: VCA had cancer cell-specific toxicity to HepG2 cells even with low concentrations of VCA (1-5 pg/ml), toxicity was observed to immortalized PDSCs and HepG2s, while proliferation of naive PDSCs was significantly increased (P < 0.05). ROS production by VCA treatment in naive PDSCs was significantly lower compared to controls (P < 0.05). Furthermore, autophagy was activated in naive PDSCs treated with VCA through increase in type II LC3 and decrease in phosphorylated mTOR. CONCLUSIONS: VCA can promote MSC proliferation through an activated autophagic mechanism. PMID- 22925502 TI - Optimization of culture of mesenchymal stem cells: a comparison of conventional plate and microcarrier cultures. AB - OBJECTIVES: There has been increasing interest in mesenchymal stem cells (MSCs) because of their potential use for regenerative therapy; however, there is no well-defined protocol for MSCs culture. This study compares techniques of conventional plate and microcarrier culturing of MSCs. METHODS AND RESULTS: Here, different conditions for isolation and expansion of rat MSCs have been examined and it was found that plating density and plating time in primary culture played important roles for culture of these rat MSCs. When plated at 10(8) /cm(2) density for 72 h, in primary culture, recycling stem cells (RS cells) predominated, and characteristics of rat MSCs (including morphology, growth rate, phenotype and differentiation potentials) remained stable during expansion until passage 14. For subculture of the cells, it was found that their growth rate when incubated at 33 degrees C was higher than those incubated at 37 degrees C, and maximal increase was 10- and 6-fold respectively. When cultured using microcarriers, at a density of 1 * 10(5) /mg beads, growth kinetics, phenotype and differentiation potentials also remained constant for cells between passage 2nd and 14th; their maximal number increased 16-fold. CONCLUSIONS: Compared to conventional plate culture, culture using gelatine porous microcarrier Cultispher S was superior for large-scale production of rat MSCs. PMID- 22925503 TI - Comparison of cell proliferation and epigenetic modification of gene expression patterns in canine foetal fibroblasts and adipose tissue-derived mesenchymal stem cells. AB - OBJECTIVES: This study compared rate of cell proliferation, viability, cell size, expression patterns of genes related to pluripotency and epigenetic modification between canine foetal fibroblasts (cFF) and canine adipose tissue-derived mesenchymal stem cells (cAd-MSC). MATERIALS AND METHODS: Proliferation pattern, cell viability as well as cell size at each passage of cFF and cAd-MSC were measured when cultures reached confluence. In addition, real-time PCR was performed to investigate expression of Dnmt1, HDAC1, OCT4, SOX2, BAX, BCL2 genes with reference to beta-actin gene expression as an endogenous control in both cell lines. RESULTS: cFF and cAd-MSC differed in number of generations, but not in doubling times, at all passages. Mean cell size of cAd-MSC was significantly smaller than that of cFF. Cell viability was significantly lower in cFFs and apoptotic level was significantly lower in cAd-MSC compared to passage-matched cFF. In the expression of genes related to pluripotency and epigenetic modification, level of HDAC1 in cAd-MSC was significantly higher than in cFF, but expression of Dnmt1 did not differ between the two groups. OCT4 and SOX2 were significantly more highly expressed in cAd-MSC compared to cFF. CONCLUSIONS: cAd MSC have higher stem-cell potential than cFF in terms of proliferation patterns, epigenetic modification and pluripotency, thus cAd-MSC could be more appropriate than cFF as donors of nuclei in somatic cell nuclear transfer for transgenesis. PMID- 22925504 TI - Hypoxia inducible factor-1alpha-mediated activation of survivin in cervical cancer cells. AB - AIM: Hypoxia, a characteristic of almost all types of solid tumors, has been associated with poor outcome in a number of human malignancies. The aim of this study was to investigate the molecular mechanisms involved in hypoxia-induced activation of the human survivin gene promoter in cervical HeLa cells. MATERIAL AND METHODS: Immunohistochemical staining was used to detect the expression of HIF-1alpha and survivin in cervical cancer samples and normal cervical samples. Under normoxic and hypoxic conditions, the expression of hypoxia inducible factor (HIF)-1alpha and survivin in cervical cancer HeLa cells was detected by quantitative reverse transcription polymerase chain reaction and Western blotting. Luciferase reporter assays was used to investigate the molecular mechanisms in hypoxia-induced survivin activation. We also studied the effect of HIF-1alpha overexpression on the expression of survivin in cervical cancer HeLa cells. RESULTS: Significant HIF-1alpha and survivin overexpression is associated with cervical cancer, and HIF-1alpha protein expression is strongly correlated with survivin protein expression. In cervical cancer cell line (HeLa), hypoxia upregulated both HIF-1alpha and survivin expression. Moreover, luciferase reporter assays using survivin core promoter demonstrated that survivin transcription was activated under hypoxia conditions and was associated with HIF 1alpha overexpression. The transcriptional activation of reporter genes in response to hypoxia is independent of potential HIF-1alpha-responsive element, located between -86 and -82 regions. HIF-1alpha overexpression significantly activated survivin expression. CONCLUSION: Our results demonstrate that survivin expression is upregulated following the induction of HIF-1alpha by hypoxia resulting from tumor formation, possibly leading to tumor progression. These findings have potential implication in developing novel cancer therapy targeting HIF-1. PMID- 22925507 TI - Clinical history and characteristics of persons with oxycodone-related deaths in Hillsborough County, Florida in 2009. AB - AIMS: To analyze toxicological findings of accidental deaths involving oxycodone to determine demographic characteristics and clinical histories. METHODS: Accidental deaths in which oxycodone was mentioned as a cause of death were analyzed. The sample included all persons deceased in Hillsborough County in 2009 where oxycodone was present. The entire sample was divided into two subgroups listing oxycodone as the primary/contributory cause of death (n=117) or oxycodone as the incidental cause of death (n=38). Differences between the two groups in demographic and clinical history variables as well as the presence and concentration of drugs were examined. RESULTS: The majority of decedents within the entire sample (N=155) were Caucasian males (58.1%) aged 50 or older. More than half of the population (52.9%) did not hold prescriptions for oxycodone. Those who died with a primary/contributory cause of death were younger, more likely to have a history of substance abuse, and more likely to have alprazalom (Xanax) present in their system. Across the entire sample, the mean oxycodone concentration level was 0.40 mg/L, with a range from 0.02 to 3.70 mg/L. Those who died with a primary/contributory cause of death had a significantly higher level of mean oxycodone concentration than those with an incidental cause of death, 0.48 mg/L compared to 0.16 mg/L. CONCLUSIONS: Results suggest that the demographic findings mirror statewide and national trends. In general, mean oxycodone concentration levels were shown to be lower than those previously reported in literature. Overlap and range of concentrations between those with a primary/contributory and incidental cause of death demonstrates the significance of individual case history and tolerance in the interpretation of postmortem drug concentrations when determining cause and manner of death. PMID- 22925506 TI - Specific morphogenetic events in mouse external genitalia sex differentiation are responsive/dependent upon androgens and/or estrogens. AB - The objective of this study was to perform a comprehensive morphologic analysis of developing mouse external genitalia (ExG) and to determine specific sexual differentiation features that are responsive to androgens or estrogens. To eliminate sex steroid signaling postnatally, male and female mice were gonadectomized on the day of birth, and then injected intraperitoneally every other day with DES (200 ng/g), DHT (1 MUg/g), or oil. On day-10 postnatal male and female ExG were dissected, fixed, embedded, serially sectioned and analyzed. We identified 10 sexually dimorphic anatomical features indicative of normal penile and clitoral differentiation in intact mice. Several (but not all) penile features were impaired or abolished as a result of neonatal castration. Those penile features remaining after neonatal castration were completely abolished with attendant clitoral development in androgen receptor (AR) mutant male mice (X(Tfm)/Y and X/Y AR-null) in which AR signaling is absent both pre- and postnatally. Administration of DHT to neonatally castrated males restored development of all 10 masculine features to almost normal levels. Neonatal ovariectomy of female mice had little effect on clitoral development, whereas treatment of ovariectomized female mice with DHT induced partial masculinization of the clitoris. Administration of DES to neonatally gonadectomized male and female mice elicited a spectrum of development abnormalities. These studies demonstrate that the presence or absence of androgen prenatally specifies penile versus clitoral identity. Differentiated penile features emerge postnatally and are sensitive to and dependent upon prenatal or pre- and postnatal androgen. Emergence of differentiated clitoral features occurs postnatally in either intact or ovariectomized females. It is likely that each penile and clitoral feature has a unique time-course of hormonal dependency/sensitivity. PMID- 22925508 TI - Sex moderates associations between prenatal glucocorticoid exposure and human fetal neurological development. AB - Maternal cortisol levels (at 15, 19, 25, 31 and 37 weeks' gestation) and fetal movement response to vibroacoustic stimulation (VAS; at 25, 31 and 37 weeks) were assessed in 190 mother-fetus pairs. Fetuses showed a response to the VAS at 25 weeks and there was evidence of increasing maturation in the response at 31 and 37 weeks. Early elevations in cortisol predicted a failure to respond to the VAS at 25 weeks and later elevations in cortisol were associated with a larger response among fetuses when assessed near term. The associations between cortisol and VAS emerged earlier and were more apparent among female fetuses than among the males. The findings provide support for the role of prenatal glucocorticoids in shaping human fetal CNS development. PMID- 22925509 TI - Infant pointing serves an interrogative function. AB - In recent years there has been a resurgence of interest in the motivations behind, and the function of, infant pointing behaviour. Many studies have converged on the view that early pointing reflects a motivation to share attention and interest with others. Under one view, it is the sharing of attention itself that is the ultimate function of pointing, and is an early manifestation of a uniquely human social cognition that is geared towards cooperation and collaboration. In the current study, we tested an alternative hypothesis in which the goal of pointing is not attention sharing itself, but the information-laden response that infants tend to receive as a result of sharing attention. If infants indeed point in order to obtain information, their pointing should be modulated by the perceived ability of the other to provide this information. In Experiment 1, 16-month-olds who interacted with a demonstrably knowledgeable experimenter pointed significantly more to novel objects than infants who interacted with an ignorant experimenter. In Experiment 2, we confirmed that this finding was due to the perceived competence of the experimenter rather than to the different ways in which the experimenter responded to infants' points. Our results suggest that one function of pointing in infancy is to obtain information from others, and that infants selectively elicit desired information from those whom they perceive could competently provide it. PMID- 22925510 TI - Neural correlates of belief- and desire-reasoning in 7- and 8-year-old children: an event-related potential study. AB - Theory of mind requires belief- and desire-understanding. Event-related brain potential (ERP) research on belief- and desire-reasoning in adults found mid frontal activations for both desires and beliefs, and selective right-posterior activations only for beliefs. Developmentally, children understand desires before beliefs; thus, a critical question concerns whether neural specialization for belief-reasoning exists in childhood or develops later. Neural activity was recorded as 7- and 8-year-olds (N = 18) performed the same diverse-desires, diverse-beliefs, and physical control tasks used in a previous adult ERP study. Like adults, mid-frontal scalp activations were found for belief- and desire reasoning. Moreover, analyses using correct trials alone yielded selective right posterior activations for belief-reasoning. Results suggest developmental links between increasingly accurate understanding of complex mental states and neural specialization supporting this understanding. PMID- 22925511 TI - Belief attribution in deaf and hearing infants. AB - Based on anticipatory looking and reactions to violations of expected events, infants have been credited with 'theory of mind' (ToM) knowledge that a person's search behaviour for an object will be guided by true or false beliefs about the object's location. However, little is known about the preconditions for looking patterns consistent with belief attribution in infants. In this study, we compared the performance of 17- to 26-month-olds on anticipatory looking in ToM tasks. The infants were either hearing or were deaf from hearing families and thus delayed in communicative experience gained from access to language and conversational input. Hearing infants significantly outperformed their deaf counterparts in anticipating the search actions of a cartoon character that held a false belief about a target-object location. By contrast, the performance of the two groups in a true belief condition did not differ significantly. These findings suggest for the first time that access to language and conversational input contributes to early ToM reasoning. PMID- 22925512 TI - Nine-month-old infants generalize object labels, but not object preferences across individuals. AB - As with all culturally relevant human behaviours, words are meaningful because they are shared by the members of a community. This research investigates whether 9-month-old infants understand this fundamental fact about language. Experiment 1 examined whether infants who are trained on, and subsequently habituated to, a new word-referent link expect the link to be consistent across a second speaker. Experiment 2 examined whether 9-month-old infants distinguish between behaviours that are shared across individuals (i.e. words) from those that are not (i.e. object preferences). The present findings indicate that infants as young as 9 months of age expect new word-referent links, but not object preferences, to be consistent across individuals. Thus, by 9 months, infants have identified at least one of the aspects of human behaviour that is shared across individuals within a community. The implications for children's acquisition of language and culture are discussed. PMID- 22925513 TI - Functional dissociation between perception and action is evident early in life. AB - The functional distinction between vision for perception and vision for action is well documented in the mature visual system. Ganel and colleagues recently provided direct evidence for this dissociation, showing that while visual processing for perception follows Weber's fundamental law of psychophysics, action violates this law. We tracked the developmental trajectory of this functional dissociation, asking whether the qualitatively different pattern observed in adults of adherence of perception but not of action to Weber's law would also be evident early in life. Children aged 5-8 and adults were asked to either estimate the size of discs (perception) or grasp discs (action) varying in diameter. Interestingly, variability of perceptual estimates increased as a function of object size in accord with Weber's law, while variability of grasping did not scale with object size, at all ages tested. This provides the first clear evidence for an early emergence of the dissociation between perception and action. PMID- 22925514 TI - Language input and acquisition in a Mayan village: how important is directed speech? AB - Theories of language acquisition have highlighted the importance of adult speakers as active participants in children's language learning. However, in many communities children are reported to be directly engaged by their caregivers only rarely (Lieven, 1994). This observation raises the possibility that these children learn language from observing, rather than participating in, communicative exchanges. In this paper, we quantify naturally occurring language input in one community where directed interaction with children has been reported to be rare (Yucatec Mayan). We compare this input to the input heard by children growing up in large families in the United States, and we consider how directed and overheard input relate to Mayan children's later vocabulary. In Study 1, we demonstrate that 1-year-old Mayan children do indeed hear a smaller proportion of total input in directed speech than children from the US. In Study 2, we show that for Mayan (but not US) children, there are great increases in the proportion of directed input that children receive between 13 and 35 months. In Study 3, we explore the validity of using videotaped data in a Mayan village. In Study 4, we demonstrate that word types directed to Mayan children from adults at 24 months (but not word types overheard by children or word types directed from other children) predict later vocabulary. These findings suggest that adult talk directed to children is important for early word learning, even in communities where much of children's early language input comes from overheard speech. PMID- 22925515 TI - Consolidation of vocabulary is associated with sleep in children. AB - Although the acquisition of a novel word is apparently rapid, adult research suggests that integration of novel and existing knowledge (measured by engagement in lexical competition) requires sleep-associated consolidation. We present the first investigation of whether a similar time-course dissociation characterizes word learning across development. Consistent with previous research but counter to adults, 7-12-year-olds showed sleep-associated consolidation effects in declarative but not procedural memory. Nevertheless, the relationship between sleep and word learning in children was remarkably similar to the pattern for adults. Following exposure to nonword competitors (e.g. biscal) in the a.m. or p.m., children's ability to recognize and recall the nonwords improved only after sleep (after approximately 12-hrs for the p.m. group and 24-hrs for the a.m. group), with performance stable 1 week later. Novel nonwords only induced lexical competition effects after sleep. These findings suggest that children utilize a dual memory system when acquiring and integrating new vocabulary and highlight sleep as integral to this process. A video abstract of this article can be viewed at http://www.youtube.com/watch?feature=youtube_gdata&v=2UNuKCAakOk&gl=GB. PMID- 22925517 TI - Phonological similarity and mutual exclusivity: on-line recognition of atypical pronunciations in 3--5-year-olds. AB - Recent research has considered the phonological specificity of children's word representations, but few studies have examined the flexibility of those representations. Tolerating acoustic-phonetic deviations has been viewed as a negative in terms of discriminating minimally different word forms, but may be a positive in an increasingly multicultural society where children encounter speakers with variable accents. To explore children's on-line processing of accented speech, preschoolers heard atypically pronounced words (e. g. 'fesh', from fish) and selected pictures from a four-item display as eye movements were tracked. Children recognized similarity between typical and accented variants, selecting the fish overwhelmingly when hearing 'fesh' (Experiment 1), even when a novel-picture alternative was present (Experiment 2). However, eye movements indicated slowed on-line recognition of accented relative to typical variants. Novel-picture selections increased with feature distance from familiar forms, but were similarly sensitive to vowel, onset, and coda changes (Experiment 3). Implications for child accent processing and mutual exclusivity are discussed. PMID- 22925516 TI - Developmental changes in the multisensory temporal binding window persist into adolescence. AB - We live in a world rich in sensory information, and consequently the brain is challenged with deciphering which cues from the various sensory modalities belong together. Determinations regarding the relatedness of sensory information appear to be based, at least in part, on the spatial and temporal relationships between the stimuli. Stimuli that are presented in close spatial and temporal correspondence are more likely to be associated with one another and thus 'bound' into a single perceptual entity. While there is a robust literature delineating behavioral changes in perception induced by multisensory stimuli, maturational changes in multisensory processing, particularly in the temporal realm, are poorly understood. The current study examines the developmental progression of multisensory temporal function by analyzing responses on an audiovisual simultaneity judgment task in 6- to 23-year-old participants. The overarching hypothesis for the study was that multisensory temporal function will mature with increasing age, with the developmental trajectory for this change being the primary point of inquiry. Results indeed reveal an age-dependent decrease in the size of the 'multisensory temporal binding window', the temporal interval within which multisensory stimuli are likely to be perceptually bound, with changes occurring over a surprisingly protracted time course that extends into adolescence. PMID- 22925518 TI - Nine-months-old infants do not need to know what the agent prefers in order to reason about its goals: on the role of preference and persistence in infants' goal-attribution. AB - Human infants readily interpret others' actions as goal-directed and their understanding of previous goals shapes their expectations about an agent's future goal-directed behavior in a changed situation. According to a recent proposal (Luo & Baillargeon, 2005), infants' goal-attributions are not sufficient to support such expectations if the situational change involves broadening the set of choice-options available to the agent, and the agent's preferences among this broadened set are not known. The present study falsifies this claim by showing that 9-month-olds expect the agent to continue acting towards the previous goal even if additional choice-options become available for which there is no preference-related evidence. We conclude that infants do not need to know about the agent's preferences in order to form expectations about its goal-directed actions. Implications for the role of action persistency and action selectivity are discussed. PMID- 22925519 TI - The nature of infants' goal representation: commentary on Hernik and Southgate. PMID- 22925520 TI - Diagnosing goal-attribution: commentary on Hernik and Southgate. PMID- 22925521 TI - Infants attribute to agents goals and dispositions. PMID- 22925522 TI - Theories, evidence and intuitions about infants' attributions of goals: a reply to commentaries by Biro and Kuhlmeier & Robson and Luo & Choi. PMID- 22925523 TI - Influence of material on the development of device-associated infections. AB - The use of implanted devices in modern orthopaedic surgery has greatly improved the quality of life for an increasing number of patients, by facilitating the rapid and effective healing of bone after traumatic fractures, and restoring mobility after joint replacement. However, the presence of an implanted device results in an increased susceptibility to infection for the patient, owing to the creation of an immunologically compromised zone adjacent to the implant. Within this zone, the ability of the host to clear contaminating bacteria may be compromised, and this can lead to biofilm formation on the surface of the biomaterial. Currently, there are only limited data on the mechanisms behind this increased risk of infection and the role of material choice. The impacts of implant material on bacterial adhesion, immune response and infection susceptibility have been investigated individually in numerous preclinical in vitro and in vivo studies. These data provide an indication that material choice does have an impact on infection susceptibility; however, the clinical implications remain to be clearly determined. PMID- 22925524 TI - Dissecting maize productivity: ideotypes associated with grain yield under drought stress and well-watered conditions. AB - To increase maize (Zea mays L.) yields in drought-prone environments and offset predicted maize yield losses under future climates, the development of improved breeding pipelines using a multi-disciplinary approach is essential. Elucidating key growth processes will provide opportunities to improve drought breeding progress through the identification of key phenotypic traits, ideotypes, and donors. In this study, we tested a large set of tropical and subtropical maize inbreds and single cross hybrids under reproductive stage drought stress and well watered conditions. Patterns of biomass production, senescence, and plant water status were measured throughout the crop cycle. Under drought stress, early biomass production prior to anthesis was important for inbred yield, while delayed senescence was important for hybrid yield. Under well-watered conditions, the ability to maintain a high biomass throughout the growing cycle was crucial for inbred yield, while a stay-green pattern was important for hybrid yield. While new quantitative phenotyping tools such as spectral reflectance (Normalized Difference Vegetation Index, NDVI) allowed for the characterization of growth and senescence patterns as well as yield, qualitative measurements of canopy senescence were also found to be associated with grain yield. PMID- 22925525 TI - Aqueous calcium sulphate as bone graft for voids following open curettage of bone tumours. AB - INTRODUCTION: Reported strategies for void filling in bone include autograft, allograft, synthetic bone substitutes or various combinations of these materials, but poor response rates and donor morbidity have created a desire to find a better option. Calcium sulphate as a stand-alone graft material reconstruct bone following curettage has not been previously reported. The purpose of this study was to assess the efficacy and radiological quality of healing, the time to healing, the functional outcomes and the complications following curettage and grafting using an injectable aqueous calcium sulphate (BonePlast; Biomet, Warsaw, IN, USA) as the sole grafting strategy. METHODS: The procedure of curettage and grafting with an aqueous solution of calcium sulphate was undertaken. The patients were regularly reviewed clinically and radiologically for a minimum of 12 months (range: 12-85 months). Forty-six procedures in 46 patients were reviewed. Radiological outcomes of healing were established and functional outcomes were obtained from each patient at annual follow-up review. RESULTS: A complete response was seen in 38 patients (83%) at a median of 6 months following the procedure (range: 1-24 months). Seven patients (15%) displayed only a partial response after a median of 13 months post-surgery (range: 12-53 months). There was one non-response to treatment (2%) after 40 months of follow-up. The mean functional score was 99%. DISCUSSION: Aqueous calcium sulphate as a sole grafting agent for void management after curettage simplifies current treatment practices and displays good bone reconstruction in a comparatively short time frame, with excellent functional results and acceptable complication rates in the setting of tumour surgery. PMID- 22925526 TI - The development of whole blood titanium levels after instrumented spinal fusion - is there a correlation between the number of fused segments and titanium levels? AB - BACKGROUND: Most modern spinal implants contain titanium and remain in the patient's body permanently. Local and systemic effects such as tissue necrosis, osteolysis and malignant cell transformation caused by implants have been described. Increasing tissue concentration and whole blood levels of ions are necessary before a disease caused by a contaminant develops. The aim of the present study was the measurement of whole blood titanium levels and the evaluation of a possible correlation between these changes and the number of fused segments. METHODS: A prospective study was designed to determine changes in whole blood titanium levels after spinal fusion and to analyze the correlation to the number of pedicle screws, cross connectors and interbody devices implanted.Blood samples were taken preoperatively in group I (n = 15), on the first, second and 10th day postoperatively, as well as 3 and 12 months after surgery.Group II (n = 16) served as a control group of volunteers who did not have any metal implants in the body. Blood samples were taken once in this group.The number of screw-rod-connections and the length of the spinal fusion were determined using radiographic pictures. This study was checked and approved by the ethical committee of the University of Tuebingen. RESULTS: The mean age in group I was 47 +/- 22 years (range 16 - 85 years). There were three male (20%) and twelve female (80%) patients. The median number of fused segments was 5 (range 1 to 11 segments).No statistically significant increase in the titanium level was seen 12 months after surgery (mean difference: -7.2 MUg/l, 95% CI: 26.9 to 12.5 MUg/l, p = 0.446). By observing the individual titanium levels, 4 out of 15 patients demonstrated an increase in titanium levels 12 months after surgery.No statistically significant correlation between fused segments (r = 0.188, p = 0.503) length of instrumentation (r = -0.329, p = 0.231), number of interbody devices (r = -0.202, p = 0.291) and increase of titanium levels over the observation period was seen. CONCLUSIONS: Instrumented spinal fusion does not lead to a statistically significant increase in whole blood titanium levels. There seems to be no correlation between the number of pedicle screws, cross connectors and interbody devices implanted and the increase of serum titanium levels. PMID- 22925527 TI - The comorbidity of chronic pain and sleep disturbances in a community adolescent sample: prevalence and association with sociodemographic and psychosocial factors. AB - PURPOSE: The comorbidity of chronic pain and sleep disturbances has received increasing research attention in Western clinical pediatric populations; yet, little is known about its sociodemographic and psychological correlates in non Western community pediatric populations. This study aimed to examine the prevalence of comorbid chronic pain and sleep disturbances and its associated factors in a community sample of Chinese adolescents. METHODS: A total of 1,518 adolescents aged from 11 to 19 years participated in this school-based study. Apart from sociodemographic background, participants were assessed on chronic pain, sleep disturbances, depression, perceived stress, and social support. Prevalence of co-occurrence of chronic pain and sleep disturbances was determined. Participants with single symptom were compared with those with symptom co-occurrence on pain characteristics and sleep patterns. Multiple regression model evaluated factors associated with symptom comorbidity. RESULTS: While the prevalence of chronic pain and sleep disturbances was 11.4% and 25.6%, respectively, the overall prevalence of comorbid chronic pain and sleep disturbances was 19.1% (95% confidence interval: 16.9, 21.4). Fully adjusted stepwise regression analysis identified being female, more depressive symptoms, and higher perceived stress to be significantly associated with comorbid symptoms. Adolescents with both symptoms reported significantly more pain sites, higher worst pain, and higher pain-associated interference than those reported chronic pain only. Participants with comorbid symptoms also had poor subjective sleep quality, greater sleep disturbances, and more daytime dysfunction than those reported sleep disturbances only. CONCLUSIONS: Our data offered preliminary evidence that comorbid chronic pain and sleep disturbances occurred among about one-fifth in the present sample of Chinese community adolescents. Future studies should examine whether the two symptoms interact with each other in affecting the physical, mental, and cognitive development of adolescents. PMID- 22925528 TI - Multilevel local anesthetic nerve blockade for the treatment of generalized vulvodynia: a pilot study. AB - INTRODUCTION: Vulvodynia is a common pain disorder among women with a major impact on sexual functioning and quality of life. There are few published studies addressing the treatment of the pain of generalized vulvodynia or of generalized vulvodynia accompanying localized pain in the region of the vulvar vestibule. AIM: A prospective, noncontrolled pilot study was conducted to assess the efficacy of a novel treatment using caudal epidural, pudendal nerve block, and vulvar infiltration of local anesthetic agents. MAIN OUTCOME MEASURES: The main outcome measure was vulvar pain as assessed by the McGill Pain Questionnaire (MPQ). The secondary outcome measures were depressed mood evaluated with the Beck Depression Inventory (BDI) and sexual functioning assessed by the Female Sexual Functioning Inventory (FSFI). METHODS: Thirty-two women with vulvodynia met inclusion criteria and 26 women completed the study. The protocol included five treatment sessions with multilevel local anesthetic nerve blockade and a follow up contact or visit 2-3 months later. RESULTS: There were significant improvements in vulvar pain as determined by both the sensory and affective components of the MPQ and in depression as assessed by the BDI. However, there were no changes in sexual functioning on the FSFI. CONCLUSION: Serial multilevel nerve block administered for the treatment of vulvodynia is a neurophysiologically based modality that may be effective and merits a placebo controlled study. PMID- 22925530 TI - Conformation of beta2glycoprotein I and its effect on coagulation. AB - beta(2)glycoprotein I (beta(2)GPI) is the major antigen in the antiphospholipid syndrome. It has been shown that beta(2)GPI can adapt to different conformations, a circular, a S-shaped and a J-shaped conformation. In literature anticoagulant properties of beta(2)GPI have been indicated, though there is no consensus on how beta(2)GPI exerts a certain action. This article will first review existing data on the conformation of beta(2)GPI. In addition, we will investigate whether the conformation of beta(2)GPI plays a role in in the proposed anticoagulant activity of beta(2)GPI. We investigated the effect of native beta(2)GPI and phospholipid bound beta(2)GPI on thrombin generation (TG). Native beta(2)GPI was found to have no significant effect on the TG regardless of the concentration of tissue factor. On the contrary, beta(2)GPI preincubated with phospholipids significantly inhibited TG triggered with low TF concentration, suggesting an effect on the intrinsic pathway. This indicates that native beta(2)GPI in circulation obtains its anticoagulant activity in the presence of anionic phospholipids such as activated blood cells thereby serving as an inhibitory modulator in hemostasis. PMID- 22925529 TI - Dissection of two soybean QTL conferring partial resistance to Phytophthora sojae through sequence and gene expression analysis. AB - BACKGROUND: Phytophthora sojae is the primary pathogen of soybeans that are grown on poorly drained soils. Race-specific resistance to P. sojae in soybean is gene for-gene, although in many areas of the US and worldwide there are populations that have adapted to the most commonly deployed resistance to P. sojae ( Rps) genes. Hence, this system has received increased attention towards identifying mechanisms and molecular markers associated with partial resistance to this pathogen. Several quantitative trait loci (QTL) have been identified in the soybean cultivar 'Conrad' that contributes to the expression of partial resistance to multiple P. sojae isolates. RESULTS: In this study, two of the Conrad QTL on chromosome 19 were dissected through sequence and expression analysis of genes in both resistant (Conrad) and susceptible ('Sloan') genotypes. There were 1025 single nucleotide polymorphisms (SNPs) in 87 of 153 genes sequenced from Conrad and Sloan. There were 304 SNPs in 54 genes sequenced from Conrad compared to those from both Sloan and Williams 82, of which 11 genes had SNPs unique to Conrad. Eleven of 19 genes in these regions analyzed with qRT-PCR had significant differences in fold change of transcript abundance in response to infection with P. sojae in lines with QTL haplotype from the resistant parent compared to those with the susceptible parent haplotype. From these, 8 of the 11 genes had SNPs in the upstream, untranslated region, exon, intron, and/or downstream region. These 11 candidate genes encode proteins potentially involved in signal transduction, hormone-mediated pathways, plant cell structural modification, ubiquitination, and basal resistance. CONCLUSIONS: These findings may indicate a complex defense network with multiple mechanisms underlying these two soybean QTL conferring resistance to P. sojae. SNP markers derived from these candidate genes can contribute to fine mapping of QTL and marker assisted breeding for resistance to P. sojae. PMID- 22925531 TI - Improved point-of-care identification of hyperfibrinolysis is needed. PMID- 22925532 TI - The role of lipopolysaccharide as a marker of immune activation in HIV-1 infected patients: a systematic literature review. AB - BACKGROUND: Recent observational studies suggest a role for lipopolysaccharide (LPS) as a marker of immune activation in HIV-infected patients, with potential repercussions on the effectiveness of antiretroviral regimens. OBJECT: A systematic review of LPS as a marker of immune activation in HIV-1 infected patients. DATA SOURCES: MEDLINE register of articles and international conference proceedings. REVIEW METHODS: Case-control studies comparing the role of plasma LPS as a marker of immune activation in HIV-infected patients versus HIV negative subjects. DATA SYNTHESIS: Two hundred and six articles were selected using MEDLINE, plus 51 studies presented at international conferences. Plasma LPS is a marker of immune activation in HIV-infected patients, determining the entry of central memory CD4+ T cells into the replication cycle and finally generating cell death. Plasma LPS probably results from immune-mediated alterations of the intestinal barrier, which can occur soon after HIV seroconversion. LPS is a likely marker of disease progression, as it drives chronic monocyte activation, and some studies suggest that hyperexpression of CCR5 receptors, related to LPS plasma levels, could be responsible for monocyte trafficking in the brain compartment and for the appearance of HIV-associated neurocognitive disorders. Long-term combination antiretroviral therapy (cART) generally reduces LPS concentrations, but rarely to the same levels as in the control group. This phenomenon probably depends on ongoing but incomplete repair of the mucosal barrier. Only in patients achieving maximal viral suppression (i.e. viral load < 2.5 cp/ml) are LPS levels comparable to healthy donors. In successfully treated patients who did not restore CD4+ T cells, one hypothesis is that the degree of residual microbial translocation, measured by LPS, alters the turnover of CD4+ T cells. CONCLUSIONS: LPS is a marker of microbial translocation, responsible for chronic immune activation in HIV-infected patients. Even in successfully treated patients, LPS values are rarely normal. Several studies suggest a role for LPS as a negative predictive marker of immune restoration in patients with blunted CD4 T cell gain. PMID- 22925533 TI - Carotid artery disease and cognitive impairment. AB - The term neurologic symptom usually relates to the loss of motor or sensory functions; cognitive deficit is mostly unrecognized in patients with severe carotid stenosis. In large population studies carotid stenosis has been shown as independent risk factor for mild cognitive impairment (MCI) and it was not due to underlying vascular risk factors. The term MCI refers to a transitional stage between cognitive changes of normal aging and vascular dementia. At this stage, cognitive decline is not severe enough to constitute dementia, but also it is beyond the cognitive functioning deficit which is expected in normal aging. Carotid stenosis detected in population older than 65 is 75% for men and 62% for women, with prevalence of stenosis >= 50% in this population 7% for men and 5% for women. There are two possible underlying pathomorphological mechanisms of cognitive changes in patients with carotid disease - cerebral emboli and hypoperfusion with or without silent brain infarctions. In both cases loss of regional cerebral autoregulation can be recognized by means of neurosonology (transcranial Doppler ultrasonography). Most of the studies which evaluated cognitive functions before and after CEA/CAS have shown improvement or no changes in cognitive functions, but no deteriorations. There are still no clear recommendations about using CEA/CAS in treating cognitive deficit in otherwise asymptomatic patients. It is important to recognize cognitive changes as a symptom of carotid disease in order to follow up such patients and include cognitive deficit as one of the criteria in calculating perioperative risk and benefit from CEA/CAS. PMID- 22925534 TI - Syphilitic aortic aneurysm with spastic paraparesis: a novel presentation and review of the literature. AB - Syphilitic aortic aneurismal erosion into the vertebral column with associated neurological dysfunction is extraordinarily rare, and the very few reported cases typically involve the descending aorta. We describe the novel presentation of a 55 year old man with a syphilitic aneurysm of the ascending aorta and arch causing spinal erosion with spastic paraparesis. Clinicians must remain cognizant that the resurgence of primary and secondary syphilis, exacerbated by the unrelenting HIV-AIDS epidemic, portends an increasing incidence of tertiary manifestations such as aortic aneurysm formation with its myriad complications including compressive myelopathy. PMID- 22925535 TI - Sporadic myopathy, myoclonus, leukoencephalopathy, neurosensory deafness, hypertrophic cardiomyopathy and insulin resistance associated with the mitochondrial 8306 T>C MTTK mutation. AB - We report a new T8306C transition in the D-stem of the MTTK gene of a 67-year-old man who manifested severe adult onset myopathy, myoclonus, leukoencephalopathy, neurosensory hypoacusis, hypertrophic cardiomyopathy and insulin resistance. No other family member was affected, suggesting that our patient was a sporadic case. The T8306C mutation was heteroplasmic in several tissues of the proband, while it was absent from his asymptomatic siblings. Single fibre analysis confirmed the segregation of higher mutational load in cytochrome c oxidase deficient fibres. The mutation T8306C is predicted to disrupt a highly conserved base pair and was not found in more than 120 controls. This finding broadens the phenotypic and molecular spectrum of mitochondrial tRNA(Lys) associated disorders. PMID- 22925536 TI - Peptidoglycan induced expression of peroxisome proliferator-activated receptor gamma in mouse peritoneal macrophages: role of ERK and JNK MAP kinases. AB - The peroxisome proliferator-activated receptor (PPAR) gamma plays an important role in macrophage inflammatory homeostasis. Here we investigate the cross talk between PPARgamma and TLR2 signaling pathway in mouse peritoneal macrophages. Real time RT-PCR and immunoblot analysis revealed that peptidoglycan (PGN) treatment of macrophages leads to biphasic effect on PPARgamma expression i.e. an early upregulation and a late suppression. Inhibition of ERK MAP kinase by PD98059 abolished the early and rapid induction of PPARgamma, while the inhibition of JNK MAP kinase by SP600125 nullifies the late inhibitory effect on the PPARgamma expression in a dose-dependent manner. Furthermore, PPARgamma knockdown macrophages showed enhanced NF-kappaB activity after PGN treatment. PGN treatment also enhances PPARgamma interaction with p65 as observed by immunoprecipitation. This interaction may inhibit NF-kappaB (p65) activity as increased nuclear localization of p65 was observed in PPARgamma knockdown macrophages after PGN treatment. PPARgamma knockdown also increased the PGN induced inflammatory cytokines (TNF-alpha, IL-1beta, IL-12p40) production. Thus, our observations suggest that PGN induces PPARgamma expression which is regulated by MAPKs activation and this enhanced PPARgamma in turn attenuate NF-kappaB activity probably via enhancing p65 nuclear export. These results provide insight into how these pathways could be modulated in inflammatory diseases. PMID- 22925537 TI - Effects of a 1-year supplementation with cholecalciferol on interleukin-6, tumor necrosis factor-alpha and insulin resistance in overweight and obese subjects. AB - Insufficient vitamin D status has been linked to autoimmune diseases, cancer and metabolic disorders, like obesity and insulin resistance. In vitro and animal studies suggest that vitamin D may play a crucial role in immune activation and inflammation. The relation between vitamin D and pro-inflammatory cytokines is not completely established. Furthermore, it is not known if the effect of vitamin D on entities of metabolic syndrome is mediated through its effect on cytokines or other biomarkers. The objectives of this study were to investigate if there is a relationship between vitamin D status and such pro-inflammatory cytokines as tumor necrosis factor-alpha (TNF-alpha), interleukin 6 (IL-6) and high sensitive C-reactive protein (hs-CRP) in patients with overweigh and obesity. We also proposed that the intervention with high dose of cholecalciferol may have effect on the cytokine levels and result in corresponding changes in the measures of insulin resistance (HOMA-IR and QUICKI). Serum levels of IL-6, TNF-alpha and hs CRP were measured in 332 overweight and obese subjects who completed a 1-year randomised intervention with either 40,000 IU vitamin D (cholecalciferol) per week or 20,000 IU vitamin D per week, or placebo. We found significant associations between IL-6, TNF-alpha, vitamin D and insulin resistance indices at baseline. One year intervention with vitamin D decreased serum IL-6 levels; however hs-CRP levels were significantly increased. Neither measures of insulin resistance, nor TNF-alpha were influenced by a 1-year vitamin D supplementation. PMID- 22925538 TI - [Infants wearing teething necklaces]. AB - Numerous infants wear teething necklaces, a quack remedy with a real risk of strangulation or aspiration of small beads. AIMS: Evaluate parental perceptions and beliefs about the use of teething necklaces and analyze parental knowledge about the associated dangers. MATERIAL AND METHODS: Between March and July 2011, in three different pediatric units of a tertiary children's hospital and a general hospital in Toulouse and Montauban (southwest France), voluntary parents were invited to be interviewed about their child wearing a teething necklace. The interviews were conducted following an anthropological approach: they were recorded and then fully transcribed and analyzed. Parents were informed that the conversation was recorded. RESULTS: During the study period, 48 children were eligible. Eleven families refused to participate, 29 parents were interviewed face to face. The children's mean age was 14 years +/- 7 months, the male:female ratio was equal to 0.8 (12 boys, 15 girls). The mean age of children when necklace wearing was started was equal to 4 +/- 2 months. The mean mother's age was 31 +/- 5 years and 33 +/- 4 years for fathers. The parents' religion was mostly Catholic (60%). Teething necklaces were mainly made of amber (n=23). Sales information about the risks associated with the necklaces was for the most part absent (92%). The most frequent positive parental perceptions were analgesic properties and a soothing remedy (73%); a birth accessory and memory (64%); an esthetic accessory (60%); a protective amulet (60%); and an alternative or additional element to other traditional therapeutics (55%). The negative parental perceptions (n=4) were an unnecessary accessory, costume jewelry, a pure commercial abuse of a popular belief, a dangerous item with a risk of strangulation, and the absence of proof of its efficacy. COMMENTS: Although parents concede that teeth eruption is benign, they fear its related symptoms. To a natural phenomenon a natural response: they use a necklace to satisfy the analogy. The parental approach of this usage is consistent with accessorizing the child to protect and help them during a difficult stage. When informed of the danger of strangulation, numerous families preferred to continue this practice; their irrational fear of seeing their child suffer surpassed their fear of the risk of strangulation. CONCLUSION: Putting necklaces on young children is dangerous. This risk must be diffused by all professionals working with small children in order to stop any publicity or sale of this ineffective product implicated in infant deaths by strangulation. PMID- 22925539 TI - [Epidemiology of orofacial clefts (1995-2006) in France (Congenital Malformations of Alsace Registry)]. AB - OBJECTIVES: To review clinical and epidemiologic data of orofacial clefts and to evaluate the efficacy and the impact of prenatal diagnosis. MATERIAL AND METHODS: A population-based retrospective study was carried out on data from the Congenital Malformations of Alsace Registry (France) between 1995 and 2006. RESULTS: A total of 321 orofacial clefts were recorded (overall prevalence, 2.1 per 1000), divided into cleft lip (CL) or cleft lip palate (CLP) (204 cases) and cleft palate (117 cases). The cleft lip and cleft lip palate CL+/-P sex-ratio was 1.87, whereas the CP sex-ratio was 1. CLs were more often unilateral than CLPs (79% versus 59%). CLs were unilateral in 79% of the cases (60/76), bilateral in 20% of the cases (15/76), and median in 1% (1/76); 55% of the unilateral CLs were right and 45% were left. CLPs were unilateral in 59% of the cases (76/128), bilateral in 39% of the cases (50/128), and median in 2% (2/128); 45% of the unilateral CLPs were right and 55% were left. The 117 CPs were divided into 50 clefts of the total palate (43%) and 67 clefts of the posterior palate (57%); 25 cases (21%) of Pierre Robin sequence were collected. Sixty-six percent of CL+/-P (134/204) were associated with other congenital anomalies, including chromosome abnormality in 31 cases and identified monogenic syndrome or association in 12 cases. The most frequent chromosome abnormalities were 16 cases of trisomy 13 and 7 cases of trisomy 18. No cases of 22q11.2 microdeletion or duplication were detected among CL+/-P. Monogenic syndromes were identified in 6% (12/204) of CL+/ P cases: Van der Woude syndrome (2 cases); CHARGE syndrome (2 cases); ectrodactyly, ectodermal dysplasia, and cleft/lip palate (EEC) syndrome (2 cases); branchiooculofacial (BOF) syndrome (1 case); Treacher-Collins syndrome (1 case); Nager syndrome (1 case); Goldenhar syndrome (1 case); holoprosencephaly spectrum (1 case); and Meckel syndrome (1 case). Forty-two percent of CPs (49/117) were associated with other congenital anomalies; chromosome abnormality was identified in 12 cases and monogenic syndrome was diagnosed in 14 cases. The most frequent chromosome abnormality was 22q11 microdeletion (5 cases). Monogenic syndromes were recognized in 12% of the CP cases (14/117): fragile X syndrome (2 cases), Meckel syndrome (2 cases), Orofaciodigital syndrome type I (OFD1) (1 case), Stickler syndrome (1 case), Larsen syndrome (1 case), Kniest syndrome (1 case), Cornelia de Lange syndrome (1 case), thanatophoric dysplasia (1 case), other unknown bone chondrodysplasia (1 case), Fryns syndrome (1 case), fetal akinesia sequence (1 case), and Silver-Russel syndrome (1 case). Fifty-two percent of CL cases (106/204) were prenatally diagnosed. An increasing tendency was observed between the 1995-2000 and 2001-2006 periods with a detection rate increasing from 47% to 56%. During the whole period, only 1 case of CP was prenatally diagnosed. Eighty-two percent of all cases (263/321) were livebirths; 8 stillbirths were reported (2%); 50 syndromic or associated cases (16%) led to medical abortion (no termination of pregnancy was performed for isolated cleft). CONCLUSION: Orofacial clefts are a frequent malformation with a total prevalence of 2.1 per 1000 total births. Sonbographic prenatal diagnosis of orofacial clefts remains difficult with a mean detection rate about 50% for CL+/-P and is extremely rare for CP. Associated malformations and genetic syndromes are frequent and require a systematic survey. This study also highlights the different pathogenic background of CL+/-P compared to CP, regarding the sex-ratio and the proportion and type of associated malformations. PMID- 22925541 TI - Editorial comment from Dr Saito to impact of hyponatremia on survival of patients with metastatic renal cell carcinoma treated with molecular targeted therapy. PMID- 22925540 TI - [Nasopharyngeal carriage of children 6 to 60 months during the implementation of the 13-valent pneumococcal conjugate vaccine]. AB - BACKGROUND: Since 2001 in France, a nasopharyngeal carriage study was set up for children six to 24 months old. Any data are available for older children (25 to 60 months). The aim of this study is to compare the nasopharyngeal carriage in children with acute otitis media (AOM) or healthy between both age groups (6/24 months versus 25/60 months). Moreover, during the study period, the 13-valent pneumococcal conjugate vaccine (PCV13) has replaced PCV7 in June 2010. METHODS: From October 2010 to June 2011, 58 pediatricians obtained nasopharyngeal swabs from children 6-60 months with acute otitis media (AOM) or healthy controls, to analyse the carriage of pneumococcus, Haemophilus influenzae, Moraxella catarrhalis, group A streptococcus and Staphylococcus aureus. RESULTS: Of the 1557 enrolled children, 1258 were 6 to 24 months old (315 healthy and 943 AOM) and 299 were 25 to 60 months (102 healthy and 197 AOM). More then 85% were PCV7 vaccinated and the children of 25/60 months were rarely PCV13 vaccinated (14.1%) compared to younger children (69.9%, P<0.001). For children 6/24 months, the Streptococcus pneumoniae carriage was higher in AOM group (57.3%) versus healthy (28.9%). By contrast for older children, the difference (58.4% versus 50%) was not significant. In the healthy group, older children carried more often S. pneumoniae than younger children (50% versus 28.9%, P<0.0001). This trend was also observed for H. influenzae carriage (49% versus 18.7%, P<0.0001). Multivariate analysis in the healthy group showed that siblings and day care center (or school) increased the carriage of S. pneumoniae and H. influenzae. CONCLUSION: These data from nasopharyngeal carriage in children 6 to 60 months old showed that pneumococcus and H. influenzae carriage is high for patients under 2 years, especially in the healthy group. Moreover, these data from the transition PCV7/PCV13, will serve as baseline in France to evaluate the impact of PCV13. PMID- 22925543 TI - Fetomaternal hemorrhage with intraplacental chorioangioma. AB - A 37-year-old Asian woman, gravid 0 para 0, was admitted to our hospital at 34 weeks and 5 days of her pregnancy for management of preeclampsia. A few days after admission, she recognized diminished fetal movement, and a non-stress test revealed a non-reassuring fetal heart rate pattern with decreased variability. A female baby weighing 1840 g was delivered by emergency cesarean section with Apgar scores of 5 and 5 at 1 and 5 min, respectively. Significant neonatal anemia with a hemoglobin level of 4.3 g/dL was observed. The elevated level of hemoglobin F (HbF) in the maternal blood accounted for 4.6% (normal?0.5%), and was indicative of the presence of fetomaternal hemorrhage (FMH). Microscopic examination of the placenta revealed chorioangioma. We report here a rare case of FMH with intraplacental chorioangioma, and discuss the relationship between these two pathologies. PMID- 22925542 TI - Sugar free, cancer free? PMID- 22925544 TI - Getting through the day: exploring patients' leisure experiences in a private hospital. AB - AIMS AND OBJECTIVES: To explore the patients' leisure experience and their leisure needs and expectations during hospitalisation in a private hospital setting. BACKGROUND: Leisure plays positive roles in patient satisfaction and has functional values. However, studies on how inpatients spend their time and hospital-based qualitative studies on leisure needs and expectation among patients were rarely conducted. Through exploring patients' perspective on leisure, nurses could improve patient satisfaction from a different dimension and enhance quality of care. DESIGN: A descriptive qualitative study based on 12 semi structural interviews. METHODS: Applied purposive sampling to select and interview a total of 16 participants, including 12 patients and four patients' significant others in a private hospital. Semi-structured interviews were conducted at the patients' bedside in summer 2011. Interviews were recorded and transcribed verbatim. Content analysis approach was used to analyse data and to categorise themes. RESULTS: Four themes were developed: (1) getting through the day, which describes how patients spend their time during hospitalisation and their daily leisure activities; (2) necessity of leisure, which reveals the reasons why patients conducted the activity; (3) resources amelioration, which describes patients' needs and satisfaction on current leisure resources in the hospital; (4) nurses' roles in leisure, which is about the involvement of nurses in patients' leisure activities. CONCLUSION: As patients understand hospital is a place for recovery, they seldom discuss or request their choices of leisure activity. This study could provide some insight into patients' needs and expectation of leisure activity during hospitalisation, allowing nurses to know the importance of providing leisure activities to patients. RELEVANCE TO CLINICAL PRACTICE: This study suggests that clinical nursing practice should support leisure provision and hospital resources management of facilities on the effects of leisure. PMID- 22925545 TI - Regionalisation of climate change sensitive forest development types for potential afforestation areas. AB - This paper describes how to use sectoral planning information from forestry to predict and up-scale information on Climate Change sensitive forest development types for potential afforestation areas. The method was developed and applied in the frame of the project RegioPower with focus on the case study region 'Oberes Elbtal-Osterzgebirge'. The data for our study was taken from forest management planning at level of the Federal State of Saxony, Germany. Here, a silvicultural system is implemented, which describes best practices to develop our actual forests into Climate Change adapted forest development types. That includes the selection of drought resistant tree species, a broad range of tree species mixtures per eligible forest development type and the tending, harvesting and regeneration strategies to be applied. This information however, exists only for forest areas and not for areas which could be potentially afforested. The eligibility of the forest development types within the actual forest areas depends on site information, such as nutrient potential, exposition and hydrological soil parameters. The regionalisation of the forest development types to landscape scale had to be based on topographical parameters from the digital elevation model and hydrological soil parameters from soil mapping. In result, we could provide maps for regional planning and decision making with spatially explicit information on the eligible forest development types based on forest management planning information. These maps form a valuable input for testing and optimising afforestation areas with regard to improving the ability of our case study region to mitigate Climate Change effects such as water erosion or drought. PMID- 22925547 TI - Role of 14-3-3-beta in the migration and invasion in human malignant glioma cell line U87MG. AB - PURPOSE: To assess the influence of 14-3-3-beta in modulating the migration and invasion of human glioma cells. METHODS: To profile the genes associated with malignant glioma cell motility, differential display-polymerase chain reaction was performed and the findings were validated by Northern blotting in the U343MG A, U87MG, and U87MG-10' human glioma cell lines. Antisense 14-3-3-beta cDNA plasmid was transfected into U87MG ('U87-YA-3'). To follow motility changes after transfection, simple scratch test and matrigel assay were performed. Morphological and cytoskeletal changes were documented by light and confocal microscopy. In addition, doubling times of the transfectant and endogenous 14-3-3 beta levels were determined in various glioma cell lines with different motilities. RESULTS: 14-3-3-beta was highly expressed in U87MG cells. U87-YA-3 cells became small and flat, and actin was depolarized. Furthermore, U87-YA-3 cell motility was inhibited markedly versus parental U87MG cells. The doubling times of transfected and parent cells were 32 and 37 hours, respectively. Endogenous 14-3-3-beta expression in the human glioma cell lines was proportional to their migratory and invasive abilities. CONCLUSION: 14-3-3-beta modulates the migration and invasion in U87MG cells, which may be useful in developing therapeutic approaches for the treatment of glioma. PMID- 22925548 TI - Rapid sonochemical synthesis of irregular nanolaminar-like Bi2WO6 as efficient visible-light-active photocatalysts. AB - Irregular Bi(2)WO(6) nanolaminars have been successfully synthesized via a rapid sonochemical approach using bismuth nitrate and tungstic acid as precursors in an aqueous solution. The characteristics of them were investigated in detail by X ray diffraction (XRD), scanning electron microscopy (SEM), transmission electron microscopy (TEM), N(2) adsorption, pore value, PL spectroscopy and UV-vis diffuse reflectance spectroscopy (UV-vis DRS). These irregular nanolaminars are of geometric shapes of orthorhombic Bi(2)WO(6) with their basal plane being (001). They possess high crystallinity, lager surface area and pore value, which means fewer traps and stronger photocatalytic activity. The growth mechanism of such special nanolaminar was related to the sonochemical synthesis route, which played a key role in the formation of Bi(2)WO(6) nanolaminar. Simultaneously, it was found that the formation of Bi(2)WO(6) nanolaminar is a time dependent process. The Bi(2)WO(6) nanolaminar has higher photocatalytic activity than bulk Bi(2)WO(6) nanoparticle obtained by refluxing method for rhodamine B (Rh.B) degradation under visible light irradiation (lambda>400 nm). PMID- 22925549 TI - Ultrasonic irradiation assisted surface modification of titanium plates to improve MC3T3-E1 cell proliferation. AB - The surface modification of titanium implants by NaOH has been widely investigated to improve their biocompatibility and bioactivity. It is very important to prepare an even network structure on titanium implants. In this work, ultrasonic irradiation (UI) is used along two different routes to obtain several modified surfaces on titanium plates: (1) the plates are first treated by a NaOH solution, and then UI is used to wash them in double distilled water; (2) the plates are modified by a NaOH solution in an ultrasonic cleaner with UI at 50 W. It is demonstrated that the UI energy can easily remove any weakly bound layers (WBL) on the titanium surface, leaving a strongly bound layer (SBL). The SBL is shown to enhance the proliferation of MC3T3-E1 preosteoblasts in comparison with the WBL. A dense and uniformly distributed nanostructure layer can be synthesized in situ on the surface of metallic titanium through a reaction between a NaOH solution and titanium under UI. The titanium plates prepared with NaOH and UI show better proliferation of preosteoblasts than titanium without UI. PMID- 22925550 TI - Acid-induced gelation behavior of soybean protein isolate with high intensity ultrasonic pre-treatments. AB - High intensity ultrasonic (HUS, 20 kHz, 400 W) pre-treatments of soybean protein isolate (SPI) improved the water holding capacity (WHC), gel strength and gel firmness (final elastic moduli) of glucono-delta-lactone induced SPI gels (GISG). Sonication time (0, 5, 20, and 40 min) had a significant effect on the above three properties. 20 min HUS-GISG had the highest WHC (95.53 +/- 0.25%), gel strength (60.90 +/- 2.87 g) and gel firmness (96340Pa), compared with other samples. Moreover, SH groups and non-covalent interactions of GISG also changed after HUS pre-treatments. The HUS GISG had denser and more uniform microstructures than the untreated GISG. Rheological investments showed that the cooling step (reduce the temperature from 95 to 25 degrees C at a speed of 2 degrees C/min) was more important for the HUS GISG network formation while the heat preservation step (keep temperature at 95 for 20 min) was more important for the untreated GISG. HUS reduced the particle size of SPI and Pearson correlation test showed that the particle size of SPI dispersions was negatively correlated with WHC, gel strength and gel firmness. PMID- 22925551 TI - [Ertapenem administered intravenously or subcutaneously for urinary tract infections caused by ESBL producing enterobacteriacea]. AB - INTRODUCTION: Ertapenem could be used to treat urinary tract infections (UTI) caused by ESBL producing enterobacteriacae (ESBL-E) and administered subcutaneously. METHOD: The authors made a retrospective study on adult patients treated with ertapenem administered intravenously or subcutaneously for UTI caused by ESBL-E, between May 2009 and August 2011 at the Chambery hospital, France. RESULTS: Twenty-five patients were treated (13 cases of prostatitis, ten of pyelonephritis, two of cystitis) mostly caused by Escherichia coli (24 cases). Subcutaneous injections were administered to 20 patients and 23 were treated through outpatient parenteral antibiotic therapy (OPAT). All patients were cured at the end of the ertapenem therapy. Urine samples collected during treatment for 12 patients were sterile. Three months after the end of the treatment, five patients had relapsed, and six had developed a UTI caused by another bacteria. CONCLUSION: Ertapenem administered intravenously or subcutaneously could be an effective treatment for UTI caused by ESBL-E, especially using OPAT. PMID- 22925552 TI - Comment on ESGE clinical guideline for biliary stenting. AB - The European Society of Gastrointestinal Endoscopy (ESGE) guidelines for biliary stenting published in 2012 are summarised and discussed. PMID- 22925553 TI - Comment on the British Society of Gastroenterology guidelines for management of autoimmune hepatitis (part 2). AB - The British Society of Gastroenterology guidelines for management of autoimmune hepatitis (AIH) were recently published in Gut. The chapters concerning the treatment of AIH are addressed here. PMID- 22925557 TI - Factors associated with inappropriate complementary feeding practices among children aged 6-23 months in Tanzania. AB - Inappropriate complementary feeding is one of the major causes of undernutrition among young children in Tanzania. Prevalence of newly developed World Health Organization complementary feeding indicators and their associated factors were determined among 2402 children aged 6-23 months in Tanzania using data from the 2010 Tanzania Demographic and Health Survey. The survey used a multistage cluster sample of 10 300 households from the eight geographical zones in the country. The prevalence of the introduction of soft, semi-solid or solid foods among infants aged 6-8 months was 92.3%. Of all the children aged 6-23 months, the prevalence of minimum dietary diversity, meal frequency and acceptable diet were 38.2%, 38.6% and 15.9%, respectively. Results from multivariate analyses indicated that the main risk factors for inappropriate complementary feeding practices in Tanzania include young child's age (6-11 months), lower level of paternal/maternal education, limited access to mass media, lack of post-natal check-ups, and poor economic status. Overall, complementary feeding practices in Tanzania, as measured by dietary diversity, meal frequency and acceptable diet, are not adequately met, and there is a need for interventions to improve the nutritional status of young children in Tanzania. PMID- 22925554 TI - Revision of reversed total shoulder arthroplasty. Indications and outcome. AB - BACKGROUND: The complications of reversed total shoulder arthroplasty (RTSA) requiring an additional intervention, their treatment options and outcome are poorly known. It was therefore the purpose of this retrospective study, to identify the reasons for revision of RTSA and to report outcomes. METHODS: Four hundred and forty-one performed RTSA implanted between 1999 and 2008 were screened. Sixty-seven of these cases had an additional intervention to treat a complication. Causes were identified in these 67 cases and the outcome of the first 37 patients who could be followed for more than two years after their first additional intervention was analyzed. RESULTS: Of 441 RTSA, 67 cases (15%) needed at least one additional intervention to treat a complication, 30 of them needed a second, eleven a third and four a fourth additional intervention. The most common complication requiring a first intervention was instability (18%) followed by hematoma or superficial wound complications (15%) and complications of the glenoid component (12%). Patients benefitted from RTSA despite the need of additional interventions as indicated by a mean increase in total Constant-Murley score from 23 points before RTSA to 46 points at final follow-up (p < 0.0001). CONCLUSIONS: Instability, hematoma or superficial wound complications and complications of the glenoid component are the most common reasons for an additional intervention after RTSA. Patients undergoing an additional intervention as treatment of these complications profit significantly as long as the prosthesis remains in place. PMID- 22925558 TI - Injectate volumes needed to reach specific landmarks in s1 transforaminal epidural injections. AB - OBJECTIVES: We identify the contrast volumes needed to reach specific landmarks during S1 transforaminal epidural injections (S1-TFEIs). DESIGN: Prospective, nonrandomized, observational human study. Setting. Academic/private pain management practice. Subjects. Forty-two patients undergoing S1-TFEIs were investigated. Thirty-seven patients were included in this study. Interventions. S1-TFEIs were performed using contrast-enhanced fluoroscopic visualization. MAIN OUTCOME MEASUREMENTS: After confirming appropriate spinal needle position, up to 5 mL of nonionic contrast was slowly injected. Under biplanar fluoroscopic guidance, contrast volumes were recorded as flow reached specific anatomic landmarks: the ipsilateral S1 pedicle, the superior aspect of the L5-S1 disc space, and across the midline of the spinous process. RESULTS: After injecting 2 mL of contrast, 100% of S1-TFEIs spread to the medial aspect of the ipsilateral superior pedicle of S1. After injecting 3.0 mL of contrast, 92% of S1-TFEIs spread to the superior aspect of the L5-S1 intervertebral disc. After injecting 4 mL of contrast, 27% of S1-TFEIs spread beyond the midline of the spinous process, but by only a few millimeters. CONCLUSIONS: This study demonstrates injectate volumes needed to reach specific anatomic landmarks in S1-TFEIs. A volume of 3.0 mL of contrast reaches the superior aspect of the L5-S1 intervertebral disc 92% of the time. PMID- 22925559 TI - A new device for simultaneous measurement of pelvic floor muscle activity and vaginal blood flow: a test in a nonclinical sample. AB - INTRODUCTION: Dyspareunia in women, defined as persistent or recurrent genital pain associated with sexual intercourse, is hypothesized to be related to (fear associated) pelvic floor hyperactivity and to diminished sexual arousal. Psychophysiological research to support these hypotheses is scarce and concentrates mostly on the role of either pelvic floor activity or sexual arousal. To investigate both factors, a measurement device that enables simultaneous assessment of pelvic floor muscle activity and genital sexual arousal would be most optimal. AIM: The aim of this study was to test a new vaginal device0-a vaginal photoplethysmograph with build-in surface electromyography (EMG)--that allows simultaneous assessment of pelvic floor muscle activity and vaginal blood flow. MAIN OUTCOME MEASURES: Genital arousal measured as vaginal pulse amplitude (VPA) and vaginal surface EMG. METHODS: Thirty-six sexually functional women participated. To investigate the sensitivity of the device for changes in genital blood flow and involuntary changes in pelvic floor activity, VPA and vaginal surface EMG were monitored during exposure to sexual and anxiety-evoking film clips. In addition, vaginal surface EMG was monitored during voluntary flick and hold contractions. RESULTS: VPA increased in response to the sexual film, and EMG values were significantly higher in response to the anxiety-evoking film. Higher EMG values in response to the anxiety film were associated with lower VPA. EMG during the instructed 3-second hold pelvic floor contractions showed, as expected, higher values during pelvic floor contractions with support of surrounding muscle groups, compared with pelvic floor muscles alone. CONCLUSION: The device is sensitive to changes in vaginal blood flow in response to sexual stimuli, and it is able to pick up small, involuntary changes in pelvic floor activity associated with anxiety. Also, the device is able to record changes in pelvic floor activity during voluntary pelvic floor contractions. This new device will be a valuable tool in further research on superficial dyspareunia. PMID- 22925560 TI - GMAC: a Matlab toolbox for spectral Granger causality analysis of fMRI data. AB - Investigation of causal interactions within brain networks using Granger causality analysis (GCA) is a key challenge in studying neural activity on the basis of functional magnetic resonance imaging (fMRI). The article describes an open-source software toolbox GMAC (Granger multivariate autoregressive connectivity) implementing multivariate spectral GCA. Available features are: fMRI data importing/exporting, network nodes definition, time series preprocessing, multivariate autoregressive modeling, spectral Granger causality indexes estimation, statistical significance assessment using surrogate data, network analysis and visualization of connectivity results. All functions have been integrated into a user-friendly graphical interface developed in the Matlab environment, easily accessible to both technical and clinical users. PMID- 22925561 TI - Identification and analysis of pig chimeric mRNAs using RNA sequencing data. AB - BACKGROUND: Gene fusion is ubiquitous over the course of evolution. It is expected to increase the diversity and complexity of transcriptomes and proteomes through chimeric sequence segments or altered regulation. However, chimeric mRNAs in pigs remain unclear. Here we identified some chimeric mRNAs in pigs and analyzed the expression of them across individuals and breeds using RNA sequencing data. RESULTS: The present study identified 669 putative chimeric mRNAs in pigs, of which 251 chimeric candidates were detected in a set of RNA sequencing data. The 618 candidates had clear trans-splicing sites, 537 of which obeyed the canonical GU-AG splice rule. Only two putative pig chimera variants whose fusion junction was overlapped with that of a known human chimeric mRNA were found. A set of unique chimeric events were considered middle variances in the expression across individuals and breeds, and revealed non-significant variance between sexes. Furthermore, the genomic region of the 5' partner gene shares a similar DNA sequence with that of the 3' partner gene for 458 putative chimeric mRNAs. The 81 of those shared DNA sequences significantly matched the known DNA-binding motifs in the JASPAR CORE database. Four DNA motifs shared in parental genomic regions had significant similarity with known human CTCF binding sites. CONCLUSIONS: The present study provided detailed information on some pig chimeric mRNAs. We proposed a model that trans-acting factors, such as CTCF, induced the spatial organisation of parental genes to the same transcriptional factory so that parental genes were coordinatively transcribed to give birth to chimeric mRNAs. PMID- 22925562 TI - Relation between expression pattern of wild-type p53 and multidrug resistance proteins in human nephroblastomas. AB - One of the best characterized resistance mechanisms of human cancer is multidrug resistance (MDR) mediated by P-glycoprotein (Pgp/MDR1) and multidrug-resistant related protein (MRP1). In addition to Pgp/MDR1 and MRP1, p53 inactivation or mutation might play a relevant role in therapeutic failure. This study involved 25 children (17 girls and 8 boys) aged 7 months to 10 years treated for unilateral Wilms' tumor. 25 tissue samples of Wilms' tumor and 5 samples of normal human kidneys were obtained from the Department of Pathological Anatomy, Jessenius Faculty of Medicine in Martin, Slovak Republic. We used an indirect immunohistochemical method to determine expression of Pgp/MDR1, MRP1 and wild type p53 in 25 tissue samples of nephroblastoma. The minority of nephroblastoma specimens showed positivity for both MDR proteins, as well as for wild-type p53. 24% of tissue samples revealed positive results for Pgp/MDR1, 48% for MRP1 and 8% for wild-type p53. Furthermore, our study showed a statistically significant difference between p53 and MRP1 protein expression (p<0.01), but not between p53 and Pgp/MDR1 (p>0.05). No correlation was found between the expression of both multidrug resistance proteins (Pgp/MDR1 and MRP1) and the expression of wild-type p53. Immunohistochemical detection of the expression of MDR proteins and wild type p53 at the time of diagnosis might assist in choosing specific chemotherapeutics to improve prognosis and therapy. PMID- 22925563 TI - In vitro infection with classical swine fever virus inhibits the transcription of immune response genes. AB - BACKGROUND: Classical swine fever virus (CSFV) can evade the immune response and establish chronic infection under natural and experimental conditions. Some genes related to antigen processing and presentation and to cytokine regulation are known to be involved in this response, but the precise mechanism through which each gene responds to CSFV infection remains unclear. RESULTS: In this study, the amplification standard curve and corresponding linear regression equations for the genes SLA-2, TAP1, SLA-DR, Ii, CD40, CD80, CD86, IFN-alpha, and IFN-beta were established successfully. Real-time RT-PCR was used to quantify the immune response gene transcription in PK-15 cells post CSFV infection. Results showed that: (1) immune response genes were generally down-regulated as a result of CSFV infection, and (2) the expression of SLA-2, SLA-DR, Ii and CD80 was significantly decreased (p < 0.001). CONCLUSION: We conclude that in vitro infection with CSFV inhibits the transcription of host immune response genes. These findings may facilitate the development of effective strategies for controlling CSF. PMID- 22925564 TI - In vitro and in vivo therapeutic efficacy of CXCR4 antagonist BKT140 against human non-small cell lung cancer. AB - OBJECTIVES: CXCR4/CXCL12 interactions promote non-small cell lung cancer (NSCLC) growth and dissemination. Furthermore, this axis might promote NSCLC resistance to chemotherapy and/or radiotherapy. Therefore, the CXCR4/CXCL12 axis constitutes an attractive therapeutic target for the treatment of NSCLC. We aimed to characterize the therapeutic efficacy of the novel CXCR4 antagonist BKT140 against human NSCLC. METHODS: We determined the CXCR4 expression in 5 NSCLC cell lines (H358, A549, H460, H1299, and L4). We then tested the colony-forming capacity and proliferation of these cells in the presence of CXCL12 and BKT140. Next, we measured the in vivo growth of A549 and H460 xenografts with or without BKT140 treatment. Finally, we examined, in vitro, the potential antiproliferative effect of BKT140 combined with cisplatin or paclitaxel and after irradiation of NSCLC cells. RESULTS: All tested cell lines expressed CXCR4 and showed increased colony formation in response to CXCL12 stimulation. BKT140 reduced the colony forming capacity of NSCLC cells. Proliferation assays demonstrated both cytotoxic and cytostatic properties for this peptide. H460 cells were the most sensitive to BKT140 and A549 cells the least. Subcutaneous administration of BKT140 significantly delayed the development of H460 xenografts and showed a similar trend for A549 xenografts. Finally, the antiproliferative effects of BKT140 appears to be additive to those of chemotherapeutic drugs and radiotherapy. CONCLUSIONS: Targeting the CXCL12/CXCR4 axis with BKT140 attenuated NSCLC cells tumor growth and augmented the effects of chemotherapy and radiotherapy. Future research will benefit from delineating the downstream mechanism of BKT140 action and defining BKT140 susceptibility markers. PMID- 22925565 TI - Stroke after coronary artery bypass grafting: preoperative predictive accuracies of CHADS2 and CHA2DS2VASc stroke risk stratification schemes. AB - OBJECTIVE: Neurologic events after coronary artery bypass grafting are an infrequent but devastating complication. This study analyzed the preoperative predictive abilities of the CHADS(2) and CHA(2)DS(2)VASc stroke scores in patients undergoing isolated coronary artery bypass grafting. METHODS: Included in the study were 2910 patients who underwent isolated coronary artery bypass grafting during a 19-year period. CHADS(2) and CHA(2)DS(2)VASc scores were computed for all patients, and outcomes were evaluated in terms of perioperative stroke and compared with 2 specific models for predicting surgical coronary artery bypass grafting stroke (Northern New England Cardiovascular Disease Study Group and Multicenter Study of Perioperative Ischemia Research Group). Perioperative stroke discrimination was quantified by computing the area under the receiver operating characteristic curve. RESULTS: Overall, 62 (2.1%) had perioperative strokes. Areas under the curve were 0.71 (95% confidence interval, 0.64-0.78) for CHADS(2), 0.72 (95% confidence interval, 0.65-0.79) for CHA(2)DS(2)VASc, 0.69 (95% confidence interval, 0.61-0.76) for Northern New England Cardiovascular Disease Study Group, and 0.73 (95% confidence interval, 0.67-0.80) for Multicenter Study of Perioperative Ischemia Research Group scores. Northern New England Cardiovascular Disease Study Group and CHA(2)DS(2)VASc scores were better at discriminating patients with particularly low or high risk of stroke. CONCLUSIONS: CHADS(2) and CHA(2)DS(2)VASc scores predicted perioperative coronary artery bypass grafting strokes with discriminatory abilities similar to those of specific predictive surgical coronary artery bypass grafting stroke models. All schemes tested showed similar limitations in discriminating patients with high postoperative stroke risk, with a high proportion being classified as having intermediate stroke risk. PMID- 22925566 TI - Size of the right ventricle-to-pulmonary artery conduit impacts mid-term outcome after the Norwood procedure in patients weighing less than 3 kg. AB - OBJECTIVE: The optimal shunt size for patients who have the Norwood operation with a right ventricle-to-pulmonary artery conduit is controversial. The goal of this study is to compare outcomes of 2 shunt sizes in this population. METHODS: Between 2002 and 2010, 75 consecutive patients diagnosed with hypoplastic left heart syndrome and its variants underwent the Norwood procedure with a right ventricle-to-pulmonary artery conduit. The outcomes of 20 neonates weighing <3 kg were analyzed. RESULTS: The cumulative 30-day stage 1 survival [corrected] was 97% (95% confidence interval, 88%-99%) for all patients (73/75), 20 of whom weighed <3 kg. Nine patients had a 6-mm (group 1) and 11 patients had a 5-mm (group 2) right ventricle-to-pulmonary artery conduit. Thirty-day stage 1 survival was 88% (8/9) in group 1 and 90% (10/11) in group 2 (P = .88). The central pulmonary artery confluence size at prebidirectional cavopulmonary shunt catheterization was 4.5 +/- 1.2 mm in group 1 and 2.5 +/- 1.0 mm in group 2 (P = .009). The mean transpulmonary gradient was higher in group 2 (7.8 +/- 3.1 mm Hg vs 4.2 +/- 1.9 mm Hg; P = .036). The incidence of pulmonary artery intervention was 16% (1/7) in group 1 and 75% (6/8) in group 2 (P = .030). Survival rate at 6 months was 66% (6/9) in group 1 and 70% (7/10) in group 2 (P = .89). CONCLUSIONS: Use of a 6-mm right ventricle-to-pulmonary artery conduit showed better central pulmonary artery growth and less need for pulmonary artery intervention in the authors' experience. PMID- 22925567 TI - Reversible pulmonary trunk banding: VII. Stress echocardiographic assessment of rapid ventricular hypertrophy in young goats. AB - BACKGROUND: Ventricle retraining with abrupt systolic overload can cause myocardial edema and necrosis, followed by late ventricular failure. Intermittent systolic overload could minimize the inadequacy of conventional pulmonary artery banding. The present study compared ventricle function under dobutamine stress in 2 protocols of systolic overload in young goats. METHODS: Nineteen young goats were divided into 3 groups: sham (n = 7; no systolic pressure overload), continuous (n = 6; systolic overload maintained for 96 hours), and intermittent (n = 6; 4 periods of 12-hour systolic overload, paired with a 12-hour resting period). Echocardiographic and hemodynamic evaluations were performed daily. The myocardial performance index and ejection fraction were evaluated at rest and during dobutamine stress. The goats were then killed for morphologic evaluation. RESULTS: The intermittent group underwent less systolic overload than the continuous group (P < .05). Nevertheless, both groups had increased right ventricular and septal masses compared with the sham group (P < .0002). Echocardiography revealed a major increase in right ventricular wall thickness in the intermittent group (+64.8% +/- 23.37%) compared with the continuous group (+43.9% +/- 19.26%; P = .015). Only the continuous group remained with significant right ventricular dilation throughout the protocol (P < .001). The intermittent group had a significantly better myocardial performance index at the end of the protocol, under resting and dobutamine infusion, compared with the continuous group (P < .012). CONCLUSIONS: Both systolic overload protocols have induced rapid right ventricular hypertrophy. However, only the intermittent group had better preservation of right ventricular function at the end of the protocol, both at rest and during dobutamine infusion. PMID- 22925568 TI - Effect of cerebral protection strategy on outcome of patients with Stanford type A aortic dissection. AB - OBJECTIVE: The aim of the present study was to assess the efficacy and mid- to long-term results of different cerebral protection techniques in the treatment of acute type A aortic dissection. METHODS: Between April 1987 and January 2011, 329 patients (220 male patients; median age, 60 years; range, 16-87) with type A aortic dissection underwent replacement of the ascending aorta or aortic arch with an open distal anastomosis. Either hypothermic circulatory arrest alone at 18 degrees C (n = 116; 35%) or combined with retrograde cerebral perfusion (n = 122; 37%) or antegrade cerebral perfusion at 25 degrees C (n = 91; 28%) was used. RESULTS: The median circulatory arrest time was 30 minutes (range, 12-92). The overall 30-day mortality was 19% (62 of 329). The 30-day mortality stratified by group was 26% (30 patients) in the hypothermic circulatory arrest group, 16% in the retrograde cerebral perfusion group (20 patients), and 13% (12 patients) in the antegrade cerebral perfusion group (P = .047). Permanent neurologic dysfunction occurred in 53 patients (16%), with statistically significant differences among the 3 groups (23% for hypothermic circulatory arrest, 12% for retrograde cerebral perfusion, and 12% for antegrade cerebral perfusion; P = .033). Univariate analysis showed a significant effect of the brain protection strategy on 30-day mortality and neurologic outcome. Multivariate analysis revealed preoperative hemodynamic instability, preoperative resuscitation, age, and operative year as independent predictors of 30-day mortality. Regarding permanent neurologic dysfunction, the multivariate analysis could not identify any independent predictors. Kaplan-Meier analyses revealed statistically significant differences among the 3 groups with a 1-, 3-, and 5-year survival rate of 84%, 79%, and 77% with antegrade cerebral perfusion, 75%, 72%, and 66% with retrograde cerebral perfusion, and 66%, 62%, and 60% with hypothermic circulatory arrest alone. CONCLUSIONS: Patients in the antegrade cerebral perfusion group had the best short- and long-term survival rates. However, during the study period, several significant improvements in the treatment of patients with type A aortic dissection were achieved; therefore, independent predictors of mortality and permanent neurologic dysfunction were difficult to identify. PMID- 22925569 TI - Discussion. PMID- 22925570 TI - Reconstruction of the feeding apparatus in Postgaardi mariagerensis provides evidence for character evolution within the Symbiontida (Euglenozoa). AB - Microbial eukaryotes living in low oxygen environments often have novel physiological and morphological features that facilitate symbiotic relationships with bacteria and other means for acquiring nutrients. Comparative studies of these features provide evidence for phylogenetic relationships and evolutionary history. Postgaardi mariagerensis, for instance, is a euglenozoan that lives in low oxygen environments and is enveloped by episymbiotic bacteria. The general ultrastructure of P. mariagerensis was described more than a decade ago and no further studies have been carried out since, mainly because these cells are difficult to obtain. Postgaardi lacks the diagnostic features found in other major euglenozoan lineages (e.g., pellicle strips and kinetoplast-like mitochondrial inclusions) and no molecular data are available, so the phylogenetic position of this genus within the Euglenozoa remains unclear. We re examined and reconstructed the ultrastructural organization of the feeding apparatus in Postgaardi by serial sectioning an existing block of resin-embedded cells. Postgaardi possesses distinctive finger-like projections within the feeding apparatus; this system has only been found in one other highly distinctive flagellate, namely the symbiontid Calkinsia. Detailed comparisons of the cytoskeleton in Postgaardi and in two symbiontids, Calkinsia and Bihospites, provided new evidence for phylogenetic relationships and character evolution in all three genera. PMID- 22925571 TI - A mathematical model of the bovine oestrous cycle: simulating outcomes of dietary and pharmacological interventions. AB - A mathematical model was constructed to simulate the bovine oestrous cycle by using nonlinear differential equations to describe the biological mechanisms which regulate the cycle. The model predicts circulating concentrations of gonadotrophin-releasing hormone, follicle-stimulating hormone, luteinizing hormone, oestradiol, inhibin and progesterone. These hormones collectively provide control and feedback mechanisms between the hypothalamus, pituitary gland and ovaries, which regulate ovarian follicular dynamics, corpus luteum function and ovulation. When follicular growth parameters are altered, the model predicts that cows will exhibit either two or three follicular waves per cycle, as seen in practice. Changes in other parameters allow the model to simulate: effects of nutrition on follicle recruitment and size of the ovulatory follicle; effects of negative energy balance on postpartum anoestrus; and effects of pharmacological intervention on hormone profiles and timing of ovulation. It is concluded that this model provides a sound basis for exploring factors that influence the bovine oestrous cycle in order to test hypotheses about nutritional and hormonal influences which, with further validation, should help to design dietary or pharmacological strategies for improving reproductive performance in cattle. PMID- 22925572 TI - The role of mitochondrial oxidation in endotoxin-induced liver-dependent swine pulmonary edema. AB - We reported previously studies in an in situ perfused swine preparation demonstrating that endotoxemia induced lung injury required the presence of the liver and that the response was accompanied by oxidative stress. To determine whether lung and liver mitochondrial oxidative stress was important to the response, we compared the effects of equimolar amounts of two antioxidants, n acetylcysteine, which does not replenish mitochondrial glutathione, and procysteine which does, on endotoxemia induced lung injury in the swine preparation. In a swine perfused liver-lung preparation, we measured physiologic, biochemical and cellular responses of liver and lung to endotoxemia with and without the drugs. Endotoxemia caused oxidation of the mitochondria-specific protein, thioredoxin-2, in both the lungs and the liver. Procysteine reduced thioredoxin-2 oxidation, attenuated hemodynamic, gas exchange, hepatocellular dysfunction, and cytokine responses and prevented lung edema. n-acetylcysteine had more modest effects and did not prevent lung edema. CONCLUSIONS: We conclude that mitochondrial oxidation may be critical to the pathogenesis of endotoxemia induced liver-dependent lung injury and that choices of antioxidant therapy for such conditions must consider the desired subcellular target in order to be optimally effective. PMID- 22925573 TI - Low titers of measles antibodies in Japanese pregnant women: a single-center study. AB - AIM: Measles during pregnancy has deleterious effects on both perinatal and maternal outcomes. In Japan, local epidemics of measles and cases of measles during pregnancy are still being reported; therefore, the seroprevalence of antibodies to measles is suspected to be still not sufficient. The aim of this study was to analyze the seroprevalence of antibodies to measles in Japanese pregnant women and estimate the percentage of these women who require vaccination or revaccination against measles. MATERIAL AND METHODS: We analyzed the seroprevalence of immunity to measles by the neutralization test in 10 349 pregnant women in the first trimester managed at the National Center for Child Health and Development between February 2004 and December 2010. The neutralization test titers were interpreted as follows: ?1:8, seropositive; =4, low-positive; ?4, seronegative. RESULTS: Of the total number of pregnant women tested, 7408 (71.6%) were seropositive, 1864 (18.0%) were low-positive, and 1079 (10.4%) were seronegative for measles antibodies, respectively. CONCLUSION: Our results revealed that 28% of our pregnant population was seronegative or low positive for measles antibodies, and thought to require revaccination or vaccination. Screening for measles immunity might be advisable for women of childbearing age. PMID- 22925574 TI - Laparoendoscopic single-site partial nephrectomy without ischemia for very small, exophytic renal masses: surgical details and functional outcomes. AB - BACKGROUND: Laparoendoscopic single-site surgery (LESS) has emerged as a natural progression from standard laparoscopy aiming to further minimize the morbidity of urologic procedures. OBJECTIVE: To describe our technique and report the surgical and functional outcomes of unclamped LESS partial nephrectomy (PN) in the treatment of small renal masses (SRMs). DESIGN, SETTING, AND PARTICIPANTS: Prospective evaluation of pre- and postoperative variables of patients undergoing the LESS-PN without ischemia between 2009 and 2012. The indications were single exophytic SRMs. SURGICAL PROCEDURE: Unclamped LESS-PN was performed through a transperitoneal approach. A pararectal Hasson access technique was preferred. Single-port access was achieved via different single-port devices. A combination of straight and articulating laparoscopic instruments was used. The tumor was excised using bipolar scissors during normal renal perfusion. Hemostasis was achieved by bipolar electrocautery, parenchymal stitches, and hemostatic agents. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Demographic, operative, postoperative, and pathologic outcomes data were recorded and analyzed. RESULTS AND LIMITATIONS: A total of 21 LESS-PN were performed (operative time: 111 +/- 41 min; blood loss: 196 +/- 195 ml: tumor size: 2.0 +/- 0.3 cm). Neither conversion to open surgery nor transfusions occurred. Three patients required conversion to standard laparoscopy. Postoperatively, three complications (Clavien grades 2, 3a, and 4) were recorded. Pathologic examination revealed 14 clear cell carcinomas, four renal cysts, two oncocytomas, and one angiomyolipoma. Hospital stay was 4.4 +/- 1.9 d. At the last follow-up (mean: 17+/-11.5 mo), no port-site, local, or distant recurrences were detected. No significant variation in serum creatinine and estimated glomerular filtration rate was observed. Subjective scar evaluation indicated 66% of patients were very satisfied/enthusiastic. Study limitations include the small sample size, the lack of a control group, the short follow-up period, and the arbitrary measure of patient's scar perception. CONCLUSIONS: Unclamped LESS-PN for selected SRMs is a safe and feasible procedure providing favorable postoperative outcomes and ensuring high levels of subjective, cosmetic satisfaction. PMID- 22925575 TI - Impact of smoking and smoking cessation on oncologic outcomes in primary non muscle-invasive bladder cancer. AB - BACKGROUND: Cigarette smoking is the best-established risk factor for urothelial carcinoma (UC) development, but the impact on oncologic outcomes remains poorly understood. OBJECTIVE: To analyse the effects of smoking status, cumulative exposure, and time from smoking cessation on the prognosis of patients with primary non-muscle-invasive bladder cancer (NMIBC). DESIGN, SETTING, AND PARTICIPANTS: We collected smoking data from 2043 patients with primary NMIBC. Smoking variables included smoking status, average number of cigarettes smoked per day (CPD), duration in years, and time since smoking cessation. Lifetime cumulative smoking exposure was categorised as light short term (<= 19 CPD, <= 19.9 yr), light long term (<= 19 CPD, >= 20 yr), heavy short term (>= 20 CPD, <= 19.9 yr) and heavy long term (>= 20 CPD, >= 20 yr). The median follow-up in this retrospective study was 49 mo. INTERVENTIONS: Transurethral resection of the bladder with or without intravesical instillation therapy. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Univariable and multivariable logistic regression and competing risk regression analyses assessed the effects of smoking on outcomes. RESULTS AND LIMITATIONS: There was no difference in clinicopathologic factors among never (24%), former (47%), and current smokers (29%). Smoking status was associated with the cumulative incidence of disease progression in multivariable analysis (p=0.003); current smokers had the highest cumulative incidences. Among current and former smokers, cumulative smoking exposure was associated with disease recurrence (p<0.001), progression (p<0.001), and overall survival (p<0.001) in multivariable analyses that adjusted for the effects of standard clinicopathologic factors and smoking status; heavy long-term smokers had the worst outcomes, followed by light long-term, heavy short-term, and light short term smokers. Smoking cessation >10 yr reduced the risk of disease recurrence (hazard ratio [HR]: 0.66; 95% confidence interval [CI], 0.52-0.84; p<0.001) and progression (HR: 0.42; 95% CI, 0.22-0.83; p=0.036) in multivariable analyses. The study is limited by its retrospective nature. CONCLUSIONS: Smoking status and a higher cumulative smoking exposure are associated with worse prognosis in patients with NMIBC. Smoking cessation >10 yr abrogates this detrimental effect. These findings underscore the need for integrated smoking cessation and prevention programmes in the management of NMIBC patients. PMID- 22925577 TI - Insights into the catalytic mechanism of 16S rRNA methyltransferase RsmE (m3U1498) from crystal and solution structures. AB - RsmE is the founding member of a new RNA methyltransferase (MTase) family responsible for methylation of U1498 in 16S ribosomal RNA in Escherichia coli. It is well conserved across bacteria and plants and may play an important role in ribosomal intersubunit communication. The crystal structure in monomer showed that it consists of two distinct but structurally related domains: the PUA (pseudouridine synthases and archaeosine-specific transglycosylases)-like RNA recognition and binding domain and the conserved MTase domain with a deep trefoil knot. Analysis of small-angle X-ray scattering data revealed that RsmE forms a flexible dimeric conformation that may be essential for substrate binding. The S adenosyl-l-methionine (AdoMet)-binding characteristic determined by isothermal titration calorimetry suggested that there is only one AdoMet molecule bound in the subunit of the homodimer. In vitro methylation assay of the mutants based on the RsmE-AdoMet-uridylic acid complex model showed key residues involved in substrate binding and catalysis. Comprehensive comparisons of RsmE with closely related MTases, combined with the biochemical experiments, indicated that the MTase domain of one subunit in dimeric RsmE is responsible for binding of one AdoMet molecule and catalytic process while the PUA-like domain in the other subunit is mainly responsible for recognition of one substrate molecule (the ribosomal RNA fragment and ribosomal protein complex). The methylation process is required by collaboration of both subunits, and dimerization is functionally critical for catalysis. In general, our study provides new information on the structure-function relationship of RsmE and thereby suggests a novel catalytic mechanism. PMID- 22925579 TI - Taking AIM at the start of translation. PMID- 22925578 TI - Characterization of transport proteins for aromatic compounds derived from lignin: benzoate derivative binding proteins. AB - In vitro growth experiments have demonstrated that aromatic compounds derived from lignin can be metabolized and represent a major carbon resource for many soil bacteria. However, the proteins that mediate the movement of these metabolites across the cell membrane have not been thoroughly characterized. To address this deficiency, we used a library representative of lignin degradation products and a thermal stability screen to determine ligand specificity for a set of solute-binding proteins (SBPs) from ATP-binding cassette (ABC) transporters. The ligand mapping process identified a set of proteins from Alphaproteobacteria that recognize various benzoate derivatives. Seven high-resolution crystal structures of these proteins in complex with four different aromatic compounds were obtained. The protein-ligand complexes provide details of molecular recognition that can be used to infer binding specificity. This structure function characterization provides new insight for the biological roles of these ABC transporters and their SBPs, which had been previously annotated as branched chain amino-acid-binding proteins. The knowledge derived from the crystal structures provides a foundation for development of sequence-based methods to predict the ligand specificity of other uncharacterized transporters. These results also demonstrate that Alphaproteobacteria possess a diverse set of transport capabilities for lignin-derived compounds. Characterization of this new class of transporters improves genomic annotation projects and provides insight into the metabolic potential of soil bacteria. PMID- 22925580 TI - Structural basis of substrate specificity and selectivity of murine cytosolic 5' nucleotidase III. AB - Cytosolic 5'-nucleotidase III (cN-III) is responsible for selective degradation of pyrimidine 5'-monoribonucleotides during maturation of reticulocytes to erythrocytes. The lack of this enzymatic activity due to genetic aberrations or lead poisoning results in a mild to moderate nonspherocytic hemolytic anemia. In affected individuals, pyrimidine nucleotides as well as their precursor polymers and their off-path metabolites accumulate in erythrocytes, interfering with their proper function in ways that are not yet fully understood. This report describes the first X-ray structure of a catalytically inactivated variant of murine cN-III with a natural substrate, uridine 5'-monophosphate, in the active site at 1.74A resolution. The structure captures in an atomic detail the closed conformation that cN-III adopts upon substrate binding. Structure and sequence analysis coupled with enzymatic characterization of several mutants confirmed that the aromatic ring of a nitrogenous base of substrate nucleotide is stabilized by parallel pi-stacking interactions with conserved aromatic rings of Trp113 and His68. The nitrogenous base is further stabilized by T-shaped stacking with the conserved aromatic ring of Tyr114, as well as by polar contacts with side chains of Thr66 and Ser117. Two water molecules help to stabilize the nucleotide binding by bridging it to protein residues Asp72 and His68 via hydrogen bonds. Finally, fully conserved Glu96 is responsible for recognition of ribose ring via two hydrogen bonds. The presented substrate complex structure elucidates how cN-III achieves specificity for pyrimidine 5'-nucleotides and how it selects against purine 5'-nucleotides. PMID- 22925581 TI - Membrane-binding mechanism of a peripheral membrane protein through microsecond molecular dynamics simulations. AB - A homologue oxysterol binding protein of yeast (Osh4) peripherally binds to organelle and plasma membranes and promotes lipid transport and membrane contact. Extensive molecular dynamics simulations of Osh4 are used to characterize the structure and mechanism of protein attachment to various model lipid membranes. A high density of negatively charged lipids (phosphatidylserine and phosphatidylinositol-4,5-biphosphate) or a low density of phosphatidylinositol 4,5-biphosphate results in a single binding conformation consisting of interactions with several loops and a portion of the mouth to the lipid binding pocket. However, Osh4 weakly and transiently binds to membranes with only zwitterionic lipids. The protein conformation in our simulations with anionic membranes agrees with previous experiments but offers an alternative description to previously proposed distinct binding regions. Specifically, distinct binding sites on Osh4 also constitute a single binding conformation with anionic membranes. Several loops interact strongly with membranes with the strongest being the beta14-beta15 loop (amino acids 253-264), but this loop binds in a nonspecific manner to any anionic lipid. We are the first to characterize the importance of an anchor in the phenylalanine loop (amino acids 236-244) to binding, which stabilizes distant interactions with the mouth and may be important in stabilizing mouth interactions for lipid release or uptake to or from membranes. PMID- 22925583 TI - Predicting atrial fibrillation inducibility in a canine model by multi-threshold spectra of the recurrence complex network. AB - The purpose of this study is to predict atrial fibrillation (AF) from epicardial signals by investigating the recurrence property of atrial activity dynamic system before AF. A novel scheme is proposed to predict AF by using multi threshold spectra of the recurrence complex network. Firstly, epicardial signals are transformed into the recurrence complex network to quantify structural properties of the recurrence in the phase space. Spectral parameters with multi threshold are used to characterize the global structure of the network. Then the feature sequential forward searching algorithm and mutual information based Maximum Relevance Minimum Redundancy criterion are used to find the optimal feature set. Finally, a support vector machine is used to predict the occurrence of AF. This method is assessed on the pre-AF epicardial signals of canine which includes the normal group A (no further AF will happen), the mild group B (the following AF time is less than 180s) and the severe group C (the following AF time is more than 180s). 25 optimal features are selected out of 180 features from each sample. With these features, sensitivity, specificity and accuracy are 99.40%, 99.70% and 99.60%, respectively, which are the best among the recurrence based methods. The results suggest that the proposed method can predict AF accurately and thus can be prospectively used in the postoperative evaluation. PMID- 22925584 TI - Design and validation of the Grip-ball for measurement of hand grip strength. AB - The Grip-ball is a new dynamometer used to evaluate grip strength, as well as for use in home-based rehabilitation of the hand and forearm. The Grip-ball consists of pressure and temperature sensors and an electronic wireless communication system contained in an airtight ball. That can be inflated to different pressures. The device has advantages over standard dynamometers in that it looks like a simple ball, and can wirelessly communicate via Bluetooth to any compatible receiver, thus have potential to be used for clinical assessment and rehabilitation in a remote setting. The reliability and reproducibility of the device were assessed for the pressure sensor itself, as well as the relationship between the force applied and the pressure measured by the Grip-ball. The initial validation was performed using the pressure sensor without the ball in order to confirm the accuracy of the sensor used. A second validation study was conducted using the Grip-ball rather than just its sensor to examine the relationship between the pressure measured inside the ball and force applied. The results showed that there is a very good correlation (r=0.997, p<0.05) between the pressure measured by the Grip-ball sensor and that measured by a Vigorimeter, thus confirming the reliability of the sensor used in the Grip-ball. A quadratic regression equation was calculated in order to predict the force applied based on the pressure measured inside the ball, and the initial pressure to which the ball was inflated (R(2)=0.97, standard error 10.9N). Such a finding compares favourably with the variability inherent in Jamar recordings, thus indicating that the Grip-ball could be used to assess grip force. An industrial version of the Grip-ball, which is currently under development, will be able to be used for the entire range of grip force in the population. PMID- 22925585 TI - A rare case of esophageal submucosal angiofibroma resected completely by endoscopic submucosal dissection. PMID- 22925586 TI - Pleural effusion and pseudocyst. PMID- 22925587 TI - Anterior cruciate ligament (ACL) reconstruction with quadriceps tendon autograft and press-fit fixation using an anteromedial portal technique. AB - BACKGROUND: This article describes an arthroscopic anterior cruciate ligament (ACL) reconstruction technique with a quadriceps tendon autograft using an anteromedial portal technique. METHODS: A 5 cm quadriceps tendon graft is harvested with an adjacent 2 cm bone block. The femoral tunnel is created through a low anteromedial portal in its anatomical position. The tibial tunnel is created with a hollow burr, thus acquiring a free cylindrical bone block. The graft is then passed through the tibial tunnel and the bone block, customized at its tip, is tapped into the femoral tunnel through the anteromedial portal to provide press-fit fixation. The graft is tensioned distally and sutures are tied over a bone bridge at the distal end of the tibial tunnel. From the cylindrical bone block harvested from the tibia the proximal end is customized and gently tapped next to the graft tissue into the tibial tunnel to assure press fitting of the graft in the tibial tunnel. The distal part of the tibial tunnel is filled up with the remaining bone.All patients were observed in a prospective fashion with subjective and objective evaluation after 6 weeks, 6 and 12 months. RESULTS: Thirty patients have been evaluated at a 12 months follow-up. The technique achieved in 96.7% normal or nearly normal results for the objective IKDC. The mean subjective IKDC score was 86.1 +/- 15.8. In 96.7% the Tegner score was the same as before injury or decreased one category. A negative or 1+ Lachman test was achieved in all cases. Pivot-shift test was negative or (+) glide in 86.7%. The mean side-to-side difference elevated by instrumental laxity measurement was 1.6 +/- 1.1 mm. Full ROM has been achieved in 92.3%. The mean single one-leg-hop index was 91.9 +/- 8.0 at the follow-up. CONCLUSIONS: Potential advantages include minimum bone loss specifically on the femoral side and graft fixation without implants. PMID- 22925588 TI - Ethnic differences in sexual dysfunction among diabetic and nondiabetic males: the Oxford Sexual Dysfunction Study. AB - INTRODUCTION: Erectile dysfunction (ED), premature ejaculation (PE), and reduced libido are common yet poorly investigated complications of diabetes especially among South Asians (SA). AIM: To determine possible variations in prevalence and interassociations of ED, PE, and reduced libido among SA and Europids with and without diabetes. METHOD: Men with diabetes and a randomly selected sample of age matched nondiabetic men from 25 general practitioners in eight primary care trusts in the United Kingdom were invited to participate in a linguistically validated questionnaire-based study in English, Hindi, Urdu, Panjabi, Tamil, and Sinhala languages. MAIN OUTCOME MEASURES: ED, assessed by International Index of Erectile Function (IIEF-5), PE, evaluated using the Premature Ejaculation Diagnostic Tool, and libido, assessed by asking participants to grade their desire for sexual activity. RESULTS: Sample size was 510 (SA: 184, Europid: 326). Mean age was 56.9 +/- 9.7 years. There was no difference in erectile function when assessed by IIEF between SA and Europids with diabetes (84.8% and 84.1%, respectively). The overall prevalence of PE was 28.8% (32.6% and 25.8% in those with and without diabetes, respectively, P = NS). Among men with diabetes, the prevalence of PE was 45.8% and 22.4% for SA and Europids, respectively (P < 0.001). In those without diabetes, this figure was 41.9% in SA and 20.2% in Europids (P < 0.001). There was a significant trend of increasing prevalence of PE with increasing severity grade of ED (P < 0.001). Reduced libido was reported by 26.9% men (32.8% and 22.0% in those with and without diabetes, respectively, P < 0.01), with no significant ethnic difference. The association between reduced libido and increasing severity grades of ED was also significant (P < 0.001). CONCLUSIONS: No significant difference was observed in the prevalence of ED between SA and Europid men with diabetes. PE was significantly more common in the SA men irrespective of their diabetes status. PMID- 22925591 TI - Intentional intrathecal opioid detoxification in 3 patients: characterization of the intrathecal opioid withdrawal syndrome. AB - OBJECTIVE: Intrathecal (IT) drug delivery systems for patients with chronic non malignant pain are intended to improve pain and quality of life and reduce side effects of systemic use. A subset of patients may have escalating pain, functional decline, and/or intolerable side effects even as IT opioid doses are increased. Discontinuation of IT medications may represent a viable treatment option but strategies to accomplish this are needed. SUBJECTS AND INTERVENTIONS: Three patients with intrathecal drug delivery systems (IDDS), inadequate pain control, and declining functionality underwent abrupt IT opioid cessation. This was accomplished through a standardized protocol with symptom-triggered administration of clonidine and buprenorphine, monitored using the clinical opiate withdrawal scale. RESULTS: Symptoms of IT withdrawal were similar in all patients and included diuresis, agitation, hyperalgesia, mild diarrhea, yawning, and taste and smell aversion. Hypertension and tachycardia were effectively controlled by clonidine administration. Classic symptoms of withdrawal, such as piloerection, chills, severe diarrhea, nausea, vomiting, diaphoresis, myoclonus, and mydriasis, were not noted. At 2 to 3 months follow-up, patients reported decreased, but ongoing pain, with improvements in functional capacity and quality of life. CONCLUSIONS: This preliminary work demonstrates the safety of abrupt IT opioid cessation utilizing standardized inpatient withdrawal protocols. To our knowledge, these are among the first reported cases of intentional, controlled IT opioid cessation without initiation of an opioid bridge: self-reported pain scores, functional capacity, and quality of life improved. The IT opioid withdrawal syndrome is characterized based upon our observations and a review of the literature. PMID- 22925589 TI - Leptospira spp. strain identification by MALDI TOF MS is an equivalent tool to 16S rRNA gene sequencing and multi locus sequence typing (MLST). AB - BACKGROUND: In this study mass spectrometry was used for evaluating extracted leptospiral protein samples and results were compared with molecular typing methods. For this, an extraction protocol for Leptospira spp. was independently established in two separate laboratories. Reference spectra were created with 28 leptospiral strains, including pathogenic, non-pathogenic and intermediate strains. This set of spectra was then evaluated on the basis of measurements with well-defined, cultured leptospiral strains and with 16 field isolates of veterinary or human origin. To verify discriminating peaks for the applied pathogenic strains, statistical analysis of the protein spectra was performed using the software tool ClinProTools. In addition, a dendrogram of the reference spectra was compared with phylogenetic trees of the 16S rRNA gene sequences and multi locus sequence typing (MLST) analysis. RESULTS: Defined and reproducible protein spectra using MALDI-TOF MS were obtained for all leptospiral strains. Evaluation of the newly-built reference spectra database allowed reproducible identification at the species level for the defined leptospiral strains and the field isolates. Statistical analysis of three pathogenic genomospecies revealed peak differences at the species level and for certain serovars analyzed in this study. Specific peak patterns were reproducibly detected for the serovars Tarassovi, Saxkoebing, Pomona, Copenhageni, Australis, Icterohaemorrhagiae and Grippotyphosa. Analysis of the dendrograms of the MLST data, the 16S rRNA sequencing, and the MALDI-TOF MS reference spectra showed comparable clustering. CONCLUSIONS: MALDI-TOF MS analysis is a fast and reliable method for species identification, although Leptospira organisms need to be produced in a time consuming culture process. All leptospiral strains were identified, at least at the species level, using our described extraction protocol. Statistical analysis of the three genomospecies L. borgpetersenii, L. interrogans and L. kirschneri revealed distinctive, reproducible differentiating peaks for seven leptospiral strains which represent seven serovars. Results obtained by MALDI-TOF MS were confirmed by MLST and 16S rRNA gene sequencing. PMID- 22925592 TI - CT-guided transforaminal cervical and lumbar epidural injections. AB - Transforaminal injections are widely used. Serious complications including strokes and paraplegia have been reported after transforaminal injections of corticosteroids, and the Afssaps (2011) has issued a warning about their use [1]. The needle must be positioned in the posterior aspect of foramen, and its correct placement validated by an injection of contrast product. It is preferable to choose cortivazol (Altim((r))) as the corticoid for injection. This procedure is simple, reproducible, and durably effective in 60 to 70% of cases. Complications and adverse effects are rare but potentially serious: allergies, blood pressure surge, vasovagal syncope, transient exacerbation of pain, infection, stroke, and paraplegia. The aim of this course is to stress the need for rigor - in the indication, the technical performance of the procedure, and the overall management of the patient. PMID- 22925593 TI - Radiofrequency ablation of bone tumours. AB - The indications for radiofrequency bone ablation in the case of benign tumours (osteoid osteoma, osteoblastoma) are curative, whereas for bone metastases, the prime aim is palliative analgesia. The failure rate for osteoid osteomas is low (<15%), and 70 to 90% of patients with metastases experience considerable relief, but if the treatment fails, it can be offered again. In the spine, heating can damage neighboring nerve structures, which means they need to be protected (CO(2) dissection). Radiofrequency ablation may be combined with an injection of cement. The osteonecrosis resulting from heating is painful and justifies performing the procedure under general anesthesia. PMID- 22925594 TI - Approaches in injections for radicular pain: the transforaminal, epidural and transfacet approaches. AB - Spinal injections must be carried out adhering to very strict conditions. However, these procedures have almost come to be seen as everyday and may be practised under quite questionable conditions. The recent reports of new and extremely serious neurological complications have changed the attitudes of those making referrals as well as the attitudes of the interventional radiologists carrying out these procedures. The range of indications for transforaminal injections has shrunk in favour of epidural injections. Where the transforaminal approach is still used, the needle must be positioned extremely accurately. A prior radioopaque contrast medium injection is essential from a safety perspective. The transforaminal epidural injection via the transfacet approach looks to be a promising alternative that is strictly avascular. PMID- 22925595 TI - Spinal injections: medico-legal and insurance considerations. AB - A series of serious accidents following spinal, cervical and lumbar foraminal injections has led French medical insurers to start discussions with professional radiologists to ask us to take the necessary measures allowing them to continue to cover the exceptional but considerable risks of these interventional radiology procedures. This article summarises the facts and the insurers' recommendations and insists on the need to adopt a new and permanent strategy to improve the quality and safety of our practice. PMID- 22925597 TI - Effects of metformin on learning and memory behaviors and brain mitochondrial functions in high fat diet induced insulin resistant rats. AB - AIM: Metformin is a first line drug for the treatment of type 2 diabetes mellitus (T2DM). Our previous study reported that high-fat diet (HFD) consumption caused not only peripheral and neuronal insulin resistance, but also induced brain mitochondrial dysfunction as well as learning impairment. However, the effects of metformin on learning behavior and brain mitochondrial functions in HFD-induced insulin resistant rats have never been investigated. MAIN METHODS: Thirty-two male Wistar rats were divided into two groups to receive either a normal diet (ND) or a high-fat diet (HFD) for 12weeks. Then, rats in each group were divided into two treatment groups to receive either vehicle or metformin (15mg/kg BW twice daily) for 21days. All rats were tested for cognitive behaviors using the Morris water maze (MWM) test, and blood samples were collected for the determination of glucose, insulin, and malondialdehyde. At the end of the study, animals were euthanized and the brain was removed for studying brain mitochondrial function and brain oxidative stress. KEY FINDINGS: We found that in the HFD group, metformin significantly attenuated the insulin resistant condition by improving metabolic parameters, decreasing peripheral and brain oxidative stress levels, and improving learning behavior, compared to the vehicle-treated group. Furthermore, metformin completely prevented brain mitochondrial dysfunction caused by long-term HFD consumption. SIGNIFICANCE: Our findings suggest that metformin effectively improves peripheral insulin sensitivity, prevents brain mitochondrial dysfunction, and completely restores learning behavior, which were all impaired by long-term HFD consumption. PMID- 22925596 TI - Computerised therapy for depression with clinician vs. assistant and brief vs. extended phone support: study protocol for a randomised controlled trial. AB - BACKGROUND: Computerised cognitive behaviour therapy (cCBT) involves standardised, automated, interactive self-help programmes delivered via a computer. Randomised controlled trials (RCTs) and observational studies have shown than cCBT reduces depressive symptoms as much as face-to-face therapy and more than waiting lists or treatment as usual. cCBT's efficacy and acceptability may be influenced by the "human" support offered as an adjunct to it, which can vary in duration and can be offered by people with different levels of training and expertise. METHODS/DESIGN: This is a two-by-two factorial RCT investigating the effectiveness, cost-effectiveness and acceptability of cCBT supplemented with 12 weekly phone support sessions are either brief (5-10 min) or extended (20-30 min) and are offered by either an expert clinician or an assistant with no clinical training. Adults with non-suicidal depression in primary care can self refer into the study by completing and posting to the research team a standardised questionnaire. Following an assessment interview, eligible referrals have access to an 8-session cCBT programme called Beating the Blues and are randomised to one of four types of support: brief-assistant, extended-assistant, brief-clinician or extended-clinician.A sample size of 35 per group (total 140) is sufficient to detect a moderate effect size with 90% power on our primary outcome measure (Work and Social Adjustment Scale); assuming a 30% attrition rate, 200 patients will be randomised. Secondary outcome measures include the Beck Depression and Anxiety Inventories and the PHQ-9 and GAD-7. Data on clinical outcomes, treatment usage and patient experiences are collected in three ways: by post via self-report questionnaires at week 0 (randomisation) and at weeks 12 and 24 post-randomisation; electronically by the cCBT system every time patients log in; by phone during assessments, support sessions and exit interviews. DISCUSSION: The study's factorial design increases its efficiency by allowing the concurrent investigation of two types of adjunct support for cCBT with a single sample of participants. Difficulties in recruitment, uptake and retention of participants are anticipated because of the nature of the targeted clinical problem (depression impairs motivation) and of the studied interventions (lack of face-to-face contact because referrals, assessments, interventions and data collection are completed by phone, computer or post). TRIAL REGISTRATION: Current Controlled Trials ISRCTN98677176. PMID- 22925598 TI - Planning target volume margin evaluation and critical structure sparing for rectal cancer patients treated prone on a bellyboard. AB - AIMS: To calculate a planning target volume (PTV) margin that would account for inter-fractional systematic and random clinical target volume positional errors for patients treated prone on a recently available couch top bellyboard and to evaluate potential critical structure dose reduction using intensity-modulated radiotherapy (IMRT) techniques. MATERIALS AND METHODS: Twenty-four patients (12 men and 12 women) were included in this study, all treated on a commercial bellyboard. Cone beam computed tomography (CBCT) data were acquired once every five fractions for a total of five images per patient. A three-dimensional-three dimensional bony anatomy auto-match was carried out off-line and the residual difference in position used as a surrogate for clinical target volume inter fractional positional errors. Systematic (Sigma) and random (sigma) variations were evaluated and used in PTV(margin)=1.96Sigma+0.7sigma. The influence of intra fractional positional errors was evaluated in the margin analysis by introducing published values. Critical structure sparing, as a function of PTV(margin) size, was investigated through the evaluation of three-dimensional conformal radiation therapy (3DCRT) and IMRT treatment plans developed using the margin derived from this work, the American Society for Radiation Oncology Contouring Atlas and the Radiation Therapy Oncology Group 0822 trial specifications. RESULTS: The PTV(margin) that accounts for only the inter-fractional positional errors was calculated to be (anterior-posterior (AP), superior-inferior (SI), left-right (LR))=(5.2mm, 3.1mm, 2.8mm). If we assumed a combined intra-fractional motion up to 3.0mm then the required PTV(margin) increased to (AP, SI, LR)=(7.0mm, 5.0mm, 5.0mm). Treatment plan evaluation showed that the bellyboard provides excellent small bowel sparing regardless of planning technique. In most cases, IMRT reduced the average femoral head, bladder and small bowel dose by 20, 15 and 40% with respect to 3DCRT planning. CONCLUSION: A PTV(margin) expansion of (AP, SI, LR)=(7.0mm, 5.0mm, 5.0mm) is required to account for all positional uncertainties. The use of a bellyboard with IMRT provides better critical structure sparing when compared with a bellyboard with 3DCRT. PMID- 22925599 TI - BaSAR-A tool in R for frequency detection. AB - Many biological processes are periodic, for example cell cycle expression, circadian rhythms and calcium oscillations. However, measured time series from these processes are commonly short and noisy, and finding frequencies in such data can be challenging. Here we present BaSAR, Bayesian Spectrum Analysis in R, a package for extracting frequency information from time series data. The software uses advanced techniques of Bayesian inference that are well suited for handling typical biological data. The core functions are designed for detecting a single key frequency, without the need for data pre-processing such as detrending. The package is freely available at CRAN - The Comprehensive R Archive Network: http://cran.r-project.org/web/packages/BaSAR. PMID- 22925600 TI - Importance of early treatment in case of spontaneous intracranial hypotension. PMID- 22925601 TI - Post-traumatic hydrocephalus is a contraindication for endoscopic third ventriculostomy: isn't it? AB - OBJECTIVES: Post-traumatic hydrocephalus (PTH) is commonly considered as a relative contraindication for endoscopic third-ventriculostomy (ETV). However, few studies are available on this topic. METHODS: An analysis of the papers published in the last ten years has been performed, in order to assess the level of evidence on which the current indication for ETV for PTH is based. References were identified by PubMed searches of clinical articles relating to both PTH and ETV. Laboratory investigations were excluded. RESULTS: Only 5 articles were selected, for a total of 15 patients with PTH treated with ETV. All these patients were described by the authors to have a communicating hydrocephalus. No complications of surgery were reported. Outcome data were not available for one patient. Thirteen out of the remaining 14 patients had a clinical improvement after the surgical procedure (93%). Direct or indirect information on pre operative ICP was available for 11 cases. Eight of them had an elevated ICP and presented a clinical improvement after ETV. CONCLUSIONS: There is no current evidence to support that PTH is a contraindication for ETV. Our data suggest that we could reconsider ETV for the treatment of PTH, especially for patients with elevated ICP. Prospective clinical trials (involving several centers, due to the difficulty of recruiting patients with PTH) are needed. PMID- 22925602 TI - Dual effects of N-acetyl-L-cysteine dependent on NQO1 activity: suppressive or promotive of 9,10-phenanthrenequinone-induced toxicity. AB - A typical antioxidant, N-acetyl-L-cysteine (NAC) generally protects cells from oxidative damage induced by reactive oxygen species (ROS). 9,10 Phenanthrenequinone (9,10-PQ), a major quinone in diesel exhaust particles, produces ROS in redox cycling following two-electron reduction by NAD(P)H:quinone oxidoreductase 1 (NQO1), which has been considered as a cause of its cyto- and genotoxicity. In this study, we show that NAC unexpectedly augments the toxicity of 9,10-PQ in cells with low NQO1 activity. In four human skin cell lines, the expression and the activity of NQO1 were lower than in human adenocarcinoma cell lines, A549 and MCF7. In the skin cells, the cytotoxicity of 9,10-PQ was significantly enhanced by addition of NAC. The formation of DNA double strand breaks accompanying phosphorylation of histone H2AX, was also remarkably augmented. On the other hand, the cyto- and genotoxicity were suppressed by addition of NAC in the adenocarcinoma cells. Two contrasting experiments: overexpression of NQO1 in CHO-K1 cells which originally expressed low NQO1 levels, and knock-down of NQO1 in the adenocarcinoma cell line A549 by transfection of RNAi, also showed that NAC suppressed 9,10-PQ-induced toxicity in cell lines expressing high NQO1 activity and enhanced it in cell lines with low NQO1 activity. The results suggested that dual effects of NAC on the cyto- and genotoxicity of 9,10-PQ were dependent on tissue-specific NQO1 activity. PMID- 22925603 TI - PSA: software for parental structure analysis of seed or seedling patches. AB - Parental structure analysis (PSA) is a computer program to analyse separate contributions of paternal and maternal parents to postdispersal plant offspring. The program provides joint estimates of maternal, paternal and cross-parental correlations within and among a set of predefined groups of seeds or seedlings, as well as derivative estimates of effective parental numbers. PSA utilizes data sets that distinguish between maternal and paternal contributions to the genotype of each offspring in the sample, but does not require parental samples per se. The approach requires assay of codominant diploid markers from both seed coat (maternally inherited) and seedling/embryo (biparentally inherited) tissues for each offspring. A simulation analysis of PSA's performance shows that it provides fairly accurate parental correlation estimates from affordable sampling effort. PSA should be of interest to plant biologists studying the interplay between dispersal, demography and genetics, as well as plant-animal interactions. PMID- 22925605 TI - Altered hemispheric symmetry found in left-sided mesial temporal lobe epilepsy with hippocampal sclerosis (MTLE/HS) but not found in right-sided MTLE/HS. AB - PURPOSE: The purpose was to investigate the altered hemispheric asymmetry in patients with mesial temporal lobe epilepsy with unilateral hippocampus sclerosis (MTLE/HS). MATERIALS AND METHODS: This study examined the hemispheric asymmetry of regional gray matter (GM) and white matter (WM) volume among a group of 13 patients with left-sided MTLE/HS, a group of 10 patients with right-sided MTLE/HS and a group of 21 age- and gender- matched healthy controls by optimized voxel based morphometry (VBM) based on magnetic resonance imaging. RESULTS: Compared to healthy controls, abnormal asymmetries were detected in the left-sided MTLE/HS patients. The left-sided MTLE/HS patients had more GM asymmetries (L 18% polymorphonuclear cells; PMNs). Slides for cytology were prepared before the same cytobrush was transferred to a tube containing 1 mL Trizol reagent. Total RNA was extracted from each cytobrush sample and analysis of il6, il8, tnfalpha, and betaactin gene expression was performed using quantitative real-time polymerase chain reaction. Cytobrush sampling provided sufficient material to prepare cytosmears and extract high quality endometrial mRNA (mean = 0.96 MUg RNA per sample). Cytokine expression varied between experimental groups with a 20-fold higher tnfalpha (P = 0.001), a 30-fold higher il6 (P = 0.01), and a greater than 50-fold higher il8 mRNA expression level (P = 0.0001) in subclinical endometritis positive versus disease-negative cows. Regression analysis of gene expression levels (cycle threshold) versus PMN frequency showed that the frequency of PMNs in the cytosmear decreased by 3.3% (P = 0.000 01), 2.3% (P = 0.015), and 2.4% (P = 0.05) for each additional cycle threshold required to detect il8, il6, and tnfalpha gene expression, respectively. Expression of the individual cytokines was positively associated: il8 and il6 (P = 0.0001); il8 and tnfalpha (P = 0.000 01); and il6 and tnfalpha (P = 0.0002). In conclusion, the endometrial cytobrush technique was successfully used to obtain material for both cytology and RNA extraction, and il8 gene expression may be useful to predict endometrial inflammation. PMID- 22925637 TI - Improvement of the post-thaw qualities of Okinawan native Agu pig sperm frozen in an extender supplemented with antiapoptotic PTD-FNK protein. AB - The technical establishment of boar sperm cryopreservation is indispensable for effective breeding of the scarce Okinawan native Agu pig. The objective was to determine whether an artificial anticell death protein (PTD-FNK protein) was capable of improving the quality of cryopreserved Agu sperm. Ejaculated Agu sperm frozen in an extender supplemented with 0, 100, 200, 300, or 400 nm PTD-FNK protein was thawed, and mitochondrial integrity and other sperm characteristics were evaluated. Treatment with 300 nm PTD-FNK protein had the most beneficial effect (P < 0.05) on mitochondrial integrity (45-59%) and sperm motility (56-67%) after freezing-thawing. In particular, the proportion of post-thaw sperm with activated caspase-9 and -3 but not caspase-8 was markedly reduced among sperm frozen in the presence of PTD-FNK protein (P < 0.05), implying protection against apoptotic-cell death in response to mitochondrial damage. There were high levels of intracellular ATP (9.4-10.5 nmol/10(8) sperm) in post-thaw sperm treated with PTD-FNK protein, and the inhibitory effect of PTD-FNK protein on activation of caspases influenced the increase in the number of sperm with intact DNA (36-53%; P < 0.05). Furthermore, the addition of PTD-FNK protein to the freezing extender strongly preserved the ability of the sperm to penetrate to mature oocytes in all individuals (60-80%; P < 0.05). In conclusion, treatment with PTD-FNK protein in the freezing extender effectively improved post-thaw qualities of fragile Agu sperm through prevention of mitochondrial dysfunction leading to apoptotic-cell death during cryopreservation. PMID- 22925633 TI - A retrospective: use of Escherichia coli as a vehicle to study phospholipid synthesis and function. AB - Although the study of individual phospholipids and their synthesis began in the 1920s first in plants and then mammals, it was not until the early 1960s that Eugene Kennedy using Escherichia coli initiated studies of bacterial phospholipid metabolism. With the base of information already available from studies of mammalian tissue, the basic blueprint of phospholipid biosynthesis in E. coli was worked out by the late 1960s. In 1970s and 1980s most of the enzymes responsible for phospholipid biosynthesis were purified and many of the genes encoding these enzymes were identified. By the late 1990s conditional and null mutants were available along with clones of the genes for every step of phospholipid biosynthesis. Most of these genes had been sequenced before the complete E. coli genome sequence was available. Strains of E. coli were developed in which phospholipid composition could be changed in a systematic manner while maintaining cell viability. Null mutants, strains in which phospholipid metabolism was artificially regulated, and strains synthesizing foreign lipids not found in E. coli have been used to this day to define specific roles for individual phospholipid. This review will trace the findings that have led to the development of E. coli as an excellent model system to study mechanisms underlying the synthesis and function of phospholipids that are widely applicable to other prokaryotic and eukaryotic systems. This article is part of a Special Issue entitled Phospholipids and Phospholipid Metabolism. PMID- 22925639 TI - Evaluation of Xist expression in preattachment equine embryos. AB - Until now, sex determination in equine embryos has been performed by detection of Y-chromosome-specific sequences only. In the present study, expression of a Barr body-specific marker, the X-inactivated-specific transcript (Xist) gene, whose gene product consists of RNA which coats and thereby inactivates one of the X chromosomes, was investigated in equine embryos produced in vivo. Preattachment embryos at different times after ovulation (Day 8: n = 9; Day 10: n = 12; Day 12: n = 15) were analyzed for Xist RNA expression using quantitative and qualitative reverse transcription-polymerase chain reaction (RT-PCR). Female and male primary equine dermal cell cultures were used as positive and negative controls, respectively. Embryos tested negative for Xist were evaluated for expression of the male-specific eSRY gene by qualitative PCR at the DNA level. From 36 embryos assessed by qualitative RT-PCR, 18 showed positive Xist expression (50%). From 29 embryos tested by quantitative RT-PCR, 16 showed positive Xist expression (55%). All of the Xist-negative equine embryos tested by quantitative PCR were positive for eSRY. We also demonstrated by strand-specific RT-PCR that in the horse, as in humans, the counter transcript Tsix seems to be truncated not reaching Exon 1. In contrast to many other species, neither Xist nor Tsix was expressed in equine male testicular tissue. The results demonstrate that expression of Xist is restricted to female equine embryos. Xist can thus be considered an X inactivation-specific marker which can be used in concert with Y-specific markers for sex determination. PMID- 22925638 TI - Standardization of a method to detect bovine sperm-bound antisperm antibodies by flow cytometry. AB - The objectives were to standardize some methodological and analytical aspects of a direct technique to detect sperm-bound antisperm antibodies (ASAs) in bovine semen using flow cytometry, including the effects of prefixation of sperm membranes with formalin buffer solution and inclusion of dead cells in the analysis. Fourteen Angus bulls, including ASA-positive (experimentally induced ASAs) and 10 reproductively normal ASA-negative bulls, were used. Fixation of sperm membranes had no significant effect on the percentage of IgG- or IgA-bound spermatozoa detected by flow cytometry. However, including dead cells in the analysis increased the percentage of IgG-bound spermatozoa in fixed (live and dead 18.6 +/- 9.7% and live 1.3 +/- 0.5%; median +/- SEM) and nonfixed samples (live and dead 18.8 +/- 9.2%, live 1.5 +/- 0.6%; P = 0.0029), as well as IgA bound spermatozoa in fixed (live and dead 16.3 +/- 6.4%, live 0.3 +/- 0.5%) and nonfixed samples (live and dead 21.4 +/- 4.6%, live 1.0 +/- 0.5%; P = 0.0041) in semen from ASA-negative bulls. Intrasample, intra-assay, and interassay coefficients of variation (CV) were 0.8%, 4.6%, and 5.3%, respectively, for determination of sperm-bound IgG, and were 2.8%, 8.4%, and 40.3% for determination of sperm-bound IgA. Despite the high interassay CV for IgA determination, all ASA-positive bulls consistently had high percentages of IgA bound spermatozoa. Flow cytometry correctly identified ASA-positive bulls. Confocal laser microscopy confirmed binding of ASAs to sperm heads and cytoplasmic droplets, and less frequently to midpieces and principal piece. In conclusion, although fixation was not necessary, dead cells should be excluded from the analysis, because ejaculates with a large proportion of dead cells can yield false-positive results. Flow cytometry was accurate and reliable for detection of sperm-bound IgG and IgA and discrimination between ASA-positive and ASA-negative bulls. PMID- 22925640 TI - Sows exposed to octylphenol in early gestation: no estrogenic effects in male piglets, but increased rate of stillbirth. AB - Octylphenol is an industrial chemical with estrogenic effects both in vitro and in vivo. In this study the effects of short-term intramuscular exposure to 0.1 mg/kg of body weight and 1.0 mg/kg of body weight in early gestation were evaluated in pregnant sows with respect to reproductive parameters in the newborn male piglets, as compared with male piglets from unexposed control sows. The male piglets were examined immediately after birth with respect to the macroscopic appearance of the reproductive organs and testosterone concentration in serum. It was not possible to identify any estrogenic effects in the newborn male piglets. However, in the sows exposed at the highest level of octylphenol, there was an increased number of stillborn piglets and an increased proportion of sows with stillborn piglets in the litter (P < 0.05). This was an unexpected finding which has not been reported previously. PMID- 22925641 TI - Generation of rabbit pluripotent stem cell lines. AB - Pluripotent stem cells have the capacity to divide indefinitely and to differentiate into all somatic cells and tissue lines. They can be genetically manipulated in vitro by knocking genes in or out, and therefore serve as an excellent tool for gene function studies and for the generation of models for some human diseases. Since 1981, when the first mouse embryonic stem cell (ESC) line was generated, many attempts have been made to generate pluripotent stem cell lines from other species. Comparative characterization of ESCs from different species would help us to understand differences and similarities in the signaling pathways involved in the maintenance of pluripotency and the initiation of differentiation, and would reveal whether the fundamental mechanism controlling self-renewal of pluripotent cells is conserved across different species. This report gives an overview of research into embryonic and induced pluripotent stem cells in the rabbit, an important nonrodent species with considerable merits as an animal model for specific diseases. A number of putative rabbit ESC and induced pluripotent stem cell lines have been described. All of them expressed stem cell-associated markers and maintained apparent pluripotency during multiple passages in vitro, but none have been convincingly proven to be fully pluripotent in vivo. Moreover, as in other domestic species, the markers currently used to characterize the putative rabbit ESCs are suboptimal because recent studies have revealed that they are not always specific to the pluripotent inner cell mass. Future validation of rabbit pluripotent stem cells would benefit greatly from a validated panel of molecular markers specific to pluripotent cells of the developing rabbit embryos. Using rabbit-specific pluripotency genes may improve the efficiency of somatic cell reprogramming for generating induced pluripotent stem cells and thereby overcome some of the challenges limiting the potential of this technology. PMID- 22925642 TI - In vitro and in vivo quality of bovine embryos in vitro produced with sex-sorted sperm. AB - In this work we analyzed the effects of three culture systems on developmental ability of bovine embryos in vitro produced with sexed sperm, the survival to vitrification (cryologic vitrification method) of such blastocysts, and their pregnancy rates after embryo transfer to recipients, both as fresh and after vitrification/warming. Finally, we measured the accuracy of the sorting protocol by a polymerase chain reaction-based method to validate the embryo sex at blastocyst stages. We confirmed an individual effect of the bull as well as development rates of embryos produced with sorted sperm lower than embryos with unsorted sperm, independent of the culture system used. The cryoresistance to vitrification of embryos produced with sexed sperm did not differ from that of conventionally produced embryos (re-expansion rates at 24 and 48 h: 74.6% vs. 75.5%, and 64.5% vs. 68.1% for embryos produced with conventional and sorted sperm, respectively; hatching rates at 48 h: 63.55% vs. 55.5% for embryos produced with conventional and sorted sperm, respectively). Finally, no significant differences were found in pregnancy rates after the embryo transfer of fresh and vitrified/warmed blastocysts (52.8% vs. 42.0%, respectively; P > 0.05). Male and female embryos produced with sorted sperm showed the same quality in terms of developmental ability, cryoresistance, and pregnancy rates after transfer. Our culture system, coupled with the vitrification in fiber plugs, provides good quality sex-known embryos which survive vitrification at similar rates than embryos produced with conventional unsorted sperm; also it produces good pregnancy rates after transfer of sexed embryos both fresh and after vitrification and warming. PMID- 22925643 TI - Extracellular calcium is involved in egg yolk-induced head-to-head agglutination of bull sperm. AB - Head-to-head agglutination of bull sperm occurs when semen is highly diluted in an egg yolk-citrate diluent without streptomycin. The objectives were to investigate causes of sperm agglutination and the underlying mechanism. Aliquots of bull semen were diluted in a base diluent (BD) supplemented with various test components and the percentage of agglutinated sperm (% AggSp) was quantified at 1, 5, 24, 48, and 72 h of incubation. When sperm were incubated at 22 degrees C, no agglutination was observed in BD for up to 72 h, whereas the % AggSp was 5.0, 41.7, 72.2, 91.1, and 92.8% in BD + 5% egg yolk (BD + EY) at 1, 5, 24, 48 and 72 h, respectively. However, no sperm agglutination was observed in BD + EY if incubation temperature was 37 degrees C. Addition of 5 or 10 mM ethylenebis (oxyethyleneni-trilo) tetra-acetic acid to BD + EY reduced the % AggSp from 95% to <5% at 72 h (P < 0.001), but addition of 5 mM CaCl(2) to BD failed to induce sperm agglutination in the absence of egg yolk, implicating calcium and other factors in egg yolk. Addition of the citrate-soluble fraction (CSF) of egg yolk to BD induced sperm agglutination similar to whole egg yolk, whereas water- and saline-soluble fractions of egg yolk were ineffective. The sperm-agglutinating efficacy of CSF (the % AggSp = 95% at 72 h) was reduced by dialysis (20%; P < 0.05), partially restored by addition of 5 mM CaCl2 (70%; P < 0.05), but the calcium effect was neutralized by addition of 5 mM ethylenebis (oxyethyleneni trilo) tetra-acetic acid (1.7%; P < 0.05), again implicating calcium. Addition of 30 MUM of a protein kinase A inhibitor (H-89) to an agglutinating diluent failed to inhibit sperm agglutination, whereas addition of 2 mM of a cAMP analogue, dbcAMP, to a nonagglutinating diluent failed to induce sperm agglutination. Agglutination status had no effect on sperm plasma membrane/acrosome status and mitochondrial membrane potential. In conclusion, calcium and other component(s) in the CSF of egg yolk induced head-to-head agglutination of bull sperm in a time and temperature-dependent manner. Although the mechanism of agglutination was not determined, the cAMP- protein kinase A signaling pathway was not involved. PMID- 22925644 TI - Prostaglandin F2alpha promotes ovulation in prepubertal heifers. AB - The objective was to determine the effects of exogenous prostaglandin F(2alpha) (PGF), with or without progesterone treatment, on first ovulation in prepubertal heifers. We tested the hypothesis that PGF has a luteolysis-independent ovulatory effect in cattle. Crossbred Angus heifers (12 to 14 mo old, 250 kg body weight, and an average body condition score of 3 out of 5) were examined by transrectal ultrasonography on two occasions, 11 days apart. Heifers in which a CL was not detected at either examination were considered prepubertal. Heifers were assigned randomly to three experimental groups: (1) PG group (N = 14); heifers were treated with a PGF analog (500 MUg cloprostenol im) 5 days after the emergence of a spontaneous (i.e., naturally occurring, noninduced) follicular wave; (2) PPG group (N = 12); heifers were given an intravaginal progesterone-releasing insert (CIDR; Pfizer Animal Health, Montreal, QC, Canada), and a follicular wave was induced with 50 mg of progesterone + 2 mg of estradiol benzoate im, and a PGF analog was given at the time of CIDR removal, on day 5 of the follicular wave (on average, 8.6 +/- 0.5 days after CIDR insertion); and (3) control group heifers were given no treatment (N = 14). Heifers were examined daily by transrectal ultrasonography from the start of the experiment to confirmation that ovulation had occurred, or to 5 days after PGF injection (PG and PPG groups) or until dominant follicles of the next follicular wave reached 8 mm (control group). The percentage of heifers that ovulated within 10 days after wave emergence was higher in PPG (10/12; 83.3%) and PG (11/14; 78.5%) groups than in control (1/14; 7.1%; P < 0.0001). Ovulations occurred 69.6 +/- 6 h and 93.8 +/- 5 h after PGF treatment in PPG and in PG groups, respectively, whereas only one heifer in the control group ovulated 96 h after day 5 of follicular wave (P = 0.13). In summary, PGF treatment was associated with ovulation in prepubertal heifers whether or not exogenous progesterone was used as a pretreatment. The hypothesis that PGF will induce ovulation by a luteolysis-independent mechanism was supported. PMID- 22925645 TI - Intravaginal sponges to synchronize estrus decrease sexual attractiveness in ewes. AB - Vaginal secretions are an important source of chemical signals, which affect ewes' attractiveness. Moreover, alterations of vaginal flora reduce sexual attractiveness of estrous ewes. As intravaginal sponges containing progestagens (widely used for estrous synchronization) affect vaginal flora, our aims were to determine if estrous ewes pretreated with intravaginal sponges were less attractive than ewes displaying spontaneous estrus, and if the addition of antibiotic to the sponge mitigated the decreased sexual attractiveness. Seventy two estrous ewes were used in experiment 1: in 36, estrus was synchronized with commercial intravaginal sponges (50 mg medroxyprogesterone acetate for 14 days, group MAP1), whereas the other 36 were given a PGF2alpha analogue 19 to 20 days earlier and displayed spontaneous estrus (group C1). In experiment 2, 72 ewes were treated with intravaginal sponges for 14 days; for 36 ewes, the sponges contained 0.02 mg oxytetracycline (group Ox), whereas there was no antibiotic in the sponges for the remaining 36 ewes (group MAP2). In both experiments, sexual attractiveness was determined in 12 groups of six estrous ewes (three MAP1 vs. three C1, and three MAP2 vs. three Ox for Experiments 1 and 2, respectively) located in a 4 * 4 m pen. Courting and mating time that each ram spent with each ewe was recorded. After 5 min, the ewe with which the ram spent more time (most attractive ewe, ranked one, scale one to six) was taken out from the pen. The procedure was repeated until the ram ranked all six ewes, and repeated in the 12 groups in both experiments. In experiment 1, C1 ewes were more attractive than MAP1 ewes (ranks: 2.9 +/- 0.3 vs. 4.1 +/- 0.3, mean +/- SEM, respectively; P < 0.002). In experiment 2, sexual attractiveness of MAP2 and Ox ewes was similar (3.5 +/- 0.3 vs. 3.4 +/- 0.3, respectively). We concluded that the use of intravaginal sponges impregnated with medroxyprogesterone acetate negatively affected ewes' sexual attractiveness, but this decrease was not mitigated by inclusion of a local antibiotic. PMID- 22925646 TI - Endocrine disruptors and female fertility: focus on (bovine) ovarian follicular physiology. AB - Throughout the previous century, the production, use and, as a result, presence of chemicals in the environment increased enormously. Consequently, humans and animals are exposed to a wide variety of chemical substances of which some possess the ability to disrupt the endocrine system in the body, thereby denominated as "endocrine disrupting chemicals" (EDCs) or "endocrine disruptors". Because the reproductive system is a target organ for endocrine disruption, EDCs are postulated as one of the possible causes of human subfertility. Within the reproductive system, the ovarian follicle can be considered as an extremely fragile microenvironment where interactions between the oocyte and its surrounding somatic cells are essential to generate a fully competent oocyte. In this review, we explore how EDCs can interfere with the well-balanced conditions in the ovarian follicle. In addition, we highlight the bovine ovarian follicle as an alternative in vitro model for EDC and broader toxicology research. PMID- 22925647 TI - Profiling of key apoptotic, stress, and immune-related transcripts during embryonic and postembryonic development of Atlantic cod (Gadus morhua L.). AB - We investigated the profiles of 25 genes involved in apoptosis (bcl-x2, casp3, casp8, ccar1, mcl1, and tpt1), immunity (bty, cathl, ifng, il1b, il6, il8, il10, lyzg, and tfa), oxidative stress (cat, gpx4, gsh-px, hsp70, hsp90a, and sod1), and stress axis (crh, pomc, grl1, and mlr) during Atlantic cod development and compared the mRNA transcript levels between samples from farmed (FB) and wild broodstock (WB) using real-time polymerase chain reaction. The suitability of nine endogenous housekeeping genes and an external standard (luciferase) as reference genes was also evaluated. The cycle threshold values of all housekeeping genes differed significantly throughout Atlantic cod development. Fertilization and hatching rates were significantly higher in WB group (95 +/- 1.8% and 89 +/- 2.8%, respectively) compared with FB (75 +/- 3.4% and 66 +/- 3.2%, respectively). Eleven target genes, namely, ccar1, casp3, bcl-x2, mcl-1, cat, gsh-px, hsp70, sod1, lyzg, il8, and grl were expressed in both groups at fertilization stage, indicating their maternal transfer. Among them, transcripts of gsh-px were more abundant in WB eggs, while the expression of hsp70 was significantly higher in FB eggs. In FB larvae, expression of cat, hsp70, hsp90a, pomc, mlr, grl1, bclx2, and il6 was significantly higher at hatching and the expression of cat, gpx4, casp3 and ccar1 was significantly higher at first feeding stages, than in WB group. These findings give an insight into the expressional changes in certain category of genes involved in the embryonic development of Atlantic cod, which may eventually determine the ultimate quality of the larvae. PMID- 22925648 TI - Birth of common marmoset (Callithrix jacchus) offspring derived from in vitro matured oocytes in chemically defined medium. AB - Optimization of oocyte culture conditions is a crucial aspect of reproductive biology and technology. In the present study, maturation of germinal vesicle stage marmoset oocytes were evaluated in the following media: Waymouth medium, Waymouth medium containing porcine follicular fluid (pFF) (Waymouth-pFF medium), and porcine oocyte medium (POM). Oocytes cultured in Waymouth-pFF medium had higher maturation rates to the metaphase II stage than those cultured in Waymouth medium (36.1% vs. 24.8%, respectively, P < 0.05), indicating the suitability of this medium for culturing marmoset oocytes. Hence, maturation of marmoset oocytes cultured in POM was subsequently evaluated. The rate of maturation to the metaphase I stage was significantly higher and degradation rates were significantly lower in oocytes cultured in POM than those cultured in Waymouth medium. In addition, three offspring were successfully obtained after transfer of embryos matured in chemically defined medium. Therefore, we concluded that POM was suitable for marmoset oocyte culture. Furthermore, this was apparently the first report of marmoset offspring derived from oocytes cultured in chemically defined medium. PMID- 22925649 TI - Long-term viability and differentiation of bovine oviductal monolayers: bidimensional versus three-dimensional culture. AB - Different in vitro models have been developed to study the interaction of gametes and embryos with the maternal tract. In cattle, the interaction of the oviduct with gametes and embryos have been classically studied using oviductal explants or monolayers (OMs). Explants are well differentiated but have to be used within 24 h after collection, whereas OMs can be used for a longer time after cell confluence but dedifferentiate during culture, losing cell polarity and ciliation. Herein, OMs were cultured either in M199 plus 10% fetal calf serum or in a semidefined culture medium (Gray's medium), in an immersed condition on collagen-coated coated microporous polyester or polycarbonate inserts under air liquid interface conditions. The influence of culture conditions on long-term viability and differentiation of OMs was evaluated through scanning electron microscopy, localization of centrin and tubulin at the confocal laser scanning microscope, and assessment of maintenance of viability of sperm bound to OMs. Findings demonstrated that OMs cultured in an immersed condition with Gray's medium retain a better morphology, do not exhibit signs of crisis at least until 3 wks postconfluence, and maintain the viability of bound sperm significantly better than parallel OMs cultured in M199 plus 10% fetal calf serum. OM culture with Gray's medium in air-liquid interface conditions on porous inserts promotes cell polarity, ciliation, and maintenance of bound sperm viability at least until 3 wks postconfluence. In conclusion, oviduct culture in Gray's medium in an immersed or air-liquid condition allows long-term culture and, in the latter case, also ciliation of bovine OMs, and may represent in vitro systems that mimick more closely the biological processes modulated by the oviduct in vivo. PMID- 22925650 TI - Optimization of cryopreservation of buffalo (Bubalus bubalis) blastocysts produced by in vitro fertilization and somatic cell nuclear transfer. AB - The objective of this study was to optimize cryopreservation conditions for buffalo in vitro produced (IVP) embryos. The in vitro fertilized (IVF) and somatic cell nuclear transferred (SCNT) blastocysts were vitrified with either 40% ethylene glycol (EG), 25% EG + 25% dimethylsulfoxide (DMSO), or 20% EG + 20% DMSO + 0.5 m sucrose, and the IVF blastocysts produced from abattoir-derived ovaries were also slow-frozen with either 10% EG or 0.05 m trehalose dehydrate + 1.8% EG + 0.4% BSA. Cryosurvival rates of blastocysts harvested on various days or at various developmental stages were also examined. In this study: (1) vitrification with 20% EG + 20% DMSO + 0.5 m sucrose had the best cryopreservation efficiency; (2) IVF and SCNT blastocysts had similar cryotolerance (P > 0.05); (3) after thawing, slow-frozen blastocysts reexpanded earlier than the vitrified blastocysts (P < 0.01); (4) cryosurvival rate of expanded blastocysts was higher than that of early blastocysts (P < 0.05); (5) cryosurvival rates of Days 5 to 7 blastocysts (Day 0 = day of IVF or SCNT) were higher than those of Days 8 to 9 blastocysts (P < 0.01); and (6) after embryo transfer, pregnancy rates for fresh and cryopreserved blastocysts were not different (P > 0.05). In conclusion, vitrification of Days 6 to 7 expanded blastocysts with 20% EG + 20% DMSO + 0.5 m sucrose was optimal for cryopreservation of buffalo IVP embryos. PMID- 22925651 TI - Maternal environment and the reproductive function of the offspring. AB - Fetal programming of metabolic diseases is now a well established concept. The scope of the Developmental Origins of Health and Disease has, however, widened and led to the identification of new targets of fetal programming, notably effects on reproductive function. Epidemiologic studies about maternal nutrition and effects on offspring's fertility are rare, but a link between impaired fetal growth, possibly caused by maternal malnutrition, and reproductive function, has been established. The methodologic limitations inherent to human epidemiologic studies can be complemented through the use of animal models, which enable experimental studies on maternal environment and its effect on reproductive functions of the offspring. Altogether, an interaction between inappropriate maternal nutrition (excess or reduced nutritional intake, micronutrient unbalance, or alcohol intake) and reproductive maturation of the offspring has been shown in a majority of experiments as summarized in this review. The exact processes through which maternal nutrition or maternal environment affect reproductive function in the offspring remain unclear but epigenetic modifications are a clear link. Further studies are needed to better understand the mechanisms involved, identify the crucial critical periods, and prevent or treat the adverse effects. PMID- 22925652 TI - PET/MRI: challenges, solutions and perspectives. AB - Already from the start of PET/CT integrating positron emission tomography (PET) and computed tomography (CT) in one instrument, there have been considerations how to combine PET and magnetic resonance imaging (MRI) so that their complementary abilities can be utilized in a single investigation. Since classical PET electronics fail in an even weak magnetic field and PET signal processing might disturb high-frequency signals of MRI, it soon became clear that new solutions had to be found to avoid mutual interferences. During the last fifteen years a number of different approaches towards PET/MRI for small animal imaging have been developed by research groups which together with their specific features are summarized in this review. Recently, PET/MRI for human imaging became available as well - this time by industrial initiatives. First some prototypes of BrainPET/MRI were developed followed by commercial products for simultaneous and non-simultaneous whole-body PET/MRI. Although only PET/MRI integrated in one scanner offers the full diversity of complementary multiparametric imaging, there are also promising applications of non simultaneous sequential PET/MRI. While describing the present instrumentation for human PET/MRI, this review discusses the challenges and promises related to this new imaging technology. PMID- 22925653 TI - Attenuation correction for PET/MR: problems, novel approaches and practical solutions. AB - Attenuation correction in PET is the primary prerequisite for quantification of the radiotracer's signal. Absolute quantification is the key to improve diagnostic performance, to enable comparisons between follow-up examinations and to perform pharmacokinetic modeling. A large fraction of the 511 keV annihilation photons from the positron emitters are scattered by the patient's body. Thus, they are discarded or do not even reach the PET detectors, while others are identified at the wrong location after being scattered. To account for these effects and thus generate quantitative PET images showing the actual activity distribution, it is necessary to determine an attenuation map with the appropriate attenuation coefficients for 511 keV photons at each voxel. In hybrid PET/CT systems, this is achieved using the information about the tissue electron density provided by the CT and adjusting it for the difference in photon energy. In PET/MR systems, there is no mechanism to directly measure the attenuation coefficients of the tissue. Determining the attenuation map in PET/MR is an important challenge involving two problems: the determination of the patient's attenuation map and the determination of the attenuation introduced by additional hardware components. We describe the approaches investigated to deal with these problems and, based on the experience with a fully integrated PET/MR system, we finally discuss potential solutions and limitations in a close to routine setting. PMID- 22925654 TI - Between-laboratory quality control of automated analysis of IgG antibodies against Aspergillus fumigatus. AB - Measurement of IgG antibodies against Aspergillus fumigatus is an important criterion for the diagnosis of aspergilloma, allergic bronchopulmonary aspergillosis, and extrinsic allergic alveolitis. In the present study, we compared IgG antibody analysis against A. fumigatus using 2 widely used automated immunochemistry systems. In a between-laboratory quality control program, good agreement was found between the results from laboratories that used the ImmunoCAP system; however, a laboratory that used the Immulite 2000 system found approx. 2 fold higher antibody levels in the quality control samples than did the ImmunoCAP system. Measurements of IgG against A. fumigatus in patient sera were significantly correlated (r(s) = 0.77, P < 0.0001). These results demonstrate that analysis of IgG antibodies against A. fumigatus with these 2 systems has reached a level of standardization that allows for direct comparison of quantitative results from different laboratories. For longitudinal analysis of IgG against A. fumigatus, reagents from the same manufacturer should be used. PMID- 22925656 TI - The classification of cancer stage microarray data. AB - Correctly diagnosing the cancer stage is most important for selecting an appropriate cancer treatment option for a patient. Recent advances in microarray technology allow the cancer stage to be predicted using gene expression patterns. The cancer stage is in ordinal scale. In this paper, we employ strict ordinal regressions including cumulative logit model in traditional statistics with data dimensionality reduction, and distribution free approaches of large margin rank boundaries implemented by the support vector machine, as well as an ensemble ranking scheme to model the cancer stage using gene expression microarray data. Predictive genes included in models are selected by univariate feature ranking, and recursive feature elimination. We perform cross-validation experiments to assess and compare classification accuracies of ordinal and non-ordinal algorithms on five cancer stage microarray datasets. We conclude that a strict ordinal classifier trained by a validated approach can predict the cancer stage more accurately than traditional non-ordinal classifiers without considering the order of cancer stages. PMID- 22925655 TI - Apoptosis signal-regulating kinase 1 is associated with the effect of claudin-6 in breast cancer. AB - BACKGROUND: Previous studies have demonstrated that claudin-6 functions as a cancer suppressor in human MCF-7 breast cancer cells. The growth inhibitory effect could be attributed to inhibition of cell proliferation and induction of apoptosis. The purpose of the current study was to examine the involvement of apoptosis signal-regulating kinase 1 (ASK1) in the anticancer effect of claudin 6. METHODS: Immunohistochemical analysis was performed to evaluate the ASK1 protein expression and the correlation between ASK1, claudin-6 and clinicopathological features in 85 samples of breast invasive ductal carcinomas (IDC). Western blotting and RT-PCR was carried out to examine the expression of ASK1 and claudin-6 in MCF-7 cell clones transfected with claudin-6. RESULTS: Immunohistochemical analysis showed that ASK1 expression was significantly related with that of claudin-6 in breast invasive ductal carcinomas (P < 0.05). In addition, a positive correlation between ASK1 and C-erb B 2 protein expression was identified (P < 0.05). Western blotting and RT-PCR consistently revealed that the level of ASK1 protein and mRNA was upregulated in MCF-7 cell clones transfected with claudin-6. CONCLUSIONS: Our data suggests, for the first time, that the ASK1 signal may play a positive role in the inhibitory effect of claudin 6 in breast cancer. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1200314318763661. PMID- 22925657 TI - Subgenotype reclassification of genotype B hepatitis B virus. AB - BACKGROUND: Nine subgenotypes from genotype B have been identified for hepatitis B virus (HBV). However, these subgenotypes were less conclusive as they were often designated based on a few representative strains. In addition, subgenotype B6 was designated twice for viruses of different origin. METHODS: All complete genome sequences of genotype B HBV were phylogenetically analyzed. Sequence divergences between different potential subgenotypes were also assessed. RESULTS: Both phylogenetic and sequence divergence analyses supported the designation of subgenotypes B1, B2, B4, and B6 (from Arctic). However, sequence divergences between previously designated B3, B5, B7, B8, B9 and another B6 (from China) were mostly less than 4%. In addition, subgenotype B3 did not form a monophyly. CONCLUSION: Current evidence failed to classify original B5, B7, B8, B9, and B6 (from China) as subgenotypes. Instead, they could be considered as a quasi subgenotype B3 of Southeast Asian and Chinese origin. In addition, previously designated B6 (from Arctic) should be renamed as B5 for continuous numbering. This novel classification is well supported by both the phylogeny and sequence divergence of > 4%. PMID- 22925658 TI - The electrically evoked long latency reflex of the biceps brachii muscle: the impact of train stimuli, preceding stimuli, and voluntary muscle contraction. AB - Long latency reflex (LLR) responses were examined over the biceps brachii (BB) at different contraction levels after electrical single or train stimuli over the ipsilateral superficial radial nerve with an inter-stimulus interval of 3ms. Two constant motor waves were present, LLR2 with a peak latency value of 53+/-4ms and LLR3 with 85+/-10ms. LLR responses showed a significant increase (twofold) in amplitudes after train stimuli compared to up to a fourfold increase after train stimuli were combined with a weight load of 1.5kg. When LLR were investigated after subsequent (1/s) stimuli by selective averaging, a significant increase in LLR2 amplitude values was seen after the third compared with the first stimulus for trains of 3 stimuli. In the present study, 3 factors exerted an influence on LLR, namely temporal summation of synaptic potentials (by train stimuli), facilitation (with higher stimulus repetition rates), and volition (resulting in muscle contraction). The augmentation behaviour of LLR may be useful for the investigation of central nervous system diseases such as e.g. movement disorders. PMID- 22925659 TI - PI3K-ERK1/2 activation contributes to extracellular H2O2 generation in amyloid beta toxicity. AB - Amyloid beta peptide (Abeta) induces hydrogen peroxide (H2O2) and superoxide generation, leading to neuronal death. Many studies have shown the involvement of NADPH oxidase, but the isotype-specific role was not assessed. Moreover, the activation status of phosphoinositide 3-kinase (PI3K) and extracellular signal regulated kinase (ERK) 1/2 is unclear in extracellular H2O2 generation. In this paper, we showed that Abeta1-42 induced extracellular H2O2 generation and the resulting cytotoxicity in a concentration-dependent manner. Nox2- and Nox4 specific siRNAs suppressed H2O2 and superoxide generation. LY294002 and U0126, inhibitors of PI3K and ERK1/2, respectively, reduced H2O2 generation in concentration-dependent manners. Furthermore, PI3K activation is responsible for ERK1/2 phosphorylation. An additional increase in H2O2 generation and corresponding cytotoxicity was observed after treatment with Abeta1-42 and glutamate. These results suggest that Abeta1-42 enhances the neuronal vulnerability to oxidative injury in Alzheimer's disease (AD) by increasing H2O2 generation. PMID- 22925660 TI - Effect of magnetic stimulation on the gene expression profile of in vitro cultured neural cells. AB - Transcranial magnetic stimulation is a non-invasive tool in clinical diagnostics and therapy for physiological and psychological diseases and has an increased application in experimental neurophysiology. Despite this, the mechanisms of magnetic stimulation of the central nervous system remain still unclear. We applied sinus-shaped high frequency magnetic fields in different stimulation patterns and repeated treatments to cell cultures derived from frontal cortex of murine embryos (BALB/cOlaHsd mice) to elucidate the effects of repetitive magnetic stimulation on the gene expression of in vitro cultured neural cells. Gene expression profiling was performed by using qRT-PCR array and single qRT-PCR analyses. Our methodological approach using microelectrode arrays data recording and analysis minimizes variations in transcriptome analysis arising from cell differentiation status and tissue complexity. With 10 significant changes in gene expression out of 171 genes using Alzheimer disease and neurodegeneration related qRT-PCR arrays we demonstrate significant impact of repetitive magnetic stimulation on the mRNA transcript of neural cell cultures. Sixteen candidate genes were analyzed using single qRT-PCR in a replicated statistical design, which provided more precise estimates of differences in expression profiles. We discussed the utility of the experimental methods used for cell culture selection and the changes in gene expression considering physiological aspects. PMID- 22925662 TI - Bill Lennarz. Foreword. PMID- 22925661 TI - Neuroprotective effect of 20(R)-ginsenoside Rg(3) against transient focal cerebral ischemia in rats. AB - Gensenosides, the active ingredients of Chinese herbal medicine Panax ginseng, have a wide spectrum of medical effects, such as anti-tumorigenic, angiosuppressive, adaptogenic, and anti-fatigue activities. In the present study, we have investigated the neuroprotective effect of 20(R)-ginsenoside Rg(3) (20(R) Rg(3)) against transient focal cerebral ischemia in male Sprague-Dawley (SD) rats. The middle cerebral artery was occluded for 2h in rats and then reperfused for 24h. The behavioral disturbance was evaluated according to neurological deficit scores, and the infarct volumes were evaluated by 2,3,5 triphenyltetrazolium chloride (TTC) staining; in addition, ischemia-mediated apoptosis was examined using the method of terminal deoxynucleotidyl transferase (TdT)-mediated d-UTP nick end labeling (TUNEL). The expressions of calpain I and caspase-3 mRNA in hippocampal CA1 region were further assayed using in situ hybridization, in order to clarify the neuroprotective mechanism of 20(R)-Rg(3). 20(R)-Rg(3) at the doses of 10 and 20mgkg(-1) i.p., but not 5mgkg(-1), showed significant neuroprotective effect in rats against focal cerebral ischemic injury by markedly reducing cerebral infarct volumes and degrading infarct rate of TTC stained coronal brain sections, and improving behavior of the animals. Our results also suggested that 20(R)-Rg(3) (10 and 20mgkg(-1)) could significantly suppress the expressions of calpain I and caspase-3 mRNA. These results indicated that 20(R)-Rg(3) attenuates the neuronal apoptosis caused by cerebral ischemia reperfusion injury and its neuprotective effect may be involved in the downregulation of calpain I and caspase-3. PMID- 22925664 TI - An interview by Dr. Ernesto Carafoli with, Editor-in-Chief of Biochemical and Biophysical Research Communications (BBRC), Dr. William Lennarz. PMID- 22925665 TI - On the size of the active site in proteases. I. Papain. 1967. PMID- 22925666 TI - Glutathione peroxidase activity in selenium-deficient rat liver. 1976. PMID- 22925667 TI - Protein and cell membrane iodinations with a sparingly soluble chloroamide, 1,3,4,6-tetrachloro-3a,6a-diphenylglycoluril. 1978. PMID- 22925668 TI - Application of phase sensitive two-dimensional correlated spectroscopy (COSY) for measurements of (1)H-(1)H spin-spin coupling constants in proteins. 1983. PMID- 22925669 TI - Improved spectral resolution in COSY (1)H NMR spectra of proteins via double quantum filtering. 1983. PMID- 22925670 TI - Alzheimer's disease: initial report of the purification and characterization of a novel cerebrovascular amyloid protein. 1984. PMID- 22925671 TI - Pituitary follicular cells secrete a novel heparin-binding growth factor specific for vascular endothelial cells. 1989. PMID- 22925672 TI - Adrenomedullin: a novel hypotensive peptide isolated from human pheochromocytoma. 1993. PMID- 22925673 TI - cDNA cloning and expression of a novel adipose specific collagen-like factor, apM1 (adipose most abundant gene transcript 1). 1996. PMID- 22925674 TI - Paradoxical decrease of an adipose-specific protein, adiponectin, in obesity. 1999. PMID- 22925675 TI - A heat-stable polypeptide component of an ATP-dependent proteolytic system from reticulocytes. 1978. PMID- 22925676 TI - Unsaturated diacylglycerol as a possible messenger for the activation of calcium activated, phospholipid-dependent protein kinase system. 1979. PMID- 22925677 TI - More than 40 years of glycobiology in Regensburg. PMID- 22925678 TI - The quest for the sea urchin egg receptor for sperm. AB - This review discusses identification, isolation and characterization of proteins mediating species-selective sperm-to-egg adhesion during sea urchin fertilization. Bindin is the only sea urchin sperm protein known to mediate species-selective sperm attachment to eggs. Two completely different egg surface proteins, 350-kDa and EBR1, have affinity for bindin and each one meets all the criteria to be a species-selective sperm receptor. Experiments suggest that sperm bindin recognizes both the sulfated O-linked oligosaccharides on the egg 350-kDa glycoprotein, and also the repeated protein sequence modules of EBR1. PMID- 22925679 TI - Fertilization in echinoderms. AB - For more than 150 years, echinoderm eggs have served as overly favored experimental model systems in which to study fertilization. Sea urchin and starfish belong to the same phylum and thus share many similarities in their fertilization patterns. However, several subtle but fundamental differences do exist in the fertilization of sea urchin and starfish, reflecting their phylogenetic bifurcation approximately 500 million years ago. In this article we review some of the seminal and recent findings that feature similarities and differences in sea urchin and starfish at fertilization. PMID- 22925680 TI - Structure of acrosome reaction-inducing substance in the jelly coat of starfish eggs: a mini review. AB - Our knowledge at present on the structure of acrosome-reaction inducing substance (ARIS) in the jelly coat of starfish eggs is summarized. ARIS ia a proteoglycan like molecule consisting of very long, linear, and highly sulfated glycans and three ARIS proteins, ARIS1-3. Detailed structures of the major glycan of ARIS and of ARIS1-3 are discussed. 3D-models of ARIS glycans are also presented. Phylogenetic distribution of ARIS proteins and/or genes indicates that ARIS genes are well preserved from the Ctenophore to Cephalochordata. In the Echinodermata, ARIS1-3 and ARIS genes were detected in all classes except for sea urchins. PMID- 22925681 TI - Semantic access to embedded words? Electrophysiological and behavioral evidence from Spanish and English. AB - Many multisyllabic words contain shorter words that are not semantic units, like the CAP in HANDICAP and the DURA (hard) in VERDURA (vegetable). The spaces between printed words identify word boundaries, but spurious identification of these embedded words is a potentially greater challenge for spoken language comprehension, a challenge that is handled by different mechanisms in different models of auditory word recognition. Subphonemic acoustic differences--subtle differences in pronunciation--often differentiate embedded words from genuine words. We examined semantic access to embedded words in two languages with different phonology by presenting carrier words followed by targets related to the embedded words and recording event-related potentials and lexical decision times in 34 Spanish/English bilinguals. No evidence of embedded word access was observed in brain activity or behavior, and this could not be attributed to subphonemic acoustic factors. The data place constraints on models of speech segmentation. PMID- 22925682 TI - Dipeptidyl peptidase-4 inhibitors and cardiovascular risk: a meta-analysis of randomized clinical trials. AB - AIMS: Preliminary data from randomized trials with metabolic outcomes have shown that treatment with dipeptidyl peptidase-4 inhibitors (DPP4i) could be associated with a reduced incidence of major cardiovascular events (MACE). The present meta analysis is aimed at verifying this protective effect, collecting all available data from randomized trials. METHODS: A comprehensive search for published and unpublished trials with a duration >=24 weeks comparing DPP4i with placebo or other drugs was performed, retrieving all MACE reported as serious adverse events together with death from any cause. Mantel-Haenzel odds ratio (MH-OR) was calculated with random effect models for MACE, myocardial infarction, stroke and mortality. When available, effects on glycated haemoglobin, lipid profile and blood pressure were also assessed and used for the estimation of the modification of risk for myocardial infarction using the UKPDS risk engine. RESULTS: A total of 70 trials, enrolling 41 959 patients with a mean follow-up of 44.1 weeks, was collected and included in the analysis. The MH-OR (95% Confidence Interval) was 0.71[0.59;0.86], 0.64[0.44;0.94], 0.77[0.48;1.24] and 0.60[0.41;0.88] for MACE, myocardial infarction, stroke and mortality, respectively. CONCLUSIONS: Treatment with DPP4i reduces the risk of cardiovascular events (particularly myocardial infarction) and all-cause mortality in patients with type 2 diabetes. The reduction in the incidence of myocardial infarction is greater than what predicted on the basis of conventional risk factors, suggesting a role for other mechanisms. PMID- 22925683 TI - Frozen-thawed embryo transfer is associated with a significantly reduced incidence of ectopic pregnancy. AB - OBJECTIVE: To compare the incidence of ectopic pregnancy (EP) after fresh ET and thawed ET. DESIGN: Retrospective cohort study. SETTING: Private fertility center. PATIENT(S): This retrospective study included 2,150 blastocyst transfers, including all 1,460 fresh autologous blastocyst transfers and all 690 transfers of autologous blastocysts derived from post-thaw extended culture of thawed bipronuclear oocytes in the 8-year study period 2004-2011. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Visualized EP and treated persistent pregnancy of unknown location. RESULT(S): The rate of visualized EP was 1.5% in pregnancies in fresh autologous cycles, which was significantly more than the rate of 0 with autologous post-thaw extended culture. The rates of treated persistent pregnancy of unknown location were 2.5% and 0.3% in these two groups, respectively, a difference that was also statistically significant (relative risk 7.3, 95% confidence interval 1.7-31.0). CONCLUSION(S): Relative to fresh transfer, thawed ET was associated with significantly reduced incidence of EP. These findings are consistent with ovarian stimulation increasing the risk of EP. PMID- 22925684 TI - Leiomyoma fibrosis inhibited by liarozole, a retinoic acid metabolic blocking agent. AB - OBJECTIVE: To study the influence of liarozole on leiomyoma cell proliferation and extracellular matrix (ECM) gene expression in immortalized leiomyoma cells. DESIGN: Laboratory study. SETTING: University hospital. PATIENT(S): None. INTERVENTION(S): Tissue culture, real-time reverse transcription-polymerase chain reaction, Western blot. MAIN OUTCOME MEASURE(S): Proliferation, messenger RNA (mRNA), and ECM protein expression. RESULT(S): Proliferation of leiomyoma cells was inhibited by treatment with liarozole at suprapharmacologic concentrations. The mRNA and protein expression of COL1A1, COL4A2, versican, fibromodulin, and fibronectin was increased in untreated leiomyoma cells compared with untreated patient-matched myometrial cells. Extracellular matrix mRNA expression was decreased in a dose-dependent manner in leiomyoma cells treated with pharmacologic concentrations of liarozole. In addition, myometrial cells treated with liarozole demonstrated no statistically significant alteration in ECM regulation. CONCLUSION(S): Liarozole inhibited ECM protein production at pharmacologic concentrations in immortalized human leiomyoma cells. Retinoic acid metabolic blocking agents represent a potential therapeutic drug family for human leiomyomas. PMID- 22925685 TI - Determination of male infertility: is the 2010 WHO reference range helpful or confusing? PMID- 22925686 TI - Role of FSH to optimize adolescent testicular growth. PMID- 22925687 TI - Limited implantation success of direct-cleaved human zygotes: a time-lapse study. AB - OBJECTIVE: To evaluate embryos with direct cleavage (<=5 hours) from two to three cells (DC2-3) and correlate this morphokinetic parameter to implantation and ongoing pregnancy. DESIGN: Clinical multicenter retrospective study. SETTING: Private in vitro fertilization (IVF) centers. PATIENT(S): From three clinics, a total of 979 treatments including 5,225 embryos using autologous or donated oocytes, of which 1,659 embryos were transferred. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Clinical pregnancy confirmed by ultrasound in week 7. RESULT(S): Of the total embryo cohort, 715 (13.7%) underwent direct cleavage from two to three cells, 1,659 embryos were transferred to recipients, and 109 of the transferred embryos cleaved directly from two to three cells (6.6%). Only one DC2 3 embryo was known to result in a clinical pregnancy (1%) and 80 (73.4%) DC2-3 embryos did not implant. Of the 1,550 embryos transferred not showing DC2-3, 203 embryos were from treatments with 100% implantation (13.1%), and 804 (51.8%) embryos did not implant. The known implantation rate of DC2-3 embryos was statistically significantly lower than for embryos with a normal cleavage pattern (1.2% vs. 20.2%, respectively). CONCLUSION(S): Embryos with DC2-3 had a statistically significantly lower implantation rate than embryos with a normal cleavage pattern, suggesting that rejection of these embryos for transfer could improve the implantation rate. PMID- 22925688 TI - Adenosine triphosphate-binding cassette transporter G2 expression in endometriosis and in endometrium from patients with and without endometriosis. AB - OBJECTIVE: To investigate adenosine triphosphate (ATP)-binding cassette transporter G2 (ABCG2) expression in endometriosis and in samples of endometrium from patients with and without endometriosis. DESIGN: Prospective study. SETTING: University hospital. PATIENT(S): Patients with and without endometriosis. INTERVENTION(S): Endometrial and endometriotic tissues obtained throughout the menstrual cycle. MAIN OUTCOME MEASURE(S): Density of ABCG2(+) microvessels, density of CD31(+) microvessels. RESULT(S): No statistically significant differences in the density of ABCG2(+) microvessels were observed between endometrium of patients with and without endometriosis in the proliferative phase and early, middle, and late secretory phases. The density of ABCG2(+) microvessels was statistically significantly higher in the menstrual endometrium of patients with endometriosis compared with patients without endometriosis. The density of ABCG2(+) microvessels was reduced in the ectopic endometrium compared with matched eutopic endometrium except in cases of deep infiltrating endometriosis. The density of ABCG2(+) microvessels was statistically significantly higher in deep infiltrating endometriosis compared with ovarian endometriosis and red and black peritoneal lesions throughout the menstrual cycle. CONCLUSION(S): ABCG2 is strongly expressed in the endothelial cells of microvessels of eutopic endometrium, and the density of ABCG2(+) microvessels is reduced in ectopic endometrium except in cases of deep infiltrating endometriosis. ABCG2(+) microvessels may represent an integral part of the pathophysiology of deep infiltrating endometriosis. PMID- 22925690 TI - Nicotinic acetylcholine receptors: from basic science to therapeutics. AB - Substantial progress in the identification of genes encoding for a large number of proteins responsible for various aspects of neurotransmitter release, postsynaptic detection and downstream signaling, has advanced our understanding of the mechanisms by which neurons communicate and interact. Nicotinic acetylcholine receptors represent a large and well-characterized family of ligand gated ion channels that is expressed broadly throughout the central and peripheral nervous system, and in non-neuronal cells. With 16 mammalian genes identified that encode for nicotinic receptors and the ability of the subunits to form heteromeric or homomeric receptors, the repertoire of conceivable receptor subtype combinations is enormous and offers unique possibilities for the design and development of new therapeutics that target nicotinic acetylcholine receptors. The aim of this review is to provide the reader with recent insights in nicotinic acetylcholine receptors from genes, structure and function to diseases, and with the latest findings on the pharmacology of these receptors. Although so far only a few nicotinic drugs have been marketed or are in late stage development, much progress has been made in the design of novel chemical entities that are being explored for the treatment of various diseases, including addiction, depression, ADHD, cognitive deficits in schizophrenia and Alzheimer's disease, pain and inflammation. A pharmacological analysis of these compounds, including those that were discontinued, can improve our understanding of the pharmacodynamic and pharmacokinetic requirements for nicotinic 'drug-like' molecules and will reveal if hypotheses on therapies based on targeting specific nicotinic receptor subtypes have been adequately tested in the clinic. PMID- 22925689 TI - Enhanced itaconic acid production in Aspergillus niger using genetic modification and medium optimization. AB - BACKGROUND: Aspergillus niger was selected as a host for producing itaconic acid due to its versatile and tolerant character in various growth environments, and its extremely high capacity of accumulating the precursor of itaconic acid: citric acid. Expressing the CAD gene from Aspergillus terreus opened the metabolic pathway towards itaconic acid in A. niger. In order to increase the production level, we continued by modifying its genome and optimizing cultivation media. RESULTS: Based on the results of previous transcriptomics studies and research from other groups, two genes : gpdA encoding the glyceraldehyde -3 dehydrogenase (GPD) and hbd1 encoding a flavohemoglobin domain (HBD) were overexpressed in A. niger. Besides, new media were designed based on a reference medium for A. terreus. To analyze large numbers of cultures, we developed an approach for screening both fungal transformants and various media in 96-well micro-titer plates. The hbd1 transformants (HBD 2.2/2.5) did not improve itaconic acid titer while the gpdA transformant (GPD 4.3) decreased the itaconic acid production. Using 20 different media, copper was discovered to have a positive influence on itaconic acid production. Effects observed in the micro-titer plate screening were confirmed in controlled batch fermentation. CONCLUSIONS: The performance of gpdA and hbd1 transformants was found not to be beneficial for itaconic acid production using the tested cultivation conditions. Medium optimization showed that, copper was positively correlated with improved itaconic acid production. Interestingly, the optimal conditions for itaconic acid clearly differ from conditions optimal for citric- and oxalic acid production. PMID- 22925691 TI - High-resolution melting analysis: a genotyping tool for population studies on Daphnia. AB - Determining genetic variation at the DNA level within and between natural populations is important for understanding the role of natural selection on phenotypic traits, but many techniques of screening for genetic variation are either cost intensive, not sensitive enough or too labour- and time-consuming. Here, we demonstrate high-resolution melting analysis (HRMA) as a cost-effective and powerful tool for screening variable target genes in natural populations. HRMA is based on monitoring the melting of PCR amplicons. Owing to saturating concentrations of a dye that binds at high concentrations to double-stranded DNA, it is possible to genotype high numbers of samples rapidly and accurately. We analysed digestive trypsins of two Daphnia magna populations as an application example for HRMA. One population originated from a pond containing toxic cyanobacteria that possibly produce protease inhibitors and the other from a pond without such cyanobacteria. The hypothesis was that D. magna clones from ponds with cyanobacteria have undergone selection by these inhibitors, which has led to different trypsin alleles. We first sequenced pooled genomic PCR products of trypsins from both populations to identify variable DNA sequences of active trypsins. Second, we screened variable DNA sequences of each D. magna clone from both populations for single nucleotide polymorphisms via HRMA. The HRMA results revealed that both populations exhibited phenotypic differences in the analysed trypsins. Our results indicate that HRMA is a powerful genotyping tool for studying the variation of target genes in response to selection within and between natural Daphnia populations. PMID- 22925692 TI - Discovery of HLA-DRB1*03:20 allele in a Taiwanese volunteer hematopoietic stem cell donor and the probable HLA-A, -B, -C and -DRB1 haplotype in association with DRB1*03:20. AB - The allele HLA-DRB1*03:20, a variant of DRB1*03, was first reported to the IMGT HLA database in April 2001 without indication on the ethnicity of the blood donor (Cell ID: HC 125775). We found a Taiwanese volunteer hematopoietic stem cell donor carries DRB1*03:20 by a sequence-based typing (SBT) method. The DNA sequence of DRB1*03:20 is identical to the sequence of DRB1*03:01:01 in exon 2, except a nucleotide substitution at position 341(T->C) (GTT->GCT at codon 85). The nucleotide replacement produced an amino acid variation at residue 85 (V->A). We hypothesize that DRB1*03:20 was probably derived from DRB1*03:01:01 via a nucleotide point mutation event. The probable HLA haplotype in association with DRB1*03:20 was deduced as A*11:02-B*58:01-C*07:02-DRB1*03:20. We here report the Taiwanese/Chinese ethnicity of DRB1*03:20. PMID- 22925693 TI - Oncolytic Vaccinia virus and radiotherapy in head and neck cancer. AB - OBJECTIVE: Oncolytic forms of attenuated Vaccinia virus are now in clinical development, assessing the compatibility of this novel treatment with radiotherapy may reveal exploitable synergistic relationships. MATERIALS AND METHODS: In vitro analyses of cell killing, cell cycle effects and caspase activation were carried out on HN3, HN5, CAL27, Detroit, SIHN5B, and PJ41 cells. In vivo studies of the virus and X-radiation were performed on H&N xenografts in CD1 nude mice. RESULTS: Cell killing in vitro was demonstrated to be dose- and time-dependent. Infection causes an increase in S-phase and sub-G1 cells. A dose dependent increase in active caspase-3 indicated induction of apoptosis. Xenografts injected with Vaccinia stabilised and frequently completely regressed. Combination with radiation generated additional cell death, induction of caspase activity and in vivo further improved long term regression rates. CONCLUSIONS: These data support continued exploration of this therapy combination and indicates potential for clinical trials in head and neck cancer. PMID- 22925694 TI - DNA methylation index and methylation profile of invasive ductal breast tumors. AB - Breast carcinogenesis is a multistep process that involves both genetic and epigenetic alterations. Identification of aberrantly methylated genes in breast tumors and their relation to clinical parameters can contribute to improved diagnostic, prognostic, and therapeutic decision making. Our objective in the present study was to identify the methylation status of 34 cancer-involved genes in invasive ductal carcinomas (IDC). Each of the 70 IDC cases analyzed had a unique methylation profile. The highest methylation frequency was detected in the WT1 (95.7%) and RASSF1 (71.4%) genes. Hierarchical cluster analysis revealed three clusters with different distribution of the prognostic factors tumor grade, lymph node metastasis, and proliferation rate. Methylation of TP73 was associated with high histological grade and high proliferation rate; methylation of RARB was associated with lymph node metastasis. Concurrent methylation of TP73 and RARB was associated with high histological grade, high proliferation rate, increased tumor size, and lymph node metastasis. Patients with more than six methylated genes had higher rates of relapse events and cancer deaths. In multivariate analysis, TP73 methylation and the methylation index were associated with disease outcome. Our results indicate that methylation index and methylation of TP73 and/or RARB are related to unfavorable prognostic factors in patients with IDC. These epigenetic markers should be validated in further studies to improve breast cancer management. PMID- 22925695 TI - Certification in molecular pathology in the United States: an update from the Association for Molecular Pathology Training and Education Committee. AB - The past 25 years have witnessed the field of molecular pathology evolving from an imprecisely defined discipline to a firmly established medical subspecialty that plays an essential role in patient care. During this time, the training, certification, and licensure requirements for directing and performing testing in a molecular pathology or molecular diagnostics laboratory have become better defined. The purpose of this document is to describe the various board certifications available to individuals seeking certification in molecular diagnostics at the level of laboratory director, supervisor, or technologist. Several national organizations offer certification in molecular pathology or molecular diagnostics for doctoral-level clinical scientists to function as the director of a molecular diagnostics laboratory. Furthermore, 12 states and Puerto Rico require licensing of medical technologists, including those working in molecular diagnostic laboratories. The information provided here updates a 2002 document by the Training and Education Committee of the Association for Molecular Pathology and has been expanded to include certification and licensing requirements for laboratory technologists. PMID- 22925696 TI - Variable morphology of the anterior coracoscapular ligament - a proposal of classification. AB - INTRODUCTION: The suprascapular region is the most common site of compression and injury to the suprascapular nerve. This often results in suprascapular nerve entrapment, a possible risk factor being the anterior coracoscapular ligament (ACSL), a structure that runs in the suprascapular notch, below the superior transverse scapular ligament. The aim of the present study is to determine morphological variation of the ACSL and to measure the reduction in size of the suprascapular opening of specimens exhibiting it. MATERIALS AND METHODS: A total of 84 human shoulders were included in the study. The following measurements were defined and performed for every ACSL: maximal length (ML), maximal proximal width (MPW) and maximal distal width (MPW). Additionally, two measurements of the suprascapular opening were collected: the area (aSSO) and the middle width (mwSSO). All of these measurements were taken using two independent methods: classical osteometry, and a new procedure based on the analysis of digital photographic documentation of the SSN taken using MultiScanBase v.14.02 software. RESULTS: The anterior coracoscapular ligaments were present in 43 shoulders (51.2%). The analysis allowed the determination of four types of ACSL: first - fan-shaped (7%), second - band-shaped (62.8%), third - bifid (11.6%) and fourth - vestigial (18.6%). The mean area as well as the middle width of the suprascapular opening in the specimens with the anterior coracoscapular ligament was smaller than in those without this structure, however, no statistically significant differences were observed. The suprascapular nerve passed inferior to the ACSL in 2 specimens, and superior to it in 41. CONCLUSION: The study presents a classification of the anterior coracoscapular ligament that has not been described in the literature and can be helpful in arthroscopic and open procedures of the suprascapular region. Knowledge of such anatomical variations confirms the safety of operative decompression to relieve entrapment of the suprascapular nerve. PMID- 22925697 TI - Extraskeletal myxoid chondrosarcoma in the lung: asymptomatic lung mass with severe anemia. AB - Extraskeletal myxoid chondrosarcoma (EMC) is a rare soft-tissue sarcoma, which primarily occurs deep in the extremities, especially in skeletal muscle, or tendon. EMC of the pleura has been described, however, no case of primary EMC arising from lung has been previously reported. We describe herein, a 51-year-old Asian female initially manifested with signs of severe anemia who presented with a lung mass unrelated to pleura that was morphologically typical EMC, with strong immunoreactivity for vimentin and NSE. Two weeks after resection, the anemia was cured. The patient continued with follow-up, without sign of abnormality 32 months after operation. Virtual slides: The virtual slides for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/2882199847396682. PMID- 22925698 TI - The association of elevated 2',5'-oligoadenylate-dependent RNase L with lung cancer correlated with deficient enzymatic activity and decreased capacity of RNase L dimerization. AB - RNase L mediates critical cellular functions including antiviral, proapoptotic, antiproliferative and tumor suppressive activities. In this study, the expression and function of RNase L in lung cancer cells were examined. Interestingly we have found that the expression of RNase L in lung cancer cells was 3- and 9-fold higher in its mRNA and protein levels, but a significant decrease of its enzymatic activity when compared to that in corresponding normal lung cells. Further investigation revealed that 2-5A-induced dimerization of the RNase L protein, a necessary prerequisite for activation of RNase L, was inhibited, as a result of that RLI, a specific inhibitor of RNase L, was remarkably up-regulated in the cancer cells. Our findings provide new insight into how cancer cells escape normal growth-regulating mechanisms to form a tumor and the information may be useful for the design of novel strategies for treating lung cancer through regulating RNase L activity. PMID- 22925700 TI - Differential effects of left/right neuropathy on rats' anxiety and cognitive behavior. AB - Chronic pain is frequently accompanied by a deterioration of emotional behavior and cognitive function. A small number of studies in humans concluded that pain associated negative affect is more pronounced when pain is localized in the left side of the body. It has been suggested that such side bias results from cortical function lateralization. It is not known, however, if other pain-associated behavioral changes are differentially affected by left- and right-sided pain. To test this hypothesis, the performance of rats with a unilateral spared nerve injury neuropathy installed in the left (SNI-L) or in the right (SNI-R) side was compared in anxiety (elevated-plus maze) and cognitive (spatial working and reference memory, attentional set-shifting task, and delay-to-signal impulsivity task) behavioral paradigms. Results show that SNI-L animals presented an increased anxiety-like profile while maintaining preserved cognitive function. On the contrary, SNI-R animals presented cognitive deficits in all tasks except in the reference memory, but displayed a normal anxiety-like profile. Our results show that left- and right-sided neuropathic pain differentially affects emotional behavior, which is in accordance with previous observations in human subjects, both in experimentally induced pain and in chronic pain conditions. Additionally, our results demonstrate that the cognitive function deterioration associated with unilateral neuropathic chronic pain conditions is also differentially affected. PMID- 22925699 TI - Epigenetic therapy with 3-deazaneplanocin A, an inhibitor of the histone methyltransferase EZH2, inhibits growth of non-small cell lung cancer cells. AB - EZH2 (enhancer of zeste homolog 2) is the catalytic subunit of PRC2 (polycomb repressive complex 2), which mediates histone methyltransferase activity and functions as transcriptional repressor involved in gene silencing. EZH2 is involved in malignant transformation and biological aggressiveness of several human malignancies. We previously demonstrated that non-small cell lung cancers (NSCLCs) also overexpress EZH2 and that high expression of EZH2 correlates with poor prognosis. Growing evidence indicates that EZH2 may be an appropriate therapeutic target in malignancies, including NSCLCs. Recently, an S-adenosyl-l homocysteine hydrolase inhibitor, 3-Deazaneplanocin A (DZNep), has been shown to deplete and inhibit EZH2. The aim of this study was to determine the effect of DZNep in NSCLC cells. Knockdown of EZH2 by small-interfering RNA (siRNA) resulted in decreased growth of four NSCLC cell lines. MTT assays demonstrated that DZNep treatment resulted in dose-dependent inhibition of proliferation in the NSCLC cell lines with a half maximal inhibitory concentration (IC50) ranging from 0.08 to 0.24 MUM. Immortalized but non-cancerous bronchial epithelial and fibroblast cell lines were less sensitive to DZNep than the NSCLC cell lines. Soft agarose assays demonstrated that anchorage-independent growth was also reduced in all three NSCLC cell lines that were evaluated using this assay. Flow cytometry analysis demonstrated that DZNep induced apoptosis and G1 cell cycle arrest in NSCLC cells, which was partially associated with cyclin A decrease and p27(Kip1) accumulation. DZNep depleted cellular levels of EZH2 and inhibited the associated histone H3 lysine 27 trimethylation. These results indicated that an epigenetic therapy that pharmacologically targets EZH2 via DZNep may constitute a novel approach to treatment of NSCLCs. PMID- 22925701 TI - Multicenter comparison study of current methods to measure 25-hydroxyvitamin D in serum. AB - OBJECTIVES: Measurement of serum 25-hydroxyvitamin D [25(OH)D] is generally considered to be a reliable indicator of vitamin D status. The recent increase in diversity of 25(OH)D assays prompted us to evaluate the performance of chromatographic methods (two in-house ID-LC-MS/MS and HPLC (ClinRep, Recipe)), a protein binding method (Cobas-25(OH)D-total, Roche) and immunochemical methods (Liaison and RIA (Diasorin), iSYS (IDS), ADVIA Centaur (Siemens), and Architect i1000 and i2000 (Abbott)). METHODS: Blood was drawn from randomly selected outpatients (N=60) at one site after informed consent. DEQAS and SRM 972 samples were obtained from the scheme organizer and NIST, respectively. Serum aliquots were prepared, frozen and transported to participating centers. Method comparison was performed according to CLSI-EP9 specifications. RESULTS: With these patient samples, and in comparison with ID-LC-MS/MS, Deming regression parameters slope, intercept and R were found to be within the ranges [0.57-1.07], [-1.7 to 6.9 nmol/L] and [0.88-0.98], respectively. 25(OH)D2 in DEQAS and SRM samples was fully recognized by chromatographic methods, but only partially by protein binding and immunochemical methods. Chromatographic methods, and to a lesser extent the protein binding assay, showed cross-reactivity with 3-epi-25(OH)D3. Agreement of 25(OH)D assays to ID-LC-MS/MS in sorting patients into distinct 25(OH)D categories varied between 53% and 88%. CONCLUSIONS: Significant bias exists between ID-LC-MS/MS and many, but not all, other 25(OH)D assays. The variable response among different assays for 25(OH)D metabolites impedes the use of uniform cut-off values for defining vitamin D status. Our results indicate the need towards further standardizing assays for 25(OH)D measurement. PMID- 22925702 TI - Study of the effect of antiviral therapy on homocysteinemia in hepatitis C virus- infected patients. AB - BACKGROUND: Hepatitis C virus (HCV) infection is one of the leading causes of chronic liver disease (CLD). About 80% of those exposed to the virus develop a chronic infection. Hyperhomocysteinemia, which is an independent risk factor for atherosclerotic vascular disease and thromboembolism, may develop in HCV-infected patients although altered alanine amino transferase (ALT) enzyme levels are generally associated with damage to liver cells. The gold standard therapy for chronic hepatitis C patients is pegylated interferon combined with an anti-viral drug (ribavirin). The current study aimed to investigate the effect of antiviral therapy on plasma homocysteine (Hcy) levels in HCV patients in addition to other parameters. METHODS: 532 HCV-infected patients and 70 healthy controls were recruited for the study. All patients were subjected to laboratory investigations including HCV-RNA levels, complete blood cell counts, serum levels of homocysteine, ALT, alkaline phosphatase (ALP), lipid profile and liver ultrasonographic examination. The outcome of treatment with pegylated interferon alpha plus ribavirin treatment and sustained virologic response (SVR) was determined 6-9 months post-therapy. RESULTS: Hyperhomocysteinemia was found in 91.35% of HCV-infected patients. The difference in plasma Hcy concentrations reached statistical significance between the patient and control groups. ALT, cholesterol and triglycerides (TGs) levels were found higher than normal in the patients group. After receiving a combined therapy for 24 weeks, 43.66% patients showed an SVR (responders); 30.98% patients were non-responders while 25.35% patients initially responded to therapy but again retrieved positive status of HCV infection six months post-therapy (relapse-cirrhotic patients). The mean levels of plasma Hcy, ALT and ALP were significantly reduced in responders within 10 weeks of therapy when compared with non-responders and relapse-cirrhotic patients. CONCLUSION: Elevated homocysteine levels in serum due to HCV infection can be reduced to normal range with the standard interferon alpha plus ribavirin treatment. This study highlights the significance of the measurement of serum homocysteine levels in the diagnosis and monitoring of HCV infection treatment in addition to other laboratory parameters. PMID- 22925703 TI - Multi-layer porous fiber-reinforced composites for implants: in vitro calcium phosphate formation in the presence of bioactive glass. AB - OBJECTIVES: Glass-fiber-reinforced composites (FRCs), based on bifunctional methacrylate resin, have recently shown their potential for use as durable cranioplasty, orthopedic and oral implants. In this study we suggest a multi component sandwich implant structure with (i) outer layers out of porous FRC, which interface the cortical bone, and (ii) inner layers encompassing bioactive glass granules, which interface with the cancellous bone. METHODS: The capability of Bioglass((r)) 45S5 granules (100-250MUm) to induce calcium phosphate formation on the surface of the FRC was explored by immersing the porous FRC-Bioglass laminates in simulated body fluid (SBF) for up to 28d. RESULTS: In both static (agitated) and dynamic conditions, bioactive glass granules induced precipitation of calcium phosphate at the laminate surfaces as confirmed by scanning electron microscopy. SIGNIFICANCE: The proposed dynamic flow system is useful for the in vitro simulation of bone-like apatite formation on various new porous implant designs containing bioactive glass and implant material degradation. PMID- 22925704 TI - Early infectious complications with transponder placement for external beam radiation therapy for prostate cancer. AB - What's known on the subject? and What does the study add? Little has been published related to transponders per se, but a number of studies relating to prostate biopsy-related infections and the increased incidence of quinolone resistant Escherichia coli have been published. The study alerts the practising urologist to the risk of quinolone-resistant E. coli in the setting of transrectally placed transponders. Furthermore, it proposes an antibiotic regimen that should reduce this risk. OBJECTIVE: To report our series of early infectious complications after placement of Calypso((r)) transponders (Calypso Medical, Seattle, WA, USA) into the prostate. PATIENTS AND METHODS: Between February 2008 and October 2010, 50 consecutive patients underwent placement of Calypso((r)) transponders into the prostate. Patients were administered ciprofloxacin 500 mg every 12 h, starting the night before the procedure and for 2 days after the procedure. Data were collected via chart review, and complications were classified according to the Clavien classification system. RESULTS: Of the 50 patients undergoing the procedure, five (10%) developed infectious complications, and three (6%) developed a grade II complication with a UTI requiring antibiotic therapy. One patient (2%) developed a grade IIIb complication with an epidural abscess and osteomyelitis of the lumbar vertebrae requiring open debridement and a lumbar fusion. One patient (2%) developed a prostatic abscess with methicillin resistant Staphylococcus aureus and subsequently died of an unrelated lower GI bleed. In 4/50 patients (8%), a culture confirmed the responsible bacteria, of which three cases were quinolone-resistant Escherichia coli. CONCLUSION: As with prostate biopsy, the emergence of quinolone-resistant E. coli remains a challenging infectious complication with transrectal prostate procedures. We propose an alternative strategy of double antibiotic coverage with one dose of oral ciprofloxacin 500 mg and gentamicin 80 mg i.m. before this procedure. PMID- 22925705 TI - Early infectious complications with transponder placement for external beam radiation therapy for prostate cancer. PMID- 22925706 TI - Photodynamic diagnostic cystoscopy. PMID- 22925707 TI - Prognostic significance of Bacillus Calmette-Guerin failure classification in non muscle-invasive bladder cancer. PMID- 22925708 TI - The prevalence and natural history of urinary symptoms among recreational ketamine users. PMID- 22925709 TI - RE: Prognostic significance of Bacillus Calmette-Guerin failure classification in non-muscle-invasive bladder cancer. PMID- 22925710 TI - September virtual issue now available. PMID- 22925712 TI - Placental growth factor and cardiac inflammation. AB - Placental growth factor (PlGF) belongs to the vascular endothelial growth factor family and is one of the most interesting candidates as an "angiogenic cytokine," capable of not only controlling angiogenic functions but also finely regulating the inflammatory response. Because inflammatory response and, in particular, recruitment of monocyte/macrophage lineage cells are processes strictly connected to the cardiovascular system in health and disease, PlGF appears to be an intriguing player in the interplay of these phenomena. This review discusses recent findings unraveling novel functions of PlGF in ruling the inflammatory response during cardiac remodeling to pressure overload and the ensuing therapeutic implications and future directions for research. PMID- 22925714 TI - Impact of emotionality on memory and meta-memory in schizophrenia using video sequences. AB - BACKGROUND AND OBJECTIVES: A vast amount of memory and meta-memory research in schizophrenia shows that these patients perform worse on memory accuracy and hold false information with strong conviction compared to healthy controls. So far, studies investigating these effects mainly used traditional static stimulus material like word lists or pictures. The question remains whether these memory and meta-memory effects are also present in (1) more near-life dynamic situations (i.e., using standardized videos) and (2) whether emotionality has an influence on memory and meta-memory deficits (i.e., response confidence) in schizophrenia compared to healthy controls. METHOD: Twenty-seven schizophrenia patients and 24 healthy controls were administered a newly developed emotional video paradigm with five videos differing in emotionality (positive, two negative, neutral, and delusional related). After each video, a recognition task required participants to make old-new discriminations along with confidence ratings, investigating memory accuracy and meta-memory deficits in more dynamic settings. RESULTS: For all but the positively valenced video, patients recognized fewer correct items compared to healthy controls, and did not differ with regard to the number of false memories for related items. In line with prior findings, schizophrenia patients showed more high-confident responses for misses and false memories for related items but displayed underconfidence for hits when compared to healthy controls, independent of emotionality. LIMITATIONS: Limited sample size and control group; combined valence and arousal indicator for emotionality; general psychopathology indicator. CONCLUSIONS: Emotionality differentially moderated memory accuracy, biases in schizophrenia patients compared to controls. Moreover, the meta-memory deficits identified in static paradigms also manifest in more dynamic settings near-life settings and seem to be independent of emotionality. PMID- 22925713 TI - Exploring the binding of BACE-1 inhibitors using comparative binding energy analysis (COMBINE). AB - BACKGROUND: The inhibition of the activity of beta-secretase (BACE-1) is a potentially important approach for the treatment of Alzheimer disease. To explore the mechanism of inhibition, we describe the use of 46 X-ray crystallographic BACE-1/inhibitor complexes to derive quantitative structure-activity relationship (QSAR) models. The inhibitors were aligned by superimposing 46 X-ray crystallographic BACE-1/inhibitor complexes, and gCOMBINE software was used to perform COMparative BINding Energy (COMBINE) analysis on these 46 minimized BACE 1/inhibitor complexes. The major advantage of the COMBINE analysis is that it can quantitatively extract key residues involved in binding the ligand and identify the nature of the interactions between the ligand and receptor. RESULTS: By considering the contributions of the protein residues to the electrostatic and van der Waals intermolecular interaction energies, two predictive and robust COMBINE models were developed: (i) the 3-PC distance-dependent dielectric constant model (built from a single X-ray crystal structure) with a q2 value of 0.74 and an SDEC value of 0.521; and (ii) the 5-PC sigmoidal electrostatic model (built from the actual complexes present in the Brookhaven Protein Data Bank) with a q2 value of 0.79 and an SDEC value of 0.41. CONCLUSIONS: These QSAR models and the information describing the inhibition provide useful insights into the design of novel inhibitors via the optimization of the interactions between ligands and those key residues of BACE-1. PMID- 22925715 TI - Electrophysiological responses of the olfactory receptors of the tick Amblyomma cajennense (Acari: Ixodidae) to host-related and tick pheromone-related synthetic compounds. AB - In the present study, host-related and tick pheromone-related chemical compounds were tested by means of the tip-recording technique in order to obtain electrophysiological responses in olfactory sensilla of non-fed Amblyomma cajennense ticks. The following chemicals were tested on the multiporose sensilla DI.1, located anterior to Haller's organ, and the sensillum DII.1, in the anterior pit of this organ: isobutyric acid, butyric acid, valeric acid, trans-2 heptenal, heptanal, benzaldehyde, salicylaldehyde, nonanal, m-, o- and p tolualdehyde, 2-furaldehyde, 3-pentanone, gamma-valerolactone and 1-octen-3-ol (which are all vertebrate-associated volatiles); and 2,6-dichlorophenol (2,6 DCP), 2-nitrophenol, methyl salicylate and nonanoic acid (tick pheromone components). These were used at 10(-3)M and 10(-2)M on at least 10 ticks per substance, and the chemicals that were found to be active at these concentrations were then tested as a series from 10(-6)M to 10(-2)M, in decadic steps, on at least 15 ticks per substance. 2,6-DCP was active on both sensilla, with detection thresholds of 10(-6)M on the DI.1 sensillum and 10(-4)M on the DII.1 sensillum. The olfactory neurons of this sensillum also responded to nonanal at the highest concentration used (10(-2)M), while those of DII.1 responded not only to 2.6 DCP but also to 2-nitrophenol (to the same extent as to 2,6-DCP) and to 1-octen-3-ol. These results confirm the importance of 2,6-DCP in the chemical ecology of A. cajennense and indicate other compounds that may interfere with the behavior of this tick and which should be investigated. PMID- 22925716 TI - Hospital costs fell as numbers of LVADs were increasing: experiences from Oslo University Hospital. AB - BACKGROUND: The current study was undertaken to examine total hospital costs per patient of a consecutive implantation series of two 3rd generation Left Ventricle Assist Devices (LVAD). Further we analyzed if increased clinical experience would reduce total hospital costs and the gap between costs and the diagnosis related grouped (DRG)-reimbursement. METHOD: Cost data of 20 LVAD implantations (VentrAssistTM) from 2005-2009 (period 1) were analyzed together with costs from nine patients using another LVAD (HeartWareTM) from 2009-June 2011 (period 2). For each patient, total costs were calculated for three phases - the pre-LVAD implantation phase, the LVAD implantation phase and the post LVAD implant phase. Patient specific costs were obtained prospectively from patient records and included personnel resources, medication, blood products, blood chemistry and microbiology, imaging and procedure costs including operating room costs. Overhead costs were registered retrospectively and allocated to the specific patient by predefined allocation keys. Finally, patient specific costs and overhead costs were aggregated into total hospital costs for each patient. All costs were calculated in 2011-prices. We used regression analyses to analyze cost variations over time and between the different devices. RESULTS: The average total hospital cost per patient for the pre-LVAD, LVAD and post-LVAD for period 1 was $ 585, 513 (range 132, 640- 1 247, 299), and the corresponding DRG- reimbursement (2009) was $ 143, 192 . The mean LOS was 54 days (range 12- 127). For period 2 the total hospital cost per patient was $ 413, 185 (range 314, 540- 622, 664) and the corresponding DRG- reimbursement (2010) was $ 136, 963. The mean LOS was 49 days (range 31- 93).The estimates from the regression analysis showed that the total hospital costs, excluding device costs, per patient were falling as the number of treated patients increased. The estimate from the trend variable was -14, 096 US$ (CI -3, 842 to -24, 349, p < 0.01). CONCLUSION: There were significant reductions in total hospital costs per patient as the numbers of patients were increasing. This can possibly be explained by a learning effect including better logistics, selection and management of patients. PMID- 22925717 TI - Saving resources: avian influenza surveillance using pooled swab samples and reduced reaction volumes in real-time RT-PCR. AB - The occurrence of highly pathogenic (HP) avian influenza (AI) H5N1 in Asia and its spread to Africa and Europe prompted costly monitoring programs of wild birds and domestic poultry. AI virus excretion is tested by examining avian swab samples by real-time reverse transcription PCR (RT-qPCR). In this study, pools of swab samples and a reagents volume reduction per RT-qPCR were evaluated as measures of economization. Viral transport medium and faecal matrices were spiked with different low pathogenic AI virus strains and tested for loss of target RNA during all processing steps as individual rayon swabs or in sample pools of 5, 10 and 15 swabs. Fresh faeces from Mallard ducks and other aquatic bird species as sample matrix resulted in loss of AIV RNA of about 90% compared to transport medium. Due to sample RNA dilution in pools the likelihood of detection of single positive samples is decreasing with increasing size of sample pools. However, pools of five samples containing only one positive sample consistently gave positive results. Similarly, no differences in detection rates were obtained when analyzing 1030 wild bird swab samples either individually or in pools of five. Reducing the reaction volume of influenza A virus generic as well as of subtype specific RT-qPCRs to 12.5 MUl (2.5 MUl template) instead of 25 MUl did not adversely affect the limit of detection of these RT-qPCRs. A significant economic benefit without impeding detection efficacy can be achieved when sample pools of five samples are analyzed by RT-qPCR using a reduction of the reaction mix to the half of the original volume. PMID- 22925719 TI - Quantitative analysis of an anti-viral immune escape compound ML-7 in feline plasma using ultra performance liquid chromatography/electrospray ionization mass spectrometry. AB - An analytical method for the quantitative measurement of ML-7, a product with possible anti-immune escape activity for feline infectious peritonitis virus (FIPV), in feline plasma was developed and validated. The sample preparation consists of a solid-phase extraction step on an MCX cartridge. ML-7 and ML-9, used as the internal standard for the analysis, were separated on an ACQUITY UPLCTM BEH C(18) reversed-phase column (1.7 MUm, 50 mm * 2.1 mm I.D.), using isocratic elution with acetonitrile and 0.1% formic acid in water as the mobile phase. Both compounds were subsequently quantified in MRM mode on a Micromass((r)) Quattro PremierTM XE triple quadrupole mass spectrometer. The use of a Thermo Scientific((r)) ExactiveTM orbitrap mass spectrometer made it possible to confirm the proposed fragmentation pattern of both ML-7 and ML-9. A validation study according to EC requirements was carried out, in which the method showed good performance. Linear behaviour was observed in the 1-2500 ng ml(-1) range, which is relevant for real sample analysis. Accuracy and precision were within the criteria requested by the EC requirements throughout this concentration range. Extraction recovery of ML-7 was 72%. Matrix effect for ML-7 was not higher than 8%. The method was successfully used for the monitoring of ML 7 in feline plasma after intravenous, subcutaneous or oral administration of an ML-7 formulation, for the determination of pharmacokinetic parameters, with a limit of quantification of 1 ng ml(-1) and a limit of detection of 0.4 ng ml(-1). The proposed method also shows good characteristics for the analysis of ML-7 in plasma of other animal species and human plasma. PMID- 22925718 TI - Development and validation of sensitive liquid chromatography/tandem mass spectrometry method for quantification of bendamustine in mouse brain tissue. AB - A liquid chromatography-tandem mass spectrometry method for quantification of bendamustine in mouse brain tissue was developed and fully validated. Methanol was used to precipitate proteins in brain tissue. Bendamustine and internal standard (chlorambucil) were separated with reverse-phase chromatography on a C 18 column with a gradient of water and 95% methanol in 0.1% formic acid. Positive mode electrospray ionization was applied with selected reaction monitoring to achieve 5 ng/ml lower limits of quantitation in mouse brain tissue. The calibration curve for bendamustine in mouse brain was linear between 5 and 2000 ng/ml. The within- and between-batch accuracy and precision of the assay were within 15% at 10, 100 and 1000 ng/ml. The recovery and matrix effect of bendamustine in mouse brain tissue ranged from 41.1% to 51.6% and 107.4% to 110.3%, respectively. The validated method was then applied to quantitate bendamustine in an animal study. Results indicate the assay can be applied to evaluate bendamustine disposition in mouse brain tissue. This assay will be applied in the future to detect and quantify bendamustine in human brain tissue samples. PMID- 22925721 TI - It's a small (integrated multidisciplinary) world. PMID- 22925720 TI - Utility of rapid antibody tests to exclude HIV-1 infection among infants and children aged <18 months in a low-resource setting. AB - BACKGROUND: Excluding HIV infection among infants and young children in resource poor settings where nucleic acid amplification tests (NAAT) are not routinely available remains a considerable challenge. OBJECTIVES: To assess the performance of two rapid HIV antibody tests (RT) used alone and in parallel for excluding HIV infection among acutely ill infants and children <18 months in comparison to NAAT in a region where maternal HIV prevalence was approximately 7%. STUDY DESIGN: Infants and children >=2<18 months admitted to hospital with an acute febrile illness had two rapid antibody tests in parallel, with single and parallel results subsequently compared against NAAT. RESULTS: HIV prevalence among 1602 enrolled infants was 3.4%. All 1526 infants with 2 negative RT were HIV negative by NAAT. All 46 infants with 2 positive RT were HIV positive by NAAT. The overall specificity of two rapid tests for excluding HIV infection was 99.5%. Sensitivity and specificity were >=99% and >98%, respectively, across all age brackets >=2<18 months. Overall sensitivity and specificity for a single RT was 98.2% and 99%, respectively, for Determine, and 85.5% and 99.6%, respectively, for Capillus. CONCLUSIONS: In a setting with a maternal HIV prevalence rate of <10%, a single negative RT had excellent specificity and two negative RT performed in parallel had a perfect negative predictive value for HIV infection among acutely ill patients <18 months of age. In this and similar settings, RT could assist with excluding HIV infection with much lower complexity and cost than NAAT. PMID- 22925724 TI - Workflow mining and outlier detection from clinical activity logs. AB - PURPOSE: The purpose of this study is twofold: (1) to derive a workflow consensus from multiple clinical activity logs and (2) to detect workflow outliers automatically and without prior knowledge from experts. METHODS: Workflow mining is used in this paper to derive consensus workflow from multiple surgical activity logs using tree-guided multiple sequence alignment. To detect outliers, a global pair-wise sequence alignment (Needleman-Wunsch) algorithm is used. The proposed method is validated for Laparoscopic Cholecystectomy (LAPCHOL). RESULTS: An activity log is directly derived for each LAPCHOL surgery from laparoscopic video using an already developed instrument tracking tool. We showed that a generic consensus can be derived from surgical activity logs using multi alignment. In total 26 surgery logs are used to derive the consensus for laparoscopic cholecystectomy. The derived consensus conforms to the main steps of laparoscopic cholecystectomy as described in best practices. Using global pair wise alignment, we showed that outliers can be detected from surgeries using the consensus and the surgical activity log. CONCLUSION: Alignment techniques can be used to derive consensus and to detect outliers from clinical activity logs. Detecting outliers particularly in surgery is a main step to automatically mine and analyse the underlying cause of these outliers and improve surgical practices. PMID- 22925723 TI - A classification of errors in lay comprehension of medical documents. AB - Emphasis on participatory medicine requires that patients and consumers participate in tasks traditionally reserved for healthcare providers. This includes reading and comprehending medical documents, often but not necessarily in the context of interacting with Personal Health Records (PHRs). Research suggests that while giving patients access to medical documents has many benefits (e.g., improved patient-provider communication), lay people often have difficulty understanding medical information. Informatics can address the problem by developing tools that support comprehension; this requires in-depth understanding of the nature and causes of errors that lay people make when comprehending clinical documents. The objective of this study was to develop a classification scheme of comprehension errors, based on lay individuals' retellings of two documents containing clinical text: a description of a clinical trial and a typical office visit note. While not comprehensive, the scheme can serve as a foundation of further development of a taxonomy of patients' comprehension errors. Eighty participants, all healthy volunteers, read and retold two medical documents. A data-driven content analysis procedure was used to extract and classify retelling errors. The resulting hierarchical classification scheme contains nine categories and 23 subcategories. The most common error made by the participants involved incorrectly recalling brand names of medications. Other common errors included misunderstanding clinical concepts, misreporting the objective of a clinical research study and physician's findings during a patient's visit, and confusing and misspelling clinical terms. A combination of informatics support and health education is likely to improve the accuracy of lay comprehension of medical documents. PMID- 22925725 TI - Discovery of potent, novel Nrf2 inducers via quantum modeling, virtual screening, and in vitro experimental validation. AB - Nuclear factor erythroid 2-related factor 2 (Nrf2) is the master transcription factor of the antioxidant response element pathway, coordinating the induction of detoxifying and antioxidant enzymes. Nrf2 is normally sequestered in the cytoplasm by Kelch-like ECH-associating protein 1 (Keap1). To identify novel small molecules that will disturb Nrf2-Keap1 binding and promote activation of the Nrf2- antioxidant response element pathway, we generated a quantum model based on the structures of known Nrf2- antioxidant response element activators. We used the quantum model to perform in silico screening on over 18 million commercially available chemicals to identify the structures predicted to activate the Nrf2- antioxidant response element pathway based on the quantum model. The top hits were tested in vitro, and half of the predicted hits activated the Nrf2 antioxidant response element pathway significantly in primary cell culture. In addition, we identified a new family of Nrf2-antioxidant response element activating structures that all have comparable activity to tBHQ and protect against oxidative stress and dopaminergic toxins in vitro. The improved ability to identify potent activators of Nrf2 through the combination of in silico and in vitro screening described here improves the speed and cost associated with screening Nrf2-antioxidant response element -activating compounds for drug development. PMID- 22925726 TI - Inhibition of quorum sensing in Pseudomonas aeruginosa by sesquiterpene lactones. AB - Six sesquiterpene lactones (SLs) of the goyazensolide and isogoyazensolide-type isolated from the Argentine herb Centratherum punctatum were evaluated on their ability to inhibit virulence factors of Pseudomonas aeruginosa ATCC 27853. Although compounds were not able to completely inhibit bacterial growth at 200MUg/ml, the SLs do altered biofilm formation, elastase activity, and production of N-acyl-homoserinelactones (AHLs) which are known quorum sensing autoinducers at lower concentration. Compounds 2, 3, and 5 displayed significant inhibitory effects on P. aeruginosa biofilm formation at 0.5MUg/ml being compound 3 (1.32MUM) the most potent (42%). Compounds 2, 3, 4, 5 and 6, inhibited 39, 44, 42, 32 and 35% the production of AHLs at 100MUg/ml and inhibited by more than 50% the elastase activity at 0.5MUg/ml. Our results clearly indicated that sesquiterpene lactones are good candidates for the development of new antimicrobial agents acting not as bactericidal but as antipathogenic agents. PMID- 22925727 TI - Silymarin potentiates the anti-inflammatory effects of Celecoxib on chemically induced osteoarthritis in rats. AB - Silymarin (SMN) is used as an antioxidant complex to attenuate the pro-oxidant effects of toxic agents. This study was carried out to investigate the effect of SMN, Celecoxib (CLX) individually and in combination on monoiodoacetate (MIA) induced osteoarthritis (OA) in rat. Forty adult Wistar rats were assigned to control and test groups. Animals in the test group following OA induction were subdivided into 4 subgroups according to the treatment profile: OA(+); received saline normal (5ml/kg, b.w.), OA(+)CLX(+); received CLX (100mg/kg, orally), OA(+)SMN(+), received SMN (50mg/kg, orally), and OA(+)CLX(+)SMN(+), received both CLX and SMN. The animals received test compounds by gastric gavage for 14 consecutive days. Animals in the OA(+) group showed a significant (p<0.01) increase in serum and synovial levels of IL-1beta, while both test compounds reduced the IL-1beta level. Both CLX and SMN lowered the OA-increased level of malondialdehyde by 77% and 79% and nitric oxide by 73% and 76%, respectively, in the synovial tissue. Special safranin O (SO) histopathological staining revealed that CLX and SMN improved the MIA-induced destruction and fibrillation in cartilage surface. CLX and SMN regulated the MIA-up regulated IL-1beta at mRNA level. The combination therapy resulted in an additive effect between CLX and SMN in biochemical, histopathological and molecular assays. These findings suggest that SMN exerts anti-inflammatory effect and also potentiates the anti inflammatory effect of CLX on MIA-induced OA. The anti-inflammatory property of SMN may attribute to its antioxidant capacity, which affects the proinflammatory mediators at translational and transcriptional level. PMID- 22925729 TI - Phenotype ontologies: are homology relations central enough? A reply to Deans et al. PMID- 22925728 TI - Heteroplasmic mutations of the mitochondrial genome cause paradoxical effects on mitochondrial functions. AB - Mitochondrial genome (mtDNA) mutation causes highly variable clinical features, and its pathogenesis is not fully understood. In this study, we analyzed the heteroplasmic mtDNA mutation C4936T (p.T156I) in ND2 of complex I and the homoplasmic mtDNA mutation A9181G (p.S219G) in ATPase 6 of complex V. Using cybrid technology, we found that in a high-glucose medium in which cultured cells mainly depend on anaerobic glycolysis for energy, the C4936T mutation inhibited cell growth by 50%. Oxygen consumption and reactive oxygen species production were also reduced by 60 and 75%, respectively. Because the subject also had conjunctiva carcinoma, we further tested whether the C4936T mutation was associated with tumor formation. In an anchorage-dependant growth test, we found that only cells with a high level of C4936T mutation formed colonies. In contrast, when the cells grew in a galactose medium in which cells were forced to generate ATP through oxidative phosphorylation, the C4936T mutation protected cells from apoptosis probably caused by the A9181G mutation. Our results suggest that the phenotype caused by mtDNA mutations may depend on the availability of the nutrients. This gene-environment interaction may contribute to the complexity of pathogenesis and clinical phenotypes caused by mtDNA mutation. PMID- 22925730 TI - Host gene expression changes in cattle infected with Alcelaphine herpesvirus 1. AB - Malignant catarrhal fever is a lymphoproliferative disease of cattle and other ungulates caused by infection with gamma-herpesviruses of the genus Macavirus. These viruses do not establish a productive infection but instead replicate in a cell-associated fashion in T lymphocytes, leading to systemic immune dysregulation and a generally fatal outcome. Despite significant progress in understanding the pathology of this disease, its pathogenesis remains unclear. To identify genes and pathways affected in clinical MCF, sixteen bovine GeneCHIP microarrays were used to assay RNA from kidney and lymph node of four MCF affected and four control Bos taurus steers. This is the first expression study of AlHV-1-MCF in the bovine host. Over 250 genes showed significant changes in gene expression in either lymph node or kidney, while expression of 35 genes was altered in both tissues. Pathway and annotation analysis of the microarray data showed that immune response and inflammatory genes were up-regulated in the kidney while proliferation-associated transcripts were additionally increased in the lymph node. The genes that showed the largest expression rises in both diseased tissues included cytotoxic enzymes and pro-inflammatory chemokines. These data are consistent with disease-induced stimulation of inflammatory responses involving interferon-gamma, including cytotoxic T cell recruitment and activation in peripheral tissues containing virus-infected cells. However it remains unclear whether the tissue damage in MCF lesions is due entirely to the activity of infected cells or whether uninfected T cells, recruited and activated at lesion sites through the action of infected cells, contribute to the pathogenesis of MCF. PMID- 22925732 TI - Results with the Talent thoracic stent graft in the VALOR trial. AB - OBJECTIVE: We report the 5-year outcomes of thoracic endovascular aneurysm repair (TEVAR) using the Medtronic Vascular Talent Thoracic Stent Graft System (Medtronic Vascular, Santa Rosa, Calif) in patients considered low or moderate risk for open surgical repair. METHODS: The Evaluation of the Medtronic Vascular Talent Thoracic Stent Graft System for the Treatment of Thoracic Aortic Aneurysms (VALOR) trial was a prospective, nonrandomized, multicenter, pivotal study conducted at 38 U.S. sites. Between December 2003 and June 2005, VALOR enrolled 195 patients who were low or moderate risk (0, 1, and 2) per the modified Society for Vascular Surgery and American Association for Vascular Surgery criteria. The patients had fusiform thoracic aortic aneurysms (TAAs) and/or focal saccular TAAs/penetrating atherosclerotic ulcers. Standard follow-up interval examinations were conducted at 1 month, 6 months, 1 year, and annually thereafter. RESULTS: Over the 5-year follow-up, 76 deaths occurred (43.9%). Freedom from all-cause mortality was 83.9% at 1 year and 58.5% at 5 years. Most deaths were due to cardiac, pulmonary or cancer-related causes. Freedom from aneurysm-related mortality (ARM) was 96.9% at 1 year and 96.1% at 5 years. There was only 1 case of ARM after the first year of follow-up. Over the 5-year follow-up period, four patients were converted to open surgery and four patients experienced aneurysm rupture. The 5-year freedom from aneurysm rupture was 97.1% and the 5-year freedom from conversion to surgery was 97.1%. The incidence of stent graft migration (>10 mm) was <= 1.8% in each year of follow-up. The rate of type I endoleak was 4.6% at 1 month, 6.3% from 1 month to 1 year, and 3.8% during year 5. The rate of type III endoleak was 1.3% at 1 month, 1.9% from 1 month to 1 year, and 1.9% during year 5. Through 5 years, 28 patients (14.4%) underwent 31 additional endovascular procedures on the original target lesion. The 5-year freedom from secondary endovascular procedures was 81.5%. CONCLUSIONS: Through 5 year follow-up in patients who were candidates for open surgical repair, TEVAR using the Talent Thoracic Stent Graft System has demonstrated sustained protection from ARM, aneurysm rupture, and conversion to surgery, and durable stent graft performance. Close patient follow-up remains essential after TEVAR. PMID- 22925731 TI - Influence of HTLV-1 on the clinical, microbiologic and immunologic presentation of tuberculosis. AB - BACKGROUND: HTLV-1 is associated with increased susceptibility to Mycobacterium tuberculosis infection and severity of tuberculosis. Although previous studies have shown that HTLV-1 infected individuals have a low frequency of positive tuberculin skin test (TST) and decreasing in lymphoproliferative responses compared to HTLV-1 uninfected persons, these studies were not performed in individuals with history of tuberculosis or evidence of M. tuberculosis infection. Therefore the reasons why HTLV-1 infection increases susceptibility to infection and severity of tuberculosis are not understood.The aim of this study was to evaluate how HTLV-1 may influence the clinical, bacteriologic and immunologic presentation of tuberculosis. METHODS: The study prospectively enrolled and followed 13 new cases of tuberculosis associated with HTLV-1 (cases) and 25 patients with tuberculosis without HTLV-1 infection (controls). Clinical findings, bacterial load in the sputum, x-rays, immunological response and death were compared in the two groups. RESULTS: There were no differences in the demographic, clinical and TST response between the two study groups. IFN-gamma and TNF-alpha production was higher in unstimulated cultures of mononuclear cells of case than in control patients (p < 0.01). While there was no difference in IFN gamma production in PPD stimulated cultures, TNF-alpha levels were lower in cases than in controls (p = 0.01). There was no difference in the bacterial load among the groups but sputum smear microscopy results became negative faster in cases than in controls. Death only occurred in two co-infected patients. CONCLUSION: While the increased susceptibility for tuberculosis infection in HTLV-1 infected subjects may be related to impairment in TNF-alpha production, the severity of tuberculosis in co-infected patients may be due to the enhancement of the Th1 inflammatory response, rather than in their decreased ability to control bacterial growth. PMID- 22925733 TI - Direct blood transfusions. PMID- 22925734 TI - Skeletal extension and calcification of reef-building corals in the central Indian Ocean. AB - Skeletal extension, density and calcification rate of 12 scleractinian coral species comprising 7 morphological groups were examined on the reef crest of Vabbinfaru platform, Maldives. Growth rates of coral specimens were measured over the period of February 2010-March 2011 using alizarin staining and direct measurements. Skeletal extension rate was highly variable between coral species. Colony morphology was a major control on the skeletal extension and calcification of coral specimens. Growth rates of Acropora and Porites corals were comparable to existing data recorded for Caribbean and Indo-Pacific reef provinces. Skeletal density was less variable between species and was typically consistent among morphological groups. Findings represent the first estimates of coral growth in the central Indian Ocean region and add to the limited growth studies available that have examined a broad range of coral growth morphologies in other reef building regions. PMID- 22925735 TI - Relative and combined effects of habitat and fishing on reef fish communities across a limited fishing gradient at Ningaloo. AB - Habitat degradation and fishing are major drivers of temporal and spatial changes in fish communities. The independent effects of these drivers are well documented, but the relative importance and interaction between fishing and habitat shifts is poorly understood, particularly in complex systems such as coral reefs. To assess the combined and relative effects of fishing and habitat we examined the composition of fish communities on patch reefs across a gradient of high to low structural complexity in fished and unfished areas of the Ningaloo Marine Park, Western Australia. Biomass and species richness of fish were positively correlated with structural complexity of reefs and negatively related to macroalgal cover. Total abundance of fish was also positively related to structural complexity, however this relationship was stronger on fished reefs than those where fishing is prohibited. The interaction between habitat condition and fishing pressure is primarily due to the high abundance of small bodied planktivorous fish on fished reefs. However, the influence of management zones on the abundance and biomass of predators and target species is small, implying spatial differences in fishing pressure are low and unlikely to be driving this interaction. Our results emphasise the importance of habitat in structuring reef fish communities on coral reefs especially when gradients in fishing pressure are low. The influence of fishing effort on this relationship may however become more important as fishing pressure increases. PMID- 22925736 TI - A new aberration-corrected, energy-filtered LEEM/PEEM instrument II. Operation and results. AB - In Part I we described a new design for an aberration-corrected Low Energy Electron Microscope (LEEM) and Photo Electron Emission Microscope (PEEM) equipped with an in-line electron energy filter. The chromatic and spherical aberrations of the objective lens are corrected with an electrostatic electron mirror that provides independent control of the chromatic and spherical aberration coefficients Cc and C3, as well as the mirror focal length. In this Part II we discuss details of microscope operation, how the microscope is set up in a systematic fashion, and we present typical results. PMID- 22925737 TI - In-situ HRTEM study of the reactive carbide phase of Co/MoS2 catalyst. AB - Hydrotreatment catalytic operations are commonly performed industrially by layered molybdenum sulfide promoted by cobalt or nickel in order to remove heteroelements (S, N, O) from fossil fuels and biofuels. Indeed, these heteroelements are responsible of the emission of pollutants when these fuels are used in vehicles. In this respect, previous studies made by our research group have shown that the active phase under steady state conditions is partially carbided while strong bending effects of MoS2 slabs were also observed. However, up to now, the morphology of the resulting Co/MoSxCy carbided catalyst has not been fully characterized. In the present study, for the first time, a chemical reaction between the carbon content of a TEM Cu/C grid and a freshly sulfide Co/MoS2 catalyst was in situ observed at 300 degrees C and 450 degrees C by HRTEM experimental techniques at ~10 nm of resolution. Results indicate that bending of MoS2 layers occurred due to carbon addition on MoS2 edge sites, as observed in stabilized catalysts after HDS reaction. Using a silicon grid, only cracks of MoS2 slabs were observed without bending effect confirming the role of structural-carbon in this change of morphology. PMID- 22925738 TI - Sample preparation methods for femtosecond electron diffraction experiments. AB - Exploring the dynamics of Charge density wave system 1T-TaS2 via femtosecond electron diffraction demonstrated the power of this technique for studying ultrafast structural phenomena in strongly correlated electron materials [1]. The results revealed first direct information on the order parameter dynamics of Charge Density Waves as well as on their photo-induced phase transition. A prerequisite to perform such experiments on modern quantum materials is the availability of laterally large (~100 MUm) and sufficiently thin (<100 nm) single crystalline samples. Different approaches to reach these specifications have been tried out and their effect on sample integrity has been investigated. Finally, using an ultra-microtome, we were able to prepare 30 nm free standing single crystalline films of 1T-TaS2 with lateral dimensions of 200 MUm * 200 MUm. We have characterized these films with different techniques for their stoichiometric and crystalline integrity, ensuring no measurable alternation of sample properties. The application of this sample thinning technique is expected to find its use in further structural dynamics studies, as well as in optical time resolved studies where homogeneous excitation profile and/or data in transmission geometry may be required. PMID- 22925739 TI - The effects of volatile anesthetics on synaptic and extrasynaptic GABA-induced neurotransmission. AB - Examination of volatile anesthetic actions at single synapses provides more direct information by reducing interference by surrounding tissue and extrasynaptic modulation. We examined how volatile anesthetics modulate GABA release by measuring spontaneous or miniature GABA-induced inhibitory postsynaptic currents (mIPSCs, sIPSCs) or by measuring action potential-evoked IPSCs (eIPSCs) at individual synapses. Halothane increased both the amplitude and frequency of sIPSCs. Isoflurane and enflurane increased mIPSC frequency while sevoflurane had no effect. These anesthetics did not alter mIPSC amplitudes. Halothane increased the amplitude of eIPSCs, with a decrease in failure rate (Rf) and paired-pulse ratio. In contrast, isoflurane and enflurane decreased the eIPSC amplitude and increased Rf, while sevoflurane decreased the eIPSC amplitude without affecting Rf. Volatile anesthetics did not change kinetics except for sevoflurane, suggesting that presynaptic mechanisms dominate changes in neurotransmission. Each anesthetic showed somewhat different GABA-induced response and these results suggest that GABA-induced synaptic transmission cannot have a uniformly common site of action as suggested for volatile anesthetics. In contrast, all volatile anesthetics concentration-dependently enhanced the GABA induced extrasynaptic currents. Extrasynaptic receptors containing alpha4 and alpha5 subunits are reported to have high sensitivities to volatile anesthetics. Also, inhibition of GABA uptake by volatile anesthetics results in higher extracellular GABA concentration, which may lead to prolonged activation of extrasynaptic GABAA receptors. The extrasynaptic GABA-induced receptors may be major site of volatile anesthetic-induced neurotransmission. This article is part of a Special Issue entitled 'Extrasynaptic ionotropic receptors'. PMID- 22925740 TI - Response to: "what's new in resuscitation strategies for the patient with multiple trauma? [Injury 2012;43(7):1021-8. doi:10.1016/j.injury.2012.03.014]". PMID- 22925743 TI - Spinal cord injury facts and figures at a glance. PMID- 22925742 TI - Re: Burns AS, O'Connell C. The challenge of spinal cord injury care in the developing world. J Spinal Cord Med. 2012; 35:3-8. PMID- 22925745 TI - Introducing the revised International Standards on documentation of remaining Autonomic Function after SCI (ISAFSCI). PMID- 22925746 TI - International standards to document remaining autonomic function after spinal cord injury. AB - This is the first guideline describing the International Standards to document remaining Autonomic Function after Spinal Cord Injury (ISAFSCI). This guideline should be used as an adjunct to the International Standards for Neurological Classification of Spinal Cord Injury (ISNCSCI) including the ASIA Impairment Scale (AIS), which documents the neurological examination of individuals with SCI. The Autonomic Standards Assessment Form is recommended to be completed during the evaluation of individuals with SCI, but is not a part of the ISNCSCI. A web-based training course (Autonomic Standards Training E Program (ASTeP)) is available to assist clinicians with understanding autonomic dysfunctions following SCI and with completion of the Autonomic Standards Assessment Form (www.ASIAlearningcenter.com). PMID- 22925747 TI - Impact of spinal cord injury on sexuality: broad-based clinical practice intervention and practical application. AB - This study focuses on the impact a spinal cord injury may have on achieving physical and emotional intimacy, and potential to maximize sexual ability and quality of life. Spinal cord injury is a traumatic, life-altering event that is usually associated with loss of motor and sensory function, as well as sexual impairment. At the time of injury, the individual is faced with devastating loss and an abundance of new information in a setting of extreme stress and challenge. In the acute rehabilitation setting, there is often a considerable void in providing education and resources regarding sexual concerns and needs. There is a positive relationship between sexual education and sexual activity. The impact of inadequate sexual counseling and education as a part of rehabilitation can be deleterious. PMID- 22925748 TI - Efficacy and satisfaction rates of oral PDE5is in the treatment of erectile dysfunction secondary to spinal cord injury: a review of literature. AB - CONCEPT: Decreased sexual function is a major concern of men with spinal cord injuries (SCIs). Treatment of erectile dysfunction (ED) through oral pharmacotherapies has been proven to be an effective way to address and treat this concern. OBJECTIVE: To find an efficacious and satisfactory treatment ED secondary to SCI through the compilation of studies that utilized the International Index of Erectile Function (IIEF) when testing phosphodiesterase V inhibitors (PDE5i). METHOD: Ten articles, which used the IIEF to study satisfaction and/or efficacy of PDE5is sildenafil, tadalafil, and vardenafil in the treatment of ED were reviewed and analyzed. Through the use of a self-made grading scale the value of each article was determined for this research. RESULTS: Sildenafil, tadalafil, and vardenafil all have been proven to be effective in treating ED in men with SCI. While sildenafil is the most thoroughly studied ED treatment for patients with SCI, tadalafil has a longer time duration effectiveness, which allows for more spontaneity in the sexual experience. Minimal adverse effects have been noted in patients with SCI using these medications; headache, flushing, and mild hypotension are the most common. In articles that study satisfaction, patients show great improvement over baseline with the use of these medications. CONCLUSION: Although there is a need for further research on the safety in long-term use of tadalafil and vardenafil, comparative studies done on all three medications show no statistically significant difference in effectiveness or satisfaction. New medications and treatment options, such as avanafil, are being studied in hope of continued improvement of sexual function in men with SCI. PMID- 22925749 TI - Epidemiology of traumatic spinal cord injury in Asia: a systematic review. AB - STUDY DESIGN: A systematic review. BACKGROUND: The number of traumatic spinal cord injury (TSCI) reports grows annually, especially in China and Korea. The epidemiological characteristics of TSCI in Asia differ from those in other countries. Thus, we compiled epidemiological factors from Asia to compare with those from other countries. METHOD: We searched articles published in any language between January 1980 to December 2011 using the terms "spinal cord injury", "traumatic spinal cord injury", "epidemiology", and "Asia". The articles were reviewed for information regarding TSCI incidence, total cases, case criteria, case source, causes of injury, male/female ratio, mean age, prospective or retrospective, neurological level of injury, extent of injury, and America Spinal Injury Association Impairment Scale (AIS)/grade. RESULTS: Epidemiological data were extracted from 39 reports in the published literature that met the inclusion criteria. Only two studies reported prevalence rates. Incidence rates ranged from 12.06 to 61.6 per million. The average age ranged from 26.8 to 56.6 years old. Men were at higher risk than women. Motor vehicle collisions (MVCs) and falls were the main causes of TSCI. However, several countries reported war wounds as the major cause. The neurological level and extent of injury were mixed, and most patients were categorized as AIS/Frankel grade A. CONCLUSION: TSCI is an important public health problem and a major cause of paralysis. We must understand the epidemiology to implement appropriate preventative measures. Asian epidemiology is different from that in other regions, so intervention measures must be established according to population specific characteristics. PMID- 22925750 TI - Potentially modifiable risk factors among veterans with spinal cord injury hospitalized for severe pressure ulcers: a descriptive study. AB - CONTEXT/OBJECTIVE: Pressure ulcers (PrUs) are a serious, costly and potentially life-long complication of spinal cord injury (SCI). Co-morbid conditions increase PrU risk, adding to the health behavior challenges faced by people with SCI. Little is known about medical co-morbidities, health beliefs, risk, protective behaviors, and readiness to improve skin care behaviors in people with SCI. This study describes the potentially modifiable medical and behavioral risk factors among veterans with SCI and severe (Stage III/IV) PrUs. DESIGN: Cross-sectional observational design. SETTING: 6 VA SCI Centers. PARTICIPANTS: Convenience sample from a larger intervention study of 148 veterans hospitalized for PrUs. INTERVENTIONS: Not applicable. OUTCOME MEASURES: Knowledge, PrU risk, skin protective behaviors, health beliefs, and practices, health locus of control, skin worsening. RESULTS: Most ulcers were stage IV (73%) and about half had 2+ PrUs. Participants reported a mean of 6.7 co-morbid conditions (respiratory, gastrointestinal, renal disease/urinary tract infection, autonomic dysreflexia, diabetes, bowel/bladder incontinence). Potential intervention opportunities include proactive assistance with management of multiple chronic conditions, substance abuse, nutrition, adherence to skin protective behaviors, readiness to change, and access to resources. Overall knowledge about PrUs was low, especially for how to prevent PrUs and what to do if skin breakdown occurs. CONCLUSION: Future research should address whether comprehensive models that include patient self-management, decision support and health care system, and proactive behavior change assistance for patients help reduce PrU incidence and recurrence in persons with SCI. TRIAL REGISTRATION: http://clinicaltrials.gov/ct2/show/NCT00105859. PMID- 22925751 TI - Anti-AQP(4) antibody in idiopathic acute transverse myelitis with recurrent clinical course: frequency of positivity and influence in prognosis. AB - BACKGROUND: The anti-aquaporin4 (anti-AQP4) antibody is specific for neuromyelitis optica (NMO), but is also found in limited forms. The presence of this antibody in acute transverse myelitis (ATM) has been associated with recurrence and conversion to NMO, but the influence on disability has not yet been described. OBJECTIVE: To describe the frequency of anti-AQP4 in ATM and analyze the influence in long-term prognosis. DESIGN: Cross-sectional and retrospective study. METHODS: Consecutive ATM cases in a multiple sclerosis center in Rio de Janeiro, Brazil, from 2000 through 2009 were reviewed. Recurrent cases tested for anti-AQP4 were selected. ATM with magnetic resonance imaging spinal cord lesions extending over three or more vertebral segments was classified as longitudinally extensive transverse myelitis (LETM); Kurtzke scale was applied at last evaluation. OUTCOME MEASURES: Frequency of anti-AQP4; severity of spinal cord dysfunction at last follow-up. RESULTS: Twenty six patients (21 female:5 male; 17 white:9 African descent) were studied. The first ATM occurred at 38.04 +/- 12.7 years. The interval between the first and the second ATM was eight months (1-150) and the number of ATM varied from two to seven. After 40.5 months (12-192) of disease, the median Expanded Disability Status Scale (EDSS) score was three (0-9). Anti-AQP4 antibody was positive in 26.9%. LETM was found in 65.4%. LETM presented later onset, higher disability and higher positivity to anti-AQP4 (LETM 41.2% versus no-LETM 0%, P = 0.024). Dysfunction at long-term follow-up was similar in anti-AQP4 positive and negative cases. CONCLUSION: The frequency of anti-AQP4 in recurrent ATM was 26.9%, increasing to 41.2% among LETM. Presence of the antibody had no influence on morbidity. PMID- 22925752 TI - Biomechanical analysis of cervical spondylotic myelopathy: the influence of dynamic factors and morphometry of the spinal cord. AB - OBJECTIVE: Patients with cervical spondylotic myelopathy (CSM) have the same clinical symptoms that vary according to the degree of spinal cord compression and the cross-sectional cord shape. We used a three-dimensional finite element method (3D-FEM) to analyze the stress distributions of the spinal cord with neck extension under three cross-sectional cord shapes. METHODS: Experimental condition for the 3D-FEM spinal cord, ligamentum flavum, and anterior compression shape (central, lateral, and diffuse types) was established. To simulate neck extension, the spinal cord was extended by 20 degrees and the ligamentum flavum was shifted distally according to movement of the cephalad lamina. RESULTS: The stress distribution in the spinal cord increased due to invagination of the ligamentum flavum into the neck extension. The range of stress distribution observed for the diffuse type was wider than for the central and lateral types. In addition, the stress distribution in the spinal cord was increased by the pincer movement of the ligamentum flavum and by the anterior compression of the spinal cord. The range of stress distribution observed for the diffuse type under antero-posterior compression was also wider than for the central and lateral types. CONCLUSION: This simulation model showed that the clinical symptoms of CSM due to compression of the diffuse type may be stronger than for the central and lateral types. Therefore, careful follow-up is recommended for anterior compression of the spinal cord of diffuse type. PMID- 22925753 TI - Spontaneous spinal epidural hematoma with hemiparesis mimicking acute cerebral infarction: two case reports. AB - CONTEXT: Acute hemiparesis is a common initial presentation of ischemic stroke. Although hemiparesis due to spontaneous spinal epidural hematoma (SSEH) is an uncommon symptom, a few cases have been reported and misdiagnosed as cerebral infarction. DESIGN: Case reports of SSEH with acute hemiparesis. FINDINGS: In these two cases, acute stroke was suspected initially and administration of intravenous alteplase therapy was considered. In one case, the presentation was neck pain and in the other case, it was Lhermitte's sign; brain magnetic resonance imaging (MRI) and magnetic resonance angiography were negative for signs of ischemic infarction, hemorrhage, or arterial dissection. Cervical MRI was performed and demonstrated SSEH. CONCLUSION: Clinicians who perform intravenous thrombolytic treatment with alteplase need to be aware of this possible contraindication. PMID- 22925754 TI - Long extensive transverse myelitis associated with aquaporin-4 antibody and breast cancer: favorable response to cancer treatment. AB - CONTEXT: Long extensive transverse myelitis (LETM) seldom develops in patients with breast cancer who are aquaporin-4 antibody (Aqp-4 Ab)-positive. Whether this association is coincidental is not well understood. FINDINGS: A 62-year-old woman presented with treatment-resistant LETM and Aqp-4 Ab. Two months later, a stage 3 invasive ductal carcinoma was detected in her right breast. Following tumor resection and chemotherapy, her neurologic symptoms and magnetic resonance imaging findings significantly improved and serum Aqp-4 Ab disappeared. The breast tumor samples of this patient and neurologically normal patients showed inflammatory infiltrates and Aqp-4 expressing cells. CONCLUSION/CLINICAL RELEVANCE: The temporal association between tumor treatment, amelioration of clinical findings, and seroreversion suggest that coexistence of cancer and LETM is not coincidental. Cancer screening should be considered at least in treatment resistant LETM cases. PMID- 22925756 TI - Furfural production from rice husk using sulfuric acid and a solid acid catalyst through a two-stage process. AB - This study aimed to optimize the conditions for furfural production from rice husk via a two-stage process: acid hydrolysis followed by dehydration using an orthogonal test design and response surface methodology, respectively. Orthogonal test design was utilized in the hydrolysis step; optimum conditions were as follows: 2.5% sulfuric acid (mass fraction), 110 degrees C reaction temperature, sulfuric acid to rice husk (L/S) ratio of 8 (g/mL), and a reaction time of 3h. According to the Box-Behnken design, the temperature, amount of catalyst, extractant volume, and reaction time were chosen as four important factors with three levels for the dehydration step. Conditions were further optimized by response surface analysis. The results showed that the optimal conditions were 177 degrees C, 120 mL extractant volume, 2.1g of catalyst, and a reaction time of 4.8h. Under the optimal conditions, the furfural yield reached 8.9%, which is consistent with the estimated value, 8.97%. PMID- 22925755 TI - A molecular survey of S. mutans and P. gingivalis oral microbial burden in human saliva using relative endpoint polymerase chain reaction (RE-PCR) within the population of a Nevada dental school revealed disparities among minorities. AB - BACKGROUND: The University of Nevada, Las Vegas School of Dental Medicine recently opened an orthodontic treatment clinic to address the needs of the racially and ethnically diverse population of Southern Nevada, primarily focusing on the treatment and care of low-income and minority patients. Although orthodontic treatment and therapy has been shown to induce changes in the oral cavity, much of this evidence was collected from traditional White, teenage orthodontic clinic populations. The primary goal of this study was to describe the microbial burden of the cariogenic and periodontal pathogens, Streptococcus mutans and Porphyromonas gingivalis within the UNLV-SDM patient population. METHODS: Representative saliva samples were collected from healthy adult patients for DNA isolation. Relative endpoint polymerase chain reaction (RE-PCR) was performed to ascertain the presence and relative microbial burden of these oral pathogens. RESULTS: Nearly one quarter (13/56) or 23.3% of these patients had elevated levels of S. mutans, while (10/56) and 17.8% of these samples were found to have elevated levels of P. gingivalis, - with (90%) of P. gingivalis-positive samples from minority patients (X2=17.921, d.f. = 1; p<0.0001). CONCLUSIONS: These findings of elevated P. gingivalis levels, primarily among minority patients, may suggest underlying oral health practices contributing to adverse oral health conditions within this population. Oral health knowledge and practices among minority patients may be strongly influenced by other factors, including education and socioeconomic status, suggesting additional research may be needed to accurately determine the most appropriate standards for care and oral health education within this patient population. PMID- 22925757 TI - Structure of an acidic polysaccharide isolated from Psychrobacter maritimus 3pS containing a bacillosamine derivative. AB - An acidic polysaccharide was obtained from Psychrobacter maritimus 3pS isolated from a Siberian cryopeg sample (Kolyma lowland). The following structure of the tetrasaccharide repeating unit of the polysaccharide was established by sugar analysis along with (1)H and (13)C NMR spectroscopy: ->2)-alpha-L-Rhap-(1->4) alpha-D-GalpNAcA-(1->3)-alpha-D-QuipNAc4NHb-(1->3)-beta-D-QuipNAc4NHb-(1-> where D-GalNAcA indicates 2-acetamido-2-deoxy-D-galacturonic acid and d-QuiNAc4NHb indicates 2-acetamido-2,4,6-trideoxy-4-[(S)-3-hydroxybutanoyl]amino-D-glucose. PMID- 22925759 TI - Armed-disarmed effect on the stability of cysteine thioglucosides. AB - Thioglucosides of cysteine show variable stability depending on the nature of the protecting groups on the glycosyl donor. Armed protecting groups (benzyl) lead to products that decompose readily while disarmed protecting groups (acetyl) lead to more stable products. Since this armed/disarmed effect of the protecting group on the stability of the thioglucosides is more pronounced for cysteine with an unprotected carboxylic group, the proposed mechanism is that decomposition is initiated by an intramolecular protonation of glycosyl sulfide and subsequent displacement of the sulfide by adventitious nucleophiles. PMID- 22925758 TI - Synthesis of glycosyl ferulate derivatives by amine-promoted glycosylation with regioselective hydrolysis using Novozym 435 and evaluation of their antioxidant properties. AB - Various glycosyl ferulates were efficiently synthesized from 2,4,6-tetra-O-acetyl alpha-D-glucopyranosyl bromide (TAGB) with amine by amine-promoted glycosylation without using heavy metal. The resulted acetylated glycosyl ferulates with acetoxyl groups at C-2, C-3 and C-4 were regioselectively deacetylated at C-4 and C-6 positions with Novozym 435. Antioxidant abilities of free ferulic acids and its synthetic glycosyl ferulates were evaluated by inhibitory effect on autoxidation of bulk methyl linoleate as well as their radical scavenging activity. The radical scavenging activity on 1,1-diphenyl-2-picrylhydrazyl (DPPH.) decreased in the order ferulic acid>sinapinic acid ~ glycosyl sinapinates ~ glycosyl ferulates>p-coumaric acid>glycosyl p-coumarates. In bulk methyl linoleate, the antioxidant activity order against autoxidation was very consistent with the scavenging activity order. The results showed that glycosyl ferulates and sinapinates were effective as well as free carboxylic acid forms. PMID- 22925760 TI - From mannose to morphan analogues: methyl alpha-D-mannoside as chiral building block for the synthesis of mono- and bicyclic sigma receptor ligands. AB - Previously the synthesis and high sigma(1) receptor affinity of mannose derived pyrans 3-5 with equatorially oriented amino groups have been reported. Herein the synthesis and receptor affinities of the corresponding axially substituted pyrans and oxa-morphans are described. Key step in the diastereoselective synthesis was an S(N)2 substitution of tosylate 10 with NaN(3). Heating of the azide 6 with acid led unexpectedly to the oxa-morphan 13, which showed remarkable affinity toward the sigma(1) receptor (K(i)=860 nM). The benzylamine 15alpha and the dimethylamine 16alpha were obtained by reduction of the azide 6 and subsequent reductive alkylation. In contrast to the equatorial amines 3-5, the axial amines 15alpha and 16alpha did not interact with the sigma(1) receptor or another investigated receptor system. PMID- 22925761 TI - A typical endo-xylanase from Streptomyces rameus L2001 and its unique characteristics in xylooligosaccharide production. AB - The activity of the extracellular xylanase produced by Streptomyces rameus L2001 against different xylans and xylooligosaccharides (XOS) was investigated. The main products of hydrolysis of birchwood xylan and oat-spelt xylan by the S. rameus L2001 xylanase were xylobiose (X2) and xylotriose (X3), suggesting that this is an endo-acting xylanase. This was confirmed by analysis of XOS degradation products. The enzyme hardly hydrolyzed X2 and X3, but hydrolyzed xylotetraose (X4) and xylopentaose (X5) producing mainly X2 and X3 through transglycosylation. Depending on the substrate, different quantities of reducing sugars were produced by the xylanase: 150 mg/g from corncob, 105 mg/g from bean culms, and 133 mg/g from bagasse. With the bagasse substrate, the xylanase yielded 2.36, 2.76, 2.03, and 2.17 mg/mL of X2, X3, X4, and X5, respectively. The structure of xylobiose and xylotriose from the hydrolysis of corncob xylan was identified by MS and NMR. The production of XOS from various agricultural wastes has potential industrial applications. This is the first report of XOS production by S. rameus L2001. PMID- 22925762 TI - Expression of heparinase I of Bacteroides stercoris HJ-15 and its degradation tendency toward heparin-like glycosaminoglycans. AB - Recombinant heparinase I was cloned from Bacteroides stercoris HJ-15 (BSrhepI), overexpressed in Escherichia coli, and intensively characterized. The complete gene of BSrhepI was identified by Southern blotting, and was overexpressed as an inclusion body. The inclusion body was solubilized with 4 M guanidine-HCl, and the denatured BSrhepI was easily purified using Ni(2+)-affinity column chromatography. The purified but denatured enzyme was then successfully refolded by dialysis against 50 mM Tris-HCl (pH 7.0) containing 1mM DTT and CaCl(2). BSrhepI was most active in 50mM Tris-HCl buffer containing 300 mM NaCl, 10 mM CaCl(2), and 1 mM DTT (pH 7.0) at 37 degrees C. This enzyme digested not only heparin, but also heparan sulfate. Through comparative HPLC-analysis of each degraded product of heparin and heparan sulfate by digestion with BSrhepI or flavobacterial heparinase I, we verified that BSrhepI has a broader spectrum of substrate specificities than other reported heparinases. PMID- 22925763 TI - Chemoenzymatic synthesis of an isoprenoid phosphate tool for the analysis of complex bacterial oligosaccharide biosynthesis. AB - Undecaprenyl Pyrophosphate Synthase (UPPS) is a key enzyme that catalyzes the production of bactoprenols, which act as membrane anchors for the assembly of complex bacterial oligosaccharides. One of the major hurdles in understanding the assembly of oligosaccharide assembly is a lack of chemical tools to study this process, since bactoprenols and the resulting isoprenoid-linked oligosaccharides lack handles or chromophores for use in pathway analysis. Here we describe the isolation of a new UPPS from the symbiotic microorganism Bacteroides fragilis, a key species in the human microbiome. The protein was purified to homogeneity and utilized to accept a chromophore containing farnesyl diphosphate analogue as a substrate. The analogue was utilized by the enzyme and resulted in a bactoprenyl diphosphate product with an easy to monitor tag associated with it. Furthermore, the diphosphate is shown to be readily converted to monophosphate using a common molecular biology reagent. This monophosphate product allowed for the investigation of complex oligosaccharide biosynthesis, and was used to probe the activity of glycosyltransferases involved in the well characterized Campylobacter jejuni N-linked protein glycosylation. Novel reagents similar to this will provide key tools for the study of uncharacterized oligosaccharide assemblies, and open the possibility for the development of rapid screening methodology for these biosynthetic systems. PMID- 22925765 TI - Design and stereoselective synthesis of a C-aryl furanoside as a conformationally constrained CHIR-090 analogue. AB - The UDP-3-O-[(R)-3-hydroxymyristoyl]-N-acetylglucosamine deacetylase (LpxC) is a promising target for the development of novel antibiotic substances against multidrug-resistant Gram-negative bacteria. The C-aryl glycoside 3 was designed as conformationally constrained analogue of the potent LpxC-inhibitor CHIR-090. The chiral pool synthesis of 3 started with D-mannose. The C-aryl glycoside 8 was synthesized stereoselectively by nucleophilic attack of 4-iodine-substituted phenyllithium and subsequent reduction with Et(3)SiH. The ester 10 was obtained in a one-pot diol cleavage, CrO(3) oxidation, and esterification. A Sonogashira reaction of the aryl iodide 11 led to the alkyne 17 which was transformed with H(2)NOH into the hydroxamic acid 3. PMID- 22925764 TI - Improved reaction pattern of an endoglycanase from Paenibacillus cookii for chitosan oligosaccharide production. AB - The reaction pattern of an endoglycanase from Paenibacillus cookii SS-24 (Pgl8A) was improved to facilitate chitosan oligosaccharide production. Based on the sequence alignment with chitosanase of a known structure, we performed site directed mutagenesis of possible substrate-binding residues in Pgl8A. The mutants were expressed in Escherichia coli cells, and their cellulase and chitosanase activities were then characterised. Our results indicated that three amino acid residues (W139, W208 and E285) were important for the substrate specificity of Pgl8A. D156 and Y390 were also essential for the cellulase and chitosanase activities of Pgl8A. The products of chitosan degradation by W139A, W208A and E285Q mutants were different from those by the wild type. A chitosan pentamer accumulated following chitosan degradation by W139A, W208A and E285Q mutants. Thus, the mutants obtained in this study are potentially useful for the production of biofunctional chitosan oligosaccharides. PMID- 22925766 TI - The structural changes of the bagasse hemicelluloses during the cooking process involving active oxygen and solid alkali. AB - This work describes the structural changes of bagasse hemicelluloses during the cooking process involving active oxygen (O(2) and H(2)O(2)) and solid alkali (MgO). The hemicelluloses obtained from the bagasse raw material, pulp, and yellow liquor were analyzed by high-performance anion-exchange chromatography (HPAEC), gel permeation chromatography (GPC), Fourier transform infrared spectroscopy (FT-IR), and (1)H-(13)C 2D hetero-nuclear single quantum coherence spectroscopy (HSQC). The results revealed that the structure of the bagasse hemicelluloses was L-arabino-(4-O-methylglucurono)-D-xylan. Some sugar units in hemicelluloses were oxidized under the cooking conditions. Additionally, the backbones and the ester linkages of hemicelluloses were heavily cleaved during the cooking process. PMID- 22925767 TI - Novel teichulosonic acid from cell wall of Streptomyces coelicolor M145. AB - The cell wall of Streptomyces coelicolor M145, a prototrophic plasmidless (SCP1( ) SCP2(-)) variant of strain S. coelicolor A3(2) contains the main glycopolymer represented by Kdn-containing teichulosonic acid with unusual structure which has not been described so far: [structure: see text]. The minor polymer was found to be a poly(diglycosyl 1-phosphate) with the following repeating unit: -6)-alpha Galp-(1->6)-alpha-GlcpNAc-(1-P-. The structures of both glycopolymers were established by using a combination of chemical and NMR spectroscopic methods. PMID- 22925768 TI - NMR assignment of structural motifs in intact beta-limit dextrin and its alpha amylase degradation products in situ. AB - An increasingly detailed and realistic view of biological processes often hinges on atomic-level characterization of biomacromolecules and of the processes they are involved in, preferably under near-physiological conditions. Structure, degradation, and synthesis of glucose storage polymers have been studied for decades with a range of analytical tools, but the detailed in situ analysis has remained an analytical challenge. Here, we report the NMR assignment of different structural motifs in the beta-limit dextrin from lintnerized maize starch as a branched alpha-glucan model system for starch, which is depleted of repetitive alpha-(1->4) glycosidic bonds at non-reducing ends but has the alpha-(1->6) branch points intact. By NMR spectroscopy at 18.7T magnetic field, we assign 12 discernible alpha-glucopyranosyl spin systems and identify them with different structural motifs. Amylolysis of the beta-limit dextrin is directly followed by real-time NMR spectroscopy and four major cleavage products are identified and assigned to different branch point structures. Overall, these NMR assignments facilitate in situ assays under realistic conditions of substrate competition, transglycosylation, and product inhibition and shed light on chemical shift tendencies in different structural motifs of branched alpha-glucans. PMID- 22925769 TI - An improved method for the synthesis of protected glycosyl fluorides from thioglycosides using N,N-diethylaminosulfur trifluoride (DAST). AB - The direct conversion of thioglycosides to glycosyl fluorides frequently used in oligosaccharide synthesis was examined using N,N-diethylaminosulfur trifluoride (DAST). Although the reaction proceeded without N-bromosuccinimide (NBS), in some cases it was found that the electrophilicity of the Vilsmeier-type electrophilic sulfinium cation species was not sufficient for the activation of certain less reactive thioglycosides. Here, we report the results of fluorination reactions of a series of monosaccharides using DAST in the absence of NBS, and also discuss the acceleration of the reaction in the presence of dimethyl(methylthio)sulfonium trifluoromethanesulfonate (DMTST) resulting in excellent product yields. PMID- 22925771 TI - The structure of the O-specific polysaccharide of the lipopolysaccharide from Yersinia enterocolitica serotype O:50 strain 3229. AB - The genus Yersinia represents Gram-negative bacteria that are widely distributed in the environment and possess lipopolysaccharide (LPS) as a major molecule on the surface of the bacterial envelope. LPS is composed of an anchoring lipid, termed lipid A, and a polysaccharide part which not only determines the bacterial serotype but may also serve as a bacteriophage receptor. Here we present the structure of the O-polysaccharide (O-PS) of Yersinia enterocolitica O:50 phage PhiR1-37-sensitive strain 3229. The structural characterization was performed utilizing 1D and 2D nuclear magnetic resonance spectroscopy and chemical analyses. The structure of the O-PS biological repeating unit was identified as >2)-alpha-L-Rhap-(1->3)-alpha-L-FucpNAc-(1->3)-alpha-L-FucpNAc-(1->3)-beta-D GlcpNAc-(1->. PMID- 22925770 TI - Synthesis of novel N-acetylneuraminic acid derivatives as substrates for rapid detection of influenza virus neuraminidase. AB - Two novel N-acetylneuraminic acid derivatives, luciferyl N-acetylneuraminic acid (1) and luciferyl 4,7-di-O-methyl-N-acetylneuraminic acid (2), were designed and synthesized as substrates for the rapid detection of influenza virus neuraminidase. The sensitivity and specificity of the assays with compound 1 or 2 as the substrate for detection of neuraminidases from influenza virus (H1N1 and H5N1) and bacteria (A. ureafaciens and C. perfringens) were evaluated. Compound 1 was sensitive to neuraminidases from both influenza virus and bacteria. Bioluminescent assays with this compound with H1N1 and H5N1 neuraminidases were approximately 20- and 16-fold more sensitive, respectively, than the fluorescent method with the commercial substrate 4-MUNANA. In contrast, compound 2 was only sensitive to the neuraminidases from influenza virus, showing approximately 10- and 8-fold greater sensitivity than 4-MUNANA for the detection of H1N1 and H5N1 neuraminidases, respectively. The data showed that compound 2 could be used in assays for detection of an influenza viral neuraminidase. PMID- 22925772 TI - Carbohydrate-steroid conjugation by Ugi reaction: one-pot synthesis of triple sugar/pseudo-peptide/spirostane hybrids. AB - The one-pot synthesis of novel molecular chimeras incorporating sugar, pseudo peptide, and steroidal moieties is described. For this, a new carbohydrate steroid conjugation approach based on the Ugi four-component reaction was implemented for the ligation of glucose and chacotriose to spirostanic steroids. The approach proved wide substrate scope, as both mono and oligosaccharides functionalized with amino, carboxy, and isocyano groups were conjugated to steroidal substrates in an efficient, multicomponent manner. Two alternative strategies based on the hydrazoic acid variant of the Ugi reaction were employed for the synthesis of tetrazole-based chacotriose-diosgenin conjugates resembling naturally occurring spirostan saponins. This is the first time that triple sugar/pseudo-peptide/steroid hybrids are produced, thus opening up an avenue of opportunities for applications in drug discovery and biological chemistry. PMID- 22925773 TI - Regioselective benzoylation of glycopyranosides by benzoic anhydride in the presence of Cu(CF3COO)2. AB - Benzoylation of methyl and benzyl glycopyranosides by benzoic anhydride in acetonitrile in the presence of copper(II) trifluoroacetate as a promoter has given monobenzoates with a good yield and high regioselectivity. The composition of monobenzoates depended both on a configuration of hydroxyl groups and on a configuration of aglycone. The simple syntheses of the monobenzoates of some glycosides are offered. PMID- 22925774 TI - The self-assembly and aqueous solubilization of [60]fullerene with disaccharides. AB - Solubilization of [60]fullerene in water by complexation with disaccharides in mixed homogeneous solvent system, is described for the first time. The complexation of extremely water-insoluble [60]fullerene dissolved in non-polar solvent toluene and extremely water-soluble disaccharides dissolved in polar solvent DMSO resulted in an unique self-assembled highly crystalline water soluble [60]fullerene-disaccharide complex. The interaction between [60]fullerene and disaccharides was found to be non-covalent and were characterized by FTIR, UV Vis, NMR, XRD, and thermogravimetric analysis. The particle size of the lactose C(60) complex was found to be monodisperse ~60 nm from Transmission Electron Microscopy (TEM) and matched with the size obtained from Static Light Scattering (SLS). Preliminary studies of radical scavenging on the most stable free radical 2,2'-diphenyl-1-picrylhydrazyl (DDPH) suggested that complex has potential biological applications. PMID- 22925775 TI - Left pulmonary artery banding to repair ipsilateral diffuse pulmonary arteriovenous fistula. AB - Congenital pulmonary arteriovenous fistula (PAVF) is a rare disease which causes hypoxemia by shunting deoxygenated blood from the pulmonary artery into pulmonary venous return. Lung transplantation is the most effective therapy to treat severe, diffuse PAVF. However, the availability of lungs for transplantation is limited in most parts in the world. For patients with diffuse PAVF affecting only one side of the lungs, ipsilateral pulmonary artery banding (PAB) is an effective treatment, but not yet standard of care. We report successful treatment of a patient with diffuse left-sided PAVF with PAB. We believe that PAB is an effective therapy for severe unilateral PAVF and may serve as a bridge to lung transplantation. PMID- 22925776 TI - SB202190 affects cell response to hydroxyurea-induced genotoxic stress in root meristems of Vicia faba. AB - Genotoxic stress caused by a variety of chemical and physical agents may lead to DNA breaks and genome instability. Response to DNA damage depends on ATM/ATR sensor kinases and their downstream proteins, which arrange cell cycle checkpoints. Activation of ATM (ataxia-telangiectasia-mutated)/ATR (ATM and Rad 3 related) signaling pathway triggers cell cycle arrest (by keeping cyclin-Cdk complexes inactive), combined with gamma-phosphorylation of histone H2A.X and induction of DNA repair processes. However, genotoxic stress activates also mitogen-activated protein kinases (MAPKs) which may control the functions of checkpoint proteins both directly, by post-translational modifications, or indirectly, by regulation of their expression. Our results indicate that in root meristem cells of Vicia faba, MAP kinase signaling pathway takes part in response to hydroxyurea-induced genotoxic stress. It is shown that SB202190, an inhibitor of p38 MAP kinase, triggers PCC (premature chromosome condensation) more rapidly, but only if cell cycle checkpoints are alleviated by caffeine. Since SB202190 and, independently, caffeine reduces HU-mediated histone H4 Lys5 acetylation, it may be that there is a cooperation of MAP kinase signaling pathways and ATM/ATR dependent checkpoints during response to genotoxic stress. PMID- 22925777 TI - The coronary endothelium behaves as a functional diffusion barrier for intravascular Angiotensin II. AB - Diverse intracoronary hormones cause their cardiac effects solely via activation of their coronary endothelial luminal membrane (CELM) receptors. To test this hypothesis for Ang II, we synthesized: a) two large polymers of Ang II (Ang II POL) and Losartan (Los-POL) which act only in the CELM's AT1R because they cannot cross the endothelial barrier and b) biotin-labeled Ang II (Ang II-Biotin) and Ang II-POL-Biotin to be identified by microscopy in tissues. Sustained coronary perfusion of Ang II (potentially diffusible) or Ang II-POL caused a positive inotropic effect (PIE) and an increase in coronary perfusion pressure (CPP) of equal magnitude that were blocked by Losartan and Los-POL. However, Ang II effects, in contrast to Ang II-POL effects, were transient due to desensitization and resulted in tachyphylaxis to a second administration of Ang II or Ang II-POL. Furthermore, if Ang II and Ang II-POL acted differently on the same receptor; a competition of effects would be expected. This was demonstrated by infusing simultaneously a molar ratio of Ang II:Ang II-POL. As this molar ratio decreased, Ang II-induced desensitization and tachyphylaxis decreased. Intravascularly administered Ang II-Biotin and Ang II-POL-Biotin remained bound and confined to the endothelium. Our results support the hypothesis and indicate intravascular Ang II, not by mass exchange with the interstitium, but by an action restricted to the CELM's AT1R, causes release of endothelial chemical messengers that exert physiological effects and modulate the effects and metabolism of paracrine Ang II. Endocrine Ang II controls and communicates with its paracrine counterparts solely through endothelial receptors. PMID- 22925778 TI - Dietary alpha-linolenic acid enhances omega-3 long chain polyunsaturated fatty acid levels in chicken tissues. AB - The effects of enriching broiler chicken diets with a vegetable source of n-3 fat in the form of alpha-linolenic acid (ALA, 18:3n-3) on the accumulation of n-3 long chain polyunsaturated fatty acids (LCPUFA) in chicken meat were investigated. Sixty unsexed one-day-old broiler chickens (Cobb 500) were randomly allocated to one of six diets (n=10 birds/diet) for 4 weeks. The ALA levels varied from 1 to 8% energy (%en) while the level of the n-6 fatty acid linoleic acid (LA, 18:2n-6) was held to less than 5%en in all diets. At harvest (day 28) the levels of n-3 LCPUFA including eicosapentaenoic acid (EPA), docosapentaenoic acid (DPA) and docosahexaenoic acid (DHA) in breast and thigh meat increased in a curvilinear manner as dietary ALA increased, reaching 4- to 9-fold above the levels seen in control birds. In contrast, arachidonic acid (AA) was reduced in response to increasing dietary ALA. PMID- 22925780 TI - The COST Action IC0604 "Telepathology Network in Europe" (EURO-TELEPATH). AB - The COST Action IC0604 "Telepathology Network in Europe" (EURO-TELEPATH) is a European COST Action that has been running from 2007 to 2011. COST Actions are funded by the COST (European Cooperation in the field of Scientific and Technical Research) Agency, supported by the Seventh Framework Programme for Research and Technological Development (FP7), of the European Union. EURO-TELEPATH's main objectives were evaluating and validating the common technological framework and communication standards required to access, transmit and manage digital medical records by pathologists and other medical professionals in a networked environment. The project was organized in four working groups. orking Group 1 "Business modeling in pathology" has designed main pathology processes - Frozen Study, Formalin Fixed Specimen Study, Telepathology, Cytology, and Autopsy -using Business Process Modeling Notation (BPMN). orking Group 2 "Informatics standards in pathology" has been dedicated to promoting the development and application of informatics standards in pathology, collaborating with Integrating the Healthcare Enterprise (IHE), Digital Imaging and Communications in Medicine (DICOM), Health Level Seven (HL7), and other standardization bodies. Working Group 3 "Images: Analysis, Processing, Retrieval and Management" worked on the use of virtual or digital slides that are fostering the use of image processing and analysis in pathology not only for research purposes, but also in daily practice. Working Group 4 "Technology and Automation in Pathology" was focused on studying the adequacy of current existing technical solutions, including, e.g., the quality of images obtained by slide scanners, or the efficiency of image analysis applications. Major outcome of this action are the collaboration with international health informatics standardization bodies to foster the development of standards for digital pathology, offering a new approach for workflow analysis, based in business process modeling. Health terminology standardization research has become a topic of high interest. Future research work should focus on standardization of automatic image analysis and tissue microarrays imaging. PMID- 22925782 TI - State of the art and trends for digital pathology. AB - Anatomic pathology is a medical specialty where both information management systems and digital images systems paly a most important role. Digital pathology is a new concept that considers all uses of this information, including diagnosis, biomedical research and education. Virtual microscopy or whole slide imaging, resulting in digital slides, is an outreaching technology in anatomic pathology. Limiting factors in the expansion of virtual microscopy are formidable storage dimension, scanning speed, quality of image and cultural change. Anatomic pathology data and images should be an important part of the patient electronic health records as well as of clinical data warehouse, epidemiological or biomedical research databases, and platforms dedicated to translational medicine. Integrating anatomic pathology to the "healthcare enterprise" can only be achieved using existing and emerging medical informatics standards like Digital Imaging and Communications in Medicine (DICOM(r)1), Health Level Seven (HL7(r)), and Systematized Nomenclature of Medicine-Clinical Terms (SNOMED CT(r)), following the recommendations of Integrating the Healthcare Enterprise (IHE(r)). The consequences of the full digitalization of pathology departments are hard to foresee, but short term issues have arisen that imply interesting challenges for health care standards bodies. PMID- 22925783 TI - State of the art in telemedicine - concepts, management, monitoring and evaluation of the telemedicine programme in Alentejo (Portugal). AB - Alentejo - one of five Portuguese continental regions - faces major problems impacting the health and social system of the region. Here, the low population density, the low educational and income level as well as an aging population have to be mentioned. Faced with the task of ensuring equal access to healthcare for all its inhabitants, the regional health authorities created the telemedicine program. From 1998 until 2000, the program developed in an experimental fashion, with teleconsultations involving a number of providers: primary health care centers, regional hospitals, and central hospitals. Between 2000 and 2010, there were a total of 135,000 telemedicine acts including teleconsultations, teleradiology (computerised tomography and x-rays), ultrasound telemedicine and telepathology. Presently, the network comprises 20 health centers and 6 hospitals, covering 4 districts. The platform is composed of high resolution videoconferencing equipment, software with patients' clinical records, an image archive, and a number of peripherals, such as electronic dermatoscopes and phonendoscopes. Teleconsultations are provided by fifteen medical specialties, across 3 district hospitals, ranging from neurology to pediatric surgery. In 2008, health authorities started the telelearning program, initially using point to point videoconferencing, and by the end of 2010, 848 healthcare professionals, across 52 locations, had participated in remote learning sessions, covering topics from chronic wound treatment, to infection control, to medical error. As of 2011, point to multipoint telelearning is also in operation. This paper provides an overview of the telemedicine program in Alentejo, including both infrastructure and operations. Preliminary results of an ongoing evaluation of the impact of teleconsultations on key indicators of the regional healthcare system are also presented (including current utilization and plans for future expansion). This article builds on the experience acquired throughout a decade of using telemedicine on an everyday basis, in a context of remarkable challenges in the delivery of accessible, equitable and quality healthcare services. PMID- 22925784 TI - Paradigm changes in health lead to paradigm changes in pathology. AB - For the sake of safety and quality of care as well as efficiency of care processes, health systems undergo a paradigm change towards personalized, ubiquitous, health services. This change includes preventive and predictive medicine based on advanced translational medicine. Here we introduce domain specific, organizational, and technical paradigms, requirements and solutions for personalized, ubiquitous, care. Emphasizing the formal aspects of modeling and implementing Telehealth and personal health (pHealth) interoperability and the entailed multidisciplinary integration, and illustrate the drivers behind and benefits of personalized medicine with a specific focus on the changing trends and impact on pathology, especially emphasizing Telepathology. PMID- 22925785 TI - Telepathology interoperability - a system architectural approach. AB - eHealth and pHealth, instantiated, e.g., in telepathology solutions, have to meet advanced interoperability challenges. Technologically supported by pervasive computing and even autonomic computing, pHealth covers many domains, scientifically managed by specialized disciplines using their specific ontologies. Therefore, semantic interoperability has to advance from a communication protocol to knowledge coordination and sharing, deploying advanced system architectures. Based on long-term work of scientific institutions and SDOs dedicated to system architectures, an interoperability framework is presented, integrating existing, emerging and even future specifications and standards for comprehensive interoperability of health and social services. The methodology is proven in many health information systems implementation and standard developments projects. PMID- 22925786 TI - Consequences of "going digital" for pathology professionals - entering the cloud. AB - New opportunities and the adoption of digital technologies will transform the way pathology professionals and services work. Many areas of our daily life as well as medical professions have experienced this change already which has resulted in a paradigm shift in many activities. Pathology is an image-based discipline, therefore, arrival of digital imaging into this domain promises major shift in our work and required mentality. Recognizing the physical and digital duality of the pathology workflow, we can prepare for the imminent increase of the digital component, synergize and enjoy its benefits. Development of a new generation of laboratory information systems along with seamless integration of digital imaging, decision-support, and knowledge databases will enable pathologists to work in a distributed environment. The paradigm of "cloud pathology" is proposed as an ultimate vision of digital pathology workstations plugged into the integrated multidisciplinary patient care systems. PMID- 22925787 TI - Digital pathology for education. AB - The use of digital slides for educational purposes (both for medical students and during pathology traineeships) will eventually accelerate the acceptance of digital pathology in general. This chapter describes the advantages of using digital slides especially for education. Also the requirements for using digital slides for this purpose are evaluated, including software requirements, the slide scanner and the IT infrastructure needed to provide a robust infrastructure to end users. PMID- 22925789 TI - Business process modeling in healthcare. AB - The importance of the process point of view is not restricted to a specific enterprise sector. In the field of health, as a result of the nature of the service offered, health institutions' processes are also the basis for decision making which is focused on achieving their objective of providing quality medical assistance. In this chapter the application of business process modelling - using the Business Process Modelling Notation (BPMN) standard is described. Main challenges of business process modelling in healthcare are the definition of healthcare processes, the multi-disciplinary nature of healthcare, the flexibility and variability of the activities involved in health care processes, the need of interoperability between multiple information systems, and the continuous updating of scientific knowledge in healthcare. PMID- 22925790 TI - State of the art in pathology business process analysis, modeling, design and optimization. AB - For analyzing current workflows and processes, for improving them, for quality management and quality assurance, for integrating hardware and software components, but also for education, training and communication between different domains' experts, modeling business process in a pathology department is inevitable. The authors highlight three main processes in pathology: general diagnostic, cytology diagnostic, and autopsy. In this chapter, those processes are formally modeled and described in detail. Finally, specialized processes such as immunohistochemistry and frozen section have been considered. PMID- 22925792 TI - Standards and specifications in pathology: image management, report management and terminology. AB - For making medical decisions, healthcare professionals require that all necessary information is both correct and easily available. Collaborative Digital Anatomic Pathology refers to the use of information technology that supports the creation and sharing or exchange of information, including data and images, during the complex workflow performed in an Anatomic Pathology department from specimen reception to report transmission and exploitation. Collaborative Digital Anatomic Pathology is supported by standardization efforts toward knowledge representation for sharable and computable clinical information. The goal of the international integrating the Healthcare Enterprise (IHE) initiative is precisely specifying how medical informatics standards should be implemented to meet specific health care needs and making systems integration more efficient and less expensive. The IHE Anatomic Pathology initiative was launched to implement the best use of medical informatics standards in order to produce, share and exchange machine readable structured reports and their evidences (including whole slide images) within hospitals and across healthcare facilities. DICOM supplements 122 and 145 provide flexible object information definitions dedicated respectively to specimen description and WSI acquisition, storage and display. The profiles "Anatomic Pathology Reporting for Public Health" (ARPH) and "Anatomic Pathology Structured Report" (APSR) provide standard templates and transactions for sharing or exchanging structured reports in which textual observations - encoded using PathLex, an international controlled vocabulary currently being mapped to SNOMED CT concepts - may be bound to digital images or regions of interest in images. Current implementations of IHE Anatomic Pathology profiles in North America, France and Spain demonstrate the applicability of recent advances in standards for Collaborative Digital Anatomic Pathology. The use of machine-readable format of Anatomic Pathology information supports the development of computer-based decision support as well as secondary use of Anatomic Pathology information for research or public health. PMID- 22925793 TI - SNOMED CT in pathology. AB - Pathology information systems have been using SNOMED II for many years, and in most cases, they are in a migration process to SNOMED CT. COST Action IC0604 (EURO-TELEPATH) has considered terminology normalization one of its strategic objectives. This paper reviews the use of SNOMED CT in healthcare, with a special focus in pathology. Nowadays, SNOMED CT is mainly used for concept search and coding of clinical data. Some ontological errors found in SNOMED CT are described. The Integrating the Healthcare Enterprise (IHE) initiative has fostered the use of SNOMED CT, also in Pathology, as recommended in the Supplement Anatomic Pathology Structured Reports of the IHE Anatomic Pathology Technical Framework. Rule governing concept post-coordination is also described. Some recent initiatives are trying to define a SNOMED CT subset for Pathology. The Spanish Society of Pathology has defined a subset for specimens and procedures in Pathology. Regarding diagnosis coding, the morphological abnormality sub-hierarchy of SNOMED CT need to be significantly extended and improved to become useful for pathologists. A consensus is needed to encode pathology reports with the adequate hierarchies and concepts. This will make the implementation of pathology structured reports more feasible. PMID- 22925795 TI - Digital pathology in personalized cancer therapy. AB - The development of small molecule inhibitors of the growth factor receptors and discovery of somatic mutations of the thyrosine kinase domain resulted in new paradigms for the cancers therapy. Digital microscopy is an important tool for surgical pathologists. The achievements in the digital pathology field have modified the workflow of pathomorphology labs, enhanced the pathologists' role in the diagnostics and increased their contribution to the personalized targeted medicine. Digital image analysis is now available in a variety of platforms to improve quantification performance of diagnostic pathology. The authors describe the state of digital microscopy as it applies to the field of quantitative immunohistochemistry of biomarkers related to the clinical personalized targeted therapy of breast cancer, non-small lung cancer and colorectal cancer: HER-2, EGFR, KRAS and BRAF genes. The information is derived from the experience of the authors and review of the literature. PMID- 22925796 TI - Digital image analysis in breast cancer: an example of an automated methodology and the effects of image compression. AB - In the current practice of pathology, the evaluation of immunohistochemical (IHC) markers represents an essential tool. The manual quantification of these markers is still laborious and subjective, and the use of computerized systems for digital image (DI) analysis has not yet resolved the problems of nuclear aggregates (clusters). Furthermore, the volume of DI storage continues to be an important problem in computer-assisted pathology. In the present study we have developed an automated procedure to quantify IHC nuclear markers in DI with a high level of clusters. Furthermore the effects of JPEG compression in the image analysis were evaluated. The results indicated that there was an agreement with the results of both methods (automated vs. manual) in almost 90% of the analyzed images. On the other hand, automated count differences increase as the compression level increase, but only in images with a high number of stained nuclei (>nuclei/image) or with high area cluster (>25MUm2). Some corrector factors were developed in order to correct this count differences. In conclusion, the proposed automated procedure is an objective, faster than manual counting and reproducible method that has more than 90% of similarity with manual count. Moreover, the results demonstrate that with correction factors, it is possible to carry out unbiased automated quantifications on IHC nuclear markers in compressed DIs. PMID- 22925797 TI - Adaptive clustering of image database (ACID) as an efficient tool for improving retrieval in a CBIR system. AB - The paper describes a content-based image retrieval (CBIR) system with relevance feedback (RF). Instead of standard relevance feedback procedure, an adaptive clustering of image database (ACID) according to particular subjective needs is introduced in our system. Images labeled by the user as relevant are collected in clusters, and their representative members are used in further searching procedure instead of all images contained in the database. By this way, some history of previous retrieving is embedded into a searching process enabling faster and more subjective retrieval. Moreover, clusters are adaptively updated after each retrieving session, following actual user's needs. The efficiency of the proposed ACID system is tested with images from Corel and MIT datasets. PMID- 22925799 TI - Automated high throughput whole slide imaging using area sensors, flash light illumination and solid state light engine. AB - BACKGROUND: Whole Slide Imagers or digital slide scanners have developed very rapidly in the last 8 years and went through three generations. Third generation instruments have just reached the market which have the stability and throughput to be used for routine clinical work. We describe in this article the technical background and reasoning behind engineering decisions we made during the development of 3DHISTECH's 3rd generation combined brightfield and fluorescent scanner. MATERIALS AND METHODS: The Panoramic 250 FLASH utilizes Plan-Apochromat 20x and 40x objectives, a 2 megapixel 3CCD camera for brightfield and a monochrome scientific CMOS camera for fluorescent scanning. A solid state light engine for fluorescent and a strobe light for bright field illumination are used. RESULTS: The system can scan 1cm2 including focusing at 45x resolution in 1 minute. It can scan a well stained DAPI, FITC, TRIC, 1cm2 fluorescent slide in 11 minutes. It can load and scan 250 slides in walk away mode. CONCLUSION: Using the latest camera technology and electronics, state of the art computer and standard microscope optical components high throughput high quality whole slide imaging is feasible and is sufficient for most of the routine diagnostic work. Extended depth of field and Z-stack scanning is possible with the use of area scan technology. PMID- 22925800 TI - Security and privacy services in pathology for enabling trustworthy personal health. AB - Ubiquitous personalized health services including ePathology require comprehensive, but trusted interoperability. Contrary to regulated traditional health services with pre-defined policies, the solutions enabled by mobile, pervasive and autonomous technology have to follow dynamic policies reflecting the customers changing health services needs, expectations and wishes as well as contextual and environmental conditions. The paper introduces an advanced approach to trustworthy architecture-centric, policy-driven pHealth solutions. To some details, it also addresses security and privacy ontologies to represent the required policies. PMID- 22925801 TI - Emerging trends: grid technology in pathology. AB - Grid technology has enabled clustering and access to, and interaction among, a wide variety of geographically distributed resources such as supercomputers, storage systems, data sources, instruments as well as special devices and services, realizing network-centric operations. Their main applications include large scale computational and data intensive problems in science and engineering. Grids are likely to have a deep impact on health related applications. Moreover, they seem to be suitable for tissue-based diagnosis. They offer a powerful tool to deal with current challenges in many biomedical domains involving complex anatomical and physiological modeling of structures from images or large image databases assembling and analysis. This chapter analyzes the general structures and functions of a Grid environment implemented for tissue-based diagnosis on digital images. Moreover, it presents a Grid middleware implemented by the authors for diagnostic pathology applications. The chapter is a review of the work done as part of the European COST project EUROTELEPATH. PMID- 22925803 TI - Evaluation of a completely automated tissue-sectioning machine for paraffin blocks. AB - Tissue sectioning automation can be a resourceful tool in processing anatomic pathology specimens. The advantages of an automated system compared with the traditional manual sectioning rely on the consistency of the final sectioned material translated into invariable thickness, uniform orientation during serial sectioning and less tissue sectioning artifacts. This technical note presents the design of an automated tissue-sectioning device and compares the sectioned specimens with normal manual tissue sectioning performed by experienced histology technician. PMID- 22925804 TI - An ultra-high speed Whole Slide Image viewing system. AB - BACKGROUND: One of the goals for a Whole Slide Imaging (WSI) system is implementation in the clinical practice of pathology. One of the unresolved problems in accomplishing this goal is the speed of the entire process, i.e., from viewing the slides through making the final diagnosis. Most users are not satisfied with the correct viewing speeds of available systems. We have evaluated a new WSI viewing station and tool that focuses on speed. METHOD: A prototype WSI viewer based on PlayStation(r)3 with wireless controllers was evaluated at the Department of Pathology at MGH for the following reasons: 1. For the simulation of signing-out cases; 2. Enabling discussion at a consensus conference; and 3. Use at slide seminars during a Continuing Medical Education course. RESULTS: Pathologists were being able to use the system comfortably after 0-15 min training. There were no complaints regarding speed. Most pathologists were satisfied with the functionality, usability and speed of the system. The most difficult situation was simulating diagnostic sign-out. CONCLUSIONS: The preliminary results of adapting the Sony PlayStation(r)3 (PS3(r)) as an ultra high speed WSI viewing system were promising. The achieved speed is consistent with what would be needed to use WSI in daily practice. PMID- 22925805 TI - A role of three-dimensional (3D) reconstruction in the classification of lung adenocarcinoma. AB - BACKGROUND: Three-dimensional (3D) reconstruction from paraffin embedded sections has been considered laborious and time-consuming. However, the high-resolution images of large object areas and different fields of view obtained by 3D reconstruction make one wonder whether it can add a new insight into lung adenocarcinoma, the most frequent histology type of lung cancer characterized by its morphological heterogeneity. OBJECTIVE: In this work, we tested whether an automated tissue sectioning machine and slide scanning system could generate precise 3D reconstruction of microanatomy of the lung and help us better understand and define histologic subtypes of lung adenocarcinoma. METHODS: Four formalin-fixed human lung adenocarcinoma resections were studied. Paraffin embedded tissues were sectioned with Kurabo-Automated tissue sectioning machine and serial sections were automatically stained and scanned with a Whole Slide Imaging device. The resulting stacks of images were 3D reconstructed by Mirax Panoramic View software. RESULTS: Two of the four specimens contained the islands of tumor cells detached in alveolar spaces that had not been described in any of the existing adenocarcinoma classifications. 3D reconstruction revealed the details of spatial distribution and structural interaction of the tumor that could hardly be observed by 2D light microscopy studies. The islands of tumor cells extended into a deeper aspect of the tissue, and were interconnected with each other and with the main tumor with a solid pattern that was surrounded by the islands. The finding raises the question whether the islands of tumor cells should be classified into a solid pattern in the current classification. CONCLUSION: The combination of new technologies enabled us to build an effective 3D reconstruction of resected lung adenocarcinomas. 3D reconstruction may help us refine the classification of lung adenocarcinoma by adding detailed spatial/structural information to 2D light microscopy evaluation. PMID- 22925809 TI - Oleic acid and glucose regulate glucagon-like peptide 1 receptor expression in a rat pancreatic ductal cell line. AB - The glucagon-like peptide 1 receptor (GLP1R) plays a critical role in glucose metabolism and has become an important target for a growing class of drugs designed to treat type 2 diabetes. In vitro studies were designed to investigate the effect of the GLP1R agonist, exenatide (Ex4), in "on-target" RIN-5mF (islet) cells as well as in "off-target" AR42J (acinar) and DSL-6A/C1 (ductal) cells in a diabetic environment. Ex4 increased islet cell proliferation but did not affect acinar cells or ductal cells at relevant concentrations. A high caloric, high fat diet is a risk factor for impaired glucose tolerance and type-2 diabetes. An in vitro Oleic acid (OA) model was used to investigate the effect of Ex4 in a high calorie, high fat environment. At 0.1 and 0.4mM, OA mildly decreased the proliferation of all pancreatic cell types. Ex4 did not potentiate the inhibitory effect of OA on cell proliferation. Akt phosphorylation in response to Ex4 was diminished in OA-treated ductal cells. GLP1R protein detected by western blot was time and concentration dependently decreased after glucose stimulation in OA treated ductal cells. In ductal cells, OA treatment altered the intracellular localization of GLP1R and its co-localization with early endosome and recycling endosomes. Chloroquine (lysosomal inhibitor), N-acetyl-l-cysteine (reactive oxygen species scavenger) and wortmannin (a phosphatidylinositol-3-kinase inhibitor), fully or partially, rescued GLP1R protein in OA-pretreated, glucose stimulated ductal cells. The impact of altered regulation on phenotype/function is presently unknown. However, these data suggest that GLP1R regulation in ductal cells can be altered by a high fat, high calorie environment. PMID- 22925810 TI - IL-27 promotes nitric oxide production induced by LPS through STAT1, NF-kappaB and MAPKs. AB - Interleukin (IL)-27, a member of the IL-6/IL-12 heterodimeric cytokine family, induces pro-inflammatory responses including early T helper (Th)1 differentiation and generation of cytotoxic T lymphocytes, and also anti-inflammatory responses including the differentiation to IL-10-producing regulatory T cells, inhibition of Th2 and Th17 differentiation, and suppression of pro-inflammatory cytokine production. Nitric oxide (NO) is a potent source of reactive nitrogen species that play an important role in killing intracellular pathogens and forms a crucial component of host defense. Inducible NO synthase (iNOS), which catalyzes the production of NO, is induced by a range of stimuli including cytokines and microbes. Recently, IL-27 was reported to play an anti-inflammatory role in microglia by blocking oncostatin M-induced iNOS expression and neuronal toxicity. In the present study, we investigated the effects of IL-27 on NO production in thioglycollate-elicited peritoneal macrophages. IL-27 together with lipopolysaccharide (LPS) induced morphological change into more spread and elongated cells and synergistically enhanced NO production. The combined stimulation also enhanced iNOS mRNA expression and the NO production was abrogated by an iNOS inhibitor, NG-monomethyl L-arginine. The synergistic NO production could be attributed to the augmented Toll-like receptor (TLR)4 mRNA expression by the combination. Signal transducer and activator of transcription (STAT)1 was indispensable for the morphological change and NO production. The combination induced nuclear factor kappaB (NF-kappaB) translocation into nuclear and phosphorylation of extracellular signal-regulated kinase (ERK), c-Jun N terminal kinase (JNK) and p38 mitogen-activated protein kinase (MAPK), and their inhibitors suppressed NO production. These results suggest that in contrast to the anti-proinflammatory role in microglia, IL-27 exerts a pro-inflammatory role by enhancing NO production in peritoneal macrophages stimulated with LPS through activation of STAT1, NF-kappaB and MAPKs. PMID- 22925811 TI - Susceptibility to chronic hepatitis C virus infection is influenced by sequence differences in immunodominant CD8+ T cell epitopes. AB - BACKGROUND & AIMS: The antiviral immune response against HCV by CD8+ T cells plays a central role in viral containment. In a large HCV genotype 1b outbreak in Ireland, HLA-B(*)08 was identified as a risk allele for chronic infection and HLA A(*)03 and HLA-B(*)27 were associated with higher clearance rates. Here we took advantage of a similar large common source HCV genotype 1b outbreak (East-German cohort) to determine the role of HLA class I alleles and the sequence of the infection source, in immunodominant CD8+ T cell epitopes for disease outcome. METHODS: HLA-type and IL28B genotype were determined in 216 patients with chronic and 95 with spontaneously resolved HCV infection. The viral sequence in immunodominant epitopes was determined in the infection source and in patients with chronic infection. RESULTS: In contrast to the Irish cohort, HLA-B(*)08, HLA A(*)03 and HLA-B(*)27 were neutral for disease outcome even when the cohort was stratified for the IL28B genotype. Sequence analysis of the immunodominant epitopes revealed that pre-existing substitutions in the infection source of both cohorts influenced the impact of the corresponding HLA-allele. The immunodominant epitopes presented by the "protective" alleles HLA-A(*)03 and -B(*)27 in the Irish cohort contained substitutions in the source virus of the East-German outbreak. Importantly, the pre-existing substitutions altered subsequent selection pressure and viral evolution in the East-German cohort. CONCLUSIONS: This study highlights that subtle sequence differences in the infection source may have profound effects on the ability to clear HCV infection in the presence of particular HLA class I alleles. PMID- 22925812 TI - Neutrophil-lymphocyte ratio reflects hepatocellular carcinoma recurrence after liver transplantation via inflammatory microenvironment. AB - BACKGROUND & AIMS: Although the Milan criteria (MC) have been used to select liver transplantation candidates among patients with hepatocellular carcinoma (HCC), many patients exceeding the MC have shown good prognosis. Preoperative neutrophil-lymphocyte ratio (NLR) is a predictor of patient prognosis, but its mechanism has never been clarified. METHODS: We assessed outcomes in 158 patients who had undergone living-donor liver transplantation (LDLT) for HCC. Recurrence free survival (RFS) was determined in patients with high (>= 4) and low (<4) NLR. Levels of expression of vascular endothelial growth factor (VEGF), interleukin (IL)-8, IL-17, CD68, and CD163 were measured. RESULTS: The 5-year RFS rate was significantly lower in patients with high (n=26) than with low (n=132) NLR (30.3% vs. 89.0%, p<0.0001), in patients with high (n=15) than with low (n=79) NLR who met the MC (73.6% vs. 100%, p=0.0008) and in patients with high (n=11) than with low (n=53) NLR who exceeded the MC (0% vs. 76.1%, p=0.0002). Tumor expression of VEGF, IL8, IL-17, CD68, and CD163 was similar in the high and low NLR groups, but serum and peritumoral IL-17 levels were significantly higher in the high-NLR group (p=0.01 each). The density of peritumoral CD163 correlated with the density of peritumoral IL-17-producing cells (p=0.04) and was significantly higher in the high-NLR group (p=0.005). CONCLUSIONS: NLR predicts outcomes after LDLT for HCC via the inflammatory tumor microenvironment. Combined with the MC, NLR may be a new criterion for LDLT candidates with HCC. PMID- 22925813 TI - Human lymphocytes cultured in 3-D bioreactors: influence of configuration on metabolite transport and reactions. AB - Peripheral blood lymphocytes isolated from healthy human donors' buffy coat were cultured in membrane bio-reactors (MBR) designed in two different configurations: a conventional hollow-fiber (HF) bundle of modified polyetheretherketone (PEEK WC) arranged in parallel, and a cross-assembled PEEK-WC and polyethersulfone (PES) HF membranes having different structural properties. Both bioreactors were experimentally compared in terms of metabolic activity of cultured cells, monitored over 8 days with respect to glucose uptake rate (GUR) and lactate production rate (LPR), and mathematically modelled by Computational Fluid Dynamics (CFD) method in order to investigate the impact of geometrical configuration and transport properties of biomaterials. The almost uniform trend of GUR from day 2 to day 7 (average of 0.0497 +/- 0.0076 ng/h cell) and the low LPR (that decreased from an initial value of 2.92 +/- 0.0055 pg/h cell to practically zero at day 8) provided evidence for superior performance of crossed HFMBR in reproducing an optimal in vitro physiological environment with quite uniform concentration distribution of species in the extracellular space of the bioreactor and able to maintain lymphocyte viability and functions. The crossed HFMBR also resulted in an enhanced production of interleukin IL-2 over 8 days (average of 0.995 +/- 0.25 pg/h/Mcell) and IL-10 in the first 3 days (average of 6.46 +/- 0.28 pg/h/Mcell) which were up to one order of magnitude higher with respect to values measured in the parallel configuration. PMID- 22925814 TI - Cationic amphiphilic alpha-helical peptides for the treatment of carbapenem resistant Acinetobacter baumannii infection. AB - The emergence of multidrug-resistant Gram-negative bacteria, in particular Acinetobacter baumannii and Pseudomonas aeruginosa, is a critical clinical problem worldwide. Antimicrobial peptides (AMPs) have received increasing attention due to their ability to overcome multidrug-resistant microbes. We recently reported that cysteine-functionalized alpha-helical peptides LLKKLLKKC and CLLKKLLKKC effectively eradicated Gram-negative bacteria in vitro. In this study, the antibacterial properties of these peptides against carbapenem resistant clinical isolates of A. baumannii were studied both in vitro and in vivo. The minimum inhibitory concentrations (MICs) of the peptides against 20 clinical isolates of carbapenem-resistant A. baumannii were determined in comparison with imipenem. The results showed that the A. baumannii isolates were more susceptible to (LLKK)(2)C than to C(LLKK)(2)C in vitro, and 90% of the 20 tested strains had an MIC of lower than or equal to 36.8 and 63.1 MUmol/L, respectively. However, the bactericidal effect of C(LLKK)(2)C was much faster than that of (LLKK)(2)C. Furthermore, these peptides also showed excellent potency in mouse models of peritonitis and pneumonia infections caused by carbapenem-resistant A. baumannii. Importantly, both peptides had a high therapeutic index (>25), but caused no significant adverse effects on the liver and kidney functions and the balance of electrolytes in the blood. These peptides can be a promising alternative treatment modality to traditional antibiotics for nosocomial bacterial infections caused by multidrug-resistant Gram-negative bacteria, especially carbapenem-resistant A. baumannii. PMID- 22925815 TI - Inducing ossification in an engineered 3D scaffold-free living cartilage template. AB - Large and complex bone defects or voids cannot rely on natural bone healing process for recovery. They require natural or engineered grafts to facilitate osteo-progenitor cell recruitment and development. In this study, we have employed an in vitro macro-sized 3D cell-based platform for investigation and application of osteogenesis. The model is based on a porous construct made of engineered living cartilaginous tissue named living hyaline cartilaginous graft (LhCG). It is scaffold-free and is solely made up of living chondrocytes and their extra cellular matrix (ECM). To evaluate the efficiency of LhCG as a viable platform for bone formation, osteoblast and human mesenchymal stem cell (hMSC) were seeded respectively into LhCG constructs, establishing a co-culture system consisting of osteo-progenitors and chondrocytes. The results showed that LhCG could support both osteoblast and hMSC maturation and differentiation to the osteogenic lineage respectively. Successful osteogenesis is also observed after subcutaneous implantation in nude mice model suggesting that bone formation could be achieved both in vitro and in vivo. Additionally, with exposure to osteogenic medium, LhCG construct without any further cell seeding expressed similar levels of osteogenic phenotype markers as the ones with hMSC seeded on. It suggests the existence of an osteoprogenitor sub-population residing within LhCG chondrocytes. Hence, it is demonstrated that LhCG, as a cartilage template, could serve as a dynamic platform to support osteogenesis and its intrinsic phenotypic flexibility may also permit a wide range of applications for stem cell research and processing. PMID- 22925816 TI - Tyroserleutide-based gene vector for suppressing VEGF expression in cancer therapy. AB - A small interfering RNA (siRNA) plasmid DNA (pYr-1.1-hU6-EGFP-siVEGF) was constructed and used for suppressing vascular endothelial growth factor (VEGF) expression and inhibiting tumor growth. Then, a (tyrosyl-seryl-leucine) polyethyleneimine-poly(ethylene glycol) (YSL-PEI-PEG) conjugate was designed and synthesized as a gene carrier for the delivery of pYr-1.1-hU6-EGFP-siVEGF plasmid. The therapeutic peptide YSL was conjugated to PEI to improve the anti cancer efficiency, and the PEG chain was introduced to reduce the serum protein adsorption and improve the stability of the complex in the systemic circulation. It was found that YSL-PEI-PEG could efficiently condense plasmid DNA when the vector/DNA weight ratio was higher than 2. Compared with PEI 25 kDa, YSL-PEI-PEG exhibited higher transfection efficiency and lower cytotoxicity. More importantly, the results showed that the gene delivery system owned strong ability to inhibit cancer cell proliferation in vitro and tumor growth in vivo. YSL-PEI-PEG has great potential as a gene vector for clinical applications. PMID- 22925817 TI - The effect of post-cesarean rectal misoprostol on intestinal motility. AB - OBJECTIVE: To determine whether rectally administered misoprostol can induce intestinal motility compared with oxytocin infusion when used to prevent primary postpartum hemorrhage after cesarean delivery. METHODS: In a prospective randomized double-blind study in Nigeria, 218 parturients undergoing cesarean delivery who had risk factors for primary postpartum hemorrhage were enrolled between July 1, 2010, and March 31, 2011. Participants received 600 MUg of rectal misoprostol or 20 intravenous units of oxytocin for 4 hours after surgery. The primary outcome was time until passage of flatus. Adverse effects, need for additional analgesic, and length of hospital stay were also assessed. RESULTS: The misoprostol group had a significantly shorter mean postoperative interval to passage of flatus (20.27 +/- 7.77 hours versus 38.34 +/- 10.98 hours; P<0.001) and commencement of regular diet (21.08 +/- 7.69 hours versus 39.13 +/- 10.94 hours; P<0.001). Gastrointestinal adverse effects were more frequent, albeit not significantly, in the misoprostol group: nausea, 6.4% versus 1.8%; vomiting, 7.3% versus 2.8%; and abdominal distension, 3.7% versus 2.8%. The need for additional analgesic was the same in the 2 groups. CONCLUSION: After cesarean delivery, rectal misoprostol had the added benefit of inducing intestinal motility. Misoprostol might be considered in a clinical setting where postoperative ileus is anticipated. PMID- 22925818 TI - Experiences of women undergoing colposcopy in southeastern Nigeria. AB - OBJECTIVE: To evaluate the experiences, preferences, and needs of women undergoing colposcopy in southeastern Nigeria. METHODS: Women undergoing colposcopy at 2 centers in southeastern Nigeria between August 1, 2009, and October 31, 2011, were interviewed using structured interviewer-administered questionnaires. RESULTS: In total, 409 women were interviewed. The majority (60.8%) of these women were satisfied with the overall process of colposcopy. Invasion of privacy and re-assuring attitude of attending clinic personnel were reported as the most dissatisfying and most satisfying aspects of colposcopy, respectively. Privacy during the procedure and written take-home information were the most frequently reported needs. Most participants preferred a female colposcopist and the presence of their spouse during colposcopic examination. CONCLUSION: Southeastern Nigerian women are less satisfied with the overall process of colposcopy than their counterparts from high-income settings. The majority of the women interviewed would have an improved colposcopic experience if their privacy concerns and information needs were addressed and their spouses allowed into the examination room. The findings from the present study should encourage existing and emerging colposcopy service providers in low-resource settings to improve both service delivery and their patients' overall colposcopic experience. PMID- 22925819 TI - Prevalence of and risk factors for pelvic organ prolapse and lower urinary tract symptoms among women in rural Nepal. AB - OBJECTIVE: To evaluate the prevalence and associated risk factors of pelvic organ prolapse (POP) and lower urinary tract symptoms (LUTS) among women seeking healthcare services in 3 discrete rural areas in Nepal. METHODS: A cross sectional study was conducted using a Nepalese-specific questionnaire to obtain demographic and personal information. Urinary symptoms were examined using the Urogenital Distress Inventory Short form questionnaire, while POP severity was staged according to the POP-Q system. The chi(2) test and multivariate logistic regression analysis were used to determine POP risk factors. RESULTS: Of the 174 women included in the analysis, 106 (60.9%) had stage II POP or greater. In all, 93 women (53.4%) had cystocele, 63 (36.2%) had rectocele, and 37 (21.3%) had uterine prolapse. Univariate analysis identified high parity; young age at first delivery; menopause; squatting or standing position during delivery; and early return to work after delivery as risk factors for POP. Multivariate logistic regression revealed that delivery in a lying position presented a lower risk for cystocele than squatting or standing (odds ratio 0.34; P<0.01). CONCLUSION: Both LUTS and POP are common among women in rural Nepal. Cystocele is the most frequent, advanced, and symptomatic form of POP observed in this population. PMID- 22925820 TI - Use of early transverse annular compression sutures for complete placenta previa during cesarean delivery. AB - OBJECTIVE: To compare the difference in maternal outcomes between early and late use of transverse annular compression sutures (TACS) during cesarean delivery among women with complete placenta previa (CPP). METHODS: A retrospective study of 36 women with CPP was conducted. Percentiles of blood loss before TACS were calculated. The transfusion rate, sensitivity, specificity, Youden index, positive predictive value, and negative predictive value were also estimated. Patients were assigned to either the early TACS group or the late TACS group based on the highest Youden index. Maternal outcomes of the 2 groups were compared. RESULTS: The Youden index for transfusion rate was highest when blood loss before TACS reached 500 mL. Blood loss before intervention in the late TACS group was significantly higher than in the early TACS group (735.0 +/- 123.7 mL versus 396.9 +/- 76.3 mL; P<0.001). More women in the late TACS group than in the early TACS group required blood transfusion (60.0% versus 12.5%; P=0.004) and the volume of blood transfused was significantly lower in the early TACS group than in the late TACS group (137.5 +/- 377.5 mL versus 806.7 +/- 619.3 mL; P=0.001). CONCLUSION: Early implementation of TACS could lead to improved maternal outcomes. PMID- 22925822 TI - Investigation into the prevalence of coccidiosis and maduramycin drug resistance in chickens in China. AB - Coccidiosis is a parasitic disease that affects the poultry industry worldwide, having major economic impacts on poultry by reducing performance and decreasing productivity. This disease not only hinders the growth of chickens but also facilitates other epidemic diseases. Coccidiosis is mainly controlled by prophylactic coccidiostats administrated in the feed. However, the extensive use of these drugs has resulted in the development of drug resistance by Eimeria spp., which causes coccidiosis. The aim of the survey was to acquire data on the prevalence of coccidiosis and drug resistance of field isolates in chickens in China. We examined 545 farms across nine different geographic provinces over a 5 year period. These included Beijing, Sichuan, Zhejiang, Shandong, Guangdong, Fujian, Liaoning Provinces, Inner Mongolia and Xinjiang Uygur Autonomous Regions. The results indicated that oocyst per gram faeces (OPG) and coccidiosis morbidity rate increased when non-prophylactic or low doses of coccidiostats were used. Coccidiosis morbidity rate in Guangdong Province was the highest, leading to greater, more frequent use of diverse types of coccidiostats. Consequently, the Guangdong Province had the most serious drug resistance problem. In contrast, coccidiosis morbidity rates in Inner Mongolia, Fujian and Liaoning were relatively low, leading to a reduced level of coccidiostats use, which resulted in less drug resistance. The threshold of a coccidiosis outbreak was an OPG level of >20000. When the OPG levels were >= 50000, chickens were in danger of clinical coccidiosis, and here coccidia generated a certain degree of resistance to the drug when administered. Coccidiostat resistance started to appear when the OPG level reached ca. 20000 using 2 mg kg(-1)/5 mg kg(-1), respectively, of maduramycin, whereas 5 mg kg(-1) of maduramycin developed severe drug resistance. PMID- 22925823 TI - Mitochondrial DNA haplotype analysis of liver fluke in bison from Bialowieza Primaeval Forest indicates domestic cattle as the likely source of infection. AB - We have determined the mitochondrial genotype of liver fluke present in Bison (Bison bonasus) from the herd maintained in the Bialowieza National Park in order to determine the origin of the infection. Our results demonstrated that the infrapopulations present in the bison were genetically diverse and were likely to have been derived from the population present in local cattle. From a consideration of the genetic structure of the liver fluke infrapopulations we conclude that the provision of hay at feeding stations may be implicated in the transmission of this parasite to the bison. This information may be of relevance to the successful management of the herd. PMID- 22925824 TI - Peptide nucleic acids in materials science. AB - This review highlights the recent methods to prepare PNA-based materials through a combination of self-assembly and self-organization processes. The use of these methods allows easy and versatile preparation of structured hybrid materials showing specific recognition properties and unique physicochemical properties at the nano- and micro-scale levels displaying potential applications in several directions, ranging from sensors and microarrays to nanostructured devices for biochips. PMID- 22925826 TI - Quantitative trait loci for response to ethanol in an intercontinental set of recombinant inbred lines of Drosophila melanogaster. AB - Alcohol, a drug widely abused, impacts the central nervous system functioning of diverse organisms. The behavioral responses to acute alcohol exposure are remarkably similar among humans and fruit flies. In its natural environment, rich in fermentation products, the fruit fly Drosophila melanogaster encounters relatively high levels of ethanol. The effects of ethanol and its metabolites on Drosophila have been studied for decades, as a model for adaptive evolution. Although extensive work has been done for elucidating patterns of genetic variation, substantially less is known about the genomic regions or genes that underlie the genetic variation of this important trait. To identify regions containing genes involved in the responses to ethanol, we used a mapping population of recombinant inbred (RIL) lines to map quantitative trait loci (QTL) that affect variation in resistance and recovery from ethanol sedation in adults and ethanol resistance in larvae. We mapped fourteen QTL affecting the response to ethanol on the three chromosomes. Seven of the QTL influence the resistance to ethanol in adults, two QTL are related to ethanol-coma recovery in adults and five affect the survival to ethanol in larvae. Most of the QTL were trait specific, suggesting that overlapping but generally unique genetic architectures underlie each trait. Each QTL explained up to 16.8% of the genetic variance among lines. Potential candidate loci contained within our QTL regions were identified and analyzed. PMID- 22925825 TI - Harpalycin 2 inhibits the enzymatic and platelet aggregation activities of PrTX III, a D49 phospholipase A2 from Bothrops pirajai venom. AB - BACKGROUND: Harpalycin 2 (HP-2) is an isoflavone isolated from the leaves of Harpalyce brasiliana Benth., a snakeroot found in northeast region of Brazil and used in folk medicine to treat snakebite. Its leaves are said to be anti inflammatory. Secretory phospholipases A2 are important toxins found in snake venom and are structurally related to those found in inflammatory conditions in mammals, as in arthritis and atherosclerosis, and for this reason can be valuable tools for searching new anti-phospholipase A2 drugs. METHODS: HP-2 and piratoxin III (PrTX-III) were purified through chromatographic techniques. The effect of HP 2 in the enzymatic activity of PrTX-III was carried out using 4-nitro-3 octanoyloxy-benzoic acid as the substrate. PrTX-III induced platelet aggregation was inhibited by HP-2 when compared to aristolochic acid and p-bromophenacyl bromide (p-BPB). In an attempt to elucidate how HP-2 interacts with PrTX-III, mass spectrometry, circular dichroism and intrinsic fluorescence analysis were performed. Docking scores of the ligands (HP-2, aristolochic acid and p-BPB) using PrTX-III as target were also calculated. RESULTS: HP-2 inhibited the enzymatic activity of PrTX-III (IC50 11.34 +/- 0.28 MUg/mL) although it did not form a stable chemical complex in the active site, since mass spectrometry measurements showed no difference between native (13,837.34 Da) and HP-2 treated PrTX-III (13,856.12 Da). A structural analysis of PrTX-III after treatment with HP-2 showed a decrease in dimerization and a slight protein unfolding. In the platelet aggregation assay, HP-2 previously incubated with PrTX-III inhibited the aggregation when compared with untreated protein. PrTX-III chemical treated with aristolochic acid and p-BPB, two standard PLA2 inhibitors, showed low inhibitory effects when compared with the HP-2 treatment. Docking scores corroborated these results, showing higher affinity of HP-2 for the PrTX-III target (PDB code: 1GMZ) than aristolochic acid and p-BPB. HP-2 previous incubated with the platelets inhibits the aggregation induced by untreated PrTX-III as well as arachidonic acid. CONCLUSION: HP-2 changes the structure of PrTX-III, inhibiting the enzymatic activity of this enzyme. In addition, PrTX-III platelet aggregant activity was inhibited by treatment with HP-2, p-BPB and aristolochic acid, and these results were corroborated by docking scores. PMID- 22925827 TI - Ewing's sarcoma: analysis of single nucleotide polymorphism in the EWS gene. AB - We aimed to investigate single nucleotide polymorphisms (SNPs) in the EWS gene breaking region in order to analyze Ewing's sarcoma susceptibility. The SNPs were investigated in a healthy subject population and in Ewing's sarcoma patients from Southern Brazil. Genotyping was performed by TaqMan(r) assay for allelic discrimination using Real-Time PCR. The analysis of incidence of SNPs or different SNP-arrangements revealed a higher presence of homozygote TT-rs4820804 in Ewing's sarcoma patients (p=0.02; Chi Square Test). About 300 bp from the rs4820804 SNP lies a palindromic hexamer (5'-GCTAGC-3') and three nucleotides (GTC), which were previously identified to be in close vicinity of the breakpoint junction in both EWS and FLI1 genes. This DNA segment surrounding the rs4820804 SNP is likely to indicate a breakpoint region. If the T-rs4820804 allele predisposes a DNA fragment to breakage, homozygotes (TT-rs4820804) would have double the chance of having a chromosome break, increasing the chances for a translocation to occur. In conclusion, the TT-rs4820804 EWS genotype can be associated with Ewing's sarcoma and the SNP rs4820804 can be a candidate marker to understand Ewing's sarcoma susceptibility. PMID- 22925828 TI - Dynamic expression profiles of virus-responsive and putative antimicrobial peptide-encoding transcripts during Atlantic cod (Gadus morhua) embryonic and early larval development. AB - Early life stage mortality is one of the problems faced by Atlantic cod aquaculture. However, our understanding of immunity in early life stage fish is still incomplete, and the information available is restricted to a few species. In the present work we investigated the expression of immune-relevant transcripts in Atlantic cod during early development. The transcripts subjected to QPCR analysis in the present study were previously identified as putative anti-viral or anti-bacterial genes in Atlantic cod using suppression subtractive hybridization (SSH) libraries, QPCR, and/or microarrays. Of the 11 genes involved in this study, only atf3, cxc chemokine and gaduscidin-1 were not detected at the transcript level in all developmental stages investigated from unfertilized egg to early larval stage. Adam22, hamp, il8, irf1, irf7, lgp2, sacsin, and stat1 transcripts were detected in unfertilized egg and 7h post-fertilization (~2-cell stage) embryos, showing maternal contribution of these immune-relevant transcripts to the early embryonic transcriptome. The Atlantic cod genes included in this study presented diverse transcript expression profiles throughout embryonic and early larval development. For example, adam22 and sacsin transcripts rose abruptly during blastula/gastrula stage and were then expressed at relatively high levels through subsequent embryonic and early larval developmental stages. A peak in irf1 and irf7 transcript expression during early segmentation suggests that these interferon pathway genes play developmental stage-specific roles during cod embryogenesis. Stat1 had increasing transcript expression throughout blastula/gastrula, segmentation, and early larval developmental stages. Atf3, cxc chemokine, gaduscidin-1, and il8 transcripts rose approximately 2-3 fold during hatching, supporting the hypothesis that there is preparation at the immune-relevant transcript expression level to deal with environmental pathogens that may be encountered during early larval development. The specific roles that interferon pathway and other immune-relevant genes play in early life stage cod, and the potential impact of their dynamic transcript expression on immune competence of Atlantic cod embryos and larvae, remain unclear and warrant further study. PMID- 22925829 TI - Studies of naturally occurring friedelane triterpenoids as insulin sensitizers in the treatment type 2 diabetes mellitus. AB - Type 2 diabetes mellitus (T2DM) is a rapidly expanding public epidemic and frequently results in severe vascular complications. In an attempt to find anti diabetic agents, we report herein on the isolation, structural elucidation and bioactivity of nine friedelane-type triterpenes (1-9) and twenty two known ones (10-31) from the root barks of Celastrus vulcanicola and Maytenus jelskii. Their structures were elucidated on the basis of spectroscopic analysis, including 1D and 2D NMR techniques. Two compounds from this series (1 and 3) exhibited increased insulin-mediated signalling, which suggests these friedelane triterpenes have potential therapeutic use in insulin resistant states. PMID- 22925830 TI - Saponins from Astragalus hareftae (NAB.) SIRJ. AB - Four cycloartane- (hareftosides A-D) and oleanane-type triterpenoids (hareftoside E) were isolated from Astragalus hareftae along with fifteen known compounds. Structures of the compounds were established as 3,6-di-O-beta-D-xylopyranosyl 3beta,6alpha,16beta,24(S),25-pentahydroxycycloartane, 3,6,24-tri-O-beta-D xylopyranosyl-3beta,6alpha,16beta,24(S),25-pentahydroxycycloartane, 3-O-beta-D xylopyranosyl-3beta,6alpha,16beta,25-tetrahydroxy-20(R),25(S)-epoxycycloartane, 16-O-beta-D-glucopyranosyl-3beta,6alpha,16beta,25-tetrahydroxy-20(R),24(S) epoxycycloartane, 3-O-[beta-D-xylopyranosyl-(1->2)-O-beta-D-glucopyranosyl-(1->2) O-beta-D-glucuronopyranosyl]-soyasapogenol B by the extensive use of 1D- and 2D NMR experiments along with ESI-MS and HR-MS analyses. PMID- 22925831 TI - What's hAPPening at synapses? The role of amyloid beta-protein precursor and beta amyloid in neurological disorders. AB - Accumulating evidence suggests that dysregulated levels of amyloid beta-protein precursor (APP) and its catabolites contribute to the impaired synaptic plasticity and seizure incidence observed in several neurological disorders, including Alzheimer's disease, fragile X syndrome, Down's syndrome, autism, epilepsy and Parkinson's disease as well as in brain injury. This review article summarizes what is known regarding the synaptic synthesis, processing and function of APP and amyloid-beta (Abeta), as well as discusses how these proteins could contribute to the altered synaptic plasticity and pathology of the aforementioned disorders. In addition, APP and its proteolytic fragments are emerging as biomarkers for neurological health, and pharmacological interventions that modulate their levels, such as secretase inhibitors, passive immunotherapy against Abeta and mGluR5 antagonists, are reviewed. PMID- 22925832 TI - Pro-inflammatory cytokines as predictors of antidepressant effects of exercise in major depressive disorder. AB - Exercise is an efficacious treatment for major depressive disorder (MDD) and has independently been shown to have anti-inflammatory effects in non-depressed subjects. Patients with MDD have elevated inflammatory cytokines but it is not known if exercise affects inflammation in MDD patients and whether these changes are clinically relevant. In the TReatment with Exercise Augmentation for Depression (TREAD) study, participants who were partial responders to a selective serotonin reuptake inhibitor were randomized to receive one of two doses of exercise: 16 kilocalories per kilogram of body weight per week (KKW), or 4 KKW for 12 weeks. Blood samples were collected before initiation and again at the end of the 12-week exercise intervention. Serum was analyzed using a multiplexed ELISA for interferon-gamma (IFN-gamma), interleukin-1beta (IL-1beta), interleukin 6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha). Higher baseline levels of TNF-alpha were associated with greater decrease in depression symptoms over the 12-week exercise period (P<0.0001). In addition, a significant positive correlation between change in IL-1beta and change in depression symptom scores was observed (P=0.04). There were no significant changes in mean level of any cytokine following the 12-week intervention, and no significant relationship between exercise dose and change in mean cytokine level. Results suggest that high TNF-alpha may differentially predict better outcomes with exercise treatment as opposed to antidepressant medications for which high TNF-alpha is linked to poor response. Our results also confirm findings from studies of antidepressant medications that tie decreasing IL-1beta to positive depression treatment outcomes. PMID- 22925833 TI - Knockdown of the glucocorticoid receptor alters functional integration of newborn neurons in the adult hippocampus and impairs fear-motivated behavior. AB - Glucocorticoids (GCs) secreted after stress reduce adult hippocampal neurogenesis, a process that has been implicated in cognitive aspects of psychopathology, amongst others. Yet, the exact role of the GC receptor (GR), a key mediator of GC action, in regulating adult neurogenesis is largely unknown. Here, we show that GR knockdown, selectively in newborn cells of the hippocampal neurogenic niche, accelerates their neuronal differentiation and migration. Strikingly, GR knockdown induced ectopic positioning of a subset of the new granule cells, altered their dendritic complexity and increased their number of mature dendritic spines and mossy fiber boutons. Consistent with the increase in synaptic contacts, cells with GR knockdown exhibit increased basal excitability parallel to impaired contextual freezing during fear conditioning. Together, our data demonstrate a key role for the GR in newborn hippocampal cells in mediating their synaptic connectivity and structural as well as functional integration into mature hippocampal circuits involved in fear memory consolidation. PMID- 22925834 TI - Genome-wide profiling of multiple histone methylations in olfactory cells: further implications for cellular susceptibility to oxidative stress in schizophrenia. PMID- 22925835 TI - A 10 year (2000-2010) systematic review of interventions to improve quality of care in hospitals. AB - BACKGROUND: Against a backdrop of rising healthcare costs, variability in care provision and an increased emphasis on patient satisfaction, the need for effective interventions to improve quality of care has come to the fore. This is the first ten year (2000-2010) systematic review of interventions which sought to improve quality of care in a hospital setting. This review moves beyond a broad assessment of outcome significance levels and makes recommendations for future effective and accessible interventions. METHODS: Two researchers independently screened a total of 13,195 English language articles from the databases PsychInfo, Medline, PubMed, EmBase and CinNahl. There were 120 potentially relevant full text articles examined and 20 of those articles met the inclusion criteria. RESULTS: Included studies were heterogeneous in terms of approach and scientific rigour and varied in scope from small scale improvements for specific patient groups to large scale quality improvement programmes across multiple settings. Interventions were broadly categorised as either technical (n = 11) or interpersonal (n = 9). Technical interventions were in the main implemented by physicians and concentrated on improving care for patients with heart disease or pneumonia. Interpersonal interventions focused on patient satisfaction and tended to be implemented by nursing staff. Technical interventions had a tendency to achieve more substantial improvements in quality of care. CONCLUSIONS: The rigorous application of inclusion criteria to studies established that despite the very large volume of literature on quality of care improvements, there is a paucity of hospital interventions with a theoretically based design or implementation. The screening process established that intervention studies to date have largely failed to identify their position along the quality of care spectrum. It is suggested that this lack of theoretical grounding may partly explain the minimal transfer of health research to date into policy. It is recommended that future interventions are established within a theoretical framework and that selected quality of care outcomes are assessed using this framework. Future interventions to improve quality of care will be most effective when they use a collaborative approach, involve multidisciplinary teams, utilise available resources, involve physicians and recognise the unique requirements of each patient group. PMID- 22925836 TI - Source analysis reveals plasticity in the auditory cortex: evidence for reduced hemispheric asymmetries following unilateral deafness. AB - OBJECTIVE: To investigate the effect of acquired unilateral deafness on hemispheric asymmetries in adult humans using cortical auditory evoked potentials. METHODS: N1 cortical auditory evoked potentials were measured from 30 channels in 18 unilateral profoundly-deaf participants (6 right-sided and 12 left sided deafness) and 18 audiogram-matched controls. Stimuli were 0.5-kHz and 4-kHz tones presented monaurally, and the data were analysed using global field power and dipole source analysis. RESULTS: There was a statistically significant difference in dipole source strength and orientation between the two groups. Similar changes (increased dipole strength and more medial orientation) were apparent after profound unilateral deafness of either ear and for both stimuli. CONCLUSIONS: The results reveal evidence of central auditory system plasticity that is consistent with animal models having experimentally induced unilateral deafness. SIGNIFICANCE: The trend towards reduced hemispheric asymmetries was reflected in the dipole source model by changes in dipole strength, location and orientation. These findings may explain the inconsistencies reported in previous studies involving dipole source analysis where location and orientation have not always been considered. PMID- 22925837 TI - Diagnostic value of lumbar root stimulation at the early stage of Guillain-Barre syndrome. AB - OBJECTIVE: The aim of this study is to investigate diagnostic value of electrical lumbar root stimulation (RS) at the laminar level in the early stage of Guillain Barre syndrome (GBS). METHODS: Fifteen patients (30 sides) and nine controls (17 sides) were included in the study. Conventional nerve conduction studies, needle electromyography, F responses and electrical lumbar RS were obtained from both groups. The needle electrical stimulation was performed at the L2-3 intervertebral level. Vastus lateralis, tibialis anterior and soleus muscles were investigated bilaterally and simultaneously in the first and fourth weeks. RESULTS: In all patients, the amplitudes elicited by lumbar RS were significantly attenuated while the conventional electrophysiological findings were normal and/or not diagnostic in 6 of 15 patients (40%) within the first week. Motor latencies by the lumbar RS were prolonged in the patients, compared to the controls, but the results were not statistically significant. CONCLUSIONS: M responses elicited by lumbar RS appear to be helpful in disclosing proximal conduction abnormalities of GBS early in the course. SIGNIFICANCE: Lumbar RS seems to be a useful method in making the diagnosis of GBS early and there is no considerable side effect of this particular method. PMID- 22925838 TI - Fixation-off sensitivity. AB - Fixation-off sensitivity (FOS) is a phenomenon induced by elimination of central vision/fixation, and may either manifest clinically with seizures or only represent an EEG abnormality. FOS is characterized by posterior or generalized epileptiform discharges that consistently occur after closing of the eyes and last as long as the eyes are closed. It is most commonly encountered in patients with idiopathic childhood occipital epilepsies, but may also be observed in cases of symptomatic or cryptogenic focal and generalized epilepsies, as well as in asymptomatic non-epileptic individuals. FOS should be differentiated from pure forms of scotosensitivity, in which EEG discharges or epileptic seizures are elicited by darkness, and from epileptiform discharges triggered by eye closure, which refer to eye closure sensitivity. Although FOS is probably associated with occipital hyperexcitability its intrinsic epileptogenic potential is presumed to be low. PMID- 22925839 TI - Consciousness, biology and quantum hypotheses. AB - Natural phenomena are reducible to quantum events in principle, but quantum mechanics does not always provide the best level of analysis. The many-body problem, chaotic avalanches, materials properties, biological organisms, and weather systems are better addressed at higher levels. Animals are highly organized, goal-directed, adaptive, selectionist, information-preserving, functionally redundant, multicellular, quasi-autonomous, highly mobile, reproducing, dissipative systems that conserve many fundamental features over remarkably long periods of time at the species level. Animal brains consist of massive, layered networks of specialized signaling cells with 10,000 communication points per cell, and interacting up to 1000 Hz. Neurons begin to divide and differentiate very early in gestation, and continue to develop until middle age. Waking brains operate far from thermodynamic equilibrium under delicate homeostatic control, making them extremely sensitive to a range of physical and chemical stimuli, highly adaptive, and able to produce a remarkable range of goal-relevant actions. Consciousness is "a difference that makes a difference" at the level of massive neuronal interactions in the most parallel interactive anatomical structure of the mammalian brain, the cortico-thalamic (C T) system. Other brain structures are not established to result in direct conscious experiences, at least in humans. However, indirect extra-cortical influences on the C-T system are pervasive. Learning, brain plasticity and major life adaptations may require conscious cognition. While brains evolved over hundreds of millions of years, and individual brains grow over months, years and decades, conscious events appear to have a duty cycle of ~100 ms, fading after a few seconds. They can of course be refreshed by inner rehearsal, re visualization, or attending to recurrent stimulus sources. These very distinctive brain events are needed when animals seek out and cope with new, unpredictable and highly valued life events, such as evading predators, gathering critical information, seeking mates and hunting prey. Attentional selection of conscious events can be observed behaviorally in animals showing coordinated receptor orienting, flexible responding, alertness, emotional reactions, seeking, motivation and curiosity, as well as behavioral surprise and cortical and autonomic arousal. Brain events corresponding to attentional selection are prominent and widespread. Attention generally results in conscious experiences, which may be needed to recruit widespread processing resources in the brain. Many neuronal processes never become conscious, such as the balance system of the inner ear. An air traveler may "see" the passenger cabin tilt downward as the plane tilts to descend for a landing. That visual experience occurs even at night, when the traveler has no external frame of spatial reference. The passenger's body tilt with respect to gravity is detected unconsciously via the hair cells of the vestibular canals, which act as liquid accelerometers. However, that sensory activity is not experienced directly. It only becomes conscious via vision and the body senses. The vestibular sense is therefore quite different from visual perception, which "reports" accurately to a conscious field of experience, so that we can point accurately to a bright star on a dark night. Vestibular input is also precise but unconscious. Conscious cognition is therefore a distinct kind of brain event. Many of its features are well established, and must be accounted for by any adequate theory. No non-biological examples are known. Penrose and Hameroff have proposed that consciousness may be viewed as a fundamental problem in quantum physics. Specifically, their 'orchestrated objective reduction' (Orch-OR) hypothesis posits that conscious states arise from quantum computations in the microtubules of neurons. However, a number of microtubule-associated proteins are found in both plant and animal cells (like neurons) and plants are not generally considered to be conscious. Current quantum-level proposals do not explain the prominent empirical features of consciousness. Notably, they do not distinguish between closely matched conscious and unconscious brain events, as cognitive-biological theories must. About half of the human brain does not support conscious contents directly, yet neurons in these "unconscious" brain regions contain large numbers of microtubules. QM phenomena are famously observer-dependent, but to the best of our knowledge it has not been shown that they require a conscious observer, as opposed to a particle detector. Conscious humans cannot detect quantum events "as such" without the aid of special instrumentation. Instead, we categorize the wavelengths of light into conscious sensory events that neglect their quantum mechanical properties. In science the burden of proof is on the proposer, and this burden has not yet been met by quantum-level proposals. While in the future we may discover quantum effects that bear distinctively on conscious cognition 'as such,' we do not have such evidence today. PMID- 22925840 TI - A prospective, randomised trial of pneumothorax therapy: manual aspiration versus conventional chest tube drainage. AB - BACKGROUND: No consensus exists on the exact treatment of pneumothorax (PTX). Some guidelines are proposing manual aspiration (MA) to be preferred over tube thoracostomy (TT) in uncomplicated primary spontaneous pneumothorax (PSP). However, only a few studies reported a direct comparison of both methods. Our aim was to re-evaluate this with a randomised trial in a single centre in the Netherlands. METHODS: Patients with a first episode of symptomatic PTX admitted to the ER or asymptomatic PTX with a size of >=20% were recruited during 2007 2009 and followed-up for one year. Randomisation between MA and TT was balanced by a computer minimisation program for cause of PTX, smoking and gender. When first MA attempt failed, a second attempt was not undertaken and patients underwent TT. (registered at ClinicalTrials.gov (NCT00556335). RESULTS: 56 patients were included. Baseline characteristics were similar. Immediate success rates were 68.0% for MA versus 80.6% for TT (p = 0.28). Two week success rates were 100% in both groups. There was a significant difference in hospital stay in favour of MA: 2.4 +/- 2.6 versus 4.4 +/- 3.3 days (p = 0.02). One year recurrence rates in MA were lower than in TT, although not statistically significant (4.0% and 12.9% p = 0.37). Predictors of immediate success were traumatic PTX and female sex. One patient died during follow-up due to heart failure. CONCLUSION: MA is simple, safe, cheap, minimal invasive in uncomplicated PSP/traumatic PTX with similar success and recurrence rates and a shorter hospital stay in comparison to TT and therefore the treatment of choice. PMID- 22925841 TI - Sublethal dietary effects of microcystin producing Microcystis on threadfin shad, Dorosoma petenense. AB - The presence of the toxic cyanobacterium Microcystis in the upper San Francisco Estuary (SFE) since 1999 is a potential but unquantified threat to the health and survival of aquatic organisms such as fish and zooplankton. The microcystins (MCs) predominantly in the LR-form (MC-LR) produced by Microcystis is hepatotoxic and a potential threat to the fishery. Concurrently, in the SFE significant declines in pelagic fish, known as the Pelagic Organism Decline (POD), has been recognized by state and federal agencies since 2000. In 2005, the presence of the toxic algal bloom, Microcystis has been hypothesized as a link to the POD by the Interagency Ecology Program Management Team. This study aims to characterize the toxic effects of Microcystis in one of the POD species, threadfin shad (Dorosoma petenense) by exposure to diets containing Microcystis harvested from the SFE. The diets contained Microcystis with 4.4 (D5) and 10.0 (D10) MUg g-1 MC-LR that was fed to threadfin shad for 57 days. The treatments were compared to the control diet, 0 MUg g-1 MC-LR (D0). Results showed that ingested Microcystis was localized in the gut by in situ hybridization and MCs were localized in the tissues of the gut, kidney and liver. Condition factor (CF) and liver and gonadal lesions were sensitive to MC exposure. There was a significant inverse relationship between CF and MC-LR with exposed fish exhibiting severe cachexia. Liver lesions of sinusoidal congestion and glycogen depletion significantly increased with increasing MC-LR concentrations, indicating hemorrhaging in the liver and poor nutritional status, respectively. In females, there was a significant increase in severe ovarian necrosis with increasing MC-LR concentration, indicating loss of reproductive potential. The results indicate that MC-LR from Microcystis significantly impairs the health and reproductive potential of threadfin shad has a potential negative effect on populations in the SFE. PMID- 22925842 TI - Toxicity assessment of Amphidinium carterae, Coolia cfr. monotis and Ostreopsis cfr. ovata (Dinophyta) isolated from the northern Ionian Sea (Mediterranean Sea). AB - In many coastal areas the abundant proliferation of microalgae producing biotoxins determines the occurrence of Harmful Algal Blooms (HABs). Their presence in temperate waters is well documented and often associated with marine toxin-derived disease. The occurrence and toxicity of three harmful microalgae (Amphidinium carterae, Coolia cfr. monotis and Ostreopsis cfr. ovata) from the northern Ionian Sea (Mediterranean Sea) is hereby reported. The three dinoflagellates were sampled both on macroalgae and water and their morphology and occurrence were compared to those of other Mediterranean sites. The toxicity of the three cultured strains was tested by Artemia salina and hemolysis tests and their effects on the first stages of the sea urchin development was also evaluated. The contemporary presence of the three species inhibited the in vitro sea urchin embryonic development. But this action could be ascribed to the sole Ostreopsis as the addition of the single species to the sea urchins embryos evidenced no effects in presence of Amphidinium or Coolia cells, and an irregular segmentation in presence of Ostreopsis. In particular, this latter species exerted a cytotoxic effect in a dose-dependent manner, with a production of deformed embryos even at very low cell concentration (42 cells mL-1). Nevertheless, when algal cell lysate was added, some effects on the sea urchin development was detected for each dinoflagellate, and also in this case Ostreopsis has proved to be the most toxic species. However, the lysate of Amphidinium and Ostreopsis strongly affects the A. salina nauplii vitality, while the hemolytic activity was very low for Amphidinium and Coolia lysate and very strong for Ostreopsis. Our results highlight the importance to monitoring the presence of these dinoflagellates whose effects may also be reflected on the early life stages of marine organisms, especially those species that are important from both an ecological and economic point of view, as the sea urchins are. PMID- 22925843 TI - [Role of intravitreal bevacizumab for resistant macular edema due to central retinal vein occlusion after failure of intravitreal triamcinolone acetonide]. AB - PURPOSE: To evaluate the efficacy of bevacizumab injection used secondarily in patients with macular edema due to central retinal vein occlusion after failure of intravitreal triamcinolone acetonide injection. PATIENTS AND METHODS: The present study represents a retrospective review of eight patients presenting with central retinal vein occlusion complicated by macular edema with central foveolar thickness greater than 350 MUm by Cirrus-OCT, Zeiss. Between 4 and 6 months after the central vein occlusion, all patients initially underwent intravitreal triamcinolone acetonide injection (4 mg/0.1 ml). In the case of functional or anatomic failure, three monthly bevacizumab injections (1.25mg/0.05 ml) were administered. Prior to each injection, an ophthalmic examination was performed, documenting visual acuity (ETDRS), biomicroscopy, IOP and central foveolar thickness (OCT 3). RESULTS: After three intravitreal bevacizumab injections, we found no improvement in visual acuity (M0 = 45.56 +/- 13 letters; M3 = 44.2 +/- 8.6 letters), and no decrease in macular thickness (M0 = 559 MUm +/- 193; M3 = 543 MUm +/- 263). No intraocular pressure spikes or endophthalmitis were observed. DISCUSSION: The lack of anatomic and functional efficacy observed in our study does not appear to be related to the method, dosage or timing of injection, nor to the presence of subretinal macroaneurysms. It may be due to a cross-resistance to these two drugs. In any event, recent approval of ranibizumab and intraocular dexamethasone implants will likely change our therapeutic approach. CONCLUSION: In case of recalcitrant macular edema secondary to central vein occlusion after failed intravitreal triamcinolone acetonide injection, secondary intravitreal bevacizumab does not appear beneficial. PMID- 22925844 TI - [Infectious complications in patients treated with anti-TNF-alpha: two cases of leishmaniasis]. AB - We report the cases of two patients treated with anti-TNF-alpha for uveitis. The first patient developed visceral leishmaniasis and the second cutaneous leishmaniasis. FIRST CASE: an 8-year-old girl was treated with corticosteroids and intravenous infliximab for juvenile idiopathic arthritis with bilateral anterior uveitis. After 12 months of treatment, she presented with fever, hepatosplenomegaly and thrombocytopenia. Visceral leishmaniasis was diagnosed, and she was treated successfully with parenteral liposomal Amphotericin-B (Ambisome((r))). Upon resolution, we re-instituted her treatment with infliximab. Second case: a 48-year-old man consulted us for severe panuveitis of the left eye with a serous retinal detachment. He was diagnosed with seronegative ankylosing spondylitis. His uveitis and arthritis were treated successfully with infliximab for 20 months, after which two cutaneous lesions appeared. The diagnosis of cutaneous leishmaniasis without visceral involvement was based on the presence of Leishmania in the skin scraping of a lesion. Intravenous infusions of infliximab were discontinued, and local treatment consisting of intralesional injections of meglumine antimonate salts (Glucantime((r))) was initiated, leading to rapid improvement. Anti-TNFalpha drugs are used frequently now. They appear promising in terms of efficacy, but one must carefully monitor patients for possible side effects, including infection. PMID- 22925845 TI - [Filtering surgery in glaucoma: comparative study of three surgical approaches]. AB - INTRODUCTION: The multiple complications observed with trabeculectomy encouraged the re-emergence of non penetrating glaucoma surgery (NPGS) in the 1980's. Since then, several modifications have been developed in order to improve success rates and safety. We describe a new variation of deep sclerectomy (DS) in which we include an autologous corneal stromal implant soaked in mitomycin C and sutured to the scleral bed. Next, we compare intraocular pressure (IOP) at 2 years in three groups: I: DS; II: DS with autologous implant soaked in mitomycin C; III: conventional trabeculectomy. PATIENTS AND METHODS: All surgeries were performed by the same surgeon. There were 40, 22 and 15 eyes with medically uncontrolled primary open angle glaucoma (POAG) in groups I, II and III, respectively. All patients underwent the usual pre- and postoperative exams over 24 months. Selected patients underwent Visante OCT (Optical Coherence Tomography) (Carl Zeiss, Meditec, Inc. Germany) examination of their anterior segments. RESULT: Age and sex distribution in all three groups showed no statistical difference. Mean preoperative IOP was 24 +/- 11 mmHg, 26 +/- 14 mmHg and 25 +/- 9 mmHg in group I, II and III, respectively (P>0.8). Mean postoperative IOP was 14 +/- 3 mmHg, 10 +/ 3 mmHg and 13 +/- 4 mmHg (P=0.05) at six months; 16 +/- 4 mmHg, 13 +/- 3 mmHg and 11 +/- 4 mmHg (P=0.02) at 12 months; and 15 +/- 4 mmHg, 12 +/- 3 mmHg and 14 +/- 4 mmHg (P=0.2) at 24 months. Mean number of eye medications dropped from 1.85, 2.18 to 1.92 (P>0.05) preoperatively in group I, II, and III, respectively, to and 0.25, 0.05 to 0.18 (P=0.02) at 24 months. Patients with a visible implant under the bleb at 24 months had a better outcome. DISCUSSION: DS with autologous implant significantly reduced IOP at 12 and 24 months. The results seem better than those obtained with collagen implants, most likely due to the persistence of the corneal implant under the bleb at 2 years. Its non-resorption and the minimal fibrosis at the level of the scleral bed may be related to the fact that it is an autologous material which has been soaked with mitomycin C. CONCLUSION: DS with autologous implant soaked in mitomycin C, an inexpensive technique, demonstrates medium-term efficacy in the surgical management of POAG. Our results suggest that our technique may enhance both success rate and efficacy in lowering IOP. Further long-term studies are needed. PMID- 22925846 TI - [Focus on interstitial keratitis]. AB - Interstitial keratitis is a non-ulcerative, non-suppurative, more or less vascularized inflammation of the corneal stroma. The corneal lesions result from the host response to bacterial, viral or parasitic antigens, or from an autoimmune response in the absence of active corneal infection. The natural history of the disease is divided into two phases: acute and cicatricial. This type of keratitis, while less common than ulcerative bacterial keratitis, is not an insignificant cause of visual loss. It is associated with systemic or infectious disease. It thus requires prompt diagnosis and etiological work-up, as well as appropriate treatment to maximize visual prognosis and avoid other complications. The main causes are bacterial infections (syphilis), viruses (40% of cases), and idiopathic (33%). PMID- 22925847 TI - Examining social physique anxiety and disordered eating in college women. The roles of social comparison and body surveillance. AB - Social physique anxiety has been found to be associated with disordered eating. However, what is not yet known is what behaviors college women may engage in that strengthen this relation. In the current study, we examined two possible moderating factors, social comparison and body surveillance. We examined whether these moderators might also generalize to trait anxiety, as well. Participants were 265 women attending a Southeastern university. Social comparison (both general and appearance-related) and body surveillance were tested as moderators of the relation between social physique anxiety and disordered eating. Results indicated that general social comparison, appearance-related social comparison, and body surveillance significantly moderated this relation. Individuals who were high in social physique anxiety and who reported high levels of general or appearance-related social comparison or body surveillance reported much higher levels of disordered eating than those with high social physique anxiety and low levels of these behaviors. Results indicated that only the trait anxiety*body surveillance interaction was significant in identifying elevated disordered eating. Results provide information regarding who may experience high levels of disordered eating in association with social physique anxiety, which has clinical implications including the conceptualization of social comparison and body surveillance as safety behaviors. PMID- 22925848 TI - Death row nutrition. Curious conclusions of last meals. AB - The growing macabre fascination with "last meals" offers a window into one's true consumption desires when one's value of the future is discounted close to zero. But in contrast to popular anecdotes and individual case studies, we created an empirical catalog of actual last meals - the final food requests of 247 individuals executed in the United States during a recent five-year period. Our content analyses reveal three key findings: (1) the average last meal is calorically rich (2756 calories) and proportionally averages 2.5 times the daily recommended servings of protein and fat, (2) the most frequent requests are also calorie dense: meat (83.9%), fried food (67.9%), desserts (66.3%), and soft drinks (60.0%), and (3) 39.9% requested branded foods or beverages. These findings are respectfully consistent with a model of environmentally contingent temporal discounting, and they are consistent with studies of how food is used to mediate feelings of stress and distress. Given that some people who are warned about the ill effects of obesity might counterintuitively engage in unhealthy overconsumption, the findings also suggest further study relating to the artificial use of mortality salience in campaigns against obesity. PMID- 22925850 TI - Graduate nurses' perceptions of mismatches between themselves and their jobs and association with intent to leave employment: a longitudinal survey. AB - BACKGROUND: Graduate nurses experience mismatches between themselves and their jobs. One of these is the demands-abilities misfit, which is a mismatch between the abilities of employees and those required by a job (demands). Another is the supplies-needs misfit, which occurs when employees' work-specific needs are not fulfilled by opportunities (called environmental supplies) work can supply to reinforce them. OBJECTIVES: The aim of this study was to investigate how graduate nurses' perceptions of the demands-abilities and supplies-needs misfits changed over time, and to examine how these misfits impact their intention to leave the jobs. DESIGN: A longitudinal study design was used. SETTING: Five hospitals in the western region of Japan cooperated in the study. PARTICIPANTS: A total of 176 graduate nurses participated in the study one or more times. From among them, 150, 109, 102, and 96 graduates participated in the study conducted in the 3rd, 6th, 9th, and 12th months of the employment, respectively. In addition, 62 graduates participated in all studies. METHODS: Surveys were distributed to the graduates 3, 6, 9 and 12 months after their employment commenced. The results were analysed using multiple regression analysis. RESULTS: The results showed that the graduates perceived both demands-abilities and supplies-needs misfits, although the degree of the demands-abilities misfit became smaller towards the end of the graduate year. As for the impact on graduates' turnover intention, the graduates' abilities and their perception of the environmental supplies served as more significant predictors of their turnover intention, rather than the misfits per se. The variances of turnover intention explained by the supplies-needs variables were greater than those explained by the demands-abilities variables from the third to ninth months into the employment. On the other hand, the variance explained by the demands-abilities variables increased towards the end of the year, and finally exceeded that of the supplies-needs variables. CONCLUSIONS: The graduates' turnover intention is complex, and may not be explained by simple demands-abilities and supplies-needs misfits. Different factors influence their turnover intention at different times to different degrees. PMID- 22925849 TI - Synergistic relationship between the Columbia University Appetitive Behavior Seminar and the satiating effect of cholecystokinin. AB - Synergism between the Columbia University Appetitive Behavior Seminar and the research program of Smith and Gibbs on the satiating effect of cholecystokinin during the past 40 years is described. The Seminar was synergistic with the research program in five ways. First, the steady parade of speakers gave us a window on the varied and interesting work going on in the field. Second, the Seminar was the kind of audience for presentations of the work-in-progress on CCK that scientists hope for and rarely find. Criticism by members of the Seminar was relentless and constructive, and ideas for further experiments or new ways to tackle problematic data poured forth. Third, members of the Seminar did experiments that facilitated the experimental success of the research program. Fourth, members of the Seminar tutored us on topics that we wanted to import into the research program on CCK. Fifth, and probably most important, members of the Seminar gave us the encouragement, good humor, and friendship so necessary for coping with the struggles of the scientific life. PMID- 22925851 TI - Interactions of inorganic oxide nanoparticles with sewage biosolids. AB - The use of nanoparticles (NPs) in manufacturing continues to increase despite the growing concern over their potential environmental and health effects. Understanding the interaction of NPs and sewage sludge is crucial for determining the ultimate fate of NPs released to municipal wastewater treatment plants (WWTPs) as those interactions will determine whether the bulk of the material is retained in the sludge or released in the effluent stream. Analyzing the affinity of aluminum oxide, cerium oxide, and silicon oxide NPs, which are commonly used in semiconductor manufacturing processes, for biosolids used in municipal WWTPs provides a basis for estimating their removal efficiency. Batch studies were performed and the NPs were shown to partition onto the cellular surface. At the maximum equilibrium values tested (75-92 mg nanoparticles/L), the concentration of Al(2)O(3), CeO(2) and SiO(2) associated with the sludge was 137, 238, and 28 mg/g-sludge VSS, respectively. These results suggest that electrostatic interactions play a major role in determining NP association with biosolids. PMID- 22925852 TI - Odour emission ability (OEA) and its application in assessing odour removal efficiency. AB - Odourous emissions from sewer networks and wastewater treatment plants (WWTPs) can significantly impact a local population. Sampling techniques such as wind tunnels and flux hood chambers are traditionally used to collect area source samples for subsequent quantification of odour emission rates using dilution olfactometry, however these methods are unsuitable for assessing liquid samples from point sources due to the large liquid volumes required. To overcome this limitation, a gas phase sample preparation method was developed for assessing the total Odour Emission Ability (OEA) from a liquid sample. The method was validated using two volatile organic sulphur compounds (VOSCs), dimethyl-trisulphide (DMTS) and bismethylthiomethane (BMTM) that are frequently detected from sewers and WWTPs and are relatively stable compared with common VOSCs like mercaptan or methyl mercaptan. The recovery rates of DMTS and BMTM were quantified by injecting a known volume of a standard liquid sample into Tedlar bags using a static injection and a dynamic injection methodology. It was confirmed that both dynamic and static injection methods at ambient condition achieved high recovery rates with no need to consider increasing evaporation by elevating the temperature. This method can also be used to assess odour removal effectiveness of liquids by comparing the OEA before and after the treatment tests. Two application examples were presented. PMID- 22925853 TI - Anaerobic digestion of corn ethanol thin stillage in batch and by high-rate down flow fixed film reactors. AB - Thin stillage (CTS) from a dry-grind corn ethanol plant was evaluated as a carbon source for anaerobic digestion (AD) by batch and high rate semi-continuous down flow stationary fixed film (DSFF) reactors. Biochemical methane potential (BMP) assays were carried out with CTS concentrations ranging from approximately 2,460 27,172 mg total chemical oxygen demand (TCOD) per litre, achieved by diluting CTS with clean water or a combination of clean water and treated effluent. High TCOD, SCOD and volatile solids (VS) removal efficiencies of 85 +/- 2, 94 +/- 0 and 82 +/- 1% were achieved for CTS diluted with only clean water at an organic concentration of 21,177 mg TCOD per litre, with a methane yield of 0.30 L methane per gram TCOD(removed) at standard temperature and pressure (STP, 0 degrees C and 1 atmosphere). Batch studies investigating the use of treated effluent for dilution showed promising results. Continuous studies employed two mesophilic DSFF anaerobic digesters treating thin stillage, operated at hydraulic retention times (HRT) of 20, 14.3, 8.7, 6.3, 5 and 4.2 d. Successful digestion was achieved up to an organic loading rate (OLR) of approximately 7.4 g TCOD L(-1)d(-1) at a 5 d HRT with a yield of 2.05 LCH(4) L(-1)d(-1) (at STP) and TCOD and VS removal efficiencies of 89 +/- 3 and 85 +/- 3%, respectively. PMID- 22925854 TI - Biochemical methane potential (BMP) of agro-food wastes from the Cider Region (Spain). AB - An inventory of agro-food industry organic waste streams with a high potential for biogas transformation was studied in a logistically viable area (Cider Region, Asturias, Spain). Three industries were selected as the most viable ones: livestock, dairy and beverage. The potential for methane production from six wastes (beverage waste, BW; milled apple waste, MA; milk waste, MK; yogurt waste, YG; fats and oils from dairy wastewater treatment, F&O and cattle manure, CM) at five different substrate:inoculum ratios (0.25, 0.50, 0.75, 1.00 and 1.50) was evaluated in laboratory batch assays. Obtained methane yields ranged from 202-549 mL STP CH(4).g VS waste(-1), and the methane content in biogas ranged from 58 76%. The ultimate practical biochemical methane potentials were slightly affected by the substrate:inoculum ratio. The estimation of the regional fluxes of waste and methane potentials suggests anaerobic digestion as a sustainable solution for the valorization of the organic wastes generated in this Region. PMID- 22925855 TI - Removal of mercaptans from a gas stream using continuous adsorption-regeneration. AB - The removal of the mercaptan, 1-methyl-1-propanethiol, from aqueous solutions using a non-porous, electrically conducting carbon-based adsorbent (Nyex 1000) was investigated. The adsorption process was found to be rapid (equilibrium capacity achieved within 5 minutes) with low adsorptive capacity (of the order of 0.4 mg g(-1)) when compared with activated carbon. Electrochemical regeneration of the Nyex 1000 in a simple divided electrochemical cell within a sequential batch treatment unit restored 100% of the adsorbent's adsorptive capacity using treatment times as low as 20 minutes by passing a current of 0.5 A. The sorptive characteristics of a Nyex-water slurry were also modelled and investigated both in a bubble column and in a continuous adsorption-regeneration treatment system. It was demonstrated that the continuous removal-destruction system could achieve a step reduction in challenge gas concentration of approximately 75% for a period of 35 minutes with a current of 5 Amps. This was attributed to mass transfer enhanced by a combination of adsorption and chemical reaction with free chlorine species generated in the electrochemical process. PMID- 22925857 TI - The usability of digestate in organic farming. AB - As organic farming prohibits the use of synthetic fertilisers, animal slurries and manures must be used. Digestate offers an alternative to these and this study reports on three experiments conducted to determine its usability in terms of: (1) the effect on earthworm populations, (2) its fertilising effects on Italian Ryegrass and wild Creeping Thistle, and (3) the suppression effects digestate has on weed emergence. The results for digestate application to field plots were intermediate between slurry and no treatment for earthworm attraction and wild thistle suppression. In glasshouse trials it led to increased ryegrass growth compared with undigested slurry. Analysis showed that the digestate had improved nitrogen availability, leading to increased plant growth, but a reduced organic matter content compared with the slurry, leading to a positive though less beneficial impact on the earthworms. Digestate therefore provides a suitable fertiliser for organic farming. This suitability could be improved by drying or separation to increase the OM content making its properties closer to those of slurry whilst still retaining the higher content of plant available nitrogen. PMID- 22925856 TI - Removal of trace organic chemical contaminants by a membrane bioreactor. AB - Emerging wastewater treatment processes such as membrane bioreactors (MBRs) have attracted a significant amount of interest internationally due to their ability to produce high quality effluent suitable for water recycling. It is therefore important that their efficiency in removing hazardous trace organic contaminants be assessed. Accordingly, this study investigated the removal of trace organic chemical contaminants through a full-scale, package MBR in New South Wales, Australia. This study was unique in the context of MBR research because it characterised the removal of 48 trace organic chemical contaminants, which included steroidal hormones, xenoestrogens, pesticides, caffeine, pharmaceuticals and personal care products (PPCPs). Results showed that the removal of most trace organic chemical contaminants through the MBR was high (above 90%). However, amitriptyline, carbamazepine, diazepam, diclofenac, fluoxetine, gemfibrozil, omeprazole, sulphamethoxazole and trimethoprim were only partially removed through the MBR with the removal efficiencies of 24-68%. These are potential indicators for assessing MBR performance as these chemicals are usually sensitive to changes in the treatment systems. The trace organic chemical contaminants detected in the MBR permeate were 1 to 6 orders of magnitude lower than guideline values reported in the Australian Guidelines for Water Recycling. The outcomes of this study enhanced our understanding of the levels and removal of trace organic contaminants by MBRs. PMID- 22925858 TI - Biological oxidation of sulphides by microorganisms present in the scum layer of UASB reactors treating domestic wastewater. AB - This study aimed at the identification of microorganisms present in the scum layer of the settler compartment of upflow anaerobic sludge blanket (UASB) reactors, and to evaluate their role in the biological oxidation of sulphides. The experiments were conducted using scum samples taken from two pilot-scale UASB reactors, both treating domestic wastewater. Microorganisms similar to Beggiatoa sp., Thiotrix sp. and species of cyanobacteria were identified based on their morphology, and most of them have been shown to be capable of carrying out sulphur oxidation. Tests of biological oxidation of sulphides using scum and cultures of the cyanobacteria Phormidium and Pseudoanabaena showed a significant decrease in the concentrations of the sulphides, suggesting that the microorganisms present in the scum layer can play a role in the minimization of odour emissions. PMID- 22925859 TI - A strategy for reducing pollutants at source in order to obtain sustainable agricultural recycling of wastewater sludge. AB - The Swedish licensing system for wastewater sludge use in agriculture, REVAQ, sets challenges. These include a maximum nominal accumulation rate of 0.2%/year on farmland, for specified metals, to be reached by 2025. Here a model is suggested, and applied for the Gothenburg regional wastewater treatment plant, Gryaab, to quantify historic sludge quality improvements and necessary future development. Local sampling campaigns covering two decades show a substantial reduction of heavy metals and ecologically harmful organic substances (such as adsorbable organic halogens, nonylphenols, phthalates, naphthalenes and polycyclic aromatic hydrocarbons) from households and society at large. For the metals studied the historic mass flow reduction to sludge varies from 1 to 2%/year for mercury, zinc and copper to 15%/year for silver. Copper needs further reduction, involving water pipes and copper roofing. Silver is rare in soil, and significant reduction from already low levels is needed to reach the accumulation goal. Further reduction of other metals involves addressing storm- and drainage water entering the sewers and the sediments already in the sewers. Fulfilling the goals of REVAQ implies national and local measures affecting public and private stakeholders including property owners, the wastewater collection system, commercial businesses and legislating authorities. PMID- 22925860 TI - ADM1 performance using SS-OFMSW with non-acclimated inoculums. AB - This paper assesses the anaerobic digestion (AD) of the source-sorted organic fraction of municipal solid waste (SS-OFMSW). For this purpose, an experimental programme was implemented involving the operation and monitoring of two bench scale anaerobic digesters, continuously fed with SS-OFMSW. The mathematical model (ADM1) was then applied to simulate the process of AD of SS-OFMSW. While start-up of the digesters was relatively slow, re-inoculation with cattle manure with effluent dilution reduced the acclimation period and achieved better stability, accommodating a feeding rate at an OLR = 2.39 kg TVS m(-3) day(-1). The high recorded methane gas production rate, reaching (0.1-2.5 m(3) CH(4)/m(3) reactor day), confirms the excellent biodegradability of the type of waste used (SS OFMSW) and its suitability for AD. Satisfactory simulations of soluble chemical oxygen demand (COD), pH, and methane composition of biogas were obtained, whereas volatile fatty acid (VFA) concentrations in both reactors were over-predicted albeit capturing its general trend. PMID- 22925861 TI - Seasonally loaded waste stabilisation ponds: a novel application for intermittent discharge. AB - This research examined the use of a single facultative pond for treatment of an intermittent discharge from a UK campsite. The system was monitored over an 11 month period to determine the optimum time for discharge in terms of quality standards. The results showed that based on organic strength, discharge was possible in winter between November and March but February was the optimum to meet nutrient and suspended solids requirements. The pond showed rapid acclimatisation to the influent wastewater, with biochemical oxygen demand removal rates during the filling period of around 60 kg ha(-1) day(-1) and removal efficiencies of ~95% after maturation. The system proved simple to operate. A major design factor is the requirement for storage of net incoming precipitation, which may provide dilution of residual pollutants but requires additional system capacity. PMID- 22925862 TI - Enhancement of nitrate removal in synthetic groundwater using wheat rice stone. AB - To enhance the efficiency of nitrate removal from synthetic groundwater, wheat rice stone (WRS) and granular activated carbon (GAC) were employed as biofilm carriers for denitrification under different HRT (hydraulic retention time) and C/N ratios. Four different ratios of GAC to WRS (0, 0.5, 1.0, and 2.0) were investigated to determine the most appropriate ratio of GAC and WRS. The NO(3)(-) N, NO(2)(-)-N, COD levels and pH of the effluent were also investigated under various HRT and C/N ratios. The results showed that the column at a GAC/WRS ratio of 1.0 performed best under a C/N ratio of 0.9 and an HRT of 8 h, with 99% nitrate being removed. In addition, little nitrite accumulation and chemical oxygen demand (COD) were observed in effluent under these conditions. These results demonstrated that, with no addition of phosphor in the influent, the nitrate removal efficiency can be enhanced by WRS because WRS can leach trace elements and phosphor to promote the growth of bacteria. PMID- 22925863 TI - Biofiltration of H(2)S with reclaimed water as a nutrient/moisture source at loading rates from 10 to 300 g H(2)S m(-3) h(-1). AB - A biofilter was evaluated with two different media under field conditions using reclaimed water as a nutrient source. Evaluation with a single medium demonstrated that H(2)S could be efficiently removed at volumetric loading rates of up to 200 g H(2)S m(-3) h(-1). After an extended period of high loading rates, the performance began to deteriorate at loading rates greater than 150 g H(2)S m( 3) h(-1) possibly due to nutrient limitations. The reclaimed water served as a nutrient source even though the primary form of nitrogen was nitrate. The reclaimed water successfully supplied nutrients at the majority of loading rates observed in the study and this was verified by stoichiometric calculations. The biofilter was converted to a dual media filter and consistent performance was also observed with the dual media filter at loading rates up to 150 g H(2)S m(-3) h(-1). The biofilter was successfully operated at loading rates higher than previously reported under field conditions. The use of nitrate in reclaimed water as a nitrogen source was successful and demonstrated the potential to eliminate the need for a separate nutrient source at a water reclamation plant. PMID- 22925864 TI - Performance evaluation and effect of biogas circulation rate of a bubble column for biological desulfurization. AB - Biological desulfurization using a bubble column reactor was investigated in a continuous biogas treatment. Rapid biogas circulation between the digester and the bubble column for biological desulfurization was used to stimulate the gas liquid mass transfer of H(2)S. A positive correlation between the biogas circulation rate and H(2)S removal rate was observed. Moreover, the increase in the circulation rate stimulated the O(2) mass transfer, eventually translating into an increase in sulfate production from the oxidation of H(2)S. Throughout the continuous experiment, the reactor retained sufficient levels of sulfide oxidizing bacteria. A comparison of the results of the continuous biogas treatment and batch tests suggests that the gas-liquid mass transfer rate of H(2)S was the rate-limiting step in the biological desulfurization in the reactor, indicating that the mass transfer efficiency of H(2)S needs to be improved to enhance the desulfurization performance. PMID- 22925865 TI - Nutrient and trace element supply in anaerobic digestion plants and effect of trace element application. AB - To investigate process behaviour and process disturbances in anaerobic digestion (AD) plants, samples of more than 1500 main digesters were taken and concentrations of macro- and micronutrients as well as volatile fatty acids were analyzed. Out of these samples, 600 digesters using energy crops only and 80 digesters using waste substrates were selected to compare the chemical composition as a result of different substrate feeding. High variations in element concentrations were found in both groups. In 60 plants with low micronutrient levels, trace elements were added and process changes were observed. A significant decrease of volatile fatty acids and an increase in digester performance were measured after trace element application. Furthermore, an increase of bacterial biomass could be detected. PMID- 22925866 TI - Influence of photoperiod on carbon dioxide and methane emissions from two pilot scale stabilization ponds. AB - Greenhouse gas (GHG) emissions (CO(2), CH(4)) from pilot-scale algal and duckweed based ponds (ABP and DBP) were measured using the static chamber methodology. Daylight and nocturnal variations of GHG and wastewater characteristics (e.g. chemical oxygen demand (COD), pH) were determined via sampling campaigns during midday (12:30-15:30) and midnight (00:30-03:30) periods. The results showed that under daylight conditions in ABP median emissions were -232 mg CO(2) m(-2) d(-1) and 9.9 mg CH(4) m(-2) d(-1), and in DBP median emissions were -1,654.5 mg CO(2) m(-2) d(-1) and 71.4 mg CH(4) m(-2) d(-1), respectively. During nocturnal conditions ABP median emissions were 3,949.9 mg CO(2) m(-2) d(-1), 12.7 mg CH(4) m(-2) d(-1), and DBP median emissions were 5,116 mg CO(2) m(-2) d(-1), 195.2 mg CH(4) m(-2) d(-1), respectively. Once data measured during daylight were averaged together with nocturnal data the median emissions for ABP were 1,566.8 mg CO(2) m(-2) d(-1) and 72.1 mg CH(4) m(-2) d(-1), whilst for DBP they were 3,016.9 mg CO(2) m(-2) d(-) and 178.9 mg CH(4) m(-2) d(-1), respectively. These figures suggest that there were significant differences between CO(2) emissions measured during daylight and nocturnal periods (p < 0.05). This shows a sink-like behaviour for both ABP and DBP in the presence of solar light, which indicates the influence of photosynthesis in CO(2) emissions. On the other hand, the fluxes of CH(4) indicated that DBP and ABP behave as net sources of CH(4) during day and night, although higher emissions were observed from DBP. Overall, according to the compound average (daylight and nocturnal emissions) both ABP and DBP systems might be considered as net sources of GHG. PMID- 22925867 TI - Recent advances in structure and reactivity of dissolved organic matter: radiation chemistry of non-isolated natural organic matter and selected model compounds. AB - The importance of natural organic matter (NOM) as a source of carbon in natural waters, as the source of reactive oxygen species, or for the complications its presence causes in treatment of natural waters, is undeniable. Recent studies have also pointed to the major photochemical role of triplet excited state of natural organic matter in the environmental fate of pharmaceutical and personal care products (PPCPs) in waters. However, the characterization of NOM is problematic due to its complex molecular structure. One approach to better understand NOM chemistry is the use of model compounds. As the condensation of a plant's phenolic compounds leads to humification and the formation of NOM, a structurally broad group of nine phenolic compounds were selected as model compounds for this study. With methods used in the discipline of radiation chemistry, the oxidative chemistry and transient spectra of these phenols were studied. In addition, the oxidative chemistry and transient spectra of a sample of NOM from the Black River, North Carolina, USA, was characterized. This natural water sample was used as received and represents the first studies of non isolated NOM by pulsed radiolysis. The results of the transient spectra of the NOM revealed that the radical intermediates were very long lived. This phenomenon was not captured using the nine model compounds suggesting that more complex compounds are needed to further our understanding of the oxidation chemistry of NOM. PMID- 22925868 TI - Development of a horizontal subsurface flow modular constructed wetland for urban runoff treatment. AB - Constructed wetlands (CWs) are well recognized as having low construction and maintenance cost and low energy requirement. However, CW design has been mainly based on rule-of-thumb approaches. In this study, the efficiency of a modular horizontal subsurface flow (HSSF) CW using four different design schemes was investigated. Based on the results, the four systems have attained more than 90% removal of total suspended solids and more than 50% removal efficiency for total phosphorus, PO(4)-P and Zn. The planted system achieved higher pollutant removal rates than the unplanted system. In terms of media, bottom ash was more effective than woodchip in reducing the pollutants. Considering the flow length, optimum removal efficiency was achieved after passing the sedimentation tank and vertical media layer; with respect to depth, more pollutants were removed in the upper sand layer than in the lower gravel layer. This study recommended a surface area of 0.25 to 0.8% of catchment area for planted CW and 0.26 to 0.9% for unplanted CW using the 7.5 to 10 mm design rainfall. PMID- 22925870 TI - Measurement and mathematical modelling of nutrient level and water quality parameters. AB - Physico-chemical water quality parameters and nutrient levels such as water temperature, turbidity, saturated oxygen, dissolved oxygen, pH, chlorophyll-a, salinity, conductivity, total nitrogen and total phosphorus, were measured from April to September 2011 in the Karaj dam area, Iran. Total nitrogen in water was modelled using an artificial neural network system. In the proposed system, water temperature, depth, saturated oxygen, dissolved oxygen, pH, chlorophyll-a, salinity, turbidity and conductivity were considered as input data, and the total nitrogen in water was considered as output. The weights and biases for various systems were obtained by the quick propagation, batch back propagation, incremental back propagation, genetic and Levenberg-Marquardt algorithms. The proposed system uses 144 experimental data points; 70% of the experimental data are randomly selected for training the network and 30% of the data are used for testing. The best network topology was obtained as (9-5-1) using the quick propagation method with tangent transform function. The average absolute deviation percentages (AAD%) are 2.329 and 2.301 for training and testing processes, respectively. It is emphasized that the results of the artificial neural network (ANN) model are compatible with the experimental data. PMID- 22925869 TI - Biofiltration of hydrogen sulfide by Sulfolobus metallicus at high temperatures. AB - Biofiltration of reduced sulfur compounds such as hydrogen sulfide has been mainly applied to emissions at mild temperatures (25 to 35 degrees C). However, an important number of industrial gaseous emission containing sulfur compounds, from diverse industrial sectors (petroleum refinery, cellulose production, smelting, rendering plants and food industries) are emitted at temperatures over 50 degrees C. Most of the studies on thermophilic systems report that a higher elimination capacity can be obtained at elevated temperature, allowing the design of smaller equipment for the same loading rate than that required for removing the same load under mesophilic conditions. A biotrickling filter inoculated with Sulfolobus metallicus, which operates at three different residence times, 60, 80 and 120 s, and two different temperatures (45 and 55 degrees C) for treating H(2)S is reported. The input loads of H(2)S were progressively increased from 0 to 100 gS/m(3). The aim of this study was to determine the capacity and ability of S. metallicus to oxidize H(2)S at high temperatures. The better removal capacity of H(2)S obtained was 37.1 +/- 1.7 gS/m(3) h at 55 degrees C for a residence time of 120 s. The difference of the removal capacity of H(2)S between the two temperatures was 4 g/m(3) h on average of sulfur removal for the different residence times. PMID- 22925871 TI - Selective separation of Cr(III) and Fe(III) from liquid effluents using a chelating resin. AB - This study aimed to assess the selective separation of Cr(III) from Fe(III) from liquid solutions by using a chelating ion exchange resin, Diaion CR 11, from Mitsubishi Chemical Corporation, in the H(+) form. Equilibrium experiments with synthetic solutions of iron and chromium were carried out in batch mode. For both metals favorable adsorption isotherms were obtained, and the experimental data were well described by the Langmuir model. However, the resin exhibited higher affinity for iron than for chromium. The regeneration experiments revealed that, for both metals, HCl provided higher removal efficiencies than H(2)SO(4) and HNO(3). Moreover, precipitation with NaOH allows selectively separate chromium and iron to be stripped from the resin. Experiments in fixed bed operation were carried out to assess the dynamic behavior of the sorption of Cr(III) and Fe(III) into the tested resin by using synthetic and industrial solutions. The experiments with industrial effluent showed that the resin can remove low levels of contaminant transition metal ions, and thus the effluent can be purified for reuse of chromium during periods of 20-25 min. The resin regeneration was achieved with a sequential treatment with HCl and NaOH/H(2)O(2). High efficiencies were observed for both monocomponent and multicomponent systems. A global strategy for separating and recovering Cr(III) from an effluent that also contains Fe(III) is presented, involving the integration of ion exchange (saturation and regeneration phases) and precipitation processes. In conclusion, our approach demonstrates that efficient separation of chromium and iron is possible if ion exchange operation in a fixed bed configuration is optimized and combined with conventional processes such as precipitation. PMID- 22925872 TI - Water quality in a surface-flow constructed treatment wetland polishing tertiary effluent from a municipal wastewater treatment plant. AB - Constructed treatment wetlands (CTWs) are unique ecotechnologies that can sustainably treat a range of wastewaters. This study focused on a 0.23 ha vegetated surface-flow CTW polishing nitrate-rich (3-6 mg-N/L) tertiary effluent from a municipal wastewater treatment plant. Water quality was monitored longitudinally in the fall of 2009 and 2010. The CTW cooled water by from around 20 degrees C to <15 degrees C in both years. Longitudinal temperature profiles were successfully modeled using an energy balance approach (2009 R(2) = 0.69; 2010 R(2) = 0.92). The magnitude of key model fitting parameters, including albedo (0.1-0.2) and convective transfer coefficient (0.1-0.9 MJ/m(2) d degrees C), were within ranges reported in the literature. In both years, dissolved oxygen decreased through the wetland from 6-7 mg/L to 3-4 mg/L, yielding an oxygen mass consumption rate of 0.08-0.09 g/m(2) d. Longitudinal nitrate profiles were well represented by the P-k-C* model (2009 R(2) = 0.88; 2010 R(2) = 0.92). First order removal rates were 20.2 m/yr in 2009 and 29.0 m/yr in 2010 at a P value of 6.0. Levels of ammonia and total phosphorus increased negligibly through the wetland, remaining below 0.25 mg/L. This study shows that vegetated surface flow CTWs are well suited to cool and polish low-BOD nitrate-dominated tertiary effluents with little degradation of other water quality parameters of concern, including phosphorus and ammonia. PMID- 22925873 TI - Sediment dynamics in shallow Lake Markermeer, The Netherlands: field/laboratory surveys and first results for a 3-D suspended solids model. AB - In 2007/08, a study was undertaken on sediment dynamics in shallow Lake Markermeer, The Netherlands. Firstly, the sediment characteristics median grain size, mud content and loss on ignition showed a spatial as well as water depth related pattern indicating wind-induced sediment transport. Sediment dynamics were investigated in a sediment trap field survey at two stations. Sediment yields, virtually all coming from sediment resuspension, were significantly correlated with wind speeds. Resuspension rates for Lake Markermeer were very high, viz. ca. 1,000 g/m(2)day as an annual average, leading to high suspended solids (SS) contents, due to the large lake area and its shallowness (high 'Dynamic Ratio'). Sediment resuspension behaviour was further investigated in preliminary laboratory experiments using a 'micro-flume', applying increasing water currents onto five Lake Markermeer sediments. Resuspension showed a clear exponential behaviour. Finally, a 3-D model was set up for water quality and SS contents in Lake Markermeer; first results showed a good agreement between modelled and actual SS contents. Construction of artificial islands and dams will reduce wind fetches and may be expected to cause a substantial decrease in lake water turbidity. PMID- 22925874 TI - Volatilization of hydrogen sulfide from a quiescent surface. AB - Air-water mass transfer of hydrogen sulfide from a shallow tank with a quiescent surface under the influence of weak wind stress on the water surface was studied numerically using a two-dimensional model. The flow field in the tank was investigated using a computational code based on a finite volume, which is used to numerically solve momentum, mass and continuity conservation equations. The results show that water phase flow field is strongly dependent on the wind induced surface velocity and the aspect ratio of the tank. Based on the numerical study, the liquid-side mass transfer coefficient is correlated with Reynolds number (R(e)), tank aspect ratio (AR) and Schmidt number (S(c)). Overall mass transfer coefficient (K(L)) values extend further downstream as the R(e) number increases. PMID- 22925875 TI - A horizontal flow biofilm reactor (HFBR) technology for the removal of methane and hydrogen sulphide at low temperatures. AB - A novel horizontal flow biofilm reactor (HFBR) has been adapted and tested for its efficiency in treating hydrogen sulphide (H(2)S) and methane (CH(4)) gas. Six pilot-scale HFBR reactors were commissioned, three each treating CH(4) and H(2)S respectively. The reactors were operated at 10 degrees C, often typical of ambient temperatures in Ireland, and were simultaneously dosed with an air mixture containing the gas in question and with synthetic wastewater (SWW). Three reactors (HFBR 1, 2 and 3), treating an air mixture containing CH(4), were operated over three phases (Phases 1-3) lasting 180 days in total. During each phase the air mixture flow rate (AFR) and the plastic media top plan surface area (TPSA) loading rate to HFBR 1, 2 and 3 were 1.2 m(3)/m(3)/h and 0.6 m(3)/m(2) TPSA/h respectively. In Phase 1 the reactors were operated in triplicate and were loaded with 8.6 g CH(4)/m(3) reactor/h (4.3 g CH(4)/m(2) TPSA/h) and a synthetic wastewater (SWW) similar to domestic sewage at 10 degrees C. During Phase 2 (reactors also operated in triplicate) the effect of temperature on the reactor performance was examined. During Phase 3 the reactors were operated independently in order to examine the effects of omitting organic carbon and adding additional nitrogen in the form of nitrate-nitrogen (NO(3)-N), rather than ammonium-nitrogen (NH(4)-N). During Phase 3, CH(4) removal efficiencies (RE) of up to 92.8% were achieved at an empty bed retention time (EBRT) of 50 min, equating to a maximum removal of 8.0 g CH(4)/m(3) reactor/h. Three additional reactors (HFBR 4, 5 and 6) were used to treat an air mixture containing H(2)S and were loaded at an AFR of 15 m(3)/m(3) reactor/h (7.5 m(3)/m(2) TPSA/h) with an average H(2)S loading rate of 3.34 g H(2)S/m(3) reactor/h (1.67 g H(2)S/m(2) TPSA/h). After 50 days of operation, the RE reached 100% for all three reactors at an EBRT of 4 min. In each reactor, profile samples of biofilm, air and liquid were taken periodically from various regions of the HFBR. These allowed detailed description of removal processes and optimisation of the reactors by detailing changes in air, liquid and biofilm composition as air moved through the reactor. PMID- 22925876 TI - Participatory and decentralized water resources management: challenges and perspectives for the North Paraiba River Basin committee - Brazil. AB - The Brazilian Water Resources Policy (Law 9433/1997) establishes participatory and decentralized management, involving civil society, water users and governmental bodies, with the basin committees as the basis of this process. Fifteen years after its implementation, it is possible to perceive accomplishments, but, at the same time, there are some difficulties in regards to the operation of the basin committees in the country. Considering the North Paraiba River Basin - which is completely included in the State of Paraiba, Northeastern Brazil, and presents great social and economic importance for the state - this article analyzes the process of formation, installation and functioning of its Basin Committee (CBH-PB), focusing on its composition, the reasons for the mobilization and demobilization of its members, the intra relations between segments, and the inter-relations between the CBH-PB and other entities of the State Water Management System (the Water Executive Agency and the State Water Resources Council). The level of decentralization and the quality of participatory management (as it is being performed at the CBH-PB) are discussed and guidelines are suggested in order to allow greater effectiveness to the committee. PMID- 22925877 TI - Performance of a modified RBC system in simulated municipal wastewater treatment. AB - A new method based on rotating biological contactor (RBC) was employed for solving the problems of long hydraulic retention times (HRT) low specific surface area and organic loading rates (OLR) in conventional RBCs. The system showed its particular adsorption ability of microorganisms in the biofilm-attaching period. Microbes on the first cage were observed in comparison with the second one. Packing biodisc also had a good shock load tolerance. It was observed that the system performance improved at higher HRTs, while at the increased level of input OLR, the removal performance worsened slightly. The positive role of rotational speed in the treatment of municipal wastewater was more pronounced in the range of 10-12 rpm. Chemical oxygen demand (COD) removal rate achieved 94% under the optimal operating conditions, which were HRT of 1.5 h, rotational speed of 9.9 rpm. The modified RBC system is highly beneficial to engineering application for better system performance and lower energy consumption. PMID- 22925878 TI - Removal of volatile organic compounds by heterogeneous ozonation on microporous synthetic alumina silicate. AB - A hybrid process combining adsorption and ozonation was examined as an alternative treatment for odorous volatile organic compounds (VOCs). Methyl ethyl ketone (MEK) was chosen to study the influence of operating parameters. Two synthetic aluminosilicates (faujasite-Y and ZSM-5) were tested for adsorption and reactivity with ozone. The adsorption equilibrium measurement on both adsorbents showed that adsorption performance depends on temperature but is not sensitive to relative humidity, due to the hydrophobic properties of the materials. Adsorbed VOCs were oxidized at low temperature when ozonated flow was sent to the reactor. Regeneration of the fixed bed was achieved at the same time, releasing mainly CO(2) and H(2)O. Intermediates of oxidation, such as 2,3-butanedione and acetic acid, were identified, leading to incomplete mineralization. The influence of concentration and humidity are discussed. Four successive cycles were tested: after the first adsorption/ozonation cycle, the adsorption efficiency was not affected during subsequent cycles. These results show that the same sample of adsorbent can be used in the treatment process for a long time. Ozonation regeneration is a promising process for VOC removal. PMID- 22925879 TI - Removal of Cu(II) ions from aqueous solutions using N-carboxymethyl chitosan. AB - N-carboxymethyl chitosan (NCMC) was synthesized by reacting chitosan with chloroacetic acid in water under triethylamine (Et(3)N) as catalyst. The chemical structures of NCMC were characterized by Fourier transform infrared (FT-IR) and hydrogen-1 nuclear magnetic resonance ((1)H-NMR) spectroscopy and confirmed that carboxymethylation occurred on the amino groups. Samples of NCMC were used for removal of Cu(II) from aqueous solution. The effects of degree of substitution of NCMC, initial pH value and adsorption kinetics on the adsorption were studied. Adsorption experiments showed that NCMC has a high adsorption speed and high adsorption capacity for remove Cu(II) from aqueous solution. The adsorption kinetics data were best fitted with the pseudo-second-order model. The experimental equilibrium data of Cu(II) on the NCMC were both fitted to the Langmuir model and Freundlich model, which revealed that the maximum capacity for monolayer saturation was 147.93 mg/g. PMID- 22925880 TI - Estimating the recreational carrying capacity of a lowland river section. AB - Recreational boating represents a major human use of inland waters in many regions. However, boating tourism may affect the ecological integrity of surface waters in multiple ways. In particular, surface waves produced by boating may disturb freshwater invertebrates, such as interrupting the filtration activity of benthic mussels. As mussels may significantly contribute to self-purification, disturbance may have crucial impacts on water quality, and thus on water tourism. In this paper we calculate the carrying capacity of a river section for sustainable boating tourism based on the preservation of water quality. This approach is complemented by spatial and social approaches for carrying capacity estimates. The ecological carrying capacity significantly decreases with lower water levels during summer. Hence, the analysis of variables that influence the river's carrying capacity allows the formation of recommendations for management measures that integrate social, touristic and ecological aspects. PMID- 22925881 TI - Marital status, social capital and health locus of control: a population-based study. AB - OBJECTIVES: To investigate the association between marital status and lack of internal health locus of control (HLC), taking economic stress and trust into account. STUDY DESIGN: Cross-sectional study. METHODS: The public health survey Skane 2008 is a postal questionnaire study (55% participation rate). A random sample was invited to participate, and 28,198 individuals aged 18-80 years agreed. Logistic regression models were used to discern associations between marital status and lack of internal HLC. The multiple regression analyses included age, country of birth, education, economic stress and 'horizontal' trust. RESULTS: In total, 33.7% of the men and 31.8% of the women lacked internal HLC. After age-adjustments, the unmarried and divorced men and the widowed women displayed significantly higher odds ratios of lack of internal HLC. The significantly higher odds ratios only remained for unmarried men throughout the multiple analyses. In contrast, divorced women had significantly lower odds ratios of lack of internal HLC than married women after adjustments for economic stress. CONCLUSIONS: Health promotion regarding HLC and related behaviours should consider men and women who are not cohabiting. Health promotion should particularly consider unmarried men due to their higher propensity to lack internal HLC. The economic conditions and exposure to economic stress among widowed and divorced women should also be highlighted. PMID- 22925882 TI - Accuracy of a panel of 5 cerebrospinal fluid biomarkers in the differential diagnosis of patients with dementia and/or parkinsonian disorders. AB - OBJECTIVE: To assess the ability of 5 cerebrospinal fluid(CSF) biomarkers to differentiate between common dementia and parkinsonian disorders. DESIGN: A cross sectional, clinic-based study. PARTICIPANTS: Cerebrospinal fluid samples (N=453) were obtained from healthy individuals serving as controls and from patients with Parkinson disease (PD), PD with dementia(PDD), dementia with Lewy bodies (DLB), Alzheimer disease (AD), progressive supranuclear palsy(PSP), multiple system atrophy (MSA), or corticobasal degeneration (CBD). SETTING: Neurology and memory disorder clinics. MAIN OUTCOME MEASURES: Cerebrospinal fluid biomarker levels in relation to clinical diagnosis. RESULTS: Cerebrospinal fluid levels of -synuclein were decreased in patients with PD, PDD, DLB, and MSA but increased in patients with AD. Cerebrospinal fluid levels of alpha-amyloid 1-42 were decreased in DLB and even further decreased in AD. Cerebrospinal fluid levels of total tau and hyperphosphorylated tau were increased in AD. Multivariate analysis revealed that these biomarkers could differentiate AD from DLB and PDD with an area under the curve of 0.90, with -synuclein and total tau contributing most to the model. Cerebrospinal fluid levels of neurofilament light chain were substantially increased in atypical parkinsonian disorders (ie, PSP, MSA,and CBD), and multivariate analysis revealed that the level of neurofilament light chain alone could differentiate PD from atypical parkinsonian disorders, with an area under the curve of 0.93. CONCLUSIONS: Ascertainment of the -synuclein level in CSF somewhat improves the differential diagnosis of AD vs DLB and PDD when combined with established AD biomarkers.The level of neurofilament light chain alone may differentiate PD from atypical parkinsonian disorders. PMID- 22925883 TI - Anatomy of the biceps tendon: implications for restoring physiological length tension relation during biceps tenodesis with interference screw fixation. AB - PURPOSE: The purpose of this study was to characterize the normal length and diameter of the long head of the biceps tendon (BT) to provide guidelines for interference screw tenodesis. METHODS: Twenty-one cadaveric shoulders were dissected. The BT length was measured from its origin to the humeral head articular margin (AM), lower subscapularis, upper pectoralis major, musculotendinous junction of the biceps (MTJ), and lower pectoralis major (LPM). Tendon diameter was measured at levels corresponding to tenodesis: (1) at the AM, (2) suprapectorally, and (3) subpectorally. RESULTS: The mean tendon length was 24.9 mm from the origin to the AM, 56.1 mm to the lower subscapularis, 73.8 mm to the upper pectoralis major, 98.5 mm to the MTJ, and 118.4 mm to the LPM. The mean tendon diameter was 6.6 mm for tenodesis at the AM, 5.1 mm for suprapectoral tenodesis, and 5.3 mm for subpectoral tenodesis. During biceps tenodesis with interference screw fixation, restoring the normal length-tension relation of the BT depends on the site of tenodesis and the depth of the bone socket. At the AM, a 25-mm bone socket on average will maintain the length-tension relation. For tenodesis more distally, the length of tendon resection varies with bone socket length. Because the MTJ is above the LPM, subpectoral tenodesis should be performed proximal to the LPM. CONCLUSIONS: This study provides guidelines for restoring the normal length-tension relation during biceps tenodesis with interference screw fixation. The simplest way to restore this relation is with tenodesis adjacent to the humeral head AM and a bone socket of 25 mm in depth. For tenodesis at more distal locations, both the length of the BT and the depth of the bone socket must be considered. CLINICAL RELEVANCE: Information about the normal BT may be useful in preserving the physiological length-tension relation during biceps tenodesis. PMID- 22925884 TI - D-2-hydroxyglutarate produced by mutant IDH1 perturbs collagen maturation and basement membrane function. AB - Isocitrate dehydrogenase-1 (IDH1) R132 mutations occur in glioma, but their physiological significance is unknown. Here we describe the generation and characterization of brain-specific Idh1 R132H conditional knock-in (KI) mice. Idh1 mutation results in hemorrhage and perinatal lethality. Surprisingly, intracellular reactive oxygen species (ROS) are attenuated in Idh1-KI brain cells despite an apparent increase in the NADP(+)/NADPH ratio. Idh1-KI cells also show high levels of D-2-hydroxyglutarate (D2HG) that are associated with inhibited prolyl-hydroxylation of hypoxia-inducible transcription factor-1alpha (Hif1alpha) and up-regulated Hif1alpha target gene transcription. Intriguingly, D2HG also blocks prolyl-hydroxylation of collagen, causing a defect in collagen protein maturation. An endoplasmic reticulum (ER) stress response induced by the accumulation of immature collagens may account for the embryonic lethality of these mutants. Importantly, D2HG-mediated impairment of collagen maturation also led to basement membrane (BM) aberrations that could play a part in glioma progression. Our study presents strong in vivo evidence that the D2HG produced by the mutant Idh1 enzyme is responsible for the above effects. PMID- 22925885 TI - Control of mitochondrial structure and function by the Yorkie/YAP oncogenic pathway. AB - Mitochondrial structure and function are highly dynamic, but the potential roles for cell signaling pathways in influencing these properties are not fully understood. Reduced mitochondrial function has been shown to cause cell cycle arrest, and a direct role of signaling pathways in controlling mitochondrial function during development and disease is an active area of investigation. Here, we show that the conserved Yorkie/YAP signaling pathway implicated in the control of organ size also functions in the regulation of mitochondria in Drosophila as well as human cells. In Drosophila, activation of Yorkie causes direct transcriptional up-regulation of genes that regulate mitochondrial fusion, such as opa1-like (opa1) and mitochondria assembly regulatory factor (Marf), and results in fused mitochondria with dramatic reduction in reactive oxygen species (ROS) levels. When mitochondrial fusion is genetically attenuated, the Yorkie induced cell proliferation and tissue overgrowth are significantly suppressed. The function of Yorkie is conserved across evolution, as activation of YAP2 in human cell lines causes increased mitochondrial fusion. Thus, mitochondrial fusion is an essential and direct target of the Yorkie/YAP pathway in the regulation of organ size control during development and could play a similar role in the genesis of cancer. PMID- 22925886 TI - Non-canonical microRNAs miR-320 and miR-702 promote proliferation in Dgcr8 deficient embryonic stem cells. AB - MicroRNAs are known to contribute significantly to stem cell phenotype by post transcriptionally regulating gene expression. Most of our knowledge of microRNAs comes from the study of canonical microRNAs that require two sequential cleavages by the Drosha/Dgcr8 heterodimer and Dicer to generate mature products. In contrast, non-canonical microRNAs bypass the cleavage by the Drosha/Dgcr8 heterodimer within the nucleus but still require cytoplasmic cleavage by Dicer. The function of non-canonical microRNAs in embryonic stem cells (ESCs) remains obscure. It has been hypothesized that non-canonical microRNAs have important roles in ESCs based upon the phenotypes of ESC lines that lack these specific classes of microRNAs; Dicer-deficient ESCs lacking both canonical and non canonical microRNAs have much more severe proliferation defect than Dgcr8 deficient ESCs lacking only canonical microRNAs. Using these cell lines, we identified two non-canonical microRNAs, miR-320 and miR-702, that promote proliferation of Dgcr8-deficient ESCs by releasing them from G1 arrest. This is accomplished by targeting the 3'-untranslated regions of the cell cycle inhibitors p57 and p21 and thereby inhibiting their expression. This is the first report of the crucial role of non-canonical microRNAs in ESCs. PMID- 22925887 TI - CpG site-specific alteration of hydroxymethylcytosine to methylcytosine beyond DNA replication. AB - Hydroxymethylcytosines (hmC), one of several reported cytosine modifications, was recently found to be enriched in embryonic stem cells and neuronal cells, and thought to play an important role in regulating gene expression and cell specification. However, unlike methylcytosines (mC), the fate of hmC beyond DNA replication is not well understood. Here, to monitor the status of hmC during DNA replication, we prepared a stable episomal vector-based monitoring system called MoCEV in 293T cells. The MoCEV system containing fully hydroxymethylated-cytosine fragments revealed a significant modification towards mC after several rounds of DNA replication. Strikingly this modification was specifically observed at the CpG sites (71.9% of cytosines), whereas only 1.1% of modified cytosines were detected at the non-CpG sites. Since the unmodified MoCEV did not undergo any DNA methylation during cell division, the results strongly suggest that somatic cells undergo hmC to mC specifically at the CpG sites during cell division. PMID- 22925888 TI - Inhibition of tumor cell growth by Sigma1 ligand mediated translational repression. AB - Treatment with sigma1 receptor (Sigma1) ligands can inhibit cell proliferation in vitro and tumor growth in vivo. However, the cellular pathways engaged in response to Sigma1 ligand treatment that contribute to these outcomes remain largely undefined. Here, we show that treatment with putative antagonists of Sigma1 decreases cell mass. This effect corresponds with repressed cap-dependent translation initiation in multiple breast and prostate cancer cell lines. Sigma1 antagonist treatment suppresses phosphorylation of translational regulator proteins p70S6K, S6, and 4E-BP1. RNAi-mediated knockdown of Sigma1 also results in translational repression, consistent with the effects of antagonist treatment. Sigma1 antagonist mediated translational repression and decreased cell size are both reversible. Together, these data reveal a role for Sigma1 in tumor cell protein synthesis, and demonstrate that small molecule Sigma1 ligands can be used as modulators of protein translation. PMID- 22925889 TI - Dissection of the Plasmodium vivax reticulocyte binding-like proteins (PvRBPs). AB - Human malaria, which is caused by infection with Plasmodium, is a serious global public health problem. The erythrocytic stages are responsible for all of the symptoms and pathologies associated with malaria. Compared with Plasmodium falciparum merozoites infected human erythrocytes, Plasmodium vivax merozoites primarily invade reticulocytes. Due to the recent availability of the P. vivax genomic and transcriptomic datasets, the P. vivax reticulocyte binding-like proteins (PvRBPs) have been updated. However, the precise roles of PvRBPs remain largely unknown. Thus, here we discuss advances in our knowledge of the molecular interactions involved in erythrocyte invasion by Plasmodium merozoites, focusing particularly on PvRBP1 and PvRBP2. We also discuss potential PvRBP receptors during reticulocyte invasion. PMID- 22925890 TI - Mechanisms of ascorbic acid stimulation of norepinephrine synthesis in neuronal cells. AB - Ascorbic acid is well known to acutely stimulate norepinephrine synthesis in neurosecretory cells, but it has also been shown over several days to increase tyrosine hydroxylase mRNA and norepinephrine synthesis in cultured neurons. Since tyrosine hydroxylase is the rate-limiting step in catecholamine synthesis, an effect of ascorbate to increase tyrosine hydroxylase protein could contribute to its ability to increase or sustain catecholamine synthesis. Therefore, we evaluated whether tyrosine hydroxylase protein expression and function is increased in SH-SY5Y neuroblastoma cells by physiologically relevant intracellular ascorbate concentrations. SH-SY5Y neuroblastoma cells did not contain ascorbate and had only very low levels of norepinephrine in culture with L-tyrosine, the substrate for tyrosine hydroxylase. However, treatment of cells with ascorbate for 6 h or more markedly increased norepinephrine synthesis, such that intracellular ascorbate and norepinephrine increased in parallel with half maximal intracellular concentrations of about 1 mM ascorbate and 150 MUM norepinephrine. This increase was enhanced by supplementing tetrahydrobiopterin, but was not mimicked by several antioxidants or by catalase or superoxide dismutase. Tyrosine hydroxylase protein expression increased at intracellular ascorbate concentrations above 1.5 mM. This contributed to norepinephrine generation, which was decreased 50-60% by inhibition of protein synthesis with cycloheximide at high intracellular ascorbate. These results suggest that expected physiologic neuronal ascorbate concentrations enhance norepinephrine synthesis both by maintaining tetrahydrobiopterin and increasing tyrosine hydroxylase expression. PMID- 22925891 TI - A conserved C-terminal motif is essential for self-interaction of Barley stripe mosaic virus China strain TGB3 protein. AB - The triple gene block (TGB) 3 protein is essential for the cell-to-cell movement of Barley stripe mosaic virus (BSMV). Previous studies have shown that TGB3, together with TGB2, facilitates the movement of TGB1 to the plasma membrane. However, the interactions among the three proteins (i.e., TGB3, TGB1, and TGB2) have not been thoroughly understood. The interactions of BSMV China strain (BSMV CH) TGB3 with itself and with other two TGB proteins were investigated using a Gal4-based yeast two-hybrid system and pull-down assays. The results show that neither TGB1 nor TGB2 interacts with TGB3. However, self-interaction was detected for TGB3. The C-terminal 37 amino acids (amino acids 87-123) containing a conserved C-terminal motif were found required for the self-interaction of TGB3. The roles of the novel property of BSMV-CH TGB3 in virus cell-to-cell movement were discussed. PMID- 22925893 TI - M-channels modulate the intrinsic excitability and synaptic responses of layer 2/3 pyramidal neurons in auditory cortex. AB - Neurons in the auditory cortex are believed to utilize temporal patterns of neural activity to accurately process auditory information but the intrinsic neuronal mechanism underlying the control of auditory neural activity is not known. The slowly activating, persistent K(+) channel, also called M-channel that belongs to the Kv7 family, is already known to be important in regulating subthreshold neural excitability and synaptic summation in neocortical and hippocampal pyramidal neurons. However, its functional role in the primary auditory cortex (A1) has never been characterized. In this study, we investigated the roles of M-channels on neuronal excitability, short-term plasticity, and synaptic summation of A1 layer 2/3 regular spiking pyramidal neurons with whole cell current-clamp recordings in vitro. We found that blocking M-channels with a selective M-channel blocker, XE991, significantly increased neural excitability of A1 layer 2/3 pyramidal neurons. Furthermore, M-channels controled synaptic responses of intralaminar-evoked excitatory postsynaptic potentials (EPSPs); XE991 significantly increased EPSP amplitude, decreased the rate of short-term depression, and increased the synaptic summation. These results suggest that M channels are involved in controlling spike output patterns and synaptic responses of A1 layer 2/3 pyramidal neurons, which would have important implications in auditory information processing. PMID- 22925892 TI - Mice carrying a complete deletion of the talin2 coding sequence are viable and fertile. AB - Mice homozygous for several Tln2 gene targeted alleles are viable and fertile. Here we show that although the expression of talin2 protein is drastically reduced in muscle from these mice, other tissues continue to express talin2 albeit at reduced levels. We therefore generated a Tln2 allele lacking the entire coding sequence (Tln2(cd)). Tln2(cd/cd) mice were viable and fertile, and the genotypes of Tln2(cd/+) intercrosses were at the expected Mendelian ratio. Tln2(cd/cd) mice showed no major difference in body mass or the weight of the major organs compared to wild-type, although they displayed a mildly dystrophic phenotype. Moreover, Tln2(cd/cd) mouse embryo fibroblasts showed no obvious defects in cell adhesion, migration or proliferation. However, the number of Tln2(cd/cd) pups surviving to adulthood was variable suggesting that such mice have an underlying defect. PMID- 22925894 TI - Probiotics promote endocytic allergen degradation in gut epithelial cells. AB - BACKGROUND AND AIMS: Epithelial barrier dysfunction plays a critical role in the pathogenesis of allergic diseases; the mechanism is to be further understood. The ubiquitin E3 ligase A20 (A20) plays a role in the endocytic protein degradation in the cells. This study aims to elucidate the role of A20 in the maintenance of gut epithelial barrier function. METHODS: Gut epithelial cell line, HT-29 cell, was cultured into monolayers to evaluate the barrier function in transwells. RNA interference was employed to knock down the A20 gene in HT-29 cells to test the role of A20 in the maintenance of epithelial barrier function. Probiotic derived proteins were extracted from the culture supernatants using to enhance the expression of A20 in HT-29 cells. RESULTS: The results showed that the knockdown of A20 compromised the epithelial barrier function in HT-29 monolayers, mainly increased the intracellular permeability. The fusion of endosome/lysosome was disturbed in the A20-deficient HT-29 cells. Allergens collected from the transwell basal chambers of A20-deficient HT-29 monolayers still conserved functional antigenicity. Treating with probiotic derived proteins increased the expression of A20 in HT-29 cells and promote the barrier function. CONCLUSION: A20 plays an important role in the maintenance of epithelial barrier function as shown by HT-29 monolayer. Probiotic derived protein increases the expression of A20 and promote the HT-29 monolayer barrier function. PMID- 22925895 TI - New fluorescent reagents specific for Ca(2+)-binding proteins. AB - Ca(2+) carries information pivotal to cell life and death via its interactions with specific binding sites in a protein. We previously developed a novel photoreactive reagent, azido ruthenium (AzRu), which strongly inhibits Ca(2+) dependent activities. Here, we synthesized new fluorescent ruthenium-based reagents containing FITC or EITC, FITC-Ru and EITC-Ru. These reagents were purified, characterized and found to specifically interact with and markedly inhibit Ca(2+)-dependent activities but not the activity of Ca(2+)-independent reactions. In contrast to many reagents that serve as probes for Ca(2+), FITC-Ru and EITC-Ru are the first fluorescent divalent cation analogs to be synthesized and characterized that specifically bind to Ca(2+)-binding proteins and inhibit their activity. Such reagents will assist in characterizing Ca(2+)-binding proteins, thereby facilitating better understanding of the function of Ca(2+) as a key bio-regulator. PMID- 22925896 TI - WT1 CpG islands methylation in human lung cancer: a pilot study. AB - BACKGROUND: CpG island hypermethylation of gene promoters and regulatory regions is a well-known mechanism of epigenetic silencing of tumor suppressors and is directly linked to carcinogenesis. Wilm's tumor gene (WT1) is a tumor suppressor protein involved in the regulation of human cell growth and differentiation and a modulator of oncogenic K Ras signaling in lung cancer. Changes in the pattern of methylation of the WT1 gene have not yet been studied in detail in human lung cancer. In this study we compared the methylation profile of WT1 gene in samples of neoplastic and non-neoplastic lung tissue taken from the same patients. METHODS: DNA was extracted from neoplastic and normal lung tissue obtained from 16 patients with non small cell lung cancer (NSCLC). The methylation status of 29 CpG islands in the 5' region of WT1 was determined by pyrosequencing. Statistical analysis was carried out by T test and Mann Whitney test. RESULTS: The mean percentage of methylation, considering all CpG islands of WT1 in the neoplastic tissues of the 16 NSCLC patients, was 16.2 +/- 3.4, whereas in the normal lung tissue from the same patients it was 5.6 +/- 1.7 (p < 0.001). Adenocarcinomas presented higher methylation levels than squamous cell carcinomas (p < 0,001). CONCLUSIONS: Methylation of WT1 gene is significantly increased in NSCLC. Both histotype and exposure to cigarette smoke heavily influence the pattern of CpG islands which undergo hypermethylation. PMID- 22925897 TI - [Candida glabrata : pathogenicity and therapy update]. AB - Chronic recurrent vulvovaginal candidiasis caused by Candida glabrata is still rare in comparison to C. albicans infection, but therapy remains more difficult. Standard agents as fluconazole or itraconazole often fail, as well as the newer systemic triazoles like voriconazole or posaconazole. Micafungin is a new echinocandin drug with a wide antifungal spectrum including rare Candida species. No clinical trials with micafungin in chronic recurrent vulvovaginal candidiasis have been undertaken. We present the initial results employing a new therapy regimen consisting of micafungin in combination with topical ciclopirox olamine. All 14 patients with chronic recurrent vulvovaginal candidiasis caused by C. glabrata were treated successfully. PMID- 22925898 TI - The RanBP2/RanGAP1*SUMO1/Ubc9 complex: a multisubunit E3 ligase at the intersection of sumoylation and the RanGTPase cycle. AB - Posttranslational modification of proteins with SUMO and the RanGTP/GDP cycle are two essential cellular mechanisms contributing directly or indirectly to almost every cellular event. The SUMO E3 ligase RanBP2 (Nup358) and the Ran GTPase activating protein (RanGAP1) are known to form a stable complex throughout the cell cycle suggesting a link between sumoylation of proteins and RanGTP hydrolysis. In a recent study we demonstrated that the stable complex of RanBP2, sumoylated RanGAP1 and Ubc9 (and not RanBP2 by itself) represents the physiologically relevant form of the SUMO ligase. Characterization of the interactions reveals an intricate proximity of two catalytic activities, sumoylation and RanGTP hydrolysis. In this ExtraView we summarize our results and discuss some ideas about a potential coupling of both processes. PMID- 22925899 TI - Removal of imidazolium ionic liquids by microbial associations: study of the biodegradability and kinetics. AB - The aim of this study was to estimate the biodegradability of the selected imidazolium ionic liquids and to determine the kinetic parameters for the biological treatment of wastewater containing these ionic liquids. Biodegradability was evaluated with the help of the Organisation for Economic Co operation and Development (OECD) tests, while oxygen uptake rate (OUR) tests were made in order to calculate the values of Monod kinetic parameters. The results obtained from both types of the tests showed that ionic liquids of chemical structure of 1-alkyl-3-methyl imidazolium bromide were poorly biodegradable and co-biodegradable compounds, although their biodegradability increased with the elongation of the alkyl chain length. At the same time the presence of the imidazolium-based ionic liquids in wastewater at concentration of 50 mg l(-1) did not inhibit biomass growth as well as did not decrease the affinity of substrate to biomass. The values of both Monod kinetic parameters, i.e., maximum specific growth rate (MU(max)) and half saturation constant (K(S)), increased with the increase in chain length of the alkyl substituent. PMID- 22925900 TI - Enhanced bio-ethanol production from cellulosic materials by semi-simultaneous saccharification and fermentation using high temperature resistant Saccharomyces cerevisiae TJ14. AB - The capability of multi-stress-tolerant Saccharomyces cerevisiae diploid strain TJ14 for the production of cellulosic bio-ethanol by semi-simultaneous saccharification and fermentation (SSSF) technology was evaluated under high temperature conditions. At 39 degrees C, the TJ14 produced 45 g/l ethanol by SSSF of 100 g (w/v)/l cellulose - a significantly higher concentration than reported in prevailing literature. PMID- 22925901 TI - Aggregation analysis of pharmaceutical human immunoglobulin preparations using size-exclusion chromatography and analytical ultracentrifugation sedimentation velocity. AB - In the pharmaceutical industry, analysis of soluble aggregates in pharmaceutical formulations is most commonly performed using size-exclusion chromatography (SEC). However, owing to concerns that aggregates can be overlooked by SEC analysis, it has been suggested that its results should be confirmed with orthogonal methods. One of the main alternative methods for SEC is analytical ultracentrifugation sedimentation velocity (AUC-SV), which has been indicated as an important tool for the measurement of protein aggregation. The present study aimed to show that AUC-SV can be effectively applied for the characterization of marketed immunoglobulin pharmaceutical preparations to support the results obtained by SEC. In addition, the present research aimed to assess the appropriateness of two integration approaches for the quantitative analysis of the SEC results. Thus, the aggregates were measured in seven different preparations of human immunoglobulins by AUC-SV and SEC, and the acquired chromatographic data were processed by using either the vertical drop method or the Gaussian skim approach, implemented in the Empower II chromatography data software (Waters, Tokyo, Japan). The results of aggregation measurements performed using AUC-SV were in good agreement with those obtained using SEC. As expected, the Gaussian skim integration approach inherently provided lower estimates of aggregation content than the results of the vertical drop method. The finding of this study confirmed the complementary nature of AUC-SV to SEC for aggregate composition analysis and underscored the important role that the different integration methods can play in the quantitative interpretation of chromatographic results. PMID- 22925903 TI - Micelle enhanced and terbium sensitized spectrofluorimetric determination of danofloxacin in milk using molecularly imprinted solid phase extraction. AB - An efficient molecularly imprinted solid phase extraction (MISPE) spectrofluorimetric method was developed to sensitively determine danofloxacin (DAN) in milk samples. Solid phase extraction procedure using MISPE cartridges was first performed on milk samples and then spectrofluorimetric determination was done at 546 nm using an excitation wavelength of 285 nm in presence of terbium and sodium dodecyl benzene sulfonate (SDBS). It was found that SDBS significantly enhanced the fluorescence intensity of the DAN-Tb(3+) complex. Various factors affecting the fluorescence intensity of DAN-Tb(3+)-SDBS system were studied and conditions were optimized. The enhanced fluorescence intensity of the system (DeltaF) showed a good linear relationship with the concentration of DAN over the range of 8.4*10(-9)-3.4*10(-7) mol L(-1) with a correlation coefficient of 0.9996. The detection limit was determined as 2.0*10(-9) mol L(-1) and the limit of quantification was determined as 6.5*10(-9) mol L(-1). The MISPE spectrofluorimetric procedure was successfully applied to the determination of DAN in milk samples. The method is simple, rapid, sensitive and allows interference free determination of DAN in complex fluorescent matrices like milk. The method can be used to determine whether the DAN residues in milk exceed MRLs or not. PMID- 22925904 TI - Gamma ray effects on optical properties of CoS nanoparticles. AB - In this work, cobalt sulfide nanoparticles powder was synthesized in AlMCM-41 molecular sieve by using ion exchange method. The influence of gamma ray radiation on the structural and optical properties of CoS/AlMCM-41 nanoparticles has been studied. Sample was irradiated by (60)Co and (137)Cs gamma ray source. The sample was characterized by X-ray diffraction (XRD), UV-Vis spectroscopy, scanning electron microscopy (SEM), FT-IR techniques and transmission electron microscopy (TEM). The XRD patterns show that nanoparticles size is increased after gamma radiation. The DRS results show that Co(2+) ions produced after gamma radiation, located in tetrahedral sites in AlMCM-41. The results indicate host materials have important role in decrease of radiation defects (RDs). The gamma ray creates free radicals and forms new bonds in CoSAlMCM-41 sample. PMID- 22925905 TI - Functionalized ZnS quantum dots as luminescent probes for detection of amino acids. AB - In this work, L-cysteine capped-ZnS quantum dots were synthesized in aqueous medium, and their interaction with some of the amino acids was studied with fluorescence spectra. The results demonstrated that histidine could effectively quench the Quantum dots emission more than other amino acids. Electron transfer process between the capping ligands and histidine was mainly responsible for the remarkable quenching effect of histidine, because according to the structure of histidine, it is the strongest acceptor among essential amino acids. Under optimum conditions, the quenched fluorescence intensity increased linearly with the concentration of histidine ranging from 1.33*10(-6) to 1.49*10(-4) mol L(-1). The limit of detection for histidine was 0.05*10(-7) mol L(-1). PMID- 22925902 TI - Detection of cancer-specific epigenomic changes in biofluids: powerful tools in biomarker discovery and application. AB - The genetic and epigenetic material originating from tumour that can be found in body fluids of individuals with cancer harbours tumour-specific alterations and represents an attractive target for biomarker discovery. Epigenetic changes (DNA methylation, histone modifications and non-coding RNAs) are present ubiquitously in virtually all types of human malignancies and may appear in early cancer development, and thus they provide particularly attractive markers with broad applications in diagnostics. In addition, because changes in the epigenome may constitute a signature of specific exposure to certain risk factors, they have the potential to serve as highly specific biomarkers for risk assessment. While reliable detection of cancer-specific epigenetic changes has proven to be technically challenging, a substantial progress has been made in developing the methodologies that allow an efficient and sensitive detection of epigenomic changes using the material originating from body fluids. In this review we discuss the application of epigenomics as a tool for biomarker research, with the focus on the analysis of DNA methylation in biofluids. PMID- 22925906 TI - Optical studies on electron beam evaporated lithium triborate films. AB - Lithium triborate (LB3) has numerous applications in scintillator for neutron detection, laser weapon and communication. LB3 films have been prepared by electron beam evaporation technique under a pressure of 1*10(-5) mbar on glass substrate at 323 K for 4 min. The crystallographic orientations and the lattice parameters (a=8.55 (2); b=5.09 (2); c=7.39 (2)A) were determined by powder XRD indicating the (111) preferential orientation of the film. The lower cut off wavelength at 325 nm with 75% transparency was measured from the UV-vis spectrum. The optical constants extinction coefficient (K), reflectance (R), the linear refractive index (1.34) and the optical energy band gap (~4.0 eV) were estimated. The photoluminescence spectrum shows the emission peak in the visible region with low concentration of oxygen defects. LB3 is found to be second harmonic generation (SHG) active using a Q-switched Nd:YAG laser (1064 nm, 9 ns, 10 Hz). The nonlinear refractive index (n(2)~10(-16) cm(2)/W) and nonlinear absorption coefficient (beta~10(-2) cm/W) reveal (Z-scan technique) that the material has negative nonlinearity and self-focusing nature. PMID- 22925907 TI - Synthesis and structural characterization of Pd(N,N-dimethylaminopropylamine)Cl2 complex--the interaction with bio-relevant ligands with reference to the effect of cysteine on the deactivation of metal-based drug. AB - The synthesis and X-ray structural characterization of Pd(DMPA)Cl(2) complex, where DMPA=N,N-dimethylaminopropylamine, is reported. The complex crystallizes in the space group P2(1)/c, a=8.8923(4), b=10.9050(5), c=11.5006(7) A, beta=120.00(18) degrees , V=948.25(8) A(3), Z=4. The palladium centre has a typical square-planar geometry with a tetrahedral distortion. Stoichiometry and stability constants of the complexes formed between [Pd(DMPA)(H(2)O)(2)](2+) and some selected DNA constituents and cytsteine are investigated at 25 degrees C and at constant 0.1M ionic strength. The concentration distribution diagrams of the various species formed are evaluated. The equilibrium constants for the displacement of coordinated ligands as inosine by cysteine are calculated. The results are expected to contribute to the chemistry of tumour therapy. PMID- 22925908 TI - Influence of substituent on UV absorption and keto-enol tautomerism equilibrium of dibenzoylmethane derivatives. AB - UV absorption spectra of dibenzoylmethane and its 23 derivatives with acetamide, tert-butyl, chloride, fluoride, hydroxyl, methyl, methoxy and nitro substituents in aromatic rings were collected. General influence of substituent on absorption maxima and absorption intensity was defined. Hyperchromic effects were observed for diketones with electron-donating groups in para postion. The keto-enol tautomerism equilibrium constant of obtained compounds was investigated with (1)H NMR spectroscopy. Significant changes of equilibrium were observed only for ortho substituted compounds. Results revealed dissimilarity of substituent effects on absorption and keto-enol tautomerism of aromatic beta-diketones. PMID- 22925909 TI - SERS activity studies of Ag/Au bimetallic films prepared by galvanic replacement. AB - Ag films on Si substrates were fabricated by immersion plating, which served as sacrificial materials for preparation of Ag/Au bimetallic films by galvanic replacement method. SEM images displayed that the sacrificial Ag films presenting island morphology experienced interesting structural evolution process during galvanic replacement reaction, and nano-scaled holes were formed in the resultant bimetallic films. SERS measurements using crystal violet as an analyte showed that SERS intensities of bimetallic films were enhanced significantly compared with that of pure Ag films and related mechanisms were discussed. Immersion plating experiment carried out on Ag films on PEN substrates fabricated by photoinduced reduction method further confirmed that galvanic replacement is an easy method to fabricate Ag/Au bimetallic and a potential approach to improve the SERS performance of Ag films. PMID- 22925910 TI - Optical, thermal and dielectric properties of Sr(II)-doped bis(thiourea)zinc(II) chloride crystals. AB - The influence of strontium doping on the properties of bis(thiourea)zinc(II) chloride (BTZC) crystals has been described. The reduction in the intensity observed in powder X-ray diffraction of doped specimen and slight shifts in vibrational frequencies confirm the lattice stress as a result of doping. The incorporation of Sr(II) into the crystal lattice was confirmed by energy dispersive X-ray spectroscopy (EDS). Surface morphological changes due to doping of the alkaline earth metal are observed by scanning electron microscopy (SEM). The crystal is transparent in the entire visible region having a lower optical cut-off at ~308 nm with a band gap energy of 4.06 eV. The DSC studies reveal the purity of the materials and no decomposition is observed up to the melting point. Dielectric studies show that the isovalent ion Sr(II)-doping altered the dielectric properties of the host crystal. PMID- 22925911 TI - The borate mineral jeremejevite Al6(BO3)5(F,OH)3--a vibrational spectroscopic study. AB - Jeremejevite is a borate mineral of aluminium and is of variable colour, making the mineral and important inexpensive jewel. The mineral contains variable amounts of F and OH, depending on origin. A comparison of the vibrational spectroscopic data is made with the published data of borate minerals. Raman spectra were averaged over a range of crystal orientations. Two intense Raman bands observed at 961 and 1067 cm(-1) are assigned to the symmetric stretching and antisymmetric stretching modes of trigonal boron. Infrared spectrum, bands observed at 1229, 1304, 1350, 1388 and 1448 cm(-1) are attributed to BOH in-plane bending modes. Intense Raman band found at 372 cm(-1) with other bands of significant intensity at 327 and 417 cm(-1) is assigned to trigonal borate bending modes. A quite intense Raman band is found at 3673 cm(-1) with other sharp Raman bands found at 3521, 3625 and 3703 cm(-1) are assigned to the stretching modes of OH. Raman and infrared spectroscopy has been used to assess the molecular structure of the mineral jeremejevite. Such research is important in the study of borate based nanomaterials. PMID- 22925912 TI - Vibrational analysis of the conformers and understanding the genesis of the internal rotational barriers of Isobutyl Cyanide molecule. AB - Molecular structure and conformational properties of Isobutyl Cyanide (IBCN) have been studied by quantum chemical methods. The quantum chemical methods predict the existence of both the Trans-Gauche (TG) and Gauche-Gauche (GG) rotameric forms of the IBCN molecule. Fresh vibrational assignments corresponding to each of the 39 normal modes are proposed for both the TG and GG rotameric forms of the molecule. The origin of the internal rotational barrier of the TG form of the molecule has been studied by the relaxation effects and with the aid of nuclear virial and natural bond orbital (NBO) analyses technique. For the barrier to internal rotation of the methyl CH(3) (I)/CH(3) (II) groups of the TG form of the IBCN molecule; the combined relaxations of the C(2)-C(3)/C(2)-C(4) bond lengths and H(10)-C(3)-H(11)/C(2)-C(4)-H(13) angles together play a significant role. PMID- 22925913 TI - Electronic spectral studies of some fluorescent probes: a comparison of two approaches. AB - Schiff base derivatives were synthesized and characterized by NMR spectra, mass and CHN analysis. The fluorescence properties of these dyes are strongly solvent dependent and the wavelength of maximum fluorescence emission shifts to red. The Kamlet-Taft and Catalan's solvent scales were found to be the most suitable for describing the solvatochromic shifts of the absorption and fluorescence emission. From the NMR chemical shifts and DFT studies, it was found that the azomethine hydrogen is anti to the amine aryl ring i.e., these dyes exist in anti conformation. DFT calculation was also carried out to determine the orientation of hydroxyl group in more stabilized minimum energy conformation. PMID- 22925914 TI - Synthesis and characterization of homotrimetallic copper complexes derived from bis(2-hydroxy-1-naphthaldehyde)oxaloyldihydrazone. AB - Copper (II) complexes [Cu(3)(nph)(MU(2)-X)(2)(H(2)O)(6)].2H(2)O [X=Cl (1), (ClO(4)) (3)] and [Cu(3)(nph)(NO(3))(2)(H(2)O)(6)] (2) have been synthesized from bis(2-hydroxy-1-naphthaldehyde)oxaloyldihydrazone in methanol medium and characterized. The structures of the complexes have been discussed in the light of data obtained from analytical, thermoanalytical, mass spectral studies, molar conductance, magnetic moment, electronic, EPR, IR, FT-IR spectroscopic studies. The molar conductance values for the complexes fall in the region 0.5-0.9 Sm(2) mol(-1) in DMSO solution indicating that all of them are non-electrolyte. The magnetic moment values for the complexes suggest weak M-M interaction in the structural unit of the complexes. The dihydrazone ligand is present in enol form in all of the complexes. Copper centre has tetragonally distorted octahedral stereochemistry in chlorido and perchlorato complexes while in nitrato complex, copper has mixed square-pyramidal and distorted-octahedral stereochemistry. The EPR parameters of the complexes indicate that the copper centre has the doublet state as the ground state. PMID- 22925915 TI - Temperature effect on the SERS signature of p-aminothiophenol: a new evidence for the production of p,p'-dimercaptoazobenzene on metallic nanostructures. AB - We investigated the effect of the temperature of the plasmonic substrate on the surface enhanced Raman scattering of p-aminothiophenol adsorbed onto a particulate film of gold nanoparticles-decorated polystyrene nanospheres. The results demonstrated that temperature induces important modifications in the overall spectral signature of the charge transfer bands, which are consistent with the generation of a new molecular species. Moreover, the analysis of the shape of the vibrational band at 1078 cm(-1) assigned to the >C-S mode, which is enhanced by electromagnetic mechanism, reveals the co-existence of two distinct bands at 1071 and 1078 cm(-1), assignable to p,p'-dimercaptoazobenzene and p aminothiophenol, respectively. PMID- 22925916 TI - Vibrational spectroscopic studies of triethoxy(4-(trifluoromethyl)-phenyl) silane and its sol-gel coating. AB - We have prepared a silica sol-gel using triethoxy (4-(trifluoromethyl)-phenyl) silane (TETFMPS) as a precursor in ethanol solution under acidic condition. The prepared sol-gel was applied to the surface treatment of aluminum for corrosion prevention. Infrared and Raman spectra of the silane coupling agent, sol-gel and sol-gel films on metal have been collected. Infrared spectroscopy has been used to study the thermal effect on the chemical composition of xerogel. Results suggested that TETFMPS molecule has a C(s) point group symmetry with the plane of reflection orthogonal to the phenyl ring and the organic part of the sol-gel film remains essentially unchanged at or below 450 degrees C but decomposes at or above 550 degrees C. After the decomposition of the organic branch, the remaining film is composed of silica. Vibrational assignments were suggested by using the collected spectroscopic data in different states along with the group vibrational frequencies and other related references. PMID- 22925917 TI - Misperception of aspect ratio in binocularly viewed surfaces. AB - The horizontal-vertical illusion, in which the vertical dimension is overestimated relative to the horizontal direction, has been explained in terms of the statistical relationship between the lengths of lines in the world, and the lengths of their projections onto the retina (Howe & Purves, 2002). The current study shows that this illusion affects the apparent aspect ratio of shapes, and investigates how it interacts with binocular cues to surface slant. One way in which statistical information could give rise to the horizontal vertical illusion would be through prior assumptions about the distribution of slant. This prior would then be expected to interact with retinal cues to slant. We determined the aspect ratio of stereoscopically viewed ellipses that appeared circular. We show that observers' judgements of aspect ratio were affected by surface slant, but that the largest image vertical:horizontal aspect ratio that was considered to be a surface with a circular profile was always found for surfaces close to fronto-parallel. This is not consistent with a Bayesian model in which the horizontal-vertical illusion arises from a non-uniform prior probability distribution for slant. Rather, we suggest that assumptions about the slant of surfaces affect apparent aspect ratio in a manner that is more heuristic, and partially dissociated from apparent slant. PMID- 22925918 TI - 9-cis-retinoic acid promotes cell adhesion through integrin dependent and independent mechanisms across immune lineages. AB - Retinoids are essential in the proper establishment and maintenance of immunity. Although retinoids are implicated in immune related processes, their role in immune cell adhesion has not been well established. In this study, the effect of 9-cis-retinoic acid (9-cis-RA) on human hematopoietic cell adhesion was investigated. 9-cis-RA treatment specifically induced cell adhesion of the human immune cell lines HuT-78, NB4, RPMI 8866 and U937. Due to the prominent role of integrin receptors in mediating immune cell adhesion, we sought to evaluate if cell adhesion was integrin-dependent. By employing a variety of integrin antagonist including function-blocking antibodies and EDTA, we establish that 9 cis-RA prompts immune cell adhesion through established integrin receptors in addition to a novel integrin-independent process. The novel integrin-independent adhesion required the presence of retinoid and was attenuated by treatment with synthetic corticosteroids. Finally, we demonstrate that 9-cis-RA treatment of primary murine B-cells induces ex vivo adhesion that persists in the absence of integrin function. Our study is the first to demonstrate that 9-cis-RA influences immune cell adhesion through at least two functionally distinct mechanisms. PMID- 22925920 TI - Esophageal tracheobronchial remnant, endoscopic ultrasound diagnosis, and surgical management. PMID- 22925919 TI - TRAF6 is functional in inhibition of TLR4-mediated NF-kappaB activation by resveratrol. AB - Resveratrol was suggested to inhibit Toll-like receptor (TLR)4-mediated activation of nuclear factor-kappaB (NF-kappaB) and Toll/interleukin-1 receptor domain-containing adaptor inducing interferon-beta (TRIF)-(TANK)-binding kinase 1, but the myeloid differentiation primary response gene 88-tumor necrosis factor receptor-associated factor 6 (TRAF6) pathway is not involved in this effect. However, involvement of TRAF6 in this process is still elusive since cross talk between TRIF and TRAF6 has been reported in lipopolysaccharide (LPS)-induced signaling. Using RAW 264.7 macrophages, we determined the effect of resveratrol on LPS-induced TRAF6 expression, ubiquitination as well as activation of mitogen activated protein (MAP) kinases and Akt in order to elucidate its involvement in TLR4 signaling. LPS-induced transient elevation in TRAF6 mRNA and protein expressions is suppressed by resveratrol. LPS induces the ubiquitination of TRAF6, which has been reported to be essential for Akt activation and for transforming growth factor-beta activated kinase-1-NAP kinase kinase 6 (MKK6) mediated p38 and c-Jun N-terminal kinase (JNK) activation. We found that resveratrol diminishes the effect of LPS on TRAF6 ubiquitination and activation of JNK and p38 MAP kinases, while it has no effect on the activation of extracellular-signal-regulated kinase (ERK)1/2. The effect of resveratrol on MAP kinase inhibition is significant since TRAF6 activation was reported to induce activation of JNK and p38 MAP kinase while not affecting ERK1/2. Moreover, Akt was identified previously as a direct target of TRAF6, and we found that, similarly to MAPKs, phosphorylation pattern of Akt followed the activation of TRAF6, and it was inhibited by resveratrol at all time points. Here, we provide the first evidence that resveratrol, by suppressing LPS-induced TRAF6 expression and ubiquitination, attenuates the LPS-induced TLR4-TRAF6, MAP kinase and Akt pathways that can be significant in its anti-inflammatory effects. PMID- 22925921 TI - Psychosocial outcomes for children with nonalcoholic fatty liver disease over time and compared with obese controls. AB - OBJECTIVES: Children with nonalcoholic fatty liver disease (NAFLD) experience compromised quality of life (QOL) akin to those with other chronic disease. Our objectives were to examine the association between NAFLD and QOL as well as other psychosocial outcomes, to compare psychosocial outcomes to obese children without known NAFLD, and to determine whether present standard care for NAFLD results in weight loss and improvement in psychosocial outcomes longitudinally. METHODS: Children with NAFLD between 8 and 18 years and obese control children without known NAFLD were consented to complete a brief psychosocial battery examining depression (Children's Depression Inventory), QOL (Pediatric Quality of Life Inventory; PedsQL), and effect of weight on self-esteem (Body-Esteem Scale for Adolescents and Adults) at baseline; and additionally for the NAFLD group after at least 6 months. RESULTS: A total of 48 children with NAFLD and 40 obese control children were enrolled. The PedsQL scores were not significantly different but the CDI total score and subscales of negative mood, ineffectiveness, and negative self-esteem as well as all of the 3 subscales of BESAA, appearance, attribution, and weight were worse in the NAFLD group compared with obese controls. The PedsQL scores also did not change after standard care in the 33 patients with NAFLD who completed the follow-up evaluations, but the CDI score differed between those whose body mass index improved or not. CONCLUSIONS: Children with NAFLD have higher levels of depression than obese controls. Outcomes did not improve with standard care. Larger longitudinal studies and appropriate interventions are required in this area. PMID- 22925922 TI - Patient satisfaction and masticatory efficiency of single implant-retained mandibular overdentures using the stud and magnetic attachments. AB - OBJECTIVES: To study patient satisfaction and masticatory efficiency of single implant-retained mandibular overdentures using the stud and magnetic attachments in a randomized clinical trial with a crossover design. METHODS: Patients received a single implant placed in the midline of the mandible and either a stud (Locator) or a magnetic (Magfit) attachment, assigned at random. Patient satisfaction, including patient comfort, speech, chewing ability and retention, and masticatory efficiency measured by chewing peanuts, were assessed before and 3 months after attachment insertion. Patient satisfaction and masticatory efficiency were evaluated again 3 months after insertion of the alternate attachment bodies. The outcomes were compared before and after insertion of the attachments and between the two types of attachments using Wilcoxon signed rank tests. RESULTS: Patient overall satisfaction, comfort, speech, chewing ability, and retention improved significantly after insertion of both types of attachment bodies (p<0.05). Masticatory efficiencies also increased in both the Locator and the Magfit groups (p<0.05). There were no statistically significant differences in patient overall satisfaction, comfort, speech, and retention between the two types of attachments (p>0.05). The Locator attachments performed better in perceived chewing ability than the Magfit (p<0.05), but there was no statistically significant difference in masticatory efficiency between the two attachment types (p>0.05). CONCLUSIONS: Clinical outcomes were significantly improved in single implant-retained mandibular overdentures using either the Locator or the Magfit magnetic attachments. There was no difference in masticatory efficiency between the two attachment types. PMID- 22925923 TI - Fibre reinforcement of two temporary composite bridge materials--effect upon flexural properties. AB - OBJECTIVES: Temporary bridges must survive for their anticipated time in clinical service. Fibre reinforcement offers a potential means of increasing the chances of achieving this. This study sought to investigate this. METHODS: This in vitro study determined the three point flexural strength and flexural fatigue characteristics of beam specimens (25 mm long * 3 mm wide * 2 mm deep) of a chairside temporary crown and bridge material (Protemp 4, 3M ESPE) and a laboratory resin composite (Ceramage, Shofu Inc.) in unreinforced and reinforced states. Reinforcement was provided by Everstick Crown and Bridge (Stick Tech Ltd.) and Ribbond THM (Ribbond Inc.). All testing was performed using an Instron Universal testing machine following one week of storage in distilled water at 37 degrees C. RESULTS: Fibre reinforcement with Everstick C&B significantly (P < 0.001) increased the mean flexural strengths of both materials. The flexural fatigue limits of both Protemp 4 and Ceramage were significantly (P < 0.001) increased by fibre incorporation. CONCLUSIONS: The observed fibre resin coupling (where Everstick C&B was used) and knitting together of fractured specimen fragments to restore specimen function (specimens where Ribbond THM was used) demonstrated the potential to enhance the durability of temporary bridges made of the materials studied here. CLINICAL SIGNIFICANCE: The incorporation of fibre reinforcement in temporary bridge materials has the potential to enhance the longevity of temporary bridges and thus reduce the need for emergency treatment. PMID- 22925924 TI - Hydrogen peroxide whitens teeth by oxidizing the organic structure. AB - OBJECTIVES: The mechanism of tooth bleaching using peroxide oxidizers is not fully understood. It is unknown whether peroxide radicals make teeth whiter by deproteinizing, demineralizing, or oxidizing tooth tissues. This study was designed to define the mechanism of tooth bleaching and determine which of tooth enamel chemical components is/are affected by bleaching. METHODS: Sixty sound teeth were collected from adult patients. The teeth were divided into 6 equal groups (n=10). Groups 1, 2, 3 and 4 were treated for 4 days with one of the following solutions: deproteinizing (NaOH) that removes organic content, demineralizing (EDTA) that decalcifies the mineral content, oxidizing (H(2)O(2)) and distilled water (control). Group 5 and 6 were pre-treated with either deproteinizing or demineralizing solutions before treating them with oxidizing solutions for 4 days. Changes in enamel elemental ratios, crystallinity index and tooth shade parameters of the treated teeth were examined by means of EDS, Raman spectroscopy and shade-spectrophotometry. The data obtained was analysed with Wilcoxon Signed-Ranks Test, and the statistical significance was set at p<0.05. RESULTS: Tooth deproteinization increased the lightness by 4.8 +/- 2.7 degrees , tooth demineralization resulted in 8.5 +/- 5.6 degrees decrease in the lightness and tooth oxidization induced 19.9 +/- 6.5 degrees increase in the lightness. Oxidization of the deproteinized teeth did not influence shade parameters, but oxidation of the demineralized teeth resulted in 10.7 +/- 5.8 degrees increase in the lightness. CONCLUSION: Hydrogen peroxide does not induce significant changes in tooth enamel organic and inorganic relative contents, and it whitens teeth just by oxidizing their organic matrix. These findings are of great clinical significance since they explain the mechanism of tooth bleaching, and help understanding its limitations and disadvantages. PMID- 22925926 TI - High rate of antibody secretion is not integral to plasma cell differentiation as revealed by XBP-1 deficiency. AB - During B cell terminal differentiation, a complex set of transcription factors interact to drive the phenotypic and functional changes leading to the development of Ab-secreting cells (ASCs). The transcription factor X-box binding protein 1 (XBP-1) is an essential part of one of the branches of the unfolded protein response (UPR). The UPR is induced when a cell has to handle large amounts of proteins, as is the case in ASCs. Although XBP-1 was initially also ascribed an indispensable function in plasma cell development, later studies of B cell-specific deletion reported a much milder consequence of XBP-1 deficiency. Our interest was to determine whether XBP-1 was integral for the differentiation of plasma cells. Using both in vitro and in vivo assays, we found efficient generation of ASCs in the absence of XBP-1. ASCs were present at normal frequencies in resting and immunized mice and displayed a pattern of surface markers typical for plasma cells. The absence of XBP-1 resulted in a reduction but not ablation of Ab secretion and the failure to develop the cellular morphology characteristic of ASCs. Thus, XBP-1 deficiency demonstrates that the gene regulatory program controlling plasma cell differentiation can proceed relatively normally in the absence of high rates of Ig secretion. PMID- 22925925 TI - SOCS3 deficiency promotes M1 macrophage polarization and inflammation. AB - Macrophages participate in both the amplification of inflammation at the time of injury and downregulation of the inflammatory response to avoid excess tissue damage. These divergent functions of macrophages are dictated by their microenvironment, especially cytokines, which promote a spectrum of macrophage phenotypes. The M1 proinflammatory phenotype is induced by LPS, IFN-gamma, and GM CSF, and IL-4, IL-13, and M-CSF induce anti-inflammatory M2 macrophages. Suppressors of cytokine signaling (SOCS) proteins function as feedback inhibitors of the JAK/STAT signaling pathway, and they can terminate innate and adaptive immune responses. In this study, we have evaluated the influence of SOCS3 on macrophage polarization and function. Macrophages obtained from LysMCre SOCS3(fl/fl) mice, which lack SOCS3 in myeloid lineage cells, exhibit enhanced and prolonged activation of the JAK/STAT pathway compared with macrophages from SOCS3(fl/fl) mice. Furthermore, SOCS3-deficient macrophages have higher levels of the M1 genes IL-1beta, IL-6, IL-12, IL-23, and inducible NO synthase owing to enhanced transcriptional activation and chromatin modifications. SOCS3-deficient M1 macrophages also have a stronger capacity to induce Th1 and Th17 cell differentiation than M1 macrophages from SOCS3(fl/fl) mice. Lastly, LPS-induced sepsis is exacerbated in LysMCre-SOCS3(fl/fl) mice and is associated with enhanced STAT1/3 activation and increased plasma levels of M1 cytokines/chemokines such as IL-1beta, TNF-alpha, IL-6, CCL3, CCL4, and CXCL11. These findings collectively indicate that SOCS3 is involved in repressing the M1 proinflammatory phenotype, thereby deactivating inflammatory responses in macrophages. PMID- 22925927 TI - Comparative and functional evaluation of in vitro generated to ex vivo CD8 T cells. AB - The generation of the cytotoxic CD8 T cell response is dependent on the functional outcomes imposed by the intrathymic constraints of differentiation and self-tolerance. Although thymic function can be partly replicated in vitro using OP9-DL1 cell cultures to yield CD8 alphabeta TCR-bearing cells from hematopoietic progenitor cells, a comprehensive and functional assessment of entirely in vitro generated CD8 T cells derived from bone marrow hematopoietic stem cells has not been established and remains controversial. In this study, we demonstrate that a phenotypic, molecular, and functional signature of in vitro derived CD8 T cells is akin to that of ex vivo CD8 T cells, although several significant differences were also observed. Transfer of in vitro derived CD8 T cells into syngeneic and immunodeficient host mice showed no graft-versus-host response, whereas a robust homeostatic proliferation was observed, respectively. These findings, along with a diverse and broad TCR repertoire expressed by the in vitro derived CD8 T cells, allowed for the successful generation of Ag-specific T cells to be obtained from an entirely in vitro generated CD8 T cell pool. These findings support the use of Ag-specific in vitro derived effector CD8 T cells for immune reconstitution approaches, which would be amenable to further tailoring for their use against viral infections or malignancies. PMID- 22925928 TI - Enolase of Streptococcus pneumoniae binds human complement inhibitor C4b-binding protein and contributes to complement evasion. AB - Streptococcus pneumoniae (pneumococcus) is a pathogen that causes severe local and life-threatening invasive diseases, which are associated with high mortality rates. Pneumococci have evolved several strategies to evade the host immune system, including complement to disseminate and to survive in various host niches. Thus, pneumococci bind complement inhibitors such as C4b-binding protein (C4BP) and factor H via pneumococcal surface protein C, thereby inhibiting the classical and alternative complement pathways. In this study, we identified the pneumococcal glycolytic enzyme enolase, a nonclassical cell surface and plasminogen-binding protein, as an additional pneumococcal C4BP-binding protein. Furthermore, we demonstrated that human, but not mouse, C4BP bound pneumococci. Recombinant enolase bound in a dose-dependent manner C4BP purified from plasma, and the interaction was reduced by increasing ionic strength. Enolase recruited C4BP and plasminogen, but not factor H, from human serum. Moreover, C4BP and plasminogen bound to different domains of enolase as they did not compete for the interaction with enolase. In direct binding assays with recombinant C4BP mutants lacking individual domains, two binding sites for enolase were identified on the complement control protein (CCP) domain 1/CCP2 and CCP8 of the C4BP alpha-chains. C4BP bound to the enolase retained its cofactor activity as determined by C4b degradation. Furthermore, in the presence of exogenously added enolase, an increased C4BP binding to and subsequently decreased C3b deposition on pneumococci was observed. Taken together, pneumococci specifically interact with human C4BP via enolase, which represents an additional mechanism of human complement control by this versatile pathogen. PMID- 22925929 TI - CD8 T cell priming in the presence of IFN-alpha renders CTLs with improved responsiveness to homeostatic cytokines and recall antigens: important traits for adoptive T cell therapy. AB - Previous mouse and human studies have demonstrated that direct IFN-alpha/beta signaling on naive CD8 T cells is critical to support their expansion and acquisition of effector functions. In this study, we show that human naive CD8 T cells primed in the presence of IFN-alpha possess a heightened ability to respond to homeostatic cytokines and to secondary Ag stimulation, but rather than differentiating to effector or memory CTLs, they preserve nature-like phenotypic features. These are qualities associated with greater efficacy in adoptive immunotherapy. In a mouse model of adoptive transfer, CD8 T cells primed in the presence of IFN-alpha are able to persist and to mediate a robust recall response even after a long period of naturally driven homeostatic maintenance. The long lasting persistence of IFN-alpha-primed CD8 T cells is favored by their enhanced responsiveness to IL-15 and IL-7, as demonstrated in IL-15(-/-) and IL-7(-/-) recipient mice. In humans, exposure to IFN-alpha during in vitro priming of naive HLA-A2(+) CD8 T cells with autologous dendritic cells loaded with MART1(26-35) peptide renders CD8 T cells with an improved capacity to respond to homeostatic cytokines and to specifically lyse MART1-expressing melanoma cells. Furthermore, in a mouse model of melanoma, adoptive transfer of tumor-specific CD8 T cells primed ex vivo in the presence of IFN-alpha exhibits an improved ability to contain tumor progression. Therefore, exposure to IFN-alpha during priming of naive CD8 T cells imprints decisive information on the expanded cells that can be exploited to improve the efficacy of adoptive T cell therapy. PMID- 22925930 TI - Analysis of the processing of seven human tumor antigens by intermediate proteasomes. AB - We recently described two proteasome subtypes that are intermediate between the standard proteasome and the immunoproteasome. They contain only one (beta5i) or two (beta1i and beta5i) of the three inducible catalytic subunits of the immunoproteasome. They are present in tumor cells and abundant in normal human tissues. We described two tumor antigenic peptides that are uniquely produced by these intermediate proteasomes. In this work, we studied the production by intermediate proteasomes of tumor antigenic peptides known to be produced exclusively by the immunoproteasome (MAGE-A3(114-122), MAGE-C2(42-50), MAGE C2(336-344)) or the standard proteasome (Melan-A(26-35), tyrosinase(369-377), gp100(209-217)). We observed that intermediate proteasomes efficiently produced the former peptides, but not the latter. Two peptides from the first group were equally produced by both intermediate proteasomes, whereas MAGE-C2(336-344) was only produced by intermediate proteasome beta1i-beta5i. Those results explain the recognition of tumor cells devoid of immunoproteasome by CTL recognizing peptides not produced by the standard proteasome. We also describe a third antigenic peptide that is produced exclusively by an intermediate proteasome: peptide MAGE C2(191-200) is produced only by intermediate proteasome beta1i-beta5i. Analyzing in vitro digests, we observed that the lack of production by a given proteasome usually results from destruction of the antigenic peptide by internal cleavage. Interestingly, we observed that the immunoproteasome and the intermediate proteasomes fail to cleave between hydrophobic residues, despite a higher chymotrypsin-like activity measured on fluorogenic substrates. Altogether, our results indicate that the repertoire of peptides produced by intermediate proteasomes largely matches the repertoire produced by the immunoproteasome, but also contains additional peptides. PMID- 22925931 TI - The comparison of spatial variation and risk factors between mosquito-borne and tick-borne diseases: Seroepidemiology of Ehrlichia canis, Anaplasma species, and Dirofilaria immitis in dogs. AB - Canine ehrlichiosis/anaplasmosis and heartworm diseases are vector-borne and zoonotic infections. To compare epidemiology of these vector-borne diseases, a community-based study was conducted to determine the seroprevalence and risk factors of Ehrlichia canis, Anaplasma sp. and Dirofilaria immitis infections among healthy pet dogs. Prevalence distribution patterns were geographically contrasting between tick-borne E. canis/Anaplasma sp. infections and mosquito borne D. immitis infection. Although highly enzootic communities of ehrlichiosis/anaplasmosis scattered in mountainous environment at elevations between 100m and 1000m, those of heartworm disease mainly distributed in urbanized plains. After multiple logistic regression analysis, it further showed that older age group and outdoor housing were associated with higher risk of heartworm infection; being male and having tick infestation associated with higher risk of E. canis infection whereas being male and free-roaming associated with higher risk of Anaplasma infection. These findings may reflect different vectors for disease transmission, and different kinetics of environment-pathogen host interaction. PMID- 22925932 TI - Serological evidence of West Nile virus infection in wild migratory and resident water birds in Eastern and Northern India. AB - To assess West Nile virus (WNV) infection in wild resident and migratory birds, we tested 3887 samples from 1784 birds belonging to 119 identified species within 30 families collected during 2008-10 from 13 states in India. The serum samples were tested for WNV antibodies initially by a competition ELISA and subsequently by a micro-plaque reduction neutralization test (Micro-PRNT), whereas tracheal and cloacal swabs were subjected to real-time RT-PCR for the detection of the WNV RNA. Twenty six birds (2.46%) out of 1058 tested showed evidence of flavivirus antibodies by ELISA. End point neutralization antibody determinations for WNV and Japanese encephalitis virus (JEV) showed that of the 22 ELISA positive sera, WNV specific neutralizing antibodies were detected in 17 samples representing nine species of wild birds (residents: Purple swamphen, Little cormorant, Little egret, Black ibis and Spot-billed duck; residents with winter influx: Common coot and Mallard; migratory birds: Ruff and Purple heron), and two samples were positive for both WNV and JEV antibodies. The WNV-specific antibodies were most commonly detected in Mallards and Common coots. WNV genomic RNA was not detected by real-time RT-PCR. The results in this study suggest that wild resident birds are infected occasionally and wild migratory birds rarely with WNV. Additionally, our study provides evidence of WNV infection in eastern and northern India for the first time. PMID- 22925933 TI - Coronary artery calcium scoring on different 64-detector scanners using a low tube voltage (80 kVp). AB - PURPOSE: The aim of this study was to compare the calcium score and reproducibility of coronary artery calcium scores obtained on the four kinds of 64-detector computed tomography (CT) scanners using standard (120 kVp) and low tube voltage (80 kVp) scan techniques. MATERIALS AND METHODS: We scanned 80 and 120 kVp on all scanners. We calculated Agatston, volume, and mass scores for coronary artery calcium scoring on each scanner and compared the coefficients of variation of the calcium scores to evaluate reproducibility of among CT scanners. RESULTS: The averages of the total mean Agatston score, total mean volume score, and total mean mass score at 80 kVp/120 kVp were 798.9/683.8, and 627.2/567.3, and 157.1/156.7, respectively. The total mean mass score was almost constant irrespective of the tube voltage. The total mean coefficients of variation for the four CT scanners were lower at 80 than 120 kVp (4.1% vs. 10.2% [total mean Agatston score], 3.2% vs. 9.6% [total mean volume score], and 3.2% vs. 9.4% [total mean mass score]). CONCLUSION: Use of the low tube voltage technique can reduce variations in the coronary artery calcium scores obtained on different CT scanners. PMID- 22925934 TI - Expression of the aryl hydrocarbon receptor pathway and cyclooxygenase-2 in dog tumors. AB - In humans, the aryl hydrocarbon receptor (AHR) gene battery constitutes a set of contaminant-responsive genes, which have been recently shown to be involved in the regulation of several patho-physiological conditions, including tumorigenesis. As the domestic dog represents a valuable animal model in comparative oncology, mRNA levels of cytochromes P450 1A1, 1A2 and 1B1 (CYP1A1, 1A2 and 1B1), AHR, AHR nuclear translocator (ARNT), AHR repressor (AHRR, whose partial sequence was here obtained) and cyclooxygenase-2 (COX2) were measured in dog control tissues (liver, skin, mammary gland and bone), in 47 mast cell tumors (MCTs), 32 mammary tumors (MTs), 5 osteosarcoma (OSA) and related surgical margins. Target genes were constitutively expressed in the dog, confirming the available human data. Furthermore, their pattern of expression in tumor biopsies was comparable to that already described in a variety of human cancers; in particular, both AHR and COX2 genes were up-regulated and positively correlated, while CYP1A1 and CYP1A2 mRNAs were generally poorly expressed. This work demonstrated for the first time that target mRNAs are expressed in neoplastic tissues of dogs, thereby increasing the knowledge about dog cancer biology and confirming this species as an useful animal model for comparative studies on human oncology. PMID- 22925935 TI - B-mode and colour Doppler ultrasonography of the milk vein and musculophrenic vein in eight cows during lactation. AB - Eight cows underwent Doppler sonographic examinations of the milk vein and musculophrenic vein from 9 days prepartum to 300 days postpartum. A 7.5-MHz linear transducer was used to determine the inner diameter of the veins and blood flow velocities and volumes on the left side in standing, non-sedated animals. Cows were weighed and milk yield measured at all examination times. The milk vein appeared as a vessel with an inner diameter of 2.01-2.30 cm immediately beneath the skin. The maximum blood flow velocity ranged from 23.84 to 35.76 cm/s before parturition, increased markedly on the day of calving (day 0), peaked at 61.14 cm/s on day 1 and slowly decreased to 23.84 cm/s by day 300. The profiles of the minimum and mean maximum flow velocities and flow volume were similar. The musculophrenic vein had an inner diameter of 0.76-1.07 cm and its distance from the surface of the skin was 1.15-1.31 cm. The profiles of the blood flow variables were irregular and did not resemble those of the milk vein. The maximum blood flow velocity ranged from 87.35 to 114.41 cm/s, the minimum velocity from 5.47 to 7.60 cm/s, the mean maximum velocity from 48.55 to 78.74 cm/s and the blood flow volume from 1.02 to 2.44 l/min. The milk vein had a larger diameter (2.16 versus 0.90 cm; P<0.01), smaller maximum, minimum and mean maximum blood flow velocities (P<0.01) and a larger blood flow volume than the musculophrenic vein (P<0.01). PMID- 22925936 TI - First detection and molecular characterization of Ehrlichia canis from dogs in Nigeria. AB - The present study aimed to detect the presence of Ehrlichia canis in naturally infected dogs in Nigeria, using a combination of PCR and sequence analysis of the 16S rRNA gene and two genes encoding the tandem repeat-containing proteins (TRPs), TRP19 and TRP36. Out of a total of 100 blood samples collected from domestic dogs presented to veterinary hospitals in Jos, the capital city of Plateau State of Nigeria, 11 were positive in nested PCR for E. canis. Sequencing results for these amplicons showed that all of the 16S rDNA sequences (1623 bp) or the TRP19 coding sequences (414 bp) were identical to each other and had very high similarities (99.3-100%) with those from other E. canis strains accessible in GenBank. The TRP36 gene sequences derived from the 11 Nigerian isolates were identical to each other except for the number of the 27-bp repeat unit in a tandem repeat region, which was found to be 8, 12 or 18. Without considering the number of tandem repeats, these sequences had 100% identity to that of the reported Cameroon 71 isolate, but distinctly differed from those obtained from other geographically distant E. canis strains previously published. A phylogenetic tree of E. canis based on the TRP36 amino acid sequences showed that the Nigerian isolates and the Cameroon 71 isolate fell into a separate clade, indicating that they may share a common ancestor. Overall, this study not only provides the first molecular evidence of E. canis infections in dogs from Nigeria but also highlights the value of the TRP36 gene as a tool to classify E. canis isolates and to elucidate their phylogeographic relationships. PMID- 22925938 TI - [Iode poisoning after several bandages]. PMID- 22925937 TI - [Amniotic fluid embolism: report of the successful outcome of a case with inaugural cardiac arrest and early DIVC complicated by hemoperitoneum of iatrogen origin and bleeding of an hepatic adenoma]. AB - Amniotic fluid embolism is a relatively rare clinical entity and with difficult medical recognition. However, it is the second leading cause of maternal mortality. We report here the case of a 32-year-old patient who underwent elective caesarean section complicated by an amniotic fluid embolism with cardiac arrest. The presence of a major disseminated intravascular coagulation favored the occurrence of a retroperitoneal hematoma of iatrogenic origin on attempt of femoral venous catheterization and that of hemoperitoneum on bleeding of an hepatic adenoma. The diagnostic of amniotic fluid embolism was confirmed by the presence of amniotic cells in the bronchoalveolar lavage. The patient survived without sequelae. PMID- 22925940 TI - [Checklist and firewall]. PMID- 22925939 TI - [Changes in kaliemia following rapid sequence induction with succinylcholine in critically ill patients]. AB - OBJECTIVE: Evaluate the changes in potassium following rapid sequence induction with succinylcholine in critically ill-patients and determine whether hospital length of stay could influence the succinylcholine-induced hyperkaliemia. STUDY DESIGN: Prospective and observational study. PATIENTS AND METHODS: After approval by our local ethical committee, we prospectively included 36 patients admitted from more than 24hours in ICU and who required succinylcholine for rapid tracheal intubation (1mg/kg). Serum potassium was measured before, 5 and 30min after succinylcholine. The incidence of life-threatening hyperkaliemia (>=6.5mmol/L) was noted. RESULTS: We could observe significant and transient increase in serum potassium (median increase of 0.45 [0.20-0.80] mmol/L at five minutes). A significant relationship was observed between the ICU length of stay and arterial potassium increase (r=0.37, P<0.05). From the ROC curve, a threshold of 12 days had an 86% sensitivity and 69% specificity in discriminating patients in whom the potassium increase was more than 1.5mmol/L. CONCLUSION: Induction with succinylcholine is followed by significant but transient hyperkaliema. The ICU length of stay before giving succinylcholine could influence significantly the amplitude of potassium increase. PMID- 22925941 TI - [Routine preinterventional tests]. PMID- 22925942 TI - [Proceedings of the 26th meeting of ENT Anesthesiology Club]. PMID- 22925943 TI - [Anticoagulation and antiphospholipid syndrome: be careful to the catastrophe]. AB - Antiphospholipid syndrome associate thromboembolic events (arterial or venous), and presence of antiphospholipid antibodies, and require anticoagulation. A catastrophic variant may develop, resulting in multiorgan failure, with high mortality rate. This article presented a patient with antiphospholipid syndrome presenting a catastrophic antiphospholipide syndrome after anticoagulation suspending for gastrointestinal bleeding. Multidisciplinary management in intensive care unit and aggressive therapies (corticosteroids, anticoagulation, plasma exchange) were essential to rescue the patient. PMID- 22925944 TI - [Continuous spinal anesthesia and pulmonary arterial hypertension]. AB - We report the use of continuous spinal anesthesia for hip fracture surgery in a patient with pulmonary arterial hypertension. Preoperative evaluation, anesthetic technique and preoperative monitoring are discussed. PMID- 22925946 TI - Korean red ginseng (Panax ginseng) ameliorates type 1 diabetes and restores immune cell compartments. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Historical records reveal that in traditional medicine, a disease similar to diabetes was treated with ginseng. Korean red ginseng has been considered beneficial as a dietary supplement for its anti diabetic potential. AIM: This study was designed to investigate the prophylactic potential of Korean red ginseng (KRG) extract (Panax ginseng C.A. Meyer Radix Rubra) in a well-established mouse model of Type 1 diabetes (T1D). MATERIALS AND METHODS: The prophylactic effect of KRG extract was evaluated in mice fed with KRG extract for two weeks prior to induction of diabetes by streptozotocin (STZ) administration. Glucose levels and glucose challenge test results of KRG-treated diabetic mice were compared to those of untreated diabetic mice and healthy control mice. Examination of the immune compartments in lymphoid organs and immunohistochemical staining of pancreas for islet cell morphology and insulin producing beta cells were performed. RESULTS: KRG extract significantly lowered blood glucose levels to an average of 250mg/dl from 350mg/dl and improved glucose challenge testing when applied as prophylaxis. Histological findings indicated that KRG extract protected against STZ-induced destruction of pancreatic tissue and restored insulin secretion. Strikingly, this effect was accompanied by restoration of lymphocytes in secondary lymphoid organs, suggesting that KRG extract facilitated immune homeostasis. CONCLUSION: This is the first report to demonstrate the prophylactic function of KRG extract in ameliorating the hyperglycemia of T1D. Immune compartments of diabetic mice were found to be preserved in KRG-treated mice suggesting that Korean red ginseng may benefit T1D patients, not only for its hypoglycemic but also for its immunomodulatory effects. PMID- 22925947 TI - Quantitatively analyze composition principle of Ma Huang Tang by structural equation modeling. AB - ETHNOPHARMACOLOGICAL RELEVANCE: In Chinese classic formulas, Ma Huang Tang (MHT), composed of Ephedra, Cassia twig, Bitter apricot kernel and Prepared licorice, has been widely used to treat cold, influenza, acute bronchitis, bronchial asthma and other pulmonary diseases. However, there is no quantitative interpretation about composition principle of MHT as well as other Chinese compound prescriptions. This study was aimed using structural equation modeling (SEM) to decipher 'monarch, minister, assistant and guide' which is the unique and integrated composition principle of Chinese compound recipes, by taking MHT for instance. MATERIALS AND METHODS: Sixteen prescriptions of different dose ratios were combined orthogonally from four herbal drugs of MHT, then their diaphoretic, antispasmodic and analgesic effects were assessed by the indicators of the rat sweating point number, the spasmolysis percentage of guinea pig trachea and the murine writhing number, respectively. Basing on SME, the systematology analysis method to complex causality, path diagrams for herbal drugs were drawn with the Amos software and the relationships of the four herbal ingredients and therapeutic effects were measured. RESULTS: Sixteen recipes induced SD rats sweating, remitted spasm of guinea pig trachea smooth muscle, and relieved ICR mouse pain due to acetic acid in comparison with animal model group or normal control groups. Three different SME models were specified and the relevant relationship was analyzed. According to the results of measured standardized path coefficients, Ephedra exerts the greatest contribution to the integral potency, so it acts as the monarch drug in MHT; Cassia twig is slightly weakly effective than Ephedra, and has the most significant interaction with Ephedra, which shows that it is the minister drug; the direct effects of Bitter apricot kernel and Prepared licorice on the integral potency are non-significant, while these two drugs have very significant synergetic effect with Ephedra or Cassia twig, thus they can be interpreted as subordinate drugs to strengthen the therapeutical effects of the monarch and minister drugs; the higher interaction values of Bitter apricot kernel suggest that it is the assistant drug, and Prepared licorice is the guide drug with lower values. CONCLUSION: SME can be used to quantitatively analyze the composition principle of Chinese compound prescriptions like MHT, which demystifies the ancient and classical system theory of traditional Chinese medicine from a totally new viewpoint. PMID- 22925949 TI - Ethics-based decision-making and health impact assessment. AB - To compare the use of health impact assessment (HIA) and the decision-making triangle (DMT) framework for evidence-informed, ethics-based decision-making and consider implications for practice. We compared HIA and the DMT approach with reference to: their use of evidence and theory; their application of ethical principles or values; and how they aid decision-making. A good fit between the HIA and DMT approaches was found. Ways in which they could be of benefit to each other were identified. The DMT approach and HIA are highly compatible: they are rooted in largely shared ethical principles or values; both involve appropriate use of evidence and theory; and both are concerned with enhancing the quality of decision-making in the interests of population health. The DMT approach and HIA are of potential value to each other: established HIA methods and tools can be of practical help in using the DMT approach; and the DMT framework provides insights to how HIA methods and processes could be improved and the vision of 'impacts that matter' widened. PMID- 22925948 TI - Regulation of Mct1 by cAMP-dependent internalization in rat brain endothelial cells. AB - In the cerebrovascular endothelium, monocarboxylic acid transporter 1 (Mct1) controls blood-brain transport of short chain monocarboxylic and keto acids, including pyruvate and lactate, to support brain energy metabolism. Mct1 function is acutely decreased in rat brain cerebrovascular endothelial cells by beta adrenergic signaling through cyclic adenosine monophosphate (cAMP); however, the mechanism for this acute reduction in transport capacity is unknown. In this report, we demonstrate that cAMP induces the dephosphorylation and internalization of Mct1 from the plasma membrane into caveolae and early endosomes in the RBE4 rat brain cerebrovascular endothelial cell line. Additionally, we provide evidence that Mct1 constitutively cycles through clathrin vesicles and recycling endosomes in a pathway that is not dependent upon cAMP signaling in these cells. Our results are important because they show for the first time the regulated and unregulated vesicular trafficking of Mct1 in cerebrovascular endothelial cells; processes which have significance for better understanding normal brain energy metabolism, and the etiology and potential therapeutic approaches to treating brain diseases, such as stroke, in which lactic acidosis is a key component. PMID- 22925950 TI - Erdheim-Chester disease. PMID- 22925951 TI - Preventive strategy against infectious diarrhea--a holistic approach. PMID- 22925952 TI - Acromegaly in a patient with Carney's complex. PMID- 22925953 TI - [Association of high altitude-induced hypoxemia to lipid profile and glycemia in men and women living at 4,100m in the Peruvian Central Andes]. AB - BACKGROUND AND OBJECTIVES: At a same altitude, people with greater hypoxemia would have higher hemoglobin (Hb) levels than less hypoxemic patients. It is not known whether higher hypoxemia levels (as measured by higher Hb values) affect basal glucose and lipid profile at an altitude of 4,100mg (Carhuamayo and Junln). MATERIALS AND METHODS: Glucose, lipid, and hemoglobin levels and body mass index (BMI) were assessed in 158 males and 348 females aged 35 to 75 years. Association of lipid and glucose levels with systolic and diastolic blood pressure (SBP and DBP) was also assessed. Results were analyzed using Student's t test, Chi-square test, analysis of variance, correlations, and linear multivariate analyses adjusted for age, sex, BMI, smoking, and education. RESULTS: Higher hemoglobin levels were directly associated to higher levels of total cholesterol (P<0.001), low density lipoprotein cholesterol (P<0.002), non-high density lipoprotein cholesterol (non-HDL) (P<0.01), and triglycerides (P<0.01). No association was found between hemoglobin and glucose (P>0.05). Levels of total cholesterol, high density lipoprotein cholesterol, triglycerides, low density lipoprotein cholesterol, and blood glucose were directly associated to DBP. CONCLUSIONS: In people living at high altitude (4100m), the non-HDL cholesterol fraction and triglycerides are directly associated to hemoglobin value, and increases in them are in turn associated to higher DBP. PMID- 22925954 TI - Are we missing the potential of action research for transformative change in medical education? PMID- 22925955 TI - Walking the talk: the need for investment in educator development. PMID- 22925956 TI - An appraisal of the literature on teaching physical examination skills. AB - AIMS AND OBJECTIVES: To discover which models for teaching physical examination skills have been proposed, and to appraise the evidence for each. METHODS: We conducted a narrative review of relevant literature from 1990-2010. We searched the databases MEDLINE, PsycINFO, and ERIC (The Education Resource Information Centre) for the terms: 'physical examination' AND 'teaching' as both MESH terms and keyword searches. We excluded web-based or video teaching, non-physical examination skills (e.g. communication skills), and articles about simulated patients or models. RESULTS: We identified five relevant articles. These five studies outlined several approaches to teaching physical examination skills, including Peyton's 4-step model, an adaptation of his model to a 6-step model; the silent run through; and collaborative discovery. There was little evidence to support one method over others. One controlled trial suggested that silent run through could improve performance of complex motor tasks, and another suggested that collaborative discovery improves students' ability to recognise key findings in cardiac examinations. COMMENTS: There are several models for teaching physical examinations, but few are designed specifically for that purpose and there is little evidence to back any one model over another. We propose an approach which adopts several key features of these models. Future research could usefully evaluate the effectiveness of the proposed models, or develop innovative practical models for teaching examination skills. PMID- 22925945 TI - [Alliance against MDRO: safeguarding antibiotics]. AB - Resistance to antibiotics has increased recently to a dramatic extend, and the pipeline of new antibiotics is almost dry for the 5 next years. Failures happen already for trivial community acquired infections, like pyelonephritis, or peritonitis, and this is likely to increase. Difficult surgical procedures, transplants, and other immunosuppressive therapies will become far more risky. Resistance is mainly due to an excessive usage of antibiotics, in all sectors, including the animal one. Action is urgently needed. Therefore, an alliance against MDRO has been recently created, which includes health care professionals, consumers, health managers, and politicians. The document highlights the different proposed measures, and represents a strong consensus between the different professionals, including general practitioners, and veterinarians. PMID- 22925957 TI - GPs' experiences of the Returner (Induction and Refreshment) scheme in Severn: a qualitative study. AB - The introduction of the General Practice Returner (since renamed the Induction and Refreshment) scheme in England by the Department of Health and London Deanery in 2002 provided placements providing training for qualified GPs seeking to return to the primary care workforce after significant time away from clinical general practice. This qualitative research study sought to explore issues around such placements and involved in-depth telephone interviews with an opportunistic sample of 14 GP returners and five trainers on their experiences of the GP returner scheme within Severn Deanery. Findings showed unequivocal and universal support from both returners and trainers for the value of the scheme. However, issues around the 'two-year rule' and funding arrangements whilst returning to practice may need to be re-addressed. GP returners reported significant improvements in their clinical skills and knowledge, understanding of changing NHS policy/protocols and enhanced perceived self-confidence. The importance of a peer-respected scheme organiser, easily accessible internationally, was felt to be crucial. Opportunities for the transferability of unique experiences from GPs returning from overseas should also be further explored. PMID- 22925958 TI - 'It's the conversation they'll learn from': improving assessments for GP Specialist Trainees in hospital posts. AB - BACKGROUND: Workplace-based assessment (WPBA) is now a central feature of postgraduate training and required for Membership of the Royal College of General Practitioners (MRCGP). A previous study established that many GP trainees question the validity and usefulness of WPBA during hospital posts. Many of the factors identified, for example superficial feedback, leniency and a 'tick box' culture, suggested that assessors may hold some of the answers about how to improve the system. AIM: To explore the views of hospital-based assessors across a range of specialities about how WPBA works with GP trainees. DESIGN: A qualitative approach was taken to explore views in-depth by means of one-to-one interviews. SETTING: Three training locations within Severn Deanery. METHODS: Consultants were sampled purposively and 15 took part in semi-structured interviews between November 2010 and May 2011. Interviews were recorded and transcribed, and analysed using a thematic framework approach. RESULTS: While WPBA provides a mandate for giving feedback to trainees, assessors say that honesty can be lacking and they find giving negative feedback hard to handle. Nonetheless, the verbal and qualitative elements of the process are valued and bring a crucial depth to the process. Assessors are not familiar with GP training requirements and would benefit from more contact with GP leads and supervisors. CONCLUSIONS: The views of assessors in this study echo those of the GP trainees in the earlier study, emphasising areas where action should be taken to strengthen the system of assessment so that WPBA improves the performance of doctors. The professional conversation and scope for free text comments hold the most potential for adding value to the process. Sharing information across hospital and GP supervisors could also help recognise high-achieving trainees, not just those who are struggling. This would help to address a central criticism that WPBA is focused on a minimum standard of competence rather than excellence, thus losing an important motivation among trainees and weakening the effect of WPBA in helping to deliver better doctors. PMID- 22925959 TI - Self-directed learning groups: a vital model for education, support and appraisal amongst sessional GPs. PMID- 22925960 TI - Patient perceptions of their role in undergraduate medical education within a primary care teaching practice. AB - CONTEXT: The importance of patient involvement as a positive contribution to both undergraduate and postgraduate medical education is now widely acknowledged. Patient contact has become an integral component of teaching, learning and assessment strategies. Research has considered the pedagogic advantage; however, a view from the patient on structure, process and outcome of their contribution has gone largely unexplored. The role of real patients in medical education is changing from passive to a more active involvement. Various commentators have called for more research into patients' perceptions of their role and involvement across a spectrum of educational activities and settings. This study offers an in-depth exploration of the patient perspective from primary care; a setting increasingly important for undergraduate medical education. The aim of this study is to explore patients' perceptions of their role in undergraduate medical education within a UK primary care setting. METHOD: A case study approach with an emphasis on data from in-depth interviews of 18 volunteer patients conducted within a purposively selected single teaching practice. The study captures patient perceptions of their experience, process and an evaluation of their involvement in medical student education. RESULTS: Findings highlight four key themes of involvement that reflect the existing literature but provide additional insights. The themes are; reflections on level of involvement and organisational support; benefits to students; perceived benefits to patients themselves; and wider benefits to medical education and educators. CONCLUSION: Patient perceptions of their involvement in clinical teaching support their key intended role within the educational process. Patients identified perceptions of benefit for students, educators and themselves. The implications of these findings are explored within the context of educational practice. PMID- 22925961 TI - 'Away day' review: linking practice development plans with personal development plans. PMID- 22925962 TI - Developing and coordinating the commissioning and leadership frameworks with the RCGP curriculum in GP training. PMID- 22925963 TI - Learning about medical leadership as a GPST3. Severn Deanery School of Primary Care leadership scholarship: a preliminary report on an innovative programme. PMID- 22925964 TI - Teach professionalism. AB - We have seen that professionalism is difficult to define and subsequently difficult to teach. The formation of a professional identity starts from the day a student embarks on their undergraduate training and extends throughout their postgraduate career. There is no one method that should be employed to teach professionalism. Instead faculty must attempt to incorporate a variety of learning opportunities throughout their formal curriculum whilst recognising and harnessing the effects of the informal and hidden curricula. PMID- 22925965 TI - Meaningful GP learning with concept mapping. PMID- 22925967 TI - Appreciation of the consultation navigation tool. PMID- 22925969 TI - Evolution in developmental phenotype space. AB - Developmental systems can produce a variety of patterns and morphologies when the molecular and cellular activities within them are varied. With the advent of quantitative modeling, the range of phenotypic output of a developmental system can be assessed by exploring model parameter space. Here I review recent examples where developmental evolution is studied using quantitative models, which increasingly rely on empirically determined molecular signaling pathways and their crosstalk. Quantitative pathway evolution may result in dramatic morphological changes. Alternatively, in many developmental systems, the phenotypic output is robust to a range of parameter variation, and cryptic developmental evolution may occur without morphological change. Formalization and measurements of the relationship between genetic variation and parameter variation in developmental models remain in their infancy. PMID- 22925968 TI - Progress in overcoming the chain association issue in bispecific heterodimeric IgG antibodies. AB - The development of bispecific antibodies has attracted substantial interest, and many different formats have been described. Those specifically containing an Fc part are mostly tetravalent, such as stabilized IgG-scFv fusions or dual-variable domain (DVD) IgGs. However, although they exhibit IgG-like properties and technical developability, these formats differ in size and geometry from classical IgG antibodies. Thus, considerable efforts focus on bispecific heterodimeric IgG antibodies that more closely mimic natural IgG molecules. The inherent chain association problem encountered when producing bispecific heterodimeric IgG antibodies can be overcome by several methods. While technologies like knobs-into-holes (KiH) combined with a common light chain or the CrossMab technology enforce the correct chain association, other approaches, e.g., the dual-acting Fab (DAF) IgGs, do not rely on a heterodimeric Fc part. This review discusses the state of the art in bispecific heterodimeric IgG antibodies, with an emphasis on recent progress. PMID- 22925970 TI - Why providers participate in clinical trials: considering the National Cancer Institute's Community Clinical Oncology Program. AB - BACKGROUND: The translation of research evidence into practice is facilitated by clinical trials such as those sponsored by the National Cancer Institute's Community Clinical Oncology Program (CCOP) that help disseminate cancer care innovations to community-based physicians and provider organizations. However, CCOP participation involves unsubsidized costs and organizational challenges that raise concerns about sustained provider participation in clinical trials. OBJECTIVES: This study was designed to improve our understanding of why providers participate in the CCOP in order to inform the decision-making process of administrators, clinicians, organizations, and policy-makers considering CCOP participation. RESEARCH METHODS: We conducted a multi-site qualitative study of five provider organizations engaged with the CCOP. We interviewed 41 administrative and clinician key informants, asking about what motivated CCOP participation, and what benefits they associated with involvement. We deductively and inductively analyzed verbatim interview transcripts, and explored themes that emerged. RESULTS: Interviewees expressed both "altruistic" and "self-interested" motives for CCOP participation. Altruistic reasons included a desire to increase access to clinical trials and feeling an obligation to patients. Self-interested reasons included the desire to enhance reputation, and a need to integrate disparate cancer care activities. Perceived benefits largely matched expressed motives for CCOP participation, and included internal and external benefits to the organization, and quality of care benefits for both patients and participating physicians. CONCLUSION: The motives and benefits providers attributed to CCOP participation are consistent with translational research goals, offering evidence that participation can contribute value to providers by expanding access to innovative medical care for patients in need. PMID- 22925971 TI - DFT and experimental prediction of negative chemical shifts of methyl protons in some piperidines. AB - The high resolution (1)H NMR spectra of four 3-ethyl-4-hydroxy-4 phenylpiperidines 1-4 have been recorded in CDCl(3), C(6)D(6), and (CD(3))(2)CO and analysed. These compounds exist in chair conformation with axial orientation of hydroxyl group at C(4) and equatorial orientation of the remaining substituents. The chemical shifts of methyl protons of ethyl group are quiet novel and surprising and are closer to TMS in CDCl(3) and somewhat higher in C(6)D(6). Changing the solvent from CDCl(3) to (CD(3))(2)CO alters the chemical shifts of these protons and they are very closer to TMS (0.01 ppm) in 3-4 and negative in 2 i.e., less than zero. The results are interpreted in terms of the magnetic anisotropic effect of the phenyl rings at C(2) and C(4) which in turn depends on the conformations of the ethyl group at C(3) and hydroxyl group at C(4). DFT studies were also performed to predict the favoured conformations of ethyl group at C(3) and hydroxyl group at C(4). Chemical shifts were also computed theoretically in the favoured conformation and they also support negative chemical shifts of 2 in acetone-d(6). PMID- 22925972 TI - Spectroscopic investigations on Pr3+ and Nd3+ doped strontium-lithium-bismuth borate glasses. AB - Spectroscopic investigations on different concentrations (0.1, 0.5, 1.0, 1.5 and 2.0mol%) of Pr(3+) and Nd(3+) doped strontium lithium bismuth borate glasses have been done. X-ray diffraction, SEM with EDS, absorption and luminescence spectra were recorded for all the glass matrices and analyzed. X-ray diffraction profiles and SEM images conformed amorphous nature of investigated glass samples. EDS spectra of host glass and Pr(3+)doped glass matrices gave information about the chemical composition of glass samples. From the absorption spectra of Pr(3+) and Nd(3+) ions, Judd-Ofelt (J-O) intensity parameters (Omega(lambda),lambda=2, 4 and 6) have been calculated and compared with other glass matrices. The emission characteristics such as radiative lifetimes (tau(R)), measured and calculated branching ratios (beta) and stimulated emission cross-sections (sigma(P)) have been obtained for the observed emission transitions of Pr(3+) and Nd(3+) ions in the above glass matrix for all the concentrations. From the emission spectra of Pr(3+) and Nd(3+) doped glass matrices, the effect of concentration on the quenching of intensity of (1)D(2)->(3)H(4) transition of Pr(3+) ion and (4)F(3/2) >(4)I(9/2), (4)I(11/2) and (4)I(13/2) transitions of Nd(3+) have been studied and discussed. PMID- 22925973 TI - Molecular structure and vibrational study of diprotonated guanazolium using DFT calculations and FT-IR and FT-Raman spectroscopies. AB - The purpose of this manuscript is to discuss our investigations of diprotonated guanazolium chloride using vibrational spectroscopy and quantum chemical methods. The solid phase FT-IR and FT-Raman spectra were recorded in the regions 4000 400cm(-1) and 3600-50cm(-1) respectively, and the band assignments were supported by deuteration effects. Different sites of diprotonation have been theoretically examined at the B3LYP/6-31G level. The results of energy calculations show that the diprotonation process occurs with the two pyridine-like nitrogen N2 and N4 of the triazole ring. The molecular structure, harmonic vibrational wave numbers, infrared intensities and Raman activities were calculated for this form by DFT/B3LYP methods, using a 6-31G basis set. Both the optimized geometries and the theoretical and experimental spectra for diprotonated guanazolium under a stable form are compared with theoretical and experimental data of the neutral molecule reported in our previous work. This comparison reveals that the diprotonation occurs on the triazolic nucleus, and provide information about the hydrogen bonding in the crystal. The scaled vibrational wave number values of the diprotonated form are in close agreement with the experimental data. The normal vibrations were characterized in terms of potential energy distribution (PED) using the VEDA 4 program. PMID- 22925974 TI - Nondestructive identification for red ink entries of seals by Raman and Fourier transform infrared spectrometry. AB - Determination of the red ink entries of seals on documents can provide valuable evidences for solving related crimes, distinguishing the truth of artworks, and so establishment of nondestructive approaches would play a key role in forensic analysis and related aspects. Raman and FT-IR spectroscopy have been applied for analyzing 105 kinds of red ink entries on documents. The dye components of the ink entries were identified by FT-Raman and confocal Raman microspectroscopy, and then the ink entries were classified into four groups based on these dye components. The ink entries were further discriminated by their FT-IR spectra according to adsorption peaks of the main components, the relative intensities of the characteristic bands and the profiles of the spectra. The results showed that 70 ink entries out of 105 have been individually identified and the remaining 35 ink entries can be divided into 13 subclasses. Combination of Raman and FT-IR spectroscopic methods can provide a powerful nondestructive discriminating tool for identification of the red ink entries of seals on papers. These approaches would have potential application in archeology, art and forensic science. PMID- 22925975 TI - Crystal structure, spectral, thermal and dielectric studies of a new zinc benzoate single crystal. AB - Single crystals of zinc benzoate with a novel structure were grown in gel media. Sodium metasilicate of gel density 1.04 g/cc at pH 6 was employed to yield transparent single crystals. The crystal structure of the compound was ascertained by single crystal X-ray diffractometry. It was noted that the crystal belongs to monoclinic system with space group P2(1)/c with unit cell parameters a=10.669(1)A, b=12.995(5)A, c=19.119(3)A, and beta=94.926(3) degrees . The crystal was seen to possess a linear polymeric structure along b-axis; with no presence of coordinated or lattice water. CHN analysis established the stoichiometric composition of the crystal. The existence of functional groups present in the single crystal system was confirmed by FT-IR studies. The thermal characteristic of the sample was analysed by TGA-DTA techniques, and the sample was found to be thermally stable up to 280 degrees C. The kinetic and thermodynamic parameters were also determined. UV-Vis spectroscopy corroborated the transparency of the crystal and revealed the optical band gap to be 4 eV. Dielectric studies showed decrease in the dielectric constant of the sample with increase in frequency. PMID- 22925976 TI - A novel surface-enhanced Raman scattering nanosensor for detecting multiple heavy metal ions based on 2-mercaptoisonicotinic acid functionalized gold nanoparticles. AB - A novel, effective and simple surface-enhanced Raman scattering (SERS) nanosensor for selectively and sensitively detecting heavy metal ions in aqueous solution has been developed in the form of 2-mercaptoisonicotinic acid (2 MNA)-modified gold nanoparticles (AuNPs). Multiple heavy metal ions can be identified and quantified by using relative peak intensity ratios of selected vibrational bands in the SERS spectra of 2 MNA. Especially, concentration of Hg(2+) and Pb(2+) ions are determined by comparing the intensity ratios of the bands 1160/1230 cm(-1) for Hg(2+) and 861/815 cm(-1) (or 815/1392 cm(-1)) for Pb(2+), with detection limits of 3.4*10(-8) and 1.0*10(-7)M, respectively. 2 MNA-AuNPs sensors show a high selectivity for Hg(2+) without masking reagent, and they can also be highly selective for Pb(2+) when using sodium thiosulphate and l-cysteine as masking reagents. These results demonstrate that these 2 MNA-AuNPs nanosensors are promising candidates for in situ heavy metal ions detection and quantification, maybe even inside living cells. PMID- 22925977 TI - Synthesis, structure, photo-responsive properties of 4-(2 fluorobenzylideneamino)antipyrine: a combined experimental and theoretical study. AB - In this work, 4-(2-fluorobenzylideneamino)antipyrine (FBIAAP) was synthesized and characterized by elemental analysis, XRD, FT-IR, FT-Raman and UV-Vis techniques as well as density functional calculations. The studied molecule adopts a trans configuration about the imine CN bond, and adjacent molecules are linked through two kinds of weak hydrogen bonds to form supramolecular layered structures along the ab plane. Vibrational spectral analyses show that the benzene moiety directly attached to the central pyrazoline shows good vibrational isolation from the other moiety of pyrazole-imino-benzene presenting good vibrational resonances. UV vis absorption bands mainly belong to n->pi and pi->pi according to the electron transfer orbital assignments for the electron absorption spectrum of FBIAAP. The first-order hyperpolarizability of FBIAAP is 44.9 times that of urea theoretically. In addition, the thermodynamic properties were also obtained theoretically from the harmonic frequencies of the optimized structure. PMID- 22925978 TI - Rotational isomers, density functional theory, vibrational spectroscopic studies, thermodynamic functions, NBO and HOMO-LUMO analyses of 2,6 Bis(chloromethyl)pyridine. AB - The FT-IR and FT-Raman spectra of 2,6-Bis(chloromethyl)pyridine (BCMP) have been recorded in the regions 4000-400 cm(-1) and 3500-100 cm(-1), respectively. The total energy calculations of BCMP were tried for the possible rotational isomers. The molecular structure, geometry optimization, vibrational frequencies were obtained by the HF and density functional theory (DFT/B3LYP) method with 6 311+G(d,p) basis set for the most stable rotational isomer "R3". The harmonic frequencies were calculated and the scaled values were compared with experimental FT-IR and FT-Raman spectra. The observed and the calculated frequencies are found to be in good agreement. The calculated HOMO and LUMO energies show that charge transfer occurs in the molecule. The stability of the molecule was analyzed using NBO analysis. The thermodynamic functions (heat capacity, entropy, vibrational partition function and Gibbs energy) were obtained for the range of temperature 100 K-700 K. PMID- 22925979 TI - Synthesis, characterization and electrochemical study of synthesis of a new Schiff base (H2cddi(t)butsalen) ligand and their two asymmetric Schiff base complexes of Ni(II) and Cu(II) with NN'OS coordination spheres. AB - A novel Schiff base (H(2)cddi(t)butsalen) ligand was prepared via condensation of Methyl-2-{N-(2'-aminoethane)}-amino-1-cyclopentenedithiocarboxylate(Hcden) and 3,5-di-tert-butyl-2-hydroxybenzaldehyde. The ligand and Ni(II) and Cu(II) complexes were characterized based on elemental analysis, IR, (1)H NMR, (13)C NMR, UV-Vis spectrometry and cyclic voltammetry. The structure of copper{methyl-2 {N-[2-(3,5-di-tert-butyl-2-hydroxyphenyl)methylidynenitrilo]ethyl}amino-1 cyclopentedithiocarboxylate has been determined by X-ray crystallography. The X ray results confirm that the geometry of the complex is slightly distorted square planar structure. The copper(II) ion coordinates to two nitrogen atoms from the imine moiety of the ligand, a sulfur atom the methyl dithiocarboxylate moiety and phenolic oxygen atom. PMID- 22925980 TI - Molecular structure, natural bond analysis, vibrational, and electronic spectra of aspartateguanidoacetatenickel(II), [Ni(Asp)(GAA)].H2O: DFT quantum mechanical calculations. AB - The aspartateguanidoacetatenickel (II) complex, [Ni(Asp)(GAA)], was synthesized and structural analysis was performed by means of the experimental methods: determination of the C, H, N and O contents, thermogravimetry, infrared and Raman spectroscopy. DFT:B3LYP/6-311G(d, p) calculations have been performed giving optimized structure and harmonic vibrational wavenumbers. Second derivative of the FT-infrared, FT-Raman and Surface Raman Enhanced Scattering (SERS) spectra, and band deconvolution analysis were also performed. Features of the FT-infrared, FT-Raman and SERS confirmed theoretical structure prediction. Full assignment of the vibrational spectrum was also supported by a carefully analysis of the distorted geometries generated by the normal modes. The Natural Bond Orbital analysis (NBO) was also carried out as a way to study the Ni (II) hybridization leading to the pseudo planar geometry of the framework, and the extension of the atomic N and O hybrid orbital of the different amino acids in the bond formation. Bands of charge transfer and d-d transitions were assigned in the UV-Vis spectrum. PMID- 22925981 TI - FTIR spectroscopy study of the structure changes of palygorskite under heating. AB - Progressive heat treatment was applied to palygorskite, and the changes of the position and intensity of its infrared vibrations, particularly those in the low wavenumber region, were monitored by use of Fourier transform infrared spectroscopy. Moreover, the responses of the impurities in palygorskite under heating were also examined. Palygorskite is characterized by two bands at 1196 and 647 cm(-1), which are attributed to the asymmetric stretching vibration of the Si-O-Si group that connects the adjacent inverse SiO(4) tetrahedrons and the H(2)O-Mg-H(2)O stretching vibration in the MgO(6) octahedra at the edges of the channels, respectively. The band at approximately 680 cm(-1) is attributed to the overlapping symmetric stretching vibrations of Si-O-Mg and Si-O-Al (VI). In addition, the 865 cm(-1) band corresponds to the amorphous carbonate impurity. PMID- 22925982 TI - Raman and infrared spectroscopic characterization of beryllonite, a sodium and beryllium phosphate mineral - implications for mineral collectors. AB - The mineral beryllonite has been characterized by the combination of Raman spectroscopy and infrared spectroscopy. SEM-EDX was used for the chemical analysis of the mineral. The intense sharp Raman band at 1011 cm(-1), was assigned to the phosphate symmetric stretching mode. Raman bands at 1046, 1053, 1068 and the low intensity bands at 1147, 1160 and 1175 cm(-1) are attributed to the phosphate antisymmetric stretching vibrations. The number of bands in the antisymmetric stretching region supports the concept of symmetry reduction of the phosphate anion in the beryllonite structure. This concept is supported by the number of bands found in the out-of-plane bending region. Multiple bands are also found in the in-plane bending region with Raman bands at 399, 418, 431 and 466 cm(-1). Strong Raman bands at 304 and 354 cm(-1) are attributed to metal oxygen vibrations. Vibrational spectroscopy served to determine the molecular structure of the mineral. The pegmatitic phosphate minerals such as beryllonite are more readily studied by Raman spectroscopy than infrared spectroscopy. PMID- 22925983 TI - Synthesis, structural elucidation and spectroscopic analysis of 3a,8b-dihydroxy-4 oxo-1H,2H,3H,3aH,4H,8bH-indeno[1,2-d]imidazolidin-2-iminium chloride. AB - Ninhydrin guanidinium chloride (3a,8b-dihydroxy-4-oxo-1H,2H,3H,3aH,4H,8bH-indeno [1,2-d]imidazolidin-2-iminium chloride) a semiorganic crystal was synthesized. The structure was determined using X-ray single crystal technique. Comparisons between the FT-IR spectrum of ninhydrin guanidinium chloride with ninhydrin were made. Melting point was found using thermal measurements. The molecular geometry, vibrational frequencies and Mulliken charges of the compound in the ground state have been calculated by the density functional theory (DFT) method with 3 21G(d,p) basis set and theoretical frequencies were compared with the experimental FT-IR spectrum. Besides, molecular electrostatic potential (MEP), frontier molecular orbitals (FMO) analysis, natural bond orbitals (NBO) and thermodynamic properties at various temperatures of the compound were investigated by theoretical calculations. PMID- 22925984 TI - Spectroscopic study of the ground and excited state prototropic equilibria of 4 azaindole. AB - The ground and singlet excited state prototropism of 4-azaindole, 4AI, in acid and basic aqueous solutions, inside and outside the pH range, has been systematically studied by using absorption and fluorescence spectroscopic techniques. These studies have thrown light on some interesting aspects on the nature and the photophysics of the 4-AI prototropic species. Thus, the changes of the 4AI absorption spectra reveal the existence of four ground state species; the pyridinic protonated cation, C (pK(a)(C)=7.5+/-0.1), the neutral molecule, N (pK(a)(N)=15.5+/-0.5), the pyrrolic deprotonated anion, A, and a previously unnoticed dication, DC (pK(a)(DC)=-4.6+/-0.4). Besides the emissions of these species, a new fluorescence profile appears in alkaline solutions at around 500nm. This extra band has been ascribed to the neutral phototautomer, NT. What is more relevant to this study is the fact that the position and the intensity of the emission band assigned to the monoprotonated cation are very different from those observed for the normal cation of the 7-azaindole, 7-AI. This together with the fact that for the formation of the DC species a cationic precursor with a quinoid structure must be invoked, have prompted us to assign this cationic emission to the isomeric CI cations. Finally, the excited-state pK(a)s of the prototropic species of 4AI have been theoretically estimated by using the Forster Weller cycle. PMID- 22925985 TI - Vibrational spectroscopic analysis of 2-chloro-5-(2,5-dimethoxy-benzylidene)-1,3 diethyl-dihydro-pyrimidine-4,6(1H,5H)-dione. AB - In the present work, a combined experimental and computational study for the optimized molecular structural parameters, FT-IR spectra, thermo-chemical parameters, total dipole moment and HOMO-LUMO energy gap for 2-chloro-5-(2,5 dimethoxy-benzylidene)-1,3-diethyl-dihydro-pyrimidine-4,6(1H,5H)-dione have been investigated using B3LYP/6-311G basis set. Our calculated results have showed that the investigated compound possesses a dipole moment of 4.9 Debye and HOMO LUMO energy gap of 3 eV which indicate high recommendations for photovoltaic devices fabrication. PMID- 22925986 TI - FT-Raman spectroscopic analysis of the most probable structures in aluminum chloride and tetrahydrofuran solutions. AB - A study by concentration-dependent Raman spectroscopy is presented for solutions of AlCl(3) in THF. The formation of small amounts of AlCl(4)(-) has been evidenced by the appearance of only one band at 348 cm(-1) in the most diluted salt solution. Another band at 330 cm(-1) starts rising with increasing salt concentration and it seems to belong to the [AlCl(3)(THF)(3)] complex. Indeed, this octahedral entity was confirmed by the quantitative analysis performed at the band envelope at 915 cm(-1). At this region, additional bands at 927 and 858 cm(-1) were observed and assigned to the C-C and C-O stretching modes, respectively, of THF molecules coordinated to the aluminum salt. Besides them, another band at 1042 cm(-1) clearly reveals the existence of this population of molecules. Although neutral octahedral complexes seem to be the major species in more concentrated salt solutions, the Raman spectra show the presence of complex ions in whole studied concentration range. PMID- 22925987 TI - Interaction between holo transferrin and HSA-PPIX complex in the presence of lomefloxacin: an evaluation of PPIX aggregation in protein-protein interactions. AB - Human serum albumin (HSA) and holo transferrin (TF) are two serum carrier proteins that are able to interact with each other, thereby altering their binding behavior toward their ligands. During the course of this study, the interaction between HSA-PPIX and TF, in the presence and absence of lomefloxacin (LMF), was for the first time investigated using different spectroscopic and molecular modeling techniques. Fluorescence spectroscopy experiments were performed in order to study conformational changes of proteins. The RLS technique was utilized to investigate the effect of LMF on J-aggregation of PPIX, which is the first report of its kind. Our findings present clear-cut evidence for the alteration of interactions between HSA and TF in the presence of PPIX and changes in drug-binding to HSA and HSA-PPIX complex upon interaction with TF. Moreover, molecular modeling studies suggested that the binding site for LMF became switched in the presence of PPIX, and that LMF bound to the site IIA of HSA. The obtained results should give new insight into research in this field and may cast some light on the dynamics of drugs in biological systems. PMID- 22925989 TI - Comparison of Expandable and Fixed Interbody Cages in a Human Cadaver Corpectomy Model: Fatigue Characteristics. AB - STUDY DESIGN: In vitro cadaver biomechanics study. OBJECTIVE: The goal of this study is to compare the in situ fatigue life of expandable versus fixed interbody cage designs. SUMMARY OF BACKGROUND DATA: Expandable cages are becoming more popular, in large part, due to their versatility; however, subsidence and catastrophic failure remain a concern. This in vitro analysis investigates the fatigue life of expandable and fixed interbody cages in a single level human cadaver corpectomy model by evaluating modes of subsidence of expandable and fixed cages as well as change in stiffness of the constructs with cyclic loading. METHODS: Nineteen specimens from 10 human thoracolumbar spines (T10-L2, L3-L5) were biomechanically evaluated after a single level corpectomy that was reconstructed with an expandable or fixed cage and anterior dual rod instrumentation. All specimens underwent 98 K cycles to simulate 3 months of postoperative weight bearing. In addition, a third group with hyperlordotic cages was used to simulate catastrophic failure that is observed in clinical practice. RESULTS: Three fixed and 2 expandable cages withstood the cyclic loading despite perfect sagittal and coronal plane fitting of the endcaps. The majority of the constructs settled in after initial subsidence. The catastrophic failures that were observed in clinical practice could not be reproduced with hyperlordotic cages. However, all cages in this group subsided, and 60% resulted in endplate fractures during deployment of the cage. CONCLUSIONS: Despite greater surface contact area, expandable cages have a trend for higher subsidence rates when compared with fixed cages. When there is edge loading as in the hyperlordotic cage scenario, there is a higher risk of subsidence and intraoperative fracture during deployment of expandable cages. PMID- 22925988 TI - Quantification of pedal edema during treatment with S(-)-amlodipine nicotinate versus amlodipine besylate in female Korean patients with mild to moderate hypertension: a 12-week, multicenter, randomized, double-blind, active controlled, phase IV clinical trial. AB - BACKGROUND: Amlodipine is a racemic mixture of (R)- and (S)-enantiomers. It has been suggested that removing the therapeutically inactive (R)-enantiomer will reduce adverse events while preserving the agent's efficacy. Women experience more adverse effects from amlodipine. OBJECTIVE: This exploratory study compared the amount of pedal edema experienced by female Korean patients with mild to moderate hypertension when receiving S(-)-amlodipine nicotinate compared with amlodipine besylate. METHODS: This study was a 12-week, multicenter, randomized, double-blind, active-controlled, Phase IV clinical trial. Female patients with mild to moderate hypertension were randomly assigned to receive either S(-) amlodipine nicotinate 2.5 to 5 mg once daily or amlodipine besylate 5 to 10 mg once daily for 12 weeks. The primary objective was to compare the change in ankle foot volume quantified by using a water displacement method after 12 weeks of therapy. The secondary objectives were to compare the changes in mean sitting systolic and diastolic blood pressures. Safety assessment included monitoring all laboratory tests, adverse events (AEs), serious AEs, and possible relation to the study medication. RESULTS: Of the 38 patients enrolled, 17 patients in each group were eligible for final analysis. In the S(-)-amlodipine nicotinate group, the mean ankle-foot volume at baseline was 1056.91 (98.15) mL, and volume after 12 weeks of treatment was 1016.68 (158.37) mL, a decrease of 40.24 (110.05) mL. In the amlodipine besylate group, mean ankle-foot volume at baseline was 1037.56 (158.30) mL, and volume after treatment was 1067.59 (152.54) mL, an increase of 30.03 (69.59) mL. There was a significant difference in the change of ankle-foot volume between the 2 groups (-70.26 mL [95% CI, -134.60 to -5.94], P = 0.028). After 12 weeks, the mean changes in sitting systolic blood pressure from baseline were not significantly different between the 2 groups (-21.82 [8.76] vs -26.82 [11.89] mm Hg; P = 0.172). Changes in mean sitting diastolic blood pressure also were not significant (-14.71 [6.94] vs -10.88 [5.81] mm Hg; P = 0.091). One patient in each group had facial edema, and another patient in the amlodipine besylate group had facial flushing. Overall, there was no significant difference in drug-related AEs between the 2 groups (P = 0.999). CONCLUSIONS: These female Korean patients with hypertension taking S(-)-amlodipine nicotinate had less ankle edema, with no significant difference in BP-lowering efficacy, compared with those taking amlodipine besylate. S(-)-amlodipine nicotinate may be a suitable alternative for patients intolerant to amlodipine besylate. (Clinical Research Information Service: CRiS, KCT0000450). PMID- 22925990 TI - Eimeria bovis: an update on parasite-host cell interactions. AB - Apicomplexan parasites are obligate intracellular protozoans and are well recognized modulators of the host cell machinery on varying levels such as host cell metabolism, MHC expression, cell cycle, or apoptosis in order to guarantee their intracellular development and survival. One of the most thoroughly examined apicomplexan pathogens demonstrating a potent manipulative capacity with respect to various host cell functions is Toxoplasma gondii, a protozoon exhibiting rapid intracellular development with small meronts in any nucleated cell, almost irrespective of the cell type or host origin. In contrast, Eimeria bovis merogony I is host- and cell type-restricted and occurs exclusively in bovine endothelial host cells. Furthermore, as a peculiarity, intracellular E. bovis meront I development is a long-lasting process (up to 3 weeks), leading to the formation of huge macromeronts of up to 300 MUm in size, containing up to 120,000 merozoites I as offspring. In consequence, the necessity for intense host cell modulation to support this particular development appears even more pressing than in other apicomplexan parasite cases. Here we review the data currently available on E. bovis-host cell interactions, indicating the intriguing capacity of this protozoan to exploit and utilize its host cell for its own benefit. PMID- 22925991 TI - Will medical examination gloves protect rescuers from defibrillation voltages during hands-on defibrillation? AB - BACKGROUND: Continuing compressions during a defibrillation shock has been proposed as a method of reducing pauses in cardiopulmonary resuscitation (CPR) but the safety of this procedure is unproven. The medical examination gloves worn by rescuers play an important role in protecting the rescuer yet the electrical characteristics of these gloves are unknown. This study examined the response of medical examination gloves to defibrillation voltages. METHODS: Part 1 of this study measured voltage-current curves for a small sample (8) of gloves. Part 2 tested more gloves (460) to determine the voltage required to produce a specific amount of current flow. Gloves were tested at two current levels: 0.1 mA and 10 mA. Testing included four glove materials (chloroprene, latex, nitrile, and vinyl) in a single layer and double-gloved. RESULTS: All gloves tested in part 1 allowed little current to flow (<1 mA) as the voltage was increased until breakdown occurred, at which point current flow increased precipitously. In part 2, 118 of 260 (45%) single gloves and 93 of 120 (77%) double gloves allowed at least 0.1 mA of current flow at voltages within the external defibrillation voltage range. Also, 6 of 80 (7.5%) single gloves and 5 of 80 (6.2%) double gloves allowed over 10 mA. CONCLUSIONS: Few of the gloves tested limited the current to levels proven to be safe. A lack of sensation during hands-on defibrillation does not guarantee that a safety margin exists. As such, we encourage rescuers to minimize rather than eliminate the pause in compressions for defibrillation. PMID- 22925992 TI - Anatomical relationships of the Air-Q supraglottic airway during elective MRI scan of brain and neck. PMID- 22925993 TI - The accuracy of human senses in the detection of neonatal heart rate during standardized simulated resuscitation: implications for delivery of care, training and technology design. AB - AIM: Auscultation and palpation are recommended methods of determining heart rate (HR) during neonatal resuscitation. We hypothesized that: (a) detection of HR by auscultation or palpation will vary by more than +/- 15BPM from actual HR; and (b) the inability to accurately determine HR will be associated with errors in management of the neonate during simulated resuscitation. SUBJECTS AND METHODS: Using a prospective, randomized, controlled study design, 64 subjects participated in three simulated neonatal resuscitation scenarios. Subjects were randomized to technique used to determine HR (auscultation or palpation) and scenario order. Subjects verbalized their numeric assessment of HR at the onset of the scenario and after any intervention. Accuracy of HR determination and errors in resuscitation were recorded. Errors were classified as errors of omission (lack of appropriate interventions) or errors of commission (inappropriate interventions). Cochran's Q and chi square test were used to compare HR detection by method and across scenarios. RESULTS: Errors in HR determination occurred in 26-48% of initial assessments and 26-52% of subsequent assessments overall. There were neither statistically significant differences in accuracy between the two techniques of HR assessment (auscultation vs palpation) nor across the three scenarios. Of the 90 errors in resuscitation, 43 (48%) occurred in association with errors in HR determination. CONCLUSIONS: Determination of heart rate via auscultation and palpation by experienced healthcare professionals in a neonatal patient simulator with standardized cues is not reliable. Inaccuracy in HR determination is associated with errors of omission and commission. More reliable methods for HR assessment during neonatal resuscitation are required. PMID- 22925994 TI - Inertial migration of erythrocytes in low-viscosity and high-shear rate microtube flows: application of simple digital in-line holographic microscopy. AB - A simple digital in-line holographic microscopy technique is applied to investigate the inertial migration of human erythrocytes in low-viscosity and high-shear rate microtube flows. The technique provides radial distribution statistics of the erythrocytes, as well as their orientation information in the tube flow. The radial distribution of human erythrocytes is found to be similar to that of spherical particles of 7 MUm in diameter. The results show that both the erythrocytes and the spherical particles are fully focused at similar radial positions as the shear-rate of the flow increases. The erythrocytes require a higher shear rate than the spherical particle to establish the fully focused state. As the radial migration of erythrocytes fully develops, more than half of the cells have symmetry axes orthogonal to the main stream and wall-normal directions. This orientation demonstrates similar hydrodynamic effects of disk shaped biconcave erythrocytes to those of the spherical particles, and consequently results in similar radial equilibrium positions. PMID- 22925995 TI - European Society of Biomechanics S.M. Perren Award 2012: the external mechanical environment can override the influence of local substrate in determining stem cell fate. AB - The aim of this study was to explore how cell-matrix interactions and extrinsic mechanical signals interact to determine stem cell fate in response to transforming growth factor-beta3 (TGF-beta3). Bone marrow derived mesenchymal stem cells (MSCs) were seeded in agarose and fibrin hydrogels and subjected to dynamic compression in the presence of different concentrations of TGF-beta3. Markers of chondrogenic, myogenic and endochondral differentiation were assessed. MSCs embedded within agarose hydrogels adopted a spherical cell morphology, while cells directly adhered to the fibrin matrix and took on a spread morphology. Free swelling agarose constructs stained positively for chondrogenic markers, with MSCs appearing to progress towards terminal differentiation as indicated by mineral staining. MSC seeded fibrin constructs progressed along an alternative myogenic pathway in long-term free-swelling culture. Dynamic compression suppressed differentiation towards any investigated lineage in both fibrin and agarose hydrogels in the short-term. Given that fibrin clots have been shown to support a chondrogenic phenotype in vivo within mechanically loaded joint defect environments, we next explored the influence of long term (42 days) dynamic compression on MSC differentiation. Mechanical signals generated by this extrinsic loading ultimately governed MSC fate, directing MSCs along a chondrogenic pathway as opposed to the default myogenic phenotype supported within unloaded fibrin clots. In conclusion, this study demonstrates that external cues such as the mechanical environment can override the influence specific substrates, scaffolds or hydrogels have on determining mesenchymal stem cell fate. The temporal data presented in this study highlights the importance of considering how MSCs respond to extrinsic mechanical signals in the long term. PMID- 22925996 TI - [How to manage Takayasu arteritis?]. AB - Thorough clinical and imaging assessment of the arterial tree when a diagnosis of Takayasu arteritis is established. Glucocorticoid as intiation therapy. Immunosuppresive agent should be considered as adjunctive therapy if resistance or dependance to glucocorticoid therapy. Supportive care, antihypertensive drugs, glucocorticoid induced osteoporosis preventive therapy, tuberculosis screening should not be forgiven. Monitoring of therapy should be clinical and supported by biological markers and imaging. Reconstructive surgery should be performed in the quiescent phase of disease. PMID- 22925997 TI - [Alveolar ridge augmentation with cortical osteotomies for dental implantation]. AB - Cortical osteotomies allow alveolar ridge augmentation so as to place dental implants of adequate size, most often in one step. This technique is reliable and allows long-lasting prosthetic restoration, without need for a graft-harvesting site. We report an expansion technique, which combines various cortical alveolar osteotomies. It allows guiding bone fractures away from the implant site during the expansion procedure. The possibility of implant placement is enlarged because exposure risks for implants are limited. The technique also preserves cortical bone structure and resistance, while allowing a larger bone augmentation movement. The diameter, axis, and crestal emergence position are optimized, thus improving the biomechanical resistance of implant restoration. A better implant position and restoration of bone anatomy and volume, supporting the gingival alveolar mucosa, improve the esthetic and prosthetic result. This technique can be used if the ridge is very narrow with limited bone elasticity. We present the various osteotomies and basic surgical steps for transversal and even vertical alveolar ridge augmentation, as well as possible modifications and clinical results. PMID- 22925998 TI - Changes in the aetiological spectrum of leg ulcers after a broad-scale intervention in a defined geographical population in Sweden. AB - OBJECTIVE: The study aims to compare the spectrum of leg ulcer aetiology in Skaraborg County in 1988 and 2002, an evaluation of 14 years of targeted leg ulcer intervention. DESIGN: Cross-sectional study within the professional health care system in Skaraborg County. MATERIALS: In 2002, 621 leg ulcer patients were identified through a cross-sectional population survey. METHODS: Half of the registered patients were randomly selected and offered clinical examination. A total of 198 patients with 246 legs underwent examination and were categorised in detail according to aetiology. Data were compared with the initial study in 1988. RESULTS: Venous incompetence was present in 140 (57%) legs and the dominating cause in 94 (38%) of the leg ulcers, 40 (16%) due to deep venous incompetence. Arterial insufficiency was identified in 90 (37%) legs and the dominating aetiological factor in 41 legs (17%), eight (3%) being critical ischaemic ulcers. The relative risk (RR) of developing a leg ulcer in 2002 vs. 1988 was 0.77. The RR of a venous ulcer was reduced by 46%, arterial by 28%, while there was an increase in diabetic ulcers by 29% and multifactorial by 42%. CONCLUSION: The aetiological spectrum of leg ulcers has changed, most likely due to a new management strategy in the care of leg ulcer patients. PMID- 22925999 TI - Aspirin as a promising drug for slow coronary flow. PMID- 22926000 TI - Treatment of inflammatory bowel disease with neural stem cells expressing choline acetyltransferase. AB - Inflammatory bowel disease (IBD) is a chronic inflammatory disorder, with increasing incidence and prevalence in the last one-half century. IBD patients suffer from autonomic vagal neuropathy and nerve dysfunction, with deficiency of acetylcholine in inflamed mucosa. Recent studies showed that death of enteric neuron in local tissue was induced during the process of IBD, which also played a crucial role in the pathogenesis of disease. Stem cells have been demonstrated a new biological treatment for IBD, therefore, we proposal that neural stem cells expressing choline acetyltransferase may enhance enteric neural cell regeneration, restore acetylcholine production in intestinal mucosa, and thus inhibit immune responses of IBD. PMID- 22926001 TI - The development of sensorimotor reflexes in albino mice; albino rats and black hooded rats. AB - The present investigation aimed to show the differences in the development of sensorimotor reflexes and their relationship to the structural changes in spinal cord, cerebellum and cerebral cortex in three rodent species. The three species are albino rats (A-Rats), black-hooded rats (B-Rats) and albino mice. The development of selected reflexes was examined from day (D1) to D21. The structural changes were investigated at D7, D14, and D21. The following reflexes were analyzed: fore-limb/hind-limb grasp, surface body righting, fore-limb hopping, chin tactile placing, visual placing and body righting in the air. The developmental pattern of the reflexes was different in three rodent species. Although the black-hooded rats and albino rats belong to the same species, they are different in their appearance and developmental pattern. The development of external features and sensorimotor reflexes appeared earlier in mice than in A Rats and B-Rats. At D7, differentiation of neurons was observed in the spinal cord while in cerebellum and cerebrum the neurons were found to be undifferentiated. At D14 and D21, the differentiated neurons were observed in spinal cord, cerebellum and cerebrum. Our data indicate that the developmental pattern of the reflexes in rodents may not be species specific but may be related to the animal strain. PMID- 22926002 TI - Cerebrospinal fluid biomarkers for clinical trials: why markers for differential diagnosis are important. PMID- 22926003 TI - Immunomodulatory effects of IP-10 chemokine along with PEI600-Tat delivery system in DNA vaccination against HPV infections. AB - Although DNA vaccines represent an attractive approach for generating antigen specific immunity, improvement of their potency is highly demanded. In the present study, three strategies including linkage to immunostimulatory molecules (N-terminal of gp96), co-administration of chemokines (IP-10 or RANTES) and PEI600-Tat as non-viral gene delivery system have been applied to enhance DNA vaccine efficacy against HPV infections. We found that C57BL/6 immunization with E7-NT-gp96 fusion gene led to increased level of IFN-gamma compared to E7 alone. The fused genes showed considerable protective potency in tumor mice model. In addition, E7-NT-gp96 delivered with PEI600-Tat was more protective against E7 expressing tumors comparing with E7-NT-gp96 alone. Our results showed that co administration of IP-10 with E7-NT-gp96 delivered by PEI600-Tat elicits significant IFN-gamma production and consequently a strong preventive response against TC-1 tumor cells in contrast to increased tumor growth by RANTES co delivery. Also in therapeutic experiment, our data showed that co-immunization of IP-10 at the same inoculation site of TC-1 along with E7-NT-gp96 delivery by PEI600-Tat is able to significantly suppress TC-1 tumor growth. The successful treatment by this immunization protocol was associated with the elevated levels of IFN-gamma and IL-2 production in the lymph nodes. These data indicated that fusion of NT-gp96 to E7 in combination with IP-10 co-administration and PEI600 Tat delivery system can synergistically enhance the potency of HPV DNA vaccines. Therefore, this approach suggests a combinational therapeutic strategy against cervical and other HPV-related cancers. PMID- 22926004 TI - Pharmacologic evidence to support clinical decision making for peripartum methadone treatment. AB - RATIONALE: Limited pharmacological data are available to guide methadone treatment during pregnancy and postpartum. OBJECTIVES: Study goals were to (1) characterize changes in methadone dose across childbearing, (2) determine enantiomer-specific methadone withdrawal kinetics from steady state during late pregnancy, (3) assess enantiomer-specific changes in methadone level/dose (L/D) ratios across childbearing, and (4) explore relationships between CYP2B6, CYP2C19, and CYP3A4 single-nucleotide polymorphisms and maternal dose, plasma concentration, and L/D. METHODS: Methadone dose changes and timed plasma samples were obtained for women on methadone (n = 25) followed prospectively from third trimester of pregnancy to 3 months postpartum. RESULTS: Participants were primarily white, Medicaid insured, and multiparous. All women increased their dose from first to end of second trimester (mean peak increase = 23 mg/day); 71 % of women increased from second trimester to delivery (mean peak increase = 19 mg/day). Half took a higher dose 3 months postpartum than at delivery despite significantly larger clearance during late pregnancy. Third trimester enantiomer specific methadone half-lives (range R-methadone 14.7-24.9 h; S-methadone, 8.02 18.9 h) were about half of those reported in non-pregnant populations. In three women with weekly 24-h methadone levels after delivery, L/D increased within 1-2 weeks after delivery. Women with the CYP2B6 Q172 variant GT genotype have consistently higher L/D values for S-methadone across both pregnancy and postpartum. CONCLUSIONS: Most women require increases in methadone dose across pregnancy. Given the shorter half-life and larger clearances during pregnancy, many pregnant women may benefit from split methadone dosing. L/D increases quickly after delivery and doses should be lowered rapidly after delivery. PMID- 22926005 TI - Sex differences in behavioral and neural cross-sensitization and escalated cocaine taking as a result of episodic social defeat stress in rats. AB - RATIONALE: Episodic social defeat stress results in cross-sensitization to cocaine, characterized by augmentation of locomotor activity, dopamine (DA) levels in the nucleus accumbens (NAc), and cocaine self-administration during a 24-h "binge" in male rats. However, females are more vulnerable than males at each phase of cocaine addiction, and while these sex differences have been replicated in rats, the role of social stress in females remains largely neglected. OBJECTIVE: This study examined sex and estrous cycle differences in behavioral and dopaminergic cross-sensitization to cocaine, as well as cocaine taking in an unlimited-access self-administration "binge." METHODS: Long-Evans rats underwent episodic social defeat and were assessed 10 days later for either (1) behavioral sensitization, as determined by locomotor activity in response to acute cocaine (10 mg/kg, i.p.), (2) neural sensitization, as determined by in vivo microdialysis of DA in the NAc shell in response to acute cocaine, or (3) intravenous self-administration of cocaine (0.3 mg/kg/infusion) in an unlimited access "binge." RESULTS: Social defeat stress resulted in behavioral and dopaminergic cross-sensitization in both sexes, but the effect was larger and longer lasting in stressed females. Furthermore, while stress engendered a longer "binge" in both sexes, females had a significantly longer "binge" duration than males. CONCLUSIONS: These data suggest that socially stressed females exhibit a larger and longer lasting behavioral and neural cross-sensitization, as well as more dysregulated cocaine taking, than males possibly due to different alterations in the dopaminergic response in the NAc. Furthermore, estrogens appear to play a facilitatory role in both behavioral and dopaminergic sensitization. PMID- 22926006 TI - Comparison of metabolic effects of ziprasidone versus olanzapine treatment in patients with first-episode schizophrenia. AB - OBJECTIVE: The objective of the study was to compare metabolic effects of ziprasidone versus olanzapine treatment in patients with first-episode schizophrenia. METHODS: In this 6-week, multicenter, open-label trial, 260 patients were randomly assigned to receive ziprasidone or olanzapine treatment (130 per group). Primary metabolic measures were changes in weight and body mass index (BMI). Secondary metabolic measures were changes in glucose, insulin, lipids, and blood pressure. Efficacy and safety were also measured additionally. RESULTS: A total number of 230 patients completed the study. The mean daily dosages were 138.2(28.6) mg for ziprasidone and 19.0(2.3) mg for olanzapine. After 6-week treatment, there were significant between-group differences in change scores on weight [4.22(3.49) kg versus -0.84(2.04) kg, p < 0.001] and BMI [1.59(1.37) versus -0.30(0.74), p < 0.001]. In addition, there were significant between-group differences in change scores on fasting plasma glucose, insulin, homeostasis model assessment 2-insulin resistance, low-density lipoprotein, total cholesterol, and triglycerides (p < 0.001); all the changes were clinically in favor of ziprasidone treatment. Both medications were effective in improving schizophrenia symptoms, but the decreases in Positive and Negative Syndrome Scale total scores of the olanzapine group were significantly greater than that of the ziprasidone group (p < 0.05). Compared with olanzapine, ziprasidone also induced more prolonging of corrected QT interval and extrapyramidal side effects (p < 0.05). Both medications were well tolerated, and no serious adverse events were observed in either group. CONCLUSIONS: Compared with olanzapine, ziprasidone treatment was associated with less adverse effects on glucose and lipid metabolism in patients with first-episode schizophrenia. PMID- 22926007 TI - Anticholinesterase insecticide retrospective. AB - The anticholinesterase (antiChE) organophosphorus (OP) and methylcarbamate (MC) insecticides have been used very effectively as contact and systemic plant protectants for seven decades. About 90 of these compounds are still in use - the largest number for any insecticide chemotype or mode of action. In both insects and mammals, AChE inhibition and acetylcholine accumulation leads to excitation and death. The cholinergic system of insects is located centrally (where it is protected from ionized OPs and MCs) but not at the neuromuscular junction. Structural differences between insect and mammalian AChE are also evident in their genomics, amino acid sequences and active site conformations. Species selectivity is determined in part by inhibitor and target site specificity. Pest population selection with OPs and MCs has resulted in a multitude of modified AChEs of altered inhibitor specificity some conferring insecticide resistance and others enhancing sensitivity. Much of the success of antiChE insecticides results from a suitable balance of bioactivation and detoxification by families of CYP450 oxidases, hydrolases, glutathione S-transferases and others. Known inhibitors for these enzymes block detoxification and enhance potency which is particularly important in resistant strains. The current market for OPs and MCs of 19% of worldwide insecticide sales is only half of that of 10 years ago for several reasons: there have been no major new compounds for 30 years; resistance has eroded their effectiveness; human toxicity problems are still encountered; the patents have expired reducing the incentive to update registration packages; alternative chemotypes or control methods have been developed. Despite this decline, they still play a major role in pest control and the increasing knowledge on their target sites and metabolism may make it possible to redesign the inhibitors for insensitive AChEs and to target new sites in the cholinergic system. The OPs and MCs are down but not out. PMID- 22926008 TI - Computer-delivered tailored intervention improves colon cancer screening knowledge and health beliefs of African-Americans. AB - We conducted a randomized controlled trial among African-American patients attending a primary-care provider visit to compare efficacy of a computer delivered tailored intervention to increase colorectal cancer (CRC) screening (n = 273) with non-tailored print material-an American Cancer Society brochure on CRC screening (n = 283). Health Belief Model constructs were used to develop tailored messages and examined as outcomes. Analysis of covariance models were used to compare changes between CRC knowledge and health belief scores at baseline and 1 week post-intervention. At 1 week, patients who received the computer-delivered tailored intervention had greater changes in CRC knowledge scores (P < 0.001), perceived CRC risk scores (P = 0.005), FOBT barriers scores (P = 0.034) and colonoscopy benefit scores (P < 0.001). Findings show that computer-delivered tailored interventions are an effective adjunct to the clinical encounter that can improve knowledge and health beliefs about CRC screening, necessary precursors to behavior change. PMID- 22926009 TI - Quantifying ongoing HIV-1 exposure in HIV-1-serodiscordant couples to identify individuals with potential host resistance to HIV-1. AB - BACKGROUND: Immunogenetic correlates of resistance to HIV-1 in HIV-1-exposed seronegative (HESN) individuals with consistently high exposure may inform HIV-1 prevention strategies. We developed a novel approach for quantifying HIV-1 exposure to identify individuals remaining HIV-1 uninfected despite persistent high exposure. METHODS: We used longitudinal predictors of HIV-1 transmission in HIV-1 serodiscordant couples to score HIV-1 exposure and define HESN clusters with persistently high, low, and decreasing risk trajectories. The model was validated in an independent cohort of serodiscordant couples. We describe a statistical tool that can be applied to other HESN cohorts to identify individuals with high exposure to HIV-1. RESULTS: HIV-1 exposure was best quantified by frequency of unprotected sex with, plasma HIV-1 RNA levels among, and presence of genital ulcer disease among HIV-1-infected partners and by age, pregnancy status, herpes simplex virus 2 serostatus, and male circumcision status among HESN participants. Overall, 14% of HESN individuals persistently had high HIV-1 exposure and exhibited a declining incidence of HIV-1 infection over time. CONCLUSIONS: A minority of HESN individuals from HIV-1-discordant couples had persistent high HIV-1 exposure over time. Decreasing incidence of infection in this group suggests these individuals were selected for resistance to HIV-1 and may be most appropriate for identifying biological correlates of natural host resistance to HIV-1 infection. PMID- 22926010 TI - Hyperinsulinemia reduces osteoblast activity in vitro via upregulation of TGF beta. AB - Affecting more than 230,000,000 patients, diabetes mellitus is one of the most frequent metabolic disorders in developed countries. Among other complications, diabetic patients have an increased fracture risk and show delayed fracture healing. During the disease progression, these patients' blood glucose and insulin levels vary significantly. Thus, the aim of this study was to analyze the effects of glucose and insulin on primary human osteoblasts. Although, in the presence of insulin and glucose, proliferation of osteoblasts was increased (1.2- to 1.7-fold), their alkaline phosphatase activity and, consequently, production of mineralized matrix were significantly reduced down to 55 % as compared to control cells (p < 0.001). Interestingly, the observed effects were mainly due to stimulation with insulin. Increase in glucose did not alter osteoblasts' function significantly but further enhanced the effects of insulin. Expression of active and total transforming growth factor beta (TGF-beta) was increased by glucose and insulin. Stimulation with both glucose and insulin induced gene expression changes (e.g., osteocalcin, Runx2, Satb2, or Stat1) comparable to treatment with recombinant TGF-beta(1), further indicating osteoblasts' dysfunction. Inhibition of TGF-beta signaling completely abolished the negative effects of glucose and insulin. In summary, glucose and insulin treatment causes osteoblast dysfunction, which is accompanied by an increased TGF-beta expression. Blocking TGF-beta signaling abrogates the functional loss observed in glucose- and insulin-treated osteoblasts, thus identifying TGF-beta as a key regulator. Therefore, increased TGF-beta expression during diabetes may be a feasible pathogenic mechanism underlying poor bone formation in uncontrolled diabetes mellitus. PMID- 22926011 TI - Estrogen stimulates the proliferation of human endometrial cancer cells by stabilizing nucleophosmin/B23 (NPM/B23). AB - Unopposed estrogen exposure is an important factor in the tumorigenesis of endometrial cancer. Nucleophosmin/B23 (NPM/B23), a phosphoprotein that has pleiotropic functions in cells, plays an important role in various cancers. However, the regulatory role of NPM/B23 in estrogen signaling in endometrial cancer has not been explored. Here, we report that NPM/B23 was required for estrogen-induced endometrial proliferation, and the increase in NPM/B23 was estrogen receptor alpha-dependent. Furthermore, estrogen increased NPM/B23 protein levels by repressing its ubiquitination and subsequently stabilizing the protein. The overexpression of the alternate reading frame (ARF) suppressed the estrogen-induced increase in the NPM/B23 protein levels, indicating that ARF inhibited the observed estrogen-mediated NPM/B23 stabilization. Our results suggest that one of the effects of estrogen on endometrial proliferation is the suppression of the NPM/B23-ARF interaction and the subsequent increase in NPM/B23 protein levels. This novel characterization of NPM/B23 in estrogen-mediated cell proliferation may extend our understanding of the tumorigenesis of steroid hormone-related cancers. PMID- 22926012 TI - MRI manifestations of adult choledochal cysts associated with biliary malignancy: a report of ten cases. AB - BACKGROUND: To retrospectively review the MRI imaging features of adult choledochal cysts associated with biliary malignancy. PATIENTS AND METHODS: Ten out of 72 cases of adult choledochal cysts were found to be associated with biliary malignancy between January 1, 2003 and April 1, 2011 in our hospital database. The following MRI findings of these ten patients were retrospectively reviewed: the type of choledochal cysts, the presence of anomalous union of the pancreaticobiliary duct (AUPBD), manifestations of biliary malignancy, and concomitant findings. RESULTS: Among the ten patients, there were five type I and five type IVA choledochal cysts. AUPBD was noted in four cases. The biliary malignancy was diagnosed as cholangiocarcinoma in seven cases (70.0%) and as gallbladder cancer in three cases. Cholangiocarcinoma manifested with irregularly thickened cyst wall (n = 2), mass with irregularly thickened cyst wall (n = 4), or multiple papillary nodules without thickened cyst wall (n = 1). Most of them showed mark enhancement (n = 4) after contrast administration. Gallbladder cancer appeared as mass with irregular thickening of the gallbladder wall with inhomogeneous enhancement. Concomitant findings included liver invasion or metastases in five cases, lymph node metastases in two cases, cholangitis and/or hepatic abscess in two cases, biliary stones in three cases. The type of choledochal cysts and the extent of malignant tumor invasion revealed by MRI were consistent with the surgical findings. CONCLUSION: Most malignancies associated with choledochal cysts are cholangiocarcinoma and gallbladder cancer. MRI is a reliable method for the detection of choledochal cysts with biliary malignant changes. MR features such as irregular thickening of the gallbladder wall or cyst wall, mass or papillary nodules are suggestive of biliary malignant changes. PMID- 22926013 TI - Improving participation in colorectal cancer screening: targets for action. AB - OBJECTIVE: Our aim was to determine whether physician-related factors influenced patient participation in colorectal cancer (CRC) screening programs and to identify patient characteristics associated with lower participation in order to facilitate the development of targeted actions to improve participation. METHOD: A retrospective cohort study was conducted in a French department during its first CRC screening campaign from June 2007 to May 2010. Data for 157,766 patients followed by 903 general practitioners (GPs) were analyzed. Patient participation was assessed using multilevel logistic modeling. RESULTS: The overall participation rate was 30% (95% confidence interval [95% CI], 29.8-30.2) and varied across the 903 GPs from 0% to 75.5% (median, 30; interquartile range, 24-35). Inter-GP variance explained only 5.5% of the participation rate variance. Participation was significantly lower in males (odds ratio [OR], 0.79; 95% CI, 0.78-0.91), the youngest age group (55-59 years, OR, 0.61; 95% CI, 0.58-0.63), and patients living in socioeconomically deprived areas (OR, 0.82; 95% CI, 0.77 0.87). CONCLUSION: Targeted actions to improve CRC screening participation should focus on patients younger than 60 years, males, and individuals living in deprived areas. Actions to enhance the influence of GPs on patient participation should be directed to the overall population of GPs. PMID- 22926015 TI - European Society of Thoracic Imaging: Abstracts from the 2012 20th Anniversary Congress, London, UK June 22-24, 2012. PMID- 22926014 TI - Impact of primary tumour resection on survival of patients with colorectal cancer and synchronous metastases treated by chemotherapy: results from the multicenter, randomised trial Federation Francophone de Cancerologie Digestive 9601. AB - OBJECTIVE: To assess the impact of primary tumour resection on overall survival (OS) of patients diagnosed with stage IV colorectal cancer (CRC). DESIGN: Among the 294 patients with non-resectable colorectal metastases enrolled in the Federation Francophone de Cancerologie Digestive (FFCD) 9601 phase III trial, which compared different first-line single-agent chemotherapy regimens, 216 patients (73%) presented with synchronous metastases at study entry and constituted the present study population. Potential baseline prognostic variables including prior primary tumour resection were assessed by univariate and multivariate Cox analyses. Progression-free survival (PFS) and OS curves were compared with the logrank test. RESULTS: Among the 216 patients with stage IV CRC (median follow-up, 33 months), 156 patients (72%) had undergone resection of their primary tumour prior to study entry. The resection and non-resection groups did not differ for baseline characteristics except for primary tumour location (rectum, 14% versus 35%; p=0.0006). In multivariate analysis, resection of the primary was the strongest independent prognostic factor for PFS (hazard ratio (HR), 0.5; 95% confidence interval [CI], 0.4-0.8; p=0.0002) and OS (HR, 0.4; CI, 0.3-0.6; p<0.0001). Both median PFS (5.1 [4.6-5.6] versus 2.9 [2.2-4.1] months; p=0.001) and OS (16.3 [13.7-19.2] versus 9.6 [7.4-12.5]; p<0.0001) were significantly higher in the resection group. These differences in patient survival were maintained after exclusion of patients with rectal primary (n=43). CONCLUSION: Resection of the primary tumour may be associated with longer PFS and OS in patients with stage IV CRC starting first-line, single-agent chemotherapy. PMID- 22926016 TI - Relationship between global structural parameters and Enzyme Commission hierarchy: implications for function prediction. AB - In protein databases there is a substantial number of proteins structurally determined but without function annotation. Understanding the relationship between function and structure can be useful to predict function on a large scale. We have analyzed the similarities in global physicochemical parameters for a set of enzymes which were classified according to the four Enzyme Commission (EC) hierarchical levels. Using relevance theory we introduced a distance between proteins in the space of physicochemical characteristics. This was done by minimizing a cost function of the metric tensor built to reflect the EC classification system. Using an unsupervised clustering method on a set of 1025 enzymes, we obtained no relevant clustering formation compatible with EC classification. The distance distributions between enzymes from the same EC group and from different EC groups were compared by histograms. Such analysis was also performed using sequence alignment similarity as a distance. Our results suggest that global structure parameters are not sufficient to segregate enzymes according to EC hierarchy. This indicates that features essential for function are rather local than global. Consequently, methods for predicting function based on global attributes should not obtain high accuracy in main EC classes prediction without relying on similarities between enzymes from training and validation datasets. Furthermore, these results are consistent with a substantial number of studies suggesting that function evolves fundamentally by recruitment, i.e., a same protein motif or fold can be used to perform different enzymatic functions and a few specific amino acids (AAs) are actually responsible for enzyme activity. These essential amino acids should belong to active sites and an effective method for predicting function should be able to recognize them. PMID- 22926017 TI - Characterization of the complete mitochondrial genomes of two whipworms Trichuris ovis and Trichuris discolor (Nematoda: Trichuridae). AB - For many years, whipworms (Trichuris spp.) have been described with a relatively narrow range of both morphological and biometrical features. Moreover, there has been insufficient discrimination between congeners (or closely related species). In the present study, we determined the complete mitochondrial (mt) genomes of two whipworms Trichuris ovis and Trichuris discolor, compared them and then tested the hypothesis that T. ovis and T. discolor are distinct species by phylogenetic analyses using Bayesian inference, maximum likelihood and maximum parsimony) based on the deduced amino acid sequences of the mt protein-coding genes. The complete mt genomes of T. ovis and T. discolor were 13,946 bp and 13,904 bp in size, respectively. Both mt genomes are circular, and consist of 37 genes, including 13 genes coding for proteins, 2 genes for rRNA, and 22 genes for tRNA. The gene content and arrangement are identical to that of human and pig whipworms Trichuris trichiura and Trichuris suis. Taken together, these analyses showed genetic distinctiveness and strongly supported the recent proposal that T. ovis and T. discolor are distinct species using nuclear ribosomal DNA and a portion of the mtDNA sequence dataset. The availability of the complete mtDNA sequences of T. ovis and T. discolor provides novel genetic markers for studying the population genetics, diagnostics and molecular epidemiology of T. ovis and T. discolor. PMID- 22926018 TI - Risk factors for the onset of nonspecific low back pain in office workers: a systematic review of prospective cohort studies. AB - OBJECTIVE: The purpose of this study was to systematically review prospective cohort studies to identify risk factors for the onset of low back pain (LBP) in office workers. METHODS: Online searches were conducted on PubMed, CINAHL Plus with full text, ScienceDirect, PEDro, ProQuest, and Scopus databases from 1980 to November 2011 using the following keywords: low back pain paired with risk or prognostic factors and office or computer or visual display unit (VDU) or visual display terminal (VDT). The methodological quality of each study was assessed using a 21-item checklist, which was divided into 2 parts: the internal validity (11 items) and descriptive quality (10 items) of studies. Strength of evidence for risk factors associated with the development of nonspecific LBP was assessed by defining 5 levels of evidence based on the number of studies and the quality score of studies. RESULTS: Eighteen full-text articles were identified, and 15 were excluded. A total of 3 articles were judged to meet the selection criteria and were included in the methodological quality assessment. Risk factors were divided into 3 groups: individual, work-related physical, and work-related psychosocial risk factors. There was strong evidence that history of LBP is a predictor of the onset of LBP. Limited evidence was found that the combination of postural risk factors and job strain is associated with the onset of LBP. CONCLUSION: After review of 3 high-quality prospective studies on the association between risk factors and the onset of nonspecific LBP in office workers, few risk factors were found to predict the onset of LBP in office workers. PMID- 22926019 TI - Paying for quality not quantity: a wisconsin health maintenance organization proposes an incentive model for reimbursement of chiropractic services. AB - OBJECTIVE: The purpose of this study is to describe a reimbursement model that was developed by one Health Maintenance Organization (HMO) to transition from fee for-service to add a combination of pay for performance and reporting model of reimbursement for chiropractic care. METHODS: The previous incentive program used by the HMO provided best-practice education and additional reimbursement incentives for achieving the National Committee for Quality Assurance Back Pain Recognition Program (NCQA-BPRP) recognition status. However, this model had not leveled costs between doctors of chiropractic (DCs). Therefore, the HMO management aimed to develop a reimbursement model to incentivize providers to embrace existing best-practice models and report existing quality metrics. The development goals included the following: it should (1) be as financially predictable as the previous system, (2) cost no more on a per-member basis, (3) meet the coverage needs of its members, and (4) be able to be operationalized. The model should also reward DCs who embraced best practices with compensation, not simply tied to providing more procedures, the new program needed to (1) cause little or no disruption in current billing, (2) be grounded achievable and defined expectations for improvement in quality, and (3) be voluntary, without being unduly punitive, should the DC choose not to participate in the program. RESULTS: The generated model was named the Comprehensive Chiropractic Quality Reimbursement Methodology (CCQRM; pronounced "Quorum"). In this hybrid model, additional reimbursement, beyond pay-for-procedures will be based on unique payment interpretations reporting selected, existing Physician Quality Reporting System (PQRS) codes, meaningful use of electronic health records, and achieving NCQA-BPRP recognition. This model aims to compensate providers using pay-for performance, pay-for-quality reporting, pay-for-procedure methods. CONCLUSION: The CCQRM reimbursement model was developed to address the current needs of one HMO that aims to transition from fee-for-service to a pay-for-performance and quality reporting for reimbursement for chiropractic care. This model is theoretically based on the combination of a fee-for-service payment, pay for participation (NCQA Back Pain Recognition Program payment), meaningful use of electronic health record payment, and pay for reporting (PQRS-BPMG payment). Evaluation of this model needs to be implemented to determine if it will achieve its intended goals. PMID- 22926020 TI - Cortical activity during speech and non-speech oromotor tasks: a magnetoencephalography (MEG) study. AB - We used whole-head magnetoencephalography to investigate cortical activity during two oromotor activities foundational to speech production. 13 adults performed mouth opening and phoneme (/pa/) production tasks to a visual cue. Jaw movements were tracked with an ultrasound-emitting device. Trials were time-locked to both stimulus onset and peak of jaw displacement. An event-related beamformer source reconstruction algorithm was used to detect areas of cortical activity for each condition. Beamformer output was submitted to iterative K-means clustering analyses. The time course of neural activity at each cluster centroid was computed for each individual and condition. Peaks were identified and latencies submitted for statistical analysis to reveal the relative timing of activity in each brain region. Stimulus locked activations for the mouth open task included a progression from left cuneus to left frontal and then right pre-central gyrus. Phoneme generation revealed the same sequence but with bilateral frontal activation. When time locked to jaw displacement, the mouth open condition showed left frontal followed by right frontal-temporal areas. Phoneme generation showed a complicated sequence of bilateral temporal and frontal areas. This study used three unique approaches (beamforming, clustering and jaw tracking) to demonstrate the temporal progression of neural activations that underlie the motor control of two simple oromotor tasks. These findings have implications for understanding clinical conditions with deficits in articulatory control or motor speech planning. PMID- 22926021 TI - Levels and predictors of airborne and internal exposure to chromium and nickel among welders--results of the WELDOX study. AB - The objective of this analysis was to investigate levels and determinants of exposure to airborne and urinary chromium (Cr, CrU) and nickel (Ni, NiU) among 241 welders. Respirable and inhalable welding fume was collected during a shift, and the metal content was determined using inductively coupled plasma mass spectrometry. In post-shift urine, CrU and NiU were measured by means of graphite furnace atom absorption spectrometry, with resulting concentrations varying across a wide range. Due to a large fraction below the limits of quantitation we applied multiple imputations to the log-transformed exposure variables for the analysis of the data. Respirable Cr and Ni were about half of the concentrations of inhalable Cr and Ni, respectively. CrU and NiU were determined with medians of 1.2 MUg/L (interquartile range <1.00; 3.61) and 2.9 MUg/L (interquartile range <1.50; 5.97). Furthermore, Cr and Ni correlated in respirable welding fume (r=0.79, 95% CI 0.74-0.85) and urine (r=0.55, 95% CI 0.44-0.65). Regression models identified exposure-modulating variables in form of multiplicative factors and revealed slightly better model fits for Cr (R(2) respirable Cr 48%, CrU 55%) than for Ni (R(2) respirable Ni 42%, NiU 38%). The air concentrations were mainly predicted by the metal content in electrodes or base material in addition to the welding technique. Respirable Cr and Ni were good predictors for CrU and NiU, respectively. Exposure was higher when welding was performed in confined spaces or with inefficient ventilation, and lower in urine when respirators were used. In conclusion, statistical modelling allowed the evaluation of determinants of internal and external exposure to Cr and Ni in welders. Welding parameters were stronger predictors than workplace conditions. Airborne exposure was lowest inside respirators with supply of purified air. PMID- 22926023 TI - Targeted therapies: New targets in Burkitt lymphoma? PMID- 22926022 TI - Emerging developments of chemoradiotherapy in stage III NSCLC. AB - Over the past decade, concomitant chemotherapy and radiotherapy has become the established treatment for patients with stage III non-small-cell lung cancer (NSCLC). Unfortunately, many patients with NSCLC are too old or have multiple comorbidities to withstand such aggressive treatments. Attempts to improve outcomes have included studies of radiotherapy dose escalation and new chemotherapy combinations, as well as adding biological agents and cancer vaccines to existing regimens. Technical radiotherapy modifications, including intensity-modulated radiotherapy and particle beam therapy, have also been investigated. Given the number of potential advances to current models of treatment development, phase III trials of any single new treatment can take years to complete, which is inadequate. To advance research within shorter timescales to improve patient outcomes, we need methods of improving clinical trial accrual, which might require changes in models of research governance, cooperative group activity, trial design and patient consent. PMID- 22926024 TI - Tailored amino acid diversity for the evolution of antibody affinity. AB - Antibodies are a unique class of proteins with the ability to adapt their binding sites for high affinity and high specificity to a multitude of antigens. Many analyses have been performed on antibody sequences and structures to elucidate which amino acids have a predominant role in antibody interactions with antigens. These studies have generally not distinguished between amino acids selected for broad antigen specificity in the primary immune response and those selected for high affinity in the secondary immune response. By studying a large data set of affinity matured antibodies derived from in vitro directed evolution experiments, we were able to specifically highlight a subset of amino acids associated with affinity improvements. In a comparison of affinity maturations using either tailored or full amino acid diversification, the tailored approach was found to be at least as effective at improving affinity while requiring fewer mutagenesis libraries than the traditional method. The resulting sequence data also highlight the potential for further reducing amino acid diversity for high affinity binding interactions. PMID- 22926025 TI - [Apathy in Parkinson's disease: clinical features, mechanisms and assessment]. AB - Apathy is a loss of motivation compared to the previous level of functioning of the subject. It affects the subject's behavior, cognition and emotional state. It is one of the main behavioral manifestations of Parkinson's disease. Although it may be a symptom of depression, it often exists as an isolated syndrome in Parkinson's disease patients. Apathy is usually not related to the severity of the motor symptoms, but frequently associated with the severity of cognitive impairment. Apathy is also a possible complication of treatment by stimulation of the subthalamic nucleus. Screening and assessment of apathy require the use of specific tools, some of which are validated in Parkinson's disease. From a pathophysiological point of view, apathy results from a dysfunction of the limbic circuit connecting the ventral striatum to orbitofrontal and anterior cingulate cortex. The dopaminergic denervation in these regions seems to play a key role, but other mechanisms are probably involved. Further studies are warranted to progress in the therapeutic management of this invalidating syndrome. PMID- 22926026 TI - Aquasoluble iron(III)-arylhydrazone-beta-diketone complexes: structure and catalytic activity for the peroxidative oxidation of C5-C8 cycloalkanes. AB - The aquasoluble Fe(III) complexes [Fe(H(2)O)(3)(L(1))]?4H(2)O (3) and [Fe(H(2)O)(3)(L(2))]?3H(2)O (4), bearing the basic forms of 5-chloro-3-(2-(4,4 dimethyl-2,6-dioxocyclohexylidene)hydrazinyl)-2-hydroxy-benzenesulfonic acid (H(3)L(1), 1) and 3-(2-(2,4-dioxopentan-3-ylidene)hydrazinyl)-2-hydroxy-5 nitrobenzenesulfonic acid (H(3)L(2), 2), were synthesized and fully characterized including by X-ray crystal structural analysis. In the channels of the water soluble 3D networks of 3 and 4, the uncoordinated water molecules are held by oxygen atoms of the carbonyl and sulfonyl groups, and by the water ligands. The Fe(III) coordination environment resembles that in the active sites of some mononuclear non-heme iron-containing enzymes. The complexes show a high catalytic activity for the peroxidative oxidation (with aqueous H(2)O(2)) of C(5)-C(8) cycloalkanes to the corresponding alcohols and ketones under mild conditions. The effects of various factors, such as amounts of oxidant, catalyst and HNO(3) additive, were investigated allowing to reach overall yields of ca. 25% and turnover numbers (TONs) up to 290. The catalytic reactions proceed via both oxygen- and carbon-radicals as shown by radical trap experiments. PMID- 22926027 TI - Two new dicopper(II) complexes with oxamido-bridged ligand: synthesis, crystal structures, DNA binding/cleavage and BSA binding activity. AB - New oxamido-bridged copper(II) complexes, [Cu(2)(oxbp)(H(2)O)(2)(NCS)(2)] (1) and [Cu(2)(oxbp)(MU-DMSO)(2)(NCS)(2)][Cu(2)(oxbp)(DMSO)(2)(NCS)(2)] (2) (H(2)oxbp=N,N'-bis(2-(diethylamino)ethyl)oxalamide), were synthesized and characterized by single-crystal X-ray diffraction, elemental analysis, IR, and electronic spectra. X-ray analysis revealed that complex 1 consists of neutral binuclear [Cu(2)(oxbp)(H(2)O)(2)(NCS)(2)] units which forms a two-dimensional network through intermolecular hydrogen bonds and complex 2 is constructed by neutral [Cu(2)(oxbp)(MU-DMSO)(2)(NCS)(2)] (2a) and [Cu(2)(oxbp)(DMSO)(2)(NCS)(2)] (2b) entities which alternately distribute to form a two-dimensional network by means of quasi MU-DMSO bridge and intermolecular hydrogen bonds. In both 1 and 2, bicopper centers are linked by the "trans-form" oxamido bridges with the distances of 5.272 A for 1 and av. 5.296 A for 2, respectively. The interaction of Cu(II) complexes with DNA was investigated by UV-visible, fluorescence emission spectrometry and agarose gel electrophoresis. The apparent binding constant (K(app)) values of 3.16*10(5) M(-1) for 1 and 4.9*10(5) M(-1) for 2 suggest moderate intercalative binding modes between the complexes and DNA. Complex 1 displayed efficient oxidative cleavage of supercoiled DNA, which might indicate that the underlying mechanism involves singlet oxygen (((1))O(2)) as reactive oxygen species. Complex 2 is characteristic of the involvement of a singlet oxygen-like entity and hydrogen peroxide in the cleavage process. In addition, our present work showed, by fluorescence spectrometry of BSA with complexes, both 1 and 2 bind to BSA with a medium affinity through a static mode which is tentatively assigned binding to Trp134 in BSA. PMID- 22926028 TI - Transport of the anti-diabetic VO2+ complexes formed by pyrone derivatives in the blood serum. AB - The biotransformation in the blood serum of the two anti-diabetic agents [VO(ema)(2)] - or BEOV - and [VO(koj)(2)] formed by ethylmaltol (Hema) and kojic acid (Hkoj) was studied with EPR spectroscopy, pH-potentiometry and DFT calculations. For comparison, the behavior of the systems with tropolone (Htrop) was also analyzed. The interaction of [VO(ema)(2)] and [VO(koj)(2)] with the most important bioligands of the serum, lactic (Hlact) and citric acid (H(3)citr), human serum transferrin (hTf), human serum albumin (HSA) and immunoglobulin G (IgG) was examined and discussed. Among the several mixed species observed, cis VO(carrier)(2)(hTf), cis-VO(carrier)(2)(HSA) and cis-VO(carrier)(2)(IgG), where carrier is ethylmaltolate or kojate, with a His-N of the protein coordinated in the equatorial position, are plausible candidates for the transport processes of the drug toward the target organs. The values of the logbeta are in the range 19.6-19.8 for the species formed by ethylmaltol and 17.4-17.6 for those formed by kojic acid. The formation of such species was confirmed through pH-titrations of the model systems VO(2+)/carrier/1-MeIm and VO(2+)/carrier/Ac-his, where 1-MeIm and Ac-his are 1-methylimidazole and N-acetylhistamine, and DFT calculations of (51)V A(z) of the model species cis-[VO(carrier)(2)(1-MeIm)] and cis [VO(carrier)(2)(Ac-his)]. The values of the stability constants for the mixed species observed were used to predict the biodistribution of VO(2+) ion between the blood serum components for concentrations of 1, 10 and 50 MUM. PMID- 22926029 TI - Structure-cytotoxicity relationship for different types of mononuclear platinum(II) complexes with 5,7-ditertbutyl-1,2,4-triazolo[1,5-a]pyrimidine. AB - To compare the in vitro cytotoxicity of platinum(II) complexes with 5,7 ditertbutyl-1,2,4-triazolo[1,5-a]pyrimidine (dbtp), three complexes were prepared: cis-[PtI(2)(dbtp)(2)] (1), cis-[Pt(NO(3))(2)(dbtp)(2)] (2) and cis [Pt(C(4)H(4)O(5))(dbtp)(2)] (3). The coordination compounds have been structurally characterized by IR; (1)H, (13)C, (15)N, (195)Pt NMR and single crystal X-ray diffraction (1). Spectroscopic studies reveal the monodentate coordination of the heterocycle ligand (dbtp) via N(3) to platinum(II) ions. In addition, the crystal structure of (1) shows that the platinum(II) ion is located in nearly square-planar PtI(2)N(2) environments with two heterocycle ligands (dbtp) arranged in a head-to-head orientation. The complexes have been screened for their cytotoxicity against two human cells: non-small cell lung carcinoma (A549) and breast cancer (T47D). All of the complexes demonstrated a significant antiproliferative activity against both cell lines. On the basis of these results, it is concluded that the cytotoxicity of the studied compounds against T47D follows the order: (3)<(1)<(2). PMID- 22926030 TI - Increased gibberellin contents contribute to accelerated growth and development of transgenic tobacco overexpressing a wheat ubiquitin gene. AB - KEY MESSAGE: Overexpressing TaUb2 promoted stem growth and resulted in early flowering in transgenic tobacco plants. Ubiquitin are involved in the production, metabolism and proper function of gibberellin. The ubiquitin-26S proteasome system (UPS), in which ubiquitin (Ub) functions as a marker, is a post translational regulatory system that plays a prominent role in various biological processes. To investigate the impact of different Ub levels on plant growth and development, transgenic tobacco (Nicotiana tabacum L.) plants were engineered to express an Ub gene (TaUb2) from wheat (Triticum aestivum L.) under the control of cauliflower mosaic virus 35S promoter. Transgenic tobacco plants overexpressing TaUb2 demonstrated an accelerated growth rate at early stage and an early flowering phenotype in development. The preceding expression of MADS-box genes also corresponded to the accelerated developmental phenotypes of the transgenic tobacco plants compared to that of wild-type (WT). Total gibberellin (GA) and active GA contents in transgenic tobacco plants were higher than those in WT at the corresponding developmental stages, and some GA metabolism genes were upregulated. Treatment with GA(3) conferred a similarly accelerated grown rate in WT plants to that of transgenic tobacco plants, while growth was inhibited when transgenic tobacco plants were treated with a GA biosynthesis inhibitor. Thus, the results suggest that Ub are involved in the production, metabolism and proper function of GA, which is important in the regulation of plant growth and development. PMID- 22926031 TI - Overexpression of allene oxide cyclase promoted tanshinone/phenolic acid production in Salvia miltiorrhiza. AB - KEY MESSAGE: This study provides a desirable candidate gene resource (SmAOC) to increase the content of valuable natural products via appropriate JA pathway genetic engineering. Jasmonates (JAs) are important signal molecules in plants. They regulate transcripts of defense and secondary biosynthetic metabolite genes in response to environmental stresses. Currently, JAs are widely used as elicitors to improve the content of useful secondary metabolism in plants. Synthesis of the naturally occurring enantiomer of various jasmonates is catalyzed by allene oxide cyclase (AOC, EC 5.3.99.6). Here, we cloned and characterized the AOC gene (SmAOC) from Salvia miltiorrhiza. As expected, SmAOC expression was induced by abiotic stimuli such as methyl jasmonate (MeJA), ultraviolet radiation (UV) and low temperature (4 degrees C) in S. miltiorrhiza plantlets. To demonstrate whether the engineered internal JAs pool by overexpressing AOC gene could promote secondary metabolism production, the SmAOC was incorporated into S. miltiorrhiza hairy roots. The results revealed that SmAOC overexpression significant enhanced the yields of tanshinone IIA, rosmarinic acid (RA) and lithospermic acid B (LAB) in S. miltiorrhiza hairy roots. In addition, expression levels for key genes involved in the biosynthetic pathway of diterpenes and phenolic acids were also altered. These suggest that genetic manipulation of AOC would be helpful for improving the production of valuable secondary metabolites by regulating the biosynthesis of JAs. PMID- 22926032 TI - Low melting point agarose beads as a standard method for plantlet regeneration from protoplasts within the Cichorium genus. AB - KEY MESSAGE: A standard method has been developed with which we are able to fully regenerate protoplasts of different Cichorium species. For the first time, endive protoplasts have been regenerated into plantlets. Protoplast regeneration is essential for somatic hybridizations. In this study, a standard method for plantlet regeneration from Cichorium protoplasts was developed. We evaluated the effect of the low melting point agarose (LMPA) bead technique on the regeneration capacity of protoplasts of seven C. intybus and four C. endivia genotypes. The LMPA bead technique was more efficient than culture in liquid or solid medium and allowed us to obtain plating efficiencies up to 4.9 % in C. intybus genotypes and efficiencies of up to 0.7 % in C. endivia genotypes. Moreover, the LMPA bead technique offers great advantages over liquid and solid culture systems: the media can be readily refreshed, protoplasts can be monitored separately, and microcalli can easily be removed from the beads. This increased efficiency was observed for all of the 11 Cichorium genotypes tested. Shoot formation was induced more efficiently when using 0.5 mg l(-1) indole-3-acetic acid-enriched medium (up to 87.5 % of the protoplast-derived calli started shoot development) compared to 1-naphthaleneacetic acid-enriched medium. The LMPA bead technique optimized in this study enabled for the first time the full plantlet regeneration from protoplasts of C. endivia genotypes and increased the protoplast regenerating ability in other Cichorium species. This fine-tuned LMPA bead technique can therefore be applied for protoplast regeneration after protoplast fusions of the genus Cichorium. PMID- 22926033 TI - Formation and identification of nitrosylmyoglobin by Staphylococcus xylosus in raw meat batters: a potential solution for nitrite substitution in meat products. AB - Staphylococcus xylosus and Pediococcus pentosaceus isolated from Chinese dried sausage were assessed for their ability to convert metmyoglobin into nitrosylmyoglobin in Mann-Rogosa-Sharp broth model systems and raw pork meat batters without the addition of nitrite. The results showed that samples in model systems with S. xylosus cultures had an absorption spectra that is typical of nitrosylmyoglobin, an obvious pink colour (judged by visual inspection) and a significantly higher a-value than the control samples or samples inoculated with P. pentosaceus. In raw meat batters, the a-values of the S. xylosus samples were almost the same as those for the meat with nitrite added. The complementary analysis of meat batter samples by photochemical information from UV-vis, electron spin resonance and resonance Raman spectroscopy revealed that the existing status of the myoglobin in meat batters inoculated with S. xylosus was mainly pentacoordinate nitrosylmyoglobin. This study provides a potential solution for nitrite substitute in meat products. PMID- 22926034 TI - Clinical value of drugs targeting inflammation for the management of coronary artery disease. AB - Atherosclerosis and cardiovascular disease are the leading cause of death worldwide. Atherosclerosis is a complex inflammatory disease that results from lipid accumulation and oxidation in the arterial wall combined with an active inflammatory reaction involving transmigration of monocytes and other inflammatory cells from the blood stream into the vessel wall. Many therapeutic approaches have been tested to treat atherosclerosis and prevent its complications, with statins being the most efficient therapy by reducing the levels of atherogenic lipoproteins and preventing major cardiovascular events. However, the risk of atherothrombotic complications still remains high, causing millions of deaths around the world each year. Extensive research has shed light on the cascade of cellular and molecular events that lead from atherosclerotic plaque formation to its rupture and have highlighted promising new therapeutic targets, each being implicated at different stages of the atherosclerotic plaque formation and progression. In this review, we briefly discuss the potential of high-density lipoprotein-based therapies, given the anti-inflammatory properties of high-density lipoprotein. We then present different approaches that tackle inflammation, including inhibition of 5-lipoxygenase, blockade of P-selectin, use of a viral-derived serpin, and interleukin-1beta inhibition. All these targets have shown encouraging results in clinical trials and support the idea that targeting inflammation could reduce cardiovascular complications in patients with coronary artery disease. PMID- 22926035 TI - Management of adults with congenital heart disease using videoconferencing across Western Canada: a 3-year experience. AB - BACKGROUND: Management of adults with congenital heart disease (ACHD) requires quaternary centres with cardiologists and cardiac surgeons who have expertise in the diagnosis and management of this patient population. We report on the feasibility of the management of ACHD patients using videoconferencing and streaming through 1 regional referral centre covering 4 western Canadian provinces, roughly 30% of Canada's land and population. METHODS: Videoconferencing sessions from January 2008 to December 2010 were systematically reviewed. Case presentations were classified as successful or unsuccessful. All patients were followed to assess whether the recommendations were acted upon. The hosting institution used the Alberta Health Services internet protocol network, while other connections used integrated service digital network. The videoconference equipment at the different sites includes Polycom HDX 9000 (Polycom, San Jose, CA), Tandberg Edge 95 (Tandberg, San Jose, CA), and Tandberg 990 (Tandberg). RESULTS: From January 2008 to December 2010 there were 26 sessions, 213 case presentations, and 177 patients discussed with an average 8.2 case presentations per session. Thirty-two case presentations were deferred, 10 of which were because of transmission errors and the remainder were because of unavailability of staff or images. Of the 177 recommendations, 124 procedures (91 surgical, 29 percutaneous, and 4 electrophysiological) were booked directly at the regional referral centre. Only 6 recommendations were not carried out (4 because of premature deaths, and 2 because of patient logistic issues). CONCLUSIONS: The results of this study illustrate that telehealth is a feasible medium for arriving at consensus recommendation in the management of ACHD patients living in a geographically diverse area. PMID- 22926036 TI - Pneumococcal endocarditis causing valve destruction in the absence of vegetations on transesophageal echocardiography: a series of 3 consecutive cases. AB - Streptococcus pneumoniae endocarditis is uncommon. It has a predilection for the aortic valve and is associated with high mortality. We present 3 consecutive cases of pneumococcal endocarditis, each preceded by a different extracardiac infection but all causing destructive aortic valve lesions associated with severe regurgitation, in the absence of vegetations on transesophageal echocardiography. This case series illustrates the aggressive nature of pneumococcal endocarditis and the need for early diagnosis. Echocardiography should be considered in all individuals with persistent extracardiac pneumococcal infections. PMID- 22926037 TI - Different expression and function of the endocannabinoid system in human epicardial adipose tissue in relation to heart disease. AB - BACKGROUND: The endocannabinoid system reportedly plays a role in the pathogenesis of cardiovascular diseases. This system is expressed also in adipose tissue, which could thus be involved in cardiac disorders through modulation of metabolically triggered inflammation. The current study aims to determine the relevance of the endocannabinoid system in epicardial adipose tissue in heart disease. METHODS: Expression of the endocannabinoid receptors CB1 and CB2, and of the endocannabinoid-degrading enzyme, fatty acid amidohydrolase, and activation of protein kinase A (PKA), phospholipase C (PLC), protein kinase C (PKC), endothelial nitric oxide synthase (eNOS) and inducible (i)NOS, and extracellular signal-regulated kinases 1 and 2 (ERK1/2) (a member of the reperfusion-injury salvage kinase pathway), were analyzed by Western blot in patients after coronary artery bypass surgery (ischemics; N = 18) or valve surgery (nonischemics; N = 15) and in preadipocytes isolated from epicardial adipose tissue. RESULTS: In ischemics, the CB1-to-CB2 expression ratio shifted toward CB1 and was accompanied by higher PKA activation. In contrast, in nonischemics, CB2, fatty acid amidohydrolase, PLC and PKC, and ERK1/2 were upregulated. Moreover, NO production and iNOS-to-eNOS ratios were higher in preadipocytes from ischemics. CONCLUSIONS: These results show a different modulation and functioning of the endocannabinoid system in ischemics compared with nonischemics. Hence, while CB2, PLC and PKC, ERK1/2, and eNOS are more strongly expressed in patients without ischemic heart disease, high CB1 and PKA expression is associated with low survival intracellular pathway activation and high iNOS activation in ischemic heart disease patients. The changes in the endocannabinoid system in ischemics may contribute to cardiac dysfunction and therefore represents a potential therapeutic target. PMID- 22926038 TI - Percutaneous vs surgical repair of mitral valve regurgitation: single institution early and midterm outcomes. AB - BACKGROUND: The objective of this study was to compare outcomes of surgical repair (SR) vs MitraClip (MC) implantation for severe mitral regurgitation (MR). METHODS: A retrospective analysis of patients treated within a single institution was performed. Patients had EuroSCORE [European System for Cardiac Operative Risk Evaluation] < 20%, left ventricular ejection fraction >=45%, and grade 3+/4+ MR. RESULTS: Fifty patients (24 [48%] MC group, 26 [52%] SR group) with EuroSCORE 7.9 +/- 5.6 were included. The MC group included 24 (48%) and the SR group 26 (52%) patients. Patients in the MC group had a significantly more complex comorbid profile (P < 0.001). Successful MC placement was in 22 patients (91.7%) and SR in 26 (100%). At discharge, no patient had grade 3+/4+ MR. There were no in hospital or 30-day deaths. At follow-up (mean 526 +/- 398 days), further mitral valve surgery was necessary in 1 (3.8%) patient in the SR group and in 2 (8.3%) patients in the MC group (P = 0.26). One-year freedom from composite end point (death, stroke, myocardial infarction, major bleeding, cardiac rehospitalization) was 75.5% (SR 83% vs MC 67%; P = 0.18). Degree of residual MR Degree of residual MR immediately after the procedure was equally distributed in both groups (P = 0.13) and the sole independent determinant for composite outcome (odds ratio, 16.9; P = 0.024). CONCLUSIONS: MC in nonsurgical candidates and SR in surgical patients showed similar perioperative and follow-up outcomes at an institution experienced with both techniques. Neither MC nor SR were independently related to outcome whenever similar degrees of acute correction with minimal residual MR were achieved. However, these findings should be interpreted within the selection biases and the numerical limitations of the present study. PMID- 22926039 TI - Do omega-3 fatty acids decrease the incidence of atrial fibrillation after open heart surgery? PMID- 22926040 TI - Red blood cell distribution width in saphenous vein graft disease. AB - BACKGROUND: Red blood cell distribution width (RDW) is related to morbidity and mortality in a wide spectrum of conditions, including atherosclerotic processes. In the present study, we aimed to investigate the significance of RDW in saphenous vein graft disease (SVGD), in which atherosclerosis plays an important pathophysiological role. METHODS: In all, 90 patients were enrolled in the study, 58 with patent SVGs and 32 with SVGD. Stable angina and/or positive stress tests were indications for coronary angiography. RDW and other laboratory parameters were measured before coronary angiography. RESULTS: Baseline characteristics of the patient groups were similar. Although triglyceride levels of the SVGD group were higher than those of the patent SVG group, the difference did not reach statistical significance (188.9 +/- 99.8 mg/dL vs 151.0 +/- 75.5 mg/dL, respectively; P = 0.068). Mean time interval after bypass surgery was longer in the SVGD group compared with the patent SVG group (7.8 +/- 4.5 years vs 5.6 +/- 3.1 years, respectively; P = 0.008). The RDW values of patients with SVGD were higher than those of patients in the patent SVG group. In logistic regression analysis, RDW and time since bypass graft were retained as independent predictors for SVGD. CONCLUSION: In the present study, we showed for the first time that RDW, which is a simple and inexpensively measured parameter used routinely in daily clinical practice, can be used as a predictor of SVGD, together with time since bypass surgery. PMID- 22926041 TI - Diagnostic value of ankle-brachial index in peripheral arterial disease: a meta analysis. AB - BACKGROUND: In a previous review, we reported that ankle brachial index (ABI) <= 0.90 could reliably identify patients with peripheral artery disease (PAD). Since then, more studies have been published which may extend the power of a meta analysis of studies of diagnostic accuracy of the ABI. MEDLINE and several other databases were searched for studies on sensitivity and specificity of using ABI <= 0.90 for PAD diagnosis compared with angiography. METHODS: Quality of each study was assessed by standards for reporting diagnostic accuracy initiative and quality assessment for studies of diagnostic accuracy tool. Heterogeneity was assessed using the Cochran Q statistic, chi(2), and inconsistency index. The area under the curve and Q* were estimated using summary receiver operator curve. The pooled diagnostic odds ratio (DOR), sensitivity, specificity, positive likelihood ratio (PLR), and negative likelihood ratio (NLR) of ABI <= 0.90 to diagnose PAD were estimated using Meta-DiSc software (Meta-DiSc, Madrid, Spain). RESULTS: Four studies comprising 569 patients (922 limbs) met inclusion criteria. Significant heterogeneity among these studies was not detected in DOR but was evident in pooled sensitivity, specificity, PLR, and NLR. The area under the curve under the summary receiver operator curve is 0.87 (standard error = 0.02) and diagnostic accuracy (Q*) is 0.80 (standard error = 0.02). Additionally, DOR was 15.33 with corresponding 95% confidence intervals of 9.39-25.02. The pooled sensitivity and specificity of ABI <= 0.90 for PAD diagnosis were 75% and 86% and the pooled PLR and NLR were 4.18 and 0.29, respectively. CONCLUSIONS: We conclude that test of ABI <= 0.90 can be a useful tool to identify PAD with serious stenosis in clinical practice. PMID- 22926042 TI - The influence of essential oil of aniseed (Pimpinella anisum, L.) on drug effects on the central nervous system. AB - Anise (Pimpinella anisum L.; Apiaceae) and its essential oil have been widely used in folk medicine, pharmacy and food industry. Since there are some data about the impact of anise on functions of central nervous system (CNS), the issue of possible interactions with drugs acting in CNS should be considered. This survey aimed to examine the influence of aniseed essential oil (EO) intake on the effects of drugs that act in CNS. The chemical profile of essential oil determined by GC-MS revealed as the main components: trans-anethole (88.49%), gamma-himachalene (3.13%), cis-isoeugenol (1.99%), and linalool (1.79%). The effects of codeine, diazepam, midazolam, pentobarbital, imipramine and fluoxetine were tested in mice after 5days of peroral pretreatment with human equivalent dose of aniseed EO (0.3mg/kg). The intake of EO led to significant increase of analgesic effect of codeine. The motor impairment caused by midazolam was enhanced in the group treated by EO. The application of diazepam decreased the number and percentage of entries in open arm in elevated maze plus test in the group pretreated with EO indicating augmented effect of drug on motor activity. EO pretreatment caused significant shortage of pentobarbital induced sleeping time when compared to control. The decrease in antidepressant effect of imipramine and fluoxetine was diminished by the pretreatment with aniseed EO. Based on the results of this study we conclude that concomitant intake of aniseed EO preparations and drugs that act on CNS should be avoided due to potential herb drug interactions, which also need further clinical confirmation. PMID- 22926043 TI - Tabebuialdehydes A-C, cyclopentene dialdehyde derivatives from the roots of Tabebuia rosea. AB - Two new cyclopentene dialdehydes, tabebuialdehydes A and B (1 and 2) and a new dihydrocyclopenta[c]furan monoaldehyde, tabebuialdehyde C (3), along with ten known compounds were isolated from the roots of Tabebuia rosea. The structures of all isolated compounds were elucidated through their physical properties and by the use of spectroscopic methods, as well as comparisons with previous literature data. Moreover, all isolated compounds were evaluated for their cytotoxicity (KB and HeLa cell lines). Compounds 6, 7 and 9 showed significant cytotoxicity against both KB and HeLa cells with IC(50) values of 1.35 and 1.15, 0.53 and 0.77, 1.79 and 0.73MUg/mL, respectively. PMID- 22926045 TI - Hairy skin exposure to VX in vitro: effectiveness of delayed decontamination. AB - The chemical warfare agents such as VX represent a threat for both military and civilians, which involves an immediate need of effective decontamination systems. Since human scalp is usually unprotected compared to other body regions covered with clothes, it could be a preferential site of exposure in case of terrorist acts. The purpose of this study was to determine if skin decontamination could be efficient when performed more than 1h after exposure. In addition, the impact of hairs in skin contamination was investigated. By using in vitro skin models, we demonstrated that about 75% of the applied quantity of VX was recovered on the skin surface 2h after skin exposition, which means that it is worth decontaminating even if contamination occurred 2h before. The stratum corneum reservoir for VX was quickly established and persistent. In addition, the presence of hairs modified the percutaneous penetration of the nerve agent by binding of VX to hairs. Hair shaft has thus to be taken into account in the decontamination process. Reactive Skin Decontamination Lotion (RSDL) and Fuller's Earth (FE) were active in the skin decontamination 45min post-exposure, but RSDL was more efficient in reducing the amount of VX either in the skin or in the hair. PMID- 22926044 TI - Enmein-type diterpenoids from the aerial parts of Isodon rubescens and their cytotoxicity. AB - Three new enmein-type diterpenoids, jianshirubesins A-C (1-3), together with ten known compounds, were isolated from the aerial parts of Isodon rubescens. Their structures were established by using spectroscopic methods, and the absolute configuration of compound 1 was confirmed by a single-crystal X-ray diffraction analysis. All compounds except 3 were evaluated for their in vitro cytotoxicity by MTT assay, and compounds 5 and 10 exhibited significant inhibitory ability on selected cell lines. PMID- 22926046 TI - Proteomic allergen-peptide/protein interaction assay for the identification of human skin sensitizers. AB - Modification of proteins by skin sensitizers is a pivotal step in T cell mediated allergic contact dermatitis (ACD). In this process small reactive chemicals interact covalently or non-covalently with cellular or extracellular skin self proteins or self-peptides to become recognized by the human immune system. Aiming to develop a novel non-animal in vitro test system for predicting sensitization potential of small reactive chemicals in human skin the allergen-peptide/protein interaction assay (APIA) has been developed. By applying modern proteomic technologies together with a target peptide containing all amino acids, the assay permits the profiling of all amino acid specific allergen-peptide interactions. Moreover, potentially crucial allergen-specific Cys-modifications are qualitatively monitored by mass spectrometry and confirmed by a dual peptide approach. Assay conditions chosen mimic the distinct human epidermal reactivity compartments of the skin surface (pH 5.5), stratum basale (pH 6.8), and typical physiological conditions (pH 7.4). An extreme as well as a moderate human contact sensitizer produced Cys-specific mass shifts, whereas a skin irritant did not. Our data indicate that MALDI-MS based and skin-related in vitro technology platforms - like the APIA - are promising tools in developing alternative non animal allergen assays. This will assist in chemical classification and next generation risk assessment strategies, including REACH and experimental immunotoxicology. PMID- 22926047 TI - Histamine at low concentrations aggravates rat liver BRL-3A cell injury induced by hypoxia/reoxygenation through histamine H2 receptor in vitro. AB - AIM: Histamine released from mast cell degranulation participates in the pathogenesis of ischemia/reperfusion injury. The purpose of our study was to define the role of histamine in hypoxia/reoxygenation mediated liver cell injury and to elucidate the underlying mechanism in vitro. METHODS: Histamine alone or in combination with H1 receptor antagonist (pyrilamine), H2 receptor antagonist (cimetidine) or H3/4 receptor antagonist (thioperamide) at different concentrations before hypoxia was added to rat liver BRL-3A cell which was subjected to 24h hypoxia followed by 4h reoxygenation. Cell proliferation, apoptosis and the changes of ultrastructure were assessed, and MDA contents, SOD activities and ALT levels were quantified as well. RESULTS: Histamine (from 10( 3) to 10(-9) M) did not affect the growth of BRL-3A cells without hypoxia treatment. However, histamine 10(-8)M significantly lowered the growth of BRL-3A cells challenged by hypoxia/reoxygenation, accompanied with concomitant elevations in MDA contents and decreases in SOD activities, all these changes were blocked by cimetidine, not by pyrilamine or thioperamide. However, histamine (above 10(-6) M) did not show exacerbating effects in BRL-3A cell subjected to hypoxia/reoxygenation. CONCLUSION: Histamine at low concentrations (10(-7)-10(-9) M) aggravates hypoxia/reoxygenation mediated BRL-3A damage through histamine H2 receptor. PMID- 22926048 TI - A bioactive probe of the oxidative pentose phosphate cycle: novel strategy to reverse radioresistance in glucose deprived human colon cancer cells. AB - The specific effects of glucose deprivation on oxidative pentose phosphate cycle (OPPC) function, thiol homeostasis, protein function and cell survival remain unclear due to lack of a glucose-sensitive chemical probe. Using p53 wild type and mutant human colon cells, we determined the effects of hydroxyethyl disulfide (HEDS) on NADPH, GSH, GSSG, total glutathione, total non-protein and protein thiol levels, the function of the DNA repair protein Ku, and the susceptibility to radiation-induced free radicals under normal glucose or glucose-deprived conditions. HEDS is rapidly detoxified in normal glucose but triggered a p53 independent metabolic stress in glucose depleted state that caused loss of NADPH, protein and non-protein thiol homeostasis and Ku function, and enhanced sensitivity of both p53 wild type and mutant cells to radiation induced oxidative stress. Additionally, high concentration of HEDS alone induced cell death in p53 wild type cells without significant effect on p53 mutant cells. HEDS offers a useful tool to gain insights into how glucose metabolism affects OPPC dependent stress-induced cellular functions and injury, including in tumor cells, where our findings imply a novel therapeutic approach to target glucose deprived tumor. Our work introduces a novel probe to address cancer metabolism and ischemic pathology. PMID- 22926049 TI - Rural nursing and quality end-of-life care: palliative care ... palliative approach ... or somewhere in-between? AB - Secondary analysis of data from 2 studies examining palliative care in rural areas was conducted with the aim to better understand how a nursing palliative approach influences quality outcomes at end-of-life. Nurses' ways of being that brought connection and comfort at end-of-life included paying attention to time, privacy, and family support. The rural context with its geography, relationships, and unique resources influenced nurses' abilities to enact a palliative approach. Findings demonstrate that urban-centric models of palliative care do not fit well in rural nursing practice and highlight the importance of understanding the rural context. PMID- 22926051 TI - Quantification of selected furocoumarins by high-performance liquid chromatography and UV-detection: capabilities and limits. AB - The performance of HPLC-UV as a means of quantifying selected furocoumarins in essential oils has been evaluated, based on a ring test validation approach. Accuracy profiles were generated, to determine bias and statistical confidence associated with determination at different concentrations, along with lower limits of quantification (LOQ). From these findings, it can be concluded that the method described may only be used in simple cases (essential oils), to measure individual furocoumarin compounds at concentrations greater than 10mg/l; the non compound-specific nature of detection by absorption in the UV range is unable to overcome the effect of interferences arising from chromatographic coelutions, such as those encountered in the analysis of complex commercial fragrance mixtures. The use of an algorithmically calculated 'spectral similarity' function, with reference to authentic standards, may be used to improve reliability in assignment and quantification. PMID- 22926050 TI - Association of neuromyelitis optica with severe and intractable pain. AB - OBJECTIVE: To contrast differences in pain and treatment outcomes between neuromyelitis optica (NMO) and multiple sclerosis (MS). DESIGN: Retrospective, cross-sectional cohort study. SETTING: Academic MS center. PATIENTS: Complete ascertainment of an academic MS center cohort of NMO and an MS comparison sample cohort. MAIN OUTCOME MEASURES: Current pain was quantified by a 10-point scale and the McGill Pain Questionnaire.Expanded Disability Status Scale score and number of involved spinal cord levels were collected in addition to testing for cognition, fatigue, depression, and quality of life. Number and types of pain medications were tabulated. RESULTS: Current pain was more common in subjects with NMO (n=29) vs MS (n=66) (86.2% vs 40.9%; P.001)and more severe on a 10-point scale (5.38 vs 1.85;P.001). Pain remained more common after controlling for disability and number of spinal cord segments(P=.03). Prescription pain medication was used more frequently in subjects with NMO compared with subjects with MS(75.9% vs 37.8%; P.001), often requiring more than 1 medication (65.5% vs 15.2%; P.001). No subject with NMO taking pain medication (22 of 29) rated their current pain as 0 of 10, whereas almost half of those taking pain medication with MS were currently free of pain (0% vs 48%; P=.006). CONCLUSIONS: Neuromyelitis optica is frequently associated with severe pain that appears insufficiently controlled by pharmacologic interventions. Future studies should evaluate the efficacy of a multidisciplinary and multimodal approach to pain management. PMID- 22926052 TI - Chiral mobile phase in ligand-exchange chromatography of amino acids: exploring the copper(II) salt anion effect with a computational approach. AB - With the use of a chiral ligand-exchange chromatography (CLEC) system operating with the O-benzyl-(S)-serine [(S)-OBS] [1,2] as the chiral mobile phase (CMP) additive to the eluent, the effect of the copper(II) anion type on retention (k) and separation (alpha) factors was evaluated, by rationally changing the following experimental conditions: salt concentration and temperature. The CLEC CMP analysis was carried out on ten amino acidic racemates and with nine different cupric salts. While the group of analytes comprised both aliphatic (leucine, isoleucine, nor-leucine, proline, valine, nor-valine, and alpha-methyl valine) and aromatic (1-aminoindan-1,5-dicarboxylic acid, phenylglycine, and tyrosine) species, representative organic (formate, methanesulfonate, and trifluoroacetate) and inorganic (bromide, chloride, fluoride, nitrate, perchlorate, and sulfate) Cu(II) salts were selected as the metal source into the eluent. This route of investigation was pursued with the aim of identifying analogies among the employed Cu(II) salts, by observing the variation profile of the selected chromatographic parameters, upon a change of the above experimental conditions. All the data were collected and analyzed through a statistical approach (PCA and k-means clustering) that revealed the presence of two behavioral classes of cupric salts, sharing the same variation profile for k and alpha values. Interestingly, this clustering can be explained in terms of ESP (electrostatic surface potential) balance (ESP(bal)) values, obtained by an ab initio calculation operated on the cupric salts. The results of this appraisal could aid the rational choice of the most suitable eluent system, to succeed in the enantioseparation of difficult-to-resolve compounds, along with the eventual scale-up to a semi-preparative level. PMID- 22926053 TI - A novel preconcentration strategy for extraction methods based on common cationic surfactants: an alternative to classical coacervative extraction. AB - A novel and simple preconcentration step for aqueous micellar solutions of the common cationic surfactant cetyltrimethylammonium bromide (CTAB) has been developed. The procedure is based on the formation of another phase (a micro droplet), not soluble in water, in which analytes (originally present in the aqueous solution) experience preconcentration. The method resembles to that of classical coacervation, but it does not require high ionic strengths neither acidic pH values. The optimum method implies mixing aqueous micellar solutions of CTAB with lithium bis[(trifluoromethane)sulfonyl]imide (Li-NTf2) in a 1:1 molar ratio with a 16.5% (v/v) of acetonitrile content, followed by vortex, heating at 65 degrees C during 2 min, and centrifugation. The obtained microdroplet containing analytes is then subjected to high-performance liquid chromatography (HPLC) with diode-array detection (DAD). The method has been applied to the determination of a group of organic contaminants including alkylphenols, polycyclic aromatic hydrocarbons and parabens, present in aqueous samples (including seawater) or solid samples (such as sediment samples, which are subjected to a previous microwave-assisted extraction). Average preconcentration factors of roughly 14 and 12 are obtained for aqueous and sediment samples, respectively; being the limits of quantification down to 0.5 MUg L-1 and 0.02 mg kg-1, respectively. PMID- 22926054 TI - A cellular automata model of enantiomer binding strengths to beta-cyclodextrin. AB - As yet, the analytical process of chromatographic enantiomer separation has not been modeled using cellular automata (CA). This approach uses mathematical systems that are easily adaptable to different enantiomer analytical binding interactions. A CA model of analyte to cyclodextrin (CD) interaction accurately (R(2)=0.9960) predicts one-to-one molecular binding strengths through correlation with experimental complex stability constants while exhibiting established chromatographic behavior (i.e. retention site dependency and band broadening). The model is expanded to enantiomer HPLC retention interactions with beta-CD that accurately predicts one-to-one binding strengths through the development of probabilistic rules and factors from chromatographic results. The proposed model predicts the strength of binding interactions and the degree of chromatographic separation (or lack thereof) of six enantiomer pairs that agree with published potential binding energies of enantiomer-(beta-CD) complexes and published experimental HPLC separations. PMID- 22926055 TI - Zeolite imidazolate frameworks 8 as sorbent and its application to sonication assisted emulsification microextraction combined with vortex-assisted porous membrane-protected micro-solid-phase extraction for fast analysis of acidic drugs in environmental water samples. AB - A novel and fast procedure, sonication-assisted emulsification microextraction combined with vortex-assisted porous membrane protected micro-solid-phase extraction (SAEME-VA-MU-SPE), was developed for the gas chromatography-mass spectrometric determination of acidic drugs from environmental water samples. One advantage of the new procedure is that any solvent immiscible with water can be used as extractant solvent of SAEME and any solid sorbent can be used for MU-SPE in the SAEME-VA-MU-SPE process. In the present work, zeolite imidazolate framework 8 (ZIF-8) was employed as extraction sorbent for MU-SPE and 1-octanol as extractant solvent for SAEME. ZIF-8 has very good thermal, chemical and water stability, which make it a suitable material for the extraction of trace analytes from aqueous samples. Under the optimized extraction conditions, the developed method exhibited low limits of detection (0.01-0.04 ng/ml), good linearity (with r2 between 0.9965 and 0.9993) from 0.5 to 50 ng/ml and satisfactory repeatability (between 4.1% and 7.6%). In essence SAEME-VA-MU-SPE is a combination of two different and efficient miniaturized techniques. It was demonstrated to be a fast, accurate, and convenient pretreatment procedure for trace analysis of environmental water samples. PMID- 22926056 TI - Stable, microfabricated thin layer chromatography plates without volume distortion on patterned, carbon and Al2O3-primed carbon nanotube forests. AB - Some of us recently described the fabrication of thin layer chromatography (TLC) plates from patterned carbon nanotube (CNT) forests via direct infiltration/coating of the CNTs by low pressure chemical vapor deposition (LPCVD) of silicon from SiH4, followed by high temperature oxidation of the CNTs and Si. Herein we present an improved microfabrication process for the preparation of these TLC plates. First, a few nanometers of carbon and/or a thin film of Al2O3 is deposited on the CNTs. This method of priming the CNTs for subsequent depositions appears to be new. X-ray photoelectron spectroscopy confirms the presence of additional oxygen after carbon deposition. After priming, the plates are coated by rapid, conformal deposition of an inorganic material that does not require subsequent oxidation, i.e., by a fast pseudo atomic layer deposition (psi-ALD) of SiO2 from trimethylaluminum and tris(tert butoxy)silanol. Unlike devices described previously, faithful reproduction of the features in the masks is still observed after oxidation. A bonded, amino phase on the resulting plates shows fast, highly efficient separations of fluorescent dyes (plate heights in the range of 1.6-7.7 MUm). Extensive characterization of the new materials by TEM, SEM, EDAX, DRIFT, and XPS is reported. A substantially lower process temperature for the removal of the CNT scaffold is possible as a result of the already oxidized materials used. PMID- 22926057 TI - Behavioural therapy of suicidality. AB - Suicidal behaviour is a serious public health issue. Suicidal behaviour includes completed suicide, suicide attempts, suicidal intent and/or plans and suicide ideation. Two prominent mechanisms, behavioural deficits, in particular poor problem-solving skills, and a certain cognitive style with overgeneralization, distortion and lack of positive expectations, have been identified in suicidal patients so far. Besides general therapy strategies, including the diagnostic process and a collaborative, confident relationship and strengthening of protective factors, specific behavioural strategies should aim at the modification of the behavioural repertoire and of cognitive strategies. The modification of the behavioural repertoire includes the direct modification of the behaviour, acquiring techniques for stress reduction and learning problem solving strategies. Applied cognitive techniques comprise such as thought stopping, examining options and alternatives, fantasizing consequences, externalizing inner voices, and reattribution. Psychotherapy with suicidal patients has a specific feature: It requires high activity of the therapist in terms of motivation and guidance of the patient. Regular assessment of the suicide risk at every session is a must. Nevertheless, the therapist should always be aware that it is impossible to prevent all suicidal acts. PMID- 22926058 TI - Stress, burnout, and job dissatisfaction in mental health workers. AB - As the industrial world has transformed toward a service economy, a particular interest has developed in mental health problems at the workplace. The risk for burnout is significantly increased in certain occupations, notably for health care workers. Beyond the effects of an extensive workload, many working hours, or long night shifts, the medical field has specific stressors. Physicians work in emotionally demanding environments with patients, families, or other medical staff. They must make quick decisions while faced with a quite frequent information overload. All of these stressors have to be weighed against a rapidly changing organizational context within medicine. Today, economics objectives have priority over medical values in health care. In principal, mental health workers should experience similar work stressors and the same contextual factors as health professionals from other medical disciplines. However, several studies have identified stressors that are unique to the psychiatric profession. These challenges range from the stigma of this profession, to particularly demanding relationships with patients and difficult interactions with other mental health professionals as part of multidisciplinary teams to personal threats from violent patients. Other sources of stress are a lack of positive feedback, low pay, and a poor work environment. Finally, patient suicide is a major stressor, upon which a majority of mental health workers report post-traumatic stress symptoms. PMID- 22926059 TI - CD40L-Tri, a novel formulation of recombinant human CD40L that effectively activates B cells. AB - CD40L has a well-established role in enhancing the immunostimulatory capacity of normal and malignant B cells, but a formulation suitable for clinical use has not been widely available. Like other TNF family members, in vivo and in vitro activity of CD40L requires a homotrimeric configuration, and growing evidence suggests that bioactivity depends on higher-order clustering of CD40. We generated a novel formulation of human recombinant CD40L (CD40L-Tri) in which the CD40L extracellular domain and a trimerization motif are connected by a long flexible peptide linker. We demonstrate that CD40L-Tri significantly expands normal CD19+ B cells by over 20- to 30-fold over 14 days and induces B cells to become highly immunostimulatory antigen-presenting cells (APCs). Consistent with these results, CD40L-Tri-activated B cells could effectively stimulate antigen specific T responses (against the influenza M1 peptide) from normal volunteers. In addition, CD40L-Tri could induce malignant B cells to become effective APCs, such that tumor-directed immune responses could be probed. Together, our studies demonstrate the potent immune-stimulatory effects of CD40L-Tri on B cells that enable their expansion of antigen-specific human T cells. The potent bioactivity of CD40L-Tri is related to its ability to self-multimerize, which may be facilitated by its long peptide linker. PMID- 22926061 TI - The role of gamma interferon in DNA vaccine-induced tumor immunity targeting simian virus 40 large tumor antigen. AB - The central role of CD4+ T lymphocytes in mediating DNA vaccine-induced tumor immunity against the viral oncoprotein simian virus 40 (SV40) large tumor antigen (Tag) has previously been described by our laboratory. In the present study, we extend our previous findings by examining the roles of IFN-gamma and Th1 associated effector cells within the context of DNA immunization in a murine model of pulmonary metastasis. Immunization of BALB/c mice with plasmid DNA encoding SV40 Tag (pCMV-Tag) generated IFN-gamma-secreting T lymphocytes that produced this cytokine upon in vitro stimulation with mKSA tumor cells. The role of IFN-gamma as a mediator of protection against mKSA tumor development was assessed via in vivo IFN-gamma neutralization, and these experiments demonstrated a requirement for this cytokine in the induction immune phase. Neutralization of IFN-gamma was associated with a reduction in Th1 cytokine-producing CD4+ and CD8+ splenocytes, as assessed by flow cytometry analysis, and provided further evidence for the role of CD4+ T lymphocytes as drivers of the cellular immune response. Depletion of NK cells and CD8+ T lymphocytes demonstrated the expendability of these cell types individually, but showed a requirement for a resident cytotoxic cell population within the immune effector phase. Our findings demonstrate the importance of IFN-gamma in the induction of protective immunity stimulated by pCMV-Tag DNA-based vaccine and help to clarify the general mechanisms by which DNA vaccines trigger immunity to tumor cells. PMID- 22926060 TI - MHC-class I-restricted CD4 T cells: a nanomolar affinity TCR has improved anti tumor efficacy in vivo compared to the micromolar wild-type TCR. AB - Clinical studies with immunotherapies for cancer, including adoptive cell transfers of T cells, have shown promising results. It is now widely believed that recruitment of CD4(+) helper T cells to the tumor would be favorable, as CD4(+) cells play a pivotal role in cytokine secretion as well as promoting the survival, proliferation, and effector functions of tumor-specific CD8(+) cytotoxic T lymphocytes. Genetically engineered high-affinity T-cell receptors (TCRs) can be introduced into CD4(+) helper T cells to redirect them to recognize MHC-class I-restricted antigens, but it is not clear what affinity of the TCR will be optimal in this approach. Here, we show that CD4(+) T cells expressing a high-affinity TCR (nanomolar K (d) value) against a class I tumor antigen mediated more effective tumor treatment than the wild-type affinity TCR (micromolar K (d) value). High-affinity TCRs in CD4(+) cells resulted in enhanced survival and long-term persistence of effector memory T cells in a melanoma tumor model. The results suggest that TCRs with nanomolar affinity could be advantageous for tumor targeting when expressed in CD4(+) T cells. PMID- 22926063 TI - BACE1 in Alzheimer's disease. AB - Targeting BACE1 (beta-site APP cleaving enzyme 1 or beta-secretase) is the focus of Alzheimer's disease (AD) research because this aspartyl protease is involved in the abnormal production of beta amyloid plaques (Abeta), the hallmark of its pathophysiology. Evidence suggests that there is a strong connection between AD and BACE1. As such, strategies to inhibit Abeta formation in the brain should prove beneficial for AD treatment. Abeta, the product of the large type1 trans membrane protein amyloid precursor protein (APP), is produced in a two-step proteolytic process initiated by BACE1 (beta-secretase) and followed by gamma secretase. Due to its apparent rate limiting function, BACE1 appears to be a prime target to prevent Abeta generation in AD. Following its discovery, the BACE1 has been cloned, its structure solved, novel physiologic substrates discovered and numerous inhibitors developed. This review focuses on elucidating the role of BACE1 to facilitate drug development in the treatment of AD. PMID- 22926062 TI - Metronomic chemotherapy with low-dose cyclophosphamide plus gemcitabine can induce anti-tumor T cell immunity in vivo. AB - Several chemotherapeutic drugs have immune-modulating effects. For example, cyclophosphamide (CP) and gemcitabine (GEM) diminish immunosuppression by regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs), respectively. Here, we show that intermittent (metronomic) chemotherapy with low dose CP plus GEM can induce anti-tumor T cell immunity in CT26 colon carcinoma bearing mice. Although no significant growth suppression was observed by injections of CP (100 mg/kg) at 8-day intervals or those of CP (50 mg/kg) at 4 day intervals, CP injection (100 mg/kg) increased the frequency of tumor peptide specific T lymphocytes in draining lymph nodes, which was abolished by two injections of CP (50 mg/kg) at a 4-day interval. Alternatively, injection of GEM (50 mg/kg) was superior to that of GEM (100 mg/kg) in suppressing tumor growth in vivo, despite the smaller dose. When CT26-bearing mice were treated with low-dose (50 mg/kg) CP plus (50 mg/kg) GEM at 8-day intervals, tumor growth was suppressed without impairing T cell function; the effect was mainly T cell dependent. The metronomic combination chemotherapy cured one-third of CT26-bearing mice that acquired tumor-specific T cell immunity. The combination therapy decreased Foxp3 and arginase-1 mRNA levels but increased IFN-gamma mRNA expression in tumor tissues. The percentages of tumor-infiltrating CD45(+) cells, especially Gr 1(high) CD11b(+) MDSCs, were decreased. These results indicate that metronomic chemotherapy with low-dose CP plus GEM is a promising protocol to mitigate totally Treg- and MDSC-mediated immunosuppression and elicit anti-tumor T cell immunity in vivo. PMID- 22926064 TI - [Wound dressings]. PMID- 22926065 TI - Clinical impact of 18F-FDG PET/CT in the pretreatment evaluation of patients with locally advanced cervical carcinoma. AB - AIM: The aim of this study was to evaluate the impact of F-fluorodeoxyglucose (F FDG) PET/computed tomography (CT) on the pretreatment evaluation of patients with locally advanced cervical carcinoma. METHOD: Forty-seven patients with stage 2b 4a cervical carcinoma underwent F-FDG PET/CT for initial staging and pretreatment evaluation. Concomitant pelvic/abdominal MRI was performed in 38 patients. The contribution of PET/CT to treatment planning was evaluated, and the prognostic performance of PET/CT was compared with that of MRI. Lymph node (LN) status on PET/CT was correlated with patient follow-up data. RESULTS: PET/CT detected hypermetabolic LNs in 39/47 patients. In 24/39 patients (62%), PET/CT was found to be superior to MRI. In 13/24 patients (54%), PET/CT detected para-aortic +/- pelvic LNs, which were not found on MRI. PET/CT successfully detected distant metastases in 10 patients and peritonitis carcinomatosa in one patient; these patients were upstaged clinically. Overall, PET/CT has led to modifications in the extent of the radiotherapy field in 34% of patients and to major alterations in treatment plans in 23% of patients with widespread disease. The frequency of PET-positive LNs was significantly lower in patients who were alive without disease at the time of last follow-up (60%) compared with patients with persistent disease and nonsurvivors (100%, P=0.012). CONCLUSION: The presence of PET-positive LNs has prognostic significance in patients with cervical carcinoma. PET/CT has the potential to show both lymphatic and distant metastases, which results in modifications to the chemoradiotherapeutic regimen. The use of PET/CT must be included in the initial workup of patients with locally advanced cervical carcinoma. PMID- 22926067 TI - Antitrypanosomal and cysteine protease inhibitory activities of alkyldiamine cryptolepine derivatives. AB - Cryptolepine derivatives containing alkyldiamine side-chains, 2, with potent inhibitory activity against Trypanosoma brucei brucei are reported. Compounds 2 showed improved activity and selectivity to T. b. brucei when compared to the lead compound. The most selective compound, 2k, presents a selectivity index value of 6200 and an IC(50) of 10nM against the parasite. These derivatives are also potent inhibitors of the trypanosome papain-like cysteine proteases cruzain, which could, at least in part, explain their antitrypanosomal activity. Overall, these compounds with good antitrypanosomal activity and selectivity provide an encouraging starting point for the rational design of new and effective antitrypanosomal agents. PMID- 22926068 TI - Synthesis and biological evaluation of a new vitamin D2 analogue. AB - A new vitamin D(2) analogue was synthesized using the Julia-Kocienski olefination. It has antiproliferative effects on cell lines from squamous cell carcinomas of colon and head and neck, but is also as hypercalcaemic as calcitriol in vivo. PMID- 22926069 TI - Phenylalanine derivatives as GPR142 agonists for the treatment of type II diabetes. AB - GPR142 is a novel GPCR that is predominantly expressed in pancreatic beta-cells. GPR142 agonists potentiate glucose-dependent insulin secretion, and therefore can reduce the risk of hypoglycemia. Optimization of our lead pyridinone phenylalanine series led to a proof-of-concept compound 22, which showed in vivo efficacy in mice with dose-dependent increase in insulin secretion and a decrease in glucose levels. PMID- 22926070 TI - Serratia marcescens meningitis: epidemiology, prognostic factors and treatment outcomes. AB - BACKGROUND/PURPOSE: Serratia marcescens is a rare pathogen of central nervous system infections. This study was to investigate the epidemiology, prognostic factors, and treatment outcomes of S. marcescens meningitis. METHODS: This retrospective analysis included 33 patients with culture-proven S. marcescens meningitis hospitalized between January 2000 and June 2011. RESULTS: Of the 33 patients enrolled, only one did not receive neurosurgery before the onset of S. marcescens meningitis. Patients with S. marcescens meningitis had higher ratios of brain solid tumors (54.5%) and neurosurgery (97.0%) with a mortality rate of 15.2%. The mean interval between the first neurosurgical procedure and the diagnosis of meningitis was 17.1 days (range, 4-51 days). Only one third generation cephalosporin-resistant S. marcescens isolate was recovered from the patients' cerebrospinal fluid (CSF) specimens. Compared with the favorable outcome group (n = 20), the unfavorable outcome group (n = 13) had a higher percentage of brain solid tumors, more intensive care unit stays, and higher Sequential Organ Failure Assessment score, CSF lactate and serum C-reactive protein concentrations at diagnosis of meningitis. Under the multiple regression analysis, CSF lactate concentration >=2-fold the upper limit of normal (ULN) was independently associated with unfavorable outcomes (odds ratio, 7.20; 95% confidence interval, 1.08-47.96; p = 0.041). CONCLUSION: S. marcescens meningitis is highly associated with neurosurgical procedures for brain solid tumors. CSF lactate concentration >=2x ULN may predict an unfavorable outcome. Its mortality is not high and empiric treatment with parenteral third-generation cephalosporins may have a satisfactory clinical response. PMID- 22926071 TI - Utility of multiplex PCR in detecting the causative pathogens for pediatric febrile neutropenia. AB - Febrile neutropenia (FN) is a life-threatening complication, and the primary cause of FN is considered to be microbial infection. Therefore, prompt and appropriate antimicrobial therapy is crucial. Clinicians usually prescribe antimicrobial therapy on the basis of presumptive and empirical data. This is because the causative pathogen for FN in blood culture (BC) analysis is detected several days after sampling. Polymerase chain reaction (PCR) analysis has been used for detecting the causative bacteria of infections. Here, we examined whether multiplex PCR is useful for detecting the causative pathogens for FN patients. We extracted DNA from the patients' whole blood and performed multiplex PCR. In total, 128 samples of 40 patients clinically diagnosed with FN were used in this study. Multiplex PCR analysis revealed the causative pathogen in 3 patients with FN; the DNA fragments amplified were those of Pseudomonas aeruginosa in 2 cases and Psedomonas putida in 1 case. These patients could be started on appropriate antimicrobial therapy a few hours after sampling. However, the DNA fragment of the causative pathogen could not be amplified by PCR in 2 patients, although BC analysis did detect the causative bacteria. Thus, we conclude that multiplex PCR is serviceable in case of FN because of its rapidness. However, BC is also indispensable to treating FN owing to its high sensitivity. PMID- 22926072 TI - Lipid profile parameters in Malaysian dyslipidemic patients. AB - INTRODUCTION: The importance of serum lipids as cardiovascular risk factors is well recognized. However, most published studies have focused on western countries. The present study aimed to describe and analyze the lipid profile parameters in Malaysian dyslipidemic patients, and to identify concomitant clinical problems and risk factors associated with cardiovascular disease (CVD) among such patients. METHODS: A retrospective record review was carried out at Hospital Universiti Sains Malaysia. The records were reviewed for 890 dyslipidemic patients who attended the hospital in 2007. Data were collected for age at time of presentation, sex, ethnicity, smoking status, pre-treatment lipid levels, and presence of associated illnesses. The study sample was classified according to the National Cholesterol Education Program Adult Treatment Panel III risk groups. RESULTS: The mean (SD) values for total cholesterol, low-density lipoprotein cholesterol, high density lipoprotein cholesterol, and triglycerides were 6.4 (1.3), 4.1 (1.3), 1.4 (0.5) and 1.9 (1.2) mmol/l, respectively. Less than half of study sample (43.1%) had coronary heart disease and coronary heart diseases equivalents, 24.3% were at moderate risk, and 32.6% were at low risk. Hypertension was present in 79.9% of the study sample, while 27.5% were diabetics. Cardiovascular disease was reported among 17.9%. Logistic regression revealed that family history of premature cardiovascular disease, higher age risk group; ethnicity and total cholesterol were predictors for the development of cardiovascular disease. CONCLUSION: The present review showed that dyslipidemic patients had high total cholesterol levels, according to National Cholesterol Education Program Adult Treatment Panel III guidelines. They were clinically diagnosed at middle age. Hypertension and diabetes were the commonest associated clinical problems. A large proportion of the patients were within the coronary heart disease or coronary heart disease risk equivalent group. Family history of premature cardiovascular disease, age, ethnicity, and total cholesterol are important risk factors for the development of cardiovascular disease in Malaysian dyslipidemic patients. PMID- 22926073 TI - Social capital and health in malaria-prevalent areas of the Solomon Islands. AB - Social capital and health have drawn much attention in public health. Employing three models, this study examines relationships between vertical/horizontal/comprehensive social capital, self-rated health, malaria infection, as well as health-related behaviors/attitudes. In Model 1, odds ratios were calculated to scrutinize the relationships between component variables of social capital and "Self-rated health," one by one. In Model 2, the variable "Health," which combined "Self-rated health" and malaria infection, was used in lieu of "Self-rated health" in Model 1. Lastly, Model 3 utilized three composite measures of social capital and examined their associations with health, and health-related behaviors/attitudes. Model 1 highlighted associations between some of the components of vertical social capital and self-rated health, whereas, in Model 2, it was elucidated that some of the constituent factors classified as horizontal social capital have significant relationships with "Health." The most comprehensive approach in this study, Model 3, found significant associations between: Horizontal Social Capital (HSC) and "Health"; HSC and infection with malaria; and Vertical Social Capital (VSC) and malaria infection. In addition, Comprehensive Social Capital (CSC) and "Health," CSC and malaria infection, and, finally, CSC and "Feeling threatened by malaria in the community" were found to be significantly associated. In conclusion, the three methods employed in this study indicated some significant associations between social capital (or its components) and health outcomes in general and social capital and malaria infection in particular. It is noteworthy that Model 3 resulted in demonstrating significant relationships between HSC, VSC, respectively on the one hand, and malaria infection, on the other. Hence, developing social capital should possibly help deal with or reduce malaria infection, particularly in nations where other resources are scarce. PMID- 22926074 TI - Development of an evaluation scale for self-monitoring by patients with heart failure. AB - Many chronic heart failure patients are hospitalized repeatedly because many of them are still uncertain about the methods necessary for managing their own health. "Self-monitoring" is a useful concept for breaking through this vicious cycle. However, there are no suitable tools to measure aspects of self- monitoring. This study aimed at the development of an evaluation scale for self monitoring by patients with chronic heart failure based on the concept of self monitoring. Outpatient with chronic heart failure completed a self-administered scale comprises 2 domains and covers 38 items. Domain 1 deals with "awareness" and "measurement" of aspects of self-monitoring, domain 2 with "interpretation" of aspects of self-monitoring. The reliability and validity of this scale were thoroughly evaluated. Of the 167 patients asked to participate in the study, 142 gave valid responses. Factor analysis showed that the domain1 comprised six factors (21 items) and the domain2 four factors (16 items). Cronbach's alpha coefficient was 0.91 for domain1, 0.89 for domain2. The intra-class correlation coefficient of total score was 0.74 for domain1, 0.67 for domain2. Concurrent validity with the Heart Failure Self-care Behavior Scale was demonstrated. The scale is reasonably reliable and valid, and was proved to be useful for assessing conditions related to patient self-monitoring. Since it has become an indicator that shows to what degree patients can perceive their own health status, and nurses have been utilizing it to provide individual support to reduce the risks of exacerbated heart failure. PMID- 22926075 TI - The cytobiological differences between two odontogenic cyst-lining keratinocytes. AB - PURPOSE: Odontogenic cysts are classified into a developmental group, including follicular cysts (FC) and keratocysts, and an inflammatory group including radicular cysts (RC). In clinical cases, we frequently encounter RC and FC. The purpose of this study was to investigate the cytobiological differences between two odontogenic cyst-lining keratinocytes using a cytobiological approach from the aspect of metabolic function and the degree of maturation of the epithelium. MATERIALS AND METHODS: Samples of odontogenic cyst-lining keratinocytes and oral keratinocytes collected at surgery, and of cultured oral keratinocytes, were analyzed (1) by immunohistochemical staining of granulocyte macrophage colony stimulating factor (GM-CSF), human beta defensin-2 (HBD-2) and chemokine receptor 6 (CCR6) expressing cell (Langerhans cell, helper T cell and suppressor T cell) antibodies, (2) by reverse transcription-polymerase chain reaction (RT-PCR) to determine the expression of GM-CSF and HBD-2 mRNA and (3) by gas chromatography to evaluate the composition of fatty acids (16:0, 18:2, 20:4) in the cell membranes of the keratinocytes. RESULTS: 1. Immunohistochemical staining indicated that HBD-2 and GM-CSF expression were higher in RC than in FC. 2. The same results were obtained from the RT-PCR analysis. 3. The % composition of palmitic acid (16:0) was significantly higher in the RC-lining keratinocytes (38.62+/-5.86%) and in the FC-lining keratinocytes (30.37+/-1.38%) than in the normal gingiva (23.00+/-1.40%). The % composition of essential fatty acids (18:2+20:4) was significantly higher in the FC-lining keratinocytes (26.20+/ 3.55%) than in the RC-lining keratinocytes (20.50+/-8.17%). CONCLUSION: The present study demonstrated definite cytobiological evidence of the differences between RC and FC. PMID- 22926076 TI - Nuclear HSP90 regulates the glucocorticoid responsiveness of PBMCs in patients with idiopathic nephrotic syndrome. AB - Resistance to glucocorticoid (GC) is a challenge for the treatment of patients with idiopathic nephrotic syndrome (INS). Most of the effects of GC are mediated by the GC receptor (GR). Heat shock protein 90 (HSP90) is an important molecular chaperone for the GR and is supposed to be the key factor in regulating GC effects. In a previous study, we found that both the expression and nuclear distribution of HSP90 were increased in GC resistant INS patients. The aim of this study is to explore how these phenomena contribute to GC resistance in INS patients. Healthy subjects and INS patients with different GC responses were recruited. The total HSP90 expression was determined by reverse transcription-PCR and flow cytometric analysis. Western blot analysis was used to evaluate the expression of nuclear HSP90. Co-immunoprecipitation and electrophoretic mobility gel shift assays were performed to explore the interaction between HSP90 and the GR in the nucleus as well as the DNA-binding activity of GR. We induced the upregulation of the expression of total HSP90 in PBMCs by treatment with interleukin-6 in vitro and found that the nuclear HSP90 level, the DNA-binding activity of the GR and the cell apoptotic responsiveness to GC remained unchanged. Furthermore, an increased nuclear HSP90 was demonstrated mainly by binding to GR in the nucleus, while the DNA-binding activity of the GR dramatically decreased in GC resistant INS patients. The present results suggest that the accumulation of HSP90 in the nucleus potentially hinders DNA-binding activity and transactivation, which may contribute to GC resistance in patients with INS. PMID- 22926077 TI - Trauma patients' elevated tumor necrosis related apoptosis inducing ligand (TRAIL) contributes to increased T cell apoptosis. AB - Immunosuppression resulting from excessive post-trauma apoptosis of hyperactivated T cells is controversial. TRAIL mediated T cell apoptosis decreases highly activated T cells' responses. Caspase-10, a particular TRAIL target, was increased in trauma patients' T cells with concomitantly elevated plasma TRAIL levels. These patients' T cells developed anergy, implicating increased TRAIL-mediated T cell apoptosis in post-trauma T cell anergy. Control T cells cultured with patients' sera containing high TRAIL levels increased their caspase-10 activity and apoptosis. Stimulated primary T cells are TRAIL apoptosis resistant. Increased plasma thrombospondin-1 and T cell expression of CD47, a thrombospondin-1 receptor, preceded patients' T cell anergy. CD47 triggering of T cells increased their sensitivity to TRAIL-induced apoptosis. Augmentation of T cell TRAIL-induced apoptosis was secondary to CD47 triggered activation of the Src homology-containing phosphatase-1 (SHP-1) and was partially blocked by a SHP 1 inhibitor. We suggest that combined post-trauma CD47 triggering, SHP-1 mediated NFkappaB suppression, and elevated TRAIL levels increase patients' CD47 expressing T cell apoptosis, thus contributing to subsequent T cell anergy. PMID- 22926078 TI - Role of SNAP29, LZTR1 and P2RXL1 genes on immune regulation in a patient with atypical 0.5 Mb deletion in 22q11.2 region. PMID- 22926080 TI - Sharpening the CALIPER: defining pre-analytic and biologic variability in children. PMID- 22926079 TI - The developing human preterm neonatal immune system: a case for more research in this area. AB - Neonates, particularly those born prematurely, are among the most vulnerable age group for morbidity and mortality due to infections. Immaturity of the innate immune system and a high need for invasive medical procedures in the context of a preterm birth make these infants highly susceptible to common neonatal pathogens. Preterm infants who survive may also suffer permanent disabilities due to organ damage resulting from either the infection itself or from the inflammatory response generated under an oxidative stress. Infections in preterm infants continue to pose important healthcare challenges. Yet, developmental maturation events in the innate immune system that underlie their excessively high vulnerability to infection remain largely understudied. In this review article, we identify pertinent knowledge gaps that must be filled in order to orient future translational research. PMID- 22926081 TI - Data modelling reveals inter-individual variability of front crawl swimming. AB - OBJECTIVES: In accordance with dynamical systems theory, which assumes that motor behaviour emerges from interacting constraints (task, organismic, environmental), this study explored the functional role of inter-individual variability in inter limb coordination. DESIGN: 63 front crawl swimmers with a range of characteristics (gender, performance level, specialty) performed seven intermittent graded speed bouts of 25m in front crawl. METHODS: Each bout was video-taped with a side-view camera from which speed, stroke rate, stroke length and index of arm coordination (IdC) were analysed for three cycles. Cluster analysis was used to classify the swimmers through speed and IdC values. RESULTS: Cluster analysis and validation showed four profiles of IdC management expressing the swimmers' characteristics as cluster 1: mainly national distance male swimmers, cluster 2: mainly international male sprinters, cluster 3: distinguished by female characteristics, and cluster 4: swimmers with the lowest level of performance. CONCLUSIONS: These profiles generated different IdC-speed regression models, which (i) showed how the swimmers adapted their motor behaviour to overcome task constraints and (ii) supported the key idea that there is not a single ideal expert model to be imitated, but rather adapted behaviour emerging from individually encountered constraints. PMID- 22926082 TI - Indoleamine 2,3-dioxygenase inhibition attenuates lipopolysaccharide induced persistent microglial activation and depressive-like complications in fractalkine receptor (CX(3)CR1)-deficient mice. AB - An impaired ability to regulate the activation of microglia by fractalkine (CX3CL1) leads to persistent neuroinflammation and behavioral alterations following lipopolysaccharide (LPS) challenge. While these responses are usually transient, LPS injection caused prolonged depressive-like behavior in fractalkine receptor deficient mice (CX3CR1(-/-)) that was associated with exaggerated microglial activation and induction of the tryptophan (TRP) degrading enzyme indoleamine 2,3-dioxygenase (IDO). IDO activation and subsequent generation of neuroactive kynurenine metabolites may have a pivotal role in the development of depression. Therefore, the purpose of this study was to determine the extent to which LPS-induced depressive-like behavior in CX3CR1(-/-) mice was dependent on IDO activation. CX3CR1(-/-) mice were implanted prior to LPS challenge with a slow release pellet of 1-methyl-tryptophan (1-MT), a competitive inhibitor of IDO. Here we show that the depressive-like behavior evident in CX3CR1(-/-) mice 72 h after LPS injection was abrogated by inhibition of IDO. LPS also decreased body weight and locomotor activity in CX3CR1(-/-) mice, but these effects were independent of 1-MT. Consistent with the increased metabolism of TRP by IDO, the ratio of 3-hydroxykynurenine (3-HK) to TRP was increased in the brain 72 h after LPS. Increased serotonin (5-HT) turnover was also evident in the brain. The LPS associated increases in both 3-HK:TRP and 5-HIAA:5-HT ratios were prevented by the inhibition of IDO. Last, IDO blockade attenuated microglial activation in the prefrontal cortex and hippocampus 72 h after LPS. Collectively these data indicate that LPS-induced IDO activation contributes to persistent microglial activation and depressive-like behavior in CX3CR1(-/-) mice. PMID- 22926084 TI - The adaptation of the Sheffield Profile for Assessment and Referral for Care (SPARC) to the Polish clinical setting for needs assessment of advanced cancer patients. AB - CONTEXT: Assessment of the needs of advanced cancer patients is a very important issue in palliative care. OBJECTIVES: The aim of the study was to adapt the Sheffield Profile for Assessment and Referral for Care (SPARC) to the Polish environment and evaluate its usefulness in needs assessment of patients with advanced cancer. METHODS: A forward-back translation of the SPARC to Polish was done. The SPARC was used once in 58 consecutive patients with advanced cancer during follow-up. The patients were enrolled from a palliative care unit (25 patients), home care (18 patients), and a day care center (15 patients). The reliability was evaluated by establishing the internal consistency using Cronbach's alpha coefficients. Content validity was analyzed in accordance with the theories of needs by Murray and Maslow as a nonstatistical method of validity assessment. Factor analysis with principal components extraction and varimax rotation of raw data was used to reduce the set of data and assess the construct validity. RESULTS: There were differences regarding religious and spiritual issues and independence and activity between patients in the palliative care unit (worse results) and those at the day care center (better scores). Communication and need for more information items were associated with psychological, social, spiritual, and treatment issues. Cronbach's alpha coefficients and factor analysis demonstrated, respectively, satisfactory reliability and construct validity of the tool. CONCLUSION: The study demonstrated that the Polish version of the SPARC is a valid and reliable tool recommended for the needs assessment and symptom evaluation of patients with advanced cancer. PMID- 22926083 TI - Elevated ratio of arachidonic acid to long-chain omega-3 fatty acids predicts depression development following interferon-alpha treatment: relationship with interleukin-6. AB - Cross-sectional studies have found that an elevated ratio of arachidonic acid to omega-3 fatty acid is associated with depression, and controlled intervention studies have found that decreasing this ratio through administration of omega-3 fatty acids can alleviate depressive symptoms. Additionally, arachidonic acid and omega-3 fatty acids have opposing effects on inflammatory signaling. Exogenous administration of the inflammatory cytokine interferon-alpha (IFN-alpha) can trigger a depressive episode in a subset of vulnerable people, though associated risk factors remain poorly understood. Using a within-subject prospective design of 138 subjects, we examined whether baseline long-chain omega-3 (docosahexaenoic acid - DHA; eicosapentaenoic acid - EPA) and omega-6 (arachidonic acid - AA; di homo-gamma-linolenic acid - DGLA) fatty acid status was associated with depression vulnerability in hepatitis C patients treated with IFN-alpha. Based on the literature, we had specific a priori interest in the AA/EPA+DHA ratio. Lower baseline DHA predicted depression incidence (p=0.04), as did elevated DGLA (p=0.02) and an elevated AA/EPA+DHA ratio (p=0.007). The AA/EPA+DHA ratio predicted depression even when controlling for other critical variables such as sleep quality and race. A higher AA/EPA+DHA ratio was positively associated with both increasing Montgomery-Asperg Depression Rating Scores over time (F=4.0; p<0.05) as well as interleukin-6 levels (F=107.4; p<0.05) but not C-reactive protein. Importantly, omega-3 and omega-6 fatty acid status was not associated with sustained viral response to IFN-alpha treatment. These prospective data support the role of fatty acid status in depression vulnerability and indicate a potential role for omega-3 fatty acids in the prevention of inflammation-induced depression. PMID- 22926085 TI - Measurement properties of the eight-item abbreviated functional assessment of cancer therapy--breast symptom index and comparison with its 37-item parent measure. AB - CONTEXT: The Functional Assessment of Cancer Therapy--Breast Symptom Index (FBSI) is an eight-item instrument extracted from the Functional Assessment of Cancer Therapy--Breast (FACT-B). There has been no formal assessment of this eight-item version. OBJECTIVES: This study aimed to examine the measurement properties of and comparability between the English and the Chinese versions of the FBSI and to compare it with its parent instrument, the FACT-B, in breast cancer patients in Singapore. METHODS: This was an observational study of 271 breast cancer patients. Known-group validity of FBSI scores was assessed using four health indicators. Convergent and divergent validity was examined by correlation coefficients between the FBSI and the FACT-B. Responsiveness was assessed in relation to longitudinal changes in performance status. Test-retest reliability was evaluated by the intraclass correlation coefficient. Multiple regression analyses were performed to compare the scores on the two language versions. Receiver operating characteristic curve analyses were used for comparison between the FBSI and the FACT-B. RESULTS: For both language versions, the FBSI demonstrated known-group validity, convergent and divergent validity, and sufficient test-retest reliability (intraclass correlation coefficient = 0.75 0.77). The English version was responsive to changes in performance status. The Chinese version was responsive to decline in performance status, but there was no conclusive evidence about its responsiveness to improvement in performance status. No practical significant difference was found in the outcomes between the two language versions despite minor difference in one item. The FBSI performed comparably with the FACT-B. CONCLUSION: The English and Chinese versions of the FBSI are valid and reliable and provide comparable FBSI scores. The English version is responsive to change, whereas the responsiveness of the Chinese version warrants further study. PMID- 22926086 TI - Sleep and sleep-wake disturbances in care recipient-caregiver dyads in the context of a chronic illness: a critical review of the literature. AB - CONTEXT: Alterations in sleep-wake patterns of care recipients and their informal caregivers are common in the context of a chronic illness. Given the current notion that sleep may be regulated within and affected by close human relationships, concurrent and interrelated sleep problems may be present in care recipient-caregiver dyads. OBJECTIVES: To critically analyze evidence regarding concurrent sleep patterns or changes in care recipient-caregiver dyads in the context of a chronic illness and address methodological and research gaps. METHODS: Using a wide range of key terms and synonyms, three electronic databases (Medline, CINAHL, and Embase) were systematically searched for the period between January 1990 and July 2011. RESULTS: Ten studies met prespecified selection criteria and were included for analysis. Study quality was fair to good on average. Seven studies were conducted in the context of dementia or Parkinson's disease, two in the context of cancer, and one study included a group of community elders with mixed related comorbidities and their informal caregivers. Bidirectional associations in the sleep of care recipient-caregiver dyads seem to exist. Concurrent and comparable nocturnal sleep disruptions also may be evident. Yet, inconsistencies in the methods implemented, and the samples included, as well as uncertainty regarding factors coaffecting sleep, still preclude safe conclusions to be drawn on. CONCLUSION: The dyadic investigation of sleep is a promising approach to the development of truly effective interventions to improve sleep quality of care recipients and their caregivers. Nevertheless, more systematic, longitudinal dyadic research is warranted to augment our understanding of co-occurrence and over time changes of sleep problems in care recipient-caregiver dyads, as well as to clarify covariates/factors that appear to contribute to these problems within the dyad and across time and context of illness. PMID- 22926087 TI - Development of fatigue in cancer survivors: a prospective follow-up study from diagnosis into the year after treatment. AB - CONTEXT: There is a lack of longitudinal studies investigating fatigue from before cancer treatment to long after successful cancer treatment. OBJECTIVES: This prospective follow-up study aimed to determine the prevalence and predictors of persistent fatigue in cancer survivors in the first year after completion of cancer treatment. METHODS: Sixty patients with various malignancies were assessed before (T1), shortly after curative cancer treatment (T2), and one year after T2 (T3). Fatigue was assessed monthly between T2 and T3. Fatigue severity was measured using the subscale of the Checklist Individual Strength. Questionnaires were used to measure impaired sleep and rest, physical activity, social support, fatigue catastrophizing, and somatic-related attributions regarding fatigue. Linear regression analyses were performed to identify predictors of persistent fatigue. RESULTS: In total, 22% of survivors had severe persistent fatigue over the last six months in the first year after cancer treatment. Fatigue at T1, T2, and negative interactions predicted the severity of persistent fatigue. Analyses without fatigue showed that more negative interactions, impaired sleep and rest, fatigue catastrophizing, and lower self-reported physical activity at T2 were associated with the severity of persistent fatigue. CONCLUSION: Twenty-two percent of the survivors had severe persistent fatigue in the year after cancer treatment. Fatigue and cognitive behavioral factors predicted persistent fatigue in the year after cancer treatment. Diagnosis or cancer treatment did not predict persistent fatigue. The implication is that cognitive behavioral therapy for postcancer fatigue, aimed at the fatigue-perpetuating factors, could be offered from two months after successful cancer treatment. PMID- 22926088 TI - The Spanish version of the Edmonton Symptom Assessment System-revised (ESAS-r): first psychometric analysis involving patients with advanced cancer. AB - CONTEXT: The Edmonton Symptom Assessment System (ESAS) is a measure widely used in palliative care for the assessment of symptoms in patients with advanced cancer. The tool has been validated in different languages, including Spanish. A revised version (ESAS-r) was developed by Watanabe et al. in 2010. OBJECTIVES: To develop the Spanish version of the ESAS-r and examine its psychometric properties. METHODS: Based on the original English version, a group of experts created a Spanish version of the ESAS-r and administered it to a group of advanced cancer patients. Patients completed the ESAS and ESAS-r and were asked for their perceptions of the tool. The psychometric properties of the ESAS-r that were analyzed were equivalence, internal consistency, and discriminant validity. RESULTS: Sixty-six patients from Spain and Guatemala participated in the survey. Patients perceived the ESAS-r to be significantly easier to understand and easier to complete than the ESAS. Significantly, patients preferred the ESAS-r (47%) to the ESAS (15%; P<0.0007). As to reliability, we found good internal consistency (Cronbach's alpha 0.86), and the equivalence of the two versions was between 0.71 and 0.94. The ESAS-r discriminates between inpatients and outpatients (Mann Whitney U test; P=0.02) and among those with different palliative performance status (Spearman's rho for pain, tiredness, drowsiness, lack of appetite, well being; P<0.01). CONCLUSION: The ESAS-r is a valid instrument with adequate psychometric characteristics. This version is preferred by patients with advanced cancer. The Spanish version of the ESAS-r can, therefore, replace the use of the ESAS. PMID- 22926089 TI - Advance directives in Japanese nursing homes. AB - CONTEXT: Advance directives are poorly understood in Japanese nursing homes. In April 2006, additional funding for end-of-life care became available as the first support for terminal care at Japanese nursing homes. OBJECTIVES: The objectives of this study were to investigate the adoption of advance directives by Japanese nursing homes, the effect of additional funding for end-of-life care in nursing homes from long-term care insurance on the use of advance directives, and the types of directives used. METHODS: A nationwide questionnaire survey of nursing homes was performed in Japan. The participants were 913 nursing homes. We investigated the prevalence of advance directives, details of the directives, and demographic data of the responders. RESULTS: Advance directives were used in 58.4% of nursing homes. The timing of introduction of the directives and the results of multivariate analysis at the facility level suggested a relation between the availability of additional funding for end-of-life care and the adoption of advance directives. Most nursing homes used instructional directives, especially directives providing an explanation and informed consent for end-of life care in the nursing home. CONCLUSION: More than half of Japanese nursing homes have introduced advance directives, and additional funding for end-of-life care is related to their introduction. Most nursing homes have adopted instructional directives, especially those providing an explanation and informed consent regarding end-of-life care at the nursing home. PMID- 22926090 TI - Factor analysis of the Pittsburgh Sleep Quality Index in breast cancer survivors. AB - CONTEXT: Sleep is a significant problem in breast cancer survivors (BCS) and measured frequently using the Pittsburgh Sleep Quality Index (PSQI). Thus, it is important to evaluate its factor structure. The two-process model of sleep regulation was the theoretical framework for this study. OBJECTIVES: To perform a confirmatory factor analysis of the PSQI in BCS and compare results between African-American and Caucasian BCS. METHODS: This was a secondary analysis of cross-sectional data using local and regional health care facilities and Eastern Cooperative Oncology Group referrals. The study included 1174 nondepressed BCS (90% Caucasian), with a mean age of 57 years and median PSQI global scores at the cutoff for poor sleep (median=6.00, interquartile range=4.00-9.00). Measurements included self-reported demographics, medical history, depression, and sleep. RESULTS: Acceptable fit was not reached for the traditional one-factor model that would be consistent with current PSQI scoring or for alternative models in the published literature from other populations. A new two-factor model (i.e., sleep efficiency and perceived sleep quality) best fit the data but nested-model comparisons by race showed different relationships by race for 1) sleep quality sleep latency and 2) sleep efficiency-sleep quality. CONCLUSION: Results were inconsistent with current PSQI scoring that assumes a single global factor and with previously published literature. Although a new two-factor model best fit the data, further quantitative and qualitative analyses are warranted to validate our results in other populations before revising PSQI scoring recommendations. Additional recommendations are described for research. PMID- 22926091 TI - Nurse executives' perceptions of end-of-life care provided in hospitals. AB - CONTEXT: With the aging of our population, almost one in five adults, or 19% of the population, will be older than 65 years by 2030. Many persons have expressed concern about the inadequate preparation of hospitals to provide high-value end of-life care for the current and anticipated population of older adults. OBJECTIVES: The purpose of this study was to explore the perceptions of nurse executives about the provision of end-of-life care in the hospital setting. METHODS: We conducted a pilot, descriptive, naturalistic, qualitative study using in-person interviews to capture nurse executives' understandings, beliefs, and perceptions of end-of-life care in their facilities. RESULTS: Data were collected from 10 nurse executives. We identified five major factors, three barriers and two facilitators, in their descriptions of provision of end-of-life care provided in the hospital: 1) communication inadequacies, 2) education inadequacies, 3) hospital system constraints, 4) hospice services availability, and 5) nurse executive advocacy. CONCLUSION: These findings highlight the need for interventions that focus on improving communication at the bedside and in transitions of care, enhancing educational interventions, and developing patient centered care systems, which translate into a higher quality end-of-life experience for patients and their family members. Nurse executives are currently an underused resource in end-of-life care but are poised to be able to champion innovative models and a culture of change that integrates high-value care for patients with serious and chronic illnesses. PMID- 22926092 TI - Putting on a happy face: emotional expression in parents of children with serious illness. AB - CONTEXT: Communication is widely acknowledged as a crucial component of high quality pediatric medical care, which is provided in situations in which parents typically experience strong emotions. OBJECTIVES: To explore emotion using the Linguistic Inquiry and Word Count (LIWC) and a self-report questionnaire to better understand the relationship between these two measures of emotion in a pediatric care context. METHODS: Sixty-nine parents of 47 children who were participants in the Decision Making in Pediatric Palliative Care Study at The Children's Hospital of Philadelphia took part in this study. Parents completed the Positive and Negative Affect Schedule (PANAS) and a semistructured interview about their children and experience with medical decision making. The transcribed interviews were analyzed with the LIWC program, which yields scores for positive and negative emotional expression. The association between LIWC and PANAS scores was evaluated using multivariate linear regression to adjust for potential confounders. RESULTS: Parents who used more positive words when speaking about the illnesses of their children and the experience of medical decision making were more likely to report lower levels of positive affect on the PANAS: increase in the standard deviation of positive emotional expression was associated with an unadjusted 7.4% decrease in the self-reported positive affect (P = 0.015) and an adjusted 7.0% decrease in the self-reported positive affect (P = 0.057) after modeling for potential confounders. Increase in the standard deviation of negative emotional expression was associated with an adjusted 9.4% increase in the self-reported negative affect (P = 0.036). CONCLUSION: The inverse relationship between parents' positive emotional expression and their self reported positive affect should remind both researchers and clinicians to be cognizant of the possibilities for emotional miscues, and consequent miscommunication, in the pediatric care setting. PMID- 22926093 TI - Emotional numbness modifies the effect of end-of-life discussions on end-of-life care. AB - CONTEXT: Overall, end-of-life (EOL) discussions are unrelated to psychological distress and associated with lower rates of aggressive care near death. Nevertheless, patients who report that they feel emotionally numb about their illness might encounter difficulties cognitively processing an EOL discussion. OBJECTIVES: We hypothesized that emotional numbness would modify the effect of EOL discussions on the receipt of less aggressive EOL care. METHODS: Data were derived from structured interviews with 290 participants in the federally-funded Coping with Cancer Study, a multisite, prospective cohort study of patients with advanced cancer followed-up till their death. Patients' reports of EOL discussions with their physician and emotional numbness were assessed at a median of 4.6 months before their death. Information about aggressive EOL care (i.e., ventilation, resuscitation in the last week of life, death in the intensive care unit) was obtained from postmortem caregiver interviews and medical charts. Main and interactive effects of EOL discussions and emotional numbness on aggressive EOL care, adjusting for potential confounds, were evaluated using multiple logistic regression. RESULTS: The likelihood of aggressive EOL care associated with having EOL discussions increased by a factor of nine (adjusted odds ratio=9.02, 95% CI 1.37, 59.6, P=0.022) for every unit increase in a patient's emotional numbness score. CONCLUSION: Emotional numbness diminishes a patient's capacity to benefit from EOL discussions. The EOL decision making may be more effective if clinical communications with emotionally numb patients are avoided. PMID- 22926095 TI - Neuroendocrinology: Tesamorelin can improve cognitive function. PMID- 22926096 TI - Thyroid gland: vandetanib for thyroid cancer. PMID- 22926094 TI - The Manchester cough in lung cancer scale: the development and preliminary validation of a new assessment tool. AB - CONTEXT: Cough is a common distressing symptom in lung cancer patients. Its assessment is hampered by the lack of a validated scale to measure the complex cough experience in this population. OBJECTIVES: To describe the development and preliminary validation of a scale to measure cough in lung cancer patients. METHODS: In the first phase, collection of qualitative data from patient interviews, a review of literature, and identification of noncancer cough scales resulted in the development of a pool of 30 items. This item pool was tested for appropriateness of content and breadth of coverage with 18 patients with lung cancer and 25 health care professionals. The second phase was the operationalization/phrasing of items. The final phase was the scale's field testing with 139 patients, 49 of whom repeated the assessment after one week. RESULTS: The first phase led to the deletion of several items and the addition of four, resulting in a final scale for field testing of 21 items. In the field testing, the scale was decreased to 10 items, eliminating items on psychometric grounds. The final scale's Cronbach alpha (internal consistency) was 0.86, item to total correlations ranged from 0.40 to 0.76, and test-retest reliability was high (intraclass correlation=0.83). CONCLUSION: We have developed a promising tool to assess cough in lung cancer, but this needs validation, and future studies should determine whether this is a sensitive and responsive tool. A fully validated tool can be used in the clinical assessment of cough in cancer patients, and as a unidimensional impact scale in the measurement of cough as an outcome in intervention studies. PMID- 22926097 TI - Endocrine disorders in pregnancy: updated guidelines for the management of thyroid disorders in pregnancy. PMID- 22926098 TI - Diabetes: Add-on to metformin in T2DM--linagliptin or glimepiride? PMID- 22926099 TI - Diabetes: Weight status affects mortality risk. PMID- 22926100 TI - Diabetes: no clear advantage for intensive blood pressure control in T2DM. PMID- 22926101 TI - An extremely thermotolerant, alkaliphilic subtilisin-like protease from hyperthermophilic Bacillus sp. MLA64. AB - The current work is a report on a new extremely thermostable protease from newly isolated hyperthermophilic Bacillus sp. MLA64. The protease was purified with a 16.5-fold increase in specific activity and 93.5% recovery. The molecular weight of the enzyme was estimated to be 24 kDa. The enzyme was extremely stable and quite active over the temperature range from 40 to 100 degrees C with an optimal temperature at 95 degrees C as well as in a wide range of pH from 6.0 to 12.5, with a superlative at pH 9.5. The enzyme activity was not enhanced in the presence of CaCl(2), indicating that the enzyme is calcium-independent. The enzyme showed high stability towards non-ionic surfactants and anionic surfactant SDS. In addition, the enzyme was relatively stable with respect to oxidizing agents. The protease was inhibited by PMSF but not by TPCK and TLCK, suggesting that it can be a subtilisin-like protease. Moreover, the N-terminal sequencing of the first 20 amino acids of the purified protease showed less homology with other well-known bacterial peptidases. In conclusion, the enzyme can be considered as a novel protease which might be a candidate for industrial processes. PMID- 22926102 TI - The novel MER transposon-derived miRNAs in human genome. AB - MicroRNAs (miRNAs) are small RNA molecules (~20-30 nucleotides) that generally act in gene silencing and translational repression through the RNA interference pathway. They generally originate from intergenic genomic regions, but some are found in genomic regions that have been characterized such as introns, exons, and transposable elements (TE). To identify the miRNAs that are derived from palindromic MERs, we analyzed MER paralogs in human genome. The structures of the palindromic MERs were similar to the hairpin structure of miRNA in humans. Three miRNAs derived from MER96 located on chromosome 3, and MER91C paralogs located on chromosome 8 and chromosome 17 were identified in HeLa, HCT116, and HEK293 cell lines. The interactions between these MER-derived miRNAs and AGO1, AGO2, and AGO3 proteins were validated by immunoprecipitation assays. The data suggest that miRNAs derived from transposable elements could widely affect various target genes in the human genome. PMID- 22926103 TI - Minority of mammalian orthologs can be regarded as physiologically closest genes. AB - Orthologs are genes from different genomes that originate from a common ancestor gene by speciation event. They are most similar by the structure of encoded proteins and therefore should have a similar function. Here I apply the principle used for detection of structural orthology for a genome-wide analysis of gene expression. For this purpose, I determine the mutual similarity rank in all-by all comparison of among-tissues expression patterns. The expression of most part of human-mouse orthologs in homologous tissues is poorly correlated (average mutual coexpression rank is only 4835 out of 18,092). Genes from evolutionarily labile gene families, which experience rapid turnover of family composition, are among those with the strongest expression change. However, the revealed phenomenon is not limited to them. There is no or very weak relationship between protein sequence divergence and mutual coexpression rank. Also, generally there is no relationship between the ratio of nonsynonymous to synonymous nucleotide substitutions and coexpression rank. This relationship is tangible only within evolutionarily labile gene families. These results indicate that despite of a similar biochemical function of orthologs reflected in the conserved protein sequence, the physiological (systemic) context of this function can be changed. Also, these results suggest that gene biochemical function and its physiological role in the organism can evolve independently. PMID- 22926104 TI - Nothing is free in life--not even prevention! PMID- 22926105 TI - Identification of a novel HLA-A2-restricted mutated Survivin epitope and induction of specific anti-HCC CTLs that could effectively cross-recognize wild type Survivin antigen. AB - Peptide vaccine based on tumor-associated antigen (TAA), which usually belongs to self-antigen with poor immunogenicity, has been considered as an attractive option for treatment of malignant tumors. The ideal TAA epitopes should have stable affinity to major histocompatibility complex (MHC) molecules and elicit strong anti-tumor immune response. Although point-mutation technology of TAA peptide may increase the binding capability to MHC molecules, some previous studies have revealed that part of the variant peptides results in lymphocyte not to effectively cross-recognize and kill the target tumor expressed wild-type TAA. Here, we designed a novel HLA-A2-restricted mutated TAA Survivin epitope nonapeptide Sur79L2 (KLSSGCAFL) that showed higher binding ability compared to wild-type peptide Sur79 (KHSSGCAFL) in T2-binding assays. To investigate whether Sur79L2 can induce Survivin-specific anti-hepatocellular carcinoma (HCC) response, we stimulated tumor-associated lymphocytes from a HCC patient with Sur79L2 in vitro. IFN-gamma release and cytotoxicity assays showed Sur79L2 could effectively cross-recognize and lysis T2 cell plus peptide Sur79 and HCC cell lines (expression of wild-type Survivin antigen) in an HLA-A2-restricted manner. In contrast, peptide Sur95 (ELTLGEFLKL) that has been reported as a very promising anti-tumor epitope in a variety of tumors except HCC were not able to generate detectable cytotoxic immune responses against HCC in this study. Our results suggest that point-mutated peptide Sur79L2 is a new HLA-A2-restricted CTL epitope and may be useful for the immunotherapy for patients with HCC. PMID- 22926109 TI - Morphological heterogeneity of the simultaneous ipsilateral invasive tumor foci in breast carcinoma: a retrospective study of 418 cases of carcinomas. AB - The aim of this paper was to assess whether the morphological appearance (i.e. histological tumor type and histological grade) of simultaneous invasive breast carcinoma foci is heterogeneous, since it is known that adjuvant therapy is established according to these parameters. Patients with simultaneous breast tumors in which only the features of the largest neoplastic focus are reported could thus be undertreated. A retrospective study of 418 cases of breast carcinomas was conducted over a 3-year period. The histological tumor types and histological grades of multifocal/multicentric carcinomas in each tumor focus were compared, and mismatches among foci were recorded. Ninety-one of the 418 cases reviewed had multiple carcinomas (21.77%). A comparison between multiple synchronous tumor foci revealed that their histological type was different in 12.08% of the cases. Mismatches among foci were also observed in 9.89% of the cases when evaluating the histological grade, and 5 out of 9 additional tumor foci with a different grade from the largest (index) tumor (55.55%) displayed a higher grade compared to the index tumor. Since the histological tumor type and histological grade of the individual foci may vary considerably within the same tumor and the additional foci may be of higher grade than the index tumor, we believe that reporting morphologic parameters with more unfavorable characteristics in addition to the parameters of the index tumor is imperative. PMID- 22926108 TI - Peri-implant bone tissues around retrieved human implants after time periods longer than 5 years: a retrospective histologic and histomorphometric evaluation of 8 cases. AB - Only rarely, it is possible to find in the literature histological reports of human retrieved implants, especially after several years of functional loading. These implants can help us in understanding the reactions of peri-implant bone. The aim of this study was to perform a histologic and histomorphometric analysis of the peri-implant tissues behavior and of the bone-titanium interface in titanium dental implants retrieved from patients after time periods longer than 5 years. The archives of the Implant Retrieval Center of the Dental School of the University of Chieti-Pescara, Italy were searched for human dental implants, retrieved after a loading period of more than 5 years. A total of 8 implants were found: 3 of these had been retrieved after 5 years, 1 after 6 years, one after 10 years, 1 after 14 years, 1 after 18 years, 1 after 22 years. Only the bone to implant contact in the three best threads was evaluated. Compact, mature, lamellar bone, with few and small marrow spaces, was present around the implants. Osteons with Haversian canals were present inside some threads, in close proximity to the interface, at both cortical and trabecular regions. Other osteons had a direction perpendicular to the direction of the long axis of the implants. Numerous reversal lines were present. At higher magnification, no gaps or fibrous, connective tissues were present at the interface. The BIC of the three best threads for all implants varied from 94 to 100 %.In conclusion, within the limitations of the present report histology showed that implants with different surfaces all presented the potential to maintain osseointegration over a long period, with a continuous remodeling at the interface, as indicated by the presence of reversal lines. PMID- 22926111 TI - New challenges in low-vision research. PMID- 22926113 TI - Guidelines for predicting performance with low vision AIDS. AB - PURPOSE: To determine predictors of success in reading with low vision aids, in terms of reading acuity, optimum acuity reserve, and maximum reading speed, for observers with vision loss from various causes. METHODS: One hundred people with vision loss affecting their daily lives participated. Clinical visual function measurements of distance acuity, contrast sensitivity, binocular threshold visual fields, and near reading performance with a MNRead chart at 40 cm were obtained. Reading performance aided by habitual low vision aids was also assessed with a MNRead chart. RESULTS: Aided reading acuity was best predicted by clinical reading acuity and contrast sensitivity. For most observers, a 2:1 acuity reserve was sufficient to achieve near-maximum reading speed, but one-third of observers with aided reading acuity better than 1.2 M required a higher acuity reserve. Aided maximum reading speed was best predicted by clinically assessed reading speed and by clinical reading acuity. CONCLUSIONS: People with vision impairment are likely to achieve 1 M with a low vision aid if their clinically assessed reading acuity is better than 0.85 logMAR. If acuity is worse than this, but contrast sensitivity is better than 1.05 logCS, 1M is also likely to be achieved. A 2:1 acuity reserve is adequate for 75% of observers, but those with good aided reading acuity may require further magnification to achieve best reading speeds. Fluent reading (>80 words per minute) is likely to be achieved if an observer reads fluently with large print at a fixed working distance and if clinically assessed reading acuity is better than 1.0 logMAR. PMID- 22926116 TI - Characterization of mitochondrial DNA control region lineages in Iraq. AB - To evaluate the utility of mtDNA control region data for the purposes of forensic DNA testing in Iraq, a sample of 182 subjects (128 Arab Muslims, 15 Kurd Muslims, 22 Assyrian Christians and 17 Mandaean Arabs) was tested. High numbers of singleton haplotypes were observed among Arabs, Kurds and Assyrians, but fewer were found in Mandaeans. High molecular diversity and low random match probabilities confirmed the value of control region data in the investigation of maternal genetic lineages among the Iraqi population. PMID- 22926117 TI - [Treatment of refractory or recurrent Clostridium difficile infection]. AB - The incidence and severity of Clostridium difficile infection (CDI) has increased over the past decades. It is related to the emergence of hypervirulent strains and increased use of antibiotics. The incidence of refractory CDI to standard therapies and the risk for recurrent CDI are also increasing. Current guidelines recommend the first recurrence to be treated with the same agent used for the initial episode. However, data are lacking to support any particular treatment strategy for severe refractory CDI or cases with multiple recurrence. Treatments currently available for CDI are inadequate to prevent recurrence. Widely used method for managing a subsequent recurrence involves tapering followed by pulsed doses of vancomycin. Other potentially effective strategies for recurrent CDI are use of other antibiotics such as fidaxomicin, nitazoxanide, rifaximin, tigecycline, and teicoplanin. There are efforts to recover gut microflora and to optimize immune response to CDI. These include use of probiotics, fecal microbiota transplantation, intravenous immunoglobulin, monoclonal antibodies directed against C. difficile toxins, and active vaccination. However treatment of patients with refractory CDI and those with multiple CDI recurrences is based on limited clinical evidence, and there is an ongoing need for continued research to improve the outcomes these patients. PMID- 22926119 TI - [Anti-inflammatory mechanism of Lactobacillus rhamnosus GG in lipopolysaccharide- stimulated HT-29 cell]. AB - BACKGROUND/AIMS: Probiotics are live non-pathogenic organisms that belong to the resident microflora, and confer health benefits by multiple mechanisms. Lactobacillus rhamnosus GG (LGG) is one of the probiotic bacteria that ameliorates intestinal injury and inflammation caused by various stimuli. We aimed to evaluate the anti-inflammatory effect and mechanism of LGG in lipopolysaccharide (LPS)-stimulated HT-29 cells. METHODS: HT-29 cells were stimulated with interleukin (IL)-1beta (2 ng/mL), tumor necrosis factor (TNF) alpha (20 ng/mL), and LPS (20 MUg/mL) in the presence or absence of LGG (107-109 colony forming units/mL). Production of the pro-inflammatory chemokine IL-8 was measured by ELISA and semi-quantitative PCR. Transcriptional activity of NF-kB responsive gene was evaluated by luciferase assay with reporter gene. Toll-like receptor 4 (TLR4) mRNA expression was assessed by semi-quantitative PCR. The IkappaBa degradation was evaluated by western blot and intranuclear translocation of NF-kappaB was determined by western blot and immunofluorescence. RESULTS: LGG did not affect the viability of HT-29 cells. Pretreatment of HT-29 cells with LGG significantly blocked TNF-alpha, and LPS induced IL-8 activation at both mRNA and protein level (p<0.05). Pretreatment of HT-29 cells with LGG attenuated LPS induced NF-kappaB nuclear translocation and also blocked LPS-induced IkappaBalpha degradation. LGG also down-regulated TLR4 mRNA activated by LPS. CONCLUSIONS: LGG attenuates LPS induced inflammation, and this may be associated with TLR4/NF kappaB down-regulation. PMID- 22926118 TI - [DNA double strand breaks in gastric epithelium with Helicobacter pylori infection]. AB - BACKGROUND/AIMS: DNA double strand breaks (DSB) is one of the critical types of DNA damage. If unrepaired, DSB is accumulated in the nucleus of cells, the cells become apoptotic or transform to tumor by way of genomic instability. Some of malignant cancers and its premalignant lesions were proven to have DSB in their nuclei. There was no report that Helicobacter pylori (H. pylori), the gastric carcinogen, induce DNA DSB in gastric epithelium in vivo. The aim of this study was to investigate whether H. pylori induce DSB in the gastric epithelial cells of chronic gastritis. METHODS: Immunohistochemical stains were performed for the DSB markers, phospho-53BP1 and gH2AX, in the gastric epithelium derived from 44 peptic ulcer disease patients before and after H. pylori eradication. DNA fragmentation assay was performed in the cell line to investigate the DNA damage by H. pylori infection. RESULTS: The mean expression score of gH2AX was significantly higher in the H. pylori infected gastric epithelium as compared to the H. pylori eradicated gastric epithelium (8.8+/-5.5 vs. 6.2+/-5.3 respectively; p=0.008). The expression score of phospho-53BP1 between before and after eradication of H. pylori was not statistically different, but tended to be higher in H. pylori infection. DNA fragmentation was developed significantly more in the cell lines after infection with H. pylori. CONCLUSIONS: DSB of DNA damage was typical feature of H. pylori infection in the gastric epithelium. PMID- 22926120 TI - [Effect of a probiotic preparation (VSL#3) in patients with mild to moderate ulcerative colitis]. AB - BACKGROUND/AIMS: Ulcerative colitis (UC) is a chronic disease that characteristically has a relapsing and remitting course. Probiotics might possibly induce remission in the treatment of active UC. Aims of our study were to assess the efficacy of VSL#3 on clinical response and colonic tissue cytokine concentration changes in patients with active UC. METHODS: Twenty-four eligible patients with mild to moderate UC received open-label VSL#3 4 sachets daily in 2 divided doses for 8 weeks. The disease activity pre- and post-VSL#3 therapy was assessed by ulcerative colitis disease activity score and colonic tissue cytokine profiling done at baseline and at week 8. RESULTS: Twenty-four patients (mean age, 43.7 years; range, 20-70 years; male/female, 15/9) were enrolled and 2 patients did not have the final endoscopic assessment. A total of 22 patients were analyzed. Intent to treat analysis demonstrated remission in 45.8% of subjects (n=11); partial response in 20.8% (n=5); no change or worse in 25.0% (n=6) of subjects. The mean ulcerative colitis disease activity index (UCDAI) scores decreased from 7.09+/-1.81 to 1.45+/-1.29 in patients with a remission (p<0.001). The mean endoscopic scores had also significantly decreased from 1.91+/-0.54 to 0.63+/-0.50 in patients with a remission (p<0.001). The concentrations of colonic cytokines did not change significantly during treatment in patients with a remission. CONCLUSIONS: Our study demonstrated that VSL#3 is effective in achieving clinical responses and remissions in patients with mild-to moderately active UC, further supporting the potential role in UC therapy. PMID- 22926121 TI - [Dietary risk factors in relation to colorectal adenoma]. AB - BACKGROUND/AIMS: The role of dietary risk factors in colorectal carcinogenesis remains unclear. We investigated the association between dietary intakes and colorectal adenomas who visited a health promotion center for a routine health check-up colonoscopy. METHODS: We conducted a retrospective case-control study using data from individuals who had colonoscopy at Seoul National University Hospital Healthcare System Gangnam Center from October 2003 to December 2007. The subjects were 242 patients (162 males and 80 females) with histopathologically confirmed colorectal adenoma, and 464 (272 males and 192 females) controls. Dietary data were obtained via 24 hour dietary recall, assisted by a registered dietitian. The student's t-test and the chi-square test were performed for the statistical comparison of means and proportions among groups. Multivariate analyses using logistic regression were performed to assess the relation between dietary intake and colorectal adenoma. RESULTS: The total average energy intake of the patients (male: 2,407.5+/-429.2 kcal, female: 1,901.3+/-316.9 kcal) was higher than the controls (male: 2,249.6+/-430.4 kcal, female: 1,752.4+/-275.0 kcal; p=0.001). High energy intake (male: OR=4.13, 95% CI=1.70-10.05, p=0.002; female: OR=4.00, 95% CI=1.51-10.61, p=0.005) and animal protein intake (male: OR=3.97, 95% CI=1.66-9.49, p=0.002; female: OR=5.76, 95% CI=1.99-16.169, p=0.001) were found to be associated with the risk of colorectal adenoma after adjusting for confounders such as age, BMI, waist circumference, metabolic syndrome and smoking. CONCLUSIONS: In summary, high energy intake and animal protein were associated with colorectal adenoma. PMID- 22926122 TI - Symptomatic improvement of diffuse esophageal spasm after botulinum toxin injection. AB - Diffuse esophageal spasm, an uncommon esophageal motility disorder, has recently been defined using high-resolution manometry. Patients with distal esophageal spasm usually complain of chest pain or dysphagia. The etiology and pathophysiology of this disorder are poorly known, and treatment options are limited. However, some options to improve symptoms are available, including endoscopic injection of botulinum toxin. Nevertheless, few reports have described the effects of endoscopic injection of botulinum toxin in patients with symptomatic diffuse esophageal spasm with clear endoscopic and high-resolution manometry images. Here, we report a case of diffuse esophageal spasm diagnosed with high-resolution manometry and treated by endoscopic injection of botulinum toxin with good results at the 7-month follow-up. PMID- 22926123 TI - A case of synchronous esophagus and stomach cancer successfully treated by combined chemotherapy. AB - Although cases of simultaneous esophagus and stomach cancer have been reported sporadically, there are rare reports of successful treatment using chemotherapy. We report a case of synchronous esophageal and gastric cancer successfully treated using docetaxel and cis-diammineedichloro-platinum (CDDP) combination chemotherapy instead of surgery. A 82-years-old man with anorexia and progressive weight loss was diagnosed with synchronous esophageal and gastric cancer by endoscopy. Both cancers were diagnosed as resectable by the preoperative clinical staging. However, surgery was contraindicated because of severe lung dysfunction. Moreover, he actively refused radiotherapy and endoscopic management. Therefore, the patient was given combined chemotherapy with docetaxel (65 mg/m2) and CDDP (60 mg/m2). The esophageal and gastric lesion completely disappeared on endoscopy, and there were no residual tumor cells on endoscopic biopsy after three cycles of chemotherapy. Metastatic lymph nodes also completely disappeared on the CT scan. The patient received a total of ten cycles of chemotherapy, without severe adverse effects. The patient remained asymptomatic for 18 months after discontinuation of the chemotherapy, without evidence of local recurrence or distant metastasis. Surgery or endoscopic treatment of both esophageal and gastric cancers is desirable, but, if medically inoperable, chemotherapy can be alternative treatment option. PMID- 22926124 TI - [A case of hepatic peribiliary cysts in a patient with alcoholic liver cirrhosis]. AB - Hepatic peribiliary cysts (HPCs) are characterized by cystic dilatations of the peribiliary glands located throughout the branches of the biliary systems. Specifically, they are mainly located along the hepatic hilum and major portal tracts. The natural history and prognosis of HPCs are uncertain. In fact, almost all HPCs have been discovered incidentally during radiological examination or autopsy, and they are considered to be clinically harmless. Recently, several cases of HPCs associated with obstructive jaundice or liver failure were reported in patients with pre-existing liver disease in several studies. However, until now there have been no reports of such a case in Korea. Herein, we report a case of HPCs that show a disease course with a poor prognosis. These HPCs developed in a 47-year-old man with progressive alcoholic liver cirrhosis. PMID- 22926125 TI - [A case of intrahepatic cholangiocarcinoma associated with Type IV choledochal cyst]. AB - Anomalous union of the pancreaticobiliary duct (AUPBD) is a congenital anomaly that is defined as a junction of the bile duct and pancreatic duct outside the duodenal wall. This anomaly results in a loss of normal sphincteric mechanisms at the pancreaticobiliary junction. As a result, regurgitation of pancreatic juice into the biliary system develops and causes choledochal cysts, choledocholithiasis, cholangitis, pancreatitis and malignancy of the biliary tract. Gallbladder cancer or common bile duct cancer associated with AUPBD and choledochal cysts have been frequently reported. But, intrahepatic cholangiocarcinoma associated with this condition has been only rarely reported. Here, we report a case of intrahepatic cholangiocarcinoma associated with AUPBD and choledochal cyst. PMID- 22926126 TI - An innovative, easily fabricated, silver nanoparticle-based titanium implant coating: development and analytical characterization. AB - Microbial colonization and biofilm formation on implanted devices represent an important complication in orthopaedic and dental surgery and may result in implant failure. Controlled release of antibacterial agents directly at the implant site may represent an effective approach to treat these chronic complications. Resistance to conventional antibiotics by pathogenic bacteria has emerged in recent years as a major problem of public health. In order to overcome this problem, non-conventional antimicrobial agents have been under investigation. In this study, polyacrylate-based hydrogel thin coatings have been electrosynthesised on titanium substrates starting from poly(ethylene glycol diacrylate)-co-acrylic acid. Silver nanoparticles (AgNPs) with a narrow size distribution have been synthesized using a "green" procedure and immobilized on Ti implant surfaces exploiting hydrogel coatings' swelling capabilities. The coatings have been characterized by XPS and SEM/EDX, while their silver release performances have been monitored by ICP-MS. The antibacterial activity of these AgNP-modified hydrogel coatings was tested evaluating in vitro inhibition growth of Staphylococcus aureus, Pseudomonas aeruginosa and Escherichia coli, among the most common pathogens in orthopaedic infections. Moreover, a preliminary investigation of the biocompatibility of silver-loaded coatings versus MG63 human osteoblast-like cells has been performed. An important point of strength of this paper, in fact, is the concern about the effect of silver species on the surrounding cell system in implanted medical devices. Silver ion release has been properly tuned in order to assure antibacterial activity while preserving osteoblasts' response at the implant interface. PMID- 22926127 TI - Organohalogen contaminants of emerging concern in Great Lakes fish: a review. AB - Organohalogen chemicals of emerging concern (CECs) have attracted much attention during the past decade and are of special importance for the Great Lakes of North America, which are together the largest surface freshwater resource on the earth. In this paper we review and summarize detection and levels of legacy contaminants in Great Lakes fish, lessons learned from legacy contaminants in advancing the analytical detection of CECs, progress and challenges in measuring CECs, and levels of CECs in Great Lakes fish reported to date. The CECs considered include chlorinated paraffins, polychlorinated naphthalenes and other chlorinated aromatics, halogenated flame retardants, and perfluorinated compounds. PMID- 22926128 TI - Surface plasmon resonance, fluorescence, and circular dichroism studies for the characterization of the binding of BACE-1 inhibitors. AB - The mechanism of action underlying beta-secretase 1 (BACE-1) inhibition was characterized by a surface plasmon resonance (SPR) method using primary amino groups to immobilize OM99-2, a well-known highly potent peptidic BACE-1 inhibitor, on the carboxyl groups of the dextran layer of a sensor chip. The diluted BACE-1 was mixed with buffer or the test compound and the mixture was flushed through the chip. BACE-1 binding to the immobilized peptide inhibitor was quantified. This SPR method was used to identify BACE-1 inhibitor binding sites and the mechanism of action (competitive/noncompetitive) and to validate findings of fluorescence resonance energy transfer (FRET) inhibition studies. To support this, a multimethodological approach (circular dichroism and fluorescence spectroscopy) was applied in parallel to FRET inhibition studies to characterize the binding modes of peptidic and nonpeptidic BACE-1 inhibitors. Circular dichroism spectroscopy served to correlate the conformation of BACE-1 with enzymatic activity and to monitor secondary structure changes upon ligand binding. In a complementary approach, direct fluorescence spectroscopy was used to characterize different BACE-1 inhibitor binding sites. The influence of pH and inhibitors on BACE-1 secondary structure was also elucidated. This multimethodological approach was applied to identify binding modes of bis(7) tacrine and myricetin in comparison with well-known peptidic inhibitors. PMID- 22926129 TI - Silicon photonic sensors incorporated in a digital microfluidic system. AB - Label-free biosensing with silicon nanophotonic microring resonator sensors has proven to be an excellent sensing technique for achieving high-throughput and high sensitivity, comparing favorably with other labeled and label-free sensing techniques. However, as in any biosensing platform, silicon nanophotonic microring resonator sensors require a fluidic component which allows the continuous delivery of the sample to the sensor surface. This component is typically based on microchannels in polydimethylsiloxane or other materials, which add cost and complexity to the system. The use of microdroplets in a digital microfluidic system, instead of continuous flows, is one of the recent trends in the field, where microliter- to picoliter-sized droplets are generated, transported, mixed, and split, thereby creating miniaturized reaction chambers which can be controlled individually in time and space. This avoids cross talk between samples or reagents and allows fluid plugs to be manipulated on reconfigurable paths, which cannot be achieved using the more established and more complex technology of microfluidic channels where droplets are controlled in series. It has great potential for high-throughput liquid handling, while avoiding on-chip cross-contamination. We present the integration of two miniaturized technologies: label-free silicon nanophotonic microring resonator sensors and digital microfluidics, providing an alternative to the typical microfluidic system based on microchannels. The performance of this combined system is demonstrated by performing proof-of-principle measurements of glucose, sodium chloride, and ethanol concentrations. These results show that multiplexed real-time detection and analysis, great flexibility, and portability make the combination of these technologies an ideal platform for easy and fast use in any laboratory. PMID- 22926130 TI - Novel method to investigate protein carbonylation by iTRAQ strategy. AB - This paper reports a novel methodology for relative quantitative analysis of carbonylation sites in proteins by exploiting a new isobaric tag for relative and absolute quantitation (iTRAQ) derivative, iTRAQ hydrazide (iTRAQH), and the analytical power of linear ion trap instruments (QqLIT). Because of its operational simplicity, avoiding time-consuming enrichment procedures, this new strategy seems to be well suited for quantitative large-scale proteomic profiling of carbonylation. PMID- 22926131 TI - HPLC-HG-ICP-MS: a sensitive and selective method for inorganic arsenic in seafood. AB - The addition of an online post-column hydride generation (HG) step to the commonly used high-performance liquid chromatography inductively coupled plasma mass spectrometry (HPLC-ICP-MS) setup for arsenic speciation proved to significantly improve the detection limits for the determination of inorganic arsenic (iAs) as arsenate in seafood samples, where the limit of detection and limit of quantification were found to be 0.0004 and 0.0014 mg kg(-1), respectively with HG. HG as an additional step further added to the selectivity of the determination of the iAs species and increased the detection and quantification of low levels of iAs (<0.002 mg kg(-1)) in samples with complicated matrices. PMID- 22926132 TI - Development, validation, and application of a liquid chromatography-tandem mass spectrometry method for the determination of 4-(methylnitrosamino)-1-(3-pyridyl) 1-butanol in human hair. AB - The tobacco-specific nitrosamine metabolite 4-(methylnitrosamino)-1-(3-pyridyl)-1 butanol (NNAL) is a valuable biomarker for human exposure to the carcinogenic nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in tobacco and tobacco smoke. In this work, an efficient and sensitive method for the analysis of NNAL in human hair was developed and validated. The hair sample was extracted by NaOH solution digestion, purified by C(18) solid-phase extraction (SPE) and molecularly imprinted solid-phase extraction, further enriched by reverse-phase ultrasound-assisted dispersive liquid-liquid microextraction (USA-DLLME) into 1.0 % aqueous formic acid, and finally analyzed by liquid chromatography-electrospray ionization tandem mass spectrometry. Good linearity was obtained in the range of 0.24-10.0 pg/mg hair with a correlation coefficient of 0.9982, when 150 mg hair was analyzed. The limit of detection and lower limit of quantification were 0.08 and 0.24 pg/mg hair, respectively. Accuracies determined from hair samples spiked with three different levels of NNAL ranged between 87.3 and 107.7 %. Intra- and inter-day relative standard deviations varied from 4.1 to 8.5 % and from 6.9 to 11.3 %, respectively. Under the optimized conditions, an enrichment factor of 20 was obtained. Finally, the developed method was applied for the analysis of NNAL in smokers' hair. The proposed sample preparation procedure combining selectivity of two-step SPE and enrichment of DLLME significantly improves the purification and enrichment of the analyte and should be useful to analyze NNAL in hair samples for cancer risk evaluation and cancer prevention in relation to exposure to the tobacco-specific carcinogen NNK. PMID- 22926133 TI - Nanoparticle-modified monolithic pipette tips for phosphopeptide enrichment. AB - We have developed nanoparticle-modified monoliths in pipette tips for selective and efficient enrichment of phosphopeptides. The 5 MUL monolithic beds were prepared by UV-initiated polymerization in 200 MUL polypropylene pipette tips and either iron oxide or hydroxyapatite nanoparticles were used for monolith modification. Iron oxide nanoparticles were prepared by a co-precipitation method and stabilized by citrate ions. A stable coating of iron oxide nanoparticles on the pore surface of the monolith was obtained via multivalent electrostatic interactions of citrate ions on the surface of nanoparticles with a quaternary amine functionalized poly(2-hydroxyethyl methacrylate-co-ethylene dimethacrylate) monolith. Hydroxyapatite nanoparticles were incorporated into the poly(2 hydroxyethyl methacrylate-co-ethylene dimethacrylate) monolith by simply admixing them in the polymerization mixture followed by in situ polymerization. The nanoparticle-modified monoliths were compared with commercially available titanium dioxide pipette tips. Performance of the developed and commercially available sorbents was demonstrated with the efficient and selective enrichment of phosphopeptides from peptide mixtures of alpha-casein and beta-casein digests followed by off-line MALDI/MS analysis. PMID- 22926135 TI - Postprocedural discitis of the vertebral spine: challenges in diagnosis, treatment and prevention. AB - BACKGROUND: Although post-procedural discitis is relatively uncommon, the consequences can be very clinically significant. AIM: We reviewed aspects on the diagnosis, management and prevention of post-procedural discitis. METHODS: We reviewed the literature published in English over the last twenty years using a variety of appropriate search terms. RESULTS: Clinical features, microbiology results, imaging and inflammatory makers should be used in diagnosis. Every effort should be made to confirm infection to avoid unnecessary antibiotics and to facilitate targeted therapy. Surgical debridement or source control is a crucial aspect of treatment and can provide diagnosis specimens to guide antibiotic treatment. When culture results are positive, antibiotic treatment should be based on the results of antibiotic susceptibilities. There are no definitive guidelines on antibiotic therapy. A combination of agents, such as a quinolone or clindamycin, with fusidic acid or rifampicin, is indicated for empirical therapy. Early intravenous to oral switch and a minimum of six weeks of antibiotic treatment is recommended. Prevention involves antimicrobial prophylaxis perioperatively, good surgical technique and minimally invasive surgery where possible. CONCLUSION: Much of the information currently available is sub-optimal with the absence of good clinical trials. Further research is required on alternative approaches to routine culture and on the potential role of local antibiotics as prevention measures. PMID- 22926136 TI - Factors affecting prevention and control of viral gastroenteritis outbreaks in care homes. AB - We assess the effect of key care quality indicators on viral gastroenteritis outbreaks and control in care homes using mandatory inspection data collected by a non-departmental public body. Outbreak occurrence was associated with care home size but not with overall quality or individual environmental standards. Care home size, hygiene and infection control standard scores were inversely associated with attack rate in residents, whereas delayed reporting to the local public health agency was associated with higher attack rates. PMID- 22926137 TI - Regional cerebral blood flow distribution during exercise: influence of oxygen. AB - We investigated regional changes in cerebral artery velocity during incremental exercise while breathing normoxia (21% O2), hyperoxia (100% O2) or hypoxia (16% O2) [n=10; randomized cross over design]. Middle cerebral and posterior cerebral arterial velocities (MCAv and PCAv) were measured continuously using transcranial Doppler ultrasound. At rest, only PCAv was reduced (-7%; P=0.016) with hyperoxia. During low-intensity exercise (40% workload maximum [Wmax]) MCAv (+17 cms(-1); +14cms(-1)) and PCAv (+9cms(-1); +14 cms(-1)) were increased above baseline with normoxia and hypoxia, respectively (P<0.05). The absolute increase from rest in MCAv was greater than the increase in PCAv between 40 and 80% Wmax with normoxia; this greater increase in MCAv was also evident at 60% Wmax with hypoxia and hyperoxia. Hyperoxic exercise resulted in larger absolute (+19 cms(-1)) and relative (+40%) increases in PCAv compared with normoxia. Our findings highlight the selective changes in PCAv during hyperoxic incremental exercise. PMID- 22926138 TI - The plant physical features selected by wildcats as signal posts: an economic approach to fecal marking. AB - The chemical signals of solitary and territorial felid species are essential for their intraspecific communication. We studied the selection of plant substrates during the fecal marking behavior of the European wildcat Felis silvestris from September 2008 to June 2009 in a protected area in Northwest Spain. The aim of the study was to examine the selection of plants as signal posts with respect to their physical characteristics. We hypothesized that wildcats deposit their fecal marks on plants with physical characteristics (e.g., size, species, and visual conspicuousness) that enhance the olfactory and visual effectiveness of the signal. Our results indicate that diameter, plant group, visual conspicuousness, and interaction between the diameter and plant group influence the decision of wildcats to deposit their fecal marks on plants. The wildcats chose plants with greater diameters and greater visual conspicuousness as scent-marking posts. Moreover, the wildcats chose woody and herbaceous plants, and certain plant species were marked more frequently than expected at random. Indeed, our results indicate that the fecal marks were not randomly distributed on the plants: the wildcats chose to place their marks on plants with certain physical characteristics that maximized the detectability of the signal by intruders and potential mates, thus facilitating the spatial distribution of the species. PMID- 22926139 TI - Paladin is an antiphosphatase that regulates neural crest cell formation and migration. AB - Although a network of transcription factors that specifies neural crest identity in the ectoderm has been defined, expression of neural crest transcription factors does not guarantee eventual migration as a neural crest cell. While much work has gone into determining regulatory relationships within the transcription factor network, the ability of protein modifications like phosphorylation to modulate the function of neural crest regulatory factors and determine when and where they are active also has crucial implications. Paladin, which was previously classified as a phosphatase based on sequence similarity, is expressed in chick neural crest precursors and is maintained throughout their epithelial to mesenchymal transition and migration. Loss of Paladin delays the expression of transcription factors Snail2 and Sox10 in premigratory neural crest cells, but does not affect accumulation of FoxD3, Cad6B or RhoB, indicating that Paladin differentially modulates the expression of genes previously thought to be coregulated within the neural crest gene regulatory network. Both gain and loss of Paladin function result in disrupted neural crest migration, reinforcing the importance of precisely regulated phosphorylation for neural crest migration. Mutation of critical, catalytic cysteine residues within Paladin's predicted phosphatase active site motifs did not abolish the function of Paladin in the neural crest. Collectively, these data indicate that Paladin is an antiphosphatase that modulates the activity of specific neural crest regulatory factors during neural crest development. Our work identifies a novel regulator of phosphorylation status that provides an additional layer of regulation in the neural crest. PMID- 22926143 TI - Towards better outcomes in Indigenous Cardiovascular Health: directions from the first and second Indigenous Cardiovascular Health Care Conferences. PMID- 22926141 TI - Abnormal interaction of VDAC1 with amyloid beta and phosphorylated tau causes mitochondrial dysfunction in Alzheimer's disease. AB - The purpose of our study was to determine the relationship between voltage dependent anion channel 1 protein (VDAC1) and amyloid beta (Abeta) and phosphorylated tau in Alzheimer's disease (AD). Using brain specimens from AD patients, control subjects and 6-, 12- and 24-month-old Abeta precursor protein (APP) transgenic mice, we studied VDAC1 protein levels. Further, we also studied the interaction between VDAC1 and Abeta (monomers and oligomers) and phosphorylated tau, using cortical issues from AD patients, control subjects, APP, APP/PS1 and 3XTg.AD mice. We also studied age- and VDAC1-linked, mutant APP/Abeta-induced mitochondrial dysfunction in APP and non-transgenic wild-type (WT) mice. We found progressively increased levels of VDAC1 in the cortical tissues from the brains of patients with AD, relative to control subjects, and significantly increased levels of VDAC1 in the cerebral cortices of 6-, 12- and 24-month-old APP transgenic mice, relative to the age-matched control WT mice. Interestingly, we found VDAC1 interacted with Abeta and phosphorylated tau in the brains from AD patients and from APP, APP/PS1 and 3XTg.AD mice. We found progressively increased mitochondrial dysfunction in APP mice relative to WT mice. These observations led us to conclude that VDAC1 interacts with Abeta, and phosphorylated tau may in turn block mitochondrial pores, leading to mitochondrial dysfunction in AD pathogenesis. Based on current study observations, we propose that reduced levels of VDAC1, Abeta and phosphorylated tau may reduce the abnormal interaction between VDAC1 and APP, VDAC1 and Abeta, and VDAC1 and phosphorylated tau; and that reduced levels of VDAC1, Abeta and phosphorylated tau may maintain normal mitochondrial pore opening and pore closure, ultimately leading to normal mitochondrial function, mitochondria supplying ATP to nerve terminals and boosting synaptic and cognitive function in AD. PMID- 22926142 TI - Mutations of EFHC1, linked to juvenile myoclonic epilepsy, disrupt radial and tangential migrations during brain development. AB - Heterozygous mutations in Myoclonin1/EFHC1 cause juvenile myoclonic epilepsy (JME), the most common form of genetic generalized epilepsies, while homozygous F229L mutation is associated with primary intractable epilepsy in infancy. Heterozygous mutations in adolescent JME patients produce subtle malformations of cortical and subcortical architecture, whereas homozygous F229L mutation in infancy induces severe brain pathology and death. However, the underlying pathological mechanisms for these observations remain unknown. We had previously demonstrated that EFHC1 is a microtubule-associated protein (MAP) involved in cell division and radial migration during cerebral corticogenesis. Here, we show that JME mutations, including F229L, do not alter the ability of EFHC1 to colocalize with the centrosome and the mitotic spindle, but act in a dominant negative manner to impair mitotic spindle organization. We also found that mutants EFHC1 expression disrupted radial and tangential migration by affecting the morphology of radial glia and migrating neurons. These results show how Myoclonin1/EFHC1 mutations disrupt brain development and potentially produce structural brain abnormalities on which epileptogenesis is established. PMID- 22926144 TI - Recommendations for the programming of implantable cardioverter-defibrillators in New Zealand. AB - AIM: Our manuscript proposes recommendations to standardise implantable cardioverter-defibrillator (ICD) programming practice in New Zealand (NZ) and provides a review of the literature behind such an initiative. BACKGROUND: Shocks have traditionally been the mainstay of ICD therapy for ventricular tachyarrhythmia. There is substantial evidence to suggest shocks may cause psychological harm, are often painful and may increase hospitalisation for heart failure. Shock therapy may be reduced by avoiding unnecessary therapy of non sustained arrhythmia, utilising anti-tachycardia pacing to terminate ventricular tachycardia and by using algorithms to identify non-ventricular rhythms with rates overlapping therapy zones. This manuscript outlines evidence-based strategies to safely reduce unnecessary shocks from ICDs and includes manufacturer-specific parameters for ease of practical use. CONCLUSION: These recommendations aim to optimise programming of ICD devices in NZ. Developed from a substantial evidence base they are intended to align national programming practice in the hope that we achieve fewer hospitalisations, improved quality of life and possibly achieve greater survival for our ICD-treated patients. PMID- 22926145 TI - Social-emotional problems in preschool-aged children: opportunities for prevention and early intervention. AB - OBJECTIVES: To estimate the prevalence of positive screens for social-emotional problems among preschool-aged children in a low-income clinical population and to explore the family context and receptivity to referrals to help guide development of interventions. DESIGN: Observational, cross-sectional study. SETTING: Two urban primary care clinics. PARTICIPANTS: A total of 254 parents of 3- and 4-year old children at 2 urban primary care clinics. MAIN OUTCOME MEASURES: Score on a standardized screen for social-emotional problems (Ages and Stages Questionnaire: Social-Emotional) and answers to additional survey questions about child care arrangements, parental depressive symptoms, and attitudes toward preschool and behavioral health referrals. RESULTS: Twenty-four percent (95% CI, 16.5%-31.5%) of children screened positive for social-emotional problems. Among those screening positive, 45% had a parent with depressive symptoms, and 27% had no nonparental child care. Among parents of children who screened positive for social-emotional problems, 79% reported they would welcome or would not mind a referral to a counselor or psychologist; only 16% reported a prior referral. CONCLUSIONS: In a clinical sample, 1 in 4 low-income preschool-aged children screened positive for social-emotional problems, and most parents were amenable to referrals to preschool or early childhood mental health. This represents an opportunity for improvement in primary prevention and early intervention for social-emotional problems. PMID- 22926146 TI - In vivo efficacy studies of layer-by-layer nano-matrix bearing kaempferol for the conditions of osteoporosis: a study in ovariectomized rat model. AB - A prototype formulation based on layer-by-layer (LbL) nano-matrix was developed to increase bioavailability of kaempferol with improved retention in bone marrow to achieve enhanced bone formation. The layer-by-layer nano-matrix was prepared by sequential adsorption of biocompatible polyelectrolytes over the preformed kaempferol-loaded CaCO(3) template. The system was pharmaceutically characterized and evaluated for osteogenic activity in ovariectomized (OVx) rats. Data have been compared to the standard osteogenic agent parathyroid hormone (PTH). Single oral dose of kaempferol loaded LbL nano-matrix formulation increased bioavailability significantly compared to unformulated kaempferol. Three months of Formulated kaempferol administration to osteopenic rats increased plasma and bone marrow Kaempferol levels by 2.8- and 1.75-fold, respectively, compared to free Kaempferol. Formulated Kaempferol increased bone marrow osteoprogenitor cells, osteogenic genes in femur, bone formation rate, and improved trabecular micro-architecture. Withdrawal of Formulated kaempferol-in OVx rats resulted in the maintenance of bone micro-architecture up to 30days, whereas micro architectural deterioration was readily observed in OVx rats treated with unformulated kaempferol-within 15days of withdrawal. The developed novel formulation has enhanced anabolic effect in osteopenic rats through increased stimulatory effect in osteoblasts. Treatment post-withdrawal sustenance of formulated kaempferol could become a strategy to enhance bioavailability of flavanoids. PMID- 22926148 TI - Techniques for the optimization of facial and nonfacial volumization with injectable poly-l-lactic acid. AB - With the recognition of the key role of volume loss in the facial aging process, injectable dermal fillers and volumizers have become increasingly important treatment options for recontouring and rejuvenating the aging face. While replacement fillers effectively correct individual lines and wrinkles, volumizing agents that replace collagen provide a longer-lasting, volume-based alternative. Poly-L-lactic acid (PLLA) has been shown to increase dermal thickness and volume for up to 2 years and beyond. Although early clinical use of this agent in patients with HIV-associated facial lipoatrophy was associated with a significant rate of nodule or papule formation, subsequent experience has helped define the proper reconstitution volumes and injection techniques for optimizing results and minimizing nodule/papule formation. While injectable PLLA has been used successfully for rejuvenation of most facial areas, increasing experience suggests that it is a versatile agent capable of providing aesthetic enhancement in multiple areas of the body, including the dorsum of the hands, the decollete, the neck, the buttocks, the medial ankles, and acne scars. Although the current published experience in these areas is limited, further studies and clinical use of injectable PLLA will clarify the potential of this agent as a minimally invasive alternative and/or adjunct to surgery for restoring volume loss in multiple anatomic areas. LEVEL OF EVIDENCE V: This journal requires that authors assign a level of evidence to each article. PMID- 22926147 TI - Aerobic fitness and the brain: increased N-acetyl-aspartate and choline concentrations in endurance-trained middle-aged adults. AB - Engagement in regular aerobic exercise is associated with cognitive benefits, but information on the mechanisms governing these changes in humans is limited. The goal of the current study was to compare neurometabolite concentrations relating to cellular metabolism, structure, and viability in endurance-trained and sedentary middle-aged adults. Twenty-eight endurance-trained and 27 sedentary adults, aged 40-65 years, underwent general health assessment, cardiorespiratory fitness measurement, neuropsychological testing, and proton magnetic resonance spectroscopy ((1)H MRS). (1)H MRS was used to examine N-acetyl-aspartate (NAA), creatine (Cr), myo-inositol (mI), choline (Cho), and glutamate (Glu) concentrations in frontal and occipitoparietal grey matter. Group differences in concentrations of NAA, Cho, mI, and Glu, calculated as ratios over Cr, were explored using ANOVA. There were no significant differences in global cognitive function, memory, and executive function performance between the groups. In comparison to sedentary adults, the endurance-trained group displayed significantly higher NAA/Cr in the frontal grey matter (F(1, 53) = 5.367, p = 0.024) and higher Cho/Cr in the occipitoparietal grey matter (F(1, 53) = 5.138, p = 0.028). Within our middle-aged sample, endurance-trained adults demonstrated higher levels of NAA/Cr in the frontal grey matter and higher Cho/Cr in the occipitoparietal grey matter. Higher levels of NAA may indicate greater neuronal integrity and higher cerebral metabolic efficiency in association with cardiorespiratory fitness, whereas increased Cho may represent increased phospholipid levels secondary to neural plasticity. PMID- 22926149 TI - New approach to shaping a ptotic breast in secondary autologous breast reconstruction. AB - Breast ptosis in women is mostly perceived as unattractive. It is associated with aging, breastfeeding, and multiple pregnancies. However, women who undergo radical mastectomy are the exception. They strive for a natural appearance and do not perceive a ptotic breast as unaesthetic. Shaping a ptotic breast from autologous tissue is one of the most challenging and difficult reconstructive procedures, especially because the risk of tissue failure has decreased significantly. The authors present their method of shaping a ptotic breast after a delayed autologous breast reconstruction. The technique, presented in detail, consists of dividing the native breast skin below the mastectomy scar into two dermocutaneous triangular flaps that carry the new breast. The dermocutaneous triangular flaps can be turned outward to decrease upper pole fullness and increase ptosis. Creating a carbon copy of the contralateral breast can be achieved during surgery. This report presents the results of the authors' method and discusses its advantages and disadvantages. In addition to its simplicity, this method gives ptosis up to grade 3 according to Regnault, frequently negating a mastopexy of the contralateral breast to reach symmetry. Equally important, the results have been stable in the long term. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. PMID- 22926152 TI - Hepatitis: HCV virologic response--new nomenclature recommendations. PMID- 22926154 TI - IBD: Regulatory T-cell therapy is a safe and well-tolerated potential approach for treating refractory Crohn's disease. PMID- 22926153 TI - The importance of the gut microbiota after bariatric surgery. AB - The gut microbiota is recognized to have an important role in energy storage and the subsequent development of obesity. To date, bariatric surgery (indicated for severe obesity) represents the only treatment that enables substantial and sustained weight loss. Bariatric surgery is also a good model to study not only the pathophysiology of obesity and its related diseases but also the mechanisms involved in their improvement after weight reduction. Scarce data from humans and animal models have demonstrated that gut microbiota composition is modified after Roux-en-Y gastric bypass (RYGB), suggesting that weight reduction could affect gut microbiota composition. However, weight loss might not be the only factor responsible for those modifications. Indeed, bariatric surgery not only improves hormonal and inflammatory status, but also induces numerous changes in the digestive tract that might account for the observed modifications of microbiota ecology. In future bariatric surgery studies in humans or mice, these major surgery-induced modifications will need to be taken into account when analyzing the link between gut microbiota composition, obesity, its complications and their improvement after bariatric surgery. This Review outlines the potential mechanisms by which the major changes in the digestive tract after bariatric surgery can affect the gut microbiota. PMID- 22926155 TI - Muscle agonist-antagonist interactions in an experimental joint model. AB - The experiments presented here and performed in anaesthetized cats aimed at studying the dynamics of interactions between antagonist muscle groups. The tendons of triceps surae muscles of both hindlimbs were connected with an artificial joint (a pulley installed on a shaft). The muscles were activated by the distributed stimulation of five filaments of cut ventral roots L7-S1 on both sides of the spinal cord; movements were evoked by the rate-modulation of the stimulation trains. The study mostly compared programs of reciprocal activation and co-activation, including different changes in stimulation rates of muscle antagonists. The most common feature of the movements in both activation modes was hysteresis of the joint angle changes in dependence on stimulus rate. Reciprocal activation appeared suitable for a precise regulation of both amplitude and velocity of the movements in direction of the agonist shortening; maximal effectiveness was achieved during full switching off the antagonist stimulation at plateaus of the movement traces. The reverse movements during decrease of the agonist's stimulation rate demonstrated an explicit nonlinear form with pronounced initial phase of the joint angle fixation. The co-activation pattern distinctly reduced the hysteresis of joint movements and suppressed the stimulation after-effects, such as the lasting residual movements after fixation of the stimulation rates. PMID- 22926156 TI - Predicting the spatiotemporal expression of local and referred acute muscle pain in individual subjects. AB - While current data suggest that all referred pain derives from common mechanisms of central sensitisation, there is a paucity of data directly comparing referral in different limbs. Does a common mechanism result in similar precepts of referral from similar stimuli in different limbs? We tested the hypothesis that, in a given subject, the incidence, intensity and spatiotemporal expression of referred pain are similar during the muscle pain induced by bolus intramuscular injection of hypertonic saline into flexor carpi radialis (FCR) and tibialis anterior (TA). We also tested the hypothesis that an increase in stimulus intensity causes a parallel increase in the incidence and intensity of local and referred pain, by comparing the responses to 5 and 10 % hypertonic saline in two groups of subjects. 29 subjects mapped areas of local and referred pain, rating intensities on a visual analogue scale every 30 s until the cessation of pain. Following an injection of 5 % hypertonic saline into TA, 86 % of subjects who had previously reported referred pain (or its absence) in the hand during FCR pain reported referred pain (or its absence) in the foot. Following an injection of the 10 % solution, 67 % of subjects reported a pattern in the lower limb that was the same as that seen in the upper limb. We conclude that the expression of referred pain is largely consistent in widely separated limb segments in individual subjects and is largely dependent on inter-subject differences. This may have implications for the development of chronic pain following an acute episode of pain. PMID- 22926157 TI - Therapeutic thoughts on the treatment of sequellae of labial-alveolar-palatal clefts in adult patients - Part 1. AB - With a worldwide incidence of 1/750 live births, facial clefts rank as the second most frequent congenital malformation. The term "sequelae" is used here to designate the conditions, which follow and are the result of labial-alveolar palatal clefts. Most sequelae stem in fact from primary treatment and not from the initial malformation. However, there is no consensus regarding a management protocol. Among the 201 European centers treating this type of malformation, 194 different protocols are used for unilateral facial clefts alone! Unfortunately, primary surgery can trigger a wide range of harmful consequences. It is for this reason that secondary surgery is called for, generally after the adolescent growth spurt. The aim is to correct the damage done by primary surgery, which can affect the nose, lips, teeth and jaws and impact functions such as speech, breathing and swallowing, as well as morphological and psychological development. Nonetheless, the children concerned are sometimes lost to treatment only to re emerge in adulthood, aware of the presence of the resultant defects and looking for facial esthetic improvement. The sequelae of labial-alveolar-palatal clefts can take on very different clinical forms according to whether the cleft has been treated or not and the type and timing of the procedures performed. The surgeon's experience will be paramount in the management of such cases, which draws heavily upon dento-maxillo-facial orthopedics. In this context, we intend, in this paper, to propose modalities for the management of labial-alveolar-palatal clefts supported by information currently available in the literature. Management of labial-alveolar-palatal clefts requires an interdisciplinary rather than a multi- or pluridisciplinary, approach. The practitioner coordinating the management must, like an orchestra conductor, ensure both the rhythm and the tempo of the treatment. The rhythm will determine the choice of chronological protocol and the tempo will govern the timing and importance given to each of the specialists involved. Practices vary from country to country but the orthodontist may be called on to assume this responsibility. PMID- 22926160 TI - Abstracts of the 23rd International Symposium on the Autonomic Nervous System, October 31 - November 3, 2012, Paradise Island, Bahamas. PMID- 22926159 TI - Differences in the location and activity of intestinal Crohn's disease lesions between adult and paediatric patients detected with MRI. AB - OBJECTIVES: To prospectively compare paediatric patients (PP) and adult patients (AP) affected by Crohn's disease (CD) in terms of the location and activity of intestinal lesions. METHODS: Forty-three children (mean age 15 years) and 43 adults (mean age 48 years) with proven CD underwent magnetic resonance enterography (MRE) to localise lesions and detect their activity in 9 segments of the small and large bowel. The results were analysed on a per patient and per segment basis. Ileo-colonoscopy was performed in all patients. P values less than 0.05 were considered statistically significant. RESULTS: Involvement of terminal ileum was significantly different in the two groups: observed in 100 % of AP (43/43) versus 58 % (23/43) of PP (P < 0.0001). Conversely, the colon was diseased in 84 % of PP versus 64 % of AP. In particular, left colonic segments were significantly more involved in PP (descending colon 53 % versus 21 %, P < 0.01; rectum 67 % versus 23 %, P < 0.0001; sigmoid colon 56 % versus 37 %, not significant), whereas caecal involvement was equal in both groups. In children the maximal disease activity was found in left colonic segments, whereas in adults it was in the terminal ileum. CONCLUSIONS: MRE detected significant differences between the two populations, showing a more extensive and severe involvement of the left colon in children but the distal ileum in adults. KEY POINTS : * MRI is useful for assessing Crohn's disease in adult and paediatric patients. * Adult and paediatric patients show different intestinal involvement on MRI. * The distal ileum is maximally involved in adults vs. the left colon in children. * The causes of the severe left colonic disease in children are unknown. * The extensive colonic involvement in children has clinical-diagnostic implications. PMID- 22926161 TI - Genotypes of the MTHFR C677T and MTRR A66G genes act independently to reduce migraine disability in response to vitamin supplementation. AB - BACKGROUND: Migraine is a chronic disabling neurovascular condition that may in part be caused by endothelial and cerebrovascular disruption induced by hyperhomocysteinaemia. We have previously provided evidence indicating that reduction of homocysteine by vitamin supplementation can reduce the occurrence of migraine in women. The current study examined the genotypic effects of methylenetetrahydrofolate reductase (MTHFR) and methionine synthase reductase (MTRR) gene variants on the occurrence of migraine in response to vitamin supplementation. METHODS: This was a 6-month randomized, double-blinded placebo controlled trial of daily vitamin B supplementation (B(6), B(9) and B(12)) on reduction of homocysteine and of the occurrence of migraine in 206 female patients diagnosed with migraine with aura. RESULTS: Vitamin supplementation significantly reduced homocysteine levels (P<0.001), severity of headache in migraine (P=0.017) and high migraine disability (P=0.022) in migraineurs compared with the placebo effect (P>0.1). When the vitamin-treated group was stratified by genotype, the C allele carriers of the MTHFR C677T variant showed a higher reduction in homocysteine levels (P<0.001), severity of pain in migraine (P=0.01) and percentage of high migraine disability (P=0.009) compared with those with the TT genotypes. Similarly, the A allele carriers of the MTRR A66G variants showed a higher level of reduction in homocysteine levels (P<0.001), severity of pain in migraine (P=0.002) and percentage of high migraine disability (P=0.006) compared with those with the GG genotypes. Genotypic analysis for both genes combined indicated that the treatment effect modification of the MTRR variant was independent of the MTHFR variant. CONCLUSION: This provided further evidence that vitamin supplementation is effective in reducing migraine and also that both MTHFR and MTRR gene variants are acting independently to influence treatment response in female migraineurs. PMID- 22926162 TI - Effect of initial heart rate on cardiac troponin and ejection fraction in patients with non-ST segment elevation myocardial infarction. AB - BACKGROUND: Increased heart rate has shown to be associated with adverse cardiovascular outcomes. This aim of this study was to find the association of troponin level and ejection fraction (EF) with triage heart rate in patients with non-ST elevation myocardial infarction (NSTEMI). It was hypothesized that heart rate at triage will be independently associated with higher troponin level and lower EF after NSTEMI. METHODS: The association of maximum troponin level and left ventricular EF with triage heart rate after adjusting for other factors known to affect these variables was assessed. RESULTS: Participants had a mean age of 68 +/- 10 years with 34% women. Unadjusted correlations using linear regression showed a correlation coefficient (r) of 0.21, P = 0.01, between heart rate and maximum troponin before cardiac catheterization and a correlation coefficient (r) of -0.26, P = 0.007, between heart rate and post-myocardial infarction EF. EF was divided into 4 categories, namely, <30%, 30% to 45%, 45% to 60% and >60%. Heart rate showed a progressive increase from higher EF to lower EF. A multivariate analysis was also performed for association of heart rate with troponin and EF separately after adjusting for other confounding factors (diabetes, hypertension, number of coronary vessels and previous myocardial infarction). All associations persisted at P <= 0.05. CONCLUSIONS: Triage heart rate is independently associated with higher troponin and lower EF in NSTEMI. PMID- 22926163 TI - High-throughput classification of clinical populations from natural viewing eye movements. AB - Many high-prevalence neurological disorders involve dysfunctions of oculomotor control and attention, including attention deficit hyperactivity disorder (ADHD), fetal alcohol spectrum disorder (FASD), and Parkinson's disease (PD). Previous studies have examined these deficits with clinical neurological evaluation, structured behavioral tasks, and neuroimaging. Yet, time and monetary costs prevent deploying these evaluations to large at-risk populations, which is critically important for earlier detection and better treatment. We devised a high-throughput, low-cost method where participants simply watched television while we recorded their eye movements. We combined eye-tracking data from patients and controls with a computational model of visual attention to extract 224 quantitative features. Using machine learning in a workflow inspired by microarray analysis, we identified critical features that differentiate patients from control subjects. With eye movement traces recorded from only 15 min of videos, we classified PD versus age-matched controls with 89.6 % accuracy (chance 63.2 %), and ADHD versus FASD versus control children with 77.3 % accuracy (chance 40.4 %). Our technique provides new quantitative insights into which aspects of attention and gaze control are affected by specific disorders. There is considerable promise in using this approach as a potential screening tool that is easily deployed, low-cost, and high-throughput for clinical disorders, especially in young children and elderly populations who may be less compliant to traditional evaluation tests. PMID- 22926164 TI - Enzyme replacement therapy in late-onset Pompe disease: a systematic literature review. AB - Glycogen storage disease type 2/Pompe disease is a progressive muscle disorder with a wide range of phenotypic presentations, caused by an inherited deficiency of acid alpha-glucosidase. Since 2004 only a limited number of patients have been treated with recombinant human alpha-glucosidase from rabbit milk whereas since 2006 enzyme replacement therapy (ERT) with alglucosidase alfa has been licensed for the treatment of Pompe disease. This systematic review evaluates the clinical efficacy and safety of alglucosidase alfa treatment of juvenile and adult patients with late-onset Pompe disease (LOPD). Studies of alglucosidase alfa treatment of LOPD patients-published up to January 2012-were identified by electronic searching of the EMBASE and MEDLINE databases, and manual searching of the reference lists. Data on ERT outcomes were extracted from selected papers and analyzed descriptively. No statistical analysis was performed owing to data heterogeneity. Twenty-one studies containing clinical data from 368 LOPD patients were analyzed. Overall, at least two-thirds of patients were stabilized or had improved creatine kinase levels and muscular and/or respiratory function following treatment with alglucosidase alfa. ERT was well tolerated; most adverse events were mild or moderate infusion-related reactions. In conclusion, alglucosidase alfa treatment is effective and well tolerated and attenuates progression of LOPD in most patients. Further research is required to investigate factors such as age at diagnosis, phenotypic presentation, and genotypic characteristics, identification of which may enable better clinical and therapeutic management of LOPD patients. PMID- 22926166 TI - Advancing neurotrophic factors as treatments for age-related neurodegenerative diseases: developing and demonstrating "clinical proof-of-concept" for AAV neurturin (CERE-120) in Parkinson's disease. AB - Neurotrophic factors have long shown promise as potential therapies for age related neurodegenerative diseases. However, 20 years of largely disappointing clinical results have underscored the difficulties involved with safely and effectively delivering these proteins to targeted sites within the central nervous system. Recent progress establishes that gene transfer can now likely overcome the delivery issues plaguing the translation of neurotrophic factors. This may be best exemplified by adeno-associated virus serotype-2-neurturin (CERE 120), a viral-vector construct designed to deliver the neurotrophic factor, neurturin to degenerating nigrostriatal neurons in Parkinson's disease. Eighty Parkinson's subjects have been dosed with CERE-120 (some 7+ years ago), with long term, targeted neurturin expression confirmed and no serious safety issues identified. A double-blind, controlled Phase 2a trial established clinical "proof of-concept" via 19 of the 24 prescribed efficacy end points favoring CERE-120 at the 12-month protocol-prescribed time point and all but one favoring CERE-120 at the 18-month secondary time point (p = 0.007 and 0.001, respectively). Moreover, clinically meaningful benefit was seen with CERE-120 on several specific protocol prescribed, pairwise, blinded, motor, and quality-of-life end points at 12 months, and an even greater number of end points at 18 months. Because the trial failed to meet the primary end point (Unified Parkinson's Disease Rating Scale motor-off, measured at 12 months), a revised multicenter Phase 1/2b protocol was designed to enhance the neurotrophic effects of CERE-120, using insight gained from the Phase 2a trial. This review summarizes the development of CERE-120 from its inception through establishing "clinical proof-of-concept" and beyond. The translational obstacles and issues confronted, and the strategies applied, are reviewed. This information should be informative to investigators interested in translational research and development for age-related and other neurodegenerative diseases. PMID- 22926165 TI - Multiple sclerosis and pregnancy: therapeutic considerations. AB - For women with multiple sclerosis (MS) who become pregnant, the risks and benefits of ongoing therapy for the health of both the mother and the fetus must be carefully considered. Based on a literature review and our MS center's standard practices, we provide guidance to aid clinical decision making in the absence of clear evidence-based clinical practice guidelines. Women seeking to achieve pregnancy should generally discontinue disease-modifying therapy use prior to attempting conception. For example, the immunosuppressant mitoxantrone is teratogenic and should be prescribed only with the assurance of effective contraception. Conception should be discouraged for patients on fingolimod, because of the limited information available on human pregnancy outcomes. Current evidence, including data from pregnancy registries for glatiramer acetate (GA), interferon beta-1a (IFNbeta-1a), and natalizumab, has not shown specific patterns of malformations suggesting teratogenicity. Pregnancy registry data have not been published for IFNbeta-1b. During breastfeeding, intravenous immunoglobulin and corticosteroids are generally safe and may be associated with a reduction in postpartum relapses; however, a washout period is recommended between corticosteroid administration and the resumption of breastfeeding. Clinical data on the use of IFNbeta, GA, and natalizumab during lactation are limited. Mitoxantrone is contraindicated during breastfeeding, and fingolimod should be avoided in nursing mothers, because of a lack of data. PMID- 22926167 TI - Tau pathology modulates Pin1 post-translational modifications and may be relevant as biomarker. AB - A prerequisite to dephosphorylation at Ser-Pro or Thr-Pro motifs is the isomerization of the imidic peptide bond preceding the proline. The peptidyl prolyl cis/trans isomerase named Pin1 catalyzes this mechanism. Through isomerization, Pin1 regulates the function of a growing number of targets including the microtubule-associated tau protein and is supposed to be deregulated Alzheimer's disease (AD). Using proteomics, we showed that Pin1 is posttranslationally modified on more than 5 residues, comprising phosphorylation, N-acetylation, and oxidation. Although Pin1 expression remained constant, Pin1 posttranslational two-dimensional pattern was modified by tau overexpression in a tau-inducible neuroblastoma cell line, in our THY-Tau22 mouse model of tauopathy as well as in AD. Interestingly, in all of these systems, Pin1 modifications were very similar. In AD brain tissue when compared with control, Pin1 is hyperphosphorylated at serine 16 and found in the most insoluble hyperphosphorylated tau fraction of AD brain tissue. Furthermore, in all tau pathology conditions, acetylation of Pin1 may also contribute to the differences observed. In conclusion, Pin1 displays several posttranslational modifications, which are specific in tauopathies and may be useful as biomarker. PMID- 22926168 TI - Trophic factors differentiate dopamine neurons vulnerable to Parkinson's disease. AB - Recent studies suggest a variety of factors characterize substantia nigra neurons vulnerable to Parkinson's disease, including the transcription factors pituitary homeobox 3 (Pitx3) and orthodenticle homeobox 2 (Otx2) and the trophic factor receptor deleted in colorectal cancer (DCC), but there is limited information on their expression and localization in adult humans. Pitx3, Otx2, and DCC were immunohistochemically localized in the upper brainstem of adult humans and mice and protein expression assessed using relative intensity measures and online microarray data. Pitx3 was present and highly expressed in most dopamine neurons. Surprisingly, in our elderly subjects no Otx2 immunoreactivity was detected in dopamine neurons, although Otx2 gene expression was found in younger cases. Enhanced DCC gene expression occurred in the substantia nigra, and higher amounts of DCC protein characterized vulnerable ventral nigral dopamine neurons. Our data show that, at the age when Parkinson's disease typically occurs, there are no significant differences in the expression of transcription factors in brainstem dopamine neurons, but those most vulnerable to Parkinson's disease rely more on the trophic factor receptor DCC than other brainstem dopamine neurons. PMID- 22926169 TI - Proficiency and retention of neonatal resuscitation skills by pediatric residents. AB - BACKGROUND: The basic knowledge and skill base to resuscitate a newborn infant is taught in the Neonatal Resuscitation Program (NRP). We hypothesize that caregivers will perform below current acceptable standards before the recertification period of two years. METHODS: This is a prospective descriptive study evaluating performance of pediatric residents' NRP knowledge and skills over time. NRP scores are used as baseline data. Follow-up is performed before the resident's first NICU rotation. Differences in the mean scores are analyzed for degree of retention. Subset score analysis is also performed. RESULTS: Eighty eight subjects completed both evaluations. Knowledge scores maintained close to passing throughout the academic year. Subset evaluation revealed significant deficits within the intubation lesson. Alarming deficits were seen in skills evaluation starting at initial NRP certification with 39.1% residents having failing scores. Mean scores were below passing for every group on follow-up testing. Subgroup analysis of skills revealed deficits in the initial phases of resuscitation (lessons 1-3). CONCLUSIONS: Deterioration of skills is seen shortly after training. It appears that knowledge is generally better retained. Discrepancies between areas of knowledge and skill deterioration indicate that proficiency in one does not necessarily indicate proficiency of the other. PMID- 22926170 TI - A systematic review of vocational interventions for young adults with autism spectrum disorders. AB - BACKGROUND AND OBJECTIVE: Many individuals with autism spectrum disorders (ASDs) are approaching adolescence and young adulthood; interventions to assist these individuals with vocational skills are not well understood. This study systematically reviewed evidence regarding vocational interventions for individuals with ASD between the ages of 13 and 30 years. METHODS: The Medline, PsycINFO, and ERIC databases (1980-December 2011) and reference lists of included articles were searched. Two reviewers independently assessed each study against predetermined inclusion/exclusion criteria. Two reviewers independently extracted data regarding participant and intervention characteristics, assessment techniques, and outcomes, and assigned overall quality and strength of evidence ratings based on predetermined criteria. RESULTS: Five studies were identified; all were of poor quality and all focused on on-the-job supports as the employment/vocational intervention. Short-term studies reported that supported employment was associated with improvements in quality of life (1 study), ASD symptoms (1 study), and cognitive functioning (1 study). Three studies reported that interventions increased rates of employment for young adults with ASD. CONCLUSIONS: Few studies have been conducted to assess vocational interventions for adolescents and young adults with ASD. As such, there is very little evidence available for specific vocational treatment approaches as individuals transition to adulthood. All studies of vocational approaches were of poor quality, which may reflect the recent emergence of this area of research. Individual studies suggest that vocational programs may increase employment success for some; however, our ability to understand the overall benefit of supported employment programs is limited given the existing research. PMID- 22926171 TI - Risk adjustment for neonatal surgery: a method for comparison of in-hospital mortality. AB - OBJECTIVE: To develop a risk-adjustment method for evaluation of in-hospital mortality after noncardiac neonatal surgery regardless of gestational age. METHODS: Infants <= 30 days old undergoing noncardiac surgical procedures were identified by using the Kids' Inpatient Database (KID) 2000 + 2003. Neonates were included regardless of gestational age. International Classification of Disease, Ninth Revision, Clinical Modification codes were used to assign procedures to 1 of 4 previously derived risk categories. Prematurity and other clinical variables were assessed in logistic regression analysis. The final multivariable model was validated in 3 independent data sets: KID 2006, Pediatric Health Information System (PHIS) 2001-2003, and PHIS 2006-2008. The model was applied to generate standardized mortality ratios for institutions within PHIS 2006-2008. RESULTS: Among 18437 eligible cases in KID 2000 + 2003, 15278 (83%) had 1 of 66 procedure codes assigned to a risk category and were eligible for analysis. In-hospital mortality for premature infants was 10.5% compared with 2.0% for full-term neonates. In addition to risk category, the clinical variables improving prediction of in-hospital death were prematurity, serious respiratory conditions, necrotizing enterocolitis, neonatal sepsis, and congenital heart disease. Area under the receiver-operator characteristic curve for the final model was 0.90. The model also showed excellent discrimination in the 3 validation data sets (0.90, 0.89, and 0.89). Within 41 institutions in PHIS, standardized mortality ratios ranged from 0.37 to 1.91. CONCLUSIONS: This validated method provides a tool for risk adjustment of neonates undergoing noncardiac surgery to allow comparative analyses of in-hospital mortality. PMID- 22926172 TI - A systematic review of long-acting beta2-agonists versus higher doses of inhaled corticosteroids in asthma. AB - OBJECTIVE: To compare the efficacy of inhaled corticosteroids (ICS) plus long acting beta2 agonist (LABA) versus higher doses of ICS in children/adolescents with uncontrolled persistent asthma. METHODS: Randomized, prospective, controlled trials published January 1996 to January 2012 with a minimum of 4 weeks of LABA+ICS versus higher doses of ICS were retrieved through Medline, Embase, Central, and manufacturer's databases. The primary outcome was asthma exacerbations requiring systemic corticosteroids; secondary outcomes were the pulmonary function test (PEF), withdrawals during the treatment period, days without symptoms, use of rescue medication, and adverse events. RESULTS: Nine studies (n = 1641 patients) met criteria for inclusion (7 compared LABA+ICS versus double ICS doses and 2 LABA+ICS versus higher than double ICS doses). There was no statistically significant difference in the number of patients with asthma exacerbations requiring systemic corticosteroids between children receiving LABA+ICS and those receiving higher doses of ICS (odds ratio = 0.76; 95% confidence interval: 0.48-1.22, P = .25, I(2) = 16%). In the subgroup analysis, patients receiving LABA+ICS showed a decreased risk of asthma exacerbations compared with higher than twice ICS doses (odds ratio = 0.48; 95% confidence interval: 0.28-0.82, P = .007, I(2)= 0). Children treated with LABA+ICS had significantly higher PEF, less use of rescue medication, and higher short-term growth than those on higher ICS doses. There were no other significant differences in adverse events. CONCLUSIONS: There were no statistically significant group differences between ICS+LABA and double doses of ICS in reducing the incidence of asthma exacerbations but it did decrease the risk comparing to higher than double doses of ICS. PMID- 22926173 TI - Diagnosis and management of childhood obstructive sleep apnea syndrome. AB - OBJECTIVES: This revised clinical practice guideline, intended for use by primary care clinicians, provides recommendations for the diagnosis and management of the obstructive sleep apnea syndrome (OSAS) in children and adolescents. This practice guideline focuses on uncomplicated childhood OSAS, that is, OSAS associated with adenotonsillar hypertrophy and/or obesity in an otherwise healthy child who is being treated in the primary care setting. METHODS: Of 3166 articles from 1999-2010, 350 provided relevant data. Most articles were level II-IV. The resulting evidence report was used to formulate recommendations. RESULTS AND CONCLUSIONS: The following recommendations are made. (1) All children/adolescents should be screened for snoring. (2) Polysomnography should be performed in children/adolescents with snoring and symptoms/signs of OSAS; if polysomnography is not available, then alternative diagnostic tests or referral to a specialist for more extensive evaluation may be considered. (3) Adenotonsillectomy is recommended as the first-line treatment of patients with adenotonsillar hypertrophy. (4) High-risk patients should be monitored as inpatients postoperatively. (5) Patients should be reevaluated postoperatively to determine whether further treatment is required. Objective testing should be performed in patients who are high risk or have persistent symptoms/signs of OSAS after therapy. (6) Continuous positive airway pressure is recommended as treatment if adenotonsillectomy is not performed or if OSAS persists postoperatively. (7) Weight loss is recommended in addition to other therapy in patients who are overweight or obese. (8) Intranasal corticosteroids are an option for children with mild OSAS in whom adenotonsillectomy is contraindicated or for mild postoperative OSAS. PMID- 22926174 TI - Bone mineral density and vitamin D status among African American children with forearm fractures. AB - OBJECTIVE: To determine whether African American children with forearm fractures have decreased bone mineral density and an increased prevalence of vitamin D deficiency (serum 25-hydroxyvitamin D level <= 20 ng/mL) compared with fracture free control patients. METHODS: This case-control study in African American children, aged 5 to 9 years, included case patients with forearm fracture and control patients without fracture. Evaluation included measurement of bone mineral density and serum 25-hydroxyvitamin D level. Univariable and multivariable analyses were used to test for associations between fracture status and 2 measures of bone health (bone mineral density and 25-hydroxyvitamin D level) while controlling for other potential confounders. RESULTS: The final sample included 76 case and 74 control patients. There were no significant differences between case and control patients in age, gender, parental education level, enrollment season, outdoor play time, height, or mean dietary calcium nutrient density. Cases were more likely than control patients to be overweight (49.3% vs 31.4%, P = .03). Compared with control patients, case patients had lower whole body z scores for bone mineral density (0.62 +/- 0.96 vs 0.98 +/- 1.09; adjusted odds ratio 0.38 [0.20-0.72]) and were more likely to be vitamin D deficient (47.1% vs 40.8%; adjusted odds ratio 3.46 [1.09-10.94]). CONCLUSIONS: These data support an association of lower bone mineral density and vitamin D deficiency with increased odds of forearm fracture among African American children. Because suboptimal childhood bone health also negatively impacts adult bone health, interventions to increase bone mineral density and correct vitamin D deficiency are indicated in this population to provide short-term and long-term benefits. PMID- 22926176 TI - Diagnosis and management of childhood obstructive sleep apnea syndrome. AB - OBJECTIVE: This technical report describes the procedures involved in developing recommendations on the management of childhood obstructive sleep apnea syndrome (OSAS). METHODS: The literature from 1999 through 2011 was evaluated. RESULTS AND CONCLUSIONS: A total of 3166 titles were reviewed, of which 350 provided relevant data. Most articles were level II through IV. The prevalence of OSAS ranged from 0% to 5.7%, with obesity being an independent risk factor. OSAS was associated with cardiovascular, growth, and neurobehavioral abnormalities and possibly inflammation. Most diagnostic screening tests had low sensitivity and specificity. Treatment of OSAS resulted in improvements in behavior and attention and likely improvement in cognitive abilities. Primary treatment is adenotonsillectomy (AT). Data were insufficient to recommend specific surgical techniques; however, children undergoing partial tonsillectomy should be monitored for possible recurrence of OSAS. Although OSAS improved postoperatively, the proportion of patients who had residual OSAS ranged from 13% to 29% in low-risk populations to 73% when obese children were included and stricter polysomnographic criteria were used. Nevertheless, OSAS may improve after AT even in obese children, thus supporting surgery as a reasonable initial treatment. A significant number of obese patients required intubation or continuous positive airway pressure (CPAP) postoperatively, which reinforces the need for inpatient observation. CPAP was effective in the treatment of OSAS, but adherence is a major barrier. For this reason, CPAP is not recommended as first line therapy for OSAS when AT is an option. Intranasal steroids may ameliorate mild OSAS, but follow-up is needed. Data were insufficient to recommend rapid maxillary expansion. PMID- 22926175 TI - Male circumcision. AB - Male circumcision consists of the surgical removal of some, or all, of the foreskin (or prepuce) from the penis. It is one of the most common procedures in the world. In the United States, the procedure is commonly performed during the newborn period. In 2007, the American Academy of Pediatrics (AAP) convened a multidisciplinary workgroup of AAP members and other stakeholders to evaluate the evidence regarding male circumcision and update the AAP's 1999 recommendations in this area. The Task Force included AAP representatives from specialty areas as well as members of the AAP Board of Directors and liaisons representing the American Academy of Family Physicians, the American College of Obstetricians and Gynecologists, and the Centers for Disease Control and Prevention. The Task Force members identified selected topics relevant to male circumcision and conducted a critical review of peer-reviewed literature by using the American Heart Association's template for evidence evaluation. Evaluation of current evidence indicates that the health benefits of newborn male circumcision outweigh the risks; furthermore, the benefits of newborn male circumcision justify access to this procedure for families who choose it. Specific benefits from male circumcision were identified for the prevention of urinary tract infections, acquisition of HIV, transmission of some sexually transmitted infections, and penile cancer. Male circumcision does not appear to adversely affect penile sexual function/sensitivity or sexual satisfaction. It is imperative that those providing circumcision are adequately trained and that both sterile techniques and effective pain management are used. Significant acute complications are rare. In general, untrained providers who perform circumcisions have more complications than well-trained providers who perform the procedure, regardless of whether the former are physicians, nurses, or traditional religious providers. Parents are entitled to factually correct, nonbiased information about circumcision and should receive this information from clinicians before conception or early in pregnancy, which is when parents typically make circumcision decisions. Parents should determine what is in the best interest of their child. Physicians who counsel families about this decision should provide assistance by explaining the potential benefits and risks and ensuring that parents understand that circumcision is an elective procedure. The Task Force strongly recommends the creation, revision, and enhancement of educational materials to assist parents of male infants with the care of circumcised and uncircumcised penises. The Task Force also strongly recommends the development of educational materials for providers to enhance practitioners' competency in discussing circumcision's benefits and risks with parents. The Task Force made the following recommendations:Evaluation of current evidence indicates that the health benefits of newborn male circumcision outweigh the risks, and the benefits of newborn male circumcision justify access to this procedure for those families who choose it. Parents are entitled to factually correct, nonbiased information about circumcision that should be provided before conception and early in pregnancy, when parents are most likely to be weighing the option of circumcision of a male child. Physicians counseling families about elective male circumcision should assist parents by explaining, in a nonbiased manner, the potential benefits and risks and by ensuring that they understand the elective nature of the procedure. Parents should weigh the health benefits and risks in light of their own religious, cultural, and personal preferences, as the medical benefits alone may not outweigh these other considerations for individual families. Parents of newborn boys should be instructed in the care of the penis, regardless of whether the newborn has been circumcised or not. Elective circumcision should be performed only if the infant's condition is stable and healthy. Male circumcision should be performed by trained and competent practitioners, by using sterile techniques and effective pain management. Analgesia is safe and effective in reducing the procedural pain associated with newborn circumcision; thus, adequate analgesia should be provided whenever newborn circumcision is performed.Nonpharmacologic techniques (eg, positioning, sucrose pacifiers) alone are insufficient to prevent procedural and postprocedural pain and are not recommended as the sole method of analgesia. They should be used only as analgesic adjuncts to improve infant comfort during circumcision. If used, topical creams may cause a higher incidence of skin irritation in low birth weight infants, compared with infants of normal weight; penile nerve block techniques should therefore be chosen for this group of newborns. Key professional organizations (AAP, the American Academy of Family Physicians, the American College of Obstetricians and Gynecologists, the American Society of Anesthesiologists, the American College of Nurse Midwives, and other midlevel clinicians such as nurse practitioners) should work collaboratively to:Develop standards of trainee proficiency in the performance of anesthetic and procedure techniques, including suturing; Teach the procedure and analgesic techniques during postgraduate training programs; Develop educational materials for clinicians to enhance their own competency in discussing the benefits and risks of circumcision with parents; Offer educational materials to assist parents of male infants with the care of both circumcised and uncircumcised penises. The preventive and public health benefits associated with newborn male circumcision warrant third-party reimbursement of the procedure. The American College of Obstetricians and Gynecologists has endorsed this technical report. PMID- 22926177 TI - Levels of neonatal care. AB - Provision of risk-appropriate care for newborn infants and mothers was first proposed in 1976. This updated policy statement provides a review of data supporting evidence for a tiered provision of care and reaffirms the need for uniform, nationally applicable definitions and consistent standards of service for public health to improve neonatal outcomes. Facilities that provide hospital care for newborn infants should be classified on the basis of functional capabilities, and these facilities should be organized within a regionalized system of perinatal care. PMID- 22926178 TI - Assessment of controversial pediatric asthma management options using GRADE. AB - OBJECTIVES: To develop explicit and transparent recommendations on controversial asthma management issues in children and to illustrate the usefulness of the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach in rating the quality of evidence and strength of recommendations. METHODS: Health care questions were formulated for 3 controversies in clinical practice: what is the most effective treatment in asthma not under control with standard-dose inhaled corticosteroids (ICS; step 3), the use of leukotriene receptor antagonist for viral wheeze, and the role of extra fine particle aerosols. GRADE was used to rate the quality of evidence and strength of recommendations after performing systematic literature searches. We provide evidence profiles and considerations about benefit and harm, preferences and values, and resource use, all of which played a role in formulating final recommendations. RESULTS: By applying GRADE and focusing on outcomes that are important to patients and explicit other considerations, our recommendations differ from those in other international guidelines. We prefer to double the dose of ICS instead of adding a long-acting beta-agonist in step 3; ICS instead of leukotriene receptor antagonist are the first choice in preschool wheeze, and extra fine particle ICS formulations are not first-line treatment in children with asthma. Recommendations are weak and based on low-quality evidence for critical outcomes. CONCLUSIONS: We provide systematically and transparently developed recommendations about controversial asthma management options. Using GRADE for guideline development may change recommendations, enhance guideline implementation, and define remaining research gaps. PMID- 22926179 TI - Effects of systematic screening and detection of child abuse in emergency departments. AB - OBJECTIVE: Although systematic screening for child abuse of children presenting at emergency departments might increase the detection rate, studies to support this are scarce. This study investigates whether introducing screening, and training of emergency department nurses, increases the detection rate of child abuse. METHODS: In an intervention cohort study, children aged 0 to 18 years visiting the emergency departments of 7 hospitals between February 2008 and December 2009 were enrolled. We developed a screening checklist for child abuse (the "Escape Form") and training sessions for nurses; these were implemented by using an interrupted time-series design. Cases of suspected child abuse were determined by an expert panel using predefined criteria. The effect of the interventions on the screening rate for child abuse was calculated by interrupted time-series analyses and by the odds ratios for detection of child abuse in screened children. RESULTS: A total of 104028 children aged 18 years or younger were included. The screening rate increased from 20% in February 2008 to 67% in December 2009. Significant trend changes were observed after training the nurses and after the legal requirement of screening by the Dutch Health Care Inspectorate in 2009. The detection rate in children screened for child abuse was 5 times higher than that in children not screened (0.5% vs 0.1%, P < .001). CONCLUSIONS: These results indicate that systematic screening for child abuse in emergency departments is effective in increasing the detection of suspected child abuse. Both a legal requirement and staff training are recommended to significantly increase the extent of screening. PMID- 22926180 TI - Circumcision policy statement. AB - Male circumcision is a common procedure, generally performed during the newborn period in the United States. In 2007, the American Academy of Pediatrics (AAP) formed a multidisciplinary task force of AAP members and other stakeholders to evaluate the recent evidence on male circumcision and update the Academy's 1999 recommendations in this area. Evaluation of current evidence indicates that the health benefits of newborn male circumcision outweigh the risks and that the procedure's benefits justify access to this procedure for families who choose it. Specific benefits identified included prevention of urinary tract infections, penile cancer, and transmission of some sexually transmitted infections, including HIV. The American College of Obstetricians and Gynecologists has endorsed this statement. PMID- 22926181 TI - The role of herd immunity in parents' decision to vaccinate children: a systematic review. AB - BACKGROUND AND OBJECTIVE: Herd immunity is an important benefit of childhood immunization, but it is unknown if the concept of benefit to others influences parents' decisions to immunize their children. Our objective was to determine if the concept of "benefit to others" has been found in the literature to influence parents' motivation for childhood immunization. METHODS: We systematically searched Medline through October 2010 for articles on parental/guardian decision making regarding child immunization. Studies were included if they presented original work, elicited responses from parents/guardians of children <18 years old, and addressed vaccinating children for the benefit of others. RESULTS: The search yielded 5876 titles; 91 articles were identified for full review. Twenty nine studies met inclusion criteria. Seventeen studies identified benefit to others as 1 among several motivating factors for immunization by using interviews or focus groups. Nine studies included the concept of benefit to others in surveys but did not rank its relative importance. In 3 studies, the importance of benefit to others was ranked relative to other motivating factors. One to six percent of parents ranked benefit to others as their primary reason to vaccinate their children, and 37% of parents ranked benefit to others as their second most important factor in decision-making. CONCLUSIONS: There appears to be some parental willingness to immunize children for the benefit of others, but its relative importance as a motivator is largely unknown. Further work is needed to explore this concept as a possible motivational tool for increasing childhood immunization uptake. PMID- 22926182 TI - Cobedding and recovery time after heel lance in preterm twins: results of a randomized trial. AB - OBJECTIVES: Cobedding of preterm twin infants provides tactile, olfactory, and auditory stimulation and may affect pain reactivity. We carried out a randomized trial to assess the effect of cobedding on pain reactivity and recovery in preterm twin neonates. METHODS: Stable preterm twins (n = 67 sets) between 28 and 36 weeks of gestational age were randomly assigned to a cobedding group (cared for in the same incubator or crib) or a standard care group (cared for in separate incubators or cribs). Pain response (determined by the Premature Infant Pain Profile [PIPP]) and time to return to physiologic baseline parameters were compared between groups with adjustment for the nonindependence of twin infants. RESULTS: Maternal and infant characteristics were not significantly different between twin infants in the cobedding and standard care groups except for 5 minute Apgar <7 and postnatal age and corrected gestational age on the day of the heel lance. Mean PIPP scores were not different between groups at 30, 60, or 120 seconds. At 90 seconds, mean PIPP scores were higher in the cobedding group (6.0 vs 5.0, P = .04). Recovery time was shorter in the cobedding group compared with the standard care group, (mean = 75.6 seconds versus 142.1 seconds, P = .001). No significant adverse events were associated with cobedding. Adjustment for nonindependence between twins and differences in baseline characteristics did not change the results. CONCLUSIONS: Cobedding enhanced the physiologic recovery of preterm twins undergoing heel lance, but did not lead to lower pain scores. PMID- 22926183 TI - Neonatal hyperbilirubinemia in the low-intermediate-risk category on the bilirubin nomogram. AB - OBJECTIVE: Predischarge bilirubin screening predicts neonatal hyperbilirubinemia. We evaluated the incidence of false-negative bilirubin screening among readmissions for hyperbilirubinemia. METHODS: In healthy term and late preterm, predominantly breastfeeding newborns, predischarge transcutaneous bilirubin values were plotted on the hour of life-specific bilirubin nomogram and confirmed with plasma total bilirubin in those with a transcutaneous reading >= 75th percentile, or between the 41st and 75th percentiles in the presence of predictive icterogenic risk factors. False-negative bilirubin screen was defined as a predischarge bilirubin value <= 75th percentile in a newborn who was subsequently readmitted for phototherapy. RESULTS: Of a total of 25439 neonates born between 2008 and 2009, 143 (0.56%) were readmitted with a mean plasma total bilirubin of 18.7 +/- 1.7 mg/dL at 125 +/- 54 hours. False-negative predischarge bilirubin screen was identified in 46 (32.2%). Of these, 6 (4.2%) were in the low risk zone (<= 40th percentile, relative risk [RR] = 1) and 40 (28%) in the intermediate-low-risk zone (41st-75th percentile, RR 7.62 [95% confidence interval 3.23-17.96]). Of those in the high-risk zones, 76 (53.1%) were in the intermediate-high-risk zone (76th-95th percentile, RR 25.32 [11.03-58.10]) and 21 (14.7%) in the high-risk zone (>95th percentile, RR 27.78 [11.23-68.70]). CONCLUSIONS: Predischarge bilirubin levels in newborns classified as low risk did not eliminate the risk of readmission for hyperbilirubinemia. All newborns including those at low risk must be vigilantly observed for subsequent hyperbilirubinemia. PMID- 22926184 TI - A three-dimensional chemo-mechanical continuum model for smooth muscle contraction. AB - Based on two fields, namely the placement and the calcium concentration, a chemo mechanically coupled three-dimensional model, describing the contractile behaviour of smooth muscles, is presented by means of a strain energy function. The strain energy function (Schmitz and Bol, 2011) is additively decomposed into a passive part, relating to elastin and collagen, and an active calcium-driven part related to the chemical contraction of the smooth muscle cells. For the description of the calcium phase the four state cross-bridge model of Hai and Murphy (Hai and Murphy, 1988) has been implemented into the finite element method. Beside three-dimensional illustrative boundary-value problems demonstrating the features of the presented modelling concept, simulations on an idealised artery document the applicability of the model to more realistic geometries. PMID- 22926186 TI - Gender violence and transdisciplinarity. PMID- 22926187 TI - Hidden behind the gunfire: young women's experiences of gang-related violence. AB - This article uses data from a 3-year multisite ethnographic research study of gangs within an English city, to explore the different ways that "gang culture" shapes the victimization experiences and everyday lives of (young) women. Victims of lethal gang violence in Research City are almost exclusively young men, rendering invisible the ways in which gangs have an impact on the lives of women living in neighborhoods with a gang presence. The article also discusses how the adoption of a transdisciplinary approach could be useful in developing a holistic picture of the impact of gang-related violence on the lives of women. PMID- 22926188 TI - Relationship power, control, and dating violence among Latina girls. AB - We drew on the theory of gender and power and grounded theory methodology to explore how 18 Latina girls conceptualized power and control within their heterosexual dating relationships. Our findings indicate that boys/men used a number of strategies to control girls, including: regulating appearances and behaviors; cheating and threatening to cheat; and physical and sexual violence. Girls used a variety of strategies to resist these attempts to control them, including: lying, flirting, and cheating; reactive violence; breaking up; and maintaining emotional distance. Girls attempted to subvert boys' attempts to control them; however, these attempts were not always successful given the constraints of gender that adolescent females must negotiate. PMID- 22926189 TI - Cellular toxicity of mutant SOD1 protein is linked to an easily soluble, non aggregated form in vitro. AB - Mutations in superoxide dismutase 1 (SOD1) are found in approximately 20% of patients with familial amyotrophic lateral sclerosis. The propensity of mutant SOD1 to form aggregates in pathologically affected cells (i.e. motor neurons) has implicated these poorly soluble protein aggregates and/or their misfolded soluble precursors as being instrumental to the disease process. We investigated the relative solubility and toxicity of four different mutant SOD1 proteins in a cell based model system and demonstrate that the mutant, misfolded SOD1 proteins that are the most soluble are also the most toxic. This toxicity was ameliorated by upregulating heat-shock protein chaperones in order to refold the soluble, misfolded protein, regardless of the presence of poorly soluble SOD1. We further demonstrate that increasing the solubility of a SOD1 mutant protein that is both poorly soluble and non-toxic, as compared to other mutant proteins, resulted in remarkably increased toxicity of the mutant SOD1. Again, this increased toxicity was attenuated by upregulating heat-shock protein chaperones in order to refold the soluble, misfolded proteins. These findings implicate easily soluble, misfolded SOD1 as being toxic to the cell and support the hypothesis that reducing solubility of mutant SOD1 proteins through aggregation may occur as a self-protective response in the cell. PMID- 22926190 TI - Preferential inactivation of Scn1a in parvalbumin interneurons increases seizure susceptibility. AB - Voltage-gated sodium channels (VGSCs) are essential for the generation and propagation of action potentials in electrically excitable cells. Dominant mutations in SCN1A, which encodes the Nav1.1 VGSC alpha-subunit, underlie several forms of epilepsy, including Dravet syndrome (DS) and genetic epilepsy with febrile seizures plus (GEFS+). Electrophysiological analyses of DS and GEFS+ mouse models have led to the hypothesis that SCN1A mutations reduce the excitability of inhibitory cortical and hippocampal interneurons. To more directly examine the relative contribution of inhibitory interneurons and excitatory pyramidal cells to SCN1A-derived epilepsy, we first compared the expression of Nav1.1 in inhibitory parvalbumin (PV) interneurons and excitatory neurons from P22 mice using fluorescent immunohistochemistry. In the hippocampus and neocortex, 69% of Nav1.1 immunoreactive neurons were also positive for PV. In contrast, 13% and 5% of Nav1.1 positive cells in the hippocampus and neocortex, respectively, were found to co-localize with excitatory cells identified by CaMK2alpha immunoreactivity. Next, we reduced the expression of Scn1a in either a subset of interneurons (mainly PV interneurons) or excitatory cells by crossing mice heterozygous for a floxed Scn1a allele to either the Ppp1r2-Cre or EMX1-Cre transgenic lines, respectively. The inactivation of one Scn1a allele in interneurons of the neocortex and hippocampus was sufficient to reduce thresholds to flurothyl- and hyperthermia-induced seizures, whereas thresholds were unaltered following inactivation in excitatory cells. Reduced interneuron Scn1a expression also resulted in the generation of spontaneous seizures. These findings provide direct evidence for an important role of PV interneurons in the pathogenesis of Scn1a-derived epilepsies. PMID- 22926193 TI - Mitophagy and Parkinson's disease: be eaten to stay healthy. AB - Parkinson's disease (PD) is one of the most prevalent neurodegenerative disorders. Pathologically, it is characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta (SNc). Although most occurrences have an unknown cause, several gene mutations have been linked to familial forms of PD. The discovery of some of the proteins encoded by these genes, including Parkin, PINK1 and DJ-1, at the mitochondria offered a new perspective on the involvement of mitochondria in PD. Specifically, these proteins are thought to be involved in the maintenance of a healthy pool of mitochondria by regulating their turnover by mitochondrial autophagy, or mitophagy. In this review, we discuss recent studies on the role of mitophagy in PD. We present three putative models whereby PINK1 and Parkin may affect mitophagy; 1) by shifting the balance between fusion and fission of the mitochondrial network, 2) by modulating mitochondrial motility and 3) by directly recruiting the autophagic machinery to damaged mitochondria. This article is part of a Special Issue entitled 'Mitochondrial function and dysfunction in neurodegeneration'. PMID- 22926194 TI - Impact of the time in an animal model of mood disorder. AB - The objective of the study is to evaluate whether intervening and testing in different rest-activity periods of the day would produce different measurements in animal behavior studies. METHODOLOGY: Thirty-five, 60-day-old male Wistar rats were submitted to an inescapable foot shock (IFS) stress model and behavioral tests (Light-Dark Box test). The animals received intervention and were tested in both light and dark phases, resulting in the following groups: control L (tested in the light), control D (tested in the dark), LL (IFS and tested in the light), LD (IFS in the light and tested in the dark), DL (IFS in the dark and tested in the light), and DD (IFS and tested in the dark). RESULTS: The Light-Dark Box test showed that control L was not significantly different from other groups in any of the parameters. However, when comparing control D with the intervention groups, we observed a difference in the mean length of time spent in the light compartment (t=2.56; p=0.045). A significant difference in the number of crossings into the light compartment was only observed between the control D and the LL and LD groups (t=-2.608; p=0.028; t=-2.571; p=0.030, respectively). The latency time for the control D group was significantly lower than that of the DD group (t=-2.556; p=0.043). CONCLUSIONS: These results show that behavior testing during the animal's period of highest activity (dark period) revealed differences caused by the intervention, whereas no differences were apparent when the control group was observed during the day. PMID- 22926192 TI - Uncoupling stimulus specificity and glomerular position in the mouse olfactory system. AB - Sensory information is often mapped systematically in the brain with neighboring neurons responding to similar stimulus features. The olfactory system represents chemical information as spatial and temporal activity patterns across glomeruli in the olfactory bulb. However, the degree to which chemical features are mapped systematically in the glomerular array has remained controversial. Here, we test the hypothesis that the dual roles of odorant receptors, in axon guidance and odor detection, can serve as a mechanism to map olfactory inputs with respect to their function. We compared the relationship between response specificity and glomerular position in genetically-defined olfactory sensory neurons expressing variant odorant receptors. We find that sensory neurons with the same odor response profile can be mapped to different regions of the bulb, and that neurons with different response profiles can be mapped to the same glomeruli. Our data demonstrate that the two functions of odorant receptors can be uncoupled, indicating that the mechanisms that map olfactory sensory inputs to glomeruli do so without regard to stimulus specificity. PMID- 22926191 TI - Astrocytic expression of HIV-1 Nef impairs spatial and recognition memory. AB - Despite the widespread use of antiretroviral therapy that effectively limits viral replication, memory impairment remains a dilemma for HIV infected people. In the CNS, HIV infection of astrocytes leads to the production of the HIV-1 Nef protein without viral replication. Post mortem studies have found Nef expression in hippocampal astrocytes of people with HIV associated dementia suggesting that astrocytic Nef may contribute to HIV associated cognitive impairment even when viral replication is suppressed. To test whether astrocytic expression of Nef is sufficient to induce cognitive deficits, we examined the effect of implanting primary rat astrocytes expressing Nef into the hippocampus on spatial and recognition memory. Rats implanted unilaterally with astrocytes expressing Nef showed impaired novel location and novel object recognition in comparison with controls implanted with astrocytes expressing green fluorescent protein (GFP). This impairment was correlated with an increase in chemokine ligand 2 (CCL2) expression and the infiltration of peripheral macrophages into the hippocampus at the site of injection. Furthermore, the Nef exposed rats exhibited a bilateral loss of CA3 neurons. These results suggest that Nef protein expressed by the implanted astrocytes activates the immune system leading to neuronal damage and spatial and recognition memory deficits. Therefore, the continued expression of Nef by astrocytes in the absence of viral replication has the potential to contribute to HIV associated cognitive impairment. PMID- 22926195 TI - Mapping geosites for geoheritage management: a methodological proposal for the regional park of Picos de Europa (Leon, Spain). AB - Mapping is a basic requirement for land use management, as effective protection of nature requires a clear delimitation of the sites involved. Additionally, mapping has other benefits for the transfer of information, as long as it is a comprehensible way of information exchange. The knowledge of geoheritage (geological heritage) and how it can be incorporated into the management of natural areas is an emerging topic. In this paper, a methodology that can be used to map geoheritage is proposed through the example of the Regional Park of Picos de Europa (Spain). Cartography is designed to be used as a tool for both prescriptive geoheritage management and land use planning processes in the protected area. The current examples of mapping consist of two groups of maps: (1) basic descriptive maps, where geosites are represented and which offer an overview of the geoheritage in the territory and (2) applied derived maps, which use the previous base cartography but also implement specific queries for management. Information codified in the derived maps may be diverse, ranging from the geosite degradation risk to the most adequate geosite use. The designed maps also achieve an important aim: They are easily interpreted and, therefore, might be used by many different professionals involved in environmental management. PMID- 22926196 TI - Experiences of parents and patients with the timing of Mucopolysaccharidosis type I (MPS I) diagnoses and its relevance to the ethical debate on newborn screening. AB - INTRODUCTION: Newborn screening (NBS) techniques have been developed for several lysosomal storage disorders (LSDs), including Mucopolysaccharidosis type I (MPS I). MPS I is an LSD with a wide phenotypic spectrum that ranges from the severe Hurler phenotype to the attenuated Scheie phenotype. To improve the ethical discussion about NBS for MPS I, we performed an interview study to explore the experiences of MPS I patients and their parents with the timings of their diagnoses. METHODS: We used a qualitative research approach consisting of 17 interviews with the parents of patients with all MPS I phenotypes and with patients with attenuated forms of MPS I. The interviews were audio-recorded, transcribed and subsequently analyzed to identify the main themes identified by the participants. RESULTS: Five important themes, focusing on the experienced disadvantages of delayed diagnosis and the advantages and disadvantages of a hypothetical earlier diagnosis, were identified in our group of participants: 1) delayed diagnosis causing parental frustration, 2) delayed diagnosis causing patient frustration, 3) early diagnosis enabling reproductive decision-making, 4) early diagnosis enabling focusing on the diagnosis, and 5) early diagnosis enabling timely initiation of treatment. There was a remarkable similarity in the experiences with timing of diagnosis between parents of patients with the severe and the attenuated forms. CONCLUSION: This was the first study to explore the personal experiences of MPS I patients and their parents with diagnostic timing. Our study identified five important themes that are highly relevant to the ethical discussion on expanding NBS programs for MPS I. PMID- 22926197 TI - Tnfalpha, Cox2 and AdipoQ adipokine gene expression levels are modulated in murine adipose tissues by both nicotine and nACh receptors containing the beta2 subunit. AB - Studies have provided evidences for the effects of nicotine on adipose tissues, as well as in inflammatory response. We hypothesized that nicotine affects adipokine gene expression in adipose tissues via specific neuronal nicotinic acetylcholine receptors (nAChRs). First, we described the expression of multiple nAChR subunit genes in mouse white and brown adipose tissues (WAT and BAT), and detected differential expression in WAT and BAT (alpha2>alpha5>beta2 and alpha2>beta2>beta4, respectively). Additionally, when nicotine was administered to wild-type mice, it significantly affected the expression of adipokine genes, such as Tnfalpha, AdipoQ, Haptoglobin and Mcp1 in WAT. Next, we demonstrated that in mice deficient for the beta2 nAChR subunit (beta2-/- mice), the expression levels of Cox2 and Ngfbeta genes in WAT, and Leptin, Cox2, AdipoQ and Haptoglobin in BAT, were significantly altered. Furthermore, interactions between mouse beta2 subunit and nicotine treatment affected the expression levels of the adipokine genes Tnfalpha, Cox2 and AdipoQ in WAT and of AdipoQ in BAT. Finally, analysis of a cellular model of cultured adipocytes demonstrated that application of nicotine after silencing of the beta2 nAChR subunit significantly elevated the expression level of Cox2 gene. Together, our data suggest a molecular link between the beta2 nACh receptor subunit and the expression levels of specific adipokines, which is also affected by nicotine. PMID- 22926198 TI - Effect of rapid cessation of enzyme replacement therapy: a report of 5 cases and a review of the literature. AB - Enzyme replacement therapy (ERT) is a treatment modality available for several of the lysosomal storage diseases including mucopolysaccharidosis type II (MPS II). We report a series of patients with MPS II (n = 5, age range at the start of ERT 11-21 years, median 15 years) and the effects of ERT cessation (range 2-8 months, median 3 months) on their clinical status. Additionally, we review previously published cases. In our series, a worsening of the patients' clinical status was observed. Symptoms after ERT discontinuation included recurrent respiratory infections (severe pneumonia) with respiratory insufficiency (80%), difficulty with walking/standing (60%), increased joint stiffness (40%), but also decreased hematological parameters (40%), renal insufficiency (40%) and death (20%). The literature review confirms that the beneficial clinical effects of ERT are soon lost if treatment is discontinued in MPS I and Pompe patients. CONCLUSIONS: 1. Rapid cessation of ERT results not only in the loss of the beneficial effects, but in a significant worsening of the patient's clinical status. 2. Decisions about the introduction of ERT, especially in patients severely affected, should be made carefully. 3. Once started, it is essential to keep an adequate administration schedule of ERT to maintain the clinical benefits of enzyme therapy. PMID- 22926199 TI - Intrathecal chlorprothixene, cis(z)-flupenthixol, chlorpromazine and fluphenazine for prolonged spinal blockades of sensory and motor functions in rats. AB - The aim of this study was to examine whether thioxanthine-type antipsychotics (chlorprothixene and cis(z)-flupenthixol) and phenothiazine-type antipsychotics (chlorpromazine and fluphenazine) produced spinal anesthesia. Using a rat model of intrathecal injection, we evaluated spinal anesthesia of antipsychotic drugs (chlorprothixene, cis(z)-flupenthixol, chlorpromazine, and fluphenazine) and bupivacaine, a known local anesthetic. At a same dose of 2.31 MUmol/kg, chlorprothixene had the most potent spinal blockades (P<0.001) and the longest duration of action (P<0.001) of motor function and nociception among those antipsychotic drugs. On the 50% effective dose (ED(50)) basis, the ranks of potencies were chlorprothixene=bupivacaine>cis(z) flupenthixol>chlorpromazine>fluphenazine (P<0.01 for the differences) in dose response studies. At an equianesthetic basis (ED(25), ED(50), and ED(75)), the spinal block duration caused by chlorprothixene, cis(z)-flupenthixol, chlorpromazine or fluphenazine was longer than that caused by bupivacaine (P<0.05). These results showed that chlorprothixene produced a similar potency and longer duration of spinal anesthesia than did bupivacaine, whereas several other antipsychotics produced less potency than did bupivacaine. PMID- 22926200 TI - Lithium dilution, pulse power analysis, and continuous thermodilution cardiac output measurements compared with bolus thermodilution in anaesthetized ponies. AB - BACKGROUND: This study compares cardiac output (CO) measurements obtained by lithium dilution (LiDCO), pulse power analysis (PulseCO), and continuous thermodilution (CTD) with bolus thermodilution (BTD) in ponies. METHODS: Eight isoflurane-anaesthetized Shetland ponies received xylazine, ketamine, and midazolam infusions (0.3, 1.2, and 0.018 mg kg(-1) h(-1), respectively). CO was measured with BTD, CTD, LiDCO, and PulseCO. Lithium was injected into the jugular vein and blood was sampled from the facial artery for lithium detection and this artery was also used for PulseCO. Measurements were obtained during four stable haemodynamic conditions in the following order: isoflurane 1% (end-tidal concentration), isoflurane 2%, isoflurane 1%, and isoflurane 1%+dobutamine 5 ug kg(-1) min(-1). RESULTS: The bias (2 sd) was 2.5 (2.1) and 0.5 (2.9) litre min( 1) for LiDCO-BTD and for CTD-BTD comparisons, respectively. The limits of agreement were wider than +/-30%; therefore, interchangeability was rejected for both comparisons. A possible error in LiDCO might explain the bias observed because CTD-BTD comparison showed less bias. Changes in PulseCO did not correlate with those of BTD and a weak correlation (r(2)=0.23; P=0.018) and concordance (Pc=0.42) was found between CTD and BTD. CONCLUSIONS: This is the first study to show a large bias for LiDCO-BTD comparison in animals receiving xylazine, ketamine, and midazolam infusions. The trending abilities of neither PulseCO nor CTD were reliable. Further studies are needed to elucidate possible influences of drugs on the accuracy of the LiDCOplus system. PMID- 22926201 TI - Capture, crawl, cross: the T cell code to breach the blood-brain barriers. AB - The central nervous system (CNS) is an immunologically privileged site to which access of circulating immune cells is tightly controlled by the endothelial blood brain barrier (BBB; see Glossary) localized in CNS microvessels, and the epithelial blood-cerebrospinal fluid barrier (BCSFB) within the choroid plexus. As a result of the specialized structure of the CNS barriers, immune cell entry into the CNS parenchyma involves two differently regulated steps: migration of immune cells across the BBB or BCSFB into the cerebrospinal fluid (CSF)-drained spaces of the CNS, followed by progression across the glia limitans into the CNS parenchyma. With a focus on multiple sclerosis (MS) and its animal models, this review summarizes the distinct molecular mechanisms required for immune cell migration across the different CNS barriers. PMID- 22926202 TI - Restoration of bone mineralization by cinacalcet is associated with a significant reduction in calcitriol-induced vascular calcification in uremic rats. AB - The present study investigated to what extent normalization of bone turnover goes along with a reduction of high-dose calcitriol-induced vascular calcifications in uremic rats. Five groups of male Sprague-Dawley rats were studied: sham-operated controls (n = 7), subtotally nephrectomized (SNX) uremic (CRF) animals (n = 12), CRF + calcitriol (vitD) (0.25 MUg/kg/day) (n = 12), CRF + vitD + cinacalcet (CIN) (10 mg/kg/day) (n = 12), and CRF + vitD + parathyroidectomy (PTX) (n = 12). Treatment started 2 weeks after SNX and continued for the next 14 weeks. High dose calcitriol treatment in hyperparathyroid rats went along with the development of distinct vascular calcification, which was significantly reduced by >50 %, in both CIN-treated and PTX animals. Compared to control animals and those of the CRF group, calcitriol treatment either in combination with CIN or PTX or not was associated with a significant increase in bone area comprising +/ 50 % of the total tissue area. However, whereas excessive woven bone accompanied by a dramatically increased osteoid width/area was seen in the CRF + vitD group, CIN treatment and PTX resulted in significantly reduced serum PTH level, which was accompanied by a distinct reduction of both the bone formation rate and the amount of osteoid. These data indicate that less efficient calcium and phosphorus incorporation in bone inherent to the severe hyperparathyroidism in vitamin D treated uremic rats goes along with excessive vascular calcification, a process which is partially reversed by CIN treatment in combination with a more efficacious bone mineralization, thus restricting the availability of calcium and phosphate for being deposited in the vessel wall. PMID- 22926203 TI - Cost-effectiveness of preventive oral health care in medical offices for young Medicaid enrollees. AB - OBJECTIVE: To estimate the cost-effectiveness of a medical office-based preventive oral health program in North Carolina called Into the Mouths of Babes (IMB). DESIGN: Observational study using Medicaid claims data (2000-2006). SETTING: Medical staff delivered IMB services in medical offices, and dentists provided dental services in offices or hospitals. PARTICIPANTS: A total of 209 285 children enrolled in Medicaid at age 6 months. INTERVENTIONS: Into the Mouths of Babes visits included screening, parental counseling, topical fluoride application, and referral to dentists, if needed. The cost-effectiveness analysis used the Medicaid program perspective and a propensity score-matched sample with regression analysis to compare children with 4 or more vs 0 IMB visits. MAIN OUTCOME MEASURES: Dental treatments and Medicaid payments for children up to age 6 years enabled assessment of the likelihood of whether IMB was cost-saving and, if not, the additional payments per hospital episode avoided. RESULTS: Into the Mouths of Babes is 32% likely to be cost-saving, with discounting of benefits and payments. On average, IMB visits cost $11 more than reduced dental treatment payments per person. The program almost breaks even if future benefits from prevention are not discounted, and it would be cost-saving with certainty if IMB services could be provided at $34 instead of $55 per visit. The program is cost effective with 95% certainty if Medicaid is willing to pay $2331 per hospital episode avoided. CONCLUSIONS: Into the Mouths of Babes improves dental health for additional payments that can be weighed against unmeasured hospitalization costs. PMID- 22926204 TI - Relationship between fragmented QRS and response to cardiac resynchronization therapy. AB - PURPOSE: Cardiac resynchronization therapy (CRT) is an effective treatment for heart failure (HF) with a wide QRS. Fragmented QRS (fQRS) on a 12-lead electrocardiography (ECG) has been shown to predict cardiac events in several patient populations. We aimed to investigate the relationship between fragmented wide QRS (f-wQRS) and left ventricular dyssynchrony and response to CRT. METHODS: Fifty-three patients with HF undergoing CRT were studied. The presence of fQRS was assessed using standardized criteria. Dyssynchrony was defined as interventricular mechanical delay (IVMD) >=40 ms and tissue Doppler velocity opposing-wall delay >=65 ms. Echocardiographic response to CRT was defined by a >=15 % reduction in left ventricular end-systolic volume at 6 months follow-up. RESULTS: Fragmented wide QRS was present in 17 (32 %) patients. Interventricular and intraventricular dyssynchrony were highly prevalent in both patient groups with f-wQRS and nonf-wQRS (64.7 % vs 75 %, p = 0.44; 70.6 % vs 72.2 %, p = 0.25). Ischemic HF was significantly higher in patients with f-wQRS than patients with nonf-wQRS (64 % vs 33 %, p = 0.03). Reverse remodeling was developed in 32 (89 %) and 6 (35 %) of patients with nonf-wQRS and f-wQRS, respectively (p = 0.001). In multivariate analysis, significant associates of response to CRT were evaluated adjusting for etiology of cardiomyopathy, QRS width, IVMD, intraventricular delay, and f-wQRS. Lack of f-wQRS was the only predictor of response to CRT (OR 1.556, 95 % CI, 0.016-0.806, p = 0.028). CONCLUSIONS: Presence of dyssynchrony is necessary but not sufficient to select appropriate candidates for CRT. Presence of f-wQRS on baseline ECG may play a role in identifying patients who may not respond to CRT. PMID- 22926206 TI - Bacterial pathogenesis: E. coli claims the driving seat for cancer. PMID- 22926207 TI - The disease burden of invasive meningococcal serogroup B disease in Canada. AB - BACKGROUND: Invasive meningococcal disease remains a rare but deadly infection in Canada. New serogroup B vaccines may offer the potential for prevention and control. This report examines the disease burden caused by serogroup B invasive meningococcal infections. METHODS: From 2002 to 2011, active, population-based metropolitan area surveillance for adult and pediatric hospital admissions for adult and pediatric hospital admissions for laboratory-confirmed infection with Neisseria meningitidis, was conducted by the 12 centers of the Canadian Immunization Monitoring Program, Active. RESULTS: A total of 769 invasive meningococcal cases occurred from 2002 to 2011; 54% (n = 413) in children with a peak incidence of 6.16 (95% confidence interval: 3.18-10.76) per 100,000 in children aged <1 year in 2009. Serogroup B accounted for the largest proportion of cases and had the highest incidence of all serogroups across all ages, with a peak incidence of 0.31 (0.23-0.40) per 100,000 in 2007. Serogroup B case fatality rate was 4.3% in children, and 21% of pediatric survivors had sequelae. B:17:P1.19 ST-269 was the most frequently detected antigenic type. CONCLUSIONS: Serogroup B invasive meningococcal infections caused substantial morbidity and mortality and are the leading cause of invasive meningococcal disease in Canada. The proportion of cases potentially preventable with the new serogroup B vaccines should be evaluated to determine whether universal immunization programs are warranted. PMID- 22926205 TI - Restricting HIV the SAMHD1 way: through nucleotide starvation. AB - HIV replication is limited by cellular restriction factors, such as APOBEC and tetherin, which themselves are counteracted by viral proteins. SAMHD1 was recently identified as a novel HIV restriction factor in myeloid cells, and was shown to be blocked by the lentiviral protein Vpx. SAMHD1 limits viral replication through an original mechanism: it hydrolyses intracellular dNTPs in non-cycling cells, thus decreasing the amount of these key substrates, which are required for viral DNA synthesis. In this Progress article, we describe how SAMHD1 regulates the pool of intracellular nucleotides to control HIV replication and the innate immune response. PMID- 22926208 TI - Maternal antibiotic exposure and risk of antibiotic resistance in neonatal early onset sepsis: a case-cohort study. AB - In a case-cohort study of early-onset sepsis, antibiotic resistance was more likely for infections in neonates born to mothers who were given antibiotics during pregnancy (odds ratio 4.6; 95% confidence interval: 1.1-19;P = 0.05). Risk of resistance increased with duration of antibiotics and number of antibiotic courses during pregnancy. Preterm birth and hospitalization during pregnancy were also associated with resistance. These risk factors should be considered when selecting empiric antibiotics for therapy of early-onset sepsis in infants. PMID- 22926209 TI - Reactogenicity and immunogenicity of an enterovirus 71 vaccine in Chinese healthy children and infants. AB - BACKGROUND: Enterovirus 71 (EV71) is highly contagious and can cause severe complications. A safe and effective vaccine is needed. We assessed the reactogenicity and immunogenicity of an inactivated, alum-adjuvanted EV71 vaccine in this study. METHODS: A randomized, double-blind, placebo-controlled clinical trial was undertaken in 360 healthy participants who were stratified into 2 age groups (6-12 and 13-60 months), and randomly allocated to receive placebo or the investigational vaccine containing 160 U, 320 U or 640 U antigen per dose by the ratio of 1:1:1:1 at days 0 and 28. Reactogenic data within 28 days after each vaccination were recorded. Blood samples were obtained on days 0, 28 and 56 for neutralizing antibody assay. RESULTS: Overall, 193 participants reported at least 1 injection-site or systemic adverse reaction with 53.3% and 54.4% participants receiving the study vaccine and placebo, respectively. Most of the reactions were mild or moderate. Three serious adverse events were observed, but none was related to vaccination. In the participants with seronegative baseline, after 2 doses all the participants receiving EV71 vaccines were seropositive and the seroconversion rates were more than 98.1%. In the participants with seropositive baseline, 1 dose induced good seroconversion rates of more than 64.3% in participants receiving EV71 vaccines. CONCLUSIONS: This study found that the inactivated EV71 vaccine was well tolerated and had good immunogenicity in healthy children and infants. A single dose induced typical booster response in the participants with a seropositive baseline, and 2 doses were needed for the immunologically naive participants. PMID- 22926210 TI - Tuberculosis in children exposed at home to multidrug-resistant tuberculosis. AB - BACKGROUND: The tuberculosis burden in children exposed at home to multidrug resistant tuberculosis (MDR-TB) is unquantified. With limited access to MDR-TB treatment, likely millions of children share the experience of chronic exposure to an infectious patient. METHODS: We conducted a retrospective cohort study of child and adult household contacts of patients treated for MDR-TB in Lima, Peru, in 1996 to 2003. The primary outcome was TB disease. We estimated prevalence of TB disease when the index case began MDR-TB treatment and incidence of TB disease over the subsequent 4 years. RESULTS: Among 1299 child contacts, 67 were treated for TB. TB prevalence was 1771 (confidence interval [CI]: 1052-2489) per 100,000 children. In 4362 child-years of follow-up, TB incidence rates per 100,000 child years were: 2079 (CI: 1302-2855) in year 1; 315 (CI: 6-624) in year 2; 634 (CI: 195-1072) in year 3; and 530 (CI: 66-994) in year 4. TB disease rates in children aged >1 year were not significantly different from those observed in adults. Children accounted for 20% of TB cases. Seven (87.5%) of 8 children tested had MDR-TB. Child contacts had TB disease rates approximately 30 times higher than children in the general population. CONCLUSIONS: Children were at high risk for TB disease when the index case started MDR-TB treatment and during the following year. These results highlight the need for implementing contact investigations and establishing systems for prompt referral and treatment of pediatric household contacts of MDR-TB patients, regardless of the age of the child. PMID- 22926211 TI - A national prospective surveillance study of acute rheumatic fever in Australian children. AB - BACKGROUND: Acute rheumatic fever (ARF) is an important cause of heart disease in Indigenous people of northern and central Australia. However, little is known about ARF in children across all Australian population groups. This national prospective study was conducted to determine patterns of disease, and populations and regions at highest risk. METHODS: The Australian Paediatric Surveillance Unit surveillance model was used to collect data on children with ARF across Australia. Children up to 15 years of age were included if they had an ARF episode diagnosed between October 1, 2007 and December 31, 2010 that met the case definition. RESULTS: ARF was identified in 151 children: 131 Indigenous Australians, 10 non-Indigenous Australians, 8 Pacific Islanders and 1 African (1 unknown). Common presenting features were joint symptoms, fever and carditis. Sydenham chorea was reported in 19% of children. Aseptic monoarthritis was a major manifestation in 19% of high-risk children. Seven non-Indigenous Australian children presented with classic, highly specific features compared with 23% of high-risk children, suggesting that subtle presentations of ARF are being missed in non-Indigenous children. Recent sore throat was reported in 33% of cases, including 25% of remote Indigenous children. There were delays in presentation to care and referral to higher-level care across urban/rural and remote areas. CONCLUSIONS: ARF may be more common than previously thought among low-risk children. These data should prompt an awareness of ARF diagnosis and management across all regions, including strategies for primary prevention. There should be renewed emphasis on treatment of sore throat in high-risk groups. PMID- 22926212 TI - Therapeutic zinc and copper supplementation in acute diarrhea does not influence short-term morbidity and growth: double-blind randomized controlled trial. AB - Our objective was to evaluate the effect of zinc and copper supplementation in acute diarrhea on morbidity and growth during 12 weeks of follow-up. In a double blind randomized controlled clinical trial of 724 children aged 6-59 months, none of the 11 evaluated outcomes showed significant association with zinc or zinc and copper supplementation. Thus, therapeutic zinc supplementation may not always yield short-term -benefits. PMID- 22926213 TI - Antiretroviral treatment strategies in highly treatment experienced perinatally HIV-infected youth. AB - BACKGROUND: There is limited information on antiretroviral (ARV) regimens and outcomes in perinatally HIV (PHIV)-infected youth. Substantial drug resistance after long-term ARV use and nonadherence hinder efforts to design suppressive regimens for PHIV-infected youth. This study compares clinical outcomes by expected activity of the prescribed ARV regimens. METHODS: A retrospective cohort study of 13- to 24-year-old PHIV-infected youth on stable ARV regimens for >=6 months was conducted at a pediatric HIV clinic. ARV regimens were retrospectively categorized as optimal or suboptimal based on accumulated genotypic resistance before study regimen initiation. RESULTS: Fifty-two patients with similar baseline characteristics met inclusion criteria (21 optimal and 31 suboptimal regimens). Patients receiving optimal regimens had significantly higher increases in CD4 than those given suboptimal regimens by week 48 of treatment (+62 versus +8 cells/mm, respectively; P = 0.04) and by the end of study period (+93 versus 1 cells/mm, respectively; P = 0.03). There were no significant differences between the groups in decline of viral load, frequency of opportunistic infections or hospitalizations or accumulation of resistance mutations. Overall, 60% of the optimal and 45% of the suboptimal groups had nonadherence during the study regimen (P = 0.3). CONCLUSIONS: PHIV-infected youth receiving optimal regimens had greater CD4 improvements but no difference in virologic outcomes compared with those receiving suboptimal regimens. In a patient population with significant nonadherence, providers must weigh the immunologic benefits of initiating an optimal regimen versus the potential risks of further resistance accumulation limiting future treatment options. PMID- 22926214 TI - Acute viral lower respiratory tract infections in Cambodian children: clinical and epidemiologic characteristics. AB - BACKGROUND: Viruses are detected in most hospitalized children admitted for acute respiratory infections. Etiologic understanding is needed to improve clinical management and prevention, particularly in resource-limited tropical countries. METHODS: A 3-year prospective descriptive study was conducted among Cambodian children admitted to 2 provincial hospitals for acute lower respiratory tract infection. Molecular detection for 18 viral pathogens using multiplex polymerase chain reaction/reverse transcription polymerase chain reactions was performed. RESULTS: We enrolled 1006 children less than 5 years of age of whom 423 (42%), 428 (42%) and 155 (16%) had pneumonia, bronchiolitis and unclassified lower respiratory tract infections, respectively. Of the 551 (55%) with documented viral infection, a single virus was detected in 491 (89%), including rhinovirus (n = 169; 34%), respiratory syncytial virus (n = 167; 34%), parainfluenza virus (n = 40; 8%), human metapneumovirus (n = 39; 8%), influenza virus (n = 31; 6%), bocavirus (n = 16; 3%), adenovirus (n = 15; 3%), coronavirus (n = 9; 2%) and enterovirus (n = 5; 1%). Coinfections with multiple viruses were detected in 6% (2 viruses detected in 59 cases; 3 viruses detected in 1 case). CONCLUSION: Similar to other tropical countries, rhinovirus and respiratory syncytial virus were the principal viral pathogens detected among children hospitalized for lower tract respiratory infection in Cambodia. PMID- 22926215 TI - Pantoea agglomerans foreign body-induced septic arthritis. AB - A 4-year-old boy was admitted because of left knee arthritis. Synovial fluid culture yielded Pantoea agglomerans identified by 16S rDNA polymerase chain reaction. Ultrasound examination revealed a foreign body in the synovial fluid. The patient underwent arthroscopy with removal of a thorn. This article highlights the need to search for a foreign body in Pantoea septic arthritis. PMID- 22926216 TI - Alteration of cytokines and chemokines during febrile episodes associated with endothelial cell damage and plasma leakage in dengue hemorrhagic fever. AB - BACKGROUND: The leakage of plasma during febrile episodes in dengue-infected patients is a severe condition leading to dengue shock syndrome. Alteration of cytokines/chemokines is suspected to be a major cause of endothelial cell damage in these patients. The study was designed to demonstrate the alteration of cytokines and chemokines in dengue-infected patients during febrile episodes. METHODS: The blood samples from 164 patients with dengue fever, dengue hemorrhagic fever and other febrile illnesses were collected daily from the day of hospitalization until discharge and also in the convalescent stage. The levels of cytokines/chemokines were determined using a sandwich chemiluminescent immunoassay, and the hematological parameters were examined by the ADVIA hematological analyzer. RESULTS: Two patterns of cytokines/chemokines alteration were detected at different time points during the febrile episode. The increased factors included interleukin (IL)-4, IL-6, IL-8, IL-10, tumor necrosis factor alpha, interferon-gamma and monocyte chemoattractant protein-1 whereas IL-1beta, IL-2, vascular endothelial growth factor and epidermal growth factor were decreased. Several cytokines were correlated with disease severity especially in dengue hemorrhagic fever/dengue shock syndrome patients. CONCLUSIONS: The alteration in the cytokine/chemokine kinetics during a febrile episode can be used as a predictor for severe dengue infection. The increased and decreased levels at different time points can indicate the disease progression related to vascular leakage in dengue hemorrhagic fever/dengue shock syndrome patients. PMID- 22926217 TI - Group A streptococcus meningitis in children. AB - OBJECTIVE: To characterize the epidemiologic burden and the molecular determinants of group A streptococcal (GAS) meningitis among the pediatric population of the state of Parana, Brazil. METHODS: Clinical and epidemiologic data were gathered by a compulsory notification system during the period 2003 to 2011. Bacterial identification, antibiotic resistance profile, emm-typing, pulsed field gel electrophoresis typing and virulence profile were analyzed by a central reference laboratory. A review of published pediatric cases of GAS meningitis from the last 45 years was undertaken and compared with the Brazilian series. RESULTS: The incidence of GAS meningitis among the pediatric population was 0.06 cases per 100,000 children per year and was associated with a case fatality rate of 43%. Neonatal age and the presence of an associated toxic shock syndrome were identified as risk factors for death. A distant focus of infection was present in more than half of the patients in the literature and in 36% in the Brazilian case series. A high diversity of emm-types was associated with GAS meningitis in Brazil. No single virulence determinant could be associated with death. CONCLUSIONS: GAS meningitis is associated with high mortality and with a high diversity of GAS emm-types and virulence determinants in Brazil. PMID- 22926218 TI - Analysis of vancomycin therapeutic drug monitoring trends at pediatric hospitals. AB - BACKGROUND: Vancomycin treatment failures in adults with methicillin-resistant Staphylococcus aureus bacteremia are well documented despite established therapeutic monitoring consensus recommendations. Vancomycin use in children has unique challenges, and consensus guidelines are lacking. We evaluated trends in vancomycin monitoring in children and estimated the impact of adult guidelines on patterns of vancomycin use. METHODS: A retrospective, descriptive study was designed. Data were obtained from the Pediatric Health Information System from 40 not-for-profit, tertiary care pediatric hospitals in the United States. Patients receiving vancomycin during hospitalizations ending July 1, 2007 through June 30, 2011 were included, and the number of vancomycin monitoring determinations per course of therapy was queried. Vancomycin utilization and monitoring practices were evaluated across institutions, age groups and time intervals. RESULTS: A total of 104,586 patients met study criteria. The mean duration of vancomycin administration was 5 (median 3, range 1-257) days. A mean of 1 (median 1, range 0 186) serum vancomycin concentration was obtained per patient; 46% of patients had none. Eighty-one percent of those receiving vancomycin more than 3 days had monitoring performed at least once. Monitoring practices did not correlate with length of therapy (r2 = 0.11). Monitoring frequency increased across all age groups (P < 0.05) after publication of adult guidelines in January 2009. CONCLUSIONS: Vancomycin monitoring practices are highly variable in children admitted to pediatric hospitals. The frequency with which serum vancomycin concentrations were monitored in children increased after the publication of the adult guidelines. Pediatric consensus guidelines should be developed to optimize patient care and resource utilization. PMID- 22926219 TI - Low rates of mother-to-child transmission of HIV-1 and risk factors for infection in Spain: 2000-2007. AB - BACKGROUND: The objective of the study was to describe temporal patterns in the management of HIV-1 infected women and their newborns and the changes over time in the mother-to-child transmission (MTCT) rates and risk factors. METHODS: A multicenter prospective observational study was performed in Madrid, Spain, from 2000 to 2007. Cohort period 1 (CP1) included births in 2000-2003 and cohort period 2 (CP2) included births in 2004-2007. RESULTS: Of the 803 HIV-infected women and their infants, 427 were in the CP1 and 376 in CP2. Almost all CP2 women received highly active antiretroviral therapy. More women in CP2 received antiretroviral treatment for >=16 weeks during pregnancy (72.0% in CP1 vs. 84.8% in CP2; P < 0.001). Overall, no differences in trends in mode of delivery were observed. The proportion of women with vaginal deliveries who had undetectable viral loads increased from 31.1% in CP1 to 42.7% in CP2 (P = 0.02). Thirteen children (1.6%, 95% confidence interval: 0.68-2.55) were HIV-1 infected by MTCT. No changes in the rates of infection were observed over time. All the cases of MTCT occurred when antiretroviral treatment was not given or was given for <16 weeks during pregnancy. CONCLUSIONS: Low MTCT rates were observed over time. Lack of timely provision of antiretroviral drugs was the main limitation to develop all preventive interventions available nowadays. Nonsustained control of viral load could be associated with residual transmission. PMID- 22926220 TI - Nosocomial rhinovirus infection in preterm infants. AB - During 11 months, all preterm infants admitted to our neonatal care facility with suspected respiratory tract infection were screened for respiratory viruses by polymerase chain reaction. Rhinovirus infection was identified in 16 infants, leading to severe respiratory compromise in most cases. Distribution of rhinovirus infections during the year showed a strong clustering trend, suggesting a major role for nosocomial transmission. PMID- 22926221 TI - Innovations in phenotyping of mouse models in the German Mouse Clinic. AB - Under the label of the German Mouse Clinic (GMC), a concept has been developed and implemented that allows the better understanding of human diseases on the pathophysiological and molecular level. This includes better understanding of the crosstalk between different organs, pleiotropy of genes, and the systemic impact of envirotypes and drugs. In the GMC, experts from various fields of mouse genetics and physiology, in close collaboration with clinicians, work side by side under one roof. The GMC is an open-access platform for the scientific community by providing phenotypic analysis in bilateral collaborations ("bottom up projects") and as a partner and driver in international large-scale biology projects ("top-down projects"). Furthermore, technology development is a major topic in the GMC. Innovative techniques for primary and secondary screens are developed and implemented into the phenotyping pipelines (e.g., detection of volatile organic compounds, VOCs). PMID- 22926222 TI - Generation of the Sotos syndrome deletion in mice. AB - Haploinsufficiency of the human 5q35 region spanning the NSD1 gene results in a rare genomic disorder known as Sotos syndrome (Sotos), with patients displaying a variety of clinical features, including pre- and postnatal overgrowth, intellectual disability, and urinary/renal abnormalities. We used chromosome engineering to generate a segmental monosomy, i.e., mice carrying a heterozygous 1.5-Mb deletion of 36 genes on mouse chromosome 13 (4732471D19Rik-B4galt7), syntenic with 5q35.2-q35.3 in humans (Df(13)Ms2Dja ( +/- ) mice). Surprisingly Df(13)Ms2Dja ( +/- ) mice were significantly smaller for their gestational age and also showed decreased postnatal growth, in contrast to Sotos patients. Df(13)Ms2Dja ( +/- ) mice did, however, display deficits in long-term memory retention and dilation of the pelvicalyceal system, which in part may model the learning difficulties and renal abnormalities observed in Sotos patients. Thus, haploinsufficiency of genes within the mouse 4732471D19Rik-B4galt7 deletion interval play important roles in growth, memory retention, and the development of the renal pelvicalyceal system. PMID- 22926224 TI - Midwives' experiences of becoming CenteringPregnancy facilitators: a pilot study in Sydney, Australia. AB - BACKGROUND: A pilot study was undertaken between 2006 and 2008 to explore the feasibility of implementing the CenteringPregnancy model of group antenatal care in Australia. The study was undertaken at two hospital antenatal clinics and two community healthcare centres in southern Sydney. This paper reports on one arm of the pilot study, known as the 'Midwives' Study', which aimed to explore the experiences of the midwives as they moved from providing traditional one-to-one antenatal care to facilitating group antenatal care. METHODS: The Australian pilot study used Action Research. Eight midwives, the group facilitators, and three researchers formed the Action Research group. A qualitative descriptive approach was undertaken to describe the experiences of the midwives. Data were collected using focus groups, surveys and checklists and analysed using thematic content analysis. FINDINGS: The midwives' initial fears and misgivings about undertaking the new role of group antenatal care gave way to a growing confidence in their abilities and group facilitation skills. They appreciated: the benefits of the CenteringPregnancy model for pregnant women; new opportunities to develop positive relationships with women and their colleagues; and the structured support and education throughout all stages of the Action Research process. CONCLUSION: The midwives were enthusiastic about their experiences of becoming CenteringPregnancy facilitators and described the benefits of this model of care compared to traditional one-to-one antenatal care. Support and education of the midwives through structured Action Research cycles enhanced the effective implementation of this new model. PMID- 22926223 TI - Beyond knockouts: cre resources for conditional mutagenesis. AB - With the effort of the International Phenotyping Consortium to produce thousands of strains with conditional potential gathering steam, there is growing recognition that it must be supported by a rich toolbox of cre driver strains. The approaches to build cre strains have evolved in both sophistication and reliability, replacing first-generation strains with tools that can target individual cell populations with incredible precision and specificity. The modest set of cre drivers generated by individual labs over the past 15+ years is now growing rapidly, thanks to a number of large-scale projects to produce new cre strains for the community. The power of this growing resource, however, depends upon the proper deep characterization of strain function, as even the best designed strain can display a variety of undesirable features that must be considered in experimental design. This must be coupled with the parallel development of informatics tools to provide functional data to the user and facilitated access to the strains through public repositories. We discuss the current progress on all of these fronts and the challenges that remain to ensure the scientific community can capitalize on the tremendous number of mouse resources at their disposal. PMID- 22926225 TI - The multiobjective based design, synthesis and evaluation of the arylsulfonamide/amide derivatives of aryloxyethyl- and arylthioethyl- piperidines and pyrrolidines as a novel class of potent 5-HT7 receptor antagonists. AB - An analysis of the virtual combinatorial library was used for refining a pilot set of 34 derivatives and designing a targeted 38-member library of the arylamide and arylsulfonamide derivatives of aryloxyethyl- and arylthioethyl- piperidines and pyrrolidines. All compounds 24-95 were synthesized according to an elaborated parallel solid-phase method and were biologically evaluated for their affinity for 5-HT(7)R. Additionally, the targeted library members were tested for 5 HT(1A), 5-HT(6), and D(2) receptors. Selected compounds of particular interest were examined for their intrinsic activity at 5-HT(7)R in vitro employing a cAMP assay. The study allowed us to identify compound 68 (4-fluoro-N-(1-{2-[(propan-2 yl)phenoxy]ethyl}piperidin-4-yl) benzenesulfonamide) as a potent 5-HT(7)R ligand (K(i) = 0.3 nM) with strong antagonistic properties (K(b) = 1 nM) and a 1450-fold selectivity over 5-HT(1A)Rs. PMID- 22926226 TI - Demethylwedelolactone derivatives inhibit invasive growth in vitro and lung metastasis of MDA-MB-231 breast cancer cells in nude mice. AB - The anticancer properties of demethylwedelolactone (DWEL) and wedelolactone (WEL), which are naturally occurring coumestans, have not been well characterized. In this study, we investigated the anti-invasive effects of synthetic WEL and DWEL on human MDA-MB-231 breast cancer cells. We found that WEL and DWEL inhibited the anchorage-independent growth and also suppressed cell motility and cell invasion of MDA-MB-231 cells. In addition, WEL and DWEL reduced the activity and expression of matrix metalloproteinases (MMPs) involved in blocking the IkappaB-alpha/NFkappaB and MEK/ERK signaling pathways in MDA-MB-231 cells. Furthermore, DWEL suppressed the metastasis and lung colonization of the tumor cells in the nude mice. Altogether, these data suggest that DWEL derivatives exert anti-invasive growth effect on breast cancer cells. PMID- 22926227 TI - Anticancer siRNA delivery by new anticancer molecule: a novel combination strategy for cancer cell killing. AB - The present report describes development of a novel, bifunctional molecule possessing both selective antiproliferative activity and siRNA transfection ability. We synthesized a series of cationic lipo-benzamides and screened for in vitro anticancer activities against a panel of cancer and non-cancer cells. The molecule with a ten carbon chain-length (C10M) significantly inhibited proliferation of cancer cells via arresting the cell cycle predominantly in the G1 phase; but did not affect non-cancerous cells. C10M effectively mediated siRNA delivery in vitro. The combined anticancer effect of the delivery of C10M together with its survivin-targeting siRNA cargo was significantly (p < 0.05) superior to that of agent alone. To our knowledge, this is the first report of a dual-purpose molecule with intrinsic anticancer activity and suitability for use in siRNA delivery. PMID- 22926228 TI - [Somatoform disorders: discussion on conceptual and diagnostic issues]. AB - In view of the forthcoming revisions of DSM-5 and ICD-11, conceptual and diagnostic issues of somatoform disorders are being discussed. Current diagnostic categories as well as criteria have been shown to have limited validity and practicability. In particular, the requirement for a lacking somatic explanation of symptoms poses several methodological and practical problems. A confusing terminology including the parallel classification of functional and somatoform disorders constitutes additional barriers to improving treatment.New classificatory approaches will probably drop the demand for the complaints to be insufficiently explained by somatic disease and thus emphasize the similarities of somatoform and somatopsychic disorders. For DSM-5, the implementation of psychobehavioral positive criteria has been suggested as contributing to both illness severity and clinical need for action. PMID- 22926229 TI - Antonio Scarpa (1752-1832). PMID- 22926230 TI - Dissociation quenching using exceptional points. AB - We examine a short way to reach an exceptional point that corresponds to a coalescence of two resonance energies. The application concerns the photodissociation of the Na2 molecule exposed to a laser field. In this case, the resonances can be correlated with the field-free vibrational states of the diatomic species. The resonances are due to the field-induced coupling with the continuum of a repulsive potential. We also draw attention to a new kind of exceptional point involving a resonance originating from a vibrational state coalescing with a shape-type resonance of the repulsive potential. A laser control scenario, aiming at the adiabatic transport from this field-free decaying state to a stable field-free vibrational state, is discussed in terms of field induced dissociation quenching. PMID- 22926231 TI - Computer simulation based selection of optimal monomer for imprinting of tri-O acetiladenosine in polymer matrix: vacuum calculations. AB - Molecularly imprinted polymers can be anticipated as synthetic imitation of natural antibodies, receptors and enzymes. In case of successful imprinting the selectivity and affinity of the imprint for substrate molecules are comparable with those of natural counterparts. The selection of the optimal functional monomer, monomer/template ratio as well as choosing of polymerization solvent is crucial determinants of the successful imprinting. In the present study the simulation approach to the development of molecular imprinting polymers for the extraction of new protein kinase ATP-competitive inhibitors is presented. By imprinting tri-O-acetyladenosine into polymer matrix the synthetic reproduction of adenosine triphosphate binding site to protein kinases can be fabricated and further used for adenosine triphosphate analogs screening in different sources. The optimized geometrical structure and energy of the pre-polymerization complexes of tri-O-acetyladenosine (template) with three different monomers methacrylic acid, 3-vinyl benzoic acid and acrylamide in vacuum were calculated using hybrid quantum mechanical/molecular mechanical (QM/MM) approach. These calculations demonstrate that methacrylic acid forms the most stable complex with template, the next is 3-vinyl benzoic acid complex and the third-acrylamide one. The bond energies of the complexes are shown to increase monotonically as more monomers are linked to the template. The same conclusions are made from purely quantum self-consistent field calculations of pre-polymerization complex energy and structure. Hybrid calculation is shown to be effective and can substantially accelerate the development of the imprinting technology. PMID- 22926232 TI - Severe propylene glycol toxicity secondary to use of anti-epileptics. AB - Propylene glycol toxicity presenting as high anion gap metabolic acidosis and osmolar gap has been extensively reported in literature, and most of them are secondary to intravenous lorazepam infusion. However, propylene glycol is used as a solvent in a number of medications that are frequently utilized in critical care setting, and hence one should be aware that the toxicity is possible from a variety of medication. Phenobarbital and phenytoin are one of those, and we hereby report a novel case of propylene glycol toxicity secondary to phenobarbital and phenytoin infusion in a patient with refractory status epilepticus. Furthermore, our patient had end-stage renal disease, which we think could have been an important precipitating factor for the toxicity. Because most of the symptoms from propylene glycol toxicity can mimic sepsis-which is very common in critical care unit patients-this life threatening scenario could be easily missed. Regular monitoring of osmolar gap is an easily available intervention in the at risk patients. PMID- 22926233 TI - A randomized, comparative, multicentric clinical trial to assess the efficacy and safety of zileuton extended-release tablets with montelukast sodium tablets in patients suffering from chronic persistent asthma. AB - Leukotriene (LT) modifiers are anti-inflammatory drugs that are useful as an add on therapy with first-line asthma-controller medications. This group includes LT synthesis inhibitors (eg, Zileuton) and receptor antagonists (eg, Montelukast), whose direct comparative clinical data are not available. This study was conducted to assess the comparative efficacy and safety of orally administered Zileuton extended-release (ER) with Montelukast sodium in patients suffering from chronic persistent asthma. Patients of 18-65 years of age with mild to moderate chronic stable asthma were randomized to treatment with Zileuton ER 2400 mg/d or Montelukast 10 mg/d for 12 weeks. Peak expiratory flow rate (PEFR) and asthma symptoms (cough, wheeze, chest tightness, and shortness of breath each on a 4 point scale) were assessed on monthly scheduled out-patient visits. Safety assessments by clinical and laboratory parameters were carried out during the course of the study. Among 210 patients eligible for efficacy assessment, PEFR improved by 64.8 +/- 52.8 (95% confidence interval: 54.8-74.7) L/min with Zileuton ER (n = 109) and 40.6 +/- 47.5 (31.3-49.9) L/min with Montelukast (n = 101; P < 0.001), whereas percent improvements were 27.0% (22.6%-31.5%) versus 18.4% (14.1%-22.7%), respectively (P = 0.006). Zileuton ER lead to >=12% PEFR improvements in 74 of 109 [67.9% (59.1%-76.7%)] patients, whereas the same was noted in 52 of 101 [51.5% (41.7%-61.2%)] patients receiving Montelukast (P = 0.015). The reduction in the mean overall symptom intensity score was also significantly better with Zileuton ER [-5.0 +/- 2.1 (4.6-5.4) versus -4.2 +/- 2.3 (3.8-4.7)] (P = 0.018); however, the same was not observed for the decline in the individual symptom scores. A lesser but not significantly different adverse event rate was reported in the Zileuton ER group than the Montelukast group with the commonest events being headache and gastrointestinal effects in both the groups. Thus, Zileuton ER seems to be more efficacious than Montelukast and well tolerated for the treatment of mild to moderate chronic persistent asthma in adult patient population. Further studies can elucidate the comparative treatment benefits of these LT modifiers in asthma management. PMID- 22926234 TI - Management of familial hypertriglyceridemia-induced pancreatitis during pregnancy with therapeutic plasma exchange: a case report and review of literature. AB - Familial severe hypertriglyceridemia (levels greater than 1000 mg/dL) is a known cause of acute pancreatitis. Pregnancy can dysregulate controlled lipid levels in women with familial hypertriglyceridemia and lead to acute pancreatitis and significant morbidity in both mother and fetus. We report a case of hypertriglyceridemia-induced pancreatitis during pregnancy that was successfully treated using therapeutic plasma exchange, resulting in delivery of a healthy preterm infant. Therapeutic plasma exchange is an effective approach to treat gestational hypertriglyceridemia-induced pancreatitis. Other treatment options include combined heparin and insulin infusion. Moreover, particular caution should be applied when interpreting the results of prothrombin time in the setting of severe hypertriglyceridemia as false elevation with testing methods could happen. PMID- 22926235 TI - Neuropoietic cytokines in normal brain development and neurodevelopmental disorders. AB - Inflammation has been implicated in a wide variety of neurological disorders and there is increasing evidence for long-term consequences of inflammation during early brain development. A number of immune mediators, termed neuropoietic cytokines, have a role in normal brain development. Neuropoietic cytokines contribute to proliferation of neural precursors; fate determination and differentiation; migration of neurons and glia; as well as cell survival and activity dependent alteration of synaptic function. Inflammation during development, therefore, may cause widespread injury to the brain by interfering with the normal balance of cytokine signalling and therefore developmental processes. This review will examine the normal role of neuropoietic cytokines and the potential contribution of inflammatory insults to a number of neurodevelopmental disorders. It will also discuss the potential for developmental inflammation to sensitise the brain to later insult, possibly contributing to neurodegenerative disorders later in life. This article is part of a Special Issue entitled 'Neuroinflammation in neurodegeneration and neurodysfunction'. PMID- 22926236 TI - Digital PCR strategies in the development and analysis of molecular biomarkers for personalized medicine. AB - The efficient delivery of personalized medicine is a key goal of healthcare over the next decade. It is likely that PCR strategies will play an important role in the delivery of this goal. Digital PCR has certain advantages over more traditional PCR protocols. In this article we will discuss the current status of digital PCR, highlighting its advantages and focusing on how it can be utilized in biomarker development and analysis, including the use of individualized biomarkers. We will explore recent developments in this field including examples of how digital PCR may integrate with next generation sequencing to deliver truly personalized medicine. PMID- 22926237 TI - Genome-wide identification of miRNA targets by PAR-CLIP. AB - miRNAs are short (20-23 nt) RNAs that are loaded into proteins of the Argonaute (AGO) family and guide them to partially complementary target sites on mRNAs, resulting in mRNA destabilization and/or translational repression. It is estimated that about 60% of the mammalian genes are potentially regulated by miRNAs, and therefore methods for experimental miRNA target determination have become valuable tools for the characterization of posttranscriptional gene regulation. Here we present a step-by-step protocol and guidelines for the computational analysis for the large-scale identification of miRNA target sites in cultured cells by photoactivatable ribonucleoside enhanced crosslinking and immunoprecipitation (PAR-CLIP) of AGO proteins. PMID- 22926238 TI - Response of elk to habitat modification near natural gas development. AB - Elk (Cervus elaphus) are known to shift habitat use in response to environmental modifications, including those associated with various forms of energy development. The specific behavioral responses underlying these trends, however, have not been effectively studied. To investigate such effects, we examined elk response to habitat alteration near natural gas wells in Las Animas County, Colorado, USA in 2008-2010. We created 10 1-ha openings in forests adjacent to 10 operating natural gas wells by removing standing timber in 2008, with concomitant establishment of 10 1-ha control sites adjacent to the same wells. On each site, we estimated elk use, indexed by pellet density, before and after timber removal. Concurrently, we measured plant production and cover, nutritional quality, species composition and biomass removed by elk and other large herbivores. Species richness and diversity, graminoid and forb cover, and graminoid and forb biomass increased on cut sites following tree removal. Differences were greater in 2010 than in 2009, and elk and deer removed more plant biomass in 2010 than 2009. Elk use of cut sites was 37 % lower than control sites in 2009, but 46 % higher in 2010. The initially lower use of cut sites may be attributable to lack of winter forage on these sites caused by timber removal and associated surface modification. The increased use of cut sites in 2010 suggested that elk possessed the behavioral capacity, over time, to exploit enhanced forage resources in the proximity of habitat modifications and human activity associated with maintenance of operating natural gas wells. PMID- 22926239 TI - What's a stream without water? Disproportionality in headwater regions impacting water quality. AB - Headwater streams are critical components of the stream network, yet landowner perceptions, attitudes, and property management behaviors surrounding these intermittent and ephemeral streams are not well understood. Our research uses the concept of watershed disproportionality, where coupled social-biophysical conditions bear a disproportionate responsibility for harmful water quality outcomes, to analyze the potential influence of riparian landowner perceptions and attitudes on water quality in headwater regions. We combine social science survey data, aerial imagery, and an analysis of spatial point processes to assess the relationship between riparian landowner perceptions and attitudes in relation to stream flow regularity. Stream flow regularity directly and positively shapes landowners' water quality concerns, and also positively influences landowners' attitudes of stream importance-a key determinant of water quality concern as identified in a path analysis. Similarly, riparian landowners who do not notice or perceive a stream on their property are likely located in headwater regions. Our findings indicate that landowners of headwater streams, which are critical areas for watershed-scale water quality, are less likely to manage for water quality than landowners with perennial streams in an obvious, natural channel. We discuss the relationships between streamflow and how landowners develop understandings of their stream, and relate this to the broader water quality implications of headwater stream mismanagement. PMID- 22926242 TI - [Treatment of hydrocephalus]. AB - CLINICAL/METHODICAL ISSUE: Modern treatment of hydrocephalus. STANDARDS OF CLINICAL AND RADIOLOGICAL METHODS: Clinically: shunting and endoscopy. Radiologically: MRT, CCT. METHODICAL INNOVATIONS: Important innovations are gravitational valves and neuroendoscopy standing for new challenges in preoperative imaging and for sufficient interpretation of postoperative imaging. PERFORMANCE: G-valves reduce the complication rate (especially overdrainage) in shunting significantly. While lacking appropriated clinical studies, the UK Shunt Registry still provides the best comparison between shunting and neuroendoscopy, after which the long-term revision rates of both methods are identical. The perioperative risk of endoscopic surgery seems to be higher than for shunts. ACHIEVEMENTS: The superiority of the G-valves in chronic hydrocephalus in comparison with other valves has recently been demonstrated in a class 1 evidence based study. The neuroendoscopy, has been,-in the absence of a contraindications , indicated by a guidelines' committee of the German Society of Neurosurgery as method of choice in occlusive hydrocephalus alternatively to shunting. PRACTICAL RECOMMENDATIONS: Preoperatively, to clarify etiology, comorbidity, and surgical planning, MRI is preferable; with planned neuroendoscopy as high-resolution detailed MRI of access-trajectory and region of interest. In post-operative CT or MRI (after endoscopic procedures always MRI) a differentiation between (sub )acute and chronic hydrocephalus is important for correct interpretation of imaging: a normalization of ventricular size is physiological only in (sub-)acute hydrocephalus, in chronic hydrocephalus, yet, sign of overdrainage. In chronic hydrocephalus, ventricles shrink usually only marginally. Solely, better delineated, vertex-near cisternae are there evidence of sufficient drainage. PMID- 22926241 TI - Mild stress of caffeine increased mtDNA content in skeletal muscle cells: the interplay between Ca2+ transients and nitric oxide. AB - Caffeine increases mitochondrial biogenesis in myotubes by evoking Ca(2+) transients. Nitric oxide (NO) also induces mitochondrial biogenesis in skeletal muscle cells via upregulation of AMP-activated protein kinase (AMPK) activity and PGC-1alpha. However, the interplay and timing sequence between Ca(2+) transients and NO releases remain unclear. Herein, we tested the hypothesis that caffeine evoked Ca(2+) transients triggered NO production to increase mtDNA in skeletal muscle cells. Ca(2+) transients were recorded with Fura-2 AM and confocal microscopy; mtDNA staining, mitochondrial membrane potential and NO level were determined using fluorescent probes PicoGreen, tetramethylrhodamine methyl ester (TMRM) and DAF-FM, respectively. In primary cultured myotubes, a subtle and moderate stress of caffeine increased mtDNA exclusively. Mitochondrial membrane potential and mtDNA were increased by 1 mM as well as 5 mM caffeine, whereas 10 mM caffeine did not change the fluorescence intensity of PicoGreen and TMRM. NO level in myocytes increased gradually following the first jump of Ca(2+) transients evoked by caffeine (5 mM) till the end of recording, when Fura-2 indicated that Ca(2+) transients recovered partly and even disappeared. Importantly, nitric oxide synthase (NOS) inhibitor (L-NAME) suppressed caffeine induced mtDNA biogenesis, whereas NO donor (DETA-NO) increased mtDNA content. These data strongly suggest that caffeine-induced mtDNA biogenesis is dose sensitive and dependent on a certain level of stress. Further, an increasing level of NO following Ca(2+) transients is required for caffeine-induced mtDNA biogenesis. Additionally, Ca(2+) transients, a usual and first response to caffeine, was either suppressed or attenuated by L-NAME, DETA-NO, AICAR and U0126, suggesting an inability to control [Ca(2+)](i) in these treated cells. There may be an important interplay between NO and Ca(2+) transients in intracellular signaling system involving NOS, AMPK and MEK. PMID- 22926243 TI - Two cases with severe lethal course of Costello syndrome associated with HRAS p.G12C and p.G12D. AB - Costello syndrome (CS) is a rare congenital disorder characterized by severe failure to thrive, coarse facial appearance, cardiac and skin abnormalities, developmental delay, intellectual disability, and predisposition to malignancies. Heterozygous de novo germline mutations in the proto-oncogene HRAS cause CS. About 80% of patients share the same mutation resulting in the amino acid change p.G12S and present a relatively homogeneous phenotype. Other less common lesions in HRAS can induce a milder phenotype on the one hand and a more severe phenotype on the other broadening the spectrum of clinical manifestations in CS-affected individuals. We report two new patients with the HRAS p.G12C and p.G12D substitutions and a severe neonatal manifestation causing death at the age of three months and 13 days, respectively. Both patients had particularly severe heart involvement with hypertrophic cardiomyopathy and tachyarrhythmia, generalized edema, and respiratory distress. In one case, hypertrophic cardiomyopathy was already noted prenatally. These cases together with other individuals harboring the rare HRAS mutations p.G12C, p.G12V, p.G12D, and p.G12E provide further evidence for a genotype-phenotype correlation that could be of importance for counseling and medical management. PMID- 22926244 TI - Imaging: refining noninvasive ultrasound evaluation of the kidneys. PMID- 22926245 TI - Transplantation: investigating the role of BAFF in kidney graft dysfunction. PMID- 22926246 TI - The role of the kidney in regulating arterial blood pressure. AB - The kidney plays a central role in the regulation of arterial blood pressure. A large body of experimental and physiological evidence indicates that renal control of extracellular volume and renal perfusion pressure are closely involved in maintaining the arterial circulation and blood pressure. Renal artery perfusion pressure directly regulates sodium excretion-a process known as pressure natriuresis-and influences the activity of various vasoactive systems such as the renin-angiotensin-aldosterone system. As a result, many researchers argue that identifying any marked rise in blood pressure requires resetting of the relationship between arterial blood pressure and urinary sodium excretion, which can occur by an array of systemic or local mechanisms. Almost all of the monogenic forms of hypertension affect sites in the kidney associated with sodium handling and transport. Experimental models of spontaneous hypertension, such as the Dahl salt-sensitive rat, have been used to study the effects of kidney transplantation on blood pressure. Results from studies of kidney transplantation indicate that pressure sensitivity to sodium intake 'follows' the kidney, meaning that the recipient of a 'salt-resistant kidney' acquires sodium resistance, and that the recipient of a 'salt-sensitive kidney' acquires pressure sensitivity. The examples above and discussed in this Review demonstrate that it should come as no surprise that most disorders that affect the kidney or the renal vasculature commonly lead to secondary forms of hypertension. PMID- 22926248 TI - Systematic review of therapies for noncyclic chronic pelvic pain in women. AB - We synthesized the literature (articles published between 1990 and May 2011) on the treatment of noncyclic and mixed cyclic/noncyclic chronic pelvic pain (CPP) in adult women. Two reviewers assessed studies against predetermined inclusion/exclusion criteria, extracted data regarding participant and intervention characteristics and outcomes, and assigned overall quality and strength of evidence ratings. Of 2081 studies, 21 addressed surgical or nonsurgical interventions. Definitions of CPP and participant characteristics varied across studies, and most studies were of poor quality, which precluded data synthesis. Although surgical and nonsurgical approaches both improved pain, neither was more effective when directly compared in 3 studies. Laparoscopic adhesiolysis or laparoscopic uterosacral nerve ablation did not further improve pain scores over diagnostic laparoscopy. The evidence to conclude that surgical intervention is either effective or ineffective or that one technique is superior to another is insufficient. Most studies on nonsurgical approaches evaluated hormonal therapies in endometriosis-associated CPP and were not placebo controlled. Few studies addressed nonhormonal or nonpharmacologic approaches. Harms reporting was limited. Overall, no nonsurgical treatment was more or less effective than another, except for the clear negative effect of raloxifene. In general, the literature addressing therapies for CPP in women is of poor quality and inconclusive. Improved characterizations of the targeted condition and interventions in CPP research, including a uniform definition and standardized evaluation, are necessary to inform treatment choices. PMID- 22926247 TI - Home haemodialysis and uraemic toxin removal: does a happy marriage exist? AB - Home-based methods of haemodialysis are becoming of increasing interest. In this article, we review theoretical and evidence-based aspects of dialysis adequacy in the home setting compared with those of standard in-centre dialysis. Owing to the flexibility it enables, home haemodialysis may allow reduced blood flow rates and the successful use of less-efficient access systems. With home haemodialysis, Kt/V(urea) targets should be pursued as recommended in current guidelines, taking into account that this parameter does not reflect a number of essential elements that affect adequacy, such as dialyser pore size or alternative timeframes factors that might be applicable to modern home haemodialysis. The use of high flux, large-pore haemodialysers is associated with improved removal of large uremic toxins and should be considered as standard in home haemodialysis where possible, although dialysis water purity is crucial. Large molecule removal is further enhanced by applying convective strategies (such as haemo[dia]filtration), but these strategies greatly increase technical complexity. Alternate-day haemodialysis is more desirable than the usual thrice weekly approach to avoid complications at the end of the long weekend interval, and it is easier to implement such a regime at home than in-centre. Frequent, prolonged, and combined frequent and prolonged dialysis regimes are all associated with improved removal and improved outcomes. All three alternative timeframes are easier to apply at home than in-centre. Home haemodialysis offers increased flexibility in adopting dialysis regimes that make it possible to improve solute removal and, therefore, outcomes. PMID- 22926249 TI - Obstetric hemorrhage and coagulation: an update. Thromboelastography, thromboelastometry, and conventional coagulation tests in the diagnosis and prediction of postpartum hemorrhage. AB - Globally, postpartum hemorrhage (PPH) is the leading cause of maternal morbidity and mortality. In the current treatment of severe PPH, first-line therapy includes transfusion of packed cells and fresh-frozen plasma in addition to uterotonic medical management and surgical interventions. In persistent PPH, tranexamic acid, fibrinogen, and coagulation factors are often administered. Secondary coagulopathy due to PPH or its treatment is often underestimated and therefore remains untreated, potentially causing progression to even more severe PPH. In most cases, medical and transfusion therapy is not based on the actual coagulation state because conventional laboratory test results are usually not available for 45 to 60 minutes. Thromboelastography and rotational thromboelastometry are point-of-care coagulation tests. A good correlation has been shown between thromboelastometric and conventional coagulation tests, and the use of these in massive bleeding in nonobstetric patients is widely practiced and it has been proven to be cost-effective. As with conventional laboratory tests, there is an influence of fluid dilution on coagulation test results, which is more pronounced with colloid fluids. Fibrinogen seems to play a major role in the course of PPH and can be an early predictor of the severity of PPH. The FIBTEM values (in thromboelastometry, reagent specific for the fibrin polymerization process) decline even more rapidly than fibrinogen levels and can be useful for early guidance of interventions. Data on thromboelastography and thromboelastometry in pregnant women are limited, particularly during the peripartum period and in women with PPH, so more research in this field is needed. PMID- 22926250 TI - Maintaining perioperative normothermia in the patient undergoing cesarean delivery. AB - Anesthesia and surgery interfere with normal thermoregulation, and nearly all patients will become hypothermic unless compensatory measures are used. Preoperative patient warming and intraoperative methods using forced air and warmed intravenous fluids are important methods for maintaining patient's core temperature during the perioperative period. The benefits of maintaining normothermia include reductions in postoperative wound infection, the risk of perioperative coagulopathy, and myocardial ischemia. These advantages, demonstrated in patients undergoing general surgery, would be expected in patients undergoing gynecological surgery but have not been specifically studied in that population. Few studies have examined the maternal and neonatal effects of hypothermia after cesarean delivery. The results conflict as to the effectiveness of maternal warming techniques used to prevent it and the effects on neonatal temperature and acid-base status at delivery. Large prospective studies will be required to show significant effects on rates of maternal wound infection after cesarean delivery. European and American national obstetrical organizations have not published recommendations regarding the perioperative thermal regulation for cesarean delivery. We review the physiology of thermal regulation and perioperative thermal management in surgical patients and the literature that has examined perioperative maternal warming for cesarean delivery. PMID- 22926251 TI - Investigating metformin for cancer prevention and treatment: the end of the beginning. AB - Laboratory research and pharmacoepidemiology are providing converging evidence that the widely used antidiabetic drug metformin has antineoplastic activity, but there are caveats. Although population studies suggest that metformin exposure is associated with reduced cancer risk and/or improved prognosis, these data are mostly retrospective and nonrandomized. Laboratory models show antineoplastic activity, but metformin concentrations used in many experiments exceed those achieved with conventional doses used for diabetes treatment. Ongoing translational research should be useful in guiding design of clinical trials, not only to evaluate metformin at conventional antidiabetic doses, where reduction of elevated insulin levels may contribute to antineoplastic activity for certain subsets of patients, but also to explore more aggressive dosing of biguanides, which may lead to reprogramming of energy metabolism in a manner that could provide important opportunities for synthetic lethality through rational drug combinations or in the context of genetic lesions associated with hypersensitivity to energetic stress. SIGNIFICANCE: There are tantalizing clues that justify the investigation of antineoplastic activities of biguanides. The complexity of their biologic effects requires further translational research to guide clinical trial design. PMID- 22926252 TI - Association between reading speed, cycloplegic refractive error, and oculomotor function in reading disabled children versus controls. AB - BACKGROUND: Approximately one in ten students aged 6 to 16 in Ontario (Canada) school boards have an individual education plan (IEP) in place due to various learning disabilities, many of which are specific to reading difficulties. The relationship between reading (specifically objectively determined reading speed and eye movement data), refractive error, and binocular vision related clinical measurements remain elusive. METHODS: One hundred patients were examined in this study (50 IEP and 50 controls, age range 6 to 16 years). IEP patients were referred by three local school boards, with controls being recruited from the routine clinic population (non-IEP patients in the same age group). A comprehensive eye examination was performed on all subjects, in addition to a full binocular vision work-up and cycloplegic refraction. In addition to the cycloplegic refractive error, the following binocular vision related data was also acquired: vergence facility, vergence amplitudes, accommodative facility, accommodative amplitudes, near point of convergence, stereopsis, and a standardized symptom scoring scale. Both the IEP and control groups were also examined using the Visagraph III system, which permits recording of the following reading parameters objectively: (i) reading speed, both raw values and values compared to grade normative data, and (ii) the number of eye movements made per 100 words read. Comprehension was assessed via a questionnaire administered at the end of the reading task, with each subject requiring 80% or greater comprehension. RESULTS: The IEP group had significantly greater hyperopia compared to the control group on cycloplegic examination. Vergence facility was significantly correlated to (i) reading speed, (ii) number of eye movements made when reading, and (iii) a standardized symptom scoring system. Vergence facility was also significantly reduced in the IEP group versus controls. Significant differences in several other binocular vision related scores were also found. CONCLUSION: This research indicates there are significant associations between reading speed, refractive error, and in particular vergence facility. It appears sensible that students being considered for reading specific IEP status should have a full eye examination (including cycloplegia), in addition to a comprehensive binocular vision evaluation. PMID- 22926253 TI - The effect of photodynamic therapy on macular sensitivity in eyes with acute central serous chorioretinopathy. AB - BACKGROUND: To evaluate the effect of half-fluence rate indocyanine green angiography (ICGA)-guided verteporfin photodynamic therapy (PDT) on macular sensitivity (MS) in eyes with acute symptomatic central serous chorioretinopathy (CSC). METHODS: Single-center consecutive case series by retrospective chart review. Sixteen eyes of 16 patients with acute CSC of 3 months duration or less, treated with half-fluence (25 mJ/cm(2)) ICGA-guided verteporfin PDT were reviewed. At baseline and after 1, 3, and 6 months, all patients underwent MS testing of the central 20 degrees , MS testing of the retinal area covered by the PDT laser spot (MSLS), and evaluation of fixation stability (FS) for the central two degrees with the MP-1 microperimeter (Nidek, Vigonza, Italy). RESULTS: Macular sensitivity improved from 16.4 +/- 3.0 dB at baseline (n = 16) to 18.2 +/- 2.4 dB (p < 0.001) at 1 month (n = 16). At the 3-month (n = 13) and 6 month (n = 12) follow-up, MS stabilized at 19.5 +/- 0.9 dB (p = 0.21) and 19.0 +/ 1.3 dB (p = 0.74), without changes when compared to respective precedent follow up. Mean MSLS improved from 12.9 +/- 5.4 dB at baseline to 16.4 +/- 4.9 dB (p < 0.001) after 1 month. At the 3- and 6-month follow-up, MSLS was 19.1 +/- 1.2 dB (p= 0.1) and 18.9 +/- 1.9 dB (p = 0.8) respectively. Mean FS at the central 2 degrees was 78.8 +/- 30.4 % before treatment and 81.8 +/- 29.5 % (p = 0.7), 81.9 +/- 27.5 % (p = 0.7) and 83.6 +/- 17.1 % (p = 0.5) respectively 1, 3 and 6 months after treatment. CONCLUSION: Half-fluence (25 mJ/cm(2)) PDT significantly increased mean MS of central 20 degrees and mean MSLS, in eyes with acute symptomatic CSC. Fixation stability was stable at baseline and throughout 6 months of follow-up. PMID- 22926254 TI - Aspheric wavefront-guided versus wavefront-guided LASIK for myopic astigmatism with the Technolas 217z100 excimer laser. AB - PURPOSE: To compare clinical outcomes of wavefront-guided LASIK with and without aspheric compensation in myopic eyes. METHODS: In this observational, single center study, 134 eyes were treated using an aspheric module in combination with wavefront-guided profiles (PTA-algorithm) and compared to 146 eyes treated with the predecessor wavefront-guided software (APT) that has no aspheric compensation. All treatment plans included the Rochester nomogram that accounts for the preoperative manifest refraction and interaction of higher order aberrations. Active eye-tracking (including cyclorotational movements) was utilized during photoablation. RESULTS: Results at the 3-month follow-up: 67 % of PTA-treated eyes and 39 % of APT-treated eyes achieved an uncorrected distance visual acuity (UDVA) of 20/20 or better. Change in mean higher order aberration root-mean-square (HOA RMS) after PTA treatments was not statistically significant (p = 0.18). The increase in HOA RMS after APT treatments was statistically significant (p = 0.003). Change in mean postop spherical aberration (SA) after PTA treatments was not statistically significant (p = 0.27). The change in SA after APT treatments was statistically significant (p = 0.001). In both cohorts, mean uncorrected low-contrast visual acuity was statistically not different to preoperative corrected values. CONCLUSIONS: Adding an aspheric compensation to wavefront-guided myopic LASIK statistically improved clinical results in terms of visual acuity and refractive outcomes. Low-contrast visual acuity was not negatively affected in either group. While in APT-treated eyes mean HOA RMS and mean SA were significantly increased postoperatively, PTA-treated eyes showed neither induced HOA RMS nor induced SA. PMID- 22926256 TI - Hematological parameters and phagocytic activity in fat snook (Centropomus parallelus) bred in captivity. AB - The objective of this work was to determine the hematological parameters and the phagocytic capacity of peritoneal macrophages of fat snook related to sex, stage of gonadal maturation and seasonal cycle. Blood was collected from 135 animals (78 females and 57 males) and used for determinations of: erythrocyte number, hematocrit, hemoglobin, erythrocyte indices mean corpuscular volume (MCV) and mean corpuscular hemoglobin concentration (MCHC), total and differential leukocyte counts, and thrombocyte count. The phagocytic capacity and phagocytic index were determined after Saccharomyces cerevisiae inoculation in the peritoneal cavity of the animals. The hematological results according to sex showed that the erythrocyte, total leukocyte and thrombocyte counts were statistically higher in males than females, with the latter showing a higher MCV. Concerning to erythrocyte count, hematocrit and hemoglobin concentration analyzed separately by sex and stage of gonadal maturation, males were found to have significantly elevated values in the mature stage and decreased levels in the resting stage. The results of the erythrocyte and leukocyte series, thrombocytes and phagocytic activity related to seasonal cycle showed significant differences in both sexes, where hematocrit and hemoglobin concentration were lower in winter and higher in the other seasons, mean corpuscular volume was higher in the summer and lower in the winter and fall, total leukocytes and thrombocytes lower in the spring and higher in the fall, lymphocytes low in the winter and summer and high in the spring and phagocytic capacity and phagocytic index high in the summer and low in the winter and fall. The results showed that the hematological values in males are statistically higher than those in females, the erythrocyte values in males increase with the progression of gonadal maturation and that winter is the season of the year least favorable for hematological and phagocytic responses for survival of fat snook kept in captivity. The parameters studied could be utilized in the evaluation of the health status of this species in captivity. PMID- 22926255 TI - Distributions and determinants of mercury concentrations in toenails among American young adults: the CARDIA Trace Element Study. AB - Since data on mercury (Hg) levels in Caucasians and African Americans (AAs) of both genders are lacking, this study aims to present toenail Hg distributions and explore the potential determinants using data from the Coronary Artery Risk Development in Young Adults Trace Element Study. Data from 4,344 Americans, aged 20-32 in 1987, recruited from Oakland, Chicago, Minneapolis, and Birmingham were used to measure toenail Hg levels by instrumental neutron-activation method. The Hg distribution was described with selected percentiles and geometric means. Multivariable linear regression (MLR) was used to examine potential determinants of Hg levels within ethnicity-gender subgroups. The geometric mean of toenail Hg was 0.212 (95 % CI = 0.207-0.218) MUg/g. Hg levels varied geographically with Oakland the highest [0.381 (0.367-0.395) MUg/g] and Minneapolis the lowest [0.140 (0.134-0.147) MUg/g]. MLR analyses showed that male gender and AA ethnicity were negatively associated with toenail Hg levels, and that age, living in Oakland city, education level, alcohol consumption, and total fish intake were positively associated with toenail Hg concentrations within each ethnicity-gender subgroup. Current smokers were found to have higher Hg only in AA men. This study suggested age, gender, ethnicity, study center, alcohol, education level, and fish consumption consistently predict toenail Hg levels. As fish consumption was the key determinant, avoiding certain types of fish that have relatively high Hg levels may be crucial in reducing Hg intake. PMID- 22926257 TI - Powerful inhibition of in-vivo growth of experimental hepatic cancers by bombesin/gastrin-releasing peptide antagonist RC-3940-II. AB - Hepatic carcinoma is a major health problem worldwide. Its incidence is increasing in Western countries and there is currently no effective systemic therapy against it. Targeted treatment modalities developed in the past few years have provided very limited success. Development of new treatment strategies is therefore essential. We investigated the effects of bombesin/gastrin-releasing peptide (BN/GRP) antagonist RC-3940-II on experimental human liver cancers in nude mice. SK-Hep-1 and Hep-G2 cancers transplanted subcutaneously into nude mice were treated daily with 10 or 20 ug of RC-3940-II. Tumor growth was monitored for 50-184 days in five experiments. Tumor gene expression was analyzed with PCR array and protein expression by immunoblotting. Characteristics of BN/GRP receptors in the tumors were analyzed by binding assays. Effects of RC-3940-II on cell proliferation were investigated in vitro. RC-3940-II inhibited the growth of SK-Hep-1 cancers in nude mice by 65-98%, with total regression in 9 of 36 tumors in three experiments. The BN/GRP antagonist inhibited the growth of Hep-G2 cancers as well by 73-82% in two experiments, being effective even on originally large tumors. Gene expression analysis showed an increase in several angiogenesis inhibitors and decrease in proangiogenic genes after RC-3940-II treatment. Receptor assays demonstrated high-affinity binding sites for BN/GRP in both tumor lines. BN/GRP antagonist RC-3940-II powerfully inhibits growth of SK-Hep-1 and Hep-G2 cancers in nude mice. Its effect may be linked to changes in expression of those cancer genes important in angiogenesis, invasion, and metastasis. RC-3940 II may be considered for further investigations in treatment of liver cancers. PMID- 22926258 TI - Ethogel topical formulation for increasing the local bioavailability of 5 fluorouracil: a mechanistic study. AB - 5-Fluorouracil (5-FU) is an anticancer drug and is considered a gold standard for the treatment of skin cancer. At present, topical chemotherapy with 5-FU is associated with the limitations of poor skin permeation, retention at target site, and skin irritation potential. In the present study, an attempt has been made to develop an ethosome-based topical gel formulation (ethogel) for skin targeting of 5-FU. The ethosomal formulation was prepared using the classical dispersion method, and loading of 5% w/w of the drug was optimized to the commercial strength of marketed 5-FU cream. Carbopol 934P was used as a gel former in 0.5, 0.75, 1.0, and 1.5% w/w concentration for preparation of ethosome based ethogel formulation. The ethogel formulation was characterized for viscosity, spreadability, extrudability, and pH. Viscosity of the developed ethogel and that of the marketed formulation was found to be 3070+/-14.7 and 2870+/-14.4 cP, respectively. An in-vitro skin permeation and deposition study was carried out across rat skin using the marketed cream and 5-FU drug solution as controls. The amount of drug deposition was found to increase 5.9- and 9.4 fold on treatment with ethogel in comparison with the marketed cream and drug solution, respectively. The result of antitumor activity evaluated using a Cytoselect 96-well cell transformation assay revealed a large reduction in tumor density with treatment with the 5-FU ethogel formulation in comparison with the marketed formulation. A significant reduction in the skin irritation potential of 5-FU ethogel formulation was also found in comparison with that of the marketed formulation as measured by the Draize test. The results of the present study demonstrated ethogel as a better alternative for increasing the local bioavailability of 5-FU in comparison to the marketed formulation. PMID- 22926259 TI - Agroinoculation of the cloned infectious cDNAs of Lettuce chlorosis virus results in systemic plant infection and production of whitefly transmissible virions. AB - Lettuce chlorosis virus (LCV) is a single stranded, positive strand RNA virus that is solely transmitted by specific whitefly vectors (Bemisia tabaci biotypes A and B) but not by mechanical leaf-rub inoculation. The roles of viral encoded proteins involved in the infection cycle of LCV have not yet been characterized due to the lack of reverse genetic tools. We present here a report of the successful development of an Agrobacterium-mediated inoculation system for the cloned cDNA constructs of LCV. The cDNAs of both LCV RNAs 1 and 2 were engineered into binary vectors in which the expression of LCV RNAs was regulated under a Cauliflower mosaic virus (CaMV) 35S promoter. In addition, by engineering the sequence elements of the Hepatitis delta virus ribozyme and the nopaline synthase 3' untranslated region immediately downstream of the last nucleotide of LCV RNAs 1 and 2 in the binary vector constructs, the in planta produced LCV transcripts were expected to bear authentic 3' termini. Both constructs were transformed into Agrobacterium tumefaciens cells and infiltrated in Nicotiana benthamiana plants. Three to four weeks post-agroinoculation, the N. benthamiana plants developed typical interveinal chlorosis and LCV infection was detected in the systemic leaves by reverse transcription-PCR. Virions purified from the LCV-infected N. benthamiana plants were flexuous rod-shaped and were transmissible by both B. tabaci biotypes A and B following membrane feeding. These results support the conclusion that Agrobacterium-mediated inoculation of LCV binary vectors in N. benthamiana plants results in LCV infection and the production of biologically active, whitefly transmissible virions. This system represents an important tool for use with reverse genetics designed for the study of LCV gene functions. PMID- 22926260 TI - Truncated contact lenses for peripheral vitrectomy. PMID- 22926261 TI - Re: Does surgical experience have an effect on the success of retinal detachment surgery? PMID- 22926262 TI - ChIA-PET analysis of transcriptional chromatin interactions. AB - Long-range chromatin contacts between specific DNA regulatory elements play a pivotal role in gene expression regulation, and a global characterization of these interactions in the 3-dimensional (3D) chromatin structure is imperative in understanding signaling networks and cell states. Chromatin Interaction Analysis using Paired-End Tag sequencing (ChIA-PET) is a method which converts functional chromatin structure into millions of short tag sequences. Combining Chromatin Immunoprecipitation (ChIP), proximity ligation and high-throughput sequencing, ChIA-PET provides a global and unbiased interrogation of higher-order chromatin structures associated with specific protein factors. Here, we describe the detailed procedures of the ChIA-PET methodology, unraveling transcription associated chromatin contacts in a model human cell line. PMID- 22926263 TI - An essential role of metalloprotease-disintegrin ADAM12 in triple-negative breast cancer. AB - In the absence of HER2 overexpression, triple-negative breast cancers (TNBCs) rely on signaling by epidermal growth factor receptor (EGFR/ErbB1/HER1) to convey growth signals and stimulate cell proliferation. Soluble EGF-like ligands are derived from their transmembrane precursors by ADAM proteases, but the identity of the ADAM that is primarily responsible for ligand release and activation of EGFR in TNBCs is not clear. Using publicly available gene expression data for patients with lymph node-negative breast tumors who did not receive systemic treatment, we show that ADAM12L is the only ADAM with an expression level significantly associated with decreased distant metastasis-free survival times. Similar effect was not observed for patients with ER-negative non-TNBCs. There was a positive correlation between ADAM12L and HB-EGF and EGFR in TNBCs, but not in ER-negative non-TNBCs. We further demonstrate that ectopic expression of ADAM12L increased EGFR phosphorylation in a mouse intraductal xenograft model of early breast cancer. Finally, we detect strong correlation between the level of anti-ADAM12L and anti-phospho-EGFR immunostaining in human breast tumors using tissue microarrays. These studies suggest that ADAM12L is the primary protease responsible for the activation of EGFR in early stage, lymph node-negative TNBCs. Thus, our results may provide novel insight into the biology of TNBC. PMID- 22926264 TI - RANKL inhibition combined with tamoxifen treatment increases anti-tumor efficacy and prevents tumor-induced bone destruction in an estrogen receptor-positive breast cancer bone metastasis model. AB - Tumor cells in bone can induce the activation of osteoclasts, which mediate bone resorption and release of growth factors and calcium from the bone matrix, resulting in a cycle of tumor growth and bone breakdown. Targeting the bone microenvironment by the inhibition of RANKL, an essential mediator of osteoclast function, not only prevents tumor-induced osteolysis but also decreases skeletal tumor burden in preclinical models. The inhibition of skeletal tumor progression after the inhibition of osteoclasts is via interruption of the "vicious cycle" of tumor/bone interactions. The majority of breast cancer patients at risk for bone metastases harbor estrogen receptor-positive (ER+) tumors. We developed a mouse model for ER+ breast cancer bone metastasis and evaluated the effect of RANKL inhibition on tumor-induced osteolysis and skeletal tumor growth both alone and in combination with tamoxifen. Luciferase-labeled MCF-7 cells (MCF-7Luc) formed metastatic foci in the hind limbs following intracardiac injection and caused mixed osteolytic/osteoblastic lesions. RANKL inhibition by OPG-Fc treatment blocked osteoclast activity and prevented tumor-induced osteolysis, as well as caused a marked decrease in skeletal tumor burden. Tamoxifen as a single agent reduced MCF-7Luc tumor growth in the hind limbs. In a combination experiment, OPG Fc plus tamoxifen resulted in significantly greater tumor growth inhibition than either single agent alone. Histologic analysis revealed a decrease in the proliferation of tumor cells by both single agents, which was enhanced in the combination treatment. Upon treatment with OPG-Fc alone or in combination with tamoxifen, there was a complete absence of osteolytic lesions, demonstrating the ability of RANKL inhibition to prevent skeletal related morbidity in an ER+ model. The combination approach of targeting osteoclasts and the bone microenvironment by RANKL inhibition and the tumor directly via hormonal therapy may provide additional benefit to reducing skeletal tumor progression in ER+ breast cancer patients. PMID- 22926266 TI - Volunteer orthopedic surgical trips in nicaragua: a cost-effectiveness evaluation. PMID- 22926265 TI - Microbial biofilm formation and catheter-associated bacteriuria in patients with suprapubic catheterisation. AB - PURPOSE: Catheter-associated bacteriuria (CAB) with transurethral catheters is almost inevitable. Suprapubic catheters (SPCs) are widely considered to decrease the risk of CAB. However, SPCs are implants similarly prone to microbial biofilm formation. The spectrum of colonising pathogens has not been investigated. The aim of this prospective study was: (1) to assess the diversity of microbial suprapubic catheter colonisation (MSPCC), (2) to identify risk factors and (3) to investigate its association with CAB and catheter-associated urinary tract infection (CA-UTI). METHODS: A total of 218 SPCs from 112 patients were studied. Urine specimens were obtained after device replacement or removal. Sonication was performed to dislodge adherent microorganisms. Data of patient sex, age, indwelling time, and underlying disease were recorded. RESULTS: Sonicate-fluid culture (SFC) detected MSPCC in 95 %. Increasing indwelling time correlated with MSPCC (p < 0.05). Negative SFC was more frequent when antibiotic prophylaxis was applied at time of catheter placement (15 vs. 2 %, p < 0.05). Most commonly isolated were Enterobacteriaceae (45.8 %), followed by Enterococcus spp. (25.7 %) and Pseudomonas aeruginosa (10.3 %). CAB and CA-UTI were observed in 95 and 11 %, respectively. CONCLUSIONS: This study provides the first analysis of MSPCC. Indwelling time increases, whereas antibiotic prophylaxis decreases the risk of MSPCC. The spectrum of pathogens is comparable to the one obtained from urethral catheter biofilms. Urine specimens could not demonstrate the microbial diversity of MSPCC. SPCs are not preferable to urethral catheters to reduce CAB. Whether the risk of CA-UTI could be minimised by SPCs remains to be clarified. PMID- 22926267 TI - A flexible-protein molecular docking study of the binding of ruthenium complex compounds to PIM1, GSK-3beta, and CDK2/Cyclin A protein kinases. AB - We employ ensemble docking simulations to characterize the interactions of two enantiomeric forms of a Ru-complex compound (1-R and 1-S) with three protein kinases, namely PIM1, GSK-3beta, and CDK2/cyclin A. We show that our ensemble docking computational protocol adequately models the structural features of these interactions and discriminates between competing conformational clusters of ligand-bound protein structures. Using the determined X-ray crystal structure of PIM1 complexed to the compound 1-R as a control, we discuss the importance of including the protein flexibility inherent in the ensemble docking protocol, for the accuracy of the structure prediction of the bound state. A comparison of our ensemble docking results suggests that PIM1 and GSK-3beta bind the two enantiomers in similar fashion, through two primary binding modes: conformation I, which is very similar to the conformation presented in the existing PIM1/compound 1-R crystal structure; conformation II, which represents a 180 degrees flip about an axis through the NH group of the pyridocarbazole moiety, relative to conformation I. In contrast, the binding of the enantiomers to CDK2 is found to have a different structural profile including a suggested bound conformation, which lacks the conserved hydrogen bond between the kinase and the ligand (i.e., ATP, staurosporine, Ru-complex compound). The top scoring conformation of the inhibitor bound to CDK2 is not present among the top-scoring conformations of the inhibitor bound to either PIM1 or GSK-3beta and vice-versa. Collectively, our results help provide atomic-level insights into inhibitor selectivity among the three kinases. PMID- 22926268 TI - Breastfeeding practices: does method of delivery matter? AB - Objective of this study was to assess the relationship between method of delivery and breastfeeding. Using data (2005-2006) from the longitudinal Infant Feeding Practices Study II (n = 3,026) we assessed the relationship between delivery method (spontaneous vaginal, induced vaginal, emergency cesarean, and planned cesarean) and breastfeeding: initiation, any breastfeeding at 4 weeks, any breastfeeding at 6 months, and overall duration. We used SAS software to analyze data using multivariable analyses adjusting for several confounders, including selected demographic characteristics, participants' pre-delivery breastfeeding intentions and attitude, and used event-history analysis to estimate breastfeeding duration by delivery method. We found no significant association between delivery method and breastfeeding initiation. In the fully adjusted models examining breastfeeding duration to 4 weeks with spontaneous vaginal delivery group as the reference, those with induced vaginal deliveries were significantly less likely to breastfeed [adjusted odds ratio (AOR) = 0.53; 95 % CI = 0.38-0.71]; and no significant relationship was observed for those who had planned or emergency cesarean deliveries. Again, compared with spontaneous vaginal delivery group, those with induced vaginal [AOR = 0.60; 96 % CI = 0.47 0.78] and emergency cesarean [AOR = 0.68; 96 % CI = 0.48-0.95] deliveries were significantly less likely to breastfeed at 6 months. Median breastfeeding duration was 45.2 weeks among women with spontaneous vaginal, 38.7 weeks among planned cesarean, 25.8 weeks among induced vaginal and 21.5 weeks among emergency cesarean deliveries. While no significant association was observed between delivery method and breastfeeding initiation; breastfeeding duration varied substantially with method of delivery, perhaps indicating a need for additional support for women with assisted deliveries. PMID- 22926269 TI - Protective factors in American Indian communities and adolescent violence. AB - With their distinct cultural heritage and rural boundaries, American Indian reservation communities offer a unique opportunity to explore protective factors that help buffer adolescents from potential risk behaviors such as violence. Prior published research on Indian communities has not explored three potential protective factors for violence-parental monitoring of adolescents and friends, adolescents' self-efficacy to avoid fighting, and adolescents' interest in learning more about their traditional culture. This paper explores the relationship between these factors and reduced risk of reported violence. In 1998, 630 American Indian students in grades 6-12 were surveyed in five Midwestern, rural Indian reservation schools. Path analysis was used to identify the direct and indirect association of the three potential protective factors with reduced violence behavior. There were significant gender differences both in perceived parental monitoring and in adolescents' self-efficacy. For female adolescents, parental monitoring had the strongest inverse relationship with female adolescents' involvement in violence. Female adolescents' self-efficacy and their interest in learning more about their culture were also inversely associated with violence and therefore potentially important protectors. Male adolescents who reported more interest in learning the tribe's culture had better self-efficacy to avoid violence. However, self-efficacy did not successfully predict their reported involvement in peer violence. These findings support exploring gender differences, parental monitoring, self-efficacy training as well as cultural elements in future violence intervention studies. Further investigation is needed to identify protective factors for risk behaviors among male adolescents and test the generalizability to non-reservation based adolescents. PMID- 22926270 TI - Applicability of 2-DE to assess differences in the protein profile between cold storage and not cold storage in nectarine fruits. AB - Cold storage is being used to increase nectarine fruits' postharvest life. However, low temperatures lead to chilling injury and limit their commercial quality and value. In this study a proteomic approach was used to compare the protein profile between control and cold storage nectarine fruits. Protein extracted from tissue was resolved by two-dimensional gel electrophoresis (2-DE) in the 4-7 pH and 10-200 kDa Mr range. Around 350 spots were well determined, and 11 from 17 spots that showed significant differences were identified by peptide mass fingerprinting (PMF) using matrix-assisted laser desorption/ionization (MALDI)-time-of-flight (TOF)-mass spectrometry (MS). Four differentially expressed proteins were characterized as allergens and were further assessed at the transcription level using quantitative real time-RT-PCR (qRT-PCR). PMID- 22926271 TI - [Hydrocephalus]. PMID- 22926272 TI - Preparation and characterization of elastin-like polypeptide scaffolds for local delivery of antibiotics and proteins. AB - Tissue engineering applications could benefit from simultaneous release of growth factors, signaling molecules, and antibiotics to obtain optimal healing of tissues. Elastin-like polypeptides (ELPs) are genetically engineered polymers that possess good biocompatibility, are biodegradable, and exhibit mechanical properties similar to natural elastin. In addition, ELPs exhibit a characteristic inverse phase transition temperature (T(t)). This T(t) behavior is widely exploited in hyperthermia mediated drug delivery. The objectives of this research were to prepare ELP hydrogel scaffolds using a novel ultrasonication method and to investigate the release of a model protein (bovine serum albumin, BSA) and a commonly used antibiotic in periodontal therapy (doxycycline) from the scaffolds at two different temperatures (25 degrees C T(t)). Both BSA and doxycycline showed a gradual time dependent release and showed a trend of higher release fractions with higher loading doses. Based on the comparison between the release profiles at the two selected temperatures, the release was higher at 37 degrees C compared to that at 25 degrees C for both the loading concentrations of doxycycline (0.05 and 0.1 % v/v) and only one of the loading concentrations of BSA (0.5 % v/v) studied, while the release was higher at 25 degrees C compared to that at 37 degrees C only for the other loading concentration of BSA (1 % v/v) studied. These results suggested that the drug molecular weight and loading concentration were significant factors that affected the release kinetics. The experiments in this study demonstrated that the ELP hydrogel scaffolds can successfully release proteins and antibiotics critical to tissue engineering. PMID- 22926273 TI - Cesarean delivery technique: evidence or tradition? A review of the evidence based cesarean delivery. AB - Cesarean delivery is the most common surgical procedure performed in the United States, yet the techniques used during this procedure often vary significantly among providers. The purpose of this review was to evaluate and outline current evidence behind the cesarean delivery technique. A search of the PubMed database was conducted using the terms cesarean section and cesarean delivery and the technique of interest, for example, cesarean section prophylactic antibiotics. Few aspects of the cesarean delivery were found to have high-quality consistent evidence to support use of a particular technique. Because many aspects of the procedure are based on limited or no data, more studies on specific cesarean delivery techniques are clearly needed. Providers should be aware of which components of the cesarean delivery are evidence-based versus not when performing this procedure. PMID- 22926274 TI - The difficult patient: borderline personality disorder in the obstetrical and gynecological patient. AB - Some patients may present quite a challenge for the health care team-from the receptionist to the social worker to the nurse and to the physician. An understanding of personality disorders can be helpful for the provider working with a complicated or "difficult" patient. Borderline personality disorder is relatively common in patients presenting with a complicated medical and psychosocial picture. Recognizing borderline personality disorder allows providers to better tailor treatment goals and expectations, manage personal reactions, set effective boundaries, and avoid potential confrontations with the difficult patient. Using a clinical case vignette, this article discusses the prevalence, etiology, diagnosis, and management of borderline personality disorder in the obstetrical and gynecological patient. PMID- 22926275 TI - Abnormal placentation: evidence-based diagnosis and management of placenta previa, placenta accreta, and vasa previa. AB - Placenta previa, placenta accreta, and vasa previa cause significant maternal and perinatal morbidity and mortality. With the increasing incidence of both cesarean delivery and pregnancies using assisted reproductive technology, these 3 conditions are becoming more common. Advances in grayscale and Doppler ultrasound have facilitated prenatal diagnosis of abnormal placentation to allow the development of multidisciplinary management plans to achieve the best outcomes for mother and baby. We present a comprehensive review of the literature on abnormal placentation including an evidence-based approach to diagnosis and management. PMID- 22926276 TI - Massive pyoderma gangrenosum in a 77 year old female with Crohn's disease responsive to adalimumab. PMID- 22926277 TI - Unintentional injury in early childhood: its relationship with childcare setting and provider. AB - We hypothesized that young children cared for by non-parents outside of the home are at higher odds of injury compared to children cared for by parents at home. Data were obtained from the 2007 National Survey of Children's Health. Parent reported injury prevalence within the last 12 months for 1-5 year-olds was compared for children with different childcare providers and settings. Child age, gender, race/ethnicity, special healthcare needs, residence in a Metropolitan Statistical Area, region of United States (U.S.), and measures of poverty, family structure, and parent education were considered as covariates in logistic regression models. The prevalence of injury in the U.S. for children aged 1-5 is 11.9 %. Children who attend childcare centers >=10 h per week have a higher injury prevalence than those cared for by parents at home (13.9 vs. 10.4 % respectively, p < 0.05), but this differs by age. Among 1-year olds, the odds of injury is lower for those with care at a center compared to at home, but among 2 5 year olds, the OR is 1.37 (95 % CI 1.04, 1.80) for childcare center versus home care, after adjusting for covariates. The relationship between care at a center and unintentional injury appears stronger when no parent in the household has a high school degree. National data indicate that children aged 2-5 who attend childcare centers may be at increased odds of injury. Future population-based studies should capture the severity and context of the injury and characteristics of the childcare center to better define this relationship. PMID- 22926278 TI - Growing rods for the treatment of scoliosis in children with cerebral palsy: a critical assessment. AB - STUDY DESIGN: Retrospective analysis. OBJECTIVE: To evaluate, in children with cerebral palsy, the following aspects of growing rod (GR) treatment for scoliosis: structural effectiveness, effect of pelvic fixation, hospital stay duration, and complications. SUMMARY OF BACKGROUND DATA: Children with cerebral palsy frequently develop severe spinal deformity and pelvic obliquity (PO). Growth-preserving strategies are attractive, but comorbidities raise the risk/benefit ratio. To our knowledge, no previous studies have focused on growth preserving spine surgery in these children. METHODS: From our multicenter patient group, we identified 27 children with cerebral palsy treated with GRs (single rod in 4; dual rods in 23 [15 extending to the pelvis]). We collected radiographical, surgical, hospital stay, and major complication data. We compared Cobb angle and PO improvement between patients with and without pelvic instrumentation via the Student t test (significance, P = 0.05). No patient required anterior spinal fusion. RESULTS: Average improvements for all patients (preoperative to latest follow-up) were: Cobb angle, 35 degrees +/- 23 degrees ; PO, 14 degrees +/- 19 degrees ; T1-S1 length, 7.9 +/- 4.4 cm; and space available for lung ratio, 0.17 +/- 0.21. For the 8 patients who underwent fusion, average improvements (preoperative to postfusion) were: Cobb angle, 43 degrees +/- 28 degrees ; PO, 2 degrees +/- 21 degrees ; T1-S1 length, 9.5 +/- 6.0 cm; and space available for lung ratio, 0.26 +/- 0.28. Pelvic GR fixation produced better PO correction (P < 0.001) but similar Cobb angle correction (P = 0.556). Hospital stays averaged 8.7 +/- 12.1 days after initial surgery, 1.4 +/- 2.5 days after lengthening (45% were outpatient procedures), and 13.4 +/- 6.2 days after fusion. The most common complication was deep wound infection (30%). CONCLUSION: GRs via a posterior-only approach are effective. Constructs extending to the pelvis control PO more effectively. However, 30% of patients experienced deep wound infection. PMID- 22926279 TI - Specific trunk and general exercise elicit similar changes in anticipatory postural adjustments in patients with chronic low back pain: a randomized controlled trial. AB - STUDY DESIGN: A randomized controlled trial. OBJECTIVE: To compare changes in self-rated disability, pain, and anticipatory postural adjustments between specific trunk exercise and general exercise in patients with chronic low back pain. SUMMARY OF BACKGROUND DATA: Chronic low back pain is associated with altered motor control of the trunk muscles. The best exercise to address altered motor control is unclear. METHODS: Sixty-four patients with chronic low back pain were randomly assigned to a specific trunk exercise group (SEG) that included skilled cognitive activation of the trunk muscles in addition to a number of other best practice exercises, whereas the general exercise group performed only seated cycling exercise. The training program lasted for 8 weeks. Self-rated disability and pain scores were collected before and after the training period. Electromyographic activity of various trunk muscles was recorded during performance of a rapid shoulder flexion task before and after training. Muscle onsets were calculated, and the latency time (in ms) between the onset of each trunk muscle and the anterior deltoid formed the basis of the motor control analysis. RESULTS: After training, disability was significantly lower in the SEG (d = 0.62, P = 0.018). Pain was reduced in both groups after training (P < 0.05), but was lower for the SEG (P < 0.05). Despite the general exercise group performing no specific trunk exercise, similar changes in trunk muscle onsets were observed in both groups after training. CONCLUSION: SEG elicited significant reductions in self-rated disability and pain, whereas similar between-group changes in trunk muscle onsets were observed. The motor control adaptation seems to reflect a strategy of improved coordination between the trunk muscles with the unilateral shoulder movement. Trunk muscle onsets during rapid limb movement do not seem to be a valid mechanism of action for specific trunk exercise rehabilitation programs. PMID- 22926280 TI - Lower preoperative Hounsfield unit measurements are associated with adjacent segment fracture after spinal fusion. AB - STUDY DESIGN: Retrospective case-control study. OBJECTIVE: To determine the association of Hounsfield unit (HU) measurements with adjacent segment fractures after spinal fusion. SUMMARY OF BACKGROUND DATA: Adjacent segment fracture is a potentially devastating complication after spinal fusion surgery in osteoporotic patient. Recently, a technique for assessing bone mineral density using HU measurements from computed tomography was described and correlated with both dual energy x-ray absorptiometry-assessed bone mineral density and compressive strength in an osseous model. METHODS: Patients with adjacent segment fractures after spinal fusion were identified from a prospectively collected patient database and matched 1:1 with nonfracture controls on the basis of age, sex, and fusion construct. Minimum follow-up was 6 months. Patients with metabolic bone disease other than osteoporosis or those taking medications known to negatively alter bone strength were excluded. HU assessment was done according to the previously published protocol using the preoperative computed tomography. RESULTS: Twenty patients had complete imaging data and could be matched to nonfracture controls. The groups were well matched with respect to age, sex, body mass index, and number of levels fused. Following the index surgical procedure, the fracture group had more positive sagittal balance than the control group (10.7 cm vs. 9.1 cm). Analysis of HU values at the fracture level showed a significantly lower value in the fracture group than in the controls (145.6 vs. 199.4, P = 0.006). Similarly, global assessment of HU across the thoracic and lumbar spines was significantly lower in the fracture group (139.9 vs. 170.1, P = 0.032). CONCLUSION: HU was significantly lower both locally and globally in the fracture cohort. Because computed tomographic scans are frequently part of preoperative planning for spinal fusion, this information should be incorporated in preoperative planning. Studies to prospectively validate HU as a predictor of adjacent segment fracture risk and to assess the effect of increasing HU preoperatively with medications for osteoporosis are needed. LEVEL OF EVIDENCE: 3. PMID- 22926281 TI - Neuroprotective effects of hypothermia after spinal cord injury in rats: comparative study between epidural hypothermia and systemic hypothermia. AB - STUDY DESIGN: An experimental comparative study on moderate epidural hypothermia (MEH) versus moderate systemic hypothermia (MSH) after spinal cord injury (SCI). OBJECTIVE: To compare neuroprotective effects of hypothermia between MEH and MSH after SCI in rats. SUMMARY OF BACKGROUND DATA: Experimental MEH or MSH has been attempted for neuroprotection after ischemic or traumatic SCI. However, there is no comparative study on neuroprotective effect of MEH and MSH after SCI. If hypothermia is to be considered as 1 modality for treating SCI, further studies on the advantages and disadvantages of hypothermia will be mandatory. METHODS: A spinal cord contusion was produced in all 32 rats, and these rats were randomly divided into 4 groups-8 rats in each group: (1) the control group (spinal cord contusion only), (2) the methylprednisolone group, (3) the MEH group (28 degrees C for 48 hr), and (4) the MSH group (32 degrees C for 48 hr). The functional recovery was assessed using Basso, Beattie, Bresnahan scale and antiapoptotic and anti-inflammatory effects were assessed. RESULTS: The Basso, Beattie, Bresnahan scale scores in both the hypothermia groups were significantly higher than that in the control group at 6 weeks. The numbers of terminal deoxynucleotidyl transferase dUTP nick end labeling-positive cells and OX-42 positive cells were significantly lower in both the MEH and MSH groups than that in the control group. The p38 mitogen-activated protein kinases expression of the treated groups was significantly lower than that of the control group. The expression of caspase 8 and caspase-9 significantly decreased in the treated groups compared with that of the control group. However, in terms of caspase-3, only the MSH group has shown to be significantly lower than that of the control group. CONCLUSION: This study presented that both systemic and epidural hypothermia demonstrated neuroprotective effects after SCI. Systemic hypothermia showed more neuroprotective effect by antiapoptotic and anti-inflammatory effects. PMID- 22926282 TI - Breast cancer in South East Asia: comparison of presentation and outcome between a middle income and a high income country. AB - BACKGROUND: There are large differences in socio-economic growth within the region of South East Asia, leading to sharp contrasts in health-systems development between countries. This study compares breast cancer presentation and outcome between patients from a high income country (Singapore) and a middle income country (Malaysia) in South East Asia. METHODS: Within the Singapore Malaysia Breast Cancer Registry we identified all consecutive patients diagnosed with breast cancer between 1993 and 2007 at the National University Hospital in Singapore (high income country, n=2,141) and the University of Malaya Medical Center in Kuala Lumpur, Malaysia (middle income country, n=3,320). We compared demographics, tumor characteristics, treatment patterns, and survival between patients from both countries. RESULTS: In Malaysia, patients were less often diagnosed with in situ breast cancer (adjusted odds ratio [ORadj] 0.2; 95% confidence interval [95% CI] 0.1-0.3), more likely to be diagnosed with late stage (III and IV) disease (ORadj for stage III 1.6; 95% CI 1.3-2.0; ORadj for stage IV 1.2; 95% CI 1.1-1.4) as compared to patients from Singapore. Univariate analysis showed that Malaysian patients were at a 72% increased risk of death as compared to Singaporeans. After adjusting for other prognostic factors, the risk decreased by only 5% (ORadj 1.67, 95% CI 1.44-1.92). CONCLUSIONS: Differences in way of presentation (except stage and tumor size) and treatment of breast cancer patients from the two countries are small. The overall survival of breast cancer patients from Malaysia is much lower than that of Singaporean patients. PMID- 22926283 TI - Hyperfractionated irradiation with 3 cycles of induction chemotherapy in stage IIIA-N2 lung cancer. AB - BACKGROUND: The purpose of the present study was to improve the prognosis of patients with stage IIIA-N2 non-small cell lung cancer (NSCLC). To achieve that goal, we performed induction chemoradiotherapy followed by surgery. METHODS: The criteria for this phase II study were <=75-year-old patients with pathologically diagnosed stage IIIA-N2 NSCLC who had performance statuses of 0 or 1 with good organ function. Three cycles of chemotherapy with paclitaxel and carboplatin were carried out, with concurrent hyperfractionated irradiation (42 Gy). After re evaluation, pulmonary resections were considered unless patients showed progressive disease. The primary endpoint was overall survival (OS), and the secondary endpoints were disease-free survival (DFS) and absence of toxicity. RESULTS: All 22 patients enrolled in this study completed the induction chemoradiotherapy without any severe complications. In these 22 patients, the 2- and 5-year OS were 81 and 47%, respectively. There were no therapy-related deaths. Surgery was subsequently performed in 19 patients (86%). Pathological complete responses were seen in 6 patients (27%), while node downstaging was obtained in 10 patients (45%). In the 19 patients who underwent surgery, the 2- and 5-year OS rates were 83 and 62%, respectively, and the 2-year DFS rate was 63%. All 6 patients with pathological complete responses survived without disease. Patients with residual multiple-station N2 showed worse OS and DFS rates than did those with downstaged and single-station N2 (P=0.026 and P<0.0001, respectively). CONCLUSIONS: This trimodal therapy was effective and well tolerated, and it is an acceptable therapeutic option for patients with locally advanced stage IIIA-N2 NSCLC. Patients without persistent multiple-station N2 showed promising survival. PMID- 22926284 TI - Tracer-based source apportionment of polycyclic aromatic hydrocarbons in PM2.5 in Guangzhou, southern China, using positive matrix factorization (PMF). AB - From 28 November to 23 December 2009, 24-h PM2.5 samples were collected simultaneously at six sites in Guangzhou. Concentrations of 18 polycyclic aromatic hydrocarbons (PAHs) together with certain molecular tracers for vehicular emissions (i.e., hopanes and elemental carbon), coal combustion (i.e., picene), and biomass burning (i.e., levoglucosan) were determined. Positive matrix factorization (PMF) receptor model combined with tracer data was applied to explore the source contributions to PAHs. Three sources were identified by both inspecting the dominant tracer(s) in each factor and comparing source profiles derived from PMF with determined profiles in Guangzhou or in the Pearl River Delta region. The three sources identified were vehicular emissions (VE), biomass burning (BB), and coal combustion (CC), accounting for 11 +/- 2%, 31 +/- 4%, and 58 +/- 4% of the total PAHs, respectively. CC replaced VE to become the most important source of PAHs in Guangzhou, reflecting the effective control of VE in recent years. The three sources had different contributions to PAHs with different ring sizes, with higher BB contributions (75 +/- 3%) to four-ring PAHs such as pyrene and higher CC contributions (57 +/- 4%) to six-ring PAHs such as benzo[ghi]perylene. Temporal variations of VE and CC contributions were probably caused by the change of weather conditions, while temporal variations of BB contributions were additionally influenced by the fluctuation of BB emissions. Source contributions also showed some spatial variations, probably due to the source emission variations near the sampling sites. PMID- 22926286 TI - Can travellers avoid bed bug bites? PMID- 22926287 TI - A voxel-based morphometry study of gray and white matter correlates of a need for uniqueness. AB - People appear to derive intrinsic satisfaction from the perception that they are unique, special, and separable from the masses, which is referred to as a need for uniqueness (NFU). NFU is a universal human trait, along with a tendency to conform to the beliefs and attitudes of others and social norms. We used voxel based morphometry and a questionnaire to determine individual NFU and its association with brain structures in healthy men (94) and women (91; age, 21.3 +/ 1.9 years). Individual NFU was associated with smaller gray matter volume of a cluster that included areas in (a) the left middle temporal gyrus, left superior temporal gyrus, and left superior temporal sulcus (STS); (b) the dorsal part of the anterior cingulate gyrus and the anterior part of the middle cingulate gyrus; and (c) the right inferior frontal gyrus and the ventral part of the precentral gyrus. Individual NFU was also associated with larger white matter concentration of a cluster that mainly included the body of the corpus callosum. These findings demonstrated that variations in NFU reflect the gray and white matter structures of focal regions. These findings suggest a biological basis for individual NFU, distributed across different gray and white matter areas of the brain. PMID- 22926285 TI - An anti-inflammatory role for leukemia inhibitory factor receptor signaling in regenerating skeletal muscle. AB - Skeletal muscle regeneration in pathology and following injury requires the coordinated actions of inflammatory cells and myogenic cells to remove damaged tissue and rebuild syncytial muscle cells, respectively. Following contusion injury to muscle, the cytokine leukemia inhibitor factor (LIF) is up-regulated and knockout of Lif negatively impacts on morphometric parameters of muscle regeneration. Although it was speculated that LIF regulates muscle regeneration through direct effects on myogenic cells, the inflammatory effects of LIF have not been examined in regenerating skeletal muscle. Therefore, the expression and function of LIF was examined using the antagonist MH35-BD during specific inflammatory and myogenic stages of notexin-induced muscle regeneration in mice. LIF protein and mRNA were up-regulated in two distinct phases following intramuscular injection of notexin into tibialis anterior muscles. The first phase of LIF up-regulation coincided with the increased expression of pro inflammatory cytokines; the second phase coincided with myogenic differentiation and formation of new myotubes. Administration of the LIF receptor antagonist MH35 BD during the second phase of LIF up-regulation had no significant effects on transcript expression of genes required for myogenic differentiation or associated with inflammation; there were no significant differences in morphometric parameters of the regenerating muscle. Conversely, when MH35-BD was administered during the acute inflammatory phase, increased gene transcripts for the pro-inflammatory cytokines Tnf (Tumor necrosis factor), Il1b (Interleukin 1beta) and Il6 (Interleukin-6) alongside an increase in the number of Ly6G positive neutrophils infiltrating the muscle were observed. This was followed by a reduction in Myog (Myogenin) mRNA, which is required for myogenic differentiation, and the subsequent number of myotubes formed was significantly decreased in MH35-BD-treated groups compared to sham. Thus, antagonism of the LIF receptor during the inflammatory phase of skeletal muscle regeneration appeared to induce an inflammatory response that inhibited subsequent myotube formation. We propose that the predominant role of LIF in skeletal muscle regeneration appears to be in regulating the inflammatory response rather than directly effecting myogenic cells. PMID- 22926288 TI - Effect of the proline-rich polypeptide complex/colostrininTM on the enzymatic antioxidant system. AB - Proline-rich polypeptide complex (PRP) and its constituent nonapeptide (NP) possess immunoregulatory and procognitive properties. PRP in the form of sublingually administered tablets called ColostrininTM improves the outcome of patients with Alzheimer's disease (AD). Free radical-induced oxidative stress has been implicated in the pathogenesis of AD. It has been previously shown that PRP and NP inhibit overproduction of reactive oxygen species, nitric oxide and proinflammatory cytokines induced by lipopolysaccharide or PMA. Antioxidant defense includes both low molecular weight components and enzymatic systems including dismutases, catalase, glutathione reductase (GSSGR) and glutathione peroxidase (GSHPx). An early event during the development of AD is lipid and protein peroxidation. PRP and NP showed no modulatory effect on lipid peroxidation. A protective effect on protein oxidation was found only when high doses of NP were used. We have previously shown, in a model of human peripheral blood mononuclear cells, that PRP/NP affects activities of superoxide dismutase and NF-kappaB. In the present study with the use of the same cell model and whole blood cells we observed an activatory effect of PRP/NP on GSHPx and GSSGR activity but not catalase. The observed effect suggests that PRP/NP can act as a modulatory agent of the "first line" of antioxidant defense. It can be assumed therefore that PRP/Colostrinin by regulation of the early phase of the redox system does not reduce but rather prevents oxidative damage. This effect may shed some light on the beneficial effect of PRP/Colostrinin in AD patients. PMID- 22926289 TI - Naftopidil and tolterodine in the medical expulsive therapy for intramural ureteral stones: a prospective randomized study. AB - We performed a randomized, prospective study to assess the possible role of combined naftopidil and tolterodine for facilitating the spontaneous expulsion of intramural ureteral stones. A total of 76 patients with intramural ureter stones were included in the study from December 2007 to February 2011. Patients were randomized to one of three treatment groups. Group A patients received naftopidil 25 mg/day, group B patients received naftopidil 25 mg/day plus tolterodine 2 mg (twice a day), and group C patients received tolterodine 2 mg (twice a day). Both groups were followed up for 2 weeks. The stone expulsion rate and time and the number of pain episodes were obtained. Subjects rated the urgency associated with each micturition using the Urinary Sensation Scale (USS). Pain descriptions were recorded by the patients using the visual analog scale (VAS). A significant difference was shown for the expulsion rate between the group C and the other two groups (P < 0.001 by log rank test). In groups A, B and C, the mean number of pain episodes was 2.25 +/- 0.90, 1.38 +/- 1.37 and 1.54 +/- 1.18, respectively. The USS score for groups A, B and C at 3 days was 2.32 +/- 0.55, 1.4 +/- 0.58 and 1.34 +/- 0.49, respectively. It was 1.75 +/- 0.44, 1.2 +/- 0.41 and 1.22 +/- 0.42, respectively, at 7 days. On the other hand, a statistically significant difference was found between groups A and B, and groups A and C in relation to the visual analog scale score on days 3 and 7, respectively. Treatment with naftopidil and tolterodine appears to be beneficial in intramural ureteral stones clearance, particularly in the intramural ureter with symptoms of vesical irritability. PMID- 22926290 TI - Mitochondria in relation to cancer metastasis: introduction to a mini-review series. AB - This introductory article and those that follow focus on the roles that mitochondria may have in cancer metastasis (spreading) that all too frequently leads to death of cancer patients. The history of cancer dates back in time to several thousand years BC and continues to this day. Although billions of dollars have been invested, numerous cancer researchers/scientists and oncologist located at universities, hospitals, cancer centers, commercial entities (companies), and government agencies have been unable to discover "magic bullets" to quickly silence most cancers. That is, agents that are effective not only in eradicating the primary tumor at its site of origin, but eradicating also distant tumors that have arisen therefrom via metastatic cells. Fortunately, in recent years some researchers have obtained evidence that the mitochondria of cancer cells are involved not only in providing in part the necessary energy (ATP) to fuel their growth, but hold the secrets to their immortality, and propensity to metastasize (spread) from their original site of origin to other body locations. This introductory article, as well as those that follow, focus on the possible roles of mitochondria in cancer metastasis as well as strategies to arrest cancer metastasis based on this knowledge. Ideally, for a patient to become "cancer free" the anticancer agent/agents used must 1) eradicate the primary tumor at its site of origin, 2) eradicate any tumors at other body locations that have arisen via metastasis, and 3) eradicate any tumor cells that remain in the blood, i.e., circulating tumor cells. One such agent that holds promise for doing all three is the small molecule 3-bromopyruvate (3BP) discovered in the author's laboratory by Dr. Young H. Ko near the turn of the century to be a potent anti-cancer agent [Ko et al.(2001) Can Lett 173:83-91]. PMID- 22926291 TI - Mapping of QTL for Fusarium head blight resistance and morphological and developmental traits in three backcross populations derived from Triticum dicoccum * Triticum durum. AB - Breeding for resistance to Fusarium head blight (FHB) in durum wheat continues to be hindered by the lack of effective resistance sources. Only limited information is available on resistance QTL for FHB in tetraploid wheat. In this study, resistance to FHB of a Triticum dicoccum line in the background of three Austrian T. durum cultivars was genetically characterized. Three populations of BC(1)F(4) derived RILs were developed from crosses between the resistant donor line T. dicoccum-161 and the Austrian T. durum recipient varieties DS-131621, Floradur and Helidur. About 130 BC(1)F(4)-derived lines per population were evaluated for FHB response using artificial spray inoculation in four field experiments during two seasons. Lines were genetically fingerprinted using SSR and AFLP markers. Genomic regions on chromosomes 3B, 4B, 6A, 6B and 7B were significantly associated with FHB severity. FHB resistance QTL on 6B and 7B were identified in two populations and a resistance QTL on 4B appeared in three populations. The alleles that enhanced FHB resistance were derived from the T. dicoccum parent, except for the QTL on chromosome 3B. All QTL except the QTL on 6A mapped to genomic regions where QTL for FHB have previously been reported in hexaploid wheat. QTL on 3B and 6B coincided with Fhb1 and Fhb2, respectively. This implies that tetraploid and hexaploid wheat share common genomic regions associated with FHB resistance. QTL for FHB resistance on 4B co-located with a major QTL for plant height and mapped at the position of the Rht-B1 gene, while QTL on 7B overlapped with QTL for flowering time. PMID- 22926292 TI - An improved framework for confound regression and filtering for control of motion artifact in the preprocessing of resting-state functional connectivity data. AB - Several recent reports in large, independent samples have demonstrated the influence of motion artifact on resting-state functional connectivity MRI (rsfc MRI). Standard rsfc-MRI preprocessing typically includes regression of confounding signals and band-pass filtering. However, substantial heterogeneity exists in how these techniques are implemented across studies, and no prior study has examined the effect of differing approaches for the control of motion-induced artifacts. To better understand how in-scanner head motion affects rsfc-MRI data, we describe the spatial, temporal, and spectral characteristics of motion artifacts in a sample of 348 adolescents. Analyses utilize a novel approach for describing head motion on a voxelwise basis. Next, we systematically evaluate the efficacy of a range of confound regression and filtering techniques for the control of motion-induced artifacts. Results reveal that the effectiveness of preprocessing procedures on the control of motion is heterogeneous, and that improved preprocessing provides a substantial benefit beyond typical procedures. These results demonstrate that the effect of motion on rsfc-MRI can be substantially attenuated through improved preprocessing procedures, but not completely removed. PMID- 22926294 TI - Unicompartmental knee arthroplasty modes of failure: wear is not the main reason for failure: a multicentre study of 418 failed knees. AB - BACKGROUND: This study originated from a symposium held by the French Hip and Knee Society (Societe francaise de la hanche et du genou [SFHG]) and was carried out to better assess the distribution of causes of unicompartmental knee arthroplasty (UKA) failures, as well as cause-specific delay to onset. HYPOTHESIS: Our working hypothesis was that most failures were traceable to wear occurring over a period of many years. MATERIALS AND METHODS: A multicentre retrospective study (25 centres) was conducted in 418 failed UKAs performed between 1978 and 2009. We determined the prevalence and time to onset of the main reasons for revision surgery based upon available preoperative findings. Additional intraoperative findings were analysed. The results were compared to those of nation wide registries to evaluate the representativeness of our study population. RESULTS: Times to revision surgery were short: 19% of revisions occurred within the first year and 48.5% within the first 5 years. Loosening was the main reason for failure (45%), followed by osteoarthritis progression (15%) and, finally, by wear (12%). Other reasons were technical problems in 11.5% of cases, unexplained pain in 5.5%, and failure of the supporting bone in 3.6%. The infection rate was 1.9%. Our results were consistent with those of Swedish and Australian registries. DISCUSSION: Our hypothesis was not confirmed. The short time to failure in most cases suggests a major role for surgical technique issues. Morbidity related to the implant per se may be seen as moderate and not greater than with total knee prostheses. The good agreement between our data and those of nationwide registries indicates that our population was representative. A finer analysis is needed, indicating that the establishment of a French registry would be of interest. PMID- 22926293 TI - Optimization of PET-MR registrations for nonhuman primates using mutual information measures: a Multi-Transform Method (MTM). AB - An important step in PET brain kinetic analysis is the registration of functional data to an anatomical MR image. Typically, PET-MR registrations in nonhuman primate neuroreceptor studies used PET images acquired early post-injection, (e.g., 0-10 min) to closely resemble the subject's MR image. However, a substantial fraction of these registrations (~25%) fail due to the differences in kinetics and distribution for various radiotracer studies and conditions (e.g., blocking studies). The Multi-Transform Method (MTM) was developed to improve the success of registrations between PET and MR images. Two algorithms were evaluated, MTM-I and MTM-II. The approach involves creating multiple transformations by registering PET images of different time intervals, from a dynamic study, to a single reference (i.e., MR image) (MTM-I) or to multiple reference images (i.e., MR and PET images pre-registered to the MR) (MTM-II). Normalized mutual information was used to compute similarity between the transformed PET images and the reference image(s) to choose the optimal transformation. This final transformation is used to map the dynamic dataset into the animal's anatomical MR space, required for kinetic analysis. The chosen transforms from MTM-I and MTM-II were evaluated using visual rating scores to assess the quality of spatial alignment between the resliced PET and reference images. One hundred twenty PET datasets involving eleven different tracers from 3 different scanners were used to evaluate the MTM algorithms. Studies were performed with baboons and rhesus monkeys on the HR+, HRRT, and Focus-220. Successful transformations increased from 77.5%, 85.8%, to 96.7% using the 0-10 min method, MTM-I, and MTM-II, respectively, based on visual rating scores. The Multi-Transform Methods proved to be a robust technique for PET-MR registrations for a wide range of PET studies. PMID- 22926295 TI - Surgical technique for repair of acute proximal hamstring tears. AB - The surgical technique for repair of acute proximal hamstring tears is relatively recent. Installation of the patient is critical. The approach is either vertical under the gluteal fold in case of a complete tear with tendon retraction of more than 6 cm, or horizontal in the gluteal fold for retraction of less than 6 cm or for partial tears. After identification and neurolysis of the sciatic nerve, transosseous tendon reinsertion is performed with three or four metal or resorbable suture anchors. A rigid brace keeping the leg at 30 degrees of flexion is worn for few days, then replaced by an articulated knee brace for 45 days, which limits extension but allows full flexion. Rehabilitation is begun early. Thirty-four patients underwent surgery for acute proximal hamstring tear and received this treatment. All of the athletic patients were able to return to their pre-injury activities after a mean 5.7 +/- 1.6 months (2.3-9.3 months). PMID- 22926296 TI - Proximal hamstring avulsion in a professional soccer player. AB - Acute hamstring strains are a common athletic injury, which may be treated non operatively with a satisfactory outcome. A complete proximal hamstring avulsion is a rare and potentially career ending injury to an elite athlete. For these high demand patients, surgical reattachment should be immediately undertaken to shorten return to sport and to improve functional outcome. This report describes the occurrence of a complete avulsion of the proximal hamstrings in a professional footballer during an international match. We highlight the clinical presentation, the appropriate diagnostic investigations, the surgical technique and the rehabilitation protocol for this injury. The successful surgical reattachment of the common hamstring tendon was confirmed by magnetic resonance imaging done 5 months after repair and allowed the player a full return to competition at 6 months after surgery. Hamstrings isokinetic peak torque was 80% at 6 months and 106% at 11 months after repair comparing with the uninjured side. PMID- 22926297 TI - TRFLP analysis reveals that fungi rather than bacteria are associated with premature yeast flocculation in brewing. AB - Premature yeast flocculation (PYF) is a sporadic fermentation problem in the brewing industry that results in incomplete yeast utilization of fermentable sugars in wort. Culture-independent, PCR-based fingerprinting techniques were applied in this study to identify the associations between the occurrence of the PYF problem during brewery fermentation with barley malt-associated microbial communities (both bacteria and fungi). Striking differences in the microbial DNA fingerprint patterns for fungi between PYF positive (PYF +ve) and negative (PYF ve) barley malts were observed using the terminal restriction fragment length polymorphism (TRFLP) technique. The presence of terminal restriction fragments (TRFs) of 360-460 bp size range, for fungal HaeIII restriction enzyme-derived TRFLP profiles appeared to vary substantially between PYF +ve and PYF -ve samples. The source of the barley malt did not influence the fungal taxa implicated in PYF. TRFLP analysis indicates bacterial taxa are unlikely to be important in causing PYF. Virtual digestion of fungal sequences tentatively linked HaeIII TRFs in the 360-460 bp size range to a diverse range of yeast/yeast like species. Findings from this study suggest that direct monitoring of barley malt samples using molecular methods could potentially be an efficient and viable alternative for monitoring PYF during brewery fermentations. PMID- 22926298 TI - Antidepressive effects of the kappa-opioid receptor agonist salvinorin A in a rat model of anhedonia. AB - Salvinorin A (SalvA), the hallucinogenic derivative of the plant Salvia divinorum, is a selective kappa-opioid receptor agonist that may also have antidepressant properties. Chronic mild stress (CMS) was applied to male and female Long-Evans rats to model anhedonia common in depression. The progressive loss in preference for a sucrose solution over plain water, a measure of anhedonia, and locomotor activity were monitored for 7 weeks. Because antidepressant medications often modify reproductive functions, endocrine glands and hormone-sensitive tissues were assessed at necropsy after the conclusion of the behavioral protocol. Three weeks of CMS exposure led to a decrease in sucrose preference. CMS was continued for 3 additional weeks and animals were randomly assigned to treatment with 1 mg SalvA/kg body weight or to a vehicle control group. The results indicate that SalvA reversed anhedonia whereas control animals continued to show a suppressed preference for the sucrose solution. In addition, no change in sucrose preference was observed in nonstressed rats that were exposed to the same dosage of SalvA. The results indicate that SalvA is an effective antidepressant agent when administered chronically to rats showing symptoms of depression similar to those observed in humans. PMID- 22926299 TI - Gallbladder cancer, a vanishing disease? AB - OBJECTIVE: Gallbladder cancer (GBC) is a rare gastrointestinal malignancy. A retrospective population-based study was conducted to evaluate trends in incidence, treatment, and outcome of GBC in the latter three decades in the south of the Netherlands. METHODS: All patients diagnosed with GBC diagnosed in the Dutch Eindhoven Cancer Registry area between 1975 and 2008 were included (n = 659). Trend analyses were conducted for treatment and survival. RESULTS: During this time period, standardized incidence in females and males plummeted from 4.5 to 0.7 and from 2.0 to 0.4 per 100,000 inhabitants, respectively. Resection rates decreased from 74.3 to 53.4 %. Chemotherapy and radiotherapy rates did not change and were used sparingly. Five-year survival remained stable (10 %) over time. CONCLUSION: The age-standardized incidence of GBC declined drastically over the last three decades. An increasing number of early cholecystectomies for gallstones may play a role. Parallel to the decreasing incidence of stomach cancer, the effective treatment of Helicobacter pylori may also have resulted in a lowered incidence of GBC. PMID- 22926300 TI - Serum estrogen and SHBG levels and breast cancer incidence among users and never users of hormone replacement therapy. AB - OBJECTIVE: Levels of endogenous estrogen and SHBG are associated with risk of breast cancer among women who have never used hormone replacement therapy (HRT). We investigated these associations in both never and baseline users of HRT. METHODS: A nested case-control study was conducted within the prospective Danish population-based 'Diet, Cancer, and Health' cohort. During follow-up, 348 eligible cases were identified among 20,861 postmenopausal women and matched to 348 controls. Baseline serum samples were analyzed for estradiol, bioavailable estradiol, estrone, estrone sulfate, and SHBG. Conditional logistic regression yielded incidence rate ratios and 95 % confidence intervals for exposures analyzed continuously and categorically in models adjusted for potential confounders. RESULTS: Modest direct associations were identified between estrogen levels and breast cancer incidence among both never and baseline HRT users. Estrone and estrone sulfate were more consistently associated among both groups than estradiol. No association was found with SHBG. CONCLUSION: Despite different hormonal profiles, higher serum estrogen levels were associated with a higher risk of breast cancer among both never and baseline HRT users. More studies are needed to support the findings for HRT users and to further investigate estrogen levels in relation to estrogen receptor-specific breast cancer and other histological and molecular subtypes. PMID- 22926301 TI - Associations of circulating retinol, vitamin E, and 1,25-dihydroxyvitamin D with prostate cancer diagnosis, stage, and grade. AB - PURPOSE: Some epidemiological studies suggest that vitamin A (retinol), vitamin E, and vitamin D (total 25-hydroxyvitamin D, 25(OH)D; 1,25-dihydroxyvitamin, 1,25(OH)(2)D) are protective against prostate cancer. However, the evidence is not conclusive, with positive and null associations reported for all three vitamins. Limitations of previous studies include small sample size, lack of population controls, and reliance on self-reported dietary intake. Few studies have explored the interactions of circulating 25(OH)D with 1,25(OH)(2)D or retinol, which are biologically plausible interactions. METHODS: We investigated the associations of circulating retinol, vitamin E, and 1,25(OH)(2)D with PSA detected prostate cancer risk, stage, and grade in a case-control study nested within the Prostate Testing for Cancer and Treatment (ProtecT) trial. We investigated the possibility of an interaction between 25(OH)D and 1,25(OH)(2)D and whether the previously observed association between 25(OH)D and prostate cancer may be modified by retinol levels. RESULTS: We included 1,433 prostate cancer cases and 1,433 healthy controls. There was no evidence of associations of circulating retinol, vitamin E, or 1,25(OH)(2)D with overall prostate cancer risk, stage (advanced vs localized), or Gleason grade (high- (>=7) vs low (<7) grade). There was no evidence of an interaction of 1,25(OH)(2)D and 25(OH)D with prostate cancer risk, stage, or grade (p interaction >= 0.24). The association between 25(OH)D and prostate cancer did not differ by retinol level (p interaction = 0.34). CONCLUSIONS: We found no evidence that retinol, vitamin E, or 1,25(OH)(2)D concentrations were associated with overall prostate cancer risk or more aggressive prostate cancer phenotypes. There was no evidence of an interaction between 25(OH)D and 1,25(OH)(2)D or retinol. PMID- 22926302 TI - CT-guided bipolar and multipolar radiofrequency ablation (RF ablation) of renal cell carcinoma: specific technical aspects and clinical results. AB - PURPOSE: This study was designed to evaluate the clinical efficacy of CT-guided bipolar and multipolar radiofrequency ablation (RF ablation) of renal cell carcinoma (RCC) and to analyze specific technical aspects between both technologies. METHODS: We included 22 consecutive patients (3 women; age 74.2 +/- 8.6 years) after 28 CT-guided bipolar or multipolar RF ablations of 28 RCCs (diameter 2.5 +/- 0.8 cm). Procedures were performed with a commercially available RF system (Celon AG Olympus, Berlin, Germany). Technical aspects of RF ablation procedures (ablation mode [bipolar or multipolar], number of applicators and ablation cycles, overall ablation time and deployed energy, and technical success rate) were analyzed. Clinical results (local recurrence-free survival and local tumor control rate, renal function [glomerular filtration rate (GFR)]) and complication rates were evaluated. RESULTS: Bipolar RF ablation was performed in 12 procedures and multipolar RF ablation in 16 procedures (2 applicators in 14 procedures and 3 applicators in 2 procedures). One ablation cycle was performed in 15 procedures and two ablation cycles in 13 procedures. Overall ablation time and deployed energy were 35.0 +/- 13.6 min and 43.7 +/- 17.9 kJ. Technical success rate was 100 %. Major and minor complication rates were 4 and 14 %. At an imaging follow-up of 15.2 +/- 8.8 months, local recurrence-free survival was 14.4 +/- 8.8 months and local tumor control rate was 93 %. GFR did not deteriorate after RF ablation (50.8 +/- 16.6 ml/min/1.73 m(2) before RF ablation vs. 47.2 +/- 11.9 ml/min/1.73 m(2) after RF ablation; not significant). CONCLUSIONS: CT-guided bipolar and multipolar RF ablation of RCC has a high rate of clinical success and low complication rates. At short-term follow-up, clinical efficacy is high without deterioration of the renal function. PMID- 22926303 TI - Synthetic approaches and pharmacological activity of 1,3,4-oxadiazoles: a review of the literature from 2000-2012. AB - This review provides readers with an overview of the main synthetic methodologies for 1,3,4-oxadiazole derivatives, and of their broad spectrum of pharmacological activities as reported over the past twelve years. PMID- 22926304 TI - Chemical composition of essential oil from Italian populations of Artemisia alba Turra (Asteraceae). AB - The use of essential oils as chemotaxonomic markers could be useful for the classification of Artemisia species and to caracterize biodiversity in the different populations. An analysis of the chemical composition of four essential oils from Italian populations of Artemisia alba Turra (collected in Sicily, Marche and Abruzzo) was investigated. In this paper an in depth study of the significant differences observed in the composition of these oils is reported. PMID- 22926305 TI - Identification and determination of Aconitum alkaloids in Aconitum herbs and Xiaohuoluo pill using UPLC-ESI-MS. AB - A rapid, specific, and sensitive ultra-performance liquid chromatography electrospray ionization-mass spectrometry (UPLC-ESI-MS) method to examine the chemical differences between Aconitum herbs and processed products has been developed and validated. Combined with chemometrics analysis of principal component analysis (PCA) and orthogonal projection to latent structural discriminate analysis, diester-diterpenoid and monoester-type alkaloids, especially the five alkaloids which contributed to the chemical distinction between Aconitum herbs and processed products, namely mesaconitine (MA), aconitine (AC), hypaconitine (HA), benzoylmesaconitine (BMA), and benzoylhypaconitine (BHA), were picked out. Further, the five alkaloids and benzoylaconitine (BAC) have been simultaneously determined in the Xiaohuoluo pill. Chromatographic separations were achieved on a C18 column and peaks were detected by mass spectrometry in positive ion mode and selected ion recording (SIR) mode. In quantitative analysis, the six alkaloids showed good regression, (r) > 0.9984, within the test ranges. The lower limit quantifications (LLOQs) for MA, AC, HA, BMA, BAC, and BHA were 1.41, 1.20, 1.92, 4.28, 1.99 and 2.02 ng.mL-1, respectively. Recoveries ranged from 99.7% to 101.7%. The validated method was applied successfully in the analysis of the six alkaloids from different samples, in which significant variations were revealed. Results indicated that the developed assay can be used as an appropriate quality control assay for Xiaohuoluo pill and other herbal preparations containing Aconitum roots. PMID- 22926306 TI - The effect of camphor and borneol on rat thymocyte viability and oxidative stress. AB - Camphor and borneol are wildly distributed in the essential oils of medicinal plants from various parts of the World. Our study has been carried out to evaluate the effect of these two bicyclic monoterpenes on rat thymocytes. Camphor and borneol at concentrations of 0.5 and 5 ug/mL did not induce significant toxicity on the immune system cells, while a significant increase of thymocyte viability was detected when cells were incubated with 50 ug/mL of camphor. A significant increase of cell viability was similarly detected when thymocytes were cultivated with borneol at concentrations of 0.5 and 5 ug/mL. The role of camphor and borneol in reactive oxygen species (ROS) production and mitochondrial membrane potential (MMP) disturbances in rat thymocytes as well as their potential mechanism(s) of action were also discussed. PMID- 22926307 TI - Evaluation of in vivo antioxidant and immunity enhancing activities of sodium aescinate injection liquid. AB - Oxidative stress is involved in the development and progression of disease. Because sodium aescinate has been reported to have immunity enhancing and antioxidative effects, we investigated its activity by employing a hepatocellular carcinoma (HCC) mouse model. Sixty BALB/c mice were randomly divided into four groups, including a 1.4 mg/kg treated group (n = 15), a 2.8 mg/kg treated group (n = 15), an untreated hepatocellular carcinoma control group (n = 15) and a normal control group (n = 15). After H22 cells were cultured for one week, we collected 2 * 106 cells and injected them subcutaneously as 0.2 mL cell suspensions in sterile saline into the right shoulder region of every mouse. The animals were monitored for changes in activity, physical condition and body weight during the experiment. The next day after injection of H22 cells, animals in these test groups received one intraperitoneal injection of drug or physiological saline for 13 days. Results showed that in the sodium aescinate injection liquid (SAIL)-treated HCC mice, serum interleukin-1 beta (IL-1beta), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), interferon-gamma (IFN-gamma), Gamma-glutamyltransferase (gamma-GT), alanine transaminase (ALT), aspartate transaminase (AST) and alkaline phosphatase (ALP) levels were significantly decreased compared with normal control mice. In addition, treatment with sodium aescinate injection liquid significantly decreased blood and liver malondialdehyde (MDA) levels, increased glutathione (GSH) levels, and antioxidant enzyme [superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GSH-Px)] activities in a dose-dependent manner. We conclude that sodium aescinate injection liquid can decrease oxidative injury and enhance immunity functions in HCC mice. PMID- 22926308 TI - Increased metal concentrations in giant sungazer lizards (Smaug giganteus) from mining areas in South Africa. AB - Environmental contaminants from anthropogenic activity such as mining can have profound health effects on the animals living in adjacent areas. We investigated whether inorganic contaminants associated with gold-mining waste discharges were accumulated by a threatened species of lizard, Smaug giganteus, in South Africa. Lizards were sampled from two mining sites and two control sites. Blood samples from the most contaminated mining site had significantly greater concentrations of lithium, sodium, aluminum, sulfur, silicon, chromium, manganese, iron, nickel, copper, tungsten, and bismuth than the remaining sites. Contaminant concentrations were not significantly related to lizard body condition, although these relationships were consistently negative. The adult sex ratio of the population inhabiting the most contaminated site also deviated from an expected 1:1 ratio in favour of female lizards. We demonstrate that lizards at these mining sites contained high concentrations of heavy metals that may be imposing as yet poorly understood costs to these lizards. PMID- 22926309 TI - Identification of quantitative trait loci in rye introgression lines carrying multiple donor chromosome segments. AB - Introgression libraries can be used to make favorable genetic variation of exotic donor genotypes available in the genetic background of elite breeding material. Our objective was to employ a combination of the Dunnett test and a linear model analysis to identify favorable donor alleles in introgression lines (ILs) that carry long or multiple donor chromosome segments (DCS). We reanalyzed a dataset of two rye introgression libraries that consisted of ILs carrying on average about four donor segments. After identifying ILs that had a significantly better per se or testcross performance than the recipient line with the Dunnett test, the linear model analysis was in most instances able to clearly identify the donor regions that were responsible for the superior performance. The precise localization of the favorable DCS allowed a detailed analysis of pleiotropic effects and the study of the consistency of effects for per se and testcross performance. We conclude that in many cases the linear model analysis allows the assignment of donor effects to individual DCS even for ILs with long or multiple donor segments. This may considerably increase the efficiency of producing sub ILs, because only such segments need to be isolated that are known to have a significant effect on the phenotype. PMID- 22926310 TI - Molecular phylogenetics of Oestroidea (Diptera: Calyptratae) with emphasis on Calliphoridae: insights into the inter-familial relationships and additional evidence for paraphyly among blowflies. AB - The superfamily Oestroidea, comprising ~15,000 species, is a large and ecologically diverse clade within the order Diptera. Among its six commonly recognized families, Calliphoridae seems to be crucial for understanding evolutionary relationships in the group, as it is recognized as a controversial paraphyletic grouping. To further investigate this matter, the ITS2, 28S, COI and 16S regions were used to infer phylogenetic relationships in Oestroidea with maximum-parsimony (MP), maximum-likelihood (ML) and Bayesian inference (BI) methods. For the BI analyses, a deep evaluation of different data partitioning strategies was conducted, including consideration of structural conformation (ITS2 and 16S) and codon position (COI) information. Results suggest the existence of two main clades in Oestroidea: (Tachinidae+Mesembrinellinae) and (Rhiniinae, (Sarcophagidae+Calliphoridae sensu stricto)). Oestridae was recovered as sister group of the remaining Oestroidea in the MP trees while it was placed closer to the (Rhiniinae+Sarcophagidae+Calliphoridae sensu stricto) group in the ML and BI trees. A paraphyletic Calliphoridae was recovered, confirming the exclusion of Rhiniinae, a clade recently promoted to family status and therefore already excluded. Mesembrinellinae could also be considered a distinct group apart from Calliphoridae, although further studies are required. Consideration of structural and codon position information led to a significant increase in the log-likelihoods of the analyses, which were accompanied by small changes in the inferred topologies, branch lengths and posterior probability support values. However, as model complexity increases, so does uncertainty across the estimated parameters, including tree topologies, and phylogenies inferred under very parameter-rich models may be less reliable even when possessing higher log likelihoods. PMID- 22926311 TI - Application of NIR spectroscopy for the quality control of mangosteen pericarp powder: quantitative analysis of alpha-mangostin in mangosteen pericarp powder and capsule. AB - Near-infrared spectroscopy (NIR) was applied to the quantitative analysis of the concentration of alpha-mangostin (aM) in mangosteen pericarp powder (MP). The predicted results from the partial least squares chemometric method of various pretreatment data were compared to obtain the best calibration model. Two different types of containers (transparent capsules and glass vials) filled with the same samples were measured. For MP mixture in vials, the calibration model involving nine principal components (PC) could predict the amount of aM most accurately based on non-pretreatment spectral data. For MP mixture in capsules, the calibration model involving nine PC could predict the amount of aM most accurately based on first-derivative pretreatment spectra. The relationships of the calibration models for both samples had sufficiently linear plots. The standard error of cross-validation for the MP mixture in vials was lower and the R(2) values of validation were higher compared to the MP mixture in capsules. The equation for prediction of the concentration of aM in MP mixtures in vials is y = 0.9775x + 0.0425 with R(2) = 0.9950 and for those in capsules is y = 1.0264x + 0.0126 with R(2) = 0.9898. Both validation results indicated that the concentrations of aM in MP mixtures were predicted with sufficient accuracy and repeatability. NIR can be a useful tool for the quality control of herbal medicine in powder form without any sample preparation. The type and the shape of the container should be considered to obtain more accurate data. PMID- 22926313 TI - Stroke: secondary stroke prevention--personalized antiplatelet therapy. PMID- 22926312 TI - Prism adaptation for spatial neglect after stroke: translational practice gaps. AB - Spatial neglect increases hospital morbidity and costs in around 50% of the 795,000 people per year in the USA who survive stroke, and an urgent need exists to reduce the care burden of this condition. However, effective acute treatment for neglect has been elusive. In this article, we review 48 studies of a treatment of intense neuroscience interest: prism adaptation training. Due to its effects on spatial motor 'aiming', prism adaptation training may act to reduce neglect-related disability. However, research failed, first, to suggest methods to identify the 50-75% of patients who respond to treatment; second, to measure short-term and long-term outcomes in both mechanism-specific and functionally valid ways; third, to confirm treatment utility during the critical first 8 weeks poststroke; and last, to base treatment protocols on systematic dose-response data. Thus, considerable investment in prism adaptation research has not yet touched the fundamentals needed for clinical implementation. We suggest improved standards and better spatial motor models for further research, so as to clarify when, how and for whom prism adaptation should be applied. PMID- 22926314 TI - Calcineurin B subunit acts as a potential agent for preventing cardiac ischemia/reperfusion injury. AB - Calcineurin B subunit (CnB) is the regulatory subunit of calcineurin (Cn), a Ca(2+)/calmodulin-dependent serine/threonine protein phosphatase. It has been reported that mice deleting the CnB gene lose nearly all Cn activity and show poor tolerance to cardiac stress; CnB gene expression is downregulated in the hearts of rats that have suffered ischemia/reperfusion (I/R) injury. Therefore, we wonder whether injection of exogenous CnB protein can prevent the rats from suffering I/R injury. In cardiomyocytes, fluorogenic labeling shows that exogenous CnB quickly enters the cell. Pretreatment of cardiomyocytes with CnB reduces apoptosis in response to hypoxia/reoxygenation injury (an in vitro model mimicking ischemia/reperfusion injury), and CsA reverses this effect by inhibiting Cn activity. Furthermore, CnB upregulates Bcl-2 and Bcl-XL expression in the process of hypoxia/reoxygenation injury, which may contribute to protecting cardiomyocytes against apoptosis. In vivo experiments shows that pretreatment with CnB improves cardiac contractile function and reduces the frequency of arrhythmias induced by global I/R injury. These findings reveal a novel function for CnB protein in cardiac stress response and suggest a possible application of CnB in coronary disease therapy. PMID- 22926316 TI - Paternal deprivation alters play-fighting, serum corticosterone and the expression of hypothalamic vasopressin and oxytocin in juvenile male mandarin voles. AB - Although early paternal deprivation significantly affects offspring behavioral and neuroendocrine development, the link between paternal deprivation and social play behavior remains unclear. Mandarin voles (Microtus mandarinus) are socially monogamous and display bi-paternal care. The present study examined the development of social play in juvenile male mandarin voles and the paternal influence on play-fighting, vasopressin- and oxytocin-immunoreactive neurons and serum corticosterone and testosterone levels. The results show that social play was more pronounced during postnatal days 28-35, differing from the ontogenetic pattern of other forms of social behavior. On postnatal day 35, the peak in play fighting activity, paternal deprivation reduced boxing/wrestling levels and vasopressin-immunoreactive neurons in the anterior hypothalamus and oxytocin immunoreactive neurons in the paraventricular nucleus, but increased vasopressin immunoreactive neurons in the paraventricular nucleus and corticosterone levels. These results suggest that mandarin voles engage in social play according to an inverted U-shaped curve in ontogeny, and paternal deprivation influences the development of offspring play-fighting; hypothalamic vasopressin, oxytocin and serum corticosterone may play a modulatory role in the alteration of play fighting elicited by paternal deprivation; decreased play-fighting may correlate with depressed vasopressin levels in the anterior hypothalamus. PMID- 22926317 TI - Characterizing the psychological distress response before and after a cancer diagnosis. AB - Psychological distress among cancer survivors is common. It is unknown if symptoms predate diagnosis or differ from patients without cancer because studies are limited to patient follow-up. Linked cohort (Wisconsin Longitudinal Study) and tumor registry records were used to assess the psychological distress response pre- to post-cancer diagnosis. Adjusted predicted probabilities of being in one of five categories of change for three psychological distress measures (depression, anxiety, well-being) were compared for participants diagnosed with cancer between 1993-1994 and 2004-2005 and participants without cancer (N = 5,162). Cancer survivors were more likely to experience clinically significant increases (>=0.8 standard deviation) in depression (15, 95 % CI = 12-18 %) and anxiety (19 %, CI = 16-22 %) compared to their no-cancer counterparts (10 %, CI = 10-11 %; 11 %, CI = 11-12 %). Cancer survivors <5 years from diagnosis were more likely to experience worsening depression. Survivors >=5 years were more likely to experience worsening anxiety. No significant results were found for well being. Characterizing the psychological distress response is a prerequisite for identifying at-risk patients and communicating expected symptoms, allowing for proactive resource provision. PMID- 22926318 TI - Complexes with mixed primary and secondary cellulose synthases are functional in Arabidopsis plants. AB - In higher plants, cellulose is synthesized by so-called rosette protein complexes with cellulose synthases (CESAs) as catalytic subunits of the complex. The CESAs are divided into two distinct families, three of which are thought to be specialized for the primary cell wall and three for the secondary cell wall. In this article, the potential of primary and secondary CESAs forming a functional rosette complex has been investigated. The membrane-based yeast two-hybrid and biomolecular fluorescence systems were used to assess the interactions between three primary (CESA1, CESA3, CESA6), and three secondary (CESA4, CESA7, CESA8) Arabidopsis (Arabidopsis thaliana) CESAs. The results showed that all primary CESAs can physically interact both in vitro and in planta with all secondary CESAs. Although CESAs are broadly capable of interacting in pairwise combinations, they are not all able to form functional complexes in planta. Analysis of transgenic lines showed that CESA7 can partially rescue defects in the primary cell wall biosynthesis in a weak cesa3 mutant. Green fluorescent protein-CESA protein fusions revealed that when CESA3 was replaced by CESA7 in the primary rosette, the velocity of the mixed complexes was slightly faster than the native primary complexes. CESA1 in turn can partly rescue defects in secondary cell wall biosynthesis in a cesa8ko mutant, resulting in an increase of cellulose content relative to cesa8ko. These results demonstrate that sufficient parallels exist between the primary and secondary complexes for cross functionality and open the possibility that mixed complexes of primary and secondary CESAs may occur at particular times. PMID- 22926319 TI - Nitric oxide-mediated maintenance of redox homeostasis contributes to NPR1 dependent plant innate immunity triggered by lipopolysaccharides. AB - The perception of lipopolysaccharides (LPS) by plant cells can lead to nitric oxide (NO) production and defense gene induction. However, the signaling cascades underlying these cellular responses have not yet been resolved. This work investigated the biosynthetic origin of NO and the role of NONEXPRESSOR OF PATHOGENESIS-RELATED GENES1 (NPR1) to gain insight into the mechanism involved in LPS-induced resistance of Arabidopsis (Arabidopsis thaliana). Analysis of inhibitors and mutants showed that LPS-induced NO synthesis was mainly mediated by an arginine-utilizing source of NO generation. Furthermore, LPS-induced NO caused transcript accumulation of alternative oxidase genes and increased antioxidant enzyme activity, which enhanced antioxidant capacity and modulated redox state. We also analyzed the subcellular localization of NPR1 to identify the mechanism for protein-modulated plant innate immunity triggered by LPS. LPS activated defense responses, including callose deposition and defense-related gene expression, were found to be regulated through an NPR1-dependent pathway. In summary, a significant NO synthesis induced by LPS contributes to the LPS-induced defense responses by up-regulation of defense genes and modulation of cellular redox state. Moreover, NPR1 plays an important role in LPS-triggered plant innate immunity. PMID- 22926320 TI - Architecture-based multiscale computational modeling of plant cell wall mechanics to examine the hydrogen-bonding hypothesis of the cell wall network structure model. AB - A primary plant cell wall network was computationally modeled using the finite element approach to study the hypothesis of hemicellulose (HC) tethering with the cellulose microfibrils (CMFs) as one of the major load-bearing mechanisms of the growing cell wall. A computational primary cell wall network fragment (10 * 10 MUm) comprising typical compositions and properties of CMFs and HC was modeled with well-aligned CMFs. The tethering of HC to CMFs is modeled in accordance with the strength of the hydrogen bonding by implementing a specific load-bearing connection (i.e. the joint element). The introduction of the CMF-HC interaction to the computational cell wall network model is a key to the quantitative examination of the mechanical consequences of cell wall structure models, including the tethering HC model. When the cell wall network models with and without joint elements were compared, the hydrogen bond exhibited a significant contribution to the overall stiffness of the cell wall network fragment. When the cell wall network model was stretched 1% in the transverse direction, the tethering of CMF-HC via hydrogen bonds was not strong enough to maintain its integrity. When the cell wall network model was stretched 1% in the longitudinal direction, the tethering provided comparable strength to maintain its integrity. This substantial anisotropy suggests that the HC tethering with hydrogen bonds alone does not manifest sufficient energy to maintain the integrity of the cell wall during its growth (i.e. other mechanisms are present to ensure the cell wall shape). PMID- 22926321 TI - MEMS-enabled implantable drug infusion pumps for laboratory animal research, preclinical, and clinical applications. AB - Innovation in implantable drug delivery devices is needed for novel pharmaceutical compounds such as certain biologics, gene therapy, and other small molecules that are not suitable for administration by oral, topical, or intravenous routes. This invasive dosing scheme seeks to directly bypass physiological barriers presented by the human body, release the appropriate drug amount at the site of treatment, and maintain the drug bioavailability for the required duration of administration to achieve drug efficacy. Advances in microtechnologies have led to novel MEMS-enabled implantable drug infusion pumps with unique performance and feature sets. In vivo demonstration of micropumps for laboratory animal research and preclinical studies include acute rapid radiolabeling, short-term delivery of nanomedicine for cancer treatment, and chronic ocular drug dosing. Investigation of MEMS actuators, valves, and other microstructures for on-demand dosing control may enable next generation implantable pumps with high performance within a miniaturized form factor for clinical applications. PMID- 22926322 TI - Challenges of using quality improvement methods in nursing homes that "need improvement". AB - OBJECTIVES: Qualitatively describe the adoption of strategies and challenges experienced by intervention facilities participating in a study targeted to improve quality of care in nursing homes "in need of improvement". To describe how staff use federal quality indicator/quality measure (QI/QM) scores and reports, quality improvement methods and activities, and how staff supported and sustained the changes recommended by their quality improvement teams. DESIGN/SETTING/PARTICIPANTS: A randomized, two-group, repeated-measures design was used to test a 2-year intervention for improving quality of care and resident outcomes in facilities in "need of improvement". Intervention group (n = 29) received an experimental multilevel intervention designed to help them: (1) use quality-improvement methods, (2) use team and group process for direct-care decision-making, (3) focus on accomplishing the basics of care, and (4) maintain more consistent nursing and administrative leadership committed to communication and active participation of staff in decision-making. RESULTS: A qualitative analysis revealed a subgroup of homes likely to continue quality improvement activities and readiness indicators of homes likely to improve: (1) a leadership team (nursing home administrator, director of nurses) interested in learning how to use their federal QI/QM reports as a foundation for improving resident care and outcomes; (2) one of the leaders to be a "change champion" and make sure that current QI/QM reports are consistently printed and shared monthly with each nursing unit; (3) leaders willing to involve all staff in the facility in educational activities to learn about the QI/QM process and the reports that show how their facility compares with others in the state and nation; (4) leaders willing to plan and continuously educate new staff about the MDS and federal QI/QM reports and how to do quality improvement activities; (5) leaders willing to continuously involve all staff in quality improvement committee and team activities so they "own" the process and are responsible for change. CONCLUSIONS: Results of this qualitative analysis can help allocate expert nurse time to facilities that are actually ready to improve. Wide-spread adoption of this intervention is feasible and could be enabled by nursing home medical directors in collaborative practice with advanced practice nurses. PMID- 22926324 TI - Effects of caffeine on session ratings of perceived exertion. AB - This study examined effects of caffeine on session ratings of perceived exertion (RPE) following 30 min constant-load cycling. Individuals (n = 15) of varying aerobic fitness completed a [Formula: see text] max trial and two 30 min cycling bouts (double-blind, counterbalanced) following ingestion of 6 mL/kg of caffeine or matched placebo. RPE overall, legs and breathing were estimated every 5 min and session RPE was estimated 30 min post-exercise using the OMNI pictorial scale. Session RPE for caffeine and placebo trails were compared using paired t test. Between-trial comparisons of HR, RPE overall, RPE legs and RPE breathing were analyzed using an independent 2 (trial) * 6 (time point) repeated measures analysis of variance (ANOVA) for each dependent variable. Caffeine resulted in a significantly lower session RPE (p < 0.05) for caffeine (6.1 +/- 2.2) versus placebo (6.8 +/- 2.1). Acute perceptual responses were significantly lower for caffeine for RPE overall (15, 20, 25, and 30 min), RPE breathing (15, 20, 25, and 30 min) and RPE legs (20 and 30 min). Survey responses post-exercise revealed greater feelings of nervousness, tremors, restlessness and stomach distress following caffeine versus placebo. Blunted acute RPE and survey responses suggest participants responded to caffeine ingestion. Caffeine decreased acute RPE during exercise which could partially account for lower session RPE responses. However, decreased session RPE could also reveal a latent analgesic affect of caffeine extending into recovery. Extending the understanding of session RPE could benefit coaches in avoiding overtraining when adjusting training programs. PMID- 22926325 TI - Identification, expression of a glycoprotein hormone receptor homolog in the amphioxus Branchiostoma belcheri with implications for origin of vertebrate GpHRs. AB - Amphioxus is phylogenetically located at the most primitive position of the chordate clade. Its endocrine system has been extensively studied; however, key information about the glycoprotein hormone (GpH) and its receptor (GpHR) in the endocrine system remained to be elucidated. In this study, a GpHR homologous gene, BbGpHR-like, has been identified in the amphioxus Branchiostoma belcheri. It contains a 1377bp open reading frame that corresponds to a deduced protein of 458 amino acid residues with a predicted molecular mass of approximately 50kDa. Phylogenetic analysis shows that BbGpHR-like is located at the position between vertebrate and invertebrate, indicating amphioxus B. belcheri is in an evolutionary transitional state between vertebrate and invertebrate in the GpHR lineage. BbGpHR-like has been successfully expressed in Pichia pastoris. Western blot analysis confirmed that the receptor produced a cross-immunoreactivity with human thyrotropin receptor (TSHR), the luteinizing hormone receptor (LHR) and the follicle-stimulating hormone receptor (FSHR). In situ hybridization and immunohistochemical analyses revealed that the BbGpHR-like transcripts and proteins were strongly distributed in the ovaries, testes and/or endostyle. These findings suggest that BbGpHR-like possibly plays an ancient and fundamental role in the control of thyroid hormone synthesis and gametogenesis in chordates. Presumably, the amphioxus BbGpHR-like represents the ancestral form of the GpHR gene prior to its split to the vertebrate paralogs gonadotropin receptor and thyrotropin receptor. PMID- 22926323 TI - High throughput measurement of Ca2+ dynamics for drug risk assessment in human stem cell-derived cardiomyocytes by kinetic image cytometry. AB - Current methods to measure physiological properties of cardiomyocytes and predict fatal arrhythmias that can cause sudden death, such as Torsade de Pointes, lack either the automation and throughput needed for early-stage drug discovery and/or have poor predictive value. To increase throughput and predictive power of in vitro assays, we developed kinetic imaging cytometry (KIC) for automated cell-by cell analyses via intracellular fluorescence Ca2+ indicators. The KIC instrument simultaneously records and analyzes intracellular calcium concentration [Ca2+](i) at 30-ms resolution from hundreds of individual cells/well of 96-well plates in seconds, providing kinetic details not previously possible with well averaging technologies such as plate readers. Analyses of human embryonic stem cell and induced pluripotent stem cell-derived cardiomyocytes revealed effects of known cardiotoxic and arrhythmogenic drugs on kinetic parameters of Ca2+ dynamics, suggesting that KIC will aid in the assessment of cardiotoxic risk and in the elucidation of pathogenic mechanisms of heart disease associated with drugs treatment and/or genetic background. PMID- 22926326 TI - Pharmacological characterization of intracellular glucocorticoid receptors in nine tissues from house sparrow (Passer domesticus). AB - Glucocorticoid hormones play a key role in the stress response, but plasma concentrations vary based on physiological, environmental, or social parameters. However, hormone titers alone do not determine organismal response. To enhance our understanding of glucocorticoid actions we can examine 'downstream' factors in the organismal stress response, measuring glucocorticoid receptors across target tissues. Here, we characterized intracellular binding sites for CORT (corticosterone, the avian glucocorticoid) in house sparrow (Passer domesticus) brain, liver, skeletal muscle, spleen, fat, testes, ovary, kidney and skin. We used radioligand binding assays to identify total capacity, relative density and affinity for CORT of intracellular receptors in each tissue. Most evidence supported two binding sites similar to mammalian low-affinity glucocorticoid receptor (GR) and a high-affinity mineralocorticoid receptor (MR) for brain, liver, kidney and testes, and only a GR-like receptor for muscle, spleen, fat, ovary and skin. However, kidney data were somewhat more complicated, possibly hinting at a mineralocorticoid function for CORT and/or GR in birds. In all tissues, GR and MR affinities were close to published house sparrow values (K(d)~6 nM for GR, and ~0.2 nM for MR). Taken together, these data show that CORT receptor distribution appears to be as widespread in birds as it is in mammals, and suggest that independent regulation of peripheral receptors in different target tissues may play a role in CORT's diverse physiological effects. PMID- 22926327 TI - Non-invasive monitoring of physiological stress in the Western lowland gorilla (Gorilla gorilla gorilla): validation of a fecal glucocorticoid assay and methods for practical application in the field. AB - Enzymeimmunoassays (EIAs) allow researchers to monitor stress hormone output via measurement of fecal glucocorticoid metabolites (FGCMs) in many vertebrates. They can be powerful tools which allow the acquisition of otherwise unobtainable physiological information from both captive animals and wild animals in remote forest habitats, such as great apes. However, methods for hormone measurement, extraction and preservation need to be adapted and validated for field settings. In preparation for a field study of Western lowland gorillas (Gorilla gorilla gorilla) in the Central African Republic we used samples from captive gorillas collected around opportunistic stressful situations to test whether four different glucocorticoid EIAs reflected adrenocortical activity reliably and to establish the lag-time from the stressor to peak excretion. We also validated a field extraction technique and established a simple, non-freezer-reliant method to preserve FGCMs in extracts long-term. We determined the rate of FGCM change over 28 days when samples cannot be extracted immediately and over 12h when feces cannot be preserved immediately in alcohol. Finally, we used repeat samples from identified individuals to test for diurnal variation in FGCM output. Two group specific assays measuring major cortisol metabolites detected the predicted FGCM response to the stressor reliably, whereas more specific cortisol and corticosterone assays were distinctly less responsive and thus less useful. We detected a lag time of 2-3 days from stressor to peak FGCM excretion. Our field extraction method performed as well as an established laboratory extraction method and FGCMs in dried extracts stored at ambient temperatures were as stable as those at -20 degrees C over 1 yr. Hormones in non-extracted feces in alcohol were stable up to 28 days at ambient temperatures. FGCMs in un-fixed gorilla feces deteriorated to almost 50% of the original values within 6h under field conditions. We detected no diurnal variation in FGCMs in samples from wild gorillas. Our study highlights the importance of thorough biological and immunological validation of FGCM assays, and presents validated, practical methods for the application of non-invasive adrenocortical monitoring techniques to field conservation contexts where it is crucially needed. PMID- 22926328 TI - Non-invasive monitoring of glucocorticoid metabolites in banded mongooses (Mungos mungo) in response to physiological and biological challenges. AB - Free-ranging banded mongooses are infected by the novel pathogen, Mycobacterium mungi in northern Botswana. A reliable method for determining stress-related physiological responses in banded mongooses will increase our understanding of the stress response in M. mungi infection. Therefore, our aim was to examine the suitability of four enzyme immunoassays (EIAs) for monitoring adrenocortical endocrine function in captive and free-ranging banded mongooses based on fecal glucocorticoid metabolite (FGM) analysis. A conducted adrenocorticotropic hormone challenge revealed suitability of a valid measurement of FGM levels in banded mongoose feces for all four tested EIAs, with an 11-oxoetiocholanolone assay detecting 11,17-dioxoandrostanes (11,17-DOA) performing best. Subsequent analyses using only this EIA showed the expected decrease in FGM concentrations 48 h after administering dexamethasone sodium phosphate. Furthermore, captive mongooses showed higher FGM concentrations during reproductive activity, agonistic encounters and depredation events. Finally, a late-stage, tuberculosis-infected moribund mongoose in a free-ranging troop had a 54-fold elevation in FGM levels relative to the rest of the troop. Measurements of gastrointestinal transit times and FGM metabolism post-defecation indicate that the time delay of FGM excretion approximately corresponded with food transit time and that FGM metabolism is minimal up to 8h post-defecation. The ability to reliably assess adrenocortical endocrine function in banded mongoose now provides a solid basis for advancing our understanding of infectious disease and endocrinology in this species. PMID- 22926329 TI - Stimulatory effects of neuropeptide Y on the growth of orange-spotted grouper (Epinephelus coioides). AB - Neuropeptide Y (NPY) is a member of the pancreatic polypeptide family which is a potent orexigenic peptide known to date in mammals and teleost. This study was carried out to investigate the effects of NPY on food intake and growth of orange spotted grouper (Epinephelus coioides). Synthetic grouper NPY (gNPY) was given orally at the dose of 0.5, 1.0 and 2.0 MUg/g feed for 50 days, results showed that NPY treatment (1.0 and 2.0 MUg/g feed) significantly increased growth rate, weight gain, feed conversion efficiency (FCE) and pituitary growth hormone (GH) mRNA level than the control group (p<0.05). Furthermore, high level secretion of gNPY was expressed and purified in the Pichia pastoris expression system. The bioactivity of recombinant gNPY was confirmed by its ability to up-regulate GH mRNA expression in vivo and in vitro and down-regulate preprosomatostatin I (PSSI) mRNA expression in vivo. These results demonstrate that NPY has stimulatory effects on food intake as well as growth of grouper as in other teleost fish, also indicate that recombinant gNPY from P. pastoris has the same bioactivity as synthetic gNPY and has the potential to be used as a feed additive for both research and aquatic application. PMID- 22926330 TI - Patient and hospital characteristics associated with inpatient severe sepsis mortality in California, 2005-2010. AB - OBJECTIVES: The primary objective of this study was to identify which patient demographic, patient health, and hospital characteristics were associated with in hospital mortality. A secondary objective was to determine the relative influence of these characteristics on mortality. DESIGN AND SETTING: Public-use data for 2005-2010 were used in this retrospective, cross-sectional analysis of discharges from nonfederal, general acute hospitals in California. A staged logistic regression approach was used to examine the relative influence of variables associated with in-hospital mortality. PATIENTS: A total of 1,213,219 patient discharges for adults (aged >=18 yrs) having International Classification of Diseases-9 diagnosis and procedure codes indicating severe sepsis. INTERVENTION: None. MEASUREMENTS AND MAIN RESULTS: Patient demographics (age, gender, race, ethnicity, and payer category), patient health status (acute transfer, Charlson Deyo comorbidity index, and organ failures), and hospital characteristics (ownership type, teaching status, bed size, annual patient days, acute discharges, emergency department visits, inpatient surgeries, severe sepsis as a percentage of all discharges, and year) were obtained from the California Office of Statewide Health Planning and Development. Overall, in-hospital mortality was 17.8%. There was a steady annual increase in the number of sepsis discharges, but a decrease in mortality throughout the study period. Mortality increased with age and was associated with white race, and Medicaid (Medi-Cal) and private insurance. Patient health status additionally explained inpatient mortality. Hospital volume measures were statistically significant in regression analysis, whereas static structural measures were not. There were modest associations between measures of annual treatment volume and likelihood of inpatient mortality, notably decreasing likelihood with more acute discharges and with greater severe sepsis volume. CONCLUSIONS: Although patient demographics and health status are the most important predictors of in-hospital mortality of patients with severe sepsis, hospital characteristics do play a substantial role. Findings regarding hospital volume can be used to improve processes and improve patient outcomes. PMID- 22926331 TI - Adenocaine and Mg(2+) reduce fluid requirement to maintain hypotensive resuscitation and improve cardiac and renal function in a porcine model of severe hemorrhagic shock*. AB - OBJECTIVES: Hypotensive resuscitation is gaining clinical acceptance in the treatment of hemorrhagic shock. Our aims were to investigate: 1) the effect of 7.5% NaCl with adenocaine (adenosine and lidocaine, AL) and AL with Mg (ALM) on fluid requirement to maintain a minimum mean arterial pressure of 50 mm Hg, and 2) the effect of a second bolus of 0.9% NaCl with AL during return of shed blood on cardiac and renal function in a porcine model of hemorrhagic shock. DESIGN: Pigs were randomized to: Sham (n = 5), Sham + ALM/AL (n = 5), hemorrhage control (n = 11), or hemorrhage + ALM/AL (n = 9). Hemorrhage animals were bled to a mean arterial pressure of 35 mm Hg. After 90 mins, pigs were fluid resuscitated with Ringers acetate and 20 mL 7.5% NaCl with ALM to maintain a target mean arterial pressure of minimum 50 mm Hg. Shed blood and 0.9% NaCl with AL were infused 30 mins later. Hemorrhage control group was subjected to the same protocol but without ALM/AL. Hemodynamics, cardiodynamics (pressure-volume analysis), oxygen consumption, and kidney function were measured for 6 hrs. SETTING: University hospital laboratory. SUBJECTS: Female farm-bred pigs. RESULTS: Fluid volume infused during hypotensive resuscitation was 40% less in the 7.5% NaCl-/ALM treated pigs than controls (25 vs. 41 mL/kg, p < .05). ALM was associated with a significant increase in dp/dtmax, end-systolic blood pressure, and systemic vascular resistance. Return of shed blood and 0.9% NaCl/AL reduced whole body oxygen consumption by 27% (p < .05), and significantly improved the end-systolic pressure-volume relationship and preload recruitable stroke work compared to controls. Glomerular filtration rate in the ALM/AL group returned to 83% of baseline compared to 54% in controls (p = .01). CONCLUSION: Resuscitation with 7.5% NaCl ALM increases cardiac function and reduces fluid requirements during hypotensive resuscitation, whereas a second AL infusion during blood resuscitation transiently reduces whole body oxygen consumption and improves cardiac and renal function. PMID- 22926332 TI - Resveratrol improves myocardial ischemia and ischemic heart failure in mice by antagonizing the detrimental effects of fractalkine*. AB - OBJECTIVES: To test the hypothesis that resveratrol would improve cardiac remodeling by inhibiting the detrimental effects of fractalkine. We previously reported that fractalkine exacerbates heart failure. Furthermore, this study sought to determine whether resveratrol targets fractalkine to improve myocardial ischemia and cardiac remodeling. DESIGN: Randomized and controlled laboratory investigation. SETTING: Research laboratory. SUBJECTS: Neonatal rat cardiac cells and C57BL/6 mice. INTERVENTIONS: Cardiac cells were treated with recombinant mouse soluble fractalkine for 24 hrs or pretreated with 25 uM resveratrol. Cardiomyocytes were exposed to anoxia/reoxygenation, H2O2, or pretreatment with resveratrol. Ex vivo murine hearts were perfusioned with soluble fractalkine or pretreated with resveratrol after global ischemia. Mice were subjected to the left coronary artery ligation to induce myocardial infarction and randomized to treatment with resveratrol or vehicle alone for 42 days. MEASUREMENTS AND MAIN RESULTS: In a murine myocardial infarction model, we found that resveratrol increased survival and delayed the progression of cardiac remodeling evaluated by serial echocardiography. At 6 wks, the heart weight/body weight ratio, lung weight/body weight ratio, and old infarct size were significantly smaller in resveratrol-treated mice than in untreated myocardial infarction mice. In cultures of neonatal rat cells, exposure to soluble fractalkine increased the atrial natriuretic peptide expression by cardiomyocytes, matrix metalloproteinase 9 and procollagen expression by fibroblasts, and intercellular adhesion molecule 1 expression by microvascular endothelial cells, while it decreased autophagy in cardiomyocytes. All these effects were blocked by coculture with resveratrol. The methyl thiazolyl tetrazolium assay showed that soluble fractalkine reduced the viability of cultured cardiomyocytes during exposure to anoxia/reoxygenation or H2O2, while pretreatment with resveratrol blocked this effect. Perfusion of ex vivo murine hearts with soluble fractalkine after global ischemia led to an increase of infarct size, which was prevented by pretreatment with resveratrol. CONCLUSION: Resveratrol alleviates the deleterious effects of fractalkine on myocardial ischemia and thus reduces subsequent cardiac remodeling. PMID- 22926333 TI - Effects of norepinephrine on mean systemic pressure and venous return in human septic shock. AB - OBJECTIVES: Norepinephrine exerts venoconstriction that could increase both the mean systemic pressure and the resistance to venous return, but this has not yet been investigated in human septic shock. We examined the relative importance of both effects and the resulting effect on venous return when decreasing the dose of norepinephrine. SETTING: Intensive care unit. PATIENTS: Sixteen septic shock patients. MEASUREMENTS: For estimating the venous return curve, we constructed the regression line between the pairs of cardiac index (pulse contour analysis) and central venous pressure values. These values were measured during 15-sec end inspiratory and end-expiratory ventilatory occlusions performed at two levels of positive end-expiratory pressure, in view of widening the range of cardiac index:central venous pressure measurements and increasing the accuracy of the regression line. The x-axis intercept of the regression line was used to estimate the mean systemic pressure and the inverse of the slope of the regression line to quantify resistance to venous return. These measurements were obtained before and after decreasing the dose of norepinephrine. Passive leg raising was performed before and after decreasing the dose of norepinephrine. MAIN RESULTS: Decreasing the dose of norepinephrine from 0.30 (0.10-1.40) to 0.19 (0.08-1.15) ug/kg/min decreased the mean systemic pressure from 33 +/- 12 mm Hg to 26 +/- 10 mm Hg (p = .0003). The slope of the multipoint cardiac index:central venous pressure relationship increased (p = .02). The resistance to venous return decreased, i.e., 1/slope decreased. Simultaneously, cardiac index decreased from 3.47 +/- 0.86 L/min/m2 to 3.28 +/- 0.76 L/min/m (p = .04), indicating a decrease in venous return. Passive leg raising increased cardiac index to a larger extent after (8% +/- 4%) than before (1% +/- 4%) decreasing norepinephrine (p = .001), suggesting an increase in unstressed blood volume at the lowest dose of norepinephrine. CONCLUSIONS: In septic shock patients, decreasing the dose of norepinephrine decreased the mean systemic pressure and, to a lesser extent, the resistance to venous return. As a result, venous return decreased. PMID- 22926334 TI - Slow O-demethylation of methyl triclosan to triclosan, which is rapidly glucuronidated and sulfonated in channel catfish liver and intestine. AB - The antibacterial personal care product triclosan is discharged in municipal waste, and converted in part by bacteria in sewage sludge and soil to its more lipid-soluble methyl ether, methyl triclosan. Triclosan and methyl triclosan have been detected in water, sediment, fish and invertebrates near sewage treatment facilities. Understanding the biotransformation of methyl triclosan and triclosan in a model food fish, the channel catfish, will be of value in assessing the likelihood that these compounds will bioaccumulate in exposed fish, and therefore potentially pass up the food chain. We hypothesize that cytochrome P450 will catalyze the O-demethylation of methyl triclosan to yield triclosan, which is likely to undergo glucuronidation or sulfonation of the phenolic hydroxyl group. Conversion of methyl triclosan to triclosan was measured by LC/MS/MS following aerobic incubation of varying concentrations of methyl triclosan with NADPH and hepatic and intestinal microsomes from untreated, 3-methylcholanthrene-treated (10 mg/kg, i.p.) or PCB-126-treated (0.1 mg/kg, i.p.) channel catfish (n=4 per treatment group). The K(m) values for methyl triclosan were similar for untreated, 3-methylcholanthrene-treated and PCB-126-treated catfish liver microsomes, ranging from 80 to 250 MUM. V(max) values for O-demethylation ranged from 30 to 150 pmol/min/mg protein, with no significant differences between controls, PCB-126-treated or 3-methylcholanthrene-treated fish, suggesting that methyl triclosan O-demethylation was not a CYP1-catalyzed reaction. Methyl triclosan O-demethylation activities in intestinal microsomes were similar to or lower than those found with liver microsomes. The calculated rate of O demethylation of methyl triclosan in catfish liver at 1 MUM, a concentration reported in exposed fish, and 21 degrees C, an early summer water temperature, is 0.10 pmol/min/mg protein. This slow rate of metabolism suggests that upon continued exposure, methyl triclosan may bioaccumulate in the channel catfish. Triclosan itself, however, was readily glucuronidated by hepatic and intestinal microsomes and sulfonated by hepatic and intestinal cytosol. Triclosan glucuronidation followed Michaelis-Menten kinetics when rates were measured across a concentration range of 5-1000 MUM, whereas triclosan sulfonation exhibited substrate inhibition at concentrations above 10-20 MUM in both intestinal and hepatic cytosol. Based on the enzyme kinetic constants measured in hepatic and intestinal fractions at 21 degrees C, triclosan at 1 MUM could be glucuronidated at rates of 23 and 3.2 pmol/min/mg protein respectively in liver and intestine, and sulfonated at rates of 277 (liver) and 938 (intestine) pmol/min/mg protein. These rates are much higher than the rates of demethylation of methyl triclosan, and suggest that triclosan would be rapidly cleared and unlikely to bioaccumulate in catfish tissues. PMID- 22926335 TI - Effects of the ionic liquid [Omim]PF6 on antioxidant enzyme systems, ROS and DNA damage in zebrafish (Danio rerio). AB - The present study examined the toxic effects of the exposure to different concentrations of the ionic liquid 1-octyl-3-methylimidazolium hexafluorophosphate for a 28-day period in zebrafish (Danio rerio) (sampled at 7, 14, 21 and 28 d). The activities of antioxidant enzymes (superoxide dismutase and catalase), levels of reactive oxygen species and DNA damage in fish livers served as the indicators to assess the toxicity of [Omim]PF(6) to zebrafish. The ionic liquid inhibited the activities of the antioxidant enzymes and caused the accumulation of ROS and DNA damage, and the results were concentration- and time dependent. Male and female fish were tested separately and no differences were observed. The results showed that the ionic liquid could induce oxidative stress and DNA damage in zebrafish and that these effects could also accumulate over time. PMID- 22926336 TI - Anti-fibrotic effects of fresh and cryopreserved human amniotic membrane in a rat liver fibrosis model. AB - The human amniotic membrane (hAM), thanks to its favorable properties, including anti-inflammatory, anti-fibrotic and pro-regenerative effects, is a well-known surgical material for many clinical applications, when used both freshly after isolation and after preservation. We have shown previously that hAM patching is a potential approach to counteract liver fibrosis. Indeed, when fresh hAM was used to cover the liver surface of rats with liver fibrosis induced by the bile duct ligation (BDL) procedure, the progression and severity of fibrosis were significantly reduced. Since cryopreservation enables safety and long-term storage of hAM but may influence its functional properties, here we compared the anti-fibrotic effects of fresh and cryopreserved hAM in rats with BDL-induced liver fibrosis. After BDL, the rat liver was covered with a piece of fresh or cryopreserved hAM, or left untreated. Six weeks later, the degree of liver fibrosis was assessed histologically using the Knodell and the METAVIR scoring systems. Digital image analysis was used to quantify the percentage of the areas of each liver section displaying ductular reaction, extracellular matrix (ECM) deposition, activated myofibroblasts and hepatic stellate cells (HSCs). Liver collagen content was also determined by spectrophotometric technique. The degree of liver fibrosis, ductular reaction, ECM deposition, and the number of activated myofibroblasts and HSCs were all significantly reduced in hAM-treated rats compared to control animals. Fresh and cryopreserved hAM produced the same anti fibrotic effects. These findings indicate that cryopreservation maintains the anti-fibrotic properties of hAM when used as a patch to reduce the severity of liver fibrosis. PMID- 22926337 TI - New fully-covered self-expandable metal stent for endoscopic ultrasonography guided intervention in infectious walled-off pancreatic necrosis (with video). AB - Endoscopic ultrasonography (EUS)-guided pancreatic pseudocyst drainage using a self-expandable metal stent (SEMS) has been reported for satisfactory drainage and endoscopic necrosectomy. Here, we described an interesting case in which successful endoscopic therapy was performed using a new SEMS in infectious walled off pancreatic necrosis. PMID- 22926338 TI - Birth weight and other perinatal characteristics and childhood leukemia in California. AB - AIMS: We conducted a large registry-based study in California to investigate the association of perinatal factors and childhood leukemia with analysis of two major subtypes, acute lymphocytic leukemia (ALL) and acute myeloid leukemia (AML). METHODS: We linked California cancer and birth registries to obtain information on 5788 cases and 5788 controls matched on age and sex (1:1). We examined the association of birth weight, gestational age, birth and pregnancy order, parental ages, and specific conditions during pregnancy and risk of total leukemia, ALL and AML using conditional logistic regression, with adjustment for potential confounders. RESULTS: The odds ratio (OR) per 1000 g increase in birth weight was 1.11 for both total leukemia and ALL. The OR were highest for babies weighing >= 4500 g with reference < 2500 g: 1.59 (95% CI: 1.05-2.40) and 1.70 (95% CI: 1.08-2.68) for total leukemia and ALL, respectively. For AML, increase in risk was also observed but the estimate was imprecise due to small numbers. Compared to average-for-gestational age (AGA), large-for-gestational age (LGA) babies were at slightly increased risk of total childhood leukemia (OR = 1.10) and both ALL and AML (OR = 1.07 and OR = 1.13, respectively) but estimates were imprecise. Being small-for-gestational age (SGA) was associated with reduced risk of childhood leukemia (OR = 0.81, 95% CI: 0.67-0.97) and ALL (OR = 0.77, 95% CI: 0.63-0.94), but not AML. Being first-born was associated with decreased risk of AML only (OR = 0.70; 95% CI: 0.53-0.93). Compared to children with paternal age <25 years, children with paternal age between 35 and 45 years were at increased risk of total childhood leukemia (OR = 1.12; 95% CI: 1.04-1.40) and ALL (OR = 1.23; 95% CI: 1.04-1.47). None of conditions during pregnancy examined or maternal age were associated with increased risk of childhood leukemia or its subtypes. CONCLUSIONS: Our results suggest that high birth weight and LGA were associated with increased risk and SGA with decreased risk of total childhood leukemia and ALL, being first-born was associated with decreased risk of AML, and advanced paternal age was associated with increased risk of ALL. These findings suggest that associations of childhood leukemia and perinatal factors depend highly on subtype of leukemia. PMID- 22926339 TI - A pilot study of low-cost, high-resolution microendoscopy as a tool for identifying women with cervical precancer. AB - Cervical cancer remains one of the leading causes of death among women in developing countries. Without resources to support Pap smear cytology and colposcopy, cost-effective approaches which enable single-visit "see-and-treat" protocols offer the potential to reduce morbidity and mortality due to this preventable disease. We carried out a pilot clinical study in Shanxi province, China, to evaluate a low-cost, high-resolution microendoscope (HRME) imaging system which enables evaluation of epithelial cell morphology in vivo. HRME images were obtained at discrete sites on the cervix in 174 women, in addition to visual inspection with acetic acid (VIA) and colposcopic examination. Of 69 sites appearing abnormal on colposcopy, only 12 showed high-grade disease (CIN2+) on pathology. Quantification of the nuclear-to-cytoplasm ratio by HRME enabled an ad hoc threshold to be defined, which correctly classified all 12 sites as abnormal, whilst classifying 38 of the remaining 57 pathology normal sites as normal. All patients with biopsy confirmed high-grade disease also tested positive for high risk human papilloma virus (HPV) DNA and were classified as abnormal by HRME. Among the remaining patients who tested positive for HPV but were either normal by colposcopy or showed = 33 mm/h, detected 1 year mortality with a negative predictive value of 96%. CONCLUSION: The high admission ESR levels are found to be related with impaired coronary flow in patients undergoing primary PCI that possibly contribute to poor short- and long-term prognosis. Therefore, admission ESR evaluation may be helpful in identifying patients with a poor prognosis. PMID- 22926350 TI - Overweight - early stage of "adipokines related cardiovascular diseases": leptin and adiponectin relation to anthropometric parametars. AB - AIM: Adipose tissue possess endocrine functions that include synthesis of various adipocytokines, which affect the metabolism of lipids and glucoses, development of atherosclerotic processes, and are involved in the development of hypertension and cardiovascular diseases. Body fat distribution is a significant risk factor for the development of obesity related diseases. Leptin and adiponectin are adipokines whose concentrations vary with the level of obesity. The aim of this research is to determine the relation of the changes in leptin and adiponectin concentrations in overweight persons with anthropometric parameters of the subjects. METHODS: The study included 40 adult, hypertensive subjects - divided into two groups according to sex, with the body mass index 25-30 kg/m2, with regular glycemia and renal function. All subjects underwent biochemical (serum lipid, glucose and creatinine level) and anthropometric measurements. Leptin concentration was determined by radioimmunoassay, while adiponectin concentration was determined by enzyme immunoassay. RESULTS: Both leptin and adiponectin concentrations significantly correlated with the waist circumference in both groups of subjects. In male subjects, leptin concentration correlated positively with the body mass index and the hip circumference, while adiponectin concentration correlated negatively with the hip circumference. CONCLUSION: Being overweight is a condition marked by pathologically altered values of leptin concentration (increased level) and adiponectin (decreased level), that are changing as the obesity level and the waist circumference increase. It can be concluded that abdominal obesity and higher body mass index increase the risk for the development of overweight-obesity-related diseases. PMID- 22926351 TI - Risk factors for intraoperative arrhythmias in general surgery patients operated under general anesthesia: our one-year experience. AB - AIM: To analyze the importance of previously un-investigated (or not completely investigated) potential risk factors for new-onset intra-operative arrhythmias in general surgery patients, operated under general anesthesia. METHODS: In this case-control study the population consisted of all patients who underwent elective non-cardiovascular, non-thoracic surgery under general inhalation anesthesia during the period of 12 months in a secondary care hospital in Foca, Republic of Srpska, Bosnia and Herzegovina, and were classified according to the American Society of Anesthesiologists classification to class I or II. Cases (n=57) included patients with at least one episode of ECG-recorded arrhythmia during general anesthesia, and controls (n=90) were sex and age matched. RESULTS: Significant association was found between intra-operative arrhythmias and history of cardiac arrhythmias in the last five years (adjusted OR 43.5; CI 2.3, 820.1; p = 0.012). Synergistic effects on intra-operative arrhythmias were found for history of cardiac arrhythmias and history of abnormal ECG, as well as for history of cardiac arrhythmias and use of propofol for induction of anesthesia. CONCLUSION: The non-cardiovascular, non-thoracic surgery patients with history of arrhythmias and ECG abnormalities deserve special attention, correction of electrolyte disturbances and avoidance of propofol for induction of general anesthesia. PMID- 22926352 TI - Effectiveness for self-monitoring of blood sugar on blood glucose control in Turkish patients with type 2 diabetes mellitus. AB - AIM: Diabetes mellitus (DM) is a chronic disease requiring continuous monitoring and treatment. Self-monitoring of blood glucose (SMBG) is frequently recommended. The purpose of the study was to evaluate effectiveness of SMBG on metabolic control in Turkish patients with type 2 DM. METHODS: The cross-sectional study enrolled type 2 diabetic patients without insulin regimen. The participants were assigned to three groups according to status of SMBG: group 1- regular, group 2 - irregular and group 3 - never SMBG implementation. RESULTS: A total of 349 patients were enrolled. There was no significant difference in mean fasting and post-prandial blood glucose, lipid profile values between the groups. The number of patients with high education level in group 1 was higher than groups 2 and 3 (p = 0.001). HbA1c level was higher in groups 2 and 3 than group 1, but not significantly (p = 0.285). Mean spot urinary albumin- creatinine ratio (ACR) in group 1 is significantly lower than in groups 2 and 3 (p = 0.008 and p = 0.044, respectively), but no significant difference was observed between group 2 and 3 (p = 0.473). CONCLUSION: The study indicated that regular use of SMBG was not superior to irregular/never use of SMBG on glycemic control, but it seemed to be good intervention for prevention of diabetic nephropathy. We suggestively offered that SMBG should be recommended for patients with a high education level to meet the goal of its use, and it should be incorporated into self-management with effective educational intervention. PMID- 22926353 TI - Evaluation of cortisol level and cell-mediated immunity response changes in individuals with post-traumatic stress disorder as a consequence of war. AB - AIM: To investigate the level of blood and urine cortisol and cell mediated immunity response changes among patients with posttraumatic stress disorder resulting from war. METHOD: In this case-control study, 20 patients with post traumatic stress disorder (PTSD) with the mean age of 41.9+7.6 and 20 healthy individuals (control group) with the mean age of 42.4+7.6 were compared. At the beginning, 24-hour urine and blood samples were obtained, and three antigens, tuberculosis, tetanus and candida were injected sub-cutaneously. Skin reaction was evaluated for each of the injections. Analysis was performed using t-test. RESULTS: There was a significant increase regarding cell-mediated immunity in cases in comparison with the controls (p =0.017) and also a significant increase of blood cortisol was observed in cases (p = 0.003). There was no significant difference in two groups regarding urine cortisol level. CONCLUSION: This study showed that there was a significant difference in the activation of cell-mediated immunity in PTSD patients as compared to the control group. This increase in activity was not due to the influence of life stressors or intensity of illness signs or following illnesses. It is recommended to study and treat the autoimmune disease in PTSD patients more seriously in the countries like Iran that were involved in war problems. PMID- 22926354 TI - Impact of gender on cellular immunity following gastrectomy in gastric cancer patients. AB - AIM: To investigate the impact of sex on white blood cells count after gastrectomy in patients with gastric cancer. METHODS: The study population included 48 patients who underwent total or subtotal gastrectomy for gastric cancer. Total white blood cells, neutrophils and lymphocytes counts of pre and postoperative day 1, 3, and 5 were reviewed from hospital database from 15 March 2009 to 1 December 2011 retrospectively. RESULTS: This investigation involved 28 male patients (58.33%) and 20 female patients (41.66%). The mean age of male and female patients was 69.4+/-14.2 and 65.2+/-15.6 year. There was a significant change in total white blood cells counts in post-operative day 3 (p= 0.041) and post-operative day 5 (p= 0.022) between males and females. Significant change was noted in post-operative day 5 for lymphocytes counts (p= 0.049). Neutrophil values indicated significant alterations in all pre and post gastrectomy days; pre-operative (p= 0.039), post-operative day 1 (p= 0.034), post-operative day 3 (p= 0.012), post-operative day 5 (p= 0.0102). CONCLUSION: In this comparison between genders, there was a significantly increased proportion of total white blood cells, neutrophils and lymphocytes in female subjects than in male individuals following gastrectomy. Our results revealed that female patients indicated more immune reactions to surgery than male patients. This research provided evidences that gender affects the cellular immunity after surgical stress. PMID- 22926355 TI - The detection of HBV DNA with polymerase chain reaction in blood donors with isolated hepatitis B core antibody. AB - AIM: To analyze the presence of HBV DNA in blood donors admitted to blood banks with HBsAg negativity and isolated anti-HBc positivity. METHODS: Sera samples of 2500 HBsAg negative donors were included in the study. HBsAg tests were assayed with VITROS analyzer. Anti-HBc total, anti-HBs, HBeAg, anti-HBe and anti-HBc IgM tests were manually studied with DIA PRO kit by employing ELISA method. HBV DNA test was evaluated with iQ5 Real Time PCR Detection System with real-time PCR method. RESULTS: A total number of 401 (16.4%) HBsAg negative blood donors had anti-HBc positivity. Forty-five of 401 (1.8%) anti-HBc positive samples were anti HBs negative. These 45 persons were evaluated for anti-HBc positivity. Thirty-six of 45 anti-HBc positive persons had only anti-HBc positivity, and other nine patients had Anti-HBe antibody. HBV DNA was detected in three (6.6 %) of 45 isolated Anti-HBc positive persons as in one of nine persons and two of 36 persons. CONCLUSION: The persons who have only HBs Ag negativity may not be appropriate to become blood donors. Anti-HBc test should be done for HBsAg negative persons. They should not be accepted as blood donors if Anti-HBc is found positive. PMID- 22926356 TI - Assessment of blood donors' satisfaction and measures to be taken to improve quality in transfusion service establishments. AB - AIM: The article focuses on the impact of blood donors' satisfaction parameters on expressed estimate of the donation process quality. Observed parameters of satisfaction were: the state of donors before blood donation, waiting time, venipuncture pain level and staff attitude. METHODS: An anonymous questionnaire was given to 1000 blood donors over the period of one month. The sample included different groups of donors by gender, age and education level. Satisfaction with the process of blood donation was expressed using 5-point Likert scale. Linear regression, multifactor ANOVA and Tukey post-hoc tests were used for the analysis. RESULTS: Blood donors' mean estimate of blood donation process was 4.8 (SD= 0.46). No objective parameters were found to have significant impact on estimates of blood donation process, while among observed subjective parameters, such as condition before blood donation (p0.05), venipunction pain level (p0.01), and staff attitude (p0.01) direct impacts were confirmed. The study also confirmed a significant impact of interaction of some of the observed parameters. CONCLUSION: This research found that blood donors' satisfaction by the quality of donation process was rather high. The process of blood donation can be improved by paying more attention to reducing the level of venipuncture pain (for example, by additional training of phlebotomists), shortening waiting time and by paying more attention to blood donors, especially in cases of painful venipuncture or long waiting times. PMID- 22926357 TI - Association between iron deficiency anemia and febrile seizure in children. AB - AIM: Febrile convulsion (FC) is a common cause of seizure in young children, with an excellent prognosis. In addition to genetic predisposition, FCs are generally thought to be induced by elemental changes such as iron deficiency. Regarding the high prevalence of febrile seizure and iron deficiency anemia in children, the aim was to investigate the role of iron deficiency anemia in FC patients. METHODS: This case-control study was performed in 500 children with febrile seizures (case) and 500 febrile children without seizures (control), referred to Mofid hospital in Tehran during one year (Nov 2009-Nov 2010). All children were aged between 6-60 months. The groups were matched in age and gender and use of supplemental iron. Laboratory tests consisted of Complete Blood Count (CBC). Serum iron, plasma ferritin and Total Iron Binding Capacity (TIBC) analyses were done in each patient. RESULTS: The patients and controls were 26.49+12.65 and 26.84+11.70 months of mean age, respectively. The amount of Hb, Hct, MCV, MCH, MCHC, RBC count, serum iron and plasma ferritin were significantly higher and TIBC was significantly lower among the cases with febrile convulsion than the controls. The incidence of iron deficiency anemia was significantly higher in controls compared with the cases (p less than 0.016). The mean of temperature peak on admission was significantly higher in the febrile convulsion group than controls. CONCLUSION: The results of this study suggest that the risk of febrile seizure occurrence in anemic children is less common as compared to non-anemic ones. PMID- 22926358 TI - AO group, AO subgroup, Garden and Pauwels classification systems of femoral neck fractures: are they reliable and reproducible? AB - AIM: To determine which of the classification systems for the femoral neck fracture between AO group, AO subgroup, Garden and Pauwels is much more reliable and reproducible to predict a method of treatment, radiological prediction of nonunion and prediction of outcomes. METHODS: Five observers classified 77 randomly selected anterior- posterior (AP) and lateral view preoperative radiographs of the femoral neck fractures according to AO group, AO subgroup, Garden and Pauwels classification systems. The procedure was repeated on the same radiographs after three months. First classification is used to calculate interobserver agreement by kappa value between observers, while the first and second classification has served to calculate intraobserver kappa value for each examiner. RESULTS: Overall mean for classification system for interobserver agreement is: AO 0.44, AO subgroup 0.17, Garden 0.41 and Pauwels 0.19. Mean intraobserver agreement for AO group was 0.56, AO subgroup 0.38, Garden 0.49 and Pauwels 0.38 coefficient kappa value. CONCLUSION: Garden and AO group are useful for the division of femoral neck fractures without displacement and with displacement, but they are not for clinical use. AO subgroup and Pauwels classification are not recommended for further use. PMID- 22926359 TI - Prognostic significance of co-overexpression of bcl-2 and c-erbB-2/neu in uterine cervix carcinomas and premalignant lesions. AB - AIM: To establish the role of co-overexpression of bcl-2 and cerbB- 2/neu protooncogenes in uterine cervix carcinogenesis, we examined 138 tissue samples of low grade cervical squamous intraepithelial lesions (SIL), high grade SIL, cervical carcinoma in situ and cervical invasive carcinoma, stage IA-IIA (study group) and 36 samples without SIL or malignancy (control group). METHODS: The expression of bcl-2 and c-erbB-2/neu was detected immunohistochemically using a monoclonal antibody. Fisher's exact test (p less than 0.05) was used to assess statistical significance. RESULTS: Co-overexpression of Bcl-2 and c-erbB-2/neu was found to increase in direct relation to the grade of the squamose intraepitelial lesions (SIL) of cervix. Statistically significant difference was found in the frequency of co-overexpression in patients with high grade SIL (12/22, p=0.006), cervical carcinoma in situ (10/22, p=0.018) and cervical invasive carcinoma (12/26, p=0.012), in relation to the control group. High sensitivity was of great diagnostic significance for the detection of these types of changes in the uterine cervix. CONCLUSION: On the basis of high predictive values it can be said that in patients with co-overexpression of bcl-2 and c-erbB 2/neu overexpression there is a great possibility that they have premalignant or malignant changes in the uterine cervix. However, a more extensive series of samples and additional tests are required to establish the prognostic significance of these oncogenes in cervical carcinogenesis. PMID- 22926360 TI - Evaluation of the relationship between heart type fatty acid binding protein levels and the risk of maternal cardiac ischemia in low risk obstetric population during delivery. AB - AIM: To investigate the heart type fatty acid binding protein (hFABP) changes during delivery in low-risk obstetric population. METHODS: Pregnant women who are at term and met the inclusion criteria were included the study. Maternal echocardiography, electrocardiography, arterial blood pressure monitoring, CK-MB, serum heart type fatty acid binding protein and troponin I levels were evaluated before and after delivery. Of the total of 100 pregnant women, mean age was 26.7+/-5, 51 pregnant had vaginal delivery and the remaining 49 had caesarean section. RESULTS: The h-FABP positivity was detected in nine (9%) subjects after the delivery as compared to values before the delivery (p=0.0035). Troponin levels were 0.013+/-0.001 before the delivery and 0.025+/-0.002 after the delivery (p= 0.0001). In the comparison of vaginal and Cesarean deliveries, h FABP positivity was detected in five of 51 subjects in the vaginal delivery group and four of 49 subjects in the cesarean delivery group (p=0.95). The changes in troponin levels were 0.01 ng/mL (-0.02 to 0.2) in the vaginal delivery group and 0.01ng/mL (-0.07 to 0.06) in the cesarean delivery group (p= 0.24). CONCLUSION: Delivery stress is associated with maternal cardiac damage as evaluated by heart type fatty acid binding protein and troponin. There was no difference between the two delivery routes in the risk of maternal cardiac damage. PMID- 22926361 TI - A comparison of pregnant subgroups with positive 50-gram glucose challenge test results to those with negative results in terms of obstetric and perinatal outcomes. AB - AIM: To compare the pregnant subgroups with positive 50-gram glucose challenge test results to those with negative results in terms of obstetric and perinatal outcomes. METHODS: A total number of 977 pregnant women were included in the study. A glucose challenge test was performed for all pregnant women. Subsequently, 3 hours 100 gram oral glucose tolerance test was performed for the patients who had a positive test. According to 50-gram glucose challenge test 1st hour glucose values, the patients were categorized into 5 subgroups (less 140, 140-159, 160-179, 180-199 and >=200). Also, the patients, whose 3 hours 100 gram oral glucose tolerance tests were positive, as well as those diagnosed with impaired glucose tolerance, were included in Group 5. All the groups were compared in terms of obstetric and perinatal outcomes. RESULTS: Cut-off scores of 50-gram glucose challenge test were found to be 153.5 mg/dl. It was observed that the glycemic values increased as the mean of delivery week decreased. The differences between all groups were found to be statistically significant with regard to macrosomia, large for gestational age, presentation anomalies, polyhydramnios, ablatio placentae, preeclampsia and gestational hypertension. Increase in the rate ratio was observed for the glycemic values, they got higher. The results showed statistically significant differences between all groups in terms of neonatal hospitalizations after birth and observation rates. CONCLUSION: The patients with a 50-gram glucose challenge test 1st hour glucose values of 180 mg/dl or higher are associated with poor perinatal and fetal outcomes. PMID- 22926362 TI - Is adenomyosis associated with the risk of endometrial cancer? AB - AIM: To evaluate an association of adenomyosis with endometrial cancer and to determine the frequency of adenomyosis at hysterectomy specimens. METHODS: This study was carried out retrospectively on pathologic specimens of hysterectomies. A total of 472 women in the period 2007-2011 enrolled to the study. All pathologies seen in hysterectomy specimens were noted. The frequency of adenomyosis and the accompanying pathologies were determined. These women were categorized into two groups according to the presence of adenomyosis. The incidence of adenomyosis was analyzed together with the endometrial cancer. RESULTS: The incidence of adenomyosis was 20.8% at hysterectomy specimens. There was no statistically significant difference between the mean age of the two groups (p = 0.069). There were 98 cases with adenomyosis and the only pathologic finding was adenomyosis, in 28 (28.5%) cases. The most common accompanying pathologies with adenomyosis were uterine myomas in 51 (52%), uterine polyps in 16 (16.3%) and endometrial carcinomas in 11 (11.2%) cases. However, statistically significant association of the presence of adenomyosis with uterine myoma (p = 0.227) and endometrial polyps (p = 0.997) and endometrial carcinoma (p = 0.771) was not found. CONCLUSION: In hysterectomy specimens, no statistically significant difference was determined between the groups with and without adenomyosis in terms of co-occurrence with endometrial carcinoma. PMID- 22926363 TI - Impact of active female smoking on controlled ovarian stimulation in intracytoplasmic sperm insemination cycles. AB - AIM: To examine the impact of smoking among females on controlled ovarian stimulation (COS), at intra-cytoplasmatic sperm injection (ICSI) outcome. METHODS: A prospective analysis of outcomes of 876 women (fresh, non donor cycles) of which 559 (63.8%) were non-smokers, 317 (36.2%) were smokers, underwent standard COS/ICSI treatment. RESULTS: Among smokers, the average time of COS, expressed in days, was significantly longer compared with non-smokers (10.5+/-2.10 vs. 10+/-1.90 p less than 0, 05). There were no registered significant differences in the number of retrieved oocytes, (10.4+/-6.8 vs10.3+/ 6.9), mature oocytes (8.6+/-5.8 vs. 8.4+/-5.9), in the group of non-smokers versus smokers. However, smoking and age have a significant impact of the number of high-quality embryos, i.e. older smokers had a lower number of high-quality transferred embryos (non-smokers >= 35 years : smokers >= 35 years; 1.9+/-1.1 vs. 1.6+/-1). On multiple logistic regression analysis, factor that had a significantly negative impact of clinical pregnancy was maternal age. CONCLUSION: Smoking among patients entering the COS and ICSI fertilization process had insignificant negative impact on the final outcome of the process resulting in reduced pregnancy rate. The chance for the pregnancy declines with age, but smoking did not significantly influence the outcome. PMID- 22926364 TI - The significance of Helicobacter pylori in patients with nasal polyposis. AB - AIM: To determine the presence of Helicobacter pylori in nasal polyps and the transmission of H. pylori from stomach to nasal polyps. METHODS: In a prospective, controlled clinical research, 35 subjects with nasal polyps and 30 controls with concha bullosa (CB) were involved, and had been subjected to endoscopic sinus surgery (ESS). In the biopsies of removed polyps and CB, polymerase chain reaction (PCR) was used for detecting the H. pylori DNA. Blood samples of the test and control group were evaluated for H. pylori immunoglobulin (Ig) G and A antibodies by ELISA. The test and control group underwent esophagogastroduodenoscopy with taking biopsies from the stomach for PCR detection of H. pylori DNA. RESULTS: In blood samples, specific IgG and IgA antibodies to H. pylori were found in 30 (85.71%) of 35 polyp patients and in 16 (53.33%) of 30 controls. In 10 (28.57%) of 35 patients H. pylori DNA was identified in the nasal polyp tissue, but it was not detected in the CB specimens. H. pylori DNA was found in the stomach mucosa samples of all test and control group of subjects. Significant statistical difference was found in the H.pylori specific IgG and IgA between the test and control group (p less 0.006) and between the polyp and control biopsy specimens of H. pylori DNA by PCR (p less 0.001). CONCLUSION: This research points to the colonisation of nasal polyps with H. pylori, the transfer of H. pylori from stomach to nasal polyps and potential role of H. pylori in emergence of nasal polyps. PMID- 22926365 TI - Quality of life in patients with larygeal/hypopharyngeal cancer following total/partial laryngectomy. AB - AIM: To estimate the quality of life (QOL) of patients with carcinoma of larynx/hypopharynx using the EORTC QLQ-C30 and QLQ-H and N35 questionnaires in relation to the reference values (RV), total (TL) / partial (PL) laryngectomy/ pharyngectomy, combined treatment (surgery, radiotherapy, chemotherapy) (CT) and the time elapsed since surgery. METHODS: The questionnaires were answered by 45 patients in the first 6 months of 2011. Sixteen (35.6%) patients had PL and 29 (64.4%) TL. Postoperatively, CT was performed in 34 (75.6%) patients (group A), and 11 (24.4%) patients (group B) only had surgery. The time elapsed from surgery of <=12 months was found in 11 (24.4%) patients in the group A1, and 34 (75.6%) of more than 12 months in the group B1. Comparison was made between all scales of the questionnaires, global (GS), functional (FS) and general symptomatic (GSS) QLQ-C30 and specific symptomatic scale (SSS) QLQ-H and N35. RESULTS: Comparing our results from all scales of both questionnaires with RV there was no statistically significant differences, except for SSS relating to speech problems (p=0.052574). Comparing PL and TL there was a decrease in FS (p=0.025517) and increased problems with speech, swallowing, sensation, coughing and social contact in SSS (p=0.017595) in TL. Comparing A and B groups, there was a decrease in FS (p=0.00531) increase of all symptoms in GSS (p=0.043388) and SSS (p=0.0505385) in the A group. Comparing A1 and B1 groups better FS (p=0.042271) was registered in A1. CONCLUSION: Quality of life of our patients is not significantly different from the QOL of similar patients in the world. Comparing all groups, QLQ-C30 and QLQ-H and N35 showed us clear differences in QOL and their clinical use is justified. PMID- 22926366 TI - Heterophoria and fusional convergence and divergence in preschool children. AB - AIM: To determine the prevalence of heterophoria, fusional convergence and divergence values and the degree of relationship between heterophoria and fusional vergence in preschool children. METHODS: For assessment of far and near heterophoria in 152 children aged 6-7, cover and prism cover tests were used. Far and near fusional vergences were measured by step vergence testing using prism bars. RESULTS: Orthophoria (-tropia) with the average values of heterophoria around 0 PD (prism diopter) were most common at far, and exophoria around 2 PD at near. The average break values of far fusional convergence and divergence were 13.7 +/- 4.4 PD and 7.3 +/- 2.1 PD, respectively. Near fusional convergence and divergence break values were 29.6 +/- 6.6 PD and 16.2 +/- 4.1 PD, respectively. The recovery values were from 1/3 to 1/2 lower than the break values. The correlation between heterophoria at far and far fusional convergence and heterohoria at near and near fusional convergence and divergence was weak, yet significant (r = 0.18 - 0.26; p less than 0.05). CONCLUSION: In preschool children the prevalence of heterophoria, and values of fusional vergence were in the ranges of values for elementary school children and adults cited in the literature. Heterophoria and fusional convergence at far, and heterophoria and fusional vergences at near have shown a weak relationship. PMID- 22926367 TI - The prevalence rate of hepatitis B and hepatitis C co-infection in HIV positive patients in Mazandaran province, Iran. AB - AIM: To investigate the prevalence rate of hepatitis B (HVB) and hepatitis C (HCV) co-infection in HIV positives in Mazandaran province. METHODS: This descriptive cross-sectional study lasted from 2008 to 2010. The population of this study included 188 HIV positive persons confirmed to be infected by tests of ELISA I, II and western blood (WB) in the hospitals of Mazandaran University of Medical Sciences and Health Services. After getting permission, 5 cc venous blood samples were taken and drawn into a lab tube without citrate. RESULTS: Among the total of 188 HIV positive patients in Mazandaran province, only 80 patients were available, 62 had moved to other provinces, and 46 had died. Of the samples, 66 (82.5%) were males and 14 (17.5%) were females with the mean age of 37. Among the patients, nine (11.3%) were co-infected with HIV/ HBV, 27(33.8%) with HIV/HCV, while 20 (25%) were co-infected with HIV/HBV/ HCV. Only one patient had travelled abroad and eight of them stated that they had used shared syringes. CONCLUSION: The differences in the rate of HBV and HCV co-infection can be due to the epidemiologic conditions of viruses with different factors including different risk factors causing infection with these factors such as the rate of virus penetrating the body, the manner of penetration, patients' health condition, patients' culture, and their socio-economic condition, etc. PMID- 22926368 TI - Occurrence of colonization and infection with multidrug-resistant organisms in a neonatal intensive care unit. AB - AIM: To determine the occurrence of colonization and subsequent infection with multidrug-resistant organisms (MDROs) among patients in the neonatal intensive care unit and to assess the yield of surveillance cultures. METHODS: Cultures of nose, throat and stool were obtained from 196 neonates admitted to the Neonatal Intensive Care Unit (NICU) at the Clinical Center of the University of Sarajevo in the six-month period upon admission and once a week if the length of stay was more than seven days. At the same time clinical relevant samples (blood, urine, CSF, wounds swabs, tracheal aspirates) were examined for presence of MDROs. Identification and antibiotic sensitivity pattern of organisms were determined according to the CLSI. RESULTS: A total of 126 (64.3%) patients were identified as colonized and 50 (25.5%) as infected with MDROs. 44.4% (56) of patients were colonized on admission. Fecal carriage was most common with extended-spectrum beta lactamase (ESBL)-producing Klebsiella pneumonia, and nose/throat with Acinetobacter baumannii. The patients become colonized more often during the first week of hospitalization (31.7%; p less .001). The infection is more observed in patients who had previously been colonized than those who had not (78% vs. 22%; p less 0.05). The most common infection was the blood infection (bacteremia). The median length of stay in neonates with an infection was 3.5 weeks and without infection 1 week (p less than 0.001). CONCLUSION: An infection was more frequently observed in patients who had been previously colonized than those who had not. Microbial surveillance is necessary to detect colonized neonates when multidrug-resistant organisms become epidemic. PMID- 22926369 TI - Acinetobacter baumannii as a cause of sepsis. AB - AIM: To analyze the frequency and antimicrobial resistance of Acinetobacter baumannii isolated from blood cultures. METHODS: Blood cultures of all consecutive patients hospitalized in different departments of the University Clinical Centre of Sarajevo from January 2003 to December 2010 were processed by "BACTEC 9120" system. The isolates were identified by conventional methods. Susceptibility testing was performed by disc-diffusion method following guidelines from the Clinical Laboratory Standards Institute (CLSI). RESULTS: A total of 93,215 blood cultures were examined, 6,338 (6.8%) were positive. Acinetobacter baumannii was isolated in 283 (4.5%) cases. Overall yearly resistance rates to antibiotics had an increasing trend during the eight year period: amicacin from 45.3% to 71.4%; gentamycin from 70.6% to 83.2%; ciprofloxacin from 60.6% to 85.8%; carbapenems (imipenem and meropenem) from 0% to 52.8%. Carbapenem-resistant Acinetobacter baumannii (CRAB) emerged in 2009 and was rapidly disseminated in intensive care units. Resistance to tobramycin and colistin was not detected. CONCLUSION: High resistance rates and an increase of Acinetobacter baumannii to all antimicrobials, especially to carbapenems, were noted. The dissemination of carbapenem-resistant isolate may indicate the appearance of untreatable infection by this organism. It points out the rationality in prescribing antimicrobial drugs. PMID- 22926370 TI - Spread of CTX-M-15 positive Providencia spp. causing urinary tract infections at the University Hospital Split in Croatia. AB - AIM: During 2010-2011, six Providencia spp. (five Providencia stuartii and one Providencia rettgeri) urine isolates with unusual resistance phenotype were collected from various hospital units at the University Hospital Split in Croatia. The aim of the study was to analyze the mechanisms of resistance to expanded-spectrum cephalosporins. METHODS: The antimicrobial susceptibility to a wide range of antibiotics was determined by broth microdilution method according to CLSI guidelines. A double-disk-synergy test (DDST) was performed to detect ESBLs. The transferability of cefotaxime resistance was determined by conjugation. The presence of genes encoding ESBLs was determined by PCR while genotyping of the isolates was performed by PFGE. RESULTS: All strains were positive for ESBL production by DDST. They were uniformly resistant to amoxycillin alone and combined with clavulanate, cefazoline, cefuroxime, ceftazidime, cefotaxime, ceftriaxone, gentamicin and ciprofloxacin. P. stuartii strains transferred cefotaxime resistance to E. coli recipient strain with frequency ranging from 10-5 to 5x10-4. Five P. stuartii strains were positive for TEM and CTX-M beta-lactamases while P. rettgeri was positive only for TEM beta lactamases. Five CTX-M producing isolates were shown to be clonally related. CONCLUSIONS: Continuous surveillance in tracking CTX-M-15- producing P. stuartii in the hospitals is necessary to prevent their spread to other hospitals and community. Global spread of ESBL positive Providencia spp all over the world is of great clinical concern. PMID- 22926371 TI - Staphylococcus aureus carriage among medical students. AB - AIM: To investigate the frequency of S. aureus isolation from the nose among students in relation to age, gender, and year of the study. METHODS: A retrospective study included 387 students who performed sanitary examination at the Department of Microbiology, School of Medicine, University of Sarajevo. The bacterial strains were identified by conventional method and the antibiotic resistance was carried out by disc diffusion method. RESULTS: The overall carriage rate of Staphylococcus aureus was 10.6%. S. aureus were isolated in 58.54% female and 41.46% male students (p more than 0.05). S. aureus was isolated in 22 (10.8%) in the age group 22-26, and in 17 (10.2%) students in the age group 27-32 The lowest prevalence of isolates was in the 33-38 age group, with only two (12.5%) (p more than 0.05). According to the year of the study, the greatest number of S. aureus strains was present in the fourth year, 21 (14.5%), while the smallest one was in the sixth year, 4 (3.3%). CONCLUSION: No significant differences were found in the frequency of isolates in relation to age and gender of students, but it was found in relation to the year of the study. The study identifies the importance of medical students as possible agents of transmission in the hospital environment. PMID- 22926372 TI - Microbial colonization of the external auditory canal and nose in hemodialysis patients. AB - AIM: The aim of our study is to determine the microbiology of the external auditory canal and nose in uremic patients on chronic dialysis. METHODS: All patients undergoing regular hemodialysis for at least 3 months were included in this study. The nasal and external auditory canal swabs were collected from 83 haemodialysed patients. RESULTS: From 83 patients (37 females, 46 males) nasal and external auditory canal cultures were obtained. Mean duration on dialysis was 41.75 +/- 45 months and mean age of patients was 61 +/- 13 years. Microflora in the nasal cavities (70/80, 87.5%) and external auditory canal (48/59, 81.3%) were similar in all culture positive patients (coagulase-negative staphylococci). Coexistence of coagulase- negative staphylococci and diphteroids was detected in 20 patients' (25.0%) nasal vestibule and in eight patients' (13.5%) external auditory canal. CONCLUSION: Microflora in the nasal cavities and external auditory canal were similar in chronic renal patients. External auditory canal microflora was not associated with history of diabetes mellitus, hepatitis status and starting date of hemodialysis in our study. PMID- 22926373 TI - Complex regional pain syndrome type I in the upper extremity - how efficient physical therapy and rehabilitation are. AB - AIM: To evaluate the effects of early started combined therapy in Complex Regional Pain Syndrome-1 (CRPS-1) on the upper extremities. METHODS: The study included 36 patients in the first stadium of CRPS-1 on the upper extremities The mean age of patients was 42.6+/-14.6, the majority of them (26 of 36) were females. The right side of the upper extremity was affected much more then the left side. They were treated by combined therapy including analgetics, electrotherapy, magneto therapy and kinesitherapy. The average length of observation was 172.1 days (from 90 to 250 days). The average length of treatment was 91.5+/-42.16 days. Intensity of pain, swelling of the extremity, the change in skin coloration and cutaneous manifestations were assessed three times, at the beginning of the treatment, after 6 weeks and at the end of the treatment. RESULTS: The pain was registered in all patients at visit 1 (average pain intensity was 5.70 +/-1.44 on 100 mm visual analogue scale), and it was progressively decreased during the treatment from 3.60+/-1.22 at the second visit to 0.34+/-0.68 at the third visit. Vasodilatation was registered in 30 (83.33%) patients and skin temperature asymmetries was found in 21 (58.33%) patients. The difference of size was detected in 30 (83.33%) patients at the first visit compared to four (11.11%) patients at the end of the treatment. There were six (16.66%) patients without swelling at the beginning compared to 26 (72.22%) at the end of the treatment (p less than 0.000). Complete healing was achieved in 32 patients (88.88%). CONCLUSION: The carefully chosen physical agents in combination with analgesic and non-steroidal anti-inflammatory drugs may benefit in patients with CRPS-1 on the upper extremity if the treatment starts as soon as possible. PMID- 22926374 TI - Prevalence of permanent and transient congenital hypothyroidism in Babol City Iran. AB - AIM: To determine the incidence of transient and permanent hypothyroidism in Babol, Iran. METHODS: The cross sectional study on 10,573 newborns who participated in a thyroid screening program in Babol between 2006 and 2008 was performed. It recalled patients who had been diagnosed in the initial screening program and treated for at least 3 years, discontinued their treatment for 4 weeks and then measured their plasma thyroid hormone concentrations. If their thyroid stimulating hormone (TSH) concentration was greater than 10 m/l they were considered to have permanent CH. T3 uptake, T4 and TSH were measured in venous blood samples. Other information collected and recorded included age, presence of diabetes, birth weight and gestational age at birth. RESULTS: The incidence of transient and permanent hypothyroidism in the studied infants was 5.7 and 20.8 per 10,000, respectively. The incidence of transient hypothyroidism in male and female infants was 16.9 and 24.6 per 10,000, respectively, and of permanent hypothyroidism in male and female infants 7.5 and 3.8 per 10,000, respectively. CONCLUSION: A noteworthy incidence of permanent hypothyroidism in infants found in this study confirms that screening programs need to be continued in our region and that interventions to address the causes of hypothyroidism are necessary. PMID- 22926375 TI - A prospective study of patients absconding from a psychiatric hospital in Iran. AB - AIM: To investigate the motivation and characteristics of patients absconding from a psychiatric ward in Iran. METHODS: A prospective study was conducted for patients who absconded from psychiatric ward in the period between July 2010 and July 2011. The variables were patients' age, gender, hospital stay, substance abuse, psychiatric diagnosis and site of absconding. All patients were interviewed to assess their motivation for absconding. RESULTS: Over a one-year period of data collection 56 absconding events were recorded, with the incidence rate of 4.24%. The mean age of absconders was 31+8.4 years, 47 (83.9%) absconders were males, 28 (50.9%) absconds happened through the park fence. Bipolar mood disorder or schizophrenia was the diagnosis of 23 (41%) absconders. The mean number of days of hospitalization in patients who left the wards was 11 days. The main motivation to abscond was boredom from the ward environment and missing the family. CONCLUSION: The risk of absconding is highest in the early days of admission especially in male, young patients with diagnosis of bipolar mood disorder or schizophrenia. PMID- 22926376 TI - Sociodemographic and clinical characteristics of hospitalized patients after suicide attempt: a twenty-year retrospective study. AB - AIM: To determine the frequency and distribution of suicide attempts relating to the manner of execution and other demographic an clinical characteristics, as well as to point to possible risk factors. METHODS: A retrospective anamnestic study was conducted covering a twenty-year period (1990 to 2010) which included 715 patients (310 males and 405 females), who were hospitalized and treated at the Psychiatric Clinic of the Clinical Center in Kragujevac following a suicide attempt. RESULTS: The incidence rate of suicide attempts was 19.5 per 100,000 citizens. The number of suicide attempts was found to be greater in females, 405 (56.5%). The greatest number of individuals was younger (25 to 34 years of age), 149 (20.9%) and the average age of the population attempting suicide was 42.6 years. The predominant mental disorder preceding the suicide attempt was depression, 346 (48.4%). The method most frequently used in the attempt was poisoning in both genders, 395 (55.3%) often by benzodiazepine overdose. The greatest number of suicide attempts occurs in spring and summer, 400 (over 50%). CONCLUSION: An increased number of hospitalizations due to suicide attempts was noted, therefore, special attention should be paid to detection and treatment of depression disorders and patients who have attempted suicide repeatedly. PMID- 22926377 TI - Psychometric properties of the Pediatric Symptom Checklist in preschool children in Serbia. AB - AIM: To demonstrate the use of the Pediatric Symptom Checklist (PSC) as a tool for screening problems in psychosocial development in preschool children in Serbia. METHODS: The form was filled out by parents to 269 children. The statistical and metric characteristics of the Pediatric Symptom Checklist were analyzed, while cut-off values were compared with the values reported from other countries. RESULTS: The PSC scale filled out by parents was found to have acceptable reliability in our sample of preschool children. A high level of reliability of the scale was achieved (a = 0.86). Average values on the scale were lower than in other analyses. There was no statistically significant difference in behavioral traits in regards to children's gender (p=0.53). Factor analysis of the Pediatric Symptom Checklist scale (promax solution) established an existence of a general factor. This general factor is structured with internal and external behavioral traits, as well as with impulsiveness and attention deficit in preschool children. Based on our cut-off value, the need of further follow up was established in 10.4% of study children (n=28, 17 male and 11 female). CONCLUSIONS: The study revealed that the PSC filled out by parents is a good tool for early and rapid identification of potential problems of psychosocial functioning of preschool children. It should be noted that a positive PSC score was not a diagnosis but an indication for additional analysis and assessment of the children and their families. PMID- 22926378 TI - Perceived parental acceptance/rejection and psychopathology in a group of sexually abused children/adolescents. AB - AIM: To investigate perceived maternal acceptance/rejection in a group of sexually abused children/adolescents. Quality of the relationship between caregiver and child has been linked to many behavioral and emotional problems of childhood. For those children/ adolescents subject to sexual abuse, perceived parental acceptance/ rejection is an important component of well being. METHODS: A total of 28 abused children/adolescents and their mothers participated in the study. The victims were sent by the court to the Uludag University Child and Adolescent Psychiatry Department for psychiatric evaluation. Numerical variables are presented with mean and standard deviation, categorical variables were presented as frequencies and percentages. Nonparametric correlation analysis was used for the relationship between psychological adjustment and perceived parental acceptance of children. RESULTS: The results of the study show that there was a significant correlation among child and mother reports of perceived acceptance. Children/adolescents also displayed more psychological adjustment than maladjustment. According to the Children's Depression Inventory, 15 victims were depressed and 13 were not. There was no remarkable difference between depressed and non-depressed subjects in terms of depression scores. Overall, the results of the study showed that both abused children/adolescents and their mothers perceived a positive relationship as measured by Perceived Parental Acceptance and Rejection Questionnaire-Control scores. CONCLUSION: The findings suggested that a well-established, healthy emotional bond is resilient to challenges, as was the case in the sexually abused children/adolescents of the study. PMID- 22926379 TI - Outpatient utilization of psychopharmaceuticals: comparison between the cities of Zagreb and Sarajevo (2006-2009). AB - AIM: To determine the real outpatient utilization of psychiatric drugs in Zagreb (Croatia) and Sarajevo (Bosnia and Herzegovina) and to compare the outpatient utilization of psychiatric drugs between this two cities. METHODS: Data on the outpatient utilization of psycholpetics and psychoanaleptics (N05 and N06) in both cities were received from pharmacies and collected during 2006-2009. Based on the data obtained, a number of DDD and DDD per 1000 inhabitants perday (DDD/1000/day) has been calculated. The data in Zagreb were received from all pharmacies in Zagreb, whereas only 50% of pharmacies in Sarajevo participated, thus an extrapolation of data for Sarajevo was required and accomplished. All drugs were classified according to the ATC system. Based on the data obtained, a number of DDD and DDD/1000/day was calculated for all N05 and N06 drugs. RESULTS: Overall utilization trend was similar between the cities Sarajevo and Zagreb and followed trends in other neighbouring countries. Total consumption of psycholeptics and psychoanaleptics in Sarajevo was 22.6% (on average) lower than in Zagreb, during the 4-year period. CONCLUSION: During the 2006-2009 period the total consumption of psychopharmaceuticals showed increasing trend with peak in 2008 with similar trend between Zagreb and Sarajevo. It is necessary to implement systematic approach to drug utilization monitoring in Sarajevo and Bosnia and Herzegovina in general in order to improve prescribing quality as it is done in Croatia. PMID- 22926380 TI - Patient's satisfaction with removable dentures after relining. AB - AIM: To reveal patients' satisfaction with their old, usually poorly fitting dentures and the effect of denture relining to the patient's satisfaction. METHODS: Thirty seven denture wearers participated in study by filling out questionnaires about their satisfaction with dentures before and after relining. In that way the data indicating the subjective patient's experience and satisfaction were collected. RESULTS: Relined removable dentures included in study were on average 5.52 years (upper) or 4.86 years old (lower). Most of study participants (57%) were satisfied with their poor fitting dentures. Statistically significant was correlation between chewing discomfort and satisfaction, and the time elapsed from last tooth extraction to denture production. As this period was shorter, chewing discomfort was greater and satisfaction with chewing lower. Majority (53.3%) of denture wearers were considerably more satisfied with the chewing ability and felt better regarding the chewing discomfort after denture relining. Minority of the patients (22%) still used an adhesive for fixing the dentures after relining. CONCLUSION: Denture relining affects patient's satisfaction with their dentures. After relining patient's masticatory function was improved, satisfaction with chewing ability and comfort were greater, and denture hygiene better. Denture relining should be performed in order to improve denture fitting to a denture bearing area, thus positively affecting patient's satisfaction with his denture(s). PMID- 22926381 TI - Study of obligations defined in agreements between parties involved in clinical trials of medicinal products in Bulgaria. AB - AIM: To analyse and assess the legislative and contractual obligations of the parties involved in the conduct of clinical trials, with identification of the needs for comprehensive contractual regulation of their rights and responsibilities. METHODS: This survey has been carried out by means of review, analysis of comprehensiveness, comparative legislative analysis and assessment of compliance with the legislation of sample of investigator and site agreements governing the process of conducting clinical trials. RESULTS: The survey comprises analyses of contractual relations between the sponsor of the study and the investigator, and between the sponsor of the study and the trial site, respectively, relevant to clinical trials which are actually conducted in Bulgaria at the time of and following the survey. Comparative method based on pre defined structured indices was employed to outline the major variances in the volume of responsibilities and obligations of the said parties to the clinical trial, as regulated by the investigator and site agreements. The analysis of comprehensiveness showed evident omissions in the regulation of relations and interactions between the parties to the agreements. CONCLUSION: The detailed contractual regulation providing for the statutory obligations and responsibilities of the parties involved in the conduct of clinical trials is a good guarantee for proper understanding of the obligations of each party and for compliance with their relevant responsibilities in view of protecting the rights of the participants in the clinical trials - patients or healthy volunteers. PMID- 22926382 TI - Evaluation of quality of life after radical prostatectomy-experience in Serbia. AB - The aim of this study was to compare health related quality of life (QoL) of patients with prostate cancer, who had undergone radical prostatectomy (RP), with patients who were carefully monitored. This prospective study included 56 patients who had undergone the radical prostatectomy (RP) and 48 non-operated patients (watchful waiting, WW). All patients filled EPIC questionnaire at baseline, 1th, 3rd, 6th and 12th month. At baseline, mean scores were similar in both groups, but one month after the surgery in RP group, patients had statistically significant lower score of urinary incontinency, urinary function and sexual function compared with WW patients. These scores were significantly higher in the 3rd, 6th and 12th month in operated patients, but there was no improvement in the WW group. Radical prostatectomy does not significantly improve quality of life. Prostatectomized patients had worse scores on the QoL scale, with exception of the urinary disturbance dimension. PMID- 22926383 TI - The first survey about the antibiotic usage in the Republic of Macedonia. AB - Development of antibiotic resistance represents a major global and Macedonian public health problem. To assess the opinion and knowledge of the citizens of Macedonia about the usage of antibiotics, voluntary and anonymous survey was realized. A total of 239 persons (age 10-67 years) were interviewed. Following information was obtained: 73.64% get antibiotics with a medical prescription; and 87.03% receiving the antibiotic on time, dosage and prescribed duration. When asked about knowledge about antibiotics, 38% of the interviewed persons gave the right answer, 43.1% of respondents made false statements that antibiotics are effective against viral infections and 25.52% did not express any opinion. PMID- 22926384 TI - The correlation of average monthly ambient sulfur dioxide concentration and the use of inhalation bronchodilators in children. AB - The aim of this study was to determine the correlation between average monthly concentrations of sulfur dioxide and a rate of prescribed inhalation bronchodilator therapy in children aged under 6 years during 2011 in Zenica city. The average monthly concentration of sulfur dioxide of 231MUg/m3 recorded in January, 82 MUg/m3 in July and 296MUg/m3 in December was noted. The monthly rate of prescribed inhalation bronchodilators in examined 100 children was 15.4% in January, 7.8% in July and 18.1% in December (r = 0.666; p less than 0.05). The increase in the average monthly concentration of sulfur dioxide in ambient air had an effect on the increase in the rate of applied inhalation bronchodilator therapy in children aged under 6 years. PMID- 22926385 TI - Takotsubo cardiomyopathy - the broken heart syndrome. AB - This report describes a case of a seventy -year old woman with the special form of acute coronary syndrome (ACS) preceded by acute emotional stress. The coronarography revealed normal coronary arteries, however cardiac enzymes and catecholamines had increased values. Electrocardiogram indicated the changes characteristic of either acute coronary syndrome or myocarditis. PMID- 22926386 TI - From hypoglycemia to right heart infarction: treatment of hypoglycemia in type 1 diabetes. AB - This case report presents a young 30-year old male patient with type 1 diabetes mellitus, who was treated for hypoglycemia and a general bad feeling. He was somnolent, pale, sweaty, hypotensive (65/40 mmHg) with bradycardia (40 beats per min) and additional workup revealed right myocardial infarction. Since diabetes causes neuropathy, it is important to keep in mind that chest pain in acute coronary syndrome can be absent in diabetic patients suggesting that if a patient with hypoglycemia has additional symptoms or if the general condition does not improve after glycemic control, additional investigation should always be performed. PMID- 22926387 TI - HbA1C - overall glycemia marker and hemolytic anemia indicator. AB - Glycated hemoglobin A1C reflects a mean glycemia over the preceding 3 months (erythrocyte life span). In diabetes management, target value is set below 6.5%, to reduce the risk of chronic complications. However, there are different conditions that lead to a shortened lifespan of erythrocytes, resulting in falsely low HbA1C value. Case presented involves a 72-year-old patient with history of diabetes and possible iatrogenic-induced autoimmune hemolytic anemia. Thus, HbA1C may be a screening test for hemolysis in non-diabetic patients with hemolytic anemia, but in diabetic population with hemolytic disease it is considered to be a very poor marker for both, overall glycemia and haemolysis. PMID- 22926388 TI - Atypical localization of lung cancer located in lobus v. azygos. AB - Lobus v. azygos (lobe of the azygos vein, azygos lobe) is an accessory lobe of the right upper lobe of the lung that corresponds to the anatomical variety. The presence of expansive lesions in it represents unusual radiographic findings. This paper presents the case of a patient with an extensive expansion process in azygos lobe, radiologically diagnosed by standard radiography (X-ray) and Multislice Computed Tomography Scan (MSCT). The process was subsequently treated surgically and confirmed histologically as a non-small-cell lung adenocarcinoma. PMID- 22926389 TI - An unusually large liver lipoma. AB - Liver lipoma is an extremely rare tumor. Its nature and behavior is not well known since available information is based mostly on individual case reports. This report presents a case of liver lipoma mimicking malignant liver tumor. The patient was 72-year female with 5-year history of right upper abdominal quadrant pain. Diagnostic work-up revealed a large liver tumor mass, suspicious of malignancy. However, patohistological analysis found it to be lipoma. Because of extremely low incidence of liver lipoma, especially large ones, appropriate diagnostic work-up is very important for its differentiation from malignant tumors. PMID- 22926390 TI - Complete spontaneous resolution of compressive chronic subdural hematoma in a patient with liver failure. AB - Chronic subdural hematoma is usually caused by minor head trauma and occurs frequently with older people. Predisposing factors include alcohol abuse, epilepsy and coagulopathy. This report presents a 65-year old woman who had a large, mixed density, left sided compressive chronic subdural hematoma diagnosed by computed tomography. She also displayed a moderate neurological deficit on admission, confusion and behavioral disorder with Glasgow Coma Score 10. The computed tomography and neurological parameters indicated the necessity of surgery. A difficult general condition and coagulation factor disorder in this patient were determinative for the decision for non-operative treatment. It is very rare that a large chronic subdural hematoma is resolved completely spontaneously, but in our case conservative treatment gave an excellent result. PMID- 22926391 TI - Modern approach in therapy of brain edema in cerebral ischemia. AB - Based on the national data register in Serbia, every 20 min a person develops acute stroke, and every 60 min one dies of the same disease. Studies have shown that during the first 24-40 hours patients develop cytotoxic brain edema and increased intracranial pressure. Up-to-date therapeutic concept must take into consideration possible pathophysiological processes, so that antiedematous therapy becomes an unavoidable segment of this program. The paper presents a female patient who had cerebral ischemia out-of- hospital to develop brain edema three years later. The diagnostic and therapeutic approach to this problem was in accordance with the National Guidelines for Brain Ischemic Disease. PMID- 22926392 TI - Giant craniopharyngioma: 9-year follow up after stereotactic Yttrium -90 instillation and microsurgical resection. AB - The primary goal in craniopharyngioma treatment is a gross total neurosurgical resection. This paper presents a case with good outcome following a gross total removal of giant juvenile craniopharyngioma. There is a strong relationship between surgical experience in treating these lesions and the probability of total tumor resection without significant morbidity and mortality. The discussion on usefulness of stereotactic instillation of radioactive Yttrium-90 in the tumor cyst and bilateral fronto-orbital microsurgical approach utilized in 12-year-old male patient was conducted. A detailed description of the operative procedure was provided with comparison to other approaches commonly used for giant craniopharingioma. The long term (9 years) and intensive follow up showed good outcome without tumor recurrence. The patient has been receiving lifelong hormones substitution. PMID- 22926393 TI - A surgical thread as a nidus for the common bile duct stone formation. AB - A 68-year old patient, who had had cholecistectomy when he was 30 years old and had been hospitalized in several occasions, with clinical presentation of recidivant cholangitis was admitted to county hospital. Computed tomography was performed, where a bile duct dilatation was noted, with suspected 12 mm concrement. After that the patient was referred to the hospital in order to undergo therapeutic endoscopic retrograde cholangiopancreatography. After performing the procedure, the presence of the concrement, 12x25mm in size was confirmed. It was evacuated during mechanical lithotripsy along with a part of surgical thread, which could not have been extracted entirely. A surgery had to be performed because the patient developed cholestasis. Forming of choledocholith most likely developed on the matrix of surgical thread, which is a rare cause of choledocholithiasis. PMID- 22926394 TI - Atypical intrauterine parvo b19 infection. AB - Human parvovirus B19 is a single-stranded DNA virus. During pregnancy, parvovirus B19 infection can be asymptomatic or cause a variety of signs of fetal damage, fetal anemia, nonimmune hydrops fetalis, spontaneous abortion and can result in fetal death. Recent improvements in diagnosing parvovirus infections and the availability of intrauterine transfusion have reduced the overall rate of fetal loss after maternal exposure. There is an approximately 30% risk of vertical transmission and 1% of hydrops. We report of the first case of vertical parvovirus B19 infection with atypical manifestations in our clinic. The neonate had pleural effusion associated with anaemia. PMID- 22926395 TI - Subcutaneous fat necrosis in newborns. AB - Subcutaneous fat necrosis of newborns is a transient, benign process in full- term or postmature neonates. It is associated with perinatal distress. Newborn stress inhibits immature enzyme system, which already has relative inability to desaturate saturated fatty acids. It leads to fat crystillisation and necrosis. Skin biopsy revealed necrotic focus and crystallisation in fat cells. Hypercalcemia may be a potential complication. PMID- 22926396 TI - Panophthalmitis after spontaneous perforation in glaucomatous eye. AB - Panophthalmitis is an acute, purulent inflammation of the eyeball that involves all its structures and extends into the orbit. A case of a fifty-seven year old male treated earlier due to glaucoma and trophic ulcus of the cornea, was presented in this paper. He was admitted to hospital with intensive orbital pain and redness of the right eye, elevated body temperature, bulbus protrusion with limited movement, chemosis, edematous cornea, hypopyon, iris of invisible drawing and relief. The ocular fundus was not visible. At the admittance, amaurosis of the right eye was present as well as spontaneous cornea perforation. The patient was treated with antibiotic, corticosteroid, analgesic and antiglaucomatous therapy. Intravitreal administration of antibiotics was impossible due to spontaneous cornea perforation. The patient was discharged from the hospital in a good general condition. The condition of the right eye was stable, there was no danger of eye loss, while infection of the same eye was cured. PMID- 22926397 TI - Neuroretinitis caused by Bartonella quintana. AB - A 57-year-old woman presented to the eye clinic for impaired vision on the left eye persisting for three months. Clinical examination revealed massive peripapillary exudate and stellate macular exudate, raising suspicion of a cat scratch disease. Tetracycline therapy was introduced, followed by azithromycin and topical corticosteroids. Serologic testing for Bartonella henselae and Bartonella quintana was performed. In the first sample, Bartonella quintana IgG titer was 128, and IgM titer 20, whereas in repeat sample the respective findings were 64 and negative. Such a titer dynamics pointed to Bartonella quintana infection. The prescribed therapy resulted in vision improvement and normalization of the clinical picture. After nine months of therapy initiation, macular exudate had almost completely disappeared. Based on the patient's history, symptoms, therapeutic response and IgM pattern, the neuroretinitis must have developed secondary to Bartonella quintana infection. PMID- 22926398 TI - Twenty one months of frontal sinus stenting. AB - The success of a frontal sinus endoscopic or external operation depends on the postoperative stenosis of the frontal sinus ostium. Formation of a stenosis can be prevented by placing a stent in the frontal sinus ostium. The period optimal for leaving the stent in the sinus ostium is yet to be established, but experts recommend a maximum six months period. This case report presents a female patient who underwent an endoscopic bilateral frontal sinus operation in 2005. Postoperatively, she developed a stenosis of the right frontal sinus recess which resulted in a series of reoperations. At the end of 2009, a Medtronix Xomed Incl Parell T-Frontal Stent was inserted by external approach. At the 21-month followup, the patient was still free from discomfort with the stent normally placed. Proper hygiene, regular monitoring and endoscopic cleansing of the patient's stent resulted in the sinus orderly functioning with the stent placed within its ostium, without incrustation or breathing difficulties and headaches as a consequence. PMID- 22926399 TI - Bilateral banding of malpositioned pulmonary artery branches. AB - This report presents two rare cases of malpositioned pulmonary artery branches managed by bilateral banding. The left-branch pulmonary artery, originating from and directly superior to the right branch, entered the posterior mediastinum before heading toward the left pulmonary hilum. The ostium of the left branch could not be visualized by midline sternotomy. Therefore, a double-subtraction technique was used to pass the banding tape around the left branch from the right side. The tape location was adjusted and confirmed by intraoperative echocardiography. PMID- 22926400 TI - Double-outlet right ventricle without interventricular communication: an unusual and challenging problem. AB - A ventriculoseptal defect (VSD) usually is present in patients with a double outlet right ventricle. This report describes a case of double-outlet right ventricle with a completely shrouded inlet VSD and no interventricular shunting. This was associated with a severely regurgitant dysplastic mitral valve. The anatomy and clinical management of the patient is discussed together with an overview of the existing literature. PMID- 22926402 TI - Overexpression of actin-depolymerizing factor blocks oxidized low-density lipoprotein-induced mouse brain microvascular endothelial cell barrier dysfunction. AB - The aim of present work was to elucidate the role of actin-depolymerizing factor (ADF), an important regulator of actin cytoskeleton, in the oxidized low-density lipoprotein (ox-LDL)-induced blood-brain barrier (BBB) disruption. The primary mouse brain microvascular endothelial cells (MBMECs) were exposed to ox-LDL. Treatment with LDL served as control. It was found that ADF mRNA level and protein expression were decreased when exposed to ox-LDL in MBMECs. Then, we investigated the influence of ADF overexpression on ox-LDL-treated MBMECs. Structurally, overexpression of ADF inhibited ox-LDL-induced F-actin formation. Functionally, overexpression of ADF attenuated ox-LDL-induced disruption of endothelial barrier marked by restoration of transendothelial electrical resistance, permeability of Evans Blue and expression of tight junction associated proteins including ZO-1 and occludin, and blocked ox-LDL-induced oxidative stress marked by inhibition of reactive oxygen species (ROS) formation and activity of NADPH oxidase and Nox2 expression. However, overexpression of ADF in control cells had no significant effect on endothelial permeability and ROS formation. In conclusion, overexpression of ADF blocks ox-LDL-induced disruption of endothelial barrier. In addition, siRNA-mediated downregulation of ADF expression aggravated ox-LDL-induced disruption of endothelial barrier and ROS formation. These findings identify ADF as a key signaling molecule in the regulation of BBB integrity and suggest that ADF might be used as a target to modulate diseases accompanied by ox-LDL-induced BBB compromise. PMID- 22926403 TI - The role of Raf-1 kinase inhibitor protein in the regulation of pancreatic beta cell proliferation in mice. AB - AIMS/HYPOTHESIS: Manoeuvres aimed at increasing beta cell mass have been proposed as regenerative medicine strategies for diabetes treatment. Raf-1 kinase inhibitor protein 1 (RKIP1) is a common regulatory node of the mitogen-activated protein kinase (MAPK) and nuclear factor kappaB (NF-kappaB) pathways and therefore may be involved in regulation of beta cell homeostasis. The aim of this study was to investigate the involvement of RKIP1 in the control of beta cell mass and function. METHODS: Rkip1 (also known as Pebp1) knockout (Rkip1 (-/-)) mice were characterised in terms of pancreatic and glucose homeostasis, including morphological and functional analysis. Glucose tolerance and insulin sensitivity were examined, followed by assessment of glucose-induced insulin secretion in isolated islets and beta cell mass quantification through morphometry. Further characterisation included determination of endocrine and exocrine proliferation, apoptosis, MAPK activation and whole genome gene expression assays. Capacity to reverse a diabetic phenotype was assessed in adult Rkip1 (-/-) mice after streptozotocin treatment. RESULTS: Rkip1 (-/-) mice exhibit a moderately larger pancreas and increased beta cell mass and pancreatic insulin content, which correlate with an overall improvement in whole body glucose tolerance. This phenotype is established in young postnatal stages and involves enhanced cellular proliferation without significant alterations in cell death. Importantly, adult Rkip1 (-/-) mice exhibit rapid reversal of streptozotocin-induced diabetes compared with control mice. CONCLUSIONS/INTERPRETATION: These data implicate RKIP1 in the regulation of pancreatic growth and beta cell expansion, thus revealing RKIP1 as a potential pharmacological target to promote beta cell regeneration. PMID- 22926404 TI - The helical flow pump with a hydrodynamic levitation impeller. AB - The helical flow pump (HFP) is a novel rotary blood pump invented for developing a total artificial heart (TAH). The HFP with a hydrodynamic levitation impeller, which consists of a multi-vane impeller involving rotor magnets, stator coils at the core position, and double helical-volute pump housing, was developed. Between the stator and impeller, a hydrodynamic bearing is formed. Since the helical volutes are formed at both sides of the impeller, blood flows with a helical flow pattern inside the pump. The developed HFP showed maximum output of 19 l/min against 100 mmHg of pressure head and 11 % maximum efficiency. The profile of the H-Q (pressure head vs. flow) curve was similar to that of the undulation pump. Hydrodynamic levitation of the impeller was possible with higher than 1,000 rpm rotation speed. The normalized index of the hemolysis ratio of the HFP to centrifugal pump (BPX-80) was from 2.61 to 8.07 depending on the design of the bearing. The HFP was implanted in two goats with a left ventricular bypass method. After surgery, hemolysis occurred in both goats. The hemolysis ceased on postoperative days 14 and 9, respectively. In the first experiment, no thrombus was found in the pump after 203 days of pumping. In the second experiment, a white thrombus was found in the pump after 23 days of pumping. While further research and development are necessary, we are expecting to develop an excellent TAH with the HFP. PMID- 22926405 TI - Mutations of complement factor I and potential mechanisms of neuroinflammation in acute hemorrhagic leukoencephalitis. AB - PURPOSE: Acute Hemorrhagic Leukoencephalitis (AHLE) is a rare demyelinating disorder of acute onset, rapid deterioration and significant morbidity and mortality. Most often described as a post-infectious complication of an upper respiratory illness, its precise pathophysiology remains unclear. We describe two pediatric patients with AHLE with partial complement factor I (FI) deficiency whose successful treatment included the interleukin-1 (IL-1) receptor antagonist, anakinra, implicating a role for FI and IL-1 in this disorder. METHODS: Extensive clinical workup of two patients presenting with AHLE revealed complement abnormalities, specifically related to the alternative pathway and its regulator, FI. Aggressive management with steroids, immunoglobulin, and anakinra ultimately led to improvement of clinical status and near return to neurologic baseline in both patients. Genetic sequencing of the FI coding regions of the patients and their families was performed. In vitro protein expression studies and immunohistochemistry of fixed brain tissue was used to investigate pathogenic mechanisms. RESULTS: Two novel mutations in FI were identified in our patients, which result in failure to secrete FI. Immunohistochemical evaluation of brain tissue demonstrated positive staining for C3, membrane attack complex (MAC) and IL-1. CONCLUSIONS: We propose AHLE is an unreported, rare phenotype for partial FI deficiency. The upregulation of C3, MAC and IL-1 with subsequent demyelination support a pathologic role for complement activation in AHLE, and suggest anakinra as an important adjunctive therapy in this disease. PMID- 22926406 TI - Patterns of salivary analytes provide diagnostic capacity for distinguishing chronic adult periodontitis from health. AB - Salivary biomarker discovery requires identification of analytes with high discriminatory capacity to distinguish disease from health, including day-to-day variations that occur in analyte levels. In this study, seven biomarkers associated with inflammatory and tissue destructive processes of periodontal disease were investigated. In a prospective cohort study design, analyte expression levels were determined in unstimulated whole saliva samples collected on multiple occasions from 30 healthy adults (i.e., orally and systemically) and 50 chronic adult periodontitis patients. Salivary levels of IL-1beta, IL-6, MMP 8, and albumin were significantly elevated (5.4 to 12.6X) and levels of IFNalpha were consistently lower (8.7X) in periodontitis patients compared with the daily variation observed in healthy adults. ROC analyses of IL-1beta, IL-6 and MMP-8 yielded areas under the curves of 0.963-0.984 for discriminating periodontitis from health. These results demonstrate that levels of salivary bioanalytes of patients who have periodontitis are uniquely different from normal levels found in healthy subjects, and a panel consisting of IL-1beta, MMP-8 and IL-6 shows particular diagnostic potential. PMID- 22926408 TI - Epidural fentanyl for postoperative analgesia after lumbar canal decompression: a randomized controlled trial. AB - BACKGROUND CONTEXT: Postoperative back pain is common after decompression surgery for lumbar stenosis and often delays discharge from hospital. Achieving regional analgesia by intraoperative delivery of epidural opiates after lumbar canal decompression is a promising approach to reduce postoperative pain and enhance early mobilization. However, there have been concerns about opiate-related complications, such as respiratory depression and urinary retention in what is generally an elderly population of patients. PURPOSE: To assess the analgesic efficacy of bolus epidural fentanyl administered intraoperatively after lumbar decompression for degenerative canal stenosis. STUDY DESIGN/SETTING: Patient blinded randomized controlled trial conducted at two university neurosurgical centers. PATIENT SAMPLE: Adults (older than 18 years) with neurogenic claudication and/or lower limb radiculopathy and concordant lumbar spinal canal stenosis demonstrated on magnetic resonance imaging. Patients with previous lumbar spinal surgery, a contraindication to fentanyl, or requiring instrumentation were excluded. OUTCOME MEASURES: The primary outcome measure was patient-reported Visual Analogue Score (VAS) for pain recorded preoperatively, in recovery, and on the first and second postoperative days if the patient remained in the hospital. Secondary outcomes were duration of surgery, length of stay, and any side effects or complications. METHODS: Patients underwent a one to three level lumbar canal decompression as required, via a midline incision, under general anesthesia. Before wound closure either no drug (control) or a 100-MUg bolus of fentanyl was administered via an epidural catheter inserted 10 cm rostral to the operated level. Patients were blinded to group allocation, and analysis was by intention to treat. The trial was approved by the National Health Service Research Ethics Service and the Medicines and Healthcare products Regulatory Agency. No commercial or other source of funding was received. RESULTS: Sixty patients were randomized, 29 to fentanyl and 31 to control. Demographics, duration of surgery, and preoperative VAS were not significantly different between the groups. VAS in recovery was significantly lower in patients treated with fentanyl (mean [standard deviation]: 2.6 [2.7] vs. 4.7 [2.4]; p=.003). Later VAS and postoperative length of stay were similar between groups. More patients in the fentanyl group required temporary urinary catheterization, but there was no significant difference in the incidence of side effects. CONCLUSIONS: Bolus epidural fentanyl provides effective short-term postoperative analgesia after lumbar canal decompression and may be a useful adjunct to pain management in patients undergoing lumbar spine surgery. PMID- 22926407 TI - Levels of circulating Th17 cells and regulatory T cells in ankylosing spondylitis patients with an inadequate response to anti-TNF-alpha therapy. AB - PURPOSE: To investigate the effects of TNF-alpha blockage on levels of circulating Th17, Treg and their related cytokines in ankylosing spondylitis (AS) patients with different response to anti-TNF-alpha therapy. METHODS: The frequencies of circulating Th17 and Treg and serum levels of related cytokines were determined using flow cytometry analysis and ELISA, respectively, in 222 AS patients both before (baseline) and 6 months after anti-TNF-alpha therapy. Therapeutic response was defined according to ASAS (Assessment in Spondyloarthritis International Society) response criteria. RESULTS: Significantly higher baseline circulating Th17 and serum TNF-alpha, IL-6, IL-17, IL-23 were observed in active AS patients than in healthy controls. After anti TNF-alpha therapy, 168 patients (75.7 %) were responders and 54 (24.3 %) were non responders. Frequencies of Th17 significantly decreased in responders, but significantly increased in non-responders. Treg increased significantly in responders but decreased significantly in non-responders. Levels of TNF-alpha, IL 6, IL-17, and IL-23 were significantly decreased in responders. In contrast, IL 17 and IL-23 significantly increased in non-responders. TGF-beta were significantly increased only in responders, whereas no significant changes were seen in IL-10 in either responders or non-responders. Spearman correlation analysis showed that frequencies of Th17 and levels of TNF-alpha, IL-6, IL-17, and IL-23 were positively correlated with BASDAI score. They were also positively correlated with BASFI score except for IL-6. Treg were found to be negatively correlated with BASDAI score. CONCLUSIONS: The beneficial effect of anti-TNF alpha therapy in AS might not only neutralize the effects of TNF-alpha but also down-regulate Th17 and Th17-related cytokines accompanied by up-regulating the Treg/TGF-beta axis in responders. PMID- 22926409 TI - Prognostic impact of pulse pressure at admission on in-hospital outcome after primary percutaneous coronary intervention for acute myocardial infarction. AB - Data regarding relationship between pulse pressure (PP) at admission and in hospital outcome in patients with acute myocardial infarction (AMI) undergoing primary percutaneous coronary intervention (PCI) are still lacking. A total of 1413 primary PCI-treated AMI patients were classified into quintiles based on admission PP (<40, n = 280; 40-48, n = 276; 49-57, n = 288; 58-70, n = 288; and >=71 mmHg, n = 281). The patients with PP < 40 mmHg tended to have higher prevalence of male, smoking, and Killip class >=3 at admission; right coronary artery, left main trunk (LMT), or multivessels as culprit lesions; larger number of diseased vessels; lower Thrombolysis in Myocardial Infarction (TIMI) grade in the infarct-related artery before/after primary PCI; and higher value of peak creatine phosphokinase concentration. Patients with PP < 40 mmHg had highest mortality, while patients with PP 49-57 mmHg had the lowest: 11.8 % (<40), 7.2 % (40-48), 2.8 % (49-57), 5.9 % (58-70), and 6.0 % (>=71 mmHg). On multivariate analysis, Killip class >=3 at admission, LMT or multivessels as culprit lesions, chronic kidney disease, and age were the independent positive predictors of the in-hospital mortality, whereas admission PP 49-57 mmHg, hypercholesterolemia, and TIMI 3 flow before/after PCI were the negative ones, but admission PP < 40 mmHg was not. These results suggest that admission PP 49-57 mmHg might be correlated with better in-hospital prognosis in Japanese AMI patients undergoing primary PCI. PMID- 22926410 TI - Cardiac tamponade as an independent condition affecting the relationship between the plasma B-type natriuretic peptide levels and cardiac function. AB - Plasma B-type natriuretic peptide (BNP) is finely regulated by the cardiac function and several extracardiac factors. Therefore, the relationship between the plasma BNP levels and the severity of heart failure sometimes seems inconsistent. The purpose of the present study was to investigate the plasma BNP levels in patients with cardiac tamponade and their changes after pericardial drainage. This study included 14 patients with cardiac tamponade who underwent pericardiocentesis. The cardiac tamponade was due to malignant diseases in 13 patients and uremia in 1 patient. The plasma BNP levels were measured before and 24-48 h after drainage. Although the patients reported severe symptoms of heart failure, their plasma BNP levels were only 71.2 +/- 11.1 pg/ml before drainage. After appropriate drainage, the plasma BNP levels increased to 186.0 +/- 22.5 pg/ml, which was significantly higher than that before drainage (P = 0.0002). In patients with cardiac tamponade, the plasma BNP levels were low, probably because of impaired ventricular stretching, and the levels significantly increased in response to the primary condition after drainage. This study demonstrates an additional condition that affects the relationship between the plasma BNP levels and cardiac function. If inconsistency is seen in the relationship between the plasma BNP levels and clinical signs of heart failure, the presence of cardiac tamponade should therefore be considered. PMID- 22926413 TI - MicroRNA regulatory networks and human disease. PMID- 22926412 TI - Recent progress in intein research: from mechanism to directed evolution and applications. AB - Inteins catalyze a post-translational modification known as protein splicing, where the intein removes itself from a precursor protein and concomitantly ligates the flanking protein sequences with a peptide bond. Over the past two decades, inteins have risen from a peculiarity to a rich source of applications in biotechnology, biomedicine, and protein chemistry. In this review, we focus on developments of intein-related research spanning the last 5 years, including the three different splicing mechanisms and their molecular underpinnings, the directed evolution of inteins towards improved splicing in exogenous protein contexts, as well as novel applications of inteins for cell biology and protein engineering, which were made possible by a clearer understanding of the protein splicing mechanism. PMID- 22926411 TI - Tumor cell migration in complex microenvironments. AB - Tumor cell migration is essential for invasion and dissemination from primary solid tumors and for the establishment of lethal secondary metastases at distant organs. In vivo and in vitro models enabled identification of different factors in the tumor microenvironment that regulate tumor progression and metastasis. However, the mechanisms by which tumor cells integrate these chemical and mechanical signals from multiple sources to navigate the complex microenvironment remain poorly understood. In this review, we discuss the factors that influence tumor cell migration with a focus on the migration of transformed carcinoma cells. We provide an overview of the experimental and computational methods that allow the investigation of tumor cell migration, and we highlight the benefits and shortcomings of the various assays. We emphasize that the chemical and mechanical stimulus paradigms are not independent and that crosstalk between them motivates the development of new assays capable of applying multiple, simultaneous stimuli and imaging the cellular migratory response in real-time. These next-generation assays will more closely mimic the in vivo microenvironment to provide new insights into tumor progression, inform techniques to control tumor cell migration, and render cancer more treatable. PMID- 22926414 TI - The function of miRNA in cardiac hypertrophy. AB - Cardiac hypertrophy is an adaptive enlargement of the myocardium in response to altered stress or injury. The cellular responses of cardiomyocytes and non cardiomyocytes to various signaling pathways should be tightly and delicately regulated to maintain cardiac homeostasis and prevent pathological cardiac hypertrophy. MicroRNAs (miRNAs) are endogenous, single-stranded, short non-coding RNAs that act as regulators of gene expression by promoting the degradation or inhibiting the translation of target mRNAs. Recent studies have revealed expression signatures of miRNAs associated with pathological cardiac hypertrophy and heart failure in humans and mouse models of heart diseases. Increasing evidence indicates that dysregulation of specific miRNAs could alter the cellular responses of cardiomyocytes and non-cardiomyocytes to specific signaling upon the pathological hemodynamic overload, leading to cardiac hypertrophy and heart failure. This review summarizes the cell-autonomous functions of cardiomyocyte miRNAs regulated by different pathways and the roles of non-cardiomyocyte miRNAs in cardiac hypertrophy. The therapeutic effects of a number of miRNAs in heart diseases are also discussed. PMID- 22926416 TI - MAPK uncouples cell cycle progression from cell spreading and cytoskeletal organization in cycling cells. AB - Integrin-mediated cytoskeletal tension supports growth-factor-induced proliferation, and disruption of the actin cytoskeleton in growth factor stimulated cells prevents the re-expression of cyclin D and cell cycle re-entry from quiescence. In contrast to cells that enter the cell cycle from G0, cycling cells continuously express cyclin D, and are subject to major cell shape changes during the cell cycle. Here, we investigated the cell cycle requirements for cytoskeletal tension and cell spreading in cycling mammalian cells that enter G1 phase from mitosis. Disruption of the actin cytoskeleton at progressive time points in G1-phase induced cell rounding, FA disassembly, and attenuated both integrin signaling and growth factor-induced p44/p42 mitogen-activated protein kinase activation. Although cyclin D expression was reduced, the expression of cyclin A and entry into S-phase were not affected. Moreover, expression of cyclin B1, progression through G2- and M-phase, and commitment to a new cell cycle occurred normally. In contrast, cell cycle progression was strongly prevented by inhibition of MAPK activity in G1-phase, whereas cell spreading, cytoskeletal organization, and integrin signaling were not impaired. MAPK inhibition also prevented cytoskeleton-independent cell cycle progression. Thus, these results uncouple the requirements for cell spreading and cytoskeletal organization from MAPK signaling, and show that cycling mammalian cells can proliferate independently of actin stress fibers, focal adhesions, or cell spreading, as long as a threshold level of MAPK activity is sustained. PMID- 22926415 TI - MicroRNAs in breast cancer initiation and progression. AB - The emerging role of microRNAs (miRNAs) in the epigenetic regulation of many cellular processes has become recognized in both basic research and translational medicine as an important way that gene expression can be fine-tuned. Breast cancer is the most frequent cancer in women, with about one million new cases diagnosed each year worldwide. Starting with the early work of miRNA profiling, more effort has now been put on functions of miRNAs in normal mammary stem cells, breast cancer initiating cells and metastatic cells, and therapy-resistant cancer cells. Future translational studies may focus on identifying miRNA signatures as cancer biomarkers and developing miRNA-based targeted therapeutics. PMID- 22926417 TI - The reverse roles of transient receptor potential canonical channel-3 and -6 in neuronal death following pilocarpine-induced status epilepticus. AB - Transient receptor potential canonical channel (TRPC) is a nonselective cation channel permeable to Ca(2+), which is expressed in many cell types, including neurons. However, the alterations in TRPC receptor expressions in response to status epilepticus (SE) have not been explored. Therefore, the present study was designated to elucidate the roles of TRPC3 and TRPC6 in neuronal death following SE. In non-SE animals, TRPC3 and TRPC6 immunoreactivity was abundantly detected in the dendrites of pyramidal cells and the cell bodies of dentate granule cells. Following SE, TRPC3 expression was significantly elevated in CA1-, CA3 pyramidal cells, and dentate granule cells, while TRPC6 expression was reduced in these regions. Pyrazole-3 (a TRPC3 inhibitor) effectively prevented up-regulation of neuronal TRPC3 expression induced by SE. Hyperforin (a TRPC6 activator) effectively prevented down-regulation of neuronal TRPC6 expression induced by SE. In addition, both Pyr3 and hyperforin effectively protected neuronal damages from SE. Therefore, the present study yields novel information regarding the role of TRPC3 and 6 in epileptogenic insults and suggests that TRPC 3 and 6 may be involved in neurodegeneration following SE. PMID- 22926418 TI - Regulation of mu opioid receptor expression in developing T cells. AB - We have previously reported that functionally active MU-opioid receptors (MOR) are constitutively expressed at relatively low levels by developing T cells in the thymus. However, very little is known about the regulation of MOR expression by immature T cells. In this report, we first attempted to determine the effect of T cell receptor-induced T cell activation on the expression of MOR. We activated T cells with either the combination of anti-CD3 and CD28, or with superantigen, and observed a substantial increase in MOR transcript expression. We also chose to examine the effect of cytokine-mediated T cell activation on the expression of this opioid receptor. We selected certain cytokines that play a role in T cell development and are known to be present at functional levels in the thymus gland. Our results show that interferon gamma (IFNgamma), IL-1beta, and IL-2, and in particular transforming growth factor-beta (TGFbeta), all induced significant increases in MOR transcript expression. On the other hand, both TNFalpha and IL-7 exhibited much weaker effects on MOR expression. These results show that MOR expression by developing T cells is strongly regulated by several cytokines involved in T cell development in the thymus gland. PMID- 22926420 TI - Microglial activation involved in morphine tolerance is not mediated by toll-like receptor 4. AB - PURPOSE: Morphine is a powerful analgesic but its effect is often diminished owing to the development of tolerance. It has been suggested that morphine activates microglia through its action on the toll-like receptor 4 (TLR4) in the spinal cord, leading to suppression of the morphine effect. However, it has not been examined whether the development of morphine tolerance is affected by the deletion and mutation of the TLR4 gene. METHODS: Mice were treated with morphine (60 mg/kg) or vehicle once daily for five consecutive days to induce morphine tolerance, which was assessed by the tail-flick test before and after the treatment period. The effect of the microglial inhibitor minocycline, and the effect of TLR4 mutation (C3H/HeJ mouse) and deletion (TLR4-knockout mouse) on the development of morphine tolerance were tested. The expression of the microglial activation marker, CD11b, in the spinal cords of TLR4-knockout and wild-type mice after morphine treatment for 5 days was assessed by reverse-transcription polymerase chain reaction. RESULTS: Minocycline attenuated the development of morphine tolerance in mice. Mutation or deletion of the TLR4 gene did not significantly affect the development of morphine tolerance. CD11b mRNA expression was increased after morphine treatment both in TLR4-knockout and wild-type mice. CONCLUSION: Microglial activation caused by a mechanism independent of TLR4 is involved in the development of morphine tolerance. Further studies are necessary to clarify the cellular mechanisms of morphine-induced microglial activation. PMID- 22926419 TI - The anesthetic urethane blocks excitatory amino acid responses but not GABA responses in isolated frog spinal cords. AB - PURPOSE: The anesthetic urethane is commonly used in physiological experiments. We tested urethane's actions on GABA receptors on the primary afferents in the spinal cord, which are one of the few areas in the adult central nervous system (CNS) that are depolarized by GABA, and on ligand-gated excitatory amino acid (EAA) receptors located on motoneurons. Both receptor types are critically important during anesthetic immobilization. METHODS: We used the isolated hemisected spinal cord of the frog in a sucrose gap chamber to record glutamate-, N-methyl-D-aspartate (NMDA)-, alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-, kainate-, and gamma-aminobutyric acid (GABA)-induced depolarizations of the dorsal root (DR) and ventral root (VR). DR potentials (DRPs) and VR potentials (VRPs) evoked by single supramaximal afferent stimuli were also studied. Urethane (10-80 mM) was applied for 10-30 min. RESULTS: Urethane depressed EAA responses on the motoneurons in a dose-dependent manner. At a clinical anesthetic concentration (10 mM), EAA-induced depolarizations were reduced by 8.1 +/- 2.2 % (n = 7, P = 0.025), but increasing the concentration to 40 mM revealed a larger, 24.7 +/- 3 % (n = 53, P = 0.0001) depressing effect of urethane on all EAA responses in the motoneurons. However, GABA and K(+) responses recorded in the DR were not altered by the presence of 10 or 40 mM urethane. Evoked DRPs and VRPs were reduced by urethane and spontaneous DR and VR potentials were suppressed by 10 or blocked by 40 mM urethane. CONCLUSION: Urethane appears to be selective for EAA-, sparing GABA responses at a clinical anesthetic concentration. Only a 10 % reduction of EAA activity seems to be necessary to induce anesthesia. PMID- 22926421 TI - Acanthocheilonema delicata n. sp. (Nematoda: Filarioidea) from Japanese badgers (Meles anakuma): description, molecular identification, and Wolbachia screening. AB - Acanthocheilonema delicata n. sp. (Filarioidea: Onchocercidae: Onchocercinae) is described based on adult filarioids and microfilariae obtained from subcutaneous connective tissues and skin, respectively, of Japanese badgers (Meles anakuma) in Wakayama Prefecture, Japan. No endemic species of the genus had been found in Japan. Recently, some filarioids (e.g., Acanthocheilonema reconditum, Dirofilaria spp., and Onchocerca spp.) have come to light as causative agents of zoonosis worldwide. The new species was readily distinguished from its congeners by morphologic characteristics such as body length, body width, esophagus length, spicule length, and the length of microfilariae. Based on the molecular data of the mitochondrial cytochrome c oxidase subunit 1 (cox1) gene, A. delicata n. sp. was included in the clade of the genus Acanthocheilonema but differed from two other congeneric species available for study, A. viteae and A. reconditum. Acanthocheilonema delicata n. sp. did not harbor Wolbachia. It is likely that the fauna of filarioids from mammals on the Japanese islands is characterized by a high level of endemicity. PMID- 22926423 TI - Kidney cancer: Is incomplete renal ablation linked to tumour progression? PMID- 22926422 TI - Sex for fun: a synthesis of human and animal neurobiology. AB - Sex is a fundamental pleasure, and crucial to the survival of our species. Though not many people would disagree with the proposition that sexual behaviour depends on the brain, the neuroscientific study of human sex is still relatively taboo and much remains to be discovered. On the contrary, excellent experimental animal models (mostly rat) are available that have uncovered major behavioural, neurochemical, and neuroanatomical characteristics of sexual behaviour. Restructuring sexual behaviour into broader terms reflecting behavioural states (wanting, liking, and inhibition) facilitates species comparison, revealing many similarities between animal and human sexual pleasure cycles, some of which can serve as potential avenues of new human sex research. In particular, behavioural and brain evidence clearly shows that motivational and consummatory phases are fundamentally distinct, and that genitally-induced sexual reward is a major factor in sexual learning mechanisms. PMID- 22926425 TI - Bladder cancer: Intravesical RNA activation--a new treatment concept. PMID- 22926424 TI - Testicular and epididymal ADAMs: expression and function during fertilization. AB - The disintegrin and metalloprotease domain-containing protein (ADAM) family of multidomain membrane proteins comprises at least 34 members in mammals. More than half of these proteins are expressed specifically or predominantly in mammalian testes and epididymis, implying their prominence in male reproduction. These reproductive ADAMs can be classified into three phylogenetic groups; designated I, II, and III. Each group displays remarkably contrasting features. Group I contains 11 ADAMs expressed in the testis. The genes that encode these proteins lack introns in their coding sequences and most of the proteins are processed into prodomain-lacking forms in mature sperm. Five ADAMs--encoded by genes with multiple exons and introns--belong to phylogenetic group II. These ADAMs are also expressed in testicular germ cells, but both prodomains and metalloprotease domains are lacking in mature sperm. Two phylogenetic group III ADAMs are synthesized in the epididymis; one of which is secreted and transferred to the sperm surface. Some of these sperm ADAMs are assembled into potentially functional complexes, including ADAM1B-ADAM2, ADAM2-ADAM3-ADAM4, ADAM2-ADAM3 ADAM5, and ADAM2-ADAM3-ADAM6. It has been suggested that ADAM2 and ADAM3 have roles in sperm-egg interactions. Mouse knockout studies have revealed that the ADAM2-ADAM3 complex is critical for in vivo sperm migratory function in the female reproductive tract. PMID- 22926426 TI - Drugs for chronic heart failure. PMID- 22926427 TI - What if? The farther shores of neuroethics: commentary on "Neuroscience may supersede ethics and law". AB - Neuroscience is clearly making enormous progress toward understanding how human brains work. The implications of this progress for ethics, law, society, and culture are much less clear. Some have argued that neuroscience will lead to vast changes, superseding much of law and ethics. The likely limits to the explanatory power of neuroscience argue against that position, as do the limits to the social relevance of what neuroscience will be able to explain. At the same time neuroscience is likely to change societies through increasing their abilities to predict future behavior, to infer subjective mental states by observing physical brain states ("read minds"), to provide evidence in some cases relevant to criminal responsibility, to provide new ways to intervene to "treat antisocial brains," and to enhance healthy brains. Neuroscience should make important cultural changes in our special, and specially negative, views of "mental" versus "physical" illness by showing that mental illness is a dysfunction of a physical organ. It will not likely change our beliefs, implicit or explicit, in free will, or spark a new conflict between science and religion akin to the creationism controversy. PMID- 22926428 TI - Self-assembling peptide-enriched electrospun polycaprolactone scaffolds promote the h-osteoblast adhesion and modulate differentiation-associated gene expression. AB - Electrospun polycaprolactone (PCL) is able to support the adhesion and growth of h-osteoblasts and to delay their degradation rate to a greater extent with respect to other polyesters. The drawbacks linked to its employment in regenerative medicine arise from its hydrophobic nature and the lack of biochemical signals linked to it. This work reports on the attempt to add five different self-assembling (SA) peptides to PCL solutions before electrospinning. The hybrid scaffolds obtained had regular fibers (SEM analysis) whose diameters were similar to those of the extracellular matrix, more stable hydrophilic (contact angle measurement) surfaces, and an amorphous phase constrained by peptides (DSC analysis). They appeared to have a notable capacity to promote the h-osteoblast adhesion and differentiation process by increasing the gene expression of alkaline phosphatase, bone sialoprotein, and osteopontin. Adding an Arg-Gly-Asp (RGD) motif to a self-assembling sequence was found to enhance cell adhesion, while the same motif condensed with a scrambled sequence did not, indicating that there is a cooperative effect between RGD and 3D architecture created by the self-assembling peptides. The study demonstrates that self assembling peptide scaffolds are still able to promote beneficial effects on h osteoblasts even after they have been included in electrospun polycaprolactone. The possibility of linking biochemical messages to self-assembling peptides could lead the way to a 3D decoration of fibrous scaffolds. PMID- 22926429 TI - Isotropic 3-D T2-weighted spin-echo for abdominal and pelvic MRI in children. AB - MRI has a fundamental role in paediatric imaging. The T2-weighted fast/turbo spin echo sequence is important because it has high signal-to-noise ratio compared to gradient-echo sequences. It is usually acquired as 2-D sections in one or more planes. Volumetric spin-echo has until recently only been possible with very long echo times due to blurring of the soft-tissue contrast with long echo trains. A new 3-D spin-echo sequence uses variable flip angles to overcome this problem. It may reproduce useful soft-tissue contrast, with improved spatial resolution. Its isotropic capability allows subsequent reconstruction in standard, curved or arbitrary planes. It may be particularly useful for visualisation of small lesions, or if large lesions distort the usual anatomical relations. We present clinical examples, describe the technical parameters and discuss some potential artefacts and optimisation of image quality. PMID- 22926430 TI - Preparation, structure and near-infrared luminescent property of Yb(III) complex with 2,4,6-pyridinetricarboxylic acid. AB - A rare earth ytterbium complex with 2,4,6-pyridinetricarboxylic acid (H(3)pta) has been synthesized by hydrothermal method, the formula is {[Yb(2)(pta)(2)(H(2)O)(3)].H(2)O}(n). The complex crystallized in monoclinic system, P2(1)/c space group with lattice parameters a = 11.6556(19)A, b = 7.8364(12), c = 22.020(4), alpha = gamma = 90o, beta = 92.120(3), Z = 4, GOF = 1.026, R1 = 0.0334, wR2 = 0.0660. The pta anions connect four rare earth Yb(III) ions with two different coordination modes. The complex exhibit intense characteristic near-infrared luminescence of Yb(III) ions at 990 nm with excitation of UV-rays. PMID- 22926432 TI - Comparison of revision strategies for failed C2-posterior cervical pedicle screws: a biomechanical study. AB - STUDY PURPOSE: With increasing usage within challenging biomechanical constructs, failures of C2 posterior cervical pedicle screws (C2-pCPSs) will occur. The purpose of the study was therefore to investigate the biomechanical characteristics of two revision techniques after the failure of C2-pCPSs. MATERIALS AND METHODS: Twelve human C2 vertebrae were tested in vitro in a biomechanical study to compare two strategies for revision screws after failure of C2-pCPSs. C2 pedicles were instrumented using unicortical 3.5-mm CPS bilaterally (Synapse/Synthes, Switzerland). Insertion accuracy was verified by fluoroscopy. C2 vertebrae were potted and fixed in an electromechanical testing machine with the screw axis coaxial to the pullout direction. Pullout testing was conducted with load and displacement data taken continuously. The peak load to failure was measured in newtons (N) and is reported as the pullout resistance (POR). After pullout, two revision strategies were tested in each vertebra. In Group-1, revision was performed with 4.0-mm C2-pCPSs. In Group-2, revision was performed with C2-pedicle bone-plastic combined with the use of a 4-mm C2-pCPSs. For the statistical analysis, the POR between screws was compared using absolute values (N) and the POR of the revision techniques normalized to that of the primary procedures (%). RESULTS: The POR of primary 3.5-mm CPSs was 1,140.5 +/- 539.6 N for Group-1 and 1,007.7 +/- 362.5 N for Group-2; the difference was not significant. In the revision setting, the POR in Group-1 was 705.8 +/- 449.1 N, representing a reduction of 38.1 +/- 32.9 % compared with that of primary screw fixation. For Group-2, the POR was 875.3 +/- 367.9 N, representing a reduction of 13.1 +/- 23.4 %. A statistical analysis showed a significantly higher POR for Group-2 compared with Group-1 (p = 0.02). Although the statistics showed a significantly reduced POR for both revision strategies compared with primary fixation (p < 0.001/p = 0.001), the loss of POR (in %) in Group-1 was significantly higher compared with the loss in Group-2 (p = 0.04). CONCLUSIONS: Using a larger-diameter screw combined with the application of a pedicle bone plastic, the POR can be significantly increased compared with the use of only an increased screw diameter. PMID- 22926433 TI - Magnetic resonance imaging-based relationships between neck muscle cross sectional area and neck circumference for adults and children. AB - BACKGROUND: Computer models and human surrogates used to study the forces and motion of the human neck under various loading conditions are based solely on adult data. Pediatric computer models and dummy surrogates used to improve the safety of children could be improved with the inclusion of previously unavailable pediatric muscle data. METHODS: Measurements of neck circumference and neck muscle cross-sectional area (CSA) were taken from ten 50th percentile adult male and ten 10-year old male volunteer subjects. Muscle cross-sectional areas were calculated from magnetic resonance images of axial cross-sections of the neck. RESULTS: Neck muscle cross-sectional area was calculated for six muscles/muscle groups. A power-law regression analysis was used to describe the relationship between neck circumference and neck muscle cross-sectional area. CONCLUSIONS: The cross-sectional area and the power-law functions determined by the data in this study provide a means of calculating muscle cross-sectional area for young children, where such data are currently unavailable. This will provide an opportunity to develop more representative pediatric neck models. PMID- 22926434 TI - Does the type of T2-weighted hyperintensity influence surgical outcome in patients with cervical spondylotic myelopathy? A review. AB - PURPOSE: To review the literature on different classifications of T2-weighted (T2W) increased signal intensity (ISI) on preoperative magnetic resonance (MR) images of patients with cervical spondylotic myelopathy (CSM). METHODS: The authors searched the databases of PubMed and Cochrane for studies that used a categorization of T2W ISI to predict the functional outcome after decompressive surgery for CSM. Selected studies were analyzed for the type of ISI classification used, patient selection, methodology and results. The level of evidence provided by each study was determined. RESULTS: Twenty-two studies fulfilled our search criteria. There were 11 prospective studies and a total of 1,508 patients were studied. The majority of studies classified ISI based on either the longitudinal extent (12 studies) or the qualitative features of the ISI (10 studies). Three studies used both parameters to classify T2W ISI. Other classifications were based on the position of ISI (1 study), presence of snake eye appearance on axial MR images (1 study) and signal intensity ratio (SIR) (1 study). Poorer functional outcomes correlated with sharp, intense ISI (6 studies) and multisegmental ISI (5 studies) (Class II evidence). Five of ten studies reported that the regression of ISI postoperatively was associated with better neurological outcomes (Class II evidence). CONCLUSIONS: Methodological variations in previous studies made it difficult to compare studies and results. Both multisegmental T2W ISI and sharp, intense T2W ISI are associated with poorer surgical outcome (Class II evidence). The regression of T2W ISI postoperatively correlates with better functional outcomes (Class II). Future studies on the significance of ISI should ensure use of a uniform grading system, standardized outcome measures and multivariate analyses to control for other preoperative variables. PMID- 22926435 TI - A longitudinal study for incidence of low back pain and radiological changes of lumbar spine in asymptomatic Japanese military young adults. AB - INTRODUCTION: The relation between radiological abnormalities on lumbar spine and low back pain (LBP) has been debated, presumably because of potential biases related to heterogeneity in selection of the subjects, radiological abnormalities at entry, or its cross-sectional observation in nature. Therefore, the aim of this study of a selected population of asymptomatic Japanese Self Defense Forces (JSDF) young adults male with normal lumbar radiographs was to investigate the incidence of newly developed lumbar degenerative changes at middle age and to study their association to LBP. SUBJECTS AND METHODS: In 1990, 84 JSDF male military servicemen aged 18 years, without a history of LBP and radiological abnormal findings, were enrolled. After 20 years, 84 subjects were underwent repeated X-ray and completed questionnaires on current LBP and lifestyle factors. RESULTS: The prevalence of LBP was demonstrated 59 %, with 85 % of them showing mild pain. Analysis of lumbar radiographs revealed that 48 % had normal findings and 52 % had degenerative changes. The association between LBP and life style factors was not demonstrated. Lumbar spine in subjects with LBP was more degenerated than in those without. Although disc space narrowing and LBP did not achieve a statistical significance, a significant correlation existed between vertebral osteophyte and LBP in univariate and multivariate analysis (OR 3.0; 95 % CI 1.227-7.333). DISCUSSION AND CONCLUSIONS: This longitudinal study demonstrated the significant association between vertebral osteophyte and incidence of mild LBP in initially asymptomatic and radiologically normal subjects. These data provide the additional information concerning the pathology of LBP, but further study is needed to clarify the clinical relevance. PMID- 22926436 TI - The effect of distraction on face and voice recognition. AB - The results of two experiments are presented which explore the effect of distractor items on face and voice recognition. Following from the suggestion that voice processing is relatively weak compared to face processing, it was anticipated that voice recognition would be more affected by the presentation of distractor items between study and test compared to face recognition. Using a sequential matching task with a fixed interval between study and test that either incorporated distractor items or did not, the results supported our prediction. Face recognition remained strong irrespective of the number of distractor items between study and test. In contrast, voice recognition was significantly impaired by the presence of distractor items regardless of their number (Experiment 1). This pattern remained whether distractor items were highly similar to the targets or not (Experiment 2). These results offer support for the proposal that voice processing is a relatively vulnerable method of identification. PMID- 22926438 TI - How broadly tuned olfactory receptors equally recognize their agonists. Human OR1G1 as a test case. AB - The molecular features that dominate the binding mode of agonists by a broadly tuned olfactory receptor are analyzed through a joint approach combining cell biology, calcium imaging, and molecular modeling. The odorant/receptor affinities, estimated through statistics accrued during molecular dynamics simulations, are in accordance with the experimental ranking. Although in many systems receptors recognize their target through a network of oriented interactions, such as H-bonding, the binding by broadly tuned olfactory receptors is dominated by non-polar terms. We show how such a feature allows chemicals belonging to different chemical families to similarly activate the receptors through compensations of interactions within the binding site. PMID- 22926437 TI - The contribution of transgenic plants to better health through improved nutrition: opportunities and constraints. AB - Malnutrition is a prevalent and entrenched global socioeconomic challenge that reflects the combined impact of poverty, poor access to food, inefficient food distribution infrastructure, and an over-reliance on subsistence mono agriculture. The dependence on staple cereals lacking many essential nutrients means that malnutrition is endemic in developing countries. Most individuals lack diverse diets and are therefore exposed to nutrient deficiencies. Plant biotechnology could play a major role in combating malnutrition through the engineering of nutritionally enhanced crops. In this article, we discuss different approaches that can enhance the nutritional content of staple crops by genetic engineering (GE) as well as the functionality and safety assessments required before nutritionally enhanced GE crops can be deployed in the field. We also consider major constraints that hinder the adoption of GE technology at different levels and suggest policies that could be adopted to accelerate the deployment of nutritionally enhanced GE crops within a multicomponent strategy to combat malnutrition. PMID- 22926439 TI - NLRP3 inflammasome activation in macrophage cell lines by prion protein fibrils as the source of IL-1beta and neuronal toxicity. AB - Prion diseases are fatal transmissible neurodegenerative diseases, characterized by aggregation of the pathological form of prion protein, spongiform degeneration, and neuronal loss, and activation of astrocytes and microglia. Microglia can clear prion plaques, but on the other hand cause neuronal death via release of neurotoxic species. Elevated expression of the proinflammatory cytokine IL-1beta has been observed in brains affected by several prion diseases, and IL-1R-deficiency significantly prolonged the onset of the neurodegeneration in mice. We show that microglial cells stimulated by prion protein (PrP) fibrils induced neuronal toxicity. Microglia and macrophages release IL-1beta upon stimulation by PrP fibrils, which depends on the NLRP3 inflammasome. Activation of NLRP3 inflammasome by PrP fibrils requires depletion of intracellular K(+), and requires phagocytosis of PrP fibrils and consecutive lysosome destabilization. Among the well-defined molecular forms of PrP, the strongest NLRP3 activation was observed by fibrils, followed by aggregates, while neither native monomeric nor oligomeric PrP were able to activate the NLRP3 inflammasome. Our results together with previous studies on IL-1R-deficient mice suggest the IL 1 signaling pathway as the perspective target for the therapy of prion disease. PMID- 22926440 TI - Maternal age and offspring adult health: evidence from the health and retirement study. AB - Advanced maternal age is associated with negative offspring health outcomes. This interpretation often relies on physiological processes related to aging, such as decreasing oocyte quality. We use a large, population-based sample of American adults to analyze how selection and lifespan overlap between generations influence the maternal age-offspring adult health association. We find that offspring born to mothers younger than age 25 or older than 35 have worse outcomes with respect to mortality, self-rated health, height, obesity, and the number of diagnosed conditions than those born to mothers aged 25-34. Controls for maternal education and age at which the child lost the mother eliminate the effect for advanced maternal age up to age 45. The association between young maternal age and negative offspring outcomes is robust to these controls. Our findings suggest that the advanced maternal age-offspring adult health association reflects selection and factors related to lifespan overlap. These may include shared frailty or parental investment but are not directly related to the physiological health of the mother during conception, fetal development, or birth. The results for young maternal age add to the evidence suggesting that children born to young mothers might be better off if the parents waited a few years. PMID- 22926441 TI - Melittin has an inhibitory effect on TNF-alpha-induced migration of human aortic smooth muscle cells by blocking the MMP-9 expression. AB - Matrix metalloproteinases-9 (MMP-9) plays an important role in the pathogenesis of atherosclerosis and migration of vascular smooth muscle cells (VSMCs) after an arterial injury. In this study, we investigated the potential molecular mechanisms underlying the anti-atheroscleroic effects of melittin, a major component of bee venom, in human aortic smooth muscle cells (HASMCs). Melttin significantly suppressed MMP-9 and MMP-2 secretion, as well as TNF-alpha-induced MMP-9 expression in the HASMCs. In addition, we found that the inhibitory effects of melittin on TNF-alpha-induced MMP-9 protein expression are associated with the inhibition of MMP-9 transcription levels. Mechanistically, Melittin suppressed TNF-alpha-induced MMP-9 activity by inhibiting the phosphorylation of p38 and ERK1/2, but did not affect the phosphorylation of JNK and Akt. Reporter gene and western blotting assays showed that melittin inhibits MMP-9 transcriptional activity by blocking the activation of NF-kappaB via IkappaBalpha signaling pathway. Moreover, the matrigel migration assay showed that melittin reduced TNF alpha-induced HASMC migration. These results suggest that melittin suppresses TNF alpha-induced HASMC migration through the selective inhibition of MMP-9 expression and provide a novel role of melittin in the anti-atherosclerotic action. PMID- 22926442 TI - Luteolin exerts anti-tumor activity through the suppression of epidermal growth factor receptor-mediated pathway in MDA-MB-231 ER-negative breast cancer cells. AB - This study investigated the inhibitory effect of luteolin on MDA-MB-231 estrogen receptor (ER) negative breast tumor growth both in vitro and in vivo. Study results showed that luteolin suppresses (3)H thymidine incorporation indicating cell growth inhibition, and this was accompanied by cell cycle arrest at the G2/M and S stages and apoptotic activity. Further analyses showed that luteolin exhibited cell cycle arrest and apoptotic activity by decreasing AKT, PLK1, cyclin B(1), cyclin A, CDC2, CDK2, and Bcl-xL expression and increasing p21 and Bax expression. Underlying mechanisms of action exerted by luteolin included the down-regulation. EGFR mRNA expression followed by the inhibition of EGF-induced MAPK activation, including the phosphorylation of ERK, p38 and AKT. Luteolin supplementation at 0.01% or 0.05% significantly reduced tumor burden in nude mice inoculated with MDA-MB-231 cells. In conclusion, luteolin effectively suppresses MDA-MB-231 ER-negative breast cancer cell growth, and its anticancer activity may be partly derived from inhibitory effects on EGFR-mediated cell survival. PMID- 22926443 TI - Dried chicory root modifies the activity and expression of porcine hepatic CYP3A but not 2C--effect of in vitro and in vivo exposure. AB - Hepatic cytochrome P450 expression and activity are dependent on many factors, including dietary ingredients. In the present study, we investigated the in vivo and in vitro effect of chicory root on hepatic CYP3A and 2C in male pigs. Chicory feeding increased the expression of CYP3A29 mRNA but not CYP2C33. Correspondingly, CYP3A activity was increased by chicory feeding, while CYP2C activity was not affected. Additionally, the in vitro effect of chicory extract on the CYP3A activity was investigated. It was shown that CYP3A activity in the microsomes from male pigs was inhibited, but this effect was eliminated by pre incubation. In both male and female pigs the CYP3A activity was increased in the presence of chicory after pre-incubation. Furthermore, gender-related differences in mRNA expression and activity were observed. CYP3A mRNA expression was greater in female pigs; this was not reflected on activity. For CYP2C, no difference in mRNA expression was observed, while CYP2C activity was greater in female pigs. Surprisingly, the expression of the constitutive androstane receptor, pregnane X receptor and aryl hydrocarbon receptor did not differ with feed or gender. In conclusion, chicory root modifies the expression and activity of CYP3A in vivo and in vitro, while CYP2C is not affected. PMID- 22926444 TI - Radiographic features associated with differing impinging hip morphologies with special attention to coxa profunda. AB - BACKGROUND: Combined with clinical examination and MRI, radiographs have been mainstays in the management femoroacetabular impingement (FAI). Because hip morphology often portends intraoperative damage, radiographic features should inform surgical management. QUESTIONS/PURPOSES: We determined (1) the radiographic features of the various hip morphologies; (2) the prevalence of radiographic coxa profunda in each group; (3) the radiographic differences between hips with and without coxa profunda; and (4) its sensitivity and specificity as a measure of global acetabular overcoverage. METHODS: We reviewed preoperative radiographs and operative notes of 144 hips that underwent surgical dislocation and correction for FAI between August 2002 and February 2011. Hips were divided into four FAI subtypes by radiographic analysis (cam, global overcoverage, retroversion, and combined) and three subtypes (cam, pincer, or combined) by intraarticular pathology. Standard radiographic measurements were performed, and we introduce a novel measurement that assesses femoral head coverage. RESULTS: We found differences in median Angle of Sharp, femoral head neck angle, and median roof length (and its subset) among the FAI morphologies. The prevalence of radiographic coxa profunda was 48% in cam hips, 85% in global overcoverage hips, 66% in retroverted hips, and 32% in combined hips. The sensitivity and specificity of radiographic coxa profunda as a measure of global overcoverage was 75% (95% CI, 0.62-0.85) and 62% (95% CI, 0.51-0.73), respectively. CONCLUSIONS: We found major differences in radiographic measurements between FAI morphologies. Radiographic coxa profunda was poorly specific for global overcoverage. Measurement of roof length and ratio should be used to determine the morphology of the impinging hip. LEVEL OF EVIDENCE: Level II, prognostic study. See Guidelines for Authors for a complete description of levels of evidence. PMID- 22926445 TI - Giant cell tumor with pathologic fracture: should we curette or resect? AB - BACKGROUND: Approximately one in five patients with giant cell tumor of bone presents with a pathologic fracture. However, recurrence rates after resection or curettage differ substantially in the literature and it is unclear when curettage is reasonable after fracture. QUESTIONS/PURPOSES: We therefore determined: (1) local recurrence rates after curettage with adjuvants or en bloc resection; (2) complication rates after both surgical techniques and whether fracture healing occurred after curettage with adjuvants; and (3) function after both treatment modalities for giant cell tumor of bone with a pathologic fracture. METHODS: We retrospectively reviewed 48 patients with fracture from among 422 patients treated between 1981 and 2009. The primary treatment was resection in 25 and curettage with adjuvants in 23 patients. Minimum followup was 27 months (mean, 101 months; range, 27-293 months). RESULTS: Recurrence rate was higher after curettage with adjuvants when compared with resection (30% versus 0%). Recurrence risk appears higher with soft tissue extension. The complication rate was lower after curettage with adjuvants when compared with resection (4% versus 16%) and included aseptic loosening of prosthesis, allograft failure, and pseudoarthrosis. Tumor and fracture characteristics did not increase complication risk. Fracture healing occurred in 24 of 25 patients. Mean Musculoskeletal Tumor Society score was higher after curettage with adjuvants (mean, 28; range, 23-30; n = 18) when compared with resection (mean, 25; range, 13-30; n = 25). CONCLUSIONS: Our observations suggest curettage with adjuvants is a reasonable option for giant cell tumor of bone with pathologic fractures. Resection should be considered with soft tissue extension, fracture through a local recurrence, or when structural integrity cannot be regained after reconstruction. LEVEL OF EVIDENCE: Level III, therapeutic study. See Guidelines for Authors for a complete description of levels of evidence. PMID- 22926446 TI - Should ACOSOG Z0011 change practice with respect to axillary lymph node dissection for a positive sentinel lymph node biopsy in breast cancer? AB - While any study can be criticized, the results of Z0011 clearly show that sentinel lymph node biopsy (SLNB) alone without axillary lymph node dissection (ALND) results in extremely low locoregional recurrence and excellent overall survival comparable to completion ALND. The observed results in this trial with SLNB alone were excellent. A prospective randomized study with results such as Z0011 should alter therapy. The skilled clinician must utilize his or her experience and the prospective randomized data of this study to improve patient care for women with breast cancer. On the other hand, ALND continues to be the standard of care for positive nodes in the axilla, with lymph node status as the most important prognostic indicator in overall survival (OS) and disease-free survival (DFS) in the management of early stage breast cancer. The advent of sentinel lymph node resection (SLNR) is challenging this notion. There is evidence to support the need for regional control of the axilla as a preventative means for locoregional recurrence and improvement in DFS. ALND is both a diagnostic and therapeutic approach that not only decreases rates of locoregional recurrence, but also guides further treatment strategies. Currently, there are no definable criteria that completely prevent patients from benefiting from ALND in the setting of metastatic disease to the axilla. It is, therefore, clear that ALND should be strongly considered in the management of the SLN-positive axilla. SLNR has its role in the management of early stage breast cancer, but whether SLNR alone should replace ALND is yet to be determined. PMID- 22926447 TI - Diffusion-weighted imaging in Sydenham's chorea. AB - PURPOSE: The purpose of this study was to determine of caudate nucleus changes in diffusion-weighted magnetic resonance imaging. METHODS: A total of 13 children (four males and nine females) with history of Sydenham's chorea and 13 healthy controls were included in to the study. Diffusion cranial magnetic resonance imaging was performed in all subjects before prednisone treatment. Prednisone (2 mg/kg/day, maximum dose 60 mg/day) was used during 4 weeks and then progressively discontinued (20 % of the initial dose was reduced at each 5 days). Two months later, magnetic resonance imaging was repeated. RESULTS: Before and after 8 weeks of prednisone treatment, apparent diffusion coefficients (ADCs) were calculated for right and left caudate nucleus. The ADC values were significantly different before treatment and 2 months after imaging. For the left caudate nucleus, ADC values before treatment (0.69 +/- 0.038) were significantly lower than after treatment (0.95 +/- 0.04). For the right caudate nucleus, ADC values before treatment (0.72 +/- 0.06 * 10(-3)) were significantly lower than after treatment (0.93 +/- 0.04 * 10(-3)). CONCLUSIONS: Although cranial and caudate nucleus magnetic resonance imaging findings were normal, the low ADC value findings in our study support the autoimmune inflammation in basal ganglia of Sydenham's chorea. PMID- 22926448 TI - Effect of layer heterogeneity on the biomechanical properties of ascending thoracic aortic aneurysms. AB - This study addressed layer-specific differences in the biomechanical response of ascending aortic aneusysms, obtained from patients during graft replacement. Tensile tests were conducted on pairs of (orthogonally directed) intimal, medial, and adventitial strips from the anterior, posterior, and two lateral quadrants. The experimental data were reduced by the Fung-type model, affording appropriate characterization of the material properties. Testing of individual layers beyond rupture disclosed their failure properties, namely their capacity to bear varying deformation and stress levels. Material parameters [Formula: see text] and [Formula: see text], specifying circumferential and longitudinal stiffness, received the highest values in the adventitia or intima and the smallest in the media, with [Formula: see text] > [Formula: see text] in every layer but the intima. Similar extensibility at failure was found among layers, whereas the adventitia was the strongest of all. Circumferentially and longitudinally directed strips from each layer did not show uniform material parameters and failure properties among regions, but most differences did not reach significance. Medial and adventitial but not intimal layers were stronger circumferentially than longitudinally. This is the first study to place emphasis on the biomechanical properties of the distinct layers of human aneurysmal aorta that may be expected to shed light into the mechanisms promoting aneurysm dissection and rupture. PMID- 22926449 TI - Distribution and risk assessment of metals in sediments from Taihu Lake, China using multivariate statistics and multiple tools. AB - Metals in the surface sediment and zoobenthos throughout Taihu Lake were investigated to explore their distribution, source and potential ecological risks. The result showed that the average metal concentration followed the order: Fe > Mn > Zn > Cr > Ni > Pb > Cu > Cd, with the highest value of 27.9 g/kg (Fe) and lowest value 0.54 mg/kg (Cd). Anthropogenic inputs were the major sources of metals, followed by geochemical processes, and organic matter is also a control for metals. Spatially, high metal concentrations were distributed in the northern lake and low concentrations in Gonghu Bay and the eastern part of the lake. Risk assessment showed that Pb had the highest ecological risk (E(r) = 10.32), followed by Cu and Ni (E(r) = 8.77-8.81), while Zn had the lowest risk (E(r) = 1.59). Analysis indicated that Corbicula sp. was more suitable for biomonitoring than Bellamya sp. PMID- 22926450 TI - Appraisal of heavy metals in groundwater in Chennai city using a HPI model. AB - Heavy metal contamination in Chennai city was evaluated using a heavy metal pollution index (HPI) model in conjunction with the spatial distribution maps. Metals such as Cd, Cr, Cu, Pb and Zn in the groundwater were determined using standard methods and the resultant data was utilized in the development of a HPI model. The metal concentrations showed a dominance in the order of Zn > Cu > Cr > Pb > Cd respectively. About 14.3 % of the samples (n = 2), exhibited high HPI (>38) and the highest value, HPI = 97.55, has been recorded from Thiruvanmiyur area. Statistical analysis revealed a positive correlation between metals such as Cd and Cr (r = 0.606), Cd and Cu (r = 0.601), Cr and Cu (r = 0.464) and Pb and Zn (r = 0.416), suggested their common origin. The spatial distribution maps of heavy metals and the HPI suggested that the SW region, especially Adyar and Thiruvanmiyur regions are highly contaminated with the metals. Industrialisation and improper waste dumping were identified as the major cause for the accumulation of metals in the groundwater of Chennai city. PMID- 22926451 TI - Increased plasma neopterin and hs-CRP levels in patients with endemic fluorosis. AB - Although fluoride induced inflammatory reactions have been shown in animals and in vitro humans, there are few studies about fluoride induced inflammatory reactions in human beings at clinical setting. We aimed to measure the plasma neopterin, a marker of activation of the monocyte/macrophage system, and high sensitivity C-reactive protein (hs-CRP) levels in patients with endemic fluorosis to investigate the possible role of inflammatory processes (monocyte/macrophage activity) in the underlying pathophysiology of fluoride toxicity at clinical level. Plasma neopterin and hs-CRP levels were determined in endemic fluorosis patients and control subjects. Plasma neopterin levels were significantly higher among patients with endemic fluorosis when compared with control group (2.40 +/- 0.66 vs. 1.63 +/- 0.27 ng/mL respectively; p < 0.001) and plasma hs-CRP levels were also significantly higher among patients with endemic fluorosis when compared with control group (2.41 +/- 1.23 vs. 1.93 +/- 0.64 mg/L respectively; p < 0.001). Plasma neopterin levels were positively correlated with urine fluoride levels (r = 0.67, p < 0.001) and serum hs-CRP levels were positively correlated with urine fluoride levels (r = 0.36, p < 0.001). We have found that plasma neopterin and hs-CRP levels are increased in patients with endemic fluorosis. We have concluded that inflammation play an important role in the pathophysiology of fluoride toxicity in patients with endemic fluorosis. PMID- 22926452 TI - Imaging findings in megacystis-microcolon-intestinal hypoperistalsis syndrome. AB - Megacystis-microcolon-intestinal hypoperistalsis syndrome (MMIHS) is a rare and frequently lethal form of severe functional intestinal obstruction more commonly found in girls. Imaging features characteristic of this disease include a large dilated bladder, microcolon and intestinal dysmotility. Additional imaging findings may include intestinal malrotation, hydronephrosis and vesicoureteral reflux. It is usually fatal in the first year of life. Because presenting clinical and imaging features can mimic other causes of neonatal bowel obstruction, we compiled examples of this disorder to help the pediatric radiologist recognize imaging findings associated with MMIHS and aid in the development of a long-term management plan and in counseling the family regarding implications of this disorder. We reviewed recent and historical literature relevant to MMIHS and present the imaging and clinical features of four patients with MMIHS treated at our institution as examples of this uncommon disorder. PMID- 22926453 TI - Standard Nutrient Agar 1 as a substitute for blood-supplemented Muller-Hinton agar for antibiograms in developing countries. AB - In the industrial world, the agar diffusion test is a standard procedure for the susceptibility testing of bacteria isolates. Beta-hemolytic Streptococcus spp. are tested with Muller-Hinton agar supplemented with 5 % blood, a so-called blood agar. The results are interpreted using standardized tables, which only exist for this type of nutrient matrix. Because of a number difficulties, both with respect to technical issues and to manual skills, blood agar is not a feasible option in many developing countries. Beta-hemolytic Streptococcus spp. also grow on Standard Nutrient Agar 1 (StNA1). This suggests using that type of nutrient medium for running agar diffusion tests. However, there are no standardized tables that can be used for interpreting the diameters of the zones of inhibition on StNA1 1. Using the existing standardized tables for blood agar to interpret cultures on StNA1 1 would be of great benefit under such circumstances where blood agar is not available. With this in mind, we conducted comparative tests to evaluate the growth characteristics of beta-hemolytic Streptococcus spp. on StNA1 1 compared to Muller-Hinton agar supplemented with 5 % sheep blood. In this study, we were able to show that beta-hemolytic Streptococcus spp. develop similar zones of inhibition on blood agar and on StNA1 1. Therefore, it is suggested that, for the interpretation of antibiograms of beta-hemolytic Streptococcus spp. performed on StNA1 1, the standard tables for blood agar can be used. PMID- 22926455 TI - Serum cystatin C concentrations are increased in human obesity in relation to over-production by the adipose tissue. PMID- 22926456 TI - Lack of evidence to support a beneficial role for glutathione depletion on body weight or glucose tolerance. PMID- 22926458 TI - Reaction between enaminones and acetylenic esters in the presence of triphenylphosphine: a convenient synthesis of alkyl 2(1-benzyl-2,4-dioxo 2,3,4,5,6,7-hexahydro-1H-indol-3-yl)acetates. AB - One-pot reaction between enaminocarbonyl compounds derived from six-membered 1,3 diketones and substituted benzylamines, and electron-deficient acetylenic esters in the presence of triphenylphosphine lead to alkyl 2-(1-benzyl-6,6-dimethyl-2,4 dioxo-2,3,4,5,6,7-hexahydro-1H-indol-3-yl)acetate derivatives in good yields. PMID- 22926459 TI - Reducing waiting time for community rehabilitation services: a controlled before and-after trial. AB - OBJECTIVE: To investigate whether a simple alternative (specific timely appointments for triage [STAT]) to the more common approach of managing demand using a waitlist with a triage system could reduce waiting time for a community rehabilitation program (CRP) without adverse impacts on patient care. DESIGN: A prospective, controlled before-and-after trial. Preintervention and postintervention data were collected for 6 months in 2 consecutive years. STAT was introduced at an intervention site and compared with a control site using a triaged waitlist. SETTING: Two musculoskeletal CRP teams within a large metropolitan health service. PARTICIPANTS: All patients referred to both sites during periods preintervention (n=483) and postintervention (n=488). INTERVENTION: Under STAT, clinicians created a specified number of assessment times each week based on average referral numbers, and patients were immediately allocated an appointment on referral. MAIN OUTCOME MEASURES: The primary outcome was the time from referral to first appointment; secondary outcomes included program duration, quality-of-life scores (using the EuroQol EQ-5D), and unplanned hospital admissions. RESULTS: Waiting time decreased from a mean of 17.5 days to 10.0 days (P<.01) at the intervention site, with no significant change at the control site. Intervention site patients were over 3 times more likely to be seen within 7 days than control site patients (odds ratio, 3.3; 95% confidence interval, 2.2-4.9). Secondary outcomes did not differ significantly between groups. CONCLUSIONS: A simple alternative to using a triaged waitlist to manage CRP referrals reduced waiting time without adversely affecting care. Results were sustained over 6 months with no additional resources. PMID- 22926460 TI - Preoperative pulmonary rehabilitation versus chest physical therapy in patients undergoing lung cancer resection: a pilot randomized controlled trial. AB - OBJECTIVE: To evaluate the effect of 4 weeks of pulmonary rehabilitation (PR) versus chest physical therapy (CPT) on the preoperative functional capacity and postoperative respiratory morbidity of patients undergoing lung cancer resection. DESIGN: Randomized single-blinded study. SETTING: A teaching hospital. PARTICIPANTS: Patients undergoing lung cancer resection (N=24). INTERVENTIONS: Patients were randomly assigned to receive PR (strength and endurance training) versus CPT (breathing exercises for lung expansion). Both groups received educational classes. MAIN OUTCOME MEASURES: Functional parameters assessed before and after 4 weeks of PR or CPT (phase 1), and pulmonary complications assessed after lung cancer resection (phase 2). RESULTS: Twelve patients were randomly assigned to the PR arm and 12 to the CPT arm. Three patients in the CPT arm were not submitted to lung resection because of inoperable cancer. During phase 1 evaluation, most functional parameters in the PR group improved from baseline to 1 month: forced vital capacity (FVC) (1.47L [1.27-2.33L] vs 1.71L [1.65-2.80L], respectively; P=.02); percentage of predicted FVC (FVC%; 62.5% [49%-71%] vs 76% [65%-79.7%], respectively; P<.05); 6-minute walk test (425.5+/-85.3m vs 475+/ 86.5m, respectively; P<.05); maximal inspiratory pressure (90+/-45.9cmH(2)O vs 117.5+/-36.5cmH(2)O, respectively; P<.05); and maximal expiratory pressure (79.7+/-17.1cmH(2)O vs 92.9+/-21.4cmH(2)O, respectively; P<.05). During phase 2 evaluation, the PR group had a lower incidence of postoperative respiratory morbidity (P=.01), a shorter length of postoperative stay (12.2+/-3.6d vs 7.8+/ 4.8d, respectively; P=.04), and required a chest tube for fewer days (7.4+/-2.6d vs 4.5+/-2.9d, respectively; P=.03) compared with the CPT arm. CONCLUSIONS: These findings suggest that 4 weeks of PR before lung cancer resection improves preoperative functional capacity and decreases the postoperative respiratory morbidity. PMID- 22926461 TI - Quality of life following third molar removal under conscious sedation. AB - AIM: The aim of this study was to assess quality of life (QoL) and degree of satisfaction among outpatients subjected to surgical extraction of all four third molars under conscious sedation. A second objective was to describe the evolution of self-reported pain measured in a visual analogue scale (VAS) in the 7 days after extraction. STUDY DESIGN: Fifty patients received a questionnaire assessing social isolation, working isolation, eating and speaking ability, diet modifications, sleep impairment, changes in physical appearance, discomfort at suture removal and overall satisfaction at days 4 and 7 after surgery. Pain was recorded by patients on a 100-mm pain visual analogue scale (VAS) every day after extraction until day 7. RESULTS: Thirty-nine patients fulfilled correctly the questionnaire. Postoperative pain values suffered small fluctuations until day 5 (range: 23 to 33 mm in a 100-mm VAS), when dicreased significantly. A positive association was observed between difficult ranked surgeries and higher postoperative pain levels. The average number of days for which the patient stopped working was 4.9. CONCLUSION: The removal of all third molars in a single appointment causes an important deterioration of the patient's QoL during the first postoperative week, especially due to local pain and eating discomfort. PMID- 22926462 TI - The impact of maternal emotional intelligence and parenting style on child anxiety and behavior in the dental setting. AB - OBJECTIVE: The present study investigated the correlations between maternal emotional intelligence (EQ), parenting style, child trait anxiety and child behavior in the dental setting. STUDY DESIGN: One-hundred seventeen children, aged 4-6 years old (mean 5.24 years), and their mothers participated in the study. The BarOn Emotional Quotient Inventory and Bumrind's parenting style questionnaire were used to quantify maternal emotional intelligence and parenting style. Children's anxiety and behavior was evaluated using the Spence Children's Anxiety Scale (SCAS) and Frankl behavior scale. RESULTS: Significant correlation was found between maternal EQ and child behavior (r=0.330; p<0.01); but not between parenting style and child behavior. There was no significant correlation between mother's total EQ and child's total anxiety; however, some subscales of EQ and anxiety showed significant correlations. There were significant correlations between authoritarian parenting style and separation anxiety (r=0.186; p<0.05) as well as authoritative parenting style and mother's EQ (r=0.286; p<0.01). There was no significant correlation between child anxiety and behavior (r = -0.81). Regression analysis revealed maternal EQ is effective in predicting child behavior (beta=0.340; p<0.01). CONCLUSION: This study provides preliminary evidence that the child's behavior in the dental setting is correlated to mother's emotional intelligence. Emotionally intelligent mothers were found to have predominantly authoritative parenting style. PMID- 22926463 TI - Ectopic third molar in the mandibular condyle: a review of the literature. AB - OBJECTIVES: To evaluate the etiopathogenesis, clinical features, therapeutic options, and surgical approaches for removal of ectopic third molars in the mandibular condyle. STUDY DESIGN: MEDLINE search of articles published on ectopic third molars in the mandibular condyle from 1980 to 2011. 14 well-documented clinical cases from the literature were evaluated together with a new clinical case provided by the authors, representing a sample of 15 patients. RESULTS: We found a mean age at diagnosis of 48.6 years and a higher prevalence in women. In 14 patients, associated radiolucent lesions were diagnosed on radiographic studies and confirmed histopathologically as odontogenic cysts. Clinical symptoms were pain and swelling in the jaw or preauricular region, trismus, difficulty chewing, cutaneous fistula and temporomandibular joint dysfunction. Treatment included conservative management in one case and in the other cases, surgical removal by intra- or extraoral approaches, the latter being the most common approach carried out. In most reported cases, serious complications were not outlined. CONCLUSIONS: The etiopathogenic theory involving odontogenic cysts in the displacement of third molars to the mandibular condyle seems to be the most relevant. They must be removed if they cause symptoms or are associated with cystic pathology. The surgical route must be planned according to the location and position of the ectopic third molar, and the possible morbidity associated with surgery. PMID- 22926464 TI - Caries risk profile of 12 year old school children in an Indian city using Cariogram. AB - OBJECTIVES: The present study was conducted with an aim to assess the caries profile of 12 year old Indian children using Cariogram. STUDY DESIGN: Hundred children were interviewed to record any illness, oral hygiene practices and fluoride exposure after obtaining a three day diet diary. Examination was done to record plaque and dental caries status. Stimulated saliva was collected and salivary flow rate, salivary buffering capacity, Streptococcus mutans and Lactobacillus were assessed. The information obtained was scored and Cariogram was created. Differences between mean decayed, missing and filled teeth (DMFT) and Cariogram risk groups were assessed using ANOVA. Spearman Correlation coefficients were used to explore correlation among Cariogram scores and individual variables. RESULTS: It was found that 21, 45, 21 and 13 children had 0 20%, 21-40%, 41-60% and 61-100% chance of avoiding caries respectively in future. Significant correlation was observed between cariogram score and DMFT, diet content, diet frequency, plaque scores, Streptococcus mutans counts and fluoride programme. CONCLUSIONS: Cariogram model can identify the caries-related factors that could be the reasons for the estimated future caries risk, and therefore help the dentist to plan appropriate preventive measures. PMID- 22926465 TI - The effects of image compression on quantitative measurements of digital panoramic radiographs. AB - OBJECTIVES: The aims of this study were to explore how image compression affects density, fractal dimension, linear and angular measurements on digital panoramic images and assess inter and intra-observer repeatability of these measurements. STUDY DESIGN: Sixty-one digital panoramic images in TIFF format (Tagged Image File Format) were compressed to JPEG (Joint Photographic Experts Group) images. Two observers measured gonial angle, antegonial angle, mandibular cortical width, coronal pulp width of maxillary and mandibular first molar, tooth length of maxillary and mandibular first molar on the left side of these images twice. Fractal dimension of the selected regions of interests were calculated and the density of each panoramic radiograph as a whole were also measured on TIFF and JPEG compressed images. Intra-observer and inter-observer consistency was evaluated with Cronbach's alpha. Paired samples t-test and Kolmogorov-Smirnov test was used to evaluate the difference between the measurements of TIFF and JPEG compressed images. RESULTS: The repeatability of angular measurements had the highest Cronbach's alpha value (0.997). There was statistically significant difference for both of the observers in mandibular cortical width (MCW) measurements (1st ob. p: 0.002; 2nd ob. p: 0.003), density (p<0.001) and fractal dimension (p<0.001) between TIFF and JPEG images. There was statistically significant difference for the first observer in antegonial angle (1st ob p< 0.001) and maxillary molar coronal pulp width (1st ob. p< 0.001) between JPEG and TIFF files. CONCLUSIONS: The repeatability of angular measurements is better than linear measurements. Mandibular cortical width, fractal dimension and density are affected from compression. Observer dependent factors might also cause statistically significant differences between the measurements in TIFF and JPEG images. PMID- 22926466 TI - Effect of 15% carbamide peroxide bleaching gel on color stability of giomer and microfilled composite resin: an in vitro comparison. AB - OBJECTIVES: The effect of 15% carbamide peroxide bleaching gel on color stability and surface topography of a giomer and a microfilled composite resin was evaluated in the present in vitro study. STUDY DESIGN: Forty discs measuring 10 mm in diameter and 1 mm in thickness were prepared from a giomer and a microfilled composite resin. Each material yielded 20 discs with completely smooth surfaces. Then a spectrophotometer was used to measure L* (lightness), a* (redness, greenness) and b* (blueness, yellowness) color coordinates of all the discs. Subsequently, the specimens were subjected to 15% carbamide peroxide bleaching gel. After measuring the color coordinates once again, color changes (DeltaE*) were calculated by the CIELAB system. Four specimens from each material (two specimens before bleaching agent application and two specimens thereafter) were viewed under an atomic force microscope (AFM) for surface topography evaluation. Data were analyzed by Mann-Whitney U and Kruskal-Wallis tests at alpha=0.05. RESULTS: There were no statistically significant differences in color changes (DeltaE*) between the two materials (P>0.05). In addition, no significant differences were detected in surface roughness between composite resin and giomer discs before and after bleaching (P>0.05 for both). However, in both materials the differences in surface roughness were significant before and after bleaching procedures (P<0.001). CONCLUSIONS: Based on the results of the present study it was concluded that 15% carbamide peroxide does not induce clinically detectable color changes in composite resin and giomer despite an increase in surface roughness. PMID- 22926467 TI - Mesenchymal dental stem cells in regenerative dentistry. AB - In the last decade, tissue engineering is a field that has been suffering an enormous expansion in the regenerative medicine and dentistry. The use of cells as mesenchymal dental stem cells of easy access for dentist and oral surgeon, immunosuppressive properties, high proliferation and capacity to differentiate into odontoblasts, cementoblasts, osteoblasts and other cells implicated in the teeth, suppose a good perspective of future in the clinical dentistry. However, is necessary advance in the known of growth factors and signalling molecules implicated in tooth development and regeneration of different structures of teeth. Furthermore, these cells need a fabulous scaffold that facility their integration, differentiation, matrix synthesis and promote multiple specific interactions between cells. In this review, we give a brief description of tooth development and anatomy, definition and classification of stem cells, with special attention of mesenchymal stem cells, commonly used in the cellular therapy for their trasdifferentiation ability, non ethical problems and acceptable results in preliminary clinical trials. In terms of tissue engineering, we provide an overview of different types of mesenchymal stem cells that have been isolated from teeth, including dental pulp stem cells (DPSCs), stem cells from human exfoliated deciduous teeth (SHEDs), periodontal ligament stem cells (PDLSCs), dental follicle progenitor stem cells (DFPCs), and stem cells from apical papilla (SCAPs), growth factors implicated in regeneration teeth and types of scaffolds for dental tissue regeneration. PMID- 22926468 TI - Surface electromyographic evaluation of jaw muscles in children with unilateral crossbite and lateral shift in the early mixed dentition. Sexual dimorphism. AB - OBJECTIVES: To examine the activity of jaw muscles at rest and during maximal voluntary clenching (MVC) in children with unilateral posterior crossbite (UPXB) and functional lateral shift in the early mixed dentition and to evaluate sex differences. MATERIAL AND METHODS: The sample included 30 children (15 males, 15 females) aged 6 to 10 years old, with UPXB and functional mandibular lateral shift (>=1.5 mm) in the early mixed dentition. sEMG activity coming from the muscle areas (anterior temporalis [AT], posterior temporalis [PT], masseter [MA] and suprahyoid [SH]) were obtained from both the crossbite (XB) and noncrossbite (NONXB) sides at mandibular rest position. sEMG activity of the bilateral AT and MA muscles sides was obtained during MVC. Asymmetry and activity indexes were calculated for each muscle area at rest and during MVC; the MA/TA ratio during MVC was also determined. RESULTS: At rest, no differences were found between sexes for any muscle areas or asymmetry and activity indexes. No differences were found between XB and NONXB sides. During MVC, however, significant sex differences were found in AT and MA activity, with higher sEMG values in males than in females, on both XB and NONXB sides. Asymmetry indexes, activity indexes and MA/AT ratios did not show significant differences between the sexes. Activity was symmetric both in males and in females. CONCLUSIONS: At rest, no sex differences were found, but during MVC males showed higher activity than did females in both XB and NONXB AT and MA muscle areas. Muscular activity was symmetrical at rest and during MVC in both sexes. Sexual dimorphism should be considered in the diagnosis and treatment of UPXB and lateral shift in the early mixed dentition. PMID- 22926469 TI - Bone metabolism and clinical study of 44 patients with bisphosphonate-related osteonecrosis of the jaws. AB - Osteonecrosis of the jaws is a clinical entity described and linked to treatment with bisphosphonates in 2003. Its real incidence is unknown and it could increase due to the large number of patients treated with these drugs, and its cumulative effect on the bone. State of the art knowledge regarding its etiopathogeny, clinical course and suitable treatments is limited. OBJECTIVES: To study the clinical characteristics of 44 patients with bisphosphonate-related osteonecrosis of the jaws and the state of their bone mineral metabolism: bone remodeling state, prevalence of fractures, bone mineral density study, and assessment of the different treatment strategies. DESIGN OF THE STUDY: Observational. Information was gathered prospectively through interviews, clinical examinations, additional tests and review of medical records. RESULTS: We studied 16 men and 28 women with a mean age of 64.7 years. Breast cancer was the most frequent underlying disease. Zoledronate was used in 82% of the cases and in the non-oncology group of patients; alendronate was the most frequently used bisphosphonate. The mean duration of the zoledronate and alendronate treatments was 25 months and 88 months respectively. The lower jaw was the most frequent location, and previous exodontias-among the triggering factors known-were the most closely linked to its onset. We found considerable osteoblastic activity in patients suffering from neoplasia, with artifacts present in their bone densitometry and a high percentage of vertebral fractures. CONCLUSIONS: According to our results, osteonecrosis of the jaws affects elderly patients. We found a direct relationship between the duration of exposure and the accumulated dose. Other relevant factors are: Poor oral and dental health, corticoids, diabetes and teeth extractions. In essence, it is a clinical diagnosis. Prevention is the best strategy to handle this clinical entity. PMID- 22926470 TI - Decayed, missing and filled teeth index and dental anomalies in long-term survivors leukaemic children: a prospective controlled study. AB - OBJECTIVE: The aim of this prospective controlled study is the comparison between long-term children survived leukaemia and a control group in terms of the decayed, missing or filled permanent teeth (DMFT) and dental anomalies. STUDY DESIGN: Fifty-two long term children survived leukaemia, aged from 8 to 15 years (27 females, 25 males; mean age 11.5 years) were evaluated for the possible effects of the anti-leukaemic therapy on dental development and compared to a control group of 52 healthy children (27 females, 25 males, mean age 11 years). All long-term children who survived were at least 24 months in continuous complete remission. The study of the dental status with a routine oral examination and panoramic radiographs was performed. The DMFT (recorded according to the WHO criteria) and dental anomalies were registered and evaluated. RESULTS: The results of this study evidence that long-term children survived leukaemia, in comparison with the control group, have an higher risk to develop dental caries and show a greater severity of dental anomalies including V-shaped roots, dental agenesis, microdontia, enamel dysplasias. CONCLUSIONS: Paediatric patients with haemathological diseases require a special attentions in dental care in addition to the antineoplastic treatment. Therefore, oral hygiene and oral health can be maintained thanks to a close cooperation between the paediatric oncohaematologists, pediatrics dental surgeons and dental hygienists. PMID- 22926471 TI - Evaluation of apical preparations performed with ultrasonic diamond and stainless steel tips at different intensities using a scanning electron microscope in endodontic surgery. AB - OBJECTIVE: The objective of our study is to analyse (with the help of scanning electron microscopes) the quality of the dental root surface and the appearance of dental cracks after performing apical preparations using two different types of ultrasonic tips. STUDY DESIGN: We used 32 single-rooted teeth that underwent a root canal and apical resection. Afterwards, the teeth were divided into 4 groups of 8 teeth each, with preparations of the apical cavities in the following manner: Group 1: stainless steel ultrasonic tip at 33 KHz. Group 2: stainless steel ultrasonic tip at 30 KHz. Group 3: diamond ultrasonic tip at 30 KHz. Group 4: diamond ultrasonic tip at 33 KHz. The quality of the root surface and the presence of cracks were evaluated by one single observer using a scanning electron microscope. RESULTS: All of the teeth in our study had cracks after the apical preparations. The mean number of cracks per tooth ranged between 6. +/- 1.9 (group 1) and 3.5 +/- 2.4 (group 4), with a significantly higher number found in the groups that used stainless steel tips (P=.03). The types of cracks produced involved: 8 complete cracks (4.5%), 167 incomplete cracks (94.4%), and 2 intradentinal cracks (1.1%), with no significant differences observed between the different frequencies used for each group. CONCLUSIONS: Stainless steel ultrasonic tips provoked a larger number of cracks than diamond tips. The frequency of vibration used did not have any effect on the number of cracks found. PMID- 22926472 TI - Implant periapical lesion: diagnosis and treatment. AB - The implant periapical lesion is the infectious-inflammatory process of the tissues surrounding the implant apex. It may be caused by different factors: contamination of the implant surface, overheating of bone during drilling, preparation of a longer implant bed than the implant itself, and pre-existing bone disease. Diagnosis is achieved by studying the presence of symptoms and signs such us pain, swelling, suppuration or fistula; in the radiograph an implant periapical radiolucency may appear. A diagnostic classification is proposed to establish the stage of the lesion, and determine the best treatment option accordingly. The following stages are distinguished: acute apical periimplantitis (non-suppurated and suppurated) and subcacute (or suppurated fistulized) apical periimplantitis. The most adequate treatment of this pathology in the acute stage and in the subacute stage if there is no loss of implant stability is apical surgery. In the subacute stage, if there is implant mobility, the extraction of the implant is necessary. PMID- 22926473 TI - Temporomandibular disorders dysfunction in headache patients. AB - OBJECTIVE: To identify the frequency of signs and symptoms of temporomandibular disorder (TMD) and its severity in individuals with headache. STUDY DESIGN: 60 adults divided into three groups of 20 individuals: chronic daily headache (CDH), episodic headache (EH) and a control group without headache (WH). Headache diagnosis was performed according to the criteria of International Headache Society and the signs and symptoms of TMD were achieved by using a clinical exam and an anamnestic questionnaire. The severity of TMD was defined by the temporomandibular index (TMI). RESULTS: The TMD signs and symptoms were always more frequent in individuals with headache, especially report of pain in TMJ area (CDH, n=16; EH, n=12; WH, n=6), pain to palpation on masseter (CDH, n=19; EH, n=16; WH, n=11) which are significantly more frequent in episodic and chronic daily headache. The mean values of temporomandibular and articular index (CDH patients) and muscular index (CDH and EH patients) were statistically higher than in patients of the control group, notably the articular (CDH=0.38; EH=0.25;WH=0.19) and muscular (CDH=0.46; EH=0.51; WH=0.26) indices. CONCLUSIONS: These findings allow us to speculate that masticatory and TMJ pain are more common in headache subjects. Besides, it seems that the TMD is more severe in headache patients. PMID- 22926474 TI - Facial disability index (FDI): adaptation to Spanish, reliability and validity. AB - OBJECTIVES: To adapt to Spanish the facial disability index (FDI) described by VanSwearingen and Brach in 1995 and to assess its reliability and validity in patients with facial nerve paresis after parotidectomy. STUDY DESIGN: The present study was conducted in two different stages: a) cross-cultural adaptation of the questionnaire and b) cross-sectional study of a control group of 79 Spanish speaking patients who suffered facial paresis after superficial parotidectomy with facial nerve preservation. The cross-cultural adaptation process comprised the following stages: (I) initial translation, (II) synthesis of the translated document, (III) retro-translation, (IV) review by a board of experts, (V) pilot study of the pre-final draft and (VI) analysis of the pilot study and final draft. RESULTS: The reliability and internal consistency of every one of the rating scales included in the FDI (Cronbach's alpha coefficient) was 0.83 for the complete scale and 0.77 and 0.82 for the physical and the social well-being subscales. The analysis of the factorial validity of the main components of the adapted FDI yielded similar results to the original questionnaire. Bivariate correlations between FDI and House-Brackmann scale were positive. The variance percentage was calculated for all FDI components. CONCLUSIONS: The FDI questionnaire is a specific instrument for assessing facial neuromuscular dysfunction which becomes a useful tool in order to determine quality of life in patients with facial nerve paralysis. Spanish adapted FDI is equivalent to the original questionnaire and shows similar reliability and validity. The proven reproducibility, reliability and validity of this questionnaire make it a useful additional tool for evaluating the impact of facial nerve paralysis in Spanish speaking patients. PMID- 22926475 TI - Lateral transport osteogenesis in maxillofacial oncology patients for rehabilitation with dental implants: a retrospective case series. AB - OBJECTIVES: To report on the use of lateral transport osteogenesis in cancer patients after maxillo/mandibular resections and on the implant survival rate in the generated bone MATERIAL AND METHODS: Four patients treated using lateral transport osteogenesis entered this descriptive study and were retrospectively studied (mean age 55; range 41-62). RESULTS: Reconstruction of segmentary defects after surgical and radiological cancer treatment on maxilla and mandible was achieved. No relevant intra- or post-operative complications occurred. No differences on implant survival were observed between patients who had received radiotherapy and those who had not. CONCLUSIONS: This approach can be considered a recommendable reconstructive option after oral cancer treatment - including radiotherapy- particularly for high-surgical-risk, collaborative patients. PMID- 22926476 TI - The comparison of outcomes of surgically treated bilateral temporomandibular joint disorder in different groups: a retrospective study. AB - OBJECTIVES: The main purpose of this study was to determine the prognosis and outcomes of the patients with bilateral temporomandibular disorder which underwent bilateral temporomandibular joint surgery in a consecutive number of patients in a retrospective study. STUDY DESIGN: Sixty five patients with 130 bilateral TMJ were included the study with the selection from consecutive 256 TMJ patients who were treated with open surgery who do not respond to conservative treatment. 65 patients were divided in to 3 main groups according to the clinical diagnosis of bilateral TMJ site. In the first group comprised 29 patients with 48 TMJ, the clinical diagnosis was bilaterally presence of anterior disc displacement with reduction (ADDR). In the second group comprised 19 patients with 26 TMJ, bilateral presence of TMD consisted of anterior disc displacement without reduction (ADDNR) on both site. In the third group comprised 27 patients with 46 TMJ, bilaterally presence of TMD consist of ADDR on one site and ADDNR on another site. The patients in three different groups were operated either high condylectomy alone or high condylectomy with additional surgical procedures. RESULTS: In the evaluation of pain relief, clicking, crepitation, headache, marked improvement was determined in all groups, but it was statistically insignificant in the comparison of 3 groups. Slight increase in maximal mouth opening was determined in the mean values of the 3 groups and also in the comparison of 3 groups it was not statistically significant. CONCLUSIONS: These similar succesfull outcomes of bilateral TMD with the respect of TMJ surgical procedures were obtained in 3 main groups although different diagnosis on the patients' groups was present. PMID- 22926478 TI - Patient-specific factors in the proximity of the inferior alveolar nerve to the tooth apex. AB - OBJECTIVES: To evaluate whether age and gender differences are predictive factors for inferior alveolar nerve position with respect to mandibular first molar roots. STUDY DESIGN: Cone-beam computed tomography scans [0.2-mm3 voxel size; n = 200 (100 males, 100 females)] of patients aged 15-65 years showing mandibular first and second molars were included in this study. Patients with pathoses that might affect inferior alveolar nerve position, including second molar and/or first premolar extraction, were excluded. Fourteen measurements (mm) were taken from the inferior alveolar nerve to the mesial and distal root apices. Subjects were grouped by age and gender. Data were analysed using two-way analyses of variance with post hoc Bonferroni corrections. RESULTS: The distance from the inferior alveolar nerve to the root apices was smaller in females than males, regardless of age (p < 0.01). Distal roots were closer to the nerve than mesial roots in both genders (p < 0.05). Total buccolingual mandibular length (at 3-mm apical level) was shorter in females than males (p < 0.01) but mean buccolingual mandibular width at the level of the inferior alveolar canal did not differ. Nerve-root apex distances were significantly shorter in males and females aged 16 25 and 56-65 years than in other age groups (p < 0.01). CONCLUSIONS: The distance between inferior alveolar nerve and mandibular first molar roots depends upon the age and gender: it is shorter in females than in males and in subjects aged 16-25 years and >55 years than in other age groups. PMID- 22926477 TI - Expression of semaphorin 3A and neuropilin 1 with clinicopathological features and survival in human tongue cancer. AB - OBJECTIVE: To investigate the association between semaphorin 3A (SEMA 3A) and its receptor neuropilin 1 (NRP1) and the clinicopathologic characteristics of patients with tongue cancer. STUDY DESIGN: Forty-three tongue squamous cell carcinoma specimens were included. Immunohistochemical staining of SEMA3A and NRP1 was performed on 15 normal tongue epithelium specimens and the 43 tumour specimens. Immunoreactivity was evaluated based on the staining intensity and distribution score. Statistical analyses were performed using Chi-squared and Spearman tests and Kaplan-Meier analysis. RESULTS: SEMA3A was significantly down regulated in tongue cancer compared with normal tongue (P=0.025), while NRP1 was over-expressed in tumours (P<0.001). SEMA3A expression inversely correlated with nodal metastasis (P=0.017). NRP1 expression did not correlate with any clinicopathological characteristics. Higher SEMA3A expression strongly predicted longer survival (P=0.005). Scores for the NRP1/SEMA3A ratio of >=1 predicted shorter survival (P=0.045). CONCLUSIONS: Aberrant expression of SEMA3A and its receptor NRP1 might be involved in the development of tongue cancer and might be useful prognostic markers in this tumour type. PMID- 22926479 TI - Multiple teeth replacement with endosseous one-piece yttrium-stabilized zirconia dental implants. AB - OBJECTIVES: The purpose of this study is to clinically and radiographically evaluate survival and success rate of multiple zirconia dental implants positioned in each patient during a follow-up period of at least 12 months up to 48 months. STUDY DESIGN: Eight patients were treated for multiple edentulism with 29 zirconia dental implants. All implants received immediate temporary restorations and 6 months after surgery were definitively restored. 6 months to 4 years after implant insertion, a clinical-radiographic evaluation was performed in order to estimate peri-implant tissues health and peri-implant marginal bone loss. RESULTS: Survival rate within follow-up period was therefore 100%. The average marginal bone loss (MBL) from baseline to 6 months was +1.375 +/- 0.388 mm; from 6 months to 1 year was +0.22 +/- 0.598 mm; from 1 year to 2 years was 0.368 +/- 0.387 mm; from 2 years to 3 years was -0.0669 +/- 0.425 mm; from 3 years to 4 years +0.048 +/- 0.262 mm. The mean marginal bone loss at 4 years from the implants insertion was +1.208 mm. CONCLUSIONS: According to several studies, when using a radiographic criterion for implant success, marginal bone loss below 0.9-1.6 mm during the first year in function can be considered acceptable. In our work, radiographic measurements of MBL showed values not exceeding 1.6 mm during the first year of loading and also 1 year up to 4 years after surgery further marginal bone loss was minimal and not significant. This peri-implant bone preservation may be associated to the absence of micro-gap between fixture and abutment since zirconia dental implants are one-piece implant. Moreover, zirconia is characterized by high biocompatibility and it accumulates significantly fewer bacteria than titanium. PMID- 22926480 TI - Tissue microarray construction for salivary gland tumors study. AB - OBJECTIVE: To describe and discuss the design, building and usefulness of tissue microarray (TMA) blocks for the study of salivary gland tumors (SGTs). STUDY DESIGN: Two hundred thirty-eight formalin-fixed, paraffin-embedded SGTs were arranged in blocks of TMA using a manual tissue arrayer. Three representative cores of 1.0, 2.0 or 3.0mm were taken from each original block and their characteristics were analyzed and described. RESULTS: It was created 12 TMA blocks that presented highly representative neoplastic cylinders. However, those neoplasias rich in cystic spaces such as mucoepidermoid carcinoma and Warthin tumor presented more difficulties to be sampled, as the neoplastic tissue available was scarce. Tissue damage and loss during TMA construction was estimated as 3.7%. CONCLUSION: Representative areas of SGTs, with relatively small loss of tissue, can be obtained with the construction of TMA blocks for molecular studies. However, tumors rich in cystic spaces present more difficulties to be adequately sampled. PMID- 22926481 TI - Effectiveness of malic acid 1% in patients with xerostomia induced by antihypertensive drugs. AB - OBJECTIVES: Assessing the clinical effectiveness of a topical sialogogue on spray (malic acid, 1%) in the treatment of xerostomia induced by antihypertensive drugs. STUDY DESIGN: This research has been carried out through a randomized double-blind clinical trial. 45 patients suffering from hypertensive drugs induced xerostomia were divided into 2 groups: the first group (25 patients) received a topical sialogogue on spray (malic acid, 1%) whereas the second group (20 patients) received a placebo. Both of them were administered on demand for 2 weeks. Dry Mouth Questionnaire (DMQ) was used in order to evaluate xerostomia levels before and after product/placebo application. Unstimulated and stimulated salivary flows rates, before and after application, were measured. All the statistical analyses were performed by using SPSS software v17.0. Different DMQ scores at the earliest and final stage of the trial were analysed by using Mann Whitney U test, whereas Student's T-test was used to analyse salivary flows. Critical p-value was established at p<0.05. RESULTS: DMQ scores increased significantly (clinical recovery) from 1.21 to 3.36 points (p<0.05) after malic acid (1%) application whereas DMQ scores increased from 1.18 to 1.34 points (p>0.05) after placebo application. After two weeks of treatment with malic acid, unstimulated salivary flow increased from 0.17 to 0.242 mL/min whereas the stimulated one increased from 0.66 to 0.92 mL/min (p<0.05). After placebo application unstimulated flow ranged from 0.152 to 0.146 mL/min and stimulated flow increased from 0.67 to 0.70 mL/min (p>0.05). CONCLUSIONS: Malic acid 1% spray improved antihypertensive-induced xerostomia and stimulated the production of saliva. PMID- 22926483 TI - Expression of transforming growth factor beta and its correlation with lipodystrophy in oral submucous fibrosis: an immunohistochemical study. AB - OBJECTIVE: In our routine review of Oral Submucous Fibrosis (OSMF) biopsies, we observed decreased adipose tissue even though most are from buccal mucosa. Pathogenesis of OSMF has demonstrated the role of Transforming Growth Factor beta (TGF beta), in causing fibrosis. This study aims to correlate the role of TGF beta with loss of adipose tissue in OSMF. STUDY DESIGN: From our archives, 84 OSMF cases (24 early and 60 advanced OSMF) were screened for adipose tissue. Immunoexpression of TGF beta in these cases were investigated. RESULTS: Adipose tissue was seen in 67% of early OSMF and in 13% of advanced cases. Early cases showed more intense TGF beta staining of epithelium, fibroblast, macrophages and inflammatory cells than the advanced cases. CONCLUSION: These findings suggest that TGF beta plays a key role in causing lipodystrophy in OSMF and is secreted more during early course of the disease than in advanced stage. PMID- 22926482 TI - Decalcifying effects of antimicrobial irrigating solutions on root canal dentin. AB - OBJECTIVE: The aim of this study was to determine the decalcifying efficacy of 7% maleic acid (MA), 2% chlorhexidine (CHX), and combinations of 7% MA + 0.2% cetrimide (CTR) and 2% CHX + 0.2% CTR, in four time periods. STUDY DESIGN: Four specimens per tooth were obtained from a 2-mm thick slice of the cervical third of the root of ten human incisors. At 1, 2, 3 and 5 minutes of immersion, the concentrations of Ca2+ were measured by atomic absorption spectrophotometry. The results were analyzed using the Mann-Whitney U-test. RESULTS: Statistically significant differences were seen for the extracted calcium in all time periods. The amount of calcium extracted by 7% MA was the highest at all four immersion times, followed by 7% MA + 0.2% CTR. Two percent CHX and its combination with 0.2% CTR extracted virtually no calcium. CONCLUSIONS: The decalcifying capacity of 7% MA and 2% CHX diminished when combined with 0.2% CTR. PMID- 22926484 TI - Self-reported bruxism mirrors anxiety and stress in adults. AB - OBJECTIVES: The aims were to analyze whether the levels of self-reported bruxism and anxiety associate among otherwise healthy subjects, and to investigate the independent effects of anxiety and stress experience on the probability of self reported bruxism. STUDY DESIGN: As part of a study on irregular shift work, a questionnaire was mailed to all employees of the Finnish Broadcasting Company with irregular shift work (number of subjects: n=750) and to an equal number of randomly selected employees in the same company with regular eight-hour daytime work. RESULTS: The response rates were 82.3% (56.6 % men) and 34.3 % (46.7 % men), respectively. Among the 874 respondents, those aware of more frequent bruxism reported significantly more severe anxiety (p<0.001). Adjusted by age and gender, frequent bruxers were more than two times more likely to report severe stress (odds ratio 2.5; 95% confidence interval 1.5-4.2) and anxiety (odds ratio 2.2; 95% confidence interval 1.3-3.6) than non-or-mild bruxers. CONCLUSIONS: Present findings suggest that self-reported bruxism and psychological states such as anxiety or stress may be related in working age subjects. PMID- 22926485 TI - Bond strength of selected composite resin-cements to zirconium-oxide ceramic. AB - OBJECTIVES: The aim of this study was to evaluate bond strengths of zirconium oxide (zirconia) ceramic and a selection of different composite resin cements. STUDY DESIGN: 130 Lava TM cylinders were fabricated. The cylinders were sandblasted with 80 um aluminium oxide or silica coated with CoJet Sand. Silane, and bonding agent and/or Clearfil Ceramic Primer were applied. One hundred thirty composite cement cylinders, comprising two dual-polymerizing (Variolink II and Panavia F) and two autopolymerizing (Rely X and Multilink) resins were bonded to the ceramic samples. A shear test was conducted, followed by an optical microscopy study to identify the location and type of failure, an electron microscopy study (SEM and TEM) and statistical analysis using the Kruskal-Wallis test for more than two independent samples and Mann-Whitney for two independent samples. Given the large number of combinations, Bonferroni correction was applied (alpha=0.001). RESULTS: Dual-polymerizing cements provided better adhesion values (11.7 MPa) than the autopolymerizing (7.47 MPa) (p-value M W<0.001). The worst techniques were Lava TM + sandblasting + Silane + Rely X; Lava TM + sandblasting + Silane + Multilink and Lava TM + CoJet + silane + Multilink. Adhesive failure (separation of cement and ceramic) was produced at a lesser force than cohesive failure (fracture of cement) (p-value M-W<0.001). Electron microscopy confirmed that the surface treatments modified the zirconium oxide ceramic, creating a more rough and retentive surface, thus providing an improved micromechanical interlocking between the cement and the ceramic. CONCLUSIONS: Best results were provided by dual-polymerizing cements associated with sandblasting or silica coating and a bonding agent containing MDP. PMID- 22926486 TI - Surgical treatment of Klippel-Feil syndrome with basilar invagination. AB - INTRODUCTION: Klippel-Feil syndrome (KFS) is a congenital cervical vertebral union caused by a failure of segmentation during abnormal development and frequently accompanies conditions such as basicranial malformation, atlas assimilation, or dens malformation. Especially in basilar invagination (BI), which is a dislocation of the dens in an upper direction, compression of the spinomedullary junction from the ventral side results in paralysis, and treatment is required. CLINICAL PRESENTATION: We present the case of a 38-year-old male patient with KFS and severe BI. Plane radiographs and computed tomography (CT) images showed severe BI, and magnetic resonance image (MRI) revealed spinal cord compression caused by invagination of the dens into the foramen magnum and atlantoaxial subluxation. Reduction by halo vest and skeletal traction were not successful. Occipitocervical fusion along with decompression of the foramen magnum, C1 laminectomy, and reduction using instruments were performed. Paralysis was temporarily aggravated and then gradually improved. Unsupported walking was achieved 24 months after surgery, and activities of daily life could be independently performed at the same time. CT and MRI revealed that dramatic reduction of vertical subluxation and spinal cord decompression were achieved. CONCLUSION: Reduction and internal fixation using instrumentation are effective techniques for KFS with BI; however, caution should be exercised because of the possibility of paralysis caused by intraoperative reduction. PMID- 22926487 TI - Expression patterns of emmprin and monocarboxylate transporter-1 in ovarian epithelial tumors. AB - Emmprin is a transmembrane glycoprotein known as a matrix metalloproteinase inducer and is highly up-regulated in malignant cancer cells. The monocarboxylate transporters (MCTs) are responsible for H(+)-linked transport of monocarboxylates across the cell membrane. It was recently demonstrated that proper plasma membrane localization and activity of MCTs require the presence of emmprin as a chaperone and that MCT-1 also acts as chaperone for emmprin. The objectives of this study were to clarify emmprin and MCT-1 expression patterns in ovarian epithelial tumors and to elucidate the clinicopathological significance of co localization of the two molecules. Immunohistochemical analysis of 205 epithelial tumors indicated that emmprin is always localized in cell membranes but its distribution differs according to tumor type: in lateral membranes in 89 % of adenomas, in lateral and basal membranes in 76 % of borderline tumors, and in membranes surrounding the entire cell in 98 % of carcinomas. Most carcinomas in situ also showed a lateral and basal expression pattern. In only 21 % of the carcinomas, the cells expressing membranous MCT-1 showed co-localized emmprin expression. Poor co-localization of the two molecules was more frequently found in serous carcinomas. However, the overall survival was not significantly different for the good and poor co-localization carcinoma groups. These findings indicate that the emmprin expression pattern might discriminate between invasive carcinomas and borderline tumors including carcinoma in situ. Moreover, there may be an as yet unidentified regulatory mechanism(s), for localization of MCT-1 and emmprin in cell membranes in vivo. PMID- 22926488 TI - Extracellular matrix and fibroblast communication following myocardial infarction. AB - The extracellular matrix (ECM) provides structural support by serving as a scaffold for cells, and as such the ECM maintains normal tissue homeostasis and mediates the repair response following injury. In response to myocardial infarction (MI), ECM expression is generally upregulated in the left ventricle (LV), which regulates LV remodeling by modulating scar formation. The ECM directly affects scar formation by regulating growth factor release and cell adhesion and indirectly affects scar formation by regulating the inflammatory, angiogenic, and fibroblast responses. This review summarizes the current literature on ECM expression patterns and fibroblast mechanisms in the myocardium, focusing on the ECM response to MI. In addition, we discuss future research areas that are needed to better understand the molecular mechanisms of ECM action, both in general and as a means to optimize infarct healing. PMID- 22926489 TI - Do fluoroscopy and postoperative radiographs correlate for periacetabular osteotomy corrections? AB - BACKGROUND: The Bernese periacetabular osteotomy (PAO) can relieve pain and restore function in patients with symptomatic acetabular dysplasia. Accurate acetabular correction is fundamental to achieving these clinical goals and presumably enhancing survivorship of the reconstruction. Fluoroscopy is used by some surgeons to assess intraoperative acetabular correction but it is unclear whether the features observed by fluoroscopy accurately reflect those on postoperative radiographs. QUESTIONS/PURPOSES: We therefore determined whether the parameters of acetabular correction of PAO correlated on intraoperative fluoroscopic imaging and postoperative radiography. METHODS: We retrospectively reviewed the imaging of 48 patients (50 hips) who underwent PAO. Intraoperative fluoroscopic AP and false profile images were obtained after final PAO correction. The intraoperative deformity correction as measured on the two fluoroscopy views was compared with the correction determined with postoperative standing plain AP pelvis and false profile radiographs using common measurements of acetabular position. RESULTS: Of all radiographic parameters, lateral center edge angle had the highest correlation between intraoperative fluoroscopy and the postoperative radiograph with an intraclass correlation coefficient (ICC) of 0.80 (0.68-0.88). Similarly, acetabular inclination and anterior center-edge angle also correlated with ICCs of 0.76 (0.61-0.85) and 0.71 (0.54-0.82), respectively. Extrusion index and medial offset distance had lower correlations with ICCs of 0.66 (0.46-0.79) and 0.46 (0.21-0.65), respectively. CONCLUSIONS: Intraoperative fluoroscopic assessment of PAO correction correlated with that from the postoperative radiographic assessment. Measurement of lateral center-edge angle shows the highest correlation with the fewest outliers. Acetabular inclination and anterior center-edge angle also correlated; extrusion index and medial offset distance should be used with more caution. PMID- 22926491 TI - Does humeral lengthening with a monolateral frame improve function? AB - BACKGROUND: Humeral lengthening by distraction osteogenesis historically has relied on bulky circular external fixators. Advances in fixator technology have allowed for the use of monolateral frames. However, it is unclear whether and to what degree function is improved after humeral lengthening. QUESTIONS/PURPOSES: We asked: (1) Does humeral lengthening performed with monolateral fixators improve function? (2) Does monolateral external fixation produce comparable restoration of length and complication rate when compared with historical results, using circular external fixation for humeral lengthening? METHODS: We retrospectively reviewed 11 patients who underwent 15 humeral lengthenings with monolateral external fixation. Clinical and radiographic data were collected, including preoperative and postoperative DASH scores as a metric of functional status. The minimum postremoval followup was 14 months (average, 38 months; range, 14-84 months). RESULTS: Fifteen humeri were lengthened an average of 7 cm (range, 4-9 cm), for a mean lengthening of 41% (range, 23%-52%). Lengthening required an average of 7 months (range, 5-8 months) of fixation, resulting in an external fixation index of 32 days/cm (range, 23-45 days/cm). The major complication rate (three of 15) and postoperative ROM (unchanged at the elbow and improved in seven of 15 shoulders) were comparable to those in previous studies using circular frames. In nine of 15 humeri for which DASH scores were available, the mean preoperative score improved from 14 to 9 after 1 year. The monolateral frame allowed the patient to keep their arm by the side without abducting the shoulder and without impinging the device into the chest wall. CONCLUSIONS: Humeral lengthening with monolateral external fixation is well tolerated by patients and an effective means of improving patient function with a complication rate similar to that for traditional circular frames. PMID- 22926490 TI - Hip ontogenesis: how evolution, genes, and load history shape hip morphotype and cartilotype. AB - BACKGROUND: Developmental hip disorders (DHDs), eg, developmental dysplasia of the hip, slipped capitis femoris epiphysis, and femoroacetabular impingement, can be considered morphology variants of the normal hip. The femoroacetabular morphology of DHD is believed to induce osteoarthritis (OA) through local cumulative mechanical overload acting on genetically controlled patterning systems and subsequent damage of joint structures. However, it is unclear why hip morphology differs between individuals with seemingly comparable load histories and why certain hips with DHD progress to symptomatic OA whereas others do not. QUESTIONS/PURPOSES: We asked (1) which mechanical factors influence growth and development of the proximal femur; and (2) which genes or genetic mechanisms are associated with hip ontogenesis. METHODS: We performed a systematic literature review of mechanical and genetic factors of hip ontogeny. We focused on three fields that in recent years have advanced our knowledge of adult hip morphology: imaging, evolution, and genetics. WHERE ARE WE NOW?: Mechanical factors can be understood in view of human evolutionary peculiarities and may summate to load histories conducive to DHD. Genetic factors most likely act through multiple genes, each with modest effect sizes. Single genes that explain a DHD are therefore unlikely to be found. Apparently, the interplay between genes and load history not only determines hip morphotype, but also joint cartilage robustness ("cartilotype") and resistance to symptomatic OA. WHERE DO WE NEED TO GO?: We need therapies that can improve both morphotype and cartilotype. HOW DO WE GET THERE?: Better phenotyping, improving classification systems of hip morphology, and comparative population studies can be done with existing methods. Quantifying load histories likely requires new tools, but proof of principle of modifying morphotype in treatment of DDH and of cartilotype with exercise is available. PMID- 22926492 TI - The withdrawn ASRTM THA and hip resurfacing systems: how have our patients fared over 1 to 6 years? AB - BACKGROUND: The Articular Surface ReplacementTM (ASRTM) metal-on-metal hip arthroplasty system (DePuy Orthopaedics, Inc, Warsaw, IN, USA) reportedly has a higher than anticipated early failure rate leading to a voluntary recall. This prompted us to evaluate all ASRTM components implanted at our center. QUESTIONS/PURPOSES: In all ASRTM components, we reported (1) revision rate, (2) blood metal ion levels, and (3) intraoperative findings for revisions related to adverse reaction to metal debris (ARMD). METHODS: We retrospectively reviewed all 172 patients (190 hips) who underwent THA (149 hips) or hip resurfacing (41 hips) with the ASRTM system. We determined failure rates. We obtained blood metal ion concentrations from 93 patients at last followup. We evaluated MRI studies and intraoperative histopathology. Minimum followup was 12 months (mean, 40 months; range, 12-74 months). RESULTS: At latest followup, we had revised 24 of 190 hips (13%): in 18 patients with THA and five patients with resurfacing. Mean time to revision was 45 months (range, 12-75 months). Mean blood concentrations were 13 MUg/L (range, 0-150 MUg/L) for cobalt and 6 MUg/L (range, 0-87 MUg/L) for chromium. Mean prerevision blood metal ion levels were higher in the revised group (cobalt: 48 MUg/L; chromium: 18 MUg/L) than in the nonrevised group (cobalt: 5 MUg/L; chromium: 2 MUg/L). ARMD was present in 14 of the 24 hips revised in this study. CONCLUSIONS: Surgeons must have a low threshold for concern for ARMD in patients with ASRTM systems. Blood metal ion levels and MRI can be used to evaluate patients with underperforming implants. Intraoperative histopathologic analysis and joint fluid cytology can help diagnose ARMD at the time of revision. LEVEL OF EVIDENCE: Level III, therapeutic study. See Instructions for Authors for a complete description of levels of evidence. PMID- 22926493 TI - Early experience with a comprehensive hip preservation service intended to improve clinical care, education, and academic productivity. AB - BACKGROUND: The field of hip preservation surgery has grown substantially over the past decade. Although open hip procedures reportedly relieve pain and restore function, arthroscopic treatment has increasingly become a reasonable alternative. In 2008, we formed a comprehensive hip preservation service (HPS) to address clinical, educational, and research needs. QUESTIONS/PURPOSES: We compared (1) volume, type, and corresponding improvement in pain and function of open and arthroscopic treatments; (2) orthopaedic resident test performance; and (3) academic productivity before and after creation of the HPS. METHODS: We retrospectively reviewed 212 patients undergoing 220 open procedures from 1996 to 2007 (Group 1) and 260 patients undergoing 298 procedures (153 open, 145 arthroscopic) from 2008 to May 2010 (Group 2). At each clinic visit, we recorded Harris hip score (HHS) and conversion to THA. Minimum followup was 1 year for Group 1 (mean, 4 years; range, 1-13 years) and Group 2 (mean, 1.5 years; range, 1 3 years). We compared orthopaedic resident performance on two standardized tests and the number of academic works (publications, book chapters, electronic media) and peer-reviewed grants funded before and after creation of the HPS. RESULTS: Mean HHS improved from 63 to 90 in Group 1 and from 76 to 91 in Group 2. Rate of conversion to THA was similar between groups despite expansion of surgical volume. Standardized orthopaedic resident test performance improved. Academic productivity as measured by publications and grant funding was facilitated by the HPS. CONCLUSIONS: Early experience with a multidisciplinary HPS was positive; it facilitated clinical volume expansion while maintaining improvement in pain and function in young adults. Additional benefits included educational and academic productivity gains. LEVEL OF EVIDENCE: Level IV, therapeutic study. See Instructions for Authors for a complete description of levels of evidence. PMID- 22926494 TI - The natural progression of adult elbow osteonecrosis related to corticosteroid treatment. AB - BACKGROUND: In patients with corticosteroid treatment, the elbow is a rare site of osteonecrosis; there is little information about the rate and risk factors of disease progression in symptomatic and asymptomatic elbows. QUESTION/PURPOSES: We determined the delay between the beginning of corticosteroid treatment and different stages of osteonecrosis and which stage and dose of steroids influenced disease progression. METHODS: Osteonecrosis related to corticosteroids was diagnosed by MRI in 50 elbows of 35 adult patients. Thirty elbows were asymptomatic at initial evaluation (19 with Stage I, 11 with Stage II osteonecrosis). Among the 20 elbows symptomatic at initial evaluation, 13 had radiographic evidence of osteonecrosis without collapse (Stage II) and seven had lesions evident only on MRI (Stage I). RESULTS: At latest followup (average, 17 years; range, 10-25 years), of the 30 previously asymptomatic elbows, pain developed in 24 and collapse occurred in 14; of the 20 previously symptomatic elbows, 15 showed collapse (seven initially with Stage I, eight with Stage II osteonecrosis). The average time between diagnosis and collapse was 8 and 5 years, respectively, for symptomatic elbows with Stages I and II osteonecrosis. Stage at initial visit, development of pain, and continuation of peak doses of corticosteroids were risk factors for disease progression in asymptomatic elbows. In symptomatic elbows, the extent in contact with the articular surface and lesion location were the main risk factors for disease progression. CONCLUSIONS: Untreated asymptomatic and symptomatic elbow osteonecrosis related to corticosteroids has a moderate likelihood of elbow collapse, with decrease in ROM, but none of the patients in this case series followed for 10 to 20 years had elbow arthroplasty. LEVEL OF EVIDENCE: Level IV, prognostic study. See Guidelines for Authors for a complete description of levels of evidence. PMID- 22926495 TI - Intravascular large B cell lymphoma presenting as anasarca: an unusual presentation of a rare lymphoma. PMID- 22926496 TI - Computer simulation of water-mediated adhesion between phospholipid bilayer and solid support functionalized with self-assembled monolayers. AB - An attempt is made to estimate, via computer simulation of the force-distance relation, the free energy of adhesion between a phosphatidylethanolamine bilayer and an alkanethiolate self-assembled monolayer (SAM) in aqueous medium. The simulations are performed using the grand canonical Monte Carlo technique and atomistic force fields. The bilayer adhesion free energy is predicted to be -22 +/- 3 mJ/m(2) (-1.4 +/- 0.2 kcal/mol) on a hydrophilic carboxyl-terminated SAM and -1 +/- 1 mJ/m(2) (-0.06 +/- 0.06 kcal/mol) on a hydrophobic methyl-terminated SAM. PMID- 22926497 TI - Serum C-reactive protein (CRP) levels in young adults can be used to discriminate between inflammatory and non-inflammatory diarrhea. AB - OBJECTIVE: To determine if the level of serum C-reactive protein (CRP) can be used to differentiate between inflammatory diarrhea and non-inflammatory diarrhea in patients with acute infectious diarrhea or acute gastrointestinal infection. METHODS: This was a retrospective study based on medical records from a single military hospital located in Daejeon, Republic of Korea. The records of 1,085 patients who presented with abdominal pain, fever (>= 37.8 degrees C), and diarrhea between May 2008 and May 2011 were reviewed, and 538 patients were selected. The eligible patients had undergone abdominal contrast tomography (CT) or colonoscopy within 3 days and blood sampling on the day of admission. The selected patients were divided into two groups on the basis of their abdominal CT or colonoscopy findings: group A, the inflammatory diarrhea group (n = 234), and group B, the non-inflammatory diarrhea group (n = 304). We then compared the clinical and laboratory characteristics of these two groups. RESULTS: Erythrocyte sedimentation rate and CRP levels were significantly higher in group A (inflammatory diarrhea) patients than group B (non-inflammatory diarrhea) patients (16.47 +/- 5.46 vs. 15.29 +/- 5.72 (P < 0.05), respectively, and 4.92 +/ 2.49 vs. 1.79 +/- 0.95 (P < 0.05), respectively). Multivariate analysis revealed that CRP level on admission was the most important predictor of inflammatory diarrhea (OR 7.39, P < 0.05). Receiver operating characteristic analysis results also showed that CRP had the highest area-under-the-curve value (0.91; 95 % confidence interval 0.88-0.93; P < 0.05) for distinguishing inflammatory diarrhea from non-inflammatory diarrhea. At a cut-off level of 3.08 mg/dL, CRP had a sensitivity of 82 % and a specificity of 85 %. CONCLUSIONS: CRP as a diagnostic marker of inflammatory diarrhea was superior to the other inflammatory markers and clinical characteristics we evaluated in this study. A patient's CRP level on admission may aid clinical decision-making, for example initiating empiric antibiotics therapy and/or performing additional clinical tests. PMID- 22926498 TI - New paradigm for studying genetic contributions to irritable bowel syndrome. PMID- 22926499 TI - Recent trends in the prevalence of Crohn's disease and ulcerative colitis in a commercially insured US population. AB - PURPOSE: Most US inflammatory bowel disease (IBD) epidemiology studies conducted to date have sampled small, geographically restricted populations and have not examined time trends. The aim of our study was to determine the prevalence of Crohn's disease (CD) and ulcerative colitis (UC) in a commercially insured US population and compare prevalences across sociodemographic characteristics and time. METHODS: Using claims data from approximately 12 million Americans, we performed three consecutive 2-year cross-sectional studies. Cases of CD and UC were identified using a previously described algorithm. Prevalence was estimated by dividing cases by individuals in the source population. Logistic regression was used to compare prevalences by region, age, and sex. RESULTS: In 2009, the prevalences of CD and UC in children were 58 [95 % confidence interval (CI) 55 60] and 34 (95 % CI 32-36), respectively. In adults, the respective prevalences were 241 (95 % CI 238-245) and 263 (95 % CI 260-266). Data analysis revealed that IBD prevalences have slightly increased over time. Based on census data, an estimated 1,171,000 Americans have IBD (565,000 CD and 593,000 UC). CONCLUSIONS: Analysis of the epidemiological data revealed an increasing burden of IBD in recent years, which may be used to inform policy. PMID- 22926500 TI - Effectiveness of concomitant enteral nutrition therapy and infliximab for maintenance treatment of Crohn's disease in adults. AB - BACKGROUND: One of the problems associated with infliximab (IFX) treatment for Crohn's disease (CD) is loss of response during maintenance therapy. AIMS: The aim of this multicenter, retrospective, cohort study was to determine whether enteral nutrition (EN) added to the IFX therapy regimen is effective for maintaining remission in adult CD patients. METHODS: Patients with CD who had started IFX therapy between April 2003 and March 2008 at any one of the seven participating medical centers and who met the following inclusion criteria were enrolled in the study: remission after triple infusions of IFX followed by IFX maintenance therapy every 8 weeks, and follow-up data available for >= 1 year. Remission was defined as a C-reactive protein (CRP) level of <0.3 mg/dL, and recurrence was defined as an increase in CRP to >= 1.5 mg/dL or shortening of the IFX interval. Patients were classified by EN dosage into two groups (EN group and non-EN group). The cumulative remission period and related factors were analyzed. RESULTS: Of the 102 adult CD patients who met the inclusion criteria, 45 were in the EN group and 57 were in the non-EN group. The cumulative remission rate was significantly higher in the EN group than in the non-EN group (P = 0.009). Multivariate analysis revealed that EN was the only suppressive factor for disease recurrence (P = 0.01). CONCLUSIONS: The results demonstrate that among this CD patient cohort, EN combined with IFX maintenance treatment was clinically useful for maintaining remission. PMID- 22926502 TI - Fluorescence determination of azithromycin in pharmaceutical formulations by using the synchronous scanning approach after its acid derivatization. AB - In this present work, a fluorescence method for azithromycin (9-deoxo-9a-aza-9a methyl-9a-homoerythromycin) determination in pharmaceutical formulations is proposed. The method is based on the synchronous fluorescence (Deltalambda = 30 nm, 482 nm) produced when azithromycin is derivatized in strong acidic medium (9.0 mol L(-1) HCl). The influence of the derivatization conditions (acid concentration, reaction time and temperature) was studied. Also, the possible reaction mechanism was discussed. In the optimized conditions, the method presented a limit of detection of 0.23 mg L(-1) and a limit of quantification of 0.76 mg L(-1). The developed procedure was successfully applied in the determination of azithromycin in pharmaceutical formulations. PMID- 22926501 TI - Prokaryotic communities differ along a geothermal soil photic gradient. AB - Geothermal influenced soils exert unique physical and chemical limitations on resident microbial communities but have received little attention in microbial ecology research. These environments offer a model system in which to investigate microbial community heterogeneity and a range of soil ecological concepts. We conducted a 16S bar-coded pyrosequencing survey of the prokaryotic communities in a diatomaceous geothermal soil system and compared communities across soil types and along a conspicuous photic depth gradient. We found significant differences between the communities of the two different soils and also predictable differences between samples taken at different depths. Additionally, we targeted three ecologically relevant bacterial phyla, Cyanobacteria, Planctomycetes, and Verrucomicrobia, for clade-wise comparisons with these variables and found strong differences in their abundances, consistent with the autecology of these groups. PMID- 22926503 TI - Arsenic contamination in soil-water-plant (rice, Oryza sativa L.) continuum in central and sub-mountainous Punjab, India. AB - In the present study, Arsenic (As) concentrations in underground water, soil, and plants (rice) and their inter-relationships in central and sub-mountainous Punjab, India were studied. Approximately, 32% of the tubewell water samples had As concentrations greater than the maximum permissible limit (10 MUg As L(-1)) set by the World Health Organization (WHO) whereas in hand pump waters, As concentrations were within the safe range (i.e. <10 MUg As L(-1)). As concentrations in tubewell waters were significantly correlated with As concentrations in surface soil (r = 0.57; P < 0.05) and plant samples (r = 0.27 0.82; P < 0.05) in central and sub-mountainous Punjab. The estimated daily intake of As through human consumption in rural and urban population was 0.016 and 0.012 MUg day(-1) kg(-1) body weight respectively. PMID- 22926504 TI - Up-regulation of CacyBP/SIP during rat breast cancer development. AB - BACKGROUND: CacyBP/SIP (calcyclin binding protein/Siah-1 interacting protein) was originally discovered in Ehrlich ascities tumor cells but was later found also in many different tumors. METHODS: To better understand the function of CacyBP/SIP in carcinogenesis, we used immunohistochemistry, Western blotting, and RT-PCR assays to study the distribution and level of CacyBP/SIP in mammary tissues after tumor induction in rat with DMBA [(dimethylbenz[a]anthracene)]. Application of such a model allowed us to monitor changes in CacyBP/SIP level during development of breast cancer. RESULTS: We found that both the protein and mRNA levels of CacyBP/SIP gradually increased in pathologically changed tissues and were highest in tumors taken 8 weeks after DMBA treatment. Similar changes as for CacyBP/SIP were detected in the level of beta-catenin. CONCLUSION: Increase in CacyBP/SIP expression during development of breast cancer, observed early in the mammary tissues with only minimal pathological changes, might suggest an important role of this protein in the process of carcinogenesis. PMID- 22926505 TI - Reversine induces cell cycle arrest, polyploidy, and apoptosis in human breast cancer cells. AB - BACKGROUND: Reversine, a small synthetic purine analogue, has been reported to be effective in tumor suppression. In the present study, we demonstrated an antitumor activity of reversine that could suppress cellular proliferation and induce cell cycle arrest and apoptosis in human breast cancer cell lines. METHODS: To evaluate whether reversine could suppress cell growth of MCF-7 and MDA-MB-231 cells and induce cell death, the cell viability, cell cycle, and apoptosis were determined in this study. RESULTS: Reversine treatment in human breast cancer cells reduced cell viability in a dose-dependent manner. Cell cycle accumulation at the G2/M phase in reversine-treated cells was also determined. Moreover, polyploidy was also found in reversine-treated cells. Apoptosis in reversine-treated cells was exhibited with PARP cleavage and caspase-3 and caspase-8 activation, but not caspase-9 activation, indicating that caspase dependent apoptosis mediated by an extrinsic pathway took place in reversine treated cells. Furthermore, reversine attenuated cell death in cells pretreated with a pan-caspase inhibitor before reversine treatment. CONCLUSIONS: In the present study, we demonstrated that reversine contributes to growth inhibition in human breast cancer cells through cell cycle arrest, polyploidy, and/or apoptosis induction. The apoptosis mediated by reversine was induced by the mitochondria independent pathway. Therefore, the potential role of reversine as a novel therapeutic agent for the treatment of breast cancer is worthy of further investigation. PMID- 22926506 TI - Magnetic resonance lymphography of sentinel lymph nodes in patients with breast cancer using superparamagnetic iron oxide: a feasibility study. AB - BACKGROUND: The sentinel lymph node (SLN) biopsy technique using superparamagnetic iron oxide (SPIO) as a tracer instead of radioisotopes has been described. To further advance this technique, we evaluated preoperative SPIO-MR sentinel lymphography to facilitate the accurate identification of the lymphatic pathways and primary SLN. METHODS: A prospective study was performed in ten patients with breast cancer and clinically negative axillary lymph nodes. None of the patients received preoperative chemotherapy. After 1.6 ml of SPIO (ferucarbotran) was injected in the subareolar breast tissue, sentinel axillary lymph nodes were detected by MRI in T2*-weighted gradient echo images and resected using the serial SPIO-SLN biopsy procedure with a handheld magnetometer. RESULTS: In one patient, gadolinium-enhanced MR imaging was performed at the same time as SPIO-MR lymphography, and this patient was excluded from further analysis. In all patients (9/9) SLNs were detected by SPIO-MR sentinel lymphography and successfully identified at surgery. The number of SLNs detected by lymphography (mean 2.7) significantly correlated with SLNs identified at surgery (mean 2.2). One patient had nodal metastases. In one patient, skin color changed to brown at the injection site and resolved spontaneously. There were no severe reactions to the procedure or complications in any patient. CONCLUSIONS: This is the first study to evaluate SPIO both as a contrast material in MR sentinel lymphography and as a tracer in SLN biopsy using an integrated method. The acquired three-dimensional imaging demonstrated excellent image quality and usefulness to identify SLN in conjunction with SLN biopsy. PMID- 22926507 TI - Factors associated with health-related quality of life in a cohort of Spanish breast cancer patients. AB - BACKGROUND: Several factors can modify health-related quality of life (HRQOL) of breast cancer survivors. The objective of the current study was to analyse the associations between HRQOL scores 1 year after breast cancer surgery and sociodemographic and clinical factors. METHODS: This was an observational, multicentre and prospective study of a cohort of patients who underwent oncological breast cancer surgery and which was followed up for 1 year. The HRQOL was assessed at 1 year after surgery using three questionnaires: EuroQol-5D, EORTC QLQ-C30 and its breast-specific module BR-23. RESULTS: A total of 364 patients participated in the study. Some factors were associated with better HRQOL 1 year after surgery: age between 60 and 69 years and under 50 years, being single or a housewife, stage I-II, invasive papillary carcinoma, breast conserving surgery (BCS) or lack of axillary dissection. However, only the following were independent predictive factors: being single or a housewife, BCS, invasive papillary carcinoma, coming from an outpatient clinic or not receiving radiotherapy. Further, some factors were independent predictors of a worse HRQOL: age over 70 years, being married, separated or widowed, stage III or not receiving adjuvant chemotherapy. CONCLUSIONS: Demographic and clinical factors can influence HRQOL, some of them independently. PMID- 22926508 TI - The decline and fall of the IGF-I receptor. AB - This review examines the effect of targeting the insulin-like growth factor 1 receptor (IGF-IR) in human cancers. The results are disappointing. The causes for the failure are discussed, as well as the possible use of the IGF-IR as a secondary target. PMID- 22926509 TI - Familial history of cancer and leukemia in children younger than 2 years of age in Brazil. AB - The objective of this study was to determine the contribution of a familial history of cancer (FHC) to the development of leukemia in children below 2 years of age. This is a national hospital-based case-control study of children 0-24 months of age recruited from 15 Brazilian hospitals from several regions providing oncological care and local general hospitals. Participants' FHC antecedents were obtained through face-to-face interviews with the mothers of cases and controls using a standardized questionnaire. Unconditional logistic regression was used to determine crude and adjusted (adj.) odds ratios (OR), and the respective 95% confidence intervals (CI), of acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) after adjustment for selected variables. FHC antecedents were obtained from 178 ALL, 51 AML, and 428 controls. FHC in second-degree relatives (grandparents, uncles, cousins) showed an adj. OR=1.66 (95% CI 1.12-2.45) for ALL. Antecedents of two or more relatives with cancer showed a statistically significant two-fold higher risk of either ALL or AML. Paternal, and joint paternal and maternal antecedents of cancer also showed statistically significant higher adj. OR, respectively: 1.80 and 1.89 for ALL, and 2.34 and 3.23 for AML. Hematological malignancies among second-degree relatives showed an adj. OR=3.48 (95% CI 1.72-7.09) for ALL. According to the anatomic site, antecedents of leukemia/lymphoma among case relatives, compared with the control ones, showed an OR=2.98 (95% CI 1.52-5.82) for ALL, whereas stomach cancer antecedents showed an OR=3.55 (95% CI 1.02-12.39) for AML. The observed results support the hypothesis that FHC antecedents are associated with leukemogenesis in children below 2 years of age. PMID- 22926510 TI - Vitamin and mineral supplements and thyroid cancer: a systematic review. AB - The purpose of this study was to consolidate epidemiological evidence for the association between dietary supplements of vitamins and minerals and thyroid cancer development, as well as to contribute to evidence-based dietary recommendations for thyroid cancer primary prevention. We carried out a systematic literature review specifically for dietary supplement and thyroid cancer risk. MEDLINE, EMBASE, and Dissertations and Theses were systematically searched to identify original epidemiological studies with a comparison group that investigated vitamin or mineral supplementation as an etiological factor for thyroid cancer. In total, 11 independent studies were identified and reviewed. Our qualitative summary showed conflicting results for common antioxidants including vitamins A, C, and E and beta-carotene in relation to thyroid cancer. Similarly, results for dietary supplement combinations as well as other individual vitamins and minerals (vitamin B complex, vitamin D, iodine, calcium, zinc, magnesium, and iron) are largely inconsistent across studies. Overall, our review suggested that the current evidence to support any protective or hazardous effect of vitamin or mineral supplements on thyroid cancer development is inconclusive and additional studies addressing previous limitations are necessary to elucidate this possible association. In particular, reverse causality is of major concern and should be addressed by prospective studies with large and representative samples. PMID- 22926511 TI - Strategy for surgical treatment of congenital subglottic stenosis in children. AB - BACKGROUND/PURPOSE: Congenital subglottic stenosis is a rare anomaly caused by thickened cricoid cartilage. We report our surgical techniques, comprising anterior cricoid split (ACS), laryngotracheoplasty (LTP), KTP laser ablation, and application of a tracheal opening retainer (TOR) into the tracheostomy site. METHODS: Nine patients have been treated since 1988. Four patients (median age 85 days; range 5 days to 6 months) underwent ACS. Another four patients (median age, 17 months; range, 5-57 months) underwent LTP using costal cartilage grafts, although two had undergone tracheostomy before LTP. One patient underwent LTP, ablation of the projecting part of the cricoid cartilage with KTP laser (LTP + Laser) and, preservation of the tracheal opening by placement of the TOR. RESULTS: All ACS and LTP patients were successfully extubated at a median of 32 days (range 23-91 days) and 23 days (range 6-31 days) postoperatively, respectively. The LTP + Laser patient was extubated 35 days after surgery and the TOR was removed asymptomatically 20 days after extubation of the stent tube. CONCLUSIONS: Anterior cricoid split is useful for patients <= 6 months old and LTP is useful for patients >6 months old and/or with tracheostomy. KTP laser ablation is effective to remove thickened parts of cricoid cartilage protecting the vocal cords. The tracheal opening preserved by the TOR works as an additional channel to safeguard respiration during the extubation process. PMID- 22926512 TI - [Reading colophons from mesopotamian clay-tablets dealing with mathematics]. PMID- 22926513 TI - [Not Available]. PMID- 22926514 TI - Heterogeneous composition of dopamine neurons of the rat A10 region: molecular evidence for diverse signaling properties. AB - The A10 region contains different neurons: dopamine (expressing tyrosine hydroxylase; TH), GABA, glutamate-only (expressing the vesicular glutamate transporter 2; VGluT2), and TH-VGluT2 (coexpressing TH and VGluT2). We used three methods to investigate proteins necessary for the synthesis (aromatic L-amino acid decarboxylase, AADC) or transport (vesicular monoamine transporter; VMAT2 or dopamine transporter; DAT) of dopamine within TH neurons in the A10 region. By in situ hybridization-immunohistochemistry, we found that all TH neurons in the A10 region had AADC, but not all had VMAT2, DAT or D2 receptors (D2R). To determine whether TH-VGluT2 neurons account for TH neurons lacking these dopamine markers, we implemented an anatomical "mirror technique", and found that not all TH-VGluT2 neurons lacked VMAT2, DAT or D2R. Next, by quantitative RT-PCR of individual micro-dissected TH neurons, we discovered two classes of TH-VGluT2 and three classes of TH-only neurons with different latero-medial distribution. Some of the TH-VGluT2 neurons had both VMAT2 and DAT (TH-VGluT2 Class 1); others lacked detectable levels of both transporters (TH-VGluT2 Class 2). Most of the TH-only neurons contained VMAT2 and DAT (TH-only Class 1), a few had DAT without detectable VMAT2 (TH-only Class 2), and others lacked detectable levels of both transporters (TH-only Class 3). We concluded that (a) the majority of TH neurons lacking DAT are TH-VGluT2 neurons, (b) very few TH-only neurons express DAT without VMAT2, and (c) TH-VGluT2 neurons lacking DAT also lack VMAT2. Thus, the A10 region contains dopamine neurons with differential compartmentalization and unique signaling properties. PMID- 22926515 TI - ARAF acts as a scaffold to stabilize BRAF:CRAF heterodimers. AB - The RAF proteins are cytosolic protein kinases that regulate cell responses to extracellular signals. There are three RAF proteins in cells, ARAF, BRAF and CRAF, and recent studies have shown that the formation of complexes by these different isoforms has an important role in their activation, particularly in response to RAF inhibitors. Here, we investigated the role of ARAF in cancer cell signaling and examined the role of ARAF in mediating paradoxical activation of the MAPK pathway in cells treated with RAF inhibitors. We show that two mutations that occur in ARAF in cancer inactivate the kinase. We also show that ARAF is not functionally redundant with CRAF and cannot substitute for CRAF downstream of RAS. We further show that ARAF binds to and is activated by BRAF and that ARAF also forms complexes with CRAF. Critically, ARAF seems to stabilize BRAF:CRAF complexes in cells treated with RAF inhibitors and thereby regulate cell signaling in a subtle manner to ensure signaling efficiency. PMID- 22926516 TI - BRCA1 mutations and luminal-basal transformation. AB - The multifunctional roles of BRCA1 include its ability to regulate transcriptional processes that control differentiation at multiple levels, as well as functioning as a tumor suppressor. Data herein demonstrate that germline mutations in Brca1 impair luminal cell lineage and mammary development, with its deficiency converting ER-positive luminal tumors into basal-like cancers. Heterozygous mutations in Brca1 lead to downregulation of a number of luminal differentiation genes, explaining how it suppresses basal-like tumors, also highlighting its importance outside of its known highly publicized role in DNA repair. PMID- 22926517 TI - miR-100 suppresses IGF2 and inhibits breast tumorigenesis by interfering with proliferation and survival signaling. AB - Dysregulation of micro RNAs is crucially implicated in tumorigenesis. We detected downregulation of miR-100 in breast cancer cells, leading to an upregulation of the proliferation- and survival-promoting oncogene insulin-like growth factor (IGF) 2. Stable overexpression of miR-100 strongly reduced IGF2 expression and inhibited tumor growth. In invasive human breast tumors, miR-100 was reduced about fourfold as compared with benign patient samples, whereas IGF2 was strongly enhanced. MiR-100 has also been shown to suppress other proteins of the IGF/mammalian target of rapamycin (mTOR) signaling cascade in different human tumors. Our results reveal miR-100 as a context-dependent master regulator of the IGF/mTOR pathway and a potential target for therapeutic approaches. PMID- 22926518 TI - Specific interactions between Smad proteins and AP-1 components determine TGFbeta induced breast cancer cell invasion. AB - Deregulation of the transforming growth factor beta (TGFbeta) signal transduction cascade is functionally linked to cancer. In early phases, TGFbeta acts as a tumor suppressor by inhibiting tumor cell proliferation, whereas in late phases, it can act as a tumor promoter by stimulating tumor cell invasion and metastasis. Smad transcriptional effectors mediate TGFbeta responses, but relatively little is known about the Smad-containing complexes that are important for epithelial mesenchymal transition and invasion. In this study, we have tested the hypothesis that specific members of the AP-1 transcription factor family determine TGFbeta signaling specificity in breast cancer cell invasion. Using a 3D model of collagen-embedded spheroids of MCF10A-MII premalignant human breast cancer cells, we identified the AP-1 transcription factor components c-Jun, JunB, c-Fos and Fra1 as essential factors for TGFbeta-induced invasion and found that various mesenchymal and invasion-associated TGFbeta-induced genes are co-regulated by these proteins. In situ proximity ligation assays showed that TGFbeta signaling not only induces complexes between Smad3 and Smad4 in the nucleus but also complexes between Smad2/3 and Fra1, whereas complexes between Smad3, c-Jun and JunB could already be detected before TGFbeta stimulation. Finally, chromatin immunoprecipitations showed that c-Jun, JunB and Fra1, but not c-Fos, are required for TGFbeta-induced binding of Smad2/3 to the mmp-10 and pai-1 promoters. Together these results suggest that in particular formation of Smad2/3 Fra1 complexes may reflect activation of the Smad/AP-1-dependent TGFbeta-induced invasion program. PMID- 22926520 TI - Src family kinases mediate cytoplasmic retention of activated STAT5 in BCR-ABL positive cells. AB - Persistent activation of the Abl tyrosine kinase in the BCR-ABL fusion protein is the major cause of chronic myeloid leukemia (CML). Among many other substrates BCR-ABL phosphorylates STAT5 and Src family kinases (SFK). Activated pSTAT5 is essential for initial transformation and maintenance of the disease. Cytokine induced phosphorylation on tyrosine 694 typically leads to nuclear accumulation of pSTAT5 and target gene expression. We verified that in BCR-ABL-positive progenitor cells from a CML patient and in K562 cells pSTAT5 is cytoplasmic. However, upon ectopic expression of BCR-ABL p210 in non-myeloid cells, co transfected STAT5A is phosphorylated on Y694 and localized in the nucleus arguing for an additional factor mediating cytoplasmic retention in CML cells. Expression of the SFK v-Src, Hck or Lyn together with STAT5A results in phosphorylation on Y694 and cytoplasmic retention. Upon coexpression of BCR-ABL and individual SFK the cytoplasmic retention of activated STAT5A mediated by v-Src and Hck but not Lyn is dominant over nuclear translocation induced by BCR-ABL. Cytoplasmic retention depends on the kinase activity of SFK and is mediated through the interaction of the SH2 domain of STAT5A with the SFK. Interestingly, nuclear accumulation of STAT5A as a result of activation by FLT3-ITD, an oncogene found in acute myeloid leukemia, cannot be prevented by coexpression of SFK. Importantly, inhibition of SFK in K562 cells restored nuclear accumulation of pSTAT5A, enhanced STAT5 target gene expression and increased colony formation. Thus, SFK mediate cytoplasmic retention of pSTAT5A in BCR-ABL-positive cells. Cytoplasmic pSTAT5A in CML cells might balance the controversial functions of STAT5 in cellular senescence and differentiation versus G1/S progression and survival. PMID- 22926519 TI - Far upstream element binding protein 1: a commander of transcription, translation and beyond. AB - The far upstream binding protein 1 (FBP1) was first identified as a DNA-binding protein that regulates c-Myc gene transcription through binding to the far upstream element (FUSE) in the promoter region 1.5 kb upstream of the transcription start site. FBP1 collaborates with TFIIH and additional transcription factors for optimal transcription of the c-Myc gene. In recent years, mounting evidence suggests that FBP1 acts as an RNA-binding protein and regulates mRNA translation or stability of genes, such as GAP43, p27(Kip) and nucleophosmin. During retroviral infection, FBP1 binds to and mediates replication of RNA from Hepatitis C and Enterovirus 71. As a nuclear protein, FBP1 may translocate to the cytoplasm in apoptotic cells. The interaction of FBP1 with p38/JTV-1 results in FBP1 ubiquitination and degradation by the proteasomes. Transcriptional and post-transcriptional regulations by FBP1 contribute to cell proliferation, migration or cell death. FBP1 association with carcinogenesis has been reported in c-Myc dependent or independent manner. This review summarizes biochemical features of FBP1, its mechanism of action, FBP family members and the involvement of FBP1 in carcinogenesis. PMID- 22926521 TI - A high resolution genomic portrait of bladder cancer: correlation between genomic aberrations and the DNA damage response. AB - One major challenge in cancer research is to understand the complex interplay between the DNA damage response (DDR), genomic integrity, and tumor development. To address these issues, we analyzed 43 bladder tumor genomes from 22 patients using single nucleotide polymorphism (SNP) arrays, and tissue expression of multiple DDR proteins, including Timeless and its interaction partner Tipin. The SNP profiles confirmed and extended known copy number alterations (CNAs) at high resolution, showed clustering of CNAs at nine common fragile sites, and revealed that most metachronous tumors were clonally related. The occurrence of many novel uniparental disomy regions (UPDs) was of potential functional importance in some tumors because UPDs spanned mutated FGFR3 and PIK3CA alleles, and also homozygous deletion of the CDKN2A tumor suppressor locus. The DDR signaling as evaluated by phospho-epitope-specific antibodies against Ser139-phosphorylated H2A histone family member X (gammaH2AX), ataxia telangiectasia mutated (ATM), and ATM- and Rad3-related (ATR) was commonly activated in tumors with both moderate and high extent of accumulated genomic aberrations, the latter tumors showing a more frequent loss of ATM expression. Strikingly, the tumor genomes exhibiting the most complex alterations were associated with a high Ki67-proliferation index, abundant Timeless but not Tipin expression, aberrant p53 expression, and homozygous CDKN2A deletions. Of clinical relevance, evaluation of a tissue microarray (TMA; n=319) showed that abundant Timeless expression was associated with risk of progression to muscle-invasive disease (P<0.0005; hazard ratio, 2.4; 95% confidence interval, 1.6-3.8) and higher T stage (P<0.05). Univariate analysis confirmed this association (P=0.006) in an independent cohort (n=241) but statistical significance was not reached in a multivariate model. Overall, our results are consistent with DDR activation preceding the accumulation of genomic aberrations. Tumors with extensive genomic rearrangements were associated with inactivation of CDKN2A, excessive proliferation, and robust Timeless expression, the latter also correlating with the risk of disease progression. Moreover, we provide evidence to suggest that UPDs likely contribute to bladder tumorigenesis. PMID- 22926522 TI - Cell death/proliferation roles for nc886, a non-coding RNA, in the protein kinase R pathway in cholangiocarcinoma. AB - We have recently identified nc886 (pre-miR-886 or vtRNA2-1) as a novel type of non-coding RNA that inhibits activation of protein kinase R (PKR). PKR's pro apoptotic role through eukaryotic initiation factor 2 alpha (eIF2alpha) phosphorylation is well established in the host defense against viral infection. Paradoxically, some cancer patients have elevated PKR activity; however, its cause and consequence are not understood. Initially, we evaluated the expression of nc886, PKR and eIF2alpha in non-malignant cholangiocyte and cholangiocarcinoma (CCA) cells. nc886 is repressed in CCA cells and this repression is the cause of PKR's activation therein. nc886 alone is necessary and sufficient for suppression of PKR via direct physical interaction. Consistently, artificial suppression of nc886 in cholangiocyte cells activates the canonical PKR/eIF2alpha cell death pathway, suggesting a potential significance of the nc886 suppression and the consequent PKR activation in eliminating pre-malignant cells during tumorigenesis. In comparison, active PKR in CCA cells does not induce phospho eIF2alpha nor apoptosis, but promotes the pro-survival nuclear factor-kappaB pathway. Thus, PKR has a dual life or death role during tumorigenesis. Similarly to the CCA cell lines, nc886 tends to be decreased but PKR tends to be activated in our clinical samples from CCA patients. Collectively from our data, we propose a tumor surveillance model for nc886's role in the PKR pathway during tumorigenesis. PMID- 22926524 TI - RBB, a novel transcription repressor, represses the transcription of HDM2 oncogene. AB - The p53 tumor suppressor is important in many aspects of cell biology. Tight regulation of p53 is thus imperative for maintaining cell homeostasis and preventing tumorigenesis. The stabilization and activity of p53 is primarily regulated by MDM2, which is encoded for by HDM2. However, how the expression and activity of MDM2 is regulated remains largely unknown. Here, we report a novel BTB and BEN domains-containing protein, RBB. We demonstrated that RBB is a novel transcriptional repressor binding specific DNA motif via a homodimer and interacting with the nucleosome remodeling and deacetylase (NuRD) complex. Genome wide transcription target analysis by ChIP sequencing revealed that RBB represses the transcription of a series of functionally important genes including HDM2. We showed that RBB recruits the NuRD complex to the internal promoter of HDM2 and inhibits the expression of MDM2 protein, leading to subsequent stabilization of tumor suppressor p53. Significantly, we showed that RBB suppresses cell proliferation and sensitizes cells to DNA damage-induced apoptosis. Our data indicate that RBB is a novel transcriptional repressor and an important regulator of p53 pathway. PMID- 22926523 TI - GAB2 induces tumor angiogenesis in NRAS-driven melanoma. AB - GAB2 is a scaffold protein with diverse upstream and downstream effectors. MAPK and PI3K signaling pathways are known effectors of GAB2. It is amplified and overexpressed in a variety of human tumors including melanoma. Here we show a previously undescribed role for GAB2 in NRAS-driven melanoma. Specifically, we found that GAB2 is co-expressed with mutant NRAS in melanoma cell lines and tumor samples and its expression correlated with metastatic potential. Co-expression of GAB2(WT) and NRAS(G12D) in melanocytes and in melanoma cells increased anchorage independent growth by providing GAB2-expressing cells a survival advantage through upregulation of BCL-2 family of anti-apoptotic factors. Of note, collaboration of GAB2 with mutant NRAS enhanced tumorigenesis in vivo and led to an increased vessel density with strong CD34 and VEGFR2 activity. We found that GAB2 facilitiated an angiogenic switch by upregulating HIF-1alpha and VEGF levels. This angiogenic response was significantly suppressed with the MEK inhibitor PD325901. These data suggest that GAB2-mediated signaling cascades collaborate with NRAS-driven downstream activation for conferring an aggressive phenotype in melanoma. Second, we show that GAB2/NRAS signaling axis is non linear and non-redundant in melanocytes and melanoma, and thus are acting independent of each other. Finally, we establish a link between GAB2 and angiogenesis in melanoma for the first time. In conclusion, our findings provide evidence that GAB2 is a novel regulator of tumor angiogenesis in NRAS-driven melanoma through regulation of HIF-1alpha and VEGF expressions mediated by RAS RAF-MEK-ERK signaling. PMID- 22926527 TI - Oil from the tropical marine benthic-diatom Navicula sp. AB - The potential of the tropical marine benthic-diatom Navicula sp. for biodiesel feedstock was investigated. Growth profiles were analyzed by changing nutrient compositions in three different media (Walne, plain seawater, and modified seawater) and irradiance intensities. Navicula sp. cells showed significant growth in Walne and modified seawater medium but not in plain seawater medium. The microalgae grew well in a pH range of 7.8-8.4, and the cells were very sensitive to the intensity of direct sunlight exposure. The average cell concentration obtained from the cultures in plain seawater, Walne, and modified seawater media at the beginning of the stationary phase was 0.70, 2.17, and 2.54 g/L, respectively. Electron spray ionization-ion trap-mass spectrometry showed that the triacylglycerols of the algae oil were identified as POP (palmitic-oleic palmitic), POO (palmitic-oleic-oleic), and OOLn (oleic-oleic-linoleic). The oil productivity of Navicula sp. cultivated in Walne and modified seawater media was 90 and 124 MUL L(-1) culture d(-1). The Navicula sp. biodiesel exhibited a kinematic viscosity of 1.299 mm(2)/s, density of 0.8347 g/mL, and internal energy of 0.90 kJ/mL. PMID- 22926525 TI - Histone methylase MLL1 has critical roles in tumor growth and angiogenesis and its knockdown suppresses tumor growth in vivo. AB - Mixed lineage leukemias (MLLs) are human histone H3 lysine-4-specific methyl transferases that have critical roles in gene expression, epigenetics and cancer. Herein, we demonstrated that antisense-mediated knockdown of MLL1 induced cell cycle arrest and apoptosis in cultured cells. Intriguingly, application of MLL1 antisense specifically knocked down MLL1 in vivo and suppressed the growth of xenografted cervical tumor implanted in nude mouse. MLL1 knockdown downregulated various growth and angiogenic factors, such as HIF1alpha, VEGF and CD31, in tumor tissue affecting tumor growth. MLL1 is overexpressed along the line of vascular network and localized adjacent to endothelial cell layer expressing CD31, indicating potential roles of MLL1 in vasculogenesis. MLL1 is also overexpressed in the hypoxic regions along with HIF1alpha. Overall, our studies demonstrated that MLL1 is a key factor in hypoxia signaling, vasculogenesis and tumor growth, and its depletion suppresses tumor growth in vivo, indicating its potential in novel cancer therapy. PMID- 22926528 TI - Clinical and cognitive profiles of patients with both Parkinson's disease and essential tremor. AB - Although Parkinson's disease (PD) and essential tremor (ET) are distinct clinical disorders, their coexistence can sometimes cause diagnostic problems. In this study, we conducted detailed investigations of patients with both ET and PD (ET PD) and compared their clinical and cognitive profiles with those of patients with only ET or only PD. This study examined three groups of patients: the first group had ET-PD concomitantly (n = 9); the second group had only ET (n = 9); the third group had only PD (n = 10). The groups were compared in terms of demographic characteristics, clinical features, and cognitive functions. With the exception of positive family histories, which were more common in ET-PD than in PD patients, we found no differences among the groups with respect to demographic characteristics (p = 0.044). PD-only patients had more akinetic-rigid type Parkinsonism (p = 0.016), and their levodopa response was better than that of ET PD patients (p = 0.017). Patients with ET-PD obtained significantly lower scores than those with pure ET on several cognitive tests, suggesting a prominent frontal-type cognitive dysfunction. In conclusion ET-PD patients differed from PD patients, showing more frequent familial tremor histories and lower levodopa responsiveness. This patient population also demonstrated more severe cognitive impairments than pure-ET patients. This result suggests that ET-PD patients are a subset of ET patients with more widespread neurodegeneration, which may indicate the presence of a syndrome that includes overlap between ET and PD. PMID- 22926529 TI - Perturbation theory in the catalytic rate constant of the Henri-Michaelis-Menten enzymatic reaction. AB - The Henry-Michaelis-Menten (HMM) mechanism of enzymatic reaction is studied by means of perturbation theory in the reaction rate constant k (2) of product formation. We present analytical solutions that provide the concentrations of the enzyme (E), the substrate (S), as well as those of the enzyme-substrate complex (C), and the product (P) as functions of time. For k (2) small compared to k ( 1), we properly describe the entire enzymatic activity from the beginning of the reaction up to longer times without imposing extra conditions on the initial concentrations E ( o ) and S ( o ), which can be comparable or much different. PMID- 22926530 TI - Amphipol-assisted folding of bacteriorhodopsin in the presence or absence of lipids: functional consequences. AB - Amphipols are short amphipathic polymers designed to stabilize membrane proteins in aqueous solutions in the absence of detergent. Bacteriorhodopsin (BR), a light driven proton pump, has been denatured, either by direct solubilization of the purple membrane in sodium dodecylsulfate (SDS) solution or by a procedure that involves delipidation with organic solvent followed by transfer to SDS, and renatured in amphipol A8-35. The effect of different renaturation procedures and of the presence or absence of lipids and the cofactor retinal have been investigated. The resulting samples have been characterized by absorbance spectroscopy, size-exclusion chromatography, thermostability measurements, and determination of photocycle kinetics. Transfer to A8-35 can be achieved by SDS precipitation, dilution, or dialysis, the first route resulting in the highest yield of refolding. Functional BR can be refolded whether in the presence or absence of lipids, higher yields being achieved in their presence. Retinal is not required for the protein to refold, but it stabilizes the refolded form and, thereby, improves folding yields. Lipids are not required for BR to perform its complete photocycle, but their presence speeds up the return to the ground state. Taken together, these data indicate that a membrane or membrane-mimetic environment is not required for correct decoding of the chemical information contained in the sequence of BR; functional folding is possible even in the highly foreign environment of lipid-free amphipols. BR interactions with lipids, however, contribute to an effective photocycle. PMID- 22926531 TI - Current treatment of mantle cell lymphoma: results of a national survey and consensus meeting. AB - In most patients, mantle cell lymphoma (MCL) shows an aggressive clinical course with a continuous relapse pattern and a median survival of only 3-5 years. In the current study generation of the European MCL Network, the addition of high-dose Ara-C to R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone)-like regimen followed by myeloablative consolidation achieved a significant improvement of progression-free survival in younger patients. In elderly patients, rituximab maintenance led to a marked prolongation of remission duration. Emerging strategies include mammalian target of rapamycin (mTOR) inhibitors, proteasome inhibitors, immune modulatory drugs, Bruton's tyrosine kinase inhibitors and others, all based on the dysregulated control of cell cycle machinery and impairment of several apoptotic pathways. Combination strategies are currently being investigated in numerous trials, but their introduction into clinical practice and current treatment algorithms remains a challenge. In the current survey, the application of the molecular targeted compounds were collected and evaluated by a representative national network of 14 haematological institutions. Optimised strategies are recommended for clinical routine. Future studies will apply individualised approaches according to the molecular risk profile of the patient. PMID- 22926532 TI - Pericentric chromosome 8 inversion, inv8(p11.2q22), associated with RUNX1/RUNX1T1 rearrangement in acute myeloid leukemia. PMID- 22926533 TI - Effect of an oxygen pressure injection (OPI) device on the oxygen saturation of patients during dermatological methyl aminolevulinate photodynamic therapy. AB - Methyl aminolevulinate photodynamic therapy (MAL-PDT) (a topical treatment used for a number of precancerous skin conditions) utilizes the combined interaction of a photosensitizer (protoporphyrin IX (PpIX)), light of the appropriate wavelength, and molecular oxygen to produce singlet oxygen and other reactive oxygen species which induce cell death. During treatment, localized oxygen depletion occurs and is thought to contribute to decreased efficacy. The aim of this study was to investigate whether an oxygen pressure injection (OPI) device had an effect on localized oxygen saturation levels and/or PpIX fluorescence of skin lesions during MAL-PDT. This study employed an OPI device to apply oxygen under pressure to the skin lesions of patients undergoing standard MAL-PDT. Optical reflectance spectrometry and fluorescence imaging were used to noninvasively monitor the localized oxygen saturation and PpIX fluorescence of the treatment area, respectively. No significant changes in oxygen saturation were observed when these data were combined for the group with OPI and compared to the group that received standard MAL-PDT without OPI. Additionally, no significant difference in PpIX photobleaching or clinical outcome at 3 months between the groups of patients was observed, although the group that received standard MAL-PDT demonstrated a significant increase (p<0.05) in PpIX fluorescence initially and both groups produced a significant decrease (p<0.05) after light irradiation. In conclusion, with this sample size, this OPI device was not found to be an effective method with which to improve tissue oxygenation during MAL-PDT. Further investigation is therefore required to find a more effective method of MAL-PDT enhancement. PMID- 22926534 TI - Low-level laser therapy in experimental model of collagenase-induced tendinitis in rats: effects in acute and chronic inflammatory phases. AB - A variety of treatments for tendinopathies is currently used or has been trialed. However, in fact, there is a remarkably little evidence that any conventional therapies are effective. In the last years, low-level laser therapy (LLLT) has been showing interesting results in inflammatory modulation in different musculoskeletal disorders, but the optimal parameters and mechanisms behind these effects are not fully understood. The aim of this study is to investigate if the LLLT modulates the acute and chronic phase of collagenase-induced tendinitis in rat by interfering in mRNA expression for matrix metalloproteinases (MMP13 and MMP1), vascular endothelial growth factor (VEGF), and anti-inflammatory mediator (interleukin (IL)-10). For such, tendinitis was induced by collagenase injection in male Wistar rats. Animals were treated with LLLT (780 nm, potency of 22 mW, 107 mW/cm(2), energy density of 7.5 J/cm(2), and energy delivered of 1.54 J) with different number of treatments in accordance with the inflammatory phase analyzed. LLLT was able to modulate mRNA gene expression of IL-10, VGEF, MMP1, and MMP13 both in acute than in chronic inflammatory phase (p<0.05). Our results suggest that LLLT with parameters employed in the present study was able to modulate IL-10, VEGF, MMP1, and MMP13 mRNA gene expression both in acute than in chronic tendon inflammation. However, further studies are needed to establish optimal parameters for LLLT. PMID- 22926535 TI - Regioselective multi-component synthesis of 1H-pyrazolo[3,4-d]pyrimidine-6(7H) thiones. AB - A variety of pyrazolo[3,4-d]pyrimidine-6(7H)-thione derivatives were easily synthesized with a novel, simple, efficient, and regioselective method via three component condensation reaction of 5-methyl-1H-pyrazol-3-amine, arylisothiocyanates, and aldehydes in the presence of catalytic amount of p toluenesulfonic acid (p-TSA) in 1-butyl-3-methylimidazolium bromide ionic liquid with excellent yields and short reaction times. PMID- 22926536 TI - Learning curve for cytoreductive surgery and hyperthermic intraperitoneal chemotherapy in peritoneal surface malignancies: analysis of two centres. AB - BACKGROUND: We assessed the learning curve (LC) of cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) in treating peritoneal surface malignancies (PSM) in two centers and evaluated in which extent surgical tutoring could abbreviate the learning process. METHODS: Six hundred and forty one cases submitted to CRS using peritonectomy procedures and HIPEC were considered. After having overcome its own LC, the NCI of Milan has provided technical assistance to Bentivoglio's centre for the development of a new PSM program since 2003. The risk-adjusted sequential probability ratio test (RA-SPRT) was employed to assess the LC of the two centers. Outcomes were incomplete cytoreduction, G3-5 morbidity (NCI-CTCAE.v3) and procedure-related mortality (PRM). RESULTS: Rates of incomplete cytoreduction, G3-5 morbidity, and PRM were 8.4%, 30.1%, and 3.9%, respectively, in the entire series. The breaking points of the LC concerning incomplete cytoreduction, G3-5 morbidity, and PRM were achieved at 141, 158, and 144 cases, in the Milan's experience, and at 126, 134, and 60 cases in the Bentivoglio's experience. CONCLUSIONS: Surgical tutoring could substantially shorten the steep LC associated with CRS and HIPEC. Our data should be confirmed by further studies on LC focusing oncological outcomes. Other factors that could influence the length of learning process should be identified. PMID- 22926537 TI - [Radiological diagnostics of inflammatory spinal diseases: what is the state of the art?]. AB - Back pain is nonspecific and allows a broad range of differential diagnoses. In the early phase of infectious or neoplastic processes conventional diagnostic radiology rarely shows groundbreaking findings. Magnetic resonance imaging (MRI) is the method of choice to detect early changes in the vertebral bodies, intervertebral discs and surrounding tissues. Fluid-sensitive, fat-suppressed sequences (STIR) and contrast media are used to distinguish infections from other diseases. Due to the typical signal intensity in T1 and T2 sequences, infections of degenerative, rheumatic, and neoplastic processes can be defined and allow the initiation of appropriate therapy. PMID- 22926538 TI - [Therapy of unspecific destructive spondylodiscitis with special consideration to sagittal alignment]. AB - Nonspecific destructive spondylodiscitis is a severe illness which is accompanied by a high mortality rate. There is agreement in the literature on the indications for surgical treatment of destructive spondylodiscitis and sagittal alignment has to be considered for the operative procedure. Therefore, the operative procedure has to make considerations for the deformity, the extent of destruction, the clinical characteristics of the patient and the extent of spondylodiscitis. PMID- 22926539 TI - [Pyogenic spondylodiscitis: therapy algorithm and a new classification for therapeutic decision-making]. AB - The incidence of pyogenic spondylodiscitis is low but has been steadily increasing in recent years. To date there has been no consensus concerning selection of the appropriate treatment, management and strategies and the recommendations for an operative strategy are still a highly controversial issue. In the literature a few statements have been published concerning therapeutic decision-making in pyogenic spondylodiscitis. The classification given in this article is based on clinical experience and retrospective data analysis considering the degree of segmental bony destruction, grade of kyphosis and instability, epidural involvement of the disease and neurological deficits, which are pivotal for therapeutic decision-making. The therapeutic procedure can be defined based on this classification. PMID- 22926540 TI - [Mycophenolate mofetil seems to be superior to azothioprine in maintenance therapy of lupus nephritis]. PMID- 22926541 TI - First septal artery originating from the left main coronary artery: a rare anomaly. PMID- 22926542 TI - Improving the science and evidence for the medical management of disasters: Utstein style. PMID- 22926544 TI - Biophysical evaluation of radiofrequency electromagnetic field effects on male reproductive pattern. AB - There are possible hazardous health effects of exposure to radiofrequency electromagnetic radiations emitted from mobile phone on the human reproductive pattern. It is more effective while keeping mobile phones in pocket or near testicular organs. Present review examines the possible concern on radio frequency radiation interaction and biological effects such as enzyme induction, and toxicological effects, including genotoxicity and carcinogenicity, testicular cancer, and reproductive outcomes. Testicular infertility or testicular cancer due to mobile phone or microwave radiations suggests an increased level of reactive oxygen species (ROS). Though generation of ROS in testis has been responsible for possible toxic effects on physiology of reproduction, the reviews of last few decades have well established that these radiations are very harmful and cause mutagenic changes in reproductive pattern and leads to infertility. The debate will be focused on bio-interaction mechanism between mobile phone and testicular cancer due to ROS formation. This causes the biological damage and leads to several changes like decreased sperm count, enzymatic and hormonal changes, DNA damage, and apoptosis formation. In the present review, physics of mobile phone including future research on various aspects has been discussed. PMID- 22926545 TI - Daidzein induced apoptosis via down-regulation of Bcl-2/Bax and triggering of the mitochondrial pathway in BGC-823 cells. AB - Daidzein belongs to the group of isoflavones, found in a wide variety of plant derived foods, especially in soybeans and soy-based foods. In this study, the effect of daidzein on human gastric carcinoma cells (BGC-823) and its mechanism were investigated. MTT assay was applied in the detection of the inhibitory effects of daidzein on cell proliferation. Hoechst-propidium iodide staining and flow cytometry were used to examine the apoptosis as well as the mitochondrial transmembrane potential. Western blotting was performed to detect the expression of apoptosis-associated proteins: cleaved PARP, cleaved caspase-9, cleaved caspase-3, Bcl-2, and Bax. Daidzein significantly inhibited the growth and proliferation of human gastric carcinoma cells (BGC-823) in a concentration- and time-dependent manner. Furthermore, it was found that an insult of daidzein to BGC-823 cells caused them to die by disruption of mitochondrial transmembrane potential, demonstrated not only by staining dead cells for phosphatidylserine but also by the up-regulation (cleaved PARP, cleaved caspase-9, cleaved caspase 3, Bax) and down-regulation (Bcl-2) of proteins associated with apoptosis and survival; whereas, the pan-caspase inhibitor z-VAD-fmk could partially rescue cells against damage of daidzein. Taken together, the results of this study demonstrate that daidzein significantly induces apoptosis via a mitochondrial pathway. Specifically, daidzein induced a change in the Bax/Bcl-2 ratios and activation of caspases-3 and -9 and the cleavage of PARP. Therefore, daidzein has the potential for use as a therapeutic agent for the treatment of gastric carcinoma. PMID- 22926546 TI - High- and low-dose OPG-Fc cause osteopetrosis-like changes in infant mice. AB - BACKGROUND: Receptor activator of nuclear factor-kappaB ligand (RANKL) inhibitors are being considered for use in children with osteogenesis imperfecta (OI). We sought to assess efficacy of two doses of a RANKL inhibitor, osteoprotegerin immunoglobulin Fc segment complex (OPG-Fc), in a growing animal model of OI, the col1alpha2-deficient mouse (oim/oim) and its wild-type controls (+/+). METHODS: Treated mice showed runting and radiographic evidence of osteopetrosis with either high- (20 mg/kg twice weekly) or low-dose (1 mg/kg/week) OPG-Fc. Because of this adverse event, OPG-Fc treatment was halted, and the mice were killed or monitored for recovery with monthly radiographs and assessment of serum osteoclast activity (tartrate-resistant acid phosphatase 5b, TRACP-5b) until 25 wk of age. RESULTS: Twelve weeks of OPG-Fc treatment resulted in radiographic and histologic osteopetrosis with no evidence of bone modeling and negative tartrate resistant acid phosphatase staining, root dentin abnormalities, and TRACP-5b activity suppression. Signs of recovery appeared 4-8 wk post-treatment. CONCLUSION: Both high- and low-dose OPG-Fc treatment resulted in osteopetrotic changes in infant mice, an outcome that was not seen in studies with the RANKL inhibitor RANK-immunoglobulin Fc segment complex (RANK-Fc) or in studies with older animals. Further investigations of RANKL inhibitors are necessary before their consideration for use in children. PMID- 22926547 TI - mPGES-1 and prostaglandin E2: vital role in inflammation, hypoxic response, and survival. AB - BACKGROUND: Apnea associated with infection and inflammation is a major medical concern in preterm infants. Prostaglandin E(2) (PGE(2)) serves as a critical mediator between infection and apnea. We hypothesize that alteration of the microsomal PGE synthase-1 (mPGES-1) PGE(2) pathway influences respiratory control and response to hypoxia. METHODS: Nine-d-old wild-type (WT) mice, mPGES-1 heterozygote (mPGES-1(+/-)), and mPGES-1 knockout (mPGES-1(-/-)) mice were used. Respiration was investigated in mice using flow plethysmography after the mice received either interleukin-1beta (IL-1beta) (10 ug/kg) or saline. Mice were subjected to a period of normoxia, subsequent exposure to hyperoxia, and finally either moderate (5 min) or severe hypoxia (until 1 min after last gasp). RESULTS: IL-1beta worsened survival in WT mice but not in mice with reduced or no mPGES-1. Reduced expression of mPGES-1 prolonged gasping duration and increased the number of gasps during hypoxia. Response to intracerebroventricular PGE(2) was not dependent on mPGES-1 expression. CONCLUSION: Activation of mPGES-1 is involved in the rapid and vital response to severe hypoxia as well as inflammation. Attenuation of mPGES-1 appears to have no detrimental effects, yet prolongs autoresuscitation efforts and improves survival. Consequently, inhibition of the mPGES-1 pathway may serve as a potential therapeutic target for the treatment of apnea and respiratory disorders. PMID- 22926548 TI - Sex-dependent changes in the pulmonary vasoconstriction potential of newborn rats following short-term oxygen exposure. AB - BACKGROUND: Chronic exposure to supplemental oxygen (O(2)) induces lung damage and mortality in a sex-dependent manner. The effect of short-term hyperoxia on the newborn pulmonary vasculature is unknown but is, however, of clinical significance in the neonatal resuscitation context. We hypothesize that short term hyperoxia has a sex-dependent effect on the pulmonary vasculature. METHODS: Following 1-h 100% O(2) exposure, the pulmonary arteries and lung tissues of newborn rats were evaluated. RESULTS: Superoxide dismutase 3 (SOD3) expression in female pups' lungs was increased as compared with that in the lungs of male pups. As compared with air-treated pups, the response of male pups to thromboxane was increased by O(2), whereas the opposite effect was documented in the vessels of female pups. The enhanced force of hyperoxia-exposed arteries of the male pups was suppressed with superoxide or peroxynitrite scavengers, and increased lung SOD activity and hydrogen peroxide content were seen in female, but not in male, rats. Hyperoxia induced an increase in lung tissue oxidative products and Rho kinase (ROCK) activity in male, but not in female, pups. CONCLUSION: A lower lung SOD content and failure to upregulate SOD activity facilitates peroxynitrite generation and ROCK activation in hyperoxia-exposed males, predisposing them to pulmonary vasoconstriction. These observations, if relevant to humans, may explain the increased mortality and higher incidence of pulmonary hypertension in male neonates. PMID- 22926549 TI - MR image overlay guidance: system evaluation for preclinical use. AB - PURPOSE: A clinical augmented reality guidance system was developed for MRI guided musculoskeletal interventions Magnetic Resonance Image Overlay System (MR IOS). The purpose of this study was to assess MRI compatibility, system accuracy, technical efficacy, and operator performance of the MR-IOS. METHODS AND MATERIALS: The impact of the MR-IOS on the MR environment was assessed by measuring image quality with signal-to-noise ratio (SNR) and signal intensity uniformity with the system in various on/off states. The system accuracy was assessed with an in-room preclinical experiment by performing 62 needle insertions on a spine phantom by an expert operator measuring entry, depth, angle, and target errors. Technical efficacy and operator performance were tested in laboratory by running an experiment with 40 novice operators (20 using freehand technique versus 20 MR-IOS-guided) with each operator inserting 10 needles into a geometric phantom. Technical efficacy was measured by comparing the success rates of needle insertions between the two operator groups. Operator performance was assessed by comparing total procedure times, total needle path distance, presumed tissue damage, and speed of individual insertions between the two operator groups. RESULTS: The MR-IOS maximally altered SNR by 2% with no perceptible change in image quality or uniformity. Accuracy assessment showed mean entry error of 1.6 +/- 0.6 mm, depth error of 0.7 +/- 0.5 mm, angle error of 1.5 +/- 1.1 degrees , and target error of 1.9 +/- 0.8 mm. Technical efficacy showed a statistically significant difference (p = 0.031) between success rates (freehand 35.0% vs. MR-IOS 80.95%). Operator performance showed: mean total procedure time of 40.3 +/- 4.4 (s) for freehand and 37.0 +/- 3.7 (s) for MR-IOS (p = 0.584), needle path distances of 152.6 +/- 15.0 mm for freehand and 116.9 +/ 8.7 mm for MR-IOS (p = 0.074), presumed tissue damage of 7,417.2 +/- 955.6 mm(2) for freehand and 6062.2 +/- 678.5 mm(2) for MR-IOS (p = 0.347), and speed of insertion 5.9 +/- 0.4 mm/s for freehand and 4.3 +/- 0.3 mm/s for MR-IOS (p = 0.003). CONCLUSION: The MR-IOS is compatible within a clinical MR imaging environment, accurate for needle placement, technically efficacious, and improves operator performance over the unassisted insertion technique. The MR-IOS was found to be suitable for further testing in a clinical setting. PMID- 22926550 TI - Changes in the choice of thyroidectomy for benign thyroid disease. AB - PURPOSES: There is an increasing trend towards performing more radical resections instead of a subtotal resection for benign thyroid disease. The aim of this study was to examine the effect of this change in practice on the surgical treatment of bilateral thyroid diseases in this unit. METHODS: The data on 367 patients that underwent a bilateral thyroidectomy were categorized by dividing the operation types into 4 groups: (1) total thyroidectomy (TT), (2) near-total thyroidectomy, (3) Dunhill procedure, and (4) bilateral subtotal thyroidectomy. RESULTS: A statistically significant change in the choice of thyroidectomy occured during the study period (p < 0.001). TT has replaced subtotal thyroidectomy (STT; bilateral subtotal thyroidectomy and Dunhill procedure) as the preferred routine surgical procedure for bilateral benign thyroid diseases in this clinic. The permanent complication rates were similar for all surgical procedures. The rate of secondary thyroidectomy for both recurrence of multinodular goiter and incidental thyroid carcinoma were significantly higher in the STT groups, than the total in the TT and near-total thyroidectomy patients. CONCLUSIONS: Total or near total thyroidectomy procedures are now being increasingly employed to treat bilateral benign thyroid disease, and are as safe as the sub-total thyroidectomy procedures, which are more conservative and associated with significantly higher recurrence rates. PMID- 22926551 TI - Minimally invasive esophagectomy for esophageal cancer: an updated review. AB - PURPOSE: The surgical, postoperative and oncologic outcomes of minimally invasive esophagectomy (MIE) for esophageal cancer were reviewed to clarify the benefits of this surgical modality. METHODS: A systematic literature search was performed using synonyms for minimally invasive or thoracoscopic esophagectomy. There were 18 retrospective cohort studies and 3 meta-analyses retrieved in this review. RESULTS: There are several minimally invasive approaches for esophageal cancer. Total MIE using both the thoracoscopic and laparoscopic approach is increasingly performed. A longer operative time and less blood loss are observed with MIE in comparison to open esophagectomy (OE). Although the benefit of MIE for reducing morbidity and mortality rates is still under debate, a shorter hospital stay was common among the studies. The oncologic outcomes of MIE were not inferior to OE, while the number of retrieved lymph nodes was greater in MIE than OE in several studies. CONCLUSION: Total MIE using a combined thoracoscopic and laparoscopic approach can be performed safely, although the benefits for short-term outcomes are still controversial. Oncologic outcomes are favorable and MIE may have an advantage in lymph node dissection over OE. The benefits of MIE should therefore be confirmed by randomized controlled trials. PMID- 22926552 TI - Primary T-cell lymphoma associated with tubulovillous adenoma of the rectum: report of a case. AB - We report what to our knowledge is the first documented case of "peripheral T cell lymphoma-not otherwise specified" (PTCL-NOS) associated with a rectal adenoma. Colorectal lymphomas are relatively uncommon, but colorectal T-cell lymphomas are extremely rare. The patient was a 92-year-old woman, referred to our hospital for investigation of anal bleeding. Rectal examination revealed a 3 cm pedunculated polypoid mass 5 cm above the anal verge. We performed a transanal local excision, and histopathological examination revealed a tubulovillous adenoma, with the diffuse proliferation of large lymphoid cells mainly discernible in the mucus membrane lamina propria, with infiltration to the submucosal layer. Immunohistochemical examination of the lymphoid cells revealed positive staining for CD3, weak staining for CD4 and CD8, and negative staining for CD5, CD10, CD20, CD56, CD79a, TIA-1, and Granzyme B. The tumor was diagnosed as PTCL-NOS associated with rectal tubulovillous adenoma. The patient died 28 days after surgery, most probably of progression of the PTCL-NOS. PMID- 22926553 TI - Postoperative outcomes of patients with hepatocellular carcinoma negative for all virus-related markers. AB - PURPOSE: The outcomes of patients with resectable hepatocellular carcinoma (HCC) negative for all virus-related markers have not yet been characterized. This study investigated the outcomes of such patients in comparison to those who had virus-related resectable HCC. METHODS: A total of 398 patients with HCC were divided into 2 groups, comprising patients in which all virus-related markers (HBs-Ag, HBs-Ab, HBe-Ag, HBe-Ab, HBc-Ab, HCV-Ab) were negative (all-negative group, n = 63) and those with at least 1 positive virus-related marker (virus related group, n = 335). The clinical characteristics, surgical data, and survival rates were compared between the groups. RESULTS: The serum AST (30 vs. 45 IU/l, P < 0.0001) and ALT (21 vs. 42 IU/l, P < 0.0001) levels were significantly lower in the all-negative group than in the virus-related group. The tumor size (4.3 vs. 3.1 cm, P < 0.0001), the prevalence of DM (46.8 vs. 25.4 %, P = 0.001), and BMI (24.8 vs. 22.9, P = 0.0023) were significantly higher in the all-negative group than in the virus-related group. HCC arose from a cirrhotic liver in a significantly higher proportion of patients in the virus related group than in the all-negative group (20.6 vs. 44.8 %, P = 0.0002). The survival outcomes were not significantly different in the 2 groups (all-negative vs. virus-related: 5-year overall survival rate, 58.2 vs. 55.2 %, P = 0.27), despite such differences in the patients' characteristics. CONCLUSIONS: The postoperative outcomes of patients with HCC are independent of the presence or absence of hepatitis viral infection. PMID- 22926555 TI - An NMR metabolomics approach for the diagnosis of leptomeningeal carcinomatosis. AB - Leptomeningeal carcinomatosis (LC) is the third most common metastatic complication of the central nervous system. However, the current modalities to reliably diagnose this condition are not satisfactory. Here, we report a preclinical proof of concept for a metabolomics-based diagnostic strategy using a rat LC model incorporating glioma cells that stably express green fluorescent protein. Cytologic diagnoses gave 66.7% sensitivity for the 7-day LC group and 0% for the 3-day LC group. MR imaging could not diagnose LC at these stages. In contrast, nuclear magnetic resonance-based metabolomics on cerebrospinal fluid detected marked differences between the normal and LC groups. Predictions based on the multivariate model provided sensitivity, specificity, and overall accuracy of 88% to 89% in both groups for LC diagnosis. Further statistical analyses identified lactate, acetate, and creatine as specific for the 7-day LC group, with glucose a specific marker of the normal group. Overall, we showed that the metabolomics approach provided both earlier and more accurate diagnostic results than cytology and MR imaging in current use. PMID- 22926554 TI - The impact of non-tumor-derived circulating nucleic acids implicates the prognosis of non-small cell lung cancer. AB - BACKGROUND: A high level of circulating DNA (cirDNA) in cancer patients has been correlated with poor outcomes. Studies have demonstrated the critical contributions of the tumor-derived cirDNA. In this report, we investigated the roles of the non-tumor-derived cirDNA (nt-cirDNA) in determining the prognosis of non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: Plasma samples from 58 advanced NSCLC patients and 52 controls were collected. The nt-cirDNA levels were assessed with qPCR assay to detect the unmethylation status of an epithelial specific marker, the SHP-1 promoter 2 (unmethylated SHP1P2). Clinicopathological correlations were analyzed. RESULTS: There was a significant increase in the total amount of cirDNA in NSCLC patients compared with controls: 4.3 ng ml(-1) [0.82-49.8] and 2.0 ng ml(-1) [0.03-26.9], respectively (p < 0.01). An increased amount of the unmethylated SHP1P2 in advanced NSCLC was also detected: 3.4 ng ml( 1) [1.2-24.8] versus 2.0 ng ml(-1) [0.03-26.9] in the controls (p = 0.026). Survival analyses revealed that high levels of total cirDNA and unmethylated SHP1P2 were significantly associated with decreased survival. However, the total cirDNA had a better prognostic correlation than the unmethylated SHP1P2. Multivariate analysis identified total cirDNA (p = 0.004) and systemic treatment (p = 0.002) as independent prognostic parameters. CONCLUSION: The level of total cirDNA in NSCLC is an important prognostic parameter that demonstrates the contributions from both tumor-derived sources and non-tumor-derived sources. PMID- 22926556 TI - Mammalian sterile 20-like kinase 1 suppresses lymphoma development by promoting faithful chromosome segregation. AB - The mammalian Hippo signaling pathway has been implicated in oncogenesis in the context of solid tumors such as hepatocellular carcinoma. Mammalian sterile 20 like kinase 1 (MST1), the core component of the Hippo signaling pathway, is highly expressed in hematopoietic cells. However, its possible impact on tumorigenesis in this setting is unknown. In this study, we provide evidence that Mst1 loss in the mouse enhances chemically and genetically induced lymphoma development by inducing chromosomal instability. Mst1 deficiency increased susceptibility to T-cell acute lymphoblastic leukemia induced by mutagen exposure. Notably, before transformation Mst1(-/-) normal thymocytes showed no changes in proliferation or apoptosis in vitro and in vivo, but they displayed elevated levels of abnormal mitotic chromosomes and aneuploidy, conditions known to promote tumorigenesis. Mst1(-/-) mice also showed accelerated formation of spontaneous lymphomas in a p53-deficient background, accompanied by severe aneuploidy. In clinical specimens of lymphoma and leukemia, we documented frequent downregulation of MST1 expression, consistent with our findings. Taken together, our findings reveal a tumor suppressive function of Mst1 based on its ability to prevent chromosomal instability in lymphocytes. PMID- 22926558 TI - Multilevel whole-genome analysis reveals candidate biomarkers in clear cell renal cell carcinoma. AB - Renal cell carcinoma (RCC) is the most common neoplasm of the kidney. We conducted an integrated analysis of copy number, gene expression (mRNA and miRNA), protein expression, and methylation changes in clear cell renal cell carcinoma (ccRCC). We used a stepwise approach to identify the most significant copy number aberrations (CNA) and identified regions of peak and broad copy number gain and loss, including peak gains (3q21, 5q32, 5q34-q35, 7p11, 7q21, 8q24, 11q13, and 12q14) and deletions (1p36, 2q34-q37, 3p25, 4q33-q35, 6q23-q27, and 9p21). These regions harbor novel tumor-related genes and miRNAs not previously reported in renal carcinoma. Integration of genome-wide expression data and gene set enrichment analysis revealed 75 gene sets significantly altered in tumors with CNAs compared with tumors without aberration. We also identified genes located in peak CNAs with concordant methylation changes (hypomethylated in copy number gains such as STC2 and CCND1 and hypermethylated in deletions such as CLCNKB, VHL, and CDKN2A/2B). For other genes, such as CA9, expression represents the net outcome of opposing forces (deletion and hypomethylation) that also significantly influences patient survival. We also validated the prognostic value of miRNA let-7i in RCCs. miR-138, located in chromosome 3p deletion, was also found to have suppressive effects on tumor proliferation and migration abilities. Our findings provide a significant advance in the delineation of the ccRCC genome by better defining the impact of CNAs in conjunction with methylation changes on the expression of cancer-related genes, miRNAs, and proteins and their influence on patient survival. PMID- 22926557 TI - Leptin and soluble leptin receptor in risk of colorectal cancer in the European Prospective Investigation into Cancer and Nutrition cohort. AB - Leptin, a peptide hormone produced primarily by the adipocytes, is hypothesized to play a role in the pathogenesis of colorectal cancer (CRC). Soluble leptin receptor (sOB-R) may regulate leptin's physiologic functions; however its relation to CRC risk is unknown. This study explored the association of leptin and sOB-R with risk of CRC in a prospective nested case-control study within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. A total of 1,129 incident CRC cases (713 colon, 416 rectal) were matched within risk sets to 1,129 controls. Conditional logistic regression was used to calculate relative risks (RR) and 95% confidence intervals (CI). After multivariable adjustment including body mass index (BMI), waist circumference, and baseline leptin concentrations, sOB-R was strongly inversely associated with CRC (RR comparing the highest quintile vs. the lowest, 0.55; 95% CI, 0.40-0.76; P(trend) = 0.0004) and colon cancer (RR, 0.42; 95% CI, 0.28-0.63, P(trend) = 0.0001); whereas no association was seen for rectal cancer (RR adjusted for BMI and waist circumference, 0.83; 95% CI, 0.48-1.44, P(trend) = 0.38). In contrast, leptin was not associated with risk of CRC (RR adjusted for BMI and waist circumference, 0.85; 95% CI, 0.56-1.29, P(trend) = 0.23). Additional adjustments for circulating metabolic biomarkers did not attenuate these results. These novel findings suggest a strong inverse association between circulating sOB-R and CRC risk, independent of obesity measures, leptin concentrations, and other metabolic biomarkers. Further research is needed to confirm the potentially important role of sOB-R in CRC pathogenesis. PMID- 22926559 TI - Natural product triptolide mediates cancer cell death by triggering CDK7 dependent degradation of RNA polymerase II. AB - Triptolide is a bioactive ingredient in traditional Chinese medicine that exhibits diverse biologic properties, including anticancer properties. Among its many putative targets, this compound has been reported to bind to XPB, the largest subunit of general transcription factor TFIIH, and to cause degradation of the largest subunit Rpb1 of RNA polymerase II (RNAPII). In this study, we clarify multiple important questions concerning the significance and basis for triptolide action at this core target. Triptolide decreased Rpb1 levels in cancer cells in a manner that was correlated tightly with its cytotoxic activity. Compound exposure blocked RNAPII at promoters and decreased chromatin-bound RNAPII, both upstream and within all genes that were examined, also leading to Ser-5 hyperphosphorylation and increased ubiqutination within the Rbp1 carboxy terminal domain. Notably, cotreatment with inhibitors of the proteasome or the cyclin-dependent kinase CDK7 inhibitors abolished the ability of triptolide to ablate Rpb1. Together, our results show that triptolide triggers a CDK7-mediated degradation of RNAPII that may offer an explanation to many of its therapeutic properties, including its robust and promising anticancer properties. PMID- 22926561 TI - Niche science: the aging stem cell. AB - Studies on stem cell aging are uncovering molecular mechanisms of regenerative decline, providing new insight into potential rejuvenating therapies. PMID- 22926560 TI - CD24 is an effector of HIF-1-driven primary tumor growth and metastasis. AB - Hypoxia drives malignant progression in part by promoting accumulation of the oncogenic transcription factor hypoxia inducible factor-1alpha (HIF-1alpha) in tumor cells. Tumor aggressiveness also relates to elevation of the cancer stem cell-associated membrane protein CD24, which has been causally implicated in tumor formation and metastasis in experimental models. Here, we link these two elements by showing that hypoxia induces CD24 expression through a functional hypoxia responsive element in the CD24 promoter. HIF-1alpha overexpression induced CD24 mRNA and protein under normoxic conditions, with this effect traced to a recruitment of endogenous HIF-1alpha to the CD24 promoter. Short hairpin RNA mediated attenuation of HIF-1alpha or CD24 expression reduced cancer cell survival in vitro and in vivo at the levels of primary and metastatic tumor growth. CD24 overexpression in HIF-1alpha-depleted cancer cells rescued this decrease, whereas HIF-1alpha overexpression in CD24-depleted cells did not. Analysis of clinical tumor specimens revealed a correlation between HIF-1alpha and CD24 levels and an association of their coexpression to decreased patient survival. Our results establish a mechanistic linkage between 2 critically important molecules in cancer, identifying CD24 as a critical HIF-1alpha transcriptional target and biologic effector, strengthening the rationale to target CD24 for cancer therapy. PMID- 22926562 TI - An unusual presentation of a common infection. AB - A 40-year-old Ghanaian woman presented with fever and exanthema. She had anemia, leukopenia, increased erythrocyte sedimentation rate (ESR), creatinin kinase, lactate dehydrogenase (LDH), and liver enzymes. She was diagnosed with schistosomiasis and was cured with praziquantel. During the following years, she developed polymyositis, chronic nephritis, and life-threatening perimyocarditis. High numbers of Epstein-Barr virus (EBV)-encoded RNA copies were demonstrated in CD8+ T-lymphocytes from endomyocardial biopsies. There was no evidence of any underlying immunosuppression or an EBV-related malignancy. Chronic active EBV infection was diagnosed, a clinical picture not described in an adult African previously. Interestingly, among all therapy attempts, only rituximab was effective at stabilizing the disease. PMID- 22926563 TI - Proteomic response of Bacillus subtilis to lantibiotics reflects differences in interaction with the cytoplasmic membrane. AB - Mersacidin, gallidermin, and nisin are lantibiotics, antimicrobial peptides containing lanthionine. They show potent antibacterial activity. All three interfere with cell wall biosynthesis by binding lipid II, but they display different levels of interaction with the cytoplasmic membrane. On one end of the spectrum, mersacidin interferes with cell wall biosynthesis by binding lipid II without integrating into bacterial membranes. On the other end of the spectrum, nisin readily integrates into membranes, where it forms large pores. It destroys the membrane potential and causes leakage of nutrients and ions. Gallidermin, in an intermediate position, also readily integrates into membranes. However, pore formation occurs only in some bacteria and depends on membrane composition. In this study, we investigated the impact of nisin, gallidermin, and mersacidin on cell wall integrity, membrane pore formation, and membrane depolarization in Bacillus subtilis. The impact of the lantibiotics on the cell envelope was correlated to the proteomic response they elicit in B. subtilis. By drawing on a proteomic response library, including other envelope-targeting antibiotics such as bacitracin, vancomycin, gramicidin S, or valinomycin, YtrE could be identified as the most reliable marker protein for interfering with membrane-bound steps of cell wall biosynthesis. NadE and PspA were identified as markers for antibiotics interacting with the cytoplasmic membrane. PMID- 22926564 TI - The urinary antibiotic 5-nitro-8-hydroxyquinoline (Nitroxoline) reduces the formation and induces the dispersal of Pseudomonas aeruginosa biofilms by chelation of iron and zinc. AB - Since cations have been reported as essential regulators of biofilm, we investigated the potential of the broad-spectrum antimicrobial and cation chelator nitroxoline as an antibiofilm agent. Biofilm mass synthesis was reduced by up to 80% at sub-MIC nitroxoline concentrations in Pseudomonas aeruginosa, and structures formed were reticulate rather than compact. In preformed biofilms, viable cell counts were reduced by 4 logs at therapeutic concentrations. Complexation of iron and zinc was demonstrated to underlie nitroxoline's potent antibiofilm activity. PMID- 22926565 TI - Experience with fosfomycin for treatment of urinary tract infections due to multidrug-resistant organisms. AB - Fosfomycin has shown promising in vitro activity against multidrug-resistant (MDR) urinary pathogens; however, clinical data are lacking. We conducted a retrospective chart review to describe the microbiological and clinical outcomes of urinary tract infections (UTIs) with MDR pathogens treated with fosfomycin tromethamine. Charts for 41 hospitalized patients with a urine culture for an MDR pathogen who received fosfomycin tromethamine from 2006 to 2010 were reviewed. Forty-one patients had 44 urinary pathogens, including 13 carbapenem-resistant Klebsiella pneumoniae (CR-Kp), 8 Pseudomonas aeruginosa, and 7 vancomycin resistant Enterococcus faecium (VRE) isolates, 7 extended-spectrum beta-lactamase (ESBL) producers, and 9 others. In vitro fosfomycin susceptibility was 86% (median MIC, 16 MUg/ml; range, 0.25 to 1,024 MUg/ml). Patients received an average of 2.9 fosfomycin doses per treatment course. The overall microbiological cure was 59%; failure was due to either relapse (24%) or reinfection UTI (17%). Microbiological cure rates by pathogen were 46% for CR-Kp, 38% for P. aeruginosa, 71% for VRE, 57% for ESBL producers, and 100% for others. Microbiological cure (n = 24) was compared to microbiological failure (n = 17). There were significantly more solid organ transplant recipients in the microbiological failure group (59% versus 21%; P = 0.02). None of the patients in the microbiological cure group had a ureteral stent, compared to 24% of patients within the microbiological failure group (P = 0.02). Fosfomycin demonstrated in vitro activity against UTIs due to MDR pathogens. For CR-KP, there was a divergence between in vitro susceptibility (92%) and microbiological cure (46%). Multiple confounding factors may have contributed to microbiological failures, and further data regarding the use of fosfomycin for UTIs due to MDR pathogens are needed. PMID- 22926566 TI - pEl1573 Carrying blaIMP-4, from Sydney, Australia, is closely related to other IncL/M plasmids. AB - Complete sequencing of pEl1573, a representative IncL/M plasmid carrying bla(IMP 4) from Sydney, Australia, revealed an ~60-kb backbone almost identical to those of IncL/M plasmids pCTX-M3, from Poland, and pCTX-M360, from China, and less closely related to pNDM-HK, pOXA-48a, and pEL60, suggesting different lineages. The ~28-kb Tn2-derived multiresistance region in pEl1573 is inserted in the same location as those in pCTX-M3 and pNDM-HK and shares some of the same components but has undergone rearrangements. PMID- 22926567 TI - Streptomycin-starved Mycobacterium tuberculosis 18b, a drug discovery tool for latent tuberculosis. AB - Mycobacterium tuberculosis 18b, a streptomycin (STR)-dependent mutant that enters a viable but nonreplicating state in the absence of STR, has been developed as a simple model for drug testing against dormant bacilli. Here, we further evaluated the STR-starved 18b (SS18b) model both in vitro and in vivo by comparing the behavior of 22 approved and experimental tuberculosis drugs. Using the resazurin reduction microplate assay (REMA), rifampin (RIF), rifapentine (RPT), TMC207, clofazimine (CFM), and linezolid (LIN) were found to be active against SS18b in vitro, and their bactericidal activity was confirmed by determining the number of CFU. A latent 18b infection was established in mice, and some of the above mentioned drugs were used for treatment, either alone or in combination with RIF. RIF, RPT, TMC207, CFM, and pyrazinamide (PZA) were all active in vivo, while cell wall inhibitors were not. A comparative kinetic study of rifamycin efficacy was then undertaken, and the results indicated that RPT clears latent 18b infection in mice faster than RIF. Intrigued by the opposing responses of live and dormant 18b cells to cell wall inhibitors, we conducted a systematic analysis of 14 such inhibitors using REMA. This uncovered an SS18b signature (CWPRED) that accurately predicted the activities of cell wall inhibitors and performed well in a blind study. CWPRED will be useful for establishing the mode of action of compounds with unknown targets, while the SS18b system should facilitate the discovery of drugs for treating latent tuberculosis. PMID- 22926568 TI - Dried blood spot analysis for therapeutic drug monitoring of linezolid in patients with multidrug-resistant tuberculosis. AB - Linezolid is a promising antimicrobial agent for the treatment of multidrug resistant tuberculosis (MDR-TB), but its use is limited by toxicity. Therapeutic drug monitoring (TDM) may help to minimize toxicity while adequate drug exposure is maintained. Conventional plasma sampling and monitoring might be hindered in many parts of the world by logistical problems that may be solved by dried blood spot (DBS) sampling. The aim of this study was to develop and validate a novel method for TDM of linezolid in MDR-TB patients using DBS sampling. Plasma, venous DBS, and capillary DBS specimens were obtained simultaneously from eight patients receiving linezolid. A DBS sampling method was developed and clinically validated by comparing DBS with plasma results using Passing-Bablok regression and Bland Altman analysis. This study showed that DBS analysis was reproducible and robust. Accuracy and between- and within-day precision values from three validations presented as bias and coefficient of variation (CV) were less than 17.2% for the lower limit of quantification and less than 7.8% for other levels. The method showed a high recovery of approximately 95% and a low matrix effect of less than 8.7%. DBS specimens were stable at 37 degrees C for 2 months and at 50 degrees C for 1 week. The ratio of the concentration of linezolid in DBS samples to that in plasma was 1.2 (95% confidence interval [CI], 1.12 to 1.27). Linezolid exposure calculated from concentrations DBS samples and plasma showed good agreement. In conclusion, DBS analysis of linezolid is a promising tool to optimize linezolid treatment in MDR-TB patients. An easy sampling procedure and high sample stability may facilitate TDM, even in underdeveloped countries with limited resources and where conventional plasma sampling is not feasible. PMID- 22926569 TI - Peptidomimetic and organometallic derivatives of primaquine active against Leishmania infantum. AB - The current treatment of visceral leishmaniasis is made difficult by the low efficacy, elevated costs, low bioavailability, and high toxicity of many of the available drugs. Primaquine, an antimalarial 8-aminoquinoline, displays activity against Leishmania spp., and several of its derivatives have been developed as potential antileishmanial drugs. However, primaquine exhibits low oral bioavailability due to oxidative deamination of its aliphatic chain. We previously developed peptidomimetic and organometallic derivatives of primaquine, with higher resistance to proteolytic degradation and oxidative deamination, which presented significant activity against primaquine-sensitive pathogens such as Plasmodium or Pneumocystis. In light of these relevant findings, we decided to evaluate these compounds against both the promastigote and intramacrophagic amastigote forms of Leishmania infantum, the agent of Mediterranean visceral leishmaniasis. We found that several of these compounds had significant activity against L. infantum. One of the peptidomimetic (3c) and one of the organometallic (7a) derivatives of primaquine were active against the clinically relevant intramacrophagic amastigote form of the parasite, causing >96% reductions in the number of amastigotes per 100 macrophages at 60 and 40 MUM, respectively, while being less cytotoxic for host cells than the reference drugs sitamaquine and miltefosine. Hence, compounds 3c and 7a represent new entries toward the development of new antileishmanial leads. PMID- 22926570 TI - Inhibition of protein synthesis on the ribosome by tildipirosin compared with other veterinary macrolides. AB - Tildipirosin is a 16-membered-ring macrolide developed to treat bacterial pathogens, including Mannheimia haemolytica and Pasteurella multocida, that cause respiratory tract infections in cattle and swine. Here we evaluated the efficacy of tildipirosin at inhibiting protein synthesis on the ribosome (50% inhibitory concentration [IC(50)], 0.23 +/- 0.01 MUM) and compared it with the established veterinary macrolides tylosin, tilmicosin, and tulathromycin. Mutation and methylation at key rRNA nucleotides revealed differences in the interactions of these macrolides within their common ribosomal binding site. PMID- 22926571 TI - Influence of vehicles used for oral dosing of test molecules on the progression of Mycobacterium tuberculosis infection in mice. AB - Preclinical evaluation of drug-like molecules requires their oral administration to experimental animals using suitable vehicles. We studied the effect of oral dosing with corn oil, carboxymethyl cellulose, dimethyl sulfoxide, and polysorbate-80 on the progression of Mycobacterium tuberculosis infection in mice. Infection was monitored by physical (survival time and body weight) and bacteriological (viable counts in lungs) parameters. Compared with water, corn oil significantly improved both sets of parameters, whereas the other vehicles affected only physical parameters. PMID- 22926572 TI - Population pharmacokinetic and pharmacodynamic modeling of amodiaquine and desethylamodiaquine in women with Plasmodium vivax malaria during and after pregnancy. AB - Amodiaquine is effective for the treatment of Plasmodium vivax malaria, but there is little information on the pharmacokinetic and pharmacodynamic properties of amodiaquine in pregnant women with malaria. This study evaluated the population pharmacokinetic and pharmacodynamic properties of amodiaquine and its biologically active metabolite, desethylamodiaquine, in pregnant women with P. vivax infection and again after delivery. Twenty-seven pregnant women infected with P. vivax malaria on the Thai-Myanmar border were treated with amodiaquine monotherapy (10 mg/kg/day) once daily for 3 days. Nineteen women, with and without P. vivax infections, returned to receive the same amodiaquine dose postpartum. Nonlinear mixed-effects modeling was used to evaluate the population pharmacokinetic and pharmacodynamic properties of amodiaquine and desethylamodiaquine. Amodiaquine plasma concentrations were described accurately by lagged first-order absorption with a two-compartment disposition model followed by a three-compartment disposition of desethylamodiaquine under the assumption of complete in vivo conversion. Body weight was implemented as an allometric function on all clearance and volume parameters. Amodiaquine clearance decreased linearly with age, and absorption lag time was reduced in pregnant patients. Recurrent malaria infections in pregnant women were modeled with a time to-event model consisting of a constant-hazard function with an inhibitory effect of desethylamodiaquine. Amodiaquine treatment reduced the risk of recurrent infections from 22.2% to 7.4% at day 35. In conclusion, pregnancy did not have a clinically relevant impact on the pharmacokinetic properties of amodiaquine or desethylamodiaquine. No dose adjustments are required in pregnancy. PMID- 22926573 TI - In vitro combination studies of benzothiazinone lead compound BTZ043 against Mycobacterium tuberculosis. AB - Benzothiazinones (BTZ) are a new class of drug candidates to combat tuberculosis that inhibit decaprenyl-phosphoribose epimerase (DprE1), an essential enzyme involved in arabinan biosynthesis. Using the checkerboard method and cell viability assays, we have studied the interaction profiles of BTZ043, the current lead compound, with several antituberculosis drugs or drug candidates against Mycobacterium tuberculosis strain H37Rv, namely, rifampin, isoniazid, ethambutol, TMC207, PA-824, moxifloxacin, meropenem with or without clavulanate, and SQ-109. No antagonism was found between BTZ043 and the tested compounds, and most of the interactions were purely additive. Data from two different approaches clearly indicate that BTZ043 acts synergistically with TMC207, with a fractional inhibitory concentration index of 0.5. TMC207 at a quarter of the MIC (20 ng/ml) used in combination with BTZ043 (1/4 MIC, 0.375 ng/ml) had a stronger bactericidal effect on M. tuberculosis than TMC207 alone at a concentration of 80 ng/ml. This synergy was not observed when the combination was tested on a BTZ resistant M. tuberculosis mutant, suggesting that DprE1 inhibition is the basis for the interaction. This finding excludes the possibility of synergy occurring through an off-target mechanism. We therefore hypothesize that sub-MICs of BTZ043 weaken the bacterial cell wall and allow improved penetration of TMC207 to its target. Synergy between two new antimycobacterial compounds, such as TMC207 and BTZ043, with novel targets, offers an attractive foundation for a new tuberculosis regimen. PMID- 22926574 TI - Activation of the unfolded protein response by 2-deoxy-D-glucose inhibits Kaposi's sarcoma-associated herpesvirus replication and gene expression. AB - Lytic replication of the Kaposi's sarcoma-associated herpesvirus (KSHV) is essential for the maintenance of both the infected state and characteristic angiogenic phenotype of Kaposi's sarcoma and thus represents a desirable therapeutic target. During the peak of herpesvirus lytic replication, viral glycoproteins are mass produced in the endoplasmic reticulum (ER). Normally, this leads to ER stress which, through an unfolded protein response (UPR), triggers phosphorylation of the alpha subunit of eukaryotic initiation factor 2 (eIF2alpha), resulting in inhibition of protein synthesis to maintain ER and cellular homeostasis. However, in order to replicate, herpesviruses have acquired the ability to prevent eIF2alpha phosphorylation. Here we show that clinically achievable nontoxic doses of the glucose analog 2-deoxy-d-glucose (2-DG) stimulate ER stress, thereby shutting down eIF2alpha and inhibiting KSHV and murine herpesvirus 68 replication and KSHV reactivation from latency. Viral cascade genes that are involved in reactivation, including the master transactivator (RTA) gene, glycoprotein B, K8.1, and angiogenesis-regulating genes are markedly decreased with 2-DG treatment. Overall, our data suggest that activation of UPR by 2-DG elicits an early antiviral response via eIF2alpha inactivation, which impairs protein synthesis required to drive viral replication and oncogenesis. Thus, induction of ER stress by 2-DG provides a new antiherpesviral strategy that may be applicable to other viruses. PMID- 22926575 TI - Activity of gallidermin on Staphylococcus aureus and Staphylococcus epidermidis biofilms. AB - Due to their abilities to form strong biofilms, Staphylococcus aureus and Staphylococcus epidermidis are the most frequently isolated pathogens in persistent and chronic implant-associated infections. As biofilm-embedded bacteria are more resistant to antibiotics and the immune system, they are extremely difficult to treat. Therefore, biofilm-active antibiotics are a major challenge. Here we investigated the effect of the lantibiotic gallidermin on two representative biofilm-forming staphylococcal species. Gallidermin inhibits not only the growth of staphylococci in a dose-dependent manner but also efficiently prevents biofilm formation by both species. The effect on biofilm might be due to repression of biofilm-related targets, such as ica (intercellular adhesin) and atl (major autolysin). However, gallidermin's killing activity on 24-h and 5-day old biofilms was significantly decreased. A subpopulation of 0.1 to 1.0% of cells survived, comprising "persister" cells of an unknown genetic and physiological state. Like many other antibiotics, gallidermin showed only limited activity on cells within mature biofilms. PMID- 22926577 TI - Quantitative proteomic analysis of human substantia nigra in Alzheimer's disease, Huntington's disease and Multiple sclerosis. AB - The substantia nigra plays important roles in the brain function and is critical in the development of many diseases, particularly Parkinson's disease. Pathological changes of the substantia nigra have also been reported in other neurodegenerative diseases. Using a quantitative proteomic approach, we investigated protein expressions in the substantia nigra of Alzheimer's disease, Huntington's disease, and Multiple sclerosis. The expression level of one hundred and four proteins that were identified in at least three samples of each group were compared with the control group, with nineteen, twenty-two and thirteen proteins differentially expressed in Alzheimer's diseases, Huntington's disease and Multiple sclerosis respectively. The result indicates that the substantia nigra also undergoes functional adaption or damage in these diseases. PMID- 22926578 TI - Unregulated gambling in South African townships: a policy conundrum? AB - This study was designed to explore the nature of informal or illegal gambling in South African townships, to investigate what motivates people to participate in this form of gambling and what they perceive are the associated benefits and dis benefits. A series of focus group workshops was conducted with two groups of gamblers, all of whom had experience of some form of township gambling: one group currently lived in townships and the other had previously resided in townships. Gambling for the township residents was a far more frequent activity than for non township residents and consumed substantially more of their time. The majority of the township residents classified themselves as unemployed, while of those who were unemployed, most people indicated that gambling was a major source of their income; some even described it as their only source of income. The most significant difference between what township and non-township residents expressed as wanting and getting from gambling was that the former indicated quite clearly and unanimously that what they sought and gained from gambling was money. Township residents were far more likely to indicate that they used gambling to balance their budgets than ex-township residents who gambled primarily at casinos. A lottery type game called "Fahfee" is the most widely spread and pervasive form of gambling and was unanimously portrayed as a necessary and beneficial form of support for the poor and unemployed. Lottery and Casino gambling were, in contrast, widely perceived by the township participants as being 'rigged' and unfair. Township Dice and cards were perceived as being 'fairer' and as allowing punters to be more in control than casino gambling. The downside of township gambling was reported to be high levels of violence, crime and insecurity surrounding, in particular, the game of Dice. There was widespread inability to calculate expected payoffs or odds, and an apparent belief that these were not particularly helpful skills for gamblers. In Fahfee, the reliance on dreams to guide choice of numbers appears to eradicate any interest in the odds, or of playing strategically. The findings of this study are preliminary but have serious policy implications for education and for gambling regulation in South Africa. PMID- 22926579 TI - An assessment of the psychometric properties of Italian version of CPGI. AB - The aim of this study was to adapt to the Italian context a very commonly used international instrument to detect problem gambling, the canadian problem gambling index (CPGI), and assess its psychometric properties. Cross-cultural adaptation of CPGI was performed in several steps and the questionnaire was administered as a survey among Italian general population (n = 5,292). Cronbach's alpha reliability coefficient was 0.87 and can be considered to be highly reliable. Construct validity was assessed first by means of a principal component analysis and then by means of confirmatory factor analysis, showing that only one factor, problem gambling, was extracted from the CPGI questionnaire (an eigenvalues of 4,684 with percentage of variance 52 %). As far as convergent validity is concerned, CPGI was compared with Lie/Bet questionnaire, a two-item screening tool for detecting problem gamblers, and with both depression and stress scales. A short form DSM-IV CIDI questionnaire was used for depression and VRS scale, a rating scale, was used for rapid stress evaluation. A strong convergent validity with these instruments was found and these findings are consistent with past research on problem gambling, where another way to confirm the validity is to determine the extent to which it correlates with other qualities or measures known to be directly related to problem gambling. In sum, despite the lack of a direct comparison with a classic gold-standard such as DSM IV, the Italian version of CPGI exhibits good psychometric properties and can be used among the Italian general population to identify at-risk problem gamblers. PMID- 22926581 TI - Distinct and effective biotransformation of hexavalent chromium by a novel isolate under aerobic growth followed by facultative anaerobic incubation. AB - A bacterial isolate (G161) with high Cr(VI)-reducing capacity was isolated from Cr(VI)-contaminated soil and identified as Leucobacter sp. on the basis of 16S rRNA gene sequence analysis. The isolate was a Gram-positive, aerobic rod. The hexavalent chromate-reducing capability of the isolate was investigated under three conditions of oxygen stress. The isolate was found to reduce Cr(VI) under all conditions but performed most effectively during aerobic growth followed by facultative anaerobic incubation. Under these conditions, the isolate tolerated K(2)Cr(2)O(7) concentrations up to 1,000 mg/l and completely reduced 400 mg/l K(2)Cr(2)O(7) within 96 h. The strain reduced Cr(VI) over a wide range of pH (6.0 11.0) and temperatures (15-45 degrees C) with optimum performance at pH 8.0 and 35 degrees C. The presence of other metals, such as Ca(2+), Co(2+), Cu(2+), Mn(2+), Ni(2+), and Zn(2+), induced no effect or else played a stimulatory role on Cr(VI)-reduction activity of the strain. The strain was tested for Cr(VI) removal in wastewaters and proved capable of completely reducing the contained Cr(VI). This is the novel report of a bacterial growth and Cr(VI)-reduction process under sequential aerobic growth and facultative anaerobic conditions. The study suggested that the isolate possesses a distinct capability for Cr(VI) reduction which could be harnessed for the detoxification of chromate contaminated wastewaters. PMID- 22926576 TI - Primary cultures of astrocytes: their value in understanding astrocytes in health and disease. AB - During the past few decades of astrocyte research it has become increasingly clear that astrocytes have taken a central position in all central nervous system activities. Much of our new understanding of astrocytes has been derived from studies conducted with primary cultures of astrocytes. Such cultures have been an invaluable tool for studying roles of astrocytes in physiological and pathological states. Many central astrocytic functions in metabolism, amino acid neurotransmission and calcium signaling were discovered using this tissue culture preparation and most of these observations were subsequently found in vivo. Nevertheless, primary cultures of astrocytes are an in vitro model that does not fully mimic the complex events occurring in vivo. Here we present an overview of the numerous contributions generated by the use of primary astrocyte cultures to uncover the diverse functions of astrocytes. Many of these discoveries would not have been possible to achieve without the use of astrocyte cultures. Additionally, we address and discuss the concerns that have been raised regarding the use of primary cultures of astrocytes as an experimental model system. PMID- 22926583 TI - [Endocrine emergencies]. PMID- 22926582 TI - The thioredoxin reductase-encoding gene ActrxR1 is involved in the cephalosporin C production of Acremonium chrysogenum in methionine-supplemented medium. AB - The thioredoxin system including thioredoxin and thioredoxin reductase (TrxR) is used for oxidative stress defenses in fungi. Based on the genomic sequence, a thioredoxin reductase-encoding gene (ActrxR1) was isolated from Acremonium chrysogenum CGMCC3.3795. Like other TrxRs, AcTrxR1 contains FAD binding domain, Redox domain, and NADPH binding domain. Disruption of ActrxR1 in A. chrysogenum led to the formation of smaller colonies and hyphal swelling in Tryptic soy agar (TSA). In chemically defined medium, the spore germination of ActrxR1 disruption mutant was strongly inhibited, which was recovered by the addition of DL methionine. The disruption mutant grew slowly on TSA compared with the wild-type strain, but it did not show to be more sensitive to exogenous hydrogen peroxide or menadione. In defined medium of fermentation supplemented with DL-methionine, the ActrxR1 disruption mutant grew normally, and its cephalosporin C production increased by about onefold compared with the wild type (73 MUg/ml for wild-type strain and 136 MUg/ml for the mutant at 5 days of fermentation). Real-time polymerase chain reaction (RT-PCR) showed that the transcriptional levels of pcbC, cefEF, and cefG were obviously enhanced in the ActrxR1 mutant at the early stage of fermentation. These results indicate that ActrxR1 is required for the normal growth of A. chrysogenum and related with cephalosporin C production in methionine-supplemented medium. PMID- 22926584 TI - [Indirect laryngoscopy/video laryngoscopy. A review of devices used in emergency and intensive care medicine in Germany]. AB - Airway management in intensive care or emergency medicine is particularly challenging and is often associated with life-threatening complications. An innovation in the field of airway management is the use of indirect laryngoscopy by means of video laryngoscopes. A digital camera or an optical system at the tip of a laryngoscope blade enables an indirect "look around the corner" to the glottis. Studies have shown that the advantages of video laryngoscopes for endotracheal intubation are particularly beneficial in difficult airway situations. However, the successful use in challenging intubations requires experience and regular use in daily practice. This review gives an overview of indirect laryngoscopes commonly used in Germany and also presents new study results for these novel devices. PMID- 22926588 TI - Abstracts of the 202nd Scientific Meeting of the Pathological Society of Great Britain & Ireland. July 3-5, 2012. Sheffield, United Kingdom. PMID- 22926585 TI - [Difficult extubation]. AB - Optimal timing of extubation following intubation substantially impacts on the prognosis of intensive care unit (ICU) patients whereby both early extubation with the risk of reintubation and delayed extubation with prolongation of mechanical ventilation need to be avoided. In most cases extubation is easy; in some cases, however, extubation may be extremely difficult or even impossible with two major reasons being responsible for this: firstly, laryngeal edema, where the cuff leak test and steroid treatment are well established procedures aimed at diagnosing and treating potential laryngeal complications and secondly, the presence of (chronic) respiratory failure despite sufficient treatment of acute respiratory failure. This can result in post-extubation failure following extubation or weaning failure and noninvasive ventilation has been increasingly used in both scenarios. Currently, specialised weaning centres are being established and certified in Germany aimed at managing the complex tasks for patients with prolonged weaning. PMID- 22926589 TI - Too good to be true? Aspirin and schizophrenia. PMID- 22926590 TI - The relationship between serum uric acid concentration and metabolic syndrome in patients with schizophrenia or schizoaffective disorder. AB - Higher prevalence rates of metabolic syndrome (MetS) in patients with schizophrenia are getting more and more attention. Uric acid (UA) has been frequently reported to be associated with MetS in the general population. Sex difference in this relationship is inconsistent. As a selective antioxidant, UA has also been found to be reduced in patients with schizophrenia, and this effect may be prominent in men. With the inconsistent presentations, higher rate of MetS but possible lower UA concentrations, the aim of this study was to investigate the relationship by sexes between serum UA concentrations and prevalence of MetS in patients with schizophrenia or schizoaffective disorder. A total of 637 patients, 342 male and 295 female, were enrolled from 36 psychiatric rehabilitation institutions. Cross-sectional anthropometrical data, biochemical analysis, and serum UA were measured. Serum UA concentrations were divided into quartiles by sexes. Modified National Cholesterol Education Program Adult Treatment Panel III criteria for Asians were used as diagnosis of MetS. After adjustment, higher UA concentrations are associated with hypertriglyceridemia, low high-density lipoprotein cholesterol level, and high blood pressure in men and with hypertriglyceridemia in women. Significantly higher odds ratios for MetS in the UA third (4.02; 95% confidence interval, 1.33-12.1) and fourth quartiles (9.28; 95% confidence interval, 2.90-29.8) compared with the lowest quartile were found in men but not in women after adjustment. These results suggest that lower UA concentrations in male patients with schizophrenia or schizoaffective disorder are associated with lower risk of MetS. PMID- 22926591 TI - A randomized, double-blind, placebo-controlled trial of fluvoxamine in patients with schizophrenia: a preliminary study. AB - Cognitive impairments in schizophrenia are associated with suboptimal psychosocial performance. Several lines of evidence have suggested that endoplasmic reticulum protein sigma-1 receptors were involved in cognitive impairments in patients with schizophrenia and that the sigma-1 receptor agonist fluvoxamine was effective in treating cognitive impairments in animal models of schizophrenia and in some patients with schizophrenia. A randomized, double blind, placebo-controlled, parallel trial of fluvoxamine adjunctive therapy in patients with schizophrenia was performed. A total of 48 patients with chronic schizophrenia were enrolled. Subjects were randomly assigned to an 8-week administration of add-on fluvoxamine (n = 24, titrated up to 150 mg/d) or placebo (n =24) in a total 12-week double-blind trial. The primary outcome measure was the Cambridge Neuropsychological Test Automated Battery (CANTAB), assessing visual memory, working memory, attention, and executive function. The secondary outcome measures were the Positive and Negative Syndrome Scale, the Scale for the Assessment of Negative Symptoms, the Quality of Life Scale, and the Montgomery Asberg Depression Rating Scale. Fluvoxamine was well tolerated. No significant time * group interaction effects were observed in the scores of the CANTAB, Positive and Negative Syndrome Scale, Scale for the Assessment of Negative Symptoms, Quality of Life Scale, or the Montgomery-Asberg Depression Rating Scale. However, in secondary analyses, the change from baseline to end point on the Spatial Working Memory strategy score (executive function) of CANTAB improved in the fluvoxamine group. This study suggests no major benefit of fluvoxamine adjunctive therapy to improve cognitive impairments in patients with schizophrenia. Nevertheless, a further study using a large sample size will be needed to confirm the secondary analyses findings. PMID- 22926592 TI - Effectiveness and cost of atypical versus typical antipsychotic treatment in a nationwide cohort of patients with schizophrenia in Germany. AB - This study investigates the effectiveness and cost of typical versus atypical antipsychotics in a nationwide German cohort of patients with schizophrenia. The study sample consisted of patients insured with 4 sickness funds (n = 8,610) who were followed up for 12 months after hospital discharge with a diagnosis of schizophrenia in 2003. Multivariate regression models were fitted to assess the relationship between outcome variables (rehospitalization, bed-days, prescriptions against adverse effects, cost) and medication type, sex, age, and severity. Severity was assessed by prior bed-days due to schizophrenia during 2000 to 2002. Risk of rehospitalization did not differ between groups but within each group severity (P = 0.0003). Males (P = 0.0016) and patients younger than 35 years (P < 0.0001) had a higher risk of rehospitalization. Number of bed-days was lower for treatment with typicals compared with atypicals (P < 0.0001); furthermore, bed-days depended on severity of disease (P < 0.0001). Prescriptions of drugs against extrapyramidal symptoms, anxiety, and agitation were higher for patients treated with typicals (P < 0.0001 for each). Mean predicted treatment cost per year was ? 6442 for atypicals versus ? 4443 for typicals (P < 0.0001). This study does not support unconditional superiority of atypicals over typicals, neither in terms of effectiveness nor in terms of cost. PMID- 22926593 TI - Neonatal complications after maternal concomitant use of SSRI and other central nervous system active drugs during the second or third trimester of pregnancy. AB - Drugs acting on the central nervous system (CNS) and given to a pregnant woman during the latter part of pregnancy may affect neonatal morbidity of the infant. Little is known on the combined effects of different categories of such drugs. The redeeming of prescriptions for CNS-active drugs during the second or third trimester of pregnancy was studied by linkage between a register of prescribed drugs and the Swedish Medical Birth Register for the deliveries during 2006-2008 (n = 15,045 live-born infants). Neonatal morbidity was defined as the presence of neonatal diagnoses of respiratory problems, hypoglycemia, convulsions, or other CNS pathologic abnormalities including intraventricular hemorrhage, or low 5 minute Apgar score. The risk of such neonatal morbidity after maternal use of selective serotonin reuptake inhibitors (SSRIs) with or without other CNS-active drugs were evaluated as odds ratios or risk ratios, comparing with unexposed infants or infants only exposed to SSRI drugs. An increased risk for neonatal morbidity was seen for most studied groups of CNS-active drugs when used alone. Benzodiazepines seemed to have a stronger effect than other sedatives/hypnotics. The combination of SSRIs with 1 or more other CNS-active drug groups increased the risk for neonatal morbidity. This was seen for all types of sedatives/hypnotics, which may suggest a confounding by indication. Polypharmacy with CNS-active drugs during the later part of the pregnancy seems to increase the occurrence of neonatal morbidity but difference in nature or strength of underlying psychiatric pathology may confound the findings. PMID- 22926594 TI - Neonatal outcomes after late-gestation exposure to selective serotonin reuptake inhibitors. AB - OBJECTIVE: This study aimed to investigate neonatal outcomes after prenatal exposure to selective serotonin reuptake inhibitors (SSRIs) during late gestation. METHODS: A retrospective cohort study was conducted using linked records from the Women's and Children's Health Network in South Australia, Australia, including the Perinatal Statistics Collection and the Hospital Pharmacy Dispensing Records. Women were eligible to participate if they gave birth to singleton, live-born infants between September 2000 and December 2008 (n = 33,965). Women were excluded if they received a dispensing for antidepressants other than SSRIs (n = 93) or an antipsychotic (n = 81). We estimated odds ratios (ORs) and 95% confidence intervals (CIs) for preterm delivery, low birth weight, small-for-gestational age, neonatal hospitalization and length of hospital admission, adjusting for sociodemographic, lifestyle, and medical factors. RESULTS: Two hundred twenty-one women received a dispensing for an SSRI during pregnancy, 1566 had a psychiatric illness but did not receive a dispensing for an SSRI, and 32,004 did not have a psychiatric illness and did not receive a dispensing for an SSRI. Compared to infants of women with a psychiatric illness but no SSRI use, infants of women exposed to SSRIs had an increased risk of preterm delivery (adjusted OR, 2.68; 95% CI, 1.83-3.93), low birth weight (adjusted OR, 2.26; 95% CI, 1.31-3.91), admission to hospital (adjusted OR, 1.92; 95% CI, 1.39-2.65), and length of hospital stay longer than 3 days (adjusted OR, 1.93; 95% CI, 1.11-3.36) but not small-for-gestational age (adjusted OR, 1.13; 95% CI, 0.65-1.94). Psychiatric illness but no SSRI use during pregnancy was only associated with an increased likelihood of neonatal hospital admission (adjusted OR, 1.21; 95% CI, 1.07-1.38). CONCLUSIONS: These results add to the growing body of evidence of an association between SSRI exposure during pregnancy and a range of adverse neonatal outcomes, but the potential for confounding according to severity of underlying maternal psychiatric illness requires further investigation. PMID- 22926595 TI - Multicenter study on the clinical effectiveness, pharmacokinetics, and pharmacogenetics of mirtazapine in depression. AB - Pharmacogenetic tests and therapeutic drug monitoring may considerably improve the pharmacotherapy of depression. The aim of this study was to evaluate the relationship between the efficacy of mirtazapine (MIR) and the steady-state plasma concentrations of its enantiomers and metabolites in moderately to severely depressed patients, taking their pharmacogenetic status into account. Inpatients and outpatients (n = 45; mean age, 51 years; range, 19-79 years) with major depressive episode received MIR for 8 weeks (30 mg/d on days 1-14 and 30-45 mg/d on days 15-56). Mirtazapine treatment resulted in a significant improvement in mean Hamilton Depression Rating Scale total score at the end of the study (P < 0.0001). There was no evidence for a significant plasma concentration-clinical effectiveness relationship regarding any pharmacokinetic parameter. The enantiomers of MIR and its hydroxylated (OH-MIR) and demethylated (DMIR) metabolites in plasma samples on days 14 and 56 were influenced by sex and age. Nonsmokers (n = 28) had higher mean MIR plasma levels than smokers (n = 17): S(+) enantiomer of MIR, 9.4 (SD, 3.9) versus 6.2 (SD, 5.5) ng/mL (P = 0.005); R(-) enantiomer of MIR, 24.4 (SD, 6.5) versus 18.5 (SD, 4.1) ng/mL (P = 0.003). Only in nonsmokers, plasma levels of S(+)-enantiomer of MIR and metabolites depended on the CYP2D6 genotype. Therefore, high CYP1A2 activity seen in smokers seems to mask the influence of the CYP2D6 genotype. In patients presenting the CYP2B6 *6/*6 genotype (n = 8), S-OH-MIR concentrations were higher those in the other patients (n = 37). Although it is not known if S-OH-MIR is associated with the therapeutic effect of MIR, the reduction of the Hamilton scores was significantly (P = 0.016) more pronounced in the CYP2B6 *6/*6-genotyped patients at the end of the study. The role of CYP2B6 in the metabolism and effectiveness of MIR should be further investigated. PMID- 22926597 TI - A randomized, double-blind study of 30 versus 20 mg dexmethylphenidate extended release in children with attention-deficit/hyperactivity disorder: late-day symptom control. AB - The objective of this study was to evaluate the safety and efficacy of dexmethylphenidate extended-release (d-MPH-ER) 30 versus 20 mg in children with attention-deficit/hyperactivity disorder (ADHD) in a 12-hour laboratory classroom setting. In a randomized, double-blind, 3-period * 3-treatment, crossover study, children aged 6 to 12 years with Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition-diagnosed ADHD previously stabilized on MPH (40-60 mg/d) or D-MPH (20-30 mg/day) [corrected] were randomized to receive D-MPH-ER 20 mg/day, 30 mg/day, [corrected] or placebo for 7 days each. Primary efficacy measurements were change in the average SKAMP-Combined [corrected] score from predose to 10, 11, and 12 hours postdose [Avg(10-12)] between 30 mg [corrected] and 20 mg D-MPH-ER. Safety was assessed by adverse events, (AEs), [corrected] vital sign monitoring, and ECGs. [corrected] A total of 165 children were randomized, and 162 included in the intent-to-treat analysis. Mean Avg (10-12) change from pre-dose [corrected] in SKAMP-Combined score was significantly greater for D-MPH-ER 30 mg (-4.47) compared with D-MPH-ER 20 mg (-2.02; P = 0.002). Most common adverse events (>= 3% in any group) were decreased appetite (6.1%, 4.9%, and 0%), headache (4.3%, 4.3%, and 1.9%), abdominal pain (3.7%, 3.1%, and 3.1%), and tachycardia (1.2%, 3.1%, and 0.6%) for D-MPH-ER 30 mg, D-MPH ER 20 mg, and placebo, respectively). Significantly greater improvement in ADHD symptoms was noted with D-MPH-ER 30 mg compared with D-MPH-ER 20 mg at hours 10 through 12. Tolerability was comparable between doses. Dexmethylphenidate extended-release 30-mg dose may provide further benefit to patients who do not maintain optimal symptom control later in the day with D-MPH-ER 20 mg. PMID- 22926596 TI - Effects of naltrexone on smoking cessation outcomes and weight gain in nicotine dependent men and women. AB - This study examined whether the opioid receptor antagonist naltrexone is efficacious in smoking cessation and whether sex moderates the response. We assessed smoking quit rates and weight gain in a double-blind randomized trial comparing oral naltrexone (n = 162) with placebo (n = 154) in nicotine-dependent participants who wanted to quit smoking. The medication was gradually titrated up to 50 mg during the week before the quit date and then maintained at this dose for 12 weeks. For the first 4 weeks after the quit date, all participants received a nicotine patch to mitigate tobacco withdrawal and attended weekly individual cognitive-behavioral smoking cessation counseling sessions. After this time, participants continued with naltrexone or placebo through 12 weeks. Follow up assessments were conducted at 26 and 52 weeks. During treatment, naltrexone (vs placebo) increased quit rates, attenuated smoking urge, and reduced weight gain. At follow-up, after medication discontinuation, the effect of naltrexone on improving quit rates was no longer evident. Men and women experienced different benefits from naltrexone; men showed greater reductions in smoking, whereas women showed greater reductions in weight gain. In sum, naltrexone showed acute efficacy in treating nicotine dependence, but after the medication was discontinued, the effect on quit rate was not maintained. Further study of naltrexone in smoking cessation treatment and reduction of cessation-related weight gain, as well as preclinical investigation of mechanisms underlying sex differences, is warranted. PMID- 22926598 TI - Predictive factors for more than 3 years' duration of central stimulant treatment in adult attention-deficit/hyperactivity disorder: a retrospective, naturalistic study. AB - There is effective short-term central stimulant (CS) treatment of attention deficit/hyperactivity disorder (ADHD) symptoms in adult ADHD, and despite this, many patients discontinue the treatment too early. The present study examines the duration of CS treatment in a Norwegian cohort of adult ADHD to identify predictors for long treatment duration (>= 3 years). The data were based on the medical records of a sample of 117 of all 119 adult ADHD patients diagnosed over a period of 8 years in a specific catchment area and treated with CS. A logistic regression model was applied to identify possible predictors for long treatment duration. The sample was severely impaired in terms of comorbidity, educational achievement, and employment. The median duration of CS treatment was 33.0 months. Use of extended-release formulations of methylphenidate predicted long treatment duration positively (odds ratio, 4.420 [95% CI, 1.875-10.419]), whereas baseline antisocial personality disorder predicted long treatment duration negatively (odds ratio, 0.210 [0.085-0.518]). This study showed that it is possible to treat severely impaired and highly comorbid adult ADHD patients with CS over years. The finding that extended-release formulations of methylphenidate predict long treatment duration supports previous research, and it is important to show this association in naturalistic samples such as in the present study. Comorbid antisocial personality disorder was a negative predictor of long CS treatment duration. Univariate analyses also indicate that comorbid substance use disorder is related to shorter duration of CS treatment. PMID- 22926599 TI - Does atomoxetine improve executive function, inhibitory control, and hyperactivity? Results from a placebo-controlled trial using quantitative measurement technology. AB - The primary objective of this study was to evaluate the efficacy of atomoxetine (ATX) on attention-deficit/hyperactivity disorder (ADHD)-related symptoms assessed as standard variables of a computer-based continuous performance test (cb-CPT) combined with a motion-tracking (MT) device. This was a 2-arm, 8-week, randomized, double-blind, placebo-controlled study in patients with ADHD (6-12 years). Therapy with ATX started with 0.5 mg/kg per day for 1 week, followed by 7 weeks on the target dosage of 1.2 mg/kg per day. Primary outcomes were cb-CPT/MT standard scores after 8 weeks using mixed models for repeated measurements. In addition, investigator-rated ADHD Rating Scale (ADHD-RS), Weekly Ratings of Evening and Morning Behavior (WREMB), and Clinical Global Impression - Severity ADHD (CGI-S-ADHD) scores were assessed. Of 128 patients randomized, 125 were evaluated (ATX/placebo: 63/62). Baseline characteristics were comparable in both groups (overall, 80.2% boys; mean [SD] age, 9.0 [1.79] years; comorbid Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition diagnosis, 40.0% oppositional defiant disorder/conduct disorder; prior stimulant treatment, 24.8%; ADHD-RS total score, 36.99 [11.56]). At week 8, all cb-CPT/MT q-scores were significantly reduced versus placebo (all P < 0.001) with effect sizes (ESs) of reaction time (RT) variation (ES = 0.71), mean RT (ES = 0.41), number of microevents (ES = 1.00), commission error rate (ES = 0.50), distance of movement (ES = 0.90), area of movement (ES = 1.08), omission error rate (ES = 0.70), time active (ES = 0.69), motion simplicity (ES = 0.38), and normalized variance of RT (ES = 0.50). Secondary end points also improved significantly in favor of ATX: ADHD-RS (total score ES = 1.30, P < 0.001; hyperactivity/impulsivity subscore ES = 1.37, P < 0.001; inattention subscore ES = 1.07, P < 0.001), WREMB (total score ES = 1.00, P < 0.001; morning subscore ES = 0.59, P = 0.002; evening subscore ES = 1.02, P < 0.001), CGI-S-ADHD (ES = 1.11, P < 0.001). The results of this study show that ATX for 8 weeks significantly reduced ADHD-related symptoms as measured by the cb-CPT/MT. PMID- 22926600 TI - The impact of acamprosate on cue reactivity in alcohol dependent individuals: a functional magnetic resonance imaging study. AB - Alcohol cue-induced brain activation has been studied extensively in alcoholics. However, little is known about the impact of standard treatment protocols on this phenomenon. The current study aimed at investigating the impact of the anticraving substance acamprosate on alcohol cue-related brain activity. Patients underwent a functional magnetic resonance imaging investigation before the beginning of medication with acamprosate or placebo (T0) and 2 weeks later (T1). All patients also received psychiatric inpatient treatment including psychotherapeutic interventions. Twenty-nine patients were included in the T0 analysis and 22 patients in the T1 analysis. At T0, a cluster in the left and right posterior cingulate cortex, covering parts of the retrosplenial cortex, was significantly associated with alcohol versus neutral cue exposure. At T1, no significant cluster was found for the alcohol-versus-neutral contrast. The analysis of the impact of acamprosate on cue-related activity in the posterior cingulate cortex cluster revealed no significant difference to placebo. These results provide further evidence for the involvement of the posterior cingulate cortex in alcohol cue exposure. However, in comparison with psychiatric inpatient treatment alone, there was no additional effect of acamprosate on cue-related brain activity. PMID- 22926601 TI - Pharmacokinetic-pharmacodynamic modeling of mood and withdrawal symptoms in relation to plasma concentrations of methadone in patients undergoing methadone maintenance treatment. AB - The aims of the present study were to characterize the relationship between plasma racemic methadone and its enantiomers' concentrations with respect to their pharmacodynamic effects and to investigate the influence of potential covariates on the pharmacodynamic parameters in patients on methadone maintenance treatment (MMT). Eighty-eight regular subjects at the Sheffield Care Trust Substance Misuse Services were studied. Samples of blood and urine were collected before the daily dose of methadone. Blood samples were taken up to 5 hours after dose. Total plasma concentrations of (RS)-methadone and total and unbound plasma concentrations of both enantiomers were measured by liquid chromatography-mass spectrometry. The Total Mood Disturbance Score (TMDS), the Objective Opioid Withdrawal Scale (OOWS), and the Subjective Opioid Withdrawal Scale (SOWS) were used as measures of mood and withdrawal. Population pharmacokinetic/pharmacodynamic analysis and subsequent multiple regression analysis were used to determine the factors influencing the pharmacodynamic effects of methadone. Significant decreases (P <= 0.04) were observed in the scores for the TMDS, SOWS, and OOWS for 5 hours after methadone dosage. The TMDS had returned to baseline by 10 hours after dose (P = 0.98), at which time the SOWS remained significantly below baseline (P = 0.001). Multiple regression analysis revealed that 33% of the overall variation in unbound (R)-methadone EC50 was explained by 3 variables, namely CYP3A activity (9%), age (16%), and sex (8%). Age also accounted for 8% and 9% of the variation in total (rac)- and (R) methadone EC50. The present study has confirmed that the duration of mood change in the present study was shorter than the effect of methadone in stabilizing withdrawal symptoms. Thus, it is likely that a once-daily dose of methadone, albeit effective for preventing withdrawal, may not be sufficient to improve mood in some patients. Finally, it was established that CYP3A activity, years of dependent use, sex, and age are major determinants of methadone EC50 with respect to TMDS. PMID- 22926602 TI - Impact of switching or initiating antipsychotic treatment on body weight during a 6-month follow-up in a cohort of patients with schizophrenia. AB - OBJECTIVE: Although weight gain is one of the most widely studied adverse effects of second-generation antipsychotics, only relatively few studies have specifically evaluated the long-term effect of switching antipsychotic medication on body weight. We aimed to evaluate the impact of switching antipsychotics on body mass index (BMI) during a 6-month follow-up period in a large cohort of patients with schizophrenia. METHOD: Data came from a 6-month prospective naturalistic survey in 6007 patients with schizophrenia. RESULTS: We prospectively studied the effect on BMI of initiating or switching antipsychotic medication after 6 months of treatment among 3801 patients with schizophrenia in a real-life setting. Patients who were being treated with clozapine or olanzapine at baseline were more likely to experience a decrease in BMI during the follow-up period than the patients who were being treated with a conventional antipsychotic (odds ratio, 2.25 and 1.68, respectively). Patients treated with aripiprazole and, to a lesser extent, those treated with risperidone were more likely to experience a decrease in BMI during follow-up than patients treated with conventional antipsychotics (odds ratio, 2.96 and 2.06, respectively). CONCLUSIONS: Our findings suggest that switching antipsychotics could be an effective strategy for reducing or preventing weight gain. PMID- 22926603 TI - Predictors of clozapine response in patients with treatment-refractory schizophrenia: results from a Danish Register Study. AB - We aimed to identify factors associated with greater clozapine response to guide targeted clozapine use. The study was based on data from the Danish Psychiatric Central Research Register and the National Prescription Database including schizophrenia patients initiating clozapine from 1997 to 2006. Cox regression was used to identify predictors of time to psychiatric hospitalization and all-cause discontinuation from first clozapine prescription. In a 2-year mirror-image design, multiple logistic regression models were used to identify predictors of psychiatric hospitalization. Among 633 schizophrenia patients starting clozapine, shorter time to admission was predicted by increasing number of different antipsychotics (hazard ratio [HR], 1.08/trial; confidence interval [CI], 1.01 1.15/trial) and admissions (HR, 1.04/admission; CI, 1.03-1.05/admission) before first clozapine prescription, earlier onset of schizophrenia (HR, 0.98/y; CI, 0.96-0.99/y), and lower clozapine dose (HR, 0.07/100 mg; CI, 0.03-0.13/100 mg). In the 2-year mirror-image model, during clozapine treatment, there was a significant reduction in bed-days (269.9 days [CI, 238.3-287.8 days] to 64.2 days [CI, 53.0-79.3 days], P < 0.001) and admissions (3.4 [CI, 3.1-3.6] to 2.2 [CI, 1.9-2.5], P < 0.011). Being admitted during clozapine treatment was also associated with more antipsychotic trials (odds ratio [OR], 1.11; CI, 1.00-1.22) and admissions before clozapine initiation (OR, 1.08; CI, 1.04-1.11) and female sex (OR, 1.84; CI, 1.31-2.58). Although the study design does not allow any causal inferences, all 3 models suggested a lower number of psychiatric hospitalizations and antipsychotic trials before clozapine initiation to be associated with greater clozapine response. PMID- 22926604 TI - Add-on treatment of quetiapine for fibromyalgia: a pilot, randomized, double blind, placebo-controlled 12-week trial. AB - Recently, second-generation antipsychotic drugs have attracted interest in the treatment of chronic pain, including fibromyalgia (FM). Preliminary uncontrolled studies have shown that quetiapine treatment may be helpful for FM patients. In this trial, we sought to examine-for the first time-the efficacy and tolerability of quetiapine as a treatment for FM and its associated psychiatric symptoms. This was a 12-week double-blind, randomized, placebo-controlled trial of quetiapine XR as an add-on treatment for FM syndrome. Fifty-one female FM patients were randomized, and a flexible dosage of 50 to 300 mg/d was used. The primary outcome was the change from baseline to end point in the Fibromyalgia Impact Questionnaire total score. Secondary outcomes included mood symptoms, sleep disturbances, and tender points. Using a low dose (mean = 132.2 mg) of quetiapine, we observed significant benefits of drug treatment on sleep, uncertain effects on FM and mood symptoms, but no effects on pain, in a small group of polymedicated FM patients. Quetiapine was generally well tolerated. PMID- 22926605 TI - Parkinsonism in elderly users of haloperidol: associated with dose, plasma concentration, and duration of use. AB - Factors that influence the variation in occurrence of antipsychotic-induced parkinsonism (AIP) in the elderly have not been well elucidated. The aim of this study was to investigate the association between parkinsonism in elderly users of haloperidol and prescribed dose, plasma concentration, and duration of use of haloperidol in a cross-sectional design. This study included 150 inpatients aged 65 years and older who were treated with haloperidol. Parkinsonism assessed by the Simpson Angus Scale was present in 46% of the included patients. Prescribed haloperidol dose varied from 0.3 to 5 mg/d. Plasma concentration ranged from 0.13 to 4.11 MUg/L, with one outlying measurement (21.43 MUg/L). Dose is moderate but significantly associated with haloperidol plasma concentration (weighted R2 = 0.32; P < 0.001). Variability in the total score on the Simpson Angus Scale could not be explained by the variability in dose, concentration (respectively R2 = 0.003 and 0.001) nor duration of use of haloperidol. Smoking showed to be not significantly protective in the development of AIP (crude odds ratio, 0.39; 95% confidence interval, 0.15-0.997; and adjusted odds ratio, 0.44; 95% confidence interval, 0.17-1.17). In a clinical practice-setting dose, neither plasma concentration nor duration of use of haloperidol is associated with an increased occurrence of AIP. This study does not support the hypothesis of the peripheral pharmacokinetic explanation for the high prevalence of AIP and differences in AIP sensitivity in the elderly during treatment with haloperidol. PMID- 22926606 TI - Akathisia and suicidal ideation in first-episode schizophrenia. AB - Patients with first-episode schizophrenia (FES) are known to be notably sensitive for developing extrapyramidal adverse effects, but the relation of akathisia and suicidal ideation has rarely been studied. The current report is an ongoing analysis of an 8-week double-blind randomized controlled multicenter trial in 289 FES, comparing risperidone and haloperidol. Assessments were conducted weekly and included the Hillside Akathisia Scale and 21-item Hamilton Depression Rating Scale ratings. Suicidal ideation was significantly associated with clinician observed akathisia, depressed mood, younger age, and use of propranolol. The allocated treatment, anxiety, and nervousness had no influence. The present findings suggest a promoting effect of akathisia on suicidal ideation can not be ruled out in patients with FES. PMID- 22926607 TI - Omega-3 fatty acid treatment, with or without cytidine, fails to show therapeutic properties in bipolar disorder: a double-blind, randomized add-on clinical trial. AB - OBJECTIVE: This study aimed to test the effects of omega-3 fatty acids (O3FA), given as fish oil capsules, with and without oral cytidine (CYT), a pyrimidine with reported preclinical and clinical antidepressant-like effects, in patients with bipolar disorder (BD). METHODS: A total of 45 outpatients with diagnosed BD (type I) according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition - Text Revision, were recruited for this 4-month, randomized, double-blind, placebo-controlled, add-on study. Treatment groups were (1) oral CYT + O3FA, (2) placebo + O3FA, and (3) placebo + placebo control. O3FA was given 2 g twice a day and CYT was administered as 1 g twice a day. RESULTS: There was no statistically significant difference among the groups in the primary outcome: study retention. Clinical measures improved in all treatment groups, and there were no significant differences between groups, including change in probability of symptoms of depression or mania, change in positive ratings of depression or mania, or change in Global Assessment of Functioning scores. Neither CYT + O3FA nor placebo + O3FA treatment was superior to placebo treatment. Rather, there was a statistically nonsignificant trend for both groups treated with O3FA to do worse than the placebo group. CONCLUSIONS: Despite preclinical studies suggesting that the effect of O3FA might be augmented with pyrimidines, add-on CYT did not substantially improve mood symptoms in BD. In addition, although a power analysis indicated that the sample size would be adequate to see beneficial effects similar to those previously reported, O3FA treatment by itself was not superior to placebo for BD. PMID- 22926608 TI - A method to assess the dissipation of the [corrected] residual effects of [corrected] hypnotics: eszopiclone versus zopiclone. AB - Next-day residual effects of single evening doses of 3 mg of eszopiclone, 7.5 mg of zopiclone, and placebo were assessed in a randomized, double-blind, placebo controlled, 3-way crossover study that used a mild sleep restriction protocol (sleep duration, 7 hours). During each period, 91 healthy volunteers spent 2 consecutive nights in the laboratory with time in bed restricted to 7 hours. Volunteers completed the Continuous Tracking Test, Critical Flicker Fusion task, Digit Symbol Substitution Test, N-back tasks, and Linear Analogue Rating Scales every half-hour from 7.5 to 11.5 hours after dose, commencing 15 minutes after awakening. Nighttime dosing of both eszopiclone (3 mg) and racemic zopiclone (7.5 mg) was associated with next-day performance impairment, and these residual effects dissipated over time. Eszopiclone did not differ from zopiclone on the primary end point, mean Continuous Tracking Test tracking error averaged from 7.5 to 9.5 hours after dose; however, a prespecified post hoc parametric analysis of reciprocal-transformed data favored eszopiclone over racemic zopiclone (P = 0.026). PMID- 22926609 TI - Suspected and confirmed fatalities associated with mephedrone (4 methylmethcathinone, "meow meow") in the United Kingdom. AB - BACKGROUND: International media have been reporting about fatalities allegedly related to mephedrone, a popular recreational stimulant, but now a proportion of them have been confirmed. We aimed here at analyzing information relating to the circumstances of mephedrone-related deaths in the United Kingdom. METHODS: Descriptive analysis of information was mainly extracted from the UK National Programme on Substance Abuse Deaths database. With an average annual response rate of 95%, UK National Programme on Substance Abuse Deaths receives information from coroners on drug-related deaths among both addicts and nonaddicts in the United Kingdom, the Channel Islands, and the Isle of Man. RESULTS: So far, 128 alleged mephedrone-associated fatalities have been reported; mephedrone was identified at postmortem in 90 cases; inquests have been concluded in 69 cases, 62 of which are analyzed here. Typical mephedrone victims were young (mean age, 28.8 years), male, and with a previous history of drug misuse. There was a notable number (18 cases [29%], 11 being from hanging) of deaths involving self harm. Mephedrone alone was identified at postmortem on 8 occasions (13% of the inquests' sample). CONCLUSIONS: Present mortality data may suggest a significant level of caution when ingesting mephedrone. Limitations include an inability to determine the exact extent of risks associated with mephedrone consumption. PMID- 22926610 TI - Association between HTR2C polymorphisms and obesity in patients without antipsychotic drugs. PMID- 22926611 TI - Clozapine levels might be affected by excessive cola consumption. PMID- 22926612 TI - Ropinirole as an effective adjunctive treatment for clozapine-resistant negative symptoms in simple schizophrenia: a case report. PMID- 22926613 TI - Rabbit syndrome following discontinuation of paliperidone in a patient with schizoaffective disorder. PMID- 22926614 TI - Characteristics of quetiapine misuse among clients of a community-based methadone maintenance program. PMID- 22926615 TI - Duloxetine-associated tardive dyskinesia resolved with fluvoxamine: a case report. PMID- 22926616 TI - DRD3, but not BDNF, genotype affects treatment response to paroxetine in major depressive disorder: a preliminary study. PMID- 22926617 TI - Treatment of late-life major depressive disorder with selective serotonin reuptake inhibitors improves the multidimensional prognostic index. PMID- 22926618 TI - Serotonin-norepinephrine reuptake inhibitor treatment for tinnitus and depression. PMID- 22926619 TI - Restoration of functionality in postpartum depressed mothers: an open-label study with escitalopram. PMID- 22926620 TI - Agomelatine may improve REM sleep behavior disorder symptoms. PMID- 22926621 TI - Mania related to mesterolone in a previously mentally healthy person. PMID- 22926622 TI - Purinergic system in the treatment of bipolar disorder: uric acid levels as a screening test in mania. PMID- 22926623 TI - Mephenesin dependence: a case series. PMID- 22926624 TI - Ramelteon dose escalation in a patient with substance misuse. PMID- 22926625 TI - Treatment with triptorelin in mentally disordered sex offenders: experience from a maximum-security hospital. PMID- 22926627 TI - Review of reactive kinetic models describing reductive dechlorination of chlorinated ethenes in soil and groundwater. AB - Reductive dechlorination is a major degradation pathway of chlorinated ethenes in anaerobic subsurface environments, and reactive kinetic models describing the degradation process are needed in fate and transport models of these contaminants. However, reductive dechlorination is a complex biological process, where many microbial populations including dechlorinating, fermentative, methanogenic, iron and sulfate reducing, interact. In this article the modeling approaches and the experimental data needed to calibrate them are reviewed, classified, and discussed. Model approaches considered include first order kinetics, Monod kinetics to describe sequential reductive dechlorination and bacterial growth, and metabolic models which simulate fermentation and redox processes interacting with reductive dechlorination processes. The review shows that the estimated kinetic parameters reported vary over a wide range, and that experimental microbial data are scarce. Very few studies have been performed evaluating the influence of sulfate and iron reduction, and contradictory conclusions on the interaction of redox processes with reductive dechlorination have been reported. The modeling approaches for metabolic reductive dechlorination employing different descriptions of the interaction between redox and dechlorination processes and competition for hydrogen are classified. The current concepts lead to different results, suggesting a need for further investigations on the interactions between the microbial communities performing dechlorination and redox processes, including the establishment of biomarkers quantifying dechlorination, and on geochemical characterization. Finally, the relevance of laboratory data and the development of practical modeling tools for field applications are discussed. PMID- 22926628 TI - Associations between interleukin-6 gene -174 C/G and -572 C/G polymorphisms and risk of gastric cancer. PMID- 22926626 TI - Examining acute and chronic effects of short- and long-chain fatty acids on peptide YY (PYY) gene expression, cellular storage and secretion in STC-1 cells. AB - PURPOSE: Peptide YY (PYY) is a gastrointestinal hormone with physiological actions regulating appetite and energy homoeostasis. The cellular mechanisms by which nutrients stimulate PYY secretion from intestinal enteroendocrine cells are still being elucidated. METHODS: This study comprehensively evaluated the suitability of intestinal STC-1 cells as an in vitro model of PYY secretion. PYY concentrations (both intracellular and in culture media) with other intestinal peptides (CCK, GLP-1 and GIP) demonstrated that PYY is a prominent product of STC 1 cells. Furthermore, acute and chronic PYY responses to 15 short (SCFAs)- and long-chain (LCFAs) dietary fatty acids were measured alongside parameters for DNA synthesis, cell viability and cytotoxicity. RESULTS: We found STC-1 cells to be reliable secretors of PYY constitutively releasing PYY into cell culture media (but not into non-stimulatory buffer). We demonstrate for the first time that STC 1 cells produce PYY mRNA transcripts; that STC-1 cells produce specific time- and concentration-dependent PYY secretory responses to valeric acid; that linoleic acid and conjugated linoleic acid 9,11 (CLA 9,11) are potent PYY secretagogues; and that chronic exposure of SCFAs and LCFAs can be detrimental to STC-1 cells. CONCLUSIONS: Our studies demonstrate the potential usefulness of STC-1 cells as an in vitro model for investigating nutrient-stimulated PYY secretion in an acute setting. Furthermore, our discovery that CLA directly stimulates L-cells to secrete PYY indicates another possible mechanism contributing to the observed effects of dietary CLA on weight loss. PMID- 22926629 TI - Flow diversion treatment: intra-aneurismal blood flow velocity and WSS reduction are parameters to predict aneurysm thrombosis. AB - BACKGROUND: To evaluate the haemodynamic changes induced by flow diversion treatment in cerebral aneurysms, resulting in thrombosis or persisting aneurysm patency over time. METHOD: Eight patients with aneurysms at the para-ophthalmic segment of the internal carotid artery were treated by flow diversion only. The clinical follow-up ranged between 6 days and 12 months. Computational fluid dynamics (CFD) analysis of pre- and post-treatment conditions was performed in all cases. True geometric models of the flow diverter were created and placed over the neck of the aneurysms by using a virtual stent-deployment technique, and the device was simulated as a true physical barrier. Pre- and post-treatment haemodynamics were compared, including mean and maximal velocities, wall-shear stress (WSS) and intra-aneurysmal flow patterns. The CFD study results were then correlated to angiographic follow-up studies. RESULTS: Mean intra-aneurysmal flow velocities and WSS were significantly reduced in all aneurysms. Changes in flow patterns were recorded in only one case. Seven of eight aneurysms showed complete occlusion during the follow-up. One aneurysm remaining patent after 1 year showed no change in flow patterns. One aneurysm rupturing 5 days after treatment showed also no change in flow pattern, and no change in the maximal inflow velocity. CONCLUSIONS: Relative flow velocity and WSS reduction in and of itself may result in aneurysm thrombosis in the majority of cases. Flow reductions under aneurysm specific thresholds may, however, be the reason why some aneurysms remain completely or partially patent after flow diversion. PMID- 22926630 TI - Advanced hybrid stress testing: a potential new paradigm combining exercise and pharmacologic stress. PMID- 22926633 TI - Electronic health record impact on work burden in small, unaffiliated, community based primary care practices. AB - BACKGROUND: The use of electronic health records (EHR) is widely recommended as a means to improve the quality, safety and efficiency of US healthcare. Relatively little is known, however, about how implementation and use of this technology affects the work of clinicians and support staff who provide primary health care in small, independent practices. OBJECTIVE: To study the impact of EHR use on clinician and staff work burden in small, community-based primary care practices. DESIGN: We conducted in-depth field research in seven community-based primary care practices. A team of field researchers spent 9-14 days over a 4-8 week period observing work in each practice, following patients through the practices, conducting interviews with key informants, and collecting documents and photographs. Field research data were coded and analyzed by a multidisciplinary research team, using a grounded theory approach. PARTICIPANTS: All practice members and selected patients in seven community-based primary care practices in the Northeastern US. KEY RESULTS: The impact of EHR use on work burden differed for clinicians compared to support staff. EHR use reduced both clerical and clinical staff work burden by improving how they check in and room patients, how they chart their work, and how they communicate with both patients and providers. In contrast, EHR use reduced some clinician work (i.e., prescribing, some lab related tasks, and communication within the office), while increasing other work (i.e., charting, chronic disease and preventive care tasks, and some lab-related tasks). Thoughtful implementation and strategic workflow redesign can mitigate the disproportionate EHR-related work burden for clinicians, as well as facilitate population-based care. CONCLUSIONS: The complex needs of the primary care clinician should be understood and considered as the next iteration of EHR systems are developed and implemented. PMID- 22926634 TI - Factors associated with non-adherence to three hypertension self-management behaviors: preliminary data for a new instrument. AB - BACKGROUND: Clinicians have difficulty in identifying patients that are unlikely to adhere to hypertension self-management. Identifying non-adherence is essential to addressing suboptimal blood pressure control and high costs. OBJECTIVES: 1) To identify risk factors associated with non-adherence to three key self-management behaviors in patients with hypertension: proper medication use, diet, and exercise; 2) To evaluate the extent to which an instrument designed to identify the number of risk factors present for non-adherence to each of the three hypertension self-management behaviors would be associated with self-management non-adherence and blood pressure. DESIGN: Cross-sectional analysis of randomized trial data. PATIENTS: Six hundred and thirty-six primary care patients with hypertension. MEASUREMENTS: 1) Demographic, socioeconomic, psychosocial, and health belief-related factors; 2) measures of self-reported adherence to recommended medication use, diet recommendations, and exercise recommendations, all collected at baseline assessment; 3) systolic blood pressure (SBP) and diastolic blood pressure (DBP). RESULTS: We identified patient factors associated with measures of non-adherence to medications, diet, and exercise in hypertension. We then combined risk factors associated with >=1 adherence measure into an instrument that generated three composite variables (medication, diet, and exercise composites), reflecting the number of risk factors present for non adherence to the corresponding self-management behavior. These composite variables identified subgroups with higher likelihood of medication non adherence, difficulty following diet recommendations, and difficulty following exercise recommendations. Composite variable levels representing the highest number of self-management non-adherence risk factors were associated with higher SBP and DBP. CONCLUSIONS: We identified factors associated with measures of non adherence to recommended medication use, diet, and exercise in hypertension. We then developed an instrument that was associated with non-adherence to these self management behaviors, as well as with blood pressure. With further study, this instrument has potential to improve identification of non-adherent patients with hypertension. PMID- 22926635 TI - Prevention of mother-to-infant transmission of influenza during the postpartum period. AB - OBJECTIVES: The optimal management of infants born to mothers with peripartum influenza infection is not known. The objective of this study is to describe our experience with a practice guideline that promotes rooming-in and breast-feeding and to determine whether infants managed in this way acquire influenza infection. STUDY DESIGN: All mothers diagnosed with influenza infection within 8 days of delivery and their infants were included. Demographics, clinical characteristics, and outcome data were collected. Mothers were contacted at ~1 month after giving birth to determine if their infants had developed any signs suggestive of influenza infection. RESULTS: Forty-two women were diagnosed with peripartum influenza over the 2003 to 2005 and 2009 to 2010 seasons. Median onset of symptoms was 3 days before delivery, and median day of diagnosis was 1 day before delivery. The 42 infants had a median gestational age of 39 weeks; none were born earlier than 35 weeks. Ninety-five percent of the infants roomed-in with their mothers. Follow-up information was available on 95% of infants by 1 month; no infants had illness suggestive of influenza through the follow-up period. CONCLUSION: A guideline for the management of infants born to mothers with peripartum influenza infection, based on attention to hand hygiene, antiviral treatment for mothers, and encouragement of rooming-in and breast-feeding, was not associated with mother-to-infant influenza transmission over three separate influenza seasons. PMID- 22926637 TI - A phase I and pharmacokinetic study of elisidepsin (PM02734) in patients with advanced solid tumors. AB - PURPOSE: To determine the maximum-tolerated dose (MTD), dose-limiting toxicity (DLT), and recommended phase II dose (RD) of elisidepsin. METHODS: Eligible patients with refractory, advanced solid tumors received elisidepsin as 24-h intravenous infusion every 3 weeks. Pharmacokinetic profiles were analyzed during cycles 1 and 2. RESULTS: Forty-two patients received elisidepsin at doses from 0.5 to 6.8 mg/m(2). The MTD was 6.8 mg/m(2), and the RD was 5.5 mg/m(2). Cohort expansion at the RD was done at a fixed dose (FD) of 10 mg, considered equivalent to 5.5 mg/m(2). DLTs (reversible grade 3 transaminase increases) occurred at 6.8 mg/m(2) (n = 2 patients), 5.5 mg/m(2) (n = 1), and 10 mg FD (n = 1). One patient with esophageal adenocarcinoma achieved complete response for >38 months, and 12 patients had disease stabilization (8 for >=3 months). Median time-to-progression for these 12 patients was 4.8 months. Plasma elisidepsin concentrations increased with dose. No drug accumulation between cycles was found. No correlation was observed between body surface area (BSA) and plasma clearance; therefore, elisidepsin was given as flat dose (in mg) in the expansion cohort at the RD and in ongoing clinical trials. CONCLUSIONS: Elisidepsin is well tolerated with predictable reversible transaminase increases. Encouraging preliminary evidence of antitumor activity was observed. PMID- 22926638 TI - A phase II study of docetaxel and oxaliplatin combination in recurrent gastric cancer patients after fluoropyrimidine and/or cisplatin adjuvant treatment: a Korean Cancer Study Group Protocol ST06-02. AB - BACKGROUND: Surgery alone is no longer an adequate standard of care for patients with resectable gastric cancer. Thus, research efforts should focus on which regimens are the most effective for patients with recurrent gastric cancer after combined treatment with surgery and perioperative or adjuvant chemotherapy. METHODS: Patients with histologically confirmed and measurable advanced gastric cancer who showed a relapse even after fluoropyrimidine and/or cisplatin-based adjuvant chemotherapy received docetaxel (35 mg/m(2)) intravenously on day 1 and 8 plus oxaliplatin (100 mg/m(2)) intravenously on day 1 every 3 weeks until disease progression or unacceptable toxicity. RESULTS: A total of 34 patients with relapsed advanced gastric cancer who had received adjuvant chemotherapy with fluoropyrimidine and/or cisplatin for a median of 6 months (range, 1-48 months) were enrolled in this trial; 22 (64.7 %) patients had been exposed to both agents. Their median age was 58 years (range, 50-68 years). The overall response rate was 55.9 % (95 % confidence interval (CI), 38.3-73.5 %), including 1 complete response and 18 partial responses. At a median follow-up duration of 28.5 months (range, 9.2-50.7 months), the median progression-free survival for all patients was 5.3 months (95 % CI, 4.4-6.1 months) and the median overall survival was 13.8 months (95 % CI, 11.1-16.4 months). The most common grade 3 or 4 hematologic and nonhematologic toxicities were neutropenia (47.1 %) and diarrhea (17.6 %), respectively. Five patients (14.7 %) experienced febrile neutropenia. CONCLUSIONS: Docetaxel and oxaliplatin combination chemotherapy was active and tolerable in patients with recurrent gastric cancer after fluoropyrimidine and/or cisplatin-based adjuvant chemotherapy. PMID- 22926639 TI - Molecular-targeted therapies for ovarian cancer. PMID- 22926641 TI - Toxicological effects of environmentally relevant lead and zinc in halophyte Suaeda salsa by NMR-based metabolomics. AB - Lead (Pb) and zinc (Zn) are two typical metal contaminants with high levels in both seawater and sediment in the intertidal zones of the Bohai Sea. Suaeda salsa is the pioneer halophyte plant in the intertidal zones of the Bohai Sea. In the present work, the short (1 week) and long term (1 month) toxicological effects of environmentally relevant concentrations of Pb and Zn were characterized in S. salsa using NMR-based metabolomics combined with antioxidant enzyme activities. After metal exposure for 1 week, no significant metabolic responses were detected in root tissues of S. salsa. The significant metabolic responses included the increase of isocaproate, glucose and fructose, and decrease of malate, citrate and sucrose in root tissues of S. salsa exposed to Pb for 1 month. The increased phosphocholine and betaine, and decreased choline were uniquely found in Zn exposed samples. The metabolic changes including decreased malate, citrate and sucrose were detected in both Pb and Zn-exposed groups. These metabolic biomarkers revealed that both Pb and Zn exposures could induce osmotic stress and disturbances in energy metabolism in S. salsa after exposures for 1 month. Overall, this work demonstrates that metabolomics can be used to elucidate toxicological effects of environmentally relevant metal contaminants using halophyte S. salsa as the bioindicator. PMID- 22926640 TI - Clinical trials and future potential of targeted therapy for ovarian cancer. AB - Ovarian cancer is the leading cause of death in women with gynecological cancer. Most patients are diagnosed at an advanced stage with a poor prognosis. Currently, surgical tumor debulking followed by chemotherapy based on platinum and taxane is the standard treatment for advanced disease. However, these patients remain at great risk for recurrence and developing drug resistance. Therefore, new treatment strategies are needed to improve outcomes for patients with advanced and recurrent ovarian cancer. Several agents targeted at particular molecules have been developed for ovarian cancer and are now entering clinical trials. The functional targets of these agents are aberrations in tumor tissues including angiogenesis, the human epidermal growth factor receptor family, poly(ADP-ribose) polymerase (PARP), mammalian target of rapamycin (mTOR) signaling pathway, and alpha-folate receptor (alpha-FR). The anti-angiogenic compound bevacizumab has been reported as the most effective targeted agent. Bevacizumab plus chemotherapy prolonged progression-free survival (PFS) both for advanced and platinum-sensitive recurrent ovarian cancer, but did not increase overall survival. A PARP inhibitor, olaparib, applied as maintenance treatment also improved PFS in platinum-sensitive relapsed ovarian cancer. Furthermore, mTOR inhibitors and a monoclonal antibody to alpha-FR, farletuzumab, are attractive treatment strategies either alone or combined with chemotherapy. Understanding the tumor molecular biology and identifying predictive biomarkers are essential steps in selecting the best treatment strategies. This article reviews available clinical data on the most promising targeted agents for ovarian cancer. PMID- 22926642 TI - The atf2 gene is involved in triacylglycerol biosynthesis and accumulation in the oleaginous Rhodococcus opacus PD630. AB - Rhodococcus opacus PD630 is an oleaginous bacterium able to accumulate large amounts of triacylglycerols (TAG) in different carbon sources. The last reaction for TAG biosynthesis is catalyzed by the bifunctional wax ester synthase/acyl CoA:diacylglycerol acyltransferase (WS/DGAT) enzymes encoded by atf genes. R. opacus PD630 possesses at least 17 putative atf homologous genes in its genome, but only atf1 and atf2 exhibited a significant DGAT activity when expressed in E. coli, as revealed in a previous study. The contribution of atf1 gene to TAG accumulation by strain PD630 has been demonstrated previously, although additional Atfs may also contribute to lipid accumulation, since the atf1 disrupted mutant is still able to produce significant amounts of TAG (Alvarez et al., Microbiology 154:2327-2335, 2008). In this study, we investigated the in vivo role of atf2 gene in TAG accumulation by R. opacus PD630 by using different genetic strategies. The atf2-disrupted mutant exhibited a decrease in TAG accumulation (up to 25-30 %, w/w) and an approximately tenfold increase in glycogen formation in comparison with the wild-type strain. Surprisingly, in contrast to single mutants, a double mutant generated by the disruption of atf1 and atf2 genes only showed a very low effect in TAG and in glycogen accumulation under lipid storage conditions. Overexpression of atf1 and atf2 genes in strain PD630 promoted an increase of approximately 10 % (w/w) in TAG accumulation, while heterologous expression of atf2 gene in Mycobacterium smegmatis caused an increase in TAG accumulation during cultivation in nitrogen-rich media. This study demonstrated that, in addition to atf1 gene, atf2 is actively involved in TAG accumulation by the oleaginous R. opacus PD630. PMID- 22926643 TI - Overexpression of CHOP alone and in combination with chaperones is effective in improving antibody production in mammalian cells. AB - Secretory capacities including folding and assembly are believed to be limiting factors in the establishment of mammalian cell lines producing high levels of recombinant therapeutic proteins. To achieve industrial success, it is also important to improve protein folding, assembly, and secretory processes in combination with increasing transcription and translation. Here, we identified the expression of CHOP/Gadd153 and GRP78, which are unfolded protein response (UPR)-related genes, correlated with recombinant antibody production in stable CHO cells. Subsequently, CHOP overexpression resulted in increasing recombinant antibody production in some mammalian cell lines, and in addition a threefold further enhancement was obtained by combining expression with UPR-related genes or ER chaperones in transient assays. Overexpression of CHOP had no effect on the biochemical characteristics of the product. These results suggest overexpression of CHOP and its combinations may be an effective method to efficiently select a single cell line with a high level of antibody production in the development of cell lines for manufacturing. PMID- 22926644 TI - Characterization of the diatomite binding domain in the ribosomal protein L2 from E. coli and functions as an affinity tag. AB - The ribosomal protein L2, a constituent protein of the 50S large ribosomal subunit, can be used as Si-tag using silica particles for the immobilization and purification of recombinant proteins (Ikeda et al. (Protein Expr Purif 71:91-95, 2010); Taniguchi et al. (Biotechnol Bioeng 96:1023-1029, 2007)). We applied a diatomite powder, a sedimentary rock mainly composed with diatoms silica, as an affinity solid phase and small ubiquitin-like modifier (SUMO) technology to release a target protein from the solid phase. The L2 (203-273) was the sufficient region for the adsorption of ribosomal protein L2 on diatomite. We comparatively analyzed the different adsorption properties of the two deleted proteins of L2 (L2 (1-60, 203-273) and L2 (203-273)) on diatomite. The time required to reach adsorption equilibrium of L2 (203-273) fusion protein on diatomite was shorter than that of L2 (1-60, 203-273) fusion protein. The maximum adsorption capacity of L2 (203-273) fusion protein was larger than that of L2 (1 60, 203-273) fusion protein. In order to study whether the L2 (203-273) can function as an affinity purification tag, SUMO was introduced as one specific protease cleavage site between the target protein and the purification tags. The L2 (203-273) and SUMO fusion protein purification method was tested using enhanced green fluorescent protein as a model protein; the result shows that the purification performance of this affinity purification method was good. The strong adsorption characteristic of L2 (203-273) on diatomite also provides a potential protein fusion tag for the immobilization of enzyme. PMID- 22926645 TI - Establishment and characterization of a novel cell line derived from human thymoma AB tumor. AB - Thymomas are low-grade epithelial tumors of the anterior mediastinum. The complexity of the disease and the lack of in vitro and in vivo models hamper the development of better therapeutics. In this study, we report a novel cell line, designated as IU-TAB-1, which was established from a patient with stage II thymoma (World Health Organization-type AB). The IU-TAB-1 cell line was established in vitro and characterized using histological and immunohistochemical staining, fluorescence-activated cell sorting, cytogenetic analyses and functional assays including in vitro and a NOD/SCID xenograft model. A whole genome gene expression analysis (Illumina) was performed on the IU-TAB-1 cell line and 34 thymomas to determine the clinical relevance of the cell line. The IU TAB-1 cell line was positive for epithelial markers (pan-cytokeratin and EpCAM/CD326) including thymic epithelial (TE) surface markers (such as CD29, CD9, CD54/ICAM-1, CD58 and CD24) and p63, and negative for B- and T-cell lineage markers. Gene expression profiling demonstrated overlapping and distinct genes between IU-TAB-1 and primary thymomas including the primary tumor (from which the cell line was derived). IU-TAB-1 cells are tumorigenic when implanted in immunodeficient mice with tumors reaching a volume of 1000 mm3 at around 130 days. The established cell line represents a biologically relevant new tool to investigate the molecular pathology of thymic malignancies and to evaluate the efficacy of novel therapeutics both in vitro and in vivo. PMID- 22926646 TI - Maxacalcitol ameliorates tubulointerstitial fibrosis in obstructed kidneys by recruiting PPM1A/VDR complex to pSmad3. AB - Tubulointerstitial fibrosis (TIF) is one of the major problems in nephrology because satisfactory therapeutic strategies have not been established. Here, we demonstrate that maxacalcitol (22-oxacalcitriol (OCT)), an analog of active vitamin D, protects the kidney from TIF by suppressing the autoinduction of transforming growth factor-beta1 (TGF-beta1). OCT suppressed the tubular injury index, interstitial volume index, collagen I positive area, and mRNA levels of extracellular matrix genes in unilateral ureteral-obstructed kidneys in rats. Although the renoprotective mechanism of active vitamin D in previous studies has been mainly attributed to the suppression of renin, OCT did not affect renal levels of renin or angiotensin II. We found that TGF-beta1 itself induces its expression in a phospho-Smad3 (pSmad3)-dependent manner, and that OCT ameliorated TIF by abrogating this 'autoinduction'. Under the stimulation of TGF-beta1, pSmad3 bound to the proximal promoter region of the TGF-beta1 gene. Both OCT and SIS3, a Smad3 inhibitor, abrogated the binding of pSmad3 to the promoter and consequently attenuated the autoinduction. TGF-beta1 increased both the nuclear levels of protein phosphatase Mg(2+)/Mn(2+)-dependent 1A (PPM1A), a pSmad3 phosphatase, and the interaction levels between the vitamin D receptor (VDR) and PPM1A. In the absence of OCT, however, the interaction between pSmad3 and PPM1A was weak; therefore, it was insufficient to dephosphorylate pSmad3. The PPM1A/VDR complex was recruited to pSmad3 in the presence of both TGF-beta1 and OCT. This recruitment promoted the dephosphorylation of pSmad3 and attenuated the pSmad3 dependent production of TGF-beta1. Our findings provide a novel approach to inhibit the TGF-beta pathway in fibrotic diseases. PMID- 22926647 TI - Widespread trypanosome infections in a population of eastern hellbenders (Cryptobranchus alleganiensis alleganiensis) in Virginia, USA. AB - Eastern hellbender salamanders (Cryptobranchus alleganiensis alleganiensis) are declining in North America and because of this the health status of individuals in several populations is closely monitored by researchers. During a health survey of hellbenders from a stream in Smyth County, VA, USA, we examined Giemsa stained blood smears of 71 animals captured during 2011 for the presence of blood parasites. We discovered an unknown species of trypanosome that was apparently widespread within this population; 40 of the 71 individuals (56.3 %) were infected. There are seven known trypanosome species of caudate amphibians; based on microscopic examination, the parasite we observed appeared most similar to Trypanosoma cryptobranchi, which was reported in this species only once before, 76 years ago, from a single animal apparently captured in Iowa. Given that some trypanosomes can adversely affect the health of their hosts, we recommend further monitoring be done in this and other hellbender populations to determine the geographic extent of the parasite and its effects on its increasingly rare host. PMID- 22926648 TI - Hemozoin accumulation in Garnham bodies of Plasmodium falciparum gametocytes. AB - Garnham bodies are curious objects exclusive in erythrocytes containing sexual forms (gametocytes) of Plasmodium falciparum. Although the name is familiar, only a few photographs of Garnham bodies (G-bodies) have been published. Considering that other objects in malaria-infected erythrocytes, such as Schuffner's dots of Plasmodium vivax and Maurer's clefts of P. falciparum, have been found to have some functions, it has become necessary to pay closer attention to G-bodies. The present study presents previously unknown features of G-bodies and suggests a protective role for them. Wild isolates of P. falciparum were encouraged to grow in vitro under conditions that promote gametocytogenesis. Thin and thick smears of the cells were stained with Giemsa stain and examined under a light microscope. Production of G-bodies was detected in two isolates both in immature and mature gametocytes. Sometimes, the objects are found both at the top and below the parasite, contrary to previous suggestion of it being only on one side. They are highly diverse in morphology, including those that are shaped like m or S. Hemozoin accumulation was detected in some of the bodies, indicating direct opening into the cystoplasm of the parasite. It is possible that hemozoin was first produced in the parasite's food vacuole before being transported to G bodies. Alternatively, hemoglobin transport vesicles could first accumulate in G bodies where metabolically released ferriprotoporphyrin IX (FP) could be polymerized; but this would need acidic environment comparable to that in food vacuole. Electron microscopy has revealed that G-bodies consist of membranous whorls and it has been demonstrated experimentally that both infected and uninfected membranes promote beta-hematin formation. Whatever the mechanism, storing hemozoin in G-bodies outside the cytoplasm of the parasite could provide intraerythrocytic sexual forms of P. falciparum additional protection against FP toxicity. PMID- 22926649 TI - A review of the validity and reliability of alcohol retail sales data for monitoring population levels of alcohol consumption: a Scottish perspective. AB - AIMS: To assess the validity and reliability of using alcohol retail sales data to measure and monitor population levels of alcohol consumption. METHODS: Potential sources of bias that could lead to under- or overestimation of population alcohol consumption based on alcohol retail sales data were identified and, where possible, quantified. This enabled an assessment of the potential impact of each bias on alcohol consumption estimates in Scotland. RESULTS: Overall, considering all the possible sources of overestimation and underestimation, and taking into account the potential for sampling variability to impact on the results, the range of uncertainty of consumption during 2010 was from an overestimate of 0.3 l to an underestimate of 2.4 l of pure alcohol per adult. This excludes the impacts of alcohol stockpiling and alcohol sold through outlets not included in the sampling frame. On balance, there is therefore far greater scope for alcohol retail sales data to be underestimating per adult alcohol consumption in Scotland than there is for overestimation. CONCLUSION: Alcohol retail sales data offer a robust source of data for monitoring per adult alcohol consumption in Scotland. Consideration of the sources of bias and a comprehensive understanding of data collection methods are essential for using sales data to monitor trends in alcohol consumption. PMID- 22926650 TI - Genetic variability and clinical spectrum of Chinese patients with limb-girdle muscular dystrophy type 2A. AB - INTRODUCTION: Previous studies of limb-girdle muscular dystrophy type 2A (LGMD2A) patients in many countries have suggested a heterogeneous genetic and clinical spectrum, but the genotypes and phenotypes of Chinese LGMD2A patients remain unclear. METHODS: We directly screened calpain-3 (CAPN3) in 18 Chinese Han subjects who exhibited severely reduced or completely absent calpain-3 expression, as determined by Western blot analysis. We subsequently analyzed genotype/phenotype correlations. RESULTS: Seventeen patients (94.4%) were identified who had at least 1 causative mutation. All 18 mutations were distributed along the entire gene, and 11 of the mutations were novel, including 4 missense mutations, 5 deletions, and 2 splicing mutations. The phenotypes of these Chinese LGMD2A patients varied from severe LGMD to distal myopathy, and even asymptomatic hyper-CK-emia. CONCLUSIONS: No evidential correlation was found between the genotypes and phenotypes of the patients assessed in this study. Western blot analysis is still a useful diagnostic method when genetic analysis is unavailable. PMID- 22926651 TI - Respiratory dialysis with an active-mixing extracorporeal carbon dioxide removal system in a chronic sheep study. AB - PURPOSE: The objective of this study was to demonstrate the safety and performance of a unique extracorporeal carbon dioxide removal system (Hemolung, ALung Technologies, Pittsburgh, PA) which incorporates active mixing to improve gas exchange efficiency, reduce exposure of blood to the circuit, and provide partial respiratory support at dialysis-like settings. METHODS: An animal study was conducted using eight domestic crossbred sheep, 6-18 months of age and 49-115 kg in weight. The sheep were sedated and intubated, and a 15.5-Fr dual lumen catheter was inserted into the right jugular vein. The catheter was connected to the extracorporeal circuit primed with heparinized saline, and flow immediately initiated. The animals were then awakened and encouraged to stand. The animals were supported in a stanchion and monitored around the clock. Anticoagulation was maintained with heparin to achieve an aPTT of 46-70 s. RESULTS: Measurements included blood flow rate through the device, carbon dioxide exchange rate, pump speed and sweep gas flow rate. Safety and biocompatibility measurements included but were not limited to plasma-free hemoglobin, hematocrit, white blood cell count, platelet count and fibrinogen. The Hemolung removed clinically significant amounts of carbon dioxide, more than 50 ml/min, at low blood flows of 350-450 ml/min, with minimal adverse effects. CONCLUSIONS: The results of 8-day trials in awake and standing sheep supported by the Hemolung demonstrated that this device can consistently achieve clinically relevant levels of carbon dioxide removal without failure and without significant risk of adverse reactions. PMID- 22926652 TI - The repeatability of Stewart's parameters and anion gap in a cohort of critically ill adult patients. AB - PURPOSE: To examine the repeatability of Stewart's parameters and anion gap in a cohort of critically ill patients and to determine the smallest detectable changes in individual patients. METHODS: A total of 161 patients were included prospectively. They underwent two subsequent blood samplings within 10 min of each other and samples were analyzed using the same central laboratory analyzer. Measured and calculated parameters from the two samples were compared. The repeatability was expressed as the smallest detectable difference (SDD), coefficient of variation (CV) and intraclass correlation coefficient (ICC). RESULTS: The mean differences +/- SD (mEq/L) for the repeated measurements were 0.1 +/- 0.76, 0.12 +/- 0.68, -0.02 +/- 1.02, and -0.08 +/- 1.05 for the apparent strong ion difference (SID(app)), effective strong ion difference (SID(eff)), strong ion gap (SIG), and albumin-corrected anion gap (AG(corr)), respectively. The SDDs (mEq/L) for SID(app), SID(eff), SIG, and AG(corr), were +/-1.49, +/ 1.33, +/-2, and +/-2.06, respectively. The CVs (%) for these variables were 1.4, 1.45, 13.3, and 4.15, respectively. The ICCs for all these variables were high, largely above 0.75. CONCLUSIONS: The repeatability of all these calculated variables was good. In repeated measurements, a change in value of these parameters exceeding 1.96?2 CV (%), the least significant change (LSC) or the SDD should be regarded as significant. Use of SDD is preferable to CV and LSC (%) because of its independence from the levels of variables and its expression in absolute units. Expressed as SDD, a SIG change value, e.g., of at least +/-2 mEq/L should be significant. PMID- 22926654 TI - Evaluation through column leaching tests of metal release from contaminated estuarine sediment subject to CO2 leakages from Carbon Capture and Storage sites. AB - The pH change and the release of organic matter and metals from sediment, due to the potential CO(2) acidified seawater leakages from a CCS (Carbon Capture and Storage) site are presented. Column leaching test is used to simulate a scenario where a flow of acidified seawater is in contact with recent contaminated sediment. The behavior of pH, dissolved organic carbon (DOC) and metals As, Cd, Cr, Cu, Ni, Pb, Zn, with liquid to solid (L/S) ratio and pH is analyzed. A stepwise strategy using empirical expressions and a geochemical model was conducted to fit experimental release concentrations. Despite the neutralization capacity of the seawater-carbonate rich sediment system, important acidification and releases are expected at local scale at lower pH. The obtained results would be relevant as a line of evidence input of CCS risk assessment, in an International context where strategies to mitigate the climate change would be applied. PMID- 22926655 TI - Sorption kinetics of ofloxacin in soils and mineral particles. AB - The environmental behavior of antibiotics is not well known and the precise environmental risk assessment is not practical. This study investigated the sorption kinetics of ofloxacin, a widely used antibiotics, on soil particles with different organic carbon contents as well as soil components (a humic acid, ferric oxide and kaolinite). Two-compartment sorption kinetics were mathematically recognized (except ferric oxide because of its very fast sorption). The apparent sorption rate and the contribution of fast sorption compartment decreased with the increased organic carbon content with the exception of humic acid, suggesting that the slow sorption sites were partially located in organo-mineral complex. The OFL concentration-dependent sorption kinetics suggested that the slow sorption compartment was not controlled by diffusion process as indicated by slower sorption at higher OFL loading. The difference between OFL sorption kinetics and those of hydrophobic organic contaminants was discussed and possible mechanism of OFL two-compartment sorption was proposed. PMID- 22926653 TI - The Berlin definition of ARDS: an expanded rationale, justification, and supplementary material. AB - PURPOSE: Our objective was to revise the definition of acute respiratory distress syndrome (ARDS) using a conceptual model incorporating reliability and validity, and a novel iterative approach with formal evaluation of the definition. METHODS: The European Society of Intensive Care Medicine identified three chairs with broad expertise in ARDS who selected the participants and created the agenda. After 2 days of consensus discussions a draft definition was developed, which then underwent empiric evaluation followed by consensus revision. RESULTS: The Berlin Definition of ARDS maintains a link to prior definitions with diagnostic criteria of timing, chest imaging, origin of edema, and hypoxemia. Patients may have ARDS if the onset is within 1 week of a known clinical insult or new/worsening respiratory symptoms. For the bilateral opacities on chest radiograph criterion, a reference set of chest radiographs has been developed to enhance inter-observer reliability. The pulmonary artery wedge pressure criterion for hydrostatic edema was removed, and illustrative vignettes were created to guide judgments about the primary cause of respiratory failure. If no risk factor for ARDS is apparent, however, objective evaluation (e.g., echocardiography) is required to help rule out hydrostatic edema. A minimum level of positive end expiratory pressure and mutually exclusive PaO(2)/FiO(2) thresholds were chosen for the different levels of ARDS severity (mild, moderate, severe) to better categorize patients with different outcomes and potential responses to therapy. CONCLUSIONS: This panel addressed some of the limitations of the prior ARDS definition by incorporating current data, physiologic concepts, and clinical trials results to develop the Berlin definition, which should facilitate case recognition and better match treatment options to severity in both research trials and clinical practice. PMID- 22926656 TI - Social relationships of nulliparous young adult females beyond the ordinary age of the first birth in a free-ranging troop of Japanese macaques (Macaca fuscata). AB - We describe the social relationships of young adult female Japanese macaques (Macaca fuscata) in a free-ranging troop in Arashiyama, Kyoto, Japan, who remained nulliparous beyond the ordinary age of first birth because of contraceptive administration. We observed 12 young nulliparous adult females (6-9 years old) for 270 h and 10 min from 2 February to 5 October 2010. The majority maintained close relationships with their mothers through proximity and grooming, whereas a few had very infrequent social interactions with their mothers. Most had asymmetrical grooming relationships; the grooming they received from unrelated adult females was less than the grooming they gave. Young adult females who had less frequent interactions with their mothers by either proximity or grooming received more grooming from a larger number of unrelated adult females than did those who had more frequent social interactions with their mothers. These results indicate that most young adult females who remained nulliparous beyond the ordinary age of first birth tended to maintain close relationships with their mothers, and their grooming relationships with unrelated adult females were inversely related to the degree of closeness with their mothers. PMID- 22926657 TI - Guideline for the clinical application, documentation and analysis of clinical studies for regional deep hyperthermia: quality management in regional deep hyperthermia. PMID- 22926658 TI - Co-existence of cyclin D1 and vascular endothelial growth factor protein expression is a poor prognostic factor for UICC stage I-III colorectal cancer patients after curative resection. AB - BACKGROUND: Angiogenesis plays an important role in the progression of colorectal cancer (CRC). Studies have indicated vascular endothelial growth factor (VEGF) is the predominant angiogenic factor. Cyclin D1 (CCND1) induces production of VEGF and is required for migration of blood vessels. Our aim was to determine the roles of CCND1 and VEGF overexpression in CRC patients. METHODS: We analyzed clinicopathological features, VEGF and CCND1 expressions by immunohistochemical (IHC) staining in 100 stage I-III CRC patients (44 were postoperative relapsed; 56 were postoperative non-relapsed) to determine the correlation between clinicopathologic features and co-existence of CCND1 and VEGF. Furthermore, the clinical outcomes of co-existence of CCND1 and VEGF were investigated. RESULTS: Multivariate analysis showed vascular invasion (P = 0.019), VEGF overexpression (P = 0.033), and high postoperative serum carcinoembryonic antigen (CEA) levels (P = 0.022) were independent predictors of postoperative relapse. Co-existence of CCND1 and VEGF overexpression had significantly poorer disease-free survival rates (P = 0.004) and overall survival rates (P = 0.001) than other phenotypes. CONCLUSIONS: Co-existence of CCND1 and VEGF overexpression would potentially assist in TNM staging systems to predict the prognosis of these patients who would benefit from intensive follow-up and therapeutic programs. PMID- 22926659 TI - Norway's high-quality center care reduces late talking in high- and low-risk groups. AB - OBJECTIVES: To examine whether attendance in Norwegian high-quality center care in the first 3 years of life buffers the negative effects of biomedical risk factors on children's late talking (LT) at 3 years of age. METHODS: Data on 75,128 children from the Norwegian Mother and Child Cohort Study were analyzed and include information on child care arrangements, LT, and a variety of covariates. A biomedical risk group (N = 6893) was constructed on the basis of information from the Medical Birth Registry of Norway on children's Apgar scores 5 minutes after birth, birth weight, and gestational age. Late talking was reported by mothers when their children were 3 years old. RESULTS: In line with previous research, children born with biomedical risk factors were at higher risk for LT at age 3 years than children born without biomedical risk factors. Child care arrangement at age 1 was not significantly related to LT at age 3 years. At both 1.5 and 3 years of age, center care attendance was related to a reduced chance of LT, independently of whether the children were in the biomedical risk group or not. However, our main hypothesis was not confirmed. Center care attendance did not buffer the negative effects of biomedical risk factors on LT for boys or girls (all p > .05). CONCLUSION: Although attendance in Norwegian center care is positive for children's language development in general, it does not buffer the negative effects of biomedical risk factors on children's LT. PMID- 22926660 TI - Screening for autism spectrum disorders in extremely preterm infants. AB - BACKGROUND: Extremely preterm (EP) infants screen positive for autism spectrum disorders (ASD) at high rates. However, it is not clear whether this is because of high rates of ASD in EPs or to high rates of false-positive screens for ASD in children with a high rate of underlying neurodevelopmental impairments. Combining a parent questionnaire designed to distinguish developmental delay from ASD with direct observation of infant behavior may more accurately screen for ASD in EPs. OBJECTIVES: To determine rates of positive screen for ASD at 18 to 22 months(m) in EPs using 3 screens; to determine factors associated with a positive screen. METHODS: Five hundred fifty-four infants born <27 weeks were screened at 18 to 22 m using the Pervasive Developmental Disorders Screening test, second edition Stage 2, and the response to name and response to joint attention items from the Autism Diagnostic Observation Schedule. Infants with severe cerebral palsy, deafness, and blindness were excluded. Associations between positive screen and neonatal/ infant characteristics were determined. RESULTS: Of 554 infants, 113 (20%) had >= 1 positive screen. 10% had a positive Pervasive Developmental Disorders Screening test, second edition, 6% response to name, 9% response to joint attention; in only 1 % all 3 screens were positive. Positive screen was associated with male gender, more hospital days, white race, lower maternal education, abnormal behavioral scores, and cognitive/ language delay. CONCLUSIONS: The use of 3 screens for ASD in EPs results in higher screen positive rates than use of 1 screen alone. Diagnostic confirmation is needed before true rates of ASD in EPs are known. PMID- 22926661 TI - Suicidal behavior in minors-diagnostic differences between children and adolescents. AB - BACKGROUND: To date, the study of suicidal behavior among minors has focused on the age group in which it is more prevalent: adolescents. We hypothesized that suicidal behavior in children stems from a different diagnosis than suicidal behavior in adolescents, and thus merits its own investigation. METHOD: We studied all minors (266) who were referred to a psychiatric emergency department due to a suicide attempt or suicidal ideation during a 3-year period. RESULT: There was an age-related difference in diagnostic distribution among minors who were referred to the emergency department because of suicidal behavior (chi(2) (7) = 24.297, P < 0.01). Attention deficit hyperactivity disorder was more prevalent among children (under 12 years old), whereas mood disorders were more prevalent among adolescents (12-18 years old). CONCLUSION: The findings of this study highlight a diagnostic difference between suicidal children and suicidal adolescents. PMID- 22926663 TI - Auditory processing in remitted major depression: a long-term follow-up investigation using 3T-fMRI. AB - Major depression is accompanied by cortical dysfunction including impaired auditory processing of non-speech stimuli. In a previous study, we could show that potent antidepressant treatment with electroconvulsive therapy (ECT) did not lead to full functional normalization of altered fMRI activation patterns in response to sine tones although depressive symptoms improved and remission was achieved in the majority of patients. In a next step, a longitudinal follow-up investigation was conducted looking on neuronal activation over time along with full remission in a subgroup of patients of the previous study in order to address the question whether changes in neuronal activation patterns reflect a more state- or trait-dependent characteristic. Results showed that although clinically remitted, patients still exhibited an increased activity of the secondary auditory cortex and multimodal recruitment of the left cuneus, an area of the visual system. However, activity of recruited secondary visual network had decreased over time. A positive correlation was observed between the number of hospital admissions during the follow-up period and activity of the secondary visual area of the left cuneus at baseline prior to ECT. Thus, although the persistence of differences in activation patterns after sine tone presentation in this follow-up investigation could argue for a potential trait marker of depression characterized by alterations in auditory processing, attenuation of neuronal activation in some areas over time suggests that changes might in part also be state-dependent. PMID- 22926662 TI - Cortical control of saccades in Parkinson disease and essential tremor. AB - A number of studies suggest that some features of essential tremor (ET) and Parkinson disease (PD) overlap. Besides tremor, also some cognitive features have been implicated in ET and PD. There is recent evidence that a common genetic mutation occurs in ET and PD. Saccadic eye movements could provide an easily quantifiable procedure to help in the differential diagnosis in early PD and ET. Being able to distinguish early on the two diseases may help in tailoring therapy. Cortical control of saccades and antisaccades as they pertain to the potential discrimination of PD and ET is reviewed. Imaging and electrophysiological studies are highlighted; however, there are still few studies. Hopefully this review will stimulate further research, in particular in the direction of differences and similarities in the neural circuits involved in PD and ET. PMID- 22926664 TI - Mitofusin 2 mutations affect mitochondrial function by mitochondrial DNA depletion. AB - Charcot-Marie-Tooth neuropathy type 2A (CMT2A) is associated with heterozygous mutations in the mitochondrial protein mitofusin 2 (Mfn2) that is intimately involved with the outer mitochondrial membrane fusion machinery. The precise consequences of these mutations on oxidative phosphorylation are still a matter of dispute. Here, we investigate the functional effects of MFN2 mutations in skeletal muscle and cultured fibroblasts of four CMT2A patients applying high resolution respirometry. While maximal activities of respiration of saponin permeabilized muscle fibers and digitonin-permeabilized fibroblasts were only slightly affected by the MFN2 mutations, the sensitivity of active state oxygen consumption to azide, a cytochrome c oxidase (COX) inhibitor, was increased. The observed dysfunction of the mitochondrial respiratory chain can be explained by a twofold decrease in mitochondrial DNA (mtDNA) copy numbers. The only patient without detectable alterations of respiratory chain in skeletal muscle also had a normal mtDNA copy number. We detected higher levels of mtDNA deletions in CMT2A patients, which were more pronounced in the patient without mtDNA depletion. Detailed analysis of mtDNA deletion breakpoints showed that many deleted molecules were lacking essential parts of mtDNA required for replication. This is in line with the lack of clonal expansion for the majority of observed mtDNA deletions. In contrast to the copy number reduction, deletions are unlikely to contribute to the detected respiratory impairment because of their minor overall amounts in the patients. Taken together, our findings corroborate the hypothesis that MFN2 mutations alter mitochondrial oxidative phosphorylation by affecting mtDNA replication. PMID- 22926665 TI - Evaluation of the efficacy and safety of biapenem against pneumonia in the elderly and a study on its pharmacokinetics. AB - Although biapenem is used in the treatment of pneumonia, the clinical data on elderly patients are yet insufficient. Therefore, the purpose of this study was evaluating the efficacy and safety of biapenem against pneumonia in the elderly and its pharmacokinetics. The subjects were patients 65 years of age or older with pneumonia. Biapenem (300 mg) was administered once to three times per day. For some cases, the drug concentrations in plasma were measured chronologically. The clinical efficacy was evaluated in reference to the improvement in subjective symptoms and objective opinion. The primary outcome was efficacy rate at the end of treatment. Biapenem was effective in 17 of 20 subject cases (85.0 %). Regarding safety, although 4 cases experienced hepatic dysfunction and 1 case had nausea, these effects were not severe in all cases and administration was continued. There was no deterioration of renal function associated with biapenem. In 13 cases in which the trough value of biapenem was measured, there were no unacceptable side effects and the trough values were generally low. It is believed that biapenem (300 mg once to three times a day), even when taken by elderly people, does not accumulate and that the dosage is safe and appropriate. The changes in the predicted concentrations calculated with the pharmacokinetic pharmacodynamic (PK-PD) software, which is based on previously reported population pharmacokinetic parameters, and those in the measured concentrations approximately matched. It is useful to plan biapenem administration using the PK PD software when performing antibiotic chemical treatment. PMID- 22926667 TI - Double- vs. single-balloon enteroscopy: and the winner is.... PMID- 22926666 TI - Obesity, weight change, and risk of adenoma recurrence: a prospective trial. AB - BACKGROUND AND STUDY AIMS: Obesity is a risk factor for colorectal neoplasia. Lifestyle modifications, including weight loss, have been advocated to reduce the risk. However, no prospective study has evaluated whether weight loss actually affects adenoma recurrence. The aim of this study was to examine whether weight change (loss or gain) over 4 years is associated with adenoma recurrence. PATIENTS AND METHODS: A total of 1826 patients with colorectal adenoma in the Polyp Prevention Trial had their height and weight measured at baseline. Adenoma recurrence was determined by end of trial colonoscopy 4 years after study entry when patients' weights were re-measured. Poisson regression models were used to evaluate body mass index (BMI), weight change over 4 years, and the risk of any adenoma and advanced adenoma recurrence. RESULTS: Adenoma recurrence was observed in 723 patients (39.6%), 118 (6.5%) of whom had advanced adenoma recurrence. Among those with baseline BMI < 25 kg/m2 (n = 466), BMI 25-29 kg/m2 (n = 868), and BMI >= 30 kg/m2 (n = 492), the recurrence rate was 34.5%, 41.0%, and 41.9%, respectively. Obesity was associated with an increased risk of adenoma recurrence (RR = 1.19; 95%CI 1.01-1.39) and advanced adenoma recurrence (RR = 1.62; 95%CI 1.01-2.57). However, when compared with those with relatively stable weight (weight change < 5 lb) over the 4-year trial, weight gain or loss was not associated with adenoma recurrence. This was consistent, regardless of the baseline BMI. CONCLUSIONS: Weight loss or gain over 4 years does not affect adenoma recurrence. This study does not support weight loss alone as an effective intervention for reducing adenoma recurrence. PMID- 22926669 TI - Active bleeding without identifiable lesion on capsule endoscopy. PMID- 22926671 TI - The risk of bearing dislocation in lateral unicompartmental knee arthroplasty using a mobile biconcave design. AB - PURPOSE: A safety study was conducted on a cohort of 25 patients who underwent lateral unicompartmental arthroplasty with a biconcave mobile-bearing insert. METHODS: The first 25 lateral mobile-bearing unicompartmental knee replacements, performed in a general hospital by one surgeon, were prospectively reviewed, with a minimum follow-up of 1 year. RESULTS: One bearing dislocation occurred 4 months postsurgery. The Oxford knee score improved in all patients from a preoperative mean of 23.3 (range 8-40, SD 8.4) to a postoperative mean of 42.1 (range 23-48, SD 6.7). General patient satisfaction at a mean follow-up of 20 months was excellent in 84 %, good in 12 % and fair in 4 %. The mechanical axis as a measure on full-leg standing radiographs improved from 5.7 degrees valgus (range 1 degrees -16 degrees , SD 4.1 degrees ) to 1.7 degrees valgus (7 degrees to -3 degrees , SD 2.1 degrees ). Mechanical alignment correction averaged 4.0 degrees (range -1 degrees to 15 degrees , SD 3.9 degrees ). CONCLUSION: The mobile biconcave insert design in the lateral unicompartmental knee replacement seems appropriate as a innovative, anatomy imitating solution, resulting in a good clinical outcome. Still, bearing dislocation remains a concern, especially in extended indication. PMID- 22926672 TI - Single-radius, multidirectional total knee replacement. AB - PURPOSE: The present study was designed to evaluate the mid-term (5- to 8-year) survival rate of a new total knee replacement (TKR) with a single-radius femoral component and a multidirectional, highly congruent tibial component, in comparison with an historical group (TKR with multi-radius design and fixed bearing). METHODS: Four hundred and thirty patients were included, of which 369 patients (86 %) completed the 5-year follow-up with Knee Society Score evaluation and radiograph examination (study group = 387, control group = 83). RESULTS: There was a significant improvement for all analysed items between pre-operative status and late follow-up. Mean knee score was 93 +/- 9 points in the study group and 88 +/- 16 points in the control group (p < 0.001). Mean flexion angle was not different (118 +/- 11 vs. 114 +/- 13 degrees). Mean functional score was 87 +/- 16 points in the study group and 71 +/- 24 points in the control group (p < 0.001). Survival rate at 5-year follow-up was 98.8 % (vs. 98.0 %) for mechanical revisions only, and 96.4 % (vs. 98.1 %) for all revisions. CONCLUSIONS: The new TKR allowed obtaining significantly better results than the fixed-bearing TKR. These results are in line with the best series published in the current literature, but there was no evidence of any superiority of this TKR against already published standards. PMID- 22926673 TI - Evaluation of depression, quality of life and body image in patients with Cushing's disease. AB - The aim of this study was to evaluate patients with Cushing's disease (CD) who had undergone transsphenoidal surgery in terms of depression, quality of life (QoL), and perception of body image in comparison to healthy controls. Forty patients with CD and 40 healthy controls matched for demographic characteristics were included in the study. The subjects were evaluated with the Beck depression inventory (BDI), the health survey-short form (SF-36) and the multidimensional body-self relations questionnaire (MBSRQ). Subgroups of the patients with CD were formed on the basis of remission status and BDI scores. In this study, QoL in the general health category and body image were lower in the patients with CD than in the healthy subjects. However, no differences in depression scores were found between the two groups. When the CD group was evaluated according to remission rate, the mean BDI score was significantly higher in the CD patients without remission than in both the CD patients with remission and the healthy subjects (p = 0.04). However, the physical functioning, bodily pain and general health scores of the CD patients without remission on the SF-36 questionnaire were lower than in the CD patients in remission and the healthy subjects (p = 0.002, p = 0.04, p = 0.002, respectively). Fitness evaluation, health evaluation and body areas satisfaction scores of the MBSRQ were significantly different in the three groups (p = 0.003, p = 0.009 and p = 0.001, respectively). In this study, patients with CD were found to have lower QoL, lower body image perception and higher levels of depression compared to healthy controls, particularly if the disease is persistant despite surgery. PMID- 22926674 TI - Normokalemic periodic paralysis is not a distinct disease. AB - INTRODUCTION: Recent molecular studies of the original cases of normokalemic periodic paralysis (normoKPP) have raised suspicions that these families actually had hyperkalemic periodic paralysis (hyperKPP) due to mutations in the skeletal muscle sodium channel gene SCN4A. However, there is still a debate about the existence of normoKPP. METHODS: We screened 230 individuals with primary periodic paralysis for mutations in the SCN4A, CACNA1S, and KCNJ2 genes. All patients had either a hyperKPP or a hypoKPP phenotype, and none had a normoKPP phenotype. RESULTS: In 4 hyperKPP patients from 2 families, molecular analyses revealed Arg675Gly and Arg675Gln mutations of SCN4A, which were previously reported to cause normoKPP. Each patient exhibited the characteristic clinical and laboratory features (including hyperkalemia during spontaneous attacks) of hyperKPP. CONCLUSION: Our findings support the notion that normoKPP is not a distinct disease. PMID- 22926675 TI - Spinal cord lesions in sporadic Parkinson's disease. AB - In this autopsy-based study, alpha-synuclein immunohistochemistry and lipofuscin pigment-Nissl architectonics in serial sections of 100 MUm thickness were used to investigate the spinal cords and brains of 46 individuals: 28 patients with clinically and neuropathologically confirmed Parkinson's disease, 6 cases with incidental Lewy body disease, and 12 age-matched controls. alpha-Synuclein inclusions (particulate aggregations, Lewy neurites/bodies) in the spinal cord were present between neuropathological stages 2-6 in all cases whose brains were staged for Parkinson's disease-related synucleinopathy. The only individuals who did not have Lewy pathology in the spinal cord were a single stage 1 case (incidental Lewy body disease) and all controls. Because the Parkinson's disease related lesions were observable in the spinal cord only after Lewy pathology was seen in the brain, it could be concluded that, within the central nervous system, sporadic Parkinson's disease does not begin in the spinal cord. In addition: (1) alpha-Synuclein-immunoreactive axons clearly predominated over Lewy bodies throughout the spinal cord and were visible in medial and anterior portions of the anterolateral funiculus. Their terminal axons formed dense alpha-synuclein immunoreactive networks in the gray matter and were most conspicuous in the lateral portions of layers 1, 7, and in the cellular islands of layer 9. (2) Notably, this axonopathy increased remarkably in density from cervicothoracic segments to lumbosacral segments of the cord. (3) Topographically, it is likely that the spinal cord alpha-synuclein immunoreactive axonal networks represent descending projections from the supraspinal level setting nuclei (locus coeruleus, lower raphe nuclei, magnocellular portions of the reticular formation). (4) Following the appearance of the spinal cord axonal networks, select types of projection neurons in the spinal cord gray matter displayed alpha synuclein-immunoreactive inclusions: chiefly, nociceptive neurons of the dorsal horn in layer 1, sympathetic and parasympathetic preganglionic neurons in layer 7, the cellular pools of alpha-motoneurons in layer 9, and the smaller motoneurons in Onuf's nucleus in layer 9 (ventral horn). The spinal cord lesions may contribute to clinical symptoms (e.g., pain, constipation, poor balance, lower urinary tract complaints, and sexual dysfunction) that occur during the premotor and motor phases of sporadic Parkinson's disease. PMID- 22926676 TI - Molecular characterization of an alpha-N-acetylgalactosaminidase from Clonorchis sinensis. AB - The alpha-N-acetylgalactosaminidase (alpha-NAGAL) is an exoglycosidase that selectively cleaves terminal alpha-linked N-acetylgalactosamines from a variety of sugar chains. A complementary DNA (cDNA) clone encoding a novel Clonorchis sinensis alpha-NAGAL (Cs-alpha-NAGAL) was identified in the expressed sequence tags database of the adult C. sinensis liver fluke. The complete coding sequence was 1,308 bp long and encoded a 436-residue protein. The selected glycosidase was manually curated as alpha-NAGAL (EC 3.2.1.49) based on a composite bioinformatics analysis including a search for orthologues, comparative structure modeling, and the generation of a phylogenetic tree. One orthologue of Cs-alpha-NAGAL was the Rattus norvegicus alpha-NAGAL (accession number: NP_001012120) that does not exist in C. sinensis. Cs-alpha-NAGAL belongs to the GH27 family and the GH-D clan. A phylogenetic analysis revealed that the GH27 family of Cs-alpha-NAGAL was distinct from GH31 and GH36 within the GH-D clan. The putative 3D structure of Cs alpha-NAGAL was built using SWISS-MODEL with a Gallus gallus alpha-NAGAL template (PDB code 1ktb chain A); this model demonstrated the superimposition of a TIM barrel fold (alpha/beta) structure and substrate binding pocket. Cs-alpha-NAGAL transcripts were detected in the adult worm and egg cDNA libraries of C. sinensis but not in the metacercaria. Recombinant Cs-alpha-NAGAL (rCs-alpha-NAGAL) was expressed in Escherichia coli, and the purified rCs-alpha-NAGAL was recognized specifically by the C. sinensis-infected human sera. This is the first report of an alpha-NAGAL protein in the Trematode class, suggesting that it is a potential diagnostic or vaccine candidate with strong antigenicity. PMID- 22926677 TI - Infection of wild mullet (Mugil cephalus) with Myxobolus episquamalis in Korea. AB - Wild mullet (Mugil cephalus) with white cysts on their scales were obtained from Yeosu on the south coast of Korea in 2009. Cyst-like plasmodia consisted of a large number of mature myxosporean spores and numerous sporogonic stages. Spores were oval-shaped in their front view, tapering anteriorly to a blunt apex, and lenticular in their lateral view. They measured 7.0 MUm (6.2-7.6) in length, 5.2 MUm (4.0-6.2) in width, and 4.9 MUm (3.8-6.0) in thickness. Polar capsules contained a polar filament with five to six turns and measured 3.5 MUm (2.5-4.5) in length and 2.0 MUm (1.6-2.3) in width. Nucleotide sequences of the 18S rRNA gene of the myxosporean parasites in our study showed 99.8 % identity with Myxobolus episquamalis Egusa, Maeno and Sorimachi, 1990 from mullet in Tunisia. These results suggest that the Myxobolus sp. found on the scales of wild mullet is M. episquamalis. In the histopathological examination, spores were observed not only in the plasmodia on the scales, but also in the intestine, pancreas, heart, kidney, stomach, gill, skin, spleen, and liver, suggesting the possibility of the coinfection by different Myxobolus species. PMID- 22926678 TI - ABC transporters as a multidrug detoxification mechanism in Rhipicephalus (Boophilus) microplus. AB - ATP-binding cassette (ABC) transporters are responsible for pumping drugs across membranes and are an important drug detoxification mechanism. Since ABC transporters act on a wide spectrum of chemical compounds, they have been associated with multidrug resistance phenotype in various parasites and cancer cells. Here, we document the presence of a Rhipicephalus (Boophilus) microplus tick population (Jaguar) resistant to four acaricide classes (organophosphates (OP), synthetic pyrethroids (SP), amitraz and macrocyclic lactones (ML)) and reveal that the cattle tick has a multidrug detoxification mechanism based on ABC transporter proteins. Acaricide toxicity was assessed using the larval packet test (LPT), and mortality data were subjected to probit analysis using a susceptible strain (POA) as reference. Larvae were pre-exposed to sub-lethal doses of the ABC-transporter inhibitors, cyclosporin A (CsA) and MK571, and subsequently treated with ivermectin, abamectin, moxidectin, chlorpyriphos, cypermethrin, or amitraz in LPT. Results show that lethal concentrations 50 % (LC(50)) of ivermectin, abamectin, moxidectin (MLs), and chlorpyriphos (OP) were significantly reduced in larvae exposed to CsA and MK571 inhibitors in the Jaguar resistant population, but LC(50) did not change in POA susceptible strain larvae. LC(50) of cypermetrin (SP) and amitraz remained unchanged in inhibitor-exposed larvae, compared to larvae from Jaguar and POA strains not exposed to inhibitor. These results suggest that ABC transporter proteins can protect ticks against a wide range of acaricides and have an important implication in drug resistance development as a multidrug detoxification mechanism. PMID- 22926679 TI - Reports of magnetic resonance images of the hip in patients with femoroacetabular impingement: is useful information provided to the orthopedic surgeon? AB - OBJECTIVE: The aim of this study was twofold: (1) To evaluate the quality of radiology reports of MR imaging/arthrography (MRI/MRA) of the hip performed on symptomatic young adults with suspected femoroacetabular impingement (FAI); and (2) to assess if MRI/MRA reports provide relevant information for surgical decision-making. MATERIALS AND METHODS: We evaluated 110 MRI/MRA reports provided by 73 radiologists from 42 institutions. The images were requested preoperatively in young adults who underwent hip-preserving surgery for treatment of FAI. The quality of reports was graded using Lee's method by two independent observers. The description of seven characteristics of the hip joint was scrutinized in order to assess if the reports contained relevant information for surgical decision-making. RESULTS: The quality of reports was Grade IIA in two cases (1.8 %), IIB in six (5.5 %), III in 60 (54.5 %), and IV in 42 (38.2 %). Relevant hip characteristics for the study of FAI were reported as follows: acetabular labrum (88.1 %), cartilage characteristics (69 %), morphology of the femoral head-neck junction (34.5 %), acetabular version (6.3 %), acetabular coverage (20.9 %), soft tissues description (82.7 %), and presence of bone marrow edema (80.9 %). The vast majority (91.8 %) of the reports described five or less relevant FAI characteristics. CONCLUSIONS: Most of the radiology reports of MRI/MRA of the hip performed on symptomatic young adults with FAI were of the highest quality. However, some characteristics believed to be important for surgical decision making in this particular group of patients were frequently not described. The inclusion of these hip joint characteristics in the radiology reports may improve the usefulness of the information provided to the orthopedic surgeon. PMID- 22926680 TI - C-arm flat-panel CT arthrography of the wrist and elbow: first experiences in human cadavers. AB - OBJECTIVE: To determine the optimal intra-articular iodine concentration for C arm flat-panel computed tomography (FPCT) arthrography using advanced joint phantoms and to evaluate its application in human cadaveric wrists and elbows. Multi-detector (MD) CT served as the standard of reference. MATERIALS AND METHODS: Joint phantoms and 10 human cadaveric wrist and elbow joints were scanned with C-arm FPCT (5-s, 8-s, and 20-s runs) and standard MDCT using different and optimal concentrations of iodinated contrast material. CT numbers of contrast material, tissue, and noise were measured and contrast-to-noise ratios (CNR) calculated for quantitative analysis. Image and depiction of cartilage, bone, and soft tissues were rated. Radiation doses were compared. RESULTS: In FPCT, iodine concentrations positively correlated with CT numbers and noise of contrast material and with radiation dose (r = 0.713-0.996, p < 0.05 each). At an iodine concentration of 45 mg/ml, CNR of cartilage and soft tissues were highest for all FPCT acquisitions and higher than in MDCT. The 20-s FPCT run performed best for image quality and depiction of anatomical structures and was rated overall equal to MDCT (p = 0.857). CONCLUSION: The optimal iodine concentration for C-arm FPCT arthrography in this study is 45 mg/ml, leading to superior CNR and image quality for an optimal FPCT protocol compared with standard MDCT arthrography in human cadaveric joints. PMID- 22926681 TI - [Reintubation using the C-MAC videolaryngoscope. Implementation in patients with difficult airways initially managed with in situ laryngeal tubes]. AB - BACKGROUND: Securing the airway with supraglottic airway devices, such as a laryngeal tube, is a regular component of most difficult airway management algorithms. It is further recommended that in emergency medicine rescuers less skilled in endotracheal intubation should use supraglottic airways as a first line device. Exchanging the laryngeal tube with an endotracheal tube can be performed with video-assisted laryngoscopy as described below. MATERIAL AND METHODS: A total of 20 adult patients with airways managed using laryngeal tubes due to actual or anticipated difficult intubation underwent endotracheal intubation using the C-MAC videolaryngoscope. After deflating the cuffs of the laryngeal tube, seeking out the glottis was done by following the constructional landmarks of the laryngeal tube, considering concordance with anatomical landmarks of the human airway. In cases of failed video-assisted endotracheal intubation, the laryngeal tube that was still in situ was reinflated to re establish ventilation of the lungs. RESULTS: In 19 out of the 20 patients the laryngeal tube could be exchanged for an endotracheal tube with the video assisted technique described. In one patient no laryngeal structures could be identified (Cormack and Lehane grade IV) even with the C-MAC videolaryngoscope and ventilation was continued via the laryngeal tube. No complications related to the video-assisted intubation technique were observed. CONCLUSIONS: The C-MAC videolaryngoscope is a mobile system which facilitates endotracheal intubation in patients with a difficult airway and a laryngeal tube in place. It is not only possible but recommended to leave the laryngeal tube in situ as a back-up when videolaryngoscopy fails. PMID- 22926682 TI - Cerebral palsy among children seen in the neurology clinic of Federal Medical Centre (FMC), Asaba. AB - Cerebral palsy (CP) is a non-progressive disorder of motor function caused by irreversible damage to the immature brain. The disorder may be associated with seizure, mental retardation, visual and hearing defects. This study was designed to determine the types of CP, the risk factors and the co-morbidities associated with the disorder. Records of patients who were seen in the neurology clinic were kept for two years (June 2009-July 2011). Medical history and examination were essentially used to determine risk factors, antenatal care and co-morbidities. Data was analyzed using SPSS soft-ware. CP made up 45 % of 60 neurological cases and 0.006 % of 4,873 patients seen in the clinic with a male to female ratio of 1.1:1. Birth asphyxia was the commonest risk factor for the development of the disorder while seizure disorder among others was the commonest co-morbid state. PMID- 22926683 TI - The autophagy protein LC3A correlates with hypoxia and is a prognostic marker of patient survival in clear cell ovarian cancer. AB - Clear cell ovarian cancer histotypes exhibit metabolic features associated with resistance to hypoxia and glucose deprivation-induced cell death. This metabolic characteristic suggests that clear cell ovarian cancers activate survival mechanisms not typical of other epithelial ovarian cancers. Here we demonstrate that microtubule-associated protein 1 light chain 3A (LC3A), a marker of autophagy, is related to hypoxia and poor prognosis in clear cell ovarian cancer. In 485 ovarian tumours, we found that LC3A was significantly associated with poor progression-free (p = 0.0232), disease-specific (p = 0.0011) and overall patient survival (p = 0.0013) in clear cell ovarian cancer patients, but not in other subtypes examined. LC3A was an independent prognostic marker of reduced disease specific [hazard ratio (HR): 2.55 (95% CI 1.21-5.37); p = 0.014] and overall survival [HR: 1.95 (95% CI 1.00-3.77); p = 0.049] in patients with clear cell ovarian carcinoma. We also found a strong link between autophagy and hypoxia as LC3A staining revealed a significant positive association with the hypoxia related proteins carbonic anhydrase-IX and HIF-1alpha. The functional link between hypoxia and autophagy was demonstrated using clear cell and high-grade serous cell lines that were subjected to hypoxia or hypoxia + glucose deprivation. Clear cell carcinoma lines displayed greater autophagy induction and were subsequently more sensitive to inhibition of autophagy under hypoxia compared to the high-grade serous lines. Together, our findings indicate that hypoxia-induced autophagy may be crucial to the clinical pathology of clear cell ovarian cancer and is a potential explanation for histological subtype differences in patient disease progression and outcomes. PMID- 22926685 TI - Proton CSI without solvent suppression with strongly reduced field gradient related sideband artifacts. AB - OBJECT: Non-water-suppressed MRSI (magnetic resonance spectroscopy imaging) offers a number of advantages; however, spectra are hampered by the sideband artifacts. The origin of those is associated with the vibration of the gradient coils, and most of the sidebands are assumed to be related to the crusher gradients. The aim was to examine the dependency between the physical direction of the crushers and the sidebands. Additionally, the possibilities of optimization of the point resolved spectroscopy sequence (PRESS) were investigated. MATERIALS AND METHODS: For the assessment of the sidebands, spectra at short echo time (TE) were collected at 3 T from standard water phantom. A homemade agar phantom was used to test the optimal strength of the crusher gradients. Optimized PRESS sequence was tested in vivo. RESULTS: The greatest sidebands were found to be associated with the crusher gradient in x-direction. Agar phantom and in vivo measurements revealed that reduction of the crusher's strength to 5 mT/m could provide a significant minimization of the sidebands without raising the unwanted signals produced by volume selection. CONCLUSION: This study demonstrates that crusher gradients in different directions produce a unique pattern of the sidebands. Moreover, optimization of the strength of crushers has been found to decrease sidebands so, the remaining part could be reduced in postprocessing. PMID- 22926686 TI - The proportion of CD34(+)CD38(low or neg) myeloblasts, but not side population frequency, predicts initial response to induction therapy in patients with newly diagnosed acute myeloid leukemia. PMID- 22926688 TI - Novel variants of grapevine leafroll-associated virus 4 and 7 detected from a grapevine showing leafroll symptoms. PMID- 22926687 TI - Overlapping prefrontal systems involved in cognitive and emotional processing in euthymic bipolar disorder and following sleep deprivation: a review of functional neuroimaging studies. AB - Prefrontal cortex (PFC) mediated cognitive and emotional processing deficits in bipolar disorder lead to functional limitations even during periods of mood stability. Alterations of sleep and circadian functioning are well-documented in bipolar disorder, but there is little research directly examining the mechanistic role of sleep and/or circadian rhythms in the observed cognitive and emotional processing deficits. We systematically review the cognitive and emotional processing deficits reliant upon PFC functioning of euthymic patients with bipolar disorder and in healthy individuals deprived of sleep. The evidence from two parallel lines of investigation suggests that sleep and circadian rhythms may be involved in the cognitive and emotional processing deficits seen in bipolar disorder through overlapping neurobiological systems. We discuss current models of bipolar highlighting the PFC-limbic connections and discuss inclusion of sleep related mechanisms. Sleep and circadian dysfunction is a core feature of bipolar disorder and models of neurobiological abnormalities should incorporate chronobiological measures. Further research into the role of sleep and circadian rhythms in cognition and emotional processing in bipolar disorder is warranted. PMID- 22926689 TI - Age as a predictive factor of testosterone improvement in male patients after bariatric surgery: preliminary results of a monocentric prospective study. AB - BACKGROUND: Male obesity can be associated with symptomatic alterations in sex hormones resulting in hypogonadism and impaired fertility. Surgical-induced weight loss can improve the sex hormone profile in men. The aim of the present study is to evaluate the levels of sex hormones in obese males before and after 6 months from bariatric surgery. Possible mechanisms and clinical implications are also discussed. METHODS: We evaluated levels of serum total testosterone (TT), sex hormone-binding globulin (SHBG), calculated free testosterone (cFT), follicular-stimulating hormone (FSH), luteinizing hormone (LH), and total estradiol (E2) in 20 male patients at the baseline and 6 months after bariatric surgery. RESULTS: Median [interquartile range] age at the time of surgery was 40.5 [27.2-46.7] years with a median [interquartile range] BMI of 43.6 [40.9 48.7] kg/m(2). The median baseline levels of TT, SHBG, cFT, LH, and FSH were reduced; levels of E2 were elevated. At 6 months from surgery, the median BMI dropped to 34.8 [31.7-40.5] kg/m(2), TT, SHBG, cFT, LH, and FSH increased, while levels of E2 decreased. The improvement in the sex hormone profile was more evident in younger patients, with a statistically significant difference in cFT following surgery and in the raise of TT and cFT between the groups of patients below and above 35 years. At multivariate analysis, the age was the best predictive factor of the postoperative variations of TT. CONCLUSIONS: These preliminary results confirm the general improvement in sex hormone profile in obese men after bariatric surgery and introduce the age as a possible contributing factor to this improvement. PMID- 22926690 TI - Obesity at diagnosis is associated with inferior outcomes in hormone receptor positive operable breast cancer. AB - BACKGROUND: Obesity has been associated with inferior outcomes in operable breast cancer, but the relation between body mass index (BMI) and outcomes by breast cancer subtype has not been previously evaluated. METHODS: The authors evaluated the relation between BMI and outcomes in 3 adjuvant trials coordinated by the Eastern Cooperative Oncology Group that included chemotherapy regimens with doxorubicin and cyclophosphamide, including E1199, E5188, and E3189. Results are expressed as hazard ratios (HRs) from Cox proportional hazards models (HR >1 indicates a worse outcome). All P values are 2-sided. RESULTS: When evaluated as a continuous variable in trial E1199, increasing BMI within the obese (BMI, >= 30 kg/m(2)) and overweight (BMI, 25-29.9 kg/m(2)) ranges was associated with inferior outcomes in hormone receptor-positive, human epidermal growth receptor 2 (HER-2)/neu-negative disease for disease-free survival (DFS; P = .0006) and overall survival (OS; P = .0007), but not in HER-2/neu-overexpressing or triple negative disease. When evaluated as a categorical variable, obesity was associated with inferior DFS (HR, 1.24; 95% confidence interval [CI], 1.06-1.46; P = .0008) and OS (HR, 1.37; 95% CI, 1.13-1.67; P = .002) in hormone receptor positive disease, but not other subtypes. In a model including obesity, disease subtype, and their interaction, the interaction term was significant for OS (P = .02) and showed a strong trend for DFS (P = .07). Similar results were found in 2 other trials (E5188, E3189). CONCLUSIONS: In a clinical trial population that excluded patients with significant comorbidities, obesity was associated with inferior outcomes specifically in patients with hormone receptor-positive operable breast cancer treated with standard chemohormonal therapy. PMID- 22926691 TI - Macrophage inflammatory protein-3 alpha (MIP-3a) is a novel serum prognostic marker in patients with colorectal cancer. AB - BACKGROUND AND OBJECTIVES: A significant prognostic difference exists among metastatic colorectal cancer (CRC) patients despite of any treatments. We identify the specific cytokines related to prognosis of metastatic CRC and assess their prognostic significance. METHODS: Stage IV CRC patients were divided into two groups according to their prognosis. Difference in serum cytokine level between these groups was determined by the cytokine array. Among the specific cytokines, macrophage inflammatory protein-3 alpha (MIP-3a) was measured using an enzyme-linked immunosorbent assay (ELISA) in the sera of 242 CRC patients. RESULTS: Several cytokines related to prognostic difference in stage IV CRC were identified. The median MIP-3a level (28.2 pg/ml) was used as a cut-off value. Increased MIP-3a was significantly associated with synchronous liver metastases and age. In univariate analysis, high MIP-3a was correlated with poor prognosis (P < 0.001). Multivariate analysis showed that high MIP-3a was an independent prognostic factor in all CRC patients (P < 0.001). In subgroup analysis, high MIP 3a was significantly associated with poor survival in patients with stage II, II/III, and IV CRC, respectively. CONCLUSIONS: Serum MIP-3a is not only an independent prognostic factor, but also an independent predictive factor for liver metastasis, which may guide the decision making of metastatic CRC patients. PMID- 22926693 TI - A new surgical stabilizing instrument for hypospadias repair. PMID- 22926694 TI - Validity of cystatin C/creatinine ratio in pediatric kidney disease. PMID- 22926692 TI - Food-induced anaphylaxis: mast cells as modulators of anaphylactic severity. AB - A food-induced anaphylactic reaction can occur within seconds to a few hours following exposure to the causal food allergen and often affects multiple organ systems including gastrointestinal, cutaneous, respiratory, and cardiovascular. A conundrum in the allergy field is that consumption of the same allergen can cause reactions of vastly different severity in separate individuals; one patient may experience a mild non-life-threatening reaction characterized by pruritis of lips or urticaria whereas another may experience a life-threatening reaction that involves respiratory and cardiovascular compromise leading to loss of consciousness and sometimes death. While there are tests available to determine the predictive risk value of a positive food challenge test or clinical reactivity, there is currently no reliable method to distinguish between individuals who are at risk of mild non-life-threatening versus life-threatening reaction. Recent research has significantly advanced our understanding of the involvement of immune pathways in the effector phase of food-induced anaphylaxis; a void remains regarding our understanding of the contribution of these pathways to severity of disease. In this review, we discuss mild non-life-threatening versus life-threatening food-induced anaphylaxis and factors (co-morbidities and immune activation) that predispose individuals to more severe disease. Furthermore, we summarize recent advancements in our understanding of the involvement of underlying immune pathways in systemic and food-induced anaphylaxis in mouse systems and discuss how these pathways may contribute to more severe disease phenotype. PMID- 22926695 TI - Comparison of effective impact among tonsillectomy alone, tonsillectomy combined with oral steroid and with steroid pulse therapy on long-term outcome of immunoglobulin A nephropathy. AB - BACKGROUND: To clarify the therapeutic impact of tonsillectomy and combined therapies of tonsillectomy plus steroid on the long-term prognosis of immunoglobulin A nephropathy (IgAN). METHODS: A retrospective study was conducted on 208 patients with IgAN between 1986 and 2009. According to the strategies for treatments, patients were divided into four groups: tonsillectomy and steroid pulse (TSP, n = 47), tonsillectomy and oral steroid (TOS, n = 33), tonsillectomy alone (T, n = 56), and N group (no particular therapy, n = 72). Multivariate analysis based on the Cox's regression model was used to assess the relative risk of reaching the outcome of doubling creatinine based on the influence of baseline prognostic factors. RESULTS: The mean observation periods were 53.8 months in the TSP group, 122.0 months in the TOS group, 102.9 months in the T group, and 84.6 months in the N group. During an observation period, serum creatinine levels doubled as follows: one in the TSP group (2.1 %), two in the TOS group (6.1 %), five in the T group (8.9 %), histological severity, and 22 in the N group (30.6 %). The Cox's regression proportional hazard model showed that gender, age, histological activity, dialysis induction risk and therapy were associated with doubling creatinine levels. Hazard ratios (95 % CI) and (P value) in T, TOS, and TSP groups versus N were 0.314 (0.11-0.93, P = 0.037), 0.213 (0.04-1.10, P = 0.065), and 0.032 (0.00-0.28, P = 0.002), respectively. CONCLUSION: A combination therapy of tonsillectomy and steroid pulse had the most significant therapeutic impact compared to other therapies. PMID- 22926696 TI - Angiographic characteristics of coronary arterial segments progressing to myocardial infarction in patients with and without chronic kidney disease. AB - BACKGROUND: Individuals with chronic kidney disease (CKD) have high rates of myocardial infarction (MI), but whether the nature of coronary lesions susceptible to plaque rupture is altered and whether the high rate of MI is related to a greater burden of atherosclerotic lesions in individuals with CKD is uncertain. METHODS: We used quantitative coronary angiography to assess atherosclerotic plaque location and characteristics at baseline and at the time of MI in 62 patients with and without CKD. Univariate and multivariable conditional logistic regression models were used to assess whether the association between pre-MI angiographic findings and MI differs in individuals with and without CKD. RESULTS: The risk of MI rose as the distance from the coronary ostium decreased both in patients with CKD (odds ratio per 10 mm 0.92 [95 % CI 0.87-0.99]) and in those without CKD (odds ratio 0.83 [95 % CI 0.75 0.93]). Although tighter degrees of coronary stenosis were associated with increased risks of MI in patients with and without CKD, the majority of MIs (70.9 % in patients with CKD and 89.5 % in those without CKD) occurred in segments with <50 % diameter stenosis at baseline. CONCLUSIONS: The characteristics of lesions progressing to MI are similar in individuals with and without CKD and the majority of events occur in areas with <50 % stenosis at baseline. Given the high burden of non-stenotic lesions in patients with CKD, an interventional strategy aimed solely at sites with high-grade stenosis is unlikely to markedly reduce the risk of MI in patients with CKD. PMID- 22926697 TI - Current therapeutic strategies for acute kidney injury. AB - Acute kidney injury (AKI) is characterized by a rapid decrease in kidney function and increased serum creatinine. The term acute renal failure (ARF) has been applied to such clinical manifestations. Despite several advances in the treatment of ARF, such as pharmacologic treatment and renal replacement therapy (RRT), the mortality rate among patients with ARF has changed little over the past four decades. It is widely recognized that ARF is associated with significantly increased morbidity and mortality especially in critically ill patients with ARF requiring RRT. Therefore, in order to improve outcomes in ARF patients, a new concept of AKI has been proposed. Recently the paradigm shift from ARF to AKI has been received by the research and clinical communities. In this review we will discuss the therapeutic strategies for AKI and focus on its management with an emphasis on RRT. PMID- 22926698 TI - Pancreatic neuroendocrine paraneoplastic optic neuropathy: confirmation with antibody to optic nerve and hepatic metastasis. AB - A 68-year-old woman presented with bilateral visual loss as the only clinical manifestation of an occult pancreatic nonsecretory neuroendocrine tumor (NET). The suspected diagnosis of paraneoplastic optic neuropathy was confirmed using immunofluorescence assays to demonstrate the presence of antibodies in the patient's serum that reacted with antigen(s) in the optic nerve and in the pancreatic NET hepatic metastasis. Treatment of the underlying cancer was followed by marked improvement in visual function. PMID- 22926699 TI - An overview of transcriptional regulation in response to toxicological insult. AB - The completion of the human genome project and the subsequent advent of DNA microarray and high-throughput sequencing technologies have led to a renaissance in molecular toxicology. Toxicogenomic data sets, from both in vivo and in vitro studies, are growing exponentially, providing a wealth of information on regulation of stress pathways at the transcriptome level. Through such studies, we are now beginning to appreciate the diversity and complexity of biological responses to xenobiotics. In this review, we aim to consolidate and summarise the major toxicologically relevant transcription factor-governed molecular pathways. It is becoming clear that different chemical entities can cause oxidative, genotoxic and proteotoxic stress, which induce cellular responses in an effort to restore homoeostasis. Primary among the response pathways involved are NFE2L2 (Nrf2), NFE2L1 (Nrf1), p53, heat shock factor and the unfolded protein response. Additionally, more specific mechanisms exist where xenobiotics act as ligands, including the aryl hydrocarbon receptor, metal-responsive transcription factor-1 and the nuclear receptor family of transcription factors. Other pathways including the immunomodulatory transcription factors NF-kappaB and STAT together with the hypoxia-inducible transcription factor HIF are also implicated in cellular responses to xenobiotic exposure. A less specific but equally important aspect to cellular injury controlled by transcriptional activity is loss of tissue-specific gene expression, resulting in dedifferentiation of target cells and compromise of tissue function. Here, we review these pathways and the genes they regulate in order to provide an overview of this growing field of molecular toxicology. PMID- 22926700 TI - Extending Hirshfeld-I to bulk and periodic materials. AB - In this work, a method is described to extend the iterative Hirshfeld-I method, generally used for molecules, to periodic systems. The implementation makes use of precalculated pseudopotential-based electron density distributions, and it is shown that high-quality results are obtained for both molecules and solids, such as ceria, diamond, and graphite. The use of grids containing (precalculated) electron densities makes the implementation independent of the solid state or quantum chemical code used for studying the system. The extension described here allows for easy calculation of atomic charges and charge transfer in periodic and bulk systems. The conceptual issue of obtaining reference densities for anions is discussed, and the delocalization problem for anionic reference densities originating from the use of a plane wave basis set is identified and handled. PMID- 22926701 TI - Editorial osteology. PMID- 22926703 TI - Successful coronary stenting in anomalous right coronary artery by using an inner catheter with mother and child technique under multislice CT guidance. AB - The ectopic location and unusual coronary course of the anomalous right coronary artery (RCA) from the left sinus of Valsalva makes percutaneous coronary intervention difficult. In this report, we describe a case of successful stent implantation in an anomalous RCA performed using a 4.5F inner catheter with a 6F guiding catheter used in the mother and child system under the guidance of multislice computed tomography. This approach was found to be safe and feasible in cases involving anomalous coronary origin because of the excellent engagement and support provided by the guiding catheter. PMID- 22926702 TI - Anti-leukemic mechanisms of pegylated arginase I in acute lymphoblastic T-cell leukemia. AB - New treatments for adults with acute lymphoblastic T-cell leukemia (T-ALL) are urgently needed, as the current rate of overall remission in these patients is only about 40 percent. We recently showed the potential therapeutic benefit of the pegylated-human-arginase I (peg-Arg I) in T-ALL. However, the mechanisms by which peg-Arg I induces an anti-T-ALL effect remained unknown. Our results show the induction of T-ALL cell apoptosis by peg-Arg I, which associated with a global arrest in protein synthesis and with the phosphorylation of the eukaryotic translation-initiation factor 2 alpha (eIF2alpha). Inhibition of eIF2alpha phosphorylation in T-ALL cells prevented the apoptosis induced by peg-Arg I, whereas the expression of a phosphomimetic eIF2alpha form increased the sensibility of T-ALL cells to peg-Arg I. Phosphorylation of eIF2alpha by peg-Arg I was mediated through kinases PERK and GCN2 and down-regulation of phosphatase GADD34. GCN2 and decreased GADD34 promoted T-ALL cell apoptosis after treatment with peg-Arg I, whereas PERK had an unexpected anti-apoptotic role. Additional results showed that phospho-eIF2alpha signaling further increased the anti leukemic effects induced by peg-Arg I in T-ALL-bearing mice. These results suggest the central role of phospho-eIF2alpha in the anti-T-ALL effects induced by peg-Arg I and support its study as a therapeutic target. PMID- 22926704 TI - A case of intervention for gastroepiploic artery bypass graft anastomosis stenosis with using a 4 Fr guiding catheter. AB - Since it was first used and reported in 1987, the gastropepiploic artery (GEA) has emerged as an effective third or isolated arterial conduit for complete bypass grafting or for use in cases of limited graft numbers or poor quality vein grafts. Percutaneous intervention on the GEA graft can pose technical challenges by virtue of its anatomy and the more common occurrence of the stenosis distally at their anastomosis with the coronary artery. Here we describe the clinical utility of a 4 Fr straight guiding catheter for treatment of stenosis in a GEA coronary bypass graft. PMID- 22926705 TI - Reocclusion caused by stent fracture implanted in the subclavian artery ostium: a case report. AB - A 47 year-old male, a woodcutter by profession, complained of severe pain in the left arm during physical stress. Eighteen months ago, a balloon-expandable stainless steel stent had been implanted in the left subclavian artery ostium. The angiography revealed a stent fracture at the origin of the left subclavian artery, this condition led to a re-obstruction of the stent. After the insertion of a self-expandable Nitinol stent, the side differences of arterial pressure and the symptoms disappeared. This is the first reported case of a stent fracture inserted at the origin of the subclavian artery without severe calcification. PMID- 22926707 TI - [17 year old young man with upper abdominal pain]. PMID- 22926706 TI - A robust genomic signature for the detection of colorectal cancer patients with microsatellite instability phenotype and high mutation frequency. AB - Microsatellite instability (MSI) occurs in 10-20% of colorectal tumours and is associated with good prognosis. Here we describe the development and validation of a genomic signature that identifies colorectal cancer patients with MSI caused by DNA mismatch repair deficiency with high accuracy. Microsatellite status for 276 stage II and III colorectal tumours has been determined. Full-genome expression data was used to identify genes that correlate with MSI status. A subset of these samples (n = 73) had sequencing data for 615 genes available. An MSI gene signature of 64 genes was developed and validated in two independent validation sets: the first consisting of frozen samples from 132 stage II patients; and the second consisting of FFPE samples from the PETACC-3 trial (n = 625). The 64-gene MSI signature identified MSI patients in the first validation set with a sensitivity of 90.3% and an overall accuracy of 84.8%, with an AUC of 0.942 (95% CI, 0.888-0.975). In the second validation, the signature also showed excellent performance, with a sensitivity 94.3% and an overall accuracy of 90.6%, with an AUC of 0.965 (95% CI, 0.943-0.988). Besides correct identification of MSI patients, the gene signature identified a group of MSI-like patients that were MSS by standard assessment but MSI by signature assessment. The MSI-signature could be linked to a deficient MMR phenotype, as both MSI and MSI-like patients showed a high mutation frequency (8.2% and 6.4% of 615 genes assayed, respectively) as compared to patients classified as MSS (1.6% mutation frequency). The MSI signature showed prognostic power in stage II patients (n = 215) with a hazard ratio of 0.252 (p = 0.0145). Patients with an MSI-like phenotype had also an improved survival when compared to MSS patients. The MSI signature was translated to a diagnostic microarray and technically and clinically validated in FFPE and frozen samples. PMID- 22926708 TI - Effects of the grade, stability, chronological classification and being either unilateral or bilateral of the slip on the treatment by in situ single screw fixation of patients with slipped capital femoral epiphysis. AB - PURPOSE: The effects of the grade, stability, chronological classification and being either unilateral or bilateral of the slip on the outcomes of the treatment by in situ single screw fixation of the Slipped capital femoral epiphysis were investigated. METHODS: 34 hips of 24 patients (7 girls, 17 boys; mean age 12.04 years; range 9-14; 14 slips acute, 7 slips acute on chronic, 13 slips chronic; 22 slips stable, 12 slips unstable; 20 slips Grade 1, 13 slips Grade 2, 1 slips Grade 3) between 2003 and 2009 were involved in the study. During the controls; range of motion, walking abnormalities, Trendelenburg test, use of assistive devices during mobilization, existence of pain and complications were evaluated. The evaluation of clinical results was made according to the average Harris Hip Score. RESULTS: 10 of 24 patients showed evidence of a slip of the contralateral hip on average 10.6 (6-16) months after the initial operation. At mean 41.52 +/- 8.08 months controls, the Harris Hip Score was found 77.41 +/- 14.66, hip-joint motions, flexion 120 degrees (70 degrees -140 degrees ), abduction 40 degrees (20 degrees -60 degrees ), internal rotation 25 degrees (10 degrees -40 degrees ). Evaluation at the last follow-up showed significant differences between single hip slip than both hip slip, stable slip than unstable slip and Grade 1 slip than Grade 2 slip. In the last control of one patient with a Grade 3 slip, avascular necrosis has been observed. Considering the effect on the clinical results of the chronological classification of the no slip, significant differences have been seen between the clinical outcomes of the acute, chronic or acute on chronic slips. DISCUSSION: The outcomes of the treatment by in situ single screw fixation are negatively affected by increase in the grade of slip, instability of the slip and existence of slip at both hips. PMID- 22926709 TI - Above- or below-elbow casts for distal third forearm fractures in children? An updated meta-analysis of the literature. PMID- 22926710 TI - Hypodense regions in unenhanced CT identify nonviable myocardium: validation versus 18F-FDG PET. AB - PURPOSE: The aim of the present study was to evaluate the accuracy of hypodense regions in non-contrast-enhanced cardiac computed tomography (unenhanced CT) to identify nonviable myocardial scar tissue. METHODS: Hypodense areas were visually identified in unenhanced CT of 80 patients in the left ventricular anterior, apical, septal, lateral and inferior myocardium and CT density was measured in Hounsfield units (HU). Findings were compared to (18)F-fluorodeoxyglucose uptake by positron emission tomography (FDG PET), which served as the standard of reference to distinguish scar (<50 % FDG uptake) from viable tissue (>=50 % uptake). RESULTS: Visually detected hypodense regions demonstrated a sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of 74, 97, 84 and 94 %, respectively. A receiver-operating characteristic (ROC) curve analysis revealed a cutoff value of mean HU at <28.8 for predicting scar tissue with an area under the curve of 0.93 yielding a sensitivity, specificity, PPV and NPV of 94, 90, 67 and 99 %, respectively. CONCLUSION: Hypodense regions in unenhanced cardiac CT scans allow accurate identification of nonviable myocardial scar tissue. PMID- 22926711 TI - Will the new advantages provided by PET in myocardial perfusion imaging help nuclear cardiology survive the test of time against conventional radiological techniques? PMID- 22926713 TI - Diagnostic value of combined 18F-FDG PET/MRI for staging and restaging in paediatric oncology. AB - PURPOSE: The present study compares the diagnostic value of (18)F fluorodeoxyglucose (FDG) positron emission tomography (PET) and MRI to combined/registered (18)F-FDG PET/MRI for staging and restaging in paediatric oncology. METHODS: Over 8 years and 2 months, 270 (18)F-FDG PET and 270 MRI examinations (mean interval 5 days) were performed in 132 patients with proven (n = 117) or suspected (n = 15) malignant disease: solid tumours (n = 64), systemic malignancy (n = 53) and benign disease (n = 15). A total of 259 suspected tumour lesions were analysed retrospectively during primary diagnosis and 554 lesions during follow-up. Image analysis was performed separately on each modality, followed by analysis of combined and registered (18)F-FDG PET/MRI imaging. RESULTS: A total of 813 lesions were evaluated and confirmed by histopathology (n = 158) and/or imaging follow-up (n = 655) after 6 months. In the separate analysis of (18)F-FDG PET and MRI, sensitivity was 86 %/94 % and specificity 85 %/38 %. Combined/registered (18)F-FDG PET/MRI led to a sensitivity of 97 %/97 % and specificity of 81 %/82 %. False-positive results ((18)F-FDG PET n = 69, MRI n = 281, combined (18)F-FDG PET/MRI n = 85, registered (18)F-FDG PET/MRI n = 80) were due to physiological uptake or post-therapeutic changes. False-negative results ((18)F-FDG PET n = 50, MRI n = 20, combined (18)F-FDG PET/MRI n = 11, registered (18)F-FDG PET/MRI n = 11) were based on low uptake or minimal morphological changes. Examination-based evaluation during follow-up showed a sensitivity/specificity of 91 %/81 % for (18)F-FDG PET, 93 %/30 % for MRI and 96 %/72 % for combined (18)F-FDG PET/MRI. CONCLUSION: For the detection of single tumour lesions, registered (18)F-FDG PET/MRI proved to be the methodology of choice for adequate tumour staging. In the examination-based evaluation, MRI alone performed better than (18)F-FDG PET and combined/registered imaging during primary diagnosis. At follow-up, however, the examination-based evaluation demonstrated a superiority of (18)F-FDG PET alone. PMID- 22926712 TI - EANM 2012 guidelines for radionuclide imaging of phaeochromocytoma and paraganglioma. AB - PURPOSE: Radionuclide imaging of phaeochromocytomas (PCCs) and paragangliomas (PGLs) involves various functional imaging techniques and approaches for accurate diagnosis, staging and tumour characterization. The purpose of the present guidelines is to assist nuclear medicine practitioners in performing, interpreting and reporting the results of the currently available SPECT and PET imaging approaches. These guidelines are intended to present information specifically adapted to European practice. METHODS: Guidelines from related fields, issued by the European Association of Nuclear Medicine and the Society of Nuclear Medicine, were taken into consideration and are partially integrated within this text. The same was applied to the relevant literature, and the final result was discussed with leading experts involved in the management of patients with PCC/PGL. The information provided should be viewed in the context of local conditions, laws and regulations. CONCLUSION: Although several radionuclide imaging modalities are considered herein, considerable focus is given to PET imaging which offers high sensitivity targeted molecular imaging approaches. PMID- 22926714 TI - Quantitative longitudinal interrelationships between brain metabolism and amyloid deposition during a 2-year follow-up in patients with early Alzheimer's disease. AB - PURPOSE: Similar regional anatomical distributions were reported for fibrillary amyloid deposition [measured by (11)C-Pittsburgh compound B (PIB) positron emission tomography (PET)] and brain hypometabolism [measured by (18)F fluorodeoxyglucose (FDG) PET] in numerous Alzheimer's disease (AD) studies. However, there is a lack of longitudinal studies evaluating the interrelationships of these two different pathological markers in the same AD population. Our most recent AD study suggested that the longitudinal pattern of hypometabolism anatomically follows the pattern of amyloid deposition with temporal delay, which indicates that neuronal dysfunction may spread within the anatomical pattern of amyloid pathology. Based on this finding we now hypothesize that in early AD patients quantitative longitudinal decline in hypometabolism may be related to the amount of baseline amyloid deposition during a follow-up period of 2 years. METHODS: Fifteen patients with mild probable AD underwent baseline (T1) and follow-up (T2) examination after 24 +/- 2.1 months with [(18)F]FDG PET, [(11)C]PIB PET, structural T1-weighted MRI and neuropsychological testing [Consortium to Establish a Registry for Alzheimer's Disease (CERAD) neuropsychological battery]. Longitudinal cognitive measures and quantitative PET measures of amyloid deposition and metabolism [standardized uptake value ratios (SUVRs)] were obtained using volume of interest (VOI)-based approaches in the frontal-lateral-retrosplenial (FLR) network and in predefined bihemispheric brain regions after partial volume effect (PVE) correction of PET data. Statistical group comparisons (SUVRs and cognitive measures) between patients and 15 well matched elderly controls who had undergone identical imaging procedures once as well as Pearson's correlation analyses within patients were performed. RESULTS: Group comparison revealed significant cognitive decline and increased mean PIB/decreased FDG SUVRs in the FLR network as well as in several AD-typical regions in patients relative to controls. Concurrent with cognitive decline patients showed longitudinal increase in mean PIB/decrease in mean FDG SUVRs over time in the FLR network and in several AD-typical brain regions. Correlation analyses of FLR network SUVRs in patients revealed significant positive correlations between PIB T1 and delta FDG (FDG T1-T2) SUVRs, between PIB T1 and PIB T2 SUVRs, between FDG T1 and PIB T2 SUVRs as well as between FDG T1 and FDG T2 SUVRs, while significant negative correlations were found between FDG T1 and delta PIB (PIB T1-T2) SUVRs as well as between FDG T2 and delta FDG (FDG T1-T2) SUVRs. These findings were confirmed in locoregional correlation analyses, revealing significant associations in the same directions for two left hemispheric regions and nine right hemispheric regions, showing the strongest association for bilateral precuneus. CONCLUSION: Baseline amyloid deposition in patients with mild probable AD was associated with longitudinal metabolic decline. Additionally, mildly decreased/relatively preserved baseline metabolism was associated with a longitudinal increase in amyloid deposition. The latter bidirectional associations were present in the whole AD-typical FLR network and in several highly interconnected hub regions (i.e. in the precuneus). Our longitudinal findings point to a bidirectional quantitative interrelationship of the two investigated AD pathologies, comprising an initial relative maintenance of neuronal activity in already amyloid-positive hub regions (neuronal compensation), followed by accelerated amyloid deposition, accompanied by functional neuronal decline (neuronal breakdown) along with cognitive decline. PMID- 22926715 TI - Weight loss surgery for mild to moderate obesity: a systematic review and economic evaluation. AB - BACKGROUND: A systematic review and economic evaluation was commissioned to determine the effectiveness and cost-effectiveness of bariatric surgery for mild [class I, body mass index (BMI) 30 to 34.99] or moderate (class II, BMI 35 to 39.99) obesity. METHODS: We searched 17 electronic resources (to February 2010) and other sources. Studies meeting predefined criteria were identified, data extracted and assessed for risk of bias using standard methodology. A model was developed to estimate cost-effectiveness. RESULTS: Two RCTs were included. Evidence from both indicated a statistically significant benefit from laparoscopic adjustable banding (LAGB) compared to a non-surgical comparator for weight loss and in obesity-related comorbidity. Both interventions were associated with adverse events. LAGB costs more than non-surgical management. For people with class I or II obesity and type 2 diabetes (T2D), the incremental cost effectiveness ratio (ICER) at 2 years is L20,159, reducing to L4,969 at 5 years and L1,634 at 20 years. Resolution of T2D makes the greatest contribution to this reduction. In people with class I obesity, the ICER is L63,156 at 2 years, L17,158 at 5 years, and L13,701 at 20 years. Cost-effectiveness results are particularly sensitive to utility gain from reduction in BMI, factors associated with poorer surgical performance and diabetes health state costs. CONCLUSIONS: Bariatric surgery appears to be a clinically effective and cost-effective intervention for people with class I or II obesity who also have T2D but is less likely to be cost-effective for people with class I obesity. PMID- 22926716 TI - Complete genome sequences of two begomoviruses infecting weeds in Venezuela. AB - The complete sequences of isolates of two new bipartite begomoviruses (genus Begomovirus, family Geminiviridae) found infecting weeds in Venezuela are provided. The names proposed for these new begomoviruses are "Datura leaf distortion virus" (DLDV), isolated from a Datura stramonium L. (family Solanaceae) plant, and "Dalechampia chlorotic mosaic virus" (DCMV), isolated from infected Dalechampia sp. (family Euphorbiaceae) and Boerhavia diffusa L. (family Nyctaginaceae) plants. Phylogenetic analysis showed that these new begomoviruses segregated in two distinct clades of New World begomoviruses. To our knowledge, this is the first record of a begomovirus infecting Dalechampia sp. plants. Also, this is the first report of a begomovirus infecting Boerhavia spp. and Datura spp. in Venezuela. PMID- 22926717 TI - Porcine kobuvirus in wild boars (Sus scrofa). AB - Fecal samples (N = 10) from 6- to 8-week-old wild boar piglets (Sus scrofa), collected from an animal park in Hungary in April 2011, were analyzed using viral metagenomics and complete genome sequencing. Kobuvirus (genus Kobuvirus, family Picornaviridae) was detected in all (100 %) specimens, with the closest nucleotide (89 %) and amino acid (94 %) sequence identity of the strain wild boar/WB1-HUN/2011/HUN (JX177612) to the prototype porcine kobuvirus S-1-HUN (EU787450). This study suggests that genetically highly similar (practically the same geno-/serotype) porcine kobuvirus circulate in wild boars, the wildlife counterparts of domestic pigs. Wild boars could be an important host and reservoir for kobuvirus. PMID- 22926719 TI - Vitamin D deficiency in patients with Graves' disease: probably something more than a casual association. PMID- 22926720 TI - Achromobacter xylosoxidans: an emerging pathogen carrying different elements involved in horizontal genetic transfer. AB - In the last few years, numerous cases of multidrug-resistant Achromobacter xylosoxidans infections have been documented in immunocompromised and cystic fibrosis patients. To gain insights into the molecular mechanisms and mobile elements related to multidrug resistance in this bacterium, we studied 24 non epidemiological A. xylosoxidans clinical isolates from Argentina. Specific primers for plasmids, transposons, insertion sequences, bla(ampC), intI1, and intI2 genes were used in PCR reactions. The obtained results showed the presence of wide host range IncP plasmids in ten isolates and a high dispersion of class 1 integrons (n = 10) and class 2 integrons (n = 3). Four arrays in the variable region (vr) of class 1 integrons were identified carrying different gene cassettes as the aminoglycoside resistance aac(6')-Ib and aadA1, the trimethoprim resistance dfrA1 and dfrA16, and the beta-lactamase bla(OXA-2). In only one of the class 2 integrons, a vr was amplified that includes sat2-aadA1. The bla(ampC) gene was found in all isolates, confirming its ubiquitous nature. Our results show that A. xylosoxidans clinical isolates contain a rich variety of genetic elements commonly associated with resistance genes and their dissemination. This supports the hypothesis that A. xylosoxidans is becoming a reservoir of horizontal genetic transfer elements commonly involved in spreading antibiotic resistance. PMID- 22926721 TI - Hemispheric asymmetry of auditory steady-state responses to monaural and diotic stimulation. AB - Amplitude modulations in the speech envelope are crucial elements for speech perception. These modulations comprise the processing rate at which syllabic (~3 7 Hz), and phonemic transitions occur in speech. Theories about speech perception hypothesize that each hemisphere in the auditory cortex is specialized in analyzing modulations at different timescales, and that phonemic-rate modulations of the speech envelope lateralize to the left hemisphere, whereas right lateralization occurs for slow, syllabic-rate modulations. In the present study, neural processing of phonemic- and syllabic-rate modulations was investigated with auditory steady-state responses (ASSRs). ASSRs to speech-weighted noise stimuli, amplitude modulated at 4, 20, and 80 Hz, were recorded in 30 normal hearing adults. The 80 Hz ASSR is primarily generated by the brainstem, whereas 20 and 4 Hz ASSRs are mainly cortically evoked and relate to speech perception. Stimuli were presented diotically (same signal to both ears) and monaurally (one signal to the left or right ear). For 80 Hz, diotic ASSRs were larger than monaural responses. This binaural advantage decreased with decreasing modulation frequency. For 20 Hz, diotic ASSRs were equal to monaural responses, while for 4 Hz, diotic responses were smaller than monaural responses. Comparison of left and right ear stimulation demonstrated that, with decreasing modulation rate, a gradual change from ipsilateral to right lateralization occurred. Together, these results (1) suggest that ASSR enhancement to binaural stimulation decreases in the ascending auditory system and (2) indicate that right lateralization is more prominent for low-frequency ASSRs. These findings may have important consequences for electrode placement in clinical settings, as well as for the understanding of low-frequency ASSR generation. PMID- 22926722 TI - Vulnerability to cavitation of central California Arctostaphylos (Ericaceae): a new analysis. AB - A recent study, 'Influence of summer marine fog and low cloud stratus on water relations of evergreen woody shrubs (Arctostaphylos: Ericaceae) in the chaparral of central California' by M. Vasey, M.E. Loik, and V.T. Parker (2012, Oecologia, in press), presented data on the vulnerability to cavitation of eight Arctostaphylos species. We reanalyzed the vulnerability data presented in this manuscript using a different statistical model and have arrived at different conclusions than those reported previously. We suggest that regional differences have not lead to differentiation in cavitation resistance among populations of an Arctostaphylos species and, contrary to the conclusions of Vasey et al., the xylem of maritime species appears to be "overbuilt" for their current environment and do not appear to be especially vulnerable to water stress. Importantly, data on vulnerability to cavitation are limited for Arctostaphylos species from these sites. More specifically, treatment factors of site and region were not replicated and therefore conclusions drawn from these data are necessarily limited. PMID- 22926723 TI - The role of fire in structuring trait variability in Neotropical savannas. AB - Intraspecific trait variability plays a fundamental role in community structure and dynamics; however, few studies have evaluated its relative importance to the overall response of communities to environmental pressures. Since fire is considered a key factor in Neotropical savannas, we investigated to what extent the functional effects of fire in a Brazilian savanna occurs via intra- or interspecific trait variability. We sampled 12 traits in communities subjected to three fire regimes in the last 12 years: annual, biennial, and protected. To evaluate fire's relative effects, we fitted a general linear mixed models with species as random and fire as fixed factors, using: (1) all species in the communities (i.e., considering intra- and interspecific variabilities); (2) 18 species common to all fire regimes (i.e., intraspecific variability only); and (3) all species with their overall average trait values (i.e., interspecific variability only). We assessed the relative role of intra- or interspecific variability by comparing the significance of each trait in the three analyses. We also compared the within and between fire variabilities with a variance component analysis. Five traits presented larger intraspecific than interspecific variability, and the main effect of fire occurred at the intraspecific level. These results confirm that it is important to consider intraspecific variability to fully understand fire-prone communities. Moreover, trait variability was larger within than among fire regimes. Thus, fire may act more as an external filter, preventing some of the species from the regional pool from colonizing the cerrado, than as an internal factor structuring the already filtered cerrado communities. PMID- 22926724 TI - Predator hunting mode influences patterns of prey use from grazing and epigeic food webs. AB - Multichannel omnivory by generalist predators, especially the use of both grazing and epigeic prey, has the potential to increase predator abundance and decrease herbivore populations. However, predator use of the epigeic web (soil surface detritus/microbe/algae consumers) varies considerably for reasons that are poorly understood. We therefore used a stable isotope approach to determine whether prey availability and predator hunting style (active hunting vs. passive web-building) impacted the degree of multichannel omnivory by the two most abundant predators on an intertidal salt marsh, both spiders. We found that carbon isotopic values of herbivores remained constant during the growing season, while values for epigeic feeders became dramatically more enriched such that values for the two webs converged in August. Carbon isotopic values for both spider species remained midway between the two webs as values for epigeic feeders shifted, indicating substantial use of prey from both food webs by both spider species. As the season progressed, prey abundance in the grazing food web increased while prey abundance in the epigeic web remained constant or declined. In response, prey consumption by the web-building spider shifted toward the grazing web to a much greater extent than did consumption by the hunting spider, possibly because passive web capture is more responsive to changes in prey availability. Although both generalist predator species engaged in multichannel omnivory, hunting mode influenced the extent to which these predators used prey from the grazing and epigeic food webs, and could thereby influence the strength of trophic cascades in both food webs. PMID- 22926725 TI - A review of global cancer burden: trends, challenges, strategies, and a role for surgeons. AB - Cancer is one of the leading causes of death worldwide. The global cancer burden (GCB) is expected to rise significantly and will disproportionately affect the less developed world (LDW). The aim of this review is to analyze the trends in GCB and describe the types, estimates, and causes of new cancer cases. The challenges and strategies associated with tackling this rising GCB are described in which surgeons can play a vital role. PMID- 22926726 TI - [Disruptive sexual behaviour among patients with dementia]. AB - In addition to diagnostically decisive cognitive problems, behavioural and psychological symptoms (BPSD) are frequent among people with dementia, including sexually related behavioural problems. This paper provides an overview on the state of knowledge about these problems. Research on this topic is hampered by the absence of unanimous definitions, aetiological classifications, and diagnostic instruments. The wide range of prevalence rates reported (1.8 - 18 %) originate from the heterogenity of study samples as well as in the variety of definitions and instruments employed. Regarding aetiology, dysfunctions in various cortical regions are being discussed. Sexually related behavioural problems are more prevalent in men and among patients with vascular, frontotemporal and Parkinson-associated forms of dementia, as compared with dementias of the Alzheimer type. The pharmacological and non-pharmacological treatment strategies published to date have not been sufficiently studied. PMID- 22926727 TI - Validity of the Thai EQ-5D in an occupational population in Thailand. AB - PURPOSE: To assess the construct validity of the Thai EuroQoL (EQ-5D) among an occupational population in Thailand. METHODS: Data were derived from a large cohort study among employees of the Electricity Generating Authority of Thailand. In 2008 and 2009, 4,850 participants completed the Thai EQ-5D and Short-Form 36 version 2 (SF-36v2). Thai preferences weights were used to convert EQ-5D health states into EQ-5D index scores. Construct validity of the Thai EQ-5D was examined by specifying and testing hypotheses about the relationships between the EQ-5D, SF-36v2, and participants' demographic and medical characteristics. RESULTS: Construct validity of the Thai EQ-5D was supported by expected relationships with SF-36v2 scale and summary scores. For example, SF-36v2 scores on the mental health scale were much lower for participants who reported having problems on the EQ-5D anxiety/depression dimension compared to those reporting no problems (mean norm-based SF-36v2 scores: 52.9 vs. 41.8, p < 0.001). Additionally, reporting a problem in a given EQ-5D dimension was generally associated with lower SF-36v2 summary scores. The EQ-5D index score distinguished between groups of participants in the expected manner, on the basis of sex, age, education and self reported health, thus providing evidence of known-groups validity. CONCLUSION: The study demonstrated good construct validity of the Thai EQ-5D in a large occupational population in Thailand. PMID- 22926728 TI - Acute mesenteric ischemia in young adults. AB - Acute mesenteric ischemia is commonly seen in old patients. This study was undertaken to show that mesenteric ischemia might be seen in individuals under 40 years of age and that its diagnosis is challenging. Twenty-six patients with acute mesenteric ischemia under the age of 40 were studied. The main symptom on admission was abdominal pain. Symptom duration varied between 12 h and 5 days. The medical history of the patients revealed that 9 had no previous diseases. Other 17 had predisposing factors in the first evaluation. None of the patients had any history of narcotic or drug abuse. Ten patients presented with signs and symptoms of sepsis and septic shock. Preoperative diagnosis was acute intestinal ischemia only in 6 patients. Preoperatively, all the patients had intestinal or colonic ischemia and necrosis; one had additional ischemia of the liver, stomach, duodenum, and pancreas. Six patients had massive intestinal necrosis. The overall postoperative complication and overall mortality rates were 61.5 and 26.9 %, respectively. Complications and mortality were determined to be associated with previous pulmonary disease, acidosis, presence of septic shock, acute renal failure, extent of the ischemia and extent of resection, second look operations, previous cardiac events, and the kind of affected bowel (colon involvement). PMID- 22926729 TI - [Clinical outcomes, health-related quality of life, and cost-effectiveness of a 6 month community- based lifestyle program for adults at increased cardiovascular risk in lower Austria]. AB - AIM: To investigate lifestyle intervention effects and cost-effectiveness of a structured 6-month exercise and nutrition program for individuals at high risk for cardiovascular disease. METHODS: Uncontrolled before and after study with assessments at baseline and six months. Adults without existing cardiovascular disease (CVD) but at increased CVD risk were eligible. The analysis was done by intention-to-treat (last-observation-carried-forward). Incremental cost effectiveness analysis was performed. Main outcome measures were changes in cardiovascular risk-factors (blood pressure, weight, body-mass index, serum lipids, blood glucose, smoking cessation, and exercise) and health-related quality of life. RESULTS: A total of 356 adults (70.5% female; mean age 48.9 years; mean body mass index 32.4; drop-out 10.4%) participated. At 6 months significant favorable effects were observed in several cardiovascular risk outcomes, exercise behaviour and health related quality of life. At an average incremental cost per life year saved for the ITT-population of 22.474 the program can be considered cost-effective. PMID- 22926730 TI - Gastroprotective effects of extracts and guttiferone A isolated from Garcinia achachairu Rusby (Clusiaceae) against experimentally induced gastric lesions in mice. AB - This study was undertaken to evaluate the gastroprotective properties of seed, leaf, and branch methanolic extracts and guttiferone A obtained from Garcinia achachairu (Clusiaceae). Mice were used in all the models, and treatments were administered orally only in pylorus-ligated model of the extracts, and drugs were administered intraduodenally. Treatment with different extracts (500 mg/kg) significantly reduced the ulcerative lesions in the ethanol/HCl-induced model; however, the seed extract was most active. When tested in different doses (50, 250, or 500 mg/kg), the seed extract of G. achaicharu showed a dose-dependent effect with a percentage of inhibition of gastric lesions of 41, 49, and 85 %, respectively. The seed extract also significantly reduced the ulcerative lesions in the indomethacin/bethanechol-induced ulcer. In this model, the percentage of inhibition of ulcer was 24, 58, and 90 %, respectively. Regarding the model of gastric secretion, a reduction of gastric juice volume and total acidity was observed, as well as an increase in gastric pH. Considering that the seed extract was the most active, it was subjected to silica gel column chromatography, leading to the isolation of guttiferone A. The isolated compound and omeprazole were evaluated in the HCl/ethanol-induced ulcer model. In this assay, both compounds at a dose of 30 mg/kg reduced the ulcerative lesions by about 75 %. These results demonstrate, for the first time, that extracts obtained from G. achachairu and guttiferone A produce gastroprotective effects, corroborating ethnomedicinal use of this plant. PMID- 22926731 TI - Cancer-associated variants and a common polymorphism of MUTYH exhibit reduced repair of oxidative DNA damage using a GFP-based assay in mammalian cells. AB - Biallelic germline mutations in the base excision repair enzyme gene MUTYH lead to multiple colorectal adenomas and carcinomas referred to as MUTYH-associated polyposis. MUTYH removes adenine misincorporated opposite the DNA oxidation product, 8-oxoguanine (OG), thereby preventing accumulation of G:C to T:A transversion mutations. The most common cancer-associated MUTYH variant proteins when expressed in bacteria exhibit reduced OG:A mismatch affinity and adenine removal activity. However, direct evaluation of OG:A mismatch repair efficiency in mammalian cells has not been assessed due to the lack of an appropriate assay. To address this, we developed a novel fluorescence-based assay of OG:A repair and measured the repair capacity of MUTYH-associated polyposis variants expressed in Mutyh-/- mouse embryonic fibroblasts (MEFs). The repair of a single site-specific synthetic lesion in a green fluorescent protein reporter leads to green fluorescent protein expression with co-expression of a red fluorescent protein serving as the transfection control. Cell lines that stably express the MUTYH associated polyposis variants G382D and Y165C have significantly lower OG:A repair versus wild-type MEFs and MEFs expressing human wild-type MUTYH. The MUTYH allele that encodes the Q324H variant is found at a frequency above 40% in samples from different ethnic groups and has long been considered phenotypically silent but has recently been associated with increased cancer risk in several clinical studies. In vitro analysis of Q324H MUTYH expressed in insect cells showed that it has reduced enzyme activity similar to that of the known cancer variant G382D. Moreover, we find that OG:A repair in MEFs expressing Q324H was significantly lower than wild-type controls, establishing that Q324H is functionally impaired and providing further evidence that this common variant may lead to increased cancer risk. PMID- 22926732 TI - Mercury exposure among artisanal gold miners in Madre de Dios, Peru: a cross sectional study. AB - INTRODUCTION: Exposure to mercury, a toxic metal, occurs primarily from inhaling mercury vapors or consuming methylmercury-contaminated fish. One third of all anthropogenic mercury emissions worldwide are from artisanal gold mining, which uses mercury to extract gold. Although recent reports suggest that the Madre de Dios region in Peru (with >30,000 artisanal miners) has extensive mercury contamination, residents had never been assessed for mercury exposure. Thus, our objective was to quantify mercury exposure among residents of an artisanal mining town in Madre de Dios and to assess risk factors for exposure. METHODS: We conducted a cross-sectional assessment of 103 residents of an artisanal gold mining town in July 2010. Each participant provided a urine and blood sample and completed a questionnaire assessing potential exposures and health outcomes. We calculated geometric mean (GM) urine total mercury and blood methylmercury concentrations and compared log-transformed concentrations between subgroups using linear regression. RESULTS: One third (34.0 %) of participants were gold miners. All participants had detectable urine total mercury (GM, 5.5 MUg/g creatinine; range, 0.7-151 MUg/g creatinine) and 91 % had detectable blood methylmercury (GM, 2.7 MUg/L; range, 0.6-10 MUg/L); 13 participants (13 %) reported having kidney dysfunction or a neurological disorder. Urine total mercury concentrations were higher among people who heated gold-mercury amalgams compared with people who never heated amalgams (p < 0.05); methylmercury concentrations were higher among fish consumers compared with nonfish consumers (p < 0.05). CONCLUSION: Our findings suggest that mercury exposure may be widespread in Huaypetue. PMID- 22926734 TI - Comprehensive method based on model free method and IKP method for evaluating kinetic parameters of solid state reactions. AB - This article presents, firstly, a short review of methods for evaluating kinetic parameters of solid state reactions and a critical analysis of the isoconversional principle of model free methods. It shows theoretically that the activation energy for complex reactions is not only a function of the reaction degree but also of heating programs, and points out that any method that attempts to extract the dependences of activation energy on conversion degree without considering the dependences of heating programs is problematic. Then an analysis is given of the invariant kinetic parameters (IKP) method and recommends an incremental version of it. Based on the incremental IKP method and model free method, a comprehensive method is proposed that predicts the degree of the dependences of activation energy on heating programs, selects reliable values of activation energy and extracts the values of variable pre-exponential factor. This comprehensive method is tested using both simulation data and experimental data, the results of which show it can not only give reliable values of kinetic parameters but also be helpful in explaining inconsistencies of kinetic results in solid state reactions. PMID- 22926733 TI - Life-threatening hyperkalemia from cream of tartar ingestion. AB - INTRODUCTION: Cream of tartar (potassium bitartrate) has a long history as a cooking aid and medicinal purgative. Despite containing large amounts of potassium, there are no well-documented cases of it causing toxicity. We report two cases in which intentional ingestions of cream of tartar resulted in life threatening hyperkalemia. In addition, we briefly review the use of cream of tartar as a historical purgative. CASE REPORTS: In both cases, individuals ingested a large quantity of cream of tartar in an effort to "clean themselves out". They manifested similar initial symptoms (vomiting), abnormal serum potassium (>8.0 mmol/L), and EKG's with peaked T waves. Both patients were treated for hyperkalemia and recovered without complication. A search for articles on an academic internet database failed to identify any cases specifically dealing with ill effects of potassium bitartrate and numerous websites continue to purport its beneficial health effects. CONCLUSION: Ingestion of cream of tartar can potentially result in life-threatening hyperkalemia. PMID- 22926735 TI - Comprehensive evaluation of a somatostatin-based radiolabelled antagonist for diagnostic imaging and radionuclide therapy. AB - PURPOSE: Targeting of tumours positive for somatostatin receptors (sst) with radiolabelled peptides is of interest for tumour localization, staging, therapy follow-up and targeted radionuclide therapy. The peptides used clinically are exclusively agonists, but recently we have shown that the radiolabelled somatostatin-based antagonist (111)In-DOTA-sst2-ANT may be preferable to agonists. However, a comprehensive study of this radiolabelled antagonist to determine its significance was lacking. The present report describes the evaluation of this novel antagonist labelled with (111)In and (177)Lu in three different tumour models. METHODS: Radiopeptide binding, internalization and dissociation studies were performed using cells expressing HEK293-rsst(2). Biodistribution studies were performed in HEK293-rsst(2), HEK293-hsst(2) and HEK293-rsst(3) xenografted mice. RESULTS: Saturation binding analysis confirmed earlier IC(50) data for (111/nat)In-DOTA-sst2-ANT and showed similar affinity of (177/nat)Lu-DOTA-sst2-ANT for the sst(2). Only low internalization was found in cell culture (6.68 +/- 0.06 % at 4 h), which was not unexpected for an antagonist, and this could be further reduced by the addition of sucrose. No internalization was observed in HEK293 cells not expressing sst. Both results indicate that the internalization was specific. (111)In-DOTA-sst2-ANT and (177)Lu DOTA-sst2-ANT were shown to target tumour xenografts expressing the rat and the human sst(2) receptor with no differences in their uptake or pharmacokinetics. The uptake in rsst(2) and hsst(2) was high (about 30 %IA/g 4 h after injection) and surprisingly long-lasting (about 20-23 %IA/g 24 h after injection). Kidney uptake was blocked by approximately 50 % by lysine or Gelofusine. CONCLUSION: These results indicate that radiolabelled somatostatin-based antagonists may be superior to corresponding agonists. The long tumour retention time of (177)Lu DOTA-sst2-ANT indicates that this new class of compounds is of relevance not only in diagnostic imaging but also in targeted radionuclide therapy of sst-positive tumours. PMID- 22926736 TI - Low penetrance alleles as risk modifiers in familial and sporadic breast cancer. AB - The aim of the study is to investigate the relevance of rs1056663 and rs2708861 HUS1 polymorphisms, and rs104548, rs2981582 and rs2910164 polymorphisms of CASP8, FGFR2 and micro RNA 146A genes, respectively, as risk modifiers in hereditary breast or ovarian cancer (BC/OC) and risk factors in sporadic BC. We performed a case-control study in 189 healthy controls (CG) and 538 BC/OC cases, 340 with familial history of BC/OC (130 carriers of BRCA1/2 mutations and 210 non carriers) and 198 sporadic BC/OC. The polymorphisms were assessed by real-time PCR using primers and fluorescent-labelled hybridization probes. We found statistically significant differences between familial BC/OC and CG for rs1056663 and rs2708861 HSU1 polymorphisms and rs2981582 FGFR2 polymorphism, particularly in non-carriers of BRCA1/2 mutations. In this group we found statistical differences for rs1056663 HSU1 and rs2981582 FGFR2 polymorphisms (p-trend < 0.006). The logistic regression confirmed that rs2981582 FGFR2 polymorphism (OR = 2.09; 95 % CI 1.35, 3.20) and the interaction between rs1056663 and rs2708861 HUS1 polymorphisms increased the risk of cancer (OR = 1.87; 95 % CI 1.19, 2.92). Furthermore, we found that the presence of rs1056663 and rs2708861 HUS1 polymorphisms is associated with early age of presentation of BC (p = 0.015) in the group of non-carriers of BRCA1/2 mutations. In addition, no association of the polymorphisms studied in sporadic BC was observed. In conclusion, the HUS1 and FGFR2 polymorphisms act as risk BC modifiers in familial BC/OC, particularly in the group of non-carriers of BRCA1/2 mutations. PMID- 22926737 TI - Delayed detection of clinically significant posterior cruciate ligament injury after peri-articular fracture around the knee of 448 patients. AB - BACKGROUND: The purpose of this study was to report the frequency with which posterior cruciate ligament (PCL) injuries occurred in combination with peri articular fractures around the knee, and to determine the frequency with which the detection of these PCL injuries was delayed (i.e., detected in an outpatient clinic after fracture treatment). METHODS: This retrospective study included 448 subjects with peri-articular fractures around the knee, including femoral shaft fractures, distal femoral fractures, patellar fractures, tibial plateau fractures, and tibial shaft fractures. The PCL injuries were detected through clinical examination, magnetic resonance imaging, and stress X-rays. We determined both the frequency of PCL injuries that occurred in combination with peri-articular fractures around the knee, and the frequency with which the detection of these PCL injuries was delayed. We also compared the frequency with which PCL injuries were associated with either isolated or combined fractures for different fracture types. RESULTS: We identified concomitant PCL injury and peri articular fracture of the knee in 7.8 % of patients. In 22 of the 35 patients with concomitant PCL injury, the detection of the PCL injury was delayed. There were significant differences in the frequency with which PCL injuries were associated with isolated or combined fractures of the femoral shaft (P = 0.04), patella (P = 0.03), and distal femur (P = 0.03). CONCLUSION: The delayed detection frequency was high for PCL injury after peri-articular fracture around the knee. PMID- 22926743 TI - Patient preferences and willingness to pay for different options of anticoagulant therapy. AB - New anticoagulant drugs alternative to vitamin K antagonists are currently under clinical evaluation. Patient's preferences should be considered in the development of new therapeutic strategies. Our study aim was to elicit patient preferences, and estimate their willingness to pay for the different treatment options. A Discrete Choice Experiment was administered to patients consecutively attending an anticoagulation clinic, either on stable oral anticoagulant therapy, or during their first visit at the time of starting therapy. Six treatment characteristics were analysed: route and number of medication administrations, frequency of monitoring, risk of some minor bleeding, the amount of attention required for drug/food interactions, requirement for dose adjustment, and out-of pocket treatment cost. Relationships between patient's preferences and their characteristics were analysed. 255 patients participated (55 % men, with a mean age 64 years; 35.7 % on stable therapy). A statistically significant importance was attributed to all but two characteristics (the amount of attention required for interaction with other drugs/food and for dose adjustment.) Monthly patient willingness to pay was 79 for tablets versus injections; 41 for once-daily versus twice-daily tablets, 25 for drugs without risk of minor bleeding events and 20 for once-monthly versus twice-monthly monitoring. Patients on stable therapy considered more important the amount of attention required for drug/food interactions than did the starters. Younger or working patients considered the reduction of monitoring frequency more important than did the older or not working patients (retired, housewives). This study elicited preferences from patients on oral anticoagulant therapy with a simple and well established method, which allows to obtain information warranted for planning optimal healthcare. PMID- 22926738 TI - Continuous glucose monitoring in type 1 diabetes. AB - Continuous glucose monitors (CGM), devices that can measure interstitial glucose in "real time," have become widely available particularly for use in patients with diabetes, and their accuracy and ease of use have greatly improved over the last decade. A number of large and well-controlled clinical trials have firmly established their usefulness in improving metabolic control (as measured by HbA1C) and decreasing time spent in hypoglycemia in adults; however, data have been less robust proving benefit in children and adolescents. Benefits are clearly linked to near-continuous wear. Insulin dosing algorithms based on CGM glucose trends have proven useful in dissecting the large volume of data generated daily by these devices, although these are imperfect tools, particularly in children. The technology is likely to be most useful when integrated with insulin pump delivery systems (sensor augmented). In this review, we concentrate on the analysis of published results of the largest trials in adults and children, including the very young, with diabetes. PMID- 22926744 TI - Early antipyretic exposure does not increase mortality in patients with gram negative severe sepsis: a retrospective cohort study. AB - Existing data suggest that antipyretic medications may have deleterious effects on immune function and may increase mortality in human infection. This study was designed to evaluate the impact of antipyretic therapy on 28-day in-hospital mortality when administered early in the course of gram-negative severe sepsis or septic shock. This study was a single-center retrospective cohort study at a 1,111-bed academic medical center of all febrile patients with gram-negative bacteremia hospitalized with severe sepsis or septic shock (n = 278) between Jan 2002 and Feb 2008. Although the raw mortality was lower in the group that received an early antipyretic medication (22 vs. 35 %, p = 0.01), patients in the early antipyretic group had higher mean arterial pressure (58.0 vs. 52.7, p = 0.01) and higher 24-h T (max) (39.3 vs. 39.0, p < 0.01). Early antipyretic therapy was not significantly associated with 28-day in-hospital mortality (adjusted OR 0.55, 0.29-1.03) in a multivariable logistic regression model controlling for APACHE-II score, hypotension, pneumonia, surgery during hospitalization, persistent fever, and in-hospital dialysis. In conclusion, early antipyretic therapy is not associated with increased mortality. PMID- 22926745 TI - Reactive oxygen species, ascorbate-glutathione pool, and enzymes of their metabolism in drought-sensitive and tolerant indica rice (Oryza sativa L.) seedlings subjected to progressing levels of water deficit. AB - Water deficit for rice is a worldwide concern, and to produce drought-tolerant varieties, it is essential to elucidate molecular mechanisms associated with water deficit tolerance. In the present study, we investigated the differential responses of nonenzymatic antioxidants ascorbate (AsA), glutathione (GSH), and their redox pool as well as activity levels of enzymes of ascorbate-glutathione cycle in seedlings of drought-sensitive rice (Oryza sativa L.) cv. Malviya-36 and drought-tolerant cv. Brown Gora subjected to water deficit treatment of -1.0 and 2.1 MPa for 24-72 h using PEG-6000 in sand cultures. Water deficit caused increased production of reactive oxygen species such as O2[Symbol: see text](-), H2O2, and HO[Symbol: see text] in the tissues, and the level of production was higher in the sensitive than the tolerant cultivar. Water deficit caused reduction in AsA and GSH and decline in their redox ratios (AsA/DHA and GSH/GSSG) with lesser decline in tolerant than the sensitive seedlings. With progressive level of water deficit, the activities of monodehydroascorbate reductase, dehydroascorbate reductase, ascorbate peroxidase (APX), and glutathione transferase increased in the seedlings of both rice cultivars, but the increased activity levels were higher in the seedlings of drought-tolerant cv. Brown Gora compared to the sensitive cv. Malviya-36. Greater accumulation of proline was observed in stressed seedlings of tolerant than the sensitive cultivar. In-gel activity staining of APX revealed varying numbers of their isoforms and their differential expression in sensitive and tolerant seedlings under water deficit. Results suggest that an enhanced oxidative stress tolerance by a well-coordinated cellular redox state of ascorbate and glutathione in reduced forms and induction of antioxidant defense system by elevated activity levels of enzymes of ascorbate glutathione cycle is associated with water deficit tolerance in rice. PMID- 22926746 TI - The reliability of arthroscopic classification of acetabular rim labrochondral disease. AB - BACKGROUND: The results of surgical treatment for femoroacetabular impingement have been increasingly reported, and more advanced intra-articular disease has been identified as an important predictive factor of outcome. Yet, the reliability of arthroscopic hip disease classification has not been well defined. Purpose/ HYPOTHESIS: To determine the intraobserver and interobserver reliability of the Beck classification of labral and articular cartilage disease (anterior-superior acetabular rim) encountered in hip arthroscopy. Secondly, we identified the sources of poor reliability that may be improved with future disease classification schemes. Our hypothesis was that the Beck classification of labral and chondral lesions would demonstrate substantial reliability, while the differentiation of early forms of disease would be a common source of disagreement. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: Four experienced hip arthroscopists reviewed standardized arthroscopic videos of 40 cases. Arthroscopic findings at the anterior-superior acetabular rim were classified using the Beck classification of labral and articular cartilage disease. Repeat classification of videos was performed at least 2 weeks later. The reliability of arthroscopic classification was defined using the average weighted Cohen kappa values and agreement rates. RESULTS: Arthroscopic classification of labral disease using the Beck classification demonstrated moderate to substantial interobserver reliability (average kappa = .62; range, .48-.78) and an overall agreement rate of 81.7%. Intraobserver reliability showed a similar level of reliability (average kappa = .65; agreement rate, 80.6%). The differentiation between labral degeneration and labral detachment was a common source of disagreement. Similarly, the Beck classification of articular cartilage disease had moderate to substantial interobserver reliability (average kappa = .65; range, .49-.78) and overall agreement rate of 57.5%. Intraobserver reliability showed a slightly better level of reliability (average kappa = .80; agreement rate, 77.5%). The differentiation between articular cartilage malacia and debonding was a common source of disagreement. CONCLUSION: The arthroscopic classification of acetabular rim disease with the Beck classification has substantial interobserver reliability. This level of reliability is similar to previously reported arthroscopic disease classifications in the knee and shoulder and seems appropriate for future outcome reporting. Future classifications that eliminate common sources of disagreement may further improve the reliability. PMID- 22926747 TI - High prevalence of self-reported symptoms of digital ischemia in elite male volleyball players in the Netherlands: a cross-sectional national survey. AB - BACKGROUND: In the past 3 years, 6 volleyball players with ischemic digits and small microemboli in the digital arteries of the dominant hand presented themselves in our hospital. These complaints were caused by an aneurysmatic dilation of the posterior circumflex humeral artery (PCHA) with distal occlusion and digital emboli in the isolateral limb. All were elite male volleyball players active in the national top league. Little is known about the exact symptoms associated with PCHA pathological lesions with digital emboli (PCHAP with DE) and its prevalence in elite volleyball players. If vascular injury can be identified at an early stage, thromboembolic complications and irreversible damage to the digits might be prevented. PURPOSE: To assess the prevalence of symptoms that are consistent with digital ischemia and may be caused by PCHAP with DE in elite male volleyball players in the Netherlands. STUDY DESIGN: Cross-sectional study; Level of evidence, 3. METHODS: A questionnaire survey was performed among elite volleyball players in the Dutch national top league and the Dutch beach volleyball team. The questionnaire was constructed using literature-based data on symptoms associated with PCHAP with DE, together with data retrieved from medical files. RESULTS: A total of 99 of the 107 athletes participated, with a response rate of 93%. The most frequently reported symptoms associated with PCHAP with DE were cold, blue, or pale digits in the dominant hand during or immediately after practice or competition. The prevalence of these symptoms ranged from 11% to 27%. The prevalence of cold digits during practice and competition was 27%. The prevalence of cold, blue, and pale digits during or immediately after practice and competition was 12%. CONCLUSION: An unexpectedly high percentage of elite volleyball players reported symptoms that are associated with PCHAP with DE in the dominant hand. Because these athletes are considered potentially at risk for developing critical digital ischemia, further analysis of the presence of digital ischemia and PCHA injury is warranted. PMID- 22926748 TI - Retraction of supraspinatus muscle and tendon as predictors of success of rotator cuff repair. AB - BACKGROUND: The structural failure rate of rotator cuff repair can exceed 50%. Important predictors for repair failure are preoperative fatty muscle infiltration and myotendinous retraction. PURPOSE: To quantitatively assess the prognostic value of preoperative retraction of both the supraspinatus muscle and tendon for the outcome of supraspinatus repair. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: In 33 shoulders with complete supraspinatus tendon ruptures subjected to arthroscopic repair, magnetic resonance imaging (MRI) scans taken preoperatively and after a mean follow-up of 24 months were studied. The exact position of the lateral extension of the supraspinatus muscle and of the tendon end was evaluated and correlated with the preoperative stage of fatty infiltration (Goutallier) and the failure rate of tendon repair. RESULTS: The mean lengthening of the muscle and tendon end was -3 mm and 4 mm in the failed repairs (n = 19) and 14 mm and 8 mm in the successful repairs (n = 14). If the supraspinatus had preoperative Goutallier stages 2 to 3 and a tendon length of less than 15 mm, the failure rate was 92%, but if the tendon length was greater than 15 mm, the failure rate was only 33%. With Goutallier stages 0 to 1, the corresponding failure rates were 57% and 25%, respectively. CONCLUSION: Rotator cuff repair lengthens the tendon, even if the repair fails. The possibility to lengthen the myotendinous unit is related to the preoperative length of the tendon. The combination of Goutallier grading and preoperative tendon length appears to be a more powerful predictor for the reparability of a tendon tear than Goutallier grading alone. PMID- 22926750 TI - A framework to implement Stakeholder participation in environmental projects. AB - Participation has emerged as an appropriate approach for enhancing natural resources management. However, despite long experimentation with participation, there are still possibilities for improvement in designing a process of stakeholder involvement by addressing stakeholder heterogeneity and the complexity of decision-making processes. This paper provides a state-of-the-art overview of methods. It proposes a comprehensive framework to implement stakeholder participation in environmental projects, from stakeholder identification to evaluation. For each process within this framework, techniques are reviewed and practical tools proposed. The aim of this paper is to establish methods to determine who should participate, when and how. The application of this framework to one river restoration case study in Switzerland will illustrate its strengths and weaknesses. PMID- 22926749 TI - Single-legged hop tests as predictors of self-reported knee function after anterior cruciate ligament reconstruction: the Delaware-Oslo ACL cohort study. AB - BACKGROUND: Single-legged hop tests are commonly used functional performance measures that can capture limb asymmetries in patients after anterior cruciate ligament (ACL) reconstruction. Hop tests hold potential as predictive factors of self-reported knee function in individuals after ACL reconstruction. HYPOTHESIS: Single-legged hop tests conducted preoperatively would not and 6 months after ACL reconstruction would predict self-reported knee function (International Knee Documentation Committee [IKDC] 2000) 1 year after ACL reconstruction. STUDY DESIGN: Cohort study (prognosis); Level of evidence, 2. METHODS: One hundred twenty patients who were treated with ACL reconstruction performed 4 single legged hop tests preoperatively and 6 months after ACL reconstruction. Self reported knee function within normal ranges was defined as IKDC 2000 scores greater than or equal to the age- and sex-specific normative 15th percentile score 1 year after surgery. Logistic regression analyses were performed to identify predictors of self-reported knee function within normal ranges. The area under the curve (AUC) from receiver operating characteristic curves was used as a measure of discriminative accuracy. RESULTS: Eighty-five patients completed single-legged hop tests 6 months after surgery and the 1-year follow-up with 68 patients classified as having self-reported knee function within normal ranges 1 year after reconstruction. The crossover hop and 6-m timed hop limb symmetry index (LSI) 6 months after ACL reconstruction were the strongest individual predictors of self-reported knee function (odds ratio, 1.09 and 1.10) and the only 2 tests in which the confidence intervals of the discriminatory accuracy (AUC) were above 0.5 (AUC = 0.68). Patients with knee function below normal ranges were over 5 times more likely of having a 6-m timed hop LSI lower than the 88% cutoff than those with knee function within normal ranges. Patients with knee function within normal ranges were 4 times more likely to have a crossover hop LSI greater than the 95% cutoff than those with knee function below normal ranges. No preoperative single-legged hop test predicted self-reported knee function within normal ranges 1 year after ACL reconstruction (all P > .353). CONCLUSION: Single-legged hop tests conducted 6 months after ACL reconstruction can predict the likelihood of successful and unsuccessful outcome 1 year after ACL reconstruction. Patients demonstrating less than the 88% cutoff score on the 6-m timed hop test at 6 months may benefit from targeted training to improve limb symmetry in an attempt to normalize function. Patients with minimal side-to-side differences on the crossover hop test at 6 months possibly will have good knee function at 1 year if they continue with their current training regimen. Preoperative single-legged hop tests are not able to predict postoperative outcomes. PMID- 22926751 TI - Protocadherin 17 acts as a tumour suppressor inducing tumour cell apoptosis and autophagy, and is frequently methylated in gastric and colorectal cancers. AB - Gastric and colorectal cancers are among the most common cancers worldwide and cause serious cancer mortality. Both epigenetic and genetic disruptions of tumour suppressor genes (TSGs) are frequently involved in their pathogenesis. Here, we studied the epigenetic and genetic alterations of a novel TSG-PCDH17 and its functions in the pathogenesis of these tumours. We found that PCDH17 was frequently silenced and methylated in almost all gastric and colorectal tumour cell lines as well as in ~95% of primary tumours, but not in normal gastric and colonic mucosa. Moreover, its deletion was detected in only 18% of gastric and 12% of colorectal cancer tissues, suggesting that epigenetic and genetic inactivation of PCDH17 are both involved in gastric and colorectal tumourigenesis. PCDH17 protein expression was significantly correlated with low tumour stage and less lymph node metastasis of gastric and colorectal cancer patients, indicating its potential as a tumour marker. Restoring PCDH17 expression inhibited tumour cell growth in vitro and in vivo through promoting apoptosis, as evidenced by increased TUNEL staining and caspase-3 activation. Furthermore, PCDH17-induced autophagy, along with increased numbers of autophagic vacuoles and up-regulated autophagic proteins Atg-5, Atg-12 and LC3B II. Thus, PCDH17 acts as a tumour suppressor, exerting its anti-proliferative activity through inducing apoptosis and autophagy, and is frequently silenced in gastric and colorectal cancers. PCDH17 methylation is a tumour-specific event that could serve as an epigenetic biomarker for these tumours. PMID- 22926752 TI - A time since onset of injection model for hepatitis C spread amongst injecting drug users. AB - Studies of hepatitis C virus (HCV) infection amongst injecting drug users (IDUs) have suggested that this population can be separated into two risk groups (naive and experienced) with different injecting risk behaviours. Understanding the differences between these two groups and how they interact could lead to a better allocation of prevention measures designed to reduce the burden of HCV in this population. In this paper we develop a deterministic, compartmental mathematical model for the spread of HCV in an IDU population that has been separated into two groups (naive and experienced) by time since onset of injection. We will first describe the model. After deriving the system of governing equations, we will examine the basic reproductive number R0, the existence and uniqueness of equilibrium solutions and the global stability of the disease free equilibrium (DFE) solution. The model behaviour is determined by the basic reproductive number, with R0 = 1 a critical threshold for endemic HCV prevalence. We will show that when R0 <= 1, and HCV is initially present in the population, the system will tend towards the globally asymptotically stable DFE where HCV has been eliminated from the population. We also show that when R0 > 1 there exists a unique non-zero equilibrium solution. Then we estimate the value of R0 from epidemiological data for Glasgow and verify our theoretical results using simulations with realistic parameter values. The numerical results suggest that if R0 > 1 and the disease is initially present then the system will tend to the unique endemic equilibrium. PMID- 22926753 TI - SC-1, a sorafenib derivative, shows anti-tumor effects in osteogenic sarcoma cells. AB - Despite significant advances in the treatment of osteosarcoma (OS), overall survival rate of OS patients has remained relatively constant for over two decades and novel approaches are needed to further improve prognosis. Here, we report the anti-tumor effect of SC-1, a novel sorafenib derivative that closely resembles sorafenib structurally but is devoid of kinase inhibitory activity, on OS cells through mediation of signal transducer and activator of transcription 3 (STAT3). SC-1 showed similar effects to sorafenib on growth inhibition and apoptosis, and downregulated phospho-STAT3 (p-STAT3) at tyrosine 705 in all tested OS cell lines (U2OS, HOS, and 143B). Expression of STAT3-driven genes, including cylcin D1 and c-myc, were also repressed by SC-1. Ectopic expression of STAT3 in 143B cells abolished apoptosis in SC-1-treated cells. Inhibition of SHP 1 decreased SC-1-induced apoptosis. SC-1 upregulated the activity of SHP-1 in tested OS cell lines in a dose-dependent manner. Finally, SC-1 reduced 143B tumor growth significantly in vivo, which was associated with downregulation of p-STAT3 and upregulation of SHP-1 activity. These data demonstrate that SC-1 has clinical potential for the treatment of OS patients. PMID- 22926755 TI - Endoscope-assisted vitrectomy for retinal detachment in an eye with microcornea. AB - BACKGROUND: We report a case of an endoscope-assisted vitrectomy for the treatment of retinal detachment associated with microcornea in a normal size globe. SUBJECTS: A 26-year-old Japanese man was referred after complaining of visual acuity loss OD. Both eyes became aphakic because of surgery for congenital cataracts in infancy. The visual acuity was 0.02 OD. The corneal diameter was 7.5 * 7.0 mm and axial length was 23.89 mm. Retinal detachment was suspected, although the details were obscure because of nystagmus and small pupils. Endoscope-assisted, 23-gauge pars plana vitrectomy and encircling buckling were performed, and reattachment of the retina was achieved. OBSERVATIONS: Retinal breaks were identified, and peripheral parts of the retina were observed by endoscopy. CONCLUSIONS: Endoscope-assisted vitrectomy may be advantageous for the management of detachment in an eye with microcornea. PMID- 22926754 TI - Short latency activation of cortex by clinically effective thalamic brain stimulation for tremor. AB - Deep brain stimulation (DBS) relieves disabling symptoms of neurologic and psychiatric diseases when medical treatments fail, yet its therapeutic mechanism is unknown. We hypothesized that ventral intermediate (VIM) nucleus stimulation for essential tremor activates the cortex at short latencies, and that this potential is related to the suppression of tremor in the contralateral arm. We measured cortical activity with electroencephalography in 5 subjects (seven brain hemispheres) across a range of stimulator settings, and reversal of the anode and cathode electrode contacts minimized the stimulus artifact, allowing visualization of brain activity. Regression quantified the relationship between stimulation parameters and both the peak of the short latency potential and tremor suppression. Stimulation generated a polyphasic event-related potential in the ipsilateral sensorimotor cortex, with peaks at discrete latencies beginning less than 1 ms after stimulus onset (mean latencies 0.9 +/- 0.2, 5.6 +/- 0.7, and 13.9 +/- 1.4 ms, denoted R1, R2, and R3, respectively). R1 showed more fixed timing than the subsequent peaks in the response (P < 0.0001, Levene's test), and R1 amplitude and frequency were both closely associated with tremor suppression (P < 0.0001, respectively). These findings demonstrate that effective VIM thalamic stimulation for essential tremor activates the cerebral cortex at approximately 1 ms after the stimulus pulse. The association between this short latency potential and tremor suppression suggests that DBS may improve tremor by synchronizing the precise timing of discharges in nearby axons and, by extension, the distributed motor network to the stimulation frequency or one of its subharmonics. PMID- 22926756 TI - Multimodality, anatomical, and diffusion-weighted fetal imaging of a spontaneously thrombosing congenital dural sinus malformation. AB - We report on the conventional and diffusion-weighted (DWI) magnetic resonance imaging (MRI) findings of a partially thrombosed torcular Herophili dural sinus malformation. DWI confirmed the intralesional partial thrombosis/blood clot characterized by restricted diffusion. In addition, focal or global intracerebral complications were excluded by fetal DWI. Our findings suggest that DWI is a valuable adjunct to the standard T1- and T2-weighted fetal MRI sequences. PMID- 22926758 TI - Bleeding risk assessment using multiple electrode aggregometry in patients following coronary artery bypass surgery. AB - Individual variability in the response to antiplatelet therapy (APT), frequently administered preoperatively, has been established by various platelet function assays and could reflect bleeding tendency after coronary artery bypass surgery (CABG). Our hypothesis is that multiple electrode whole-blood aggregometry (MEA) can identify patients at risk for excessive bleeding. We enrolled 211 patients (155 male and 56 female) undergoing isolated CABG in a prospective observational study. Patients were divided into four groups with respect to their preoperative APT management. MEA, using the ASPI and the ADP test, was performed prior to surgery. The primary endpoint was chest tube output (CTO) and the secondary endpoint was perioperative packed red blood cell concentrate (PRBC) administration. Patients were characterized as bleeders if their 24 h CTO exceeded the 75th percentile of distribution. 24 h CTO value of 11.33 ml/kg presented 75th percentile of distribution, thus cut-off value for "bleeder category". The proportion of patients characterized as bleeders was significantly different among the groups in regard to preoperative APT (p = 0.039). Significant differences in both ASPI (p < 0.001) and ADP (p = 0.038) tests were observed between different preoperative APT groups. Significant correlations between the ASPI test (r = -0.170, p = 0.014) and ADP test (r = -0.206, p = 0.003) with 24 h CTO were found. The receiver operating curve revealed an ASPI test value of <20 area under curve (AUC) units (AUC 0.603, p = 0.023) and an ADP test <73 AUC (AUC 0.611, p = 0.009) as a "bleeder" determinant. The proportion of patients transfused with PRBC did not significantly differ among the groups in regard to preoperative APT (p = 0.636). Comparison of the ASPI test values between patients with respect to PRBC administration revealed lower values in the ASPI test in a group of patients transfused with PRBC (mean, 27.88 vs. 40.32 AUC, p = 0.002). Our study showed that MEA is a useful method of predicting CABG patients with excessive postoperative bleeding. PMID- 22926759 TI - Predictors of male microchimerism. AB - The association between microchimerism acquired primarily through pregnancy and later disease is of increasing scientific interest. Because this line of research is new and little is known about the nature of microchimerism, studies of microchimerism are potentially vulnerable to error from confounding and reverse causation. To address the issue of confounding, we conducted an analysis of predictors of male microchimerism in 272 female participants of the Danish Diet, Cancer and Health cohort. Buffy coat DNA was tested for Y chromosome presence as a marker of male microchimerism. First, we used logistic regression and thereafter random forest modeling to evaluate the ability of a range of reproductive, lifestyle, hospital or clinic visit history, and other variables to predict whether women tested positive for male microchimerism. We found some indication that current use of contraceptive pills and hormone replacement therapy reduced the odds of testing positive for male microchimerism. However, prediction of male microchimerism presence was poor based on the available variables. Studies of the possible role of male microchimerism in maternal health and disease are therefore unlikely to be heavily confounded by the variables examined in the present investigation. More research focused on acquisition, retention and clearing of male cells in the maternal circulation is needed. PMID- 22926760 TI - Molecular cloning and expression of caspase-3 in the protandrous cinnamon clownfish, Amphiprion melanopus, during sex change. AB - The caspase-3 appears to be a key protease in the apoptotic pathway. We identified caspase-3 complementary DNAs from the ovaries of the protandrous cinnamon clownfish (Amphiprion melanopus), and investigated its mRNA and proteins, and activity levels during the sex change (I, mature male; II, male at 90 days after removing of the female; and III, mature female). The nucleotide sequence of the caspase-3 cDNA was 969 base pairs in length with open reading frames encoding peptides of 282 amino acids. The caspase-3 mRNA and protein, and activity levels in stages of the mature gonad are higher than those of the development gonad stage. To understand the effect of gonadotropin-releasing hormone (GnRH) on gonad apoptosis, we examined expression of genes caspase-3 mRNA and activity level in immature cinnamon clownfish gonads after GnRH analogue (GnRHa). The findings support the hypothesis that caspase-3 expression is associated with both testicular and ovarian development, and suggests that it may play a role in the control of ovarian development in cinnamon clownfish. Also, we demonstrate that GnRH agonists stimulate caspase-3 production which can in turn stimulate apoptosis. The present study provides a framework for better understanding of the role of caspase-3 during sex change processes in fish. PMID- 22926761 TI - Consistent scheme for computing standard hydrogen electrode and redox potentials. AB - The standard hydrogen electrode (SHE) potential in aqueous solution was evaluated with new computational procedure that provides the Gibbs energy of a proton in aqueous solution from the experimental pK(a) value and the Gibbs energy change by deprotonation reactions of several neutral alcohol molecules. With our computational scheme, the CCSD(T)/aug-cc-pVDZ method provides the SHE potential of 4.52 V, which is almost the same as the experimental SHE potential. This scheme also reproduces well the redox potentials of several typical reactions within almost 0.1 V. B3LYP also gives excellent redox potentials of the same reactions with almost the same accuracy with our new computational scheme. PMID- 22926762 TI - Tbx18 function in epicardial development. AB - AIMS: The embryonic epicardium is a source of smooth muscle cells and fibroblasts of the coronary vasculature and of the myocardium, but the molecular circuits that direct the temporal and spatial generation of these cell types from epicardium-derived cells are only partly known. We aimed to elucidate the functional significance of the conserved epicardial expression of the T-box transcription factor gene Tbx18 using transgenic technology in the mouse. METHODS AND RESULTS: We show by cellular and molecular analyses that in Tbx18-deficient mice the epicardium is formed normally and that epicardial cells undergo an epithelial-mesenchymal transition, differentiate into smooth muscle cells and fibroblasts, and form a normal coronary vasculature and fibrous skeleton. Prolonged expression of Tbx18 in epicardium-derived cells by a transgenic approach in vivo does not affect the differentiation and migratory behaviour of these cells. In contrast, epicardial misexpression of a transcriptional activator version of Tbx18, Tbx18VP16, results in premature smooth muscle differentiation of epicardial cells. Inhibition of Notch and transforming growth factor beta receptor signalling in Tbx18VP16 expressing epicardial cells in explant cultures reverts this phenotype. CONCLUSION: Tbx18 is dispensable for epicardial development, yet a repressive T-box function may be required to prevent premature smooth muscle cell differentiation by repressing transforming growth factor beta receptor and Notch signalling in the embryonic epicardium. PMID- 22926763 TI - Prognostic significance of tetraspanin CD151 in newly diagnosed glioblastomas. AB - BACKGROUND: Tetraspanin CD151 is a positive effector of cancer invasion and metastasis. METHODS: We investigated the expression of CD151 by immunohistochemistry in 211 cases of grade I to IV gliomas. Additionally, we performed O6-methylguanin-DNA methyltransferase (MGMT) methylation analysis using real-time methylation-specific PCR in 36 patients with glioblastoma, and the prognostic significance of these biomarkers in glioblastomas was evaluated. RESULTS: Overexpression of CD151 was observed in a significant proportion (55.6%) of glioblastomas, while CD151 was rarely overexpressed in most of grade I to III glial tumors. CD151 overexpression was closely associated with MGMT methylation (P = 0.014), and it was a prognostic factor for predicting worse overall survival (OS; P = 0.002) and progression-free survival (PFS; P = 0.043). We also found that combination of CD151 overexpression and MGMT methylation better stratified the patients' OS (P = 0.001) and PFS (P = 0.009). In multivariate analysis, CD151 overexpression was an independent prognostic factor for predicting OS over MGMT methylation (P = 0.012). CONCLUSIONS: CD151 seems to have a critical role for high-grade progression in astroglial tumors. Furthermore, CD151 is a good tissue marker that can be used easily in a daily practice for predicting worse prognosis in patients with glioblastoma. PMID- 22926764 TI - Association analysis of LCE3C-LCE3B deletion in Tunisian psoriatic population. AB - An association between a common deletion comprising the late cornified envelope LCE3B and LCE3C genes (LCE3C_LCE3B-del) and psoriasis has been reported in Caucasian and Asian populations. To investigate whether this deletion plays a role in the genetic of psoriasis in Tunisian population, we determined the LCE3C_LCE3B-del genotype in 180 Ps patients and 208 healthy controls from different regions of Tunisia. The LCE3B and LCE3C gene variant was determined in the patients through PCR amplification and the SPSS software package. The frequency of the LCE3C_LCE3B-del was similar between patients and healthy controls. Subanalyses by family history revealed that the frequency of LCE3C_LCE3B-del was significantly higher in patients with a positive family history than in control individuals, as well as in individuals with a positive family history versus those without in the case cohort. However, no significant difference was observed between psoriatic patients with no family history and controls. We also evaluated the relationship between LCE3C_LCE3B-del and PSORS1. No significant epistatic effect was observed suggesting that there was no significant epistasis of the two loci in the Tunisian population. Our findings indicate that the LCE3C_LCE3B-del might play a role in familial psoriasis in the Tunisian population. PMID- 22926765 TI - Mass spectrometry based proteomics, background, status and future needs. AB - An overview of the background for proteomics and a description of the present state of art are given with a description of the main strategies in proteomics. The advantages and limitations of the two major strategies, 2D-gel based and LC MS based, are discussed and a combination for the two, CeLC-MS is described. A number of challenging problems which have been solved using different proteomics strategies including the advantage of organell enrichment or modifications specific peptide isolation to get deeper into the proteome are described. Finally the present status and future needs discussed. PMID- 22926767 TI - Sclerosing angiomatoid nodular transformation of the spleen (SANT): multimodality imaging appearance of five cases with radiology-pathology correlation. AB - OBJECTIVE: Sclerosing angiomatoid nodular transformation (SANT) is an extremely rare splenic lesion first reported in 2004, representing an unusual reaction of splenic red pulp to stromal inflammation or vascular injury. There are very few descriptions of the imaging appearance of SANT in the literature. We present five pathologically proven cases of SANT, with a description of the imaging appearance using multiple different modalities, as well as correlation with the histopathologic features of the lesion. CONCLUSION: While there are several imaging features of SANT which have been described in the literature, it is not routinely possible to make a prospective diagnosis based on the imaging features alone. Moreover, it may not be possible to exclude malignancy based on the imaging features, and splenectomy may be required in certain cases. PMID- 22926766 TI - Sample preparation for the analysis of membrane proteomes by mass spectrometry. AB - The low abundance and highly hydrophobic nature of most membrane proteins make their analysis more difficult than that for common soluble proteins. Successful membrane protein identification is largely dependent on the sample preparation including the enrichment and dissolution of the membrane proteins. A series of conventional and newly developed methods has been applied to the enrichment of low-abundance membrane proteins at membrane and/or protein levels and to the dissolution of hydrophobic membrane proteins. However, all the existing methods have inherent advantages and limitations. Up to now, there has been no unique method that can universally be employed to solve all the problems and more efforts are needed in improving sample preparation for the analysis of membrane proteomes. PMID- 22926768 TI - Abstracts of the XXXVIIth Sir Peter Freyer Memorial Lecture and Surgical Symposium. September 7-8, 2012. Galway, Ireland. PMID- 22926769 TI - Post-surgical hemorrhagic infarction of the adrenal gland as the first clinical manifestation of antiphospholipid syndrome after 43 years of antibody-positivity. AB - We report on a male patient who tested positive for antiphospholipid antibodies for 43 years without thromboembolic manifestation of antiphospholipid syndrome (APS). He has been followed up in a prospective cohort study since 2001. Following his second hip replacement surgery, the patient developed acute adrenal failure due to bilateral hemorrhagic infarction. Prophylactic anticoagulation, surgery, or an immunological reaction to blood transfusion may have triggered this late and unusually located primary manifestation of APS in our patient. PMID- 22926770 TI - Anatomical variation of the accessory thoracodorsal artery as a direct cutaneous perforator. AB - The thoracodorsal artery perforator flap is a versatile flap for the reconstruction of various soft tissue defects. Several anatomical variations of thoracodorsal artery have been described and an "accessory thoracodorsal artery" which has a separate and direct origin from the axillary artery has been reported. In this report, we describe a very unusual direct cutaneous perforator, which ran in a subfascial course above the latissimus dorsi muscle and was found to originate directly from the axillary artery. Based on these findings, surgeons should be aware of the possible existence of this unusual anatomical variation during surgery to avoid missing this perforator. PMID- 22926771 TI - World Health Organization-defined eosinophilic disorders: 2012 update on diagnosis, risk stratification, and management. AB - DISEASE OVERVIEW: The eosinophilias encompass a broad range of nonhematologic (secondary or reactive) and hematologic (primary, clonal) disorders with potential for end-organ damage. DIAGNOSIS: Hypereosinophilia has generally been defined as a peripheral blood eosinophil count greater than 1,500/mm(3) and may be associated with tissue damage. After exclusion of secondary causes of eosinophilia, diagnostic evaluation of primary eosinophilias relies on a combination of morphologic review of the blood and marrow, standard cytogenetics, fluorescent in situ-hybridization, flow immunocytometry, and T-cell clonality assessment to detect histopathologic or clonal evidence for an acute or chronic myeloid or lymphoproliferative disorder. RISK STRATIFICATION: Disease prognosis relies on identifying the subtype of eosinophilia. After evaluation of secondary causes of eosinophilia, the 2008 World Health Organization establishes a semimolecular classification scheme of disease subtypes including "myeloid and lymphoid neoplasms with eosinophilia and abnormalities of PDGFRA, PDGFRB, or FGFR1," chronic eosinophilic leukemia, not otherwise specified' (CEL, NOS), lymphocyte-variant hypereosinophilia, and idiopathic hypereosinophilic syndrome (HES), which is a diagnosis of exclusion. RISK-ADAPTED THERAPY: The goal of therapy is to mitigate eosinophil-mediated organ damage. For patients with milder forms of eosinophilia (e.g., <1,500/mm(3) ) without symptoms or signs of organ involvement, a watch and wait approach with close-follow-up may be undertaken. Identification of rearranged PDGFRA or PDGFRB is critical because of the exquisite responsiveness of these diseases to imatinib. Corticosteroids are first line therapy for patients with lymphocyte-variant hypereosinophilia and HES. Hydroxyurea and interferon-alpha have demonstrated efficacy as initial treatment and steroid-refractory cases of HES. In addition to hydroxyurea, second line cytotoxic chemotherapy agents and hematopoietic cell transplant have been used for aggressive forms of HES and CEL with outcomes reported for limited numbers of patients. Although clinical trials have been performed with anti IL-5 (mepolizumab) and anti-CD52 (alemtuzumab) antibodies, their therapeutic role in primary eosinophilic diseases and HES has yet to be established. PMID- 22926772 TI - Molecular identification of traces from the White-tailed Sea Eagle. AB - PURPOSE: Over the preceeding decades, after periods of dramatic decline and extinction in many parts of Europe, the White-tailed Sea Eagle (Haliaeetus albicilla) has re-colonized traditional breeding areas. However, this large apex predator remains threatened, not only by the bioaccumulation of environmental pollutants, but also by targeted poisoning and poaching. In connection with a forensic case, a novel PCR assay was developed for the sensitive and specific detection of sea eagle DNA traces in questioned samples of unknown origin. METHODS: The assay amplifies a fragment of the popular phylogenetic marker gene cytochrome b. Primers were designed to bind sites with relatively high variability between homologous sequences from H. albicilla and other related European birds of prey. RESULTS: Assay sensitivity was sufficient for single cell analysis. Specificity was tested in vitro and the primers did not cross-detect DNA from humans, chicken and the following raptors: Common Buzzard (Buteo buteo), Northern Goshawk (Accipiter gentilis), Red Kite (Milvus milvus) and Black Kite (Milvus migrans). Applicability for the analysis of poor quality samples was demonstrated with extracts from field-collected small molted down feathers that did not contain detectable amounts of sea eagle nuclear DNA. Amplicons of the expected size were generated, purified and sequenced. Sequence data were subjected to Basic Local Alignment Search Tool analysis and affiliated with cytochrome b from H. albicilla. CONCLUSIONS: The novel PCR primers allowed for the correct assignment of traces from H. albicilla, even in mixed samples and in cases with limited and degraded biological material. PMID- 22926773 TI - What is toxic in infants and children? PMID- 22926774 TI - Evaluation of the accuracy of different molar teeth measurements in assessing sex. AB - Teeth are considered to be a very useful tissue for sex determination and molars are among the most dimorphic teeth. Even though mesiodistal (MD) and buccolingual (BL) crown diameters are usually employed for sex assessment, alternative measurements like MD and BL cervical diameters as well as crown and cervical diagonal diameters have been developed. This study explores the utility of crown and cervical MD, BL and diagonal measurements of molars in sex assessment when used separately. A total of 254 permanent molars (excluded third molars) from 101 individuals (51 males, 50 females) from the Athens Collection were examined. Stepwise discriminant analysis was used to evaluate the accuracy of each diameter group in assessing sex. It was found that the accuracy ranges from 65.5 to 88.4 %. Cervical diagonal diameters are the most accurate followed by crown diagonal diameters, and crown and cervical MD and BL diameters. Therefore the high classification accuracy of diagonal diameters show that these measurements are more reliable for sex determination than the traditional MD and BL and can be considered a promising method for sex assessment from human teeth. PMID- 22926775 TI - Circumstantial and toxicological features of deaths from self-administered intravenous anesthetic/narcotic agents. AB - For a better understanding of circumstantial and toxicological findings of fatalities resulting from self-administration of intravenous anesthetic/narcotic agents, medico-legal autopsy files of the State Institute of Legal and Social Medicine Berlin from 1998 to 2011 were reviewed retrospectively. Of a total of 15,300 autopsies, 9 cases of such deaths were identified, and all were health care professionals. Medical supplies for injection were found still on, or near, the body at the scene. Anesthetic/narcotic agents detected were classified into 3 categories, and administered solely or in combination. Propofol was the most common agent, being detected in 6 cases. In 2 out of 6 cases, propofol was detected substantially above therapeutic levels and was considered the cause of death. In the remaining 4 cases, propofol levels were within the therapeutic range, but propofol intoxication was considered as lethal due to it being administered by rapid continuous injection. In 5 cases, injection of opioid narcotics was fatal. Alongside the 2 propofol-detected cases, there was one case where a higher-than-therapeutic level of piritramide and a therapeutic level of alfentanil was identified. Despite suspected usage, remifentanil was not detected due to its rapid metabolism by elastases in one case, and sufentanil was undetectable due to putrefaction in another, but death was attributed to their potent respiratory depressant effects without respiratory assistance. Benzodiazepines were detected in 4 cases. All of them were used together with propofol or opioids, and contributed to death by inhibiting respiration. It is essential to consider means of administration as well as additive or synergistic effects of combined agents when interpreting toxicological results in such cases. PMID- 22926777 TI - Socioeconomic distribution of emissions and resource use in Ireland. AB - This paper aims to determine emissions polluted directly and indirectly by an average person, for each household type, across a wide range of emissions. There are five household type categories: location, income decile, household composition, size and number of disabled residents. Ireland's Sustainable Development Model (ISus) is used which allows the analysis of direct and indirect sources of pollution per household as the model is based on an input-output methodology. Four sets of results are presented: first for greenhouse gas emissions, second for air pollutants, third for persistent organic pollutants and lastly for metals. An analysis section shows how the picture changes when one controls for the size and income of households. All results analysed are for the year 2006. Most greenhouse gas and metal emissions are polluted via indirect means, although direct sources of emissions play a role for CO(2), SO(2) and CO. The results suggest that the richest decile is the biggest emitter and poorer and larger households are seen to emit the least per person. It is also shown that household income has a stronger relationship with pollution than household size per person. PMID- 22926776 TI - Plant 14-3-3 proteins as spiders in a web of phosphorylation. AB - Protein phosphorylation is essential for many aspects of plant growth and development. To fully modulate the activity of specific proteins after phosphorylation, interaction with members of the 14-3-3 family is necessary. 14-3 3 Proteins are important for many processes because they "assist" a wide range of target proteins with divergent functions. In this review, we will describe how plant 14-3-3 proteins are as spiders in a web of phosphorylation: they act as sensors for phospho-motifs, they themselves are phosphorylated with unknown consequences and they have kinases as target, where some of these phosphorylate 14-3-3 binding motifs in other proteins. Two specific classes of 14-3-3 targets, protein kinases and transcription factors of the bZIP and basic helix-loop-helix like families, with important and diverse functions in the plant as a whole will be discussed. An important question to be addressed in the near future is how the interaction with 14-3-3 proteins has diverged, both structurally and functionally, between different members of the same protein family, like the kinases and transcription factors. PMID- 22926778 TI - Evaluating the ability of current energy use assessment methods to study contrasting livestock production systems. AB - Environmental impact assessment of agriculture has received increased attention over recent decades, leading to development of numerous methods. Among them, three deal with energy use: Energy Analysis (EA), Ecological Footprint (EF) and Emergy synthesis (Em). Based on a review of 197 references applying them to a variety of agricultural systems, this paper evaluates their ability to assess energy use. While EF assesses energy use as land use via a global accounting approach in which energy is only one component of the assessment, EA and Em are energy-focused and appear more appropriate to highlight ways to increase energy use efficiency. EA presents a clear methodology via fossil energy use and its associated impacts but does not consider all energy sources. With inclusion of natural and renewable resources, Em focuses on other energy resources, such as solar radiation and energy from labour, but does not present impact indicators nor establish a clear link between activities and their environmental impacts. Improvements of the EA and Em methods could increase their ability to perform realistic and unbiased energy analysis or the diversity of livestock systems encountered in the world. First, to consider all energy sources, as Em does, EA could include solar radiation received by farm surfaces and energy expenditure by humans and animals to accomplish farm operations. Second, boundaries of the studied system in EA and Em must include draft animals, humans and communal grazing lands. Third, special attention should be given to update and locally adapt energy coefficients and transformities. PMID- 22926782 TI - Development of domino processes by using 7-silylcycloheptatrienes and its analogues. AB - 7-Silyl- and 7-silylmethylcycloheptatrienes were shown to react with acylnitroso reagents at room temperature, through their norcaradiene forms, to generate the corresponding cycloadducts 5 a-b and 6 a-b as single diastereomers. The course of the reaction was dramatically modified by changing the reaction conditions. Using a polar medium, functionalized cyclohexa-1,3-dienes 7 a-b and bicyclic compounds 13 a-b were instead generated, incorporating one or two amino groups. Similar behavior was observed by using other dienophiles, including triazolinedione, but also activated aldehydes and ketones. A tentative mechanism has been proposed to rationalize the formation of both classes of products that relies on a domino process involving four consecutive elementary steps, in this order: 1) electrocyclic process, 2) hetero-Diels-Alder reaction, 3) cyclopropane ring opening, and 4) hetero-Diels-Alder reaction. Trapping of the cationic intermediate and isolation of the primary cycloadduct provide support for this hypothesis. An enantioselective version of the cascade using cycloheptatriene 4 b and aldehydes and ketones, under copper(II) catalysis was also carried out, leading to cyclohexa-1,3-dienes 21, 28, and 30 with enantioselectivities up to 93 % ee. Finally, elaboration of the intermediates above has been carried out, opening a straightforward access to sugar mimics 42-43 and complex polycyclic systems 36 and 39. PMID- 22926781 TI - Dystonia with brain manganese accumulation resulting from SLC30A10 mutations: a new treatable disorder. AB - BACKGROUND: The first gene causing early-onset generalized dystonia with brain manganese accumulation has recently been identified. Mutations in the SLC30A10 gene, encoding a manganese transporter, cause a syndrome of hepatic cirrhosis, dystonia, polycythemia, and hypermanganesemia. METHODS: We present 10-year longitudinal clinical features, MRI data, and treatment response to chelation therapy of the originally described patient with a proven homozygous mutation in SLC30A10. RESULTS: The patient presented with early-onset generalized dystonia and mild hyperbilirubinemia accompanied by elevated whole-blood manganese levels. T1-sequences in MRI showed hyperintensities in the basal ganglia and cerebellum, characteristic of manganese deposition. Treatment with intravenous disodium calcium edetate led to clinical improvement and reduction of hyperintensities in brain imaging. CONCLUSIONS: We wish to highlight this rare disorder, which, together with Wilson's disease, is the only potentially treatable inherited metal storage disorder to date, that otherwise can be fatal as a result of complications of cirrhosis. (c) 2012 Movement Disorder Society. PMID- 22926783 TI - Effects of low frequency electromagnetic field on proliferation of human epidermal stem cells: An in vitro study. AB - To investigate the effects of low frequency electromagnetic fields (EMF) on the proliferation of epidermal stem cells, human epidermal stem cells (hESC) were isolated, expanded ex vivo, and then exposed to a low frequency EMF. The test and control cells were placed under the same environment. The test cells were exposed for 30 min/day to a 5 mT low frequency EMF at 1, 10, and 50 Hz for 3, 5, or 7 days. The effects of low frequency EMF on cell proliferation, cell cycle, and cell-surface antigen phenotype were investigated. Low frequency EMF significantly enhanced the proliferation of hESC in the culture medium in a frequency-dependent manner, with the highest cell proliferation rate at 50 Hz (P < 0.05). Exposure to a low frequency EMF significantly increased the percentage of cells at the S phase of the cell cycle, coupled with a decrease in the percentage of cells in the G1 phase (P < 0.05) but the effect was not frequency dependent. The percentage of CD29(+) /CD71(-) cells remained unchanged in the low frequency EMF exposed hESC. The results suggested that low frequency EMF influenced hESC proliferation in vitro, and this effect was related to the increased proportion of cells at the S phase. PMID- 22926784 TI - Evaluation of the efficacy of additional measures introduced for the protection of healthcare personnel handling antineoplastic drugs. AB - OBJECTIVES: Due to their adverse effects, antineoplastic drugs are considered as a potential health risk to healthcare personnel. The objective of the study was to compare the surface contamination level of the conventional preparation room and outpatient clinic before and after the implementation of a set of additional protective measures. METHODS: The measures were targeted at eliminating potential sources of environmental contamination, and modification of the cleaning procedure. The measures introduced into the preparation room consisted of (i) the introduction of manual cleaning of drug vials before they enter the preparation room, (ii) the modification of the routine cleaning procedure performed at the end of each working day (i.e. shifting the cleaning of the isolators as the most contaminated objects from the beginning of the cleaning process to the end), and (iii) the introduction of regular cleaning of the work table every 2 h. The measures introduced into the outpatient clinic consisted of (i) replacement of the standard infusion sets with multichannel sets for safe drug administration, (ii) the introduction of self-cleaning seats to the patient lavatories supporting hygienic and contamination-free seated urination, and (iii) replacement of standard infusion stands with wall-mounted stands, supporting the regular and proper cleaning of the floor beneath. To determine the surface contamination level with antineoplastic drugs, cyclophosphamide and platinum were determined in wipe samples with high performance liquid chromatography with tandem mass spectrometry and inductively coupled plasma mass spectrometry. RESULTS: In the preparation room, depending on the sampling spot and analyte, median concentrations ranged from 5 to 267 pg cm(-2) and from 2 to 368 pg cm(-2) before and after implementation of the measures, respectively. In the outpatient clinic, median concentrations ranged from 5 to 5310 pg cm(-2) and from <0.2 to 574 pg cm( 2) before and after implementation of the measures, respectively. Depending on the sampling spot, median contamination of the outpatient clinic with cyclophosphamide and platinum was reduced by 57-99% and 61-98%, respectively. CONCLUSIONS: The measures implemented in the outpatient clinic were shown to reduce workplace contamination effectively. Therefore, they can be recommended also for other workplaces where antineoplastic drugs are administered. In contrast, measures implemented in the preparation room, where relatively strict regulations had already been adopted before the study, were less effective. To decrease the actual contamination of the preparation room, other protective measures (e.g. closed-system transfer devices) should be considered. PMID- 22926785 TI - Personal exposures to asbestos fibers during brake maintenance of passenger vehicles. AB - INTRODUCTION: Brake linings and brake pads are among the asbestos-containing products that are readily available in Colombia. When sold separated from their support, brake linings require extensive manipulation involving several steps that include drilling, countersinking, riveting, bonding, cutting, beveling, and grinding. Without this manipulation, brake linings cannot be installed in a vehicle. The manipulation process may release asbestos fibers, which may expose brake mechanics to the fibers. METHODS: Three brake repair shops located in Bogota (Colombia) were sampled for 3 or 4 consecutive days using US National Institute for Occupational Safety and Health (NIOSH) methods 7400 and 7402. Standard procedures for quality control were followed during the sampling process, and asbestos samples were analyzed by an American Industrial Hygiene Association accredited laboratory. Personal samples were collected to assess full shift and short-term exposures. Area samples were also collected close to the brake-lining manipulation equipment and within office facilities. Activities were documented during the sampling process. RESULTS: Using Phase Contrast Microscopy Equivalent counts to estimate air asbestos concentrations, all personal samples [i.e. 8-h time-weighted averages (TWAs) and 30-min personal samples] were in compliance with the US Occupational Safety and Health Administration standards. Personal asbestos concentrations based on transmission electron microscopy counts were extremely high, ranging from 0.006 to 3.493 f cm(-3) for 8-h TWA and from 0.015 to 8.835 f cm(-3) for 30-min samples. All asbestos fibers detected were chrysotile. Cleaning facilities and grinding linings resulted in the highest asbestos exposures based on transmission electron microscopy counts. There were also some samples that did not comply with the NIOSH's recommended exposure limits. CONCLUSION: The results indicate that the brake mechanics sampled are exposed to extremely high asbestos concentrations (i.e. based on transmission electron microscopy counts), suggesting that this occupational group could be at excess risk of asbestos-related diseases. PMID- 22926786 TI - Morphological changes, chitinolytic enzymes and hydrophobin-like proteins as responses of Lecanicillium lecanii during growth with hydrocarbon. AB - Lecanicillium lecanii, Verticillium chlamydosporium, V. fungicola var flavidum and Beauveria bassiana were evaluated on their growth with pure n-hexane, toluene and n-hexane:toluene 17:83 (v:v) mixture. Another set of treatments were conducted with colloidal chitin as additional carbon source. All the strains of Lecanicillium were able to grow using hydrocarbons with or without the addition of chitin, although the presence of hydrocarbons showed significant inhibition evidenced by measured biomass, radial growth and microscopic analyses. Degradation of n-hexane ranged within 43 and 62 % and it was higher than that with toluene. The strains L460, L157 and L2149, which presented the highest growth, were further selected for determinations of hydrocarbon consumptions in microcosms. Strain L157 showed the highest consumption of n-hexane (55.6 %) and toluene (52.9 %) as sole carbon source and it also displayed activities of endochitinases, N-acetylhexosaminidase and production of hydrophobins class I and II. PMID- 22926787 TI - [Where can suicide prevention be applied? Proposal of a 6-phase model for suicidal crises]. PMID- 22926788 TI - [Personality disorders are emotional disorders--pro & contra. Pro]. PMID- 22926789 TI - [Personality disorders are emotional disorders--pro & contra. Contra]. PMID- 22926790 TI - [Association between fear of stigma, depressive and anxiety symptoms in patients with somatoform pain disorder]. AB - OBJECTIVES: There is still poor acceptance for pain without somatic causes, and patients with somatoform pain disorder carry a stigma per se. The aim of this study was to identify predictors of fear of stigma including depression, anxiety and somatisation among patients with somatoform pain disorder. METHODS: 132 patients with somatoform pain disorder were investigated by using the Link Stigma Questionnaire, the Beck Depression Inventory, the State-Trait Anxiety Inventory, the Whiteley-Index, and the Checklist for Somatisation. RESULTS: Multiple linear regression analysis showed a significant positive association between fear of stigma and symptoms of depression and a negative association with patients' age. CONCLUSIONS: This is one of the first studies investigating this question among patients with somatoform pain disorder. Findings might indicate the importance of depressive symptoms for developing fear of stigma. PMID- 22926791 TI - [Are there different tendencies in the ordering of care and confinement between urban and rural areas? A Bavarian comparison between Munich and Alpine region]. AB - OBJECTIVE: To compare long-term trends in legal guardianship policy and involuntary psychiatric admissions in urban and rural areas for people suffering from mental illness. METHOD: New and current legal guardianships as well as involuntary admissions according to Guardianship Law and also to Commitment Law were examined from 1998 to 2010. RESULTS: All investigated variables (new and current legal guardianships as well as involuntary admissions) increased significantly along assessed period of time. Current guardianship rates are lower in urban area. On the other hand, rates of involuntary admissions according to Guardianship Law are in urban area 3fold higher and those according to Commitment Law doubled. New and current guardianships' ratio as well as ratio between involuntary admissions according Commitment Law and Guardianship Law remained quite stable. DISCUSSION: The large differences in legal guardianship policy and involuntary treatment between urban and rural regions cannot be explained on the basis of available data. The role of community-based care networks in the process of reducing involuntary admissions should be further examined. PMID- 22926792 TI - [Gender differences in response to CBT-orientated multimodal treatment in depressed patients with chronic pain]. AB - OBJECTIVE: Although gender differences are increasingly the focus of current research, gender aspects in the response to pharmacological and non pharmacological treatment of depression still remain unclear. The aim of this study was to analyze the impact of gender on the outcome of a CBT-orientated multimodal treatment in depressed outpatients with chronic pain. METHODS: A total of 298 patients (154 women) underwent a standardized five-week CBT-orientated multimodal treatment. Depressive symptoms were measured at the beginning and end of the treatment with the German version of the Center for Epidemiological Studies Depression Scale (CES-D). RESULTS: The improvement of depressive symptoms showed an effect size (ES) of 0.81 in the total sample. However, women improved considerably more (ES 0.96) than did men (ES 0.65) and these gender differences are seen in the complete sample (t = 2.757, df = 296, p = 0.006) as well as in the group without received antidepressants (t = 2.325, df = 151, p = 0.021). CONCLUSION: Women with a depressive disorder and chronic pain benefit significantly more from a CBT-orientated multimodal treatment and exhibit a considerably greater reduction of depressive symptoms than do men. These distinctions are not due to differences in received antidepressant medication, psychiatric comorbidities or educational background. PMID- 22926793 TI - [Internet addiction as a co-morbid disorder among patients of german addiction rehabilitation facilities: an exploratory investigation of clinical prevalence]. AB - OBJECTIVE: Excessive internet use is being discussed as a non-substance-related addiction disorder. Estimations of its prevalence show that 1% of the German general population is affected by internet addiction. However, it is still unclear, whether internet addiction as a co-morbid disorder is also common among patients of the general health care system, especially in patients being treated in inpatient addiction rehabilitation centers. It seems plausible that these patients have a heightened proneness to co-morbid internet addiction. METHODS: In order to address this issue, a government-funded cooperation project was conducted. Within six months every new patient admitted to one of 15 rehabilitation facilities was screened for internet addiction. RESULTS: 4.2% of the patients fulfilled criteria for internet addiction. Male patients of younger age with main diagnosis of cannabis dependence or pathological gambling were found to be at higher risk. CONCLUSIONS: Internet addiction is more common among patients of the rehabilitation system than in the general population. Especially young, male patients in treatment for cannabis dependence or pathological gambling are at risk for co-morbid internet addiction. It is recommended that regular screening for internet addiction should be implemented in facilities with patients at risk in order to offer indicative treatment. PMID- 22926794 TI - [Expert opinions of forensic psychiatrists regarding laws of subsequent preventive detention]. AB - OBJECTIVE: With regard to changes in the German law of preventive detention--a sentence handed down to offenders who committed a grave offence and are considered a danger to public safety, similar to the preventive detention law in New Zealand--an online survey amongst forensic psychiatrists has been conducted between July and October 2011. Questions have been raised regarding the necessity of preventive detention, subsequent preventive detention (the possibility of imposing "preventive detention" after sentencing, which was ruled a violation of the European Convention of Human Rights by the European Court of Human Rights), and the Therapy Placement Act from January 1st, 2011. METHODS: Participants have been contacted via email and participation was anonymous. An online-platform has been established, and has been open for about four months. RESULTS: Most participants have been familiar with either court reports regarding preventive detention or the content of the Therapy Placement Act. Less than one third had already answered issues considering this new law. All participants have considered preventive detention as necessary, but subsequent preventive detention as well as the Therapy Placement Act as not required. CONCLUSIONS: The Therapy Placement Act was considered to be modified by involving an interdisciplinary advisory board. Terms of "psychiatric disorder" should be defined or replaced, and frequency of psychiatric assessment should be reduced. PMID- 22926795 TI - Hand preference for pointing and language development in toddlers. AB - The aim of this study was to investigate the relationship between hand preference for communicative gestures and language during development. Hand preference for pointing gestures and level of language were assessed in 46 toddlers between 12 and 30 months of age. Results showed a right-hand preference for pointing and the use of a developmental quotient (DQ) for language revealed a significant correlation between the degree of hand preference and DQ for language in children with a quotient above 100. Thus, these children were more right-handed for pointing gestures as DQ increased. These results highlight the close association between the development of hand preference for pointing and the speed of language development, suggesting a new direction for studies of language-gesture links in toddlers. PMID- 22926796 TI - Wussinomics: the state of competitive efficiency in private health insurance. PMID- 22926797 TI - Unique bioactive polyphenolic profile of guava (Psidium guajava) budding leaf tea is related to plant biochemistry of budding leaves in early dawn. AB - BACKGROUND: Guava leaf tea (GLT), exhibiting a diversity of medicinal bioactivities, has become a popularly consumed daily beverage. To improve the product quality, a new process was recommended to the Ser-Tou Farmers' Association (SFA), who began field production in 2005. The new process comprised simplified steps: one bud-two leaves were plucked at 3:00-6:00 am, in the early dawn period, followed by withering at ambient temperature (25-28 degrees C), rolling at 50 degrees C for 50-70 min, with or without fermentation, then drying at 45-50 degrees C for 70-90 min, and finally sorted. RESULTS: The product manufactured by this new process (named herein GLTSF) exhibited higher contents (in mg g(-1), based on dry ethyl acetate fraction/methanolic extract) of polyphenolics (417.9 +/- 12.3) and flavonoids (452.5 +/- 32.3) containing a compositional profile much simpler than previously found: total quercetins (190.3 +/- 9.1), total myricetin (3.3 +/- 0.9), total catechins (36.4 +/- 5.3), gallic acid (8.8 +/- 0.6), ellagic acid (39.1 +/- 6.4) and tannins (2.5 +/- 9.1). CONCLUSION: We have successfully developed a new process for manufacturing GLTSF with a unique polyphenolic profile. Such characteristic compositional distribution can be ascribed to the right harvesting hour in the early dawn and appropriate treatment process at low temperature, avoiding direct sunlight. PMID- 22926798 TI - Gastric juice microRNA-421 is a new biomarker for screening gastric cancer. AB - MicroRNA-421 (miR-421) plays crucial roles during carcinogenesis and is a potential tumor marker in the diagnosis of several types of cancers. However, whether miR-421 in gastric juice, which is specific for gastric tissue, can be used as a biomarker for gastric cancer screening is unclear. In the present study, real-time quantitative reverse transcription-polymerase chain reaction was used to analyze miR-421 levels in gastric juice from patients with gastric cancer or benign gastric disease, or normal. A receiver operating characteristic (ROC) curve was constructed to evaluate the diagnostic values. The results showed that gastric juice levels of miR-421 in patients with gastric cancer were significantly different from those in benign gastric diseases (P < 0.001). The area under the ROC curve of miR-421 was up to 0.767 (95 % CI = 0.684-0.850). The levels of miR-421 in gastric juice from gastric patients were not significantly associated with the main clinicopathological factors such as tumor size, Lauren's classification, and Borrmann's classification. For the detection of early gastric cancer, the use of gastric juice miR-421 showed a remarkable improvement compared with the use of serum carcinoembryonic antigen alone. These results indicated that gastric juice miRNAs such as miR-421 are useful biomarkers for screening gastric cancer. PMID- 22926799 TI - Developmental stage-specific contribution of LGR5(+) cells to basal and luminal epithelial lineages in the postnatal mammary gland. AB - The leucine-rich repeat-containing heterotrimeric guanine nucleotide-binding protein-coupled receptor 5 (LGR5) has been identified as a marker of cycling stem cells in several epithelial tissues, including small intestine, colon, stomach and hair follicle. To investigate whether LGR5 also marks mammary epithelial stem cells, we performed in situ lineage-tracing studies and mammary gland reconstitutions with LGR5-expressing mammary epithelial cells. Interestingly, the LGR5 progeny population in mammary epithelium switches from the luminal to the myoepithelial compartment during the first 12 days of postnatal development, likely reflecting local changes in Wnt signalling. Together, our findings point to a stage-specific contribution of LGR5-expressing cells to luminal and basal epithelial lineages during postnatal mammary gland development. PMID- 22926800 TI - Pain relief during hysterosalpingography: role of intracervical block. AB - PURPOSE: Hysterosalpingography (HSG) is an important tool for evaluation of tubal factors in infertility. It does not require anesthesia but can be a painful procedure. Thus, this study was undertaken to establish the role of intracervical block as pain relief modality for HSG. METHODS: This prospective, randomized study included hundred women attending the Department of Obstetrics and Gynecology, at a tertiary care centre in India. They were divided randomly through a computer generated table into two groups of 50 women each. In the study group, women received intracervical block along with premedication whereas in the control group women received premedication alone. Each patient was asked to rate her pain at six different points of time (T1-T6) during HSG using Visual analogue scale (VAS) and Verbal descriptive score. The difference in pain scores amongst the two groups was analyzed using independent t test. RESULTS: Reduction of pain was observed from placement of tenaculum till end of procedure (T3-T6) with intracervical block (p < 0.05). Pain remained at a statistically lower level during the most painful steps i.e. traction of the cervix (VAS: 2.080.49 cm, 95 % C I 1.18-2.98 vs. 4.21.15 cm, 95 % CI 3.3-5.1, p = 0.001) and with the insertion of dye (VAS: 2.640.49, 95 % CI 1.7-3.5 vs. 5.121.45. 95 % CI 4.3-6.0, p = 0.001) in the study group as compared to control group. CONCLUSION: Intracervical block can be offered to all women undergoing HSG to make the procedure less painful and thus improve the compliance. PMID- 22926801 TI - A rare cause of maternal near miss: report from a developing country. PMID- 22926802 TI - Giant struma ovarii. PMID- 22926803 TI - Functional arterial spin labeling: Optimal sequence duration for motor activation mapping in clinical practice. AB - PURPOSE: To determine the minimal optimal functional arterial spin labeling (fASL) sequence duration allowing steady and reproducible motor activation mapping. MATERIALS AND METHODS: Three magnetic resonance imaging (MRI) sessions including fASL and blood oxygenation level-dependent (BOLD) functional MRI (fMRI) sequences were performed on 12 healthy subjects at 3T with a 32-channel coil. The raw 7-minute fASL sequence was truncated to obtain six fASL sequences with durations ranging from 1-6 minutes. All the resulting fASL activations were compared between themselves and with both the 7-minute fASL and BOLD activations. Quantitative parameters assessed activation location (activated volume, barycenter, and distance between barycenters), activation quantification (activation-related cerebral blood flow), and intraindividual reproducibility across fMRI sessions. The statistical analysis was based on analysis of variance (ANOVA) and Tukey's multiple comparisons. RESULTS: Four-minute fASL achieved steady location and quantification of activation with the activated volume corresponding to 81% of the 7-minute fASL volume and a barycenter located 1.2 mm from the 7-minute fASL barycenter and 3.0 mm from the BOLD fMRI barycenter. Four minute fASL reproducibility was high and statistically equivalent to 7-minute values. CONCLUSION: A 4-minute fASL sequence is thus a reliable tool for motor activation mapping and suitable for use in clinical practice. PMID- 22926804 TI - Kalman filter techniques for accelerated Cartesian dynamic cardiac imaging. AB - In dynamic MRI, spatial and temporal parallel imaging can be exploited to reduce scan time. Real-time reconstruction enables immediate visualization during the scan. Commonly used view-sharing techniques suffer from limited temporal resolution, and many of the more advanced reconstruction methods are either retrospective, time-consuming, or both. A Kalman filter model capable of real time reconstruction can be used to increase the spatial and temporal resolution in dynamic MRI reconstruction. The original study describing the use of the Kalman filter in dynamic MRI was limited to non-Cartesian trajectories because of a limitation intrinsic to the dynamic model used in that study. Here the limitation is overcome, and the model is applied to the more commonly used Cartesian trajectory with fast reconstruction. Furthermore, a combination of the Kalman filter model with Cartesian parallel imaging is presented to further increase the spatial and temporal resolution and signal-to-noise ratio. Simulations and experiments were conducted to demonstrate that the Kalman filter model can increase the temporal resolution of the image series compared with view sharing techniques and decrease the spatial aliasing compared with TGRAPPA. The method requires relatively little computation, and thus is suitable for real-time reconstruction. PMID- 22926807 TI - Honesty in critically reflective essays: an analysis of student practice. AB - In health professional education, reflective practice is seen as a potential means for self-improvement from everyday clinical encounters. This study aims to examine the level of student honesty in critical reflection, and barriers and facilitators for students engaging in honest reflection. Third year physiotherapy students, completing summative reflective essays on clinical encounters using the modified Gibbs cycle, were invited to participate in an anonymous online survey. Student knowledge and beliefs about reflective practice, and disclosure of the truthfulness of their reflections, were assessed using a mixed method approach. A total of 34 students, from a maximum possible of 48 (71 %), participated in the study activities. A total of 68 % stated that they were at least 80 % truthful about their experiences. There was general student consensus that reflective practice was important for their growth as a clinician. Students questioned the belief that the reflection needed to be based on a factual experience. Reflective practice can be a valuable addition to the clinical education of health care professionals, although this value can be diminished through dishonest reflections if it is not carefully implemented. Student influences on honest reflection include; (1) the design of any assessment criteria, and (2) student knowledge and competency in applying critical reflection. PMID- 22926808 TI - Motion analysis of light-powered autonomous silver chloride nanomotors. AB - Powered by UV light, nano/micrometer-sized silver chloride particles exhibit autonomous movement and form "schools" in aqueous solution, i.e. regions in which the number density of particles is significantly higher than the global average. In this paper, the silver chloride particles in such a system are classified by their proximity to other AgCl particles--be they isolated, coupled or schooled- and their motion paths are tracked and analyzed. By plotting time-averaged mean squared displacements of each particle over various time intervals from 0.1 s to 15.0 s, we discover different diffusive behaviors for the three classes of silver chloride particles. PMID- 22926809 TI - Inertial microfluidics with multi-particle collision dynamics. AB - Using the method of multi-particle collision dynamics (MPCD), we investigate inertial focussing in microfluidic channels that gives rise to the Segre Silberberg effect. At intermediate Reynolds numbers, we model the motion of a spherical colloid in a circular microchannel under pressure-driven flow. We determine the radial distribution function and show how its width and the location of its maximum are strongly influenced by the colloid size and the Reynolds number of the Poiseuille flow. We demonstrate that MPCD is well suited for calculating mean values for the lift force acting on the colloid in the cross sectional plane and for its mean axial velocity. We introduce a Langevin equation for the cross-sectional motion whose steady state is the Boltzmann distribution that contains the integrated lift force as potential energy. It perfectly coincides with the simulated radial distribution function. PMID- 22926810 TI - Active compaction of crosslinked driven filament networks. AB - The contractile ability of active materials relies on the interplay of force exerting and force-bearing structures. However, the complexity of interactions and limited parameter control of many model systems are major obstacles in advancing our understanding of the underlying fundamental principles. To shed light on these principles we introduce and analyse a minimal reconstituted system, consisting of highly concentrated actin filaments that are crosslinked by alpha-actinin and actively transported in the two-dimensional geometry of a motility assay. This minimal system actively compacts and evolves into highly compact fibres that exceed the length of the individual filaments by two orders of magnitude. We identify the interplay between active transport and crosslinking to be responsible for the observed active compaction. This enables us to control the structure and the length scale of active compaction. PMID- 22926811 TI - The first complete genome sequences of clinical isolates of human coronavirus 229E. AB - Human coronavirus 229E has been identified in the mid-1960s, yet still only one full-genome sequence is available. This full-length sequence has been determined from the cDNA-clone Inf-1 that is based on the lab-adapted strain VR-740. Lab adaptation might have resulted in genomic changes, due to insufficient pressure to maintain gene integrity of non-essential genes. We present here the first full length genome sequence of two clinical isolates. Each encoded gene was compared to Inf-1. In general, little sequence changes were noted, most could be attributed to genetic drift, since the clinical isolates originate from 2009 to 2010 and VR740 from 1962. Hot spots of substitutions were situated in the S1 region of the Spike, the nucleocapsid gene, and the non-structural protein 3 gene, whereas several deletions were detected in the 3'UTR. Most notable was the difference in genome organization: instead of an ORF4A and ORF4B, an intact ORF4 was present in clinical isolates. PMID- 22926812 TI - Analysis of full-length sequences of two Citrus yellow mosaic badnavirus isolates infecting Citrus jambhiri (Rough Lemon) and Citrus sinensis L. Osbeck (Sweet Orange) from a nursery in India. AB - Citrus yellow mosaic badna virus (CMBV), a member of the Family Caulimoviridae, Genus Badnavirus is the causative agent of mosaic disease among Citrus species in southern India. Despite its reported prevalence in several citrus species, complete information on clear functional genomics or functional information of full-length genomes from all the CMBV isolates infecting citrus species are not available in publicly accessible databases. CMBV isolates from Rough Lemon and Sweet Orange collected from a nursery were cloned and sequenced. The analysis revealed high sequence homology of the two CMBV isolates with previously reported CMBV sequences implying that they represent new variants. Based on computational analysis of the predicted secondary structures, the possible functions of some CMBV proteins have been analyzed. PMID- 22926814 TI - [On our own behalf]. PMID- 22926815 TI - [Screening performance of first trimester nuchal translucency, ductus venosus blood flow and tricuspid regurgitation for cardiac defects]. AB - The present article summarises current knowledge on the risk of fetal cardiac malformations in fetuses with increased nuchal translucency (NT), abnormal ductus venosus blood flow pattern and tricuspid regurgitation. The risk of congenital heart disease (CHD) increases with increasing NT. However, nuchal translucency screening is only modestly efficient in the detection of congenital heart disease in low-risk pregnancies. If the nuchal translucency is normal, abnormal ductus venosus blood flow and tricuspid regurgitation show low sensitivities as single screening parameters. The combination of all 3 markers might increase the detection rates. Fetal echocardiography at 20 weeks of gestation is recommended in foetuses with an NT >=95th percentile, as the incidence of CHD increases 2.5 fold. When the NT measurement is >=99th percentile, the risk of CHD increases 10 fold. In this high-risk group and in fetuses with tricuspid regurgitation and/or an abnormal DV flow pattern along with an increased NT, first or early second trimester echocardiography performed by experts is warranted. The early examination of the fetal heart should be completed by a detailed echocardiogram at around 20 weeks of gestation. PMID- 22926816 TI - [Fetal cardiac interventions]. AB - Fetal cardiac interventions are being performed with growing success by a minimally invasive percutaneous and transthoracic approach. The primary aim of these interventions is to minimise postnatal morbidity and mortality, rarely also to achieve intrauterine survival. Valvuloplasty in utero for severe aortic stenosis is performed in order to achieve sufficient growth of the left ventricle and to make a later biventricular repair possible. In rare cases with hydrops secondary to massive left ventricular dilatation and mitral insufficiency it is used as a salvage therapy. Premature obstruction of the foramen ovale can be treated by balloon atrioseptoplasty or stenting of the atrial septum with the aim to attain a decompression of the left atrium and consequently of the pulmonary veins. This might reduce the extent of pulmonary hypertension and the resulting vascular and parenchymal changes in affected infants. Intrauterine valvuloplasty of a highly stenotic pulmonary valve or a pulmonary atresia with intact ventricular septum in order to prevent hypoplasia of the right ventricle and to enable postnatal biventricular repair is only rarely justified. Currently these intrauterine cardiac interventions are limited to a small group of fetuses with cardiac defects. However, with enhanced imaging modalities and equipment and with growing experience, fetal cardiac interventions are likely to increase in the next years. PMID- 22926817 TI - [Intrauterine inflammation and its sequelae: does chorioamnionitis really matter for outcome of very low birth weight infants?]. AB - Infections in utero and chorioamnionitis are major risk factors for spontaneous, very early premature birth. Thus chorioamnionitis contributes significantly to prematurity-associated morbidity and mortality. Evidence for a gestation independent effect of chorioamnionitis on the outcome of very low birth weight infants is much more difficult to obtain as most of the studies addressing this issue lack a normal "control group", as prematurity is mostly associated with some kind of prenatal pathology with a potential influence on neonatal outcome. Moreover, major advances in perinatal and neonatal care for this high-risk group have mitigated the impact of chorioamnionitis on morbidity and mortality of very low birth weight infants. Histological chorioamnionitis is associated with a lower incidence and severity of respiratory distress syndrome. However, short term maturational effects on the lung are associated with a higher susceptibility for postnatal noxious events, such as mechanical ventilation, thus contributing to the risk of bronchopulmonary dysplasia. Data regarding the importance of chorioamnionitis for brain damage of the very premature infant are inconsistent although meta-analyses have shown an increased risk of cystic periventricular leukomalacia and cerebral palsy after exposure to inflammation in utero. Very recent epidemiological studies suggest a role of chorioamnionitis in the aetiology and pathogenesis of retinopathy of prematurity. PMID- 22926818 TI - [Effects of antenatal inflammation on the developing lung]. AB - The developing lung and immune systems are very plastic and their developmental pathway can be influenced by various endogenous and/or exogenous factors. In the last years translational research with various animal models has been helpful to answer some basic questions about the effect of chorioamnionitis on maturation and development of the foetal lung and immune system. Chorioamnionitis can induce a cascade of lung injury, pulmonary inflammation and remodelling in the foetal lung. Chorioamnionitis-induced IL-1 production is consistently associated with lung maturation, induced by enhancing surfactant protein and lipid synthesis. IL 1 therefore seems to be the main link between lung inflammation and lung maturation, which largely prevents RDS in preterm infants. On the other hand, chorioamnionitis can also cause structural lung changes and affect the expression of growth factors, like TGF-beta, CTGF, FGF-10 or BMP-4, which are crucial for branching morphogenesis. These changes result in alveolar and microvascular simplification similar to BPD. Neonatal outcome may also be affected by chorioamnionitis by modulating the efficacy of the immune system. Chorioamnionitis can induce LPS-tolerance (endotoxin hyporesponsiveness/immunoparalysis), which may prevent further foetal lung damage but increases susceptibility to postnatal infections. The inflammatory and developmental signalling pathways affected by chorioamnionitis form delicately regulated networks, which interact with each other to control lung development. In addition to chorioamnionitis, these pathways can be affected by other prenatal (steroid) or postnatal factors (mechanical ventilation, oxygen exposure, infection, steroids). Because the postnatal response to injury appears to be highly dependent on prenatal exposures, the "secondary hit" hypothesis is very plausible, in which exposure to chorioamnionitis is a predisposition for the development of adverse neonatal outcomes. PMID- 22926819 TI - Nosocomial sepsis in neonatal intensive care: inevitable or preventable? AB - Very low birth weight (VLBW) infants are at high risk to develop a neonatal nosocomial sepsis. The incidence of neonatal nosocomial, late-onset sepsis (LOS) is about 20-30%, but a rate of up to 43% has been reported among neonates with a birth weight of 400-750 g. Preventive and treatment strategies for neonatal sepsis in VLBW infants are aiming to enhance the infant's host defence mechanisms. Neonatal immunodeficiencies include quantitative and qualitative deficits in phagocytes, complement components, and immunoglobulins. A considerable number of immune strategies has been investigated in carefully designed multicentre trials. These include exchange transfusion, neutrophil transfusion, hematopoietic growth factors such as granulocyte-macrophage colony stimulating factor (GM-CSF) and granulocyte colony-stimulating factor (G-CSF), intravenous immunoglobulins (IVIG), and others. Since none of these interventions was able to reduce the mortality rate of immature preterm infants, the current evidence does not support the use of any of the immune strategies for prevention or treatment of neonatal sepsis. Decreasing the burden of intensive care and following strict hygiene programs at NICUs may be the most promising current strategies to minimise nosocomial infection. PMID- 22926820 TI - [Breech presentation - more than just caesarean vs. spontaneous birth]. AB - The cesarean section rate and the associated complications are still rising in Germany. An important indication is term breech in singletons. Not significant data concerning a higher morbidity or mortality in vaginal breech birth indicate the cesarean but a deficit in education and experience. PMID- 22926821 TI - Cognitive testing in the diagnosis of Parkinsonian disorders: a lawn mower for the hare's corner? PMID- 22926822 TI - Lipid stability during the frozen storage of fillets from silver catfish exposed in vivo to the essential oil of Lippia alba (Mill.) NE Brown. AB - BACKGROUND: Lippia alba is effective in sedating and reducing stress to fish during transportation. Because some in vitro studies have demonstrated the antioxidant activity of L. alba, we hypothesized that its use in vivo could result in antioxidant effects post mortem. Therefore, in this study we evaluated whether the essential oil of L. alba (EO) used as sedative for fish transport would increase the lipid stability of fillets from silver catfish during frozen storage. RESULTS: The exposure to the EO in vivo did not affect conjugated diene values. However, EO (30 and 40 uL L(-1)) delayed the peak formation of peroxides (from the third to the sixth month of storage) and thiobarbituric reactive substances (from the ninth to the twelfth month of storage) when compared to control fillets. After exposure to 40 uL L(-1) EO the free fatty acid content was higher than for control at the start of fillet storage, with no differences among groups thereafter. CONCLUSION: The essential oil of L. alba used as sedative in the water to transport silver catfish can delay lipid oxidation of fillets during frozen storage. Thus L. alba may be a promising source of natural active compounds for use in aquaculture and the food industry. PMID- 22926824 TI - Validation of experimental whole-body SAR assessment method in a complex indoor environment. AB - Experimentally assessing the whole-body specific absorption rate (SAR(wb) ) in a complex indoor environment is very challenging. An experimental method based on room electromagnetics theory (accounting only the line-of-sight as specular path) is validated using numerical simulations with the finite-difference time-domain method. Furthermore, the method accounts for diffuse multipath components (DMC) in the total absorption rate by considering the reverberation time of the investigated room, which describes all the losses in a complex indoor environment. The advantage of the proposed method is that it allows discarding the computational burden because it does not use any discretizations. Results show good agreement between measurement and computation at 2.8 GHz, as long as the plane wave assumption is valid, that is, at large distances from the transmitter. Relative deviations of 0.71% and 4% have been obtained for far-field scenarios, and 77.5% for the near field-scenario. The contribution of the DMC in the total absorption rate is also quantified here, which has never been investigated before. It is found that the DMC may represent an important part of the total absorption rate; its contribution may reach up to 90% for certain scenarios in an indoor environment. PMID- 22926825 TI - Environment and mobility: a view from four discourses. AB - Debate and literature on the link between degrading environments and human mobility has been increasing exponentially. There is little concrete evidence, however, of efforts or policies that support the management of environmentally influenced mobility. Through discourse analysis using Q-methodology, this research aimed to scrutinize the standoff between opposing views under a fresh lens. One-hundred and ninety-seven experts from 49 nations completed an on-line survey asking them to sort, by level of agreement, 42 statements gleaned from the literature concerning the environment-mobility nexus. Four very different discourses emerged: determined humanists, benevolent pragmatists, cynical protectionists, and critical realists. The complexity of these discourses helps explain the stalemate while confirming the inappropriateness of one-sided terminology and linear quantifications. Despite diametrically opposed viewpoints, experts unanimously agree that human mobility is connected to environmental change. Dissection of these social perspectives builds a new foundation for the Rio+20 analysis and policy deliberations related to environmentally influenced human mobility. PMID- 22926826 TI - Identifying novel spatiotemporal regulators of innate immunity. AB - The innate immune response plays a critical role in pathogen clearance. However, dysregulation of innate immunity contributes to acute inflammatory diseases such as sepsis and many chronic inflammatory diseases including asthma, arthritis, and Crohn's disease. Pathogen recognition receptors including the Toll-like family of receptors play a pivotal role in the initiation of inflammation and in the pathogenesis of many diseases with an inflammatory component. Studies over the last 15 years have identified complex innate immune signal transduction pathways involved in inflammation that have provided many new potential therapeutic targets to treat disease. We are investigating several novel genes that exert spatial and in some cases temporal regulation on innate immunity signaling pathways. These novel genes include Tbc1d23, a RAB-GAP that inhibits innate immunity. In this review, we will discuss inflammation, the role of inflammation in disease, innate immune signal transduction pathways, and the use of spatiotemporal regulators of innate immunity as potential targets for discovery and therapeutics. PMID- 22926827 TI - The role of glycogen synthase in the development of hyperglycemia in type 2 diabetes: 'To store or not to store glucose, that's the question'. AB - This review deals with the role of glycogen storage in skeletal muscle for the development of insulin resistance and type 2 diabetes. Specifically, the role of the enzyme glycogen synthase, which seems to be locked in its hyperphosphorylated and inactivated state, is discussed. This defect seems to be secondary to ectopic lipid disposition in the muscle cells. These molecular defects are discussed in the context of the overall pathophysiology of hyperglycemia in type 2 diabetic subjects. PMID- 22926829 TI - Abstracts of the 28th International Conference on Pharmacoepidemiology & Therapeutic Risk Management. August 23-26, 2012. Barcelona, Spain. PMID- 22926828 TI - Human hyolaryngeal movements show adaptive motor learning during swallowing. AB - The hyoid bone and larynx elevate to protect the airway during swallowing. However, it is unknown whether hyolaryngeal movements during swallowing can adjust and adapt to predict the presence of a persistent perturbation in a feed forward manner (adaptive motor learning). We investigated adaptive motor learning in nine healthy adults. Electrical stimulation was administered to the anterior neck to reduce hyolaryngeal elevation, requiring more strength to swallow during the perturbation period of this study. We assessed peak hyoid bone and laryngeal movements using videofluoroscopy across thirty-five 5-ml water swallows. Evidence of adaptive motor learning of hyolaryngeal movements was found when (1) participants showed systematic gradual increases in elevation against the force of electrical stimulation and (2) hyolaryngeal elevation overshot the baseline (preperturbation) range of motion, showing behavioral aftereffects, when the perturbation was unexpectedly removed. Hyolaryngeal kinematics demonstrates adaptive, error-reducing movements in the presence of changing and unexpected demands. This is significant because individuals with dysphagia often aspirate due to disordered hyolaryngeal movements. Thus, if rapid motor learning is accessible during swallowing in healthy adults, patients may be taught to predict the presence of perturbations and reduce errors in swallowing before they occur. PMID- 22926830 TI - Multidimensionally encoded magnetic resonance imaging. AB - Magnetic resonance imaging (MRI) typically achieves spatial encoding by measuring the projection of a q-dimensional object over q-dimensional spatial bases created by linear spatial encoding magnetic fields (SEMs). Recently, imaging strategies using nonlinear SEMs have demonstrated potential advantages for reconstructing images with higher spatiotemporal resolution and reducing peripheral nerve stimulation. In practice, nonlinear SEMs and linear SEMs can be used jointly to further improve the image reconstruction performance. Here, we propose the multidimensionally encoded (MDE) MRI to map a q-dimensional object onto a p dimensional encoding space where p > q. MDE MRI is a theoretical framework linking imaging strategies using linear and nonlinear SEMs. Using a system of eight surface SEM coils with an eight-channel radiofrequency coil array, we demonstrate the five-dimensional MDE MRI for a two-dimensional object as a further generalization of PatLoc imaging and O-space imaging. We also present a method of optimizing spatial bases in MDE MRI. Results show that MDE MRI with a higher dimensional encoding space can reconstruct images more efficiently and with a smaller reconstruction error when the k-space sampling distribution and the number of samples are controlled. PMID- 22926832 TI - Confined compression and torsion experiments on a pHEMA gel in various bath concentrations. AB - The constitutive behaviour of cartilaginous tissue is the result of complex interaction between electrical, chemical and mechanical forces. Electrostatic interactions between fixed charges and mobile ions are usually accounted for by means of Donnan osmotic pressure. Recent experimental data show, however, that the shear modulus of articular cartilage depends on ionic concentration even if the strain is kept constant. Poisson-Boltzmann simulations suggest that this dependence is intrinsic to the double-layer around the proteoglycan chains. In order to verify this premise, this study measures whether--at a given strain- this ionic concentration-dependent shear modulus is present in a polymerized hydroxy-ethyl-methacrylate gel or not. A combined 1D confined compression and torque experiment is performed on a thin cylindrical hydrogel sample, which is brought in equilibrium with, respectively, 1, 0.1 and 0.03 M NaCl. The sample was placed in a chamber that consists of a stainless steel ring placed on a sintered glass filter, and on top a sintered glass piston. Stepwise ionic loading was cascaded by stepwise 1D compression, measuring the total stress after equilibration of the sample. In addition, a torque experiment was interweaved by applying a harmonic angular displacement and measuring the torque, revealing the relation between aggregate shear modulus and salt concentration at a given strain. PMID- 22926833 TI - Actinomycetes genome engineering approaches. AB - This review provides an overview of new technologies for DNA manipulations in actinomycetes exploiting recombinogenic engineering (Flp-FRT, Cre-loxP, Dre-rox, Tn5, GusA and I-SceI systems). We will describe some new vectors recently developed for engineering of complex phenotypes in actinomycetes. Several site specific recombinases, transposons, reporter genes and I-SceI endonuclease have been utilized for genome manipulation in actinomycetes. Novel molecular tools will help to overcome many technical difficulties and will encourage new efforts to address the function of actinomycete genes. PMID- 22926831 TI - Assessing protein conformational sampling methods based on bivariate lag distributions of backbone angles. AB - Despite considerable progress in the past decades, protein structure prediction remains one of the major unsolved problems in computational biology. Angular sampling-based methods have been extensively studied recently due to their ability to capture the continuous conformational space of protein structures. The literature has focused on using a variety of parametric models of the sequential dependencies between angle pairs along the protein chains. In this article, we present a thorough review of angular-sampling-based methods by assessing three main questions: What is the best distribution type to model the protein angles? What is a reasonable number of components in a mixture model that should be considered to accurately parameterize the joint distribution of the angles? and What is the order of the local sequence-structure dependency that should be considered by a prediction method? We assess the model fits for different methods using bivariate lag-distributions of the dihedral/planar angles. Moreover, the main information across the lags can be extracted using a technique called Lag singular value decomposition (LagSVD), which considers the joint distribution of the dihedral/planar angles over different lags using a nonparametric approach and monitors the behavior of the lag-distribution of the angles using singular value decomposition. As a result, we developed graphical tools and numerical measurements to compare and evaluate the performance of different model fits. Furthermore, we developed a web-tool (http://www.stat.tamu.edu/~madoliat/LagSVD) that can be used to produce informative animations. PMID- 22926834 TI - Variations in maternal care associated with differences in female rat reproductive behavior in a group-mating environment. AB - Maternal care influences the development of sexual behavior in pair mating rats, under laboratory conditions. This study examined the effect of variations in maternal care in a group-mating condition. Groups of two low and two high licking/grooming (LG) female offspring mated with two males in a large pacing chamber for 36 hr. Sexual behaviors were scored for the first 15 vaginal-cervical stimulations (VCS) and the entire 36 hr. Low LG females spent more time mating, required more time to receive an intromission after entering the male compartment. They also received more ejaculations compared to high LG females during the first 15 VCS. This difference disappeared as mating continued. Males were more responsive to high than low females. No pregnancy rate difference was seen between the two female phenotypes, demonstrating that variation in maternal care received results in two mating strategies that are both reproductively successful under group-mating conditions. PMID- 22926835 TI - [Cartilage regeneration]. AB - Articular cartilage damage is challenging to treat. The patient has to deal with pain, functional impairment and compromized quality of life. Ultimately, he has to face the risk of early total joint replacement. A variety of treatment options is available to improve the situation for the patient. Mosaicplasty, bone marrow stimulating techniques and cell-based methods have been in clinical use for years. This article explains preoperative diagnosis and classification systems of cartilage lesions and presents different cartilage repair procedures and their indications. PMID- 22926836 TI - Total synthesis of (-)-jiadifenin. AB - As easy as ABCD: (-)-Jiadifenin was synthesized in eighteen reaction steps from 1 [(E)-(4'-bromo-2'-butenyl)oxy]-4-methoxybenzene. Key features of this synthesis include: 1) Ireland-Claisen rearrangement to produce the two contiguous quaternary centers at C5 and C6 simultaneously, 2) intramolecular Pauson-Khand reaction (IMPKR) to concurrently construct the A and B rings, and 3) [2+2] photo cycloaddition to generate the all-carbon quaternary center at C9. PMID- 22926837 TI - Are attachment dimensions associated with infertility-related stress in couples undergoing their first IVF treatment? A study on the individual and cross-partner effect. AB - STUDY QUESTION: Are attachment anxiety and avoidance dimensions in female and male partners in couples seeking infertility treatment associated with her and his infertility-related stress? SUMMARY ANSWER: Attachment dimensions are significantly associated with several aspects of infertility stress in couples undergoing IVF treatment. WHAT IS KNOWN AND WHAT THIS PAPER ADDS: Attachment dimensions of anxiety and avoidance (where highly anxious individuals fear rejection and are preoccupied with maintaining proximity to their partner and highly avoidant individuals are uncomfortable with intimacy and prefer to maintain distance from their partner) may influence the well being of individuals undergoing IVF/ICSI treatment. This study showed that one partner's attachment dimensions had a direct effect on the infertility-related stress of the other partner. DESIGN: Cross-sectional study of consecutive couples before starting their first IVF/ICSI treatment in 2009-2011 at the ANDROS clinic in Palermo, Italy. PARTICIPANTS AND SETTING: Three hundred and fifty-nine couples undergoing fertility treatments were invited to participate in the research. The final sample comprised 316 females and 316 males who filled out the psychological questionnaires (Experiences in Close Relationships; Fertility Problem Inventory; State scale of State-Trait Anxiety Inventory). The participants included patients who had a primary infertility diagnosis and were about to undergo their first IVF or ICSI treatment. DATA ANALYSIS METHOD: Paired t-tests were used to examine gender differences on the study variables (attachment anxiety, attachment avoidance, infertility stress, state anxiety, etc.). Associations between infertility-related stress and the study variables were explored using hierarchical stepwise multivariate linear regression analyses. MAIN RESULTS AND THE ROLE OF CHANCE: Attachment anxiety and attachment avoidance were significantly associated with global infertility stress in both women (beta = 0.24, P < 0.01 and beta = 0.27, P < 0.01) and men (beta = 0.23, P < 0.01 and beta = 0.37, P < 0.01). Regarding the cross-partner effects, men's infertility stress and relationship concerns were associated with their partners' attachment avoidance (beta = 0.10 P < 0.05 and beta = 0.12, P < 0.05); and the infertility stress of women and the scores for need of parenthood were associated with their partners' attachment anxiety (beta = 0.14 P < 0.05 and beta = 0.16, P < 0.05). BIAS, CONFOUNDING AND OTHER REASONS FOR CAUTION: The study data are cross sectional, and specifically focus on associations between adult attachment style and infertility stress. Treating the data from couples as independent observations may be a limitation of the analysis. Potential moderators of such relationships (e.g. coping strategies, stress appraisal) are not included in this study. STUDY FUNDING/COMPETING INTEREST(S): This research was supported by funds provided by Centro Andros S.r.l., Palermo, Italy. The authors declare no financial or commercial conflicts of interest in this study. PMID- 22926838 TI - Health-related quality of life in women with newly diagnosed polycystic ovary syndrome randomized between clomifene citrate plus metformin or clomifene citrate plus placebo. AB - STUDY QUESTION: What is the health-related quality of life (HRQoL) in women with polycystic ovary syndrome (PCOS) undergoing ovulation induction with clomifene citrate (CC) combined with metformin compared with those using CC combined with placebo? SUMMARY ANSWER: Overall quality of life in women with PCOS treated with CC plus metformin was significantly lower than in women treated with CC plus placebo. WHAT IS KNOWN ALREADY: There are no data on HRQoL in adult women who receive ovulation induction with the purpose of conceiving. Women with PCOS have higher scores on depression and anxiety scales and lower QoL scores than women without PCOS. STUDY DESIGN, SIZE AND DURATION: This study was a secondary analysis of a multi-centre RCT completed between June 2001 and May 2004. The randomization was stratified per centre, and the centres received blinded, numbered containers with medication. There were172 women available for the HRQoL assessment: 85 were allocated to metformin and 87 were allocated to placebo. PARTICIPANTS, SETTING AND METHODS: The Rotterdam Symptom Checklist (RSCL), a standard self-administered questionnaire, was used to assess physical symptoms, psychological distress, activity levels and overall HRQoL. MAIN RESULTS AND THE ROLE OF CHANCE: In the intention to treat analysis, we found differences between the treatment groups with respect to physical symptoms and overall HRQoL. Physical well-being was significantly impaired in women allocated to metformin but not in women allocated to placebo. The increase in physical symptoms in the metformin group was caused by side-effects typical of metformin, and was most pronounced at Week 1 (mean difference 12 [95% confidence interval (CI): 8-16] and still apparent at Week 16 [mean difference 7 (95% CI 2-12]. Overall well-being was significantly impaired in the metformin group compared with the placebo group [mean difference 13 (95% CI 6-20)]. LIMITATIONS AND REASONS FOR CAUTION: RSCL measurements were available only for three quarters of the participants. Although the number of missing questionnaires and the baseline measurements, were comparable between the treatment groups, some form of selection bias cannot be ruled out. WIDER IMPLICATIONS OF THE FINDINGS: Our finding that metformin was more burdensome than placebo, strengthens the recommendation that CC only and not CC plus metformin should be the drug of choice in this patient population. STUDY FUNDING/COMPETING INTEREST(S): None of the authors declared a conflict of interest. There was no study funding. TRIAL REGISTRATION NUMBER: ISRCTN55906981. PMID- 22926839 TI - The combination of polyalanine expansion mutation and a novel missense substitution in transcription factor FOXL2 leads to different ovarian phenotypes in blepharophimosis-ptosis-epicanthus inversus syndrome (BPES) patients. AB - STUDY QUESTION: What are the implications of multiple alterations of the forkhead box L2 (FOXL2) gene in blepharophimosis-ptosis-epicanthus inversus syndrome (BPES) patients? SUMMARY ANSWER: A multi-mutation of FOXL2, consisting of the expansion of the polyalanine tract from 14 to 24 residues (FOXL2-Ala24), an novel Y186C substitution from c.557A>G, and a synonymous variant (c.505G>A), had a cumulative effect on ovarian phenotypes in BPES patients. WHAT IS KNOWN ALREADY: Mutations in FOXL2, a gene encoding a forkhead transcription factor cause BPES. Overall, the expansion of the polyalanine tract of FOXL2 from 14 to 24 residues (FOXL2-Ala24) accounts for 30% of intragenic mutations. STUDY DESIGN, SIZE, DURATION: In this study, patients from seven BPES families and six sporadic cases were included. PARTICIPANTS/MATERIALS, SETTING, METHODS: We conducted an extensive clinical, hormonal and functional study in 20 patients carrying the expansion of the polyalanine tract of FOXL2 associated with BPES. A multi mutation of FOXL2 was detected in one BPES family that showed more severe BPES symptoms. Subcellular localization and transactivation studies were performed for the constructs of FOXL2-Ala24, Y186C and FOXL2-Ala24-Y186C. MAIN RESULTS: We described the first multi-mutation of FOXL2 (c. [672_701dup30; 557A>G]) that leads to the polyalanine expansion of +10 residues (FOXL2-Ala24) combined with an Y186C substitution and a synonymous variant in a Chinese BPES family. This multi mutation genotype was associated with more serious BPES clinical manifestations and the development of esotropia in the right eye. In in vitro studies, the multi mutation affected the function of FOKL2 on the StAR promoter and DK3, and induced more aggressive aggregation and mislocalization of FOXL2 protein. The synonymous variant, while not affecting amino acid coding, causes a change in the RNA stem loop structure. LIMITATIONS, REASONS FOR CAUTION: The multi-mutation of FOXL2 was detected in one BPES family and it needs to be validated further by more BPES subjects. WIDER IMPLICATIONS OF THE FINDINGS: The results of our study contribute new insights into the research field of BPES caused by the multi-mutation of FOXL2. STUDY FUNDING/COMPETING INTERESTS: This study was supported by Shanghai Leading Academic Discipline Project (Grant number S30205) and Shanghai Jiao Tong University School of Medicine Doctor Innovation Fund (Grant number 201131). The authors have no competing interests to declare. PMID- 22926840 TI - Herbal supplements in pregnancy: unexpected results from a multicentre study. AB - STUDY QUESTION: How common is the use of herbal supplements during pregnancy and does it adversely affect the pregnancy outcome? SUMMARY ANSWER: The use of herbal products during pregnancy is very common and daily almond oil spreading is associated with preterm birth (PTB). WHAT IS KNOWN AND WHAT THIS PAPER ADDS: Herbal drugs are often promoted as 'natural' and 'safe' and such claims attract pregnant women. More than a quarter of Italian pregnant women consume herbs every day for at least 3 months during pregnancy. We raise an alert over the habit of daily almond oil spreading since it seems to be associated with PTB. DESIGN: A multicenter retrospective cohort study performed over a 15-month period. PARTICIPANTS AND SETTING: Seven hundred women interviewed within 3 days of childbirth, in three public hospitals in northern Italy. MAIN RESULTS AND ROLE OF CHANCE: One hundred and eighty-nine women were considered 'regular users', since they consumed herbs every day, for at least 3 months. Almond oil, chamomile and fennel were the most commonly used herbs. Both length of gestation and birthweight were affected by herb consumption. Almond oil users showed more pre term birth (29 of 189) than non-users (51 of 511). After adjusting for multiple pregnancies, smoking, advanced age and drug intake, almond oil users maintained an increased risk to give birth <37th week (odds ratio = 2.09, 95% confidence interval: 1.08-4.08). BIAS, CONFOUNDING AND OTHER REASONS FOR CAUTION: The association between daily spreading of almond oil and PTB only raises a hypothesis that requires confirmation in larger trials devoted to this topic. The relatively small sample size did not allow the investigation of other adverse pregnancy outcomes in herb users. GENERALIZABILITY TO OTHER POPULATIONS: The population under investigation did not significantly differ from the general population attending the same hospitals. STUDY FUNDING/COMPETING INTEREST(S): No conflict of interest exists. The study has been supported by a public grant from the University of Modena and Reggio Emilia. TRIAL REGISTRATION NUMBER: None. PMID- 22926841 TI - Surgical versus medical treatment for endometriosis-associated severe deep dyspareunia: I. Effect on pain during intercourse and patient satisfaction. AB - STUDY QUESTION: Does surgical or medical treatment for endometriosis-associated severe deep dyspareunia achieve better results in terms of patients' satisfaction (main study outcome), variation of coital pain and frequency of intercourse? SUMMARY ANSWER: Surgery and progestin therapy were equally effective in the treatment of deep dyspareunia in women with rectovaginal endometriosis, whereas medical therapy performed significantly better than excisional treatment in those without deeply infiltrating lesions. WHAT IS KNOWN AND WHAT THIS PAPER ADDS: Conservative surgery and hormonal therapies have been used independently for endometriosis-associated deep dyspareunia with inconsistent results. This study reports a direct comparison between the two treatment options in women with severe pain during intercourse. DESIGN: Patient preference, parallel cohort study with a 12-month follow-up. The effect of conservative surgery at laparoscopy was compared with treatment with a low-dose of norethisterone acetate per os (2.5 mg/day) in women with persistent/recurrent severe deep dyspareunia after first line surgery. PARTICIPANTS AND SETTING: A total of 51 patients chose repeat surgery and 103 progestin treatment. Patient satisfaction was graded according to a five-category scale. Variations in pain during intercourse were measured by means of a 100-mm visual analogue scale. MAIN RESULTS AND THE ROLE OF CHANCE: In the surgery group, a marked and rapid short-term dyspareunia score reduction was observed, followed by partial recurrence of pain. The pain relief effect of the progestin was more gradual, but progressive throughout the study period. At a 12 month follow-up, the frequency of intercourse per month (mean +/- SD) was 4.6 +/- 1.8 in the surgery group and 5.3 +/- 1.5 in the norethisterone acetate group (P = 0.02). A total of 22/51 (43%) women were satisfied in the surgery group compared with 61/103 (59%) in the progestin group [adjusted odds ratios (OR), 0.36; 95% confidence interval (CI), 0.16-0.82; P = 0.015]. Corresponding figures in women with and without rectovaginal endometriotic lesions were, respectively, 13/24 (54%) versus 18/35 (51%; adjusted OR, 0.77; 95% CI, 0.22-2.67; P = 0.68), and 9/27 (33%) versus 43/68 (63%; adjusted OR, 0.23; 95% CI, 0.07-0.76, P = 0.02). BIAS, CONFOUNDING, AND OTHER REASONS FOR CAUTION: Treatments were not randomly assigned, and distribution of participants as well as of dropouts between study arms was unbalanced. However, the possibility of choosing the treatment allowed assessment of the maximum potential effect size of the interventions. GENERALIZABILITY TO OTHER POPULATIONS: Caucasian patients able to choose their treatment. STUDY FUNDING/COMPETING INTEREST(S): This study was supported by a research grant from the University of Milan School of Medicine (PUR number 2009 ATE-0570). None of the authors have a conflict of interest. PMID- 22926842 TI - Monitoring fertility (semen analysis) by cancer survivors who banked sperm prior to cancer treatment. AB - STUDY QUESTION: What medical and psychological variables predict why men with banked sperm do not return for semen analysis after their cancer treatment has ended? SUMMARY ANSWER: Men who decline the offer of semen analysis are less likely to have reported adverse side effects during cancer treatment, and have a more negative experience of banking sperm and a more negative attitude towards disposal of their stored semen than those who attend. WHAT IS KNOWN ALREADY: Previous authors have noted that male cancer survivors seem reluctant to have their fertility tested after their treatment has ended. Moreover, the utilization rates of banked sperm are very low (<10%) and the majority of samples are kept for many years without being used. STUDY DESIGN, SIZE AND DURATION: A cross sectional study of 499 cancer survivors who were sent a questionnaire about their views on sperm banking, fertility and post-treatment semen analysis between April 2008 and December 2010. PARTICIPANTS AND SETTING: Men (aged 18-55 years) who had banked sperm in Sheffield and Nottingham (UK) prior to gonadotoxic treatment for cancer more than 5 years previously. MAIN RESULTS AND THE ROLE OF CHANCE: Completed questionnaires were received from 193 men (38.7% response rate) whose samples had been banked for 9.18 +/- 3.70 years (range = 4.94-26.21) and whose current age was 35.08 +/- 7.08 years (range = 21.58-54.34; mean +/- SD). One third (35.8%) had never attended for semen analysis. In multivariate analysis, the odds of not attending for semen analysis were significantly greater among men who did not experience adverse treatment side effects [odds ratio (OR) = 5.72, 95% confidence interval (CI) = 2.10-15.56], who reported a more negative experience of banking sperm (OR = 1.82, 95% CI = 1.17-2.82) and a more negative attitude to disposal of their stored semen (OR = 1.56, 95% CI = 1.01-2.42). LIMITATIONS AND REASONS FOR CAUTION: Only 38.7% of those eligible agreed to take part. We do not know the characteristics of men who declined to take part, if they agreed to attend semen analysis without completing the questionnaire or whether they had chosen to have semen analysis performed elsewhere (e.g. private sector). Some of the measures used (e.g. experience of banking sperm) relied on men's recall of events many years previously. WIDER IMPLICATIONS OF THE FINDINGS: New strategies are required to encourage these men to engage with fertility monitoring programmes if sperm banks are to be used cost-effectively and men are to be given appropriate fertility advice. STUDY FUNDING AND COMPETING INTERESTS: This paper was supported by funding from Cancer Research-UK to C.E., A.A.P. and R.R. (C481/A8141). The views expressed are those of the authors. No competing interests declared. PMID- 22926843 TI - Global human tissue profiling and protein network analysis reveals distinct levels of transcriptional germline-specificity and identifies target genes for male infertility. AB - BACKGROUND: Mammalian spermatogenesis is a process that involves a complex expression program in both somatic and germ cells present in the male gonad. A number of studies have attempted to define the transcriptome of male meiosis and gametogenesis in rodents and primates. Few human transcripts, however, have been associated with testicular somatic cells and germ cells at different post-natal developmental stages and little is known about their level of germline specificity compared with non-testicular tissues. METHODS: We quantified human transcripts using GeneChips and a total of 47 biopsies from prepubertal children diagnosed with undescended testis, infertile adult patients whose spermatogenesis is arrested at consecutive stages and fertile control individuals. These results were integrated with data from enriched normal germ cells, non-testicular expression data, phenotype information, predicted regulatory DNA-binding motifs and interactome data. RESULTS: Among 3580 genes for which we found differential transcript concentrations in somatic and germ cells present in human testis, 933 were undetectable in 45 embryonic and adult non-testicular tissues, including many that were corroborated at protein level by published gene annotation data and histological high-throughput protein immunodetection assays. Using motif enrichment analyses, we identified regulatory promoter elements likely involved in germline development. Finally, we constructed a regulatory disease network for human fertility by integrating expression signals, interactome information, phenotypes and functional annotation data. CONCLUSIONS: Our results provide broad insight into the post-natal human testicular transcriptome at the level of cell populations and in a global somatic tissular context. Furthermore, they yield clues for genetic causes of male infertility and will facilitate the identification of novel cancer/testis genes as targets for cancer immunotherapies. PMID- 22926844 TI - Fertilization rates are improved after IVF if the corona radiata is left intact in vitrified-warmed human oocytes. AB - BACKGROUND: Before human MII oocytes are vitrified they are usually denuded from their cumulus cells. In this study we wanted to investigate the effects of an intact corona radiata on the vitrification and fertilization of human oocytes. METHODS: The study comprised two different parts. In Part 1, 36 MII stage oocytes, from 6 patients, were randomly assigned into a control group, a group of vitrified-warmed oocytes without a corona radiata and a group of vitrified-warmed oocytes with an intact corona radiata. In each group of 12, 6 oocytes were used for evaluation of the zona pellucida solubility (hardening) and another 6 oocytes were used for the analysis of their ultrastructure. In addition, six polyspermically fertilized oocytes were used as positive controls for zona pellucida hardening. In Part 2, 16 patients in total produced 107 fresh and 98 vitrified-warmed oocytes, with or without an intact corona radiata. All oocytes were fertilized via conventional IVF and embryos were transferred according to our standard ET routines. The oocyte survival and fertilization rates, embryo quality and pregnancy and implantation rates were evaluated. RESULTS: There were no differences in oocyte survival, zona pellucida solubility (hardening) or the number of cortical granules between the vitrified-warmed and fresh oocytes. There were also no differences in the zona pellucida solubility and the number of cortical granules between vitrified-warmed oocytes with or without an intact corona radiata. However, the oocytes with an intact corona radiata had a higher fertilization rate after conventional IVF insemination. No differences were seen in the survival and cleavage rates, the percentage of high-quality embryos or the clinical outcome. CONCLUSIONS: Zona hardening and ultrastructural damage do not seem to occur in vitrified human oocytes. An intact corona radiata in vitrified warmed oocytes retains their fertilization capacity in conventional IVF, but does not improve the embryo quality. Poor fertilizing capacities of vitrified-warmed oocytes without an intact corona radiata seem to have been due to the complete removal of the cumulus cells. PMID- 22926845 TI - The ENDOCARE questionnaire guides European endometriosis clinics to improve the patient-centeredness of their care. AB - STUDY QUESTION: How patient-centered are two included specialized endometriosis clinics relative to each other and how can they improve the patient-centeredness of their care? SUMMARY ANSWER: The validated ENDOCARE questionnaire (ECQ) reliably concluded that the adjusted overall patient-centeredness did not differ between the clinics, that each clinic was significantly more patient-centered for 2 out of 10 dimensions of patient-centered endometriosis care and that clinics 1 and 2 had to improve 8 and 13 specific care aspects, respectively. WHAT IS KNOWN ALREADY: Patient-centered endometriosis care is essential to high-quality care and is defined by 10 dimensions. The ECQ was developed, validated and proved to be reliable in a European setting of self-reported endometriosis patients but had not yet been used at a clinic level for quality management. STUDY DESIGN, SIZE, DURATION: A cross-sectional survey was disseminated in 2011 to all 514 women diagnosed with endometriosis during a laparoscopy indicated for pain and/or infertility during a retrospective 2-year period (2009-2010) in two university clinics from two different European countries. PARTICIPANTS/MATERIALS, SETTING, METHODS: In total 337 patients completed the ECQ (216 and 121 per clinic). Respondents had a mean age of 34.3 years. Three in four reported a surgical diagnosis of moderate or severe endometriosis and the majority reported surgical treatment by a multidisciplinary team. The ECQ assessed the 10 dimensions of patient-centeredness, more specifically whether the health-care performance, as perceived by patients, measured up to what is important to patients in general. MAIN RESULTS: The ECQ was completed by 337 respondents (response rate = 65.6%). Reliability and validity of the ECQ for use on clinic level were confirmed. Clinics did not differ in overall mean importance scores; importance rankings of the ECQ dimensions were almost identical. The overall patient-centeredness scores (PCS), adjusted for education level, did not discriminate between the clinics. However, the adjusted PCS for the dimensions 'clinic staff' and 'technical skills' were significantly better in clinic 1, whereas the dimensions 'physical comfort' and 'access to care' were significantly better in clinic 2. There were 8 (clinic 1) and 13 (clinic 2) targets identified for joint and cross-clinic improvement. LIMITATIONS, REASONS FOR CAUTION: Response rates were relatively high. Recall bias was the most important limitation and research in more clinics is needed to define the statistical discriminative value of the ECQ. WIDER IMPLICATIONS OF THE FINDINGS: European endometriosis clinics can use the validated ECQ for reliable assessment of their 'patient-centeredness', for comparison with others and for setting specific targets to improve the patient centeredness of their endometriosis care, to plan interventions, and to evaluate their effectiveness. STUDY FUNDING/COMPETING INTEREST: This work was funded by KU Leuven and European Network of Endometriosis (ENE), supported by the European Commission (Public Health Executive Agency). No competing interests are declared. PMID- 22926847 TI - Brain injury in newborn babies: we can't afford to get it wrong. PMID- 22926846 TI - Eutopic endometrium and peritoneal, ovarian and colorectal endometriotic tissues express a different profile of nectin-1, -3, -4 and nectin-like molecule 2. AB - STUDY QUESTION: How is the expression of nectins and nectin-like molecules (Necls) detected by immunostaining altered by endometriosis? SUMMARY ANSWER: Our results suggest that Nectin-1, -3, -4 and Necl-2 may contribute to the pathogenesis of endometriosis. Immunostaining of nectins and Necls varies according to the anatomical location of endometriosis. WHAT IS KNOWN AND WHAT THIS PAPER ADDS: Nectin and Necl molecules are immunoglobulin-like cell adhesion molecules involved in apoptosis, cell proliferation and in metastases. Previous studies have demonstrated the involvement of adhesion molecules in the development of endometriotic lesions but no data exist on immunostaining of nectins and Necls molecules in endometriosis. DESIGN, PARTICIPANTS AND SETTING: This retrospective study was conducted in a tertiary-care hospital (Tenon Hospital, Paris, France). Samples were collected from 55 women undergoing endometrial biopsy or surgery for endometriosis and 20 controls having hysterectomy or endometrial biopsy for other reasons; multiple samples were collected from 15 women. We studied the immunostaining of Nectin-1, -3, -4 and Necl-2 in secretory and proliferative endometrium from women with (n = 20) or without endometriosis (i.e. control group, n = 20), and in peritoneal (n = 20), ovarian (n = 20) and colorectal endometriosis (n = 20). MAIN RESULTS: Semi quantitative immunostaining demonstrated that (1) Necl-2 staining was stronger in all types of endometriotic lesions than in the eutopic endometrium from patients with endometriosis (P < 0.0125) and in ovarian endometriotic cysts compared with other locations (P < 0.001); (2) Nectin-3 staining was stronger in the eutopic endometrium of patients with endometriosis compared with controls (P = 0.03) and in all endometriotic lesions compared with the eutopic endometrium from patients with endometriosis (P < 0.0125); (3) Nectin-4, staining was stronger in the eutopic endometrium of patients with endometriosis compared with controls (P = 0.04) and (4) Nectin-1 staining was significantly increased in colorectal endometriosis compared with other locations (P = 0.004). BIAS, CONFOUNDING AND OTHER REASONS FOR CAUTION: We did not assess the pattern of expression in endometriosis of all nectins and Necl molecules. Indeed, Necl-5 is implicated in many pathophysiological processes such as cell movement and proliferation with potential relevance to endometriosis. GENERALISABILITY TO OTHER POPULATIONS: At present, few data on implication of nectins and Necl molecules in endometriosis exist. Hence, our results should be confirmed by further quantitative studies at protein or RNA levels. STUDY FUNDING/COMPETING INTEREST(S): No funding source. All the authors declare no conflict of interest. PMID- 22926848 TI - Psychiatric comorbidities and epilepsy: is it the old story of the chicken and the egg? PMID- 22926849 TI - Neonatal encephalopathy: an inadequate term for hypoxic-ischemic encephalopathy. AB - This Point of View article addresses neonatal encephalopathy (NE) presumably caused by hypoxia-ischemia and the terminology currently in wide use for this disorder. The nonspecific term NE is commonly utilized for those infants with the clinical and imaging characteristics of neonatal hypoxic-ischemic encephalopathy (HIE). Multiple magnetic resonance imaging studies of term infants with the clinical setting of presumed hypoxia-ischemia near the time of delivery have delineated a topography of lesions highly correlated with that defined by human neuropathology and by animal models, including primate models, of hypoxia ischemia. These imaging findings, coupled with clinical features consistent with perinatal hypoxic-ischemic insult(s), warrant the specific designation of neonatal HIE. PMID- 22926850 TI - Accelerating progress in induced pluripotent stem cell research for neurological diseases. AB - In 2006, Yamanaka's group pioneered a method for reprogramming somatic cells by introducing definite transcription factors, which enabled the generation of induced pluripotent stem cells (iPSCs) with pluripotency comparable to that of embryonic stem cells. These iPSCs are attracting considerable attention for their potential in rejection-tolerance personalized replacement therapy. In recent years, patient-derived iPSCs have been used to recapitulate the phenotypes of neurological diseases and broaden our understanding of the pathogenesis of many neurological diseases, including those of late onset. It is now expected that iPSCs will serve as an unlimited source of disease-specific neural cells for use in disease modeling. This review outlines current progress in neurodegenerative disease research involving iPSCs and discusses the potential roles iPSCs may play in helping researchers elucidate the pathological processes of neurodegenerative diseases and in drug discovery and regenerative medicine. PMID- 22926851 TI - Familial cortical myoclonus with a mutation in NOL3. AB - OBJECTIVE: Myoclonus is characterized by sudden, brief involuntary movements, and its presence is debilitating. We identified a family suffering from adult onset, cortical myoclonus without associated seizures. We performed clinical, electrophysiological, and genetic studies to define this phenotype. METHODS: A large, 4-generation family with a history of myoclonus underwent careful questioning, examination, and electrophysiological testing. Thirty-five family members donated blood samples for genetic analysis, which included single nucleotide polymorphism mapping, microsatellite linkage, targeted massively parallel sequencing, and Sanger sequencing. In silico and in vitro experiments were performed to investigate functional significance of the mutation. RESULTS: We identified 11 members of a Canadian Mennonite family suffering from adult onset, slowly progressive, disabling, multifocal myoclonus. Somatosensory evoked potentials indicated a cortical origin of the myoclonus. There were no associated seizures. Some severely affected individuals developed signs of progressive cerebellar ataxia of variable severity late in the course of their illness. The phenotype was inherited in an autosomal dominant fashion. We demonstrated linkage to chromosome 16q21-22.1. We then sequenced all coding sequence in the critical region, identifying only a single cosegregating, novel, nonsynonymous mutation, which resides in the gene NOL3. Furthermore, this mutation was found to alter post-translational modification of NOL3 protein in vitro. INTERPRETATION: We propose that familial cortical myoclonus is a novel movement disorder that may be caused by mutation in NOL3. Further investigation of the role of NOL3 in neuronal physiology may shed light on neuronal membrane hyperexcitability and pathophysiology of myoclonus and related disorders. PMID- 22926852 TI - Thrombin facilitates seizures through activation of persistent sodium current. AB - OBJECTIVE: An epileptic seizure is frequently the presenting sign of intracerebral hemorrhage (ICH) caused by stroke, head trauma, hypertension, and a wide spectrum of disorders. However, the cellular mechanisms responsible for occurrence of seizures during ICH have not been established. During intracerebral bleeding, blood constituents enter the neuronal tissue and produce both an acute and a delayed effect on brain functioning. Among the blood components, only thrombin has been shown to evoke seizures immediately after entering brain tissue. In the present study, we tested the hypothesis that thrombin increases neuronal excitability in the immature brain through alteration of voltage-gated sodium channels. METHODS: The thrombin effect on neuronal excitability and voltage-gated sodium channels was assessed using extracellular and intracellular recording techniques in the hippocampal slice preparation of immature rats. RESULTS: We show that thrombin increased neuronal excitability in the immature hippocampus in an N-methyl-D-aspartate-independent manner. Application of thrombin did not alter transient voltage-gated sodium channels and action potential threshold. However, thrombin significantly depolarized the membrane potential and produced a hyperpolarizing shift of tetrodotoxin-sensitive persistent voltage-gated sodium channel activation. This effect of thrombin was attenuated by application of protease-activated receptor-1 and protein kinase C antagonists. INTERPRETATION: Our data indicate that thrombin amplifies the persistent voltage-gated sodium current affecting resting membrane potential and seizure threshold at the network level. Our results provide a novel explanation as to how ICH in newborns results in seizures, which may provide avenues for therapeutic intervention in the prevention of post-ICH seizures. PMID- 22926853 TI - A randomized, double-blind, phase 2 study of erythropoietin in optic neuritis. AB - OBJECTIVE: Based on findings in animal models of autoimmune optic nerve inflammation, we have assessed the safety and efficacy of erythropoietin in patients presenting with a first episode of optic neuritis. METHODS: Patients with optic neuritis who attended the University Hospitals of Homburg/Saar, Gottingen, or Hamburg (Germany) were included in this double-blind, placebo controlled, phase 2 study (ClinicalTrials.gov, NCT00355095). They were randomly assigned to groups receiving either 33,000IU recombinant human erythropoietin intravenously daily for 3 days or placebo as an add-on therapy to methylprednisolone. The primary outcome parameter was change in retinal nerve fiber layer (RNFL) thickness after 16 weeks. Secondary outcome parameters included optic nerve atrophy as assessed by magnetic resonance imaging, and changes in visual acuity, visual field, and visual evoked potentials (VEPs). RESULTS: Forty patients were assigned to the treatment groups (21/19 erythropoietin/placebo). Safety monitoring revealed no relevant issues. Thirty seven patients (20/17 erythropoietin/placebo) were analyzed for the primary endpoint according to the intention-to-treat protocol. RNFL thinning was less apparent after erythropoietin treatment. Thickness of the RNFL decreased by a median of 7.5MUm by week 16 (mean +/- standard deviation, 10.55 +/- 17.54MUm) compared to a median of 16.0MUm (22.65 +/- 29.18MUm) in the placebo group (p = 0.0357). Decrease in retrobulbar diameter of the optic nerve was smaller in the erythropoietin group (p = 0.0112). VEP latencies at week 16 were shorter in erythropoietin-treated patients than in the placebo group (p = 0.0011). Testing of visual functions revealed trends toward an improved outcome after erythropoietin treatment. INTERPRETATION: These results give the first indications that erythropoietin might be neuroprotective in optic neuritis. PMID- 22926854 TI - 2010 McDonald criteria for diagnosing pediatric multiple sclerosis. AB - OBJECTIVE: The diagnosis of multiple sclerosis (MS) rests on confirmation of central nervous system inflammatory disease that is disseminated in space and time, as evidenced clinically or by magnetic resonance imaging (MRI). The 2010 McDonald criteria simplified MRI requirements, and newly proposed that the criteria are also suitable for the diagnosis of pediatric MS. METHODS: In a national prospective incident cohort study of children with acute demyelination observed for a minimum of 24 months, baseline and serial clinical and MRI examinations were used to retrospectively evaluate the 2010 and 2005 McDonald criteria using clinically relapsing disease as the gold standard. RESULTS: Of 212 eligible participants, 34 experienced 2 or more clinical attacks, 58 met the 2010 criteria, and 42 met 2005 McDonald criteria. The 2010 criteria demonstrated high sensitivity (100%), specificity (86%), positive predictive value (76%), and negative predictive value (100%) for children older than 11 years with non-acute disseminated encephalomyelitis (ADEM) presentations, as did the 2005 McDonald criteria. In younger children with a non-ADEM presentation, PPV of the 2010 criteria was only 55%. None of the 50 children with ADEM met clinical criteria for MS, but 10 met 2010 and 4 met 2005 criteria. INTERPRETATION: Both 2005 and 2010 McDonald criteria identify children with relapsing-remitting MS, although caution is suggested when applying these criteria in younger children. The 2010 McDonald criteria are simple and enable an early diagnosis of MS, but are not suited for application in the context of ADEM-like presentations. PMID- 22926855 TI - Vitamin D status predicts new brain magnetic resonance imaging activity in multiple sclerosis. AB - OBJECTIVE: We sought to determine whether vitamin D status is associated with developing new T2 lesions or contrast-enhancing lesions on brain magnetic resonance imaging (MRI) in relapsing multiple sclerosis (MS). METHODS: EPIC is a 5-year longitudinal MS cohort study at the University of California at San Francisco. Participants had clinical evaluations, brain MRI, and blood draws annually. From the overall cohort, we evaluated patients with clinically isolated syndrome or relapsing-remitting MS at baseline. In univariate and multivariate (adjusted for age, sex, ethnicity, smoking, and MS treatments) repeated measures analyses, annual 25-hydroxyvitamin D levels were evaluated for their association with subsequent new T2-weighted and gadolinium-enhancing T1-weighted lesions on brain MRI, clinical relapses, and disability (Expanded Disability Status Scale [EDSS]). RESULTS: A total of 2,362 3T brain MRI scans were acquired from 469 subjects. In multivariate analyses, each 10ng/ml higher 25-hydroxyvitamin D level was associated with a 15% lower risk of a new T2 lesion (incidence rate ratio [IRR], 0.85; 95% confidence interval [CI], 0.76-0.95; p = 0.004) and a 32% lower risk of a gadolinium-enhancing lesion (IRR, 0.68; 95% CI, 0.53-0.87; p = 0.002). Each 10ng/ml higher vitamin D level was associated with lower subsequent disability (-0.047; 95% CI, -0.091 to -0.003; p = 0.037). Higher vitamin D levels were associated with lower, but not statistically significant, relapse risk. Except for the EDSS model, all associations were stronger when the within-person change in vitamin D level was the predictor. INTERPRETATION: Vitamin D levels are inversely associated with MS activity on brain MRI. These results provide further support for a randomized trial of vitamin D supplementation. PMID- 22926856 TI - Glucose metabolism and pancreatic defects in spinal muscular atrophy. AB - OBJECTIVE: Spinal muscular atrophy (SMA) is the number 1 genetic killer of young children. It is caused by mutation or deletion of the survival motor neuron 1 (SMN1) gene. Although SMA is primarily a motor neuron disease, metabolism abnormalities such as metabolic acidosis, abnormal fatty acid metabolism, hyperlipidemia, and hyperglycemia have been reported in SMA patients. We thus initiated an in-depth analysis of glucose metabolism in SMA. METHODS: Glucose metabolism and pancreas development were investigated in the Smn(2B/-) intermediate SMA mouse model and type I SMA patients. RESULTS: Here, we demonstrate in an SMA mouse model a dramatic cell fate imbalance within pancreatic islets, with a predominance of glucagon-producing alpha cells at the expense of insulin-producing beta cells. These SMA mice display fasting hyperglycemia, hyperglucagonemia, and glucose resistance. We demonstrate similar abnormalities in pancreatic islets from deceased children with the severe infantile form of SMA in association with supportive evidence of glucose intolerance in at least a subset of such children. INTERPRETATION: Our results indicate that defects in glucose metabolism may play an important contributory role in SMA pathogenesis. PMID- 22926857 TI - miR-206 regulates brain-derived neurotrophic factor in Alzheimer disease model. AB - OBJECTIVE: Alzheimer disease (AD) brains are deficient in brain-derived neurotrophic factor (BDNF), which regulates synaptic plasticity and memory. MicroRNAs (miRNAs) are ~22-nucleotide small noncoding RNAs that control a variety of physiological and disease processes. Here, we show that miR-206 regulates BDNF and memory function in AD mice. METHODS: Expression of miRNAs was analyzed in Tg2576 AD transgenic mice and human AD brain samples. Regulation of BDNF by a selected miRNA was validated by in silico prediction, target gene luciferase assay, and dendritic spine responses in neurons. AM206, a neutralizing inhibitor of miR-206 (antagomir), was injected into the third ventricle of Tg2576 mice, after which memory function, synaptogenesis, neurogenesis, and target gene expression were assessed. For noninvasive delivery, antagomirs were administered intranasally. RESULTS: The brains of Tg2576 mice and the temporal cortex of human AD brains had increased levels of miR-206. This miRNA targeted BDNF transcripts, and AM206 prevented the detrimental effects of amyloid-beta42 on BDNF and dendritic spine degeneration in Tg2576 neurons. Injection of AM206 into the cerebral ventricles of AD mice increased the brain levels of BDNF and improved their memory function. In parallel, AM206 enhanced the hippocampal synaptic density and neurogenesis. Furthermore, intranasally administered AM206 also reached the brain and increased BDNF levels and memory function in AD mice. INTERPRETATION: Our findings demonstrate a novel miRNA-dependent regulation of BDNF in AD and suggest possible therapeutic approaches, such as noninvasive intranasal delivery of AM206. PMID- 22926858 TI - Real time quaking-induced conversion analysis of cerebrospinal fluid in sporadic Creutzfeldt-Jakob disease. AB - OBJECTIVE: Current cerebrospinal fluid (CSF) tests for sporadic Creutzfeldt-Jakob disease (sCJD) are based on the detection of surrogate markers of neuronal damage such as CSF 14-3-3, which are not specific for sCJD. A number of prion protein conversion assays have been developed, including real time quaking-induced conversion (RT-QuIC). The objective of this study is to investigate whether CSF RT-QuIC analysis could be used as a diagnostic test in sCJD. METHODS: An exploratory study was undertaken that analyzed 108 CSF samples from patients with neuropathologically confirmed sCJD or from control patients. Of the 108 CSF samples, 56 were from sCJD patients (30 female, 26 male; aged 31-84 years; mean age, 62.3 +/- 13.5 years), and 52 were from control patients (26 female, 26 male; aged 43-84 years; mean age, 67.8 +/- 10.4 years). A confirmatory group of 118 patients was subsequently examined that consisted of 67 cases of neuropathologically confirmed sCJD (33 female, 34 male; aged 39-82 years; mean age, 67.5 +/- 9.0 years) and 51 control cases (26 female, 25 male; aged 36-87 years; mean age, 63.5 +/- 11.6 years). RESULTS: The exploratory study showed that RT-QuIC analysis had a sensitivity of 91% and a specificity of 98% for the diagnosis of sCJD. These results were confirmed in the confirmatory study, which showed that CSF RT-QuIC analysis had a sensitivity and specificity of 87% and 100%, respectively. INTERPRETATION: This study shows that CSF RT-QuIC analysis has the potential to be a more specific diagnostic test for sCJD than current CSF tests. PMID- 22926860 TI - Comment on "solvent exposures and Parkinson disease risk in twins". PMID- 22926859 TI - Concurrent acute brain infarcts in patients with monocular visual loss. AB - OBJECTIVE: Embolism from a proximal source to the retinal circulation could be a sign of embolism from the same source to the hemispheric circulation. We sought to determine the frequency of acute brain infarcts on diffusion-weighted imaging (DWI) in patients with monocular visual loss of presumed ischemic origin (MVL). METHODS: We retrospectively studied 129 consecutive patients with MVL secondary to retinal ischemia. All patients underwent DWI, comprehensive ophthalmologic and neurologic examination, and diagnostic evaluations for the underlying etiology. Statistical analyses explored univariate and multivariate predictors of DWI evidence of acute brain infarcts. RESULTS: DWI revealed concurrent acute brain infarct(s) in 31 of the 129 patients (24%). The probability of positive DWI was higher in embolic versus nonembolic MVL (28 vs 8%, p = 0.04), in MVL characterized by permanent visual loss versus transient symptoms (33 vs 18%, p = 0.04), and in MVL associated with concurrent hemispheric symptoms versus isolated MVL (53 vs 20%, p < 0.01). Patients with positive DWI were more likely to harbor a major underlying etiology as compared to those with normal DWI (odds ratio, 3.7; 95% confidence interval, 1.5-9.4). INTERPRETATION: This study demonstrates that MVL does not always represent an isolated disease of the retina; approximately 1 of every 4 patients with MVL demonstrates acute brain infarcts on DWI. Because patients with concurrent brain infarcts are more likely to exhibit a cardiac or vascular source of embolism, imaging evidence of brain injury in patients with MVL may be a useful marker to guide the timing and extent of diagnostic examinations. PMID- 22926862 TI - Assay selection affects John Cunningham virus serostatus classification in multiple sclerosis. PMID- 22926864 TI - Nigral pathology in older persons without Parkinson disease. PMID- 22926866 TI - Whole exome sequencing identifies KCNQ2 mutations in Ohtahara syndrome. PMID- 22926867 TI - Brain death in children: why does it have to be so complicated? PMID- 22926870 TI - NerveCenter: August 2012. Supreme Court upholds Healthcare Reform Law: uncertainty remains, but change seems inevitable. PMID- 22926869 TI - Note to aspiring clinician scientists: skies are clearing. PMID- 22926872 TI - Prodromal diagnosis of Parkinson's disease. PMID- 22926873 TI - Distribution of isoflavones and coumestrol in neglected tropical and subtropical legumes. AB - BACKGROUND: Isoflavones and coumestrol from dietary legumes are plant constituents showing multiple beneficial effects on humans. Owing to their ability to bind with mammalian estrogenic receptors and thereby intervention in several kinds of hormone-related cancers, they have received much attention. Soybean (Glycine max) is currently the major source of isoflavonoids in human diet. However, dozens of tropical and subtropical leguminous species remain unexplored for their isoflavonoids content. RESULTS: We have analyzed 55 extracts from 41 tropical and subtropical legume species used either in human or animal diet by high-performance liquid chromatography for the content of soy isoflavones, biochanin A, daidzein, daidzin, formononetin, genistein, genistin, sissotrin, ononin and the coumestan coumestrol. Genistein and biochanin A were the most abundant compounds. The highest content of genistein was found in aerial parts of Andira macrothyrsa, seeds of Pachyrhizus tuberosus and aerial parts of Calopogonium mucunoides (598, 250 and 184 ug g(-1), respectively) and biochanin A in aerial parts of Cratylia argentea, C. mucunoides and flowers of A. macrothyrsa (76, 53 and 40 ug g(-1), respectively). CONCLUSION: None of the samples tested was richer overall source of soy isoflavones and coumestrol than soybean; nevertheless several species (C. mucunoides or A. macrothyrsa) may serve as a promising source of individual compounds. PMID- 22926875 TI - Climate change is a big challenge, not only for society but also for science itself. PMID- 22926874 TI - Millimeter waves: acoustic and electromagnetic. AB - This article is the presentation I gave at the D'Arsonval Award Ceremony on June 14, 2011 at the Bioelectromagnetics Society Annual Meeting in Halifax, Nova Scotia. It summarizes my research activities in acoustic and electromagnetic millimeter waves over the past 47 years. My earliest research involved acoustic millimeter waves, with a special interest in diagnostic ultrasound imaging and its safety. For the last 21 years my research expanded to include electromagnetic millimeter waves, with a special interest in the mechanisms underlying millimeter wave therapy. Millimeter wave therapy has been widely used in the former Soviet Union with great reported success for many diseases, but is virtually unknown to Western physicians. I and the very capable members of my laboratory were able to demonstrate that the local exposure of skin to low intensity millimeter waves caused the release of endogenous opioids, and the transport of these agents by blood flow to all parts of the body resulted in pain relief and other beneficial effects. PMID- 22926876 TI - ECOSUPPORT: a pilot study on decision support for Baltic sea environmental management. PMID- 22926877 TI - Reconstructing the development of Baltic sea eutrophication 1850-2006. AB - A comprehensive reconstruction of the Baltic Sea state from 1850 to 2006 is presented: driving forces are reconstructed and the evolution of the hydrography and biogeochemical cycles is simulated using the model BALTSEM. Driven by high resolution atmospheric forcing fields (HiResAFF), BALTSEM reproduces dynamics of salinity, temperature, and maximum ice extent. Nutrient loads have been increasing with a noteworthy acceleration from the 1950s until peak values around 1980 followed by a decrease continuing up to present. BALTSEM shows a delayed response to the massive load increase with most eutrophic conditions occurring only at the end of the simulation. This is accompanied by an intensification of the pelagic cycling driven by a shift from spring to summer primary production. The simulation indicates that no improvement in water quality of the Baltic Sea compared to its present state can be expected from the decrease in nutrient loads in recent decades. PMID- 22926878 TI - Atmospheric nutrient input to the Baltic sea from 1850 to 2006: a reconstruction from modeling results and historical data. AB - In this study, a consistent basin-wise monthly time series of the atmospheric nutrient load to the Baltic Sea during 1850-2006 was compiled. Due to the lack of a long time series (1850-1960) of nutrient deposition to the Baltic Sea, the data set was compiled by combining a time series of deposition data at the Baltic Nest Institute from 1970 to 2006, published historical monitoring data and deposition estimates, as well as recent modeled Representative Concentration Pathways (RCP) emission estimates. The procedure for nitrogen compounds included estimation of the deposition in a few intermediate reference years, linear interpolation between them, and the decomposition of annual deposition into a seasonal deposition pattern. As no reliable monitoring results were found for the atmospheric deposition of phosphorus during the early period of our study, we used published estimates for the temporal and spatial pattern of the phosphorus load. PMID- 22926879 TI - Impact of climate change on ecological quality indicators and biogeochemical fluxes in the Baltic sea: a multi-model ensemble study. AB - Multi-model ensemble simulations using three coupled physical-biogeochemical models were performed to calculate the combined impact of projected future climate change and plausible nutrient load changes on biogeochemical cycles in the Baltic Sea. Climate projections for 1961-2099 were combined with four nutrient load scenarios ranging from a pessimistic business-as-usual to a more optimistic case following the Helsinki Commission's (HELCOM) Baltic Sea Action Plan (BSAP). The model results suggest that in a future climate, water quality, characterized by ecological quality indicators like winter nutrient, summer bottom oxygen, and annual mean phytoplankton concentrations as well as annual mean Secchi depth (water transparency), will be deteriorated compared to present conditions. In case of nutrient load reductions required by the BSAP, water quality is only slightly improved. Based on the analysis of biogeochemical fluxes, we find that in warmer and more anoxic waters, internal feedbacks could be reinforced. Increased phosphorus fluxes out of the sediments, reduced denitrification efficiency and increased nitrogen fixation may partly counteract nutrient load abatement strategies. PMID- 22926880 TI - Extremes of temperature, oxygen and blooms in the Baltic sea in a changing climate. AB - In the future, the Baltic Sea ecosystem will be impacted both by climate change and by riverine and atmospheric nutrient inputs. Multi-model ensemble simulations comprising one IPCC scenario (A1B), two global climate models, two regional climate models, and three Baltic Sea ecosystem models were performed to elucidate the combined effect of climate change and changes in nutrient inputs. This study focuses on the occurrence of extreme events in the projected future climate. Results suggest that the number of days favoring cyanobacteria blooms could increase, anoxic events may become more frequent and last longer, and salinity may tend to decrease. Nutrient load reductions following the Baltic Sea Action Plan can reduce the deterioration of oxygen conditions. PMID- 22926881 TI - Modeling nutrient transports and exchanges of nutrients between shallow regions and the open Baltic sea in present and future climate. AB - We quantified horizontal transport patterns and the net exchange of nutrients between shallow regions and the open sea in the Baltic proper. A coupled biogeochemical-physical circulation model was used for transient simulations 1961 2100. The model was driven by regional downscaling of the IPCC climate change scenario A1B from two global General Circulation Models in combination with two nutrient load scenarios. Modeled nutrient transports followed mainly the large scale internal water circulation and showed only small circulation changes in the future projections. The internal nutrient cycling and exchanges between shallow and deeper waters became intensified, and the internal removal of phosphorus became weaker in the warmer future climate. These effects counteracted the impact from nutrient load reductions according to the Baltic Sea Action Plan. The net effect of climate change and nutrient reductions was an increased net import of dissolved inorganic phosphorus to shallow areas in the Baltic proper. PMID- 22926882 TI - Climate change impact on riverine nutrient load and land-based remedial measures of the Baltic sea action plan. AB - To reduce eutrophication of the Baltic Sea, all nine surrounding countries have agreed upon reduction targets in the HELCOM Baltic Sea Action Plan (BSAP). Yet, monitoring sites and model concepts for decision support are few. To provide one more tool for analysis of water and nutrient fluxes in the Baltic Sea basin, the HYPE model has been applied to the region (called Balt-HYPE). It was used here for experimenting with land-based remedial measures and future climate projections to quantify the impacts of these on water and nutrient loads to the sea. The results suggest that there is a possibility to reach the BSAP nutrient reduction targets by 2100, and that climate change may both aggravate and help in some aspects. Uncertainties in the model results are large, mainly due to the spread of the climate model projections, but also due to the hydrological model. PMID- 22926883 TI - Uncertainties in a Baltic sea food-web model reveal challenges for future projections. AB - Models that can project ecosystem dynamics under changing environmental conditions are in high demand. The application of such models, however, requires model validation together with analyses of model uncertainties, which are both often overlooked. We carried out a simplified model uncertainty and sensitivity analysis on an Ecopath with Ecosim food-web model of the Baltic Proper (BaltProWeb) and found the model sensitive to both variations in the input data of pre-identified key groups and environmental forcing. Model uncertainties grew particularly high in future climate change scenarios. For example, cod fishery recommendations that resulted in viable stocks in the original model failed after data uncertainties were introduced. In addition, addressing the trophic control dynamics produced by the food-web model proved as a useful tool for both model validation, and for studying the food-web function. These results indicate that presenting model uncertainties is necessary to alleviate ecological surprises in marine ecosystem management. PMID- 22926884 TI - Impact of climate change on fish population dynamics in the Baltic sea: a dynamical downscaling investigation. AB - Understanding how climate change, exploitation and eutrophication will affect populations and ecosystems of the Baltic Sea can be facilitated with models which realistically combine these forcings into common frameworks. Here, we evaluate sensitivity of fish recruitment and population dynamics to past and future environmental forcings provided by three ocean-biogeochemical models of the Baltic Sea. Modeled temperature explained nearly as much variability in reproductive success of sprat (Sprattus sprattus; Clupeidae) as measured temperatures during 1973-2005, and both the spawner biomass and the temperature have influenced recruitment for at least 50 years. The three Baltic Sea models estimate relatively similar developments (increases) in biomass and fishery yield during twenty-first century climate change (ca. 28 % range among models). However, this uncertainty is exceeded by the one associated with the fish population model, and by the source of global climate data used by regional models. Knowledge of processes and biases could reduce these uncertainties. PMID- 22926885 TI - How will ocean acidification affect Baltic sea ecosystems? an assessment of plausible impacts on key functional groups. AB - Increasing partial pressure of atmospheric CO2 is causing ocean pH to fall-a process known as 'ocean acidification'. Scenario modeling suggests that ocean acidification in the Baltic Sea may cause a <= 3 times increase in acidity (reduction of 0.2-0.4 pH units) by the year 2100. The responses of most Baltic Sea organisms to ocean acidification are poorly understood. Available data suggest that most species and ecologically important groups in the Baltic Sea food web (phytoplankton, zooplankton, macrozoobenthos, cod and sprat) will be robust to the expected changes in pH. These conclusions come from (mostly) single species and single-factor studies. Determining the emergent effects of ocean acidification on the ecosystem from such studies is problematic, yet very few studies have used multiple stressors and/or multiple trophic levels. There is an urgent need for more data from Baltic Sea populations, particularly from environmentally diverse regions and from controlled mesocosm experiments. In the absence of such information it is difficult to envision the likely effects of future ocean acidification on Baltic Sea species and ecosystems. PMID- 22926886 TI - Climate change in the Baltic sea region: a cross-country analysis of institutional stakeholder perceptions. AB - Before climate change is considered in long-term coastal management, it is necessary to investigate how institutional stakeholders in coastal management conceptualize climate change, as their awareness will ultimately affect their actions. Using questionnaires in eight Baltic Sea riparian countries, this study examines environmental managers' awareness of climate change. Our results indicate that problems related to global warming are deemed secondary to short term social and economic issues. Respondents agree that problems caused by global warming will become increasingly important, but pay little attention to adaptation and mitigation strategies. Current environmental problems are expected to continue to be urgent in the future. We conclude that an apparent gap exists between decision making, public concerns, and scientific consensus, resulting in a situation in which the latest evidence rarely influences commonly held opinions. PMID- 22926887 TI - Estimating risk factors and perinatal outcomes for gestational diabetes and impaired glucose tolerance in teen mothers. AB - BACKGROUND: Our objective was to identify potentially modifiable risk factors and outcomes for gestational diabetes and impaired glucose tolerance in a contemporary American teen population. METHODS: We conducted a retrospective cohort analysis of all teenage deliveries (<=18 years old) at one institution over a 4-year period with documented oral glucose tolerance testing. All cases of gestational diabetes and impaired glucose tolerance were identified using the Carpenter and Coustan diagnostic criteria and compared with teenage mothers with normal glucose tolerance testing. RESULTS: Of the 670 included teen deliveries, 668 were either African American or Hispanic/Latino; 31 (5%) were diagnosed with gestational diabetes (n = 5) or impaired glucose tolerance (n = 26). Higher maternal prepregnancy body mass index (34.3 +/- 7.8 vs 30.3 +/- 6.4, p = 0.001) and morbid obesity (body mass index >= 35 kg/m(2) , RR 2.0, 95% CI 1.1-3.6) were associated with gestational diabetes and impaired glucose tolerance. There was no association with weight gain above the Institute of Medicine recommended levels (RR 1.6, 95% CI 0.77-3.4). On postpregnancy follow up, three of the five (60%) teens with gestational diabetes and none of the 26 (0%) teens with impaired glucose tolerance were diagnosed with diabetes mellitus. CONCLUSIONS: Higher prepregnancy body mass index, especially morbid obesity, places the gravid teen at higher risk for development of gestational diabetes and impaired glucose tolerance in pregnancy. The potentially modifiable nature of these risk factors coupled with the emerging teen obesity epidemic underscores the need for increased public health focus on this problem. PMID- 22926888 TI - Prospective study of therapeutic spiral enteroscopy in patients with surgically altered anatomy. AB - BACKGROUND: Spiral enteroscopy is rapidly emerging, along with double- and single balloon enteroscopy, as a paramount method to evaluate lesions in the deep small bowel. While the latter two methods have been used to manage patients with surgically altered anatomy, there are few reports on the role of spiral enteroscopy in this group. Our principal aim was to characterize the therapeutic uses of spiral enteroscopy in patients with surgically altered anatomy. METHODS AND RESULTS: Patients with surgically altered anatomy who failed management with conventional endoscopic methods for therapeutic indications were included in this prospective series at our tertiary referral center. The spiral technique was used to control variceal bleeding, dilate enteral anastomotic narrowing, and perform pancreaticobiliary interventions in seven patients. The cases were performed quickly and effectively and the need for surgery was obviated in all cases. CONCLUSION: The spiral enteroscopy system has significant therapeutic potential in patients with surgically altered anatomy. PMID- 22926889 TI - Centralisation of upper-GI cancer services: is the hub quicker than the spoke? AB - BACKGROUND: The aim of this study was to assess whether patients diagnosed with oesophageal or gastric cancer at a local district general hospital (the "spoke") have a similar temporal pathway through the decision-making and treatment process compared to those patients presenting at the centralised, tertiary hospital (the "hub"). METHODS: Between April 2010 and April 2011, patients with a new diagnosis of oesophagogastric cancer from both hub and spoke hospitals were analysed. Data regarding diagnosis, time from diagnosis to multidisciplinary meeting (MDM) discussion, and time from MDM decision to first treatment were all recorded. Statistical analysis was performed using parametric two-tailed t test to assess significance. RESULTS: There was a statistically significant increase in the time from diagnosis to MDM discussion at the spoke hospital compared to the hub (13.3 days vs. 25.67 days; p = 0.001). However, time to first treatment (surgery, palliative therapy, neoadjuvant therapy, or best supportive care) was significantly increased in the hub hospital compared to the spoke (43.4 days vs. 25.5 days; p = 0.023). CONCLUSIONS: Notwithstanding its limitations, this study is the first of its kind to show that there is a disparity in the management pathways of patients who first present to a regional hospital rather than the tertiary centre. Patients at the spoke hospital have a longer lead time into the MDM but nonoperative treatment appears to be delivered more quickly locally. PMID- 22926890 TI - Pancreatic duct stenting for the duration of ERCP only does not prevent pancreatitis after accidental pancreatic duct cannulation: a prospective randomized trial. AB - BACKGROUND: Pancreatic duct stent placement during endoscopic retrograde cholangiopancreatography (ERCP) has been recommended in patients at risk for post ERCP pancreatitis. However, the optimal duration of stent placement remains an open question. Our aim was to compare the efficacy of pancreatic stenting for the duration of ERCP only with spontaneous dislodgment/deferred endoscopic removal in preventing post-ERCP pancreatitis after accidental wire-guided pancreatic duct cannulation. METHODS: All patients in whom accidental wire-guided pancreatic duct cannulation had occurred during ERCP underwent immediate 5-Fr unflanged pigtail pancreatic duct stenting before attempting any other endoscopic maneuver. At the end of the ERCP, patients were randomly assigned to immediate stent removal (group A) or to leaving the stent in place (group B). Assessment of post-ERCP pancreatitis was blind. RESULTS: Post-ERCP pancreatitis occurred in 6/21 (29 %) patients in group A and in 0/19 patients in group B (P = 0.021); the two groups were well matched for their baseline characteristics. Post-ERCP pancreatitis was mild in two patients, moderate in two patients, and severe in two patients. Stents dislodged spontaneously in 14/19 (74 %) patients within 24-96 h; uneventful endoscopic removal was carried out after 96 h in 5 cases. Proximal stent migration did not occur in any case. CONCLUSIONS: Pancreatic duct stent placement for the duration of ERCP only does not prevent post-ERCP pancreatitis. Pancreatic stents should be left in place until spontaneous dislodgment occurs or endoscopic removal is deemed timely. 5-Fr unflanged pigtail stents remain in place for a period sufficient to prevent post-ERCP pancreatitis and do not migrate proximally. PMID- 22926891 TI - Integrated operation systems and voice recognition in minimally invasive surgery: comparison of two systems. AB - BACKGROUND: Integrated operation systems were developed for centralization and easy control of all components within the operating room (OR). These systems represent central units that use communication technology to connect and control various components of the OR. Voice control that is independent of the speaker has been a pioneering innovation in the central control of different OR components. The aim of the present study was to evaluate the utility of two voice activated control systems, the Siemens Integrated OR System (SIOS, Siemens Medical Solutions, Siemens AG) and the OR1 (Karl Storz GmbH & Co. KG), for delivery of commands to specific OR equipment. METHODS: To compare the two systems, actions such as adjusting the operating table, increasing gas pressure, switching on the video recorder, and controlling the endolight source were defined according to a study protocol. These actions were to be executed by test persons through speech and manual control after a suitable training period. The parameters evaluated were training time, time to execute each action, number of repeated commands, and number of functional errors. RESULTS: Seventy-four test persons from five nations were selected to participate. The numbers of repeated commands and functional errors differed significantly between systems in all user groups in favor of the SIOS (mean repeated commands for surgeons: SIOS, 2.4; OR1, 14.7, p < 0.0001). CONCLUSION: The SIOS voice control was more effective and more reliable than that of the OR1. Importantly, unlike the OR1, the SIOS produced no functional errors. The appropriate conditions for greater acceptance of these systems must be considered, together with additional technical improvements and possible combinations of advantages of the available systems. PMID- 22926892 TI - Minimally invasive approaches to extrapancreatic cholangiocarcinoma. AB - BACKGROUND: Due to the perceived difficulty in dissecting gallbladder cancers and extrapancreatic cholangiocarcinomas off of the portal structures and in performing complex biliary reconstructions, very few centers have used minimally invasive techniques to remove these tumors. Furthermore, due to the relative rarity of these tumors when compared to hepatocellular carcinoma, only a few reports have focused on short- and long-term results. METHODS: We performed a review by combining the experience of three international centers with expertise in complex minimally invasive hepatobiliary surgery. Patients were entered into a database prospectively. All patients with gallbladder cancer and cholangiocarcinoma were analyzed; patients with distal cholangiocarcinomas who underwent laparoscopic pancreatoduodenectomies were excluded. Patients were divided according to if they had gallbladder cancer, hilar cholangiocarcinoma, or intrahepatic cholangiocarcinoma. RESULTS: A total of 15 patients underwent laparoscopic resection for gallbladder cancer and 10 for preoperatively suspected gallbladder cancer, and 5 underwent laparoscopic completion procedures. An average of four lymph nodes (range = 1-11) were retrieved and all patients had an R0 resection. One patient (7 %) required conversion to an open procedure. No patients developed a biliary fistula, required percutaneous drainage, or had endoscopic stent placement. One patient had a recurrence at 3 months despite a negative final pathological margin, and a second patient had a distant recurrence at 20 months with a mean follow-up of 23 months. Nine patients underwent laparoscopic hepatectomy for intrahepatic cholangiocarcinoma. All anastomoses were completed laparoscopically. Biliary fistula was seen in two patients, one of which died after a transhepatic percutaneous biliary drain resulted in uncontrollable intra-abdominal hemorrhage despite reoperation. A third patient developed a pulmonary embolism. Thus, the morbidity and mortality rates were 33 and 11 %, respectively. One patient was converted to open and six patients (66 %) are alive with a median follow-up of 22 months. Five patients underwent minimally invasive resection for hilar cholangiocarcinoma; of these, two also required laparoscopic major hepatectomy. The mean estimated blood loss (EBL) was 240 mL (range = 0-400 mL) and the median length of stay (LOS) was 15 days (range = 11-21 days). All patients are alive with a median follow-up of 11 months (range = 3-18 months). None of the 29 patients developed port site recurrences. CONCLUSION: Minimally invasive approaches to gallbladder cancer and intrahepatic and extrahepatic cholangiocarcinoma seem feasible and safe in the short term. Larger series with longer follow-up are needed to see if there are any long-term disadvantages or advantages to laparoscopic resection of extrapancreatic cholangiocarcinoma. PMID- 22926893 TI - Less pain after transvaginal/transumbilical cholecystectomy than after the classical laparoscopic technique: short-term results of a matched-cohort study. AB - BACKGROUND: Natural orifice surgery (NOS) is gaining acceptance as an alternative to the traditional laparoscopic technique, especially for cholecystectomy through the transvaginal route. However, NOS remains controversial concerning expected advantages in terms of short- and long-term outcomes and potential side effects. This study was designed to compare short-term outcomes between transvaginal/transumbilical and classical laparoscopic cholecystectomy (LC). METHODS: A prospective matched-cohort study compared the authors' first 50 transvaginal/transumbilical cholecystectomies (TVC) with a group of 50 classical LCs from the corresponding period matched in terms of age, body mass index, and American Society of Anesthesiology classification. In both groups, elective surgery was performed for symptomatic cholecystolithiasis. In the NOS group, a hybrid procedure was performed with one transumbilical rigid instrument and two transvaginal rigid instruments. A numeric rating scale was used for daily pain assessment, initiated postoperatively in the recovery room. Both groups were compared with regard to length of surgery, intra- and postoperative complications, length of hospital stay, postoperative pain, and consumption of analgesics. RESULTS: The length of surgery and the rate of complications were similar in the two groups. But significant advantages were found for the transvaginal access in terms of pain using Numeric Rating Scale (NRS) on the day of surgery (NRS, 1.5/10 vs 3.1/10; p = 0.003) as well as in the morning (NRS, 1.9/10 vs 2.8/10; p = 0.047) and in the evening (NRS, 1.1/10 vs 1.8/10; p = 0.025) of postoperative day 1, and with regard to the length of the postoperative hospital stay (2.7 vs 3.4 days; p = 0.035). CONCLUSIONS: The findings show that TVC is a safe procedure for female patients. It has a risk comparable with that of classic LC, causes significantly less pain in the early postoperative period, and leads to a significantly shorter hospital stay. Prospective randomized trials are necessary to confirm these results. PMID- 22926895 TI - Dynamic and simultaneous MR measurement of R1 and R2* changes during respiratory challenges for the assessment of blood and tissue oxygenation. AB - This work presents a novel method for the rapid and simultaneous measurement of R1 and R2* relaxation rates. It is based on a dynamic short repetition time steady-state spoiled multigradient-echo sequence and baseline R1 and B1 measurements. The accuracy of the approach was evaluated in simulations and a phantom experiment. The sensitivity and specificity of the method were demonstrated in one volunteer and in four patients with intracranial tumors during carbogen inhalation. We utilized (DeltaR2*, DeltaR1) scatter plots to analyze the multiparametric response amplitude of each voxel within an area of interest. In normal tissue R2* decreased and R1 increased moderately in response to the elevated blood and tissue oxygenation. A strong negative DeltaR2* and DeltaR1 response was observed in veins and some tumor areas. Moderate positive DeltaR2* and DeltaR1 response amplitudes were found in fluid-rich tissue as in cerebrospinal fluid, peritumoral edema, and necrotic areas. The multiparametric approach was shown to increase the specificity and sensitivity of oxygen-enhanced MRI compared to measuring DeltaR2* or DeltaR1 alone. It is thus expected to provide an optimal tool for the identification of tissue areas with low oxygenation, e.g., in tumors with compromised oxygen supply. PMID- 22926894 TI - Laparoscopic repair of giant hiatus hernia: prosthesis is not required for successful outcome. AB - BACKGROUND: Giant hiatus hernia (GHH) are difficult to manage effectively. This study reports a laparoscopic, prosthesis-free technique to repair of GHH. METHODS: Retrospective analysis of a prospectively populated database of a single surgeon's experience of GHH (>30 % intrathoracic stomach) repair using a novel, uniform technique was performed. Routine postoperative endoscopy, quality of life (QOL), and Visick scoring was conducted. RESULTS: Surgery was conducted in 100 patients (70F, 30 M). Mean (standard deviation [SD]) age was 69.1 (+/-11.4), median (interquartile range) ASA was 2 (range, 2-3), and mean (SD) body mass index (BMI) was 29.1 (+/-4.5). Mean follow-up was 574.1 (+/-240.5) days. One (1 %) patient was converted to an open procedure due to technical issues. Median stay was 2.5 days (range, 2-4). One postoperative death occurred secondary to respiratory sepsis. Eight (8 %) patients had perioperative complications: 4 major (PE, non-ST elevation MI, postoperative bleed managed conservatively, infected mediastinal fluid collection); and 4 minor (pneumothorax, asymptomatic troponin leak, subacute small bowel obstruction, and urinary retention). Ninety-nine (99 %) patients had objective screening for recurrence at 3-6 months. Two (2 %) patients have had symptomatic recurrence of their hiatus hernia; both involved a recurrent fundal herniation. Another seven (7 %) had small (<2 cm), asymptomatic recurrences diagnosed only on routine follow-up. Seven (7 %) patients have required reintervention for dysphagia with endoscopic dilatation conducted to good effect in all cases. Two (2 %) patients have required revisional surgery: one for a symptomatic recurrence at 3 months and a second for recurrent mediastinal collection. The Visick score fell from a mean (SD) of 3 (+/-1.1) to 1.7 (+/-0.8) postoperatively (p < 0.0001). The mean (SD) QOL preoperatively was 87.8 (+/-24) versus 109.1 (+/-22.3) postoperatively (p < 0.0001). CONCLUSIONS: GHH can be managed safely and effectively laparoscopically, without the use of a prosthesis. PMID- 22926897 TI - [Clinical diagnosis and management of asthma in 2012]. PMID- 22926896 TI - Barriers to oral cancer screening: a focus group study of rural Black American adults. AB - OBJECTIVE: Mortality from mouth and throat cancer (MTC) is higher among Black Americans than White Americans partially because of late stage detection through screening. The disparity in mortality is particularly problematic among Black Americans living in rural areas who have limited access to preventative resources. Our study explored barriers to screening for MTC among Black Americans. METHODS: We conducted nine focus groups among rural Black Americans age 40 years and older (N = 80). RESULTS: Content coding of the transcripts of the focus groups revealed three primary barriers to screening. Lack of knowledge (e.g., not knowing about MTC and not knowing MTC symptoms) accounted for 31.8% of all barriers mentioned, lack of resources (e.g., lack of money and health insurance) accounted for 25.0% of all barriers mentioned, and fear (e.g., fear of screening and diagnosis) accounted for 22.9% of all barriers mentioned. CONCLUSIONS: We placed these barriers within the Theory of Planned Behavior and conclude that interventions aimed at increasing MTC screening among rural Black Americans should first focus on changing people's attitudes about screening by increasing knowledge about MTC and reducing fear. PMID- 22926898 TI - [Cardiac sarcoidosis--unsolved clinical problem]. PMID- 22926899 TI - [Non-invasive ventilation in Poland in 2012]. PMID- 22926900 TI - [The use of multi-color flow cytometry for identification of functional markers of nTregs in patients with severe asthma]. AB - INTRODUCTION: At present, severe asthma is a particular clinical problem. An important role is attributed to dysfunction of nTreg subpopulations of lymphocytes in the pathogenesis of asthma. Therefore, the purpose of this study was to identify markers of nTreg cell function in patients with severe and mild to moderate asthma. MATERIAL AND METHODS: The study included sixty patients with asthma (30 with severe and 30 with mild to moderate asthma). The control group comprised 30 healthy volunteers. The diagnosis of asthma was confirmed accordance with generally accepted recommendations (GINA 2008). nTreg immunophenotype CD4/CD25/CD127/FoxP3/GITR/CD152/CCR5/ /CCR7 was evaluated by multicolor flow cytometry. RESULTS: We showed a significant reduction in the percentage of nTreg (76%) cells and the expression of CD152 (46.2%) in patients with severe asthma compared with mild-moderate asthma (85.5% and 86.7%; p < 0.05). It was observed that the transcription factor FoxP3 expression in nTreg cells positively correlated with FEV1 in patients with severe asthma (r = 0.53; p < 0.05). It was also found that the ratio nTregCCR5*/TeffCCR5* was significantly reduced in patients with severe asthma (0.91) compared with mild-moderate (1.58) asthma and control groups (1.55; p < 0.001). CONCLUSIONS: There are phenotypic differences in nTreg lymphocytes between patients with severe and mild-moderate asthma. This fact may confirm nTreg cell dysfunction and indicate that the potential markers (FoxP3, CD152, CCR5), can be used to monitor the effectiveness of treatment of bronchial asthma, especially severe disease. PMID- 22926901 TI - [Profile of adults suffering from asthma in Poland--results of PulmoScreen study]. AB - INTRODUCTION: Adult patients with diagnosis of asthma remain largely under the care of primary care physicians (general practitioners). Thus, they play an important role in diagnosing and treating this population. The aim of the study was to characterize of adults with asthma remaining under the care of Polish general practitioners (GP) as well as to evaluate the use of diagnostic tools and treatment in light of GINA recommendations. MATERIAL AND METHODS: This questionnaire study included a representative sample of 1852 general practitioners (GPs) who were asked to complete questionnaires on the diagnosis and treatment of their patients with asthma. RESULTS: Altogether 1250 GPs provided information about 10 981patients. Controlled asthma had 21.2% patients, 46.9% partly controlled, and 31.9% uncontrolled asthma. Allergy skin prick tests were performed in 64.8%, bronchial reversibility tests in 58.1% and bronchial provocation tests in 9.8% of patients. Spirometry results were obtained for 41.9% of patients. In the last year 16.6% of patients underwent emergency intervention due to asthma exacerbation and 18.1% required hospitalization. CONCLUSIONS: In Polish asthma patients the frequency of allergological and pulmonological visits as well as the frequency of spirometric assessment are poorly associated with asthma control level. The diagnostic tests recommended by international and national guidelines for the management of asthma are performed too seldom. Hospitalizations and emergency interventions related to asthma exacerbations are found in a large portion of patients and depend on their gender and asthma control level. Asthma has a negative impact on everyday activity in more than half of patients. Proper assessment of the level of causes asthma control according to GINA guidelines poses problems to Polish general practitioners. PMID- 22926902 TI - [Impact of social risk factors on treatment outcome in patients with culture positive pulmonary tuberculosis (CPPTB)]. AB - INTRODUCTION: The aim of the study was to evaluate the impact of social risk factors on treatment outcome among culturepositive patients treated for active pulmonary tuberculosis in three separate districts - Warsaw, Gdansk and Siedlce - in years 1995 and 2000. MATERIAL AND METHODS: We retrospectively reviewed medical records of patients who were notified in 1995 and 2000 and were treated in hospitals and dispensaries. Alcohol abuse and homelessness were recognized as risk factors associated with tuberculosis and nonadherence to treatment. Treatment outcome was evaluated using treatment indicators defined by the World Health Organisation: cured, treatment completed, treatment defaulted, treatment failure and other results of treatment. RESULTS: Seven hundred and eight patients with culture positive pulmonary tuberculosis were included (373 in 1995 and 335 in 2000). There were 85 patients with risk factors in 1995 and 101 patients in 2000. 80 of participants in 1995 and 69 in 2000 abused alcohol, 5 and 32 were classified as homeless, respectively. Among alcohol abusers treatment success rates according to the WHO definition (either bacteriologic cured or treatment completed) were 45.1% in 1995 and 53.6% in 2000. Among patients not abusing alcohol treatment success rates were 63.8% and 54.1%, respectively. The differences were statistically significant (p = 0.005 in 1995 and p = 0.0186 in 2000). In 1995 forty percent of homeless patients had succeeded treatment, while the rate of treatment success among non-homeless was 60%. Because of small number included in homeless group the difference was not statistically significant (p = 0.6532). In 2000 treatment success rate among homeless participants was 25% and among non-homeless - 57.1%, which was highly statistically significant (p = 0.001). CONCLUSION: Alcohol abuse and homelessness were associated with bad treatment outcome among patients with pulmonary tuberculosis. Interventions to improve treatment adherence in patients considered to be at risk for default are necessary. PMID- 22926903 TI - The impact of timeliness of care on survival in non-small cell lung cancer patients. AB - INTRODUCTION: It is uncertain whether timeliness improves clinical outcomes in lung cancer patients. The goal of the study was to analyse the influence of patient's and doctor's delays on survival of unselected population of NSCLC patients. MATERIAL AND METHODS: From 1995 to 1998, 8705 squamous cell lung cancer patient's and 1881 adenocarcinoma patient's were registered in Pulmonary Outpatients Clinics in all parts of Poland and subsequently in National Tuberculosis and Lung Diseases Research Institute Register (NTLDRIR). RESULTS: The median time from first symptom(s) to the beginning of a treatment was 92 days (mean -138.5 days).The median waiting time between first symptom(s) and first visit to a doctor's was 30 days (mean 57 days) and from first visit to a doctor's to referral to a chest physician - was 17 days (mean 41days). Diagnosis of the NSCLC was established in a mean time of 71 days (median 40 days), but chest physician diagnosed patients in a mean time of 51days (median 28 days). The multivariate analysis revealed that ECOG performance status (PS) 2 (HR = 1.4) and 3+4 (HR = 2.23), clinical stage of the disease II (HR = 1.32), III (HR = 1.41), and IV (HR = 1.82) were independent negative predictors of survival. Non surgically treated patients had worse prognosis than patients treated surgically (HR = 3.03). Lack of patient's delay had a significant positive impact on survival (HR = 0.88), particularly for patients in PS 0+1 (HR = 0.9) and 3+4 (HR = 0.9). Lack of doctor's delay was a negative predictive factor of survival (HR = 1.14). It was observed particularly in patients in performance status 2 (HR = 1.28). CONCLUSIONS: The patient's delay and lack of doctor's delay had a negative impact on survival of NSCLC patients. PMID- 22926904 TI - [Six-minute walk test in sarcoidosis patients with cardiac involvement]. AB - INTRODUCTION: Cardiac involvement in sarcoidosis is of critical importance, due to the poor prognosis if this organ manifestation is left undiagnosed and untreated. The six-minute walk test (6 MWT) is a useful test to evaluate exercise tolerance of sarcoid patients. We aimed to assess the 6 MWT value in diagnosis, course and treatment monitoring of patients with cardiac sarcoidosis. MATERIAL AND METHODS: 47 patients were included: 22 with pulmonary sarcoidosis and cardiac involvement (13 women, 9 men), 25 with pulmonary sarcoidosis, with no changes in the heart (15 women, 10 men), and 18 healthy volunteers as controls (12 women, 6 men). Out of 22 patients with cardiac involvement 11 were treated for heart sarcoidosis with prednisone (9 pts - initial dose 60 mg daily and 2 pts - 40 mg daily). 11 pts in this group were not treated. In all patients sarcoidosis was confirmed histopatologically. Magnetic resonance imaging was used to diagnose involvement of the heart. In the studied groups we assessed: heart rate (HR), oxygen saturation, and distance in 6 MWT and Borg dyspnea score. RESULTS: Patients with cardiac sarcoidosis desaturated more during exercise (DSaO2max = 3.5 +/- 3.2 vs. 0.38 +/- 0.69; p = 0.004) and had a lower increase of HR in first minute during the 6 MWT (DHR1 = 21.81 +/- 11.72 vs. 50.61 +/- 12.35; p = 0.0001) when compared to healthy subjects. Significantly lower increase of HR in first minute of 6 MWT was observed in patients with cardiac sarcoidosis when compared to patients with pulmonary sarcoidosis with no cardiac involvement (DHR1 = 21.81 +/- 11.72 vs. 38.8 +/- 18.17, p = 0.01). After introduction of treatment in sarcoidosis group, significantly higher (p = 0.02) increase of HR in first minute of 6 MWT as compared to baseline test was observed. CONCLUSIONS: The six-minute walk test is useful in diagnosing cardiac involvement in sarcoidosis. The increase in HR during exercise and decrease degree of desaturation were a good predictors of the response to therapy. PMID- 22926905 TI - [Gefitinib in patients with advanced non-small-cell lung cancer]. AB - INTRODUCTION: Patients with advanced non-small cell lung cancer (NSCLC) have a very poor prognosis. Individualization of treatment and identification of therapeutic molecular targets may improve outcomes. Gefitinib was introduced recently among several other molecular-targeted drugs of activity in NSCLC. Gefitinib is indicated for patients diagnosed with advanced or disseminated NSCLC with an activating mutation in the EGFR (epidermal growth factor receptor) gene. The paper summarize experience with gefitinib in the Department of Lung and Thoracic Tumors of Maria Sklodowska-Curie Memorial Cancer Centre and Institute in Warsaw. MATERIAL AND METHODS: The group of 11 patients diagnosed with advanced NSCLC and activating mutations in the EGFR gene was analyzed. Patients were treated from April 2010 to April 2011. Tolerability, objective response rate (ORR) and progression free survival (PFS), which was calculated by the Kaplan Meier method, were assessed. RESULTS: Median observation time from the start of gefitinib treatment was 14 months (range 4,8-19 months). The rate of one-year survival in this group of patients was 91% (10 patients) with 54% of patients (6 patients) surviving one year without progression of disease. The ORR rate of 82% and median PFS 11.4 months were reached. No treatment-related deaths were reported. Among the complications skin toxicity (82%) and diarrhea (45%) were most frequently observed, in most cases the Common Toxicity Criteria for Adverse Events (CTCAE) first grade. CONCLUSIONS: The results confirm the literature data on the efficacy and safety profile of gefitinib in the treatment of patients with the diagnosis of advanced NSCLC and activating mutation in the EGFR gene. PMID- 22926906 TI - [The incidence of alpha-1-antitrypsin (A1AT) deficiency alleles in population of Central Poland--preliminary results from newborn screening]. AB - Inherited alpha-1 antitrypsin deficiency (A1ATD) is listed among the three most common genetic disorders in Caucasians. It considerably increases the risk of progressive obstructive lung diseases, mostly chronic obstructive pulmonary disease. Data on the A1ATD prevalence in Poland are scarce, no studies with large enough groups representative for whole Polish population have been performed. Here, we present the preliminary data on the incidence of A1AT main deficiency alleles from the newborn screening in Mazovia (Central Poland) region. Real-time PCR genotyping and A1AT blood concentration measurement by nephelometry were performed from the dry blood spots (DBS) samples of 658 newborns. Deficiency alleles PI*Z i PI*S were present in 28 children, respectively in 2.8% and 1.5%. Their existence corresponded with significantly lower A1AT blood concentration. Estimated incidence of deficiency alleles was 13,7/1000 (95% CI 5.8-21.5) for PI*Z and 7.6/1000 (95% CI 1.7- 13.5) for PI*S. The calculated prevalence for the main deficiency genotype ZZ was 1/5345. The study is on-going. PMID- 22926907 TI - [Bronchial asthma in obesity--a distinct phenotype of asthma?]. AB - Asthma and obesity have a considerable impact on public health and their prevalence has increased in recent years. Numerous large cross-sectional and prospective studies performed in adults, adolescents, and children throughout the world supports the hypothesis that obesity is an independent risk factor for asthma. The pathogenetic basis for asthma and obesity associations in humans is not well established. Obesity is capable of reducing pulmonary compliance, lung volumes, and the diameter of peripheral respiratory airways, and may influence on airway hyperresponsiveness. The increase of adipose tissue in obese subjects leads to a systemic inflammatory state, which produces a rise in the serum concentrations of several pro-inflammatory cytokines, chemokines and adipokines. The proinflammatory adipokines (leptin, resistin) and antiinflammatory (adiponectin) may be causally associated with asthma, however human studies are inconclusive. Obese asthma patients very often demonstrate increased asthma severity and relative corticosteroid resistance. Some studies suggest improvements in the disease with weight loss in obese asthma patients. Recently published data suggest that obese asthma patients may represent a distinct phenotype of asthma. PMID- 22926908 TI - [May a COPD patient benefit from rehabilitation associated with pharmacological treatment?]. AB - Chronic obstructive pulmonary disease (COPD) patients are known to be physically inactive due to exertion dyspnea. Improvement of physical capacity leads to reduction of symptoms severity, increases PFT values, decreases the number of infectious exacerbations and, generally, improves the quality of life and prognosis. Therefore rehabilitation plays a crucial role in the treatment of COPD patients. It has been demonstrated that the use of bronchodilating drugs prior to physical exertion enables rehabilitation by diminishing the shortness of breath. PMID- 22926909 TI - New onset diabetes in a patient with active tuberculosis. AB - The present report describes the coincidence of pulmonary tuberculosis (TB) and metabolic disorder such as diabetes. A patient's bronchoalveolar lavage was found to be positive for acid-fast bacilli (AFB) with following growth of Mycobacterium tuberculosis and complete sensitivity to first line anti-TB drugs. At the same time, the patient presented with typical diabetes manifestation and subsequently required insulin therapy. Combined treatment resulted in significant clinical improvement and gradual resolution of both TB and diabetes symptoms. Therefore, we would like to highlight the value of appropriate medical management of these disorders sharing at least some clinical symptoms and signs such as weight loss and fatigue. Moreover, a growing body of evidence indicates that diabetes may play a role as a risk factor for TB. Consequently, the increasing diabetes prevalence may be a danger to TB control. PMID- 22926910 TI - [Interstitial lung disease in patients with primary biliary cirrhosis]. AB - Primary biliary cirrhosis (PBC) is a chronic autoimmune disorder of unknown etiology. The disease affects middle-aged women and is characterized by the destruction of the intralobular bile ducts that causes consequent cholestasis. AMA is a hallmark of PBC, composed mostly of IgG and IgM class. The M2 antibody is the most specific one, with sensitivity range of 54-98% depending on type of test used. PBC is often accompanied by other autoimmune diseases, such as Sjogrens syndrome, thyroiditis, rheumatoid arthritis, dermatomyositis, polymyositis. Interstitial lung disease (ILD) has been reported in patients with primary biliary cirrhosis but its frequency and nature are poorly understood. We report pulmonary involvement in the course of PBC in 4 middle-aged women. Histopatological examination of lung specimens was available in three patients: two presented with sarcoid - like granulomas, one with lymphocytic interstitial pneumonia (LIP). In one patient the diagnosis of pulmonary fibrosis was based on clinical and radiological features. Because of abnormal pulmonary function tests (PFT) results all the patients were treated with prednisone, one, additionally with azathioprine. The treatment was successful in all of the patients. PMID- 22926911 TI - [Non-invasive home mechanical ventilation: qualification, initiation, and monitoring]. AB - Following the introduction of non-invasive positive pressure ventilation (NPPV), the number of patients using home mechanical ventilation has increased substantially and continues to rise worldwide. This is primarily explained by both the effectiveness and comfort that are offered by NPPV in most patients, and particularly in patients with chest wall and neuromuscular diseases. For clinically stable patients the qualification for NPPV largely depends on the presence of complaints or signs of (nocturnal) hypoventilation with accompanying hypercapnia. For patients who are referred by an ICU there are additional prerequisites. In any case, the aims of NPPV should be met and NPPV should be effective. The initiation of NPPV, whether in the clinic or not, should always be tailored to the individual patient. Based on effectiveness, safety, and comfort, the best ventilator has to be chosen. Although with modern interfaces NPPV may be provided continuously, for continuing NPPV over the years, adding manual and/or mechanical cough augmentation techniques is usually mandatory. To control the ongoing effectiveness of NPPV regular monitoring of the patient is essential, and nowadays transcutaneous measurement of CO2 seems the most reliable and appropriate technique. For trend analysis, downloaded data of modern ventilators may be helpful as well. The ultimate goal of NPPV, to prevent tracheotomy, can only be reached if the patient has continuous access to a centre with expertise in cough augmentation techniques and both nocturnal and diurnal NPPV. PMID- 22926913 TI - Prior service utilization in detained youth with mental health needs. AB - This study examined the prevalence of mental health needs and rates of service utilization among youth detained in a metropolitan juvenile justice system in California. Of the 345 youth in the sample, 265 (76.8 %) qualified for high or acute mental health need and 210 (60.9 %) had at least one prior contact with mental health services. No differences in mental health need were found across ethnicities; however rates of prior service utilization significantly differed (chi(2) = 19.18, p < 0.001). Asian and Pacific Islander participants were less likely to have had prior contact with county services than any other ethnic group. PMID- 22926914 TI - Classification of patients from time-course gene expression. AB - Classifying patients into different risk groups based on their genomic measurements can help clinicians design appropriate clinical treatment plans. To produce such a classification, gene expression data were collected on a cohort of burn patients, who were monitored across multiple time points. This led us to develop a new classification method using time-course gene expressions. Our results showed that making good use of time-course information of gene expression improved the performance of classification compared with using gene expression from individual time points only. Our method is implemented into an R-package: time-course prediction analysis using microarray. PMID- 22926915 TI - Studies on the mechanism of B(C6F5)3-catalyzed hydrostannylation of propargylic alcohol derivatives. AB - Sleight of hydride: B(C(6)F(5))(3) catalyzes the hydrostannylation of propargylic alcohols in a regio- and stereoselective manner. This Lewis acid first abstracts a hydride from the stannane, thus forming a borohydride/stannyl cation pair, the stability of which depends on solvent and ligands. Deuterium-labeling experiments showed that the source that delivers a hydride to the alkenyl cation is not the borohydride but rather a second molecule of stannane. PMID- 22926917 TI - Computational modeling, synthesis, and antioxidant potential of novel phenylcarbamoylbenzoic acid analogs in combating oxidative stress. AB - A new series of phenylcarbamoylbenzoic acid analogs were designed, synthesized, and evaluated for their in vitro antioxidant activity, aiming to find a lead for the treatment of oxidative stress. The target compounds were prepared by substituting the core phenylcarbamoylbenzoic acid moiety with certain functionalities via simple and efficient synthetic strategies. A molecular modeling study was performed to evaluate the recognition of target compounds at the 3MNG binding pocket. The docking data revealed that compounds 8c and 9a selectively bind to the crucial amino acid residues in the active site of 3MNG. The in vitro antioxidant activity was determined by ABTS antioxidant assay. Compounds 8c, 9a, and 9b showed high antioxidant activity and are thus promising as potent antioxidant leads. PMID- 22926916 TI - Whole chromosome aneuploidy: big mutations drive adaptation by phenotypic leap. AB - Despite its widespread existence, the adaptive role of aneuploidy (the abnormal state of having an unequal number of different chromosomes) has been a subject of debate. Cellular aneuploidy has been associated with enhanced resistance to stress, whereas on the organismal level it is detrimental to multicellular species. Certain aneuploid karyotypes are deleterious for specific environments, but karyotype diversity in a population potentiates adaptive evolution. To reconcile these paradoxical observations, this review distinguishes the role of aneuploidy in cellular versus organismal evolution. Further, it proposes a population genetics perspective to examine the behavior of aneuploidy on a populational versus individual level. By altering the copy number of a significant portion of the genome, aneuploidy introduces large phenotypic leaps that enable small cell populations to explore a wide phenotypic landscape, from which adaptive traits can be selected. The production of chromosome number variation can be further increased by stress- or mutation-induced chromosomal instability, fueling rapid cellular adaptation. PMID- 22926918 TI - Clinical Outcomes After Insulin Initiation in Patients with Type 2 Diabetes: 24 Month Results from INSTIGATE. AB - INTRODUCTION: To examine changes in insulin regimens and glycemic control during the 24 months after initiation of insulin in patients with type 2 diabetes mellitus. METHODS: Data were collected over a 24-month period from patients requiring insulin initiation as part of usual care, in a prospective, observational study. Changes in insulin regimens and hemoglobin A(1c) (HbA(1c)) were examined within countries (Germany, Greece, Spain) and overall. RESULTS: Prandial insulin only was most commonly initiated in Germany, while basal or premixed formulations were initiated in Greece and Spain. In Germany, compared with Greece or Spain, the patients were slightly younger and had a shorter diabetes duration when initiating insulin. For patients overall, 76.1% did not change their insulin regimen between initiation and 24 months. The most obvious change was a shift from prandial to basal/bolus in Germany, with almost doubling of mean daily insulin dose; in Greece and Spain, more patients stopped using insulin and the trend to more complex regimens was not seen. Overall, mean (SD) HbA(1c) decreased from baseline (9.4 [1.7]%) to 6 months (7.2 [1.0]%), but with little further change through 24 months (7.2 [1.1]%). HbA(1c) change with basal/bolus insulin (-2.6 [2.0]%, baseline 10.1%) was greater than with basal only (-2.0 [1.8]%, baseline 9.3%). Mean HbA(1c) less than 7% was achieved and maintained over 24 months in Germany, but was not achieved at any time in Greece or Spain. CONCLUSIONS: Within 24 months of insulin initiation, the majority of patients with type 2 diabetes remained on the same insulin regimen initially instigated, despite the well-established progressive loss of prandial and basal endogenous insulin secretion. Adequate glycemic control was best achieved where insulin dosage adjustments and insulin intensification took place. PMID- 22926919 TI - Secure Dynamic access control scheme of PHR in cloud computing. AB - With the development of information technology and medical technology, medical information has been developed from traditional paper records into electronic medical records, which have now been widely applied. The new-style medical information exchange system "personal health records (PHR)" is gradually developed. PHR is a kind of health records maintained and recorded by individuals. An ideal personal health record could integrate personal medical information from different sources and provide complete and correct personal health and medical summary through the Internet or portable media under the requirements of security and privacy. A lot of personal health records are being utilized. The patient-centered PHR information exchange system allows the public autonomously maintain and manage personal health records. Such management is convenient for storing, accessing, and sharing personal medical records. With the emergence of Cloud computing, PHR service has been transferred to storing data into Cloud servers that the resources could be flexibly utilized and the operation cost can be reduced. Nevertheless, patients would face privacy problem when storing PHR data into Cloud. Besides, it requires a secure protection scheme to encrypt the medical records of each patient for storing PHR into Cloud server. In the encryption process, it would be a challenge to achieve accurately accessing to medical records and corresponding to flexibility and efficiency. A new PHR access control scheme under Cloud computing environments is proposed in this study. With Lagrange interpolation polynomial to establish a secure and effective PHR information access scheme, it allows to accurately access to PHR with security and is suitable for enormous multi-users. Moreover, this scheme also dynamically supports multi-users in Cloud computing environments with personal privacy and offers legal authorities to access to PHR. From security and effectiveness analyses, the proposed PHR access scheme in Cloud computing environments is proven flexible and secure and could effectively correspond to real-time appending and deleting user access authorization and appending and revising PHR records. PMID- 22926921 TI - Insecticide susceptibility status in three medically important species of mosquitoes, Anopheles stephensi, Aedes aegypti and Culex quinquefasciatus, from Bruhat Bengaluru Mahanagara Palike, Karnataka, India. AB - BACKGROUND: Development of resistance among mosquito vectors of diseases is of growing concern in many countries of the subtropics, including much of India. The distributions of susceptibility/resistance to insecticides are scarcely recorded and are unknown in many parts of India. This manuscript reports the susceptibility status among strains of Anopheles stephensi, Aedes aegypti and Culex quinquefasciatus collected from different geographical areas of Bruhat Bengaluru Mahanagara Palike (BBMP), Karnataka, to six conventionally used insecticides. RESULTS: An. stephensi, Ae. aegypti and Cx. quinquefasciatus from different geographic areas showed susceptibility towards temephos. However, susceptibility was meagre for most of the other insecticides used in the study. Strong resistance to propoxur was reported in Ullala (RR(90) = 467.1) and Bannerghatta (RR(90) = 12,265) populations of An. stephensi and Ae. aegypti respectively. RR(90) >= 12,830 was recorded as higher in the Yelahanka (YLK) population of Cx. quinquefasciatus to neem. Significant differences at LC(50) and LC(90) concentrations were observed against various insecticides in different mosquito populations. Resistance was observed against some of the larvicides for the diagnostic dose recommended by WHO. CONCLUSION: The results form baseline data on the susceptibility status of three medically important mosquito vectors of diseases to commonly used insecticides in the field at present emphasise the importance of carrying out more effective and planned vector control measures. PMID- 22926920 TI - Overexpression of CCL20 and its receptor CCR6 predicts poor clinical prognosis in human gliomas. AB - Recent studies have demonstrated that the chemokine CCL20 and its receptor CCR6 may be involved in tumorigenesis, tumor progression and metastatic spread of various human malignancies. The aim of this study was to investigate the clinicopathological significance and prognostic value of CCL20 and CCR6 expression in human malignant glioma. CCL20 and CCR6 expression in human gliomas and nonneoplastic brain tissues was measured by immunohistochemistry. The association of CCL20 and CCR6 expression with clinicopathological factors or prognosis in glioma patients was statistically analyzed. The expression levels of CCL20 and CCR6 proteins were both up-regulated in glioma tissues. There was a significantly positive correlation between the expression of the two markers (r = 0.88; P < 0.001). In addition, the overexpressions of CCL20 and CCR6 were both detected in high-grade glioma tissues compared with those in low-grade tissues and increased with ascending tumor World Health Organization (WHO) grades (P = 0.006 and 0.008, respectively). The increased expressions of CCL20 and CCR6 proteins were also significantly correlated with low Karnofsky performance score (both P = 0.01). Moreover, univariate analysis found that CCL20 expression (P = 0.002), CCR6 expression (P = 0.002) and CCL20/CCR6 co-expression (P < 0.001) were all significantly associated with poor prognosis. In particular, glioma patients with CCL20/CCR6 co-expression have the shortest overall survival. Multivariate analysis further identified the expression levels of CCL20 and CCR6 to be independent prognostic factors. Our data suggest for the first time that CCL20 and CCR6 might play an important role in the regulation of aggressiveness in human gliomas. The up-regulation of CCL20 and CCR6 might be closely associated with poor clinical outcome of patients with gliomas. PMID- 22926922 TI - Can bronchoscopic airway anatomy be an indicator of autism? AB - Bronchoscopic evaluations revealed that some children have double branching of bronchi (designated "doublets") in the lower lungs airways, rather than normal, single branching. Retrospective analyses revealed only one commonality in them: all subjects with doublets also had autism or autism spectrum disorder (ASD). That is, 49 subjects exhibited the presence of initial normal anatomy in upper airway followed by doublets in the lower airway. In contrast, the normal branching pattern was noted in all the remaining 410 subjects who did not have a diagnosis of autism/ASD. We propose that the presence of doublets might be an objective, reliable, and valid biologic marker of autism/ASD. PMID- 22926924 TI - Halophilic hydrolases as a new tool for the biotechnological industries. AB - Halophilic micro-organisms are able to survive in high salt concentrations because they have developed diverse biochemical, structural and physiological modifications, allowing the catalytic synthesis of proteins with interesting physicochemical and structural properties. The main characteristic of halophilic enzymes that allows them to be considered as a novel alternative for use in the biotechnological industries is their polyextremophilicity, i.e. they have the capacity to be thermostable, tolerate a wide range of pH, withstand denaturation and tolerate high salt concentrations. However, there have been relatively few studies on halophilic enzymes, with some being based on their isolation and others on their characterisation. These enzymes are scarcely researched because attention has been focused on other extremophile micro-organisms. Only a few industrial applications of halophilic enzymes, principally in the fermented food, textile, pharmaceutical and leather industries, have been reported. However, it is important to investigate applications of these enzymes in more biotechnological processes at both the chemical and the molecular level. This review discusses the modifications of these enzymes, their industrial applications and research perspectives in different biotechnological areas. PMID- 22926923 TI - Non-spin-echo 3D transverse hadamard encoded proton spectroscopic imaging in the human brain. AB - A non-spin-echo multivoxel proton MR localization method based on three dimensional transverse Hadamard spectroscopic imaging is introduced and demonstrated in a phantom and the human brain. Spatial encoding is achieved with three selective 90 degrees radiofrequency pulses along perpendicular axes: The first two create a longitudinal +/-M(Z) Hadamard order in the volume of interest. The third pulse spatially Hadamard-encodes the +/-M(Z)s in the volume of interest in the third direction while bringing them to the transverse plane to be acquired immediately. The approaching-ideal point spread function of Hadamard encoding and very short acquisition delay yield signal-to-noise-ratios of 20 +/- 8, 23 +/- 9, and 31 +/- 10 for choline, creatine, and N-acetylaspartate in the human brain at 1.5 T from 1 cm(3) voxels in 21 min. The advantages of transverse Hadamard spectroscopic imaging are that unlike gradient (Fourier) phase-encoding: (i) the volume of interest does not need to be smaller than the field of view to prevent aliasing; (ii) the number of partitions in each direction can be small, 8, 4, or even 2 at no cost in point spread function; (iii) the volume of interest does not have to be contiguous; and (iv) the voxel profile depends on the available B1 and pulse synthesis paradigm and can, therefore, at least theoretically, approach "ideal" "1" inside and "0" elsewhere. PMID- 22926925 TI - The relation among NGF, EGF and insulin is important for triggering pancreatic beta cell apoptosis. AB - BACKGROUND: Nerve growth factor (NGF) is a well-known mediator for maintaining the survival of neurons, while recent studies report that its absence induces apoptosis in cultured beta cells of humans and rats. However, its relationship with other growth factors that have important roles in the survival and function of beta cells such as epidermal growth factor (EGF) has not yet been elucidated. The aim of this study was to investigate the effects of NGF withdrawal on the synthesis and secretion of EGF, insulin with respect to beta cell apoptosis in hyperglycemic rats. METHOD: beta cells were isolated from euglycemic and streptozotocin-induced hyperglycemic rats and treated with NGF neutralizing antibody for withdrawal of NGF in culture medium. NGF, EGF and insulin levels in cell lysates and secretion samples were measured by enzyme-linked immunosorbent assay, and their gene expressions were determined by real-time reverse transcription polymerase chain reaction assay. Apoptosis was quantitatively determined by cytoplasmic histone-associated DNA fragments. RESULTS: Nerve growth factor neutralization triggered beta cell apoptosis. In addition decreased insulin, increased NGF and EGF were observed at gene expression and protein levels by NGF neutralization. Moreover, NGF withdrawal decreased secretion of these peptides from beta cells. Although the alterations seemed to be similar under euglycemic and hyperglycemic conditions, NGF withdrawal more strongly affected beta cells of hyperglycemic rats. CONCLUSIONS: These important findings indicate that NGF is an important regulator for the synthesis and secretion of EGF and insulin from the beta cells. Moreover, results suggested that NGF withdrawal causes apoptosis by decreasing EGF, NGF and insulin secretion from beta cells of hyperglycemic rats. PMID- 22926926 TI - Apicidin induces endoplasmic reticulum stress- and mitochondrial dysfunction associated apoptosis via phospholipase Cgamma1- and Ca(2+)-dependent pathway in mouse Neuro-2a neuroblastoma cells. AB - Apicidin, a fungal metabolite that functions as a histone deacetylase inhibitor, induces apoptosis in cancer cells. We investigated the molecular mechanisms of the anti-cancer effects of apicidin in mouse Neuro-2a neuroblastoma cells. Apicidin induced apoptotic cell death and activation of caspase-12, -9, and -3. Apicidin induced expression of endoplasmic reticulum (ER) stress-associated proteins, including CCAAT/enhancer binding protein homologous protein (CHOP), cleavage of activating transcription factor 6alpha, and phosphorylation of eukaryotic initiation factor 2alpha. Inhibition of ER stress by CHOP knockdown or using the ER stress inhibitors, salubrinal and 4-phenylbutyric acid, reduced apicidin-induced cell death. Apicidin induced reactive oxygen species accumulation and mitochondrial membrane potential loss. An antioxidant, N-acetyl cysteine, reduced apicidin-induced cell death, CHOP expression, and mitochondrial dysfunction. In addition, apicidin increased cytosolic Ca(2+), which was blocked by 2-aminoethoxydiphenyl borate, an antagonist of inositol 1,4,5-trisphosphate receptor, and BAPTA-AM, an intracellular Ca(2+) chelator. 2-Aminoethoxydiphenyl borate and BAPTA-AM inhibited apicidin-induced cell death and ER stress. Interestingly, apicidin induced phosphorylation of phospholipase Cgamma1 (PLCgamma1) and epidermal growth factor receptor (EGFR), and inhibition of PLCgamma1 and EGFR reduced cell death and ER stress. Finally, apicidin-induced histone H3 hyperacetylation and reduction of histone deacetylase 2 mRNA expression were not affected by either a PLCgamma1 inhibitor, U73122, or the antioxidant, N-acetyl cysteine. Taken together, the results suggest that apicidin induces apoptosis by ER stress and mitochondrial dysfunction via PLCgamma1 activation, Ca(2+) release, and reactive oxygen species accumulation in Neuro-2a neuroblastoma cells. PMID- 22926927 TI - Germans in Russia--a comment on Morozova et al. (2012). PMID- 22926928 TI - Expeditious synthesis of tetrasubstituted helical alkenes by a cascade of palladium-catalyzed C-H activations. AB - Twisted molecules: A modular approach for the synthesis of tetrasubstituted helical alkenes by a palladium-catalyzed norbornene-mediated domino reaction is presented. This intermolecular domino process allows the formation of three C-C bonds in one operation through a C-H activation/carbopalladation/C-H activation sequence. PMID- 22926929 TI - Synthesizing artificial cells from giant unilamellar vesicles: state-of-the art in the development of microfluidic technology. AB - Microfluidic technology - the manipulation of fluids at micrometer scales - has revolutionized many areas of synthetic biology. The bottom-up synthesis of "minimal" cell models has traditionally suffered from poor control of assembly conditions. Giant unilamellar vesicles (GUVs) are good models of living cells on account of their size and unilamellar membrane structure. In recent years, a number of microfluidic approaches for constructing GUVs has emerged. These provide control over traditionally elusive parameters of vesicular structure, such as size, lamellarity, membrane composition, and internal contents. They also address sophisticated cellular functions such as division and protein synthesis. Microfluidic techniques for GUV synthesis can broadly be categorized as continuous-flow based approaches and droplet-based approaches. This review presents the state-of-the-art of microfluidic technology, a robust platform for recapitulating complex cellular structure and function in synthetic models of biological cells. PMID- 22926930 TI - CCN5 Expression in mammals. III. Early embryonic mouse development. AB - CCN proteins play crucial roles in development, angiogenesis, cell motility, matrix turnover, proliferation, and other fundamental cell processes. Early embryonic lethality in CCN5 knockout and over-expressing mice led us to characterize CCN5 distribution in early development. Previous papers in this series showed that CCN5 is expressed widely in mice from E9.5 to adult; however, its distribution before E9.5 has not been studied. To fill this gap in our knowledge of CCN5 expression in mammals, RT-PCR was performed on preimplantation murine embryos: 1 cell, 2 cell, 4 cell, early morula, late morula, and blastocyst. CCN5 mRNA was not detected in 1, 2, or 4 cell embryos. It was first detected at the early morula stage and persisted to the preimplantation blastocyst stage. Immunohistochemical staining showed widespread CCN5 expression in post-implantation blastocysts (E4.5), E5.5, E6.5, and E7.5 stage embryos. Consistent with our previous study on E9.5 embryos, this expression was not limited to a particular germ layer or cell type. The widespread distribution of CCN5 in early embryos suggests a crucial role in development. PMID- 22926931 TI - RAPID: a routine assurance pipeline for imaging of diffusion. AB - Despite the widespread adoption of diffusion MRI techniques, there is still no consensus on a comprehensive quality assurance routine specific for diffusion acquisitions. We propose here a routine assurance pipeline for imaging of diffusion. The routine simply comprises diffusion-weighted acquisitions on a phantom; each repetition lasts less than 5 min and can be performed using a variety of isotropic test liquids. The proposed QA script checks for the linearity of G, the uniformity of Gmax across the field-of-view, the mutual agreement of gradient power across the three logical axes and the temporal stability. Optionally, the routine can correct for the mutual agreement of gradient power along the three axes, returning a set of gradient orientations to be used in data analysis. The effectiveness of the scheme in the presence of mismatched gradient amplitudes is reported using both simulations and in vivo data. The script is freely available online. PMID- 22926932 TI - High-level of resistance to spinosad, emamectin benzoate and carbosulfan in populations of Thrips tabaci collected in Israel. AB - BACKGROUND: The onion thrips, Thrips tabaci Lindeman, is a major pest of several crop plants in the genus Allium, such as onions, garlic and chives. In Israel, these crops are grown in open fields and in protected housing. This thrips is usually controlled by the application of chemical insecticides. In recent years, spinosad, emamectin benzoate and carbosulfan have been the major insecticides used for the control of the onion thrips. In the last 4 years, growers of chives and green onion from several regions of Israel have reported a significant decrease in the efficacy of insecticides used to control the onion thrips. RESULTS: The susceptibility of 14 populations of the onion thrips, collected mainly from chives between the years 2007 and 2011, to spinosad, emamectin benzoate and carbosulfan was tested using a laboratory bioassay. The majority of the populations showed significant levels of resistance to at least one of the insecticides. LC(50) values calculated for two of the studied populations showed that the resistance factor for spinosad compared with the susceptible population is 21 393, for carbosulfan 54 and for emamectin benzoate 36. Only two populations, collected from organic farms, were susceptible to the insecticides tested. CONCLUSION: This is the first report of a high resistance level to spinosad, the major insecticide used to control the onion thrips. Resistance cases to spinosad were associated with failures to control the pest. Populations resistant to spinosad also had partial or complete resistance to other insecticides used for controlling the onion thrips. PMID- 22926933 TI - Toxicokinetics of metformin-associated lactic acidosis with continuous renal replacement therapy. AB - A 70-year-old diabetic male patient with a baseline serum creatinine of 1.4 mg/dL presented with nausea and vomiting. He was diagnosed with metformin-associated lactic acidosis and acute kidney injury. He was managed with continuous veno venous hemodiafiltration (CVVHDF). By measuring metformin concentration at different time intervals, we calculated the apparent volume of distribution of metformin at 34.7 L. The decline in serum metformin followed single-compartment first-order kinetics with an elimination rate constant of 0.0418/h and a serum half-life of 16.5 h; no metformin rebound was seen after discontinuation of CVVHDF. Using the previously calculated volume of distribution we calculated the expected serum metformin concentration 25 h post CVVHDF to be 3.0-3.7 MUg/mL. The measured serum metformin of 3.4 MUg/ml fell within the predicted range. During CVVHDF, dialyzer metformin clearance approximates 88.7 % of dialyzer urea clearance and 90.1 % of dialyzer creatinine clearance. PMID- 22926934 TI - Current practices in determining return to play following head injury in professional football in the UK. AB - OBJECTIVE: To investigate the awareness of English football team doctors of the 'Consensus in Sport' (CIS) guidelines for the assessment and management of concussion, and to identify adherence to these internationally accepted recommendations. METHOD: A questionnaire was sent to Club Medical Officers of all the 92 English Football league teams. RESULTS: The majority (55.6%) of teams in the English Football Association (FA) do not routinely follow the CIS guidelines. Only 21% of teams routinely record an approved preseason cognitive score and only 42% complete a recommended postconcussion assessment. One-third are still using outdated fixed periods of abstinence following a concussion. CONCLUSIONS: FA players are not being treated according to the guidelines recommended by International sporting organisations. The endorsement of the CIS guidelines by the English FA would ensure that all medical teams have a sound and safe protocol for managing concussed players and making return to play decisions. PMID- 22926935 TI - Prognostic factors for sustained work participation in early osteoarthritis: a follow-up study in the Cohort Hip and Cohort Knee (CHECK). AB - OBJECTIVE: To identify prognostic factors for the 2-year course of work participation in early osteoarthritis (OA) of hips or knees. METHODS: In this prospective cohort study, questionnaire data from 925 subjects was analyzed. Rate ratios were calculated to compare work participation with the general Dutch population, corrected for age, sex and education. The overall participation rate at T(2) was compared to baseline. Personal factors, self-reported health status (Western Ontario McMasters Arthritis Index-WOMAC), medical consumption and physical work demands were compared between subjects with sustained work participation and subject who stopped working; factors that differed significantly were included in a logistic regression analysis. RESULTS: Work participation in the cohort (mean age 58, 79 % females) decreased from 51 to 46 %, a similar rate to the general population. Subjects who continued working were younger than those who stopped working (mean 4.2 years) and they had less frequently reported sick-leave at baseline; the regression model included both factors. 11 % Of the workers reported sick-leave in the past year because of hip/knee complaints (similar to baseline). 20 % Reported work adaptations, compared to 14 % at baseline. CONCLUSION: The 2-year course of work participation of people with early OA was similar to the general Dutch population. Sustained work participation was predicted by lower age, not by OA related factors. PMID- 22926936 TI - What are the diagnostic criteria for migraine-associated vertigo? PMID- 22926939 TI - Web-based sex diaries and young adult men who have sex with men: assessing feasibility, reactivity, and data agreement. AB - We compared quantitative diary data with retrospective survey data collected from a cohort of young adult men who have sex with men (MSM) in Seattle, Washington. Ninety-five MSM, aged 16-30 years, completed web-based surveys every 3 months and were randomized to 4 diary submission schedules: every 2 weeks, once a week, twice a week, or never. We calculated diary completion rates and assessed agreement between daily diary data and aggregate retrospective survey data for sexual behavior measures. Over 6 months, 78 % of participants completed at least 80 % of their diary days, and the 2-week schedule had the highest and most consistent completion rate. The majority of sexual behavior and substance use measures had strong agreement between the diary and retrospective survey data (i.e., kappa >0.80 or concordance correlation coefficient >=0.75), although we observed poorer agreement for some measures of numbers of anal sex acts. There were no significant differences in mean responses across diary schedules. We observed some evidence of reactivity (i.e., a difference in behavior associated with diary completion). Participants not assigned diaries reported significantly more unprotected anal sex acts and were more likely to be newly diagnosed with HIV or another sexually transmitted infection compared to those assigned active diary schedules. This study suggests that sexual behavior data collected from young adult MSM during 3-month retrospective survey--an interval commonly used in sexual behavior research--are likely valid. Diaries, however, may have greater utility in sexual behavioral research in which counts, timing, sequence, or within-person variation over time are of particular import. PMID- 22926937 TI - Reducing nasal morbidity after skull base reconstruction with the nasoseptal flap: free middle turbinate mucosal grafts. AB - OBJECTIVES/HYPOTHESIS: The nasoseptal flap provides hearty vascularized tissue for reconstruction of expanded endonasal approaches (EEA); however, it produces donor site morbidity due to exposed cartilage. Mucosalization of the septum requires 12 weeks, multiple debridements, and frequent saline rinses. This study addresses the reduction of nasal morbidity by grafting middle turbinate mucosa onto the exposed septum. STUDY DESIGN: Small prospective study with retrospective analysis of a larger cohort. METHODS: Fifteen patients undergoing EEA of the ventral skull base were prospectively enrolled. In seven cases, the sacrificed middle turbinate mucosa was harvested and placed as a free mucosal graft on the septal cartilage. In eight controls, middle turbinate grafting was not performed due to tumor involvement. Septal mucosalization and crusting of all patients was quantified at follow-up appointments. An additional 46 patients were retrospectively identified who received middle turbinate grating on their exposed septal cartilage, and mucosalization rates were determined from clinical records. RESULTS: Three weeks after initial operation, the mucosalization rate was 70% versus 5% in the graft and nongraft groups, respectively. At postoperative week 6, the mucosalization and crusting were 97% and 5% for the graft group versus 60% and 85% for the nongraft group. Mucosalization rates in the retrospective graft series agreed with the prospective series. CONCLUSIONS: Despite donor site morbidity, the nasoseptal flap is becoming the standard of care for skull base reconstruction due to its reliability in reestablishing a barrier between the subarachnoid space and the sinonasal tract. It is possible to dramatically increase the rate of septal mucosalization and decrease crusting by using a middle turbinate free mucosal graft. PMID- 22926940 TI - Proliferation and harvest of human mesenchymal stem cells using new thermoresponsive nanocomposite gels. AB - For tissue engineering and regenerative medicine, stem cells should be effectively cultured in vitro. New thermoresponsive nanocomposite gels (MD-NC gels), consisting of inorganic clay (hectorite) and copolymers composed of hydrophobic 2-methoxyethyl acrylate (MEA) and hydrophilic N,N-dimethylacrylamide (DMAA) units, could be applied in cell culture and cell harvesting without trypsinization, specifically using mesenchymal stem cells (MSCs). The composition of the MD-NC gel (the ratio of the two monomer types and the clay content) was found to determine its swelling properties in the culture medium, thermosensitivity, protein adsorption, and cell attachment and proliferation. Various kinds of human cells, including MSCs, osteoblast (HOS) cells, fibroblast (NHDF) cells, and epithelial cells could be effectively cultured on MD-NC gels. In particular, on an MD10-NC2 gel with relatively low DMAA and clay content, the cells could be harvested by decreasing the temperature, either as a cell sheet (MSCs or NHDF cells) or as a population of suspension cells (HOS cells). Further, it was found that the MD10-NC2 gel is suitable for stem cell differentiation. Because of their thermosensitivity, controllable modulus, and surface properties, MD-NC gels are promising cell culture substrates useful for tissue engineering and regenerative medicine. PMID- 22926941 TI - Podocyte-specific overexpression of metallothionein mitigates diabetic complications in the glomerular filtration barrier and glomerular histoarchitecture: a transmission electron microscopy stereometric analysis. AB - BACKGROUND: We previously demonstrated that cellular and extracellular components of the blood-urine barrier in renal glomeruli are susceptible to damage in OVE transgenic mice, a valuable model of human diabetic nephropathy that expresses profound albuminuria. METHODS: To test our hypothesis that glomerular filtration barrier damage in OVE mice may be the result of oxidative insult to podocytes, 150-day-old bi-transgenic OVENmt diabetic mice that overexpress the antioxidant metallothionein specifically in podocytes were examined by enzyme-linked immunosorbent assay for albuminuria mitigation and by unbiased transmission electron microscopy (TEM) stereometry for protection from chronic structural diabetic complications. RESULTS: Although blood glucose and HbA(1c) levels were indistinguishable in OVE and OVENmt animals, albuminuria was significantly reduced (average >7-fold) in OVENmt mice through 8 months of age. Interestingly, the Nmt transgene provided significant glomerular protection against diabetic nephropathic complications outside of the podocyte. Glomerular filtration barrier damage was reduced in OVENmt mice, including significantly increased area occupied by endothelial luminal fenestrations (~13%), significantly reduced glomerular basement membrane (GBM) thickening (~17%) and significantly less podocyte effacement (~18%). In addition, OVENmt mice exhibited significantly reduced glomerular volume (~50%), fewer glomerular endothelial cells (~33%), fewer mesangial cells (~57%) and fewer total glomerular cells (~40%). CONCLUSIONS: These results provide evidence of oxidative damage to podocytes induces primary diabetic nephropathic features including severe and sustained albuminuria, specific glomerular filtration barrier damage and alterations in glomerular endothelial and mesangial cell number. Importantly, these diabetic complications are significantly mitigated by podocyte targeted metallothionein overexpression. PMID- 22926942 TI - Cobalt-catalyzed addition of arylzinc reagents to alkynes to form ortho alkenylarylzinc species through 1,4-cobalt migration. PMID- 22926943 TI - Searching for Hif1-alpha interacting proteins in renal cell carcinoma. AB - INTRODUCTION: Kidney tumours are frequently characterised by hypoxic conditions due to a local imbalance between oxygen (O2) supply and consumption. Hif1-alpha regulates angiogenesis, tumour growth, tumour progression, metastatic spread, and glucose metabolism by acting as a transcription factor for relevant genes. Here, we describe an immunohistochemical study of Hif1-alpha, a comprehensive computational study of Hif1-alpha interacting proteins (HIPs), an analysis correlating expression levels of Hif1-alpha with upstream and downstream proteins, and an analysis of the utility of Hif1-alpha for prognosis in a cohort of patients with renal cell carcinoma. MATERIALS AND METHODS: The patient cohort included 80 patients. For immunohistochemistry evaluation, tissue microarrays were constructed. The IntAct, MINT, and BOND databases were used for the HIP approach. The Kruskal-Wallis test was used for comparing protein expression with pathology measurements. Correlation was expressed as the Pearson coefficient. RESULTS: Hif1-alpha expression correlates significantly with the "clear" histological subtype of renal cell carcinoma (p < 0.01). The samples with the worst prognoses related to the pathological variables analysed showed the highest levels of Hif1-alpha expression. Significant correlations were found with Bcl-2, CAIX, C-kit, EGFR, TGF-beta, proteins of the VEGF family, proteins related to differentiation (such as Notch1 and Notch3) and certain metabolic enzymes. Bioinformatic analysis suggested 45 evidence-based HIPs and 4 complexes involving protein Hif1-alpha. CONCLUSIONS: This work summarises the multifaceted role of Hif1-alpha in the pathology of renal cell carcinomas, and it identifies HIPs that could help provide mechanistic explanations for the different behaviours seen in tumours. PMID- 22926944 TI - Accuracy and axilla sparing potentials of sentinel lymph node biopsy with methylene blue alone performed before versus after neoadjuvant chemotherapy in breast cancer: a single institution experience. AB - INTRODUCTION: The timing of sentinel lymph node biopsy (SLNB) of breast cancer in the neoadjuvant setting is still controversial. We retrospectively analyzed a Chinese patient cohort with neoadjuvant chemotherapy (NAC) to evaluate the accuracy and axilla sparing potentials of different SLNB timings with methylene blue alone for lymphatic mapping. MATERIALS AND METHODS: Patients with NAC and axillary lymph node dissection (ALND) and either pre- or post-NAC SLNB were eligible. Clinicopathological characteristics, identification rate (IR), false negative rate (FNR), accuracy, and positive-predictive value were calculated and compared between the pre- and post-NAC SLNB group using appropriate statistical methods. Axilla sparing potentials of different SLNB timings were evaluated and compared. RESULTS: One hundred and fifteen eligible cases were included, and 58 had pre-NAC SLNB while the other 57 had post-NAC SLNB. Both groups were comparable in clinicopathological characteristics, neoadjuvant treatments and pathologic complete response rate. IR, FNR, and accuracy of SLNB, as pre-NAC versus post-NAC, were 100 versus 98.2 % (P = 0.496), 0 versus 8.0 % (P = 0.181), and 100 versus 96.4 % (P = 0.239), respectively. Post-NAC SLNB had significantly higher positive-predictive value for ALNs than pre-NAC SLNB (70.0 vs. 36.4 %, P = 0.014), suggesting as high as 63.6 % of ALND performed in the pre-NAC group could have been avoided while only 30 % of ALND in the post-NAC group were theoretically unnecessary. CONCLUSIONS: Both SLNB timings of breast cancer patients with NAC were feasible and accurate. Although pre-NAC SLNB tends to be better in accuracy, post-NAC SLNB is significantly superior in terms of axilla sparing. PMID- 22926947 TI - Imidacloprid as a contact arrestant for larvae of the European chafer, Amphimallon majale. AB - BACKGROUND: Manipulative studies of the behavioral response of soil-dwelling insects to insecticides and other antagonists are stymied by the difficulties of observing and interpreting interactions played out below ground. Six experiments were carried out using X-ray radiography to quantify the movement of the European chafer, Amphimallon majale (Razoumowsky), larvae in response to imidacloprid and how this was affected by host plant cues and cold temperature. RESULTS: The movement of third instars was arrested in imidacloprid-treated soil at >= 0.6 ppm concentration. At >= 0.8 ppm, the arrestant effect of imidacloprid was stronger than the attraction cue posed by germinating grass seed. There was a less disruptive effect on dispersal distance in vertical versus lateral panels. In vertical panels, there was a less disruptive effect on downward movement under a cold temperature treatment that simulated overwintering conditions. CONCLUSION: Larvae of A. majale do not remotely detect imidacloprid in the soil; they neither evade contact, nor are repelled after contact. Imidacloprid thereby acts as a contact arrestant to disrupt grub movement. This finding might help to explain the synergistic effect of imidacloprid in combination with other biological agents for white grub control, and its effects on grub overwintering behavior. PMID- 22926945 TI - Dynamic regulation of cancer stem cells and clinical challenges. AB - A small population of cancer cells referred to as cancer stem cells (CSCs) have received particular attention, as they have been revealed to acquire stem cell like properties and become the main cause of tumor propagation, metastasis and drug resistance. The CSC theory of tumor formation was believed to follow the hierarchical model initially, and therefore many CSC-targeted therapy methods were expected to cure cancer by eradicating CSCs. However, subsequent CSC research has revealed that rather than a distinct entity, the CSC is a dynamic status that can be continually dedifferentiated from progenitor or differentiated cancer cells. Elucidation of this bidirectional transition mechanism would help perfect the CSC theory and be of great value in the development of more effective anti-cancer drugs. Here, we reviewed the mechanisms of reciprocal conversion between non-CSCs and CSCs. Moreover, several approaches of target CSCs and non CSCs together with unbiased eradication of all cancer cells are also discussed. PMID- 22926948 TI - 1,1-diamino-2,2-dinitroethylenes are always zwitterions. AB - The nitration of tetraiodoethylene (7) yields 1,1-diiodo-2,2-dinitroethylene (8). The latter reacts with alkylamines 9 or alkyldiamines 11 to give the corresponding acyclic 1,1-diamino-2,2-dinitroethylenes 10 or their cyclic analogs 12, respectively. On the basis of liquid and solid-state (13)C and (15)N NMR data, x-ray analysis and ab initio calculations, we suggest that the title compounds are always zwitterionic and that the C(A)-C(N) bond is not a true double bond. PMID- 22926949 TI - Prognostic factors and survival unique to surgically treated p16+ oropharyngeal cancer. AB - OBJECTIVES/HYPOTHESIS: Current head and neck epidemiology demonstrates a steadily increasing incidence of p16+ human papillomavirus-related oropharynx squamous cell cancer (OPSCC). This distinct tumor subtype is associated with better survival outcomes. There is a growing recognition of the need to define management regimens that take into account the inherent patho-biological attributes of these cancers and provide optimum oncological control with minimum morbidity. This is facilitated by a clear understanding of the prognostic variables that predict disease outcome in patients with p16+ OPSCC. To provide prognostic estimates, pathological staging and histopathological parameters are usually superior to clinical staging. However, knowledge of pathological predictors is sparse, mainly because of commonly employed nonsurgical management policies utilizing chemoradiotherapy. Minimally invasive approaches to the oropharynx, particularly transoral laser microsurgery (TLM), are well-reported effective primary treatments for oropharynx cancers. From such series, it is feasible to conduct a detailed appraisal based on pathologic information from surgical specimens of both the primary and neck, to establish prognosticators unique to p16+ oropharynx cancer patients. STUDY DESIGN: A prospectively assembled database of oropharynx cancer patients treated with primary TLM +/- neck dissection +/- adjuvant therapy from 1996 to 2010, analyzed retrospectively for survival and recurrence. METHODS: The fundamental inclusion criteria were: 1) previously untreated biopsy-proven OPSCC treated with primary TLM +/- neck dissection, 2) diffuse p16 positivity in the surgical specimen, 3) availability for adjuvant therapy, if indicated, and 4), minimum follow-up of 12 months or to death. Cox proportional hazard regression analyses were used to identify variables that were prognostic for disease-free survival (DFS), the primary end point of the study, as well as disease-specific survival (DSS) and overall survival. Kaplan-Meier survival estimates and patterns of disease recurrence were also assessed. We also explored concordance for T and N staging, when assessed by clinical (cT, cN) and pathological (cT, pT) measures. RESULTS: Of 211 patients in the TLM database, 171 met all the eligibility criteria. The median follow-up was 47 months. The 3- and 5-year Kaplan-Meier estimates for DFS were 91% and 88%, respectively, whereas for DSS they were 95.5% and 94.4%, respectively. A total of 12 (7%) recurrences occurred: two local, four regional, and six distant. Of all T stage categories, pT4 tumors were strongest predictors of poorer DFS. cT4 tonsil primaries, ever smoking status, three or more metastatic nodes, pN2b+ stage, and radiation-based adjuvant therapy were other prognosticators for DFS. Angioinvasion and T3-T4 tumors were prognostic for reduced DSS, although smoking parameters were not. Extracapsular spread, N stage, and margins were nonprognosticators. Recursive partitioning analysis defined high- and low-risk groupings of prognosticators. Downstaging of clinical T stage was observed for 31% of tumors on application of pathological classification. CONCLUSIONS: We document a well-delineated set of prognostic variables that specifically and accurately identify individuals at risk of reduced outcomes in an otherwise good prognosis p16+ OPSCC cohort. Based on these prognosticators, appropriate patient counseling, adjuvant treatment recommendations, and stratification for trials can more accurately be made. We also observed an additional edge conferred by TLM toward more accurate clinical as well as pathological T staging. PMID- 22926950 TI - Medullary thick ascending limb buffer vasoconstriction of renal outer-medullary vasa recta in salt-resistant but not salt-sensitive rats. AB - We have demonstrated previously that paracrine signaling occurs between medullary thick ascending limb (mTAL) and the contractile pericytes of outer-medullary vasa recta (VR), termed "tubular-vascular cross-talk." The aim of the current study was to determine whether tubular-vascular cross-talk has a functional effect on vasoconstrictor responses to angiotensin II and to determine whether this is altered in the Dahl salt-sensitive (SS) rat. Studies were performed on salt resistant consomic SS.13 Brown Norway (BN) and SS rats using a novel outer medullary tissue strip preparation in which freshly isolated VRs within VR bundles were perfused either alone or in combination with nearby mTAL. In VRs from SS.13BN rats, angiotensin II (1 umol/L) increased VR bundle intracellular Ca2+ concentration 19+/-9 nmol/L (n=8) and reduced focal diameter in perfused VRs by -20+/-7% (n=5). In the presence of nearby mTAL, however, VR bundle intracellular Ca2+ concentration (-9+/-8 nmol/L; n=8) and VR diameter (-1+/-4%, n=7) in SS.13BN rats were unchanged by angiotensin II. In contrast, in Dahl SS rats, angiotensin II resulted in rapid and sustained increase in VR bundle intracellular Ca2+ concentration (89+/-48 nmol/L, n=7; 50+/-24%, n=8) and a reduction in VR diameter of (-17+/-7%, n=7; -11+/-4%, n=5) in both isolated VRs and VRs with nearby mTAL, respectively. In VRs with mTAL from SS13BN rats, inhibiton of purinergic receptors resulted in an increase in VR bundle intracellular Ca2+ concentration, indicating that purinergic signaling buffers vasoconstriction. Importantly, our in vitro data were able to predict medullary blood flow responses to angiotensin II in SS and SS.13BN rats in vivo. We conclude that paracrine signaling from mTAL buffers angiotensin II vasoconstriction in Dahl salt-resistant SS.13BN rats but not SS rats. PMID- 22926951 TI - Renal liver-type fatty acid binding protein attenuates angiotensin II-induced renal injury. AB - To investigate the role of human liver-type fatty acid binding protein (hL-FABP) in angiotensin (Ang) II-induced renal injury, Ang II was infused systemically into hL-FABP chromosomal transgenic (Tg) and wild-type (WT) mice (Tg-Ang II and WT-Ang II) for 28 days. Control mice were injected with saline only (Tg-control and WT-control). hL-FABP was expressed in proximal tubules of Tg mice. After a high-dose injection of Ang II, renal gene and protein expressions of hL-FABP in Tg-Ang II mice increased significantly compared with Tg-control mice. Urinary excretion of L-FABP was significantly greater in Tg-Ang II than in Tg-control mice. Blood pressure levels in both groups increased to a similar extent. Upregulation of monocyte chemoattractant protein 1 expression, macrophage infiltration in the interstitium, tubulointerstitial damage, and depositions of type I and III collagens were observed in both Tg-Ang II and WT-Ang II mice. However, these effects were less pronounced in Tg-Ang II compared with WT-Ang II mice. The level of renal N-(hexanoyl)lysine, an oxidative stress marker, was significantly higher in WT-Ang II than in Tg-Ang II mice. In conclusion, renal hL FABP reduced oxidative stress in Ang II-induced renal injury and attenuated tubulointerstitial damage. PMID- 22926952 TI - Aging and the renin-angiotensin system. PMID- 22926953 TI - Estimation of aortic blood pressures and pulse wave velocity in obese children: a technological perspective. PMID- 22926954 TI - Blood pressure in 12-year-old children is associated with fatty acid composition of human milk: the prevention and incidence of asthma and mite allergy birth cohort. AB - Breastfed individuals have a lower blood pressure than formula-fed individuals. Supplementation with n-3 long-chain polyunsaturated fatty acids in adults is also associated with a lower blood pressure. We studied whether children receiving human milk with a relatively high content of n-3 long-chain polyunsaturated fatty acids have a lower blood pressure at age 12 years, and, if so, whether this association is explained by the n-3 long-chain polyunsaturated fatty acids content in erythrocyte membranes at age 12 years. Within a 12-year follow-up of a population-based birth cohort, we compared blood pressure of 205 never-breastfed children and 109 children who had fatty acid composition of their mothers' breast milk measured during lactation. In addition, 973 children had information on erythrocyte fatty acid composition and blood pressure at age 12 years. Children who received human milk with an n-3 long-chain polyunsaturated fatty acids content above the median (ie, 0.51 weight percentage) had a 4.79-mm Hg lower systolic (95% CI, -7.64 to -1.94) and a 2.47-mm Hg lower diastolic (95% CI, -4.45 to -0.49) blood pressure at age 12 years than never-breastfed children. N-3 long chain polyunsaturated fatty acids levels in human milk below the median value and current n-3 long-chain polyunsaturated fatty acid status were not associated with blood pressure at age 12 years. Thus, a relatively high content of n-3 long-chain polyunsaturated fatty acids in human milk is associated with a lower blood pressure in children at age 12 years, a finding not explained by current n-3 long chain polyunsaturated fatty acids status. PMID- 22926955 TI - Methods of solving rapid binding target-mediated drug disposition model for two drugs competing for the same receptor. AB - The target-mediated drug disposition (TMDD) model has been adopted to describe pharmacokinetics for two drugs competing for the same receptor. A rapid binding assumption introduces total receptor and total drug concentrations while free drug concentrations C (A) and C (B) are calculated from the equilibrium (Gaddum) equations. The Gaddum equations are polynomials in C (A) and C (B) of second degree that have explicit solutions involving complex numbers. The aim of this study was to develop numerical methods to solve the rapid binding TMDD model for two drugs competing for the same receptor that can be implemented in pharmacokinetic software. Algebra, calculus, and computer simulations were used to develop algorithms and investigate properties of solutions to the TMDD model with two drugs competitively binding to the same receptor. A general rapid binding approximation of the TMDD model for two drugs competing for the same receptor has been proposed. The explicit solutions to the equilibrium equations employ complex numbers, which cannot be easily solved by pharmacokinetic software. Numerical bisection algorithm and differential representation were developed to solve the system instead of obtaining an explicit solution. The numerical solutions were validated by MATLAB 7.2 solver for polynomial roots. The applicability of these algorithms was demonstrated by simulating concentration time profiles resulting from exogenous and endogenous IgG competing for the neonatal Fc receptor (FcRn), and darbepoetin competing with endogenous erythropoietin for the erythropoietin receptor. These models were implemented in ADAPT 5 and Phoenix WinNonlin 6.0, respectively. PMID- 22926956 TI - Enhanced osteogenesis by collagen-binding peptide from bone sialoprotein in vitro and in vivo. AB - Bone sialoprotein (BSP) is a mineralized, tissue-specific, and noncollagenous protein. The binding of BSP to collagen is thought to be important for the initiation of bone mineralization and formation. In this study, we elucidated the osteogenic efficiency of the collagen-binding (CB) peptide derived from BSP in vitro and in vivo. The CB peptide increased osteoblastic differentiation marker gene and protein expression without affecting cell proliferation. The osteoblastic differentiation by the CB peptide is performed by the activation of extracellular signal-regulated kinase (ERK1/2) and protein kinase B (Akt). Notably, the activation of CB peptide-induced osteogenic differentiation was completely blocked to the basal level by the specific inhibitors for ERK1/2 (U0126) and Akt (LY294002). In vivo results further demonstrated that the CB peptide-coated hydroxyapatite scaffold was able to induce bone formation in the bone defect. Taken together, the CB peptide can be developed as an osteoblastic differentiation agent as well as a fusion biomaterial for bone regeneration therapy. PMID- 22926958 TI - Enzymatic sculpting of nanoscale and microscale surface topographies. PMID- 22926957 TI - Patients with small left ventricular size undergoing balloon aortic valvuloplasty have worse intraprocedural outcomes. AB - OBJECTIVES: To evaluate the impact of left ventricular (LV) chamber size on procedural and hospital outcomes of patients undergoing aortic valvuloplasty. BACKGROUND: Balloon aortic valvuloplasty (BAV) is used as an integral step during transcatheter aortic valve implantation. Patients with small, thickened ventricles are thought to have more complications during and following BAV. METHODS: Retrospective study of consecutive patients with severe, symptomatic calcific aortic stenosis who underwent retrograde BAV at Massachusetts General Hospital. We compared patients with left ventricular end-diastolic diameters (LVEDD) <4.0 cm (n = 31) to those with LVEDD >=4.0 cm (n = 78). Baseline and procedural characteristics as well as clinical outcomes were compared. Multivariate logistic regression was used for the adjusted analysis. RESULTS: Patients with smaller LV chamber size were mostly women (80.7% vs. 19.4%, P < 0.01) and had a smaller body surface area (BSA), (1.61 +/- 0.20 m(2) vs. 1.79 +/- 0.25 m(2) , P < 0.01). Patients with smaller LV chamber size had higher ejection fractions and thicker ventricles. Otherwise, baseline characteristics were similar. The intraprocedural composite of death, cardiopulmonary arrest, intubation, hemodynamic collapse, and tamponade was higher for patients with LVEDD < 4.0 cm (32.3% v. 11.5%, P = 0.01). Adjusting for age, gender, BSA, LV pressure, and New York Heart Association class, LVEDD < 4.0 cm remained an independent predictor of procedural (OR 5.1, 95% CI 1.4-18.2) and in-hospital complications (OR 3.8, 95% CI 1.2-11.6). CONCLUSIONS: Compared to patients undergoing BAV with LVEDD >=4.0 cm, those with smaller LV chambers had worse procedural and in-hospital outcomes. PMID- 22926959 TI - Enhancing specific binding of L929 fibroblasts: effects of multi-scale topography of GRGDY peptide modified surfaces. AB - Surface chemical composition and roughness caused by micro/nano-topographical structures are two predominant factors in determining cellular response. A series of gold nanoparticle layers (GNPLs) with increasing surface roughness are prepared by depositing gold nanoparticles onto planar gold films. Glycine arginine-glycine-aspartic acid-tyrosine (GRGDY) peptide is then conjugated to the surface through poly[oligo(ethylene glycol) methacrylate] polymer brushes as spacers. The pristine micro/nano-roughness structures significantly inhibit L929 cell growth. After modification with POEGMA-GRGDY, however, the micro/nano structures greatly enhance L929 cell-specific interactions while maintaining superior low-fouling ability compared to planar gold. PMID- 22926960 TI - Histopathologic features of atypical glands on prostate biopsy: nucleolar size is a predictor of subsequent detection of prostatic adenocarcinoma. AB - BACKGROUND: Patients whose prostate biopsy reveals the presence of atypical glands suspicious for carcinoma (AGSC) are subject to close monitoring and repeat biopsies, perhaps unnecessarily, as clinicians do not have a clear basis for understanding and stratifying the significance of these findings. METHODS: In a retrospective, blinded manner, we histopathologically examined initial biopsies reported as AGSC (82 patients, 93 foci). On subsequent biopsies, 31 (38%)/5 (6%) patients were found to have prostate cancer (PCA)/AGSC, respectively, while no carcinoma (NOCA) was identified in the remainder (56%) of cases. RESULTS: Nucleolar grade (on a scale of 1-4 with "1" denoting small, inconspicuous nucleoli and "4" denoting macronucleoli) was significantly higher in PCA cases than in NOCA cases whether comparing all AGSC foci (P = 0.006) or when considering the highest grade in each patient (P = 0.009). However, the number of AGSC per focus was similar (P = 0.926) between PCA (mean +/- SD: 7.03 +/- 5.35) and NOCA (mean +/- SD: 7.13 +/- 4.44). Adjacent (P = 0.117) and separate (P = 0.457) high-grade prostatic intraepithelial neoplasia was found in 8/37 (22%) foci and 12/31 (39%) cases in PCA, respectively, and in 4/48 (8%) foci and 13/46 (28%) cases in NOCA, respectively. The presence of intraluminal dense secretion, crystalloid, or mucin in AGSC did not show a statistically significant correlation between PCA [5/37 (14%)] and NOCA [10/48 (21%)] (P = 0.567). CONCLUSIONS: Our study may thus clarify the significance of AGSC on prostate biopsy and suggests that the size of nucleoli in AGSC is a positive predictor of subsequent detection of prostatic adenocarcinoma. PMID- 22926961 TI - The use of MALDI-TOF-MS and in silico studies for determination of antimicrobial peptides' affinity to bacterial cells. AB - Several methods have been proposed for determining the binding affinity of antimicrobial peptides (AMPs) to bacterial cells. Here the utilization of MALDI TOF-MS was proposed as a reliable and efficient method for high throughput AMP screening. The major advantage of the technique consists of finding AMPs that are selective and specific to a wide range of Gram-negative and -positive bacteria, providing a simple reliable screening tool to determine the potential candidates for broad spectrum antimicrobial drugs. As a prototype, amp-1 and -2 were used, showing highest activity toward Gram-negative and -positive membranes respectively. In addition, in silico molecular docking studies with both peptides were carried out for the membranes. In silico results indicated that both peptides presented affinity for DPPG and DPPE phospholipids, constructed in order to emulate an in vivo membrane bilayer. As a result, amp-1 showed a higher complementary surface for Gram-negative while amp-2 showed higher affinity to Gram-positive membranes, corroborating MS analyses. In summary, results here obtained suggested that in vitro methodology using MALDI-TOF-MS in addition to theoretical studies may be able to improve AMP screening quality. PMID- 22926962 TI - MRI in H1N1 encephalitis. AB - Novel influenza A (H1N1) virus has been largely associated with respiratory complications. The exact frequency of neurological complications is not known, but are more common in children. There are very few reports of MRI findings in H1N1 encephalitis and none from India. The authors report MRI findings in an infant with H1N1 encephalitis. The diagnosis was made based on history, viral serological tests and imaging findings. PMID- 22926963 TI - GAL4 enhancer traps that can be used to drive gene expression in developing Drosophila spermatocytes. AB - The Drosophila testis has proven to be a valuable model organ for investigation of germline stem cell (GSC) maintenance and differentiation as well as elucidation of the genetic programs that regulate differentiation of daughter spermatogonia. Development of germ cell specific GAL4 driver transgenes has facilitated investigation of gene function in GSCs and spermatogonia but specific GAL4 tools are not available for analysis of postmitotic spermatogonial differentiation into spermatocytes. We have screened publically available pGT1 strains, a GAL4-encoding gene trap collection, to identify lines that can drive gene expression in late spermatogonia and early spermatocytes. While we were unable to identify any germline-specific drivers, we did identify an insertion in the chiffon locus, which drove expression specifically in early spermatocytes within the germline along with the somatic cyst cells of the testis. PMID- 22926964 TI - Overexpression of genes of the fatty acid biosynthetic pathway leads to accumulation of sterols in Saccharomyces cerevisiae. AB - Saccharomyces cerevisiae strains with deregulated sterol and fatty acid biosynthesis pathways were analysed for sterol and fatty acid content and mRNA profiles, with the aim of identifying interactions between lipid biosynthesis pathways. Acetyl CoA carboxylase ACC1 and fatty acid synthases FAS1/FAS2 were overexpressed in wild-type and squalene-overproducing strains. ACC1 overexpression led to decreased fatty acid content in the squalene-overproducing strain (factor of 0.7), while sterols and squalene were increased (factor of 1.5). In the wild-type strain, ACC1 overexpression led to increased levels of both fatty acids and squalene/sterols (factors of 4.0 and 1.7, respectively). This parallel activation of the two pathways seems to be due to transcriptional co-regulation of ACC1 and HMG1. While FAS1 and FAS2 overexpression had no effect in the wild-type strain, FAS2 overexpression induced significant increase of sterols and squalene (factors of 7.2 and 1.3, respectively) and a concomitant decrease of both saturated and unsaturated fatty acids in the squalene overproducing strain (factor of 0.6). The microarray expression profiles showed that genes upregulated in ACC1-overexpressing strains are FAS1, ERG11, ERG28, ERG5, ERG2 and ERG20, supporting the observed increase of zymosterol and saturated fatty acids. The high ACC1 expression level due to overexpression correlated with increased transcript levels of sphingolipid and sterol biosynthesis genes. The relationship between was shown using the Pathway Studio program. PMID- 22926965 TI - Earliest record of Platychoerops (Primates, Plesiadapidae), a new species from Mouras Quarry, Mont de Berru, France. AB - Plesiadapids are extinct relatives of extant euarchontans (primates, dermopterans, and scandentians), which lived in North America and Europe during the Paleocene and Early Eocene. The only genus of plesiadapid whose species are absent from Paleocene strata is Platychoerops. Further, Platychoerops is the only group found in sediments post-dating the Paleocene-Eocene boundary (PEB) by a substantial period of time based on large samples. It is also substantially different from other plesiadapids in dental features thought to reflect ecology. Its evolution has been linked to the rapid global climate change and faunal turnover marking the PEB. Platychoerops and Plesiadapis tricuspidens have been reconstructed as members of a single lineage by some authors. We describe a specimen (right p3-m3) that we attribute to a new species, Platychoeropsantiquus, from the unequivocally Paleocene (MP6) Mouras Quarry of Mont de Berru, France. It has strong morphological affinities to Platychoerops daubrei yet co-occurs with many specimens of Plesiadapis tricuspidens, as well as the plesiadapid Chiromyoides campanicus. The existence of a species of Platychoerops prior to the PEB decouples the evolution of Platychoerops from the climate change and faunal turnover event associated with the PEB. Furthermore, the co-occurrence of Platychoerops with P. tricuspidens refutes the idea of a single lineage for these taxa. Instead, Platychoerops may be more closely related to North American Plesiadapis cookei (a previous alternate hypothesis). We suggest character displacement in a Paleocene immigrant population of P. cookei resulting from competition with sympatric P. tricuspidens, as a likely scenario for the evolution of Platychoerops. PMID- 22926966 TI - Encapsulation of contrast imaging agents by polypropyleneimine-based dendrimers. AB - Polypropyleneimines (PPIs) functionalized by glycerol-based entities are prepared and characterized by diffusion-ordered spectroscopy NMR. Showing low cytotoxicity against MRC5 fibroblasts, their encapsulation capacities of gadolinium complexes was evaluated. T(1) measurements were performed to determine the relaxivity of the encapsulated gadopentetate dimeglumine (GdBOPTA) in dendrimers of fourth and fifth generation (GD-PPI-4 and GD-PPI-5). Comparison of the GdBOPTA relaxivity and the relaxivity of GdBOPTA-loaded dendrimers showed a slight increase of the gadolinium chelate relaxivity. PMID- 22926967 TI - An insight into transcatheter aortic valve implantation-a perspective from multidetector-computed tomography. AB - Transcatheter aortic valve implantation (TAVI) has now become an acceptable alternative to surgical aortic valve replacement for patients with severe aortic stenosis at high risk. The early enthusiasm for this technology has not diminished but rather has developed at an unprecedented rate over the last decade. Alongside the developments in implantation technique, transcatheter design, and postprocedural care, cardiac imaging modalities have also had to concurrently evolve to meet the perpetual demand for lower peri- and postprocedural complication rates. Although transthoracic and transesophageal echocardiography remain vital in patient's selection and periprocedural guidance, there is now emerging evidence that indicates that multidetector-computed tomography (MDCT) may also have an equally important role to play. The aim of the current review is to examine the modern role of MDCT in assessing patients with aortic stenosis being considered for TAVI. PMID- 22926968 TI - Synthesis of gold-silver luminescent honeycomb aggregates by both solvent-based and solvent-free methods. AB - Heterometallic clusters with strong luminescence have been synthesized (see picture: Au(C=CPh)(2)yellow-red, Ag(2)blue, Ored) from the metalloligand unit [Au(C=CPh)PPh(3) ] (yellow/red bars) by using both standard solvent-based and solvent-free reactions. The aggregates are stabilized only by acetylide-metal or metal-metal interactions, and their nuclearity is controlled through the addition of different donor ligands. PMID- 22926969 TI - Polyfluorene nanoparticles coated with folate-functionalized triblock copolymer: effective agents for targeted cell imaging. AB - An ultra-bright fluorescence probe comprising conjugated polymer nanoparticles is developed for biological imaging. Highly blue fluorescent polyfluorene nanoparticles (PF-NPs) stabilized by sodium dodecylsulfate with an average diameter of 100 nm are prepared by a miniemulsion technique. A folate-conjugated cationic triblock copolymer is employed to coat negatively charged PF-NPs via electrostatic interaction for specific cell imaging of folate receptor over expressing cancer cells. The coated PF-NPs show a similar size and morphology to the pristine PF-NPs, while the fluorescence intensity is enhanced. Such surface functionalized PF-NPs are demonstrated to be suitable probes for efficient cell imaging of folate receptor over-expressing KB cells by CLSM and flow cytometry. PMID- 22926970 TI - Gene expression analysis in prostate cancer: the importance of the endogenous control. AB - BACKGROUND: Aberrant gene expression is a hallmark of cancer. Quantitative reverse-transcription PCR (qRT-PCR) is the gold-standard for quantifying gene expression, and commonly employs a house-keeping gene (HKG) as an endogenous control to normalize results; the choice of which is critical for accurate data interpretation. Many factors, including sample type, pathological state, and oxygen levels influence gene expression including putative HKGs. The aim of this study was to determine the suitability of commonly used HKGs for qRT-PCR in prostate cancer. METHODS: Prostate cancer (LNCaP, 22Rv1, PC3, and DU145) and normal (PWR1E and RWPE1) cell lines were cultured in air and hypoxia. The performance of 16 HKGs was assessed using Normfinder and coefficient of variation. In silico promoter analysis was performed to identify putative hypoxia response elements (HREs). The impact of the endogenous control on expression levels of HIF1A and GSTP1 was investigated by qRT-PCR in cell lines and tissue specimens respectively. RESULTS: Hypoxia altered expression of several HKGs: IPO8, B2M, and PGK1. The most stably expressed HKGs were ACTB, PPIA, and UBC. Both UBC and ACTB showed constitutive expression of HIF1A in air and hypoxia, while PGK1 falsely implied a sixfold hypoxia-induced down-regulation. In prostate tumors, UBC and PGK1 both revealed down-regulation of GSTP1 relative to matched benign, whereas ACTB showed variability. CONCLUSIONS: This study demonstrates that no universal endogenous control exists for gene expression studies, even within one disease type. It highlights the importance of validating expression of intended HKGs between different sample types and environmental exposures. PMID- 22926971 TI - Advanced mass calibration and visualization for FT-ICR mass spectrometry imaging. AB - Mass spectrometry imaging by Fourier transform ion cyclotron resonance (FT-ICR) yields hundreds of unique peaks, many of which cannot be resolved by lower performance mass spectrometers. The high mass accuracy and high mass resolving power allow confident identification of small molecules and lipids directly from biological tissue sections. Here, calibration strategies for FT-ICR MS imaging were investigated. Sub-parts-per-million mass accuracy is demonstrated over an entire tissue section. Ion abundance fluctuations are corrected by addition of total and relative ion abundances for a root-mean-square error of 0.158 ppm on 16,764 peaks. A new approach for visualization of FT-ICR MS imaging data at high resolution is presented. The "Mosaic Datacube" provides a flexible means to visualize the entire mass range at a mass spectral bin width of 0.001 Da. The high resolution Mosaic Datacube resolves spectral features not visible at lower bin widths, while retaining the high mass accuracy from the calibration methods discussed. PMID- 22926972 TI - Structural and energetic effects in the molecular recognition of acetylated amino acids by 18-crown-6. AB - Absolute 18-crown-6 (18C6) binding affinities of four protonated acetylated amino acids (AcAAs) are determined using guided ion beam tandem mass spectrometry techniques. The AcAAs examined in this work include: N-terminal acetylated lysine (N(alpha)-AcLys), histidine (N(alpha)-AcHis), and arginine (N(alpha)-AcArg) as well as side chain acetylated lysine (N(epsilon)-AcLys). The kinetic-energy dependent cross sections for collision-induced dissociation (CID) of the (AcAA)H(+)(18C6) complexes are analyzed using an empirical threshold law to extract absolute 0 and 298 K (AcAA)H(+)-18C6 bond dissociation energies (BDEs) after accounting for the effects of multiple collisions, kinetic and internal energy distributions of the reactants, and unimolecular dissociation lifetimes. Theoretical electronic structure calculations are performed to determine stable geometries and energetics for neutral and protonated 18C6 and the AcAAs as well as the proton bound complexes of these species, (AcAA)H(+)(18C6), at the B3LYP/6 311+G(2d,2p)//B3LYP/6-31 G* and M06/6-311+G(2d,2p)//B3LYP/6-31G* levels of theory. For all four (AcAA)H(+)(18C6) complexes, loss of neutral 18C6 corresponds to the most favorable dissociation pathway. At elevated energies, products arising from sequential dissociation of the primary CID product, H(+)(AcAA), are also observed. Protonated N(alpha)-AcLys exhibits a greater 18C6 binding affinity than other protonated N(alpha)-AcAAs, suggesting that the side chains of Lys residues are the preferred binding sites for 18C6 complexation to peptides and proteins. N(alpha)-AcLys exhibits a greater 18C6 binding affinity than N(epsilon) AcLys, suggesting that binding of 18C6 to the side chain of Lys residues is more favorable than to the N-terminal amino group of Lys. PMID- 22926973 TI - A spectrum of basaloid morphology in a subset of EBV-associated "lymphoepithelial carcinomas" of major salivary glands. AB - Nasopharyngeal carcinomas of the undifferentiated or lymphoepithelial type are most commonly seen in South East Asians. Identical tumors have also been described at a variety of other sites including lung, skin and salivary gland and have been referred to by a number of names including lymphoepithelial carcinoma (LEC). LECs of major salivary gland are extremely rare. They are particularly common amongst the Inuit populations of the arctic region including Greenland (Denmark), Canada and Alaska, as well as South East Asians. Within the Inuit group, this tumor represents the majority of all salivary gland carcinomas. Amongst primary LEC of major salivary gland, most cases reported in the literature have represented typical nasopharynx-like tumors. Variants of Epstein Barr Virus (EBV) associated LEC have not been described previously, to the best of our knowledge. In this report, we describe 4 EBV-associated major salivary gland LECs with prominent basaloid morphology, which represent 22 % of a cohort of 18 salivary LECs from an Inuit population in Greenland. The features described in these cases raise a differential diagnosis of other basaloid tumors, particularly in light of the salivary gland location. A basaloid variant of LEC in major salivary gland should be recognized, especially in highly prone populations, to avoid misdiagnosis of other more common salivary tumors. PMID- 22926974 TI - Comparing cytosolic expression to peroxisomal targeting of the chimeric L1/L2 (ChiDeltaH-L2) gene from human papillomavirus type 16 in the methylotrophic yeasts Pichia pastoris and Hansenula polymorpha. AB - The chimeric ChiDeltaH-L2 gene from human papillomavirus type 16, consisting of structural proteins L1 and L2, was successfully expressed in the cytosol of both Pichia pastoris and Hansenula polymorpha during methanol induction. In addition, a novel approach was employed whereby ChiDeltaH-L2 was targeted to the peroxisome using peroxisomal targeting sequence 1 (PTS1) to compare ChiDeltaH-L2 yields in the peroxisome vs the cytosol. The ChiDeltaH-L2 gene was yeast-optimized and cloned into plasmids aimed at genomic integration. Levels of intracellular ChiDeltaH-L2 accumulation in the cytosol were highest in P. pastoris KM71 strain KMChiDeltaH-L2 (1.43 mg/l), compared to the maximum production level of 0.72 mg/l obtained with H. polymorpha. ChiDeltaH-L2 targeting to the peroxisome was successful; however, it appeared to negatively affect ChiDeltaH-L2 production in both P. pastoris and H. polymorpha. PMID- 22926976 TI - A novel complete radiation protection system eliminates physician radiation exposure and leaded aprons. AB - BACKGROUND: Occupational health hazards associated with fluoroscopic-based procedures are well known, including a high prevalence of orthopedic problems, and those related to radiation exposure, particularly cancer and cataracts. This article reports the "first-in-man" clinical experience with a novel radiation protection system designed to eliminate radiation exposure to operators and thereby obviate the need for orthopedically burdensome leaded aprons. The Trinity Radiation Protection System consists of a combination of fixed shields, radiation drapes, and interconnecting flexible radiation resistant materials creating a complete radiation protection environment for the operators, yet maintaining full and unimpeded contact with the patient and total control of all operational elements of the catheterization equipment. METHODS AND RESULTS: This report constitutes an analysis of 19 nonrandomized cases in which operator radiation exposure data were collected (Trinity Radiation Protection System n = 10 cases versus standard shielding alone n = 9). In all cases performed with the Trinity System, there was neither any measurable significant radiation exposure in any anatomic region nor for the total case, whereas operators performing cases with standard shielding were exposed to radiation in all regions of their bodies (total per case exposure differences P < 0.0001). CONCLUSION: The novel radiation protection system described is the first to provide a complete radiation barrier that eliminates radiation exposure to operators, thereby obviating the need for orthopedically burdensome leaded aprons. This approach to radiation protection has promise to enhance the safety and occupational health of medical personnel in the catheterization laboratory. PMID- 22926978 TI - Immunotherapy with dendritic cells in an animal model of early pulmonary metastatic squamous cell carcinoma. AB - OBJECTIVES/HYPOTHESIS: Distant metastases is becoming a more frequently recognized pattern of treatment failure in patients with squamous cell carcinoma of the head and neck (SCCHN). In this study, we evaluated the effect of a dendritic cell (DC)-based vaccine in an early pulmonary metastatic murine model with the aim of providing an effective treatment for SCCHN patients presenting with occult pulmonary metastasis. STUDY DESIGN: In vivo animal experiments were conducted in C3H/He immunocompetent mice using the SCCVII syngeneic squamous carcinoma cell line. METHODS: SCCVII cells were injected through the tail vein to establish early pulmonary metastases. Bone marrow-derived DCs were cultured and educated with ultraviolet B-irradiated apoptotic SCCVII cells before adoptive transfer into the inguinal area. Control groups were vaccinated with normal saline, naive DCs, or apoptotic tumor cells. RESULTS: In the apoptotic SCCVII pulsed DC group, the number of pulmonary tumor nodules was reduced, extirpated lung weight was less, and survival was longer than in control groups. Differences were statistically significant (P < .0001). Specific antitumor immunity was established only in the pulsed DC group, which was confirmed by an interferon gamma enzyme-linked immunosorbent assay. CONCLUSIONS: In an early pulmonary metastatic SCC murine model, systemic antitumor responses can be elicited by adoptive transfers of DCs, which were primed with apoptotic tumor cells. We hope this study will help improve overall survival of patients with SCCHN, especially when they have early or occult pulmonary metastasis. PMID- 22926979 TI - Soprano singing in gibbons. AB - Diversifications in primate vocalization, including human speech, are believed to reflect evolutionary modifications in vocal anatomy and physiology. Gibbon song is acoustically unique, comprising loud, melodious, penetrating pure tone-like calls. In a white-handed gibbon, Hylobates lar, the fundamental frequency (f(0) ) of song sounds is amplified distinctively from the higher harmonics in normal air. In a helium-enriched atmosphere, f(0) does not shift, but it is significantly suppressed and 2f(0) is emphasized. This implies that the source is independent of the resonance filter of the supralaryngeal vocal tract (SVT) in gibbons, in contrast to musical wind instruments, in which the filter primarily determines f(0) . Acoustic simulation further supported that gibbons' singing is produced analogously to professional human soprano singing, in which a precise tuning of the first formant (F(1) ) of the SVT to f(0) amplifies exclusively the f(0) component of the source. Thus, in gibbons, as in humans, dynamic control over the vocal tract configuration, rather than anatomical modifications, has been a dominant factor in determining call structure. The varied dynamic movements were adopted in response to unique social and ecological pressures in gibbons, allowing monogamous gibbons to produce pure-tonal melodious songs in the dense tropical forests with poor visibility. PMID- 22926981 TI - Affective experience in ecologically relevant contexts is dynamic and not progressively attenuated during pregnancy. AB - Pregnancy is thought to diminish a woman's appraisal of and affective response to stressors. To examine this assumption, we used an electronic diary and an ecological momentary assessment strategy to record women's (n = 85) experiences of positive and negative affect five times each day over 2 days within each trimester of pregnancy. The women also completed the Edinburgh Postnatal Depression Scale in each trimester. Multilevel modeling indicated nonlinear patterns for both positive and negative affect that differed by the level of depressive symptoms. The findings suggest that changes in the psychological experience over the course of pregnancy are dynamic and not progressively attenuated. PMID- 22926980 TI - Strain-specific hyperkyphosis and megaesophagus in Add1 null mice. AB - The three adducin proteins (alpha, beta, and gamma) share extensive sequence, structural, and functional homology. Heterodimers of alpha- and beta-adducin are vital components of the red cell membrane skeleton, which is required to maintain red cell elasticity and structural integrity. In addition to anemia, targeted deletion of the alpha-adducin gene (Add1) reveals unexpected, strain-dependent non-erythroid phenotypes. On an inbred 129 genetic background, Add1 null mice show abnormal inward curvature of the cervicothoracic spine with complete penetrance. More surprisingly, a subset of 129-Add1 null mice develop severe megaesophagus, while examination of peripheral nerves reveals a reduced number of axons in 129-Add1 null mice at four months of age. These unforeseen phenotypes, described here, reveal new functions for adducin and provide new models of mammalian disease. PMID- 22926982 TI - Thermo-switchable antibacterial activity. AB - A copolymer system of 2-aminoethyl methacrylate and N-isopropylacrylamide comprises novel properties: changes in conformation and hydrophilicity upon heating influence the antibacterial activity and result in a switchable biocidal effect. The copolymers are characterized via NMR, MALDI-ToF MS, phase transition behavior, and antibacterial tests with E. coli or B. subtilis. MIC and MBC are determined using standard dilution methods, temperature-dependence via incubation at different temperatures and cytotoxicity by MTT tests. The copolymers exhibit lower MIC in globule than coil conformation, crosslinking on cotton results in non-leaching materials with better antibacterial activity above than below the phase-transition point. PMID- 22926983 TI - Conditioned suppression is an inverted-U function of footshock intensity. AB - Most theories of associative learning assert that conditioned responding to a target cue is a monotonically increasing function of unconditioned-stimulus (US) intensity. In a lick suppression preparation with rats, a cue was paired with a 0.4-, 0.6-, 0.8-, 1.0-, 1.2-, or 1.4-mA footshock in Experiment 1a, and with a 0.3-, 0.8-, 1.3-, or 1.8-mA footshock in Experiment 1b. Subsequent suppression in response to the cue was an inverted-U function of the US intensity. In Experiment 2, we demonstrated that massive extinction of the training context and compound conditioning can each attenuate the response decrement caused by training with a high-intensity US. The sometimes-competing-retrieval model (Stout & Miller, Psychological Review 114:759-783, 2007) provides a better fit to these data than do several other models of associative learning. PMID- 22926984 TI - Venepuncture-associated peripheral nerve injuries. PMID- 22926985 TI - Effects of microtopographic patterns on platelet adhesion and activation on titanium oxide surfaces. AB - This study systematically investigated the effects of microtopographic patterns of titanium oxide on platelet adhesion and activation in order to reveal the mechanisms of interactions between platelet and surface topography. Periodic arrays of groove and pillar patterns with dimensions ranging from submicron to several micrometers were fabricated by photolithography and deep reactive-ion etching on silicon substrates, followed by the sputter deposition of titanium oxide (TiO(2)). Platelet adhesion and activation on TiO(2) patterned surfaces were evaluated by lactate dehydrogenase (LDH) and GMP-140 assays, respectively. The morphology of adherent platelets was examined by scanning electron microscope (SEM). The results showed that the microtopographic patterns were able to effectively manipulate the platelet response by varying geometry and size of patterns. A groove pattern resulted in much higher levels of platelet adhesion and activation than a pillar pattern. The study revealed that a difference in pattern size led to two distinctive modes of platelet adhesion: the "bridging" mode in which platelets can bridge over spacing between adjacent patterns when spacing size is smaller than 1.5 MUm; and the "full-contact" mode in which platelets cannot bridge but fully contact the entire surface when spacing size is larger than 3 MUm. Our analysis indicates good correlations between platelet behavior and hydrophobicity/wetting anisotropy in "bridging" mode, and effective surface contact area in "full-contact" mode. PMID- 22926986 TI - Adaptive social learning strategies in temporally and spatially varying environments : how temporal vs. spatial variation, number of cultural traits, and costs of learning influence the evolution of conformist-biased transmission, payoff-biased transmission, and individual learning. AB - Long before the origins of agriculture human ancestors had expanded across the globe into an immense variety of environments, from Australian deserts to Siberian tundra. Survival in these environments did not principally depend on genetic adaptations, but instead on evolved learning strategies that permitted the assembly of locally adaptive behavioral repertoires. To develop hypotheses about these learning strategies, we have modeled the evolution of learning strategies to assess what conditions and constraints favor which kinds of strategies. To build on prior work, we focus on clarifying how spatial variability, temporal variability, and the number of cultural traits influence the evolution of four types of strategies: (1) individual learning, (2) unbiased social learning, (3) payoff-biased social learning, and (4) conformist transmission. Using a combination of analytic and simulation methods, we show that spatial-but not temporal-variation strongly favors the emergence of conformist transmission. This effect intensifies when migration rates are relatively high and individual learning is costly. We also show that increasing the number of cultural traits above two favors the evolution of conformist transmission, which suggests that the assumption of only two traits in many models has been conservative. We close by discussing how (1) spatial variability represents only one way of introducing the low-level, nonadaptive phenotypic trait variation that so favors conformist transmission, the other obvious way being learning errors, and (2) our findings apply to the evolution of conformist transmission in social interactions. Throughout we emphasize how our models generate empirical predictions suitable for laboratory testing. PMID- 22926987 TI - Combining the power of Ti(III)-mediated processes for easy access to hydroxylated polycyclic terpenoids: synthesis of sesterstatin 1 and C-D rings of aspergilloxide. AB - A straightforward access to polyhydroxylated terpenoids based on two key titanocene(III)-mediated reactions is presented: the "head-to-tail" Barbier-type addition of prenyl chlorides to alpha,beta-unsaturated aldehydes, which allows the introduction of hydroxy groups at desirable positions of the acyclic precursor, and the subsequent bioinspired radical cyclisation. This methodology has been also used in the first total synthesis of pentacyclic sesterstatin 1 and a model compound of the C-D rings of aspergilloxide. PMID- 22926988 TI - Bipedicles chest flap: a novel technique for the reconstruction of anterior neck defect. AB - This paper presents our surgical technique and the results of using bipedicled superior chest flaps for head and neck reconstructions. The study design consisted of a case series of surgical technique. The study was conducted at tertiary referral centers with otorhinolaryngology-head and neck surgery departments. In seven patients, we used bipedicled superior chest flaps for reconstruction of anterior cutaneous neck defects due to surgery for the recurrence of laryngopharyngeal carcinoma. The largest flap size was 45 * 14 cm. All donor sites were closed primarily with advancement in the lateral part and split thickness skin grafts in the superior midline of chest. The highest point of reconstruction was in the hypopharynx internally and hyoid externally. All flaps survived without major complications. A bipedicled upper chest flap can reliably cover the skin defects that create following salvage total laryngectomies in patients with advanced stage tumors with skin involvement. PMID- 22926989 TI - The misdiagnosis of external auditory canal carcinoma. AB - External auditory canal (EAC) carcinomas are frequently misdiagnosed. The aim of this study was to conduct a review of misdiagnosed cases and analyze the factors involved. This study was a retrospective assessment. Eighteen of 44 EAC carcinoma cases seen at the Eye and ENT Hospital were misdiagnosed. All medical records were retrospectively analyzed for the age, sex, presenting symptoms, type of misdiagnosis, computed tomographic (CT) or magnetic resonance imaging (MRI) findings, stage of the cancer, surgical approach, histopathological examination, adjunctive therapy (postoperative radiotherapy) and outcomes of treatment. Six cases were misdiagnosed as otitis media, five cases were misdiagnosed as otitis externa, and two cases were misdiagnosed as external auditory canal cholesteatomas. Other misdiagnoses were stenosis of the EAC, ear neuralgia, furuncle of the EAC, benign neoplasm of the EAC and pre-auricular fistula. Our analyses suggest that a biopsy should be conducted to obtain a histopathological diagnosis if an EAC carcinoma is suspected, in case otitis media or otitis externa does not respond to routine anti-bacterials. Head and neck MRI should be used to explore the involvement of soft tissues. Patients with bloody ear discharge and otalgia, particularly with temporal bone erosion seen in a CT scan, are highly likely to have a malignant carcinoma of the temporal bone. PMID- 22926990 TI - Septal stapler use during septum surgery. AB - Although discussions regarding nasal packing are still ongoing, to eliminate any possible complications, surgeons have used nasal packing for many years. Septoplasty is one of the most frequently performed operations by head and neck surgeons. Any methods to diminish the surgical time or bring comfort to the surgeon will be well appreciated. In this study, we attempted to demonstrate the usefulness of the stapler method by comparing preoperative and postoperative results from the visual analog scale (VAS), nasal obstruction symptom evaluation (NOSE), rhinosinusitis quality of life questionnaire (RQLQ), and acoustic rhinomanometry values. In addition, we evaluated pain scores, postoperative complications, and breathing after nasal packing, stapling, and trans-septal suturing techniques. Patients were divided into three groups. In the first group, deviated cartilage was removed or repositioned and mucoperichondrial flaps were closed with a bioresorbable stapler after septoplasty. Four or five staples were placed on the septum. In the second group, the septum was sutured continuously with 4/0 Pegelak (Dogsan TR). In the third group, Merocel packs were used without any sutures and were kept for 48 h. Nasal packing leads to patient discomfort after septal surgery; however, there is no difference in patient comfort between closing the mucoperichondrial flaps by suturing the septum or using a stapler. After surgery, there were no differences between the groups in terms of successful breathing. This situation was assessed by endoscopic examination and acoustic rhinomanometry. Thus, there was no objective or subjective difference. Stapling increases the doctor's comfort level and surgical time is optimized. Although experienced surgeons can easily suture the septum, less experienced ones have some difficulty; therefore, stapling may provide more benefit to the latter. Further, four staples are sufficient to close the septum. PMID- 22926991 TI - Different expressions of erbB1/2 and tight junction proteins in hypertrophic inferior turbinates and nasal polyps. AB - Both inferior turbinate hypertrophy and nasal polyp formation entail the enlargement of the nasal mucosa caused by rhinosinusitis, but their macro/microscopic and clinical findings differ markedly. This study aimed at investigating differences in the expressions of erbB1/2 and the tight junction proteins, claudin-1 and tricellulin, in the two tissues. Ten inferior turbinates and ten nasal polyps were collected. The expressions of erbB1/2, claudin-1, and tricellulin were examined by fluorescence immunohistochemistry and by quantitative real-time transcription-polymerase chain reaction (qRT-PCR). The eosinophil count and % of nasal gland area in the mucosa were also measured. The fluorescence intensities in the inferior turbinates were higher for erbB1/2 and lower for claudin-1 than those in the nasal polyps. The results of qRT-PCR were consistent with the immunohistochemical findings for erbB1/2. The quantity of tricellulin mRNA was significantly higher in the inferior turbinates than in the nasal polyps. The % of nasal gland area was significantly higher but the eosinophil count was significantly lower in the inferior turbinate than in the nasal polyp. These results suggest that the underlying pathogenesis of hypertrophic inferior turbinates and nasal polyps is likely to differ with respect to regeneration/proliferation and thus the remodeling process. PMID- 22926992 TI - Angiographic and clinical characteristics of type 1 versus type 2 perioperative myocardial infarction. AB - OBJECTIVES: The aim of this study was to analyze clinical and angiographic differences between the two etiologic subtypes of perioperative myocardial infarction (PMI). BACKGROUND: PMI is believed to occur by either reduced coronary blood flow attributable to acute plaque rupture and thrombosis (type 1) or primary increase in oxygen demand in the setting of stable but stenotic lesions (type 2). Incidence and mortality rates of PMI are substantial, but angiographic and clinical features are not well characterized. METHODS: Consecutive patients with PMI were classified as "type 1" or "type 2" based on angiographic characteristics of culprit lesions. Clinical and angiographic characteristics of each subtype were compared using statistical analyses. RESULTS: Of the 54 patients analyzed, 32 (59%) cases had type 1 PMI, whereas 22 others (41%) had type 2 PMI. Compared with type 2 patients, those with type 1 PMI more often had ECG (electrocardiogram) ST elevation (53% versus 23%, P = 0.026), greater peak troponin (15.3 ng/dl versus 5.3 ng/dl, P = 0.035), higher preoperative mean blood pressure (103 mm Hg versus 93 mm Hg, P = 0.009), greater decrease in mean intraoperative blood pressure (-36 mm Hg versus -26 mm Hg, P = 0.015). Type I patients trended toward greater in-hospital mortality (16% versus 5%, P = 0.38) and length of hospitalization (13.5 days versus 9.0 days, P = 0.13). CONCLUSIONS: These results demonstrate that PMI not only results from "demand ischemia" but also that in nearly 60% of cases the cause is acute plaque rupture. Patients with PMI attributable to plaque rupture suffer more intraoperative hypotension, greater transmural ischemia, larger infarct size, and trended toward worse outcome. PMID- 22926993 TI - Molecular and cellular basis for diastolic dysfunction. AB - Heart failure with preserved ejection fraction (HFpEF) is highly prevalent and is frequently associated with metabolic risk factors. Patients with HFpEF have only a slightly lower mortality than patients with HF and reduced EF. The pathophysiology of HFpEF is currently incompletely understood, which precludes specific therapy. Both HF phenotypes demonstrate distinct cardiac remodeling processes at the macroscopic, microscopic, and ultrastructural levels. Increased diastolic left-ventricular (LV) stiffness and impaired LV relaxation are important features of HFpEF, which can be explained by changes in the extracellular matrix and the cardiomyocytes. In HFpEF, elevated intrinsic cardiomyocyte stiffness contributes to high diastolic LV stiffness. Posttranslational changes in the sarcomeric protein titin, affecting titin isoform expression and phosphorylation, contribute to elevated cardiomyocyte stiffness. Increased nitrosative/oxidative stress, impaired nitric oxide bioavailability, and down-regulation of myocardial cyclic guanosine monophosphate and protein kinase G signaling could trigger posttranslational modifications of titin, thereby augmenting cardiomyocyte and LV diastolic stiffness. PMID- 22926995 TI - A concise synthesis of (-)-aplyviolene facilitated by a strategic tertiary radical conjugate addition. PMID- 22926996 TI - Genetic variant on PDGFRL associated with Behcet disease in Chinese Han populations. AB - Behcet disease is a complex multisystem disorder. This study aimed to explore the predisposition of PDGFRL at the 8p21.3 locus with Behcet disease and its expression level for different genotypes. A two-stage association study was performed in 719 patients and 1,820 controls for 26 tagSNPs in the PDGFRL gene. Real-time PCR and Bonferroni correction were performed. The first-stage study showed that SNP rs17633132 was associated with Behcet disease (Pc = 5.20 * 10( 3)). Replication and combined studies showed consistent association for rs17633132 T allele and TT genotype (replication: Pc = 3.90 * 10(-4) and 5.70 * 10(-3); combined: Pc = 2.05 * 10(-6) and 3.20 * 10(-4)). No haplotype in PDGFRL was associated with Behcet disease. The expression of PDGFRL in skin from rs17633132 CC genotype individuals was increased compared to that in those with the CT or TT genotype (P = 0.028, P = 0.032, respectively). This study identified a Behcet-disease-associated gene, PDGFRL, and suggests its involvement of Behcet disease by modulating its transcription. PMID- 22926994 TI - Imaging the myocardial microcirculation post-myocardial infarction. AB - The myocardial microcirculation provides the vital pressure control and metabolic homeostasis for normal muscle function. Microvascular dysfunction is implicated in chronic cardiac disease and can signify higher risk, but its effect in acute myocardial infarction (AMI) can be profound. Modern management of AMI is focussed entirely on timely epicardial coronary patency, but as a result can leave microcirculatory devastation in its wake. The 'no-reflow' phenomenon occurs in up to 40 % of those successfully reperfused following an ST-elevation AMI (STEMI), and reflects significant microvessel injury that at its most severe involves both microvascular obstruction (MVO) and intramyocardial haemorrhage. Myocardial contrast echocardiography and cardiac magnetic resonance imaging have both led the field in establishing MVO as the prime determinant of adverse left ventricular (LV) remodeling, LV dysfunction, heart failure and increased mortality. These imaging techniques will be essential to support future research endeavours and shift focus to the maintenance of microvascular flow in AMI. PMID- 22926997 TI - Stem cell research points the way to the cell of origin for intracranial germ cell tumours. AB - Germ cell tumours found in the brain (intracranial GCTs) are a very unusual class of tumour for two reasons. First, they include a very diverse range of histological subtypes classified together due to their proposed common cell of origin. Second, this proposed cell of origin, the germ cell progenitor, would not normally be found in the tissue where these tumours arise. This is in contrast to all other primary brain tumours, in which the cell of origin is believed to be a brain cell. Indeed, no other class of primary cancer arises from a cell from a distant organ. This theory for the origins of intracranial GCTs has been in place for many decades, but recent data arising from studies of induced pluripotency for regenerative medicine raise serious questions about this dogma. Here we review the cellular origins of intracranial GCTs in the light of these new data and reanalyse the existing data on the biology of this unusual class of tumours. Together, these considerations lead us to conclude that the evidence now falls in favour of a model in which these tumours arise from the transformation of endogenous brain cells. This theory should inform future studies of the aetiology of these tumours and so lead the way to animal models in which to study their development and potential biological therapeutics. PMID- 22926998 TI - Special issue on computational models of classical conditioning guest editors' introduction. AB - In the present special issue, the performance of current computational models of classical conditioning was evaluated under three requirements: (1) Models were to be tested against a list of previously agreed-upon phenomena; (2) the parameters were fixed across simulations; and (3) the simulations used to test the models had to be made available. These requirements resulted in three major products: (a) a list of fundamental classical-conditioning results for which there is a consensus about their reliability; (b) the necessary information to evaluate each of the models on the basis of its ordinal successes in accounting for the experimental data; and (c) a repository of computational models ready to generate simulations. We believe that the contents of this issue represent the 2012 state of the art in computational modeling of classical conditioning and provide a way to find promising avenues for future model development. PMID- 22926999 TI - A configural theory of attention and associative learning. AB - A formal account of the relationship between attention and associative learning is presented within the framework of a configural theory of discrimination learning. The account is based on a connectionist network in which the entire pattern of stimulation presented on a trial activates a configural unit that then enters into an association with the trial outcome. Attention is assumed to have two roles within this network. First, the salience of the stimuli at the input to the network can be increased if they are relevant to the occurrence of reinforcement and decreased if they are irrelevant. Second, the associability of configural units can increase on trials when the outcome is surprising and decrease when the outcome is not surprising. PMID- 22927000 TI - Exploring a latent cause theory of classical conditioning. AB - We frame behavior in classical conditioning experiments as the product of normative statistical inference. According to this theory, animals learn an internal model of their environment from experience. The basic building blocks of this internal model are latent causes-explanatory constructs inferred by the animal that partition observations into coherent clusters. Generalization of conditioned responding from one cue to another arises from the animal's inference that the cues were generated by the same latent cause. Through a wide range of simulations, we demonstrate where the theory succeeds and where it fails as a general account of classical conditioning. PMID- 22927001 TI - Solving Pavlov's puzzle: attentional, associative, and flexible configural mechanisms in classical conditioning. AB - This article introduces a new "real-time" model of classical conditioning that combines attentional, associative, and "flexible" configural mechanisms. In the model, attention to both conditioned (CS) and configural (CN) stimuli are modulated by the novelty detected in the environment. Novelty increases with the unpredicted presence or absence of any CS, unconditioned stimulus (US), or context. Attention regulates the magnitude of the associations CSs and CNs form with other CSs and the US. We incorporate a flexible configural mechanism in which attention to the CN stimuli increases only after the model has unsuccessfully attempted learn input-output combinations with CS-US associations. That is, CSs become associated with the US and other CSs on fewer trials than they do CNs. Because the CSs activate the CNs through unmodifiable connections, a CS can become directly and indirectly (through the CN) associated with the US or other CSs. In order to simulate timing processes, we simply assume that a CS is formed by a temporal spectrum of short-duration CSs that are activated by the nominal CS trace. The model accurately describes 94 % of the basic properties of classical conditioning, using fixed model parameters and simulation values in all simulations. PMID- 22927002 TI - Modeling attention in associative learning: two processes or one? AB - Certain studies of associative learning show that attention is more substantial to cues that have a history of being predictive of an outcome than to cues that are irrelevant. At the same time, other studies show that attention is more substantial to cues whose outcomes are uncertain than to cues whose outcomes are predictable. This has led to the suggestion of there being two kinds of attention in associative learning: one based upon a mechanism that allocates attention to a cue on the basis of its predictiveness, the other based upon a mechanism that allocates attention to a cue on the basis of its prediction error (e.g., Le Pelley, Quarterly Journal of Experimental Psychology, 57B, 193-243, 2004). As an alternative, it has been demonstrated that the effects of both predictiveness and uncertainty can be accounted for with only one kind of attention: one that emphasizes the role of prediction (Esber & Haselgrove, Proceedings of the Royal Society B, 278, 2553-2561, 2011). Here, we consider the alternative: whether the effects of predictiveness and uncertainty can be reconciled with a model of learning that emphasizes the role of prediction error (Pearce, Kaye, & Hall, 1982). Simulations of this model reveal that, in many cases, it too is able to account for the influence of predictiveness and uncertainty in associative learning. PMID- 22927003 TI - Evaluating the TD model of classical conditioning. AB - The temporal-difference (TD) algorithm from reinforcement learning provides a simple method for incrementally learning predictions of upcoming events. Applied to classical conditioning, TD models suppose that animals learn a real-time prediction of the unconditioned stimulus (US) on the basis of all available conditioned stimuli (CSs). In the TD model, similar to other error-correction models, learning is driven by prediction errors--the difference between the change in US prediction and the actual US. With the TD model, however, learning occurs continuously from moment to moment and is not artificially constrained to occur in trials. Accordingly, a key feature of any TD model is the assumption about the representation of a CS on a moment-to-moment basis. Here, we evaluate the performance of the TD model with a heretofore unexplored range of classical conditioning tasks. To do so, we consider three stimulus representations that vary in their degree of temporal generalization and evaluate how the representation influences the performance of the TD model on these conditioning tasks. PMID- 22927004 TI - Elemental representation and configural mappings: combining elemental and configural theories of associative learning. AB - In this article, we present our first attempt at combining an elemental theory designed to model representation development in an associative system (based on McLaren, Kaye, & Mackintosh, 1989) with a configural theory that models associative learning and memory (McLaren, 1993). After considering the possible advantages of such a combination (and some possible pitfalls), we offer a hybrid model that allows both components to produce the phenomena that they are capable of without introducing unwanted interactions. We then successfully apply the model to a range of phenomena, including latent inhibition, perceptual learning, the Espinet effect, and first- and second-order retrospective revaluation. In some cases, we present new data for comparison with our model's predictions. In all cases, the model replicates the pattern observed in our experimental results. We conclude that this line of development is a promising one for arriving at general theories of associative learning and memory. PMID- 22927005 TI - Normalization between stimulus elements in a model of Pavlovian conditioning: showjumping on an elemental horse. AB - Harris and Livesey. Learning & Behavior, 38, 1-26, (2010) described an elemental model of associative learning that implements a simple learning rule that produces results equivalent to those proposed by Rescorla and Wagner (1972), and additionally modifies in "real time" the strength of the associative connections between elements. The novel feature of this model is that stimulus elements interact by suppressively normalizing one another's activation. Because of the normalization process, element activity is a nonlinear function of sensory input strength, and the shape of the function changes depending on the number and saliences of all stimuli that are present. The model can solve a range of complex discriminations and account for related empirical findings that have been taken as evidence for configural learning processes. Here we evaluate the model's performance against the host of conditioning phenomena that are outlined in the companion article, and we present a freely available computer program for use by other researchers to simulate the model's behavior in a variety of conditioning paradigms. PMID- 22927006 TI - Performance factors in associative learning: assessment of the sometimes competing retrieval model. AB - Previous simulations revealed that the sometimes competing retrieval model (SOCR; Stout & Miller, Psychological Review, 114, 759-783, 2007), which assumes local error reduction, can explain many cue interaction phenomena that elude traditional associative theories based on total error reduction. Here, we applied SOCR to a new set of Pavlovian phenomena. Simulations used a single set of fixed parameters to simulate each basic effect (e.g., blocking) and, for specific experiments using different procedures, used fitted parameters discovered through hill climbing. In simulation 1, SOCR was successfully applied to basic acquisition, including the overtraining effect, which is context dependent. In simulation 2, we applied SOCR to basic extinction and renewal. SOCR anticipated these effects with both fixed parameters and best-fitting parameters, although the renewal effects were weaker than those observed in some experiments. In simulation 3a, feature-negative training was simulated, including the often observed transition from second-order conditioning to conditioned inhibition. In simulation 3b, SOCR predicted the observation that conditioned inhibition after feature-negative and differential conditioning depends on intertrial interval. In simulation 3c, SOCR successfully predicted failure of conditioned inhibition to extinguish with presentations of the inhibitor alone under most circumstances. In simulation 4, cue competition, including blocking (4a), recovery from relative validity (4b), and unblocking (4c), was simulated. In simulation 5, SOCR correctly predicted that inhibitors gain more behavioral control than do excitors when they are trained in compound. Simulation 6 demonstrated that SOCR explains the slower acquisition observed following CS-weak shock pairings. PMID- 22927007 TI - ERalpha signaling regulates MMP3 expression to induce FasL cleavage and osteoclast apoptosis. AB - The benefits of estrogens on bone health are well established; how estrogens signal to regulate bone formation and resorption is less well understood. We show here that 17beta-estradiol (E2)-induced apoptosis of bone-resorbing osteoclasts is mediated by cleavage and solubilization of osteoblast-expressed Fas ligand (FasL). U2OS-ERalpha osteoblast-like cells expressing an EGFP-tagged FasL at the C-terminus showed decreased fluorescence after E2 treatment, indicative of a cleavage event. Treatment of U2OS-ERalpha cultures with a specific MMP3 inhibitor in the presence of E2 blocked FasL cleavage and showed an increase in the number of EGFP-FasL+ cells. siRNA experiments successfully knocked down MMP3 expression and restored full-length FasL to basal levels. E2 treatment of both human and murine primary osteoblasts showed upregulation of MMP3 mRNA expression, and calvarial organ cultures showed increased expression of MMP3 protein and colocalization with the osteoblast-specific RUNX2 after E2 treatment. In addition, osteoblast cell cultures derived from ERalphaKO mice showed decreased expression of MMP3 but not MMP7 and ADAM10, two known FasL proteases, demonstrating that ERalpha signaling regulates MMP3. Also, conditioned media of E2-treated calvarial osteoblasts showed an approximate sixfold increase in the concentration of soluble FasL, indicating extensive cleavage, and soluble FasL concentrations were reduced in the presence of a specific MMP3 inhibitor. Finally, to show the role of soluble FasL in osteoclast apoptosis, human osteoclasts were cocultured with MC3T3 osteoblasts. Both a specific MMP3 inhibitor and an MMP inhibitor cocktail preserved osteoclast differentiation and survival in the presence of E2 and demonstrate the necessity of MMP3 for E2 induced osteoclast apoptosis. These experiments further define the molecular mechanism of estrogen's bone-protective effects by inducing osteoclast apoptosis through upregulation of MMP3 and FasL cleavage. PMID- 22927008 TI - Chronic family economic hardship, family processes and progression of mental and physical health symptoms in adolescence. AB - Research has documented the relationship between family stressors such as family economic hardship and marital conflict and adolescents' mental health symptoms, especially depressive symptoms. Few studies, however, have examined the processes whereby supportive parenting lessens this effect and the progression of mental health and physical health symptoms in adolescence. The present study investigates the influences of chronic family economic hardship on adolescents' multiple health problem symptoms (i.e., symptoms of anxiety, and depression and physical complaints) through parents' marital conflict, and supportive parenting; it also examines how there adolescents' health problems mutually influence one another throughout adolescence. We used Structural Equation Modeling to analyze data from a longitudinal sample of European American mothers, fathers, and target adolescents (N = 451, 53% female) to examine direct and indirect effects. Findings generally supported the hypothesized model. Chronic family economic hardship contributed to mental and physical health problems of adolescents. This influence largely was mediated through supportive parenting. Moreover, supportive parenting buffered marital conflict on depressive symptoms of adolescents. Also, there was a tendency for females to show more stable depressive symptoms than males. The study demonstrates key mediating pathways and additional moderating influences based on the family stress model and also highlights the importance of improving health resources for adolescents. PMID- 22927010 TI - Pleistocene-Holocene boundary in Southern Arabia from the perspective of human mtDNA variation. AB - It is now known that several population movements have taken place at different times throughout southern Arabian prehistory. One of the principal questions under debate is if the Early Holocene peopling of southern Arabia was mainly due to input from the Levant during the Pre-Pottery Neolithic B, to the expansion of an autochthonous population, or some combination of these demographic processes. Since previous genetic studies have not been able to include all parts of southern Arabia, we have helped fill this lacuna by collecting new population datasets from Oman (Dhofar) and Yemen (Al-Mahra and Bab el-Mandab). We identified several new haplotypes belonging to haplogroup R2 and generated its whole genome mtDNA tree with age estimates undertaken by different methods. R2, together with other considerably frequent southern Arabian mtDNA haplogroups (R0a, HV1, summing up more than 20% of the South Arabian gene pool) were used to infer the past effective population size through Bayesian skyline plots. These data indicate that the southern Arabian population underwent a large expansion already some 12 ka. A founder analysis of these haplogroups shows that this expansion is largely attributed to demographic input from the Near East. These results support thus the spread of a population coming from the north, but at a significantly earlier date than presently considered by archaeologists. Our data suggest that some of the mtDNA lineages found in southern Arabia have persisted in the region since the end of the Last Ice Age. PMID- 22927011 TI - Increased risk of getting sudden sensorineural hearing loss in patients with chronic kidney disease: a population-based cohort study. AB - OBJECTIVES/HYPOTHESIS: To examine the risk of getting Sudden Sensorineural Hearing Loss (SSHL) among patients with chronic kidney disease (CKD). STUDY DESIGN: A retrospective cohort study. METHODS: Population-based representative insurance claims data were used to examine the risk of getting SSHL among patients with chronic kidney disease. Data extracted from the Taiwan National Health Insurance Research Database yielded 37,421 patients with newly diagnosed renal insufficiency and 37,421 subjects without renal insufficiency from between 2000 and 2004. RESULTS: The incidence of SSHL at the end of 2009 was determined. The incidence of SSHL was 1.57 times higher in the CKD-carrying group compared to the incidence in the non-CKD group (10.24 vs. 6.52 per 10,000 person-years), with adjusted hazard ratio (HR) of 1.46 (95% CI = 1.194-1.787) using Cox proportional hazard regressions. Age was an independent risk factor of getting SSHL, with adjusted HRs of 2.01, 3.178, and 2.285 for age ranges of 35 ~ 49, 50 ~ 64 and >= 65 compared with age range of 0 ~ 35. Diabetes Mellitus was another independent risk factor with HR of 1.31 (95% CI = 1.003-1.711). CONCLUSIONS: Present results suggested a significant association between CKD and increased risk of getting SSHL. Comorbidity of diabetes in patients with CKD appeared to be associated with increased risk of getting SSHL, especially for the patients who are 35 years of age and older. PMID- 22927009 TI - Gender-specific relationships between depressive symptoms, marijuana use, parental communication and risky sexual behavior in adolescence. AB - A large body of research has identified correlates of risky sexual behavior, with depressive symptoms and marijuana use among the most consistent psychosocial predictors of sexual risk. However, substantially less research has examined the relationship between these risk variables and adolescent risky sexual behavior over time as well as the interaction of these individual-level predictors with family-level variables such as parenting factors. Additionally, most studies have been restricted to one index of risky sexual behavior, have not taken into account the complex role of gender, and have not controlled for several of the factors that independently confer risk for risky sexual behavior. Therefore, the current study investigated the association between depressive symptoms and parameters of parenting on marijuana use, number of sexual partners and condom usage measured 9 months later for both boys and girls. Participants were 9th and 10th grade adolescents (N = 1,145; 57.7% female). We found that depressive symptoms may be a gender-specific risk factor for certain indices of risky sexual behavior. For boys only, marijuana use at Time 2 accounted for the variance in the relationship between depressive symptoms at Time 1 and number of partners at Time 2. Additionally, strictness of family rules at Time 1 was associated with the number of partners with whom girls engaged in sex at Time 2, but only among those with lower levels of depressive symptoms at Time 1. Results from the current investigation speak to the utility of examining the complex, gender specific pathways to sexual risk in adolescents. Findings suggest that treatment of mental health and substance use problems may have important implications in rates of risky sexual behavior and, conceivably, controlling the high rates of serious individual and public health repercussions. PMID- 22927012 TI - Biochemical and conformational characterization of a leucine aminopeptidase from Geobacillus thermodenitrificans NG80-2. AB - In order to search for valuable and extremely thermo-stable enzymes that could be used in the protein hydrolysis industry, the gene corresponding to a leucine aminopeptidase from Geobacillus thermodenitrificans NG80-2 (GtLAP) was cloned and expressed in E. coli. The recombinant enzyme was purified, and its characteristics were examined. Meanwhile, potential applications of GtLAP in the hydrolysis of anchovy proteins were also investigated. GtLAP was overexpressed in IPTG-induced E. coli BL21 (pET28a-LAP) as a soluble protein, and was purified to homogeneity by nickel-chelate chromatography to a specific activity of 125 +/- 8.75 U/mg proteins. The molecular mass of GtLAP was estimated to be 55 kDa by SDS PAGE analysis. The optimal reaction temperature and pH of GtLAP were 70 degrees C and 8.0, respectively. Under optimal conditions, GtLAP showed a marked preference for Leu-p-nitroanilide, followed by Met- and Phe-derivatives. Activity of GtLAP was strongly stimulated by Ni2+ ions, but was strongly inhibited by Hg2+. Conformational studies via circular dichroism spectroscopy indicated that various factors could influence the secondary structure of GtLAP to various extents and further induce changes in enzymatic activity. Results of hydrolytic experiment showed that combining GtLAP with endogenous enzymes could significantly increase the degree of hydrolysis to anchovy proteins and concentrations of free amino acids in hydrolysates. In this regard, GtLAP could potentially be used in the protein hydrolysis industry. PMID- 22927013 TI - Fungal rock phosphate solubilization using sugarcane bagasse. AB - The effects of different doses of rock phosphate (RP), sucrose, and (NH(4))(2)SO(4) on the solubilization of RP from Araxa and Catalao (Brazil) by Aspergillus niger, Penicillium canescens, Eupenicillium ludwigii, and Penicillium islandicum were evaluated in a solid-state fermentation (SSF) system with sugarcane bagasse. The factors evaluated were combined following a 2(3) + 1 factorial design to determine their optimum concentrations. The fitted response surfaces showed that higher doses of RP promoted higher phosphorus (P) solubilization. The addition of sucrose did not have effects on P solubilization in most treatments due to the presence of soluble sugars in the bagasse. Except for A. niger, all the fungi required high (NH(4))(2)SO(4) doses to achieve the highest level of P solubilization. Inversely, addition of (NH(4))(2)SO(4) was inhibitory to P solubilization by A. niger. Among the fungi tested, A. niger stood out, showing the highest solubilization capacity and for not requiring sucrose or (NH(4))(2)SO(4) supplementation. An additional experiment with A. niger showed that the content of soluble P can be increased by adding higher RP doses in the medium. However, P yield decreases with increasing RP doses. In this experiment, the maximal P yield (approximately 60 %) was achieved with the lower RP dose (3 g L(-1)). Our results show that SSF can be used to obtain a low cost biofertilizer rich in P combining RP, sugarcane bagasse, and A. niger. Moreover, sugarcane bagasse is a suitable substrate for SSF aiming at RP solubilization, since this residue can supply the C and N necessary for the metabolism of A. niger within a range that favors RP solubilization. PMID- 22927014 TI - Diversity and metabolic potential of culturable root-associated bacteria from Origanum vulgare in sub-Himalayan region. AB - Study of rhizospheric bacteria from important plants is very essential, as they are known to influence plant growth and productivity, and also produce industrially important metabolites. Origanum vulgare is a perennial medicinal aromatic plant rich in phenolic antioxidants. Present study investigates the diversity of culturable root-associated bacteria from this plant in Palampur, India, which constitutes a unique ecosystem due to high rain fall, wide temperature fluctuations and acidic soil. Both root endophytes and rhizospheric soil bacteria were isolated, which resulted in a total of 120 morphologically different isolates. They were found to group into 21 phylotypes based on restriction fragment length polymorphism analysis. Growth medium composition had significant effect on the diversity of the isolated bacterial populations. The isolates were characterized for various metabolic, plant growth promoting (PGP) and other biotechnologically useful activities, based on which they were clustered into groups by principal component analysis. Majority of the isolates belonged to gamma-Proteobacteria and Firmicutes. Pseudomonas and Stenotrophomonas were the most dominant species and together constituted 27.5 % of the total isolates. Many isolates, especially gamma-Proteobacteria, showed very high PGP activities. Few isolates exhibited very high antioxidant activity, which may find potential applications in food and health industries. Firmicutes were catabolically the most versatile group and produced several hydrolytic enzymes. To the best of our knowledge, it is the first study describing rhizospheric microbial community of O. vulgare. PMID- 22927015 TI - Cultivable psychrotolerant yeasts associated with Antarctic marine sponges. AB - Unlike filamentous fungi and bacteria, very little is known about cultivable yeasts associated with marine sponges, especially those from Antarctic seas. During an expedition to King George Island, in the Antarctica, samples of 11 marine sponges were collected by scuba-diving. From these sponges, 20 psychrotolerant yeast isolates were obtained. Phylogenetic analyses of D1/D2 and ITS rRNA gene sequences revealed that the marine ascomycetous yeast Metschnikowia australis is the predominant organism associated with these invertebrates. Other species found belonged to the Basidiomycota phylum: Cystofilobasidium infirmominiatum, Rhodotorula pinicola, Leucosporidiella creatinivora and a new yeast from the Leucosporidiella genus. None of these yeasts have been previously associated with marine sponges. A screening to estimate the ability of these yeasts as producers of extracellular enzymatic activities at several pH and temperature conditions was performed. Several yeast isolates demonstrated amylolytic, proteolytic, lipolytic or cellulolytic activity, but none of them showed xylanolytic activity under the conditions assayed. To our knowledge, this work is the first description of cultivable yeasts associated with marine sponges from the Antarctic sea. PMID- 22927017 TI - To screen or not to screen...: a comment on Lepore et Al. PMID- 22927016 TI - Maternal experiences with everyday discrimination and infant birth weight: a test of mediators and moderators among young, urban women of color. AB - BACKGROUND: Racial/ethnic disparities in birth weight persist within the USA. PURPOSE: The purpose of this study is to examine the association between maternal everyday discrimination and infant birth weight among young, urban women of color as well as mediators (depressive symptoms, pregnancy distress, and pregnancy symptoms) and moderators (age, race/ethnicity, and attributions of discrimination) of this association. METHODS: A total of 420 women participated (14-21 years old; 62 % Latina, 38 % Black), completing measures of everyday discrimination and moderators during their second trimester of pregnancy and mediators during their third trimester. Birth weight was primarily recorded from medical record review. RESULTS: Path analysis demonstrated that everyday discrimination was associated with lower birth weight. Depressive symptoms mediated this relationship, and no tested factors moderated this relationship. CONCLUSIONS: Given the association between birth weight and health across the lifespan, it is critical to reduce discrimination directed at young, urban women of color so that all children can begin life with greater promise for health. PMID- 22927018 TI - Hybrid polyoxotungstates as functional comonomers in new cross-linked catalytic polymers for sustainable oxidation with hydrogen peroxide. AB - Anchoring terminal octenyl tails on molecular polyoxotungstates yield polymerizable organic-inorganic monomers with formula [{CH(2)=CH(CH(2))(6)Si}(x)O(y)SiW(w)O(z)](4-) [x = 2, w = 11, y = 1, z = 39 (1); x = 2, w = 10, y = 1, z = 36 (2); and x = 4, w = 9, y = 3, z = 34 (3)]. These molecular hybrids can use aqueous hydrogen peroxide to catalyze the selective oxidation of organic sulfides in CH(3)CN. Copolymerization of 1-3 with methyl methacrylate and ethylene glycol dimethacrylate leads to porous materials with a homogeneous distribution of the functional monomers, as indicated by converging evidence from FTIR spectroscopy and electronic microscopy. The catalytic polymers activate hydrogen peroxide for oxygen transfer, as demonstrated by the quantitative and selective oxidation of methyl p-tolyl sulfide, which was screened as model substrate. The hybrid material containing monomer 2 was also tested in n-octane to evaluate its potential for the oxidation and removal of dibenzothiophene, a well-known gasoline contaminant. PMID- 22927019 TI - A case of late-onset sustained ventricular tachycardia following deployment of Amplatzer-type perimembranous VSD occluder. AB - Transcatheter closure of ventricular septal defect (VSD) has been widely used worldwide. Despite high success rate and minimal operative mortality, arrhythmia during and post-operation has been frequently observed. However, sustained ventricular tachycardia following deployment of occluder has not been reported. In this present case, we present one rare case of late-onset sustained ventricular tachycardia, which developed 71 hr after deployment of an Amplatzer type occluder for perimembranous VSD (PmVSD) in a 3-year and 5-month-old boy. The sustained ventricular tachycardia was successfully corrected with the administration of lidocaine, amiodarone, and dexamethasone. The reoccurrence of ventricular tachycardia was not observed in the most recent follow-up at 6 month. In summary, the current case indicated that sustained ventricular tachycardia could occur following deployment of Amplatzer-type occluder for PmVSD, which could be corrected with antiarrhythmic drugs. PMID- 22927020 TI - Efficacy and safety of photodynamic therapy with temoporfin in curative treatment of recurrent carcinoma of the oral cavity and oropharynx. AB - Therapeutic options for recurrent carcinoma of the upper aerodigestive tract (UADT) are limited. The prognosis of these tumours remains poor with significant rate of recurrence and a lower median survival time. Photodynamic therapy (PDT) is a relatively new therapeutic alternative which combines the use of a photosensitising agent and light to induce a cytotoxic effect on the tissues. This is a retrospective single-centre study carried out in patients with a recurrence of an oral cavity or oropharyngeal carcinoma or a second appearance of tumour in a previously irradiated area. There were no metastases in lymph nodes or other organs. Laser treatment was carried out 96 h after temoporfin (Foscan((r))) injection. In our series we had 14 cases with a complete response, 1 partial response. Overall survival at 1 year was 72 % and 36 % at 5 years. Disease-specific survival at 1 year was 82 % and 45 % at 5 years. Recurrence-free survival at 1 year was 52 % and 34 % at 5 years. Side effects mainly described are pain in the area of illumination, well controlled. PDT with Foscan((r)) gives useful results in terms of survival and improvement in quality of life with few adverse events or severe complications. The fact that it has low toxicity and that treatment sessions can be repeated mean it should be considered in the therapeutic armamentarium for recurrent carcinoma of the UADT. PMID- 22927021 TI - Cytotoxic and genotoxic characterization of titanium dioxide, gadolinium oxide, and poly(lactic-co-glycolic acid) nanoparticles in human fibroblasts. AB - Engineered nanomaterials have become prevalent in our everyday life. While the popularity of using nanomaterials in consumer products continues to rise, increasing awareness of nanotoxicology has also fuelled efforts to accelerate our understanding of the ill effects that different nanomaterials can bring to biological systems. In this study, we investigated the potential cytotoxicity and genotoxicity of three nanoparticles: titanium dioxide (TiO(2)), terbium-doped gadolinium oxide (Tb-Gd(2)O(3)), and poly(lactic-co-glycolic acid) (PLGA). To evaluate nanoparticle-induced genotoxicity more realistically, a human skin fibroblast cell line (BJ) with less mutated genotype compared with cancer cell line was used. The nanoparticles were first characterized by size, morphology, and surface charge. Cytotoxicity effects of the nanoparticles were then evaluated by monitoring the proliferation of treated BJ cells. Genotoxic influence was ascertained by profiling DNA damage via detection of gammaH2AX expression. Our results suggested that both TiO(2) and Tb-Gd(2)O(3) nanoparticles induced cytotoxicity in a dose dependent way on BJ cells. These two nanomaterials also promoted genotoxicity via DNA damage. On the contrary, PLGA nanoparticles did not induce significant cytotoxic or genotoxic effects on BJ cells. PMID- 22927022 TI - Infectious myelitis. AB - Infections are an uncommon but very important etiology of myelitis as a correct diagnosis would allow for timely treatment and recovery. The term "myelitis" is generally used to describe an inflammatory pathologic process affecting the spinal cord and causing an interruption of the ascending and descending pathways, and, therefore, partial or complete loss of function. The onset may be acute or subacute, and the etiology may be cumbersome to determine. This article will review the most recently published literature regarding the infectious agents causing myelitis with an emphasis on diagnosis and treatment. PMID- 22927023 TI - Poststroke emotional incontinence: is it depression? PMID- 22927025 TI - Total syntheses of amphidinolides B, G, and H. AB - Not one, not two, but three: Total syntheses of amphidinolides B, G, and H, which exhibit strong, nanogram-scale cytotoxicity against various tumor cell lines, have been executed. The synthetic strategy relied on implementation of a diene construction protocol and a diastereoselective aldol process. The 26- and 27 membered macrocyclic lactone rings were efficiently constructed by using ring closing metathesis (RCM). PMID- 22927024 TI - Using pictures and words to understand recognition memory deterioration in amnestic mild cognitive impairment and Alzheimer's disease: a review. AB - Difficulty recognizing previously encountered stimuli is one of the earliest signs of incipient Alzheimer's disease (AD). Work over the last 10 years has focused on how patients with AD and those in the prodromal stage of amnestic mild cognitive impairment make recognition decisions for visual and verbal stimuli. Interestingly, both groups of patients demonstrate markedly better memory for pictures over words, to a degree that is significantly greater in magnitude than their healthy older counterparts. Understanding this phenomenon not only helps to conceptualize how memory breaks down in AD, but also potentially provides the basis for future interventions. This review critically examines recent recognition memory work using pictures and words in the context of the dual process theory of recognition and current hypotheses of cognitive breakdown in the course of very early AD. PMID- 22927026 TI - JP-45/JSRP1 variants affect skeletal muscle excitation-contraction coupling by decreasing the sensitivity of the dihydropyridine receptor. AB - JP-45 (also JP45; encoded by JSRP1) is an integral protein constituent of the skeletal muscle sarcoplasmic reticulum junctional face membrane interacting with Ca(v) 1.1 (the alpha.1 subunit of the voltage-sensing dihydropyridine receptor, DHPR) and the luminal calcium-binding protein calsequestrin. Two JSRP1 variants have been found in the human population: c.323C>T (p.P108L) in exon 5 and c.449G>C (p.G150A) in exon 6, but nothing is known concerning the incidence of these polymorphisms in the general population or in patients with neuromuscular diseases nor the impact of the polymorphisms on excitation-contraction (EC) coupling. In the present report, we investigated the frequencies of these two JSRP1 polymorphisms in the Swiss malignant hyperthermia population and studied the functional impact of the variants on EC coupling. Our results show that the polymorphisms are equally distributed among malignant hyperthermia negative, malignant hyperthermia equivocal, and malignant hyperthermia susceptible individuals. Interestingly, however, the presence of either one of these JP-45 variants decreased the sensitivity of the DHPR to activation. The presence of a JSRP1 variant may explain the variable phenotype seen in patients with malignant hyperthermia carrying the same mutation and, more importantly, may counteract the hypersensitivity of EC coupling caused by mutations in the RYR1 gene. PMID- 22927027 TI - The psychologist said quickly, "dialogue descriptions modulate reading speed!". AB - In the present study, we investigated whether the semantic content of a dialogue description can affect reading times on an embedded quote, to determine whether the speed at which a character is described as saying a quote influences how quickly it is read. Yao and Scheepers (Cognition, 121:447-453, 2011) previously found that readers were faster to read direct quotes when the preceding context implied that the talker generally spoke quickly, an effect attributed to perceptual simulation of talker speed. For the present study, we manipulated the speed of a physical action performed by the speaker independently from character talking rate to determine whether these sources have separable effects on perceptual simulation of a direct quote. The results showed that readers spent less time reading direct quotes described as being said quickly, as compared to those described as being said slowly (e.g., John walked/bolted into the room and said energetically/nonchalantly, "I finally found my car keys."), an effect that was not present when a nearly identical phrase was presented as an indirect quote (e.g., John . . . said energetically that he finally found his car keys.). The speed of the character's movement did not affect direct-quote reading times. Furthermore, fast adverbs were themselves read significantly faster than slow adverbs, an effect that we attribute to implicit effects on the eye movement program stemming from automatically activated semantic features of the adverbs. Our findings add to the literature on perceptual simulation by showing that these effects can be instantiated with only a single adverb and are strong enough to override the effects of global sentence speed. PMID- 22927028 TI - Predominant role of PDGF receptor transactivation in Wnt3a-induced osteoblastic cell proliferation. AB - Previous studies have shown that Wnt3a enhances the proliferation and inhibits the osteogenic differentiation of human mesenchymal stem cells (hMSCs). In this study, we investigated the signaling pathways involved in Wnt3a-induced osteoblastic cell proliferation. Experiments with DKK1, a natural antagonist of Lrp5/6, indicated that Wnt/beta-catenin did not play a major role in Wnt3a induced osteoblastic cell proliferation. The use of selective inhibitors of known mitogenic pathways implicates Src family kinases (SFKs) and a protein kinase C (PKC) in this cellular response. Time-dependent analysis of signaling molecules activated by Wnt3a in MC3T3-E1 cells revealed parallel activation of the canonical pathway and of several tyrosine kinases, including SFKs and PDGF receptors (PDGF-Rs). Functional analysis with specific inhibitors suggested a major role of PDGF-Rs in mediating Wnt3a-induced cell proliferation. Further investigation with an si-RNA approach confirmed a predominant role of this receptor in this cellular response. The use of soluble decoy PDGF-Rs that can sequester extracellular PDGFs excluding that part of the increased PDGF receptor phosphorylation by Wnt3a was the result of autocrine production of PDGFs. A selective SFK inhibitor blunted the enhanced PDGF-R phosphorylation and cell proliferation induced by Wnt3a. Studies of initial events involved in the regulation of this pathway suggest a role of dishevelled. In conclusion, data presented in this study indicate that cell proliferation induced by Wnt3a in osteoblastic cells is mediated by a dishevelled-dependent and beta-catenin independent pathway, which involves the transactivation of PDGF receptors. PMID- 22927031 TI - Interindividual variation in transdermal and oral drug deliveries. AB - It is generally assumed that the topical absorption of drugs is subject to more interindividual variation than the oral absorption of drugs. To date, we are unaware of any clinical studies or meta-analyses that compare the interindividual variation of transdermal and oral drug deliveries for a large number of medications. In this research article, the absorption data for 10 medications that can be used as an oral medication or a transdermal patch were compiled, and from the collected data, the interindividual variance was calculated for topical and oral absorption as an overall average and by drug. This research article also briefly reviews the pharmacokinetics and pharmacodynamics of transdermal and oral drug absorption. Our results indicate that there is considerable interindividual variation in topical and oral absorption for the 10 medications investigated. Yet, surprisingly, the calculated overall mean and median coefficient of variation (CV) for topical and oral absorption were comparable (within 10% of each other). Therefore, the interindividual variation in topical and oral absorption may not be as divergent as assumed previously. In a drug-by-drug comparison, certain medications demonstrated considerably more variation when absorbed orally versus topically and vice versa. It is unclear why certain drugs had less variation in absorption when delivered topically versus orally (or vice versa). However, patterns in drug molecular weight (MW) or octanol partition coefficient (log K(OCT) ) could not totally explain these findings. In our analysis, the previously reported correlation between MW or log K(OCT) and interindividual variation in absorption could only be replicated when plotting the topical absorption CV and MW. What became clear from our analysis is that the drug itself is an important variable when considering which route of delivery (oral or topical) will provide the least amount of interindividual variation. Our study had many limitations because of study design, which may have affected our calculations and conclusions. Further experimentation is needed to support and reveal the basic science of skin or drug chemistry that can further explain these findings. PMID- 22927032 TI - Characterization of Lactobacillus brevis L62 strain, highly tolerant to copper ions. AB - Lactic acid bacteria (LAB) as starter culture in food industry must be suitable for large-scale industrial production and possess the ability to survive in unfavorable processes and storage conditions. Approaches taken to address these problems include the selection of stress-resistant strains. In food industry, LAB are often exposed to metal ions induced stress. The interactions between LAB and metal ions are very poorly investigated. Because of that, the influence of non toxic, toxic and antioxidant metal ions (Zn, Cu, and Mn) on growth, acid production, metal ions binding capacity of wild and adapted species of Leuconostoc mesenteroides L3, Lactobacillus brevis L62 and Lactobacillus plantarum L73 were investigated. The proteomic approach was applied to clarify how the LAB cells, especially the adapted ones, protect themselves and tolerate high concentrations of toxic metal ions. Results have shown that Zn and Mn addition into MRS medium in the investigated concentrations did not have effect on the bacterial growth and acid production, while copper ions were highly toxic, especially in static conditions. Leuc. mesenteroides L3 was the most efficient in Zn binding processes among the chosen LAB species, while L. plantarum L73 accumulated the highest concentration of Mn. L. brevis L62 was the most copper resistant species. Adaptation had a positive effect on growth and acid production of all species in the presence of copper. However, the adapted species incorporated less metal ions than the wild species. The exception was adapted L. brevis L62 that accumulated high concentration of copper ions in static conditions. The obtained results showed that L. brevis L62 is highly tolerant to copper ions, which allows its use as starter culture in fermentative processes in media with high concentration of copper ions. PMID- 22927033 TI - Circulating microRNAs in plasma as early detection markers for breast cancer. AB - In recent years, circulating miRNAs have attracted a great deal of attention as promising novel markers for various diseases. Here, we investigated their potential to serve as minimally invasive, early detection markers for breast cancer in blood plasma. We profiled miRNAs extracted from the plasma of early stage breast cancer patients (taken at the time-point of diagnosis) and healthy control individuals using TaqMan low-density arrays (TLDA). Selected candidates identified in the initial screen were further validated in an extended study cohort of 207 individuals including 127 sporadic breast cancer cases and 80 healthy controls via RT-qPCR. Four miRNAs (miR-148b, miR-376c, miR-409-3p and miR 801) were shown to be significantly upregulated in the plasma of breast cancer patients. ROC curve analysis showed that the combination of only three miRNAs (miR-148b, miR-409-3p and miR-801) had an equal discriminatory power between breast cancer cases and healthy controls as all four miRNAs together (AUC = 0.69). In conclusion, the identified miRNAs might be of potential use in the development of a multimarker blood-based test to complement and improve early detection of breast cancer. Such a multimarker blood test might for instance provide a prescreening tool, especially for younger women, to facilitate decisions about which individuals to recommend for further diagnostic tests. PMID- 22927034 TI - Hydrothermal reaction kinetics and pathways of phenylalanine alone and in binary mixtures. AB - We examined the behavior of phenylalanine in high-temperature water (HTW) at 220, 250, 280, and 350 degrees C. Under these conditions, the major product is phenylethylamine. The minor products include styrene and phenylethanol (1 phenylethanol and 2-phenylethanol), which appear at higher temperatures and longer batch holding times. Phenylethylamine forms via decarboxylation of phenylalanine, styrene forms via deamination of phenylethylamine, and phenylethanol forms via hydration of styrene. We quantified the molar yields of each product at the four temperatures, and the carbon recovery was between 80-100 % for most cases. Phenylalanine disappearance follows first-order kinetics with an activation energy of 144 +/- 14 kJ mol-1 and a pre-exponential factor of 10(12.4 +/- 1.4) min-1. A kinetics model based on the proposed pathways was consistent with the experimental data. Effects of five different salts (NaCl, NaNO3, Na2 SO4, KCl, K2 HPO4) and boric acid (H3BO3) on phenylalanine behavior at 250 degrees C have also been elucidated. These additives increase phenylalanine conversion, but decrease the yield of phenylethylamine presumably by promoting formation of high molecular weight compounds. Lastly, binary mixtures of phenylalanine and ethyl oleate have been studied at 350 degrees C and three different molar concentration ratios. The presence of phenylalanine enhances the conversion of ethyl oleate and molar yields of fatty acid. Higher concentration of ethyl oleate leads to increased deamination of phenylethylamine and hydration of styrene. Amides are also formed due to the interaction of oleic acid/ethyl oleate and phenylethylamine/ammonia and lead to a decrease in the fatty acid yields. Taken collectively, these results provide new insights into the reactions of algae during its hydrothermal liquefaction to produce crude bio-oil. PMID- 22927036 TI - Enantioselective organocatalytic one-pot amination/aza-Michael/aldol condensation reaction sequence: synthesis of 3-pyrrolines with a quaternary stereocenter. AB - Primary amine-catalyzed direct conversion of alpha,alpha-disubstituted aldehydes into 3-pyrrolines with a quaternary stereocenter is reported. The one-pot enantioselective sequence is based on a alpha-amination, an aza-Michael addition of hydrazine, an aldol condensation dehydratation and proceeds with good yields and excellent levels of enantioselectivity. Synthetically attractive applications including the formation of aziridinopyrrolidine or epoxypyrrolidine derivatives with good yields and selectivities are also described. PMID- 22927035 TI - Functional and molecular aspects of biotin uptake via SMVT in human corneal epithelial (HCEC) and retinal pigment epithelial (D407) cells. AB - Sodium-dependent multivitamin transporter (SMVT) is a vital transmembrane protein responsible for translocating biotin and other essential cofactors such as pantothenate and lipoate. Unlike primary cultures of corneal and retinal pigment epithelial (RPE) cells, immortalized cells can be subcultured many times, yet maintain their physiological properties. Hence, the purpose of this study was to delineate the functional and molecular aspects of biotin uptake via SMVT on immortalized human corneal epithelial (HCEC) and RPE (D407) cells. Functional aspects of [(3)H] biotin uptake were studied in the presence of different concentrations of unlabeled biotin, pH, temperature, metabolic inhibitors, ions, substrates, structural analogs and biotinylated prodrug (Biotin-Acyclovir (B ACV)). Molecular identity of SMVT was examined with reverse transcription polymerase chain reaction. Biotin uptake was found to be saturable in HCEC and D407 cells with K (m) of 296.2 +/- 25.9 and 863.8 +/- 66.9 MUM and V (max) of 77.2 +/- 2.2 and 308.3 +/- 10.7 pmol/mg protein/min, respectively. Uptake was found to be pH, temperature, energy, and sodium-dependent. Inhibition of biotin uptake was observed in the presence of structural analogs and specific substrates. Further, uptake was lowered in the presence of B-ACV indicating the translocation of biotinylated prodrug by SMVT. A distinct band at 774 bp confirmed the molecular existence of SMVT in both the cells. This study shows for the first time the functional and molecular presence of SMVT in HCEC and D407 cells. Therefore, these cell lines may be utilized as in vitro models to study the cellular translocation of biotin-conjugated prodrugs. PMID- 22927037 TI - Characterization of periodic upper limb movement disorder in a patient with restless arms syndrome. AB - BACKGROUND: Restless legs syndrome (RLS) and the frequently associated periodic limb movements (PLM) are common neurological disorders whose pathophysiology remains elusive. We report on the case of a 40-year-old patient presenting with severe restlessness in the upper limbs, a poorly known variant of RLS. CASE REPORT: Video-polysomnography was performed because of the associated poor sleep quality and daytime sleepiness evocative of PLM. An electromyogram of the extensor carpi radialis muscle was added. Remarkably, our patient had movements of repeated extension of the small finger that contrasted with the extension of the hallux, characteristic for PLM. Pramipexol was an effective treatment relieving the patient's upper limbs of discomfort and ameliorating her restless sleep. CONCLUSIONS: Involvement of the upper limbs in RLS is relatively common, but restlessness may be located on the upper limbs solely. One should be aware of the upper limb variant, and that treatment by dopaminergic agonists proves to be very efficient. PMID- 22927038 TI - Exploratory analysis of estimated acoustic peak rarefaction pressure, recanalization, and outcome in the transcranial ultrasound in clinical sonothrombolysis trial. AB - PURPOSE: Acoustic peak rarefaction pressure (APRP) is the main factor that influences ultrasound-enhanced thrombolysis. We sought to determine whether recanalization rate and functional outcomes in the Transcranial Ultrasound in Clinical SONothrombolysis (TUCSON) trial could be predicted by estimated in vivo APRP. METHODS: We developed an acoustic attenuation model to estimate the in vivo APRP at the arterial occlusion site in each subject of the TUCSON trial with CT scans eligible for measurements. Variables included temporal bone thickness, depth of arterial occlusion site, and average attenuation of skin and brain tissues. Recanalization was defined as partial or complete using the Thrombolysis in Brain Infarction flow grades. Functional independence was assessed at 3 months using the modified Rankin Scale score (mRS, 0-1). RESULTS: APRP was calculated in 20 acute ischemic stroke patients treated with sonothrombolysis (mean age, 64 +/- 15 years, 65% men; median NIHSS score, 13; IQR, 6-17). The mean APRP was 30.2 +/- 15.5 kPa (range, 8-68 kPa). Patients with persisting occlusion had nonsignificantly lower APRP than patients with partial or complete recanalization (25.2 +/- 8.0 versus 32.3 +/- 17.7 kPa; p = 0.228). Patients who were functionally independent at 3 months had nonsignificantly higher APRP than patients with worse outcome (35.1 +/- 19.5 versus 25.9 +/- 11.2 kPa; p = 0.217). CONCLUSIONS: Our exploratory analysis suggests a potentially important role of successful energy delivery to augment thrombolysis with 2-MHz ultrasound in acute ischemic stroke patients. PMID- 22927040 TI - Genistein affects ovarian folliculogenesis: a stereological study. AB - The effects of short-term genistein exposure on ovarian folliculogenesis in immature rats were examined stereologically. To determine whether genistein acts as an estrogen agonist or antagonist, the results were compared with the effects of 17alpha-ethynylestradiol. Immature female rats received 50 mg/kg/bw of genistein in dimethyl sulfoxide subcutaneously daily for three consecutive days from 18 to 20 days. The second group was injected with 1 MUg/kg/bw of 17alpha ethynylestradiol in olive oil in the same schedule. Each group had a corresponding control. Genistein increased ovary and ovarian stroma volumes by 18.50% (P < 0.05) and 53.40% (P < 0.05), respectively, and changed the parenchyma to stroma ratio in favor of stroma. Genistein induced decreases in the number of primordial (by 17.23%; P < 0.05), primary (16.62%; P < 0.05), and secondary follicles (12.29%: P < 0.05), whereas the number of atretic secondary follicles increased (5.10-fold; P < 0.05). The number of healthy large follicles was raised by 27.3% (P < 0.05), accompanied by 35.64% more atretic large follicles (P < 0.05). Similarly to genistein, estradiol changed the parenchyma to stroma ratio in favor of stroma, and reduced the number of primordial follicles, but the number of primary follicles was elevated. There were more healthy and atretic small and large follicles. In conclusion, genistein acted as an estrogen antagonist and had an inhibitory effect on the initial phase of folliculogenesis. In the other phases, genistein acted as an estrogen agonist, stimulating transition from the preantral to antral stage of folliculogenesis, and altering the ratio of follicular parenchyma and ovarian stroma in favor of stroma. PMID- 22927041 TI - Forming tertiary organolithiums and organocuprates from nitrile precursors and their bimolecular reactions with carbon electrophiles to form quaternary carbon stereocenters. PMID- 22927039 TI - Pathogenesis of ANCA-associated vasculitis. AB - Antineutrophil cytoplasmic autoantibodies (ANCA)-associated vasculitides (AAV) are a group of systemic vasculitis syndromes characterized by inflammation and necrosis of blood vessel walls. Genetic, epigenetic, and environmental factors contribute to the etiology and pathogenesis of AAV. On the basis of currently available clinical and experimental evidence, it is reasonable to believe that, in predisposed patients, different triggers can lead to the production of autoantibodies (ANCA) that, in the context of an inflammatory environment, can cause tissue inflammation and vascular injury. Several different pathways and mechanisms in the pathogenesis of AAV are described in this contemporary review. PMID- 22927042 TI - High yield isolation of BMP-2 from bone and in vivo activity of a combination of BMP-2/TGF-beta1. AB - A high-yield purification procedure for protein fractions derived from porcine bone matrix extracts is described, which has a high abundance of bone morphogenetic protein-2 (BMP-2). Naturally derived pBMP-2, ~5 MUg per kilogram of porcine bone matrix, was isolated by using a 300 kDa membrane before chromatographic processing on heparin affinity media. The elution of pBMP-2 and transforming growth factor-beta(1) (TGF-beta(1)) revealed morphogen peaks that were unresolved on Prosep((r)) medium, but resolved on hydroxyapatite medium. Antagonism was observed in animal studies when the two proteins were combined in specific doses. The TGF-beta(1) fraction alone was not active in the rodent heterotopic in vivo bioassay, confirming previously obtained results. PMID- 22927043 TI - Transcatheter closure of a large ASD from the femoral vein in a patient with Budd Chiari syndrome. AB - Anomalies of the inferior vena cava are rare in patients with isolated atrial septal defect (ASD). When present, they usually preclude successful transcatheter closure of the ASD using the femoral route. We report a case of a large secundum ASD in a 3-year-old child, who had a chronic Budd-Chiari syndrome incidentally detected on the cardiac catheterization table. We were able to successfully deploy the device from the femoral route itself using a collateral channel to reach the heart and then using the pulmonary vein deployment technique to successfully close the defect. PMID- 22927044 TI - G protein regulator 1 (GPR-1) localizes to cortical sites of artificial mechanical indentation in Caenorhabditis elegans zygotes. AB - Cytokinesis and spindle positioning require the cortical force regulator G Protein Regulator 1/2 (GPR-1/2). GPR-1/2 is thought to localize to sites of cortical force generation. Does GPR-1/2 also act as a sensor for mechanical stimulation? I mechanically stimulated the cortex by indenting it with a glass needle and observed the cortical localization of a YFP::GPR-1 transgene. I found that cortical YFP::GPR-1 accumulated at the site of mechanical indentation. This phenomenon occurred on most of the cortical areas except the site of prospective cytokinesis furrow formation. This result suggests that GPR-1/2 can sense mechanical properties of the cortex, which may be important for GPR-1/2 function regulating spindle positioning and cytokinesis. PMID- 22927045 TI - Host and bacterial phenotype variation in adhesion of Streptococcus mutans to matched human hosts. AB - The commensal pathogen Streptococcus mutans uses AgI/II adhesins to adhere to gp340 adsorbed on teeth. Here we analyzed isolates of S. mutans (n = 70 isolates) from caries and caries-free human extremes (n = 19 subjects) by multilocus sequence typing (MLST), AgI/II full-length gene sequencing, and adhesion to parotid saliva matched from the strain donors (nested from a case-control sample of defined gp340 and acidic proline-rich protein [PRP] profiles). The concatenated MLST as well as AgI/II gene sequences showed unique sequence types between, and identical types within, the subjects. The matched adhesion levels ranged widely (40% adhesion range), from low to moderate to high, between subjects but were similar within subjects (or sequence types). In contrast, the adhesion avidity of the strains was narrow, normally distributed for high, moderate, or low adhesion reference saliva or pure gp340 regardless of the sequence type. The adhesion of S. mutans Ingbritt and matched isolates and saliva samples correlated (r = 0.929), suggesting that the host specify about four fifths (r(2) = 0.86) of the variation in matched adhesion. Half of the variation in S. mutans Ingbritt adhesion to saliva from the caries cases-controls (n = 218) was explained by the primary gp340 receptor and PRP coreceptor composition. The isolates also varied, although less so, in adhesion to standardized saliva (18% adhesion range) and clustered into three major AgI/II groups (groups A, B(1), and B(2)) due to two variable V-region segments and diverse AgI/II sequence types due to a set of single-amino-acid substitutions. Isolates with AgI/II type A versus types B(1) and B(2) tended to differ in gp340 binding avidity and qualitative adhesion profiles for saliva gp340 phenotypes. In conclusion, the host saliva phenotype plays a more prominent role in S. mutans adhesion than anticipated previously. PMID- 22927046 TI - Mannose-capped Lipoarabinomannan from Mycobacterium tuberculosis induces soluble tumor necrosis factor receptor production through tumor necrosis factor alpha converting enzyme activation. AB - Primary Mycobacterium tuberculosis infection results in granuloma formation in lung tissue. A granuloma encapsulates mycobacterium-containing cells, thereby preventing dissemination and further infection. Tumor necrosis factor alpha (TNF alpha) is a host-protective cytokine during M. tuberculosis infection due to its role in promoting and sustaining granuloma formation. TNF activity is regulated through the production of soluble TNF receptors (sTNFRI and sTNFRII). Therefore, we examined the potential production of endogenous sTNFRs during M. tuberculosis infection. Using the murine model of aerosol M. tuberculosis infection, we determined that levels of sTNFR production were elevated in bronchoalveolar lavage fluid 1 month following infection. An investigation of M. tuberculosis cell wall components identified that the known virulence factor mannose-capped lipoarabinomannan (ManLAM) was sufficient to induce sTNFR production, with sTNFRII being produced preferentially compared with sTNFRI. ManLAM stimulated the release of sTNFRs without TNF production, which corresponded to an increase in TNF-alpha-converting enzyme (TACE) activity. To determine the relevance of these findings, serum samples from M. tuberculosis-infected patients were tested and found to have an increase in the sTNFRII/sTNFRI ratio. These data identify a mechanism by which M. tuberculosis infection can promote the neutralization of TNF and furthermore suggest the potential use of the sTNFRII/sTNFRI ratio as an indicator of tuberculosis disease. PMID- 22927047 TI - Comparative transcriptomic and proteomic analyses of Trichomonas vaginalis following adherence to fibronectin. AB - The morphological transformation of Trichomonas vaginalis from an ellipsoid form in batch culture to an adherent amoeboid form results from the contact of parasites with vaginal epithelial cells and with immobilized fibronectin (FN), a basement membrane component. This suggests host signaling of the parasite. We applied integrated transcriptomic and proteomic approaches to investigate the molecular responses of T. vaginalis upon binding to FN. A transcriptome analysis was performed by using large-scale expressed-sequence-tag (EST) sequencing. A total of 20,704 ESTs generated from batch culture (trophozoite-EST) versus FN amoeboid trichomonad (FN-EST) cDNA libraries were analyzed. The FN-EST library revealed decreased amounts of transcripts that were of lower abundance in the trophozoite-EST library. There was a shift by FN-bound organisms to the expression of transcripts encoding essential proteins, possibly indicating the expression of genes for adaptation to the morphological changes needed for the FN adhesive processes. In addition, we identified 43 differentially expressed proteins in the proteomes of FN-bound and unbound trichomonads. Among these proteins, cysteine peptidase, glyceraldehyde-3-phosphate dehydrogenase (an FN binding protein), and stress-related proteins were upregulated in the FN-adherent cells. Stress-related genes and proteins were highly expressed in both the transcriptome and proteome of FN-bound organisms, implying that these genes and proteins may play critical roles in the response to adherence. This is the first report of a comparative proteomic and transcriptomic analysis after the binding of T. vaginalis to FN. This approach may lead to the discovery of novel virulence genes and affirm the role of genes involved in disease pathogenesis. This knowledge will permit a greater understanding of the complex host-parasite interplay. PMID- 22927048 TI - The alveolar epithelial cell chemokine response to pneumocystis requires adaptor molecule MyD88 and interleukin-1 receptor but not toll-like receptor 2 or 4. AB - Pneumocystis is an opportunistic fungal pathogen that causes pneumonia in a variety of clinical settings. An early step in Pneumocystis infection involves the attachment of organisms to alveolar epithelial cells (AECs). AECs produce chemokines in response to Pneumocystis stimulation, but the upstream host pathogen interactions that activate AEC signaling cascades are not well-defined. MyD88 is an adaptor molecule required for activation of proinflammatory signaling cascades following Toll-like receptor (TLR)-dependent recognition of conserved molecular patterns on pathogens. To determine whether the TLR/MyD88 pathway is required for the AEC chemokine response to Pneumocystis, wild-type (WT) and MyD88 deficient AECs were incubated with Pneumocystis. As expected, WT AECs produced CCL2 and CXCL2 following Pneumocystis stimulation. In contrast, MyD88-deficient AECs were severely impaired in their ability to respond to Pneumocystis. MyD88 deficient AECs did not display Pneumocystis-induced Jun N-terminal protein kinase activation and produced much less chemokine than Pneumocystis-stimulated WT AECs. Using a panel of TLR agonists, primary murine AECs were found to respond vigorously to TLR2 and TLR4 agonists. However, the AEC chemokine response to Pneumocystis did not require TLR2 or TLR4. Surprisingly, the interleukin-1 receptor (IL-1R) was required for an AEC chemokine response to Pneumocystis. The role of MyD88 in early responses during Pneumocystis infection was supported by in vivo studies demonstrating that MyD88-deficient mice showed impaired Pneumocystis-stimulated chemokine production and impaired inflammatory cell recruitment. These data indicate an important role for MyD88 in the AEC inflammatory response to Pneumocystis. PMID- 22927049 TI - The Yfe and Feo transporters are involved in microaerobic growth and virulence of Yersinia pestis in bubonic plague. AB - The Yfe/Sit and Feo transport systems are important for the growth of a variety of bacteria. In Yersinia pestis, single mutations in either yfe or feo result in reduced growth under static (limited aeration), iron-chelated conditions, while a yfe feo double mutant has a more severe growth defect. These growth defects were not observed when bacteria were grown under aerobic conditions or in strains capable of producing the siderophore yersiniabactin (Ybt) and the putative ferrous transporter FetMP. Both fetP and a downstream locus (flp for fet linked phenotype) were required for growth of a yfe feo ybt mutant under static, iron limiting conditions. An feoB mutation alone had no effect on the virulence of Y. pestis in either bubonic or pneumonic plague models. An feo yfe double mutant was still fully virulent in a pneumonic plague model but had an ~90-fold increase in the 50% lethal dose (LD(50)) relative to the Yfe(+) Feo(+) parent strain in a bubonic plague model. Thus, Yfe and Feo, in addition to Ybt, play an important role in the progression of bubonic plague. Finally, we examined the factors affecting the expression of the feo operon in Y. pestis. Under static growth conditions, the Y. pestis feo::lacZ fusion was repressed by iron in a Fur dependent manner but not in cells grown aerobically. Mutations in feoC, fnr, arcA, oxyR, or rstAB had no significant effect on transcription of the Y. pestis feo promoter. Thus, the factor(s) that prevents repression by Fur under aerobic growth conditions remains to be identified. PMID- 22927051 TI - Neutrophil extracellular traps exhibit antibacterial activity against burkholderia pseudomallei and are influenced by bacterial and host factors. AB - Burkholderia pseudomallei is the causative pathogen of melioidosis, of which a major predisposing factor is diabetes mellitus. Polymorphonuclear neutrophils (PMNs) kill microbes extracellularly by the release of neutrophil extracellular traps (NETs). PMNs play a key role in the control of melioidosis, but the involvement of NETs in killing of B. pseudomallei remains obscure. Here, we showed that bactericidal NETs were released from human PMNs in response to B. pseudomallei in a dose- and time-dependent manner. B. pseudomallei-induced NET formation required NADPH oxidase activation but not phosphatidylinositol-3 kinase, mitogen-activated protein kinases, or Src family kinase signaling pathways. B. pseudomallei mutants defective in the virulence-associated Bsa type III protein secretion system (T3SS) or capsular polysaccharide I (CPS-I) induced elevated levels of NETs. NET induction by such mutants was associated with increased bacterial killing, phagocytosis, and oxidative burst by PMNs. Taken together the data imply that T3SS and the capsule may play a role in evading the induction of NETs. Importantly, PMNs from diabetic subjects released NETs at a lower level than PMNs from healthy subjects. Modulation of NET formation may therefore be associated with the pathogenesis and control of melioidosis. PMID- 22927050 TI - Leptospira interrogans catalase is required for resistance to H2O2 and for virulence. AB - Pathogenic Leptospira spp. are likely to encounter higher concentrations of reactive oxygen species induced by the host innate immune response. In this study, we characterized Leptospira interrogans catalase (KatE), the only annotated catalase found within pathogenic Leptospira species, by assessing its role in resistance to H(2)O(2)-induced oxidative stress and during infection in hamsters. Pathogenic L. interrogans bacteria had a 50-fold-higher survival rate under H(2)O(2)-induced oxidative stress than did saprophytic L. biflexa bacteria, and this was predominantly catalase dependent. We also characterized KatE, the only annotated catalase found within pathogenic Leptospira species. Catalase assays performed with recombinant KatE confirmed specific catalase activity, while protein fractionation experiments localized KatE to the bacterial periplasmic space. The insertional inactivation of katE in pathogenic Leptospira bacteria drastically diminished leptospiral viability in the presence of extracellular H(2)O(2) and reduced virulence in an acute-infection model. Combined, these results suggest that L. interrogans KatE confers in vivo resistance to reactive oxygen species induced by the host innate immune response. PMID- 22927052 TI - Cathelicidin antimicrobial peptide expression is not induced or required for bacterial clearance during salmonella enterica infection of human monocyte derived macrophages. AB - Salmonella enterica serovar Typhimurium is able to resist antimicrobial peptide killing by induction of the PhoP-PhoQ and PmrA-PmrB two-component systems and the lipopolysaccharide (LPS) modifications they mediate. Murine cathelin-related antimicrobial peptide (CRAMP) has been reported to inhibit S. Typhimurium growth in vitro and in vivo. We hypothesize that infection of human monocyte-derived macrophages (MDMs) with Salmonella enterica serovar Typhi and S. Typhimurium will induce human cathelicidin antimicrobial peptide (CAMP) production, and exposure to LL-37 (processed, active form of CAMP/hCAP18) will lead to upregulation of PmrAB-mediated LPS modifications and increased survival in vivo. Unlike in mouse macrophages, in which CRAMP is upregulated during infection, camp gene expression was not induced in human MDMs infected with S. Typhi or S. Typhimurium. Upon infection, intracellular levels of DeltaphoPQ, DeltapmrAB, and PhoP(c) S. Typhi decreased over time but were not further inhibited by the vitamin D(3)-induced increase in camp expression. MDMs infected with wild-type (WT) S. Typhi or S. Typhimurium released similar levels of proinflammatory cytokines; however, the LPS modification mutant strains dramatically differed in MDM-elicited cytokine levels. Overall, these findings indicate that camp is not induced during Salmonella infection of MDMs nor is key to Salmonella intracellular clearance. However, the cytokine responses from MDMs infected with WT or LPS modification mutant strains differ significantly, indicating a role for LPS modifications in altering the host inflammatory response. Our findings also suggest that S. Typhi and S. Typhimurium elicit different proinflammatory responses from MDMs, despite being capable of adding similar modifications to their LPS structures. PMID- 22927053 TI - Palladium-catalyzed carbonylation reaction of aryl bromides with 2 hydroxyacetophenones to form flavones. AB - Flavone of the month: a general and efficient method for the palladium-catalyzed carbonylative synthesis of flavones has been developed. Starting from aryl bromides and 2-hydroxyacetophenones, the corresponding flavones have been isolated in good yields. PMID- 22927054 TI - Methylsulfonyl polychlorinated biphenyls in fish from an electronic waste recycling site in South China: levels, congener profiles, and chiral signatures. AB - Great concerns have been raised about the fate and effects of polychlorinated biphenyls (PCBs) and other organic contaminants contained in electronic waste (e waste) exported from industrialized countries at midlatitudes to subtropical and tropical regions. Information on the metabolites of these chemicals, for example, methylsulfonyl-PCBs (MeSO(2)-PCBs) in wildlife from the later regions is scarce. In the present study, 17 MeSO(2)-PCBs, including five chiral congeners, were detected in the muscle, liver, and brain tissues of two benthic fish species- northern snakehead and mud carp--from a small pond near an electronic waste recycling site in South China. The mean concentrations of the sum of the MeSO(2) PCBs ranged from 80 to 340 ng/g lipid weight in the tissues, with relative higher levels in the liver than the muscle and brain tissues. These levels were one order of magnitude greater than the highest levels of MeSO(2)-PCBs previously reported in fish. The 3'-MeSO(2)-CB 87, 3'- and 4'-MeSO(2)-CB 101, 4-MeSO(2)-CB 110, and 4-MeSO(2)-CB 149 were dominant, collectively comprising more than 55% of the total MeSO(2)-PCBs. Except for 4-MeSO(2)-CB149, all of the investigated chiral MeSO(2)-PCBs displayed a clear, congener-specific enantiomeric enrichment in the tissues. No tissue-specific enantioselective retention of the enantiomers was observed in the investigated fish. This is the first report on chiral signatures of MeSO(2)-PCBs in fish tissues. PMID- 22927056 TI - Evaluation of effects of Fc domain high-mannose glycan on antibody stability. AB - Elevated levels of CH2 domain N-linked high-mannose (HM) glycans are commonly observed in therapeutic monoclonal antibodies at various stages of the development. The effect of HM glycans on antibody stability was evaluated by using two approaches. In the first approach, immunoglobulin G (IgG) 1 material containing 21% HM was incubated at 29 degrees C for 6 weeks and fractionated into monomeric and aggregate species by using size-exclusion chromatography (SEC). These fractions were analyzed for the levels of HM. No significant difference was observed in the amount of HM in aggregate and monomer fractions indicating that the HM-containing fractions did not have a greater tendency to form aggregates. In the second approach, both IgG1 material and IgG2 material were separated by Concanavalin-A affinity chromatography into a HM-enriched fraction and a HM depleted fraction, respectively. Real-time and accelerated stability studies were carried out with these fractions together with untreated samples under standard formulation conditions. The stability of these fractions over time was monitored using SEC and cation-exchange chromatography. No significant difference was observed in rates of aggregation or charge variant formation. These data indicate that HM glycans had no effect on the IgG1 and IgG2 product's stability under the formulation conditions studied. PMID- 22927055 TI - Extrarenal perivascular epithelioid cell tumors (PEComas) respond to mTOR inhibition: clinical and molecular correlates. AB - Perivascular epithelioid cell tumors (PEComas) are a group of rare mesenchymal tumors that typically show both melanocytic and smooth muscle cell features. Some types of PEComa are seen at high frequency in tuberous sclerosis complex (TSC). The TSC1 and TSC2 genes are commonly mutated in both TSC-associated and sporadic PEComas, and mTOR signaling pathway activation is also common in these tumors. Preliminary reports have indicated that the mTOR inhibitors sirolimus and related drugs have activity in some patients with non-TSC-associated PEComa. Here, we report on the use of these medications in the treatment of five consecutive patients with extrarenal nonpulmonary PEComas seen at one institution. Three complete responses, one partial response and one case of progression were seen. Molecular studies identified TSC2 aberrations in four of these patients, and TFE3 translocation was excluded in the resistant case. A review of all published cases as well as those reported here indicates that partial or complete response was seen in 6 of 11 PEComas, with 5 of 6 having a complete response. These findings highlight the consistent though incomplete activity of mTOR inhibitors in the treatment of PEComas. PMID- 22927057 TI - Fusion of [(18)F]FDG PET with fluorescence diffuse optical tomography to improve validation of probes and tumor imaging. AB - PURPOSE: Given the progress of fluorescence diffuse optical tomography (fDOT) technology, here, we study the additional benefits provided by multimodal PET/fDOT imaging by comparing the biodistribution of 2-deoxy-2-[(18)F]fluoro-D glucose ([(18)F]FDG) in tumors with three fluorescent probes: a glucose analog, a protease activatable optical probe, and a ligand of alphavbeta3 integrin. PROCEDURES: Sequential fDOT/PET/computed tomography (CT) imaging of mice was performed with a custom multimodal mouse support that allows the subject to be transferred between the fDOT and the PET/CT scanners. Experiments were performed in xenografted tumor models derived from the human breast cancer line MDA-MB 231 and compared to ex vivo analysis. RESULTS: The three-dimensional signals showed that the fluorescent glucose analog is not colocalized with [(18)F]FDG, raising questions about its use as a surrogate probe of the PET tracer. Fusion of [(18)F]FDG with the other fluorescent probes showed evidence of high variability both for the protease activity and the alphavbeta3 integrin expression during tumor growth. CONCLUSION: The added value of hybrid PET/fDOT over the two modalities was demonstrated for cross-validation of probes and for better characterization of tumor models. PMID- 22927058 TI - Photocatalytic and photoelectrochemical water oxidation over metal-doped monoclinic BiVO(4) photoanodes. AB - The visible-light-induced water oxidation ability of metal-ion-doped BiVO(4) was investigated and of 12 metal ion dopants tested, only W and Mo dramatically enhanced the water photo-oxidation activity of bare BiVO(4); Mo had the highest improvement by a factor of about six. Thus, BiVO(4) and W- or Mo-doped (2 atom %) BiVO(4) photoanodes about 1 MUm thick were fabricated onto transparent conducting substrate by a metal-organic decomposition/spin-coating method. Under simulated one sun (air mass 1.5G, 100 mW cm(-2)) and at 1.23 V versus a reversible hydrogen electrode, the highest photocurrent density (J(PH)) of about 2.38 mA cm(-2) was achieved for Mo doping followed by W doping (J(PH) ~ 1.98 mA cm(-2)), whereas undoped BiVO(4) gave a J(PH) value of about 0.42 mA cm(-2). The photoelectrochemical water oxidation activity of W- and Mo-doped BiVO(4) photoanodes corresponded to the incident photon to current conversion efficiency of about 35 and 40 % respectively. Electrochemical impedance spectroscopy and Mott-Schottky analysis indicated a positive flat band shift of about 30 mV, a carrier concentration 1.6-2 times higher, and a charge-transfer resistance reduced by 3-4-fold for W- or Mo-doped BiVO(4) relative to undoped BiVO(4). Electronic structure calculations revealed that both W and Mo were shallow donors and Mo doping generated superior conductivity to W doping. The photo-oxidation activity of water on BiVO(4) photoanodes (undoped 1.3). Diploid T1a,b cancers were associated with negative lymph node status (p = 0.003). Among aneuploid cancers only low-hyperploid tumors were associated with positive lymph node status (p = 0.03). The histopathological features of low-hyperploid group of T1a,b cancers did not differ from the other three ploidy groups of cancers, except for lower S-phase fraction of tumor cells in low-hyperploid group compared to high-hyperploid group (p = 0.01). Our data showed that near-diploid hyperploid T1a,b cancers are associated with higher risk of lymph node involvement despite similar clinicopathological features shared with other ploidy classes of T1a,b tumors. PMID- 22927064 TI - Sham surgery controls in Parkinson's disease clinical trials: views of participants. AB - BACKGROUND: Sham surgery controls are increasingly used in neurosurgical clinical trials in Parkinson's disease (PD) but remain controversial. We interviewed participants of such trials, specifically examining their understanding and attitudes regarding sham surgery. METHODS: We conducted semistructured qualitative interviews with participants of 3 sham surgery-controlled trials for PD, focusing on their understanding of sham design, their reactions to it, its impact on decision making, and their understanding of posttrial availability of the experimental intervention and its impact on decisions to participate. RESULTS: All subjects (n = 90) understood the 2-arm design; most (86%) described the procedural differences between the arms accurately. Ninety-two percent referred to scientific or regulatory reasons as rationales for the sham control, with 62% specifically referring to the placebo effect. Ninety-one percent said posttrial availability of the experimental intervention had a strong (48%) or some (43%) influence on their decision to participate, but only 68% understood the conditions for posttrial availability. CONCLUSIONS: Most subjects in sham surgery-controlled PD trials comprehend the sham surgery design and its rationale. Although there is room for improvement, most subjects of sham surgery trials appear to be adequately informed. PMID- 22927065 TI - Impact of short-term perfusion on cell retention for 3D bioconstruct development. AB - Perfusion culture is a commonly used dynamic culture technique in tissue engineering for promoting higher cell number growth. Under perfusion culture, the cell number could be co-influenced by cell detachment and cell proliferation. However, previous studies have mainly focused on the perfusion effects on cell proliferation but largely ignored the aspect of cell detachment. This work demonstrates that perfusion as small as 2.3 mL/min have induced cell loss compared with static culture even for a culture period of 12 minutes Both perfusion rate and direction have influenced the cell retention in the construct. In general, higher perfusion rates have caused more cell loss, largely due to the induced higher flow shear. The influence of perfusion directions on cell retention has been closely related to cell distribution in the construct. The study shows that cell retention is an important aspect that is worth more research attention and should be considered for cell number analysis in 3D construct development. PMID- 22927066 TI - Biomechanical properties of novel biodegradable poly epsilon-caprolactone chitosan scaffolds. AB - AIM: To investigate the biomechanical properties of poly epsilon-caprolactone (PCL)-chitosan (CS) scaffolds fabricated by the melt stretching and multilayer deposition technique. METHODS: The PCL-CS scaffolds containing CS at 0% (pure PCL), 10%, and 20% by weight were prepared. For the monolayer scaffolds, shear and blending tests simulating the reconstruction of orbital floor defects (situation A) and mandibular defects (situation B) were conducted. For the 3-D scaffolds, compression tests of their superior and lateral aspects were done. RESULTS: For the monolayer scaffolds, the pure PCL group had remarkably lower shear strength than the other groups (P > 0.05). In situation A, all groups withstood the forces without any significant difference. In situation B, the pure PCL group could withstand the forces remarkably lower than those of the other group (P < 0.05). The 3-D scaffolds of all groups could withstand compressive forces directed towards their superior aspects. However, they could not withstand the forces directed towards their lateral aspects at the limited strain. CONCLUSIONS: The monolayer scaffolds were suitable for reconstruction of the orbital floor and mandibular defects under light load-bearing conditions. The 3-D scaffolds could be used in the high load bearing-areas only if the forces were directed at their superior aspects. PMID- 22927067 TI - Unusual radial artery calcification as contraindication to radial artery access? PMID- 22927068 TI - [Embryonic stem cells and regeneration-promoting drug research & development]. PMID- 22927069 TI - [Expression of Junctophilin 1 during cardiogenesis of mouse embryonic stem cells and rat embryos]. AB - OBJECTIVE: To investigate the expression of Junctophilin 1 (JP1) in cardiogenesis of mammalian. METHODS: Cardiac differentiation of embryonic stem cells (ESCs) was generated by hanging drop method. Fetal heart was obtained from the rats aged d 14-20 of gestation. The expression of JP1 and JP2 during cardiogenesis of ESCs and rat embryos was analyzed by RT-PCR or Western blotting. Immunofluorescence staining was employed to reveal the distribution of JP1 and JP2 in embryoid body (EB), probing for merging of JP1 and JP2 and cardiac sarcomeric alpha-Actinin or Troponin-T. Percentage of JP1 and JP2-positive staining cells was analyzed quantitatively by FCS on d17. RESULTS: JP1 mRNA was up-regulated at the early stage (d 5-11) and then decreased. The expression of JP1 protein was up-regulated at the early stage (d 7-9), then decreased gradually and disappeared after d 15. While JP2 gene and protein expression increased in a time-dependent manner during cardiogenesis of rat embryos. The results of immunofluorescence staining showed that there was a parallel co-localization of JP2 with Troponin-T or alpha-Actinin on d17, while JP1 failed to express in the sarcomeric positive area at the same time point. Furthermore, FCS analysis showed that about 16.59% of cells were JP2 positive, while no cells were stained positively for JP1 in d17 EBs. CONCLUSION: JP1 gene is expressed during the whole process of cardiogenesis, while JP1 protein only appears on the early stage. The expression of JP1 in cardiogenesis of ESCs is consistent with that of rat embryos. PMID- 22927070 TI - [Expression of metabotropic glutamate receptor 4 in cardiomyocytes differentiated from mouse embryonic stem cells in vitro]. AB - OBJECTIVE: To investigate the expression of metabotropic glutamate receptor 4 (mGluR4) in cardiomyocytes differentiated from mouse embryonic stem cells (ES cells). METHODS: ES cells were differentiated into cardiomyocytes with hanging drop cultures. Retinoic acid (RA) and dimethyl sulfoxide (DMSO) were used as positive and negative controls, respectively. The co-expression of cardiac sarcomeric protein (alpha-actinin or troponin-T) and mGluR4 were verified by immunocytochemistry and flow cytometry analysis. The mRNA and protein expressions of mGluR4 were verified by RT-PCR and Western blot analysis, respectively. Meanwhile, the expression of mGluR4 in prenatal mouse heart was also examined. RESULTS: mGluR4 was expressed in both mouse ES cells and ES cell-derived cardiomyocytes. The level of mGluR4 protein expression decreased during the maturation of the cardiomyocytes. The co-expression rate of mGluR4 and Troponin T in the beating embryoid bodies (EBs) was only (3.00 +/-1.00)%. On the other hand, mGluR4 gene and protein expressions showed remarkable down-regulation in the development of mouse fetal heart, which was not detected in mouse adult heart. CONCLUSION: The expression of mGluR4 is down-regulated in the cardiomyocyte differentiation of ES cells. The trend of expression is consistent with that in the prenatal mouse heart development. PMID- 22927071 TI - [Phenotype-based primary screening for drugs promoting neuronal subtype differentiation in embryonic stem cells with light microscope]. AB - OBJECTIVE: To set up a platform for phenotype-based primary screening of drug candidates promoting neuronal subtype differentiation in embryonic stem cells (ES) with light microscope. METHODS: Hanging drop culture 4-/4+ method was employed to harvest the cells around embryoid body (EB) at differentiation endpoint. Morphological evaluation for neuron-like cells was performed with light microscope. Axons for more than three times of the length of the cell body were considered as neuron-like cells. The compound(s) that promote neuron-like cells was further evaluated. Icariin (ICA, 10(-6)mol/L) and Isobavachin (IBA, 10( 7)mol/L) were selected to screen the differentiation-promoting activity on ES cells. Immunofluorescence staining with specific antibodies (ChAT, GABA) was used to evaluate the neuron subtypes. RESULTS: The cells treated with IBA showed neuron-like phenotype, but the cells treated with ICA did not exhibit the morphological changes. ES cells treated with IBA was further confirmed to be cholinergic and GABAergic neurons. CONCLUSION: Phenotypic screening with light microscope for molecules promoting neuronal differentiation is an effective method with advantages of less labor and material consuming and time saving, and false-positive results derived from immunofluorescence can be avoided. The method confirms that IBA is able to facilitate ES cells differentiating into neuronal cells, including cholinergic neurons and GABAergic neurons. PMID- 22927073 TI - [Construction of directional differentiation model from mouse embryonic stem cells to Leydig-like cells in vitro]. AB - OBJECTIVE: To construct a directional differentiation model from mouse embryonic stem cells into leydig-like cells in vitro. METHODS: Mouse ES-D3 cells were transfected with plasmid containing steroidogenic factor 1 (SF-1) gene, then treated with RA and 8Br-cAMP, while the cells transfected with empty plasmid were used as the negative controls. The morphology of leydig-like cells differentiated from ES-D3 cells was observed with light microscopy. The expression levels of StAR, P450scc and 3beta-HSD were detected by RT-PCR, Western Blot and fluorescence microscopy analysis in leydig-like cells derived from the ES cells. RESULTS: ES-D3 cells were transfected with plasmid containing SF-1 gene successfully, and SF-1 was expressed 24 h after transfection. The SF-1 transfected ES-D3 cells were induced by RA and 8Br-cAMP to differentiate into leydig-like cells. The differentiated cells showed spindle shape with tentacles, which expressed the specific protein marker for leydig cells 3beta-HSD1 and P450scc. Meanwhile, in these leydig-like cells, the expression of StAR increased compared with control group. 3beta-HSD1, P450scc and StAR were not detected in negative control group. CONCLUSION: When the ES-D3 cells are transfected with SF 1 plasmid and then treated with RA and 8Br-cAMP, the cells are able to differentiate into leydig-like cells, indicating that the model of directional differentiation of ES cells into leydig-like cells has been constructed successfully. PMID- 22927072 TI - [Establishment of optimized neuronal differentiation-promoting model derived from P19 embryonic carcinoma cells]. AB - OBJECTIVE: To establish an optimized primary drug screen model of neuronal differentiation using P19 embryonal carcinoma cells. METHODS: The final concentration of retinoid acid (RA), days of suspension culture, manner of adherent culture, suitable cell density and adherent culture medium were tested, respectively. Two stages of neuronal differentiation were examined based on morphological changes and immunocytochemistry analysis of neuronal specific protein beta-tubulin III. RESULTS: On d 8 of differentiation culture, neuron-like cells were observed with final concentration of 1 MUmol/L RA. Neuron-like network was formed on d 16 of neuronal differentiation. beta-tubulin III was positively stained on both stages, indicating P19 cells were differentiated into neurons. CONCLUSION: The model using RA to induce P19 embryonic carcinoma cells to differentiate into neuron-like cells has been successfully established, which may provide a rapid, phenotypic cell-based platform for primary screening of neurogenesis-promoting drugs. PMID- 22927074 TI - [Ginsenoside Rg1 antagonizes beta-amyloid peptide-induced apoptosis in primarily cultured rat neurons via mitochondrial pathway]. AB - OBJECTIVE: To assess the neuroprotective effects of ginsenoside Rg1 against beta amyloid peptide (Abeta(25-35))-induced apoptosis in primarily cultured rat cortical neurons. METHODS: Primarily cultured cortical neurons were obtained from embryonic (E18d) rat fetus and maintained in neurobasal medium for 7d. Primary neurons pretreated with 1 MUmol/L, 10 MUmol/L or 20 MUmol/L Rg1 for 24 h were challenged with 10 MUmol/L Abeta(25-35) for 72 h. Morphological changes of neurons were evaluated; mitochondrial membrane potential (DeltaPsim) was measured; with JC-1 staining and the expression of neural apoptosis-related proteins was detected by Western blot analysis. RESULTS: Exposure to Abeta(25-35) for 72 h caused serious neural cell insults. A pretreatment with Rg1 significantly reduced Abeta(25-35)induced cell death in a dose-dependent manner, with a maximal effect (-90%) obtained at 20 MUmol/L. The JC-1 staining results demonstrated the loss of DeltaPsim after Abeta(25-35) treatment, while Rg1 maintained the normal level of DeltaPsim. A series of mitochondrion-mediated apoptotic events happened after Abeta(25-35) treatment, such as decrease of Bcl 2/Bax, release of cytochrome C and activation of caspase 9 and caspase 3, which were all blocked by Rg1 pretreatment. Both estrogen receptor (ER) antagonist ICI182, 780 and glucocorticoid receptor (GR) antagonist RU486 blocked the antiapoptotic effects of Rg1. CONCLUSION: Ginsenoside Rg1 protects primary cultured rat cortical neurons from Abeta(25-35)-induced injury, which may be associated with mitochondrion-mediated antiapoptosis pathway. PMID- 22927075 TI - [Effect of chronic lead exposure on expression of autophagy-associated proteins in rat hippocampus]. AB - OBJECTIVE: To investigate the effects of chronic lead exposure on expression of autophagy-associated proteins in rat hippocampus. METHODS: SD rats were randomly divided into three groups: control group was given distilled water, lead-exposed groups were given 0.5 g/L (low-dose) or 2.0 g/L(high-dose) lead acetate solution in drinking water. The rat pups started to drink the lead content water until 60 d maturity. The lead contents in blood and brain samples were analyzed by graphite furnace atomic absorption spectrophotometry. The expressions of Beclin 1, LC3, LAMP2 and cathepsin B proteins were detected by Western blot and immunohistochemistry. RESULTS: Compared with control group, the contents of lead were significantly higher in blood and hippocampus samples in chronic lead exposed rats (P<0.01). Western blot showed that the expression of Beclin 1 and LC3-II/LC3-I increased significantly in high dose lead-exposed group compared with control group (P<0.05 or P<0.001). The confocal laser immunostaining results demonstrated that increased immunofluorescence staining of cathepsin B in hippocampal neurons compared with control animals. CONCLUSION: The disturbance of autophagy-lysosome signaling molecules might be partially contribute to neurotoxicity of chronic lead exposure. PMID- 22927077 TI - [Development of datasets for basic medical information system]. AB - OBJECTIVE: To develop dataset for basic medical information system. METHODS: All items of basic medical information system dataset were drafted by literature review, brain storm and group discussion. A Delphi study was conducted to evaluate and adjust the candidate items; then items were finalized based on comprehensive scores. RESULTS: The final dataset developed through two-round Delphi study contained 20 first-level items, 102 second-level items, 40 third level items and 88 fourth-level items. The response rates were 71.79% and 92.86% in round 1 and 2, respectively. The authority coefficient was both 0.77 and the coordination coefficient of the specialists' opinion was 0.239 and 0.516, respectively. CONCLUSION: The dataset for basic medical information system determined from Delphi study is credible and can be used for development of related software. PMID- 22927076 TI - [Distribution diversity of integrins and calcium channels on major human and mouse host cells of Leptospira species]. AB - OBJECTIVE: To determine the distribution of integrins and calcium channels on major human and mouse host cells of Leptospira species. METHODS: The expression of beta1, beta2 and beta3 integrins was detected with immunofluorescence assay on the surface of human monocyte line THP-1, mouse mononuclear-macrophage-like cell line J774A.1, human vascular endothelial cell line HUVEC, mouse vascular endothelial cell EOMA, human hepatocyte line L-02, mouse hepatocyte line Hepa1-6, human renal tubular epithelial cell line HEK-293, mouse glomerular membrane epithelial cell line SV40-MES13, mouse collagen blast line NIH/3T3, human and mouse platelets. The distribution of voltage gate control calcium channels Cav3.1, Cav3.2, Cav3.3 and Cav2.3, and receptor gate calcium channels P(2)X(1), P(2)2X(2), P(2)X(3), P(2)X(4), P(2)X(5), P(2)X(6) and P(2)X(7) were determined with Western blot assay. RESULTS: beta1 integrin proteins were positively expressed on the membrane surface of J774A.1, THP-1, HUVEC, EOMA, L-02, Hepa1-6 and HEK-239 cells as well as human and mouse platelets. beta2 integrin proteins were expressed on the membrane surface of J774A.1, THP-1, HUVEC, EOMA, and NIH/3T3 cells. beta3 integrin proteins were expressed on the membrane surface of J774A.1, THP-1, HUVEC, EOMA, Hepa1-6, HEK-239 and NIH/3T3 cells as well as human and mouse platelets. P(2)X(1) receptor gate calcium channel was expressed on the membrane surface of human and mouse platelets, while P(2)X(5) receptor gate calcium channel was expressed on the membrane surface of J774A.1, THP-1, L-02, Hepa1-6, HEK-239 and HUVEC cells. However, the other calcium channels were not detected on the tested cell lines or platelets. CONCLUSION: There is a large distribution diversity of integrins and calcium channel proteins on the major human and mouse host cells of Leptospira species, which may be associated with the differences of leptospira-induced injury in different host cells. PMID- 22927078 TI - [Effect of Colquhounia root tablet on IL-2 and IFN-gamma mRNA expression in rats with experimental allergic encephalomyelitis]. AB - OBJECTIVE: To investigate the effect of Colquhounia root tablet on IL-2 and IFN gamma mRNA expression in experimental allergic encephalomyelitis (EAE) of rats. METHODS: The allergic encephalomyelitis model was established in Wistar rats by immunization with myelin basic protein of spinal cord of guinea pig and complete Freund's adjuvant. The rats in treatment group received Colquhounia root tablet (300 mg*kg(-1), BID). The symptom of EAE was observed; pathological feature and myelin of brain and spinal cord were detected with HE stain and Loyez's stain, respectively. The expressions of IL-2 and IFN-gamma mRNA were assayed by RT-PCR. RESULTS: No EAE symptoms were developed in treatment group, the expressions of IL 2 and IFN-gamma mRNA were 0.345 +/- 0.032 and 0.353 +/- 0.023, which were significantly lower than those of model group (P<0.01). The histopathologic examinations revealed that less inflammation cells around vessels and demyelination in white matter of brain and spinal cords were observed in treatment group than in model group. CONCLUSION: Colquhounia root tablets are effective in treatment of EAE of rats, which may be associated with inhibition of the expression of IL-2 and IFN-gamma mRNA. PMID- 22927079 TI - [A method for simultaneous assay of propulsion and absorption in small intestine]. AB - OBJECTIVE: To develop a method for simultaneous assay of propulsion and absorption in small intestine. METHODS: The mice were administrated through gastric tube with mixed reagents containing 0.12% phenol red, D-xylose (1.25%, 2.5% and 5%) and 15% gelatin. The influence of phenol red on D-xylose absorption and the influence of D-xylose on small intestine propulsion rate were investigated by measuring serum concentration of D-xylose with phloroglucinol method. RESULTS: At 10 min, no significant difference was found between 5% D xylose mixed reagent group and 5% D-xylose control. At 15 min, small intestine propulsion rate in 5% D-xylose mixed reagent group, but not in 2.5% and 1.25% D xylose mixed reagent groups, was significantly higher than in phenol red control (P<0.05). CONCLUSION: Gastric administration of mixed reagent containing 0.12% phenol red, 5% D-xylose and 15% gelatin can simultaneously assay propulsion and absorption of small intestine in mice. PMID- 22927080 TI - [Screening and identification of high-yield poly(beta-malic acid) bacterial strain]. AB - OBJECTIVE: To isolate and identify the high-yield poly-malic acid (PMLA) bacterial strains from the nature. METHODS: Samples were collected and cultured. The high-yield PMLA bacterial strains were screened through morphological observation, qualitative PMLA tests by HPLC and ITS sequence analysis on the isolated bacterial strains. RESULTS: A high-yield PMLA strain II 04 was isolated, the yield of PMLA of the strain reached to 26.23g/L in the rotary shaker at 25 degree for 7d. From morphological observation and ITS sequences analysis, the strain belonged to Aureobasidium pullulans, and named as Aureobasidium pullulans ZUCC-41. CONCLUSION: A high-yield bacterial strain has been isolated from the nature and identified to be Aureobasidium pullulans. PMID- 22927081 TI - [Preparation of diazepam transdermal gel and its bioavailability]. AB - OBJECTIVE: To prepare diazepam transdermal gel and to assess its bioavailability. METHODS: Using Carbopol 934 as a gel matrix, the diazepam transdermal gel was prepared with glycerol as the humectant and azone as penetration enhancer. The penetration rate of diazepam through excised rabbit skin was measured by Franz diffusion cell and HPLC method. Using diazepam tablets as control, the relative bioavailability of diazepam gel was determined in rabbits. RESULTS: The transdermal flux of diazepam gel was 39.26 g/cm(2)/h and the bioavailability of diazepam gel was 36.25%. CONCLUSION: Diazepam gel prepared in the study would be developed as a novel transdermal preparation. PMID- 22927082 TI - [Characteristics of pulmonary valve annular motion identified by quantitative tissue velocity imaging in children with pulmonary hypertension]. AB - OBJECTIVE: To investigate the characteristics of pulmonary valve annular motion by quantitative tissue velocity imaging (QTVI) in children with pulmonary hypertension. METHODS: The pulmonary valve annular motion was assessed by QTVI in 32 children with pulmonary hypertension and 32 healthy children. The QTVI sample volume was set at the point of pulmonary valve annulus to acquire speed-time curve and the parameters from the views of parasternal aortic short-axis or subxiphoid right ventricular outflow long-axis. The parameters of pulmonary valve annular motion of children with pulmonary hypertension were compared to those of normal children. RESULTS: The speed-time curve of pulmonary valve annulus was similar with that of tricuspid annulus in normal children. Compared to normal children, the ratio of Ea/Aa (the velocity parameter of pulmonary valve annular motion) was significantly lower in children with pulmonary hypertension (0.68 +/ 0.36 Compared with 1.18 +/-0.43, P<0.001); and the value of QTVI-Tei index at the pulmonary annulus was significantly higher (0.82 +/-0.34 Compared with 0.37 +/ 0.05, P<0.001). The QTVI-Tei index was positively correlated with the resistance of pulmonary vessel (r=0.556, P<0.001). CONCLUSION: The ratio of Ea/Aa is decreased, the value of QTVI-Tei index is increased and QTVI-Tei index is positively correlated with the resistance of pulmonary vessel in children with pulmonary hypertension. PMID- 22927083 TI - [Echocardiographic diagnosis of partial anomalous pulmonary venous connection]. AB - OBJECTIVE: To investigate partial anomalous pulmonary venous connection (PAPVC) with echocardiography. METHODS: The right ventricular volume overload was detected by routine echocardiography in 37 child patients, who underwent further echocardiography to find the abnormal locations of pulmonary vein opening at superior, inferior vena cava and right atrium. The ultrasound results were compared with surgical findings. RESULTS: In 30 patients the ultrasound diagnosis was consistent with surgery results, 7 were misdiagnosed by ultrasound with a detective rate of 81.1 %. All 37 PAPVC patients presented varying degrees of right heart enlargement; PAPVC combined with atrial septal defect (ASD) was found in 34 cases. CONCLUSION: The possibility of PAPVC should be considered when unexplained right heart volume overload was detected by echocardiography. Superior, inferior vena cava and right atrium should be inspected when the pulmonary veins were not seen in echocardiography. PMID- 22927084 TI - [Nrf2 as a chemoprevention target in gastrointestinal carcinoma]. AB - Gastrointestinal tract carcinoma is one of the leading causes of cancer-related death in China. Chemoprevention has been considered as a potential approach to control this type of disease. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a redox-sensitive transcription factor that protects cells from oxidative/electrophilic stresses by activating the expression of a battery of cytoprotective genes through the antioxidant response element (ARE). Recently, Nrf2 has emerged as a novel target for chemoprevention. Several natural or synthetic chemicals, which activate Nrf2/ARE signaling pathway, have showed effect in animal models, and promises in many ongoing clinical trials. This review summarizes the recent findings on the regulation of Nrf2/ARE signaling pathway, and the developments in both preclinical and clinical studies. PMID- 22927085 TI - [Type I interferon and bacterial infection]. AB - Interferons (IFNs) are cytokines playing an important role in immune responses. Interferons are classified into two distinct types according to specific interferon receptors(IFNR). Type I IFNs include IFN-alpha and IFN-beta, whereas IFN-gamma is type II IFN. It is well known that type I IFNs have important roles in the host defense against viruses through activation of interferon receptor A (IFNAR). However, many recent studies have also demonstrated that type I IFNs have effects on immune responses to bacterial infection. This review focuses on the immune regulation of type I IFN-mediated signal pathways in bacterial infections such as Listeria monocytogenes, Streptococcus, Mycobacterium tuberculosis, Bacillus anthracis, Legionella, Pseudomonas aeruginosa and others. PMID- 22927086 TI - Phase transition of a cobalt-free perovskite as a high-performance cathode for intermediate-temperature solid oxide fuel cells. AB - It is generally recognized that the phase transition of a perovskite may be detrimental to the connection between cathode and electrolyte. Moreover, certain phase transitions may induce the formation of poor electronic and ionic conducting phase(s), thereby lowering the electrochemical performance of the cathode. Here, we present a study on the phase transition of a cobalt-free perovskite (SrNb(0.1)Fe(0.9)O(3-delta), SNF) and evaluate its effect on the electrochemical performance of the fuel cell. SNF exists as a primitive perovskite structure with space group P4mm (99) at room temperature. As evidenced by in situ high-temperature X-ray diffraction measurements over the temperature range of 600 to 1000 degrees C, SNF undergoes a transformation to a tetragonal structure with a space group I4/m (87). This phase transition is accompanied by a moderate change in the volume, allowing a good cathode/electrolyte interface on thermal cycling. According to the electrochemical impedance spectroscopy evaluation, the I4/m phase exhibits positive effects on the cathode's performance, showing the highest oxygen reduction reaction activity of cobalt free cathodes reported so far. This activity improvement is attributed to enhanced oxygen surface processes. PMID- 22927088 TI - The molecular engineering of organic sensitizers for solar-cell applications. AB - Positive to the core: ullazine has both strong electron-donating and weak accepting properties. This heterocycle was incorporated into sensitizers for dye sensitized solar cells (DSCs). One of these sensitizers demonstrated strong light absorption across the UV/Vis region. The corresponding DSC device has a maximum IPCE of 95 % at 520 nm, with a power conversion efficiency of 8.4 %. PMID- 22927087 TI - Myocarditis: diagnosis and treatment. AB - OPINION STATEMENT: Myocarditis is a condition that can have a very wide clinical spectrum ranging from asymptomatic forms to fatal disease, but mostly presenting as new onset heart failure with reduced left ventricular ejection fraction, with or without viral syndrome. This condition is an important cause of sudden cardiac death in young patients. High risk features include second and third degree atrioventricular block or malignant arrhythmias. The diagnostic work-up may be challenging, but non-invasive imaging, primarily cardiac magnetic resonance, plays an increasingly important role, although endomyocardial biopsy is still considered a gold standard for diagnosis. Most importantly, myocarditis can transition to non-ischemic cardiomyopathy with eventually poor outcome. In this review, we will summarize the data on different diagnostic and treatment modalities of this disease. PMID- 22927089 TI - Phenolic diterpenes from rosemary suppress cAMP responsiveness of gluconeogenic gene promoters. AB - The cAMP/protein kinase A/cAMP response element (CRE)-binding protein pathway is important for various physiological aspects including regulation of gluconeogenic gene expression. Rosemary, a well-known herb, has been reported to decrease blood glucose levels. We found that methanol extracts of rosemary suppressed forskolin (FSK)-stimulated luciferase expression under the control of CRE, as well as the promoters for cytosolic phosphoenolpyruvate carboxykinase (PEPCK-C) and glucose-6 phosphatase (G6Pase) catalytic subunit genes in human hepatoma HepG2 cells. Three abietane-type diterpenes and two flavonoids were isolated from the rosemary extracts. Among these, 7-O-methylrosmanol (1) and royleanonic acid (3) effectively suppressed FSK-induced luciferase expression under the control of the CRE, PEPCK-C and G6Pase gene promoters. PEPCK-C and G6Pase, which play a key role in the homeostatic regulation of blood glucose levels, are important for managing type II diabetes mellitus. Therefore, the ability of rosemary and its components to suppress cAMP responsiveness of the PEPCK-C or G6Pase gene may contribute to its antihyperglycemic activity. PMID- 22927090 TI - Aiptasia pulchella: a tropical cnidarian representative for laboratory ecotoxicological research. AB - An urgent need exists to identify suitable tropical marine species for use in the development of sensitive and reliable test methods for routine laboratory ecotoxicological testing. Corals are a group of organisms not represented in routine ecotoxicology due to inherent difficulties in laboratory husbandry, and sea anemones from the same phylum (cnidaria) may be useful proxies. Aiptasia pulchella is a tropical symbiotic sea anemone with a wide geographic range. It is well suited to laboratory conditions and has been used extensively in research. However, its suitability as a toxicity test species has not been investigated. Assessment of juvenile recruitment in laboratory and semi-outdoor conditions showed higher production in semi-outdoor conditions; however, laboratory rearing produced enough recruits to run routine toxicity tests. In investigations of the sensitivity of A. pulchella to contaminants, acute tests were conducted on 1- to 2-mm juveniles using copper. Lethal concentration, 50% (LC50) values at 96 h estimated from tests using five and 10 replicates ranged from 30 to 83 and 60 to 90 ug/L, respectively, and a 28-d LC50 of 26 ug/L was estimated. During the present study, sublethal endpoints were investigated; chronic assessment of inhibited asexual reproduction looks promising (12-d effective concentration, 50% [EC50] 15 ug/L) and should be assessed further. Aiptasia pulchella is a species worthy of investigation as a cnidarian representative, and will be an invaluable contribution to tropical marine ecotoxicologists. PMID- 22927091 TI - Color Doppler ultrasound-guided transducer compression of post biopsy bleeding of kidney transplants. AB - BACKGROUND: Color Doppler ultrasound (CDUS) has a potential of early detection of post biopsy bleeding. We describe CDUS guidance in planning, acquisition, and, in the case of bleeding, compression of the needle tract in biopsy procedures of kidney transplants. METHODS: Eighty-three kidney transplant biopsy procedures performed on clinical indication were performed in 71 adult patients, 25 women, mean age 51 years, using CDUS and 18-G biopsy needles. Bleeding needle tracts were compressed using CDUS guidance. RESULTS: CDUS immediately detected blood leakage and facilitated compression of the bleeding needle tract in 34 (41%) of the 83 procedures, including 53 (25%) of 215 needle passes. In 34 bleeding procedures, the mean duration of the longest bleeding time after a needle pass was 124 seconds (median, 20 seconds; range, 3-1440 seconds). In 12 of these procedures (35%), the bleeding time was 30 seconds or more. In six procedures (18%), a bleeding of 120 seconds or more was observed. Complications included seven small hematomas. Five hematomas developed in procedures where the longest duration CD bleeding was 120 seconds or more. CONCLUSIONS: CDUS detects bleeding and facilitates direct transducer compression of the needle tract in a substantial portion of biopsy procedures of kidney transplants. Only minor hematomas occurred. PMID- 22927093 TI - Microdosing: a critical assessment of human data. AB - Ultrasensitive analytical methodologies have now made possible the ability to characterize the pharmacokinetics (PK) of compounds following administration to humans of a minute, subpharmacologic dose, a microdose. This has the potential to provide pre-IND information to help in early candidate selection, but only if such information is reasonably predictive of PK at pharmacologic doses. The published clinical data in this area are critically assessed and perspectives drawn. The place of microdosing, alone and coupled with other innovative methodologies, both pre-IND and during clinical development, is considered as a way forward to improve the efficiency and informativeness of drug development. PMID- 22927092 TI - Protocadherin-17 function in Zebrafish retinal development. AB - Cadherin cell adhesion molecules play crucial roles in vertebrate development including the development of the retina. Most studies have focused on examining functions of classic cadherins (e.g. N-cadherin) in retinal development. There is little information on the function of protocadherins in the development of the vertebrate visual system. We previously showed that protocadherin-17 mRNA was expressed in developing zebrafish retina during critical stages of the retinal development. To gain insight into protocadherin-17 function in the formation of the retina, we analyzed eye development and differentiation of retinal cells in zebrafish embryos injected with protocadherin-17 specific antisense morpholino oligonucleotides (MOs). Protocadherin-17 knockdown embryos (pcdh17 morphants) had significantly reduced eyes due mainly to decreased cell proliferation. Differentiation of several retinal cell types (e.g. retinal ganglion cells) was also disrupted in the pcdh17 morphants. Phenotypic rescue was achieved by injection of protocadherin-17 mRNA. Injection of a vivo-protocadherin-17 MO into one eye of embryonic zebrafish resulted in similar eye defects. Our results suggest that protocadherin-17 plays an important role in the normal formation of the zebrafish retina. PMID- 22927094 TI - Pathogenesis of Parkinson's disease. AB - Parkinson's disease is a common adult-onset neurodegenerative disorder whose pathogenesis remains essentially unknown. Currently, it is believed that the neurodegenerative process in Parkinson's disease is a combination of both cell autonomous and non-cell-autonomous mechanisms. Proposed cell-autonomous mechanisms include alterations in mitochondrial bioenergetics, dysregulation of calcium homeostasis, and impaired turnover of mitochondria. As for the proposed non-cell-autonomous mechanisms, they involve prion-like behavior of misfolded proteins and neuroinflammation. This suggests that cell death in Parkinson's disease is caused by a multifactorial cascade of pathogenic events and argues that effective neuroprotective therapy for Parkinson's disease may have to rely on multiple drug interventions. PMID- 22927095 TI - Growing old but not growing apart: twin similarity in the latter half of the lifespan. AB - While a substantial amount of behavioral genetic research has helped to characterize developmental trends in twin similarity in early life, relatively little is known about changes in twin similarity with age in adulthood. We investigated age moderation of twin similarity for a composite measure of cognitive ability, depression symptomatology and hand grip strength in a cross sectional sample of 2,332 like-sex pairs of Danish twins age 46-96 years. All three outcomes were strongly correlated with age, indicating that the three phenotypes analyzed are not developmentally static. Nonetheless, in moderated regression analysis we found no evidence of declining twin similarity for any of the three outcomes in either zygosity group. Moreover, biometric analysis of the twin data revealed minimal differences in heritability estimates across the age range sampled. While small sample size limits our ability to draw firm conclusions at very advanced ages, these findings call into question the hypothesis that the cumulative impact of life experiences diminishes twin similarity at least through age 80. We hypothesize that twins are able to maintain similarity over extended periods of time because in part they are able to construct similar environments that reinforce that similarity. PMID- 22927096 TI - Immunomodulatory effects of low dose chemotherapy and perspectives of its combination with immunotherapy. AB - Given that cancer is one of the main causes of death worldwide, many efforts have been directed toward discovering new treatments and approaches to cure or control this group of diseases. Chemotherapy is the main treatment for cancer; however, a conventional schedule based on maximum tolerated dose (MTD) shows several side effects and frequently allows the development of drug resistance. On the other side, low dose chemotherapy involves antiangiogenic and immunomodulatory processes that help host to fight against tumor cells, with lower grade of side effects. In this review, we present evidence that metronomic chemotherapy, based on the frequent administration of low or intermediate doses of chemotherapeutics, can be better than or as efficient as MTD. Finally, we present some data indicating that noncytotoxic concentrations of antineoplastic agents are able to both up-regulate the immune system and increase the susceptibility of tumor cells to cytotoxic T lymphocytes. Taken together, data from the literature provides us with sufficient evidence that low concentrations of selected chemotherapeutic agents, rather than conventional high doses, should be evaluated in combination with immunotherapy. PMID- 22927097 TI - Postoperative effect of radiofrequency treatments on the rabbit dermal collagen fibrillary matrix. AB - This study quantitatively examined the short and mid-long term effects of radiofrequency (RF) treatment on the normal dermal collagen fibrils of live rabbits. Effects were evaluated by histology and scanning probe microscopy analysis of dermal tissues treated using three RF energy levels (10, 20, and 30 W) and either a single- or multiple-pass procedure. Progressive changes in the morphology of rabbit dermal collagen fibrils were investigated over a 30-day post treatment period. All RF-treated groups, except for the low-energy group (10 W), displayed more prominent inflammatory responses compared to the control. This inflammatory response was more prominent a day after treatment. Dermal tissues 30 days after RF treatment exhibited prominent myofibroblast activity associated with collagen contractile activity during wound healing in addition to chronic inflammation. A decrease in the morphology of dermal collagen fibrils after RF treatment continued until seven days postoperatively. The collagen fibril diameter increased to near baseline at 30 days postoperatively. Low-energy and multi-pass treatments resulted in greater collagen fibril contraction and recovery at the nanostructural level at 30 days postoperatively than did a single high-energy treatment. PMID- 22927098 TI - Compulsive reading. PMID- 22927099 TI - Acid-catalyzed dehydration of fructose into 5-hydroxymethylfurfural by cellulose derived amorphous carbon. AB - Carbonaceous solid (CS) catalysts with --SO3H, --COOH, and phenolic --OH groups were prepared by incomplete hydrothermal carbonization of cellulose followed by either sulfonation with H2SO4 to give carbonaceous sulfonated solid (CSS) material or by both chemical activation with KOH and sulfonation to give activated carbonaceous sulfonated solid (a-CSS) material. The obtained carbon products (CS, CSS, and a-CSS) were amorphous; the CSS material had a small surface area (<0.5 m2 g-1) and a high --SO3H group concentration (0.953 mmol g 1), whereas the a-CSS material had a large surface area (514 m2 g -1) and a low -SO3H group concentration (0.172 mmol g-1). The prepared materials were evaluated as catalysts for the dehydration of fructose to 5-hydroxymethylfurfural (5-HMF) in the ionic liquid 1-butyl-3-methylimidazolium chloride ([BMIM][Cl]). Remarkably high 5-HMF yields (83 %) could be obtained efficiently (80 degrees C and 10 min reaction time). CSS and a-CSS catalysts had similar catalytic activities and efficiencies for the conversion of fructose to 5-HMF in [BMIM][Cl]; this could be explained by the trade-off between --SO3H group concentration (high for CSS) and surface area (high for a-CSS). The cellulose-derived catalysts and ionic liquid exhibited constant activity for five successive recycles, and thus, the methods developed provide a renewable strategy for biomass conversion. PMID- 22927100 TI - A provisional strategy for treating true bifurcation lesions employing a scoring balloon for the side branch: final results of the AGILITY trial. AB - BACKGROUND: The provisional approach for bifurcation stenting with side-branch balloon angioplasty is associated with dissections and suboptimal results requiring kissing balloon techniques or bailout stenting. We hypothesized that using a scoring balloon for the side branch and a drug-eluting stent for the main vessel might improve outcomes of true bifurcation lesions. METHODS AND RESULTS: A total of 93 patients with complex bifurcations were enrolled in a multicenter, single-arm, prospective clinical trial. A drug-eluting stent was deployed in the main vessel following dilatation of the side-branch stenosis with a scoring balloon. The overall angiographic success rate was 93.5%, and procedural success rate was 91.4%. The final diameter stenosis was 13.9% +/- 7.2% for the main vessel and 33.3% +/- 22.9% for the side branch. Crossover to stent deployment in the side branch was required in 10.8%. The postscoring balloon dissection rate was 8.2% and 6% (all <= class C) for the main vessel and side branch respectively, which was reduced to 1.1 and 2.1% poststenting. At 9-month follow up, the composite MACE rate [cardiac death, myocardial infarction, or target lesion revascularization (TLR)] was 5.4%, including a TLR rate of 3.3% (1.1% from hospital discharge to 9 months). CONCLUSION: The 9-month results of the AGILITY trial support a simple provisional strategy for treating complex true bifurcation lesions with deployment of a drug-eluting stent in the main vessel after dilatation of the side-branch vessel with a scoring balloon. This strategy was associated with excellent and safe procedural results, a low rate of crossover to side-branch stenting, and favorable outcomes. PMID- 22927101 TI - Biomarkers for trials of neuroprotection in Parkinson's disease. AB - With increased understanding of disease pathogenesis and the foreseeable reality of disease-modifying therapies, there is a growing need to find biomarkers that will allow early (preferably preclinical) detection of disease and that will provide an independent readout of disease progression. In this article, we review a variety of markers, with a focus on functional imaging techniques, which while imperfect, currently provide the best approach to this problem. We consider the limitations of functional imaging of the dopamine system in assessing the progression of Parkinson's Disease (PD) as well as the potential use of structural imaging and emerging progress in other biochemical and molecular markers. While there is no single biomarker that will satisfy all requirements, some combination is likely to be of great use in identifying those subjects most likely to benefit from neuroprotective therapies, as well as in monitoring the effects of these interventions. PMID- 22927102 TI - Antifungal compounds from the rhizome and roots of Ferula hermonis. AB - The antifungal activity of hexane, dichloromethane, methanol and aqueous extracts from the rhizome and root of Ferula hermonis was assayed in vitro by the agar disk diffusion method against a panel of human opportunistic and pathogenic fungi. Among them, the hexane and dichloromethane extracts showed the highest activity particularly against the dermatophytes Microsporum gypseum and Tricophyton mentagrophytes as well as the yeast Candida lactis-condensi. Activity guided fractionation of both extracts using an agar overlay bioautographic method led to the isolation of two antifungal compounds which were identified as the daucane aryl esters jaeschkeanadiol p-hydroxybenzoate (ferutinin) and jaeschkeanadiol benzoate (teferidin). Determination of minimal inhibitory concentration (MIC) and minimal fungicidal concentration (MFC) values of both compounds evidenced a stronger antifungal activity for ferutinin than for teferidin. Particularly, T. mentagrophytes was the most sensitive strain with MIC and MFC values ranging from 8 to 256 ug/mL. PMID- 22927103 TI - Construction of microenvironment onto titanium substrates to regulate the osteoblastic differentiation of bone marrow stromal cells in vitro and osteogenesis in vivo. AB - To mimic the extracellular matrix of natural bone, apatite/gelatin composite was deposited onto nanostructured titanium substrates via a coprecipitation method, which was pretreated by potassium hydroxide and heat treatment to generate an anticorrosive nanostructured layer. The successful formation of the apatite/gelatin nanocomposite onto titanium surfaces was revealed by Fourier transform infrared spectroscopy, field-emission scanning electron microscopy, atomic force microscopy (AFM), and thin film X-ray diffraction (TF-XRD) measurements, respectively. The immunofluorescence staining of vinculin revealed that the apatite/gelatin nanocomposite deposited titanium substrate was favorable for cell adhesion. More importantly, bone marrow stromal cells cultured onto the apatite/gelatin nanocomposite deposited titanium substrates displayed significantly higher (p < 0.05 or p < 0.01) proliferation and differentiation levels of alkaline phosphatase, mRNA expressions of osteocalcin (OC), osteopontin (OPN), and collagen type I (Col I), and OC content after culture for 7, 14, and 21 days, respectively, which was also revealed by the immunofluorescence analysis of OC and OPN expression. The deposition of apatite/gelatin nanocomposite improved bone density (p < 0.05) and bone-implant contact rate (p < 0.05), which was reflected by microcomputed tomography analysis and histological evaluation in vivo using a rabbit model. This work provides an approach to fabricate high performance titanium-based implants with enhanced bone osseointegration. PMID- 22927104 TI - Proportion cured models applied to 23 cancer sites in Norway. AB - Statistical cure is reached when a group of patients has the same mortality as cancer-free individuals. Cure models predict the cured proportion and the median survival of fatal cases. Cure models have seldom been applied and tested systematically across all major cancer sites. Incidence and follow-up data on 23 cancer sites recorded at the Cancer Registry of Norway 1963-2007 were obtained. Mixture cure models were fitted to obtain trends and up-to-date estimates (based on period approach) assuming cured and uncured groups exist. The model converged for cancers of the mouth and pharynx, oesophagus, stomach, colon, rectum, liver, gallbladder, pancreas, lung and trachea, ovary, kidney, bladder, CNS, non-Hodgkin lymphoma (only for males) and leukemia. The proportion of cured patients increased 1963-2002 for both sexes, with the largest changes (in percent) seen for leukemia (46.4 and 46.7) and CNS (35.9, 42.0), males given first. Median survival time for the uncured cases increased for colon and rectal cancer, and there was a three- fold increase in median survival time for patients with fatal ovarian cancers. Cancers of bladder and CNS had the highest up-to-date proportion cured (in percent), 67.4 and 64.0, respectively, pancreas and liver were amongst the lowest (5.7 and 9.9, respectively). Cure models are useful when monitoring progress in cancer care, but must be applied and interpreted with caution. The absolute estimates of the cure proportion are speculative and should not be calculated where cure is not medically anticipated. PMID- 22927105 TI - Dental unit waterline management: historical perspectives and current trends. AB - Interest in and concern about the biofilms that occur in dental waterlines have been increasing in recent years. Dental unit waterlines harbor considerable amounts of bacteria that are derived from the biofilm on the inner surface of these lines. This continuous reservoir of bacteria carries the potential of causing infection to patients and dental workers. The majority of dental procedures require the use of water for cooling instruments, irrigation, and oral rinsing, so it is extremely important that the water used in oral procedures is of a high quality. The present study illustrates the conditions in waterline tubing that favor development of biofilms, and discusses the level of risk that such microbial growth poses for both dental professionals and their patients. The different methods to circumvent this problem are reviewed, and the recent recommendations that should be adopted in the dental clinic to provide the patients with water of acceptable microbiological standards are discussed. PMID- 22927106 TI - Can we get more from the Epworth Sleepiness Scale (ESS) than just a single score? A confirmatory factor analysis of the ESS. AB - PURPOSE: The Epworth Sleepiness Scale (ESS) is a widely used tool for measuring sleepiness. In addition to providing a single measure of sleepiness (a one-factor structure), the ESS also has the capacity to provide additional information about specific factors that facilitate sleep onset, including a person's posture, activity and environment. These features of sleepiness are referred to as somnificity. This study evaluates and compares the fit of a one-factor structure (sleepiness) and three-factor structure (reflecting low, medium and high levels of somnificity) for the ESS. METHODS: All participants (a community sample N = 356 and a clinical sample N = 679) were administered the ESS. Confirmatory factor analysis was used to evaluate and compare the fit of one- and three-factor models of the ESS. RESULTS: In both samples, a three-factor structure (community sample adjusted X (2) = 2.95, root mean square error of approximation (RMSEA) = 0.07, Comparative Fit Index (CFI) = 0.95; clinical sample adjusted X (2) = 3.98, RMSEA = 0.07, CFI = 0.98) provided a level of model fit that was at least as good as the one-factor structure (community sample adjusted X (2) = 5.01, RMSEA = 0.11, CFI = 0.87; clinical sample adjusted X (2) = 8.87, RMSEA = 0.11, CFI = 0.92). CONCLUSIONS: In addition to a single measure of sleepiness, the ESS can provide subscale scores which relate to three underlying levels of somnificity. These findings suggest that the ESS can be used to measure an individual's overall sleep propensity as well as more specific measures of sleep propensity in low, moderate and high levels of situational somnificity. PMID- 22927107 TI - The sleep position trainer: a new treatment for positional obstructive sleep apnoea. AB - BACKGROUND: Positional obstructive sleep apnoea (POSA), defined as a supine apnoea-hypopnoea index (AHI) twice or more as compared to the AHI in the other positions, occurs in 56 % of obstructive sleep apnoea patients. Positional therapy (PT) is one of several available treatment options for these patients. So far, PT has been hampered by compliance problems, mainly because of the usage of bulky masses placed in the back. In this article, we present a novel device for treating POSA patients. METHODS: Patients older than 18 years with mild to moderate POSA slept with the Sleep Position Trainer (SPT), strapped to the chest, for a period of 29 +/- 2 nights. SPT measures the body position and vibrates when the patient lies in supine position. RESULTS: Thirty-six patients were included; 31 patients (mean age, 48.1 +/- 11.0 years; mean body mass index, 27.0 +/- 3.7 kg/m(2)) completed the study protocol. The median percentage of supine sleeping time decreased from 49.9 % [20.4-77.3 %] to 0.0 % [range, 0.0-48.7 %] (p < 0.001). The median AHI decreased from 16.4 [6.6-29.9] to 5.2 [0.5-46.5] (p < 0.001). Fifteen patients developed an overall AHI below five. Sleep efficiency did not change significantly. Epworth Sleepiness Scale decreased significantly. Functional Outcomes of Sleep Questionnaire increased significantly. Compliance was found to be 92.7 % [62.0-100.0 %]. CONCLUSIONS: The Sleep Position Trainer applied for 1 month is a highly successful and well-tolerated treatment for POSA patients, which diminishes subjective sleepiness and improves sleep-related quality of life without negatively affecting sleep efficiency. Further research, especially on long-term effectiveness, is ongoing. PMID- 22927108 TI - Pronounced risk of nontraumatic osteonecrosis of the femoral head among cigarette smokers who have never used oral corticosteroids: a multicenter case-control study in Japan. AB - BACKGROUND: Cigarette smoking has been linked to an increased risk of nontraumatic osteonecrosis of the femoral head (ONFH) in previous studies. However, the effect of smoking amount, duration and cessation, and interaction with corticosteroids remains unclear. The purpose of this study was to precisely evaluate the effects of smoking and the interaction with corticosteroid use. METHODS: This was a multicenter, matched case-control study in Japan. Cases were defined as patients who were newly diagnosed with ONFH at an initial visit or during the previous year if they were referred patients. For each case, matched controls were selected from patients without ONFH. The matching conditions were sex, age, and ethnicity. A logistic regression model was used to compute odds ratios (OR) and 95 % confidence intervals (95 % CI). RESULTS: We compared 72 cases with 244 matched controls. ORs were 3.89 (95 % CI 1.46-10.4) for current smokers, 3.89 (1.22-12.4) for smokers consuming more than 20 cigarettes per day, 4.26 (1.32-13.7) for smokers with 26 pack-years or more, and 3.11 (0.92-11.5) for smokers with a history of 29 years or more, with significant or marginally significant dose-response relationships. OR for current smokers was 10.3 among those who had never used corticosteroids and 1.56 among past or current corticosteroid users (P for interaction 0.010). CONCLUSIONS: Our results revealed that heavier cigarette smoking was associated with a higher risk of ONFH. The elevated risk from cigarette smoking was markedly pronounced among those who had never used oral corticosteroids. PMID- 22927109 TI - A novel in vitro model of ischaemic preconditioning: its effect on cell viability in human skeletal muscle and a possible explanation for the 'second window of protection'. AB - BACKGROUND: The ischaemia-reperfusion (IR) injury causes significant morbidity. Ischaemic preconditioning (IPC) is a technique for limiting the effects of the IR injury. Its potential has not yet been harnessed in orthopaedics. AIMS: To establish a novel in vitro IR model using a human skeletal muscle cell line. Secondly, to introduce simulated IPC to the model and examine the effect of this on cell viability. METHODS: A human skeletal muscle cell line was cultured in vitro. Placing the cells in a hypoxic buffer and a closed hypoxic environment simulated ischaemia. Reversing this process simulated reperfusion. IPC was simulated by alternate cycles of ischaemia and reperfusion. Cell viability comparisons were made between control and experimental groups of cells. RESULTS: A reproducible in vitro IR model was established. The addition of simulated IPC is associated with increased cell death at 12 and 24 h of reperfusion. Significantly greater cell survival is seen in the IPC group when measured at 72 h reperfusion. CONCLUSIONS: We hypothesise that IPC initially decreases cell number. The remaining cells are more robust. This selected cell line then expands over the course of 72 h and displays greater resistance to the IR injury. This theory can help explain delayed preconditioning. PMID- 22927110 TI - Chemistry and bioactivity of an artificial adenosylpeptide B(12) cofactor. AB - Artificial influence: We describe a semi-artificial adenosylpeptide B(12) that behaves as a cofactor in B(12)-dependent enzymatic reactions and demonstrate that the peptide backbone influences its chemical properties and modulates its bioactivity in vitro and in vivo. Inhibition of the growth of L. delbrueckii is demonstrated, thus providing a potentially powerful approach for the development of antibacterial and antiproliferative compounds. PMID- 22927111 TI - Introduction to special issue on neuroimmunology in brain development and disease. PMID- 22927112 TI - T-5224, a selective inhibitor of c-Fos/activator protein-1, attenuates lipopolysaccharide-induced liver injury in mice. AB - The effect of T-5224, a selective inhibitor of c-Fos/activator protein (AP)-1, on lipopolysaccharide (LPS) induced liver injury was examined in mice. Administration of LPS (10 mg kg(-1), i.p.) markedly increased serum levels of tumor necrosis factor-alpha (TNFalpha), high mobility group box 1 (HMGB1), alanine aminotransferase/aspartate aminotransferase (ALT/AST), liver tissue levels of macrophage-inflammatory protein-1 alpha (MIP-1alpha) and monocyte chemoattractant protein-1 (MCP-1), as well as hepatic necrosis and inflammation, leading to 67 % lethality. Administration of T-5224 (300 mg kg(-1), p.o.) after intraperitoneal injection of LPS imparted appreciable protection against acute elevations in serum levels of TNFalpha, HMGB1, ALT/AST as well as in liver tissue levels of MIP-1alpha and MCP-1, and reduced the lethality (27 %). These data indicate that T-5224 ameliorates liver injury and improves survival through decreasing production of proinflammatory cytokines and chemokines in endotoxemic mice. PMID- 22927113 TI - Contribution of the Actinobacteria to the growing diversity of lantibiotics. AB - Currently, 76 lantibiotics have been described; the vast majority being produced by members of the Firmicute phylum of bacteria. There is a growing number being identified from the Actinobacteria phylum and some of these exhibit novel modifications leading to an increased functional diversity among lantibiotics. In this review, we discuss the currently characterized lantibiotics highlighting the expanding diversity provided by those from the Actinobacteria. This increased diversity has the potential to expand lantibiotic applications as antimicrobials in foods and pharmaceuticals. In addition, a phylogenetic classification system based on the full prepropeptide sequences showed remarkable consistency with current classification systems and may provide a more rapid and convenient means for classifying lantibiotics. PMID- 22927114 TI - The synthesis and the chemical and physical properties of non-aqueous silylamine solvents for carbon dioxide capture. AB - Silylamine reversible ionic liquids were designed to achieve specific physical properties in order to address effective CO2 capture. The reversible ionic liquid systems reported herein represent a class of switchable solvents where a relatively non-polar silylamine (molecular liquid) is reversibly transformed to a reversible ionic liquid (RevIL) by reaction with CO2 (chemisorption). The RevILs can further capture additional CO2 through physical absorption (physisorption). The effects of changes in structure on (1) the CO2 capture capacity (chemisorption and physisorption), (2) the viscosity of the solvent systems at partial and total conversion to the ionic liquid state, (3) the energy required for reversing the CO2 capture process, and (4) the ability to recycle the solvents systems are reported. PMID- 22927115 TI - Effect of switching to risperidone after unsuccessful treatment with aripiprazole on plasma monoamine metabolites level in the treatment of acute schizophrenia. AB - OBJECTIVE: In the treatment of acute schizophrenia, risperidone and aripiprazole are both placed the first line antipsychotics. These two antipsychotics have different pharmacological effects. We investigated the effects of risperidone on plasma levels of homovanillic acid (HVA) and 3-methoxy-4hydroxyphenylglycol after unsuccessful aripiprazole treatment in acute schizophrenia. METHODS: Ten Japanese patients with acute schizophrenia were enrolled to this study. Plasma levels of monoamine metabolites were analyzed with high-performance liquid chromatography with electrochemical detection. RESULTS: Risperidone improved the symptoms and 4 of 10 patients were responders. Risperidone showed a tendency to decrease plasma HVA (pHVA) levels in responders (p = 0.068), but not in non-responders (p = 1.0). At baseline, pHVA levels of responders were significantly higher than that of non responders (p = 0.033). A trend for negative correlation was found between pHVA at baseline and the changes in Positive and Negative Syndrome Scale-Total (p = 0.061, r = -0.61). CONCLUSION: Our results suggest that high pHVA level before switching may predict good response to the second line antipsychotics after unsuccessful first antipsychotic treatment. If aripiprazole is not effective in acute schizophrenia, switching to risperidone may be effective and reasonable strategy for improving symptoms. PMID- 22927116 TI - Absolute abundance and function of intestinal drug transporters: a prerequisite for fully mechanistic in vitro-in vivo extrapolation of oral drug absorption. AB - The use of whole body physiological-based pharmacokinetic (PBPK) models linked with in vitro-in vivo extrapolation (IVIVE) of kinetic parameters from laboratory experiments, has become embedded within many of the pharmaceutical industry and is used even as part of regulatory submissions. These include the influence of transporter proteins on drug disposition, a subject for which we have witnessed an increasing awareness. A combination of the development of high-powered analytical techniques and antibody-based technology, together with a realization that an understanding of absolute transporter protein abundances together with activity can potentially enhance the modelling of transporter kinetics by PBPK IVIVE link models. This review summarizes the mechanistic approaches to integrate suitable non-biased in vitro transporter kinetic data relevant to the intestine (i.e. 'intrinsic' K(i) , 'intrinsic' K(m) ), by in vitro system modelling for these kinetic inputs with the advantages of, and challenges for, generating these data for input into PBPK models. This step is considered as a prerequisite for mechanistic modelling of the oral absorption for drugs that are substrates for transporters. Various approaches are provided to integrate intestinal transporter expression into PBPK models with a perspective on the incorporation of the absolute abundance/activity of transporters to enhance the predictive power of the models. We define the key intestinal tissue and functional expression-based scaling factors required. The objective is to use these for facilitating the extrapolation from in vitro intestinal transporter assays to the in vivo system, using absolute quantification methodologies. The models could be used to elucidate the complex relationship and relative importance of metabolizing enzymes and transporters in drug disposition and toxicity. PMID- 22927117 TI - Stormwater contaminant loading following southern California wildfires. AB - Contaminant loading associated with stormwater runoff from recently burned areas is poorly understood, despite the fact that it has the potential to affect downstream water quality. The goal of the present study is to assess regional patterns of runoff and contaminant loading from wildfires in urban fringe areas of southern California. Postfire stormwater runoff was sampled from five wildfires that each burned between 115 and 658 km(2) of natural open space between 2003 and 2009. Between two and five storm events were sampled per site over the first one to two years following the fires for basic constituents, metals, nutrients, total suspended solids, and polycyclic aromatic hydrocarbons (PAHs). Results were compared to data from 16 unburned natural areas and six developed sites. Mean copper, lead, and zinc flux (kg/km(2)) were between 112- and 736-fold higher from burned catchments and total phosphorus was up to 921 fold higher compared to unburned natural areas. Polycyclic aromatic hydrocarbon flux was four times greater from burned areas than from adjacent urban areas. Ash fallout on nearby unburned watersheds also resulted in a threefold increase in metals and PAHs. Attenuation of elevated concentration and flux values appears to be driven mainly by rainfall magnitude. Contaminant loading from burned landscapes has the potential to be a substantial contribution to the total annual load to downstream areas in the first several years following fires. PMID- 22927118 TI - The bikini area and bikini line as a location for anterior subcutaneous pelvic fixation: an anatomic and clinical investigation. AB - Anterior external fixation for pelvic fractures has been the standard for acute stabilization but definitive treatment often leads to pin tract infection, is uncomfortable, and limits patient mobility. We recently developed a subcutaneous anterior pelvic fixator which addresses these issues (INFIX). The objective of this study is to introduce the Bikini Area and Bikini Line as the subcutaneous anatomical location where this apparatus is placed. A study was preformed on eight cadaveric specimens to define the location of the subcutaneous device with respect to anatomic structures. We examined 23 people of various body mass indexes to examine the anterior pelvic anatomy. This was followed by implantation on 42 individuals in whom we reviewed CT scans to assess the location of the implant. We asked these same 42 individuals whether they could sit, stand, and lie on their sides and if they had any discomfort. We measured the dimensions of 26 retrieved rods to approximate the curve of the Bikini Line. Finally in 14 individuals we performed vascular ultrasound to assess the flow in the iliac and femoral vessels with the implant in place in the sitting and standing position. Neurovascular structures are not affected by placing the INFIX device at the Bikini Line, patients are comfortable, mobile and complications are minimized by this procedure. A rod placed on the Bikini Line which connects screws inserted into the anterior inferior iliac spine on each side does not interfere with sitting, standing, or the neurovascular structures. PMID- 22927120 TI - Bioequivalence of long half-life drugs--informative sampling determination--using truncated area in parallel-designed studies for slow sustained-release formulations. AB - A simulation study was done to determine if 72 h is the most informative sampling duration for bioequivalence (BE) determination in parallel-designed BE studies with drugs that have half-lives of at least 30 h. The impact of absorption and elimination half-lives on informative sampling was evaluated. Two-treatment parallel-designed BE studies using a one-compartment oral absorption model with half-lives of 30 and 350 h was simulated. Area under the curve (AUC) values were truncated at 12-360 h. Experimental BE data [median time to reach the maximum concentration (T(max) ) = 20 h and low clearance = 0.192 L/h) indicated a decrease and then an increase in the intrasubject variability [root mean square error (RMSE)] for truncated AUC as a function of time. Simulations supported these findings with the highest probability of passing the BE confidence interval criteria being between 60 and 96 h, depending on half-life and percent coefficient of variation. The 30-h simulation exhibited a minimum in RMSE at 24-h truncation that continued to increase up to 360 h, whereas the 350-h simulation exhibited a minimum at 60 h, which increased after 96 h. Power curves at the 350 h half-life showed higher probabilities of rejection of BE for true test/reference ratios greater than 0.9. For parallel-designed BE studies, sampling beyond 120 h will not affect the BE decision and therefore is unnecessary. PMID- 22927119 TI - Prediction of Alzheimer's disease and mild cognitive impairment using cortical morphological patterns. AB - This article describes a novel approach to extract cortical morphological abnormality patterns from structural magnetic resonance imaging (MRI) data to improve the prediction accuracy of Alzheimer's disease (AD) and its prodromal stage, i.e., mild cognitive impairment (MCI). Conventional approaches extract cortical morphological information, such as regional mean cortical thickness and regional cortical volumes, independently at different regions of interest (ROIs) without considering the relationship between these regions. Our approach involves constructing a similarity map where every element in the map represents the correlation of regional mean cortical thickness between a pair of ROIs. We will demonstrate in this article that this correlative morphological information gives significant improvement in classification performance when compared with ROI based morphological information. Classification performance is further improved by integrating the correlative information with ROI-based information via multi kernel support vector machines. This integrated framework achieves an accuracy of 92.35% for AD classification with an area of 0.9744 under the receiver operating characteristic (ROC) curve, and an accuracy of 83.75% for MCI classification with an area of 0.9233. In differentiating MCI subjects who converted to AD within 36 months from non-converters, an accuracy of 75.05% with an area of 0.8426 under ROC curve was achieved, indicating excellent diagnostic power and generalizability. The current work provides an alternative approach to extraction of high-order cortical information from structural MRI data for prediction of neurodegenerative diseases such as AD. PMID- 22927121 TI - Generation of a novel mouse model for the inducible depletion of macrophages in vivo. AB - Macrophages play an essential role in tissue homeostasis, innate immunity, inflammation, and wound repair. Macrophages are also essential during development, severely limiting the use of mouse models in which these cells have been constitutively deleted. Consequently, we have developed a transgenic model of inducible macrophage depletion in which macrophage-specific induction of the cytotoxic diphtheria toxin A chain (DTA) is achieved by administration of doxycycline. Induction of the DTA protein in transgenic animals resulted in a significant 50% reduction in CD68+ macrophages of the liver, spleen, and bone over a period of 6 weeks. Pertinently, the macrophages remaining after doxycycline treatment were substantially smaller and are functionally impaired as shown by reduced inflammatory cytokine production in response to lipopolysaccharide. This inducible model of macrophage depletion can now be utilized to determine the role of macrophages in both development and animal models of chronic inflammatory diseases. PMID- 22927122 TI - The enemy within us: lessons from the 2011 European Escherichia coli O104:H4 outbreak. AB - In response to the 2011 European health alert caused by a pathogenic Escherichia coli O104:H4 outbreak, the European Academy of Microbiology (EAM), established by the Federation of European Microbiological Societies (FEMS), convened a meeting in Paris on November 30th, 2011 on 'EHEC infection and control' attended by world renowned experts in pathogenic E. coli. The major aims of this group were to review the scientific issues raised by the outbreak, to assess the handling of the crisis at the scientific and political levels, and to propose future actions. Several conclusions, which will have impact on future potential E. coli outbreaks, are outlined here. PMID- 22927124 TI - Microelectrode recording during deep brain stimulation and ablative procedures. PMID- 22927123 TI - Blood oxygenation level-dependent (BOLD)-based techniques for the quantification of brain hemodynamic and metabolic properties - theoretical models and experimental approaches. AB - The quantitative evaluation of brain hemodynamics and metabolism, particularly the relationship between brain function and oxygen utilization, is important for the understanding of normal human brain operation, as well as the pathophysiology of neurological disorders. It can also be of great importance for the evaluation of hypoxia within tumors of the brain and other organs. A fundamental discovery by Ogawa and coworkers of the blood oxygenation level-dependent (BOLD) contrast opened up the possibility to use this effect to study brain hemodynamic and metabolic properties by means of MRI measurements. Such measurements require the development of theoretical models connecting the MRI signal to brain structure and function, and the design of experimental techniques allowing MR measurements to be made of the salient features of theoretical models. In this review, we discuss several such theoretical models and experimental methods for the quantification of brain hemodynamic and metabolic properties. The review's main focus is on methods for the evaluation of the oxygen extraction fraction (OEF) based on the measurement of the blood oxygenation level. A combination of the measurement of OEF and the cerebral blood flow (CBF) allows an evaluation to be made of the cerebral metabolic rate of oxygen consumption (CMRO2 ). We first consider in detail the magnetic properties of blood - magnetic susceptibility, MR relaxation and theoretical models of the intravascular contribution to the MR signal under different experimental conditions. We then describe a 'through space' effect - the influence of inhomogeneous magnetic fields, created in the extravascular space by intravascular deoxygenated blood, on the formation of the MR signal. Further, we describe several experimental techniques taking advantage of these theoretical models. Some of these techniques - MR susceptometry and T2 based quantification of OEF - utilize the intravascular MR signal. Another technique - quantitative BOLD - evaluates OEF by making use of through-space effects. In this review, we target both scientists just entering the MR field and more experienced MR researchers interested in the application of advanced BOLD based techniques to the study of the brain in health and disease. PMID- 22927125 TI - Analysis of potential mercury policies: the impact of stream basin characteristics on susceptible populations. AB - Human exposure to Hg through fish consumption from local waterways is an ongoing concern to regulatory decision makers. Previously described population exposure and bioaccumulation models were combined to analyze the impact of potential policies on susceptible populations. The combined model simulated the problem of Hg exposure by examining the system from the point of Hg in the water column to its concentration in population biomarkers. Evaluated policy scenarios included the protectiveness of fish consumption advisories, total maximum daily load changes, and watershed management strategies. Simulations indicated that the characteristics of a basin combined with the unique pattern of intake rates of susceptible populations determine the risk associated with fish consumption from a given waterway. Each population had a unique pattern of biomarker response to changes in fish tissue Hg. Management strategies that lowered bioaccumulation rates also reduced ecosystem services. Reducing fish tissue contamination through reductions in Hg loading to watersheds is a long-term solution. For the short term, fish consumption advisories should be used to protect populations from adverse exposures. The combination of characteristics of the basin and the populations that fish from the waterway should be the determinant for setting advisories. PMID- 22927126 TI - Controversies regarding the pathophysiology of perioperative myocardial infarction. PMID- 22927129 TI - Probing translation initiation through ligand binding to the 5' mRNA coding region. AB - Secondary structure matters: We have constructed artificial intragenic riboswitches to probe ribosome accessibility to the 5' mRNA coding region at three-base resolution in Escherichia coli. We show that only mRNA folding stability in the +1 to +15 nt region affects the translation process. PMID- 22927130 TI - Factors associated with early and late failure of dental implants. AB - Osseointegration is a good indication of the clinical success of titanium implants referring to the direct anchorage of such implants to the surrounding host bone. Despite the high success rate of endosseous dental implants, they do fail. A lack of primary stability, surgical trauma, and infection seem to be the most important causes of early implant failure. Early signs of infection may be an indication of a much more critical result than if the same complications occur later, because of disturbance of the primary bone healing process. Occlusal overload and periimplantitis seem to be the most important factors associated with late failure. Suboptimal implant design and improper prosthetic constructions are among those risk factors responsible for implant complications and failure. This concise review highlights the main causes associated with early and late implant failure, as thorough knowledge of this unavoidable clinical fact is essential in the field of oral implantology. PMID- 22927132 TI - Endobronchial ultrasound fine-needle aspiration biopsy of pulmonary non-small cell carcinoma with subclassification by immunohistochemistry panel. AB - BACKGROUND: With the introduction of new treatment modalities and guidelines, it is important to subclassify primary pulmonary non-small cell carcinoma (NSCCA). Subsequent treatment and testing is dependent on accurate subclassification. Endobronchial ultrasound fine-needle aspiration (EBUS FNA) is used for primary evaluation and diagnosis, and can provide a cell block for ancillary testing. METHODS: EBUS FNA cases from primary pulmonary NSCCA with an immunohistochemical (IHC) panel performed on a cell block with concomitant surgical pathology biopsy were analyzed. Cell block preparations underwent an IHC panel including monoclonal antibodies for napsin A (nap-A), thyroid transcription factor (TTF-1), p63, and cytokeratin 5/6 (CK5/6). RESULTS: A total of 81 cases from 81 patients were identified. Of these, 69 cases (85%) were provided a specific diagnosis of adenocarcinoma (ADCA) or squamous cell carcinoma (SCCA) on the EBUS FNA. In 12 cases (15%), a diagnosis of NSCCA, not otherwise specified was provided. For specific subclassifications, there were 35 ADCA cases, 34 SCCA cases, and 12 NSCCA, not otherwise specified cases. For ADCA, nap-A showed granular cytoplasmic staining and TTF-1 nuclear staining. For SCCA, CK5/6 showed cytoplasmic staining and p63 nuclear staining. Surgical pathology concomitant material was present in 29 of 81 cases with 18 correlations and 11 noncorrelations. CONCLUSIONS: With new treatment guidelines for patients with primary pulmonary NSCCA, specific diagnosis is increasingly important. EBUS FNA with cell block provided a specific subclassification of NSCCA in 85% of cases when used in conjunction with a specific IHC panel including nap-A, TTF-1, CK5/6, and p63. PMID- 22927131 TI - Is there a relationship between hyperactivity/inattention symptoms and poor oral health? Results from the GINIplus and LISAplus study. AB - OBJECTIVES: A few clinical observations reported that children with attention deficit hyperactivity disorder (ADHD) have poor oral health compared to children without ADHD. However, evidence is not conclusive. We assess the association between hyperactivity/inattention and oral health in a population-based study. MATERIAL AND METHODS: As part of the ongoing birth cohort studies German Infant Nutritional Intervention-plus (GINIplus) and Influences of lifestyle-related factors on the immune system and the development of allergies in childhood-plus (LISAplus), 1,126 children at age 10 years (+/-10.2) from Munich (Germany) were included in the present analysis. During the dental examination, oral hygiene, non-cavitated and cavitated caries lesions, dental trauma, and enamel hypomineralization (EH) in the permanent dentition (MIH/1) were recorded. Children with a Molar-Incisor-Hypomineralization were subcategorized into those with EH on at least one first permanent molar (MIH/1A), and on at least one first permanent molar and permanent incisor (MIH/1B). Data on children's hyperactivity/inattention symptoms were collected by parent-reported Strength and Difficulties Questionnaire. Logistic regressions and zero-inflated Poisson regression models were applied adjusted for gender, parental education, parental income, and methylphenidate or atomoxetine medication. RESULTS: Logistic regressions showed that non-cavitated caries lesions were positively related with the presence of hyperactivity/inattention (ORadj = 1.51,CI95% = 1.08-2.11). When adjusted for parental background, an association showed between hyperactivity/inattention symptoms and MIH/1A but did not reach statistical significance (ORadj = 1.59,CI95% = 1.00-2.53). CONCLUSIONS: Children with borderline and abnormal values of hyperactivity/inattention symptoms showed more non-cavitated caries lesions. Severe levels of hyperactivity/inattention may contribute to a higher risk for MIH/1A in school age. CLINICAL RELEVANCE: Adequate dental preventive care for children with hyperactivity/inattention, especially from a low social background, is of importance for optimal caries prevention. PMID- 22927133 TI - Metal-free aerobic alcohol oxidation: intensification under three-phase flow conditions. AB - The selective oxidation of alcohols is a pivotal transformation within industrial and synthetic chemistry. In this contribution we use O2 as terminal oxidant and (H)NO(x) species as oxygen shuttle in order to mediate the oxidation of primary and secondary alcohols under the influence of a solid acid catalyst. Process optimization and intensification through the use of a continuous three-phase flow reactor is demonstrated. Space-time yields were found to increase by two orders of magnitude with respect to batch experiments, along with additional gains in selectivity and a decrease of N2O formation. PMID- 22927134 TI - Characteristics of bipolar disorder patients given antidepressants. AB - Evidence concerning efficacy of antidepressants in bipolar disorder remains inconsistent and inconclusive. As the appropriate clinical use for such patients remains unclear, we characterized outpatients with bipolar disorders who were or were not treated with antidepressants. Clinical data were collected systematically from consecutive outpatients in 11 participating Argentine mood disorder clinics in 2007-2008. Diagnoses met DSM-IV criteria, supported by structured interviews based on the MINI-500. Of 338 outpatients diagnosed with bipolar I (45.0%), II (29.3%), or not-otherwise-specified (NOS) (25.7%) disorder, 128 (37.9%) received antidepressants. Subjects given antidepressants or not did not differ significantly by presence or severity of current depression or being suicidal but were more likely to be women. Bipolar I disorder patients were three times less likely than types II or NOS to receive an antidepressant, with or without a mood-stabilizer or antimanic agent. Despite inconclusive evidence for efficacy and safety of antidepressants in various phases of bipolar disorders, 37.9% of such patients were receiving an antidepressant in 11 Argentine outpatient clinics. Antidepressant treatment was least likely with type I disorder and was independent of current depression and not associated with more use of mood-stabilizing or antimanic agents. PMID- 22927135 TI - Evo-devo in the era of gene regulatory networks. AB - Advanced genomics tools enable powerful new strategies for understanding complex biological processes, including development. By extension, we should be able to use these methods in a comparative fashion to capture evolutionary mechanisms. This requires a capacity to go deep and broad, to analyze developmental gene regulatory networks in many organisms, especially nontraditional models. As we usher in a new era of next-generation GRN (gene regulatory network) analysis, it is important to ask how to evaluate the evolution of network interactions. Particularly problematic, as always, is defining "independence": Are two character traits found together because they are functionally linked or because of historical accident? The same basic question applies to understanding developmental GRN evolution. However, the essential difference here is that a GRN defines a causal chain of events. An understanding of causal relations--how Genes A and B work in concert to drive expression of Genes C and D to create a new Territory E--gives hope for establishing "trait independence" in a way that purely correlative arguments--the association of the expression of Gene D in Territory E--never could. Insight into causality provides the key to interpretation, as seen in this simplified scenario. Real-world networks bring new degrees of complexity, but the elucidation of causal relations remains the same. Has the day arrived when a single laboratory has the wherewithal to conduct multiorganism gene network projects in parallel? No. However, we argue that day is closer than one might suppose. We describe how a speedboat GRN project in one's favorite nonmodel organism(s) might look and provide a framework for comparative network analysis. PMID- 22927137 TI - Repeated dosing of piperine induced gene expression of P-glycoprotein via stimulated pregnane-X-receptor activity and altered pharmacokinetics of diltiazem in rats. AB - This study investigated the effect of piperine on the gene expression of P glycoprotein (P-gp) as well as pregnane-X-receptor (PXR) activity and also its implication on the bioavailability of diltiazem, a P-gp substrate. The effect of piperine on the systemic exposure of diltiazem was examined in rats after the intravenous and oral administration of diltiazem with/without 2 week pretreatment with piperine. Compared with the control group given diltiazem (20 mg/kg) alone, the pretreatment with piperine (10 or 20 mg/kg, once daily for 2 weeks) decreased the oral exposure of diltiazem by 36-48% in rats. Consequently, the bioavailability of oral diltiazem was significantly lower (p < 0.05) after the 2 week pretreatment with piperine. The pretreatment with piperine for 2 weeks also reduced the systemic exposure of desacetyldiltiazem, a major active metabolite of diltiazem by approximately 73%, accompanied by a significant decrease in the metabolite-parent ratio. In contrast to the oral pharmacokinetics, piperine did not affect the intravenous pharmacokinetics of diltiazem in rats. Immunoblot analysis indicated that the protein expression level of intestinal P-gp was significantly enhanced after the 2 week pretreatment with piperine in rats. In addition, piperine increased the PXR reporter activity in human hepatoma cells. Taken together, the 2 week pretreatment with piperine significantly induced intestinal P-gp expression in conjunction with stimulated PXR activity and decreased the oral exposure of diltiazem and desacetyldiltiazem in rats. PMID- 22927136 TI - Creating females? Developmental effects of 17alpha-ethynylestradiol on the mangrove rivulus' ovotestis. AB - Interest in the occurrence and fate of trace organic contaminants in the aquatic environment and their potential effects on all organisms has increased over the past two decades. Researches on contaminants have included both natural and synthetic estrogenic contaminants, neuroactive pharmaceuticals, and other endocrine disrupting chemicals that are mediated by the androgen and progesterone receptors. Exposure to very low concentrations (ng/L or parts per trillion) of compounds such as 17alpha-ethynylestradiol (EE(2)), a synthetic estrogen, can affect gonadal development, viability and production of eggs, fertilization rate, and sexual differentiation in fishes. Researchers and aquaculturists have used exposures to relatively higher concentrations of androgens and estrogens, for example 17alpha-methyltestosterone and EE(2), respectively, to direct sexual differentiation in a number of fishes. Rivulus is an androdioecious teleost that in nature exists mostly as selfing, simultaneous hermaphrodites as well as a small number of males that outcross with hermaphrodites. No one has either collected females in the wild or created functional females in the laboratory. This study had two goals: (1) to develop a reliable protocol to produce female rivulus to enable downstream technologies such as embryo injections and (2) to investigate developmental effects of EE(2) on the sexual outcome, reproductive health, and relevant gene expression in rivulus. With these goals in mind, we exposed newly hatched rivulus to nominal concentrations of 0.1, 0.5, or 1.0 parts per million (ppm) EE(2) for 4 weeks, grew them to maturity in control water, and then compared egg production; production and viability of embryos; age of reproductive maturity; and gene expression in the brain, gonad, and liver. Expression levels of seven genes with known relevance to gonadal development and function (cyp19a1b, cyp19a1a, dmrt1, figalpha, ERalpha, ERbeta, and vtg) were measured using quantitative polymerase chain reaction (PCR). There was a significant decrease in cyp19a1a gene expression in the brain, corresponding to increased exposure to EE(2). Gonadal gene expression for cyp19a1a, ERalpha, and dmrt1 also decreased in response to EE(2). Vtg expression in the liver was unaffected. Our hypothesis that exposure to EE(2) during gonadal differentiation would direct female development was not supported by the data. However, treated fish exhibited impaired reproductive health that included reduced expression of relevant genes and, importantly, decreased fertility, increased sterility, and delay of age of reproductive maturity. The results of this study suggest that the development and maintenance of a simultaneous hermphrodite ovotestis may be particularly sensitive to its hormonal milieu. PMID- 22927138 TI - Subacute toxicity of nano-selenium compared to other selenium species in mice. AB - Sixteen groups of mice were fed diets containing different selenium species to compare their toxicity. Inorganic sodium selenate and sodium hydroselenite, elementary nanoSe, organic Sel-Plex, and Lacto-MicroSelenium were administered for 14 d at concentrations of 0.5, 5, and 50 ppm Se, equivalent to 0.5, 5, and 50 mg Se/kg food, corresponding to an estimated 4, 40, and 400 ug/kg body weight/d Se uptake, respectively. At the end of the treatment, body, liver, spleen, kidney, heart, and brain weights were measured, mice were subjected to necropsy, and histological examinations were performed on the liver. At lower Se doses (0.5 and 5 ppm) a moderate reduction was observed in the number of bone marrow and white blood cells and in granulocyte-macrophage colony-forming units (GM-CFUs) relative to the untreated control group of mice. A comparison of lowest toxic doses of sodium selenite in mice (0.5 ppm) and mallard (10 ppm) indicates that birds are more resistant to Se than rodents. In mice, a small but measurable weight loss was observed after 5 ppm selenate and LactoMicroSe treatment. The most significant changes took place after 50-ppm administration in body and spleen weight, hematology, and liver histology. Toxicity was more pronounced when inorganic Se was applied than after subacute application of Sel-Plex, nanoSe, or LactoMicroSe. To summarize the effects, the authors' 14-d murine subacute toxicity study showed that the toxicity of Se species decreased in the following order: selenate > selenite > nanoSe > Sel-Plex > LactoMicroSe. PMID- 22927139 TI - First hand accounts of events in the laboratory of Prof. Eduard Pernkopf. Interviews by Seyed Hossein Aharinejad and Stephen W Carmichael. AB - Eduard Pernkopf was responsible for one of the best anatomy atlases of all time. He was also an active National Socialist during the Third Reich. Some have questioned whether his political affiliation influenced the procurement of anatomic specimens for his Atlas. Profs. Walter Kraus, Alfred Gisel, and Werner Platzer, who worked directly or indirectly with Pernkopf, were interviewed in 2006. We present transcripts of those interviews. The reader may evaluate their recollections in light of the political and social forces active in that period of history. PMID- 22927140 TI - Formulation approaches to short interfering RNA and MicroRNA: challenges and implications. AB - RNA interference has emerged as a potentially powerful tool in the treatment of genetic and acquired diseases by delivering short interfering RNA (siRNA) or microRNA (miRNA) to target genes, resulting in their silencing. However, many physicochemical and biological barriers have to be overcome to obtain efficient in vivo delivery of siRNA and miRNA molecules to the organ/tissue of interest, thereby enabling their effective clinical therapy. This review discusses the challenges associated with the use of siRNA and miRNA and describes the nonviral delivery strategies used in overcoming these barriers. More specifically, emphasis has been placed on those technologies that have progressed to clinical trials for both local and systemic siRNA and miRNA delivery. PMID- 22927141 TI - Distinct laterality alterations distinguish mild cognitive impairment and Alzheimer's disease from healthy aging: statistical parametric mapping with high resolution MRI. AB - Laterality of human brain varies under healthy aging and diseased conditions. The alterations in hemispheric asymmetry may embed distinct biomarkers linked to the disease dynamics. Statistical parametric mapping based on high-resolution magnetic resonance imaging (MRI) and image processing techniques have allowed automated characterization of morphological features across the entire brain. In this study, 149 subjects grouped in healthy young, healthy elderly, mild cognitive impairment (MCI), and Alzheimer's disease (AD) were investigated using multivariate analysis for regional cerebral laterality indexed by surface area, curvature index, cortical thickness, and subjacent white matter volume measured on high-resolution MR images. Asymmetry alteration of MCI and AD were characterized by marked region-specific reduction, while healthy elderly featured a distinct laterality shift in the limbic system in addition to regional asymmetry loss. Lack of the laterality shift in limbic system and early loss of asymmetry in entorhinal cortex may be biomarkers to identify preclinical AD among other dementia. Multivariate analysis of hemispheric asymmetry may provide information helpful for monitoring the disease progress and improving the management of MCI and AD. PMID- 22927142 TI - Increasing the recipient benefit/donor risk ratio by lowering the graft size requirement for living donor liver transplantation. AB - In living donor liver transplantation (LDLT), a right liver graft is larger than a left liver graft and hence leads to better recipient survival. However, in comparison with donor left hepatectomy, donor right hepatectomy carries a higher donor risk. We estimated the expansion of the applicability of left liver living donor liver transplantation (LLDLT) by lowering the graft weight (GW)/standard liver volume (SLV) ratio in increments of 5%. Consecutive LDLT cases were included in this study. The results of computed tomography volumetry provided the graft volume measurements, and the GW was derived from the graft volume with the conversion factor of 1.19 mL/g. We tried to estimate how many more times LLDLT would have been feasible if the GW/SLV requirement had been lowered to 40%, 35%, 30%, or 25%. In all, 361 consecutive donor-recipient pairs underwent LDLT. Right liver living donor liver transplantation (RLDLT) accounted for 95% of the LDLT cases. Most recipients were male (74.2%), and most donors were female (60.4%). The median GW/SLV ratio was 46% (47% for RLDLT and 37% for LLDLT, P < 0.001). Two of the 218 female donors donated the left liver, and 12 of the 93 female recipients received a left liver. In 147 of the 173 cases (85%) when the donor was female and the recipient was male, the GW/SLV ratio did not reach 30%. LLDLT could have been performed more often than 5% of the time if a lower GW/SLV requirement had been adopted. With GW/SLV ratios >= 40%, >= 35%, >= 30%, and >= 25%, the proportion of LLDLT cases would have risen from 5% to 5.8%, 12.5%, 29.1%, and 62.3%, respectively. LLDLT could have been performed approximately twice as often with every 5% reduction of the GW/SLV requirement. In conclusion, lowering the graft size requirement could improve the applicability of LLDLT and hence reduce donor risk. PMID- 22927144 TI - Retraction. ''Use of an upper midline incision for living donor partial hepatectomy: a series of 143 consecutive cases''. PMID- 22927143 TI - Mortality associated with carbapenem-resistant Klebsiella pneumoniae infections in liver transplant recipients. PMID- 22927145 TI - Chinese experts' consensus on the diagnosis and treatment of osteonecrosis of the femoral head in adults. PMID- 22927146 TI - Research status and application prospects of digital technology in orthopaedics. AB - In the last 10 years, basic and clinical research in orthopaedics has developed rapidly. Understanding of orthopaedic disorders involves not only routine diagnosis, but also the pursuit of highly efficient and accurate three dimensional imaging of the intra- and extra-medullary distribution, form and structure of orthopaedic disorders, thus allowing scientific evaluation of the indications for surgery, drawing up of the best surgical plan, minimization of operative trauma and the earliest possible restoration of limb function. Meanwhile, the most important type of basic research, which was previously biomechanical research, has gradually become computational biomechanics based on in vitro cadaver experiments. This review aims to summarize the research status and application prospects of digital technology in orthopaedics, including virtual reality technology, reverse engineering and rapid prototyping techniques, computational biomechanics, computer navigation technology and management of digitization of medical records. PMID- 22927147 TI - Current application of beta-tricalcium phosphate composites in orthopaedics. AB - Presently, bioceramic materials have been extensively used in spinal surgery as bone grafts; however, there are some limitations for bioceramic materials. Calcium sulfate is rapidly absorbed in vivo, the degradation of which often occurs prior to the formation of new bones. Hydroxyapatite (HA) is hardly absorbed, which blocks the formation of new bones and remodeling, and results in poor local stability or permanent stress concentration. Only beta-tricalcium phosphate (beta-TCP) is relatively balanced between scaffold absorption and bone formation. And it is a good biodegradable ceramic material that could supply a large quantity of calcium ion and sulfate ion as well as scaffold structure for bone regeneration. However, the problem of single beta-TCP is lack of osteoinductivity and osteogenicity, which restricts its application. Therefore beta-TCP composite materials have been used in the field of orthopaedics in recent decades, which fully use excellent properties of other bone repairing materials, such as biodegradability, osteoinductivity, osteogenicity and osteoconductivity. These materials make up for the deficiencies of single beta TCP and endow beta-TCP with more biological and physical properties. PMID- 22927148 TI - Relationship of surgical accuracy and clinical outcomes in Charite lumbar disc replacement. AB - OBJECTIVE: To retrospectively assess the clinical and functional outcomes of a group of patients receiving Charite lumbar disc replacement and to compare those outcomes to the corresponding surgical technical accuracy. METHODS: A retrospective study of all patients treated over a 3-year period was undertaken. Objective pain scores were quantified from 1 to 10. Short Form 36-Health Survey (SF-36v2) scores were compared to Australian population norms. Surgical placements were radiographically classified. Heterotopic ossification, disc height restoration and angle-defined instability were assessed using established protocols. RESULTS: Twenty-five patients were identified with three patients lost to follow-up. Average follow-up was 34 months. Ideal surgical placement was achieved in five (33%) single-level and three (37.5%) dual-level disc replacements. Sub-optimal surgical placement was seen in nine (60%) single-level and five (62.5%) dual-level disc replacements. Poor surgical placement was observed in a single-level disc replacement. All patients demonstrated a reduction in objective pain score (P < 0.05). SF-36v2 outcomes were superior in single-level compared to dual-level and ideal compared to sub-optimal replacements (P < 0.05). CONCLUSION: The hypothesis that ideal surgical placements are associated with improved clinical and functional outcomes in total lumbar disc replacement was confirmed. PMID- 22927149 TI - Biphasic calcium phosphate contained within a polyetheretherketone cage with and without plating for anterior cervical discectomy and fusion. AB - OBJECTIVE: To evaluate the properties of a combination bone graft consisting of biphasic calcium phosphate ceramic, polyetheretherketone (PEEK) cage in one- and two-level surgery. METHODS: Over a 12-month time period, a prospective single surgeon series of 75 patients were included in the study and 58 patients selected based on adequate data points. From these 58 patients, 32 were supplemented with anterior plate fixation and 26 patients without plating. Duration of clinical follow-up was a mean of 12.4 months (range, 6-26 months) in the Plated Group and 10.5 months (range, 6-21 months) in the Non-Plated Group. RESULTS: A 100% fusion rate with nil graft related complications was achieved in the Plated group compared with 96.2% fusion and 11.5% subsidence rates reported in the Non-Plated group. Patients in both groups experienced statistically significant improvement in pain and functional outcomes compared to their pre-operative status; however, there was no significant difference in outcome between the Plated and Non-Plated Groups. CONCLUSIONS: Biphasic calcium phosphate ceramic contained within a PEEK cage is an effective implant for use in anterior cervical surgery with high fusion rates and good clinical outcome. PMID- 22927150 TI - Gunshot femoral fractures with vascular injury: a retrospective analysis. AB - OBJECTIVE: To retrospectively investigate the experience at one urban level one trauma center with gunshot femoral fractures with vascular injury and to examine the implication of surgical sequence with regards to short-term complications and ischaemia time. METHODS: We performed a retrospective study of 24 patients treated at an urban level one trauma center over a 10-year period with low velocity gunshot wounds resulting in femur fractures and major vascular injury. Data were stratified according to sequence of surgical intervention. RESULTS: The mean age was 31.3 years. Mean time to revascularization was highest in patients undergoing definitive orthopaedic fixation first (660 min) and lowest in patient undergoing shunting first (210 min). Most complications in patients undergoing vascular repair first, included two disrupted repairs requiring immediate revision after subsequent orthopaedic fixation. Other complications included compartment syndrome and one amputation. CONCLUSION: Surgical sequence did not appear to impact the outcome with regard to limb loss, compartment syndrome, or mortality. Orthopaedic repair following vascular repair, however, is a risk for disruption of the vascular repair. We suggest that close and early direct communication between the orthopaedic and vascular surgeons take place in order to facilitate a satisfactory outcome. PMID- 22927151 TI - Value of bone scan imaging in determining painful vertebrae of osteoporotic vertebral compression fractures patients with contraindications to MRI. AB - OBJECTIVE: To assess the value of bone scan imaging in determining painful vertebrae of osteoporotic vertebral compression fractures (OVCFs) patients with contraindications to MRI. METHODS: Twenty-three OVCFs patients with contraindications to MRI, diagnosed and treated in our hospital between December 2007 and November 2010, were enrolled in this retrospective study. There were 18 females and five males, aged from 57 to 87 years, with a mean age of 69.5 years. All patients underwent X-ray, CT scans examinations and bone scan to determine painful vertebrae. After the painful vertebra was defined, percutaneous kyphoplasty (PKP) was performed. Efficacy of PKP was assessed with visual analog (VAS) pain scale and the Oswestry Disability Index (ODI) preoperatively, postoperatively and during final follow-up assessments. RESULTS: The painful vertebrae shown on radiological films did not accord with those found based on bone scan imaging, with a high rate of incongruent findings (27.3%, 9/33). Radiological films showed 33 vertebrae with fractures, but only 26 vertebrae (22 patients) were selected as painful vertebrae for PKP based on bone scan imaging. There were statistically significant differences in mean VAS and ODI between the preoperative and the postoperative assessments; no significant differences were observed between postoperative and final follow-up assessments. CONCLUSIONS: For the OVCFs patients with contraindications to MRI, bone scan imaging could be used to determine painful vertebrae, which is an effective method. PMID- 22927152 TI - Management of neglected elbow dislocations in a setting with low clinical resources. AB - OBJECTIVE: To investigate the effect of open reduction operative treatment in neglected elbow dislocation. METHODS: Between January 2009 and October 2010, 13 patients (mean, 27 years, nine men and four women) with old unreduced posterior dislocation of the elbow were treated by open reduction and removal of fibrous tissue between distal humerus and ulna with Kirschner wire fixation with or without triceps lengthening in our hospital. RESULTS: The patients were followed up for a mean of 18 (range, 14-22) months. The mean operating time was 69.53 (range, 56-90) min. Mean operative blood loss 361.53 mL (range, 300-450 mL), mean tourniquet time 51.92 min (range, 46-70 min). According to the Mayo Elbow Performance Index at the final follow-up, 11 patients had satisfactory outcomes (six excellent, five good) and two patients had unsatisfactory outcomes (one fair and one poor). The mean score was 87. Nine patients had no pain, two had mild pain during repetitive elbow movements or weight lifting, and two had moderate pain. The mean pain score was 38 (range, 15-45). At the final follow-up, two patients had signs of instability; the mean score was 15. Seven achieved a flexion range of 105 degrees to 130 degrees , two achieved 100 degrees , two achieved 95 degrees , one achieved 80 degrees , and one 60 degrees . CONCLUSION: Operative treatment of late-presenting, unreduced elbow dislocation is effective in restoring the joint to a painless, stable and functional limb. PMID- 22927153 TI - Pulmonary cement embolism associated with percutaneous vertebroplasty or kyphoplasty: a systematic review. AB - Therapeutic vertebral cement augmentation for the treatment of painful skeletal diseases, although widely applied for more than several decades, still has not thoroughly resolve the problem of cement extravasation. Based on a review of literature published, the present study was to provide a systematic review of the current understanding of pulmonary cement embolism (PCE) associated with percutaneous vertebroplasty (PVP) or percutaneous kyphoplasty (PKP), and to summarize the incidence, clinical features, prophylaxis and therapeutic management of PCE after vertebral cement reinforcement. The reported incidence of PCE ranges widely, from 2.1% to 26%. Asymptomatic PCE is a common condition without permanent clinical sequelae. Nevertheless, it is emergent once a symptomatic PCE is presented. Close attention and effective pre-measures should be taken to avoid this catastrophic complication. PMID- 22927154 TI - Isolated Crytococcus neoformans osteomyelitis of the proximal femur: a case report and review of literature. PMID- 22927155 TI - Significantly displaced femoral head component in a dissociated bipolar hip hemiarthroplasty. PMID- 22927156 TI - Atraumatic heterotopic ossification of iliopsoas muscle: a case report. PMID- 22927157 TI - Caffeine and risk of Parkinson's disease in a large cohort of men and women. AB - Caffeine consumption has been associated with a reduced risk of Parkinson's disease (PD). The association is strong and consistent in men, but uncertain in women, possibly because of an interaction with hormone replacement therapy (HRT). We sought to confirm these findings using data on PD incidence in the Cancer Prevention Study II Nutrition Cohort (CPS II-Nutrition), a large, prospective study of men and women. We conducted a prospective study of caffeine intake and risk of PD within the CPS II Nutrition Cohort. Intakes of coffee and other sources of caffeine were assessed at baseline. Incident cases of PD (n = 317; 197 men and 120 women) were confirmed by treating physicians and medical record review. Relative risks (RRs) were estimated using proportional hazards models, adjusting for age, smoking, and alcohol consumption. After adjustment for age, smoking, and alcohol intake, high caffeine consumption was associated with a reduced risk of PD. The RR comparing the 5th to the 1st quintile of caffeine intake was 0.43 (95% confidence interval [CI]: 0.26, 0.71; P trend = <0.002) in men, and 0.61 (95% CI: 0.34, 1.09; P trend = 0.05) in women. Among women, this association was stronger among never users of HRT (RR = 0.32) than among ever users (RR = 0.81; P interaction = 0.15). Consumption of decaffeinated coffee was not associated with PD risk. Findings from this large, prospective study of men and women are consistent with a protective effect of caffeine intake on PD incidence, with an attenuating influence of HRT in women. (c) 2012 Movement Disorder Society. PMID- 22927158 TI - Microactuator device for integrated measurement of epithelium mechanics. AB - Mechanical forces are among important factors that drive cellular function and organization. We present a microfabricated device with on-chip actuation for mechanical testing of single cells. An integrated immersible electrostatic actuator system is demonstrated that applies calibrated forces to cells. We conduct stretching experiments by directly applying forces to epithelial cells adhered to device surfaces functionalized with collagen. We measure mechanical properties including stiffness, hysteresis and visco-elasticity of adherent cells. PMID- 22927159 TI - Palliative stent placement in vertical vein in a 1.4 kg infant with obstructed supracardiac total anomalous pulmonary venous connection. AB - Temporary relief of obstructed total anomalous pulmonary venous connection (TAPVC) may stabilize the preoperative clinical status. We report a 1.4 kg infant with obstructed supracardiac TAPVC to right sided superior vena cava, double outlet right ventricle, pulmonary atresia, major aortopulmonary collateral arteries, and atrioventricular septal defect. A palliative percutaneous stent was successfully placed and resulted in immediate clinical improvement. We performed a review of literature regarding interventional procedures for relief of obstructed TAPVC and found 17 cases including stent placement (13), balloon angioplasty (3), and Hybrid procedure (1). We conclude that temporary stent placement in obstructed TAPVC is feasible and efficacious in relieving pulmonary venous obstruction. The procedure can lead to subsequent surgical repair in a more favorable clinical status and has special significance in the low birth weight infant. PMID- 22927160 TI - Gene expression array analysis to determine tissue of origin of carcinoma of unknown primary: cutting edge or already obsolete? PMID- 22927161 TI - Accumulated state of the Yukon River watershed: part I critical review of literature. AB - A consistent methodology for assessing the accumulating effects of natural and manmade change on riverine systems has not been developed for a whole host of reasons including a lack of data, disagreement over core elements to consider, and complexity. Accumulated state assessments of aquatic systems is an integral component of watershed cumulative effects assessment. The Yukon River is the largest free flowing river in the world and is the fourth largest drainage basin in North America, draining 855,000 km(2) in Canada and the United States. Because of its remote location, it is considered pristine but little is known about its cumulative state. This review identified 7 "hot spot" areas in the Yukon River Basin including Lake Laberge, Yukon River at Dawson City, the Charley and Yukon River confluence, Porcupine and Yukon River confluence, Yukon River at the Dalton Highway Bridge, Tolovana River near Tolovana, and Tanana River at Fairbanks. Climate change, natural stressors, and anthropogenic stresses have resulted in accumulating changes including measurable levels of contaminants in surface waters and fish tissues, fish and human disease, changes in surface hydrology, as well as shifts in biogeochemical loads. This article is the first integrated accumulated state assessment for the Yukon River basin based on a literature review. It is the first part of a 2-part series. The second article (Dube et al. 2013a, this issue) is a quantitative accumulated state assessment of the Yukon River Basin where hot spots and hot moments are assessed outside of a "normal" range of variability. PMID- 22927162 TI - Synthesis and evaluation of a selective fluorogenic Pup derived assay reagent for Dop, a potential drug target in Mycobacterium tuberculosis. AB - A litter of pups: The synthesis and in vitro evaluation of new Pup-based fluorogenic substrates for Dop, the mycobacterial depupylase, are described. A full-length Pup-amidomethylcoumarin conjugate as well as an amino-terminus truncated analogue exhibited high sensitivity and specificity towards hydrolysis by Dop. The substrates developed here might find application as high-throughput screening assay reagents for the identification of Dop inhibitors. PMID- 22927163 TI - Blood oxygenation level-dependent functional MRI signal turbulence caused by ultrahigh spatial resolution: numerical simulation and theoretical explanation. AB - High-spatial-resolution functional MRI (fMRI) can enhance image contrast and improve spatial specificity for brain activity mapping. As the voxel size is reduced, an irregular magnetic fieldmap will emerge as a result of less local averaging, and will lead to abnormal fMRI signal evolution with respect to the image acquisition TE. In this article, we report this signal turbulence phenomenon observed in simulations of ultrahigh-spatial-resolution blood oxygenation level-dependent (BOLD) fMRI (voxel size of less than 50 * 50 * 50 um3). We present a four-level coarse-to-fine multiresolution BOLD fMRI signal simulation. Based on the statistical histogram of an intravoxel fieldmap, we reformulate the intravoxel dephasing summation (a form of Riemann sum) into a new formula that is a discrete Fourier transformation of the intravoxel fieldmap histogram (a form of Lebesgue sum). We interpret the BOLD signal formation by relating its magnitude (phase) to the even (odd) symmetry of the fieldmap histogram. Based on multiresolution BOLD signal simulation, we find that the signal turbulence mainly emerges at the vessel boundary, and that there are only a few voxels (less than 10%) in an ultrahigh-resolution image that reveal turbulence in the form of sparse point noise. Our simulation also shows that, for typical human brain imaging of the cerebral cortex with millimeter resolution, TE < 30 ms and B0 = 3 T, we are unlikely to observe BOLD signal turbulence. Overall, the main causes of voxel signal turbulence include a high spatial resolution, high field, long TE and large vessel. PMID- 22927164 TI - Net trophic transfer efficiencies of polychlorinated biphenyl congeners to lake trout (Salvelinus namaycush) from its prey. AB - Lake trout (Salvelinus namaycush) were fed bloater (Coregonus hoyi) in eight laboratory tanks over a 135-d experiment. At the start of the experiment, four to nine fish in each tank were sacrificed, and the concentrations of 75 polychlorinated biphenyl (PCB) congeners within these fish were determined. Polychlorinated biphenyl congener concentrations were also determined in the 10 lake trout remaining in each of the eight tanks at the end of the experiment as well as in the bloater fed to the lake trout. Each lake trout was weighed at the start and the end of the experiment, and the amount of food eaten by the lake trout was recorded. Using these measurements, net trophic transfer efficiency (gamma) from the bloater to the lake trout in each of the eight tanks was calculated for each of the 75 congeners. Results showed that gamma did not vary significantly with the degree of chlorination of the PCB congeners, and gamma averaged 0.66 across all congeners. However, gamma did show a slight, but significant, decrease as log K(OW) increased from 6.0 to 8.2. Activity level of the lake trout did not have a significant effect on gamma. PMID- 22927165 TI - Investigation of the effect of ibuprofen on the healing of osseointegrated oral implants. AB - OBJECTIVE: To investigate the effect of a 1-week postoperative course of 600 mg of ibuprofen taken four times a day on marginal bone level around oral implants. MATERIALS AND METHODS: Twenty-eight patients were allocated to the ibuprofen group (14 patients) or no-ibuprofen group (14 patients). Overall, 57 implants were inserted, 31 implants in the ibuprofen group and 26 in the no-ibuprofen group. The primary outcome measure was the change in marginal bone level around oral implants from baseline (2 weeks postplacement) to the 3- and 6-month radiographic examinations. The paralleling technique and a film holder coupled to a beam-aiming device were used to take the periapical radiographs. Measurement of changes in bone level was made using a viewing box and *8 magnifier. RESULTS: Three subjects were withdrawn from the therapy early as they did not complete the dose of ibuprofen (e.g. because of self-reported stomach upset). The mean marginal mesial bone loss from the baseline was 0.37 mm at the 3-month and 0.27 mm at the 6-month follow up for the ibuprofen group, while the corresponding values for the no-ibuprofen group were 0.15 mm and 0.08 mm. The mean marginal distal bone loss from the baseline was 0.42 mm at the 3-month and 0.2 mm at the 6 month follow up for the ibuprofen group, while the corresponding values for the no-ibuprofen group were 0.08 mm and 0.15 mm. There were no significant differences between the ibuprofen and no-ibuprofen groups when comparing the bone changes. CONCLUSION: Administration of a short course of systemic ibuprofen for postoperative pain management following implant insertion may not have a significant effect on the marginal bone loss around oral implants in the early healing phase. PMID- 22927166 TI - TectoRNP: self-assembling RNAs with peptide recognition motifs as templates for chemical peptide ligation. AB - TectoRNA, an artificial RNA with self-assembling ability, has been employed as a structural platform for RNA nanotechnology and RNA synthetic biology. In this study, tectoRNA was applied as a specific template for chemical peptide ligation. On the basis of a self-assembling tectoRNA, we designed and constructed a template RNA that facilitates peptide ligation depending on controlled dimer formation. Two RNA-binding peptides were recognized by two peptide-binding RNA motifs embedded in the template RNA, and chemical ligation was promoted because of the entropic effect of Mg(2+) -dependent dimerization. In a series of biochemical analyses, we determined the relationship between the structures of the tectoRNA-based templates and the extent of acceleration in peptide ligation. PMID- 22927167 TI - Exploiting stem cell therapy: the 3rd meeting of stem cell research Italy. AB - The study of stem cells is one of the most exciting areas of contemporary biomedical research. During the 3rd Joint Meeting of Stem Cell Research Italy (June 2012, Ferrara, Italy), scientists from different multidisciplinary areas explored new frontiers of basic and applied stem cell research with key lectures and oral presentations. There was a public debate on ethics during the opening ceremony, specifically on the limits and potentialities of adult and embryonic stem cells. Some scientists presented basic research data showing evolutionary aspects, which could be of interest in understanding specific biological phenomena. Others focused on "dangerous liaisons" between gene transfer vectors and the human genome. Some speakers provided insight into current stem cell therapies, such as those involving human epithelial stem cells for treatment of skin diseases. Other researchers presented data on close-to-therapy findings, such as the use of mesenchymal stem cells in brain repair. Of note, during the meeting, spotlights were focused on major issues that have to be considered for GMP stem cell production for cell therapy. In "Meet the Expert" sessions, specialists presented innovative technologies such as a next-generation sequencing system. Finally, the meeting provided an excellent opportunity for young scientists to show their findings, and to discuss with each other and with internationally recognized experts. PMID- 22927168 TI - Smoothing the path: reducing biliary complications, addressing small-for-size syndrome, and making other adaptations to decrease the risk for living donor liver transplant recipients. AB - KEY POINTS: 1. Over the course of the past 2 decades, living donor liver transplantation (LDLT) has become increasingly successful because many of the technical issues plaguing it have been resolved. 2. Although donor safety remains a concern, most challenges related to the recipient's surgery are now better understood, and they appear surmountable. 3. The following concepts need to be addressed for optimal recipient outcomes to be achieved: a. Reduction of the risk of small-for-size syndrome in LDLT (ie, the management of 4 factors: the recipient status, the portal pressure and inflow, the venous outflow, and the graft-to-recipient weight ratio/graft quality). b. Reduction of the risk of surgical complications (biliary complications, reconstitution of the middle hepatic vein outflow in the right lobe graft, and safe hepatic artery and portal vein reconstruction). c. Other adaptations for improving recipient outcomes (adaptations related to LDLT and adaptations common to deceased donor liver transplantation and LDLT). PMID- 22927169 TI - Preparation and characterization of surface-engineered coarse microcrystalline cellulose through dry coating with silica nanoparticles. AB - A popular grade of microcrystalline cellulose (MCC) exhibits excellent tabletability, but marginal flowability for high-speed tableting operations. Accordingly, an enhancement in flowability, while preserving its tabletability, will make it a more useful excipient in pharmaceutical tablet formulations, especially for the direct compression process. In this work, we show that surface coating by silica nanoparticles, using either a dry comilling process or simple mechanical blending, is a valid strategy for achieving the goal. The effects of milling intensity, either the number of comilling cycles or blending time, and silica loading level have been evaluated. Results show that surface deposition of 0.1% silica nanoparticles substantially improves the flowability of this grade of MCC while preserving a significant portion of its tabletability. Higher silica loading leads to better flowability, but at the cost of reduced tabletability. However, even up to 2.0% silica deposition, its tabletability remains superior. PMID- 22927173 TI - Preface to the special section on piezotronics. PMID- 22927170 TI - Long-Term survival of anoxia despite rapid ATP decline in embryos of the annual killifish Austrofundulus limnaeus. AB - Embryos of the annual killifish Austrofundulus limnaeus can survive for months in the complete absence of oxygen. Survival of anoxia is associated with entry into a state of metabolic dormancy known as diapause. However, extreme tolerance of anoxia is retained for several days of post-diapause development. Rates of heat dissipation in diapause II and 4 days post-diapause II embryos were measured under aerobic conditions and during the transition into anoxia. Phosphorylated adenylate compounds were quantified in embryos during entry into anoxia and after 12 hr of aerobic recovery. Rates of heat dissipation were not affected by exposure to anoxia in diapause II embryos, while post-diapause II embryos experienced a profound decrease in heat dissipation. ATP decreased substantially in both developmental stages upon exposure to anoxia, and all indicators of cellular energetic status indicated energetic stress, at least based on the mammalian paradigm. The rate of decline in ATP is the most acute reported for any vertebrate. The mechanisms responsible for cellular survival despite a clear dysregulation between energy production and energy consumption remain to be identified. Necrotic and apoptotic cell death in response to hypoxia contribute to poor survival during many diseases and pathological conditions in mammals. Understanding the mechanisms that are in place to prevent maladaptive cell death in embryos of A. limnaeus may greatly improve treatment strategies in diseases that involve hypoxia and reperfusion injuries. PMID- 22927174 TI - Neuropsychiatric symptoms, apolipoprotein E gene, and risk of progression to cognitive impairment, no dementia and dementia: the Aging, Demographics, and Memory Study (ADAMS). AB - OBJECTIVE: To examine the relationship of neuropsychiatric symptoms and apolipoprotein E (APOE) epsilon4 allele status to dementia at baseline and progression to dementia in older adults with and without cognitive impairment, no dementia (CIND). METHODS: Adults (n = 856) 71 years and older (mean age = 79.15 years), 12.8% ethnic minority and 60.6% women, completed neuropsychological tests and APOE genotyping, and a proxy informant completed the Neuropsychiatric Inventory. RESULTS: After adjusting for age and education, neuropsychiatric symptoms and APOE epsilon4 were independently associated with CIND and dementia status at baseline (compared with cognitively normal). Further, neuropsychiatric symptoms predicted progression to dementia at 16- to 18-month follow-up among participants with CIND at baseline; the presence of these symptoms decreased the risk of progression from normal to CIND or dementia at 36 to 48 months. CONCLUSION: Findings provide cross-sectional and longitudinal support for the role of neuropsychiatric symptoms in the prediction of cognitive impairment, particularly dementia. APOE epsilon4, although important, may be a less robust predictor. This investigation highlights the importance of behavioral symptoms, such as neuropsychiatric symptom status or frequency/severity, as predictors of future cognitive decline. PMID- 22927177 TI - The occurrence of postoperative atrial fibrillation according to different surgical settings in cardiac surgery patients. AB - OBJECTIVES: Atrial fibrillation is the most common arrhythmia after cardiac surgery. The pathogenesis of postoperative atrial fibrillation is multifactorial. The aim of the study was to analyse preoperative, intraoperative and postoperative factors and their relationships with the occurrence and duration of atrial fibrillation. METHODS: One hundred and ninety-six patients with coronary heart disease (152 men, age 62.7 +/- 10.1 years) underwent surgical revascularization. Extracorporeal circulation was used in 64 patients and minimal extracorporeal circulation was used in 75 patients. Fifty-seven patients underwent surgery without extracorporeal circulation. During the first three postoperative days, subjects were monitored for the duration and incidence of atrial fibrillation, laboratory markers of inflammation (C-reactive protein, leucocytes) and serum potassium. RESULTS: Demographic data and associated cardiovascular diseases in the groups were not statistically different. The overall incidence of atrial fibrillation was 56% (110 patients). The highest incidence of atrial fibrillation was found in the extracorporeal circulation subgroup, with a significantly lower incidence using minimal extracorporeal circulation, and in patients operated on without extracorporeal circulation (75 vs 47 vs 46%, P <0.001). The longest duration of atrial fibrillation was found in patients operated on with extracorporeal circulation compared with minimal extracorporeal circulation, and without extracorporeal circulation (9.7 +/- 11.6 vs 4.9 +/- 8.3 vs 3.1 +/- 5.2, P <=0.001). The incidence of postoperative atrial fibrillation significantly correlated with elevation of inflammatory markers (C reactive protein, leucocytes) compared with patients who were free of atrial fibrillation (P <=0.001, P <=0.05). The values of serum potassium were not significantly different. The relationship between postoperative atrial fibrillation and echocardiographic parameters was not confirmed. CONCLUSIONS: The use of extracorporeal circulation leads to a higher incidence of postoperative atrial fibrillation compared with the use of minimal extracorporeal circulation or with surgery without extracorporeal circulation, probably due to enhanced systemic inflammatory response. PMID- 22927179 TI - Computed intranasal spray penetration: comparisons before and after nasal surgery. AB - BACKGROUND: Quantitative methods for comparing intranasal drug delivery efficiencies pre- and postoperatively have not been fully utilized. The objective of this study is to use computational fluid dynamics techniques to evaluate aqueous nasal spray penetration efficiencies before and after surgical correction of intranasal anatomic deformities. METHODS: Ten three-dimensional models of the nasal cavities were created from pre- and postoperative computed tomography scans in 5 subjects. Spray simulations were conducted using a particle size distribution ranging from 10 MUm to 110 MUm, a spray speed of 3 m/second, plume angle of 68 degrees, and with steady state, resting inspiratory airflow present. Two different nozzle positions were compared. Statistical analysis was conducted using Student t test for matched pairs. RESULTS: On the obstructed side, posterior particle deposition after surgery increased by 118% and was statistically significant (p = 0.036), while anterior particle deposition decreased by 13% and was also statistically significant (p = 0.020). The fraction of particles that bypassed the airways either pre- or postoperatively was less than 5%. Posterior particle deposition differences between obstructed and contralateral sides of the airways were 113% and 30% for pre- and postsurgery, respectively. Results showed that nozzle positions can influence spray delivery. CONCLUSION: Simulations predicted that surgical correction of nasal anatomic deformities can improve spray penetration to areas where medications can have greater effect. Particle deposition patterns between both sides of the airways are more evenly distributed after surgery. These findings suggest that correcting anatomic deformities may improve intranasal medication delivery. For enhanced particle penetration, patients with nasal deformities may explore different nozzle positions. PMID- 22927180 TI - Feasibility and safety of transcatheter closure of atrial septal defects with deficient posterior rim. AB - OBJECTIVES: To evaluate the feasibility and safety of percutaneous closure of complex secundum-type atrial septal defects (ASD) in patients with posterior inferior rim deficiency. BACKGROUND: Transcatheter approach is the method of choice for ASD closure; however, up to now 20% of the defects are not considered suitable for percutaneous intervention because of the lack of surrounding rims, especially the posterior-inferior. METHODS: A total of 268 patients were evaluated between March 2005 and April 2011 for ASD closure. Twenty-four patients (9%) were not considered suitable for a percutaneous intervention and referred to surgery due to inadequate rims or a large defect diameter. Out of the remaining 244 patients, 25 (10,2%) had posterior-inferior rim deficiency and represent our study group. RESULTS: After failure of the conventional approach, alternative techniques were attempted. In 16 patients, an adjusted deployment and alignment maneuver approach was successful. In 5 other patients, a slide out technique was successfully performed by exploiting the right upper pulmonary vein. Finally in the remaining 4 patients, ASD closure was obtained by completely re-orienting the system with a jugular approach. No peri-procedural complications occurred, and at 12-month transesophageal echocardiography evaluation no residual shunt could be detected. CONCLUSIONS: Our data show the feasibility of percutaneous approach for ASD closure in presence of a deficient posterior-inferior rim. The procedural success is strictly related to correct sizing and demonstration of a balloon notch on fluoroscopy. Long-term follow-up supports efficacy of the procedure in these selected cases. PMID- 22927178 TI - New synaptic and molecular targets for neuroprotection in Parkinson's disease. AB - The defining anatomical feature of Parkinson's disease (PD) is the degeneration of substantia nigra pars compacta (SNc) neurons, resulting in striatal dopamine (DA) deficiency and in the subsequent alteration of basal ganglia physiology. Treatments targeting the dopaminergic system alleviate PD symptoms but are not able to slow the neurodegenerative process that underlies PD progression. The nucleus striatum comprises a complex network of projecting neurons and interneurons that integrates different neural signals to modulate the activity of the basal ganglia circuitry. In this review we describe new potential molecular and synaptic striatal targets for the development of both symptomatic and neuroprotective strategies for PD. In particular, we focus on the interaction between adenosine A2A receptors and dopamine D2 receptors, on the role of a correct assembly of NMDA receptors, and on the sGC/cGMP/PKG pathway. Moreover, we also discuss the possibility to target the cell death program parthanatos and the kinase LRRK2 in order to develop new putative neuroprotective agents for PD acting on dopaminergic nigral neurons as well as on other basal ganglia structures. PMID- 22927181 TI - A positively charged surface patch is important for hainantoxin-IV binding to voltage-gated sodium channels. AB - Hainantoxin-IV (HNTX-IV), isolated from the venom of the spider Ornithoctonus hainana, is a specific antagonist of tetrodotoxin-sensitive (TTX-S) voltage-gated sodium channels in rat dorsal root ganglion (DRG) cells. It adopts an inhibitor cystine knot motif, and structural analysis revealed a positively charged patch consisting of Arg26, Lys27, His28, Arg29 and Lys32 distributed on its molecular surface. Our previous study demonstrated that Lys27 and Arg29 but not Arg26 were critical residues for HNTX-IV binding to TTX-S sodium channels. In the present study, we examined the roles of His28 and Lys32 in the interaction of HNTX-IV with its target. Two mutants, HNTX-IV-H28D and HNTX-IV-K32A, were generated by solid-phase chemical synthesis and purified by reverse-phase HPLC after refolding and oxidation, yielding two compounds of high purity with monoisotopic masses of 3962.66 and 3927.70 Da, respectively, as determined by MALDI-TOF mass spectrometry. This indicated the presence of six cysteine residues forming three disulfide bonds. Moreover, circular dichroism spectroscopy analysis demonstrated that the substitution of His28 or Lys32 did not affect the overall structure of HNTX-IV. The inhibitory activity of HNTX-IV-H28D and HNTX-IV-K32A against TTX-S sodium channels in rat DRG cells was analyzed by whole-cell patch-clamp technique. The IC(50) values for the mutants were 0.57 and 5.80 MUM (17-fold and 170-fold lower than the activity of the native toxin), indicating that His28 and Lys32 may be important for the inhibitory activity of HNTX-IV. Taken together, our results suggest that the positively charged patch might be the binding site for the interaction of HNTX-IV with TTX-S sodium channels. These findings might contribute to the elucidation of the structure and function relationship of HNTX IV. PMID- 22927182 TI - Hyperfine coupling constants on inner-sphere water molecules of Gd(III)-based MRI contrast agents. AB - Herein we present a theoretical investigation of the hyperfine coupling constants (HFCCs) on the inner-sphere water molecules of [Gd(H(2)O)(8)](3+) and different Gd(III)-based magnetic resonance imaging contrast agents such as [Gd(DOTA)(H(2)O)](-), [Gd(DTPA)(H(2)O)](2-), [Gd(DTPA-BMA)(H(2)O)] and [Gd(HP DO3A)(H(2)O)]. DFT calculations performed on the [Gd(H(2)O)(8)](3+) model system show that both hybrid-GGA functionals (BH&HLYP, B3PW91 and PBE1PBE) and the hybrid meta-GGA functional TPSSh provide (17)O HFCCs in close agreement with the experimental data. The use of all-electron relativistic approaches based on the DKH2 approximation and the use of relativistic effective core potentials (RECP) provide results of essentially the same quality. The accurate calculation of HFCCs on the [Gd(DOTA)(H(2)O)](-), [Gd(DTPA)(H(2)O)](2-), [Gd(DTPA-BMA)(H(2)O)] and [Gd(HP-DO3A)(H(2)O)] complexes requires an adequate description of solvent effects. This was achieved by using a mixed cluster/continuum approach that includes explicitly two second-sphere water molecules. The calculated isotropic (17)O HFCCs (A(iso)) fall within the range 0.40-0.56 MHz, and show deviations from the corresponding experimental values typically lower than 0.05 MHz. The A(iso) values are significantly affected by the distance between the oxygen atom of the coordinated water molecule and the Gd(III) ion, as well as by the orientation of the water molecule plane with respect to the Gd-O vector. (1)H HFCCs of coordinated water molecules and (17)O HFCCs of second-sphere water molecules take values close to zero. PMID- 22927183 TI - The 57th birthday of koilocytes. PMID- 22927184 TI - Ten patient stories illustrating the extraordinarily diverse clinical features of patients with thrombotic thrombocytopenic purpura and severe ADAMTS13 deficiency. AB - Patients with thrombotic thrombocytopenic purpura (TTP) and severe ADAMTS13 deficiency are often considered to have typical clinical features. However, our experience is that there is extraordinary diversity of the presenting features and the clinical courses of these patients. This diversity is illustrated by descriptions of 10 patients. The patients illustrate that ADAMTS13 activity may be normal initially but severely deficient in subsequent episodes. Patients with established diagnoses of systemic infection as the cause of their clinical features may have undetectable ADAMTS13 activity. Patients may have a prolonged prodrome of mild symptoms with only microangiopathic hemolytic anemia and thrombocytopenia or they may have the sudden onset of critical illness with multiple organ involvement. Patients may die rapidly or recover rapidly; they may require minimal treatment or extensive and prolonged treatment. Patients may have acute and severe neurologic abnormalities before microangiopathic hemolytic anemia and thrombocytopenia occur. Patients may have concurrent TTP and systemic lupus erythematosus. Patients may have hereditary ADAMTS13 deficiency as the etiology of their TTP rather than acquired autoimmune ADAMTS13 deficiency. These patients' stories illustrate the clinical spectrum of TTP with ADAMTS13 deficiency and emphasize the difficulties of clinical diagnosis. PMID- 22927185 TI - Severe lateral tibial bowing with short stature in two siblings--a provisionally novel syndrome. AB - In this report, we describe two siblings with short stature and severe lateral tibial bowing. In the younger sibling, the bowing was bilateral, while in the older sib, it was unilateral. However, both showed bilateral abnormalities of the distal tibial epiphyses and growth plates. Pseudoarthrosis of the left distal tibial metaphysis and subsequent spontaneous resolution of the abnormality occurred in the younger sibling. The fibulas of both children were of normal diameter and were straight, except for the distal ends. Surgery has almost completely corrected the lower leg bowing in both patients. The type of tibial bowing seen in these children can be associated with a number of syndromes, such as neurofibromatosis type I, Weismann-Netter syndrome, and a variety of environmental caused disorders, such as vitamin D deficient rickets. However, the severity of the bowing present in our patients and the absence of other clinical features differentiates this condition from those reported in the literature. We posit that the condition in the children presented here represents an as yet undescribed syndrome, which is likely to be of genetic origin. PMID- 22927189 TI - New technologies pave way for fetal personalized medicine: fetal genomic sequencing holds promise but heightens ethical concerns. PMID- 22927190 TI - Long-term follow-up of newborn screening often falls short: public awareness and specialist shortages are also problems, report says. PMID- 22927192 TI - Thermoresponsive macroporous scaffolds prepared by emulsion templating. AB - A versatile method to prepare non-covalently crosslinked polyHIPEs hydrogels from oil-in-water high internal phase emulsions (HIPEs) whose aqueous phase contained thermo-responsive linear polymers is described. The interconnected pore structure of the polyHIPEs is maintained by reversible physical aggregation of thermo responsive polymer chains in an aqueous environment. This method to prepare interconnected porous hydrogels using a thermal trigger in the guise of thermo responsive polymers by emulsion templating requires no chemical reaction during solidification of the template. This particular feature could provide a safer route to injectable scaffolds as issues of polymerisation/crosslinking chemistry and residual initiator fragments or monomers do not arise. PMID- 22927193 TI - Pharmacokinetic and pharmacodynamic modeling for the effect of sodium-glucose cotransporter inhibitors on blood glucose level and renal glucose excretion in db/db mice. AB - The purpose of this study is to characterize the relationship between pharmacokinetics (PK) and pharmacodynamics (PD) of sodium-glucose cotransporter (SGLT) inhibitors. PK-PD studies of SGLT inhibitors (CH4941527 and T-1095), which have different half-life and selectivity to SGLT2, were performed using db/db mice. The time courses of compound concentration in plasma, blood glucose (BG), and renal glucose excretion were measured after a single oral administration of each SGLT inhibitor. An indirect-response PK-PD model was developed, in which it was assumed that an SGLT inhibitor enhances renal glucose excretion and the enhanced glucose excretion reduces BG. In the PK-PD study, both SGLT inhibitors increased renal glucose excretion and reduced BG in a dose-dependent manner. The present PK-PD model could suitably capture the effect of SGLT inhibitors and the effect shown suggested that the BG reduction could be explained by the enhanced renal glucose excretion. There were no great differences in the estimated PD parameters between the two inhibitors and they were comparable to the data from previously reported pharmacological studies. The present PK-PD model is helpful for understanding the plasma concentration-dependent effect of SGLT inhibitors on renal glucose excretion and BG. PMID- 22927194 TI - Feeding underground: kinematics of feeding in caecilians. AB - Caecilians are limbless amphibians that have evolved distinct cranial and postcranial specializations associated with a burrowing lifestyle. Observations on feeding behavior are rare and restricted to above-ground feeding in laboratory conditions. Here we report data on feeding in tunnels using both external video and X-ray recordings of caecilians feeding on invertebrate prey. Our data show feeding kinematics similar to those previously reported, including the pronounced neck bending observed during above-ground feeding. Our data illustrate, however, that caecilians may be much faster than previously suspected, with lunge speeds of up to 7 cm sec(-1). Although gape cycles are often slow (0.67 +/- 0.29 sec), rapid jaw closure is observed during prey capture, with cycle times and jaw movement velocities similar to those observed in other terrestrial tetrapods. Finally, our data suggest that gape angles may be large (64.8 +/- 18 degrees ) and that gape profiles are variable, often lacking distinct slow and fast opening and closing phases. These data illustrate the importance of recording naturalistic feeding behavior and shed light on how these animals are capable of capturing and processing prey in constrained underground environments. Additional data on species with divergent cranial morphologies would be needed to better understand the co-evolution between feeding, burrowing, and cranial design in caecilians. PMID- 22927195 TI - Frequency, prevalence, incidence and risk factors associated with visual hallucinations in a sample of patients with Parkinson's disease: a longitudinal 4 year study. AB - OBJECTIVE: To examine the prevalence, incidence and risk factors associated with visual hallucinations (VHs) amongst people suffering from Parkinson's disease (PD). METHODS: We recruited 513 patients with PD from movement disorder and PD clinics within three sites in the UK. Patients were interviewed using a series of standardised clinical rating scales at baseline, 12, 24 and 36 months. Data relating to VHs were collected using the North-East Visual Hallucinations Interview. Prevalence rates for VHs at each assessment were recorded. Associations were determined using multiple regression analysis. RESULTS: Cross sectional prevalence rates for VHs at baseline, 12, 24 and 36 months indicated VHs in approximately 50% of patients. A cumulative frequency of 82.7% of cases at the end of the study period exhibited VHs. The incidence rate for VHs was 457 cases per 1000 population. Longer disease duration, greater impairment in activities of daily living and higher rates of anxiety were most commonly associated with VHs. No factors predictive of VHs could be ascertained. CONCLUSIONS: When examined longitudinally, VHs affect more patients than is commonly assumed in cross-sectional prevalence studies. Clinicians should routinely screen for VHs throughout the disease course. Disease duration, impairment in activities of daily living and anxiety presented as co-morbidities associated with VHs in PD, and therefore those presenting with VHs should be screened for anxiety disorder and vice versa. PMID- 22927196 TI - Ion channel phosphorylopathy: a link between genomic variation and human disease. AB - Voltage-gated ion channels (VGIC) regulate many important physiological events, including muscle contraction, brain function, and secretion. Mutations that inhibit or up-regulate VGIC activities can dramatically interfere with the normal function of several organs, leading to unpredictable failure and therefore poor quality of life or even death. Many genomic variations that change amino acids in cytoplasmic domains of ion channels have been found to be associated with several diseases, including cardiac arrhythmias and neurodegeneration. However, a mechanism linking these mutations to ion channel malfunction has not been clearly established and in some cases is totally unknown. This concept article gives an overview on a possible mechanism by which disease-associated mutations in cytoplasmic domains of ion channels can affect channel activity by creating or disrupting phosphorylation sites for specific kinases. We call these events "ion channel phosphorylopathies". Understanding ion channel phosphorylopathies offers the opportunity to find a mechanism linking genomic variations to human disease and is crucial to the process of designing an effective pharmacological strategy. PMID- 22927197 TI - The design of a heterocellular 3D architecture and its application to monitoring the behavior of cancer cells in response to the spatial distribution of endothelial cells. AB - The spatial cell distribution is one of the critical features for governing cellular interactions and their consequent behaviors. Here we suggest a novel method of building a hierarchical cellular structure by stacking cell-attached microplate structures with specific configurations within hydrogel layers. This method is applied to the reconstruction of the 3D architecture of a liver lobule and the development of an experimental model of the various phases of cancer angiogenesis. PMID- 22927199 TI - Novel multifunctional graphene sheets with encased Au/Ag nanoparticles for advanced electrochemical analysis of organic compounds. AB - This work is the first presentation of the synthesis of few-layer graphene decorated with gold and silver nanoparticles (Gr-Au-Ag) by chemical vapor deposition over a catalytic system formed of bimetallic Au-Ag nanoclusters supported on MgO and with methane used as the source of carbon. The sheetlike morphology of the graphene nanostructures, with mean sizes in the range of hundreds of nanometers, was observed by high-resolution electron microscopy. The distinctive feature found in all the samples was the regular rectangular or square shapes. This multi-component organic-inorganic nanomaterial was used to modify a platinum substrate and subsequently employed for the detection of carbamazepine, an anti-convulsion drug. UV/Vis spectroscopy revealed that a strong hypochromism occurred over time, after mixing solutions of graphene-Au-Ag with carbamazepine. This can be attributed to pi-pi stacking between the aromatic groups of the two compounds. Linear sweep voltammetry (LCV) provided evidence that the modified platinum substrate presented a significant electrocatalytic reaction toward the oxidation of carbamazepine. The intensity of the current was found to increase by up to 2.5 times, and the oxidation potential shifted from +1.5 to +1.35 V(Ag/AgCl) in comparison with the unmodified electrode. Electrochemical impedance spectroscopy (EIS) was further used to thoroughly assess the activity of the platinum electrode that was modified by the deposition of the Gr-Au-Ag composites in the presence of various concentrations of carbamazepine. The experimental EIS records were used for the generation of an equivalent electrical circuit, based on the charge-transfer resistance (R(ct)), Warburg impedance (Z(D)), solution resistance (R(s)), and a constant phase element (CPE) that characterizes the non-ideal interface capacitive responses. PMID- 22927200 TI - High prevalence of confirmed, but also of potential and believed, neuropathic pain in pain clinics. AB - BACKGROUND AND AIMS: Epidemiological data about neuropathic pain are still scarce. A national survey, based on neurologic clinical diagnosis, was performed to determine its prevalence among patients attending pain clinics. METHODS: An epidemiological cross-sectional study involving pain clinics across all regions in Spain was carried out. Pain specialists evaluated the medical files and the clinical condition of patients attending their practices systematically during 1 day. They used the revised definition and grading system proposed in 2008 to decide whether a given patient had definite (i.e., confirmed), probable (potential) or possible (believed) neuropathic pain. Also, they provided a diagnostic label for neuropathic pain conditions and appraised treatment adequacy. RESULTS: In a single day, 178 pain specialists provided data from 2173 patients. Definite, probable and possible neuropathic pain was cited in 639 (29.4%), 304 (14.0%) and 97 (4.5%) patients, respectively. Almost two-thirds of these were women. A diagnostic label of primary pure central and/or peripheral neuropathic pain was cited in 344 (15.8%) patients. The most common diagnostic label (568 patients) was low back pain or sciatica causing mixed neuropathic pain. Definite neuropathic pain diagnosis was less likely in patients with mixed pain conditions and in women derived from primary care. Co-morbid depressive or anxiety symptoms were usual. CONCLUSIONS: Definite (confirmed) neuropathic pain alone was as prevalent as neuropathic pain ascertained with screening questionnaires in prior recent European studies. The clinical relevance of the surplus of patients with potential and believed neuropathic pain ascertained by clinicians is uncertain. PMID- 22927201 TI - A randomized trial of oral betamethasone to reduce ataxia symptoms in ataxia telangiectasia. AB - No controlled studies exist regarding the pharmaceutical reduction of ataxia symptoms in ataxia telangiectasia (A-T). In a multicenter, double-blind, randomized, placebo-controlled crossover trial, oral betamethasone (BETA) and placebo were compared in terms of their reduction of ataxia symptoms as assessed with the International Cooperative Ataxia Rating Scale (ICARS). In this study of 13 A-T children, betamethasone reduced the ICARS total score by a median of 13 points in the intent-to-treat population and 16 points in the per-protocol population (ie, median percent decreases of ataxia symptoms of 28% and 31%, respectively). In conclusion, Oral betamethasone could be a promising therapy to relieve ataxia symptoms in A-T patients; however, long-term effectiveness and safety must be established. (Current Controlled Trials, number ISRCTN08774933.) PMID- 22927202 TI - Comparison of 3-year clinical outcomes between classic crush and modified mini crush technique in coronary bifurcation lesions. AB - OBJECTIVES: We aimed to compare long-term clinical outcomes between modified mini crush (modi-MC) technique with classic crush (crush) technique for treatment of bifurcation lesions. BACKGROUND: The modi-MC technique showed excellent procedural success and favorable 9-month clinical outcomes. METHODS: From January 2005 to November 2009, we enrolled patients with de novo bifurcation lesions treated with modi-MC (n = 112 lesions in 111 patients) and crush technique (n = 69 lesions in 67 patients). Primary endpoint was rate of major adverse cardiac events (MACE), a composite of all-cause death, myocardial infarction (MI), and target lesion revascularization (TLR) at 3 years. RESULTS: There was no significant difference in baseline characteristics. The modi-MC technique showed a significantly higher success rate of final kissing balloon inflation (84.1 vs. 98.2%, P = 0.001). After 3 years, MACE rate was significantly lower in the modi MC group (25.4 vs. 12.6%, P = 0.030). The incidence of all-cause death was 7.5 vs. 2.7% (P = 0.087), MI was 4.5 vs. 1.8% (P = 0.290), TLR was 17.4 vs. 8.9% (P = 0.093) and stent thrombosis was 3.0 vs. 1.8% (P = 0.632) in the crush and modi-MC groups, respectively. CONCLUSIONS: The modified mini-crush technique showed more favorable 3-year clinical outcomes compared to the classic crush technique. PMID- 22927203 TI - Perceptions of a mobile technology on learning strategies in the anatomy laboratory. AB - Mobile technologies offer new opportunities to improve dissection learning. This study examined the effect of using an iPad-based multimedia dissection manual during anatomy laboratory instruction on learner's perception of anatomy dissection activities and use of time. Three experimental dissection tables used iPads and three tables served as a control for two identical sessions. Trained, non-medical school anatomy faculty observers recorded use of resources at two minute intervals for 20 observations per table. Students completed pre- and post perception questionnaires. We used descriptive and inferential analyses. Twenty one control and 22 experimental students participated. Compared with controls, experimental students reported significantly (P < 0.05) less reliance on paper and instructor resources, greater ability to achieve anatomy laboratory objectives, and clarity of the role of dissection in learning anatomy. Experimental students indicated that the iPad helped them in dissection. We observed experimental students more on task (93% vs. 83% of the time) and less likely to be seeking an instructor (2% vs. 32%). The groups received similar attention from instructors (33% vs. 37%). Fifty-nine percent of the time at least one student was looking at the iPad. Groups clustered around the iPad a third of their time. We conclude that the iPad-manual aided learner engagement, achieved instructional objectives, and enhanced the effectiveness and efficiency of dissection education. PMID- 22927205 TI - The association between supraorbital ethmoid air cells and orbital proptosis in patients with chronic rhinosinusitis. AB - BACKGROUND: Orbital proptosis is a known possible complication in patients with chronic rhinosinusitis (CRS). This study was undertaken to determine the association of sinus anatomy and anatomic variants with the predisposition for such a complication. METHODS: All adult patients (n = 16) with orbital proptosis were identified from a prospectively-collected database at a tertiary institution. These were compared with a series of randomly-selected patients (n = 50) diagnosed with chronic sinusitis and who had undergone sinus computed tomography. The presence or absence of supraorbital ethmoid air cells (SOECs) was noted and compared between the 2 groups. The primary sinus anatomy responsible for the proptosis was also identified. Statistical analysis was performed using the chi squared test. RESULTS: Sixteen patients with orbital proptosis were identified, of which all but 1 had SOECs present. Causal analysis showed that in all but 1 case the SOECs were the cause of proptosis. Of the 50 patients with CRS but without proptosis, only 13 had SOECs present and 37 patients did not (chi squared = 22.8, p = 0.000002). CONCLUSION: SOECs appear to be highly associated with and most often are responsible for orbital proptosis in patients with CRS. PMID- 22927204 TI - Tau phosphorylation pathway genes and cerebrospinal fluid tau levels in Alzheimer's disease. AB - Alzheimer's disease (AD) is characterized by the presence in the brain of amyloid plaques, consisting predominately of the amyloid beta peptide (Abeta), and neurofibrillary tangles, consisting primarily of tau. Hyper-phosphorylated-tau (p tau) contributes to neuronal damage, and both p-tau and total-tau (t-tau) levels are elevated in AD cerebrospinal fluid (CSF) compared to cognitively normal controls. Our hypothesis was that increased ratios of CSF phosphorylated-tau levels relative to total-tau levels correlate with regulatory region genetic variation of kinase or phosphatase genes biologically associated with the phosphorylation status of tau. Eighteen SNPs located within 5' and 3' regions of 5 kinase and 4 phosphatase genes, as well as two SNPs within regulatory regions of the MAPT gene were chosen for this analysis. The study sample consisted of 101 AD patients and 169 cognitively normal controls. Rs7768046 in the FYN kinase gene and rs913275 in the PPP2R4 phosphatase gene were both associated with CSF p-tau and t-tau levels in AD. These SNPs were also differentially associated with either CSF t-tau (rs7768046) or CSF p-tau (rs913275) relative to t-tau levels in AD compared to controls. These results suggest that rs7768046 and rs913275 both influence CSF tau levels in an AD-associated manner. PMID- 22927206 TI - Arboreal habitat structure affects locomotor speed and perch choice of white footed mice (Peromyscus leucopus). AB - Arboreal habitats pose several challenges for locomotion resulting from narrow cylindrical surfaces, steep slopes, and secondary branches that can form obstructions. We used laboratory trials to test whether different diameters, slopes, or complexity of branches affected maximum speeds and perch choice of the semi-arboreal white-footed mouse (Peromyscus leucopus). We tested locomotor performance of mice running horizontally and up and down 45 degrees slopes for cylindrical artificial branches with five diameters ranging from 10 to 116 mm and on a subset of diameters for cylinders that were horizontal and had pegs (e.g., secondary branches) every 10 or 20 cm. Slope, diameter, and presence of pegs on top of cylinders had significant and interactive effects on locomotor performance. On horizontal cylinders the speed of mice increased with increased diameter among the three smallest diameters, but changed little with further increases in diameter, whereas for sloped surfaces the extreme diameters had lower speeds than an intermediate diameter. For a given diameter, the speeds of mice were usually faster when running horizontally rather than running uphill or downhill. The presence of pegs greatly decreased running speed compared to unobstructed surfaces, but the magnitude of this effect decreased as diameter increased. The difficulties of maintaining balance and avoiding toppling may have caused much of the decrease in speed and associated increased amounts of pausing. Only 1 of 11 choice tests detected a significant bias of mice favoring the perch that maximized locomotor performance. PMID- 22927208 TI - Preparation and evaluation of single and co-engineered combination inhalation carrier formulations for the treatment of asthma. AB - Two combination dry powder inhalation formulations were engineered via spray drying and co-spray drying salbutamol base (SB) and beclomethasone dipropionate (BDP). The aerosol performances of the individual drugs, a physical mix and the co-spray-dried particle systems were investigated after blending with conventional lactose carrier, under realistic dose regimes. Furthermore, each system was evaluated in terms of the physicochemical properties and via high throughput Raman microscopy (to study co-association and deposition patterns after in vitro aerosolisation studies). In general, analysis of the aerosol performance (measured using a next-generation impactor) of the single drug and physical mix formulations suggested that SB and BDP have significantly different stage-deposition profiles. Such observations were further substantiated by scanning electron microscopy, where SB-BDP agglomeration could be observed in the physical mix. Stage deposition from the SB-BDP co-spray-dried powders were different than that for the physical mix, wherein the amount of SB and BDP on each stage was equivalent; suggesting that the two drugs could be targeted and deposited at the same location on the lung epithelia. Raman microscopy of the physical mix and co-spray-dried formulations also confirmed the differences in stage deposition between formulations and co-localised deposition for the co spray-dried formulation. PMID- 22927209 TI - Graphene-based electrodes. AB - Graphene, the thinnest two dimensional carbon material, has become the subject of intensive investigation in various research fields because of its remarkable electronic, mechanical, optical and thermal properties. Graphene-based electrodes, fabricated from mechanically cleaved graphene, chemical vapor deposition (CVD) grown graphene, or massively produced graphene derivatives from bulk graphite, have been applied in a broad range of applications, such as in light emitting diodes, touch screens, field-effect transistors, solar cells, supercapacitors, batteries, and sensors. In this Review, after a short introduction to the properties and synthetic methods of graphene and its derivatives, we will discuss the importance of graphene-based electrodes, their fabrication techniques, and application areas. PMID- 22927210 TI - MT1-selective melatonin receptor ligands: synthesis, pharmacological evaluation, and molecular dynamics investigation of N-{[(3-O substituted)anilino]alkyl}amides. AB - The design of compounds selective for the MT1 melatonin receptor is still a challenging task owing to the limited knowledge of the structural features conferring selectivity for the MT1 subtype, and only few selective compounds have been reported so far. N-(Anilinoalkyl)amides are a versatile class of melatonin receptor ligands that include nonselective MT1/MT2 agonists and MT2-selective antagonists. We synthesized a new series of N-(anilinoalkyl)amides bearing 3 arylalkyloxy or 3-alkyloxy substituents at the aniline ring, looking for new potent and MT1-selective ligands. To evaluate the effect of substituent size and shape on binding affinity and intrinsic activity, both flexible and conformationally constrained derivatives were prepared. The phenylbutyloxy substituent gave the best result, providing the partial agonist 4 a, which was endowed with high MT1 binding affinity (pKi=8.93) and 78-fold selectivity for the MT1 receptor. To investigate the molecular basis for agonist recognition, and to explain the role of the 3-arylalkyloxy substituent, we built a homology model of the MT1 receptor based on the beta2 adrenergic receptor crystal structure in its activated state. A binding mode for MT1 agonists is proposed, as well as a hypothesis regarding the receptor structural features responsible for MT1 selectivity of compounds with lipophilic arylalkyloxy substituents. PMID- 22927211 TI - Characterization of TLR4 agonist effects on alhydrogel(r) sedimentation: a novel application of laser scattering optical profiling. AB - Aluminum salt formulations such as Alhydrogel(r) have been used for decades as effective and safe vaccine adjuvants. Aluminum salts have a high adsorptive capacity for vaccine antigens and other immunomodulatory molecules such as Toll like receptor (TLR) agonists. However, the characterization of some Alhydrogel(r) adsorbed TLR agonists is challenging, requiring destructive analysis, complex instrumentation, and/or desorption method development. In this report, we characterize the effects of an Alhydrogel(r)-adsorbed synthetic Toll-like receptor 4 (TLR4) agonist on aluminum salt sedimentation behavior using laser scattering optical profiling. This method facilitates the detection of the effects on aluminum salt sedimentation behavior of low amounts of adsorbed TLR4 agonist (<30 MUM) with a minimum of sample preparation and analysis time by collecting light transmission simultaneously from the complete vertical profile of the sample. PMID- 22927212 TI - Principal component analysis of chemical shift perturbation data of a multiple ligand-binding system for elucidation of respective binding mechanism. AB - Chemical shift perturbations (CSPs) in NMR spectra provide useful information about the interaction of a protein with its ligands. However, in a multiple ligand-binding system, determining quantitative parameters such as a dissociation constant (K(d) ) is difficult. Here, we used a method we named CS-PCA, a principal component analysis (PCA) of chemical shift (CS) data, to analyze the interaction between bovine beta-lactoglobulin (betaLG) and 1-anilinonaphthalene-8 sulfonate (ANS), which is a multiple-ligand-binding system. The CSP on the binding of ANS involved contributions from two distinct binding sites. PCA of the titration data successfully separated the CSP pattern into contributions from each site. Docking simulations based on the separated CSP patterns provided the structures of betaLG-ANS complexes for each binding site. In addition, we determined the K(d) values as 3.42 * 10-4 M2 and 2.51 * 10-3 M for Sites 1 and 2, respectively. In contrast, it was difficult to obtain reliable K(d) values for respective sites from the isothermal titration calorimetry experiments. Two ANS molecules were found to bind at Site 1 simultaneously, suggesting that the binding occurs cooperatively with a partial unfolding of the betaLG structure. On the other hand, the binding of ANS to Site 2 was a simple attachment without a significant conformational change. From the present results, CS-PCA was confirmed to provide not only the positions and the K(d) values of binding sites but also information about the binding mechanism. Thus, it is anticipated to be a general method to investigate protein-ligand interactions. PMID- 22927213 TI - Lysosome-dependent pathways as a unifying theme in Parkinson's disease. AB - Although the pathogenesis of Parkinson's disease (PD) is considered multifactorial, evidence from genetics and cell biology has implicated specific molecular pathways. This article summarizes evidence that suggests that the level of intracellular alpha-synuclein is critical for the onset of neurodegeneration with Lewy bodies and dependent, to a large extent, on lysosomal degradation. The function of other key proteins that emerged from genetics is discussed: Pink1 and Parkin regulate the degradation of damaged mitochondria by the lysosome (mitophagy). Glucocerebrosidase and ATP13A2 are important components of this degradative organelle. VPS35 and LRRK2 may regulate trafficking within lysosome dependent pathways, such as autophagy and endosomal vesicle recycling. Clinically, diffuse alpha-synucleinopathy or dementia seems to correlate with mutations which interfere with the broader function of lysosomal pathways, whereas a predominantly motor syndrome and nigrostriatal degeneration is associated with specific defects in mitophagy. Based on these studies, it is proposed that a protein network involved in trafficking to, or degradation by, lysosomes could be sufficient to explain the phenotypic spectrum within PD in a unifying biochemical pathway. PMID- 22927215 TI - Understanding the role of water in aqueous ruthenium-catalyzed transfer hydrogenation of ketones. AB - We report an accurate computational study of the role of water in transfer hydrogenation of formaldehyde with a ruthenium-based catalyst using a water specific model. Our results suggest that the reaction mechanism in aqueous solution is significantly different from that in the gas phase or in methanol solution. Previous theoretical studies have shown a concerted hydride and proton transfer in the gas phase (M. Yamakawa, H. Ito, R. Noyori, J. Am. Chem. Soc. 2000, 122, 1466-1478;J.-W. Handgraaf, J. N. H. Reek, E. J. Meijer, Organometallics 2003, 22, 3150-3157; D. A. Alonso, P. Brandt, S. J. M. Nordin, P. G. Andersson, J. Am. Chem. Soc. 1999, 121, 9580-9588; D. G. I. Petra, J. N. H. Reek, J.-W. Handgraaf, E. J. Meijer, P. Dierkes, P. C. J. Kamer, J. Brussee, H. E. Schoemaker, P. W. N. M. van Leeuwen, Chem. Eur. J. 2000, 6, 2818-2829), whereas a delayed, solvent-mediated proton transfer has been observed in methanol solution (J.-W. Handgraaf, E. J. Meijer, J. Am. Chem. Soc. 2007, 129, 3099-3103). In aqueous solution, a concerted transition state is observed, as in the previous studies. However, only the hydride is transferred at that point, whereas the proton is transferred later by a water molecule instead of the catalyst. PMID- 22927214 TI - Urinary isoflavonoids and risk of coronary heart disease. AB - BACKGROUND: Whether soy food consumption may protect against coronary heart disease (CHD) remains controversial. No previous study has used biomarkers of soy intake in assessing the relationship between soy consumption and CHD. Biomarkers that reflect both intake and metabolism may be more informative than self-reports of dietary intake. METHODS: We examined associations of urinary isoflavonoids, a biomarker of soy or soy isoflavone intake, with risk of CHD in a case-control study nested within two prospective cohort studies of Chinese adults in Shanghai. Cases were defined as subjects with no history of CHD at baseline who developed incident CHD during follow-up. Control subjects were randomly selected from those who remained free of CHD and matched to cases by sex, age, date and time of sample collection and antibiotic use. Baseline urinary isoflavonoids (daidzein, genistein, glycitein, equol, O-desmethylangolensin, dihydrodaidzein and dihydrogenistein) were compared between cases (n = 377) and control subjects (n = 753). Conditional logistic regression was used to evaluate the associations. RESULTS: Total urinary isoflavonoids were not associated with CHD in either women or men. However, urinary equol excretion showed a significant inverse association with CHD in women. The adjusted odds ratios (95% confidence intervals) for CHD across increasing quartiles of equol levels in women were 1 (reference), 0.61 (0.32, 1.15), 0.51 (0.26, 0.98) and 0.46 (0.24, 0.89) (P = 0.02 for trend). CONCLUSIONS: Our study suggests for the first time that equol, a bioactive metabolite of soy isoflavone daidzein, may be inversely associated with risk of CHD in women. PMID- 22927216 TI - Incidence of patent foramen ovale and migraine headache in adults with congenital heart disease with no known cardiac shunts. AB - The purpose of this study was to understand why patients with adult congenital heart disease (CHD) but no obvious shunt have an increased frequency of migraine headaches (MH). CHD patients with no known cardiac shunts (CHD-NKS), based on their echocardiographic or angiographic procedures, were tested for a right-to left shunt using agitated saline contrast transcranial Doppler (TCD). Medical records of 2,920 patients from the UCLA Adult CHD Center were screened to participate in a study to evaluate the prevalence of MH in adults with CHD; 182 patients (6.23%) had CHD-NKS; of these, 60 (30%) underwent a TCD; 23 (38%) tested positive and 37 (62%) tested negative for a right-to-left shunt (P = 0.01 compared with controls). The frequency of MH was 43% in CHD-NKS compared with 11% in controls (P < 0.0001). TCD demonstrated right-to-left shunting in approximately 2/3 of patients with pulmonary stenosis, the Marfan syndrome and congenitally corrected transposition of great vessels, 1/4 of patients with bicuspid aortic valve, 1/5 of patients with mitral valve prolapse and all patients with Ebstein's anomaly. Approximately half of these experienced MH. Patients who had MH did not show a higher frequency of right-to-left shunt when compared with patients without MH (P = 0.57). In conclusion, CHD patients with conditions usually not associated with a shunt have a higher than expected prevalence of PFO which permits intermittent right-to-left shunting undetected by standard non-contrast TTE and TEE; the increased prevalence of right-to-left shunting may partially explain the higher than expected frequency of migraines. PMID- 22927217 TI - A novel sinonasal endoscopy scoring system: the discharge, inflammation, and polyps/edema (DIP) score. AB - BACKGROUND: There is an increasing need for a validated grading system to assess sinusitis severity as observed on endoscopic examination. Existing endoscopy scales have limitations in complexity, validation, and/or applicability. We present a novel and straightforward endoscopic scoring system measuring discharge, inflammation, and polyps/edema (DIP). The aim of this study is to determine correlation of the DIP score with existing sinus endoscopy scoring systems, and to determine interrater and test-retest reliability. METHODS: This retrospective cohort includes a total of 29 patients who underwent functional endoscopic sinus surgery (FESS) for chronic rhinosinusitis. Sinus endoscopy videos were scored in a random and blinded fashion by 3 rhinologists (S.D.P., A.N.G., A.H.M.) using the Lund-Kennedy Endoscopic Score (LKES), the Perioperative Sinus Endoscopy (POSE) score, and the DIP score. Pearson correlation coefficients, interrater reliability and test-retest reliability were determined. RESULTS: The results of this study show that the DIP score correlates well (p < 0.0001) with the existing LKES and POSE (Pearson correlation coefficients of 0.78 and 0.90, respectively). The interrater reliability intraclass correlation coefficient (ICC) is highest for the DIP score (0.87), followed by the POSE score (0.84) and the LKES (0.78). Test-retest reliability ICC is highest for the DIP score (0.78), followed by the POSE score (0.59) and the LKES (0.53). CONCLUSION: The DIP score is a novel and straightforward endoscopic sinus scoring system that shows substantial test-retest and interrater reliability in the post-FESS population. It also demonstrates a high correlation with existing scoring parameters (LKES and POSE). PMID- 22927218 TI - Stem cell bioengineering at the interface of systems-based models and high throughput platforms. AB - Stem cell functions are regulated by a combination of molecular signals that are provided both intrinsically and from the local microenvironment. The complexity of these mechanisms has encouraged the use of interdisciplinary experimental strategies, such as bioengineering methods, to address fundamental questions in stem cell biology. These approaches have primarily aimed to (1) develop tools for the improved control of microenvironmental cues and genetic perturbations, (2) integrate high-throughput technologies to broaden the experimental state space and facilitate systematic examination of combinatorial signals, and (3) construct systems-based models to better define stem cell processes through an understanding of the interdependence of the individual signaling components. Cooperative advancements in these areas will continue to contribute to the evolution of stem cell-based therapeutics. PMID- 22927219 TI - Modulation of pain by emotional sounds: a laser-evoked potential study. AB - BACKGROUND: Previous studies have shown increases in experimental pain during induction of a negative emotion with visual stimuli, verbal statements or unpleasant odours. The goal of the present study was to analyse the spatio temporal activation patterns underlying pain augmentation during negative emotional sounds. METHODS: Negative (e.g., crying), positive (e.g., laughter) and neutral (e.g., distant traffic) sound samples of 4 s duration were presented while noxious laser stimuli were administered to the dorsum of the right hand in 16 healthy participants. The electroencephalographic laser-evoked potentials (LEPs) were modelled using six equivalent source dipoles located in the left and right fronto-opercular/anterior-insular cortex, left parietal operculum, left primary somatosensory cortex, medial parietal cortex and left medial temporal cortex. RESULTS: Negative emotional sounds were associated with stronger pain than neutral or positive sounds. The source activity in the left medial temporal cortex, purportedly involving hippocampal formation, in the epoch 294-330 ms was greater during negative than neutral or positive sounds. In the left fronto opercular/anterior-insular cortex, negative sounds failed to show the positive potential component at around 260 ms that was observed during positive and especially during neutral sounds. CONCLUSIONS: Results suggest increased input of pain-related information into the hippocampal formation when listening to negative emotional sounds, which may in turn facilitate temporal binding between representations of noxious and other behaviourally relevant stimuli, and perhaps associative learning. Absence of the positive potential component fronto opercular/anterior-insular cortex during negative sounds points to a slow attentional disengagement from pain and increased awareness of the painful stimulus. PMID- 22927220 TI - Joining the un-joinable: adhesion between low surface energy polymers using tetrapodal ZnO linkers. AB - Tetrapodal ZnO crystals are used for mechanical interlocking of PTFE and cross linked PDMS, classically non-adhesive polymers. This novel approach is straightforward and easily applicable and leads to a peel strength that is higher than 200 N m(-1) without chemical modification of the surfaces. The shape of these fillers emerged as a crucial aspect of the interlocking mechanism. PMID- 22927221 TI - Bidirectional sex change induced by sex steroid implantation in the hermaphrodite fish, Pseudolabrus sieboldi. AB - Sex steroids have been suggested to be involved in gonadal sex change in hermaphrodite fish. Aromatase, the enzyme that catalyzes the conversion of androgens into estrogens, is a principal enzyme regulating gonadal sex. However, the detailed functions of each steroid hormone remain to be evaluated. Recent studies have demonstrated that estradiol-17beta (E2) is synthesized via estrone (E1) in some hermaphrodite species. On the other hand, 11-ketotestosterone (11KT) is produced in the testis via testosterone (T). In this study, we hypothesized that E1 and T are also involved in the sex change as precursors for E2 and 11KT, respectively. We implanted females of the wrasse, Pseudolabrus sieboldi, with T and 11KT, and males with E1 and E2, by use of sustained-release capsules. In females, testicular tissues and body color change were observed after androgen administration, in which 11KT was more effective than T. In contrast, after estrogen administration, the gonads of males contained oocytes. In females, the administration of T and 11KT resulted in reduced serum E2 levels. Conversely, serum 11KT levels decreased in the E1- and E2-treated males. Thus, we successfully induced bidirectional sex change in the gonad by estrogen and androgen administration in vivo. Moreover, this study raises the possibility that E1 and T are involved in the sex change as precursors for E2 and 11KT, respectively. PMID- 22927223 TI - Lymph node metastasis between sternocleidomastoid and sternohyoid muscle in clinically node-positive papillary thyroid carcinoma. AB - BACKGROUND: There have been few reports on lymph node metastasis between sternocleidomastoid and sternohyoid muscle (originally LNSS) in clinically node positive (cN+) papillary thyroid carcinoma (PTC). Therefore, our objective was to investigate the significance of LNSS metastasis. METHODS: A total of 115 patients with cN+ PTC underwent a neck dissection with LNSS, as a separate pathologic specimen to be analyzed for the correlation between LNSS and sex, age, tumor size, tumor site, initial or reoperative treatment, lateral cervical lymph nodes, and central compartment metastasis. RESULTS: The positive rate of LNSS was 22.6%. LNSS metastasis was correlated with a primary site in the inferior pole, the lateral nodal metastasis, level III and level IV nodal metastasis, but not with other clinical parameters. CONCLUSION: In cN+ PTC, especially a primary site in the inferior pole, level III and/or level IV metastasis, attention should be given to excising the nodal tissue in LNSS. PMID- 22927224 TI - Asymmetric 4-aryl-1,4-dihydropyridines potentiate mutant cystic fibrosis transmembrane conductance regulator (CFTR). AB - Some of the genetic mutations that cause cystic fibrosis (CF) impair the gating of the cystic fibrosis transmembrane conductance regulator (CFTR) Cl(-) ion channel. This defect can be corrected with pharmacological tools (potentiators) that belong to various chemical families, including the 1,4-dihydropyridines (DHPs). A small set of asymmetric 4-aryl-DHPs was synthesized, and each racemic couple was tested in a functional assay carried out on cells expressing the G1349D, DeltaF508, and G551D mutants. The most active racemates were subjected to chiral separation by HPLC, and the pure enantiomers were tested to evaluate any gains in activity. Although three enantiomers demonstrated high potency (K(d) values less than 0.09, 0.1, and 0.5 MUM in G1349D, DeltaF508, and G551D, respectively), in general, the screening of pure enantiomers did not produce a great diversity in potency values. It is probable that the degree of DHP asymmetry considered in our analysis is still insufficient with respect to that allowed in a putative DHP binding site in CFTR, so that the site could equally accommodate both enantiomers. PMID- 22927225 TI - Sequential radiofrequency ablation and surgical debulking for unresectable colorectal carcinoma: thermo-surgical ablation. AB - BACKGROUND AND OBJECTIVES: Despite decreasing frequency, local recurrences of unresectable colorectal cancer (CRC) remain difficult problems. These patients have few treatment options with conventional therapy. Preliminary results of sequential radiofrequency ablation (RFA) and surgical debulking (thermo-surgical ablation) suggest this technique may have benefit. METHODS: We reviewed a prospective database of patients undergoing thermo-surgical ablation for unresectable colorectal carcinoma from 2003 to 2011. RESULTS: Sixteen patients were treated with unresectable, recurrent abdomino-pelvic colorectal carcinoma: 11 in pelvis; 4 with isolated aortic/retroperitoneal disease; and 1 with pelvic and peri-adrenal/retroperitoneal disease. Eleven patients had recurrent rectal cancer and five had recurrent colon cancer. Median overall and 3-year actuarial survivals were 15 months and 24%, respectively. Median and 3-year PFS was 12 months and 19%, respectively. Three patients without disease have survived 0.75, 4.0, and 7.0 years. Two patients died at 5.0 and 5.5 years. A disease-free interval (DFI) of >24 months after initial resection was associated with longer overall survival (60 months vs. 4 months; P = 0.001). CONCLUSIONS: Thermo surgical debulking appears to have a role in the treatment of some patients with recurrent, unresectable CRC; those patients with DFI >24 months after initial surgery benefited the most. PMID- 22927226 TI - Variation in chlorotoluron photodegradation rates as a result of seasonal changes in the composition of natural waters. AB - BACKGROUND: It is important to understand the degradation of organic molecules in surface waters to ensure that risk assessments, intended to prevent adverse effects on human health and the environment, are robust. One important degradation mechanism in surface waters is photodegradation. This process is generally studied in laboratory test systems, and the significance of the results is then extrapolated to the field. The aim of this work was to assess how fluctuations in the composition of surface water influence the photodegradation rate of chlorotoluron. RESULTS: Photodegradation DT(50) values in the lake (mean = 26.0 days) and pond (mean = 26.0 days) were significantly slower than in the river (mean = 6.8 days) and stream (mean = 7.3 days) samples. The DT(50) values in the pond and lake samples were similar to the direct photolysis value (mean = 28.6 days). Photodegradation was significantly faster in the stream and river samples, suggesting that indirect photolysis was significant in those waters. Principal component analysis indicated a strong inverse correlation between nitrate concentration and degradation rate. CONCLUSIONS: Nitrate concentration had a strong influence on the rate of photodegradation, with increasing nitrate concentrations sharply reducing the DT(50) . However, this effect was restricted to a narrow concentration range and levelled off quite quickly, such that further increases in the nitrate concentration had no significant effect on the rate of degradation. Extrapolating photodegradation rates of chlorotoluron from the laboratory to the field should be relatively straightforward, provided the nitrate concentrations in the waters are known. PMID- 22927227 TI - Switching properties of a spiropyran-cucurbit[7]uril supramolecular assembly: usefulness of the anchor approach. AB - A nitrospiropyran, which was modified with a cadaverine-derived anchor, was investigated with respect to its thermally induced isomerizations, hydrolytic stability of the merocyanine form, and photochromic ring closure. The host-guest complexation of the anchor by the cucurbit[7]uril macrocycle, evidenced by absorption titration, NMR spectroscopy, and electrospray ionization mass spectrometry, produced significant improvements of the switching properties of the photochrome: 1) appearance of the merocyanine form about 70 times faster, 2) practically unlimited hydrolytic stability of the merocyanine (two and a half days without any measureable decay), and 3) fast, clean, and fatigue-resistant photoinduced ring closure back to the spiro form. The importance of an adequate molecular design of the anchor was demonstrated by including control experiments with spiropyrans with a shorter linker or without such structural asset. PMID- 22927228 TI - One-pot/sequential native chemical ligation using N-sulfanylethylanilide peptide. AB - N-Sulfanylethylanilide (SEAlide) peptides were developed with the aim of achieving facile synthesis of peptide thioesters by 9-fluorenylmethyloxycarbonyl (Fmoc)-based solid-phase peptide synthesis (Fmoc SPPS). Initially, SEAlide peptides were found to be converted to the corresponding peptide thioesters under acidic conditions. However, the SEAlide moiety was proved to function as a thioester in the presence of phosphate salts and to participate in native chemical ligation (NCL) with N-terminal cysteinyl peptides, and this has served as a powerful protein synthesis methodology. The reactivity of a SEAlide peptide (anilide vs. thioester) can be easily tuned with or without the use of phosphate salts. This interesting property of SEAlide peptides allows sequential three fragment or unprecedented four-fragment ligation for efficient one-pot peptide/protein synthesis. Furthermore, dual-kinetically controlled ligation, which enables three peptide fragments simultaneously present in the reaction to be ligated in the correct order, was first achieved using a SEAlide peptide. Beyond our initial expectations, SEAlide peptides have served in protein chemistry fields as very useful crypto-peptide thioesters. PMID- 22927229 TI - 3Drefine: consistent protein structure refinement by optimizing hydrogen bonding network and atomic-level energy minimization. AB - One of the major limitations of computational protein structure prediction is the deviation of predicted models from their experimentally derived true, native structures. The limitations often hinder the possibility of applying computational protein structure prediction methods in biochemical assignment and drug design that are very sensitive to structural details. Refinement of these low-resolution predicted models to high-resolution structures close to the native state, however, has proven to be extremely challenging. Thus, protein structure refinement remains a largely unsolved problem. Critical assessment of techniques for protein structure prediction (CASP) specifically indicated that most predictors participating in the refinement category still did not consistently improve model quality. Here, we propose a two-step refinement protocol, called 3Drefine, to consistently bring the initial model closer to the native structure. The first step is based on optimization of hydrogen bonding (HB) network and the second step applies atomic-level energy minimization on the optimized model using a composite physics and knowledge-based force fields. The approach has been evaluated on the CASP benchmark data and it exhibits consistent improvement over the initial structure in both global and local structural quality measures. 3Drefine method is also computationally inexpensive, consuming only few minutes of CPU time to refine a protein of typical length (300 residues). 3Drefine web server is freely available at http://sysbio.rnet.missouri.edu/3Drefine/. PMID- 22927230 TI - The impact of intra-operative sufentanil dosing on post-operative pain, hyperalgesia and morphine consumption after cardiac surgery. AB - BACKGROUND: There is an ongoing debate whether opioids when used for intra operative analgesia may enhance post-operative pain. We studied the effect of two different intra-operative dosings of sufentanil on post-operative morphine consumption, pain and hyperalgesia after cardiac anaesthesia. METHODS: Forty-two male patients (age: 48-74 years) undergoing first-time coronary artery bypass graft surgery were randomized to one of two groups receiving total intravenous anaesthesia with propofol and a target controlled infusion of sufentanil with a target of 0.4 ng/mL (group SL, n = 20) or 0.8 ng/mL (group SH, n = 22) plasma concentration. Post-operative morphine requirement in the first 48 h was assessed using patient-controlled analgesia (PCA). Pain rating during deep inspiration, and the extent of primary and secondary hyperalgesia near the sternotomy wound were assessed. RESULTS: The post-operative morphine requirements in the first 48 h were 0.68 +/- 0.21 mg/kg in group SL and 0.96 +/- 0.44 mg/kg in group SH (p < 0.05). In group SL, pain during deep inspiration was significantly lower on the first post-operative day (p < 0.05). Primary hyperalgesia had its maximum on the second and third post-operative day, without a difference between the two groups. The extent of secondary mechanical pinprick hyperalgesia was not different between the groups. DISCUSSION: Intra-operative dosing of sufentanil significantly influenced post-operative morphine consumption, pain and hyperalgesia. For cardiac anaesthesia in combination with propofol, a sufentanil target concentration of 0.4 ng/mL may be preferable. PMID- 22927231 TI - Microfabricated platforms to modulate and monitor T cell synapse assembly. AB - Immunological synapse (IS) is a complex supramolecular structure formed at the interface between T cells and antigen presenting cells (APCs) during T cell antigen recognition. Microfabricated platforms have made great contributions to our understanding of the assembly dynamics and functional roles of the T cell synapses over the last decade. Here, we review three different types of microfabricated platforms developed to modulate and monitor the T cell synapse assembly. Firstly, multi-protein micropatterned surfaces presenting key ligands for T cell activation that can modulate the spatial distribution of receptors/signaling molecules in T cell synapses are described. Secondly, micropatterned supported bilayers that can modulate the dynamics of T cell receptor (TCR) microclusters are introduced. Lastly, T-APC pair arrays that allow for improved fluorescence live cell imaging are discussed. PMID- 22927232 TI - Porous carbon spheres from energetic carbon precursors using ultrasonic spray pyrolysis. AB - Porous carbon spheres with unique structures and morphologies are prepared from energetic carbon precursors, alkali propiolates, via ultrasonic spray pyrolysis. Aerosolized liquid droplets containing alkali propiolates act as microreactors that confine the thermal decomposition of energetic precursors and lead to the formation of several unprecedented carbon morphologies. PMID- 22927234 TI - Paradigms for adaptive statistical information designs: practical experiences and strategies. AB - In the last decade or so, interest in adaptive design clinical trials has gradually been directed towards their use in regulatory submissions by pharmaceutical drug sponsors to evaluate investigational new drugs. Methodological advances of adaptive designs are abundant in the statistical literature since the 1970s. The adaptive design paradigm has been enthusiastically perceived to increase the efficiency and to be more cost effective than the fixed design paradigm for drug development. Much interest in adaptive designs is in those studies with two-stages, where stage 1 is exploratory and stage 2 depends upon stage 1 results, but where the data of both stages will be combined to yield statistical evidence for use as that of a pivotal registration trial. It was not until the recent release of the US Food and Drug Administration Draft Guidance for Industry on Adaptive Design Clinical Trials for Drugs and Biologics (2010) that the boundaries of flexibility for adaptive designs were specifically considered for regulatory purposes, including what are exploratory goals, and what are the goals of adequate and well controlled (A&WC) trials (2002). The guidance carefully described these distinctions in an attempt to minimize the confusion between the goals of preliminary learning phases of drug development, which are inherently substantially uncertain, and the definitive inference-based phases of drug development. In this paper, in addition to discussing some aspects of adaptive designs in a confirmatory study setting, we underscore the value of adaptive designs when used in exploratory trials to improve planning of subsequent A&WC trials. One type of adaptation that is receiving attention is the re-estimation of the sample size during the course of the trial. We refer to this type of adaptation as an adaptive statistical information design. Specifically, a case example is used to illustrate how challenging it is to plan a confirmatory adaptive statistical information design. We highlight the substantial risk of planning the sample size for confirmatory trials when information is very uninformative and stipulate the advantages of adaptive statistical information designs for planning exploratory trials. Practical experiences and strategies as lessons learned from more recent adaptive design proposals will be discussed to pinpoint the improved utilities of adaptive design clinical trials and their potential to increase the chance of a successful drug development. PMID- 22927233 TI - Epithelial permeability alterations in an in vitro air-liquid interface model of allergic fungal rhinosinusitis. AB - BACKGROUND: Chronic rhinosinusitis (CRS) is an inflammatory upper-airway disease with numerous etiologies. Patients with a characteristic subtype of CRS, allergic fungal rhinosinusitis (AFRS), display increased expression of T helper 2 (Th2) cytokines and antigen-specific immunoglobulin E (IgE). Various sinonasal inflammatory conditions are associated with alterations in epithelial barrier function. The aim of this study was to compare epithelial permeability and intercellular junctional protein expression among cultured primary sinonasal cells from AFRS patients vs noninflammatory controls. METHODS: Epithelial cells isolated from paranasal sinus mucosa of AFRS and noninflammatory control patients were grown to confluence on permeable supports and transitioned to air-liquid interface (ALI). Transepithelial resistance (TER) was measured with a horizontal Ussing chamber to characterize the functional permeability of each cell type. After TER recordings were complete, a panel of intercellular junctional proteins was assessed by Western blot and immunofluorescence labeling followed by confocal microscopy. RESULTS: After 12 samples were measured from each group, we observed a 41% mean decrease in TER in AFRS cells (296 +/- 89 ohms * cm(2) ) compared to control (503 +/- 134 ohms * cm(2) , p = 0.006). TER deficits observed in AFRS were associated with decreased expression of the tight junction proteins occludin and junctional adhesion molecule-A (JAM-A), and increased expression of a leaky tight junction protein claudin-2. CONCLUSION: Cultured sinonasal epithelium from AFRS patients displayed increased epithelial permeability and altered expression of intercellular junctional proteins. Given that these cells were not incubated with inflammatory cytokines in vitro, the cultured AFRS epithelial alterations may represent a retained modification in protein expression from the in vivo phenotype. PMID- 22927235 TI - Decreased fecal corticosterone levels due to domestication: a comparison between the white-backed Munia (Lonchura striata) and its domesticated strain, the Bengalese finch (Lonchura striata var. domestica) with a suggestion for complex song evolution. AB - The Bengalese finch (BF; Lonchura striata var. domestica) is a domesticated strain of the white-backed munia (WBM; Lonchura striata). Environmental stresses activate the hypothalamic-pituitary-adrenal (HPA) axis and release corticosterone (CORT). We hypothesized that domesticated songbirds have reduced CORT levels because of reduced levels of environmental stresses (compared to wild conditions) and reductions in the role of CORT, which is necessary for survival in the wild. However, no study has examined the effects of domestication on songbird CORT levels. To explore the domestication effects, we compared CORT levels between domesticated BFs and their wild ancestors WBMs. We also compared CORT levels between bought and aviary-raised BFs, and between wild-caught and captive-raised WBMs to examine the influence of being raised. However, blood collection causes stress, which affects endocrine dynamics and makes continuous sampling difficult in small birds. Therefore, we used a non-invasive method to measure fecal CORT. Parallelism between diluted fecal extracts and a CORT standard, extraction efficiency, and ACTH challenge demonstrated the effectiveness of this method. This study demonstrates that BFs have lower fecal CORT than do WBMs, regardless of whether the WBMs were wild-caught or captive-raised. In addition, BFs sing more complex songs than WBMs. Considerable evidence suggests that song complexity is related to CORT levels. Previously, we found that the corticosteroid receptors were expressed in song-control areas of the BF brain. Based on these results, we hypothesize that reduced CORT levels through domestication might be one factor allowing for the development of more complex songs in BFs. PMID- 22927236 TI - Lack of association between cancer history and PARKIN genotype: a family based study in PARKIN/Parkinson's families. AB - A number of publications have attributed a tumor suppressive (TS) function to PARKIN, a gene associated with recessive familial early onset Parkinson's disease (EOPD). Discoveries of PARKIN deletions and point mutations in tumors, functional studies, and data from mouse models have been presented to support the hypothesis. We have asked whether PARKIN mutations are associated with history of cancer in humans. We interviewed 431 participants who were screened for PARKIN mutations, including 149 EOPD cases and their family members, who were unaware of mutation status. We found no significant difference in self-reported history of cancer among carriers of one or two PARKIN mutations and noncarriers, odds ratio 0.75 (95% confidence interval 0.27-1.83). In particular, no increase in cancer history was seen among homozygous and compound heterozygous mutation carriers compared to noncarriers. Therefore, we hypothesize that published studies attributing TS capability to PARKIN merit further exploration and we present a reevaluation of these data with respect to patterns of mutation frequencies in normal and cancer cells. We conclude that although Parkin may exert a suppressive effect in mice, further studies are required prior to assigning a TS function to PARKIN in humans. PMID- 22927237 TI - Marker-free, tissue-specific expression of Cry1Ab as a safe transgenic strategy for insect resistance in rice plants. AB - BACKGROUND: Rice is the major food resource for nearly half of the global population; however, insect infestation could severely affect the production of this staple food. To improve rice insect resistance and reduce the levels of Bt toxin released into the environment, the Cry1Ab gene was conjugated to the rice rbcS promoter to express Bt toxin in specific tissues of transgenic plants. RESULTS: Eight marker-free, T(2) lines were separated from the T(0) cotransformants. Using RT-PCR, high levels of Cry1Ab expression were detected in the leaf but not in the seed. The Cry1Ab protein level ranged from 1.66 to 3.31 ug g(-1) in the leaves of four transgenic lines, but was barely detectable in their seeds by ELISA. Bioassays showed that the mortality rate of silkworm larvae feeding on mulberry leaves dipped in transgenic rice flour and pollen was less than that of the positive control (KMD), and that their average weight was higher than that of KMD, suggesting that the Cry1Ab protein was not expressed in the seed and pollen. CONCLUSION: The transgene conferred a high level of resistance to insects and biosafety to the rice plants, which could be directly used in rice breeding. PMID- 22927238 TI - Modeling, synthesis and biological evaluation of potential retinoid X receptor selective agonists: novel halogenated analogues of 4-[1-(3,5,5,8,8-pentamethyl 5,6,7,8-tetrahydro-2-naphthyl)ethynyl]benzoic acid (bexarotene). AB - The synthesis of halogenated analogues of 4-[1-(3,5,5,8,8-pentamethyl-5,6,7,8 tetrahydro-2-naphthyl)ethynyl]benzoic acid (1), known commonly as bexarotene, and their evaluation for retinoid X receptor (RXR)-specific agonist performance is described. Compound 1 is FDA approved to treat cutaneous T-cell lymphoma (CTCL); however, bexarotene treatment can induce hypothyroidism and elevated triglyceride levels, presumably by disrupting RXR heterodimer pathways for other nuclear receptors. The novel halogenated analogues in this study were modeled and assessed for their ability to bind to RXR and stimulate RXR homodimerization in an RXRE-mediated transcriptional assay as well as an RXR mammalian-2-hybrid assay. In an array of eight novel compounds, four analogues were discovered to promote RXR-mediated transcription with EC(50) values similar to that of 1 and are selective RXR agonists. Our approach also uncovered a periodic trend of increased binding and homodimerization of RXR when substituting a halogen atom for a proton ortho to the carboxylic acid on 1. PMID- 22927239 TI - RAF-targeted therapy for hepatocellular carcinoma in the regenerating liver. AB - BACKGROUND: Post-operative liver regeneration may contribute to tumor recurrence. There is a theoretical need for an adjuvant therapy that can suppress tumor growth without adversely affecting post-operative liver regeneration. OBJECTIVE: To evaluate the effect of RAF inhibitor Sorafenib on cell viability and proliferation of hepatoma cells and hepatocytes in vitro and in an in vivo rat model. METHODS: Cell viability, DNA synthesis, and RAF/MAPK kinase activity in the primary hepatocyte and hepatoma cell lines were investigated after Sorafenib exposure. Sequence analysis of the B-RAF gene in hepatic cells was determined. Tumor markers were compared within the rats after 70% hepatectomy with or without daily oral gavages of Sorafenib. Liver regeneration was assessed by liver function tests and proliferation markers. RESULTS: Primary hepatocytes showed higher cell viability, proliferation rate, and stronger RAF/MAPK kinase activity compared with hepatoma cell lines. The in vivo tumor volumes, size, and metastases were significantly decreased (P < 0.05) whereas no significant change in liver regeneration related to Sorafenib exposure was found (P > 0.05). B-RAF V600E mutation was not detected neither in the hepatic cells nor untransformed hepatocytes. CONCLUSIONS: The RAF targeted inhibitor can reduce tumor growth without retarding liver regeneration in this experiment. PMID- 22927241 TI - Continuing professional development in musculoskeletal domains. PMID- 22927242 TI - A new dielectric metamaterial building block with a strong magnetic response in the sub-1.5-micrometer region: silicon colloid nanocavities. AB - A new dielectric metamaterial building block based on high refractive index silicon spherical nanocavities with Mie resonances appearing in the near infrared optical region is prepared and characterized. It is demonstrated both experimentally and theoretically that a single silicon nanocavity supports well defined and robust magnetic resonances, even in a liquid medium environment, at wavelength values up to six times larger than the cavity radius. PMID- 22927243 TI - Investigative and clinical applications of synthetic immune synapses. AB - The immune synapse (IS) has emerged as a compelling model of cell-cell communication. This interface between a T cell and antigen-presenting cell (APC) serves as a key point in coordinating the immune response. A distinguishing feature of this interface is that juxtacrine signaling molecules form complex patterns that are defined at micrometer and submicrometer scales. Moreover, these patterns are highly dynamic. While cellular and molecular approaches have provided insight into the influence of these patterns on cell-cell signaling, replacing the APC with a synthetic, micro/nanoengineered surface promises a new level of sophistication to these studies. Micropatterning of multiple ligands onto a surface, for example, allowed the direct demonstration that T cells can sense and respond to microscale geometry of the IS. Supported lipid bilayers have captured the lateral mobility of natural ligands, allowing insight into this complex property of the cell-cell interface in model systems. Finally, engineered surfaces have allowed the study of forces and mechanosensing in T cell activation, an emerging area of immune cell research. In addition to providing new insight into biophysical principles, investigations into IS function may allow control over ex vivo T cell expansion. Bioreactors based on these concepts may find immediate application in enhancing cellular-based immunotherapy. PMID- 22927244 TI - Cytosolic sensing of extracellular self-DNA transported into monocytes by the antimicrobial peptide LL37. AB - The intracellular location of nucleic acid sensors prevents recognition of extracellular self-DNA released by dying cells. However, on forming a complex with the endogenous antimicrobial peptide LL37, extracellular DNA is transported into endosomal compartments of plasmacytoid dendritic cells, leading to activation of Toll-like receptor-9 and induction of type I IFNs. Whether LL37 also transports self-DNA into nonplasmacytoid dendritic cells, leading to type I IFN production via other intracellular DNA receptors is unknown. Here we found that LL37 very efficiently transports self-DNA into monocytes, leading the production of type I IFNs in a Toll-like receptor-independent manner. This type I IFN induction was mediated by double-stranded B form DNA, regardless of its sequence, CpG content, or methylation status, and required signaling through the adaptor protein STING and TBK1 kinase, indicating the involvement of cytosolic DNA sensors. Thus, our study identifies a novel link between the antimicrobial peptides and type I IFN responses involving DNA-dependent activation of cytosolic sensors in monocytes. PMID- 22927245 TI - Loss of p53 accelerates the complications of myelodysplastic syndrome in a NUP98 HOXD13-driven mouse model. AB - The nucleoporin gene NUP98 is fused to several genes including HOXD13 in patients with myelodysplastic syndromes (MDS), acute myeloid leukemia, and chronic myeloid leukemia, blast crisis. Genetically engineered mice that express a NUP98-HOXD13 (NHD13) transgene (Tg) display the phenotypic features of MDS, including cytopenias, bone marrow dysplasia, and transformation to acute leukemia. Here we show that short-term treatment with the p53 inhibitor Pifithrin-alpha partially and transiently rescued the myeloid and lymphoid abnormalities found in NHD13(+) Tg mice, with no improvement in the anemia, while the genetic deletion of 2 alleles of p53 rescued both the myeloid progenitor cell and long-term hematopoietic stem cell compartments. Nonetheless, loss of one or both alleles of p53 did not rescue the MDS phenotype, but instead exacerbated the MDS phenotype and accelerated the development of acute myeloid leukemia. Our studies suggest that while targeting p53 may transiently improve hematopoiesis in MDS, over the long-term, it has detrimental effects, raising caution about abrogating its function to treat the cytopenias that accompany this disease. PMID- 22927246 TI - Final results of a multicenter trial addressing role of CSF flow cytometric analysis in NHL patients at high risk for CNS dissemination. AB - This prospective study compared diagnostic and prognostic value of conventional cytologic (CC) examination and flow cytometry (FCM) of baseline samples of cerebrospinal fluid (CSF) in 174 patients with newly diagnosed aggressive non Hodgkin lymphoma (NHL). FCM detected a neoplastic population in the CSF of 18 of 174 patients (10%), CC only in 7 (4%; P < .001); 11 patients (14%) were discordant (FCM(+)/CC(-)). At a median follow-up of 46 months, there were 64 systemic progressions and 10 CNS relapses, including 2 patients with both systemic and CNS relapses. Two-year progression-free and overall survival were significantly higher in patients with FCM(-) CSF (62% and 72%) compared with those FCM(+) CSF (39% and 50%, respectively), with a 2-year CNS relapse cumulative incidence of 3% (95% confidence interval [CI], 0-7) versus 17% (95% CI, 0-34; P = .004), respectively. The risk of CNS progression was significantly higher in FMC(+)/CC(-) versus FCM(-)/CC(-) patients (hazard ratio = 8.16, 95% CI, 1.45-46). In conclusion, FCM positivity in the CSF of patients with high-risk NHL is associated with a significantly higher CNS relapse risk and poorer outcome. The combination of IV drugs with a higher CNS bioavailability and intrathecal chemotherapy is advisable to prevent CNS relapses in FCM(+) patients. PMID- 22927247 TI - B-cell receptor triggers drug sensitivity of primary CLL cells by controlling glucosylation of ceramides. AB - Survival of chronic lymphocytic leukemia (CLL) cells is triggered by several stimuli, such as the B-cell receptor (BCR), CD40 ligand (CD40L), or interleukin-4 (IL-4). We identified that these stimuli regulate apoptosis resistance by modulating sphingolipid metabolism. Applying liquid chromatography electrospray ionization tandem mass spectrometry, we revealed a significant decrease of proapoptotic ceramide in BCR/IL-4/CD40L-stimulated primary CLL cells compared with untreated controls. Antiapoptotic glucosylceramide levels were significantly increased after BCR cross-linking. We identified BCR engagement to catalyze the crucial modification of ceramide to glucosylceramide via UDP-glucose ceramide glucosyltransferase (UGCG). Besides specific UGCG inhibitors, our data demonstrate that IgM-mediated UGCG expression was inhibited by the novel and highly effective PI3Kdelta and BTK inhibitors CAL-101 and PCI-32765, which reverted IgM-induced resistance toward apoptosis of CLL cells. Sphingolipids were recently shown to be crucial for mediation of apoptosis via mitochondria. Our data reveal ABT-737, a mitochondria-targeting drug, as interesting candidate partner for PI3Kdelta and BTK inhibition, resulting in synergistic apoptosis, even under protection by the BCR. In summary, we identified the mode of action of novel kinase inhibitors CAL-101 and PCI-32765 by controlling the UGCG-mediated ceramide/glucosylceramide equilibrium as a downstream molecular switch of BCR signaling, also providing novel targeted treatment options beyond current chemotherapy-based regimens. PMID- 22927248 TI - Allogeneic mesenchymal stem cell treatment alleviates experimental and clinical Sjogren syndrome. AB - Sjogren syndrome (SS) is a systemic autoimmune disease characterized by dry mouth and eyes, and the cellular and molecular mechanisms for its pathogenesis are complex. Here we reveal, for the first time, that bone marrow mesenchymal stem cells in SS-like NOD/Ltj mice and human patients were defective in immunoregulatory functions. Importantly, treatment with mesenchymal stem cells (MSCs) suppressed autoimmunity and restored salivary gland secretory function in both mouse models and SS patients. MSC treatment directed T cells toward Treg and Th2, while suppressing Th17 and Tfh responses, and alleviated disease symptoms. Infused MSCs migrated toward the inflammatory regions in a stromal cell-derived factor-1-dependent manner, as neutralization of stromal cell-derived factor-1 ligand CXCR4 abolished the effectiveness of bone marrow mesenchymal stem cell treatment. Collectively, our study suggests that immunologic regulatory functions of MSCs play an important role in SS pathogenesis, and allogeneic MSC treatment may provide a novel, effective, and safe therapy for patients with SS. PMID- 22927249 TI - Mechanism of platelet dense granule biogenesis: study of cargo transport and function of Rab32 and Rab38 in a model system. AB - Dense granules are important in platelet aggregation to form a hemostatic plug as evidenced by the increased bleeding time in mice and humans with dense granule deficiency. Dense granules also are targeted by antiplatelet agents because of their role in thrombus formation. Therefore, the molecular understanding of the dense granule and its biogenesis is of vital importance. In this work, we establish a human megakaryocytic cell line (MEG-01) as a model system for the study of dense granule biogenesis using a variety of cell biology and biochemical approaches. Using this model system, we determine the late endocytic origin of these organelles by colocalization of the internalized fluid phase marker dextran with both mepacrine and transmembrane dense granule proteins. By mistargeting of mutant dense granule proteins, we demonstrate that sorting signals recognized by adaptor protein-3 are necessary for normal transport to dense granules. Furthermore, we show that tissue-specific Rab32 and Rab38 are crucial for the fusion of vesicles containing dense granule cargo with the maturing organelle. This work sheds light on the biogenesis of dense granules at the molecular level and opens the possibility of using this powerful model system for the investigation of new components of the biogenesis machinery. PMID- 22927250 TI - Biphenotypic B-lymphoid/myeloid cells expressing low levels of Pax5: potential targets of BAL development. AB - The expression of Pax5 commits common lymphoid progenitor cells to B-lymphoid lineage differentiation. Little is known of possible variations in the levels of Pax5 expression and their influences on hematopoietic development. We have developed a retroviral transduction system that allows for the study of possible intermediate stages of this commitment by controlling the levels of Pax5 expressed in Pax5-deficient progenitors in vitro and in vivo. Retroviral transduction of Pax5-deficient pro-/pre-B cell lines with a doxycycline-inducible (TetON) form of the human Pax5 (huPax5) gene yielded cell clones that could be induced to different levels of huPax5 expression. Clones inducible to high levels developed B220(+)/CD19(+)/IgM(+) B cells, while clones with low levels differentiated to B220(+)/CD19(-)/CD11b(+)/Gr-1(-) B-lymphoid/myeloid biphenotypic cells in vitro and in vivo. Microarray analyses of genes expressed at these lower levels of huPax5 identified C/ebpalpha, C/ebpdelta, Pu.1, Csf1r, Csf2r, and Gata-3 as myeloid-related genes selectively expressed in the pro-/pre B cells that can develop under myeloid/lymphoid conditions to biphenotypic cells. Therefore, reduced expression of huPax5 during the induction of early lymphoid progenitors to B-lineage-committed cells can fix this cellular development at a stage that has previously been seen during embryonic development and in acute lymphoblastic lymphoma-like biphenotypic acute leukemias. PMID- 22927252 TI - The development of an early warning system for climate-sensitive disease risk with a focus on dengue epidemics in Southeast Brazil. AB - Previous studies demonstrate statistically significant associations between disease and climate variations, highlighting the potential for developing climate based epidemic early warning systems. However, limitations include failure to allow for non-climatic confounding factors, limited geographical/temporal resolution, or lack of evaluation of predictive validity. Here, we consider such issues for dengue in Southeast Brazil using a spatio-temporal generalised linear mixed model with parameters estimated in a Bayesian framework, allowing posterior predictive distributions to be derived in time and space. This paper builds upon a preliminary study by Lowe et al. but uses extended, more recent data and a refined model formulation, which, amongst other adjustments, incorporates past dengue risk to improve model predictions. For the first time, a thorough evaluation and validation of model performance is conducted using out-of-sample predictions and demonstrates considerable improvement over a model that mirrors current surveillance practice. Using the model, we can issue probabilistic dengue early warnings for pre-defined 'alert' thresholds. With the use of the criterion 'greater than a 50% chance of exceeding 300 cases per 100,000 inhabitants', there would have been successful epidemic alerts issued for 81% of the 54 regions that experienced epidemic dengue incidence rates in February-April 2008, with a corresponding false alarm rate of 25%. We propose a novel visualisation technique to map ternary probabilistic forecasts of dengue risk. This technique allows decision makers to identify areas where the model predicts with certainty a particular dengue risk category, to effectively target limited resources to those districts most at risk for a given season. PMID- 22927254 TI - Kinematics and center of mass mechanics during terrestrial locomotion in northern lapwings (Vanellus vanellus, Charadriiformes). AB - Avian bipedalism is best studied in derived walking/running specialists. Here, we use kinematics and center of mass (CoM) mechanical energy patterns to investigate gait transitions of lapwings-migratory birds that forage on the ground, and therefore may need a trade-off between the functional demands of terrestrial locomotion and long distance flights. The animals ran on a treadmill while high speed X-ray videos were recorded within the sustainable speed range. Instantaneous CoM mechanics were computed from integrating kinematics and body segment properties. Lapwings exhibit similar locomotor characteristics to specialized walking/running birds, but have less distinct gaits. At slow speeds no clear separation between vaulting (i.e., walking) and bouncing (i.e., running) energy patterns exists. Mechanical energy recovery of non-bouncing gaits correlates poorly with speed and suggests inefficient use of the inverted pendulum mechanism. Speed ranges of gaits overlap considerably, especially those of grounded running, a gait with CoM mechanics indicative of running but without an aerial phase, and aerial phase running, with no preferential gait at most speeds. Compliant limb morphology and grounded running in birds can be regarded as an evolutionary constraint, but lapwings effectively make use of advantages offered by this gait for a great fraction of their speed range. Thus, effective usage of grounded running during terrestrial locomotion is suggested generally to be a part of striding avian bipedalism-even in species not specialized in walking/running locomotion. PMID- 22927251 TI - Fluvastatin inhibits FLT3 glycosylation in human and murine cells and prolongs survival of mice with FLT3/ITD leukemia. AB - FLT3 is frequently mutated in acute myeloid leukemia (AML), but resistance has limited the benefit of tyrosine kinase inhibitors (TKI). We demonstrate that statins can impair FLT3 glycosylation, thus leading to loss of surface expression and induction of cell death, as well as mitigation of TKI resistance. Immunofluorescence microscopy confirms a reduction in surface localization and an increase in intracellular FLT3/internal tandem duplication (ITD) accumulation. This aberrant localization was associated with increased STAT5 activation but inhibition of both MAPK and AKT phosphorylation. Growth inhibition studies indicate that FLT3/ITD-expressing cells were killed with an IC(50) within a range of 0.2-2MUM fluvastatin. Several mechanisms of resistance could be circumvented by fluvastatin treatment. An increase in the IC(50) for inhibition of phosphorylated FLT3/ITD by lestaurtinib caused by exogenous FLT3 ligand, resistance to sorafenib caused by the D835Y or FLT3/ITD N676K mutations, and activation of the IL-3 compensatory pathway were all negated by fluvastatin treatment. Finally, fluvastatin treatment in vivo reduced engraftment of BaF3 FLT3/ITD cells in Balb/c mice. These results demonstrate that statins, a class of drugs already approved by the US Food and Drug Administration, might be repurposed for the management of FLT3 mutant acute myeloid leukemia cases either alone or in conjunction with FLT3 TKI. PMID- 22927255 TI - Involvement of the MLL gene in adult T-lymphoblastic leukemia. AB - While the MLL "recombinome" is relatively well characterized in B-cell precursor acute lymphoblastic leukemia (BCP ALL), available data for adult acute T lymphoblastic leukemia (T-ALL) are scarce. We performed fluorescence in situ hybridization (FISH) for an MLL split signal on 223 adult T-ALL samples obtained within the framework of the German Multicenter ALL 07/2003 therapy trial. Three biphenotypic leukemias (T-ALL/AML) were also included in the analysis. Samples showing any alteration by FISH were further investigated to characterize the MLL aberration. In addition, they were investigated for common genetic lesions known in T-ALL. Twenty-two cases (9.5%) showed an abnormal MLL signal by FISH analysis. Most of these appeared to be deletions or gains but in five cases (2.1%) a chromosomal translocation involving the MLL gene was identified. The translocation partners and chromosomal breakpoints were molecularly characterized. Three T-ALLs had an MLL-AF6/t(6;11) and two biphenotypic leukemias had an MLL-ELL/t(11;19). The chromosomal breakpoints in two of the MLL-AF6 positive cases were located outside the classical MLL major breakpoint cluster known from BCP ALL. In conclusion, the spectrum of MLL translocation partners in adult T-ALL much more resembles that of AML than that of BCP ALL and thus the mechanisms by which MLL contributes to leukemogenesis in adult T-ALL appear to differ from those in BCP ALL. Proposals are made for the diagnostic assessment of MLL fusion genes in adult T-ALL. PMID- 22927256 TI - Systemic effects of thiamethoxam and chlorantraniliprole seed treatments on adult Lissorhoptrus oryzophilus (Coleoptera: Curculionidae) in rice. AB - BACKGROUND: Feeding assays using adult rice water weevils and foliage of plants treated as seeds with chlorantraniliprole and thiamethoxam at different rates were conducted to evaluate the systemic adulticidal and feeding effects. Dose mortality relationships were determined for thiamethoxam seed treatments by combining leaf area lost due to feeding and insecticide residues analyzed by LC/MS/MS. Changes in adulticidal activity of thiamethoxam were also investigated by contrasting adult mortalities at the 5-6-leaf and tillering stages of rice. RESULTS: Adult weevil mortalities and leaf consumption rates on foliage were affected in thiamethoxam but not in chlorantraniliprole treatments when rice was at the 6-7-leaf stage. The LD(50) for weevils feeding on thiamethoxam-treated rice at the 2-3-leaf stage was 447 pg insecticide weevil(-1) (95% CL: 25-830 pg weevil(-1)) but was lower (142 pg weevil(-1); 95% CL: 102-180 pg weevil(-1)) in experiments with 3-4-leaf-stage plants. Mortalities on leaves from 5-6-leaf-stage plants were consistently higher than on leaves from tillering plants. Thiamethoxam residues measured by ELISA increased with seed treatment rate and differed between plant stages. CONCLUSION: The LD(50) values developed in this study are the first values for leaf-feeding insects on foliage of plants treated as seeds with thiamethoxam. The attrition of adulticidal activity of thiamethoxam in foliage of older plants may help to explain the reduced effectiveness of seed treatments against rice water larvae that is seen at later stages of rice growth in field studies. The differential activity of these two seed treatments on adults suggests that adult mortality contributes to the field efficacy of thiamethoxam but not to that of chlorantraniliprole. PMID- 22927257 TI - Plasmonic nanostructures for SERRS multiplexed identification of tumor-associated antigens. PMID- 22927258 TI - Gram-scale solution-phase synthesis of selective sodium bicarbonate co-transport inhibitor S0859: in vitro efficacy studies in breast cancer cells. AB - Na(+)-coupled HCO(3)(-) transporters (NBCs) mediate the transport of bicarbonate ions across cell membranes and are thus ubiquitous regulators of intracellular pH. NBC dysregulation is associated with a range of diseases; for instance, NBCn1 is strongly up-regulated in a model of ErbB2-dependent breast cancer, a malignant and widespread cancer with no targeted treatment options, and single-nucleotide polymorphisms in NBCn1 genetically link to breast cancer development and hypertension. The N-cyanosulfonamide S0859 has been shown to selectively inhibit NBCs, and its availability on the gram scale is therefore of significant interest to the scientific community. Herein we describe a short and efficient synthesis of S0859 with an overall yield of 45 % from commercially available starting materials. The inhibitory effect of S0859 on recovery of intracellular pH after an acid load was verified in human and murine cancer cell lines in Ringer solutions. However, S0859 binds very strongly to components in plasma, and accordingly, measurements on isolated murine tissues showed no effect of S0859 at concentrations up to 50 MUM. PMID- 22927259 TI - Differential expression of basement membrane type IV collagen alpha2 and alpha6 chains as a prognostic factor in patients with extrahepatic bile duct carcinoma. AB - BACKGROUND: The destruction of the basement membrane (BM) is the first step in cancer invasion and metastasis. Type IV collagen is a major component of the BM, and is composed of six genetically distinct alpha(IV) chains; alpha1(IV) to alpha6(IV). The loss of alpha5(IV) and alpha6(IV) chains from the epithelial BM at the early stage of cancer invasion has been reported in several types of cancers. However, the expression of alpha5(IV) and alpha6(IV) chains in extrahepatic bile duct carcinoma (EBDC) remains unclear. METHODS: We examined the expression of alpha(IV) chains by immunohistochemistry using 71 resected EBDC specimens. Prognostic significance of alpha(IV) chains was examined by Cox regression and Kaplan-Meier analyses. RESULTS: In the invasive cancer, the expression of alpha6(IV) chain in the BM was lost partially or completely preceded by the loss of alpha2(IV) chain. The loss of alpha6(IV) chain in the BM of the invasive cancer was related to the tumor classification, TNM stages, and the expression of alpha2(IV) chain. The patients with alpha2(IV)-negative and alpha6(IV)-negative chains had significantly poorer prognosis than those with alpha2(IV)-positive and alpha6(IV)-positive/negative chains (P = 0.04). CONCLUSIONS: The loss of alpha2(IV) and alpha6(IV) chains might be a useful prognostic factor in patients with EBDC. PMID- 22927261 TI - Influence of different cellular environments on [(3)H]DASB radioligand binding. PMID- 22927262 TI - Encephalitis and CSF increased level of interferon-alpha in Kikuchi-Fujimoto disease. AB - Neurological manifestations have been reported in Kikuchi-Fujimoto disease (KFD). Characteristics of brain lesions are not defined. In addition, no biological indexes are known to help clinicians along the diagnosis process. The authors describe encephalitis associated with KFD. Brain MRI, positron emission tomography (PET) scan and a large biological assessment including interferon alpha (INF-alpha) level measurement in cerebrospinal fluid (CSF) were performed. A 39-year-old man with chronic headaches developed diplopia, slow ideation and behavioural disturbances. MRI showed brain lesions particularly in the pontine region and internal temporal lobes with enhancement of the perivacular space and the walls of the lateral ventricle. The IFN-alpha level was increased in the CSF without viral infection. Cervical and mediastinal adenitis were evident as a hypermetabolic focus on a PET scan, and biopsy confirmed the diagnosis of KFD. The encephalitis spontaneously remitted. The authors characterised brain lesions especially related to KFD in association with increased of IFN-alpha level in the CSF. PMID- 22927263 TI - Multiple gunshot carotico-jugular fistulas. AB - The development of post-traumatic fistula between the carotid artery and jugular vein is an extremely rare clinical condition. The authors present a 28-year-old patient, who sustained a gunshot injury to the right side of the neck 6 years ago, with undiagnosed contralateral carotico-jugular fistula. PMID- 22927264 TI - Bilateral primary spontaneous pneumothoraces postcaesarean section--another reason to avoid general anaesthesia in pregnancy. AB - A 36-year-old, healthy, primiparous female underwent a caesarean section under general anaesthetic. She had previously had a severe reaction to dye during a myelogram and therefore, had declined epidural analgesia or regional anaesthesia. Induction and maintenance of anaesthesia was uneventful, but on emergence, and before tracheal extubation, the patient coughed on the endotracheal tube and almost immediately developed right-sided subcutaneous emphysema of the face and neck. At this point her oxygen saturation began to fall and she was noted to be difficult to ventilate. Clinically and radiologically, she had a right-sided pneumothorax which was treated immediately with intercostal drain insertion. She went on to develop a left pneumothorax which also required intercostal drain insertion. She made an uneventful recovery and was discharged 8 days later. A subsequent CT scan of her chest revealed no pre-existing primary pulmonary pathology that would have accounted for the pneumothoraces. PMID- 22927265 TI - Ichthyosis prematurity syndrome with separation of fetal membranes and neonatal asphyxia. AB - Ichthyosis prematurity syndrome (IPS) is a rare inherited skin disorder. Children are born prematurely with thick skin and have been found to develop neonatal asphyxia due to occlusions in the bronchial tree from debris in the amniotic fluid. At 31 weeks of gestation, separation of amniotic and chorionic membranes was identified as well as polyhydramnion. The child was born 2 weeks later, with thickened skin with a granular appearance and required immediate ventilation and intensive care. At 2 years of age, the patient has developed an atopic skin condition with severe itching, recurrent skin infections, food intolerance and periods of wheezing. Prenatal observation of separation of foetal membranes or dense amniotic fluid may be signs of IPS and severe complication immediately after birth. PMID- 22927266 TI - Haematuria and the retro-aortic left renal vein. AB - The authors present the case of a 10-year-old boy with a 2-year history of intermittent macroscopic haematuria. After exclusion of other causes of haematuria through history, examination and a number of investigations, MRI revealed the finding of a retro-aortic left renal vein, which appeared to be compressed between the aorta and the L3 vertebral body. The retro-aortic left renal vein or 'posterior nutcracker syndrome" is a rare but important cause of haematuria and other manifestations of left renal vein hypertension. A discussion about the implications of this finding in children with symptoms consistent with left renal vein hypertension, and the potential options for management is undertaken. PMID- 22927267 TI - Rare sarcoma presented as sinusitis. AB - Myxofibrosarcoma (MFS) also known as myxoid variant of malignant fibrous histocytoma is one of the most common soft tissue sarcomas of the extremities in adult and elderly patients with rare occurrences in head and neck region. Low grade MFS is unusual among low-grade sarcomas because it often recurs relentlessly and multiplies despite wide local resection with gross negative margins. We report a case of extreme rarity and a tumour of aggressive nature in the maxillary sinus, which presented with non-specific sinonasal symptoms and we present a review of the radiological and histopathological characteristics of this rare tumour and recent evidence of management. PMID- 22927268 TI - A young man presenting with paralysis after vigorous exercise. AB - Thyrotoxic periodic paralysis (TPP) is a rare metabolic disorder characterised by muscular weakness and paralysis in predisposed thyrotoxic patients. Although patients with TPP are almost uniformly men of Asian descent, cases have been reported in Caucasian and other ethnic populations. The rapid increase in ethnic diversity in Western and European nations has led to increase in TPP reports, where it was once considered exceedingly rare. Correcting the hypokalaemic and hyperthyroid state tends to reverse the paralysis. However, failure to recognise the condition may lead to delay in diagnosis and serious consequences including respiratory failure and death. We describe a young man who was diagnosed with hyperthyroidism who presented with acute paralysis. The clinical characteristics, pathophysiology and management of TTP are reviewed. PMID- 22927269 TI - Heterotopic ossification of the elbows in a major petrol burn. AB - A case of a young man who developed heterotopic ossification (HO) in his elbows following an accident where he sustained petrol burns to over 60% of his body. His injuries necessitated intubation, escharotomies and a protracted intensive care unit stay that was complicated by septicaemia. Several weeks after the injury, he was diagnosed with HO in his right elbow, followed by the left elbow a week later. He was commenced on an non-steroidal anti-inflammatory drug, a long term course of a bisphosphonate and regular physiotherapy. He is now waiting for the HO bone to mature before having definitive excision of his lesions in 12-18 months time. PMID- 22927270 TI - Allantoid cyst in the umbilical cord diagnosed with B-flow ultrasound. AB - Allantiod cysts are true cysts in the umbilical cord. They arise from persistent structures of allantois, and the cysts are filled with urine because of a connection to the urinary bladder. Allantoid cysts are located centrally in the umbilical cord and separate the umbilical cord vessels. B-flow ultrasound is a new technique illustrating blood flow. This method is independent of the insonation angle and therefore superior to Doppler ultrasound visualising long segments of vessels with a winding course. The authors present a case with allantoid cysts diagnosed with B-flow ultrasound. PMID- 22927271 TI - Arteriovenous fistula complication following MRI. AB - Health professionals should be aware of medical procedures that cause vascular access complications. This case describes a haemodialysis patient who experienced pain, swelling and bruising over a radiocephalic fistula following MRI. Exactly the same signs and symptoms were evident following a second scan performed 3 months later. Plausible explanations include a radio frequency-induced electrical current being formed at the arteriovenous fistula, or varying gradients of the MRI sequence stimulating peripheral nerves, leading to a site of increased tissue stimulation. Of note, a juxta-anastomotic venous stenosis was confirmed by fistulogram 4 days after the second scan, although whether this access failure was due to the MRI scan per se could not be ascertained. Nevertheless, these previously undocumented observations suggest that careful patient and fistula monitoring is required when completing MRI scans in those with an arteriovenous fistula. PMID- 22927272 TI - Exercise associated hyponatraemia leading to tonic-clonic seizure. AB - A 34-year-old Filipino lady presented to the emergency department with breathlessness and muscle cramping following a Bikram yoga workout. The patient reported sweating excessively while performing 90 min of strenuous exertion in a humidified room heated to an ambient temperature of 40.6 degrees C. After the workout she drank 3.5 litres of water before experiencing breathlessness, severe muscle cramps, nausea and general malaise. Initial investigations revealed severe hyponatraemia (120 mmol/l). Despite early sodium replacement the patient dropped her Glasgow coma scale to 9/15 and developed tonic clonic seizures, requiring intubation and admission to the intensive care unit. The hyponatraemia was slowly corrected on the intensive care unit and the patient made a full recovery over the course of 5 days. This case highlights the dangers of overzealous fluid replacement following severe exertion in a hot environment. PMID- 22927273 TI - Management of the treatment of glenohumeral instability in patients with extensive bone defect. PMID- 22927274 TI - The medical mystery of the fatty mesentery. AB - An 86-year-old gentleman presented with a 3-month history of nausea, anorexia and excruciating generalised abdominal pain. He had been discharged a week earlier from another hospital. No diagnosis had been made. Clinically the patient was feverish, with a palpable, tender and poorly defined mass in his epigastrium. He had elevated inflammatory markers and deranged electrolytes. An ultrasound scan revealed thickening and hyper echogenicity of the small bowel mesentery. A CT scan was recommended; this revealed a diagnosis of mesenteric panniculitis. First described in 1924, mesenteric panniculitis is a benign inflammatory condition of the bowel mesentery. With only a handful of cases being reported in the UK, the authors thought that they had come across a rarity. This case report focuses on the aetiology, diagnosis, pathology and treatment of mesenteric panniculitis. By examining the literature, the authors also suggest that it is relatively underdiagnosed and may be more common than first thought. PMID- 22927275 TI - Hormonal effect on gingiva: pubertal gingivitis. PMID- 22927276 TI - Recurrent femoral hernia and associated ovarian pathology. AB - The following case describes an ovarian tumour presenting in a highly unusual manner-in the form of a recurrent femoral hernia. Recurrent femoral herniae are unusual and should prompt awareness of underlying pathology causing increased intra-abdominal pressure. PMID- 22927277 TI - Congenitally missing primary mandibular lateral incisors: a case of rare occurrence. AB - We are reporting a rare case of missing teeth in primary dentition. The case reported with the chief complaint of missing teeth in the lower front tooth region. The concern of the parents was missing primary teeth but they were also worried about the permanent successors. Thorough evaluation of the primary dentition visually and permanent dentition radiographically was done. There was missing 72 and 82.Along with these, there were few permanent teeth, that is, lack of initiation of 35 and 45 and 22 was evident. The case was non-syndromic. At present, the case is under follow-up. PMID- 22927278 TI - Choroidal rupture and optic nerve injury with equipment designated as 'child safe'. AB - Blunt ocular trauma from a child's plastic foam-covered toy baseball bat caused traumatic optic neuropathy and choroidal rupture in a 9-year-old child. The examination revealed a visual acuity of 6/60, a relative afferent pupillary defect, optic nerve swelling, commotio retinae and retinal haemorrhages. There was no orbital fracture or intraorbital haematoma on CT scanning. Optical coherence tomography showed macular oedema and disruption of the retinal pigment epithelium and Bruch's membrane. The child was admitted for intravenous methylprednisolone and discharged on topical steroid treatment. At 1 month follow-up, visual acuity had improved to 6/12. Optic nerve swelling had resolved and the fundus had two crescent-shaped choroidal rupture scars. Choroidal rupture and optic neuropathy can be secondary to indirect trauma, and even when the mechanism of injury is with a piece of equipment designated as suitable for children, serious ocular injury can occur. PMID- 22927279 TI - Is live problem better than dead cert? AB - Cholecystoduodenal fistula is a type of biliary enteric fistula that can occur as a result of chronic cholecystitis. The majority of cases are diagnosed and their subsequent management planned intraoperatively. Previous reports have focused on successful laparoscopic management. We report three cases of elective cholecystectomy that were diagnosed intraoperatively with a cholecystoduodenal fistula (CDF). The first two cases were managed laparoscopically. In case 3 further continuation of surgery would have subjected the patient to significant risk of further harm. Instead the patient underwent cholecyststomy with insertion of Foley's catheter and venting gastrostomy. All three patients made a full recovery postoperatively. CDF can be of varying severity. Our third case highlights the use of damage limitation surgery when carrying on is at risk of harm. Treatment therefore needs to be tailor made for each fistula identified. PMID- 22927281 TI - False-positive pH aspirates after nasogastric tube insertion in head and neck tumour. AB - Nasogastric (NG) feeding tubes are commonly inserted to supplement enteral nutrition in certain patient groups, including those with head and neck cancers where swallowing may be compromised. An NHS National Patient Safety Alert was released in 2011 detailing ongoing cases of significant morbidity and mortality attached to the incorrect placement of NG feeding tubes in hospital inpatients. Since 2005, there were 21 deaths and 79 cases of harm nationally due to feeding into the lung through misplaced tubes. pH testing remains the first-line method of placement confirmation, with chest x-ray used when no aspirate is gained or where pH testing fails to confirm suitable acidity. We present a case report describing false-positive NG tube placement confirmation tests in a patient with head and neck cancer, who was administered feed into lung parenchyma with significant morbidity. We discuss the case for specific NG tube placement protocols in head and neck cancer patients. PMID- 22927280 TI - Solid-pseudopapillary carcinoma: a case study and literature review. AB - Solid-pseudopapillary tumour (SPT) is a rare exocrine tumour of the pancreas and is considered to have low malignant potential. Few morphological criteria are used to predict malignant behaviour such as equivocal perineural invasion, angioinvasion and invasion to surrounding tissue, and should be designated as solid-pseudopapillary carcinoma (SPC). We report a case of SPC. Clinical and radiological findings are typical for SPT with no metastatic disease. There is no tumour recurrence after 4 months postresection. Clinical history and radiological findings were retrieved from the patient's record sheet and Viarad system. H&E staining and few immunoproxidase staining were reviewed by several pathologists. The histological findings are typical for SPT, with additional perineural invasion. There is no angioinvasion or capsular invasion identified. This is our first experience in diagnosing and managing SPC. We look forward to seeing the patient's disease status during her next routine follow-up. We expect good disease-free survival and very low risk of tumour recurrence, in view of only one risk factor (perineural invasion) and uninvolved surgical margins by the tumour. PMID- 22927282 TI - Gallbladder malakoplakia in type 2 diabetes mellitus: a rare entity. AB - Gallbladder malakoplakia in type 2 diabetes mellitus is a rare condition. Differentiating malakoplakia, which is a more aggressive disease condition with possible genetic abnormality from a more benign but closely related condition such as xanthogranulomatous cholecystitis, is of prognostic importance in postoperative patient management and follow-up. PMID- 22927283 TI - Genital tuberculosis with variable presentation: a series of three cases. AB - Tuberculosis (TB) is still frequently observed in third-world countries like Africa and Asia. Here we report three cases of genital TB with variable presentation. First case was a lady of reproductive age group who presented with polymenorrhagia and postcoital bleeding with unhealthy cervix. Histopathology of cervical tissue revealed tubercular cervicitis. Second and third cases presented with different complaints like discharge per vaginum, postcoital bleeding and pain in lower abdomen with growth over the cervix. Cervical biopsy was inconclusive of TB but endometrial tissue sampling for TB PCR was positive. This shows that newer diagnostic marker test can help us to detect secondary genital TB. PMID- 22927284 TI - Cushing syndrome associated with an adrenal tumour. AB - Cushing syndrome (CS) in children is a rare disorder that is most frequently caused by an adrenal tumour or a pituitary corticotrophin-secreting adenoma. The management is challenging and requires an individualised approach and multidisciplinary care. We present the case of a 23-month-old female child with a history of excessive weight gain, growth failure, hirsutism, acne and behavioural difficulties. Investigations revealed elevated serum midnight cortisol and 24 h urinary free cortisol. Overnight dexamethasone suppression testing showed no suppression of cortisol levels. Abdominal imaging revealed a right sided suprarenal mass. She underwent right adrenalectomy and the histology showed an adrenal cortical carcinoma. There was clinical improvement with catch-up growth and weight normalisation. Despite being rare in clinical practice, in a child with weight gain, hirsuitism and growth failure the diagnosis must be considered. The overall prognosis of CS in childhood is good, but challenges remain to ensure normal growth and body composition. PMID- 22927285 TI - Gastrointestinal stromal tumour presenting as gastroduodenal intussusception. AB - Gastroduodenal intussusception secondary to gastrointestinal stromal tumour is a very rare cause for intestinal obstruction. The diagnosis of this condition can be challenging, as symptoms are often non-specific and intermittent. This article reports a case where the diagnosis was made preoperatively with abdominal imaging and was treated by a combination of endoscopic reduction and laparoscopic resection. PMID- 22927286 TI - A misguided 'pill in the pocket' approach with flecainide leading to cardiac arrest. PMID- 22927287 TI - DNA-tailored plasmonic nanoparticles for biosensing applications. AB - The plasmonic properties of metallic nanoparticles (NPs) such as Au and Ag NPs and the plasmonic coupling between them are of enormous interest for their strong and controllable optical signal enhancement and manipulation capabilities. The strong optical properties of these plasmonic structures are promising for various biosensing applications, but the widespread use of these structures is limited largely due to the absence of high-yield synthetic method for targeted nanoprobes with nanometer precision and the poor understanding of the plasmonics of these structures. DNA is a promising material that can be used as both specific biorecognition and versatile synthetic template in forming and controlling plasmonic nanostructures and their aggregations. In this article, we provide an overview and perspective of recent advances in the use of DNA-tailored plasmonic nanostructures in biosensing applications. PMID- 22927288 TI - Enhanced energy storage and suppressed dielectric loss in oxide core-shell polyolefin nanocomposites by moderating internal surface area and increasing shell thickness. AB - Dielectric loss in metal oxide core/Al(2)O(3) shell polypropylene nanocomposites scales with the particle surface area. By moderating the interfacial surface area between the phases and using increasing shell thicknesses, dielectric loss is significantly reduced, and thus the energy stored within, and recoverable from, capacitors fabricated from these materials is significantly increased, to as high as 2.05 J/cm(3). PMID- 22927289 TI - Designing a series of decision-theoretic phase II trials in a small population. AB - This paper introduces a decision-theoretic design for a series of phase II trials. Instead of designing phase II trials individually, we proposed a development plan that consists of a series of phase II trials and one phase III trial such that the long-term expected utility on the whole is optimized. The phase II trials are conducted sequentially, and patients are recruited sequentially to each phase II trial. At each interim stage, a decision is made to continue recruiting patients to the current trial, to stop and recommend the treatment proceeds to a phase III trial, to stop and initiate a new phase II trial or to stop and cease the development plan. The methodology uses a hybrid approach in which it is assumed that the data from the final phase III trial will be analysed using a classical frequentist hypothesis test. The expected power of this test based on some specified prior distribution for the effect of the experimental treatment is then used in a utility function, which is used to obtain the optimal design for the whole series of trials. PMID- 22927290 TI - Enhancing human nucleus pulposus cells for biological treatment approaches of degenerative intervertebral disc diseases: a systematic review. AB - Intervertebral disc (IVD) degeneration has been described as an aberrant, cell mediated, age- and genetics-dependent molecular degeneration process, which can be accelerated by nutritional, mechanical and toxic factors. Collective involvement of these factors can result in structural failures, which are often associated with pain. Current treatment approaches are restricted to symptomatic therapies, not addressing options of restoring structural or biological deterioration of the IVD as the underlying problem. Therapeutic potentials of IVD cell transplantation, biomaterials, inhibiting or activating bioactive factors, including gene-therapeutic approaches, have been shown in vitro or in small animal models. Since human degenerative IVD cells display distinctive features with regard to cell biology and regenerative potential, we attempted a systematic review, investigating the in vitro response of human nucleus pulposus cells to different stimuli. Therefore, we conducted an electronic database search on Medline through July 2011 to identify, compare and discuss publications concerning the effects of cell-cell stimulation, bioactive factors, biomaterials and combinations thereof in terms of cell isolation, proliferation, differentiation and matrix protein synthesis. This survey and discussion might serve as a source for designing future biological treatment strategies for the human IVD. PMID- 22927292 TI - Necrotic granulomatous pseudotumor following metal-on-metal hip arthroplasty: a potential mimic of sarcoma on fine needle aspiration cytology. AB - A 69-year-old female presented with left leg pain 4 months after total hip replacement for left hip joint protrusio acetabuli. A "cystic" mass lesion was identified radiologically in relation to the arthroplasty and an initial CT guided core needle biopsy showed a spindle cell proliferation with associated necrosis, interpreted as suspicious for malignancy. A repeat CT-guided fine needle aspiration showed necrosis, "ghost" spindle cells, aggregates of histiocytes, giant cells, and inflammatory cells as well as scattered large atypical spindle cells. The simultaneously obtained core biopsy showed extensive necrosis with ghost spindle cells that was surrounded by CD68+ histiocytes, which in turn were surrounded by a predominantly CD3+, CD4+ lymphocytic infiltrate. A diagnosis of necrotic granulomatous pseudotumor was made after a diagnosis of sarcoma was initially entertained. This unusual tissue response is rarely seen after metal-on-metal arthroplasty, occurs more often in females and may represent a type-IV hypersensitivity reaction incited by very small-sized particulate metallic debris that forms haptens in association with serum proteins. PMID- 22927293 TI - Diagnosis of phosphaturic mesenchymal tumor (mixed connective tissue type) by cytopathology. AB - Oncogenic osteomalacia (OO) is a rare paraneoplastic condition in which a bone or soft tissue tumor induces biochemical and clinical signs and symptoms of osteomalacia (or rickets) most often by the production of the phosphaturic protein, fibroblast growth factor-23. Phosphaturic mesenchymal tumor, mixed connective tissue type (PMTMCT) is a rare, histologically distinct tumor that represents the most common cause of OO. As the clinical diagnosis of OO is typically suspected on the basis of clinical and biochemical features and the presence of a bone or soft tissue tumor, cytologic examination might potentially provide the necessary pathologic confirmation of OO. In this case of a 46-year old female with clinical stigmata of OO and a right distal humeral mass, we report that the fine-needle aspiration findings of short, cytologically bland spindled cells embedded in a fine, fibrillary stromal-rich matrix and the presence of osteoclast-type giant cells associated with the stromal matrix provide strong pathological evidence for PMTMCT and assist in pathologically confirming the clinical impression of OO, thus alleviating the need for a more invasive diagnostic surgical procedure. PMID- 22927294 TI - The cytologic diagnosis of epithelioid myxofibrosarcoma: a case report. AB - The epithelioid variant of myxofibrosarcoma is a rare but recently described entity. We report a case of an elderly woman who presented with a slowly enlarging mass of the right lower extremity. Fine-needle aspiration (FNA) cytology revealed a malignant epithelioid neoplasm. The smears of the aspirate material were highly cellular and contained a dominant population of cells with uniform round-to-oval nuclei and cytoplasmic vacuolization, arranged in loosely cohesive aggregates and linear arrays within a myxoid background. A second minor population of cells consisted of aggregates of bland spindled cells. On resection, the neoplasm proved to be an epithelioid myxofibrosarcoma. To our knowledge, the cytologic features of epithelioid myxofibrosarcoma have not previously been documented. Herein, we discuss the cytologic features of epithelioid myxofibrosarcoma as seen on FNA biopsy and its distinction from other epithelioid neoplasms of soft tissue. PMID- 22927295 TI - Spindle-cell hemangioma (spindle-cell hemangioendothelioma): a diagnosis on fine needle aspiration cytology. PMID- 22927296 TI - Sarcoma redux: past, present, and future. PMID- 22927298 TI - Elucidation of steroid glycosides in Anemarrhena asphodeloides extract by means of comprehensive two-dimensional reversed-phase/polyamine chromatography with mass spectrometric detection. AB - In the work presented here, a novel approach to comprehensive two-dimensional liquid chromatography is evaluated. Reversed-phase liquid chromatography was employed for the first-dimension separation and polyamine chromatography was chosen for the second-dimension separation mode. The two dimensions are highly orthogonal and the separation efficacy of the developed octadecylsilica * polyamine was tested by separating an extract from Anemarrhena asphodeloides. The steroid glycosides identified by comprehensive two-dimensional liquid chromatography in this experiment were compared to those obtained for monodimensional liquid chromatography. The comprehensive two-dimensional liquid chromatography system, thanks to the complementary separation selectivity and enhanced peak capacity provided by the two columns, allowed to distribute five compounds of low amounts otherwise unachievable by monodimensional liquid chromatography. In addition, four steroid isomers with similar fragmentation characteristics in MS/MS spectra, were newly separated based on their different chemical structures. PMID- 22927297 TI - Aberrant promoter methylation of beta-1,4 galactosyltransferase 1 as potential cancer-specific biomarker of colorectal tumors. AB - Epigenetic alterations, such as CpG islands methylation and histone modifications, are recognized key characteristics of cancer. Glycogenes are a group of genes which epigenetic status was found to be changed in several tumors. In this study, we determined promoter methylation status of the glycogene beta 1,4-galactosyltransferase 1 (B4GALT1) in colorectal cancer patients. Methylation status of B4GALT1 was assessed in 130 colorectal adenocarcinomas, 13 adenomas, and in paired normal tissue using quantitative methylation specific PCR (QMSP). B4GALT1 mRNA expression was evaluated in methylated/unmethylated tumor and normal specimens. We also investigated microsatellite stability and microsatellite instability status and KRAS/BRAF mutations. Discriminatory power of QMSP was assessed by receiving operating curve (ROC) analysis on a training set of 24 colorectal cancers and paired mucosa. The area under the ROC curve (AUC) was 0.737 (95% confidence interval [CI]:0.591-0.881, P = 0.005) with an optimal cutoff value of 2.07 yielding a 54% sensitivity (95% CI: 35.1%-72.1%) and a specificity of 91.7% (95% CI: 74.1%-97.7%). These results were confirmed in an independent validation set where B4GALT1 methylation was detected in 52/106 patients. An inverse correlation was observed between methylation and B4GALT1 mRNA expression levels (r = -0.482, P = 0.037). Significant differences in methylation levels and frequencies was demonstrated in invasive lesions as compared with normal mucosa (P = 0.0001) and in carcinoma samples as compared with adenoma (P = 0.009). B4GALT1 methylation is a frequent and specific event in colorectal cancer and correlates with downregulation of mRNA expression. These results suggest that the glycogene B4GALT1 represent a valuable candidate biomarker of invasive phenotype of colorectal cancer. PMID- 22927302 TI - Correspondence. PMID- 22927301 TI - Selective detection of multicarboxylate anions based on "turn on" electron transfer by self-assembled molecular rectangles. AB - Two new large molecular rectangles (4 and 5) were obtained by the reaction of two different dinuclear arene ruthenium complexes [Ru(2)(arene)(2)(OOOO)(2)Cl(2)] (arene = p-cymene; OOOO = 2,5-dihydroxy-1,4-benzoquinonato (2), 6,11-dihydroxy 5,12-naphthacene dionato (3)) with the unsymmetrical amide NN (N-[4-(pyridin-4 ylethynyl)phenyl]isonicotinamide) donor ligand 1 in methanol in the presence of AgO(3)SCF(3), forming tetranuclear cations of the general formula [Ru(4)(arene)(4)(NN)(2)(OOO O)(2)](4+). Both rectangles were isolated in good yields as triflate salts and were characterized by multinuclear NMR, ESI-MS, UV/Vis, and photoluminescence spectroscopy. The crystal structure of 5 was determined by X-ray diffraction. Luminescent rectangle 5 was used for anion sensing with an amide ligand as a hydrogen-bond donor and an arene-ruthenium acceptor as a signaling unit. Rectangle 5 strongly bound multicarboxylate anions, such as oxalate, tartrate, and citrate, in UV/Vis titration experiments in 1:1 ratios, in contrast to monoanions, such as F(-), Cl(-), NO(3)(-), PF(6)(-), CH(3)COO(-), and C(6)H(5)COO(-). The fluorescence titration experiment showed a large fluorescence enhancement of 5 upon binding to multicarboxylate anions, which could be attributed to blocking of the photoinduced electron transfer process from the arene-ruthenium moiety to the amidic donor in 5; this was likely to be a result of hydrogen bonding between the ligand and the anion. On the other hand, rectangle 5 was not selective towards any other anions. To the naked eye, multicarboxylate anions in a solution of 5 in methanol appear greenish upon irradiation with UV light. PMID- 22927303 TI - Synthesis and characterization of two PET radioligands for the metabotropic glutamate 1 (mGlu1) receptor. AB - The metabotropic glutamate 1 receptor (mGlu1) is an important protein in the regulation of glutamate transmission in the brain, and believed to be involved in disorders such as ischemia, epilepsy, neuropathic pain, anxiety, and schizophrenia. The goal of this study was to evaluate two selective mGlu1 antagonists [(11) C]3 and [(18) F]4 as potential PET radioligands for the in vivo imaging of the mGlu1 receptor. Biodistribution studies in rats indicated high uptake of [(11) C]3 and [(18) F]4 in the brain. The highest activity level was found in the cerebellum, followed by striatum, hippocampus, frontal cortex, and medulla, in a pattern consistent with the distribution of mGlu1 receptor in rat. At 30 min postinjection, the activity ratio of cerebellum to medulla was 4.5 for [(11) C]3, indicating a high degree of specific binding, while specific binding was lower for [(18) F]4 (cerebellum to medulla activity ratio of 2.0). Moreover, binding of the radioligands [(11) C]3 and [(18) F]4 in mGlu1 receptor-rich region such as cerebellum was blocked by pretreatment of the rats with their respective unlabeled compound or the selective mGlu1 antagonist (compound 5, 2 mg/kg each), but not by the selective mGlu2 antagonist LY341495, or the selective mGlu5 antagonist MPEP (2 mg/kg), thus indicating the binding specificity and selectivity of [(11) C]3 and [(18) F]4 to the mGlu1 receptor. However, in imaging experiments in baboons [(11) C]3 displayed a small specific binding signal only in the cerebellum, while the specific binding of [(18) F]4 was difficult to detect. Species differences in receptor density and affinity of the radioligands in large part account for the differences in the behavior of [(11) C]3 and [(18) F]4 in rats and baboons. Radioligands with higher affinity and/or lower lipophilicity are needed to successfully image the mGlu1 receptor in humans. PMID- 22927304 TI - Identification and characterization of 2,5-dimethoxy-3,4-dimethyl-beta phenethylamine (2C-G)--a new designer drug. AB - This study presents and discusses the mass spectrometric, infrared spectroscopic and nuclear magnetic resonance spectroscopic data of 2,5-dimethoxy-3,4-dimethyl beta-phenethylamine (2C-G), a new designer drug. A powder sample containing 2C-G was seized in Poland in 2011. The paper focuses on a comparison of the analytical features of 2C-G and other members of the 2C-series, in order to assess the possibility of unequivocal identification. The occurrence of intense peak at m/z = 178 and different intensities of the ions at m/z = 165 and 180 in the gas chromatography-electron impact-mass spectrometry (GC-EI/MS) spectrum of 2C-G made it possible to distinguish it from 2C-E. Differences in relative intensities of the ions at m/z = 192, 179 and 177 were observed for GC-EI/MS spectra of TFAA derivatives of 2C-G and 2C-E. An identical set of ions was recorded for these substances using the liquid chromatography-electrospray ionization/quadrupole time of flight mass spectrometry (LC-ESI/QTOFMS) method in both MS and tandem mass spectrometry (MS/MS) mode, but the distinction was possible based on differences in the ion intensities at m/z = 193.1223 and 178.0988. The Fourier transform infrared (FTIR) spectrum of 2C-G was significantly different from other members of the 2C-series, with a characteristic doublets at 993-1014 cm(-1) and 1099-1124 cm(-1) , and the ratio of bands at higher wavenumbers. Final elucidation of the structure of 2C-G was carried out by (1) H and (13) C NMR spectroscopy. The study indicated that the marketing of analogues of controlled substances poses a real analytical challenge for forensic laboratories, and the application of sophisticated methods is often required for unequivocal identification of a new substance. PMID- 22927305 TI - Polymerizing nonfluorescent monomers without incorporating any fluorescent agent produces strong fluorescent polymers. PMID- 22927306 TI - Regression with incomplete covariates and left-truncated time-to-event data. AB - Studies of chronic diseases routinely sample individuals subject to conditions on an event time of interest. In epidemiology, for example, prevalent cohort studies aiming to evaluate risk factors for survival following onset of dementia require subjects to have survived to the point of screening. In clinical trials designed to assess the effect of experimental cancer treatments on survival, patients are required to survive from the time of cancer diagnosis to recruitment. Such conditions yield samples featuring left-truncated event time distributions. Incomplete covariate data often arise in such settings, but standard methods do not deal with the fact that individuals' covariate distributions are also affected by left truncation. We describe an expectation-maximization algorithm for dealing with incomplete covariate data in such settings, which uses the covariate distribution conditional on the selection criterion. We describe an extension to deal with subgroup analyses in clinical trials for the case in which the stratification variable is incompletely observed. PMID- 22927307 TI - Characterization of recombinant human bone morphogenetic protein-2 delivery from injectable hyaluronan-based hydrogels by means of 125I-radiolabelling. AB - This study presents a thorough in vitro and in vivo characterization of the delivery of bone morphogenetic protein 2 (BMP-2) from a hyaluronan-based hydrogel system. The in vitro release of BMP-2 from similar hydrogels has previously been studied by enzyme-linked immunosorbent assay (ELISA), by which only a fraction of the loaded protein is detected. In the current study, (125) I radiolabelling was used instead to monitor BMP-2 in vitro and in vivo. To minimize protein loss during handling, (125) I-BMP-2 adsorption to different tubes was studied at different times and temperatures. The data showed that Protein LoBind tubes exhibited the lowest protein affinity. Furthermore, a biphasic release profile of biologically active BMP-2 was observed both in vitro and in vivo, with the initial fast phase during the first week, followed by a slower release during the remaining 3 weeks. The initial fast-release phase corresponded to the early bone formation observed after 8 days in an ectopic model in rats. Bone volume and mineral content increased until day 14, after which a decrease in bone volume was observed, possibly due to resorption in response to decreased amounts of released BMP-2. Overall, the results suggested that cautious protein handling and a reliable quantification technique are essential factors for successful design of a BMP-2 delivery system. PMID- 22927308 TI - Poly-gene fusion transcripts and chromothripsis in prostate cancer. AB - Complex genome rearrangements are frequently observed in cancer but their impact on tumor molecular biology is largely unknown. Recent studies have identified a new phenomenon involving the simultaneous generation of tens to hundreds of genomic rearrangements, called chromothripsis. To understand the molecular consequences of these events, we sequenced the genomes and transcriptomes of two prostate tumors exhibiting evidence of chromothripsis. We identified several complex fusion transcripts, each containing sequence from three different genes, originating from different parts of the genome. One such poly-gene fusion transcript appeared to be expressed from a chain of small genomic fragments. Furthermore, we detected poly-gene fusion transcripts in the prostate cancer cell line LNCaP, suggesting they may represent a common phenomenon. Finally in one tumor with chromothripsis, we identified multiple mutations in the p53 signaling pathway, expanding on recent work associating aberrant DNA damage response mechanisms with chromothripsis. Overall, our data show that chromothripsis can manifest as massively rearranged transcriptomes. The implication that multigenic changes can give rise to poly-gene fusion transcripts is potentially of great significance to cancer genetics. PMID- 22927309 TI - Qualitative and quantitative determination of COPs in Cypriot meat samples using HPLC determination of the most effective sample preparation procedure. AB - This research work describes the development of a fast high-performance liquid chromatography method for the simultaneous determination of five important cholesterol oxidation products (COPs). The influence of various experimental parameters, such as the composition of the mobile phase, the flow rate and the column temperature, were investigated. Baseline separation was achieved by using acetonitrile-methanol-water-isopropanol (67:27:5:1) as a mobile phase with a 10 degrees C column temperature. The developed method demonstrated good linearity and high reproducibility, with relative standard deviation values below 1.26% for all the COPs that were examined. The method was then applied, for the first time, to Cypriot smoked-meat products (lountza and hiromeri). The presence of COPs in these products suggests that the preparation of the meat products, and particularly the smoking process, possibly favors the oxidation of cholesterol. Finally, three different sample preparation procedures were evaluated and the optimum procedure was determined based on recovery, precision and simplicity. PMID- 22927310 TI - Opp-dibenzoporphyrins as a light-harvester for dye-sensitized solar cells. AB - New opp-dibenzoporphyrins were prepared in a concise method that was based on a Pd(0)-catalyzed cascade reaction. These porphyrins, which contained carboxylic acid linker groups on benzene rings that were fused to the porphyrin at their beta,beta'-positions, were examined as sensitizers for dye-sensitized solar cells for the first time. Whereas all of the porphyrins showed solar-energy-to electricity conversion, an opp-dibenzoporphyrin with conjugated carboxylic-acid linkers displayed the highest conversion efficiency and an exceptionally high J(sc) value. Cyclic voltammetry of these porphyrins suggested that the fusion of two aromatic benzene rings onto the periphery of the porphyrin lowered the HOMO LUMO energy gap; the incorporation of a conjugated carboxylic-acid linker group decreased the HOMO-LUMO gap even further. These CV data are consistent with DFT calculations for these porphyrins and agree well with the UV/Vis absorption- and fluorescence spectra of these porphyrins. PMID- 22927311 TI - Brazil: the country of proteomics. PMID- 22927316 TI - Risk factors for KPC-producing Klebsiella pneumoniae enteric colonization upon ICU admission. AB - OBJECTIVES: To identify risk factors for KPC-producing Klebsiella pneumoniae (KPC Kp) enteric colonization at intensive care unit (ICU) admission. Recently, the emergence and spread of KPC-producing Enterobacteriaceae in healthcare facilities has become an important issue. Understanding the extent of the reservoir in ICUs may be important for targeted intervention. METHODS: A prospective observational study of all patients (n = 405) admitted to an ICU was conducted during a 22 month period. Rectal samples were taken from each patient within 12-48 h of admission and were inoculated in selective chromogenic agar. K. pneumoniae isolates were characterized by standard methodology. Antibiotic susceptibility testing (agar disc diffusion method), MIC determination (Etest), identification of carbapenemase-producing isolates (Hodge test) and determination of KPC production (boronic acid-imipenem disc test) were performed. The presence of the bla(KPC) gene was confirmed by PCR. Epidemiological data were collected from the ICU computerized database and patient chart reviews. RESULTS: Upon ICU admission, 52/405 (12.8%) patients were colonized with KPC-Kp that was associated with the following risk factors: previous ICU stay (OR 12.5; 95% CI 1.8-86.8), chronic obstructive pulmonary disease (OR 6.3; 95% CI 1.2-31.9), duration of previous hospitalization (OR 1.3; 95% CI 1.1-1.4), previous use of carbapenems (OR 5.2; 95% CI 1.0-26.2) and previous use of beta-lactams/beta-lactamase inhibitors (OR 6.7; 95% CI 1.4-32.9). For patients previously hospitalized on peripheral wards the following risk factors were identified: duration of hospitalization prior to ICU admission (OR 1.1; 95% CI 1.1-1.3), number of comorbidities (OR 1.9; 95% CI 1.1-3.5) and number of antimicrobials administered (OR 2.1; 95% CI 1.3-3.3). CONCLUSIONS: The high prevalence of KPC-Kp enteric carriage in ICU patients at admission dictates the importance of implementation of infection control measures and strict antibiotic policies prior to ICU transfer. PMID- 22927317 TI - Sports drug testing for erythropoiesis-stimulating agents and autologous blood transfusion. PMID- 22927318 TI - Effective microPET imaging of brain 5-HT(1A) receptors in rats with [(18) F]MeFWAY by suppression of radioligand defluorination. AB - INTRODUCTION: [(18) F]MeFWAY has been developed for imaging the serotonin 1A receptors in the brain. The purpose of this study were to verify the metabolic stability of [(18) F]MeFWAY, to measure the degree of defluorination of [(18) F]MeFWAY in vivo, to investigate methods of inhibition of defluorination of [(18) F]MeFWAY, and to assess the efficacy of [(18) F]MeFWAY in rat brains in vivo. METHODS: MicroPET experiments in rats were conducted to confirm the distribution of radioactivity in the brain. Nondisplaceable binding potential (BP(ND) ) in the hippocampus and frontal cortex were also analyzed. Miconazole and fluconazole were tested for the ability to suppress defluorination of [(18) F]MeFWAY. We conducted a blockade and displacement experiment by treating with WAY-100635. RESULTS: In vitro stability tests showed that MeFWAY was very stable in serum for 6 h, but PET revealed that authentic [(18) F]MeFWAY underwent significant defluorination in vivo. In vitro inhibition study against decreasing parent activity in liver microsomes, miconazole and fluconazole suppressed metabolic elimination of MeFWAY. However, in the PET study, fluconazole showed more potent inhibitory activity than miconazole. In the suppression of metabolizing enzymes using fluconazole, radioactivity in skull was dramatically decreased by 81% (compared with 69% with miconazole) and it was coupled with an increase in brain uptake. Moreover, BP(ND) in hippocampus was 5.53 and 2.66 in frontal cortex. The blockade and displacement study showed the specificity of [(18) F]MeFWAY to 5 HT(1A) receptors. CONCLUSION: In the rat brain, [(18) F]MeFWAY microPET showed skull uptake due to defluorination in vivo. We can effectively overcome this drawback with fluconazole. PMID- 22927319 TI - A wafer-level integrated white-light-emitting diode incorporating colloidal quantum dots as a nanocomposite luminescent material. AB - High-brightness, color-tunable colloidal quantum dots are incorporated in 3D nanoporous GaN to create a nanocomposite material (CQD/NP-GaN), which is demonstrated to be an effective approach for a wavelength down-conversion nanomaterial in solid-state lighting. The white-light-emitting diode (LED) made from a blue GaN-based LED and the CQD/NP-GaN shows an increase of extraction efficiency by a factor of 2, a controllable white color, and a down-conversion quantum efficiency as high as 82%. PMID- 22927320 TI - Hippocampal neurons inhibit meal onset. AB - There is extensive research regarding the neural mechanisms involved in satiety and meal termination; in contrast, there is very limited understanding of how meal onset is regulated. On the basis of several converging lines of evidence, we hypothesized that hippocampal neurons form a memory of a meal and inhibit meal onset during the postprandial period. As a first step, we tested whether reversible inactivation of the hippocampus with muscimol infusions after the end of one meal would accelerate the onset of the next meal. To test this, adult male Sprague-Dawley rats (N = 23) were implanted with a cannula aimed at the right or left dorsal hippocampus and then trained to consume a 32% sucrose solution at a scheduled time daily. On the experimental day, hippocampal neuronal activity was temporarily disrupted during the postprandial period by infusing muscimol (0.5 MUg/MUl; 1 MUl) 5 min after the rats stopped consuming the sucrose solution. Compared to vehicle infusions, muscimol infusions significantly decreased the latency to start the postinfusion meal and increased the size of the postinfusion meal. In addition, muscimol disrupted the relationship between the size of a meal and length of the following postprandial period. These effects of muscimol on meal onset were not due to an effect on the speed of consumption. Collectively, these findings are consistent with the hypothesis that hippocampal neurons suppress meal initiation during the postprandial period. Given that overeating can impair hippocampal function, these findings suggest that impaired hippocampal functioning is a cause and consequence of overeating and obesity. PMID- 22927321 TI - Comparing competing risk outcomes within principal strata, with application to studies of mother-to-child transmission of HIV. AB - In randomized trials to prevent breast milk transmission of human immunodeficiency virus (HIV) from mother to infant, investigators are often interested in assessing the effect of a treatment or intervention on the cumulative risk of HIV infection by time (age) t in infants who are alive and uninfected at a certain time point tau(0) < t. Such comparisons are challenging for two reasons. First, infants are typically randomized at birth (time 0 < tau(0) ) such that comparisons between trial arms among the subset of infants alive and uninfected at tau(0) are subject to selection bias. Second, in most mother-to-child transmission (MTCT) trials competing risks are often present, such as death or cessation of breastfeeding prior to HIV infection. In this paper, we present methods for assessing the causal effect of a treatment on competing risk outcomes within principal strata. In MTCT trials, the causal effect of interest is that of treatment on the risk of HIV infection by time t > tau(0) within the principal stratum of infants who would be alive and uninfected by tau(0) regardless of randomization assignment. We develop large sample nonparametric bounds and a semiparametric sensitivity analysis model for drawing inference about this causal effect. We present a simulation study demonstrating that the proposed methods perform well in finite samples. We apply the proposed methods to a large, recent MTCT trial. PMID- 22927322 TI - Nickel(II)-dipyridylphosphine-catalyzed enantioselective hydrosilylation of ketones in air. AB - Out of thin air: Catalytic amounts of nickel(II) salt and non-racemic dipyridylphosphine ligand, as well as the stoichiometric hydride source PhSiH(3), formed an effective catalyst system for the Ni(II)-catalyzed asymmetric hydrosilylation of a diverse range of electron-deficient aryl alkyl ketones with enantioselectivities up to 90% ee. The practical potential of the protocol was evinced by its good air-stability. PMID- 22927323 TI - Hydrogel substrate stiffness and topography interact to induce contact guidance in cardiac fibroblasts. AB - Previous studies demonstrated the importance of substrate stiffness and topography on the phenotype of many different cell types including fibroblasts. Yet the interaction of these two physical parameters remains insufficiently characterized, in particular for cardiac fibroblasts. Most studies focusing on contact guidance use rigid patterned substrates. It is not known how the ability of cardiac fibroblasts to follow grooves and ridges changes as the substrate stiffness is decreased to match the range of stiffness found in native heart tissues. This report demonstrates a significant interactive effect of substrate stiffness and topography on cardiac fibroblast elongation and orientation using polyacrylamide substrates of different stiffness and topography. PMID- 22927325 TI - Regulation of microglia development and homeostasis. AB - Microglia represent the resident macrophages of the central nervous system (CNS) and account for 10% of the adult glial cell population in the normal brain. Although microglial cells are thought to contribute to most pathological conditions including CNS infections, neuroinflammatory lesions, brain tumors, and neurodegenerative diseases, their exact role in CNS development, homeostasis, and disease remains poorly understood. In contrast to most macrophage populations, microglia survive high-dose ionizing radiation and maintain themselves locally and independently of circulating precursors in the steady state. However, controversies remain on the origin of microglia in the brain and whether they could potentially be repopulated by circulating myeloid precursors after brain injury. Microglia-targeted therapies through the use of genetically modified circulating hematopoietic cells proved to be a promising therapeutic strategy for the treatment of brain diseases. It is thus of great importance to understand the contribution and developmental cues of circulating myeloid cells as potential microglia progenitors to the adult pool of microglia in the steady state and under inflammatory conditions. PMID- 22927324 TI - Bulk physicochemical, interconnectivity, and mechanical properties of calcium phosphate cements-fibrin glue composites for bone substitute applications. AB - Calcium phosphate cements (CPCs) and fibrin glue (FG) are used for surgical applications. Their combination is promising to create bone substitutes able to promote cell attachment and bone remodeling. This study proposes a novel approach to create CPC-FG composites by simultaneous CPC setting and FG fibrinogenesis. CPC-FG composites were obtained by mixing CPC powders, i.e. alpha-tricalcium phosphate, dicalcium phosphate anhydrous and precipitated hydroxyapatite, with FG powder components, i.e. fibrinogen and thrombin, and a 2% Na(2) HPO(4) solution. To study the effect of FG quantity and fibrinogenesis kinetics, long and fast setting FGs were evaluated in amounts of 0.125, 0.250, and 0.500 mL on CPC-FG composites. Physicochemical, interconnectivity, and mechanical properties were measured. Scanning electron microscopy, Micro-computed tomography (MU-CT), X-ray diffraction, and Fourier transform Infrared spectroscopy (FTIR) analyzed morphology, structure, crystallographic, and chemical composition, respectively. FG fibrinogenesis was performed within the CPC. FTIR confirmed this and its interfacial bonding with CPC. MU-CT confirmed a good FG distribution. FG addition affected the CPC when compared with pristine CPC. Adding FG to CPC changed their morphology, density, porosity, setting, cohesion, injectability, interconnectivity, crystallographic and chemical composition and mechanical properties. Moreover, 0.500 mL of long setting FG modified the observed fracture behavior of the CPC-FG. PMID- 22927326 TI - Unraveling stress-induced toxicity properties of graphene oxide and the underlying mechanism. AB - Graphene oxide shows stress-induced toxicity properties in vivo under different pathophysiological conditions. A dual-path chemical mechanism, involving the overproduction of hydroxyl radicals and the formation of oxidizing cytochrome c intermediates, is responsible for the toxicity properties. PMID- 22927328 TI - Microarray-based prediction of Parkinson's disease using clinical data as additional response variables. AB - Recent discoveries and developments in the field of genomics have led to the commercialization of novel diagnostic devices for studying disease or estimating therapeutic outcomes in individual patients. With this emerging field, the emphasis is shifting to integration of clinical research into product development. Data acquisition is primary in the initial exploratory phase of product development, and during the process of sample collection and data generation in clinical microarray studies, great amounts of additional information, such as demographic, clinical, and study design variables associated with the data, are often accumulated and made available. Including additional information in classification has been addressed in many different ways. However, in previous studies, the additional information have consistently been treated as extra predictors, which can be a problem for future prediction if such information are not available or collectable for the new samples. We instead propose to adopt a method called canonical partial least squares, which for our purpose, only uses the additional information at the model building stage to stabilize the construction of a classifier for disease status from microarray data. The canonical partial least squares method is compared with regular partial least squares for the classification of Parkinson's disease from gene expression in peripheral blood samples and also through computer simulations. The present study showed that including clinical data in the model building produces simpler and more stable models for prediction of Parkinson's disease from gene expression data. PMID- 22927327 TI - Improved fat water separation with water selective inversion pulse for inversion recovery imaging in cardiac MRI. AB - PURPOSE: To develop an improved chemical shift-based water-fat separation sequence using a water-selective inversion pulse for inversion recovery 3D contrast-enhanced cardiac magnetic resonance imaging (MRI). MATERIALS AND METHODS: In inversion recovery sequences the fat signal is substantially reduced due to the application of a nonselective inversion pulse. Therefore, for simultaneous visualization of water, fat, and myocardial enhancement in inversion recovery-based sequences such as late gadolinium enhancement imaging, two separate scans are used. To overcome this, the nonselective inversion pulse is replaced with a water-selective inversion pulse. Imaging was performed in phantoms, nine healthy subjects, and nine patients with suspected arrhythmogenic right ventricular cardiomyopathy plus one patient for tumor/mass imaging. In patients, images with conventional turbo-spin echo (TSE) with and without fat saturation were acquired prior to contrast injection for fat assessment. Subjective image scores (1 = poor, 4 = excellent) were used for image assessment. RESULTS: Phantom experiments showed a fat signal-to-noise ratio (SNR) increase between 1.7 to 5.9 times for inversion times of 150 and 300 msec, respectively. The water-selective inversion pulse retains the fat signal in contrast-enhanced cardiac MR, allowing improved visualization of fat in the water-fat separated images of healthy subjects with a score of 3.7 +/- 0.6. Patient images acquired with the proposed sequence were scored higher when compared with a TSE sequence (3.5 +/- 0.7 vs. 2.2 +/- 0.5, P < 0.05). CONCLUSION: The water-selective inversion pulse retains the fat signal in inversion recovery-based contrast enhanced cardiac MR, allowing simultaneous visualization of water and fat. PMID- 22927329 TI - Nitrous-acid-mediated synthesis of iron-nitrosyl-porphyrin: pH-dependent release of nitric oxide. AB - Two iron-nitrosyl-porphyrins, nitrosyl[meso-tetrakis(3,4,5 trimethoxyphenylporphyrin]iron(II) acetic acid solvate (3) and nitrosyl[meso tetrakis(4-methoxyphenylporphyrin]iron(II) CH(2)Cl(2) solvate (4), were synthesized in quantitative yield by using a modified procedure with nitrous acid, followed by oxygen-atom abstraction by triphenylphosphine under an argon atmosphere. These nitrosyl porphyrins are in the {FeNO}(7) class. Under an argon atmosphere, these compounds are relatively stable over a broad range of pH values (4-8) but, under aerobic conditions, they release nitric oxide faster at high pH values than that at low pH values. The generated nitric-oxide-free iron(III) porphyrin can be re-nitrosylated by using nitrous acid and triphenylphosphine. The rapid release of NO from these Fe(II) complexes at high pH values seems to be similar to that in nitrophorin, a nitric-oxide-transport protein, which formally possesses Fe(III). However, because the release of NO occurs from ferrous nitrosyl-porphyrin under aerobic conditions, these compounds are more closely related to nitrobindin, a recently discovered heme protein. PMID- 22927330 TI - Non-adhesive behavior of new nanostructured PNIPAM surfaces towards specific neurodegenerative proteins: application to storage and titration of Tau proteins. AB - New nonfouling tubes are developed and their influence on the adhesion of neuroproteins is studied. The biomarkers are considered as single components (recombinant prion and Tau proteins) or in a solution of native and pathological forms. The samples are stored for 24 h at 4 degrees C in virgin and treated tubes layered with two different nanostructured coatings based on poly(N isopropylacrylamide) with either a positive or a neutral charge, and the protein adhesion is monitored. The recombinant protein with a high pI is repelled from the nanostructured surface that has a negative zeta potential, whereas the recombinant protein with the lower pI is attracted. Furthermore, in the case of complex solutions, neutral nanostructured surfaces are able to retain all amyloid biomarkers. PMID- 22927331 TI - The inflammatory chemokine CXC motif ligand 16 triggers platelet activation and adhesion via CXC motif receptor 6-dependent phosphatidylinositide 3-kinase/Akt signaling. AB - RATIONALE: The recently discovered chemokine CXC motif ligand 16 (CXCL16) is highly expressed in atherosclerotic lesions and is a potential pathogenic mediator in coronary artery disease. OBJECTIVE: The aim of this study was to test the role of CXCL16 on platelet activation and vascular adhesion, as well as the underlying mechanism and signaling pathway. METHODS AND RESULTS: Reverse transcriptase polymerase chain reaction, Western blotting, confocal microscopy, and flow cytometry revealed that CXCL16-specific receptor, CXC motif receptor 6, is highly expressed in platelets. According to flow cytometry and confocal microscopy, stimulation of platelets with CXCL16 induced platelet degranulation, integrin alpha(IIb)beta(3) activation, and shape change. CXCL16 increased Akt phosphorylation (Thr(308)/Ser(473)), an effect abrogated by phosphatidylinositide 3-kinase inhibitors wortmannin (100 nmol/L) and LY294002 (25 umol/L). The phosphatidylinositide 3-kinase inhibitors and Akt inhibitor SH-6 (20 umol/L) further diminished CXCL16-induced platelet activation. CXCL16-mediated platelet degranulation, integrin alpha(IIb)beta(3) activation, and Akt phosphorylation were blunted in platelets lacking CXCL16-specific receptor CXC motif receptor 6. CXCL16-induced platelet activation was abrogated in Akt1- or Akt2-deficient platelets. CXCL16 enhanced platelet adhesion to endothelium in vitro after high arterial shear stress (2000(-s)) and to injured vascular wall in vivo after carotid ligation. CXCL16-induced stimulation of platelet adhesion again was prevented by phosphatidylinositide 3-kinase and Akt inhibitors. Apyrase and antagonists of platelet purinergic receptors P(2)Y(1) (MRS2179, 100 umol/L) and especially P(2)Y(12) (Cangrelor, 10 umol/L) blunted CXCL16-triggered platelet activation as well as CXCL16-induced platelet adhesion under high arterial shear stress in vitro and after carotid ligation in vivo. CONCLUSIONS: The inflammatory chemokine CXCL16 triggers platelet activation and adhesion via CXC motif receptor 6-dependent phosphatidylinositide 3-kinase/Akt signaling and paracrine activation, suggesting a decisive role for CXCL16 in linking vascular inflammation and thrombo-occlusive diseases. PMID- 22927333 TI - Immobilization of cell-binding peptides on poly-epsilon-caprolactone film surface to biomimic the peripheral nervous system. AB - Cell-material interactions are crucial for cell adhesion and proliferation on biomaterial surfaces. Immobilization of biomolecules leads to the formation of biomimetic substrates, improving cell response. We introduced RGD (Arg-Gly-Asp) sequences on poly-epsilon-caprolactone (PCL) film surfaces using thiol chemistry to enhance Schwann cell (SC) response. XPS elemental analysis indicated an estimate of 2-3% peptide functionalization on the PCL surface, comparable with carbodiimide chemistry. Contact angle was not remarkably reduced; hence, cell response was only affected by chemical cues on the film surface. Adhesion and proliferation of Schwann cells were enhanced after PCL modification. Particularly, RGD immobilization increased cell attachment up to 40% after 6 h of culture. It was demonstrated that SC morphology changed from round to very elongated shape when surface modification was carried out, with an increase in the length of cellular processes up to 50% after 5 days of culture. Finally RGD immobilization triggered the formation of focal adhesion related to higher cell spreading. In summary, this study provides a method for immobilization of biomolecules on PCL films to be used in peripheral nerve repair, as demonstrated by the enhanced response of Schwann cells. PMID- 22927332 TI - Interleukin-27 receptor limits atherosclerosis in Ldlr-/- mice. AB - RATIONALE: Atherosclerosis is a chronic inflammatory disease of the arterial wall. Several proinflammatory cytokines are known to promote atherosclerosis, but less is known about the physiological role of anti-inflammatory cytokines. Interleukin (IL)-27 is a recently discovered member of the IL-6/IL-12 family. The IL-27 receptor is composed of IL-27 receptor A (WSX-1) and gp130 and is required for all established IL-27 signaling pathways. The expression of the IL-27 subunit Ebi3 is elevated in human atheromas, yet its function in atherosclerosis remains unknown. OBJECTIVE: The aim of this study was to test the role of IL-27 receptor signaling in immune cells in atherosclerosis development. METHODS AND RESULTS: Atherosclerosis-prone Ldlr(-/-) mice transplanted with Il27ra(-/-) bone marrow and fed Western diet for 16 weeks developed significantly larger atherosclerotic lesions in aortic roots, aortic arches, and abdominal aortas. Augmented disease correlated with increased accumulation of CD45(+) leukocytes and CD4(+) T cells in the aorta, which produced increased amounts of IL-17A and tumor necrosis factor. Several chemokines, including CCL2, were upregulated in the aortas of Ldlr(-/-) mice receiving Il27ra(-/-) bone marrow, resulting in accumulation of CD11b(+) and CD11c(+) macrophages and dendritic cells in atherosclerotic aortas. CONCLUSIONS: The absence of anti-inflammatory IL-27 signaling skews immune responses toward T-helper 17, resulting in increased production of IL-17A and tumor necrosis factor, which in turn enhances chemokine expression and drives the accumulation of proatherogenic myeloid cells in atherosclerotic aortas. These findings establish a novel antiatherogenic role for IL-27 receptor signaling, which acts to suppress the production of proinflammatory cytokines and chemokines and to curb the recruitment of inflammatory myeloid cells into atherosclerotic aortas. PMID- 22927334 TI - Histone deacetylase activity is required for human oligodendrocyte progenitor differentiation. AB - The molecular mechanisms controlling human oligodendrocyte development are poorly characterized. Microarray analysis of human oligodendrocyte progenitor cells (OPCs) and immature oligodendrocytes revealed that specific-class I histone deacetylase (HDAC) target genes were actively repressed during oligodendrocyte commitment. Although epigenetic regulation of oligodendrocyte differentiation has been established in rodent development, the role of HDACs in human OPCs remains undefined. We used HDAC inhibitors (HDACi) trichostatin A (TSA) and sodium butyrate to determine the importance of HDAC activity in human primary OPC differentiation. Treatment with either drug resulted in significant dose dependent inhibition of O4(+) oligodendrocyte cell differentiation, reduction of oligodendrocyte morphological maturation, and downregulation of myelin basic protein mRNA. High dose TSA treatment was also associated with reduction in OPC proliferation. HDACi treatment prevented downregulation of SOX2, ID4, and TCF7L2 mRNAs but did not regulate HES5, suggesting that targets of HDAC repression may differ between species. These results predict that HDACi treatment would impair proliferation and differentiation by parenchymal oligodendrocyte progenitors, and thereby degrade their potential for endogenous repair in human demyelinating disease. (c) 2012 Wiley Periodicals, Inc. PMID- 22927335 TI - Automated truncation method for myocardial T2* measurement in thalassemia. AB - PURPOSE: To propose an automated truncation method for myocardial T2* measurement and evaluate this method on a large population of patients with iron loading in the heart and scanned at multiple magnetic resonance imaging (MRI) centers. MATERIALS AND METHODS: A total of 550 thalassemia patients were scanned at 20 international centers using a variety of MR scanners (Siemens, Philips, or GE). A single mid-ventricular short axis slice was imaged. All patient data were anonymized before the T2* were measured by expert observers using standard techniques. These same datasets were then retrospectively processed using the proposed automated truncation method by another independent observer and the resulting T2* measurements were compared with those of expert readings. RESULTS: The T2* measurements using the automated method showed good agreement with those measured by expert observers using standard techniques (P = 0.95) with a low coefficient of variation (1.6%). CONCLUSION: This study demonstrates feasibility and good reproducibility of a new automated truncation method for myocardial T2* measurement. This approach simplifies the overall analysis and can be easily incorporated into T2* analysis software to facilitate further development of a fully automated myocardial tissue iron quantification. PMID- 22927336 TI - A new general synthetic strategy for phase-pure complex functional materials. AB - The ability of ionic liquids to solvate inorganic salts completely has to date never been employed in the synthesis of complex inorganic materials. Here, we demonstrate that complex functional oxides, even those traditionally considered extremely difficult to synthesize in bulk, such as quinternary superconductors, are produced with no impurity phases and on timescales that are much shorter than other synthetic techniques. PMID- 22927337 TI - Functionalization of pristine graphene with conjugated polymers through diradical addition and propagation. AB - Hanging on: Pristine graphene was grafted with conjugated polymers through addition and propagation of diradicals generated from Bergman cyclization of enediyne-containing dendrimers. The surface functionalization was confirmed with TGA, FTIR and Raman spectroscopy, and AFM analysis. The sp(2) network of graphene is only slightly destroyed, as revealed by conductivity measurements. PMID- 22927338 TI - Tunable pH-sensitive poly(beta-amino ester)s synthesized from primary amines and diacrylates for intracellular drug delivery. AB - The pH sensitivity of a series of PbAEs synthesized from primary amines and diacrylates is studied. By changing alkyl groups of the amine monomers, the pKb can be tuned across a broad range (from 3.5 to 7.2). Micelles formed from a PEG PbAE block copolymer retain the pH sensitivity of PbAE and can stably load hydrophobic molecules under neutral pH, while quickly dissociate and release their cargoes at pH ~ 6.0. When the chemotherapy drug DOX is loaded, the micelles show efficient cell proliferation inhibition to HeLa cells and fast intracellular release. Thus, the primary-amine-based PbAEs are shown to be promising in the construction of intracellular targeting drug delivery systems. PMID- 22927339 TI - Latency of ECG displays of hospital telemetry systems: a science advisory from the American Heart Association. PMID- 22927340 TI - On the biodegradability, mechanical behavior, and cytocompatibility of amorphous Mg72 Zn23 Ca5 and crystalline Mg70 Zn23 Ca5 Pd2 alloys as temporary implant materials. AB - The evolution of microstructure and mechanical properties of almost fully amorphous Mg(72) Zn(23) Ca(5) and crystalline Mg(70) Zn(23) Ca(5) Pd(2) alloys during immersion in Hank's balanced salt solution (HBSS), as well as their cytocompatibility, are investigated in order to assess the feasibility of both materials as biodegradable implants. Though the crystalline Mg(70) Zn(23) Ca(5) Pd(2) sample shows lower wettability and more positive corrosion potential, this sample degrades much faster upon incubation in HBSS as a consequence of the formation of micro-galvanic couples between the nobler Pd-rich dendrites and the surrounding phases. After 22-h immersion, the concentration of Mg ions in the HBSS medium containing the Mg(70) Zn(23) Ca(5) Pd(2) sample is six times larger than for Mg(72) Zn(23) Ca(5) . Due to the Zn enrichment and the incipient porosity, the mechanical properties of the Mg(72) Zn(23) Ca(5) sample improve within the first stages of biodegradation (i.e., hardness increases while the Young's modulus decreases, thus rendering an enhanced wear resistance). Cytocompatibility studies reveal that neither Mg(72) Zn(23) Ca(5) nor Mg(70) Zn(23) Ca(5) Pd(2) are cytotoxic, although preosteoblast cell adhesion is to some extent precluded, particularly onto the surface of Mg(70) Zn(23) Ca(5) Pd(2) , because of the relatively high hydrophobicity. Because of their outstanding properties and their time-evolution, the use of the Pd-free alloy in temporary implants such as screws, stents, and sutures is envisioned. PMID- 22927341 TI - Endothelins reciprocally regulate VEGF-A and angiopoietin-1 production in cultured rat astrocytes: implications on astrocytic proliferation. AB - Vascular endothelial growth factors (VEGFs) and angiopoietins (ANGs) are involved in pathophysiological responses in damaged nerve tissues. Astrocytes produce VEGFs and ANGs upon brain ischemia and traumatic injury. To clarify the extracellular signals regulating VEGF and ANG production, effects of endothelins (ETs), a family of endothelium-derived peptides, were examined in cultured rat astrocytes. ET-1 (100 nM) and Ala(1,3,11,15)-ET-1 (100 nM), an ET(B) receptor agonist, increased VEGF-A mRNA levels in cultured astrocytes, while ANG-1 mRNA was decreased by ETs. ET-1 did not affect astrocytic VEGF-B, placental growth factor (PLGF), and ANG-2 mRNA levels. The effects of ET-1 on VEGF-A and ANG-1 mRNAs were inhibited by BQ788, an ET(B) antagonist. Release of VEGF-A proteins from cultured astrocytes was increased by ET-1. In contrast, ET-1 reduced release of astrocytic ANG-1. Exogenous ET-1 (100 nM) and VEGF(165) (100 ng/mL), an isopeptide of VEGF-A, stimulated bromodeoxyuridine (BrdU) incorporation into cultured astrocytes. Treatment with ET-1 and VEGF(165) increased the numbers of cyclin D1-positive astrocytes. Exogenous ANG-1 (250 ng/mL) did not stimulate the BrdU incorporation. Increases in BrdU incorporation by ET-1 and VEGF(165) were not affected by ANG-1. In 60-70% confluent cultures, SU4312 (10 MUM), a VEGF receptor tyrosine kinase inhibitor, partially reduced the effects of ET-1 on BrdU incorporation and cyclin D1 expression. ET-induced BrdU incorporation and cyclin D1 expression were reduced by a neutralizing antibody against VEGF-A. Our findings suggest that ET-1 is a factor regulating astrocytic VEGF-A and ANG-1, and that increased VEGF-A production potentiates ET-induced astrocytic proliferation by an autocrine mechanism. PMID- 22927342 TI - Characterization of fast and slow diffusion from diffusion-weighted MRI of pediatric Crohn's disease. AB - PURPOSE: To characterize fast and slow diffusion components in diffusion-weighted magnetic resonance imaging (DW-MRI) of pediatric Crohn's disease (CD). Overall diffusivity reduction as measured by the apparent diffusion coefficient (ADC) in patients with CD has been previously demonstrated. However, the ADC reduction may be due to changes in either fast or slow diffusion components. In this study we distinguished between the fast and slow diffusion components in the DW-MRI signal decay of pediatric CD. MATERIALS AND METHODS: We acquired MRI from 24 patients, including MR enterography (MRE) and DW-MRI with 8 b-values (0-800 s/mm(2)). We characterized fast and slow diffusivity by intravoxel incoherent motion (IVIM) model parameters (f, D*, D), and overall diffusivity by ADC values. We determined which model best described the DW-MRI signal decay. We assessed the influence of the IVIM model parameters on the ADC. We evaluated differences in model parameter values between the enhancing and nonenhancing groups. RESULTS: The IVIM model described the observed data significantly better than the ADC model (P = 0.0088). The ADC was correlated with f (r = 0.67, P = 0.0003), but not with D (r = 0.39, P = 0.062) and D* (r = -0.39, P = 0.057). f values were significantly lower (P < 0.003) and D* values were significantly higher (P = 0.03) in the enhancing segments, while D values were not significantly different between the groups (P = 0.14). CONCLUSION: For this study population the IVIM model provides a better description of the DW-MRI signal decay than the ADC model. The reduced ADC is related to changes in the fast diffusion rather than to changes in the slow diffusion. PMID- 22927343 TI - Benzo[1,2-d:4,5-d']bisimidazoles as a convenient platform towards dyes that are capable of excited-state intramolecular proton transfer and of two-photon absorption. AB - New, strongly fluorescent benzo[1,2-d:4,5-d']bisimidazoles have been prepared by the reaction of Bandrowski's base with various aldehydes. Their structures were carefully designed to achieve efficient excited-state intramolecular proton transfer and good two-photon-absorption (2PA) cross-sections. Functional dyes that possessed both high fluorescence quantum yields and large Stokes shifts were prepared. A pi-expanded D-A-D derivative that possessed Phi(fl)=50 % and sigma(2)=230 GM in the spectroscopic area of interest for biological imaging is an excellent candidate as a fluorescent probe. Thanks to the presence of two reactive amino groups, such compounds can be easily transformed into probes for bioconjugation. All of these benzo[1,2-d:4,5-d']bisimidazoles were also strongly fluorescent in the solid state. PMID- 22927346 TI - Different hyaluronic acid morphology modulates primary articular chondrocyte behavior in hyaluronic acid-coated polycaprolactone scaffolds. AB - Scaffolds for cartilage tissue engineering should promote both adequate biomechanical environment and chondrogenic stimulation. Hyaluronic acid (HA) has been used in cartilage engineering for its chondrogenic and chondroprotective properties, nevertheless its mechanical properties are limited. Influence of HA microstructure in chondrocyte response has not been addressed yet. In this work, polycaprolactone (PCL) scaffolds were modified using HA following two coating strategies: coating in one step (PCL-HA1s) yields a gel-like phase within the scaffold, whereas a two-step reaction (PCL-HA2s) yields a thin HA layer coating internal surfaces of PCL structure. Chondrocytes were seeded in the scaffolds and cultured in dedifferentiating conditions up to 3 weeks and analyzed using a total DNA assay and sulfated glycosaminoglycan (sGAG) determination assay; cell morphology and extracellular matrix secretion were assessed by electron microscopy as well as immunofluorescent imaging (collagen I, collagen II, aggrecan, CD44). Cells proliferate in all samples and no cytotoxicity is observed. PCL-HA1s shows higher sGAG production per cell than PCL and PCL-HA2s at all times. Presence of hyaluronic acid promotes qualitative expression of CD44 surface markers and aggrecan (more visible in PCL-HA1s than PCL-HA2s), whereas in dedifferentiating conditions, expression of CD44 and aggrecan can hardly be detected in pure PCL scaffolds. Collagen type II seems more prominent in PCL HA2s; although PCL-HA2s shows markers for COL II, aggrecan and CD44, quantitative ECM production is not improved with respect to PCL. It is thus likely that CD44 activation is not sufficient for explaining the better response in PCL-HA1s. PMID- 22927345 TI - What Drosophila spermatocytes tell us about the mechanisms underlying cytokinesis. AB - Cytokinesis separates the genomic material and organelles of a dividing cell equitably into two physically distinct daughter cells at the end of cell division. This highly choreographed process involves coordinated reorganization and regulated action of the actin and microtubule cytoskeletal systems, an assortment of motor proteins, and membrane trafficking components. Due to their large size, the ease with which exquisite cytological analysis may be performed on them, and the availability of numerous mutants and other genetic tools, Drosophila spermatocytes have provided an excellent system for exploring the mechanistic basis for the temporally programmed and precise spatially localized events of cytokinesis. Mutants defective in male meiotic cytokinesis can be easily identified in forward genetic screens by the production of multinucleate spermatids. In addition, the weak spindle assembly checkpoint in spermatocytes, which causes only a small delay of anaphase onset in the presence of unattached chromosomes, allows investigation of whether gene products required for spindle assembly and chromosome segregation are also involved in cytokinesis. Perhaps due to the large size of spermatocytes and the requirement for two rapid-fire rounds of division without intervening S or growth phases during meiosis, male meiotic mutants have also revealed much about molecular mechanisms underlying new membrane addition during cytokinesis. Finally, cell type-specific differences in the events that set up and complete cytokinesis are emerging from comparison of spermatocytes with cells undergoing mitosis either elsewhere in the organism or in tissue culture. PMID- 22927347 TI - An alkalophilic laccase from Rheinheimera species isolate: production and biobleaching of kraft pulp. AB - Medium optimization was carried out to enhance laccase production from a novel Rheinheimera species, isolated from industrial effluent. Out of the 15 variables tested by Placket-Burman design (PBD)-yeast extract, soyabean meal, and peptone were the positively significant ones, enhancing laccase production. Both simple and complex sugars showed a negative effect on laccase production. Central composite design (CCD) of experiments, using the three positively significant variables in combinations, showed that laccase production was not affected by molar carbon, molar nitrogen levels or molar C/N ratio. Maximum laccase yield of 2.5 * 10(5) nkat L(-1) , 31 fold enhancement over the unoptimized medium, was achieved when soyabean meal (0.6%) was used alone as medium showing that laccase production was substrate dependent. Laccase was used, in the presence of 2 mM ABTS, for the biobleaching of eucalyptus kraft pulp resulting in kappa number reduction by 20% and brightness increase by 2.9%. Biobleaching improved further by sequential application of an alkalophilic xylanase (X) and laccase-ABTS system (LAS) that decreased kappa number by 10, 15, and 35%, increased brightness by 2.7, 3.2, and 5.9% as compared to X treated, LAS treated and untreated control, respectively. XLAS treatment resulted in 15, 13, 10.9% increase in burst factor, tear factor, and viscosity with a 20% reduced consumption of elemental chlorine and hypochlorite. PMID- 22927348 TI - Introducing the "personal perspective" series. PMID- 22927349 TI - The variability in tissue proteomics. AB - Variability is one of the most critical issues of concern in clinical proteomics. In this issue of Proteomics Clinical Applications, Yoshida et al. [Proteomics Clin. Appl. 2012, 6, 412-417] describe the effects of blood and number of washes on the human glomerular proteome isolated from the kidney by laser microdissection. The blood-derived proteins occupied almost 50% of all the identified proteins in the unwashed samples, whereas varying the number of washes (from 1-5) with PBS yielded only 43-80% of the proteins identified in each sample that were common in all samples. This urges caution to all proteomists to carefully consider sample preservation and preparation for tissue proteome analysis. PMID- 22927350 TI - Using lectins in biomarker research: addressing the limitations of sensitivity and availability. AB - Carbohydrates have fundamental roles throughout biology, yet they have not been as well studied as proteins and nucleic acids, in part due to limitations in the experimental tools. Improved methods for studying glycans could spur significant advances in the understanding and application of glycobiology. The use of affinity reagents, such as lectins and glycan-binding antibodies, is a valuable complement to methods involving mass spectrometry and chromatography. This article addresses two limitations that have prevented the broader experimental use of glycan-binding proteins: sensitivity and availability. The sensitivity limitation stems from the poor affinity that many glycan-binding proteins have as isolated analytical reagents. To address this problem, I propose making use of multivalent interactions between lectins and glycans, mimicking those frequently found in the biological setting. Recent experiments show that a practical technique for producing lectin multimers can significantly improve detection sensitivity. The second limitation, availability, is the difficulty of finding and obtaining glycan-binding proteins that recognize less common or arbitrarily defined glycan structures. To address this problem, I propose translating the wealth of existing glycan array data into a quantitative, searchable database of the specificities of glycan-binding proteins. Such a resource would allow us to more easily identify proteins with defined specificities and perform detailed comparisons between reagents. Solutions to these two limitations could lead to the more effective use of, and a broader range of, glycan-binding reagents. PMID- 22927351 TI - Potential biomarkers for early detection of acute graft-versus-host disease. AB - Acute graft-versus-host disease (aGVHD) is the main complication of allogeneic hematopoietic stem cell transplantation (HCT), resulting in considerable morbidity and mortality. Currently, the diagnosis of aGVHD is largely made based on clinical parameters and invasive biopsies. For the past 20 years, researchers have been trying to find reliable biomarkers to enable early and accurate diagnosis of aGVHD. Although a number of potential aGVHD biomarkers have been published, as yet, no validated diagnostic test is available. Proteomics encompasses a broad range of rapidly developing technologies, which have shown tremendous promise for early detection of aGVHD. In this article, we review the current state of aGVHD biomarker discovery, provide a summary of the key proteins of interest and the most common analytical procedures for the clinic, as well as outlining the significant challenges faced in their use. PMID- 22927352 TI - Plasma and urine proteomic profiles in childhood idiopathic nephrotic syndrome. AB - PURPOSE: Idiopathic nephrotic syndrome (NS) is characterized by proteinuria, edema, and hypoalbuminemia. The aim of the study was to identify differentially expressed proteins in urine and plasma during NS compared with remission. EXPERIMENTAL DESIGN: Plasma and urine samples were collected during NS and at remission. Proteomic profiling was performed by iTRAQ labeling followed by nano LC-MS/MS to yield data on relative protein amounts. Protein validation was performed by ELISA. RESULTS: A total of 388 and 425 proteins were detected in plasma and urine, respectively. In total, 18 plasma and 38 urinary proteins were significantly altered (p <0.05). E-cadherin was one of the proteins with reduced urinary concentration during NS, a finding validated by ELISA. The slit diaphragm protein P-cadherin was identified by nano-LC-MS/MS and shown to be reduced in urine during NS by ELISA. CONCLUSIONS AND CLINICAL RELEVANCE: The present study identified more than 50 differentially altered proteins comparing NS with remission. Several proteins were found to be linked to the major clinical symptoms of NS, and further studies must elucidate if P-cadherin is involved in proteinuria during NS, and if low urinary E-cadherin level is linked to altered epithelial cell to cell contact in the distal part of the nephron. PMID- 22927353 TI - Tryptic peptide screening for primary immunodeficiency disease by LC/MS-MS. AB - PURPOSE: Early diagnosis of primary immunodeficiency disorders (PIDDs) is critical for maximizing patient survival and clinical outcomes. Consequently, there is significant interest in developing broad-based, high-throughput, screening approaches capable of utilizing small blood volumes to identify patients with PIDD. EXPERIMENTAL DESIGN: We developed a novel proteomic screening approach using tandem mass spectrometry to simultaneously identify specific signature peptides derived from the transmembrane protein cluster of differentiation 3 (CD3)E and the intracellular proteins Wiskott-Aldrich syndrome protein (WASP) and Bruton's tyrosine kinase (BTK) as markers of three life threatening PIDDs; severe combined immunodeficiency, Wiskott-Aldrich syndrome, and X-linked Agammaglobulinemia. Signature peptides were analyzed by LC/MS-MS in proteolytically digested lysates from cell lines and white blood cells (WBCs). The amount of each peptide was determined by the ratio of the signature peptide peak area to that of a known amount of labeled standard peptide. Peptide concentrations were normalized to actin. RESULTS: We show that signature peptides from CD3E, WASP, and BTK were readily detected in proteolytically digested cell lysate and their absence could correctly identify PIDD patients. CONCLUSIONS AND CLINICAL RELEVANCE: This proof of concept study demonstrates the applicability of this approach to screen for PIDD and raises the possibility that it could be further multiplexed to identify additional PIDDs and potentially other disorders. PMID- 22927354 TI - Proteomic approach to human kidney glomerulus prepared by laser microdissection from frozen biopsy specimens: exploration of proteome after removal of blood derived proteins. AB - PURPOSE: Abundance of blood-derived proteins in glomeruli prepared by laser microdissection from human kidney biopsy specimens has hampered in-depth proteomic analysis of glomeruli. We attempted to establish experimental platform for in-depth proteomic analysis of glomeruli by removal of blood-derived proteins from frozen biopsy samples. EXPERIMENTAL DESIGN: Frozen sections of biopsy samples were exposed to repeated PBS washes prior to laser microdissection to remove blood-derived proteins, and glomerular dissectants were analyzed by MS. The depth of proteomic analysis was evaluated by dynamic range of identified proteins and detection of low-abundance proteins. RESULTS: Two times PBS washes of frozen sections effectively eliminated blood-derived proteins in laser microdissected glomeruli and gave an increased number of identified proteins. Analysis of glomeruli from single specimens by a linear ion trap-Orbitrap mass analyzer generated nonredundant, high-confidence datasets of more than 400 identified proteins with high reproducibility, which attained to a considerable depth of the glomerulus proteome as revealed by a wide dynamic range and identification of low-abundance proteins. CONCLUSIONS AND CLINICAL RELEVANCE: Implementation of washing of frozen section with PBS successfully removed blood derived proteins and resulted in an in-depth proteomic analysis of laser microdissected glomeruli, suggesting applicability to clinical study. PMID- 22927359 TI - Total synthesis of indole-derived allocolchicine analogues exhibiting strong apoptosis-inducing activity. AB - A series of novel pyrrolo-allocolchicine derivatives (containing a 1-methyl-1H indol-5-yl moiety replacing ring C) was synthesized. The tetracyclic ring system was constructed by Suzuki-Miyaura cross-coupling of a 1-methylindole-5-boronate with an ortho-iodo-dihydrocinnamic acid derivative and subsequent intramolecular Friedel-Crafts acylation. After reduction of the resulting ketone, the nitrogen functionality was introduced in a Mitsunobu-type reaction by using zinc azide followed by LiAlH(4) reduction. Structural assignments were supported by X-ray crystallography. The compounds synthesized were then tested against BJAB tumor cells and found to exhibit pronounced cytotoxic activity (proliferation inhibition and apoptosis induction). The ketone 24 b was even active at sub nanomolar concentration. In addition, the antitumor potential of the compounds was confirmed by using B lymphoid cell lines. PMID- 22927361 TI - Polar body cytokinesis. AB - Polar body cytokinesis is the physical separation of a small polar body from a larger oocyte or ovum. This maternal meiotic division shares many similarities with mitotic and spermatogenic cytokinesis, but there are several distinctions, which will be discussed in this review. We synthesize results from many different model species, including those popular for their genetics and several that are more obscure in modern cell biology. The site of polar body division is determined before anaphase, by the eccentric, cortically associated meiotic spindle. Depending on the species, either the actin or microtubule cytoskeleton is required for spindle anchoring. Chromatin is necessary and sufficient to elicit differentiation of the associated cortex, via Ran-based signaling. The midzone of the anaphase spindle serves as a hub for regulatory complexes that elicit Rho activation, and ultimately actomyosin contractile ring assembly and contraction. Polar body cytokinesis uniquely requires another Rho family GTPase, Cdc42, for dynamic reorganization of the polar cortex. This is perhaps due to the considerable asymmetry of this division, wherein the polar body and the oocyte/ovum have distinct fates and very different sizes. Thus, maternal meiotic cytokinesis appears to occur via simultaneous polar relaxation and equatorial contraction, since the polar body is extruded from the spherical oocyte through the nascent contractile ring. As such, polar body cytokinesis is an interesting and important variation on the theme of cell division. PMID- 22927360 TI - Cellular interactions and stimulated biological functions mediated by nanostructured carbon for tissue reconstruction and tracheal tubes and sutures. AB - Nylon 6,6 is used for biological applications including gastrointestinal segments, tracheal tubes and sutures, vascular graft, and for hard tissue reconstruction. While it is a relatively inexpensive polymer, it is not widely acceptable as a preferred biomaterial because of bioactivity. To this end, we have discovered the exciting evidence that introduction of a novel nanostructured carbon, graphene, in the void space between the nylon chains and processing at elevated pressure favorably stimulates cellular functions and provides high degree of cytocompatibility. The cell-substrate interactions on stand alone Nylon 6,6 and Nylon 6,6-graphene oxide hybrid system were investigated in terms of cell attachment, viability, proliferation, and assessment of proteins, actin, vinculin, and fibronectin. The enhanced biological functions in the nanostructured hybrid system are attributed to relatively superior hydrophilicity of the surface and to the presence of graphene. Furthermore, it is proposed that the negatively charged graphene interacts with the polar nature of cells and the culture medium, such that the interaction is promoted through polar forces. This is accomplished by investigating cell attachment, proliferation, and morphology, including cytomorphometry evaluation, and quantitative assessment of prominent proteins, actin, vinculin, and fibronectin that are sensitive to cell-substrate interactions. Osteoblasts were studied to establish the practical viability of the hybrid nanostructured biomaterial. The study strengthens the foundation for utilizing nano- or quantum-size effects of nanostructured biomaterials. PMID- 22927362 TI - Bioenergetics and pathway of acid blue 113 degradation by Staphylococcus lentus. AB - Bioreaction calorimetric studies of degradation of the dye acid blue 113 by Staphylococcus lentus are reported for the first time. The heat released during the dye degradation process can be successfully measured using reaction calorimeter. Power time and oxygen uptake rate (OUR) profile followed each other suggesting that heat profiles could monitor the progress of the dye degradation in biocalorimetry. The shifts observed in power-time profile indicated three distinct phases of the bioprocess indicating simultaneous utilization of glucose (primary) and dye (secondary carbon source). Secretion of azoreductase enzyme enhanced the degradation process. Optimization of aeration and agitation rates was observed to be vital to efficient dye degradation. The degradative pathway for acid blue 113 by S. lentus was delineated via high-performance liquid chromatography (HPLC), Fourier transform infrared spectroscopy (FT-IR), and gas chromatography coupled with mass spectrometry (GC-MS) analyses. Interestingly the products of degradation were found to have low toxicity, as per cytotoxicity measurements. PMID- 22927363 TI - Azobenzene polyesters used as gate-like scaffolds in nanoscopic hybrid systems. AB - The synthesis and characterisation of new capped silica mesoporous nanoparticles for on-command delivery applications is reported. Functional capped hybrid systems consist of MCM-41 nanoparticles functionalised on the external surface with polyesters bearing azobenzene derivatives and rhodamine B inside the mesopores. Two solid materials, Rh-PAzo8-S and Rh-PAzo6-S, containing two closely related polymers, PAzo8 and PAzo6, in the pore outlets have been prepared. Materials Rh-PAzo8-S and Rh-PAzo6-S showed an almost zero release in water due to steric hindrance imposed by the presence of anchored bulky polyesters, whereas a large delivery of the cargo was observed in the presence of an esterase enzyme due to the progressive hydrolysis of polyester chains. Moreover, nanoparticles Rh PAzo8-S and Rh-PAzo6-S were used to study the controlled release of the dye in intracellular media. Nanoparticles were not toxic for HeLa cells and endocytosis mediated cell internalisation was confirmed by confocal microscopy. Furthermore, the possible use of capped materials as a drug-delivery system was demonstrated by the preparation of a new mesoporous silica nanoparticle functionalised with PAzo6 and loaded with the cytotoxic drug camptothecin (CPT-PAzo6-S). Following cell internalisation and lysosome resident enzyme-dependent gate opening, CPT PAzo6-S induced CPT-dependent cell death in HeLa cells. PMID- 22927364 TI - Digital holographic microtomography for high-resolution refractive index mapping of live cells. AB - Quantification of three-dimensional (3D) refractive index (RI) with sub-cellular resolution is achieved by digital holographic microtomography (DHMUT) using quantitative phase images measured at multiple illumination angles. The DHMUT system achieves sensitive and fast phase measurements based on iterative phase extraction algorithm and asynchronous phase shifting interferometry without any phase monitoring or active control mechanism. A reconstruction algorithm, optical diffraction tomography with projection on convex sets and total variation minimization, is implemented to substantially reduce the number of angular scattered fields needed for reconstruction without sacrificing the accuracy and quality of the reconstructed 3D RI distribution. Tomogram of a living CA9-22 cell is presented to demonstrate the performance of the method. Further, a statistical analysis of the average RI of the nucleoli, the nucleus excluding the nucleoli and the cytoplasm of twenty CA9-22 cells is performed. PMID- 22927366 TI - A pumpless perfusion cell culture cap with two parallel channel layers keeping the flow rate constant. AB - This article presents a novel pumpless perfusion cell culture cap, the gravity driven flow rate of which is kept constant by the height difference of two parallel channel layers. Previous pumpless perfusion cell culture systems create a gravity-driven flow by means of the hydraulic head difference (Deltah) between the source reservoir and the drain reservoir. As more media passes from the source reservoir to the drain reservoir, the source media level decreases and the drain media level increases. Thus, previous works based on a gravity-driven flow were unable to supply a constant flow rate for the perfusion cell culture. However, the proposed perfusion cell culture cap can supply a constant flow rate, because the media level remains unchanged as the media moves laterally through each channel having same media level. In experiments, using the different fluidic resistances, the perfusion cap generated constant flow rates of 871 +/- 27 MUL h( 1) and 446 +/- 11 MUL h(-1) . The 871 and 446 MUL h(-1) flow rates replace the whole 20 mL medium in the petri dish with a fresh medium for days 1 and 2, respectively. In the perfusion cell (A549 cell line) culture with the 871 MUL h( 1) flow rate, the proposed cap can maintain a lactate concentration of about 2200 nmol mL(-1) and an ammonia concentration of about 3200 nmol mL(-1) . Moreover, although the static cell culture maintains cell viability for 5 days, the perfusion cell culture with the 871 MUL h(-1) flow rate can maintain cell viability for 9 days. PMID- 22927365 TI - Centralspindlin: at the heart of cytokinesis. AB - The final step in the cell cycle is the formation of two genetically identical daughter cells by cytokinesis. At the heart of cytokinesis in animal cells is the centralspindlin complex which is composed of two proteins, a kinesin-like protein, Mitotic kinesin-like protein 1, and a Rho GTPase activating protein (RhoGAP), CYK-4. Through its targeted localization to a narrow region of antiparallel microtubule overlap immediately following chromosome segregation, centralspindlin initiates central spindle assembly. Centralspindlin has several critical functions during cell division including positioning of the division plane, regulation of Rho family GTPases, as well as midbody assembly and abscission. In this review, we will examine the biochemistry of centralspindlin and its multiple functions during cell division. Remarkably, several of its critical functions are somewhat unexpected. Although endowed with motor domains, centralspindlin has an important role in generating stable, antiparallel microtubule bundles. Although it contains a Rho family GAP domain, it has a central role in the activation of RhoA during cytokinesis. Finally, centralspindlin functions as a motor protein complex, as a scaffold protein for key regulators of abscission and as a conventional RhoGAP. Because of these diverse functions, centralspindlin lies at the heart of the cytokinetic mechanism. PMID- 22927367 TI - Intracerebral quantitative chromophore estimation from reflectance spectra captured during deep brain stimulation implantation. AB - Quantification of blood fraction (f(blood)), blood oxygenation (S(O2)), melanin, lipofuscin and oxidised and reduced Cytochrome aa 3 and c was done from diffuse reflectance spectra captured in cortex, white matter, globus pallidus internus (GPi) and subthalamus during stereotactic implantations of 29 deep brain stimulation (DBS) electrodes with the aim of investigating whether the chromophores can give physiological information about the targets for DBS. Double sided Mann-Whitney U-tests showed more lipofuscin in GPi compared to white matter and subthalamus (p < 0.05). Compared to the other structures, f(blood) was significantly higher in cortex (p < 0.05) and S(O2) lower in GPi (p < 0.05). Median values and range for f(blood) were 1.0 [0.2-6.0]% in the cortex, 0.3 [0.1 8.2]% in white matter, 0.2 [0.1-0.8]% in the GPi and 0.2 [0.1-11.7]% in the subthalamus. Corresponding values for S(O2) was 20 [0-81]% in the cortex, 29 [0 78]% in white matter, 0 [0-0]% in the GPi and 0 [0-92]% in the subthalamus. In conclusion, the measurements indicate very low oxygenation and blood volume for DBS patients, especially in the GPi. It would be of great interest to investigate whether this is due to the disease, the normal situation or an artefact of doing invasive measurements. PMID- 22927368 TI - Highly dispersed TiO6 units in a layered double hydroxide for water splitting. AB - A family of photocatalysts for water splitting into hydrogen was prepared by distributing TiO(6) units in an MTi-layered double hydroxide matrix (M = Ni, Zn, Mg) that displays largely enhanced photocatalytic activity with an H(2) production rate of 31.4 MUmol h(-1) as well as excellent recyclable performance. High-angle annular dark-field scanning transmission electron microscopy (HAADF STEM) mapping and XPS measurement reveal that a high dispersion of TiO(6) octahedra in the layered doubled hydroxide (LDH) matrix was obtained by the formation of an M(2+)-O-Ti network, rather different from the aggregation state of TiO(6) in the inorganic layered material K(2)Ti(4)O(9). Both transient absorption and photoluminescence spectra demonstrate that the electron-hole recombination process was significantly depressed in the Ti-containing LDH materials relative to bulk Ti oxide, which is attributed to the abundant surface defects that serve as trapping sites for photogenerated electrons verified by positron annihilation and extended X-ray absorption fine structure (EXAFS) techniques. In addition, a theoretical study on the basis of DFT calculations demonstrates that the electronic structure of the TiO(6) units was modified by the adjacent MO(6) octahedron by means of covalent interactions, with a much decreased bandgap of 2.1 eV, which accounts for its superior water-splitting behavior. Therefore, the dispersion strategy for TiO(6) units within a 2D inorganic matrix can be extended to fabricate other oxide or hydroxide catalysts with greatly enhanced performance in photocatalysis and energy conversion. PMID- 22927369 TI - Specificity of maltase to maltose in three different directions of reaction: hydrolytic, vanillyl alcohol glucoside and vanillyl alcohol isomaltoside synthesis. AB - Vanillyl alcohol glucoside is very attractive molecule due to its very powerful physiological activity. In this article, a detailed kinetic study of transglucosylation of vanillyl alcohol was performed. It was demonstrated that this reaction is very efficient (selectivity factor is 149) and occurred by a ping-pong mechanism with inhibition by glucose acceptor. At low concentration of vanillyl alcohol one additional transglucosylation product was detected. Its structure was determined to be alpha-isomaltoside of vanillyl alcohol, indicating that vanillyl alcohol glucoside is a product of the first transglucosylation reaction and a substrate for second, so the whole reaction mechanism was proposed. It was demonstrated that the rate of isomaltoside synthesis is two orders of magnitude smaller than glucoside synthesis, and that maltase has interestingly high K(m) value to maltose when vanillyl alcohol glucoside is second transglucosylation substrate. PMID- 22927370 TI - Catalytic asymmetric construction of spiro(gamma-butyrolactam-gamma butyrolactone) moieties through sequential reactions of cyclic imino esters with Morita-Baylis-Hillman bromides. AB - Spiro(gamma-butyrolactam-gamma-butyrolactone): a route to enantioenriched spiro(gamma-butyrolactam-gamma-butyrolactone) compounds, a valuable motif for drug discovery, was developed by use of a highly efficient copper(I)/TF BiphamPhos-catalyzed tandem Michael addition-elimination of homoserine lactone derived cyclic imino esters with Morita-Baylis-Hillman (MBH) bromides, followed by treatment with para-toluenesulfonic acid. PMID- 22927371 TI - Global distribution of microbial abundance and biomass in subseafloor sediment. AB - The global geographic distribution of subseafloor sedimentary microbes and the cause(s) of that distribution are largely unexplored. Here, we show that total microbial cell abundance in subseafloor sediment varies between sites by ca. five orders of magnitude. This variation is strongly correlated with mean sedimentation rate and distance from land. Based on these correlations, we estimate global subseafloor sedimentary microbial abundance to be 2.9?10(29) cells [corresponding to 4.1 petagram (Pg) C and ~0.6% of Earth's total living biomass]. This estimate of subseafloor sedimentary microbial abundance is roughly equal to previous estimates of total microbial abundance in seawater and total microbial abundance in soil. It is much lower than previous estimates of subseafloor sedimentary microbial abundance. In consequence, we estimate Earth's total number of microbes and total living biomass to be, respectively, 50-78% and 10-45% lower than previous estimates. PMID- 22927372 TI - Escape from Adaptive Conflict follows from weak functional trade-offs and mutational robustness. AB - A fundamental question in molecular evolution is how proteins can adapt to new functions while being conserved for an existing function at the same time. Several theoretical models have been put forward to explain this apparent paradox. The most popular models include neofunctionalization, subfunctionalization (SUBF) by degenerative mutations, and dosage models. All of these models focus on adaptation after gene duplication. A newly proposed model named "Escape from Adaptive Conflict" (EAC) includes adaptive processes before and after gene duplication that lead to multifunctional proteins, and divergence (SUBF). Support for the importance of multifunctionality for the evolution of new protein functions comes from two experimental observations. First, many enzymes have highly evolvable promiscuous side activities. Second, different structural states of the same protein can be associated with different functions. How these observations may be related to the EAC model, under which conditions EAC is possible, and how the different models relate to each other is still unclear. Here, we present a theoretical framework that uses biophysical principles to infer the roles of functional promiscuity, gene dosage, gene duplication, point mutations, and selection pressures in the evolution of proteins. We find that selection pressures can determine whether neofunctionalization or SUBF is the more likely evolutionary process. Multifunctional proteins, arising during EAC evolution, allow rapid adaptation independent of gene duplication. This becomes a crucial advantage when gene duplications are rare. Finally, we propose that an increase in mutational robustness, not necessarily functional optimization, can be the sole driving force behind SUBF. PMID- 22927373 TI - Targeting collagen strands by photo-triggered triple-helix hybridization. AB - Collagen remodeling is an integral part of tissue development, maintenance, and regeneration, but excessive remodeling is associated with various pathologic conditions. The ability to target collagens undergoing remodeling could lead to new diagnostics and therapeutics as well as applications in regenerative medicine; however, such collagens are often degraded and denatured, making them difficult to target with conventional approaches. Here, we present caged collagen mimetic peptides (CMPs) that can be photo-triggered to fold into triple helix and bind to collagens denatured by heat or by matrix metalloproteinase (MMP) digestion. Peptide-binding assays indicate that the binding is primarily driven by stereo-selective triple-helical hybridization between monomeric CMPs of high triple-helical propensity and denatured collagen strands. Photo-triggered hybridization allows specific staining of collagen chains in protein gels as well as photo-patterning of collagen and gelatin substrates. In vivo experiments demonstrate that systemically delivered CMPs can bind to collagens in bones, as well as prominently in articular cartilages and tumors characterized by high MMP activity. We further show that CMP-based probes can detect abnormal bone growth activity in a mouse model of Marfan syndrome. This is an entirely new way to target the microenvironment of abnormal tissues and could lead to new opportunities for management of numerous pathologic conditions associated with collagen remodeling and high MMP activity. PMID- 22927374 TI - In situ observation of peptide bond formation at the water-air interface. AB - We report unambiguous spectroscopic evidence of peptide bond formation at the air water interface, yielding a possible mechanism providing insight into the formation of modern ribosomal peptide bonds, and a means for the emergence of peptides on early Earth. Protein synthesis in aqueous environments, facilitated by sequential amino acid condensation forming peptides, is a ubiquitous process in modern biology, and a fundamental reaction necessary in prebiotic chemistry. Such reactions, however, are condensation reactions, requiring the elimination of a water molecule for every peptide bond formed, and are thus unfavorable in aqueous environments both from a thermodynamic and kinetic point of view. We use the hydrophobic environment of the air-water interface as a favorable venue for peptide bond synthesis, and demonstrate the occurrence of this chemistry with in situ techniques using Langmuir-trough methods and infrared reflection absorption spectroscopy. Leucine ethyl ester (a small amino acid ester) first partitions to the water surface, then coordinates with Cu(2+) ions at the interface, and subsequently undergoes a condensation reaction selectively forming peptide bonds at the air-water interface. PMID- 22927375 TI - Near-atomic resolution structural model of the yeast 26S proteasome. AB - The 26S proteasome operates at the executive end of the ubiquitin-proteasome pathway. Here, we present a cryo-EM structure of the Saccharomyces cerevisiae 26S proteasome at a resolution of 7.4 A or 6.7 A (Fourier-Shell Correlation of 0.5 or 0.3, respectively). We used this map in conjunction with molecular dynamics-based flexible fitting to build a near-atomic resolution model of the holocomplex. The quality of the map allowed us to assign alpha-helices, the predominant secondary structure element of the regulatory particle subunits, throughout the entire map. We were able to determine the architecture of the Rpn8/Rpn11 heterodimer, which had hitherto remained elusive. The MPN domain of Rpn11 is positioned directly above the AAA-ATPase N-ring suggesting that Rpn11 deubiquitylates substrates immediately following commitment and prior to their unfolding by the AAA-ATPase module. The MPN domain of Rpn11 dimerizes with that of Rpn8 and the C-termini of both subunits form long helices, which are integral parts of a coiled-coil module. Together with the C-terminal helices of the six PCI-domain subunits they form a very large coiled-coil bundle, which appears to serve as a flexible anchoring device for all the lid subunits. PMID- 22927376 TI - Regulating synthetic gene networks in 3D materials. AB - Combining synthetic biology and materials science will enable more advanced studies of cellular regulatory processes, in addition to facilitating therapeutic applications of engineered gene networks. One approach is to couple genetic inducers into biomaterials, thereby generating 3D microenvironments that are capable of controlling intrinsic and extrinsic cellular events. Here, we have engineered biomaterials to present the genetic inducer, IPTG, with different modes of activating genetic circuits in vitro and in vivo. Gene circuits were activated in materials with IPTG embedded within the scaffold walls or chemically linked to the matrix. In addition, systemic applications of IPTG were used to induce genetic circuits in cells encapsulated into materials and implanted in vivo. The flexibility of modifying biomaterials with genetic inducers allows for patterned placement of these inducers that can be used to generate distinct patterns of gene expression. Together, these genetically interactive materials can be used to characterize genetic circuits in environments that more closely mimic cells' natural 3D settings, to better explore complex cell-matrix and cell cell interactions, and to facilitate therapeutic applications of synthetic biology. PMID- 22927377 TI - Structure and dynamics of protein waters revealed by radiolysis and mass spectrometry. AB - Water is critical for the structure, stability, and functions of macromolecules. Diffraction and NMR studies have revealed structure and dynamics of bound waters at atomic resolution. However, localizing the sites and measuring the dynamics of bound waters, particularly on timescales relevant to catalysis and macromolecular assembly, is quite challenging. Here we demonstrate two techniques: first, temperature-dependent radiolytic hydroxyl radical labeling with a mass spectrometry (MS)-based readout to identify sites of bulk and bound water interactions with surface and internal residue side chains, and second, H(2)(18)O radiolytic exchange coupled MS to measure the millisecond dynamics of bound water interactions with various internal residue side chains. Through an application of the methods to cytochrome c and ubiquitin, we identify sites of water binding and measure the millisecond dynamics of bound waters in protein crevices. As these MS based techniques are very sensitive and not protein size limited, they promise to provide unique insights into protein-water interactions and water dynamics for both small and large proteins and their complexes. PMID- 22927378 TI - Cancer radiotherapy based on femtosecond IR laser-beam filamentation yielding ultra-high dose rates and zero entrance dose. AB - Since the invention of cancer radiotherapy, its primary goal has been to maximize lethal radiation doses to the tumor volume while keeping the dose to surrounding healthy tissues at zero. Sadly, conventional radiation sources (gamma or X rays, electrons) used for decades, including multiple or modulated beams, inevitably deposit the majority of their dose in front or behind the tumor, thus damaging healthy tissue and causing secondary cancers years after treatment. Even the most recent pioneering advances in costly proton or carbon ion therapies can not completely avoid dose buildup in front of the tumor volume. Here we show that this ultimate goal of radiotherapy is yet within our reach: Using intense ultra short infrared laser pulses we can now deposit a very large energy dose at unprecedented microscopic dose rates (up to 10(11) Gy/s) deep inside an adjustable, well-controlled macroscopic volume, without any dose deposit in front or behind the target volume. Our infrared laser pulses produce high density avalanches of low energy electrons via laser filamentation, a phenomenon that results in a spatial energy density and temporal dose rate that both exceed by orders of magnitude any values previously reported even for the most intense clinical radiotherapy systems. Moreover, we show that (i) the type of final damage and its mechanisms in aqueous media, at the molecular and biomolecular level, is comparable to that of conventional ionizing radiation, and (ii) at the tumor tissue level in an animal cancer model, the laser irradiation method shows clear therapeutic benefits. PMID- 22927379 TI - Realistic simulations of the coupling between the protomotive force and the mechanical rotation of the F0-ATPase. AB - The molecular origin of the action of the F(0) proton gradient-driven rotor presents a major puzzle despite significant structural advances. Although important conceptual models have provided guidelines of how such systems should work, it has been challenging to generate a structure-based molecular model using physical principles that will consistently lead to the unidirectional proton driven rotational motion during ATP synthesis. This work uses a coarse-grained (CG) model to simulate the energetics of the F(0)-ATPase system in the combined space defined by the rotational coordinate and the proton transport (PTR) from the periplasmic side (P) to the cytoplasmic side (N). The model establishes the molecular origin of the rotation, showing that this effect is due to asymmetry in the energetics of the proton path rather than only the asymmetry of the interaction of the Asp on the c-ring helices and Arg on the subunit-a. The simulation provides a clear conceptual background for further exploration of the electrostatic basis of proton-driven mechanochemical systems. PMID- 22927380 TI - Landau spectrum and twin boundaries of bismuth in the extreme quantum limit. AB - The Landau spectrum of bismuth is complex and includes many angle-dependent lines in the extreme quantum limit. The adequacy of single-particle theory to describe this spectrum in detail has been an open issue. Here, we present a study of angle resolved Nernst effect in bismuth, which maps the angle-resolved Landau spectrum for the entire solid angle up to 28 T. The experimental map is in good agreement with the results of a theoretical model with parabolic dispersion for holes and an extended Dirac Hamiltonian for electrons. The angular dependence of additional lines in the Landau spectrum allows us to uncover the mystery of their origin. They correspond to the lines expected for the hole Landau levels in a secondary crystal tilted by 108 degrees , the angle between twinned crystals in bismuth. According to our results, the electron reservoirs of the two identical tilted crystals have different chemical potentials, and carriers across the twin boundary have different concentrations. An exceptional feature of this junction is that it separates two electron-hole compensated reservoirs. The link between this edge singularity and the states wrapping a three-dimensional electron gas in the quantum limit emerges as an outstanding open question. PMID- 22927381 TI - Brown carbon and internal mixing in biomass burning particles. AB - Biomass burning (BB) contributes large amounts of black carbon (BC) and particulate organic matter (POM) to the atmosphere and contributes significantly to the earth's radiation balance. BB particles can be a complicated optical system, with scattering and absorption contributions from BC, internal mixtures of BC and POM, and wavelength-dependent absorption of POM. Large amounts of POM can also be externally mixed. We report on the unique ability of multi-wavelength photo-acoustic measurements of dry and thermal-denuded absorption to deconstruct this complicated wavelength-dependent system of absorption and mixing. Optical measurements of BB particles from the Four Mile Canyon fire near Boulder, Colorado, showed that internal mixtures of BC and POM enhanced absorption by up to 70%. The data supports the assumption that the POM was very weakly absorbing at 532 nm. Enhanced absorption at 404 nm was in excess of 200% above BC absorption and varied as POM mass changed, indicative of absorbing POM. Absorption by internal mixing of BC and POM contributed 19( +/- 8)% to total 404 nm absorption, while BC alone contributed 54( +/- 16)%. Approximately 83% of POM mass was externally mixed, the absorption of which contributed 27( +/- 15)% to total particle absorption (at 404 nm). The imaginary refractive index and mass absorption efficiency (MAE) of POM at 404 nm changed throughout the sampling period and were found to be 0.007 +/- 0.005 and 0.82 +/- 0.43 m(2) g(-1), respectively. Our analysis shows that the MAE of POM can be biased high by up to 50% if absorption from internal mixing of POM and BC is not included. PMID- 22927382 TI - Fine-tuning gene networks using simple sequence repeats. AB - The parameters in a complex synthetic gene network must be extensively tuned before the network functions as designed. Here, we introduce a simple and general approach to rapidly tune gene networks in Escherichia coli using hypermutable simple sequence repeats embedded in the spacer region of the ribosome binding site. By varying repeat length, we generated expression libraries that incrementally and predictably sample gene expression levels over a 1,000-fold range. We demonstrate the utility of the approach by creating a bistable switch library that programmatically samples the expression space to balance the two states of the switch, and we illustrate the need for tuning by showing that the switch's behavior is sensitive to host context. Further, we show that mutation rates of the repeats are controllable in vivo for stability or for targeted mutagenesis--suggesting a new approach to optimizing gene networks via directed evolution. This tuning methodology should accelerate the process of engineering functionally complex gene networks. PMID- 22927383 TI - Pyranopterin conformation defines the function of molybdenum and tungsten enzymes. AB - We have analyzed the conformations of 319 pyranopterins in 102 protein structures of mononuclear molybdenum and tungsten enzymes. These span a continuum between geometries anticipated for quinonoid dihydro, tetrahydro, and dihydro oxidation states. We demonstrate that pyranopterin conformation is correlated with the protein folds defining the three major mononuclear molybdenum and tungsten enzyme families, and that binding-site micro-tuning controls pyranopterin oxidation state. Enzymes belonging to the bacterial dimethyl sulfoxide reductase (DMSOR) family contain a metal-bis-pyranopterin cofactor, the two pyranopterins of which have distinct conformations, with one similar to the predicted tetrahydro form, and the other similar to the predicted dihydro form. Enzymes containing a single pyranopterin belong to either the xanthine dehydrogenase (XDH) or sulfite oxidase (SUOX) families, and these have pyranopterin conformations similar to those predicted for tetrahydro and dihydro forms, respectively. This work provides keen insight into the roles of pyranopterin conformation and oxidation state in catalysis, redox potential modulation of the metal site, and catalytic function. PMID- 22927384 TI - Universal mechanism for Anderson and weak localization. AB - Localization of stationary waves occurs in a large variety of vibrating systems, whether mechanical, acoustical, optical, or quantum. It is induced by the presence of an inhomogeneous medium, a complex geometry, or a quenched disorder. One of its most striking and famous manifestations is Anderson localization, responsible for instance for the metal-insulator transition in disordered alloys. Yet, despite an enormous body of related literature, a clear and unified picture of localization is still to be found, as well as the exact relationship between its many manifestations. In this paper, we demonstrate that both Anderson and weak localizations originate from the same universal mechanism, acting on any type of vibration, in any dimension, and for any domain shape. This mechanism partitions the system into weakly coupled subregions. The boundaries of these subregions correspond to the valleys of a hidden landscape that emerges from the interplay between the wave operator and the system geometry. The height of the landscape along its valleys determines the strength of the coupling between the subregions. The landscape and its impact on localization can be determined rigorously by solving one special boundary problem. This theory allows one to predict the localization properties, the confining regions, and to estimate the energy of the vibrational eigenmodes through the properties of one geometrical object. In particular, Anderson localization can be understood as a special case of weak localization in a very rough landscape. PMID- 22927385 TI - The Monod-Wyman-Changeux allosteric model accounts for the quaternary transition dynamics in wild type and a recombinant mutant human hemoglobin. AB - The acknowledged success of the Monod-Wyman-Changeux (MWC) allosteric model stems from its efficacy in accounting for the functional behavior of many complex proteins starting with hemoglobin (the paradigmatic case) and extending to channels and receptors. The kinetic aspects of the allosteric model, however, have been often neglected, with the exception of hemoglobin and a few other proteins where conformational relaxations can be triggered by a short and intense laser pulse, and monitored by time-resolved optical spectroscopy. Only recently the application of time-resolved wide-angle X-ray scattering (TR-WAXS), a direct structurally sensitive technique, unveiled the time scale of hemoglobin quaternary structural transition. In order to test the generality of the MWC kinetic model, we carried out a TR-WAXS investigation in parallel on adult human hemoglobin and on a recombinant protein (HbYQ) carrying two mutations at the active site [Leu(B10)Tyr and His(E7)Gln]. HbYQ seemed an ideal test because, although exhibiting allosteric properties, its kinetic and structural properties are different from adult human hemoglobin. The structural dynamics of HbYQ unveiled by TR-WAXS can be quantitatively accounted for by the MWC kinetic model. Interestingly, the main structural change associated with the R-T allosteric transition (i.e., the relative rotation and translation of the dimers) is approximately 10-fold slower in HbYQ, and the drop in the allosteric transition rate with ligand saturation is steeper. Our results extend the general validity of the MWC kinetic model and reveal peculiar thermodynamic properties of HbYQ. A possible structural interpretation of the characteristic kinetic behavior of HbYQ is also discussed. PMID- 22927386 TI - Manipulating superconducting fluctuations by the Little-Parks-de Gennes effect in ultrasmall Al loops. AB - The destruction of superconducting phase coherence by quantum fluctuations and the control of these fluctuations are a problem of long-standing interest, with recent impetus provided by the relevance of these issues to the pursuit of high temperature superconductivity. Building on the work of Little and Parks, de Gennes predicted more than three decades ago that superconductivity could be destroyed near half-integer-flux quanta in ultrasmall loops, resulting in a destructive regime, and restored by adding a superconducting side branch, which does not affect the flux quantization condition. We report the experimental observation of this Little-Parks-de Gennes effect in Al loops prepared by advanced e-beam lithography. We show that the effect can be used to restore the lost phase coherence by employing side branches. PMID- 22927387 TI - Arthropods in amber from the Triassic Period. AB - The occurrence of arthropods in amber exclusively from the Cretaceous and Cenozoic is widely regarded to be a result of the production and preservation of large amounts of tree resin beginning ca. 130 million years (Ma) ago. Abundant 230 million-year-old amber from the Late Triassic (Carnian) of northeastern Italy has previously yielded myriad microorganisms, but we report here that it also preserves arthropods some 100 Ma older than the earliest prior records in amber. The Triassic specimens are a nematoceran fly (Diptera) and two disparate species of mites, Triasacarus fedelei gen. et sp. nov., and Ampezzoa triassica gen. et sp. nov. These mites are the oldest definitive fossils of a group, the Eriophyoidea, which includes the gall mites and comprises at least 3,500 Recent species, 97% of which feed on angiosperms and represents one of the most specialized lineages of phytophagous arthropods. Antiquity of the gall mites in much their extant form was unexpected, particularly with the Triassic species already having many of their present-day features (such as only two pairs of legs); further, it establishes conifer feeding as an ancestral trait. Feeding by the fossil mites may have contributed to the formation of the amber droplets, but we find that the abundance of amber during the Carnian (ca. 230 Ma) is globally anomalous for the pre-Cretaceous and may, alternatively, be related to paleoclimate. Further recovery of arthropods in Carnian-aged amber is promising and will have profound implications for understanding the evolution of terrestrial members of the most diverse phylum of organisms. PMID- 22927388 TI - Foldon unfolding mediates the interconversion between M(pro)-C monomer and 3D domain-swapped dimer. AB - The C-terminal domain (M(pro)-C) of SARS-CoV main protease adopts two different fold topologies, a monomer and a 3D domain-swapped dimer. Here, we report that M(pro)-C can reversibly interconvert between these two topological states under physiological conditions. Although the swapped alpha(1)-helix is fully buried inside the protein hydrophobic core, the interconversion of M(pro)-C is carried out without the hydrophobic core being exposed to solvent. The 3D domain swapping of M(pro)-C is activated by an order-to-disorder transition of its C-terminal alpha(5)-helix foldon. Unfolding of this foldon promotes self-association of M(pro)-C monomers and functions to mediate the 3D domain swapping, without which M(pro)-C can no longer form the domain-swapped dimer. Taken together, we propose that there exists a special dimeric intermediate enabling the protein core to unpack and the alpha(1)-helices to swap in a hydrophobic environment, which minimizes the energy cost of the 3D domain-swapping process. PMID- 22927389 TI - Computational design of genomic transcriptional networks with adaptation to varying environments. AB - Transcriptional profiling has been widely used as a tool for unveiling the coregulations of genes in response to genetic and environmental perturbations. These coregulations have been used, in a few instances, to infer global transcriptional regulatory models. Here, using the large amount of transcriptomic information available for the bacterium Escherichia coli, we seek to understand the design principles determining the regulation of its transcriptome. Combining transcriptomic and signaling data, we develop an evolutionary computational procedure that allows obtaining alternative genomic transcriptional regulatory network (GTRN) that still maintains its adaptability to dynamic environments. We apply our methodology to an E. coli GTRN and show that it could be rewired to simpler transcriptional regulatory structures. These rewired GTRNs still maintain the global physiological response to fluctuating environments. Rewired GTRNs contain 73% fewer regulated operons. Genes with similar functions and coordinated patterns of expression across environments are clustered into longer regulated operons. These synthetic GTRNs are more sensitive and show a more robust response to challenging environments. This result illustrates that the natural configuration of E. coli GTRN does not necessarily result from selection for robustness to environmental perturbations, but that evolutionary contingencies may have been important as well. We also discuss the limitations of our methodology in the context of the demand theory. Our procedure will be useful as a novel way to analyze global transcription regulation networks and in synthetic biology for the de novo design of genomes. PMID- 22927390 TI - Chemical synthesis and X-ray structure of a heterochiral {D-protein antagonist plus vascular endothelial growth factor} protein complex by racemic crystallography. AB - Total chemical synthesis was used to prepare the mirror image (D-protein) form of the angiogenic protein vascular endothelial growth factor (VEGF-A). Phage display against D-VEGF-A was used to screen designed libraries based on a unique small protein scaffold in order to identify a high affinity ligand. Chemically synthesized D- and L- forms of the protein ligand showed reciprocal chiral specificity in surface plasmon resonance binding experiments: The L-protein ligand bound only to D-VEGF-A, whereas the D-protein ligand bound only to L-VEGF A. The D-protein ligand, but not the L-protein ligand, inhibited the binding of natural VEGF(165) to the VEGFR1 receptor. Racemic protein crystallography was used to determine the high resolution X-ray structure of the heterochiral complex consisting of {D-protein antagonist + L-protein form of VEGF-A}. Crystallization of a racemic mixture of these synthetic proteins in appropriate stoichiometry gave a racemic protein complex of more than 73 kDa containing six synthetic protein molecules. The structure of the complex was determined to a resolution of 1.6 A. Detailed analysis of the interaction between the D-protein antagonist and the VEGF-A protein molecule showed that the binding interface comprised a contact surface area of approximately 800 A(2) in accord with our design objectives, and that the D-protein antagonist binds to the same region of VEGF-A that interacts with VEGFR1-domain 2. PMID- 22927391 TI - Avoiding mangrove destruction by avoiding carbon dioxide emissions. PMID- 22927392 TI - Seasonal migration to high latitudes results in major reproductive benefits in an insect. AB - Little is known of the population dynamics of long-range insect migrants, and it has been suggested that the annual journeys of billions of nonhardy insects to exploit temperate zones during summer represent a sink from which future generations seldom return (the "Pied Piper" effect). We combine data from entomological radars and ground-based light traps to show that annual migrations are highly adaptive in the noctuid moth Autographa gamma (silver Y), a major agricultural pest. We estimate that 10-240 million immigrants reach the United Kingdom each spring, but that summer breeding results in a fourfold increase in the abundance of the subsequent generation of adults, all of which emigrate southward in the fall. Trajectory simulations show that 80% of emigrants will reach regions suitable for winter breeding in the Mediterranean Basin, for which our population dynamics model predicts a winter carrying capacity only 20% of that of northern Europe during the summer. We conclude not only that poleward insect migrations in spring result in major population increases, but also that the persistence of such species is dependent on summer breeding in high-latitude regions, which requires a fundamental change in our understanding of insect migration. PMID- 22927393 TI - Molecular basis for coupling the plasma membrane to the actin cytoskeleton during clathrin-mediated endocytosis. AB - Dynamic actin filaments are a crucial component of clathrin-mediated endocytosis when endocytic proteins cannot supply enough energy for vesicle budding. Actin cytoskeleton is thought to provide force for membrane invagination or vesicle scission, but how this force is transmitted to the plasma membrane is not understood. Here we describe the molecular mechanism of plasma membrane-actin cytoskeleton coupling mediated by cooperative action of epsin Ent1 and the HIP1R homolog Sla2 in yeast Saccharomyces cerevisiae. Sla2 anchors Ent1 to a stable endocytic coat by an unforeseen interaction between Sla2's ANTH and Ent1's ENTH lipid-binding domains. The ANTH and ENTH domains bind each other in a ligand dependent manner to provide critical anchoring of both proteins to the membrane. The C-terminal parts of Ent1 and Sla2 bind redundantly to actin filaments via a previously unknown phospho-regulated actin-binding domain in Ent1 and the THATCH domain in Sla2. By the synergistic binding to the membrane and redundant interaction with actin, Ent1 and Sla2 form an essential molecular linker that transmits the force generated by the actin cytoskeleton to the plasma membrane, leading to membrane invagination and vesicle budding. PMID- 22927394 TI - Protein cysteine phosphorylation of SarA/MgrA family transcriptional regulators mediates bacterial virulence and antibiotic resistance. AB - Protein posttranslational modifications (PTMs), particularly phosphorylation, dramatically expand the complexity of cellular regulatory networks. Although cysteine (Cys) in various proteins can be subject to multiple PTMs, its phosphorylation was previously considered a rare PTM with almost no regulatory role assigned. We report here that phosphorylation occurs to a reactive cysteine residue conserved in the staphylococcal accessary regulator A (SarA)/MarR family global transcriptional regulator A (MgrA) family of proteins, and is mediated by the eukaryotic-like kinase-phosphatase pair Stk1-Stp1 in Staphylococcus aureus. Cys-phosphorylation is crucial in regulating virulence determinant production and bacterial resistance to vancomycin. Cell wall-targeting antibiotics, such as vancomycin and ceftriaxone, inhibit the kinase activity of Stk1 and lead to decreased Cys-phosphorylation of SarA and MgrA. An in vivo mouse model of infection established that the absence of stp1, which results in elevated protein Cys-phosphorylation, significantly reduces staphylococcal virulence. Our data indicate that Cys-phosphorylation is a unique PTM that can play crucial roles in bacterial signaling and regulation. PMID- 22927395 TI - An injury-response mechanism conserved across kingdoms determines entry of the fungus Trichoderma atroviride into development. AB - A conserved injury-defense mechanism is present in plants and animals, in which the production of reactive oxygen species (ROS) and lipid metabolism are essential to the response. Here, we describe that in the filamentous fungus Trichoderma atroviride, injury results in the formation of asexual reproduction structures restricted to regenerating cells. High-throughput RNA-seq analyses of the response to injury in T. atroviride suggested an oxidative response and activation of calcium-signaling pathways, as well as the participation of lipid metabolism, in this phenomenon. Gene-replacement experiments demonstrated that injury triggers NADPH oxidase (Nox)-dependent ROS production and that Nox1 and NoxR are essential for asexual development in response to damage. We further provide evidence of H(2)O(2) and oxylipin production that, as in plants and animals, may act as signal molecules in response to injury in fungi, suggesting that the three kingdoms share a conserved defense-response mechanism. PMID- 22927396 TI - Delaying aging and the aging-associated decline in protein homeostasis by inhibition of tryptophan degradation. AB - Toxicity of aggregation-prone proteins is thought to play an important role in aging and age-related neurological diseases like Parkinson and Alzheimer's diseases. Here, we identify tryptophan 2,3-dioxygenase (tdo-2), the first enzyme in the kynurenine pathway of tryptophan degradation, as a metabolic regulator of age-related alpha-synuclein toxicity in a Caenorhabditis elegans model. Depletion of tdo-2 also suppresses toxicity of other heterologous aggregation-prone proteins, including amyloid-beta and polyglutamine proteins, and endogenous metastable proteins that are sensors of normal protein homeostasis. This finding suggests that tdo-2 functions as a general regulator of protein homeostasis. Analysis of metabolite levels in C. elegans strains with mutations in enzymes that act downstream of tdo-2 indicates that this suppression of toxicity is independent of downstream metabolites in the kynurenine pathway. Depletion of tdo 2 increases tryptophan levels, and feeding worms with extra L-tryptophan also suppresses toxicity, suggesting that tdo-2 regulates proteotoxicity through tryptophan. Depletion of tdo-2 extends lifespan in these worms. Together, these results implicate tdo-2 as a metabolic switch of age-related protein homeostasis and lifespan. With TDO and Indoleamine 2,3-dioxygenase as evolutionarily conserved human orthologs of TDO-2, intervening with tryptophan metabolism may offer avenues to reducing proteotoxicity in aging and age-related diseases. PMID- 22927398 TI - Fueling fibrosis in chronic hepatitis C. PMID- 22927397 TI - Secreted protein, acidic and rich in cysteine-like 1 (SPARCL1) is down regulated in aggressive prostate cancers and is prognostic for poor clinical outcome. AB - Prostate cancer is the second leading cause of cancer death among United States men. However, disease aggressiveness is varied, with low-grade disease often being indolent and high-grade cancer accounting for the greatest density of deaths. Outcomes are also disparate among men with high-grade prostate cancer, with upwards of 65% having disease recurrence even after primary treatment. Identification of men at risk for recurrence and elucidation of the molecular processes that drive their disease is paramount, as these men are the most likely to benefit from multimodal therapy. We previously showed that androgen-induced expression profiles in prostate development are reactivated in aggressive prostate cancers. Herein, we report the down-regulation of one such gene, Sparcl1, a secreted protein, acidic and rich in cysteine (SPARC) family matricellular protein, during invasive phases of prostate development and regeneration. We further demonstrate a parallel process in prostate cancer, with decreased expression of SPARCL1 in high-grade/metastatic prostate cancer. Mechanistically, we demonstrate that SPARCL1 loss increases the migratory and invasive properties of prostate cancer cells through Ras homolog gene family, member C (RHOC), a known mediator of metastatic progression. By using models incorporating clinicopathologic parameters to predict prostate cancer recurrence after treatment, we show that SPARCL1 loss is a significant, independent prognostic marker of disease progression. Thus, SPARCL1 is a potent regulator of cell migration/invasion and its loss is independently associated with prostate cancer recurrence. PMID- 22927399 TI - Serum Response Factor (SRF)-cofilin-actin signaling axis modulates mitochondrial dynamics. AB - Aberrant mitochondrial function, morphology, and transport are main features of neurodegenerative diseases. To date, mitochondrial transport within neurons is thought to rely mainly on microtubules, whereas actin might mediate short-range movements and mitochondrial anchoring. Here, we analyzed the impact of actin on neuronal mitochondrial size and localization. F-actin enhanced mitochondrial size and mitochondrial number in neurites and growth cones. In contrast, raising G actin resulted in mitochondrial fragmentation and decreased mitochondrial abundance. Cellular F-actin/G-actin levels also regulate serum response factor (SRF)-mediated gene regulation, suggesting a possible link between SRF and mitochondrial dynamics. Indeed, SRF-deficient neurons display neurodegenerative hallmarks of mitochondria, including disrupted morphology, fragmentation, and impaired mitochondrial motility, as well as ATP energy metabolism. Conversely, constitutively active SRF-VP16 induced formation of mitochondrial networks and rescued huntingtin (HTT)-impaired mitochondrial dynamics. Finally, SRF and actin dynamics are connected via the actin severing protein cofilin and its slingshot phosphatase to modulate neuronal mitochondrial dynamics. In summary, our data suggest that the SRF-cofilin-actin signaling axis modulates neuronal mitochondrial function. PMID- 22927400 TI - Insulin stimulation of SREBP-1c processing in transgenic rat hepatocytes requires p70 S6-kinase. AB - Insulin activates sterol regulatory element-binding protein-1c (SREBP-1c) in liver, thereby increasing fatty acid and triglyceride synthesis. We created a line of transgenic rats that produce epitope-tagged human SREBP-1c in liver under control of the constitutive apolipoprotein E promoter/enhancer. This system allows us to dissect the pathway by which insulin stimulates SREBP-1c processing without interference by the insulin-mediated increase in SREBP-1c mRNA. Rats are used because freshly isolated rat hepatocytes respond much more robustly to insulin than do mouse hepatocytes. The data reveal that insulin-mediated stimulation of SREBP-1c processing requires the mechanistic target of rapamycin complex 1 (mTORC1), which also is required for insulin-mediated SREBP-1c mRNA induction. However, in contrast to mRNA induction, insulin stimulation of SREBP 1c processing is blocked by an inhibitor of p70 S6-kinase. The data indicate that the pathways for insulin enhancement of SREBP-1c mRNA and proteolytic processing diverge after mTORC1. Stimulation of processing requires the mTORC1 target p70 S6 kinase, whereas induction of mRNA bypasses this enzyme. Insulin stimulation of both processes is blocked by glucagon. The transgenic rat system will be useful in further defining the molecular mechanism for insulin stimulation of lipid synthesis in liver in normal and diabetic states. PMID- 22927401 TI - Regulation of beta catenin signaling and parathyroid hormone anabolic effects in bone by the matricellular protein periostin. AB - Periostin (Postn) is a matricellular protein preferentially expressed by osteocytes and periosteal osteoblasts in response to mechanical stimulation and parathyroid hormone (PTH). Whether and how periostin expression influences bone anabolism, however, remains unknown. We investigated the skeletal response of adult Postn(-/-) and Postn(+/+) mice to intermittent PTH. Compared with Postn(+/+), Postn(-/-) mice had a lower bone mass, cortical bone volume, and strength response to PTH. PTH-stimulated bone-forming indices were all significantly lower in Postn(-/-) mice, particularly at the periosteum. Furthermore, in vivo stimulation of Wnt-beta-catenin signaling by PTH, as evaluated in TOPGAL reporter mice, was inhibited in the absence of periostin (TOPGAL;Postn(-/-) mice). PTH stimulated periostin and inhibited MEF2C and sclerostin (Sost) expression in bone and osteoblasts in vitro. Recombinant periostin also suppressed Sost expression, which was mediated through the integrin alphaVbeta3 receptor, whereas periostin-blocking antibody prevented inhibition of MEF2C and Sost by PTH. In turn, administration of a Sost-blocking antiboby partially restored the PTH-mediated increase in bone mass in Postn(-/-) mice. In addition, primary osteoblasts from Postn(-/-) mice showed a lower proliferation, mineralization, and migration, both spontaneously and in response to PTH. Osteoblastic gene expression levels confirmed a defect of Postn(-/-) osteoblast differentiation with and without PTH, as well as an increased osteoblast apoptosis in the absence of periostin. These data elucidate the complex role of periostin on bone anabolism, through the regulation of Sost, Wnt beta-catenin signaling, and osteoblast differentiation. PMID- 22927402 TI - Persistent cannabis users show neuropsychological decline from childhood to midlife. AB - Recent reports show that fewer adolescents believe that regular cannabis use is harmful to health. Concomitantly, adolescents are initiating cannabis use at younger ages, and more adolescents are using cannabis on a daily basis. The purpose of the present study was to test the association between persistent cannabis use and neuropsychological decline and determine whether decline is concentrated among adolescent-onset cannabis users. Participants were members of the Dunedin Study, a prospective study of a birth cohort of 1,037 individuals followed from birth (1972/1973) to age 38 y. Cannabis use was ascertained in interviews at ages 18, 21, 26, 32, and 38 y. Neuropsychological testing was conducted at age 13 y, before initiation of cannabis use, and again at age 38 y, after a pattern of persistent cannabis use had developed. Persistent cannabis use was associated with neuropsychological decline broadly across domains of functioning, even after controlling for years of education. Informants also reported noticing more cognitive problems for persistent cannabis users. Impairment was concentrated among adolescent-onset cannabis users, with more persistent use associated with greater decline. Further, cessation of cannabis use did not fully restore neuropsychological functioning among adolescent-onset cannabis users. Findings are suggestive of a neurotoxic effect of cannabis on the adolescent brain and highlight the importance of prevention and policy efforts targeting adolescents. PMID- 22927403 TI - Human blood metabolite timetable indicates internal body time. AB - A convenient way to estimate internal body time (BT) is essential for chronotherapy and time-restricted feeding, both of which use body-time information to maximize potency and minimize toxicity during drug administration and feeding, respectively. Previously, we proposed a molecular timetable based on circadian-oscillating substances in multiple mouse organs or blood to estimate internal body time from samples taken at only a few time points. Here we applied this molecular-timetable concept to estimate and evaluate internal body time in humans. We constructed a 1.5-d reference timetable of oscillating metabolites in human blood samples with 2-h sampling frequency while simultaneously controlling for the confounding effects of activity level, light, temperature, sleep, and food intake. By using this metabolite timetable as a reference, we accurately determined internal body time within 3 h from just two anti-phase blood samples. Our minimally invasive, molecular-timetable method with human blood enables highly optimized and personalized medicine. PMID- 22927404 TI - Interactions between the termini of lumen enzymes and shell proteins mediate enzyme encapsulation into bacterial microcompartments. AB - Bacterial microcompartments (MCPs) are a widespread family of proteinaceous organelles that consist of metabolic enzymes encapsulated within a protein shell. For MCPs to function specific enzymes must be encapsulated. We recently reported that a short N-terminal targeting sequence of propionaldehyde dehydrogenase (PduP) is necessary and sufficient for the packaging of enzymes into a MCP that functions in 1,2-propanediol (1,2-PD) utilization (Pdu) by Salmonella enterica. Here we show that encapsulation is mediated by binding of the PduP targeting sequence to a short C-terminal helix of the PduA shell protein. In vitro studies indicated binding between PduP and PduA (and PduJ) but not other MCP shell proteins. Alanine scanning mutagenesis determined that the key residues involved in binding are E7, I10, and L14 of PduP and H81, V84, and L88 of PduA. In vivo targeting studies indicated that the binding between the N terminus of PduP and the C terminus of PduA is critical for encapsulation of PduP within the Pdu MCP. Structural models suggest that the N terminus of PduP and C terminus of PduA both form helical structures that bind one another via the key residues identified by mutagenesis. Cumulatively, these results show that the N-terminal targeting sequence of PduP promotes its encapsulation by binding to MCP shell proteins. This is a unique report determining the mechanism by which a MCP targeting sequence functions. We propose that specific interactions between the termini of shell proteins and lumen enzymes have general importance for guiding the assembly and the higher level organization of bacterial MCPs. PMID- 22927405 TI - Pathogenic bacterium Helicobacter pylori alters the expression profile of p53 protein isoforms and p53 response to cellular stresses. AB - The p53 protein plays a central role in the prevention of tumorigenesis. Cellular stresses, such as DNA damage and aberrant oncogene activation, trigger induction of p53 that halts cellular proliferation and allows cells to be repaired. If cellular damage is beyond the capability of the repair mechanisms, p53 induces apoptosis or cell cycle arrest, preventing damaged cells from becoming cancerous. However, emerging evidence suggests that the function of p53 needs to be considered as isoform-specific. Here, we report that the expression profile of p53 can be shifted toward inhibitory p53 isoforms by the pathogenic bacterium Helicobacter pylori, which is known for its strong association with gastric cancer and gastric mucosa-associated lymphoid tissue lymphoma. We found that interaction of H. pylori with gastric epithelial cells, mediated via the cag pathogenicity island, induces N-terminally truncated Delta133p53 and Delta160p53 isoforms in human cells. Induction of an orthologous p53 isoform, Delta153p53, was also found in H. pylori-infected Mongolian gerbils. The p53 isoforms inhibit p53 and p73 activities, induce NF-kappaB, and increase survival of infected cells. Expression of Delta133p53, in response to H. pylori infection, is regulated by phosphorylation of c-Jun and activation of activator protein-1 dependent transcription. Together, these results provide unique insights into the regulation of p53 protein and may contribute to the understanding of tumorigenesis associated with H. pylori. PMID- 22927406 TI - Structural and mechanistic insights into bisphenols action provide guidelines for risk assessment and discovery of bisphenol A substitutes. AB - Bisphenol A (BPA) is an industrial compound and a well known endocrine-disrupting chemical with estrogenic activity. The widespread exposure of individuals to BPA is suspected to affect a variety of physiological functions, including reproduction, development, and metabolism. Here we report that the mechanisms by which BPA and two congeners, bisphenol AF and bisphenol C (BPC), bind to and activate estrogen receptors (ER) alpha and beta differ from that used by 17beta estradiol. We show that bisphenols act as partial agonists of ERs by activating the N-terminal activation function 1 regardless of their effect on the C-terminal activation function 2, which ranges from weak agonism (with BPA) to antagonism (with BPC). Crystallographic analysis of the interaction between bisphenols and ERs reveals two discrete binding modes, reflecting the different activities of compounds on ERs. BPA and 17beta-estradiol bind to ERs in a similar fashion, whereas, with a phenol ring pointing toward the activation helix H12, the orientation of BPC accounts for the marked antagonist character of this compound. Based on structural data, we developed a protocol for in silico evaluation of the interaction between bisphenols and ERs or other members of the nuclear hormone receptor family, such as estrogen-related receptor gamma and androgen receptor, which are two known main targets of bisphenols. Overall, this study provides a wealth of tools and information that could be used for the development of BPA substitutes devoid of nuclear hormone receptor-mediated activity and more generally for environmental risk assessment. PMID- 22927408 TI - Signing at the beginning makes ethics salient and decreases dishonest self reports in comparison to signing at the end. AB - Many written forms required by businesses and governments rely on honest reporting. Proof of honest intent is typically provided through signature at the end of, e.g., tax returns or insurance policy forms. Still, people sometimes cheat to advance their financial self-interests-at great costs to society. We test an easy-to-implement method to discourage dishonesty: signing at the beginning rather than at the end of a self-report, thereby reversing the order of the current practice. Using laboratory and field experiments, we find that signing before-rather than after-the opportunity to cheat makes ethics salient when they are needed most and significantly reduces dishonesty. PMID- 22927407 TI - Net -1 frameshifting on a noncanonical sequence in a herpes simplex virus drug resistant mutant is stimulated by nonstop mRNA. AB - Ribosomal frameshifting entails slippage of the translational machinery during elongation. Frameshifting permits expression of more than one polypeptide from an otherwise monocistronic mRNA, and can restore expression of polypeptides in the face of frameshift mutations. A common mutation conferring acyclovir resistance in patients with herpes simplex virus disease deletes one cytosine from a run of six cytosines (C-chord) in the viral thymidine kinase (tk) gene. However, this mutation does not abolish TK activity, which is important for pathogenicity. To investigate how this mutant retains TK activity, we engineered and analyzed viruses expressing epitope-tagged TK. We found that the mutant's TK activity can be accounted for by low levels of full-length TK polypeptide produced by net -1 frameshifting during translation. The efficiency of frameshifting was relatively high, 3-5%, as the polypeptide from the reading frame generated by the deletion, which lacks stop codons (nonstop), was poorly expressed mainly because of inefficient protein synthesis. Stop codons introduced into this reading frame greatly increased its expression, but greatly decreased the level of full-length TK, indicating that frameshifting is strongly stimulated by a new mechanism, nonstop mRNA, which we hypothesize involves stalling of ribosomes on the polyA tail. Mutational studies indicated that frameshifting occurs on or near the C chord, a region lacking a canonical slippery sequence. Nonstop stimulation of frameshifting also occurred when the C-chord was replaced with a canonical slippery sequence from HIV. This mechanism thus permits biologically and clinically relevant TK synthesis, and may occur more generally. PMID- 22927409 TI - An insect-specific P450 oxidative decarbonylase for cuticular hydrocarbon biosynthesis. AB - Insects use hydrocarbons as cuticular waterproofing agents and as contact pheromones. Although their biosynthesis from fatty acyl precursors is well established, the last step of hydrocarbon biosynthesis from long-chain fatty aldehydes has remained mysterious. We show here that insects use a P450 enzyme of the CYP4G family to oxidatively produce hydrocarbons from aldehydes. Oenocyte directed RNAi knock-down of Drosophila CYP4G1 or NADPH-cytochrome P450 reductase results in flies deficient in cuticular hydrocarbons, highly susceptible to desiccation, and with reduced viability upon adult emergence. The heterologously expressed enzyme converts C(18)-trideuterated octadecanal to C(17)-trideuterated heptadecane, showing that the insect enzyme is an oxidative decarbonylase that catalyzes the cleavage of long-chain aldehydes to hydrocarbons with the release of carbon dioxide. This process is unlike cyanobacteria that use a nonheme diiron decarbonylase to make alkanes from aldehydes with the release of formate. The unique and highly conserved insect CYP4G enzymes are a key evolutionary innovation that allowed their colonization of land. PMID- 22927410 TI - Endonuclease VIII-like 1 (NEIL1) promotes short-term spatial memory retention and protects from ischemic stroke-induced brain dysfunction and death in mice. AB - Recent findings suggest that neurons can efficiently repair oxidatively damaged DNA, and that both DNA damage and repair are enhanced by activation of excitatory glutamate receptors. However, in pathological conditions such as ischemic stroke, excessive DNA damage can trigger the death of neurons. Oxidative DNA damage is mainly repaired by base excision repair (BER), a process initiated by DNA glycosylases that recognize and remove damaged DNA bases. Endonuclease VIII-like 1 (NEIL1) is a DNA glycosylase that recognizes a broad range of oxidative lesions. Here, we show that mice lacking NEIL1 exhibit impaired memory retention in a water maze test, but no abnormalities in tests of motor performance, anxiety, or fear conditioning. NEIL1 deficiency results in increased brain damage and a defective functional outcome in a focal ischemia/reperfusion model of stroke. The incision capacity on a 5-hydroxyuracil-containing bubble substrate was lower in the ipsilateral side of ischemic brains and in the mitochondrial lysates of unstressed old NEIL1-deficient mice. These results indicate that NEIL1 plays an important role in learning and memory and in protection of neurons against ischemic injury. PMID- 22927411 TI - Evolution of multiple, mutually orthogonal prolyl-tRNA synthetase/tRNA pairs for unnatural amino acid mutagenesis in Escherichia coli. AB - The site-specific incorporation of unnatural amino acids (UAAs) into proteins in living cells relies on an engineered tRNA/aminoacyl-tRNA synthetase (tRNA/aaRS) pair, orthogonal to the host cell, to deliver the UAA of choice in response to a unique nonsense or frameshift codon. Here we report the generation of mutually orthogonal prolyl-tRNA/prolyl-tRNA synthase (ProRS) pairs derived from an archaebacterial ancestor for use in Escherichia coli. By reprogramming the anticodon-binding pocket of Pyrococcus horikoshii ProRS (PhProRS), we were able to identify synthetase variants that recognize engineered Archaeoglobus fulgidus prolyl-tRNAs (Af-tRNA(Pro)) with three different anticodons: CUA, AGGG, and CUAG. Several of these evolved PhProRSs show specificity toward a particular anticodon variant of Af-tRNA(Pro), whereas others are promiscuous. Further evolution of the Af-tRNA(Pro) led to a variant exhibiting significantly improved amber suppression efficiency. Availability of a prolyl-tRNA/aaRS pair should enable site-specific incorporation of proline analogs and other N-modified UAAs into proteins in E. coli. The evolution of mutually orthogonal prolyl-tRNA/ProRS pairs demonstrates the plasticity of the tRNA-aaRS interface and should facilitate the incorporation of multiple, distinct UAAs into proteins. PMID- 22927412 TI - No third-party punishment in chimpanzees. AB - Punishment can help maintain cooperation by deterring free-riding and cheating. Of particular importance in large-scale human societies is third-party punishment in which individuals punish a transgressor or norm violator even when they themselves are not affected. Nonhuman primates and other animals aggress against conspecifics with some regularity, but it is unclear whether this is ever aimed at punishing others for noncooperation, and whether third-party punishment occurs at all. Here we report an experimental study in which one of humans' closest living relatives, chimpanzees (Pan troglodytes), could punish an individual who stole food. Dominants retaliated when their own food was stolen, but they did not punish when the food of third-parties was stolen, even when the victim was related to them. Third-party punishment as a means of enforcing cooperation, as humans do, might therefore be a derived trait in the human lineage. PMID- 22927413 TI - Heritable yeast prions have a highly organized three-dimensional architecture with interfiber structures. AB - Yeast prions constitute a "protein-only" mechanism of inheritance that is widely deployed by wild yeast to create diverse phenotypes. One of the best characterized prions, [PSI(+)], is governed by a conformational change in the prion domain of Sup35, a translation-termination factor. When this domain switches from its normal soluble form to an insoluble amyloid, the ensuing change in protein synthesis creates new traits. Two factors make these traits heritable: (i) the amyloid conformation is self-templating; and (ii) the protein-remodeling factor heat-shock protein (Hsp)104 (acting together with Hsp70 chaperones) partitions the template to daughter cells with high fidelity. Prions formed by several other yeast proteins create their own phenotypes but share the same mechanistic basis of inheritance. Except for the amyloid fibril itself, the cellular architecture underlying these protein-based elements of inheritance is unknown. To study the 3D arrangement of prion assemblies in their cellular context, we examined yeast [PSI(+)] prions in the native, hydrated state in situ, taking advantage of recently developed methods for cryosectioning of vitrified cells. Cryo-electron tomography of the vitrified sections revealed the prion assemblies as aligned bundles of regularly spaced fibrils in the cytoplasm with no bounding structures. Although the fibers were widely spaced, other cellular complexes, such as ribosomes, were excluded from the fibril arrays. Subtomogram image averaging, made possible by the organized nature of the assemblies, uncovered the presence of an additional array of densities between the fibers. We suggest these structures constitute a self-organizing mechanism that coordinates fiber deposition and the regulation of prion inheritance. PMID- 22927414 TI - Unifying the spatial epidemiology and molecular evolution of emerging epidemics. AB - We introduce a conceptual bridge between the previously unlinked fields of phylogenetics and mathematical spatial ecology, which enables the spatial parameters of an emerging epidemic to be directly estimated from sampled pathogen genome sequences. By using phylogenetic history to correct for spatial autocorrelation, we illustrate how a fundamental spatial variable, the diffusion coefficient, can be estimated using robust nonparametric statistics, and how heterogeneity in dispersal can be readily quantified. We apply this framework to the spread of the West Nile virus across North America, an important recent instance of spatial invasion by an emerging infectious disease. We demonstrate that the dispersal of West Nile virus is greater and far more variable than previously measured, such that its dissemination was critically determined by rare, long-range movements that are unlikely to be discerned during field observations. Our results indicate that, by ignoring this heterogeneity, previous models of the epidemic have substantially overestimated its basic reproductive number. More generally, our approach demonstrates that easily obtainable genetic data can be used to measure the spatial dynamics of natural populations that are otherwise difficult or costly to quantify. PMID- 22927415 TI - Structure of Nectin-2 reveals determinants of homophilic and heterophilic interactions that control cell-cell adhesion. AB - Nectins are members of the Ig superfamily that mediate cell-cell adhesion through homophilic and heterophilic interactions. We have determined the crystal structure of the nectin-2 homodimer at 1.3 A resolution. Structural analysis and complementary mutagenesis studies reveal the basis for recognition and selectivity among the nectin family members. Notably, the close proximity of charged residues at the dimer interface is a major determinant of the binding affinities associated with homophilic and heterophilic interactions within the nectin family. Our structural and biochemical data provide a mechanistic basis to explain stronger heterophilic versus weaker homophilic interactions among these family members and also offer insights into nectin-mediated transinteractions between engaging cells. PMID- 22927416 TI - Predictive computation of genomic logic processing functions in embryonic development. AB - Gene regulatory networks (GRNs) control the dynamic spatial patterns of regulatory gene expression in development. Thus, in principle, GRN models may provide system-level, causal explanations of developmental process. To test this assertion, we have transformed a relatively well-established GRN model into a predictive, dynamic Boolean computational model. This Boolean model computes spatial and temporal gene expression according to the regulatory logic and gene interactions specified in a GRN model for embryonic development in the sea urchin. Additional information input into the model included the progressive embryonic geometry and gene expression kinetics. The resulting model predicted gene expression patterns for a large number of individual regulatory genes each hour up to gastrulation (30 h) in four different spatial domains of the embryo. Direct comparison with experimental observations showed that the model predictively computed these patterns with remarkable spatial and temporal accuracy. In addition, we used this model to carry out in silico perturbations of regulatory functions and of embryonic spatial organization. The model computationally reproduced the altered developmental functions observed experimentally. Two major conclusions are that the starting GRN model contains sufficiently complete regulatory information to permit explanation of a complex developmental process of gene expression solely in terms of genomic regulatory code, and that the Boolean model provides a tool with which to test in silico regulatory circuitry and developmental perturbations. PMID- 22927417 TI - Putative DNA/RNA helicase Schlafen-11 (SLFN11) sensitizes cancer cells to DNA damaging agents. AB - DNA-damaging agents (DDAs) constitute the backbone of treatment for most human tumors. Here we used the National Cancer Institute Antitumor Cell Line Panel (the NCI-60) to identify predictors of cancer cell response to topoisomerase I (Top1) inhibitors, a widely used class of DDAs. We assessed the NCI-60 transcriptome using Affymetrix Human Exon 1.0 ST microarrays and correlated the in vitro activity of four Top1 inhibitors with gene expression in the 60 cell lines. A single gene, Schlafen-11 (SLFN11), showed an extremely significant positive correlation with the response not only to Top1 inhibitors, but also to Top2 inhibitors, alkylating agents, and DNA synthesis inhibitors. Using cells with endogenously high and low SLFN11 expression and siRNA-mediated silencing, we show that SLFN11 is causative in determining cell death and cell cycle arrest in response to DDAs in cancer cells from different tissues of origin. We next analyzed SLFN11 expression in ovarian and colorectal cancers and normal corresponding tissues from The Cancer Genome Atlas database and observed that SLFN11 has a wide expression range. We also observed that high SLFN11 expression independently predicts overall survival in a group of ovarian cancer patients treated with cisplatin-containing regimens. We conclude that SLFN11 expression is causally associated with the activity of DDAs in cancer cells, has a broad expression range in colon and ovarian adenocarcinomas, and may behave as a biomarker for prediction of response to DDAs in the clinical setting. PMID- 22927418 TI - Structural basis for entropy-driven cellulose binding by a type-A cellulose binding module (CBM) and bacterial expansin. AB - Components of modular cellulases, type-A cellulose-binding modules (CBMs) bind to crystalline cellulose and enhance enzyme effectiveness, but structural details of the interaction are uncertain. We analyzed cellulose binding by EXLX1, a bacterial expansin with ability to loosen plant cell walls and whose domain D2 has type-A CBM characteristics. EXLX1 strongly binds to crystalline cellulose via D2, whereas its affinity for soluble cellooligosaccharides is weak. Calorimetry indicated cellulose binding was largely entropically driven. We solved the crystal structures of EXLX1 complexed with cellulose-like oligosaccharides to find that EXLX1 binds the ligands through hydrophobic interactions of three linearly arranged aromatic residues in D2. The crystal structures revealed a unique form of ligand-mediated dimerization, with the oligosaccharide sandwiched between two D2 domains in opposite polarity. This report clarifies the molecular target of expansin and the specific molecular interactions of a type-A CBM with cellulose. PMID- 22927419 TI - Photoperiodic regulation of the C-repeat binding factor (CBF) cold acclimation pathway and freezing tolerance in Arabidopsis thaliana. AB - The CBF (C-repeat binding factor) pathway has a major role in plant cold acclimation, the process whereby certain plants increase in freezing tolerance in response to low nonfreezing temperatures. In Arabidopsis thaliana, the pathway is characterized by rapid cold induction of CBF1, CBF2, and CBF3, which encode transcriptional activators, followed by induction of CBF-targeted genes that impart freezing tolerance. At warm temperatures, CBF transcript levels are low, but oscillate due to circadian regulation with peak expression occurring at 8 h after dawn (zeitgeber time 8; ZT8). Here, we establish that the CBF pathway is also regulated by photoperiod at warm temperatures. At ZT8, CBF transcript levels in short-day (SD; 8-h photoperiod) plants were three- to fivefold higher than in long-day plants (LD; 16-h photoperiod). Moreover, the freezing tolerance of SD plants was greater than that of LD plants. Genetic analysis indicated that phytochrome B (PHYB) and two phytochrome-interacting factors, PIF4 and PIF7, act to down-regulate the CBF pathway and freezing tolerance under LD conditions. Down regulation of the CBF pathway in LD plants correlated with higher PIF4 and PIF7 transcript levels and greater stability of the PIF4 and PIF7 proteins under LD conditions. Our results indicate that during the warm LD growing season, the CBF pathway is actively repressed by PHYB, PIF4, and PIF7, thus mitigating allocation of energy and nutrient resources toward unneeded frost protection. This repression is relieved by shortening day length resulting in up-regulation of the CBF pathway and increased freezing tolerance in preparation for coming cold temperatures. PMID- 22927420 TI - Regulation of planar growth by the Arabidopsis AGC protein kinase UNICORN. AB - The spatial coordination of growth is of central importance for the regulation of plant tissue architecture. Individual layers, such as the epidermis, are clonally propagated and structurally maintained by symmetric cell divisions that are oriented along the plane of the layer. The developmental control of this process is poorly understood. The simple cellular basis and sheet-like structure of Arabidopsis integuments make them an attractive model system to address planar growth. Here we report on the characterization of the Arabidopsis UNICORN (UCN) gene. Analysis of ucn integuments reveals localized distortion of planar growth, eventually resulting in an ectopic multicellular protrusion. In addition, ucn mutants exhibit ectopic growth in filaments and petals, as well as aberrant embryogenesis. We further show that UCN encodes an active AGC VIII kinase. Genetic, biochemical, and cell biological data suggest that UCN suppresses ectopic growth in integuments by directly repressing the KANADI transcription factor ABERRANT TESTA SHAPE. Our findings indicate that UCN represents a unique plant growth regulator that maintains planar growth of integuments by repressing a developmental regulator involved in the control of early integument growth and polarity. PMID- 22927421 TI - Selective complexity and adaptive mortuary behavior. PMID- 22927423 TI - Neural coding and perceptual detection in the primate somatosensory thalamus. AB - The contribution of the sensory thalamus to perception and decision making is not well understood. We addressed this problem by recording single neurons in the ventral posterior lateral (VPL) nucleus of the somatosensory thalamus while trained monkeys judged the presence or absence of a vibrotactile stimulus of variable amplitude applied to the skin of a fingertip. We found that neurons in the VPL nucleus modulated their firing rate as a function of stimulus amplitude, and that such modulations accounted for the monkeys' overall psychophysical performance. These neural responses did not predict the animals' decision reports in individual trials, however. Moreover, the sensitivity to changes in stimulus amplitude was similar when the monkeys' performed the detection task and when they were not required to report stimulus detection. These results suggest that the primate somatosensory thalamus likely provides a reliable neural representation of the sensory input to the cerebral cortex, where sensory information is transformed and combined with other cognitive components associated with behavioral performance. PMID- 22927424 TI - Modeling early bactericidal activity in murine tuberculosis provides insights into the activity of isoniazid and pyrazinamide. AB - Standard tuberculosis (TB) treatment includes an initial regimen containing drugs that are both rapidly bactericidal (isoniazid) and sterilizing (rifampin and pyrazinamide), and ethambutol to help prevent the emergence of drug resistance. Antagonism between isoniazid and pyrazinamide has been demonstrated in a TB treatment mouse model. Because isoniazid's bactericidal activity is greatest during the initial two treatment days, we hypothesized that removing isoniazid after the second day would increase the effectiveness of the standard regimen. To test this hypothesis, we developed a mouse model to measure the early bactericidal activity (EBA) of drug regimens designed to analyze the essentiality of both isoniazid and pyrazinamide during the first 14 d of therapy. Our results clearly indicate that discontinuation of isoniazid after the second day of treatment increases the EBA of standard therapy in the mouse model, whereas omitting pyrazinamide during the first 14 d was detrimental. Substitution of moxifloxacin for isoniazid on day 3 did not increase the EBA compared with only removing isoniazid after day 2. Our data show that a mouse model can be used to analyze the EBA of TB drugs, and our findings support pursuing clinical trials to evaluate the possible benefit of removing isoniazid after the first 2 treatment days. PMID- 22927425 TI - Memory CD4+ T-cell-mediated protection depends on secondary effectors that are distinct from and superior to primary effectors. AB - Whether differences between naive cell-derived primary (1 degrees ) and memory cell-derived secondary (2 degrees ) CD4(+) T-cell effectors contribute to protective recall responses is unclear. Here, we compare these effectors directly after influenza A virus infection. Both develop with similar kinetics, but 2 degrees effectors accumulate in greater number in the infected lung and are the critical component of memory CD4(+) T-cell-mediated protection against influenza A virus, independent of earlier-acting memory-cell helper functions. Phenotypic, functional, and transcriptome analyses indicate that 2 degrees effectors share organ-specific expression patterns with 1 degrees effectors but are more multifunctional, with more multicytokine (IFN-gamma(+)/IL-2(+)/TNF(+))-producing cells and contain follicular helper T-cell populations not only in the spleen and draining lymph nodes but also in the lung. In addition, they express more CD127 and NKG2A but less ICOS and Lag-3 than 1 degrees effectors and express higher levels of several genes associated with survival and migration. Targeting two differentially expressed molecules, NKG2A and Lag-3, reveals differential regulation of 1 degrees and 2 degrees effector functions during pathogen challenge. PMID- 22927426 TI - MARCKS protein mediates hydrogen peroxide regulation of endothelial permeability. AB - Impairment of endothelial barrier function is implicated in many vascular and inflammatory disorders. One prevalent mechanism of endothelial dysfunction is an increase in reactive oxygen species under oxidative stress. Previous reports have demonstrated that hydrogen peroxide (H(2)O(2)), a highly stable reactive oxygen species that modulates physiological signaling pathways, also enhances endothelial permeability, but the mechanism of this effect is unknown. Here, we identify the actin-binding protein myristoylated alanine-rich C-kinase substrate (MARCKS) as a key mediator of the H(2)O(2)-induced permeability change in bovine aortic endothelial cells. MARCKS knockdown and H(2)O(2) treatment alter the architecture of the actin cytoskeleton in endothelial cells, and H(2)O(2) induces the phosphorylation and translocation of MARCKS from the cell membrane to the cytosol. Using pharmacological inhibitors and small interference RNA constructs directed against specific proteins, we uncover a signaling cascade from Rac1 to Abl1, phospholipase Cgamma1, and PKCdelta that is triggered by H(2)O(2) and leads to MARCKS phosphorylation. Our findings establish a distinct role for MARCKS in the regulation of H(2)O(2)-induced permeability change in endothelial cells, and suggest potential new therapeutic targets for the treatment of disorders involving oxidative stress and altered endothelial permeability. PMID- 22927427 TI - Low-density lipoprotein receptor overexpression enhances the rate of brain-to blood Abeta clearance in a mouse model of beta-amyloidosis. AB - The apolipoprotein E (APOE)-epsilon4 allele is the strongest genetic risk factor for late-onset, sporadic Alzheimer's disease, likely increasing risk by altering amyloid-beta (Abeta) accumulation. We recently demonstrated that the low-density lipoprotein receptor (LDLR) is a major apoE receptor in the brain that strongly regulates amyloid plaque deposition. In the current study, we sought to understand the mechanism by which LDLR regulates Abeta accumulation by altering Abeta clearance from brain interstitial fluid. We hypothesized that increasing LDLR levels enhances blood-brain barrier-mediated Abeta clearance, thus leading to reduced Abeta accumulation. Using the brain Abeta efflux index method, we found that blood-brain barrier-mediated clearance of exogenously administered Abeta is enhanced with LDLR overexpression. We next developed a method to directly assess the elimination of centrally derived, endogenous Abeta into the plasma of mice using an anti-Abeta antibody that prevents degradation of plasma Abeta, allowing its rate of appearance from the brain to be measured. Using this plasma Abeta accumulation technique, we found that LDLR overexpression enhances brain-to-blood Abeta transport. Together, our results suggest a unique mechanism by which LDLR regulates brain-to-blood Abeta clearance, which may serve as a useful therapeutic avenue in targeting Abeta clearance from the brain. PMID- 22927428 TI - Resolvin E1 promotes phagocytosis-induced neutrophil apoptosis and accelerates resolution of pulmonary inflammation. AB - Inappropriate neutrophil activation contributes to the pathogenesis of acute lung injury (ALI). Apoptosis is essential for removal of neutrophils from inflamed tissues and timely resolution of inflammation. Resolvin E1 (RvE1) is an endogenous lipid mediator derived from the omega-3 polyunsaturated fatty acid eicosapentaenoic acid that displays proresolving actions. Because the balance of prosurvival and proapoptosis signals determines the fate of neutrophils, we investigated the impact of RvE1 on neutrophil apoptosis and the outcome of neutrophil-mediated pulmonary inflammation in mice. Culture of human neutrophils with RvE1 accelerated apoptosis evoked by phagocytosis of opsonized Escherichia coli or yeast. RvE1 through the leukotriene B(4) receptor BLT1 enhanced NADPH oxidase-derived reactive oxygen species generation and subsequent activation of caspase-8 and caspase-3. RvE1 also attenuated ERK and Akt-mediated apoptosis suppressing signals from myeloperoxidase, serum amyloid A, and bacterial DNA, shifting the balance of pro- and anti-survival signals toward apoptosis via induction of mitochondrial dysfunction. In mice, RvE1 treatment enhanced the resolution of established neutrophil-mediated pulmonary injury evoked by intratracheal instillation or i.p. administration of live E. coli or intratracheal instillation of carrageenan plus myeloperoxidase via facilitating neutrophil apoptosis and their removal by macrophages. The actions of RvE1 were prevented by the pan-caspase inhibitor zVAD-fmk. These results identify a mechanism, promotion of phagocytosis-induced neutrophil apoptosis and mitigation of potent anti-apoptosis signals, by which RvE1 could enhance resolution of acute lung inflammation. PMID- 22927429 TI - Global mapping of translation initiation sites in mammalian cells at single nucleotide resolution. AB - Understanding translational control in gene expression relies on precise and comprehensive determination of translation initiation sites (TIS) across the entire transcriptome. The recently developed ribosome-profiling technique enables global translation analysis, providing a wealth of information about both the position and the density of ribosomes on mRNAs. Here we present an approach, global translation initiation sequencing, applying in parallel the ribosome E site translation inhibitors lactimidomycin and cycloheximide to achieve simultaneous detection of both initiation and elongation events on a genome-wide scale. This approach provides a view of alternative translation initiation in mammalian cells with single-nucleotide resolution. Systemic analysis of TIS positions supports the ribosome linear-scanning mechanism in TIS selection. The alternative TIS positions and the associated ORFs identified by global translation initiation sequencing are conserved between human and mouse cells, implying physiological significance of alternative translation. Our study establishes a practical platform for uncovering the hidden coding potential of the transcriptome and offers a greater understanding of the complexity of translation initiation. PMID- 22927430 TI - CCL2/CCR2 chemokine signaling coordinates survival and motility of breast cancer cells through Smad3 protein- and p42/44 mitogen-activated protein kinase (MAPK) dependent mechanisms. AB - Increased cell motility and survival are important hallmarks of metastatic tumor cells. However, the mechanisms that regulate the interplay between these cellular processes remain poorly understood. In these studies, we demonstrate that CCL2, a chemokine well known for regulating immune cell migration, plays an important role in signaling to breast cancer cells. We report that in a panel of mouse and human breast cancer cell lines CCL2 enhanced cell migration and survival associated with increased phosphorylation of Smad3 and p42/44MAPK proteins. The G protein-coupled receptor CCR2 was found to be elevated in breast cancers, correlating with CCL2 expression. RNA interference of CCR2 expression in breast cancer cells significantly inhibited CCL2-induced migration, survival, and phosphorylation of Smad3 and p42/44MAPK proteins. Disruption of Smad3 expression in mammary carcinoma cells blocked CCL2-induced cell survival and migration and partially reduced p42/44MAPK phosphorylation. Ablation of MAPK phosphorylation in Smad3-deficient cells with the MEK inhibitor U0126 further reduced cell survival but not migration. These data indicate that Smad3 signaling through MEK p42/44MAPK regulates CCL2-induced cell motility and survival, whereas CCL2 induction of MEK-p42/44MAPK signaling independent of Smad3 functions as an alternative mechanism for cell survival. Furthermore, we show that CCL2-induced Smad3 signaling through MEK-p42/44MAPK regulates expression and activity of Rho GTPase to mediate CCL2-induced breast cancer cell motility and survival. With these studies, we characterize an important role for CCL2/CCR2 chemokine signaling in regulating the intrinsic relationships between breast cancer cell motility and survival with implications on the metastatic process. PMID- 22927431 TI - RIP1 protein-dependent assembly of a cytosolic cell death complex is required for inhibitor of apoptosis (IAP) inhibitor-mediated sensitization to lexatumumab induced apoptosis. AB - Searching for new strategies to trigger apoptosis in rhabdomyosarcoma (RMS), we investigated the effect of two novel classes of apoptosis-targeting agents, i.e. monoclonal antibodies against TNF-related apoptosis-inducing ligand (TRAIL) receptor 1 (mapatumumab) and TRAIL receptor 2 (lexatumumab) and small-molecule inhibitors of inhibitor of apoptosis (IAP) proteins. Here, we report that IAP inhibitors synergized with lexatumumab, but not with mapatumumab, to reduce cell viability and to induce apoptosis in several RMS cell lines in a highly synergistic manner (combination index <0.1). Cotreatment-induced apoptosis was accompanied by enhanced activation of caspase-8, -9, and -3; loss of mitochondrial membrane potential; and caspase-dependent apoptosis. In addition, IAP inhibitor and lexatumumab cooperated to stimulate the assembly of a cytosolic complex containing RIP1, FADD, and caspase-8. Importantly, knockdown of RIP1 by RNA interference prevented the formation of the RIP1.FADD.caspase-8 complex and inhibited subsequent activation of caspase-8, -9, and -3; loss of mitochondrial membrane potential; and apoptosis upon treatment with IAP inhibitor and lexatumumab. In addition, RIP1 silencing rescued clonogenic survival of cells treated with the combination of lexatumumab and IAP inhibitor, thus underscoring the critical role of RIP1 in cotreatment-induced apoptosis. By comparison, the TNFalpha-blocking antibody Enbrel had no effect on IAP inhibitor/lexatumumab induced apoptosis, indicating that an autocrine TNFalpha loop is dispensable. By demonstrating that IAP inhibitors and lexatumumab synergistically trigger apoptosis in a RIP1-dependent but TNFalpha-independent manner in RMS cells, our findings substantially advance our understanding of IAP inhibitor-mediated regulation of TRAIL-induced cell death. PMID- 22927433 TI - Identification of a novel role for dematin in regulating red cell membrane function by modulating spectrin-actin interaction. AB - The membrane skeleton plays a central role in maintaining the elasticity and stability of the erythrocyte membrane, two biophysical features critical for optimal functioning and survival of red cells. Many constituent proteins of the membrane skeleton are phosphorylated by various kinases, and phosphorylation of beta-spectrin by casein kinase and of protein 4.1R by PKC has been documented to modulate erythrocyte membrane mechanical stability. In this study, we show that activation of endogenous PKA by cAMP decreases membrane mechanical stability and that this effect is mediated primarily by phosphorylation of dematin. Co sedimentation assay showed that dematin facilitated interaction between spectrin and F-actin, and phosphorylation of dematin by PKA markedly diminished this activity. Quartz crystal microbalance measurement revealed that purified dematin specifically bound the tail region of the spectrin dimer in a saturable manner with a submicromolar affinity. Pulldown assay using recombinant spectrin fragments showed that dematin, but not phospho-dematin, bound to the tail region of the spectrin dimer. These findings imply that dematin contributes to the maintenance of erythrocyte membrane mechanical stability by facilitating spectrin actin interaction and that phosphorylation of dematin by PKA can modulate these effects. In this study, we have uncovered a novel functional role for dematin in regulating erythrocyte membrane function. PMID- 22927432 TI - Open conformation of ezrin bound to phosphatidylinositol 4,5-bisphosphate and to F-actin revealed by neutron scattering. AB - Ezrin is a member of the ezrin-radixin-moesin family (ERM) of adapter proteins that are localized at the interface between the cell membrane and the cortical actin cytoskeleton, and they regulate a variety of cellular functions. The structure representing a dormant and closed conformation of an ERM protein has previously been determined by x-ray crystallography. Here, using contrast variation small angle neutron scattering, we reveal the structural changes of the full-length ezrin upon binding to the signaling lipid phosphatidylinositol 4,5 bisphosphate (PIP(2)) and to F-actin. Ezrin binding to F-actin requires the simultaneous binding of ezrin to PIP(2). Once bound to F-actin, the opened ezrin forms more extensive contacts with F-actin than generally depicted, suggesting a possible role of ezrin in regulating the interfacial structure and dynamics between the cell membrane and the underlying actin cytoskeleton. In addition, using gel filtration, we find that the conformational opening of ezrin in response to PIP(2) binding is cooperative, but the cooperativity is disrupted by a phospho-mimic mutation S249D in the 4.1-ezrin/radixin/moesin (FERM) domain of ezrin. Using surface plasmon resonance, we show that the S249D mutation weakens the binding affinity and changes the kinetics of 4.1-ERM to PIP(2) binding. The study provides the first structural view of the activated ezrin bound to PIP(2) and to F-actin. PMID- 22927434 TI - Extra- and intracellular imaging of human matrix metalloprotease 11 (hMMP-11) with a cell-penetrating FRET substrate. AB - Matrix metalloprotease 11 (MMP-11), a protease associated with invasion and aggressiveness of cancerous tissue, was postulated as a prognostic marker for pancreatic, breast, and colon cancer patients. Expression analysis, however, did not reveal localization and regulation of this protease. Thus, cellular tools for the visualization of MMP-11 are highly desirable to monitor presence and activity and to elucidate the functional role of MMP-11. Therefore, fluorescein-Dabcyl labeled Foerster resonance energy transfer (FRET) substrates were developed. The design focused on enhanced peptide binding to human MMP-11, employing an unusual amino acid for the specificity pocket P1'. The addition of several arginines resulted in a cell-permeable FRET substrate SM-P124 (Ac-GRRRK(Dabcyl) GGAANC(MeOBn)RMGG-fluorescein). In vitro evaluation of SM-P124 with human MMP-11 showed a 25-fold increase of affinity (k(cat)/K(m) = 9.16 * 10(3) m(-1) s(-1), K(m) = 8 MUm) compared with previously published substrates. Incubation of pancreatic adenocarcinoma cell line MIA PaCa-2 and mamma adenocarcinoma cell line MCF-7 with the substrate SM-P124 (5 MUm) indicated intra- and extracellular MMP 11 activity. A negative control cell line (Jurkat) showed no fluorescent signal either intra- or extracellularly. Negative control FRET substrate SM-P123 produced only insignificant extracellular fluorescence without any intracellular fluorescence. SM-P124 therefore enabled intra- and extracellular tracking of MMP 11-overexpressing cancers such as pancreatic and breast adenocarcinoma and might contribute to the understanding of the activation pathways leading to MMP-11 mediated invasive processes. PMID- 22927435 TI - Discovery of novel inhibitors of a disintegrin and metalloprotease 17 (ADAM17) using glycosylated and non-glycosylated substrates. AB - A disintegrin and metalloprotease (ADAM) proteases are implicated in multiple diseases, but no drugs based on ADAM inhibition exist. Most of the ADAM inhibitors developed to date feature zinc-binding moieties that target the active site zinc, which leads to a lack of selectivity and off-target toxicity. We hypothesized that secondary binding site (exosite) inhibitors should provide a viable alternative to active site inhibitors. Potential exosites in ADAM structures have been reported, but no studies describing substrate features necessary for exosite interactions exist. Analysis of ADAM cognate substrates revealed that glycosylation is often present in the vicinity of the scissile bond. To study whether glycosylation plays a role in modulating ADAM activity, a tumor necrosis factor alpha (TNFalpha) substrate with and without a glycan moiety attached was synthesized and characterized. Glycosylation enhanced ADAM8 and -17 activities and decreased ADAM10 activity. Metalloprotease (MMP) activity was unaffected by TNFalpha substrate glycosylation. High throughput screening assays were developed using glycosylated and non-glycosylated substrate, and positional scanning was conducted. A novel chemotype of ADAM17-selective probes was discovered from the TPIMS library (Houghten, R. A., Pinilla, C., Giulianotti, M. A., Appel, J. R., Dooley, C. T., Nefzi, A., Ostresh, J. M., Yu, Y., Maggiora, G. M., Medina-Franco, J. L., Brunner, D., and Schneider, J. (2008) Strategies for the use of mixture-based synthetic combinatorial libraries. Scaffold ranking, direct testing in vivo, and enhanced deconvolution by computational methods. J. Comb. Chem. 10, 3-19; Pinilla, C., Appel, J. R., Borras, E., and Houghten, R. A. (2003) Advances in the use of synthetic combinatorial chemistry. Mixture-based libraries. Nat. Med. 9, 118-122) that preferentially inhibited glycosylated substrate hydrolysis and spared ADAM10, MMP-8, and MMP-14. Kinetic studies revealed that ADAM17 inhibition occurred via a non-zinc-binding mechanism. Thus, modulation of proteolysis via glycosylation may be used for identifying novel, potentially exosite binding compounds. The newly described ADAM17 inhibitors represent research tools to investigate the role of ADAM17 in the progression of various diseases. PMID- 22927436 TI - A viral, transporter associated with antigen processing (TAP)-independent, high affinity ligand with alternative interactions endogenously presented by the nonclassical human leukocyte antigen E class I molecule. AB - The transporter associated with antigen processing (TAP) enables the flow of viral peptides generated in the cytosol by the proteasome and other proteases to the endoplasmic reticulum, where they complex with nascent human leukocyte antigen (HLA) class I. Later, these peptide-HLA class I complexes can be recognized by CD8(+) lymphocytes. Cancerous cells and infected cells in which TAP is blocked, as well as individuals with unusable TAP complexes, are able to present peptides on HLA class I by generating them through TAP-independent processing pathways. Here, we identify a physiologically processed HLA-E ligand derived from the D8L protein in TAP-deficient vaccinia virus-infected cells. This natural high affinity HLA-E class I ligand uses alternative interactions to the anchor motifs previously described to be presented on nonclassical HLA class I molecules. This octameric peptide was also presented on HLA-Cw1 with similar binding affinity on both classical and nonclassical class I molecules. In addition, this viral peptide inhibits HLA-E-mediated cytolysis by natural killer cells. Comparison between the amino acid sequences of the presenting HLA-E and HLA-Cw1 alleles revealed a shared structural motif in both HLA class molecules, which could be related to their observed similar cross-reactivity affinities. This motif consists of several residues located on the floor of the peptide binding site. These data expand the role of HLA-E as an antigen-presenting molecule. PMID- 22927437 TI - Endothelial heparan sulfate 6-O-sulfation levels regulate angiogenic responses of endothelial cells to fibroblast growth factor 2 and vascular endothelial growth factor. AB - Fibroblast growth factor 2 (FGF2) and vascular endothelial growth factor 165 (VEGF(165)) are potent pro-angiogenic growth factors that play a pivotal role in tumor angiogenesis. The activity of these growth factors is regulated by heparan sulfate (HS), which is essential for the formation of FGF2/FGF receptor (FGFR) and VEGF(165)/VEGF receptor signaling complexes. However, the structural characteristics of HS that determine activation or inhibition of such complexes are only partially defined. Here we show that ovarian tumor endothelium displays high levels of HS sequences that harbor glucosamine 6-O-sulfates when compared with normal ovarian vasculature where these sequences are also detected in perivascular area. Reduced HS 6-O-sulfotransferase 1 (HS6ST-1) or 6-O sulfotransferase 2 (HS6ST-2) expression in endothelial cells impacts upon the prevalence of HS 6-O-sulfate moieties in HS sequences, which consist of repeating short, highly sulfated S domains interspersed by transitional N-acetylated/N sulfated domains. 1-40% reduction in 6-O-sulfates significantly compromises FGF2- and VEGF(165)-induced endothelial cell sprouting and tube formation in vitro and FGF2-dependent angiogenesis in vivo. Moreover, HS on wild-type neighboring endothelial or smooth muscle cells fails to restore endothelial cell sprouting and tube formation. The affinity of FGF2 for HS with reduced 6-O-sulfation is preserved, although FGFR1 activation is inhibited correlating with reduced receptor internalization. These data show that 6-O-sulfate moieties in endothelial HS are of major importance in regulating FGF2- and VEGF(165) dependent endothelial cell functions in vitro and in vivo and highlight HS6ST-1 and HS6ST-2 as potential targets of novel antiangiogenic agents. PMID- 22927438 TI - Kcnh1 voltage-gated potassium channels are essential for early zebrafish development. AB - The Kcnh1 gene encodes a voltage-gated potassium channel highly expressed in neurons and involved in tumor cell proliferation, yet its physiological roles remain unclear. We have used the zebrafish as a model to analyze Kcnh1 function in vitro and in vivo. We found that the kcnh1 gene is duplicated in teleost fish (i.e. kcnh1a and kcnh1b) and that both genes are maternally expressed during early development. In adult zebrafish, kcnh1a and kcnh1b have distinct expression patterns but share expression in brain and testis. Heterologous expression of both genes in Xenopus oocytes revealed a strong conservation of characteristic functional properties between human and fish channels, including a unique sensitivity to intracellular Ca(2+)/calmodulin and modulation of voltage dependent gating by extracellular Mg(2+). Using a morpholino antisense approach, we demonstrate a strong kcnh1 loss-of-function phenotype in developing zebrafish, characterized by growth retardation, delayed hindbrain formation, and embryonic lethality. This late phenotype was preceded by transcriptional up-regulation of known cell-cycle inhibitors (p21, p27, cdh2) and down-regulation of pro proliferative factors, including cyclin D1, at 70% epiboly. These results reveal an unanticipated basic activity of kcnh1 that is crucial for early embryonic development and patterning. PMID- 22927439 TI - Inhibition of neddylation represses lipopolysaccharide-induced proinflammatory cytokine production in macrophage cells. AB - Cullin-RING E3 ligases (CRLs) are a class of ubiquitin ligases that control the proteasomal degradation of numerous target proteins, including IkappaB, and the activity of these CRLs are positively regulated by conjugation of a Nedd8 polypeptide onto Cullin proteins in a process called neddylation. CRL-mediated degradation of IkappaB, which normally interacts with and retains NF-kappaB in the cytoplasm, permits nuclear translocation and transactivation of the NF-kappaB transcription factor. Neddylation occurs through a multistep enzymatic process involving Nedd8 activating enzymes, and recent studies have shown that the pharmacological agent, MLN4924, can potently inhibit Nedd8 activating enzymes, thereby preventing neddylation of Cullin proteins and preventing the degradation of CRL target proteins. In macrophages, regulation of NF-kappaB signaling functions as a primary pathway by which infectious agents such as lipopolysaccharides (LPSs) cause the up-regulation of proinflammatory cytokines. Here we have analyzed the effects of MLN4924, and compared the effects of MLN4924 with a known anti-inflammatory agent (dexamethasone), on certain proinflammatory cytokines (TNF-alpha and IL-6) and the NF-kappaB signaling pathway in LPS stimulated macrophages. We also used siRNA to block neddylation to assess the role of this molecular process during LPS-induced cytokine responsiveness. Our results demonstrate that blocking neddylation, either pharmacologically or using siRNA, abrogates the increase in certain proinflammatory cytokines secreted from macrophages in response to LPS. In addition, we have shown that MLN4924 and dexamethasone inhibit LPS-induced cytokine up-regulation at the transcriptional level, albeit through different molecular mechanisms. Thus, neddylation represents a novel molecular process in macrophages that can be targeted to prevent and/or treat the LPS-induced up-regulation of proinflammatory cytokines and the disease processes associated with their up-regulation. PMID- 22927440 TI - Neutrophil elastase modulates cytokine expression: contribution to host defense against Pseudomonas aeruginosa-induced pneumonia. AB - There is accumulating evidence that following bacterial infection, the massive recruitment and activation of the phagocytes, neutrophils, is accompanied with the extracellular release of active neutrophil elastase (NE), a potent serine protease. Using NE-deficient mice in a clinically relevant model of Pseudomonas aeruginosa-induced pneumonia, we provide compelling in vivo evidence that the absence of NE was associated with decreased protein and transcript levels of the proinflammatory cytokines TNF-alpha, MIP-2, and IL-6 in the lungs, coinciding with increased mortality of mutant mice to infection. The implication of NE in the induction of cytokine expression involved at least in part Toll-like receptor 4 (TLR-4). These findings were further confirmed following exposure of cultured macrophages to purified NE. Together, our data suggest strongly for the first time that NE not only plays a direct antibacterial role as it has been previously reported, but released active enzyme can also modulate cytokine expression, which contributes to host protection against P. aeruginosa. In light of our findings, the long held view that considers NE as a prime suspect in P. aeruginosa associated diseases will need to be carefully reassessed. Also, therapeutic strategies aiming at NE inhibition should take into account the physiologic roles of the enzyme. PMID- 22927441 TI - Spectroscopic and kinetic investigation of the fully reduced and mixed valence states of ba3-cytochrome c oxidase from Thermus thermophilus: a Fourier transform infrared (FTIR) and time-resolved step-scan FTIR study. AB - The complete understanding of a molecular mechanism of action requires the thermodynamic and kinetic characterization of different states and intermediates. Cytochrome c oxidase reduces O(2) to H(2)O, a reaction coupled to proton translocation across the membrane. Therefore, it is necessary to undertake a thorough characterization of the reduced form of the enzyme and the determination of the electron transfer processes and pathways between the redox-active centers. In this study Fourier transform infrared (FTIR) and time-resolved step-scan FTIR spectroscopy have been applied to study the fully reduced and mixed valence states of cytochrome ba(3) from Thermus thermophilus. We used as probe carbon monoxide (CO) to characterize both thermodynamically and kinetically the cytochrome ba(3)-CO complex in the 5.25-10.10 pH/pD range and to study the reverse intramolecular electron transfer initiated by the photolysis of CO in the two-electron reduced form. The time-resolved step-scan FTIR data revealed no pH/pD dependence in both the decay of the transient Cu(B)(1+)-CO complex and rebinding to heme a(3) rates, suggesting that no structural change takes place in the vicinity of the binuclear center. Surprisingly, photodissociation of CO from the mixed valence form of the enzyme does not lead to reverse electron transfer from the reduced heme a(3) to the oxidized low-spin heme b, as observed in all the other aa(3) and bo(3) oxidases previously examined. The heme b-heme a(3) electron transfer is guaranteed, and therefore, there is no need for structural rearrangements and complex synchronized cooperativities. Comparison among the available structures of ba(3)- and aa(3)-cytochrome c oxidases identifies possible active pathways involved in the electron transfer processes and key structural elements that contribute to the different behavior observed in cytochrome ba(3). PMID- 22927442 TI - Three different functional microdomains in the hepatitis C virus hypervariable region 1 (HVR1) mediate entry and immune evasion. AB - High genetic heterogeneity is an important characteristic of hepatitis C virus (HCV) that contributes to its ability to establish persistent infection. The hypervariable region 1 (HVR1) that includes the first 27 amino acid residues of the E2 envelope glycoprotein is the most variable region within the HCV polyprotein. HVR1 plays a major role in both HCV cell entry and immune evasion, but the respective contribution of specific amino acid residues is still unclear. Our mutagenesis analyses of HCV pseudoparticles and cell culture-derived HCV using the H77 isolate indicate that five residues at positions 14, 15, and 25-27 mediate binding of the E2 protein to the scavenger receptor class B, type I receptor, and any residue herein is indispensable for HCV cell entry. The region spanning positions 16-24 contains the sole neutralizing epitope and is dispensable for HCV entry, but it is involved in heparan binding. More importantly, this region is necessary for the enhancement of HCV entry by high density lipoprotein and interferes with virus neutralization by E2-neutralizing antibodies. Residues at positions 1-13 are also dispensable for HCV entry, but they can affect HCV infectivity by modulating binding of the envelope protein to scavenger receptor class B, type I. Mutations occurring at this site may confer resistance to HVR1 antibodies. These findings further our understanding about the mechanisms of HCV cell entry and the significance of HVR1 variation in HCV immune evasion. They have major implications for the development of HCV entry inhibitors and prophylactic vaccines. PMID- 22927443 TI - MicroRNA miR-214 regulates ovarian cancer cell stemness by targeting p53/Nanog. AB - Previous studies have shown aberrant expression of miR-214 in human malignancy. Elevated miR-214 is associated with chemoresistance and metastasis. In this study, we identified miR-214 regulation of ovarian cancer stem cell (OCSC) properties by targeting p53/Nanog axis. Enforcing expression of miR-214 increases, whereas knockdown of miR-214 decreases, OCSC population and self renewal as well as the Nanog level preferentially in wild-type p53 cell lines. Furthermore, we found that p53 is directly repressed by miR-214 and that miR-214 regulates Nanog through p53. Expression of p53 abrogated miR-214-induced OCSC properties. These data suggest the critical role of miR-214 in OCSC via regulation of the p53-Nanog axis and miR-214 as a therapeutic target for ovarian cancer. PMID- 22927444 TI - Spider glue proteins have distinct architectures compared with traditional spidroin family members. AB - Adhesive spider glues are required to perform a variety of tasks, including web construction, prey capture, and locomotion. To date, little is known regarding the molecular and structural features of spider glue proteins, in particular bioadhesives that interconnect dragline or scaffolding silks during three dimensional web construction. Here we use biochemical and structural approaches to identify and characterize two aggregate gland specific gene products, AgSF1 and AgSF2, and demonstrate that these proteins co-localize to the connection joints of both webs and wrapping silks spun from the black widow spider, Latrodectus hesperus. Protein architectures are markedly divergent between AgSF1 and AgSF2, as well as traditional spider silk fibroin family members, suggesting connection joints consist of a complex proteinaceous network. AgSF2 represents a nonglycosylated 40-kDa protein that has novel internal amino acid block repeats with the consensus sequence NVNVN embedded in a glycine-rich matrix. Analysis of the amino acid sequence of AgSF1 reveals pentameric QPGSG iterations that are similar to conserved modular elements within mammalian elastin, a rubber-like elastomeric protein that interfaces with collagen. Wet-spinning methodology using purified recombinant proteins show AgSF1 has the potential to self-assemble into fibers. X-ray fiber diffraction studies performed on these synthetic fibers reveal the presence of noncrystalline domains that resemble classical rubber networks. Collectively, these data support that the aggregate gland serves to extrude a protein mixture that contains substances that allow for the self assembly of fiber-like structures that interface with dragline silks to mediate prey capture. PMID- 22927445 TI - Intracellular interaction of interleukin (IL)-32alpha with protein kinase Cepsilon (PKCepsilon ) and STAT3 protein augments IL-6 production in THP-1 promonocytic cells. AB - IL-32alpha is known as a proinflammatory cytokine. However, several evidences implying its action in cells have been recently reported. In this study, we present for the first time that IL-32alpha plays an intracellular mediatory role in IL-6 production using constitutive expression systems for IL-32alpha in THP-1 cells. We show that phorbol 12-myristate 13-acetate (PMA)-induced increase in IL 6 production by IL-32alpha-expressing cells was higher than that by empty vector expressing cells and that this increase occurred in a time- and dose-dependent manner. Treatment with MAPK inhibitors did not diminish this effect of IL 32alpha, and NF-kappaB signaling activity was similar in the two cell lines. Because the augmenting effect of IL-32alpha was dependent on the PKC activator PMA, we tested various PKC inhibitors. The pan-PKC inhibitor Go6850 and the PKCepsilon inhibitor Ro-31-8220 abrogated the augmenting effect of IL-32alpha on IL-6 production, whereas the classical PKC inhibitor Go6976 and the PKCdelta inhibitor rottlerin did not. In addition, IL-32alpha was co-immunoprecipitated with PMA-activated PKCepsilon, and this interaction was totally inhibited by the PKCepsilon inhibitor Ro-31-8220. PMA-induced enhancement of STAT3 phosphorylation was observed only in IL-32alpha-expressing cells, and this enhancement was inhibited by Ro-31-8220, but not by Go6976. We demonstrate that IL-32alpha mediated STAT3 phosphorylation by forming a trimeric complex with PKCepsilon and enhanced STAT3 localization onto the IL-6 promoter and thereby increased IL-6 expression. Thus, our data indicate that the intracellular interaction of IL 32alpha with PKCepsilon and STAT3 promotes STAT3 binding to the IL-6 promoter by enforcing STAT3 phosphorylation, which results in increased production of IL-6. PMID- 22927447 TI - Metagenomic and metabolomic characterization of rabies encephalitis: new insights into the treatment of an ancient disease. AB - Rabies virus (RV) infection is a fatal nervous system disorder. We describe a patient who died of rabies despite a neuroprotective intervention. Neuropathology showed neuronal loss with abundant RV antigen, genome, and Negri bodies, accompanied by intense neuroinflammation, including by CD8(+) T lymphocyte infiltrates. Deep sequencing and real-time reverse-transcription polymerase chain reaction revealed RNA encoding a bat RV strain together with inflammatory gene induction. RV-infected brain demonstrated reduced neuronal metabolites with an anaerobic metabolic profile by nuclear magnetic resonance (NMR) spectroscopy. These multiplatform studies highlight the extent of ongoing viral replication coupled with inflammation in treated rabies, indicative of a neurological immune reconstitution inflammatory syndrome. PMID- 22927446 TI - Autophagy-related gene 7 (ATG7) and reactive oxygen species/extracellular signal regulated kinase regulate tetrandrine-induced autophagy in human hepatocellular carcinoma. AB - Tetrandrine, a bisbenzylisoquinoline alkaloid isolated from the broadly used Chinese medicinal herb Stephaniae tetrandrae, exhibits potent antitumor effects and has the potential to be used as a cancer chemotherapeutic agent. We previously reported that high concentrations of tetrandrine induce apoptosis in liver cancer cells. Here, we found that in human hepatocellular carcinoma (HCC) cells, a low dose of tetrandrine (5 MUm) induced the expression of LC3-II, resulted in the formation of acidic autophagolysosome vacuoles (AVOs), and caused a punctate fluorescence pattern with the GFP-LC3 protein, which all are markers for cellular autophagy. Tetrandrine induced the production of intracellular reactive oxygen species (ROS), and treatment with ROS scavengers significantly abrogated the tetrandrine-induced autophagy. These results suggest that the generation of ROS plays an important role in promoting tetrandrine-induced autophagy. Tetrandrine-induced mitochondrial dysfunction resulted in ROS accumulation and autophagy. ROS generation activated the ERK MAP kinase, and the ERK signaling pathway at least partially contributed to tetrandrine-induced autophagy in HCC cells. Moreover, we found that tetrandrine transcriptionally regulated the expression of autophagy related gene 7 (ATG7), which promoted tetrandrine-induced autophagy. In addition to in vitro studies, similar results were also observed in vivo, where tetrandrine caused the accumulation of ROS and induced cell autophagy in a tumor xenograft model. Interestingly, tetrandrine treatment also induced autophagy in a ROS-dependent manner in C. elegans muscle cells. Therefore, these findings suggest that tetrandrine is a potent autophagy agonist and may be a promising clinical chemotherapeutic agent. PMID- 22927448 TI - Interleukin 17A as an effective target for anti-inflammatory and antiparasitic treatment of toxoplasmic uveitis. AB - BACKGROUND: Toxoplasmosis is the most common cause of posterior uveitis in immunocompetent subjects. The requirement of limiting both parasite multiplication and tissue destruction suggests that the balance between T-helper (Th) 17 and T-regulatory cells is an important factor in toxoplasmosis-induced retinal damage. METHODS: In a prospective clinical study of acute ocular toxoplasmosis, we assessed the cytokine pattern in aqueous humors of 10 affected patients. To determine the immunological mechanisms, we evaluated intraocular inflammation, parasite load, and immunological responses using messenger RNA and protein levels in a mouse model. Anti-interleukin 17A (IL-17A) monoclonal antibodies (mAbs) were administered with the parasite to evaluate the role of IL 17A. RESULTS: Severe ocular inflammation and cytokine patterns comparable to human cases were observed, including IL-17A production. Neutralizing IL-17A decreased intraocular inflammation and parasite load in mice. Detailed studies revealed up-regulation of T-regulatory and Th1 pathways. When interferon gamma (IFN-gamma) was neutralized concomitantly, the parasite multiplication rate was partially restored. CONCLUSIONS: Local IL-17A production by resident cells plays a central role in the pathology of ocular toxoplasmosis. The balance between Th17 and Th1 responses (especially IFN-gamma) is crucial for the outcome of infection. This data reveals new in vivo therapeutic approaches by repressing inflammatory pathways using intravitreal injection of IL-17A mAbs. PMID- 22927449 TI - Modest nonadherence to antiretroviral therapy promotes residual HIV-1 replication in the absence of virological rebound in plasma. AB - BACKGROUND: Modern antiretroviral therapy (ART) regimens are widely assumed to forgive modest nonadherence, because virological suppression in plasma is common at adherence levels of >70%. Yet, it is unknown whether human immunodeficiency virus type 1 (HIV-1) replication is completely suppressed at these levels of adherence. METHODS: We longitudinally quantified levels of cell-associated HIV-1 RNA and DNA in 40 patients (median duration of successful ART before study initiation, 46 months), whose 1-week adherence to therapy prior to the sampling moments was measured electronically. RESULTS: Patients were constantly 100% adherent (the optimal-adherence group), demonstrated improving adherence over time (the improving-adherence group), or neither of the above (the poor-adherence group). Adherence never decreased to <70% in any patient, and no rebound in plasma virological levels was observed. Nevertheless, poor adherence but not optimal or improving adherence caused a significant longitudinal increase in cell associated HIV RNA levels (P = .006). Time-weighted changes and regression slopes of viral RNA load for the poor-adherence group were significantly higher than those for the optimal-adherence group (P < .01). CONCLUSIONS: Because ART only blocks infection of new cells but not viral RNA transcription in cells infected before therapy initiation, the observed effects strongly suggest that modest nonadherence can cause new cycles of HIV-1 replication that are undetectable by commercial plasma viral load assays. PMID- 22927451 TI - Determinants of antiviral effectiveness in influenza virus A subtype H5N1. AB - BACKGROUND: Oseltamivir is widely used as treatment for influenza virus A subtype H5N1 (hereafter, "H5N1") infection but, like any intervention, is not always effective. METHODS: We used Avian Influenza Registry data from 10 countries to examine the risk of death in 215 patients with confirmed H5N1 infection who were treated with oseltamivir, according to viral clade, age, respiratory failure, and adjunctive treatment with corticosteroids or antibiotics. RESULTS: The median age of infected individuals was 18 years, and 50% were male. The highest fatality rate occurred in a country with clade 2.1 virus circulation, and the lowest occurred in countries with clade 2.2 virus circulation (P < .001). In univariate analyses, age of <=5 years and treatment <=2 days after symptom onset were protective against fatality. When accounting for all risk factors, early initiation of oseltamivir was found to be particularly effective in individuals without respiratory failure (odds ratio, 0.17; P = .04). Patients who had advanced respiratory failure requiring ventilatory support at the time of oseltamivir initiation were more likely to die from the episode of H5N1 infection than patients who did not (P < .001). Adjunctive therapy did not improve the likelihood of surviving the episode. CONCLUSIONS: Oseltamivir is especially effective for treating H5N1 infection when given early and before onset of respiratory failure. The effect of viral clade on fatality and treatment response deserves further investigation. PMID- 22927450 TI - A single-nucleotide polymorphism in CYP2B6 leads to >3-fold increases in efavirenz concentrations in plasma and hair among HIV-infected women. AB - BACKGROUND: Efavirenz exhibits marked interindividual variability in plasma levels and toxicities. Prior pharmacogenetic studies usually measure exposure via single plasma levels, examine limited numbers of polymorphisms, and rarely model multiple contributors. We analyzed numerous genetic and nongenetic factors impacting short-term and long-term exposure in a large heterogeneous population of human immunodeficiency virus (HIV)-infected women. METHODS: We performed 24 hour intensive pharmacokinetic studies in 111 women receiving efavirenz under actual-use conditions and calculated the area-under-the-concentration-time curve (AUC) to assess short-term exposure; the efavirenz concentration in hair was measured to estimate long-term exposure. A total of 182 single-nucleotide polymorphisms (SNPs) and 45 haplotypes in 9 genes were analyzed in relationship to exposure by use of multivariate models that included a number of nongenetic factors. RESULTS: Efavirenz AUCs increased 1.26-fold per doubling of the alanine aminotransferase level and 1.23-fold with orange and/or orange juice consumption. Individuals with the CYP2B6 516TT genotype displayed 3.5-fold increases in AUCs and 3.2-fold increases in hair concentrations, compared with individuals with the TG/GG genotype. Another SNP in CYP2B6 (983TT) and a p-glycoprotein haplotype affected AUCs without substantially altering long-term exposure. CONCLUSIONS: This comprehensive pharmacogenomics study showed that individuals with the CYP2B6 516TT genotype displayed >3-fold increases in both short-term and long-term efavirenz exposure, signifying durable effects. Pharmacogenetic testing combined with monitoring of hair levels may improve efavirenz outcomes and reduce toxicities. PMID- 22927452 TI - Predicting susceptibility to norovirus GII.4 by use of a challenge model involving humans. AB - BACKGROUND: GII.4 is the predominant norovirus genotype worldwide. Challenge models involving humans have shown the association of human histo-blood group antigens (HBGAs) and susceptibility to infection with Norwalk virus (GI.1 norovirus), but the association of HBGAs and infection with other noroviruses is based on results of epidemiological studies. We performed the first GII.4 challenge study involving humans and prospectively evaluated the relationship between HBGAs and norovirus infection and associated illness. METHODS: Forty healthy adults (23 secretors and 17 nonsecretors of HBGAs) were challenged with 5 10(4) reverse-transcription polymerase chain reaction (RT-PCR) units of GII.4 norovirus. Subjects were assessed daily for clinical illness, and stool specimens were evaluated for norovirus by RT-PCR. Infection was defined by detection of norovirus and/or seroconversion to GII.4 antibody. RESULTS: Of the 23 secretors, 16 (70%) were infected with norovirus, 13 (57%) became ill (characterized by vomiting and/or diarrhea), and 12 (52%) developed norovirus-associated illness. In contrast, only 1 nonsecretor (5.9%) became ill, and another nonsecretor shed virus for a single day (P < .001 for each variable, compared with secretors). Infection occurred in secretors regardless of ABO blood group. Illness was mild to moderate in severity and lasted 1-3 days. CONCLUSIONS: Secretor status determined the susceptibility to norovirus GII.4 challenge. This human challenge model should be useful for evaluating norovirus vaccines and antiviral agents. Clinical trials registration. NCT01322503. PMID- 22927453 TI - GB virus C viremia is associated with higher levels of double-negative T cells and lower T-cell activation in HIV-infected individuals receiving antiretroviral therapy. AB - Double-negative T cells (DNTCs; ie, CD3(+)CD4(-)CD8(-) T cells) play a role in limiting chronic immune activation. GB virus C (GBV-C) infection is associated with reduced T-cell activation in human immunodeficiency virus (HIV)-infected individuals. T-cell activation and DNTCs were measured in HIV-infected subjects with a nondetectable HIV load. GBV-C-viremic subjects had significantly reduced CD4(+) and CD8(+) T-cell activation (P = .003 and .034, respectively) and significantly increased DNTCs (P = .038), compared with nonviremic subjects. GBV C load correlated with DNTC percentage (P = .004). Thus, GBV-C infection is associated with an increase in DNTCs, which may contribute to reduced immune activation during HIV infection. PMID- 22927455 TI - Cardiovascular disease risk in HIV infection and endothelial progenitor cells. PMID- 22927454 TI - An adaptive randomized trial of an intermittent dosing schedule of aerosolized ribavirin in patients with cancer and respiratory syncytial virus infection. AB - A continuous dosing schedule of aerosolized ribavirin has been used for respiratory syncytial virus (RSV) upper respiratory tract infection and lower respiratory tract infection (LRTI) but is associated with high cost and inconvenient administration. We conducted an adaptive randomized trial to evaluate the effectiveness of an intermittent dosing schedule of ribavirin versus that of a continuous dosing schedule of ribavirin in preventing RSV LRTIs in 50 hematopoietic stem cell transplant recipients or patients with hematologic malignancies. LRTI occurred in 3 patients (9%) receiving the intermittent schedule and in 4 (22%) receiving the continuous schedule, with a 0.889 posterior probability. Because the intermittent schedule is easy to administer and has a higher efficacy than the continuous schedule, we recommend the intermittent schedule for patients who are at risk for RSV LRTI. Clinical Trials Registration. NCT00500578. PMID- 22927457 TI - Obesity, influenza virus infection, and hypovitaminosis D. PMID- 22927458 TI - Invasive candidiasis: new insights presaging new therapeutic approaches? PMID- 22927460 TI - Letter by Naylor regarding article, "very urgent carotid endarterectomy confers increased procedural risk". PMID- 22927461 TI - Letter by Hiltunen and Jolkkonen regarding article, "secondary neurodegeneration in remote regions after focal cerebral infarction: a new target for stroke management?". PMID- 22927462 TI - The FATP1-DGAT2 complex facilitates lipid droplet expansion at the ER-lipid droplet interface. AB - At the subcellular level, fat storage is confined to the evolutionarily conserved compartments termed lipid droplets (LDs), which are closely associated with the endoplasmic reticulum (ER). However, the molecular mechanisms that enable ER-LD interaction and facilitate neutral lipid loading into LDs are poorly understood. In this paper, we present evidence that FATP1/acyl-CoA synthetase and DGAT2/diacylglycerol acyltransferase are components of a triglyceride synthesis complex that facilitates LD expansion. A loss of FATP1 or DGAT2 function blocked LD expansion in Caenorhabditis elegans. FATP1 preferentially associated with DGAT2, and they acted synergistically to promote LD expansion in mammalian cells. Live imaging indicated that FATP1 and DGAT2 are ER and LD resident proteins, respectively, and electron microscopy revealed FATP1 and DGAT2 foci close to the LD surface. Furthermore, DGAT2 that was retained in the ER failed to support LD expansion. We propose that the evolutionarily conserved FATP1-DGAT2 complex acts at the ER-LD interface and couples the synthesis and deposition of triglycerides into LDs both physically and functionally. PMID- 22927463 TI - Organelle positioning in muscles requires cooperation between two KASH proteins and microtubules. AB - Striated muscle fibers are characterized by their tightly organized cytoplasm. Here, we show that the Drosophila melanogaster KASH proteins Klarsicht (Klar) and MSP-300 cooperate in promoting even myonuclear spacing by mediating a tight link between a newly discovered MSP-300 nuclear ring and a polarized network of astral microtubules (aMTs). In either klar or msp-300(DeltaKASH), or in klar and msp-300 double heterozygous mutants, the MSP-300 nuclear ring and the aMTs retracted from the nuclear envelope, abrogating this even nuclear spacing. Anchoring of the myonuclei to the core acto-myosin fibrillar compartment was mediated exclusively by MSP-300. This protein was also essential for promoting even distribution of the mitochondria and ER within the muscle fiber. Larval locomotion is impaired in both msp-300 and klar mutants, and the klar mutants were rescued by muscle specific expression of Klar. Thus, our results describe a novel mechanism of nuclear spacing in striated muscles controlled by the cooperative activity of MSP 300, Klar, and astral MTs, and demonstrate its physiological significance. PMID- 22927464 TI - Bacterial protein translocation requires only one copy of the SecY complex in vivo. AB - The transport of proteins across the plasma membrane in bacteria requires a channel formed from the SecY complex, which cooperates with either a translating ribosome in cotranslational translocation or the SecA ATPase in post translational translocation. Whether translocation requires oligomers of the SecY complex is an important but controversial issue: it determines channel size, how the permeation of small molecules is prevented, and how the channel interacts with the ribosome and SecA. Here, we probe in vivo the oligomeric state of SecY by cross-linking, using defined co- and post-translational translocation intermediates in intact Escherichia coli cells. We show that nontranslocating SecY associated transiently through different interaction surfaces with other SecY molecules inside the membrane. These interactions were significantly reduced when a translocating polypeptide inserted into the SecY channel co- or post translationally. Mutations that abolish the interaction between SecY molecules still supported viability of E. coli. These results show that a single SecY molecule is sufficient for protein translocation. PMID- 22927465 TI - gamma-Tubulin plays a key role in inactivating APC/C(Cdh1) at the G(1)-S boundary. AB - A gamma-tubulin mutation in Aspergillus nidulans, mipA-D159, causes failure of inactivation of the anaphase-promoting complex/cyclosome (APC/C) in interphase, resulting in failure of cyclin B (CB) accumulation and removal of nuclei from the cell cycle. We have investigated the role of CdhA, the A. nidulans homologue of the APC/C activator protein Cdh1, in gamma-tubulin-dependent inactivation of the APC/C. CdhA was not essential, but it targeted CB for destruction in G(1), and APC/C(CdhA) had to be inactivated for the G(1)-S transition. mipA-D159 altered the localization pattern of CdhA, and deletion of the gene encoding CdhA allowed CB to accumulate in all nuclei in strains carrying mipA-D159. These data indicate that mipA-D159 causes a failure of inactivation of APC/C(CdhA) at G(1)-S, perhaps by altering its localization to the spindle pole body, and, thus, that gamma tubulin plays an important role in inactivating APC/C(CdhA) at this point in the cell cycle. PMID- 22927466 TI - Dishevelled stabilization by the ciliopathy protein Rpgrip1l is essential for planar cell polarity. AB - Cilia are at the core of planar polarity cellular events in many systems. However, the molecular mechanisms by which they influence the polarization process are unclear. Here, we identify the function of the ciliopathy protein Rpgrip1l in planar polarity. In the mouse cochlea and in the zebrafish floor plate, Rpgrip1l was required for positioning the basal body along the planar polarity axis. Rpgrip1l was also essential for stabilizing dishevelled at the cilium base in the zebrafish floor plate and in mammalian renal cells. In rescue experiments, we showed that in the zebrafish floor plate the function of Rpgrip1l in planar polarity was mediated by dishevelled stabilization. In cultured cells, Rpgrip1l participated in a complex with inversin and nephrocystin-4, two ciliopathy proteins known to target dishevelled to the proteasome, and, in this complex, Rpgrip1l prevented dishevelled degradation. We thus uncover a ciliopathy protein complex that finely tunes dishevelled levels, thereby modulating planar cell polarity processes. PMID- 22927467 TI - SUMOylated SoxE factors recruit Grg4 and function as transcriptional repressors in the neural crest. AB - A growing number of transcriptional regulatory proteins are known to be modified by the small ubiquitin-like protein, SUMO. Posttranslational modification by SUMO may be one means by which transcriptional regulatory factors that play context dependent roles in multiple processes can be regulated such that they direct the appropriate cellular and developmental outcomes. In early vertebrate embryos, SUMOylation of SoxE transcription factors profoundly affects their function, inhibiting their neural crest-inducing activity and promoting ear formation. In this paper, we provide mechanistic insight into how SUMO modification modulates SoxE function. We show that SUMOylation dramatically altered recruitment of transcriptional coregulator factors by SoxE proteins, displacing coactivators CREB-binding protein/p300 while promoting the recruitment of a corepressor, Grg4. These data demonstrate that SoxE proteins can function as transcriptional repressors in a SUMO-dependent manner. They further suggest a novel multivalent mechanism for SUMO-mediated recruitment of transcriptional coregulatory factors. PMID- 22927468 TI - Rad53 is essential for a mitochondrial DNA inheritance checkpoint regulating G1 to S progression. AB - The Chk2-mediated deoxyribonucleic acid (DNA) damage checkpoint pathway is important for mitochondrial DNA (mtDNA) maintenance. We show in this paper that mtDNA itself affects cell cycle progression. Saccharomyces cerevisiae rho(0) cells, which lack mtDNA, were defective in G1- to S-phase progression. Deletion of subunit Va of cytochrome c oxidase, inhibition of F(1)F(0) adenosine triphosphatase, or replacement of all mtDNA-encoded genes with noncoding DNA did not affect G1- to S-phase progression. Thus, the cell cycle progression defect in rho(0) cells is caused by loss of DNA within mitochondria and not loss of respiratory activity or mtDNA-encoded genes. Rad53p, the yeast Chk2 homologue, was required for inhibition of G1- to S-phase progression in rho(0) cells. Pif1p, a DNA helicase and Rad53p target, underwent Rad53p-dependent phosphorylation in rho(0) cells. Thus, loss of mtDNA activated an established checkpoint kinase that inhibited G1- to S-phase progression. These findings support the existence of a Rad53p-regulated checkpoint that regulates G1- to S-phase progression in response to loss of mtDNA. PMID- 22927469 TI - Clinical features of schwannomatosis: a retrospective analysis of 87 patients. AB - BACKGROUND: Schwannomatosis is a recently recognized form of neurofibromatosis characterized by multiple noncutaneous schwannomas, a histologically benign nerve sheath tumor. As more cases are identified, the reported phenotype continues to expand and evolve. We describe the spectrum of clinical findings in a cohort of patients meeting established criteria for schwannomatosis. METHODS: We retrospectively reviewed the clinical records of patients seen at our institution from 1995-2011 who fulfilled either research or clinical criteria for schwannomatosis. Clinical, radiographic, and pathologic data were extracted with attention to age at onset, location of tumors, ophthalmologic evaluation, family history, and other stigmata of neurofibromatosis 1 (NF1) or NF2. RESULTS: Eighty seven patients met the criteria for the study. The most common presentation was pain unassociated with a mass (46%). Seventy-seven of 87 (89%) patients had peripheral schwannomas, 49 of 66 (74%) had spinal schwannomas, seven of 77 (9%) had nonvestibular intracranial schwannomas, and four of 77 (5%) had intracranial meningiomas. Three patients were initially diagnosed with a malignant peripheral nerve sheath tumor; however, following pathologic review, the diagnoses were revised in all three cases. Chronic pain was the most common symptom (68%) and usually persisted despite aggressive surgical and medical management. Other common diagnoses included headaches, depression, and anxiety. CONCLUSIONS: Peripheral and spinal schwannomas are common in schwannomatosis patients. Severe pain is difficult to treat in these patients and often associated with anxiety and depression. These findings support a proactive surveillance plan to identify tumors by magnetic resonance imaging scan in order to optimize surgical treatment and to treat associated pain, anxiety, and depression. PMID- 22927470 TI - Socioeconomically but not medically deprived? PMID- 22927471 TI - Fifty shades of brown: perivascular fat, thermogenesis, and atherosclerosis. PMID- 22927472 TI - Natural killer cells in pulmonary arterial hypertension: a force on the dim or the bright side? PMID- 22927474 TI - Acute aortic regurgitation. PMID- 22927473 TI - Metabolomic profiling for the identification of novel biomarkers and mechanisms related to common cardiovascular diseases: form and function. PMID- 22927475 TI - Surgical technique and peripheral artery disease. PMID- 22927476 TI - Petrified myocardium: the age of stone? PMID- 22927477 TI - Heritable pulmonary arterial hypertension with elevated pulmonary wedge pressure. PMID- 22927479 TI - Letter by Neeland and de Lemos regarding article, "Rates of cardiac catheterization cancelation for ST-segment elevation myocardial infarction after activation by emergency medical services or emergency physicians: results from the North Carolina Catheterization Laboratory Activation Registry". PMID- 22927480 TI - Letter by Damman et al regarding articles, "Long-term cardiovascular mortality after procedure-related or spontaneous myocardial infarction in patients with non ST-segment elevation acute coronary syndrome: a collaborative analysis of individual patient data from the FRISC II, ICTUS, and RITA-3 Trials (FIR)" and "American College of Cardiology/American Heart Association/European Society of Cardiology/World Heart Federation universal definition of myocardial infarction classification system and the risk of cardiovascular death: observations from the TRITON-TIMI 38 Trial (Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition With Prasugrel-Thrombolysis in Myocardial Infarction 38)". PMID- 22927481 TI - Human suppressive neutrophils CD16bright/CD62Ldim exhibit decreased adhesion. AB - Neutrophils are essential effector cells in host defense against invading pathogens. Regulation of adhesion, migration, and chemotactic processes is important in the homing and activation of these cells. We recently described three distinct subsets of circulating human neutrophils in peripheral blood during acute systemic inflammation. One subset, CD16(bright)/CD62L(dim), has immune suppressive characteristics because it can inhibit T-cell proliferation. The other two subsets consist of banded CD16(dim)/CD62L(bright) and phenotypically mature (normal) CD16(bright)/CD62L(bright) neutrophils. The current study was designed to determine the adhesion characteristics of these different neutrophil subsets. Analysis of adhesion to activated endothelium under flow conditions revealed that CD16(bright)/CD62L(dim) neutrophils adhered less compared with CD16(bright)/CD62L(bright) and CD16(dim)/CD62L(bright) neutrophils. This decrease in binding capacity could be mimicked in the other neutrophil subsets by blocking L-selectin. Chemotaxis of CD16(bright)/CD62L(dim) neutrophils to the end-target chemoattractant N-formylmethionine-leucine-phenylalanine was lower compared with that for the CD16(dim)/CD62L(bright) neutrophil subset, whereas chemotaxis to cell-derived chemoattractant CXCL8 was comparable. Our data indicate that capture on endothelium under flow conditions, a key mechanism necessary for extravasation, of CD16(bright)/CD62L(dim) neutrophils to inflammatory sites is attenuated, which may facilitate migration of these cells to other tissue localizations. Modulation of this process is a potential target to manipulate inflammation because potentiation of this immune suppression might aid in anti-inflammatory therapy. PMID- 22927482 TI - Phase I study of the antiangiogenic antibody bevacizumab and the mTOR/hypoxia inducible factor inhibitor temsirolimus combined with liposomal doxorubicin: tolerance and biological activity. AB - PURPOSE: Preclinical data suggest that combining the mTOR/hypoxia-inducible factor (HIF) inhibitor temsirolimus and the antiangiogenesis antibody bevacizumab may augment antitumor activity as well as resensitize cells to anthracyclines. EXPERIMENTAL DESIGN: We initiated a phase I study of bevacizumab and temsirolimus plus liposomal doxorubicin in patients with advanced malignancies. Patients (N = 136) were enrolled according to a modified 3 + 3 design plus dose expansion in responsive tumor types. RESULTS: The most common cancers were breast (n = 29), epithelial ovarian (n = 23), and colorectal cancer (n = 17). The median number of prior chemotherapy regimens was four (range: 0-16). Grade 3 or higher adverse events (> 5%) included pancytopenia, mucositis, hand-foot syndrome, hypertension, and fistula. This regimen led to a 21% (n = 28) stable disease (SD) >= 6 months and 21% (n = 29) rate of partial or complete remission [PR/CR; (total SD >= 6 months/PR/CR = 42% (n = 57)]. PR/CR was most common in parotid gland adenocarcinoma (4/6, 67%), metaplastic breast cancer (5/12, 42%), endometrial endometrioid carcinoma (6/15, 40%), and in patients with a PIK3CA mutation and/or a PTEN mutation/loss (11/28, 39%). The maximum tolerated dose was liposomal doxorubicin 30 mg/m(2) and bevacizumab 15 mg/kg every three weeks with temsirolimus 25 mg weekly. CONCLUSIONS: Patients tolerated bevacizumab and temsirolimus together with liposomal doxorubicin. Further evaluation, especially in patients with parotid, metaplastic breast, and endometrial endometrioid cancer, and in patients with PIK3CA and/or PTEN aberrations is warranted. PMID- 22927483 TI - Ontogeny and sorafenib metabolism. AB - PURPOSE: To investigate the role of ontogeny in sorafenib metabolism to the equipotent active metabolite sorafenib N-oxide. EXPERIMENTAL DESIGN: Steady-state pharmacokinetic studies of sorafenib and metabolites were conducted in 30 children and young adults (17 males; median age, 9.5 years) receiving sorafenib 150 mg/m(2) or 200 mg/m(2) twice daily. Sorafenib metabolism was evaluated in vitro at 10 MUmol/L using a panel of purified human cytochrome P450 (CYP) enzymes. Sorafenib metabolism and CYP3A4 expression was evaluated in 52 human liver samples from donors of <=20 years old. The drug-drug interaction potential between sorafenib and azole antifungal agents was evaluated in vitro and in vivo. RESULTS: No age-related differences in sorafenib apparent oral clearance were observed. Mean sorafenib N-oxide metabolite ratio was 0.27 +/- 0.14. In children of <=10 years of age, boys had approximately 2-fold higher N-oxide ratios than girls (0.40 +/- 0.15 vs. 0.22 +/- 0.12, P = 0.026). Of the CYPs evaluated, sorafenib was exclusively metabolized to sorafenib N-oxide by CYP3A4. A trend for increased N-oxide formation in boys was observed in liver samples, which correlated with CYP3A4 mRNA expression. Posaconazole and voriconazole potently inhibited sorafenib N-oxide formation in vitro, and reduced sorafenib N-oxide formation in 3 children given sorafenib concurrent with azoles. CONCLUSION: We have identified several factors affecting interpatient variability in sorafenib metabolism to the active N-oxide metabolite including age, sex, and concurrent treatment with azole antifungals. This knowledge may provide important considerations for the clinical use of sorafenib in children and possibly other kinase inhibitors undergoing CYP3A4-mediated metabolism. PMID- 22927484 TI - Developing and validating continuous genomic signatures in randomized clinical trials for predictive medicine. AB - PURPOSE: It is highly challenging to develop reliable diagnostic tests to predict patients' responsiveness to anticancer treatments on clinical endpoints before commencing the definitive phase III randomized trial. Development and validation of genomic signatures in the randomized trial can be a promising solution. Such signatures are required to predict quantitatively the underlying heterogeneity in the magnitude of treatment effects. EXPERIMENTAL DESIGN: We propose a framework for developing and validating genomic signatures in randomized trials. Codevelopment of predictive and prognostic signatures can allow prediction of patient-level survival curves as basic diagnostic tools for treating individual patients. RESULTS: We applied our framework to gene-expression microarray data from a large-scale randomized trial to determine whether the addition of thalidomide improves survival for patients with multiple myeloma. The results indicated that approximately half of the patients were responsive to thalidomide, and the average improvement in survival for the responsive patients was statistically significant. Cross-validated patient-level survival curves were developed to predict survival distributions of individual future patients as a function of whether or not they are treated with thalidomide and with regard to their baseline prognostic and predictive signature indices. CONCLUSION: The proposed framework represents an important step toward reliable predictive medicine. It provides an internally validated mechanism for using randomized clinical trials to assess treatment efficacy for a patient population in a manner that takes into consideration the heterogeneity in patients' responsiveness to treatment. It also provides cross-validated patient-level survival curves that can be used for selecting treatments for future patients. PMID- 22927485 TI - Increasing use of radical prostatectomy for nonlethal prostate cancer in Sweden. AB - PURPOSE: The number of patients in Sweden treated with radical prostatectomy for localized prostate cancer has increased exponentially. The extent to which this increase reflects treatment of nonlethal disease detected through prostate specific antigen (PSA) screening is unknown. EXPERIMENTAL DESIGN: We undertook a nationwide study of all 18,837 patients with prostate cancer treated with radical prostatectomy in Sweden from 1988 to 2008 with complete follow-up through 2009. We compared cumulative incidence curves, fit Cox regression and cure models, and conducted a simulation study to determine changes in treatment of nonlethal cancer, in cancer-specific survival over time, and effect of lead-time due to PSA screening. RESULTS: The annual number of radical prostatectomies increased 25 fold during the study period. The 5-year cancer-specific mortality rate decreased from 3.9% [95% confidence interval (CI), 2.5-5.3] among patients diagnosed between 1988 and 1992 to 0.7% (95% CI, 0.4-1.1) among those diagnosed between 1998 and 2002 (P(trend) < 0.001). According to the cure model, the risk of not being cured declined by 13% (95% CI, 12%-14%) with each calendar year. The simulation study indicated that only about half of the improvement in disease specific survival could be accounted for by lead-time. CONCLUSION: Patients overdiagnosed with nonlethal prostate cancer appear to account for a substantial and growing part of the dramatic increase in radical prostatectomies in Sweden, but increasing survival rates are likely also due to true reductions in the risk of disease-specific death over time. Because the magnitude of harm and costs due to overtreatment can be considerable, identification of men who likely benefit from radical prostatectomy is urgently needed. PMID- 22927486 TI - 'Tempos' management in primary care: a key factor for classifying adverse events, and improving quality and safety. AB - BACKGROUND: The role of time management in safe and efficient medicine is important but poorly incorporated into the taxonomies of error in primary care. This paper addresses the lack of time management, presenting a framework integrating five time scales termed 'Tempos' requiring parallel processing by GPs: the disease's tempo (unexpected rapid evolutions, slow reaction to treatment); the office's tempo (day-to-day agenda and interruptions); the patient's tempo (time to express symptoms, compliance, emotion); the system's tempo (time for appointments, exams, and feedback); and the time to access to knowledge. The art of medicine is to control all of these tempos in parallel and simultaneously. METHOD: Two qualified physicians reviewed a sample of 1046 malpractice claims from one liability insurer to determine whether a medical injury had occurred and, if so, whether it was due to one or more tempo-related problems. 623 of these reports were analysed in greater detail to identify the prevalence and characteristics of claims and related time management errors. RESULTS: The percentages of contributing factors were as follows: disease tempo, 37.9%; office tempo, 13.2%; patient tempo, 13.8%; out-of-office coordination tempo, 22.6%; and GP's access to knowledge tempo, 33.2%. CONCLUSION: Although not conceptualised in most error taxonomies, the disease and patient tempos are cornerstones in risk management in primary care. Traditional taxonomies describe events from an analytical perspective of care at the system level and offer opportunities to improve organisation, process, and evidence-based medicine. The suggested classification describes events in terms of (unsafe) dynamic control of parallel constraints from the carer's perspective, namely the GP, and offers improvement on how to self manage and coordinate different contradictory tempos and day-to-day activities. Further work is needed to test the validity and usefulness of this approach. PMID- 22927487 TI - Preventable deaths due to problems in care in English acute hospitals: a retrospective case record review study. AB - INTRODUCTION: Monitoring hospital mortality rates is widely recommended. However, the number of preventable deaths remains uncertain with estimates in England ranging from 840 to 40 000 per year, these being derived from studies that identified adverse events but not whether events contributed to death or shortened life expectancy of those affected. METHODS: Retrospective case record reviews of 1000 adults who died in 2009 in 10 acute hospitals in England were undertaken. Trained physician reviewers estimated life expectancy on admission, to identified problems in care contributing to death and judged if deaths were preventable taking into account patients' overall condition at that time. RESULTS: Reviewers judged 5.2% (95% CI 3.8% to 6.6%) of deaths as having a 50% or greater chance of being preventable. The principal problems associated with preventable deaths were poor clinical monitoring (31.3%; 95% CI 23.9 to 39.7), diagnostic errors (29.7%; 95% CI 22.5% to 38.1%), and inadequate drug or fluid management (21.1%; 95% CI 14.9 to 29.0). Extrapolating from these figures suggests there would have been 11 859 (95% CI 8712 to 14 983) adult preventable deaths in hospitals in England. Most preventable deaths (60%) occurred in elderly, frail patients with multiple comorbidities judged to have had less than 1 year of life left to live. CONCLUSIONS: The incidence of preventable hospital deaths is much lower than previous estimates. The burden of harm from preventable problems in care is still substantial. A focus on deaths may not be the most efficient approach to identify opportunities for improvement given the low proportion of deaths due to problems with healthcare. PMID- 22927488 TI - A nationwide hospital survey on patient safety culture in Belgian hospitals: setting priorities at the launch of a 5-year patient safety plan. AB - OBJECTIVE: To measure patient safety culture in Belgian hospitals and to examine the homogeneous grouping of underlying safety culture dimensions. METHODS: The Hospital Survey on Patient Safety Culture was distributed organisation-wide in 180 Belgian hospitals participating in the federal program on quality and safety between 2007 and 2009. Participating hospitals were invited to submit their data to a comparative database. Homogeneous groups of underlying safety culture dimensions were sought by hierarchical cluster analysis. RESULTS: 90 acute, 42 psychiatric and 11 long-term care hospitals submitted their data for comparison to other hospitals. The benchmark database included 55 225 completed questionnaires (53.7% response rate). Overall dimensional scores were low, although scores were found to be higher for psychiatric and long-term care hospitals than for acute hospitals. The overall perception of patient safety was lower in French-speaking hospitals. Hierarchical clustering of dimensions resulted in two distinct clusters. Cluster I grouped supervisor/manager expectations and actions promoting safety, organisational learning-continuous improvement, teamwork within units and communication openness, while Cluster II included feedback and communication about error, overall perceptions of patient safety, non-punitive response to error, frequency of events reported, teamwork across units, handoffs and transitions, staffing and management support for patient safety. CONCLUSION: The nationwide safety culture assessment confirms the need for a long-term national initiative to improve patient safety culture and provides each hospital with a baseline patient safety culture profile to direct an intervention plan. The identification of clusters of safety culture dimensions indicates the need for a different approach and context towards the implementation of interventions aimed at improving the safety culture. Certain clusters require unit level improvements, whereas others demand a hospital-wide policy. PMID- 22927489 TI - Participatory healthcare-provider orientation to improve artemether-lumefantrine based drug treatment of uncomplicated malaria: a cluster quasi-experimental study. AB - OBJECTIVES: To assess the effect of participatory healthcare-provider orientation in enhancing patient knowledge, appropriate prescribing and dispensing of artemether-lumefantrine, during drug treatment of uncomplicated malaria. METHODS: A cluster quasi-experimental study. The authors developed strategies to address challenges encountered by healthcare providers during clinical management of malaria. The primary outcome was patient knowledge on prescribed malaria drug treatment. Secondary outcomes were appropriate prescribing and provision of adequate drug dispensing information. The authors used generalised estimating equation logistic regression to investigate correlates of appropriate use of artemether-lumefantrine. RESULTS: The proportion of patients or caretakers of paediatric patients sufficiently knowledgeable about malaria treatment increased from 16/85 (18.8%) at baseline to 33/96 (34.4%) at evaluation, OR 2.26 (95% CI 1.13 to 4.49), p=0.020, in the intervention, and fell slightly from 49/134 (36.6%) to 35/114 (30.7%), OR 0.77, (95% CI 0.45 to 1.31), p=0.331 in the control district. This was enhanced by the existence of drug-dispensing standard operating procedures (adjusted OR 1.85, 95% CI 0.98 to 3.50; p=0.057). The proportion of appropriate prescriptions increased from 61/87 (70.1%) to 94/112 (83.9%) in the intervention district, OR 2.23 (95% CI 1.13 to 4.40), p=0.020 and reduced from 91/115 (79.1%) to 75/112 (67.0%) in the control district, OR 0.53, (95% CI 0.29 to 0.97), p=0.040. The frequency of adequately dispensed prescriptions increased in the intervention district (34(32.4%) to 53(45.3%), OR 1.73 (95% CI 1.00 to 2.99), p=0.050) but decreased in the control location (94 (69.6%) to 71 (52.6%), OR 0.48 (95% CI 0.29 to 0.80), p=0.004). CONCLUSIONS: Participatory healthcare-provider orientation enhanced patient knowledge, healthcare provider prescribing and dispensing of artemether-lumefantrine, bolstered by adequate medication counselling and use of drug-dispensing standard operating procedures. PMID- 22927490 TI - Visualising differences in professionals' perspectives on quality and safety. AB - BACKGROUND: The safety-and-quality movement is now two decades old. Errors persist despite best efforts, indicating that there are entrenched overt and perhaps less explicit barriers limiting the success of improvement efforts. OBJECTIVES AND HYPOTHESES: To examine the perspectives of five groups of healthcare workers (administrative staff, nurses, medical practitioners, allied health and managers) and to compare and contrast their descriptions of quality and-safety activities within their organisation. Differences in perspectives can be an indicator of divergence in the conceptualisation of, and impetus for, quality-improvement strategies which are intended to engage healthcare professions and staff. DESIGN, SETTING AND PARTICIPANTS: Study data were collected in a defined geographical healthcare jurisdiction in Australia, via individual and group interviews held across four service streams (aged care and rehabilitation; mental health; community health; and cancer services). Data were collected in 2008 and analysed, using data-mining software, in 2009. RESULTS: Clear differences in the perspectives of professional groups were evident, suggesting variations in the perceptions of, and priorities for, quality and safety. CONCLUSIONS: The visual representation of quality and safety perspectives provides insights into the conceptual maps currently utilised by healthcare workers. Understanding the similarity and differences in these maps may enable more effective targeting of interprofessional improvement strategies. PMID- 22927491 TI - Analysis of risk of medical errors using structural-equation modelling: a 6-month prospective cohort study. AB - BACKGROUND: Medical-error analyses have been conducted to determine the root cause of adverse events and near misses. More precise determination of the cause and-effect relationship likely will require a prospective design path analysis including both direct and indirect effects. METHODS: The authors performed a 6 month prospective cohort study using structural-equation modelling (SEM). Of the 879 nurses approached, 789 (89.8%) were included in the final analysis. Potential predictors provided for analysis included age, years of nursing experience, mean frequency of night shifts per month, nursing-specific job stressors, degree of depression, frequency of feeling unskilled, feeling time pressure, feeling a lack of communication between self and other hospital staff members, frequency of suffering from sleep disturbance and frequency of feeling a decrease in attention. The authors regarded a latent variable composed of frequencies for near misses and adverse events as an outcome. RESULTS AND CONCLUSION: The SEM model constructed in this study suggested that potential root causes (exogenous variables directly or indirectly connected to the outcome which are not affected by other variables) were years of nursing experience, feeling unskilled, job stressors and sleep disturbance, with estimated standardised total (direct and indirect) effects of -0.22, 0.21, 0.008 and 0.005, respectively. A prospective design path analysis using the SEM model for both direct and indirect effects enabled a statistical exploration of root causes and estimation of their impact on the outcome. Our findings suggested such an analysis to be useful in devising countermeasures against medical errors. PMID- 22927492 TI - Predictors of likelihood of speaking up about safety concerns in labour and delivery. AB - BACKGROUND: Despite widespread emphasis on promoting 'assertive communication' by care givers as essential to patient-safety-improvement efforts, little is known about when and how clinicians speak up to address safety concerns. In this cross sectional study, the authors use a new measure of speaking up to begin exploring this issue in maternity care. METHODS: The authors developed a scenario-based measure of clinician's assessment of potential harm and likelihood of speaking up in response to perceived harm. The authors embedded this scale in a survey with measures of safety climate, teamwork climate, disruptive behaviour, work stress, and personality traits of bravery and assertiveness. The survey was distributed to all registered nurses and obstetricians practising in two US Labour & Delivery units. RESULTS: The response rate was 54% (125 of 230 potential respondents). Respondents were experienced clinicians (13.7+/-11 years in specialty). A higher perception of harm, respondent role, specialty experience and site predicted the likelihood of speaking up when controlling for bravery and assertiveness. Physicians rated potential harm in common clinical scenarios lower than nurses did (7.5 vs 8.4 on 2-10 scale; p<0.001). Some participants (12%) indicated they were unlikely to speak up, despite perceiving a high potential for harm in certain situations. DISCUSSION: This exploratory study found that nurses and physicians differed in their harm ratings, and harm rating was a predictor of speaking up. This may partially explain persistent discrepancies between physicians and nurses in teamwork climate scores. Differing assessments of potential harms inherent in everyday practice may be a target for teamwork intervention in maternity care. PMID- 22927493 TI - Effects of plant-community composition on the vectorial capacity and fitness of the malaria mosquito Anopheles gambiae. AB - Dynamics of Anopheles gambiae abundance and malaria transmission potential rely strongly on environmental conditions. Female and male An. gambiae use sugar and are affected by its absence, but how the presence or absence of nectariferous plants affects An. gambiae abundance and vectorial capacity has not been studied. We report on four replicates of a cohort study performed in mesocosms with sugar poor and sugar-rich plants, in which we measured mosquito survival, biting rates, and fecundity. Survivorship was greater with access to sugar-rich plant species, and mortality patterns were age-dependent. Sugar-poor populations experienced Weibull mortality patterns, and of four populations in the sugar-rich environment, two female and three male subpopulations were better fitted by Gompertz functions. A tendency toward higher biting rates in sugar-poor mesocosms, particularly for young females, was found. Therefore, vectorial capacity was pulled in opposing directions by nectar availability, resulting in highly variable vectorial capacity values. PMID- 22927494 TI - North American birds as potential amplifying hosts of Japanese encephalitis virus. AB - Japanese encephalitis virus (JEV) is an emerging arbovirus, and inter-continental spread is an impending threat. The virus is maintained in a transmission cycle between mosquito vectors and vertebrate hosts, including birds. We detected variation in interspecies responses among North American birds to infection with strains of two different JEV genotypes (I and III). Several native North American passerine species and ring-billed gulls had the highest average peak viremia titers after inoculation with a Vietnamese (genotype I) JEV strain. Oral JEV shedding was minimal and cloacal shedding was rarely detected. The majority of birds, both viremic (72 of 74; 97.3%) and non-viremic (31 of 37; 83.8%), seroconverted by 14 days post-inoculation and West Nile virus-immune individuals had cross-protection against JEV viremia. Reservoir competence and serologic data for a variety of avian taxa are important for development of JEV surveillance and control strategies and will aid in understanding transmission ecology in the event of JEV expansion to North America. PMID- 22927495 TI - Assessment of the molecular marker of Plasmodium falciparum chloroquine resistance (Pfcrt) in Senegal after several years of chloroquine withdrawal. AB - As a result of widespread antimalarial drug resistance, all African countries with endemic malaria have, in recent years, changed their malaria treatment policy. In Senegal, the health authorities changed from chloroquine (CQ) to a combination of sulfadoxine-pyrimethamine (SP) plus amodiaquine (AQ) in 2003. Since 2006, the artemisinin combination therapies (ACTs) artemether-lumefantrine (AL) and artesunate plus amodiaquine (AS/AQ) were adopted for uncomplicated malaria treatment. After several years of CQ withdrawal, the current study wished to determine the level of CQ resistance at the molecular level in selected sites in Senegal, because the scientific community is interested in using CQ again. Finger prick blood samples were collected from Plasmodium falciparum-positive children below the age of 10 years (N = 474) during cross-sectional surveys conducted in two study sites in Senegal with different malaria transmission levels. One site is in central Senegal, and the other site is in the southern part of the country. All samples were analyzed for single nucleotide polymorphisms (SNPs) in the P. falciparum CQ resistance transporter gene (Pfcrt; codons 72-76) using polymerase chain reaction (PCR) sequence-specific oligonucleotide probe (SSOP) enzyme-linked immunosorbent assay (ELISA) and real time PCR methods. In total, the 72- to 76-codon region of Pfcrt was amplified in 449 blood samples (94.7%; 285 and 164 samples from the central and southern sites of Senegal, respectively). In both study areas, the prevalence of the Pfcrt wild type single CVMNK haplotype was very high; in central Senegal, the prevalence was 70.5% in 2009 and 74.8% in 2010, and in southern Senegal, the prevalence was 65.4% in 2010 and 71.0% in 2011. Comparing data with older studies in Senegal, a sharp decline in the mutant type Pfcrt prevalence is evident: from 65%, 64%, and 59.5% in samples collected from various sites in 2000, 2001, and 2004 to approximately 30% in our study. A similar decrease in mutant type prevalence is noted in other neighboring countries. With the continued development of increased CQ susceptibility in many African countries, it may be possible to reintroduce CQ in the near future in a drug combination; it could possibly be given to non vulnerable groups, but it demands close monitoring of possible reemergence of CQ resistance development. PMID- 22927496 TI - Occurrence of Paracoccidioides lutzii in the Amazon region: description of two cases. AB - Paracoccidioidomycosis (PCM), the most important human systemic mycosis in Latin America, is known to be caused by at least four different phylogenetic lineages within the Paracoccidioides brasiliensis complex, including S1, PS2, PS3, and Pb01-like group. Herein, we describe two cases of PCM in patients native from the Amazon region. The disease was originally thought to have been caused by P. brasiliensis. Despite the severity of the cases, sera from the patients were negative in immunodiffusion tests using the standard exoantigen from P. brasiliensis B-339. However, a positive response was recorded with an autologous preparation of Paracoccidioides lutzii exoantigen. A phylogenetic approach based on the gp43 and ARF loci revealed high similarity between our clinical isolates and the Pb01-like group. The occurrence of PCM caused by P. lutzii in the Brazilian Amazon (Para State) was thus proven. The incidence of PCM caused by P. lutzii may be underestimated in northern Brazil. PMID- 22927497 TI - In vitro antileishmanial drug susceptibility of clinical isolates from patients with Indian visceral leishmaniasis--status of newly introduced drugs. AB - Regional variations in susceptibility of Leishmania donovani clinical isolates have been reported to antimonials but not other antileishmanial drugs. Therefore, we evaluated the susceptibility of four antileishmanial drugs in clinical use in 28 clinical isolates from endemic and non-endemic regions in the J774A.1 macrophage cell line, and we found increased tolerance of miltefosine and paromomycin in isolates from a patient from a high endemic region. Effective dose for 90% killing (ED(90)) values were significantly higher for miltefosine (P = 0.005) and paromomycin (P = 0.02) in isolates from the high endemic region, although there were no significant differences between ED(50) values for paromomycin, miltefosine, and amphotericin B in the non- versus endemic region isolates. This report is the first of higher ED(90) values for miltefosine and paromomycin indicating susceptibility difference between regions for these newly introduced drugs by the parasite, and their use should be carefully monitored through directly observed therapy or multidrug treatment to preserve their efficacy for longer periods. PMID- 22927498 TI - Income and health in Accra, Ghana: results from a time use and health study. AB - This paper uses newly collected household survey data from Accra, Ghana, to investigate whether incomes affect acute and chronic health outcomes in settings that can be considered representative for the large and rapidly growing urban centers of sub-Saharan Africa. The Time Use and Health Study in Accra collected information on incomes, current health status, and health care use from 5,484 persons in 1,250 households, each repeatedly sampled on a rolling basis for a period of 13 weeks. Data collection took place during September 2008-March 2010 to capture seasonal variations. The study found that incomes varied widely between households, and that a high fraction of persons lived below the poverty line. Despite this level of income poverty and an overall remarkably high burden of treatable disease, no systematic differences in self-reported and objectively measured health conditions were detected across socioeconomic groups. PMID- 22927499 TI - Use of fecal occult blood tests as epidemiologic indicators of morbidity associated with intestinal schistosomiasis during preventive chemotherapy in young children. AB - There is a need for field-applicable markers to assess morbidity associated with intestinal schistosomiasis, especially in the context of preventive chemotherapy in young children. We investigated whether fecal occult blood (FOB) point-of-care tests could be used to assess intestinal pathology over a 12-month period in a cohort of 382 children (< 5 years of age). We found a strong association between egg-patent schistosomiasis and FOB at baseline (odds ratio [OR] = 3.1, P < 0.0001), 6 months (OR = 3.4, P < 0.0001), and 12 months (OR = 3.5, P < 0.0001), despite repeated chemotherapy. There were tendencies for prevalence of FOB to decrease in children who became egg negative and increase in those who became egg positive. Our results demonstrate overt disease in children less than five years of age. We therefore propose that FOB is useful for assessing dynamics of intestinal morbidity in young children at the community level and monitoring changes in morbidity after mass chemotherapy. PMID- 22927500 TI - Kinematic and kinetic evaluation of the stance phase of stair ambulation in persons with stroke and healthy adults: a pilot study. AB - This study describes and contrasts the kinematics and kinetics of stair ambulation in people with chronic stroke and healthy control subjects. Three dimensional motion data were collected from 10 persons with stroke (7 males) and 10 sex and age-matched older adults as they ascended and descended an instrumented staircase at self-selected speed with and without a handrail. Ankle, knee and hip joint angle and moment profiles were generated during stance and range of motion and peak moments were contrasted between groups, sides (stroke only) and condition. Cadence was lower in stroke than controls, although the kinematic profiles appeared similar during ascent and decent. Notable differences in joint kinetics were evident as the peak extensor moments were typically lower on the affected side in stroke compared with controls and the less affected side. These differences accounted for the lower magnitude net extensor support moment. The lower affected side hip abductor moments likely limited lateral stability. Handrail use tended to reduce the peak moments on the affected side only leading to more side-to-side differences than occurred without the handrail. The findings reveal differences in task performance between stroke and healthy groups that help inform rehabilitation practice. PMID- 22927501 TI - Age-related differences in center of pressure measures during one-leg stance are time dependent. AB - The aim of this study was to evaluate the changes in center of pressure (COP) movement in four time intervals (5, 10, 15 and 30 s) during a one-leg stance test performed by young and elderly adults. Twelve young adults (mean 20 years) and 12 elderly subjects (mean 68 years) participated in this study. The subjects performed three 30 s trials of an eyes open one-leg stance test on a force platform, in which the COP parameter was computed at four points in time from same original COP signal. Significant differences were found between the young and elderly adults (P < .007) only at the 10, 15 and 30 s intervals. For both groups, COP changes were significantly different between the 5 s time interval and other intervals (10, 15 and 30 s). In conclusion, these results pointed out that age-related difference in COP changes were time dependent. This suggests that the use of longer durations increases the possibility of distinguishing more subtle differences in postural strategy among different groups of subjects. PMID- 22927503 TI - Humeral head translation after a suprascapular nerve block. AB - Subacromial impingement syndrome is the most common shoulder disorder. Abnormal superior translation of the humeral head is believed to be a major cause of this pathology. The first purpose of the study was to examine the effects of suprascapular nerve block on superior translation of the humeral head and scapular upward rotation during dynamic shoulder elevation. The secondary purpose was to assess muscle activation patterns during these motions. Twenty healthy subjects participated in the study. Using fluoroscopy and electromyography, humeral head translation and muscle activation were measured before and after a suprascapular nerve block. The humeral head was superiorly located at 60 degrees of humeral elevation, and the scapula was more upwardly rotated from 30 to 90 degrees of humeral elevation after the block. The differences were observed during midrange of motion. In addition, the deltoid muscle group demonstrated increased muscle activation after the nerve block. The study's results showed a compensatory increase in humeral head translation, scapular upward rotation, and deltoid muscle activation due to the nerve block. These outcomes suggest that increasing muscular strength and endurance of the supraspinatus and infraspinatus muscles could prevent any increased superior humeral head translation. This may be beneficial in reducing shoulder impingement or rotator cuff tears over time. PMID- 22927504 TI - What is the influence of cambered running surface on lower extremity muscle activity? AB - Running on a road for fitness, sport, or recreation poses unique challenges to the runner, one of which is the camber of the surface. Few studies have examined the effects of camber on running, namely, kinematic studies of the knee and ankle. There is currently no information available regarding muscle response to running on a cambered road surface. The purpose of this study was to investigate the effects of a cambered road on lower extremity muscle activity, as measured by electromyography in recreational runners. In addition, this study examined a true outdoor road surface, as opposed to a treadmill surface. The mean muscle activity of the tibialis anterior, lateral gastrocnemius, vastus medialis oblique, biceps femoris, and gluteus medius were studied. Fifteen runners completed multiple running trials on cambered and level surfaces. During the stance phase, mean activities of tibialis anterior, lateral gastrocnemius, and vastus medialis oblique were greater on the gutter side than the crown side. There were no differences in mean muscle activity during the swing phase. The findings of this study suggest that running on a road camber alters the activity of select lower extremity muscles possibly in response to lower extremity compensations to the cambered condition. PMID- 22927505 TI - Cognitive outcomes following contemporary treatment without cranial irradiation for childhood acute lymphoblastic leukemia. AB - BACKGROUND: Treatment of acute lymphoblastic leukemia (ALL) has included the use of prophylactic cranial irradiation in up to 20% of children with high-risk disease despite known cognitive risks of this treatment modality. METHODS: Patients enrolled on the St Jude ALL Total Therapy Study XV, which omitted prophylactic cranial irradiation in all patients, were assessed 120 weeks after completion of consolidation therapy (n = 243) using a comprehensive cognitive battery. chi(2) analysis was used to compare the percentage of below-average performers among the entire ALL patient group to the expected rate based on the normative sample. Univariate logistic regression was used to estimate the effect of intensity of chemotherapy (treatment arm), age at diagnosis, and sex on the probability of below-average performance. All statistical tests were two-sided. RESULTS: Overall, the ALL group had a statistically significantly higher risk for below-average performance on a measure of sustained attention (67.31% more than 1 SD below the normative mean for omission errors, P < .001) but not on measures of intellectual functioning, academic skills, or memory. Patients given higher intensity chemotherapy were at greater risk for below-average performance compared with those given lower intensity therapy on measures of processing speed (27.14% vs 6.25%, P = .009) and academic abilities (Math Reasoning: 18.60% vs 3.90%, P = .008; Word Reading: 20.00% vs 2.60%, P = .007; Spelling: 27.91% vs 3.90%, P = .001) and had higher parent-reported hyperactivity (23.00% vs 9.84%, P = .018) and learning problems (35.00% vs 16.39%, P = .005). Neither age at diagnosis nor sex was associated with risk for below-average cognitive performance. CONCLUSIONS: Omitting cranial irradiation may help preserve global cognitive abilities, but treatment with chemotherapy alone is not without risks. Caregiver education and development of interventions should address both early attention deficits and cognitive late effects. PMID- 22927507 TI - Relationship between muscle architecture and joint performance during concentric contractions in humans. AB - The purpose of this study was to examine the relationship between muscle architecture of the triceps brachii (TB) and joint performance during concentric elbow extensions. Twenty-two men performed maximal isometric and concentric elbow extensions against various loads. Joint torque and angular velocity during concentric contractions were measured, and joint power was calculated. Muscle length, cross-sectional areas, and volume of TB were measured from magnetic resonance images. Pennation angle (PA) of TB at rest was determined by ultrasonography. The PA was significantly correlated with the maximal isometric torque (r = .471), but not to the torque normalized by muscle volume (r = .312). A significant correlation was found between PA and the angular velocity at 0 kg load (r = .563), even when the angular velocity was normalized by the muscle length (r = .536). The PA was significantly correlated with the maximal joint power (r = .519), but not with the power normalized by muscle volume (r = .393). These results suggest that PA has a positive influence on the muscle shortening velocity during an unloaded movement, but does not have a significant influence on the maximum power generation in untrained men. PMID- 22927506 TI - When progressive disease does not mean treatment failure: reconsidering the criteria for progression. AB - Although progression-based endpoints, such as progression-free survival, are often key clinical trial endpoints for anticancer agents, the clinical meaning of "objective progression" is much less certain. As scrutiny of progression-based endpoints in clinical trials increases, it should be remembered that the Response Evaluation Criteria In Solid Tumors (RECIST) progression criteria were not developed as a surrogate for survival. Now that progression-free survival has come to be an increasingly important trial endpoint, the criteria that define progression deserve critical evaluation to determine whether alternate definitions of progression might facilitate the development of stronger surrogate endpoints and more meaningful trial results. In this commentary, we review the genesis of the criteria for progression, highlight recent data that question their value as a marker of treatment failure, and advocate for several research strategies that could lay the groundwork for a clinically validated definition of disease progression in solid tumor oncology. PMID- 22927508 TI - False-positive human T-lymphotropic virus serology after intravenous immunoglobulin transfusion. PMID- 22927511 TI - Resolving the market mysteries of medical isotopes. PMID- 22927509 TI - Incidence and causes of end-stage renal disease among Aboriginal children and young adults. AB - BACKGROUND: Although Aboriginal adults have a higher risk of end-stage renal disease than non-Aboriginal adults, the incidence and causes of end-stage renal disease among Aboriginal children and young adults are not well described. METHODS: We calculated age- and sex-specific incidences of end-stage renal disease among Aboriginal people less than 22 years of age using data from a national organ failure registry. Incidence rate ratios were used to compare rates between Aboriginal and white Canadians. To contrast causes of end-stage renal disease by ethnicity and age, we calculated the odds of congenital diseases, glomerulonephritis and diabetes for Aboriginal people and compared them with those for white people in the following age strata: 0 to less than 22 years, 22 to less than 40 years, 40 to less than 60 years and older than 60 years. RESULTS: Incidence rate ratios of end-stage renal disease for Aboriginal children and young adults (age < 22 yr, v. white people) were 1.82 (95% confidence interval [CI] 1.40-2.38) for boys and 3.24 (95% CI 2.60-4.05) for girls. Compared with white people, congenital diseases were less common among Aboriginal people aged less than 22 years (odds ratio [OR] 0.56, 95% CI 0.36-0.86), and glomerulonephritis was more common (OR 2.18, 95% CI 1.55-3.07). An excess of glomerulonephritis, but not diabetes, was seen among Aboriginal people aged 22 to less than 40 years. The converse was true (higher risk of diabetes, lower risk of glomerulonephritis) among Aboriginal people aged 40 years and older. INTERPRETATION: The incidence of end-stage renal disease is higher among Aboriginal children and young adults than among white children and young adults. This higher incidence may be driven by an increased risk of glomerulonephritis in this population. PMID- 22927512 TI - Advances in the management of colonic diverticulitis. PMID- 22927513 TI - Checklists. PMID- 22927514 TI - Muehrcke lines. PMID- 22927515 TI - Professionalism: the importance of trust. PMID- 22927516 TI - Enter at your own risk: government changes to comprehensive care for newly arrived Canadian refugees. PMID- 22927517 TI - Among medicine's most enduring myths. PMID- 22927518 TI - The effect of external compression on the mechanics of muscle contraction. AB - The velocity at which a muscle fascicle will shorten, and hence the force that it can develop, depends on its gearing within the muscle belly. Muscle fascicle length depends on both its pennation and the thickness of the muscle. It was expected that external compression would reduce the muscle thickness and pennation and thus cause a reduction to the gearing of the fascicles relative to the muscle belly. Structural properties of the medial gastrocnemius muscle were visualized using B-mode ultrasound in six subjects. Measurements were taken during cyclical isotonic contractions at three different ankle torques and with the application of no, one, or two elastic compression bandages to the lower leg. Ankle torques and angular velocities were unaffected by the external compression. External compression did, however, reduce the muscle thickness and the fascicle pennation and resulted in a decrease in the gearing within the muscle belly. Reductions in gearing would result in an increase in the muscle fascicle shortening velocity that would reduce the force-generating potential of the fascicles. It is suggested that externally applied compression should not be considered a way to enhance muscle performance when based on the structural mechanics. PMID- 22927519 TI - Not all aggressive adult T-cell leukemia/lymphoma subtypes are created equal. PMID- 22927520 TI - Use of aspirin, other nonsteroidal anti-inflammatory drugs, and acetaminophen and postmenopausal breast cancer incidence. AB - PURPOSE: The associations between use of aspirin, other nonsteroidal anti inflammatory drugs (NSAIDs), and acetaminophen and breast cancer incidence in postmenopausal women are uncertain. We examined these associations with breast cancer, both overall and by molecular subtype. PATIENTS AND METHODS: We observed 84,602 postmenopausal women, free of cancer in 1980, until June 2008 and prospectively collected data on analgesic use, reproductive history, and other lifestyle factors using biennial questionnaires. Proportional hazards models were used to estimate multivariable relative risks (RRs) and 95% CIs. RESULTS: We documented 4,734 cases of incident invasive breast cancer. Compared with nonuse of aspirin, multivariable RRs of regular aspirin use (>= two tablets per week) for more than 20 years were 0.91 for overall breast cancer (95% CI, 0.81 to 1.01; P(trend) = 0.16), 0.90 for estrogen receptor (ER) -positive progesterone receptor (PR) -positive breast cancer (95% CI, 0.77 to 1.06; P(trend) = 0.17), and 0.91 for ER-negative PR-negative breast cancer (95% CI, 0.68 to 1.22; P(trend) = 0.97). Results did not vary appreciably by past or current use, days per week of use, or dosage of use. Use of other NSAIDs and acetaminophen was largely not significantly associated with breast cancer risk. Additionally, use of higher doses of each analgesic (>= six tablets per week) for more than 10 years was generally not significantly associated with risk of breast cancer, either overall or by subtype. Furthermore, largely no substantial associations were noted for breast cancer molecular subtypes, including luminal A, luminal B, triple negative, basal-like, human epidermal growth factor receptor 2 positive, cyclooxygenase-2 (COX-2) negative, and COX-2 positive. CONCLUSION: Our study suggests that use of aspirin, other NSAIDs, and acetaminophen is not importantly associated with risk of postmenopausal breast cancer, either overall or by specific subtype. PMID- 22927521 TI - Tumor stage affects risk and prognosis of contralateral breast cancer: results from a large Swedish-population-based study. AB - PURPOSE: The number of breast cancer survivors at risk of developing contralateral breast cancer (CBC) is increasing. However, ambiguity remains regarding risk factors and prognosis for women with CBC. PATIENTS AND METHODS: In a cohort of 42,670 women with breast cancer in the Uppsala/Orebro and Stockholm regions in Sweden in 1992 to 2008, we assessed risk factors for and prognosis of metachronous CBC by using survival analysis. Breast cancer-specific survival for women with CBC was evaluated and compared with results for women with unilateral breast cancer (UBC) by using time-dependent Cox-regression modeling. RESULTS: An increased risk for CBC was observed among women who had primary breast cancer with >= 10 involved lymph nodes compared with node-negative women (adjusted hazard ratio [HR], 1.8; 95% CI, 1.2 to 2.7). The prognosis was poorer in women with CBC than with UBC. The hazard of dying from breast cancer was especially high for women with a short interval time to CBC (adjusted HR, 2.3; 95% CI, 1.8 to 2.8 for CBC diagnosed <= 5 years v UBC) and gradually decreased with longer follow-up time but remained higher than the hazard originating from the primary tumor for >= 10 years. CONCLUSION: Women with advanced-stage primary breast cancer had an increased risk of developing CBC. CBC is associated with an increased risk of dying from breast cancer throughout a long period of follow-up after the primary tumor. Our findings suggest that the event of CBC marks a new clinical situation in terms of investigations for metastases, treatment considerations, and follow-up strategy. PMID- 22927522 TI - Progress against solid tumors in danger: the metastatic breast cancer example. PMID- 22927523 TI - Aspirin use and the risk of prostate cancer mortality in men treated with prostatectomy or radiotherapy. AB - PURPOSE: Experimental evidence suggests that anticoagulants (ACs) may inhibit cancer growth and metastasis, but clinical data have been limited. We investigated whether use of ACs was associated with the risk of death from prostate cancer. PATIENTS AND METHODS: This study comprised 5,955 men in the Cancer of the Prostate Strategic Urologic Research Endeavor database with localized adenocarcinoma of the prostate treated with radical prostatectomy (RP) or radiotherapy (RT). Of them, 2,175 (37%) were receiving ACs (warfarin, clopidogrel, enoxaparin, and/or aspirin). The risk of prostate cancer-specific mortality (PCSM) was compared between the AC and non-AC groups. RESULTS: After a median follow-up of 70 months, risk of PCSM was significantly lower in the AC group compared with the non-AC group (3% v 8% at 10 years; P < .01). The risks of disease recurrence and bone metastasis were also significantly lower. In a subgroup analysis by clinical risk category, the reduction in PCSM was most prominent in patients with high-risk disease (4% v 19% at 10 years; P < .01). The benefit from AC was present across treatment modalities (RT or RP). Analysis by type of AC medication suggested that the PCSM reduction was primarily associated with aspirin. Multivariable analysis indicated that aspirin use was independently associated with a lower risk of PCSM (adjusted hazard ratio, 0.43; 95% CI, 0.21 to 0.87; P = .02). CONCLUSION: AC therapy, particularly aspirin, was associated with a reduced risk of PCSM in men treated with RT or RP for prostate cancer. The association was most prominent in patients with high-risk disease. PMID- 22927524 TI - Single nucleotide polymorphisms and anthracycline cardiotoxicity in children: potential implications for adult oncology. PMID- 22927527 TI - Making genuine progress against metastatic breast cancer. PMID- 22927526 TI - Meta-analysis of cognitive functioning in breast cancer survivors previously treated with standard-dose chemotherapy. AB - PURPOSE: Evidence is mixed regarding long-term cognitive deficits in patients treated with chemotherapy. Previous meta-analyses have not focused specifically on the postchemotherapy period and have not incorporated several recent studies. The goal of the current study was to conduct a meta-analysis of cognitive functioning in breast cancer survivors who were treated with chemotherapy >= 6 months previously. METHODS: A search of PubMed, PsycInfo, Cumulative Index to Nursing and Allied Health Literature, and Cochrane Library yielded 2,751 abstracts, which were independently evaluated by pairs of raters. Meta-analysis was conducted on 17 studies of 807 patients previously treated with standard-dose chemotherapy for breast cancer. Neuropsychological tests were categorized according to eight cognitive domains: attention, executive functioning, information processing, motor speed, verbal ability, verbal memory, visual memory, and visuospatial ability. RESULTS: Deficits in cognitive functioning were observed in patients treated with chemotherapy relative to controls or prechemotherapy baseline in the domains of verbal ability (g = -0.19; P < .01) and visuospatial ability (g = -0.27; P < .01). Patients treated with chemotherapy performed worse than noncancer controls in verbal ability and worse than patients treated without chemotherapy in visuospatial ability (both P < .01). Age, education, time since treatment, and endocrine therapy did not moderate observed cognitive deficits in verbal ability or visuospatial ability (all P >= .51). CONCLUSION: Results indicate that, on average, observed cognitive deficits in patients with breast cancer previously treated with chemotherapy are small in magnitude and limited to the domains of verbal ability and visuospatial ability. This information can be used to inform interventions to educate patients with breast cancer regarding the long-term impact of chemotherapy on cognitive functioning. PMID- 22927525 TI - Phase II trial of cetuximab with or without paclitaxel in patients with advanced urothelial tract carcinoma. AB - PURPOSE: The benefit of salvage chemotherapy is modest in metastatic urothelial cancer. We conducted a randomized, noncomparative phase II study to measure the efficacy of cetuximab with or without paclitaxel in patients with previously treated urothelial cancer. PATIENTS AND METHODS: Patients with metastatic urothelial cancer who received one line of chemotherapy in the perioperative or metastatic setting were randomly assigned to 4-week cycles of cetuximab 250 mg/m(2) with or without paclitaxel 80 mg/m(2) per week. We used early progression as an indicator of futility. Either arm would close if seven of the initial 15 patients in that arm progressed at the first disease evaluation at 8 weeks. RESULTS: We enrolled 39 evaluable patients. The single-agent cetuximab arm closed after nine of the first 11 patients progressed by 8 weeks. The combination arm completed the full accrual of 28 patients, of whom 22 patients (78.5%) had visceral disease. Twelve of 28 patients had progression-free survival greater than 16 weeks. The overall response rate was 25% (95% CI, 11% to 45%; three complete responses and four partial responses). The median progression-free survival was 16.4 weeks (95% CI, 12 to 25.1 weeks), and the median overall survival was 42 weeks (95% CI, 30.4 to 78 weeks). Treatment-related grade 3 and 4 adverse events that occurred in at least two patients were rash (six cases), fatigue (five cases), and low magnesium (three cases). CONCLUSION: Although it had limited activity as a single agent, cetuximab appears to augment the antitumor activity of paclitaxel in previously treated urothelial cancers. The cetuximab and paclitaxel combination merits additional study to establish its role in the treatment of urothelial cancers. PMID- 22927528 TI - Breast cancer risk reduction: no pain, no gain? PMID- 22927529 TI - Accumulating evidence for the effect of chemotherapy on cognition. PMID- 22927531 TI - Treatment of pulmonary metastases in children with stage IV nephroblastoma with risk-based use of pulmonary radiotherapy. AB - PURPOSE: The purpose of this study was to determine the outcome of children with nephroblastoma and pulmonary metastases (PM) treated according to International Society of Pediatric Oncology (SIOP) 93-01 recommendations using pulmonary radiotherapy (RT) in selected patients. PATIENTS AND METHODS: Patients (6 months to 18 years) were treated with preoperative chemotherapy consisting of 6 weeks of vincristine, dactinomycin, and epirubicin or doxorubicin. If pulmonary complete remission (CR) was not obtained, metastasectomy was considered. Patients in CR received three-drug postoperative chemotherapy, whereas patients not in CR were switched to a high-risk (HR) regimen with an assessment at week 11. If CR was not obtained, pulmonary RT was mandatory. RESULTS: Two hundred thirty-four of 1,770 patients had PM. Patients with PM were older (P < .001) and had larger tumor volumes compared with nonmetastatic patients (P < .001). Eighty-four percent of patients were in CR postoperatively, with 17% requiring metastasectomy. Thirty five patients (16%) had multiple inoperable PM and required the HR protocol. Only 14% of patients received pulmonary RT during first-line treatment. For patients with PM, 5-year event-free survival rate was 73% (95% CI, 68% to 79%), and 5-year overall survival (OS) rate was 82% (95% CI, 77% to 88%). Five-year OS was similar for patients with local stage I and II disease (92% and 90%, respectively) but lower for patients with local stage III disease (68%; P < .001). Patients in CR after chemotherapy only and patients in CR after chemotherapy and metastasectomy had a better outcome than patients with multiple unresectable PM (5-year OS, 88%, 92%, and 48%, respectively; P < .001). CONCLUSION: Following the SIOP protocol, pulmonary RT can be omitted for a majority of patients with PM and results in a relatively good outcome. PMID- 22927530 TI - Prognostic significance of signet ring gastric cancer. AB - PURPOSE: Studies in Asia have questioned the dictum that signet ring cell carcinoma (SRC) has a worse prognosis than other forms of gastric cancer. Our study determined differences in presentation and outcomes between SRC and gastric adenocarcinoma (AC) in the United States. PATIENTS AND METHODS: The National Cancer Institute Surveillance, Epidemiology, and End Results database was reviewed for SRC and AC from 2004 to 2007. RESULTS: We reviewed 10,246 cases of patients with gastric cancer, including 2,666 of SRC and 7,580 of AC. SRC presented in younger patients (61.9 v 68.7 years; P < .001) and less often in men (52.7% v 68.7%; P < .001). SRC patients were more frequently black (11.3% v 10.9%), Asian (16.4% v 13.2%), American Indian/Alaska Native (0.9% v 0.8%), or Hispanic (23.3% v 14.0%; P < .001). SRC was more likely to be stage T3-4 (45.8% v 33.3%), have lymph node spread (59.7% v 51.8%), and distant metastases (40.2% v 37.6%; P < .001). SRC was more likely to be found in the lower (30.7% v 24.2%) and middle stomach (30.6% v 20.7%; P < .001). Median survival was not different between the two (AC, 14.0 months v SRC, 13.0 months; P = .073). Multivariable analyses demonstrated SRC was not associated with mortality (hazard ratio [HR], 1.05; 95% CI, 0.96 to 1.11; P = .150). Mortality was associated with age (HR, 1.01; 95% CI, 1.01 to 1.02; P < .001), black race (HR, 1.10; 95% CI, 1.01 to 1.20; P = .026), and tumor grade. Variables associated with lower mortality risk included Asian race (HR, 0.83; 95% CI, 0.77 to 0.91; P < .001) and surgery (HR, 0.37; 95% CI, 0.34 to 0.39; P < .001). CONCLUSION: In the United States, SRC significantly differs from AC in extent of disease at presentation. However, when adjusted for stage, SRC does not portend a worse prognosis. PMID- 22927532 TI - Evidence for therapeutic drug monitoring of targeted anticancer therapies. AB - Therapeutic drug monitoring (TDM) provides valuable guidance for dose adjustment of antibiotics, immunosuppressives, antiepileptics, and other drugs, but its use for traditional anticancer therapies has been limited. Perhaps the most important obstacle is the impractical requirement of multiple blood samples to adequately define systemic exposure of drugs that have a short elimination half-life and are given by intermittent intravenous injections. However, the newer targeted anticancer therapies have different pharmacokinetic (PK) and dosing characteristics compared with traditional cytotoxic drugs, making it possible to estimate the steady-state drug exposure with a single trough-level measurement. Recent evidence indicates that certain PK parameters, including trough levels, are correlated with clinical outcomes for many of these agents, including imatinib, sunitinib, rituximab, and cetuximab. Although the current evidence is insufficient to mandate TDM in routine practice, a concerted investigation should be encouraged to determine whether the steady-state trough measurements of targeted agents will have a practical place in the clinical care of patients with cancer. PMID- 22927534 TI - Hurdles and complexities of codon 13 KRAS mutations. PMID- 22927535 TI - Pre-operative diagnosis of pancreatic abscess from a penetrating fish bone. PMID- 22927533 TI - Clinical significance of tumor-associated inflammatory cells in metastatic neuroblastoma. AB - PURPOSE: Children diagnosed at age >= 18 months with metastatic MYCN-nonamplified neuroblastoma (NBL-NA) are at high risk for disease relapse, whereas those diagnosed at age < 18 months are nearly always cured. In this study, we investigated the hypothesis that expression of genes related to tumor-associated inflammatory cells correlates with the observed differences in survival by age at diagnosis and contributes to a prognostic signature. METHODS: Tumor-associated macrophages (TAMs) in localized and metastatic neuroblastomas (n = 71) were assessed by immunohistochemistry. Expression of 44 genes representing tumor and inflammatory cells was quantified in 133 metastatic NBL-NAs to assess age dependent expression and to develop a logistic regression model to provide low- and high-risk scores for predicting progression-free survival (PFS). Tumors from high-risk patients enrolled onto two additional studies (n = 91) served as independent validation cohorts. RESULTS: Metastatic neuroblastomas had higher infiltration of TAMs than locoregional tumors, and metastatic tumors diagnosed in patients at age >= 18 months had higher expression of inflammation-related genes than those in patients diagnosed at age < 18 months. Expression of genes representing TAMs (CD33/CD16/IL6R/IL10/FCGR3) contributed to 25% of the accuracy of a novel 14-gene tumor classification score. PFS at 5 years for children diagnosed at age >= 18 months with NBL-NA with a low- versus high-risk score was 47% versus 12%, 57% versus 8%, and 50% versus 20% in three independent clinical trials, respectively. CONCLUSION: These data suggest that interactions between tumor and inflammatory cells may contribute to the clinical metastatic neuroblastoma phenotype, improve prognostication, and reveal novel therapeutic targets. PMID- 22927536 TI - A voluminous glomus tumor of the leg. PMID- 22927537 TI - Bronchoesophageal fistula secondary to broncholith. PMID- 22927539 TI - Hibernoma. PMID- 22927538 TI - Is chronic fatigue syndrome the same illness as fibromyalgia: evaluating the 'single syndrome' hypothesis. AB - Chronic fatigue syndrome (CFS) and fibromyalgia (FM) are medically unexplained syndromes that can and often do co-occur. For this reason, some have posited that the two are part of the same somatic syndrome--examples of symptom amplification. This hypothesis would suggest that few differences exist between the two syndromes. To evaluate this interpretation, we have searched the literature for articles comparing CFS to FM, reviewing only those articles which report differences between the two. This review presents data showing differences across a number of parameters--implying that the underlying pathophysiology in CFS may differ from that of FM. We hope that our review encourages other groups to look for additional differences between CFS and FM. By continuing to preserve the unique illness definitions of the two syndromes, clinicians will be able to better identify, understand and provide treatment for these individuals. PMID- 22927540 TI - Left heart border straightening in severe mitral stenosis. PMID- 22927541 TI - Erlotinib-associated dermatological toxicity. PMID- 22927542 TI - Patellar fracture: atypical presentation of parathyroid bone disease. PMID- 22927543 TI - Vitamin prescription for the prevention and treatment of Wernicke's encephalopathy. PMID- 22927544 TI - The autophagy-senescence connection in chemotherapy: must tumor cells (self) eat before they sleep? AB - Exposure of MCF-7 breast tumor cells or HCT-116 colon carcinoma cells to clinically relevant concentrations of doxorubicin (Adriamycin; Farmitalia Research Laboratories, Milan, Italy) or camptothecin results in both autophagy and senescence. To determine whether autophagy is required for chemotherapy induced senescence, reactive oxygen generation induced by Adriamycin was suppressed by N-acetyl cysteine and glutathione, and the induction of ataxia telangiectasia mutated, p53, and p21 was modulated pharmacologically and/or genetically. In all cases, autophagy and senescence were collaterally suppressed. The close association between autophagy and senescence indicated by these experiments reflects their collateral regulation via common signaling pathways. The potential relationship between autophagy and senescence was further examined through pharmacologic inhibition of autophagy with chloroquine and 3-methyl adenine and genetic ablation of the autophagy-related genes ATG5 and ATG7. However, inhibition of autophagy by pharmacological and genetic approaches could not entirely abrogate the senescence response, which was only reduced and/or delayed. Taken together, our findings suggest that autophagy and senescence tend to occur in parallel, and furthermore that autophagy accelerates the development of the senescent phenotype. However, these responses are not inexorably linked or interdependent, as senescence can occur when autophagy is abrogated. PMID- 22927545 TI - Na+,K+-ATPase functionally interacts with the plasma membrane Na+,Ca2+ exchanger to prevent Ca2+ overload and neuronal apoptosis in excitotoxic stress. AB - Using a fluorescent viability assay, immunocytochemistry, patch-clamp recordings, and Ca(2+) imaging analysis, we report that ouabain, a specific ligand of the Na(+),K(+)-ATPase cardiac glycoside binding site, can prevent glutamate receptor agonist-induced apoptosis in cultured rat cortical neurons. In our model of excitotoxicity, a 240-min exposure to 30 MUM N-methyl-d-aspartate (NMDA) or kainate caused apoptosis in ~50% of neurons. These effects were accompanied by a significant decrease in the number of neurons that were immunopositive for the antiapoptotic peptide Bcl-2. Apoptotic injury was completely prevented when the agonists were applied together with 0.1 or 1 nM ouabain, resulting in a greater survival of neurons, and the percentage of neurons expressing Bcl-2 remained similar to those obtained without agonist treatments. In addition, subnanomolar concentrations of ouabain prevented the increase of spontaneous excitatory postsynaptic current's frequency and the intracellular Ca(2+) overload induced by excitotoxic insults. Loading neurons with 1,2-bis(2-aminophenoxy)ethane-N,N,N',N' tetraacetic acid or inhibition of the plasma membrane Na(+),Ca(2+)-exchanger by 2 (2-(4-(4-nitrobenzyloxy)phenyl)ethyl)isothiourea methanesulfonate (KB-R7943) eliminated ouabain's effects on NMDA- or kainite-evoked enhancement of spontaneous synaptic activity. Our data suggest that during excitotoxic insults ouabain accelerates Ca(2+) extrusion from neurons via the Na(+),Ca(2+) exchanger. Because intracellular Ca(2+) accumulation caused by the activation of glutamate receptors and boosted synaptic activity represents a key factor in triggering neuronal apoptosis, up-regulation of Ca(2+) extrusion abolishes its development. These antiapoptotic effects are independent of Na(+),K(+)-ATPase ion transport function and are initiated by concentrations of ouabain that are within the range of an endogenous analog, suggesting a novel functional role for Na(+),K(+)-ATPase in neuroprotection. PMID- 22927546 TI - Foot forces induced through Tai Chi push-hand exercises. AB - The low impact forces of Tai Chi push-hand exercises may be particularly suited for older people and for those with arthritis; however, the biomechanics of push hand exercises have not previously been reported. This paper examines the ground reaction forces (GRFs) and plantar force distributions during Tai Chi push-hand exercises in a stationary stance with and without an opponent. Ten male Tai Chi practitioners participated in the study. The GRFs of each foot were measured in three perpendicular directions using two force plates (Kistler). The plantar force distribution of each foot was measured concurrently using an insole sensor system (Novel). The results showed that the average maximum vertical GRF of each foot was not more than 88% +/- 6.1% of the body weight and the sum of the vertical forces (103% +/- 1.4%) generated by the two feet approximately equals the body weight at any one time. The horizontal GRFs generated by the two feet were in the opposite directions and the measured mean peak values were not more than 12% +/- 2.8% and 17% +/- 4.3% of the body weight in the medio-lateral and antero-posterior directions respectively. Among the nine plantar areas, the toes sustained the greatest plantar force. This study indicates that push-hand exercises generate lower vertical forces than those induced by walking, bouncing, jumping and Tai Chi gait, and that the greatest plantar force is located in the toe area, which may have an important application in balance training particularly for older adults. PMID- 22927547 TI - Multiple sclerosis alters the mechanical work performed on the body's center of mass during gait. AB - Patients with multiple sclerosis (MS) have less-coordinated movements of the center of mass resulting in greater mechanical work. The purpose of this study was to quantify the work performed on the body's center of mass by patients with MS. It was hypothesized that patients with MS would perform greater negative work during initial double support and less positive work in terminal double support. Results revealed that patients with MS perform less negative work in single support and early terminal double support and less positive work in the terminal double support period. However, summed over the entire stance phase, patients with MS and healthy controls performed similar amounts of positive and negative work on the body's center of mass. The altered work throughout different periods in the stance phase may be indicative of a failure to capitalize on passive elastic energy mechanisms and increased reliance upon more active work generation to sustain gait. PMID- 22927548 TI - Interaction between thorax, lumbar, and pelvis movements in the transverse plane during gait at three velocities. AB - We determined the angular range of motion and the relative timing of displacement in the thorax, lumbar spine, and pelvis in the transverse plane during treadmill walking at three velocities. Nine healthy young females walked on a treadmill for three minutes at 0.40, 0.93, and 1.47 m/s. The position of seven reflective markers and three rigs placed on the thorax, lumbar spine, and pelvis were recorded at 200 Hz by an eight-camera motion capture system. As gait velocity increased, stride length increased, cycle time decreased, and angular displacement in the thorax and L1 decreased but increased at the pelvis and L5 (all P < .05). The time of maxi- mal angular rotation occurred in the following sequence: pelvis, L5, L3, L1, and thorax (P < .001). The thorax and L1 and L3 were in-phase for shorter duration as gait velocity increased, and this reduction was especially large, approx. 32% (P < .05), between thorax and pelvis. As gait velocity increased, the pelvis rotated earlier, causing the shortening of in phase duration between thorax and pelvis. These data suggest that, as gait velocity increases, pelvis rotation dictates trunk rotation in the transverse plane during gait in healthy young females. PMID- 22927549 TI - Cancer immunoediting by the innate immune system in the absence of adaptive immunity. AB - Cancer immunoediting is the process whereby immune cells protect against cancer formation by sculpting the immunogenicity of developing tumors. Although the full process depends on innate and adaptive immunity, it remains unclear whether innate immunity alone is capable of immunoediting. To determine whether the innate immune system can edit tumor cells in the absence of adaptive immunity, we compared the incidence and immunogenicity of 3'methylcholanthrene-induced sarcomas in syngeneic wild-type, RAG2(-/-), and RAG2(-/-)x gammac(-/-) mice. We found that innate immune cells could manifest cancer immunoediting activity in the absence of adaptive immunity. This activity required natural killer (NK) cells and interferon gamma (IFN-gamma), which mediated the induction of M1 macrophages. M1 macrophages could be elicited by administration of CD40 agonists, thereby restoring editing activity in RAG2(-/-)x gammac(-/-) mice. Our results suggest that in the absence of adaptive immunity, NK cell production of IFN-gamma induces M1 macrophages, which act as important effectors during cancer immunoediting. PMID- 22927552 TI - Magnetic correlations in a layered iridate, Na2IrO3. AB - Analysis of published data gathered on a sample of Na(2)IrO(3), held deep inside the antiferromagnetic phase at 1.58 K, shows that iridium magnetic dipole moments, measured in resonant x-ray Bragg diffraction, lie in the a-c plane of the monoclinic crystal and enclose an angle ~118 degrees with the c-axis. These findings, together with bulk measurements, are united in a plausible magnetic ground state for an iridium ion constructed from a Kramers doublet. A magnetic space group, derived from the chemical space group C2/m (unique axis b), possesses an anti-translation, to accommodate antiferromagnetic order, and an odd, two-fold axis of rotation symmetry on the b-axis, C'(2b), placing Ir magnetic dipoles perpendicular to the b-axis. Anapoles (toroidal dipoles) are predicted to be likewise confined to the a-c plane, and magnetic charges forbidden. PMID- 22927550 TI - Chemokine-dependent T cell migration requires aquaporin-3-mediated hydrogen peroxide uptake. AB - Chemokine-dependent trafficking is indispensable for the effector function of antigen-experienced T cells during immune responses. In this study, we report that the water/glycerol channel aquaporin-3 (AQP3) is expressed on T cells and regulates their trafficking in cutaneous immune reactions. T cell migration toward chemokines is dependent on AQP3-mediated hydrogen peroxide (H(2)O(2)) uptake but not the canonical water/glycerol transport. AQP3-mediated H(2)O(2) transport is essential for the activation of the Rho family GTPase Cdc42 and the subsequent actin dynamics. Coincidentally, AQP3-deficient mice are defective in the development of hapten-induced contact hypersensitivity, which is attributed to the impaired trafficking of antigen-primed T cells to the hapten-challenged skin. We therefore suggest that AQP3-mediated H(2)O(2) uptake is required for chemokine-dependent T cell migration in sufficient immune response. PMID- 22927553 TI - Stimulated luminescence emission from localized recombination in randomly distributed defects. AB - We present a new kinetic model describing localized electronic recombination through the excited state of the donor (d) to an acceptor (a) centre in luminescent materials. In contrast to the existing models based on the localized transition model (LTM) of Halperin and Braner (1960 Phys. Rev. 117 408-15) which assumes a fixed d -> a tunnelling probability for the entire crystal, our model is based on nearest-neighbour recombination within randomly distributed centres. Such a random distribution can occur through the entire volume or within the defect complexes of the dosimeter, and implies that the tunnelling probability varies with the donor-acceptor (d-a) separation distance. We first develop an 'exact kinetic model' that incorporates this variation in tunnelling probabilities, and evolves both in spatial as well as temporal domains. We then develop a simplified one-dimensional, semi-analytical model that evolves only in the temporal domain. An excellent agreement is observed between thermally and optically stimulated luminescence (TL and OSL) results produced from the two models. In comparison to the first-order kinetic behaviour of the LTM of Halperin and Braner (1960 Phys. Rev. 117 408-15), our model results in a highly asymmetric TL peak; this peak can be understood to derive from a continuum of several first order TL peaks. Our model also shows an extended power law behaviour for OSL (or prompt luminescence), which is expected from localized recombination mechanisms in materials with random distribution of centres. PMID- 22927554 TI - Time to move on from 'time-to-first': should all events be included in the analysis of clinical trials? PMID- 22927551 TI - Dual-reactive B cells are autoreactive and highly enriched in the plasmablast and memory B cell subsets of autoimmune mice. AB - Rare dual-reactive B cells expressing two types of Ig light or heavy chains have been shown to participate in immune responses and differentiate into IgG(+) cells in healthy mice. These cells are generated more often in autoreactive mice, leading us to hypothesize they might be relevant in autoimmunity. Using mice bearing Igk allotypic markers and a wild-type Ig repertoire, we demonstrate that the generation of dual-kappa B cells increases with age and disease progression in autoimmune-prone MRL and MRL/lpr mice. These dual-reactive cells express markers of activation and are more frequently autoreactive than single-reactive B cells. Moreover, dual-kappa B cells represent up to half of plasmablasts and memory B cells in autoimmune mice, whereas they remain infrequent in healthy mice. Differentiation of dual-kappa B cells into plasmablasts is driven by MRL genes, whereas the maintenance of IgG(+) cells is partly dependent on Fas inactivation. Furthermore, dual-kappa B cells that differentiate into plasmablasts retain the capacity to secrete autoantibodies. Overall, our study indicates that dual-reactive B cells significantly contribute to the plasmablast and memory B cell populations of autoimmune-prone mice suggesting a role in autoimmunity. PMID- 22927555 TI - Effect of ivabradine on recurrent hospitalization for worsening heart failure in patients with chronic systolic heart failure: the SHIFT Study. AB - AIMS: We explored the effect of treatment with ivabradine, a pure heart rate slowing agent, on recurrent hospitalizations for worsening heart failure (HF) in the SHIFT trial. METHODS AND RESULTS: SHIFT was a double-blind clinical trial in which 6505 patients with moderate-to-severe HF and left ventricular systolic dysfunction, all of whom had been hospitalized for HF during the preceding year, were randomized to ivabradine or to placebo on a background of guideline recommended HF therapy (including maximized beta-blockade). In total, 1186 patients experienced at least one additional HF hospitalization during the study, 472 suffered at least two, and 218 suffered at least 3. Patients with additional HF hospitalizations had more severe disease than those without. Ivabradine was associated with fewer total HF hospitalizations [902 vs. 1211 events with placebo; incidence rate ratio, 0.75, 95% confidence interval (CI), 0.65-0.87, P = 0.0002] during the 22.9-month median follow-up. Ivabradine-treated patients evidenced lower risk for a second or third additional HF hospitalization [hazard ratio (HR): 0.66, 95% CI, 0.55-0.79, P < 0.001 and HR: 0.71, 95% CI, 0.54-0.93, P = 0.012, respectively]. Similar observations were made for all-cause and cardiovascular hospitalizations. CONCLUSION: Treatment with ivabradine, on a background of guidelines-based HF therapy, is associated with a substantial reduction in the likelihood of recurrent hospitalizations for worsening HF. This benefit can be expected to improve the quality of life and to substantially reduce health-care costs. PMID- 22927556 TI - Stenting technique, gender, and age are associated with cardioprotection by ischaemic postconditioning in primary coronary intervention: a systematic review of 10 randomized trials. AB - AIMS: We sought to perform a systematic review and meta-analysis to evaluate the potential factors affecting ischaemic postconditioning (IPoC) for patients with ST-segment elevation acute myocardial infarction (STEMI) in primary percutaneous coronary intervention (PCI). METHODS AND RESULTS: Ten randomized controlled trials (RCTs) on IPoC reporting myocardial enzyme levels or left ventricular ejection fraction (LVEF) in a total of 560 STEMI patients were identified in PubMed, EMBase, and Cochrane Library (up to February 2012). Compared with controls, IPoC significantly reduced elevated cardiac enzyme levels [standardized mean difference = -0.84; 95% confidential interval (CI): -1.26 to -0.43; P < 0.00001; heterogeneity test, I(2) = 81.0%] and improved LVEF [weighted mean difference (WMD) = 3.98%; 95% CI: 1.27-6.70%; P = 0.004; heterogeneity test, I(2) = 87.1%]. The effect on LVEF remained significant after 1 year (WMD = 5.04%; 95% CI: 4.20-5.88%; P < 0.00001; heterogeneity test, I(2) = 0.0%). Univariate meta regression analysis suggested that the major sources of significant heterogeneity (P < 0.1) were the use of direct-stenting technique (%) (coefficient = -0.886; P = 0.069; adjusted R(2) = 0.34) and male proportion (%) (coefficient = -0.022; P = 0.098; adjusted R(2) = 0.28) for myocardial enzyme levels, and age (coefficient = -1.34; P = 0.025; adjusted R(2)= 0.55) for LVEF (%). Subsequent multivariate regression and subgroup analysis confirmed these results. CONCLUSION: Available evidence from this systematic review and meta-analysis of 10 RCTs suggests that IPoC may confer cardioprotection in terms of myocardial enzyme levels and LVEF for STEMI during primary PCI. These effects are more pronounced among young and male patients, and those in whom direct-stenting techniques were used. Future studies should focus on the mortality in high-quality, large-scale clinical trials with long-term follow-up. PMID- 22927558 TI - Getting to the heart of the matter: cardiac involvement in transthyretin-related amyloidosis. PMID- 22927557 TI - Statins suppress apolipoprotein CIII-induced vascular endothelial cell activation and monocyte adhesion. AB - AIMS: Activation of vascular endothelial cells (ECs) contributes importantly to inflammation and atherogenesis. We previously reported that apolipoprotein CIII (apoCIII), found abundantly on circulating triglyceride-rich lipoproteins, enhances adhesion of human monocytes to ECs in vitro. Statins may exert lipid independent anti-inflammatory effects. The present study examined whether statins suppress apoCIII-induced EC activation in vitro and in vivo. METHODS AND RESULTS: Physiologically relevant concentrations of purified human apoCIII enhanced attachment of the monocyte-like cell line THP-1 to human saphenous vein ECs (HSVECs) or human coronary artery ECs (HCAECs) under both static and laminar shear stress conditions. This process mainly depends on vascular cell adhesion molecule-1 (VCAM-1), as a blocking VCAM-1 antibody abolished apoCIII-induced monocyte adhesion. ApoCIII significantly increased VCAM-1 expression in HSVECs and HCAECs. Pre-treatment with statins suppressed apoCIII-induced VCAM-1 expression and monocyte adhesion, with two lipophilic statins (pitavastatin and atorvastatin) exhibiting inhibitory effects at lower concentration than those of hydrophilic pravastatin. Nuclear factor kappaB (NF-kappaB) mediated apoCIII induced VCAM-1 expression, as demonstrated via loss-of-function experiments, and pitavastatin treatment suppressed NF-kappaB activation. Furthermore, in the aorta of hypercholesterolaemic Ldlr(-/-) mice, pitavastatin administration in vivo suppressed VCAM-1 mRNA and protein, induced by apoCIII bolus injection. Similarly, in a subcutaneous dorsal air pouch mouse model of leucocyte recruitment, apoCIII injection induced F4/80+ monocyte and macrophage accumulation, whereas pitavastatin administration reduced this effect. CONCLUSIONS: These findings further establish the direct role of apoCIII in atherogenesis and suggest that anti-inflammatory effects of statins could improve vascular disease in the population with elevated plasma apoCIII. PMID- 22927559 TI - Improved outcome of cardiogenic shock at the acute stage of myocardial infarction: a report from the USIK 1995, USIC 2000, and FAST-MI French nationwide registries. AB - AIM: The historical evolution of incidence and outcome of cardiogenic shock (CS) in acute myocardial infarction (AMI) patients is debated. This study compared outcomes in AMI patients from 1995 to 2005, according to the presence of CS. METHOD AND RESULTS: Three nationwide French registries were conducted 5 years apart, using a similar methodology in consecutive patients admitted over a 1 month period. All 7531 AMI patients presenting <=48 h of symptom onset were included. The evolution of mortality was compared in the 486 patients with CS vs. those without CS. The incidence of CS tended to decrease over time (6.9% in 1995; 5.7% in 2005, P = 0.07). Thirty-day mortality was considerably higher in CS patients (60.9 vs. 5.2%). Over the 10-year period, mortality decreased for both patients with (70-51%, P = 0.003) and without CS (9-4%, P < 0.001). In CS patients, the use of percutaneous coronary intervention (PCI) increased from 20 to 50% (P < 0.001). Time period was an independent predictor of early mortality in CS patients (OR for death, 2005 vs. 1995 = 0.45; 95% CI: 0.27-0.75, P = 0.005), along with age, diabetes, and smoking status. When added to the multivariate model, PCI was associated with decreased mortality (OR = 0.38; 95% CI: 0.24-0.58, P < 0.001). In propensity-score-matched cohorts, CS patients with PCI had a significantly higher survival. CONCLUSIONS: Cardiogenic shock remains a clinical concern, although early mortality has decreased. Improved survival is concomitant with a broader use of PCI and recommended medications at the acute stage. Beyond the acute stage, however, 1-year survival has remained unchanged. PMID- 22927560 TI - Gibbs free energy and equilibrium states in the Si/Si oxide systems. AB - In this paper, the equilibrium states in the Si/Si oxide systems formed as a result of the phase separation of nonstoichiometric silicon oxide films are studied. The expressions for the Gibbs free energy of Si oxide and Si/Si oxide systems are derived thermodynamically. The transformations of the Gibbs free energy in the amorphous Si/Si oxide and the crystalline Si/Si oxide systems with the change in the amount of separated silicon and the composition of the silicon oxide phase are analyzed. By minimizing the Gibbs free energy of these systems, the equilibrium stoichiometry indices of silicon oxide are calculated as functions of its initial stoichiometry and the temperature. The solubility limits of Si in SiO(2) in equilibrium with amorphous and crystalline Si are determined. The obtained results form the basis for the development of a complete thermodynamic theory of phase separation in nonstoichiometric silicon oxide films with the formation of Si nanoinclusions in the silicon oxide matrix. PMID- 22927561 TI - Multi-step magnetization of the Ising model on a Shastry-Sutherland lattice: a Monte Carlo simulation. AB - The magnetization behaviors and spin configurations of the classical Ising model on a Shastry-Sutherland lattice are investigated using Monte Carlo simulations, in order to understand the fascinating magnetization plateaus observed in TmB(4) and other rare-earth tetraborides. The simulations reproduce the 1/2 magnetization plateau by taking into account the dipole-dipole interaction. In addition, a narrow 2/3 magnetization step at low temperature is predicted in our simulation. The multi-step magnetization can be understood as the consequence of the competitions among the spin-exchange interaction, the dipole-dipole interaction, and the static magnetic energy. PMID- 22927562 TI - Magnetic glass in shape memory alloy: Ni45Co5Mn38Sn12. AB - The first order martensitic transition in the ferromagnetic shape memory alloy Ni(45)Co(5)Mn(38)Sn(12) is also a magnetic transition and has a large field induced effect. While cooling in the presence of a field this first order magnetic martensite transition is kinetically arrested. Depending on the cooling field, a fraction of the arrested ferromagnetic austenite phase persists down to the lowest temperature as a magnetic glassy state, similar to the one observed in various intermetallic alloys and in half doped manganites. A detailed investigation of this first order ferromagnetic austenite (FM-A) to low magnetization martensite (LM-M) state transition as a function of temperature and field has been carried out by magnetization measurements. Extensive cooling and heating in unequal field (CHUF) measurements and a novel field cooled protocol for isothermal MH measurements (FC-MH) are utilized to investigate the glass like arrested states and show a reverse martensite transition. Finally, we determine a field-temperature (HT) phase diagram of Ni(45)Co(5)Mn(38)Sn(12) from various magnetization measurements which brings out the regions where thermodynamic and metastable states coexist in the HT space, clearly depicting this system as a 'magnetic glass'. PMID- 22927563 TI - External longitudinal titanium support for the repair of complex pectus excavatum in adults. AB - Several techniques exist for the repair of complex pectus excavatum. The placement of retrosternal metal bars improves the results by reducing the recurrence rate, but entails several possible risks, complications and disadvantages. A new method, specifically conceived for the repair of severe, asymmetric forms in adult patients, is reported. The corrected bone is fixed in the proper position by two, patient-customized, titanium struts, externally screwed to the manubrium and sternal body. Any retrosternal bar is thus avoided, reducing possible complications, without hampering the chest wall dynamic. In this particularly difficult issue, this technique provides long-term good functional, mechanical and cosmetic results and does not entail a second surgery for struts removal. PMID- 22927564 TI - Noncollinear spin reorientation transition in S = 1 ferromagnetic thin films. AB - An in-plane spin reorientation transition in thin ferromagnetic films is discussed in terms of the thermodynamics of inhomogeneous low-dimensional systems based on a Neel sublattices concept while using a spin 1 Heisenberg Hamiltonian. The model allows us to investigate in a straightforward manner the layer dependent phenomena. In this context, we propose a model of noncollinear magnetization structure based on the appropriate distribution of the anisotropy parameters inside the Fe films on W(110). The spin reorientation transition originates at the Fe/W(110) interface and proceeds via noncollinear magnetization structure toward the surface with increasing film thickness in accordance with the experimental findings. The temperature-driven spin reorientation transition in freestanding Fe films and in Fe/W(110) systems is also discussed in detail. PMID- 22927565 TI - Animal minds: from computation to evolution. PMID- 22927566 TI - What is comparable in comparative cognition? AB - To understand how complex, or 'advanced' various forms of cognition are, and to compare them between species for evolutionary studies, we need to understand the diversity of neural-computational mechanisms that may be involved, and to identify the genetic changes that are necessary to mediate changes in cognitive functions. The same overt cognitive capacity might be mediated by entirely different neural circuitries in different species, with a many-to-one mapping between behavioural routines, computations and their neural implementations. Comparative behavioural research needs to be complemented with a bottom-up approach in which neurobiological and molecular-genetic analyses allow pinpointing of underlying neural and genetic bases that constrain cognitive variation. Often, only very minor differences in circuitry might be needed to generate major shifts in cognitive functions and the possibility that cognitive traits arise by convergence or parallel evolution needs to be taken seriously. Hereditary variation in cognitive traits between individuals of a species might be extensive, and selection experiments on cognitive traits might be a useful avenue to explore how rapidly changes in cognitive abilities occur in the face of pertinent selection pressures. PMID- 22927567 TI - Coevolution of learning and data-acquisition mechanisms: a model for cognitive evolution. AB - A fundamental and frequently overlooked aspect of animal learning is its reliance on compatibility between the learning rules used and the attentional and motivational mechanisms directing them to process the relevant data (called here data-acquisition mechanisms). We propose that this coordinated action, which may first appear fragile and error prone, is in fact extremely powerful, and critical for understanding cognitive evolution. Using basic examples from imprinting and associative learning, we argue that by coevolving to handle the natural distribution of data in the animal's environment, learning and data-acquisition mechanisms are tuned jointly so as to facilitate effective learning using relatively little memory and computation. We then suggest that this coevolutionary process offers a feasible path for the incremental evolution of complex cognitive systems, because it can greatly simplify learning. This is illustrated by considering how animals and humans can use these simple mechanisms to learn complex patterns and represent them in the brain. We conclude with some predictions and suggested directions for experimental and theoretical work. PMID- 22927568 TI - Simple minds: a qualified defence of associative learning. AB - Using cooperation in chimpanzees as a case study, this article argues that research on animal minds needs to steer a course between 'association-blindness'- the failure to consider associative learning as a candidate explanation for complex behaviour--and 'simple-mindedness'--the assumption that associative explanations trump more cognitive hypotheses. Association-blindness is challenged by the evidence that associative learning occurs in a wide range of taxa and functional contexts, and is a major force guiding the development of complex human behaviour. Furthermore, contrary to a common view, association-blindness is not entailed by the rejection of behaviourism. Simple-mindedness is founded on Morgan's canon, a methodological principle recommending 'lower' over 'higher' explanations for animal behaviour. Studies in the history and philosophy of science show that Morgan failed to offer an adequate justification for his canon, and subsequent attempts to justify the canon using evolutionary arguments and appeals to simplicity have not been successful. The weaknesses of association blindness and simple-mindedness imply that there are no short-cuts to finding out about animal minds. To decide between associative and yet more cognitive explanations for animal behaviour, we have to spell them out in sufficient detail to allow differential predictions, and to test these predictions through observation and experiment. PMID- 22927569 TI - The brain's connective core and its role in animal cognition. AB - This paper addresses the question of how the brain of an animal achieves cognitive integration--that is to say how it manages to bring its fullest resources to bear on an ongoing situation. To fully exploit its cognitive resources, whether inherited or acquired through experience, it must be possible for unanticipated coalitions of brain processes to form. This facilitates the novel recombination of the elements of an existing behavioural repertoire, and thereby enables innovation. But in a system comprising massively many anatomically distributed assemblies of neurons, it is far from clear how such open-ended coalition formation is possible. The present paper draws on contemporary findings in brain connectivity and neurodynamics, as well as the literature of artificial intelligence, to outline a possible answer in terms of the brain's most richly connected and topologically central structures, its so called connective core. PMID- 22927570 TI - Cognition in insects. AB - A traditional view of cognition is that it involves an internal process that represents, tracks or predicts an external process. This is not a general characteristic of all complex neural processing or feedback control, but rather implies specific forms of processing giving rise to specific behavioural capabilities. In this paper, I will review the evidence for such capabilities in insect navigation and learning. Do insects know where they are, or do they only know what to do? Do they learn what stimuli mean, or do they only learn how to behave? PMID- 22927571 TI - Biological and artificial cognition: what can we learn about mechanisms by modelling physical cognition problems using artificial intelligence planning techniques? AB - Do we fully understand the structure of the problems we present to our subjects in experiments on animal cognition, and the information required to solve them? While we currently have a good understanding of the behavioural and neurobiological mechanisms underlying associative learning processes, we understand much less about the mechanisms underlying more complex forms of cognition in animals. In this study, we present a proposal for a new way of thinking about animal cognition experiments. We describe a process in which a physical cognition task domain can be decomposed into its component parts, and models constructed to represent both the causal events of the domain and the information available to the agent. We then implement a simple set of models, using the planning language MAPL within the MAPSIM simulation environment, and applying it to a puzzle tube task previously presented to orangutans. We discuss the results of the models and compare them with the results from the experiments with orangutans, describing the advantages of this approach, and the ways in which it could be extended. PMID- 22927572 TI - Associative learning and animal cognition. AB - Associative learning plays a variety of roles in the study of animal cognition from a core theoretical component to a null hypothesis against which the contribution of cognitive processes is assessed. Two developments in contemporary associative learning have enhanced its relevance to animal cognition. The first concerns the role of associatively activated representations, whereas the second is the development of hybrid theories in which learning is determined by prediction errors, both directly and indirectly through associability processes. However, it remains unclear whether these developments allow associative theory to capture the psychological rationality of cognition. I argue that embodying associative processes within specific processing architectures provides mechanisms that can mediate psychological rationality and illustrate such embodiment by discussing the relationship between practical reasoning and the associative-cybernetic model of goal-directed action. PMID- 22927573 TI - Chimpanzee 'folk physics': bringing failures into focus. AB - Differences between individuals are the raw material from which theories of the evolution and ontogeny of cognition are built. For example, when 4-year-old children pass a test requiring them to communicate the content of another's falsely held belief, while 3-year-olds fail, we know that something must change over the course of the third year of life. In the search for what develops or evolves, the typical route is to probe the extents and limits of successful individuals' ability. Another is to focus on those that failed, and find out what difference or lack prevented them from passing the task. Recent research in developmental psychology has harnessed individual differences to illuminate the cognitive mechanisms that emerge to enable success. We apply this approach to explaining some of the failures made by chimpanzees when using tools to solve problems. Twelve of 16 chimpanzees failed to discriminate between a complete and a broken tool when, after being set down, the ends of the broken one were aligned in front of them. There was a correlation between performance on this aligned task and another in which after being set down, the centre of both tools was covered, suggesting that the limiting factor was not the representation of connection, but memory or attention. Some chimpanzees that passed the aligned task passed a task in which the location of the broken tool was never visible but had to be inferred. PMID- 22927574 TI - Are there geniuses among the apes? AB - We are often asked whether some apes are smarter than others. Here we used two individual-based datasets on cognitive abilities to answer this question and to elucidate the structure of individual differences. We identified some individuals who consistently scored well across multiple tasks, and even one individual who could be classified as exceptional when compared with her conspecifics. However, we found no general intelligence factor. Instead, we detected some clusters of certain abilities, including inferences, learning and perhaps a tool-use and quantities cluster. Thus, apes in general and chimpanzees in particular present a pattern characterized by the existence of some smart animals but no evidence of a general intelligence factor. This conclusion contrasts with previous studies that have found evidence of a g factor in primates. However, those studies have used group-based as opposed to the individual-based data used here, which means that the two sets of analyses are not directly comparable. We advocate an approach based on testing multiple individuals (of multiple species) on multiple tasks that capture cognitive, motivational and temperament factors affecting performance. One of the advantages of this approach is that it may contribute to reconcile the general and domain-specific views on primate intelligence. PMID- 22927575 TI - Linking behavioural syndromes and cognition: a behavioural ecology perspective. AB - With the exception of a few model species, individual differences in cognition remain relatively unstudied in non-human animals. One intriguing possibility is that variation in cognition is functionally related to variation in personality. Here, we review some examples and present hypotheses on relationships between personality (or behavioural syndromes) and individual differences in cognitive style. Our hypotheses are based largely on a connection between fast-slow behavioural types (BTs; e.g. boldness, aggressiveness, exploration tendency) and cognitive speed-accuracy trade-offs. We also discuss connections between BTs, cognition and ecologically important aspects of decision-making, including sampling, impulsivity, risk sensitivity and choosiness. Finally, we introduce the notion of cognition syndromes, and apply ideas from theories on adaptive behavioural syndromes to generate predictions on cognition syndromes. PMID- 22927576 TI - Individual variation in cognitive performance: developmental and evolutionary perspectives. AB - Animal cognition experiments frequently reveal striking individual variation but rarely consider its causes and largely ignore its potential consequences. Studies often focus on a subset of high-performing subjects, sometimes viewing evidence from a single individual as sufficient to demonstrate the cognitive capacity of a species. We argue that the emphasis on demonstrating species-level cognitive capacities detracts from the value of individual variation in understanding cognitive development and evolution. We consider developmental and evolutionary interpretations of individual variation and use meta-analyses of data from published studies to examine predictors of individual performance. We show that reliance on small sample sizes precludes robust conclusions about individual abilities as well as inter- and intraspecific differences. We advocate standardization of experimental protocols and pooling of data between laboratories to improve statistical rigour. Our analyses show that cognitive performance is influenced by age, sex, rearing conditions and previous experience. These effects limit the validity of comparative analyses unless developmental histories are taken into account, and complicate attempts to understand how cognitive traits are expressed and selected under natural conditions. Further understanding of cognitive evolution requires efforts to elucidate the heritability of cognitive traits and establish whether elevated cognitive performance confers fitness advantages in nature. PMID- 22927577 TI - Core systems of geometry in animal minds. AB - Research on humans from birth to maturity converges with research on diverse animals to reveal foundational cognitive systems in human and animal minds. The present article focuses on two such systems of geometry. One system represents places in the navigable environment by recording the distance and direction of the navigator from surrounding, extended surfaces. The other system represents objects by detecting the shapes of small-scale forms. These two systems show common signatures across animals, suggesting that they evolved in distant ancestral species. As children master symbolic systems such as maps and language, they come productively to combine representations from the two core systems of geometry in uniquely human ways; these combinations may give rise to abstract geometric intuitions. Studies of the ontogenetic and phylogenetic sources of abstract geometry therefore are illuminating of both human and animal cognition. Research on animals brings simpler model systems and richer empirical methods to bear on the analysis of abstract concepts in human minds. In return, research on humans, relating core cognitive capacities to symbolic abilities, sheds light on the content of representations in animal minds. PMID- 22927579 TI - Effect of pre-accession physical fitness on training injuries among US Army recruits. AB - OBJECTIVE: To evaluate the association of pre-accession physical fitness, as measured by a five-minute step test, with incidence of overuse injuries and outpatient healthcare utilization among male United States (US) Army recruits. PARTICIPANTS: US Army male trainees who met weight standards and took a pre accession fitness test. METHODS: In this prospective cohort study, incidence and outpatient healthcare visits for overuse injuries during the first 90 days of military service were compared between recruits who failed the pre-accession step test with those who passed. RESULTS: The hazard rate ratio for injury among recruits who failed the fitness test compared to those who passed the test was 1.31 (95% C.I = 1.20-1.44). Among the subset of recruits with at least one medical encounter for an overuse injury, the utilization rate ratio for subjects who failed the fitness test versus those who passed was 1.15 (95% C.I = 1.09 1.22). Other factors associated with increased risk of injury or healthcare utilization include age, body mass index, and smoking history. CONCLUSIONS: Risk of injury and utilization were associated with fitness test results. These findings may have implications for military accession and training policy as well as for other physically demanding training programs such as police, fire fighters and athletes. PMID- 22927578 TI - Modularity, comparative cognition and human uniqueness. AB - Darwin's claim 'that the difference in mind between man and the higher animals ... is certainly one of degree and not of kind' is at the core of the comparative study of cognition. Recent research provides unprecedented support for Darwin's claim as well as new reasons to question it, stimulating new theories of human cognitive uniqueness. This article compares and evaluates approaches to such theories. Some prominent theories propose sweeping domain-general characterizations of the difference in cognitive capabilities and/or mechanisms between adult humans and other animals. Dual-process theories for some cognitive domains propose that adult human cognition shares simple basic processes with that of other animals while additionally including slower-developing and more explicit uniquely human processes. These theories are consistent with a modular account of cognition and the 'core knowledge' account of children's cognitive development. A complementary proposal is that human infants have unique social and/or cognitive adaptations for uniquely human learning. A view of human cognitive architecture as a mosaic of unique and species-general modular and domain-general processes together with a focus on uniquely human developmental mechanisms is consistent with modern evolutionary-developmental biology and suggests new questions for comparative research. PMID- 22927580 TI - Effort-reward imbalance and video display unit postural risk factors interact in women on the incidence of musculoskeletal symptoms. AB - OBJECTIVE: This study investigated gender-specific interaction between effort reward imbalance and video display unit (VDU) postural risk factors at work on the incidence of self-reported musculoskeletal symptoms in the shoulder-neck, lower back and upper limbs regions. PARTICIPANTS: A cohort of 2,431 VDU users - consisting of white-collar workers in three Canadian public service organizations - was assessed on postural risk factors and effort-reward imbalance at work. METHODS: After a mean follow-up time of three years, the six-month incidence proportion of musculoskeletal symptoms in each body region was measured. Interaction was estimated with the attributable proportion of cases due to interaction. RESULTS: For women, two significant attributable proportions due to interaction between effort-reward imbalance and postural risk factors were observed in the shoulder-neck (64%) and upper limbs (57%) regions, while an interaction of 25%, although not significant, was observed in the lower back. No interaction was observed for men. CONCLUSIONS: This interaction means that, among women, when effort-reward imbalance and postural risk factors are simultaneously present, the incidence of musculoskeletal symptoms is greater than the sum of effects of the individual factors. Successful interventions on either one of these exposures would thus have the supplemental benefit of preventing cases due to interaction. PMID- 22927581 TI - Inter-rater reliability of the 'Merkmalprofile zur Eingliederung Leistungsgewandelter und Behinderter in Arbeit' (MELBA) in young disabled adults with psychosocial limitations. AB - OBJECTIVE: To evaluate the inter-rater reliability of the Merkmalprofile zur Eingliederung Leistungsgewandelter und Behinderter in Arbeit (MELBA). PARTICIPANTS: Twenty-five young adults with psychosocial limitations. METHODS: The MELBA measures work ability in five themes: cognitive, social, work performance, psychomotor characteristics and cultural/technical communication, divided into 29 work-related items, which are assessed by work-related tasks and by observations during work performance. Two raters independently evaluated one participant during the same time/test and independently assigned scores on 19~items out of 29. For this observational study the inter-rater reliability, expressed as the Intraclass Correlation Coefficient (ICC), was calculated for every item. An ICC of at least 0.75 was considered as showing good reliability, below 0.75 was considered poor to moderate reliability. RESULTS: The ICC for six items was good: comprehension (0.81), attentiveness (0.84), problem solving (0.79), imagination (0.88), independence (0.79) and speed of reaction (1.0) showed good reliability. CONCLUSION: Especially the items of cognitive characteristics of the MELBA showed a good inter-rater reliability and can be used to measure work ability in people with psychosocial limitations. PMID- 22927582 TI - A qualitative approach to assessing work ability. AB - PROBLEM: We often need to be able to assess the extent to which individuals have or lack work ability. For this we need instruments. Most of the instruments available have flaws. They either lack validity or they use roundabout methods when collecting information about the individual's work ability. OBJECTIVES: The aim of this paper is to present a conceptual model for constructing a questionnaire that can be used for assessing work ability. METHODS: The methods used are philosophical, i.e. analytical and deductive. A conceptual theory is provided, and based on the resulting definition of the concept of "work ability" conclusions are drawn regarding how to assess work ability. RESULTS: When constructing quantitative instruments, we can increase validity through using a more strict definition of work ability. However, such an approach will only solve some of the problems noted above. The proposal is, instead, to create a qualitative questionnaire, founded on a definition of "work ability", which focuses on the concrete problems concerning the work ability of the individual. Finally, a sketch of such an instrument is provided, with questions covering all the relevant aspects of work ability. CONCLUSION: The qualitative questionnaire proposed is believed to be superior to more traditional (quantitative) instruments for assessing a person's work ability, as well as for finding solutions to her problems concerning work ability. PMID- 22927583 TI - Support and process in individual placement and support: a multiple case study. AB - OBJECTIVE: This multiple case study investigated support and process in the Individual Placement and Support (IPS) approach from individual client, longitudinal, and Person-Environment-Occupation (PEO) model perspectives. PARTICIPANTS: Five IPS-participants, or cases, with severe mental illness (SMI) who worked a minimum of 4 hours a week entered the study. METHODS: A multiple data collection method was used over a period of 12 months and included IPS vocational profiles and plans as well as various instruments and questionnaires concerning socio-demographics, work performance, limitations, and accommodations. Both within- and across-case analyses were performed. RESULTS: The IPS-process concerned job search support, job-matches (PEO-match), and adjustment of the PEO match by providing accommodations by on- and off-worksite support. All participants had limitations concerning social interactions and handling symptoms/tolerating stress. Several accommodations were made for the same limitations, mostly directed towards the social environment. Prior work experience, disclosure, and not being in an acute phase of illness seemed important to the support provided. CONCLUSIONS: This study has visualised the support and process in IPS and provided a theoretical framework, the PEO-model, to detect limitations and provide IPS-support. The organization of IPS-support and methods of providing it to individuals may be important for job tenure and employment success. PMID- 22927584 TI - Ergonomics work assessment in rural industrial settings: a student occupational therapy project. AB - This case study describes a student occupational therapy (OT) program, the creation of a worksite assessment project as a part of a Community Connections: Partners for Learning and Service grant funded by Health Resources and Services Administration. The primary goals were to design occupation-based community learning experiences in a variety of rural community settings, so that students might benefit from participating in the community based learning and: based on the results, embed occupation-based learning into existing occupational therapy curriculum. The components of the project and the ergonomics content of the OT education program are described; details of the work assessment are presented with analysis of data from the student evaluation of this project. PMID- 22927585 TI - The Work-Health-Check (WHC): a brief new tool for assessing psychosocial stress in the workplace. AB - OBJECTIVE: Brief, psychometrically robust questionnaires assessing work-related psychosocial stressors are lacking. The purpose of the study is to evaluate the psychometric properties of a brief new questionnaire for assessing sources of work-related psychosocial stress. PARTICIPANTS: Managers, blue- and white-collar workers (n= 628 at measurement point one, n=459 at measurement point two), sampled from an online panel of a German marketing research institute. METHODS: We either developed or identified appropriate items from existing questionnaires for ten scales, which are conceptually based in work stress models and reflected either work-related demands or resources. Factorial structure was evaluated by confirmatory factor analyses (CFA). Scale reliability was assessed by Cronbach's Alpha, and test-retest; correlations with work-related efforts demonstrated convergent and discriminant validity for the demand and resource scales, respectively. Scale correlations with health indicators tested criterion validity. RESULTS: All scales had satisfactory reliability (Cronbach's Alpha: 0.74-0.93, retest reliabilities: 0.66-0.81). CFA supported the anticipated factorial structure. Significant correlations between job-related efforts and demand scales (mean r=0.44) and non-significant correlations with the resource scales (mean r=0.07) suggested good convergent and discriminant validity, respectively. Scale correlations with health indicators demonstrated good criterion validity. CONCLUSION: The WHC appears to be a brief, psychometrically robust instrument for assessing work-related psychosocial stressors. PMID- 22927586 TI - Socialization and organizational citizenship behavior among Turkish primary and secondary school teachers. AB - OBJECTIVE: The aim of the present study is to investigate the effects of organizational socialization levels of employees on organizational citizenship behavior (OCB). PARTICIPANTS: A total of 185 (70 female, 115 male) teachers were sampled at 27 primary and secondary schools. Their ages ranged from 23 to 55 years, with a mean (SD) of 36 (5.1). In this sample, 100 (54.1%) worked in primary schools, and 85 (45.9%) worked in secondary schools. METHODS: A three part questionnaire was designed for the study. The research scales were self report measures of organizational socialization, OCB, and demographic variables. The hypothesized model was tested using Pearson correlation analyses and multiple regression analyses. RESULTS: The teachers demonstrated high level socialization (Mean 4.2, SD 0.7) and OCB (Mean 4.0, SD 0.54). Understanding, coworker support, and performance proficiency explained significant variance in organizational citizenship behavior; however, there was no relationship (p=0.286) between the organizational goals and values and OCB. CONCLUSIONS: The findings contribute to our understanding of the relationship between the level of organizational socialization and organizational citizenship behavior in educational settings. These findings suggest that high level organizational socialization supports organizational citizenship behavior in primary and secondary school teachers. PMID- 22927587 TI - Belief in a just world and depression in elderly nursing home residents. AB - OBJECTIVE: Belief in a just world (BJW) modulates people's abilities to cope with anxiety, fear, and life transitions and thus depression and its debilitating effects. Little is known about how Belief in a just world modulates these coping abilities in elderly nursing home residents or their levels of depression either. PARTICIPANTS: A sample of 354 cognitively able elderly nursing home residents in Lebanon was selected for the study. METHODS: This study, therefore, explored elderly belief in a just world (BJW-S) by gender and length of time in elderly homes in its relation to levels of depression as measured by the Geriatric Depression Rating Scale (GDS) and the Mini-Mental State Examination screening instrument for older adults. RESULTS: The findings showed no main significant effects for gender or length-of-stay on level of depression. The chief significant difference found was for scores on the belief in a just world scale and levels of depression. Those who had high scores on belief in a just world scored low on depression, and vice-versa. CONCLUSIONS: Therefore, a strong belief in a just world seemed to act as a preventative or coping mechanism against depression from initial transition forward for elderly nursing home residents. PMID- 22927588 TI - A cross-sectional study of the demographic, cultural, clinical and rehabilitation associated variables predicting return to employment after disability onset in an Asian society. AB - OBJECTIVES: This study examined the rate of return to work, and to find demographic, clinical and functional factors associated with successful re employment after in-patient rehabilitation. METHODS: We performed a cross sectional cohort study of Singaporeans aged 15 and above who underwent inpatient rehabilitation in a Singapore hospital between 2000 and 2007. Phone interviews were conducted in 2007 to 2008, via a structured questionnaire to evaluate factors of return to work. RESULTS: Four hundred and eight patients met with the inclusion criteria, and 123 participants completed the questionnaire. Forty-five (44.7%) participants successfully returned to work with a mean time of 7 months post-discharge. Statistical significant differences were found between the "return to work" group and "non-return to work" group based on age group (p=0.04), education level (p=0.001), pre-morbid job category (0.013) and functional status (p<0.0005) as determined by Functional Independence Measure scores. Cox regression analysis controlling the period between discharge and survey indicated that higher FIM scores and higher education level predicted successful re-employment. CONCLUSION: This result re-affirmed the importance of functional status to the success of return-to-work in Singapore. Further qualitative studies might be useful in exploring the social or environmental factors affecting return-to-work outcomes. PMID- 22927589 TI - The effect of load on biomechanics during an overhead lift in the WorkHab Functional Capacity Evaluation. AB - OBJECTIVE: The role of biomechanics during the overhead lift has not been widely investigated. This study aimed to evaluate any change in biomechanics between safe minimum and safe maximum overhead lifts during the WorkHab Functional Capacity Evaluation. METHOD: Thirty healthy participants (age range 18-22 years) were videotaped completing the overhead lift. Images at the beginning (0/3), one third (1/3), two-thirds (2/3), and end of lift (3/3) were collected for the minimum and safe maximum lifts Measurement of joint angles of the wrist, elbow, shoulder and sagittal spine using Dartfish Prosuite software was completed. Paired t-tests were used to analyse the differences in joint angles between lifts. RESULTS: Participants' biomechanics changed between the minimum and maximum lifts In comparison to minimum lifts, there was increased wrist ulnar deviation (10.50, 95% CI 4.39, 16.61, p=0.002), increased shoulder flexion (7.26, 95% CI 0.50, 14.01, p=0.036), increased thoracic extension (-3.40, 95% CI -5.36, 1.45, p=0.001), increased lumbar extension (3.75, 95% CI 1.39, 6.12, p=0.003), and decreased elbow flexion (-11.28, 95% CI -18.57, -4.00, p=0.004) in the maximum lifts. CONCLUSIONS: The results of this study provide insight into biomechanical changes during the overhead lifting, and support the clinical judgements made by the WorkHab assessor in determining safe maximal lift. PMID- 22927590 TI - Return to work after a serious hand injury. AB - OBJECTIVES: This paper explores factors important for return to work (RTW) in people who have sustained a serious hand injury. PARTICIPANTS: Forty people aged 19-64, with a severe or major hand injury were recruited consecutively during 2005-2007. METHODS: A self-administered and study specific questionnaire, including demographic data and standardised questionnaires for function, disability, daily occupations, health, quality of life, sense of coherence and several open questions was sent out by mail twelve months after injury. Open questions regarding RTW were also included. RESULTS: The results showed that 27 people had returned to work within twelve months and 13 had not. Factors related to RTW and general work motivations were divided into individual factors, and factors related to the work environment and rehabilitation. The most prominent differences between the groups were individual factors, such as higher perceived disability, reduced hand function, and dissatisfaction with daily occupations resulting in a lower physical quality of life. The no RTW group had also more ward days (inpatient care) and lower sense of coherence. CONCLUSIONS: These findings support the idea that the RTW process can be more dependent on the person's own ability and motivation than on the severity of the hand injury. Suggestions for intervention and further studies are presented in the discussion. PMID- 22927591 TI - Social support at work and leisure time and its association with self-rated health and sickness absence. AB - OBJECTIVE: The aim of this longitudinal study is to investigate how different aspects of social support at work and in leisure time are associated with self rated health and sickness absence. PARTICIPANTS: The 541 participants in the study were representative for a working population in the public sector in Sweden with a majority being woman. METHODS: Most of the variables were created from data from a questionnaire in March-April 2005. There were four independent variables and two dependent variables. The dependent were based on data from November 2006. A logistic regression model was used for the analysis of associations. A separate model was adapted for each of the explanatory variables for each outcome, which gave five models per independent variable. RESULTS: The study has given a greater awareness of the importance of employees receiving social support, regardless of type of support or from whom the support is coming. CONCLUSION: Social support has a strong association with SRH in a longitudinal perspective and no association between social support and sickness absence. PMID- 22927592 TI - Prevalence and risk factors of work-related musculoskeletal disorders in the catering industry: a systematic review. AB - OBJECTIVE: This paper aims to systematically explore the prevalence and risk factors of Work-related Musculoskeletal Disorders (WMSDs) in the catering industry by reviewing relevant published literature with the goal of developing future prevention strategies. METHODS: The systematic review was carried out in nine English medical databases, two Chinese-dominated full-text databases and seven web sites with the designated search strategies. Studies were included if they met the defined inclusion criteria hierarchically to investigate prevalence and or risk factors associated with WMSDs in the catering industry with appropriate epidemiological methodology. RESULTS: Nine English databases yielded 634 citations, and two Chinese databases yielded 401 citations, although only five English and three Chinese studies passed the inclusion criteria. Three fourths of the studies were cross-sectional. The prevalence of WMSDs varied from 3% to 86% depending on the type of establishment and positions. The most important risk factors were physical job demands, such as work posture, force applied, and repeated movement. CONCLUSIONS: The lack of epidemiological information about WMSDs in the catering industry is apparent. Further studies are needed to investigate the relation among prevalence, risk factors and forms of WMSDs, in particular the interaction of risk factors in psychosocial aspects of the catering industry. PMID- 22927593 TI - Employers' perspective: when a return to work is the objective for persons with reduced mobility. AB - OBJECTIVE: Although the inclusion of persons with disabilities in the workforce is at the top of the policy agenda in Norway, the number of people with disabilities who return to work (RTW) is rather low. Studies have found that, in addition to disabled people's physical ability level, employers' attitudes and skills seem to be of vital importance for a positive return process. The objective of this study was therefore to examine the inclusion process from the employers' perspective, by gathering knowledge regarding the factors that employers experience as essential for positive RTW for persons with reduced mobility. PARTICIPANTS: Fifteen managers from six different counties, representing private, public and state-owned companies participating in the study, together with staff from local employment offices. METHODS: Using an exploratory approach, the study identified key elements for a successful RTW, expressed in six focus group discussions on themes of importance for a return to work. RESULTS: The analyses identified three important processes in leadership: the inclusion process, the adjustment process, and the process related to costs and bureaucracy. CONCLUSIONS: The study indicated that a positive RTW was based on the workplace leader's communication skills, and the necessary adaptations being made at the work place. Besides the welfare benefits, the employers also called attention to the coordination of public services, and the way in which providers present their assistance, as essential for a positive work re-entry process for employees with reduced function. PMID- 22927594 TI - The analysis of a group-mediated cognitive-behavioral corporate physical activity intervention. AB - OBJECTIVE: To describe and evaluate the use of a group-mediated cognitive behavioral (GMCB) exercise intervention approach within a corporate environment. PARTICIPANTS: Twenty (n(males) = 17, n(females) = 3) employees from two departments within a large Canadian resource company took part in the study. The average age was 43.50 years (SD = 8.60, range = 29 to 60) for males and 49.70 years (SD) = 6.40, range = 45 to 57) for females. METHODS: A mixed methods case study approach was adopted to assess the response to and effectiveness of the GMCB program within a corporate setting. These included field notes, weekly fitness logs, anthropometric measurements, and end of program focus group sessions. RESULTS: Qualitative measures pointed toward positive outcomes while quantitative results found significant decreases in body mass index, body fat percentage, and waist girth over the duration of the program. Descriptive statistics revealed an increase in exercise frequency and a strong preference for unstructured, group or mixed (i.e., group and individual) based activity during the program. CONCLUSION: The GMCB protocol can be successful at encouraging physical fitness within a corporate environment with the potential to address other health and wellness issues and to aid in vocational team building. PMID- 22927595 TI - Learning in occupational transitions: a study of the process following job loss. AB - OBJECTIVE: This article examines how workers supported by outplacement services engage with an occupational transition through problem solving and learning. PARTICIPANTS: The participants were 23 mid-life redundant white collar workers with at least eight years in their sector, organization or occupation. The selected interviewees either participated in training to broaden their professional competence or did not make any such 'expansive' efforts. METHODS: The study was based on narrative interviews, which enabled a detailed cross case examination of individuals' actions and choices and how the process unfolds over time. RESULTS: The results showed that people treat their job loss as a practical problem to be solved using various strategies. This problem-solving process is structured, with people passing similar crossroads defining particular challenges and opportunities giving people limited sets of choices. CONCLUSION: The results point to the significance of creativity and learning in occupational transitions. PMID- 22927596 TI - Prevalence of and factors associated with musculoskeletal symptoms in the spine attributed to computer use in undergraduate students. AB - OBJECTIVE: This study aimed to investigate the 3-month prevalence of musculoskeletal symptoms at the spine attributed to computer use and to identify biopsychosocial factors associated with the prevalence in undergraduate students. PARTICIPANTS: Undergraduate students who studied at a public university in Thailand. METHODS: A cross-sectional survey was conducted with a self administered questionnaire delivered to 3,545 students. RESULTS: A total of 2,511 students (73.7%) returned the questionnaires. Cervical symptoms (22.3%) were the most frequently reported, followed by thoracic (11%) and lumbar symptoms (10.7%). Females, daily computer use greater than three hours and too-high keyboard's position were significantly associated with a high prevalence of cervical symptoms. A significant association was found between higher undergraduate year of the study and too-high keyboard's position and a high prevalence of thoracic symptoms. Higher undergraduate year of the study and daily computer use greater than three hours were significantly related to a high prevalence of lumbar symptoms. Better-than-normal mental health status was associated with a low prevalence of lumbar symptoms. CONCLUSION: Spinal symptoms are common among undergraduate students. Various factors were identified to be associated with high prevalence of spinal symptoms. Further research investigating the causal relation between these factors and musculoskeletal symptoms should be conducted. PMID- 22927597 TI - A validation study comparing two self-reported upper extremity symptom surveys with clinical examinations for upper extremity musculoskeletal disorders. AB - OBJECTIVE: Evaluate the validity of two self-report symptoms surveys with two disorder classification protocols. PARTICIPANTS: 100 graduate students at a private school in the Southwest United States. METHODS: Study participants completed two self-report upper extremity musculoskeletal symptoms surveys: a nine item 10 cm Visual Analogue Scale (VAS) and a nine item Likert categorical scale anchored from "None" to "Very severe". Clinical examinations were administered using two musculoskeletal disorder classification protocols. RESULTS: For the nine body regions, concordance between the two self-report symptoms scales ranged from 0.49-0.75. Overall there was greater than 80% agreement for the two disorder classification protocols. Using either symptom survey with either disorder classification protocol provided high sensitivities and specificities (Youden's J >= 0.70). Three of possible six symptom survey/classification protocol pairings provided high sensitivities and specificities across all disorder groups. CONCLUSION: In this graduate student sample, none of the self-report symptom survey-classification protocol pairings was demonstratively more useful than any other pairing for studies of musculoskeletal disorders among computer users. PMID- 22927598 TI - "Coffee Stands": a vocational rehabilitation project in the community for people coping with mental disorders. AB - OBJECTIVES: The "Coffee Stands" project was developed to provide a work place where individuals with long term mental illness can receive job training within the community. It is similar to a supported employment program, except that it does not provide individual job placement services. The objective of the study was to describe the participants who worked at the "coffee stands", with respect to their participation in occupations, functional cognition, executive functions and awareness, perception of their quality of life (QoL), satisfaction and self esteem. Moreover, the study aimed at examining whether changes occurred in these variables during the 6-month period in which participants worked at the coffee stands. METHODS: Participants included 44 people with chronic mental illness; 27 men and 17 women, mean age 43.43 (SD = 9.02); mean years of education 11.81 (SD = 1.83); mean age of illness onset 27.72 (SD = 11.12) and mean number of hospitalizations 3.27 (SD = 2.64). All signed an informed consent to participate in the study. A battery of eight instruments measuring the various variables was administered at two points in time; at the beginning of the work at the coffee stands and 6 months later. RESULTS: Indicated that the training was successful and that participants were able to maintain an average 3 hours of work daily, demonstrating an improvement in their perception of their ability to work. In the area of planning, they needed structure, suggesting some difficulties in executive functions, but they seemed to be aware of their difficulties. After 6 months, participants showed improvements in health related measures of QoL and satisfaction, but not in self esteem. CONCLUSIONS: The findings strengthen the premise that people coping with an emotional disorder place great importance on working, are able to work and derive satisfaction from their work. PMID- 22927599 TI - Between unemployment and employment: experience of unemployed long-term pain sufferers. AB - OBJECTIVE: This study explored and analysed how patients experienced possibilities for, and barriers to, work return after participation in a multi professional pain-rehabilitation program followed by a coached work-training program (CWT). PARTICIPANTS: Eleven informants (8 women/3 men) with long-term musculoskeletal pain who had participated in the CWT program for 4-21 months (mean=11) comprised the study. METHODS: A qualitative emergent design was used. Data collected with interviews were analysed using the constant comparison method of grounded theory. Triangulation in researchers were used. RESULTS: The analyses of the interviews resulted in the development of a three-category theoretical model, which was named "a way back to work". The main category "Experience of a way back to work" consisted of the informants' experience during the process between unemployment and employment. The category "Support" describes the help the informants received from various actors, and the category "Negative response" describes negative responses from the actors involved, which was an important barrier in the process between unemployment and employment. CONCLUSION: Professional individualised support, participants feeling involved in their rehabilitation process, coaching at real workplaces and multi-professional team including health care personnel, were valuable during the process towards work. PMID- 22927601 TI - Use of recreation activities as positive coping with chronic stress and mental health outcomes associated with unemployment of people with disabilities. AB - OBJECTIVE: This paper provides an outline of the complex relationship among stress, unemployment, mental health, and participation in recreation activities as a possible adaptive coping strategy for people with disabilities. METHODS: This paper is a result of a two-phase review of the literature. Phase one included review of articles that examined the relationship among unemployment, stress, and mental health outcomes for people with disabilities. Phase two included articles that examined the efficacy of recreation activities as a means of buffering stress. RESULTS: Research indicates a cyclical process that occurs when people with disabilities experience unemployment; this unemployment often leads to chronic stress which in turn leads to negative mental health, symptoms that create further barriers to unemployment. Recreation activities that are physically active, culturally relevant, and conducive to relaxation were found to be effective at reducing the types of stressors experienced with unemployment. CONCLUSIONS: A complex relationship among unemployment, stress, mental health, and participation in recreation activities as a possible adaptive coping strategy exists for people with disabilities. An understanding of the types of recreation activities that are likely to reduce specific stressors associated with unemployment may be beneficial to consider as part of a comprehensive treatment plan when working with individuals with disabilities as they engage in the job seeking process. PMID- 22927600 TI - A validation study of the Four-Dimensional Symptom Questionnaire (4DSQ) in insurance medicine. AB - OBJECTIVE: This study aimed to evaluate the criterion validity and the diagnostic accuracy of the Four-Dimensional Symptom Questionnaire (4DSQ) regarding the identification of depressive and anxiety disorders in an insurance medicine setting. PARTICIPANTS: Our sample consisted of 230 individuals who applied for a work disability benefit due to mental health problems. METHODS: Depressive and anxiety disorders were assessed using the 4DSQ and the Composite International Diagnostic Interview (CIDI). Internal consistency was determined by calculating Cronbach's alpha values. Criterion validity was evaluated by regression techniques. A Receiver Operating Characteristic (ROC) analysis was performed to evaluate diagnostic accuracy. RESULTS: Of the 230 participants 109 (47.4%) had a current DSM-IV depressive disorder and 146 (63.5%) an anxiety disorder. The 4DSQ scales showed an excellent internal consistency. The depression scale of the 4DSQ had specific sensitivity for major depressive disorder. The anxiety scale was also sensitive for the anxiety disorders. The area under the ROC curve (AUC) indicated good diagnostic accuracy of the 4DSQ for assessing depressive and/or anxiety disorders: AUC-value 0.81 for both depression and anxiety. CONCLUSIONS: Although the 4DSQ shows good criterion validity and diagnostic accuracy with respect to depressive and anxiety disorders in applicants for a work disability benefit due to mental health problems, the feasibility of the 4DSQ as a screening measure for depressive and anxiety disorders is limited due to the high prevalence of depressive and anxiety disorders. PMID- 22927602 TI - Effect of shoulder rotation, upper arm rotation and elbow flexion in a repetitive gripping task. AB - OBJECTIVES: To investigate the effects of upper limb postures on discomfort score for repetitive gripping task. PARTICIPANTS: Eighteen right handed male participants volunteered in the experimental investigations. METHOD: The present study was divided into two experiments. A Full factorial design of 2 (Two shoulder rotation angles) * 3 (Three elbow flexion angles) * 3 (Three upper arm rotation angles) was used. The effect of postures on MVC grip strength, Grip endurance and on discomfort score, for a repetitive task at 150 N +/- 5 N with exertions 15 per minute was recorded. In a supplementary experiment, the EMG recordings were also taken for validating the effect of elbow flexion angle. RESULTS: ANOVA showed that the main effects of postures were not significant on MVC grip, except elbow flexion (p < 0.001). The endurance time was also significant (p=0.0100) for elbow flexion and there was no effect of other postures. The second experiment showed that the effect of shoulder rotation, elbow flexion and forearm rotation was significant (p <0.001) on discomfort score. The EMG activity of the muscles also showed that FDP and ECRB muscles had maximum reduction in median frequencies of the EMG signals of the respective muscles at 45 degrees elbow flexion angle. CONCLUSIONS: The main effects of elbow flexion angle, shoulder rotation and forearm rotation were significant on discomfort score for the repetitive gripping task of the present study. PMID- 22927603 TI - Investigation of work-related musculoskeletal disorders in wall plastering jobs within the construction industry. AB - OBJECTIVE: The aim of this study was to investigate the work-related musculoskeletal disorders (WMSDs) among workers in wall plastering jobs within the construction industry. PARTICIPANTS: A total of 43 workers within three workplaces participated in the study. METHODS: Subjects were interviewed using self-report charts. During the task duration, observation of the workplace was carried out using a Workplace Ergonomic Risk Assessment (WERA) method. RESULTS: An analysis of WERA assessment, the wrist score for WERA body part was >4 in 86% of workers, while wrist pain or discomfort was reported by 86%, yielding a significant association between WERA body part score and self-reported pain (chi(2)=16.12; p=0.000). The WERA body part score for the shoulder regions during wall plastering job yielded a score > 4 in 93% and caused shoulder pain or discomfort in 91%, the association being significant (chi(2)=12.58; p=0.000). The back regions for WERA body part score was >4 in 91% of workers, with 98% reporting pain or back discomfort, with a significant association (chi(2)=9.98; p=0.002). CONCLUSIONS: These results showed that statistically significance for the wrist, shoulder and back regions of the individual WERA body part scores were affecting the worker and lead to the development of pain or discomfort among workers in wall plastering jobs. PMID- 22927604 TI - How can organisations influence their older employees' decision of when to retire? AB - OBJECTIVE: This article reports on a study of older employees of a large public service organisation and examines their experiences of employment and their intentions to retire. METHODS: This study collected qualitative data through focus group interviews with 42 participants. RESULTS: Key themes derived from data analysis with regard to influences on retirement intentions included: personal, organizational and legislative influences. CONCLUSIONS: The study concludes that organisations can retain their older workers longer if they provide sufficient support, the work offered is satisfying, and part-time work is available. Regular review of employees' performance and satisfaction is required to maximize the productivity and retention of older workers. PMID- 22927605 TI - Employability and work ability: returning to the labour market after long-term absence. AB - OBJECTIVE: The aim of this study was to analyse how people who return to the labour market after long-term sickness absenteeism and subsequent job loss differ in employability, work ability, health, educational level, age, and gender, compared to those who do not. PARTICIPANTS: The cohort consisted of 191 individuals, 20 men and 171 women, whose employment was terminated because they had not been able to return to their regular work after taking a long-term sick leave and rehabilitation measures. METHODS: This study is based on a postal questionnaire sent out to a cohort of previous employees in a Swedish municipality in 2008. RESULTS: At the time of the survey, 39% of the respondents had returned to the labour market and the remaining 61% had not. Return to the labour market after a long-term sick leave was positively associated with male gender, young age, and work ability, i.e. the ability to work with respect to health and work-related demands. Employability, educational level, and health were not significantly associated with a return to the labour market. CONCLUSIONS: In the discourse on employability, work ability is often neglected even though it is a central aspect of an individual's ability to obtain new employment. PMID- 22927606 TI - The development of the Model of Occupational Self Efficacy: an occupational therapy practice model to facilitate returning to work after a brain injury. AB - OBJECTIVE: The purpose of this article is to describe the methodology used in order to develop the Model of Occupational Self Efficacy: An occupational therapy practice model to facilitate returning to work after a brain injury. PARTICIPANTS: Nine males and one female participated in the study. METHODS: Face to face, semi structured individual interviews were conducted and data were analyzed using a qualitative approach to explicate patterns and themes. The study was conducted in two phases, namely, Phase one described the lived experience of individuals with brain injury who had returned to work and Phase two described the development of the model by means of theory generation methodology. RESULTS: Four themes emerged that reflected the lived experiences for people returning to work after a brain injury. (1) A sense of loss of former self; (2) Uncertainty about the future; (3) The road to acceptance and believing in yourself; and (4) Participation in occupation enables growth. The above themes contributed to the central concept called Occupational Self Efficacy that resulted in the development of the occupational therapy practice model. CONCLUSIONS: The findings of the study suggest that theory generation methodology is adequate for the conceptual development of an occupational therapy practice model. PMID- 22927607 TI - Work organisation conditions, alcohol misuse: the moderating role of personality traits. AB - OBJECTIVE: The moderating role of personality traits between work organization conditions and alcohol misuse by Canadian workers was examined. PARTICIPANTS: Longitudinal data came from Statistics Canada's National Population Health Survey (NPHS). METHODS: Data had a hierarchical structure and were analyzed using multilevel logistic regression models. RESULTS: The multilevel analyis revealed that skill utilisation at work increased by 7% the risk of being part of an alcohol misuse group. Similarly, psychological demands at work, and being confronted with an irregular work schedule increased alcohol misuse respectively by 69 and 611%. Inversely, workers confronted with a job insecurity and those benefitting from social support at work had a respective 12 and 5% lower risk of being part of an alcohol misuse group. As for personnality traits, self-esteem increased by 17% the risk of alcohol misuse, while sense of coherence decreased the risk by 1%. Finally, self-esteem moderated by 3% the impact of physical demands at work on workers'alcohol misuse. CONCLUSIONS: This study builds upon previous research, since no prior study was able to identify the moderating role that self-esteem plays between physical demands at work, and worker's alcohol misuse. PMID- 22927608 TI - Breaking into the world of employment: the vocational experience of South African male ex-offenders. AB - OBJECTIVE: The study is aimed at exploring, describing and understanding the experiences and perceptions of male ex-offenders with regards to their participation in skills development and/or training programmes. METHODS: The research methodology utilised the qualitative research paradigm, specifically using the tradition of phenomenology. To gather data from the participants, focus groups and face to face interviews were conducted, consisting of broad questions followed by probes to gain an in-depth description of participants' experiences and perceptions. PARTICIPANTS: Five males who were classified as being ex offenders and one female (key informant) participated in the study. RESULTS: Three themes emerged that reflected the vocational experience of ex offenders: 1) A sense of distrust, 2) A sense of support: Giving back to the community through learning and doing, 3) Working towards change through capacity building. CONCLUSIONS: The findings of the study suggest that occupational therapy practitioners as well as correctional service personnel should identify and eliminate the barriers that impacts on return to work intervention programmes. Professionals working with offenders and ex-offenders should incorporate the enablers identified in this study when designing return to work programmes. PMID- 22927609 TI - Clinical and demographic factors associated with employment status in US military veterans returning from Iraq and Afghanistan. AB - OBJECTIVE: To determine the association between clinical and demographic factors with employment status in post-deployment US military veterans returning from Iraq and Afghanistan. PARTICIPANTS: 169 OIF/OEF veterans seen at a post deployment clinic between December of 2009 and May of 2010. METHODS: Data was collected retrospectively on employment status, age, marital status, gender, pre deployment education, ratings of sleep disturbance, pain, and depression, and mild traumatic brain injury (mTBI) or PTSD diagnosis. RESULTS: Unemployment was highly prevalent in this sample (45%). Of the demographic and clinical factors examined, only a self-report of global depression severity was significantly associated with a higher prevalence of unemployment in multivariate analysis (odds ratio [OR] 0.21, 95% confidence interval [CI] 0.10-0.47). Age greater than 40 demonstrated a positive association with employment status that was of borderline statistical significance ([OR] 2.8, 95% confidence interval [CI] 1.0 8.1). Prior diagnoses of mTBI or PTSD, and current sleep or pain symptoms, were not associated with employment status. CONCLUSIONS: Individuals with more severe self-reported depression had a higher prevalence of unemployment. Future prospective studies are needed to better understand which factors determine employment status in returning veterans. PMID- 22927610 TI - The economic cost of return to work: an employer's perspective. AB - BACKGROUND: Although return-to-work (RTW) interventions have been shown to be cost-effective, most previous economic analyses have focused on the insurer's perspective. Employers can also incur costs when supporting the RTW of their employees. OBJECTIVE: To identify a key set of items for estimating the costs of RTW interventions from the employer's perspective, and to identify and value the costs and consequences of a RTW intervention. PARTICIPANTS: Employers with knowledge of the economic costs of RTW. METHODS: A survey of 10 workplaces with RTW programs was conducted. The survey consisted of semi-structured interviews with a human resources or occupational health and safety representative from each enrolled workplace. RESULTS: The interviews were reviewed and from them key items were identified for estimating the costs of RTW interventions from the employer's perspective. Employers identified the following costs: medical, equipment, training and education, wage replacement and productivity, and claims administration when assisting an employee's RTW. CONCLUSIONS: Even in a jurisdiction with workers' compensation insurance, employers incur costs associated with RTW programs. It is important to consider these costs, from the perspective of the employer, when studying the cost-effectiveness of RTW interventions or programs. PMID- 22927611 TI - Analyzing what nurses do during work in a hospital setting: a feasibility study using video. AB - OBJECTIVE: Patient transfers have been implicated as a contributing factor in the high work-related musculoskeletal disorder (MSD) rate in nursing. However, documenting how much time is spent doing such tasks, compared to other less biomechanically stressful tasks in the workplace, has been limited, and not performed to date using a video-based approach. Therefore, the purpose of this study was to determine the feasibility of documenting all job-related nursing tasks performed during a typical shift in a hospital setting using video. PARTICIPANTS: Ten female nurses from an acute care hospital who worked in different units and during all three shifts. METHODS: Nurses working in different units of the hospital were videotaped performing their normal job-related tasks for a 2 hour period. Video records were subsequently analyzed to identify and categorize all tasks performed by each nurse. RESULTS: Overall, nurses spent less than 7% of their time during patient moving and transfer activities. One third of their time was spent walking, standing and sitting, 19.8% charting, 14.7% in patient care, 13.9% preparing medicines, 9.5% in housekeeping, and about 3% in self-care. CONCLUSIONS: This study showed that video-based methods are feasible for documenting what nurses do in the workplace. It also highlighted the diversity and non-repetitive nature of the workplace tasks nurses perform and suggests that ergonomic assessments of the cumulative effects of work on nurses in the field should focus on more than just patient handling activities. PMID- 22927612 TI - Experiencing work as a daily challenge: the case of scleroderma. AB - OBJECTIVE: Little is known about the physical and discretionary aspects of work that people with scleroderma (SSc) find difficult. This article describes the findings from a study that explored the challenges and adaptations made by individuals with SSc to continue to work. PARTICIPANTS: Thirty-two employed individuals with SSc participated. Participants were predominantly women (82%), white (79%), and well educated (M = 16.9 years). The average age was 47.3 years, and 60.6% were married. Mean disease duration was 9.7 years, and 56.2% had diffuse SSc. Mean years on the job was 10.2 (SD +/- 8.8), and 71.9% worked at least 35 hours per week. METHODS: Participants engaged in a single structured interview about work-related challenges and adaptations. Content and thematic analysis was used to identify key themes across the interviews. RESULTS: Employees with SSc experienced Work as a daily challenge. This central theme described the general work experience for most participants. Three subthemes described their specific experiences: The work environment: Opportunities, challenges, and accommodations; Career planning; and Supportive others. CONCLUSIONS: The participants were anxious to find scenarios that allowed them to continue to work. Worksite accommodations and flexibility in scheduling can make the difference between working and disability. PMID- 22927613 TI - Work ability as obscure, complex and unique: views of Swedish occupational therapists and physicians. AB - The concept of work ability is not clearly defined although it has a central place in vocational rehabilitation. Several health professions are involved in assessing work ability, physicians and occupational therapists are two of these. OBJECTIVE: The purpose of this study was to explore occupational therapist and physician views about work ability and experiences in assessing work ability. PARTICIPANTS: Fourteen physicians and 23 occupational therapists participated in seven focus group discussions that were audio taped and transcribed verbatim. METHODS: Qualitative content analysis was used. Each author performed an individual preliminary analysis. These analyses were later discussed and refined in the research team and a workshop. The final categorization resulted in one theme, four categories and 13 sub-categories. RESULTS: The overall theme expressed work ability as an obscure, complex and unique concept. The four categories illustrate the affecting factors and confirm the complex structure of work ability: the person, the context of life, the work, and the society. Physicians expressed greater difficulty in assessing work ability than occupational therapists did, because they have fewer instruments to access this concept. CONCLUSIONS: Assessment of work ability requires team cooperation with several different professionals. Cooperation could increase accuracy in issuing sickness certification and strengthens the ability of identifying individual requirements for rehabilitation. PMID- 22927614 TI - Biopsychosocial determinants of work outcomes of workers with occupational injuries receiving compensation: a prospective study. AB - OBJECTIVES: The evolution of musculoskeletal disorders and the adjustment to its consequences is a complex, multidimensional process determined by biopsychosocial factors. Despite the plethora of research in this field, little consensus has emerged about its main risk factors. The aims of the present study are to investigate the capacity of biopsychosocial variables to predict active involvement in a return to work process. PARTICIPANTS: A sample (N=62) of workers with mostly chronic occupational injuries receiving compensation benefits from the CSST [Quebec Workers' Compensation Board] was recruited. METHODS: Questionnaires were administered at baseline and subjects were followed prospectively and assessed again after 2 and 8 months. RESULTS: The variables under investigation were: age, gender, duration of symptoms, pain severity, disability, work importance, work support, work satisfaction, recovery expectations, depression, anxiety, global distress severity index, post-traumatic symptoms and readiness to change. After multivariate analysis, we found gender, work recovery expectations and importance of work to be predictive of work outcomes at 2 months. After 8 months, age, medical consolidation, trauma symptoms, work support and importance of work were predictive of work outcomes. CONCLUSION: The results show the importance of addressing chronic work disability in research and rehabilitation from a multidimensional perspective although psychosocial variables were the most significant predictors in this study. PMID- 22927615 TI - The cross-cultural adaptation of the work role functioning questionnaire to Dutch. AB - OBJECTIVE: The study objectives were to perform a cross-cultural adaptation of the Work Role Functioning Questionnaire, a health-related work outcome measure, into Dutch and to assess the questionnaire's reliability and validity in the Dutch context (WRFQ-DV). PARTICIPANTS: 40 workers with a health problem (duration > one month). METHODS: The WRFQ translation and adaptation were conducted using a systematic approach with the following steps: forward translation, synthesis, back-translation, consolidation of translations with expert committee, and pre testing. To evaluate the comprehensibility, usability, applicability and completeness of the translated questionnaire, a total of 40 interviews with workers with a health problem were performed. RESULTS: The questionnaire translation was conducted without major difficulties. During the process, questionnaire instructions were modified and 5 items reformulated based on the participants' responses. Participants were positive on the comprehensibility, usability, applicability and completeness of the questionnaire, and also made suggestions for the further development of the WRFQ-DV. Furthermore, the study shows promising results concerning the psychometric properties of the WRFQ-DV (e.g. Cronbach's alphas for the subscales between 0.70 and 0.91, and good content validity). CONCLUSIONS: The results indicate that the cross-cultural adaptation of the WRFQ-DV was successful and that the psychometric properties of the translated version are promising. PMID- 22927616 TI - Contingent self-esteem, stressors and burnout in working women and men. AB - OBJECTIVE: A high work involvement is considered central in the burnout process. Yet, research investigating how high work involvement and psychosocial stressors relate to burnout is scarce. High involvement in terms of performance-based self esteem (PBSE) refers to individuals' strivings to validate self-worth by achievements, a disposition linked to poor health. The aim of the present study was to examine longitudinally PBSE in relation to burnout while also taking into account work- and private life stressors. PARTICIPANTS: The sample consisted of 2121 working women and men. METHODS: Main- and mediation effects were investigated using hierarchical regression analysis. RESULTS: The results showed performance-based self-esteem mediated partially between the stressors and burnout. Performance-based self-esteem was the strongest predictor of burnout over time, followed by private life stressors. Women experienced more work stress than did men. Men had stronger associations between work stressors and burnout, while women had stronger associations between performance-based self-esteem and burnout. CONCLUSIONS: Individual characteristics along with both private life and work stressors are important predictors of burnout. Factors associated with burnout differ somewhat between women and men. PMID- 22927617 TI - Post-injury symptoms after work related traumatic brain injury in Canadian population. AB - OBJECTIVES: To examine the nature and extent of persistent post-injury symptoms of persons who have experienced a work-related traumatic brain injury (WrTBI) in Ontario, Canada. METHODS: Using a retrospective case series design, post-injury symptoms, occupation, and work factors were examined for WrTBIs among an adult population. Data were abstracted from medical records of individuals who sustained a WrTBI and were discharged from a referral-based outpatient neurology service between the years of 1998 and 2001. RESULTS: Of the 435 individuals who sustained a WrTBI, most were >= 45 years of age and male. Approximately 50% had injuries to the head only, while others had multiple injuries. The most common post-injury symptoms were headaches (85.1%), memory changes (74.3%), and mood/personality changes (68.3%). A small subset of individuals reported very long-term post-injury symptoms, and a majority of individuals had not yet returned to work. CONCLUSIONS: This study profiles the demographic and clinical characteristics of an outpatient injured worker population with a history of WrTBI which provides a basis for the planning and implementation of assessment and treatment programs for this clinical population. PMID- 22927618 TI - Descriptive analysis of work and non-work related motor vehicle collisions in Kingston, Ontario. AB - OBJECTIVE: To determine the proportion of MVC injuries occurring while working, and to compare the age, sex, injury, and season the collision occurred between those involved in work and non-work related MVCs. METHODS: The Kingston and Region Injury Surveillance Program (KRISP), a subset of the Canadian Hospitals Injury Reporting and Prevention Program, was used to identify MVCs occurring between January 1, 2000 and December 31, 2007. Variables analyzed included the characteristics of the injured patient, the type of injury, and factors associated with the collision. Descriptive statistics were computed and a non parametric test for trend was calculated. RESULTS: Work-related MVC injuries accounted for 4.6% of all MVC injuries reported in the KRISP database. Work related MVCs occurred with greater frequency in winter months and injured more males than females compared to non-work related MVCs. Pattern of injury differed among males and patient disposition differed among both males and females. CONCLUSIONS: There are important differences in terms of patient demographics and factors associated with the collision between those injured in work and non-work related MVCs. PMID- 22927619 TI - Strategies used to handle stress by academic physicians at a university hospital. AB - OBJECTIVE: Research is limited regarding occupational stress and coping strategies among academic physicians; professionals whose work situation includes the three areas of clinical practice, research, and teaching. The aim was to gain knowledge of stress-coping strategies used by academic physicians. PARTICIPANTS: Seventeen academic physicians employed at the University Hospital, Linkoping, Sweden. METHODS: Qualitative analyses were conducted of data from five focus group interviews. RESULTS: We identified eight different categories of coping strategies, e.g. self-awareness, time management, to cut corners, and to be in control. We also attempted to fit the dimensions of coping strategies into the models proposed by Folkman and Lazarus and Beehr and McGrath, respectively. The strategies were predominantly used to prevent stress from occurring, to manage anticipated stress, or to handle stress when occurring. Furthermore, the majority of the strategies identified could be placed in the problem-focused category, which we divided in a behavioural and a cognitive sub-category and in a new cognitive problem-focused and emotion-focused category. CONCLUSION: The study contributes to a wider understanding of the stress coping strategies academic physicians use. Further studies are needed to determine the consequences of these findings in order to enable the design of measures to reduce and prevent stress among academic physicians. PMID- 22927620 TI - Metabolic syndrome and sleep duration in police officers. AB - OBJECTIVES: To examine associations for sleep quality and quantity with metabolic syndrome (MS) and its five components in police officers. PATIENTS OR PARTICIPANTS: The study population consisted of 98 randomly selected officers (39 women and 59 men) for whom MS and sleep data were available. METHODS: Sleep duration (categorized as short < 6 hours, long >= 6 hours) for the past week and quality of sleep were collected by interviewer-administered questionnaires. MS was assessed using standard criteria. Generalized linear models were used to assess associations between sleep duration or sleep quality and MS, and the mean number of MS components. RESULTS: Metabolic syndrome was present in 22.0% and 2.6% of the male and female officers, respectively. Women with short sleep had a significantly higher mean number of MS components (mean=1.43) than those with longer sleep (mean=0.81, p=0.0316). Officers who stopped breathing during the night had more MS components (mean=2.43) compared to those who did not (mean =1.13, p=0.0206). CONCLUSIONS: Sleep duration and quality were associated with the mean number of MS components, particularly in women. Future research should examine these associations prospectively, in a larger cohort, exploring possible gender differences. PMID- 22927622 TI - From the Editor. PMID- 22927621 TI - Musculoskeletal health in South Georgia farmworkers: a mixed methods study. AB - OBJECTIVE: Musculoskeletal injuries are recognized as an important health issue for farmworkers. This study aimed to assess musculoskeletal health in South Georgia farmworkers through an exploration of pain status, health beliefs, occupational tasks, work conditions, access to care, and demographics. PARTICIPANTS: Interviews were conducted with 83 farmworkers at pro bono medical clinics. METHODS: Mixed methods interview topics, based upon an adapted theoretical model, included: work history, current work practices, musculoskeletal symptoms, health beliefs, acculturation, general health, access to care, and demographics. RESULTS: Pain was reported by 81.9% of participants. The low back (57.4%) and mid back (52.9%) were the most commonly reported sites of pain. Adapted model constructs were identified quantitatively and qualitatively. Open-ended responses described health beliefs, barriers to accessing care, and farmworkers' sense of responsibility to provide for their families. CONCLUSIONS: Data revealed that musculoskeletal pain is common and suggest associations with work tasks and conditions. Numerous barriers to accessing care exist and must be considered. Solutions may include farm-based prevention, enhanced education, improved measurement tools, and ongoing use of ecological models to guide research and interventions. PMID- 22927623 TI - Experiences of factors contributing to women's ability to make informed decisions about the process of rehabilitation and return to work: a focus group study. AB - OBJECTIVE: Functional, interactive and critical skills to use and act on health information, i.e. health literacy, are central preconditions for decision-making. To construct a decision aid that strengthens women's abilities to make decisions during sick leave, knowledge is needed about factors that increase health literacy. The aim of this study was for that reason to explore and describe women's experiences of factors that contribute to their ability to make informed decisions about the process of rehabilitation and return to work. PARTICIPANTS: Nineteen women with a period of sick leave during the previous 12 months participated. METHODS: A qualitative design with a focus group methodology was used. The qualitative data analysis was based on five focus group discussions. RESULTS: A number of factors emerged that were experienced as supporting. They were distributed over five qualitative categories. Trusting in, valuing and using one's own resources, taking the initiative and obtaining information were described as crucial to making well-founded decisions. Being coached by a professional or being supported by significant others were other factors that contributed to decision-making. The women also experienced that a trustful, transparent, continuous relationship with the professionals involved in the rehabilitation process contributed to well-founded decisions. CONCLUSIONS: The factors experienced as contributing to sick-listed women's ability to make informed decisions were both personal and environmental. Some have a connection with theories that conceptualize intentional relationships and self-efficacy. The factors may be useful as an initial source for the development of a decision aid for women. PMID- 22927624 TI - Are rehabilitation programmes enabling clients to return to work? Return to work perspectives of individuals with mild to moderate brain injury in South Africa. AB - OBJECTIVE: To describe the perceptions and experiences of individuals with brain injury with regard to return to work rehabilitation programmes. PARTICIPANTS: Nine males and one female who were diagnosed with a moderate to mild brain injury participated in the study. METHODS: In-depth interviews were conducted and data were analyzed using a qualitative approach to explicate patterns and themes. RESULTS: Two themes emerged that reflected the lived experiences of individuals with brain injury regarding intervention programmes that influenced their ability to return to work after the brain injury: 1) Enablers of return to work programmes, 2) Barriers related to return to work programmes. CONCLUSIONS: Occupational therapy practitioners as well as rehabilitation personnel should identify and eliminate the barriers that impact on return to work intervention programmes, incorporate the enablers identified in this study when designing return to work programmes. PMID- 22927625 TI - Employees' perception of organizational support: a qualitative investigation in the Indian information technology (IT) industry. AB - OBJECTIVES: Organizational support relates to an organization's readiness to reward increased work effort and to meet socio-emotional needs. This study investigated the various constructs of employees' perceptions of organizational support in the Indian context, with specific reference to the information technology (IT) industry. PARTICIPANTS: Thirty six semi-structured interviews were conducted from three different organizations over a period of four months. The participants were employed as Project Managers, Team Leaders and Executives in these organizations operating in Pune and were selected via randomized quota sampling to reflect a mix of age, positions, genders and experience with organization. METHODS: Qualitative methods were used in order to collect the data, through phenomenological principles. RESULTS: Discussion with the participants led to the emergence of five different themes which influence employees' perception of organizational support. These were: materialistic support, supervisor support, building reciprocal relationships, Organizational justice and intentions to leave. CONCLUSIONS: This study provided a tentative starting point towards the greater understanding of the employee's perceived notion of organizational support. Based on the study findings, there is an imperative that the human resource department and organizational forerunners continue to use research findings to support IT professionals in various ways in order to improve their quality of work life. PMID- 22927626 TI - Becoming a member of the work force: perceptions of adults with Asperger Syndrome. AB - OBJECTIVE: Research has shown that comparatively few adults with Asperger Syndrome (AS) participate in the competitive work force. The purpose of this study was to gain in-depth knowledge about contextual factors, which contribute to successful labor market participation in some adults with AS. PARTICIPANTS: This study was conducted by indepth-interviewing six adults with AS working in the competitive job market in Switzerland. METHODS: A developmental and hermeneutic narrative approach was used for data collection and analysis. Two in depth narrative interviews were conducted with each participant. A narrative analysis according to the theories of Paul Ricoeur was performed. RESULTS: Results showed that participants received pre-vocational requisites during their childhood through parents and friends that provided a feeling of security in social contexts. For participants, a supportive school setting resulted in academic achievements. The narratives reveal participants' capacities for understanding and adapting to social norms. Participants' understanding of their own needs was essential to the successful labor market participation. However, disclosure is rare and social stigma is still present. CONCLUSIONS: This study showed that successful labor participation of adults with AS can be enhanced through adequate social support already in the early stages of an individual's lifetime. PMID- 22927628 TI - Does KIM what she promises to do? PMID- 22927632 TI - First clinical experience in carbon ion scanning beam therapy: retrospective analysis of patient positional accuracy. AB - Our institute has constructed a new treatment facility for carbon ion scanning beam therapy. The first clinical trials were successfully completed at the end of November 2011. To evaluate patient setup accuracy, positional errors between the reference Computed Tomography (CT) scan and final patient setup images were calculated using 2D-3D registration software. Eleven patients with tumors of the head and neck, prostate and pelvis receiving carbon ion scanning beam treatment participated. The patient setup process takes orthogonal X-ray flat panel detector (FPD) images and the therapists adjust the patient table position in six degrees of freedom to register the reference position by manual or auto- (or both) registration functions. We calculated residual positional errors with the 2D-3D auto-registration function using the final patient setup orthogonal FPD images and treatment planning CT data. Residual error averaged over all patients in each fraction decreased from the initial to the last treatment fraction [1.09 mm/0.76 degrees (averaged in the 1st and 2nd fractions) to 0.77 mm/0.61 degrees (averaged in the 15th and 16th fractions)]. 2D-3D registration calculation time was 8.0 s on average throughout the treatment course. Residual errors in translation and rotation averaged over all patients as a function of date decreased with the passage of time (1.6 mm/1.2 degrees in May 2011 to 0.4 mm/0.2 degrees in December 2011). This retrospective residual positional error analysis shows that the accuracy of patient setup during the first clinical trials of carbon ion beam scanning therapy was good and improved with increasing therapist experience. PMID- 22927633 TI - Doctor, I can taste the local anaesthetic through my forehead! PMID- 22927634 TI - A report of an outbreak of toxicity from a novel drug of abuse: ERIC-3. AB - BACKGROUND: Novel drugs of abuse are becoming more common in the UK, and they represent particular difficulties in management. We present a case series of toxicity due to a novel substance Eric-3. METHODS: This was a retrospective case note review over a 6-month period. Patients were included if their presentation was due to ingestion of Eric-3. Physiological data, symptoms, outcome and destination of the patient from the ED were collected. Postmortem toxicological analysis was obtained for one of the patients who died. RESULTS: 41 attendances were identified from 18 patients. Two patients died and five were admitted to ITU. Heart rate and temperature on arrival tended to be above normal (mean heart rate was 112 bpm, with an SD of 18; mean temperature was 37.45 degrees with an SD of 0.95 degrees ). 63.4% of attendances included agitation and 34.1% choreiform movements. alpha-Methyltryptamine and 3-/4-flouroephedrine were found in the blood of one of the patients who died. CONCLUSIONS: In this outbreak, Eric 3 gave symptoms similar to other stimulants. It may have been a novel substance 3 /4-flouroephedrine. It underlines the need for prospective data collection and information sharing. PMID- 22927635 TI - Effects of flashlight guidance on chest compression performance in cardiopulmonary resuscitation in a noisy environment. AB - BACKGROUND: In real cardiopulmonary resuscitation (CPR), noise can arise from instructional voices and environmental sounds in places such as a battlefield and industrial and high-traffic areas. A feedback device using a flashing light was designed to overcome noise-induced stimulus saturation during CPR. This study was conducted to determine whether 'flashlight' guidance influences CPR performance in a simulated noisy setting. MATERIALS AND METHODS: We recruited 30 senior medical students with no previous experience of using flashlight-guided CPR to participate in this prospective, simulation-based, crossover study. The experiment was conducted in a simulated noisy situation using a cardiac arrest model without ventilation. Noise such as patrol car and fire engine sirens was artificially generated. The flashlight guidance device emitted light pulses at the rate of 100 flashes/min. Participants also received instructions to achieve the desired rate of 100 compressions/min. CPR performances were recorded with a Resusci Anne mannequin with a computer skill-reporting system. RESULTS: There were significant differences between the control and flashlight groups in mean compression rate (MCR), MCR/min and visual analogue scale. However, there were no significant differences in correct compression depth, mean compression depth, correct hand position, and correctly released compression. The flashlight group constantly maintained the pace at the desired 100 compressions/min. Furthermore, the flashlight group had a tendency to keep the MCR constant, whereas the control group had a tendency to decrease it after 60 s. CONCLUSION: Flashlight-guided CPR is particularly advantageous for maintaining a desired MCR during hands-only CPR in noisy environments, where metronome pacing might not be clearly heard. PMID- 22927636 TI - Research in an influenza pandemic. PMID- 22927637 TI - Meta-analysis of biventricular vs. right ventricular pacing mode in patients with atrial fibrillation undergoing atrioventricular nodal ablation: what was the quality of the included trials? PMID- 22927638 TI - RBF binding to both canonical E2F targets and noncanonical targets depends on functional dE2F/dDP complexes. AB - The retinoblastoma (RB) family of proteins regulate transcription. These proteins lack intrinsic DNA-binding activity but are recruited to specific genomic locations through interactions with sequence-specific DNA-binding factors. The best-known target of RB protein (pRB) is the E2F transcription factor; however, many other chromatin-associated proteins have been described that may allow RB family members to act at additional sites. To gain a perspective on the scale of E2F-dependent and E2F-independent functions, we generated genome-wide binding profiles of RBF1 and dE2F proteins in Drosophila larvae. RBF1 and dE2F2 associate with a large number of binding sites at genes with diverse biological functions. In contrast, dE2F1 was detected at a smaller set of promoters, suggesting that it overrides repression by RBF1/dE2F2 at a specific subset of targets. Approximately 15% of RBF1-bound regions lacked consensus E2F-binding motifs. To test whether RBF1 action at these sites is E2F independent, we examined dDP mutant larvae that lack any functional dE2F/dDP heterodimers. As measured by chromatin immunoprecipitation-microarray analysis (ChIP-chip), ChIP-quantitative PCR (qPCR), and cell fractionation, the stable association of RBF1 with chromatin was eliminated in dDP mutants. This requirement for dDP was seen at classic E2F regulated promoters and at promoters that lacked canonical E2F-binding sites. These results suggest that E2F/DP complexes are essential for all genomic targeting of RBF1. PMID- 22927639 TI - Mex3c mutation reduces adiposity and increases energy expenditure. AB - The function of MEX3C, the mammalian homolog of Caenorhabditis elegans RNA binding protein muscle excess 3 (MEX-3), was unknown until our recent report that MEX3C is necessary for normal postnatal growth and enhances the expression of local bone Igf1 expression. Here we report the pivotal role of Mex3c in energy balance regulation. Mex3c mutation caused leanness in both heterozygous and homozygous transgenic mice, as well as a more beneficial blood glucose and lipid profile in homozygous transgenic mice, in both sexes. Although transgenic mice showed normal food intake and fecal lipid excretion, they had increased energy expenditure independent of physical activity. Mutant mice had normal body temperature, Ucp1 expression in brown adipose tissue, and muscle and liver fatty acid oxidation. Mex3c is expressed in neurons and is detectable in the arcuate nucleus, the ventromedial nucleus, and the dorsomedial nucleus of the hypothalamus. Mex3c was not detected in NPY or POMC neurons but was detected in leptin-responsive neurons in the ventromedial nucleus. Mex3c and Leptin double mutant mice were growth retarded and obese and had blood profiles similar to those of ob/ob mice but showed none of the steatosis observed in ob/ob mice. Our data show that Mex3c is involved in energy balance regulation. PMID- 22927640 TI - Functions and regulation of circular dorsal ruffles. AB - Cells construct a number of plasma membrane structures to meet a range of physiological demands. Driven by juxtamembrane actin machinery, these actin-based membrane protrusions are essential for the operation and maintenance of cellular life. They are required for diverse cellular functions, such as directed cell motility, cell spreading, adhesion, and substrate/matrix degradation. Circular dorsal ruffles (CDRs) are one class of such structures characterized as F-actin rich membrane projections on the apical cell surface. CDRs commence their formation minutes after stimulation as flat, open, and immature ruffles and progressively develop into fully enclosed circular ruffles. These "rings" then mature and contract centrifugally before subsiding. Serving a critical function in receptor internalization and cell migration, CDRs are thus highly dynamic but transient formations. Here, we review the current state of knowledge concerning the regulation of circular dorsal ruffles. We focus specifically on the biochemical pathways leading to CDR formation in order to better define the roles and functions of these enigmatic structures. PMID- 22927641 TI - MiR-146a and NF-kappaB1 regulate mast cell survival and T lymphocyte differentiation. AB - The transcription factor NF-kappaB regulates the expression of a broad number of genes central to immune and inflammatory responses. We identified a new molecular network that comprises specifically the NF-kappaB family member NF-kappaB1 (p50) and miR-146a, and we show that in mast cells it contributes to the regulation of cell homeostasis and survival, while in T lymphocytes it modulates T cell memory formation. Increased mast cell survival was due to unbalanced expression of pro- and antiapoptotic factors and particularly to the complete inability of p50 deleted mast cells to induce expression of miR-146a, which in the context of mast cell survival acted as a proapoptotic factor. Interestingly, in a different cellular context, namely, human and mouse primary T lymphocytes, miR-146a and NF kappaB p50 did not influence cell survival or cytokine production but rather T cell expansion and activation in response to T cell receptor (TCR) engagement. Our data identify a new molecular network important in modulating adaptive and innate immune responses and show how the same activation-induced microRNA (miRNA) can be similarly regulated in different cell types even in response to different stimuli but can still determine very different outcomes, likely depending on the specific transcriptome. PMID- 22927642 TI - Glycogen synthase kinase 3 inhibition promotes lysosomal biogenesis and autophagic degradation of the amyloid-beta precursor protein. AB - Alzheimer's disease (AD) has been associated with altered activity of glycogen synthase kinase 3 (GSK3) isozymes, which are proposed to contribute to both neurofibrillary tangles and amyloid plaque formation. However, the molecular basis by which GSK3 affects the formation of Abeta remains unknown. Our aim was to identify the underlying mechanisms of GSK3-dependent effects on the processing of amyloid precursor protein (APP). For this purpose, N2a cells stably expressing APP carrying the Swedish mutation were treated with specific GSK3 inhibitors or transfected with GSK3alpha/beta short interfering RNA. We show that inhibition of GSK3 leads to decreased expression of APP by enhancing its degradation via an increase in the number of lysosomes. This induction of the lysosomal/autophagy pathway was associated with nuclear translocation of transcription factor EB (TFEB), a master regulator of lysosomal biogenesis. Our data indicate that GSK3 inhibition reduces Abeta through an increase of the degradation of APP and its carboxy-terminal fragment (CTF) by activation of the lysosomal/autophagy pathway. These results suggest that an increased propensity toward autophagic/lysosomal alterations in AD patients could have consequences for neuronal function. PMID- 22927643 TI - Late-stage maturation of the Rieske Fe/S protein: Mzm1 stabilizes Rip1 but does not facilitate its translocation by the AAA ATPase Bcs1. AB - The final step in the assembly of the ubiquinol-cytochrome c reductase or bc(1) complex involves the insertion of the Rieske Fe/S cluster protein, Rip1. Maturation of Rip1 occurs within the mitochondrial matrix prior to its translocation across the inner membrane (IM) in a process mediated by the Bcs1 ATPase and subsequent insertion into the bc(1) complex. Here we show that the matrix protein Mzm1 functions as a Rip1 chaperone, stabilizing Rip1 prior to the translocation step. In the absence of Mzm1, Rip1 is prone to either proteolytic degradation or temperature-induced aggregation. A series of Rip1 truncations were engineered to probe motifs necessary for Mzm1 interaction and Bcs1-mediated translocation of Rip1. The Mzm1 interaction with Rip1 persists in Rip1 variants lacking its transmembrane domain or containing only its C-terminal globular Fe/S domain. Replacement of the globular domain of Rip1 with that of the heterologous folded protein Grx3 abrogated Mzm1 interaction; however, appending the C-terminal 30 residues of Rip1 to the Rip1-Grx3 chimera restored Mzm1 interaction. The Rip1 Grx3 chimera and a Rip1 truncation containing only the N-terminal 92 residues each induced stabilization of the bc(1):cytochrome oxidase supercomplex in a Bcs1 dependent manner. However, the Rip1 variants were not stably associated with the supercomplex. The induced supercomplex stabilization by the Rip1 N terminus was independent of Mzm1. PMID- 22927644 TI - Replication fork collapse and genome instability in a deoxycytidylate deaminase mutant. AB - Ribonucleotide reductase (RNR) and deoxycytidylate deaminase (dCMP deaminase) are pivotal allosteric enzymes required to maintain adequate pools of deoxyribonucleoside triphosphates (dNTPs) for DNA synthesis and repair. Whereas RNR inhibition slows DNA replication and activates checkpoint responses, the effect of dCMP deaminase deficiency is largely unknown. Here, we report that deleting the Schizosaccharomyces pombe dcd1(+) dCMP deaminase gene (SPBC2G2.13c) increases dCTP ~30-fold and decreases dTTP ~4-fold. In contrast to the robust growth of a Saccharomyces cerevisiae dcd1Delta mutant, fission yeast dcd1Delta cells delay cell cycle progression in early S phase and are sensitive to multiple DNA-damaging agents, indicating impaired DNA replication and repair. DNA content profiling of dcd1Delta cells differs from an RNR-deficient mutant. Dcd1 deficiency activates genome integrity checkpoints enforced by Rad3 (ATR), Cds1 (Chk2), and Chk1 and creates critical requirements for proteins involved in recovery from replication fork collapse, including the gammaH2AX-binding protein Brc1 and Mus81 Holliday junction resolvase. These effects correlate with increased nuclear foci of the single-stranded DNA binding protein RPA and the homologous recombination repair protein Rad52. Moreover, Brc1 suppresses spontaneous mutagenesis in dcd1Delta cells. We propose that replication forks stall and collapse in dcd1Delta cells, burdening DNA damage and checkpoint responses to maintain genome integrity. PMID- 22927645 TI - GTPase ARFRP1 is essential for normal hepatic glycogen storage and insulin-like growth factor 1 secretion. AB - The GTPase ADP-ribosylation factor-related protein 1 (ARFRP1) is located at the trans-Golgi compartment and regulates the recruitment of Arf-like 1 (ARL1) and its effector golgin-245 to this compartment. Here, we show that liver-specific knockout of Arfrp1 in the mouse (Arfrp1(liv-/-)) resulted in early growth retardation, which was associated with reduced hepatic insulin-like growth factor 1 (IGF1) secretion. Accordingly, suppression of Arfrp1 in primary hepatocytes resulted in a significant reduction of IGF1 release. However, the hepatic secretion of IGF-binding protein 2 (IGFBP2) was not affected in the absence of ARFRP1. In addition, Arfrp1(liv-/-) mice exhibited decreased glucose transport into the liver, leading to a 50% reduction of glycogen stores as well as a marked retardation of glycogen storage after fasting and refeeding. These abnormalities in glucose metabolism were attributable to reduced protein levels and intracellular retention of the glucose transporter GLUT2 in Arfrp1(liv-/-) livers. As a consequence of impaired glucose uptake into the liver, the expression levels of carbohydrate response element binding protein (ChREBP), a transcription factor regulated by glucose concentration, and its target genes (glucokinase and pyruvate kinase) were markedly reduced. Our data indicate that ARFRP1 in the liver is involved in the regulation of IGF1 secretion and GLUT2 sorting and is thereby essential for normal growth and glycogen storage. PMID- 22927646 TI - Acid ceramidase (ASAH1) represses steroidogenic factor 1-dependent gene transcription in H295R human adrenocortical cells by binding to the receptor. AB - Adrenocorticotropin (ACTH) signaling increases glucocorticoid production by promoting the interaction of transcription factors and coactivator proteins with the promoter of steroidogenic genes. The nuclear receptor steroidogenic factor 1 (SF-1) is essential for steroidogenic gene transcription. Sphingosine (SPH) is a ligand for SF-1. Moreover, suppression of expression of acid ceramidase (ASAH1), an enzyme that produces SPH, increases the transcription of multiple steroidogenic genes. Given that SF-1 is a nuclear protein, we sought to define the molecular mechanisms by which ASAH1 regulates SF-1 function. We show that ASAH1 is localized in the nuclei of H295R adrenocortical cells and that cyclic AMP (cAMP) signaling promotes nuclear sphingolipid metabolism in an ASAH1 dependent manner. ASAH1 suppresses SF-1 activity by directly interacting with the receptor. Chromatin immunoprecipitation (ChIP) assays revealed that ASAH1 is recruited to the promoter of various SF-1 target genes and that ASAH1 and SF-1 colocalize on the same promoter region of the CYP17A1 and steroidogenic acute regulatory protein (StAR) genes. Taken together, these results demonstrate that ASAH1 is a novel coregulatory protein that represses SF-1 function by directly binding to the receptor on SF-1 target gene promoters and identify a key role for nuclear lipid metabolism in regulating gene transcription. PMID- 22927648 TI - Preliminary results from an indoor radon thoron survey in Hungary. AB - More than half of the radiation dose of natural origin comes from radon. However, according to some surveys in certain cases, the radiation dose originating from thoron may be considerable. Among the factors disturbing the measurement of radon, the presence of thoron may also influence the measured radon value, making the estimated radiation exposure imprecise. Thoron has previously been surveyed, mainly in Asia; however, recent surveys for some European locations have found that significant thoron concentrations also need to be considered. In this survey, several types of commercially available SSNTDs (solid-state nuclear track detectors) capable of measuring both radon and thoron were placed at the same time in 73 houses and 7 workplaces in Hungary with 3-month exposition periods. In order to measure thoron, the distance of the detector sets was fixed as 15-20 cm from the walls. The radon concentration was measured with five types of SSNTDs: NRPB, NRPB SSI, Raduet, DTPS and DRPS. The first four types had relatively good accordance (within +/- 10 %), but the results of the DRPS detectors were considerably lower when compared with other detectors for radon concentrations over 100 Bq m(-3). The thoron averages were provided by two different types of detectors: Raduet and DTPS. The difference between their average results was more than 30 % and was six times the maximum values. Therefore, the thoron measurement results were judged to be erroneous, and their measurement protocol should be clearly established for future work. PMID- 22927649 TI - Determination of radon level and radon effective dose rate using SSNTD in dwellings in the Bathinda district of Punjab, India. AB - The problem of indoor radon has attracted a great deal of attention worldwide as radon is the largest contributor to the total natural radiation dose. The dwellings belonging to the Bathinda district of Punjab, India, are investigated for the yearly average of indoor radon concentrations using solid-state nuclear track detectors. The annual average indoor radon values in the study area vary from 122.30 to 147.10 Bq m(-3), which is well within the recommended action level given by the International Commission on Radiological Protection. The calculated lifetime fatality risk values vary from 1.61 to 1.94. The seasonal variations and the contribution of building materials and ventilation conditions to the indoor radon in dwellings are also discussed. PMID- 22927647 TI - Wnt antagonist SFRP1 functions as a secreted mediator of senescence. AB - Cellular senescence has emerged as a critical tumor suppressive mechanism in recent years, but relatively little is known about how senescence occurs. Here, we report that secreted Frizzled-related protein 1 (SFRP1), a secreted antagonist of Wnt signaling, is oversecreted upon cellular senescence caused by DNA damage or oxidative stress. SFRP1 is necessary for stress-induced senescence caused by these factors and is sufficient for the induction of senescence phenotypes. We present evidence suggesting that SFRP1 functions as a secreted mediator of senescence through inhibition of Wnt signaling and activation of the retinoblastoma (Rb) pathway and that cancer-associated SFRP1 mutants are defective for senescence induction. PMID- 22927650 TI - Intercomparison of patient CTDI surveys in three countries. AB - The results of large-scale computed tomography (CT) patient dose surveys from the USA, UK and Germany undertaken during the period 1999-2001 were reviewed. The mean values for volume-weighted CT dose index (CTDI(vol)) and dose length product (DLP) were extracted. For head CT examinations, the reported values for the three surveys were similar with a mean CTDI(vol) of 59+/-6 mGy and a mean DLP of 760+/ 90 mGy cm. For the body, the values for CTDI(vol) in the USA (21+/-5 mGy) were nearly double those in the European countries (12+/-2 mGy). Average head CTDI(vol) values are comparable with the diagnostic reference levels (DRLs) recommended by the European Commission and the UK Health Protection Agency, but lower than the value of 75 mGy, which is currently used in the USA. DRLs for abdominal imaging are nearly a factor of 2 lower in the UK (14 mGy) than in other parts of the European Community and the USA (25 mGy). PMID- 22927651 TI - Estimation of distribution coefficient of natural radionuclides in soil around uranium mines and its effect with ionic strength of water. AB - The distribution coefficient, K(d) in soil is an important parameter to predict the migration of contaminants. In this study, uranium (U) and its decay products thorium (Th), radium (Ra), bismuth (Bi), lead (Pb) and polonium (Po), which may contaminate the soil and ground water around uranium mining areas, have been considered. Soil and ground water samples were collected from a proposed uranium mining site in India. The soil samples were characterised for different parameters affecting the K(d) values. The batch sorption method was employed to measure the K(d) of different radionuclides. The important factors affecting the batch method for K(d) estimation were identified and optimised. The variation of K(d) was observed with different ionic strength water samples. Results showed high K(d) values for Th(IV), Po(IV) and Pb(II) (log K(d) ~4) and low K(d) (log K(d) ~2-3) for U(VI), Ra(II) and Bi(III) in all three types of water with different ionic strength. PMID- 22927652 TI - Field experience on indoor radon, thoron and their progenies with solid-state detectors in a survey of Kosovo and Metohija (Balkan region). AB - Since 1996/97, indoor radon has been measured in scattered locations around Kosovo. In the most recent campaign, apart from radon, thoron and Rn and Tn progenies have also been measured. The current survey involves 48 houses, in which different detectors have been deployed side-by-side in one room, in order to measure indoor radon and thoron gas with RADUET devices based on CR-39 detectors (analysed by Japanese collaborators) and with direct thoron and radon progeny sensor (DTPS and DRPS) devices based on LR-115 detectors (analysed by collaborators from India). Estimated arithmetic mean values of concentrations in 48 houses are 122 Bq m(-3) for radon and 136 Bq m(-3) for thoron. Those for equilibrium equivalent radon concentration and equilibrium equivalent thoron concentration based on measurements in 48 houses are 40 and 2.1 Bq m(-3), respectively. The arithmetic mean value of the equilibrium factor is estimated to be 0.50 +/- 0.23 for radon and 0.037 +/- 0.041 for thoron. The preliminary results of these measurements are reported, particularly regarding DTPS and DRPS being set up in real field conditions for the first time in the Balkan region. The results are to be understood under the caveat of open questions related to measurement protocols which yield reproducible and representative results, and to quality assurance of Tn and Rn/Tn progeny measurements in general, some of which are discussed. PMID- 22927653 TI - A study to determine the differences between the displayed dose values for two full-field digitalmammography units and values calculated using a range of Monte Carlo-based techniques:a phantom study. AB - Modern full-field digital mammography (FFDM) units display the mean glandular dose (MGD) and the entrance or incident air kerma (K) to the breast following each exposure. Information on how these values are calculated is limited and knowing how displayed MGD values compare and correlate to conventional Monte Carlo-based methods is useful. From measurements done on polymethyl methacrylate (PMMA) phantoms, it has been shown that displayed and calculated MGD values are similar for thin to medium thicknesses and appear to differ with larger PMMA thicknesses. As a result, a multiple linear regression analysis on the data was performed to generate models by which displayed MGD values on the two FFDM units included in the study may be converted to the Monte-Carlo values calculated by conventional methods. These models should be a useful tool for medical physicists requiring MGD data from FFDM units included in this paper and should reduce the survey time spent on dose calculations. PMID- 22927655 TI - Measures against increased environmental radiation dose by the TEPCO Fukushima Dai-ichi NPP accident in some local governments in the Tokyo metropolitan area: focusing on examples of both Kashiwa and Nagareyama cities in Chiba prefecture. AB - The accident of the Fukushima Dai-ichi nuclear power plant of Tokyo Electric Power Cooperation (TEPCO) after the great east Japan earthquake (11 March 2011) elevated the background level of environmental radiation in Eastern Japan. Around the Tokyo metropolitan area, especially around Kashiwa and Nagareyama cities, the ambient dose equivalent rate has been significantly increased after the accident. Responding to strong requests from citizens, the local governments started to monitor the ambient dose equivalent rate precisely and officially, about 3 months after the accident had occurred. The two cities in cooperation with each other also organised a local forum supported by three radiation specialists. In this article, the activities of the local governments are introduced, with main focus on radiation monitoring and measurements. Topics are standardisation of environmental radiation measurements for ambient dose rate, dose mapping activity, investigation of foodstuff and drinking water, lending survey meters to citizens, etc. Based on the data and facts mainly gained by radiation monitoring, risk management and relating activity have been organised. 'Small consultation meetings in kindergartens', 'health consultation service for citizens', 'education meeting on radiation protection for teachers, medical staffs, local government staffs, and leaders of active volunteer parties' and 'decontamination activity', etc. are present key activities of the risk management and restoration around the Tokyo metropolitan area. PMID- 22927654 TI - Radioprotective effects of (-)-epigallocatechin-3-gallate on human erythrocyte/granulocyte lineages. AB - Epigallocatechin-3-gallate (EGCg) is widely recognised as a powerful antioxidant and free radical scavenger. This study examined the radioprotective effects of EGCg on human granulopoiesis and erythropoiesis. Highly purified human CD34(+) haematopoietic stem/progenitor cells were prepared from human placental/umbilical cord blood. The cells were exposed to X rays at a dose rate of ~1 Gy min(-1) and then cultured in a medium supplemented with either granulocyte colony-stimulating factor (G-CSF) or erythropoietin (EPO). EGCg (100 nM) was added to the culture immediately before or after X-irradiation. The concentration of 100-nM EGCg was determined in the authors' previous study. The number of granulocyte and erythrocyte colonies generated by X-irradiated CD34(+) cells decreased in a dose dependent manner. Although EGCg addition yielded an ~2-fold increase in the proliferation of each haematopoietic progenitor, no significant protective effect was observed in the surviving fraction of granulocyte progenitors (G-CSF alone: D(0)=1.06 Gy, n=1.14). However, EGCg addition before or after irradiation conferred a significantly higher protective effect on erythrocyte colony formation compared with the control (EPO alone: D(0)=0.66 Gy, n=1.56; EGCg (before): D(0)=0.43 Gy, n=5.48). EGCg addition before irradiation significantly improved the survival of erythroid progenitors subjected to radiation of <1 Gy. These results suggest that EGCg is more protective of erythropoiesis than granulopoiesis from radiation damage. PMID- 22927656 TI - Environmental radiation at Izu-Oshima after the Fukushima Daiichi nuclear power plant accident. AB - Environmental radiation at Izu-Oshima Island was observed 6 months after the accident at the Fukushima Daiichi Nuclear Power Plant (F1-NPP). A car-borne survey of the dose rate in air was conducted over the entire island and the results were compared with measurements performed in 2005 (i.e. before the accident). The activity concentrations of (134)Cs and (137)Cs were also measured using a germanium detector. The dose rate in air was found to be 2.9 +/- 1.2 times higher than that in 2005 and (134)Cs was detected on Izu-Oshima Island. These results are attributed to the accident at the F1-NPP. PMID- 22927657 TI - Radiation protective effect of hypoxia-inducible factor-1alpha (HIF-1alpha) on human oral squamous cell carcinoma cell lines. AB - We examined the effects of 5-Gy radiation on the expression of hypoxia-inducible factor-1alpha (HIF-1alpha) and the radiosensitivity of five human oral squamous cell carcinoma (OSCC) cell lines (SAS, Ca9-22, TT, BSC-OF and IS-FOM). In all of the cell lines, HIF-1alpha was expressed in mRNA, and radiation had no influence on gene transcription. The number of apoptotic cells increased 72 h after irradiation in cell lines SAS, Ca9-22 and TT cells, indicating low transcriptional levels of HIF-1alpha, and the levels of non-cleaved caspase-3, an executioner of apoptosis, and non-cleaved poly (adenosine diphosphate-ribose) polymerase (PARP), a marker of DNA damage early in apoptosis, decreased simultaneously. Conversely, radiation failed to induce apoptosis or to decrease expression of non-cleaved caspase-3 and PARP in cell lines BSC-OF and IS-FOM cells that expressed high levels of HIF-1alpha. BSC-OF and IS-FOM cells exhibited high migratory capacity. When CoCl(2) was present in the medium, HIF-1alpha expression increased along with the survival of Ca9-22 cells after radiation exposure. These results suggest that OSCC cells expressing high levels of HIF 1alpha are resistant to radiation. HIF-1alpha can be used to control the short term radiosensitivity of cells. PMID- 22927658 TI - Thoron experimental room at the National Institute of Radiological Sciences (NIRS), Japan. AB - A new thoron ((220)Rn) experimental room (TER) was established at National Institute of Radiological Sciences in 2011 to respond to the appearance of new passive devices for (220)Rn and its progeny ((212)Pb, (212)Bi) measurement. The room volume is 21.7 m(3) with a low air exchange rate, 0.016 h(-1). Environmental parameters, such as temperature, relative and absolute humidities, wind speed, aerosol distribution and concentration, are monitored, but not controlled. Commercially available lantern mantles (500 pcs), which can generate maximum concentrations of 6000 Bq m(-3) of (220)Rn and 2000 Bq m(-3) of its progeny, are used as a (220)Rn source. Based on preliminary results from the TER, stable and homogenised concentrations of (220)Rn and its progeny can be ensured; therefore, in the near future the room will be used for testing measuring instruments. PMID- 22927659 TI - Radionuclides in the adriatic sea and related dose-rate assessment for marine biota. AB - Artificial and natural radionuclides were determined in the Adriatic Sea in the seawater and sediment samples in the period from 2007 to 2011. The sampling areas were coastal waters of Slovenia, Croatia and Albania, together with the deepest part of the Adriatic in South Adriatic Pit and Otranto strait. Sampling locations were chosen to take into account all major geological and geographical features of this part of the Adriatic Sea and possible coastal influences. After initial sample preparation steps, samples were measured by gamma-ray spectrometry. In the seawater 40K activity concentrations were in the range from 6063 to 10519 Bq m-3, 137Cs from 1.6 to 3.8 Bq m-3, 226Ra from 23 to 31 Bq m-3, 228Ra from 1 to 25 Bq m 3 and 238U from 64 to 490 Bq m-3. The results of sediment samples showed that 40K was in the range from 87 to 593 Bq kg-1, 137Cs from 0.8 to 7.3 Bq kg-1, 226Ra from 18 to 35 Bq kg-1, 228Ra from 4 to 29 Bq kg-1 and 238U from 14 to 120 Bq kg 1. In addition, the ERICA Assessment Tool was used for the assessment of dose rates for reference marine organisms using the activity concentrations of the determined radionuclides in seawater. The assessment showed that for the most of the organisms, the dose rates were within the background levels, indicating that the determined values for seawater does not pose a significant risk for the most of marine biota. In the study, the results are critically discussed and compared with other similar studies worldwide. Generally, the activity concentrations of the examined radionuclides did not differ from those reported for the rest of the Mediterranean Sea. PMID- 22927660 TI - Radon in Finnish apartment buildings. AB - The 106 866 dwellings measured for radon in Finland so far by Radiation and Nuclear Safety Authority include 5560 apartments. The radon concentrations in ground-contact apartments are similar to those in low-rise residential buildings located in the same area. The values in apartments above the first floor do not significantly depend on the floor level, being typically one-third of those in ground-contact apartments. The radon values in new ground-contact apartments are lower than in those built in the 1990s, apparently because of lesser soil gas intake into new buildings. Radon in upper floors originates from building materials, and concentrations there have remained unaltered. PMID- 22927661 TI - Preoperative embolization of spinal tumors: variables affecting intraoperative blood loss after embolization. AB - BACKGROUND: Preoperative embolization of spinal tumors is often used to reduce blood loss from surgery. Intraoperative blood loss, even in patients who undergo embolization, is potentially multifactorial; embolization techniques, surgical procedures or tumor characteristics may affect intraoperative blood loss. PURPOSE: To retrospectively analyze factors affecting intraoperative blood loss in patients who had undergone spinal tumor embolization; and to assess the safety of the procedure. MATERIAL AND METHODS: Sixty-two patients (median age, 60 years) with a tumor involving the thoracic (n = 42) or lumbar (n = 20) spine underwent preoperative tumor embolization with particles. Multiple variables, including patient characteristics, tumor characteristics, embolization techniques, and surgical procedures, were evaluated with respect to intraoperative blood loss and transfusion requirement. Complications related to the embolization procedures were also recorded. Univariate and multivariate analysis were performed to analyze the variables affecting the intraoperative blood loss and transfusion requirement. RESULTS: Complete or near-complete tumor embolization was achieved in 47 patients. The average estimated blood loss (EBL) and packed red blood cells units transfused during surgery were 2554 mL (range, 250-11,000 mL) and 7 units (range, 0-28 units), respectively. Univariate analysis indicated tumor volume, surgical approach, and invasiveness of the spinal surgery to be significant variables affecting EBL. Tumor histology and extent, tumor vascularity, degree of embolization, and size of embolic particle did not affect operative blood loss. On multivariate analysis, invasiveness of the surgery was the only variable that influenced EBL. Two patients developed irreversible neurologic deficits following embolization. CONCLUSION: Embolization technique or completeness has a limited effect on operative blood loss after preoperative spinal tumor embolization. Operative blood loss from spinal surgery is dependent primarily on the invasiveness of the surgery. Although preoperative embolization is a relatively safe procedure, there remains a risk of cord ischemia. PMID- 22927662 TI - Cryothermal vs. radiofrequency ablation as atrial flutter therapy: a randomized comparison. AB - AIMS: Radiofrequency (RF) ablation of the cavotricuspid isthmus (CTI) is an effective treatment for atrial flutter (AFL). However, RF may injure cardiac structures such as the atrio-ventricular node or the right coronary artery and is usually painful. This prospective, randomized study compares cryoablation (Cryo) with RF ablation regarding efficacy, safety, and perceived pain. METHODS AND RESULTS: One-hundred and fifty-three patients (78 Cryo; 75 RF) with CTI-dependent AFL--median age 65 years (range 34-82), 140 men (91%)--were randomized to Cryo or RF. Primary endpoint was demonstration of long-term efficacy defined as no symptomatic recurrence of AFL at the 6-month follow-up. Radiofrequency ablation was performed with a 3.5 mm open-irrigated-tip catheter and Cryo with a 9 F, 8 mm tip catheter. Ablation endpoint was bidirectional CTI block. Pain was evaluated with a visual analogue scale (VAS; 0-10). The acute success rate was 92% for Cryo and 95% for RF (P = 0.58). Procedural time was longer in the Cryo group (152 +/- 54 min) than the RF group (116 +/- 41 min) (P < 0.001). Cryoablation was considerably less painful compared with RF (mean VAS-Cryo 0.7 +/- 1.2 vs. VAS-RF 4.6 +/- 2.0; P < 0.001). Success rate at 6-month follow-up was 93% (73 of 78) for Cryo and 97% (73 of 75) for RF (P = 0.86). No major adverse events occurred in any group. CONCLUSION: Cryoablation of isthmus-dependent AFL is not inferior to RF but with significantly less procedure-related pain. PMID- 22927663 TI - Ivabradine for inappropriate sinus tachycardia: another piece of evidence. PMID- 22927664 TI - Epicardial ablation of monomorphic ventricular tachycardia storm in hypertrophic cardiomyopathy. PMID- 22927666 TI - Should all patients undergoing atrioventricular junction ablation receive cardiac resynchronization therapy? PMID- 22927665 TI - Lead complications, device infections, and clinical outcomes in the first year after implantation of cardiac resynchronization therapy-defibrillator and cardiac resynchronization therapy-pacemaker. AB - AIMS: The decision to implant a cardiac resynchronization therapy (CRT) system with (defibrillator, CRT-D) or without (pacemaker, CRT-P) cardioverter defibrillator should weigh its benefits and risks. This study examined the (i) incidence of loss of capture and infectious complications and (ii) 1-year clinical outcomes of 402 CRT-D and CRT-P recipients enrolled in the MASCOT study. METHODS AND RESULTS: The indications for CRT-D or CRT-P were posed by the implanting physicians. All (i) losses of atrial and right and left ventricular capture, (ii) system-related infections, and (iii) clinical outcomes, including hospitalizations for worsening heart failure (HF) and deaths from all causes, were recorded up to 1 year of follow-up. Cardiac resynchronization therapy defibrillator was implanted in 228 (57%) and CRT-P in 174 (43%) patients. The incidence of loss of capture was greater in CRT-D with 21 patients (9.2%) than in CRT-P with 6 patient (3.5%) recipients (P = 0.01), while the infection rates were 1.3% (3 patients) and 1.2% (2 patients), respectively (ns). In the CRT-D group, 42 of 228 patients (18.4%) died or were hospitalized for HF, compared with 38 of 174 patients (21.8%) in the CRT-P group (ns). In the CRT-D group, 23 patients (10.1%) were hospitalized for worsening HF and 20 (8.8%) patients died, vs. 22 (12.6%) and 19 (10.9%) patients, respectively, in the CRT-P group (ns for both comparisons). CONCLUSIONS: Cardiac resynchronization therapy-defibrillator was implanted in 57% of candidates for CRT. Within 1 year after device implant, the incidence of loss of capture at any lead was nearly three-fold greater among CRT D than among CRT-P recipients. System-related infections were infrequent and clinical outcomes were similar in both groups. PMID- 22927667 TI - Inhibition of TGF-beta enhances the in vivo antitumor efficacy of EGF receptor targeted therapy. AB - EGF receptor (EGFR)-targeted monoclonal antibodies (mAb), such as cetuximab, execute their antitumor effect in vivo via blockade of receptor-ligand interactions and engagement of Fcgamma receptors on immune effector cells that trigger antibody-dependent cell-mediated cytotoxicity (ADCC). We show that tumors counteract the in vivo antitumor activity of anti-EGFR mAbs by increasing tumor cell-autonomous expression of TGF-beta. We show that TGF-beta suppresses the expression of key molecular effectors of immune cell-mediated cytotoxicity, including Apo2L/TRAIL, CD95L/FasL, granzyme B, and IFN-gamma. In addition to exerting an extrinsic inhibition of the cytotoxic function of immune effectors, TGF-beta-mediated activation of AKT provides an intrinsic EGFR-independent survival signal that protects tumor cells from immune cell-mediated apoptosis. Treatment of mice-bearing xenografts of human head and neck squamous cell carcinoma with cetuximab resulted in emergence of resistant tumor cells that expressed relatively higher levels of TGF-beta compared with untreated tumor bearing mice. Although treatment with cetuximab alone forced the natural selection of TGF-beta-overexpressing tumor cells in nonregressing tumors, combinatorial treatment with cetuximab and a TGF-beta-blocking antibody prevented the emergence of such resistant tumor cells and induced complete tumor regression. Therefore, elevated levels of TGF-beta in the tumor microenvironment enable tumor cells to evade ADCC and resist the antitumor activity of cetuximab in vivo. Our results show that TGF-beta is a key molecular determinant of the de novo and acquired resistance of cancers to EGFR-targeted mAbs, and provide a rationale for combinatorial targeting of TGF-beta to improve anti-EGFR-specific antibody therapy of EGFR-expressing cancers. PMID- 22927668 TI - Polyunsaturated fatty acid concentration predicts myelin integrity in early-phase psychosis. AB - BACKGROUND: White matter (WM) abnormalities have been implicated in schizophrenia, yet the mechanisms underlying these abnormalities are not fully understood. Several lines of evidence suggest that polyunsaturated fatty acids (PUFAs) play a role in myelination, and there is substantial evidence documenting decreased PUFA concentrations in schizophrenia. We therefore hypothesized that lower membrane PUFA concentrations may be related to reduced WM integrity in schizophrenia and related disorders. METHODS: In 30 male patients with a recent onset psychotic disorder, erythrocyte membrane PUFA concentrations were assessed and diffusion tensor imaging was performed with voxelwise analysis. RESULTS: Lower total PUFA concentration was associated with lower fractional anisotropy (FA) throughout the corpus callosum and bilateral parietal, occipital, temporal and frontal WM (P < .05, corrected). Of the individual PUFAs, lower arachidonic acid concentration, and to a lesser extent, lower nervonic acid, linoleic acid, and docosapentaenoic acid concentration were significantly associated with lower FA. PUFA concentrations were inversely associated with radial diffusivity but showed little association with axial diffusivity. Greater severity of negative symptoms was associated with lower nervonic acid concentration and lower FA values. CONCLUSIONS: Membrane PUFA concentrations appear to be robustly related to brain WM integrity in early phase psychosis. These findings may provide a basis for studies to investigate the effects of PUFA supplementation on WM integrity and associated symptomatology in early psychosis. PMID- 22927669 TI - Prior haloperidol, but not olanzapine, exposure augments the pursuit of reward cues: implications for substance abuse in schizophrenia. AB - Drug abuse and addiction are excessively common in schizophrenia. Chronic antipsychotic treatment might contribute to this comorbidity by inducing supersensitivity within the brain's dopamine system. Dopamine supersensitivity can enhance the incentive motivational properties of reward cues, and reward cues contribute to the maintenance and severity of drug addiction. We have shown previously that rats withdrawn from continuous haloperidol (HAL) treatment (via subcutaneous minipump) develop dopamine supersensitivity and pursue reward cues more vigorously than HAL-naive rats following an amphetamine (AMPH) challenge. Atypical antipsychotic drugs are thought to be less likely than typicals to produce dopamine supersensitivity. Thus, we compared the effects of HAL and the atypical antipsychotic olanzapine (OLZ) on the pursuit of reward cues. Rats were trained to associate a light-tone cue with water then treated with HAL or OLZ. Following antipsychotic withdrawal, we assessed AMPH-induced enhancement of lever pressing for the cue. Withdrawal from HAL, but not from OLZ, enhanced this effect. HAL, but not OLZ, also enhanced AMPH-induced psychomotor activation and c fos mRNA expression in the caudate-putamen. Thus, prior HAL, but not OLZ, enhanced conditioned reward following an AMPH challenge, and this was potentially linked to enhanced behavioral sensitivity to AMPH and AMPH-induced engagement of the caudate-putamen. These findings suggest that HAL, but not an atypical like OLZ, modifies reward circuitry in ways that increase responsiveness to reward cues. Because enhanced responsiveness to reward cues can promote drug-seeking behavior, it should be investigated whether atypical antipsychotics might be a preferential option in schizophrenic patients at risk for drug abuse or addiction. PMID- 22927670 TI - Is the prevalence of metabolic syndrome and metabolic abnormalities increased in early schizophrenia? A comparative meta-analysis of first episode, untreated and treated patients. AB - We aimed to discover whether metabolic complications of schizophrenia (SZ) are present in first episode (FE) and unmedicated (UM) patients, in comparison with patients established on antipsychotic medication (AP). METHOD: A systematic search, critical appraisal, and meta-analysis were conducted of studies to December 2011 using Medline, PsycINFO, Embase and experts. Twenty-six studies examined FE SZ patients (n = 2548) and 19 included UM SZ patients (n = 1325). For comparison we identified 78 publications involving 24 892 medicated patients who had chronic SZ already established on AP. RESULTS: In UM, the overall rate of metabolic syndrome (MetS) was 9.8% using any standardized criteria. Diabetes was found in only 2.1% and hyperglycaemia (>100 mg/dl) in 6.4%. In FE, the overall MetS rate was 9.9%, diabetes was found in only 1.2%, and hyperglycaemia in 8.7%. In UM and FE, the rates of overweight were 26.6%, 22%; hypertriglyceridemia 16.9%, 19.6%; low HDL 20.4%, 21.9%; high blood pressure 24.3%, 30.4%; smoking 40.2%, 46.8%, respectively. In both groups all metabolic components and risk factors were significantly less common in early SZ than in those already established on AP. Waist size, blood pressure and smoking were significantly lower in UM compared with FE. CONCLUSION: There is a significantly lower cardiovascular risk in early SZ than in chronic SZ. Both diabetes and pre diabetes appear uncommon in the early stages, especially in UM. However, smoking does appear to be elevated early after diagnosis. Clinicians should focus on preventing initial cardiometabolic risk because subsequent reduction in this risk is more difficult to achieve, either through behavioral or pharmacologic interventions. PMID- 22927671 TI - Neurocognitive performance stability in a multiplex multigenerational study of schizophrenia. AB - Certain cognitive measures are heritable and differentiate individuals at risk for schizophrenia from unaffected family members and healthy comparison subjects. These deficits in neurocognitive performance in patients with schizophrenia appear stable in the short-term. However, the duration of most, but not all, longitudinal studies is modest and the majority have relied on traditional average performance measures to examine stability. Using a computerized neurocognitive battery (CNB), we assessed mean performance (accuracy and speed) and intra-individual variability (IIV) in a longitudinal study aimed to examine neurocognitive stability in European-American multiplex families with schizophrenia. Thirty-four patients with schizophrenia, 65 unaffected relatives, and 45 healthy comparison subjects completed the same computerized neurocognitive assessment over approximately 5 years. Measures of mean performance showed that patients had stable accuracy performance but were slower in many neurocognitive domains over time as compared with unaffected family members and healthy subjects. Furthermore, patients and family members showed dissociable patterns of change in IIV for speed across cognitive domains: compared with controls, patients showed higher across-task IIV in performance compared with family members, who showed lower across-task IIV. Patients showed an increase in IIV over time, whereas family members showed a decrease. These findings suggest that measures of mean performance and IIV of speed during a CNB may provide useful information about the genetic susceptibility in schizophrenia. PMID- 22927672 TI - Neurocognition in the extended psychosis phenotype: performance of a community sample of adolescents with psychotic symptoms on the MATRICS neurocognitive battery. AB - Neurocognitive dysfunction is well established in psychosis, but recent work suggests that processing speed deficits might represent a particularly important cognitive deficit. A number of significant confounds, however, such as disease chronicity and antipsychotic medication use, have been shown to affect processing speed, causing debate as to the core cognitive features of psychosis. We adopted a novel strategy of testing neurocognitive performance in the "extended psychosis phenotype," involving community-based adolescents who are not clinically psychotic but who report psychotic symptoms and who are at increased risk of psychosis in adulthood. This allows investigation of the earliest cognitive factors associated with psychosis risk, while excluding potential confounds such as disease chronicity and antipsychotic use. A population sample of 212 school going adolescents aged 11-13 years took part in this study. Psychotic symptoms were assessed using the psychosis section of the Schedule for Affective Disorders and Schizophrenia. Neurocognition was assessed using the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) consensus neurocognitive battery. Adolescents with psychotic symptoms performed significantly more poorly on 3 processing speed tasks: Trail Making Test-A (F = 3.3, P < .05), Trail Making Test-B (F = 3.1, P < .05), and digit symbol coding task (F = 7.0, P < .001)-as well as on a nonverbal working memory (spatial span) task (F = 3.2, P < .05). Our findings support the idea that neurocognitive impairment, and processing speed impairment in particular, is a core feature of psychosis risk. This group likely demonstrates some of the earliest cognitive impairments associated with psychosis vulnerability. PMID- 22927673 TI - Diagnostic specificity of neurophysiological endophenotypes in schizophrenia and bipolar disorder. AB - BACKGROUND: The utility of an endophenotype depends on its ability to reduce complex disorders into stable, genetically linked phenotypes. P50 and P300 event related potential (ERP) measures are endophenotype candidates for schizophrenia; however, their abnormalities are broadly observed across neuropsychiatric disorders. This study examined the diagnostic efficiency of P50 and P300 in schizophrenia as compared with healthy and bipolar disorder samples. Supplemental ERP measures and a multivariate classification approach were evaluated as methods to improve specificity. METHODS: Diagnostic classification was first modeled in schizophrenia (SZ = 50) and healthy normal (HN = 50) samples using hierarchical logistic regression with predictors blocked by 4 levels of analysis: (1) P50 suppression, P300 amplitude, and P300 latency; (2) N100 amplitude; (3) evoked spectral power; and (4) P50 and P300 hemispheric asymmetry. The optimal model was cross-validated in a holdout sample (SZ = 34, HN = 31) and tested against a bipolar (BP = 50) sample. RESULTS: P50 and P300 endophenotypes classified SZ from HN with 71% accuracy (sensitivity = .70, specificity = .72) but did not differentiate SZ from BP above chance level. N100 and spectral power measures improved classification accuracy of SZ vs HN to 79% (sensitivity = .78, specificity = .80) and SZ vs BP to 72% (sensitivity = .74, specificity = .70). Cross validation analyses supported the stability of these models. CONCLUSIONS: Although traditional P50 and P300 measures failed to differentiate schizophrenia from bipolar participants, N100 and evoked spectral power measures added unique variance to classification models and improved accuracy to nearly the same level achieved in comparison of schizophrenia to healthy individuals. PMID- 22927674 TI - Is a structured, manualized, evidence-based treatment protocol culturally competent and equivalently effective among American Indian parents in child welfare? AB - In a statewide implementation, the manualized SafeCare home-based model was effective in reducing child welfare recidivism and producing high client satisfaction. Concerns about the effectiveness and acceptability of structured, manualized models with American Indians have been raised in the literature, but have rarely been directly tested. This study tests recidivism reduction equivalency and acceptability among American Indian parents. A subpopulation of 354 American Indian parents was drawn from a larger trial that compared services with versus without modules of the SafeCare model. Outcomes were 6-year recidivism, pre/post/follow-up measures of depression and child abuse potential, and posttreatment consumer ratings of working alliance, service satisfaction, and cultural competency. Recidivism reduction among American Indian parents was found to be equivalent for cases falling within customary SafeCare inclusion criteria. When extended to cases outside customary inclusion boundaries, there was no apparent recidivism advantage or disadvantage. Contrary to concerns, SafeCare had higher consumer ratings of cultural competency, working alliance, service quality, and service benefit. Findings support using SafeCare with American Indians parents who meet customary SafeCare inclusion criteria. Findings do not support concerns in the literature that a manualized, structured, evidence-based model might be less effective or culturally unacceptable for American Indians. PMID- 22927675 TI - Telmisartan prevents excess-salt-induced exacerbated (malignant) hypertension in spontaneously hypertensive rats. AB - The effects of angiotensin receptor blocker, diuretic, a calcium antagonist, and their combination were evaluated on the progression of cardiovascular and renal damage in spontaneously hypertensive rats (SHRs) given excess salt. To this end, 8-week male SHRs were divided into 7 groups. The control group (C) received normal NaCl (0.6%) diet. All other groups were given 8% NaCl rat chow. In addition, group 2 was given placebo (tap water alone), group 3 the angiotensin receptor antagonist telmisartan (10 mg/kg per d), group 4 received the diuretic chlorothiazide (80 mg/kg per d), group 5 was given telmisartan plus the diuretic, group 6 was given the calcium antagonist amlodipine (10 mg/kg per d), and group 7 was given telmisartan plus amlodipine. All treatments lasted for 8 weeks. Compared with controls, mean arterial pressure (MAP), renal blood flow, coronary flow reserve, minimal coronary vascular resistance, diastolic time constant, and maximal rate of ventricular pressure fall were all adversely affected by salt loading. Increased left ventricular mass with marked cardiac fibrosis was also found in the salt-overloaded SHR group. Telmisartan normalized all indices except MAP, whereas diuretic and amlodipine only partially restored cardiac functional and mass indexes. Combination therapy with telmisartan and either diuretic or amlodipine also normalized all indices including arterial pressure. These data suggest that (1) cardiovascular damage induced by excess salt in the SHRs was not pressure dependent; (2) compared with the calcium antagonist and diuretic, blockade of angiotensin receptors was extremely effective in this model. PMID- 22927676 TI - A 1536-well quantitative high-throughput screen to identify compounds targeting cancer stem cells. AB - Tumor cell subpopulations called cancer stem cells (CSCs) or tumor-initiating cells (TICs) have self-renewal potential and are thought to drive metastasis and tumor formation. Data suggest that these cells are resistant to current chemotherapy and radiation therapy treatments, leading to cancer recurrence. Therefore, finding new drugs and/or drug combinations that cause death of both the differentiated tumor cells as well as CSC populations is a critical unmet medical need. Here, we describe how cancer-derived CSCs are generated from cancer cell lines using stem cell growth media and nonadherent conditions in quantities that enable high-throughput screening (HTS). A cell growth assay in a 1536-well microplate format was developed with these CSCs and used to screen a focused collection of oncology drugs and clinical candidates to find compounds that are cytotoxic against these highly aggressive cells. A hit selection process that included potency and efficacy measurements during the primary screen allowed us to efficiently identify compounds with potent cytotoxic effects against spheroid derived CSCs. Overall, this research demonstrates one of the first miniaturized HTS assays using CSCs. The procedures described here should enable further testing of the effect of compounds on CSCs and help determine which pathways need to be targeted to kill them. PMID- 22927677 TI - Glioma-propagating cells as an in vitro screening platform: PLK1 as a case study. AB - Gliomas are the most devastating of primary adult malignant brain tumors. These tumors are highly infiltrative and can arise from cells with extensive self renewal capability and chemoresistance, frequently termed glioma-propagating cells (GPCs). GPCs are thus the plausible culprits of tumor recurrence. Treatment strategies that eradicate GPCs will greatly improve disease outcome. Such findings support the use of GPCs as in vitro cellular systems for small-molecule screening. However, the nuances in using GPCs as a cellular screening platform are not trivial. These slow-growing cells are typically cultured as suspension, spheroid structures in serum-free condition supplemented with growth factors. Consequently, replenishment of growth factors throughout the screening period must occur to maintain cells in their undifferentiated state, as the more lineage committed, differentiated cells are less tumorigenic. We present a case study of a small-molecule screen conducted with GPCs and explain how unique sphere activity assays were implemented to distinguish drug efficacies against the long term, self-renewing fraction, as opposed to transient-amplifying progenitors, the latter of which are detected in conventional viability assays. We identified Polo like kinase 1 as a regulator of GPC survival. Finally, we leveraged on public glioma databases to illustrate GPC contribution to disease progression and patient survival outcome. PMID- 22927678 TI - Reportable neurologic diseases in refugee camps in 19 countries. AB - BACKGROUND: Approximately one-third of refugees worldwide live in refugee camps. Selected neurologic diseases are actively reported in some refugee camps. METHODS: The United Nations High Commissioner for Refugees monitors health visits in refugee camps with the assistance of more than 25 partner organizations using standardized case definitions. Neurologic diseases were selected and searched for the years 2008 to 2011. The number of health care visits for a neurologic disease was calculated and divided by the aggregated number of reporting months available for each refugee camp ("visits per camp-month"). RESULTS: Five neurologic diseases were reported from 127 refugee camps in 19 countries. Visits for chronic, noncommunicable diseases including epilepsy (53,941 visits in 1,426 camp months, 48% female) and cerebrovascular disease (4,028 visits in 1,333 camp months, 51% female) far exceeded those for neurologic infectious diseases (acute flaccid paralysis/poliomyelitis, 78 visits in 3,816 camp-months, 42% female; leprosy, 74 visits in 3,816 camp-months, 66% female; meningitis, 477 visits in 3,816 camp-months, 51% female). In 2011, these diseases accounted for 31,349 visits globally with 91% of visits for epilepsy. CONCLUSIONS: Targeted programs addressing epilepsy and stroke among refugees in camps should become a priority and indicate that other chronic neurologic diseases that may be under- or misdiagnosed may also be common in refugee camps. Given that significant under reporting is likely, our findings demonstrate the pressing need for coordinated preventive and interventional measures for epilepsy and stroke in refugee camps. PMID- 22927679 TI - Early stroke mortality, patient preferences, and the withdrawal of care bias. AB - OBJECTIVE: Early mortality is a potential measure of the quality of care provided to hospitalized stroke patients. Whether in-hospital stroke mortality is reflective of deviations from evidence-based practices or patient/family preferences on life-sustaining measures is unclear. METHODS: All ischemic stroke mortalities at an academic medical center were reviewed to better understand the causes of inpatient stroke mortality. RESULTS: Among 37 deaths or discharges to hospice in 2009, 36 occurred after a patient/family decision to withdraw/withhold potentially life-sustaining interventions. An independent survey of 3 vascular neurologists revealed that some early deaths could have been delayed beyond 30 days if patients or families had agreed to more aggressive measures. From these data, we estimate the magnitude of a "withdrawal of care" bias to be approximately 40% of the observed short-term mortality. CONCLUSIONS: Acute stroke mortality may be more reflective of patient/family preferences than the provision of evidence-based care. PMID- 22927680 TI - Tadpole pupil. PMID- 22927681 TI - Teaching NeuroImages: isolated hypothalamic hamartoma vs Pallister-Hall syndrome: imaging and clinical correlation. PMID- 22927682 TI - CAG repeat expansion in Huntington disease determines age at onset in a fully dominant fashion. PMID- 22927683 TI - The tremor network targeted by successful VIM deep brain stimulation in humans. PMID- 22927684 TI - Hypothermia and corpus callosum agenesis in Shapiro syndrome: too cold, even for a Viking. PMID- 22927685 TI - Reverberating TCD flow pattern in brain death. PMID- 22927686 TI - Febrile seizures: possible outcomes. PMID- 22927687 TI - Flavored cigar smoking among U.S. adults: findings from the 2009-2010 National Adult Tobacco Survey. AB - INTRODUCTION: Under its authority to regulate tobacco products, the U.S. Food and Drug Administration prohibited certain characterizing flavors in cigarettes in September 2009; however, flavored cigars are still permitted to be manufactured, distributed, and sold. This study assessed the prevalence and correlates of flavored cigar smoking among U.S. adults. METHODS: Data were obtained from the 2009-2010 National Adult Tobacco Survey, a national landline and cell phone survey of adults aged >= 18 years old residing in the 50 U.S. states and the District of Columbia. National and state estimates of flavored cigar use were calculated overall and among current cigar smokers; national estimates were calculated by sex, age, race/ethnicity, educational attainment, annual household income, U.S. Census Region, and sexual orientation. RESULTS: The national prevalence of flavored cigar smoking was 2.8% (95% confidence interval [CI] = 2.6%-3.1%; state range: 0.6%-5.7%) and was greater among those who were male, younger in age, non-Hispanic Other race, less educated, less wealthy, and lesbian, gay, bisexual, or transgendered (LGBT). Nationally, the prevalence of flavored cigar use among cigar smokers was 42.9% (95% CI = 40.1%-45.7%; state range: 11.1%-71.6%) and was greater among those who were female, younger in age, Hispanic, non-Hispanic Other race, less educated, less wealthy, and LGBT. CONCLUSIONS: More than two fifths of current cigar smokers report using flavored cigars. Disparities in flavored cigar use also exist across states and subpopulations. Efforts to curb flavored cigar smoking have the potential to reduce the prevalence of overall cigar smoking among U.S. adults, particularly among subpopulations with the greatest burden. PMID- 22927688 TI - Age, job characteristics and coronary health. AB - BACKGROUND: Workplace demographics are changing in many European countries with a higher proportion of older workers in employment. Research has shown that there is an association between job strain and cardiovascular disease, but this relationship is unclear for the older worker. AIMS: To investigate the association between job strain and a coronary event comparing younger and older male workers. METHODS: Cases with a first-time coronary event were recruited from four coronary/intensive care units (1999-2001). Matched controls were recruited from the case's general practitioner surgery. Physical measurements were taken and self-administered questionnaires completed with questions on job characteristics, job demands and control. Unconditional logistic regression was carried out adjusting for classical cardiovascular risk factors. RESULTS: There were 227 cases and 277 matched controls. Age stratified analyses showed a clear difference between younger (<50 years) and older (>=50 years) workers with regard to the exposure of job strain (job demands and control) and the association between these factors and cardiovascular disease. Older workers who had a coronary event were four times as likely to have high job strain [OR = 4.09 (1.29 13.02)] and more likely to report low job control [OR = 0.83 (0.72-0.95)]. CONCLUSIONS: Job control emerged as a potential protective factor for heart disease and this evidence was stronger in the older male worker. Nevertheless, they were significantly more likely to have job strain. These results suggest that older workers may be more susceptible to job strain. PMID- 22927689 TI - Measuring implementation of evidence-based guidance on promoting workers' health. AB - BACKGROUND: The National Health Service (NHS) employs 1.4 million people in England. In health care, improved workforce health has been associated with improved outcomes for patients. The UK's National Institute for Health and Clinical Excellence (NICE) has produced evidence-based guidance on improving workers' health. However, the extent of implementation of evidence-based guidance has not previously been measured. AIMS: To measure progress with implementation of NICE guidance on workplace health and identify opportunities to improve this. METHODS: All NHS organizations in England were invited to participate in an audit of implementation of NICE guidance. A web-based tool was developed to collect information on the extent to which each organization had implemented NICE guidance addressing health promotion in the workplace. RESULTS: The number of organizations that participated was 282. These employed a total of 868 979 workers. Organizations were more likely to involve staff in planning and designing an organizational approach to each topic where health and well-being was a regular board agenda item. Those with an overarching strategy were more likely to have staff health and well-being as a regular board agenda item (P < 0.05) and more likely to have specific policies for obesity, physical activity and promoting mental well-being (all P <0.01). CONCLUSIONS: Implementation of NICE guidance on health at work is incomplete across the NHS in England. Implementation was more complete where boards were leading health and well-being plans and the workforce were actively involved. There is scope to improve the implementation of evidence-based guidance to improve workers' health. PMID- 22927690 TI - The role of advanced nursing practice in occupational health. AB - BACKGROUND: There is a concern that current specialist occupational health (OH) training programmes in the UK are not delivering nurses equipped to deal with the challenges of emerging practice. The development of new training programmes and advanced nurse practitioner (ANP) roles provide a potential solution. Although a model of advanced nursing practice has been developing, its relevance to OH has not been assessed. AIMS: To collate information about OH nurses in the UK, their levels of training, and to collect their views on the relevance of ANP competencies to the specialty. METHODS: An online questionnaire survey was carried out using a database of nurses working in OH. Each nurse received a direct invitation to participate with a link to the survey and one reminder. RESULTS: Nine hundred and ninety-eight responses were included in the analysis. Eighty nine per cent had a specialist qualification in OH. A large majority of respondents believed that almost all the generic ANP competencies were important in current and future OH nursing practice. Only a few competencies (examination, diagnosis, referral, treatment) were felt to be more important in the future than currently. Over half (57%) agreed that in the future where OH nurses were working as specialists they should be trained as advanced nurse practitioners. Seventy one per cent of OH nurses agreed that a new multi-disciplinary qualification would be beneficial. CONCLUSIONS: OH nurses recognize that ANP competencies are important to their current and future practice. There is enthusiasm in OH nursing for the introduction of advanced nursing practice and a new training programme. PMID- 22927691 TI - Childhood ataxia: current understanding and future directions. PMID- 22927692 TI - A review of Friedreich ataxia clinical trial results. AB - There are now 21 agents or classes of therapeutic agents in the Friedreich ataxia research pipeline (http://www.curefa.org/pipeline.html) that have been developed in the 15 years since the discovery of the frataxin gene, with the ongoing characterization of its mutations and the resulting molecular pathology. Twenty four studies are currently posted on ClinicalTrials.gov. Twenty-seven works discussing the results of clinical trials in Friedreich ataxia have been published. In 2010, 42 public (National Institutes of Health) and private (Friedreich Ataxia Research Alliance, Muscular Dystrophy Association, and National Ataxia Foundation) grants were funded for translational and clinical research in Friedreich ataxia. Millions of dollars from public, private, and industry-based initiatives have been dedicated to research in Friedreich ataxia therapeutics. Despite this vigorous international effort, there is as yet no proven disease-modifying therapy for Friedreich ataxia. PMID- 22927694 TI - Methods to assess cost-effectiveness and value of further research when data are sparse: negative-pressure wound therapy for severe pressure ulcers. AB - Health care resources are scarce, and decisions have to be made about how to allocate funds. Often, these decisions are based on sparse or imperfect evidence. One such example is negative-pressure wound therapy (NPWT), which is a widely used treatment for severe pressure ulcers; however, there is currently no robust evidence that it is effective or cost-effective. This work considers the decision to adopt NPWT given a range of alternative treatments, using a decision analytic modeling approach. Literature searches were conducted to identify existing evidence on model parameters. Given the limited evidence base, a second source of evidence, beliefs elicited from experts, was used. Judgments from experts on relevant (uncertain) quantities were obtained through a formal elicitation exercise. Additionally, data derived from a pilot trial were also used to inform the model. The 3 sources of evidence were collated, and the impact of each on cost-effectiveness was evaluated. An analysis of the value of further information indicated that a randomized controlled trial may be worthwhile in reducing decision uncertainty, where from a set of alternative designs, a 3-arm trial with longer follow-up was estimated to be the most efficient. The analyses presented demonstrate how allocation decisions about medical technologies can be explicitly informed when data are sparse and how this kind of analyses can be used to guide future research prioritization, not only indicating whether further research is worthwhile but what type of research is needed and how it should be designed. PMID- 22927695 TI - Interpreting patient decisional conflict scores: behavior and emotions in decisions about treatment. AB - BACKGROUND: Patient decision aids facilitate treatment decisions. They are often evaluated in terms of their effect on decisional conflict, as measured by the Decisional Conflict Scale (DCS). It is unclear to what extent lower DCS scores are accompanied by observable patient behavior or emotions. OBJECTIVE: To help interpret DCS scores. DESIGN: In a Dutch university hospital, statements on behaviors or emotions during decision making were collected from asymptomatic aneurysm patients and healthy employees. Subsequently, they rated the intensity of decisional conflict that each statement expresses on a 1 to 10 scale. Selected statements were prospectively tested in aneurysm patients and cancer patients facing treatment dilemmas. MEASUREMENTS: Associations between patients' DCS scores and reported behavior and emotions were analyzed using logistic regression analysis. RESULTS: Participants provided 363 statements on behaviors and emotions during decision making, of which 28 were mentioned more than 4 times. Nine forms of behavior and emotions were selected as they were graded with the least variable median ratings of intensity of decisional conflict. Among 100 patients facing a treatment dilemma, each point increase in DCS lowered their odds for "immediately making the decision" (odds ratio [OR], 0.96; 95% confidence interval [CI], 0.93-0.98), whereas the odds of "fretting regularly" (OR, 1.05; 95% CI, 1.02-1.08) and "feeling nervous when thinking of the decision" (OR, 1.04; 95% CI, 1.01-1.06) where higher. CONCLUSIONS: A decrease in decisional conflict scores leads to less decision postponing behavior, fretting, and nervousness. Research should focus on which DCS scores are needed to make deliberate decisions and which scores hinder patients in decision making. PMID- 22927696 TI - Estimating health state utility values for joint health conditions: a conceptual review and critique of the current evidence. AB - BACKGROUND: Analysts frequently estimate the health state utility values (HSUVs) for joint health conditions (JHCs) using data from cohorts with single health conditions. The methods can produce very different results, and there is currently no consensus on the most appropriate technique. OBJECTIVE: To conduct a detailed critical review of existing empirical literature to gain an understanding of the reasons for differences in results and identify where uncertainty remains that may be addressed by further research. RESULTS: Of the 11 studies identified, 10 assessed the additive method, 10 the multiplicative method, 7 the minimum method, and 3 the combination model. Two studies evaluated just 1 of the techniques, whereas the others compared results generated using 2 or more. The range of actual HSUVs can influence general findings, and methods are sometimes compared using descriptive statistics that may not be appropriate for assessing predictive ability. None of the methods gave consistently accurate results across the full range of possible HSUVs, and the values assigned to normal health influence the accuracy of the methods. CONCLUSIONS: Within the limitations of the current evidence base, we would advocate the multiplicative method, conditional on adjustment for baseline utility, as the preferred technique to estimate HSUVs for JHCs when using mean values obtained from cohorts with single conditions. We would recommend that a range of sensitivity analyses be performed to explore the effect on results when using the estimated HSUVs in economic models. Although the linear models appeared to give more accurate results in the studies we reviewed, these models require validating in external data before they can be recommended. PMID- 22927697 TI - Multicohort models in cost-effectiveness analysis: why aggregating estimates over multiple cohorts can hide useful information. AB - BACKGROUND: Models used in cost-effectiveness analysis (CEA) of screening programs may include 1 or many birth cohorts of patients. As many screening programs involve multiple screens over many years for each birth cohort, the actual implementation of screening often involves multiple concurrent recipient cohorts. Consequently, some advocate modeling all recipient cohorts rather than 1 birth cohort, arguing it more accurately represents actual implementation. However, reporting the cost-effectiveness estimates for multiple cohorts on aggregate rather than per cohort will fail to account for any heterogeneity in cost-effectiveness between cohorts. Such heterogeneity may be policy relevant where there is considerable variation in cost-effectiveness between cohorts, as in the case of cancer screening programs with multiple concurrent recipient birth cohorts, each at different stages of screening at any one point in time. OBJECTIVE: The purpose of this study is to illustrate the potential disadvantages of aggregating cost-effectiveness estimates over multiple cohorts, without first considering the disaggregate estimates. Analysis. We estimate the cost effectiveness of 2 alternative cervical screening tests in a multicohort model and compare the aggregated and per-cohort estimates. We find instances in which the policy choices suggested by the aggregate and per-cohort results differ. We use this example to illustrate a series of potential disadvantages of aggregating CEA estimates over cohorts. CONCLUSIONS: Recent recommendations that CEAs should consider the cost-effectiveness of more than just a single cohort appear justified, but the aggregation of estimates across multiple cohorts into a single estimate does not. PMID- 22927698 TI - The choice of a noninformative prior on between-study variance strongly affects predictions of future treatment effect. AB - PURPOSE: Bayesian random-effects meta-analyses require the analyst to specify the prior distribution for between-study variance of the treatment effect. We assessed the sensitivity of prediction and other outputs of the meta-analysis to the choice of this prior. METHODS: We reanalyzed 7 published meta-analyses (5-14 trials) with rare (event rates <5%), moderate (15%-50%), and frequent binary outcomes (>50%). We examined 10 noninformative priors: inverse gamma on between study variance (tau (2)), 2 uniforms on each of the between-study standard deviation (tau) and tau (2), uniform shrinkage on tau (2), DuMouchel shrinkage on tau, half-normal on tau (2), and half-normal priors on tau with large and small variances. For each analysis, we calculated the posterior distributions for tau, the population treatment effect in current studies, and the predicted treatment effect in a future study. We assessed goodness of fit using total residual deviance, the deviance information criterion, and predictive deviance (by cross validations). RESULTS: According to total residual deviance, the best-fitting priors were uniform on tau (2). According to predictive deviance, half-normal on tau (2) and the shrinkage priors were optimal. Across analyses with the 10 priors, there were no important differences in the posteriors for the population treatment effect, but there were substantial differences in the posteriors for tau and predictions. The priors that fitted best according to predictive deviance resulted in less uncertainty around predictions of future treatment effect. CONCLUSIONS: In this sample of Bayesian meta-analyses with binary outcomes, the choice of noninformative prior for between-study variance affected model fit and the predictions of future treatment effect. When the predictive distribution is of interest, we highly recommend examination of multiple prior distributions for between-study variance, especially the half-normal on tau (2) and the shrinkage priors. PMID- 22927699 TI - Pneumolabyrinth following eustachian tube insufflation. PMID- 22927700 TI - Preparing heart and mind following prenatal diagnosis of complex congenital heart defect. AB - Drawing on attachment and caregiving theory and the concept of motivation, the purpose of this descriptive study was to examine parents' retrospective accounts of their prenatal experiences after receiving the diagnosis of a fetal heart defect. These parents constituted a subgroup of participants in a larger longitudinal study of parenting an infant with a complex congenital heart defect. Data were derived from 14 semistructured interviews with 13 mothers and 3 fathers in the home or hospital setting. A directed content analysis yielded a central category of preparing heart and mind for infant caregiving. Preparing heart and mind is a preliminary caregiving goal within the caregiving system that generates intentions and expectations indicative of specific caregiving motivations to relate to the baby, handle circumstances practically, and manage infant medical care. A theoretical model illustrates the prenatal process these parents engaged in to provide care to their infants with life-threatening medical conditions. PMID- 22927701 TI - Anticipatory loss and early mastectomy for young female BRCA1/2 mutation carriers. AB - Young women who carry BRCA1/2 mutations face difficult decisions in managing their hereditary breast/ovarian cancer risk. Through this National Cancer Institute study, we sought to understand the process by which some young women choose risk-reducing bilateral mastectomy (RRBM) instead of alternative risk management options. Data indicate that electing to undergo RRBM, although difficult, is experienced as a way to sidestep potentially devastating outcomes, such as stressful and costly high-risk screening, chemotherapy or radiation, or putting loved ones through the challenges of a cancer diagnosis. The decision to pursue RRBM is often the product of screening fatigue, encouragement from loved ones, and/or a sense of urgency to put one's high-risk period behind one. By understanding how young carriers make decisions about surgical risk reduction, providers can better guide, counsel, and support patients in the important tasks surrounding this life-changing medical decision, thereby helping to increase the duration and quality of their lives. PMID- 22927703 TI - Promoting successful aging through competitive sports participation: insights from older adults. AB - In this study we explored the experience of competing in the Senior Games and the resultant contributions to the successful aging of older adults. We used in-depth interviews with older adults who participated in the National Senior Games. Analysis of the data produced five central themes: (a) perseverance, (b) career development and significant effort, (c) personal and social benefits, (d) unique ethos, and (e) identification as a senior athlete. We found that participating in the Senior Games as a form of serious leisure enhanced the well-being of older adults and could be utilized as a means by which to maintain a healthy lifestyle. PMID- 22927702 TI - Primary care physicians' prevention counseling with patients with multiple morbidity. AB - The prevalence of multiple health conditions, or multiple morbidity (MM), is increasing. Providing medical care for adults with MM presents challenges, including balancing disease management with prevention. We conducted in-depth semistructured interviews with 12 primary care physicians to explore their perspectives on prevention counseling among patients with MM. Participants described the complex relationship between disease management and prevention, highlighted the importance of patient motivation, and discussed various strategies to promote receptivity to prevention recommendations. The perceived potential benefits of prevention recommendations encouraged physicians to persist with such counseling, despite challenges presented by visit time constraints, reimbursement procedures, and concerns over futility. Physicians recommended the development of alternate care delivery and reimbursement models to overcome challenges of the existing health care system and to meet the prevention needs of patients with MM. We explore the implications of these findings for maximizing the health and quality of life of adults with MM. PMID- 22927704 TI - The US military experience with fresh whole blood during the conflicts in Iraq and Afghanistan. AB - Since its introduction in the early part of the last century, fresh whole blood (FWB) has been used by the US military as a battlefield expedient resuscitation method, even after the development of component therapy in the 1960s. In the recent conflicts in Iraq and Afghanistan, FWB was used once more, often collected in the setting of a walking blood bank (WBB). Considerable research and opinion from military circles has cited these experiences and sparked renewed interest in FWB as an effective resuscitation tool in the setting of trauma. Despite efforts by the US military to improve the effectiveness and safety of FWB through a series of widely published guidelines, transfusion transmitted infections (TTI) remain a vexing challenge. These experiences in Iraq and Afghanistan will help inform a larger discussion regarding the reintroduction of FWB in civilian trauma resuscitation. PMID- 22927705 TI - Poverty and Inequality in the Rural Brazilian Amazon: A Multidimensional Approach. AB - This paper analyses poverty and inequality dynamics among smallholders along the Transamazon High-way. We measure changes in poverty and inequality for original settlers and new owners, contrasting income-based with multidimensional indices of well-being. Our results show an overall reduction in both poverty and inequality among smallholders, although poverty decline was more pronounced among new owners, while inequality reduction was larger among original settlers. This trend suggests that families have an initial improvement in livelihood and well being which tends to reach a limit later-a sign of structural limitations common to rural areas and maybe a replication of boom and bust trends in local economies among Amazonian municipalities. In addition, our multidimensional estimates of well-being reveal that some economically viable land use strategies of smallholders (e.g., pasture) may have important ecological implications for the regional landscape. These findings highlight the public policy challenges for fostering sustainable development among rural populations. PMID- 22927706 TI - Darcy Permeability of Hollow Fiber Bundles Used in Blood Oxygenation Devices. AB - Many industrial and biomedical devices (e.g. blood oxygenators and artificial lungs) use bundles of hollow fiber membranes for separation processes. Analyses of flow and mass transport within the shell-side of the fiber bundles most often model the bundle for simplicity as a packed bed or porous media, using a Darcy permeability coefficient estimated from the Blake-Kozeny equation to account for viscous drag from the fibers. In this study, we developed a simple method for measuring the Darcy permeability of hollow fiber membrane bundles and evaluated how well the Blake-Kozeny (BK) equation predicted the Darcy permeability for these bundles. Fiber bundles were fabricated from commercially available Celgard(r) *30-240 fiber fabric (300 MUm outer diameter fibers @ 35 and 54 fibers/inch) and from a fiber fabric with 193 MUm fibers (61 fibers/inch). The fiber bundles were mounted to the bottom of an acrylic tube and Darcy permeability was determined by measuring the elapsed time for a column of glycerol solution to flow through a fiber bundle. The ratio of the measured Darcy permeability to that predicted from the BK equation varied from 1.09 to 0.56. A comprehensive literature review suggested a modified BK equation with the "constant" correlated to porosity. This modification improved the predictions of the BK equation, with the ratio of measured to predicted permeability varying from 1.13 to 0.84. PMID- 22927707 TI - "Incidentaloma" of the liver: management of a diagnostic and therapeutic dilemma. AB - The continuous development of highly sensitive clinical imaging increased the detection of focal lesions of the liver. These accidentally detected liver tumors without liver-specific symptoms such as cholestasis have been named "incidentalomas." Diagnostic tools such as sonography, computed tomography, or magnetic resonance imaging are used increasingly in asymptomatic individuals without defined suspected diagnoses in the setting of general prevention or followup after a history of malignancy. But despite continuous improvement of diagnostics, some doubt regarding the benign or malign behavior of a tumor remains. In case an asymptomatic hemangioma or FNH can be preoperatively detected with certainty, the indication for surgery must be very strict. In case of symptomatic liver lesions surgical resection should only be indicated with tumor specific symptoms. In the remaining cases of benign lesions of the liver, a "watch and wait" strategy is recommended. In case of uncertain diagnosis, especially in patients with positive history of a malignant tumor or the suspected diagnosis of hepatocellular adenoma, surgical resection is indicated. Due to the continuous improvement of surgical techniques, liver resection should be done in the laparoscopic technique. Laparoscopic surgery has lower morbidity and shorter hospitalization than open technique. PMID- 22927708 TI - Serum levels of asymmetric dimethylarginine and apelin as potential markers of vascular endothelial dysfunction in early rheumatoid arthritis. AB - OBJECTIVES: Impaired endothelial function represents the early stage of atherosclerosis, which is typically associated with systemic inflammatory diseases like rheumatoid arthritis (RA). As modulators of endothelial nitric oxide synthase expression, asymmetric-dimethylarginine (ADMA) and apelin might be measured in the blood of RA patients to detect early atherosclerotic changes. We conducted a prospective, case-control study to investigate serum ADMA and apelin profiles of patients with early-stage RA (ERA) before and after disease-modifying antirheumatic drug (DMARD) therapy. METHODS: We enrolled 20 consecutively diagnosed, treatment-naive patients with ERA and 20 matched healthy controls. Serum ADMA and apelin levels and the 28-joint disease activity scores (DAS28) were assessed before and after 12 months of DMARDs treatment. All patients underwent ultrasonographic assessment for intima-media tickness (IMT) evaluation. RESULTS: In the ERA group, ADMA serum levels were significantly higher than controls at baseline (P = 0.007) and significantly decreased after treatment (P = 0.012 versus controls). Baseline serum apelin levels were significantly decreased in this group (P = 0.0001 versus controls), but they were not significantly altered by treatment. IMT did not show significant changes. CONCLUSIONS: ERA is associated with alterations of serum ADMA and apelin levels, which might be used as biomarkers to detect early endothelial dysfunction in these patients. PMID- 22927709 TI - Inflammatory mediators in induced sputum and airway hyperresponsiveness in cough variant asthma during long-term inhaled corticosteroid treatment. AB - OBJECTIVE: This study aimed to investigate improvements in inflammatory mediator levels in induced sputum and airway hyperresponsiveness (AHR) in cough variant asthma (CVA) during long-term inhaled corticosteroid (ICS) treatment. PATIENTS AND METHODS: Patients with CVA (N = 35) and classic asthma (N = 26) and healthy subjects (N = 24) were recruited into this study. All patients were treated with budesonide (400 MUg/day). Measurement of inflammatory mediators in induced sputum and PD20-FEV(1) (the accumulated provocative dose resulting in a 20% decrease in FEV(1)) in histamine-challenged subjects was performed every three months after the start of medication. Interleukin- (IL-) 5 and IL-10 were assayed by ELISA, and the percentage of eosinophils was detected with Giemsa stain. Trends during the follow-up period were analyzed using a general linear model. RESULTS: Inflammatory mediator levels in induced sputum and PD20-FEV(1) in patients with CVA and classic asthma differed from those in the control group, although no differences were found in the two asthmatic groups. PD20-FEV(1) significantly increased in CVA patients after ICS treatment for 3 months, while classic asthma patients exhibited a delayed change in AHR. After ICS treatment, levels of IL-5 and IL-10 as well as the percentage of eosinophils in the CVA group were altered at 3 months and 6 months, respectively. Accordingly, the level of inflammatory mediators in classic asthma changed more slowly. CONCLUSION: CVA has a greater improvement in airway inflammation and airway hyperresponsiveness (AHR) than classic asthma with respect to inhaled corticosteroid (ICS). Short-term ICS considerably reduces AHR although longer treatment is required for complete control of airway inflammation. PMID- 22927712 TI - Genetic and environmental etiologies of reading difficulties: DeFries-Fulker analysis of reading performance data from twin pairs and their nontwin siblings. AB - Reading performance data from 254 pairs of identical (MZ) and 420 pairs of fraternal (DZ) twins, 8.0 to 20.0 years of age, were subjected to multiple regression analyses. An extension of the DeFries-Fulker (DF) analysis (DeFries & Fulker, 1985, 1988) that facilitated inclusion of data from 303 of their nontwin siblings was employed. In addition to providing estimates of heritability, this analysis yields a test of the difference between shared environmental influences for twins versus siblings (Astrom et al., 2011). Results suggest that proband reading deficits are due substantially to genetic factors (.67 +/- .07, p < .001), and that shared environmental influences are significantly higher for members of twin pairs than for those of twins and their nontwin siblings (viz., .25 versus .17, p = .02). PMID- 22927710 TI - Genetic markers of cardiovascular disease in rheumatoid arthritis. AB - Cardiovascular (CV) disease is the most common cause of premature mortality in patients with rheumatoid arthritis (RA). It is the result of an accelerated atherosclerotic process. Both RA and atherosclerosis are complex polygenic diseases. Besides traditional CV risk factors and chronic inflammation, a number of studies have confirmed the role of genetic factors in the development of the atherogenesis observed in RA. In this regard, besides a strong association between the HLA-DRB1*04 shared epitope alleles and both endothelial dysfunction, an early step in the atherosclerotic process, and clinically evident CV disease, other polymorphisms belonging to genes implicated in inflammatory and metabolic pathways, located inside and outside the HLA region, such as the 308 variant (G > A, rs1800629) of the TNFA locus, the rs1801131 polymorphism (A > C; position + 1298) of the MTHFR locus, or a deletion of 32 base pairs on the CCR5 gene, seem to be associated with the risk of CV disease in patients with RA. Despite considerable effort to decipher the genetic basis of CV disease in RA, further studies are required to better establish the genetic influence in the increased risk of CV events observed in patients with RA. PMID- 22927713 TI - Reproductive counseling by clinic healthcare workers in Durban, South Africa: perspectives from HIV-infected men and women reporting serodiscordant partners. AB - BACKGROUND: Understanding HIV-infected patient experiences and perceptions of reproductive counseling in the health care context is critical to inform design of effective pharmaco-behavioral interventions that minimize periconception HIV risk and support HIV-affected couples to realize their fertility goals. METHODS: We conducted semistructured, in-depth interviews with 30 HIV-infected women (with pregnancy in prior year) and 20 HIV-infected men, all reporting serodiscordant partners and accessing care in Durban, South Africa. We investigated patient reported experiences with safer conception counseling from health care workers (HCWs). Interview transcripts were reviewed and coded using content analysis for conceptual categories and emergent themes. RESULTS: The study findings indicate that HIV-infected patients recognize HCWs as a resource for periconception related information and are receptive to speaking to a HCW prior to becoming pregnant, but seldom seek or receive conception advice in the clinic setting. HIV nondisclosure and unplanned pregnancy are important intervening factors. When advice is shared, patients reported receiving a range of information. Male participants showed particular interest in accessing safer conception information. CONCLUSIONS: HIV-infected men and women with serodiscordant partners are receptive to the idea of safer conception counseling. HCWs need to be supported to routinely initiate accurate safer conception counseling with HIV infected patients of reproductive age. PMID- 22927714 TI - Evaluating safer conception options for HIV-serodiscordant couples (HIV-infected female/HIV-uninfected male): a closer look at vaginal insemination. AB - HIV serodiscordant couples represent at least half of all HIV-affected couples worldwide. Many of these couples have childbearing desires. Safer methods of conception may allow for pregnancy while minimizing the risk of sexual transmission of HIV. In serodiscordant partnerships with an HIV-infected female and HIV-uninfected male, vaginal insemination of a partner's semen during the fertile period coupled with 100% condom use may be the safest method of conception. PMID- 22927715 TI - Contraception for the HIV-positive woman: a review of interactions between hormonal contraception and antiretroviral therapy. AB - BACKGROUND: Preventing unintended pregnancy in HIV-positive women can significantly reduce maternal-to-child HIV transmission as well as improve the woman's overall health. Hormonal contraceptives are safe and effective means to avoid unintended pregnancy, but there is concern that coadministration of antiretroviral drugs may alter contraceptive efficacy. MATERIALS AND METHODS: We performed a literature search of PubMed and Ovid databases of articles published between January 1980 and February 2012 to identify English-language reports of drug-drug interactions between hormonal contraceptives (HCs) and antiretroviral drugs (ARVs). We also reviewed the FDA prescribing information of contraceptive hormone preparations and antiretrovirals for additional data and recommendations. RESULTS: Twenty peer-reviewed publications and 42 pharmaceutical package labels were reviewed. Several studies of combined oral contraceptive pills (COCs) identified decreased serum estrogen and progestin levels when coadministered with certain ARVs. The contraceptive efficacy of injectable depot medroxyprogesterone acetate (DMPA) and the levonorgestrel intrauterine system (LNG-IUS) were largely unaffected by ARVs, while data on the contraceptive patch, ring, and implant were lacking. CONCLUSIONS: HIV-positive women should be offered a full range of hormonal contraceptive options, with conscientious counseling about possible reduced efficacy of COCs and the contraceptive implant when taken with ARVs. DMPA and the LNG-IUS maintain their contraceptive efficacy when taken with ARVs. PMID- 22927716 TI - Tools used to assess medical students competence in procedural skills at the end of a primary medical degree: a systematic review. AB - The objective was to systematically review the literature to identify and grade tools used for the end point assessment of procedural skills (e.g., phlebotomy, IV cannulation, suturing) competence in medical students prior to certification. The authors searched eight bibliographic databases electronically - ERIC, Medline, CINAHL, EMBASE, Psychinfo, PsychLIT, EBM Reviews and the Cochrane databases. Two reviewers independently reviewed the literature to identify procedural assessment tools used specifically for assessing medical students within the PRISMA framework, the inclusion/exclusion criteria and search period. Papers on OSATS and DOPS were excluded as they focused on post-registration assessment and clinical rather than simulated competence. Of 659 abstracted articles 56 identified procedural assessment tools. Only 11 specifically assessed medical students. The final 11 studies consisted of 1 randomised controlled trial, 4 comparative and 6 descriptive studies yielding 12 heterogeneous procedural assessment tools for analysis. Seven tools addressed four discrete pre certification skills, basic suture (3), airway management (2), nasogastric tube insertion (1) and intravenous cannulation (1). One tool used a generic assessment of procedural skills. Two tools focused on postgraduate laparoscopic skills and one on osteopathic students and thus were not included in this review. The levels of evidence are low with regard to reliability - kappa = 0.65-0.71 and minimum validity is achieved - face and content. In conclusion, there are no tools designed specifically to assess competence of procedural skills in a final certification examination. There is a need to develop standardised tools with proven reliability and validity for assessment of procedural skills competence at the end of medical training. Medicine graduates must have comparable levels of procedural skills acquisition entering the clinical workforce irrespective of the country of training. PMID- 22927717 TI - Medical students' approaches to learning over a full degree programme. AB - Students take three approaches to learning and studying: deep, surface and strategic, influenced by the learning environment. Following the General Medical Council's report "Tomorrow's Doctors," a deep approach was cultivated in Years 1 and 2 of a university undergraduate medical programme by introducing explicit written learning objectives constructed according to Biggs' SOLO taxonomy, problem-based learning and constructively aligned in-course assignments and examinations. The effect of these changes was measured with the Approaches to Study Skills Inventory for Students (ASSIST). Scores were highest for a deep approach and lowest for a surface approach and showed relatively little change during the degree programme, apart from a slight fall in the scores for a surface approach, particularly for students undertaking an intercalated science degree. Possible explanations include: students' approaches may be established prior to university entry; deep scores were already high at the beginning of the programme and may be difficult to increase further; the changes in learning environment may not be strong enough to alter approaches which students perceive as having been successful. PMID- 22927719 TI - Sleep deprivation alters rat ventral prostate morphology, leading to glandular atrophy: a microscopic study contrasted with the hormonal assays. AB - We investigated the effect of 96 h paradoxical sleep deprivation (PSD) and 21-day sleep restriction (SR) on prostate morphology using stereological assays in male rats. After euthanasia, the rat ventral prostate was removed, weighed, and prepared for conventional light microscopy. Microscopic analysis of the prostate reveals that morphology of this gland was altered after 96 h of PSD and 21 days of SR, with the most important alterations occurring in the epithelium and stroma in the course of both procedures compared with the control group. Both 96 h PSD and 21-day SR rats showed lower serum testosterone and higher corticosterone levels than control rats. The significance of our result referring to the sleep deprivation was responsible for deep morphological alterations in ventral prostate tissue, like to castration microscopic modifications. This result is due to the marked alterations in hormonal status caused by PSD and SR. PMID- 22927721 TI - A collaborative molecular modeling environment using a virtual tunneling service. AB - Collaborative researches of three-dimensional molecular modeling can be limited by different time zones and locations. A networked virtual environment can be utilized to overcome the problem caused by the temporal and spatial differences. However, traditional approaches did not sufficiently consider integration of different computing environments, which were characterized by types of applications, roles of users, and so on. We propose a collaborative molecular modeling environment to integrate different molecule modeling systems using a virtual tunneling service. We integrated Co-Coot, which is a collaborative crystallographic object-oriented toolkit, with VRMMS, which is a virtual reality molecular modeling system, through a collaborative tunneling system. The proposed system showed reliable quantitative and qualitative results through pilot experiments. PMID- 22927720 TI - Challenging regional psoriasis and ustekinumab biotherapy: impact of the patterns of disease. AB - In some patients, psoriasis appears refractory to many treatments, particularly when the disease is confined to some specific body regions. In this respect, palmoplantar psoriasis and palmoplantar pustulosis are possibly related conditions in their immunopathomechanisms involving Il-12, IL-23, and Th17. Nail psoriasis and scalp psoriasis are two other particular psoriasis manifestations. Accordingly, ustekinumab was tested in a few of these patients. The present paper is limited to peer-reviewed case reports. Data were not supported by bioinstrumental assessments and controlled trials. Overall, they are indicative of potential efficacy. The cost-effectiveness and the risk-benefit assessments merit further investigations. PMID- 22927718 TI - Role of calcium and mitochondria in MeHg-mediated cytotoxicity. AB - Methylmercury (MeHg) mediated cytotoxicity is associated with loss of intracellular calcium (Ca2+) homeostasis. The imbalance in Ca2+ physiology is believed to be associated with dysregulation of Ca2+ intracellular stores and/or increased permeability of the biomembranes to this ion. In this paper we summarize the contribution of glutamate dyshomeostasis in intracellular Ca2+ overload and highlight the mitochondrial dysfunctions induced by MeHg via Ca2+ overload. Mitochondrial disturbances elicited by Ca2+ may involve several molecular events (i.e., alterations in the activity of the mitochondrial electron transport chain complexes, mitochondrial proton gradient dissipation, mitochondrial permeability transition pore (MPTP) opening, thiol depletion, failure of energy metabolism, reactive oxygen species overproduction) that could culminate in cell death. Here we will focus on the role of oxidative stress in these phenomena. Additionally, possible antioxidant therapies that could be effective in the treatment of MeHg intoxication are briefly discussed. PMID- 22927722 TI - Maternal moderate physical training during pregnancy attenuates the effects of a low-protein diet on the impaired secretion of insulin in rats: potential role for compensation of insulin resistance and preventing gestational diabetes mellitus. AB - The effects of pregestational and gestational low-to-moderate physical training on insulin secretion in undernourished mothers were evaluated. Virgin female Wistar rats were divided into four groups as follows: control (C, n = 5); trained (T, n = 5); low-protein diet (LP, n = 5); trained with a low-protein diet (T + LP, n = 5). Trained rats ran on a treadmill over a period of 4 weeks before mate (5 days week-1 and 60 min day-1, at 65% of VO(2max)). At pregnancy, the intensity and duration of the exercise were reduced. Low-protein groups were provided with an 8% casein diet, and controls were provided with a 17% casein diet. At third day after delivery, mothers and pups were killed and islets were isolated by collagenase digestion of pancreas and incubated for a further 1 h with medium containing 5.6 or 16.7 mM glucose. T mothers showed increased insulin secretion by isolated islets incubated with 16.7 mM glucose, whereas LP group showed reduced secretion of insulin by isolated islets when compared with both C and LP + T groups. Physical training before and during pregnancy attenuated the effects of a low-protein diet on the secretion of insulin, suggesting a potential role for compensation of insulin resistance and preventing gestational diabetes mellitus. PMID- 22927723 TI - Microbial communities and their performances in anaerobic hybrid sludge bed-fixed film reactor for treatment of palm oil mill effluent under various organic pollutant concentrations. AB - The anaerobic hybrid reactor consisting of sludge and packed zones was operated with organic pollutant loading rates from 6.2 to 8.2 g COD/L day, composed mainly of suspended solids (SS) and oil and grease (O&G) concentrations between 5.2 to 10.2 and 0.9 to 1.9 g/L, respectively. The overall process performance in terms of chemical oxygen demands (COD), SS, and O&G removals was 73, 63, and 56%, respectively. When the organic pollutant concentrations were increased, the resultant methane potentials were higher, and the methane yield increased to 0.30 L CH4/g COD(removed). It was observed these effects on the microbial population and activity in the sludge and packed zones. The eubacterial population and activity in the sludge zone increased to 6.4 * 109 copies rDNA/g VSS and 1.65 g COD/g VSS day, respectively, whereas those in the packed zone were lower. The predominant hydrolytic and fermentative bacteria were Pseudomonas, Clostridium, and Bacteroidetes. In addition, the archaeal population and activity in the packed zone were increased from to 9.1 * 107 copies rDNA/g VSS and 0.34 g COD CH4/g VSS day, respectively, whereas those in the sludge zone were not much changed. The most represented species of methanogens were the acetoclastic Methanosaeta, the hydrogenotrophic Methanobacterium sp., and the hydrogenotrophic Methanomicrobiaceae. PMID- 22927724 TI - Mercury toxicity on sodium pump and organoseleniums intervention: a paradox. AB - Mercury is an environmental poison, and the damage to living system is generally severe. The severity of mercury poisoning is consequent from the fact that it targets the thiol-containing enzymes, irreversibly oxidizing their critical thiol groups, consequently leading to an inactivation of the enzyme. The Na+/K+-ATPase is a sulfhydryl protein that is sensitive to Hg2+ assault. On the other hand, organoseleniums are a class of pharmacologically promising compounds with potent antioxidant effects. While Hg2+ oxidizes sulfhydryl groups of Na+/K+-ATPase under in vitro and in vivo conditions, the organoselenium compounds inhibit Na+/K+ ATPase in vitro but enhance its activities under in vivo conditions with concomitant increase in the level of endogenous thiols. Paradoxically, it appears that these two thiol oxidants can be used to counteract one another under in vivo conditions, and this hypothesis serves as the basis for this paper. PMID- 22927726 TI - Histopathology of optic nerve pit-associated maculopathy. AB - PURPOSE: To describe the histopathologic findings of an eye bank specimen containing an optic nerve pit with associated serous elevation of the macula and cavernous atrophy of the optic nerve. METHODS: An eye bank specimen found to have an optic nerve pit with serous elevation of the macula was grossly examined and photographed. The globe was processed for both light and scanning electron microscopy. RESULTS: The scanning electron microscopic study of this eye with an optic nerve pit revealed holes in the diaphanous membrane overlying the nerve at the edge of the optic pit. Serial histopathology sections revealed a connection between the holes overlying the optic pit and the subretinal space via a schisis like cavity in the retina. CONCLUSION: The discovery of an optic nerve pit with coexisting serous detachment of the macula in an eye bank eye and subsequent pathological evaluation provides support for current theories into the mechanism of the visual loss in this condition. Our finding supports syneretic vitreous to be the source of the subretinal fluid. PMID- 22927727 TI - Central corneal thickness and corneal endothelial characteristics in healthy, cataract, and glaucoma patients. AB - PURPOSE: The aim of this study was to describe and compare endothelial cell parameters and central corneal thickness (CCT) in four different groups of patients (patients with cataract, patients with glaucoma, elderly healthy subjects, and young healthy subjects) and identify correlations between these characteristics, patient age, and sex. METHODS: Before conducting invasive procedures, 104 patients were examined using a non-contact specular microscope. Parameters examined included endothelial cell density (ECD), percentage of regular hexagonal cells (6A), average size of endothelial cells (Ave), and CCT. Patients' ages and sexes were also noted. RESULTS: A total of 47 (45%) patients were men and 57 (55%) were women. CCT, ECD, 6A, and Ave in cataract group were 540 (+/-64) MUm, 2633 (+/-430) cells/mm(2), 60 (+/-10)%, and 390 (+/-66) MUm, respectively; these values in the glaucoma group were 553 (+/-32) MUm, 2484 (+/ 82) cells/mm(2), 60 (+/-10)%, and 397 (+/-58) MUm. In the elderly group these figures were 545 (+/- 39) MUm, 2394 (+/-416) cells/mm(2), 64 (+/-10)%, and 386 (+/-43) MUm; and in young healthy subjects the values were 555 (+/-43) MUm, 2940 (+/-345) cells/mm(2), 66 (+/-10)%, and 345 (+/-42) MUm. A weak inverse correlation was observed between ECD and subject age (r = -0.459; P < 0.05) and between ECD and CCT (r = 0.232; P < 0.05). CCT was inversely correlated with patient age (r = -0.13; P = 0.189), but statistically significant data was observed only for the glaucoma group (r = -0.572; P < 0.05). CONCLUSION: ECD in young subjects was higher than in elderly subjects in all groups; these patients have more endothelial cells and smaller, thicker corneas. The corneal endothelium cells in males have more regular hexagonal cells than do females. No difference in CCT and the ECD was observed between sexes. CCT and average size of endothelial cells do not differ between groups. PMID- 22927728 TI - Anterior uveitis after treatment of age-related macular degeneration with ranibizumab and bevacizumab: uncommon complication. AB - The authors describe one case of anterior uveitis after treatment of age-related macular degeneration with both antiangiogenic drugs: ranibizumab and bevacizumab. The case is described as a complication of ranibizumab and bevacizumab due to an inflammatory process. Several reasons are suggested to explain this possibility, and the authors conclude that the main cause remains unknown. PMID- 22927729 TI - Two cases of ocular sarcoidosis in which vitreous cytology was useful for supporting the diagnosis. AB - The purpose of this paper is to report two cases of sarcoidosis with conflicting signs in which vitreous cytology was useful for supporting the diagnosis. Case 1 was a 56-year-old man who was referred with blurred vision, and was found to have iridocyclitis, vitreous opacities, and optic neuritis bilaterally. He also had a swelling of both mandibular glands. He received pulsed corticosteroid therapy, but the vitreous opacities and papilledema did not resolve. The second case was a 77-year-old man referred with blurred vision, and both eyes had snowball-like vitreous opacities and optic neuritis. The ocular findings in both cases strongly suggested sarcoidosis, but the systemic findings did not meet the diagnostic criteria for sarcoidosis. We performed pars plana vitrectomy to remove the vitreous opacities, and the collected vitreous samples were sent for cytological analyses. Epithelioid and multinucleated giant cells pathognomonic of sarcoidosis were found in the vitreous samples which enabled us to make a diagnosis of sarcoidosis. Vitreous cytology can help in supporting a diagnosis of sarcoidosis, especially in cases of ocular inflammation suggesting sarcoidosis but systemic findings that do not satisfy the diagnostic criteria for this disease. PMID- 22927725 TI - Reactive oxygen species in health and disease. AB - During the past decades, it became obvious that reactive oxygen species (ROS) exert a multitude of biological effects covering a wide spectrum that ranges from physiological regulatory functions to damaging alterations participating in the pathogenesis of increasing number of diseases. This review summarizes the key roles played by the ROS in both health and disease. ROS are metabolic products arising from various cells; two cellular organelles are intimately involved in their production and metabolism, namely, the endoplasmic reticulum and the mitochondria. Updates on research that tremendously aided in confirming the fundamental roles of both organelles in redox regulation will be discussed as well. Although not comprehensive, this review will provide brief perspective on some of the current research conducted in this area for better understanding of the ROS actions in various conditions of health and disease. PMID- 22927731 TI - Central retinal artery occlusion in a patient with ANCA-negative Churg-Strauss syndrome. AB - Ocular involvement in Churg-Strauss syndrome is infrequent. We describe the case of a 54-year-old woman with eosinophilia and involvement of the respiratory tract, skin, and peripheral nervous system, fulfilling the American College of Rheumatology criteria for Churg-Strauss syndrome. The patient presented with acute, painless vision loss in her right eye. Central retinal artery occlusion (CRAO) without accompanying retinal vasculitis was diagnosed by angiographic findings and funduscopic findings of retinal whitening with a cherry-red spot. Although her antineutrophil cytoplasmic antibody (ANCA) status was negative, CRAO was thought to be an ocular manifestation of Churg-Strauss syndrome, and appropriate treatment was planned. She was treated with high-dose corticosteroids and anticoagulant therapy. Her macular edema improved, but visual recovery was poor. Specific therapy to alter inflammation, blood coagulation, and rheology reportedly plays an important role in ANCA-positive patients with Churg-Strauss syndrome who develop CRAO. Regardless of ANCA status, high-dose corticosteroids should be considered for CRAO in patients with Churg-Strauss syndrome, as discussed in this case. PMID- 22927730 TI - Current options for the treatment of optic neuritis. AB - Optic neuritis can be defined as typical (associated with multiple sclerosis, improving independent of steroid treatment), or atypical (not associated with multiple sclerosis, steroid-dependent improvement). Causes of atypical optic neuritis include connective tissue diseases (eg, lupus), vasculitis, sarcoidosis, or neuromyelitis optica. In this manuscript, updated treatment options for both typical and atypical optic neuritis are reviewed. Conventional treatments, such as corticosteroids, therapeutic plasma exchange, and intravenous immunoglobulin therapy are all discussed with commentary regarding evidence-based outcomes. Less commonly used treatments and novel purported therapies for optic neuritis are also reviewed. Special scenarios in the treatment of optic neuritis - pediatric optic neuritis, acute demyelinating encephalomyelitis, and optic neuritis occurring during pregnancy - are specifically examined. PMID- 22927732 TI - A sliding technique to load thin endothelial donor lamella onto Busin glide for Descemet-stripping automated endothelial keratoplasty. AB - We describe a modified technique for loading donor corneal endothelial lamella onto a Busin glide((r)) without causing wrinkles, as part of the procedure of Descemet-stripping automated endothelial keratoplasty. Briefly, after punching out a composite of the donor-endothelial lamella and a microkeratome-dissected cap, several drops of dispersive ophthalmic viscosurgical device are placed onto the endothelial surface. The Busin glide surface is then wetted with several drops of balanced salt solution. After the composite is transferred onto the Busin glide, hydrodissection of the potential space between the donor-endothelial lamella and the microkeratome-dissected cap is carefully performed to enable smooth detachment of these two lamellae. Whereas simply dragging the donor endothelial lamella directly onto the glide can cause wrinkling or folding of the donor lamella, this technique enables smooth detachment of the composite without wrinkle or fold formation, and results in less endothelial cell damage. PMID- 22927733 TI - Five-year visual results of intravitreal bevacizumab in refractory inflammatory ocular neovascularization. AB - PURPOSE: To assess the 5-year visual outcome of intravitreal bevacizumab in inflammatory ocular neovascularization. METHODS: Retrospective, multicenter, consecutive case series of eight patients with inflammatory ocular neovascularization refractory to standard therapy who were treated with intravitreal bevacizumab and followed for 5 years after first injection. The outcome measures included improvement of best-corrected visual acuity expressed as logarithm of minimum angle of resolution. RESULTS: Mean best-corrected visual acuity significantly improved from 0.58 at baseline (6/23 or 20/76; standard deviation = 0.32) to 0.20 at final assessment (6/10 or 20/32; standard deviation = 0.25) (n = 8; P = 0.02), a gain of 3.8 lines (median: three injections; eight eyes; eight patients). No ocular or systemic complications from intravitreal bevacizumab were noted. CONCLUSION: At 5 years, intravitreal bevacizumab sustained significant visual improvement in ocular neovascularization due to a variety of inflammatory ocular diseases without major complications after a median of three injections. PMID- 22927734 TI - Resolution of vitreomacular traction following intravitreal triamcinolone acetonide injection in an eye with branch retinal vein occlusion. AB - A 60-year-old woman with a past medical history of branch retinal vein occlusion presented with decreased vision and metamorphopsia in her left eye. A fundus examination revealed a tortuous retinal vein with a few retinal hemorrhages in the inferotemporal quadrant. Optical coherence tomography revealed a partially separated posterior vitreous membrane pulling up the fovea. The patient refused surgical treatment so intravitreal triamcinolone acetonide (4 mg/0.1 mL) was administered. The patient reported resolution of symptoms in her left eye following this treatment, but her visual acuity did not show any improvement. Optical coherence tomography scanning revealed a complete detachment of the posterior hyaloid with release of the vitreomacular traction. In patients with vitreomacular traction and branch retinal vein occlusion, the combination of the possible vitreous liquefaction and mechanical increase of vitreous volume caused by an intravitreal injection with a degree of reduction in retinal thickness may play a role in the resolution of vitreomacular traction. PMID- 22927735 TI - Bowman's layer encystment in cases of persistent Acanthamoeba keratitis. AB - BACKGROUND: The purpose of this study was to report Acanthamoeba encystment in Bowman's layer in Japanese cases of persistent Acanthamoeba keratitis (AK). METHODS: Laser confocal microscopic images of the cornea were obtained in vivo from 18 consecutive eyes from 17 confirmed AK patients. Retrospectively, 14 cases treated over 4 months were categorized as a nonpersistent group and three cases that required prolonged therapy for more than 6 months were categorized as a persistent group. Clinical outcomes based on final best-corrected visual acuity were retrospectively analyzed, and selected confocal images were evaluated qualitatively for abnormal findings. RESULTS: The final best-corrected visual acuity was significantly lower (P < 0.01) for patients in the persistent group compared with that in the nonpersistent group. At the initial visit, in vivo confocal microscopy demonstrated Acanthamoeba cysts exclusively in the epithelial layer in both the nonpersistent group (80%) and the persistent group (100%). At a subsequent follow-up visit, numerous Acanthamoeba cysts were observed in the epithelial cell layer and in Bowman's layer in all patients with persistent AK, but Acanthamoeba cysts were undetectable in all cases with nonpersistent AK tested. CONCLUSION: Invasion of cysts into Bowman's layer was characteristically observed in patients with persistence of AK. This finding suggests that invasion of Acanthamoeba cysts into Bowman's layer may be a useful predictor for a persistent clinical course. PMID- 22927736 TI - Steroid-induced ocular hypertension in Asian children with severe vernal keratoconjunctivitis. AB - BACKGROUND: We describe clinical characteristics and risk factors for corticosteroid response in children with severe vernal keratoconjunctivitis (VKC). DESIGN: Retrospective, noncontrolled, comparative case series. PARTICIPANTS: Patients from three tertiary centers in Singapore. METHODS: We reviewed patients with severe VKC (clinical grade > 2) who were on topical steroid therapy, with a minimum follow-up period of 1 year post-presentation. Logistic regression was used to determine risk factors for corticosteroid response. MAIN OUTCOME MEASURE: Corticosteroid response was defined as intraocular pressure (IOP) >21 mmHg (three consecutive readings), or a rise of more than 16 mmHg from baseline, after commencement of steroid therapy in the absence of other possible causes of raised IOP. RESULTS: Forty-one of 145 (28.3%) patients developed a corticosteroid response, of which eight (5.5%) progressed to glaucoma. The overall mean age of onset of VKC was 9.9 +/- 4.4 years. Longer duration of corticosteroid use (OR, 5.06; 95% CI: 1.04-25.56; P = 0.45) and topical dexamethasone 0.01% (OR, 2.25; 95% CI: 1.99-5.08; P = 0.40) were associated with corticosteroid response. Mixed type of VKC (OR, 9.76; 95% CI: 3.55-26.77; P < 0.001), the presence of limbal neovascularization of >= three quadrants (OR, 6.33; 95% CI: 2.36-16.97; P < 0.001), and corneal involvement (OR, 3.51; 95% CI: 1.31-9.41; P = 0.012) were significant clinical risk factors after adjusting for potential confounders such as age, sex, ethnicity, duration, and type of corticosteroid used. CONCLUSION: Children on long-term oral corticosteroids with severe, mixed-type VKC and corneal involvement are more likely to develop corticosteroid response, and may require early treatment to prevent progression to glaucoma. PMID- 22927737 TI - Evaluation of nepafenac in prevention of macular edema following cataract surgery in patients with diabetic retinopathy. AB - BACKGROUND: The purpose of this study was to evaluate nepafenac ophthalmic suspension 0.1% (Nevanac((r)); Alcon Research Ltd) in the prevention of macular edema following cataract surgery in diabetic retinopathy patients. METHODS: This was a multicenter, randomized, double-masked, vehicle-controlled study of 263 adult diabetic patients with nonproliferative diabetic retinopathy requiring cataract surgery. Patients were randomized (1:1) to instill nepafenac or vehicle three times daily beginning 1 day prior to surgery through day 90. Efficacy included the percentage of patients who developed macular edema (>=30% increase in central subfield macular thickness from baseline) and the percentage of patients with decreases of more than five letters in best-corrected visual acuity from day 7 to 90. RESULTS: A significantly lower percentage of patients in the nepafenac group developed macular edema relative to patients in the vehicle group (3.2% versus 16.7%; P < 0.001). A significantly lower percentage of patients in the nepafenac group had best-corrected visual acuity decreases of more than five letters relative to patients in the vehicle group on day 30 (P < 0.001), day 60 (P = 0.002), and day 90 (P = 0.006). The mean central subfield macular thickness and mean percent change from baseline in macular volume were also significantly lower in the nepafenac group versus the vehicle group at days 14 through 90 (P <= 0.005). No safety issues or trends were identified when dosing was increased to 90 days that negatively impacted the favorable benefit/risk profile of nepafenac. CONCLUSION: Nepafenac demonstrated statistically significant and clinically relevant advantages compared with vehicle in preventing macular edema and maintaining visual acuity in diabetic patients following cataract surgery. These advantages were seen at multiple time points over the course of the 90-day therapy period. There was no clinically relevant increase in risk from 90 days dosing compared with 14 days. Therefore, with a similar safety profile and benefit in preventing macular edema and maintaining vision, the risk/benefit to the diabetic patient undergoing cataract surgery appears to be positive. PMID- 22927739 TI - Conservative treatment for late-onset bleb leaks after trabeculectomy with mitomycin C in patients with ocular surface disease. AB - BACKGROUND: Sodium hyaluronate and autologous serum eye drops are used to treat ocular surface disease (OSD) and are reported to prevent and treat late-onset bleb leaks following trabeculectomy with mitomycin C. In this study, we evaluated the efficacy of a combination of sodium hyaluronate and autologous serum eye drops and treatment for obstructive meibomian gland dysfunction as a therapy for late-onset bleb leaks after trabeculectomy with mitomycin C. METHODS: This was a retrospective, interventional, nonsimultaneous study of 12 subjects (12 eyes) of mean age of 64.3 +/- 18.3 years with OSD and apparent late-onset bleb leaks following trabeculectomy with mitomycin C between 1998 and 2008. We compared patients diagnosed with leakages before July 2005, who had been treated with separate eye drop solutions containing 0.1% sodium hyaluronate, 50% autologous serum, and 0.3% ofloxacin (sodium hyaluronate and autologous serum group, n = 7), with patients diagnosed from August 2005 to December 2008, who were treated with a combination of eye drops (0.1% sodium hyaluronate, 50% autologous serum, and 0.08% levofloxacin hydrate) and eyelid massage and warm compresses for obstructive meibomian gland dysfunction (combination eye drop group, n = 5). RESULTS: Leakage was resolved in one patient (14.3%) in the separately treated sodium hyaluronate and autologous serum eye drop group and in five patients (100%) in the combination eye drop group (P = 0.015). The period after resolution of leakage with conservative treatment was 23 months in the one eye in the sodium hyaluronate and autologous serum group and 36-61 (mean 52.4 +/- 10.1) months in the five eyes in the combination eye drop group. CONCLUSION: Late-onset bleb leaks following trabeculectomy with mitomycin C can be treated effectively using a combination of sodium hyaluronate and autologous serum eye drops, eyelid massage, and warm compresses. Furthermore, combining eye drops may improve patient adherence to the drug regimen by decreasing the frequency of administration. PMID- 22927740 TI - Long-term follow-up after vitrectomy to treat idiopathic full-thickness macular holes: visual acuity and macular complications. AB - BACKGROUND: To assess time-course changes in best-corrected visual acuity (BCVA) up to 5 years after vitrectomy to treat idiopathic full-thickness macular holes (MHs) and identify the relationship of the changes to postoperative complications. METHODS: Twenty-three consecutive patients with an idiopathic MH underwent vitrectomy without adjuvant treatment. BCVA and complications were assessed postoperatively. RESULTS: Twenty-two of 23 (95.7%) MHs closed after the first surgery, with a final anatomic success rate of 100%. The time course of the BCVA was analyzed in 20 cases in which data were obtained for over 5 years. The BCVA improved by 0.43 logarithm of the minimum angle of resolution (logMAR) unit 6 months postoperatively (P < 0.001) and continuously improved by 0.05, 0.06, and 0.07 logMAR units between 6 months and 1 year, 1 year and 3 years (by 0.11 logMAR unit between 6 months and 3 years; P = 0.049), and 3 years and 5 years (P = 0.018) postoperatively, respectively. Macular complications developed in seven (35%) of the 20 cases; the mean BCVA at 5 years in these cases was significantly (P < 0.001) worse than in cases without complications. CONCLUSION: The BCVA might improve gradually for 5 years after vitrectomy to treat MHs. However, the macular complications that can develop postoperatively could limit that possibility. PMID- 22927741 TI - Occult choroidal neovascularization after successful macular hole surgery treated with ranibizumab. AB - PURPOSE: To report on a case that developed an atypical form of occult choroidal neovascularization (CNV) after successful macular hole surgery. METHODS: Visual acuity change, color fundus photographs, fluorescein and indocyanine green angiograms, and optical coherence tomography results were compared throughout the follow-up duration. PATIENTS: A 64-year-old woman with a macular hole in the right eye and drusen in both eyes underwent pars plana vitrectomy, internal limiting membrane peeling, and gas tamponade. One month after the operation she developed occult CNV, in which pigment epithelial detachment and fine retinal pigment epithelial (RPE) layer wrinkles were observed under the completely sealed macular hole. After 3-monthly intravitreal injections of ranibizumab, the lesion did not change significantly. CONCLUSION: CNV can develop after otherwise successful macular hole surgery, especially in patients with pre-existing aging changes in the macula, such as drusen. Care should be taken in such patients, to prevent the development of CNV after macular hole surgery. PMID- 22927742 TI - Changes in corneal thickness following vitreous surgery. AB - PURPOSE: We investigated changes in corneal thickness following vitreous surgery and determined whether such changes can be used to evaluate the invasiveness of a vitrectomy. PATIENTS AND METHODS: This retrospective, consecutive, comparative study examined 20 eyes that had undergone 23-gauge vitrectomy. Corneal thickness was measured prior to as well as following 1 week, 1 month, and 3 months after surgery. Measurements were performed at the center and at points 3 mm superior, inferior, nasal, and temporal to the center. RESULTS: Across the 20 cases, postoperative data showed a significant increase at 1 week after surgery at all points, but recovery to preoperative levels was evident only 1 month after surgery (P < 0.05, paired t-test test). In the rhegmatogenous retinal detachment group (n = 9), mean corneal thickness 1 week after vitrectomy showed a significant increase at all points, but had recovered to preoperative levels by 1 month. In the proliferative diabetic retinopathy group (n = 5), mean corneal thickness at 1 week after vitrectomy showed a significant increase at central, inferior, and temporal points, but had recovered to preoperative levels by 1 month. In the epiretinal membrane group (n = 6), a significant difference in thickness was apparent only at the superior point between baseline and at 1 week, but had recovered to preoperative levels by 1 month. In all groups, no significant differences in thickness were apparent at any of the measurement points between preoperative measurements and at 3 months after surgery (P < 0.05, Wilcoxon signed-rank test). CONCLUSIONS: Measurement of corneal thickness is useful for assessing the extent of surgical stress following vitrectomy. PMID- 22927743 TI - Results of nonendoscopic endonasal dacryocystorhinostomy. AB - BACKGROUND: Surgical scarring on the face and disrupted anatomy in the medial canthal area following external dacryocystorhinostomy (DCR) can be avoided by an endonasal approach. This study examined the outcome of direct visualization endonasal DCR, performed by young surgeons and residents. METHODS: A retrospective case series of 75 consecutive endonasal DCRs performed under direct visualization from July 2002 to July 2004 were reviewed. Surgery was performed by surgeons and residents who had received no special training in the procedure. Full success was defined as no symptoms of tearing after surgery and anatomical patency with fluorescein flow on nasal endoscopy or patency to lacrimal syringing. Partial success was defined as a tearing decrease compared with prior to surgery and with anatomical patency, and failure was defined as no significant improvement in persistent tearing. The average follow-up duration was 26.83 +/- 16.26 (range 6-55) months. RESULTS: Seventy-five DCRs were performed on 63 patients (four male, 59 female) of mean age 49.44 +/- 16.63 (range 21-85) years. The surgery was successful in 54/75 eyes (72%), 37/54 eyes (68.5%), and 30/42 eyes (71.4%) at 6, 12, and 24 months, respectively. Partial success was achieved in 13/75 (17.3%), 9/54 (16.7%), and 9/42 (21.4%), and the failure rates were 10.7%, 14.8%, and 7.1% at 6, 12, and 24 months, respectively. The overall functional success with this technique was 74.7% and the overall anatomical patency was 92.0%. There were no serious complications arising from the surgery; three minor complications were documented, ie, an incorrectly placed silicone tube in the lower canaliculus, tube prolapse, and postoperative bleeding which needed nasal packing and eventually a developed retention cyst in the nasal cavity. CONCLUSION: Endonasal DCR under direct visualization is a simple technique with minimal complications and a low learning curve, without the necessity for expensive instruments. PMID- 22927744 TI - Comparison of ocular-surface disease index questionnaire, tearfilm break-up time, and Schirmer tests for the evaluation of the tearfilm in computer users with and without dry-eye symptomatology. AB - OBJECTIVE: To compare the diagnostic values of the Schirmer's and tearfilm breakup time (TBUT) tests and the Ocular Surface Disease Index (OSDI) in dry-eye syndrome. SUBJECTS AND METHODS: Thirty-five employees of Umraniye Training and Research Hospital who used computers in their daily work participated in this prospective study. All participants completed the OSDI. Following routine ophthalmologic examination, the TBUT and Schirmer's test were undertaken and outcomes were compared. RESULTS: The mean age was 29.09 +/- 6.73 (range 20-46) years. Mean OSDI questionnaire, TBUT, and Schirmer's test scores were detected as 37.12 +/- 19.05 (range 4-75), 11.37 +/- 3.69 seconds (range 4-18 seconds), and 25.80 +/- 8.43 mm (range 6-35 mm), respectively. There was a significant inverse correlation between the OSDI and TBUT scores (r = -0.385, P = 0.022). No significant correlation existed between the OSDI and Schirmer's test scores. CONCLUSION: Dry eye is a common problem among computer users. The OSDI questionnaire, used together with the TBUT, is easily performed and may be of benefit in supporting the diagnosis of dry-eye syndrome. PMID- 22927745 TI - Factors associated with visual recovery after sub-Tenon injection of triamcinolone acetonide in diabetic macular edema. AB - BACKGROUND: The purpose of this retrospective chart review was to evaluate factors associated with improvement of visual acuity after a single sub-Tenon injection of triamcinolone acetonide in patients with diabetic macular edema. METHODS: We reviewed the medical records for 63 consecutive eyes with diabetic macular edema treated by sub-Tenon injection of triamcinolone acetonide and assessed at 2 months postoperatively. We evaluated changes in morphology, foveal photoreceptor status, and parafoveal cystic change, and also measured the central retinal thickness and macular volume. The association of these factors with improvement of vision (logarithm of the minimum angle of resolution, logMAR) was investigated. RESULTS: Eyes were classified as having cystoid macular edema (CME, n = 52), serous retinal detachment (n = 24), or diffuse diabetic macular edema (n = 4). In eyes with CME, the mean logMAR of visual acuity improved significantly (P = 0.003) from 0.35 +/- 0.31 at baseline to 0.29 +/- 0.29 after 2 months. However, there was no significant improvement of visual acuity in the eyes with serous retinal detachment or diffuse diabetic macular edema after sub-Tenon injection of triamcinolone acetonide (P = 0.549 and P = 0.545, respectively). The central retinal thickness and macular volume were both reduced significantly after sub-Tenon injection of triamcinolone acetonide in eyes with CME and serous retinal detachment. However, improvement of visual acuity in the eyes with CME was not correlated with the reduction of central retinal thickness or macular volume. Parafoveal cystic changes showed significant improvement after sub-Tenon injection of triamcinolone acetonide in eyes with CME. Photoreceptor status was significantly associated with the visual prognosis in eyes with CME, but not in eyes with serous retinal detachment. CONCLUSION: Visual acuity improved significantly after sub-Tenon injection of triamcinolone acetonide without photoreceptor recovery in eyes with CME. Improvement of parafoveal cystic changes in the eyes with CME suggests that bipolar cells or their accessory cells might have displayed functional recovery. PMID- 22927746 TI - Real-world impact of reminder packaging on antihypertensive treatment adherence and persistence. AB - BACKGROUND: Patient medication adherence is multidimensional and poses significant concerns to health care professionals. One aspect of adherence is a patient forgetting to take their prescribed medication, which may be improved with reminder packaging (RP). The objective of this analysis was to assess the impact of RP on patient adherence to antihypertensive therapy. METHODS: This retrospective, propensity score-matched study evaluated patients switching to a single-pill combination of valsartan-hydrochlorothiazide in RP compared with patients remaining on the combination without reminder packaging (non-RP). Patients receiving combination therapy between April 1, 2009 and July 31, 2010 were eligible for inclusion. Patients were propensity score-matched on baseline adherence and background demographic variables, including comorbidities. Medication possession ratio, proportion of days covered, time to refill, and time to discontinuation were evaluated as primary measures of subsequent adherence and persistence. RESULTS: In a total of 9266 matched patients (4633 participants in both cohorts), adherence was significantly higher in the RP cohort compared with patients in the non-RP cohort (medication possession ratio, RP 80% versus non-RP 73%; proportion of days covered, RP 76% versus non-RP 63%; both P < 0.001). Refill timing was 10 days for RP patients versus 16 days for non-RP patients (P < 0.001). Similar trends were observed with respect to time to discontinuation (RP 196 days, non-RP 174 days; P < 0.001). A higher proportion of RP patients remained on therapy compared with non-RP patients, with patients in the RP group being 17% less likely to discontinue therapy compared with patients in the non-RP group (hazards ratio 0.833; 95% confidence interval 0.793-0.875). CONCLUSION: This real-world assessment of differences in adherence and persistence rates demonstrated that patients receiving RP were more adherent and persistent with their treatment regimens. PMID- 22927747 TI - Parents' views on growth hormone treatment for their children: psychosocial issues. AB - BACKGROUND: We evaluated the opinions of parents in The Netherlands concerning treatment of their children with growth hormone, and examined beliefs and perceptions about treatment and quality of health care communication and support. METHODS: An Internet survey was completed by 69 parents who had children prescribed growth hormone and were part of the Patient Intelligence Panel. Acceptance of the diagnosis and treatment was investigated with reference to four topics, ie, search and quality of information, involvement in decision-making process, operational aspects, and emotional problems and support. RESULTS: Among the parents surveyed, 48% reported a lack of freedom to choose the type of growth hormone device that best suited their needs, 92% believed that their children (and they themselves) would benefit if the children self-administered growth hormone, and 65% believed training to support self-administration would be helpful. According to 79%, the availability of support from another parent with experience of treating their own child with growth hormone, alongside their doctor, would be valuable. Thirty-seven percent of the parents indicated that their children felt anxious about administration of growth hormone, and 83% of parents would appreciate psychological support to overcome their anxiety. An increase in reluctance to receive treatment with growth hormone was observed by 40% of parents after the children reached puberty, and 57% of these parents would appreciate psychological support to overcome this reluctance. CONCLUSION: Understanding how growth hormone treatments and their implications are perceived by parents is a first step towards addressing quality of growth hormone treatment, which may be instrumental in improving adherence. The data show a need for support and involvement of parents in the process of choosing a growth hormone device. This decision-making process may be instrumental in improving acceptance and diminishing emotional problems for children using growth hormone. PMID- 22927748 TI - Three in one: safety, efficacy, and patient acceptability of triple fixed-dose combination medicine in the management of hypertension. AB - Hypertensive patients whose blood pressures are more than 20 mmHg above their goal will often require three or more medications. Careful selection of medications whose actions are complementary or have an improved adverse effect profile when combined can affect not only the blood pressure but also patient acceptance, thus improving persistence in taking the medications as prescribed. This review will highlight the three single-pill three-drug combinations currently available in the US and will address their efficacy, safety, and tolerability. All three include the dihydropyridine calcium-channel blocker, amlodipine, and the thiazide diuretic, hydrochlorothiazide. They each contain a different renin-angiotensin system blocker. One includes the angiotensin-receptor blocker, olmesartan, while another contains valsartan. The third combination includes the direct renin inhibitor, aliskiren. All three fixed-dose combinations (FDC) at maximum doses of each component lowers the blood pressure of patients with stage II hypertension by 37 to 40 mmHg systolic and 21 to 25 mmHg diastolic, which is superior to any two of the components that comprise the three-drug FDC. These drugs are effective in males and females, the elderly, diabetics, minority populations, and patients with metabolic syndrome. Triple-drug FDCs are well tolerated with a low incidence of adverse effects, the most common being peripheral edema related to amlodipine. Extrapolation of data from two-drug FDC suggests that medication compliance (adherence and persistence) should be better with these FDCs than with the individual components taken as separate medications, although additional studies are necessary to confirm this. PMID- 22927749 TI - Improvement of interferon-beta related skin reactions after diluent halving: first experience of five patients. AB - BACKGROUND: The spectrum of side effects related to interferon beta-1b (INF-1b) treatment may compromise long-term adherence. METHODS: Five INF-1b-treated multiple sclerosis patients with poor skin tolerability and clinical stability were instructed to dissolve the established (250 MUg) INF-1b dose in half (0.5 mL) the standard diluent (1.0 mL, 0.54% sodium chloride solution), and were followed for 9 months. RESULTS: Halving the volume of the treatment diluent was associated with significant improvement of skin side effects profile in all patients. The improvement was sustained for 9 months. CONCLUSION: Halving the volume of the INF-1b diluent could represent a different strategy to optimize skin tolerability and adherence in some multiple sclerosis patients. PMID- 22927750 TI - Greek surgical patients' satisfaction related to perioperative anesthetic services in an academic institute. AB - BACKGROUND: Patient satisfaction is an increasingly appreciated measure of outcome for health care procedures. The purpose of this study was to evaluate Greek surgical patients' satisfaction with perioperative anesthetic services and to determine which factors maximize satisfaction level through all phases of perioperative care. METHODS: Adult Greek patients admitted for elective surgery in an academic hospital were included in the study. Three separate questionnaires were constructed: Q1 (patients who underwent general anesthesia alone or combined with epidural) and Q2 (patients who received regional anesthesia alone) covered perioperative anesthetic care; Q3 covered postoperative analgesia services in the ward (patient-controlled analgesia or epidural analgesia) provided by our anesthesiologist-centered analgesia care team. Principal component analysis with varimax rotation was used separately for each questionnaire, and extracted factors were entered into multiple logistic regression with patient satisfaction as the dependent binary variable. Statistical significance level was set at P < 0.05. RESULTS: Three hundred and forty-five patients were included. Q1 questionnaire (answered by 282 patients) included four dimensions: communication with the anesthesiologist, sense of cold/shivering, pain, and nausea. Q2 questionnaire (answered by 63 patients) included three dimensions: communication with the anesthesiologist, sense of cold/shivering, and nausea/anxiety. Q3 questionnaire (answered by 237 patients) included five dimensions: anesthesiologist intervention upon symptoms, pain, care by the anesthesiologist/physical activity, nausea/vomiting, and anesthesiologist behavior. The communication dimension score in Q1 and Q2, sense of shivering in Q2, and pain management and anesthesiologist behavior dimension scores in Q3 were significantly associated with patient satisfaction. Overall satisfaction rates were high (according to the questionnaire, the observed percentage was in the range of 96.3%-98.6%). CONCLUSION: Greek surgical patients reported high satisfaction with perioperative anesthesia care. Interaction between patient and anesthesiologists during all periods of study, absence of shivering in regional anesthesia, and adequate postoperative pain control in the ward were significant predictors of patient satisfaction in the present Greek surgical population. PMID- 22927751 TI - Characterization of outcomes 1 year after endoscopic thermal vapor ablation for patients with heterogeneous emphysema. AB - INTRODUCTION: Endoscopic lung volume reduction has been developed as a therapeutic option for advanced emphysema. Six-month results following treatment with endoscopic thermal vapor ablation (InterVapor; Uptake Medical, Tustin, CA) were described previously, and here we report observations from the 12-month assessment. METHODS: Two multicenter, international, single-arm trials of InterVapor (unilateral upper lobe treatment) in patients with upper lobe predominant emphysema were conducted. INCLUSION CRITERIA: forced expiratory volume in 1 second (FEV(1)) 15%-45% predicted, residual volume > 150%, total lung capacity > 100%, 6-minute walk distance (6MWD) > 140 m, and diffusing capacity for carbon monoxide > 20% predicted. Efficacy endpoints: spirometry, body plethysmography, lung volumes by high-resolution computed tomography, St George's Respiratory Questionnaire, modified Medical Research Council dyspnea scale, and 6MWD. All adverse events were collected and independently adjudicated. RESULTS: Forty four patients were treated at a mean (standard deviation) age of 63 (5.6) years, FEV(1) 0.86 mL (0.25 mL) (n = 22 men and 22 women). Mean (standard deviation) changes from baseline at 12 months were: FEV(1) 86.2 mL (173.8 mL), St George's Respiratory Questionnaire -11.0 (14.0) units, treated lobar volume from high-resolution computed tomography -751.8 mL (653.9 mL), residual volume -302.8 mL (775.6 mL), 6MWD 18.5 m (63.7 m), and modified Medical Research Council dyspnea scale score -0.83 (0.97) (P < 0.05 for all except 6MWD). Improvements were numerically larger at 6 versus 12 months. GOLD stage III and IV patients had similar outcomes at 6 months; however, improvements relative to baseline were numerically higher in GOLD stage IV patients. Larger improvements were observed in patients with higher heterogeneity. In total, 39 serious adverse events were reported in 23 patients with 10 events in 8 patients between 6 and 12 months. CONCLUSION: Unilateral lobar InterVapor treatment of heterogeneous emphysema improved lung function and health outcomes 1 year following treatment. The magnitude of improvement was larger at 6 months compared to 12 months. Improvements relative to baseline continue to be exhibited at 12 months despite the expected disease related decline over time. PMID- 22927752 TI - Assessment of COPD wellness tools for use in primary care: an IPCRG initiative. AB - COPD is considered a complex disease and global problem that is predicted to be the third most common cause of death by 2030. While managing this chronic condition, primary health care practitioners are faced with the ongoing challenge of achieving good quality of life and overall "wellness" for those affected. As such, a practical tool for monitoring quality of life in a clinical setting is required. However, due to the wide variety of general and disease-specific tools from which to choose, primary health care practitioners are given minimal guidance as to which tool may be most appropriate. To address these challenges, the International Primary Care Respiratory Group (IPCRG) proposed the creation of a user's guide for primary health care practitioners to assess "wellness" in COPD patients in an everyday clinical setting. This short report outlines the process by which the IPCRG Users' Guide to COPD "Wellness" Tools was developed. It also describes why this guide has the potential to be of great value in guiding primary health care practitioners to improve patient wellness. PMID- 22927754 TI - Association of plasma adiponectin levels with cellular hydration state measured using bioelectrical impedance analysis in patients with COPD. AB - BACKGROUND: It is widely recognized that chronic obstructive pulmonary disease (COPD) includes a variety of extra pulmonary complications and comorbidities. Recently, adiponectin was shown to regulate cellular metabolism in humans. Cellular hydration state is affected by a variety of hormonal factors and regulates cellular metabolic state. Therefore, this study was designed to determine whether adiponectin is a possible factor involved in cellular hydration state in COPD. METHODS: Thirty patients with COPD and 41 age-matched controls participated in the study. Plasma levels of total and high molecular weight (HMW) adiponectin were measured and anthropometry and pulmonary function tests were conducted. Intracellular water (ICW), extracellular water (ECW), and ECW/ICW ratio, which are parameters of cellular hydration state, were measured using bioelectrical impedance analysis. RESULTS: Higher levels of total and HMW adiponectin in plasma were found in patients with COPD compared with levels in controls. A significant inverse correlation was observed between body mass index and plasma levels of total and HMW adiponectin in the control group. However, this significant correlation was not observed in patients with COPD. The plasma levels of total and HMW adiponectin were also not significantly correlated with any pulmonary function parameters in patients with COPD. Regarding the state of cellular hydration, the plasma levels of total adiponectin were inversely correlated with the ECW/ICW ratio and positively with ICW values in patients with COPD. Moreover, closer correlations were found between these parameters and plasma HMW adiponectin levels. CONCLUSION: The results of the present study suggest a novel association of the plasma adiponectin with cellular hydration state in patients with COPD. Accordingly, lower adiponectin levels may result in cellular shrinkage, leading to metabolic malfunction at a cellular level. Thus, our findings provide new insights regarding the preventive roles of adiponectin in the progression of comorbidities in COPD. PMID- 22927753 TI - Epidemiology of chronic obstructive pulmonary disease: a literature review. AB - The aim of this study is to quantify the burden of chronic obstructive pulmonary disease (COPD)--incidence, prevalence, and mortality--and identify trends in Australia, Canada, France, Germany, Italy, Japan, The Netherlands, Spain, Sweden, the United Kingdom, and the United States of America. A structured literature search was performed (January 2000 to September 2010) of PubMed and EMBASE, identifying English-language articles reporting COPD prevalence, incidence, or mortality. Of 2838 articles identified, 299 full-text articles were reviewed, and data were extracted from 133 publications. Prevalence data were extracted from 80 articles, incidence data from 15 articles, and mortality data from 58 articles. Prevalence ranged from 0.2%-37%, but varied widely across countries and populations, and by COPD diagnosis and classification methods. Prevalence and incidence were greatest in men and those aged 75 years and older. Mortality ranged from 3-111 deaths per 100,000 population. Mortality increased in the last 30-40 years; more recently, mortality decreased in men in several countries, while increasing or stabilizing in women. Although COPD mortality increased over time, rates declined more recently, likely indicating improvements in COPD management. In many countries, COPD mortality has increased in women but decreased in men. This may be explained by differences in smoking patterns and a greater vulnerability in women to the adverse effects of smoking. PMID- 22927755 TI - Liver cell specific targeting by the preS1 domain of hepatitis B virus surface antigen displayed on protein nanocages. AB - Protein nanocages are self-organized complexes of oligomers whose three dimensional architecture can been determined in detail. These structures possess nanoscale inner cavities into which a variety of molecules, including therapeutic or diagnostic agents, can be encapsulated. These properties yield these particles suitable for a new class of drug delivery carrier, or as a bioimaging reagent that might respond to biochemical signals in many different cellular processes. We report here the design, synthesis, and biological characterization of a hepatocyte-specific nanocage carrying small heat-shock protein. These nanoscale protein cages, with a targeting peptide composed of a preS1 derivative from the hepatitis B virus on their surfaces, were prepared by genetic engineering techniques. PreS1-carrying nanocages showed lower cytotoxicity and significantly higher specificity for human hepatocyte cell lines than other cell lines in vitro. These results suggested that small heat-shock protein-based nanocages present great potential for the development of effective targeted delivery of various agents to specific cells. PMID- 22927756 TI - Echographic detectability of optoacoustic signals from low-concentration PEG coated gold nanorods. AB - PURPOSE: To evaluate the diagnostic performance of gold nanorod (GNR)-enhanced optoacoustic imaging employing a conventional echographic device and to determine the most effective operative configuration in order to assure optoacoustic effectiveness, nanoparticle stability, and imaging procedure safety. METHODS: The most suitable laser parameters were experimentally determined in order to assure nanoparticle stability during the optoacoustic imaging procedures. The selected configuration was then applied to a novel tissue-mimicking phantom, in which GNR solutions covering a wide range of low concentrations (25-200 pM) and different sample volumes (50-200 MUL) were exposed to pulsed laser irradiation. GNR-emitted optoacoustic signals were acquired either by a couple of single-element ultrasound probes or by an echographic transducer. Off-line analysis included: (a) quantitative evaluation of the relationships between GNR concentration, sample volume, phantom geometry, and amplitude of optoacoustic signals propagating along different directions; (b) echographic detection of "optoacoustic spots," analyzing their intensity, spatial distribution, and clinical exploitability. MTT measurements performed on two different cell lines were also used to quantify biocompatibility of the synthesized GNRs in the adopted doses. RESULTS: Laser irradiation at 30 mJ/cm(2) for 20 seconds resulted in the best compromise among the requirements of effectiveness, safety, and nanoparticle stability. Amplitude of GNR-emitted optoacoustic pulses was proportional to both sample volume and concentration along each considered propagation direction for all the tested boundary conditions, providing an experimental confirmation of isotropic optoacoustic emission. Average intensity of echographically detected spots showed similar behavior, emphasizing the presence of an "ideal" GNR concentration (100 pM) that optimized optoacoustic effectiveness. The tested GNRs also exhibited high biocompatibility over the entire considered concentration range. CONCLUSION: An optimal configuration for GNR-enhanced optoacoustic imaging was experimentally determined, demonstrating in particular its feasibility with a conventional echographic device. The proposed approach can be easily extended to quantitative performance evaluation of different contrast agents for optoacoustic imaging. PMID- 22927758 TI - In vitro removal of toxic heavy metals by poly(gamma-glutamic acid)-coated superparamagnetic nanoparticles. AB - BACKGROUND: Chelation therapy involving organic chelators for treatment of heavy metal intoxication can cause cardiac arrest, kidney overload, mineral deficiency, and anemia. METHODS: In this study, superparamagnetic iron oxide nanoparticles (SPIONs) modified with an edible biopolymer poly(gamma-glutamic acid) (PGA) were synthesized by coprecipitation method, characterized and evaluated for their removal efficiency of heavy metals from a metal solution, and simulated gastrointestinal fluid (SGIF). RESULTS: Instrumental characterization of bare- and PGA-SPIONs revealed 7% coating of PGA on SPIONs with a spherical shape and an iron oxide spinel structure belonging to magnetite. The particle sizes as determined from transmission electron microscopy images were 8.5 and 11.7 nm for bare- and PGA-SPIONs, respectively, while the magnetization values were 70.3 and 61.5 emu/g. Upon coating with PGA, the zeta potentials were shifted from positive to negative at most of the environmental pH (3-8) and biological pH (1-8), implying good dispersion in aqueous suspension and favorable conditions for heavy metal removal. Batch studies showed rapid removal of lead and cadmium with the kinetic rates estimated by pseudo-second-order model being 0.212 and 0.424 g/mg . min, respectively. A maximum removal occurred in the pH range 4-8 in deionized water and 5-8 in SGIF corresponding to most gastrointestinal pH except for the stomach. Addition of different ionic strengths (0.001-1 M sodium acetate) and essential metals (Cu, Fe, Zn, Mg, Ca, and K) did not show any marked influence on lead removal by PGA-SPIONs, but significantly reduced the binding of cadmium. Compared to deionized water, the lead removal from SGIF was high at all pH with the Langmuir monolayer removal capacity being 98.70 mg/g for the former and 147.71 mg/g for the latter. However, a lower cadmium removal capacity was shown for SGIF (23.15 mg/g) than for deionized water (31.13 mg/g). CONCLUSION: These results suggest that PGA-SPIONs could be used as a metal chelator for clinical treatment of metal poisoning. PMID- 22927759 TI - Studying the effect of particle size and coating type on the blood kinetics of superparamagnetic iron oxide nanoparticles. AB - PURPOSE: Magnetic resonance imaging (MRI), one of the most powerful imaging techniques available, usually requires the use of an on-demand designed contrast agent to fully exploit its potential. The blood kinetics of the contrast agent represent an important factor that needs to be considered depending on the objective of the medical examination. For particulate contrast agents, such as superparamagnetic iron oxide nanoparticles (SPIOs), the key parameters are particle size and characteristics of the coating material. In this study we analyzed the effect of these two properties independently and systematically on the magnetic behavior and blood half-life of SPIOs. METHODS: Eleven different SPIOs were synthesized for this study. In the first set (a), seven carboxydextran (CDX)-coated SPIOs of different sizes (19-86 nm) were obtained by fractionating a broadly size-distributed CDX-SPIO. The second set (b) contained three SPIOs of identical size (50 nm) that were stabilized with different coating materials, polyacrylic acid (PAA), poly-ethylene glycol, and starch. Furthermore, small PAA SPIOs (20 nm) were synthesized to gain a global insight into the effects of particle size vs coating characteristics. Saturation magnetization and proton relaxivity were determined to represent the magnetic and imaging properties. The blood half-life was analyzed in rats using MRI, time-domain nuclear magnetic resonance, and inductively coupled plasma optical emission spectrometry. RESULTS: By changing the particle size without modifying any other parameters, the relaxivity r(2) increased with increasing mean particle diameter. However, the blood half-life was shorter for larger particles. The effect of the coating material on magnetic properties was less pronounced, but it had a strong influence on blood kinetics depending on the ionic character of the coating material. CONCLUSION: In this report we systematically demonstrated that both particle size and coating material influence blood kinetics and magnetic properties of SPIO independently. These data provide key information for the selection of a contrast agent for a defined application and are additionally valuable for other nano areas, such as hyperthermia, drug delivery, and nanotoxicology. PMID- 22927757 TI - Nanotechnology-based approaches in anticancer research. AB - Cancer is a highly complex disease to understand, because it entails multiple cellular physiological systems. The most common cancer treatments are restricted to chemotherapy, radiation and surgery. Moreover, the early recognition and treatment of cancer remains a technological bottleneck. There is an urgent need to develop new and innovative technologies that could help to delineate tumor margins, identify residual tumor cells and micrometastases, and determine whether a tumor has been completely removed or not. Nanotechnology has witnessed significant progress in the past few decades, and its effect is widespread nowadays in every field. Nanoparticles can be modified in numerous ways to prolong circulation, enhance drug localization, increase drug efficacy, and potentially decrease chances of multidrug resistance by the use of nanotechnology. Recently, research in the field of cancer nanotechnology has made remarkable advances. The present review summarizes the application of various nanotechnology-based approaches towards the diagnostics and therapeutics of cancer. PMID- 22927760 TI - Biofunctionalization of a titanium surface with a nano-sawtooth structure regulates the behavior of rat bone marrow mesenchymal stem cells. AB - BACKGROUND: The topography of an implant surface can serve as a powerful signaling cue for attached cells and can enhance the quality of osseointegration. A series of improved implant surfaces functionalized with nanoscale structures have been fabricated using various methods. METHODS: In this study, using an H(2)O(2) process, we fabricated two size-controllable sawtooth-like nanostructures with different dimensions on a titanium surface. The effects of the two nano-sawtooth structures on rat bone marrow mesenchymal stem cells (BMMSCs) were evaluated without the addition of osteoinductive chemical factors. RESULTS: These new surface modifications did not adversely affect cell viability, and rat BMMSCs demonstrated a greater increase in proliferation ability on the surfaces of the nano-sawtooth structures than on a control plate. Furthermore, upregulated expression of osteogenic-related genes and proteins indicated that the nano-sawtooth structures promote osteoblastic differentiation of rat BMMSCs. Importantly, the large nano-sawtooth structure resulted in the greatest cell responses, including increased adhesion, proliferation, and differentiation. CONCLUSION: The enhanced adhesion, proliferation, and osteogenic differentiation abilities of rat BMMSCs on the nano-sawtooth structures suggest the potential to induce improvements in bone-titanium integration in vivo. Our study reveals the key role played by the nano-sawtooth structures on a titanium surface for the fate of rat BMMSCs and provides insights into the study of stem cell nanostructure relationships and the related design of improved biomedical implant surfaces. PMID- 22927761 TI - Incorporation of a selective sigma-2 receptor ligand enhances uptake of liposomes by multiple cancer cells. AB - BACKGROUND: The sigma-2 receptor is an attractive target for tumor imaging and targeted therapy because it is overexpressed in multiple types of solid tumors, including prostate cancer, breast cancer, and lung cancer. SV119 is a synthetic small molecule that binds to sigma-2 receptors with high affinity and specificity. This study investigates the utility of SV119 in mediating the selective targeting of liposomal vectors in various types of cancer cells. METHODS: SV119 was covalently linked with polyethylene glycol-dioleyl amido aspartic acid conjugate (PEG-DOA) to generate a novel functional lipid, SV119-PEG DOA. This lipid was utilized for the preparation of targeted liposomes to enhance their uptake by cancer cells. Liposomes with various SV119 densities (0, 1, 3, and 5 mole%) were prepared and their cellular uptake was investigated in several tumor cell lines. In addition, doxorubicin (DOX) was loaded into the targeted and unmodified liposomes, and the cytotoxic effect on the DU-145 cells was evaluated by MTT assay. RESULTS: Liposomes with or without SV119-PEG-DOA both have a mean diameter of approximately 90 nm and a neutral charge. The incorporation of SV119 PEG-DOA significantly increased the cellular uptake of liposomes by the DU-145, PC-3, A549, 201T, and MCF-7 tumor cells, which was shown by fluorescence microscopy and the quantitative measurement of fluorescence intensity. In contrast, the incorporation of SV119 did not increase the uptake of liposomes by the normal BEAS-2B cells. In a time course study, the uptake of SV119 liposomes by DU-145 cells was also significantly higher at each time point compared to the unmodified liposomes. Furthermore, the DOX-loaded SV119 liposomes showed significantly higher cytotoxicity to DU-145 cells compared to the DOX-loaded unmodified liposomes. CONCLUSION: SV119 liposomes were developed for targeted drug delivery to cancer cells. The targeting efficiency and specificity of SV119 liposomes to cancer cells was demonstrated in vitro. The results of this study suggest that SV119-modified liposomes might be a promising drug carrier for tumor targeted delivery. PMID- 22927763 TI - Recombinant human decorin suppresses liver HepG2 carcinoma cells by p21 upregulation. AB - BACKGROUND: Decorin is a multifunctional molecule of the extracellular matrix and impedes different kinds of tumor cell growth, but the role and molecular mechanism by which decorin inhibits HepG2 cells is not fully understood. Our objective was to construct recombinant human decorin (pcDNA3.1-DCN) and to explore the mechanism by which it inhibits HepG2 cells. METHODS: This experiment was divided into three groups, ie, a control group, an empty vector group, and a pcDNA3.1-DCN group. pcDNA3.1-DCN was constructed using recombinant DNA technology, and the vector for pcDNA3.1-DCN and pcDNA3.1 was then transfected into HepG2 cells using Lipofectamine 2000. RESULTS: Compared with cells in the control group and in the empty vector group, growth of cells in the pcDNA3.1-DCN group was significantly suppressed, the ratios of cells in the G0/G1 phases and proportion of early apoptotic cells were significantly increased, and the level of p21(WAF1/CIP1) (p21) protein was markedly upregulated (P < 0.05). However, there was no significant difference among the three groups in p53 protein expression (P > 0.05). CONCLUSION: The pcDNA3.1-DCN vector was successfully constructed and transfected into HepG2 cells, and decorin overexpression suppressed the growth of HepG2 cells by upregulation of p21 via a p53-independent pathway. PMID- 22927764 TI - Impact of estradiol-valerate/dienogest on work productivity and activities of daily living in European and Australian women with heavy menstrual bleeding. AB - BACKGROUND: The purpose of this study was to quantify the impact of estradiol valerate/dienogest (E(2)V/DNG; Qlaira((r))/Natazia((r))) on work productivity and activities of daily living in European and Australian women with heavy menstrual bleeding. METHODS: Women aged 18-54 years with a confirmed diagnosis of heavy menstrual bleeding and no recognizable pathology were recruited across nine European countries (the Czech Republic, Finland, Germany, Hungary, The Netherlands, Poland, Sweden, UK, and Ukraine) and Australia. The women were randomized to receive either E(2)V/DNG (n = 149) or placebo (n = 82) for seven treatment cycles (196 days). The outcomes assessed included work productivity (ie, productivity while at work) and activities of daily living, measured on a Likert scale from 0 to 10 (with higher values denoting higher impairment levels) at baseline and at the end of the third and seventh cycles (days 84 and 196). The equivalent monetary value associated with the changes in work productivity and activities of daily living was also calculated. RESULTS: Across all the countries, greater improvements from baseline to the end of treatment were observed with E(2)V/DNG treatment than placebo in work productivity (46.0% versus 15.1%) and activities of daily living (55.6% versus 30.8%). In 2008, savings associated with improvements in work productivity and activities of daily living due to E(2)V/DNG treatment (net of placebo improvement) were estimated to be between US$22-62 and US$18-56 per month (in purchasing power parity of US$), respectively. CONCLUSION: E(2)V/DNG has a consistent positive impact on work productivity and activities of daily living in European and Australian women with heavy menstrual bleeding. These improvements were associated with a reduction in monetary burden of heavy menstrual bleeding compared with the placebo group, consistent with the response to treatment observed. PMID- 22927762 TI - Novel micelle formulation of curcumin for enhancing antitumor activity and inhibiting colorectal cancer stem cells. AB - BACKGROUND AND METHODS: Curcumin has extraordinary anticancer properties but has limited use due to its insolubility in water and instability, which leads to low systemic bioavailability. We have developed a novel nanoparticulate formulation of curcumin encapsulated in stearic acid-g-chitosan oligosaccharide (CSO-SA) polymeric micelles to overcome these hurdles. RESULTS: The synthesized CSO-SA copolymer was able to self-assemble to form nanoscale micelles in aqueous medium. The mean diameter of the curcumin-loaded CSO-SA micelles was 114.7 nm and their mean surface potential was 18.5 mV. Curcumin-loaded CSO-SA micelles showed excellent internalization ability that increased curcumin accumulation in cancer cells. Curcumin-loaded CSO-SA micelles also had potent antiproliferative effects on primary colorectal cancer cells in vitro, resulting in about 6-fold greater inhibition compared with cells treated with a solution containing an equivalent concentration of free curcumin. Intravenous administration of curcumin-loaded CSO SA micelles marginally suppressed tumor growth but did not increase cytotoxicity to mice, as confirmed by no change in body weight. Most importantly, curcumin loaded CSO-SA micelles were effective for inhibiting subpopulations of CD44(+)/CD24(+) cells (putative colorectal cancer stem cell markers) both in vitro and in vivo. CONCLUSION: The present study identifies an effective and safe means of using curcumin-loaded CSO-SA micelles for cancer therapy. PMID- 22927766 TI - The role of gender inequities in women's access to reproductive health care: a population-level study of Namibia, Kenya, Nepal, and India. AB - BACKGROUND: The role of gender inequities in explaining women's access to reproductive health care was examined in four countries (two sub-Saharan African and two South Asian countries). The extent of gender inequities varies across and within countries, and is rooted in the different cultural practices and gender norms within these different countries, and differences in the status and autonomy of women. METHODS: Demographic and Health Survey data from women aged 15 49 years within these countries were analyzed with multivariate logistic regression analysis to examine the role of multidimensional characteristics of gender inequities, operationalized as access to skilled antenatal care, tetanus toxoid injection during pregnancy, and access to skilled antenatal care. RESULTS: Significant associations were found between several dimensions of gender inequities (with the exception of decision-making autonomy) and reported use of maternal reproductive health care services. Several pathways of influence between the outcome and exposure variables were also identified. CONCLUSION: Dimensions of gender inequities (with the exception of decision-making autonomy) differentially influenced woman's use of reproductive health care services, thus highlighting the urgent need for concerted and sustained efforts to change these harmful traditional values if several of these countries are to meet Millennium Development Goal-5. PMID- 22927765 TI - Potential role of tenofovir vaginal gel for reduction of risk of herpes simplex virus in females. AB - A surprising result of the groundbreaking CAPRISA-004 trial, which demonstrated the efficacy of vaginal tenofovir 1% gel in reducing the risk of human immunodeficiency virus (HIV)-1 infection by 39% in heterosexual women, was the added benefit of this microbicide in reducing acquisition of herpes simplex virus type 2 (HSV-2) by 51%. HSV-2 is the most common cause of genital ulcer disease worldwide, and is responsible for considerable morbidity among women and neonates. The virus is further implicated in increasing the risk of both HIV acquisition and transmission, and may have additional adverse consequences in HIV coinfected persons, making HSV-2 prevention an important clinical and public health objective. While tenofovir had not previously been widely considered to be an anti-herpes drug, in vitro activity against HSV is well documented, raising interest in potential future applications of tenofovir and its prodrugs in HSV-2 control. This article reviews the currently available data for tenofovir as an anti-herpes agent, as well as unanswered questions about delivery systems, drug formulation, rectal administration, drug resistance, and clinical applications. PMID- 22927767 TI - Factors associated with acceptability of child adoption as a management option for infertility among women in a developing country. AB - BACKGROUND: Adoption as a treatment option for infertility amongst those that cannot access and/or afford assisted reproduction is not well accepted in developing countries. This study sets out to determine the willingness of infertile women in developing countries to adopt a child and factors that influence women's attitude to adoption. METHODS: We conducted a questionnaire survey of consecutive infertile patients who attended the gynecological clinic of a regional teaching hospital over a 2-month period. Information on demographics, fertility history, and attitude to adoption was obtained, and the data were analyzed using SPSS version 16.0. Tests of statistical significance were used where appropriate at the 95% confidence level. RESULTS: The majority of respondents were aware of child adoption, and the most common source of information was friends (47.8%), followed by the media (39.7%); 42.6% of respondents were willing to adopt if their infertility became intractable. The main reasons given by those unwilling to adopt were culture (78.3%) and family constraints (13.45%). On univariate analysis of factors associated with a favorable or unfavorable attitude to adoption, awareness of adoption (P = 0.002), duration of infertility > 5 years (P = 0.015), no living child (P = 0.007), tertiary education (P < 0.001), pressure from parents (P = 0.041), household yearly income >= $650 (P < 0.001), and belief that treatment will bring about the desired results (P < 0.001) were significant, and all except awareness of adoption turned out to be significant on multiple logistic regression analysis. CONCLUSION: There was a high level of awareness about child adoption among all respondents. However, the acceptability of adoption was significantly lower among poor women and those with limited education. Community advocacy and mobilization, especially through the media as well as via health care providers, will go a long way towards enlightening and enhancing the uptake of adoption among women in Nigeria. PMID- 22927768 TI - Uterine prolapse prevention in Eastern Nepal: the perspectives of women and health care professionals. AB - Uterine prolapse is a major reproductive health issue in Nepal. There is a wide range of literature available on the causes and risk factors of uterine prolapse and on the ways to prevent and treat it. There is still a lack of published evidence on what prevention and treatment services are working well or the attitudes toward them. This paper presents the findings of a qualitative study on primary and secondary prevention of uterine prolapse in Eastern Nepal. METHOD: The study involved eight focus group discussions with 71 women in six villages of the eastern districts of Siraha and Saptari and 14 qualitative interviews with health professionals from the local to central level. The group discussions and interviews covered the awareness levels of uterine prolapse and its prevention and treatment, as well as participants' opinions on and experiences with the services offered. RESULTS: It was found that patriarchy, gender discrimination, and cultural traditions such as early marriage and pregnancy make it difficult for people to discontinue uterine prolapse risk behaviors. Women are aware of risk factors, prevention, and treatment, but are powerless to change their situations. Health professionals and women are fond of surgery as treatment, but opinions on the use of ring pessaries and pelvic floor muscle training are split. CONCLUSION: The main recommendation that can be drawn from this study is that research on the effectiveness of early treatments, such as ring pessaries and exercise, should be conducted. Furthermore, the involvement of other target groups (husbands, adolescents, and mothers-in-law) needs to be increased in order to make it easier for women to adapt low-risk behaviors. Finally, uterine prolapse prevention should be better integrated in national reproductive health services. Enforcing transparency, monitoring systems, and collaborations are important factors that should be considered as well. PMID- 22927770 TI - Emerging treatment options for management of malignant ascites in patients with ovarian cancer. AB - Malignant ascites affects approximately 10% of patients with recurrent epithelial ovarian cancer and is associated with troublesome symptoms, including abdominal pressure and distension, dyspnea, bloating, pelvic pain, and bowel/bladder dysfunction. To date, no effective therapy has been identified for the treatment of malignant ascites in patients with recurrent, advanced ovarian cancer. In this article, we discuss currently existing options for the treatment of ascites associated with ovarian cancer, and review the literature as it pertains to novel, targeted therapies. Specifically, preclinical and clinical trials exploring the use of the antiangiogenic agents, bevacizumab and vascular endothelial growth factor-trap, as well as the nonangiogenic agent, catumaxomab, will be reviewed. Despite current limitations in treatment, knowledge regarding management options in the palliation of ascites is critical to practicing physicians. Ultimately, as with all novel therapies, symptom relief and treatment goals must be weighed against patient discomfort and potentially significant adverse events. PMID- 22927769 TI - Video-assisted laparoscopy for the detection and diagnosis of endometriosis: safety, reliability, and invasiveness. AB - Endometriosis is a highly enigmatic disease with multiple presentations ranging from infertility to severe pain, often causing significant morbidity. Video assisted laparoscopy (VALS) has now replaced laparotomy as the gold standard for the diagnosis and management of endometriosis. While imaging has a role in the evaluation of some patients, histologic examination is needed for a definitive diagnosis. Laboratory evaluation currently has a minor role in the diagnosis of endometriosis, although studies are underway investigating serum markers, genetic studies, and endometrial sampling. A high index of suspicion is essential to accurately diagnose this complex condition, and a multidisciplinary approach is often indicated. The following review discusses laparoscopic diagnosis of endometriosis from the pre-operative evaluation of patients suspected of having endometriosis to surgical technique for safe and adequate laparoscopic diagnosis of the condition and postsurgical care. PMID- 22927771 TI - Zn2+-SCMC versus HA for preventing intraperitoneal adhesions: a rat model study. AB - BACKGROUND: Intraperitoneal adhesion is a serious surgical postoperative complication. Using a rat model, we compared the effectiveness of intraperitoneally administered zinc-modified sodium carboxymethyl cellulose (Zn(2+)-SCMC) and hyaluronic acid (HA) in preventing postoperative intraperitoneal adhesions. MATERIALS AND METHODS: Peritoneal adhesions were induced in 120 Wistar rats by scraping the cecal mucosa. The rats were randomized into a no treatment group (n = 40) or into a treatment group in which 3 ml of HA (n = 40) or Zn(2+)-SCMC (n = 40) was administered intraperitoneally before the abdominal wall was closed. Following sacrifice two weeks later, the intraperitoneal adhesions were scored and tissues were examined histologically using HE staining. RESULTS: Eight animals died, five in the untreated group (mortality rate, 12.5%), two in the HA group (mortality rate, 5.0%) and one in the Zn(2+)-SCMC group (mortality rate, 2.5%). Relative to the untreated group, the incidence of intraperitoneal adhesions was 77.5% in the HA and 48.7% in the Zn(2+)-SCMC group, with the incidence significantly lower in the Zn(2+)-SCMC group (P < 0.001). Both agents prevented intraperitoneal adhesions by promoting the repair of the abdominal serosa. CONCLUSIONS: Administration of Zn(2+)-SCMC was more effective in preventing intraperitoneal adhesions than HA. PMID- 22927772 TI - Clinical application of pharmacogenetic-based warfarin-dosing algorithm in patients of Han nationality after rheumatic valve replacement: a randomized and controlled trial. AB - BACKGROUND: The polymorphisms of VKORC1 and CYP2C9 play increasingly important roles in the inter-individual variability in warfarin dose. This study aimed to evaluate the feasibility of clinical application of pharmacogenetic-based warfarin-dosing algorithm in patients of Han nationality with rheumatic heart disease after valve replacement in a randomized and controlled trial. METHODS: One hundred and one consecutive patients of Han nationality with rheumatic heart disease undergoing valve surgery were enrolled and randomly assigned to an experimental group (n=50, based on CYP2C9 and VKORC1 genotypes, pharmacogenetic based "predicted warfarin dose" for 3 days and then was adjusted to INR until stable warfarin maintenance dose) or a control group (n=51, 2.5mg/d for 3 days and then was adjusted to INR until stable warfarin maintenance dose). All included patients were followed for 50 days after initiation of warfarin therapy. The primary end-point was the time to reach a stable warfarin maintenance dose. RESULTS: During the follow-up, 84.0% patients in the experimental group and 58.8% patients in the control group received warfarin maintenance dose. Compared with control group, patients in the experimental group had shorter mean time elapse from initiation of warfarin therapy until warfarin maintenance dose (27.5+/-1.8 d versus 34.7+/-1.8 d, p<0.001). Cox regression revealed that group (HR for experimental versus control group: 1.568, 95%CI 1.103-3.284) and age were two significant variables related to the time elapse from initiation of warfarin therapy until warfarin maintenance dose. The predicted warfarin maintenance dose was prominently correlated with the actual warfarin maintenance dose (r=0.684, p<0.001). CONCLUSION: Based on CYP2C9 and VKORC1 genotypes, the pharmacogenetic based warfarin-dosing algorithm may shorten the time elapse from initiation of warfarin therapy until warfarin maintenance dose. It is feasible for the clinical application of the pharmacogenetic-based warfarin-dosing algorithm in patients of Han nationality with rheumatic heart disease after valve replacement. PMID- 22927773 TI - Osteogenic differentiation of dental follicle stem cells. AB - BACKGROUND: Stem cells are defined as clonogenic cells capable of self-renewal and multi-lineage differentiation. A population of these cells has been identified in human Dental Follicle (DF). Dental Follicle Stem Cells (DFSCs) were found in pediatric unerupted wisdom teeth and have been shown to differentiate, under particular conditions, into various cell types of the mesenchymal tissues. AIM: The aim of this study was to investigate if cells isolated from DF show stem features, differentiate toward osteoblastic phenotype and express osteoblastic markers. METHODS: We studied the immunophenotype of DFSCs by flow cytometric analysis, the osteoblastic markers of differentiated DFSCs were assayed by histochemical methods and real-time PCR. RESULTS: We demonstrated that DFSCs expressed a heterogeneous assortment of makers associated with stemness. Moreover DFSCs differentiated into osteoblast-like cells, producing mineralized matrix nodules and expressed the typical osteoblastic markers, Alkaline Phosphatase (ALP) and Collagen I (Coll I). CONCLUSION: This study suggests that DFSCs may provide a cell source for tissue engineering of bone. PMID- 22927774 TI - Validation of the prediction model for success of vaginal birth after cesarean delivery in Japanese women. AB - AIM: To validate a previously developed prediction model for vaginal birth after cesarean (VBAC) using a Japanese cohort. METHODS: We performed a cohort study of all term pregnant women with a vertex position, singleton gestation, and one prior low transverse cesarean delivery attempting a trial of labor between April 1985 and March 2010. Variables necessary for the prediction of successful VBAC were maternal age, pre-pregnancy body mass index, ethnicity, prior vaginal delivery, prior VBAC, and indication for prior cesarean delivery. They were extracted from medical records and put into the formula that calculates an individual woman's predicted VBAC success rate. The predicted rates were then partitioned into deciles and compared with the actual VBAC rates. The predictive ability of the model was assessed with a receiver operating characteristic and the area under the curve (AUC) was determined. RESULTS: Seven hundred and twenty five women who met the inclusion criteria had complete data available, of which 664 (91.6%) had VBAC. The predicted probability of VBAC, as calculated by the regression equation, was significantly higher in those who had a successful trial of labor (median 80.1%, interquartile range 71.5-88.7) than those who did not (median 69.4%, interquartile range 59.9-78.9, P<0.001). The predictive model had AUC of 0.80, which was comparative to the originally described one. When the predicted rates were each deciles of over 70%, the actual success rates were more than 90%. CONCLUSION: The previously published prediction model for VBAC developed in the USA is also available to Japanese women. PMID- 22927775 TI - Prevention of propofol injection pain in children: a comparison of pretreatment with tramadol and propofol-lidocaine mixture. AB - BACKGROUND: The pain on propofol injection is considered to be a common and difficult to eliminate problem in children. In this study, we aimed to compare the efficacy of pretreatment with tramadol 1 mg.kg(-1)and propofol-lidocaine 20 mg mixture for prevention of propofol induced pain in children. METHODS: One hundred and twenty ASA I-II patients undergoing orthopedic and otolaryngological surgery were included in this study and were divided into three groups with random table numbers. Group C (n=39) received normal saline placebo and Group T (n=40) received 1 mg.kg(-1) tramadol 60 sec before propofol (180 mg 1% propofol with 2 ml normal saline) whereas Group L (n=40) received normal saline placebo before propofol-lidocaine mixture (180 mg 1% propofol with 2 ml %1 lidocaine). One patient in Group C was dropped out from the study because of difficulty in inserting an iv cannula. Thus, one hundred and nineteen patients were analyzed for the study. After given the calculated dose of propofol, a blinded observer assessed the pain with a four-point behavioral scale. RESULTS: There were no significant differences in patient characteristics and intraoperative variables (p>0.05) except intraoperative fentanyl consumption and analgesic requirement one hr after surgery among the groups (p<0.05). Both tramadol 1 mg.kg(-1) and lidocaine 20 mg mixture significantly reduced propofol pain when compared with control group. Moderate and severe pain were found higher in control group (p<0.05). The incidence of overall pain was 79.4% in the control group, 35% in tramadol group, 25% in lidocaine group respectively (p<0.001). CONCLUSIONS: Pretreatment with tramadol 60 sec before propofol injection and propofol lidocaine mixture were significantly reduced propofol injection pain when compared to placebo in children. PMID- 22927776 TI - Interaction between polymorphisms of DNA repair genes significantly modulated bladder cancer risk. AB - DNA repair is a primary defense mechanism against damage caused by exogenous and endogenous sources. We examined the associations between bladder cancer and 7 polymorphisms from 5 genes involved in the maintenance of genetic stability (MMR: MLH1-93G>A; BER: XRCC1--77T>C and Arg399Gln; NER:XPC Lys939Gln and PAT +/-; DSBR:ATM G5557A and XRCC7 G6721T) in 302 incident bladder cancer cases and 311 hospital controls. Genotyping was done using a polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) technique. The homozygous variant of XRCC7 G6721T (Odds Ratio [OR]: 2.36; 95% Confidence Interval [CI]: 1.13-4.92) was associated with increased bladder cancer risk. In an analysis of combined genotypes, the combination of XRCC1Arg399Gln (Gln allele) with XRCC1-77 T/T led to an increase in risk (OR: 1.61; 95% CI: 1.10-2.36). Moreover, when the XPCLys939Gln (Gln allele) (nucleotide excision repair [NER]) was present together with XRCC7 (T allele) (double strand break repair [DSBR]), the bladder cancer risk dramatically increased (OR: 4.42; 95% CI: 1.23-15.87). Our results suggest that there are multigenic variations in the DNA repair pathway involved in bladder cancer susceptibility, despite the existence of ethnic group differences. PMID- 22927777 TI - Mannose binding lectin and macrophage migration inhibitory factor gene polymorphisms in Turkish children with cardiomyopathy: no association with MBL2 codon 54 A/B genotype, but an association between MIF -173 CC genotype. AB - Myocardial inflammation is one of the commonest mechanisms in cardiomyopathy (CMP). Mannose binding lectin (MBL) is a key molecule in innate immunity, while macrophage migration inhibitory factor (MIF) is a constitutive element of the host defenses. We investigated the possible association between polymorphisms of MBL2 and MIF genes and CMP in Turkish children. Twenty-children with CMP and 30 healthy controls were analyzed for codon 54 A/B polymorphism in MBL, and -173 G/C polymorphism in MIF genes by using PCR-RFLP methods. No significant difference was found between genotypes and alleles of MBL2 gene codon 54 A/B polymorphism in patients and controls (p>0.05). However, serum uric acid levels was found higher in dilated CMP patients with AA genotype. Frequency of MIF -173 CC genotype was significantly higher in patients (p<0.05), and sodium levels were higher in patients with MIF -173 CC genotype. This study is the first to investigate the MBL and MIF gene polymorphisms in Turkish children with CMP. We conclude that CC genotype of MIF (-173) polymorphism may be a risk factor for CMP patients. However, further studies with larger samples are needed to address the exact role of this polymorphism in CMP. PMID- 22927778 TI - Acetate activation in Methanosaeta thermophila: characterization of the key enzymes pyrophosphatase and acetyl-CoA synthetase. AB - The thermophilic methanogen Methanosaeta thermophila uses acetate as sole substrate for methanogenesis. It was proposed that the acetate activation reaction that is needed to feed acetate into the methanogenic pathway requires the hydrolysis of two ATP, whereas the acetate activation reaction in Methanosarcina sp. is known to require only one ATP. As these organisms live at the thermodynamic limit that sustains life, the acetate activation reaction in Mt. thermophila seems too costly and was thus reevaluated. It was found that of the putative acetate activation enzymes one gene encoding an AMP-forming acetyl CoA synthetase was highly expressed. The corresponding enzyme was purified and characterized in detail. It catalyzed the ATP-dependent formation of acetyl-CoA, AMP, and pyrophosphate (PP(i)) and was only moderately inhibited by PP(i). The breakdown of PP(i) was performed by a soluble pyrophosphatase. This enzyme was also purified and characterized. The pyrophosphatase hydrolyzed the major part of PP(i) (K(M) = 0.27 +/- 0.05 mM) that was produced in the acetate activation reaction. Activity was not inhibited by nucleotides or PP(i). However, it cannot be excluded that other PP(i)-dependent enzymes take advantage of the remaining PP(i) and contribute to the energy balance of the cell. PMID- 22927779 TI - Thermal adaptation of the archaeal and bacterial lipid membranes. AB - The physiological characteristics that distinguish archaeal and bacterial lipids, as well as those that define thermophilic lipids, are discussed from three points of view that (1) the role of the chemical stability of lipids in the heat tolerance of thermophilic organisms: (2) the relevance of the increase in the proportion of certain lipids as the growth temperature increases: (3) the lipid bilayer membrane properties that enable membranes to function at high temperatures. It is concluded that no single, chemically stable lipid by itself was responsible for the adaptation of surviving at high temperatures. Lipid membranes that function effectively require the two properties of a high permeability barrier and a liquid crystalline state. Archaeal membranes realize these two properties throughout the whole biological temperature range by means of their isoprenoid chains. Bacterial membranes meet these requirements only at or just above the phase-transition temperature, and therefore their fatty acid composition must be elaborately regulated. A recent hypothesis sketched a scenario of the evolution of lipids in which the "lipid divide" emerged concomitantly with the differentiation of archaea and bacteria. The two modes of thermal adaptation were established concurrently with the "lipid divide." PMID- 22927780 TI - The use of parsimonious questionnaires in occupational health surveillance: psychometric properties of the short Italian version of the effort/reward imbalance questionnaire. AB - PURPOSE: To perform a parsimonious measurement of workplace psychosocial stress in routine occupational health surveillance, this study tests the psychometric properties of a short version of the original Italian effort-reward imbalance (ERI) questionnaire. METHODS: 1,803 employees (63 percent women) from 19 service companies in the Italian region of Latium participated in a cross-sectional survey containing the short version of the ERI questionnaire (16 items) and questions related to self-reported health, musculoskeletal complaints and job satisfaction. Exploratory factor analysis, internal consistency of scales and criterion validity were utilized. RESULTS: The internal consistency of scales was satisfactory. Principal component analysis enabled to identify the model's main factors. Significant associations with health and job satisfaction in the majority of cases support the notion of criterion validity. A high score on the effort-reward ratio was associated with an elevated odds ratio (OR = 2.71; 95% CI 1.86-3.95) of musculoskeletal complaints in the upper arm. CONCLUSIONS: The short form of the Italian ERI questionnaire provides a psychometrically useful tool for routine occupational health surveillance, although further validation is recommended. PMID- 22927781 TI - Determinants of electricity consumption intensity in China: analysis of cities at subprovince and prefecture levels in 2009. AB - China has experienced great social and economic vicissitudes that caused the vast complexity and uncertainty for electricity consumption. This paper attempts to identify the main determinants of the electricity consumption intensity by using the data from Chinese cities at subprovince and prefecture levels in 2009. The key category factors, including urban morphology, industrial structure, regulation context, urbanization degree, price, natural condition, and resource endowment, are abstracted and the influence of these determinants is evaluated by adopting the finite mixture models. The variation of each determinant across regions, the comparative weights of all the factors, and the detailed classifications of the cities are reported for facilitating the understanding of electricity consumption in China. The corresponding policies for electricity administration are addressed as well. PMID- 22927782 TI - The effectiveness of liraglutide in nonalcoholic fatty liver disease patients with type 2 diabetes mellitus compared to sitagliptin and pioglitazone. AB - BACKGROUND. Liraglutide leading to improve not only glycaemic control but also liver inflammation in non-alcoholic fatty liver disease (NAFLD) patients. AIMS. The aim of this study is to elucidate the effectiveness of liraglutide in NAFLD patients with type 2 diabetes mellitus (T2DM) compared to sitagliptin and pioglitazone. METHODS. We retrospectively enrolled 82 Japanese NAFLD patients with T2DM and divided into three groups (liraglutide: N = 26, sitagliptin; N = 36, pioglitazone; N = 20). We compared the baseline characteristics, changes of laboratory data and body weight. RESULTS. At the end of follow-up, ALT, fast blood glucose, and HbA1c level significantly improved among the three groups. AST to platelet ratio significantly decreased in liraglutide group and pioglitazone group. The body weight significantly decreased in liraglutide group (81.8 kg to 78.0 kg, P < 0.01). On the other hands, the body weight significantly increased in pioglitazone group and did not change in sitagliptin group. Multivariate regression analysis indicated that administration of liraglutide as an independent factor of body weight reduction for more than 5% (OR 9.04; 95% CI 1.12-73.1, P = 0.04). CONCLUSIONS. Administration of liraglutide improved T2DM but also improvement of liver inflammation, alteration of liver fibrosis, and reduction of body weight. PMID- 22927783 TI - Foetal exposure to maternal passive smoking is associated with childhood asthma, allergic rhinitis, and eczema. AB - OBJECTIVE: We examined the hypothesis that foetal exposure to maternal passive smoking is associated with childhood asthma, allergic rhinitis, and eczema. METHODS. The study was a population-based cross-sectional survey of Hong Kong Chinese children aged <=14 years carried out in 2005 to 2006. RESULTS. Foetal exposure to maternal passive smoking was significantly associated with wheeze ever (OR 2.05; 95% CI 1.58-2.67), current wheeze (OR 2.06; 95% CI 1.48-2.86), allergic rhinitis ever (OR 1.22; 95% CI 1.09-1.37), and eczema ever (OR 1.61; 95% CI 1.38-1.87). Foetal exposure to maternal active smoking was significantly associated with asthma ever (OR 2.10; 95% CI 1.14-3.84), wheeze ever (OR 2.46; 95% CI 1.27-4.78), and current wheeze (OR 2.74; 95% CI 1.24-6.01) but not with allergic rhinitis ever (OR 1.01; 95% CI 0.70-1.46) or eczema ever (OR 1.38; 95% CI 0.87-2.18). The dose response relationship between wheeze ever and current wheeze with increasing exposure, from no exposure to maternal passive smoking and then to maternal active smoking, further supports causality. CONCLUSION. There is significant association between foetal exposure to maternal passive smoking and maternal active smoking with childhood asthma and related atopic illnesses. Further studies are warranted to explore the potential causal relationship. PMID- 22927785 TI - Psychometric properties of the existence subscale of the purpose in life questionnaire for Chinese adolescents in Hong Kong. AB - The current study aims to test the psychometric properties of the Existence Subscale of the Purpose in Life Questionnaire (EPIL) for early adolescence. The Purpose in Life Questionnaire (PIL), originally created by Craumbaugh and Maholick, is a 20-item scale measuring different dimensions of life purposes. The current study selected seven items representative of the existence dimension to form another scale, the EPIL. The analysis was based on 2842 early adolescents, ranging from 11 to 14 years old. Principal axis factoring found one factor, with 60% variance being explained. Cronbach's alpha for the EPIL was 0.89, which was high. The factor structure was stable across genders. Criterion-related validity was determined when the scale was used to differentiate volunteers and nonvolunteers. Construct validity was found when the scale was associated with life satisfaction. The results give support to the fact that the EPIL could be used alone to measure the psychological well-being of early adolescents and the appropriateness of the EPIL in adolescent research. PMID- 22927784 TI - Exercise training prevents decrease in luminal capillary diameter of skeletal muscles in rats with type 2 diabetes. AB - The purpose of this study was to examine whether exercise training can prevent microangiopathy of skeletal muscles in rats with type 2 diabetes and if succinate dehydrogenase (SDH) activity, an indicator of mitochondrial oxidative enzyme activity, is involved in the prevention of microangiopathy. Six-week-old male Goto-Kakizaki (GK) rats and age-matched male Wistar rats (control group (Con)) were used. GK rats were randomly assigned to nonexercise (DB) and exercise (DBEx) groups. The DBEx group was trained on a treadmill 5 times a week for 3 weeks. No significant differences in the capillary-to-fibre ratio or the capillary density were observed between the 3 groups. The luminal capillary diameter of the DB group was significantly lower than that of the Con group, whereas the capillary diameter of the DBEx group was significantly higher than that of the DB group. In addition, SDH activity was significantly higher in the DBEx group than in the Con and DB groups. Microangiopathy of skeletal muscles in type 2 diabetes was correlated with a decrease in the luminal capillary diameter, which was prevented by exercise training. Thus, the mitochondrial oxidative capacity appears to be involved in the overall mechanism by which exercise prevents microangiopathy. PMID- 22927786 TI - In vitro antilisterial properties of crude methanol extracts of Garcinia kola (Heckel) seeds. AB - Crude methanol extracts of Garcinia kola (Heckel) seeds were screened for their antilisterial activities against 42 Listeria bacteria isolated from wastewater effluents. The extract had activity against 45% of the test bacteria and achieved minimum inhibitory concentrations (MICs) ranging between 0.157 and 0.625 mg/mL. The rate of kill of the extract was determined against four representative Listeria species in the study, and the results showed that the highest percentage of bacteria cells were killed after the maximum exposure time of 2 h at the highest concentration of 4 * MIC value, with the maximum number of bacteria cells killed being for L. ivanovii (LEL 30) 100%, L. monocytogenes (LAL 8) 94.686%, L. ivanovii (LEL 18) 60.330%, and L. grayi (LAL 15) 56.071% We therefore conclude that the nature of inhibition of the crude methanol extracts of Garcinia kola seeds can be either bactericidal or bacteriostatic depending on the target Listeria species and can also differ among same species as evidenced by L. ivanovii strains LEL 30 and LEL 18. PMID- 22927787 TI - Characteristics of Streptococcus pneumoniae strains colonizing upper respiratory tract of healthy preschool children in Poland. AB - Antibiotic resistant and invasive pneumococci may spread temporally and locally in day care centers (DCCs). We examined 267 children attending four DCCs located in the same city and 70 children staying at home in three seasons (autumn, winter, and spring) to determine prevalence, serotype distribution, antibiotic resistance patterns, and transmission of pneumococcal strains colonizing upper respiratory tract of healthy children without antipneumococcal vaccination. By pheno- and genotyping, we determined clonality of pneumococci, including drug resistant strains. The average carriage of pneumococci in three seasons was 38.2%. 73.4% and 80.4% of the isolates belonged to serotypes present in 10- and 13-valent conjugate vaccine, respectively. Among the pneumococcal strains, 33.3% were susceptible to all antimicrobial tested and 39.2% had decreased susceptibility to penicillin. Multidrug resistance was common (35.7%); 97.5% of drug-resistant isolates represented serotypes included to 10- and 13-valent conjugate vaccine. According to BOX-PCR, clonality definitely was observed only in case of serotype 14. Multivariate analysis determined DCC attendance as strongly related to pneumococcal colonization in all three seasons, but important seasonal differences were demonstrated. In children attending DCCs, we observed dynamic turnover of pneumococcal strains, especially penicillin nonsusceptible and multidrug resistant, which were mostly distributed among serotypes included to available pneumococcal conjugate vaccines. PMID- 22927788 TI - Antibiotic susceptibility profile of Aeromonas species isolated from wastewater treatment plant. AB - This study assessed the prevalence of antibiotic-resistant Aeromonas species isolated from Alice and Fort Beaufort wastewater treatment plant in the Eastern Cape Province of South Africa. Antibiotic susceptibility was determined using the disc diffusion method, and polymerase chain reaction (PCR) assay was employed for the detection of antibiotics resistance genes. Variable susceptibilities were observed against ciprofloxacin, chloramphenicol, nalidixic acid, gentamicin, minocycline, among others. Aeromonas isolates from both locations were 100% resistant to penicillin, oxacillin, ampicillin, and vancomycin. Higher phenotypic resistance was observed in isolates from Fort Beaufort compared to isolates from Alice. Class A pse1 beta-lactamase was detected in 20.8% of the isolates with a lower detection rate of 8.3% for bla(TEM) gene. Class 1 integron was present in 20.8% of Aeromonas isolates while class 2 integron and TetC gene were not detected in any isolate. The antibiotic resistance phenotypes observed in the isolates and the presence of beta-lactamases genes detected in some isolates are of clinical and public health concern as this has consequences for antimicrobial chemotherapy of infections associated with Aeromonas species. This study further supports wastewater as potential reservoirs of antibiotic resistance determinants in the environment. PMID- 22927789 TI - Design, kinematic optimization, and evaluation of a teleoperated system for middle ear microsurgery. AB - Middle ear surgery involves the smallest and the most fragile bones of the human body. Since microsurgical gestures and a submillimetric precision are required in these procedures, the outcome can be potentially improved by robotic assistance. Today, there is no commercially available device in this field. Here, we describe a method to design a teleoperated assistance robotic system dedicated to the middle ear surgery. Determination of design specifications, the kinematic structure, and its optimization are detailed. The robot-surgeon interface and the command modes are provided. Finally, the system is evaluated by realistic tasks in experimental dedicated settings and in human temporal bone specimens. PMID- 22927790 TI - Impact of the spittlebug Mahanarva spectabilis on signal grass. AB - The aim of this study was to determine the damage in Brachiaria ruziziensis (Germain & Edvard) according to the density of and exposure time to adults of Mahanarva spectabilis (Distant, 1909) (Hemiptera:Cercopidae). Each plant was kept with 0, 12, 18, or 24 adults of M. spectabilis for five or ten days. Then, the insects were removed from the plant, and the following parameters were evaluated: content and loss of chlorophyll, visual damage score, shoot dry mass, and the capability for regrowth. In fact, plants exposed to the highest level of infestation for 10 days showed an 80.97% loss of chlorophyll, which is 25% higher than that shown by the plants exposed for five days. The damage score also increased with infestation levels. In the levels of 12 and 18 adults per plant, the damage score increased with increasing time of exposure. The dry mass content was higher in plants exposed to 24 insects for 10 days, suggesting that the attack of spittlebugs caused premature drying of the plant. These effects caused significant reduction in the number of tillers of infested plants. Our results indicate that exposure to adults of M. spectabilis causes significant damage and affects the development and persistence of B. ruziziensis plants. PMID- 22927791 TI - A simple approach for measuring emission patterns of vapor phase mercury under temperature-controlled conditions from soil. AB - In an effort to study the possible effects of climate change on the behavior of atmospheric mercury (Hg), we built a temperature-controlled microchamber system to measure its emission from top soils. To this end, mercury vapour emission rates were investigated in the laboratory using top soil samples collected from an urban area. The emissions of Hg, when measured as a function of soil temperature (from ambient levels up to 70 degrees C at increments of 10 degrees C), showed a positive correlation with rising temperature. According to the continuous analyses of the Hg vapor given off by the identical soil samples, evasion rate diminished noticeably with increasing number of repetitions. The experimental results, if examined in terms of activation energy (Ea), showed highly contrasting patterns between the single and repetitive runs. Although the results of the former exhibited Ea values smaller than the vaporization energy of Hg (i.e., <14 Kcal mol(-1)), those of the latter increased systematically with increasing number of repetitions. As such, it is proposed that changes in the magnitude of Ea values can be used as a highly sensitive criterion to discriminate the important role of vaporization from other diverse (biotic/abiotic) processes occurring in the soil layer. PMID- 22927792 TI - Leishmania spp. epidemiology of canine leishmaniasis in the Yucatan Peninsula. AB - Canine Leishmaniasis is widespread in various Mexican states, where different species of Leishmania have been isolated from dogs. In the present study, we describe the detection of L. braziliensis, L. infantum, and L. mexicana in serum of dogs from the states of Yucatan and Quintana Roo in the Yucatan Peninsula (Mexico). A total of 412 sera were analyzed by ELISA using the total extract of the parasite and the iron superoxide dismutase excreted by different trypanosomatids as antigens. We found the prevalence of L. braziliensis to be 7.52%, L. infantum to be 6.07%, and L. mexicana to be 20.63%, in the dog population studied. The results obtained with ELISA using iron superoxide dismutase as the antigen were confirmed by western blot analysis with its greater sensitivity, and the agreement between the two techniques was very high. PMID- 22927793 TI - Pruning brain vasculature for efficiency. PMID- 22927794 TI - LAB-1 targets PP1 and restricts Aurora B kinase upon entrance into meiosis to promote sister chromatid cohesion. AB - Successful execution of the meiotic program depends on the timely establishment and removal of sister chromatid cohesion. LAB-1 has been proposed to act in the latter by preventing the premature removal of the meiosis-specific cohesin REC-8 at metaphase I in C. elegans, yet the mechanism and scope of LAB-1 function remained unknown. Here we identify an unexpected earlier role for LAB-1 in promoting the establishment of sister chromatid cohesion in prophase I. LAB-1 and REC-8 are both required for the chromosomal association of the cohesin complex subunit SMC-3. Depletion of lab-1 results in partial loss of sister chromatid cohesion in rec-8 and coh-4 coh-3 mutants and further enhanced chromatid dissociation in worms where all three kleisins are mutated. Moreover, lab-1 depletion results in increased Aurora B kinase (AIR-2) signals in early prophase I nuclei, coupled with a parallel decrease in signals for the PP1 homolog, GSP-2. Finally, LAB-1 directly interacts with GSP-1 and GSP-2. We propose that LAB-1 targets the PP1 homologs to the chromatin at the onset of meiosis I, thereby antagonizing AIR-2 and cooperating with the cohesin complex to promote sister chromatid association and normal progression of the meiotic program. PMID- 22927796 TI - Evolution-based drug discovery: antifungal also disrupts blood vessel formation. PMID- 22927795 TI - Evolutionarily repurposed networks reveal the well-known antifungal drug thiabendazole to be a novel vascular disrupting agent. AB - Studies in diverse organisms have revealed a surprising depth to the evolutionary conservation of genetic modules. For example, a systematic analysis of such conserved modules has recently shown that genes in yeast that maintain cell walls have been repurposed in vertebrates to regulate vein and artery growth. We reasoned that by analyzing this particular module, we might identify small molecules targeting the yeast pathway that also act as angiogenesis inhibitors suitable for chemotherapy. This insight led to the finding that thiabendazole, an orally available antifungal drug in clinical use for 40 years, also potently inhibits angiogenesis in animal models and in human cells. Moreover, in vivo time lapse imaging revealed that thiabendazole reversibly disassembles newly established blood vessels, marking it as vascular disrupting agent (VDA) and thus as a potential complementary therapeutic for use in combination with current anti angiogenic therapies. Importantly, we also show that thiabendazole slows tumor growth and decreases vascular density in preclinical fibrosarcoma xenografts. Thus, an exploration of the evolutionary repurposing of gene networks has led directly to the identification of a potential new therapeutic application for an inexpensive drug that is already approved for clinical use in humans. PMID- 22927797 TI - Challenges for HIV pre-exposure prophylaxis among men who have sex with men in the United States. PMID- 22927799 TI - An alternative framework for analyzing financial protection in health. PMID- 22927798 TI - Effects of intensive blood pressure lowering on cardiovascular and renal outcomes: a systematic review and meta-analysis. AB - BACKGROUND: Guidelines recommend intensive blood pressure (BP) lowering in patients at high risk. While placebo-controlled trials have demonstrated 22% reductions in coronary heart disease (CHD) and stroke associated with a 10-mmHg difference in systolic BP, it is unclear if more intensive BP lowering strategies are associated with greater reductions in risk of CHD and stroke. We did a systematic review to assess the effects of intensive BP lowering on vascular, eye, and renal outcomes. METHODS AND FINDINGS: We systematically searched Medline, Embase, and the Cochrane Library for trials published between 1950 and July 2011. We included trials that randomly assigned individuals to different target BP levels. We identified 15 trials including a total of 37,348 participants. On average there was a 7.5/4.5-mmHg BP difference. Intensive BP lowering achieved relative risk (RR) reductions of 11% for major cardiovascular events (95% CI 1%-21%), 13% for myocardial infarction (0%-25%), 24% for stroke (8%-37%), and 11% for end stage kidney disease (3%-18%). Intensive BP lowering regimens also produced a 10% reduction in the risk of albuminuria (4%-16%), and a trend towards benefit for retinopathy (19%, 0%-34%, p = 0.051) in patients with diabetes. There was no clear effect on cardiovascular or noncardiovascular death. Intensive BP lowering was well tolerated; with serious adverse events uncommon and not significantly increased, except for hypotension (RR 4.16, 95% CI 2.25 to 7.70), which occurred infrequently (0.4% per 100 person-years). CONCLUSIONS: Intensive BP lowering regimens provided greater vascular protection than standard regimens that was proportional to the achieved difference in systolic BP, but did not have any clear impact on the risk of death or serious adverse events. Further trials are required to more clearly define the risks and benefits of BP targets below those currently recommended, given the benefits suggested by the currently available data. PMID- 22927800 TI - The role of HIV-related stigma in utilization of skilled childbirth services in rural Kenya: a prospective mixed-methods study. AB - BACKGROUND: Childbirth with a skilled attendant is crucial for preventing maternal mortality and is an important opportunity for prevention of mother-to child transmission of HIV. The Maternity in Migori and AIDS Stigma Study (MAMAS Study) is a prospective mixed-methods investigation conducted in a high HIV prevalence area in rural Kenya, in which we examined the role of women's perceptions of HIV-related stigma during pregnancy in their subsequent utilization of maternity services. METHODS AND FINDINGS: From 2007-2009, 1,777 pregnant women with unknown HIV status completed an interviewer-administered questionnaire assessing their perceptions of HIV-related stigma before being offered HIV testing during their first antenatal care visit. After the visit, a sub-sample of women was selected for follow-up (all women who tested HIV-positive or were not tested for HIV, and a random sample of HIV-negative women, n = 598); 411 (69%) were located and completed another questionnaire postpartum. Additional qualitative in-depth interviews with community health workers, childbearing women, and family members (n = 48) aided our interpretation of the quantitative findings and highlighted ways in which HIV-related stigma may influence birth decisions. Qualitative data revealed that health facility birth is commonly viewed as most appropriate for women with pregnancy complications, such as HIV. Thus, women delivering at health facilities face the risk of being labeled as HIV positive in the community. Our quantitative data revealed that women with higher perceptions of HIV-related stigma (specifically those who held negative attitudes about persons living with HIV) at baseline were subsequently less likely to deliver in a health facility with a skilled attendant, even after adjusting for other known predictors of health facility delivery (adjusted odds ratio = 0.44, 95% CI 0.22-0.88). CONCLUSIONS: Our findings point to the urgent need for interventions to reduce HIV-related stigma, not only for improving quality of life among persons living with HIV, but also for better health outcomes among all childbearing women and their families. PMID- 22927801 TI - Diagnosing severe falciparum malaria in parasitaemic African children: a prospective evaluation of plasma PfHRP2 measurement. AB - BACKGROUND: In African children, distinguishing severe falciparum malaria from other severe febrile illnesses with coincidental Plasmodium falciparum parasitaemia is a major challenge. P. falciparum histidine-rich protein 2 (PfHRP2) is released by mature sequestered parasites and can be used to estimate the total parasite burden. We investigated the prognostic significance of plasma PfHRP2 and used it to estimate the malaria-attributable fraction in African children diagnosed with severe malaria. METHODS AND FINDINGS: Admission plasma PfHRP2 was measured prospectively in African children (from Mozambique, The Gambia, Kenya, Tanzania, Uganda, Rwanda, and the Democratic Republic of the Congo) aged 1 month to 15 years with severe febrile illness and a positive P. falciparum lactate dehydrogenase (pLDH)-based rapid test in a clinical trial comparing parenteral artesunate versus quinine (the AQUAMAT trial, ISRCTN 50258054). In 3,826 severely ill children, Plasmadium falciparum PfHRP2 was higher in patients with coma (p = 0.0209), acidosis (p<0.0001), and severe anaemia (p<0.0001). Admission geometric mean (95%CI) plasma PfHRP2 was 1,611 (1,350-1,922) ng/mL in fatal cases (n = 381) versus 1,046 (991-1,104) ng/mL in survivors (n = 3,445, p<0.0001), without differences in parasitaemia as assessed by microscopy. There was a U-shaped association between log(10) plasma PfHRP2 and risk of death. Mortality increased 20% per log(10) increase in PfHRP2 above 174 ng/mL (adjusted odds ratio [AOR] 1.21, 95%CI 1.05-1.39, p = 0.009). A mechanistic model assuming a PfHRP2-independent risk of death in non-malaria illness closely fitted the observed data and showed malaria-attributable mortality less than 50% with plasma PfHRP2<=174 ng/mL. The odds ratio (OR) for death in artesunate versus quinine-treated patients was 0.61 (95%CI 0.44-0.83, p = 0.0018) in the highest PfHRP2 tertile, whereas there was no difference in the lowest tertile (OR 1.05; 95%CI 0.69-1.61; p = 0.82). A limitation of the study is that some conclusions are drawn from a mechanistic model, which is inherently dependent on certain assumptions. However, a sensitivity analysis of the model indicated that the results were robust to a plausible range of parameter estimates. Further studies are needed to validate our findings. CONCLUSIONS: Plasma PfHRP2 has prognostic significance in African children with severe falciparum malaria and provides a tool to stratify the risk of "true" severe malaria-attributable disease as opposed to other severe illnesses in parasitaemic African children. PMID- 22927802 TI - Functional roles for synaptic-depression within a model of the fly antennal lobe. AB - Several experiments indicate that there exists substantial synaptic-depression at the synapses between olfactory receptor neurons (ORNs) and neurons within the drosophila antenna lobe (AL). This synaptic-depression may be partly caused by vesicle-depletion, and partly caused by presynaptic-inhibition due to the activity of inhibitory local neurons within the AL. While it has been proposed that this synaptic-depression contributes to the nonlinear relationship between ORN and projection neuron (PN) firing-rates, the precise functional role of synaptic-depression at the ORN synapses is not yet fully understood. In this paper we propose two hypotheses linking the information-coding properties of the fly AL with the network mechanisms responsible for ORN-->AL synaptic-depression. Our first hypothesis is related to variance coding of ORN firing-rate information -once stimulation to the ORNs is sufficiently high to saturate glomerular responses, further stimulation of the ORNs increases the regularity of PN spiking activity while maintaining PN firing-rates. The second hypothesis proposes a tradeoff between spike-time reliability and coding-capacity governed by the relative contribution of vesicle-depletion and presynaptic-inhibition to ORN-->AL synaptic-depression. Synaptic-depression caused primarily by vesicle-depletion will give rise to a very reliable system, whereas an equivalent amount of synaptic-depression caused primarily by presynaptic-inhibition will give rise to a less reliable system that is more sensitive to small shifts in odor stimulation. These two hypotheses are substantiated by several small analyzable toy models of the fly AL, as well as a more physiologically realistic large-scale computational model of the fly AL involving 5 glomerular channels. PMID- 22927803 TI - Modeling of gap gene expression in Drosophila Kruppel mutants. AB - The segmentation gene network in Drosophila embryo solves the fundamental problem of embryonic patterning: how to establish a periodic pattern of gene expression, which determines both the positions and the identities of body segments. The gap gene network constitutes the first zygotic regulatory tier in this process. Here we have applied the systems-level approach to investigate the regulatory effect of gap gene Kruppel (Kr) on segmentation gene expression. We acquired a large dataset on the expression of gap genes in Kr null mutants and demonstrated that the expression levels of these genes are significantly reduced in the second half of cycle 14A. To explain this novel biological result we applied the gene circuit method which extracts regulatory information from spatial gene expression data. Previous attempts to use this formalism to correctly and quantitatively reproduce gap gene expression in mutants for a trunk gap gene failed, therefore here we constructed a revised model and showed that it correctly reproduces the expression patterns of gap genes in Kr null mutants. We found that the remarkable alteration of gap gene expression patterns in Kr mutants can be explained by the dynamic decrease of activating effect of Cad on a target gene and exclusion of Kr gene from the complex network of gap gene interactions, that makes it possible for other interactions, in particular, between hb and gt, to come into effect. The successful modeling of the quantitative aspects of gap gene expression in mutant for the trunk gap gene Kr is a significant achievement of this work. This result also clearly indicates that the oversimplified representation of transcriptional regulation in the previous models is one of the reasons for unsuccessful attempts of mutant simulations. PMID- 22927804 TI - Prediction of mutational tolerance in HIV-1 protease and reverse transcriptase using flexible backbone protein design. AB - Predicting which mutations proteins tolerate while maintaining their structure and function has important applications for modeling fundamental properties of proteins and their evolution; it also drives progress in protein design. Here we develop a computational model to predict the tolerated sequence space of HIV-1 protease reachable by single mutations. We assess the model by comparison to the observed variability in more than 50,000 HIV-1 protease sequences, one of the most comprehensive datasets on tolerated sequence space. We then extend the model to a second protein, reverse transcriptase. The model integrates multiple structural and functional constraints acting on a protein and uses ensembles of protein conformations. We find the model correctly captures a considerable fraction of protease and reverse-transcriptase mutational tolerance and shows comparable accuracy using either experimentally determined or computationally generated structural ensembles. Predictions of tolerated sequence space afforded by the model provide insights into stability-function tradeoffs in the emergence of resistance mutations and into strengths and limitations of the computational model. PMID- 22927805 TI - Defining the nature of thermal intermediate in 3 state folding proteins: apoflavodoxin, a study case. AB - The early stages of the thermal unfolding of apoflavodoxin have been determined by using atomistic multi microsecond-scale molecular dynamics (MD) simulations complemented with a variety of experimental techniques. Results strongly suggest that the intermediate is reached very early in the thermal unfolding process and that it has the properties of an "activated" form of the native state, where thermal fluctuations in the loops break loop-loop contacts. The unrestrained loops gain then kinetic energy corrupting short secondary structure elements without corrupting the core of the protein. The MD-derived ensembles agree with experimental observables and draw a picture of the intermediate state inconsistent with a well-defined structure and characteristic of a typical partially disordered protein. Our results allow us to speculate that proteins with a well packed core connected by long loops might behave as partially disordered proteins under native conditions, or alternatively behave as three state folders. Small details in the sequence, easily tunable by evolution, can yield to one or the other type of proteins. PMID- 22927806 TI - Diversity and noise effects in a model of homeostatic regulation of the sleep wake cycle. AB - Recent advances in sleep neurobiology have allowed development of physiologically based mathematical models of sleep regulation that account for the neuronal dynamics responsible for the regulation of sleep-wake cycles and allow detailed examination of the underlying mechanisms. Neuronal systems in general, and those involved in sleep regulation in particular, are noisy and heterogeneous by their nature. It has been shown in various systems that certain levels of noise and diversity can significantly improve signal encoding. However, these phenomena, especially the effects of diversity, are rarely considered in the models of sleep regulation. The present paper is focused on a neuron-based physiologically motivated model of sleep-wake cycles that proposes a novel mechanism of the homeostatic regulation of sleep based on the dynamics of a wake-promoting neuropeptide orexin. Here this model is generalized by the introduction of intrinsic diversity and noise in the orexin-producing neurons, in order to study the effect of their presence on the sleep-wake cycle. A simple quantitative measure of the quality of a sleep-wake cycle is introduced and used to systematically study the generalized model for different levels of noise and diversity. The model is shown to exhibit a clear diversity-induced resonance: that is, the best wake-sleep cycle turns out to correspond to an intermediate level of diversity at the synapses of the orexin-producing neurons. On the other hand, only a mild evidence of stochastic resonance is found, when the level of noise is varied. These results show that disorder, especially in the form of quenched diversity, can be a key-element for an efficient or optimal functioning of the homeostatic regulation of the sleep-wake cycle. Furthermore, this study provides an example of a constructive role of diversity in a neuronal system that can be extended beyond the system studied here. PMID- 22927807 TI - Evolutionary dynamics of strategic behavior in a collective-risk dilemma. AB - A collective-risk social dilemma arises when a group must cooperate to reach a common target in order to avoid the risk of collective loss while each individual is tempted to free-ride on the contributions of others. In contrast to the prisoners' dilemma or public goods games, the collective-risk dilemma encompasses the risk that all individuals lose everything. These characteristics have potential relevance for dangerous climate change and other risky social dilemmas. Cooperation is costly to the individual and it only benefits all individuals if the common target is reached. An individual thus invests without guarantee that the investment is worthwhile for anyone. If there are several subsequent stages of investment, it is not clear when individuals should contribute. For example, they could invest early, thereby signaling their willingness to cooperate in the future, constantly invest their fair share, or wait and compensate missing contributions. To investigate the strategic behavior in such situations, we have simulated the evolutionary dynamics of such collective-risk dilemmas in a finite population. Contributions depend individually on the stage of the game and on the sum of contributions made so far. Every individual takes part in many games and successful behaviors spread in the population. It turns out that constant contributors, such as constant fair sharers, quickly lose out against those who initially do not contribute, but compensate this in later stages of the game. In particular for high risks, such late contributors are favored. PMID- 22927808 TI - Model-free reconstruction of excitatory neuronal connectivity from calcium imaging signals. AB - A systematic assessment of global neural network connectivity through direct electrophysiological assays has remained technically infeasible, even in simpler systems like dissociated neuronal cultures. We introduce an improved algorithmic approach based on Transfer Entropy to reconstruct structural connectivity from network activity monitored through calcium imaging. We focus in this study on the inference of excitatory synaptic links. Based on information theory, our method requires no prior assumptions on the statistics of neuronal firing and neuronal connections. The performance of our algorithm is benchmarked on surrogate time series of calcium fluorescence generated by the simulated dynamics of a network with known ground-truth topology. We find that the functional network topology revealed by Transfer Entropy depends qualitatively on the time-dependent dynamic state of the network (bursting or non-bursting). Thus by conditioning with respect to the global mean activity, we improve the performance of our method. This allows us to focus the analysis to specific dynamical regimes of the network in which the inferred functional connectivity is shaped by monosynaptic excitatory connections, rather than by collective synchrony. Our method can discriminate between actual causal influences between neurons and spurious non causal correlations due to light scattering artifacts, which inherently affect the quality of fluorescence imaging. Compared to other reconstruction strategies such as cross-correlation or Granger Causality methods, our method based on improved Transfer Entropy is remarkably more accurate. In particular, it provides a good estimation of the excitatory network clustering coefficient, allowing for discrimination between weakly and strongly clustered topologies. Finally, we demonstrate the applicability of our method to analyses of real recordings of in vitro disinhibited cortical cultures where we suggest that excitatory connections are characterized by an elevated level of clustering compared to a random graph (although not extreme) and can be markedly non-local. PMID- 22927809 TI - Artificial neural networks trained to detect viral and phage structural proteins. AB - Phages play critical roles in the survival and pathogenicity of their hosts, via lysogenic conversion factors, and in nutrient redistribution, via cell lysis. Analyses of phage- and viral-encoded genes in environmental samples provide insights into the physiological impact of viruses on microbial communities and human health. However, phage ORFs are extremely diverse of which over 70% of them are dissimilar to any genes with annotated functions in GenBank. Better identification of viruses would also aid in better detection and diagnosis of disease, in vaccine development, and generally in better understanding the physiological potential of any environment. In contrast to enzymes, viral structural protein function can be much more challenging to detect from sequence data because of low sequence conservation, few known conserved catalytic sites or sequence domains, and relatively limited experimental data. We have designed a method of predicting phage structural protein sequences that uses Artificial Neural Networks (ANNs). First, we trained ANNs to classify viral structural proteins using amino acid frequency; these correctly classify a large fraction of test cases with a high degree of specificity and sensitivity. Subsequently, we added estimates of protein isoelectric points as a feature to ANNs that classify specialized families of proteins, namely major capsid and tail proteins. As expected, these more specialized ANNs are more accurate than the structural ANNs. To experimentally validate the ANN predictions, several ORFs with no significant similarities to known sequences that are ANN-predicted structural proteins were examined by transmission electron microscopy. Some of these self-assembled into structures strongly resembling virion structures. Thus, our ANNs are new tools for identifying phage and potential prophage structural proteins that are difficult or impossible to detect by other bioinformatic analysis. The networks will be valuable when sequence is available but in vitro propagation of the phage may not be practical or possible. PMID- 22927810 TI - Allosteric communication across the native and mutated KIT receptor tyrosine kinase. AB - A fundamental goal in cellular signaling is to understand allosteric communication, the process by which signals originated at one site in a protein propagate dependably to affect remote functional sites. Here, we describe the allosteric regulation of the receptor tyrosine kinase KIT. Our analysis evidenced that communication routes established between the activation loop (A-loop) and the distant juxtamembrane region (JMR) in the native protein were disrupted by the oncogenic mutation D816V positioned in the A-loop. In silico mutagenesis provided a plausible way of restoring the protein communication detected in the native KIT by introducing a counter-balancing second mutation D792E. The communication patterns observed in the native and mutated KIT correlate perfectly with the structural and dynamical features of these proteins. Particularly, a long-distance effect of the D816V mutation manifested as an important structural re-organization of the JMR in the oncogenic mutant was completely vanished in the double mutant D816V/D792E. This detailed characterization of the allosteric communication in the different forms of KIT, native and mutants, was performed by using a modular network representation composed of communication pathways and independent dynamic segments. Such representation permits to enrich a purely mechanistic interaction-based model of protein communication by the introduction of concerted local atomic fluctuations. This method, validated on KIT receptor, may guide a rational modulation of the physiopathological activities of other receptor tyrosine kinases. PMID- 22927811 TI - The regulation of ant colony foraging activity without spatial information. AB - Many dynamical networks, such as the ones that produce the collective behavior of social insects, operate without any central control, instead arising from local interactions among individuals. A well-studied example is the formation of recruitment trails in ant colonies, but many ant species do not use pheromone trails. We present a model of the regulation of foraging by harvester ant (Pogonomyrmex barbatus) colonies. This species forages for scattered seeds that one ant can retrieve on its own, so there is no need for spatial information such as pheromone trails that lead ants to specific locations. Previous work shows that colony foraging activity, the rate at which ants go out to search individually for seeds, is regulated in response to current food availability throughout the colony's foraging area. Ants use the rate of brief antennal contacts inside the nest between foragers returning with food and outgoing foragers available to leave the nest on the next foraging trip. Here we present a feedback-based algorithm that captures the main features of data from field experiments in which the rate of returning foragers was manipulated. The algorithm draws on our finding that the distribution of intervals between successive ants returning to the nest is a Poisson process. We fitted the parameter that estimates the effect of each returning forager on the rate at which outgoing foragers leave the nest. We found that correlations between observed rates of returning foragers and simulated rates of outgoing foragers, using our model, were similar to those in the data. Our simple stochastic model shows how the regulation of ant colony foraging can operate without spatial information, describing a process at the level of individual ants that predicts the overall foraging activity of the colony. PMID- 22927812 TI - Five mechanisms of manipulation by bacterial effectors: a ubiquitous theme. PMID- 22927813 TI - A novel virulence strategy for Pseudomonas aeruginosa mediated by an autotransporter with arginine-specific aminopeptidase activity. AB - The opportunistic human pathogen, Pseudomonas aeruginosa, is a major cause of infections in chronic wounds, burns and the lungs of cystic fibrosis patients. The P. aeruginosa genome encodes at least three proteins exhibiting the characteristic three domain structure of autotransporters, but much remains to be understood about the functions of these three proteins and their role in pathogenicity. Autotransporters are the largest family of secreted proteins in Gram-negative bacteria, and those characterised are virulence factors. Here, we demonstrate that the PA0328 autotransporter is a cell-surface tethered, arginine specific aminopeptidase, and have defined its active site by site directed mutagenesis. Hence, we have assigned PA0328 with the name AaaA, for arginine specific autotransporter of P. aeruginosa. We show that AaaA provides a fitness advantage in environments where the sole source of nitrogen is peptides with an aminoterminal arginine, and that this could be important for establishing an infection, as the lack of AaaA led to attenuation in a mouse chronic wound infection which correlated with lower levels of the cytokines TNFalpha, IL 1alpha, KC and COX-2. Consequently AaaA is an important virulence factor playing a significant role in the successful establishment of P. aeruginosa infections. PMID- 22927814 TI - The Irish potato famine pathogen Phytophthora infestans translocates the CRN8 kinase into host plant cells. AB - Phytopathogenic oomycetes, such as Phytophthora infestans, secrete an arsenal of effector proteins that modulate plant innate immunity to enable infection. We describe CRN8, a host-translocated effector of P. infestans that has kinase activity in planta. CRN8 is a modular protein of the CRN effector family. The C terminus of CRN8 localizes to the host nucleus and triggers cell death when the protein is expressed in planta. Cell death induction by CRN8 is dependent on its localization to the plant nucleus, which requires a functional nuclear localization signal (NLS). The C-terminal sequence of CRN8 has similarity to a serine/threonine RD kinase domain. We demonstrated that CRN8 is a functional RD kinase and that its auto-phosphorylation is dependent on an intact catalytic site. Co-immunoprecipitation experiments revealed that CRN8 forms a dimer or multimer. Heterologous expression of CRN8 in planta resulted in enhanced virulence by P. infestans. In contrast, in planta expression of the dominant negative CRN8(R469A;D470A) resulted in reduced P. infestans infection, further implicating CRN8 in virulence. Overall, our results indicate that similar to animal parasites, plant pathogens also translocate biochemically active kinase effectors inside host cells. PMID- 22927815 TI - A unique bivalent binding and inhibition mechanism by the yatapoxvirus interleukin 18 binding protein. AB - Interleukin 18 (IL18) is a cytokine that plays an important role in inflammation as well as host defense against microbes. Mammals encode a soluble inhibitor of IL18 termed IL18 binding protein (IL18BP) that modulates IL18 activity through a negative feedback mechanism. Many poxviruses encode homologous IL18BPs, which contribute to virulence. Previous structural and functional studies on IL18 and IL18BPs revealed an essential binding hot spot involving a lysine on IL18 and two aromatic residues on IL18BPs. The aromatic residues are conserved among the very diverse mammalian and poxviruses IL18BPs with the notable exception of yatapoxvirus IL18BPs, which lack a critical phenylalanine residue. To understand the mechanism by which yatapoxvirus IL18BPs neutralize IL18, we solved the crystal structure of the Yaba-Like Disease Virus (YLDV) IL18BP and IL18 complex at 1.75 A resolution. YLDV-IL18BP forms a disulfide bonded homo-dimer engaging IL18 in a 2?2 stoichiometry, in contrast to the 1?1 complex of ectromelia virus (ECTV) IL18BP and IL18. Disruption of the dimer interface resulted in a functional monomer, however with a 3-fold decrease in binding affinity. The overall architecture of the YLDV-IL18BP:IL18 complex is similar to that observed in the ECTV-IL18BP:IL18 complex, despite lacking the critical lysine phenylalanine interaction. Through structural and mutagenesis studies, contact residues that are unique to the YLDV-IL18BP:IL18 binding interface were identified, including Q67, P116 of YLDV-IL18BP and Y1, S105 and D110 of IL18. Overall, our studies show that YLDV-IL18BP is unique among the diverse family of mammalian and poxvirus IL-18BPs in that it uses a bivalent binding mode and a unique set of interacting residues for binding IL18. However, despite this extensive divergence, YLDV-IL18BP binds to the same surface of IL18 used by other IL18BPs, suggesting that all IL18BPs use a conserved inhibitory mechanism by blocking a putative receptor-binding site on IL18. PMID- 22927817 TI - Quantifying the diversification of hepatitis C virus (HCV) during primary infection: estimates of the in vivo mutation rate. AB - Hepatitis C virus (HCV) is present in the host with multiple variants generated by its error prone RNA-dependent RNA polymerase. Little is known about the initial viral diversification and the viral life cycle processes that influence diversity. We studied the diversification of HCV during acute infection in 17 plasma donors, with frequent sampling early in infection. To analyze these data, we developed a new stochastic model of the HCV life cycle. We found that the accumulation of mutations is surprisingly slow: at 30 days, the viral population on average is still 46% identical to its transmitted viral genome. Fitting the model to the sequence data, we estimate the median in vivo viral mutation rate is 2.5*10-5 mutations per nucleotide per genome replication (range 1.6-6.2*10-5), about 5-fold lower than previous estimates. To confirm these results we analyzed the frequency of stop codons (N = 10) among all possible non-sense mutation targets (M = 898,335), and found a mutation rate of 2.8-3.2*10-5, consistent with the estimate from the dynamical model. The slow accumulation of mutations is consistent with slow turnover of infected cells and replication complexes within infected cells. This slow turnover is also inferred from the viral load kinetics. Our estimated mutation rate, which is similar to that of other RNA viruses (e.g., HIV and influenza), is also compatible with the accumulation of substitutions seen in HCV at the population level. Our model identifies the relevant processes (long-lived cells and slow turnover of replication complexes) and parameters involved in determining the rate of HCV diversification. PMID- 22927818 TI - Surface alpha-1,3-glucan facilitates fungal stealth infection by interfering with innate immunity in plants. AB - Plants evoke innate immunity against microbial challenges upon recognition of pathogen-associated molecular patterns (PAMPs), such as fungal cell wall chitin. Nevertheless, pathogens may circumvent the host PAMP-triggered immunity. We previously reported that the ascomycete Magnaporthe oryzae, a famine-causing rice pathogen, masks cell wall surfaces with alpha-1,3-glucan during invasion. Here, we show that the surface alpha-1,3-glucan is indispensable for the successful infection of the fungus by interfering with the plant's defense mechanisms. The alpha-1,3-glucan synthase gene MgAGS1 was not essential for infectious structure development but was required for infection in M. oryzae. Lack or degradation of surface alpha-1,3-glucan increased fungal susceptibility towards chitinase, suggesting the protective role of alpha-1,3-glucan against plants' antifungal enzymes during infection. Furthermore, rice plants secreting bacterial alpha-1,3 glucanase (AGL-rice) showed strong resistance not only to M. oryzae but also to the phylogenetically distant ascomycete Cochlioborus miyabeanus and the polyphagous basidiomycete Rhizoctonia solani; the histocytochemical analysis of the latter two revealed that alpha-1,3-glucan also concealed cell wall chitin in an infection-specific manner. Treatment with alpha-1,3-glucanase in vitro caused fragmentation of infectious hyphae in R. solani but not in M. oryzae or C. miyabeanus, indicating that alpha-1,3-glucan is also involved in maintaining infectious structures in some fungi. Importantly, rapid defense responses were evoked (a few hours after inoculation) in the AGL-rice inoculated with M. oryzae, C. miyabeanus and R. solani as well as in non-transgenic rice inoculated with the ags1 mutant. Taken together, our results suggest that alpha-1,3-glucan protected the fungal cell wall from degradative enzymes secreted by plants even from the pre-penetration stage and interfered with the release of PAMPs to delay innate immune defense responses. Because alpha-1,3-glucan is nondegradable in plants, it is reasonable that many fungal plant pathogens utilize alpha-1,3-glucan in the innate immune evasion mechanism and some in maintaining the structures. PMID- 22927816 TI - Elucidation of hepatitis C virus transmission and early diversification by single genome sequencing. AB - A precise molecular identification of transmitted hepatitis C virus (HCV) genomes could illuminate key aspects of transmission biology, immunopathogenesis and natural history. We used single genome sequencing of 2,922 half or quarter genomes from plasma viral RNA to identify transmitted/founder (T/F) viruses in 17 subjects with acute community-acquired HCV infection. Sequences from 13 of 17 acute subjects, but none of 14 chronic controls, exhibited one or more discrete low diversity viral lineages. Sequences within each lineage generally revealed a star-like phylogeny of mutations that coalesced to unambiguous T/F viral genomes. Numbers of transmitted viruses leading to productive clinical infection were estimated to range from 1 to 37 or more (median = 4). Four acutely infected subjects showed a distinctly different pattern of virus diversity that deviated from a star-like phylogeny. In these cases, empirical analysis and mathematical modeling suggested high multiplicity virus transmission from individuals who themselves were acutely infected or had experienced a virus population bottleneck due to antiviral drug therapy. These results provide new quantitative and qualitative insights into HCV transmission, revealing for the first time virus host interactions that successful vaccines or treatment interventions will need to overcome. Our findings further suggest a novel experimental strategy for identifying full-length T/F genomes for proteome-wide analyses of HCV biology and adaptation to antiviral drug or immune pressures. PMID- 22927819 TI - Upregulation of retinal dehydrogenase 2 in alternatively activated macrophages during retinoid-dependent type-2 immunity to helminth infection in mice. AB - Although the vitamin A metabolite retinoic acid (RA) plays a critical role in immune function, RA synthesis during infection is poorly understood. Here, we show that retinal dehydrogenases (Raldh), required for the synthesis of RA, are induced during a retinoid-dependent type-2 immune response elicited by Schistosoma mansoni infection, but not during a retinoid-independent anti-viral immune response. Vitamin A deficient mice have a selective defect in T(H)2 responses to S. mansoni, but retained normal LCMV specific T(H)1 responses. A combination of in situ imaging, intra-vital imaging, and sort purification revealed that alternatively activated macrophages (AAMphi) express high levels of Raldh2 during S. mansoni infection. IL-4 induces Raldh2 expression in bone marrow derived macrophages in vitro and peritoneal macrophages in vivo. Finally, in vivo derived AAMphi have an enhanced capacity to induce Foxp3 expression in CD4+ cells through an RA dependent mechanism, especially in combination with TGF-beta. The regulation of Raldh enzymes during infection is pathogen specific and reflects differential requirements for RA during effector responses. Specifically, AAMphi are an inducible source of RA synthesis during helminth infections and T(H)2 responses that may be important in regulating immune responses. PMID- 22927820 TI - Ago HITS-CLIP expands understanding of Kaposi's sarcoma-associated herpesvirus miRNA function in primary effusion lymphomas. AB - KSHV is the etiological agent of Kaposi's sarcoma (KS), primary effusion lymphoma (PEL), and a subset of multicentricCastleman's disease (MCD). The fact that KSHV encoded miRNAs are readily detectable in all KSHV-associated tumors suggests a potential role in viral pathogenesis and tumorigenesis. MiRNA-mediated regulation of gene expression is a complex network with each miRNA having many potential targets, and to date only few KSHV miRNA targets have been experimentally determined. A detailed understanding of KSHV miRNA functions requires high through putribonomics to globally analyze putative miRNA targets in a cell type specific manner. We performed Ago HITS-CLIP to identify viral and cellular miRNAs and their cognate targets in two latently KSHV-infected PEL cell lines. Ago HITS CLIP recovered 1170 and 950 cellular KSHV miRNA targets from BCBL-1 and BC-3, respectively. Importantly, enriched clusters contained KSHV miRNA seed matches in the 3'UTRs of numerous well characterized targets, among them THBS1, BACH1, and C/EBPbeta. KSHV miRNA targets were strongly enriched for genes involved in multiple pathways central for KSHV biology, such as apoptosis, cell cycle regulation, lymphocyte proliferation, and immune evasion, thus further supporting a role in KSHV pathogenesis and potentially tumorigenesis. A limited number of viral transcripts were also enriched by HITS-CLIP including vIL-6 expressed only in a subset of PEL cells during latency. Interestingly, Ago HITS-CLIP revealed extremely high levels of Ago-associated KSHV miRNAs especially in BC-3 cells where more than 70% of all miRNAs are of viral origin. This suggests that in addition to seed match-specific targeting of cellular genes, KSHV miRNAs may also function by hijacking RISCs, thereby contributing to a global de-repression of cellular gene expression due to the loss of regulation by human miRNAs. In summary, we provide an extensive list of cellular and viral miRNA targets representing an important resource to decipher KSHV miRNA function. PMID- 22927821 TI - Protease cleavage leads to formation of mature trimer interface in HIV-1 capsid. AB - During retrovirus particle maturation, the assembled Gag polyprotein is cleaved by the viral protease into matrix (MA), capsid (CA), and nucleocapsid (NC) proteins. To form the mature viral capsid, CA rearranges, resulting in a lattice composed of hexameric and pentameric CA units. Recent structural studies of assembled HIV-1 CA revealed several inter-subunit interfaces in the capsid lattice, including a three-fold interhexamer interface that is critical for proper capsid stability. Although a general architecture of immature particles has been provided by cryo-electron tomographic studies, the structural details of the immature particle and the maturation pathway remain unknown. Here, we used cryo-electron microscopy (cryoEM) to determine the structure of tubular assemblies of the HIV-1 CA-SP1-NC protein. Relative to the mature assembled CA structure, we observed a marked conformational difference in the position of the CA-CTD relative to the NTD in the CA-SP1-NC assembly, involving the flexible hinge connecting the two domains. This difference was verified via engineered disulfide crosslinking, revealing that inter-hexamer contacts, in particular those at the pseudo three-fold axis, are altered in the CA-SP1-NC assemblies compared to the CA assemblies. Results from crosslinking analyses of mature and immature HIV-1 particles containing the same Cys substitutions in the Gag protein are consistent with these findings. We further show that cleavage of preassembled CA-SP1-NC by HIV-1 protease in vitro leads to release of SP1 and NC without disassembly of the lattice. Collectively, our results indicate that the proteolytic cleavage of Gag leads to a structural reorganization of the polypeptide and creates the three-fold interhexamer interface, important for the formation of infectious HIV-1 particles. PMID- 22927822 TI - Abc3-mediated efflux of an endogenous digoxin-like steroidal glycoside by Magnaporthe oryzae is necessary for host invasion during blast disease. AB - Magnaporthe oryzae, which causes the devastating rice-blast disease, invades its host plants via a specialized infection structure called the appressorium. Previously, we showed that the ATP-Binding Cassette 3 transporter is necessary for appressorial function (host penetration) in M. oryzae. However, thus far, the molecular basis underlying impaired appressorial function in the abc3Delta remains elusive. We hypothesized that the abc3Delta appressoria accumulate excessive amounts of specific efflux substrate(s) of the Abc3 transporter in M. oryzae. We devised an innovative yeast-based strategy and identified Abc3 Transporter efflux Substrate (ATS) to be a digoxin-like endogenous steroidal glycoside that accumulates to inhibitory levels in M. oryzae abc3Delta appressoria. Exogenous ATS altered cell wall biogenesis and viability in wild type Schizosaccharomyces pombe, but not in S. pombe expressing M. oryzae Abc3. We show that ATS associates with the Translation Elongation factor Tef2 in M. oryzae, and propose that ATS regulates ion homeostasis during pathogenesis. Excessive ATS accumulation, either intracellularly due to impaired efflux in the abc3Delta or when added exogenously to the wild type, renders M. oryzae nonpathogenic. Furthermore, we demonstrate that the host penetration defects in the abc3Delta are due to aberrant F-actin dynamics as a result of altered Tef2 function and/or ion homeostasis defects caused by excess accumulation of ATS therein. Rather surprisingly, excessive exogenous ATS or digoxin elicited the hypersensitive response in rice, even in the absence of the blast fungus. Lastly, reduced disease symptoms in the inoculated host plants in the presence of excessive digoxin suggest a potential use for such related steroidal glycosides in controlling rice-blast disease. PMID- 22927824 TI - A quantitative comparison of the similarity between genes and geography in worldwide human populations. AB - Multivariate statistical techniques such as principal components analysis (PCA) and multidimensional scaling (MDS) have been widely used to summarize the structure of human genetic variation, often in easily visualized two-dimensional maps. Many recent studies have reported similarity between geographic maps of population locations and MDS or PCA maps of genetic variation inferred from single-nucleotide polymorphisms (SNPs). However, this similarity has been evident primarily in a qualitative sense; and, because different multivariate techniques and marker sets have been used in different studies, it has not been possible to formally compare genetic variation datasets in terms of their levels of similarity with geography. In this study, using genome-wide SNP data from 128 populations worldwide, we perform a systematic analysis to quantitatively evaluate the similarity of genes and geography in different geographic regions. For each of a series of regions, we apply a Procrustes analysis approach to find an optimal transformation that maximizes the similarity between PCA maps of genetic variation and geographic maps of population locations. We consider examples in Europe, Sub-Saharan Africa, Asia, East Asia, and Central/South Asia, as well as in a worldwide sample, finding that significant similarity between genes and geography exists in general at different geographic levels. The similarity is highest in our examples for Asia and, once highly distinctive populations have been removed, Sub-Saharan Africa. Our results provide a quantitative assessment of the geographic structure of human genetic variation worldwide, supporting the view that geography plays a strong role in giving rise to human population structure. PMID- 22927823 TI - ADCC develops over time during persistent infection with live-attenuated SIV and is associated with complete protection against SIV(mac)251 challenge. AB - Live-attenuated strains of simian immunodeficiency virus (SIV) routinely confer apparent sterilizing immunity against pathogenic SIV challenge in rhesus macaques. Understanding the mechanisms of protection by live-attenuated SIV may provide important insights into the immune responses needed for protection against HIV-1. Here we investigated the development of antibodies that are functional against neutralization-resistant SIV challenge strains, and tested the hypothesis that these antibodies are associated with protection. In the absence of detectable neutralizing antibodies, Env-specific antibody-dependent cell mediated cytotoxicity (ADCC) emerged by three weeks after inoculation with SIVDeltanef, increased progressively over time, and was proportional to SIVDeltanef replication. Persistent infection with SIVDeltanef elicited significantly higher ADCC titers than immunization with a non-persistent SIV strain that is limited to a single cycle of infection. ADCC titers were higher against viruses matched to the vaccine strain in Env, but were measurable against viruses expressing heterologous Env proteins. In two separate experiments, which took advantage of either the strain-specificity or the time-dependent maturation of immunity to overcome complete protection against SIV(mac)251 challenge, measures of ADCC activity were higher among the SIVDeltanef-inoculated macaques that remained uninfected than among those that became infected. These observations show that features of the antibody response elicited by SIVDeltanef are consistent with hallmarks of protection by live-attenuated SIV, and reveal an association between Env-specific antibodies that direct ADCC and apparent sterilizing protection by SIVDeltanef. PMID- 22927825 TI - SLX-1 is required for maintaining genomic integrity and promoting meiotic noncrossovers in the Caenorhabditis elegans germline. AB - Although the SLX4 complex, which includes structure-specific nucleases such as XPF, MUS81, and SLX1, plays important roles in the repair of several kinds of DNA damage, the function of SLX1 in the germline remains unknown. Here we characterized the endonuclease activities of the Caenorhabditis elegans SLX-1-HIM 18/SLX-4 complex co-purified from human 293T cells and determined SLX-1 germline function via analysis of slx-1(tm2644) mutants. SLX-1 shows a HIM-18/SLX-4 dependent endonuclease activity toward replication forks, 5'-flaps, and Holliday junctions. slx-1 mutants exhibit hypersensitivity to UV, nitrogen mustard, and camptothecin, but not gamma irradiation. Consistent with a role in DNA repair, recombination intermediates accumulate in both mitotic and meiotic germ cells in slx-1 mutants. Importantly, meiotic crossover distribution, but not crossover frequency, is altered on chromosomes in slx-1 mutants compared to wild type. This alteration is not due to changes in either the levels or distribution of double strand breaks (DSBs) along chromosomes. We propose that SLX-1 is required for repair at stalled or collapsed replication forks, interstrand crosslink repair, and nucleotide excision repair during mitosis. Moreover, we hypothesize that SLX 1 regulates the crossover landscape during meiosis by acting as a noncrossover promoting factor in a subset of DSBs. PMID- 22927826 TI - SCS3 and YFT2 link transcription of phospholipid biosynthetic genes to ER stress and the UPR. AB - The ability to store nutrients in lipid droplets (LDs) is an ancient function that provides the primary source of metabolic energy during periods of nutrient insufficiency and between meals. The Fat storage-Inducing Transmembrane (FIT) proteins are conserved ER-resident proteins that facilitate fat storage by partitioning energy-rich triglycerides into LDs. FIT2, the ancient ortholog of the FIT gene family first identified in mammals has two homologs in Saccharomyces cerevisiae (SCS3 and YFT2) and other fungi of the Saccharomycotina lineage. Despite the coevolution of these genes for more than 170 million years and their divergence from higher eukaryotes, SCS3, YFT2, and the human FIT2 gene retain some common functions: expression of the yeast genes in a human embryonic kidney cell line promotes LD formation, and expression of human FIT2 in yeast rescues the inositol auxotrophy and chemical and genetic phenotypes of strains lacking SCS3. To better understand the function of SCS3 and YFT2, we investigated the chemical sensitivities of strains deleted for either or both genes and identified synthetic genetic interactions against the viable yeast gene-deletion collection. We show that SCS3 and YFT2 have shared and unique functions that connect major biosynthetic processes critical for cell growth. These include lipid metabolism, vesicular trafficking, transcription of phospholipid biosynthetic genes, and protein synthesis. The genetic data indicate that optimal strain fitness requires a balance between phospholipid synthesis and protein synthesis and that deletion of SCS3 and YFT2 impacts a regulatory mechanism that coordinates these processes. Part of this mechanism involves a role for SCS3 in communicating changes in the ER (e.g. due to low inositol) to Opi1-regulated transcription of phospholipid biosynthetic genes. We conclude that SCS3 and YFT2 are required for normal ER membrane biosynthesis in response to perturbations in lipid metabolism and ER stress. PMID- 22927827 TI - SEMA3A, a gene involved in axonal pathfinding, is mutated in patients with Kallmann syndrome. AB - Kallmann syndrome (KS) associates congenital hypogonadism due to gonadotropin releasing hormone (GnRH) deficiency and anosmia. The genetics of KS involves various modes of transmission, including oligogenic inheritance. Here, we report that Nrp1(sema/sema) mutant mice that lack a functional semaphorin-binding domain in neuropilin-1, an obligatory coreceptor of semaphorin-3A, have a KS-like phenotype. Pathohistological analysis of these mice indeed showed abnormal development of the peripheral olfactory system and defective embryonic migration of the neuroendocrine GnRH cells to the basal forebrain, which results in increased mortality of newborn mice and reduced fertility in adults. We thus screened 386 KS patients for the presence of mutations in SEMA3A (by Sanger sequencing of all 17 coding exons and flanking splice sites) and identified nonsynonymous mutations in 24 patients, specifically, a frameshifting small deletion (D538fsX31) and seven different missense mutations (R66W, N153S, I400V, V435I, T688A, R730Q, R733H). All the mutations were found in heterozygous state. Seven mutations resulted in impaired secretion of semaphorin-3A by transfected COS-7 cells (D538fsX31, R66W, V435I) or reduced signaling activity of the secreted protein in the GN11 cell line derived from embryonic GnRH cells (N153S, I400V, T688A, R733H), which strongly suggests that these mutations have a pathogenic effect. Notably, mutations in other KS genes had already been identified, in heterozygous state, in five of these patients. Our findings indicate that semaphorin-3A signaling insufficiency contributes to the pathogenesis of KS and further substantiate the oligogenic pattern of inheritance in this developmental disorder. PMID- 22927828 TI - Polysome profiling in liver identifies dynamic regulation of endoplasmic reticulum translatome by obesity and fasting. AB - Obesity-associated metabolic complications are generally considered to emerge from abnormalities in carbohydrate and lipid metabolism, whereas the status of protein metabolism is not well studied. Here, we performed comparative polysome and associated transcriptional profiling analyses to study the dynamics and functional implications of endoplasmic reticulum (ER)-associated protein synthesis in the mouse liver under conditions of obesity and nutrient deprivation. We discovered that ER from livers of obese mice exhibits a general reduction in protein synthesis, and comprehensive analysis of polysome-bound transcripts revealed extensive down-regulation of protein synthesis machinery, mitochondrial components, and bile acid metabolism in the obese translatome. Nutrient availability also plays an important but distinct role in remodeling the hepatic ER translatome in lean and obese mice. Fasting in obese mice partially reversed the overall translatomic differences between lean and obese nonfasted controls, whereas fasting of the lean mice mimicked many of the translatomic changes induced by the development of obesity. The strongest examples of such regulations were the reduction in Cyp7b1 and Slco1a1, molecules involved in bile acid metabolism. Exogenous expression of either gene significantly lowered plasma glucose levels, improved hepatic steatosis, but also caused cholestasis, indicating the fine balance bile acids play in regulating metabolism and health. Together, our work defines dynamic regulation of the liver translatome by obesity and nutrient availability, and it identifies a novel role for bile acid metabolism in the pathogenesis of metabolic abnormalities associated with obesity. PMID- 22927829 TI - Retrovolution: HIV-driven evolution of cellular genes and improvement of anticancer drug activation. AB - In evolution strategies aimed at isolating molecules with new functions, screening for the desired phenotype is generally performed in vitro or in bacteria. When the final goal of the strategy is the modification of the human cell, the mutants selected with these preliminary screenings may fail to confer the desired phenotype, due to the complex networks that regulate gene expression in higher eukaryotes. We developed a system where, by mimicking successive infection cycles with HIV-1 derived vectors containing the gene target of the evolution in their genome, libraries of gene mutants are generated in the human cell, where they can be directly screened. As a proof of concept we created a library of mutants of the human deoxycytidine kinase (dCK) gene, involved in the activation of nucleoside analogues used in cancer treatment, with the aim of isolating a variant sensitizing cancer cells to the chemotherapy compound Gemcitabine, to be used in gene therapy for anti-cancer approaches or as a poorly immunogenic negative selection marker for cell transplantation approaches. We describe the isolation of a dCK mutant, G12, inducing a 300-fold sensitization to Gemcitabine in cells originally resistant to the prodrug (Messa 10K), an effect 60 times stronger than the one induced by the wt enzyme. The phenotype is observed in different tumour cell lines irrespective of the insertion site of the transgene and is due to a change in specificity of the mutated kinase in favour of the nucleoside analogue. The mutations characterizing G12 are distant from the active site of the enzyme and are unpredictable on a rational basis, fully validating the pragmatic approach followed. Besides the potential interest of the G12 dCK variant for therapeutic purposes, the methodology developed is of interest for a large panel of applications in biotechnology and basic research. PMID- 22927830 TI - Reprogramming of H3K27me3 is critical for acquisition of pluripotency from cultured Arabidopsis tissues. AB - In plants, multiple detached tissues are capable of forming a pluripotent cell mass, termed callus, when cultured on media containing appropriate plant hormones. Recent studies demonstrated that callus resembles the root-tip meristem, even if it is derived from aerial organs. This finding improves our understanding of the regeneration process of plant cells; however, the molecular mechanism that guides cells of different tissue types to form a callus still remains elusive. Here, we show that genome-wide reprogramming of histone H3 lysine 27 trimethylation (H3K27me3) is a critical step in the leaf-to-callus transition. The Polycomb Repressive Complex 2 (PRC2) is known to function in establishing H3K27me3. By analyzing callus formation of mutants corresponding to different histone modification pathways, we found that leaf blades and/or cotyledons of the PRC2 mutants curly leaf swinger (clf swn) and embryonic flower2 (emf2) were defective in callus formation. We identified the H3K27me3-covered loci in leaves and calli by a ChIP-chip assay, and we found that in the callus H3K27me3 levels decreased first at certain auxin-pathway genes. The levels were then increased at specific leaf genes but decreased at a number of root regulatory genes. Changes in H3K27me3 levels were negatively correlated with expression levels of the corresponding genes. One possible role of PRC2-mediated H3K27me3 in the leaf-to-callus transition might relate to elimination of leaf features by silencing leaf-regulatory genes, as most leaf-preferentially expressed regulatory genes could not be silenced in the leaf explants of clf swn. In contrast to the leaf explants, the root explants of both clf swn and emf2 formed calli normally, possibly because the root-to-callus transition bypasses the leaf gene silencing process. Furthermore, our data show that PRC2-mediated H3K27me3 and H3K27 demethylation act in parallel in the reprogramming of H3K27me3 during the leaf-to-callus transition, suggesting a general mechanism for cell fate transition in plants. PMID- 22927831 TI - Chemical genetics reveals a specific requirement for Cdk2 activity in the DNA damage response and identifies Nbs1 as a Cdk2 substrate in human cells. AB - The cyclin-dependent kinases (CDKs) that promote cell-cycle progression are targets for negative regulation by signals from damaged or unreplicated DNA, but also play active roles in response to DNA lesions. The requirement for activity in the face of DNA damage implies that there are mechanisms to insulate certain CDKs from checkpoint inhibition. It remains difficult, however, to assign precise functions to specific CDKs in protecting genomic integrity. In mammals, Cdk2 is active throughout S and G2 phases, but Cdk2 protein is dispensable for survival, owing to compensation by other CDKs. That plasticity obscured a requirement for Cdk2 activity in proliferation of human cells, which we uncovered by replacement of wild-type Cdk2 with a mutant version sensitized to inhibition by bulky adenine analogs. Here we show that transient, selective inhibition of analog-sensitive (AS) Cdk2 after exposure to ionizing radiation (IR) enhances cell-killing. In extracts supplemented with an ATP analog used preferentially by AS kinases, Cdk2(as) phosphorylated the Nijmegen Breakage Syndrome gene product Nbs1-a component of the conserved Mre11-Rad50-Nbs1 complex required for normal DNA damage repair and checkpoint signaling-dependent on a consensus CDK recognition site at Ser432. In vivo, selective inhibition of Cdk2 delayed and diminished Nbs1 Ser432 phosphorylation during S phase, and mutation of Ser432 to Ala or Asp increased IR-sensitivity. Therefore, by chemical genetics, we uncovered both a non-redundant requirement for Cdk2 activity in response to DNA damage and a specific target of Cdk2 within the DNA repair machinery. PMID- 22927832 TI - Persistence of inflammatory response to intense exercise in diabetic rats. AB - In this study we evaluated the onset and resolution of inflammation in control and streptozotocin-induced diabetic rats subjected to a single session of intense exercise. The following measurements were carried out prior to, immediately after, and 2 and 24 hours after exercise: plasma levels of proinflammatory cytokines (TNF-alpha, IL-1beta, IL-6, CINC-2alpha/beta, MIP-3alpha, and IL-6), immunoglobulins (IgA and IgM), acute phase proteins (CRP and C3), and creatine kinase (CK) activity. We also examined the occurrence of macrophage death by measurements of macrophages necrosis (loss of membrane integrity) and DNA fragmentation. An increase was observed in the concentration of IL-1beta (3.3 fold) and TNF-alpha (2.0-fold) and in the proportion of necrotic macrophages (4.5 fold) in diabetic rats 24 hours after exercise, while the control group showed basal measurements. Twenty-four hours after the exercise, serum CK activity was elevated in diabetic rats but not in control animals. We concluded that lesion and inflammations resulting from intense exercise were greater and lasted longer in diabetic animals than in nondiabetic control rats. PMID- 22927833 TI - The common C49620T polymorphism in the sulfonylurea receptor gene SUR1 (ABCC8) in patients with gestational diabetes and subsequent glucose metabolism abnormalities. AB - AIM: The aim of this study is to investigate the relationship between the common C49620T polymorphism in the sulfonylurea receptor (SUR1) gene and glucose metabolism, beta-cell secretory function and insulin resistance in women with a history of gestational diabetes (GDM). MATERIAL AND METHODS: Study group included 199 women, diagnosed GDM within the last 5-12 years and control group of comparable 50 women in whom GDM was excluded during pregnancy. Blood glucose and insulin levels were measured during oral glucose tolerance test. Indices of insulin resistance (HOMA-IR) and beta-cell function (HOMA %B) were calculated. In all patients, the C49620T polymorphism in intron 15 of the SUR1 gene was determined. RESULTS: The distribution of the studied polymorphism in the two groups did not differ from each other (chi(2) = 0.34, P = 0.8425). No association between the distribution of polymorphisms and coexisting glucose metabolism disorders (chi(2) = 7,13, P = 0, 3043) was found. No association was also observed between the polymorphism and HOMA %B or HOMA-IR. CONCLUSIONS: The polymorphism C49620T in the SUR1 gene is not associated with insulin resistance and/or insulin secretion in women with a history of GDM and does not affect the development of GDM, or the development of glucose intolerance in the studied population. PMID- 22927834 TI - Associations of existing diabetes, gestational diabetes, and glycosuria with offspring IQ and educational attainment: the Avon Longitudinal Study of Parents and Children. AB - INTRODUCTION: Results from studies examining associations of maternal diabetes in pregnancy with offspring cognitive outcomes have been inconclusive. METHODS: We used data from the Avon Longitudinal Study of Parents and Children, a UK prospective pregnancy cohort. Outcomes were School Entry Assessment (SEA) scores (age 4, N = 6, 032) and WISC-III IQ (age 8, N = 5, 282-5,307) and General Certificate of Secondary Education (GCSE) results (age 16, N = 7, 615). RESULTS: Existing diabetes, gestational diabetes, and, to a lesser extent, glycosuria were associated with lower offspring SEA scores (age 4), IQ (age 8), and GCSE results (age 16) even when adjusting for offspring sex, maternal age, prepregnancy BMI, smoking in pregnancy, parity, caesarean section, maternal education, and occupational social class. Offspring of mothers with existing diabetes had a threefold risk of achieving no GCSEs graded A*-C, whilst offspring of women with gestational diabetes had, on average, a five point lower IQ compared to offspring of women with no diabetes or glycosuria. CONCLUSIONS: Maternal diabetes in pregnancy is consistently associated with lower offspring cognition and educational attainment though confidence intervals were wide. The weaker associations with glycosuria suggest a dose-dependent adverse association with IQ. PMID- 22927835 TI - Cleansing formulations that respect skin barrier integrity. AB - Surfactants in skin cleansers interact with the skin in several manners. In addition to the desired benefit of providing skin hygiene, surfactants also extract skin components during cleansing and remain in the stratum corneum (SC) after rinsing. These side effects disrupt SC structure and degrade its barrier properties. Recent applications of vibrational spectroscopy and two-photon microscopy in skin research have provided molecular-level information to facilitate our understanding of the interaction between skin and surfactant. In the arena of commercial skin cleansers, technologies have been developed to produce cleansers that both cleanse and respect skin barrier. The main approach is to minimize surfactant interaction with skin through altering its solution properties. Recently, hydrophobically modified polymers (HMPs) have been introduced to create skin compatible cleansing systems. At the presence of HMP, surfactants assemble into larger, more stable structures. These structures are less likely to penetrate the skin, thereby resulting in less aggressive cleansers and the integrity of the skin barrier is maintained. In this paper, we reviewed our recent findings on surfactant and SC interactions at molecular level and provided an overview of the HM technology for developing cleansers that respect skin barrier. PMID- 22927836 TI - The effect of bifid triple viable on immune function of patients with ulcerative colitis. AB - Objective. To study effect and its mechanism of Bifid Triple Viable for initially treating ulcerative colitis with 5-aminosalicylic acid. Methods. 82 patients, who were firstly diagnosed as ulcerative colitis, were randomized into experiment group (41 cases, treated with Bifid Triple Viable and Etiasa) and control group (41 cases, treated with Etiasa). The clinic symptom score, colon mucosa inflammation score, and some immune indices were detected and compared between two groups before and two months after treatment. Results. Two months after treatment, the clinical symptom score, colon mucosa inflammation score, and IL 1beta expression in colon mucosa decreased significantly (P < 0.01), and IL-10 and IgA expressions in colon mucosa increased significantly (P < 0.01). Those differences were more marked in experiment group than control group (P < 0.05). However, peripheral blood T cell subgroup, immunoglobulins, and complements had no significant difference between two groups two months after treatment, but the ratio of peripheral blood CD4+ T cell to CD8+ T cell in experiment group increased more than that in control group (P < 0.05). Conclusion. Bifid Triple Viable contributed to Etiasa to treat ulcerative colitis in inducing remission period, which was perhaps related to affecting the patient's immune function. PMID- 22927837 TI - Usefulness of Background Coloration in Detection of Esophago-Pharyngeal Lesions Using NBI Magnification. AB - Background and Aim. We evaluated the usefulness of background coloration (BC), a color change in the area between intrapapillary capillary loops (IPCLs) in the early esophago-pharyngeal lesions using NBI with magnificaiton. Methods. Between April 2004 and March 2010, a total of 294 esophago-pharyngeal lesions were examined using NBI with magnification, and the presence of BC and IPCL patterns were assessed. Using BC, discrimination of squamous cell carcinoma (SCC) or high grade neoplasia (HGN) from low-grade neoplasia (LGN) or nonatypia was conducted. Results. Among 294 lesions, 209 lesions (71.1%) were positive for BC, while 85 (28.9%) were negative. In the BC-positive group, 187 lesions (89.5%) were diagnosed as SCC/HGN. And 68 lesions (80.0%) in the BC-negative group were diagnosed as LGN/nonatypia. Overall accuracy of BC to discriminate SCC/HGN from LGN/nonatypia was 87.3%. The sensitivity and specificity were 91.9%, 76.7%. BC could discriminate SCC/HGN from LGN/nonatypia accurately (P < 0.0001). Among 68 lesions classified into the IPCL type IV, the BC-positive group (n = 26) included 21 SCC/HGN lesions, while there were 36 LGN/nonatypia lesions in the 42 BC negative lesions. Conclusions. BC is a useful finding in differentiating SCC/HGN from LGN/nonatypia lesions in the esophagus especially when it is combined with IPCL pattern classification. PMID- 22927838 TI - Pulmonary Complications following Cytoreductive Surgery and Perioperative Chemotherapy in 147 Consecutive Patients. AB - Cytoreductive surgery (CRS) with hyperthermic perioperative chemotherapy (HIPEC) has become a treatment option for selected patients with peritoneal metastases (PMs) from gastrointestinal malignancies. The purpose of this study is to evaluate our most recent data regarding pulmonary complications (respiratory distress, pleural effusion, and pneumonia) and attempt to identify risk factors associated with this management plan. This study includes the most recent 4-year experience with appendiceal and colorectal carcinomatosis patients treated in a uniform manner between January 1, 2006 and December 31, 2009. A prospective morbidity and mortality database was maintained and pulmonary adverse events were analyzed with special attention to subphrenic peritonectomy. There were 147 consecutive patients with a mean age of 49.9 years. Fourteen patients (10%) presented grades I-IV pulmonary complications for a total of 26 events. The peritonectomy of right upper quadrant was performed in 74% and right plus left in 49% of the patients. Statistically, there were no more pulmonary complications among patients submitted to peritoneal stripping of right or right and left hemidiaphragm as compared to no subdiaphragmatic peritonectomy (P = 1.00 and P = 0.58, resp.). In an analysis of 18 quantitative indicators and clinical variables with pulmonary adverse events, only blood replacement greater than six units showed a significant correlation (P = 0.0062). Pulmonary adverse events were observed in 10% of patients having CRS and HIPEC. Subphrenic peritonectomy was not a specific risk factor for developing these adverse events. PMID- 22927839 TI - Adjuvant bidirectional chemotherapy with intraperitoneal pemetrexed combined with intravenous Cisplatin for diffuse malignant peritoneal mesothelioma. AB - Cytoreductive surgery (CRS) with heated intraoperative intraperitoneal chemotherapy (HIPEC) has emerged as optimal treatment for diffuse malignant peritoneal mesothelioma (DMPM) showing median survivals of 36-92 months. However, recurrences occur frequently even in patients undergoing optimal cytreduction and are often confined to the abdomen. We initiated a Phase II study of adjuvant intraperitoneal pemetrexed combined with intravenous cisplatin for patients undergoing CRS and HIPEC for DMPM. The treatment consisted of pemetrexed 500 mg/m(2) intraperitoneally and cisplatin 50 mg/m(2) intravenously given simultaneously on day 1 of every 21 day cycle for 6 cycles. The primary endpoint of the study was treatment related toxicity. From July 2007 until July 2009 ten patients were enrolled. Nine of 10 completed all 6 cycles of adjuvant treatment per protocol. The most common toxicities were fatigue, nausea and abdominal pain grade 1 or 2. There was one grade 3 toxicity consisting of a catheter infection. The median survival for all 10 patients was 33.5 months. Pharmacokinetic analysis of intraperitoneal pemetrexed showed a peritoneal to plasma area under the curve ratio of 70. Our study shows that adjuvant intravenous cisplatin and intraperitoneal pemetrexed can be used following CRS and HIPEC for DMPM with low morbidity. PMID- 22927840 TI - Molecular Mechanisms Underlying Anti-Inflammatory Actions of 6 (Methylsulfinyl)hexyl Isothiocyanate Derived from Wasabi (Wasabia japonica). AB - 6-(Methylsulfinyl)hexyl isothiocyanate (6-MSITC) is a major bioactive compound in wasabi (Wasabia japonica), which is a typical Japanese pungent spice. Recently, in vivo and in vitro studies demonstrated that 6-MSITC has several biological properties, including anti-inflammatory, antimicrobial, antiplatelet, and anticancer effects. We previously reported that 6-MSITC strongly suppresses cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), and cytokines, which are important factors that mediate inflammatory processes. Moreover, molecular analysis demonstrated that 6-MSITC blocks the expressions of these factors by suppressing multiple signal transduction pathways to attenuate the activation of transcriptional factors. Structure-activity relationships of 6 MSITC and its analogues containing an isothiocyanate group revealed that methylsulfinyl group and the length of alkyl chain of 6-MSITC might be related to high inhibitory potency. In this paper, we review the anti-inflammatory properties of 6-MSITC and discuss potential molecular mechanisms focusing on inflammatory responses by macrophages. PMID- 22927841 TI - Subarachnoid versus General Anesthesia in Penile Prosthetic Implantation: Outcomes Analyses. AB - The leading patient complaint during the perioperative period for penile prosthesis implantation is postoperative pain, while emesis and urticaria also affect the procedure's perceived success. In analyzing surgical outcomes, assessment of the anesthetic for postoperative pain and side effects should be included. This paper retrospectively reviews 90 consecutive, primary inflatable penile prosthetic operations performed by a single surgeon at one private medical center. Fifty-seven patients were included in final analysis. Patients who had more than one procedure that day or who used chronic pain medication were excluded. The type and amount of each drug used for each respective side effect (within the first 24 hours after procedure) were compared to determine relative benefit. Twenty patients received general anesthesia (denoted herein as "GA") and 37 received spinal (or also known as subarachnoid) anesthesia (denoted herein as "SA"). Patients receiving GA had significantly greater (P < 0.0001) occurrence and amount of intravenous pain treatment than those receiving SA. Patients with SA required less intravenous pain medication and less treatment for nausea/emesis. PMID- 22927842 TI - High-intensity focused ultrasound for prostate cancer: long-term followup and complications rate. AB - Introduction. As it is well known, High Intensity Focused Ultrasound (HIFU) is a minimally invasive procedure for prostate cancer. Many investigators reported their series of patients, demonstrating the effectiveness of the treatment. The most majority of Authors, however, do not report the side effects and the complications of the procedure, which is the aim of our study. The diagnosis and management of complications is discussed, and the oncologic outcome is reported in terms of quality of life. Materials and Methods. We report our experience in 89 patients, low-, intermediate-, and high-risk patients according with D'Amico classification. All data collected along the study were analyzed, including side effects and complications of the procedure. Results. Our series demonstrates the effectiveness of the procedure, in line with larger series reported in literature by other investigators. The most important side effects are sexual function impairment and transient incontinence in a minority of cases. Minor complications are reported as well as rare cases of major complications, which can require surgical treatment. PMID- 22927843 TI - Eye diseases and impaired vision as possible risk factors for recurrent falls in the aged: a systematic review. AB - Background. Recurrent falls are common among the aged. Vision is needed in maintaining balance, and impaired vision may be an intrinsic risk factor of recurrent falls. The aim was to perform a systematic review about the relationships between eye diseases or impaired vision and the risk of recurrent falls in the aged. Material and Methods. MEDLINE and CINAHL databases were searched in order to find longitudinal epidemiological studies about the associations between eye diseases or impaired vision and the risk of recurrent falls. Altogether 19 studies were found. A qualitative systematic analysis of these studies was performed. Results and Conclusions. The evidence about poor depth perception/stereoacuity and poor low-contrast visual acuity as risk factors of recurrent falls is quite convincing. Discrepant vision, a decrease in visual acuity, and loss of visual field may be risk factors, but more studies are needed. The results concerning the relationships between poor visual acuity and poor contrast sensitivity and the risk of recurrent falls are controversial. More studies about the relationships between different measures of vision and the risk of recurrent falls are needed before final conclusions about poor vision as a risk factor for recurrent falling can be done. PMID- 22927844 TI - Complement Attack against Aspergillus and Corresponding Evasion Mechanisms. AB - Invasive aspergillosis shows a high mortality rate particularly in immunocompromised patients. Perpetually increasing numbers of affected patients highlight the importance of a clearer understanding of interactions between innate immunity and fungi. Innate immunity is considered to be the most significant host defence against invasive fungal infections. Complement represents a crucial part of this first line defence and comprises direct effects against invading pathogens as well as bridging functions to other parts of the immune network. However, despite the potency of complement to attack foreign pathogens, the prevalence of invasive fungal infections is increasing. Two possible reasons may explain that phenomenon: First, complement activation might be insufficient for an effective antifungal defence in risk patients (due to, e.g., low complement levels, poor recognition of fungal surface, or missing interplay with other immune elements in immunocompromised patients). On the other hand, fungi may have developed evasion strategies to avoid recognition and/or eradication by complement. In this review, we summarize the most important interactions between Aspergillus and the complement system. We describe the various ways of complement activation by Aspergillus and the antifungal effects of the system, and also show proven and probable mechanisms of Aspergillus for complement evasion. PMID- 22927845 TI - Sentinel node mapping for breast cancer: current situation. AB - Axillary node status is a major prognostic factor in early-stage disease. Traditional staging needs levels I and II axillary lymph node dissection. Axillary involvement is found in 10%-30% of patients with T1 (<2 cm) tumours. Sentinel lymph node biopsy is a minimal invasive method of checking the potential nodal involvement. It is based on the assumption of an orderly progression of lymph node invasion by metastatic cells from tumour site. Thus, when sentinel node is free of metastases the remaining nodes are free, too (with a false negative rate lesser than 5%). Moreover, Randomized trials demonstrated a marked reduction of complications associated with the sentinel lymph node biopsy when compared with axillary lymph node dissection. Currently, the sentinel node biopsy procedure is recognized as the standard treatment for stages I and II. In these stages, this approach has a positive node rate similar to those observed after lymphadenectomy, a significant decrease in morbidity and similar nodal relapse rates at 5 years. In this review, the indications and contraindications of the sentinel node biopsy are summarized and the methodological aspects discussed. Finally, the new technologic and histologic developments allow to develop a more accurate and refinate technique that can achieve virtually the identification of 100% of sentinel nodes and reduce the false negative rate. PMID- 22927846 TI - Immune microenvironment in tumor progression: characteristics and challenges for therapy. AB - The tumor microenvironment plays a critical role in cancer development, progression, and control. The molecular and cellular nature of the tumor immune microenvironment influences disease outcome by altering the balance of suppressive versus cytotoxic responses in the vicinity of the tumor. Recent developments in systems biology have improved our understanding of the complex interactions between tumors and their immunological microenvironment in various human cancers. Effective tumor surveillance by the host immune system protects against disease, but chronic inflammation and tumor "immunoediting" have also been implicated in disease development and progression. Accordingly, reactivation and maintenance of appropriate antitumor responses within the tumor microenvironment correlate with a good prognosis in cancer patients. Improved understanding of the factors that shape the tumor microenvironment will be critical for the development of effective future strategies for disease management. The manipulation of these microenvironmental factors is already emerging as a promising tool for novel cancer treatments. In this paper, we summarize the various roles of the tumor microenvironment in cancer, focusing on immunological mediators of tumor progression and control, as well as the significant challenges for future therapies. PMID- 22927848 TI - Treatment Choices Based on OncotypeDx in the Breast Oncology Care Setting. AB - Introduction. This study aimed to evaluate whether OncotypeDx test results predict receipt of adjuvant chemotherapy in breast cancer patients who received an OncotypeDx recurrence score (RS). Materials and Methods. Pathology records were used to identify breast cancer patients who had OncotypeDx testing between December 2004 and January 2009 (n = 118). Patient sociodemographic information, tumor characteristics, RS, and treatment-specific data were collected via chart review. RS was classified as follows: low (RS <= 17), intermediate (RS = 18-30), or high (RS >= 31). Bivariate analyses were conducted to investigate the relationship between adjuvant chemotherapy receipt and each sociodemographic and clinical characteristic; significant sociodemographic and clinical variables were included in a multivariable logistic regression model. Results. In multivariable analysis controlling for tumor size, histologic grade, and nuclear grade, only RS remained significantly associated with chemotherapy uptake. Relative to low RS, an intermediate (adjusted odds ratio [AOR], 21.24; 95% confidence interval [CI], 3.62-237.52) or high (AOR, 15.07; 95% CI, 1.28-288.21) RS was associated with a greater odds of chemotherapy uptake. Discussion. Results indicate that RS was significantly associated with adjuvant chemotherapy uptake, suggesting that OncotypeDx results were used to inform treatment decision making, although it is unclear if and how the information was conveyed to patients. PMID- 22927849 TI - Associations between Intake of Folate, Methionine, and Vitamins B-12, B-6 and Prostate Cancer Risk in American Veterans. AB - Prostate cancer (PC) is the second leading cause of cancer death in men. Recent reports suggest that excess of nutrients involved in the one-carbon metabolism pathway increases PC risk; however, empirical data are lacking. Veteran American men (272 controls and 144 PC cases) who attended the Durham Veteran American Medical Center between 2004-2009 were enrolled into a case-control study. Intake of folate, vitamin B12, B6, and methionine were measured using a food frequency questionnaire. Regression models were used to evaluate the association among one carbon cycle nutrients, MTHFR genetic variants, and prostate cancer. Higher dietary methionine intake was associated with PC risk (OR = 2.1; 95%CI 1.1-3.9) The risk was most pronounced in men with Gleason sum <7 (OR = 2.75; 95%CI 1.32- 5.73). The association of higher methionine intake and PC risk was only apparent in men who carried at least one MTHFR A1298C allele (OR = 6.7; 95%CI = 1.6-27.8), compared to MTHFR A1298A noncarrier men (OR = 0.9; 95%CI = 0.24-3.92) (p interaction = 0.045). There was no evidence for associations between B vitamins (folate, B12, and B6) and PC risk. Our results suggest that carrying the MTHFR A1298C variants modifies the association between high methionine intake and PC risk. Larger studies are required to validate these findings. PMID- 22927850 TI - Association of active human herpesvirus-6, -7 and parvovirus b19 infection with clinical outcomes in patients with myalgic encephalomyelitis/chronic fatigue syndrome. AB - Frequency of active human herpesvirus-6, -7 (HHV-6, HHV-7) and parvovirus B19 (B19) infection/coinfection and its association with clinical course of ME/CFS was evaluated. 108 ME/CFS patients and 90 practically healthy persons were enrolled in the study. Viral genomic sequences were detected by PCR, virus specific antibodies and cytokine levels-by ELISA, HHV-6 variants-by restriction analysis. Active viral infection including concurrent infection was found in 64.8% (70/108) of patients and in 13.3% (12/90) of practically healthy persons. Increase in peripheral blood leukocyte DNA HHV-6 load as well as in proinflammatory cytokines' levels was detected in patients during active viral infection. Definite relationship was observed between active betaherpesvirus infection and subfebrility, lymphadenopathy and malaise after exertion, and between active B19 infection and multijoint pain. Neuropsychological disturbances were detected in all patients. The manifestation of symptoms was of more frequent occurrence in patients with concurrent infection. The high rate of active HHV-6, HHV-7 and B19 infection/coinfection with the simultaneous increase in plasma proinflammatory cytokines' level as well as the association between active viral infection and distinctive types of clinical symptoms shows necessity of simultaneous study of these viral infections for identification of possible subsets of ME/CFS. PMID- 22927847 TI - The insulin and igf-I pathway in endocrine glands carcinogenesis. AB - Endocrine cancers are a heterogeneous group of diseases that may arise from endocrine cells in any gland of the endocrine system. These malignancies may show an aggressive behavior and resistance to the common anticancer therapies. The etiopathogenesis of these tumors remains mostly unknown. The normal embryological development and differentiation of several endocrine glands are regulated by specific pituitary tropins, which, in adult life, control the function and trophism of the endocrine gland. Pituitary tropins act in concert with peptide growth factors, including the insulin-like growth factors (IGFs), which are considered key regulators of cell growth, proliferation, and apoptosis. While pituitary TSH is regarded as tumor-promoting factor for metastatic thyroid cancer, the role of other pituitary hormones in endocrine cancers is uncertain. However, multiple molecular abnormalities of the IGF system frequently occur in endocrine cancers and may have a role in tumorigenesis as well as in tumor progression and resistance to therapies. Herein, we will review studies indicating a role of IGF system dysregulation in endocrine cancers and will discuss the possible implications of these findings for tumor prevention and treatment, with a major focus on cancers from the thyroid, adrenal, and ovary, which are the most extensively studied. PMID- 22927852 TI - Monitoring Edentulism in Older New Zealand Adults over Two Decades: A Review and Commentary. AB - Historically, New Zealand has had the highest rates of edentulism in the world, but that rate has been falling quickly in recent decades. In 1997, projections were made for edentulism prevalence among 65-74-year-olds using national survey data from 1976 (where it was 72.3%) to 1988 (58.6%). That process assumed a logistic decline in edentulism, given that it would never have been 100% and will never get to 0%. This paper examines the validity of the projections using the estimate (29.6%) from the third national oral health survey, conducted in 2009 and considers the implications of this fall. PMID- 22927851 TI - Prevention and treatment of postoperative infections after sinus elevation surgery: clinical consensus and recommendations. AB - Introduction. Maxillary sinus surgery is a reliable and predictable treatment option for the prosthetic rehabilitation of the atrophic maxilla. Nevertheless, these interventions are not riskless of postoperative complications with respect to implant positioning in pristine bone. Aim. The aim of this paper is to report the results of a clinical consensus of experts (periodontists, implantologists, maxillofacial surgeons, ENT, and microbiology specialists) on several clinical questions and to give clinical recommendations on how to prevent, diagnose, and treat postoperative infections. Materials and Methods. A panel of experts in different fields of dentistry and medicine, after having reviewed the available literature on the topic and taking into account their long-standing clinical experience, gave their response to a series of clinical questions and reached a consensus. Results and Conclusion. The incidence of postop infections is relatively low (2%-5.6%). A multidisciplinary approach is advisable. A list of clinical recommendation are given. PMID- 22927853 TI - Melatonin: bone metabolism in oral cavity. AB - Throughout life, bone tissue undergoes a continuous process of resorption and formation. Melatonin, with its antioxidant properties and its ability to detoxify free radicals, as suggested by Conconi et al. (2000) may interfere in the osteoclast function and thereby inhibit bone resorption, as suggested by Schroeder et al. (1981). Inhibition of bone resorption may be enhanced by a reaction of indoleamine in osteoclastogenesis. That it has been observed melatonin, at pharmacological doses, decrease bone mass resorption by suppressing through down regulation of the RANK-L, as suggested by Penarrocha Diago et al. (2005) and Steflik et al. (1994). These data point an osteogenic effect towards that may be of melatonin of clinical importance, as it could be used as a therapeutic agent in situations in which would be advantageous bone formation, such as in the treatment of fractures or osteoporosis or their use as, a bioactive surface on implant as suggested by Lissoni et al. (1991). PMID- 22927854 TI - Dental pain in children with intellectual disabilities: caregivers' perspective. AB - Purpose. Description of pain is generally difficult in children, and more so in those with intellectual disabilities (ID). Aim. This study is aimed at evaluating dental pain from caregivers' perspective in children with ID. Methods. The study sampled 86 children (33 with ID, 53 normally developing) ages ranges from birth to 16 years old among those visiting the School of Dentistry, King Abdulaziz University, Saudi Arabia. Caregivers were asked about their awareness of dental pain in their wards using the Dental Discomfort Questionnaire (DDQ+). The children were examined for dental caries and periodontal status. Results. The mean DDQ+ in children with ID (4.55 +/- 3.46) was not significantly different from that in healthy children (4.19 +/- 3.26, P = 0.7). Children with ID had more salivation (P = 0.01) and were putting their hands inside their mouths more often (P = 0.003). Conclusions. Caregivers can recognize dental pain-related behaviors in children with ID such as excessive salivation and putting hands inside the mouth more often. PMID- 22927855 TI - Opinions on Dental Erosive Lesions, Knowledge of Diagnosis, and Treatment Strategies among Norwegian Dentists: A Questionnaire Survey. AB - This study aimed to investigate dentists' general experience, knowledge about diagnosis, and treatment of dental erosive wear in young adults. A questionnaire was sent to 1262 Norwegian public dental health-employed dentists. The response rate was 60%. Results indicated that most dentists recorded erosive wear, half of them used a specific scoring system, and half registered lesions at the tooth surface level. Lesions were reported most often on palatal surfaces of upper anterior teeth (79% of dentists), on occlusal surfaces of lower 1st molars (74%), and on upper 1st molars (32%). Half the dentists used clinical photographs for documentation and 60% made study models. While 40% reported more erosive lesions in males, 36% reported no gender differences. High intake of carbonated beverages and acidic juices were reported as the most common cause by 97% and 72% of the dentists, respectively. Only 21% of dentists recorded the patient's dietary history, and 73% never measured saliva secretion. The majority (78%) of the dentists treated patients with erosive wear themselves. In general, the survey suggests that the dentists are relatively up to date regarding the clinical recording, diagnosis, and treatment of dental erosive wear. However, dietary and salivary analyses were not given priority, and early, preventive treatment was lacking. PMID- 22927856 TI - Osteodifferentiation of human preadipocytes induced by strontium released from hydrogels. AB - In recent years, there has been an increasing interest in interactive application principles of biology and engineering for the development of valid biological systems for tissue regeneration, such as for the treatment of bone fractures or skeletal defects. The application of stem cells together with biomaterials releasing bioactive factors promotes the formation of bone tissue by inducing proliferation and/or cell differentiation. In this study, we used a clonal cell line from human adipose tissue-derived mesenchymal stem cells (hADSCs or preadipocytes), named PA2-E12, to evaluate the effects of strontium (Sr(2+)) released in the culture medium from an amidated carboxymethylcellulose (CMCA) hydrogel enriched with different Sr(2+) concentrations on osteodifferentiation. The osteoinductive effect was evaluated through both the expression of alkaline phophatase (ALP) activity and the hydroxyapatite (HA) production during 42 days of induction. Present data have shown that Sr(2+) released from CMCA promotes the osteodifferentiation induced by an osteogenic medium as shown by the increase of ALP activity at 7 and 14 days and of HA production at 14 days. In conclusion, the use of biomaterials able to release in situ osteoinductive agents, like Sr(2+), could represent a new strategy for future applications in bone tissue engineering. PMID- 22927858 TI - Aromatic Compound-Dependent Staphylococcus aureus Is Safe in a Nasal Colonization Leukopenic Murine Model. AB - Staphylococcus aureus nasal carriage is a risk factor for individuals suffering from trauma, surgical procedures, invasive devices, and/or decreased immunity. Recently, we demonstrated that artificial nasal colonization with an attenuated S. aureus mutant reduced by bacterial interference with the colonization of pathogenic strains of S. aureus. This could be an optional tool to diminish the rate of S. aureus infections in hospitalized patients. The aim of this study was to construct a safe DeltaaroA mutant of S. aureus and to discriminate it from nasal colonizing and osteomyelitis S. aureus isolates by SmaI pulsed-field gel electrophoresis (PFGE) typing. The DeltaaroA mutant, named RD17, exhibited an LD(50) (3.2 * 10(6) colony-forming unit (CFU)) significantly higher than that of the parental strain (2.2 * 10(3) CFU). The colony number of the RD17 mutants recovered from nares of leukopenic mice was similar to that observed in the animals of the control group. Therefore, the DeltaaroA mutant was demonstrated to be safe due to maintaining low growth levels in the nares regardless of immune status of the animals. PFGE typing allowed the unequivocal identification of the S. aureus and differentiation of aroA mutants in nasal colonizing and osteomyelitis isolates. This information could be important to discriminate endogenous infections from laboratory strains of S. aureus. PMID- 22927859 TI - Weight Gain and Hair Loss during Anti-TNF Therapy. AB - Objectives. To investigate the incidence of weight gain and hair loss as adverse effects of anti-TNF therapy in rheumatic diseases. Methods. Patients using anti TNF therapy, who are followed in rheumatology clinic, were interviewed using a questionnaire to investigate the side effects of anti-TNF therapy. Patients who complained of hair loss and weight gain were asked additional questions concerning the relationship of these adverse effects to anti-TNF use, whether therapy was stopped because of these adverse effects and if the adverse effects reversed after stopping therapy. The files were reviewed to follow the weight change before, during, and after discontinuation of anti-TNF. Results. One hundred fifty consecutive patients (82 RA, 34 ankylosing spondylitis, 32 psoriatic arthritis, and 4 for other indications) were interviewed .Weight gain was observed in 20 patients (13.3%) with average gain of 5.5 Kg. Anti-TNF was stopped in five patients because of this adverse effect. Hair loss during anti TNf therapy was reported in five females (3.3%) and anti-TNF therapy was stopped in all of them. Conclusion. Weight gain and hair loss appear to be associated with anti-TNF therapy and may be one reason for discontinuing the therapy. PMID- 22927860 TI - Bardet-Biedl Syndrome, Crohn Disease, Primary Sclerosing Cholangitis, and Autoantibody Positive Thyroiditis: A Case Report and A Review of a Cohort of BBS Patients. AB - Bardet-Biedel syndrome (BBS) is a rare autosomal recessive, genetically heterogeneous ciliopathy. Although the disease has been described in a patient with psoriasis, individuals with BBS are not known to be at risk of developing autoimmune disorders. Our objective was to describe a 14-year-old patient with BBS who presented with Crohn disease (CD), primary sclerosing cholangitis (PSC), and thyroiditis in the context of a cohort review at Sainte-Justine Hospital and to alert clinicians to the increased risk of autoimmune disorders in these patients. The cohort contained fifteen patients (9 boys), followed from 1968 to 2009 during a median period of 12 years (range 9 months-26 years). Three of the 15 patients (20%) developed a chronic autoimmune disease: one had juvenile rheumatoid arthritis; a second one had type 1 diabetes mellitus in association with Hashimoto thyroiditis and psoriasis; a third one developed CD, PSC, and Hashimoto thyroiditis. As chronic autoimmune diseases occurred in 20% of our cohort of children with BBS, it is appropriate to keep this association in mind during the followup. PMID- 22927857 TI - Established Principles and Emerging Concepts on the Interplay between Mitochondrial Physiology and S-(De)nitrosylation: Implications in Cancer and Neurodegeneration. AB - S-nitrosylation is a posttranslational modification of cysteine residues that has been frequently indicated as potential molecular mechanism governing cell response upon redox unbalance downstream of nitric oxide (over)production. In the last years, increased levels of S-nitrosothiols (SNOs) have been tightly associated with the onset of nitroxidative stress-based pathologies (e.g., cancer and neurodegeneration), conditions in which alterations of mitochondrial homeostasis and activation of cellular processes dependent on it have been reported as well. In this paper we aim at summarizing the current knowledge of mitochondria-related proteins undergoing S-nitrosylation and how this redox modification might impact on mitochondrial functions, whose impairment has been correlated to tumorigenesis and neuronal cell death. In particular, emphasis will be given to the possible, but still neglected implication of denitrosylation reactions in the modulation of mitochondrial SNOs and how they can affect mitochondrion-related cellular process, such as oxidative phosphorylation, mitochondrial dynamics, and mitophagy. PMID- 22927861 TI - An unusual localization of a pleomorphic adenoma in the rhinopharynx. AB - Pleomorphic adenoma is the most common benign tumor of the parotid glands. Rarely it may arise from minor salivary glands of the upper aerodigestive tract. A 57 year-old woman was admitted at our institution presenting with nasal obstruction. Endoscopic evaluation revealed a pedicled mass in the rhinopharynx. After radiological examination, we opted for a transnasal endoscopic-assisted excision of the mass under general anaesthesia. Histological evaluation deponed for pleomorphic adenoma with clear surgical margins. No endoscopic evidence of local recurrence has been shown after 48 months of followup. In the literature, few cases of pleomorphic adenoma arising in the rhinopharynx have been reported. The introduction of endoscopy, as shown by our experience, leads to important benefits in the identification, treatment, and followup of such rhinopharyngeal benign tumors. PMID- 22927863 TI - Silent intravascular lymphoma initially manifesting as a unilateral adrenal incidentaloma. AB - Intravascular large B-cell lymphoma (IVLBCL) is a rare subtype of malignant lymphoma. Although the involvement of adrenal glands in IVLBCL is often observed, primary adrenal IVLBCL is rare. Most reported cases of adrenal IVLBCL showed bilateral lesions resulting in rapidly progressive adrenal failure and poor prognosis. Here, we report a case of slowly progressive primary adrenal IVLBCL manifesting initially with unilateral adrenal incidentaloma. This case is a silent IVLBCL and shows that the enlargement of both adrenal glands can be followed. PMID- 22927862 TI - Williams-Beuren's Syndrome: A Case Report. AB - Williams-Beuren syndrome is a rare familial multisystem disorder occurring in 1 per 20,000 live births. It is characterized by congenital heart defects (CHD), skeletal and renal anomalies, cognitive disorder, social personality disorder and dysmorphic facies. We present a case of Williams syndrome that presented to us with heart murmur and cognitive problem. A 5-year-old girl referred to pediatric cardiologist because of heart murmurs. She had a systolic murmur (2-3/6) in right upper sternal border with radiation to right cervical region. She also had a bulge forehead. Angiography showed mild supra valvular aortic stenosis and mild multiple peripheral pulmonary stenosis. Fluorescent in situ hybridization (FISH) was performed and the result was: 46.XX, ish del (7q11.2) (ELN X1) (7q22 X2) ELN deletion compatible with Williams syndrome. Peripheral pulmonary artery stenosis is associated with Noonan syndrome, Alagille syndrome, Cutis laxa, Ehler-Danlos syndrome, and Silver-Russel syndrome. The patient had peripheral pulmonary artery stenosis, but no other signs of these syndromes were present, and also she had a supravalvular aortic stenosis which was not seen in other syndromes except Williams syndrome. Conclusion. According to primary symptoms, paraclinical and clinical finding such as dysmorphic facies, cognitive disorder and congenital heart defect, Williams syndrome was the first diagnosis. We suggest a more attention for evaluating heart murmur in childhood period, especially when the patient has abnormal facial features or mental problem. PMID- 22927864 TI - Highlights for the management of a child with hypertension. AB - Over the past several decades, childhood hypertension has undergone a considerable conceptual change, as hypertension is a predictor of future development of cardiovascular disease in adults. Childhood hypertension has distinctive features that distinguish it from hypertension in adults. Pediatric hypertension is often secondary. It is widely believed that therapeutic intervention at an early age favorably modifies the long-term outcome of hypertension. Despite its significance as a cause for morbidity, childhood hypertension is underdiagnosed and less studied with many basic issues remaining contentious. PMID- 22927865 TI - A systematic review of the clinimetric properties of habitual physical activity measures in young children with a motor disability. AB - Aim. To identify and systematically review the clinimetric properties of habitual physical activity (HPA) measures in young children with a motor disability. Method. Five databases were searched for measures of HPA including: children aged <6.0 years with a neuromuscular disorder, physical activity defined as "bodily movement produced by skeletal muscles causing caloric expenditure", reported HPA as duration, frequency, intensity, mode or energy expenditure, and evaluated clinimetric properties. The quality of papers was assessed using the COSMIN checklist. A targeted search of identified measures found additional studies of typically developing young children (TDC). Results. Seven papers assessing four activity monitors met inclusion criteria. Four studies were of good methodological quality. The Minimod had good ability to measure continuous walking but the demonstrated poor ability to measure steps during free-living activities. The Intelligent Device for Energy Expenditure and Activity and Ambulatory Monitoring Pod showed poor ability to measure activity during both continuous walking and free-living activities. The StepWatch showed good ability to measure steps during continuous walking in TDC. Interpretation. Studies assessing the clinimetric properties of measures of HPA in this population are urgently needed to allow assessment of the relationship between HPA and health outcomes in this group. PMID- 22927866 TI - Natural Peptides with Potential Applications in Drug Development, Diagnosis, and/or Biotechnology. PMID- 22927867 TI - Substance p regulates environmental tobacco smoke-enhanced tracheal smooth muscle responsiveness in mice. AB - Environmental tobacco smoke (ETS) is an environmental trigger that leads to airway inflammation and airway hyperresponsiveness (AHR) in susceptible individuals and animals, but the underlying mechanism is not fully understood. Substance P (SP) release from sensory nerve fibers has been linked to AHR. The present experiments characterize the role of SP in tracheal smooth muscle on ETS increased airway responses. The mice were exposed to either sidestream tobacco smoke (SS), a surrogate to ETS, or filtered air (FA) for 1 day or 5 consecutive days. Contractions of tracheal smooth muscle to SP and electrical field stimulation (EFS) were not significantly altered in 1 of day SS-exposed mice. However, 5 of days SS exposure significantly increased airway smooth muscle contractions to SP and EFS. Administration of CP-99994, an antagonist of the neurokinin (NK)1 receptor, attenuates the SS exposure-enhanced tracheal smooth muscle responses to EFS. Furthermore, the immunohistochemistry showed that SP nerve fibers were increased in tracheal smooth muscle after 5 of days SS exposure. These results suggest that the increased SP production may contribute to SS-enhanced smooth muscle responsiveness in mice trachea. PMID- 22927868 TI - Aspirin exacerbated respiratory disease. PMID- 22927869 TI - Aspirin sensitivity and chronic rhinosinusitis with polyps: a fatal combination. AB - Aspirin-exacerbated respiratory disease (AERD) refers to aspirin sensitivity, chronic rhinosinusitis (CRS), nasal polyposis, asthma, eosinophil inflammation in the upper and lower airways, urticaria, angioedema, and anaphylaxis following the ingestion of NSAIDs. Epidemiologic and pathophysiological links between these diseases are established. The precise pathogenesis remains less defined, even though there is some progress in the understanding of several molecular mechanisms. Nevertheless, these combinations of diseases in patients classified by AERD constitute a fatal combination and may be difficult to treat with standard medical and surgical interventions. This paper reviews in brief the epidemiology, clinical features, diagnosis, molecular pathogenesis, and specific therapies of patients classified by AERD and postulates future attempts to gain new insights into this disease. PMID- 22927870 TI - Trends in nutrition and exercise counseling among adolescents in the health care environment. AB - PURPOSE: Obesity is a serious health threat, particularly among racial/ethnic minorities and those who are uninsured, yet little is known about the implementation of nutrition or exercise counseling or the combination of both among these groups. Trends in counseling by race/ethnicity and types of insurance were examined. METHODS: Trend analyses were conducted with the California Health Interview Surveys among those ages 12-17 for the period 2003-2009. RESULTS: Race/Ethnicity: Receipt of both counseling methods declined from 2003-2009 for all racial/ethnic groups, except Hispanics and Whites, for whom increases in counseling began after 2007. Hispanics and African Americans generally reported higher levels of nutrition than exercise counseling, while Whites generally reported higher levels of exercise than nutrition counseling for the study period. INSURANCE TYPE: Receipt of both counseling methods appeared to decline from 2003-2009 among all insurance types, although after 2007, a slight increase was observed for the low-cost/free insurance group. Those with private health insurance generally received more exercise counseling than nutrition counseling over the study period. CONCLUSIONS: Counseling among all racial/ethnic groups and insurance types is warranted, but particularly needed for African Americans, American Indian/Alaska Natives, and the uninsured as they are at highest risk for developing obesity. Institutional and policy changes in the health care environment will be beneficial in helping to promote obesity-related counseling. PMID- 22927871 TI - The place of immunotherapy in the management of HCV-induced vasculitis: an update. AB - Patients with chronic hepatitis C virus (HCV) can develop systemic cryoglobulinemic vasculitis. Combination of pegylated-interferon alpha and ribavirin is the first-line treatment of this condition. However, in case of severe or life-threatening manifestations, absence of a virological response, or autonomized vasculitis, immunotherapy (alone or in addition to the antiviral regimen) is necessary. Rituximab is to date the only biologic with a sufficient level of evidence to support its use in this indication. Several studies have demonstrated that rituximab is highly effective when cryoglobulinaemic vasculitis is refractory to antiviral regimen, that association of rituximab with antiviral regimen may induce a better and faster clinical remission, and, recently, that rituximab is more efficient than traditional immunosuppressive treatments. Some issues with regard to the optimal dose of rituximab or its use as maintenance treatment remain unsolved. Interestingly, in balance with this anti-inflammatory strategy, a recent pilot study reported the significant expansion of circulating regulatory T lymphocytes with concomitant clinical improvement in patients with refractory HCV-induced cryoglobulinaemic vasculitis using low dose of subcutaneous interleukin-2. This paper provides an updated overview on the place of immunotherapy, especially biologics, in the management of HCV-induced cryoglobulinaemic vasculitis. PMID- 22927874 TI - Chinese medicine in diabetic peripheral neuropathy: experimental research on nerve repair and regeneration. AB - Diabetic peripheral neuropathy (DPN) is one of the most common complications of chronic diabetes mellitus. Pathological characteristics of DPN include axonal atrophy, nerve demyelination, and delayed regeneration of peripheral sensory nerve fibers. The goal of treatment in DPN is not only to ameliorate neurological symptoms but also to slow or reverse the underlying neurodegenerative process. Schwann cells and neurotrophic factors play important roles in the repair and regeneration of peripheral nerves. The present paper reviews current studies and evidence regarding the neurological effects of traditional Chinese medicine, with an emphasis on recent developments in the area of nerve repair and regeneration in DPN. PMID- 22927873 TI - Vaccination with enzymatically cleaved GPI-anchored proteins from Schistosoma mansoni induces protection against challenge infection. AB - The flatworm Schistosoma mansoni is a blood fluke parasite that causes schistosomiasis, a debilitating disease that occurs throughout the developing world. Current schistosomiasis control strategies are mainly based on chemotherapy, but many researchers believe that the best long-term strategy to control schistosomiasis is through immunization with an antischistosomiasis vaccine combined with drug treatment. In the search for potential vaccine candidates, numerous tegument antigens have been assessed. As the major interface between parasite and mammalian host, the tegument plays crucial roles in the establishment and further course of schistosomiasis. Herein, we evaluated the potential of a GPI fraction, containing representative molecules located on the outer surface of adult worms, as vaccine candidate. Immunization of mice with GPI anchored proteins induced a mixed Th1/Th2 type of immune response with production of IFN-gamma and TNF-alpha, and low levels of IL-5 into the supernatant of splenocyte cultures. The protection engendered by this vaccination protocol was confirmed by 42% reduction in worm burden, 45% reduction in eggs per gram of hepatic tissue, 29% reduction in the number of granulomas per area, and 53% reduction in the granuloma fibrosis. Taken together, the data herein support the potential of surface-exposed GPI-anchored antigens from the S. mansoni tegument as vaccine candidate. PMID- 22927875 TI - Enzyme Hydrolysates from Stichopus horrens as a New Source for Angiotensin Converting Enzyme Inhibitory Peptides. AB - Stichopus horrens flesh was explored as a potential source for generating peptides with angiotensin-converting enzyme (ACE) inhibitory capacity using 6 proteases, namely alcalase, flavourzyme, trypsin, papain, bromelain, and protamex. Degree of hydrolysis (DH) and peptide profiling (SDS-PAGE) of Stichopus horrens hydrolysates (SHHs) was also assessed. Alcalase hydrolysate showed the highest DH value (39.8%) followed by flavourzyme hydrolysate (32.7%). Overall, alcalase hydrolysate exhibited the highest ACE inhibitory activity (IC(50) value of 0.41 mg/mL) followed by flavourzyme hydrolysate (IC(50) value of 2.24 mg/mL), trypsin hydrolysate (IC(50) value of 2.28 mg/mL), papain hydrolysate (IC(50) value of 2.48 mg/mL), bromelain hydrolysate (IC(50) value of 4.21 mg/mL), and protamex hydrolysate (IC(50) value of 6.38 mg/mL). The SDS-PAGE results showed that alcalase hydrolysate represented a unique pattern compared to others, which yielded potent ACE inhibitory peptides with molecular weight distribution lower than 20 kDa. The evaluation of the relationship between DH and IC(50) values of alcalase and flavourzyme hydrolysates revealed that the trend between those parameters was related to the type of the protease used. We concluded that the tested SHHs would be used as a potential source of functional ACE inhibitory peptides for physiological benefits. PMID- 22927876 TI - Evidence-Based ZHENG: A Traditional Chinese Medicine Syndrome. PMID- 22927877 TI - The chinese herbal decoction danggui buxue tang inhibits angiogenesis in a rat model of liver fibrosis. AB - In this study, we investigated the anti-angiogenic effect of the Chinese herbal decoction Danggui Buxue Tang (DBT; Radix Astragali and Radix Angelicae sinensis in 5 : 1 ratio) in a rat model of liver fibrosis, in order to elucidate its mechanisms of action against liver fibrosis. Liver fibrosis was induced with CCl(4) and high-fat food for 6 weeks, and the rats were treated with oral doses of DBT (6 g raw herbs/kg/d) and N-Acetyl-L-cysteine (NAC; 0.1 g/kg/d). The results showed that both DBT and NAC attenuated liver fibrosis and neo angiogenesis. Furthermore, DBT and NAC improved SOD activity but decreased MDA content and 8-OH-dG in fibrotic livers, with DBT being more effective than NAC. DBT decreased the expression of VEGF, Ang1 and TGF-beta1 and their signaling mediators, whereas NAC had no effect on VEGF and VEGFR2 expression. Both DBT and NAC reduced HIF-1alpha gene and protein expression in fibrotic livers, with DBT being more effective. These data clearly demonstrate that the anti-fibrotic properties of DBT are related to its ability to inhibit angiogenesis and its anti angiogenic mechanisms are associated with improving oxidative stress, regulating the expression and signaling of angiogenic factors, and especially modulating HIF 1alpha in fibrotic livers. PMID- 22927872 TI - Role of immune escape mechanisms in Hodgkin's lymphoma development and progression: a whole new world with therapeutic implications. AB - Hodgkin's lymphoma represents one of the most frequent lymphoproliferative syndromes, especially in young population. Although HL is considered one of the most curable tumors, a sizeable fraction of patients recur after successful upfront treatment or, less commonly, are primarily resistant. This work tries to summarize the data on clinical, histological, pathological, and biological factors in HL, with special emphasis on the improvement of prognosis and their impact on therapeutical strategies. The recent advances in our understanding of HL biology and immunology show that infiltrated immune cells and cytokines in the tumoral microenvironment may play different functions that seem tightly related with clinical outcomes. Strategies aimed at interfering with the crosstalk between tumoral Reed-Sternberg cells and their cellular partners have been taken into account in the development of new immunotherapies that target different cell components of HL microenvironment. This new knowledge will probably translate into a change in the antineoplastic treatments in HL in the next future and hopefully will increase the curability rates of this disease. PMID- 22927878 TI - Furanodiene induces endoplasmic reticulum stress and presents antiproliferative activities in lung cancer cells. AB - Furanodiene (FUR) is a natural terpenoid isolated from Curcumae Rhizoma, a well known Chinese medicinal herb that presents antiproliferation activities in several cancer cell lines. In this study, we demonstrated that FUR concentration dependently inhibits the cell proliferation of A549, NIH-H1299, and 95-D lung cancer cells. beta-elemene, another terpenoid isolated from Curcumae Rhizoma, exhibited weaker antiproliferative effects in A549 and NIH-H1299 cells and activities similar to FUR in 95-D cells. FUR significantly inhibited colony formation in A549 and 95-D cells and upregulated both the mRNA and protein expression levels of binding immunoglobulin protein (BIP) and C/EBP homologous protein (CHOP), indicating that endoplasmic reticulum (ER) stress is induced. FUR treatment led to the accumulation of CHOP in the nucleus, which further confirms induction of ER stress. Furthermore, combined treatment of FUR with paclitaxel showed significant synergetic activities in NIH-H1299 and 95-D cells, suggesting its potential roles in combination therapy. These findings provide a basis for the further study of the anticancer effects in vivo and the internal mechanisms of FUR. PMID- 22927879 TI - The effects of virgin coconut oil on bone oxidative status in ovariectomised rat. AB - Virgin coconut oil (VCO) was found to have antioxidant property due to its high polyphenol content. The aim of this study was to investigate the effect of the virgin coconut oil on lipid peroxidation in the bone of an osteoporotic rat model. Normal female Sprague-Dawley rats aged 3 months old were randomly divided into 4 groups, with 8 rats in each group: baseline, sham, ovariectomised (OVX) control group, and OVX given 8% VCO in the diet for six weeks. The oxidative status of the bone was assessed by measuring the index of lipid peroxidation, which is malondialdehyde (MDA) concentration, as well as the endogenous antioxidant enzymes glutathione peroxidase (GPX) and superoxide dismutase (SOD) in the tibia at the end of the study. The results showed that there was a significant decrease in MDA levels in the OVX-VCO group compared to control group. Ovariectomised rats treated with VCO also had significantly higher GPX concentration. The SOD level seemed to be increased in the OVX-VCO group compared to OVX-control group. In conclusion, VCO prevented lipid peroxidation and increased the antioxidant enzymes in the osteoporotic rat model. PMID- 22927880 TI - Differential Association of Uncoupling Protein 2 Polymorphisms with Pattern Identification among Korean Stroke Patients: A Diagnostic System in Traditional Korean Medicine. AB - Uncoupling protein 2 (UCP2), a mitochondrial protein present in many organs and cell types, is known to dissipate the proton gradient formed by the electron transport chain. Its function is correlated with predictive parameters, such as obesity, diabetes, and metabolic syndromes. We analyzed the distribution of UCP2 polymorphisms in stroke patients diagnosed with one of the following four stroke subtypes based on the TKM standard pattern identification (PI): Qi-deficiency (QD), Dampness and Phlegm (D&P), Yin-deficiency (YD), and Fire and Heat (F&D). We studied a total of 1,786 stroke patients (397/QD, 645/D&P, 223/YD, and 522/F&D, 586/normal). Genotyping for the G-1957A, G-866A and A55V UCP2 polymorphisms was performed using the TaqMan. G-866A and A55V were significantly associated with the D&P and H&F subtypes. The frequency of subjects with the A allele of G-866A was significantly lower than the frequency of subjects with the GG type. The A55V polymorphism was also shown similar effect with G-866A in the dominant model. In contrast, no SNPs were shown to be associated with the QD or YD subtypes in this study. These results showed that the G-866A and A55V UCP2 polymorphisms may be genetic factors for specific PI types among Korean stroke patients. PMID- 22927882 TI - WNT10B Polymorphism in Korean Stroke Patients with Yin Deficiency Pattern. AB - WNT10B has been indicated as a potential regulator of adipogenesis in vivo and in vitro models of obesity. In this study, we analyzed the distribution of WNT10B polymorphism in elderly Korean subjects with cerebral infarction (CI) and Yin Deficiency pattern and Non-Yin Deficiency pattern. A total of 630 CI patients, including 75 with Yin Deficiency pattern and 555 with Non-Yin Deficiency pattern, participated in this study. SNP (G-607C) genotyping was conducted by primer extension using TaqMan probe; five percent of subjects were regenotyped by direct sequencing to confirm the accuracy of the genotyping. The results were analyzed using a multiple logistic regression model to evaluate the genetic association between the G-607C variant and Yin Deficiency pattern. The frequency of the CC genotype of G-607C in the Yin Deficiency pattern group (29.33%) was significantly higher than that in the Non-Yin Deficiency pattern group (23.96%) (P = 0.0339 , OR = 2.005 (1.054-3.814)) in a recessive model. This is the first study to demonstrate an association between a WNT10B polymorphism and the Yin Deficiency pattern of traditional Korean medicine (TKM) in a CI patient population. These results suggest that G-607C might be used as a diagnostic genetic marker for Yin Deficiency pattern in stroke patients and in the development of personalized medical care. PMID- 22927881 TI - Systematic review of yoga for pregnant women: current status and future directions. AB - Objectives. Yoga is used for a variety of immunological, neuromuscular, psychological, and pain conditions. Recent studies indicate that it may be effective in improving pregnancy, labour, and birth outcomes. The purpose of this paper is to evaluate the existing literature on yoga for pregnancy. Methods. Six databases were searched using the terms "yoga AND pregnancy" and "yoga AND [post natal OR post-partum]". Trials were considered if they were controlled and evaluated a yoga intervention. All studies were evaluated for methodological quality according to the Jadad scale and the Delphi List. Results. Six trials were identified: three were randomized controlled trials (RCTs) and three were controlled trials (CTs). The methodological quality and reporting ranged from 0-5 on the Jadad scale and from 3-6 on the Delphi List. Findings from the RCT studies indicate that yoga may produce improvements in stress levels, quality of life, aspects of interpersonal relating, autonomic nervous system functioning, and labour parameters such as comfort, pain, and duration. Conclusions. The findings suggest that yoga is well indicated for pregnant women and leads to improvements on a variety of pregnancy, labour, and birth outcomes. However, RCTs are needed to provide more information regarding the utility of yoga interventions for pregnancy. PMID- 22927883 TI - Endothelium-Dependent Vasorelaxant Effect of Butanolic Fraction from Caryocar brasiliense Camb. Leaves in Rat Thoracic Aorta. AB - Caryocar brasiliense Camb. "pequi" is a native plant from the Cerrado region of Brazil that contains bioactive components reported to be antioxidant agents. Previous work has demonstrated that dietary supplementation with pequi decreased the arterial pressure of volunteer athletes. We found that the crude hydroalcoholic extract (CHE) of C. brasiliense leaves relaxed, in a concentration dependent manner, rat aortic rings precontracted with phenylephrine, and that the butanolic fraction (BF) produced an effect similar to that of the CHE. Aortic relaxation induced by BF was abolished by endothelium removal, by incubation of the nitric oxide synthase inhibitor L-NAME, or the soluble guanylatecyclase inhibitor ODQ. However, incubation with atropine and pyrilamine had no effect on the BF-induced vasorelaxation. Moreover, this effect was not inhibited by indomethacin and tetraethylammonium. The concentration-response curve to calcium in denuded-endothelium rings was not modified after incubation with BF, and the vasorelaxation by BF in endothelium-intact rings precontracted with KCl was abolished after incubation with L-NAME. In addition, administration of BF in anesthetized rats resulted in a reversible hypotension. The results reveal that C. brasiliense possesses both in vivo and in vitro activities and that the vascular effect of BF involves stimulation of the nitric oxide/cyclic GMP pathway. PMID- 22927884 TI - Effects of tocotrienol and lovastatin combination on osteoblast and osteoclast activity in estrogen-deficient osteoporosis. AB - Statins are HMGCoA reductase inhibitors and had been demonstrated to stimulate bone formation in rodents after high oral doses. Observational studies on patients treated with oral statins were varied. Delta-tocotrienol had been found to stimulate the cleavage of HMGCoA reductase and inhibit its activity. Tocotrienols were found to have both catabolic and anabolic effects on bone in different animal models of osteoporosis. The current study aimed to ascertain the effects of delta-tocotrienol and lovastatin combination on biochemical and static bone histomorphometric parameters in a postmenopausal rat model at clinically tolerable doses. 48 Sprague Dawley female rats were randomly divided into 6 groups: (1) baseline control group; (2) sham-operated control group; (3) ovariectomised control group; (4) ovariectomised and 11 mg/kg lovastatin; (5) ovariectomised and 60 mg/kg delta-tocotrienol; (6) ovariectomised and 60 mg/kg delta-tocotrienol + 11 mg/kg lovastatin. These treatments were given daily via oral gavage for 8 weeks. Delta-tocotrienol plus lovastatin treatment significantly increased bone formation and reduced bone resorption compared to the other groups. Therefore, the combined treatment may have synergistic or additive effects and have the potential to be used as an antiosteoporotic agent in patients who are at risk of both osteoporosis and hypercholesterolemia, especially in postmenopausal women. PMID- 22927885 TI - Frequency of yoga practice predicts health: results of a national survey of yoga practitioners. AB - Background. Yoga shows promise as a therapeutic intervention, but relationships between yoga practice and health are underexplored. Purpose. To examine the relationship between yoga practice and health (subjective well-being, diet, BMI, smoking, alcohol/caffeine consumption, sleep, fatigue, social support, mindfulness, and physical activity). Methods. Cross-sectional, anonymous internet surveys distributed to 4307 randomly selected from 18,160 individuals at 15 US Iyengar yoga studios; 1045 (24.3%) surveys completed. Results. Mean age 51.7 (+/- 11.7) years; 84.2% female. Frequency of home practice favorably predicted (P < .001): mindfulness, subjective well-being, BMI, fruit and vegetable consumption, vegetarian status, sleep, and fatigue. Each component of yoga practice (different categories of physical poses, breath work, meditation, philosophy study) predicted at least 1 health outcome (P < .05). Conclusions. Home practice of yoga predicted health better than years of practice or class frequency. Different physical poses and yoga techniques may have unique health benefits. PMID- 22927886 TI - Ribosomal stress, p53 activation and the tanning response. AB - Melanocytes (MC) sit along the epidermal basal layer, largely quiescent except for constitutive melanin production. They are usually only activated after sun exposure. The recent paper by McGowan et al. (1) describes a novel mechanism by which melanocytes are induced to proliferate upon p53 activation in adjacent keratinocytes (KC). In this study, small subunit ribosomal protein mutations cause a dramatic activation of p53 that we propose mimics important aspects of the skin sunburn response after ultraviolet radiation (UVR) exposure. McGowan et al. show that the phenotype of their hyperpigmented mouse mutants results from p53-dependent upregulation of KITLG, a cytokine that binds to the KIT receptor on melanocytes and influences melanin synthesis, melanocyte proliferation, and dictates MC localization at the dermo-epidermal junction. These findings extend our knowledge about skin stress responses, in particular, how p53 activity in keratinocytes is central to the regulation of melanocyte behaviour. PMID- 22927887 TI - Sparse reconstruction for bioluminescence tomography based on the semigreedy method. AB - Bioluminescence tomography (BLT) is a molecular imaging modality which can three dimensionally resolve the molecular processes in small animals in vivo. The ill posedness nature of BLT problem makes its reconstruction bears nonunique solution and is sensitive to noise. In this paper, we proposed a sparse BLT reconstruction algorithm based on semigreedy method. To reduce the ill-posedness and computational cost, the optimal permissible source region was automatically chosen by using an iterative search tree. The proposed method obtained fast and stable source reconstruction from the whole body and imposed constraint without using a regularization penalty term. Numerical simulations on a mouse atlas, and in vivo mouse experiments were conducted to validate the effectiveness and potential of the method. PMID- 22927888 TI - Recursive feature selection with significant variables of support vectors. AB - The development of DNA microarray makes researchers screen thousands of genes simultaneously and it also helps determine high- and low-expression level genes in normal and disease tissues. Selecting relevant genes for cancer classification is an important issue. Most of the gene selection methods use univariate ranking criteria and arbitrarily choose a threshold to choose genes. However, the parameter setting may not be compatible to the selected classification algorithms. In this paper, we propose a new gene selection method (SVM-t) based on the use of t-statistics embedded in support vector machine. We compared the performance to two similar SVM-based methods: SVM recursive feature elimination (SVMRFE) and recursive support vector machine (RSVM). The three methods were compared based on extensive simulation experiments and analyses of two published microarray datasets. In the simulation experiments, we found that the proposed method is more robust in selecting informative genes than SVMRFE and RSVM and capable to attain good classification performance when the variations of informative and noninformative genes are different. In the analysis of two microarray datasets, the proposed method yields better performance in identifying fewer genes with good prediction accuracy, compared to SVMRFE and RSVM. PMID- 22927889 TI - Uncertainty quantification in simulations of epidemics using polynomial chaos. AB - Mathematical models based on ordinary differential equations are a useful tool to study the processes involved in epidemiology. Many models consider that the parameters are deterministic variables. But in practice, the transmission parameters present large variability and it is not possible to determine them exactly, and it is necessary to introduce randomness. In this paper, we present an application of the polynomial chaos approach to epidemiological mathematical models based on ordinary differential equations with random coefficients. Taking into account the variability of the transmission parameters of the model, this approach allows us to obtain an auxiliary system of differential equations, which is then integrated numerically to obtain the first-and the second-order moments of the output stochastic processes. A sensitivity analysis based on the polynomial chaos approach is also performed to determine which parameters have the greatest influence on the results. As an example, we will apply the approach to an obesity epidemic model. PMID- 22927891 TI - Orthodontic management of silver-russell syndrome. A case report. AB - This case report describes the orthodontic management of a 10-year-old female with Silver-Russell syndrome by means of gradual expansion of the mandibular dental arch using removable appliances and subsequent comprehensive treatment of malocclusion by means of fixed appliances. PMID- 22927890 TI - Quantitative imaging of young's modulus of soft tissues from ultrasound water jet indentation: a finite element study. AB - Indentation testing is a widely used approach to evaluate mechanical characteristics of soft tissues quantitatively. Young's modulus of soft tissue can be calculated from the force-deformation data with known tissue thickness and Poisson's ratio using Hayes' equation. Our group previously developed a noncontact indentation system using a water jet as a soft indenter as well as the coupling medium for the propagation of high-frequency ultrasound. The novel system has shown its ability to detect the early degeneration of articular cartilage. However, there is still lack of a quantitative method to extract the intrinsic mechanical properties of soft tissue from water jet indentation. The purpose of this study is to investigate the relationship between the loading unloading curves and the mechanical properties of soft tissues to provide an imaging technique of tissue mechanical properties. A 3D finite element model of water jet indentation was developed with consideration of finite deformation effect. An improved Hayes' equation has been derived by introducing a new scaling factor which is dependent on Poisson's ratios v, aspect ratio a/h (the radius of the indenter/the thickness of the test tissue), and deformation ratio d/h. With this model, the Young's modulus of soft tissue can be quantitatively evaluated and imaged with the error no more than 2%. PMID- 22927892 TI - Anti-helicobacter pylori activities of shoya powder and essential oils of thymus vulgaris and eucalyptus globulus. AB - BACKGROUND: Helicobacter pylori, an infective agent of more than 50% of the world population is prominent to be the main causative factor in the etiologies of chronic, active or type B gastritis, peptic and duodenal ulcer, gastric carcinoma, and mucosa-associated lymphoid tumors. A high prevalence of this bacterium in dental plaque is always reported. Pharmacological treatment of H. pylori infections includes administration of 3-fold therapeutic regimens which are typically used to suppress H. pylori activity. However, antibiotic resistance frequently develops as a consequence of such treatment. Thus, searching for alternative therapies for H. pylori infections is of special interest. MATERIALS AND METHODS: In this study, anti H. pylori activities of a traditional antimicrobial drug so-called Shoya and also essential oils of Thymus vulgaris and Eucalyptus globulus were investigated using antimicrobial analysis and serological screening methods. RESULTS: The agar dilution method results revealed the Shoya with the highest inhibitory effect against H. pylori. Also serological screening on tested mice showed a significant effect of this drug in lowering the sera amount of anti H. pylori specific IgA and IgG titers. Both of the essential oils showed different degrees of antibacterial effect against H. pylori. CONCLUSION: The obtained results showed the antibacterial effect of Shoya powder and Essential oils from Thymus vulgaris and Eucalyptus globulus and purposes new therapeutical alternatives to control the H. pylori infection. Additional studies and clinical trials are necessary to approve the use of these data in health care and pharmacopeia systems. PMID- 22927894 TI - Patellofemoral arthroplasty: a systematic review of the literature. AB - Identification and management of patients with isolated patellofemoral osteoarthritis are challenging. Many of these patients present at a young age and it is important to distinguish degenerative change in the patellofemoral articulation from the other various causes of anterior knee pain. Once the diagnosis of isolated patellofemoral arthrosis has been made non-operative and conservative surgical techniques should be exhausted fully before prosthetic arthroplasty is considered. This review focuses on the use of arthroplasty for isolated patellofemoral arthrosis, in particular comparing the use of total knee against selective patellofemoral joint replacements. PMID- 22927893 TI - The operative management of patella malalignment. AB - Management of patellofemoral joint pathology is challenging as a result of the unique and complex organization of static forces and dynamic factors contributing to its functional capacity. Anterior knee pain is a common musculoskeletal complaint seen daily in the practices of primary care physicians, rheumatologists, and orthopedic surgeons. The key to successful treatment lies not only in the correct diagnosis of a chondral defect, but more importantly, in the accurate identification of associated pathomechanical factors. Appreciating the pathoanatomic basis of the disease and addressing imbalances and anatomical abnormalities should guide treatment.Despite the complexity of the interplay of various components it is essential to attempt to describe patellar malalignement as a clinical entity in order to proceed with appropriate surgical management and successful outcomes. The goals of patellofemoral re- alignment surgery should be to create both a stable environment for optimal extensor mechanism performance and an appropriate load transmission for optimal cartilage wear and joint loading. In the context of this article we will review the operative management of patellofemoral malalignment; the indications for surgery, the different techniques available and the evidence regarding their effectiveness.A large number of procedures have been employed and they have all undergone various modifications over the course of the years. The majority of publications are retrospective series in poorly defined population groups. There are significant methodological inconsistencies and as a result there is lack of strong evidence base for the majority of these procedures. PMID- 22927895 TI - Intra-Arterial MSC Transplantation Restores Functional Capacity After Skeletal Muscle Trauma. AB - INTRODUCTION: Skeletal muscle trauma leads to severe functional deficits, which cannot be addressed by current treatment options. Our group could show the efficacy of local transplantation of mesenchymal stroma cells (MSCs) for the treatment of injured muscles. While local application of MSCs has proven to be effective, we hypothesized that a selective intra-arterial transplantation would lead to a better distribution of the cells and so improved physiological recovery of muscle function. MATERIALS AND METHODOLOGY: 18 female Sprague Dawley rats received an open crush trauma of the left soleus muscle. Autologous MSC were transduced using dsCOP-GFP and 2.5 x 10(6)cells were transplanted into the femoral artery of 9 animals one week after trauma. Control animals (n=9) received a saline injection. Cell tracking, analysis of tissue fibrosis and muscle force measurements were performed after 3 weeks. RESULTS: Systemic MSC-therapy improved the muscle force significantly compared to control (fast twitch: 82.4%, tetany: 61.6%, p = 0.02). The histological analysis showed no differences in the quantity of fibrotic tissue. Histological examination revealed no cells in the traumatized muscle tissue 21 days after transplantation. CONCLUSIONS: The present study demonstrated an effect of systemically administered MSCs in the treatment of skeletal muscle injuries. For possible future therapeutic approaches a systemic application of MSCs seems to present an alternative to a local administration. Such systemic treatment would be preferable since it allows functional improvement and possible cellular concentration at injury sites that are not easily accessible. PMID- 22927896 TI - Traumatic ceramic femoral head fracture: an initial misdiagnosis. AB - BACKGROUND AND PURPOSE: Ceramic heads are widely used in modern total hip arthroplasty (THA). Although a rare complication, fractures of ceramic heads are described in the literature, evoking uncertainties regarding the in vivo stability of this material, especially when impaction of a fractured ceramic head can lead to disastrous results. METHODS: In this case report, we present a fracture of a ceramic head after trauma. A misinterpretation of the initial radiographs led to severe fragmentation of the ceramic head two weeks after the incident, later resulting in complete destruction of the arthroplasty. RESULTS AND INTERPRETATION: Remarkably, radiographs obtained more than one year after the trauma led to this delayed diagnosis. A single radiographic evaluation, especially in patients with persistent pain after major trauma, with a ceramic head in a THA, seems to be insufficient. PMID- 22927897 TI - The neural processing of second language comprehension modulated by the degree of proficiency: a listening connected speech FMRI study. AB - While the neural network encompassing the processing of the mother tongue (L1) is well defined and has revealed the existence of a bilateral ventral pathway and a left dorsal pathway in which 3 loops have been defined, the question of the processing of a second language (L2) is still a matter of debate. Among variables accounting for the discrepancies in results, the degree of L2 proficiency appears to be one of the main factors. The present study aimed at assessing both pathways in L2, making it possible to determine the degree of mastery of the different speech components (prosody, phonology, semantics and syntax) that are intrinsically embedded within connected speech and that vary according to the degree of proficiency using high degrees of prosodic information. Two groups of high and moderate proficiency in L2 performed an fMRI comprehension task in L1 and L2. The modifications in brain activity observed within the dorsal and the ventral pathways according to L2 proficiency suggest that different processes of L2 are supported by differences in the integrated activity within distributed networks that included the left STSp, the left Spt and the left pars triangularis. PMID- 22927898 TI - Structure-function analysis of Rgs1 in Magnaporthe oryzae: role of DEP domains in subcellular targeting. AB - BACKGROUND: Rgs1, a prototypical Regulator of G protein Signaling, negatively modulates the cyclic AMP pathway thereby influencing various aspects of asexual development and pathogenesis in the rice-blast fungus Magnaporthe oryzae. Rgs1 possesses tandem DEP motifs (termed DEP-A and DEP-B; for Dishevelled, Egl-10, Pleckstrin) at the N-terminus, and a Galpha-GTP interacting RGS catalytic core domain at the C-terminus. In this study, we focused on gaining further insights into the mechanisms of Rgs1 regulation and subcellular localization by characterizing the role(s) of the individual domains and the full-length protein during asexual development and pathogenesis in Magnaporthe. METHODOLOGY/PRINCIPAL FINDINGS: Utilizing western blot analysis and specific antisera against the N- and C-terminal halves of Rgs1, we identify and report the in vivo endoproteolytic processing/cleavage of full-length Rgs1 that yields an N-terminal DEP and a RGS core domain. Independent expression of the resultant DEP-DEP half (N-Rgs1) or RGS core (C-Rgs1) fragments, failed to complement the rgs1Delta defects in colony morphology, aerial hyphal growth, surface hydrophobicity, conidiation, appressorium formation and infection. Interestingly, the full-length Rgs1 mCherry, as well as the tagged N-terminal DEP domains (individually or in conjunction) localized to distinct punctate vesicular structures in the cytosol, while the catalytic RGS core motif was predominantly vacuolar. CONCLUSIONS/SIGNIFICANCE: Based on our data from sequence alignments, immuno-blot and microscopic analysis, we propose that the post-translational proteolytic processing of Rgs1 and the vacuolar sequestration of the catalytic RGS domain represents an important means of down regulating Rgs1 function and thus forming an additional and alternative means of regulating G protein signaling in Magnaporthe. We further hypothesize the prevalence of analogous mechanisms functioning in other filamentous fungi. Furthermore, we conclusively assign a specific vesicular/membrane targeting function for the N-terminal DEP domains of Rgs1 in the rice-blast fungus. PMID- 22927899 TI - Preserved self-awareness following extensive bilateral brain damage to the insula, anterior cingulate, and medial prefrontal cortices. AB - It has been proposed that self-awareness (SA), a multifaceted phenomenon central to human consciousness, depends critically on specific brain regions, namely the insular cortex, the anterior cingulate cortex (ACC), and the medial prefrontal cortex (mPFC). Such a proposal predicts that damage to these regions should disrupt or even abolish SA. We tested this prediction in a rare neurological patient with extensive bilateral brain damage encompassing the insula, ACC, mPFC, and the medial temporal lobes. In spite of severe amnesia, which partially affected his "autobiographical self", the patient's SA remained fundamentally intact. His Core SA, including basic self-recognition and sense of self-agency, was preserved. His Extended SA and Introspective SA were also largely intact, as he has a stable self-concept and intact higher-order metacognitive abilities. The results suggest that the insular cortex, ACC and mPFC are not required for most aspects of SA. Our findings are compatible with the hypothesis that SA is likely to emerge from more distributed interactions among brain networks including those in the brainstem, thalamus, and posteromedial cortices. PMID- 22927900 TI - Neuronal LR11 expression does not differentiate between clinically-defined Alzheimer's disease and control brains. AB - Alzheimer's disease (AD) is the leading cause of dementia in the elderly. Because the pathological changes underlying this disease can begin decades prior to the onset of cognitive impairment, identifying the earliest events in the AD pathological cascade has critical implications for both the diagnosis and treatment of this disease. We previously reported that compared to autopsy confirmed healthy control brain, expression of LR11 (or SorLA) is markedly reduced in AD brain as well as in a subset of people with mild cognitive impairment (MCI), a prodromal clinical stage of AD. Recent studies of the LR11 gene SORL1 have suggested that the association between SORL1 single nucleotide polymorphisms (SNPs) and AD risk may not be universal. Therefore, we sought to confirm our earlier findings in a population chosen solely based on clinical criteria, as in most genetic studies. Quantitative immunohistochemistry was used to measure LR11 expression in 43 cases from the Religious Orders Study that were chosen based on a final pre-mortem clinical diagnosis of MCI, mild/moderate AD or no cognitive impairment (NCI). LR11 expression was highly variable in all three diagnostic groups, with no significant group differences. Low LR11 cases were identified using the lowest tertile of LR11 expression observed across all cases as a threshold. Contrary to previous reports, low LR11 expression was found in only 29% of AD cases. A similar proportion of both the MCI and NCI cases also displayed low LR11 expression. AD-associated lesions were present in the majority of cases regardless of diagnostic group, although we found no association between LR11 levels and pathological variables. These findings suggest that the relationship between LR11 expression and the development of AD may be more complicated than originally believed. PMID- 22927902 TI - Crystal structure of Lymnaea stagnalis AChBP complexed with the potent nAChR antagonist DHbetaE suggests a unique mode of antagonism. AB - Nicotinic acetylcholine receptors (nAChRs) are pentameric ligand-gated ion channels that belong to the Cys-loop receptor superfamily. These receptors are allosteric proteins that exist in different conformational states, including resting (closed), activated (open), and desensitized (closed) states. The acetylcholine binding protein (AChBP) is a structural homologue of the extracellular ligand-binding domain of nAChRs. In previous studies, the degree of the C-loop radial extension of AChBP has been assigned to different conformational states of nAChRs. It has been suggested that a closed C-loop is preferred for the active conformation of nAChRs in complex with agonists whereas an open C-loop reflects an antagonist-bound (closed) state. In this work, we have determined the crystal structure of AChBP from the water snail Lymnaea stagnalis (Ls) in complex with dihydro-beta-erythroidine (DHbetaE), which is a potent competitive antagonist of nAChRs. The structure reveals that binding of DHbetaE to AChBP imposes closure of the C-loop as agonists, but also a shift perpendicular to previously observed C-loop movements. These observations suggest that DHbetaE may antagonize the receptor via a different mechanism compared to prototypical antagonists and toxins. PMID- 22927901 TI - Clitocine reversal of P-glycoprotein associated multi-drug resistance through down-regulation of transcription factor NF-kappaB in R-HepG2 cell line. AB - Multidrug resistance (MDR) is one of the major reasons for failure in cancer chemotherapy and its suppression may increase the efficacy of therapy. The human multidrug resistance 1 (MDR1) gene encodes the plasma membrane P-glycoprotein (P gp) that pumps various anti-cancer agents out of the cancer cell. R-HepG2 and MES SA/Dx5 cells are doxorubicin induced P-gp over-expressed MDR sublines of human hepatocellular carcinoma HepG2 cells and human uterine carcinoma MES-SA cells respectively. Herein, we observed that clitocine, a natural compound extracted from Leucopaxillus giganteus, presented similar cytotoxicity in multidrug resistant cell lines compared with their parental cell lines and significantly suppressed the expression of P-gp in R-HepG2 and MES-SA/Dx5 cells. Further study showed that the clitocine increased the sensitivity and intracellular accumulation of doxorubicin in R-HepG2 cells accompanying down-regulated MDR1 mRNA level and promoter activity, indicating the reversal effect of MDR by clitocine. A 5'-serial truncation analysis of the MDR1 promoter defined a region from position -450 to -193 to be critical for clitocine suppression of MDR1. Mutation of a consensus NF-kappaB binding site in the defined region and overexpression of NF-kappaB p65 could offset the suppression effect of clitocine on MDR1 promoter. By immunohistochemistry, clitocine was confirmed to suppress the protein levels of both P-gp and NF-kappaB p65 in R-HepG2 cells and tumors. Clitocine also inhibited the expression of NF-kappaB p65 in MES-SA/Dx5. More importantly, clitocine could suppress the NF-kappaB activation even in presence of doxorubicin. Taken together; our results suggested that clitocine could reverse P-gp associated MDR via down-regulation of NF-kappaB. PMID- 22927903 TI - Shelf-life evaluation of bilayered human skin equivalent, MyDermTM. AB - Skin plays an important role in defense against infection and other harmful biological agents. Due to its fragile structure, skin can be easily damaged by heat, chemicals, traumatic injuries and diseases. An autologous bilayered human skin equivalent, MyDermTM, was engineered to provide a living skin substitute to treat critical skin loss. However, one of the disadvantages of living skin substitute is its short shelf-life, hence limiting its distribution worldwide. The aim of this study was to evaluate the shelf-life of MyDermTM through assessment of cell morphology, cell viability, population doubling time and functional gene expression levels before transplantation. Skin samples were digested with 0.6% Collagenase Type I followed by epithelial cells dissociation with TrypLE Select. Dermal fibroblasts and keratinocytes were culture-expanded to obtain sufficient cells for MyDermTM construction. MyDermTM was constructed with plasma-fibrin as temporary biomaterial and evaluated at 0, 24, 48 and 72 hours after storage at 4 degrees C for its shelf-life determination. The morphology of skin cells derived from MyDermTM remained unchanged across storage times. Cells harvested from MyDermTM after storage appeared in good viability (90.5%+/-2.7% to 94.9%+/-1.6%) and had short population doubling time (58.4+/-8.7 to 76.9+/-19 hours). The modest drop in cell viability and increased in population doubling time at longer storage duration did not demonstrate a significant difference. Gene expression for CK10, CK14 and COL III were also comparable between different storage times. In conclusion, MyDermTM can be stored in basal medium at 4 degrees C for at least 72 hours before transplantation without compromising its functionality. PMID- 22927904 TI - The effectiveness of U.S. public health surveillance systems for situational awareness during the 2009 H1N1 pandemic: a retrospective analysis. AB - BACKGROUND: The 2009 H1N1 outbreak provides an opportunity to learn about the strengths and weaknesses of current U.S. public health surveillance systems and to identify implications for measuring public health emergency preparedness. METHODOLOGY/PRINCIPAL FINDINGS: We adopted a "triangulation" approach in which multiple contemporary data sources, each with different expected biases, are compared to identify time patterns that are likely to reflect biases versus those that are more likely to be indicative of actual infection rates. This approach is grounded in the understanding that surveillance data are the result of a series of decisions made by patients, health care providers, and public health professionals about seeking and providing health care and about reporting cases to health authorities. Although limited by the lack of a gold standard, this analysis suggests that children and young adults are over-represented in many pH1N1 surveillance systems, especially in the spring wave. In addition, the nearly two-month delay between the Northeast and the South in the Fall peak in some surveillance data seems to at least partially reflect regional differences in concerns about pH1N1 rather than real differences in pH1N1 infection rates. CONCLUSIONS/SIGNIFICANCE: Although the extent of the biases suggested by this analysis cannot be known precisely, the analysis identifies underlying problems with surveillance systems--in particular their dependence on patient and provider behavior, which is influenced by a changing information environment--that could limit situational awareness in future public health emergencies. To improve situational awareness in future health emergencies, population-based surveillance systems such as telephone surveys of representative population samples and seroprevalence surveys in well-defined population cohorts are needed. PMID- 22927905 TI - Association of interarm systolic blood pressure difference with atherosclerosis and left ventricular hypertrophy. AB - An interarm systolic blood pressure (SBP) difference of 10 mmHg or more have been associated with peripheral artery disease and adverse cardiovascular outcomes. We investigated whether an association exists between this difference and ankle brachial index (ABI), brachial-ankle pulse wave velocity (baPWV), and echocardiographic parameters. A total of 1120 patients were included in the study. The bilateral arm blood pressures were measured simultaneously by an ABI form device. The values of ABI and baPWV were also obtained from the same device. Clinical data, ABI<0.9, baPWV, echocariographic parameters, and an interarm SBP difference >=10 mmHg were compared and analyzed. We performed two multivariate forward analyses for determining the factors associated with an interarm SBP difference >=10 mmHg [model 1: significant variables in univariate analysis except left ventricular mass index (LVMI); model 2: significant variables in univariate analysis except ABI<0.9 and baPWV]. The ABI<0.9 and high baPWV in model 1 and high LVMI in model 2 were independently associated with an interarm SBP difference >=10 mmHg. Female, hypertension, and high body mass index were also associated with an interarm SBP difference >=10 mmHg. Our study demonstrated that ABI<0.9, high baPWV, and high LVMI were independently associated with an interarm SBP difference of 10 mmHg or more. Detection of an interarm SBP difference may provide a simple method of detecting patients at increased risk of atherosclerosis and left ventricular hypertrophy. PMID- 22927906 TI - Genometa--a fast and accurate classifier for short metagenomic shotgun reads. AB - Metagenomic studies use high-throughput sequence data to investigate microbial communities in situ. However, considerable challenges remain in the analysis of these data, particularly with regard to speed and reliable analysis of microbial species as opposed to higher level taxa such as phyla. We here present Genometa, a computationally undemanding graphical user interface program that enables identification of bacterial species and gene content from datasets generated by inexpensive high-throughput short read sequencing technologies. Our approach was first verified on two simulated metagenomic short read datasets, detecting 100% and 94% of the bacterial species included with few false positives or false negatives. Subsequent comparative benchmarking analysis against three popular metagenomic algorithms on an Illumina human gut dataset revealed Genometa to attribute the most reads to bacteria at species level (i.e. including all strains of that species) and demonstrate similar or better accuracy than the other programs. Lastly, speed was demonstrated to be many times that of BLAST due to the use of modern short read aligners. Our method is highly accurate if bacteria in the sample are represented by genomes in the reference sequence but cannot find species absent from the reference. This method is one of the most user friendly and resource efficient approaches and is thus feasible for rapidly analysing millions of short reads on a personal computer. AVAILABILITY: The Genometa program, a step by step tutorial and Java source code are freely available from http://genomics1.mh-hannover.de/genometa/ and on http://code.google.com/p/genometa/. This program has been tested on Ubuntu Linux and Windows XP/7. PMID- 22927907 TI - Evaluation of ADAM-12 as a diagnostic biomarker of ectopic pregnancy in women with a pregnancy of unknown location. AB - BACKGROUND: Ectopic pregnancy (EP) remains the most life-threatening acute condition in modern gynaecology. It remains difficult to diagnose early and accurately. Women often present at emergency departments in early pregnancy with a 'pregnancy of unknown location' (PUL) and diagnosis/exclusion of EP is challenging due to a lack of reliable biomarkers. Recent studies suggest that serum levels of a disintegrin and metalloprotease protein-12 (ADAM-12) can be used differentiate EP from viable intrauterine pregnancy (VIUP). Here we describe a prospective study evaluating the performance of ADAM-12 in differentiating EP from the full spectrum of alternative PUL outcomes in an independent patient cohort. METHODOLOGY/PRINCIPAL FINDINGS: Sera were collected from 120 patients at their first clinical presentation with a PUL and assayed for ADAM-12 by ELISA. Patients were categorized according to final pregnancy outcomes. Serum ADAM-12 concentrations were increased in women with histologically-confirmed EP (median 442 pg/mL; 25%-75% percentile 232-783 pg/mL) compared to women with VIUP (256 pg/mL; 168-442 pg/mL) or miscarriage (192 pg/mL; 133-476 pg/mL). Serum ADAM-12 did not differentiate histologically-confirmed EP from spontaneously resolving PUL (srPUL) (416 pg/mL; 154-608 pg/mL). The diagnostic potential of ADAM-12 was only significant when 'ambiguous' PUL outcomes were excluded from the analysis (AROC = 0.6633; P = 0.03901). CONCLUSIONS/SIGNIFICANCE: When measured in isolation, ADAM-12 levels had limited value as a diagnostic biomarker for EP in our patient cohort. The development of a reliable serum biomarker-based test for EP remains an ongoing challenge. PMID- 22927908 TI - Cytosolic phospholipase A2 alpha/arachidonic acid signaling mediates depolarization-induced suppression of excitation in the cerebellum. AB - BACKGROUND: Depolarization-induced suppression of excitation (DSE) at parallel fiber-Purkinje cell synapse is an endocannabinoid-mediated short-term retrograde plasticity. Intracellular Ca(2+) elevation is critical for the endocannabinoid production and DSE. Nevertheless, how elevated Ca(2+) leads to DSE is unclear. METHODOLOGY/PRINCIPAL FINDINGS: We utilized cytosolic phospholipase A(2) alpha (cPLA(2)alpha) knock-out mice and whole-cell patch clamp in cerebellar slices to observed the action of cPLA(2)alpha/arachidonic acid signaling on DSE at parallel fiber-Purkinje cell synapse. Our data showed that DSE was significantly inhibited in cPLA(2)alpha knock-out mice, which was rescued by arachidonic acid. The degradation enzyme of 2-arachidonoylglycerol (2-AG), monoacylglycerol lipase (MAGL), blocked DSE, while another catabolism enzyme for N arachidonoylethanolamine (AEA), fatty acid amide hydrolase (FAAH), did not affect DSE. These results suggested that 2-AG is responsible for DSE in Purkinje cells. Co-application of paxilline reversed the blockade of DSE by internal K(+), indicating that large conductance Ca(2+)-activated potassium channel (BK) is sufficient to inhibit cPLA(2)alpha/arachidonic acid-mediated DSE. In addition, we showed that the release of 2-AG was independent of soluble NSF attachment protein receptor (SNARE), protein kinase C and protein kinase A. CONCLUSIONS/SIGNIFICANCE: Our data first showed that cPLA(2)alpha/arachidonic acid/2-AG signaling pathway mediates DSE at parallel fiber-Purkinje cell synapse. PMID- 22927909 TI - Cytochrome P450 2B diversity and dietary novelty in the herbivorous, desert woodrat (Neotoma lepida). AB - Detoxification enzymes play a key role in plant-herbivore interactions, contributing to the on-going evolution of ecosystem functional diversity. Mammalian detoxification systems have been well studied by the medical and pharmacological industries to understand human drug metabolism; however, little is known of the mechanisms employed by wild herbivores to metabolize toxic plant secondary compounds. Using a wild rodent herbivore, the desert woodrat (Neotoma lepida), we investigated genomic structural variation, sequence variability, and expression patterns in a multigene subfamily involved in xenobiotic metabolism, cytochrome P450 2B (CYP2B). We hypothesized that differences in CYP2B expression and sequence diversity could explain differential abilities of woodrat populations to consume native plant toxins. Woodrats from two distinct populations were fed diets supplemented with either juniper (Juniperus osteosperma) or creosote bush (Larrea tridentata), plants consumed by woodrats in their respective desert habitats. We used Southern blot and quantitative PCR to determine that the genomic copy number of CYP2B in both populations was equivalent, and similar in number to known rodent copy number. We compared CYP2B expression patterns and sequence diversity using cloned hepatic CYP2B cDNA. The resulting sequences were very diverse, and clustered into four major clades by amino acid similarity. Sequences from the experimental treatments were distributed non-randomly across a CYP2B tree, indicating unique expression patterns from woodrats on different diets and from different habitats. Furthermore, within each major CYP2B clade, sequences shared a unique combination of amino acid residues at 13 sites throughout the protein known to be important for CYP2B enzyme function, implying differences in the function of each major CYP2B variant. This work is the most comprehensive investigation of the genetic diversity of a detoxification enzyme subfamily in a wild mammalian herbivore, and contributes an initial genetic framework to our understanding of how a wild herbivore responds to critical changes in its diet. PMID- 22927910 TI - A switch role of Src in the biphasic EGF signaling of ER-negative breast cancer cells. AB - It is well established that epidermal growth factor (EGF) is a potent mitogen in cells expressing EGF receptor (EGFR). However, a body of evidence indicated that the effects of mitogenic EGF signaling exhibit a non-monotonic, or biphasic dose response curve; EGF at low concentrations elicits a mitogenic signaling pathway to stimulate cell proliferation while at high concentrations, EGF inhibits cell growth. However, the molecular mechanism underlying this paradoxical effect of EGF on cell proliferation remains largely unknown. Here, we investigated the molecular mechanisms underlying the biphasic EGF signaling in ER-negative breast cancer MDA-MB-231 and MDA-MB-436 cells, both of which express endogenous EGFR. We found that EGF at low concentrations induced the phosphorylation of the Src-Y416 residue, an event to activate Src, while at high concentrations allowed Src-Y527 phosphorylation that inactivates Src. EGF at 10 ng/ml also induced phosphorylation of the MAPK/ERK and activated cyclin D1 promoter activity through the Src/EGFR/STAT5 pathways but not at a higher concentration (500 ng/ml). Our results thus demonstrated that Src functions as a switch of EGF signaling depending on concentrations of EGF. PMID- 22927911 TI - Dengue virus serotype 2 blocks extracellular signal-regulated kinase and nuclear factor-kappaB activation to downregulate cytokine production. AB - BACKGROUND: Dengue virus (DENV) infection is the most common mosquito-borne viral disease threatening human health around the world. Type I interferon (IFN) and cytokine production are crucial in the innate immune system. We previously reported that DENV serotype 2 (DENV-2) induced low levels of interferon regulatory factor 3 and NF-kappaB activation, thus leading to reduced production of IFN-beta in the early phase of infection. Here, we determined whether DENV infection not only hampers type I IFN activation but also cytokine production triggered by Toll-like receptor (TLR) signaling. METHODOLOGY/PRINCIPAL FINDINGS: We used quantitative RT-PCR and found that only low levels of IFN-beta and inflammatory cytokines such as interleukin 10 (IL-10), IL-12 and tumor necrosis factor alpha (TNFalpha) mRNA were detected in DENV-2-infected bone-marrow-derived dendritic cells. Furthermore, DENV-2 infection repressed cytokine production triggered by TLR signaling. To elucidate the molecular mechanisms underlying this suppression event, we measured NF-kappaB activation by p65 nuclear translocation and luciferase reporter assay and found that NF-kappaB activation triggered by TLR ligands was blocked by DENV-2 infection. As well, extracellular signal regulated kinase (ERK) activity was suppressed by DENV-2 infection. CONCLUSIONS/SIGNIFICANCE: To downregulate the host innate immunity, DENV-2 by itself is a weak inducer of type I IFN and cytokines, furthermore DENV-2 can also block the TLR-triggered ERK-NF-kappaB activation and cytokine production. PMID- 22927912 TI - Pseudogenes as weaknesses of ACTB (Actb) and GAPDH (Gapdh) used as reference genes in reverse transcription and polymerase chain reactions. AB - The genes encoding beta-actin (ACTB in human or Actb in mouse) and glyceraldehyde 3-phosphate dehydrogenase (GAPDH in human or Gapdh in mouse) are the two most commonly used references for sample normalization in determination of the mRNA level of interested genes by reverse transcription (RT) and ensuing polymerase chain reactions (PCR). In this study, bioinformatic analyses revealed that the ACTB, Actb, GAPDH and Gapdh had 64, 69, 67 and 197 pseudogenes (PGs), respectively, in the corresponding genome. Most of these PGs are intronless and similar in size to the authentic mRNA. Alignment of several PGs of these genes with the corresponding mRNA reveals that they are highly homologous. In contrast, the hypoxanthine phosphoribosyltransferase-1 gene (HPRT1 in human or Hprt in mouse) only had 3 or 1 PG, respectively, and the mRNA has unique regions for primer design. PCR with cDNA or genomic DNA (gDNA) as templates revealed that our HPRT1, Hprt and GAPDH primers were specific, whereas our ACTB and Actb primers were not specific enough both vertically (within the cDNA) and horizontally (compared cDNA with gDNA). No primers could be designed for the Gapdh that would not mis-prime PGs. Since most of the genome is transcribed, we suggest to peers to forgo ACTB (Actb) and GAPDH (Dapdh) as references in RT-PCR and, if there is no surrogate, to use our primers with extra caution. We also propose a standard operation procedure in which design of primers for RT-PCR starts from avoiding mis-priming PGs and all primers need be tested for specificity with both cDNA and gDNA. PMID- 22927913 TI - Silencing of XB130 is associated with both the prognosis and chemosensitivity of gastric cancer. AB - XB130 is a newly characterized adaptor protein that was reported to promote thyroid tumor growth, but its role in the progression of other kinds of cancer such as gastric cancer (GC) remains unknown. Accordingly, we investigated the association between XB130 expression and the prognosis of GC patients. The subjects were 411 patients with GC in stages I to IV. XB130 expression was examined in surgical specimens of GC. Kaplan-Meier analysis and the Cox proportional hazards model were used to assess the prognostic significance of XB130 for survival and recurrence. Moreover, GC cells stably transfected with XB130 short hairpin RNA were established to analyze the effect of XB130 on sensitivity of chemotherapy. The results show that both XB130 mRNA and protein expression were detectable in normal gastric tissues. The overall survival time of stage IV patients and the disease-free period after radical resection of GC in stage I-III patients were significantly shorter when immunohistochemical staining for XB130 was low than when staining was high (both p<0.05). XB130 expression also predicted tumor sensitivity to several chemotherapy agents. Viability of both XB130-silenced SGC7901 cells and wild-type cells was suppressed by 5 fluorouracil (5-FU), cisplatin, and irinotecan in a dose-dependent way, but cisplatin and irinotecan were more sensitive against sXB130-silenced GC cells and 5-FU showed higher sensitivity to wild-type cells. When treated by 5-FU, patients with high expression of XB130 tumors had a higher survival rate than those with low expression tumors. These findings indicate that reduced XB130 protein expression is a prognostic biomarker for shorter survival and a higher recurrence rate in patients with GC, as well as for the response to chemotherapy. PMID- 22927914 TI - Maternal vitamin D deficiency delays glomerular maturity in F1 and F2 offspring. AB - BACKGROUND: There is a high prevalence of vitamin D insufficiency in women of reproductive age. METHODS: This work studied the first two generations of offspring (F1 and F2) of Swiss mice from mothers fed one of two diets: SC (standard chow) or VitD- (vitamin D-deficient). Functional and developmental kidney measurements were taken. RESULTS: The first two generations of the VitD- group had higher blood pressure at 6 months of age than the offspring of the SC group as well as an increase in renin and AT1r expression. However, at all ages, both F1 and F2 VitD- mice had shorter glomerular diameters, and diet played a significant role in the total variation. Both the F1 and F2 generations of the VitD- group had more immature glomeruli than offspring from the SC group. Immature glomeruli begin to disappear at 10 days, but at this age, F1-VitD- mice had more immature and mature glomeruli than F1-SC mice. At 6 months of age, F1 VitD- mice exhibited more glomeruli, while F2-VitD- mice exhibited the same number of glomeruli as F2-SC mice, but fewer glomeruli compared to the F1-VitD group. Both diet and generation account for the total variation in the number of glomeruli. Decreases in urine output and podocin expression and increases in urea and creatinine in the urine were observed in F1 offspring. CONCLUSION: These findings demonstrate that maternal vitamin D deficiency accompanies changes in the renal expression of important factors that may retard the maturation of glomeruli by extending the period of nephrogenesis. PMID- 22927915 TI - Fetal liver blood flow distribution: role in human developmental strategy to prioritize fat deposition versus brain development. AB - Among primates, human neonates have the largest brains but also the highest proportion of body fat. If placental nutrient supply is limited, the fetus faces a dilemma: should resources be allocated to brain growth, or to fat deposition for use as a potential postnatal energy reserve? We hypothesised that resolving this dilemma operates at the level of umbilical blood distribution entering the fetal liver. In 381 uncomplicated pregnancies in third trimester, we measured blood flow perfusing the fetal liver, or bypassing it via the ductus venosus to supply the brain and heart using ultrasound techniques. Across the range of fetal growth and independent of the mother's adiposity and parity, greater liver blood flow was associated with greater offspring fat mass measured by dual-energy X-ray absorptiometry, both in the infant at birth (r = 0.43, P<0.001) and at age 4 years (r = 0.16, P = 0.02). In contrast, smaller placentas less able to meet fetal demand for essential nutrients were associated with a brain-sparing flow pattern (r = 0.17, p = 0.02). This flow pattern was also associated with a higher degree of shunting through ductus venosus (P = 0.04). We propose that humans evolved a developmental strategy to prioritize nutrient allocation for prenatal fat deposition when the supply of conditionally essential nutrients requiring hepatic inter-conversion is limited, switching resource allocation to favour the brain if the supply of essential nutrients is limited. Facilitated placental transfer mechanisms for glucose and other nutrients evolved in environments less affluent than those now prevalent in developed populations, and we propose that in circumstances of maternal adiposity and nutrient excess these mechanisms now also lead to prenatal fat deposition. Prenatal developmental influences play important roles in the human propensity to deposit fat. PMID- 22927916 TI - The first identified nucleocytoplasmic shuttling herpesviral capsid protein: herpes simplex virus type 1 VP19C. AB - VP19C is a structural protein of herpes simplex virus type 1 viral particle, which is essential for assembly of the capsid. In this study, a nuclear export signal (NES) of VP19C is for the first time identified and mapped to amino acid residues 342 to 351. Furthermore, VP19C is demonstrated to shuttle between the nucleus and the cytoplasm through the NES in a chromosomal region maintenance 1 (CRM1)-dependent manner involving RanGTP hydrolysis. This makes VP19C the first herpesviral capsid protein with nucleocytoplasmic shuttling property and adds it to the list of HSV-1 nucleocytoplasmic shuttling proteins. PMID- 22927918 TI - Human matching behavior in social networks: an algorithmic perspective. AB - We argue that algorithmic modeling is a powerful approach to understanding the collective dynamics of human behavior. We consider the task of pairing up individuals connected over a network, according to the following model: each individual is able to propose to match with and accept a proposal from a neighbor in the network; if a matched individual proposes to another neighbor or accepts another proposal, the current match will be broken; individuals can only observe whether their neighbors are currently matched but have no knowledge of the network topology or the status of other individuals; and all individuals have the common goal of maximizing the total number of matches. By examining the experimental data, we identify a behavioral principle called prudence, develop an algorithmic model, analyze its properties mathematically and by simulations, and validate the model with human subject experiments for various network sizes and topologies. Our results include i) a 1/2-approximate maximum matching is obtained in logarithmic time in the network size for bounded degree networks; ii) for any constant epsilon > 0, a (1 - epsilon)-approximate maximum matching is obtained in polynomial time, while obtaining a maximum matching can require an exponential time; and iii) convergence to a maximum matching is slower on preferential attachment networks than on small-world networks. These results allow us to predict that while humans can find a "good quality" matching quickly, they may be unable to find a maximum matching in feasible time. We show that the human subjects largely abide by prudence, and their collective behavior is closely tracked by the above predictions. PMID- 22927917 TI - Antagonistic regulation, yet synergistic defense: effect of bergapten and protease inhibitor on development of cowpea bruchid Callosobruchus maculatus. AB - The furanocoumarin compound bergapten is a plant secondary metabolite that has anti-insect function. When incorporated into artificial diet, it retarded cowpea bruchid development, decreased fecundity, and caused mortality at a sufficient dose. cDNA microarray analysis indicated that cowpea bruchid altered expression of 543 midgut genes in response to dietary bergapten. Among these bergapten regulated genes, 225 have known functions; for instance, those encoding proteins related to nutrient transport and metabolism, development, detoxification, defense and various cellular functions. Such differential gene regulation presumably facilitates the bruchids' countering the negative effect of dietary bergapten. Many genes did not have homology (E-value cutoff 10(-6)) with known genes in a BlastX search (206), or had homology only with genes of unknown function (112). Interestingly, when compared with the transcriptomic profile of cowpea bruchids treated with dietary soybean cysteine protease inhibitor N (scN), 195 out of 200 coregulated midgut genes are oppositely regulated by the two compounds. Simultaneous administration of bergapten and scN attenuated magnitude of change in selected oppositely-regulated genes, as well as led to synergistic delay in insect development. Therefore, targeting insect vulnerable sites that may compromise each other's counter-defensive response has the potential to increase the efficacy of the anti-insect molecules. PMID- 22927919 TI - The functional upregulation of piriform cortex is associated with cross-modal plasticity in loss of whisker tactile inputs. AB - BACKGROUND: Cross-modal plasticity is characterized as the hypersensitivity of remaining modalities after a sensory function is lost in rodents, which ensures their awareness to environmental changes. Cellular and molecular mechanisms underlying cross-modal sensory plasticity remain unclear. We aim to study the role of different types of neurons in cross-modal plasticity. METHODOLOGY/PRINCIPAL FINDINGS: In addition to behavioral tasks in mice, whole cell recordings at the excitatory and inhibitory neurons, and their two-photon imaging, were conducted in piriform cortex. We produced a mouse model of cross modal sensory plasticity that olfactory function was upregulated by trimming whiskers to deprive their sensory inputs. In the meantime of olfactory hypersensitivity, pyramidal neurons and excitatory synapses were functionally upregulated, as well as GABAergic cells and inhibitory synapses were downregulated in piriform cortex from the mice of cross-modal sensory plasticity, compared with controls. A crosswire connection between barrel cortex and piriform cortex was established in cross-modal plasticity. CONCLUSION/SIGNIFICANCE: An upregulation of pyramidal neurons and a downregulation of GABAergic neurons strengthen the activities of neuronal networks in piriform cortex, which may be responsible for olfactory hypersensitivity after a loss of whisker tactile input. This finding provides the clues for developing therapeutic strategies to promote sensory recovery and substitution. PMID- 22927920 TI - In vivo optical imaging of tumor and microvascular response to ionizing radiation. AB - Radiotherapy is a widely used cancer treatment. However, understanding how ionizing radiation affects tumor cells and their vasculature, particularly at cellular, subcellular, genetic, and protein levels, has been limited by an inability to visualize the response of these interdependent components within solid tumors over time and in vivo. Here we describe a new preclinical experimental platform combining intravital multimodal optical microscopy for cellular-level longitudinal imaging, a small animal x-ray microirradiator for reproducible spatially-localized millimeter-scale irradiations, and laser-capture microdissection of ex vivo tissues for transcriptomic profiling. Using this platform, we have developed new methods that exploit the power of optically enabled microscopic imaging techniques to reveal the important role of the tumor microvasculature in radiation response of tumors. Furthermore, we demonstrate the potential of this preclinical platform to study quantitatively--with cellular and sub-cellular details--the spatio-temporal dynamics of the biological response of solid tumors to ionizing radiation in vivo. PMID- 22927921 TI - Confidence in emotion perception in point-light displays varies with the ability to perceive own emotions. AB - One central issue in social cognitive neuroscience is that perceiving emotions in others relates to activating the same emotion in oneself. In this study we sought to examine how the ability to perceive own emotions assessed with the Toronto Alexithymia Scale related to both the ability to perceive emotions depicted in point-light displays and the confidence in these perceptions. Participants observed video scenes of human interactions, rated the depicted valence, and judged their confidence in this rating. Results showed that people with higher alexithymia scores were significantly less confident about their decisions, but did not differ from people with lower alexithymia scores in the valence of their ratings. Furthermore, no modulating effect of social context on the effect of higher alexithymia scores was found. It is concluded that the used stimuli are fit to investigate the kinematic aspect of emotion perception and possibly separate people with high and low alexithymia scores via confidence differences. However, a general difference in emotion perception was not detected in the present setting. PMID- 22927922 TI - Cannabinoid receptor type 2 functional variant influences liver damage in children with non-alcoholic fatty liver disease. AB - Non-alcoholic fatty liver disease (NAFLD) comprises a spectrum of disease ranging from simple steatosis to inflammatory steatohepatitis (NASH) with different degrees of fibrosis that can ultimately progress to cirrhosis. Accumulating evidence suggests the involvement of the endocannabinoid-system in liver disease and related complications. In particular, hepatoprotective properties for Cannabinoid Receptor type 2 (CB2) have been shown both through experimental murine models of liver injury and association study between a CB2 functional variant, Q63R, and liver enzymes in Italian obese children with steatosis.Here, in order to clarify the role of CB2 in severity of childhood NAFLD, we have investigated the association of the CB2 Q63R variant, with histological parameters of liver disease severity in 118 Italian children with histologically proven NAFLD.CB2 Q63R genotype was assigned performing a TaqMan assay and a general linear model analysis was used to evaluate the association between the polymorphism and the histological parameters of liver damage.We have found that whereas CB2 Q63R variant is not associated with steatosis or fibrosis, it is associated with the severity of the inflammation (p = 0.002) and the presence of NASH (p = 0.02).Our findings suggest a critical role for CB2 Q63R variant in modulating hepatic inflammation state in obese children and in the consequent increased predisposition of these patients to liver damage. PMID- 22927923 TI - Electrophysiological evidence for immature processing capacity and filtering in visuospatial working memory in adolescents. AB - The present study investigated the development of visuospatial working memory (VSWM) capacity and the efficiency of filtering in VSWM in adolescence. To this end, a group of IQ-matched adults and adolescents performed a VSWM change detection task with manipulations of WM-load and distraction, while performance and electrophysiological contralateral delay activity (CDA) were measured. The CDA is a lateralized ERP marker of the number of targets and distracters that are selectively encoded/maintained in WM from one hemifield of the memory display. Significantly lower VSWM-capacity (Cowan's K) was found in adolescents than adults, and adolescents' WM performance (in terms of accuracy and speed) also suffered more from the presence of distracters. Distracter-related CDA responses were partly indicative of higher distracter encoding/maintenance in WM in adolescents and were positively correlated with performance measures of distracter interference. This correlation suggests that the higher interference of distracters on WM performance in adolescents was caused by an inability to block distracters from processing and maintenance in WM. The lower visuospatial WM-capacity (K) in adolescents in the high load (3 items) condition was accompanied by a trend (p<.10) towards higher CDA amplitudes in adolescents than adults, whereas CDA amplitudes in the low load (1 item) condition were comparable between adolescents and adults. These findings point to immaturity of frontal parietal WM-attention networks that support visuospatial WM processing in adolescence. PMID- 22927924 TI - Multi-target regulation by small RNAs synchronizes gene expression thresholds and may enhance ultrasensitive behavior. AB - Cells respond to external cues by precisely coordinating multiple molecular events. Co-regulation may be established by the so-called single-input module (SIM), where a common regulator controls multiple targets. Using mathematical modeling, we compared the ability of SIM architectures to precisely coordinate protein levels despite environmental fluctuations and uncertainties in parameter values. We find that post-transcriptional co-regulation as exemplified by bacterial small RNAs (sRNAs) is particularly robust: sRNA-mediated regulation establishes highly synchronous gene expression thresholds for all mRNA targets without a need for fine-tuning of kinetic parameters. Our analyses reveal that the non-catalytic nature of sRNA action is essential for robust gene expression synchronization, and that sRNA sequestration effects underlie coupling of multiple mRNA pools. This principle also operates in the temporal regime, implying that sRNAs could robustly coordinate the kinetics of mRNA induction as well. Moreover, we observe that multi-target regulation by a small RNA can strongly enhance ultrasensitivity in mRNA expression when compared to the single target case. Our findings may explain why bacterial small RNAs frequently coordinate all-or-none responses to cellular stress. PMID- 22927925 TI - Excitability of jcBNST neurons is reduced in alcohol-dependent animals during protracted alcohol withdrawal. AB - Alcohol dependence and withdrawal has been shown to cause neuroadaptive changes at multiple levels of the nervous system. At the neuron level, adaptations of synaptic connections have been extensively studied in a number of brain areas and accumulating evidence also shows the importance of alcohol dependence-related changes in the intrinsic cellular properties of neurons. At the same time, it is still largely unknown how such neural adaptations impact the firing and integrative properties of neurons. To address these problems, here, we analyze physiological properties of neurons in the bed nucleus of stria terminalis (jcBNST) in animals with a history of alcohol dependence. As a comprehensive approach, first we measure passive and active membrane properties of neurons using conventional current clamp protocols and then analyze their firing responses under the action of simulated synaptic bombardment via dynamic clamp. We find that most physiological properties as measured by DC current injection are barely affected during protracted withdrawal. However, neuronal excitability as measured from firing responses under simulated synaptic inputs with the dynamic clamp is markedly reduced in all 3 types of jcBNST neurons. These results support the importance of studying the effects of alcohol and drugs of abuse on the firing properties of neurons with dynamic clamp protocols designed to bring the neurons into a high conductance state. Since the jcBNST integrates excitatory inputs from the basolateral amygdala (BLA) and cortical inputs from the infralimbic and the insular cortices and in turn is believed to contribute to the inhibitory input to the central nucleus of the amygdala (CeA) the reduced excitability of the jcBNST during protracted withdrawal in alcohol-dependent animals will likely affect ability of the jcBNST to shape the activity and output of the CeA. PMID- 22927926 TI - Amyloid-beta peptide binds to cytochrome C oxidase subunit 1. AB - Extracellular and intraneuronal accumulation of amyloid-beta aggregates has been demonstrated to be involved in the pathogenesis of Alzheimer's disease (AD). However, the precise mechanism of amyloid-beta neurotoxicity is not completely understood. Previous studies suggest that binding of amyloid-beta to a number of macromolecules has deleterious effects on cellular functions. Mitochondria were found to be the target for amyloid-beta, and mitochondrial dysfunction is well documented in AD. In the present study we have shown for the first time that Abeta 1-42 bound to a peptide comprising the amino-terminal region of cytochrome c oxidase subunit 1. Phage clone, selected after screening of a human brain cDNA library expressed on M13 phage and bearing a 61 amino acid fragment of cytochrome c oxidase subunit 1, bound to Abeta 1-42 in ELISA as well as to Abeta aggregates present in AD brain. Abeta 1-42 and cytochrome c oxidase subunit 1 co immunoprecipitated from mitochondrial fraction of differentiated human neuroblastoma cells. Likewise, molecular dynamics simulation of the cytochrome c oxidase subunit 1 and the Abeta 1-42 peptide complex resulted in a reliable helix helix interaction, supporting the experimental results. The interaction between Abeta 1-42 and cytochrome c oxidase subunit 1 may explain, in part, the diminished enzymatic activity of respiratory chain complex IV and subsequent neuronal metabolic dysfunction observed in AD. PMID- 22927927 TI - Ultrasensitive cDNA detection of dengue virus RNA using electrochemical nanoporous membrane-based biosensor. AB - A nanoporous alumina membrane-based ultrasensitive DNA biosensor is constructed using 5'-aminated DNA probes immobilized onto the alumina channel walls. Alumina nanoporous membrane-like structure is carved over platinum wire electrode of 76 um diameter dimension by electrochemical anodization. The hybridization of complementary target DNA with probe DNA molecules attached inside the pores influences the pore size and ionic conductivity. The biosensor demonstrates linear range over 6 order of magnitude with ultrasensitive detection limit of 9.55*10(-12) M for the quantification of ss-31 mer DNA sequence. Its applicability is challenged against real time cDNA PCR sample of dengue virus serotype1 derived from asymmetric PCR. Excellent specificity down to one nucleotide mismatch in target DNA sample of DENV3 is also demonstrated. PMID- 22927928 TI - Understanding libertarian morality: the psychological dispositions of self identified libertarians. AB - Libertarians are an increasingly prominent ideological group in U.S. politics, yet they have been largely unstudied. Across 16 measures in a large web-based sample that included 11,994 self-identified libertarians, we sought to understand the moral and psychological characteristics of self-described libertarians. Based on an intuitionist view of moral judgment, we focused on the underlying affective and cognitive dispositions that accompany this unique worldview. Compared to self identified liberals and conservatives, libertarians showed 1) stronger endorsement of individual liberty as their foremost guiding principle, and weaker endorsement of all other moral principles; 2) a relatively cerebral as opposed to emotional cognitive style; and 3) lower interdependence and social relatedness. As predicted by intuitionist theories concerning the origins of moral reasoning, libertarian values showed convergent relationships with libertarian emotional dispositions and social preferences. Our findings add to a growing recognition of the role of personality differences in the organization of political attitudes. PMID- 22927930 TI - Do laying hens with keel bone fractures experience pain? AB - The European ban on battery cages has forced a change towards the use of non-cage or furnished cage systems, but unexpectedly this has been associated with an increased prevalence of keel bone fractures in laying hens. Bone fractures are acutely painful in mammals, but the effect of fractures on bird welfare is unclear. We recently reported that keel bone fractures have an effect on bird mobility. One possible explanation for this is that flying becomes mechanically impaired. However it is also possible that if birds have a capacity to feel pain, then ongoing pain resulting from the fracture could contribute to decreased mobility. The aim was to provide proof of concept that administration of appropriate analgesic drugs improves mobility in birds with keel fracture; thereby contributing to the debate about the capacity of birds to experience pain and whether fractures are associated with pain in laying hens. In hens with keel fractures, butorphanol decreased the latency to land from perches compared with latencies recorded for these hens following saline (mean (SEM) landing time (seconds) birds with keel fractures treated with butorphanol and saline from the 50, 100 and 150 cm perch heights respectively 1.7 (0.3), 2.2 (0.3), p = 0.05, 50 cm; 12.5 (6.6), 16.9 (6.7), p = 0.03, 100 cm; 20.6 (7.4), 26.3 (7.6), p = 0.02 150 cm). Mobility indices were largely unchanged in birds without keel fractures following butorphanol. Critically, butorphanol can be considered analgesic in our study because it improved the ability of birds to perform a complex behaviour that requires both motivation and higher cognitive processing. This is the first study to provide a solid evidential base that birds with keel fractures experience pain, a finding that has significant implications for the welfare of laying hens that are housed in non-cage or furnished caged systems. PMID- 22927929 TI - Early-to-mid gestation fetal testosterone increases right hand 2D:4D finger length ratio in polycystic ovary syndrome-like monkeys. AB - A smaller length ratio for the second relative to the fourth finger (2D:4D) is repeatedly associated with fetal male-typical testosterone (T) and is implicated as a biomarker for a variety of traits and susceptibility to a number of diseases, but no experimental human studies have been performed. The present study utilizes the rhesus monkey, a close relative of humans, and employs discrete gestational exposure of female monkeys to fetal male-typical T levels for 15-35 days during early-to-mid (40-76 days; n = 7) or late (94-139 days; n = 7) gestation (term: 165 days) by daily subcutaneous injection of their dams with 10 mg T propionate. Such gestational exposures are known to enhance male-typical behavior. In this study, compared to control females (n = 19), only early-to-mid gestation T exposure virilizes female external genitalia while increasing 2D:4D ratio in the right hand (RH) by male-like elongation of RH2D. RH2D length and 2D:4D positively correlate with androgen-dependent anogenital distance (AG), and RH2D and AG positively correlate with duration of early-to-mid gestation T exposure. Male monkeys (n = 9) exhibit a sexually dimorphic 2D:4D in the right foot, but this trait is not emulated by early-to-mid or late gestation T exposed females. X-ray determined phalanx measurements indicate elongated finger and toe phalanx length in males, but no other phalanx-related differences. Discrete T exposure during early-to-mid gestation in female rhesus monkeys thus appears to increase RH2D:4D through right-side biased, non-skeletal tissue growth. As variation in timing and duration of gestational T exposure alter male-like dimensions of RH2D independently of RH4D, postnatal RH2D:4D provides a complex biomarker for fetal T exposure. PMID- 22927931 TI - Alexithymia and the processing of emotional facial expressions (EFEs): systematic review, unanswered questions and further perspectives. AB - Alexithymia is characterized by difficulties in identifying, differentiating and describing feelings. A high prevalence of alexithymia has often been observed in clinical disorders characterized by low social functioning. This review aims to assess the association between alexithymia and the ability to decode emotional facial expressions (EFEs) within clinical and healthy populations. More precisely, this review has four main objectives: (1) to assess if alexithymia is a better predictor of the ability to decode EFEs than the diagnosis of clinical disorder; (2) to assess the influence of comorbid factors (depression and anxiety disorder) on the ability to decode EFE; (3) to investigate if deficits in decoding EFEs are specific to some levels of processing or task types; (4) to investigate if the deficits are specific to particular EFEs. Twenty four studies (behavioural and neuroimaging) were identified through a computerized literature search of Psycinfo, PubMed, and Web of Science databases from 1990 to 2010. Data on methodology, clinical characteristics, and possible confounds were analyzed. The review revealed that: (1) alexithymia is associated with deficits in labelling EFEs among clinical disorders, (2) the level of depression and anxiety partially account for the decoding deficits, (3) alexithymia is associated with reduced perceptual abilities, and is likely to be associated with impaired semantic representations of emotional concepts, and (4) alexithymia is associated with neither specific EFEs nor a specific valence. These studies are discussed with respect to processes involved in the recognition of EFEs. Future directions for research on emotion perception are also discussed. PMID- 22927933 TI - Pre-clinical development of BCG.HIVA(CAT), an antibiotic-free selection strain, for HIV-TB pediatric vaccine vectored by lysine auxotroph of BCG. AB - In the past, we proposed to develop a heterologous recombinant BCG prime recombinant modified vaccinia virus Ankara (MVA) boost dual pediatric vaccine platform against transmission of breast milk HIV-1 and Mycobacterium tuberculosis (Mtb). In this study, we assembled an E. coli-mycobacterial shuttle plasmid pJH222.HIVA(CAT) expressing HIV-1 clade A immunogen HIVA. This shuttle vector employs an antibiotic resistance-free mechanism based on Operator-Repressor Titration (ORT) system for plasmid selection and maintenance in E. coli and lysine complementation in mycobacteria. This shuttle plasmid was electroporated into parental lysine auxotroph (safer) strain of BCG to generate vaccine BCG.HIVA(CAT). All procedures complied with Good Laboratory Practices (GLPs). We demonstrated that the episomal plasmid pJH222.HIVA(CAT) was stable in vivo over a 20-week period, and genetically and phenotypically characterized the BCG.HIVA(CAT) vaccine strain. The BCG.HIVA(CAT) vaccine in combination with MVA.HIVA induced HIV-1- and Mtb-specific interferon gamma-producing T-cell responses in newborn and adult BALB/c mice. On the other hand, when adult mice were primed with BCG.HIVA(CAT) and boosted with MVA.HIVA.85A, HIV-1-specific CD8(+) T-cells producing IFN-gamma, TNF-alpha, IL-2 and CD107a were induced. To assess the biosafety profile of BCG.HIVA(CAT)-MVA.HIVA regimen, body mass loss of newborn mice was monitored regularly throughout the vaccination experiment and no difference was observed between the vaccinated and naive groups of animals. Thus, we demonstrated T-cell immunogenicity of a novel, safer, GLP-compatible BCG vectored vaccine using prototype immunogen HIVA. Second generation immunogens derived from HIV-1 as well as other major pediatric pathogens can be constructed in a similar fashion to prime protective responses soon after birth. PMID- 22927932 TI - The octadecaneuropeptide ODN protects astrocytes against hydrogen peroxide induced apoptosis via a PKA/MAPK-dependent mechanism. AB - Astrocytes synthesize and release endozepines, a family of regulatory peptides, including the octadecaneuropeptide (ODN) an endogenous ligand of both central type benzodiazepine (CBR) and metabotropic receptors. We have recently shown that ODN exerts a protective effect against hydrogen peroxide (H(2)O(2))-induced oxidative stress in astrocytes. The purpose of the present study was to determine the type of receptor and the transduction pathways involved in the protective effect of ODN in cultured rat astrocytes. We have first observed a protective activity of ODN at very low concentrations that was abrogated by the metabotropic ODN receptor antagonist cyclo(1-8)[DLeu(5)]OP, but not by the CBR antagonist flumazenil. We have also found that the metabotropic ODN receptor is positively coupled to adenylyl cyclase in astrocytes and that the glioprotective action of ODN upon H(2)O(2)-induced astrocyte death is PKA- and MEK-dependent, but PLC/PKC independent. Downstream of PKA, ODN induced ERK phosphorylation, which in turn activated the expression of the anti-apoptotic gene Bcl-2 and blocked the stimulation by H(2)O(2) of the pro-apoptotic gene Bax. The effect of ODN on the Bax/Bcl-2 balance contributed to abolish the deleterious action of H(2)O(2) on mitochondrial membrane integrity and caspase-3 activation. Finally, the inhibitory effect of ODN on caspase-3 activity was shown to be PKA and MEK dependent. In conclusion, the present results demonstrate that the potent glioprotective action of ODN against oxidative stress involves the metabotropic ODN receptor coupled to the PKA/ERK-kinase pathway to inhibit caspase-3 activation. PMID- 22927934 TI - A role of tomato UV-damaged DNA binding protein 1 (DDB1) in organ size control via an epigenetic manner. AB - Epigenetic modification generally refers to phenotypic changes by a mechanism other than changes in DNA sequence and plays a significant role in developmental processes. In this study, we found that overexpression of one alternatively spliced tomato DDB1 transcript, DDB1(F) that is prevalently present in all tested tissues, resulted in reduction of organ size. Transgenic plants constitutively expressing the DDB1(F) from a strong cauliflower mosaic virus (CaMV) 35S promoter displayed moderately reduced size in vegetative organs (leaves and stems) and radically decreased size in reproductive organs (flowers, seeds and fruits), in which several genes encoding negative regulators for cell division were upregulated. Significantly, reduction of organ size conferred by overexpression of DDB1(F) transgene appears not to segregate in the subsequent generations, suggesting the phenotypic alternations are manipulated in an epigenetic manner and can be transmitted over generations. This notion was further substantiated by analysis of DNA methylation level at the SlWEE1 gene (encoding a negative regulator of cell division), revealing a correlation between less methylation in the promoter region and elevated expression level of this gene. Thus, our results suggest DDB1 plays an important role in regulation of the epigenetic state of genes involved in organogenesis, despite the underlying mechanism remains to be elucidated. PMID- 22927935 TI - Lasting consequences of traumatic events on behavioral and skeletal parameters in a mouse model for post-traumatic stress disorder (PTSD). AB - BACKGROUND: Post-traumatic stress disorder (PTSD) is an anxiety disorder that not only affects mental health, but may also affect bone health. However, there have been no studies to examine the direct relationship between PTSD and bone. METHODOLOGY/PRINCIPAL FINDINGS: We employed electric shocks in mice to simulate traumatic events that cause PTSD. We also injected the anxiogenic drug FG-7142 prior to electric shocks. Electric shocks created lasting conditioned fear memory in all mice. In young mice, electric shocks elicited not only behavioral response but also skeletal response, and injection of FG-7142 appeared to increase both types of response. For example in behavioral response within the first week, mice shocked alone froze an average of 6.2 sec in 10 sec tests, and mice injected with FG-7142 froze 7.6 sec, both significantly different (P<0.05) from control mice, which only froze 1.3 sec. In skeletal response at week 2, shocks alone reduced 6% bone mineral content (BMC) in total body (P = 0.06), while shocks with FG-7142 injection reduced not only 11% BMC (P<0.05) but also 6% bone mineral density (BMD) (P<0.05). In addition, FG-7142 injection also caused significant reductions of BMC in specific bones such as femur, lumbar vertebra, and tibia at week 3. Strong negative correlations (R(2) = -0.56, P<0.05) and regression (y = 0.2527 0.0037 * x, P<0.01) between freezing behavior and total body BMC in young mice indicated that increased contextual PTSD-like behavior was associated with reduced bone mass acquisition. CONCLUSIONS/SIGNIFICANCE: This is the first study to document evidence that traumatic events induce lasting consequences on both behavior and skeletal growth, and electric shocks coupled with injection of anxiogenic FG-7142 in young mice can be used as a model to study the effect of PTSD-like symptoms on bone development. PMID- 22927936 TI - A probabilistic model for cell population phenotyping using HCS data. AB - High Content Screening (HCS) platforms allow screening living cells under a wide range of experimental conditions and give access to a whole panel of cellular responses to a specific treatment. The outcome is a series of cell population images. Within these images, the heterogeneity of cellular response to the same treatment leads to a whole range of observed values for the recorded cellular features. Consequently, it is difficult to compare and interpret experiments. Moreover, the definition of phenotypic classes at a cell population level remains an open question, although this would ease experiments analyses. In the present work, we tackle these two questions. The input of the method is a series of cell population images for which segmentation and cellular phenotype classification has already been performed. We propose a probabilistic model to represent and later compare cell populations. The model is able to fully exploit the HCS specific information: "dependence structure of population descriptors" and "within-population variability". The experiments we carried out illustrate how our model accounts for this specific information, as well as the fact that the model benefits from considering them. We underline that these features allow richer HCS data analysis than simpler methods based on single cellular feature values averaged over each well. We validate an HCS data analysis method based on control experiments. It accounts for HCS specificities that were not taken into account by previous methods but have a sound biological meaning. Biological validation of previously unknown outputs of the method constitutes a future line of work. PMID- 22927937 TI - Determining the diet of larvae of western rock lobster (Panulirus cygnus) using high-throughput DNA sequencing techniques. AB - The Western Australian rock lobster fishery has been both a highly productive and sustainable fishery. However, a recent dramatic and unexplained decline in post larval recruitment threatens this sustainability. Our lack of knowledge of key processes in lobster larval ecology, such as their position in the food web, limits our ability to determine what underpins this decline. The present study uses a high-throughput amplicon sequencing approach on DNA obtained from the hepatopancreas of larvae to discover significant prey items. Two short regions of the 18S rRNA gene were amplified under the presence of lobster specific PNA to prevent lobster amplification and to improve prey amplification. In the resulting sequences either little prey was recovered, indicating that the larval gut was empty, or there was a high number of reads originating from multiple zooplankton taxa. The most abundant reads included colonial Radiolaria, Thaliacea, Actinopterygii, Hydrozoa and Sagittoidea, which supports the hypothesis that the larvae feed on multiple groups of mostly transparent gelatinous zooplankton. This hypothesis has prevailed as it has been tentatively inferred from the physiology of larvae, captive feeding trials and co-occurrence in situ. However, these prey have not been observed in the larval gut as traditional microscopic techniques cannot discern between transparent and gelatinous prey items in the gut. High throughput amplicon sequencing of gut DNA has enabled us to classify these otherwise undetectable prey. The dominance of the colonial radiolarians among the gut contents is intriguing in that this group has been historically difficult to quantify in the water column, which may explain why they have not been connected to larval diet previously. Our results indicate that a PCR based technique is a very successful approach to identify the most abundant taxa in the natural diet of lobster larvae. PMID- 22927938 TI - A model of the intracellular response of an olfactory neuron in Caenorhabditis elegans to odor stimulation. AB - We developed a mathematical model of a hypothetical neuronal signal transduction pathway to better understand olfactory perception in Caenorhabditis elegans. This worm has only three pairs of olfactory receptor neurons. Intracellular Ca(2+) decreases in one pair of olfactory neurons in C. elegans, the AWC neurons, following application of an attractive odor and there is a transient increase in intracellular Ca(2+) following removal of odor. The magnitude of this increase is positively correlated with the duration of odor stimulation. Additionally, this Ca(2+) transient is induced by a cGMP second messenger system. We identified likely candidates for the signal transduction molecules functioning in this system based on available gene expression and physiological data from AWCs. Our model incorporated a G-protein-coupled odor receptor, a G-protein, a guanylate cyclase as the G-protein effector, and a single phosphodiesterase. Additionally, a cyclic-nucleotide-gated ion channel and a voltage-gated ion channel that mediated calcium influx were incorporated into the model. We posited that, upon odor stimulation, guanylate cyclase was suppressed by the G-protein and that, upon cessation of the stimulus, the G-protein-induced suppression ceased and cGMP synthesis was restored. A key element of our model was a Ca(2+)-dependent negative feedback loop that ensured that the calcium increases were transient. Two guanylate cyclase-activating proteins acted on the effector guanylate cyclase to negatively regulate cGMP signaling and the resulting calcium influx. Our model was able to closely replicate in silico three important features of the calcium dynamics of AWCs. Specifically, in our simulations, [Ca(2+)] increased rapidly and reached its peak within 10 s after the odor stimulus was removed, peak [Ca(2+)] increased with longer odor exposure, and [Ca(2+)] decreased during a second stimulus that closely followed an initial stimulus. However, application of random background signal ('noise') showed that certain components of the pathway were particularly sensitive to this noise. PMID- 22927939 TI - A mesenchymal stromal cell gene signature for donor age. AB - Human aging is associated with loss of function and regenerative capacity. Human bone marrow derived mesenchymal stromal cells (hMSCs) are involved in tissue regeneration, evidenced by their capacity to differentiate into several lineages and therefore are considered the golden standard for cell-based regeneration therapy. Tissue maintenance and regeneration is dependent on stem cells and declines with age and aging is thought to influence therapeutic efficacy, therefore, more insight in the process of aging of hMSCs is of high interest. We, therefore, hypothesized that hMSCs might reflect signs of aging. In order to find markers for donor age, early passage hMSCs were isolated from bone marrow of 61 donors, with ages varying from 17-84, and clinical parameters, in vitro characteristics and microarray analysis were assessed. Although clinical parameters and in vitro performance did not yield reliable markers for aging since large donor variations were present, genome-wide microarray analysis resulted in a considerable list of genes correlating with human age. By comparing the transcriptional profile of aging in human with the one from rat, we discovered follistatin as a common marker for aging in both species. The gene signature presented here could be a useful tool for drug testing to rejuvenate hMSCs or for the selection of more potent, hMSCs for cell-based therapy. PMID- 22927940 TI - Tracking moving identities: after attending the right location, the identity does not come for free. AB - Although tracking identical moving objects has been studied since the 1980's, only recently the study into tracking moving objects with distinct identities has started (referred to as Multiple Identity Tracking, MIT). So far, only behavioral studies into MIT have been undertaken. These studies have left a fundamental question regarding MIT unanswered, is MIT a one-stage or a two-stage process? According to the one-stage model, after a location has been attended, the identity is released without effort. However, according to the two-stage model, there are two effortful stages in MIT, attending to a location, and attending to the identity of the object at that location. In the current study we investigated this question by measuring brain activity in response to tracking familiar and unfamiliar targets. Familiarity is known to automate effortful processes, so if attention to identify the object is needed, this should become easier. However, if no such attention is needed, familiarity can only affect other processes (such as memory for the target set). Our results revealed that on unfamiliar trials neural activity was higher in both attentional networks, and visual identification networks. These results suggest that familiarity in MIT automates attentional identification processes, thus suggesting that attentional identification is needed in MIT. This then would imply that MIT is essentially a two-stage process, since after attending the location, the identity does not seem to come for free. PMID- 22927941 TI - Different subtypes of GABA-A receptors are expressed in human, mouse and rat T lymphocytes. AB - gamma-Aminobutyric acid (GABA) is the most prominent neuroinhibitory transmitter in the brain, where it activates neuronal GABA-A receptors (GABA-A channels) located at synapses and outside of synapses. The GABA-A receptors are primary targets of many clinically useful drugs. In recent years, GABA has been shown to act as an immunomodulatory molecule. We have examined in human, mouse and rat CD4(+) and CD8(+) T cells which subunit isoforms of the GABA-A channels are expressed. The channel physiology and drug specificity is dictated by the GABA-A receptor subtype, which in turn is determined by the subunit isoforms that make the channel. There were 5, 8 and 13 different GABA-A subunit isoforms identified in human, mouse and rat CD4(+) and CD8(+) T cells, respectively. Importantly, the gamma2 subunit that imposes benzodiazepine sensitivity on the GABA-A receptors, was only detected in the mouse T cells. Immunoblots and immunocytochemistry showed abundant GABA-A channel proteins in the T cells from all three species. GABA-activated whole-cell transient and tonic currents were recorded. The currents were inhibited by picrotoxin, SR95531 and bicuculline, antagonists of GABA-A channels. Clearly, in both humans and rodents T cells, functional GABA-A channels are expressed but the subtypes vary. It is important to bear in mind the interspecies difference when selecting the appropriate animal models to study the physiological role and pharmacological properties of GABA-A channels in CD4(+) and CD8(+) T cells and when selecting drugs aimed at modulating the human T cells function. PMID- 22927942 TI - Fluoroquinolone-mediated inhibition of cell growth, S-G2/M cell cycle arrest, and apoptosis in canine osteosarcoma cell lines. AB - Despite significant advancements in osteosarcoma research, the overall survival of canine and human osteosarcoma patients has remained essentially static over the past 2 decades. Post-operative limb-spare infection has been associated with improved survival in both species, yet a mechanism for improved survival has not been clearly established. Given that the majority of canine osteosarcoma patients experiencing post-operative infections were treated with fluoroquinolone antibiotics, we hypothesized that fluoroquinolone antibiotics might directly inhibit the survival and proliferation of canine osteosarcoma cells. Ciprofloxacin or enrofloxacin were found to inhibit p21(WAF1) expression resulting in decreased proliferation and increased S-G(2)/M accumulation. Furthermore, fluoroquinolone exposure induced apoptosis of canine osteosarcoma cells as demonstrated by cleavage of caspase-3 and PARP, and activation of caspase-3/7. These results support further studies examining the potential impact of quinolones on survival and proliferation of osteosarcoma. PMID- 22927943 TI - Rbm15-Mkl1 interacts with the Setd1b histone H3-Lys4 methyltransferase via a SPOC domain that is required for cytokine-independent proliferation. AB - The Rbm15-Mkl1 fusion protein is associated with acute megakaryoblastic leukemia (AMKL), although little is known regarding the molecular mechanism(s) whereby this fusion protein contributes to leukemogenesis. Here, we show that both Rbm15 and the leukemogenic Rbm15-Mkl1 fusion protein interact with the Setd1b histone H3-Lys4 methyltransferase (also known as KMT2G). This interaction is direct and requires the Rbm15 SPOC domain and the Setd1b LSD motif. Over-expression of Rbm15 Mkl1 in the 6133 megakaryoblastic leukemia cell line, previously established by expression of the Rbm15-Mkl1 fusion protein in mice (Mercher et al., [2009] J. Clin. Invest. 119, 852-864), leads to decreased levels of endogenous Rbm15 and increased levels of endogenous Mkl1. These cells exhibit enhanced proliferation and cytokine-independent cell growth, which requires an intact Rbm15 SPOC domain that mediates interaction between the Rbm15-Mkl1 fusion protein and the Setd1b methyltransferase. These results reveal altered Setd1b complex function and consequent altered epigenetic regulation as a possible molecular mechanism that mediates the leukemogenic activity of the Rbm15-Mkl1 fusion protein in AMKL. PMID- 22927944 TI - Breast cancer metastasis suppressor 1 regulates hepatocellular carcinoma cell apoptosis via suppressing osteopontin expression. AB - Breast cancer metastasis suppressor 1 (BRMS1) was originally identified as an active metastasis suppressor in human breast cancer. Loss of BRMS1 expression correlates with tumor progression, and BRMS1 suppresses several steps required for tumor metastasis. However, the role of BRMS1 in hepatocellular carcinoma (HCC) remains elusive. In this study, we found that the expression level of BRMS1 was significantly down-regulated in HCC tissues. Expression of BRMS1 in SK-Hep1 cells did not affect cell growth under normal culture conditions, but sensitized cells to apoptosis induced by serum deprivation or anoikis. Consistently, knockdown of endogenous BRMS1 expression in Hep3B cells suppressed cell apoptosis. We identified that BRMS1 suppresses osteopontin (OPN) expression in HCC cells and that there is a negative correlation between BRMS1 and OPN mRNA expression in HCC tissues. Moreover, knockdown of endogenous OPN expression reversed the anti-apoptosis effect achieved by knockdown of BRMS1. Taken together, our results show that BRMS1 sensitizes HCC cells to apoptosis through suppressing OPN expression, suggesting a potential role of BRMS1 in regulating HCC apoptosis and metastasis. PMID- 22927945 TI - A genetic investigation of the KEOPS complex in halophilic Archaea. AB - KEOPS is an important cellular complex conserved in Eukarya, with some subunits conserved in Archaea and Bacteria. This complex was recently found to play an essential role in formation of the tRNA modification threonylcarbamoyladenosine (t(6)A), and was previously associated with telomere length maintenance and transcription. KEOPS subunits are conserved in Archaea, especially in the Euryarchaea, where they had been studied in vitro. Here we attempted to delete the genes encoding the four conserved subunits of the KEOPS complex in the euryarchaeote Haloferax volcanii and study their phenotypes in vivo. The fused kae1-bud32 gene was shown to be essential as was cgi121, which is dispensable in yeast. In contrast, pcc1 (encoding the putative dimerizing unit of KEOPS) was not essential in H. volcanii. Deletion of pcc1 led to pleiotropic phenotypes, including decreased growth rate, reduced levels of t(6)A modification, and elevated levels of intra-cellular glycation products. PMID- 22927946 TI - The effects of rhythmic sensory cues on the temporal dynamics of human gait. AB - Walking is a complex, rhythmic task performed by the locomotor system. However, natural gait rhythms can be influenced by metronomic auditory stimuli, a phenomenon of particular interest in neurological rehabilitation. In this paper, we examined the effects of aural, visual and tactile rhythmic cues on the temporal dynamics associated with human gait. Data were collected from fifteen healthy adults in two sessions. Each session consisted of five 15-minute trials. In the first trial of each session, participants walked at their preferred walking speed. In subsequent trials, participants were asked to walk to a metronomic beat, provided through visually, aurally, tactile or all three cues (simultaneously and in sync), the pace of which was set to the preferred walking speed of the first trial. Using the collected data, we extracted several parameters including: gait speed, mean stride interval, stride interval variability, scaling exponent and maximum Lyapunov exponent. The extracted parameters showed that rhythmic sensory cues affect the temporal dynamics of human gait. The auditory rhythmic cue had the greatest influence on the gait parameters, while the visual cue had no statistically significant effect on the scaling exponent. These results demonstrate that visual rhythmic cues could be considered as an alternative cueing modality in rehabilitation without concern of adversely altering the statistical persistence of walking. PMID- 22927947 TI - Copper chelator induced efficient episodic memory recovery in a non-transgenic Alzheimer's mouse model. AB - Alzheimer's disease (AD) is a neurodegenerative syndrom involving many different biological parameters, including the accumulation of copper metal ions in Abeta amyloid peptides due to a perturbation of copper circulation and homeostasis within the brain. Copper-containing amyloids activated by endogenous reductants are able to generate an oxidative stress that is involved in the toxicity of abnormal amyloids and contribute to the progressive loss of neurons in AD. Since only few drugs are currently available for the treatment of AD, we decided to design small molecules able to interact with copper and we evaluated these drug candidates with non-transgenic mice, since AD is mainly an aging disease, not related to genetic disorders. We created a memory deficit mouse model by a single icv injection of Abeta(1-42) peptide, in order to mimic the early stage of the disease and the key role of amyloid oligomers in AD. No memory deficit was observed in the control mice with the antisense Abeta(42-1) peptide. Here we report the capacity of a new copper-specific chelating agent, a bis-8 aminoquinoline PA1637, to fully reverse the deficit of episodic memory after three weeks of treatment by oral route on non-transgenic amyloid-impaired mice. Clioquinol and memantine have been used as comparators to validate this fast and efficient mouse model. PMID- 22927949 TI - Ocular axial length and its associations in Chinese: the Beijing Eye Study. AB - PURPOSE: To investigate the normative data of ocular axial length and its associations in Chinese. METHOD: The population-based Beijing Eye Study 2011 is a cross-sectional study performed in Greater Beijing. The study included 3468 individuals (1963 (56.6%) women) with a mean age of 64.6+/-9.8 years (range: 50 93 years). A detailed ophthalmic and medical examination was performed. Axial length was measured by optical low-coherence reflectometry. RESULTS: Axial length measurements were available for 3159 (91.1%) study participants. Mean axial length was 23.25+/-1.14 mm (range: 18.96-30.88 mm). In multivariate analysis, axial length was significantly associated with the systemic parameters of higher age (P<0.001), higher body height (P = 0.003), higher level of education (P<0.001) and urban region of habitation (P<0.001), and with the ocular parameters of thicker central cornea (P = 0.001), higher corneal curvature radius (P<0.001), deeper anterior chamber (P<0.001), thicker lens (P<0.001), more myopic refractive error (P<0.001), larger pupil diameter (P = 0.018), and higher best corrected visual acuity (P<0.001). It was additionally and negatively associated with the lens vault (P<0.001). In highly myopic eyes, axial length was significantly associated with lower level of education (P = 0.008), more myopic refractive error (P<0.001), and lower best corrected visual acuity (P = 0.034). CONCLUSIONS: Mean ocular axial length in the older adult population of Greater Beijing (23.25+/-1.14 mm) was similar to the value measured in other urban populations and was higher than in a rural Central Indian population. The association between axial length and older age may potentially be associated with a survival artifact. The association between axial length and body height agrees with the general association between anthropomorphic measures and eye globe size. The association with the level of education and urban region of habitation confirms with previous studies. In contrast in highly myopic eyes, axial length was negatively associated with educational level and best corrected visual acuity. PMID- 22927948 TI - Dietary fiber, carbohydrate quality and quantity, and mortality risk of individuals with diabetes mellitus. AB - BACKGROUND: Dietary fiber, carbohydrate quality and quantity are associated with mortality risk in the general population. Whether this is also the case among diabetes patients is unknown. OBJECTIVE: To assess the associations of dietary fiber, glycemic load, glycemic index, carbohydrate, sugar, and starch intake with mortality risk in individuals with diabetes. METHODS: This study was a prospective cohort study among 6,192 individuals with confirmed diabetes mellitus (mean age of 57.4 years, and median diabetes duration of 4.4 years at baseline) from the European Prospective Investigation into Cancer and Nutrition (EPIC). Dietary intake was assessed at baseline (1992-2000) with validated dietary questionnaires. Cox proportional hazards analysis was performed to estimate hazard ratios (HRs) for all-cause and cardiovascular mortality, while adjusting for CVD-related, diabetes-related, and nutritional factors. RESULTS: During a median follow-up of 9.2 y, 791 deaths were recorded, 306 due to CVD. Dietary fiber was inversely associated with all-cause mortality risk (adjusted HR per SD increase, 0.83 [95% CI, 0.75-0.91]) and CVD mortality risk (0.76[0.64-0.89]). No significant associations were observed for glycemic load, glycemic index, carbohydrate, sugar, or starch. Glycemic load (1.42[1.07-1.88]), carbohydrate (1.67[1.18-2.37]) and sugar intake (1.53[1.12-2.09]) were associated with an increased total mortality risk among normal weight individuals (BMI<=25 kg/m(2); 22% of study population) but not among overweight individuals (P interaction<=0.04). These associations became stronger after exclusion of energy misreporters. CONCLUSIONS: High fiber intake was associated with a decreased mortality risk. High glycemic load, carbohydrate and sugar intake were associated with an increased mortality risk in normal weight individuals with diabetes. PMID- 22927950 TI - Gene expression profiling during conidiation in the rice blast pathogen Magnaporthe oryzae. AB - Conidiation of phytopathogenic fungi is a key developmental process that plays a central role in their life cycles and in epidemics. However, there is little information on conidiation-induced molecular changes in the rice blast fungus Magnaporthe oryzae. As a first step to understand conidiogenesis in this fungus, we measured genome-wide gene expression profiles during conidiation using a whole genome oligonucleotide microarray. At a two-fold expression difference, approximately 4.42% and 4.08% of genes were upregulated and downregulated, respectively, during conidiation. The differentially expressed genes were functionally categorized by gene ontology (GO) term analysis, which demonstrated that the gene set encoded proteins that function in metabolism, cell wall biosynthesis, transcription, and molecule transport. To define the events of the complicated process of conidiogenesis, another set of microarray experiments was performed using a deletion mutant for MoHOX2, a stage-specific transcriptional regulator essential for conidial formation, which was expressed de novo in a conidiation-specific manner in M. oryzae. Gene expression profiles were compared between the wild-type and the DeltaMohox2 mutant during conidiation. This analysis defined a common gene set that was upregulated in the wild-type and downregulated in the DeltaMohox2 mutant during conidiation; this gene set is expected to include conidiation-related downstream genes of MoHOX2. We identified several hundred genes that are differentially-expressed during conidiation; our results serve as an important resource for understanding the conidiation, a process in M. oryzae, which is critical for disease development. PMID- 22927951 TI - Synergistic effects of nanosecond pulsed electric fields combined with low concentration of gemcitabine on human oral squamous cell carcinoma in vitro. AB - Treatment of cancer often involves uses of multiple therapeutic strategies with different mechanisms of action. In this study we investigated combinations of nanosecond pulsed electric fields (nsPEF) with low concentrations of gemcitabine on human oral cancer cells. Cells (Cal-27) were treated with pulse parameters (20 pulses, 100 ns in duration, intensities of 10, 30 and 60 kV/cm) and then cultured in medium with 0.01 ug/ml gemcitabine. Proliferation, apoptosis/necrosis, invasion and morphology of those cells were examined using MTT, flow cytometry, clonogenics, transwell migration and TEM assay. Results show that combination treatments of gemcitabine and nsPEFs exhibited significant synergistic activities versus individual treatments for inhibiting oral cancer cell proliferation and inducing apoptosis and necrosis. However, there was no apparent synergism for cell invasion. By this we demonstrated synergistic inhibition of Cal-27 cells in vitro by nsPEFs and gemcitabine. Synergistic behavior indicates that these two treatments have different sites of action and combination treatment allows reduced doses of gemcitabine and lower nsPEF conditions, which may provide better treatment for patients than either treatment alone while reducing systemic toxicities. PMID- 22927952 TI - Estimation of the relative sensitivity of the comparative tuberculin skin test in tuberculous cattle herds subjected to depopulation. AB - Bovine tuberculosis (bTB) is one of the most serious economic animal health problems affecting the cattle industry in Great Britain (GB), with incidence in cattle herds increasing since the mid-1980s. The single intradermal comparative cervical tuberculin (SICCT) test is the primary screening test in the bTB surveillance and control programme in GB and Ireland. The sensitivity (ability to detect infected cattle) of this test is central to the efficacy of the current testing regime, but most previous studies that have estimated test sensitivity (relative to the number of slaughtered cattle with visible lesions [VL] and/or positive culture results) lacked post-mortem data for SICCT test-negative cattle. The slaughter of entire herds ("whole herd slaughters" or "depopulations") that are infected by bTB are occasionally conducted in GB as a last-resort control measure to resolve intractable bTB herd breakdowns. These provide additional post mortem data for SICCT test-negative cattle, allowing a rare opportunity to calculate the animal-level sensitivity of the test relative to the total number of SICCT test-positive and negative VL animals identified post-mortem (rSe). In this study, data were analysed from 16 whole herd slaughters (748 SICCT test positive and 1031 SICCT test-negative cattle) conducted in GB between 1988 and 2010, using a bayesian hierarchical model. The overall rSe estimate of the SICCT test at the severe interpretation was 85% (95% credible interval [CI]: 78-91%), and at standard interpretation was 81% (95% CI: 70-89%). These estimates are more robust than those previously reported in GB due to inclusion of post-mortem data from SICCT test-negative cattle. PMID- 22927953 TI - Critical motor number for fractional steps of cytoskeletal filaments in gliding assays. AB - In gliding assays, filaments are pulled by molecular motors that are immobilized on a solid surface. By varying the motor density on the surface, one can control the number N of motors that pull simultaneously on a single filament. Here, such gliding assays are studied theoretically using brownian (or Langevin) dynamics simulations and taking the local force balance between motors and filaments as well as the force-dependent velocity of the motors into account. We focus on the filament stepping dynamics and investigate how single motor properties such as stalk elasticity and step size determine the presence or absence of fractional steps of the filaments. We show that each gliding assay can be characterized by a critical motor number, N(c). Because of thermal fluctuations, fractional filament steps are only detectable as long as N < N(c). The corresponding fractional filament step size is l/N where l is the step size of a single motor. We first apply our computational approach to microtubules pulled by kinesin-1 motors. For elastic motor stalks that behave as linear springs with a zero rest length, the critical motor number is found to be N(c) = 4, and the corresponding distributions of the filament step sizes are in good agreement with the available experimental data. In general, the critical motor number N(c) depends on the elastic stalk properties and is reduced to N(c) = 3 for linear springs with a nonzero rest length. Furthermore, N(c) is shown to depend quadratically on the motor step size l. Therefore, gliding assays consisting of actin filaments and myosin-V are predicted to exhibit fractional filament steps up to motor number N = 31. Finally, we show that fractional filament steps are also detectable for a fixed average motor number as determined by the surface density (or coverage) of the motors on the substrate surface. PMID- 22927954 TI - Expression of wild-type Rp1 protein in Rp1 knock-in mice rescues the retinal degeneration phenotype. AB - Mutations in the retinitis pigmentosa 1 (RP1) gene are a common cause of autosomal dominant retinitis pigmentosa (adRP), and have also been found to cause autosomal recessive RP (arRP) in a few families. The 33 dominant mutations and 6 recessive RP1 mutations identified to date are all nonsense or frameshift mutations, and almost exclusively (38 out of 39) are located in the 4(th) and final exon of RP1. To better understand the underlying disease mechanisms of and help develop therapeutic strategies for RP1 disease, we performed a series of human genetic and animal studies using gene targeted and transgenic mice. Here we report that a frameshift mutation in the 3(rd) exon of RP1 (c.686delC; p.P229QfsX35) found in a patient with recessive RP1 disease causes RP in the homozygous state, whereas the heterozygous carriers are unaffected, confirming that haploinsufficiency is not the causative mechanism for RP1 disease. We then generated Rp1 knock-in mice with a nonsense Q662X mutation in exon 4, as well as Rp1 transgenic mice carrying a wild-type BAC Rp1 transgene. The Rp1-Q662X allele produces a truncated Rp1 protein, and homozygous Rp1-Q662X mice experience a progressive photoreceptor degeneration characterized disorganization of photoreceptor outer segments. This phenotype could be prevented by expression of a normal amount of Rp1 protein from the BAC transgene without removal of the mutant Rp1-Q662X protein. Over-expression of Rp1 protein in additional BAC Rp1 transgenic lines resulted in retinal degeneration. These findings suggest that the truncated Rp1-Q662X protein does not exert a toxic gain-of-function effect. These results also imply that in principle gene augmentation therapy could be beneficial for both recessive and dominant RP1 patients, but the levels of RP1 protein delivered for therapy will have to be carefully controlled. PMID- 22927955 TI - Rock sparrow song reflects male age and reproductive success. AB - The evolution of mating signals is closely linked to sexual selection. Acoustic ornaments are often used as secondary sexual traits that signal the quality of the signaller. Here we show that song performance reflects age and reproductive success in the rock sparrow (Petronia petronia). In an Alpine population in south east France, we recorded the songs of males and assessed their genetic breeding success by microsatellite analysis. In addition to temporal and spectral song features, we also analysed for the first time whether the sound pressure level of bird song reflects reproductive success. Males with higher breeding success sang at a lower rate and with a higher maximum frequency. We found also that older males gained more extra-pair young and had a higher overall breeding success, although they also differed almost significantly by having a higher loss of paternity in their own nests. Older males could be distinguished from yearlings by singing at lower rate and higher amplitudes. Our findings suggest that song rate may be used as a signal of age and together with song pitch as a signal of reproductive success in this species. Alternatively, younger and less successful males might try to compensate their inferior status by increased song rates and lower pitch. Independent of age and quality, high-amplitude songs correlated with paternity loss in the own nest, suggesting that in this species song amplitude is not an indicator of male quality but high-intensity songs may be rather a response to unfaithful social mates. PMID- 22927956 TI - Skin TLR7 triggering promotes accumulation of respiratory dendritic cells and natural killer cells. AB - The TLR7 agonist imiquimod has been used successfully as adjuvant for skin treatment of virus-associated warts and basal cell carcinoma. The effects of skin TLR7 triggering on respiratory leukocyte populations are unknown. In a placebo controlled experimental animal study we have used multicolour flow cytometry to systematically analyze the modulation of respiratory leukocyte subsets after skin administration of imiquimod. Compared to placebo, skin administration of imiquimod significantly increased respiratory dendritic cells (DC) and natural killer cells, whereas total respiratory leukocyte, alveolar macrophages, classical CD4+ T helper and CD8+ T killer cell numbers were not or only moderately affected. DC subpopulation analyses revealed that elevation of respiratory DC was caused by an increase of respiratory monocytic DC and CD11b(hi) DC subsets. Lymphocyte subpopulation analyses indicated a marked elevation of respiratory natural killer cells and a significant reduction of B lymphocytes. Analysis of cytokine responses of respiratory leukocytes after stimulation with Klebsiella pneumonia indicated reduced IFN-gamma and TNF-alpha expression and increased IL-10 and IL-12p70 production after 7 day low dose skin TLR7 triggering. Additionally, respiratory NK cytotoxic activity was increased after 7d skin TLR7 triggering. In contrast, lung histology and bronchoalveolar cell counts were not affected suggesting that skin TLR7 stimulation modulated respiratory leukocyte composition without inducing overt pulmonary inflammation. These data suggest the possibility to modulate respiratory leukocyte composition and respiratory cytokine responses against pathogens like Klebsiella pneumonia through skin administration of a clinically approved TLR7 ligand. Skin administration of synthetic TLR7 ligands may represent a novel, noninvasive means to modulate respiratory immunity. PMID- 22927957 TI - Fabrication of polypyrrole/graphene oxide composite nanosheets and their applications for Cr(VI) removal in aqueous solution. AB - In this paper, we report on the simple, reliable synthesis of polypyrrole (PPy)/graphene oxide (GO) composite nanosheets by using sacrificial-template polymerization method. Herein, MnO(2) nanoslices were chosen as a sacrificial template to deposit PPy, which served as the oxidant as well. During the polymerization of pyrrole on surface of GO nanosheets, MnO(2) component was consumed incessantly. As a result, the PPy growing on the surface of GO nanosheets has the morphology just like the MnO(2) nanoslices. This method can provide the fabrication of PPy nanostructures more easily than conventional route due to its independence of removing template, which usually is a complex and tedious experimental process. The as-prepared PPy/GO composite nanosheets exhibited an enhanced properties for Cr(VI) ions removal in aqueous solution based on the synergy effect. The adsorption capacity of the PPy/GO composite nanosheets is about two times as large as that of conventional PPy nanoparticles. We believe that our findings can open a new and effective avenue to improve the adsorption performance in removing heavy metal ions from waste water. PMID- 22927958 TI - Selection of microsatellite markers for bladder cancer diagnosis without the need for corresponding blood. AB - Microsatellite markers are used for loss-of-heterozygosity, allelic imbalance and clonality analyses in cancers. Usually, tumor DNA is compared to corresponding normal DNA. However, normal DNA is not always available and can display aberrant allele ratios due to copy number variations in the genome. Moreover, stutter peaks may complicate the analysis. To use microsatellite markers for diagnosis of recurrent bladder cancer, we aimed to select markers without stutter peaks and a constant ratio between alleles, thereby avoiding the need for a control DNA sample. We investigated 49 microsatellite markers with tri- and tetranucleotide repeats in regions commonly lost in bladder cancer. Based on analysis of 50 blood DNAs the 12 best performing markers were selected with few stutter peaks and a constant ratio between peaks heights. Per marker upper and lower cut off values for allele ratios were determined. LOH of the markers was observed in 59/104 tumor DNAs. We then determined the sensitivity of the marker panel for detection of recurrent bladder cancer by assaying 102 urine samples of these patients. Sensitivity was 63% when patients were stratified for LOH in their primary tumors. We demonstrate that up-front selection of microsatellite markers obliterates the need for a corresponding blood sample. For diagnosis of bladder cancer recurrences in urine this significantly reduces costs. Moreover, this approach facilitates retrospective analysis of archival tumor samples for allelic imbalance. PMID- 22927959 TI - Stratification of Archaea in the deep sediments of a freshwater meromictic lake: vertical shift from methanogenic to uncultured archaeal lineages. AB - As for lineages of known methanogens, several lineages of uncultured archaea were recurrently retrieved in freshwater sediments. However, knowledge is missing about how these lineages might be affected and structured according to depth. In the present study, the vertical changes of archaeal communities were characterized in the deep sediment of the freshwater meromictic Lake Pavin. For that purpose, an integrated molecular approach was performed to gain information on the structure, composition, abundance and vertical stratification of archaeal communities thriving in anoxic freshwater sediments along a gradient of sediments encompassing 130 years of sedimentation. Huge changes occurred in the structure and composition of archaeal assemblages along the sediment core. Methanogenic taxa (i.e. Methanosaeta and Methanomicrobiales) were progressively replaced by uncultured archaeal lineages (i.e. Marine Benthic Group-D (MBG-D) and Miscellaneous Crenarchaeal Group (MCG)) which are suspected to be involved in the methane cycle. PMID- 22927960 TI - Runx2 haploinsufficiency ameliorates the development of ossification of the posterior longitudinal ligament. AB - Ossification of the Posterior Longitudinal Ligament (OPLL) is a disease that is characterized by the ectopic calcification of the ligament; however, the pathogenesis of OPLL remains to be investigated. We attempted to identify the in vivo role of Runx2, a master regulator of osteoblast differentiation and skeletal mineralization, in the pathogenesis of OPLL. The expression of Runx2 in the ligament was examined using in situ hybridization and immunohistochemistry and by monitoring the activity of a LacZ gene that was inserted into the Runx2 gene locus. To investigate the functional role of Runx2, we studied ENPP1(ttw/ttw) mice, a mouse model of OPLL, that were crossed with heterozygous Runx2 mice to decrease the expression of Runx2, and we performed histological and quantitative radiological analyses using 3D-micro CT. Runx2 was expressed in the ligament of wild-type mice. The induction of Runx2 expression preceded the development of ectopic calcification in the OPLL-like region of the ENPP1(ttw/ttw) mice. Runx2 haploinsufficiency ameliorated the development of ectopic calcification in the ENPP1(ttw/ttw) mice. Collectively, this study demonstrated that Runx2 is expressed in an OPLL-like region, and its elevation is a prerequisite for developing the complete OPLL-like phenotype in a mouse model of OPLL. PMID- 22927961 TI - PKH26 staining defines distinct subsets of normal human colon epithelial cells at different maturation stages. AB - BACKGROUND AND AIM: Colon crypts are characterized by a hierarchy of cells distributed along the crypt axis. Aim of this paper was to develop an in vitro system for separation of epithelial cell subsets in different maturation stages from normal human colon. METHODOLOGY AND MAJOR FINDINGS: Dissociated colonic epithelial cells were stained with PKH26, which allows identification of distinct populations based on their proliferation rate, and cultured in vitro in the absence of serum. The cytofluorimetric expression of CK20, Msi-1 and Lgr5 was studied. The mRNA levels of several stemness-associated genes were also compared in cultured cell populations and in three colon crypt populations isolated by microdissection. A PKH(pos) population survived in culture and formed spheroids; this population included subsets with slow (PKH(high)) and rapid (PKH(low)) replicative rates. Molecular analysis revealed higher mRNA levels of both Msi-1 and Lgr-5 in PKH(high) cells; by cytofluorimetric analysis, Msi-1(+)/Lgr5(+) cells were only found within PKH(high) cells, whereas Msi-1(+)/Lgr5(-) cells were also observed in the PKH(low) population. As judged by qRT-PCR analysis, the expression of several stemness-associated markers (Bmi-1, EphB2, EpCAM, ALDH1) was highly enriched in Msi-1(+)/Lgr5(+) cells. While CK20 expression was mainly found in PKH(low) and PKH(neg) cells, a small PKH(high) subset co-expressed both CK20 and Msi-1, but not Lgr5; cells with these properties also expressed Mucin, and could be identified in vivo in colon crypts. These results mirrored those found in cells isolated from different crypt portions by microdissection, and based on proliferation rates and marker expression they allowed to define several subsets at different maturation stages: PKH(high)/Lgr5(+)/Msi-1(+)/CK20(-), PKH(high)/Lgr5(-)/Msi-1(+)/CK20(+), PKH(low)/Lgr5(-)/Msi-1(+)/Ck20(-), and PKH(low)/Lgr5(-)/Msi-1(-)/CK20(+) cells. CONCLUSIONS: Our data show the possibility of deriving in vitro, without any selection strategy, several distinct cell subsets of human colon epithelial cells, which recapitulate the phenotypic and molecular profile of cells in a discrete crypt location. PMID- 22927962 TI - Executive functions profile in extreme eating/weight conditions: from anorexia nervosa to obesity. AB - BACKGROUND: Extreme weight conditions (EWC) groups along a continuum may share some biological risk factors and intermediate neurocognitive phenotypes. A core cognitive trait in EWC appears to be executive dysfunction, with a focus on decision making, response inhibition and cognitive flexibility. Differences between individuals in these areas are likely to contribute to the differences in vulnerability to EWC. The aim of the study was to investigate whether there is a common pattern of executive dysfunction in EWC while comparing anorexia nervosa patients (AN), obese subjects (OB) and healthy eating/weight controls (HC). METHODS: Thirty five AN patients, fifty two OB and one hundred thirty seven HC were compared using the Wisconsin Card Sorting Test (WCST); Stroop Color and Word Test (SCWT); and Iowa Gambling Task (IGT). All participants were female, aged between 18 and 60 years. RESULTS: There was a significant difference in IGT score (F(1.79); p<.001), with AN and OB groups showing the poorest performance compared to HC. On the WCST, AN and OB made significantly more errors than controls (F(25.73); p<.001), and had significantly fewer correct responses (F(2.71); p<.001). Post hoc analysis revealed that the two clinical groups were not significantly different from each other. Finally, OB showed a significant reduced performance in the inhibition response measured with the Stroop test (F(5.11); p<.001) compared with both AN and HC. CONCLUSIONS: These findings suggest that EWC subjects (namely AN and OB) have similar dysfunctional executive profile that may play a role in the development and maintenance of such disorders. PMID- 22927963 TI - An active factor from tomato root exudates plays an important role in efficient establishment of mycorrhizal symbiosis. AB - Root exudates play an important role in the early signal exchange between host plants and arbuscular mycorrhizal fungi. M161, a pre-mycorrhizal infection (pmi) mutant of the tomoto (Solanum lycopersicum) cultivar Micro-Tom, fails to establish normal arbuscular mycorrhizal symbioses, and produces exudates that are unable to stimulate hyphal growth and branching of Glomus intraradices. Here, we report the identification of a purified active factor (AF) that is present in the root exudates of wild-type tomato, but absent in those of M161. A complementation assay using the dual root organ culture system showed that the AF could induce fungal growth and branching at the pre-infection stage and, subsequently, the formation of viable new spores in the M161 background. Since the AF-mediated stimulation of hyphal growth and branching requires the presence of the M161 root, our data suggest that the AF is essential but not sufficient for hyphal growth and branching. We propose that the AF, which remains to be chemically determined, represents a plant signal molecule that plays an important role in the efficient establishment of mycorrhizal symbioses. PMID- 22927964 TI - Receptor diversity and host interaction of bacteriophages infecting Salmonella enterica serovar Typhimurium. AB - BACKGROUND: Salmonella enterica subspecies enterica serovar Typhimurium is a gram negative pathogen causing salmonellosis. Salmonella Typhimurium-targeting bacteriophages have been proposed as an alternative biocontrol agent to antibiotics. To further understand infection and interaction mechanisms between the host strains and the bacteriophages, the receptor diversity of these phages needs to be elucidated. METHODOLOGY/PRINCIPAL FINDINGS: Twenty-five Salmonella phages were isolated and their receptors were identified by screening a Tn5 random mutant library of S. Typhimurium SL1344. Among them, three types of receptors were identified flagella (11 phages), vitamin B(12) uptake outer membrane protein, BtuB (7 phages) and lipopolysaccharide-related O-antigen (7 phages). TEM observation revealed that the phages using flagella (group F) or BtuB (group B) as a receptor belong to Siphoviridae family, and the phages using O-antigen of LPS as a receptor (group L) belong to Podoviridae family. Interestingly, while some of group F phages (F-I) target FliC host receptor, others (F-II) target both FliC and FljB receptors, suggesting that two subgroups are present in group F phages. Cross-resistance assay of group B and L revealed that group L phages could not infect group B phage-resistant strains and reversely group B phages could not infect group L SPN9TCW-resistant strain. CONCLUSIONS/SIGNIFICANCE: In this report, three receptor groups of 25 newly isolated S. Typhimurium-targeting phages were determined. Among them, two subgroups of group F phages interact with their host receptors in different manner. In addition, the host receptors of group B or group L SPN9TCW phages hinder other group phage infection, probably due to interaction between receptors of their groups. This study provides novel insights into phage-host receptor interaction for Salmonella phages and will inform development of optimal phage therapy for protection against Salmonella. PMID- 22927965 TI - HGF and direct mesenchymal stem cells contact synergize to inhibit hepatic stellate cells activation through TLR4/NF-kB pathway. AB - AIMS: Bone marrow-derived mesenchymal stem cells (BMSCs) can reduce liver fibrosis. Apart from the paracrine mechanism by which the antifibrotic effects of BMSCs inhibit activated hepatic stellate cells (HSCs), the effects of direct interplay and juxtacrine signaling between the two cell types are poorly understood. The purpose of this study was to explore the underlying mechanisms by which BMSCs modulate the function of activated HSCs. METHODS: We used BMSCs directly and indirectly co-culture system with HSCs to evaluate the anti-fibrosis effect of BMSCs. Cell proliferation and activation were examined in the presence of BMSCs and HGF. c-met was knockdown in HSCs to evaluate the effect of HGF secreted by BMSCs. The TLR4 and Myeloid differentiation primary response gene 88(MyD88) mRNA levels and the NF-kB pathway activation were determined by real time PCR and western blotting analyses. The effect of BMSCs on HSCs activation was investigated in vitro in either MyD88 silencing or overexpression in HSCs. Liver fibrosis in rats fed CCl(4) with and without BMSCs supplementation was compared. Histopathological examinations and serum biochemical tests were compared between the two groups. RESULTS: BMSCs remarkably inhibited the proliferation and activation of HSCs by interfering with LPS-TLR4 pathway through a cell-cell contact mode that was partially mediated by HGF secretion. The NF-kB pathway is involved in HSCs activation inhibition by BMSCs. MyD88 over expression reduced the BMSC inhibition of NF-kB luciferase activation. BMSCs protected liver fibrosis in vivo. CONCLUSION: BMSCs modulate HSCs in vitro via TLR4/MyD88/NF-kB signaling pathway through cell-cell contact and secreting HGF. BMSCs have therapeutic effects on cirrhosis rats. Our results provide new insights into the treatment of hepatic fibrosis with BMSCs. PMID- 22927966 TI - Veins improve fracture toughness of insect wings. AB - During the lifetime of a flying insect, its wings are subjected to mechanical forces and deformations for millions of cycles. Defects in the micrometre thin membranes or veins may reduce the insect's flight performance. How do insects prevent crack related material failure in their wings and what role does the characteristic vein pattern play? Fracture toughness is a parameter, which characterises a material's resistance to crack propagation. Our results show that, compared to other body parts, the hind wing membrane of the migratory locust S. gregaria itself is not exceptionally tough (1.04+/-0.25 MPa?m). However, the cross veins increase the wing's toughness by 50% by acting as barriers to crack propagation. Using fracture mechanics, we show that the morphological spacing of most wing veins matches the critical crack length of the material (1132 um). This finding directly demonstrates how the biomechanical properties and the morphology of locust wings are functionally correlated in locusts, providing a mechanically 'optimal' solution with high toughness and low weight. The vein pattern found in insect wings thus might inspire the design of more durable and lightweight artificial 'venous' wings for micro-air-vehicles. Using the vein spacing as indicator, our approach might also provide a basis to estimate the wing properties of endangered or extinct insect species. PMID- 22927967 TI - Inhibitory effect of mTOR activator MHY1485 on autophagy: suppression of lysosomal fusion. AB - Autophagy is a major degradative process responsible for the disposal of cytoplasmic proteins and dysfunctional organelles via the lysosomal pathway. During the autophagic process, cells form double-membraned vesicles called autophagosomes that sequester disposable materials in the cytoplasm and finally fuse with lysosomes. In the present study, we investigated the inhibition of autophagy by a synthesized compound, MHY1485, in a culture system by using Ac2F rat hepatocytes. Autophagic flux was measured to evaluate the autophagic activity. Autophagosomes were visualized in Ac2F cells transfected with AdGFP-LC3 by live-cell confocal microscopy. In addition, activity of mTOR, a major regulatory protein of autophagy, was assessed by western blot and docking simulation using AutoDock 4.2. In the result, treatment with MHY1485 suppressed the basal autophagic flux, and this inhibitory effect was clearly confirmed in cells under starvation, a strong physiological inducer of autophagy. The levels of p62 and beclin-1 did not show significant change after treatment with MHY1485. Decreased co-localization of autophagosomes and lysosomes in confocal microscopic images revealed the inhibitory effect of MHY1485 on lysosomal fusion during starvation-induced autophagy. These effects of MHY1485 led to the accumulation of LC3II and enlargement of the autophagosomes in a dose- and time-dependent manner. Furthermore, MHY1485 induced mTOR activation and correspondingly showed a higher docking score than PP242, a well-known ATP-competitive mTOR inhibitor, in docking simulation. In conclusion, MHY1485 has an inhibitory effect on the autophagic process by inhibition of fusion between autophagosomes and lysosomes leading to the accumulation of LC3II protein and enlarged autophagosomes. MHY1485 also induces mTOR activity, providing a possibility for another regulatory mechanism of autophagy by the MHY compound. The significance of this study is the finding of a novel inhibitor of autophagy with an mTOR activating effect. PMID- 22927968 TI - Rhamnose-inducible gene expression in Listeria monocytogenes. AB - Acid production from rhamnose is a characteristic phenotype of Listeria monocytogenes. We report the identification of the rhamnose transport and utilization operon located at lmo2846 to lmo2851, including the rhamnose dependent promoter P(rha). Expression of reporter genes under control of P(rha) on a single copy integration vector demonstrated its suitability for inducible gene expression in L. monocytogenes. Transcription initiation from P(rha) is dose dependent, and a concentration as low as 100 uM rhamnose was found sufficient for induction. Moreover, P(rha) is subject to glucose catabolite repression, which provides additional options for strict control of expression. Infection of human THP1 macrophages revealed that P(rha) is repressed in intracellular L. monocytogenes, which is explained by the absence of rhamnose in the cytosol and possible interference by catabolite repression. The P(rha) promoter provides a novel and useful tool for triggering gene expression in extracellular L. monocytogenes, whereas intracellular conditions prevent transcription from this promoter. PMID- 22927969 TI - Differential regulation of Smad3 and of the type II transforming growth factor beta receptor in mitosis: implications for signaling. AB - The response to transforming growth factor-beta (TGF-beta) depends on cellular context. This context is changed in mitosis through selective inhibition of vesicle trafficking, reduction in cell volume and the activation of mitotic kinases. We hypothesized that these alterations in cell context may induce a differential regulation of Smads and TGF-beta receptors. We tested this hypothesis in mesenchymal-like ovarian cancer cells, arrested (or not) in mitosis with 2-methoxyestradiol (2ME2). In mitosis, without TGF-beta stimulation, Smad3 was phosphorylated at the C-terminus and linker regions and localized to the mitotic spindle. Phosphorylated Smad3 interacted with the negative regulators of Smad signaling, Smurf2 and Ski, and failed to induce a transcriptional response. Moreover, in cells arrested in mitosis, Smad3 levels were progressively reduced. These phosphorylations and reduction in the levels of Smad3 depended on ERK activation and Mps1 kinase activity, and were abrogated by increasing the volume of cells arrested in mitosis with hypotonic medium. Furthermore, an Mps1 dependent phosphorylation of GFP-Smad3 was also observed upon its over-expression in interphase cells, suggesting a mechanism of negative regulation which counters increases in Smad3 concentration. Arrest in mitosis also induced a block in the clathrin-mediated endocytosis of the type II TGF-beta receptor (TbetaRII). Moreover, following the stimulation of mitotic cells with TGF-beta, the proteasome-mediated attenuation of TGF-beta receptor activity, the degradation and clearance of TbetaRII from the plasma membrane, and the clearance of the TGF beta ligand from the medium were compromised, and the C-terminus phosphorylation of Smad3 was prolonged. We propose that the reduction in Smad3 levels, its linker phosphorylation, and its association with negative regulators (observed in mitosis prior to ligand stimulation) represent a signal attenuating mechanism. This mechanism is balanced by the retention of active TGF-beta receptors at the plasma membrane. Together, both mechanisms allow for a regulated cellular response to TGF-beta stimuli in mitosis. PMID- 22927970 TI - Melanosomal dynamics assessed with a live-cell fluorescent melanosomal marker. AB - Melanocytes present in skin and other organs synthesize and store melanin pigment within membrane-delimited organelles called melanosomes. Exposure of human skin to ultraviolet radiation (UV) stimulates melanin production in melanosomes, followed by transfer of melanosomes from melanocytes to neighboring keratinocytes. Melanosomal function is critical for protecting skin against UV radiation, but the mechanisms underlying melanosomal movement and transfer are not well understood. Here we report a novel fluorescent melanosomal marker, which we used to measure real-time melanosomal dynamics in live human epidermal melanocytes (HEMs) and transfer in melanocyte-keratinocyte co-cultures. A fluorescent fusion protein of Ocular Albinism 1 (OA1) localized to melanosomes in both B16-F1 cells and HEMs, and its expression did not significantly alter melanosomal distribution. Live-cell tracking of OA1-GFP-tagged melanosomes revealed a bimodal kinetic profile, with melanosomes exhibiting combinations of slow and fast movement. We also found that exposure to UV radiation increased the fraction of melanosomes exhibiting fast versus slow movement. In addition, using OA1-GFP in live co-cultures, we monitored melanosomal transfer using time-lapse microscopy. These results highlight OA1-GFP as a specific and effective melanosomal marker for live-cell studies, reveal new aspects of melanosomal dynamics and transfer, and are relevant to understanding the skin's physiological response to UV radiation. PMID- 22927971 TI - Expression of eukaryotic initiation factor 5A and hypusine forming enzymes in glioblastoma patient samples: implications for new targeted therapies. AB - Glioblastomas are highly aggressive brain tumors of adults with poor clinical outcome. Despite a broad range of new and more specific treatment strategies, therapy of glioblastomas remains challenging and tumors relapse in all cases. Recent work demonstrated that the posttranslational hypusine modification of the eukaryotic initiation factor 5A (eIF-5A) is a crucial regulator of cell proliferation, differentiation and an important factor in tumor formation, progression and maintenance. Here we report that eIF-5A as well as the hypusine forming enzymes deoxyhypusine synthase (DHS) and deoxyhypusine hydroxylase (DOHH) are highly overexpressed in glioblastoma patient samples. Importantly, targeting eIF-5A and its hypusine modification with GC7, a specific DHS-inhibitor, showed a strong antiproliferative effect in glioblastoma cell lines in vitro, while normal human astrocytes were not affected. Furthermore, we identified p53 dependent premature senescence, a permanent cell cycle arrest, as the primary outcome in U87-MG cells after treatment with GC7. Strikingly, combined treatment with clinically relevant alkylating agents and GC7 had an additive antiproliferative effect in glioblastoma cell lines. In addition, stable knockdown of eIF-5A and DHS by short hairpin RNA (shRNA) could mimic the antiproliferative effects of GC7. These findings suggest that pharmacological inhibition of eIF-5A may represent a novel concept to treat glioblastomas and may help to substantially improve the clinical course of this tumor entity. PMID- 22927972 TI - Combined esophageal intraluminal impedance, pH and skin conductance monitoring to detect discomfort in GERD infants. AB - BACKGROUND: The clinical significance of weakly acidic reflux in infants is unclear. Skin conductance is a novel not-invasive method to evaluate discomfort. The aim of our study was to evaluate reflux-induced discomfort in infants with gastroesophageal reflux disease using simultaneously combined skin conductance and esophageal multichannel intraluminal impedance and pH monitoring. METHODOLOGY/PRINCIPAL FINDINGS: Infants with gastroesophageal reflux symptoms were investigated for almost 20 hours divided into 120-second intervals. Temporal relationships between refluxes and discomfort were evaluated calculating the symptom association probability. Twelve infants aged 17-45 days were studied. Out of 194.38 hours of adequate artifact-free MII/pH and skin conductance monitoring, 584 reflux events were observed; 35.78% were positive for stress, of which 16.27% were acid and 83.73% weakly acidic. A significant association between refluxes and discomfort (p<0.05) was present in all infants. The intervals with reflux events showed increased skin conductance values compared to reflux-free intervals (p<0.001); SC values were similar for acid and weakly acidic reflux events. CONCLUSION/SIGNFICANCE: Discomfort was significantly associated with reflux events and did not differ between weakly acidic and acid refluxes. Our results may raise concerns about the over-prescription use of antacid drugs in the management of gastroesophageal reflux symptoms in infancy. PMID- 22927973 TI - High-tech hip implant for wireless temperature measurements in vivo. AB - When walking long distances, hip prostheses heat up due to friction. The influence of articulating materials and lubricating properties of synovia on the final temperatures, as well as any potential biological consequences, are unknown. Such knowledge is essential for optimizing implant materials, identifying patients who are possibly at risk of implant loosening, and proving the concepts of current joint simulators. An instrumented hip implant with telemetric data transfer was developed to measure the implant temperatures in vivo. A clinical study with 100 patients is planned to measure the implant temperatures for different combinations of head and cup materials during walking. This study will answer the question of whether patients with synovia with poor lubricating properties may be at risk for thermally induced bone necrosis and subsequent implant failure. The study will also deliver the different friction properties of various implant materials and prove the significance of wear simulator tests. A clinically successful titanium hip endoprosthesis was modified to house the electronics inside its hollow neck. The electronics are powered by an external induction coil fixed around the joint. A temperature sensor inside the implant triggers a timer circuit, which produces an inductive pulse train with temperature-dependent intervals. This signal is detected by a giant magnetoresistive sensor fixed near the external energy coil. The implant temperature is measured with an accuracy of 0.1 degrees C in a range between 20 degrees C and 58 degrees C and at a sampling rate of 2-10 Hz. This rate could be considerably increased for measuring other data, such as implant strain or vibration. The employed technique of transmitting data from inside of a closed titanium implant by low frequency magnetic pulses eliminates the need to use an electrical feedthrough and an antenna outside of the implant. It enables the design of mechanically safe and simple instrumented implants. PMID- 22927974 TI - Linking foraging decisions to residential yard bird composition. AB - Urban bird communities have higher densities but lower diversity compared with wildlands. However, recent studies show that residential urban yards with native plantings have higher native bird diversity compared with yards with exotic vegetation. Here we tested whether landscape designs also affect bird foraging behavior. We estimated foraging decisions by measuring the giving-up densities (GUD; amount of food resources remaining when the final forager quits foraging on an artificial food patch, i.e seed trays) in residential yards in Phoenix, AZ, USA. We assessed how two yard designs (mesic: lush, exotic vegetation; xeric: drought-tolerant and native vegetation) differed in foraging costs. Further, we developed a statistical model to calculate GUDs for every species visiting the seed tray. Birds foraging in mesic yards depleted seed trays to a lower level (i.e. had lower GUDs) compared to birds foraging in xeric yards. After accounting for bird densities, the lower GUDs in mesic yards appeared largely driven by invasive and synanthropic species. Furthermore, behavioral responses of individual species were affected by yard design. Species visiting trays in both yard designs had lower GUDs in mesic yards. Differences in resource abundance (i.e., alternative resources more abundant and of higher quality in xeric yards) contributed to our results, while predation costs associated with foraging did not. By enhancing the GUD, a common method for assessing the costs associated with foraging, our statistical model provided insights into how individual species and bird densities influenced the GUD. These differences we found in foraging behavior were indicative of differences in habitat quality, and thus our study lends additional support for native landscapes to help reverse the loss of urban bird diversity. PMID- 22927975 TI - Phylogeography of the crown-of-thorns starfish in the Indian Ocean. AB - BACKGROUND: Understanding the limits and population dynamics of closely related sibling species in the marine realm is particularly relevant in organisms that require management. The crown-of-thorns starfish Acanthaster planci, recently shown to be a species complex of at least four closely related species, is a coral predator infamous for its outbreaks that have devastated reefs throughout much of its Indo-Pacific distribution. METHODOLOGY/PRINCIPAL FINDINGS: In this first Indian Ocean-wide genetic study of a marine organism we investigated the genetic structure and inferred the paleohistory of the two Indian Ocean sister species of Acanthaster planci using mitochondrial DNA sequence analyses. We suggest that the first of two main diversification events led to the formation of a Southern and Northern Indian Ocean sister-species in the late Pliocene-early Pleistocene. The second led to the formation of two internal clades within each species around the onset of the last interglacial. The subsequent demographic history of the two lineages strongly differed, the Southern Indian Ocean sister species showing a signature of recent population expansion and hardly any regional structure, whereas the Northern Indian Ocean sister-species apparently maintained a constant size with highly differentiated regional groupings that were asymmetrically connected by gene flow. CONCLUSIONS/SIGNIFICANCE: Past and present surface circulation patterns in conjunction with ocean primary productivity were identified as the processes most likely to have shaped the genetic structure between and within the two Indian Ocean lineages. This knowledge will help to understand the biological or ecological differences of the two sibling species and therefore aid in developing strategies to manage population outbreaks of this coral predator in the Indian Ocean. PMID- 22927976 TI - Quantitative analysis of alpha-synuclein solubility in living cells using split GFP complementation. AB - Presently incurable, Parkinson's disease (PD) is the most common neurodegenerative movement disorder and affects 1% of the population over 60 years of age. The hallmarks of PD pathogenesis are the loss of dopaminergic neurons in the substantia nigra pars compacta, and the occurrence of proteinaceous cytoplasmic inclusions (Lewy bodies) in surviving neurons. Lewy bodies are mainly composed of the pre-synaptic protein alpha-synuclein (alphasyn), an intrinsically unstructured, misfolding-prone protein with high propensity to aggregate. Quantifying the pool of soluble alphasyn and monitoring alphasyn aggregation in living cells is fundamental to study the molecular mechanisms of alphasyn-induced cytotoxicity and develop therapeutic strategies to prevent alphasyn aggregation. In this study, we report the use of a split GFP complementation assay to quantify alphasyn solubility. Particularly, we investigated a series of naturally occurring and rationally designed alphasyn variants and showed that this method can be used to study how alphasyn sequence specificity affects its solubility. Furthermore, we demonstrated the utility of this assay to explore the influence of the cellular folding network on alphasyn solubility. The results presented underscore the utility of the split GFP assay to quantify alphasyn solubility in living cells. PMID- 22927977 TI - Developmental dynamics of post-selection thymic DN iNKT. AB - BACKGROUND: Invariant natural killer T (iNKT) cells develop in the thymus and branch off from the maturation pathway of conventional T cell at the DP stage. While different stages of iNKT cellular development have been defined, the actual time that iNKT cell precursors spend at each stage is still unknown. METHODOLOGY/PRINCIPAL FINDING: Here we report on maturation dynamics of post selection DN iNKT cells by injecting wild-type DP(dim) thymocytes into the thymus of TCRalpha(-/-) mice and using the Valpha14-Jalpha18 rearrangements as a molecular marker to follow the maturation dynamics of these cells. CONCLUSION/SIGNIFICANCE: This study shows that the developmental dynamics of DN iNKT cells in DP(dim) are very rapid and that it takes less than 1 day to down regulate CD4 and CD8 and become DN. These DN cells are precursors of peripheral DN iNKT cells and appear in the spleen in 1-2 days. Thymic DN iNKT residents are predominantly derived from cells that quickly return from the periphery. The expansion of a very small subset of DN iNKT precursors could also play a small role in this process. These data are an example of measuring T cell maturation in the thymus and show that the maturation dynamics of selected DN iNKT cells fall within the same general time frame as conventional alphabeta T cells. PMID- 22927978 TI - Mutualisms and population regulation: mechanism matters. AB - For both applied and theoretical ecological science, the mutualism between ants and their hemipteran partners is iconic. In this well-studied interaction, ants are assumed to provide hemipterans protection from natural enemies in exchange for nutritive honeydew. Despite decades of research and the potential importance in pest control, the precise mechanism producing this mutualism remains contested. By analyzing maximum likelihood parameter estimates of a hemipteran population model, we show that the mechanism of the mutualism is direct, via improved hemipteran growth rates, as opposed to the frequently assumed indirect mechanism, via harassment of the specialist parasites and predators of the hemipterans. Broadly, this study demonstrates that the management of mutualism based ecosystem services requires a mechanistic understanding of mutualistic interactions. A consequence of this finding is the counter intuitive demonstration that preserving ant participation in the ant-hemipteran mutualism may be the best way of insuring pest control. PMID- 22927979 TI - Caspase-2-dependent dendritic cell death, maturation, and priming of T cells in response to Brucella abortus infection. AB - Smooth virulent Brucella abortus strain 2308 (S2308) causes zoonotic brucellosis in cattle and humans. Rough B. abortus strain RB51, derived from S2308, is a live attenuated cattle vaccine strain licensed in the USA and many other countries. Our previous report indicated that RB51, but not S2308, induces a caspase-2 dependent apoptotic and necrotic macrophage cell death. Dendritic cells (DCs) are professional antigen presenting cells critical for bridging innate and adaptive immune responses. In contrast to Brucella-infected macrophages, here we report that S2308 induced higher levels of apoptotic and necrotic cell death in wild type bone marrow-derived DCs (WT BMDCs) than RB51. The RB51 and S2308-induced BMDC cell death was regulated by caspase-2, indicated by the minimal cell death in RB51 and S2308-infected BMDCs isolated from caspase-2 knockout mice (Casp2KO BMDCs). More S2308 bacteria were taken up by Casp2KO BMDCs than wild type BMDCs. Higher levels of S2308 and RB51 cells were found in infected Casp2KO BMDCs compared to infected WT BMDCs at different time points. RB51-infected wild type BMDCs were mature and activated as shown by significantly up-regulated expression of CD40, CD80, CD86, MHC-I, and MHC-II. RB51 induced the production of cytokines TNF-alpha, IL-6, IFN-gamma and IL12/IL23p40 in infected BMDCs. RB51-infected WT BMDCs also stimulated the proliferation of CD4(+) and CD8(+) T cells compared to uninfected WT BMDCs. However, the maturation, activation, and cytokine secretion are significantly impaired in Casp2KO BMDCs infected with RB51 or Salmonella (control). S2308-infected WT and Casp2KO BMDCs were not activated and could not induce cytokine production. These results demonstrated that virulent smooth strain S2308 induced more apoptotic and necrotic dendritic cell death than live attenuated rough vaccine strain RB51; however, RB51, but not its parent strain S2308, induced caspase-2-mediated DC maturation, cytokine production, antigen presentation, and T cell priming. PMID- 22927980 TI - The S100A10 subunit of the annexin A2 heterotetramer facilitates L2-mediated human papillomavirus infection. AB - Mucosotropic, high-risk human papillomaviruses (HPV) are sexually transmitted viruses that are causally associated with the development of cervical cancer. The most common high-risk genotype, HPV16, is an obligatory intracellular virus that must gain entry into host epithelial cells and deliver its double stranded DNA to the nucleus. HPV capsid proteins play a vital role in these steps. Despite the critical nature of these capsid protein-host cell interactions, the precise cellular components necessary for HPV16 infection of epithelial cells remains unknown. Several neutralizing epitopes have been identified for the HPV16 L2 minor capsid protein that can inhibit infection after initial attachment of the virus to the cell surface, which suggests an L2-specific secondary receptor or cofactor is required for infection, but so far no specific L2-receptor has been identified. Here, we demonstrate that the annexin A2 heterotetramer (A2t) contributes to HPV16 infection and co-immunoprecipitates with HPV16 particles on the surface of epithelial cells in an L2-dependent manner. Inhibiting A2t with an endogenous annexin A2 ligand, secretory leukocyte protease inhibitor (SLPI), or with an annexin A2 antibody significantly reduces HPV16 infection. With electron paramagnetic resonance, we demonstrate that a previously identified neutralizing epitope of L2 (aa 108-120) specifically interacts with the S100A10 subunit of A2t. Additionally, mutation of this L2 region significantly reduces binding to A2t and HPV16 pseudovirus infection. Furthermore, downregulation of A2t with shRNA significantly decreases capsid internalization and infection by HPV16. Taken together, these findings indicate that A2t contributes to HPV16 internalization and infection of epithelial cells and this interaction is dependent on the presence of the L2 minor capsid protein. PMID- 22927981 TI - Somatosensory profiles but not numbers of somatosensory abnormalities of neuropathic pain patients correspond with neuropathic pain grading. AB - Due to the lack of a specific diagnostic tool for neuropathic pain, a grading system to categorize pain as 'definite', 'probable', 'possible' and 'unlikely' neuropathic was proposed. Somatosensory abnormalities are common in neuropathic pain and it has been suggested that a greater number of abnormalities would be present in patients with 'probable' and 'definite' grades. To test this hypothesis, we investigated the presence of somatosensory abnormalities by means of Quantitative Sensory Testing (QST) in patients with a clinical diagnosis of neuropathic pain and correlated the number of sensory abnormalities and sensory profiles to the different grades. Of patients who were clinically diagnosed with neuropathic pain, only 60% were graded as 'definite' or 'probable', while 40% were graded as 'possible' or 'unlikely' neuropathic pain. Apparently, there is a mismatch between a clinical neuropathic pain diagnosis and neuropathic pain grading. Contrary to the expectation, patients with 'probable' and 'definite' grades did not have a greater number of abnormalities. Instead, similar numbers of somatosensory abnormalities were identified for each grade. The profiles of sensory signs in 'definite' and 'probable' neuropathic pain were not significantly different, but different from the 'unlikely' grade. This latter difference could be attributed to differences in the prevalence of patients with a mixture of sensory gain and loss and with sensory loss only. The grading system allows a separation of neuropathic and non-neuropathic pain based on profiles but not on the total number of sensory abnormalities. Our findings indicate that patient selection based on grading of neuropathic pain may provide advantages in selecting homogenous groups for clinical research. PMID- 22927982 TI - A functional and structural Mongolian Scots pine (Pinus sylvestris var. mongolica) model integrating architecture, biomass and effects of precipitation. AB - Mongolian Scots pine (Pinus sylvestris var. mongolica) is one of the principal tree species in the network of Three-North Shelterbelt for windbreak and sand stabilisation in China. The functions of shelterbelts are highly correlated with the architecture and eco-physiological processes of individual tree. Thus, model assisted analysis of canopy architecture and function dynamic in Mongolian Scots pine is of value for better understanding its role and behaviour within shelterbelt ecosystems in these arid and semiarid regions. We present here a single-tree functional and structural model, derived from the GreenLab model, which is adapted for young Mongolian Scots pines by incorporation of plant biomass production, allocation, allometric rules and soil water dynamics. The model is calibrated and validated based on experimental measurements taken on Mongolian Scots pines in 2007 and 2006 under local meteorological conditions. Measurements include plant biomass, topology and geometry, as well as soil attributes and standard meteorological data. After calibration, the model allows reconstruction of three-dimensional (3D) canopy architecture and biomass dynamics for trees from one- to six-year-old at the same site using meteorological data for the six years from 2001 to 2006. Sensitivity analysis indicates that rainfall variation has more influence on biomass increment than on architecture, and the internode and needle compartments and the aboveground biomass respond linearly to increases in precipitation. Sensitivity analysis also shows that the balance between internode and needle growth varies only slightly within the range of precipitations considered here. The model is expected to be used to investigate the growth of Mongolian Scots pines in other regions with different soils and climates. PMID- 22927983 TI - Development of an aptamer-based concentration method for the detection of Trypanosoma cruzi in blood. AB - Trypanosoma cruzi, a blood-borne parasite, is the etiological agent of Chagas disease. T. cruzi trypomastigotes, the infectious life cycle stage, can be detected in blood of infected individuals using PCR-based methods. However, soon after a natural infection, or during the chronic phase of Chagas disease, the number of parasites in blood may be very low and thus difficult to detect by PCR. To facilitate PCR-based detection methods, a parasite concentration approach was explored. A whole cell SELEX strategy was utilized to develop serum stable RNA aptamers that bind to live T. cruzi trypomastigotes. These aptamers bound to the parasite with high affinities (8-25 nM range). The highest affinity aptamer, Apt68, also demonstrated high specificity as it did not interact with the insect stage epimastigotes of T. cruzi nor with other related trypanosomatid parasites, L. donovani and T. brucei, suggesting that the target of Apt68 was expressed only on T. cruzi trypomastigotes. Biotinylated Apt68, immobilized on a solid phase, was able to capture live parasites. These captured parasites were visible microscopically, as large motile aggregates, formed when the aptamer coated paramagnetic beads bound to the surface of the trypomastigotes. Additionally, Apt68 was also able to capture and aggregate trypomastigotes from several isolates of the two major genotypes of the parasite. Using a magnet, these parasite-bead aggregates could be purified from parasite-spiked whole blood samples, even at concentrations as low as 5 parasites in 15 ml of whole blood, as detected by a real-time PCR assay. Our results show that aptamers can be used as pathogen specific ligands to capture and facilitate PCR-based detection of T. cruzi in blood. PMID- 22927984 TI - Dissociated neural processing for decisions in managers and non-managers. AB - Functional neuroimaging studies of decision-making so far mainly focused on decisions under uncertainty or negotiation with other persons. Dual process theory assumes that, in such situations, decision making relies on either a rapid intuitive, automated or a slower rational processing system. However, it still remains elusive how personality factors or professional requirements might modulate the decision process and the underlying neural mechanisms. Since decision making is a key task of managers, we hypothesized that managers, facing higher pressure for frequent and rapid decisions than non-managers, prefer the heuristic, automated decision strategy in contrast to non-managers. Such different strategies may, in turn, rely on different neural systems. We tested managers and non-managers in a functional magnetic resonance imaging study using a forced-choice paradigm on word-pairs. Managers showed subcortical activation in the head of the caudate nucleus, and reduced hemodynamic response within the cortex. In contrast, non-managers revealed the opposite pattern. With the head of the caudate nucleus being an initiating component for process automation, these results supported the initial hypothesis, hinting at automation during decisions in managers. More generally, the findings reveal how different professional requirements might modulate cognitive decision processing. PMID- 22927985 TI - Biological and biochemical characterization of mice expressing prion protein devoid of the octapeptide repeat region after infection with prions. AB - Accumulating lines of evidence indicate that the N-terminal domain of prion protein (PrP) is involved in prion susceptibility in mice. In this study, to investigate the role of the octapeptide repeat (OR) region alone in the N terminal domain for the susceptibility and pathogenesis of prion disease, we intracerebrally inoculated RML scrapie prions into tg(PrPDeltaOR)/Prnp(0/0) mice, which express mouse PrP missing only the OR region on the PrP-null background. Incubation times of these mice were not extended. Protease-resistant PrPDeltaOR, or PrP(Sc)DeltaOR, was easily detectable but lower in the brains of these mice, compared to that in control wild-type mice. Consistently, prion titers were slightly lower and astrogliosis was milder in their brains. However, in their spinal cords, PrP(Sc)DeltaOR and prion titers were abundant and astrogliosis was as strong as in control wild-type mice. These results indicate that the role of the OR region in prion susceptibility and pathogenesis of the disease is limited. We also found that the PrP(Sc)DeltaOR, including the pre-OR residues 23-50, was unusually protease-resistant, indicating that deletion of the OR region could cause structural changes to the pre-OR region upon prion infection, leading to formation of a protease-resistant structure for the pre-OR region. PMID- 22927986 TI - Prevalence and follow-up of occult HCV infection in an Italian population free of clinically detectable infectious liver disease. AB - BACKGROUND: Occult hepatitis C virus infection (OCI) is a recently described phenomenon characterized by undetectable levels of HCV-RNA in serum/plasma by current laboratory assays, with identifiable levels in peripheral blood mononuclear cells (PBMCs) and/or liver tissue by molecular tests with enhanced sensitivity. Previous results from our group showed an OCI prevalence of 3.3% in a population unselected for hepatic disease. The present study aimed to evaluate OCI prevalence in a larger cohort of infectious liver disease-free (ILDF) subjects. Clinical follow-up of OCI subjects was performed to investigate the natural history of the infection. METHODS AND FINDINGS: 439 subjects referred to a Turin Blood Bank for phlebotomy therapy were recruited. They included 314 ILDF subjects, 40 HCV-positive subjects and 85 HBV-positive subjects, of whom 7 were active HBV carriers. Six subjects (4/314 ILDF subjects [1.27%] and 2/7 active HBV carriers [28%]) were positive for HCV-RNA in PBMCs, but negative for serological and virological markers of HCV, indicating OCI. HCV genotypes were determined in the PBMCs of 3/6 OCI subjects two had type 1b; the other had type 2a/2c. OCI subjects were followed up for at least 2 years. After 12 months only one OCI persisted, showing a low HCV viral load (3.73*10(1) UI/ml). By the end of follow up all OCI subjects were negative for HCV. No seroconversion, alteration of liver enzyme levels, or reduction of liver synthesis occurred during follow-up. CONCLUSIONS: This study demonstrated the existence of OCI in ILDF subjects, and suggested a high OCI prevalence among active HBV carriers. Follow-up suggested that OCI could be transient, with a trend toward the decrease of HCV viral load to levels undetectable by conventional methods after 12-18 months. Confirmation studies with a longer follow-up period are needed for identification of the OCI clearance or recurrence rates, and to characterize the viruses involved. PMID- 22927987 TI - The association between prenatal psychosocial stress and blood pressure in the child at age 5-7 years. AB - OBJECTIVE: Prenatal maternal stress could have permanent effects on the offspring's tissue structure and function, which may predispose to cardiovascular diseases. We investigated whether maternal psychosocial stress is a prenatal factor affecting the blood pressure (BP) of offspring. STUDY DESIGN: In the Amsterdam Born Children and their Development (ABCD) study, around gestational week 16, depressive symptoms, state-anxiety, pregnancy-related anxiety, parenting daily hassles and job strain were recorded by questionnaire. A cumulative stress score was also calculated (based on 80(th) percentiles). Systolic and diastolic BP and mean arterial pressure (MAP) were measured in the offspring at age 5-7 years. Inclusion criteria were: no use of antihypertensive medication during pregnancy; singleton birth; no reported cardiovascular problems in the child (N = 2968 included). RESULTS: After adjustment for confounders, the single stress scales were not associated with systolic and diastolic BP, MAP and hypertension (p>0.05). The presence of 3-4 psychosocial stressors prenatally (4%) was associated with 1.5 mmHg higher systolic and diastolic BP (p = 0.046; p = 0.04) and 1.5 mmHg higher MAP in the offspring (p = 0.02) compared to no stressors (46%). The presence of 3-4 stressors did not significantly increase the risk for hypertension (OR 1.8; 95% CI 0.93.4). Associations did not differ between sexes. Bonferroni correction for multiple testing rendered all associations non significant. CONCLUSIONS: The presence of multiple psychosocial stressors during pregnancy was associated with higher systolic and diastolic BP and MAP in the child at age 5-7. Further investigation of maternal prenatal stress may be valuable for later life cardiovascular health. PMID- 22927989 TI - GTP-binding-defective ARL4D alters mitochondrial morphology and membrane potential. AB - ARL4D, ARL4A, and ARL4C are closely related members of the ADP-ribosylation factor/ARF-like protein (ARF/ARL) family of GTPases. All three ARL4 proteins contain nuclear localization signals (NLSs) at their C-termini and are primarily found at the plasma membrane, but they are also present in the nucleus and cytoplasm. ARF function and localization depends on their controlled binding and hydrolysis of GTP. Here we show that GTP-binding-defective ARL4D is targeted to the mitochondria, where it affects mitochondrial morphology and function. We found that a portion of endogenous ARL4D and the GTP-binding-defective ARL4D mutant ARL4D(T35N) reside in the mitochondria. The N-terminal myristoylation of ARL4D(T35N) was required for its localization to mitochondria. The localization of ARL4D(T35N) to the mitochondria reduced the mitochondrial membrane potential (DeltaPsim) and caused mitochondrial fragmentation. Furthermore, the C-terminal NLS region of ARL4D(T35N) was required for its effect on the mitochondria. This study is the first to demonstrate that the dysfunctional GTP-binding-defective ARL4D is targeted to mitochondria, where it subsequently alters mitochondrial morphology and membrane potential. PMID- 22927988 TI - Impaired spermatogenesis and gr/gr deletions related to Y chromosome haplogroups in Korean men. AB - Microdeletion of the Azoospermia Factor (AZF) regions in Y chromosome is a well known genetic cause of male infertility resulting from spermatogenetic impairment. However, the partial deletions of AZFc region related to spermatogenetic impairment are controversial. In this study, we characterized partial deletion of AZFc region in Korean patients with spermatogenetic impairment and assessed whether the DAZ and CDY1 contributes to the phenotype in patients with gr/gr deletions. Total of 377 patients with azoo-/oligozoospermia and 217 controls were analyzed using multiplex polymerase chain reaction (PCR), analysis of DAZ-CDY1 sequence family variants (SFVs), and quantitative fluorescent (QF)-PCR. Of the 377 men with impaired spermatogenesis, 59 cases (15.6%) had partial AZFc deletions, including 32 gr/gr (8.5%), 22 b2/b3 (5.8%), four b1/b3 (1.1%) and one b3/b4 (0.3%) deletion. In comparison, 14 of 217 normozoospermic controls (6.5%) had partial AZFc deletions, including five gr/gr (2.3%) and nine b2/b3 (4.1%) deletions. The frequency of gr/gr deletions was significantly higher in the azoo-/oligozoospermic group than in the normozoospermic control group (p = 0.003; OR = 3.933; 95% CI = 1.509-10.250). Concerning Y haplogroup, we observed no significant differences in the frequency of gr/gr deletions between the case and the control groups in the YAP+ lineages, while gr/gr deletion were significantly higher in azoo-/oligozoospermia than normozoospermia in the YAP- lineage (p = 0.004; OR = 6.341; 95% CI = 1.472 27.312). Our data suggested that gr/gr deletion is associated with impaired spermatogenesis in Koreans with YAP- lineage, regardless of the gr/gr subtypes. PMID- 22927990 TI - A mitogenomic re-evaluation of the bdelloid phylogeny and relationships among the Syndermata. AB - Molecular and morphological data regarding the relationships among the three classes of Rotifera (Bdelloidea, Seisonidea, and Monogononta) and the phylum Acanthocephala are inconclusive. In particular, Bdelloidea lacks molecular-based phylogenetic appraisal. I obtained coding sequences from the mitochondrial genomes of twelve bdelloids and two monogononts to explore the molecular phylogeny of Bdelloidea and provide insight into the relationships among lineages of Syndermata (Rotifera + Acanthocephala). With additional sequences taken from previously published mitochondrial genomes, the total dataset included nine species of bdelloids, three species of monogononts, and two species of acanthocephalans. A supermatrix of these 10-12 mitochondrial proteins consistently recovered a bdelloid phylogeny that questions the validity of a generally accepted classification scheme despite different methods of inference and various parameter adjustments. Specifically, results showed that neither the family Philodinidae nor the order Philodinida are monophyletic as currently defined. The application of a similar analytical strategy to assess syndermate relationships recovered either a tree with Bdelloidea and Monogononta as sister taxa (Eurotatoria) or Bdelloidea and Acanthocephala as sister taxa (Lemniscea). Both outgroup choice and method of inference affected the topological outcome emphasizing the need for sequences from more closely related outgroups and more sophisticated methods of analysis that can account for the complexity of the data. PMID- 22927991 TI - Pathogen webs in collapsing honey bee colonies. AB - Recent losses in honey bee colonies are unusual in their severity, geographical distribution, and, in some cases, failure to present recognized characteristics of known disease. Domesticated honey bees face numerous pests and pathogens, tempting hypotheses that colony collapses arise from exposure to new or resurgent pathogens. Here we explore the incidence and abundance of currently known honey bee pathogens in colonies suffering from Colony Collapse Disorder (CCD), otherwise weak colonies, and strong colonies from across the United States. Although pathogen identities differed between the eastern and western United States, there was a greater incidence and abundance of pathogens in CCD colonies. Pathogen loads were highly covariant in CCD but not control hives, suggesting that CCD colonies rapidly become susceptible to a diverse set of pathogens, or that co-infections can act synergistically to produce the rapid depletion of workers that characterizes the disorder. We also tested workers from a CCD-free apiary to confirm that significant positive correlations among pathogen loads can develop at the level of individual bees and not merely as a secondary effect of CCD. This observation and other recent data highlight pathogen interactions as important components of bee disease. Finally, we used deep RNA sequencing to further characterize microbial diversity in CCD and non-CCD hives. We identified novel strains of the recently described Lake Sinai viruses (LSV) and found evidence of a shift in gut bacterial composition that may be a biomarker of CCD. The results are discussed with respect to host-parasite interactions and other environmental stressors of honey bees. PMID- 22927992 TI - A functional screen identifies specific microRNAs capable of inhibiting human melanoma cell viability. AB - Malignant melanoma is an aggressive form of skin cancer with poor prognosis. Despite improvements in awareness and prevention of this disease, its incidence is rapidly increasing. MicroRNAs (miRNAs) are a class of small RNA molecules that regulate cellular processes by repressing messenger RNAs (mRNAs) with partially complementary target sites. Several miRNAs have already been shown to attenuate cancer phenotypes, by limiting proliferation, invasiveness, tumor angiogenesis, and stemness. Here, we employed a genome-scale lentiviral human miRNA expression library to systematically survey which miRNAs are able to decrease A375 melanoma cell viability. We highlight the strongest inhibitors of melanoma cell proliferation, including the miR-15/16, miR-141/200a and miR-96/182 families of miRNAs and miR-203. Ectopic expression of these miRNAs resulted in long-term inhibition of melanoma cell expansion, both in vitro and in vivo. We show specifically miR-16, miR-497, miR-96 and miR-182 are efficient effectors when introduced as synthetic miRNAs in several melanoma cell lines. Our study provides a comprehensive interrogation of miRNAs that interfere with melanoma cell proliferation and viability, and offers a selection of miRNAs that are especially promising candidates for application in melanoma therapy. PMID- 22927993 TI - Morphophysiological differences between the metapleural glands of fungus-growing and non-fungus-growing ants (Hymenoptera, Formicidae). AB - The metapleural gland is an organ exclusive to ants. Its main role is to produce secretions that inhibit the proliferation of different types of pathogens. The aim of the present study was to examine the morphophysiological differences between the metapleural gland of 3 non-fungus-growing ants of the tribes Ectatommini, Myrmicini, and Blepharidattini and that of 5 fungus-growing ants from 2 basal and 3 derived attine genera. The metapleural gland of the non-fungus growing ants and the basal attine ants has fewer secretory cells than that of the derived attine ants (leaf-cutting ants). In addition, the metapleural gland of the latter had more clusters of secretory cells and sieve plates, indicating a greater storage capacity and demand for secretion in these more advanced farming ants. The glands of the derived attine ants also produced higher levels of polysaccharides and acidic lipids than those of Myrmicini, Blepharidattini, and basal attines. Our results confirm morphophysiological differences between the metapleural glands of the derived attines and those of the basal attines and non fungus-growing ants, suggesting that the metapleural glands of the derived attines (leaf-cutting ants) are more developed in morphology and physiology, with enhanced secretion production (acidic lipids and protein) to protect against the proliferation of unwanted fungi and bacteria in the fungal garden, it is possible that leaf-cutting ants may have evolved more developed metapleural glands in response to stronger pressure from parasites. PMID- 22927994 TI - Computational prediction of conformational B-cell epitopes from antigen primary structures by ensemble learning. AB - MOTIVATION: The conformational B-cell epitopes are the specific sites on the antigens that have immune functions. The identification of conformational B-cell epitopes is of great importance to immunologists for facilitating the design of peptide-based vaccines. As an attempt to narrow the search for experimental validation, various computational models have been developed for the epitope prediction by using antigen structures. However, the application of these models is undermined by the limited number of available antigen structures. In contrast to the most of available structure-based methods, we here attempt to accurately predict conformational B-cell epitopes from antigen sequences. METHODS: In this paper, we explore various sequence-derived features, which have been observed to be associated with the location of epitopes or ever used in the similar tasks. These features are evaluated and ranked by their discriminative performance on the benchmark datasets. From the perspective of information science, the combination of various features can usually lead to better results than the individual features. In order to build the robust model, we adopt the ensemble learning approach to incorporate various features, and develop the ensemble model to predict conformational epitopes from antigen sequences. RESULTS: Evaluated by the leave-one-out cross validation, the proposed method gives out the mean AUC scores of 0.687 and 0.651 on two datasets respectively compiled from the bound structures and unbound structures. When compared with publicly available servers by using the independent dataset, our method yields better or comparable performance. The results demonstrate the proposed method is useful for the sequence-based conformational epitope prediction. AVAILABILITY: The web server and datasets are freely available at http://bcell.whu.edu.cn. PMID- 22927995 TI - Effects of extreme-duration heavy load carriage on neuromuscular function and locomotion: a military-based study. AB - Trekking and military missions generally consist of carrying heavy loads for extreme durations. These factors have been separately shown to be sources of neuromuscular (NM) fatigue and locomotor alterations. However, the question of their combined effects remains unresolved, and addressing this issue required a representative context. PURPOSE: The aim was to investigate the effects of extreme-duration heavy load carriage on NM function and walking characteristics. METHODS: Ten experienced infantrymen performed a 21-h simulated military mission (SMM) in a middle-mountain environment with equipment weighing ~27 kg during battles and ~43 kg during marches. NM function was evaluated for knee extensors (KE) and plantar flexors (PF) pre- and immediately post-SMM using isometric maximal voluntary contraction (MVC) measurement, neural electrical stimulation and surface EMG. The twitch-interpolation method was used to assess central fatigue. Peripheral changes were examined by stimulating the muscle in the relaxed state. The energy cost, mechanical work and spatio-temporal pattern of walking were also evaluated pre-/post-SMM on an instrumented treadmill in three equipment conditions: Sportswear, Battle and March. RESULTS: After the SMM, MVC declined by -10.2+/-3.6% for KE (P<0.01) and -10.7+/-16.1% for PF (P = 0.06). The origin of fatigue was essentially peripheral for both muscle groups. A trend toward low-frequency fatigue was detected for KE (5.5%, P = 0.08). These moderate NM alterations were concomitant with a large increase in perceived fatigue from pre- (rating of 8.3+/-2.2) to post-SMM (15.9+/-2.1, P<0.01). The SMM-related fatigue did not alter walking energetics or mechanics, and the different equipment carried on the treadmill did not interact with this fatigue either. CONCLUSION: this study reports the first data on physiological and biomechanical consequences of extreme-duration heavy load carriage. Unexpectedly, NM function alterations due to the 21-h SMM were moderate and did not alter walking characteristics. CLINICAL TRIAL REGISTRATION: Name: Effect of prolonged military exercises with high load carriage on neuromuscular fatigue and physiological/biomechanical responses. Number: NCT01127191. PMID- 22927996 TI - Active chronic sarcoidosis is characterized by increased transitional blood B cells, increased IL-10-producing regulatory B cells and high BAFF levels. AB - BACKGROUND: Sarcoidosis is a multisystemic disease of unknown etiology characterized by a disproportionate Th1 granulomatous immune response in the organs involved. Plasmatic hypergammaglobulinemia and B cell accumulation in granulomatous lesions suggest the possible role of humoral immune responses in the pathogenesis of sarcoidosis. The purpose of this study is to describe B cell peripheral compartment in sarcoidosis. METHODOLOGY/PRINCIPAL FINDINGS: We analyzed blood B cell subsets and BAFF levels in 33 patients with chronic sarcoidosis (active sarcoidosis n = 18; inactive sarcoidosis n = 15) and 18 healthy donors. Active chronic sarcoidosis patients had significantly less circulating memory B cells (p<0.01), more transitional (p<0.01) and increased numbers of IL-10-producing regulatory B cells (p<0.05) compared with healthy donors and patients with inactive sarcoidosis. BAFF serum levels were significantly higher in patients with active sarcoidosis (p<0.01 versus healthy donors and inactive sarcoidosis patients) and strongly correlated with serum hypergammaglobulinemia (r = 0.53, p<0.01) and angiotensin converting enzyme levels (r = 0.61, p = <0.01). CONCLUSIONS/SIGNIFICANCE: These data show that there is an altered B cell homeostasis in active sarcoidosis and suggest BAFF antagonist drugs as potential new treatments of this disease. PMID- 22927997 TI - Social familiarity reduces reaction times and enhances survival of group-living predatory mites under the risk of predation. AB - BACKGROUND: Social familiarity, which is based on the ability to recognise familiar conspecific individuals following prior association, may affect all major life activities of group-living animals such as foraging, reproduction and anti-predator behaviours. A scarcely experimentally tested explanation why social familiarity is beneficial for group-living animals is provided by limited attention theory. Limited attention theory postulates that focusing on a given task, such as inspection and assessment of unfamiliar group members, has cognitive and associated physiological and behavioural costs with respect to the attention paid to other tasks, such as anti-predator vigilance and response. Accordingly, we hypothesised that social familiarity enhances the anti-predator success of group-living predatory mites, Phytoseiulus persimilis, confronted with an intraguild predator, the predatory mite Amblyseius andersoni. METHODOLOGY/PRINCIPAL FINDINGS: We videotaped and analysed the response of two P. persimilis larvae, held in familiar or unfamiliar pairs, to attacks by a gravid A. andersoni female, using the behavioural analyses software EthoVision Pro(r). Familiar larvae were more frequently close together, reacted more quickly to predator attacks, survived more predator encounters and survived longer than unfamiliar larvae. SIGNIFICANCE: In line with the predictions of limited attention theory, we suggest that social familiarity improves anti-predator behaviours because it allows prey to shift attention to other tasks rather than group member assessment. PMID- 22927998 TI - Gelsolin induces colorectal tumor cell invasion via modulation of the urokinase type plasminogen activator cascade. AB - Gelsolin is a cytoskeletal protein which participates in actin filament dynamics and promotes cell motility and plasticity. Although initially regarded as a tumor suppressor, gelsolin expression in certain tumors correlates with poor prognosis and therapy-resistance. In vitro, gelsolin has anti-apoptotic and pro-migratory functions and is critical for invasion of some types of tumor cells. We found that gelsolin was highly expressed at tumor borders infiltrating into adjacent liver tissues, as examined by immunohistochemistry. Although gelsolin contributes to lamellipodia formation in migrating cells, the mechanisms by which it induces tumor invasion are unclear. Gelsolin's influence on the invasive activity of colorectal cancer cells was investigated using overexpression and small interfering RNA knockdown. We show that gelsolin is required for invasion of colorectal cancer cells through matrigel. Microarray analysis and quantitative PCR indicate that gelsolin overexpression induces the upregulation of invasion promoting genes in colorectal cancer cells, including the matrix-degrading urokinase-type plasminogen activator (uPA). Conversely, gelsolin knockdown reduces uPA levels, as well as uPA secretion. The enhanced invasiveness of gelsolin-overexpressing cells was attenuated by treatment with function-blocking antibodies to either uPA or its receptor uPAR, indicating that uPA/uPAR activity is crucial for gelsolin-dependent invasion. In summary, our data reveals novel functions of gelsolin in colorectal tumor cell invasion through its modulation of the uPA/uPAR cascade, with potentially important roles in colorectal tumor dissemination to metastatic sites. PMID- 22927999 TI - TRPA1 mediates mechanical sensitization in nociceptors during inflammation. AB - Inflammation is a part of the body's natural response to tissue injury which initiates the healing process. Unfortunately, inflammation is frequently painful and leads to hypersensitivity to mechanical stimuli, which is difficult to treat clinically. While it is well established that altered sensory processing in the spinal cord contributes to mechanical hypersensitivity (central sensitization), it is still debated whether primary afferent neurons become sensitized to mechanical stimuli after tissue inflammation. We induced inflammation in C57BL/6 mice via intraplantar injection of Complete Freund's Adjuvant. Cutaneous C fibers exhibited increased action potential firing to suprathreshold mechanical stimuli. We found that abnormal responses to intense mechanical stimuli were completely suppressed by acute incubation of the receptive terminals with the TRPA1 inhibitor, HC-030031. Further, elevated responses were predominantly exhibited by a specific subgroup of C fibers, which we determined to be C-Mechano Cold sensitive fibers. Thus, in the presence of HC-030031, C fiber mechanical responses in inflamed mice were not different than responses in saline-injected controls. We also demonstrate that injection of the HC-030031 compound into the hind paw of inflamed mice alleviates behavioral mechanical hyperalgesia without affecting heat hyperalgesia. Further, we pharmacologically anesthetized the TRPA1 expressing fibers in vivo by co-injecting the membrane-impermeable sodium channel inhibitor QX-314 and the TRPA1 agonist cinnamaldehyde into the hind paw. This approach also alleviated behavioral mechanical hyperalgesia in inflamed mice but left heat hypersensitivity intact. Our findings indicate that C-Mechano Cold sensitive fibers exhibit enhanced firing to suprathreshold mechanical stimuli in a TRPA1-dependent manner during inflammation, and that input from these fibers drives mechanical hyperalgesia in inflamed mice. PMID- 22928000 TI - The role of dorsal anterior cingulate cortex in the regulation of craving by reappraisal in smokers. AB - RATIONALE AND OBJECTIVE: Drug cues can induce craving for drugs of abuse. Dysfunctional regulation of emotion and motivation regarding rewarding objects appears to be an integral part of addiction. It has been found that cognitive strategies decreased the intensity of craving in addicts. Reappraisal strategy is a type of cognitive strategy that requires participants to reinterpret the meaning of an emotional situation. In addition, studies have found that activation of the dorsal anterior cingulate cortex (dACC) is associated with the selection and application of cognitive reappraisal. In present study, we sought to determine whether such cognitive regulation engages the dACC and improves inhibition of craving in smokers. METHODS: Sixteen smokers underwent functional magnetic resonance imaging (fMRI) during performance of a cigarette reward conditioning procedure with cognitive reappraisal. We focused our analyses on the dACC as a key structure of cognitive control of craving. Cue induced craving under different conditions was obtained. Correlational analysis between the functional response in the dACC and the subjective craving was performed. RESULTS: We found that using a cognitive reappraisal was successful in decreasing the conditioned craving. Right dACC (BA 24/32) engaged in the cognitive reappraisal. In addition, the individual's subjective craving was negatively correlated with the right dACC activation. CONCLUSIONS: These findings suggest that the dACC are important substrates of Inhibition of cue induced craving in smokers. Cognitive regulation by cognitive reappraisal may help addicted individuals avoid the anticipated situations where they are exposed to conditioned cues. PMID- 22928001 TI - A carboxy-terminal trimerization domain stabilizes conformational epitopes on the stalk domain of soluble recombinant hemagglutinin substrates. AB - Recently, a new class of broadly neutralizing anti-influenza virus antibodies that target the stalk domain of the viral hemagglutinin was discovered. As such, induction, isolation, characterization, and quantification of these novel antibodies has become an area of intense research and great interest. Since most of these antibodies bind to conformational epitopes, the structural integrity of hemagglutinin substrates for the detection and quantification of these antibodies is of high importance. Here we evaluate the binding of these antibodies to soluble, secreted hemagglutinins with or without a carboxy-terminal trimerization domain based on the natural trimerization domain of T4 phage fibritin. The lack of such a domain completely abolishes binding to group 1 hemagglutinins and also affects binding to group 2 hemagglutinins. Additionally, the presence of a trimerization domain positively influences soluble hemagglutinin stability during expression and purification. Our findings suggest that a carboxy-terminal trimerization domain is a necessary requirement for the structural integrity of stalk epitopes on recombinant soluble influenza virus hemagglutinin. PMID- 22928002 TI - Preserved ex vivo inflammatory status in decidual cells from women with preterm labor and subclinical intrauterine infection. AB - OBJECTIVE: To compare the inflammatory response preserved ex vivo by decidual cells isolated from women who experienced preterm labor with and without subclinical intrauterine infection. METHODS: Fetal membranes were obtained after cesarean section from 35 women who delivered before 37 weeks of gestation following spontaneous preterm labor, with no clinical evidence of intrauterine infection. Decidua was microbiologically tested and cultured. Concentrations of anti-inflammatory cytokines (IL-2, IL-4, IL-10), pro-inflammatory cytokines (IL 6, IL-8, IL-1beta and TNF-alpha), and matrix metalloproteinases (MMP-1, MMP-2, MMP-3, MMP-7, MMP-8, MMP-9) were measured in the supernatants using Bio-Plex, and prostaglandin E(2) (PGE(2)) was measured by enzyme immunoassay. RESULTS: Subclinical infection was confirmed in 10 women (28.5%). Microorganisms isolated were Ureaplasma urealyticum (4), group B streptococci (3), Gardnerella vaginalis (1), and Escherichia coli (2). We found a significant increase of pro inflammatory cytokines and a significant decrease of anti-inflammatory cytokines in supernatants from decidual cells obtained from women with preterm labor and subclinical intrauterine infection compared to women without infection. Secretion of MMP-1, MMP-8, MMP-9 and PGE(2) was significantly higher in infected women. Secretion of IL-8 by decidual cells from infected women persisted upon repeated in vitro culture passages. CONCLUSIONS: Almost 30% of idiopathic preterm labor cases were associated with subclinical intrauterine infection, and decidual cells isolated from these cases preserved an ex vivo inflammatory status after in vivo bacterial exposure. PMID- 22928003 TI - Full restoration of Brucella-infected dendritic cell functionality through Vgamma9Vdelta2 T helper type 1 crosstalk. AB - Vgamma9Vdelta2 T cells play an important role in the immune response to infectious agents but the mechanisms contributing to this immune process remain to be better characterized. Following their activation, Vgamma9Vdelta2 T cells develop cytotoxic activity against infected cells, secrete large amounts of cytokines and influence the function of other effectors of immunity, notably cells playing a key role in the initiation of the adaptive immune response such as dendritic cells. Brucella infection dramatically impairs dendritic cell maturation and their capacity to present antigens to T cells. Herein, we investigated whether V T cells have the ability to restore the full functional capacities of Brucella-infected dendritic cells. Using an in vitro multicellular infection model, we showed that: 1/Brucella-infected dendritic cells activate Vgamma9Vdelta2 T cells through contact-dependent mechanisms, 2/activated Vgamma9Vdelta2 T cells induce full differentiation into IL-12 producing cells of Brucella-infected dendritic cells with functional antigen presentation activity. Furthermore, phosphoantigen-activated Vgamma9Vdelta2 T cells also play a role in triggering the maturation process of dendritic cells already infected for 24 h. This suggests that activated Vgamma9Vdelta2 T cells could be used to modulate the outcome of infectious diseases by promoting an adjuvant effect in dendritic cell based cellular therapies. PMID- 22928004 TI - Inappropriateness of medication prescriptions to elderly patients in the primary care setting: a systematic review. AB - BACKGROUND: Inappropriate medication prescription is a common cause of preventable adverse drug events among elderly persons in the primary care setting. OBJECTIVE: The aim of this systematic review is to quantify the extent of inappropriate prescription to elderly persons in the primary care setting. METHODS: We systematically searched Ovid-Medline and Ovid-EMBASE from 1950 and 1980 respectively to March 2012. Two independent reviewers screened and selected primary studies published in English that measured (in)appropriate medication prescription among elderly persons (>65 years) in the primary care setting. We extracted data sources, instruments for assessing medication prescription appropriateness, and the rate of inappropriate medication prescriptions. We grouped the reported individual medications according to the Anatomical Therapeutic and Chemical (ATC) classification and compared the median rate of inappropriate medication prescription and its range within each therapeutic class. RESULTS: We included 19 studies, 14 of which used the Beers criteria as the instrument for assessing appropriateness of prescriptions. The median rate of inappropriate medication prescriptions (IMP) was 20.5% [IQR 18.1 to 25.6%.]. Medications with largest median rate of inappropriate medication prescriptions were propoxyphene 4.52 (0.10-23.30)%, doxazosin 3.96 (0.32 15.70)%, diphenhydramine 3.30 (0.02-4.40)% and amitriptiline 3.20 (0.05-20.5)% in a decreasing order of IMP rate. Available studies described unequal sets of medications and different measurement tools to estimate the overall prevalence of inappropriate prescription. CONCLUSIONS: Approximately one in five prescriptions to elderly persons in primary care is inappropropriate despite the attention that has been directed to quality of prescription. Diphenhydramine and amitriptiline are the most common inappropriately prescribed medications with high risk adverse events while propoxyphene and doxazoxin are the most commonly prescribed medications with low risk adverse events. These medications are good candidates for being targeted for improvement e.g. by computerized clinical decision support. PMID- 22928005 TI - Epidemiology of invasive pneumococcal disease in older people in Spain (2007 2009): implications for future vaccination strategies. AB - BACKGROUND: Recently, the 13-valent pneumococcal conjugate vaccine (PCV13) has been recommended for adults. We analyzed the epidemiology of invasive pneumococcal disease (IPD) in older adults in Spain before PCV13 introduction. METHODOLOGY/PRINCIPAL FINDINGS: IPD episodes, defined as clinical findings together with an invasive pneumococcal isolate, were prospectively collected from patients aged over 65 years in three hospitals in Spain from 2007 to 2009. A total of 335 IPD episodes were collected. Pneumonia was the main clinical syndrome, while chronic obstructive pulmonary disease, diabetes mellitus and cancer were the main underlying diseases. Pneumococcal isolates were serotyped and the molecular typing was performed by PFGE/MLST. PCV13 serotypes accounted for 59.3% of isolates, the most prevalent being serotypes 19A (15.1%), 3 (9.6%), 7F (7.5%), 14 (6.9%) and 1 (5.4%). The most frequent non-PCV13 serotypes were serotypes 16F (4.5%), 22F (3.6%), 24F (3.3%) and 6C (2.1%). The most common genotypes were CC230 (8.5%, serotypes 19A and 24F), CC156 (8.2%, serotypes 9V and 14), ST191 (7.9%, serotype 7F), CC260 (6.6%, serotype 3), ST306 (5.2%, serotype 1), CC30 (4.6%, serotype 16F) and ST433 (3.6%, serotype 22F). Comparing the 335 IPD isolates to 174 invasive pneumococci collected at the same hospitals in 1999 2000, PCV7 serotypes decreased (45.4% vs 18.4%,p<0.001), non-PCV7 serotypes included in PCV13 increased (26.4% vs 41.0%,p = 0.001) and two non-PCV13 serotypes increased (serotype 6C 0% vs 2.1%, p = 0.05; serotype 24F 0.6% vs 3.3%, p = 0.04,). CONCLUSION: In our older adult population two serotypes (19A and 3) included in PCV13 accounted for about a quarter of IPD episodes in people >=65 years. Non-PCV13 emerging serotypes should be carefully monitored in future surveillance studies. PMID- 22928006 TI - High gamma-radiation sensitivity is associated with increased gastric cancer risk in a Chinese Han population: a case-control analysis. AB - Hypersensitivity to radiation exposure has been suggested to be a risk factor for the development of several malignancies, but not including gastric cancer. In this case-control study, radiation sensitivity as measured by chromatid breaks per cell (b/c) was examined in cultured peripheral blood lymphocytes (PBLs) from 517 patients with gastric cancer and 525 healthy controls. Our results showed that b/c values were significantly higher in cases than in controls (Mean [SD], 0.47 [0.20] vs. 0.34 [0.17]; P<0.001). Using the 50(th) percentile value for controls (0.34 b/c) as the cutoff point, unconditional logistic regression analysis revealed that gamma-radiation-sensitive individuals were at significantly higher risk for gastric cancer (adjusted odds ratio [OR] 2.01, 95% confidence interval [CI] 1.49-3.13). Quartile stratification analysis indicated a dose-response relationship between gamma-radiation sensitivity and gastric cancer risk (P for trend <0.001). When using the subjects in first quartile of b/c values as reference, the adjusted ORs and corresponding CIs for the subjects in second, third, and fourth quartiles were 1.48 (0.91-2.17), 2.42 (1.76-3.64), and 3.40 (2.11-5.29), respectively. The gamma-radiation sensitivity was related to age and smoking status. In addition, a clear joint effect on cancer risk was found between gamma-Radiation sensitivity and smoking status. The risk for ever smokers with high sensitivity was higher than those for never smokers with high sensitivity and ever smokers with low sensitivity (OR [CI], 4.67 [2.31-6.07] vs. 2.14 [1.40-3.06] vs. 2.42 [1.57-3.95], respectively). No significant interaction was found between both factors (P for interaction= 0.42). We conclude that chromatid radiosensitivity is associated with gastric cancer susceptibility in a Chinese population. PMID- 22928007 TI - Ionizing radiation induces stemness in cancer cells. AB - The cancer stem cell (CSC) model posits the presence of a small number of CSCs in the heterogeneous cancer cell population that are ultimately responsible for tumor initiation, as well as cancer recurrence and metastasis. CSCs have been isolated from a variety of human cancers and are able to generate a hierarchical and heterogeneous cancer cell population. CSCs are also resistant to conventional chemo- and radio-therapies. Here we report that ionizing radiation can induce stem cell-like properties in heterogeneous cancer cells. Exposure of non-stem cancer cells to ionizing radiation enhanced spherogenesis, and this was accompanied by upregulation of the pluripotency genes Sox2 and Oct3/4. Knockdown of Sox2 or Oct3/4 inhibited radiation-induced spherogenesis and increased cellular sensitivity to radiation. These data demonstrate that ionizing radiation can activate stemness pathways in heterogeneous cancer cells, resulting in the enrichment of a CSC subpopulation with higher resistance to radiotherapy. PMID- 22928008 TI - Low socioeconomic status is associated with prolonged times to assessment and treatment, sepsis and infectious death in pediatric fever in El Salvador. AB - BACKGROUND: Infection remains the most common cause of death from toxicity in children with cancer in low- and middle-income countries. Rapid administration of antibiotics when fever develops can prevent progression to sepsis and shock, and serves as an important indicator of the quality of care in children with acute lymphoblastic leukemia and acute myeloid leukemia. We analyzed factors associated with (1) Longer times from fever onset to hospital presentation/antibiotic treatment and (2) Sepsis and infection-related mortality. METHOD: This prospective cohort study included children aged 0-16 years with newly diagnosed acute leukemia treated at Benjamin Bloom Hospital, San Salvador. We interviewed parents/caregivers within one month of diagnosis and at the onset of each new febrile episode. Times from initial fever to first antibiotic administration and occurrence of sepsis and infection-related mortality were documented. FINDINGS: Of 251 children enrolled, 215 had acute lymphoblastic leukemia (85.7%). Among 269 outpatient febrile episodes, median times from fever to deciding to seek medical care was 10.0 hours (interquartile range [IQR] 5.0-20.0), and from decision to seek care to first hospital visit was 1.8 hours (IQR 1.0-3.0). Forty-seven (17.5%) patients developed sepsis and 7 (2.6%) died of infection. Maternal illiteracy was associated with longer time from fever to decision to seek care (P = 0.029) and sepsis (odds ratio [OR] 3.06, 95% confidence interval [CI] 1.09 8.63; P = 0.034). More infectious deaths occurred in those with longer travel time to hospital (OR 1.36, 95% CI 1.03-1.81; P = 0.031) and in families with an annual household income =20 *10(3) mmHg*beats*min(-1) (p<0.01). CONCLUSION: Upon reperfusion of a NHBD heart, early evaluation, at the time of organ procurement, of cardiac hemodynamic parameters, as well as easily accessible markers of metabolism and necrosis seem to accurately predict subsequent contractile recovery and could thus potentially be of use in guiding the decision of accepting the ischemic heart for transplantation. PMID- 22928010 TI - Anticancer activity of MPT0E028, a novel potent histone deacetylase inhibitor, in human colorectal cancer HCT116 cells in vitro and in vivo. AB - Recently, histone deacetylase (HDAC) inhibitors have emerged as a promising class of drugs for treatment of cancers, especially subcutaneous T-cell lymphoma. In this study, we demonstrated that MPT0E028, a novel N-hydroxyacrylamide-derived HDAC inhibitor, inhibited human colorectal cancer HCT116 cell growth in vitro and in vivo. The results of NCI-60 screening showed that MPT0E028 inhibited proliferation in both solid and hematological tumor cell lines at micromolar concentrations, and was especially potent in HCT116 cells. MPT0E028 had a stronger apoptotic activity and inhibited HDACs activity more potently than SAHA, the first therapeutic HDAC inhibitor proved by FDA. In vivo murine model, the growth of HCT116 tumor xenograft was delayed and inhibited after treatment with MPT0E028 in a dose-dependent manner. Based on in vivo study, MPT0E028 showed stronger anti-cancer efficacy than SAHA. No significant body weight difference or other adverse effects were observed in both MPT0E028-and SAHA-treated groups. Taken together, our results demonstrate that MPT0E028 has several properties and is potential as a promising anti-cancer therapeutic drug. PMID- 22928011 TI - XB130 mediates cancer cell proliferation and survival through multiple signaling events downstream of Akt. AB - XB130, a novel adaptor protein, mediates RET/PTC chromosome rearrangement-related thyroid cancer cell proliferation and survival through phosphatidyl-inositol-3 kinase (PI3K)/Akt pathway. Recently, XB130 was found in different cancer cells in the absence of RET/PTC. To determine whether RET/PTC is required of XB130-related cancer cell proliferation and survival, WRO thyroid cancer cells (with RET/PTC mutation) and A549 lung cancer cells (without RET/PTC) were treated with XB130 siRNA, and multiple Akt down-stream signals were examined. Knocking-down of XB130 inhibited G(1)-S phase progression, and induced spontaneous apoptosis and enhanced intrinsic and extrinsic apoptotic stimulus-induced cell death. Knocking down of XB130 reduced phosphorylation of p21Cip1/WAF1, p27Kip1, FOXO3a and GSK3beta, increased p21Cip1/WAF1protein levels and cleavages of caspase-8 and-9. However, the phosphorylation of FOXO1 and the protein levels of p53 were not affected by XB130 siRNA. We also found XB130 can be phosphorylated by multiple protein tyrosine kinases. These results indicate that XB130 is a substrate of multiple protein tyrosine kinases, and it can regulate cell proliferation and survival through modulating selected down-stream signals of PI3K/Akt pathway. XB130 could be involved in growth and survival of different cancer cells. PMID- 22928012 TI - Aldehyde dehydrogenase 1, a potential marker for cancer stem cells in human sarcoma. AB - Tumors contain a small population of cancer stem cells (CSC) proposed to be responsible for tumor maintenance and relapse. Aldehyde dehydrogenase 1 (ALDH1) activity has been used as a functional stem cell marker to isolate CSCs in different cancer types. This study used the Aldefluor(r) assay and fluorescence activated cell sorting (FACS) analysis to isolate ALDH1(high) cells from five human sarcoma cell lines and one primary chordoma cell line. ALDH1(high) cells range from 0.3% (MUG-Chor1) to 4.1% (SW-1353) of gated cells. Immunohistochemical staining, analysis of the clone formation efficiency, and xCELLigence microelectronic sensor technology revealed that ALDH1(high) cells from all sarcoma cell lines have an increased proliferation rate compared to ALDH1(low) cells. By investigating of important regulators of stem cell biology, real-time RT-PCR data showed an increased expression of c-Myc, beta-catenin, and SOX-2 in the ALDH1(high) population and a significant higher level of ABCG2. Statistical analysis of data demonstrated that ALDH1(high) cells of SW-982 and SW-1353 showed higher resistance to commonly used chemotherapeutic agents like doxorubicin, epirubicin, and cisplatin than ALDH1(low) cells. This study demonstrates that in different sarcoma cell lines, high ALDH1 activity can be used to identify a subpopulation of cells characterized by a significantly higher proliferation rate, increased colony forming, increased expression of ABC transporter genes and stemness markers compared to control cells. In addition, enhanced drug resistance was demonstrated. PMID- 22928013 TI - Class IA phosphatidylinositol 3-kinase p110alpha regulates phagosome maturation. AB - Of the various phosphatidylinositol 3- kinases (PI3Ks), only the class III enzyme Vps34 has been shown to regulate phagosome maturation. During studies of phagosome maturation in THP-1 cells deficient in class IA PI3K p110alpha, we discovered that this PI3K isoform is required for vacuole maturation to progress beyond acquisition of Rab7 leading to delivery of lysosomal markers. Bead phagosomes from THP-1 cells acquired p110alpha and contained PI3P and PI(3,4,5)P3; however, p110alpha and PI(3,4,5)P3 levels in phagosomes from p110alpha knockdown cells were decreased. Phagosomes from p110alpha knock down cells showed normal acquisition of both Rab5 and EEA-1, but were markedly deficient in the lysosomal markers LAMP-1 and LAMP-2, and the lysosomal hydrolase, beta-galactosidase. Phagosomes from p110alpha deficient cells also displayed impaired fusion with Texas Red dextran-loaded lysosomes. Despite lacking lysosomal components, phagosomes from p110alpha deficient cells recruited normal levels of Rab7, Rab-interacting lysosomal protein (RILP) and homotypic vacuole fusion and protein sorting (HOPs) components Vps41 and Vps16. The latter observations demonstrated that phagosomal Rab7 was active and capable of recruiting effectors involved in membrane fusion. Nevertheless, active Rab7 was not sufficient to bring about the delivery of lysosomal proteins to the maturing vacuole, which is shown for the first time to be dependent on a class I PI3K. PMID- 22928014 TI - Blunted IL17/IL22 and pro-inflammatory cytokine responses in the genital tract and blood of HIV-exposed, seronegative female sex workers in Kenya. AB - BACKGROUND: Identifying the immune correlates of reduced susceptibility to HIV remains a key goal for the HIV vaccine field, and individuals who are HIV exposed, seronegative (HESN) may offer important clues. Reduced systemic immune activation has been described in HESN individuals. Conversely, pro-inflammatory T cell subsets, particularly CD4+ T cells producing the cytokine IL17 (Th17 cells), may represent a highly susceptible target for HIV infection after sexual exposure. Therefore, we characterized the cellular pro-inflammatory and IL17/IL22 cytokine immune milieu in the genital mucosa and blood of HESN female sex workers (FSWs). METHODS AND RESULTS: Blinded lab personnel characterized basal and mitogen-induced gene and cytokine immune responses in the cervix and blood of HESN FSWs (n = 116) and non-FSW controls (n = 17) using qPCR and ELISA. IL17 and IL22 production was significantly reduced in both the cervix and blood of HESNs, both in resting cells and after mitogen stimulation. In addition, HESN participants demonstrated blunted production of both pro-inflammatory cytokines and beta-chemokines. DISCUSSION AND CONCLUSIONS: We conclude that HIV exposure without infection was associated with blunted IL17/IL22 and pro-inflammatory responses, both systemically and at the site of mucosal HIV exposure. It will be important for further studies to examine the causal nature of the association and to define the cell subsets responsible for these differences. PMID- 22928015 TI - Change in rainfall drives malaria re-emergence in Anhui Province, China. AB - Malaria is re-emerging in Anhui Province, China after a decade long' low level of endemicity. The number of human cases has increased rapidly since 2000 and reached its peak in 2006. That year, the malaria cases accounted for 54.5% of total cases in mainland China. However, the spatial and temporal patterns of human cases and factors underlying the re-emergence remain unclear. We established a database containing 20 years' (1990-2009) records of monthly reported malaria cases and meteorological parameters. Spearman correlations were used to assess the crude association between malaria incidence and meteorological variables, and a polynomial distributed lag (PDL) time-series regression was performed to examine contribution of meteorological factors to malaria transmission in three geographic regions (northern, mid and southern Anhui Province), respectively. Then, a two-year (2008-2009) prediction was performed to validate the PDL model that was created by using the data collected from 1990 to 2007. We found that malaria incidence decreased in Anhui Province in 1990s. However, the incidence has dramatically increased in the north since 2000, while the transmission has remained at a relatively low level in the mid and south. Spearman correlation analyses showed that the monthly incidences of malaria were significantly associated with temperature, rainfall, relative humidity, and the multivariate El Nino/Southern Oscillation index with lags of 0-2 months in all three regions. The PDL model revealed that only rainfall with a 1-2 month lag was significantly associated with malaria incidence in all three regions. The model validation showed a high accuracy for the prediction of monthly incidence over a 2-year predictive period. Malaria epidemics showed a high spatial heterogeneity in Anhui Province during the 1990-2009 study periods. The change in rainfall drives the reemergence of malaria in the northern Anhui Province. PMID- 22928016 TI - Ex vivo SIV-specific CD8 T cell responses in heterozygous animals are primarily directed against peptides presented by a single MHC haplotype. AB - The presence of certain MHC class I alleles is correlated with remarkable control of HIV and SIV, indicating that specific CD8 T cell responses can effectively reduce viral replication. It remains unclear whether epitopic breadth is an important feature of this control. Previous studies have suggested that individuals heterozygous at the MHC class I loci survive longer and/or progress more slowly than those who are homozygous at these loci, perhaps due to increased breadth of the CD8 T cell response. We used Mauritian cynomolgus macaques with defined MHC haplotypes and viral inhibition assays to directly compare CD8 T cell efficacy in MHC-heterozygous and homozygous individuals. Surprisingly, we found that cells from heterozygotes suppress viral replication most effectively on target cells from animals homozygous for only one of two potential haplotypes. The same heterozygous effector cells did not effectively inhibit viral replication as effectively on the target cells homozygous for the other haplotype. These results indicate that the greater potential breadth of CD8 T cell responses present in heterozygous animals does not necessarily lead to greater antiviral efficacy and suggest that SIV-specific CD8 T cell responses in heterozygous animals have a skewed focus toward epitopes restricted by a single haplotype. PMID- 22928017 TI - Carbon monoxide reduces neuropathic pain and spinal microglial activation by inhibiting nitric oxide synthesis in mice. AB - BACKGROUND: Carbon monoxide (CO) synthesized by heme oxygenase 1 (HO-1) exerts antinociceptive effects during inflammation but its role during neuropathic pain remains unknown. Our objective is to investigate the exact contribution of CO derived from HO-1 in the modulation of neuropathic pain and the mechanisms implicated. METHODOLOGY/PRINCIPAL FINDINGS: We evaluated the antiallodynic and antihyperalgesic effects of CO following sciatic nerve injury in wild type (WT) or inducible nitric oxide synthase knockout (NOS2-KO) mice using two carbon monoxide-releasing molecules (CORM-2 and CORM-3) and an HO-1 inducer (cobalt protoporphyrin IX, CoPP) daily administered from days 10 to 20 after injury. The effects of CORM-2 and CoPP on the expression of HO-1, heme oxygenase 2 (HO-2), neuronal nitric oxide synthase (NOS1) and NOS2 as well as a microglial marker (CD11b/c) were also assessed at day 20 after surgery in WT and NOS2-KO mice. In WT mice, the main neuropathic pain symptoms induced by nerve injury were significantly reduced in a time-dependent manner by treatment with CO-RMs or CoPP. Both CORM-2 and CoPP treatments increased HO-1 expression in WT mice, but only CoPP stimulated HO-1 in NOS2-KO animals. The increased expression of HO-2 induced by nerve injury in WT, but not in NOS2-KO mice, remains unaltered by CORM 2 or CoPP treatments. In contrast, the over-expression of CD11b/c, NOS1 and NOS2 induced by nerve injury in WT, but not in NOS2-KO mice, were significantly decreased by both CORM-2 and CoPP treatments. These data indicate that CO alleviates neuropathic pain through the reduction of spinal microglial activation and NOS1/NOS2 over-expression. CONCLUSIONS/SIGNIFICANCE: This study reports that an interaction between the CO and nitric oxide (NO) systems is taking place following sciatic nerve injury and reveals that increasing the exogenous (CO-RMs) or endogenous (CoPP) production of CO may represent a novel strategy for the treatment of neuropathic pain. PMID- 22928018 TI - Siderocalin/Lcn2/NGAL/24p3 does not drive apoptosis through gentisic acid mediated iron withdrawal in hematopoietic cell lines. AB - Siderocalin (also lipocalin 2, NGAL or 24p3) binds iron as complexes with specific siderophores, which are low molecular weight, ferric ion-specific chelators. In innate immunity, siderocalin slows the growth of infecting bacteria by sequestering bacterial ferric siderophores. Siderocalin also binds simple catechols, which can serve as siderophores in the damaged urinary tract. Siderocalin has also been proposed to alter cellular iron trafficking, for instance, driving apoptosis through iron efflux via BOCT. An endogenous siderophore composed of gentisic acid (2,5-dihydroxybenzoic acid) substituents was proposed to mediate cellular efflux. However, binding studies reported herein contradict the proposal that gentisic acid forms high-affinity ternary complexes with siderocalin and iron, or that gentisic acid can serve as an endogenous siderophore at neutral pH. We also demonstrate that siderocalin does not induce cellular iron efflux or stimulate apoptosis, questioning the role siderocalin plays in modulating iron metabolism. PMID- 22928019 TI - Object/context specific memory deficits following medial frontal cortex damage in mice. AB - Recent evidence suggests that the medial prefrontal cortex (MFC) is important for processing contextual information. Here we evaluate the performance of mice with MFC damage in a discrimination task that requires an association between an object and the context in which it was experienced (the object/context mismatch task), as well as a version of the novel object preference task that does not require knowledge of contextual information to resolve. Adult C57/BL6 mice received aspiration lesions of the MFC or control surgery. Upon recovery, mice were tested in the object/context mismatch and novel object preference tasks. The object/context mismatch task involved exposing mice to two different contexts, each of which housed a unique pair of identical objects. After a brief delay, mice were re-exposed to one of the contexts, this time with one object that was congruent with that context and one that was not. Novel object preference was performed within a single context, housing an identical pair of objects. After the initial exposure and following a brief delay, mice were re-exposed to the context, this time housing a familiar and a novel object. Control mice were able to successfully resolve the object/context mismatch and novel object preference discriminations, investigating the incongruent/novel object within each task significantly greater than chance. Mice with MFC damage experienced deficits in the object/context mismatch task but not the novel object preference task. These findings add to a growing body of evidence that demonstrate a critical role for the MFC in contextual information processing. PMID- 22928020 TI - The lethal toxin from Australian funnel-web spiders is encoded by an intronless gene. AB - Australian funnel-web spiders are generally considered the most dangerous spiders in the world, with envenomations from the Sydney funnel-web spider Atrax robustus resulting in at least 14 human fatalities prior to the introduction of an effective anti-venom in 1980. The clinical envenomation syndrome resulting from bites by Australian funnel-web spiders is due to a single 42-residue peptide known as delta-hexatoxin. This peptide delays the inactivation of voltage-gated sodium channels, which results in spontaneous repetitive firing and prolongation of action potentials, thereby causing massive neurotransmitter release from both somatic and autonomic nerve endings. Here we show that delta-hexatoxin from the Australian funnel-web spider Hadronyche versuta is produced from an intronless gene that encodes a prepropeptide that is post-translationally processed to yield the mature toxin. A limited sampling of genes encoding unrelated venom peptides from this spider indicated that they are all intronless. Thus, in distinct contrast to cone snails and scorpions, whose toxin genes contain introns, spiders may have developed a quite different genetic strategy for evolving their venom peptidome. PMID- 22928021 TI - Evaluating the relationship between competition and productivity within a native grassland. AB - Ideas about how plant competition varies with productivity are rooted in classic theories that predict either increasing (Grime) or invariant (Tilman) competition with increasing productivity. Both predictions have received experimental support, although a decade-old meta-analysis supports neither. Attempts to reconcile the conflicting predictions and evidence include: expanding the theory to include other conditions (e.g. stress gradient hypothesis), development of indices to differentiate either the 'intensity' or 'importance' of competition, a focus on resource supply and demand, and explicit recognition that both growth and survival may exhibit different relationships with productivity. To determine which of these theories accurately predict how competition varies with productivity within a native grassland site, we estimated competitive intensity and relative competitive importance using 22 species across the range of productivity naturally occurring within that site. Plant performance was measured as survival and size with and without neighbours and the local environment was quantified according to variability in standing crop, gross water supply, and net water supply. On average, neighbours weakly facilitated seedling survival, but strongly reduced seedling growth. For both seedling survival and growth, relative competitive importance and competitive intensity declined with some measure of productivity; neighbour effects on survival declined with standing crop, while effects on growth declined with gross water supply. These results add to the growing evidence that plant-plant interactions vary among life history components with different life history components contingent upon separate environmental factors. Although the range of productivity measured in this study was not large, our results do not support the theories of Grime or Tilman. However, our results are consistent with the meta-analysis and parts of other theories, although no single theory is capable of explaining the entirety of these results. This suggests that, at least in moderately productive grasslands, new theory needs to be developed. PMID- 22928022 TI - Transcriptome analysis of the silkworm (Bombyx mori) by high-throughput RNA sequencing. AB - The domestic silkworm, Bombyx mori, is a model insect with important economic value for silk production that also acts as a bioreactor for biomaterial production. The functional complexity of the silkworm transcriptome has not yet been fully elucidated, although genomic sequencing and other tools have been widely used in its study. We explored the transcriptome of silkworm at different developmental stages using high-throughput paired-end RNA sequencing. A total of about 3.3 gigabases (Gb) of sequence was obtained, representing about a 7-fold coverage of the B. mori genome. From the reads that were mapped to the genome sequence; 23,461 transcripts were obtained, 5,428 of them were novel. Of the 14,623 predicted protein-coding genes in the silkworm genome database, 11,884 of them were found to be expressed in the silkworm transcriptome, giving a coverage of 81.3%. A total of 13,195 new exons were detected, of which, 5,911 were found in the annotated genes in the Silkworm Genome Database (SilkDB). An analysis of alternative splicing in the transcriptome revealed that 3,247 genes had undergone alternative splicing. To help with the data analysis, a transcriptome database that integrates our transcriptome data with the silkworm genome data was constructed and is publicly available at http://124.17.27.136/gbrowse2/. To our knowledge, this is the first study to elucidate the silkworm transcriptome using high-throughput RNA sequencing technology. Our data indicate that the transcriptome of silkworm is much more complex than previously anticipated. This work provides tools and resources for the identification of new functional elements and paves the way for future functional genomics studies. PMID- 22928023 TI - Developmental regulation of protein O-GlcNAcylation, O-GlcNAc transferase, and O GlcNAcase in mammalian brain. AB - O-GlcNAcylation is a common posttranslational modification of nucleocytoplasmic proteins by beta-N-acetylglucosamine (GlcNAc). The dynamic addition and removal of O-GlcNAc groups to and from proteins are catalyzed by O-linked N acetylglucosamine transferase (O-GlcNAc transferase, OGT) and beta-N acetylglucosaminidase (O-GlcNAcase, OGA), respectively. O-GlcNAcylation often modulates protein phosphorylation and regulates several cellular signaling and functions, especially in the brain. However, its developmental regulation is not well known. Here, we studied protein O-GlcNAcylation, OGT, and OGA in the rat brain at various ages from embryonic day 15 to the age of 2 years. We found a gradual decline of global protein O-GlcNAcylation during developmental stages and adulthood. This decline correlated positively to the total protein phosphorylation at serine residues, but not at threonine residues. The expression of OGT and OGA isoforms was regulated differently at various ages. Immunohistochemical studies revealed ubiquitous distribution of O-GlcNAcylation at all ages. Strong immunostaining of O-GlcNAc, OGT, and OGA was observed mostly in neuronal cell bodies and processes, further suggesting the role of O-GlcNAc modification of neuronal proteins in the brain. These studies provide fundamental knowledge of age-dependent protein modification by O-GlcNAc and will help guide future studies on the role of O-GlcNAcylation in the mammalian brain. PMID- 22928024 TI - Epigenetic modification of gene expression in honey bees by heterospecific gland secretions. AB - BACKGROUND: In the honey bee (Apis mellifera), queen and workers have different behavior and reproductive capacity despite possessing the same genome. The primary substance that leads to this differentiation is royal jelly (RJ), which contains a range of proteins, amino acids, vitamins and nucleic acids. MicroRNA (miRNA) has been found to play an important role in regulating the expression of protein-coding genes and cell biology. In this study, we characterized the miRNAs in RJ from two honey bee sister species and determined their possible effect on transcriptome in one species. METHODOLOGY/PRINCIPAL FINDINGS: We sequenced the miRNAs in RJ either from A. mellifera (RJM) or A. cerana (RJC). We then determined the global transcriptomes of adult A. mellifera developed from larvae fed either with RJM (mRJM) or RJC (mRJC). Finally we analyzed the target genes of those miRNA that are species specific or differentially expressed in the two honey bee species. We show that there were differences in miRNA between RJM and RJC, and that transcriptomes of adult A. mellifera were affected by the two types of RJ. A high proportion (23.3%) of the affected genes were target genes of differential miRNAs. CONCLUSION: We show for the first time that there are differences in miRNAs in RJ between A. mellifera and A. cerana. Further, the differences in transcriptomes of bees reared from these two RJs might be related to miRNA differences of the two species. This study provides the first evidence that heterospecific royal jelly can modify gene expression in honey bees through an epigenetic mechanism. PMID- 22928025 TI - An in silico study of the differential effect of oxidation on two biologically relevant G-quadruplexes: possible implications in oncogene expression. AB - G-quadruplex structures, formed from guanine rich sequences, have previously been shown to be involved in various physiological processes including cancer-related gene expression. Furthermore, G-quadruplexes have been found in several oncogene promoter regions, and have been shown to play a role in the regulation of gene expression. The mutagenic properties of oxidative stress on DNA have been widely studied, as has the association with carcinogenesis. Guanine is the most susceptible nucleotide to oxidation, and as such, G-rich sequences that form G quadruplexes can be viewed as potential "hot-spots" for DNA oxidation. We propose that oxidation may destabilise the G-quadruplex structure, leading to its unfolding into the duplex structure, affecting gene expression. This would imply a possible mechanism by which oxidation may impact on oncogene expression. This work investigates the effect of oxidation on two biologically relevant G quadruplex structures through 500 ns molecular dynamics simulations on those found in the promoter regions of the c-Kit and c-Myc oncogenes. The results show oxidation having a detrimental effect on stability of the structure, substantially destabilising the c-Kit quadruplex, and with a more attenuated effect on the c-Myc quadruplex. Results are suggestive of a novel route for oxidation-mediated oncogenesis and may have wider implications for genome stability. PMID- 22928026 TI - Fertility and pregnancy-associated beta-cell proliferation in mice deficient in proglucagon-derived peptides. AB - Proglucagon, which is encoded by the glucagon gene (Gcg), is the precursor of several peptide hormones, including glucagon and glucagon-like peptide 1 (GLP-1). Whereas glucagon stimulates hepatic glycogenolysis and gluconeogenesis, GLP-1 stimulates insulin secretion to lower blood glucose and also supports beta-cell proliferation and protection from apoptotic stimuli. Pregnancy is a strong inducer of change in islet function, however the roles of proglucagon-derived peptides in pregnancy are only partially understood. In the present study, we analyzed fertility and pregnancy-associated changes in homozygous glucagon-green fluorescent protein (gfp) knock-in mice (Gcg(gfp/gfp)), which lack all the peptides derived from proglucagon. Female Gcg(gfp/gfp) mice could deliver and raise Gcg(gfp/gfp) pups to weaning and Gcg(gfp/gfp) pups from Gcg(gfp/gfp) dams were viable and fertile. Pregnancy induced beta-cell proliferation in Gcg(gfp/gfp) mice as well as in control mice. However, serum insulin levels in pregnant Gcg(gfp/gfp) females were lower than those in control pregnant females under ad libitum feeding, and blood glucose levels in pregnant Gcg(gfp/gfp) females were higher after gestational day 12. Gcg(gfp/gfp) females showed a decreased pregnancy rate and smaller litter size. The rate of successful breeding was significantly lower in Gcg(gfp/gfp) females and was not improved by experience of breeding. Taken together, proglucagon-derived peptides are not required for pregnancy-associated beta-cell proliferation, however, are required for regulation of blood glucose levels and normal reproductive capacity. Gcg(gfp/gfp) mice may serve as a novel model to analyze the effect of mild hyperglycemia during late gestational periods. PMID- 22928027 TI - Efficient delivery of DNA and morpholinos into mouse preimplantation embryos by electroporation. AB - Mouse preimplantation development is characterized by three major transitions and two lineage segregations. Each transition or lineage segregation entails pronounced changes in the pattern of gene expression. Thus, research into the function of genes with obvious changes in expression pattern will shed light on the molecular basis of preimplantation development. We have described a simplified and effective method--electroporation--of introducing plasmid DNA and morpholinos into mouse preimplantation embryos and verified effectiveness of this approach by testing the procedure on the endogenous gene Oct4. Before electroporation, the zona pellucida was weakened by the treatment of acid Tyrode's solution. Then we optimized the parameters such as voltage, pulse duration, number of pulses and repeats, and applied these parameters to subsequent experiments. Compared with the control groups, the number of apoptotic cells and the expression and localization of OCT3/4 or CDX2 was not significantly changed in blastocysts developed from 1-cell embryos, which were electroporated with pIRES2-AcGFP1-Nuc eukaryotic expression vector or mismatched morpholino oligonucleotides. Furthermore, electroporated plasmid DNA and morpholinos targeting the endogenous gene Oct4 were able to sharply down regulate expression of OCT4 protein and actually cause expected phenotypes in mouse preimplantation embryos. In conclusion, plasmid DNA and morpholinos could be efficient delivered into mouse preimplantation embryos by electroporation and exert their functions, and normal development of preimplantation embryos was not affected. PMID- 22928028 TI - Detection of the heterogeneous O-glycosylation profile of MT1-MMP expressed in cancer cells by a simple MALDI-MS method. AB - BACKGROUND: Glycosylation is an important and universal post-translational modification for many proteins, and regulates protein functions. However, simple and rapid methods to analyze glycans on individual proteins have not been available until recently. METHODS/PRINCIPAL FINDINGS: A new technique to analyze glycopeptides in a highly sensitive manner by matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS) using the liquid matrix 3AQ/CHCA was developed recently and we optimized this technique to analyze a small amount of transmembrane protein separated by SDS-PAGE. We used the MALDI-MS method to evaluate glycosylation status of membrane-type 1 matrix metalloproteinase (MT1-MMP). O-glycosylation of MT1-MMP is reported to modulate its protease activity and thereby to affect cancer cell invasion. MT1-MMP expressed in human fibrosarcoma HT1080 cells was immunoprecipitated and resolved by SDS-PAGE. After in-gel tryptic digestion of the protein, a single droplet of the digest was applied directly to the liquid matrix on a MALDI target plate. Concentration of hydrophilic glycopeptides within the central area occurred due to gradual evaporation of the sample solution, whereas nonglycosylated hydrophobic peptides remained at the periphery. This specific separation and concentration of the glycopeptides enabled comprehensive analysis of the MT1-MMP O-glycosylation. CONCLUSIONS/SIGNIFICANCE: We demonstrate, for the first time, heterogeneous O-glycosylation profile of a protein by a whole protein analysis using MALDI-MS. Since cancer cells are reported to have altered glycosylation of proteins, this easy-to-use method for glycopeptide analysis opens up the possibility to identify specific glycosylation patterns of proteins that can be used as new biomarkers for malignant tumors. PMID- 22928029 TI - Eco-label conveys reliable information on fish stock health to seafood consumers. AB - Concerns over fishing impacts on marine populations and ecosystems have intensified the need to improve ocean management. One increasingly popular market based instrument for ecological stewardship is the use of certification and eco labeling programs to highlight sustainable fisheries with low environmental impacts. The Marine Stewardship Council (MSC) is the most prominent of these programs. Despite widespread discussions about the rigor of the MSC standards, no comprehensive analysis of the performance of MSC-certified fish stocks has yet been conducted. We compared status and abundance trends of 45 certified stocks with those of 179 uncertified stocks, finding that 74% of certified fisheries were above biomass levels that would produce maximum sustainable yield, compared with only 44% of uncertified fisheries. On average, the biomass of certified stocks increased by 46% over the past 10 years, whereas uncertified fisheries increased by just 9%. As part of the MSC process, fisheries initially go through a confidential pre-assessment process. When certified fisheries are compared with those that decline to pursue full certification after pre-assessment, certified stocks had much lower mean exploitation rates (67% of the rate producing maximum sustainable yield vs. 92% for those declining to pursue certification), allowing for more sustainable harvesting and in many cases biomass rebuilding. From a consumer's point of view this means that MSC-certified seafood is 3-5 times less likely to be subject to harmful fishing than uncertified seafood. Thus, MSC certification accurately identifies healthy fish stocks and conveys reliable information on stock status to seafood consumers. PMID- 22928030 TI - Engineering of an artificial light-modulated potassium channel. AB - Ion Channel-Coupled Receptors (ICCRs) are artificial receptor-channel fusion proteins designed to couple ligand binding to channel gating. We previously validated the ICCR concept with various G protein-coupled receptors (GPCRs) fused with the inward rectifying potassium channel Kir6.2. Here we characterize a novel ICCR, consisting of the light activated GPCR, opsin/rhodopsin, fused with Kir6.2. To validate our two-electrode voltage clamp (TEVC) assay for activation of the GPCR, we first co-expressed the apoprotein opsin and the G protein-activated potassium channel Kir3.1(F137S) (Kir3.1*) in Xenopus oocytes. Opsin can be converted to rhodopsin by incubation with 11-cis retinal and activated by light induced retinal cis->trans isomerization. Alternatively opsin can be activated by incubation of oocytes with all-trans-retinal. We found that illumination of 11 cis-retinal-incubated oocytes co-expressing opsin and Kir3.1* caused an immediate and long-lasting channel opening. In the absence of 11-cis retinal, all-trans retinal also opened the channel persistently, although with slower kinetics. We then used the oocyte/TEVC system to test fusion proteins between opsin/rhodopsin and Kir6.2. We demonstrate that a construct with a C-terminally truncated rhodopsin responds to light stimulus independent of G protein. By extending the concept of ICCRs to the light-activatable GPCR rhodopsin we broaden the potential applications of this set of tools. PMID- 22928031 TI - Mutations in Escherichia coli aceE and ribB genes allow survival of strains defective in the first step of the isoprenoid biosynthesis pathway. AB - A functional 2-C-methyl-D-erythritol 4-phosphate (MEP) pathway is required for isoprenoid biosynthesis and hence survival in Escherichia coli and most other bacteria. In the first two steps of the pathway, MEP is produced from the central metabolic intermediates pyruvate and glyceraldehyde 3-phosphate via 1-deoxy-D xylulose 5-phosphate (DXP) by the activity of the enzymes DXP synthase (DXS) and DXP reductoisomerase (DXR). Because the MEP pathway is absent from humans, it was proposed as a promising new target to develop new antibiotics. However, the lethal phenotype caused by the deletion of DXS or DXR was found to be suppressed with a relatively high efficiency by unidentified mutations. Here we report that several mutations in the unrelated genes aceE and ribB rescue growth of DXS defective mutants because the encoded enzymes allowed the production of sufficient DXP in vivo. Together, this work unveils the diversity of mechanisms that can evolve in bacteria to circumvent a blockage of the first step of the MEP pathway. PMID- 22928032 TI - Multi-session transcranial direct current stimulation (tDCS) elicits inflammatory and regenerative processes in the rat brain. AB - Transcranial direct current stimulation (tDCS) is increasingly being used in human studies as an adjuvant tool to promote recovery of function after stroke. However, its neurobiological effects are still largely unknown. Electric fields are known to influence the migration of various cell types in vitro, but effects in vivo remain to be shown. Hypothesizing that tDCS might elicit the recruitment of cells to the cortex, we here studied the effects of tDCS in the rat brain in vivo. Adult Wistar rats (n = 16) were randomized to either anodal or cathodal stimulation for either 5 or 10 consecutive days (500 uA, 15 min). Bromodeoxyuridine (BrdU) was given systemically to label dividing cells throughout the experiment. Immunohistochemical analyses ex vivo included stainings for activated microglia and endogenous neural stem cells (NSC). Multi session tDCS with the chosen parameters did not cause a cortical lesion. An innate immune response with early upregulation of Iba1-positive activated microglia occurred after both cathodal and anodal tDCS. The involvement of adaptive immunity as assessed by ICAM1-immunoreactivity was less pronounced. Most interestingly, only cathodal tDCS increased the number of endogenous NSC in the stimulated cortex. After 10 days of cathodal stimulation, proliferating NSC increased by ~60%, with a significant effect of both polarity and number of tDCS sessions on the recruitment of NSC. We demonstrate a pro-inflammatory effect of both cathodal and anodal tDCS, and a polarity-specific migratory effect on endogenous NSC in vivo. Our data suggest that tDCS in human stroke patients might also elicit NSC activation and modulate neuroinflammation. PMID- 22928033 TI - A quantitative assay for the juvenile hormones and their precursors using fluorescent tags. AB - BACKGROUND: The juvenile hormones (JHs) are sesquiterpenoid compounds that play a central role in insect reproduction, development and behavior. The lipophilic nature of JHs and their precursors, in conjunction with their low concentration in tissues and susceptibility to degradation had made their quantification difficult. A variety of methods exist for JH quantification but few can quantify on the femtomole range. Currently applied methods are expensive and time consuming. In the present study we sought to develop a novel method for accurate detection and quantification of JHs and their precursors. METHODS: A sensitive and robust method was developed to quantify the precursor, farnesoic acid (FA) and juvenile hormone III (JH III) in biological samples. The assay is based on the derivatization of analytes with fluorescent tags, with subsequent analysis by reverse phase high performance liquid chromatography coupled to a fluorescent detector (HPLC-FD). The carboxyl group of FA was derivatized with 4-Acetamido-7 mercapto-2,1,3-benzoxadiazole (AABD-SH). Tagging the epoxide group of JH III required a two-step reaction: the opening of the epoxide ring with sodium sulfide and derivatization with the fluorescent tag 4-(N,N-Dimethylaminosulfonyl)-7-(N chloroformylmethyl-N-methylamino)-2,1,3-benzoxadiazole (DBD-COCl). CONCLUSIONS: The method developed in the present study showed high sensitivity, accuracy and reproducibility. Linear responses were obtained over the range of 10-20 to 1000 fmols. Recovery efficiencies were over 90% for JH III and 98% for FA with excellent reproducibility. SIGNIFICANCE: The proposed method is applicable when sensitive detection and accurate quantification of limited amount of sample is needed. Examples include corpora allata, hemolymph and whole body of female adult Aedes aegypti and whole body Drosophila melanogaster. A variety of additional functional groups can be targeted to add fluorescent tags to the remaining JH III precursors. PMID- 22928034 TI - Perinatal Na+ overload programs raised renal proximal Na+ transport and enalapril sensitive alterations of Ang II signaling pathways during adulthood. AB - BACKGROUND: High Na(+) intake is a reality in nowadays and is frequently accompanied by renal and cardiovascular alterations. In this study, renal mechanisms underlying perinatal Na(+) overload-programmed alterations in Na(+) transporters and the renin/angiotensin system (RAS) were investigated, together with effects of short-term treatment with enalapril in terms of reprogramming molecular alterations in kidney. METHODOLOGY/PRINCIPAL FINDINGS: Male adult Wistar rats were obtained from dams maintained throughout pregnancy and lactation on a standard diet and drinking water (control) or 0.17 M NaCl (saline group). Enalapril (100 mg/l), an angiotensin converting enzyme inhibitor, was administered for three weeks after weaning. Ninety day old offspring from dams that drank saline presented with proximal tubules exhibiting increased (Na(+)+K(+))ATPase expression and activity. Ouabain-insensitive Na(+)-ATPase activity remained unchanged but its response to angiotensin II (Ang II) was lost. PKC, PKA, renal thiobarbituric acid reactive substances (TBARS), macrophage infiltration and collagen deposition markedly increased, and AT(2) receptor expression decreased while AT(1) expression was unaltered. Early treatment with enalapril reduced expression and activity of (Na(+)+K(+))ATPase, partially recovered the response of Na(+)-ATPase to Ang II, and reduced PKC and PKA activities independently of whether offspring were exposed to high perinatal Na(+) or not. In addition, treatment with enalapril per se reduced AT(2) receptor expression, and increased TBARS, macrophage infiltration and collagen deposition. The perinatally Na(+)-overloaded offspring presented high numbers of Ang II positive cortical cells, and significantly lower circulating Ang I, indicating that programming/reprogramming impacted systemic and local RAS. CONCLUSIONS/SIGNIFICANCE: Maternal Na(+) overload programmed alterations in renal Na(+) transporters and in its regulation, as well as severe structural lesions in adult offspring. Enalapril was beneficial predominantly through its influence on Na(+) pumping activities in adult offspring. However, side effects including down regulation of PKA, PKC and AT(2) receptors and increased TBARS could impair renal function in later life. PMID- 22928035 TI - Is "football for all" safe for all? Cross-sectional study of disparities as determinants of 1-year injury prevalence in youth football programs. AB - BACKGROUND: Football (soccer) is endorsed as a health-promoting physical activity worldwide. When football programs are introduced as part of general health promotion programs, equal access and limitation of pre-participation disparities with regard to injury risk are important. The aim of this study was to explore if disparity with regard to parents' educational level, player body mass index (BMI), and self-reported health are determinants of football injury in community based football programs, separately or in interaction with age or gender. METHODOLOGY/PRINCIPAL FINDINGS: Four community football clubs with 1230 youth players agreed to participate in the cross-sectional study during the 2006 season. The study constructs (parents' educational level, player BMI, and self reported health) were operationalized into questionnaire items. The 1-year prevalence of football injury was defined as the primary outcome measure. Data were collected via a postal survey and analyzed using a series of hierarchical statistical computations investigating associations with the primary outcome measure and interactions between the study variables. The survey was returned by 827 (67.2%) youth players. The 1-year injury prevalence increased with age. For youths with parents with higher formal education, boys reported more injuries and girls reported fewer injuries than expected; for youths with lower educated parents there was a tendency towards the opposite pattern. Youths reporting injuries had higher standardized BMI compared with youths not reporting injuries. Children not reporting full health were slightly overrepresented among those reporting injuries and underrepresented for those reporting no injury. CONCLUSION: Pre-participation disparities in terms of parents' educational level, through interaction with gender, BMI, and self-reported general health are associated with increased injury risk in community-based youth football. When introduced as a general health promotion, football associations should adjust community-based youth programs to accommodate children and adolescents with increased pre-participation injury risk. PMID- 22928036 TI - Activin A promotes neuronal differentiation of cerebrocortical neural progenitor cells. AB - BACKGROUND: Activin A is a protein that participates principally in reproductive functions. In the adult brain, Activin is neuroprotective, but its role in brain development is still elusive. METHODOLOGY/PRINCIPAL FINDINGS: We studied if Activin A influences proliferation, differentiation or survival in rat cerebrocortical neural progenitor cells (NPC). After stimulation of NPC with Activin A, phosphorylation and nuclear translocation of Smad 2/3 were induced. In proliferating NPC, Activin produced a significant decrease in cell area and also a discrete increase in the number of neurons in the presence of the mitogen Fibroblast Growth Factor 2. The percentages of cells incorporating BrdU, or positive for the undifferentiated NPC markers Nestin and Sox2, were unchanged after incubation with Activin. In differentiating conditions, continuous treatment with Activin A significantly increased the number of neurons without affecting astroglial differentiation or causing apoptotic death. In cells cultured by extended periods, Activin treatment produced further increases in the proportion of neurons, excluding premature cell cycle exit. In clonal assays, Activin significantly increased neuronal numbers per colony, supporting an instructive role. Activin-induced neurogenesis was dependent on activation of its receptors, since incubation with the type I receptor inhibitor SB431542 or the ligand-trap Follistatin prevented neuronal differentiation. Interestingly, SB431542 or Follistatin by themselves abolished neurogenesis and increased astrogliogenesis, to a similar extent to that induced by Bone Morphogenetic Protein (BMP)4. Co-incubation of these Activin inhibitors with the BMP antagonist Dorsomorphin restored neuronal and astrocytic differentiation to control levels. CONCLUSIONS: Our results show an instructive neuronal effect of Activin A in cortical NPC in vitro, pointing out to a relevant role of this cytokine in the specification of NPC towards a neuronal phenotype. PMID- 22928037 TI - The proteins PDIP3 and ZC11A associate with the human TREX complex in an ATP dependent manner and function in mRNA export. AB - The conserved TREX complex, which contains UAP56, Aly, CIP29, and the multi subunit THO complex, functions in mRNA export. Recently, several putative new components of the human TREX complex were identified by mass spectrometry. Here, we investigated the function of two of these, PDIP3 and ZC11A. Our data indicate that both of these proteins are components of a common TREX complex and function in mRNA export. Recently, we found that both CIP29 and Aly associate with the DEAD box helicase UAP56 and with the TREX complex in an ATP-dependent manner. We now show that this is also the case for PDIP3 and ZC11A. Thus, together with previous work, our data indicate that the TREX complex participates in multiple ATP-dependent interactions. PMID- 22928038 TI - miR290-5p/292-5p activate the immunoglobulin kappa locus in B cell development. AB - Regulated expression of miRNAs influences development in a wide variety of contexts. We report here that miR290-5p (100049710) and miR292-5p (100049711) are induced at the pre-B stage of murine B cell development and that they influence assembly of the Igkappa light chain gene (243469) by contributing to the activation of germline Igkappa transcription (kappaGT). We found that upon forced over-expression of miR290-5p/292-5p in Abelson Murine Leukemia Virus (AMuLV) transformed pro-B cells, two known activators of kappaGT, E2A (21423) and NF kappaB (19697), show increased chromosomal binding to the kappa intronic enhancer. Conversely, knockdown of miR290-5p/292-5p in AMuLV pro-B cells blunts drug-induced activation of kappaGT. Furthermore, miR290-5p/292-5p knockdown also diminishes kappaGT activation, but not Rag1/2 (19373, 19374) expression, in an IL 7 dependent primary pro-B cell culture system. In addition, we identified a deficiency in kappaGT induction in miR290 cluster knockout mice. We hypothesize that increased expression of miR290-5p and miR292-5p contributes to the induction of kappaGT at the pre-B stage of B cell development through increased binding of NF-kappaB and E2A to kappa locus regulatory sequences. PMID- 22928039 TI - Cultural evolution and perpetuation of arbitrary communicative conventions in experimental microsocieties. AB - Previous studies have shown that iconic graphical signs can evolve into symbols through repeated usage within dyads and interacting communities. Here we investigate the evolution of graphical signs over chains of participants. In these chains (or "replacement microsocieties"), membership of an interacting group changed repeatedly such that the most experienced members were continually replaced by naive participants. Signs rapidly became symbolic, such that they were mutually incomprehensible across experienced members of different chains, and new entrants needed to learn conventionalised meanings. An objective measure of graphical complexity (perimetric complexity) showed that the signs used within the microsocieties were becoming progressively simplified over successive usage. This is the first study to show that the signs that evolve in graphical communication experiments can be transmitted to, and spontaneously adopted by, naive participants. This provides critical support for the view that human communicative symbols could have evolved culturally from iconic representations. PMID- 22928040 TI - Genistein suppresses prostate cancer growth through inhibition of oncogenic microRNA-151. AB - Genistein has been shown to suppress the growth of several cancers through modulation of various pathways. However, the effects of genistein on the regulation of oncogenic microRNA-151 (miR-151) have not been reported. In this study, we investigated whether genistein could alter the expression of oncogenic miR-151 and its target genes that are involved in the progression and metastasis of prostate cancer (PCa). Real-time RT-PCR showed that the expression of miR-151 was higher in PC3 and DU145 cells compared with RWPE-1 cells. Treatment of PC3 and DU145 cells with 25 uM genistein down-regulated the expression of miR-151 compared with vehicle control. Inhibition of miR-151 in PCa cells by genistein significantly inhibited cell migration and invasion. In-silico analysis showed that several genes (CASZ1, IL1RAPL1, SOX17, N4BP1 and ARHGDIA) suggested to have tumor suppressive functions were target genes of miR-151. Luciferase reporter assays indicated that miR-151 directly binds to specific sites on the 3'UTR of target genes. Quantitative real-time PCR analysis showed that the mRNA expression levels of the five target genes in PC3 and DU145 were markedly changed with miR 151 mimics and inhibitor. Kaplan-Meier curves and log-rank tests revealed that high expression levels of miR-151 had an adverse effect on survival rate. This study suggests that genistein mediated suppression of oncogenic miRNAs can be an important dietary therapeutic strategy for the treatment of PCa. PMID- 22928041 TI - Systematic review and meta-analysis of the relationship between EPHX1 polymorphisms and colorectal cancer risk. AB - BACKGROUND: Microsomal epoxide hydrolase (EPHX1) plays an important role in both the activation and detoxification of PAHs, which are carcinogens found in cooked meat and tobacco smoking. Polymorphisms at exons 3 and 4 of the EPHX1 gene have been reported to be associated with variations in EPHX1 activity. The aim of this study is to quantitatively summarize the relationship between EPHX1 polymorphisms and colorectal cancer (CRC) risk. METHODS: Two investigators independently searched the Medline, Embase, CNKI, and Chinese Biomedicine Databases for studies published before June 2012. Summary odds ratios (ORs) and 95% confidence intervals (CIs) for EPHX1 Tyr113His (rs1051740) and His139Arg (rs2234922) polymorphisms and CRC were calculated in a fixed-effects model and a random effects model when appropriate. RESULTS: This meta-analysis yielded 14 case control studies, which included 13 studies for Tyr113His (6395 cases and 7893 controls) and 13 studies for His139Arg polymorphisms (5375 cases and 6962 controls). Overall, the pooled results indicated that EPHX1 Tyr113His polymorphism was not associated with CRC risk; while the His139Arg polymorphism was significantly associated with decreased CRC risk (Arg/His vs. His/His, OR = 0.90, 95%CI = 0.83-0.98; dominant model, OR = 0.92, 95%CI = 0.85-0.99). The statistically significant association between EPHX1 His139Arg polymorphism and CRC was observed among Caucasians and population-based case-control studies. This association showed little heterogeneity and remained consistently strong when analyses were limited to studies in which genotype frequencies were in Hardy Weinberg equilibrium, or limited to studies with matched controls. When cumulative meta-analyses of the two associations were conducted by studies' publication time, the results were persistent and robust. CONCLUSION: This meta analysis suggests that EPHX1 Tyr113His polymorphism may be not associated with CRC development; while the EPHX1 His139Arg polymorphism may have a potential protective effect on CRC. PMID- 22928042 TI - Methylation by a unique alpha-class N4-cytosine methyltransferase is required for DNA transformation of Caldicellulosiruptor bescii DSM6725. AB - Thermophilic microorganisms capable of using complex substrates offer special advantages for the conversion of lignocellulosic biomass to biofuels and bioproducts. Members of the gram-positive bacterial genus Caldicellulosiruptor are anaerobic thermophiles with optimum growth temperatures between 65 degrees C and 78 degrees C and are the most thermophilic cellulolytic organisms known. In fact, they efficiently use biomass non-pretreated as their sole carbon source and in successive rounds of application digest 70% of total switchgrass substrate. The ability to genetically manipulate these organisms is a prerequisite to engineering them for use in conversion of these complex substrates to products of interest as well as identifying gene products critical for their ability to utilize non-pretreated biomass. Here, we report the first example of DNA transformation of a member of this genus, C. bescii. We show that restriction of DNA is a major barrier to transformation (in this case apparently absolute) and that methylation with an endogenous unique alpha-class N4-Cytosine methyltransferase is required for transformation of DNA isolated from E. coli. The use of modified DNA leads to the development of an efficient and reproducible method for DNA transformation and the combined frequencies of transformation and recombination allow marker replacement between non-replicating plasmids and chromosomal genes providing the basis for rapid and efficient methods of genetic manipulation. PMID- 22928043 TI - Where we look when we drive with or without active steering wheel control. AB - Current theories on the role of visuomotor coordination in driving agree that active sampling of the road by the driver informs the arm-motor system in charge of performing actions on the steering wheel. Still under debate, however, is the nature of visual cues and gaze strategies used by drivers. In particular, the tangent point hypothesis, which states that drivers look at a specific point on the inside edge line, has recently become the object of controversy. An alternative hypothesis proposes that drivers orient gaze toward the desired future path, which happens to be often situated in the vicinity of the tangent point. The present study contributed to this debate through the analyses of the distribution of gaze orientation with respect to the tangent point. The results revealed that drivers sampled the roadway in the close vicinity of the tangent point rather than the tangent point proper. This supports the idea that drivers look at the boundary of a safe trajectory envelop near the inside edge line. Furthermore, the study investigated for the first time the reciprocal influence of manual control on gaze control in the context of driving. This was achieved through the comparison of gaze behavior when drivers actively steered the vehicle or when steering was performed by an automatic controller. The results showed an increase in look-ahead fixations in the direction of the bend exit and a small but consistent reduction in the time spent looking in the area of the tangent point when steering was passive. This may be the consequence of a change in the balance between cognitive and sensorimotor anticipatory gaze strategies. It might also reflect bidirectional coordination control between the eye and arm-motor systems, which goes beyond the common assumption that the eyes lead the hands when driving. PMID- 22928044 TI - Post-disturbance plant community dynamics following a rare natural-origin fire in a Tsuga canadensis forest. AB - Opportunities to directly study infrequent forest disturbance events often lead to valuable information about vegetation dynamics. In mesic temperate forests of North America, stand-replacing crown fire occurs infrequently, with a return interval of 2000-3000 years. Rare chance events, however, may have profound impacts on the developmental trajectories of forest ecosystems. For example, it has been postulated that stand-replacing fire may have been an important factor in the establishment of eastern hemlock (Tsuga canadensis) stands in the northern Great Lakes region. Nevertheless, experimental evidence linking hemlock regeneration to non-anthropogenic fire is limited. To clarify this potential relationship, we monitored vegetation dynamics following a rare lightning-origin crown fire in a Wisconsin hemlock-hardwood forest. We also studied vegetation in bulldozer-created fire breaks and adjacent undisturbed forest. Our results indicate that hemlock establishment was rare in the burned area but moderately common in the scarified bulldozer lines compared to the reference area. Early successional, non-arboreal species including Rubus spp., Vaccinium angustifolium, sedges (Carex spp.), grasses, Epilobium ciliatum, and Pteridium aquilinium were the most abundant post-fire species. Collectively, our results suggest that competing vegetation and moisture stress resulting from drought may reduce the efficacy of scarification treatments as well as the usefulness of fire for preparing a suitable seedbed for hemlock. The increasing prevalence of growing season drought suggests that silvicultural strategies based on historic disturbance regimes may need to be reevaluated for mesic species. PMID- 22928045 TI - Structural determinants of the outer shell of beta-carboxysomes in Synechococcus elongatus PCC 7942: roles for CcmK2, K3-K4, CcmO, and CcmL. AB - Cyanobacterial CO(2)-fixation is supported by a CO(2)-concentrating mechanism which improves photosynthesis by saturating the primary carboxylating enzyme, ribulose 1, 5-bisphosphate carboxylase/oxygenase (RuBisCO), with its preferred substrate CO(2). The site of CO(2)-concentration is a protein bound micro compartment called the carboxysome which contains most, if not all, of the cellular RuBisCO. The shell of beta-type carboxysomes is thought to be composed of two functional layers, with the inner layer involved in RuBisCO scaffolding and bicarbonate dehydration, and the outer layer in selective permeability to dissolved solutes. Here, four genes (ccmK2-4, ccmO), whose products were predicted to function in the outer shell layer of beta-carboxysomes from Synechococcus elongatus PCC 7942, were investigated by analysis of defined genetic mutants. Deletion of the ccmK2 and ccmO genes resulted in severe high CO(2)-requiring mutants with aberrant carboxysomes, whilst deletion of ccmK3 or ccmK4 resulted in cells with wild-type physiology and normal ultrastructure. However, a tandem deletion of ccmK3-4 resulted in cells with wild-type carboxysome structure, but physiologically deficient at low CO(2) conditions. These results revealed the minimum structural determinants of the outer shell of beta-carboxysomes from this strain: CcmK2, CcmO and CcmL. An accessory set of proteins was required to refine the function of the pre-existing shell: CcmK3 and CcmK4. These data suggested a model for the facet structure of beta-carboxysomes with CcmL forming the vertices, CcmK2 forming the bulk facet, and CcmO, a "zipper protein," interfacing the edges of carboxysome facets. PMID- 22928046 TI - DNA double strand breaks but not interstrand crosslinks prevent progress through meiosis in fully grown mouse oocytes. AB - There is some interest in how mammalian oocytes respond to different types of DNA damage because of the increasing expectation of fertility preservation in women undergoing chemotherapy. Double strand breaks (DSBs) induced by ionizing radiation and agents such as neocarzinostatin (NCS), and interstrand crosslinks (ICLs) induced by alkylating agents such as mitomycin C (MMC), are toxic DNA lesions that need to be repaired for cell survival. Here we examined the effects of NCS and MMC treatment on oocytes collected from antral follicles in mice, because potentially such oocytes are readily collected from ovaries and do not need to be in vitro grown to achieve meiotic competency. We found that oocytes were sensitive to NCS, such that this ionizing radiation mimetic blocked meiosis I and caused fragmented DNA. In contrast, MMC had no impact on the completion of either meiosis I or II, even at extremely high doses. However, oocytes treated with MMC did show gamma-H2AX foci and following their in vitro maturation and parthenogenetic activation the development of the subsequent embryos was severely compromised. Addition of MMC to 1-cell embryos caused a similarly poor level of development, demonstrating oocytes have eventual sensitivity to this ICL-inducing agent but this does not occur during their meiotic division. In oocytes, the association of Fanconi Anemia protein, FANCD2, with sites of ICL lesions was not apparent until entry into the embryonic cell cycle. In conclusion, meiotic maturation of oocytes is sensitive to DSBs but not ICLs. The ability of oocytes to tolerate severe ICL damage and yet complete meiosis, means that this type of DNA lesion goes unrepaired in oocytes but impacts on subsequent embryo quality. PMID- 22928047 TI - Measuring cation dependent DNA polymerase fidelity landscapes by deep sequencing. AB - High-throughput recording of signals embedded within inaccessible micro environments is a technological challenge. The ideal recording device would be a nanoscale machine capable of quantitatively transducing a wide range of variables into a molecular recording medium suitable for long-term storage and facile readout in the form of digital data. We have recently proposed such a device, in which cation concentrations modulate the misincorporation rate of a DNA polymerase (DNAP) on a known template, allowing DNA sequences to encode information about the local cation concentration. In this work we quantify the cation sensitivity of DNAP misincorporation rates, making possible the indirect readout of cation concentration by DNA sequencing. Using multiplexed deep sequencing, we quantify the misincorporation properties of two DNA polymerases- Dpo4 and Klenow exo(-)--obtaining the probability and base selectivity of misincorporation at all positions within the template. We find that Dpo4 acts as a DNA recording device for Mn(2+) with a misincorporation rate gain of ~2%/mM. This modulation of misincorporation rate is selective to the template base: the probability of misincorporation on template T by Dpo4 increases >50-fold over the range tested, while the other template bases are affected less strongly. Furthermore, cation concentrations act as scaling factors for misincorporation: on a given template base, Mn(2+) and Mg(2+) change the overall misincorporation rate but do not alter the relative frequencies of incoming misincorporated nucleotides. Characterization of the ion dependence of DNAP misincorporation serves as the first step towards repurposing it as a molecular recording device. PMID- 22928048 TI - Glycoform and net charge heterogeneity in gp120 immunogens used in HIV vaccine trials. AB - BACKGROUND: The RV144 clinical trial showed for the first time that vaccination could provide modest but significant protection from HIV-1 infection. To understand the protective response, and to improve upon the vaccine's efficacy, it is important to define the structure of the immunogens used in the prime/boost regimen. Here we examined the heterogeneity in net charge, attributable to glycoform variation, of the gp120 immunogens contained in the AIDSVAX B/E vaccine. METHODOLOGY/PRINCIPAL FINDINGS: Isoelectric focusing and glycosidase digestion were used to assess variation in net charge of the gp120s contained in the AIDSVAX B/E vaccine used in the RV144 trial. We observed 16 variants of MN rgp120 and 24 variants of A244-rgp120. Glycoform variation in gp120 produced in Chinese hamster ovary cells was compared to glycoform variation in gp120 produced in the 293F human embryonic kidney cell line, often used for neutralization assays. We found that gp120 variants produced in CHO cells were distinctly more acidic than gp120 variants produced in 293 cells. The effect of glycoform heterogeneity on antigenicity was assessed using monoclonal antibodies. The broadly neutralizing PG9 MAb bound to A244-rgp120, but not to MN-rgp120, whether produced in CHO or in 293. However, PG9 was able to bind with high affinity to MN rgp120 and A244-rgp120 produced in 293 cells deficient in N acetylglucosaminyltransferase I. CONCLUSIONS/SIGNIFICANCE: MN- and A244-rgp120 used in the RV144 trial exhibited extensive heterogeneity in net charge due to variation in sialic acid-containing glycoforms. These differences were cell line dependent, affected the antigenicity of recombinant envelope proteins, and may affect assays used to measure neutralization. These studies, together with recent reports documenting broadly neutralizing antibodies directed against carbohydrate epitopes of gp120, suggest that glycoform variation is a key variable to be considered in the production and evaluation of subunit vaccines designed to prevent HIV infection. PMID- 22928049 TI - Seroprevalence of antibodies to avian influenza A (H5) and A (H9) viruses among market poultry workers, Hanoi, Vietnam, 2001. AB - BACKGROUND: The frequency of avian influenza A virus infections among poultry workers is not well understood. METHODS: A seroprevalence study of market poultry workers and persons without occupational poultry exposure was conducted during 2001 in Hanoi, Vietnam. Sera were tested for avian influenza H5 and H9 antibodies by microneutralization and Western blot assays. RESULTS: Seroprevalence of H5 and H9 antibodies was 4% and 3% in poultry workers and 1% and 3.5% in non-poultry workers, respectively. CONCLUSIONS: Seroprevalence of H5 and H9 antibodies was low among Hanoi market poultry workers in 2001, but can serve as a baseline for additional studies. PMID- 22928050 TI - Interleukin-1 receptor-associated kinase 2- and protein kinase D1-dependent regulation of IRAK-monocyte expression by CpG DNA. AB - As a part of the negative feedback mechanism, CpG DNA induces IRAK-M expression in monocytic cells. In the present study we investigated a biochemical signaling pathway and the transcription factors responsible for CpG DNA-mediated Irak-m gene expression. CpG DNA-induced Irak-m expression did not require new protein synthesis and was regulated at the transcriptional level through an endosomal pH sensitive TLR9/MyD88 signaling pathway. Over-expression of the dominant negative (DN) form of or gene-specific knockdown of signaling modulators in the TLR9 pathway demonstrated that IRAK4, IRAK1, IRAK2, and PKD1 are required for Irak-m transcription induced by CpG DNA. Over-expression of DN-IRAK1 only partially, but significantly, inhibited CpG DNA-induced Irak-m promoter activity. While IRAK1 was critical for the initial phase, IRAK2 was required for the late phase of TLR9 signaling by sustaining activation of PKD1 that leads to activation of NF-kappaB and MAPKs. Irak-m promoter-luciferase reporters with alterations in the predicted cis-acting transcriptional regulatory elements revealed that the NF-kappaB consensus site in the Irak-m promoter region is absolutely required for Irak-m gene expression. AP-1 and CREB binding sites also contributed to the optimal Irak m expression by CpG DNA. Collectively, our results demonstrate that IRAK2 plays a key role in the TLR9-mediated transcriptional regulation of Irak-m expression by sustaining activation of PKD1 and NF-kappaB. PMID- 22928051 TI - Phaeobacter gallaeciensis reduces Vibrio anguillarum in cultures of microalgae and rotifers, and prevents vibriosis in cod larvae. AB - Phaeobacter gallaeciensis can antagonize fish-pathogenic bacteria in vitro, and the purpose of this study was to evaluate the organism as a probiont for marine fish larvae and their feed cultures. An in vivo mechanism of action of the antagonistic probiotic bacterium is suggested using a non-antagonistic mutant. P. gallaeciensis was readily established in axenic cultures of the two microalgae Tetraselmis suecica and Nannochloropsis oculata, and of the rotifer Brachionus plicatilis. P. gallaeciensis reached densities of 10(7) cfu/ml and did not adversely affect growth of algae or rotifers. Vibrio anguillarum was significantly reduced by wild-type P. gallaeciensis, when introduced into these cultures. A P. gallaeciensis mutant that did not produce the antibacterial compound tropodithietic acid (TDA) did not reduce V. anguillarum numbers, suggesting that production of the antibacterial compound is important for the antagonistic properties of P. gallaeciensis. The ability of P. gallaeciensis to protect fish larvae from vibriosis was determined in a bath challenge experiment using a multidish system with 1 larva per well. Unchallenged larvae reached 40% accumulated mortality which increased to 100% when infected with V. anguillarum. P. gallaeciensis reduced the mortality of challenged cod larvae (Gadus morhua) to 10%, significantly below the levels of both the challenged and the unchallenged larvae. The TDA mutant reduced mortality of the cod larvae in some of the replicates, although to a much lesser extent than the wild type. It is concluded that P. gallaeciensis is a promising probiont in marine larviculture and that TDA production likely contributes to its probiotic effect. PMID- 22928052 TI - Transcriptomic signature of Leishmania infected mice macrophages: a metabolic point of view. AB - We analyzed the transcriptional signatures of mouse bone marrow-derived macrophages at different times after infection with promastigotes of the protozoan parasite Leishmania major. Ingenuity Pathway Analysis revealed that the macrophage metabolic pathways including carbohydrate and lipid metabolisms were among the most altered pathways at later time points of infection. Indeed, L. major promastiogtes induced increased mRNA levels of the glucose transporter and almost all of the genes associated with glycolysis and lactate dehydrogenase, suggesting a shift to anaerobic glycolysis. On the other hand, L. major promastigotes enhanced the expression of scavenger receptors involved in the uptake of Low-Density Lipoprotein (LDL), inhibited the expression of genes coding for proteins regulating cholesterol efflux, and induced the synthesis of triacylglycerides. These data suggested that Leishmania infection disturbs cholesterol and triglycerides homeostasis and may lead to cholesterol accumulation and foam cell formation. Using Filipin and Bodipy staining, we showed cholesterol and triglycerides accumulation in infected macrophages. Moreover, Bodipy-positive lipid droplets accumulated in close proximity to parasitophorous vacuoles, suggesting that intracellular L. major may take advantage of these organelles as high-energy substrate sources. While the effect of infection on cholesterol accumulation and lipid droplet formation was independent on parasite development, our data indicate that anaerobic glycolysis is actively induced by L. major during the establishment of infection. PMID- 22928053 TI - The crystal structures of the tryparedoxin-tryparedoxin peroxidase couple unveil the structural determinants of Leishmania detoxification pathway. AB - Leishmaniasis is a neglected disease caused by Leishmania, an intracellular protozoan parasite which possesses a unique thiol metabolism based on trypanothione. Trypanothione is used as a source of electrons by the tryparedoxin/tryparedoxin peroxidase system (TXN/TXNPx) to reduce the hydroperoxides produced by macrophages during infection. This detoxification pathway is not only unique to the parasite but is also essential for its survival; therefore, it constitutes a most attractive drug target. Several forms of TXNPx, with very high sequence identity to one another, have been found in Leishmania strains, one of which has been used as a component of a potential anti leishmanial polyprotein vaccine. The structures of cytosolic TXN and TXNPx from L. major (LmTXN and LmTXNPx) offer a unique opportunity to study peroxide reduction in Leishmania parasites at a molecular level, and may provide new tools for multienzyme inhibition-based drug discovery. Structural analyses bring out key structural features to elucidate LmTXN and LmTXNPx function. LmTXN displays an unusual N-terminal alpha-helix which allows the formation of a stable domain swapped dimer. In LmTXNPx, crystallized in reducing condition, both the locally unfolded (LU) and fully folded (FF) conformations, typical of the oxidized and reduced protein respectively, are populated. The structural analysis presented here points to a high flexibility of the loop that includes the peroxidatic cysteine which facilitates Cys52 to form an inter-chain disulfide bond with the resolving cysteine (Cys173), thereby preventing over-oxidation which would inactivate the enzyme. Analysis of the electrostatic surface potentials of both LmTXN and LmTXNPx unveils the structural elements at the basis of functionally relevant interaction between the two proteins. Finally, the structural analysis of TXNPx allows us to identify the position of the epitopes that make the protein antigenic and therefore potentially suitable to be used in an anti-leishmanial polyprotein vaccine. PMID- 22928054 TI - Atypical systemic leishmaniasis to be considered in the differential of patients presenting with depressed immunity. AB - BACKGROUND: Systemic leishmaniasis has been known to present with prolonged fever, hepatosplenomegaly and wasting. Beside this classical form, a sub-clinical form has been identified. It is described with either one or two of the above symptoms missing; other findings have been reported instead, such as lymphadenopathy and anemia. In this report, we reveal a third unsuspected form which we are referring to as "atypical". METHODOLOGY/PRINCIPAL FINDINGS: Patients suspected to be immune-deficient were referred to our immunology specialized laboratory to study some aspects of their immune functions (not normally covered in the general laboratory). Multiple specialized tests were performed, including microscopic examinations using appropriate stains, and mainly cultures of biopsies on several types of specialized media. 19.4% of 160 patients were found to have close to normal laboratory profiles, but exhibited dysfunctional macrophages laden with Leishmania parasites. CONCLUSIONS/SIGNIFICANCE: Findings such as the ones we obtained allowed us to uncover the presence of patients with an atypical form of systemic leishmaniasis. It presents with symptoms masquarading a condition in which the immune system is non functional. This predisposes patients to recurrent secondary infections resulting in clinical pictures with a great variety of signs and symptoms. These findings alerted us to the fact that systemic leishmaniasis presents with a much wider spectrum of signs and symptoms than so far suspected and is far more common than diagnosed to date. Furthermore, among these 31 patients was a number of adults. This proved that in our area systemic leishmaniasis is surely not limited to the pediatric age group. Our recommendation is to entertain the diagnosis of atypical systemic leishmaniasis in any patient with an unexplained depressed immunity state and in whom no obvious immunologic defect can be identified. PMID- 22928055 TI - Combining hydrology and mosquito population models to identify the drivers of Rift Valley fever emergence in semi-arid regions of West Africa. AB - BACKGROUND: Rift Valley fever (RVF) is a vector-borne viral zoonosis of increasing global importance. RVF virus (RVFV) is transmitted either through exposure to infected animals or through bites from different species of infected mosquitoes, mainly of Aedes and Culex genera. These mosquitoes are very sensitive to environmental conditions, which may determine their presence, biology, and abundance. In East Africa, RVF outbreaks are known to be closely associated with heavy rainfall events, unlike in the semi-arid regions of West Africa where the drivers of RVF emergence remain poorly understood. The assumed importance of temporary ponds and rainfall temporal distribution therefore needs to be investigated. METHODOLOGY/PRINCIPAL FINDINGS: A hydrological model is combined with a mosquito population model to predict the abundance of the two main mosquito species (Aedes vexans and Culex poicilipes) involved in RVFV transmission in Senegal. The study area is an agropastoral zone located in the Ferlo Valley, characterized by a dense network of temporary water ponds which constitute mosquito breeding sites. The hydrological model uses daily rainfall as input to simulate variations of pond surface areas. The mosquito population model is mechanistic, considers both aquatic and adult stages and is driven by pond dynamics. Once validated using hydrological and entomological field data, the model was used to simulate the abundance dynamics of the two mosquito species over a 43-year period (1961-2003). We analysed the predicted dynamics of mosquito populations with regards to the years of main outbreaks. The results showed that the main RVF outbreaks occurred during years with simultaneous high abundances of both species. CONCLUSION/SIGNIFICANCE: Our study provides for the first time a mechanistic insight on RVFV transmission in West Africa. It highlights the complementary roles of Aedes vexans and Culex poicilipes mosquitoes in virus transmission, and recommends the identification of rainfall patterns favourable for RVFV amplification. PMID- 22928056 TI - Potential for rabies control through dog vaccination in wildlife-abundant communities of Tanzania. AB - Canine vaccination has been successful in controlling rabies in diverse settings worldwide. However, concerns remain that coverage levels which have previously been sufficient might be insufficient in systems where transmission occurs both between and within populations of domestic dogs and other carnivores. To evaluate the effectiveness of vaccination targeted at domestic dogs when wildlife also contributes to transmission, we applied a next-generation matrix model based on contract tracing data from the Ngorongoro and Serengeti Districts in northwest Tanzania. We calculated corresponding values of R(0), and determined, for policy purposes, the probabilities that various annual vaccination targets would control the disease, taking into account the empirical uncertainty in our field data. We found that transition rate estimates and corresponding probabilities of vaccination-based control indicate that rabies transmission in this region is driven by transmission within domestic dogs. Different patterns of rabies transmission between the two districts exist, with wildlife playing a more important part in Ngorongoro and leading to higher recommended coverage levels in that district. Nonetheless, our findings indicate that an annual dog vaccination campaign achieving the WHO-recommended target of 70% will control rabies in both districts with a high level of certainty. Our results support the feasibility of controlling rabies in Tanzania through dog vaccination. PMID- 22928058 TI - Emergency department visits for traumatic brain injury in older adults in the United States: 2006-08. AB - INTRODUCTION: Traumatic brain injury (TBI) can be complicated among older adults due to age-related frailty, a greater prevalence of chronic conditions and the use of anticoagulants. We conducted this study using the latest available, nationally-representative emergency department (ED) data to characterize visits for TBI among older adults. METHODS: We used the 2006-2008 National Hospital Ambulatory Medical Care - Emergency Department (NHAMCS-ED) data to examine ED visits for TBI among older adults. Population-level estimates of triage immediacy, receipt of a head computed tomography (CT) and/or head magnetic resonance imaging (MRI), and hospital admission by type were used to characterize 1,561 sample visits, stratified by age <65 and >=65 years of age. RESULTS: Of ED visits made by persons >=65 years of age, 29.1% required attention from a physician within 15 minutes of arrival; 82.1% required a head CT, and 20.9% required hospitalization. Persons >=65 years of age were 3 times more likely to receive a head CT or MRI compared to younger patients presenting with TBI (adjusted odds ratio [aOR] 3.2; 95% confidence interval [CI], 1.8-5.8), and were 4 times more likely to be admitted to an intensive care unit, step-down unit, or surgery (aOR 4.1; 95% CI 2.1-8.0) compared to younger patients presenting with TBI, while controlling for sex and race. CONCLUSION: Results demonstrate increased emergent service delivery for older persons presenting with TBI. As the United States population ages and continues to grow, TBI will become an even more important public health issue that will place a greater demand on the healthcare system. PMID- 22928057 TI - Involvement of CD4+ Foxp3+ regulatory T cells in persistence of Leishmania donovani in the liver of alymphoplastic aly/aly mice. AB - Visceral leishmaniasis (VL) is a chronic and fatal disease in humans and dogs caused by the intracellular protozoan parasites, Leishmania donovani and L. infantum (L. chagasi). Relapse of disease is frequent in immunocompromised patients, in which the number of VL cases has been increasing recently. The present study is aimed to improve the understanding of mechanisms of L. donovani persistence in immunocompromised conditions using alymphoplastic aly/aly mice. Hepatic parasite burden, granuloma formation and induction of regulatory T cells were determined for up to 7 months after the intravenous inoculation with L. donovani promastigotes. While control aly/+ mice showed a peak of hepatic parasite growth at 4 weeks post infection (WPI) and resolved the infection by 8 WPI, aly/aly mice showed a similar peak in hepatic parasite burden but maintained persistent in the chronic phase of infection, which was associated with delayed and impaired granuloma maturation. Although hepatic CD4(+)Foxp3(+) but not CD8(+)Foxp3(+) T cells were first detected at 4 WPI in both strains of mice, the number of CD4(+)Foxp3(+) T cells was significantly increased in aly/aly mice from 8 WPI. Immunohistochemical analysis demonstrated the presence of Foxp3(+) T cells in L. donovani-induced hepatic granulomas and perivascular neo-lymphoid aggregates. Quantitative real-time PCR analysis of mature granulomas collected by laser microdissection revealed the correlation of Foxp3 and IL-10 mRNA level. Furthermore, treatment of infected aly/aly mice with anti-CD25 or anti-FR4 mAb resulted in significant reductions in both hepatic Foxp3(+) cells and parasite burden. Thus, we provide the first evidence that CD4(+)Foxp3(+) Tregs mediate L. donovani persistence in the liver during VL in immunodeficient murine model, a result that will help to establish new strategies of immunotherapy against this intracellular protozoan pathogen. PMID- 22928059 TI - Do-Not-Resuscitate Orders in Fatal Toxic Exposures: A Poison Center's Review. AB - INTRODUCTION: Self-exposure is a leading method for suicide both in the United States and worldwide and thus is a major preventable public health issue. Surrogate decision makers are tasked with making medical decisions for the patient while keeping the patient's wishes in mind. Decisions related to code status become more complicated when the patient's situation is the result of a suicidal act. The objectives were to 1) determine how frequently Do Not Resuscitate orders (DNR orders) are placed for the intentionally self-exposed (ISE) patient using the Regional Poison Control Center (RPCC) data, and 2) identify if DNR orders in intentionally self-exposed patients were placed before or after development of poor prognostic signs. METHODS: We analyzed all exposure related deaths reported to the RPCC from January 1, 2000 to December 31, 2010. We reviewed data for the following: exposure intent, exposure substance, outcome, age, code status, date of DNR/withdrawal of care order, previous suicide attempts, and poor prognostic signs. RESULTS: Of the 476 total deaths, nearly half were the result of an intentional self-exposure (n= 235; 49.4%). Most deaths, when code status was reported, had advanced cardiac life support, or "full codes" (n=131; 55.6%). Of the total deaths with a DNR or withdrawal of care order (n=104), over half were from an ISE (n=55; 52.9%). A higher percentage of the ISEs had a DNR order/withdrawal of care order; however, it was not a statistically significant difference OR 1.23 (95% CI 0.64, 2.37). of intent, patients treated as full codes were on average 19.5 years younger than the DNR orders group. Only 2 DNR orders were placed prior to development of poor prognostic signs. Unintentional self-exposures consumed a mean of 1.4 substances (range 1 to 4). ISEs consumed a mean of 2.3 substances (range 1 to 19). CONCLUSION: People are often asked to make life-and-death decisions for a loved one. The nature of the exposure can complicate the issue if the exposure has an antidote or is known to have a limited effect. Further study is needed to assess the extent of these cases and to identify optimal management guidelines or policy to aid both the medical teams caring for these patients and the surrogate decision makers. PMID- 22928060 TI - Feasibility study of social media to reduce intimate partner violence among gay men in metro atlanta, georgia. AB - Intimate Partner Violence (IPV) is a major public health issue occurring in the United States and globally. While little is known in general about IPV, understanding about the prevalence of physical IPV among gay men is even more obscure. There is a clear disparity in violence research attention focused on this vulnerable segment of society. This cross-sectional survey study was conducted to examine the feasibility of enrolling 100 gay men from Atlanta into an IPV survey study. The survey was administered via Facebook. Ninety-nine usable surveys were collected. Chi-square tests reveal that minority ethnic status, illicit drug use, and non-disclosed orientation status were all significantly associated with positive IPV reports--in terms of both victimization as well as perpetration. Overall, the majority of the study sample indicated that they believe IPV is a health problem in the Atlanta gay community. These findings bear importance for the Atlanta gay community and public health professionals who must address this nearly invisible yet increasing public health issue. PMID- 22928061 TI - Vitamin D: Its role in disease prevention. AB - Evidence that vitamin D reduces the risk of many types of disease is increasing exponentially. In 2011, 3,100 publications with "vitamin D" in the title or abstract were published, up from 2,606 in 2010, 1,303 in 2005, and 796 in 2000. A committee operating under the auspices of the Institute of Medicine (IOM) of the US National Academies reviewed the evidence for beneficial effects of vitamin D. Their report, issued at the end of 2010,(1) found what they considered to be strong evidence for only one health outcome: skeletal health. They considered beneficial evidence only from published randomized controlled trials (RCTs) focused mainly on skeletal health. In contrast, to justify concern about higher vitamin D intake and serum 25(OH)D concentrations, they used data from nested case-control studies reporting U-shaped outcomes of prediagnostic serum 25 hydroxyvitamin D [25(OH)D] for cancer and all-cause mortality rates. They set the daily recommended intake of vitamin D at 600-800 IU for most children and adults and defined vitamin D sufficiency as a serum 25(OH)D level above 20 ng/ml (50 nmol/l). They also set a daily upper intake of 4,000 IU of vitamin D(3) and called for more RCTs to determine nonskeletal health effects. As of this writing, more than 130 journal publications have criticized the IOM report as being too conservative. One summarized the problems succinctly: "The IOM recommendations for vitamin D fail in a major way on logic, on science, and on effective public health guidance. Moreover, by failing to use a physiological referent, the IOM approach constitutes precisely the wrong model for development of nutritional policy."(2). PMID- 22928062 TI - Youssef et al. make a strong case for addressing 25(OH)D concentration (vitamin D status) in hospitalized patients with infections. AB - Correcting vitamin D deficiency in the outpatient setting has become commonplace and is a routine in many primary care practices. This extension into the inpatient setting is timely and logical. The benefits of vitamin D testing continue to be demonstrated. PMID- 22928064 TI - Why randomized controlled trials of calcium and vitamin D sometimes fail. AB - The importance of nutrients for promotion of health and prevention of disease has long been recognized. Nonetheless, scientists are still trying to delineate the optimal intakes of various nutrients and their potential benefits for different populations. To that end, evidence-based medicine (EBM) has been applied to the study of nutrition. EBM methods basically call for the use of randomized controlled trials (RCTs) to establish causal connection between the intervention and any particular endpoint. This paper focuses on problems that arise in the use of RCTS to establish a causal link between nutrients and various clinical endpoints. While many RCTS of calcium and vitamin D have been positive, many others have been null. In this paper, we discuss the reasons why effective nutrient agents may be found to be ineffective in particular studies, giving examples of such null results, and focusing on the nearly universal failure to consider biological criteria in designing RCTs. Our purpose is (1) to inform future study design so as to ensure that relevant biological facts are considered and (2) to aid in the interpretation of the abundant, but often inconsistent literature on this topic. PMID- 22928063 TI - Differences in vitamin D status may account for unexplained disparities in cancer survival rates between African and white Americans. AB - Considerable disparities in cancer survival rates exist between African Americans (AAs) and white Americans (WAs). Various factors such as differences in socioeconomic status (SES), cancer stage at time of diagnosis, and treatment which this analysis considers primary explanatory factors-have accounted for many of these differences. An additional factor not usually considered is vitamin D. Previous studies have inversely correlated higher solar ultraviolet-B (UVB) doses and serum 25-hydroxyvitamin D (25(OH)D) concentrations with incidence and/or mortality rates for about 20 types of cancer and improved survival rates for eight types of cancer. Because of darker skin pigmentation, AAs have 40% lower serum 25(OH)D concentrations than WAs. This study reviews the literature on disparities in cancer survival between AAs and WAs. The journal literature indicates that there are disparities for 13 types of cancer after consideration of SES, stage at diagnosis and treatment: bladder, breast, colon, endometrial, lung, ovarian, pancreatic, prostate, rectal, testicular, and vaginal cancer; Hodgkin lymphoma and melanoma. Solar UVB doses and/or serum 25(OH)D concentrations have been reported inversely correlated with incidence and/or mortality rates for all of these cancers. This finding suggests that future studies should consider serum 25(OH)D concentrations in addressing cancer survival disparities through both measurements of serum 25(OH)D concentrations and increasing serum 25(OH)D concentrations of those diagnosed with cancer, leading to improved survival rates and reduced disparities. PMID- 22928065 TI - Vitamin D and sepsis: An emerging relationship. AB - Vitamin D insufficiency and sepsis are both highly prevalent worldwide problems and this article reviews the emerging science that is defining the intersections of these conditions. The importance of vitamin D's role in skeletal health has long been understood but recent evidence is beginning to highlight its role in the functioning of other physiologic systems of the body. Basic science data reveal its integral role in local immune responses to pathogens and the systemic inflammatory pathways of sepsis. Furthermore, clinical scientists have found associations with respiratory infections, critical illness and sepsis but the causal relationship and its clinical impact have yet to be clearly defined. The article ends with speculations on the connections between racial disparities and seasonal differences in sepsis and vitamin D insufficiency. PMID- 22928066 TI - Beneficial effects of UV radiation other than via vitamin D production. AB - Most of the positive effects of solar radiation are mediated via ultraviolet-B (UVB) induced production of vitamin D in skin. However, several other pathways may exist for the action of ultraviolet (UV) radiation on humans as focused on in this review. One is induction of cosmetic tanning (immediate pigment darkening, persistent pigment darkening and delayed tanning). UVB-induced, delayed tanning (increases melanin in skin after several days), acts as a sunscreen. Several human skin diseases, like psoriasis, vitiligo, atopic dermatitis and localized scleroderma, can be treated with solar radiation (heliotherapy) or artificial UV radiation (phototherapy). UV exposure can suppress the clinical symptoms of multiple sclerosis independently of vitamin D synthesis. Furthermore, UV generates nitric oxide (NO), which may reduce blood pressure and generally improve cardiovascular health. UVA-induced NO may also have antimicrobial effects and furthermore, act as a neurotransmitter. Finally, UV exposure may improve mood through the release of endorphins. PMID- 22928067 TI - Vitamin D supplementation in pre-dialysis chronic kidney disease: A systematic review. AB - Vitamin D deficiency is associated with a variety of skeletal, cardiometabolic, and immunologic co-morbidities that are present in chronic kidney disease (CKD). We performed a systematic review to investigate the effects of vitamin D supplementation, in the form of ergocalciferol or cholecalciferol, on various health outcomes in early CKD. Seventeen clinical trials were identified, only two of which were randomized, placebo controlled trials. The majority of studies supplementing with > 2,000 IU/day of cholecalciferol achieved optimal vitamin D status, whereas studies supplementing with ergocalciferol were less consistent. Studies varied widely in their effects on lowering serum parathyroid hormone concentrations. Few studies investigated effects of vitamin D treatment on other clinical health indicators in early CKD. Rigorous studies are necessary to investigate optimal vitamin D dosing strategies in early CKD for the maintenance of adequate vitamin D status, management of secondary hyperparathyroidism and improvement of non-skeletal related clinical outcomes. PMID- 22928068 TI - Does vitamin D deficiency contribute to erectile dysfunction? AB - Erectile dysfunction (ED) is a multifactorial disease, and its causes can be neurogenic, psychogenic, hormonal and vascular. ED is often an important indicator of cardiovascular disease (CVD) and a powerful early marker for asymptomatic CVD. Erection is a vascular event, and ED is often a vascular disease caused by endothelial damage and subsequent inhibition of vasodilation. We show here that risk factors associated with a higher CVD risk also associate with a higher ED risk. Such factors include diabetes mellitus, hypertension, arterial calcification and Inflammation in the vascular endothelium. Vitamin D deficiency is one of several dynamics that associates with increased CVD risk, but to our knowledge, it has not been studied as a possible contributor to ED. Here we examine research linking ED and CVD and discuss how vitamin D influences CVD and its classic risk factors-factors that also associate to increased ED risk. We also summarize research indicating that vitamin D associates with reduced risk of several nonvascular contributing factors for ED. We conclude that VDD contributes to ED. This hypothesis should be tested through observational and intervention studies. PMID- 22928069 TI - Vitamin D and asthma. AB - Asthma, one of the most prevalent diseases affecting people worldwide, is a chronic respiratory disease characterized by heightened airway inflammation, airway hyperresponsiveness and airflow obstruction in response to specific triggers. While the specific mechanisms responsible for asthma are not well understood, changing environmental factors associated with urban lifestyles may underlie the increased prevalence of the disorder. Vitamin D is of particular interest in asthma since vitamin D concentrations decrease with increased time spent indoors, decreased exposure to sunlight, less exercise, obesity, and inadequate calcium intake. Additionally, a growing body of literature suggests that there is a relationship between vitamin D status and respiratory symptoms, presumably through immunomodulatory effects of vitamin D. This review discusses vitamin D as it relates to asthma across the age spectrum, with a focus on human studies. PMID- 22928070 TI - Potential benefits of vitamin D for patients with systemic lupus erythematosus. AB - Systemic lupus erythematosus (SLE) is a complex multi-system autoimmune disease. Vitamin D deficiency has been proposed as an environmental trigger of disease onset and as a contributor to increased SLE activity. SLE patients are prone to develop vitamin D deficiency because of photosensitivity leading to sun avoidance and other sun protective measures. The impact of vitamin D on immune function previously seen in vitro and in cross-sectional studies has now been shown in prospective human studies, strengthening the evidence that there is a connection between SLE and vitamin D status. This review describes the role of vitamin D on immune function, prevalence of vitamin D deficiency in patients with SLE, identify risk factors for deficiency, describe the consequences of deficiency in SLE patients, and review current vitamin D recommendations for patients with SLE. PMID- 22928071 TI - Does the evidence for an inverse relationship between serum vitamin D status and breast cancer risk satisfy the Hill criteria? AB - A wide range of epidemiologic and laboratory studies combined provide compelling evidence of a protective role of vitamin D on risk of breast cancer. This review evaluates the scientific evidence for such a role in the context of the A.B. Hill criteria for causality, in order to assess the presence of a causal, inverse relationship, between vitamin D status and breast cancer risk. After evaluation of this evidence in the context of Hill's criteria, it was found that the criteria for a causal relationship were largely satisfied. Studies in human populations and the laboratory have consistently demonstrated that vitamin D plays an important role in the prevention of breast cancer. Vitamin D supplementation is an urgently needed, low cost, effective, and safe intervention strategy for breast cancer prevention that should be implemented without delay. In the meantime, randomized controlled trials of high doses of vitamin D(3) for prevention of breast cancer should be undertaken to provide the necessary evidence to guide national health policy. PMID- 22928072 TI - Influence of drugs on vitamin D and calcium metabolism. AB - In the past, interactions between drugs and vitamin D have received only little or no attention in the health care practices. However, since more and more drugs are used for the treatment of patients, this topic is increasingly relevant. Several drugs can interfere with the vitamin D and bone metabolism. Drugs that activate the pregnane X receptor can disrupt vitamin D metabolism and vitamin D function. Beside this, the medication oriented supplementation of vitamin D can ameliorate the pharmacologic action of some drugs, such as bisphosphonates, cytostatics and statins. PMID- 22928073 TI - Vitamin D's potential to reduce the risk of hospital-acquired infections. AB - Health care-associated and hospital-acquired infections are two entities associated with increased morbidity and mortality. They are highly costly and constitute a great burden to the health care system. Vitamin D deficiency (< 20 ng/ml) is prevalent and may be a key contributor to both acute and chronic ill health. Vitamin D deficiency is associated with decreased innate immunity and increased risk for infections. Vitamin D can positively influence a wide variety of microbial infections. Herein we discuss hospital-acquired infections, such as pneumonia, bacteremias, urinary tract and surgical site infections, and the potential role vitamin D may play in ameliorating them. We also discuss how vitamin D might positively influence these infections and help contain health care costs. Pending further studies, we think it is prudent to check vitamin D status at hospital admission and to take immediate steps to address existing insufficient 25-hydroxyvitamin D levels. PMID- 22928074 TI - An ecological study of cancer mortality rates in California, 1950-64, with respect to solar UVB and smoking indices. AB - PURPOSE: This paper addresses whether nonmelanoma skin cancer (NMSC) mortality rates can serve as a useful index of population ultraviolet-B (UVB) irradiance and vitamin D production in a manner that affects the risk of internal cancers METHODS: This analysis uses the ecological study approach with cancer mortality rate data from 19 state economic areas in California. This paper uses age-adjusted data for those aged 40 y or older. Two additional indices for solar UVB doses were also used: latitude and surface UVB doses for July 1992 from the total ozone mapping spectrometer. Lung cancer mortality rates served as the index of the health effects of smoking RESULTS: Significant inverse correlations with NMSC mortality rate in multiple linear regression analyses were found during the period 1950-64 for eight types of cancer for males: bladder, brain, colon, gastric, prostate, and rectal cancer; multiple myeloma; and non Hodgkin lymphoma. No similar results emerged for females with respect to all three UVB indices. Their NMSC mortality rates averaged 60% lower than those for males. Lung cancer mortality rates were directly correlated with three types of cancer for males: laryngeal, oral, and renal. No significant correlations with NMSC mortality rates appeared for later periods CONCLUSIONS: NMSC mortality rates were found inversely correlated with internal cancers for males in the period 1950-64. After that period, no further such correlations were found. The reasons may hypothetically include reduced NMSC mortality rates, high immigration rates, movement from rural to urban locations and reduced solar UVB irradiance. PMID- 22928075 TI - Evidence-based D-bate on health benefits of vitamin D revisited. AB - Vitamin D has received worldwide attention not only for its importance for bone health in children and adults but also for reducing risk for many chronic diseases including autoimmune diseases, type 2 diabetes, heart disease, many cancers and infectious diseases. Vitamin D deficiency is pandemic due to the fact that most humans have depended on sun for their vitamin D requirement which they now either avoid or wear sun protection for fear of skin cancer. There are few foods that naturally contain vitamin D. Some countries permit vitamin D fortification especially dairy products, some cereals and juice products. The Institute of Medicine made its recommendations based on a population-based model; the Endocrine Society's Practice Guidelines on Vitamin D was for the prevention and treatment of vitamin D deficiency, which helps explain the differences in the recommendations. The Guidelines defined vitamin D deficiency as a 25 hydroxyvitamin D < 20 ng/mL, insufficiency as 21-29 ng/mL and sufficiency as 30 100 ng/mL. To prevent vitamin D deficiency The Guidelines recommended vitamin D intake should be: children < 1 y 400-1,000 IU/d, children 1-18 y 600-1,000 IU/d and adults 1,500-2,000 IU/d. PMID- 22928076 TI - Pilot study of vitamin D supplementation in adults with cystic fibrosis pulmonary exacerbation: A randomized, controlled trial. AB - BACKGROUND: Vitamin D insufficiency is common in cystic fibrosis (CF) and vitamin D repletion may have an important role in improving clinical outcomes in CF. This randomized, placebo-controlled, pilot study examined the feasibility and impact of a single, large dose of cholecalciferol on vitamin D status and clinical outcomes in subjects with CF. METHODS: Thirty adults with were randomized in a double-blinded, pilot study to receive 250,000 IU cholecalciferol or placebo within 48 h of hospital admission for a pulmonary exacerbation. Concentrations of 25-hydroxyvitamin D (25(OH)D), clinical outcomes and potential adverse events were assessed up to one year after randomization. Mixed effects linear regression models were used to evaluate the difference in mean serum concentrations and log-rank analyses were used to evaluate survival. RESULTS: Data from all subjects was analyzed. Serum 25(OH)D concentrations increased from a mean of 30.6 +/- 3.2 ng/mL to 58.1 +/- 3.5 ng/mL (p < 0.001) at one week and 36.7 +/- 2.6 ng/mL by 12 weeks (p = 0.06) in the vitamin D group; in contrast, serum 25(OH)D concentrations remained unchanged in the placebo group. Unadjusted, one-year survival and hospital-free days were increased in the vitamin D group (p = 0.029, p = 0.036; respectively). There was also a trend toward increased IV antibiotic therapy-free days in the vitamin D group (p = 0.073). There were no signs of hypervitaminosis D or adverse events. Serum PTH and calcium concentrations were similar across both groups. CONCLUSIONS: In this pilot study, a single, oral bolus of cholecalciferol increased serum 25(OH)D concentrations and was associated with a trend toward improved clinical outcomes in CF subjects hospitalized for a pulmonary exacerbation. Further investigation is needed into the clinical impact of improved vitamin D status in patients with CF. PMID- 22928077 TI - Effect of follow-up time on the relation between prediagnostic serum 25 hydroxyvitamin D and all-cause mortality rate. AB - Evidence continues to mount that vitamin D reduces the risk and mortality rates of many types of disease. However, evidence from prospective cohort studies is sometimes weaker than that from case-control and ecological studies. A suggested reason for this discrepancy is that, because serum levels of 25-hydroxyvitamin D [25(OH)D] change over time, a single 25(OH)D concentration measurement taken at study enrollment does not reliably indicate 25(OH)D concentration related to the health outcome. To evaluate this suggestion further, this paper plots results from 12 prospective cohort studies of all-cause mortality rate vs. follow-up time. The regression fit to the hazard ratio per 20-nmol/l increase in serum 25(OH)D concentration vs. time increased from 0.82 (95% CI, 0.67-1.02) for 6 y to 0.96 (95% CI, 0.90-1.01) for 14 y. The value extrapolated for zero follow-up time was 0.72 (95% CI, 0.50-1.03), giving a hazard ratio reduction 3.5 times higher than the standard result from the meta-analysis [0.92 (95% CI, 0.89-0.95)]. Using the example of the Vitamin D Pooling Project of Rarer Cancers, this paper also discusses follow-up time's effect in interpreting prospective cohort studies of cancer outcome. This paper recommends that meta-analyses of prospective cohort studies account for follow-up time and, if possible, that studies measure serum 25(OH)D concentration every 2-4 y. PMID- 22928078 TI - Role of solar UVB irradiance and smoking in cancer as inferred from cancer incidence rates by occupation in Nordic countries. AB - A large body of evidence indicates that solar ultraviolet-B (UVB) irradiance and vitamin D reduce the risk of incidence and death for many types of cancer. However, most of that evidence comes from midlatitude regions, where solar UVB doses are generally high in summer. Data on cancer standardized incidence ratios (SIRs) by sex and 54 occupation categories based on 1.4 million male and 1.36 million female cancer cases for 1961-2005 in the five Nordic countries provide the basis for an ecological study of the role of solar UVB in the risk of many types of cancer at high latitudes. Lip cancer SIRs less lung cancer SIRs for men was the best index of solar UVB dose, which was weakly inversely correlated with both melanoma and nonmelanoma skin cancer (NMSC) SIRs. Lung cancer SIRs were used as the index of the effects of smoking. For men, the UVB index was significantly inversely correlated with 14 types of internal cancer-bladder, breast, colon, gallbladder, kidney, laryngeal, liver, lung, oral, pancreatic, pharyngeal, prostate, rectal and small intestine cancer. For women, the same UVB index was inversely correlated with bladder, breast and colon cancer. These results generally agree with findings from other studies. These results provide more support for the UVB-vitamin D-cancer hypothesis and suggest that widespread fear of chronic solar ultraviolet (UV) irradiance may be misplaced. PMID- 22928080 TI - Cholesterol-lowering effect of allicin on hypercholesterolemic ICR mice. AB - Allicin was discussed as an active compound with regard to the beneficial effects of garlic in atherosclerosis. The aim of this study was to investigate the cholesterol-lowering properties of allicin. In order to examine its effects on hypercholesterolemia in male ICR mice, this compound with doses of 5, 10, or 20 mg/kg body weight was given orally daily for 12 weeks. Changes in body weight and daily food intake were measured regularly during the experimental period. Final contents of serum cholesterol, triglyceride, glucose, and hepatic cholesterol storage were determined. Following a 12-week experimental period, the body weights of allicin-fed mice were less than those of control mice on a high cholesterol diet by 38.24 +/- 7.94% (P < 0.0001) with 5 mg/kg allicin, 39.28 +/- 5.03% (P < 0.0001) with 10 mg/kg allicin, and 41.18 +/- 5.00% (P < 0.0001) with 20 mg/kg allicin, respectively. A decrease in daily food consumption was also noted in most of the treated animals. Meanwhile, allicin showed a favorable effect in reducing blood cholesterol, triglycerides, and glucose levels and caused a significant decrease in lowering the hepatic cholesterol storage. Accordingly, both in vivo and in vitro results demonstrated a potential value of allicin as a pronounced cholesterol-lowering candidate, providing protection against the onset of atherosclerosis. PMID- 22928079 TI - Is vitamin D status relevant to metabolic syndrome? AB - Review of the evidence on hypovitaminosis D as a risk factor for metabolic syndrome and its sequelae, T2DM and CVD, suggests long-term vitamin D repletion could reduce these risks. There is mechanistic evidence for protective effects for MetS and the balance of evidence, (cross-sectional and prospective), supports this postulate. Much of the data so far available from randomized controlled trials is weakened by inadequate power, low vitamin D dosages, starting supplementation too late in life or after MetS disorders have developed or, most importantly, by non-inclusion of many recognizable confounders. On balance, therefore, maintenance of US 2010 recommended intakes for bone protection has the potential to prove protective for MetS. Supplementation has been shown to increase survival in patients with cardiac disorders; whether higher doses would provide useful protection for apparently healthy people in the general population awaits the outcomes of ongoing randomized-controlled trials that, it is hoped, will prove or disprove causality for hypovitaminosis D in MetS and its long-term ill-effects. PMID- 22928081 TI - Yeast colonies: a model for studies of aging, environmental adaptation, and longevity. AB - When growing on solid surfaces, yeast, like other microorganisms, develops organized multicellular populations (colonies and biofilms) that are composed of differentiated cells with specialized functions. Life within these populations is a prevalent form of microbial existence in natural settings that provides the cells with capabilities to effectively defend against environmental attacks as well as efficiently adapt and survive long periods of starvation and other stresses. Under such circumstances, the fate of an individual yeast cell is subordinated to the profit of the whole population. In the past decade, yeast colonies, with their complicated structure and high complexity that are also developed under laboratory conditions, have become an excellent model for studies of various basic cellular processes such as cell interaction, signaling, and differentiation. In this paper, we summarize current knowledge on the processes related to chronological aging, adaptation, and longevity of a colony cell population and of its differentiated cell constituents. These processes contribute to the colony ability to survive long periods of starvation and mostly differ from the survival strategies of individual yeast cells. PMID- 22928082 TI - Kluyveromyces lactis: a suitable yeast model to study cellular defense mechanisms against hypoxia-induced oxidative stress. AB - Studies about hypoxia-induced oxidative stress in human health disorders take advantage from the use of unicellular eukaryote models. A widely extended model is the fermentative yeast Saccharomyces cerevisiae. In this paper, we describe an overview of the molecular mechanisms induced by a decrease in oxygen availability and their interrelationship with the oxidative stress response in yeast. We focus on the differential characteristics between S. cerevisiae and the respiratory yeast Kluyveromyces lactis, a complementary emerging model, in reference to multicellular eukaryotes. PMID- 22928083 TI - Growth culture conditions and nutrient signaling modulating yeast chronological longevity. AB - The manipulation of nutrient-signaling pathways in yeast has uncovered the impact of environmental growth conditions in longevity. Studies using calorie restriction show that reducing glucose concentration of the culture media is sufficient to increase replicative and chronological lifespan (CLS). Other components of the culture media and factors such as the products of fermentation have also been implicated in the regulation of CLS. Acidification of the culture media mainly due to acetic acid and other organic acids production negatively impacts CLS. Ethanol is another fermentative metabolite capable of inducing CLS reduction in aged cells by yet unknown mechanisms. Recently, ammonium was reported to induce cell death associated with shortening of CLS. This effect is correlated to the concentration of NH(4) (+) added to the culture medium and is particularly evident in cells starved for auxotrophy-complementing amino acids. Studies on the nutrient-signaling pathways regulating yeast aging had a significant impact on aging-related research, providing key insights into mechanisms that modulate aging and establishing the yeast as a powerful system to extend knowledge on longevity regulation in multicellular organisms. PMID- 22928084 TI - Does vitamin C and E supplementation impair the favorable adaptations of regular exercise? AB - The detrimental outcomes associated with unregulated and excessive production of free radicals remains a physiological concern that has implications to health, medicine and performance. Available evidence suggests that physiological adaptations to exercise training can enhance the body's ability to quench free radicals and circumstantial evidence exists to suggest that key vitamins and nutrients may provide additional support to mitigate the untoward effects associated with increased free radical production. However, controversy has risen regarding the potential outcomes associated with vitamins C and E, two popular antioxidant nutrients. Recent evidence has been put forth suggesting that exogenous administration of these antioxidants may be harmful to performance making interpretations regarding the efficacy of antioxidants challenging. The available studies that employed both animal and human models provided conflicting outcomes regarding the efficacy of vitamin C and E supplementation, at least partly due to methodological differences in assessing oxidative stress and training adaptations. Based on the contradictory evidence regarding the effects of higher intakes of vitamin C and/or E on exercise performance and redox homeostasis, a permanent intake of non-physiological dosages of vitamin C and/or E cannot be recommended to healthy, exercising individuals. PMID- 22928088 TI - Low CD4/CD8 Ratio in Bronchus-Associated Lymphoid Tissue Is Associated with Lung Allograft Rejection. AB - Background. Bronchus-associated lymphoid tissue (BALT) has been associated with lung allograft rejection in rat transplant models. In human transplant recipients, BALT has not been linked to clinically significant rejection. We hypothesize that the immunohistochemical composition of BALT varies with the presence of acute lung allograft rejection. Methods. We retrospectively examined 40 human lung allograft recipients transplanted from 3/1/1999 to 6/1/2008. Patients were grouped by frequency and severity of acute rejection based on International Society of Heart Lung Transplant (ISHLT) criteria. Transbronchial biopsies were reviewed for BALT by a blinded pathologist. BALT if present was immunohistochemically stained to determine T-and B-cell subpopulations. Results. BALT presence was associated with an increased frequency of acute rejection episodes in the first year after transplantation. Patients with a lower CD4/CD8 ratio had an increased rejection rate; however, BALT size or densities of T-cell and B-cell subpopulations did not correlate with rejection rate. Conclusion. The presence of BALT is associated with an increased frequency of rejection one year after transplant. The lower the CD4/CD8 ratio, the more acute rejection episodes occur in the first year after transplantation. The immunohistochemical composition of BALT may predict patients prone to frequent episodes of acute cellular rejection. PMID- 22928089 TI - Neurodegenerative Shielding by Curcumin and Its Derivatives on Brain Lesions Induced by 6-OHDA Model of Parkinson's Disease in Albino Wistar Rats. AB - Study was undertaken to evaluate the neurodegenerative defending potential of curcumin (CUR), demethoxycurcumin (DMC), and bisdemethoxycurcumin (BDMC) on 6 hydroxydopamine-(6-OHDA) induced Parkinsonism model in rats. Curcuminoids were administered (60 mg/kg, body weight, per oral) for three weeks followed by unilateral injection of 6-OHDA on 22nd day (10 MUg/2 MUL) into the right striatum leading to extensive loss of dopaminergic cells. The behavioral observations, biochemical markers, quantification of dopamine (DA), DOPAC, and HVA followed by dopamine (D(2)) receptor binding assay and tyrosine hydroxylase (TH, using immunohistochemistry) were evaluated using HPLC after three weeks of lesion. Pretreated animals showed significant protection against neuronal degeneration compared to lesion animals by normalizing the deranged levels of biomarkers and showed the potency in the order CUR > DMC > BDMC. The same order of effectiveness was observed in D(2) receptors binding assay and TH immunohistochemistry study. We conclude that curcuminoids appear to shield progressive neuronal degeneration from increased oxidative attack in 6-OHDA-lesioned rats through its free radical scavenging mechanism, and DA, DOPAC, and HVA enhancing capabilities in the sequence of efficacy CUR > DMC > BDMC. Further, curcuminoids may have potential utility in treatment of many more oxidative stress-induced neurodegenerative disorders. PMID- 22928086 TI - Regular physical exercise as a strategy to improve antioxidant and anti inflammatory status: benefits in type 2 diabetes mellitus. AB - Over the last 30 years the combination of both a sedentary lifestyle and excessive food availability has led to a significant increase in the prevalence of obesity and aggravation of rates of metabolic syndrome and type 2 diabetes mellitus (T2DM). Several lines of scientific evidence have been demonstrating that a low level of physical activity and decreased daily energy expenditure leads to the accumulation of visceral fat and, consequently, the activation of the oxidative stress/inflammation cascade, which underlies the development of insulin resistant T2DM and evolution of micro, and macrovascular complications. This paper focuses on the pathophysiological pathways associated with the involvement of oxidative stress and inflammation in the development of T2DM and the impact of regular physical exercise (training) as a natural antioxidant and anti-inflammatory strategy to prevent evolution of T2DM and its serious complications. PMID- 22928090 TI - A Concept for Selection of Codon-Suppressor tRNAs Based on Read-Through Ribosome Display in an In Vitro Compartmentalized Cell-Free Translation System. AB - Here is presented a concept for in vitro selection of suppressor tRNAs. It uses a pool of dsDNA templates in compartmentalized water-in-oil micelles. The template contains a transcription/translation trigger, an amber stop codon, and another transcription trigger for the anticodon- or anticodon loop-randomized gene for tRNA(Ser). Upon transcription are generated two types of RNAs, a tRNA and a translatable mRNA (mRNA-tRNA). When the tRNA suppresses the stop codon (UAG) of the mRNA, the full-length protein obtained upon translation remains attached to the mRNA (read-through ribosome display) that contains the sequence of the tRNA. In this way, the active suppressor tRNAs can be selected (amplified) and their sequences read out. The enriched anticodon (CUA) was complementary to the UAG stop codon and the enriched anticodon-loop was the same as that in the natural tRNA(Ser). PMID- 22928085 TI - Diet and aging. AB - Nutrition has important long-term consequences for health that are not only limited to the individual but can be passed on to the next generation. It can contribute to the development and progression of chronic diseases thus effecting life span. Caloric restriction (CR) can extend the average and maximum life span and delay the onset of age-associated changes in many organisms. CR elicits coordinated and adaptive stress responses at the cellular and whole-organism level by modulating epigenetic mechanisms (e.g., DNA methylation, posttranslational histone modifications), signaling pathways that regulate cell growth and aging (e.g., TOR, AMPK, p53, and FOXO), and cell-to-cell signaling molecules (e.g., adiponectin). The overall effect of these adaptive stress responses is an increased resistance to subsequent stress, thus delaying age related changes and promoting longevity. In human, CR could delay many diseases associated with aging including cancer, diabetes, atherosclerosis, cardiovascular disease, and neurodegenerative diseases. As an alternative to CR, several CR mimetics have been tested on animals and humans. At present, the most promising alternatives to the use of CR in humans seem to be exercise, alone or in combination with reduced calorie intake, and the use of plant-derived polyphenol resveratrol as a food supplement. PMID- 22928087 TI - Regulation of ROS production and vascular function by carbon monoxide. AB - Carbon monoxide (CO) is a gaseous molecule produced from heme by heme oxygenase (HO). CO interacts with reduced iron of heme-containing proteins, leading to its involvement in various cellular events via its production of mitochondrial reactive oxygen species (ROS). CO-mediated ROS production initiates intracellular signal events, which regulate the expression of adaptive genes implicated in oxidative stress and functions as signaling molecule for promoting vascular functions, including angiogenesis and mitochondrial biogenesis. Therefore, CO generated either by exogenous delivery or by HO activity can be fundamentally involved in regulating mitochondria-mediated redox cascades for adaptive gene expression and improving blood circulation (i.e., O(2) delivery) via neovascularization, leading to the regulation of mitochondrial energy metabolism. This paper will highlight the biological effects of CO on ROS generation and cellular redox changes involved in mitochondrial metabolism and angiogenesis. Moreover, cellular mechanisms by which CO is exploited for disease prevention and therapeutic applications will also be discussed. PMID- 22928091 TI - Biotechnological Potential of Agro Residues for Economical Production of Thermoalkali-Stable Pectinase by Bacillus pumilus dcsr1 by Solid-State Fermentation and Its Efficacy in the Treatment of Ramie Fibres. AB - The production of a thermostable and highly alkaline pectinase by Bacillus pumilus dcsr1 was optimized in solid-state fermentation (SSF) and the impact of various treatments (chemical, enzymatic, and in combination) on the quality of ramie fibres was investigated. Maximum enzyme titer (348.0 +/- 11.8 Ug(-1) DBB) in SSF was attained, when a mixture of agro-residues (sesame oilseed cake, wheat bran, and citrus pectin, 1 : 1 : 0.01) was moistened with mineral salt solution (a(w) 0.92, pH 9.0) at a substrate-to-moistening agent ratio of 1 : 2.5 and inoculated with 25% of 24 h old inoculum, in 144 h at 40 degrees C. Parametric optimization in SSF resulted in 1.7-fold enhancement in the enzyme production as compared to that recorded in unoptimized conditions. A 14.2-fold higher enzyme production was attained in SSF as compared to that in submerged fermentation (SmF). The treatment with the enzyme significantly improved tensile strength and Young's modulus, reduction in brittleness, redness and yellowness, and increase in the strength and brightness of ramie fibres. PMID- 22928093 TI - Psychosocial Correlates among Adolescents of Responses to HIV Prevention Interventions. PMID- 22928092 TI - Physical activity targeted at maximal lipid oxidation: a meta-analysis. AB - Exercise is recognized as a part of the management of obesity and diabetes. Various protocols of exercise are proposed for the management of obesity, diabetes, and other metabolic diseases. One of the strategies proposed by several authors is low intensity endurance training targeted at the level of maximal oxidation. Large series using this technique are lacking. Addressing this issue, we performed a meta-analysis of the studies on anthropometric measurements. From a database of 433 articles, 15 were selected, including 279 subjects with 6 different populations. Studies duration ranged from 2 months to 12 months. Concerning weight loss, in the intervention versus control analysis, five studies with 185 participants were included with a significant effect size favors exercise (P = 0.02) without significant heterogeneity (I(2) = 0.0%, P = 0.83). Further randomized controlled trials for comparing it with other exercise protocols and defining its dose effectiveness on large samples are needed. PMID- 22928094 TI - Derecruitment test and surfactant therapy in patients with acute lung injury. AB - Introduction. A recruitment maneuver (RM) may improve gas exchange in acute lung injury (ALI). The aim of our study was to assess the predictive value of a derecruitment test in relation to RM and to evaluate the efficacy of RM combined with surfactant instillation in patients with ALI. Materials and Methods. Thirteen adult mechanically ventilated patients with ALI were enrolled into a prospective pilot study. The patients received protective ventilation and underwent RM followed by a derecruitment test. After a repeat RM, bovine surfactant (surfactant group, n = 6) or vehicle only (conventional therapy group, n = 7) was instilled endobronchially. We registered respiratory and hemodynamic parameters, including extravascular lung water index (EVLWI). Results. The derecruitment test decreased the oxygenation in 62% of the patients. We found no significant correlation between the responses to the RM and to the derecruitment tests. The baseline EVLWI correlated with changes in SpO(2) following the derecruitment test. The surfactant did not affect gas exchange and lung mechanics but increased EVLWI at 24 and 32 hrs. Conclusions. Our study demonstrated no predictive value of the derecruitment test regarding the effects of RM. Surfactant instillation was not superior to conventional therapy and might even promote pulmonary edema in ALI. PMID- 22928095 TI - Does Personality Predict Depression and Use of an Internet-Based Intervention for Depression among Adolescents? AB - Background. Focus upon depression and prevention of its occurrence among adolescents is increasing. Novel ways of dealing with this serious problem have become available especially by means of internet-based prevention and treatment programs of depression and anxiety. The use of Internet-based intervention programs among adolescents has revealed some difficulties in implementation that need to be further elucidated. The aim of this study is to investigate the association between personality and adolescent depression and the characteristics of users of an Internet-based intervention program. Method. The Junior Temperament and Character Inventory (JTCI), the General Self-Efficacy scale (GSE) and the Centre for Epidemiological Studies-Depression scale (CES-D) have been administered to a sample (n = 1234) of Norwegian senior high-school students. Results. Multiple regression analysis revealed associations between depression and gender, and several JTCI domains and facets. In line with previous findings in adults, high Harm Avoidance and low Self-Directedness emerged as the strongest predictors of adolescent depressive symptoms. Further, in logistic regression analysis with the covariates JTCI, GSE and CES-D, the only significant variables predicting use/non-use were the CES-D and the temperament domain Reward Dependence. Conclusion. The results in this study revealed level of depressive symptoms as the strongest predictor of the use of the Internet based intervention and that personality might provide useful information about the users. PMID- 22928096 TI - Religious and spiritual factors in depression: review and integration of the research. AB - Depressive symptoms and religious/spiritual (R/S) practices are widespread around the world, but their intersection has received relatively little attention from mainstream mental health professionals. This paper reviews and synthesizes quantitative research examining relationships between R/S involvement and depressive symptoms or disorders during the last 50 years (1962 to 2011). At least 444 studies have now quantitatively examined these relationships. Of those, over 60% report less depression and faster remission from depression in those more R/S or a reduction in depression severity in response to an R/S intervention. In contrast, only 6% report greater depression. Of the 178 most methodologically rigorous studies, 119 (67%) find inverse relationships between R/S and depression. Religious beliefs and practices may help people to cope better with stressful life circumstances, give meaning and hope, and surround depressed persons with a supportive community. In some populations or individuals, however, religious beliefs may increase guilt and lead to discouragement as people fail to live up to the high standards of their religious tradition. Understanding the role that R/S factors play in preventing depression, facilitating its resolution, or leading to greater depression will help clinicians determine whether this is a resource or a liability for individual patients. PMID- 22928098 TI - Multimodal treatment of gastric cancer: surgery, chemotherapy, radiotherapy, and timing. PMID- 22928097 TI - Survival implications associated with variation in mastectomy rates for early staged breast cancer. AB - Despite a 20-year-old guideline from the National Institutes of Health (NIH) Consensus Development Conference recommending breast conserving surgery with radiation (BCSR) over mastectomy for woman with early-stage breast cancer (ESBC) because it preserves the breast, recent evidence shows mastectomy rates increasing and higher-staged ESBC patients are more likely to receive mastectomy. These observations suggest that some patients and their providers believe that mastectomy has advantages over BCSR and these advantages increase with stage. These beliefs may persist because the randomized controlled trials (RCTs) that served as the basis for the NIH guideline were populated mainly with lower-staged patients. Our objective is to assess the survival implications associated with mastectomy choice by patient alignment with the RCT populations. We used instrumental variable methods to estimate the relationship between surgery choice and survival for ESBC patients based on variation in local area surgery styles. We find results consistent with the RCTs for patients closely aligned to the RCT populations. However, for patients unlike those in the RCTs, our results suggest that higher mastectomy rates are associated with reduced survival. We are careful to interpret our estimates in terms of limitations of our estimation approach. PMID- 22928099 TI - Minimally invasive transforaminal lumbar interbody fusion: a perspective on current evidence and clinical knowledge. AB - This paper reviews the current published data regarding open transforaminal lumbar interbody fusion (TLIF) in relation to minimally invasive transforaminal lumbar interbody fusion (MI-TLIF). Introduction. MI-TLIF, a modern method for lumbar interbody arthrodesis, has allowed for a minimally invasive method to treat degenerative spinal pathologies. Currently, there is limited literature that compares TLIF directly to MI-TLIF. Thus, we seek to discuss the current literature on these techniques. Methods. Using a PubMed search, we reviewed recent publications of open and MI-TLIF, dating from 2002 to 2012. We discussed these studies and their findings in this paper, focusing on patient-reported outcomes as well as complications. Results. Data found in 14 articles of the literature was analyzed. Using these reports, we found mean follow-up was 20 months. The mean patient study size was 52. Seven of the articles directly compared outcomes of open TLIF with MI-TLIF, such as mean duration of surgery, length of post-operative stay, blood loss, and complications. Conclusion. Although high-class data comparing these two techniques is lacking, the current evidence supports MI-TLIF with outcomes comparable to that of the traditional, open technique. Further prospective, randomized studies will help to further our understanding of this minimally invasive technique. PMID- 22928100 TI - The role of fluorine-18-fluorodeoxyglucose positron emission tomography in evaluating the response to treatment in patients with multiple myeloma. AB - Background and Aim. Fluorine-18-fluorodeoxyglucose positron emission tomography (FDG-PET) is well recognized as a powerful diagnostic tool in the initial staging of patients with multiple myeloma (MM). The aim of this paper is to perform a systematic review about the usefulness of FDG-PET or PET/CT in evaluating the response to treatment in patients with MM. Methods. The scientific literature about the role of FDG-PET or PET/CT in evaluating the response to treatment in patients affected by MM was systematically reviewed. Results. Ten studies about the role of FDG-PET or PET/CT in evaluating treatment response in MM were retrieved and discussed. Conclusions. FDG-PET or PET/CT seems to be helpful in assessing the response to treatment in patients with MM and in the evaluation of possible sites of recurrent or progressive disease. PMID- 22928101 TI - Dolphin-Assisted Therapy: Claims versus Evidence. AB - The purpose of this paper is to review and critique studies that have been conducted on dolphin-assisted therapy for children with various disorders. Studies have been released claiming swimming with dolphins is therapeutic and beneficial for children with autism, attention deficit hyperactivity disorder, physical disabilities, and other psychological disorders. The majority of the studies conducted supporting the effectiveness of dolphin-assisted therapy have been found to have major methodological concerns making it impossible to draw valid conclusions. Readers will be informed of the history of, theory behind, and variations of dolphin-assisted therapy along with a review and critique of studies published which purportedly support its use. PMID- 22928102 TI - High complement factor I activity in the plasma of children with autism spectrum disorders. AB - Autism spectrum disorders (ASDs) are neurodevelopmental and behavioural syndromes affecting social orientation, behaviour, and communication that can be classified as developmental disorders. ASD is also associated with immune system abnormality. Immune system abnormalities may be caused partly by complement system factor I deficiency. Complement factor I is a serine protease present in human plasma that is involved in the degradation of complement protein C3b, which is a major opsonin of the complement system. Deficiency in factor I activity is associated with an increased incidence of infections in humans. In this paper, we show that the mean level of factor I activity in the ASD group is significantly higher than in the control group of typically developed and healthy children, suggesting that high activity of complement factor I might have an impact on the development of ASD. PMID- 22928104 TI - Experiences of siblings of individuals with autism spectrum disorders. AB - The purpose of this study was to explore the experiences of siblings of individuals with autism spectrum disorders (ASDs) and identify their self reported support needs. We conducted in-person semi-structured interviews with 12 siblings aged 7 to 15 of children aged 6 to 15 with ASDs. Employing a qualitative collective case study research method, we conducted cross-case analyses to address our research questions. Three major themes emerged: (a) descriptions of the sibling subsystem (b) cohesion between and among the siblings, and (c) adaptability of the participant siblings to having family members with ASDs. Discussion of these findings and recommendations for future research contributes to the existing literature on siblings of children with disabilities. PMID- 22928103 TI - Is autism a member of a family of diseases resulting from genetic/cultural mismatches? Implications for treatment and prevention. AB - Several lines of evidence support the view that autism is a typical member of a large family of immune-related, noninfectious, chronic diseases associated with postindustrial society. This family of diseases includes a wide range of inflammatory, allergic, and autoimmune diseases and results from consequences of genetic/culture mismatches which profoundly destabilize the immune system. Principle among these consequences is depletion of important components, particularly helminths, from the ecosystem of the human body, the human biome. Autism shares a wide range of features in common with this family of diseases, including the contribution of genetics/epigenetics, the identification of disease inducing triggers, the apparent role of immunity in pathogenesis, high prevalence, complex etiologies and manifestations, and potentially some aspects of epidemiology. Fortunately, using available resources and technology, modern medicine has the potential to effectively reconstitute the human biome, thus treating or even avoiding altogether the consequences of genetic/cultural mismatches which underpin this entire family of disease. Thus, if indeed autism is an epidemic of postindustrial society associated with immune hypersensitivity, we can expect that the disease is readily preventable. PMID- 22928106 TI - Intracellular and extracellular redox status and free radical generation in primary immune cells from children with autism. AB - The modulation of the redox microenvironment is an important regulator of immune cell activation and proliferation. To investigate immune cell redox status in autism we quantified the intracellular glutathione redox couple (GSH/GSSG) in resting peripheral blood mononuclear cells (PBMCs), activated monocytes and CD4 T cells and the extracellular cysteine/cystine redox couple in the plasma from 43 children with autism and 41 age-matched control children. Resting PBMCs and activated monocytes from children with autism exhibited significantly higher oxidized glutathione (GSSG) and percent oxidized glutathione equivalents and decreased glutathione redox status (GSH/GSSG). In activated CD4 T cells from children with autism, the percent oxidized glutathione equivalents were similarly increased, and GSH and GSH/GSSG were decreased. In the plasma, both glutathione and cysteine redox ratios were decreased in autistic compared to control children. Consistent with decreased intracellular and extracellular redox status, generation of free radicals was significantly elevated in lymphocytes from the autistic children. These data indicate primary immune cells from autistic children have a more oxidized intracellular and extracellular microenvironment and a deficit in glutathione-mediated redox/antioxidant capacity compared to control children. These results suggest that the loss of glutathione redox homeostasis and chronic oxidative stress may contribute to immune dysregulation in autism. PMID- 22928105 TI - HLA Immune Function Genes in Autism. AB - The human leukocyte antigen (HLA) genes on chromosome 6 are instrumental in many innate and adaptive immune responses. The HLA genes/haplotypes can also be involved in immune dysfunction and autoimmune diseases. It is now becoming apparent that many of the non-antigen-presenting HLA genes make significant contributions to autoimmune diseases. Interestingly, it has been reported that autism subjects often have associations with HLA genes/haplotypes, suggesting an underlying dysregulation of the immune system mediated by HLA genes. Genetic studies have only succeeded in identifying autism-causing genes in a small number of subjects suggesting that the genome has not been adequately interrogated. Close examination of the HLA region in autism has been relatively ignored, largely due to extraordinary genetic complexity. It is our proposition that genetic polymorphisms in the HLA region, especially in the non-antigen-presenting regions, may be important in the etiology of autism in certain subjects. PMID- 22928107 TI - Human myocardial protein pattern reveals cardiac diseases. AB - Proteomic profiles of myocardial tissue in two different etiologies of heart failure were investigated using high performance liquid chromatography (HPLC)/Fourier transform ion cyclotron resonance mass spectrometry (FT-ICR MS). Right atrial appendages from 10 patients with hemodynamically significant isolated aortic valve disease and from 10 patients with isolated symptomatic coronary heart disease were collected during elective cardiac surgery. As presented in an earlier study by our group (Baykut et al., 2006), both disease forms showed clearly different pattern distribution characteristics. Interesting enough, the classification patterns could be used for correctly sorting unknown test samples in their correct categories. However, in order to fully exploit and also validate these findings there is a definite need for unambiguous identification of the differences between different etiologies at molecular level. In this study, samples representative for the aortic valve disease and coronary heart disease were prepared, tryptically digested, and analyzed using an FT-ICR MS that allowed collision-induced dissociation (CID) of selected classifier masses. By using the fragment spectra, proteins were identified by database searches. For comparison and further validation, classifier masses were also fragmented and analyzed using HPLC-/Matrix-assisted laser desorption ionization (MALDI) time-of-flight/time-of-flight (TOF/TOF) mass spectrometry. Desmin and lumican precursor were examples of proteins found in aortic samples at higher abundances than in coronary samples. Similarly, adenylate kinase isoenzyme was found in coronary samples at a higher abundance. The described methodology could also be feasible in search for specific biomarkers in plasma or serum for diagnostic purposes. PMID- 22928108 TI - Cellular cofactors of lentiviral integrase: from target validation to drug discovery. AB - To accomplish their life cycle, lentiviruses make use of host proteins, the so called cellular cofactors. Interactions between host cell and viral proteins during early stages of lentiviral infection provide attractive new antiviral targets. The insertion of lentiviral cDNA in a host cell chromosome is a step of no return in the replication cycle, after which the host cell becomes a permanent carrier of the viral genome and a producer of lentiviral progeny. Integration is carried out by integrase (IN), an enzyme playing also an important role during nuclear import. Plenty of cellular cofactors of HIV-1 IN have been proposed. To date, the lens epithelium-derived growth factor (LEDGF/p75) is the best studied cofactor of HIV-1 IN. Moreover, small molecules that block the LEDGF/p75-IN interaction have recently been developed for the treatment of HIV infection. The nuclear import factor transportin-SR2 (TRN-SR2) has been proposed as another interactor of HIV IN-mediating nuclear import of the virus. Using both proteins as examples, we will describe approaches to be taken to identify and validate novel cofactors as new antiviral targets. Finally, we will highlight recent advances in the design and the development of small-molecule inhibitors binding to the LEDGF/p75-binding pocket in IN (LEDGINs). PMID- 22928110 TI - The role of education and intellectual activity on cognition. AB - Although educational attainment has been consistently related to cognition in adulthood, the mechanisms are still unclear. Early education, and other social learning experiences, may provide the skills, knowledge, and interest to pursue intellectual challenges across the life course. Therefore, cognition in adulthood might reflect continued engagement with cognitively complex environments. Using baseline data from the Baltimore Experience Corps Trial, multiple mediation models were applied to examine the combined and unique contributions of intellectual, social, physical, creative, and passive lifestyle activities on the relationship between education and cognition. Separate models were tested for each cognitive outcome (i.e., reading ability, processing speed, memory). With the exception of memory tasks, findings suggest that education-cognition relations are partially explained by frequent participation in intellectual activities. The association between education and cognition was not completely eliminated, however, suggesting that other factors may drive these associations. PMID- 22928111 TI - Social isolation and aging in zambia: examining the possible predictors. AB - This research paper examined social isolation and aging in Zambia by examining possible predictors. The paper produces evidence on risk factors likely to engender social isolation among the elderly population of Zambia. Snowball sampling was undertaken to select 690 adults aged 60 and over in communities as well as those living in homes for the aged. A structured questionnaire was used to solicit information from respondents. Results show that old people in Zambia experience forms of social isolation which exhibit themselves (but not limited to) through such factors as loss of appetite, stress, moody, hopeless, useless, unhappy, and lonely. On balance, however, the direction of association and the number of statistically significant findings suggest that associations between variables examined and risk factors associated with social isolation amongst older people in this analysis could explain the overall situation occuring currently in Zambia and probably other developing countries. In view of this, this study recommends that further work is needed to identify and explain details of factors of social isolation using techniques such as focus group discussions as well as in-depth interviews with key informants. Such approaches may even help to explain why, for example, sex seems not to be significant in determining indicators of social isolation. PMID- 22928109 TI - Virtual interactomics of proteins from biochemical standpoint. AB - Virtual interactomics represents a rapidly developing scientific area on the boundary line of bioinformatics and interactomics. Protein-related virtual interactomics then comprises instrumental tools for prediction, simulation, and networking of the majority of interactions important for structural and individual reproduction, differentiation, recognition, signaling, regulation, and metabolic pathways of cells and organisms. Here, we describe the main areas of virtual protein interactomics, that is, structurally based comparative analysis and prediction of functionally important interacting sites, mimotope-assisted and combined epitope prediction, molecular (protein) docking studies, and investigation of protein interaction networks. Detailed information about some interesting methodological approaches and online accessible programs or databases is displayed in our tables. Considerable part of the text deals with the searches for common conserved or functionally convergent protein regions and subgraphs of conserved interaction networks, new outstanding trends and clinically interesting results. In agreement with the presented data and relationships, virtual interactomic tools improve our scientific knowledge, help us to formulate working hypotheses, and they frequently also mediate variously important in silico simulations. PMID- 22928113 TI - Role of self-expandable metal stents in acute variceal bleeding. AB - Acute variceal bleeding continues to be associated with significant mortality. Current standard of care combines hemodynamic stabilization, antibiotic prophylaxis, pharmacological agents, and endoscopic treatment. Rescue therapies using balloon tamponade or transjugular intrahepatic portosystemic shunt are implemented when first-line therapy fails. Rescue therapies have many limitations and are contraindicated in some cases. Placement of fully covered self-expandable metallic stent is a promising therapeutic technique that can be used to control bleeding in cases of refractory esophageal bleeding as an alternative to balloon tamponade. These stents can be left in place for as long as two weeks, allowing for improvement in liver function and institution of a more definitive treatment. PMID- 22928114 TI - Orthodontic tooth movement with clear aligners. AB - Clear aligners provide a convenient model to measure orthodontic tooth movement (OTM). We examined the role of in vivo aligner material fatigue and subject specific factors in tooth movement. Fifteen subjects seeking orthodontic treatment at the University of Florida were enrolled. Results were compared with data previously collected from 37 subjects enrolled in a similar protocol. Subjects were followed prospectively for eight weeks. An upper central incisor was programmed to move 0.5 mm. every two weeks using clear aligners. A duplicate aligner was provided for the second week of each cycle. Weekly polyvinyl siloxane (PVS) impressions were taken, and digital models were fabricated to measure OTM. Initial and final cone beam computed tomography (CBCT) images were obtained to characterize OTM. Results were compared to data from a similar protocol, where subjects received a new aligner biweekly. No significant difference was found in the amount of OTM between the two groups, with mean total OTM of 1.11 mm. (standard deviation (SD) 0.30) and 1.07 mm. (SD 0.33) for the weekly aligner and biweekly control groups, respectively (P = 0.72). Over eight weeks, in two-week intervals, material fatigue does not play a significant role in the rate or amount of tooth movement. PMID- 22928115 TI - The Platelet Function Analyzer (PFA-100) as a Screening Tool in Neurosurgery. AB - We investigated whether the inclusion of the PFA-100 in the preoperative screening of neurosurgical patients might reduce perioperative bleeding complications. Patients with intracranial space-occupying lesions who were scheduled for neurosurgery underwent routine preoperative PFA-100 testing. In case of an abnormal PFA test, patients received prophylactic treatment with desmopressin. 93 consecutive patients were compared to 102 consecutive patients with comparable characteristics operated before introduction of the PFA-100 testing. 2 patients (2.2%) in the PFA group and 2 patients (2.0%) in the non-PFA group experienced clinically relevant intracranial bleeding confirmed by computed tomography (OR 1.05, 95% CI 0.39-2.82; P = 1.0). Transfusions were not significantly different between the two groups. 13 (14.0%) patients in the PFA group and 5 (4.9%) patients in the non-PFA group received desmopressin (OR 3.2, 95% CI 1.1-9.2; P = 0.045). Preoperative screening with the PFA-100 did result in a significant increase in the administration of desmopressin, which could not reduce perioperative bleeding complications or transfusions. PMID- 22928116 TI - Predisposing individual characteristics and perinatal outcomes of women in the Tokyo metropolitan area who initiate prenatal care late in their pregnancy: a case-control study. AB - Purpose. The purpose of this study was to investigate the individual characteristics and perinatal outcomes of women who initiate prenatal care late in their pregnancy in the Tokyo metropolitan area. Methods. Retrospective study. The study enrolled all women at our hospital who initiated prenatal care after 22 weeks of gestation (late attenders) and control women who initiated prenatal care prior to 11 weeks of gestation participated in the study at the National Center for Global Health and Medicine between January 1, 2007 and June 30, 2011. We compared the maternal characteristics and perinatal outcomes of late attenders with those of the control group. Results. A total of 121 late attenders and 1,787 controls were enrolled. Late attenders had a higher incidence of unmarried compared with the control group (P < 0.01). There were no differences in the incidence of preterm delivery and low birth weight; however, babies of the late attenders had a higher incidence of admission to the neonatal intensive care unit compared with the control group (P < 0.01). Conclusions. Our results indicate that there is a pressing need for further steps to promote the importance of receiving prenatal care during pregnancy. PMID- 22928112 TI - Genetic and biochemical alterations in non-small cell lung cancer. AB - Despite significant advances in the detection and treatment of lung cancer, it causes the highest number of cancer-related mortality. Recent advances in the detection of genetic alterations in patient samples along with physiologically relevant animal models has yielded a new understanding of the molecular etiology of lung cancer. This has facilitated the development of potent and specific targeted therapies, based on the genetic and biochemical alterations present in the tumor, especially non-small-cell lung cancer (NSCLC). It is now clear that heterogeneous cell signaling pathways are disrupted to promote NSCLC, including mutations in critical growth regulatory proteins (K-Ras, EGFR, B-RAF, MEK-1, HER2, MET, EML-4-ALK, KIF5B-RET, and NKX2.1) and inactivation of growth inhibitory pathways (TP53, PTEN, p16, and LKB-1). How these pathways differ between smokers and non-smokers is also important for clinical treatment strategies and development of targeted therapies. This paper describes these molecular targets in NSCLC, and describes the biological significance of each mutation and their potential to act as a therapeutic target. PMID- 22928117 TI - Quality of Life Assessment in Patients with Multiple Sclerosis Receiving Interferon Beta-1a: A Comparative Longitudinal Study of Avonex and Its Biosimilar CinnoVex. AB - Background. Multiple sclerosis (MS) is an autoimmune inflammatory disease of central nervous system (CNS). MS affects quality of Life (QOL) due to physical disability and other associated problems. Disease-modifying agents like interferon beta (IFNB) have been widely utilized in this patient population; however, their frequency, route of administration, side effects, high cost, and also the question of whether they are truly beneficial for longer-term outcomes and QOL need to be further investigated. Objectives. To assess QOL in patients with multiple sclerosis receiving interferon beta-1a (Avonex or CinnoVex) and in order to compare QOL in groups receiving Avonex and CinnoVex, respectively, also, to evaluate whether the more cost-effective biosimilar form of IFNB (CinnoVex) has the same effect on QOL and can be substituted for Avonex. Methods. We conducted a 30-month, nonrandomized longitudinal study and recruited a total of 92 patients diagnosed with relapsing-remitting MS. The patients were distributed in Avonex and CinnoVex groups with 46 patients in each group. Quality of life was assessed by means of MSQOL-54 questionnaire, four times a year, at baseline and at months 4, 8, and 12 of the study. Results. Mean age +/- SD was 30.5 +/- 8.9 and 32.3 +/- 9.0 years in Avonex and CinnoVex groups, respectively, and P value of gender was different (P value : 0.036). The physical health composite scores were 61.8 and 59.8 (P values 0.677 and 0.884) for Avonex and CinnoVex groups, in that order. The results of the study revealed no significant difference between the two groups with regard to physical health, health perception, energy, and role limitations due to physical problems, pain, sexual and social function, and physical health distress scores. Further, interferon therapy did not significantly impact patients' QOL after a year of treatment with either Avonex or CinnoVex. Conclusions. According to the present study, treatment with IFNB (Avonex or CinnoVex) did not affect QOL during a year of therapy. Further studies with longer follow-up periods are required to assess the value of interferons on long-term outcomes and patient's QOL. PMID- 22928118 TI - Evaluation of the Effects of Sativex (THC BDS: CBD BDS) on Inhibition of Spasticity in a Chronic Relapsing Experimental Allergic Autoimmune Encephalomyelitis: A Model of Multiple Sclerosis. AB - This study investigated the antispasticity potential of Sativex in mice. Chronic relapsing experimental allergic encephalomyelitis was induced in adult ABH mice resulting in hind limb spasticity development. Vehicle, Sativex, and baclofen (as a positive control) were injected intravenously and the "stiffness" of limbs assessed by the resistance force against hind limb flexion. Vehicle alone caused no significant change in spasticity. Baclofen (5 mg/kg) induced approximately a 40% peak reduction in spasticity. Sativex dose dependently reduced spasticity; 5 mg/kg THC + 5 mg/kg CBD induced approximately a 20% peak reduction; 10 mg/kg THC + 10 mg/kg CBD produced approximately a 40% peak reduction in spasticity. Sativex has the potential to reduce spasticity in an experimental mouse model of multiple sclerosis (MS). Baclofen reduced spasticity and served as a positive control. Sativex (10 mg/kg) was just as effective as baclofen, providing supportive evidence for Sativex use in the treatment of spasticity in MS. PMID- 22928119 TI - Oropharyngeal Cancer Survival: A Population-Based Study of Patients Diagnosed between 1978 and 2002. AB - Objective. This paper aims at studying oropharyngeal cancer survival from the Population-Based Cancer Registry of Zaragoza, Spain, for the 1978-2002 period. Methods. The survival rates were calculated by the Kaplan-Meier method, and the automated calculation method of the Catalan Institute of Oncology was utilized to obtain the relative survival. Results. The oropharyngeal cancer survival rate was 61.3% in the first year and 33.9% in the fifth year. One-year relative survival was 62.2% (CI 95%: 57.4-67.4), and five-year relative survival was 36.6% (CI 95%: 31.8-42.1). Comparison of survival rates by sex revealed statistically significant differences (P value = 0.017) with better survival in women. There were no differences when comparing the three age groups and the three studied time periods 1978-1986, 1987-1994, and 1995-2002. Conclusions. The data suggests that there were no significant changes in oropharyngeal cancer survival in the province of Zaragoza throughout the years. PMID- 22928121 TI - Hemisection: a window of hope for freezing tooth. AB - Advances in dentistry, as well as the increased desire of patients to maintain their dentition, have led to treatment of teeth that once would have been removed. Mandibular first molars are the most commonly extracted teeth due to dental caries and periodontal disease. These teeth are the major standpoint for occlusion, and also have a wide pericemental area. Hence, any defect in the root either mesial or distal, extraction is the most common treatment planned. Under specific conditions, only the diseased part of the tooth can be extracted after an endodontic treatment. A modified fixed partial denture design is fabricated to splint the remaining portion of the tooth to adjacent teeth. This procedure though daunting can be easily achieved and maintained successfully. PMID- 22928120 TI - The stemness phenotype model. AB - The identification of a fraction of cancer stem cells (CSCs) associated with resistance to chemotherapy in most solid tumors leads to the dogma that eliminating this fraction will cure cancer. Experimental data has challenged this simplistic and optimistic model. Opposite to the classical cancer stem cell model, we introduced the stemness phenotype model (SPM), which proposed that all glioma cells possess stem cell properties and that the stemness is modulated by the microenvironment. A key prediction of the SPM is that to cure gliomas all gliomas cells (CSCs and non-CSCs) should be eliminated at once. Other theories closely resembling the SPM and its predictions have recently been proposed, suggesting that the SPM may be a useful model for other type of tumors. Here, we review data from other tumors that strongly support the concepts of the SPM applied to gliomas. We include data related to: (1) the presence of a rare but constant fraction of CSCs in established cancer cell lines, (2) the clonal origin of cancer, (3) the symmetrical division, (4) the ability of "non-CSCs" to generate "CSCs," and (5) the effect of the microenvironment on cancer stemness. The aforenamed issues that decisively supported the SPM proposed for gliomas can also be applied to breast, lung, prostate cancer, and melanoma and perhaps other tumors in general. If the glioma SPM is correct and can be extrapolated to other types of cancer, it will have profound implications in the development of novel modalities for cancer treatment. PMID- 22928122 TI - Small Intestinal Obstruction with Intussusception due to Acute Myeloid Leukemia: A Case Report. AB - Myeloid sarcoma is known to precede the development of acute myeloid leukemia (AML) and can be the only clinical manifestation. Gastrointestinal involvement by AML is rare with the commonest site being small intestine. Patients present with vague abdominal pain and/or obstruction. Prognosis is usually poor as most of them rapidly progress to AML. We report a case of 25-year-old man with complaints of abdominal pain and vomiting of one-year duration. OGD scopy revealed infiltration of lesser curvature of stomach. Subsequently patient came back within a week with signs and symptoms of acute intestinal obstruction for which an ileal resection was done. Although the histology of stomach biopsy and ileal segments showing similar features were thought to be non-Hodgkin's lymphoma, immunohistochemistry confirmed the diagnosis of myeloid sarcoma. Bone marrow investigations confirmed involvement by AML. Patient succumbed to the disease due to extensive involvement of AML. This case highlights the primary gastrointestinal manifestation of AML which can often prove to be a diagnostic difficulty clinically and histologically. Prompt diagnosis is essential to hasten the management. PMID- 22928123 TI - Crohn's disease presenting with pyogenic liver abscess: a case report. AB - Pyogenic liver abscess (PLA) is a rare extraintestinal complication of Crohn's disease (CD), and the clinical and laboratory findings may emulate the reactivation of CD, therefore, delaying diagnosis. In this paper the patient presented with PLA as the initial manifestation of CD and experienced severe disease. The finding of PLA was established by computed tomography and initial treatment involved percutaneous drainage and antibiotics. The diagnosis of CD was made after colonoscopy and histological investigations. PMID- 22928124 TI - Successful Management of Acute Catastrophic Juvenile Vaginal Bleeding in Glanzmann's Thromboasthenia by Uterine Tamponade: A Case Report and Review of The Literature. AB - Glanzmann's thromboasthenia (GT) is a rare platelet disorder, due to membrane defects involving glycoprotein GP IIb/IIIa complex. Symptoms appear in infancy with episodes of bruising, gingival bleeding, epistaxis, or at the time of menarche acute episode of uterine bleeding. Hormonal therapy and antifibrinolytic agents are first-line treatment. Platelet transfusion is given to control hemorrhage when medical treatment fails. However, repeated transfusions may result in development of platelet refractioness, due to development of antibodies against membrane glycoprotein. Activated recombinant FVII is licensed for use in acute control of bleeding in GT. Here we report a case of acute juvenile uterine bleeding at menarche, which responded successfully to uterine tamponade. To our knowledge, this is the first case report on use of balloon tamponade for control of acute catastrophic juvenile bleeding at menarche. PMID- 22928125 TI - A paraneoplastic syndrome characterized by extremity swelling with associated inflammatory infiltrate heralds aggressive transformation of myelodysplastic syndromes/myeloproliferative neoplasms to acute myeloid leukemia: a case series. AB - There has been a long history of reports describing a variety of paraneoplastic phenomena associated with myelodysplastic syndromes, particularly those with autoimmune manifestations. We report here a series of patients with an antecedent myelodysplastic syndrome (MDS) or myeloproliferative neoplasm (MPN) that underwent aggressive transformation to acute myeloid leukemia (AML). In each case, the transformation to AML was preceded by an inflammatory syndrome characterized by unilateral extremity swelling and an associated inflammatory skin infiltrate, as well as other signs of inflammation, including profound hyperferritinemia without evidence of a hemophagocytic syndrome. We suggest that such an inflammatory syndrome may herald aggressive transformation of MDS/MPN to AML. Patients with known MDS/MPN who present with these features may benefit from early bone marrow examination to assess disease status. Early intervention with corticosteroids in select patients may result in improvement or resolution of the symptoms and permit intensive therapy for AML to be delivered. PMID- 22928126 TI - Planned pregnancy in a chronic myeloid leukemia patient in molecular remission. AB - Excellent response rates and a good quality of life have been observed since the introduction of tyrosine kinase inhibitors (TKIs) in chronic myeloid leukemia (CML) treatment. Consequently, some challenges began to appear in CML women in child-bearing age wishing to become pregnant. Currently, many women around the world are in stable major/complete molecular response MMR/CMR (MMR: <0.1% BCR ABL/ABL and CMR: undetectable BCR-ABL mRNA by RQ-PCR transcript levels on the international scale). The condition of stable MMR/CMR is linked to a long-term virtual absence of progression to the accelerated and blastic phase and to the possibility of stopping the TKI treatment with the maintenance of a condition of CMR in a proportion of cases. Imatinib teratogenic and prescribing information prohibits the use of it during pregnancy. We describe the case of a 36-year-old female patient with CML in chronic phase who stopped imatinib after 2 years in major molecular response (MMR) to plan a pregnancy. Molecular monitoring by RQ PCR was performed quarterly. She achieved a safe pregnancy and delivery maintaining an optimal molecular response throughout the pregnancy. Isolated literature reports have been described, but no formal advice has been described at present time. PMID- 22928127 TI - Paradoxical Immune Reconstitution Syndrome Presenting as Acute Respiratory Distress Syndrome in a Leukemia Patient during Neutrophil Recovery. AB - Immune reconstitution inflammatory syndrome (IRIS) in the setting of antiretroviral therapy is well described, but it is not as common in non-HIV patients; here, we present a case of immune reconstitution inflammatory syndrome presenting as acute respiratory distress syndrome in a leukemia patient who had neutropenic fever and septic shock after high-dose cytarabine. During neutropenia recovery, his chest X-ray showed progressive worsening despite being on adequate therapy, we started him on steroids which resulted in significant clinical improvement. PMID- 22928128 TI - Primary burkitt lymphoma of the chest wall. AB - Burkitt lymphoma (BL) originating in the skin and soft tissue at any site is exceedingly rare. This paper is about a case of primary sporadic BL that presented as an isolated, rapidly enlarging chest wall mass arising from skin and/or soft tissue in an adult. As with other BL presentations, this patient was treated with aggressive chemotherapy with central nervous system (CNS) chemoprophylaxis, but he later died because of sepsis. PMID- 22928129 TI - Fatal fulminant hepatic failure from adenovirus in allogeneic bone marrow transplant patients. AB - We report two cases of fatal hepatic failure in patients who received matched unrelated bone marrow transplantation. Both patients presented with high fevers, abnormal liver functions tests, and hypodense lesions in the liver by CT scan. Histologic examination of postmortem liver samples demonstrated extensive necrosis, and immunohistochemistry was positive for adenovirus. PMID- 22928130 TI - Degenrative fibroid and sclerosing peritonitis. AB - Sclerosing peritonitis is a rare condition characterised by ascites, peritoneal and bowel wall thickening. Causes reported in the literature include luteal ovarian the comas, peritoneal dialysis, peritoneal chemotherapy and liver cirrhosis. We report an interesting case of a woman presenting with diarrhoea, abdominal distension, ascites and pleural effusion. She was subsequently diagnosed with Sclerosing Peritonitis caused by a degenerating fibroid which was successfully treated by Total Abdominal Hysterectomy and Bilateral Salpingoophrectomy. PMID- 22928131 TI - Retroperitoneal extraovarian fibrothecoma mimicking a malignant epithelial ovarian carcinoma. AB - Background. Fibrothecomas are benign sex cord-stromal tumors which rarely originate outside of the ovary. To date, two such cases have been reported in the literature. We report the third case of an extraovarian fibrothecoma and the first presenting similarly to a metastatic epithelial ovarian cancer. Clinical History. We describe a 62-year-old woman with history, physical examination, and imaging suggestive of metastatic ovarian cancer. CA-125 was elevated at 1291 U/mL. Paracenteses were negative for malignant cells and core biopsy showed spindle cell proliferation. A primary debulking surgery for a presumed ovarian cancer was planned. Method and Results. At surgery, 6 liters of ascites were drained. The uterus, ovaries, peritoneum, and omentum were normal. An 18 * 11 * 7 cm retroperitoneal mass was found between the left ureter and the sigmoid mesocolon, wrapped with sigmoid colon. Fallopian tubes and ovaries were normal. The mass was resected en bloc with the sigmoid colon, uterus, ovaries, and omentum. Microscopically, there was spindle cell proliferation typical of fibrothecoma. No ovarian tissue was identified in association with the tumor. Conclusion. This third case of extraovarian fibrothecoma highlights the importance of obtaining histologic evidence of malignancy prior to initiating neoadjuvant chemotherapy for a presumed ovarian cancer. PMID- 22928132 TI - Complete hydatidiform mole presenting as a placenta accreta in a twin pregnancy with a coexisting normal fetus: case report. AB - A twin pregnancy with a complete hydatidiform mole and a coexisting normal fetus (CHMF) is a rare clinical scenario, and it carries many associated pregnancy and postnatal risks. Limited numbers of case studies exist reporting an outcome of live birth, and only three prior cases report the presentation of a hydatidiform mole as a placenta previa. We report a case of CHMF with the molar component presenting antenatally as a placenta previa, which ultimately resulted in placenta accreta at the time of delivery. A live male infant was delivered at 34 weeks' gestation via planned cesarean section, and a hysterectomy was performed following unsuccessful removal of the molar component. We additionally utilized previously described methods of placing internal iliac balloons and ureteral stents prior to delivery. In such a high-risk pregnancy with a known molar previa component, these surgical preparation measures may be of benefit. PMID- 22928133 TI - Complications associated with insertion of intrauterine pressure catheters: an unusual case of uterine hypertonicity and uterine perforation resulting in fetal distress after insertion of an intrauterine pressure catheter. AB - Insertion of intrauterine pressure catheters is a routine procedure performed in labor and delivery departments, with few associated complications. There are several reports of maternal and neonatal morbidity associated with the use of intrauterine pressure catheters and their rare adverse outcomes. We report an unusual case of uterine hypertonicity resulting in fetal distress, immediately after the placement of an intrauterine pressure catheter. An emergent Cesarean section was performed for fetal distress and revealed a 5 cm vertical rent in the posterior lower uterine segment. The uterine perforation was repaired intraoperatively. Mother and infant did well and were discharged home on postoperative day four. PMID- 22928134 TI - Obstetric management of a patient with narcolepsy and cataplexy: a case report. AB - We report the management of a patient who suffers from narcolepsy and cataplexy and presented to the clinic at 14 weeks of gestation. Her symptoms were resistant to modafinil but controlled with clomipramine and amphetamine. Discussion concerning mode of delivery for these patients is scarce in the literature. We discuss some issues surrounding the antenatal management and counselling regarding mode of delivery and postpartum care. PMID- 22928135 TI - Complete response of liver metastasis of gastric cancer treated by s-1 chemoradiotherapy: a case report. AB - This paper presents a case of suspected liver metastasis of gastric cancer and a virtual complete response to S-1 chemoradiotherapy. A 69-year-old man underwent distal gastrectomy for gastric cancer in 2008. Multiple liver metastases occurred in 2009. He underwent 15 courses of S-1 therapy and radiation therapy (37.5 Gy). Abdominal computed tomography showed virtual complete disappearance of liver metastasis after chemoradiotherapy. Hence, this case was interpreted as a complete response. No sign of recurrence was noted 18 months after complete response was confirmed. S-1 chemoradiotherapy is likely to be effective in treating patients with liver metastases of gastric cancer. PMID- 22928136 TI - Solitary neurofibroma of the frontal sinus. AB - Isolated or solitary neurofibromas of the paranasal sinuses are rare. Mostly, they involve the maxillary sinus and so far, a solitary neurofibroma of the frontal sinus has never been reported in the literature. We present a case of frontal sinus neurofibroma treated successfully with surgical excision. A 28-year old male presented with forehead swelling and computed tomography images revealed a tumor involving the left frontal sinus. Histopathological examination showed the tumor to be a neurofibroma. We discuss the clinical and pathological characteristics of neurofibroma arising in the nasal cavity and paranasal sinuses. PMID- 22928137 TI - Acute mastoiditis in a newborn with aural atresia. AB - Acute mastoiditis in the newborn is a very rare disease. Herein we report a case of a 28-day-old child with right aural atresia and ipsilateral mastoiditis requiring mastoidectomy. To our knowledge, this is the youngest case reported in the literature. Issues on diagnosis and management of mastoiditis in cases of aural atresia are further discussed. Based on our experience and on previous reported cases we conclude that mastoiditis is difficult to diagnose in a child with aural atresia. Moreover, mastoidectomy may be necessary, although identification of the facial nerve and consequent treatment of the atresia are usually too difficult to perform simultaneously. PMID- 22928138 TI - Multiple osteomas in middle ear. AB - Since the first description of middle ear osteomas by Thomas in 1964, only few reports were published within the English literatures (Greinwalid et al., 1998; Shimizu et al., 2003; Cho et al., 2005; and Jang et al., 2009), and only one case of the multiple osteomas in middle ear was described by Kim et al., 2006, which arose from the promontory, lateral semicircular canal, and epitympanum. Here we describe a patient with multiple middle ear osteomas arising from the promontory, incus, Eustachian tube, and bony semicanal of tensor tympani muscle. This patient also contracted the chronic otitis media in the ipsilateral ear. The osteomas were successfully removed by performing type III tympanoplasty in one stage. PMID- 22928139 TI - Benign intracranial hypertension: a diagnostic dilemma. AB - Benign intracranial hypertension (BIH) (also known as pseudotumor cerebri and empty sella syndrome) remains a diagnostic challenge to most physicians. The modified Dandy criteria consist of, the classic findings of headache, pulsatile tinnitus, papilledema, and elevated cerebrospinal fluid (CSF) pressure, however, these are rarely collectively present in any one patient. Furthermore, these findings can wax and wane over time. Due to the nature of this disease, both signs and symptoms may be intermittent, making definitive diagnosis difficult. Newer imaging studies, particularly the magnetic resonance venogram (MRV) along with a constellation of correlative findings and associated diseases have given new impetus in the diagnosis, treatment, and pathophysiology of this disease. This has led the authors to offer modifications to the classic Dandy criteria. This report presents three representative cases of BIH highlighting many of the newer advances in both diagnosis and treatment of this perplexing disorder. PMID- 22928140 TI - Cutaneous neuroendocrine carcinoma of the external auditory canal: a case report and review of the literature. AB - Cutaneous neuroendocrine carcinoma (cNEC) is rarely seen in the external ear. In this paper, we newly describe a patient with cNEC in his right external auditory canal, followed by a further discussion on the clinical features, diagnosis, and treatments of cNEC of the external ear. A review of the literature showed that cNEC of the external auditory canal generally presents as asymptomatic and that pathology yields the most confirmative diagnosis. A wide resection with adjuvant radiotherapy and chemotherapy is recommended. The overall prognosis of this condition is poor. PMID- 22928141 TI - Using primary care parenting interventions to improve outcomes in children with developmental disabilities: a case report. AB - Parenting is central to the health and well-being of children. Children with developmental disabilities have been shown to be at increased risk of developing emotional and behavioral problems. Parent training programs are effective interventions for improving child behavior and family functioning. This paper describes the outcomes of a brief 4-session parenting intervention (Primary Care Stepping Stones Triple P) targeting compliance and cooperative play skills in an 8-year-old girl with Asperger's disorder and ADHD combined type. The intervention was associated with decreases in child behavior problems, increases in parenting confidence, and decreases in dysfunctional parenting styles. This paper demonstrates that low-intensity parenting interventions can lead to significant improvements in child behavior and family functioning. Such brief interventions are cost effective, can be widely disseminated, and have been designed to be delivered within primary health care settings. Pediatricians can play a key role in identifying parents in need of assistance and in helping them access evidence based parenting interventions. PMID- 22928142 TI - Novel Autosomal Recessive c10orf2 Mutations Causing Infantile-Onset Spinocerebellar Ataxia. AB - Recessive mutations in genes encoding mitochondrial DNA replication machinery lead to mitochondrial DNA depletion syndromes. This genetically and phenotypically heterogeneous group includes infantile onset spinocerebellar ataxia (OMIM# 271245) a neurodegenerative disease caused by mutations in the mtDNA helicase gene, c10orf2, with an increased frequency in the Finnish population due to a founder mutation. We describe a child of English descent who presented with a severe phenotype of IOSCA as a result of two-novel mutations in the c10orf2 gene. This paper expands the phenotypic spectrum of IOSCA and adds further evidence for the presence of a genotype-phenotype correlation among patients with recessive mutations in this gene. PMID- 22928143 TI - Surgical Ligation of Extrahepatic Shunt under Guidance of Doppler Ultrasound, Portography, and Portal Pressure Monitoring. AB - A 54-year-old man with chronic hepatitis C was admitted to our hospital because of a disturbance of consciousness and hyperammonemia. Abdominal angiography revealed a portosystemic shunt between the superior mesenteric vein and inferior vena cava. Endoscopic examination showed no varix. As interventional treatment was unsuccessful, surgical ligation of the shunt was performed. After surgery, portography revealed a huge shunt. Before ligation, the portal pressure, portal flow speed, and volume at the umbilical portion were 24 H(2)O. 5.6 cm/s and 203 ml/min, respectively. Finally the shunt was ligated. The portal flow speed and volume increased for 14 days following surgery and then stabilized. No varices were observed postoperatively. Doppler ultrasound, portography, and portal pressure monitoring can be used to reveal haemodynamic changes in the portal system and justify surgical ligation of portosystemic shunt. PMID- 22928144 TI - Fetal intervention in right outflow tract obstructive disease: selection of candidates and results. AB - Objectives. To describe the process of selection of candidates for fetal cardiac intervention (FCI) in fetuses diagnosed with pulmonary atresia-critical stenosis with intact ventricular septum (PA/CS-IVS) and report our own experience with FCI for such disease. Methods. We searched our database for cases of PA/CS-IVS prenatally diagnosed in 2003-2012. Data of 38 fetuses were retrieved and analyzed. FCI were offered to 6 patients (2 refused). In the remaining it was not offered due to the presence of either favourable prognostic echocardiographic markers (n = 20) or poor prognostic indicators (n = 12). Results. The outcome of fetuses with PA/CS-IVS was accurately predicted with multiparametric scoring systems. Pulmonary valvuloplasty was technically successful in all 4 fetuses. The growth of the fetal right heart and hemodynamic parameters showed a Gaussian-like behaviour with an improvement in the first weeks and slow worsening as pregnancy advanced, probably indicating a restenosis. Conclusions. The most likely type of circulation after birth may be predicted in the second trimester of pregnancy by means of combining cardiac dimensions and functional parameters. Fetal pulmonary valvuloplasty in midgestation is technically feasible and in well-selected cases may improve right heart growth, fetal hemodynamics, and postnatal outcome. PMID- 22928145 TI - Patterns of Change in Cognitive Function over Six Months in Adults with Chronic Heart Failure. AB - Few investigators have studied cognition over time in adults with heart failure (HF). A battery of neuropsychological tests was administered to 279 adults with chronic systolic or diastolic HF at baseline, three and six months. Growth mixture modeling (GMM) was used to model the measure anticipated to be most sensitive, the digit symbol substitution task (DSST). We describe how and why the DSST patterns change over time. Other measures of cognition were examined to identify consistency with the DSST patterns. The sample was predominantly male (63.2%), Caucasian (62.7%), mean age 62 years. The best fit GMM revealed two trajectories of DSST scores: Average processing speed group (40.5%) and Below Average processing speed (59.9%). Neither group changed significantly over the six month study. Other measures of cognition were consistent with the DSST patterns. Factors significantly associated with increased odds of being in the Below Average processing speed group included older age, male gender, Non Caucasian race, less education, higher ejection fraction, high comorbid burden, excessive daytime sleepiness, and higher BMI. As some of the factors related to cognitive impairment are modifiable, research is needed to identify interventions to preserve and improve cognition in these patients. PMID- 22928146 TI - Strategies to prevent anthracycline-related congestive heart failure in survivors of childhood cancer. AB - Cardiovascular complications are a leading cause of therapy-related morbidity and mortality in long-term survivors of childhood malignancy. In fact, childhood cancer survivors are at a 15-fold risk of developing CHF compared to age-matched controls. There is a strong dose-dependent association between anthracycline exposure and risk of CHF, and the incidence increases with longer followup. Outcome following diagnosis of CHF is generally poor, with overall survival less than 50% at 5 years. The growing number of childhood cancer survivors makes it imperative that strategies be developed to prevent symptomatic heart disease in this vulnerable population. We present here an overview of the current state of knowledge regarding primary, secondary, and tertiary prevention strategies for childhood cancer survivors at high risk for CHF, drawing on lessons learned from prevention studies in nononcology populations as well as from the more limited experience in cancer survivors. PMID- 22928147 TI - Tau protein: function and pathology. PMID- 22928149 TI - Spawning coordination of mates in a shell brooding cichlid. AB - Aim. External fertilisation requires synchronisation of gamete release between the two sexes. Adequate synchronisation is essential in aquatic media because sperm is very short-lived in water. In the cichlid Lamprologus callipterus, fertilisation of the eggs takes place inside an empty snail shell, where females stay inside the shell and males have to ejaculate into the shell opening. This spawning pattern makes the coordination of gamete release difficult. Methods. This study examined the synchronisation of males and females during egg laying. Results. The results showed that the male initiates each spawning sequence and that sperm release and egg laying are very well synchronised. 68% of all sperm releases occurred at exactly the same time when the female laid an egg, and 99% of ejaculations occurred within +/-5 seconds from egg deposition. On average 95 eggs are laid one by one with intervals of several minutes between subsequent eggs, leading to a total spawning duration in excess of six hours. Conclusions. We discuss this exceptional spawning pattern and how it might reflect a conflict between the sexes, with males attempting to induce egg laying and females extending the egg laying period to raise the chance for parasitic males to participate in spawning. PMID- 22928148 TI - Cognitive deterioration and associated pathology induced by chronic low-level aluminum ingestion in a translational rat model provides an explanation of Alzheimer's disease, tests for susceptibility and avenues for treatment. AB - A translational aging rat model for chronic aluminum (Al) neurotoxicity mimics human Al exposure by ingesting Al, throughout middle age and old age, in equivalent amounts to those ingested by Americans from their food, water, and Al additives. Most rats that consumed Al in an amount equivalent to the high end of the human total dietary Al range developed severe cognitive deterioration in old age. High-stage Al accumulation occurred in the entorhinal cortical cells of origin for the perforant pathway and hippocampal CA1 cells, resulting in microtubule depletion and dendritic dieback. Analogous pathological change in humans leads to destruction of the perforant pathway and Alzheimer's disease dementia. The hippocampus is thereby isolated from neocortical input and output normally mediated by the entorhinal cortex. Additional evidence is presented that Al is involved in the formation of neurofibrillary tangles, amyloid plaques, granulovacuolar degeneration, and other pathological changes of Alzheimer's disease (AD). The shared characteristics indicate that AD is a human form of chronic Al neurotoxicity. This translational animal model provides fresh strategies for the prevention, diagnosis, and treatment of AD. PMID- 22928151 TI - Portable RF-Sensor System for the Monitoring of Air Pollution and Water Contamination. AB - Monitoring air pollution including the contents of VOC, O(3), NO(2), and dusts has attracted a lot of interest in addition to the monitoring of water contamination because it affects directly to the quality of living conditions. Most of the current air pollution monitoring stations use the expensive and bulky instruments and are only installed in the very limited area. To bring the information of the air and water quality to the public in real time, it is important to construct portable monitoring systems and distribute them close to our everyday living places. In this work, we have constructed a low-cost portable RF sensor system by using 400 MHz transceiver to achieve this goal. Accuracy of the measurement was comparable to the ones used in the expensive and bulky commercial air pollution forecast systems. PMID- 22928150 TI - Genetic innovation in vertebrates: gypsy integrase genes and other genes derived from transposable elements. AB - Due to their ability to drive DNA rearrangements and to serve as a source of new coding and regulatory sequences, transposable elements (TEs) are considered as powerful evolutionary agents within genomes. In this paper, we review the mechanism of molecular domestication, which corresponds to the formation of new genes derived from TE sequences. Many genes derived from retroelements and DNA transposons have been identified in mammals and other vertebrates, some of them fulfilling essential functions for the development and survival of their host organisms. We will particularly focus on the evolution and expression of Gypsy integrase (GIN) genes, which have been formed from ancient event(s) of molecular domestication and have evolved differentially in some vertebrate sublineages. What we describe here is probably only the tip of the evolutionary iceberg, and future genome analyses will certainly uncover new TE-derived genes and biological functions driving genetic innovation in vertebrates and other organisms. PMID- 22928152 TI - Tissue-engineered skin: bottleneck or breakthrough. AB - During the past few years, tissue-engineered skin constructs has offered great promise in the treatment of deep burns and various skin-related disorders. The overall impact of bioengineered skin research, as a multidisciplinary field, has also enhanced our understanding of the structure-function relations and the physiological processes of tissue regeneration within these constructed three dimensional skin models. Despite of the fact that currently available bioengineered skin products have a range of problems such as patient safety, clinical efficacy and convenience of use, they are still one of the most advanced strategies because of their wide use and potential development in the biomedical field. Here, the challenges and developments in tissue-engineered skin research are discussed. Central to the discussion is the extensive application and future prospects of these bioengineered skin constructs. PMID- 22928153 TI - Primus stove burns: a persisting problem in developing countries. AB - Primus stoves account for a large proportion of burn injuries in the developing world. The mechanism of these injuries is closely linked with factors relating to stove design, fuel characteristics and the socioeconomic profile of victims. We review the current literature on these injuries with particular attention to the injury mechanisms and epidemiological data available. We additionally summarize the initiatives so far developed worldwide for their prevention and define directions for further research into reducing the burden associated with Primus stove burn injuries. PMID- 22928154 TI - Improving the angiogenic potential of collagen matrices by covalent incorporation of Astragalus polysaccharides. AB - The high degree of degradation and the low angiogenic capabilities of temporary tissue substitutes still represent a major challenge in the field of tissue engineering. In an attempt to meet some of these challenges we covalently incorporated Astragalus polysaccharides, a plant extract with angiogenic properties, into collagen matrices. This contribution aims at developing a three dimensional scaffold for temporarily covering tissue defects in tissue engineering and wound healing e.g. third degree burn wounds. Collagen matrices were modified by incorporating Astragalus polysaccharides (Ap) by means of covalent cross-linking with the watersoluble carbodiimide EDC. Matrices with different Ap/EDC ratios were prepared. After intensively washing of collagen matrices, the Ap modified and non-modified collagen matrices were exposed to the chorioallantoic membrane or implanted into subcutaneous pockets of rats. The number of capillaries in the chorioallantoic membrane in the vicinity of the samples, the hemoglobin contents within the explants and the hydroxyproline contents in the tissues attached to the explants were enhanced. Immunohistochemical evaluation of the explants revealed an increase in the recruitment of CD34+-cells in the modified matrices, indicative of improved angiogenic capabilities. To explore the underlying mechanisms, human umbilical vascular endothelial cells (HUVECs) were exposed to varying concentrations of Ap, collagen I and combinations thereof. The proliferative and chemotactic activities of HUVECs, as well as the protein expression of integrin alphaV, were strongly enhanced. The modification of collagen matrices with Astragalus polysaccharides of Ap with the cross-linking agent EDC leads to matrices with an increased angiogenic potential. The angiogenic capabilities of the modified collagen matrices appeared to depend on the Ap to EDC ratio. The presented results demonstrate that the incorporation of Astragalus polysaccharides into collagen matrices is an interesting and promising alternative for making wound dressings more angiogenic and improving their capabilities for covering tissue defects. PMID- 22928155 TI - Will silk fibroin nanofiber scaffolds ever hold a useful place in Translational Regenerative Medicine? AB - Presently, some view silk fibroin-based biomaterials as obsolete, being outperformed by a host of newly discovered biomaterials. But several lines of evidence support the notion that silk fibroin proteins, especially those from B. mori and spiders and their recombinant forms, particularly in the form of electrospun nanofiber scaffolds, still represent promising tools for human tissue engineering/regeneration. Inevitably, the allure of recently reported biomaterials turns away many scientists and resources from the aim of more deeply elucidating the biological interactions of the various kinds of silk fibroin nanofiber scaffolds in vivo. But, even the biological features of newly reported biomaterials are not investigated in adequate depth. Hence, collaborative efforts among biomaterialists, biomedical experts, and private firms must be undertaken on a much greater scale than hitherto done to assess the real usefulness of silk fibroin proteins, thereby allowing or denying their useful introduction into the fields of Translational Regenerative Medicine. PMID- 22928156 TI - Aggregation of erythrocytes in burn disease. AB - The manuscript describes experiments designed to examine factors that influence erythrocytes aggregation within the blood of burn patients. Results showed that the rate and degree of erythrocytes aggregation increased significantly in burn patients, and what is especially unfavorable for microcirculation, erythrocytes disaggregation decreased. We show that normalization of blood plasma contents completely restores erythrocytes aggregation and disaggregation of burn patients. The rate and degree of aggregation was also increased as the fibrinogen concentration increased. It is found that fibrinogen-induced aggregation of erythrocytes is accompanied by "saturation" effect. The aggregation was not affected by monoclonal antibodies against platelet GPIIb/IIIa receptors. The level of oxidized fibrinogen in blood plasma of burn patients increased by about two fold. However, correlation between the level of oxidized fibrinogen and erythrocytes aggregation was not found. The level of medium molecular peptides increased sharply in blood plasma from burn patients. This increase was accompanied by a dose-dependent increase in erythrocytes aggregation. Based on these results the authors conclude that in burn patients erythrocytes aggregation is affected by changes in the contents of blood plasma, specifically fibrinogen and the product of its transformation - fibrin fibrin monomer. PMID- 22928157 TI - Toxic epidermal necrolysis - management issues and treatment options. AB - Toxic epidermal necrolysis (TEN) and Steven-Johnson syndrome (SJS) are characterized by extensive necrosis and cleavage of the epidermis from the dermis akin to a superficial or partial thickness burn. Sepsis is the usual cause of mortality but much of the pathophysiologic process results from an outpouring of cytokines and matrixmetalloproteinases (MMPs) which have a destructive effect on the extracellular matrix and may play a part in the epidermal/dermal cleavage seen with this disease. Recent attention has been focused on the modulation of proteases in an attempt to decrease the MMP-mediated destruction. Nanocrystalline silver (NCS) is one such agent that has good anti-microbial efficacy, but is also effective in modulating MMP levels. Twelve cases of confirmed TEN that were treated with NCS were analyzed with a view to assessing efficacy and setting logical guidelines for managing this condition, particularly in relation to immunosupressed patients. From this study important issues have been highlighted for discussion. PMID- 22928158 TI - The biological roles of ITGB4BP and its potential effect on fibrosis. AB - Fibrosis is the end result of pathologic wound healing and is characterized by inflammation, excessive proliferation of fibroblasts, and abnormal deposition of extracellular matrix (ECM) proteins. Despite the advanced treatments for the fibrotic diseases, as well as the researches on the fibrosis, pathologic fibrotic diseases remain to be hard cured and the molecular mechanism of fibrosis is still unclear. In our previous studies we found ITGB4BP was involved in the myofibroblast differentiation. However there were no studies about the roles of ITGB4BP in fibrosis. On this background this review explores the basic features and the biological function of ITGB4BP which might imply the underlying cellular and molecular mechanism in the regulation of fibrotic diseases. PMID- 22928159 TI - Evolution of a Level I Trauma System: changes in injury mechanism and its impact in the delivery of care. AB - BACKGROUND: Mechanisms of injury in trauma populations evolve over time as a result of system changes, prevention and safety activities, and shifts in population composition. Such changes have implications for reimbursement and resource utilization within all trauma centers. This study examines the evolution of trauma mechanisms at a regional Level I trauma center over 10 years to document the impact of these changes. METHODS: After IRB approval, the trauma registry was queried for total trauma admissions over 10 years. Data points of mechanism of injury, ISS, age, mortality, financial information, and discharge disposition were obtained. Statistical significance was determined by Chi square analysis. RESULTS: Total admissions increased steadily over the course of the 10 years studied. The percentage of motor vehicle crashes (MVC) decreased, while falls increased. Fall patients were older, with lower ISS and with longer length of stay. Mortality rates were higher, but statistically similar to those of the population as a whole. Fall patients were more frequently discharged to skilled nursing facilities. Federally supported Medicare programs increased steadily as a portion of payer mix. CONCLUSIONS: Mechanism of injury within our regional Level I trauma center changed over time with MVC as a percentage of blunt trauma mechanisms decreasing as falls increased. Falls are now a leading mechanism for traumatic injury, even at tertiary referral systems, and will continue to rise in incidence as the population of America ages. This change has direct implications for reimbursement and resource utilization. Current scoring systems employed by trauma centers do not predict this trend well. PMID- 22928160 TI - Burn injury in Bangladesh: electrical injury a major contributor. AB - Electrical injury is a major cause of burn injury and significant cause of mortality, morbidity and disability. To explore the proportional incidence of thermal and electrical burn injuries in Bangladesh, a population-based cross sectional survey was conducted between January and December 2003. Nationally representative data was collected from 171,366 rural and urban households, comprising of a total population of 819,429.The study was designed to describe the proportional incidence of thermal, electrical and chemical cause of burn in Bangladesh. Electrical injury constituted about one third of the total burn injuries. Among the total 1,999 injuries about 31% were due to electrical injuries, about 26% were due to flame, about 25% were due to hot liquid, over 16% by hot object, about 2% by chemical and less than 1% were due to explosives. The incidence of death rate was 3.97 per 100,000 populations per year. Thermal burn was found as the major cause of death due to burn injures and constituted 58% of the total deaths due to burn. Electrical injuries caused 42% of the deaths. It was estimated that more than 5,600 people die due to burn and electrical injuries every year in Bangladesh considering the incidence rate of 3.97 per 100,000 populations per year in the 150 million population. Electrical injury including lightning constitute about one third of the burn related mortality, morbidity and disabilities. Rural people and children are the more vulnerable group. Electrical injury needs to be included as a special component in a burn prevention strategy, particularly in rural Bangladesh. PMID- 22928161 TI - The role of nerve growth factor in the prophylaxis and treatment of diabetic foot ulcers. AB - Diabetic foot ulcers are still particularly difficult to heal. Therefore, preventing and therapeutic adjuncts are increasingly being explored. Nerve growth factor (NGF) is a promising agent exhibiting beneficial actions on both diabetic peripheral neuropathy, one of the main causes of foot ulcers, and on ulcer healing. Indeed, preclinical research in animal models of diabetes has revealed the trophic effect of NGF on small C-fibres, while phase 2 human trials have provided evidence for a favourable effect on sensory neuropathy. However, the results of a phase 3 trial were moderate and, therefore, not enough to encourage widespread use of NGF in the treatment of diabetic neuropathy. Available literature on the role of NGF on diabetic wound healing is sparse but encouraging. Exogenous supplementation of NGF or the use of alternative techniques to increase its endogenous expression could emerge as a protective and therapeutic modality for diabetic foot ulcers in addition to standard treatment and other growth factors. The present review provides an outlook on the role of NGF in the prophylaxis and treatment of diabetic foot ulcers. PMID- 22928162 TI - Computational and systems biology in trauma and sepsis: current state and future perspectives. AB - Trauma, often accompanied by hemorrhage, is a leading cause of death worldwide, often leading to inflammation-related late complications that include sepsis and multiple organ failure. These secondary complications are a manifestation of the complexity of biological responses elicited by trauma/hemorrhage, responses that span most, if not all, cell types, tissues, and organ systems. This daunting complexity at the patient level is manifest by the near total dearth of available therapeutics, and we suggest that this dire condition is due in large part to the lack of a rational, systems-oriented framework for drug development, clinical trial design, in-hospital diagnostics, and post-hospital care. We have further suggested that mechanistic computational modeling can form the basis of such a rational framework, given the maturity of systems biology/computational biology. Herein, we briefly summarize the state of the art of these approaches, and highlight the biological insights and novel hypotheses derived from these approaches. We propose a rational framework for transitioning through the currently fragmented process from identification of biological networks that are potential therapeutic targets, through clinical trial design, to personalized diagnosis and care. Insights derived from systems and computational biology in trauma and sepsis include the centrality of Damage-Associated Molecular Pattern molecules as drivers of both beneficial and detrimental inflammation, along with a novel view of multiple organ dysfunction as a cascade of containment failures with distinct implications for therapy. Finally, we suggest how these insights might be best implemented to drive transformational change in the fields of trauma and sepsis. PMID- 22928163 TI - The Th-17 response and its potential role in post-injury pulmonary complications. AB - Trauma is a leading cause of death and morbidity among all ages and constitutes a major public health problem. This burden is initially directed at stabilizing direct injury, however, post-trauma complications are common and prolong costly ICU stays. Among these complications are acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). While care for these pulmonary complications has now been standardized and prevention continues to improve, the true pathophysiology has not been elucidated. Current evidence suggests that the activation of a pro-inflammatory cascade plays an important role in the pathogenesis of trauma related lung injury. Additionally, there is a novel T-cell response that has been shown to be intricately involved in other non-traumatic lung diseases and multiple inflammatory diseases. With the recent discovery of this novel T-helper subset (Th-17) and the main effector cytokine, IL-17, there is the potential for further categorizing the biologic mechanism leading to ALI and ARDS. By utilizing the discoveries provided by animal models and further investigation into local and systemic cytokine profiles in human trauma victims, the information gained holds promise in the development of unique therapeutic modalities for the treatment and prevention of ARDS following traumatic injury. PMID- 22928164 TI - The role of the TGF-beta family in wound healing, burns and scarring: a review. AB - It is estimated worldwide that over 6 million people per annum experience a burn injury. Despite advances in management and improved survival rates, the incidence of hypertrophic scarring remains high. These scars are particularly common after burns and are often raised, red, hard and may cause abnormal sensations. Such pathological scarring can lead to severe functional impairment, psychological morbidity, and costly long term healthcare. Wound healing is an inherent process which restores the integrity of the skin after injury and although scarring is a frequent by-product, the scarless wound healing observed in early human gestational fetuses suggests that it is not an essential component of the response. This has lead to a large body of research attempting to understand the mechanisms behind scarring and in turn prevent it. One of the main focuses of recent research has been the role played by the growth factor TGF-beta in the process of both wound healing and scar formation. The three isoforms (TGF-beta1, TGF-beta2 and TGF-beta3) appear to have overlapping functions and predominantly mediate their effects through the intracellular SMAD pathway. Initial research suggested that TGF-beta1 was responsible for the fibrotic scarring response whereas the scarless wound healing seen in fetal wounds was due to increased levels of TGF-beta3. However, the reality appears to be far more complex and it is unlikely that simply altering the ratio of TGF-beta isoforms will lead to scarless wound healing. Other aspects of the TGF-beta system that appear promising include the downstream mediator CTGF, the proteoglycan decorin and the binding protein p311. Other putative mechanisms which may underlie the pathogenesis of hypertrophic scars include excessive inflammation, excessive angiogenesis, altered levels of matrix metalloproteinases, growth factors, and delayed apoptosis of fibrotic myofibroblasts either due to p53 genetic alterations or tensile forces across the wound. If an effective treatment for hypertrophic scars following burns injury is to be developed then further work must be carried out to understand the basic mechanisms of pathological scarring. PMID- 22928165 TI - Nanomaterials and nanotechnology for skin tissue engineering. AB - A recent literature review of the field shows that tissue-engineered skin has been in clinical use for the last several decades and that, over this time the technology has advanced rapidly. Despite this progress no synthetic skin yet produced has completely replicated normal, healthy skin. Therefore, researchers must continue to develop materials that successfully overcome the problems with current skin tissue substitutes. This paper is a comprehensive review of the prospects for nanotechnology and nanomaterials to close this gap by mimicking surface properties for reconstruction of a variety of skin tissues. In addition, a number of commercially available products that regenerate different layers of the burn-damaged or chronically wounded skin are reviewed. PMID- 22928166 TI - Effects of In vitro hemodilution, hypothermia and rFVIIa addition on coagulation in human blood. AB - INTRODUCTION: Coagulopathy can occur after hemorrhage, trauma and resuscitation, and has been associated with dilution of coagulation factors and hypothermia. Recombinant activated Factor VII (rFVIIa) has been used, often as a last resort, to improve hemostasis in trauma/hemorrhage patients with coagulopathy. The aim of this study was to further characterize the effects of rFVIIa on various coagulation parameters and the influence of temperature and hemodilution. METHODS: WHOLE BLOOD FROM HEALTHY HUMAN VOLUNTEERS WAS INCUBATED IN A COMBINATION OF THREE CONDITIONS: undiluted or diluted 40% with either lactated Ringer's solution or Hextend, at 37 degrees C or 34 degrees C, and with and without rFVIIa (1.26 MUg/ml, final concentration). Blood or plasma, as appropriate, was measured for coagulation by thrombin generation, thromboelastography (TEG), prothrombin Time (PT) and activated partial thromboplastin (aPTT). RESULTS: Incubation of plasma at 34 degrees C significantly elevated thrombin generation, and prolonged PT and aPTT. Dilution of blood or plasma with 40% Hextend, but not lactated Ringer's, had a significant effect on TEG parameters, and prolonged PT and aPTT. In control conditions (37 degrees C, 0 dilution), the addition of rFVIIa to human plasma or whole blood led to a significant change in all TEG parameters, and Lagtime for thrombin generation, but not to PT or aPTT. CONCLUSION: Theses data show that thrombin generation is affected by hypothermia, but not 40% dilution. TEG is affected by 40% dilution with Hextend, but not by hypothermia. PT and aPTT are significantly affected by both hypothermia and dilution. Recombinant FVIIa caused a greater change in thrombin generation at 34 degrees C as compared to 37 degrees C, and a greater change in PT at 40% dilution, suggesting that the effect of rFVIIa on coagulation is both temperature and dilution dependant. PMID- 22928167 TI - Mangled lower extremity: can we trust the amputation scores? AB - BACKGROUND: Limb injuries represent a constant and severe problem. Several lower limb injuries are more frequent than upper limb injuries. Over time, in an attempt to quantify the severity of traumas and to establish guidelines for the decision whether to save or amputate a mangled extremity, several scoring systems have been reported. Most refer to bone fractures, soft tissue damage, vascular, nerves and tendon lesions. MATERIALS AND METHODS: Articles dealing with mangled lower extremities published in the last 15 years were analyzed. Other inclusion criteriaincluded:articles reporting MESS, PSI, LSI, and Gustillo-Anderson scores, studies based on groups of more than 25 patients, and English language articles. We tried to determine if there was good correlation between amputation recommendations and various scores of injury, with regard to combat wounds and civilian injuries, in adult and pediatric groups. RESULTS: Thirty-two papers fulfilled our criteria; in 17 of these, correlation between mangled extremity scores and the decision to amputate or salvage the limb was well-defined. Good correlation between MESS and amputation was found in 25% of the papers. The highest correlation was found for pediatric injuries and combined adult and pediatric combat injuries. CONCLUSIONS: The mangled extremity is a long-lasting, unsolved problem, with much debate and a large number of protocols and scoring systems, but with no unanimously-accepted solution. Many mangled extremities are borderline cases, and the decision to amputate or to salvage a limb must be carefully assessed. With advances in the medical field over the last 15 years, more mangled lower extremities are salvaged, especially in civilian injuries. PMID- 22928169 TI - International Journal of Burns and Trauma: Editorial Board (2012) e-Century Publishing Corporation. PMID- 22928168 TI - Screening of potential small volume resuscitation products using a severe hemorrhage sedated swine model. AB - BACKGROUND: Small volumes of resuscitation products to sustain survival until definitive care are desired in extreme environments due to limited resources. A severe controlled hemorrhage model in sedated, sexually mature miniature swine has been developed to evaluate these products. Valproic Acid (VPA) and Pentoxifylline (PTX) have been suggested as potential products for small volume resuscitation following hemorrhage predominately in anesthetized small animal models. We evaluated the survival time of VPA and PTX in the swine model. METHODS: Fifteen male miniature swine weighing 41.1 +/- 2.9 kg were sedated and hemorrhaged 60% of estimated blood volume over 1 hr and treated with one of the following: 1) VPA at 400 mg/kg in a volume of 1.33 ml/kg over 2 min (n=4); 2) VPA at 300 mg/kg in a volume of 2 ml/kg over 30 min (n=3); 3) PTX at 50 mg/kg in a volume of 2 ml/kg over 2 min (n=4); 4) saline vehicle at 2 ml/kg over 2 min (n=4). Survival times were compared to non-resuscitated historic controls (n=16). Survival was determined from the end of hemorrhage/initiation of treatment. RESULTS: Median (95% CI) survival times were: Control 55.7 (17.5 - 86) min; VPA (400 mg/kg) 6 (4 - 8) min; VPA (300 mg/kg) 17.5 (12 - 24.5) min; PTX 60.8 (21 - 75) min; and vehicle 92 (15 - 180) min. No treatment increased survival time compared to controls and there were no significant differences in percent survival among groups. CONCLUSION: In this sedated severe hemorrhage model VPA and PTX were unacceptable as small volume resuscitation products at the concentrations and delivery rates used because of early deaths. Considering that these drugs are FDA approved for other indications at lower doses the present data suggest that further investigation of mechanisms involved are warranted. PMID- 22928170 TI - Screening for chronic kidney disease: U.S. Preventive Services Task Force recommendation statement. AB - DESCRIPTION: New U.S. Preventive Services Task Force (USPSTF) recommendation statement on screening for chronic kidney disease (CKD). METHODS: The USPSTF reviewed evidence on screening for CKD, including evidence on screening, accuracy of screening, early treatment, and harms of screening and early treatment. POPULATION: This recommendation applies to asymptomatic adults without diagnosed CKD. Testing for and monitoring CKD for the purpose of chronic disease management (including testing and monitoring patients with diabetes or hypertension) are not covered by this recommendation. RECOMMENDATION: The USPSTF concludes that the evidence is insufficient to assess the balance of benefits and harms of routine screening for CKD in asymptomatic adults (I statement). PMID- 22928172 TI - The overuse of diagnostic imaging and the Choosing Wisely initiative. PMID- 22928173 TI - Comparative effectiveness of warfarin and new oral anticoagulants for the management of atrial fibrillation and venous thromboembolism: a systematic review. AB - BACKGROUND: New oral anticoagulants (NOACs), including direct thrombin inhibitors (DTIs) and factor Xa (FXa) inhibitors, are emerging alternatives for prophylaxis and treatment of atrial fibrillation (AF) and venous thromboembolism (VTE). PURPOSE: To compare the benefits and harms of NOACs versus warfarin for AF and VTE. DATA SOURCES: MEDLINE, EMBASE, and the Cochrane Database of Systematic Reviews from January 2001 through July 2012; U.S. Food and Drug Administration (FDA) database for adverse event reports. STUDY SELECTION: English-language, randomized, controlled trials (RCTs) comparing NOACs with warfarin for management of AF or VTE and observational studies and FDA reports on adverse effects. DATA EXTRACTION: Two independent reviewers abstracted data and rated study quality and strength of evidence. DATA SYNTHESIS: Six good-quality RCTs compared NOACs (2 DTI studies, 4 FXa inhibitor studies) with warfarin. In AF, NOACs decreased all-cause mortality (risk ratio [RR], 0.88 [95% CI, 0.82 to 0.96]); in VTE, NOACs did not differ for mortality or VTE outcomes. Across indications, adverse effects of NOACs compared with warfarin were fatal bleeding (RR, 0.60 [CI, 0.46 to 0.77]), major bleeding (RR, 0.80 [CI, 0.63 to 1.01]), gastrointestinal bleeding (RR, 1.30 [CI, 0.97 to 1.73]), and discontinuation due to adverse events (RR, 1.23 [CI, 1.05 to 1.44]). Subgroup analyses suggest a higher risk for myocardial infarction with DTIs than with FXa inhibitors. Bleeding risk for NOACs may be increased in persons older than 75 years or those receiving warfarin who have good control. LIMITATION: There were no head-to-head comparisons of NOACs and limited data on harms. CONCLUSION: New oral anticoagulants are a viable option for patients receiving long-term anticoagulation. Treatment benefits compared with warfarin are small and vary depending on the control achieved by warfarin treatment. PRIMARY FUNDING SOURCE: Department of Veterans Affairs. PMID- 22928174 TI - Ethics of commercial screening tests. PMID- 22928175 TI - Complications associated with alloplastic implants in rhinoplasty. AB - OBJECTIVE: To evaluate the incidence of infection and extrusion of porous high density polyethylene (pHDPE) and expanded polytetrafluoroethylene (ePTFE) implants used in rhinoplasty at a high-volume, academic facial plastic surgery practice. METHODS: A total of 662 rhinoplasty procedures performed by 3 faculty surgeons from 1999 to 2008 were retrospectively reviewed. Patient demographics, medical comorbidities, operative details, and postoperative course findings were collected from patient records. RESULTS: The incidence of postoperative infection was 2.8% (19 of 662 patients). In each case of infection, alloplastic material had been used. Infections occurred in 1 in 5 rhinoplasty procedures in which pHDPE implants were used. In patients in whom ePTFE was used alone, the infection rate was 5.3%. Exposure developed in 12% of patients in whom an alloplast was used during surgery. Factors notably not associated with infection on bivariate analysis included sex, surgeon, purpose of procedure (functional vs cosmetic), current tobacco use, or history of cocaine use (P > .05 for all). CONCLUSIONS: To our knowledge, this study represents the largest evaluation of the use of pHDPE implants in rhinoplasty to date. Our findings are in contrast to those of previous studies regarding the use of pHDPE in rhinoplasty and parallel to those regarding the use of ePTFE. Caution is strongly recommended when considering the use of pHDPE in rhinoplasty. PMID- 22928176 TI - Long-acting beta2-agonist step-off in patients with controlled asthma. AB - BACKGROUND: Because of concerns about the safety of long-acting beta(2)-agonist (LABA) use in patients with asthma, withdrawal of the LABA is recommended by the US Food and Drug Administration once asthma is controlled by combination therapy with a LABA and inhaled corticosteroid (ICS). OBJECTIVE: To perform a systematic review and meta-analysis assessing evidence supporting the discontinuation of LABA therapy once asthma control has been achieved with a combination of ICS and LABA. DATA SOURCES: MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials databases were searched (through August 2010), references of identified studies and selected narrative review articles were evaluated, registries of clinical trials were reviewed, and manufacturers of LABAs were contacted. STUDY SELECTION: Randomized controlled trials of discontinuation of LABA therapy in patients with asthma controlled with a combination of ICS and LABA. DATA EXTRACTION: Two reviewers independently screened each title and abstract in the initial searches and then the full text of each nominated article to extract data for analyses. RESULTS: Of 1492 screened articles, only 5 trials involving patients aged 15 years or older fulfilled a priori-specified inclusion criteria. Results did not favor the LABA step-off approach compared with no change in treatment. The LABA step-off regimen increased asthma impairment, with worse Asthma Quality of Life Questionnaire score (mean difference [95% CI], 0.32 [0.14 0.51] points lower); worse Asthma Control Questionnaire score (0.24 [0.13-0.35] points higher); fewer symptom-free days (9.15% [1.62%-16.69%] less); and greater risk of withdrawal from study resulting from lack of efficacy or loss of asthma control (risk ratio, 3.27 [2.16-4.96]). Risk of exacerbations and deaths after LABA step-off were not evaluable because of the small number of events and short duration of follow-up. CONCLUSIONS: Evidence suggests that discontinuing LABA therapy in adults and older children with asthma controlled with a combination of ICSs and LABAs results in increased asthma-associated impairment. Additional trials measuring all long-term patient-important outcomes are needed. PMID- 22928177 TI - A sense of calling and primary care physicians' satisfaction in treating smoking, alcoholism, and obesity. PMID- 22928179 TI - Thriving of the fittest: comment on "fitness and the development of chronic conditions in later life". PMID- 22928178 TI - Midlife fitness and the development of chronic conditions in later life. AB - BACKGROUND The association between cardiorespiratory fitness (fitness) and mortality is well described. However, the association between midlife fitness and the development of nonfatal chronic conditions in older age has not been studied. METHODS To examine the association between midlife fitness and chronic disease outcomes in later life, participant data from the Cooper Center Longitudinal Study were linked with Medicare claims. We studied 18 670 healthy participants (21.1% women; median age, 49 years) who survived to receive Medicare coverage from January 1, 1999, to December 31, 2009. Fitness estimated by Balke treadmill time was analyzed as a continuous variable (in metabolic equivalents [METs]) and according to age- and sex-specific quintiles. Eight common chronic conditions were defined using validated algorithms, and associations between midlife fitness and the number of conditions were assessed using a modified Cox proportional hazards model that stratified the at-risk population by the number of conditions while adjusting for age, body mass index, blood pressure, cholesterol and glucose levels, alcohol use, and smoking. RESULTS After 120 780 person-years of Medicare exposure with a median follow-up of 26 years, the highest quintile of fitness (quintile 5) was associated with a lower incidence of chronic conditions compared with the lowest quintile (quintile 1) in men (15.6 [95% CI, 15.0-16.2] vs 28.2 [27.4-29.0] per 100 person-years) and women (11.4 [10.5-12.3] vs 20.1 [18.7 vs 21.6] per 100 person-years). After multivariate adjustment, higher fitness (in METs) was associated with a lower risk of developing chronic conditions in men (hazard ratio, 0.95 [95% CI, 0.94-0.96] per MET) and women (0.94 [0.91-0.96] per MET). Among decedents (2406 [12.9%]), higher fitness was associated with lower risk of developing chronic conditions relative to survival (compression hazard ratio, 0.90 [95% CI, 0.88-0.92] per MET), suggesting morbidity compression. CONCLUSIONS In this cohort of healthy middle-aged adults, fitness was significantly associated with a lower risk of developing chronic disease outcomes during 26 years of follow-up. These findings suggest that higher midlife fitness may be associated with the compression of morbidity in older age. PMID- 22928180 TI - Black clouds and black boxes: comment on "Long-acting beta2-agonist step-off in patients with controlled asthma". PMID- 22928182 TI - Reducing radiology use on an inpatient medical service: choosing wisely. PMID- 22928181 TI - Comparative effectiveness of 2 beta-blockers in hypertensive patients. AB - BACKGROUND: Randomized controlled trials have demonstrated the efficacy of selected beta-blockers for preventing cardiovascular (CV) events in patients following myocardial infarction (MI) or with heart failure (HF). However, the effectiveness of beta-blockers for preventing CV events in patients with hypertension has been questioned recently, but it is unclear whether this is a class effect. METHODS: Using electronic medical record and health plan data from the Cardiovascular Research Network Hypertension Registry, we compared incident MI, HF, and stroke in patients who were new beta-blocker users between 2000 and 2009. Patients had no history of CV disease and had not previously filled a prescription for a beta-blocker. Cox proportional hazards regression was used to examine the associations of atenolol and metoprolol tartrate with incident CV events using both standard covariate adjustment (n = 120,978) and propensity score-matching methods (n = 22,352). RESULTS: During follow-up (median, 5.2 years), there were 3517 incident MI, 3272 incident HF, and 3664 incident stroke events. Hazard ratios for MI, HF, and stroke in metoprolol tartrate users were 0.99 (95% CI, 0.97-1.02), 0.99 (95% CI, 0.96-1.01), and 0.99 (95% CI, 0.97-1.02), respectively. An alternative approach using propensity score matching yielded similar results in 11,176 new metoprolol tartrate users, who were similar to 11,176 new atenolol users with regard to demographic and clinical characteristics. CONCLUSIONS: There were no statistically significant differences in incident CV events between atenolol and metoprolol tartrate users with hypertension. Large registries similar to the one used in this analysis may be useful for addressing comparative effectiveness questions that are unlikely to be resolved by randomized trials. PMID- 22928183 TI - Observational comparative effectiveness studies of drug therapies: high-quality answers or important clinical questions?: comment on "Comparative effectiveness of 2 beta-blockers in hypertensive patients". PMID- 22928184 TI - Association of changes in clinical characteristics and management with improvement in survival among patients with ST-elevation myocardial infarction. AB - CONTEXT: The contemporary decline in mortality reported in patients with ST segment elevation myocardial infarction (STEMI) has been attributed mainly to improved use of reperfusion therapy. OBJECTIVE: To determine potential factors beyond reperfusion therapy-associated with improved survival in patients with STEMI over a 15-year period. DESIGN, SETTING, AND PATIENTS: Four 1-month French nationwide registries, conducted 5 years apart (between 1995, 2000, 2005, 2010), including a total of 6707 STEMI patients admitted to intensive care or coronary care units. MAIN OUTCOME MEASURES: Changes over time in crude 30-day mortality, and mortality standardized to the 2010 population characteristics. RESULTS: Mean (SD) age decreased from 66.2 (14.0) to 63.3 (14.5) years, with a concomitant decline in history of cardiovascular events and comorbidities. The proportion of younger patients increased, particularly in women younger than 60 years (from 11.8% to 25.5%), in whom prevalence of current smoking (37.3% to 73.1%) and obesity (17.6% to 27.1%) increased. Time from symptom onset to hospital admission decreased, with a shorter time from onset to first call, and broader use of mobile intensive care units. Reperfusion therapy increased from 49.4% to 74.7%, driven by primary percutaneous coronary intervention (11.9% to 60.8%). Early use of recommended medications increased, particularly low-molecular-weight heparins and statins. Crude 30-day mortality decreased from 13.7% (95% CI, 12.0-15.4) to 4.4% (95% CI, 3.5-5.4), whereas standardized mortality decreased from 11.3% (95% CI, 9.5-13.2) to 4.4% (95% CI, 3.5-5.4). Multivariable analysis showed a consistent reduction in mortality from 1995 to 2010 after controlling for clinical characteristics in addition to the initial population risk score and use of reperfusion therapy, with odds mortality ratios of 0.39 (95%, 0.29-0.53, P <.001) in 2010 compared with 1995. CONCLUSION: In France, the overall rate of cardiovascular mortality among patients with STEMI decreased from 1995 to 2010, accompanied by an increase in the proportion of women younger than 60 years with STEMI, changes in other population characteristics, and greater use of reperfusion therapy and recommended medications. PMID- 22928186 TI - Early warning systems: help or hindrance? PMID- 22928185 TI - An uncommon cause of intracerebral hemorrhage in a healthy truck driver. AB - OBJECTIVES: To describe a case and review literature for intracerebral hemorrhage caused by migraine. DESIGN: Case report. SETTING: Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts. PATIENT: A 54-year-old truck driver with a 2-year history of atypical headaches. RESULTS: A 54-year-old right-handed truck driver was seen in consultation with a 2-year history of atypical headaches.The headaches were dull, throbbing, gradually progressive,and limited over the left occipital area. They were accompanied by right visual field deficit, diplopia, and,at times, confusion. These headaches were notably different from the usual migraine headaches he had been having for more than 20 years. Brain imaging revealed left parieto-occipital lobar hemorrhage. Further investigations ruled out arteriovenous malformations. He did not have any vascular risk factors, including hypertension. Migraine-associated intracerebral hemorrhage was considered to be the most likely diagnosis. CONCLUSIONS: Intracerebral hemorrhage associated with migraine is believed to result from vasoconstriction leading to ischemia of the walls of blood vessels, making them leaky and porous. It is important to be aware of this phenomenon because vasoactive medications used to treat migraine can further aggravate the vasoconstriction and hence the intracerebral bleed. PMID- 22928187 TI - America takes action on disease prevention. PMID- 22928188 TI - Malawi breathes new life into childhood pneumonia care. PMID- 22928189 TI - Profile: NIH's disease detectives. PMID- 22928190 TI - Apologising for Nazi medicine: a constructive starting point. PMID- 22928191 TI - Large B-cell non-Hodgkin lymphoma relapsing with meningeal localization. PMID- 22928195 TI - [How can we make child and adolescent psychiatry attractive for young clinicians?]. PMID- 22928196 TI - Supplements: a scorecard. PMID- 22928197 TI - Palliative care: surprising benefits from an underused therapy. PMID- 22928198 TI - On call. In your October 2010 issue you discussed blood in the urine. I don't have that problem, but during my annual checkup last week, my doctor found protein in my urine. Is it a serious problem? And what should I do about it? PMID- 22928199 TI - On call. I am a 73-year-old man and I've been diagnosed with epididymitis, which has been quite painful--to say the least. I would appreciate your comments about the cause, cure, and any other implications of having this problem. PMID- 22928200 TI - On call. My 59-year-old husband just came home after being hospitalized for a mild heart attack. He was only in the hospital for five days and he feels great, though he does have to take three prescription medicines plus aspirin. I'm writing because my husband 's doctor doesn't want him to go back to work for another six weeks even though his job doesn't involve any lifting. I think the stress of staying home would be worse that going to work. Please advise. PMID- 22928201 TI - When sex gives more pain than pleasure. Dyspareunia is a common problem for many postmenopausal women. PMID- 22928202 TI - Managing osteoarthritis of the knee. There are many treatments short of surgical replacement. PMID- 22928203 TI - Compression stockings after deep-vein thrombosis: knee-highs or thigh-highs? PMID- 22928204 TI - Ask the doctor. I've seen advertisements for mangosteen juice claiming it has lots of antioxidants and health benefits, including anticancer effects. Is there any truth to this? PMID- 22928205 TI - Ask the doctor. I like to look tanned, but I'm somewhat fair-skinned and can't be in the sun much. Are self-tanning lotions and sprays a good idea? Are they safe? PMID- 22928206 TI - Ask the doctor. In the January issue, you recommended the Harvard Healthy Eating Plate, which includes only one to two servings of dairy a day. Don't we need more than that to get enough calcium? PMID- 22928207 TI - Tendon pain: don't assume it's tendinitis. PMID- 22928208 TI - Controlling essential tremor. PMID- 22928209 TI - Are you at risk for oral cancer? PMID- 22928210 TI - When a common prostate problem persists. PMID- 22928211 TI - I've been diagnosed with diverticulosis. Does this mean I can no longer eat nuts and seeds? PMID- 22928213 TI - Alleviating MRI anxiety: know what to expect. PMID- 22928212 TI - How do I get rid of a toenail fungus? PMID- 22928214 TI - Photoreduction of NADP(+) in photosystem II of higher plants: requirement for manganese. AB - The effects of reversible managanese extraction on NADP(+) photoreduction were studied with higher plant subchloroplast preparations of photosystem II (PS II). Under anaerobic conditions, when the reaction centers (RCs) of PS II are "closed" (i.e. in the state [P680 Pheo] QA), and in the presence of ferredoxin-ferredoxin NADP(+) reductase, NADP(+) reduction is observed at a rate of 0.8-1.1 MUmol/mg x chlorophyII x h. After complete removal of manganese from PS II, the rate of NADP(+) reduction is reduced 40-5- fold. Upon the addition of Mn at a concentration of approx. 4 Mn atoms per reaction center, the NADP reduction is restored up to 85-90% of the initial value, When half of this amount of Mn is combined with about 40 times of the equivalent concentration of other divalent ions (Ca2+, Sr2+, Mg2+ etc) the reaction is also reactivated. Dinoseb (10-6M) an inhibitor of electron transfer in PS II prevents NADP(+) photoreduction. It is concluded that under conditions when the first quinone acceptor, Q(A), is in its reduced state (QA), electrons are transferred from reduced pheophytin (Pheo(-)) to NADP(+), indicating that PS II can reduce NADP(+) without the participation of PS I. On the basis of these and literature data, and alternate pathway for electron phototransfer in PS II reaction centers of higher plants is suggested. Some problems concerning the Z-scheme are discussed. PMID- 22928215 TI - [Magnetic interaction of manganese with pheophytin anion-radical and chlorophyll cation-radical in reaction centers of the photosystem II]. AB - The influence of Mn on saturation curves of ESR spectra of Ph(-) and P(+)(680) at 1-200K in samples with different content of Mn has been studied. An analysis of these data and those on photoinduced changes of fluorescence yield of chlorophyll leads to the conclusion that the Mn-containing centre in Photosystem 2 is a cluster of 4 Mn atoms, two of which can be replaced by Mg(2+) or any other divalent metal. The distances between Mn Na Ph as well as between Mn and P(680) have been estimated. PMID- 22928216 TI - [ESR signals of photosystem II after complete removal of manganese from pea subchloroplast particles]. AB - The effect of reversible extraction of Mn on ESR signal II arising from the oxidized secondary electron donor (Z+) and the ESR doublet signal related to reduced spin-coupled pheophytin (pheo -) and "primary" electron acceptor (PA- -Fe (2+)) has been studied in oxygen evolving preparations of the photosystem 2. It is demonstrated that Mn extraction does not affect both dark and photoinduced ESR signal II and ESR doublet. A conclusion is made that Mn is not a component of the secondary electron donor Z of the Photosystem 2 and its complete removal has no effect on the exchange interaction of Pheo(-) and the PQ(-) -Fe(2+) complex. PMID- 22928218 TI - [Epidemiology of world health. Abstracts of the Congress of International Epidemiology. September 12-14, 2012. Brussels, Belgium]. PMID- 22928217 TI - [Effect of light-harvesting complex reduction on the photosynthetic unit value and the number of reaction centers in photosystems from mutants of Chlamydomonas reinhardtii]. PMID- 22928219 TI - [Study of oxygen accumulation in pea chloroplasts with spin labels]. AB - Oxygen evolution in chloroplasts was studied by nitroxide fatty probes, introduced into chloroplasts membranes. The values of K(e)[O2] were determined from the measuring kinetics of nitroxide reduction under permanent illumination at two values of the microwave field, where K(e) was the constant of spin exchange between nitroxide and oxygen, [O2] --oxygen concentration. It was shown that in chloroplasts membranes, in contrast to liposomes there was no oxygen in the dark. This observation can be explained by oxygen consumption in various biochemical reactions. The values of K(e)[O2] were measured under permanent illumination. The highest value of K(e)[O2]=1.2.10(-5) s(-2) was observed in the middle of the membrane. At temperatures above 400C and below -200C oxygen was not evolved. PMID- 22928220 TI - Addressing women's health needs and improving birth outcomes: results from a peer to-peer state Medicaid learning project. AB - High rates of maternal mortality, infant mortality, and preterm births, as well as continuing disparities in pregnancy outcomes, have prompted a number of state Medicaid agencies to focus on improving the quality and continuity of care delivered to women of childbearing age. As part of a peer-to-peer learning project, seven Medicaid agencies worked to develop the programs, policies, and infrastructures needed to identify and reduce women's health risks either prior to or between pregnancies. The states also identified public health strategies. These strategies led to a policy checklist to help leaders in other states identify improvement opportunities that fit within their programs' eligibility requirements, quality improvement objectives, and health system resources. Many of the identified programs and policies may help states use the upcoming expansion of the Medicaid program to improve women's health and thereby reduce adverse birth outcomes. PMID- 22928221 TI - Hospitals on the path to accountable care: highlights from a 2011 national survey of hospital readiness to participate in an accountable care organization. AB - Accountable care organizations (ACOs) are forming in communities across the country. In ACOs, health care providers take responsibility for a defined patient popu-lation, coordinate their care across settings, and are held jointly accountable for the quality and cost of care. This issue brief reports on results from a survey that assesses hospitals' readiness to participate in ACOs. Results show we are at the beginning of the ACO adop-tion curve. As of September 2011, only 13 percent of hospital respondents reported partici-pating in an ACO or planning to participate within a year, while 75 percent reported not considering participation at all. Survey results indicate that physician-led ACOs are the second most common governance model, far exceeding payer-led models, highlighting an encouraging paradigm shift away from acute care and toward primary care. Findings also point to significant gaps, including the infrastructure needed to take on financial risks and to manage population health. PMID- 22928222 TI - Including safety-net providers in integrated delivery systems: issues and options for policymakers. AB - Health care reform legislation has spurred efforts to develop integrated health care delivery systems that seek to coordinate the continuum of health services. These systems may be of particular benefit to patients who face barriers to accessing care or have multiple health conditions. But it remains to be seen how safety-net providers, including community health centers and public hospitals- which have long experience in caring for these vulnerable populations--will be included in integrated delivery systems. This issue brief explores key considerations for incorporating safety-net providers into integrated delivery systems and discusses the roles of state and federal agencies in sup-porting and testing models of integrated care delivery. The authors conclude that the most important principles in creating integrated delivery systems for vulnerable populations are: (1) an emphasis on primary care; (2) coordination of all care, including behavioral, social, and public health services; and (3) accountability for population health outcomes. PMID- 22928223 TI - Skin collagen in rheumatoid arthritis, and the effect of corticosteroids. PMID- 22928224 TI - [New concept of TIA and its countermeasure]. PMID- 22928225 TI - Simulation in Kansas practical nursing programs. AB - This article discusses the lack of pediatric clinical experiences for practical nursing programs in Kansas (specifically in the Kansas City, Kansas Metropolitan area). The need for pediatric experience along with how pediatric simulation experience can enhance these programs is discussed. A quantitative research study evaluating at how implementation of a simulation activity into the practical nurse core curriculum impacts knowledge, student confidence, and satisfaction is explored. PMID- 22928226 TI - Transitioning the practical nursing student into practice: outcomes of a geriatric initiative. AB - Schools of nursing for practical nursing students typically follow the traditional model of acute care facilities. The purpose of this pilot study was to evaluate an initiative project examining the use of a skilled nursing facility as a final clinical site in a practical nursing program. The pilot study proved to generate a successful academic and practice partnership between the school of nursing and skilled nursing facility, provide opportunities for students to gain confidence and practice in caring for older adults, and meet the goals and outcomes of the clinical practicum. Clinical experiences offered in a skilled nursing facility prepare practical nursing students to care for older adults and transition from student to graduate. PMID- 22928227 TI - Robotics in nursing. PMID- 22928229 TI - What kind of doctor am I? PMID- 22928228 TI - Meeting today's challenge. PMID- 22928230 TI - Office screening for dementia. PMID- 22928231 TI - Clinical and pathological examples of Alzheimer's disease, dementia with Lewy bodies, and frontotemporal dementia. AB - Dementia syndromes usually consist of distinct clinical and pathological phenotypes. A careful history is required to document the onset and progression of symptoms to generate the differential diagnosis. New biomarker tests can provide evidence to increase diagnostic certainty. Disease-specific interventions, based on advances in genetic and molecular biomarkers, are likely to have the greatest impact when given in preclinical and early symptomatic phases. PMID- 22928232 TI - Depression and the aging brain. PMID- 22928233 TI - Treatment of neuropsychiatric symptoms in dementia. PMID- 22928234 TI - Delirium in the elderly. PMID- 22928235 TI - Managing older adult driving safety in the primary care setting. PMID- 22928236 TI - Family caregiving during healthy aging and illness. PMID- 22928237 TI - Rhode Island Children's Hospital Emergency Department visits for oral health conditions, 2006 - 2010. PMID- 22928238 TI - Eastern equine encephalitis: MRI findings in two patients. PMID- 22928239 TI - When regulations and quality of life clash. PMID- 22928240 TI - I want to be at least a 10: the impact of changes in metrics and labeling for ESAs. PMID- 22928241 TI - A crucial lifeline: reducing mortality in the first 120 days. AB - Data from the United States Renal Data System shows that mortality and hospitalization rates for prevalent ESRD patients is high and has only gradually improved year after year. Furthermore, the same rates are even higher for patients in the first year of care, especially the first 120 days. Renal Ventures Coaching for Actions, Results, and Empowerment (RVCARE) was developed to reduce the high mortality and hospitalization risk, improve cardiovascular disease, decrease the use of catheters, offer optimal modalities of therapy, and change other outcomes in incident patients undergoing in-center hemodialysis. The results demonstrate that it is indeed possible to positively affect these outcomes, even in a small dialysis organization (SDO). PMID- 22928242 TI - Should we limit participation in the ESRD Program? PMID- 22928243 TI - Joint Commission Center for Transforming Healthcare releases targeted solutions tool for hand-off communications. PMID- 22928244 TI - Managing corridor clutter--part 1. PMID- 22928245 TI - Clarification: Eligibility for advanced inpatient diabetes care certification. PMID- 22928246 TI - Safer drugs for kids. PMID- 22928247 TI - Brain science in the classroom. PMID- 22928248 TI - How healthy is your ocean? PMID- 22928249 TI - Ready, set, implant. PMID- 22928250 TI - The import of the Higgs boson. PMID- 22928252 TI - Meteor hunt. PMID- 22928251 TI - Not worth the risk? For bank robbers, crime rarely pays. PMID- 22928253 TI - Chickpea revolution. A better bean is boosting Ethiopia's economy. PMID- 22928254 TI - I think, therefore I spell. PMID- 22928255 TI - Clean sweep. PMID- 22928256 TI - Hollywood Killed the video star. PMID- 22928257 TI - Super Humanity. PMID- 22928258 TI - Can we keep getting smarter? PMID- 22928259 TI - The case of the sleeping slayer. PMID- 22928260 TI - How we all will live to be 100. PMID- 22928262 TI - The edge of ambition. 10 projects that push the boundaries of the engineered world. PMID- 22928261 TI - Mind in motion. PMID- 22928263 TI - Machines of the infinite. PMID- 22928264 TI - Questions for the next million years. PMID- 22928265 TI - The great climate experiment. PMID- 22928266 TI - Beyond the quantum horizon. PMID- 22928267 TI - Conspiracy contradictions. Why people who believe in one conspiracy are prone to believe others. PMID- 22928268 TI - Which creatures live the longest? The key indicator for animals may be total energy expended over a lifetime. PMID- 22928269 TI - The cardiovascular physician assistant: the angel in the room. PMID- 22928271 TI - Is this papule on the thigh concerning? PMID- 22928270 TI - Can coconut oil replace caprylidene for Alzheimer disease? PMID- 22928272 TI - Bloodstream infections: the risks and benefits of intravascular catheters. PMID- 22928273 TI - Multiple sclerosis: a comprehensive review for the physician assistant. PMID- 22928274 TI - Statin-induced rhabdomyolysis and dermatomyositis: a rare combination. PMID- 22928275 TI - Effects of online genetics education on physician assistant interviewing skills. AB - OBJECTIVES: This study was designed to evaluate the impact of an Internet-based educational program on clinically relevant communication behaviors. METHODS: A randomized trial enrolled 50 physician assistants (PAs); 40 PAs completed the trial (18 in the intervention group and 22 in the control group). Participants conducted simulated visits that were coded for completeness of family history, referral for genetic services, and overall interviewing style using the Roter Interaction Analysis System (RIAS). RESULTS: Compared with PAs in the control group, PAs who took the Web course elicited more complete family histories (7.2 vs 5.0 of a 13-member pedigree; t = 2.3, P < .05) and more detailed cancer histories (3.2 vs 2.3 of five affected family members; t = 2.7, P < .001) but did not make more genetics referrals. Overall, intervention-group PAs used a less patient-centered interviewing style than controls (1.9 vs 3.2; t = 2.8, P < .01). CONCLUSIONS: More comprehensive assessment of family history was associated with lower patient-centeredness, suggesting a need for caution with regard to unintended consequences of targeted communication interventions on interviewing style. PMID- 22928276 TI - Avoiding overtransfusion: an update on risks and latest indications. PMID- 22928277 TI - A gynecologic approach to evaluation of pelvic masses in women. PMID- 22928278 TI - The safety and efficacy of physician assistants as first assistant surgeons in cardiac surgery. AB - This study is a retrospective review of 956 patients comparing cases first assisted by physician assistants (PAs) to those first-assisted by surgeons, examining whether PAs can function safely and efficiently in the role of first assistant surgeon for cardiac surgery. No differences were found between the two cohorts. PMID- 22928279 TI - Leadership case study: Martha Flores, PA-C. PMID- 22928280 TI - Does lubricant adversely affect the results of conventional cervical cytology? PMID- 22928281 TI - Tanning bed use causes melanoma. PMID- 22928282 TI - On taking down a colleague: is there an ethical mandate to report? PMID- 22928283 TI - Calcification and atrophy of the hand, arm, and elbow. PMID- 22928284 TI - Kitchen medicine: focusing in an obscure diagnosis. PMID- 22928285 TI - Case of the month. Intussusception. PMID- 22928286 TI - Phosphine resistance in Tribolium castaneum and Rhyzopertha dominica from stored wheat in Oklahoma. AB - Phosphine gas, or hydrogen phosphide (PH3), is the most common insecticide applied to durable stored products worldwide and is routinely used in the United States for treatment of bulk-stored cereal grains and other durable stored products. Research from the late 1980s revealed low frequencies of resistance to various residual grain protectant insecticides and to phosphine in grain insect species collected in Oklahoma. The present work, which used the same previously established discriminating dose bioassays for phosphine toxicity as in the earlier study, evaluated adults of nine different populations of red flour beetle, Tribolium castaneum (Herbst), and five populations of lesser grain borer, Rhyzopertha dominica (F.) collected from different geographic locations in Oklahoma. One additional population for each species was a laboratory susceptible strain. Discriminating dose assays determined eight out of the nine T. castaneum populations, and all five populations of R. dominica, contained phosphine resistant individuals, and highest resistance frequencies were 94 and 98%, respectively. Dose-response bioassays and logit analyses determined that LC99 values were approximately 3 ppm for susceptible and 377 ppm for resistant T. castaneum, and approximately 2 ppm for susceptible and 3,430 ppm for resistant R. dominica. The most resistant T. castaneum population was 119-fold more resistant than the susceptible strain and the most resistant R. dominica population was over 1,500-fold more resistant. Results suggest a substantial increase in phosphine resistance in these major stored-wheat pests in the past 21 yr, and these levels of resistance to phosphine approach those reported for other stored grain pest species in other countries. PMID- 22928287 TI - Estimating the economic cost of one of the world's major insect pests, Plutella xylostella (Lepidoptera: Plutellidae): just how long is a piece of string? AB - Since 1993, the annual worldwide cost of diamondback moth, Plutella xylostella (L.) (Lepidoptera: Plutellidae), control has been routinely quoted to be US$1 billion. This estimate requires updating and incorporation of yield losses to reflect current total costs of the pest to the world economy. We present an analysis that estimates what the present costs are likely to be based on a set of necessary, but reasoned, assumptions. We use an existing climate driven model for diamondback moth distribution and abundance, the Food and Agriculture Organization country Brassica crop production data and various management scenarios to bracket the cost estimates. The "length of the string" is somewhere between US$1.3 billion and US$2.3 billion based on management costs. However, if residual pest damage is included then the cost estimates will be even higher; a conservative estimate of 5% diamondback moth-induced yield loss to all crops adds another US$2.7 billion to the total costs associated with the pest. A conservative estimate of total costs associated with diamondback moth management is thus US$4 billion-US$5 billion. The lower bound represents rational decision making by pest managers based on diamondback moth abundance driven by climate only. The upper estimate is due to the more normal practice of weekly insecticide application to vegetable crops and the assumption that canola (Brassica napus L.) is treated with insecticide at least once during the crop cycle. Readers can decide for themselves what the real cost is likely to be because we provide country data for further interpretation. Our analysis suggests that greater efforts at implementation of even basic integrated pest management would reduce insecticide inputs considerably, reducing negative environmental impacts and saving many hundreds of millions of dollars annually. PMID- 22928288 TI - Characteristics of honey bee and non-Apis bee (Hymenoptera) farms in Canada. AB - Here, we present a farm-level, Canada-wide analysis of Canadian bee farms in 2006; this article is the first report to distinguish between honey bee (Apis mellifera L.) farms and non-Apis bee (Hymenoptera) farms. Farms are characterized according to bee species, bee stocks, and whether the farm makes 50% or more of gross sales from bee-related activities. Farm characteristics, including bee stocks, gross sales, capital investments, land base, specialization, location, and operator demographics, are reported for the different farm types and sizes. Non-Apis bee farms are revealed to be a nontrivial part of the Canadian bee industry: 21.2% of Canadian bee farms have non-Apis bees and 16.6% have exclusively non-Apis bees. Important differences between honey bee farms and non Apis bee farms also are found. These differences include the more land-intensive nature of non-Apis bee farms and the finding that non-Apis bee farms have greater diversity in terms of their primary commodity, even at higher bee stock levels. PMID- 22928289 TI - Effects of brood pheromone (SuperBoost) on consumption of protein supplement and growth of honey bee (Hymenoptera: Apidae) colonies during fall in a northern temperate climate. AB - Honey bee, Apis mellifera L. (Hymenoptera: Apidae), nutrition is vital for colony growth and maintenance of a robust immune system. Brood rearing in honey bee colonies is highly dependent on protein availability. Beekeepers in general provide protein supplement to colonies during periods of pollen dearth. Honey bee brood pheromone is a blend of methyl and ethyl fatty acid esters extractable from cuticle of honey bee larvae that communicates the presence of larvae in a colony. Honey bee brood pheromone has been shown to increase protein supplement consumption and growth of honey bee colonies in a subtropical winter climate. Here, we tested the hypothesis that synthetic brood pheromone (SuperBoost) has the potential to increase protein supplement consumption during fall in a temperate climate and thus increase colony growth. The experiments were conducted in two locations in Oregon during September and October 2009. In both the experiments, colonies receiving brood pheromone treatment consumed significantly higher protein supplement and had greater brood area and adult bees than controls. Results from this study suggest that synthetic brood pheromone may be used to stimulate honey bee colony growth by stimulating protein supplement consumption during fall in a northern temperate climate, when majority of the beekeepers feed protein supplement to their colonies. PMID- 22928290 TI - Influence of toxic bait type and starvation on worker and queen mortality in laboratory colonies of Argentine ant (Hymenoptera: Formicidae). AB - The efficacy of toxic baits should be judged by their ability to kill entire ant colonies, including the colony queen or queens. We studied the efficacy of four toxic baits to the Argentine ant, Linepithema humile (Mayr) (Hymenoptera: Formicidae). These baits were Xstinguish that has the toxicant fipronil, Exterm an-Ant that contains both boric acid and sodium borate, and Advion ant gel and Advion ant bait arena that both have indoxacarb. Experimental nests contained 300 workers and 10 queen ants that were starved for either 24 or 48 h before toxic bait exposure. The efficacy of the toxic baits was strongly influenced by starvation. In no treatment with 24-h starvation did we observe 100% worker death. After 24-h starvation three of the baits did not result in any queen deaths, with only Exterm-an-Ant producing an average of 25% mortality. In contrast, 100% queen and worker mortality was observed in colonies starved for 48 h and given Xstinguish or Exterm-an-Ant. The baits Advion ant gel and Advion ant bait arena were not effective against Argentine ants in these trials, resulting in <60% mortality in all treatments. Because of the strong influence of starvation on bait uptake, control efficacy may be maximized by applying bait when ants are likely to be starved. Our results suggest queen mortality must be assessed in tests for toxic bait efficacy. Our data indicate that of these four baits, Xstinguish and Exterm-an-Ant are the best options for control of Argentine ants in New Zealand. PMID- 22928291 TI - Use of flax oil to influence honey bee nestmate recognition. AB - Fatty acids, normally found in comb wax, have a strong influence on nestmate recognition in honey bees, Apis mellifera L. Previous work has shown that bees from different colonies, when treated with 16- or 18-carbon fatty acids, such as oleic, linoleic, or linolenic acids, are much less likely to fight than bees from two colonies when only one of the two is treated. Previous work also shows that the influence of comb wax on recognition has practical applications; transfer of empty comb between colonies, before merger of those colonies, reduces fighting among workers within the merged colony. Flax oil contains many of the same fatty acids as beeswax. Here, we tested the hypothesis that treatment of individual bees with flax oil affects nestmate recognition; the results proved to be consistent with this hypothesis and showed that treated bees from different colonies were less likely to fight than untreated bees. These results suggest that flax oil may be useful in facilitating colony mergers. PMID- 22928292 TI - Enhanced attraction of Plutella xylostella (Lepidoptera: Plutellidae) to pheromone-baited traps with the addition of green leaf volatiles. AB - Diamondback moth, Plutella xylostella (L.) (Lepidoptera: Plutellidae), is one of the most serious pests of Brassicaceae crops worldwide. Electrophysiological and behavioral responses of P. xylostella to green leaf volatiles (GLVs) alone or together with its female sex pheromone were investigated in laboratory and field. GLVs 1-hexanol and (Z)-3-hexen-1-ol elicited strong electroantennographic responses from unmated male and female P. xylostella, whereas (Z)-3-hexenyl acetate only produced a relatively weak response. The behavioral responses of unmated moths to GLVs were further tested in Y-tube olfactometer experiments. (E) 2-Hexenal, (Z)-3-hexen-1-ol, and (Z)-3-hexenyl acetate induced attraction of males, reaching up to 50%, significantly higher than the response to the unbaited control arm. In field experiments conducted in 2008 and 2009, significantly more moths were captured in traps baited with synthetic sex pheromone with either (Z) 3-hexenyl acetate alone or a blend of (Z)-3-hexenyl acetate, (Z)-3-hexen-1-ol, and (E)-2-hexenal compared with sex pheromone alone and other blend mixtures. These results demonstrated that GLVs could be used to enhance the attraction of P. xylostella males to sex pheromone-baited traps. PMID- 22928293 TI - Acute toxicities and sublethal effects of some conventional insecticides on Trichogramma chilonis (Hymenoptera: Trichogrammatidae). AB - The acute toxicity of 10 conventional insecticides to adult of Trichogramma chilonis Ishii (Hymenoptera: Trichogrammatidae) was bioassayed by membrane method, and then their sublethal effects on the parasitoid were evaluated in the laboratory. Based on sublethal concentration (LC30) values at 8 h after treatment, we determined that adult T. chilonis were the most susceptible to chlorfenapyr, followed by fipronil, spinosad, avermectins, beta-cypermethrin, and cartap, with lethal concentration (LC)30 values of 0.3133, 0.3269, 1.5408, 3.2961, 6.1469, and 9.021 mg/liter, respectively. The field-recommended concentrations of chlorfluazuron, indoxacarb, Bacillus thuringiensis, and tebufenozide caused <30% mortality of treated adults; therefore, they were used to evaluate sublethal effects on the parasitoid. After treatment with sublethal concentration of fipronil and avermectins, the longevity of treated females (1.2 and 1.6 d) was significantly shortened and fecundity (34.7 and 1.6) was remarkably decreased; consequently, the life-table parameters (R0, r(m), lambda, and T) of T. chilonis were statistically lower than those in the control. Cartap and spinosad also reduced longevity (8 and 7.9 d) and fecundity (110.77 and 117.2) of treated adults, but cartap enhanced the female percentage of F1 offspring (61.6%), resulting a statistical higher R0, r(m), and lambda of treated T. chilonis. In contrast, chlorfluazuron and tebufenozide increased longevity (16.4 and 15.4 d) and fecundity (248 and 256.9) of treated adults but slightly decreased the female percentage of F1 offspring (31.4 and 38.1%). Although chlorfenapyr showed no adverse influence on longevity and fecundity, it remarkably reduced the female percentage of F1 offspring (13.5%), leading to a lower R0, r(m), and lambda of treated T. chilonis. Indoxacarb, B. thuringiensis, and beta-cypermethrin had no obvious sublethal effects on the longevity and fecundity of treated adults. Based on these results, we consider B. thuringienesis, chlorfluazuron, indoxacarb, beta-cypermethrin, and tebufenozide safe to T. chilonis, suggesting that these insecticides are compatible with this parasitoid when being used in the field. However, fipronil, chlorfenapyr, spinosad, and avermectins were very harmful to T. chilonis. Timing of application of these insecticides was critical. PMID- 22928294 TI - The utility of camptothecin as a synergist of Bacillus thuringiensis var. kurstaki and nucleopolyhedroviruses against Trichoplusia ni and Spodoptera exigua. AB - We studied the effect of combining microbial pesticides with camptothecin (CPT) on the mortality of two lepidopteran insects: Trichoplusia ni (Hubner) and Spodoptera exigua (Hubner). CPT is an alkaloid that is often used as an anticancer agent. Here, CPT was evaluated as a microbial pesticide synergist of Bacillus thuringiensis (Bt) and insect baculovirus. The toxicity of CPT and its synergistic effects on two microbial pesticides were studied using the diet overlay method. Bioassay results showed that CPT significantly enhances the toxicity of Bt variety kurstaki to S. exigua and T ni. In addition, CPT strongly enhanced the infectivity of Autographa californica (Speyer) multinucleocapsid nucleopolyhedrovirus (AcMNPV) and S. exigua nucleopolyhedrovirus (SeMNPV). Using light microscopy, we found that CPT disrupts the peritrophic membrane of T. ni larvae and severely affects the structure of the midgut, resulting in an abnormal gut lumen morphology. We speculate that CPT increases toxicity by affecting the permeability of the peritrophic membrane. PMID- 22928295 TI - Optimizing metabolic stress disinfection and disinfestation components to control Pseudococcus longispinus. AB - Metabolic stress disinfection and disinfestation (MSDD) has been demonstrated to effectively control longtailed mealybug, Pseudococcus longispinus (Targioni Tozzetti). Standard components previously used for testing MSDD system included a 30-min physical phase of short cycles pressure changes followed by a 60-min chemical phase using ethanol vapor at 10 kPa. This study investigated the effect of varying the following MSDD components on mealybug mortality: duration of the physical and chemical phases, ethanol concentration, and extent of vacuum during the chemical phase. Mealybug mortality responses were analyzed, and the components were optimized using binary logistical regression to achieve 99% mortality of three life stages of the longtailed mealybug (adults, second- and third-instar nymphs and crawlers). Data indicated that the optimal components to achieve 99% mortality of all life stages were a 30-min physical phase and a 45 min chemical phase with 275 mg/liter ethanol at 30 kPa. Optimized components were obtained using binary logistical regression models. These optimized components yielded a 15-min reduction in total treatment time and a 20-kPa decrease in pressure during the chemical phase. Achievement of optimal insecticidal efficacy required all four MSDD components. Nevertheless, optimization and validation achieved 17 and 22% reductions in duration of treatment time and extent of vacuum, respectively. PMID- 22928296 TI - Export of commercial Hass avocados from Argentina poses negligible risk of Ceratitis capitata (Diptera: Tephritidae) infestation. AB - Argentina has to meet quarantine restrictions because of the Mediterranean fruit fly, Ceratitis capitata (Wiedemann) (Diptera: Tephritidae), to export 'Hass' avocados, Persea americana Miller, to certain countries. Hass avocado at the hard, mature green stage is potentially a conditional nonhost for C. capitata and could open export markets without the need for a quarantine treatment. Trapping data from 1998 to 2006 showed that C. capitata was present in avocado orchards, particularly early in the harvest season. The host status of hard, mature green Hass avocado to C. capitata was evaluated using laboratory and field cage tests under no-choice conditions and by assessing natural levels of infestation in commercially harvested fruit from the main avocado production area. In total, 2,250 hard, mature green avocado fruit were exposed to 11,250 gravid females for 24 or 48 h after harvest in laboratory or field cages, and no infestations were found. During 11 seasons, 5,949 fruit in total were sampled from the trees and 992 fruit were collected from the ground, and in none of them were any live or dead fruit fly larvae found. Inspection of >198,000 commercial fruit at the packinghouse from 1998 to 2011 showed no symptoms of fruit fly infestation. These data exceed the published standards for determination of nonhost status, as well as the Probit 9 standard for development of quarantine treatments. Hass avocado harvested at the hard, mature green stage was not infested by C. capitata and seems to pose a negligible quarantine risk. As a consequence, no postharvest treatment or other quarantine actions should be required by importing countries. PMID- 22928297 TI - Trap capture of three economically important fruit fly species (Diptera: Tephritidae): evaluation of a solid formulation containing multiple male lures in a Hawaiian coffee field. AB - Invasive fruit flies (Diptera: Tephritidae) pose a global threat to agriculture through direct damage to food crops and the accompanying trade restrictions that often result. Early detection is vital to controlling fruit flies, because it increases the probability of limiting the growth and spread of the invasive population and thus may greatly reduce the monetary costs required for eradication or suppression. Male-specific lures are an important component of fruit fly detection, and three such lures are used widely: trimedlure (TML), cue lure (CL), and methyl eugenol (ME), attractive to Mediterranean fruit fly, Ceratitis capitata (Wiedemann); melon fly, Bactrocera cucurbitae (Coquillett); and oriental fruit fly, Bactrocera dorsalis (Hendel), respectively. In California, Florida, and Texas, the two Bactrocera lures are applied to separate species-specific traps as liquids (with a small amount of the insecticide naled added), whereas TML is delivered as a solid plug in another set of traps. Thus, the detection protocol involves considerable handling time as well as potential contact with a pesticide. The purpose of this study was to compare trap capture between liquid male lures and "trilure" wafers that contain TML, ME, raspberry ketone (RK, the hydroxy equivalent of CL), and the toxicant DDVP embedded within a solid matrix. Field studies were conducted in a Hawaiian coffee (Coffea arabica L.) field where the three aforementioned species co-occur, showed that the wafer captured at least as many flies as the liquid baits for all three species. This same result was obtained in comparisons using both fresh and aged (6-wk) baits. Moreover, the wafers performed as well as the single-lure traps in an ancillary experiment in which TML plugs were substituted for liquid TML. Additional experiments demonstrated explicitly that the presence of ME and RK had no effect on captures of C. capitata males and similarly that the presence of TML had no effect on the capture of B. cucurbitae or B. dorsalis males. PMID- 22928298 TI - Three-dimensional temporal and spatial distribution of adult Rhyzopertha dominica in stored wheat and corn under different temperatures, moisture contents, and adult densities. AB - Three-dimensional temporal and spatial distributions of adult Rhyzopertha dominica (F.) at adult densities of 1.0, 5.0, and 10.0 adults per kg grain and at 20 +/- 1, 25 +/- 1, and 30 +/- 1 degrees C were determined in 1.5 t bins filled with wheat (Triticum aestivum L.) with 11.0 +/- 0.8, 13.0 +/- 0.6, and 15.0 +/- 0.5% moisture content (wet basis) or corn (Zea mays L.) with 13.0 +/- 0.2% moisture content (wet basis). At each of five sampled locations, grain was separated into three 15-kg vertical layers, and adult numbers in each layer were counted. Inside both corn and wheat, adults did not prefer any location in the same layer except at high introduced insect density in wheat. The adults were recovered from any layer of the corn and >12, 65, and 45% of adults were recovered in the bottom layer of the corn at 20, 25, and 30 degrees C; respectively. However, <1% of adults were recovered in the bottom layer of wheat. Numbers of adults correlated with those in adjacent locations in both vertical and horizontal directions, and the temporal continuous property existed in both wheat and corn. Adults had highly clumped distribution at any grain temperature and moisture content. This aggregation behavior decreased with the increase of adult density and redistribution speed. Grain type influenced their redistribution speed, and this resulted in the different redistribution patterns inside wheat and corn bulks. These characterized distribution patterns could be used to develop sampling plans and integrated pest management programs in stored grain bins. PMID- 22928299 TI - Phenology of Dasineura oxycoccana (Diptera: Cecidomyiidae) on cranberry and blueberry indicates potential for gene flow. AB - Dasineura oxycoccana (Johnson) (Diptera: Cecidomyiidae) is a pest of cranberry, Vaccinium macrocarpon (Aiton) (Ericales: Ericaceae), and highbush blueberry, Vaccinium corymbosum (L.) (Ericales: Ericaceae), in North America. In British Columbia, Canada, D. oxycoccana was first found on highbush blueberry in 1991 and then on cranberry seven years later. Because many cranberry and highbush blueberry farms are adjacent to one another, we hypothesized that D. oxycoccana was moving from highbush blueberry onto cranberry. Cranberry and highbush blueberry differ in phenology, and adaptation to these different phenologies may result in host races or cryptic species on these two crops. We recognized the alternative hypothesis that D. oxycoccana had arrived as immature stages with cranberry vines imported from another region of North America. During spring and summer, we recorded the phenology of D. oxycoccana and the development of plant shoots from three cranberry and three highbush blueberry farms to determine whether the opportunity exists for successful movement of D. oxycoccana between the two crops. Our results show that D. oxycoccana from cranberry and highbush blueberry overlap in phenology for much of the season, indicating a high potential for movement and gene flow. However, differences were seen in number of larvae per shoot, location of pupae, and heat unit accumulation during larval development suggesting that instead there may be the potential for host race or cryptic species formation. PMID- 22928300 TI - Dispersal behavior of neonate European corn borer (Lepidoptera: Crambidae) on Bt corn. AB - European corn borer, Ostrinia nubilalis (Hubner) (Lepidoptera: Crambidae), has historically been a significant economically important insect pest of corn (Zea mays L.) in the United States and Canada. The development in the 1990s of genetically modified corn expressing genes derived from Bacillus thuringiensis (Bt) that encodes insecticidal crystalline (Cry) proteins has proven to be effective in controlling this insect as well as other corn pests. The purpose of this study was to assess the movement and dispersal behavior of neonate European corn borer on Bt corn. We examined differences in neonate European corn borer dispersal behavior for the first 4 h after eclosion in the field among a stacked pyramid (Cry1F X Cry1Ab X Cry34/35Ab1) Bt corn, a Cry1F Bt corn, and a non-Bt sweet corn; and in the laboratory among a Bt corn hybrid containing Cry1F, a hybrid containing Cry1Ab, a pyramid combining these two hybrids (Cry1F X Cry1Ab), and a non-Bt near isoline corn. In field experiments, we found that dispersal was significantly higher on Bt corn compared with sweet corn. In laboratory experiments, dispersal was significantly higher on Cry1Ab Bt corn and Cry1F X Cry1Ab Bt corn than on non-Bt near isoline corn. Results indicated that neonate dispersal may be significantly greater in Bt cornfields compared with non-Bt cornfields. The findings on dispersal behavior in this study will be useful in evaluating the efficacy of a blended seed refuge system for managing European corn borer resistance in Bt corn. PMID- 22928301 TI - Acromyrmex octospinosus (Hymenoptera: Formicidae) management: effects of TRAMILs fungicidal plant extracts. AB - Leaf-cutting ants, Acromyrmex octospinosus (Reich), are considering among the most important pest species of the New World. Until now, the main insecticides used for controlling these ants were synthetic chemicals. Leaf-cutting ants live in obligate symbiosis with abasidiomycete fungus, Leucocoprinus gongylophorus (Heim) Moeller. The crucial role of this symbiotic partner in the nest of leaf cutting ants has prompted us to focus on A. octospinosus management through the use of fungicides in our study. Five parts of plants identified for their antifungal potential through TRAMIL ethnopharmacological surveys were tested: 1) bulbs of Allium cepa L.; 2) seed pods of Allium sativum L.; 3) green fruits of Lycopersicon esculentum L.; 4) leaves of Manihot esculenta Crantz; and 5) leaves of Senna alata (L.) Roxburgh. One plant extract with strong fungicidal activity (S. alata) against L. gongylophorus was found. The other extracts had lesser fungistatic or fungicidal effects depending on the concentrations used. The data presented in this study showed that TRAMILs fungicidal plant extracts have potential to control the symbiotic fungus of leaf cutting ants, in particular a foliage extract of S. alata. PMID- 22928302 TI - Effect of the natural pesticide spinosad (GF-120 formulation) on the foraging behavior of Plebeia moureana (Hymenoptera: Apidae). AB - In this study we evaluated the effects of the biorational pesticide, Spinosad (GF 120 formulation), on foraging behavior in the stingless bee Plebeia moureana (Ayala). Several foragers were individually trained to collect an unscented 1.0 M sucrose solution (31% sucrose wt:wt) from a blue plate in one arm of a Y-tube maze. The other arm offered plain water on a yellow plate. After 20-30 visits to the setup, the sucrose solution was exchanged for a sucrose solution mixed with one of five concentrations of GF-120 and 30 consecutive choices of each bee were recorded. Interestingly, the foragers collected the sucrose solution with GF-120 at all concentrations. Our results show that: 1) the GF-120 formulation, when applied at the recommended concentration and mixed with food, does not discourage engaged foragers and, 2) foraging behavior over time is not significantly impaired by the continuous collection of GF-120. PMID- 22928303 TI - Repellency of essential oils to Frankliniella occidentalis (Thysanoptera: Thripidae) as affected by type of oil and polymer release. AB - Eight essential oils [0.125-1.0% (vol:vol) in acetone] were separately deposited on leaf disks to evaluate their potential to repel western flower thrips, Frankliniella occidentalis (Pergande) (Thysanoptera: Thripidae), adult females. Two of the best-performing essential oils were incorporated into polymer matrices of methyl cellulose or alginate [0.5 or 1% (wt:vol)] to verify the potential of the polymer to extend repellency of oils over time (24-120 h). Results showed that at a concentration of 0.5%, Thymus vulgaris L. (common thyme) and Satureja montana L. (winter savory) were the most repellent essential oils. For these two treatments, no western flower thrips were counted on treated leaf disks 60 min after the start of the test. T. serpyllum and O. compactum also showed repellency values > or = 90% at this concentration. With both the alginate and methyl cellulose polymers, the incorporation of polymers into treatment solutions containing 0.5% concentrations of S. montana and T. serpyllum resulted in higher repellency compared with treatment solutions lacking these polymers for a minimum of 3 d. For the alginate polymer, differences associated with polymer concentrations were most dramatic. High repellency was maintained for 4 d when a 0.5% concentration of the alginate was used in combination with a 0.5% concentration of S. montana. The use of repellent oils with polymers that extend their repellency may prove useful for both pre- and postharvest applications in flower crops. PMID- 22928304 TI - Western corn rootworm larval movement in SmartStax seed blend scenarios. AB - Insect resistance management (IRM) can extend the lifetime of management options, but depends on extensive knowledge of the biology of the pest species involved for an optimal plan. Recently, the Environmental Protection Agency (EPA) registered seed blends refuge for two of the transgenic Bacillus thuringiensis (Bt) corn products targeting the western corn rootworm, Diabrotica virgifera virgifera LeConte. Larval movement between Bt and isoline plants can be detrimental to resistance management for high dose Bt products because the larger larvae can be more tolerant of the Bt toxins. We assessed movement of western corn rootworm larvae among four spatial arrangements of SmartStax corn (expressing both the Cry34/35Ab1 and Cry3Bb1 proteins) and isoline plants by infesting specific plants with wild type western corn rootworm eggs. Significantly fewer western corn rootworm larvae, on average, were recovered from infested SmartStax plants than infested isoline plants, and the SmartStax plants were significantly less damaged than corresponding isoline plants. However, when two infested isoline plants surrounded a SmartStax plant, a significant number of larvae moved onto the SmartStax plant late in the season. These larvae caused significant damage both years and produced significantly more beetles than any other plant configuration in the study (including isoline plants) in the first year of the study. This plant configuration would occur rarely in a 5% seed blend refuge and may produce beetles of a susceptible genotype because much of their initial larval development was on isoline plants. Results are discussed in terms of their potential effects on resistance management. PMID- 22928305 TI - Crop sequence effects on root maggot (Diptera: Anthomyiidae: Delia spp.) infestations in canola. AB - Strong market demand for canola, Brassica napus L., has prompted some western Canadian producers to increase the frequency of this crop in rotations with other crop species, but the impact of this practice on canola insect pests has not been determined. Here, we investigate 12 cropping sequences involving canola over a 3 yr period (2008-2010 inclusive) at five locations across western Canada. Cropping sequences varied from continuous production of two herbicide-tolerant canola varieties, to production in two of 3 yr, to canola production in one of the 3 yr. Treatments analyzed were the frequency and timing of canola within the rotational sequence. Damage by larvae of root maggots (Diptera: Anthomyiidae: Delia spp.) to canola taproots increased as the study progressed, particularly in 2010 after canola had been grown continuously for 3 yr. Yield declined with continuous canola production, and differences were greatest in 2010. At mean canola crop prices for 2010, the yield reduction from continuous production amounted to economic losses of approximately Can$282-$377/ha. Crop quality, in terms of oil and protein concentrations of harvested seed, was affected more by crop variety than cropping sequence. Crop sequence effects for root maggot damage, yield, and seed quality were relatively stable in the presence of environmental (location) variation. Results of our study suggest that continuous canola production could be unsustainable over the long-term even though market forces currently provide incentive for this practice. PMID- 22928306 TI - Seasonal population dynamics of the potato psyllid (Hemiptera: Triozidae) and its associated pathogen "Candidatus Liberibacter solanacearum" in potatoes in the southern great plains of North America. AB - The potato psyllid, Bactericera cockerelli (Sulc) (Hemiptera: Triozidae), and its associated pathogen "Candidatus Liberibacter solanacearum" (Ca. L. solanacearum), the putative causal agent of zebra chip (ZC) disease in potatoes (Solanum tuberosum L.), were sampled in commercial potato fields and untreated control plots for 3 yr in multiple locations in Texas, Kansas, Nebraska, and Colorado. Populations of the potato psyllid varied across years and across potato growing regions. However, the percentage of potato psyllids infected with Ca. L. solanacearum although variable across years, was consistently highest in the Lower Rio Grande Valley of Texas (LRGV), the reported overwintering location for this pest. The numbers of Ca. L. solanacearum-infected psyllids collected on field traps and large nymphs counted on leaf samples were both positively correlated with the final percentage of ZC in tubers. In the LRGV, where vector and disease pressure is the highest, population levels of immature life stages of the psyllid and percentage of ZC differed greatly between commercial and untreated fields. These results show that the pest management program that was used can be effective at controlling development of the psyllid and ultimately reducing the incidence of ZC. PMID- 22928307 TI - Field evaluation of attractive lures for the fruit fly Bactrocera minax (Diptera: Tephritidae) and their potential use in spot sprays in Hubei Province (China). AB - The Chinese citrus fruit fly, Bactrocera minax (Enderlein) is a univoltine Tephritidae pest that infests Citrus species. Field trials were conducted in 2010 to determine the potential use of a lure based on enzymatical-hydrolyzed beer yeast as liquid bait (hereafter named H-protein bait) for B. minax in the Hubei province, China. In a citrus orchard, we compared the attractiveness among aqueous solutions of H-protein bait, GF-120 fruit fly bait, sugar-vinegar-wine mixture, torula yeast, and Jufeng attractant when used in traps and in spot sprays, that is, lures used in combination with the insecticide trichlorphon. The H-protein bait was the most attractive lure in traps, ensnaring significantly more adults than sugar-vinegar-wine mixture, torula yeast, and Jufeng attractant, in decreasing efficiency order. In spot sprays those with H-protein bait killed significantly more female and male flies within 40 min than those with sugar vinegar-wine mixture, GF-120, Jufeng attractant, and the control. In addition, the total number of flies killed by H-protein bait during the spot spray duration was higher than other treatments. Our results demonstrated that the H-protein bait may be a useful tool in citrus orchards in China to monitor B. minax populations as well as to manage this pest when used in spot sprays. PMID- 22928308 TI - True bug (Heteroptera) impact on cocoa fruit mortality and productivity. AB - The real impact of true bug damage on cocoa pods has never been assessed precisely. We conducted a 2-yr study on 1,080 cocoa trees on 36 farms in Cameroon to assess the contribution of true bugs to fruit mortality and production loss. The cocoa fruiting cycle, fruit mortality, and damage caused by true bugs as well as other pests and diseases were monitored on a weekly basis. True bug damage also was described on 2,500 ripe pods per year. Pod weight, bean number, and bean weight were measured and compared for different degrees and types of damage on the ripe pods. Our results showed that true bugs were the main external cause of young fruit abortion. They reduced the abundance of young fruit by up to 10%. In contrast, although one-third of the ripe pods sampled had true bug lesions, only 4% were moderately to heavily damaged. The mean weight of ripe pods was reduced by 12% when there was medium to heavy damage. While the mean weight of wet beans was reduced significantly (by 3-10%), the number of beans per pod was not changed by damage. Despite the reduction in mean weight, the overall weight of beans for the pods sampled was reduced by <2%. Therefore, our study confirmed the common assumption that the economic impact of true bug damage on mature pods is negligible on cocoa farms in Cameroon. However, true bugs have a significant impact on young fruit mortality. PMID- 22928309 TI - Influence of intensity and duration of regulated deficit irrigation on Erythroneura elegantula (Hemiptera: Cicadellidae) on grape. AB - We conducted studies in a Paso Robles, CA, grape (Vitis vinifera L.) vineyard in 2002 and 2003 to estimate the impact of regulated deficit irrigation (RDI) intensity and duration on western grape leafhopper, Erythroneura elegantula Osborn. Treatments were based on deficit intensity, 50 and 25% of standard irrigation (moderate and severe deficits, respectively), and deficit duration, 3 or 6 wk time, initiated at the grape phenological stage of berry set. The standard irrigation served as the control, and was intended to be as close to 100% of evapotranspiration (1.0 ETc) for grape in this area. Each week we took counts ofleafhopper nymphs and estimated stomatal conductance, and at the end of each leafhopper generation we counted live, hatched and parasitized leafhopper eggs. Second generation leafhopper nymphal density was lowered by about 38 and 70% in 2002 and 2003, respectively, but in 2003 only the severe deficit had a negative effect on the third generation. This same pattern was seen in oviposition: second generation egg density was reduced by about 44% in the deficit treatments, but in the third generation only the severe deficit was lower than the control. There was little difference between the 3 vs. 6 wk duration in nymphal or egg density. The differences among treatments in second generation peak nymphal density were greater than the differences in second generation hatched eggs, suggesting that in addition to egg mortality, the deficits also affected nymphal mortality. Management strategies for maintaining leafhopper density low in the second generation and third generations include maintaining a sub-1.0 ETc irrigation strategy after the main RDI period, or reinstating the RDI to correspond to the third generation. PMID- 22928310 TI - Reflective mulch and acibenzolar-S-methyl treatments relative to thrips (Thysanoptera: Thripidae) and tomato spotted wilt virus incidence in tomato. AB - Management of thrips-transmitted tomato spotted wilt (TSW) virus typically relies on tactics that either reduce the thrips vector numbers or change the plant's response to the virus to reduce economic loss. We attempted to quantify the interaction between two such tactics, reflective mulch and the plant activator acibenzolar-S-methyl (Actigard), respectively, on a TSW-susceptible tomato hybrid. A split plot experiment was conducted in 2009 and 2010 where main-plots were three types of plastic mulch (two metalized reflective vs. black) and subplots consisted of a range of plant defense activator applications. TSW pressure varied over year with 80% of untreated plants having TSW in 2009 where as <7% of plants was infected in 2010. No significant interaction between mulch and subplots was found relative to thrips and marketable yield in either year. In 2009, the seasonal average of Frankliniella fusca (Hinds) populations and incidence of TSW were significantly lower and yield significantly higher on both reflective mulches than on black mulch. Seasonal averages of thrips and fruit yield differed significantly among treatments of acibenzolar-S-methyl. However, there was a significant acibenzolar-S-methyl by mulch interaction relative to TSW incidence. In 2009, a minimum of acibenzolar-S-methyl at transplant plus foliar treatments at 10 and 20 d after transplant was required to significantly reduce TSW incidence compared with untreated plants before harvest. Under lower TSW pressure in 2010, average TSW incidence was significantly less in all plots treated with acibenzolar-S-methyl treated plots compared with the check. Acibenzolar-S-methyl treatments functioned better with the thrips reducing tactic, ultraviolet-reflective mulch. We propose that acibenzolar-S-methyl is less effective than metalized reflective mulch in reducing the incidence of TSW in tomato. PMID- 22928311 TI - Adaptation of indigenous larval parasitoids to Tuta absoluta (Lepidoptera: Gelechiidae) in Italy. AB - Tuta absoluta (Meyrick) (Lepidoptera: Gelechiidae) is a serious threat to tomato (Solanum lycopersicum L.) crops in South America. In Europe, after its first detection in Spain in 2006, it rapidly spread through the Mediterranean basin, reaching Italy 2 yr later. The aim of our work was to find indigenous effective biological control agents and to evaluate their potential role in the control of larval populations of T. absoluta in controlled conditions. Nine species of larval parasitoids emerged from field-collected tomato leaves infested by T. absoluta. The most abundant, Necremnus near artynes (Walker) and Necremnus near tidius (Walker) (Hymenoptera: Eulophidae), were tested in laboratory parasitism trials. Furthermore, because the species N. artynes and N. tidius are each reported in literature as an ectoparasitoid of Cosmopterix pulchrimella Chambers (Lepidoptera: Cosmopterigidae) on upright pellitory plants, olfactometer bioassays were performed to assess the response of our parasitoids to the odors of tomato and pellitory leaves infested by T absoluta and C. pulchrimella, respectively, compared with healthy ones. Both Necremnus species showed good adaptation to the invasive pest, and we observed a high larval mortality of T. absoluta because of host feeding and parasitism. Even olfactory responses highlighted a preference of both wasps for tomato plants infested by the exotic pest. These preliminary results demonstrated a high suitability of these indigenous natural enemies for controlling T. absoluta. Further investigations are needed to confirm their role as potential biological agents in commercial tomato plantations. PMID- 22928312 TI - Comparison of scarab grub populations and associated pathogens and parasitoids in warm- or cool-season grasses used on transitional zone golf courses. AB - Seven different turfgrass species or mixes used on golf courses in the United States' transitional climatic zone were maintained as randomized and replicated plots in separate stands mowed at fairway (1.6 cm) or rough (6.4 cm) cutting heights and sampled in autumn to assess the density and species composition of scarab grubs; incidence of disease and parasitism thereof; and extent of turf damage from foraging insectivorous skunks, Mephitis mephitis. Influence of grass species on parasitism by spring or autumn-active tiphiid wasps was further assessed on implanted grubs in open enclosures. Masked chafers (Cyclocephala spp.) were three-fold more abundant than Japanese beetle, Popillia japonica Newman, grubs in plots of Zoysia and Cynodon sp. mowed at fairway height, and P. japonica were five-fold more abundant than masked chafer grubs in cool-season turf plots mowed at rough height. Phyllophaga spp. accounted for <1% of grubs in the samples. Milky disease bacteria (Paenibacillus sp.) were the predominant pathogens of Cyclocephala spp., followed by Serratia sp. bacteria and gregarines (Stictospora cf. villani). Cyclocephala grub densities, milky disease incidence (25%), and parasitism by the native tiphiid Tiphia pygidialis Alien (10-12%) were especially high in zoysiagrass. Japanese beetle grubs were infected by Paenibacillus, Serratia, Stictospora, and microsporidia (Ovavesicula sp.), but incidence of individual pathogens was relatively low (<6%) and similar among grasses within each stand. Few nematode-infected grubs were found. Skunk damage was mainly in the cool-season fairway-height grasses, probably reflecting difficulty in foraging in the much tougher stolons and rhizomes of the warm season turfgrasses. The degree of natural suppression of scarab grubs provided by endemic pathogens or parasitoids is unlikely to be compromised by the grass species used on a particular site. PMID- 22928313 TI - Fumigant toxicity of plant essential oils against Camptomyia corticalis (Diptera: Cecidomyiidae). AB - The toxicity of 98 plant essential oils against third instars of cecidomyiid gall midge Camptomyia corticalis (Loew) (Diptera: Cecidomyiidae) was examined using a vapor-phase mortality bioassay. Results were compared with that of a conventional insecticide dichlorvos. Based on 24-h LC50 values, all essential oils were less toxic than dichlorvos (LC50, 0.027 mg/cm3). The LC50 of caraway (Carum carvi L.) seed, armoise (Artemisia vulgaris L.), clary sage (Salvia sclarea L.), oregano (Origanum vulgare L.), lemongrass [Cymbopogon citratus (DC.) Stapf], niaouli (Melaleuca viridiflora Gaertner), spearmint (Mentha spicata L.), cassia especial (Cinnamomum cassia Nees ex Blume), Dalmatian sage (Salvia offcinalis L.), red thyme (Thymus vulgaris L.), bay [Pimenta racemosa (P. Mill.) J.W. Moore], garlic (Allium sativum L.), and pennyroyal (Mentha pulegium L.) oils is between 0.55 and 0.60 mg/cm3. The LC50 of cassia (C. cassia, pure and redistilled), white thyme (T. vulgaris), star anise (Illicium verum Hook.f.), peppermint (Mentha X piperita L.), wintergreen (Gaultheria procumbens L.), cinnamon (Cinnamomum zeylanicum Blume) bark, sweet marjoram (Origanum majorana L.), Roman chamomile [Chamaemelum nobile (L.) All.], eucalyptus (Eucalyptus globulus Labill.), rosemary (Rosmarinus officinalis L.),Virginian cedarwood (Juniperus virginiana L.), pimento berry [Pimenta dioica (L.) Merr.], summer savory (Satureja hortensis L.), lavender (Lavandula angustifolia Mill.), and coriander (Coriandrum sativum L.) oils is between 0.61 and 0.99 mg/cm3. All other essential oils tested exhibited low toxicity to the cecidomyiid larvae (LC50, >0.99 mg/cm3). Global efforts to reduce the level of highly toxic synthetic insecticides in the agricultural environment justify further studies on the active essential oils as potential larvicides for the control of C. corticalis populations as fumigants with contact action. PMID- 22928314 TI - Evaluation of monitoring traps with novel bait for navel orangeworm (Lepidoptera: Pyralidae) in California almond and pistachio orchards. AB - Experiments conducted in three almond, Prunus dulcis (Rosales: Rosaceae), orchards and three pistachio, Pistacia vera (Sapindales: Anicardiaceae), orchards in 2009 and 2010, and determined that sticky bottom wing traps baited with ground pistachio mummies, or a combination of ground pistachio plus ground almond mummies, trapped more adult female navel orangeworm, Amyelois transitella (Walker) (Lepidoptera: Pyralidae), than did traps baited with ground almond mummies alone. During both years of this study, 2.9 and 1.8 more moths were caught in traps baited with pistachio mummies compared with traps baited with almond mummies in almond orchards and pistachio orchards, respectively. Also, traps located in pistachio orchards caught 5.9 and 8.3 times more navel orangeworm than were trapped from almond orchards in 2009 and 2010, respectively. Implications for use of this novel baited trap in almond and pistachio orchard integrated pest management programs are discussed. PMID- 22928315 TI - Effect of trap color and orientation on the capture of Aphelinus mali (Hymenoptera: Aphelinidae), a parasitoid of woolly apple aphid (Hemiptera: Aphididae). AB - The factors affecting trap capture of adult Aphelinus mali (Haldeman) (Hymenoptera: Aphelinidae) were studied in 2010-2011 in eastern Washington apple (Malus spp.) orchards infested with its host woolly apple aphid, Eriosoma lanigerum (Hausmann) (Hemiptera: Aphididae). The initial study of white sticky cards indicated that traps stapled to the trunk in a vertical orientation had the highest capture. A factorial experiment of three colors (clear, white, and yellow) by three orientations (trunk, scaffold, and hanging) indicated that yellow traps and traps on trunks caught higher numbers ofA. mali. For this reason, the recommended trap for this natural enemy is a yellow trap stapled to the trunk. Having a readily available and effective sampling method for this species may be helpful in implementing biological control programs and assessing the impact of different spray regimes. PMID- 22928316 TI - Evaluation of monitoring traps for Drosophila suzukii (Diptera: Drosophilidae) in North America. AB - Drosophila suzukii Matsumura (Diptera: Drosophilidae), a recent invasive pest of small and stone fruits, has been detected in more than half of the U.S. states, and in Canada, Mexico, and Europe. Upon discovery, several different trap designs were recommended for monitoring. This study compared the trap designs across seven states/provinces in North America and nine crop types. Between May and November 2011, we compared a clear cup with 10 side holes (clear); a commercial trap with two side holes (commercial); a Rubbermaid container with mesh lid and rain tent (Haviland), and with 10 side holes and no tent (modified Haviland); a red cup with 10 side holes (red); and a white container with mesh lid and rain tent (Van Steenwyk). Although fly catches among traps varied per site, overall, the Haviland trap caught the most D. suzukii, followed by the red, Van Steenwyk, and clear trap. The modified Haviland and commercial trap had low captures. Among five crop types in Oregon, a clear cup with mesh sides (Dreves) also was tested and caught the most flies. Traps with greater entry areas, found in mesh traps, caught more flies than traps with smaller entry areas. In terms of sensitivity and selectivity, traps that caught more flies likewise caught flies earlier, and all traps caught 26-31% D. suzukii out of the total Drosophila captured. Future trap improvements should incorporate more entry points and focus on selective baits to improve efficiency and selectivity with regard to the seasonal behavior of D. suzukii. PMID- 22928317 TI - Cage study of spinosad-based bait efficacy on Bactrocera cucurbitae, Dacus ciliatus, and Dacus demmerezi (Diptera: Tephritidae) in Reunion Island. AB - On Reunion Island, Bactrocera cucurbitae (Coquillett), Dacus ciliatus (Loew), and Dacus demmerezi (Bezzi) cause severe damage to Cucurbit crops. The aim of the study was to test in field cages the effectiveness of Syneis-appat (Dow AgroSciences), a spinosad-based bait (0.02% of spinosad) on both attraction and mortality of young adults (6-9 d old) of these three species. The effects of gender were also evaluated for all species whereas the effects of protein deprivation were tested with B. cucurbitae only. For the first 15 min after application, significantly more B. cucurbitae adults (21.7 +/- 1.8%) were attracted to the bait than D. demmerezi (7.6 +/- 2.4%) and D. ciliatus (2.7 +/- 1.4%); the subsequent response (30-75 min after bait application) of D. demmerezi was statistically similar to that recorded for B. cucurbitae; whereas the response ofD. ciliatus to the bait was consistently significantly lower. Adult mortality was significantly higher for B. cucurbitae (94.6 +/- 0.7%) than for D. demmerezi (85.7 +/- 2.1%), and was significantly higher for the latter than for D. ciliatus (60.4 +/- 4.4%). Sex had no significant effect on the mortality rate for each species. The efficiency of the bait was the same for B. cucurbitae adults regardless whether or not the diet included proteins. Overall, Syneis appat appears to be more effective against B. cucurbitae and B. demmerezi than against D. ciliatus. In Reunion Island, this bait could constitute a useful component in the framework of Integrated Pest Management. PMID- 22928318 TI - Injury to apical meristem of cranberry by Dasineura oxycoccana (Diptera: Cecidomyiidae) reduces production of floral-units in the next growing season. AB - Cranberry tipworm, Dasineura oxycoccana Johnson (a gall-making fly), disrupts normal growth of cranberry (Vaccinium macrocarpon Aiton) by injuring the apical meristem of shoots or uprights. The impact of larval feeding injury on reproductive parameters of cranberry was determined, from one growing season to next, at upright (Maine and Massachusetts, 2008-2009) and plot levels (Massachusetts, 2009-2010 and 2010-2011). We also estimated the proportions of uprights injured because of tipworm feeding at several cranberry production sites (Massachusetts and Maine) and the proportions of uprights that produced flowers and fruits in the next growing season. Tipworm-injured uprights tagged at the end of the growing season did not produce floral-units (following year) across sites in both Massachusetts and Maine. There was significant variation among the sampled sites in the proportions of tipworm-injured uprights and also in the proportions of uprights with flowers in the next growing season (Massachusetts and Maine). A trend was apparent wherein sites with higher tipworm injury levels had relatively lower flowering proportions in the next growing season. However, sites in Massachusetts did not differ in the proportions of uprights that set fruit and in a replicated study, significant reduction in tipworm injury at plot level (using insecticide) did not impact flower and fruit production in the next growing season. PMID- 22928319 TI - Efficacy of Leptospermum petersonii oil, on Plutella xylostella, and its parasitoid, Trichogramma pretiosum. AB - The efficacy of lemon-scented tea tree oil (LSO), Leptospermum petersonii (FM. Bailey), was evaluated against the diamondback moth, Plutella xylostella (L.) under laboratory conditions. Feeding activity and development of larval stages were significantly reduced on broccoli leaves that had been dipped in LSO. Oviposition deterrence was also found when an adult stage was exposed to treated leaves. Fecundity dropped by >50% at concentrations >0.5%. The LC50 value for third instar larvae was estimated to be 2.93% 7 d after treatment. Experiments were also conducted under greenhouse conditions to assess the efficacy of LSO against the diamond-back moth. Our results suggest that LSO has modest potential for development as a botanical insecticide. The oil was also tested at concentrations from 0.5 to 6% for oviposition deterrence of an egg parasitoid of the diamondback moth, Trichogramma pretiosum (Riley). LSO deterred parasitization in choice tests but not in no-choice tests. LSO did not cause mortality of T. pretiosum during 24 h in a contact toxicity test. We conclude that LSO had no significant effects on the parasitoid, and therefore LSO is compatible with this biocontrol agent for integrated management of the diamondback moth. PMID- 22928320 TI - Efficacy of commercial baits and new active ingredients against firebrats and silverfish (Zygentoma: Lepismatidae). AB - Commercial baits containing boric acid, hydramethynon, and indoxacarb were tested against the firebrat, Thermobia domestica (Packard), and silverfish, Lepisma saccharina L. (both Zygentoma: Lepismatidae), under laboratory conditions. Three boric acid baits were consumed in significantly smaller amounts than untreated control food and did not effectively control either species. Baits containing hydramethylnon and indoxacarb were consumed in greater amounts than boric acid baits, but were relatively ineffective, with LT50 values >9 d. Presence or absence of competitive untreated food did not consistently affect bait efficacy. A ground oat matrix was used to evaluate the potential effectiveness of abamectin, chlorfenapyr, dinotefuran, fipronil, hydramethylnon, metaflumizone, and novaluron baits. The most effective compound was chlorfenapyr. At 0.05 and 0.20% (wt:wt) rates, chlorfenapyr baits produced LT50 values, for both species, ranging from 2 to 4 d. All other compounds had LT50 values >7 d. PMID- 22928321 TI - Baseline susceptibility of Planococcus ficus (Hemiptera: Pseudococcidae) from California to select insecticides. AB - Between 2006 and 2008, 20 populations of Planococcus ficus (Signoret), from Coachella and San Joaquin Valleys of California were measured in the laboratory for susceptibility to buprofezin, chlorpyrifos, dimethoate, methomyl, and imidacloprid. Toxicity was assessed using a petri dish bioassay technique for contact insecticides and by a systemic uptake technique for imidacloprid. Mixed life stages were tested for susceptibility to all insecticides except for buprofezin, which was measured against early and late instars (first, second, and third). Dose-response regression lines from the mortality data established LC50 and LC99 values by both techniques. Responses of populations from the two geographical locations to all five insecticides varied, in some cases significantly. Variations in susceptibility to each insecticide among sample sites showed a sevenfold difference for buprofezin, 11-fold to chlorpyrifos, ninefold to dimethoate, 24-fold to methomyl, and 8.5-fold to imidacloprid. In spite of susceptibility differences between populations, baseline toxicity data revealed that all five insecticides were quite effective based on low LC50s. Chlorpyrifos was the most toxic compound to Planococcus ficus populations as shown by lowest LC50s. Buprofezin was toxic to all immature stages but was more potent to first instars. The highest LC99 estimated by probit analysis of the bioassay data of all 20 populations for each compound was selected as a candidate discriminating dose for use in future resistance monitoring efforts. Establishment of baseline data and development of resistance monitoring tools such as bioassay methods and discriminating doses are essential elements of a sustainable management program for Planococcus ficus. PMID- 22928322 TI - Lack of fitness costs associated with acetamiprid resistance in Bemisia tabaci (Hemiptera: Aleyrodidae). AB - Sweetpotato whitefly, Bemisia tabaci (Gennadius) (Hemiptera: Aleyrodidae), is a devastating pest that can cause severe damage to a range of crops by direct feeding and by plant virus transmission. Because of indiscriminate use of insecticides, this whitefly has developed resistance to several insecticides, including neonicotinoids. Our objectives were to determine fitness components affected by acetamiprid resistance in B. tabaci. Assay results showed that selection with acetamiprid had removed heterozygotes from the field population because the survival rate of the resistant population was significantly greater than that of the field population at a very high dose. Comparison of various life traits between the acetamiprid-selected (Aceta-SEL) population and three other populations showed that the numbers of eggs laid by acetamiprid Aceta-SEL population were significantly lower compared with that of other populations but that the proportions of eggs hatched were significantly higher. However, the time taken by nymphal stages of the Aceta-SEL population to develop was significantly higher than that of the susceptible populations. The intrinsic rate of increase, net reproductive rate, mean generation time, and doubling time of Aceta-SEL was significantly higher than Lab-PK and UNSEL populations, but the growth index was similar for all populations. The growth index and high intrinsic value of Aceta SEL population suggest that the resistance allele may not have detrimental impact. The lack of fitness costs in B. tabaci could promote the rapid development of resistance to acetamiprid and other neonicotinoids. This resistance could threaten the sustainability of whitefly management program on genetically engineered cotton (Gossypium hirsutum L.) where neonicotinoids are being sprayed to manage sucking pests in the field. PMID- 22928323 TI - Adaptation by western corn rootworm (Coleoptera: Chrysomelidae) to Bt maize: inheritance, fitness costs, and feeding preference. AB - We examined inheritance of resistance, feeding behavior, and fitness costs for a laboratory-selected strain of western corn rootworm, Diabrotica virgifera virgifera LeConte (Coleoptera: Chrysomelidae), with resistance to maize (Zea maize L.) producing the Bacillus thuringiensis Berliner (Bt) toxin Cry3Bb1. The resistant strain developed faster and had increased survival on Bt maize relative to a susceptible strain. Results from reciprocal crosses of the resistant and susceptible strains indicated that inheritance of resistance was nonrecessive. No fitness costs were associated with resistance alleles in the presence of two entomopathogenic nematode species, Steinernema carpocapsae Weiser and Heterorhabditis bacteriophora Poinar. Larval feeding studies indicated that the susceptible and resistant strains did not differ in preference for Bt and non-Bt root tissue in choice assays. PMID- 22928324 TI - Residual bioassay to assess the toxicity of Acaricides against Aceria guerreronis (Acari: Eriophyidae) under laboratory conditions. AB - Aceria guerreronis Keifer (Acari: Eriophyidae) is considered a major pest of the coconut (Cocos nucifera L.), and the use of pesticides is the current method to control it. However, no standard toxicological tests exist to select and assess the efficiency of molecules against the coconut mite. The aim of this study was to develop a methodology that allows for the evaluation of the relative toxicity of acaricides to A. guerreronis through rapid laboratory procedures. We confined A. guerreronis on arenas made out of coconut leaflets and tested two application methods: immersing the leaf fragments in acaricides and spraying acaricides on the leaf fragments under a Potter spray tower. In the latter application method, we sprayed leaf fragments both populated with and devoid of mites. We evaluated the comparative toxicity of two populations (Itamaraca and Petrolina, Pernambuco, Brazil) by spraying on leaflets without mites and submitted the mortality data to probit analysis after 24 h of exposure. No difference was observed in the LC50, regardless of whether the leaflets were immersed or sprayed with acaricide (abamectin, chlorfenapyr or fenpyroximate). The toxicity of chlorfenapyr and fenpyroximate did not differ, irrespective of whether it was applied directly to the leaflet or to the mite; however, the toxicity of abamectin was higher when applied directly to the mite. Chlorpyrifos and abamectin toxicities were lower for the Petrolina population than for the Itamaraca population. Immersing and spraying coconut leaflets can be used to assess the mortality of A. guerreronis under laboratory conditions. PMID- 22928325 TI - Toxicity of thiamethoxam and mixtures of chlorantraniliprole plus acetamiprid, esfenvalerate, or thiamethoxam to neonates of oriental fruit moth (Lepidoptera: Tortricidae). AB - To assess the toxicity ofthiamethoxam and three mixtures of insecticides to oriental fruit moth, Grapholita molesta (Busck) (Lepidoptera: Tortricidae), we added the insecticides to diet and fed it to neonates of two laboratory colonies; mortality was assessed after 96 h. Thiamethoxam was much less toxic than insecticides previously tested. Five of six analyses of the joint action of chlorantraniliprole plus acetamiprid, esfenvalerate, or thiamethoxam indicated that toxicity was not independent and not correlated. For chlorantraniliprole plus acetamiprid, mortality was slightly lower than expected at low concentrations and greater than expected at high concentrations. For chlorantraniliprole plus esfenvalerate, mortality was less than expected at nearly all concentrations, suggesting antagonism despite the two compounds' different modes of action. For chlorantraniliprole plus thiamethoxam, observed mortality exceeded expected mortality at low concentrations, but this trend did not continue at higher concentrations. Although the null hypothesis of independent and uncorrelated toxicity was rejected for chlorantraniliprole plus acetamiprid and chlorantraniliprole plus thiamethoxam in three of four analyses, differences between observed and expected mortality were minor and inconsistent over the range of concentrations tested. We do not expect these mixtures to exhibit significant synergism or antagonism in the field. Apparent antagonism between chlorantraniliprole and esfenvalerate is particularly relevant because these insecticides (or chlorantraniliprole plus a different pyrethroid) may be used together in apples or peaches for control of oriental fruit moth and hemipteran pests. The effectiveness of each insecticide against oriental fruit moth might be reduced in such applications. PMID- 22928326 TI - Validation of reference genes for gene expression studies in Aphis glycines (Hemiptera: Aphididae). AB - Quantitative real-time polymerase chain reaction (qRT-PCR) is a common and robust tool for accurate quantification of mRNA transcripts. To normalize results, a housekeeping gene ([HKG], reference gene or endogenous control gene) is mandatory. Soybean aphid, Aphis glycines Matsumura (Hemiptera: Aphididae), is a significant soybean, Glycine max (L.) Merr., pest, yet gene expression and functional genomics studies are hindered by a lack of stable HKGs. We evaluated seven potential HKGs (SDFS, succinate dehydrogenase flavoprotein subunit; EF1a, elongation factor-la; HEL, helicase; GAPDH, glyceraldehyde-3 phosphate dehydrogenase; RPS9, ribosomal protein S9; TBP, TATA-box binding protein; and UBQ, ubiquitin-conjugating protein) to determine the most efficient HKGs that have stable expression among tissues, developmental stages, and aphids fed on susceptible and host plant-resistant soybean. HKG stability was determined using GeNorm and NormFinder. Results from three different experimental conditions revealed high stability of TBP compared with the other HKGs profiled across the samples assayed. RPS9 showed stable expression among aphids on susceptible and resistant plants, whereas EF1a showed stable expression in tissues and developmental stages. Therefore, we recommend the TBP as a suitable HKG for efficient normalization among treatments, tissues, and developmental stages of A. glycines. In addition, RPS9 may be used for host-plant resistance experiments and EF1a could be considered for testing differential expression across tissues or developmental stages. These results will enable a more accurate and reliable normalization of qRT-PCR data in A. glycines. PMID- 22928327 TI - Digestive proteolytic and amylolytic activities and feeding responses of Helicoverpa armigera (Lepidoptera: Noctuidae) on different host plants. AB - Digestive proteolytic and amylolytic activities and feeding responses of fifth instar larvae of Helicoverpa armigera (Hubner) on different host plants including chickpea (cultivars Arman, Hashem, Azad, and Binivich), common bean (cultivar Khomein), white kidney bean (cultivar Dehghan), red kidney bean (cultivar Goli), cowpea (cultivar Mashhad), tomato (cultivar Meshkin), and potato (cultivars Agria and Satina) were studied under laboratory conditions (25 +/- 1 degrees C, 65 +/- 5% RH and a photoperiod of 16:8 [L:D] h). Our results showed that the highest protease activity in optimal pH was on cultivar Dehghan (8.717 U/mg) and lowest one was on Meshkin (3.338 U/mg). In addition, the highest amylase activity in optimal pH was on cultivar Dehghan (0.340 mU/mg) and lowest was on Meshkin (0.088 mU/mg). The larval weight of fifth instar H. armigera showed significant difference, being heaviest on Binivich (125.290 +/- 5.050 mg) and lightest on Meshkin (22.773 +/- 0.575 mg). Furthermore, the highest and lowest values of food consumed were on Goli (362.800 +/- 27.500 mg) and Satina (51.280 +/- 4.500 mg), respectively. In addition, the lowest values of prepupal and pupal weight were on Meshkin (32.413 +/- 0.980 and 41.820 +/- 1.270 mg, respectively). The results indicated that tomato (Meshkin) was unsuitable host for feeding fifth instar larvae of H. armigera. PMID- 22928328 TI - Whitefly population dynamics and evaluation of whitefly-transmitted tomato yellow leaf curl virus (TYLCV)-resistant tomato genotypes as whitefly and TYLCV reservoirs. AB - Sweetpotato whitefly, Bemisia tabaci (Gennadius), and whitefly-transmitted tomato yellow leaf curl virus (TYLCV) are major threats to tomato production in the southeastern United States. TYLCV was introduced to Florida from the Caribbean islands and has spread to other southern states of the United States. In Georgia, in recent years, the incidence of TYLCV has been steadily increasing. Studies were conducted to monitor population dynamics of whiteflies in the vegetable production belt of Georgia, to evaluate TYLCV-resistant genotypes against whiteflies and TYLCV, and to assess the potential role of resistant genotypes in TYLCV epidemiology. Monitoring studies indicated that the peak incidence of whiteflies varied seasonally from year to year. In general, whitefly populations were not uniformly distributed. Tomato genotypes exhibited minor differences in their ability to support whitefly populations. TYLCV symptoms were visually undetectable in all but one resistant genotype. The infection rates (visually) in susceptible genotypes ranged from 40 to 87%. Greenhouse inoculations with viruliferous whiteflies followed by polymerase chain reaction (PCR) indicated that up to 100% of plants of resistant genotypes were infected, although predominantly symptomless. TYLCV acquisition by whiteflies from TYLCV-infected genotypes was tested by PCR; TYLCV acquisition rates from resistant genotypes were less than from susceptible genotypes. Nevertheless, this difference did not influence TYLCV transmission rates from resistant to susceptible genotypes. Results emphasize that resistant genotypes can serve as TYLCV and whitefly reservoirs and potentially influence TYLCV epidemics. PMID- 22928329 TI - Evaluation of corn germplasm lines for multiple ear-colonizing insect and disease resistance. AB - Ear-colonizing insects and diseases that reduce yield and impose health threats by mycotoxin contaminations in the grain, are critical impediments for corn (Zea mays L.) production in the southern United States. Ten germplasm lines from the Germplasm Enhancement of Maize (GEM) Program in Ames, IA, and Raleigh, NC, and 10 lines (derived from GEM germplasm) from the Texas Agricultural Experiment Station in Lubbock, TX, were examined in 2007 and 2008 with local resistant and susceptible controls. Four types of insect damage and smut disease (Ustilago maydis) infection, as well as gene X environment (G X E) interaction, was assessed on corn ears under field conditions. Insect damage on corn ears was further separated as cob and kernel damage. Cob penetration rating was used to assess corn earworm [Helicoverpa zea (Boddie)] and fall armyworm [Spodoptera frugiperda (J.E. Smith)] feeding on corn cobs, whereas kernel damage was assessed using three parameters: 1) percentage of kernels discolored by stink bugs (i.e., brown stink bug [Euschistus serous (Say)], southern green stink bug [Nezara viridula (L.)], and green stink bug [Chinavia (Acrosternum) hilare (Say)]; 2) percentage of maize weevil (Sitophilus zeamais Motschulsky)-damaged kernels; and 3) percentage of kernels damaged by sap beetle (Carpophilus spp.), "chocolate milkworm" (Moodna spp.), and pink scavenger caterpillar [Pyroderces (Anatrachyntis) rileyi (Walsingham)]. The smut infection rates on ears, tassels, and nodes also were assessed. Ear protection traits (i.e., husk tightness and extension) in relation to insect damage and smut infection also were examined. Significant differences in insect damage, smut infection, and husk protection traits were detected among the germplasm lines. Three of the 20 germplasm lines were identified as being multiple insect and smut resistant. Of the three lines, entries 5 and 7 were derived from DKXL370, which was developed using corn germplasm from Brazil, whereas entry 14 was derived from CUBA117. PMID- 22928330 TI - Location of the mechanism of resistance to Amphorophora agathonica (Hemiptera: Aphididae) in red raspberry. AB - The aphid Amphorophora agathonica Hottes (Hemiptera: Aphididae) is an important virus vector in red (Rubus idaeus L.) and black (Rubus occidentalis L.) raspberries in North America. Raspberry resistance to A. agathonica in the form of a single dominant gene named Ag1 has been relied upon to help control aphid transmitted plant viruses; however, the mechanism of resistance to the insect is poorly understood. Aphid feeding was monitored using an electrical penetration graph on the resistant red raspberry 'Tulameen' and compared with a susceptible control, 'Vintage'. There were no differences in pathway feeding behaviors of aphids as they moved toward the phloem. Once in the phloem, however, aphids feeding on resistant plants spent significantly more time salivating than on susceptible plants, and ingested significantly less phloem sap. This suggests that a mechanism for resistance to A. agathonica is located in the phloem. Reduced ingestion of phloem may result in inefficient acquisition of viruses and is a likely explanation for the lack of aphid-transmitted viruses in plantings of resistant cultivars. PMID- 22928331 TI - Influence of nutrition on male development and reproduction in Tribolium castaneum. AB - Tribolium beetles have evolved over several thousand years to colonize and exploit various food products that vary widely in their nutritional quality. Here Tribolium castaneum was used as a model organism to explore the effect of nutritional quality on male development and reproduction. The results showed, when tested across different qualities of nutritional diets, Tribolium males developed faster and their body size was larger on a high-quality diet, and there were significant correlations between male developmental traits. However, Tribolium males fed different nutritional diets did not show significant variation in olfactory attractiveness, mating rate, insemination rate, sperm defense (P1), sperm offense (P2), and reproductive success within a population context (RSPC). Moreover, there was no significant correlation of male reproductive performances except RSPC with developmental traits, and except for P2 and RSPC, no significant correlations between male reproductive performances. Therefore, although male developmental performance was significantly influenced by diet quality, reproductive performance was not. We discussed these findings and their sexual selection implications in light of its habitat. PMID- 22928332 TI - A defective notice of intent now less of a problem for plaintiffs. PMID- 22928333 TI - MSMS membership serves up a banquet of benefits for physicians. PMID- 22928334 TI - The road to reform an uphill climb. PMID- 22928335 TI - Don't make patients compete for attention with your EMR system. PMID- 22928336 TI - Developing a physician retention plan for your practice. PMID- 22928337 TI - The automakers and Michigan's health care. Times of stress, times of innovation. PMID- 22928338 TI - Seasonal and 2009 H1N1 influenza update. An update from the Michigan Department of Community Health. PMID- 22928340 TI - In my opinion: When patients ask about health care reform. PMID- 22928339 TI - Be a part of team medicine. PMID- 22928341 TI - What action can be taken against a physician for providing false expert witness testimony? PMID- 22928343 TI - Electronic medical records may not reduce liability. PMID- 22928342 TI - Things you need to know about health information funding and technology standards. PMID- 22928344 TI - Being a healer informs state representative's role in Lansing. Interview by Maria Bianchi. PMID- 22928345 TI - Selling your recruits on Michigan. PMID- 22928346 TI - World medical relief to distribute refurbished pacemakers. PMID- 22928347 TI - Keeping our children out of harm's way. PMID- 22928348 TI - To care is human. PMID- 22928349 TI - Differential effects of hGH and IGF-I on body proportions. AB - The differential growth effects of hGH and IGF-I on the upper/lower (U/L) body segment in relation to height (Ht) were analyzed in 15 patients with isolated Growth hormone deficiency (IGHD,:7M, 8F) mean age 5.0 +/- 3.2 (SD) years treated with hGH; 21 patients with multiple pituitary hormone deficiency including growth hormone (MPHD: 14M, 7F) aged 10.0 +/- 3.8, treated with hGH; 9 patients with Laron Syndrome (LS) (4M,5F) aged 6.9 +/- 5.6 years treated with IGF-I; 9 boys with intrauterine growth retardation (IUGR) aged 6.3 +/- 1.25 years treated by hGH; and 22 boys with idiopathic short stature (ISS) aged 8.0 +/- 1.55 years treated by hGH. The dose of hGH was 33 microg/kg/day, that of IGF-I 180-200 microg/kg/day. RESULTS: the U/L body segment ratio in IGHD patients decreased from 2.3 +/- 0.7 to 1.1 +/- 0.7 (p <0.001), and the Ht SDS increased from -4.9 +/ 1.3 to 2.3 +/- 1 (p < 0.001) following treatment. In MPHD patients the U/L body segment decreased from 1.1 +/- 1.1 to -0.6 +/- 1.0 (p < 0.001), and the Ht SDS increased from -3.3 +/- 1.4 to -2.5 +/- 1.0 (p < 0.009). In the LS group the U/L body segment ratio did not change with IGF-I treatment but Ht improved from -6.1 +/- 1.3 to -4.6 +/- 1.2 (p < 0.001), The differential growth response of the children with IUGR and with ISS resembled that of the children with LS. CONCLUSIONS: hGH and IGF-I act differentially on the spine and limbs. PMID- 22928350 TI - Changes in body composition of university students in a country in socio-economic transition. AB - AIM: The present study examined body composition of students and aimed to evaluate their risk for obesity. METHODS: Height, body mass, body mass index (BMI), triceps skinfold, the percentage of body fat tissue as determined from triceps skinfold, and waist circumference were analysed in 286 20-year old subjects, born in the forties, sixties and eighties of the last century. Percentage of overweight was determined according to BMI, triceps skinfold, and waist circumference. RESULTS: The results indicate that a positive secular increase continues in height, body mass, triceps skinfold, the percentage of body fat tissue, and waist circumference for both genders. BMI did not identify a statistically significant increase in the percentage of overweight students over three generations, while triceps skinfold and waist circumference demonstrated statistically significant increases in accumulation of peripheral and abdominal fat, especially in females. CONCLUSION: The findings confirm that according to BMI Slovenia experiences an intermediate level of overweight young males, but a relatively low level of overweight females. However, when other measures for assessing overweight are considered, it is indisputable that in young Slovenians overweight and thus obesity-related health risks are increasing in both genders. PMID- 22928351 TI - Socioeconomic covariates and their impact on the opportunity for natural selection in a riparian tribe of Northeast India. AB - The intensity of natural selection correlates with various bio-social variables which influence the genetic structure of a population. In this paper it has been sought to find out the influence of variable environmental setting and economic condition on selection intensity among the Mising tribal population of Assam, Northeast India. Detailed reproductive pattern of 309 post menopausal women is obtained and a comparison has been made between different environmental as well as economic backgrounds. The impact of secular change on selection intensity has been assessed. For this study I have proposed a modified formula of Johnston & Kensinger's (1971) index for selection intensity. Crow's index of selection intensity has also been used for comparative analyses. After considering standard statistical procedure, a clear disparity of selection intensity has been noticed in terms of varying socioeconomic condition as well as habitational background. It can be concluded from the study that environmental factors act more in terms of selection pressure on infants rather than the other post natal stages. PMID- 22928352 TI - Gender differences in nutritional behavior and weight status during early and late adolescence. AB - The current study aimed to determine gender differences in nutritional habits, eating behaviour, weight status, body image and weight control practices during early and late adolescence. 677 Viennese pupils (253 boys and 424 girls) between the ages 10 and 18 years (x = 14.1 yrs; +/- 2.2) were enrolled in the study. Weight status was determined by means of body mass index percentiles. To assess eating behavior, food preferences, body image and weight control practices, a 48 item questionnaire was developed. Significant gender differences in weight status were observable during late adolescence only. Girls are significantly less satisfied with their body weight. Furthermore, girls practice dieting and weight control to avoid any weight gain more frequently than boys. Gender differences in eating behavior intensified from early to late adolescence. From early to late adolescence, meal size decreased among girls, while it remains stabile or increased among boys. Boys eat generally more than girls. Furthermore, boys preferred meat and fast food while girls consumed fruits, vegetables and healthy food significantly more frequently. These gender differences are explained by gender specific energetic demands and culture typical beauty ideals. PMID- 22928353 TI - Body mass reconstruction on the basis of selected skeletal traits. AB - The objective of this paper is: to estimate the body mass of the skeletons with the mechanical method (femoral head body mass estimation method--FH) and non mechanical method (stature/living bi-iliac breadth body mass estimation method- ST/LBIB); to compare the reliability and potential use of results obtained with both methods. The material (46 skeletons, 26 males, 20 females) used in the study came from the medieval burial ground in Cedynia, Poland. Body mass reconstruction according to non-mechanical method was made using equations proposed by Ruff et al. (2005). Body mass estimation based on the mechanical method was calculated using formulas proposed by Ruff et al. (1995). In the mechanical body mass reconstruction method, femoral superoinferior breadth was used. Reconstruction of body weight using the non-mechanical method was based on maximum pelvic breadth and reconstructed body height. The correlation between bi-iliac breadth and femoral head measurements and the correlation between femoral head and reconstructed body height were also calculated. The significance of differences between the body mass of male and female individuals was tested with the Mann Whitney U-test. The significance of differences between body mass values obtained with the mechanical (FH) and the non-mechanical method (ST/ LBIB) was tested using Pearson's correlation. The same test was used for the calculation of the relationship between bi-iliac breadth and femoral head measurements and between femoral head and reconstructed body height. In contrast to females, in males there is no statistically significant correlation between body mass estimated with the mechanical method (FH) and the non-mechanical method (ST/LBIB). In both sexes there was not statistically significant correlation between bi-iliac breadth and femoral head measurements. Only in the females group the correlation between femoral head and reconstructed body height was statistically significant. It is worth to continue the research. The obtained results would be a valuable contribution to the knowledge on body mass reconstruction methods. PMID- 22928354 TI - A method for estimating age of Danish medieval sub-adults based on long bone length. AB - The preferred method for aging archaeological sub-adult skeletons is by dental examination. In cases where no dental records are available, age estimation may be performed according to epiphyseal union, skeletal elements or diaphyseal lengths. Currently no data have been produced specifically for aging archaeological Danish sub-adults from the medieval period based on diaphyseal lengths. The problem with using data on Danish samples, which have been derived from a different population, is the possibility of skewing age estimates. In this study 58 Danish archaeological sub-adults were examined, aged from approximately six years to twenty-one years. The samples were aged according to two dental methods: Haavikko and Ubelaker. Regression formulae were constructed for aging according to their diaphyseal lengths both for individual long bones and combinations of upper and lower long bones. This study indicated that with the regression formulae developed, estimation of age can be done with reasonable results on Danish sub-adults. The Danish data were then compared to data from a different archaeological sample and a modern sample. It showed that the modern data indicated a consistently lower age compared to this sample which increased until reaching a maximum of nearly five years and six months. When comparing the archaeological data to this study, the growth profile crossed over at 12.5 years with a maximum age difference before the cross point of two years and three months lower for the archaeological data. After the cross point there was a maximum difference of three years and four months higher for the archaeological data. This study has shown the importance of using data for age estimation for archaeological material which has been developed specifically for that population. In addition it has presented a possible solution for Danish sub-adult material when dental material is not available. PMID- 22928355 TI - Frequency and patterning of bone trauma in the late medieval population (13th 16th century) from Dugopolje, southern Croatia. AB - The aim of this paper is to test the hypothesis of an increased level of interpersonal violence in Dugopolje during the late medieval period as testified by written sources. In order to accomplish this, an analysis and comparison of frequencies and patterning of long bone and craniofacial fractures between sex and age categories in the Dugopolje skeletal sample was performed. In total 209 excellently preserved adult skeletons were analysed: 111 males and 98 females. The total long bone fracture frequency is 1.5% (29/1910) with a significantly higher frequency in males compared to females. Most of the long bone injuries occurred as a result of accidents, probably due to rugged mountainous terrain, while a certain portion of trauma resulted from deliberate violence. Significantly higher fracture frequencies in males could be a result of a strict sexual division of labour where males performed more physically demanding and risky tasks, as witnessed by historical sources. 26 out of 119 complete adult crania (21.8%) exhibit skeletal trauma with significantly higher frequencies in males. Perimortem trauma was observed in one individual while antemortem healed sharp force lesions were registered in five individuals (all males). The predominance of frontal craniofacial injuries, as well as the presence ofperimortem trauma and sharp force lesions, suggests the presence of deliberate violence in this community. Although the indicators of deliberate violence were recorded predominantly in males, suggesting that intentional violence in Dugopolje was exclusively males' prerogative, the presence of nasal fracture in a female skeleton might point to a male towards female violence. Presented bioarchaeological data are in accordance with the written documents thus corroborating the claims of an increased level of deliberate interpersonal violence in the late medieval population from Dugopolje. PMID- 22928356 TI - Absence of foramen spinosum and abnormal middle meningeal artery in cranial series. AB - In comparative and evolutionary aspects in humans, the middle meningeal artery enters the cranium through the foramen spinosum, whereas in great apes the middle meningeal artery can enter the cranium through foramen spinosum, through foramen ovale or through petrosphenoid fissure. Generally, in nonhuman primates the anterior meningeal system is associated with the ophthalmic branch of the internal carotid artery. The vessels joining the two systems pass through the additional channels: the superior orbital fissure or through the cranio-orbital foramen. In anatomically modern humans, the absence of foramen spinosum involves abnormal development and course of the middle meningeal artery and it is usually accompanied with replacement of the conventional middle meningeal artery with such, arising from the ophthalmic artery system. In these cases the middle meningeal artery most often enters the middle cranial fossa through the superior orbital fissure and rarely through the meningo-orbital foramen. All skulls, investigated in the present study, belonged to adult individuals of both sexes, conditionally grouped into three cranial series--contemporary male, medieval male, and medieval female series. The absence of foramen spinosum was established only among the medieval male and female series--in 1 (0.70%) male and in 1 (0.72%) female skull on the right side and in 3 (2.13%) female skulls on the left side. In 1 (0.72%) female skull, a small atypically located foramen spinosum was established on the right side. In all of the described cases, the intracranial meningeal grooves started from the lateral edge of the superior orbital fissure and probably reflect the ophthalmic origin of the middle meningeal artery. PMID- 22928357 TI - Analysis of mercury levels in historical bone material from syphilitic subjects- pilot studies (short report). AB - The aim of the present work is to study the remains of seven individuals with typical symptoms of tertiary syphilis in terms of mercury content in bones, thereby verifying whether they were subjected to treatment and, if they were, how long their organisms were exposed to toxic mercury fumes. Mercury was used, mainly in the Middle Ages and in the early modern period, as a preventive measure in case of individuals suffering from syphilis, a venereal disease, and also leprosy. Syphilitic patients treated this way should demonstrate increased concentration of mercury in their bones. The skeletons studied in the present work originate from various archaeological sites in southern and north-central Poland. The analyses concerned individuals with diagnosed syphilis as well as healthy individuals who constituted the control group. The analyses were performed by the LA-ICP-MS technique, with the use of laser Nd: YAG, Macro, 266 nm, New Wave, USA, coupled with Spectrometer Elan DRC-e Perkin Elmer, USA. The content analysis of the studied bone material revealed with high probability that the contact method of mercurial treatment was used only in the case of two women from north-central Poland, deceased at the turn of the 15th century at the earliest. PMID- 22928358 TI - The influence of components of diet on the symptoms of ADHD in children. AB - In most children with ADHD the cause of the disease is not exactly known, and its etiology is multifactorial. The conventional treatment is based on the combination of behavioral and psychological therapy and the pharmacotherapy. The pharmacotherapy has a high effectiveness in ADHD treatment, but it is often associated with undesirable side effects, such as: loss of appetite and weight, growth inhibition, abdominal pain, headaches, sleeping problems and increased blood pressure. In the recent years, much attention was devoted to the issue of an appropriate diet in this disease, especially when the standard pharmacotherapy is not effective. The diet of pregnant and lactating woman, and child may have an impact on the development and deepening of the hyperkinetic syndrome. There is much evidence to indicate that it is linked to nutritional factors. Chronic deficiencies of certain minerals such as zinc, iron, magnesium and iodine and insufficient dietary intake of long-chain polyunsaturated fatty acids may have a significant impact on the development and deepening of the symptoms of ADHD in children. A crucial role in the diet of pregnant and lactating women, and child plays also polyunsaturated omega-3 fatty acids, mainly DHA, which are necessary for proper development and function of brain. Their chronic deficiency may contribute to increase risk of ADHD in children. The authors of several studies also demonstrated the positive impact of the elimination food products containing synthetic food additives, like artificial food dyes and preservatives on the behavior of children with ADHD. The beneficial effects brought also the elimination of food products, that are rich in salicylates. It was found that the intake of food products with a low glycemic index helps to reduce symptoms in some hyperactive children. Providing an appropriate supply of nutrients and minerals and elimination of certain food products from diet is especially important during intensive growth and development of the child. In this article the issues concerning the role of the diet in treatment of the children with diagnosed ADHD and the importance of deficiency of certain minerals and long chain polyunsaturated fatty acids in pregnancy and child growth was discussed. There is a need for further studies in this area to evaluate the potential effectiveness of the diet in treating the symptoms of ADHD. PMID- 22928359 TI - [Nutritional factors in prevention of Alzheimer's disease]. AB - Nutritional patterns affect significantly man's body at each age. The elderly- with their eating habits and diseases they have overcome--often require specific dietary intervention. A proper and well-balanced diet is an important element of lifestyle that may become a factor facilitating the so-called healthy, successful ageing and delay the development of noninfectious, chronic metabolic diseases that are in majority of cases diagnosed in elder people. Neurodegenerative diseases have been classified amongst chronic diseases yet with still controversial etiology. Nevertheless, it is speculated that some nutritional factors, including the appropriate intake of B-group vitamins, antioxidative vitamins and polyunsaturated fatty acids, are likely to play a significant role in their prevention and therapy. A diet rich in vegetables and fruits, whole-meal bread, milk and dairy products as well as containing fish, plant oils and nuts provides all indispensable nutrients. The appropriate merging of these food products into dishes--widely described in literature as the Mediterranean diet- facilitates leading a long life in health. PMID- 22928360 TI - [Caffeine--common ingredient in a diet and its influence on human health]. AB - Caffeine is widely consumed by people of all ages. In the last period a market of caffeine-containing products, particularly energy drinks and food supplements increased. Caffeine for years is under discussion, whether has positive whether adverse impact on health. Children are a group of special anxieties. Caffeine is a stimulant of central nervous system and therefore is probably the most commonly used psychoactive substance in the world. The physiological effect of caffeine and the lack of nutrition value causes a great interest its impact on health, especially with reference to the risk of cardiovascular diseases. Results of scientific research are not clear. The influence of caffeine on the human body is conditioned with the individual metabolism of caffeine which also depends on many endogenic and environmental factors. According to the current knowledge moderate caffeine intake by healthy adults at a dose level of 400 mg a day is not associated with adverse effects, but it also depends on other health determinants of a lifestyle. Excessive caffeine consumption can cause negative health consequences such as psychomotor agitation, insomnia, headache, gastrointestinal complaints. Adverse effect of caffeine intoxication is classified in World Health Organization's International Classification of Diseases (ICD-10). Metabolism of caffeine by pregnant woman is slowed down. Caffeine and its metabolites pass freely across the placenta into a fetus. For this reason pregnant women should limit caffeine intake. Children and adolescents should also limit daily caffeine consumption. It results from the influence of caffeine on the central nervous system in the period of rapid growth and the final stage of brain development, calcium balance and sleep duration. Average daily caffeine consumption in European countries ranging from 280-490 mg. The highest caffeine intake is in Scandinavian countries what results from the great consumption of the coffee. As far as caffeine consumption by Polish population is concerned there is very few data in this subject so far. In the nineties of the previous century it was 141 mg per day, whereas according to recent survey daily caffeine intake by women from the Warsaw region was 251 mg and 15% of examined women consumed an excessive quantity of caffeine (> or = 400 mg). Smokers consume more caffeine than nonsmokers, similarly to persons with mental illnesses. With reference to the caffeine consumption it should be underline that caffeine content in coffee and tea beverages varies greatly depending on the method of brewing whereas the content of caffeine in many brands of energy drinks can much vary. This should be taken into account in the daily caffeine intake. PMID- 22928361 TI - [CETP gene TaqIB polymorphism and plasma lipids in patients with overweight and obesity]. AB - BACKGROUND: Ongoing research shows an increase in mortality in patients with low levels of serum cholesterol, which is caused by decreasing the fraction of high density lipoprotein cholesterol (HDL-C) and low-density lipoprotein (LDL-C). OBJECTIVE: The aim of our study was to assess the relationship between the CETP gene TaqI polymorphism and concentrations of selected parameters of lipid metabolism in patients with overweight and obesity. MATERIALS AND METHOD: The study involved 73 people aged 24-68 years. Android obesity was found in 90.4% of women, including 66.7% in the HDL-C levels above 50 mg/dL. RESULTS: Most of abdominal obesity was the B1B2 heterozygotes (38.1%). Abdominal obesity was present in 48.4% of men, including 25.8% in B1B2 heterozygotes and in 67.7% of HDL > 40 mg/dl. It was found statistically insignificant higher levels of TG, TC, LDL-C, the percentage of fat mass (% FM) in patients with genotype B2B2 compared to those with genotype B1B1 and B1B2. In women, higher levels of TC, LDL-C and HDL-C were found in the presence of B1B2 genotype, whereas a higher concentration of all lipid fractions studied showed the men with the B2B2 genotype, who also had the highest % FM. CONCLUSIONS: The results indicate that in obese men Tag1B polymorphism may be an independent factor influencing HDL-cholesterol. PMID- 22928362 TI - [Fatty acids intake and serum lipids profile in overweighted and obese adults]. AB - BACKGROUND: Many epidemiologic, experimental, and clinical studies have shown that the amounts and type of fat in the diet influence plasma lipid levels. Dietary fat has been shown to have a role in cardiovascular diseases. OBJECTIVES: The purpose of this study was to describe the relationship between dietary fatty acids and serum lipids in 150 overweight adults. MATERIAL AND METHODS: The examinations were performed in 150 adults, aged from 25 to 65 years with overweight and obese. Fat intakes are estimated from one 24-hour dietary recall interview. Data obtained with 24-hour questionnaire method were calculated with computer program Dieta 4. Statistical analysis was performed using a computer program Statistica. RESULTS: Mean energy intake amounted 2579.2 +/- 786.2 kcal per day. The fat intake provided 34.6 +/- 8.5% of total energy, including saturated fatty acid--13.6% of total energy. Saturated fatty acids was not correlated with lipid profiles. Stearic acid was inversely correlated with the high-density lipoprotein. There were no signifificant associations between stearic acid and total cholesterol and plasma LDL cholesterol. Monounsaturated fat, including the oleic acid were affected lipid profiles by decreased total cholesterol and LDL-C. PUFA was correlated with decreased total cholesterol and plasma LDL cholesterol. Inverse correlation between arachidonic acid and HDL-C and between linoleic acid and LDL-C was observed. CONCLUSIONS: This study indicates that the type of fat, but not only the total amount of fat, predicts serum cholesterol and its fractions levels. The proportion of SFA, MUFA, PUFA in diet determines their effect on serum lipids profile. PMID- 22928363 TI - [The use of low-caloric diet with modified fatty acids pool in the therapy of the metabolic syndrome]. AB - BACKGROUND: Abdominal obesity is the main component of the metabolic syndrome. Hyperplasia of visceral adipose tissue leads to numerous metabolic disorders: hypertension, dyslipidemia, insulin resistance. This clustering of the most hazardous risk factors is directly linked to type 2 diabetes and cardiovascular disease. OBJECTIVE: The aim of presented trial was to evaluate the use of low caloric diet (1200-1500 kcal/day) with modified fatty acids pool in dietetic therapy of the metabolic syndrome and additionally to estimate the total risk of various cardiovascular disease outcomes. MATERIAL AND METHODS: 23 obese patients aged 22-65 years: 14 men (44.0 +/- 10.9 years) and 9 women (49.7 +/- 11.3 years) with metabolic syndrome (according to NCEP ATPIII) were randomly divided into 2 groups: examined (II) and control (I) with PUFA n-3/n-6 ratio 1:5 and 1:10 respectively. There were no difference in diet composition between groups. Dietary fiber intake was over 29 g/day and both diets provide 28% of total energy from fats, 53% from carbohydrates and 18% from proteins, with < 200 mg cholesterol/day. Anthropometric (body mass, waist and hip circumference) and biochemical (plasma concentration of: glucose, triglicerydes, total cholesterol, LDL and HDL cholesterol) indicators, body composition and the value of blood pressure were controlled. RESULTS: After 12 weeks trial there was significant decrease in measured parameters noted: body mass (8.2 +/- 1.6 kg; p < 0.001), waist circumference (13.4 +/- 2.4 cm; p < 0.001), systolic and diastolic blood pressure: 11.5 +/- 2.2 mmHg and 7.1 +/- 09 mmHg; (p = 0.0003 i p = 0.0008) respectively. The reduction in total risk of developing coronary heart disease measured by Framingham risk score and SCORE algorithm was observed. There was no statistically significant difference between the effects of both groups: PUFA n 3/n-6 1:5 and 1:10. CONCLUSIONS: . These results suggest that the individually matched low-caloric diet with decreased saturated fats intake, increased intake of PUFA n-3 and dietary fibers are crucial in metabolic syndrome therapy and efficiently decrease total cardiovascular risk in these patients. PMID- 22928364 TI - [Assessment of stimulant use especially caffeine intake in selected group of the breastfeeding women]. AB - BACKGROUND: Taking into account the negative impact of stimulants, including alcohol, nicotine and excessive consumption of caffeine on the baby and his mother, a very important is to stop or to restrict their use, especially during pregnancy and lactation. OBJECTIVE: Purpose of the study was to evaluate alcohol consumption, cigarette smoking, tobacco smoke exposure and caffeine consumption in breastfeeding women from Masovian Province. MATERIAL AND METHOD: The survey was conducted from September 2010 till March 2011. The study group consisted of 102 breastfeeding women aged 19-38 years. Information on alcohol consumption, smoking and exposure to tobacco smoke was obtained by questionnaire interview. The results about caffeine intake were obtained using 3-day dietary records method and food frequency questionnaire method. Source of information about the caffeine content in products were the published literature, in the case of energy drinks the manufacturer's label. RESULTS: Among all women surveyed (n = 102), up 17% of respondents declared alcohol consumption, cigarette smoking of 6% and 15% of passive exposure to tobacco smoke. The average caffeine consumption in a group called "caffeine consumers" (n = 94) was 127.4 +/- 76.0 mg/person/day for 3-day dietary records method and 163.4 +/- 100.6 mg/person/day for the food frequency questionnaire method. The correlation coefficient between the used methods was r = 0.71 (p < 0.001). The main sources of caffeine, regardless of the method of data collection were: black tea, which provided about 60% of caffeine and ground coffee (about 20%) and instant coffee (about 13%). CONCLUSIONS: Despite general knowledge about the harmful effects of smoking cigarette/tobacco smoke exposure and the consumption of alcohol and foods high in caffeine, some respondents did not halt the use of these stimulants during lactation, indicating a need for an education in this field. PMID- 22928365 TI - [The assessment of beta-carotene, lycopene and lutein intake selected group of adults]. AB - BACKGROUND: Carotenoids as biologically active compounds, found in products of plant origin, have a beneficial impact on human health by protecting it against the development of many diseases. People and animals do not have the ability to synthesize these compounds de novo, they must be regularly supplied with food. OBJECTIVE: The aim of this study was to evaluate intake of selected carotenoids and indicate their main sources in the daily food ration in adults. MATERIAL AND METHOD: The study was conducted in autumn and spring season, in 2010-2011, among 512 adults, aged 18-97 years, from the urban environment of the central Poland. Food frequency questionnaire method was used to assess the intake of carotenoids. RESULTS: The mean intake of beta-carotene, lycopene and lutein was respectively 6.3; 7.0 and 2.7 mg/person/day. Level of education was a factor which significantly influenced on all carotenoids intake. Persons with higher level of education consumed significantly higher amounts of carotenoids in relation to persons with primary level of education. It was also found statistically significantly higher beta-carotene intake by women when compared to men. Persons with evidence of overweight or obesity consumed significantly more lycopene. The main sources of beta-carotene were fresh vegetables (62%), including carrot (37%). The largest amounts of lycopene came from processed tomato (50%) and fresh tomatoes (32%). Sources of lutein were total vegetables which contributed to diet over 80%, including fresh vegetables (55%). CONCLUSIONS: The main source of carotenoids in the diet of Polish adults were vegetables and their products, and the level of education was the most differentiating factor in the their total intake. PMID- 22928367 TI - [Diet supplements in nutrition of sport mastery school students]. AB - INTRODUCTION: In Polish society, for some time now, a growing interest in supplementation of the diet has been observed. This problem addresses particularly to sportsmen and physically active persons. It is often due to belief that customary diet does not supply organism with necessary food ingredients. There are also some threats connected with supplementation of the diet. Problems addressed to supplementation of the diet are particularly important for young sportsmen, including students of sport mastery schools. OBJECTIVE: The aim of the study was the evaluation of the diet supplementation used by the students of sport mastery school in Western Pomeranian district. MATERIAL AND METHOD: The study was carried out in the group of 76 students, aged 15 to 19, practicing walleyball (girls n = 39) and football (boys n = 37) at the sport mastery school in Police (western Pomeranian district). The interview method has been applied. A significance of differences, for the analysed factor, due to a sport discipline practiced was calculated based on Chi2 (Statistica 9). RESULTS: The results of the study confirmed the students of sport mastery school to supplement their diets. The diet supplementation being more frequent for boys (67.6%) with magnesium (57-64%) noted as the most frequently used supplement, followed with vitamin-mineral agents and L-carnitine. Essential differences were noted for reasons of diet supplementation and sources of information used on supplements between the sport disciplines practiced. CONCLUSIONS: It can be stated, based on the obtained results, that for supplementation of the diet among students of sport mastery school in Police is popular, even though there was no previous recognition of its necessity. The most frequent supplements users were football players with magnesium being the most frequently chosen supplement. Based on the above a regular training of sportsmen, including also coaches training young people, on the rational feeding habits would be advisable. PMID- 22928366 TI - [Evaluation of selected cereal products as a source of thiamine and niacin in diet]. AB - BACKGROUND: The priority of the modern diet should be as follows, low processed cereal products that contain high level fiber and vitamins B as well as the products that have low glycemic index. The best source of thiamine and niacin are grain food products which regulate body energy balance, nervous system, circulation as well as fulfill the role as cofactors of enzymes in the human body. OBJECTIVE: The purpose of this study was to determine and evaluate the concentration of thiamine and niacin in selected cereal products. MATERIAL AND METHOD: Eleven kinds of pasta and rice were used in this studies. Thiamine and niacin were determined in the free form. During the analytical process the acid hydrolysis and enzymatic technique were used. The HPLC method with ultraviolet for determination of thiamine and niacin were applied. The content of thiamine was determined by the length of the 254 nm and niacin 258 nm waves in various cereal products. RESULTS: The obtained results shown that the best source of thiamine and niacin was wild rice (0.59 +/- 0.02 mg and 6.13 +/- 0.06 mg respectively) while the lowest content of analyzed vitamins was in the examined vitamin-enriched pasta bits (0.06 +/- 0.01 mg and 0.42 +/- 0.02 mg). CONCLUSIONS: The analyzed cereal products were characterized by a variable content of tested vitamins. The most significant amount of vitamins B is higher in the examined rice than pasta. It was shown that the richest source of thiamine and niacin was the wild rice. PMID- 22928368 TI - [The fat content and fatty acids composition in selected products of the convenience food]. AB - INTRODUCTION: An increasing pace of life and a lack of time for meals preparation at home, observed in many countries worldwide, have led to an increased consumption of convenient food products. This term refers to highly processed food products that are either ready-to-eat or may be consumed after short culinary processing. Convenience foods include: dinner courses, salads, cereals, creams, broths, pizzas, roasts, as well as frozen products ready-to-eat after short heat treatment. OBJECTIVE: The aim of this study was to assess the fat content and fatty acids composition of frozen products belonging to convenience food. MATERIAL AND METHOD: Material for analysis comprised of 30 following food products: fish and seafood products, pizza, casseroles and meat products. The fat content was determined using Folch method and the fatty acids composition using gas chromatography technique. RESULTS: The analyzed products contained from 1.2% to 26.9% of fat. The saturated fatty acids (SFA) content ranged from 8.7% to 53.2%, while the monounsaturated fatty acids (MUFA)--from 24.0% to 68.7% of total fatty acids. The polyunsaturated fatty acids (PUFA) percentage accounted for 8,1% to 48,8% and trans isomers--for 0.2% to 6.1% of total fatty acids. CONCLUSIONS: The fat and fatty acid contents showed large differences in products depending on their composition and preparation techniques declared by the producer. Most of the analyzed fish and seafood products were characterized by the fat content ranged from 11% to 14% with the high percentage of fatty acids favorable from nutritional point of view, MUFA and PUFA. The composition of fatty acids from pizza and casseroles was less favorable, due to high proportion of SFA and also trans isomers. PMID- 22928369 TI - [The content of some nutrients and potentially harmful components in edible potatoes purchased in the retail network]. AB - BACKGROUND: For majority of Polish people potatoes are indispensable component of daily diet. Boiled or steamed potatoes are considered as food meeting the requirements of right nourishment. They are a source of nutrient components, however, potatoes may contain undesirable compounds. OBJECTIVE: The aim of this work was evaluation of dry matter and some nutritients (starch, vitamin C) and potentially toxic (nitrates (V), reducing sugars) constituents in edible potatoes purchased in a retail network in Szczecin in spring and autumn seasons. MATERIAL AND METHODS: The estimation included 25 samples of different potatoes cultivars. Studies were conducted in autumn (October 2008 and 2009) and in spring (March 2009 and 2010). In the samples the content of the following constituents was determined: dry matter (by drying to constant matter), starch (Evers's method), vitamin C (Tillmans's method), reducing sugars (Luff-Schoorl's method) and nitrates (V) (by method with the use of phenol-disulphanic acid). RESULTS: It was stated that there were significant differences between the samples regarding the content of the tested constituents. Concentration of dry matter and starch ranged 14.50-21.23% and 9.25-15.05%, respectively. In potato tubers, which were under the researches in autumn and spring, mean contents of these constituents were nearly the same. Mean concentrations of vitamin C were almost two times lower in potatoes bought in spring (8.47 and 7.77 mg x 100 g(-1)) than in autumn (15.61 and 14.80 mg x 100 g(-1)). The content of reducing sugars exceeded the recommended highest level (0.5%) in the majority of the tested samples. Accumulation of these constituents occurred especially in potatoes available in markets in spring (mean 1.69 and 1.25%). Only in a few samples the content of nitrates (V) was higher than 200 mg NO3-/kg f. m. CONCLUSIONS: The majority of potatoes samples was characterized by a low content of dry matter (< 20%), very low (< 13%) or low (13.0-14.4%) content of starch and low concentration of nitrates (V). Potatoes available in markets in spring contained little vitamin C but a lot of reducing sugars. Due to the possibility of toxic acrylamide formation they should be fried occasionally. PMID- 22928370 TI - [Level of knowledge on food and nutrition among groups of pupils of the last class of secondary schools]. AB - BACKGROUND: Common nutritional faults affect health of many Poles. Health state of Poles is worse than most of Europeans and is not improving. Nutritional behaviors of young people are caused by limited nutritional knowledge learned during consecutive stages of school education. Nutritional education is considered less important, theoretical knowledge and practice is not correlated and teacher's knowledge is limited. OBJECTIVE: The aim of this study was to study different school programs and to assess the level of nutritional knowledge among selected pupils of last classes of secondary school in Warsaw. MATERIALS AND METHODS: The study was conducted in November 2008 on 210 students with the specific author's questionnaire. RESULTS: There is wide nutritional educational program in schools starting from kindergarten through schools of different levels. The nutritional education program is not consistent likely due to dispersion of material among different subjects. In nutritional knowledge tests none of the pupil reached 75% of maximum points and half of them did not reach 50%. Pupils did not know what is their energetic requirement (answers differ from 100 kcal/day to 10000 kcal/day). They were unable to determine the caloric of oil (only 1/3 knows that it is the most caloric product). More than half of pupils answered that sugar is the most caloric product. The knowledge of vitamin and minerals content is completely not known to pupils. Most of pupils were unable to correctly indicate two products which are the sources of vitamin C (approximately 60%), vitamin A (almost 75%) and iron (over 60%). Pupils have more information on protein sources. Surprisingly it was easier for them to indicate products which are not a good source of valuable proteins than the good source of proteins. Pupils did not know what is recommended frequency of milk, fish, vegetables and plant oil consumption. CONCLUSIONS: Results indicate that the core curriculum of education is proper but students had little knowledge of nutrition. The majority of respondents (95%) did not received half of the available points, and nobody scored very good result. It has been found that there is insufficient knowledge of products energy values and energy daily requirements for teenagers, sources of nutrients, as well as basic nutritional guidelines. PMID- 22928371 TI - [Junior secondary and secondary school students' knowledge level about atherosclerosis risk factors and prevention]. AB - BACKGROUND: Cardiovascular diseases cause about 50% of deaths in Poland. These disorders most frequently result from atherosclerotic changes in arteries. Knowledge on the prevention and elimination of risk factors is vital in reducing the development of atherosclerosis and other non-infectious chronic diseases. OBJECTIVE: The aim of the study was the assessment of junior secondary and secondary school students knowledge pertaining to atherosclerosis risk factors and prevention. MATERIAL AND METHOD: 197 students participated in the project, with 97 attending junior secondary and 100--secondary school in the voivodship of Malopolskie. The junior and upper secondary level pupils originated from small towns (86.6%, 51%) and villages (13.4%, 49%) of the Bochnia and Tuchow districts. The study was conducted in May 2010 by means of a diagnostic survey including an anonymous questionnaire. RESULTS: As risk factors encouraging the development of atherosclerosis to the greatest extent the junior secondary school students selected overweight and obesity, high cholesterol levels, fast food consumption and smoking. The majority of the junior secondary school pupils (61%) and those from the upper secondary level (85%) stated that what should be undertaken in the prevention and treatment of atherosclerosis is the reduction or elimination of food products rich in cholesterol, such as egg yolks, cream, butter, fatty meat. More than half of the junior and upper secondary school level pupils (57%) knew that the consumption of saturated fatty acids should be reduced as a preventive means against cardiovascular diseases. More than 73% of the junior and 85% of the upper secondary school pupils indicated the important role played by physical activity and maintaining a proper body mass in prevention and treatment of atherosclerosis. CONCLUSIONS: The youth's knowledge ofatherosclerosis development risk factors was insufficient. Secondary school students displayed a higher level of knowledge with regard to prophylaxis and dangers pertaining to non-infectious chronic diseases than the respondents attending junior secondary school. PMID- 22928372 TI - [Level of knowledge of the meat products as the main source of sodium in the diet among the students of Lublin]. AB - BACKGROUND: Salt is one of the most commonly used spice. However, too high and too frequent supply of this component may be a source of serious health risks. Knowledge of the salt content in food products and the ability to compose a diet with adequate sodium content are crucial to their health and quality of life. OBJECTIVE: To assessment of the level of knowledge of the Lublin University students on technological and physiological role of salt and its sources in the diet, particularly meat products. MATERIALS AND METHODS: The study by interview with the author's questionnaire survey conducted in December 2010 among Lublin students. In the study participated 200 students (88 women and 77 men). For the analysis 165 correctly completed questionnaires were used. RESULTS: . The results showed that the knowledge of students involved in the production and evaluation of food and human nutrition on the physiological role of technology and knowledge of the sources of salt and salt in the diet, particularly meat products, is at a low level, comparable to the knowledge of students of non-food lines. Three quarters of students do not realize how much is the average daily intake of salt, and more than 80% do not know the recommended norm of consumption of this ingredient. Approximately 50% of respondents could correctly give examples of foods that are the main source of salt in the diet. However, only less than one quarter of them, although often eat meat products is not aware that it is these products are the most serious source of salt. CONCLUSIONS: The knowledge of students about the technology and physiological role of salt and its sources in the diet was low. Most students were not familiar with the recommended daily intake for the salt. The study students identified groups of food products as the main source of salt in the diet. However, they did not used their knowledge in the mode of nutrition. PMID- 22928373 TI - [Selected aspects of style behaviours among the hotel industry employees]. AB - BACKGROUND: The mode of nutrition, physical activity and the lifestyle are very important elements influencing on the health of employees. OBJECTIVE: The subject of this study was to evaluate the selected aspects of lifestyle of a group of hotel employees. MATERIAL AND METHOD: The questionnaire-based research was carried out in a group of 241 employees of the hotel industry (121 women and 120 men). RESULTS: The prevalent eating model in the group involved 3 meals daily, and was more frequent in men (62.9% vs. 47.9%; P < 0.05) who ate less regularly than women (28.6% vs. 55.5%; P < 0.001). Fast-food bars were more often frequented by men (a few times a week: 17.1% vs. 7%; P < 0.05). Fish were consumed a few times weekly by 21.1% of women and 30% of men, while vegetables a few times daily by 25.4% of women and 15.7% of men. Women more frequently consumed a few portions of fruit daily (25.4% vs. 8.6%; P < 0.01). As for alcohols, women more frequently opted for wine (49.3% vs. 18.6%; P < 0.001), while men chose beer (50% vs. 33.3%; P < 0.01) and hard liquors (31.4% vs. 17.4%; P < 0.01). The frequency of alcohol consumption was higher in men (P < 0.001). Recreational physical activity in leisure time was undertaken by 15.2% of women and 20.7% of men who simultaneously reported a higher range of physical activity than women (P < 0.01). Women more frequently opted for fitness exercises, while men for team games (P < 0.001). The role of physical activity in reducing emotional pressure was noticed by 18.7% of women and 29.8% of men (P < 0.05). It has also been demonstrated that the subjective rating of physical fitness dropped together with the increase of BMI (P < 0.05). Persons who perceived their fitness level as very good had a BMI of 22.1 kg/m2, while persons with a low rating of fitness had a BMI of 23.7 kg/m2. CONCLUSIONS: The studies have shown the prevalence of nutritional mistakes and a low level of recreational physical activity, as well as diversification of certain health behaviours depending on the sex. PMID- 22928374 TI - Occurrence of sensitivity during at-home and in-office tooth bleaching therapies with or without use of light sources. AB - The aim of this study was to evaluate the effect of tooth bleaching with 10% carbamide peroxide (CP) or 35% hydrogen peroxide (HP), with or without quartz tungsten-halogen light or hybrid source LED/infrared laser exposition on the occurrence duration, intensity and location of tooth sensitivity Forty patients were selected and randomly divided into four groups: GI--home bleaching with CP for 4 hours a day, over the course of 3 weeks; GII--three sessions of HP with three 10-minute applications at each session and no light source; GIII--the same procedure as GII with quartz-tungsten-halogen light irradiation; GIV--the same procedure as GII with LED/laser light irradiation. The evaluation included an appointment with each patient before and after each HP bleaching session or each weekly CP bleaching and 7, 30 and 180 days after the end of treatment. The Kruskal-Wallis test revealed that the duration and intensity of post-treatment sensitivity were significantly higher for HP than for CP (p< 0.05), and symptoms were located predominantly in anterior teeth. All bleaching methods generated sensitivity, which was more frequent in anterior teeth. However, treatment with CP generated lower sensitivity than treatment with HP independently of the light sources. PMID- 22928375 TI - Antibacterial activity of a plant extract and its potential for disinfecting gutta-percha cones. AB - This study evaluated the antibacterial activity of Rosmarinus officinalis extract and its potential for disinfecting guttapercha (GP) cones. In the first experiment, a hydro-alcoholic extract of Rosmarinus officinalis (leaves) in a dilution ratio of 10% m/v was tested against Enterococcus faecalis by using the disk diffusion method. Positive and negative controls were 70% cereal alcohol and antibiotics, respectively. The procedures were performed in triplicate, and the diameters of the zones of growth inhibition were measured with a caliper after 24 h at 37 degrees C. In the second experiment, the disinfection procedures were evaluated on GP cones artificially contaminated with Enterococcus faecalis. The R. officinalis extract was compared with 2% chlorhexidine digluconate and 2.5% sodium hypochlorite, using a direct exposure test (5 min treatment). Sterilized and non-disinfected cones were used as negative and positive controls, respectively. After 24 h of incubation, bacterial counts were taken. For both experiments, the data were statistically analyzed by Kruskall-Wallis and Tukey's tests (p < 0.05). The plant extract produced zones of inhibition comparable to those of tested antibiotics. Significant GP cone disinfection was verified with all disinfectant solutions, with no significant difference between them. R. officinalis extract showed bactericidal effect on Enterococcus faecalis and capacity to disinfect GP cones contamined with it. PMID- 22928376 TI - Does bonding to dentin reduce microleakage of composite restorations? AB - This study evaluated the effect of adhesive application only to enamel on the marginal microleakage of composite resin restorations performed with different adhesive systems. Standardized cylinder-shaped cavities were prepared on the buccal surface of eighty bovine incisors. Two etch-and-rinse (Adper Scotchbond Multi-purpose [3M ESPE, St. Paul, MN USA] and Adper Single Bond 2 [3M ESPE]) and two self-etching (Clearfil SE Bond [Kuraray, Osaka, Japan] and Adper Prompt [3M ESPE]) adhesive systems were evaluated. The adhesives were applied only to enamel or to both dentin and enamel. After adhesive light-activation, the cavities were restored with composite resin. The samples were coated with two layers of nail polish, except an area of 1-mm wide around of the restoration, and immersed in a methylene blue solution. Afterwards, the specimens were ground in order to obtain powder which was immersed in absolute alcohol. The solutions were centrifuged and the supernatant was analyzed using an absorbance spectrophotometer. Linear regression was used to estimate the dye concentration. Data were analyzed using ANOVA and Tukey's tests (alpha = 0.05). The etch-and-rinse adhesives showed lower microleakage means compared to those of the self-etching adhesives. Adper Prompt presented higher microleakage means. There was no difference between the modes of application of the adhesive on the cavity for all adhesive systems, except for Clearfil SE Bond. This showed lower microleakage when applied to the whole cavity. Bonding to dentin may not reduce microleakage of composite restorations. PMID- 22928377 TI - Effect of bleaching on shear bond strength to dentin of etch-and-rinse and self etching primer adhesives. AB - This study evaluated in vitro the influence of enamel bleaching on bond strength to dentin. One hundred and twenty bovine incisors were divided into 12 groups (n = 10), according to adhesive system: Adper Single Bond 2 (ASB2), Prime & Bond 2.1 (PB), Adhese (AD) and Clearfil SE Bond (SE). The experimental groups were exposed to 10% carbamide peroxide for 4 hours a day over a period of 10 days. After the bleaching, they remained stored in artificial saliva for a further 24 hours or 7 days. The control groups were stored in artificial saliva for 24 hs. Resin composite (Z250) cylinders were made, and the specimens were stored in distilled water (37 degrees C/24 h), until the shear strength test was performed. The results were statistically analyzed using ANOVA 3-way and Turkey's test (a < 0.05). The highest mean value of experimental groups was obtained for ASB2 (7 d) and the lowest for PB (24 h). Significant differences were observed for bleaching and adhesive system, but not for storage time. Moreover, the interaction between the factors under study was shown to be significant. Statistical differences were observed between the tested adhesives for the different bleaching situations and storage times. It may be concluded that dental enamel bleaching and storage time in artificial saliva interfered with the bond strength to subjacent dentin provided by the Prime & Bond 2.1 and Clearfil SE Bond. PMID- 22928378 TI - Comparison of oral streptococci biofilm in caries-free and caries-affected preschool Mexican children. AB - Interaction of oral streptococci biofilm is the main etiological factor for dental caries. The aim of the study was to compare oral streptococci (OS) distribution in the biofilm of primary dentition from caries-free and caries affected preschool Mexican children. This cross-sectional study involved 40 caries-free and 40 caries-affected children with primary dentition. Each child was examined using the dmfs index, DNA was extracted from saliva and presence of OS was determined by PCR. Data obtained showed no statistical difference regarding age and gender (P > 0.05). Streptococcus mutans (Smut), Streptococcus sobrinus (Ssob) and their combination showed significant statistical differences between groups (P < 0.05). Smut, Streptococcus sanguinis and Streptococcus gordonii had an inverse relation with dmfs index and Ssob had a direct relation similar to combined with Smut. Smut-Ssob combined with other OS showed statistical differences (P < 0.05). In free-caries group Streptococcus gordonii was more frequently identified than Smut. The ratio Smut/Streptococcus sanguinis could represent a high risk of dental caries development; this ratio was higher in the caries-affected (1.18) than in the caries-free group (0.32). In conclusion, OS play an important role in dental caries predisposition and severity, not only the presence of Smut and Srob, but also the complexity and distribution of OS in the biofilm. PMID- 22928379 TI - Effect of articaine on calcium transport in sarcoplasmic reticulum membranes isolated from medial pterygoid muscle. AB - Local anesthetics used in dentistry have myotoxic effects. Articaine, also known as carticaine, is one of the local anesthetics most widely used in clinical dentistry. The aim of this work was to describe its effect on the sarcoplasmic reticulum Ca-ATPase isolated from medial pterygoid muscle. Ca-ATPase enzymatic activity was determined by a colorimetric method and ATP-dependent calcium uptake with a radioisotopic technique. Articaine inhibited both Ca-ATPase activity and calcium uptake in a concentration-dependent manner. Both inhibitory effects became evident at articaine concentrations lower than those employed in clinical dentistry. Half-maximal inhibitory concentrations (K) were 15.1 +/- 1.8 mM (n = 6) and 25.2 +/- 1.6 mM (n = 6) for enzymatic activity and calcium uptake, respectively. Preincubation of sarcoplasmic reticulum membranes with articaine enhanced Ca-ATPase activity in the absence of calcium ionophore, suggesting an ionophoric-like effect of the local anesthetic. We conclude that the inhibitory effect of articaine on the sarcoplasmic reticulum Ca-ATPase isolated from medial pterygoid muscle is due to a direct interaction of the anesthetic with the enzyme and to the increased membrane permeability to calcium induced by this drug. PMID- 22928380 TI - Influence of re-using reversible hydrocolloids on the linear alteration of coating models. AB - Reusing reversible hydrocolloids too many times may cause alterations of the coating model and produce unsatisfactory RPPs. The aim of this study was to analyze the linear alterations of coating models reproduced from molds obtained with two commercial brands of reversible hydrocolloid (RH) with 15 reuse cycles of the material. A metal model was used with 4 marks (A, B, C and D) on which the distances AB, BC, CD, DA, BD and AC could be measured lineally. Ten models were divided into two groups according commercial brand of RH: group VIPI-Duplicator VIPI and group K27--Duplicator K27l. The RH was heated in a microwave oven and poured into a flask containing the model. The mold was filled with the ethyl silicate coating, and after crystallization, refractory models were obtained. This was repeated in the 15 re-use cycles of each RH. The refractory models obtained from the 1st, 5th, 10th and 15th times of re-use of RHs were measured under a measuring microscope. The means were submitted to the Analysis of Variance, Tukey and Dunnet tests, to a 5% level of significance. Group VIPI showed linear alterations in relation to the plaster models, for distances AB (1 use = -1.25% and 5th re-use = -1.20%); AD (1st use = 0.76%, 10th re-use = 0.65% and 15th re-use = 0.52%); BD (1st use = 0.58%). Both commercial brands analyzed produced coating models with acceptable linear alterations in up to 15 reuse cycles, no statistical difference being observed between them. PMID- 22928381 TI - Periodontal response to subgingival restorations in dogs with periodontitis. AB - The aim of this study was to evaluate the periodontal response to subgingival restorations in dogs with naturally occurring periodontitis. At the baseline, the experimental teeth from three dogs (2nd and 3rd upper premolars and 2nd, 3rd and 4th lower premolars) were randomly assigned to Resin-modified Glass Ionomer Cement (RMGIC) and Amalgam (AM) restorations or controls (CT) at the buccal sites with (SUPRA+) or without mechanical supragingival plaque control (SUPRA) and maintained for 90 days. Clinical [Periodontal Probing Depth (PPD), Clinical Attachment Loss (CAL), and Gingival Margin Recession (GMR)], histological (connective tissue inflammatory and epithelium condition) and histometric evaluation (distance between the apical border of the cavity and the bone level and between the apical extension of the epithelium and the bone level) were performed by a calibrated blinded examiner. Better clinical (especially regarding CAL) and histological results (unaltered epithelium and less severe inflammatory connective tissue) were observed associated with RMGIC sites. Histometric evaluation showed less bone loss associated to RMGIC. Overall, SUPRA+ sites presented less inflammatory response. It could be concluded that in dogs with periodontitis, subgingival RMGIC restorations, especially in the presence of supragingival plaque control, elicited better periodontal response than AM restorations. PMID- 22928382 TI - Misfit profile of dental bridges. AB - Clinical evidence has shown that dental bridge (DB) misfit is more frequent than individual crown restoration misfit, and that it causes restorative failures. A comparative study of misfit profiles was performed for the most common clinical situations in mouth rehabilitation procedures with fixed restorations: gold-cast DB and porcelain metal alloy DB. Evidence from this study may lead dentists to consider the advantages and weaknesses of one structure type over the other. The results obtained showed two different profiles, with the porcelain metal alloy (PMA) DB being less predictable than the gold-cast DB. The posterior abutment restoration tends to come apart distally from the tooth structure and get closer to the mesial aspect, while keeping distal-medial separation with respect to the anterior abutment. The gold-cast DBs showed a separation pattern in which the distal end comes away from the molar and the medial end from the premolar, getting clearly closer to the faces next to the pontic: its distal aspect gets closer to the premolar and mesially to the molar The study has also shown that even though the adaptive patterns are different, is less in PMA than in gold alloys, the latter being used only in a small percentage of clinical indications in oral rehabilitation, mainly due to aesthetic demands and high costs. The impact of this research in clinical dentistry is that PMA DBs have shown worst marginal adaptation areas where clinically, there is lack of vision or inaccessibility for appropriate dental preparation. PMID- 22928383 TI - Analysis of surface roughness of human enamel exposed to bleaching agent and submitted to brushing. AB - The aim of this study was to assess in vitro the surface roughness (Ra) of human enamel exposed or not exposed to the action of a bleaching agent containing 10% carbamide peroxide (CP) after brushing with different dentifrices. Ninety-six human enamel specimens were divided into 2 groups: GI--exposed to the action of 10% CP; GII--not exposed. These were subdivided into 4 brushing subgroups: (CEW) Close-Up Extra Whitening, (CUB) Colgate Ultra Branco, (CCP) Crest Cavity Protection and (DW) Deionized Water. The specimens from Group GI were exposed to 10% CP for 6 hours/14 days and those from Group GII were stored in artificial saliva for 14 days. Then they were submitted to 35.600 brushing cycles. Ra was measured before and after brushing. Ra difference was compared by two-way ANOVA. Ra was compared between subgroups using ANOVA and Tukey's test. Ra was compared between groups using T-test (alpha = 0.05). Final and initial Ra were compared by Paired t-test; using SPSS (15.0). Two-way ANOVA difference in the outcome revealed that the use of bleaching agent did not affect the difference in Ra (p = 0.45). Brushing significantly influenced the difference in Ra (p < 0.001), but the interaction between the two factors was not significant (p = 0.20). Among the brushing subgroups, a significant increase in Ra was observed for Subgroup CEW- GI: Rai 0.691 (0.112)a, Raf 0.993 (0.264)a; Raf-Rai: 0.303a (43. 7%)--G2: Rai 0.794 (0.167)a, Raf 1.006 (0.488)a; Raf-Rai: 0.212a (26.7%) with a statistical difference for Subgroup CUB--GI: Rai 0.639 (0.163)a, Raf 0.506 (0.113)b; Raf-Rai: -0.133b (-20.8%)--GII: Rai 0.647(0.166)a, Raf 0.472b (0.260); Raf-Rai: -0.134b ( 0.27%). Regardless of whether or not the enamel had been exposed to 10% CP, Ra values varied according to the abrasives in the composition of the different dentifrices. PMID- 22928384 TI - Effect of light-curing unit and adhesive system on marginal adaptation of class v composite restorations. AB - The aim of this study was to evaluate the effect of light-curing units (LED or halogen) on the marginal adaptation of composite restorations performed with etch and-rinse and self-etching adhesive. Class V cavities were prepared on bovine teeth with the gingival margin on dentin and the incisal margin on enamel. The cavities were restored with a micro-hybrid resin composite using an etch-and rinse (Single Bond 2--SB) or a self-etching adhesive (Clearfil SE Bond--CL). The light-activations were performed using halogen lamp (Optilux 501--QTH) or second generation light-emitting diode (Radii-Cal--LED) (n = 10). After finishing and polishing the restorations, epoxy replicas were prepared. The marginal adaptation was analyzed under scanning electronic microscopy with 500x of magnification. The greatest gap width at each margin was recorded. Data were submitted to Mann Whitney and Wilcoxon tests (a = 0.05). SB and CL showed similar behavior of enamel margins when the light-activations were performed with QTH. The same was observed for dentin margins with LED. When the LED was used, higher gap measurements at enamel margins were observed with CL, while higher gap values in dentin were observed for SB within QTH. No significant difference between substrates was found when CL was used. However, SB had significantly higher gap measurements in dentin. The light-curing unit seems to affect the marginal adaptation of resin composite restorations. However this effect was dependent on the adhesive and the location of the margin. PMID- 22928385 TI - Psychological factors related to temporomandibular disorders: an evaluation of students preparing for college entrance examinations. AB - The aim of this study was to research how stress and anxiety affected the development of temporomandibular disorders (TMD) in 55 high school graduates at two different times: six months before and one the week before their college entrance examinations. The American Academy of Orofacial Pain (AAOP) Questionnaire, Lipp's Stress for Adults Inventory (ISSL) and the Beck Anxiety Inventory (BAI) were used to evaluate TMD, stress and anxiety, respectively. The data were submitted to Pearson's and Spearman's correlation tests. At first the results showed higher positive correlation between anxiety and TMD than between stress and TMD. Out of the total participants, 36% had TMD, and of these, only 12.7% had no psychological disorder. One week before the tests there were high positive correlations between TMD and the psychological factors studied, and 50.9% of the students had TMD, of which only 9% had no psychological disorder The most prevalent signs of TMD symptomatology were joint sounds and headache, followed by neck pain. It was concluded that students preparing to take college entrance examinations are a potential risk group for developing TMD due to psychological factors generating anxiety and stress. Anxiety becomes more significant as the semester progresses, and both anxiety and stress increase as the examination dates approach. PMID- 22928386 TI - The presence of periodontopathogens associated with the tumour necrosis factor alpha expression in patients with different periodontal status. AB - The purpose of this study was to investigate the relationship between P gingivalis, T forsythia, T denticola, P intermedia, and A. actinomycetemcomitans in the sulci or pockets of patients with gingivitis (G), mild chronic periodontitis (MiCP), moderate chronic periodontitis (MoCP) and severe periodontitis (SP), and the expression of TNF-alpha in gingival tissue associated with clinical parameters. Six patients with G, 7 with MiCP, 23 with MoCP and 7 with SP were recruited. Pathogens obtained from the sulci or pockets were identified by PCR, and expression of TNF-alpha from gingival tissue was analysed Probing depth (PD), clinical attachment level (CAL) and loss of bone were recorded. P gingivalis was detected at the following rates: 16.6% in subjects with G 57.1% in MiCP 57.8 % in MoCP and 58.1% in SP (p < 0.05). P intermedia was not identified in subjects with G A. actinomycetemcomitans was only identified in subjects with MoCP (31.5%) and SP (42.8%). T denticola and T forsythia were identified in all subject groups. Bacterial combinations were identified as follows: P denticola + P intermedia and PR intermedia + T forsythia were associated (p = 0.04, p = 0.02) with the presence of TNF-alpha mRNA in 20% and 25% of subjects, respectively. P gingivalis + A. Actinomycetemcomitans andA. actinomycetemcomitans + T forsythia were associated with severe PD and CAL, respectively. The association between the presence of P intermedia and expression levels of TNF-alpha was significant (p = 0.05). These results indicate that the proportion of patients with P gingivalis increases with the progression of disease. We observed that the presence of P intermedia may trigger the expression of TNF-alpha and cause a worsening of the patient's clinical status. PMID- 22928387 TI - Evaluation of the roughness of composite resins submitted to different surface treatments. AB - The aim of this study was to evaluate the surface roughness of restorative composite resins after polishing with aluminum oxide discs and applying an adhesive layer The following composite resins were used: Filtek Z250 (hybrid, 3MESPE, A2) and Filtek Supreme XT (nanofilled, 3M ESPE, A2E). Thirty specimens of each composite were made using a condensation silicone mold (5.0 x 2.0 mm) into which the composites were inserted and submitted to light pressure. After polymerization using the halogen light source Curing Light 2500 (3M) for 40 seconds, the specimens were assigned to the following groups: G1-Z250/CO- control, did not receive any treatment; G2-Z250/SL--the specimens underwent finishing and polishing with Sof-Lex discs; G3-Z250/ADE, application of an adhesive layer on the top of the specimen and light curing for 20 seconds. Groups G4, G5 and G6 followed the same treatment sequence, but using Filtek Supreme XT The specimens were stored in deionized water at 37 degrees C for 24 h. Three readings of surface roughness were made for each specimen. The results were submitted to variance analysis by Two-Way ANOVA Test and Tukey HSD Test. The mean values obtained were: G3 (0.2325 +/- 0.1484 microm) and G6 (0.2266 +/- 0.0463 microm), which were higher than the other groups and did not differ statistically from each other. Groups G1 (0.1023 +/- 0.0464 microm), G4 (0.1083 +/- 0.0241 microm), G5 (0.1160 +/- 0.0252 microm) and G2 (0.1360 +/- 0.0131 microm) had the lowest average roughness and did not differ statistically among each other. It was concluded that the Sof-Lex discs performed better for the surface treatment of the composites resins tested, producing similar values of surface roughness for both composites. Covering with dentin adhesive increased the surface roughness in both composites. PMID- 22928388 TI - Influence of different materials and techniques to transfer molding in multiple implants. AB - The aim of this study was to compare different materials and techniques used in transfer molding of multiple implants, by evaluating the space between implants and superstructure. Four external hexagon implants were fixed in a master template and the same on a superstructure. Transfer molding of implants were done using the direct and indirect techniques, with transfers united or not, using the union chemically activated acrylic resin (QA) and other groups polymerized acrylic resin (FT), and sectioned and not split. The casts were made with polyether and models divided into 8 groups (n = 5). The space between the superstructure and the master implants was measured with a microscope and the data was analyzed statistically by Student's t test (p < 0.05). For the material of union there was no significant difference, except when the groups were compared with the resin Duralay QA (G4) and the resin Duolay FT (G8) and groups using resins Duolay QA (G5) and Duolay FT (G7) for the union of the transfers. When comparing the groups who had the union between the transfers and sectioned again united with those in which the union was not severed there was no statistically significant difference. QA resin was superior to the FT with respect to the union of transfers. Techniques with united transfers or not were similar. PMID- 22928389 TI - Alteration of hemostasis in patients treated with subgingival NSAIDs during periodontal therapy. AB - The use of topical NSAIDs to complement periodontal therapy could help resolve the inflammatory process and clinical signs of the disease more rapidly. A randomized clinical trial was performed on 59 patients, of whom 33 had chronic periodontitis and 26 were healthy controls. All diseased patients underwent scaling and root planing in one quadrant per week with subgingival application of gel 48 hours after each session. Gel was applied to healthy patients with the same frequency. Four types of gel were used, containing respectively placebo, acetylsalicylic acid (ASA) 1%, Ketoprofene (KTP) 1% and Ketoprofene 2%. The following clinical variables were studied: probing depth, attachment level, dental mobility, plaque index, gingival index and bleeding on probing; as well as the biochemical variables: bleeding time (Ivy), platelet count in whole blood and platelet-rich plasma, and platelet aggregation induced by different agonists. Regarding clinical results, ASA was the most effective in reducing probing depth, gingival index and bleeding on probing (p < 0.05). KTP 1% and 2% behaved similarly to each other and less effectively than ASA but differed significantly from placebo (p < 0.05). Regarding biochemical tests, ASA had a highly significant inhibitory effect on platelet aggregation for all the agonists used. KTP 2% produced similar though weaker responses. KTP 1% only showed alteration in the first aggregation phase at maximum ADP concentration of and none at the minimum concentration (p < 0.05). PMID- 22928390 TI - Effect of increased dwell times for solvent evaporation on the bond strength and degree of conversion of an ethanol-based adhesive system. AB - This study evaluated the influence of the prolonged setting time of an ethanol based adhesive system on the dentin bond strength and degree of conversion. Labial and lingual surfaces of fifteen human third molars were flattened until the dentin was exposed and randomly allocated to 3 groups (n = 10), according to the dwell time between the application of two consecutive layers of the adhesive system (Adper Single Bond Plus, 3M ESPE) and light activation: G1--control (no extra dwell time); G2 and G3--dwell time of 30 seconds and 60 seconds, respectively. After light curing, two cylinders (1.4 x 1 mm) of composite resin (Filtek Flow, 3M ESPE) were bonded to each surface and submitted to micro-shear testing, 24 hours after light curing. A similar adhesive procedure was used for the degree of conversion evaluation using Fourier transform infrared spectroscopy (FTIR). Significant differences between bond strength values (p = 0.0003) and degrees of conversion (p = 0.0004) were detected. The bond strength of G3 (60 second dwell time) was statistically higher than that of other groups. G1 (control) and G2 (30-second dwell time) presented similar results. Values of degree of conversion indicated that both the 30-second and 60-second dwell times resulted in similar and greater percentages of conversion. The use of a longer dwell time (60 seconds) might provide better solvent volatilization and monomer infiltration; bringing benefits to dentin bonding using simplified etch & rinse adhesive systems. PMID- 22928391 TI - Shrinkage stress and degree of conversion of a dental composite submitted to different photoactivation protocols. AB - The aim of this study was to evaluate the polymerization stress and degree of conversion of a composite submitted to different photoactivation protocols. The composite Filtek Z350 was placed in the central perforation of a photoelastic disc and polymerized using a LED-based curing unit (BluePhase II--Ivoclar Vivadent) with energy density of 12, 24 or 36 J/cm2 using the following photopolymerization protocols: continuous high intensity (HI: 1200 mW/cm2 during 10, 20 or 30s), continuous low intensity (LI: 650 mW/cmz during 18, 36 or 54s) and soft-start (SS: 150 mW/cm2 during 5 s + 1200 mW/cm2 during 9, 19 or 29s) (n = 5). Photoelastic analysis was used to evaluate polymerization shrinkage stress and FTIR was performed to determine the degree of conversion of the composite. ANOVA 3-way procedure was used to determine the significance of the main effects and their interactions followed by two-way ANOVA for each time was performed (p < 0.05). Shrinkage stress increased with higher values of energy. No statistically significant differences on polymerization shrinkage stress were found between high and low intensity activation modes. Soft-start method generated stresses that were statistically lower than continuous modes except when 12 J/cm2 was applied. Similar degree of conversion was observed for photoactivation modes used, except for soft-start mode with 12, 24 and 36J/cm2 that showed lowest levels of conversion. Energy density and activation mode influenced polymerization shrinkage stress, but no benefit on degree of conversion was observed. PMID- 22928392 TI - The lacuno-canalicular system (LCS) and osteocyte network of alveolar bone by confocal laser scanning microscopy (CLSM). AB - The osteocyte lacuno-canalicular system (OLCS) is a large network intercommunicating the lacunae and canaliculi which contain the osteocytes and their cytoplasmic processes within the mineralized bone matrix. The vitality and functioning of the osteocytes and cytoplasmic processes depend upon this intercommunication. To date, the 3-dimensional features of OLCS in the alveolar bone have not been studied; therefore the aim of this study was to use confocal scanning microscopy to do so. Samples of alveolar bone from male Wistar rats were fixed in buffer formalin and stained with basic fuchsin to visualize the lacuno canalicular system. In decalcified samples of the same bone, the actin was labeled using fluorescent phallotoxin to visualize the osteocyte network. The samples were observed at the level of the mesial root of the first upper molar in bucco-palatal direction using a confocal laser scanning microscope. The results showed that in the area near the inner aspect (bundle bone) of the buccal plate, the osteocyte lacunae are oval-shaped and relatively uniform in size, aligned parallel to each other and with their major axes parallel to the periodontal bone surface, and the osteocytes are oval-shaped, with their main axes perpendicular to the periodontal bone surface, and the cytoplasmic processes irradiate in all directions. In the area near the inner aspect (bundle bone) of the palatal plate, the osteocyte lacunae are rounded, have different sizes and their orientation does not follow any specific pattern, and the osteocyte bodies have major axes parallel to the periodontal surface, a larger number of cytoplasmic processes, and run in a straighter direction than in the buccal plate. These results will contribute to the understanding of the changes that may occur in OLCS microarchitecture as a result of a pathological process, surgical technique or force applied to the alveolar bone. PMID- 22928393 TI - Periodontal conditions in a group of Colombian type 2 diabetic patients with different degrees of metabolic control. AB - The aim of this study was to measure the occurrence of severe chronic periodontitis in a group of Colombian type 2 diabetes patients. A group of type 2 diabetic patients regularly attending a diabetes program was selected according to specific criteria. Demographic, medical and periodontal variables were recorded. A randomized half-mouth examination was performed, including plaque index, bleeding on probing, pocket depth and clinical attachment level. They were compared to a group of individuals without diabetes, based on different criteria; the first was the presence of > or = 2 interproximal sites with CAL > or = 6 mm, and > or = 1 interproximal sites with PD > or = 5 mm; the second was presence of > or = 50% percentage of bleeding on probing, and > or = 20% sites showing PD > or = 4 mm. The effect of metabolic control was analyzed. Results were tested through Chi-square, Mann-Whitney, Kruskal-Wallis and Pearson correlation tests. Seventy-two subjects with type 2 diabetes were compared to 39 subjects without diabetes of a similar age. Diabetic subjects had a fair degree of metabolic control, HbA1c 7.94% (1.60). Occurrence of severe chronic periodontitis was similar for both groups when using diagnostic criteria based on CAL levels, 22.22%, but was greater for subjects with diabetes when using criteria based on periodontal inflammation, 23.07% versus 5.12%. Degree of metabolic control had a relation to periodontal parameters. Colombian type 2 diabetes subjects demonstrated poorer periodontal conditions than non-diabetic individuals. PMID- 22928394 TI - Relationship between dental status and family, school and socioeconomic level. AB - The aim of this study was to analyze the association between the knowledge, attitudes, practices and formal schooling ofparents and the oral health status in schoolchildren enrolled in educational institutions of different socioeconomic levels, using dental caries as the tracer disease. A convenience sample of 300 school children aged 6-14 years old and living in Mar del Plata city, Argentina, was composed according to income characterization in three strata: low, middle and high income. The children were grouped according to age (6-8, 9-11 and 12-14 years old). A validated questionnaire on knowledge, attitudes and oral health practices was administered to parents. Children were examined for dental and gingival status. DMFS, dmfs, plaque and gingival bleeding indexes were determined. Mean and SEM and/or frequency distribution of each variable were determined and diferences assessed by ANOVA, chi-squared, Yates chi-squared and Scheffe tests (p < 0.05). Association among variables was tested by chi-squared test. The children from low income families showed significantly higher levels oforal disease in all the studied age groups. These families revealed significantly less healthy practices and attitudes along with lower formal schooling level. Dental indicators were inversely and significantly associated with parents' knowledge, attitudes and formal schooling and with plaque index. Bleeding on probing was inversely and significantly associated with plaque index, parents 'formal schooling and practices. Plaque index was found to be inversely associated with parents' knowledge, attitudes and formal schooling. Parents 'knowledge, formal schooling, attitudes and health practices are intervening variables on oral health status ofschool children and an intervention field with potential impactfor the oral component of health. PMID- 22928395 TI - [The new editors of Monaldi Archives for Chest Disease--cardiac series]. PMID- 22928396 TI - [Systems medicine as a scientific method for individualizing therapies in cardiology]. PMID- 22928397 TI - [Ultrasounds in cardiology: democratic but appropriate use!]. PMID- 22928398 TI - [Atherosclerosis of the lower extremities as a linked comorbidity in Patients Admitted for cardiac rehabilitation (THINKPAD): rationale, design, and study group]. AB - Peripheral arterial disease (PAD) is a frequent comorbidity among patients entering cardiac rehabilitation (CR) programmes and an important source of disability and impaired prognosis. The prevalence of PAD across the wide range of conditions for CR is poorly understood, as far as its impact on drug optimization and intervention delivered. The "ATHerosclerosis of the lower extremities as a liNKed comorbidity in Patients Admitted for carDiac rehabilitation" (THINKPAD) study was carried out by the Italian Association for Cardiovascular Prevention, Rehabilitation and Epidemiology (GICR-IACPR) in order to explore PAD both as a comorbidity and a primary indication at the entry of CR. The study was a retrospective case series. In the study period (from May 1, 2012 to June 30, 2012), data on consecutive patients discharged from 17 CR units in Northern Italy were collected. Web-based electronic case report forms (e-CRF), accessible in a dedicated section of the IACPR website (www.iacpr.it), were used for data entry, and data were transferred via web to a central database. The data collection instrument was designed with a multiple choice format, with jump menus or select boxes and obligatory items. A sample size of 1,300 subjects is expected, with first data available by the end of 2012. PMID- 22928399 TI - [Groups with volunteers cardiac surgery patients: experience in a cardiovascular rehabilitation department]. AB - OBJECTIVES: This article aimed to describe a new experience activated inside of a more general psychological approach for patients who underwent cardiac surgery intervention. MATERIAL AND METHODS: The first 100 patients taking part to the groups were subjected to a questionnaire in order to evaluate the satisfaction degree of the meeting. RESULTS: The questionnaire results, showed on the whole a good rating of the meeting. In addition to quantitative results, we express and discuss in this paper some considerations concerning the obtained results. CONCLUSIONS: Preliminary data analysis show that volunteers previously submitted to cardiac surgery seem to offer an important contribution to the psychological support of patients recently undergone cardiac surgery. PMID- 22928400 TI - Role of a multidisciplinary program in improving outcomes in cognitively impaired heart failure older patients. AB - BACKGROUND: Cognitive impairment (CI) frequently complicates Heart failure (HF) and is associated with increased mortality and morbidity. Previous studies reported that nurse-lead home-based multidisciplinary program (MP) may not improve the prognosis of this high-risk group. In the present study, we analysed the relative effectiveness of an integrated hospital-based MP in patients with cognitive impairment. METHODS: Consecutive (n = 173) community-living outpatients aged > 70 years (mean 77 +/- 6, 48% women) randomized to a MP (n = 86) or usual care (UC) (n = 87) were enrolled in stable clinical conditions. Cognitive status was assessed by means of Folstein Mini Mental State Examination (MMSE). RESULTS: CI (MMSE < or = 24) was present in 41.6% (42,5% UC vs 40.7% MP p =ns). The variables independently associated to CI were: older age, education level <5 years, anemia and severe renal dysfunction. During a 2-year follow-up, 59 patients died (31.4%) with no significant difference between intervention group. At multivariate analysis, in the entire cohort, CI was independently associated to death (HR 2,07 7[95%CI 1,097-3,931]), HF admissions (2,133[1,346-3,381]), death/HF admissions (1,784[1,132-2,811]) and all-cause admissions (1,473[1,008 2,153]. When considered according to intervention groups, CI was independently associated to all-cause death (3,603 [1,553-8,358], death/HF admissions (2,029[1,200-3,432]) and HF admissions (2,474[1,406-4,353]) but not to all-cause admissions. The assignment of patients with CI to MP was associated to a significant reduction in HF admissions vs UC (0,503[0,253-0,999] (all interaction tests p = ns). CONCLUSIONS: This study suggests that CI is very common and associated to worse prognosis in heart failure and that hospital-based MP seems to improve outcomes in these patients through reduction of heart failure hospital admission. PMID- 22928401 TI - Psychological profiles derived by cluster analysis of Minnesota Multiphasic Personality Inventory and long term clinical outcome after coronary artery by pass grafting. AB - BACKGROUND: To evaluate the psychological characteristics of coronary heart disease (CHD) patients after coronary artery bypass grafting (CABG) by cluster analysis of Minnesota Multiphasic Personality Inventory (MMPI-2) questionnaires and to assess the impact of the profiles obtained on long-term outcome. METHODS: 229 CHD patients admitted to cardiac rehabilitation filled in self-administered MMPI-2 questionnaires early after CABG. We assessed the relation between MMPI-2 profiles derived by cluster analysis, clinical characteristics and outcome at 3 year follow-up. RESULTS: Among the 215 patients (76% men, median age 66 years) with valid criteria in control scales, we identified 3 clusters (G) with homogenous psychological characteristics: G1 patients (N = 75) presented somatoform complaints but overall minimal psychological distress. G2 patients (N=72) presented type D personality traits. G3 subjects (N=68) showed a trend to cynicism, mild increases in anger, social introversion and hostility. Clusters overlapped for clinical characteristics such as smoking (G1 21%, G2 24%, G3 24%, p ns), previous myocardial infarction (G1 43%, G2 47%, G3 49% p ns), LV ejection fraction (G1 60 [51-60]; G2 58 [49-60]; G3 60 [55-60], p ns), 3-vessel-disease prevalence (G1 69%, G2 65%, G3 71%, p ns). Three-year event rates were comparable (G1 15%; G2 18%; G3 15%) and Kaplan-Meier curves overlapped among clusters (p ns). CONCLUSIONS: After CABG, the interpretation of MMPI-2 by cluster analysis is useful for the psychological and personological diagnosis to direct psychological assistance. Conversely, results from cluster analysis of MMPI-2 do not seem helpful to the clinician to predict long term outcome. PMID- 22928402 TI - [Endothelial dysfunction in type 2 diabetic patients with normal coronary arteries. A peripheral arterial tonometry study]. AB - AIM: to evaluate endothelial function (EF) in diabetic and non-diabetic patients without CAD by peripheral artery tonometry (PAT) technique. METHODS: a cohort of 94 patients (55 men and 39 postmenopausal women; mean age 63 +/- 9 years) undergoing coronary angiography was divided into 2 groups: 58 patients with DM and (group 1) and 36 patients without DM. Endothelial dysfunction (ED) was assessed by digital pulse amplitude, using a fingertip peripheral arterial tonometry (PAT). As a measure of ED, reactive hyperemia index (RHI) was calculated as the ratio of the digital pulse volume during reactive hyperemia following 5 min ischemia and its basal value. RESULTS: prevalence of cardiovascular risk factors was similar between the two groups. RHI values were significantly lower in diabetic patients compared to non-diabetics (1.72 +/- 0.34 vs 2.00 +/- 0.44; p < 0.005) and they correlated with levels of glycosylated hemoglobin (p = 0.05; r = -0.266). CONCLUSION: despite similar level of other risk factors, EF was much more impaired in diabetic patients than in non diabetics. These evidences further support the impact of DM on cardiovascular risk. PMID- 22928403 TI - [The Italian Network for Heart Failure five years after the publication of the Italian "Consensus conference on the management of heart failure"]. AB - In the year 2006 the Italian Association of Hospital Cardiologists (ANMCO) promoted a Consensus Conference among professional Scientific Societies in order to redefine the role and core responsibilities of each health professionals involved in heart failure management in a novel integrated network. Five years later, a questionnaire has been proposed to each Italian Regional President of the Association, in order to assess the implementation of the proposed management strategies in the different clinical scenarios of the Italian Regions. Although the Document utilization is not homogeneous through Italy, it is still considered a valuable tool of work. PMID- 22928404 TI - Phenological tracking enables positive species responses to climate change. AB - Earlier spring phenology observed in many plant species in recent decades provides compelling evidence that species are already responding to the rising global temperatures associated with anthropogenic climate change. There is great variability among species, however, in their phenological sensitivity to temperature. Species that do not phenologically "track" climate change may be at a disadvantage if their growth becomes limited by missed interactions with mutualists, or a shorter growing season relative to earlier-active competitors. Here, we set out to test the hypothesis that phenological sensitivity could be used to predict species performance in a warming climate, by synthesizing results across terrestrial warming experiments. We assembled data for 57 species across 24 studies where flowering or vegetative phenology was matched with a measure of species performance. Performance metrics included biomass, percent cover, number of flowers, or individual growth. We found that species that advanced their phenology with warming also increased their performance, whereas those that did not advance tended to decline in performance with warming. This indicates that species that cannot phenologically "track" climate may be at increased risk with future climate change, and it suggests that phenological monitoring may provide an important tool for setting future conservation priorities. PMID- 22928405 TI - Characterizing species abundance distributions across taxa and ecosystems using a simple maximum entropy model. AB - The species abundance distribution (SAD) is one of themost studied patterns in ecology due to its potential insights into commonness and rarity, community assembly, and patterns of biodiversity. It is well established that communities are composed of a few common and many rare species, and numerous theoretical models have been proposed to explain this pattern. However, no attempt has been made to determine how well these theoretical characterizations capture observed taxonomic and global-scale spatial variation in the general form of the distribution. Here, using data of a scope unprecedented in community ecology, we show that a simple maximum entropy model produces a truncated log-series distribution that can predict between 83% and 93% of the observed variation in the rank abundance of species across 15 848 globally distributed communities including birds, mammals, plants, and butterflies. This model requires knowledge of only the species richness and total abundance of the community to predict the full abundance distribution, which suggests that these factors are sufficient to understand the distribution for most purposes. Since geographic patterns in richness and abundance can often be successfully modeled, this approach should allow the distribution of commonness and rarity to be characterized, even in locations where empirical data are unavailable. PMID- 22928406 TI - Critical patch sizes for food-web modules. AB - Because patch size and connectivity may strongly impact the assemblage of species that occur on a patch, the types of food-web interactions that occur among those species may also depend on spatial structure. Here, we identify whether food-web interactions among salt-marsh-inhabiting arthropods vary with patch size and connectivity, and how such changes in trophic structure might feed back to influence the spatial distribution of prey. In a multiyear survey, patch restricted predators exhibited steeper occupancy-patch-size relationships than herbivores, and species' critical patch sizes were correlated with overall rarity. As a result, the presence of food-web modules depended strongly on patch size: large and well-connected patches supported complex food-web modules, but only the simplest modules involving the most abundant species were found on small patches. Habitat-generalist spiders dominated on small patches, and predation pressure from such species may contribute to the observed lower densities of mesopredators on small patches. Overall, patch size and connectivity influenced the types of modules present on a patch through differential loss of rare, patch restricted predators, but predation by generalist predators may be a key mechanism influencing the spatial structure of certain prey species. PMID- 22928407 TI - Insect herbivory and propagule pressure influence Cirsium vulgare invasiveness across the landscape. AB - A current challenge in ecology is to better understand the magnitude, variation, and interaction in the factors that limit the invasiveness of exotic species. We conducted a factorial experiment involving herbivore manipulation (insecticide-in water vs. water-only control) and seven densities of introduced nonnative Cirsium vulgare (bull thistle) seed. The experiment was repeated with two seed cohorts at eight grassland sites uninvaded by C. vulgare in the central Great Plains, USA. Herbivory by native insects significantly reduced thistle seedling density, causing the largest reductions in density at the highest propagule inputs. The magnitude of this herbivore effect varied widely among sites and between cohort years. The combination of herbivory and lower propagule pressure increased the rate at which new C. vulgare populations failed to establish during the initial stages of invasion. This experiment demonstrates that the interaction between biotic resistance by native insects, propagule pressure, and spatiotemporal variation in their effects were crucial to the initial invasion by this Eurasian plant in the western tallgrass prairie. PMID- 22928408 TI - Prey-predator dynamics in rotifers: density-dependent consequences of spatial heterogeneity due to surface attachment. AB - Classical models of prey-predator interactions assume that per capita prey consumption is dependent on prey density alone and that prey consumption (functional response) and consumer proliferation (numerical response) operate on the same timescales and without time lags. Several modifications have been proposed for resolving this timescale discrepancy, including variants where the functional response depends on both prey and predator densities. A microcosm system with the rotifer Brachionus 'Nevada' feeding on the prasinophyte Tetraselmis sp. showed significant (P < 0.0005) increases in steady-state biomasses of both prey and predators with increasing carrying capacity (represented by total phosphorus of the growth medium), which is inconsistent with predictions based on the traditional prey-only-dependent functional response. We provide data indicating that surfaces where the predator can attach provide a high-quality habitat for rotifers, which can result in a predator dependent functional response. We also show that partitioning between the attached and free-swimming habitats was fast compared to the timescale of the numerical response. When attached to surfaces, rotifers maximized net energy gain by avoiding the high cost of swimming and by increased food capture due to reduced viscous drag. A mathematical model with prey-dependent functional response and wall-attached and free-swimming fractions of the population describes our data adequately. We discuss the implications of this finding for extrapolating microcosm experiments to systems with other surface-to-volume ratios, and to what extent our findings may apply to other popular model organisms for prey-predator interaction. PMID- 22928409 TI - Competitive exclusion within the predator community influences the distribution of a threatened prey species. AB - While much effort has been made to quantify how landscape composition influences the distribution of species, the possibility that geographical differences in species interactions might affect species distributions has received less attention. Investigating a predator-prey setting in a boreal forest ecosystem, we empirically show that large-scale differences in the predator community structure and small-scale competitive exclusion among predators affect the local distribution of a threatened forest specialist more than does landscape composition. Consequently, even though the landscape parameters affecting Siberian flying squirrel (Pteromys volans) distribution (prey) did not differ between nest sites of the predators Northern Goshawks (Accipiter gentilis) and Ural Owls (Strix uralensis), flying squirrels were heterospecifically attracted by goshawks in a region where both predator species were present. No such effect was found in another region where Ural Owls were absent. These results provide evidence that differences in species interactions over large spatial scales may be a major force influencing the distribution and abundance patterns of species. On the basis of these findings, we suspect that subtle species interactions might be a central reason why landscape models constructed to predict species distributions often fail when applied to wider geographical scales. PMID- 22928410 TI - A generalized approach to modeling and estimating indirect effects in ecology. AB - The need to model and test hypotheses about complex ecological systems has led to a steady increase in use of path analytical techniques, which allow the modeling of multiple multivariate dependencies reflecting hypothesized causation and mechanisms. The aim is to achieve the estimation of direct, indirect, and total effects of one variable on another and to assess the adequacy of whole models. Path analytical techniques based on maximum likelihood currently used in ecology are rarely adequate for ecological data, which are often sparse, multi-level, and may contain nonlinear relationships as well as nonnormal response data such as counts or proportion data. Here I introduce a more flexible approach in the form of the joint application of hierarchical Bayes, Markov chain Monte Carlo algorithms, Shipley's d-sep test, and the potential outcomes framework to fit path models as well as to decompose and estimate effects. An example based on the direct and indirect interactions between ants, two insect herbivores, and a plant species demonstrates the implementation of these techniques, using freely available software. PMID- 22928412 TI - Testing a pyroclimatic hypothesis on the Mexico-United States border. AB - The "pyroclimatic hypothesis" proposed by F. Biondi and colleagues provides a basis for testable expectations about climatic and other controls of fire regimes. This hypothesis asserts an a priori relationship between the occurrence of widespread fire and values of a relevant climatic index. Such a hypothesis provides the basis for predicting spatial and temporal patterns of fire occurrence based on climatic control. Forests near the Mexico-United States border offer a place to test the relative influence of climatic and other controls in mountain ranges that are ecologically similar and subject to broadly similar top-down climatic influence, but with differing cultural influences. We tested the pyroclimatic hypothesis by comparing fire history information from the Mesa de las Guacamayas, a mountain range in northwestern Chihuahua, with previously published fire data from the Chiricahua Mountains, in southeastern Arizona, approximately 150 km away. We developed a priori hypothetical models of fire occurrence and compared their performance to empirical climate-based models. Fires were frequent at all Mesa de las Guacamayas study sites through the mid 20th century and continued uninterrupted to the present at one site, in contrast to nearly complete fire exclusion after 1892 at sites in the Chiricahua Mountains. The empirical regression models explained a higher proportion of the variability in fire regime associated with climate than did the a priori models. Actual climate-fire relationships diverged in each country after 1892. The a priori models predicted continuing fires at the same rate per century as prior to 1892; fires did in fact continue in Mexico, albeit with some alteration of fire regimes, but ceased in the United States, most likely due to changes in land use. The cross-border comparison confirms that a frequent-fire regime could cease without a climatic cause, supporting previous arguments that bottom-up factors such as livestock grazing can rapidly and drastically alter surface fire regimes. Understanding the historical patterns of climate controls on fire could inform the use of historical data as ecological reference conditions and for future sustainability. PMID- 22928411 TI - Sinks for nitrogen inputs in terrestrial ecosystems: a meta-analysis of 15N tracer field studies. AB - Effects of anthropogenic nitrogen (N) deposition and the ability of terrestrial ecosystems to store carbon (C) depend in part on the amount of N retained in the system and its partitioning among plant and soil pools. We conducted a meta analysis of studies at 48 sites across four continents that used enriched 15N isotope tracers in order to synthesize information about total ecosystem N retention (i.e., total ecosystem 15N recovery in plant and soil pools) across natural systems and N partitioning among ecosystem pools. The greatest recoveries of ecosystem 15N tracer occurred in shrublands (mean, 89.5%) and wetlands (84.8%) followed by forests (74.9%) and grasslands (51.8%). In the short term (< 1 week after 15N tracer application), total ecosystem 15N recovery was negatively correlated with fine-root and soil 15N natural abundance, and organic soil C and N concentration but was positively correlated with mean annual temperature and mineral soil C:N. In the longer term (3-18 months after 15N tracer application), total ecosystem 15N retention was negatively correlated with foliar natural abundance 15N but was positively correlated with mineral soil C and N concentration and C:N, showing that plant and soil natural-abundance 15N and soil C:N are good indicators of total ecosystem N retention. Foliar N concentration was not significantly related to ecosystem 15N tracer recovery, suggesting that plant N status is not a good predictor of total ecosystem N retention. Because the largest ecosystem sinks for 15N tracer were below ground in forests, shrublands, and grasslands, we conclude that growth enhancement and potential for increased C storage in aboveground biomass from atmospheric N deposition is likely to be modest in these ecosystems. Total ecosystem 15N recovery decreased with N fertilization, with an apparent threshold fertilization rate of 46 kg N x ha(-1) x yr(-1) above which most ecosystems showed net losses of applied 15N tracer in response to N fertilizer addition. PMID- 22928413 TI - Decomposing the mid-Holocene Tsuga decline in eastern North America. AB - The mid-Holocene decline of Tsuga canadensis (hereafter Tsuga) populations across eastern North America is widely perceived as a synchronous event, driven by pests/pathogens, rapid climate change, or both. Pattern identification and causal attribution are hampered by low stratigraphic density of pollen-sampling and radiometric dates at most sites, and by absence of highly resolved, paired pollen and paleoclimate records from single sediment cores, where chronological order of climatic and vegetational changes can be assessed. We present an intensely sampled (contiguous 1-cm intervals) record of pollen and water table depth (inferred from testate amoebae) from a single core spanning the Tsuga decline at Irwin Smith Bog in Lower Michigan, with high-precision chronology. We also present an intensively sampled pollen record from Tower Lake in Upper Michigan. Both sites show high-magnitude fluctuations in Tsuga pollen percentages during the pre-decline maximum. The terminal decline is dated at both sites ca. 5000 cal yr BP, some 400 years later than estimates from other sites and data compilations. The terminal Tsuga decline was evidently heterochronous across its range. A transient decline ca. 5350 cal yr BP at both sites may correspond to the terminal decline at other sites in eastern North America. At Irwin Smith Bog, the terminal Tsuga decline preceded an abrupt and persistent decline in water table depths by approximately 200 years, suggesting the decline was not directly driven by abrupt climate change. The Tsuga decline may best be viewed as comprising at least three phases: a long-duration pre-decline maximum with high-magnitude and high-frequency fluctuations, followed by a terminal decline at individual sites, followed in turn by two millennia of persistently low Tsuga populations. These phases may not be causally linked, and may represent dynamics taking place at multiple temporal and spatial scales. Further progress toward understanding the phenomenon requires an expanded network of high-resolution pollen and paleoclimate chronologies. PMID- 22928414 TI - Impacts of climate variability and human colonization on the vegetation of the Galapagos Islands. AB - A high-resolution (2-9 year sampling interval) fossil pollen record from the Galapagos Islands, which spans the last 2690 years, reveals considerable ecosystem stability. Vegetation changes associated with independently derived histories of El Nino Southern Oscillation variability provided evidence of shifts in the relative abundance of individual species rather than immigration or extinction. Droughts associated with the Medieval Climate Anomaly induced rapid ecological change that was followed by a reversion to the previous state. The paleoecological data suggested nonneutral responses to climatic forcing in this ecosystem prior to the period of human influence. Human impacts on the islands are evident in the record. A marked decline in long-term codominants of the pollen record, Alternanthera and Acalypha, produced a flora without modern analogue before 1930. Intensified animal husbandry after ca. 1930 may have induced the local extinction of Acalypha and Alternanthera. Reductions in populations of grazing animals in the 1970s and 1980s did not result in the return of the native flora, but in invasions by exotic species. After ca. 1970 the trajectory of habitat change accelerated, continuously moving the ecosystem away from the observed range of variability in the previous 2690 years toward a novel ecosystem. The last 40 years of the record also suggest unprecedented transport of lowland pollen to the uplands, consistent with intensified convection and warmer wet seasons. PMID- 22928415 TI - Mapping the niche space of soil microorganisms using taxonomy and traits. AB - The biodiversity of microbial communities has important implications for the stability and functioning of ecosystem processes. Yet, very little is known about the environmental factors that define the microbial niche and how this influences the composition and activity of microbial communities. In this study, we derived niche parameters from physiological response curves that quantified microbial respiration for a diverse collection of soil bacteria and fungi along a soil moisture gradient. On average, soil microorganisms had relatively dry optima (0.3 MPa) and were capable of respiring under low water potentials (-2.0 MPa). Within their limits of activity, microorganisms exhibited a wide range of responses, suggesting that some taxa may be able to coexist by partitioning the moisture niche axis. For example, we identified dry-adapted generalists that tolerated a broad range of water potentials, along with wet-adapted specialists with metabolism restricted to less-negative water potentials. These contrasting ecological strategies had a phylogenetic signal at a coarse taxonomic level (phylum), suggesting that the moisture niche of soil microorganisms is highly conserved. In addition, variation in microbial responses along the moisture gradient was linked to the distribution of several functional traits. In particular, strains that were capable of producing biofilms had drier moisture optima and wider niche breadths. However, biofilm production appeared to come at a cost that was reflected in a prolonged lag time prior to exponential growth, suggesting that there is a trade-off associated with traits that allow microorganisms to contend with moisture stress. Together, we have identified functional groups of microorganisms that will help predict the structure and functioning of microbial communities under contrasting soil moisture regimes. PMID- 22928416 TI - Separating selection by diurnal and nocturnal pollinators on floral display and spur length in Gymnadenia conopsea. AB - Most plants attract multiple flower visitors that may vary widely in their effectiveness as pollinators. Floral evolution is expected to reflect interactions with the most important pollinators, but few studies have quantified the contribution of different pollinators to current selection on floral traits. To compare selection mediated by diurnal and nocturnal pollinators on floral display and spur length in the rewarding orchid Gymnadenia conopsea, we manipulated the environment by conducting supplemental hand-pollinations and selective pollinator exclusions in two populations in central Norway. In both populations, the exclusion of diurnal pollinators significantly reduced seed production compared to open pollination, whereas the exclusion of nocturnal pollinators did not. There was significant selection on traits expected to influence pollinator attraction and pollination efficiency in both the diurnal and nocturnal pollination treatment. The relative strength of selection among plants exposed to diurnal and nocturnal visitors varied among traits and populations, but the direction of selection was consistent. The results suggest that diurnal pollinators are more important than nocturnal pollinators for seed production in the study populations, but that both categories contribute to selection on floral morphology. The study illustrates how experimental manipulations can link specific categories of pollinators to observed selection on floral traits, and thus improve our understanding of how species interactions shape patterns of selection. PMID- 22928417 TI - Plant-mediated and nonadditive effects of two global change drivers on an insect herbivore community. AB - Warmer temperatures can alter the phenology and distribution of individual species. However, differences across species may blur community-level phenological responses to climate or cause biotic homogenization by consistently favoring certain taxa. Additionally, the response of insect communities to climate will be subject to plant-mediated effects, which may or may not overshadow the direct effect of rising temperatures on insects. Finally, recent evidence for the importance of interaction effects between global change drivers suggests that phenological responses of communities to climate may be altered by other drivers. We used a natural temperature gradient (generated by elevation and topology), combined with experimental nitrogen fertilization, to investigate the effects of elevated temperature and globally increasing anthropogenic nitrogen deposition on the structure and phenology of a seminatural grassland herbivore assemblage (lepidopteran insects). We found that both drivers, alone and in combination, severely altered how the relative abundance and composition of species changed through time. Importantly, warmer temperatures were associated with biotic homogenization, such that herbivore assemblages in the warmest plots had more similar species composition than those in intermediate or cool plots. Changes in herbivore composition and abundance were largely mediated by changes in the plant community, with increased nonnative grass cover under high treatment levels being the strongest determinant of herbivore abundance. In addition to compositional changes, total herbivore biomass more than doubled under elevated nitrogen and increased more than fourfold with temperature, bearing important functional implications for herbivores as consumers and as a prey resource. The crucial role of nonnative plant dominance in mediating responses of herbivores to change, combined with the frequent nonadditive (positive and negative) effects of the two drivers, and the differential responses of species, highlight that understanding complex ecosystem responses will benefit from multifactor, multitrophic experiments at community scales or larger. PMID- 22928418 TI - Herbivory by an introduced Asian weevil negatively affects population growth of an invasive Brazilian shrub in Florida. AB - The enemy release hypothesis (ERH) is often cited to explain why some plants successfully invade natural communities while others do not. This hypothesis maintains that plant populations are regulated by coevolved enemies in their native range but are relieved of this pressure where their enemies have not been co-introduced. Some studies have shown that invasive plants sustain lower levels of herbivore damage when compared to native species, but how damage affects fitness and population dynamics remains unclear. We used a system of co-occurring native and invasive Eugenia congeners in south Florida (USA) to experimentally test the ERH, addressing deficiencies in our understanding of the role of natural enemies in plant invasion at the population level. Insecticide was used to experimentally exclude insect herbivores from invasive Eugenia uniflora and its native co-occurring congeners in the field for two years. Herbivore damage, plant growth, survival, and population growth rates for the three species were then compared for control and insecticide-treated plants. Our results contradict the ERH, indicating that E. uniflora sustains more herbivore damage than its native congeners and that this damage negatively impacts stem height, survival, and population growth. In addition, most damage to E. uniflora, a native of Brazil, is carried out by Myllocerus undatus, a recently introduced weevil from Sri Lanka, and M. undatus attacks a significantly greater proportion of E. uniflora leaves than those of its native congeners. This interaction is particularly interesting because M. undatus and E. uniflora share no coevolutionary history, having arisen on two separate continents and come into contact on a third. Our study is the first to document negative population-level effects for an invasive plant as a result of the introduction of a novel herbivore. Such inhibitory interactions are likely to become more prevalent as suites of previously noninteracting species continue to accumulate and new communities assemble worldwide. PMID- 22928419 TI - Combining optimal defense theory and the evolutionary dilemma model to refine predictions regarding plant invasion. AB - Optimal defense theory posits that plants with limited resources deploy chemical defenses based on the fitness value of different tissues and their probability of attack. However, what constitutes optimal defense depends on the identity of the herbivores involved in the interaction. Generalists, which are not tightly coevolved with their many host plants, are typically deterred by chemical defenses, while coevolved specialists are often attracted to these same chemicals. This imposes an "evolutionary dilemma" in which generalists and specialists exert opposing selection on plant investment in defense, thereby stabilizing defenses at intermediate levels. We used the natural shift in herbivore community composition that typifies many plant invasions to test a novel, combined prediction of optimal defense theory and the evolutionary dilemma model: that the within-plant distribution of defenses reflects both the value of different tissues (i.e., young vs. old leaves) and the relative importance of specialist and generalist herbivores in the community. Using populations of Verbascum thapsus exposed to ambient herbivory in its native range (where specialist and generalist chewing herbivores are prevalent) and its introduced range (where only generalist chewing herbivores are prevalent), we illustrate significant differences in the way iridoid glycosides are distributed among young and old leaves. Importantly, high-quality young leaves are 6.5x more highly defended than old leaves in the introduced range, but only 2x more highly defended in the native range. Additionally, defense levels are tracked by patterns of chewing damage, with damage restricted mostly to low-quality old leaves in the introduced range, but not the native range. Given that whole-plant investment in defense does not differ between ranges, introduced mullein may achieve increased fitness simply by optimizing its within-plant distribution of defense in the absence of certain specialist herbivores. PMID- 22928420 TI - Match/mismatch between the Mytilus edulis larval supply and seston quality: effect on recruitment. AB - We considered Cushing's match/mismatch theory in a heterotrophic environment and hypothesized that settlement and recruitment success in blue mussel are higher when the food supply is rich in polyunsaturated and essential fatty acids (PUFA/EFA). To test this hypothesis, we monitored larval development as well as fatty acid composition in trophic resources during two successive reproductive seasons. The decoupling we found between the presence of competent larvae in the water column and settlement rates strongly suggests that metamorphosis is delayed until conditions are suitable. In both years, the major mussel settlement peak was synchronized with a phytoplanktonic pulse rich in EFA, consisting of a large autotrophic bloom in 2007 and a short but substantial peak of picoeukaryotes in 2008. These results suggest a "trophic settlement trigger" that indirectly affects recruitment by strongly improving the settlement rate. Despite similar larval settlement rates during both years, the lower 2007 recruitment likely resulted from a mismatch with a high lipid-quality trophic resource. The seasonal trophic conditions differed greatly between the two years, with fatty acids profiles reflecting heterotrophic plankton production in 2007 and mostly autotrophic production in 2008. In agreement with Cushing's theory, our results highlight a match/mismatch, related to the food lipid quality rather than food quantity. For the first time, we show that the recruitment in marine bivalves may be dependent on phytoplanktonic pulses characterized by high levels of PUFA. PMID- 22928421 TI - The role of individual behavior type in mediating indirect interactions. AB - Trait-mediated indirect interactions (TMII) play an important role in structuring natural communities, and numerous studies have experimentally demonstrated their presence in a variety of systems. However, these studies have largely examined the presence or absence of traits that are responsible for these interactions, without considering natural variation between individuals in the extent to which these traits are manifested. We used a well-documented TMII to investigate the importance of individual behavior type for determining the strength of the TMII. The toadfish Opsanus tau has an indirect positive influence on bivalve survival because the mud crab Panopeus herbstii, a consumer of bivalves, reduces foraging effort in the presence of toadfish. We quantified variation in the strength of persistent individual mud crab responses to toadfish and resulting variation in the strength of TMII. We demonstrate that the strength of this TMII is strongly influenced by mud crab size and behavior type, strengthening with the intensity of response of individual mud crabs to toadfish predator cues. Further, we demonstrate that the spatial distribution within intertidal oyster reefs of crabs with different behavior types is not random; mud crabs inhabiting subtidal areas, where predator cues are more persistent, are significantly less responsive to toadfish cues than mud crabs from intertidal areas. This spatial behavioral structure should lead to spatial variation in the strength of TMII. Given the widespread importance of TMII and the broad occurrence of individual personality or behavior types across numerous taxa, these results should be generally applicable. The distribution of behavior types within a population may therefore be a useful metric for improving our ability to predict the strength of TMII. PMID- 22928422 TI - The interaction between reproductive cost and individual quality is mediated by oceanic conditions in a long-lived bird. AB - Environmental variability, costs of reproduction, and heterogeneity in individual quality are three important sources of the temporal and interindividual variations in vital rates of wild populations. Based on an 18-year monitoring of an endangered, recently described, long-lived seabird, Monteiro's Storm-Petrel (Oceanodroma monteiroi), we designed multistate survival models to separate the effects of the reproductive cost (breeders vs. nonbreeders) and individual quality (successful vs. unsuccessful breeders) in relation to temporally variable demographic and oceanographic properties. The analysis revealed a gradient of individual quality from nonbreeders, to unsuccessful breeders, to successful breeders. The survival rates of unsuccessful breeders (0.90 +/- 0.023, mean +/- SE) tended to decrease in years of high average breeding success and were more sensitive to oceanographic variation than those of both (high-quality) successful breeders (0.97 +/- 0.015) and (low-quality) nonbreeders (0.83 +/- 0.028). Overall, our results indicate that reproductive costs act on individuals of intermediate quality and are mediated by environmental harshness. PMID- 22928423 TI - Neighborhood and habitat effects on vital rates: expansion of the Barred Owl in the Oregon coast ranges. AB - In this paper, we modify dynamic occupancy models developed for detection nondetection data to allow for the dependence of local vital rates on neighborhood occupancy, where neighborhood is defined very flexibly. Such dependence of occupancy dynamics on the status of a relevant neighborhood is pervasive, yet frequently ignored. Our framework permits joint inference about the importance of neighborhood effects and habitat covariates in determining colonization and extinction rates. Our specific motivation is the recent expansion of the Barred Owl (Strix varia) in western Oregon, USA, over the period 1990-2010. Because the focal period was one of dramatic range expansion and local population increase, the use of models that incorporate regional occupancy (sources of colonists) as determinants of dynamic rate parameters is especially appropriate. We began our analysis of 21 years of Barred Owl presence/nondetection data in the Tyee Density Study Area (TDSA) by testing a suite of six models that varied only in the covariates included in the modeling of detection probability. We then tested whether models that used regional occupancy as a covariate for colonization and extinction outperformed models with constant or year-specific colonization or extinction rates. Finally we tested whether habitat covariates improved the AIC of our models, focusing on which habitat covariates performed best, and whether the signs of habitat effects are consistent with a priori hypotheses. We conclude that all covariates used to model detection probability lead to improved AIC, that regional occupancy influences colonization and extinction rates, and that habitat plays an important role in determining extinction and colonization rates. As occupancy increases from low levels toward equilibrium, colonization increases and extinction decreases, presumably because there are more and more dispersing juveniles. While both rates are affected, colonization increases more than extinction decreases. Colonization is higher and extinction is lower in survey polygons with more riparian forest. The effects of riparian forest on extinction rates are greater than on colonization rates. Model results have implications for management of the invading Barred Owl, both through habitat alteration and removal. PMID- 22928424 TI - Why are metapopulations so rare? AB - Roughly 40 years after its introduction, the metapopulation concept is central to population ecology. The notion that local populations and their dynamics may be coupled by dispersal is without any doubt of great importance for our understanding of population-level processes. A metapopulation describes a set of subpopulations linked by (rare) dispersal events in a dynamic equilibrium of extinctions and recolonizations. In the large body of literature that has accumulated, the term "metapopulation" is often used in a very broad sense; most of the time it simply implies spatial heterogeneity. A number of reviews have recently addressed this problem and have pointed out that, despite the large and still growing popularity of the metapopulation concept, there are only very few empirical examples that conform with the strict classical metapopulation (CM) definition. In order to understand this discrepancy between theory and observation, we use an individual-based modeling approach that allows us to pinpoint the environmental conditions and the life-history attributes required for the emergence of a CM structure. We find that CM dynamics are restricted to a specific parameter range at the border between spatially structured but completely occupied and globally extinct populations. Considering general life history attributes, our simulations suggest that CMs are more likely to occur in arthropod species than in (large) vertebrates. Since the specific type of spatial population structure determines conservation concepts, our findings have important implications for conservation biology. Our model suggests that most spatially structured populations are panmictic, patchy, or of mainland-island type, which makes efforts spent on increasing connectivity (e.g., corridors) questionable. If one does observe a true CM structure, this means that the focal metapopulation is on the brink of extinction and that drastic conservation measures are needed. PMID- 22928425 TI - Cartilage repair in the knee: part III. Foreword. PMID- 22928426 TI - The cartilage-bone interface. AB - In the knee joint, the purpose of the cartilage-bone interface is to maintain structural integrity of the osteochondral unit during walking, kneeling, pivoting, and jumping--during which tensile, compressive, and shear forces are transmitted from the viscoelastic articular cartilage layer to the much stiffer mineralized end of the long bone. Mature articular cartilage is integrated with subchondral bone through a approximately 20 to approximately 250 microm thick layer of calcified cartilage. Inside the calcified cartilage layer, perpendicular chondrocyte-derived collagen type II fibers become structurally cemented to collagen type I osteoid deposited by osteoblasts. The mature mineralization front is delineated by a thin approximately 5 microm undulating tidemark structure that forms at the base of articular cartilage. Growth plate cartilage is anchored to epiphyseal bone, sometimes via a thin layer of calcified cartilage and tidemark, while the hypertrophic edge does not form a tidemark and undergoes continual vascular invasion and endochondral ossification (EO) until skeletal maturity upon which the growth plates are fully resorbed and replaced by bone. In this review, the formation of the cartilage-bone interface during skeletal development and cartilage repair, and its structure and composition are presented. Animal models and human anatomical studies show that the tidemark is a dynamic structure that forms within a purely collagen type II-positive and collagen type I-negative hyaline cartilage matrix. Cartilage repair strategies that elicit fibrocartilage, a mixture of collagen type I and type II, are predicted to show little tidemark/calcified cartilage regeneration and to develop a less stable repair tissue-bone interface. The tidemark can be regenerated through a bone marrow driven growth process of EO near the articular surface. PMID- 22928427 TI - Osteochondral autograft transplantation/mosaicplasty. AB - The treatment of full-thickness chondral lesions remains a challenging clinical dilemma. The natural history of untreated lesions results in radiographic deterioration and suboptimal clinical outcome scores. Interventions such as marrow stimulating procedures elicit fibrocartilaginous healing. These have demonstrated some utility but concerns exist about the long-term prognosis. Mosaicplasty is an intervention that can treat full thickness defects with preservation of hyaline cartilage, which may improve the long-term outcomes. It is indicated for patients with isolated lesions between 1 and 4 cm2 in a stable knee with appropriate alignment. The procedure can be performed either open or arthroscopically depending on the surgeon's experience. Graft harvest and placement can be technically demanding. Congruency of the grafts is an essential part of the procedure. If placed in a convex location the central graft may need to be slightly longer. Graft prominence of > 1 mm is poorly tolerated. Clinical results thus far have demonstrated excellent results when mosaicplasty is performed with appropriate indications. PMID- 22928428 TI - Osteochondral allograft transplantation in the knee. AB - Fresh osteochondral allograft (OCA) transplantation has over a 100-year clinical history. Many clinical and basic scientific studies have been performed with the result that allografting is now a part of the "cartilage repair paradigm" for the treatment of chondral or osteochondral lesions. In the knee joint, allografting has also been successfully used in complex joint reconstruction for the treatment of osteonecrosis, fracture malunion, and selected cases of osteoarthritis. Unlike many other cartilage repair techniques, OCA have the ability to restore mature, hyaline articular cartilage to the affected area. By virtue of their composite structure (cartilage and bone), allografts also can restore diseased or damaged bone often present in large or complex lesions. Nevertheless, OCA present unique and important difficulties in their clinical application, such as allograft tissue availability, safety issues, and immunologic response to the graft. Ongoing investigations continue to clarify the indications, surgical techniques, and clinical outcomes of fresh OCA. PMID- 22928429 TI - Improved preservation of fresh osteochondral allografts for clinical use. AB - INTRODUCTION: Fresh osteochondral allografts (OCAs) have been used clinically to treat cartilage focal defects of the knee for over 30 years. Over the last decade, significant research has been performed to develop and improve protocols for preservation of osteochondral tissue before transplantation into patients for treatment of cartilage defects. This work has resulted in preservation protocols that allow for maintenance of OCA tissues for time periods sufficient for clinical use based on disease testing requirements in the United States. However, graft quality and the window for clinical use of these tissues could be greatly enhanced from current levels. MATERIALS AND METHODS: Femoral condyles from 14 dogs were harvested and stored in one of the three proprietary media composition (M-1, M-2, M-3) and container condition (C-1, C-2, C-3) at 25 degrees C for 63 days. Viability of the OCA was determined using a proprietary media metabolic assay and live cell fluorescent microscopy. Media biomarker concentrations were analyzed to determine the metabolic activity of tissue. RESULTS: Media protein biomarkers were detected throughout the culture period, indicating OCAs remain metabolically active at 25 degrees C, and biomarker levels correlated with tissue viability. Viable chondrocyte density was maintained at day 0 levels throughout the depth of the tissue in the M-3 media using container condition C-3 after 63 days in storage. The media metabolic assay correlated strongly to cell viability of the OCA tissue. CONCLUSION: These data indicate that near day 0 tissue viability can be maintained for up to 63 days when OCAs are stored at 25 degrees C in the correct conditions. Further, tissue viability could be assessed nondestructively using media biomarkers and the media metabolic assay. If the preservation protocol reported here can be validated for safety and functional outcome, it could then be employed in tissue banks throughout the world, decreasing the number of grafts discarded and improving quality of life for thousands of patients affected by cartilage defects. PMID- 22928430 TI - The basic science of the patella: structure, composition, and function. AB - The patella is the largest sesamoid bone in the body. The patellofemoral joint provides an integral articulating component of the extensor mechanism of the knee joint. A detailed description of patella anatomy, embryology and development, neurovascular anatomy, biomechanical function, and imaging modalities is provided in this article. Common patellar pathologies such as patellar instability, trochlear dysplasia, patella alta and baja, and patellofemoral joint arthritis as well as patellofemoral arthroplasty as a treatment option are also discussed. An understanding of the normal anatomy and biomechanics of the patella is a necessary prerequisite for understanding the pathogenesis of disorders involving the knee. PMID- 22928431 TI - An institution-specific analysis of ACL reconstruction failure. AB - The purpose of this study was to determine the most common causes of failed anterior cruciate ligament reconstruction (ACLR) using modern reconstructive techniques at a single, high-volume institution. In addition, the clinical outcomes of patients undergoing revision ACLR will be reported. The surgical logs of four senior knee surgeons were retrospectively reviewed for all patients who had undergone ACLR between 2002 and 2009. Patients were excluded if they did not have both the primary and revision surgery on the same knee with the same surgeon. Out of 1944 ACL reconstructions, 28 patients (56 reconstructions) were included in the study. Radiographic studies, operative reports, KT-1000 scores, and chart notes were used to identify all potential factors that may have led to failure. All patients were invited to return for a follow-up examination and survey. Of the 28 patients, the mean age at the index and revision procedure was 22 +/- 11 (range, 12 to 50) and 24 +/- 11 (range, 14 to 57), respectively. In 20 cases, the cause of failure was determined to be acute trauma (sports, work, or accident); in 1 case, the cause was biologic failure; while in 7 cases, the cause was technical error. During the study period the surgeons performed a combined total of 1944 procedures, for an overall failure rate of 1.8%. Twenty patients (71%) were available for follow-up at a mean 30.2 +/- 17.7 months. The overall postrevision outcomes were good to excellent for a majority of patients, with an average Lysholm score of 84 +/- 15.5 and International Knee Documentation Committee score of 77.2 +/- 13.8. The pre- and postoperative KT-1000 scores were 12.1 +/- 2.8 and 6.7 +/- 2.8, respectively. The results from this study suggest that traumatic re-injury, and not surgical/surgeon error, is the most common cause of ACLR failure using anatomic reconstructive principles and strong fixation. In addition, good to excellent outcomes following revision ACLR can be expected in the majority of patients. PMID- 22928433 TI - The efficacy of combined cryotherapy and compression compared with cryotherapy alone following anterior cruciate ligament reconstruction. AB - While cryotherapy has been shown to decrease postoperative pain after anterior cruciate ligament (ACL) reconstruction, less is known of the effects of combined cryotherapy and compression. The goal of this study was to compare subjective and objective patient outcomes following ACL reconstruction with combined compression and cryotherapy compared with traditional ice therapy alone. Patients undergoing ACL reconstruction were randomized to cryotherapy/compression device (group 1) or a standardized ice pack (group 2). Both groups were instructed to use the ice or cryotherapy/compression device three times per day and return to the clinic at 1, 2, and 6 weeks postoperatively. Patient-derived outcome measurements used in this study consisted of the visual analog scale (VAS), the Lysholm knee score, Short Form-36 (SF-36), and single assessment numerical evaluation (SANE). Circumferential measurements of the knee at three locations (1 cm proximal to patella, mid-patella, and 1 cm distal to patella) were also obtained as a measure of postoperative edema. Narcotic medication use was recorded by questionnaire. The primary outcome measure (VAS) was significantly different among groups in the preoperative measurement, despite similarities in group demographics. Baseline VAS for group 1 was 54.9 compared with group 2 at 35.6 (p = 0.01). By 6 weeks, this had lowered to 28.1 and 40.3, respectively, resulting in a significant 27 point decrease in mean VAS for group 1 (p < 0.0001). However, the small increase in VAS for group 2 was not significant (p = 0.34). No significant differences were noted for the Lysholm, SF-36, or SANE scores either between groups or time points. Furthermore, no significant differences were noted for any of the circumferential measurements either between groups or time points. Of all patients, 83% of group 1 discontinued narcotic use by 6 weeks, compared with only 28% of group 2 (p = 0.0008). The use of combined cryotherapy and compression in the postoperative period after ACL reconstruction results in improved, short-term pain relief and a greater likelihood of independence from narcotic use compared with cryotherapy alone. PMID- 22928432 TI - Comparison of Kneelax and KT-1000 knee ligament arthrometers. AB - Two commercially available knee ligament arthrometers (KT-1000 MEDmetric Corporation, San Diego, California and Kneelax MR Systems, Haarlem, The Netherlands) were used to measure anterior tibial translation. In this study 91 subjects with no history of knee pathology were tested using both devices. Both normal knees were tested and comparison of recorded anterior translation (millimeters) was performed. Absolute numbers at forces of 67N, 89N, 134N, and manual maximum displacements were recorded. Side-to-side differences were calculated and data were compared. There was a significant difference found between the absolute values of each device. The KT-1000 was found to record greater values in millimeters of translation. Although the absolute values were significantly different, the side-to-side differences were not significantly different between devices. PMID- 22928434 TI - TKA results are not compromised by previous arthroscopic procedures. AB - This study investigated whether two or more previous arthroscopic procedures had an effect on the outcomes of total knee arthroplasty (TKA). We compared 60 patients (62 knees) who had a mean age of 56 years, a mean follow-up of 39 months (range, 26 to 68 months), and a minimum of two arthroscopic procedures before their TKA with a group of patients (n = 438) who underwent TKAs without any previous knee surgery. Clinical outcome was evaluated using Knee Society objective and function scores. Implant survivorship, with revision for aseptic component failure as an end point, was 98% in both cohorts. In the postarthroscopic group, the mean Knee Society objective and function scores improved to a mean of 92 and 89 points, respectively. Radiographic analysis did not find any differences between the two groups. In conclusion, the authors did not find that earlier arthroscopic procedures negatively affected the outcome of TKA. PMID- 22928436 TI - [Work environment of Japanese surgeons]. PMID- 22928435 TI - Prospective long-term evaluation of meniscal allograft transplantation procedure: a minimum of 7-year follow-up. AB - This study reports the long-term effectiveness of meniscal allograft transplantation performed by a single senior operating surgeon. In this study 22 meniscus transplantations in 22 patients were evaluated at a minimum of 7-year follow-up (mean 8.5 +/- 1.3 years) using standardized scoring scales. Subgroup analysis was performed to stratify outcomes based on medial (59.1%) versus lateral (40.9%) meniscus transplantation, and transplantations performed in isolation (36.4%) versus those performed concomitantly (63.6%). Patients reported significant improvement in all scoring scales (p < 0.05). Average satisfaction was 8.8 out of 10. All the patients were completely or mostly satisfied with the results of their surgery. Overall subjective knee condition improved from 3.5 to 6.9 (p < 0.05). Patients undergoing medial compartment repair and combined transplantations reported greater improvement from baseline to followup than did their counterparts. An overall success rate of 88% was found for all patients at the final follow-up. Based on this data, meniscal allograft transplantation is a viable treatment option for meniscal-deficient patients in reducing pain, increasing range of motion, and improving patient function and satisfaction at a minimum of 7 years postsurgery. PMID- 22928437 TI - [Board certified surgeon in Japan]. PMID- 22928438 TI - [Survey of rare diseases in endocrine surgery and establishment of practice guidelines in Japan]. PMID- 22928439 TI - [The MEN consortium of Japan]. AB - Multiple endocrine neoplasia (MEN) is not as well recognized in Asia, including Japan, as in the West. The clinical features of MEN and management conditions have yet to be clarified in Japan. Thus, we established a MEN study group designated the MEN Consortium of Japan in 2008. Its missions are to: 1) clarify the current status of clinical management of MEN; 2) promote basic research; 3) improve the diagnosis and treatment of MEN; 4) undertake public relations to increase awareness of MEN; and 5) support and collaborate with patient advocacy groups, etc. Clinical and genetic information on more than 1,000 patients was collected and analyzed. The database established by the MEN Consortium of Japan is the first such database for Asian patients and is one of the most extensive MEN databases worldwide. This is anticipated to promote clarification of the current status of MEN in Japan and improve future clinical management. PMID- 22928440 TI - [Results of multiple endocrine neoplasia type 1 in Japan from a multicenter database]. AB - The results of 208 and 560 patients with multiple endocrine neoplasia type 1 (MEN1) in Japan were analyzed from a multicenter database. The most common primary tumors are hyperparathyroid, followed by gastoroenteropancreatic neuroendocrine tumors (GEPNET) and pituitary tumors. After these three types of tumor, many adrenocortical tumors and bronchial and thymic neuroendocrine tumors were reported. Most MEN-related deaths were due to metastasis and the recurrence of GEPNET or thymic neuroendocrine tumors. MEN1 is a disease in which many specialties are involved and it should be in managed by diagnostic treatment in recognition of the broad spectrum of tumors which may occur. PMID- 22928441 TI - [Multiple endocrine neoplasia type 2 in Japan: large-scale analysis of data from the MEN consortium of Japan]. AB - Multiple endocrine neoplasia type 2 (MEN2) is an autosomal, dominantly inherited disease characterized by medullary thyroid carcinoma, pheochromocytoma, and primary hyperparathyroidism and is divided into types 2A and 2B. Familial medullary thyroid carcinoma (FMTC) is characterized by the presence of medullary thyroid carcinoma alone in family members and is considered to be one of the subtypes of MEN2. Clinical and genetic data on 505 Japanese patients from 275 MEN2 or FMTC families registered at 54 medical institutions were collected by the MEN Consortium of Japan. The diagnosis was MEN2A in 343 (67.9%) patients, MEN2B in 29 (5.7%), FMTC in 103 (20.4%), and unclassified in 30 (5.9%). Medullary thyroid carcinoma was found in 91.2% of patients (437/479), pheochromocytoma in 45.6% (212/465), and primary hyperparathyroidism in 8.1% (37/457). RET genetic testing was performed in 410 patients, and the germline RET mutation was found in 98.8% (397/402). PMID- 22928442 TI - [The anaplastic thyroid carcinoma research consortium of Japan]. AB - Anaplastic thyroid carcinoma (ATC) is one of the most lethal neoplasia in humans, with a disease-specific mortality rate approaching 100%. ATC is uncommon and represents only 1-2% of all thyroid carcinomas. The aggressive nature and rarity of this disease make it difficult to improve the quality of evidence on it. To date, most existing knowledge of ATC is derived from single-institution studies with limited cohorts and short-term follow-up. To obtain further insights into this "orphan disease," we established the ATC Research Consortium of Japan (ATCCJ) in January 2009 as a multicenter registry that accumulates, analyzes, and reviews all information on ATC available in the country. As of July 2011, the ATCCJ database included 721 cases of ATC from 38 institutions. Using the database, the members of the ATCCJ have performed several retrospective studies, covering prognostic factors, therapeutic strategies, and pathologic features of ATC. Moreover, prospective trials are being planned as multicenter collaborations to determine the most beneficial treatment, with the ultimate purpose of improving the survival rate of patients with ATC. PMID- 22928443 TI - [Analysis of long-term survivors in anaplastic thyroid carcinoma]. AB - We analyzed the clinicopathologic and therapeutic factors associated with long term survival in 449 patients with anaplastic carcinoma registered with the Anaplastic Thyroid Carcinoma Consortium of Japan. Univariate analysis showed a significant relationship between long-term survival of more than 1 year and the following factors: the appearance of acute symptom; WBC < 10,000/mm3, tumor diameter < 5.0 cm; tumor remnant in the thyroid gland after surgery; no distant metastasis at initial diagnosi; complete resection of gross tumor; and administration of external irradiation (40 Gy) and chemotherapy. In multivariate analysis, only tumor diameter (< 5.0cm), complete resection of gross tumor, and external irradiation (40 Gy) showed a significant correlation with long-term survival. Only 31 of the 449 patients (7%) had these 3 factors, and 20 (65%) of them survived for more than 1 year. Among patients in any stage or with any prognostic index score who received little treatment, very few survived for more than 1 year. In contrast, many patients who received intensive combination therapy survived for more than 1 year. The results of this study suggest that sufficient intensive combination therapy has practical significance for patients with anaplastic carcinoma, except for those with advanced-stage disease. PMID- 22928444 TI - [Etiology and clinical guidelines for the diagnosis and treatment of pheochromocytoma in Japan]. AB - Although pheochromocytoma is one curable cause of endocrine hypertension, approximately 10% of patients have malignant disease. Since the histopathologic diagnosis of malignancy at the time of first surgery is difficult and malignancy is confirmed only after the detection of metastasis, it is a representative intractable rare disease without effective treatment. A nationwide survey in Japan in 2009 found 2,600 cases of benign pheochromocytoma and 320 of malignant pheochromocytoma. There was no gender bias among patients, and the average age of onset was 40 to 45 years. Sixty-five percent were symptomatic including hypertension, but 35% were asymptomatic and found occasionally as incidentaloma Extraadrenal, bilateral, malignant, and familial cases each represented 10% of the total. A task force of the Ministry of Health, Labour and Welfare of Japan established the diagnostic criteria and clinical guidelines for pheochromocytoma/paraganglioma and malignant pheochromocytoma/paraganglioma. Typical cases of pheochromocytoma are readily diagnosed based on high catecholamine levels and imaging of tumor localization and can be cured by surgical resection of the tumor. In contrast, since no effective treatment for malignant pheochromocytoma has been established, a combination of various treatments including the administration of a-blockers, 131-MIBG irradiation, and cisplatin/vinblastine/dacarbazine chemotherapy, and radiation of bone metastases is recommended. Careful long-term follow-up is essential even in patients with benign pheochromocytoma. PMID- 22928445 TI - [The present and prospects for robotic surgery in gastrointestinal surgeries]. PMID- 22928446 TI - [Fukushima health management survey after the nuclear accident at Tokyo Electolic Power Company's Fukushima No. 1 Nuclear Power Plant--especially for thyroid ultrasound examination]. PMID- 22928447 TI - [What we can learn from a case of medical malpractice--compensatory damages awarded to a patient with autonomic ataxia on administrative leave for emotional distress arising out of alleged inappropriate remarks made by his industrial physician]. PMID- 22928448 TI - [The tips and pitfall of distal bypass for critical limb ischemia]. PMID- 22928449 TI - [Practical use of doctor's assistant]. AB - Many researchers have focused on the introduction of mid-level providers (MLP) in order to reduce the number of doctors treating patients in the hospital. However, the establishment of MLPs in Japan still takes time. The process could be accelerated by relieving doctors of clerical work by employing auxiliary personnel. This hospital employs 22 auxiliary people to perform clerical work for the doctors, which are referred to as "doctor's assistants (DA)". The system is connected with the medical treatment fee system. Two DA are assigned cardiovascular surgery and conduct various other activities. These activities include: 1. Temporary creation of various medical documents. 2. Vicarious execution of electronic medical recoding system input. 3. Support of scientific activity. 4. Input of all data into the JACVSD Database. In addition, they participate in a round of cardiovascular surgery and inform the patient or family of the surgical schedule. They also cooperate with personnel from other specialties or department. The DA thus plays a crucial role in "team medical treatment." PMID- 22928451 TI - The changing face of dentistry? PMID- 22928452 TI - Ethical marketing in 'aesthetic' ('esthetic') or 'cosmetic dentistry' part 2. AB - This is the second article in a series of three. It is essential to find out from patients what it is that they hope to achieve when requesting an improvement in their dental appearance. Their expectations, hopes and fears need to be explored in detail. The long-term biologic costs of some invasive procedures need to be explained to patients in advance so that they can make properly informed decisions. Failure to do so renders the practitioner vulnerable to a charge of behaving unethically. The differences between ethical marketing and selling are explained including the historic development of marketing. CLINICAL RELEVANCE: A practical approach, using a modification of the Edward de Bono Six Thinking Hats model is described to help ethical practitioners to develop sound treatment plans when dealing with complex aesthetic problems. PMID- 22928453 TI - The ovate pontic for fixed bridgework. AB - The provision of fixed prosthodontic restorations that meets the patient's functional and aesthetic demands can be challenging, especially in the anterior maxilla. It requires close communication with the technician and knowledge of the available options. This article will outline the options for pontic design and focus on the ovate pontic, which has the potential to provide the most aesthetic outcome. This should equip the practitioner with the knowledge as to which pontic to prescribe if such a challenge arises. CLINICAL RELEVANCE: Fixed bridgework is a commonly prescribed prosthesis for the replacement of missing teeth. In order for this to be provided successfully, the practitioner should have a working knowledge of the available options for pontic design.This is especially important in cases where aesthetic demands are high. PMID- 22928454 TI - Tumoral calcinosis: a dental literature review and case report. AB - Tumoral calcinosis (TC) is a rare familial disease characterized by abnormal peri articular calcification in affected joints, without any associated renal, metabolic or collagen vascular disease. It is characterized by usual hyperphosphataemia with normal serum calcium and alkaline phosphatase values. There are only a few reported cases ofTC patients with dental findings. This article reviews the dental literature and describes progressive gingival, alveolar and mandibular tori enlargement in a 41-year-old female from Zimbabwe with tumoral calcinosis. CLINICAL RELEVANCE: Tumoral calcinosis is a rare disorder of mineral metabolism with oral manifestations. PMID- 22928455 TI - Aesthetic preview: a novel approach. AB - Planning the final aesthetic result of restorative treatment is a key skill needed by the clinician to ensure predictable success. This paper aims to review current techniques that may be used by clinicians for an aesthetic preview, whilst also highlighting a simple technique that may be readily utilized in practice. CLINICAL RELEVANCE: It is considered good practice to give patients an aesthetic preview of the end result prior to commencing active treatment. This article demonstrates the different techniques available and those that are easily utilized in general practice. The aesthetic preview is of benefit to both the clinician and technician in defining treatment goals and improving communication. PMID- 22928456 TI - Reducing the risk of failure in complete denture patients. AB - This paper aims to review the factors associated with an increased risk of failure in complete denture patients, based on the strength of the available evidence base. These include accuracy of jaw relations, a poorly formed mandibular ridge, poor quality dentures and patient neuroticism. Clinical strategies for overcoming these issues are described with particular reference to impression-taking and jaw relations. CLINICAL RELEVANCE: Identifying potential problems will help to improve outcomes for edentulous patients treated with conventional complete dentures. PMID- 22928457 TI - Follow the leader: part 1--what is leadership? PMID- 22928458 TI - Oral cancer: comprehending the condition, causes, controversies, control and consequences. 18. Dental management. PMID- 22928459 TI - Technique tips--Modified Hawley retainer. PMID- 22928460 TI - Physical signs for the general dental practitioner. Case 96. Nail deformities. PMID- 22928461 TI - Where we are headed and how we get there. PMID- 22928462 TI - A voice for choice: Thoughts on DEA license renewal and patient drug-seeking behavior. PMID- 22928463 TI - A natural progression: Equine dentistry at the University of Minnesota Veterinary Medical Center. PMID- 22928464 TI - Not just in the "ivory tower": research in your office for your patients! PMID- 22928465 TI - Tooth autotransplantation: an overview and case study. AB - It is not uncommon for children or young adults to have congenitally missing teeth or early loss of teeth from trauma or caries. The restorative options are typically bridges, implants, and removable appliances. Often overlooked and misunderstood, another treatment option exists in autotransplantation, where a tooth is moved from one site to another in the same individual. Autotransplantation is well studied and has predictable results comparable to implants, with reported success rates often greater than 90%. This article will provide an overview of autotransplantation plantation, its indications, advantages, complications, and treatment considerations, along with a case of a third molar autotransplant that will serve to highlight these points. PMID- 22928466 TI - The introverted dentist, or, I don't need to be fixed because I am not broken. PMID- 22928467 TI - Off on the right foot. PMID- 22928468 TI - DNAzyme-based rolling-circle amplification DNA machine for ultrasensitive analysis of microRNA in Drosophila larva. AB - We present a highly sensitive colorimetric method for microRNA (miRNA) detection. This method is based on a rolling-circle amplification (RCA) DNA machine, which integrates RCA, nicking enzyme signal amplification and DNAzyme signal amplification. The DNA machine is triggered by the hybridization of target miRNA with a rational designed padlock DNA template and activated by RCA. The resulting RCA product then autonomously replicates a multiple machinery cutter cycle and generates accumulated amount of products. Specifically, the DNA product in the present work is designed as a horseradish peroxidase (HRP)-mimicking DNAzyme, which could that catalyze a colorimetric reaction and generate colored product. Through these cascade amplifications, microRNA (miRNA) as low as 2 aM could be detected. As an example of in vivo application, miRNA from single Drosophila larva was successfully analyzed. Drosophila is a model organism that provides a powerful genetic tool to study gene functions. Study of Drosophila miRNAs has brought us knowledge of its biogenesis and biological functions. The analysis of miRNA typically requires a pretreatment process of extracting total RNAs from target cells, followed by quantitative analysis of target miRNA in total RNA samples, which nevertheless suffers from laborious total RNA extraction and time consuming processes and poor limit of detection. Meanwhile, the tiny size of Drosophila makes it difficult to accurately measure trivial changes of its cellular miRNA levels. The ability to detect ultralow concentration of miRNA of the proposed method enables the analysis the expression of mir-1 in single Drosophila larva. We thus expect that the strategy may open new avenues for in situ miRNA analysis in single cell or living animals. PMID- 22928469 TI - High current density and nonlinearity combination of selection device based on TaO(x)/TiO2/TaO(x) structure for one selector-one resistor arrays. AB - We demonstrate a high-performance selection device by utilizing the concept of crested oxide barrier to suppress the sneak current in bipolar resistive memory arrays. Using a TaO(x)/TiO(2)/TaO(x) structure, high current density over 10(7) A cm(-2) and excellent nonlinear characteristics up to 10(4) were successfully demonstrated. On the basis of the defect chemistry and SIMS depth profile result, we found that some Ta atoms gradually diffused into TiO(2) film, and consequently, the energy band of the TiO(2) film was symmetrically bent at the top and bottom TaO(x)/TiO(2) interfaces and modified as a crested oxide barrier. Furthermore, the one selector-one resistor device exhibited significant suppression of the leakage current, indicating excellent selector characteristics. PMID- 22928470 TI - Can a short nap and bright light function as implicit learning and visual search enhancers? AB - The present study examined effects of a short nap (20 min) and/or bright light (2000 lux) on visual search and implicit learning in a contextual cueing task. Fifteen participants performed a contextual cueing task twice a day (1200-1330 h and 1430-1600 h) and scored subjective sleepiness before and after a short afternoon nap or a break period. Participants served a total of four experimental conditions (control, short nap, bright light and short nap with bright light). During the second task, bright light treatment (BLT) was applied in the two of the four conditions. Participants performed both tasks in a dimly lit environment except during the light treatment. Results showed that a short nap reduced subjective sleepiness and improved visual search time, but it did not affect implicit learning. Bright light reduced subjective sleepiness. A short nap in the afternoon could be a countermeasure against sleepiness and an enhancer for visual search. Practitioner Summary: The study examined effects of a short afternoon nap (20 min) and/or bright light (2000 lux) on visual search and implicit learning. A short nap is a powerful countermeasure against sleepiness compared to bright light exposure in the afternoon. PMID- 22928471 TI - Trade-offs in visual attention and the enhancement of memory specificity for positive and negative emotional stimuli. AB - Emotional influences on memory can lead to trade-offs in memory for gist or detail and trade-offs in memory for central or peripheral aspects of an event. Attentional narrowing has often been proposed as a theoretical explanation for this pattern of findings with negative emotion. These trade-offs have been less extensively investigated with positive emotion. In three experiments, we investigate memory for specific visual details of positive and negative stimuli, examine central-peripheral trade-offs in memory, and assess the hypothesis that attentional narrowing contributes to emotional enhancement of memory specificity. We found that memory for details was enhanced by negative and positive emotion. Central-peripheral trade-offs were found in memory for negative emotional stimuli but not in memory for positive emotional stimuli. These trade-offs with negative emotion were associated with attentional narrowing at the time of encoding, as measured by eye movements. There were no attentional effects at the time of encoding found with positive emotional stimuli. Evidence was found for the attentional narrowing hypothesis of memory specificity and central-peripheral trade-offs in memory for negative emotional events. Alternative explanations for the positive emotional enhancement of memory specificity are required. PMID- 22928472 TI - Morphology and ion-conductivity of gelatin-LiClO4 films: fractional diffusion analysis. AB - Biopolymers are expected to replace synthetic polymers in the quest for cost effective, environment friendly, and pollution free technology. We report here a study on gelatin films with different concentrations of lithium perchlorate, which may be a candidate for electrolyte material in solid polymer batteries. Morphology studies and impedance spectroscopy both are done on the same set of samples. We study the microstructure of the film by SEM and try to see if a correlation between impedance spectroscopy results and features of gel morphology can be identified. A network structure is revealed in the SEM images where details of the network parameters appear to depend on the salt fraction. Analysis of the impedance measurements is done using a physically meaningful model based on material properties instead of the usual equivalent circuit formalism, where circuit elements are difficult to interpret. We find that anomalous diffusion of charge carriers plays an important role; this is incorporated through a fractional calculus approach. PMID- 22928473 TI - Single-step thioetherification by indium-catalyzed reductive coupling of carboxylic acids with thiols. AB - Direct thioetherification from a variety of aromatic carboxylic acids and thiols using a reducing system combined with InBr(3) and 1,1,3,3-teramethyldisiloxane (TMDS) in a one-pot procedure is demonstrated. It was also found that a system combined with InI(3) and TMDS underwent thioetherification of aliphatic carboxylic acids with thiols. PMID- 22928474 TI - A modified rhomboid flap: the "diamond flap". PMID- 22928475 TI - Peptide bond hydrolysis catalyzed by the Wells-Dawson Zr(alpha2-P2W17O61)2 polyoxometalate. AB - In this paper we report the first example of peptide hydrolysis catalyzed by a polyoxometalate complex. A series of metal-substituted Wells-Dawson polyoxometalates were synthesized, and their hydrolytic activity toward the peptide bond in glycylglycine (GG) was examined. Among these, the Zr(IV)- and Hf(IV)-substituted ones were the most reactive. Detailed kinetic studies were performed with the Zr(IV)-substituted Wells-Dawson type polyoxometalate K(15)H[Zr(alpha(2)-P(2)W(17)O(61))(2)].25H(2)O which was shown to act as a catalyst for the hydrolysis of the peptide bond in GG. The speciation of K(15)H[Zr(alpha(2)-P(2)W(17)O(61))(2)].25H(2)O which is highly dependent on the pD, concentration, and temperature of the solution, was fully determined with the help of (31)P NMR spectroscopy and its influence on the GG hydrolysis rate was examined. The highest reaction rate (k(obs) = 9.2 (+/-0.2) * 10(-5) min(-1)) was observed at pD 5.0 and 60 degrees C. A 10-fold excess of GG was hydrolyzed in the presence of K(15)H[Zr(alpha(2)-P(2)W(17)O(61))(2)].25H(2)O proving the principles of catalysis. (13)C NMR data suggested the coordination of GG to the Zr(IV) center in K(15)H[Zr(alpha(2)-P(2)W(17)O(61))(2)].25H(2)O via its N terminal amine group and amide carbonyl oxygen. These findings were confirmed by the inactivity of K(15)H[Zr(alpha(2)-P(2)W(17)O(61))(2)].25H(2)O toward the N blocked analogue acetamidoglycylglycinate and the inhibitory effect of oxalic, malic, and citric acid. Triglycine, tetraglycine, and pentaglycine were also fully hydrolyzed in the presence of K(15)H[Zr(alpha(2) P(2)W(17)O(61))(2)].25H(2)O yielding glycine as the final product of hydrolysis. K(15)H[Zr(alpha(2)-P(2)W(17)O(61))(2)].25H(2)O also exhibited hydrolytic activity toward a series of other dipeptides. PMID- 22928476 TI - Comparison of autologous serum eye drops with different diluents. AB - PURPOSE: To compare the effect of autologous serum eye drops with different diluents in patients with dry eyes and persistent epithelial defects. METHODS: Patients of Sjogren's syndrome (Group I), non-Sjogren's syndrome (group II) with dry eye, and persistent epithelial defects (Group III) were included. The eyes of each group were randomly treated with one of the following autologous serum eye drops: 100% serum (AS(100)), 50% serum with normal saline (AS(50NS)); 50% serum with sodium hyaluronate (AS(50HA)); or 50% serum with ceftazidime (AS(50CEF)). The differences in dry eye symptoms, Schirmer test I, tear break-up time (TBUT), corneal staining, and speed in epithelial healing were studied. RESULTS: In Group I, AS(100) showed fewer symptoms than AS(50NS), AS(50HA) and AS(50CEF) (all p < 0.01). AS(100) showed significantly better effect than AS(50NS), AS(50HA) and AS(50CEF) in decreasing corneal staining at the time point of 12-week post treatment (p = 0.041, p < 0.001 and p < 0.001, respectively). In Group II, AS(100) was more effective than AS(50CEF) in decreasing symptoms and decreasing corneal staining (all p < 0.05). There was no significant difference in symptom and corneal staining between AS(100) and AS(50NS). In Group III, AS(100) was the most effective in achieving quick epithelial closure. CONCLUSION: In the eyes with Sjogren syndrome and persistent epithelial defects, AS(100) was the most effective in decreasing symptoms, corneal epitheliopathy and promoting fast closure of wound. In the eyes with non-Sjogren syndrome, AS(100) and AS(50NS) have similar effects in decreasing symptoms and corneal epitheliopathy. PMID- 22928477 TI - Waved with open eyelids 2 (woe2) is a novel spontaneous mouse mutation in the protein phosphatase 1, regulatory (inhibitor) subunit 13 like (Ppp1r13l) gene. AB - BACKGROUND: Waved with open eyelids 2 (woe2) is a novel autosomal recessive mouse mutation that arose spontaneously in our animal facility. Upon initial evaluation, mutant mice exhibited eyelids open at birth (EOB) and wavy fur phenotypes. The goals of this study were to phenotypically characterize the woe2 mice and to identify the gene harboring the mutation responsible for the woe2 phenotype. RESULTS: Histological analysis of woe2 embryos identified the failure of embryonic eyelid closure. Clinical and histological analysis of woe2 adult eyes identified severe corneal opacities, abnormalities of the anterior segment of the eye, and the absence of meibomian glands. Abnormalities in the fur texture and the absence of meibomian glands prompted us to evaluate other epidermal appendages: skin, teeth, and nails--as well as lacrimal, mammary, salivary, sebaceous and sweat glands. No obvious morphological differences between WT and woe2 mice were identified in these tissues. However, the analysis of woe2 identified cardiac abnormalities. Positional cloning of the woe2 locus identified a 1308 bp deletion in the Ppp1r13l gene. The deletion resulted in an aberrant Ppp1r13l(Deltaexon9-11) transcript that lacks exons 9, 10 and 11 resulting in a premature stop and a loss of 223 amino acids from the C-terminal end of the putative mutant PPP1R13L protein. Immunohistological analysis during eye development identified expression of PPP1R13L in the palpebral epidermis, palpebral and bulbar conjunctiva, corneal epithelium and meibomian glands. CONCLUSIONS: The woe2 mouse harbors a novel deletion within the Ppp1r13l gene, likely resulting in a complete loss of PPP1R13L function. Results from this study provide evidence that PPP1R13L has an essential role in embryonic eyelid closure as well in development of meibomian glands and the anterior segment of the eye. The woe2 mice are a useful model for investigation of the role of PPP1R13L, especially during ocular and eyelid development. PMID- 22928478 TI - Expression of voltage-gated sodium channel Nav1.3 is associated with severity of traumatic brain injury in adult rats. AB - During the secondary injury period after traumatic brain injury (TBI), depolarization of neurons mediated by voltage-gated sodium channels (VGSCs) leads to cellular abnormalities and neurological dysfunction. Alterations in expression of different alpha subunits of VGSCs can affect early brain pathology following TBI. This study detected the expression of Nav1.3 mRNA and protein in the rat cortex post-TBI. Adult male Sprague-Dawley rats were randomly assigned to sham TBI, mild-TBI (mTBI), or severe-TBI (sTBI) groups. TBI was induced using a fluid percussion device at magnitudes of 1.5-1.6 atm (mTBI) and 2.9-3.0 atm (sTBI). Nav1.3 mRNA and protein levels in the ipsilateral-injured cortex were examined at 2 h, 12 h, 24 h, and 72 h post-TBI by real-time reverse transcriptase quantitative polymerase chain reaction and Western blot. Brains were collected at 24 h, 72 h, and 7 days post-TBI for TUNEL staining and cell count analysis. Immunofluorescence was performed to localize expression of Nav1.3 protein in the ipsilateral-injured cortex. Expression of Nav1.3 mRNA and protein were significantly upregulated in mTBI and sTBI groups when compared with the sham-TBI group at 2 h and 12 h post-TBI. Nav1.3 mRNA and protein levels in the sTBI group were much higher than in the mTBI group at 12 h post-TBI. TUNEL-positive cell numbers were significantly higher in the sTBI group than in the mTBI at 24 h, 72 h, and 7 days post-TBI. Expression of Nav1.3 was observed predominantly in neurons of the cortex. These findings indicated significant upregulation in the expression of Nav1.3 mRNA and protein in the rat ipsilateral-injured cortex at the very early stage post-TBI, and were also correlated with TBI severity. PMID- 22928479 TI - Malignant melanoma and tumor necrosis factor-alpha inhibitors: a case report and review of the literature. PMID- 22928480 TI - Phase II trial of RAD001 and bicalutamide for castration-resistant prostate cancer. AB - Study Type--Therapy (cohort) Level of Evidence 2a. What's known on the subject? and What does the study add? Despite expanding treatment options for castration resistant prostate cancer (CRPC), therapies with long response duration remain intangible due to prostate cancer cells' natural ability to develop iterative resistance. Androgen receptor (AR) signaling has been shown to play a critical role in CRPC and its expression is regulated by the PI3K-Akt pathway. Thus inhibition of AR signalling and PI3K-Akt-mTOR (a downstream mediator of the PI3K Akt pathway) pathway is a logical combination in CRPC and we report a phase II trial of RAD001 and bicalutamide. Our study is the first clinical trial report of an AR inhibitor of PI3K-Akt-mTOR. The AR pathway and the PI3K-Akt-mTOR pathway are two of the most relevant growth pathway for CRPC. Despite low efficacy results from our trial there will be significant interest in the field for these data (dose, schedule, response, toxicity, trial design) as newer generations of both AR inhibitors and PI3K-Akt-mTOR inhibitors are in development and likely will be tested in combination in CRPC. OBJECTIVES: * To determine best overall response and duration of response of RAD001, a selective inhibitor of mammalian target of rapamycin, in combination with bicalutamide in castration-resistant prostate cancer (CRPC). * To characterize the toxicity profile of RAD001 in combination with bicalutamide in patients with CRPC. PATIENTS AND METHODS: * A phase II study was conducted to explore the efficacy and tolerability of RAD001 (10 mg daily) in combination with bicalutamide (50 mg daily) in men with progressive CRPC. * The primary endpoint was a composite of prostate-specific antigen (PSA) level and measurable disease response by standard criteria. * This single-stage trial with a sample size of 38 eligible patients provided 90% power to differentiate a response rate of >= 40% from a response rate of <= 20%, as expected for bicalutamide alone (alpha= 0.10, power = 0.90). RESULTS: * In total, 36 men were enrolled, with a median (range) age of 68 (60-72) years and median (range) baseline PSA level of 22.2 (8.4-121.3) ng/mL, and 89% had metastatic disease. * There were 31 (86%) patients had previously used bicalutamide for a median duration of 7.4 months. * There were two patients with a confirmed PSA level decline >= 50%. * The median (interquartile range) time to progression was 8.7 (7.9-15.9) weeks. * The most common toxicity was grade 1/2 mucositis, which was observed in 20 (56%) patients. CONCLUSION: * The combination of RAD001 and bicalutamide in men with CRPC was well tolerated but had low activity and failed to achieve the primary endpoint of improved response compared to the results previously achieved for bicalutamide alone in this population. PMID- 22928482 TI - Transient ischaemic attack in a case of a morbidly obese girl associated with metabolic syndrome. PMID- 22928481 TI - Three new chondrosarcoma cell lines: one grade III conventional central chondrosarcoma and two dedifferentiated chondrosarcomas of bone. AB - BACKGROUND: Chondrosarcoma is the second most common primary sarcoma of bone. High-grade conventional chondrosarcoma and dedifferentiated chondrosarcoma have a poor outcome. In pre-clinical research aiming at the identification of novel treatment targets, the need for representative cell lines and model systems is high, but availability is scarce. METHODS: We developed and characterized three cell lines, derived from conventional grade III chondrosarcoma (L835), and dedifferentiated chondrosarcoma (L2975 and L3252) of bone. Proliferation and migration were studied and we used COBRA-FISH and array-CGH for karyotyping and genotyping. Immunohistochemistry for p16 and p53 was performed as well as TP53 and IDH mutation analysis. Cells were injected into nude mice to establish their tumorigenic potential. RESULTS: We show that the three cell lines have distinct migrative properties, L2975 had the highest migration rate and showed tumorigenic potential in mice. All cell lines showed chromosomal rearrangements with complex karyotypes and genotypic aberrations were conserved throughout late passaging of the cell lines. All cell lines showed loss of CDKN2A, while TP53 was wild type for exons 5-8. L835 has an IDH1 R132C mutation, L2975 an IDH2 R172W mutation and L3252 is IDH wild type. CONCLUSIONS: Based on the stable culturing properties of these cell lines and their genotypic profile resembling the original tumors, these cell lines should provide useful functional models to further characterize chondrosarcoma and to evaluate new treatment strategies. PMID- 22928483 TI - Neuropeptide alterations in the infundibular nucleus of Huntington's disease patients. AB - Data from transgenic mouse models of Huntington's disease (HD) suggest that dysfunction of the hypothalamic infundibular nucleus (INF) (in rodents, the arcuate nucleus) may contribute to unintended weight loss and insatiable appetite among HD patients. Using post-mortem paraffin-embedded tissue, we assessed the total number of INF neurones by thionin staining and four major regulatory neuropeptides in the INF of HD patients by immunocytochemistry and in situ hybridisation. In HD patients, the total number of neurones in the INF was unchanged compared to control subjects (P = 0.92), whereas it contained over 30% less neuropeptide Y-immunoreactive (IR) neurones (P = 0.016), as well as reduced peptide levels, in fibres to the paraventricular and ventromedial nucleus (P = 0.003, P = 0.005, respectively). Conversely, neuropeptide Y mRNA expression levels were increased three-fold (P = 0.047). No changes were observed in the number of neurones immunoreactive for alpha-melanocyte-stimulating hormone, agouti-related peptide, and cocaine- and amphetamine-regulated transcript (P >= 0.17). Our findings suggest changes in the pathology of the INF neuropeptide Y expressing neurones in HD patients without changes in other (an)orexigenic neuropeptides and without neuronal cell loss. These findings indicate that unintended weight loss in patients suffering from this disease may be partly a result of neuropeptidergic alterations in the hypothalamic infundibular nucleus. PMID- 22928484 TI - Accurate Diagnosis of Mesothelioma: More Important Than Ever. PMID- 22928485 TI - Histological lesions induced by exogenous pigment in dyed Indian glassfish, Pseudambassis ranga (Hamilton). PMID- 22928486 TI - Fungi, bacteria and soil pH: the oxalate-carbonate pathway as a model for metabolic interaction. AB - The oxalate-carbonate pathway involves the oxidation of calcium oxalate to low magnesium calcite and represents a potential long-term terrestrial sink for atmospheric CO(2). In this pathway, bacterial oxalate degradation is associated with a strong local alkalinization and subsequent carbonate precipitation. In order to test whether this process occurs in soil, the role of bacteria, fungi and calcium oxalate amendments was studied using microcosms. In a model system with sterile soil amended with laboratory cultures of oxalotrophic bacteria and fungi, the addition of calcium oxalate induced a distinct pH shift and led to the final precipitation of calcite. However, the simultaneous presence of bacteria and fungi was essential to drive this pH shift. Growth of both oxalotrophic bacteria and fungi was confirmed by qPCR on the frc (oxalotrophic bacteria) and 16S rRNA genes, and the quantification of ergosterol (active fungal biomass) respectively. The experiment was replicated in microcosms with non-sterilized soil. In this case, the bacterial and fungal contribution to oxalate degradation was evaluated by treatments with specific biocides (cycloheximide and bronopol). Results showed that the autochthonous microflora oxidized calcium oxalate and induced a significant soil alkalinization. Moreover, data confirmed the results from the model soil showing that bacteria are essentially responsible for the pH shift, but require the presence of fungi for their oxalotrophic activity. The combined results highlight that the interaction between bacteria and fungi is essential to drive metabolic processes in complex environments such as soil. PMID- 22928487 TI - Mitochondrial ROS-K+ channel signaling pathway regulated secretion of human pulmonary artery endothelial cells. AB - The objective was to investigate the molecular mechanism of mitochondrial reactive oxygen species (ROS) signaling regulation of pulmonary artery endothelial cell (HPAEC) secretion in the condition of oxidative stress. Acrolein (40 MUM) induced HPAEC mitochondrial generation of ROS, rotenone (2 MUmol/L) blocked mitochondrial respiratory chain complex I, cesium chloride (CsCl, 40 mmol/L)blocked K(+)channels, and saline (0.9 g/dl) were used as control. The generations of NOS, ET-1 and VEGF were determined with ELISA in the condition of different treatment reagents namely acrolein, acrolein plus rotenone, acrolein plus CsCl and saline. In the different reagent treatment of HPAECs, acrolein increased mitochondrial ROS, membrane potential, Kv1.5 mRNA and protein expression, intracellular calcium and the generation of NOS (determining NO production), ET-1 and VEGF, and those were reduced by rotenone. CsCl decreased the increment of membrane potential, the elevation of intracellular calcium and the upregulation of NOS, E-1 and VEGF expressions, which were induced by acrolein. The present study demonstrated that mitochondrial ROS-K(+)channel regulated HPAEC secretion of NO, ET-1 and VEGF in the condition of oxidative stress. Kv1.5 channel may be an important component of ROS-K+ channel signaling pathway, and intracellular calcium contributed to mitochondrial ROS-K(+) channel signaling modulation of HPAEC secretion. PMID- 22928489 TI - Templated nanopores for robust functional surface porosity in poly(methyl methacrylate). AB - A novel "sink and etch" technique is used to generate stable surface nanoporosity in poly(methyl methacrylate). Layer-by-layer assembly is first used to conformally coat PMMA substrates with a uniform layer of silica nanoparticles. Thermal annealing is then applied to cause sinking and engulfment of the silica nanoparticles into the thermoplastic PMMA surface. By selectively etching away the layer of embedded silica nanoparticles, a conformal porous layer of inversely templated structure can be obtained in the PMMA surface. Characterization with atomic force microscopy shows that a variety of nanoporous surface morphologies can be achieved simply by controlling the duration and temperature of thermal annealing. The nanoporous surfaces consisting of either as assembled silica nanoparticles or templated inverse porosity in PMMA were compared in terms of their antireflective (AR) properties. Measuring AR properties provided a quantitative means to compare the stability of these porous AR surfaces before and after several cleaning cycles. Our results show that while both types of surface porosity can provide excellent AR properties (optimized for 300-400 nm), the porous layer generated by the "sink and etch" technique showed superior mechanical stability. PMID- 22928488 TI - Context and force field dependence of the loss of protein backbone entropy upon folding using realistic denatured and native state ensembles. AB - The loss of conformational entropy is the largest unfavorable quantity affecting a protein's stability. We calculate the reduction in the number of backbone conformations upon folding using the distribution of backbone dihedral angles (phi,psi) obtained from an experimentally validated denatured state model, along with all-atom simulations for both the denatured and native states. The average loss of entropy per residue is TDeltaS(BB)(U-N) = 0.7, 0.9, or 1.1 kcal.mol(-1) at T = 298 K, depending on the force field used, with a 0.6 kcal.mol(-1) dispersion across the sequence. The average equates to a decrease of a factor of 3-7 in the number of conformations available per residue (f = Omega(Denatured)/Omega(Native)) or to a total of f(tot) = 3(n)-7(n) for an n residue protein. Our value is smaller than most previous estimates where f = 7 20, that is, our computed TDeltaS(BB)(U-N) is smaller by 10-100 kcal mol(-1) for n = 100. The differences emerge from our use of realistic native and denatured state ensembles as well as from the inclusion of accurate local sequence preferences, neighbor effects, and correlated motions (vibrations), in contrast to some previous studies that invoke gross assumptions about the entropy in either or both states. We find that the loss of entropy primarily depends on the local environment and less on properties of the native state, with the exception of alpha-helical residues in some force fields. PMID- 22928490 TI - Prescription of nonselective NSAIDs, coxibs and gastroprotective agents in the era of rofecoxib withdrawal - a 617,400-patient study. AB - BACKGROUND: Gastroprotective strategies are recommended for nonsteroidal anti inflammatory drug (NSAID) users at risk of upper gastrointestinal (UGI) complications. AIM: To compare the use of gastroprotective strategies in NSAID users in three countries, and the subsequent impact of rofecoxib withdrawal. METHODS: We conducted a population-based cohort study in three general practice (GP) databases: (i) United Kingdom's (UK) GP Research Database (1998-2008); (ii) Italy's (IT) Health Search/CSD Longitudinal Patient Database (2000-2007); and (iii) the Dutch (NL) Integrated Primary Care Information database (1996-2006). Study cohorts comprised incident NSAID users >=50 years. Preventive strategies included: (i) co-prescription of gastroprotective agents; or (ii) cyclooxygenase 2-selective inhibitor use. Under-use was defined as no gastroprotection in patients with >=1 UGI risk factor (history of UGI event, age >=65 years, concomitant use of anticoagulants, antiplatelets or glucocorticoids). Interrupted time-series analysis was performed to assess the impact of rofecoxib withdrawal on preventive strategies. RESULTS: The study populations consisted of 384 649 UK, 177 747 IT and 55 004 NL NSAID users. In UK, under-use of preventive strategies fell from 91% to 71% [linear trend (lt) P = 0.001], in NL from 92% to 58% (lt P < 0.001) and in IT from 90% to 76% (lt P = 0.38) in high-risk NSAID users. In 2000 and 2006, under-use was significantly lower in NL compared with UK and IT (P < 0.001) in high-risk users. After rofecoxib's withdrawal, under-use increased significantly in UK and NL. CONCLUSIONS: The prescription of gastropreventive strategies followed a similar pattern across countries. Despite a temporary negative effect of rofecoxib withdrawal on under-use, improvement of gastroprotection with nonsteroidal anti-inflammatory drugs was observed. PMID- 22928492 TI - Descriptive and factor analysis of the Developmental Coordination Disorder Questionnaire (DCDQ'07) in a population-based sample of children with and without Developmental Coordination Disorder. AB - BACKGROUND: The Developmental Coordination Disorder Questionnaire (DCDQ'07) discriminates children with Developmental Coordination Disorder (DCD) from their peers. Studies employing the DCDQ have typically used clinical samples. To further validate the DCDQ'07, this study: (1) described its distributions in a population-based sample, and a sample of children with DCD; (2) explored sex and age differences at important cut-points; and (3) examined its factor structure. METHODS: This secondary analysis of data collected from 23 schools (n = 3151) included a sample of 3070 children (1526 boys, 1544 girls) and a sample of 122 children (73 boys, 49 girls) who met DCD diagnostic criteria. DCDQ'07 distributions were described by age and sex. Chi-square analyses were conducted using three clinically important percentile ranges; a factor analysis explored the construct validity of DCDQ scores. RESULTS: Parents of 3070 children (97.4%) completed the questionnaire independently. Significant sex differences were noted in both samples. Significant differences in proportions by sex, and DCDQ means by age were found in the population sample. A three-factor solution was found, accounting for 70.3% of the variance. CONCLUSIONS: This is one of the largest studies using the DCDQ'07 with a non-clinical sample. The three-factor solution, including item loading, was consistent with previous research. When using DCDQ cut-offs it is important to consider sex and age. PMID- 22928493 TI - The biological roles of glutaredoxins. AB - Grxs (glutaredoxins) are small ubiquitous redox enzymes. They are generally involved in the reduction of oxidative modifications using glutathione. Grxs are not only able to reduce protein disulfides and the low-molecular-mass antioxidant dehydroascorbate, but also represent the major enzyme class responsible for deglutathionylation reactions. Functional proteomics, including interaction studies, comparative activity measurements using heterologous proteins and structural analysis are combined to provide important insights into the crucial function of Grxs in cellular redox networks. Summarizing the current understanding of Grxs, with a special focus on organelle-localized members across species, genus and kingdom boundaries (including cyanobacteria, plants, bacteria, yeast and humans) lead to two different classifications, one according to sequence structure that gives insights into the diversification of Grxs, and another according to function within the cell that provides a basis for assessing the different roles of Grxs. PMID- 22928494 TI - The role of visual spatial attention in adult developmental dyslexia. AB - The present study investigated the nature of visual spatial attention deficits in adults with developmental dyslexia, using a partial report task with five-letter, digit, and symbol strings. Participants responded by a manual key press to one of nine alternatives, which included other characters in the string, allowing an assessment of position errors as well as intrusion errors. The results showed that the dyslexic adults performed significantly worse than age-matched controls with letter and digit strings but not with symbol strings. Both groups produced W shaped serial position functions with letter and digit strings. The dyslexics' deficits with letter string stimuli were limited to position errors, specifically at the string-interior positions 2 and 4. These errors correlated with letter transposition reading errors (e.g., reading slat as "salt"), but not with the Rapid Automatized Naming (RAN) task. Overall, these results suggest that the dyslexic adults have a visual spatial attention deficit; however, the deficit does not reflect a reduced span in visual-spatial attention, but a deficit in processing a string of letters in parallel, probably due to difficulty in the coding of letter position. PMID- 22928495 TI - Guaiazulene: a new treatment option for recalcitrant diaper dermatitis in NICU patients. AB - AIM: Based on a maternal observation, we aimed to evaluate the treatment effectiveness of guaiazulene (GA) containing local pomade in the high-risk neonates with recalcitrant diaper dermatitis (RDD). METHODS: We included 30 NICU patients of RDD, with level II-III aged between 22 and 67 days. Study group patients (n = 20) were treated with GA containing local pomade (0.05 g/100 g). Control group consisted of patients who had extended antifungal treatment. A visual scale was used to assess the response to treatment at the end of a week. Scoring was done at the beginning of the treatment, on the first, third and seventh days. RESULTS: Statistically significant differences in visual scores were determined between the two groups at the initial and following days of the treatment. In study group, improvements at the first and third days of the treatment were better than those of control group. Additionally, complete recovery rate in study group was better than that in controls. CONCLUSION: Having beneficial but no adverse effects, GA containing local pomade provided rapid recovery in risky neonates with RDD, who required rapid improvement. PMID- 22928496 TI - Comparison of the fatty acid composition of maternal blood and cord blood of mothers who delivered healthy full-term babies, preterm babies, and full-term small for gestational age infants. AB - OBJECTIVE: The aim of this study was to determine and compare the fatty acid (FA) profile of maternal blood and cord blood of children born at term (group A); those born prematurely (group B); and children born with hypotrophic features (group C). METHODS: The study consisted of 109 women. FA composition was determined by gas chromatography-mass spectrometry. RESULTS: Twenty-two FAs were identified in the maternal blood and 33 FAs were identified in the cord blood. Significant differences in the levels of C18:3n-6 and C20:5n-3 were noted when comparing the FA composition of maternal blood samples from the three different groups (A, B, and C). Seven statistical differences were detected in the cord blood. They concerned C12:0, C18:0, C18:1c, C18:3n-6, C20:0, C20:3n-6, and C20:4n 6. CONCLUSION: Our research has shown that the FA profile of both the maternal blood and the cord blood undergoes changes in response to pregnancy duration and the presence of reduced fetal growth. Statistical differences between groups B and C compared with group A, show that the placental-fetal transport of FA in group B and C infants may differ from that of group A children. PMID- 22928497 TI - Safety of labor induction with prostaglandin E2 in grandmultiparous women. AB - OBJECTIVE: The aim of this study was to assess the safety of labor induction with vaginal prostaglandin E2 (PGE2) in grandmultiparous women. METHODS: We conducted a retrospective cohort study of 1376 grandmultiparous women who underwent induction of labor with low dose PGE2. The primary outcome was uterine rupture and secondary outcomes included mode of delivery, postpartum hemorrhage and five minutes Apgar score. RESULTS: One case was diagnosed with uterine rupture (0.07%). Vaginal delivery was achieved in 1329 (96.6%) patients, whereas 47 (3.4%) patients had emergent cesarean delivery. Five minutes Apgar score <=7 was recorded in three cases (0.2%). There was no correlation between parity and cesarean delivery rate or low Apgar score. There were no significant differences between the grandmultiparous and great-grandmultiparous patients regarding cesarean delivery rate (3.1 vs. 5%, P = 0.12), operative vaginal delivery rate (2 vs. 2.3%, P = 0.74) or postpartum hemorrhage rate (0.8 vs. 1.1%, P = 0.6). CONCLUSIONS: Low dose PGE2 is a safe and efficient method for induction of labor in grandmultiparous and great-grandmultiparous women. PMID- 22928499 TI - Postnatal growth restriction and predictors of nutritional outcome in very low birth weight infants fed human milk and assisted by the Kangaroo Mother Care method. AB - OBJECTIVE: [corrected] The study sought to determine the prevalence of postnatal growth restriction (PNGR) and the predictors of nutritional outcome in very low birth weight (VLBW) infants. METHODS: Cross-sectional study conducted in a maternity school between July 2005 and August 2006. One-hundred and twelve VLBW infants were assessed during hospitalization, fed unfortified human milk and assisted by Kangaroo Mother Care. The dependent variables included the number of days required to reach minimum weight and regain birth weight, the percentage of weight loss, and the deterioration of nutritional status. These parameters were converted into a factor termed "nutritional outcome" using factor analysis. Multiple linear regressions were used to identify predictors of nutritional outcome. RESULTS: PNGR was observed in 89.3% of the infants at hospital discharge. The predictors of nutritional outcome were: appropriate-for gestational-age infants, children of mothers aged <= 20 years old, need for mechanical ventilation, longer stays in the neonatal intensive care unit, and a greater number of days to achieve full enteral nutrition. CONCLUSION: It is important to know the factors that negatively influence the nutritional outcome of VLBW infants, as these can be modified through the improvement of perinatal care and can reduce PNGR. PMID- 22928500 TI - Green ergonomics: definition and scope. AB - This paper demonstrates that the goals of ergonomics (i.e. effectiveness, efficiency, health, safety and usability) are closely aligned with the goals of design for environmental sustainability. In this paper, the term 'green ergonomics' is conceptualised to specifically describe ergonomics interventions with a pro-nature emphasis. Green ergonomics is focused on the bi-directional connections between human systems and nature. This involves looking at (1) how ergonomics design and evaluation might be used to conserve, preserve, and restore nature and (2) how ecosystem services might be harnessed to facilitate the improved wellbeing and effectiveness of human systems. The paper proposes the scope of green ergonomics based on these bi-directional relationships in the areas of the design of low resource systems and products, the design of green jobs, and the design for behaviour change. Suggestions for further work in the green ergonomics domain are also made. PRACTITIONER SUMMARY: Given the enormous environmental challenges facing modern industrial society, this paper encourages ergonomics science to embrace a pro-nature understanding of work design and research. This paper sets out the role for green ergonomics based on an appreciation of the human-nature connections that have been integrated with our understanding of ergonomics science and practice. PMID- 22928498 TI - Effects of labor on placental fatty acid beta oxidation. AB - OBJECTIVE: To measure the effect labor exerts on fatty acid (FA) oxidation in term human placentas, and to compare enzymes expression and activity between placenta and liver. METHODS: Placental samples were collected: (a) scheduled non labored cesarean section and (b) normal vaginal delivery at or beyond 37 weeks. Long and medium-chain FA oxidation were measured using (3)H-labeled FA, ATP concentration was measured via commercial kit. Activity and expression levels of 11 FA enzymes were measured and results compared to both human and mouse liver. RESULTS: Placentas undergoing labor had significantly decreased palmitate oxidation and ATP levels. Octanoic acid oxidation was 10-fold higher than palmitic acid oxidation. No difference in expression or activity level was detected between the groups. CONCLUSION: Term human placentas express all the enzymes required to oxidize FA, at a rate 20-fold lower than liver. FA Oxidation is not likely an important placental energy source during labor. Further work is needed to determine the functionality of this pathway in placenta. PMID- 22928501 TI - Intravitreal triamcinolone acetonide versus pars plana vitrectomy for pseudophakic cystoid macular edema. AB - PURPOSE: To compare the efficacy of intravitreal triamcinolone acetonide injection versus 23-gauge pars plana vitrectomy with internal limiting membrane peeling for the treatment of chronic pseudophakic cystoid macular edema (CME) after uncomplicated cataract surgery. METHODS: This retrospective, comparative, consecutive case series study included 39 patients with chronic pseudophakic CME. Twenty eyes in 20 patients were treated with intravitreal triamcinolone acetonide injection (IVT group), and 19 eyes in 19 patients were treated with pars plana vitrectomy with internal limiting membrane peeling (PPV group). In both groups, complete ophthalmologic examinations were performed before and after procedures. Findings were compared between the groups. RESULTS: Both groups experienced a significant improvement in visual acuity and macular thickness after 12 months follow-up. At months 1 and 2, the IVT group showed a significant improvement in visual acuity and a significant reduction in macular thickness compared with the PPV group (p < 0.05), but these differences were not statistically significant between the groups after the 12-month period. CONCLUSION: Both intravitreal steroid injection and pars plana vitrectomy with internal limiting membrane peeling had a favorable effect on visual and anatomic results in patients with chronic pseudophakic CME. However, surgical treatment had no advantage over intravitreal triamcinolone acetonide injection after 12-months follow-up. PMID- 22928502 TI - Design of poly(ethylene glycol)-functionalized hydrophilic carbon clusters for targeted therapy of cerebrovascular dysfunction in mild traumatic brain injury. AB - Traumatic brain injury (TBI) involves the elaboration of oxidative stress that causes cerebrovascular dysfunction, including impairment of autoregulation of cerebral blood flow. Currently, there is no clinically effective antioxidant treatment for these pathologies. Most currently available antioxidants act through mechanisms in which the antioxidant either transfers the radical or requires regeneration, both of which are impaired in the toxic post-TBI environment. We previously reported that single-walled carbon nanotubes (SWCNTs) and ultrashort SWCNTs possess antioxidant activity, and their characteristics suggest that radical annihilation is the major mechanism. We have now developed a biologically compatible class of carbon-based nanovectors, poly(ethylene glycol) functionalized hydrophilic carbon clusters (PEG-HCCs) that can be further functionalized with antibodies, and hence show promise as targeted drug delivery platforms. Here we report that PEG-HCCs possess innate antioxidant activity and can be rapidly targeted via an antibody to the P-selectin antigen in a model of injured cultured brain endothelial cells. One immediate application of this therapy is to vascular dysfunction that accompanies TBI and worsens outcome in the face of systemic hypotension. These in vitro results support the need for further investigation in animal models. PMID- 22928504 TI - Cell polarity and asymmetric cell division: the C. elegans early embryo. AB - Cell polarity is crucial for many functions including cell migration, tissue organization and asymmetric cell division. In animal cells, cell polarity is controlled by the highly conserved PAR (PARtitioning defective) proteins. par genes have been identified in Caenorhabditis elegans in screens for maternal lethal mutations that disrupt cytoplasmic partitioning and asymmetric division. Although PAR proteins were identified more than 20 years ago, our understanding on how they regulate polarity and how they are regulated is still incomplete. In this chapter we review our knowledge of the processes of cell polarity establishment and maintenance, and asymmetric cell division in the early C. elegans embryo. We discuss recent findings that highlight new players in cell polarity and/or reveal the molecular details on how PAR proteins regulate polarity processes. PMID- 22928505 TI - Phosphoinositide lipids and cell polarity: linking the plasma membrane to the cytocortex. AB - Many cell types in animals and plants are polarized, which means that the cell is subdivided into functionally and structurally distinct compartments. Epithelial cells, for example, possess an apical side facing a lumen or the outside environment and a basolateral side facing adjacent epithelial cells and the basement membrane. Neurons possess distinct axonal and dendritic compartments with specific functions in sending and receiving signals. Migrating cells form a leading edge that actively engages in pathfinding and cell-substrate attachment, and a trailing edge where such attachments are abandoned. In all of these cases, both the plasma membrane and the cytocortex directly underneath the plasma membrane show differences in their molecular composition and structural organization. In this chapter we will focus on a specific type of membrane lipids, the phosphoinositides, because in polarized cells they show a polarized distribution in the plasma membrane. They furthermore influence the molecular organization of the cytocortex by recruiting specific protein binding partners which are involved in the regulation of the cytoskeleton and in signal transduction cascades that control polarity, growth and cell migration. PMID- 22928506 TI - The role of secretory and endocytic pathways in the maintenance of cell polarity. AB - Epithelial cells line virtually every organ cavity in the body and are important for vectorial transport through epithelial monolayers such as nutrient uptake or waste product excretion. Central to these tasks is the establishment of epithelial cell polarity. During organ development, epithelial cells set up two biochemically distinct plasma membrane domains, the apical and the basolateral domain. Targeting of correct constituents to each of these regions is essential for maintaining epithelial cell polarity. Newly synthesized transmembrane proteins destined for the basolateral or apical membrane domain are sorted into separate transport carriers either at the TGN (trans-Golgi network) or in perinuclear REs (recycling endosomes). After initial delivery, transmembrane proteins, such as nutrient receptors, frequently undergo multiple rounds of endocytosis followed by re-sorting in REs. Recent work in epithelial cells highlights the REs as a potent sorting station with different subdomains representing individual targeting zones that facilitate the correct surface delivery of transmembrane proteins. PMID- 22928507 TI - Continuous endocytic recycling of tight junction proteins: how and why? AB - Tight junctions consist of many proteins, including transmembrane and associated cytoplasmic proteins, which act to provide a barrier regulating transport across epithelial and endothelial tissues. These junctions are dynamic structures that are able to maintain barrier function during tissue remodelling and rapidly alter it in response to extracellular signals. Individual components of tight junctions also show dynamic behaviour, including migration within the junction and exchange in and out of the junctions. In addition, it is becoming clear that some tight junction proteins undergo continuous endocytosis and recycling back to the plasma membrane. Regulation of endocytic trafficking of junctional proteins may provide a way of rapidly remodelling junctions and will be the focus of this chapter. PMID- 22928508 TI - Crucial polarity regulators in axon specification. AB - Cell polarization is critical for the correct functioning of many cell types, creating functional and morphological asymmetry in response to intrinsic and extrinsic cues. Neurons are a classical example of polarized cells, as they usually extend one long axon and short branched dendrites. The formation of such distinct cellular compartments (also known as neuronal polarization) ensures the proper development and physiology of the nervous system and is controlled by a complex set of signalling pathways able to integrate multiple polarity cues. Because polarization is at the basis of neuronal development, investigating the mechanisms responsible for this process is fundamental not only to understand how the nervous system develops, but also to devise therapeutic strategies for neuroregeneration. The last two decades have seen remarkable progress in understanding the molecular mechanisms responsible for mammalian neuronal polarization, primarily using cultures of rodent hippocampal neurons. More recent efforts have started to explore the role of such mechanisms in vivo. It has become clear that neuronal polarization relies on signalling networks and feedback mechanisms co-ordinating the actin and microtubule cytoskeleton and membrane traffic. The present chapter will highlight the role of key molecules involved in neuronal polarization, such as regulators of the actin/microtubule cytoskeleton and membrane traffic, polarity complexes and small GTPases. PMID- 22928509 TI - Cell wars: regulation of cell survival and proliferation by cell competition. AB - During cell competition fitter cells take over the tissue at the expense of viable, but less fit, cells, which are eliminated by induction of apoptosis or senescence. This probably acts as a quality-control mechanism to eliminate suboptimal cells and safeguard organ function. Several experimental conditions have been shown to trigger cell competition, including differential levels in ribosomal activity or in signalling pathway activation between cells, although it is unclear how those differences are sensed and translated into fitness levels. Many of the pathways implicated in cell competition have been previously linked with cancer, and this has led to the hypothesis that cell competition could play a role in tumour formation. Cell competition could be co-opted by cancer cells to kill surrounding normal cells and boost their own tissue colonization. However, in some cases, cell competition could have a tumour suppressor role, as cells harbouring mutations in a subset of tumour suppressor genes are killed by wild type cells. Originally described in developing epithelia, competitive interactions have also been observed in some stem cell niches, where they play a role in regulating stem cell selection, maintenance and tissue repopulation. Thus competitive interactions could be relevant to the maintenance of tissue fitness and have a protective role against aging. PMID- 22928510 TI - The control of gene expression and cell proliferation by the epithelial apical junctional complex. AB - The AJC (apical junctional complex) of vertebrate epithelial cells orchestrates cell-cell adhesion and tissue barrier function. In addition, it plays a pivotal role in signalling. Several protein components of the AJC, e.g. the cytoplasmic proteins beta-catenin, p120-catenin and ZO (Zonula Occludens)-2, can shuttle to the nucleus, where they interact with transcription factors to regulate gene expression and cell proliferation. Other junctional proteins, e.g. angiomotin, alpha-catenin and cingulin, are believed to act by sequestering either transcription factors, such as YAP (Yes-associated protein), or regulators of small GTPases, such as GEF (guanine-nucleotide-exchange factor)-H1, at junctions. The signalling activities of AJC proteins are triggered by different extracellular and intracellular cues, including cell density, and physiological or pathological activation of developmentally regulated pathways, such as the Wnt pathway. The interplay between junctional protein complexes, the actin cytoskeleton and signalling pathways is of crucial importance in the regulation of gene expression and cell proliferation. PMID- 22928511 TI - Apicobasal polarity and cell proliferation during development. AB - Cell polarization and cell division are two fundamental cellular processes. The mechanisms that establish and maintain cell polarity and the mechanisms by which cells progress through the cell cycle are now fairly well understood following decades of experimental work. There is also increasing evidence that the polarization state of a cell affects its proliferative properties. The challenge now is to understand how these two phenomena are mechanistically connected. The aim of the present chapter is to provide an overview of the evidence of cross talk between apicobasal polarity and proliferation, and the current state of knowledge of the precise mechanism by which this cross-talk is achieved. PMID- 22928512 TI - The Hippo pathway: key interaction and catalytic domains in organ growth control, stem cell self-renewal and tissue regeneration. AB - The Hippo pathway is a conserved pathway that interconnects with several other pathways to regulate organ growth, tissue homoeostasis and regeneration, and stem cell self-renewal. This pathway is unique in its capacity to orchestrate multiple processes, from sensing to execution, necessary for organ expansion. Activation of the Hippo pathway core kinase cassette leads to cytoplasmic sequestration of the nuclear effectors YAP (Yes-associated protein) and TAZ (transcriptional coactivator with PDZ-binding motif), consequently disabling their transcriptional co-activation function. Components upstream of the core kinase cassette have not been well understood, especially in vertebrates, but are gradually being elucidated and include cell polarity and cell adhesion proteins. PMID- 22928513 TI - Epithelial cell polarity: what flies can teach us about cancer. AB - Epithelial cells are polarized along their apical-basal axis. Much of the cellular machinery that goes into establishing and maintaining epithelial cell polarity is evolutionarily conserved. Model organisms, including the fruit fly, Drosophila melanogaster, are thus particularly useful for the study of cell polarity. Work in Drosophila has identified several important components of the polarity machinery and has also established the surprising existence of a secondary cell polarity pathway required only under conditions of energetic stress. This work has important implications for the understanding of human cancer. Most cancers are epithelial in origin, and the loss of cell polarity is a critical step towards malignancy. Thus a better understanding of how polarity is established and maintained in epithelial cells will help us to understand the process of malignant transformation and may lead to improved therapies. In the present chapter we discuss the current understanding of how epithelial cell polarity is regulated and the known associations between polarity factors and cancer. PMID- 22928514 TI - The Scribble-Dlg-Lgl polarity module in development and cancer: from flies to man. AB - The Scribble, Par and Crumbs modules were originally identified in the vinegar (fruit) fly, Drosophila melanogaster, as being critical regulators of apico-basal cell polarity. In the present chapter we focus on the Scribble polarity module, composed of Scribble, discs large and lethal giant larvae. Since the discovery of the role of the Scribble polarity module in apico-basal cell polarity, these proteins have also been recognized as having important roles in other forms of polarity, as well as regulation of the actin cytoskeleton, cell signalling and vesicular trafficking. In addition to these physiological roles, an important role for polarity proteins in cancer progression has also been uncovered, with loss of polarity and tissue architecture being strongly correlated with metastatic disease. PMID- 22928515 TI - Reusable solid-phase microextraction coating for direct immersion whole-blood analysis and extracted blood spot sampling coupled with liquid chromatography tandem mass spectrometry and direct analysis in real time-tandem mass spectrometry. AB - Three different biocompatible polymers were tested and evaluated in order to improve the whole-blood biocompatibility of previously developed C18 polyacrylonitrile (C18-PAN) thin-film solid-phase microextraction (SPME) coating. Among all methods of modification, UV-dried thin PAN-over C18-PAN provided the best results. This coating presented reusable properties and reproducible extraction efficiency for at least 30 direct extractions of diazepam from whole blood [relative standard deviation (RSD) = 12% using external calibration and 4% using isotope dilution calibration]. The amount of absolute recovery for direct immersion analysis and based on the free concentration of diazepam in blood matrix was about 4.8% (desorption efficiency = 98%). The limit of quantitation (LOQ) for the developed solid-phase microextraction liquid chromatography-tandem mass spectrometry (SPME-LC-MS/MS) method for direct whole-blood analysis was 0.5 ng/mL. The optimized modification of the coating was then used for an extracted blood spot (EBS) sampling approach, a new sampling method which is introduced to address the limitations of dried blood spot sampling. EBS was evaluated using LC MS/MS and direct analysis in real time (DART)-MS/MS, where, for a 5 MUL blood spot, LOQs of 0.2 and 1 MUg/mL, respectively, were achieved for extraction of diazepam. PMID- 22928517 TI - Tender cutaneous nodules of the legs: diagnosis and clinical clues to diagnosis. AB - BACKGROUND: "Tender cutaneous nodules of the legs" is a common manifestation in dermatology. Histopathological investigation is usually required for this condition, because clinical data are frequently insufficient to make a definite diagnosis. OBJECTIVE: To identify and analyze the causes of patients presenting with tender leg nodules and to reveal clinical clues that could help to differentiate causes. MATERIALS AND METHODS: The medical records and histopathological slides of patients presenting with tender cutaneous nodules of the legs between January 2005 and December 2007 were retrospectively reviewed. RESULTS: Of the total of 154 patients, 122 (79.2%) were female. Definite diagnoses were categorized into four groups: inflammation (84.4%); infection (5.8%); tumor (6.5%); and nonspecific (3.2%). The most common cause in the inflammation group was erythema nodosum. The infections found were Acremonium spp., Penicillium sp., Mycobacterium abscessus, Mycobacterium fortuitum and Mycobacterium leprae. The tumors included leiomyoma, leukemia cutis, and lymphomas. Clinical data that correlated with and could be used as clues for the inflammation group were female sex (P = 0.03, OR 6.43) and lower leg involvement (P = 0.03, OR 7.14). LIMITATIONS: The retrospective manner of this study is a limitation. CONCLUSION: Various inflammatory conditions, infections, and tumors can present as tender cutaneous nodules of the legs. Female sex and lower leg involvement were clinical data that could be used as clues for the diagnoses in the inflammation group. However, histopathological investigation is still crucial to determine a definite diagnosis in patients presenting with tender cutaneous nodules of the legs. PMID- 22928518 TI - Rotational and translational diffusion of spin probes in room-temperature ionic liquids. AB - We have studied the rotational and translational diffusion of the spin probe 4 hydroxy-2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPOL) in five imidazolium-based room-temperature ionic liquids (RTILs) and glycerol by means of X-band electron paramagnetic resonance (EPR) spectroscopy. Rotational correlation times and rate constants of intermolecular spin exchange have been determined by analysis of the EPR line shape at various temperatures and spin probe concentrations. The model of isotropic rotational diffusion cannot account for all spectral features of TEMPOL in all RTILs. In highly viscous RTILs, the rotational mobility of TEMPOL differs for different molecular axes. The translational diffusion coefficients have been calculated from spin exchange rate constants. To this end, line shape contributions stemming from Heisenberg exchange and from the electron-electron dipolar interaction have been separated based on their distinct temperature dependences. While the Debye-Stokes-Einstein law is found to apply for the rotational correlation times in all solvents studied, the dependence of the translational diffusion coefficients on the Stokes parameter T/eta is nonlinear; i.e., deviations from the Stokes-Einstein law are observed. The effective activation energies of rotational diffusion are significantly larger than the corresponding values for translational motion. Effects of the identity of the RTIL cations and anions on the activation energies are discussed. PMID- 22928519 TI - UK prostate charities merge. PMID- 22928520 TI - Community neonatal practices and its association with skilled birth attendance in rural Haryana, India. AB - AIM: The study aimed to document home-based neonatal care practices and their association with type of birth attendance. METHODS: This study was conducted in rural Haryana on mothers who had delivered a live baby one to 2 months prior to interview. The study instrument, administered through home visits, had questions related to cord care, breastfeeding, thermal care, baby handling and healthcare seeking. Logistic regression was performed to test for association [OR; 95% CI] of key newborn care practices with skilled birth attendance. RESULTS: Of the 415 mothers interviewed, 26.7% applied nothing on umbilicus; 15% were kept in skin-to skin contact with mother; 20.2% were exclusively breastfed in first month. Seeking care in private sector and cost incurred in the treatment for a neonatal illness was significantly higher for male babies. Delivery by skilled birth attendant (68.5%) was associated with applying nothing on the cord [1.8; 1.01 3.25], in skin-to-skin contact with mother for >= 6 h a day [2.21; 1.18-4.13], bathing the baby after third day [14.63; 6.85-31.21] and exclusive breastfeeding [8.84; 3.42-22.8]. CONCLUSION: The results of this study call for not only upscaling skilled birth attendance but also improving the quality of care currently provided. PMID- 22928516 TI - Cutaneous squamous cell carcinoma and human papillomavirus: is there an association? AB - BACKGROUND: The role of human papillomavirus (HPV) in the induction and maintenance of cervical, anogenital, and some oropharyngeal carcinomas is well recognized, but its role in cutaneous squamous cell carcinoma (SCC) remains to be elucidated. HPV is thought to act as a possible cocarcinogen in the development of SCC. OBJECTIVE: To review the literature assessing the correlation between and possible causation of HPV and cutaneous SCC in immunocompetent and immunocompromised populations. METHODS: We reviewed HPV sampling and detection methods, epidemiologic studies examining HPV carriage in immunocompetent and immunosuppressed individuals, and evidence asserting an association between HPV and cutaneous SCC. RESULTS: Although an abundant body of evidence points toward a link between HPV and cutaneous SCC, many studies indicate otherwise. Recent studies have focused on viral activity in addition to DNA presence. CONCLUSION: The possibility exists that HPV may play a role in the induction but not maintenance of cutaneous SCC. PMID- 22928521 TI - Identity-based inhibitory processing during focused attention. AB - Recent data suggest that the operating principles governing inhibition of distractor-related activity may deviate from dominant models describing inhibitory processing during selective attention. Here we aimed to gain a better understanding of these data in order to determine whether they actually defy premises of current models. In addition to providing evidence against noninhibitory accounts of the data (see especially Experiment 6), the results support three main novel findings that challenge current theories. First, the data provide evidence that inhibition overpowered excitation from ongoing external input (Experiments 1-4), which suggests that inhibitory control processes are more powerful than current models indicate. Second, negative effects emerged even when targets appeared alone (Experiment 5), which suggests that selection does not play an essential role in triggering inhibitory processing. Third, relatively early distractor-related activity was affected, which supports a role for inhibition prior to action control (Experiment 3). These findings suggest a need to revise current models describing inhibition of distracting information during selective attention. PMID- 22928522 TI - Using Mendelian randomization to determine causative factors in cardiovascular disease. PMID- 22928523 TI - Pain and stress assessment after retinopathy of prematurity screening examination: indirect ophthalmoscopy versus digital retinal imaging. AB - BACKGROUND: Increasingly, neonatal clinics seek to minimize painful experiences and stress for premature infants. Fundoscopy performed with a binocular indirect ophthalmoscope is the reference examination technique for screening of retinopathy of prematurity (ROP), and it is associated with pain and stress. Wide field digital retinal imaging is a recent technique that should be evaluated for minimizing infant pain and stress. METHODS: The purpose of the study was to assess and compare the impact of using a binocular indirect ophthalmoscope (BIO), or wide-field digital retinal imaging (WFDRI) on pain and stress in infants undergoing ROP screening examination. This was a comparative evaluation study of two screening procedures. Ophthalmologic examinations (N = 70) were performed on 24 infants with both BIO and WFDRI. Pain assessments were performed with two specific neonatal scales (Crying, requires oxygen, increased vital signs, expression and sleeplessness, CRIES and, Premature infant pain profile, PIPP) just prior to the examination, and 30 seconds, 1 hour, and 24 hours later after ending the examination. RESULTS: Changes over time were significantly different between BIO and WFDRI with both scales (PIPP score, p = .007, and CRIES score, p = .001). Median PIPP score (interquartile interval) at baseline was 4 (3-5). At 30 seconds the score was 8 (6-9) for BIO and 6 (5-7) for WFDRI, respectively. The increase in PIPP score between baseline and 30 seconds was significantly lower with WFDRI (p = .006). The median increase in CRIES score from baseline to 30 seconds was 1 point lower for WFDRI than for BIO (p < .001). No significant difference in response remained at 1 hour or 24 hour assessments. CONCLUSIONS: A transient short-term pain and stress response occurs with both BIO and WFDRI. Infants examined for screening of ROP with digital retinal imaging present less pain and stress at 30 seconds following completion of the exam when compared with binocular indirect ophthalmoscopy. PMID- 22928524 TI - Argentivorous molecules: structural evidence for Ag(+)-pi interactions in solution. AB - Tetra-armed cyclens bearing aromatic side arms were prepared by the reductive amination of cyclen with substituted benzaldehydes. When equimolar amounts of Ag(+) ions were added to the ligands, the aromatic rings covered the Ag(+) ions incorporated in the ligand cavities, as if the aromatic ring "petals" caught the Ag(+) ions in the way an insectivorous plant (Venus flytrap) catches insects. The ligands are called "argentivorous molecules". Evidence of intramolecular Ag(+)-pi interactions in solution and in the solid state is reported. PMID- 22928525 TI - Analysis of a comprehensive dataset of diversity generating retroelements generated by the program DiGReF. AB - BACKGROUND: Diversity Generating Retroelements (DGRs) are genetic cassettes that can introduce tremendous diversity into a short, defined region of the genome. They achieve hypermutation through replacement of the variable region with a strongly mutated cDNA copy generated by the element-encoded reverse transcriptase. In contrast to "selfish" retroelements such as group II introns and retrotransposons, DGRs impart an advantage to their host by increasing its adaptive potential. DGRs were discovered in a bacteriophage, but since then additional examples have been identified in some bacterial genomes. RESULTS: Here we present the program DiGReF that allowed us to comprehensively screen available databases for DGRs. We identified 155 DGRs which are found in all major classes of bacteria, though exhibiting sporadic distribution across species. Phylogenetic analysis and sequence comparison showed that DGRs move between genomes by associating with various mobile elements such as phages, transposons and plasmids. The DGR cassettes exhibit high flexibility in the arrangement of their components and easily acquire additional paralogous target genes. Surprisingly, the genomic data alone provide new insights into the molecular mechanism of DGRs. Most notably, our data suggest that the template RNA is transcribed separately from the rest of the element. CONCLUSIONS: DiGReF is a valuable tool to detect DGRs in genome data. Its output allows comprehensive analysis of various aspects of DGR biology, thus deepening our understanding of the role DGRs play in prokaryotic genome plasticity, from the global down to the molecular level. PMID- 22928526 TI - The return of the city-state: urban governance and the New York City H1N1 pandemic. AB - This article examines New York City's response to the 2009 H1N1 pandemic in the context of the post-9/11 US security regime. While the federal level 'all hazards' approach made for greater depth of support, it also generated unrealistic assumptions at odds with an effective local response. The combination of structurally induced opportunity and actor specific strengths (size, expertise) made for effective local governance by the New York City Department of Health and Mental Hygiene. By underlining the importance of locality as a first line of defence and linking defence function to policy initiative in regard to health governance, this study illustrates the continuing relevance of Weber's insight into the institutional structure of the city. PMID- 22928527 TI - Mild, reversible reaction of iridium(III) amido complexes with carbon dioxide. AB - Unlike some other Ir(III) hydrides, the aminopyridine complex [(2-NH(2) C(5)NH(4))IrH(3)(PPh(3))(2)] (1-PPh(3)) does not insert CO(2) into the Ir-H bond. Instead 1-PPh(3) loses H(2) to form the cyclometalated species [(kappa(2)-N,N-2 NH-C(5)NH(4))IrH(2)(PPh(3))(2)] (2-PPh(3)), which subsequently reacts with CO(2) to form the carbamato species [(kappa(2)-O,N-2-OC(O)NH C(5)NH(4))IrH(2)(PPh(3))(2)] (10-PPh(3)). To study the insertion of CO(2) into the Ir-N bond of the cyclometalated species, a family of compounds of the type [(kappa(2)-N,N-2-NR-C(5)NH(4))IrH(2)(PR'(3))(2)] (R = H, R' = Ph (2-PPh(3)); R = H, R' = Cy (2-PCy(3)); R = Me, R' = Ph (4-PPh(3)); R = Ph, R' = Ph (5-PPh(3)); R = Ph, R' = Cy (5-PCy(3))) and the pyrimidine complex [(kappa(2)-N,N-2-NH C(4)N(2)H(3))IrH(2)(PPh(3))(2)] (6-PPh(3)) were prepared. The rate of CO(2) insertion is faster for the more nucleophilic amides. DFT studies suggest that the mechanism of insertion involves initial nucleophilic attack of the nitrogen lone pair of the amide on CO(2) to form an N-bound carbamato complex, followed by rearrangement to the O-bound species. CO(2) insertion into 1-PPh(3) is reversible in the presence of H(2) and treatment of 10-PPh(3) with H(2) regenerates 1 PPh(3), along with Ir(PPh(3))(2)H(5). PMID- 22928528 TI - Expression of genes involved in susceptibility to multifactorial autoimmune diseases: estimating genotype effects. AB - Several single nucleotide polymorphisms (SNPs) have been associated with susceptibility to autoimmune diseases, but the mechanisms responsible for the associations are poorly understood. To test the hypothesis that the variation of the basal levels of the gene products is significantly influenced by genetic polymorphism, we investigated whether SNPs in genes CD40, CD28, CTLA4, CD80, CD86, BAFF and IL6 are affecting mRNA or protein expression. The surface expression of the proteins on unstimulated monocytes, B cells, NK cells, CD4+ T cells and CD8+ T cells, as well as the mRNA levels in peripheral blood mononuclear cells (PBMC) was compared among healthy volunteers with different genotypes. Despite the low basal expression level and large interindividual variation, average BAFF expression was significantly higher in carriers of genotype C/C of the BAFF-871C>T SNP (rs9514828) when compared with carriers of the C/T and T/T genotypes. Genotype C/C carriers presented higher levels of the protein on CD8+ T cells, monocytes and NK cells and of mRNA in PBMC. Moreover, carriers of T allele of CTLA4-318C>T (rs5742909) showed a significantly increased expression of CTLA-4 on CD8+ T cells. No significant variation among genotypes was found in the protein or mRNA levels of other investigated genes. PMID- 22928529 TI - A modified Glasgow Blatchford Score improves risk stratification in upper gastrointestinal bleed: a prospective comparison of scoring systems. AB - BACKGROUND: Several risk scoring systems exist for upper gastrointestinal bleed (UGIB). We hypothesised that a modified Glasgow Blatchford Score (mGBS) that eliminates the subjective components of the GBS might perform as well as current scoring systems. AIM: To compare the performance of the mGBS to the most widely reported scoring systems for prediction of clinical outcomes in patients presenting with UGIB. METHODS: Prospective cohort study from 9/2010 to 9/2011. Accuracy of the mGBS was compared with the full GBS, full Rockall Score (RS) and clinical RS using area under the receiver operating characterstics-curve (AUC). PRIMARY OUTCOME was need for clinical intervention: blood transfusion, endoscopic, radiological or surgical intervention. Secondary outcome was repeat bleeding or mortality. RESULTS: One hundred and ninety-nine patients were included. Median age was 56 with 40% women. Thirty-two per cent patients required blood transfusion, 24% endoscopic interventions, 0.5% radiological intervention, 0 surgical interventions, 5% had repeat bleeding and 0.5% mortality. PRIMARY OUTCOME: the mGBS (AUC 0.85) performed as well as the GBS (AUC = 0.86, P = 0.81), and outperformed the full RS (AUC 0.75, P = 0.005) and clinical RS (AUC 0.66, P < 0.0001). Secondary outcome: the mGBS (AUC 0.83) performed as well as the GBS (AUC 0.81, P = 0.38) and full RS (AUC 0.69, and outperformed the clinical RS (AUC 0.59, P = 0.0007). CONCLUSIONS: The modified Glasgow Blatchford Score performed as well as the full Glasgow Blatchford Score while outperforming both Rockall Scores for prediction of clinical outcomes in American patients with upper gastrointestinal bleed. By eliminating the subjective components of the Glasgow Blatchford Score, the modified Glasgow Blatchford Score may be easier to use and therefore more easily implemented into routine clinical practice. PMID- 22928530 TI - The effect of post-natal mental distress amongst Indian and Pakistani mothers living in England on children's behavioural outcomes. AB - BACKGROUND: Low socio-economic status (SES), post-natal mental distress and parenting impact child mental health and future well-being. There are unexplained differences in child mental health between South Asian ethnic minority groups living in the UK that may be due to variation in, and differential mediation of, these factors. METHODS: We used multivariate multiple regression analysis of the effect of symptoms of mental distress, socio-demographic variables and warmth of parenting on child internalizing and externalizing scores at age seven (measured in 2010) in a population cohort of English children whose mothers were of Indian (n = 211) and Pakistani (n = 260) origin. RESULTS: In the fully adjusted models the legacy of mental distress was visible for both internalizing (beta coefficient 1.52, P = 0.04) and externalizing (1.68, P = 0.01) behaviour in the Pakistani children, and on the Indian children's internalizing (2.08, P = 0.008) but not externalizing (0.84, P = 0.204) behaviour. Lower SES was associated with worse behavioural scores for the Pakistani children, and warmth of parenting on Indian children's externalizing scores. CONCLUSIONS: Symptoms of post-natal mental distress are associated with Indian and Pakistani child outcomes at age seven. The finding that warmth of parenting had a stronger association on Indian children's externalizing scores than mental distress might be explained by differences in the expression of SES on family characteristics and functioning between the two ethnic groups. PMID- 22928531 TI - Maternal morbidity on 147 triplets: single institution experience. AB - OBJECTIVES: To evaluate the incidence and characteristics of maternal complications in triple pregnancies. An additional objective was to study the relation between assisted reproductive techniques and maternal complications. MATERIAL AND METHODS: Retrospective study on 147 triplets assisted at the Gynecology and Obstetrics department of La Paz University Hospital between 2000 and 2010. We analyzed the incidence of maternal complications and their relation to assisted reproductive techniques. RESULTS: One triplet was observed every 711 pregnancies. The most frequent maternal complications were spontaneous preterm labor (56%), premature rupture of membranes (28.9%), anemia (24.4%) and preeclampsia (20.4%). Triplets conceived by assisted reproductive techniques were significantly more likely to develop spontaneous preterm labor than spontaneous pregnancies (60% vs. 40%, respectively; p = 0.045). CONCLUSIONS: Triplets have a very high risk of maternal complications such as preeclampsia. Moreover, the presence of spontaneous preterm labor is more frequent in triplets conceived by assisted reproductive techniques than in those spontaneously conceived. PMID- 22928532 TI - Sonographic assessment of post-cesarean section uterine scar in pregnant women. AB - PURPOSE: To detect location of uterine cesarean scar in relation to cervix in pregnancies with previous cesarean section (CS) and to compare location between elective and emergent previous CS. STUDY DESIGN: Prospective study, 91 pregnant women with previous low transverse CS. Two groups: previous elective [36 (39.6%)] and emergent CS [55 (60.4%)]. Transvaginal ultrasound was performed between 14 and 16 weeks. Cervical length (CL) and distance between external oss to hypoechogenic line (EO-HL distance), which describes location of cesarean scar, were measured. Surgical incision was considered cervical when EO-HL distance was smaller than CL. RESULTS: Mean CL and EO-HL distance: 45.4 + 7. 0 and 39.0 + 9.4 mm, respectively for all patients. No significant differences were observed in CL (45.9 + 6.2 vs. 45.1 + 8.5 mm; p = not significant [NS]) and EO-HL distance (40.7 + 9.7 vs. 37.9 + 9.1 mm; p = NS) between both groups. Sixty-four cases (70.3%) had cervical scar, eight (8.8%) at the level of the internal oss and 19 (20.9) in the lower uterine segment. No significant difference was observed between both groups regarding location of scar (cervix -72 vs. 67% emergent vs. elective, respectively; p = NS). CONCLUSION: CS incisions are mostly performed in cervix, in elective as well as in emergent operations. PMID- 22928533 TI - Perfusion with magnesium sulfate increases sFlt-1 secretion only in the fetal side of placenta of women with preeclampsia. AB - OBJECTIVE: To examine the effect of magnesium sulfate (MgSO(4)) on sFlt (soluble fms-like tyrosine kinase)-1 in the fetal and maternal compartments of normotensive and preeclamptic placentas. METHODS: Cotyledons of term normotensive and preeclamptic placentas were dually perfused for six hours, with control medium and MgSO(4) (6-7 mg %) in the maternal reservoir. Perfusate sFlt-1 concentrations were measured. RESULTS: Median sFlt-1 concentration was higher in the maternal than in the fetal side in both groups and perfusion media (p < 0.0001). When perfused with control medium, the maternal side median sFlt-1 concentration was higher in the preeclampsia than in the control group (p < 0.0001). After perfusion with MgSO(4), the median maternal and fetal sides perfusate sFlt-1 concentration were higher in the preeclampsia than in the control group (p < 0.0001). In comparison to perfusion with control medium, the median sFlt-1 concentration of normal pregnant women decreased in the fetal and increased in the maternal side. In the preeclampsia group, only median fetal side sFlt-1 concentration increased. CONCLUSION: In contrast to normal pregnant women, perfusion with MgSO(4) of preeclamptic placentas did not increase their sFlt-1 concentration. This may indicate that MgSO(4) role may be limited to its anti eclamptic and does not affect the anti-angiogenic state associated with preeclampsia. PMID- 22928534 TI - Histologic chorioamnionitis at term: implications for the progress of labor and neonatal wellbeing. AB - OBJECTIVE: The aim of the present study was to evaluate: i) the rate of histologic chorioamnionitis in relation to the onset of labor and mode of delivery; ii) influence of clinical parameters on the risk of histologic chorioamnionitis in laboring women; iii) neonatal outcome in relation to histologic chorioamnionitis. METHODS: A cohort study was conducted on 395 healthy women at term, with singleton uneventful pregnancy, of which 195 with spontaneous onset of labor and 200 with elective cesarean section. All placentas, collected after delivery, were examined for the diagnosis of histologic chorioamnionitis. Mode of delivery, presence of bacterial infection of placenta and membranes, maternal clinical parameters and neonatal outcome were recorded. RESULTS: The rate of histologic chorioamnionitis in women with spontaneous onset of labor was significantly higher than in those experiencing elective cesarean section (28.7% vs. 11.5%). Nulliparity and the duration of labor were independent variables associated with acute histologic chorioamnionitis. The presence of histologic chorioamnionitis did not affect neonatal outcome. CONCLUSIONS: The present study showed a highest rate of histological chorionamniositis in women delivering after spontaneous onset of term labor, although the mode of delivery either vaginally or by emergency cesarean section was not influenced by the presence of this pathological condition. PMID- 22928535 TI - Management of term newborns following maternal intrapartum fever. AB - OBJECTIVE: To evaluate the diagnostic and therapeutic approach to full term neonates born to mothers with intrapartum fever. METHODS: In a retrospective study, neonates born to mothers with intrapartum fever, (>= 37.8 degrees C), were compared to control group matched by gestational age and birthweight. RESULTS: Overall, 159 singleton full term neonates born to women with intrapartum fever (study group) were compared to 159 control infants. No differences in neonatal outcomes were found between the two groups except for a higher rate of meconium stained amniotic fluid in the maternal-fever group. There were no cases of neonatal infection, severe neonatal morbidity, or neonatal mortality in either of the groups. Full sepsis workup and intravenous antibiotic treatment were provided to 17.6% of the neonates in the study group. Logistic regression analysis revealed that delivery by Cesarean section was the only factor independently associated with the decision to perform a full sepsis work up and antibiotic treatment in cases of maternal intrapartum fever (OR 32.0, 95% CI 9.4-112.1). CONCLUSIONS: In low-risk women with asymptomatic intrapartum fever, neonatal infection is uncommon, so that aggressive evaluation and management of these infants may not be necessary and should be balanced against the low risk of neonatal sepsis. PMID- 22928536 TI - Natural history of fetal renal pyelectasis. AB - OBJECTIVE: To follow the natural progression of fetal renal pyelectasis detected in the mid second trimester ultrasound in an unselected obstetric population. STUDY DESIGN: Single-centered, retrospective study that included all level II ultrasounds done from Jan 2008 to Dec 2009. The initial level II ultrasound was done in the mid second trimester. The renal pyelectasis detected on the antenatal ultrasound (AUS) was classified as mild (5-7 mm), moderate (7.1-9 mm), or severe (>9.1 mm). Postnatal outcomes were classified as "Resolved", "Improving", or "Worsened". RESULTS: Ninety-eight cases of fetal renal pyelectasis were detected. Sixteen patients were excluded. Of the remaining 82 cases of fetal pyelectasis, 32 (39%) were mild, 21 (25.6%) moderate, and 29 (35.4%) severe. In 74 (90.2%) infants, pyelectasis resolved, remained stable, or improved in the postnatal ultrasound. In eight (9.8%) infants, pyelectasis worsened. CONCLUSION: Totally, 90.2% of pyelectasis detected on AUS resolved spontaneously, remained stable or improved. The magnitude of fetal renal pyelectasis did not correlate with postnatal outcome. All fetal renal pyelectasis >= 5 mm detected on the mid second trimester ultrasound should be followed antenatally. Those fetuses with persistent pyelectasis should be evaluated after birth and followed until resolution of pyelectasis or until a diagnosis is obtained. PMID- 22928537 TI - Labor induction with prostaglandin E2: characteristics of response and prediction of failure. AB - OBJECTIVE: To characterize the response to labor induction with prostaglandin E2 (PGE2) and to identify risk factors for induction failure. METHODS: A prospective controlled study of women admitted for labor induction with PGE2. Maternal characteristics, Bishop score and sonographic cervical length were documented at admission. The change in cervical characteristics and the emergence of uterine contractions following each application of PGE2 were analyzed. RESULTS: Of the 88 women who were included in the study, 19 (21.6%) failed to response to PGE2. The following factors were independently associated with induction failure: nulliparity (odds ratio [OR] = 5.9, 95% confidence interval (CI): 1.2-30.2), pre pregnancy body mass index >25 kg/m2 (OR = 5.4, 95% CI: 1.1-26.5), Bishop score <4 (OR = 2.3, 95% CI: 1.05-14.4), cervical length <25 mm (OR = 0.2, 95% CI: 0.1-0.8) and the development of uterine contractions in response to the first application of PGE2 (OR = 0.4, 95% CI: 0.1-0.93). Overall, most women required only one (60.9%) or two (85.5%) applications of PGE2 to achieve successful induction. The number of applications of PGE2 required to achieve successful induction was related to parity and cervical status at presentation. CONCLUSIONS: Overall, most women who eventually respond to PGE2 do so following the first two applications of PGE2, and the contribution of subsequent applications is relatively small and related to cervical status at admission. PMID- 22928538 TI - Success rate and challenges of fetal anesthesia for ultrasound guided fetal intervention by maternal opioid and benzodiazepine administration. AB - OBJECTIVE: The safe and effective methods of fetal anesthesia/analgesia during ultrasound guided direct fetal procedure are yet to be determined. The authors investigated whether maternal diazepam/fentanyl administration meets this purpose. METHODS: The medical/anesthesia records were retrospectively reviewed in cases between 2001 and 2010 at a tertiary perinatal center. Success rate as well as maternal and fetal complications were analysed. RESULTS: Among the 150 procedures in 118 fetuses, diazepam 10 mg and fentanyl 200 ug sufficiently prevented fetal movement upon the procedure in 56% of the procedures. Supplemental anesthetic agents such as nitrous oxide and propofol were needed in other cases. No serious maternal complication was noted, while fetal cardiac arrest/severe bradycardia was noted in three fetuses, one of which was successfully resuscitated by intracardiac adrenalin injection. CONCLUSIONS: Maternal diiazepam/fentanyl administration offered adequate fetal condition without significant maternal complications. Since these procedures are performed to treat severe fetal conditions, preparation for fetal resuscitation is also important. PMID- 22928539 TI - Medical successes and couples' psychological problems in assisted reproduction treatment: a narrative based medicine approach. AB - OBJECTIVE: 1) To explore the psychological processes that develop in women and men during their first pregnancy obtained with assisted reproduction treatment; 2) to individuate the main plot that women and men use to recount their transition to parenthood. METHODS: A face-to-face semi-structured autobiographical interview was administered. The interview was aimed to investigate the story of pregnancy. Interviews were transcribed verbatim and analyzed in order to merge principal themes. PARTICIPANTS: 15 Italian couples waiting for the first child after a conception with assisted reproductive technologies. RESULTS: Medically assisted pregnancy constitutes an extremely stressful, highly medicalised experience, that the couple, however, narrated according to a basic plot consisting in four phases: doubt, final sentence, victory, monitoring. CONCLUSIONS: Results suggest that physicians can benefit from knowing the phases that infertile couples experience during pregnancy because these can serve as a framework to use in monitoring their transition to parenthood and in planning psychological support and health interventions for them. PMID- 22928540 TI - Herb remedies during pregnancy: a systematic review of controlled clinical trials. AB - OBJECTIVE: The use of herbal remedies has been documented both among various patient groups and in the general population to promote health. The aim of this systematic review is to analyze the benefits of herb use during pregnancy. METHODS: A systematic literature search covering the period from January 1990 to September 2010 was performed using various electronic databases. Randomized controlled clinical trials (RCTs) were included. Paper quality was evaluated using the Jadad scale. RESULTS: Of the 511 articles identified, 14 RCTs were eligible. Ginger was the most investigated remedy and was consistently reported to ameliorate nausea and vomiting during pregnancy better than placebo; its efficacy in doing so was noted to be equal to that of vitamin B6 and dimenhydrinate. A single trial also supported the use of Hypericum perforatum for wound healing. Cranberry, however, was not efficacious in the treatment of urinary tract infections; finally, raspberry leaf did not shorten the first stage of labor, and garlic did not prevent pre-eclampsia. CONCLUSIONS: Despite the widespread, popular use of herbal remedies during pregnancy, too few studies have been devoted to specific clinical investigations. With the exception of ginger, there is no data to support the use of any other herbal supplement during pregnancy. PMID- 22928541 TI - Levonorgestrel used for emergency contraception during lactation-a prospective observational cohort study on maternal and infant safety. AB - OBJECTIVE: To identify possible effects of levonorgestrel used as an emergency contraceptive during breastfeeding on mothers and their infants. STUDY DESIGN: A prospective observational cohort study of all women who contacted the Teratology Information Service between January, 2005 and January, 2010. Breastfeeding women who used levonorgestrel as an emergency contraceptive (study group) were compared to breastfeeding women who used either ethynodiol diacetate or desogestrel (control group). Women were followed for 6-24 months. Main outcome measures were adverse maternal and infant effects and continuation of breastfeeding. RESULTS: We followed 71 of 128 study group women and 72 of 100 control group women. Maternal adverse effects were mainly vaginal bleeding, which was less frequent in the study vs. control group (16 of 71 vs. 27 of 72, p = 0.068). Decreased lactation was uncommon and similar in both groups. Breastfeeding was reinitiated within less than 8 h in 75% of the levonorgestrel group women. Adverse infant effects were rare (0 of 72 infants vs. 2 of 72 infants, p = 0.5 in the study vs. control group). CONCLUSIONS: Our findings support the safety of using levonorgestrel as an emergency contraceptive during lactation without the need for withholding breastfeeding. PMID- 22928542 TI - Fetal abstinence: differing viewpoints? PMID- 22928544 TI - Existence of micrometer-scale water droplets at solvent/air interfaces. AB - Standard surface energy balances using literature values for pure liquids predict that water droplets are unstable at the liquid/air interfaces of many common organic solvents. While the behavior of macroscopic drops in the presence of solvents has been studied, the study of droplets in the micrometer size regime and the possible role of line tension are notably absent. In this article, we experimentally investigate the existence and stability of such micrometer-scale droplets formed at air/solvent interfaces and the possible roles played by partial solubility of organic liquids in water and solvent migration in the lowering of the key air/water surface tension. Three solvents are studied: toluene, butyl acetate, and chloroform, using a technique to optically monitor both condensation and manual deposition of water microdroplets onto air/solvent surfaces. This demonstrates both the existence of stable water droplets and allows measurement of the contact angles at the solvent/water/air interface. Contact angles are shown to be independent of droplet size (diameters: 2-30 MUm), ruling out a line tension stabilization mechanism for droplets of radii greater than 1 MUm. The interfacial tensions of the deposited water droplets are independently measured using an equivalent macroscopic experiment, which yield results consistent with the partial miscibility of toluene and butyl acetate in water. A discrepancy is observed for chloroform, for which possible mechanisms are discussed. PMID- 22928543 TI - Motor vehicle crash-related subdural hematoma from real-world head impact data. AB - Abstract Approximately 1,700,000 people sustain a traumatic brain injury (TBI) each year and motor vehicle crashes (MVCs) are a leading cause of hospitalization from TBI. Acute subdural hematoma (SDH) is a common intracranial injury that occurs in MVCs associated with high mortality and morbidity rates. In this study, SDH volume and midline shift have been analyzed in order to better understand occupant injury by correlating them to crash and occupant parameters. Fifty-seven head computed tomography (CT) scans were selected from the Crash Injury Research Engineering Network (CIREN) with Abbreviated Injury Scale (AIS) level 3+ SDH. Semi-automated methods were used to isolate the intracranial volume. SDH and additional occupant intracranial injuries were segmented across axial CT images, providing a total SDH injury volume. SDH volume was correlated to crash parameters and occupant characteristics. Results show a positive correlation between SDH volume and crash severity in near-side and frontal crashes. Additionally, the location of the resulting hemorrhage varied by crash type. Those with greater SDH volumes had significantly lower Glasgow Coma Scale (GCS) scores at the crash site in near-side crashes. Age and fracture type were found to be significant contributors to SDH volume. This study is a volumetric analysis of real world brain injuries and known MVC impacts. The results of this study demonstrate a relationship among SDH volume, crash mechanics, and occupant characteristics that provide a better understanding of the injury mechanisms of MVC-associated TBI. PMID- 22928545 TI - Small-molecule-based affinity chromatography method for antibody purification via nucleotide binding site targeting. AB - The conserved nucleotide binding site (NBS), found within the Fab variable domain of antibodies, remains a not-so-widely known and underutilized site. Here we describe a novel affinity chromatography method that utilizes the NBS as a target for selectively purifying antibodies from complex mixtures. The affinity column was prepared by coupling indole butyric acid (IBA), which has a monovalent affinity for the NBS with a K(d) ranging between 1 and 8 MUM, to ToyoPearl resin resulting in the NBS targeting affinity column (NBS(IBA)). The proof-of-concept studies performed using the chimeric pharmaceutical antibody rituximab demonstrated that antibodies were selectively captured and retained on the NBS(IBA) column and were successfully eluted by applying a mild NaCl gradient at pH 7.0. Furthermore, the NBS(IBA) column consistently yielded >95% antibody recovery with >98% purity, even when the antibody was purified from complex mixtures such as conditioned cell culture supernatant, hybridoma media, and mouse ascites fluid. The results presented in this study establish the NBS(IBA) column as a viable small-molecule-based affinity chromatography method for antibody purification with significant implications in industrial antibody production. Potential advantages of the NBS(IBA) platform are improved antibody batch quality, enhanced column durability, and reduced overall production cost. PMID- 22928548 TI - Anti-nociceptive and anti-inflammatory activities of Azadirachta indica fruit skin extract and its isolated constituent azadiradione. AB - This study was carried out to evaluate the anti-nociceptive and anti-inflammatory activities of carbon tetrachloride extract (CTCE) of Azadirachta indica fruit skin and its isolated constituent azadiradione at two different dose levels (50 and 100 mg kg-1 body weight). Anti-nociceptive screening by writhing test and hot plate technique supported both peripheral and central mechanisms, respectively. Anti-inflammatory activity was observed using carrageenan-induced paw oedema model. The results concluded that the animals treated with 100 mg kg-1 dose of CTCE and azadiradione exhibited significant anti-nociceptive and anti inflammatory activities. This study had rationalised the ethnomedicinal use of the plant for wound, burns and injury by tribal people. PMID- 22928550 TI - Identification of factors that affect the adoption of an ergonomic intervention among Emergency Medical Service workers. AB - This study explored factors contributing to intervention adoption decisions among Emergency Medical Service (EMS) workers. Emergency Medical Service workers (n = 190), from six different organisations, participated in a two-month longitudinal study following the introduction of a patient transfer-board (also known as slide board) designed to ease lateral transfers of patients to and from ambulance cots. Surveys administered at baseline, after one month and after two months sampled factors potentially influencing the EMS providers' decision process. 'Ergonomics Advantage' and 'Patient Advantage' entered into a stepwise regression model predicting 'intention to use' at the end of month one (R (2 )= 0.78). After the second month, the stepwise regression indicated only two factors were predictive of intention to use: 'Ergonomics Advantage,' and 'Endorsed by Champions' (R (2 )= 0.58). Actual use was predicted by: 'Ergonomics Advantage' and 'Previous Tool Experience.' These results relate to key concepts identified in the diffusion of innovation literature and have the potential to further ergonomics intervention adoption efforts. Practitioner Summary. This study explored factors that potentially facilitate the adoption of voluntarily used ergonomics interventions. EMS workers were provided with foldable transfer-boards (slideboards) designed to reduce the physical demands when laterally transferring patients. Factors predictive of adoption measures included perceived ergonomics advantage, the endorsement by champions, and prior tool experience. PMID- 22928549 TI - Revelation of a catalytic calcium-binding site elucidates unusual metal dependence of a human apyrase. AB - Human soluble calcium-activated nucleotidase 1 (hSCAN-1) represents a new family of apyrase enzymes that catalyze the hydrolysis of nucleotide di- and triphosphates, thereby modulating extracellular purinergic and pyrimidinergic signaling. Among well-characterized phosphoryl transfer enzymes, hSCAN-1 is unique not only in its unusual calcium-dependent activation, but also in its novel phosphate-binding motif. Its catalytic site does not utilize backbone amide groups to bind phosphate, as in the common P-loop, but contains a large cluster of acidic ionizable side chains. By employing a state-of-the-art computational approach, we have revealed a previously uncharacterized catalytic calcium-binding site in hSCAN-1, which elucidates the unusual calcium-dependence of its apyrase activity. In a high-order coordination shell, the newly identified calcium ion organizes the active site residues to mediate nucleotide binding, to orient the nucleophilic water, and to facilitate the phosphoryl transfer reaction. From ab initio QM/MM molecular dynamics simulations with umbrella sampling, we have characterized a reverse protonation catalytic mechanism for hSCAN-1 and determined its free energy reaction profile. Our results are consistent with available experimental studies and provide new detailed insight into the structure-function relationship of this novel calcium-activated phosphoryl transfer enzyme. PMID- 22928551 TI - Biologic skin substitutes and their applications in dermatology. PMID- 22928552 TI - The role of vehicle interactions on permeation of an active through model membranes and human skin. AB - Previous work from this group has focused on the molecular mechanism of alcohol interaction with model membranes, by conducting thermodynamic and kinetic analyses of alcohol uptake, membrane partitioning and transport studies of a model compound (i.e. methyl paraben) in silicone membranes. In this article, similar membrane transport and partitioning studies were conducted in silicone membranes to further extend the proposed model of alcohol interactions with silicone membranes to include other vehicles more commonly used in dermal formulations, that is, isopropyl myristate (IPM), dimethyl isosorbide (DMI), polyethylene glycol (PEG) 200, PEG 400 and Transcutol P(r) (TC). More importantly, membrane partitioning studies were conducted using human SC to evaluate the application of the proposed model of solvent-enhanced permeation in simple model membranes for the more complex biological tissue. The findings support a model of vehicle interactions with model membranes and skin where high solvent uptake promotes drug partitioning (i.e. K) by enabling the solute to exist within the solvent fraction/solvent-rich areas inside the membrane or skin in a concentration equivalent to that in the bulk solvent/vehicle. High solvent sorption may also ultimately impact on the membrane diffusional characteristics, and thus the diffusion coefficient of the solute across the membrane. The implications for skin transport are that increased partitioning of a drug into the SC may be achieved by (i) selecting vehicles that are highly taken up by the skin and also (ii) by having a relatively high concentration (i.e. molar fraction) of the drug in the vehicle. It follows that, in cases where significant co-transport of the solvent into and across the skin may occur, its depletion from the formulation and ultimately from the skin may lead to drug crystallization, thus affecting dermal absorption. PMID- 22928553 TI - Phage typing in dermatitis cruris pustulosa et atrophicans: does staphylococcal carrier status have a role? AB - BACKGROUND: Dermatitis cruris pustulosa et atrophicans (DCPA) is a form of chronic folliculitis of the legs with a multifactorial etiopathogenesis, seen primarily in tropical countries. Staphylococcus aureus has been isolated from the pustules in earlier studies, although the organisms isolated have not been further characterized. MATERIALS AND METHODS: Patients with DCPA, who attended the Dermatology outpatient clinic at JIPMER, Pondicherry, India, during the study period (December 2006-June 2008) were included. Pus from the lesions as well as swabs from carrier sites (nares, axillae, and gluteal fold) were cultured. Staphylococcus aureus isolates were subjected to phage typing at the National Staphylococcal Phage Typing Center, Department of Microbiology, Maulana Azad Medical College, New Delhi, India. RESULTS: Thirty-seven patients were included in the study. Pus from the folliculitic lesions grew S. aureus in 32 (86.49%) patients. Based on the comparison of antibiotic sensitivity patterns, isolates from pus and carrier sites were found to be similar in 15 patients. Phage typing established the organism to be identical in five of these patients. CONCLUSIONS: Characterization of S. aureus in DCPA shows that there is no specific phage type that is uniformly responsible for the lesions in most patients. However, in view of the unclear etiology of this condition, the pathogenicity of a staphylococcal carrier state in individual patients needs to be addressed. PMID- 22928554 TI - The contextual interference effect in visual feature binding: what does it say about the role of attention in binding? AB - The effects of blocked versus mixed presentation were tested on visual feature binding, assuming that blocked presentation enhances focused attention, whilst mixed presentation recruits extra attentional resources for intratrial as well as intertrial processing. The contextual interference effect suggests that although performance due to mixed presentation is either similar or worse than blocked presentation when tested immediately, it is better when tested after an interval. We explored whether this robust empirical effect, common in psychomotor performance, would be evident in visual feature binding. Stimuli were conjunctions of shape, colour, and location. Study-test intervals from 0 to 2,500 ms were used with a swap detection task. In Experiments 1A and 1B, participants ignored locations to detect shape-colour bindings. In Experiments 2A and 2B, they ignored shapes to detect colour-location binding. In Experiments 3A and 3B, they ignored colours to detect shape-location bindings. Whilst Experiments 1A, 2A, and 3A used blocked presentation, Experiments 1B, 2B, and 3B used mixed presentation of study-test intervals. The results of these experiments and a replication experiment using a within-subjects design showed that the contextual interference effect appeared when spatial attention was engaged, but not when attention was object based. PMID- 22928556 TI - Association of symptoms with urodynamic findings in men with overactive bladder syndrome. AB - Study Type--Therapy (review) Level of Evidence 4. What's known on the subject? and What does the study add? It is known that overactive bladder (OAB) symptoms correlate weakly with urodynamic findings, especially in female patients. The study shows that OAB symptoms also correlate weakly with urodynamic findings in male patients. More than third of male patients with OAB symptoms had evidence of BOO. The study finds that a pressure flow study is of benefit in the evaluation of this group of patients. OBJECTIVE: * To assess the correlation between overactive bladder (OAB) symptoms with urodynamic (UD) findings in men. PATIENTS AND METHODS: * We conducted a retrospective study of all UD studies involving men with OAB symptoms. * All UD studies were carried out at a single centre from 1994 to 2009 and were reported by one urology specialist. RESULTS: * There were 668 UD reports included in the final analysis. All patients had symptoms of urgency with or without urgency incontinence (UI). * There was a weak correlation between OAB symptoms and UD findings. * All storage symptoms, except frequency, correlated with a finding of detrusor overactivity (DO). * Severity of urgency correlated inversely with a finding of bladder outlet obstruction (BOO). * Both nocturia and frequency correlated inversely with maximum cystometric capacity. * More than 75% of patients had concomitant voiding symptoms. Severity of voiding symptoms (slow stream and incomplete emptying) correlated inversely with documentation of DO. Voiding symptoms were predictors of BOO, while severe urgency was a negative predictor for BOO. CONCLUSIONS: * There were weak correlations between OAB symptoms and UD findings. Most men with OAB symptoms had concomitant voiding symptoms and more than a third (43%) of these had evidence of BOO. * A pressure flow study is of benefit in the evaluation of patients with OAB symptoms. PMID- 22928555 TI - Structure and stability of duplex DNA containing (5'S)-5',8-cyclo-2' deoxyadenosine: an oxidatively generated lesion repaired by NER. AB - Cellular respiration and ionizing radiation generate 5',8-cyclo-2' deoxyribonucleosides, a special type of DNA damage that involves two modifications in the same nucleotide. These lesions evade the action of base excision glycosylases, and their removal is a function of the nucleotide excision repair pathway. Diastereomeric 5',8-cyclo-2'-deoxyadenosine blocks mammalian DNA replication, diminishes the levels of DNA transcription, and induces transcriptional mutagenesis. Using solution state NMR spectroscopy and restrained molecular dynamics simulations, we have determined the structure of an undecameric DNA duplex having a centrally located (5'S)-5',8-cyclo-2' deoxyadenosine residue paired to T. The damaged duplex structure is a right handed helix having Watson-Crick base-pair alignments throughout, and 2 deoxyribose puckers within the B-form conformation. Only small structural perturbations are observed at the lesion-containing and 5'-flanking base pair. The 2-deoxyribose of the damaged nucleotide adopts the O4'-exo conformation, and the S-cdA.T base pair is propeller twisted. The 5'-lesion-flanking base is tilted forming a significantly buckled base pair with its partner guanine. Analysis of UV-melting curves indicates mild thermal and thermodynamic destabilization on the damaged duplex. The S-cdA.T duplex structure shows many similarities to and some intriguing differences from the recently reported structure of an S-cdG.dC duplex31 that suggest different lesion site dynamics. PMID- 22928557 TI - Targeting the vascular endothelial growth factor in hematologic malignancies. AB - There exists increasing evidence that apart from solid tumors, angiogenic growth factors also play important roles in the development and/or maintenance of hematolymphoid malignancies. Thus, in these cancers, angiogenesis and bone marrow microvessel density often correlate with prognosis and disease burden. Several reports speculated on the role of angiogenesis and the resulting possible therapeutic options in hematologic malignancies. The most prominent angiogenic factor, vascular endothelial growth factor (VEGF), is expressed in a number of established leukemic cell lines as well as in freshly isolated human leukemias and lymphomas, and several human leukemias express VEGF receptor 1 and/or VEGF receptor 2. VEGF/VEGF-receptor interactions are also involved in proliferation, migration, and survival of leukemic cells by autocrine and paracrine mechanisms. As a consequence, a possible drugable effect by inhibiting VEGF signaling in different hematologic malignancies has been discussed. This review focuses on angiogenesis-independent effects of VEGF on survival and proliferation of leukemic or lymphoma cells and on possible therapeutic approaches using anti VEGF/VEGF-receptor therapies to inhibit proliferation or induce apoptosis of malignant cells in hematologic diseases. PMID- 22928558 TI - Ru(CO)-salen-catalyzed synthesis of enantiopure aziridinyl ketones and formal asymmetric synthesis of (+)-PD 128907. AB - Aziridination of vinyl ketones using SESN(3) in the presence Ru(CO)-salen complex 1 provides the enantiopure aziridinyl ketones that can serve as useful chiral building blocks. A formal asymmetric synthesis of (+)-PD 128907 was achieved in an eight-step sequence via aziridination. PMID- 22928559 TI - Chromatin structure, epigenetic mechanisms and long-range interactions in the human insulin locus. AB - Regulation of gene expression in eukaryotes is largely dependent on variations in chromatin structure. More recently, it has become clear that this may involve not only local chromatin organization but also distant regulatory elements that participate in large-scale chromatin architecture within the nucleus. We describe recent methods that make possible the detection of such structures and apply them to analysis of the human insulin (INS) locus in pancreatic islets. We show that the INS gene is part of an extended 'open' chromatin domain that includes adjacent genes as well. We also find that in islets, the INS promoter is in physical contact with distant sites on the same human chromosome and notably, with the SYT8 gene, located nearly 300 kb away. The strength of the contact between INS and SYT8 is increased by glucose, and this results in stimulation of SYT8 expression. Inhibition of INS transcription decreases SYT8 expression. Furthermore, downregulation of SYT8 results in decreased secretion of insulin. Our results thus establish the existence of a regulatory network between the INS gene and other distant genes through long-range physical interactions, and suggest that such networks may have general importance for insulin biology and diabetes. PMID- 22928560 TI - Emerging roles of non-coding RNAs in pancreatic beta-cell function and dysfunction. AB - Pancreatic beta-cells play a central role in glucose homeostasis by tightly regulating insulin release according to the organism's demand. Impairment of beta cell function due to hostile environment, such as hyperglycaemia and hyperlipidaemia, or due to autoimmune destruction of beta-cells, results in diabetes onset. Both environmental factors and genetic predisposition are known to be involved in the development of the disease, but the exact mechanisms leading to beta-cell dysfunction and death remain to be characterized. Non-coding RNA molecules, such as microRNAs (miRNAs), have been suggested to be necessary for proper beta-cell development and function. The present review aims at summarizing the most recent findings about the role of non-coding RNAs in the control of beta-cell functions and their involvement in diabetes. We will also provide a perspective view of the future research directions in the field of non coding RNAs. In particular, we will discuss the implications for diabetes research of the discovery of a new communication mechanism based on cell-to-cell miRNA transfer. Moreover, we will highlight the emerging interconnections between miRNAs and epigenetics and the possible role of long non-coding RNAs in the control of beta-cell activities. PMID- 22928561 TI - MicroRNAs in pancreas development. AB - The development of the pancreas is a tightly regulated process involving extensive morphogenesis, proliferation and differentiation of the epithelium. The finely orchestrated control of gene expression plays a key role in this equilibrium by coordinating the expression of selected gene products at specific moments and in precise locations. MicroRNAs (miRNAs) are small non-coding RNAs that function in general as negative regulators of gene transcripts by interacting with the three prime untranslated regions (3'UTR) of target mRNAs. MiRNAs modulate the expression of numerous target genes that are involved in a variety of cellular systems. Hence the homeostatic control of miRNA biosynthesis and activity is important for the fine-tuning of many physiological processes such as cell differentiation, cell proliferation and organ development. In the present review, we will focus on the implication of these miRNAs on the development of the pancreas and more specifically on beta-cells. PMID- 22928562 TI - Metabolic programming of insulin action and secretion. AB - Type 2 diabetes (T2D), also known as non-insulin dependent diabetes mellitus, arises as a consequence of peripheral insulin resistance in combination with an inability of pancreatic islet beta-cells to secrete adequate amounts of insulin. It is widely recognized that the current environment (e.g. an unhealthy diet and sedentary lifestyle) contributes to this process. In recent years, however, the role of the early environment, particularly nutrition, has emerged as an important factor capable of influencing health and disease risk of an individual, including risk of T2D. The impact of early environment on glucose metabolism has been extensively studied. Compelling evidence from epidemiological studies and animal models suggests that early nutrition can affect insulin action as a mediator of glucose homeostasis in peripheral tissues and as an important regulator of appetite and body weight. The early environment can also affect beta cell mass and function, and hence insulin secretion. The molecular mechanisms underlying the relationship between a suboptimal early environment and impaired insulin action and secretion is thought to include epigenetic modifications of the foetal genome, oxidative stress and mitochondrial dysfunction. PMID- 22928563 TI - Islet function in obese adolescents. AB - Concurrent with the epidemic of childhood obesity, an unprecedented increase in the prevalence of several adiposity-related complications in this age group has emerged. In particular, type 2 diabetes (T2D), once considered an illness restricted to adulthood, is progressively affecting more and more adolescents, and represents now roughly 20-45% of new-onset cases in this age group. To unravel the pathogenesis of diabetes development during adolescence, many studies have focused on defining early defects in both insulin sensitivity and secretion that might be implicated in the natural history of the disease. Although a lot still need to be clarified, studies have shown that the progression from normal glucose tolerance to T2D involves intermediate stages of impaired fasting glucose and/or impaired glucose tolerance, also known as prediabetes. Insulin resistance and beta-cell dysfunction represent the two major key pathogenetic defects underlying the progression to diabetes in obese youth. In this review, we have sought to mainly describe the role of beta-cell function in relation to the ambient insulin resistance in the development of T2D in obese adolescents. PMID- 22928565 TI - Nutrition-/diet-induced changes in gene expression in pancreatic beta-cells. AB - beta-Cell dysfunction is a critical component in the development of type 2 diabetes. Whilst both genetic and environmental factors contribute to the development of the disease, relatively little is known about the molecular network that is responsible for diet-induced functional changes in pancreatic beta-cells. Recent genome-wide association studies for diabetes-related traits have generated a large number of candidate genes that constitute possible links between dietary factors and the genetic susceptibility for beta-cell failure. Here, we summarize recent approaches for identifying nutritionally regulated transcripts in islets on a genome-wide scale. Polygenic mouse models for type 2 diabetes have been instrumental for investigating the mechanism of diet-induced beta-cell dysfunction. Enhanced oxidative metabolism, triggered by a combination of dietary carbohydrates and fat, appears to play a critical role in the pathophysiology of diet-induced impairment of islets. More systematic studies of gene-diet interactions in beta-cells of rodent models in combination with genetic profiling might reveal the regulatory circuits fundamental for the understanding of diet-induced impairments of beta-cell function in humans. PMID- 22928566 TI - Metabolic stress, IAPP and islet amyloid. AB - Amyloid forms within pancreatic islets in type 2 diabetes from aggregates of the beta-cell peptide islet amyloid polypeptide (IAPP). These aggregates are toxic to beta-cells, inducing beta-cell death and dysfunction, as well as inciting islet inflammation. The beta-cell is subject to a number of other stressors, including insulin resistance and hyperglycaemia, that may contribute to amyloid formation by increasing IAPP production by the beta-cell. beta-Cell dysfunction, evident as impaired glucose-stimulated insulin secretion and defective prohormone processing and exacerbated by metabolic stress, is also a likely prerequisite for islet amyloid formation to occur in type 2 diabetes. Islet transplants in patients with type 1 diabetes face similar stressors, and are subject to rapid amyloid formation and impaired proinsulin processing associated with progressive loss of beta-cell function and mass. Declining beta-cell mass is predicted to increase metabolic demand on remaining beta-cells, promoting a feed-forward cycle of beta cell decline. PMID- 22928564 TI - Interactions between genetic background, insulin resistance and beta-cell function. AB - An interaction between genes and the environment is a critical component underlying the pathogenesis of the hyperglycaemia of type 2 diabetes. The development of more sophisticated techniques for studying gene variants and for analysing genetic data has led to the discovery of some 40 genes associated with type 2 diabetes. Most of these genes are related to changes in beta-cell function, with a few associated with decreased insulin sensitivity and obesity. Interestingly, using quantitative traits based on continuous measures rather than dichotomous ones, it has become evident that not all genes associated with changes in fasting or post-prandial glucose are also associated with a diagnosis of type 2 diabetes. Identification of these gene variants has provided novel insights into the physiology and pathophysiology of the beta-cell, including the identification of molecules involved in beta-cell function that were not previously recognized as playing a role in this critical cell. PMID- 22928567 TI - Bimodal impact of skeletal muscle on pancreatic beta-cell function in health and disease. AB - Diabetes is a complex disease that affects many organs directly or indirectly. Type 2 diabetes mellitus is characterized by insulin resistance with a relative deficiency in insulin secretion. It has become apparent that inter-organ communication is of great importance in the pathophysiology of diabetes. Far from being an inert tissue in terms of inter-organ communication, it is now recognized that skeletal muscle can secrete so-called myokines that can impact on the function of distant organs/tissues both favourably and unfavourably. We have proposed that communication between insulin-resistant skeletal muscle and beta cells occurs in diabetes. This is a novel route of communication that we further suggest is modified by the prevailing degree of insulin resistance of skeletal muscle. This review focuses on the various myokines [interleukin-6 (IL-6), tumor necrosis factor-alpha, CXCL10, follistatin and IL-8] which have been identified either after different types of exercise or in the secretome from control and insulin-resistant human skeletal myotubes. We will also summarize studies on the impact of several myokines on pancreatic beta-cell proliferation, survival and function. PMID- 22928568 TI - Impairment of GLP1-induced insulin secretion: role of genetic background, insulin resistance and hyperglycaemia. AB - One major risk factor of type 2 diabetes is the impairment of glucose-induced insulin secretion which is mediated by the individual genetic background and environmental factors. In addition to impairment of glucose-induced insulin secretion, impaired glucagon-like peptide (GLP)1-induced insulin secretion has been identified to be present in subjects with diabetes and impaired glucose tolerance, but little is known about its fundamental mechanisms. The state of GLP1 resistance is probably an important mechanism explaining the reduced incretin effect observed in type 2 diabetes. In this review, we address methods that can be used for the measurement of insulin secretion in response to GLP1 in humans, and studies showing that specific diabetes risk genes are associated with resistance of the secretory function of the beta-cell in response to GLP1 administration. Furthermore, we discuss other factors that are associated with impaired GLP1-induced insulin secretion, for example, insulin resistance. Finally, we provide evidence that hyperglycaemia per se, the genetic background and their interaction result in the development of GLP1 resistance of the beta cell. We speculate that the response or the non-response to therapy with GLP1 analogues and/or dipeptidyl peptidase-4 (DPP-IV) inhibitors is critically dependent on GLP1 resistance. PMID- 22928570 TI - Glucose metabolism: key endogenous regulator of beta-cell replication and survival. AB - Recent studies in mice have shown that pancreatic beta-cells have a significant potential for regeneration, suggesting that regenerative therapy for diabetes is feasible. Genetic lineage tracing studies indicate that beta-cell regeneration is based on the replication of fully differentiated, insulin-positive beta-cells. Thus, a major challenge for this field is to identify and enhance the molecular pathways that control beta-cell replication and mass. We review evidence, from human genetics and mouse models, that glucose is a major signal for beta-cell replication. The mitogenic effect of blood glucose is transmitted via glucose metabolism within beta-cells, and through a signalling cascade that resembles the pathway for glucose-stimulated insulin secretion. We introduce the concept that the individual beta-cell workload, defined as the amount of insulin that an individual beta-cell must secrete to maintain euglycaemia, is the primary determinant of replication, survival and mass. We also propose that a cell autonomous pathway, similar to that regulating replication, appears to be responsible for at least some of the toxic effects of glucose on beta-cells. Understanding and uncoupling the mitogenic and toxic effects of glucose metabolism on beta-cells may allow for the development of effective regenerative therapies for diabetes. PMID- 22928569 TI - Neurofunctional imaging of beta-cell dynamics. AB - Here, we outline how islet cells use autocrine and paracrine 'circuits' of classical neurotransmitters and their corresponding receptors and transporters to communicate with vicinal beta-cells to regulate glucose-stimulated insulin secretion. Many of these same circuits operate in the central nervous system and can be visualized by molecular imaging. We discuss how these techniques might be applied to measuring the dynamics of beta-cell function in real time. PMID- 22928571 TI - Repair of diverse diabetic defects of beta-cells in man and mouse by pharmacological glucokinase activation. AB - Glucokinase activators (GKAs) are being developed and clinically tested for potential antidiabetic therapy. The potential benefits and limitations of this approach continue to be intensively debated. To contribute to the understanding of experimental pharmacology and therapeutics of GKAs, we have tested the efficacy of one of these agents (Piragliatin) in isolated islets from humans with type 2 diabetes mellitus (T2DM), from mice with glucokinase (GK) mutations induced by ethyl-nitroso-urea (ENU) as models of Maturity Onset Diabetes of the Young linked to GK and Permanent Neonatal Diabetes Mellitus linked to GK (PNDM GK) and finally of islets rendered glucose insensitive by treatment with the sulphonyl urea compound glyburide in organ culture. We found that the GKA repaired the defect in all three instances as manifest in increased glucose induced insulin release and elevated intracellular calcium responses. The results show the remarkable fact that acute pharmacological activation of GK reverses secretion defects of beta-cells caused by molecular mechanism that differ vastly in nature, including the little understood multifactorial lesion of beta-cells in T2DM of man, the complex GK mutations in mice resembling GK disease and acute sulphonylurea failure of mouse beta-cells in tissue culture. The implications of these results are to be discussed on the theoretical basis underpinning the strategy of developing these drugs and in light of recent results of clinical trials with GKAs that failed for little understood reasons. PMID- 22928572 TI - Role of K(ATP) channels in beta-cell resistance to oxidative stress. AB - The importance of K(ATP) channels in stimulus-secretion coupling of beta-cells is well established, although they are not indispensable for the maintenance of glycaemic control. This review article depicts a new role for K(ATP) channels by showing that genetic or pharmacological ablation of these channels protects beta cells against oxidative stress. Increased production of oxidants is a crucial factor in the pathogenesis of type 2 diabetes mellitus (T2DM). T2DM develops when beta-cells can no longer compensate for the high demand of insulin resulting from excess fuel intake. Instead beta-cells start to secrete less insulin and beta cell mass is diminished by apoptosis. Both, reduction of insulin secretion and beta-cell mass induced by oxidative stress, are prevented by deletion or inhibition of K(ATP) channels. These findings may open up new insights into the early treatment of T2DM. PMID- 22928574 TI - beta-Cell preservation and regeneration in diabetes by modulation of beta-cell Ca2+ homeostasis. AB - Ca(2+) extrusion from the beta-cell is mediated by two processes the Na/Ca exchanger (NCX) and the plasma membrane Ca(2+) -ATPase (PMCA). Gain of function studies show that overexpression of NCX or PMCA leads to endoplasmic reticulum (ER) Ca(2+) depletion with subsequent ER stress, decrease in beta-cell proliferation and beta-cell death by apoptosis. Interestingly, chronic exposure to cytokines or high free fatty acid concentrations also induce ER Ca(2+) depletion and beta-cell death in diabetes. Loss of function studies show, on the contrary, that heterozygous inactivation of NCX1 (Ncx1(+/-)) leads to an increase in beta-cell function (insulin production and release), and a fivefold increase in both beta-cell mass and proliferation. The mutation also increases beta-cell resistance to hypoxia, and Ncx1(+/-) islets show a two to four times higher rate of diabetes cure than Ncx1(+/+) islets when transplanted in diabetic animals. Thus, down-regulation of the Na/Ca exchanger leads to various changes in beta cell function that are opposite to the major abnormalities seen in diabetes. This provides a unique model for the prevention and treatment of beta-cell dysfunction in diabetes and following islet transplantation. PMID- 22928573 TI - The diabetic beta-cell: hyperstimulated vs. hyperexcited. AB - Hyperglycaemia has multiple effects on beta-cells, some clearly prosecretory, including hyperplasia and elevated insulin content, but eventually, a 'glucotoxic' effect which leads to pancreatic beta-cell dysfunction, reduced beta cell mass and insulin deficiency, is an important part of diabetes pathophysiology. Myriad underlying cellular and molecular processes could lead to such dysfunction. High glucose will stimulate glycolysis and oxidative phosphorylation, which will in turn increase beta-cell membrane excitability through K(ATP) channel closure. Chronic hyperexcitability will then lead to persistently elevated [Ca(2+)](i), a key trigger to insulin secretion. Thus, at least a part of the consequence of 'hyperstimulation' by glucose has been suggested to be a result of 'hyperexcitability' and chronically elevated [Ca(2+)](i). This link is lost when the [glucose], K(ATP) -channel activity link is broken, either pharmacologically or genetically. In isolated islets, such studies reveal that hyperexcitability causes a largely reversible chronic loss of insulin content, but in vivo chronic hyperexcitability per se does not lead to beta-cell death or loss of insulin content. On the other hand, chronic inexcitability in vivo leads to systemic diabetes and consequential beta-cell death, even while [Ca(2+)](i) remains low. PMID- 22928576 TI - Modulation of beta-cell function: a translational journey from the bench to the bedside. AB - Both decreased insulin secretion and action contribute to the pathogenesis of type 2 diabetes (T2D) in humans. The insulin receptor and insulin signalling proteins are present in the rodent and human beta-cell and modulate cell growth and function. Insulin receptors and insulin signalling proteins in beta-cells are critical for compensatory islet growth in response to insulin resistance. Rodents with tissue-specific knockout of the insulin receptor in the beta-cell (betaIRKO) show reduced first-phase glucose-stimulated insulin secretion (GSIS) and with aging develop glucose intolerance and diabetes, phenotypically similar to the process seen in human T2D. Expression of multiple insulin signalling proteins is reduced in islets of patients with T2D. Insulin potentiates GSIS in isolated human beta-cells. Recent studies in humans in vivo show that pre-exposure to insulin increases GSIS, and this effect is diminished in persons with insulin resistance or T2D. beta-Cell function correlates to whole-body insulin sensitivity. Together, these findings suggest that pancreatic beta-cell dysfunction could be caused by a defect in insulin signalling within beta-cell, and beta-cell insulin resistance may lead to a loss of beta-cell function and/or mass, contributing to the pathophysiology of T2D. PMID- 22928575 TI - Autocrine regulation of insulin secretion. AB - Impaired insulin secretion from pancreatic beta-cells is a major factor in the pathogenesis of type 2 diabetes. The main regulator of insulin secretion is the plasma glucose concentration. Insulin secretion is modified by other nutrients, circulating hormones and the autonomic nervous system, as well as local paracrine and autocrine signals. Autocrine signalling involves diffusible molecules that bind to receptors on the same cell from which they have been released. The first transmitter to be implicated in the autocrine regulation of beta-cell function was insulin itself. The importance of autocrine insulin signalling is underscored by the finding that mice lacking insulin receptors in beta-cells are glucose intolerant. In addition to insulin, beta-cells secrete a variety of additional substances, including peptides (e.g. amylin, chromogranin A and B and their cleavage products), neurotransmitters (ATP and gamma-aminobutyric acid) and ions (e.g. zinc). Here we review the autocrine effects of substances secreted from beta-cells, with a focus on acute effects in stimulus-secretion coupling, present some novel data and discuss the general significance of autocrine signals for the regulation of insulin secretion. PMID- 22928577 TI - Short-term intensified insulin treatment in type 2 diabetes: long-term effects on beta-cell function. AB - The natural history of type 2 diabetes (T2DM) is characterized by progressive deterioration of pancreatic beta-cell function, leading to worsening glycemia over time. As current antidiabetic therapies have not yet been shown to profoundly alter this natural history, many patients ultimately will require exogenous insulin therapy to obtain adequate glycemic control. Interestingly, the temporary use of short-term intensive insulin therapy early in the course of T2DM has recently emerged as a therapeutic option that may offer favourable long-term effects on beta-cell function. Indeed, after receiving this treatment, many patients will experience sustained euglycemia without requiring any antidiabetic therapy. This apparent 'remission' of diabetes is likely secondary to improved beta-cell function and can last for more than a year, although it is not sustained and hyperglycemia eventually will return. Nevertheless, owing to its effects on beta-cell function, short-term intensive insulin therapy holds promise as a means for modifying the natural history of T2DM and warrants further study in this context. In this report, we will review the rationale and evidence underlying this interesting therapeutic option, and its implications for both clinical research and the management of patients with T2DM. PMID- 22928578 TI - The hyperstimulated beta-cell: prelude to diabetes? PMID- 22928579 TI - Predictors of abstinence among smokers recruited actively to quitline support. AB - AIMS: Active recruitment of smokers increases the reach of quitlines; however, some quitlines restrict proactive telephone counselling (i.e. counsellor initiated calls) to smokers ready to quit within 30 days. Identifying characteristics associated with successful quitting by actively recruited smokers could help to distinguish those most likely to benefit from proactive telephone counselling. This study assessed the baseline characteristics of actively recruited smokers associated with prolonged abstinence at 4, 7 and 13 months and the proportion achieving prolonged abstinence that would miss out on proactive telephone counselling if such support was offered only to smokers intending to quit within 30 days at baseline. DESIGN: Secondary analysis of a randomized controlled trial in which the baseline characteristics associated with prolonged abstinence were examined. SETTING: New South Wales (NSW) community, Australia. PARTICIPANTS: A total of 1562 smokers recruited at random from the electronic NSW telephone directory. MEASUREMENTS: Baseline socio-demographic and smoking-related characteristics associated with prolonged abstinence at 4, 7 and 13 months post recruitment. FINDINGS: Waiting more than an hour to smoke after waking and intention to quit within 30 days at baseline predicted five of the six prolonged abstinence measures. If proactive telephone counselling was restricted to smokers who at baseline intended to quit within 30 days, 53.8-65.9% of experimental group participants who achieved prolonged abstinence would miss out on telephone support. CONCLUSIONS: Less addicted and more motivated smokers who are actively recruited to quitline support are more likely to achieve abstinence. Most actively recruited smokers reported no intention to quit within the next 30 days, but such smokers still achieved long-term abstinence. PMID- 22928580 TI - Carbonyl diazide, OC(N3)2: synthesis, purification, and IR spectrum. AB - Carbonyl diazide (1), OC(N(3))(2), is prepared by reaction of triphosgene and tetra-n-butylammonium azide in a solution of diethyl ether or dimethyl ether. The advantage of this synthetic method, relative to other procedures, is that the use of triphosgene, OC(OCCl(3))(2), mitigates the need to use highly poisonous reagents such as phosgene, OCCl(2), or chlorofluorocarbonyl, OC(Cl)F. The identity and purity of OC(N(3))(2) are established by gas-phase IR spectroscopy, which reveals the presence of both syn-syn and anti-syn conformers. Computed anharmonic vibrational frequencies and infrared intensities of carbonyl diazide (1) display excellent agreement with experiment, and reveal the presence of strong Fermi resonances. PMID- 22928582 TI - Comment on the ionization energy of B2F4. PMID- 22928581 TI - Detection of infliximab levels and anti-infliximab antibodies: a comparison of three different assays. AB - BACKGROUND: Formation of antibodies to infliximab (ATI) inversely correlates with functional drug levels and clinical outcome. Comparison of drug levels and anti drug antibody monitoring is hampered by lack of standardisation. AIM: To determine the correlation between three different assays for measuring infliximab and ATI. METHODS: Serum samples and spiked controls (total 62) were evaluated in a blinded way in infliximab and ATI assays developed by Sanquin Amsterdam, Netherlands (A), Laboratory for Pharmaceutical Biology, KU Leuven, Belgium (B) and a commercially available kit from Biomedical Diagnostics (BMD), Paris, France (C) performed by the University Medical Center Groningen (UMCG), Netherlands. RESULTS: All infliximab assays showed a linear quantitative correlation (Pearson r = 0.91 for A vs. B, 0.83 for A vs. C and 0.73 for B vs. C). Assay C detected infliximab in 11 samples (18%) not detected by A and B, including samples containing only ATI. All ATI assays showed a good linear correlation (Pearson r = 0.95 for A vs. B, 0.99 for A vs. C and 0.97 for B vs. C). Assay A detected ATI in five samples with low ATI that were not detected by assays B and C. Assay B did not detect ATI in three patient samples with low ATI according to assays A and C. CONCLUSIONS: There is a good correlation of infliximab and antibodies to infliximab measurements between these assays. Nevertheless, the Biomedical Diagnostics kit detected false positive infliximab levels in 18% of the samples. PMID- 22928583 TI - Reduced risk of death with warfarin - results of an observational nationwide study of 20 442 patients with atrial fibrillation and ischaemic stroke. AB - BACKGROUND: Warfarin is demonstrated to be superior in efficacy over antiplatelet agents for the prevention of stroke, but the relationship between warfarin and mortality is less clear. Our aim was to investigate this relationship in a large cohort of unselected patients with atrial fibrillation and ischaemic stroke. METHODS: This observational study was based on patients who were discharged alive and registered in the Swedish Stroke Register in 2001 through 2005. Vital status was retrieved by linkage to the Swedish Cause of Death Register. We calculated a propensity score for the likelihood of warfarin prescription at discharge from hospital. The risk of death and 95% confidence intervals were estimated in Cox regression models. RESULTS: Out of the 20 442 patients with atrial fibrillation and ischaemic stroke (mean age = 79.5 years), 31% (n = 6399) were prescribed warfarin. After adjustment for the propensity score, warfarin was associated with a reduced risk of death (0.67; 95% confidence interval, 0.63-0.71). The crude rate (per 100 person-years) of fatal non-haemorrhagic stroke was lower in patients who received warfarin (1.60; 95% confidence interval, 1.34-1.89) compared to those who received antiplatelet (6.83; 95% confidence interval, 6.42 7.25). The rates (per 100 person-years) of fatal haemorrhagic stroke were 0.21 (95% confidence interval, 0.12-0.32) and 0.43 (95% confidence interval, 0.34 0.55) in patients prescribed warfarin and antiplatelet therapy, respectively. CONCLUSIONS: In addition to its established benefit for stroke prevention, warfarin therapy in patients with atrial fibrillation and ischaemic stroke was associated with a reduced risk of death, without an increased risk of fatal haemorrhagic stroke. PMID- 22928585 TI - Why do Romanian junior high school students start to smoke? AB - BACKGROUND: Adolescence is a crucial period in the development of smoking behaviour. To develop efficient prevention programmes for teenagers, it is essential to understand why adolescents start to smoke. The objective of this study was to assess the predictors of smoking onset among Romanian junior high school students aged 13-14. METHODS: The data were obtained from a two-wave, 9 month longitudinal study carried out among 504 junior high school non-smokers from Cluj-Napoca, Romania. Questionnaires assessed smoking behaviour, attitudes, social influence, self-efficacy and intention regarding smoking (motivational variables), as well as different sociodemographic features. RESULTS: The results from the logistic regression analysis revealed that baseline lower self-efficacy in refraining from smoking in several social situations, baseline pressures from peers to smoke and baseline intentions to smoke significantly increased the risk of non-smokers to become smokers at follow-up 9 months later. CONCLUSIONS: These findings underline that reinforcing social self-efficacy to refuse smoking, resisting peer pressures and maintaining negative intentions regarding smoking are essential ingredients for smoking prevention programmes among Romanian junior high school students. PMID- 22928584 TI - A moderate increase in ambient temperature modulates the Atlantic cod (Gadus morhua) spleen transcriptome response to intraperitoneal viral mimic injection. AB - BACKGROUND: Atlantic cod (Gadus morhua) reared in sea-cages can experience large variations in temperature, and these have been shown to affect their immune function. We used the new 20K Atlantic cod microarray to investigate how a water temperature change which, simulates that seen in Newfoundland during the spring summer (i.e. from 10 degrees C to 16 degrees C, 1 degrees C increase every 5 days) impacted the cod spleen transcriptome response to the intraperitoneal injection of a viral mimic (polyriboinosinic polyribocytidylic acid, pIC). RESULTS: The temperature regime alone did not cause any significant increases in plasma cortisol levels and only minor changes in spleen gene transcription. However, it had a considerable impact on the fish spleen transcriptome response to pIC [290 and 339 significantly differentially expressed genes between 16 degrees C and 10 degrees C at 6 and 24 hours post-injection (HPI), respectively]. Seventeen microarray-identified transcripts were selected for QPCR validation based on immune-relevant functional annotations. Fifteen of these transcripts (i.e. 88%), including DHX58, STAT1, IRF7, ISG15, RSAD2 and IkappaBalpha, were shown by QPCR to be significantly induced by pIC. CONCLUSIONS: The temperature increase appeared to accelerate the spleen immune transcriptome response to pIC. We found 41 and 999 genes differentially expressed between fish injected with PBS vs. pIC at 10 degrees C and sampled at 6HPI and 24HPI, respectively. In contrast, there were 656 and 246 genes differentially expressed between fish injected with PBS vs. pIC at 16 degrees C and sampled at 6HPI and 24HPI, respectively. Our results indicate that the modulation of mRNA expression of genes belonging to the NF-kappaB and type I interferon signal transduction pathways may play a role in controlling temperature-induced changes in the spleen's transcript expression response to pIC. Moreover, interferon effector genes such as ISG15 and RSAD2 were differentially expressed between fish injected with pIC at 10 degrees C vs. 16 degrees C at 6HPI. These results substantially increase our understanding of the genes and molecular pathways involved in the negative impacts of elevated ambient temperature on fish health, and may also be valuable to our understanding of how accelerated global climate change could impact cold-water marine finfish species. PMID- 22928586 TI - Comprehensive two-dimensional ultrahigh-pressure liquid chromatography for separations of polymers. AB - Online comprehensive two-dimensional liquid chromatography (LC * LC) is a technique of great importance, because it offers much higher peak capacities than separations in a single dimension. When analyzing polymer samples, LC * LC can provide detailed information on two mutually dependent polymer distributions. Because both molecular-weight distributions and chemical-composition distributions are typically present in synthetic copolymers, combinations of interactive LC with size-exclusion chromatography (SEC) are especially useful for (co)polymer analyses. Commonly applied SEC separations in the second dimension take several minutes, so that a total LC * LC experiment typically requires several hours. This renders LC * LC unsuitable for routine analysis. In the present study we have explored possibilities to perform fast and efficient online comprehensive two-dimensional analysis of polymers using contemporary ultrahigh pressure liquid chromatography in both dimensions (UHPLC * UHPLC). Gradient elution UHPLC in the first dimension allowed efficient separations of polymers based on their chemical composition. SEC at ultrahigh-pressure conditions in the second dimension offered very fast, yet efficient separations based on molecular size. The demonstrated UHPLC * UHPLC separations of industrial polymers could be performed within 1 h and provided comprehensive information on two-dimensional distributions. PMID- 22928587 TI - Self-assembly and photopolymerization of sub-2 nm one-dimensional organic nanostructures on graphene. AB - While graphene has attracted significant attention from the research community due to its high charge carrier mobility, important issues remain unresolved that prevent its widespread use in technologically significant applications such as digital electronics. For example, the chemical inertness of graphene hinders integration with other materials, and the lack of a bandgap implies poor switching characteristics in transistors. The formation of ordered organic monolayers on graphene has the potential to address each of these challenges. In particular, functional groups incorporated into the constituent molecules enable tailored chemical reactivity, while molecular-scale ordering within the monolayer provides sub-2 nm templates with the potential to tune the electronic band structure of graphene via quantum confinement effects. Toward these ends, we report here the formation of well-defined one-dimensional organic nanostructures on epitaxial graphene via the self-assembly of 10,12-pentacosadiynoic acid (PCDA) in ultrahigh vacuum (UHV). Molecular resolution UHV scanning tunneling microscopy (STM) images confirm the one-dimensional ordering of the as-deposited PCDA monolayer and show domain boundaries with symmetry consistent with the underlying graphene lattice. In an effort to further stabilize the monolayer, in situ ultraviolet photopolymerization induces covalent bonding between neighboring PCDA molecules in a manner that maintains one-dimensional ordering as verified by UHV STM and ambient atomic force microscopy (AFM). Further quantitative insights into these experimental observations are provided by semiempirical quantum chemistry calculations that compare the molecular structure before and after photopolymerization. PMID- 22928588 TI - Community-acquired lobar pneumonia in children in the era of universal 7-valent pneumococcal vaccination: a review of clinical presentations and antimicrobial treatment from a Canadian pediatric hospital. AB - BACKGROUND: Community-acquired pneumonia (CAP) is a common cause of pediatric admission to hospital. The objectives of this study were twofold: 1) to describe the clinical characteristics of CAP in children admitted to a tertiary care pediatric hospital in the pneumococcal vaccination era and, 2) to examine the antimicrobial selection in hospital and on discharge. METHODS: A retrospective review of healthy immunocompetent children admitted to a tertiary pediatric hospital from January 2007 to December 2008 with clinical features consistent with pneumonia and a radiographically-confirmed consolidation was performed. Clinical, microbiological and antimicrobial data were collected. RESULTS: One hundred and thirty-five hospitalized children with pneumonia were evaluated. Mean age at admission was 4.8 years (range 0-17 years). Two thirds of patients had been seen by a physician in the 24 hours prior to presentation; 56 (41.5%) were on antimicrobials at admission. 52 (38.5%) of patients developed an effusion, and 22/52 (42.3%) had pleural fluid sampled. Of 117 children who had specimens (blood/pleural fluid) cultured, 9 (7.7%) had pathogens identified (7 Streptococcus pneumoniae, 1 Group A Streptococcus, and 1 Rhodococcus). 55% of patients received 2 or more antimicrobials in hospital. Cephalosporins were given to 130 patients (96.1%) in hospital. Only 21/126 patients (16.7%) were discharged on amoxicillin. The median length of stay was 3 days (IQR 2-4) for those without effusion and 9 (IQR 5-13) for those with effusion. No deaths were related to pneumonia. CONCLUSIONS: This study provides comprehensive data on the clinical characteristics of hospitalized children with CAP in the pneumococcal 7-valent vaccine era. Empiric antimicrobial choice at our institution is variable, highlighting a need for heightened antimicrobial stewardship. PMID- 22928589 TI - Cord blood culture in hypoxia: making the cells feel at home. PMID- 22928590 TI - Can electromyographic arousal be detected visually on the Datex-Ohmeda S/5TM anesthesia monitor? AB - BACKGROUND: Electroencephalogram (EEG)-based depth of anaesthesia monitoring is susceptible to contaminating electromyographic (EMG) activity. Many authorities have suggested that anaesthesiologists using these monitors should interpret the raw EEG waveform seen on the anaesthesia monitor. METHODS: In 34 patients anaesthetized with propofol using two doses of rocuronium (0.6 and 1.2 mg/kg), we studied whether the EMG arousal can be detected visually on the anaesthesia monitor. The Bispectral Index (BIS) and Entropy biosignals on the monitor were recorded with a video camera, and the one-channel EEG recorded by the Entropy strip was collected on a laptop computer. The recordings and the one-channel EEG were analyzed offline by two experts (anaesthesiologist and neurophysiologist), both with a long experience on anaesthesia-related EEG. RESULTS: EMG arousal existed in 14/34 and 13/33 patients in the BIS and Entropy biosignals, respectively. The anaesthesiologist detected EMG on the monitor in 7/14 patients with BIS (sensitivity 50%) and in 4/13 patients with Entropy (31%). The clinical neurophysiologist detected EMG in 6/14 (43%) patients with BIS and in 5/13 (38%) with Entropy. The specificity of the EMG analyses was 55 and 65% with BIS, and 85 and 90% with Entropy. EMG arousal was detected in BIS biosignal in 10/17 and 4/17 patients with 0.6 and 1.2 mg/kg doses of rocuronium (P = 0.04). CONCLUSIONS: In contrast to many EEG phenomena, EMG activity cannot be accurately detected visually from the raw EEG on the anaesthesia monitor. Further development in the quality of the anaesthesia monitors is warranted. PMID- 22928591 TI - Sensitive skin: an overview. AB - Sensitive skin is a condition of subjective cutaneous hyper-reactivity to environmental factors. Subjects experiencing this condition report exaggerated reactions when their skin is in contact with cosmetics, soaps and sun screens, and they often report worsening after exposure to dry and cold climate. Although no sign of irritation is commonly detected, itching, burning, stinging and a tight sensation are constantly present. Generally substances that are not commonly considered irritants are involved in this abnormal response.Sensitive skin and subjective irritation are widespread but still far from being completely defined and understood. A correlation between sensitive skin and constitutional anomalies and/or other triggering factors such as occupational skin diseases or chronic exposure to irritants has been hypothesized. Recent findings suggest that higher sensitivity can be due to different mechanisms. Hyper-reactors may have a thinner stratum corneum with a reduced corneocyte area causing a higher transcutaneous penetration of water-soluble chemicals. Alterations in vanilloid receptors and changes in neuronal transmission have been described. Monitoring skin parameters such as barrier function, proclivity to irritation, corneocyte size and sensorial transmission can also be useful to identify regional differences in skin sensitivity. PMID- 22928592 TI - Circulating platelets as a source of the damage-associated molecular pattern HMGB1 in patients with systemic sclerosis. AB - The link between platelet activation and vascular injury in Systemic Sclerosis (SSc) is poorly characterized. Here we report that platelet activation results in i) the translocation from the cytoplasm to the surface of HMGB1, a prototypical DAMP signal associated with tissue regeneration and ii) the release of platelet derived microparticles (PDMUP) expressing HMGB1. Decreased HMGB1 content (334.6 +/- 21.2 vs 587.1 +/- 11.1 AUF, P < 0.001) and HMGB1 translocation to the outer leaflet of the plasma membrane (17.8 +/- 3.5 vs 4.5 +/- 0.5%, P < 0.001) characterize circulating platelets of SSc patients (n = 29) when compared with age-matched healthy controls (HC, n = 20). Conversely, a significantly higher fraction of PDMUP in the blood of SSc patients, but not of HC, consistently expose (HMGB1 (MFI 62.8 +/- 3.95 vs 4.3 +/- 0.7). Platelet HMGB1 depletion is significantly associated in SSc patients with degranulation and with expression of P-selectin and of tissue factor as well as with fibrinogen binding to their plasma membrane. These findings indicate that platelets represent a source of HMGB1, an ancestral signal of necrosis, in the vasculature of SSc patients, possible contributing to persistent microvascular injury and endothelial cell activation. PMID- 22928593 TI - A new phenylethanoid glucoside from Jacaranda mimosifolia. AB - This study reports the isolation of a new phenylethanoid glucoside (1) from the leaves of Jacaranda mimosifolia along with jacaranone (2), followed by the comparative estimation of total antioxidant compounds, total polyphenols and total flavonoids from different solvent extracts of the leaves and flowers. The total antioxidant activity was evaluated by both DPPH and ABTS free-radical scavenging assay methods from different solvent extracts of J. mimosifolia leaves and flowers. The antioxidant activities of the purified compounds (1 and 2) were detected by DPPH-TLC method. PMID- 22928594 TI - Effect of positive surgical margins after initial surgical resection for basal cell carcinoma. PMID- 22928595 TI - Medical device on pharmacists' work-related musculoskeletal complaints and burnouts. AB - This study analysed the total number of consumed vials of chemotherapy drugs during the year 2007 to determine workloads, and investigated the effects of using the Spike medical device in contrast to the use of traditional needles on oncology pharmacists' dispensing time, muscle soreness, work-related burnout and fatigue symptoms. Work-related burnout and physiological symptoms were measured using the Copenhagen Burnout Inventory (CBI) and a visual analogue pain scale. The Spike device significantly reduced the time spent in drawing up fluorouracil (39.46 +/- 9.43 s vs. 57.13 +/- 13.47 s) or cisplatin (29.65 +/- 11.22 s vs. 60.93 +/- 20.54 s) compared with traditional needles (P < 0.001). The CBI burnout score improved significantly with the Spike device (53.21 +/- 8.58 vs. 73.21 +/- 5.42; P = 0.007) because finger and palm muscle soreness complaints and subjective fatigue symptoms for eye tiredness and shoulder-wrist pain were significantly reduced (P < 0.05). Practitioner Summary The pharmacist needs to exert hand strength to counter the vial back-suction pressure to draw out the medical liquid, and confirm the volume during the drawing antineoplastic drug procedure. This study aimed to determine the effects of using a medical device, instead of a needle, on pharmacists' work-related musculoskeletal complaints and burnouts. PMID- 22928596 TI - Varicella presenting as atypical vesicular lesions and fulminant hepatitis in an adolescent with leukemia. PMID- 22928597 TI - Total synthesis of (+)-Sch 725680: inhibitor of mammalian A-, B-, and Y-family DNA polymerases. AB - The total synthesis of (+)-Sch 725680, a member of the hydrogenated azaphilone family, has been accomplished. The synthesis confirmed the absolute configuration and biological activities of the natural product. A key reaction to construct a hydrogenated azaphilone core skeleton is a Ti-mediated aldol reaction. PMID- 22928599 TI - Is "Inhibition of Return" due to the inhibition of the return of attention? AB - Inhibition of Return (IOR) is usually explained in terms of orienting-reorienting of attention, emphasizing an underlying mechanism that inhibits the return of attention to previously selected locations. Recent data challenge this explanation to the extent that the IOR effect is observed at the location where attention is oriented to, where no reorienting of attention is needed. To date, these studies have involved endogenous attentional selection of attention and thus indicate a dissociation between the voluntary attention of spatial attention and the IOR effect. The present work demonstrates a dissociation between the involuntary orienting of spatial attention and the IOR effect. We combined nonpredictive peripheral cues with nonpredictive central orienting cues (either arrows or gaze). The IOR effect was observed to operate independent of involuntary spatial orienting. These data speak against the "reorienting hypothesis" of IOR. We suggest an alternative explanation whereby the IOR effect reflects a cost in detecting a new event (the target) at the location where another event (a cue) was coded before. PMID- 22928598 TI - Formation and repair of pyridyloxobutyl DNA adducts and their relationship to tumor yield in A/J mice. AB - The nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is a known human carcinogen. It generates methyl and pyridyloxobutyl DNA adducts. The role of the methyl DNA adducts has been well-established in the tumorigenic properties of NNK. However, the role of the pyridyloxobutyl DNA adducts is unclear. Four pyridyloxobutyl DNA adducts have been characterized: 7-[4-3-(pyridyl)-4-oxobut-1 yl]guanine (7-pobG), O2-[4-3-(pyridyl)-4-oxobut-1-yl]-cytodine (O2-pobC), O2-[4-3 (pyridyl)-4-oxobut-1yl]thymidine (O2-pobdT), and O6-[4-3-(pyridyl)-4-oxobut-1-yl] 2'-deoxyguanosine (O6-pobdG). Mutagenic O6-pobdG is thought to contribute to the tumorigenic properties of the pyridyloxobutylation pathway. It is repaired by O6 alkylguanine-DNA alkyltransferase (AGT). To explore the role of O6-pobdG formation and repair in the tumorigenic properties of NNK, A/J mice were given single or multiple doses of the model pyridyloxobutylating agent 4-(acetoxymethyl nitrosamino)-1-(3-pyridyl)-1-butanone (NNKOAc) in the presence or absence of the AGT depletor, O6-benzylguanine. Levels of the four pyridyloxobutyl DNA adducts were measured in the lung at 8, 48, or 96 h following treatment and compared to the lung tumorigenic activity of these treatments. AGT depletion had only a modest effect on the levels of O6-pobdG and did not increase tumor formation. Three pyridyloxobutyl DNA adducts, 7-pobG, O2-pobdT, and O6-pobdG, persisted in lung DNA at significant levels for up to 96 h post-treatment, suggesting that all three adducts may contribute to the tumorigenic properties of NNK. PMID- 22928600 TI - Mice fed on a diet enriched with genetically engineered multivitamin corn show no sub-acute toxic effects and no sub-chronic toxicity. AB - Multivitamin corn is a novel genetically engineered variety that simultaneously produces high levels of beta-carotene, ascorbate and folate, and therefore has the potential to address simultaneously multiple micronutrient deficiencies caused by the lack of vitamins A, B9 and C in developing country populations. As part of the development process for genetically engineered crops and following European Food Safety Authority (EFSA) recommendations, multivitamin corn must be tested in whole food/feed sub-chronic animal feeding studies to ensure there are no adverse effects, and potential allergens must be identified. We carried out a 28-day toxicity assessment in mice, which showed no short-term sub-acute evidence of diet-related adverse health effects and no difference in clinical markers (food consumption, body weight, organ/tissue weight, haematological and biochemical blood parameters and histopathology) compared to mice fed on a control diet. A subsequent 90-day sub-chronic feeding study again showed no indications of toxicity compared to mice fed on control diets. Our data confirm that diets enriched with multivitamin corn have no adverse effects on mice, do not induce any clinical signs of toxicity and do not contain known allergens. PMID- 22928602 TI - A charge-orbital balance picture of doping in colloidal quantum dot solids. AB - We present a framework--validated using both modeling and experiment--to predict doping in CQD films. In the ionic semiconductors widely deployed in CQD films, the framework reduces to a simple accounting of the contributions of the oxidation state of each constituent, including both inorganic species and organic ligands. We use density functional theory simulations to confirm that the type of doping can be reliably predicted based on the overall stoichiometry of the CQDs, largely independent of microscopic geometrical bonding configurations. Studies employing field-effect transistors constructed from CQDs that have undergone various chemical treatments, coupled with Rutherford backscattering and X-ray photoelectron spectroscopy to provide compositional analysis, allow us to test and confirm the proposed model in an experimental framework. We investigate both p- and n-type electronic doping spanning a wide range of carrier concentrations from 10(16) cm(-3) to over 10(18) cm(-3), and demonstrate reversible switching between p- and n-type doping by changing the CQD stoichiometry. We show that the summation of the contributions from all cations and anions within the film can be used to predict accurately the majority carrier type. The findings enable predictable control over majority carrier concentration via tuning of the overall stoichiometry. PMID- 22928601 TI - Molecular and morphologic correlates of the alternative lengthening of telomeres phenotype in high-grade astrocytomas. AB - Recent studies suggest that the telomere maintenance mechanism known as alternative lengthening of telomeres (ALT) is relatively more common in specific glioma subsets and strongly associated with ATRX mutations. We retrospectively examined 116 high-grade astrocytomas (32 pediatric glioblastomas, 65 adult glioblastomas, 19 anaplastic astrocytomas) with known ALT status using tissue microarrays to identify associations with molecular and phenotypic features. Immunohistochemistry was performed using antibodies against ATRX, DAXX, p53 and IDH1(R132H) mutant protein. EGFR amplification was evaluated by fluorescence in situ hybridization (FISH). Almost half of fibrillary and gemistocytic astrocytomas (44%) demonstrated ALT. Conversely all gliosarcomas (n = 4), epithelioid (n = 2), giant cell (n = 2) and adult small cell astrocytomas (n = 7) were ALT negative. The ALT phenotype was positively correlated with the presence of round cells (P = 0.002), microcysts (P < 0.0002), IDH1 mutant protein (P < 0.0001), ATRX protein loss (P < 0.0001), strong P53 immunostaining (P < 0.0001) and absence of EGFR amplification (P = 0.004). There was no significant correlation with DAXX expression. We conclude that ALT represents a specific phenotype in high-grade astrocytomas with distinctive pathologic and molecular features. Future studies are required to clarify the clinical and biological significance of ALT in high-grade astrocytomas. PMID- 22928603 TI - Abstracts of the 7th Scientific and Annual Meeting of the European Society of Coloproctology. September 26-28, 2012. Vienna, Austria. PMID- 22928604 TI - Reactive gastropathy is associated with inflammatory conditions throughout the gastrointestinal tract. AB - BACKGROUND: The epidemiology of reactive gastropathy and its relationship with other conditions of the gastrointestinal tract associated with NSAID use have not been evaluated. AIMS: To test the hypothesis that if reactive gastropathy shares common aetiological factors with these conditions, the analysis of a large cohort would unveil associations. METHODS: We queried a national pathology database for subjects with a diagnosis of reactive gastropathy; controls were patients with normal gastric biopsies. We also extracted diagnoses of H. pylori infection, intestinal metaplasia, duodenal lymphocytosis, duodenitis, ileitis, microscopic colitis and focal colitis. RESULTS: Of 504 011 patients with gastric biopsies, 69 101 had oesophageal, 166 134 duodenal, 13 010 ileal and 83 334 colonic biopsies. Reactive gastropathy was diagnosed in 15.6% of patients, H. pylori infection in 10.3% and normal gastric mucosa in 16.3%. Reactive gastropathy was evenly distributed across the US and increased from 2.0% in the first decade of life to >20% in octogenarians. Compared with controls, reactive gastropathy was significantly associated with Barrett's mucosa (OR 1.21 95% CI 1.16-129); duodenitis (OR 1.36; 95% CI 1.28-1.44); duodenal intraepithelial lymphocytosis (OR 1.25; 95% CI 1.13-1.39); active ileitis (OR 1.88; 95% CI 1.47-2.40); focal active colitis (OR 1.57; 95% CI 1.33-1.86); and collagenous colitis (OR 1.50; 95% CI 1.12-2.03). CONCLUSIONS: Reactive gastropathy, a common histopathological feature of the stomach, shows an age-dependent rise and is associated with changes of the digestive tract believed to be caused by NSAID use or duodenogastric reflux. However, a large fraction of reactive gastropathy remains unexplained; its frequent occurrence merits further efforts at elucidating its aetiology. PMID- 22928605 TI - Chromosomal differences between European and North American Atlantic salmon discovered by linkage mapping and supported by fluorescence in situ hybridization analysis. AB - BACKGROUND: Geographical isolation has generated a distinct difference between Atlantic salmon of European and North American Atlantic origin. The European Atlantic salmon generally has 29 pairs of chromosomes and 74 chromosome arms whereas it has been reported that the North American Atlantic salmon has 27 chromosome pairs and an NF of 72. In order to predict the major chromosomal rearrangements causing these differences, we constructed a dense linkage map for Atlantic salmon of North American origin and compared it with the well-developed map for European Atlantic salmon. RESULTS: The presented male and female genetic maps for the North American subspecies of Atlantic salmon, contains 3,662 SNPs located on 27 linkage groups. The total lengths of the female and male linkage maps were 2,153 cM and 968 cM respectively, with males characteristically showing recombination only at the telomeres. We compared these maps with recently published SNP maps from European Atlantic salmon, and predicted three chromosomal reorganization events that we then tested using fluorescence in situ hybridization (FISH) analysis. The proposed rearrangements, which define the differences in the karyotypes of the North American Atlantic salmon relative to the European Atlantic salmon, include the translocation of the p arm of ssa01 to ssa23 and polymorphic fusions: ssa26 with ssa28, and ssa08 with ssa29. CONCLUSIONS: This study identified major chromosomal differences between European and North American Atlantic salmon. However, while gross structural differences were significant, the order of genetic markers at the fine-resolution scale was remarkably conserved. This is a good indication that information from the International Cooperation to Sequence the Atlantic salmon Genome, which is sequencing a European Atlantic salmon, can be transferred to Atlantic salmon from North America. PMID- 22928606 TI - Metal cation binding to gas-phase pentaalanine: divalent ions restructure the complex. AB - Ion-neutral complexes of pentaalalanine with several singly- and doubly charged metal ions are examined using conformation analysis by infrared multiple photon dissociation (IRMPD) spectroscopy and density functional theory (DFT) computations. The infrared spectroscopy in the 1500-1800 cm(-1) region is found to be conformationally informative; in particular, the frequency of the C?O stretching mode of the terminal carboxyl group is diagnostic for hydrogen bonding of the terminal hydroxyl. The doubly charged alkaline earth metal ions (Ca(2+) and Ba(2+)) enforce a highly structured chelation shell around the metal ion, with six strongly bound Lewis-basic chelation sites, and no hydroxyl hydrogen bonding. With the more weakly binding alkali metal ions (Na(+), K(+), and Cs(+)), structures with intramolecular hydrogen bonds are more favorable, leading to dominance of conformations with lower degrees of metal ion chelation. The favored coordination mode correlates with ionic charge and binding strength but is not related to the ionic radius of the metal ion. PMID- 22928607 TI - Mortality and causes of death in the Familial Intracranial Aneurysm study. AB - BACKGROUND: Higher mortality for patients with aneurysmal subarachnoid haemorrhage has been reported. AIMS: In families with intracranial aneurysms, we sought to determine whether mortality among subjects with intracranial aneurysm (affected) was higher and related to rupture, compared with unaffected family members. METHODS: Subjects enrolled in the Familial Intracranial Aneurysm protocol were contacted yearly and their status was obtained. If reported to be deceased, the cause of death was verified by available records. A Cox proportional hazards model was utilized to compare mortality rates. RESULTS: Of the 2794 subjects, 1073 were affected and 1721 were unaffected. There were 8525 person-years of follow-up (mean 3.05 +/- 1.73 years) and 85 deaths. Age at study entry for the affected (58.4 +/- 11.9 years) was significantly older (P < 0.0001) than for the unaffected (52.2 +/- 16.1). After adjusting for age, the overall mortality rate for the affected subjects was not significantly different from that for the unaffected (Rate Ratio [RR] 1.26, 95% confidence interval 0.82-1.93, P = 0.292). There was a strong effect modification due to age. The mortality rate ratio of the affected to the unaffected who were <=60 years of age was RR = 3.48 (95% confidence interval: 1.59-7.63, P = 0.002), the rate for the affected subjects who were >=60 was less than the rate for the unaffected (RR = 0.69, 95% confidence interval: 0.404-1.19, P = 0.178). The affected who had ruptures had 2.62 times the mortality rate as those without ruptures (95% confidence interval 1.43-4.80, P = 0.002). CONCLUSION: The overall mortality was similar for the affected and unaffected subjects in this cohort. Among the affected only, those with ruptured intracranial aneurysm had a higher mortality rate than those without ruptured. PMID- 22928608 TI - The contributing role of real-life hand skill performance in self-care function of children with and without disabilities. AB - BACKGROUND: Children's hand skills when performing in real-life contexts have been commonly thought as a possible determinant of their self-care function; however, there is a paucity of research investigating this potential predictive relationship. The purpose of this study was to provide evidence regarding whether children's real-life hand skill performance is contributive to or predictive of their self-care function by considering other child and cultural factors. METHODS: A total of 139 typically developing children and 114 with disabilities, ages 2-12 years from Australia and Taiwan, participated in the study. The outcome measures used were the Assessment of Children's Hand Skills (a measure of real life hand skill performance) and the Personal Living Skills subscale of the Vineland Adaptive Behavior Scales - Classroom Edition (a measure of self-care function). RESULTS: Hierarchical regression analysis revealed that the children's demographic variables (age, gender, disability status, handedness and cultural context) accounted for 43% of the variance of the self-care function in the combined group of children with and without disabilities. Age, presence of disability and cultural context were the statistically significant independent factors. However, after the entry of the real-life hand skill performance factor, the contributing values of age and disability status decreased and the age factor became non-significant. The hand skill performance factor was found to be the strongest, and its addition led to significant increments of 24.6% of the explained variance for children's self-care function. Similar results were also found in the regression analyses based on separate groups of typically developing children or those with disabilities. CONCLUSIONS: The findings provide evidence that children's real-life hand skill performance is a contributing factor of their self-care function. The assessment of children's hand skill performance in real-life contexts is therefore needed. PMID- 22928609 TI - Characterization of polymerized liposomes using a combination of dc and cyclical electrical field-flow fractionation. AB - Characterization of polymerized liposomes (PolyPIPosomes) was carried out using a combination of normal dc electrical field-flow fractionation and cyclical electrical field-flow fractionation (CyElFFF) as an analytical technique. The constant nature of the carrier fluid and channel configuration for this technique eliminates many variables associated with multidimensional analysis. CyElFFF uses an oscillating field to induce separation and is performed in the same channel as standard dc electrical field-flow fractionation separation. Theory and experimental methods to characterize nanoparticles in terms of their sizes and electrophoretic mobilities are discussed in this paper. Polystyrene nanoparticles are used for system calibration and characterization of the separation performance, whereas polymerized liposomes are used to demonstrate the applicability of the system to biomedical samples. This paper is also the first to report separation and a higher effective field when CyElFFF is operated at very low applied voltages. The technique is shown to have the ability to quantify both particle size and electrophoretic mobility distributions for colloidal polystyrene nanoparticles and PolyPIPosomes. PMID- 22928610 TI - ExBox: a polycyclic aromatic hydrocarbon scavenger. AB - A template-directed protocol, which capitalizes on donor-acceptor interactions, is employed to synthesize a semi-rigid cyclophane (ExBox(4+)) that adopts a box like geometry and is comprised of pi-electron-poor 1,4-phenylene-bridged ("extended") bipyridinium units (ExBIPY(2+)). ExBox(4+) functions as a high affinity scavenger of an array of different polycyclic aromatic hydrocarbons (PAHs), ranging from two to seven fused rings, as a result of its large, accommodating cavity (approximately 3.5 A in width and 11.2 A in length when considering the van der Waals radii) and its ability to form strong non-covalent bonding interactions with pi-electron-rich PAHs in either organic or aqueous media. In all, 11 PAH guests were observed to form inclusion complexes with ExBox(4+), with coronene being the largest included guest. Single-crystal X-ray diffraction data for the 11 inclusion complexes ExBox(4+)?PAH as well as UV/vis spectroscopic data for 10 of the complexes provide evidence of the promiscuity of ExBox(4+) for the various PAHs. Nuclear magnetic resonance spectroscopy and isothermal titration calorimetric analyses of 10 of the inclusion complexes are employed to further characterize the host-guest interactions in solution and determine the degree with which ExBox(4+) binds each PAH compound. As a proof-of concept, a batch of crude oil from Saudi Arabia was subjected to extraction with the water-soluble form of the PAH receptor, ExBox.4Cl, resulting in the isolation of different aromatic compounds after ExBox.4Cl was regenerated. PMID- 22928611 TI - C-H bond functionalization under metalation-deprotonation process: regioselective direct arylation of 3-aminoimidazo[1,2-a]pyrazine. AB - Concerted metalation deprotonation (CMD) approach with appropriate proton shuttle precursor, base, and solvent (PivOH-K(2)CO(3)-toluene) has rendered a regioselective Pd-catalyzed C6-arylation of 3-aminoimidazo[1,2-a]pyrazine, a therapeutically relevant scaffold accessible by multicomponent reaction. The arylation of this heteroarene suffers from competing C5 and C2'-arylation reactions, while the developed process has virtually eliminated these competing arylations. Density functional calculations for CMD C-H activation at C6, C5, C8, and C2' sites imply that the energy barrier with distortion energy penalty as major contributing component influences the regioselectivity. PMID- 22928612 TI - Composites of cationic nanofibrillated cellulose and layered silicates: water vapor barrier and mechanical properties. AB - Composites of trimethylammonium-modified nanofibrillated cellulose and layered silicates (TMA-NFC/LS) were prepared by high-shear homogenization followed by pressure filtration and vacuum hot-pressing, which gave rise to particularly homogeneous dispersion of the silicate particles. Thirteen different clays and micas were employed. Water vapor barrier and mechanical properties (tensile strength, E-modulus, strain at break) of the composite films were investigated, considering the effects of layered silicate types and their concentration (in the range of 0 to 85 wt %). Good interactions between TMA-NFC and LS were obtained due to electrostatic attraction between cationic fibrils and anionic silicate layers, and even favored by high-shear homogenization process. Furthermore, oriented TMA-NFC/LS composite structure was achieved. Layered silicates exerted a pronounced influence on the water vapor barrier and mechanical properties; however, there was no common trend reflecting their types. The transport of water molecules through TMA-NFC/LS composites was studied considering both diffusion and adsorption mechanisms. As a result, diffusion pathways were proposed based on two new and one well-known models: the "native network", "covered fiber composite", and "fiber-brick composite" models. Importantly, it was found that the insertion of layered silicate particles did not improve automatically the barrier properties as indicated by the commonly used "fiber-brick composite" model. Mica R120 at a 50 wt % loading in composites with TMA-NFC matrix showed 30 fold improved water vapor permeability and 5-fold higher E-modulus compared to commercially used base paper. PMID- 22928613 TI - Predicting outcomes and assessing control with alternate glycemic markers. PMID- 22928614 TI - Clinical outcomes associated with referral-based continuous glucose monitoring using a central standardized interpretation strategy. AB - BACKGROUND: Continuous glucose monitoring (CGM) devices can present a challenge to health providers given the sheer amount of data collected. A referral-based system using a centralized standard interpretation completed by a specialist could highlight the most pertinent information and provide recommendations. SUBJECTS AND METHODS: Professional (retrospective) CGM reports from an outpatient academic endocrinology clinic were formally interpreted by one of two specialists. General recommendations for therapy adjustments were made to each patient's referring provider without a face-to-face visit using only the CGM download and patient logs. Findings were characterized as well as change in hemoglobin A1c (HbA1c) by 6 and 12 months. RESULTS: Patients with baseline HbA1c values above 8.1% experienced a significant reduction (-0.36 +/- 0.80%) at 6 months post-CGM (P = 0.035), whereas those with baseline HbA1c below 8.1% experienced an equally significant increase (0.36 +/- 0.83%, P = 0.032), most likely because of interventions that addressed hypoglycemia. Hypoglycemia was common, and unrecognized overnight hypoglycemia lasting over 2 h occurred in 48% of patients. There were no differences in findings or in HbA1c changes among pump compared with non-pump users. In total, 69% of patients had a change in management by the referring provider within 1 month. CONCLUSIONS: The data suggest that some patients benefited, in the form of reductions in HbA1c, from centralized referral and interpretation of professional CGM regardless of modality of insulin therapy. Considerations for methods to improve coordination with referring providers for follow-up care are needed. PMID- 22928616 TI - Sweet kiss of dying cell: sialidase activity on apoptotic cell is able to act toward its neighbors. AB - Apoptotic cells and subcellular microparticles expose increased sialidase activity on their surfaces, which results from caspase-3 dependent activation of plasma membrane associated Neuraminidase-1 (Neu1). Desialylation of dying cells is also known to promote efferocytosis. The intriguing question remained whether sialidase on the surface of dying cell merely acts on self targets (cis-action), or whether it can also cleave glycoepitopes of neighboring cells (trans-action). Here, we co-incubated human viable and apoptotic Jurkat lymphocytes or neutrophils with human erythrocytes and evaluated their glycoprofile for terminal sialic acids by agglutination assay, flow cytometry, ELISA and dot-blot analyses. Data suggest that erythrocytes were desialylated as soon as 3 hours after co incubation with apoptotic cells, but not with viable ones. After co-incubation of L929 murine fibroblasts with viable or apoptotic murine L1210 cells the L929 cells gained a desialylated glycoprofile, only after co-incubation with apoptotic cells. Our data suggests that activated sialidase(s) on the surfaces of apoptotic cells are capable to desialylate neighboring cells in trans. PMID- 22928615 TI - Low-level lasers as an adjunct in periodontal therapy in patients with diabetes mellitus. AB - BACKGROUND: Diabetes mellitus (DM) increases the risk of periodontitis, and severe periodontitis often coexists with severe DM. The proposed dual pathway of tissue destruction suggests that control of chronic periodontal infection and gingival inflammation is essential for achieving long-term control of DM. The purpose this study is to evaluate the effects of low-level laser therapy (LLLT) by exfoliative cytology in patients with DM and gingival inflammation. SUBJECTS AND METHODS: Three hundred patients were divided in three equal groups: Group 1 consisted of patients with periodontitis and type 1 DM, Group 2 of patients with periodontitis and type 2 DM, and Group 3 of patients with periodontitis (control group). After oral examination, smears were taken from gingival tissue, and afterward all of the patients received oral hygiene instructions, removal of dental plaque, and full-mouth scaling and root planing. A split-mouth design was applied; on the right side of jaws GaAlAs LLLT (670 nm, 5 mW, 14 min/day) (model Mils 94; Optica Laser, Sofia, Bulgaria) was applied for five consecutive days. After the therapy was completed, smears from both sides of jaws were taken. The morphometric analysis was done using the National Institutes of Health Image software program and a model NU2 microscope (Carl Zeiss, Jena, Germany). RESULTS: Investigated parameters were significantly lower after therapy compared with values before therapy. After therapy on the side subjected to LLLT, there was no significantly difference between patients with DM and the control group. CONCLUSIONS: It can be concluded that LLLT as an adjunct in periodontal therapy reduces gingival inflammation in patients with DM and periodontitis. PMID- 22928617 TI - A note on cognitive dissonance and malingering. AB - This paper proposes that malingered symptoms may become internalized due to the self-deceptive power of cognitive dissonance. Studies demonstrating how other deception may turn into self-deception are briefly discussed, as are clinical notions about the overlap between malingering and medically unexplained symptoms. In our view this literature showcases the relevance of cognitive dissonance for research on malingering. A cognitive dissonance perspective may help to clarify how ambiguous sensations may escalate into subjectively compelling symptoms. This perspective suggests that malingered symptom reports are more than just a complication during psychological evaluation. It may generate new research avenues and may clarify practically relevant issues. PMID- 22928618 TI - Suppression of lipopolysaccharide and galactosamine-induced hepatic inflammation by red grape pomace. AB - Grape pomace is generated in the production process of wine and grape juices and is an industrial waste. This study investigated whether an intake of grape pomace was able to suppress chronic inflammation induced by lipopolysaccharide (LPS) and galactosamine (GalN) in vivo. When Sprague-Dawley rats were orally given methanolic extracts from red and white grape pomace, the extracts inhibited the LPS/GalN-evoked activation of nuclear factor-kappaB (NF-kappaB) dose-dependently, and red grape pomace exerted a stronger effect than white grape one. Next, rats were fed an AIN93 M-based diet containing 5% red grape pomace for 7 days, followed by the intraperitoneal injection of LPS and GalN. The intake of the red grape pomace-supplemented diet was found to suppress the LPS/GalN-induced activation of NF-kappaB and expression of inducible nitric oxide synthase and cyclooxygenase-2 proteins. These results suggest that red grape pomace may contain an abundance of effective compound(s) for anti-inflammatory action. PMID- 22928619 TI - Working towards a test for screening visual skills in a complex visual environment. AB - We developed a test for screening visual skills under similar conditions as at workplace. The test was administered to 207 participants, recruited in the working population. Six-digit numbers were super-imposed on a video of a drive and presented for 300 ms in the central visual field and in the periphery. Participants reported whether or not the integer '3' was included in the numbers. Normative data for the test were computed using 150 data sets of participants reporting not to take drugs and with an age ranging between 15 y and 67 y. Participants performed better in the central visual field than in periphery. The test could successfully be completed by participants of all ages without the need of adjustment of settings. Comparison of 46 data sets recorded in participants taking drugs (30 y-68 y) with age matched participants not taking drugs demonstrates an additional potential application of the test. Practitioner Summary: Developed test delivers comparative estimates of visual skills within short time and appears as valuable and cheap complementation to current testing procedures in industrial practice. The test can be used in a preventive and in educative manner to monitor effects of factors like fatigue, sleep deprivation or drug consumption. PMID- 22928620 TI - Antibiogram testing of pediatric skin infections in the era of methicillin resistant Staphylococci aureus: an Egyptian University Hospital-based study. AB - BACKGROUND: Community-associated methicillin-resistant Staphylococci aureus (CA MRSA) pediatric skin infections have been reported worldwide. However, little is known about pathogens' implications in Egyptian children, and beta-lactams are still the empiric antimicrobials prescribed. This warrants Egyptian studies on antibiogram testing of pediatric skin infections. OBJECTIVES: To determine antibiotic susceptibility patterns of bacterial isolates from Egyptian pediatric skin infections to find out if we need reconsideration of the empiric beta-lactam antimicrobial therapy. MATERIALS AND METHODS: Throughout an eight-month cross sectional study, antibiogram testing was conducted on bacterial isolates from pediatric skin infections. Determination of inducible resistance to clindamycin using D-test was performed for isolates susceptible to clindamycin and resistant to erythromycin. RESULTS: One-hundred and 21 children (mean age 6.9 years +/- 3 SD) presented with pyogenic skin infections. Methicillin-sensitive Staphylococci aureus (MSSA) were isolated from 114 children, associated with group A Streptococci (GAS) in four of them, while GAS were the only isolates in three patients. A diagnosis of CA-MRSA was fulfilled in four children. Antibiotic susceptibilities differed between isolated organisms but with no statistically significant differences between susceptibility patterns of isolates from primary skin infections and those from secondary infection of skin diseases. Positive D test was detected in five MSSA isolates. CONCLUSIONS: CA-MRSA skin infections are not common among Egyptian children and, therefore, beta-lactams are still effective empiric antimicrobial therapy for most infections. Antibiogram testing from suppurative skin lesions are, however, better to be recommended to guide individual therapy. Clindamycin should not be considered for susceptible isolates unless they are erythromycin susceptible or D-test negative. PMID- 22928621 TI - Benefit finding through caring: the cancer caregiver experience. AB - OBJECTIVES: The aim of this study was to explore benefit finding in cancer carers taking account of timeline and care recipient, in relation to burden of care, perceived stress, optimism, resilience, self efficacy, perceived support and psychological distress. METHODS: A cohort sequential survey was conducted with a group of 842 female cancer carers who were caring for a spouse, a parent or a child. A stress-coping model of benefit finding was proposed and tested. RESULTS: Analysis supported the stress-coping model for global benefit finding and also the multidimensional model of benefit finding and identified important differences on outcome measures depending on care recipient and timeline. CONCLUSIONS: This study concludes that a focus on benefit finding interventions may be useful in the area, but that a developmental approach taking into account the relationship between carer and the carer recipient is required. PMID- 22928622 TI - The effects of functional electrical stimulation on walking in hereditary and spontaneous spastic paraparesis. AB - OBJECTIVES: To investigate in people with spastic paraparesis (SP): 1) the factors contributing to foot drop and reduced toe clearance while walking; 2) short-term effects of bilateral functional electrical stimulation (FES) of the common peroneal nerve. MATERIALS AND METHODS: Long term (>0.5 years) users of FES with SP were compared to matched controls (N = 11 per group). Ankle strength and plantarflexor stiffness and walking kinematics were objectively recorded. The effects of FES on: 1) perceived efficacy; 2) muscle torque and ankle motion; 3) clinical outcome measures and walking kinematics were assessed. Results were compared using an analysis of covariance. RESULTS: Ankle weakness and stiffness is higher among people with SP. Higher plantarflexor stiffness is associated with reduced swing phase dorsiflexion; higher toe clearance while walking is associated with increased hip flexion. FES increases dorsiflexor torque, improves toe clearance and dorsiflexion in swing phase, and significantly improves walking speed (p < 0.05). CONCLUSIONS: There are multiple causes of tripping in people with SP; FES reduces foot drop and improves walking speed. PMID- 22928623 TI - Variation in lumbar punctures for early onset neonatal sepsis: a nationally representative serial cross-sectional analysis, 2003-2009. AB - BACKGROUND: Whether lumbar punctures (LPs) should be performed routinely for term newborns suspected of having early onset neonatal sepsis (EONS) is subject to debate. It is unclear whether variations in performance of LPs for EONS may be associated with patient, hospital, insurance or regional factors. Our objective was to identify characteristics associated with the practice of performing LPs for suspected EONS in a nationally representative sample. METHODS: Utilizing data from the 2003, 2006 and 2009 Kids' Inpatient Database (KID) compiled by the Agency for Healthcare Research and Quality, we examined the frequency and characteristics of term, normal-birth weight newborns receiving an LP for EONS. Survey-weighting was applied for national estimates and used in chi squared and multivariable regression analysis. RESULTS: In 2009, there were 13,694 discharges for term newborns that underwent LPs for apparent EONS. Newborns having LPs performed were more likely to be covered by Medicaid vs. private insurance (51.9 vs. 45.1 percent; p < 0.001), be born in urban vs. rural hospitals (94.8 vs. 87.3 percent; p < 0.001), teaching vs. non-teaching (60.8 vs. 43.1 percent; p < 0.001) and children's hospitals vs. non-children's (23.0 vs. 11.2 percent; p < 0.001). Lastly, newborns having LPs performed were disproportionately born in the Northeast census region (p = 0.03). In multi-year adjusted analysis, infants with Medicaid coverage, and those born in urban or teaching hospitals, consistently had higher odds of having an LP performed. CONCLUSIONS: We found pronounced variation in LPs performed for EONS, even when adjusting for clinical conditions that would prompt LPs. These findings indicate practice variations in newborn care that merit further examination and explanation. PMID- 22928625 TI - Alcohol and the unborn. PMID- 22928624 TI - High-level gait disorder: associations with specific white matter changes observed on advanced diffusion imaging. AB - BACKGROUND AND PURPOSE: High-level gait disorder (HLGD) is a debilitating disorder causing mobility decline in the elderly. Although its clinical characteristics are well described, its anatomical and pathophysiological underpinnings are poorly understood. This study examined the anatomical distribution of white matter (WM) changes in patients with mild to moderate HLGD of the cautious/disequilibrium type, using advanced magnetic resonance imaging (MRI) methods. METHODS: Thirteen patients with HLGD, 9 elderly and 13 middle-aged healthy controls were scanned using diffusion tensor imaging, Q-space imaging, and conventional MRI. The regions of significant differences between the HLGD group and the elderly control group were defined, and the mean fractional anisotropy and displacement values of these areas were extracted. RESULTS: The HLGD patients had lower fractional anisotropy and higher displacement values in regions related to the motor system, including those along the corticospinal tract and the superior cerebellar peduncles, as well as in cognitive and affective-related areas, including the anterior limbs of the internal capsule and the genu of the corpus callosum. CONCLUSIONS: The anatomical distribution associated with HLGD of the cautious/disequilibrium type involves WM pathways that convey motor-related, cognitive and affective-related functions. The underlying pathological process leading to these changes most probably includes demyelination. PMID- 22928626 TI - Alcohol and fetal risk: a property of the drink or the drinker? PMID- 22928627 TI - Kinematics matters: a new eye-tracking investigation of animated triangles. AB - Eye movements have been recently recorded in participants watching animated triangles in short movies that normally evoke mentalizing (Frith-Happe animations). Authors have found systematic differences in oculomotor behaviour according to the degree of mental state attribution to these triangles: Participants made longer fixations and looked longer at intentional triangles than at triangles moving randomly. However, no study has yet explored kinematic characteristics of Frith-Happe animations and their influence on eye movements. In a first experiment, we have run a quantitative kinematic analysis of Frith Happe animations and found that the time triangles spent moving and the distance between them decreased with the mentalistic complexity of their movements. In a second experiment, we have recorded eye movements in 17 participants watching Frith-Happe animations and found that some differences in fixation durations and in the proportion of gaze allocated to triangles between the different kinds of animations were entirely explained by low-level kinematic confounds. We finally present a new eye-tracking measure of visual attention, triangle pursuit duration, which does differentiate the different types of animations even after taking into account kinematic cofounds. However, some idiosyncratic kinematic properties of the Frith-Happe animations prevent an entirely satisfactory interpretation of these results. The different eye-tracking measures are interpreted as implicit and line measures of the processing of animate movements. PMID- 22928628 TI - Spitzoid and non-spitzoid melanoma in children: a prognostic comparative study. AB - BACKGROUND: Spitzoid melanoma is a rare melanoma subtype often developing in children with unknown biological potential. OBJECTIVES: To compare the clinical and histopathological factors that influence the biological behaviour between spitzoid and non-spitzoid childhood melanoma, to establish if the spitzoid subset of melanoma has different prognosis than other types of childhood melanomas. METHODS: A comparison of the prognostic significance of clinical and pathological findings between 38 spitzoid (SM) and 99 non-spitzoid melanomas (N-SM) in children and teenagers younger than 18 years referred to UT - MD Anderson Cancer Center during the period 1992-2007. RESULTS: Children with SM were significantly younger than those with N-SM, had more frequently multiple melanocytic nevi, nodular melanoma subtype with vertical growth phase, high Breslow thickness and mitotic rate, positive sentinel lymph node biopsy and more advanced stage. N-SM had more often associated nevus. However, the mortality rate in the SM group was lower (5.9%) than in the N-SM group (12.0%). This study has two major limitations. Small size of both groups does not allow reaching statistically significant differences regarding mortality. Using metastatic potential as an inclusion criterion for SM could result in a sample selection bias of the most aggressive group of SM. CONCLUSIONS: Although SM patients had poorer prognostic factors than N-SM patients, slightly lower mortality rate was detected in the SM group. This less aggressive behaviour could be due to lower potential for widespread distant metastases than conventional melanomas or younger age of children with SM. PMID- 22928629 TI - (alpha-NaYbF4:Tm(3+))/CaF2 core/shell nanoparticles with efficient near-infrared to near-infrared upconversion for high-contrast deep tissue bioimaging. AB - We describe the development of novel and biocompatible core/shell (alpha NaYbF(4):Tm(3+))/CaF(2) nanoparticles that exhibit highly efficient NIR(in) NIR(out) upconversion (UC) for high contrast and deep bioimaging. When excited at ~980 nm, these nanoparticles emit photoluminescence (PL) peaked at ~800 nm. The quantum yield of this UC PL under low power density excitation (~0.3 W/cm(2)) is 0.6 +/- 0.1%. This high UC PL efficiency is realized by suppressing surface quenching effects via heteroepitaxial growth of a biocompatible CaF(2) shell, which results in a 35-fold increase in the intensity of UC PL from the core. Small-animal whole-body UC PL imaging with exceptional contrast (signal-to background ratio of 310) is shown using BALB/c mice intravenously injected with aqueously dispersed nanoparticles (700 pmol/kg). High-contrast UC PL imaging of deep tissues is also demonstrated, using a nanoparticle-loaded synthetic fibrous mesh wrapped around rat femoral bone and a cuvette with nanoparticle aqueous dispersion covered with a 3.2 cm thick animal tissue (pork). PMID- 22928630 TI - Induction, rapid fixation and retention of mutations in vegetatively propagated banana. AB - Mutation discovery technologies have enabled the development of reverse genetics for many plant species and allowed sophisticated evaluation of the consequences of mutagenesis. Such methods are relatively straightforward for seed-propagated plants. To develop a platform suitable for vegetatively propagated species, we treated isolated banana shoot apical meristems with the chemical mutagen ethyl methanesulphonate, recovered plantlets and screened for induced mutations. A high density of GC-AT transition mutations were recovered, similar to that reported in seed-propagated polyploids. Through analysis of the inheritance of mutations, we observed that genotypically heterogeneous stem cells resulting from mutagenic treatment are rapidly sorted to fix a single genotype in the meristem. Further, mutant genotypes are stably inherited in subsequent generations. Evaluation of natural nucleotide variation showed the accumulation of potentially deleterious heterozygous alleles, suggesting that mutation induction may uncover recessive traits. This work therefore provides genotypic insights into the fate of totipotent cells after mutagenesis and suggests rapid approaches for mutation based functional genomics and improvement of vegetatively propagated crops. PMID- 22928631 TI - A synthetic method for palladium-catalyzed stannylation at the 5- and 6-benzo positions of indoles. AB - The stannylation of indole derivatives proceeds in good yields under palladium catalysis (5 mol %) without protection of the indolic nitrogen. The general utility of both PdCl(2)(PhCN)(2)/PCy(3) and Pd(2)dba(3)/PCy(3) as catalytic systems for the stannylation of three indole derivatives, with varying degrees of electron density, is presented. PMID- 22928632 TI - Comparison of quantitative estimation of intracerebral hemorrhage and infarct volumes after thromboembolism in an embolic stroke model. AB - BACKGROUND: Strokes have both ischemic and hemorrhagic components, but most studies of experimental stroke only address the ischemic component. This is likely because investigations of hemorrhagic transformation are hindered by the lack of methods based on unbiased principles for volume estimation. AIMS: We evaluated different methods for estimating the volume of infarcts, hemorrhages, after embolic middle cerebral artery occlusion with or without thrombolysis. METHODS: An experimental thromboembolytic rat model was used in this study. The rats underwent surgery and were placed in two groups. Group 1 was treated with saline, and group 2 was treated with 20 mg/kg recombinant tissue plasminogen activator to promote intracerebral hemorrhages. Stereology, semiautomated computer estimation, and manual erythrocyte counting were used to test the precision and efficiency of determining the size of the infarct and intracerebral hemorrhage. RESULTS: No differences were observed in the infarct volume or amount of bleeding when comparing the three methods of volume estimation. Although semiautomated computer estimation and manual erythrocyte counting provided similar results as the stereological measurements, the stereological method was the most efficient and advantageous. CONCLUSIONS: We found that stereology was the superior method for quantification of hemorrhagic volume, especially for rodent petechial bleeding, which is otherwise difficult to measure. Our results suggest the possibility of measuring both the ischemic and the hemorrhagic components of stroke, two parameters that may be differentially regulated when therapeutic regimens are tested. PMID- 22928633 TI - Off-host aggregation in the non-fed, female brown dog tick, Rhipicephalus sanguineus (Latreille), is induced by tick excreta and enhanced by low relative humidity. AB - We report that Rhipicephalus sanguineus (Ixodida: Ixodidae) faeces and its main component, guanine, act as assembly pheromones in short-range Petri plate bioassays. Arrestment activity in response to guanine was lower than that in response to natural excreta, indicating the presence of other active ingredients in natural excreta. The selective removal of appendages was used to establish the important roles played by the palps and the front pair of legs in the detection of the pheromone. Reaction to chemically pure guanine at varying concentrations occurred without a dose response; thus only the presence of guanine, not a critical amount, is required to induce assembly. Higher speed and intensity of clustering occurred at 33% relative humidity (RH). We conclude that female adults of R. sanguineus are more prone to assemble under dry conditions that match the arid microhabitats preferred by this species and that this tendency allows this tick to reside in human dwellings and dog kennels that maintain standards of comfort at 30-50% RH. Cleaning or removing tick excreta-covered surfaces on which ticks aggregate from within and around human dwellings may prove useful as a means of interfering with the establishment of off-host clusters of R. sanguineus. PMID- 22928634 TI - Quantum mechanical study of pre-dissociation enhancement of linear and nonlinear polarizabilities of (TeO2)(n) oligomers as a key to understanding the remarkable dielectric properties of TeO2 glasses. AB - The effects of intermolecular interactions of TeO(2) molecules in the (TeO(2))(n) oligomers on the polarizability (alpha) and second hyperpolarizability (gamma) are investigated by the use of a density functional method. A significant intermolecular distance dependence of both quantities is observed. The huge dissociation-induced polarizability enhancement is analyzed in terms of the molecular orbital evolution. It is shown that the obtained results can provide a new look at the microscopic origin of the extraordinary dielectric properties of TeO(2) glass. PMID- 22928637 TI - Making do with what we have: Use your bootstraps. PMID- 22928635 TI - Regulatory elements of Caenorhabditis elegans ribosomal protein genes. AB - BACKGROUND: Ribosomal protein genes (RPGs) are essential, tightly regulated, and highly expressed during embryonic development and cell growth. Even though their protein sequences are strongly conserved, their mechanism of regulation is not conserved across yeast, Drosophila, and vertebrates. A recent investigation of genomic sequences conserved across both nematode species and associated with different gene groups indicated the existence of several elements in the upstream regions of C. elegans RPGs, providing a new insight regarding the regulation of these genes in C. elegans. RESULTS: In this study, we performed an in-depth examination of C. elegans RPG regulation and found nine highly conserved motifs in the upstream regions of C. elegans RPGs using the motif discovery algorithm DME. Four motifs were partially similar to transcription factor binding sites from C. elegans, Drosophila, yeast, and human. One pair of these motifs was found to co-occur in the upstream regions of 250 transcripts including 22 RPGs. The distance between the two motifs displayed a complex frequency pattern that was related to their relative orientation.We tested the impact of three of these motifs on the expression of rpl-2 using a series of reporter gene constructs and showed that all three motifs are necessary to maintain the high natural expression level of this gene. One of the motifs was similar to the binding site of an orthologue of POP-1, and we showed that RNAi knockdown of pop-1 impacts the expression of rpl-2. We further determined the transcription start site of rpl-2 by 5' RACE and found that the motifs lie 40-90 bases upstream of the start site. We also found evidence that a noncoding RNA, contained within the outron of rpl 2, is co-transcribed with rpl-2 and cleaved during trans-splicing. CONCLUSIONS: Our results indicate that C. elegans RPGs are regulated by a complex novel series of regulatory elements that is evolutionarily distinct from those of all other species examined up until now. PMID- 22928636 TI - Lewis acid trapping of an elusive copper-tosylnitrene intermediate using scandium triflate. AB - High-valent copper-nitrene intermediates have long been proposed to play a role in copper-catalyzed aziridination and amination reactions. However, such intermediates have eluded detection for decades, preventing the unambiguous assignments of mechanisms. Moreover, the electronic structure of the proposed copper-nitrene intermediates has also been controversially discussed in the literature. These mechanistic questions and controversy have provided tremendous motivation to probe the accessibility and reactivity of Cu(III)-NR/Cu(II)N(*)R species. In this paper, we report a breakthrough in this field that was achieved by trapping a transient copper-tosylnitrene species, 3-Sc, in the presence of scandium triflate. The sufficient stability of 3-Sc at -90 degrees C enabled its characterization with optical, resonance Raman, NMR, and X-ray absorption near edge spectroscopies, which helped to establish its electronic structure as Cu(II)N(*)Ts (Ts = tosyl group) and not Cu(III)NTs. 3-Sc can initiate tosylamination of cyclohexane, thereby suggesting Cu(II)N(*)Ts cores as viable reactants in oxidation catalysis. PMID- 22928638 TI - Dual effects of hydrogen sulphide on focal cerebral ischaemic injury via modulation of oxidative stress-induced apoptosis. AB - 1. Hydrogen sulphide (H2S), one of three signalling gasotransmitters, plays an important role in oxidative stress and apoptosis. However, the effects of H2S on oxidative stress-induced apoptosis in focal cerebral ischaemic injury in rats have not been clarified. 2. In the present study, sodium hydrosulphide (NaHS) was used as the H2S donor. Eighty-four Sprague-Dawley rats were randomly divided into six groups: sham, sham + low-dose (2.8 mg/kg) NaHS, sham + high-dose (11.2 mg/kg) NaHS, infarct, infarct + low-dose NaHS and infarct + high-dose NaHS. The focal cerebral ischaemic model was created by cranially inserting a nylon thread with a rounded tip into an internal carotid artery. Rats were killed 21 h after administration of NaHS. 3. In the infarct + low-dose NaHS compared with infarct group, infarct volume was significantly decreased and injury to the mitochondria in nerve cells was mitigated. Furthermore, significant increases were seen in mitochondrial superoxide dismutase and glutathione peroxidase activity and neuronal bcl-2 protein levels, whereas mitochondrial malondialdehyde content and neuronal bax and caspase 3 protein levels were significantly decreased, in the infarct + low-dose NaHS compared with infarct group. The effects seen in the infarct group were significantly aggravated in the infarct + high-dose NaHS group. 4. The findings of the present study provide novel evidence for the dual effects of H2S on focal cerebral ischaemic injury via modulation of oxidative stress-induced apoptosis. PMID- 22928639 TI - Development and implementation of centralized simulation training: evaluation of feasibility, acceptability and construct validity. AB - WHAT'S KNOWN ON THE SUBJECT? AND WHAT DOES THE STUDY ADD?: A competent urologist should not only have effective technical skills, but also other attributes that would make him/her a complete surgeon. These include team-working, communication and decision-making skills. Although evidence for effectiveness of simulation exists for individual simulators, there is a paucity of evidence for utility and effectiveness of these simulators in training programmes that aims to combine technical and non-technical skills training. This article explains the process of development and validation of a centrally coordinated simulation program (Participants - South-East Region Specialist Registrars) under the umbrella of the British Association for Urological Surgeons (BAUS) and the London Deanery. This program incorporated training of both technical (synthetic, animal and virtual reality models) and non-technical skills (simulated operating theatres). OBJECTIVES: To establish the feasibility and acceptability of a centralized, simulation-based training-programme. Simulation is increasingly establishing its role in urological training, with two areas that are relevant to urologists: (i) technical skills and (ii) non-technical skills. MATERIALS AND METHODS: For this London Deanery supported pilot Simulation and Technology enhanced Learning Initiative (STeLI) project, we developed a structured multimodal simulation training programme. The programme incorporated: (i) technical skills training using virtual-reality simulators (Uro-mentor and Perc-mentor [Symbionix, Cleveland, OH, USA], Procedicus MIST-Nephrectomy [Mentice, Gothenburg, Sweden] and SEP Robotic simulator [Sim Surgery, Oslo, Norway]); bench-top models (synthetic models for cystocopy, transurethral resection of the prostate, transurethral resection of bladder tumour, ureteroscopy); and a European (Aalborg, Denmark) wet-lab training facility; as well as (ii) non-technical skills/crisis resource management (CRM), using SimMan (Laerdal Medical Ltd, Orpington, UK) to teach team-working, decision-making and communication skills. The feasibility, acceptability and construct validity of these training modules were assessed using validated questionnaires, as well as global and procedure/task-specific rating scales. RESULTS: In total 33, three specialist registrars of different grades and five urological nurses participated in the present study. Construct-validity between junior and senior trainees was significant. Of the participants, 90% rated the training models as being realistic and easy to use. In total 95% of the participants recommended the use of simulation during surgical training, 95% approved the format of the teaching by the faculty and 90% rated the sessions as well organized. A significant number of trainees (60%) would like to have easy access to a simulation facility to allow more practice and enhancement of their skills. CONCLUSIONS: A centralized simulation programme that provides training in both technical and non-technical skills is feasible. It is expected to improve the performance of future surgeons in a simulated environment and thus improve patient safety. PMID- 22928641 TI - The wrap-up: a unique forum to support pediatric residents when faced with the death of a child. AB - OBJECTIVE: The project intended to describe the format of the Wrap-up, a unique multidisciplinary guided debriefing following a child's death. Specific feedback from pediatric residents was sought to assess the model. METHODS: The Wrap-ups were timely (within 48 hours of a death), consistent (conducted after each pediatric intensive care unit (PICU) death), multidisciplinary (all care providers were invited), and specifically conducted by someone trained in postdeath facilitation. The role of the conductor was focused on being inclusive, navigating the discussion, diffusing areas of conflict or angst, and managing the tone of the meeting. Resident feedback was obtained by a one-time (May 2010) anonymous internet-based survey, with both open-ended free-text questions and five-point Likert scale queries. Surveyed were all residents rotating though the PICU between 2007 and 2010. Open-ended free-text responses were analyzed using content analysis methods by combining recurrent themes and organizing by main components of the Wrap-up. Quantitative responses, via a five-point Likert scale, were averaged. RESULTS: Between 2007 and 2010, there were 36 PICU deaths. The average age was nine years old. All deaths had an accompanying conductor-led Wrap up occurring, on average, two days after the death. Sixty percent (27/45) of pediatric residents completed the survey. Their qualitative responses showed that the key components (timely, multidisciplinary, and specifically conducted) of the Wrap-ups were valuable. Quantitatively, they agreed or strongly agreed that the consistent Wrap-ups improved end-of-life care, teamwork, stress surrounding the death, and the ability to care for others. CONCLUSION: The Wrap-up, a unique forum for debriefing after a pediatric death, was well-received by residents and assisted them with processing, understanding, and resolving their experience regarding the pediatric death. The Wrap-up was a valuable addition to residents' experience and education in pediatric critical care medicine and can be replicated in other institutions. PMID- 22928640 TI - Use of intravenous acetaminophen (paracetamol) in a pediatric patient at the end of life: case report. AB - BACKGROUND: For the better part of 100 years, acetaminophen (or paracetamol as it is known outside of the United States) has been a common first-line analgesic in pediatrics and is typically well tolerated with minimal side effects. Its use as an anti-pyretic is also well-documented and thus it is used broadly for symptom control in the general pediatric population. DISCUSSION: In pediatric palliative care, acetaminophen is also used as an adjuvant to opioid therapy for pain as well as an anti-pyretic. For many pediatric patients near end-of-life, however, the ability to tolerate oral intake is diminished and rectal suppository administration can be distressing or contraindicated as in the setting of neutropenia, thus limiting use of acetaminophen by its usual routes. In Europe and Australia, an intravenous formulation of acetaminophen has been used for many years and has only recently become available in the United States. CONCLUSION: Here, we describe a case using intravenous acetaminophen in a pediatric patient at the end of life. PMID- 22928642 TI - Preparation of N-alkyl 2-pyridones via a lithium iodide promoted O- to N-alkyl migration: scope and mechanism. AB - An efficient and inexpensive LiI-promoted O- to N-alkyl migration of 2-benzyloxy , 2-allyloxy-, and 2-propargyloxypyridines and heterocycles is reported. The reaction produces the corresponding N-alkyl 2-pyridones and analogues under green, solvent-free conditions in good to excellent yields (30 examples, 20-97% yield). This method has been shown to be intermolecular and requires heat and lithium cation to occur. PMID- 22928643 TI - Pain-related fear is associated with cognitive task avoidance: exploration of the cogniphobia construct in a recurrent headache sample. AB - Pain-related fear is related to self-reported avoidance of physical activities that might induce pain (kinesiophobia), as well as diminished physical performance in non-headache chronic pain. A related concept, "cogniphobia," has been proposed by others, which suggests that individuals high in headache-related fear will avoid cognitive tasks (by putting forth less effort) in an attempt to minimize the risk of bringing on or exacerbating existing headache symptoms. In the present study we explored the psychological, cognitive, and behavioral correlates of cogniphobia in 74 young adults with frequent headaches. Latent variable analysis of the cogniphobia measure revealed a component focused on fear of headache pain and avoidance of behaviors that would induce pain, which was related to sustained attention performance, performance on a symptom validity measure, and pressure pain threshold on the head, consistent with existing kinesiophobia research in non-headache pain. Results have implications for neuropsychological assessment in headache; pain-related fear may be related to diminished effort on neuropsychological tasks. PMID- 22928645 TI - Effect of chemical modification of graphene on mechanical, electrical, and thermal properties of polyimide/graphene nanocomposites. AB - Chemically modified graphene sheets were dispersed in a high-performance polyimide (PI) matrix using polyamic acid (PAA)/graphene nanocomposite as a precursor. PI nanocomposite films with different loadings of graphene sheets were prepared by thermal imidization of the as-prepared PAA/graphene nanocomposites. Graphene oxide (GO) synthesized by Hummer's method was chemically reduced with various reducing agents to produce reduced GOs (rGOs). The incorporation of only 5 wt% GO resulted in an ~12-fold and ~18-fold increase in the tensile strength and tensile modulus of PI, respectively, while the PI/rGO nanocomposites were found to have relatively inferior tensile properties. The superior mechanical properties of the PI/GO nanocomposites were attributed to the good dispersion and effective stress transfer between the polymer and GO sheets, as evidenced by the results from X-ray diffraction (XRD) and morphological studies. Furthermore, the PI/GO nanocomposites exhibited higher loading capacity than PI/rGO. The thermo oxidative stability of PI was also remarkably improved with the addition of both GO and rGOs, but rGOs had a more pronounced effect. The electrical conductivity of PI/rGO nanocomposites was higher than that of PI/GO, suggesting restoration of the graphene basal plane upon the reduction of GO. The highest electrical conductivity was achieved for the l-ascorbic acid reduced GO-reinforced PI nanocomposites. PMID- 22928646 TI - Neutrophil extracellular traps in sterile inflammation: the story after dying? AB - Evidences accumulated that the death of neutrophils are not the end of their missions. The neutrophil extracellular traps (NETs), web-like structure, formed after neutrophils dying contribute greatly to immune defense, in both innate and adaptive immunity. Interestingly, previous studies revealed that the generation and activation of NETs do not only rely on bacteria induction, but also in patients with sterile inflammatory diseases, implying an undeniable correlation between NETs and these diseases. This review summarized the latest findings that the crucial roles of NETs in sterile inflammatory diseases, as well as novel targeted therapy based on these new discoveries. PMID- 22928647 TI - One novel deletion and one splicing mutation of the LKB1 gene in two Chinese patients with Peutz-Jeghers syndrome. AB - Peutz-Jeghers syndrome (PJS) is an uncommon autosomal dominant inherited disease, characterized by the occurrence of gastrointestinal hamartomatous polyps and pigmentation of the lips, buccal mucosa, and digits. Patients with PJS have a significant risk for developing tumors in multiple organs. Germline mutation of the LKB1 gene, which encodes a serine/threonine kinase that acts as a tumor suppressor, has been identified as a cause of PJS. The current study included two Chinese PJS probands and their available family members, as well as 200 unrelated healthy controls for comparison. Genomic DNA was extracted from the peripheral blood of these subjects. The nine coding exons and flanking introns of the LKB1 gene in the two probands and their family members were amplified by polymerase chain reaction (PCR) and then directly sequenced. Mutations identified in the patients were checked in the 200 healthy controls by PCR and denaturing high performance liquid chromatography. Total RNA was extracted from the patient who was found to have a dubious splice site mutation and his available family members. Reverse transcription PCR was performed to identify the abnormal splicing caused by the splice site mutation. Two types of mutations were detected in the two PJS families. One type was a previously unreported 30-base-pair deletion in exon 4, and the other was an intron mutation that affected splicing. None of the 200 controls had either of these two types of mutations. The results provide support that mutation of the LKB1 gene is a cause of PJS, and expand the spectrum of LKB1 gene mutations. PMID- 22928644 TI - Trichodesmium--a widespread marine cyanobacterium with unusual nitrogen fixation properties. AB - The last several decades have witnessed dramatic advances in unfolding the diversity and commonality of oceanic diazotrophs and their N2 -fixing potential. More recently, substantial progress in diazotrophic cell biology has provided a wealth of information on processes and mechanisms involved. The substantial contribution by the diazotrophic cyanobacterial genus Trichodesmium to the nitrogen influx of the global marine ecosystem is by now undisputable and of paramount ecological importance, while the underlying cellular and molecular regulatory physiology has only recently started to unfold. Here, we explore and summarize current knowledge, related to the optimization of its diazotrophic capacity, from genomics to ecophysiological processes, via, for example, cellular differentiation (diazocytes) and temporal regulations, and suggest cellular research avenues that now ought to be explored. PMID- 22928648 TI - Designing for sustainability: ergonomics--carpe diem. AB - Sustainability is a global issue that has worldwide attention but the role of ergonomics in designing for sustainability is poorly understood and seldom considered. An analysis of the literature on ergonomics, design and sustainability was conducted via a search of electronic databases: Scopus, Business Source Complete, Google Scholar, Emerald Publishing, Academic Search Premiere, Web of Science, Discover and Ergonomics Abstracts, for the years 1995 2012. A total of 1934 articles fulfilled the search criteria, but content analysis of the abstracts indicated that only 14 refereed articles addressed the main search criteria. Of those seven were in ergonomics journals and seven were in other journals (and were not written by ergonomists). It is concluded that the contribution of ergonomics to sustainability and sustainable design has been limited, even though the goals of sustainability and ergonomics are congruent. Ergonomists have not been at the forefront of research contributing to sustainability - and it is time for them to 'seize the day' - 'carpe diem'. PRACTITIONER SUMMARY: This literature review shows that ergonomics contribution to sustainability is limited but since there is congruence between the disciplines it calls for ergonomists to become more involved and to seize the day - carpe diem. PMID- 22928649 TI - Infant brain structures, executive function, and attention deficit/hyperactivity problems at preschool age. A prospective study. AB - BACKGROUND: Neuroimaging findings have provided evidence for a relation between variations in brain structures and attention deficit/hyperactivity disorder (ADHD). However, longitudinal neuroimaging studies are typically confined to children who have already been diagnosed with ADHD. In a population-based study, we aimed to characterize the prospective association between brain structures measured during infancy and executive function and attention deficit/hyperactivity problems assessed at preschool age. METHODS: In the Generation R Study, the corpus callosum length, the gangliothalamic ovoid diameter (encompassing the basal ganglia and thalamus), and the ventricular volume were measured in 784 6-week-old children using cranial postnatal ultrasounds. Parents rated executive functioning at 4 years using the behavior rating inventory of executive function-preschool version in five dimensions: inhibition, shifting, emotional control, working memory, and planning/organizing. Attention deficit/hyperactivity problems were assessed at ages 3 and 5 years using the child behavior checklist. RESULTS: A smaller corpus callosum length during infancy was associated with greater deficits in executive functioning at 4 years. This was accounted for by higher problem scores on inhibition and emotional control. The corpus callosum length during infancy did not predict attention deficit/hyperactivity problem at 3 and 5 years, when controlling for the confounders. We did not find any relation between gangliothalamic ovoid diameter and executive function or Attention deficit/hyperactivity problem. CONCLUSIONS: Variations in brain structures detectible in infants predicted subtle impairments in inhibition and emotional control. However, in this population-based study, we could not demonstrate that early structural brain variations precede symptoms of ADHD. PMID- 22928650 TI - A meta-analysis of the accuracy and precision of the ultrasonic cardiac output monitor (USCOM). AB - The ultrasonic cardiac output monitor is a non-invasive, continuous-wave Doppler monitor that can be used to measure cardiac output. Its accuracy and precision in peri-operative and critical care has been assessed with varied results. We conducted a meta-analysis to calculate a pooled mean bias, precision and percentage error for this device. Six studies were suitable for inclusion into a pooled parametric analysis consisting of 320 measurements. The mean weighted bias was -0.39 l.min(-1) (95% CI -0.25 to -0.53 l.min(-1) ), precision 1.27 l.min(-1) and percentage error 42.7% (95% CI 38.5-46.9%). The ultrasonic cardiac output monitor achieved similar agreement with bolus thermodilution to that of other minimally invasive methods of peri-operative cardiac output monitoring, and may have a useful role in cardiac output monitoring. PMID- 22928651 TI - Spinal-peripheral neurostimulation (SPN) for bilateral postherniorrhaphy pain: a case report. AB - OBJECTIVE: ?? Postherniorrhaphy pain is a not uncommon, and difficult to treat, pain condition. Success with different methods of neurostimulation has been reported in the literature in the last decade. We assess the use of a new modality of neuromodulation--??spinal-??peripheral neurostimulation (SPN). MATERIALS AND METHODS: ?? We report the results of treatment of a patient with bilateral, intractable postherniorrhaphy pain with SPN. RESULTS: ?? Significant reduction in pain and decrease in opioid consumption have been achieved. CONCLUSION: ?? SPN can be an effective treatment for postherniorrhaphy pain resistant to conservative management. PMID- 22928652 TI - Structural characterization of an arabinogalactan-protein from the fruits of Lycium ruthenicum. AB - A water-soluble arabinogalactan-protein (AGP), designated LRGP3, was isolated from the fruits of Lycium ruthenicum Murr. Its average molecular weight was 75.6 kDa. Monosaccharide composition analysis revealed that it was composed of rhamnose, arabinose, and galactose in a molar ratio of 1.0:14.9:10.4. Protein accounted for 1.7% of the AGP and was rich in hydroxyproline. On the basis of monosaccharide composition, partial acid hydrolysis, methylation analysis, ESI MS, and NMR spectroscopy, LRGP3 was characterized as a highly branched polysaccharide with a backbone of (1->3)-linked beta-D-galactopyranosyl residues, many of which were substituted at the O-6 position by galactosyl or arabinosyl groups. The branches were composed of (1->5)-linked arabinose, (1->2)-linked arabinose, (1->6)-linked galactose, (1->3)-linked galactose, and (1->2,4)-linked rhamnose, and the major nonreducing termini were alpha-L-arabinofuranosyl residues. PMID- 22928653 TI - Religious involvement and physical and emotional functioning among African Americans: the mediating role of religious support. AB - OBJECTIVES: Religious social support may in part account for the relationship between religious involvement and health-related outcomes. African Americans, on average, tend to have relatively high levels of religious involvement, and suffer a higher burden of health conditions than other groups. This study aimed to examine whether religious social support played a mediating role between religious involvement and physical and emotional functioning, and depressive symptoms. DESIGN: The study used a cross sectional telephone survey among a national probability sample of African Americans (n = 803). Study participants completed telephone interviews and data were analysed using structural equation modelling. MAIN OUTCOME MEASURES: Physical and emotional functioning and depressive symptoms served as study outcomes. RESULTS: In both the emotional functioning and depressive symptoms models, the indirect effect test from religious behaviours to emotional religious support indicated evidence for mediation. There was no mediation for the physical functioning model. CONCLUSION: Implications for faith-based health promotion interventions are discussed. PMID- 22928655 TI - MRI-based brain structure volumes in temporal lobe epilepsy patients and their unaffected siblings: a preliminary study. AB - INTRODUCTION: Investigating the heritability of brain structure may be useful in simplifying complicated genetic studies in temporal lobe epilepsy (TLE). A preliminary study is presented to determine if volume deficits of candidate brain structures present at a higher rate in unaffected siblings than controls subjects. METHODS: T1-weighted MR images was acquired for 28 TLE patients, a same sex unaffected sibling of 12 of these and 28 normal controls. Selected brain structure volumes were measured using an automated whole brain segmentation technique. Candidate brain structure endophenotypes were determined and group differences were investigated between (1) controls and patients and (2) controls and siblings. ICC's were used to measure the quantitative volumetric association within each sibling pair. RESULTS: TLE patients demonstrated a significantly lower cerebral white matter, bilateral hippocampus, thalamus, and left entorhinal cortex volumes when compared with controls. A significant deficit in cerebral white matter (CWM) was common to patient and nonaffected siblings when compared with controls. Furthermore, a significant correlation was revealed between patients and siblings in CWM and bilateral thalamus. CONCLUSION: The findings suggest an overlap in the neurodevelopmental genes responsible for both brain structure and the expression of the disease. Further work is ongoing to confirm these findings. PMID- 22928656 TI - The human being's spiritual experiences in a mental healthcare context; their positive and negative meaning and impact on health--a hermeneutic approach. AB - The study aims at describing different meanings of patients' spiritual experiences and their impact on patients' health in mental healthcare. The different contents of patients' spiritual experiences are often understood by caregivers as the expressions of patients' religious speculation. The study has a hermeneutic approach, inspired by Gadamer. Its theoretical pre-understanding is Caring Science perspective, according to which the human being is a unity of body, psyche and spirit. The sources are 32 stories selected from William James' book (1956) The Varieties of Religious Experience. They are hermeneutically interpreted and discussed in the light of international research on patients' spirituality to gain a deeper understanding. The results are three main themes: (i) the positive meanings of spirituality, (ii) the negative meanings of spirituality and (iii) the both negative and positive meaning of spirituality. Therefore, it is a very important task for mental caregivers to address patients' spiritual dimension to help them adequately. PMID- 22928654 TI - Probiotics to improve outcomes of colic in the community: protocol for the Baby Biotics randomised controlled trial. AB - BACKGROUND: Infant colic, characterised by excessive crying/fussing for no apparent cause, affects up to 20% of infants under three months of age and is a great burden to families, health professionals and the health system. One promising approach to improving its management is the use of oral probiotics. The Baby Biotics trial aims to determine whether the probiotic Lactobacillus reuteri DSM 17938 is effective in reducing crying in infants less than three months old (<13.0 weeks) with infant colic when compared to placebo. METHODS/DESIGN: DESIGN: Double-blind, placebo-controlled randomised trial in Melbourne, Australia. PARTICIPANTS: 160 breast and formula fed infants less than three months old who present either to clinical or community services and meet Wessel's criteria of crying and/or fussing. INTERVENTION: Oral once-daily Lactobacillus reuteri (1x108 cfu) versus placebo for one month. PRIMARY OUTCOME: Infant crying/fussing time per 24 hours at one month. SECONDARY OUTCOMES: i) number of episodes of infant crying/fussing per 24 hours and ii) infant sleep duration per 24 hours (at 7, 14, 21, 28 days and 6 months); iii) maternal mental health scores, iv) family functioning scores, v) parent quality adjusted life years scores, and vi) intervention cost-effectiveness (at one and six months); and vii) infant faecal microbiota diversity, viii) infant faecal calprotectin levels and ix) Eschericia coli load (at one month only). ANALYSIS: Primary and secondary outcomes for the intervention versus control groups will be compared with t tests and non-parametric tests for continuous data and chi squared tests for dichotomous data. Regression models will be used to adjust for potential confounding factors. Intention-to-treat analysis will be applied. DISCUSSION: An effective, practical and acceptable intervention for infant colic would represent a major clinical advance. Because our trial includes breast and formula-fed babies, our results should generalise to most babies with colic. If cost effective, the intervention's simplicity is such that it could be widely taken up as a new standard of care in the primary and secondary care sectors. TRIAL REGISTRATION: Current Controlled Trials ISRCTN95287767. PMID- 22928657 TI - Nanometer-scale infrared spectroscopy of heterogeneous polymer nanostructures fabricated by tip-based nanofabrication. AB - There is a significant need for chemical identification and chemical imaging of nanofabricated structures and devices, especially for multiple materials integrated at the nanometer scale. Here we present nanofabrication, chemical identification, and nanometer-scale chemical imaging of polymer nanostructures with better than 100 nm spatial resolution. Polymer nanostructures of polyethylene, polystyrene, and poly(3-dodecylthiophene-2,5-diyl) were fabricated by tip-based nanofabrication. Nanometer-scale infrared measurements using atomic force microscopy infrared spectroscopy (AFM-IR) obtained quantitative chemical spectra of these nanostructures. We show chemical imaging of intersecting patterns of nanometer-scale polymer lines of different chemical compositions. The results indicate that for closely packed heterogeneous nanostructures, the spatial resolution of AFM-IR is not limited by nanometer-scale thermal diffusion, but is instead limited by the cantilever sensitivity and the signal-to-noise ratio of the AFM-IR system. PMID- 22928658 TI - Gender differences in the incentive salience of adult and infant faces. AB - Facial appearance can motivate behaviour and elicit activation of brain circuits putatively involved in reward. Gender differences have been observed for motivation to view beauty in adult faces--heterosexual women are motivated by beauty in general, while heterosexual men are motivated to view opposite-sex beauty alone. Although gender differences have been observed in sensitivity to infant cuteness, infant faces appear to hold equal incentive salience among men and women. In the present study, we investigated the incentive salience of attractiveness and cuteness in adult and infant faces, respectively. We predicted that, given alternative viewing options, gender differences would emerge for motivation to view infant faces. Heterosexual participants completed a "pay-per view" key-press task, which allowed them to control stimulus duration. Gender differences were found such that infants held greater incentive salience among women, although both sexes differentiated infant faces based on cuteness. Among adult faces, men exerted more effort than women to view opposite-sex faces. These findings suggest that, contrary to previous reports, gender differences do exist in the incentive salience of infant faces as well as opposite-sex faces. PMID- 22928659 TI - How (European) currency and means of payment may be helpful in the daily practical assessment of thickness of psoriasis plaques: a vignette about a haptic 'numismatic' approach. PMID- 22928660 TI - Belatacept: in adult kidney transplant recipients. AB - Belatacept is a second-generation cytotoxic T-lymphocyte-associated antigen-4-Ig fusion protein, which down-regulates T-cell response, and is used in the prophylaxis of organ rejection in adults receiving a kidney transplant. This article reviews the pharmacologic properties of belatacept and its clinical efficacy and tolerability in kidney transplant recipients. In the well designed, phase III trials BENEFIT and BENEFIT-EXT (in patients receiving kidneys from living/standard-criteria or extended-criteria donors, respectively), a belatacept based treatment regimen was noninferior to a cyclosporine (ciclosporin)-based regimen with regard to patient and graft survival and acute graft rejection rate, and was significantly superior to the cyclosporine-based regimen with regard to the rate of renal impairment (in BENEFIT only), at 12 months. Belatacept-based treatment showed long-term efficacy and remained effective after 2, 3, and 4 years with regard to these endpoints. Belatacept was generally well tolerated in patients with kidney transplants from living, standard-criteria, or extended criteria donors. The most serious adverse events that have been reported with belatacept treatment are post-transplant lymphoproliferative disorder, other malignancies, and serious infections. At month 12, the incidence of new-onset diabetes mellitus after transplant was significantly lower with belatacept than with cyclosporine, and belatacept recipients had significantly lower blood pressure and a significantly smaller increase in certain lipid levels than cyclosporine recipients. PMID- 22928661 TI - Cyclin-dependent kinase modulators and cancer therapy. AB - The cell cycle of eukaryotic cells varies greatly from species to species and tissue to tissue. Since an erroneous control of the cell cycle can have disastrous consequences for cellular life, there are genetically programmed signals, so-called cell cycle checkpoints, which ensure that all events of each stage are completed before beginning the next phase. Among the numerous molecules involved in this process, the most important are the cyclin-dependent kinases (CDKs), proteins that are activated only when bound to cyclins (regulatory proteins with fluctuating concentrations). In general, more CDKs are overexpressed in cancer cells than in normal cells, which explains why cancer cells divide uncontrollably. Succeeding in modulating CDK activity with pharmacological agents could result in decreasing the abnormal proliferation rate of cancer cells. This review offers an overview of CDK-cyclin complexes in relation to different cell cycle phases, an analysis of CDK activation and inhibition of molecular mechanisms, and an extensive report, including clinical trials, regarding four new drugs acting as CDK modulators: alvocidib, P276-00, SNS-032 and seliciclib. PMID- 22928662 TI - Immunogenicity assessment of recombinant human c1-inhibitor: an integrated analysis of clinical studies. AB - BACKGROUND AND OBJECTIVE: Recombinant human C1-inhibitor (rhC1INH) is used to treat acute angioedema attacks in hereditary angioedema (HAE) due to a genetic C1INH deficiency. Recombinant proteins in general may induce antibody responses and therefore evaluation of such responses in the target population is an essential step in the clinical development program of a recombinant protein. Here we report the assessment of the immunogenicity of rhC1INH in symptomatic HAE patients. METHODS: Blood samples collected before and after administration of rhC1INH were tested for antibodies against plasma-derived (pd) or rhC1INH, or against host-related impurities (HRI). Above cut-off screening results were confirmed with displacement assays, and also tested for neutralizing anti-C1INH antibodies. Finally, the relation of antibodies to clinical efficacy and safety of rhC1INH was analyzed. RESULTS: Data from 155 HAE patients who received 424 treatments with rhC1INH were analyzed. 1.5% of all pre-exposure tests and 1.3% of all post-exposure tests were above the cut-off level in the screening assay for anti-C1INH antibodies. Six patients (3.9%) had anti-rhC1INH antibodies positive in the confirmatory assay. In two patients, confirmed antibodies were pre existing with no increase post-exposure; in three patients, the antibodies occurred on a single occasion post-exposure; and in one patient, on subsequent occasions post-exposure. Neutralizing anti-pdC1INH antibodies were not found. Anti-HRI antibodies in the screening assay occurred in <0.7% of the tests before exposure to rhC1INH, in <1.9% after first exposure and in <3.1% after repeat treatment with rhC1INH. Five patients had anti-HRI antibodies positive in the confirmatory assay. In one patient, the antibodies were pre-existing, whereas in three of the 155 rhC1INH-treated patients (1.9%), confirmed anti-HRI antibodies occurred at more time points. Antibody findings were not associated with altered efficacy of rhC1INH or adverse events. CONCLUSION: These results indicate a reassuring immunosafety profile of rhC1INH as a treatment for acute HAE attacks. PMID- 22928664 TI - Interrogating near-infrared electrogenerated chemiluminescence of Au25(SC2H4Ph)18(+) clusters. AB - The electrochemistry, near-infrared photoluminescence (NIR-PL) spectroscopy, and electrogenerated chemiluminescence (ECL) of Au(25)(SC(2)H(4)Ph)(18)(+)C(6)F(5)CO(2)(-) (Au(25)(+)) clusters were investigated. For the first time, NIR-ECL emission was observed in both annihilation and coreactant paths. Our newly developed spooling spectroscopy was employed during the ECL evolution and devolution processes along with explicit NIR-PL spectroscopy to elucidate light generation mechanisms. It was discovered that the electronic relaxation of the Au(25)(-) excited state to the ground state plays a key role in giving off ECL at 893 nm, while intermediate, strong, and weak NIR-PL emissions at 719/820, 857, and 1080 nm can be attributed to the excited states higher than the HOMO-LUMO gap, across the HOMO-LUMO gap, and of semi-rings, respectively. PMID- 22928665 TI - Advances in understanding of chemical bonding: inputs from experimental and theoretical charge density analysis. AB - The development of charge density analysis has undergone a major renaissance in the last two decades. In recent years, the characterization of bonding features associated with atoms in molecules and in crystals has been explored using high resolution X-ray diffraction data (laboratory or synchrotron) complemented by high level ab initio theoretical calculations. The extraction of one electron topological properties, namely, electrostatic charges, dipole moment and higher moments, electrostatic potential, electric field gradients, in addition to evaluation of the local kinetic and potential energy densities, have contributed toward an understanding of the electron density distributions in molecular solids. New topological descriptors, namely, the source function (SF) and electron localization function (ELF) provide additional information as regards characterization of the topology of the electron density. In addition, delocalization indices have also been developed to account for bonding features pertinent to M-M bonds. The evaluation of these properties have contributed significantly toward the understanding of intra- and intermolecular bonding features in organic, inorganic, and biomolecules in the crystalline phase, with concomitant applications in the understanding of chemical reactivity and material/biological properties. In recent years, the focus has strongly shifted toward the understanding of structure-property relationships in organometallic complexes containing labile M-C bonds in the crystal structure with subsequent implications in catalysis. This perspective aims to highlight the major developments in electron density measurements in the past few years and provides pointers directed toward the potential use of this technique in future applications for an improved understanding of chemical bonding in systems that have been unexplored. PMID- 22928663 TI - Inhibition of cytosolic Phospholipase A2 prevents prion peptide-induced neuronal damage and co-localisation with Beta III Tubulin. AB - BACKGROUND: Activation of phospholipase A2 (PLA2) and the subsequent metabolism of arachidonic acid (AA) to prostaglandins have been shown to play an important role in neuronal death in neurodegenerative disease. Here we report the effects of the prion peptide fragment HuPrP106-126 on the PLA2 cascade in primary cortical neurons and translocation of cPLA2 to neurites. RESULTS: Exposure of primary cortical neurons to HuPrP106-126 increased the levels of phosphorylated cPLA2 and caused phosphorylated cPLA2 to relocate from the cell body to the cellular neurite in a PrP-dependent manner, a previously unreported observation. HuPrP106-126 also induced significant AA release, an indicator of cPLA2 activation; this preceded synapse damage and subsequent cellular death. The novel translocation of p-cPLA2 postulated the potential for exposure to HuPrP106-126 to result in a re-arrangement of the cellular cytoskeleton. However p-cPLA2 did not colocalise significantly with F-actin, intermediate filaments, or microtubule associated proteins. Conversely, p-cPLA2 did significantly colocalise with the cytoskeletal protein beta III tubulin. Pre-treatment with the PLA2 inhibitor, palmitoyl trifluoromethyl ketone (PACOCF3) reduced cPLA2 activation, AA release and damage to the neuronal synapse. Furthermore, PACOCF3 reduced expression of p cPLA2 in neurites and inhibited colocalisation with beta III tubulin, resulting in protection against PrP-induced cell death. CONCLUSIONS: Collectively, these findings suggest that cPLA2 plays a vital role in the action of HuPrP106-126 and that the colocalisation of p-cPLA2 with beta III tubulin could be central to the progress of neurodegeneration caused by prion peptides. Further work is needed to define exactly how PLA2 inhibitors protect neurons from peptide-induced toxicity and how this relates to intracellular structural changes occurring in neurodegeneration. PMID- 22928666 TI - Positive crosstalk between arginase-II and S6K1 in vascular endothelial inflammation and aging. AB - Augmented activities of both arginase and S6K1 are involved in endothelial dysfunction in aging. This study was to investigate whether or not there is a crosstalk between arginase and S6K1 in endothelial inflammation and aging in senescent human umbilical vein endothelial cells and in aging mouse models. We show increased arginase-II (Arg-II) expression/activity in senescent endothelial cells. Silencing Arg-II in senescent cells suppresses eNOS-uncoupling, several senescence markers such as senescence-associated-beta-galactosidase activity, p53 S15, p21, and expression of vascular adhesion molecule-1 (VCAM1) and intercellular adhesion molecule-1 (ICAM1). Conversely, overexpressing Arg-II in nonsenescent cells promotes eNOS-uncoupling, endothelial senescence, and enhances VCAM1/ICAM1 levels and monocyte adhesion, which are inhibited by co-expressing superoxide dismutase-1. Moreover, overexpressing S6K1 in nonsenescent cells increases, whereas silencing S6K1 in senescent cells decreases Arg-II gene expression/activity through regulation of Arg-II mRNA stability. Furthermore, S6K1 overexpression exerts the same effects as Arg-II on endothelial senescence and inflammation responses, which are prevented by silencing Arg-II, demonstrating a role of Arg-II as the mediator of S6K1-induced endothelial aging. Interestingly, mice that are deficient in Arg-II gene (Arg-II(-/-) ) are not only protected from age-associated increase in Arg-II, VCAM1/ICAM1, aging markers, and eNOS-uncoupling in the aortas but also reveal a decrease in S6K1 activity. Similarly, silencing Arg-II in senescent cells decreases S6K1 activity, demonstrating that Arg-II also stimulates S6K1 in aging. Our study reveals a novel mechanism of mutual positive regulation between S6K1 and Arg-II in endothelial inflammation and aging. Targeting S6K1 and/or Arg-II may decelerate vascular aging and age-associated cardiovascular disease development. PMID- 22928668 TI - The surgeon as educator: fundamentals of faculty training in surgical specialties. AB - OBJECTIVE: To explore faculty training in the field of surgical specialities with a focus on the educational aspect of faculty training. Teaching is an important commitment for academic surgeons alongside duties of patient care, research and continuing professional development. Educating surgical faculty in the skills of teaching is becoming increasingly important and the realisation that clinical expertise does not necessarily translate to teaching expertise has led to the notion that faculty members require formal training in teaching methods and educational theory to teach effectively. The aim of faculty training or development is to increase knowledge and skills in teaching, research and administration of faculty members. MATERIALS AND METHODS: A range of resources, e.g. journal articles, books and online literature was reviewed to investigate faculty development programmes in surgery. Various issues were addressed, e.g. the need for faculty development, evaluating the various types of training programmes and their outcomes, and exploring barriers to faculty training. Recommendations were provided based on the findings. RESULTS: There is increased recognition that faculty members require basic training in educational theory and teaching skills to teach effectively. Most faculty training programmes are workshops and short courses, which use participant satisfaction as an outcome measure. However, there is growing consensus that longer term interventions, e.g. seminar series, longitudinal programmes and fellowships, produce more sustainable change in learning, behaviour and organisational culture. Barriers to faculty development include lack of protected time, reward and recognition for teaching. CONCLUSION: Recommendations are made including better documentation of faculty training interventions within surgery, further investigation into the effectiveness of long- vs short-term interventions, improved methodology, and increased recognition and reward for educational accomplishments. PMID- 22928667 TI - One-pot phosphine-catalyzed syntheses of quinolines. AB - In this study we developed an efficient one-pot procedure for the preparation of 3-substituted and 3,4-disubstituted quinolines from stable starting materials (activated acetylenes reacting with o-tosylamidobenzaldehydes and o tosylamidophenones, respectively) under mild conditions. The reaction appears to operate under a general base catalysis mechanism, instigated by the beta phosphonium enoate alpha-vinyl anion generated in situ through nucleophilic addition of PPh(3) to the activated alkyne. Michael addition of the deprotonated tosylamides to the activated alkynes and subsequent rapid aldol cyclization led to the formation of labile N-tosyldihydroquinoline intermediates. Driven by aromatization, detosylation of the dihydroquinoline intermediates occurred readily in the presence of dilute aqueous HCl to give the final quinoline products. PMID- 22928669 TI - Prediction of vascular risk after stroke - protocol and pilot data of the Prospective Cohort with Incident Stroke (PROSCIS). AB - RATIONALE: Long-term risk of vascular disease is substantially increased after stroke with several models proposed to predict subsequent stroke and other vascular events after an index event. However, recent validation studies demonstrate limited predictive properties of available prognostic models. AIMS: We aim to determine prediction models of different complexity for the combined vascular end-point of stroke, myocardial infarction, and vascular death at three years after first-ever stroke. An independent external validation of the developed models will be performed. DESIGN: Prospective observational hospital based cohort study of patients after first-ever stroke. METHODS: The new predictive models will be developed using the following steps: (1) Development of a basic score based on clinical history data (e.g. hypertension, myocardial infarction, and atrial fibrillation); (2) Development of an advanced score including additional factors such as blood-based biomarkers and results of vascular imaging; (3) Comparing the models fit using different methods (discrimination, calibration); (4) Assessment of clinical utility of an advanced score using methods based on reclassification tables (e.g. net reclassification improvement, integrated discrimination improvement, decision curve analysis); and (5) Investigation of external validity. OUTCOMES: Primary outcome is a combined vascular end-point composed of stroke, myocardial infarction, and vascular death at three-years after stroke. Furthermore, each component of the composite end point will be investigated individually and the patterns and time points of risk transitions between vascular end-points and stroke sub-types will be determined. PMID- 22928670 TI - The Stroop task: comparison between the original paradigm and computerized versions in children and adults. AB - The Stroop task has a long-standing history in psychological research and diagnostics, and many variants have emerged. Computerized versions have recently gained popularity because of their applicability in brain-imaging studies. It remains unclear, however, whether computerized versions are content valid with reference to the original task. We compare the performance in the original task with two computerized versions. All three versions show high test-retest reliability and are able to elicit interference effects, but to varying degrees. However, performances in the computerized versions and in the original task do not correlate. The transition from oral to manual response and from listed to single stimulus presentation seems not only to diminish the interference effect, but also to alter its nature in such a way that it no longer looks genuinely "Stroop-like". These findings have important clinical implications on the use and interpretation of computerized Stroop tasks in children and adults. PMID- 22928671 TI - Obstetric hemorrhage-related maternal mortality and morbidity. PMID- 22928672 TI - Renal function, fitness, and mortality in women. PMID- 22928673 TI - Cues and regulatory pathways involved in natural competence and transformation in pathogenic and environmental Gram-negative bacteria. AB - Bacterial genomics is flourishing, as whole-genome sequencing has become affordable, readily available and rapid. As a result, it has become clear how frequently horizontal gene transfer (HGT) occurs in bacteria. The potential implications are highly significant because HGT contributes to several processes, including the spread of antibiotic-resistance cassettes, the distribution of toxin-encoding phages and the transfer of pathogenicity islands. Three modes of HGT are recognized in bacteria: conjugation, transduction and natural transformation. In contrast to the first two mechanisms, natural competence for transformation does not rely on mobile genetic elements but is driven solely by a developmental programme in the acceptor bacterium. Once the bacterium becomes competent, it is able to take up DNA from the environment and to incorporate the newly acquired DNA into its own chromosome. The initiation and duration of competence differ significantly among bacteria. In this review, we outline the latest data on representative naturally transformable Gram-negative bacteria and how their competence windows differ. We also summarize how environmental cues contribute to the initiation of competence in a subset of naturally transformable Gram-negative bacteria and how the complexity of the niche might dictate the fine tuning of the competence window. PMID- 22928674 TI - Defining the developmental parameters of temper loss in early childhood: implications for developmental psychopathology. AB - BACKGROUND: Temper modulation problems are both a hallmark of early childhood and a common mental health concern. Thus, characterizing specific behavioral manifestations of temper loss along a dimension from normative misbehaviors to clinically significant problems is an important step toward identifying clinical thresholds. METHODS: Parent-reported patterns of temper loss were delineated in a diverse community sample of preschoolers (n = 1,490). A developmentally sensitive questionnaire, the Multidimensional Assessment of Preschool Disruptive Behavior (MAP-DB), was used to assess temper loss in terms of tantrum features and anger regulation. Specific aims were: (a) document the normative distribution of temper loss in preschoolers from normative misbehaviors to clinically concerning temper loss behaviors, and test for sociodemographic differences; (b) use Item Response Theory (IRT) to model a Temper Loss dimension; and (c) examine associations of temper loss and concurrent emotional and behavioral problems. RESULTS: Across sociodemographic subgroups, a unidimensional Temper Loss model fit the data well. Nearly all (83.7%) preschoolers had tantrums sometimes but only 8.6% had daily tantrums. Normative misbehaviors occurred more frequently than clinically concerning temper loss behaviors. Milder behaviors tended to reflect frustration in expectable contexts, whereas clinically concerning problem indicators were unpredictable, prolonged, and/or destructive. In multivariate models, Temper Loss was associated with emotional and behavioral problems. CONCLUSIONS: Parent reports on a developmentally informed questionnaire, administered to a large and diverse sample, distinguished normative and problematic manifestations of preschool temper loss. A developmental, dimensional approach shows promise for elucidating the boundaries between normative early childhood temper loss and emergent psychopathology. PMID- 22928675 TI - Sustaining person-environment fit with a changing workforce. AB - Data on health and lifestyle from the Naval service cohort study of occupational stress form the background to a discussion of employee health and the sustainability of a healthy workforce in relation to secular changes - in particular, the increasing prevalence of obesity. One thousand two hundred and forty-one Naval personnel returned questionnaires in 2007 and 2011 and reported their body mass index (BMI), alcohol consumption and smoking, general health and health conditions such as back pain and high blood pressure on both occasions. Health risk due to high BMI and waist circumference in 2011 was predicted by low participation in exercise in 2007. Those performing physically demanding work in 2007 were more likely to be in the 'no risk' category in 2011. High BMI in 2007 was associated with the development of back pain, musculoskeletal conditions and high blood pressure in 2011. The findings are discussed in relation to two aspects of sustainability: the sustainability of current ergonomics practice in relation to health and safety; and the role of ergonomics in sustaining a healthy and productive workforce. PRACTITIONER SUMMARY: Evidence is presented for the benefits of exercise in sustaining employee health and for an association between a high BMI and a number of common health complaints that have traditionally been tackled through workplace ergonomics. This evidence can be used to support the development of workplace design concepts that promote physical activity. PMID- 22928676 TI - Plasmacytoid dendritic cells control B cell-derived IL-10 production. AB - Plasmacytoid dendritic cells (pDC) exert contradictory roles: they represent major players in the pathogenesis of type I interferon-mediated autoimmunity but contribute to tolerance in the transplant setting. In this study we describe pDC as cellular enhancers of B cell-derived IL-10 production, a mechanism recently described as relevant in maintaining peripheral tolerance. Our data demonstrate that in human peripheral blood pDC augment IL-10 production in B cells in response to TLR7 and -9 ligands. They further show that pDC themselves produce IL 10 in response to TLR stimulation, most prominently after triggering of TLR7. Additionally, the data indicate that the positive regulatory effect of pDC on IL 10 production is not due to type I interferon production or other soluble factors. We conclude that pDC/B cell contact is essential for B cell-mediated immune suppression. PMID- 22928677 TI - Bronchial intubation could be detected by the visual stethoscope techniques in pediatric patients. AB - BACKGROUND: We created a system that allows the visualization of breath sounds (visual stethoscope). AIM: We compared the visual stethoscope technique with auscultation for the detection of bronchial intubation in pediatric patients. METHODS: In the auscultation group, an anesthesiologist advanced the tracheal tube, while another anesthesiologist auscultated bilateral breath sounds to detect the change and/or disappearance of unilateral breath sounds. In the visualization group, the stethoscope was used to detect changes in breath sounds and/or disappearance of unilateral breath sounds. The distance from the edge of the mouth to the carina was measured using a fiberoptic bronchoscope. RESULTS: Forty pediatric patients were enrolled in the study. At the point at which irregular breath sounds were auscultated, the tracheal tube was located at 0.5 +/ 0.8 cm on the bronchial side from the carina. When a detectable change of shape of the visualized breath sound was observed, the tracheal tube was located 0.1 +/ 1.2 cm on the bronchial side (not significant). At the point at which unilateral breath sounds were auscultated or a unilateral shape of the visualized breath sound was observed, the tracheal tube was 1.5 +/- 0.8 or 1.2 +/- 1.0 cm on the bronchial side, respectively (not significant). CONCLUSIONS: The visual stethoscope allowed to display the left and the right lung sound simultaneously and detected changes of breath sounds and unilateral breath sound as a tracheal tube was advanced. PMID- 22928680 TI - Haematology and biochemistry of warru (Petrogale lateralis MacDonnell Ranges race) in captivity and the wild. AB - OBJECTIVE: Use haematology, biochemistry and protein electrophoresis analyses to establish reference values for, and describe the health status of, wild and captive colonies of critically endangered warru (black-footed rock-wallaby: Petrogale lateralis MacDonnell Ranges race). METHODS: Blood samples were taken from warru in three wild colonies (Alalka, Kalka, New Well) in the A nangu Pitjantjatjara Yankunytjatjara Lands in north-west South Australia (SA) and from captive animals at Monarto Zoo, SA. General haematology, serum biochemistry and protein electrophoresis analyses were conducted and results used to establish reference ranges. For the parameters that are indicative of a population's health, comparisons among the study sites were completed using analysis of variance. RESULTS: General haematology results suggested that warru were not experiencing chronic anaemia and the protein electrophoresis values indicated that colonies were not suffering from population-wide disease. However, the lower superoxide dismutase, retinol, total carotenoids and ascorbic acid values for New Well warru suggested those animals had a lower plane of nutrition than those at Kalka and Alalka. Higher urea concentrations in New Well and Alalka warru could be a reflection of the absence of reliable free water at these sites. CONCLUSION: The results have implications for the management of in situ colonies, including potentially using supplementary feeding to improve nutrition, and suggested that these animals were not suffering from disease. The study presents the first blood reference values for P. lateralis and, potentially, a methodology for other threatened species recovery programs to follow to establish the health of their populations. PMID- 22928681 TI - Can dogs carry the global pandemic candidate avian influenza virus H9N2? AB - BACKGROUND: H9N2 avian influenza virus (AIV) is one of the most widely circulating viruses in Eurasia. Recent studies have shown that the molecular recombination of H9N2 and H1N1 could pose a pandemic threat. Mammals that are susceptible to subtype H9N2 may contribute to the spread of the virus. OBJECTIVE: To determine the susceptibility of 1-year-old dogs to H9N2 AIV. PROCEDURE: H9N2 AIV infection was experimentally reproduced in 1-year-old dogs. The animals were intranasally inoculated with a titre of 10(7.5) (50% egg infective dose) of H9N2 AIV isolated from a broiler farm during an outbreak. The animals in the contact group were exposed to contaminated surfaces. RESULTS: Clinical signs including sneezing, coughing and nasal discharge were observed in the inoculated and contact groups. The virus was detected in nasal swab, faecal and buffy coat samples of dogs in both the inoculated and contact groups and both groups developed antibody titres against AIV H9N2 subtype. CONCLUSION: H9N2 AIV isolated from outbreaks in a broiler farm can easily infect dogs and infected animals shed the virus. Because many Asian countries are facing frequent outbreaks of H9N2 infection in the poultry industry, dogs could be a potentially important source of virus transmission within and between poultry farms. PMID- 22928682 TI - Clinical evaluation of alfaxalone as an anaesthetic induction agent in dogs less than 12 weeks of age. AB - OBJECTIVE: To assess the efficacy of alfaxalone as an anaesthetic induction agent for dogs aged less than 12 weeks. MATERIALS AND METHODS: The study group comprised 25 juvenile dogs aged less than 12 weeks that were presented for surgical desexing. Dogs were aged by dentition, examined and weighed prior to premedication with acepromazine, atropine and morphine. At 20-30 min after premedication, animals were anaesthetised with intravenous alfaxalone administered to effect, using a target maximum expected dose of 2 mg/kg. Dogs were intubated and anaesthesia was maintained with isoflurane in oxygen administered with a non-rebreathing system. Subjective measures of anaesthetic quality and vital signs were recorded from enrollment to recovery. Descriptive and comparative statistics were used to analyse and present collected data. RESULTS: The mean (+/- SD) dose of alfaxalone for induction was 1.7 (+/- 0.3) mg/kg body weight. Subjective measures of anaesthetic quality indicated acceptable induction, maintenance and recovery standards. Measured cardiovascular and respiratory parameters were well maintained. CONCLUSION: Alfaxalone in 2 hydroxypropyl-beta-cyclodextrin (Alfaxan(r)) is a suitable injectable anaesthetic induction agent for dogs aged less than 12 weeks requiring anaesthesia. PMID- 22928683 TI - Serum cardiac troponin I concentrations in horses with cardiac disease. AB - OBJECTIVES: To measure the cardiac troponin I (cTnI) concentration in horses and determine whether it could be used in the diagnosis of myocardial disease, as well as determining the association between cTnI and survival. DESIGN: Prospective, observational study. PROCEDURE: Physical examination, echocardiography, telemetric electrocardiography and postmortem were used to diagnose cardiac disease. Diagnoses were grouped as myocardial disease, structural heart disease or lone arrhythmia. Blood samples were collected at admission for cTnI analysis and the results were compared with those for 18 healthy horses. RESULTS: In total, 49 horses were admitted with cardiac disease. Elevated cTnI concentration (>0.03 ng/mL) was observed in a greater proportion of horses with myocardial disease (7/7), compared with healthy horses (0/18; P < 0.0001), horses with structural heart disease (7/25; P = 0.001), and horses with a lone arrhythmia (2/17; P = 0.0001). The median cTnI concentration for horses with myocardial disease was 17.5 ng/mL (range 0.78-49.87 ng/mL), which was higher than in the healthy horses (0.01 ng/mL, range 0.01-0.03 ng/mL; P < 0.0001). Of the 49 horses with cardiac disease, the median cTnI concentration for non survivors (0.28 ng/mL, range 0.01-49.87 ng/mL) was higher than for survivors (0.01 ng/mL, range 0.01-30.31 ng/mL; P = 0.0035). However, the proportion of surviving horses with an elevated cTnI (10/39, 26%) was not significantly different from the proportion of non-surviving horses with an elevated cTnI (6/10, 60%; P = 0.060). CONCLUSIONS: cTnI is elevated in horses with myocardial disease and elevated to a lesser degree in some horses with structural heart disease or lone arrhythmias. The association between cTnI concentration and survival was not clear. PMID- 22928684 TI - Combination fibrinolytic therapy in the treatment of chronic septic pleuropneumonia in a Thoroughbred gelding. AB - This report documents the treatment of a case of chronic pleuropneumonia in a 3 year-old Thoroughbred gelding. A recombinant tissue plasminogen activator (tenecteplase) and a recombinant deoxyribonucleic acidase (alphadornase) were infused into the pleural cavity as adjunctive therapy in the early stages of treatment. Instillation of fibrinolytic drugs was associated with a subjective reduction in the amount of fibrin deposition and decreased fluid accumulation within the pleural cavities. Fibrinolytic therapy may be a useful adjunctive therapy in selected cases of intrapleural disease in horses. PMID- 22928685 TI - Meat inspection in the Australian red-meat industries: past, present and future. AB - Postmortem inspection of carcases and offal has been a cornerstone of consumer protection in the red-meat industry for over a century. In 2011, there began strong moves to reform the traditional process of meat inspection applied to cattle, sheep and goats in Australia. A major motivation was the widespread acceptance that organoleptic inspection does little to control the most important hazards in meat products - microbial pathogens derived from gut flora. The watershed reforms in international trade provided another incentive by encouraging the application of a risk-based approach to food safety, which allows for the discontinuation of processes that do not enhance public health outcomes. As well, there was a strong imperative to ensure that resources allocated to quality assurance delivered maximum economic benefit for both consumers and processors. This review discusses how the role of meat inspection is likely to evolve into the future under the influence of these forces. It summarises how the current system was derived through repeated modification over time, mainly to satisfy the requirements of trading partners. Major developments are summarised, focusing especially on how the inclusion of particular organoleptic techniques was initially justified and the relevance of these to modern meat production. Overall, analysis of past and present practices suggests that in the future both public health and efficiency will be better served by strategically integrating the most effective elements of traditional organoleptic inspection with information from the preslaughter period and the use of modern technology for rapid and accurate detection of hazards. PMID- 22928687 TI - Quality assessment of systematic reviews or meta-analyses of nursing interventions conducted by Korean reviewers. AB - BACKGROUND: A systematic review is used to investigate the best available evidence of clinical safety and effectiveness of healthcare intervention. This requires methodological rigor in order to minimize bias and random error. The purpose of this study is to assess the quality of systematic reviews or meta analyses for nursing interventions conducted by Korean researchers. METHODS: We searched electronic databases from 1950 to July 2010, including ovidMEDLINE, ovidEMBASE, and Korean databases, including KoreaMed, Korean Medical Database, and Korean studies Information Service System etc. Two reviewers independently screened and selected all references, and assessed the quality of systematic reviews or meta-analyses using the "Assessment of Multiple Systematic Reviews" (AMSTAR) tool. RESULTS: Twenty two systematic reviews or meta-analyses were included in this study. The median overall score (out of 11) for included reviews was 5 (range 2-11) and the mean overall score for AMSTAR was 4.7 (95% confidence interval 3.8-5.7). Nine out of 22 reviews were rated as low quality (AMSTAR score 0-4), 11 were rated as moderate quality (AMSTAR score 5-8), and two reviews were categorized as high quality (AMSTAR score 9-11). CONCLUSIONS: The methodological quality of published reviews on nursing interventions conducted by Korean reviewers was assessed as low to moderate. In order to use the best available evidence in clinical decision making, reviewers should conduct systematic reviews or meta- analyses using rigorous research methods. PMID- 22928688 TI - Transcranial Doppler with bubble study as a method to detect extracardiac right to-left shunts in patients with ischemic stroke. AB - BACKGROUND AND PURPOSE: Paradoxical embolism through extracardiac right-to-left shunts (ECRLS) may represent an under-detected stroke mechanism. Stroke patients without evidence of cardiac right-to-left shunt (RLS) on echocardiogram may benefit from transcranial Doppler with bubble study (TCD-b) to aid in recognition of stroke etiology. This study assesses the usefulness of TCD-b in the stroke evaluation. METHODS: Retrospective cohort study of consecutive patients undergoing TCD-b performed in our neurovascular laboratory from February 2005 to August 2009. Echocardiography results were reviewed in patients with positive TCD b. Detailed medical record review was performed on patients with positive TCD-b and negative echocardiogram findings for RLS. RESULTS: Of 502 patients undergoing TCD-b, 48.4% (n = 243) had a positive study suggesting the presence of RLS. Of these, 59.2% (n = 144) had an echocardiogram demonstrating a cardiac RLS, 26% (n = 63) had echocardiograms without evidence of cardiac RLS, and 14.8% (n = 36) had no echocardiogram. Data on the evaluation to determine source of potential shunting in patients with discrepant findings was available in 11(17.5%). Of these, 63.6% (7/11) had potential mechanisms for positive TCD-b: one pulmonary arteriovenous malformation (AVM), one arteriovenous fistula thrombus, one parietal AVM, and four had malignancy. CONCLUSIONS: TCD-bubble studies may prove useful in uncovering treatable causes of stroke. PMID- 22928689 TI - Suicide rates and income in Sao Paulo and Brazil: a temporal and spatial epidemiologic analysis from 1996 to 2008. AB - BACKGROUND: In a classical study, Durkheim noted a direct relation between suicide rates and wealth in the XIX century France. Since that time, several studies have verified this relationship. It is known that suicide rates are associated with income, although the direction of this association varies worldwide. Brazil presents a heterogeneous distribution of income and suicide across its territory; however, evaluation for an association between these variables has shown mixed results. We aimed to evaluate the relationship between suicide rates and income in Brazil, State of Sao Paulo (SP), and City of SP, considering geographical area and temporal trends. METHODS: Data were extracted from the National and State official statistics departments. Three socioeconomic areas were considered according to income, from the wealthiest (area 1) to the poorest (area 3). We also considered three regions: country-wide (27 Brazilian States and 558 Brazilian micro-regions), state-wide (645 counties of SP State), and city-wide (96 districts of SP city). Relative risks (RR) were calculated among areas 1, 2, and 3 for all regions, in a cross-sectional approach. Then, we used Joinpoint analysis to explore the temporal trends of suicide rates and SaTScan to investigate geographical clusters of high/low suicide rates across the territory. RESULTS: Suicide rates in Brazil, the State of SP, and the city of SP were 6.2, 6.6, and 5.4 per 100,000, respectively. Taking suicide rates of the poorest area (3) as reference, the RR for the wealthiest area was 1.64, 0.88, and 1.65 for Brazil, State of SP, and city of SP, respectively (p for trend <0.05 for all analyses). Spatial cluster of high suicide rates were identified at Brazilian southern (RR = 2.37), state of SP western (RR = 1.32), and city of SP central (RR = 1.65) regions. A direct association between income and suicide were found for Brazil (OR = 2.59) and the city of SP (OR = 1.07), and an inverse association for the state of SP (OR = 0.49). CONCLUSIONS: Temporospatial analyses revealed higher suicide rates in wealthier areas in Brazil and the city of SP and in poorer areas in the State of SP. We further discuss the role of socioeconomic characteristics for explaining these discrepancies and the importance of our findings in public health policies. Similar studies in other Brazilian States and developing countries are warranted. PMID- 22928690 TI - Birhombic flap, a modified bilobed flap, for repair of nasal defect. AB - BACKGROUND: Reconstruction of longitudinal defects of the lateral nasal alar might be challenging. Reconstruction with a bilobed flap is common for round defects normally the bilobed flap is less suited for longitudinal defects. OBJECTIVE: We describe a birhombic flap for longitudinal defect. METHODS: Demonstration of the technique and practical application for this kind of reconstruction. RESULTS: The bilobed flap is a very useful flap for lateral nasal tip or distal alar reconstruction. We show that a small modification of the flap allows to cover also longitudinal defects on the lateral tip of the nose. As the first lobe movement corresponds more to the rhomboid transposition flap, we prefer to call it birhombic flap. CONCLUSION: The birhombic flap has its place in reconstructive surgery. This flap has a specific indication and precise advantages to other repairs in particular to the bilobed flap. PMID- 22928691 TI - Palliative chemotherapy in elderly patients with metastatic colorectal cancer: do we know how it should be used? PMID- 22928692 TI - Survival of cervical cancer patients in Germany in the early 21st century: a period analysis by age, histology, and stage. AB - PURPOSE: Population-based studies on cervical cancer providing survival estimates by age, histology, and stage have been sparse. We aimed to derive most up-to-date and detailed survival estimates for cervical cancer patients in Germany. METHODS: We used a pooled German national dataset including data from 11 cancer registries covering a population of 33 million people. Included were 15 685 patients diagnosed with cervical cancer from 1997 to 2006. Period analysis was performed to calculate the five-year relative survival (RS) 2002-2006. Trends in survival between 2002 and 2006 were examined using model-based period analysis. Age adjustment was done using five age groups (15-44, 45-54, 55-64, 65-74, and 75 + years). RESULTS: Overall, age-adjusted five-year relative survival in 2002-2006 was 64.7%. A strong age gradient was observed, with five-year RS decreasing from 81.7% in age group 15-49 years to 46.3% in age group 70 + years. Prognosis furthermore strongly varied by stage, with age-adjusted five-year RS reaching 84.6% for localized, 48.2% for regional, and 17.9% for distant stage. From 2002 to 2006, a significant improvement (4.7 percent units) in overall age-adjusted five-year RS was seen. The improvement was most pronounced for age groups 55-64 years (from 54.2 to 65.6%) and 65-74 years (from 50.0 to 58.1%). CONCLUSION: In this first comprehensive population-based study from Germany, prognosis of cervical cancer strongly varied by age and stage. Prognosis continued to improve, in particular in age range 55-74 years, in the five-year period assessed. PMID- 22928693 TI - Molecular subtyping of male breast cancer using alternative definitions and its prognostic impact. AB - BACKGROUND: Male breast cancer (MBC) is an uncommon disease and there is limited information on the prognostic impact of routinely used clinicopathological parameters. MATERIAL AND METHODS: In a retrospective setting, we reviewed 197 MBC patients with accessible paraffin-embedded tumor tissue and clinicopathological data. Immunohistochemical (IHC) stainings were performed on tissue microarrays and histological grading on conventional slides. Cox proportional regression models were applied for uni- and multivariate analyses using breast cancer death as the event. RESULTS: Estrogen receptor (ER) and progesterone receptor positivity were demonstrated in 93% and 77% of patients, respectively. Nottingham histologic grade (NHG) III was seen in 41% and HER2 positivity in 11%. Classification into molecular subtypes using IHC markers according to three alternative definitions revealed luminal A and luminal B in 81% vs. 11%; 48% vs. 44% and 41% vs. 42% of cases. Two cases of basal-like were identified, but no cases of HER2-like. Factors associated with an increased risk of breast cancer death were node positivity (HR 4.5; 95% CI 1.8-11.1), tumor size > 20 mm (HR 3.3; 95% CI 1.4-7.9) and ER negativity (HR 10.9; 95% CI 3.2-37.9). No difference in breast cancer death between the luminal subgroups was demonstrated, regardless of definition. CONCLUSION: MBC tumors were more often of high grade, whereas HER2 overexpression was as frequent as in FBC. Lymph nodes, tumor size and ER status were independent predictors of breast cancer death. The prognostic impact of molecular subtyping in MBC seems to differ from that previously established in FBC. PMID- 22928694 TI - Treatment and survival analyses of malignant mesothelioma in Japan. AB - BACKGROUND: There are few reports concerning treatment strategies and their contributions to survival of patients with malignant mesothelioma (MM) in Japan. MATERIAL AND METHODS: We extracted all death cases due to MM between 2003 and 2008. The diagnosis of MM was confirmed in 929 cases. Histological subtypes was determined in 709 cases, including 396 (55.9%) epithelioid, 154 (21.7%) sarcomatoid, 126 (17.8%) biphasic, and 33 (4.7%) other types. RESULTS AND CONCLUSION: Median overall survival (OS) of all MM cases was 7.7 months (95% confidence interval, 7.1-8.3). Median OS of patients with epithelioid MM was significantly longer than that of patients with biphasic (p = 0.030) or sarcomatoid (p < 0.001) MM. Surgical resection was performed in 172 patients (18.5%) and 449 (48.3%) received systemic chemotherapy. Survival of patients treated with both surgery and systemic chemotherapy was favorable. Median OS of patients in the late phase of the study period (2006-2008) was significantly longer than that in the early phase (2003-2005) (8.1 vs. 7.5 months, p = 0.008). Independent favorable prognostic factors included age younger than 70 years, female gender, epithelioid subtype, and clinical stage I-III. Multivariate analysis demonstrated that patients who had radical surgery and systemic chemotherapy showed a longer survival, though this could be due to selection bias of patients. PMID- 22928695 TI - Are they really incidental after all? PMID- 22928696 TI - Influence of methylenetetrahydrofolate reductase C677T gene polymorphisms in Algerian infertile men with azoospermia or severe oligozoospermia. AB - AIMS: The C677T allele of the methylenetetrahydrofolate reductase (MTHFR) gene has been suggested to represent a risk factor for male infertility. To confirm this association, the distribution of the single-nucleotide polymorphism C677T was investigated in idiopathic infertile Algerian patients with nonobstructive azoospermia (NOA) or severe oligoasthenoteratozoospermia (OAT). A case-control study was carried out, including 74 idiopathic infertile Algerian patients with NOA (n=46) or severe OAT (n=28) and 84 fertile men as controls. Polymorphism C677T was studied by polymerase chain reaction-restriction fragment length polymorphism, and the results were statistically analyzed. RESULTS: The frequency of genotypes MTHFR 677CC, 677CT, and 677TT in idiopathic infertile men with NOA was 43.48%, 41.30%, and 15.22%; 39.29%, 50%, and 10.71% regarding the severe oligozoospermic men; and 42.86%, 45.24%, and 11.90% in the control group. CONCLUSIONS: The data suggest that the C677T MTHFR polymorphism is not a risk factor for idiopathic male subfertility in an Algerian population. PMID- 22928697 TI - Actors, observers, and the estimation of task duration. AB - People are often wrong in estimating both how long tasks have taken in the past and how long they will take in the future. Bias could be due to factors such as task involvement, an individual's engagement or motivation in completing the task, or aspects of the task such as its relative duration or memory storage size associated with it. We examined time estimation bias in actors (likely to experience high levels of task involvement) and observers (likely to experience low levels of task involvement) for both predictions of and memory of task duration. Results suggest that bias appears to be due to memory storage size rather than to involvement with the task. PMID- 22928698 TI - Involvement of Rab6 in the regulation of phagocytosis against virus infection in invertebrates. AB - Phagocytosis, which is of fundamental importance for innate and adaptive immunity in animals, is driven by organization of the actin cytoskeleton. To date, however, the molecular events involved in the regulation of phagocytosis through reorganization of actin by small G proteins remains to be elucidated. To address this issue, the molecular mechanism of Rab6 in phagocytosis against virus infection in invertebrates was characterized in this study. The results showed that the Rab6 obtained from shrimp could interact with actin to regulate shrimp hemocyte phagocytosis through induction of the rearrangement of actin to protect against white spot syndrome virus (WSSV) infection. The Rab6 protein in Drosophila melanogaster shared the same mechanism of action as that of Rab6 in shrimp, indicating that the function of Rab6 in phagocytosis was conserved in invertebrates. By comparison with the early marker (Rab5) and late marker (LAMP1) of phagosomes, Rab6 was critically involved in the regulation of actin organization throughout the entire phagocytosis process. The presence of the evolutionarily conserved amino acid sequences of Rab6 in invertebrates and vertebrates indicated a conserved mechanism of Rab6 function in phagocytosis of animals. Therefore, our findings presented novel molecular events in the regulation of phagocytosis by small G proteins. PMID- 22928699 TI - The role of Transjugular Intrahepatic Portosystemic Stent-Shunt (TIPSS) in the management of variceal hemorrhage. AB - BACKGROUND: Variceal bleeding in cirrhosis represents a lethal complication of their disease. In the last 20 years, management of AVH has improved greatly with reduction in mortality from 43% in 1980 to 15% in 2000. AIM: Advances in endoscopic therapy, pharmacologic agents including vasoconstrictor therapy and antibiotics have played a large part in improving outcomes, but the role of Transjugular Intrahepatic Portosystemic Stent-Shunt (TIPSS) remains controversial, which this review will cover. METHODS: MEDLINE search for the following terms was performed to July 2011: variceal hemorrhage, portal hypertension, cirrhosis, transjugular intrahepatic portosystemic stent-shunt (TIPSS), PTFE, covered stents. Where possible randomized controlled studies were used for this review, although uncontrolled studies were also included if they made a significant contribution to the literature. RESULTS: Literature used for the present study was selected from a total of 252 publications and abstracts from meetings. RESULTS: TIPSS has been used as a salvage therapy after initial medical and endoscopic therapy for the bleed given its high success rate in arresting uncontrolled variceal bleeding. The recent trial by Garcia- Pagan et al. suggested beneficial effects of an earlier covered TIPSS in those at high risk of treatment failure (Childs C and those who are Childs B with active bleeding). CONCLUSIONS: TIPSS can reduce failure to control bleeding and rebleeding as well as mortality with no increase in the risk of hepatic encephalopathy.This needs to be confirmed in further trials. However, it is clear that prevention of rebleeding is the key to improved outcomes following a variceal bleed. PMID- 22928700 TI - Water droplet bouncing and superhydrophobicity induced by multiscale hierarchical nanostructures. AB - Superhydrophobicity of multiscale hierarchical structures and bouncing phenomenon of a water droplet on the superhydrophobic surface were studied. The multiscale hierarchical structures of carbon nanotube/ZnO and ZnO/carbon nanofiber were produced by the hydrothermal method. The multiscale hierarchical structure showed superhydrophobicity with a static contact angle (CA) larger than 160 degrees due to increased air pockets in the Cassie-Baxter state. The water bouncing effect observed on the multiscale hierarchical nanostructure was explained by the free energy barrier (FEB) analysis and finite element simulation. The multiscale hierarchical nanostructure showed low FEBs which provoke high CA and bouncing phenomenon due to small energy dissipation toward receding and advancing directions. PMID- 22928701 TI - Nanocomposite gold-silk nanofibers. AB - Cell-biomaterial interactions can be controlled by modifying the surface chemistry or nanotopography of the material, to induce cell proliferation and differentiation if desired. Here we combine both approaches in forming silk nanofibers (SNFs) containing gold nanoparticles (AuNPs) and subsequently chemically modifying the fibers. Silk fibroin mixed with gold seed nanoparticles was electrospun to form SNFs doped with gold seed nanoparticles (SNF(seed)). Following gold reduction, there was a 2-fold increase in particle diameter confirmed by the appearance of a strong absorption peak at 525 nm. AuNPs were dispersed throughout the AuNP-doped silk nanofibers (SNFs(Au)). The Young's modulus of the SNFs(Au) was almost 70% higher than that of SNFs. SNFs(Au) were modified with the arginine-glycine-aspartic acid (RGD) peptide. Human mesenchymal stem cells that were cultured on RGD-modified SNF(Au) had a more than 2-fold larger cell area compared to the cells cultured on bare SNFs; SNF(Au) also increased cell size. This approach may be used to alter the cell-material interface in tissue engineering and other applications. PMID- 22928702 TI - Impact of metformin monotherapy versus metformin with oestrogen-progesterone on lipids in adolescent girls with polycystic ovarian syndrome. AB - OBJECTIVE: Hyperinsulinaemia is an important determinant of the polycystic ovarian syndrome (PCOS). In addition to lifestyle measures, therapeutic strategies include the use of oestrogen-progesterone combination pills (EP), and insulin sensitizers such as metformin, either alone or in combination. Data are limited regarding the impact of metformin alone vs metformin with EP on cardiometabolic risk in overweight adolescents with PCOS. We hypothesized that metformin alone would lead to an improvement in HbA1C and lipid levels in overweight adolescent girls with PCOS compared with meformin with EP. STUDY DESIGN: Retrospective clinic-based therapy. PATIENTS AND MEASUREMENTS: We examined the effects of therapy with metformin alone (n = 14) vs metformin with EP (n = 13) on HbA1C and lipid parameters over 10-14 months in 27 overweight girls, drawn from a clinic population of adolescents with PCOS. RESULTS: The groups did not differ for age, body mass index (BMI), HbA1C or baseline lipids. After at least 10 months, the metformin only group compared with the metformin and EP group had a decrease in total cholesterol (-0.605 +/- 0.100 vs 0.170 +/- 0.348 mm, P = 0.02, nonparametric test) and triglycerides (-0.342 +/- 0.184 vs 0.262 +/- 0.133 mm, P = 0.02), despite similar changes in BMI (-1.6 +/- 0.7 vs 0.6 +/- 2.1 kg/m(2) , P = 0.25) and HbA1C (0.03 +/- 0.06 vs 0.03 +/- 0.13%, P = 0.99). Differences between groups remained significant after controlling for baseline parameters and for changes in BMI. CONCLUSION: Metformin alone more effectively improves lipid parameters than metformin with EP in adolescent PCOS, as indicated by a decrease in total cholesterol and triglycerides. This effect is not related to BMI changes. PMID- 22928703 TI - Single application of high-intensity focused ultrasound as a first-line therapy for clinically localized prostate cancer: 5-year outcomes. AB - Study Type--Therapy (case series) Level of Evidence 4. What's known on the subject? and What does the study add? High-intensity focused ultrasound (HIFU) therapy has been proposed for the treatment of localized prostate cancer (PCa) for all risk levels of tumour recurrence. The study adds data on the efficacy of a single HIFU application in the treatment of PCa with different risks of recurrence. Durable cancer control was achieved in 81.7% of patients with low risk disease, with rates of efficacy declining in intermediate- and high-risk tumours. The data suggest that the principal domain for minimal invasive HIFU should be low-risk disease. OBJECTIVE: * To report cancer control results after a single application of high-intensity focused ultrasonography (HIFU) in patients with localized prostate cancer (PCa), stratified by tumour recurrence risk according to D'Amico risk classification. PATIENTS AND METHODS: * In a retrospective single-centre study, we analysed the outcomes of patients with localized PCa who were treated with curative intent between December 2002 and October 2006 using an Ablatherm HIFU device (EDAP-TMS, France). * Transurethral resection of the prostate or adenomectomy were performed before HIFU to downsize large prostate glands. * Oncological failure was determined by the occurrence of biochemical relapse, positive biopsy and/or metastasis. Biochemical relapse was defined as a PSA nadir +1.2 ng/mL (Stuttgart definition), or as a rise in PSA level to >= 0.5 ng/mL if PSA doubling time was <= 6 months. Kaplan-Meier analysis was performed for survival estimates. RESULTS: * A total of 191 consecutive patients were included in the study. The median (range) patient age was 69.7 (51 82) years, and 38, 34 and 28% of these patients were in the low-, intermediate- and high-risk groups, respectively. * The median (range) follow-up was 52.8 (0.2 79.8) months. * At 5 years, overall and cancer-specific survival rates were 86.3% and 98.4%, respectively. * Stratified by risk group, negative biopsy rates were 84.2%, 63.6%, and 67.5% (P = 0.032), 5-year biochemical-free survival rates were 84.8%, 64.9% and 54.9% (P< 0.01), and 5-year disease-free survival rates were 81.7%, 53.2% and 51.2% (P < 0.01), respectively. CONCLUSION: * Single-session HIFU is recommended as a curative approach in elderly patients with low-risk PCa. Patients at higher risk of tumour progression should be counselled regarding the likely need for salvage therapy, including repeat HIFU. PMID- 22928704 TI - Oromucosal midazolam: a guide to its use in paediatric patients with prolonged acute convulsive seizures. AB - Oromucosal midazolam (BuccolamTM), a benzodiazepine, is approved in the EU for the treatment of paediatric patients (aged 3 months to <18 years) with acute, prolonged, convulsive seizures. In clinical trials in children with prolonged, acute, convulsive seizures, oromucosal midazolam was at least as effective as rectal diazepam and as effective as intravenous diazepam in the treatment of seizures and was generally well tolerated. It has several advantages over rectal diazepam, the previous gold standard of treatment, such as having a more convenient and socially acceptable administration route. PMID- 22928705 TI - Validation of the Totaled Health Risks In Vascular Events (THRIVE) score for outcome prediction in endovascular stroke treatment. AB - BACKGROUND: We recently developed the Totaled Health Risks In Vascular Events (THRIVE) score to predict outcomes after endovascular stroke treatment. The THRIVE score, which incorporates age, National Institutes of Health Stroke Scale score, and three medical comorbidities (hypertension, diabetes mellitus, and atrial fibrillation), was developed using data from the Mechanical Embolus Removal in Cerebral Ischemia (MERCI) and Multi MERCI trials. AIMS: We set out to perform external validation of the THRIVE score using data from the largest registry of endovascular stroke treatment performed to date, the Merci Registry. METHODS: We compared the performance of the THRIVE score in two different data sets: the development cohort (the MERCI and Multi MERCI trials, n = 305) and a validation cohort (the Merci Registry, a prospective multicenter registry of patients undergoing endovascular stroke treatment, n = 1000). We examined the predictive utility of the THRIVE score across the range of clinical outcomes and used receiver-operator characteristics curve analysis to compare score performance in the two data sets. RESULTS: The THRIVE score predicted good outcome, death, and the full range of the modified Rankin Scale in a similar fashion between the MERCI trials and the Merci Registry. Receiver-operator characteristics curve comparisons showed no statistically significant difference in the performance of the THRIVE score between the two data sets: for good outcome, the receiver-operator characteristics area under the curve was 0.293 for the MERCI trials and 0.266 for the Merci Registry (P = 0.47) and for death, the receiver-operator characteristics area under the curve was 0.692 for the MERCI trials and 0.717 for the Merci Registry (P = 0.48). The THRIVE score and vessel recanalization were also found to be independent and unrelated predictors of clinical outcome. CONCLUSIONS: The THRIVE score reliably predicts outcomes after endovascular stroke treatment and may be useful as a clinical prognostic tool and to perform severity adjustments in stroke clinical research. PMID- 22928706 TI - Suzuki-Miyaura coupling of aryl iodides, bromides, and chlorides catalyzed by bis(thiazole) pincer palladium complexes. AB - Bis(thiazole) pincer palladium complexes showed efficient catalytic activity for the Suzuki-Miyaura coupling of aryl halides, allowing the synthesis of biaryls with very high turnover numbers and turnover frequencies. The complexes were successfully applied in the scalable and green synthesis of the key intermediates of bioactive LUF5771 and its analogues. PMID- 22928707 TI - Direct substitution of primary allylic amines with sulfinate salts. AB - The NH(2) group in primary allylic amines was substituted directly by sulfinate salts with excellent regio- and stereoselectivities. In the presence of 0.1 mol % [Pd(allyl)Cl](2), 0.4 mol % 1,4-bis(diphenylphosphino)butane (dppb), and excess boric acid, a range of alpha-unbranched primary allylic amines were smoothly substituted with sodium sulfinates in an alpha-selective fashion to give structurally diverse allylic sulfones in good to excellent yields with exclusive E selectivity. Replacing dppb with 1,1'-bi-2-naphthol (BINOL) allowed unsymmetric alpha-chiral primary allylic amines to be transformed into the corresponding allylic sulfones in good to excellent yields with excellent retention of ee. Importantly, the reaction complements known asymmetric methods in substrate scope via its unique ability to provide alpha-chiral allylic sulfones with high optical purity starting from unsymmetric allylic electrophiles. PMID- 22928708 TI - In vivo brain microdialysis to evaluate FITC-dextran encapsulated immunopegylated nanoparticles. AB - CONTEXT: Delivery of drugs and dyes through intact blood-brain barrier (BBB) is extremely sought-after. A safe and reliable measurement of delivery efficacy in live animals is necessary. OBJECTIVE: To investigate the brain uptake of FITC dextran MW 4000 (FD4) by CD71/OX-26 coated nanoparticles by microdialysis sampling and fluorescence/confocal microscopy. MATERIALS AND METHODS: Methoxy poly(ethylene glycol)-poly(lactide) (Met-PEG-PLA) and maleimide-poly(ethylene glycol)-poly(lactide) (Mal-PEG-PLA) nanoparticles were prepared by nanoprecipitation. The surfaces of the prepared nanoparticles were embellished with CD-71/OX-26 antibodies for brain targeting. Male Sprague Dawley rats received 0.4 mg/kg FD4 and equivalent nanoparticulate formulation through lateral tail vein. Animals were euthanized 24 h postadministration, after which the tissues were harvested and analyzed for FD4 concentrations. Tissues were fixed with paraformaldehyde, cryotomed to 20 um sections, and analyzed by Total Internal Reflection microscopy. RESULTS: Particle sizes of 200 +/- 25 nm and zeta potentials of -18 +/- 1 mV were obtained. FD4 concentrations, determined using in vivo brain microdialysis, were high on the first day (~360 ng/mL) compared to 60 ng/mL on the following 2 days. The nanoparticle treated animals showed significantly higher (p < 0.05) FD4 concentrations in the brain than pure-FD4 treated animals. Immunopegylated nanoparticles sustained and enhanced Central nervous system (CNS) concentration of hydrophilic dye for at least 3 days. CONCLUSION: Immunopegylated nanoparticles produce enhanced and sustained uptake of brain permeability marker FD4 relative to controls. PMID- 22928709 TI - Macrostate identification from biomolecular simulations through time series analysis. AB - This paper builds upon the need for a more descriptive and accurate understanding of the landscape of intermolecular interactions, particularly those involving macromolecules such as proteins. For this, we need methods that move away from the single conformation description of binding events, toward a descriptive free energy landscape where different macrostates can coexist. Molecular dynamics simulations and molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) methods provide an excellent approach for such a dynamic description of the binding events. An alternative to the standard method of the statistical reporting of such results is proposed. PMID- 22928711 TI - Evaluation of variability and quality control procedures for a receptor-binding assay for paralytic shellfish poisoning toxins. AB - The receptor-binding assay (RBA) method for determining saxatoxin (STX) and its numerous analogues, which cause paralytic shellfish poisoning (PSP) in humans, was evaluated in a single laboratory study. Each step of the assay preparation procedure including the performance of the multi-detector TopCount(r) instrument was evaluated for its contribution to method variability. The overall inherent RBA variability was determined to be 17%. Variability within the 12 detectors was observed; however, there was no reproducible pattern in detector performance. This observed variability among detectors could be attributed to other factors, such as pipetting errors. In an attempt to reduce the number of plates rejected due to excessive variability in the method's quality control parameters, a statistical approach was evaluated using either Grubbs' test or the Student's t test for rejecting outliers in the measurement of triplicate wells. This approach improved the ratio of accepted versus rejected plates, saving cost and time for rerunning the assay. However, the potential reduction in accuracy and the lack of improvement in precision suggests caution when using this approach. The current study has recommended an alternate quality control procedure for accepting or rejecting plates in place of the criteria currently used in the published assay, or the alternative of outlier testing. The recommended procedure involves the development of control charts to monitor the critical parameters identified in the published method (QC sample, EC50, slope of calibration curve), with the addition of a fourth critical parameter which is the top value (100% binding) of the calibration curve. PMID- 22928710 TI - Comparative chemogenomics to examine the mechanism of action of dna-targeted platinum-acridine anticancer agents. AB - Platinum-based drugs have been used to successfully treat diverse cancers for several decades. Cisplatin, the original compound of this class, cross-links DNA, resulting in cell cycle arrest and cell death via apoptosis. Cisplatin is effective against several tumor types, yet it exhibits toxic side effects and tumors often develop resistance. To mitigate these liabilities while maintaining potency, we generated a library of non-classical platinum-acridine hybrid agents and assessed their mechanisms of action using a validated genome-wide screening approach in Saccharomyces cerevisiae and in the distantly related yeast Schizosaccharomyces pombe. Chemogenomic profiles from both S. cerevisiae and S. pombe demonstrate that several of the platinum-acridines damage DNA differently than cisplatin based on their requirement for distinct modules of DNA repair. PMID- 22928712 TI - Validity of verbal autopsy method to determine causes of death among adults in the urban setting of Ethiopia. AB - BACKGROUND: Verbal autopsy has been widely used to estimate causes of death in settings with inadequate vital registries, but little is known about its validity. This analysis was part of Addis Ababa Mortality Surveillance Program to examine the validity of verbal autopsy for determining causes of death compared with hospital medical records among adults in the urban setting of Ethiopia. METHODS: This validation study consisted of comparison of verbal autopsy final diagnosis with hospital diagnosis taken as a "gold standard". In public and private hospitals of Addis Ababa, 20,152 adult deaths (15 years and above) were recorded between 2007 and 2010. With the same period, a verbal autopsy was conducted for 4,776 adult deaths of which, 1,356 were deceased in any of Addis Ababa hospitals. Then, verbal autopsy and hospital data sets were merged using the variables; full name of the deceased, sex, address, age, place and date of death. We calculated sensitivity, specificity and positive predictive values with 95% confidence interval. RESULTS: After merging, a total of 335 adult deaths were captured. For communicable diseases, the values of sensitivity, specificity and positive predictive values of verbal autopsy diagnosis were 79%, 78% and 68% respectively. For non-communicable diseases, sensitivity of the verbal autopsy diagnoses was 69%, specificity 78% and positive predictive value 79%. Regarding injury, sensitivity of the verbal autopsy diagnoses was 70%, specificity 98% and positive predictive value 83%. Higher sensitivity was achieved for HIV/AIDS and tuberculosis, but lower specificity with relatively more false positives. CONCLUSION: These findings may indicate the potential of verbal autopsy to provide cost-effective information to guide policy on communicable and non communicable diseases double burden among adults in Ethiopia. Thus, a well structured verbal autopsy method, followed by qualified physician reviews could be capable of providing reasonable cause specific mortality estimates in Ethiopia. However, the limited generalizability of this study due to the fact that matched verbal autopsy deaths were all in-hospital deaths in an urban center, thus results may not be generalizable to rural home deaths. Such application and refinement of existing verbal autopsy methods holds out the possibility of obtaining replicable, sustainable and internationally comparable mortality statistics of known quality. Similar validation studies need to be undertaken considering the limitation of medical records as "gold standard" since records may not be confirmed using laboratory investigations or medical technologies. The validation studies need to address child and maternal causes of death and possibly all underlying causes of death. PMID- 22928713 TI - Platelets, complement and tissue inflammation. AB - The release of immunoregulatory and inflammatory molecules following platelet activation has been invariably associated with the expression of tissue injury in several clinical conditions including trauma, organ transplantation, inflammatory bowel diseases and autoimmune diseases. We present a thorough review of the available information on the role of platelets and their interaction with complement cascade on the expression of tissue inflammation and organ damage. We propose that in autoimmune diseases and conditions associated with ischemia/reperfusion, platelets are decorated with complement, become activated and lodge tissues inappropriately to spread the inflammatory process. Interventions such as limiting complement decoration and suppression of signaling processes leading to platelet activation should be met with clinical benefit. PMID- 22928714 TI - Ultrasound detection of guidewires in-plane during pediatric central venous catheterization. AB - OBJECTIVE/AIM: To assess the usefulness of longitudinal ultrasound images of guidewires for pediatric central venous catheter (CVC) placement. BACKGROUND: To avoid arterial placement of a CVC, it is important to ensure that the guidewires are in the internal jugular vein (IJV) before inserting the dilators. Ultrasound confirmation of the guidewire position may eliminate accidental arterial dilation during CVC cannulation. METHODS: Fifty pediatric patients undergoing general endotracheal anesthesia for cardiovascular surgery were enrolled. The mean +/- sd value for age was 14.8 +/- 16.8 months; height, 69.1 +/- 14.6 cm; and weight, 7.1 +/- 3.2 kg. Longitudinal ultrasound images of guidewires in or around the right IJV during pediatric CVC placement were acquired using an L10-5 MHz probe (TiTAN((r)); SonoSite Co., Tokyo, Japan), with the neck of the patient fully extended and the head turned 15-30 degree to the left. RESULTS: In 42 (84%) patients, guidewires were visible in the lumen of the IJV. However, in 8 (16%) patients, guidewires were not visible. Longitudinal imaging of guidewires was achieved with high probability (100%) in children in whom the distance from the clavicle to the angle of the mandible was more than 59 mm, in whom the distance from the clavicle to the puncture site was more than 30 mm, or in children taller than 65 cm. All cannulations were confirmed to be CVCs by chest radiography. CONCLUSIONS: To confirm the insertion of dilators into veins in children, we recommend that longitudinal images of the guidewires should be initially acquired. PMID- 22928715 TI - Dose escalation may be effective in patients with psoriasis after treatment failure or suboptimal response, but switching to adalimumab is the most cost effective measure in different scenarios. PMID- 22928716 TI - A first national survey of knowledge, attitudes and behaviours towards schizophrenia, bipolar disorders and autism in France. AB - BACKGROUND: In order to support evidence-based policies for reduction of stigma, a better understanding of its components: ignorance (knowledge), prejudice (attitude) and discrimination (behaviour) is necessary. This study explores public perceptions and quantifies stigma for three chronic mental disorders: autism, schizophrenia and bipolar disorders in France. METHODS: Survey of 1000 adults selected from an established market research panel. The 21-item questionnaire explored knowledge, attitudes and behaviours toward each disorder. RESULTS: Although 95% respondents recognized the names of each disorder fewer than 70% could report specific characteristics and only 33% considered that publically available information was adequate; most respondents identified the media as their main resource. Labeling of conditions in a negative way was frequent (61%) when referring to mental disorders in general, but fell significantly (18%) when linked to an individual with a disorder. Individuals with schizophrenia are assumed to be dangerous; 65% respondents would engage in social distancing from such an individual, versus 29% for bipolar disorders and 7% for autism (p < 0.001). In contrast to other disorders, discrimination against schizophrenia was only partly attenuated in those with familiarity with mental disorders (through personal or family illness). CONCLUSION: This first population based survey in France shows that attitudes towards bipolar disorders and autism are less prejudicial than towards schizophrenia. However, most public attitudes and behaviours towards different disorders appear to be based on assumptions rather than knowledge or evidence suggesting a generic information or anti-stigma programme is unlikely to be effective. PMID- 22928718 TI - Patients' efforts to justify wellness in a comprehensive cancer clinic. AB - Conversation analysis (CA) is employed to examine oncology interviews within a comprehensive cancer clinic. Data are drawn from a sampling of 75 video-recorded and transcribed encounters involving 30 oncologists. During history-taking, by expanding answers to doctor's questions designed to solicit "yes/no" responses, patients manage constraints on interaction by initiating and pursuing distinct courses of action. One prominent set of nonconforming actions involves how cancer patients "justify wellness" and contest doctors' orientations to sickness. In response, doctors treat patients' expansions as dispreferred (e.g., through lack of acknowledgment or topic shift) because they do not conform with questions designed to solicit minimal answers. Patients initiate "justifying wellness" by invoking epistemic knowledge, using extreme language to optimize medical histories, emphasizing and bolstering wellness claims, and reporting healthy lifestyles. As a resource for managing vulnerability in the face of cancer, and for advancing resilient stances toward health and healing, patients attempt to counter the likelihood, severity, and overall threat of cancer. These and related actions ward off otherwise troubling diagnoses and, directly or indirectly, make the case for minimal or even dismissing the need for ongoing cancer care. Implications are raised for recalibrating "sick role" and "well role" activities as practical achievements, distributions of yes/no questions and expanded answers, a benign theory of social order in cancer clinics, the importance of responding to patients' wellness efforts, and the need for a more refined understanding of moments when hurting patients report, demonstrate, and seek treatment for various cancer-related problems. PMID- 22928719 TI - Randomized, double-blind, placebo-controlled study of safety and efficacy of miltefosine in antihistamine-resistant chronic spontaneous urticaria. AB - BACKGROUND: Chronic spontaneous urticaria (CSU), a mast cell-driven condition, is debilitating, common, and hard to treat. Miltefosine, a lipid raft modulator, can inhibit mast cell responses in vivo. OBJECTIVE: To study the safety and efficacy of systemic miltefosine treatment in CSU patients resistant to standard-dosed antihistamines. METHODS: In this investigator-initiated multicentre, randomized, double-blind, placebo-controlled study, CSU patients were treated for 4 weeks with daily doses of up to 150-mg miltefosine (n = 47) or placebo (n = 26). Disease activity was assessed using the urticaria activity score. Safety and tolerability of miltefosine were also assessed. RESULTS: After 4 weeks of treatment, Urticaria Activity Score (UAS7) levels were substantially more reduced in miltefosine-treated patients (-6.3 vs. -3.5 in placebo-treated patients; P = 0.05). Also, the number of weals, but not the intensity of pruritus, was significantly reduced in miltefosine-treated patients vs. placebo-treated patients (P = 0.02). In general, adverse events were frequent in both groups (miltefosine: 88%, placebo: 65% of patients) but mostly mild to moderate in severity. We did not observe any serious adverse events. CONCLUSIONS: The results of this study indicate that miltefosine is an effective and safe treatment option for CSU patients who do not respond to standard-dosed antihistamines. PMID- 22928717 TI - Annual Research Review: Resilient functioning in maltreated children--past, present, and future perspectives. AB - BACKGROUND: Through a process of probabilistic epigenesis, child maltreatment progressively contributes to compromised adaptation on a variety of developmental domains central to successful adjustment. These developmental failures pose significant risk for the emergence of psychopathology across the life course. In addition to the psychological consequences of maltreatment, a growing body of research has documented the deleterious effects of abuse and neglect on biological processes. Nonetheless, not all maltreated children develop maladaptively. Indeed, some percentage of maltreated children develops in a resilient fashion despite the significant adversity and stress they experience. METHODS: The literature on the determinants of resilience in maltreated children is selectively reviewed and criteria for the inclusion of the studies are delineated. RESULTS: The majority of the research on the contributors to resilient functioning has focused on a single level of analysis and on psychosocial processes. Multilevel investigations have begun to appear, resulting in several studies on the processes to resilient functioning that integrate biological/genetic and psychological domains. CONCLUSIONS: Much additional research on the determinants of resilient functioning must be completed before we possess adequate knowledge based on a multiple levels of analysis approach that is commensurate with the complexity inherent in this dynamic developmental process. Suggestions for future research on the development of resilient functioning in maltreated children are proffered and intervention implications are discussed. PMID- 22928721 TI - Intercellular carbon nanotube translocation assessed by flow cytometry imaging. AB - The fate of carbon nanotubes in the organism is still controversial. Here, we propose a statistical high-throughput imaging method to localize and quantify functionalized multiwalled carbon nanotubes in cells. We give the first experimental evidence of an intercellular translocation of carbon nanotubes. This stress-induced longitudinal transfer of nanomaterials is mediated by cell released microvesicles known as vectors for intercellular communication. This finding raises new critical issues for nanotoxicology, since carbon nanotubes could be disseminated by circulating extracellular cell-released vesicles and visiting several cells in the course of their passage into the organism. PMID- 22928720 TI - Brain MRI and magnetic resonance spectroscopy findings in patients with hyperargininemia. AB - BACKGROUND AND PURPOSE: Hyperargininemia (HA) is a rare autosomal recessive metabolic disorder and the neuroimaging features of this disease have seldom been reported. Hyperammonemic encephalopathy is uncommon in HA, and the clinical presentation of HA is distinct from other urea cycle disorders. This paper describes the brain MRI findings and a magnetic resonance spectroscopy (MRS) study of a series of Brazilian HA patients. METHODS: Brain MR images were obtained in eight male and two female patients with the classic HA phenotype. Six patients were evaluated twice. Single-voxel (1)H-MRS was also performed in six of the patients. RESULTS: Only 1 patient, with less severe neurological symptoms, had normal MRI images. A variable degree of cerebral atrophy was noted in the other patients, and 3 patients also presented mild symptoms of cerebellar atrophy. MRS indicated no metabolic abnormalities in any patient. CONCLUSIONS: We present the MRI and MRS findings of a large series of HA patients. Variable degrees of brain atrophy and mild cerebellar atrophy were observed, and these findings were not specific. No metabolic abnormality was observed using MRS in this series of patients. PMID- 22928722 TI - Herbal hepatotoxicity: a tabular compilation of reported cases. AB - BACKGROUND: Herbal hepatotoxicity is a field that has rapidly grown over the last few years along with increased use of herbal products worldwide. AIMS: To summarize the various facets of this disease, we undertook a literature search for herbs, herbal drugs and herbal supplements with reported cases of herbal hepatotoxicity. METHODS: A selective literature search was performed to identify published case reports, spontaneous case reports, case series and review articles regarding herbal hepatotoxicity. RESULTS: A total of 185 publications were identified and the results compiled. They show 60 different herbs, herbal drugs and herbal supplements with reported potential hepatotoxicity, additional information including synonyms of individual herbs, botanical names and cross references are provided. If known, details are presented for specific ingredients and chemicals in herbal products, and for references with authors that can be matched to each herbal product and to its effect on the liver. Based on stringent causality assessment methods and/or positive re-exposure tests, causality was highly probable or probable for Ayurvedic herbs, Chaparral, Chinese herbal mixture, Germander, Greater Celandine, green tea, few Herbalife products, Jin Bu Huan, Kava, Ma Huang, Mistletoe, Senna, Syo Saiko To and Venencapsan((r)). In many other publications, however, causality was not properly evaluated by a liver specific and for hepatotoxicity-validated causality assessment method such as the scale of CIOMS (Council for International Organizations of Medical Sciences). CONCLUSIONS: This compilation presents details of herbal hepatotoxicity, assisting thereby clinical assessment of involved physicians in the future. PMID- 22928723 TI - Can the uncertainty appraisal associated with emotion cancel the effect of the hunch period in the Iowa Gambling Task? AB - Research has given little attention to the influence of incidental emotions on the Iowa Gambling Task (IGT), in which processing of the emotional cues associated with each decision is necessary to make advantageous decisions. Drawing on cognitive theories of emotions, we tested whether uncertainty associated emotion can cancel the positive effect of the hunch period, by preventing participants from developing a tendency towards advantageous decisions. Our explanation is that uncertainty appraisals initiate deliberative processing that is irrelevant to process emotional cues, contrary to intuitive processing (Kahneman, 2003; Tiedens & Linton, 2001). As expected, uncertainty associated emotion cancelled the positive effect of the hunch period in the IGT compared to certainty-associated emotion: disgusted participants (certainty associated emotion) and sad participants induced to feel certainty developed a stronger tendency towards advantageous decisions than sad participants induced to feel uncertainty. We discuss the importance of the core components that trigger incidental emotions to predict decision making. PMID- 22928724 TI - Conus consors snail venom proteomics proposes functions, pathways, and novel families involved in its venomic system. AB - For some decades, cone snail venoms have been providing peptides, generally termed conopeptides, that exhibit a large diversity of pharmacological properties. However, little attention has been devoted to the high molecular mass (HMM) proteins in venoms of mollusks. In order to shed more light on cone snail venom HMM components, the proteins of dissected and injected venom of a fish hunting cone snail, Conus consors, were extensively assessed. HMM venom proteins were separated by two-dimensional polyacrylamide gel electrophoresis and analyzed by mass spectrometry (MS). The MS data were interpreted using UniProt database, EST libraries from C. consors venom duct and salivary gland, and their genomic information. Numerous protein families were discovered in the lumen of the venom duct and assigned a biological function, thus pointing to their potential role in venom production and maturation. Interestingly, the study also revealed original proteins defining new families of unknown function. Only two groups of HMM proteins passing the venom selection process, echotoxins and hyaluronidases, were clearly present in the injected venom. They are suggested to contribute to the envenomation process. This newly devised integrated HMM proteomic analysis is a big step toward identification of the protein arsenal used in a cone snail venom apparatus for venom production, maturation, and function. PMID- 22928725 TI - Mapping the active site helix-to-strand conversion of CxxxxC peroxiredoxin Q enzymes. AB - Peroxiredoxins (Prx) make up a family of enzymes that reduce peroxides using a peroxidatic cysteine residue; among these, members of the PrxQ subfamily are proposed to be the most ancestral-like yet are among the least characterized. In many PrxQ enzymes, a second "resolving" cysteine is located five residues downstream from the peroxidatic Cys, and these residues form a disulfide during the catalytic cycle. Here, we describe three hyperthermophilic PrxQ crystal structures originally determined by the RIKEN structural genomics group. We reprocessed the diffraction data and conducted further refinement to yield models with R(free) values lowered by 2.3-7.2% and resolution extended by 0.2-0.3 A, making one, at 1.4 A, one of the best resolved peroxiredoxins to date. Comparisons of two matched thiol and disulfide forms reveal that the active site conformational change required for disulfide formation involves a transition of ~20 residues from a pair of alpha-helices to a beta-hairpin and 3(10)-helix. Each conformation has ~10 residues with a high level of disorder providing slack that allows the dramatic shift, and the two conformations are anchored to the protein core by distinct nonpolar side chains that fill three hydrophobic pockets. Sequence conservation patterns confirm the importance of these and a few additional residues for function. From a broader perspective, this study raises the provocative question of how to make use of the valuable information in the Protein Data Bank generated by structural genomics projects but not described in the literature, perhaps remaining unrecognized and certainly underutilized. PMID- 22928726 TI - Morphology control in block copolymer films using mixed solvent vapors. AB - Solvent vapor annealing of block copolymer thin films can produce a range of morphologies different from the equilibrium bulk morphology. By systematically varying the flow rate of two different solvent vapors (toluene and n-heptane) and an inert gas, phase maps showing the morphology versus vapor pressure of the solvents were constructed for 45 kg/mol polystyrene-block-polydimethylsiloxane diblock copolymer films of different thicknesses. The final morphology was correlated with the swelling of the block copolymer and homopolymer films and the solvent vapor annealing conditions. Self-consistent field theory is used to model the effects of solvent swelling. These results provide a framework for predicting the range of morphologies available under different solvent vapor conditions, which is important in lithographic applications where precise control of morphology and critical dimensions are essential. PMID- 22928727 TI - NK cells inhibit T-bet-deficient, autoreactive Th17 cells. AB - The differentiation and maintenance of Th17 cells require a unique cytokine milieu and activation of lineage-specific transcription factors. This process appears to be antagonized by the transcription factor T-bet, which controls the differentiation of Th1 cells. Considering that T-bet-deficient (T-bet(-/-) ) mice are largely devoid of natural killer (NK) cells due to a defect in the terminal maturation of these cells, and because NK cells can influence the differentiation of T helper cells, we investigated whether the absence of NK cells in T-bet deficient mice contributes to the augmentation of autoreactive Th17 cell responses. We show that the loss of T-bet renders the transcription factors Rorc and STAT3 highly responsive to activation by stimuli provided by NK cells. Furthermore, reconstitution of T-bet(-/-) mice with wild-type NK cells inhibited the development of autoreactive Th17 cells through NK cell-derived production of IFN-gamma. These results identify NK cells as critical regulators in the development of autoreactive Th17 cells and Th17-mediated pathology. PMID- 22928728 TI - Nurse assistants' experience of an intervention focused on a palliative care approach for older people in residential care. AB - BACKGROUND: Nurse assistants working in residential care facilities need support to ensure that they provide high-quality care for the residents and support for relatives, from admission to bereavement. AIM: The aim was to describe the nurse assistants' experience of how an intervention with a palliative care approach, had influenced them in their work in residential care for older people. PARTICIPANTS: Fourteen nurse assistants working in three different municipal residential care facilities. METHODS: Data were collected by means of semi structured individual interviews following an intervention consisting of study circles combined with workshops. The data were analysed using content analysis. RESULT: The nurse assistants felt that, through the intervention, they had gained insight into their understanding of the importance of quality of care. This included an increased awareness of, and respect for, residents' and relatives' needs, and an increased understanding of the importance of the outcome of encounters with residents and their relatives. After the intervention, they also felt there was increased openness and understanding between colleagues. However, the nurse assistants also expressed frustration over obstacles to implementing a palliative care approach, such as lack of resources and supportive leadership. CONCLUSION: The nurse assistants felt that the intervention was positive and encouraged them to provide more person-centred care within the framework of a palliative care approach. Although the intervention was intended to involve and support the management, it was not sufficient. Nurse assistants described lack of resources and supportive leadership. There is, therefore, a need to place greater emphasis on leadership and their support of nurse assistants so that they can provide high-quality care. IMPLICATIONS FOR PRACTICE: To support nurse assistants in the provision of care, clear leadership and opportunities to discuss and reflect on issues associated with care, including systematic improvement work in practice, appear to be essential to ensure high-quality care. PMID- 22928729 TI - Patient versus healthcare professional spontaneous adverse drug reaction reporting: a systematic review. AB - BACKGROUND: Increasing numbers of national pharmacovigilance schemes are accepting adverse drug reaction (ADR) reports from patients. The extent to which patient ADR reports contribute to pharmacovigilance requires comparisons to be made with reports from healthcare professionals (HCPs). OBJECTIVE: This systematic review was conducted to identify all comparative studies of patient and HCP ADR reports to national pharmacovigilance schemes. METHODS: We conducted a systematic review (which complied with the PRISMA statement) and a narrative synthesis of the results. Electronic databases (1996-2011) were searched, including MEDLINE, EMBASE and PHARM-Line, and supplementary searching of reference lists of included studies, authors' personal reference lists and internet searches was carried out. Studies that compared patient and HCP ADR reports submitted to national reporting schemes were considered for inclusion. Independent, duplicate data extraction, quality assessment and risk of bias were undertaken. RESULTS: Of the 949 hits generated, three comparative studies were identified and included in this review. These studies were conducted on the national pharmacovigilance schemes in the Netherlands, Denmark and the UK. Considerable variation was observed across the national schemes in terms of the proportion of total ADR reports submitted by patients. Some of this variation may be explained by the duration that the schemes have been in operation. The number of serious ADR reports as a percentage of total reports was similar for patients compared with HCPs within each study, but varied across studies. Similarities were shown with the Netherlands and the UK in terms of drugs reported. Both studies featured statins and proton pump inhibitors in the top five drugs. Clear differences were shown between patients and HCPs in the body systems affected by ADRs as well as the therapeutic categories reported in both the UK and Danish studies. There was considerable similarity when considering the nature of ADRs reported. The Dutch study also showed similarities between patients and physicians in terms of the types of drugs for which ADRs were reported. CONCLUSIONS: Despite the large and increasing number of national pharmacovigilance schemes that accept ADR reports from patients, few comparative studies have been undertaken of patient and HCP reporting. Comparison across schemes is challenging because of differences in reporting processes, the inclusion criteria of schemes and different reporter types. The true value of patient ADR reports to pharmacovigilance will remain unknown unless more comparative evaluations are undertaken. This systematic review has highlighted both similarities and differences between reporter behaviour, the implications of which, in terms of signal generation, require further exploration. PMID- 22928730 TI - Validation of multivariate outlier detection analyses used to identify potential drug-induced liver injury in clinical trial populations. AB - BACKGROUND: Potential severe liver injury is identified in clinical trials by ALT >3 * upper limits of normal (ULN) and total bilirubin >2 * ULN, and termed 'Hy's Law' by the US FDA. However, there is limited evidence or validation of these thresholds in clinical trial populations. Using liver chemistry data from clinical trials, decision boundaries were built empirically with truncated robust multivariate outlier detection (TRMOD), in a statistically robust manner, and then compared with these fixed thresholds. Additionally, as the analysis of liver chemistry change from baseline has been recently suggested for the identification of liver signals, fold-baseline data was also assessed. OBJECTIVE: The aim of the study was to examine and validate the performance of fixed and empirically derived thresholds for severe liver injury in generally healthy clinical trial populations (i.e. populations without underlying renal, haematological or liver disease). METHODS: Using phase II-IV clinical trial data, ALT and total bilirubin data were analysed using outlier detection methods to compare with empirically derived and fixed thresholds of the FDA's Hy's Law limits, which were then assessed graphically with the FDA's evaluation of Drug-Induced Serious Hepatotoxicity (eDISH) assessing fold-ULN, as well as a modified eDISH (mDISH) to assess fold-baseline liver chemistries. Data from 28 phase II-IV clinical trials conducted by GlaxoSmithKline were aggregated and analysed by the TRMOD algorithm to create decision boundaries. The data consisted of 18 672 predominantly female subjects with a mean age of 44 years and without known liver disease. RESULTS: Among generally healthy clinical trial subjects, the empirically-derived TRMOD boundaries were approximately equivalent to 'Hy's Law'. TRMOD boundaries for identifying outliers were an ALT limit of 3.4 * ULN and a bilirubin limit of 2.1 * ULN, compared with the FDA's 'Hy's Law' of 3 * ULN and bilirubin 2 * ULN. Inter laboratory data variations were observed across the 28 studies, and were diminished by use of baseline-corrected data. By applying TRMOD to baseline corrected data, these boundaries became ALT limit of 3.8 * baseline and bilirubin limit of 4.8 * baseline. Cumulative incidence plots of liver signals identified over time were examined. TRMOD analyses identified normative boundaries and outliers that provide comparative data to detect liver signals in similar trial populations. CONCLUSIONS: TRMOD liver chemistry analyses of clinical trial data in generally healthy subjects have confirmed the FDA's Hy's Law threshold as a robust means of detecting liver safety outliers. TRMOD evaluation of liver chemistry data, by both fold-ULN and fold-baseline, provides complementary analyses and valuable normative data for comparison in similar patient populations. No liver signal is present when new clinical trial data from similar patient populations lies within these normative boundaries. Use of baseline corrected data diminishes inter-laboratory variation and may be more sensitive to possible drug effects. We suggest examining liver chemistries using graphical depictions of both ULN-corrected data (eDISH) and baseline-corrected data (mDISH), as complementary methods. PMID- 22928731 TI - Editorial comment: Single application of high-intensity focused ultrasound as a first-line therapy for clinically localized prostate cancer: 5-year outcomes. PMID- 22928732 TI - Enhanced oral bioavailability of calcium using bovine serum albumin microspheres. AB - Low oral bioavailability of calcium leads to impairment of calcium homeostasis particularly during the high requirement phases of human growth. The objective of the current study was to prepare microspheres of calcium using bovine serum albumin and assess its viability to enhance the oral bioavailability. Microspheres of calcium were prepared by emulsion chemical cross linking method, characterized, evaluated for in vitro release and in vivo absorption. The prepared microspheres were found to be spherical in shape with smooth surface. High entrapment efficiency (>50%), desired particle size (<10 um), high zeta potential values (-30.91 +/- 3.06 to -34.65 +/- 1.01 mV) and low polydispersity indices (0.61 +/- 0.04 to 0.88 +/- 0.05) were recorded in the prepared microspheres. In vitro release profile suggests that <10% of calcium was discharged in the gastric media (in 30 min) from the microspheres prepared using higher drug/polymer ratio (1:1, formulation F4). The pharmacokinetic data obtained in Sprague-Dawley rats showed that the rate and extent of calcium absorption was significantly enhanced following the administration of microspheres. The serum calcium level profiles indicate that the C(max) and AUC(0 alpha) were significantly higher (p < 0.001) when calcium was administered from microspheres when compared to control. Rapid absorption of calcium was also observed from microspheres and may be attributed to a greater uptake into intestinal Peyer's patches. Given the excellent results in the in vivo studies, it can be concluded that calcium loaded bovine serum albumin microspheres could be an effective and promising approach for the oral therapy of calcium. Indeed, this approach can be an alternative to parenteral therapy in acute hypocalcaemia as well. PMID- 22928733 TI - Neutron diffraction of acetazolamide-bound human carbonic anhydrase II reveals atomic details of drug binding. AB - Carbonic anhydrases (CAs) catalyze the hydration of CO(2) forming HCO(3)(-) and a proton, an important reaction for many physiological processes including respiration, fluid secretion, and pH regulation. As such, CA isoforms are prominent clinical targets for treating various diseases. The clinically used acetazolamide (AZM) is a sulfonamide that binds with high affinity to human CA isoform II (HCA II). There are several X-ray structures available of AZM bound to various CA isoforms, but these complexes do not show the charged state of AZM or the hydrogen atom positions of the protein and solvent. Neutron diffraction is a useful technique for directly observing H atoms and the mapping of H-bonding networks that can greatly contribute to rational drug design. To this end, the neutron structure of H/D exchanged HCA II crystals in complex with AZM was determined. The structure reveals the molecular details of AZM binding and the charged state of the bound drug. This represents the first determined neutron structure of a clinically used drug bound to its target. PMID- 22928734 TI - Somatic mutations of PHF6 in patients with chronic myeloid leukemia in blast crisis. PMID- 22928735 TI - Glycosidase inhibition by all 10 stereoisomeric 2,5-dideoxy-2,5-iminohexitols prepared from the enantiomers of glucuronolactone. AB - The enantiomers of glucuronolactone are excellent chirons for the synthesis of the 10 stereoisomeric 2,5-dideoxy-2,5-iminohexitols by formation of the pyrrolidine ring by nitrogen substitution at C2 and C5, with either retention or inversion of configuration; the stereochemistry at C3 may be adjusted during the synthesis to give seven stereoisomers from each enantiomer. A definitive side-by side comparison of the glycosidase inhibition of a panel of 13 glycosidases showed that 8 of the 10 stereoisomers showed significant inhibition of at least one glycosidase. PMID- 22928737 TI - Isolation, identification and enrichment of type a spermatogonia from the testis of chinese cross-bred buffaloes (swamp * river). AB - The proportion of type A spermatogonia in the isolated testis cells is a prerequisite for conducting experiments and the manipulation of these germ cells. Thus, this study was designed to examine the wide range of strategies for the isolation, identification and enrichment of type A spermatogonia in pre-pubertal buffalo calves (3-6 months). Histological findings revealed the presence of maximum number of type A spermatogonia at 5 months, which was further confirmed by DBA immunohistochemistry. In a newly modified strategy for the isolation of testis tissues, mincing followed by trituration and two rounds of digestion with collagenase, hyaluronidase and DNase yielded more than 95% testis cell population. Differential plating with laminin, poly-l-lysine and gelatin significantly (p < 0.05) affected the purity of type A spermatogonia. Among these extracellular matrix (ECMs) molecules, laminin and gelatin performed well and reached at a purity of 39.38 +/- 1.21% and 32.15 +/- 1.60%, respectively. In addition, combination of laminin and gelatin followed by Percoll centrifugation performed the best and yielded >90% type A spermatogonial purity. Moreover, viability of the cells was not affected (p > 0.05) irrespective of different enrichment methods. In conclusion, type A spermatogonia isolation and enrichment system was developed using different ECM molecules in buffaloes, which will aid in solving wide range of problems especially fertility-related problems and transgenic animal production in buffaloes. PMID- 22928736 TI - Irreversible inhibitors of c-Src kinase that target a nonconserved cysteine. AB - We have developed the first irreversible inhibitors of wild-type c-Src kinase. We demonstrate that our irreversible inhibitors display improved potency and selectivity relative to that of their reversible counterparts. Our strategy involves modifying a promiscuous kinase inhibitor with an electrophile to generate covalent inhibitors of c-Src. We applied this methodology to two inhibitor scaffolds that exhibit increased cellular efficacy when rendered irreversible. In addition, we have demonstrated the utility of irreversible inhibitors in studying the conformation of an important loop in kinases that can control inhibitor selectivity and cause drug resistance. Together, we have developed a general and robust framework for generating selective irreversible inhibitors from reversible, promiscuous inhibitor scaffolds. PMID- 22928738 TI - Anesthesia for surgery related to craniosynostosis: a review. Part 1. AB - The management of children with craniosynostosis is multidisciplinary and has evolved significantly over the past five decades. The treatment is primarily surgical. The anesthetic challenges continue to be the management of massive blood transfusion and prolonged anesthesia in small children, often further complicated by syndrome-specific issues. This two-part review aims to provide an overview of the anesthetic considerations for these children. This first part describes the syndromes associated with craniosynostosis, the provision of services in the UK, surgical techniques, preoperative issues, and the induction and maintenance of anesthesia. The second part of this review will explore hemorrhage control, the use of blood products, metabolic disturbance, and postoperative issues. PMID- 22928739 TI - Vanishing thyroid tumors: a diagnostic dilemma after ultrasonography-guided fine needle aspiration. AB - BACKGROUND: Fine-needle aspiration (FNA) is the most accurate and cost-effective method for evaluating thyroid nodules. However, FNA-induced secondary changes completely replacing thyroid tumors (vanishing tumors) may create a novel problem. In this study, we highlight the diagnostic and management issues associated with the unintended consequences of ultrasonography (US)-guided FNA. METHODS: Fourteen thyroid glands (11 women and 3 men, ages 33-64 years) with vanishing tumors were prospectively identified between 2009 and 2012 upon surgical resection. Cytology and histopathology slides were reviewed, and second opinions were obtained when necessary. RESULTS: The cytology of the 14 vanishing tumors was suspicious/positive for papillary thyroid carcinoma (PTC) in 5, indeterminate (atypia of unknown significance) in 5, benign in 2, follicular neoplasm in 1, and nondiagnostic in 1 nodule. Upon thyroidectomy, the vanishing tumors ranged in size from 0.4 to 3.5 cm (median 0.7 cm). Microscopically, the nodules showed cystic degeneration, organizing hemorrhage, granulation tissue, fibrosis, and microcalcifications. In seven tumors, a few residual malignant cells (PTC in five) or residual benign follicles (hemorrhagic cyst in two) at the periphery of the vanishing tumors helped with the final diagnosis. The remaining seven tumors were completely replaced by FNA-induced secondary changes, and had the cytology diagnosis of benign in one, follicular neoplasm in one, and suspicious/positive for PTC in five. Of the latter five, two showed additional separate foci of PTC, while three vanishing tumors (0.5, 1.2, and 1.6 cm) had no residual malignant cells and no additional carcinoma leading to a final diagnosis of negative for malignancy. CONCLUSIONS: US-guided FNA may lead to complete obliteration of thyroid nodules, rendering final diagnosis upon thyroidectomy difficult or impossible. In these unusual circumstances, the possibility that the surgical pathology may be nonrepresentative should be considered if the cytologic features on FNA are sufficient by themselves to support a definitive diagnosis of PTC. PMID- 22928740 TI - CARRS Surveillance study: design and methods to assess burdens from multiple perspectives. AB - BACKGROUND: Cardio-metabolic diseases (CMDs) are a growing public health problem, but data on incidence, trends, and costs in developing countries is scarce. Comprehensive and standardised surveillance for non-communicable diseases was recommended at the United Nations High-level meeting in 2011. AIMS: To develop a model surveillance system for CMDs and risk factors that could be adopted for continued assessment of burdens from multiple perspectives in South-Asian countries. METHODS: DESIGN: Hybrid model with two cross-sectional serial surveys three years apart to monitor trend, with a three-year prospective follow-up of the first cohort.Sites: Three urban settings (Chennai and New Delhi in India; Karachi in Pakistan), 4000 participants in each site stratified by gender and age.Sampling methodology: Multi-stage cluster random sampling; followed by within household participant selection through a combination of Health Information National Trends Study (HINTS) and Kish methods.Culturally-appropriate and methodologically-relevant data collection instruments were developed to gather information on CMDs and their risk factors; quality of life, health-care utilisation and costs, along with objective measures of anthropometric, clinical and biochemical parameters. The cohort follow-up is designed as a pilot study to understand the feasibility of estimating incidence of risk factors, disease events, morbidity, and mortality. RESULTS: The overall participant response rate in the first cross-sectional survey was 94.1% (Chennai 92.4%, n = 4943; Delhi 95.7%, n = 4425; Karachi 94.3%, n = 4016). 51.8% of the participants were females, 61.6% < 45years, 27.5% 45-60years and 10.9% >60 years. DISCUSSION: This surveillance model will generate data on prevalence and trends; help study the complex life-course patterns of CMDs, and provide a platform for developing and testing interventions and tools for prevention and control of CMDs in South-Asia. It will also help understanding the challenges and opportunities in establishing a surveillance system across countries. PMID- 22928741 TI - Validation of FDG uptake in the arterial wall as an imaging biomarker of atherosclerotic plaques with 18F-fluorodeoxyglucose positron emission tomography computed tomography (FDG-PET/CT). AB - BACKGROUND AND PURPOSE: From the literature, the prevalence of fluorodeoxyglucose (FDG) uptake in large artery atherosclerotic plaques shows great heterogeneity. We retrospectively reviewed 100 consecutive patients who underwent FDG-positron emission tomography-computed tomography (PET/CT) imaging of their whole body, to evaluate FDG uptake in the arterial wall. MATERIALS AND METHODS: We retrospectively evaluated 100 whole-body PET-CT scans. The PET images coregistered with CT were reviewed for abnormal 18F-FDG uptake. The mean standard uptake value (SUV) was measured in regions of interest (ROIs). The prevalence of PET+ plaques was determined based on the qualitative PET review, used as the gold standard in a receiver-operating characteristic (ROC) curve analysis to determine an optimal threshold for the quantitative PET analysis. RESULTS: The qualitative, visual assessment demonstrated FDG uptake in the arterial walls of 26 patients. A total of 85 slices exhibited FDG uptake within the arterial wall of 37 artery locations. 11, 17, and 2 patients exhibited FDG uptake within the wall of carotid arteries, of the aorta, and of the iliac arteries, respectively. Only 4 of the 26 patients had positive FDG uptake in more than one artery location. In terms of quantitative analysis, a threshold of 2.8 SUV was associated with a negative predictive value of 99.4% and a positive predictive value of 100% to predict qualitative PET+ plaques. A threshold of 1.8 SUV was associated with a negative predictive value of 100% and a positive predictive value of 99.4%. Area under the ROC curve was .839. CONCLUSION: The prevalence of PET uptake in arterial walls in a consecutive population of asymptomatic patients is low and usually confined to one type of artery, and its clinical relevance in terms of vulnerability to ischemic events remains to be determined. PMID- 22928742 TI - Primary upper-limb lymphoedema. AB - BACKGROUND: Lymphoedema is a general term used to designate pathological, regional accumulation of protein-rich fluid. It can be either primary or secondary, and mainly occurs after cancer treatment. OBJECTIVES: To analyse the clinical and lymphoscintigraphic characteristics of primary upper-limb lymphoedema (ULL). METHODS: All of the patients with ULL were recruited at a single Department of Lymphology between January 2007 and December 2011. RESULTS: In total, 60 patients (33 female, 27 male) were enrolled. For the 54 noncongenital lymphoedemas, the mean age at onset was 38.5 (range 3-82) years. Lymphoedema was unilateral in 51 patients (85%). It always affected the hand, and less often the forearm (55%) or upper arm (23%). Eleven patients (18%) developed cellulitis after onset of lymphoedema, and 21 patients (35%) had associated lower limb lymphoedema (LLL). Forty-six patients (with 49 lymphoedematous limbs) underwent lymphoscintigraphy: axillary lymph node uptake was diminished in 18 (37%), absent in 24 (49%) and normal in seven limbs (14%). Among the 43 patients with unilateral lymphoedema and lymphoscintigraphy, 28 had epitrochlear node visualization, suggesting a rerouting through the deep lymphatic system, with 15 only on the lymphoedematous limb and 22 on the contralateral nonlymphoedematous limb. The median follow-up period was 103 months, and 57/60 patients (95%) considered their lymphoedema to be stable. CONCLUSIONS: Primary ULL appears later in life than LLL, without predominance in either sex. Infectious complications are rare and patients considered the lymphoedema volume stable throughout life. PMID- 22928743 TI - The N-terminal domain of the myelin enzyme 2',3'-cyclic nucleotide 3' phosphodiesterase: direct molecular interaction with the calcium sensor calmodulin. AB - 2',3'-cyclic nucleotide 3'-phosphodiesterase (CNPase) is a quantitatively major enzyme in myelin, where it localizes to the non-compact regions and is bound to the membrane surface. Although its catalytic activity in vitro has been characterized, the physiological function and in vivo substrate of CNPase remain unknown. Especially the N-terminal domain has been poorly characterized; previously, we have shown it is involved in CNPase dimerization and RNA binding. Here, we show that purified CNPase binds to the calcium sensor protein calmodulin (CaM) in a calcium-dependent manner; the binding site is in the N-terminal domain of CNPase. CaM does not affect the phosphodiesterase activity of CNPase in vitro, nor does it influence polyadenylic acid binding. The colocalization of CNPase and CaM during Schwann cell myelination in culture was observed, and CaM antagonists induced the colocalization of CNPase with microtubules in differentiated CG-4 oligodendrocytes. An analysis of post-translational modifications of CNPase from rat brain revealed the presence of two novel phosphorylation sites on Tyr110 and Ser169 within the N-terminal domain. The results indicate a role for the N terminal domain of CNPase in mediating multiple molecular interactions and provide a starting point for detailed structure-function studies on CNPase and its N-terminal domain. PMID- 22928745 TI - Associations between caregiving, social support, and well-being among parents of children with childhood apraxia of speech. AB - This study tested a path model that examined the impact of contextual caregiving variables (i.e., severity of child's symptoms, caregiving demands, and perceived caregiving) and different forms of received romantic partner social support (i.e., emotional, esteem, network, tangible, and information) on depressive and somatic symptoms among parents with a child diagnosed with childhood apraxia of speech (CAS), a severe childhood speech disorder. In total, 169 parents of a child with CAS participated in this study. Results provide some support for one stress process model of caregiving, which further highlights the need to look at relational variables as mediators between contextual stressors and health outcomes in caregiving contexts. PMID- 22928744 TI - Learning from failure--rationale and design for a study about discontinuation of randomized trials (DISCO study). AB - BACKGROUND: Randomized controlled trials (RCTs) may be discontinued because of apparent harm, benefit, or futility. Other RCTs are discontinued early because of insufficient recruitment. Trial discontinuation has ethical implications, because participants consent on the premise of contributing to new medical knowledge, Research Ethics Committees (RECs) spend considerable effort reviewing study protocols, and limited resources for conducting research are wasted. Currently, little is known regarding the frequency and characteristics of discontinued RCTs. METHODS/DESIGN: Our aims are, first, to determine the prevalence of RCT discontinuation for specific reasons; second, to determine whether the risk of RCT discontinuation for specific reasons differs between investigator- and industry-initiated RCTs; third, to identify risk factors for RCT discontinuation due to insufficient recruitment; fourth, to determine at what stage RCTs are discontinued; and fifth, to examine the publication history of discontinued RCTs.We are currently assembling a multicenter cohort of RCTs based on protocols approved between 2000 and 2002/3 by 6 RECs in Switzerland, Germany, and Canada. We are extracting data on RCT characteristics and planned recruitment for all included protocols. Completion and publication status is determined using information from correspondence between investigators and RECs, publications identified through literature searches, or by contacting the investigators. We will use multivariable regression models to identify risk factors for trial discontinuation due to insufficient recruitment. We aim to include over 1000 RCTs of which an anticipated 150 will have been discontinued due to insufficient recruitment. DISCUSSION: Our study will provide insights into the prevalence and characteristics of RCTs that were discontinued. Effective recruitment strategies and the anticipation of problems are key issues in the planning and evaluation of trials by investigators, Clinical Trial Units, RECs and funding agencies. Identification and modification of barriers to successful study completion at an early stage could help to reduce the risk of trial discontinuation, save limited resources, and enable RCTs to better meet their ethical requirements. PMID- 22928746 TI - Fractionally delta-doped oxide superlattices for higher carrier mobilities. AB - A two-dimensional (2D) electron gas system in an oxide heterostructure serves as an important playground for novel phenomena. Here, we show that, by using fractional delta-doping to control the interface's composition in La(x)Sr(1 x)TiO(3)/SrTiO(3) artificial oxide superlattices, the filling-controlled 2D insulator-metal transition can be realized. The atomic-scale control of d electron band filling, which in turn contributes to the tuning of effective mass and density of the charge carriers, is found to be a fascinating route to substantially enhanced carrier mobilities. PMID- 22928747 TI - Structural insight into the mechanism of oxygen activation and substrate selectivity of flavin-dependent N-hydroxylating monooxygenases. AB - SidA from the human pathogen Aspergillus fumigatus catalyzes the generation of N(5)-hydroxyornithine in the biosynthesis of siderophores, a reaction essential for virulence. The crystal structures of SidA in complex with ornithine and lysine reveal the geometry of the interactions among flavin, NADP(+), and the substrate amine group that underlie the hydroxylation reaction. The structural elucidation of the enzyme in complex with arginine provides insight into the role of electrostatics and hydrogen bonding in the mechanism of oxygen activation in this family of enzymes. PMID- 22928748 TI - A review of the pharmacology and clinical uses of pimobendan. AB - OBJECTIVE: To review the pharmacology, research developments, and clinical uses of pimobendan DATA SOURCES: Original research articles and clinical studies from 1984 to August 2011. VETERINARY DATA SYNTHESIS: Pimobendan is approved for use in dogs for the treatment of congestive heart failure (CHF) secondary to chronic valvular heart disease (CVHD) and dilated cardiomyopathy (DCM). Expert-based veterinary guidelines recommend the use of pimobendan in the management of acute, hospital-based therapy for patients with CHF attributable to CVHD. CONCLUSIONS: The use of pimobendan, an inodilator with phosphodiesterase 3 (PDE3) inhibitory and calcium-sensitizing properties, is regarded as a component of the standard of care in the management of dogs with CHF secondary to both DCM and CVHD. Further studies are warranted to confirm the safety and efficacy of pimobendan for the off-label use of this drug in asymptomatic CVHD, pulmonary arterial hypertension, asymptomatic myocardial diseases, CHF from all other causes and in cats with CHF. PMID- 22928749 TI - Early nutritional support is associated with decreased length of hospitalization in dogs with septic peritonitis: A retrospective study of 45 cases (2000-2009). AB - OBJECTIVE: To determine whether the timing and route of nutritional support strategy affect length of hospitalization in dogs with naturally occurring septic peritonitis. DESIGN: Retrospective study encompassing cases from 2000 to 2009. SETTING: University teaching hospital. ANIMALS: Forty-five dogs that survived septic peritonitis. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Nutritional strategy for each dog was categorized as either enteral nutrition (EN: free choice voluntary eating or assisted tube feeding) or central parenteral nutrition (CPN). Early nutritional support was defined as consistent caloric intake initiated within 24 hours postoperatively. Consistent caloric intake occurring after 24 hours was defined as delayed nutritional support. Data reflective of nutritional status included body condition score, serum albumin concentration, and duration of inappetence before and during hospitalization. Body weight change from the beginning to the end of hospitalization was calculated. A modified Survival Prediction Index 2 score was calculated for each dog at admission. Additional clinical data recorded for comparison of illness severity included indicators of severe inflammation (eg, presence of toxic changes in neutrophils and immature neutrophils), coagulopathy (eg, prolonged prothrombin time and activated partial thromboplastin time), the use of vasopressors and blood transfusions, and presence of concurrent illnesses. Nutrition-related complications were classified as mechanical, metabolic, or septic complications. Multivariate linear regression analyses were used to determine the relationship of nutritional strategy with hospitalization length, while considering the presence of nutrition-related complications, the nutritional status- and illness severity-related variables. While controlling for other variables, dogs that received early nutrition had significantly shorter hospitalization length (by 1.6 days). No statistically significant association was found between route of nutrition and hospitalization length. The presence of concurrent illnesses and nutrition-related metabolic complications were also associated with longer hospitalization length (by 2.1 and 2.4 days, respectively). CONCLUSION: Early nutritional support in dogs with septic peritonitis is associated with a shorter hospitalization length. PMID- 22928750 TI - Curvilinear relationship between phonological working memory load and social emotional modulation. AB - Accumulating evidence suggests that working memory load is an important factor for the interplay between cognitive and facial-affective processing. However, it is unclear how distraction caused by perception of faces interacts with load related performance. We developed a modified version of the delayed match-to sample task wherein task-irrelevant facial distracters were presented early in the rehearsal of pseudoword memoranda that varied incrementally in load size (1 syllable, 2-syllables, or 3-syllables). Facial distracters displayed happy, sad, or neutral expressions in Experiment 1 (N=60) and happy, fearful, or neutral expressions in Experiment 2 (N=29). Facial distracters significantly disrupted task performance in the intermediate load condition (2-syllable) but not in the low or high load conditions (1- and 3-syllables, respectively), an interaction replicated and generalised in Experiment 2. All facial distracters disrupted working memory in the intermediate load condition irrespective of valence, suggesting a primary and general effect of distraction caused by faces. However, sad and fearful faces tended to be less disruptive than happy faces, suggesting a secondary and specific valence effect. Working memory appears to be most vulnerable to social-emotional information at intermediate loads. At low loads, spare capacity is capable of accommodating the combinatorial load (1-syllable plus facial distracter), whereas high loads maximised capacity and deprived facial stimuli from occupying working memory slots to cause disruption. PMID- 22928751 TI - Oxidative stress acts on special membrane proteins to reduce the viability of Pseudomonas syringae pv tomato. AB - Reactive oxygen species (ROS) play a vital role in reducing the viability of invading pathogens during plant-pathogen interactions. To understand how oxidative stress caused by ROS reduces cell viability, it is important to identify the proteins affected by ROS. In the present study, we investigated the changes in the expression of proteins from the outer and inner membrane fractions in Pseudomonas syringae pv tomato DC3000 under oxidative stress through membrane subproteomics. A total number of 17 differentially expressed proteins from the outer and inner membrane fractions were identified, among which 11 proteins belong to transporters, such as porins and ABC transporters. Their abundance was all decreased under oxidative stress, indicating that transporters are likely to be affected by oxidative stress. The function of two identified transporters was further characterized by constructing their gene mutant and overexpression strains. We found that mutation of one transporter gene PSPTO_1720 rendered Pseudomonas more sensitive to oxidative stress, whereas overexpression of this gene made the strain more resistant. By comparison, the mutant and overexpression strains of another transporter gene PSPTO_2152 exhibited the same sensitivity to oxidative stress compared with the wild-type. Our data suggest that oxidative stress reduces the viability of bacterial cells by acting on special transporters. PMID- 22928752 TI - Testicular microlithiasis is not a risk factor for the production of antisperm antibody in infertile males. AB - Testicular microlithiasis (TM) is a pathological event characterised by the presence of microliths within the testicular entities, and such calcium deposition is thought to have deleterious impacts on the structure of blood testis barrier (BTB). Breaches in the BTB appear to be a risk factor for antisperm antibody (ASA) production, which is reported to have negative influence on human fertility. Thus, the theories are provocative that ASA formation is elicited in TM men, and the resultant ASA will accordingly affect the fecundity in these men. To illustrate these hypotheses, this study enrolled 22 infertile men incidentally diagnosed with TM by testicular ultrasound evaluation. Sperm samples were collected, and direct immunobead test was used to determine the ASA levels. None of the infertile men with TM were found to display significant levels of ASA, whilst relatively abnormal sperm parameters in these cases were revealed by semen analysis. These observations suggest that TM exposure does not increase the risk of ASA production in infertile men, and therefore, ASA is discarded as an active participant in the development of infertility in TM men. Nevertheless, disrupted spermatogenesis resulting from TM may, at least in part, have certain implications for the pathogenesis of TM-associated infertility. PMID- 22928753 TI - A facile route to recover intrinsic graphene over large scale. AB - The intrinsic properties of initially p-type doped graphene (grown by chemical vapor deposition (CVD)) can be recovered by buffered oxide etch (BOE) treatment, and the dominant factor governing p-type doping is identified as the H(2)O/O(2) redox system. Semi-ionic C-F bonding prevents the reaction between the products of the H(2)O/O(2) redox system and graphene. BOE-treated graphene field effect transistors (FETs) subsequently exposed to air, became p-type doped due to recovery of the H(2)O/O(2) redox system. In comparison, poly(methyl methacrylate) (PMMA)-coated graphene FETs had improved stability for maintaining the intrinsic graphene electronic properties. PMID- 22928754 TI - A systematic review of the effectiveness and cost-effectiveness of bilateral multichannel cochlear implants in adults with severe-to-profound hearing loss. AB - BACKGROUND: In the UK, approximately 10 000 people have cochlear implants, more than 99% with a unilateral implant. Evidence shows that adults implanted bilaterally may benefit from binaural advantages; however, systematic review evidence is limited. OBJECTIVES OF THE REVIEW: To conduct a systematic review to discover the evidence for effectiveness and cost-effectiveness of using bilateral cochlear implants in adults with severe-to-profound hearing loss by comparing their effectiveness with unilateral cochlear implantation or unilateral cochlear implantation and acoustic hearing aid in the contralateral ear. TYPE OF REVIEW: Systematic review. SEARCH STRATEGY: This examined 16 electronic databases, plus bibliographies and references for published and unpublished studies. EVALUATION METHOD: Abstracts were independently assessed against inclusion criteria by two researchers, and disagreements were resolved. Selected papers were then retrieved and further independently assessed in a similar way. Included studies had their data extracted by one reviewer and checked by another. RESULTS: Searches yielded 2892 abstracts producing 19 includable studies. Heterogeneity between studies precluded meta-analysis. However, all studies reported that bilateral cochlear implants improved hearing and speech perception: one randomised controlled trial found a significant binaural benefit over the first ear alone for speech and noise from the front (12.6 +/- 5.4%, P < 0.001) and when noise was ipsilateral to the first ear (21 +/- 6%, P < 0.001); and another found a significant benefit for spatial hearing at 3 and 9 months post-implantation compared with pre implantation [mean difference (sd) scores: 3 months = 1.46 (0.83-2.09), P < 0.01].Quality of life results varied, showing bilateral implantation may improve quality of life in the absence of worsening tinnitus. Limited cost-effectiveness evidence showed that bilateral implantation is probably only cost-effective at a willingness-to-pay threshold above L62 000 per quality adjusted life year. CONCLUSIONS: Despite inconsistency in the quality of available evidence, the robustness of systematic review methods gives weight to the positive findings of included studies demonstrating that bilateral implantation is clinically effective in adults but unlikely to be cost-effective. PMID- 22928755 TI - Racial disparities in African Americans with diabetes: process and outcome mismatch. AB - BACKGROUND: Over the past 2 decades, numerous studies have demonstrated the existence of racial disparities in patient care in the United States. Specifically, African Americans with diabetes are less likely to have recommended process of care measures performed and outcome benchmarks for quality of care. OBJECTIVES: To evaluate the delivery of diabetes care (processes and outcomes) associated with racial categories using a national web-based registry-the American Osteopathic Association Clinical Assessment Program (AOA-CAP). STUDY DESIGN: A retrospective analysis of data retrieved from the AOA-CAP database on outcomes and process measures for diabetes. METHODS: A total of 10,699 Caucasian and African American patients who received diabetes care had data entered into the AOA-CAP registry between July 1, 2005, and October 30, 2010. African Americans represented 3123 patients (29%), Caucasians 7576 (71%). Demographic, process of care, and outcomes comparisons between ethnicities were carried out using ?2 and t tests. Composite measures of process and outcomes of diabetes care were created to investigate the effect of race on care. RESULTS: The process of care composite measure was significantly different among African American patients (P = .02) who were more likely to receive all indicated care than Caucasian patients (33.9% vs 31.6%). Evaluation of the composite outcome measure, which quantifies the percentage of patients achieving control of all 3 intermediate outcomes, was (P <.001) lower in African Americans than in Caucasians (8.1% vs 12.3%). CONCLUSIONS: African American patients with diabetes were as likely or more likely to have recommended process of care measures performed. In spite of this, intermediate diabetes outcomes were still poorer in the same African American population. PMID- 22928756 TI - Cardiac risk is not associated with hypertension treatment intensification. AB - OBJECTIVES: Considering cardiovascular (CV) risk could make clinical care more efficient and individualized, but most practice guidelines focus on single risk factors. We sought to determine if hypertension treatment intensification (TI) is more likely in patients with elevated CV risk. STUDY DESIGN: Prospective cohort study of 856 US veterans with diabetes and elevated blood pressure (BP). METHODS: We used multilevel logistic regression to compare TI across 3 CV risk groups: those with history of heart disease, a high-risk primary prevention group (10 year event risk >20% but no history of heart disease), and those with low/ medium CV risk (10-year event risk <20%). RESULTS: There were no significant differences in TI rates across risk groups, with adjusted odds ratios (ORs) of 1.19 (95% confidence interval 0.77-1.84) and 1.18 (0.76-1.83) for high-risk patients and those with a history of CVD, respectively, compared with those of low/medium risk. Several individual risk factors were associated with higher rates of TI: systolic BP, mean BP in the prior year, and higher glycated hemoglobin. Self reported home BP <140/90 mm Hg was associated with lower rates of TI. Incorporating CV risk into TI decision algorithms could prevent an estimated 38% more cardiac events without increasing the number of treated patients. CONCLUSIONS: While an individual's BP alters clinical decisions about TI, overall CV risk does not appear to play a role in clinical decision making. Adoption of TI decision algorithms that incorporate CV risk could substantially enhance the efficiency and clinical utility of CV preventive care. PMID- 22928757 TI - A technology solution for the high-tech diagnostic imaging conundrum. AB - OBJECTIVES: (1) To describe a unique initiative to implement a standardized system of electronic decision support for ambulatory orders for hightech diagnostic imaging (HTDI) statewide, and (2) to evaluate the impact of a pilot version of that system, plus prior notification on the volume of such orders. STUDY DESIGN: Description of the initiative and analysis of aggregated claims data. METHODS: Claims data for HTDI studies were aggregated from the main health plans in the state from 2003 to 2010 by the regional quality improvement collaborative that also facilitated the pilot and subsequent initiative being implemented in 2011 throughout Minnesota. RESULTS: Aggregate ambulatory statewide orders for HTDI tests increased from 32 to 41 per 1000 members from 2003 to 2006 (9% per year) at which point the rate leveled off through 2010. This trajectory change was simultaneous with implementation of an electronic medical record-based decision-support system for all ambulatory HTDI orders from 45% of the physicians in the state, as well as a prior notification/authorization approach by payers for the rest of the HTDI orders. CONCLUSIONS: Although it is not possible to disentangle the effects of these separate approaches, the much greater physician acceptance of the decision support system has led payers to financially support the creation of a unique statewide implementation of a version of this system to replace prior notification/authorization approaches. PMID- 22928758 TI - Primary nonadherence to medications in an integrated healthcare setting. AB - OBJECTIVES: To measure primary nonadherence (PNA) rates for 10 therapeutic drug groups and identify factors associated with PNA to chronic and acute medications. STUDY DESIGN: Retrospective cohort study. METHODS: New prescriptions written in an integrated healthcare system for study drugs were identified between December 1, 2009, and February 28, 2010. PNA was defined as the failure to fill a prescription within 14 days of when it was written. PNA rates were calculated by drug group and descriptive statistics were performed. Multivariable logistic regression was used to identify significant patient, provider, and prescription characteristics associated with PNA. Results were stratified by acute versus chronic treatment. RESULTS: A total of 569,095 new prescriptions were written during the 3-month period. Across all drug groups, the PNA rate was 9.8%. PNA rates for individual drug groups varied and were highest for osteoporosis medications (22.4%) and antihyperlipidemics (22.3%). Patients who filled at least 1 prescription in the prior year (odds ratio [OR], 95% confidence interval [CI] for acute = 0.06 [0.06-0.07], for chronic = 0.11 [0.10-0.12]) or had a prescription for a symptomatic disease (OR = 0.51 [0.48-0.53]) were more likely to fill their prescription. Patients were more likely to be primary nonadherent if they were black (OR acute = 1.30 [1.25-1.36], chronic = 1.26 [1.18-1.33]) or treatment-naive to therapy (OR acute = 2.52 [2.36-2.7], chronic=1.07 [1.03 1.12]). CONCLUSIONS: Overall PNA was 9.8% but individual PNA rates varied by therapeutic drug group. Factors of PNA were mostly consistent across drug groups, but some depended on whether the treatment was acute or chronic. PMID- 22928759 TI - Which components of health information technology will drive financial value? AB - OBJECTIVES: The financial effects of electronic health records (EHRs) and health information exchange (HIE) are largely unknown, despite unprecedented federal incentives for their use. We sought to understand which components of EHRs and HIE are most likely to drive financial savings in the ambulatory, inpatient, and emergency department settings. STUDY DESIGN: Framework development and a national expert panel. METHODS: We searched the literature to identify functionalities enabled by EHRs and HIE across the 3 healthcare settings. We rated each of 233 functionality-setting combinations on their likelihood of having a positive financial effect. We validated the top-scoring functionalities with a panel of 28 national experts, and we compared the high-scoring functionalities with Stage 1 meaningful use criteria. RESULTS: We identified 54 high-scoring functionality- setting combinations, 27 for EHRs and 27 for HIE. Examples of high-scoring functionalities included providing alerts for expensive medications, providing alerts for redundant lab orders, sending and receiving imaging reports, and enabling structured medication reconciliation. Of the 54 high-scoring functionalities, 25 (46%) are represented in Stage 1 meaningful use. Many of the functionalities not yet represented in meaningful use correspond with functionalities that focus directly on healthcare utilization and costs rather than on healthcare quality per se. CONCLUSIONS: This work can inform the development and selection of future meaningful use measures; inform implementation efforts, as clinicians and hospitals choose from among a "menu" of measures for meaningful use; and inform evaluation efforts, as investigators seek to measure the actual financial impact of EHRs and HIE. PMID- 22928760 TI - Patient medical group continuity and healthcare utilization. AB - OBJECTIVES: To measure continuity among medical groups of insured patients over a 5-year period and to test whether group continuity of care is associated with healthcare utilization and costs. STUDY DESIGN: Retrospective observational study. METHODS: We studied natural patient behavior by using insurance claims data in the absence of any medical group or health plan incentives for continuity. We conducted the study through a retrospective analysis of administrative data of 121,780 patients enrolled from 2005 to 2009 in HealthPartners, a large nonprofit Minnesota health plan. Each year, patients were attributed to the medical group where they received the greatest number of primary care visits. Multilevel multiple regression models were used to estimate the association of annualized medical cost and utilization with attribution and continuity categories. RESULTS: Although patients with high medical group continuity were older and had more comorbidities than patients with medium or low continuity of care, they had a consistently lower probability of any inpatient expenditure or any emergency department (ED) utilization and lower total medical costs. CONCLUSIONS: Although a small proportion, health plan members who visited a primary care provider but had low or medium continuity among medical groups had higher inpatient and ED use than those with high continuity. Improved coordination and integration has potential to lower utilization and costs in this group. PMID- 22928761 TI - Cost-sharing and initiation of disease-modifying therapy for multiple sclerosis. AB - OBJECTIVES: To assess the effects of patient cost sharing on initiation of disease-modifying therapies (DMTs) in multiple sclerosis (MS). STUDY DESIGN: Retrospective claims database study of privately insured patients newly diagnosed with MS between 2004 and 2008 from 33 large employers. METHODS: We assessed the effects of plan-level cost-sharing on DMT initiation during a 2-year follow-up period after diagnosis. Incident cases were identified by 2 or more claims with ICD-9 codes for MS within a year, subsequent to a year with no such claims. Covariates for adjustment included age, gender, relationship to primary beneficiary, comorbid conditions, and calendar year, as well as unobserved factors that did not vary within plans over time. RESULTS: Out of a sample of 3460 patients meeting criteria for inclusion, only 17% initiated a DMT within 2 years of diagnosis. An increase in the cost-sharing rate from zero to the 95th percentile (17.8%) was predicted to decrease initiation within 2 years of diagnosis by 2.9 percentage points, or 12.7% (P = .019). CONCLUSIONS: High cost sharing is associated with delayed initiation of effective MS therapies. PMID- 22928762 TI - Slowing Medicare spending growth: reaching for common ground. PMID- 22928764 TI - Demographic analysis of randomized controlled trials in bladder cancer. AB - WHAT'S KNOWN ON THE SUBJECT? AND WHAT DOES THE STUDY ADD?: Results from well designed randomized controlled trials usually provide the strongest evidence possible in favour of one medical intervention over another. For this reason, it is of paramount importance to conduct such trials in bladder cancer, where randomized trials are lacking, in particular to answer questions that have so far confounded us or to investigate the efficacy of new diagnostic tools or interventions. This study provides a demographic analysis of randomized controlled trials published in bladder cancer between the years of 1995 and 2010, with only 238 articles identified. Less than one-third of these reported a statistical power calculation, and only 8% were double-blinded. With many publications inaccurately labelled as randomized trials, we reveal the scarcity of trials performed over the given time period, even compared with other cancers with similar incidence, and highlight the need for more well designed trials to be conducted. OBJECTIVE: To demographically examine randomized controlled trials (RCTs) that have been conducted in bladder cancer over a predefined time period. METHODS: Various techniques have been described to detect RCTs using different databases. We searched the MEDLINE database by crossing the heading 'Urinary bladder neoplasms' with the MeSHs 'Clinical trial$.mp. OR clinical trial.pt. OR random:.mp. OR tu.xs.' between 1995 and 2010. For the RCTs identified, analysis was performed on each RCT, placing particular emphasis on modality of intervention, cohort size, principal author, region, journal type, disease status, histology, blinding, number of centres involved, performance of a statistical power calculation, accrual status and trial support. RESULTS: Of 5002 RCT bladder cancer papers retrieved over the given period, only 238 represented actual RCTs after manual appraisal. More than half of the RCTs investigated medical and surgical therapies (54.2%), and only half had a sample size of >100 patients. A small percentage of studies were double-blinded (8.0%), and there was an almost equal distribution of multicentre vs single centre trials (54.6% vs 45.4%). More studies were conducted in Europe (61.3%) than the rest of the world combined, with urologists principally the lead investigators in the majority (72.3%). Most studies were conducted on patients with urothelial carcinoma (97.1%), with less than one-third reporting a statistical power calculation (31.5%). CONCLUSIONS: Only 238 RCTs were published for bladder cancer between 1995 and 2010. RCTs are under-utilized in bladder cancer. More trials need to be designed with larger sample sizes in order to optimize diagnostic and treatment strategies for patients with bladder cancer. PMID- 22928765 TI - Substrate-assisted catalytic mechanism of O-GlcNAc transferase discovered by quantum mechanics/molecular mechanics investigation. AB - In higher eukaryotes, a variety of proteins are post-translationally modified by adding O-linked N-acetylglucosamine (GlcNAc) residue to serine or threonine residues. Misregulation of O-GlcNAcylation is linked to a wide variety of diseases, such as diabetes, cancer, and neurodegenerative diseases, including Alzheimer's disease. GlcNAc transfer is catalyzed by an inverting glycosyltransferase O-GlcNAc transferase (uridine diphospho-N acetylglucosamine:polypeptide beta-N-acetylaminyltransferase, OGT) that belongs to the GT-B superfamily. The catalytic mechanism of this metal-independent glycosyltransferase is of primary importance and is investigated here using QM(DFT)/MM methods. The structural model of the reaction site used in this paper is based on the crystal structures of OGT. The entire enzyme-substrate system was partitioned into two different subsystems: the QM subsystem containing 198 atoms, and the MM region containing 11,326 atoms. The catalytic mechanism was monitored by means of three two-dimensional potential energy maps calculated as a function of three predefined reaction coordinates at different levels of theory. These potential energy surfaces revealed the existence of a concerted S(N)2-like mechanism, in which a nucleophilic attack by O(Ser), facilitated by proton transfer to the catalytic base, and the dissociation of the leaving group occur almost simultaneously. The transition state for the proposed reaction mechanism at the MPW1K level was located at C1-O(Ser) = 1.92 A and C1-O1 = 3.11 A. The activation energy for this passage was estimated to be ~20 kcal mol(-1). These calculations also identified, for the first time for glycosyltransferases, the substrate-assisted mechanism in which the N-acetamino group of the donor participates in the catalytic mechanism. PMID- 22928766 TI - Reduced cerebral blood flow within the default-mode network and within total gray matter in major depression. AB - The default-mode network (DMN) was shown to have aberrant blood oxygenation-level dependent (BOLD) activity in major depressive disorder (MDD). While BOLD is a relative measure of neural activity, cerebral blood flow (CBF) is an absolute measure. Resting-state CBF alterations have been reported in MDD. However, the association of baseline CBF and CBF fluctuations is unclear in MDD. Therefore, the aim was to investigate the CBF within the DMN in MDD, applying a strictly data-driven approach. In 22 MDD patients and 22 matched healthy controls, CBF was acquired using arterial spin labeling (ASL) at rest. A concatenated independent component analysis was performed to identify the DMN within the ASL data. The perfusion of the DMN and its nodes was quantified and compared between groups. The DMN was identified in both groups with high spatial similarity. Absolute CBF values within the DMN were reduced in MDD patients (p<0.001). However, after controlling for whole-brain gray matter CBF and age, the group difference vanished. In patients, depression severity was correlated with reduced perfusion in the DMN in the posterior cingulate cortex and the right inferior parietal lobe. Hypoperfusion within the DMN in MDD is not specific to the DMN. Still, depression severity was linked to DMN node perfusion, supporting a role of the DMN in depression pathobiology. The finding has implications for the interpretation of BOLD functional magnetic resonance imaging data in MDD. PMID- 22928767 TI - In vivo studies on the oridonin-loaded nanostructured lipid carriers. AB - Oridonin (ORI)-loaded Nanostructured lipid carriers (NLC) were prepared by emulsion-evaporation and low temperature-solidification technique, and evaluated for morphological observation, particle size, zeta potential and in vitro drug release. Next, the characteristics of biodistribution and pharmacokinetics in vivo were examined. The average particle size of resultant NLC was 245.2 nm and the zeta potential was found to be -38.77 mV. The in vivo characteristics of ORI loaded NLC were studied after intravenous administration using Kunming strain mice as experimental animals. An ORI control solution was studied parallelly. In tested organs, the distribution of ORI-loaded NLC to liver was higher than that of free drug. ORI-loaded NLC showed higher AUC (area under tissue concentration time curve) values and circulated in the blood stream for a longer time compared with ORI solution. These results support the potential applications of NLC for the delivery of ORI. PMID- 22928768 TI - Chemo- and regioselective monosulfonylation of nonprotected carbohydrates catalyzed by organotin dichloride under mild conditions. AB - The catalytic regioselective monosulfonylation of nonprotected carbohydrates using organotin dichloride under mild conditions is examined. The carbohydrates were chemo- and regioselectively converted to the corresponding monosulfonates in the presence of monoalcohols using catalytic dibutyltin dichloride. The regioselectivity of the sulfonylation is attributed to the intrinsic character of the carbohydrates derived from the relative stereochemistry between their hydroxy groups. PMID- 22928769 TI - Guideline on the investigation and management of acute transfusion reactions. Prepared by the BCSH Blood Transfusion Task Force. AB - Although acute non-haemolytic febrile or allergic reactions (ATRs) are a common complication of transfusion and often result in little or no morbidity, prompt recognition and management are essential. The serious hazards of transfusion haemovigilance organisation (SHOT) receives 30-40 reports of anaphylactic reactions each year. Other serious complications of transfusion, such as acute haemolysis, bacterial contamination, transfusion-related acute lung injury (TRALI) or transfusion-associated circulatory overload (TACO) may present with similar clinical features to ATR. This guideline describes the approach to a patient developing adverse symptoms and signs related to transfusion, including initial recognition, establishing a likely cause, treatment, investigations, planning future transfusion and reporting within the hospital and to haemovigilance organisations. Key recommendations are that adrenaline should be used as first line treatment of anaphylaxis, and that transfusions should only be carried out where patients can be directly observed and where staff are trained in manging complications of transfusion, particularly anaphylaxis. Management of ATRs is not dependent on classification but should be guided by symptoms and signs. Patients who have experienced an anaphylactic reaction should be discussed with an allergist or immunologist, in keeping with UK resuscitation council guidelines. PMID- 22928770 TI - Difference equations with the Allee effect and the periodic Sigmoid Beverton-Holt equation revisited. AB - In this paper, we investigate the long-term behaviour of solutions of the periodic Sigmoid Beverton-Holt equation [Formula: see text] where the a ( n ) and delta( n ) are p-periodic positive sequences. Under certain conditions, there are shown to exist an asymptotically stable p-periodic state and a p-periodic Allee state with the property that populations smaller than the Allee state are driven to extinction while populations greater than the Allee state approach the stable state, thus accounting for the long-term behaviour of all initial states. This appears to be the first study of the equation with variable delta. The results are discussed with possible interpretations in Population Dynamics with emphasis on fish populations and smooth cordgrass. PMID- 22928771 TI - Spontaneous and transient defence against bacteriophage by phase-variable glucosylation of O-antigen in Salmonella enterica serovar Typhimurium. AB - As natural killers of bacteria, bacteriophages have forced bacteria to develop a variety of defence mechanisms. The alteration of host receptors is one of the most common bacterial defence strategies against phage infection, which completely blocks phage attachment but comes at a potential fitness cost to the bacteria. Here, we report the cost-free, transient emergence of phage resistance in Salmonella enterica subspecies enterica serovar Typhimurium through a phase variable modification of the O-antigen. Phage SPC35 typically requires BtuB as a host receptor but also uses the Salmonella O12-antigen as an adsorption-assisting apparatus for the successful infection of S. Typhimurium. The alpha-1,4 glucosylation of galactose residues in the O12-antigen by phase variably expressed O-antigen glucosylating genes, designated the (LT) (2) gtrABC1 cluster, blocks the adsorption-assisting function of the O12-antigen. Consequently, it confers transient SPC35 resistance to Salmonella without any mutations to the btuB gene. This temporal switch-off of phage adsorption through phase-variable antigenic modification may be widespread among Gram-negative bacteria-phage systems. PMID- 22928772 TI - Real-time noninvasive imaging of fatty acid uptake in vivo. AB - Detection and quantification of fatty acid fluxes in animal model systems following physiological, pathological, or pharmacological challenges is key to our understanding of complex metabolic networks as these macronutrients also activate transcription factors and modulate signaling cascades including insulin sensitivity. To enable noninvasive, real-time, spatiotemporal quantitative imaging of fatty acid fluxes in animals, we created a bioactivatable molecular imaging probe based on long-chain fatty acids conjugated to a reporter molecule (luciferin). We show that this probe faithfully recapitulates cellular fatty acid uptake and can be used in animal systems as a valuable tool to localize and quantitate in real time lipid fluxes such as intestinal fatty acid absorption and brown adipose tissue activation. This imaging approach should further our understanding of basic metabolic processes and pathological alterations in multiple disease models. PMID- 22928773 TI - Sickness certification as a complex professional and collaborative activity--a qualitative study. AB - BACKGROUND: Physicians have an important but problematic task to issue sickness certifications. A manifold of studies have identified a wide spectrum of medical and insurance-related problems in sickness certification. Despite educational efforts aiming to improve physicians' knowledge of social insurance medicine there are no signs of reduction of these problems. We hypothesised that the quality deficits is not only due to lack of knowledge among issuing physicians. The aim of the study was to explore physicians' challenges when handling sickness certification in relation to their professional roles as physicians and to their interaction with different stakeholders. METHODS: One hundred seventy-seven physicians in Stockholm County, Sweden, participated in a sick-listing audit program. Participants identified challenges in handling sick-leave issues and formulated action plans for improvement. Challenges and responsible stakeholders were identified in the action plans. To deepen the understanding facilitators of the program were interviewed. A qualitative content analysis was performed exploring challenge categories and categories of stakeholders with responsibility to initiate actions to improve the quality of the sick-listing process. The challenge categories were then related by their content to professional competence roles in accord with the Canadian Medical Education Directions for Specialists (CanMEDS) framework and to the stakeholder categories. RESULTS: Seven categories of challenges were identified. Practitioner patient interaction, Work capacity assessment, Interaction with the Social Insurance Administration, The patient's workplace and the labour market, Sick-listing practice, Collaboration and resource allocation within the Health Care System, Leadership and routines at the Health Care Unit. The challenges were related to all seven CanMEDS roles. Five categories of stakeholders were identified and several stakeholders were involved in each challenge category. CONCLUSIONS: Physicians performing sickness certification tasks experience a complex variety of challenges. From physician perspective actions to handle these need to be initiated in interaction with both medical and non-medical stakeholders. The relation between the challenges and a well-established professional competence framework revealed a complex pattern. Thus, from a public health perspective, educational activities aimed to improve the sick-listing process should address all physician competences including identification and interaction with stakeholders, and not just knowledge of social insurance medicine. PMID- 22928774 TI - Silver as an antimicrobial: facts and gaps in knowledge. AB - Silver has been used for centuries. Today, silver and silver nanoparticles (AgNPs) are used in a wide range of healthcare, food industry, domiciliary applications, and are commonly found in hard surface materials and textiles. Such an extensive use raises questions about its safety, environmental toxicity and the risks associated with microbial resistance and cross-resistance. If the mechanisms of antimicrobial action of ionic silver (Ag+) have been studied, there is little understanding of AgNPs interactions with microorganisms. There have been excellent reviews on the bacterial resistance mechanisms to silver, but there is a paucity of information on resistance to AgNPs. Silver toxicity and accumulation in the environment has been studied and there is a better understanding of silver concentration and species in different environmental compartments. However, owing to the increased applications of silver and AgNPs, questions remain about the presence and consequences of AgNPs in the environment. This review provides an historical perspective of silver usage, an overview of applications, and combined information of microbial resistance and toxicity. Owing the evidence provided in this review, a call for a better understanding and control of silver usage, and for tighter regulations of silver and AgNPs usage is proposed. PMID- 22928775 TI - Scaling the druggability landscape of human bromodomains, a new class of drug targets. PMID- 22928776 TI - Differential neurite outgrowth is required for axon specification by cultured hippocampal neurons. AB - Formation of an axon is the first morphological evidence of neuronal polarization, visible as a profound outgrowth of the axon compared with sibling neurites. One unsolved question on the mechanism of axon formation is the role of axon outgrowth in axon specification. This question was difficult to assess, because neurons freely extend their neurites in a conventional culture. Here, we leveraged surface nano/micro-modification techniques to fabricate a template substrate for constraining neurite lengths of cultured neurons. Using the template, we asked (i) Do neurons polarize even if all neurites cannot grow sufficiently long? (ii) Would the neurite be fated to become an axon if only one was allowed to grow long? A pattern with symmetrical short paths (20 MUm) was used to address the former question, and an asymmetrical pattern with one path extended to 100 MUm for the latter. Axon formation was evaluated by tau-1/MAP2 immunostaining and live-cell imaging of constitutively-active kinesin-1. We found that (1) neurons cannot polarize when extension of all neurites is restricted and that (2) when only a single neurite is permitted to grow long, neurons polarize and the longest neurite becomes the axon. These results provide clear evidence that axon outgrowth is required for its specification. PMID- 22928777 TI - Autophagy and apoptosis-related genes in chronic liver disease and hepatocellular carcinoma. AB - BACKGROUND: Dysregulation of autophagy is important in the pathogenesis of many diseases, including cancer. Several aspects of the biological role of autophagy are however still unclear and the relationship between apoptosis and autophagy, particularly in the liver has yet to be thoroughly explored. In this study we evaluated the expression of Beclin 1 (one of the main autophagocytic agents, which bridges autophagy, apoptosis and both differentiation), and both pro- (Bad, Bax) and anti-apoptotic (Bcl-2, Bcl-xL) factors in liver samples from patients with different stages of liver disease. METHODS: The study concerned 93 patients from 49 cases of chronic hepatitis (CH) (30 HCV and 19 HBV-related), 13 of cirrhosis (CIRR) (10 HCV and 3 HBV-related), 21 of hepatocellular carcinoma (both HCC and peritumoral tissues [PHCC]), and 10 controls (CONTR). Real-time PCR and Western blotting were used to measure mRNA and protein expression levels. RESULTS: Beclin 1 mRNA levels were lower in HCC than in CH (P = 0.010) or CIRR (P = 0.011), and so were the Bcl-xL transcripts (P < 0.0001). Bad mRNA levels were higher in CH and CIRR than in CONTR, while Bax transcripts were increased in all tissues (P = 0.036). PHCC expressed the highest Bcl-2 mRNA levels. HBV-related CH tissues showed significantly higher Bcl-xL and Bad mRNA levels than HCV-related CH (P = 0.003 and P = 0.016, respectively). CONCLUSIONS: High Beclin 1, Bcl-xL and Bad levels in CH and CIRR tissues suggest an interaction between autophagy and apoptosis in the early and intermediate stages of viral hepatitis. In HCC these processes seem to be downregulated, probably enabling the survival and growth of neoplastic hepatocytes. PMID- 22928778 TI - Reversible splenial lesion in postpartum cerebral angiopathy: a case report. AB - Reversible lesions on magnetic resonance imaging that transiently restrict diffusion in the splenium of the corpus callosum (SCC) without any other accompanying lesions have been reported in various clinical conditions. We offer the first report of postpartum cerebral angiopathy with reversible SCC lesions. PMID- 22928779 TI - Optimising technical skills and physical loading in small-sided basketball games. AB - Differences in physiological, physical, and technical demands of small-sided basketball games related to the number of players, court size, and work-to-rest ratios are not well characterised. A controlled trial was conducted to compare the influence of number of players (2v2/4v4), court size (half/full court) and work-to-rest ratios (4x2.5 min/2x5 min) on the demands of small-sided games. Sixteen elite male and female junior players (aged 15-19 years) completed eight variations of a small-sided game in randomised order over a six-week period. Heart rate responses and rating of perceived exertion (RPE) were measured to assess the physiological load. Movement patterns and technical elements were assessed by video analysis. There were ~60% more technical elements in 2v2 and ~20% more in half court games. Heart rate (86 +/- 4% & 83 +/- 5% of maximum; mean +/- SD) and RPE (8 +/- 2 & 6 +/- 2; scale 1-10) were moderately higher in 2v2 than 4v4 small-sided games, respectively. The 2v2 format elicited substantially more sprints (36 +/-12%; mean +/-90% confidence limits) and high intensity shuffling (75 +/-17%) than 4v4. Full court games required substantially more jogging (9 +/-6%) compared to half court games. Fewer players in small-sided basketball games substantially increases the technical, physiological and physical demands. PMID- 22928780 TI - The authoritative metaphor and social change: Surgeon General C. Everett Koop's Direct Mailer, "Understanding AIDS". AB - In 1988, Surgeon General C. Everett Koop published "Understanding AIDS," the nation's first and only direct mailing sent to every private home in the country. His appeals therein were driven by what we label authoritative metaphors. Communicated by and/or attributed to persons of authority, authoritative metaphors capitalize on the symbolic force of sanctioned power by appealing to the ethos of office. In "Understanding AIDS," we find that Koop drew from his positions as a surgeon and a general, respectively, to equate AIDS with an unprecedented plague and an unprecedented war. He created new authoritative metaphors out of the vestiges of familiar metaphors related to disease and public health and thereby portrayed AIDS as a recognizable but decisively unique dilemma requiring distinct preventative behaviors. PMID- 22928781 TI - Fluctuation-mediated optical screening of nanoparticles. AB - Inspired by biological motors, we propose a guiding principle for selectively separating nanoparticles (NPs) by efficiently using the light-induced force (LIF) and thermal fluctuations. We demonstrate the possibility of transporting metallic NPs of different sizes with a size-selection accuracy of less than 10 nm even at room temperature by designing asymmetric spatiotemporal light fields. This technique will lead to unconventional nanoextraction processes based on light and fluctuations. PMID- 22928782 TI - The amino-acid substituents of dipeptide substrates of cathepsin C can determine the rate-limiting steps of catalysis. AB - We examined the cathepsin C-catalyzed hydrolysis of dipeptide substrates of the form Yaa-Xaa-AMC, using steady-state and pre-steady-state kinetic methods. The substrates group into three kinetic profiles based upon the broad range observed for k(cat)/K(a) and k(cat) values, pre-steady-state time courses, and solvent kinetic isotope effects (sKIEs). The dipeptide substrate Gly-Arg-AMC displayed large values for k(cat)/K(a) (1.6 +/- 0.09 MUM(-1) s(-1)) and k(cat) (255 +/- 6 s(-1)), an inverse sKIE on k(cat)/K(a) ((D)(k(cat)/K(a)) = 0.6 +/- 0.15), a modest, normal sKIE on k(cat) ((D)k(cat) = 1.6 +/- 0.2), and immeasurable pre steady-state kinetics, indicating an extremely fast pre-steady-state rate (>400 s(-1)). (Errors on fitted values are omitted in the text for clarity but may be found in Table 2.) These results conformed to a kinetic model where the acylation (k(ac)) and deacylation (k(dac)) half-reactions are very fast and similar in value. The second substrate type, Gly-Tyr-AMC and Ser-Tyr-AMC, the latter the subject of a comprehensive kinetic study (Schneck et al. (2008) Biochemistry 47, 8697-8710), were found to be less active substrates compared to Gly-Arg-AMC, with respective k(cat)/K(a) values of 0.49 +/- 0.07 MUM(-1 )s(-1) and 5.3 +/- 0.5 MUM( 1 )s(-1), and k(cat) values of 28 +/- 1 s(-1) and 25 +/- 0.5 s(-1). Solvent kinetic isotope effects for Ser-Tyr-AMC were found to be inverse for k(cat)/K(a) ((D)(k(cat)/K(a)) = 0.74 +/- 0.05) and normal for k(cat) ((D)k(cat) = 2.3 +/- 0.1) but unlike Gly-Arg-AMC, pre-steady-state kinetics of Gly-Tyr-AMC and Ser-Tyr AMC were measurable and characterized by a single-exponential burst, with fast transient rates (490 s(-1) and 390 s(-1), respectively), from which it was determined that k(ac) ? k(dac) ~ k(cat). The third substrate type, Gly-Ile-AMC, gave very low values of k(cat)/K(a) (0.0015 +/- 0.0001 MUM(-1) s(-1)) and k(cat) (0.33 +/- 0.02 s(-1)), no sKIEs, ((D)(k(cat)/K(a)) = 1.05 +/- 0.5 and (D)k(cat) = 1.06 +/- 0.4), and pre-steady-state kinetics exhibited a discernible, but negligible, transient phase. For this third class of substrate, kinetic modeling was consistent with a mechanism in which k(dac) > k(ac) ~ k(cat), and for which an isotope-insensitive step in the acylation half-reaction is the slowest. The combined results of these studies suggested that the identity of the amino acid at the P(1) position of the substrate is the main determinant of catalysis. On the basis of these kinetic data, together with crystallographic studies of substrate analogues and molecular dynamics analysis with models of acyl-enzyme intermediates, we present a catalytic model derived from the relative rates of the acylation vs deacylation half-reactions of cathepsin C. The chemical steps of catalysis are proposed to be dependent upon the conformational freedom of the amino acid substituents for optimal alignment for thiolation (acylation) or hydrolysis (deacylation). These studies suggest ideas for inhibitor design for papain-family cysteine proteases and strategies to progress drug discovery for other classes of disease-relevant cysteine proteases. PMID- 22928783 TI - Fetal mediastinal tumor of neuroepithelial origin in a case of missed abortion. AB - We report a rare case of a primitive embryonal tumor discovered in the upper anterior mediastinum during routine autopsy of a macerated fetus at the 18th week of gestation. Our diagnosis was based on autopsy findings and histologic examination, which showed neuroepithelial differentiation of the tumor with frequent ependymal-type rosette formation; no structures of other germ cell layer origin were revealed. Additional positive immunohistochemical staining for CD56, CD57, and neurofilament protein confirmed the neural origin of the tumor, whereas the genetic analysis showed no MYCN gene amplification and no 11q23 deletion or rearrangement of EWS locus (22q12). Our findings exclude the possibility of teratoma and support the diagnosis of undifferentiated primitive tumor of neuroepithelial origin uncommonly located in the anterior mediastinum at the early 2nd trimester of gestation in a case of missed abortion. PMID- 22928784 TI - Increased oxidative stress in foam cells obtained from hemodialysis patients. AB - Premature atherosclerosis represents the main cause of mortality among end-stage renal disease patients (ESRD). Increased inflammation and oxidative stress are involved in initiation and progression of the atherosclerotic plaque. As foam cells are capable of producing significant amounts of inflammatory mediators and free radicals, we hypothesized that foam cells from uremic patients could produce more inflammation and oxidative stress than foam cells from normal people and be, somehow, involved in the accelerated atherosclerosis of uremia. To test this hypothesis, the levels of a few markers of inflammation and oxidative stress: Tumor necrosis factor-alpha, inducible nitric oxide synthase, malondialdehyde, nitric oxide by-products were measured in the supernatants of macrophage-derived foam cells cultures from 18 hemodialysis patients and 18 apparently healthy individuals controls. Malondialdehyde levels in the supernatant of cell cultures (macrophages stimulated or not with native and oxidized lipoprotein) were significantly increased in uremic patients; no statistically significant difference was found between the supernatant concentrations of nitric oxide by products, inducible nitric oxide synthase activity, and tumor necrosis factor alpha between patients and controls. Our results, obtained with human macrophages and macrophage-derived foam cells, are compatible with the theory that increased cellular oxidative stress and inflammatory activity in ESRD patients could accelerate the atherosclerotic process. The present culture protocol showed it is possible to use human mononuclear cells to evaluate the oxidative metabolism of foam cells, which are considered to be the initial step of atherosclerotic lesions. PMID- 22928785 TI - Randomized phase II study of danusertib in patients with metastatic castration resistant prostate cancer after docetaxel failure. AB - OBJECTIVE: To determine the efficacy and toxicity of danusertib (formerly PHA 739358) administered i.v. over two different dosing schedules with equivalent dose intensity in patients with metastatic castration-resistant prostate cancer with progressive disease after docetaxel-based treatment. PATIENTS AND METHODS: In this open-label, multicentre phase II trial 88 patients were randomly assigned (1:1 ratio) to receive either danusertib 330 mg/m(2) over 6 h i.v. on days 1, 8 and 15 (arm A, n = 43) or 500 mg/m(2) over 24 h i.v. on days 1 and 15 (arm B, n = 38), every 4 weeks. The primary endpoint chosen for this exploratory study was PSA response rate at 3 months. RESULTS: Sixty patients (31/43 in arm A and 29/38 in arm B) were evaluable for the primary endpoint. Median progression-free survival was 12 weeks in both arms. PSA response occurred in one patient in each arm; best overall response was stable disease in eight (18.6%) and 13 (34.2%) patients in arms A and B, respectively. Eleven out of 81 (13.6%) treated patients had stable disease for >=6 months. Danusertib was generally well tolerated; the most common grade 3 and 4 drug-related adverse event was neutropenia which occurred in 37.2% (arm A) and 15.8% (arm B) of the patients. CONCLUSION: Danusertib monotherapy shows minimal efficacy in patients with castration resistant prostate cancer. Further studies are required to establish specific biomarkers predictive for either response or prolonged disease stabilization. PMID- 22928788 TI - Appeal to the European food safety authority. PMID- 22928786 TI - Cavernous antioxidant effect of green tea, epigallocatechin-3-gallate with/without sildenafil citrate intake in aged diabetic rats. AB - This study aimed to assess the cavernous antioxidant effect of green tea (GT), epigallocatechin-3-gallate (EGCG) with/without sildenafil citrate intake in aged diabetic rats. One hundred and four aged male white albino rat were divided into controls that received ordinary chow, streptozotocin (STZ)-induced aged diabetic rats, STZ-induced diabetic rats on infused green tea, induced diabetic rats on epigallocatechin-3-gallate and STZ-induced diabetic rats on sildenafil citrate added to EGCG. After 8 weeks, dissected cavernous tissues were assessed for gene expression of eNOS, cavernous malondialdehyde (MDA), glutathione peroxidase (GPx), cyclic guanosine monophosphate (cGMP), and serum testosterone (T). STZ induced diabetic rats on GT demonstrated significant increase in cavernous eNOS, cGMP, GPx and significant decrease in cavernous MDA compared with diabetic rats. Diabetic rats on EGCG demonstrated significant increase in cavernous eNOS, cGMP, GPx and significant decrease in cavernous MDA compared with diabetic rats or diabetic rats on GT. Diabetic rats on EGCG added to sildenafil showed significant increase in cavernous eNOS, cGMP and significant decrease in cavernous MDA compared with other groups. Serum T demonstrated nonsignificant difference between the investigated groups. It is concluded that GT and EGCG have significant cavernous antioxidant effects that are increased if sildenafil is added. PMID- 22928790 TI - 'Persistant bilateral relative central scotomas induced by taking an excessive dose of sildenafil'. PMID- 22928792 TI - Stereoselective rhodium-catalyzed [3 + 2 + 1] carbocyclization of alkenylidenecyclopropanes with carbon monoxide: theoretical evidence for a trimethylenemethane metallacycle intermediate. AB - The theoretically inspired development of a Rh-catalyzed [3 + 2 + 1] carbocyclization of carbon- and heteroatom-tethered alkenylidenecyclopropanes (ACPs) with CO for the stereoselective construction of cis-fused bicyclohexenones is described. This study demonstrates that the ring opening of alkylidenecyclopropane proceeds through a Rh(III)-trimethylenemethane complex, which undergoes rate-determining carbometalation through a transition state that accurately predicts the stereochemical outcome for this process. The experimental studies demonstrate the validity of this approach and include the first highly enantioselective reaction involving an ACP to highlight further the synthetic utility of this transformation. PMID- 22928793 TI - Myelomatous meningeal infiltration detected by magnetic resonance imaging. PMID- 22928794 TI - A chemoselective, one-pot transformation of aldehydes to nitriles. AB - This paper describes a procedure for direct conversion of aldehydes to nitriles using O-(diphenylphosphinyl)hydroxylamine (DPPH). Aldehydes are smoothly transformed to their corresponding nitriles by heating with DPPH in toluene. The reaction can be accomplished in the presence of alcohol, ketone, ester, or amine functionality. PMID- 22928795 TI - Home care program for patients at high risk of hospitalization. AB - OBJECTIVE: To assess the efficacy of a home care program designed to improve access to medical care for older adults with multiple chronic conditions who are at risk for hospitalization. STUDY DESIGN: Randomized controlled trial in which participants were assigned to the home care intervention (Choices for Healthy Aging [CHA]) program or usual care. METHODS: The intervention group consisted of 298 older adults at risk of hospitalization as determined by a risk stratification tool. Measures included satisfaction with medical care, medical service use, and costs of medical care. RESULTS: The intervention group reported significantly greater satisfaction with care than usual care recipients (t test = 2.476; P = .014). CHA patients were less likely than usual care patients to be admitted to the hospital (25.6% and 37.1%, respectively; P = .02). There were no differences in terms of costs of care between the home care and usual care groups. CONCLUSIONS: Provision of home care to older adults at high risk of hospitalization may improve satisfaction with care while reducing hospitalizations. Lack of difference in medical costs suggests that managed care organizations need to consider targeting rather than using risk stratification measures when designing programs for high-risk groups. PMID- 22928796 TI - Questioning the widely publicized savings reported for North Carolina Medicaid. PMID- 22928797 TI - Preventable hospitalizations and Medicare managed care: a small area analysis. AB - OBJECTIVE: To examine the association between preventable hospitalization rates and proportions of managed care enrollment at the primary care service area level. STUDY DESIGN: Multivariate design. METHODS: The study used the Healthcare Cost and Utilization Project State Inpatient Data from the Agency for Healthcare Research and Quality for Arizona, Massachusetts, and New York for the years 1995 and 2005 to examine the association between preventable hospitalization rates and proportions of managed care enrollment in 1995 and 2005. The period 1995-2005 was marked by the beginning and end of several legislative and policy initiatives causing changes in elderly hospitalization patterns as well as Medicare managed care enrollment patterns. The study used ordinary least squares regressions, adjusting for heteroscedasticity. A cross-sectional analysis was used to examine the association each year. A pooled sample analysis over years tested the changes in relative contributions of managed care over time. RESULTS: Preventable hospitalization rates were inversely associated with Medicare managed enrollment in both years. This association was, however, found to be weaker in 2005 than in 1995. The decline in contributions of managed care was also statistically significant. CONCLUSIONS: Despite increased managed care enrollment, the role of Medicare managed care in explaining declines in preventable hospitalization rates diminished over time. The results could be explained by the growth of private fee for-service types of managed care plans and the resultant decline in emphasis on care coordination relative to health maintenance organization plans. PMID- 22928798 TI - Measuring migraine-related quality of care across 10 health plans. AB - OBJECTIVES: To refine a previously published standardized quality and utilization measurement set for migraine care and to establish performance benchmarks. STUDY DESIGN: Retrospective application of the migraine measurement set to health plan data in order to assess patterns of health service utilization. METHODS: Measurement specifications were applied to data from 10 health plans for measurement year 2009. RESULTS: Of the 2.9 million continuously enrolled members of the health plans, 138,004 (4.7%) met inclusion criteria for the migraine population. Of these, 26% did not have a migraine diagnosis, but were utilizing migraine drugs; 12% had a computed tomography scan within the year (range 8%-25% across plans); and 8% had magnetic resonance imaging (range 6%-11%). Nearly 18% of the migraineurs had 1 or more visits to an emergency department/urgent care center for migraine; few (6%) were followed up with primary care visits. Approximately one-fourth of the migraineurs were not being routinely monitored by a physician. Medication utilization also was examined for members of the migraine population with pharmacy benefits. A significant proportion (42%) were given a migraine preventive, 38% had at least 1 prescription for a triptan, and 2% of those on triptans were potentially overutilizing the medication. Among patients aged 18 to 49 years who were given triptans, 3% had a cardiac contraindication; this percentage rose to 7% for patients aged 50 to 64 years. CONCLUSIONS: This study demonstrates the value of standardized measures in identifying potential quality issues for migraine care, including underdiagnosis, overutilization of imaging, and underutilization of preventive drugs. PMID- 22928799 TI - Impact of point-of-care case management on readmissions and costs. AB - OBJECTIVE: To measure the impact of point-of-care case management by a team of diverse clinical specialists at a large medical group on 30-day readmissions and associated costs. STUDY DESIGN: An intent-to-treat, historical, baseline cohort comparison design. METHODS: A case management team employed by a managed care organization was integrated into the point of care at 4 medical offices of a medical group to provide services to health plan members who were medically hospitalized. Measures included case management process measures, 30-day readmissions and associated costs, and total savings. RESULTS: Among eligible members, 93% were enrolled in the case management program. In the baseline cohort, 17.60% of members were readmitted within 30 days, compared with 12.08% in the intervention group. Regression models identified case management intervention, prospective risk score, and Medicaid insurance coverage as significantly associated with readmissions and associated costs. Annual savings in 30-day inpatient utilization costs were $1040.74 per member, which considerably exceeded the costs of the program. CONCLUSIONS: Point-of-care case management can be an effective strategy for reducing readmissions and associated costs. Providing services at the point of care allows for greater convenience for members and increased collaboration with physicians. This strategy of a managed care organization collaborating with medical groups and hospitals has the potential to enhance outcomes in accountable care organizations and to support patientcentered medical homes. PMID- 22928800 TI - Impact of a program encouraging the use of generic antipsychotics. AB - OBJECTIVE: Recent research suggests that second generation antipsychotics (SGAs) may be used more often than clinically warranted. An intervention consisting of academic detailing and a prescriber survey was employed to encourage the reduction of newly prescribed on-patent SGAs. DESIGN: Quasi-experimental quality improvement trial. METHODS: Academic detailing consisted of educational lectures and a pocket guide on the latest effectiveness, safety, and cost data for SGAs and first-generation antipsychotics. Detailing was coupled with a required 20 item survey of provider decision making completed prior to prescriptions for on patent SGAs at a Veterans Health Administration medical center between October 2007 and May 2009. The survey identified the medication, treated diagnosis, comorbid psychiatric and medical diagnoses, reasons for the medication, prior medications, and provider professional status. The outcome was the number of new SGA prescriptions per month. RESULTS: The sample included 2176 surveys. The Spearman correlation between the number of prescriptions and the intervention month (range = 1-18) was 0.25 (P = .31), indicating no reduction. The most common medication prescribed was quetiapine (55.8%). The distributions of diagnoses were fairly even among schizophrenia, bipolar disorder, other affective disorders, and posttraumatic stress disorder (17.0, 28.2, 25.8, and 20.4%, respectively). The 3 most common reasons for prescribing an SGA were to improve efficacy (49.8%), reduce side effects (29.1%), and increase sleep or sedation (34.5%). CONCLUSIONS: Academic detailing coupled with a provider survey did not decrease the rate of new prescriptions for on-patent SGAs. Reasons for prescribing SGAs were not consistent with recent research findings regarding efficacy and side effects. PMID- 22928801 TI - Evaluation of bioreductive activation of anticancer drugs idarubicin and mitomycin C by NADH-cytochrome b5 reductase and cytochrome P450 2B4. AB - This study attempted to investigate the ability of microsomal NADH-cytochrome b5 reductase and cytochrome P450 2B4 to reductively activate idarubicin and mitomycin C. In vitro plasmid DNA damage experiments and assays using purified hepatic enzymes were employed to examine their respective roles in the metabolic activation of anticancer drugs. Mitomycin C was found to be not a good substrate for microsomal b5 reductase unlike P450 reductase. It produced low amounts of strand breaks in DNA when incubated with b5 reductase and its one-electron reduction by purified enzyme was found as negligible. Our findings revealed that P450 reductase-mediated metabolism of idarubicin resulted in a large increase in single-strand DNA breaks, whereas, b5 reductase neither catalyzed the reduction of idarubicin nor mediated the formation of DNA damage in the presence of idarubicin. The reconstitution studies, on the other hand, have identified rabbit liver CYP2B4 isozyme as being a potential candidate enzyme for reductive bioactivation of idarubicin and mitomycin C. Thus, the present novel findings strongly suggest that while b5 reductase could not play a key role in the cytotoxic and/or antitumor effects of idarubicin and mitomycin C, CYP2B4 could potentiate their activity in combination with P450 reductase. PMID- 22928802 TI - Evaluation of transporter-mediated hepatic uptake in a non-radioactive high throughput assay: a study of kinetics, species difference and plasma protein effect. AB - 1. In this manuscript we describe a non-radioactive, high-throughput method to evaluate hepatic uptake using cryopreserved hepatocytes. We have validated the uptake of pravastatin with different amounts of hepatocytes and the impact of the oil layer used in separation. The time- and concentration-dependent uptake profiles of several anionic and cationic charged drugs were evaluated. The results with our method compare favourably with the literature for pravastatin, atorvastatin and estrone 3-sulfate. 2. Two approaches for kinetic determination (temperature difference and fitting the linear and non-saturable passive diffusion rate in the equation, i.e. V = (V(max) * S)/(K(m) + S) + P(dif) * S) have been evaluated. Kinetic studies indicate that the different approaches for determining passive diffusion can affect K(m) and V(max), but not the clearance of active uptake (V(max)/K(m)). 3. Using pravastatin as a probe substrate, species differences were observed in the organic anion-transporting polypeptide (OATP) 1B1 and 1B3 activities. Plasma protein significantly reduced the uptake of atorvastatin, but not pravastatin. 4. Our data suggests that evaluation of the role of active uptake in hepatic clearance in humans should consider the relative ratio of active uptake to passive diffusion, species differences and plasma protein binding when applying in vitro uptake data. PMID- 22928803 TI - Combining strength training and botulinum neurotoxin intervention in children with cerebral palsy: the impact on muscle morphology and strength. AB - PURPOSE: Investigate the combination effects of strength training and Botulinum Toxin Type-A (BoNT-A) on muscle strength and morphology in children with Cerebral Palsy (CP). METHODS: Fifteen children receiving BoNT-A, classified as Spastic Diplegic CP, GMFCS I-II, and aged 5-12 years were recruited for this study. Randomly allocated to 10 weeks of strength training either before or after BoNT A, children were assessed over 6 months. Eight of the 15 children also completed a control period. The Modified Ashworth Scale measured spasticity. The Goal Attainment Scale (GAS) assessed achievement of functional goals. Magnetic Resonance Imaging assessed muscle volume (MV). Instrumented dynamometry assessed strength. RESULTS: Spasticity was significantly reduced following BoNT-A injection (p = 0.033). Children made significant isokinetic strength gains (mean p = 0.022, ES = 0.57) in the intervention period compared to the control period (mean p = 0.15, ES = 0.56). Irrespective of timing, significant strength improvements were seen immediately (10 weeks) and over 6 months for all children. This was also the case for improvements in the GAS (immediately: mean p = 0.007, ES = 4.17, 6 months: mean p = 0.029, ES = 0.99), and improvements in MV in all assessed muscles. CONCLUSION: The simultaneous use of BoNT-A and strength training was successful in spasticity reduction, improving strength and achieving functional goals, over and above treatment with BoNT-A alone. Muscles targeted for BoNT-A injection should be included in strength training. IMPLICATIONS FOR REHABILITATION: Cerebral Palsy* Botulinum toxin type-A (BoNT-A) and strength training are available interventions that, on their own have found success in managing spasticity and muscle weakness (both significant motor impairments), respectively in children with Cerebral Palsy (CP). * This study has demonstrated that the concurrent treatment of BoNT-A and strength training can achieve positive outcomes in terms of strength, spasticity and for the achievement of set functional goals. * The results of this study show that the improved muscle strength can be associated with hypertrophy, which could indicate the potential role of strength training in altering the rate of muscle growth, in an aim to improve the failure of muscle growth associated with CP. * Home based strength training, based on a child's individual goals is shown to be successful in improving strength and goal attainment for children with CP. PMID- 22928804 TI - Stress shifts the response of the bed nucleus of the stria terminalis to an anxiogenic mode. AB - The bed nucleus of the stria terminalis (BNST) is critically implicated in anxiety behavior and control of the hypothalamus-pituitary-adrenal axis. Having previously shown that chronic stress triggers dendritic/synaptic remodeling in specific nuclei of the BNST, we characterised the pattern of activation of neurons within different regions of the BNST under basal conditions and after an anxiogenic stimulus in control and stressed rats. Under basal conditions, stressed, but not control, animals displayed increased cFOS expression in the dorsomedial nucleus and decreased activation of the principal nucleus. This pattern resembled that observed in controls that had been exposed to the anxiogenic stimulus. Subsequent analysis of various BNST subnuclei revealed differential patterns of gene expression in controls and stressed animals. We found decreased levels of corticotropin-releasing hormone 1 receptor mRNA expression in the dorsomedial and fusiform nuclei, and a global increase in the levels of corticotropin-releasing hormone 2 receptor in the principal nucleus. In addition, we found subnuclei-specific increases in GABA(A) and NR2B receptors in stressed animals, which suggest changes in the GABAergic and glutamergic innervation of the BNST. Importantly, these findings were associated with increased anxiety-like behavior and impaired control of the hypothalamus pituitary-adrenal axis in stressed animals. In summary, these data reveal that chronic stress shifts the pattern of response of the BNST to an anxiogenic mode and provide new information on the underlying mechanisms of the stress-induced hypercorticalism and hyperanxious status. PMID- 22928805 TI - Can linked emergency department data help assess the out-of-hospital burden of acute lower respiratory infections? A population-based cohort study. AB - BACKGROUND: There is a lack of data on the out-of-hospital burden of acute lower respiratory infections (ALRI) in developed countries. Administrative datasets from emergency departments (ED) may assist in addressing this. METHODS: We undertook a retrospective population-based study of ED presentations for respiratory-related reasons linked to birth data from 245,249 singleton live births in Western Australia. ED presentation rates <9 years of age were calculated for different diagnoses and predictors of ED presentation <5 years were assessed by multiple logistic regression. RESULTS: ED data from metropolitan WA, representing 178,810 births were available for analysis. From 35,136 presentations, 18,582 (52.9%) had an International Classification of Diseases (ICD) code for ALRI and 434 had a symptom code directly relating to an ALRI ICD code. A further 9600 presentations had a non-specific diagnosis. From the combined 19,016 ALRI presentations, the highest rates were in non-Aboriginal children aged 6-11 months (81.1/1000 child-years) and Aboriginal children aged 1 5 months (314.8/1000). Croup and bronchiolitis accounted for the majority of ALRI ED presentations. Of Aboriginal births, 14.2% presented at least once to ED before age 5 years compared to 6.5% of non-Aboriginal births. Male sex and maternal age <20 years for Aboriginal children and 20-29 years for non-Aboriginal children were the strongest predictors of presentation to ED with ALRI. CONCLUSIONS: ED data can give an insight into the out-of-hospital burden of ALRI. Presentation rates to ED for ALRI were high, but are minimum estimates due to current limitations of the ED datasets. Recommendations for improvement of these data are provided. Despite these limitations, ALRI, in particular bronchiolitis and croup are important causes of presentation to paediatric EDs. PMID- 22928806 TI - Genetic variability among Trichuris ovis isolates from different hosts in Guangdong Province, China revealed by sequences of three mitochondrial genes. AB - This study examined sequence variation in three mitochondrial DNA (mtDNA) regions, namely cytochrome c oxidase subunit 1 (cox1), NADH dehydrogenase subunit 5 (nad5) and cytochrome b (cytb), among Trichuris ovis isolates from different hosts in Guangdong Province, China. A portion of the cox1 (pcox1), nad5 (pnad5) and cytb (pcytb) genes was amplified separately from individual whipworms by PCR, and was subjected to sequencing from both directions. The size of the sequences of pcox1, pnad5 and pcytb was 618, 240 and 464 bp, respectively. Although the intra-specific sequence variations within T. ovis were 0-0.8% for pcox1, 0-0.8% for pnad5 and 0-1.9% for pcytb, the inter-specific sequence differences among members of the genus Trichuris were significantly higher, being 24.3-26.5% for pcox1, 33.7-56.4% for pnad5 and 24.8-26.1% for pcytb, respectively. Phylogenetic analyses using combined sequences of pcox1, pnad5 and pcytb, with three different computational algorithms (maximum likelihood, maximum parsimony and Bayesian inference), indicated that all of the T. ovis isolates grouped together with high statistical support. These findings demonstrated the existence of intra-specific variation in mtDNA sequences among T. ovis isolates from different hosts, and have implications for studying molecular epidemiology and population genetics of T. ovis. PMID- 22928807 TI - Actinobaculum schaalii an emerging pediatric pathogen? AB - BACKGROUND: Actinobaculum schaalii was first described as a causative agent for human infection in 1997. Since then it has mainly been reported causing urinary tract infections (UTI) in elderly individuals with underlying urological diseases. Isolation and identification is challenging and often needs molecular techniques. A. schaalii is increasingly reported as a cause of infection in humans, however data in children is very limited. CASE PRESENTATION: We present the case of an 8-month-old Caucasian boy suffering from myelomeningocele and neurogenic bladder who presented with a UTI. An ultrasound of the urinary tract was unremarkable. Urinalysis and microscopy showed an elevated leukocyte esterase test, pyuria and a high number of bacteria. Empiric treatment with oral co trimoxazole was started.Growth of small colonies of Gram-positive rods was observed after 48 h. Sequencing of the 16S rRNA gene confirmed an A. schaalii infection 9 days later. Treatment was changed to oral amoxicillin for 14 days. On follow-up urinalysis was normal and urine cultures were negative. CONCLUSIONS: A.schaalii is an emerging pathogen in adults and children. Colonization and subsequent infection seem to be influenced by the age of the patient. In young children with high suspicion of UTI who use diapers or in children who have known abnormalities of their urogenital tract, infection with A. schaalii should be considered and empiric antimicrobial therapy chosen accordingly. PMID- 22928808 TI - Dietary chlorophyll metabolites catalyze the photoreduction of plasma ubiquinone. AB - Ubiquinol is a plasma antioxidant. The mechanisms responsible for maintenance of plasma ubiquinol are poorly understood. Here, we show that metabolites of chlorophyll can be found in blood plasma of animals that are given a chlorophyll rich diet. We also show that these metabolites catalyze the reduction of plasma ubiquinone to ubiquinol in the presence of ambient light, in vitro. We propose that dietary chlorophyll or its metabolites, together with light exposure, regulate plasma redox status through maintaining the ubiquinol pool. PMID- 22928809 TI - Black blood MRI in suspected large artery primary angiitis of the central nervous system. AB - OBJECTIVES: Single case reports suggest that black blood MRI (T1-weighted fat and blood suppressed sequences with and without contrast injection; BB-MRI) may visualize intracranial vessel wall contrast enhancement (CE) in primary angiitis of the central nervous system (PACNS). In this single-center observational pilot study we prospectively investigated the value of BB-MRI in the diagnosis of large artery PACNS. METHODS: Patients with suspected large artery PACNS received a standardized diagnostic program including BB-MRI. Vessel wall CE was graded (grade 0-2) by two experienced readers blinded to clinical data and correlated to the final diagnosis. RESULTS: Four of 12 included patients received a final diagnosis of PACNS. All of them showed moderate (grade 1) to strong (grade 2) vessel wall CE at the sites of stenosis. A moderate (grade 1) vessel wall CE grade was also observed in 6 of the remaining 8 patients in whom alternative diagnoses were made: arteriosclerotic disease (n = 4), intracranial dissection (n = 1), and Moyamoya disease (n = 1). CONCLUSIONS: Our pilot study demonstrates that vessel wall CE is a frequent finding in PACNS and its mimics. Larger trials will be necessary to evaluate the utility of BB-MRI in the diagnostic workup of PACNS. PMID- 22928811 TI - Communicating stigma about body size. AB - Body-size stigma is a well-documented phenomenon, particularly for large bodies (Puhl & Brownell, 2003), but few studies have investigated the features of body related stigma communication. This article uses Smith's (2007a) stigma communication framework to analyze descriptions of male and female bodies of various sizes for their stigma content. Analyses reveal that elements of stigma communication appeared in 46.5% of comments across all bodies. The most common elements of stigma communication were severe labeling and negative comparison to body ideals. The most stigmatized body was the large male body; the second most stigmatized body was the very small female body. This article shows that stigmatizing communication occurs across the spectrum of body sizes for both genders. The implications of weight-based stigma communication on emotional and physical health are discussed. Implications for future health communication interventions aimed at decreasing body size stigma are presented. PMID- 22928810 TI - Structural and functional analysis of the NLRP4 pyrin domain. AB - NLRP4 is a member of the nucleotide-binding and leucine-rich repeat receptor (NLR) family of cytosolic receptors and a member of an inflammation signaling cascade. Here, we present the crystal structure of the NLRP4 pyrin domain (PYD) at 2.3 A resolution. The NLRP4 PYD is a member of the death domain (DD) superfamily and adopts a DD fold consisting of six alpha-helices tightly packed around a hydrophobic core, with a highly charged surface that is typical of PYDs. Importantly, however, we identified several differences between the NLRP4 PYD crystal structure and other PYD structures that are significant enough to affect NLRP4 function and its interactions with binding partners. Notably, the length of helix alpha3 and the alpha2-alpha3 connecting loop in the NLRP4 PYD are unique among PYDs. The apoptosis-associated speck-like protein containing a CARD (ASC) is an adaptor protein whose interactions with a number of distinct PYDs are believed to be critical for activation of the inflammatory response. Here, we use co-immunoprecipitation, yeast two-hybrid, and nuclear magnetic resonance chemical shift perturbation analysis to demonstrate that, despite being important for activation of the inflammatory response and sharing several similarities with other known ASC-interacting PYDs (i.e., ASC2), NLRP4 does not interact with the adaptor protein ASC. Thus, we propose that the factors governing homotypic PYD interactions are more complex than the currently accepted model, which states that complementary charged surfaces are the main determinants of PYD-PYD interaction specificity. PMID- 22928812 TI - Asymmetric Michael additions of alpha-nitrocyclohexanone to aryl nitroalkenes catalyzed by natural amino acid-derived bifunctional thioureas. AB - A series of new thiourea catalysts prepared from natural amino acids have been applied in organocatalytic asymmetric Michael additions of alpha nitrocyclohexanone to nitroalkenes. The resulting addition products are formed with excellent enantioselectivities (up to an er of 98:2) in good yields (up to 90%). PMID- 22928813 TI - Combination hemodialysis and centrifugal therapeutic plasma exchange: 18 years of Canadian experience. AB - Hemodialysis (HD) and therapeutic plasma exchange (TPE) are extracorporeal treatments that may both be required in the same patient. When provided separately, 7-8 hours of therapy time is required. Simultaneous administration of both therapies can reduce time and personnel requirements. We report our 18-year institutional experience with combination HD and centrifugal TPE therapy. During combination therapy, the TPE circuit is attached to the HD circuit through an extension blood line connected to the HD venous return line, allowing simultaneous operation of both circuits. The HD circuit is anticoagulated with heparin and the TPE circuit with regional citrate. Blood flow rates through the HD circuit can reach 350 mL/min with plasma removal rates in the TPE circuit up to 60 mL/min. Ninety-two patients received a total of 621 treatments between December 1993 and July 2011. All treatments were completed within 4 hours. No major treatment-related adverse events occurred and less than 10% of treatments were complicated by minor events. Main indications for treatment were ANCA (anti neutrophilic cytoplasmic antibody) vasculitis (n = 25), Goodpasture's/antiglomerular basement membrane disease (n = 24), adult thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (n = 24), and acute antibody mediated renal transplant rejection (n = 8). Overall rates of renal recovery, in hospital mortality, and overall mortality at 18-year follow-up were 45% (41/ 92), 2% (2/92), and 21% (19/ 92), respectively, compatible with published literature. Combination HD and TPE is safe, efficient, and requires less human resources and time than conventional sequential therapy. It should be considered in patients whose treatment regimen includes HD and TPE. PMID- 22928814 TI - The case for partial nephrectomy: action is required. PMID- 22928817 TI - The complete mitochondrial genome of black grunt Hapalogenys nigripinnis. AB - The complete sequence of the mitochondrial genome of Hapalogenys nigripinnis was determined in this study. The genome was 16,478 bp in size with a base composition of 28.6% A, 15.8% G, 27.4% T, and 28.2% C, containing a typical structure of 13 protein-coding genes, 2 ribosomal RNA genes, 22 transfer RNA genes, and 1 noncoding control region. The genomic composition, organization, and gene order of H. nigripinnis was similar to that obtained in most vertebrates. These results may provide molecular information on the future phylogenetic relationships of H. nigripinnis and its position within the suborder Percoidei. PMID- 22928815 TI - A relevant long-term impact of the circulation of a potentially contaminated vaccine on the distribution of scrapie in Italy. Results from a retrospective cohort study. AB - A sudden increase in the incidence of scrapie in Italy in 1997 was subsequently linked to the use of a potentially infected vaccine against contagious agalactia. The relative risk for the exposed farms ranged between 6 and 40. The aim of this study was to assess the long-term impact of exposure to the potentially scrapie contaminated vaccine on the Italian classical scrapie epidemic. We carried out a retrospective cohort study, fitting mixed-effects Poisson regression models, dividing national geographic areas into exposure categories on the basis of the vaccine circulation levels. We took into account the sensitivity of the surveillance system applied in the different areas. The population attributable fraction (PAF) was used to assess the impact on the total population of farms associated with the effect of circulation of the vaccine. The provinces where the vaccine was more often sold were noted to have a higher level of disease when compared to those provinces where the vaccine was sold less often (incidence rate ratio [IRR]: 2.7; 95% confidence interval [CI]: 1.1-6.5). The population attributable fraction was high (68.4%). Standardization techniques allowed to account for the potential of geographical variability in the sensitivity of the Italian surveillance system. Although the number of the directly exposed farms was limited, an important long-term impact of the vaccine circulation could be quantified in terms of secondary outbreaks likely due to the exchange of animals from directly exposed flocks. PMID- 22928816 TI - Change in quality of life of medically hospitalized patients--a one-year follow up study. AB - OBJECTIVES: To examine changes in quality of life (QOL) among elderly medically hospitalized patients one year after hospitalization, and to explore factors associated with the changes. METHODS: A one-year follow-up study included 363 (175 men) medical inpatients with age range 65-98 (mean 80.2, SD 7.5) years. Information was collected at baseline and follow-up using the WHOQOL-BREF questionnaire assessing the physical, psychological, social and environment domain of QOL as the dependent variable, and the Mini-Mental State Examination, Lawton and Brody's scales for physical self-maintenance and instrumental activities of daily living, the Hospital Anxiety and Depression scale and assistance in living as the independent variables. RESULTS: The mean score of the physical domain of QOL had increased (mean change 0.6, SD 2.5; p < 0.01); the mean score of the environmental domain had decreased (mean change -2.1, SD 1.2; p < 0.01); and, the mean scores of the psychological and social domains of QOL were unchanged (mean change -0.2, SD 1.8 and mean change -0.1, SD 1.5, respectively) at follow-up. Improved individual QOL at a one-year follow-up was associated with improved health (cognitively, physically and emotionally) after hospitalization, and with health situation at baseline. Being in need of assistance was associated with reduced QOL. CONCLUSION: Good cognitive, physical and emotional health at baseline and follow-up were associated with improved QOL in previously hospitalized elderly patients independent of their need for assistance in living. PMID- 22928818 TI - Impact of reference gene selection for type 2 cannabinoid receptor gene expression studies in human spermatozoa. AB - Quantitative real-time polymerase chain reaction (qRT-PCR) has been employed to study the gene expression profiles in human spermatozoa, but accurate analysis is dependent upon normalisation of data against an endogenous control. beta-Actin (ACTB) and glyceraldehyde-3-phosphate dehydrogenase (GAPDH) are the most commonly used reference genes for normalisation of gene expression in human spermatozoa, but the expression of these genes in many tissues has considerable variation under different physiological, pathological and experimental conditions which limits their effectiveness in normalisation. The expression stability of a panel of 12 reference genes was studied in normal and pathological human spermatozoa using geNorm and NormFinder software. Although there were some discrepancies in the ranking of reference gene stability, each software program ranked B2 M, ACTB, CYC1 and 18S RNA within the top 5 and recommended the combined use of at least two reference genes. Normalisation of qRT-PCR data for the cannabinoid receptor type 2 in spermatozoa using the different housekeeping genes demonstrated how, without validation, conflicting results are obtained. We recommend that the arbitrary use of reference genes should be avoided and the validation of reference gene stability should be undertaken prior to every study. For normalisation of CB2 expression, we would recommend using the geometric mean of B2 M and ACTB. PMID- 22928820 TI - Nocturnin in the demosponge Suberites domuncula: a potential circadian clock protein controlling glycogenin synthesis in sponges. AB - Sponges are filter feeders that consume a large amount of energy to allow a controlled filtration of water through their aquiferous canal systems. It has been shown that primmorphs, three-dimensional cell aggregates prepared from the demosponge Suberites domuncula and cultured in vitro, change their morphology depending on the light supply. Upon exposure to light, primmorphs show a faster and stronger increase in DNA, protein and glycogen content compared with primmorphs that remain in the dark. The sponge genome contains nocturnin, a light/dark-controlled clock gene, the protein of which shares a high sequence similarity with the related molecule of higher metazoans. The sponge nocturnin protein was found showing a poly(A)-specific 3'-exoribonuclease activity. In addition, the cDNA of the glycogenin gene was identified for subsequent expression studies. Antibodies against nocturnin were raised and used in parallel with the cDNA to determine the regional expression of nocturnin in intact sponge specimens; the highest expression of nocturnin was seen in the epithelial layer around the aquiferous canals. Quantitative PCR analyses revealed that primmorphs after transfer from light to dark show a 10-fold increased expression in the nocturnin gene. In contrast, the expression level of glycogenin decreases in the dark by 3-4-fold. Exposure of primmorphs to light causes a decrease in nocturnin transcripts and a concurrent increase in glycogenin transcripts. It was concluded that sponges are provided with the molecular circadian clock protein nocturnin that is highly expressed in the dark where it controls the stability of a key metabolic enzyme, glycogenin. PMID- 22928819 TI - Benzamil sensitive ion channels contribute to volume regulation in canine chondrocytes. AB - BACKGROUND AND PURPOSE: Chondrocytes exist within cartilage and serve to maintain the extracellular matrix. It has been postulated that osteoarthritic (OA) chondrocytes lose the ability to regulate their volume, affecting extracellular matrix production. In previous studies, we identified expression of epithelial sodium channels (ENaC) in human chondrocytes, but their function remained unknown. Although ENaC typically has Na(+) transport roles, it is also involved in the cell volume regulation of rat hepatocytes. ENaC is a member of the degenerin (Deg) family, and ENaC/Deg-like channels have a low conductance and high sensitivity to benzamil. In this study, we investigated whether canine chondrocytes express functional ENaC/Deg-like ion channels and, if so, what their function may be. EXPERIMENTAL APPROACH: Canine chondrocytes were harvested from dogs killed for unassociated welfare reasons. We used immunohistochemistry and patch-clamp electrophysiology to investigate ENaC expression and video microscopy to analyse the effects of pharmacological inhibition of ENaC/Deg on cell volume regulation. KEY RESULTS: Immunofluorescence showed that canine chondrocytes expressed ENaC protein. Single-channel recordings demonstrated expression of a benzamil-sensitive Na(+) conductance (9 pS), and whole-cell experiments show this to be approximately 1.5 nS per cell with high selectivity for Na(+) . Benzamil hyperpolarized chondrocytes by approximately 8 mV with a pD2 8.4. Chondrocyte regulatory volume decrease (RVI) was inhibited by benzamil (pD2 7.5) but persisted when extracellular Na(+) ions were replaced by Li(+) . CONCLUSION AND IMPLICATIONS: Our data suggest that benzamil inhibits RVI by reducing the influx of Na(+) ions through ENaC/Deg-like ion channels and present ENaC/Deg as a possible target for pharmacological modulation of chondrocyte volume. PMID- 22928821 TI - Recent advances in the development of new treatments for celiac disease. AB - INTRODUCTION: Celiac disease is a common autoimmune condition induced by dietary gluten in genetically susceptible individuals. So far, the only available treatment for the disorder is a lifelong strict gluten-free diet, because of which small intestinal histological changes recover and symptoms disappear. However, gluten-free dieting is restrictive, and nutritionally less than optimal, and gluten is difficult to avoid. AREAS COVERED: With improving insight into the pathogenesis of celiac disease, several possible drug targets have been suggested. The new strategies include degradation of gluten intraluminally, reduction of mucosal permeability, inhibition of the transglutaminase 2 enzyme, blocking antigen presentation by HLA-DQ2 or HLA-DQ8, modulation of the immune responses of many cytokines, and vaccination. EXPERT OPINION: Non-dietary treatment options are warranted either as adjunctive therapy together with dieting or to replace the gluten-free diet. The key question is whether the envisaged novel drug is able to prevent gluten-induced small intestinal mucosal injury as efficiently as a strict gluten-free diet, alleviating symptoms and signs of the disease. Furthermore, the gluten dose that can be detoxified, if at all, must be established. The new drug should also be as safe as dietary treatment. Several novel treatment options are under development. PMID- 22928822 TI - Treatment of diabetes using traditional Chinese medicine: past, present and future. AB - Diabetes is a major medical problem that imperils public health. Over two thousand years ago, Traditional Chinese Medicine (TCM) called diabetes-related symptoms "Xiaoke" disease. In ancient China, TCM and Chinese herbal medicines were used widely in treating Xiaoke and abundant experience has been accumulated. This article discusses the TCM theory on diabetes and its achievements in the prevention and treatment of diabetes in the past. Using Chinese herbal medicine, recent progress in diabetes therapeutics, including data from clinical trials, are presented. Mechanistic studies from basic research are discussed. Yin-yang balance and a holistic approach of TCM may complement diabetes treatment in Western medicine. With continuous efforts, TCM could play a more important role in fighting this disease. PMID- 22928823 TI - Traditional Japanese herbal (kampo) medicines and treatment of ocular diseases: a review. AB - Herbal medicines have been used clinically in Eastern Asia, and traditional Japanese herbal (Kampo) formulas are approved as ethical drugs. The Kampo formulas are mixtures of the crude extracts of several herbs, each of which contains multiple components. Numerous investigators have reported that some herbal medicines are efficacious for treating several human diseases. We reviewed the literature on traditional herbal medicines and treatment of ocular diseases. Oral Orengedoku-to and Kakkon-to inhibit postoperative uveitis in humans. Oral Goshajinki-gan improved ocular surface disorders in patients with type 1 diabetes mellitus. Oral Hachimijio-gan increased retinal blood flow. Keishi-bukuryo-gan Sho might be associated with vitreoretinopathy in patients with type 2 diabetes mellitus. Oral Hachimijio-gan and Goshajinki-gan delayed lens opacification in rats and mice. Oral Sairei-to, Orengedoku-to, Senkanmeimoku-to, Scutellariae radix extract, Gardeniae fructus extract, topical Liguisticum wallichii rhizoma extract, and intravenous injection of tetramethylpyrazine, baicalin, baicalein, wogonin, and crocetin inhibited some forms of experimental uveitis in rabbits. Topical glycyrrhizinate improved allergic conjunctivitis in humans and rats. Oral crocetin improved eyestrain in humans. Oral berberine diminished experimental uveitis in rats. Baicalein, wogonin, berberine, and berberrubine inhibited in vitro expression of several cytokines in cultured retinal pigment epithelial cells. Some Kampo formulas are efficacious for treating several ocular diseases in humans and animals. Some herbal extracts and their components inhibit some forms of experimental uveitis. PMID- 22928824 TI - Randomized controlled pilot study: pain intensity and pressure pain thresholds in patients with neck and low back pain before and after traditional East Asian "gua sha" therapy. AB - Gua Sha is a traditional East Asian healing technique where the body surface is "press-stroked" with a smooth-edged instrument to raise therapeutic petechiae that last 2-5 days. The technique is traditionally used in the treatment of both acute and chronic neck and back pain. This study aimed to measure the effects of Gua Sha therapy on the pain ratings and pressure pain thresholds of patients with chronic neck pain (CNP) and chronic low back pain (CLBP). A total of 40 patients with either CNP or CLBP (mean age 49.23 +/- 10.96 years) were randomized to either a treatment group (TG) or a waiting list control group (WLC). At baseline assessment (T1), all patients rated their pain on a 10 cm visual analog scale (VAS). Patients' pressure pain thresholds (PPT) at a site of maximal pain (pain maximum) and an adjacent (pain-adjacent) site were also established. The treatment group then received a single Gua Sha treatment. Post-intervention measurements were taken for both groups at T2, seven days after baseline assessment (T1), using the same VAS and PPT measurements in precisely the same locations as at T1. Final analysis were conducted with 21 patients with CNP and 18 patients with CLBP. The study groups were equally distributed with regard to randomization. Patients in both the CNP and the CLBP treatment groups reported pain reduction (p < 0.05) and improved health status from their one Gua Sha treatment, as compared to the waiting list group. Pain sensitivity improved in the TG in CNP, but not in CLBP patients, possibly due to higher pressure sensitivity in the neck area. No adverse events were reported. These results suggest that Gua Sha may be an effective treatment for patients with chronic neck and low back pain. Further study of Gua Sha is warranted. PMID- 22928825 TI - Differential localization of pain-related neural responses during acupuncture stimulation using Blood Oxygen Level Dependent (BOLD) fMRI in a canine model. AB - The objective of this study was to differentiate the neuronal responses, which was related or unrelated, to pain associated with acupuncture stimulation, and to localize the brain regions with response to stimulation that is unrelated to pain by using Blood Oxygen Level Dependent (BOLD) functional MRI (fMRI). BOLD fMRI was performed in six normal healthy beagle dogs, during placebo and verum acupuncture stimulations, at the right side of BL60 (KunLun) acupoint before and after local anesthesia of the acupoint. The order of the four sessions was placebo; verum acupuncture stimulation; before local anesthesia; and followed by the same stimulation after local anesthesia. One-sample t-test analysis was performed to localize the activated or deactivated areas, during both pre-anesthesia and post anesthesia. In order to compare the pre-anesthesia to post-anesthetic responses, and placebo to verum acupuncture stimulation, within-subject analysis was performed. The post-anesthetic verum acupuncture stimulation resulted in increased activations in the left somatic afferent area I and II, right visual and auditory association area, and the descending reticular activating system of the brainstem. In addition, differential areas during post-anesthesia compared to that of the pre-anesthesia were in the left olfactory peduncle and descending reticular activating system of the brainstem. These results indicate that the areas of specific neural pathway are considered to be unrelated to the pain response during acupuncture stimulation. PMID- 22928827 TI - Inhibition of Na(+)/K(+) -ATPase by antcins, unique steroid-like compounds in Antrodia camphorate. AB - The inhibition of Na(+)/K(+) -ATPase by versatile steroid-like compounds contributes to the putative therapeutic effects of many Chinese medicinal cardiac products via the same molecular mechanism triggered by cardiac glycosides. Five major steroid-like compounds, antcin A, B, C, H, and K were isolated from Niuchangchih (Antrodia camphorata), a unique Taiwan mushroom, and all inhibited Na(+)/K(+) -ATPase. Antcin A exhibited significantly higher inhibitory potency than the other four antcins, though weaker than ginsenoside Rh2 . In contrast, cortisone (an analogous steroid with anti-inflammatory effects stronger than antcin A) showed no detectable inhibitory potency. Molecular modeling has shown that antcins bind to Na(+)/K(+) -ATPase with the steroidal skeleton structurally upside-down in comparison with ginsenoside Rh2 . The inhibitory potency of antcin A is attributed to steroidal hydrophobic interaction within the binding pocket and the formation of three hydrogen bonds between its carboxyl group and two cationic residues around the cavity entrance of Na(+)/K(+) -ATPase. The presence of an additional carbonyl or hydroxyl group at C7 of the other four antcins leads to severe repulsion in the hydrophobic pocket, and thus significantly reduces inhibitory potency. It is proposed that antcin A is a bi functional compound that exerts anti-inflammatory effects and that enhances blood circulation via two different molecular mechanisms. PMID- 22928826 TI - Anti-diabetic atherosclerosis effect of Prunella vulgaris in db/db mice with type 2 diabetes. AB - Diabetes mellitus is the leading cause of vascular complications such as atherosclerosis. This study was designed to investigate whether Prunella vulgaris (APV) would inhibit diabetic atherosclerosis in db/db mice with type 2 diabetes. The db/db mice were treated with high fat/high cholesterol (HFHC) diet and an aqueous extract of APV (100 and 200 mg/kg/day) for eight weeks to examine the long-term effect on metabolic abnormalities and diabetic atherosclerosis. APV treatment markedly lowered blood glucose and systolic blood pressure. The db/db mice experienced an increase in blood urea nitrogen as well as a decrease of creatinine clearance, the latter of which was restored by treatment with APV. Treatment with APV markedly decreased total plasma cholesterol, triglyceride, and LDL-cholesterol and also increased the HDL-cholesterol. In addition, malondialdehyde and TGF-beta1 were decreased by treatment of APV. On the other hand, total NO level was decreased in db/db mice. However, the NO level was increased by treatment with APV, suggesting an association with vascular dysfunction. Vascular relaxation of aortic rings by acetylcholine or SNP inducement was ameliorated by APV in a dose-dependent manner. Damage of vascular intima and hypertrophic of media were observed in db/db mice; however its dysfunction was improved by the treatment of APV. APV treatment significantly reduced the aortic expressions of ICAM-1, VCAM-1, ET-1, and nitrotyrosine. Furthermore, expression of eNOS in aortic was remarkably increased by APV treatment. Taken together, APV suppressed hyperglycemia and diabetic vascular dysfunction in HFHC diet-db/db mice. The present data suggest that Prunella vulgaris may prevent development of diabetic atherosclerosis. PMID- 22928828 TI - Rubus coreanus inhibits oxidized-LDL uptake by macrophages through regulation of JNK activation. AB - Oxidized low-density lipoprotein (oxLDL) contributes to atherosclerosis in part by being taken up into macrophages via scavenger receptors and leading to foam cell formation. Herbal compounds that have been used to treat blood stasis (a counterpart of atherosclerosis) for centuries include extracts of medicinal plants in the Rosaceae and Leguminosae families. In this study, we investigated the effect of the unripe Rubus coreanus (Korean black raspberry) fruit extract on oxLDL uptake by murine macrophage cells. In the presence of Rubus coreanus extract (RCE), Dil-labeled oxLDL uptake was inhibited in a dose-dependent manner. SP600125, a specific JNK inhibitor, inhibited the uptake of Dil-oxLDL into macrophages. RCE also inhibited JNK phosphorylation in a time- and dose-dependent manner in macrophages treated with oxLDL. These results indicate that among the mitogen-activated protein kinases, JNK phosphorylation is inhibited by RCE, which is likely the mechanism underlying the RCE-induced inhibition of oxLDL uptake by macrophages. PMID- 22928829 TI - Longan seed extract reduces hyperuricemia via modulating urate transporters and suppressing xanthine oxidase activity. AB - Hyperuricemia causes gouty arthritis, kidney disease, heart disease, and other diseases. Xanthine oxidase (XOD) and urate transporters play important roles in urate homeostasis. Numerous plants have been identified as XOD inhibitors. Longan seeds are known to contain high levels of polyphenols such as corilagin, gallic acid and ellagic acid. We examined the effect of longan seed extract on XOD inhibition and urate transporters GLUT1 and GLUT9 using both in vitro and in vivo assays. The results showed that dried longan seed extract (LSE) and its active components inhibited XOD dose-dependently in vitro. LSE inhibited uric acid production and XOD activity in normal liver cells (clone-9 cells) and was not cytotoxic under the concentration of 200 MUg/ml. For the in vivo study, Sprague Dawley (SD) rats were given intraperitoneally for thirty minutes with or without allopurinol (a XOD inhibitor, 3.5 mg/kg) or LSE (80 mg/kg) and then injected intraperitioneally with 250 mg/kg of oxonic acid and 300 mg/kg of hypoxanthine intragastrically. LSE was able to reduce serum uric acid level and XOD activity in hyperuricemic rats. However, LSE or allopurinol did not inhibit the liver XOD activities. On the other hand, GLUT1 protein was suppressed in kidney and GLUT9 was induced in liver from experimental rats and LSE or allopurinol decreased GLUT9 but increased GLUT1 protein level in the liver and kidney, respectively. These results confirmed the claimed effect of longan seeds on gout and other complications and suggested that its urate reducing effect might be due to modulation of urate transporters and inhibition of circulating xanthine oxidase. PMID- 22928830 TI - The memory-ameliorating effects of Artemisia princeps var. orientalis against cholinergic dysfunction in mice. AB - Artemisia princeps var. orientalis (Compositae) is widely distributed in China, Japan and Korea and is known to have anti-inflammatory and anti-oxidative activities. The ethyl acetate fraction of ethanolic extract of A. princeps var. orientalis (AEA) was found to inhibit acetylcholinesterase activity in a dose dependent manner in vitro (IC(50) value: 541.4 +/- 67.5 MUg/ml). Therefore, we investigated the effects of AEA on scopolamine-induced learning and memory impairment using the passive avoidance, the Y-maze, and the Morris water maze tasks in mice. AEA (100 or 200 mg/kg, p.o.) significantly ameliorated scopolamine induced cognitive impairments in the passive avoidance and Y-maze tasks (p < 0.05). In the Morris water maze task, AEA (200 mg/kg, p.o.) significantly shortened escape latencies in training trials and increased both swimming time spent in the target zone and probe crossing numbers during the probe trial as compared with scopolamine-treated mice (p < 0.05). Additionally, the ameliorating effect of AEA on scopolamine-induced memory impairment was antagonized by a subeffective dose of MK-801. These results suggest that AEA could be an effective treatment against cholinergic dysfunction and its effect is mediated by the enhancement of the cholinergic neurotransmitter system via NMDA receptor signaling or acetylcholinesterase inhibition. PMID- 22928831 TI - Viola yedoensis liposoluble fraction ameliorates lipopolysaccharide-induced acute lung injury in mice. AB - Viola yedoensis is a component of traditional Chinese herb medicine for inflammatory diseases. Chemical constituents of V. yedoensis have been shown to possess antibacterial, anti-HIV, and anticoagulant effects in experimental research; however, their anti-inflammatory properties remain to be demonstrated. In this study, a mouse model of lipopolysaccharide (LPS)-induced acute lung injury was used to investigate the effect of petroleum ether fraction of V. yedoensis (PEVY) on inflammation in vivo. After being shown to have anti complementary activity in vitro, PEVY was orally administered to the mice at doses of 2, 4, and 8 mg/kg. Treatment with PEVY significantly decreased the wet to-dry weight ratio of the lung, total cells, red blood cells, protein concentration, and myeloperoxidase activity in bronchoalveolar lavage fluid. PEVY markedly attenuated lung injury with improved lung morphology and reduced complement deposition. In addition, PEVY suppressed the expression of pro inflammatory cytokines, TNF-alpha, IL-1beta, and IL-6. Taken together, PEVY protects the lung from acute injury, potentially via inhibiting the activation of the complement system and excessive production of proinflammatory mediators. PMID- 22928832 TI - Evaluation of the genotoxicity of extracts of Houttuynia cordata Thunb. AB - The present study was conducted to evaluate the activity of methanol extracts from Houttuynia cordata Thunb. (HC) in a reverse mutation assay in Salmonella typhimurium, and a chromosome aberration assay in the Chinese hamster ovary (CHO) cell line and to evaluate its effect on the occurrence of polychromatic erythrocytes in mice. In the reverse mutation assay using Salmonella typhimurium TA98, TA100, TA1535, and TA1537 and Escherichia coli WP2urvA(-), methanol extracts of HC (5, 2.5, 1.25, 0.62, or 0.312 mg/plate) did not induce reverse mutations in the presence or absence of an S9 metabolic activation mixture. In the chromosome aberration test using CHO cells, methanol extracts (1.25, 2.5 or 5 MUg/ml) caused a few incidences of structural and numerical aberrations, in both of absence or presence of an S9 metabolic activation mixture, but in comparison with the positive control group, these incidences were not significantly increased. In the mouse micronucleus test, no significant increases in the occurrence of micronucleated polychromatic erythrocytes were observed in male ICR mice that were orally administered methanol extracts of HC at doses of 2.0, 1.0, or 0.5 g/kg. From these results, we concluded that the methanol extracts of HC did not induce harmful effects on genes in bacteria, a mammalian cell system or in mouse bone marrow cells. Thus, HC's use for health promotion and/or a sick remedy for humans may be safe. PMID- 22928833 TI - Antiviral effect of cimicifugin from Cimicifuga foetida against human respiratory syncytial virus. AB - Human respiratory syncytial virus (RSV) causes serious infection of the lower respiratory tract in children and an effective antiviral therapy against the viral pathogen remains unavailable. We previously demonstrated that the oriental medicinal plant, Cimicifuga foetida L. (C. foetida), possessed inhibitory activity against RSV. Since cimicifugin is a major constituent of C. foetida, we sought to examine in this study its anti-RSV effect on both the human upper (HEp 2) and lower (A549) respiratory tract cell lines. Results revealed that cimicifugin dose-dependently inhibited RSV-induced plaque formation in both HEp-2 and A549 cells (p < 0.0001), with a superior effect in the latter cell type (p < 0.0001). The antiviral activity of cimicifugin was time-dependent (p < 0.0001) and was most effective when cells were treated with the compound before viral inoculation. Additional experiments demonstrated that cimicifugin could inhibit viral attachment (p < 0.0001) and viral internalization (p < 0.0001). Furthermore, the drug could potentiate heparin's effect against attachment of RSV, particularly in A549 cells. Enzyme-linked immunosorbent assay (ELISA) analysis of antiviral cytokines induction revealed that cimicifugin could also stimulate epithelial cells to secrete IFN-beta to counteract viral infection. Taken together, these results indicate that cimicifugin is an efficient antiviral agent against RSV infection. We suggest that cimicifugin might be useful for the management of RSV pathogenesis. PMID- 22928834 TI - Chemical compositions, anti-inflammatory, antiproliferative and radical scavenging activities of Actinidia callosa var. ephippioides. AB - Oxidative stress and inflammation are related to several chronic diseases including cancer. Actinidia callosa var. ephippioides (ACE) is a special folk medicinal plant from Taiwan. The aim of this study is to evaluate the antioxidant, anti-inflammatory, and antiproliferative activities of the methanol extract and fractions from the stem of ACE. Trolox Equivalent Antioxidant Capacity (TEAC), 1,1-Diphenyl-2-picrylhydrazyl (DPPH) scavenging activity, total phenolic content, flavonoid content, inhibition on nitric oxide (NO) productions by LPS-induced RAW264.7 cell, and on lung cancer cell proliferation were employed. Among all fractions, ethyl-acetate fraction (EA-ACE) showed higher TEAC, DPPH radical scavenging activities, polyphenol and flavonoid contents, respectively. EA-ACE also decreased the LPS-induced NO production and expressions of inducible nitric-oxide synthase (iNOS) in RAW264.7 cells. EA-ACE had the highest antiproliferative activity with an IC(50) (The concentrations required for inhibition of 50% of cell viability) of 469.17 +/- 3.59 MUg/mL. Catechin also had good effects in the antioxidant and anti-inflammatory activities. Catechin might be an important bioactive compound in the stem of ACE. The above experimental data indicated that the stem of ACE is a potent antioxidant medicinal plant, and such efficacy may be mainly attributed to its polyphenolic compounds. PMID- 22928835 TI - KHC-4 anti-cancer effects on human PC3 prostate cancer cell line. AB - A bicyclic chemical structure, such as that found in flavonoids, was discovered to have anti-cancer activity. Further synthetic structural modification created a series of 2-phenyl-4-quinolone analogs, especially KHC-4, with the same bicyclic chemical structure. This new structure was reported to have stronger anti-cancer activity. In KHC-4 treatments for 72 h on human prostate cancer PC3 cells, cytotoxic effects (IC(50) =0.1 MUM) increased dose dependently, causing Cdk1/cyclin B1 complex activity mannered cell cycle and proliferation. KHC-4 treatments suppressed Bcl-2 and Bcl-xL protein levels and upregulated Bax. At the same concentration, pro-caspase 9 protein was cleaved to an activated form, leading to cell apoptosis. Furthermore, the MMP-2 protein levels also decreased through KHC-4 treatment in PC3. In conclusion, KHC-4 presents great prostate cancer therapeutic effects for cell proliferation inhibition, induction of apoptosis and protection against tumor migration. PMID- 22928836 TI - Anti-inflammatory and anti-allergic effect of Agaricus blazei extract in bone marrow-derived mast cells. AB - In this study, the anti-inflammatory and anti-allergic effects of the chloroform soluble extract of Agaricus blazei in mouse bone marrow-derived mast cells (BMMCs) were investigated. The chloroform-soluble extract inhibited IL-6 production in PMA plus A23187-stimulated BMMCs, and down-regulated the phosphorylation of Akt. In addition, this extract demonstrated inhibition of the degranulation of beta-hexosaminidase and the production of IL-6, prostaglandin D(2) and leukotriene C(4) in PMA plus A23187-induced BMMCs. In conclusion, the chloroform-soluble extract of Agaricus blazei exerted anti-inflammatory and anti allergic activities mediated by influencing IL-6, prostaglandin D(2), leukotriene C(4), and the phosphorylation of Akt. PMID- 22928837 TI - Pistacia chinensis inhibits NO production and upregulates HO-1 induction via PI 3K/Akt pathway in LPS stimulated macrophage cells. AB - Pistacia chinensis has been used for various purposes in China including as an understock for grafting Pistacia vera. However, little attention was given to its health promoting effects. Therefore, in this study, we investigated the effect of Pistacia chinensis methanolic extract (PCME) containing resorcinol class of phenolic lipids on pro-inflammatory mediators and heme oxygenase-1(HO-1) in lipopolysaccharide stimulated RAW264.7 cells. While PCME (2.5-10 MUg/ml) inhibited mRNA expressions of inducible nitric oxide synthase (iNOS), cyclooxygenase 2 (COX-2), tumor necrosis factor (TNF)-alpha, interleukin (IL) 1beta, and interleukin (IL)-6, it up-regulated HO-1 expression. Likewise, PCME inhibited iNOS protein expression, but not COX-2, and reduced nitric oxide (NO) release. Moreover, Phosphorylated c-Jun N-terminal Kinase (JNK) was attenuated dose-dependently in PCME pre-treated RAW264.7 cells. In addition, PCME up regulated HO-1 protein expression was diminished by pre-treatment of PI-3K inhibitor. Furthermore, nuclear factor erythroid 2 related factor 2 (Nrf2) repressor was attenuated time-dependently during PCME treatment. Taken together, our study showed (for the first time) that PCME inhibited NO production and up regulated HO-1 induction via PI-3K/Akt pathway, suggesting the role of Pistacia chinensis as potential sources of anti-inflammatory and antioxidant natural compounds. PMID- 22928838 TI - Opposite effects of ketamine and deep brain stimulation on rat thalamocortical information processing. AB - Sensory and cognitive deficits are common in schizophrenia. They are associated with abnormal brain rhythms, including disturbances in gamma frequency (30-80 Hz) oscillations (GFO) in cortex-related networks. However, the underlying anatomofunctional mechanisms remain elusive. Clinical and experimental evidence suggests that these deficits result from a hyporegulation of glutamate N-methyl-D aspartate receptors. Here we modeled these deficits in rats with ketamine, a non competitive N-methyl-D-aspartate receptor antagonist and a translational psychotomimetic substance at subanesthetic doses. We tested the hypothesis that ketamine-induced sensory deficits involve an impairment of the ability of the thalamocortical (TC) system to discriminate the relevant information from the baseline activity. Furthermore, we wanted to assess whether ketamine disrupts synaptic plasticity in TC systems. We conducted multisite network recordings in the rat somatosensory TC system, natural stimulation of the vibrissae and high frequency electrical stimulation (HFS) of the thalamus. A single systemic injection of ketamine increased the amount of baseline GFO, reduced the amplitude of the sensory-evoked TC response and decreased the power of the sensory-evoked GFO. Furthermore, cortical application of ketamine elicited local and distant increases in baseline GFO. The ketamine effects were transient. Unexpectedly, HFS of the TC pathway had opposite actions. In conclusion, ketamine and thalamic HFS have opposite effects on the ability of the somatosensory TC system to discriminate the sensory-evoked response from the baseline GFO during information processing. Investigating the link between the state and function of the TC system may conceptually be a key strategy to design innovative therapies against neuropsychiatric disorders. PMID- 22928839 TI - Epidemiology of serogroup B invasive meningococcal disease in Ontario, Canada, 2000 to 2010. AB - BACKGROUND: Invasive meningococcal disease (IMD) caused by serogroup B is the last major serogroup in Canada to become vaccine-preventable. The anticipated availability of vaccines targeting this serogroup prompted an assessment of the epidemiology of serogroup B disease in Ontario, Canada. METHODS: We retrieved information on confirmed IMD cases reported to Ontario's reportable disease database between January 1, 2000 and December 31, 2010 and probabilistically linked these cases to Public Health Ontario Laboratory records. Rates were calculated with denominator data obtained from Statistics Canada. We calculated a crude number needed to vaccinate using the inverse of the infant (<1 year) age specific incidence multiplied by expected vaccine efficacies between 70% and 80%, and assuming only direct protection (no herd effects). RESULTS: A total of 259 serogroup B IMD cases were identified in Ontario over the 11-year period. Serogroup B was the most common cause of IMD. Incidence ranged from 0.11 to 0.27/100,000/year, and fluctuated over time. Cases ranged in age from 13 days to 101 years; 21.4% occurred in infants, of which 72.7% were <6 months. Infants had the highest incidence (3.70/100,000). Case-fatality ratio was 10.7% overall. If we assume that all infant cases would be preventable by vaccination, we would need to vaccinate between 33,784 and 38,610 infants to prevent one case of disease. CONCLUSIONS: Although rare, the proportion of IMD caused by serogroup B has increased and currently causes most IMD in Ontario, with infants having the highest risk of disease. Although serogroup B meningococcal vaccines are highly anticipated, our findings suggest that decisions regarding publicly funding serogroup B meningococcal vaccines will be difficult and may not be based on disease burden alone. PMID- 22928840 TI - GenNon-h: generating multiple sequence alignments on nonhomogeneous phylogenetic trees. AB - BACKGROUND: A number of software packages are available to generate DNA multiple sequence alignments (MSAs) evolved under continuous-time Markov processes on phylogenetic trees. On the other hand, methods of simulating the DNA MSA directly from the transition matrices do not exist. Moreover, existing software restricts to the time-reversible models and it is not optimized to generate nonhomogeneous data (i.e. placing distinct substitution rates at different lineages). RESULTS: We present the first package designed to generate MSAs evolving under discrete time Markov processes on phylogenetic trees, directly from probability substitution matrices. Based on the input model and a phylogenetic tree in the Newick format (with branch lengths measured as the expected number of substitutions per site), the algorithm produces DNA alignments of desired length. GenNon-h is publicly available for download. CONCLUSION: The software presented here is an efficient tool to generate DNA MSAs on a given phylogenetic tree. GenNon-h provides the user with the nonstationary or nonhomogeneous phylogenetic data that is well suited for testing complex biological hypotheses, exploring the limits of the reconstruction algorithms and their robustness to such models. PMID- 22928841 TI - Measuring the processes of change for increasing blood donation in black adults. AB - BACKGROUND: Blacks have significantly lower blood donation rates than whites. Many views, experiences, and behaviors associated with blood donation are unique to black culture. Evidence suggests that culturally tailored health promotion programs help with increasing black blood donation. To be effective, tailored interventions should be based on valid and reliable measures. The Transtheoretical Model's (TTM) Processes of Change (POC) construct provides an assessment of participants' covert and overt activities and experiences in blood donation. This study describes development and validation of POC for increasing blood donation tailored to blacks. STUDY DESIGN AND METHODS: Cross-sectional measure development with online survey dissemination was used in 566 blacks in the Northeastern United States. Factor analytic structural modeling procedures were used to examine validity of the POC measure. Blood donation POC were examined in participants representing a range of blood donation history and intentions (nondonors, sometimes donors, regular donors) based on an established algorithm. RESULTS: Confirmatory analyses replicated the theoretically expected structure of POC scales which is a 10-factor, fully correlated best-fit model. Expected POC patterns by Stages of Change based on theoretical and empirical predictions were confirmed. The range of effect sizes for 10 POC were eta(2) = 0.04 to 0.25, indicating that TTM POC are strong strategies in blood donation decision making for blacks and can be applied to interventions to increase blood donation for a minority population. CONCLUSION: POC measure was internally and externally valid in a sample of blacks. Interventions can utilize the POC measure to guide stage-matched interventions to encourage use of relevant experiential and behavioral strategies to increase blood donation. PMID- 22928842 TI - Extending communication for patients with disorders of consciousness. AB - BACKGROUND AND PURPOSE: The difficulty of distinguishing disorders of consciousness from certain disorders of communication leads to the possibility of false diagnosis. Our aim is to communicate with patients with disorders of consciousness through asking them to answer questions with "yes/no" by performing mental imagery tasks using functional magnetic resonance imaging (fMRI). METHODS: A 1.5 T fMRI study with 5 patients and a control group is presented. Speech comprehension, mental imagery, and question-answer tests were performed. RESULTS: The imagery task of mental calculation produced equally distinct activation patterns when compared to navigation and motor imagery in controls. For controls, we could infer answers to questions based on imagery activations. Two patients produced activations in similar areas to controls for certain imagery tasks, however, no activations were observed for the question-answer task. CONCLUSIONS: The results from 2 patients provide independent support of similar work by others with 3 T fMRI, and demonstrate broader clinical utility for these tests at 1.5 T despite lower signal-to-noise ratio. Based on the control results, mental calculation adds a robust imagery task for use in future studies of this kind. PMID- 22928843 TI - Mitochondrial ADP/ATP carrier: preventing conformational changes by point mutations inactivates nucleotide transport activity. AB - The mitochondrial ADP/ATP carrier (Ancp) is a paradigm of the mitochondrial carrier family (MCF); its members allow metabolic fluxes between mitochondria and the cytosol. The members of the MCF share numerous structural and functional characteristics. Ancp is very specifically inhibited by two classes of compounds, which stabilize the carrier in two different conformations involved in nucleotide transport. Resolution of the atomic structure of the bovine Ancp, in complex with one of its specific inhibitors, is that of the carrier open toward the intermembrane space. To gain insights into the interconversion from one conformation to the other, we introduced point mutations in the yeast carrier at positions Cys73 in the first matrix loop and Tyr97 and Gly298 in transmembrane helices 2 and 6. We demonstrate in this paper that they impair stabilization of the carrier in one conformation or the other, resulting in an almost complete inactivation of nucleotide transport in both cases. The results are discussed on the basis of the atomic structure of the conformation open to the cytosol. These mutant proteins could afford convenient tools for undertaking structural studies of both conformations of the yeast carrier. PMID- 22928844 TI - Long-term social stress induces nitric oxide-independent endothelial dysfunction in normotensive rats. AB - As chronic stress is a significant risk factor for several cardiovascular disorders, this study investigated the hypothesis that long-term stress produced by crowding may lead to alterations in nitric oxide (NO) production and NO dependent relaxation in the course of stress, resulting in endothelial dysfunction and hypertension in Wistar-Kyoto (WKY) rats. For this purpose, male WKY rats were divided into control (480 cm2/rat, four rats/cage, n = 8) and crowded (200 cm2/rat, five rats/cage, n = 10) groups for 8 or 12 weeks. Vasorelaxation was evaluated in vitro as a response to acetylcholine (ACh) of femoral arteries pre-contracted by serotonin, before and after NO synthase inhibition (N (G)-nitro-l-arginine methyl ester, 300 MUmol/l). Crowding increased plasma corticosterone concentration but failed to affect blood pressure (determined by tail-cuff plethysmography) of rats. NO production was unchanged in the hypothalamus and left ventricle of both stressed groups; however it was significantly elevated in the aorta. Maximal ACh-induced relaxation was elevated significantly after 8-week stress, but reduced after 12 weeks. Stress elevated the NO-dependent component and reduced the NO-independent component of ACh induced relaxation in both crowded groups. However, a reduction in the NO independent component was more pronounced after 12-week versus 8-week stress. In conclusion, elevated endothelium-dependent relaxation was observed after 8-week stress, while the extension of stress exposure resulted in a reduction in arterial relaxation associated with a more pronounced decrease of its NO independent component. Thus, elevation of the NO-dependent component of relaxation can be considered as an adaptation mechanism, and impairment of NO independent relaxation might be the initial step in chronic stress-induced cardiovascular disorders. PMID- 22928845 TI - Optimizing blood pigment analysis in cerebrospinal fluid for the diagnosis of subarachnoid haemorrhage--a practical approach. AB - BACKGROUND: Patients presenting with sudden severe headache may have a subarachnoid haemorrhage (SAH). After a normal head computer tomography (CT), a lumbar puncture is routinely performed to rule out SAH. Photospectrometry is then used to detect bilirubin in cerebrospinal fluid (CSF). Photospectrometric analysis of CSF reaches a high sensitivity, but a low specificity for SAH. This low specificity necessitates extensive additional research to rule out cerebral aneurysm accompanied by high costs and risk of complications. OBJECTIVE: The objective of this study was to retrospectively evaluate two different CSF interpretation methods using photospectrometry in patients presenting with acute headache. The first of these is the Leiden method, an iterative model using a standard calculation. The second is the UK NEQAS guideline, which uses the original spectrum in combination with a decision tree. Our goal was to obtain retrospective data on patients screened with both methods to improve specificity of CSF research. RESULTS: We included 361 patients in this study; 47 of these had a raised bilirubin concentration in the CSF according to the Leiden method. In only nine of these 47 patients was an aneurysm found; in the other patients the Leiden test was positive for other reasons (viral meningitis, hyperbilirubinaemia, etc.). Of the 47 patients with raised bilirubin, 24 could be re-evaluated using the UK NEQAS. Of these 24 patients, five had an aneurysm. No aneurysms were found in patients with a negative result according to the UK NEQAS guideline. CONCLUSION: Our data show that a raised bilirubin calculated using the Leiden method seems to have a lower specificity than the UK NEQAS guideline. For practical reasons, it seems advantageous to use the Leiden method as a screening method and use the UK NEQAS guideline if a positive result is found. PMID- 22928846 TI - Enantioselective construction of pyrroloindolines via chiral phosphoric acid catalyzed cascade Michael addition-cyclization of tryptamines. AB - Enantioselective construction of pyrroloindolines via chiral phosphoric acid catalyzed cascade Michael addition-cyclization of tryptamines has been realized. With 5 mol % of chiral phosphoric acid, enantioenriched pyrroloindoline derivatives were obtained in good yields and enantioselectivity (up to 95% yield and 83% ee) from readily available tryptamines and enones. PMID- 22928847 TI - Emotional regulation and bodily sensation: interoceptive awareness is intact in borderline personality disorder. AB - Emotional dysregulation is a core component of borderline personality disorder (BPD). Theoretical models suggest that deficits in labeling physiological sensations of emotion contribute to affective instability in BPD. Interoceptive awareness refers to the ability to perceive changes in internal bodily states, and is linked to the subjective experience and control of emotions. The authors tested whether differences in interoceptive awareness accounted for emotional instability in BPD. Patients diagnosed with BPD (n = 24) were compared to healthy controls (n = 30) on two established measures of interoceptive awareness, a heartbeat perception task and a heartbeat monitoring task. Contrary to their hypothesis, the authors observed no significant differences in objective measures of interoceptive awareness. Their findings provide strong evidence against the notion that difficulties in emotional regulation in BPD are connected to differences in interoceptive awareness. PMID- 22928848 TI - Maternal transmission of borderline personality disorder symptoms in the community-based Greifswald Family Study. AB - The authors longitudinally investigated the familial transmission of mothers' BPD symptoms to their offspring, taking maternal depression into consideration. The sample consisted of 323 offspring and their mothers from the community-based Greifswald Family Study. These families were examined for the first time when the children were about 15 years old (T(0)), and again 5 years later (T(1)), using self-ratings and interviews. Regression analyses revealed that maternal BPD symptoms and depression at T(0) were significant predictors of a number of BPD criteria that offspring met at T(1). Furthermore, the analyses also predicted offspring's general psychopathology. In sum, the authors' findings provide evidence for familial aggregation of BPD symptoms and heightened levels of general psychopathology in offspring of mothers with high levels of BPD features, pointing to the need for providing early intervention for this high-risk group. PMID- 22928850 TI - Paranoid personality disorder. AB - Paranoid personality disorder (PPD) is currently included in DSM-IV's "odd cluster" or "cluster A." In the present article, the authors review available information pertaining to the psychometric properties of PPD, as derived from the relevant literature and from databases of personality disorder study groups. There is comparatively little published evidence for the reliability and validity of PPD, and researchers by and large have tended not to study the disorder, either because of investigators' difficulty recruiting individuals with PPD into research studies, or (as seems more likely) because the trait-paranoia from which many psychiatric patients suffer has seemed better explained by other DSM-IV disorders on Axis I and/or Axis II than by PPD. Given the scant empirical evidence on PPD, it seems reasonable to remove it as an independent diagnosis from the next edition of DSM, and instead to encourage clinicians to code trait paranoia using a dimensional approach. PMID- 22928852 TI - Circadian sleep-wake cycles, well-being, and light therapy in borderline personality disorder. AB - Individuals with borderline personality disorder (BPD) frequently suffer from sleep disturbances. The authors investigated circadian rhythms, sleep, and well being in women with BPD in their habitual life conditions during 3 weeks with morning light therapy (LT) and 3 weeks without LT (oLT). Sleep-wake cycles were measured using wrist actimetry, proximal skin temperature as an indirect index of relaxation, as well as weekly salivary melatonin to document the internal circadian rhythm phase. Questionnaires assessed clinical state throughout the 6 week protocol. Ten matched healthy women followed the same 6-week protocol without light treatment. Women with BPD had significantly worse subjective sleep quality and reduced daytime alertness compared to controls. Sleep-wake cycles in BPD ranged from highly disturbed to extremely regular patterns. Melatonin and proximal skin temperature profiles revealed appropriate synchronization of the circadian system with the sleep-wake cycle in most BPD women and in all controls. Morning LT significantly phase-advanced activity in BPD compared to oLT, shortened sleep duration, decreased movement time, and increased skin temperature during sleep (a marker of relaxation). Although general depression scores and borderline symptoms did not change, daytime alertness improved with morning LT, and atypical depression scores were attenuated. Morning LT is a potential adjunct treatment for BPD. PMID- 22928853 TI - Axis II disorders and cigarette smoking among adults from the general population. AB - The present study examined whether personality disorders (PDs) are associated with cigarette smoking, and the possible influence of nicotine dependence, sociodemographic variables, and the presence of any lifetime Axis I mental disorder in these relationships. The sample was made up of 1,081 adult participants from the Spanish general population and was stratified by smoking status (519 smokers and 562 nonsmokers). PDs were assessed by means of the International Personality Disorder Examination Questionnaire, Module DSM-IV. Results indicated that participants with a paranoid, a narcissistic, a borderline, an antisocial, or an obsessive-compulsive PD had a higher probability for being smokers and for being nicotine-dependent. The only exception was the schizoid PD, because participants with this Axis II disorder had a lower probability for being nicotine-dependent smokers. The association between PDs and smoking was maintained even after adjusting for all covariates. Findings are discussed in relation to the influence of Axis II disorders on smoking cessation interventions. PMID- 22928855 TI - Personality disorders and outcome of inpatient treatment for depression: a 1-year prospective follow-up study. AB - This study examines the relationship of personality disorders (PDs) with the outcome of an inpatient treatment for depression. One hundred sixty-eight inpatients with unipolar depression (41% with PD according to SCID-II) were assessed at admission, discharge, and 1-year follow-up. Patients without as well as with PD showed a significant and comparable intake-to-discharge symptom reduction in all inventories. At posttreatment, patients with PD scored higher in self-report measures of symptom severity (Brief Symptom Inventory, Beck Depression Inventory) than patients without PD, due to their higher symptom levels at intake. However, there was no difference in clinician-rated therapy outcome (Hamilton Rating Scale for Depression [17-item version], Global Assessment of Functioning Scale, Clinical Global Impression Scale) between both patient groups at discharge. At 1-year follow-up, patients without PD maintained their treatment outcome, whereas patients with PD showed a slight increase in symptom severity, compared to discharge. The results suggest that a difference in acute treatment outcome between depressed patients with and without PD may be found using self-ratings but not expert ratings of symptom severity. Furthermore, the importance of subsequent outpatient treatment that takes into account the special needs of depressed patients with comorbid PD is highlighted. PMID- 22928856 TI - Schizotypal personality disorder. AB - Early phenomenological descriptions of schizophrenia have acknowledged the existence of milder schizophrenia spectrum disorders characterized by the presence of attenuated symptoms typically present in chronic schizophrenia. The investigation of the schizophrenia spectrum disorders offers an opportunity to elucidate the pathophysiological mechanisms giving rise to schizophrenia. Differences and similarities between subjects with schizotypal personality disorder (SPD), the prototypical schizophrenia personality disorder, and chronic schizophrenia have been investigated with genetic, neurochemical, imaging, and pharmacological techniques. Patients with SPD and the more severely ill patients with chronic schizophrenia share cognitive, social, and attentional deficits hypothesized to result from common neurodevelopmentally based cortical temporal and prefrontal pathology. However, these deficits are milder in SPD patients due to their capacity to recruit other related brain regions to compensate for dysfunctional areas. Individuals with SPD are also less vulnerable to psychosis due to the presence of protective factors mitigating subcortical DA hyperactivity. Given the documented close relationship to other schizophrenic disorders, SPD will be included in the psychosis section of DSM-5 as a schizophrenia spectrum disorder as well as in the personality disorder section. PMID- 22928857 TI - A rapid electrochemical procedure for the detection of Hg(0) produced by mercuric reductase: application for monitoring Hg-resistant bacteria activity. AB - In this work, gold microelectrodes are employed as traps for the detection of volatilized metallic mercury produced by mercuric reductase (MerA) extracted from an Hg-resistant Pseudomonas putida strain FB1. The enzymatic reduction of Hg (II) to Hg (0) was induced by NADPH cofactor added to the samples. The amount of Hg(0) accumulated on the gold microelectrode surface was determined by anodic stripping voltammetry (ASV) after transferring the gold microelectrode in an aqueous solution containing 0.1 M HNO(3) + 1 M KNO(3). Electrochemical measurements were combined with spectrofluorometric assays of NADPH consumption to derive an analytical expression for the detection of a relative MerA activity of different samples with respect to that of P. putida. The method developed here was employed for the rapid determination of MerA produced by bacteria harbored in soft tissues of clams (Ruditapes philippinarum), collected in high Hg polluted sediments of Northern Adriatic Sea in Italy. PMID- 22928858 TI - Family history interview of a broad phenotype in specific language impairment and matched controls. AB - The aim was to study a broader phenotype of language-related diagnoses and problems in three generations of relatives of children with specific language impairment (SLI). Our study is based on a family history interview of the parents of 59 children with SLI and of 100 matched control children, exploring the prevalence of problems related to language, reading, attention, school achievement and social communication as well as diagnoses such as attention deficit hyperactivity disorder (ADHD), autism, Asperger syndrome, dyslexia, mental retardation, cleft palate and stuttering. The results show a spectrum of language-related problems in families of SLI children. In all three generations of SLI relatives, we found significantly higher prevalence rates of language, literacy and social communication problems. The risk of one or both parents having language-related diagnoses or problems was approximately six times higher for the children with SLI (85%) than for the control children (13%) (odds ratio = 37.2). We did not find a significantly higher prevalence of the diagnoses ADHD, autism or Asperger syndrome in the relatives of the children with SLI. However, significantly more parents of the children with SLI had problems with attention/hyperactivity when compared with the parents of controls. Our findings suggest common underlying mechanisms for problems with language, literacy and social communication, and possibly also for attention/hyperactivity symptoms. PMID- 22928859 TI - Activation of PLC by an endogenous cytokine (GBP) in Drosophila S3 cells and its application as a model for studying inositol phosphate signalling through ITPK1. AB - Using immortalized [3H]inositol-labelled S3 cells, we demonstrated in the present study that various elements of the inositol phosphate signalling cascade are recruited by a Drosophila homologue from a cytokine family of so-called GBPs (growth-blocking peptides). HPLC analysis revealed that dGBP (Drosophila GBP) elevated Ins(1,4,5)P3 levels 9-fold. By using fluorescent Ca2+ probes, we determined that dGBP initially mobilized Ca2+ from intracellular pools; the ensuing depletion of intracellular Ca2+ stores by dGBP subsequently activated a Ca2+ entry pathway. The addition of dsRNA (double-stranded RNA) to knock down expression of the Drosophila Ins(1,4,5)P3 receptor almost completely eliminated mobilization of intracellular Ca2+ stores by dGBP. Taken together, the results of the present study describe a classical activation of PLC (phospholipase C) by dGBP. The peptide also promoted increases in the levels of other inositol phosphates with signalling credentials: Ins(1,3,4,5)P4, Ins(1,4,5,6)P4 and Ins(1,3,4,5,6)P5. These results greatly expand the regulatory repertoire of the dGBP family, and also characterize S3 cells as a model for studying the regulation of inositol phosphate metabolism and signalling by endogenous cell surface receptors. We therefore created a cell-line (S3ITPK1) in which heterologous expression of human ITPK (inositol tetrakisphosphate kinase) was controlled by an inducible metallothionein promoter. We found that dGBP stimulated S3ITPK1 cells did not synthesize Ins(3,4,5,6)P4, contradicting a hypothesis that the PLC-coupled phosphotransferase activity of ITPK1 [Ins(1,3,4,5,6)P5+Ins(1,3,4)P3->Ins(3,4,5,6)P4+Ins(1,3,4,6)P4] is driven solely by the laws of mass action [Chamberlain, Qian, Stiles, Cho, Jones, Lesley, Grabau, Shears and Spraggon (2007) J. Biol. Chem. 282, 28117-28125]. This conclusion represents a fundamental breach in our understanding of ITPK1 signalling. PMID- 22928861 TI - The effects of abrupt antipsychotic discontinuation in cognitively impaired older persons: a pilot study. AB - BACKGROUND: Antipsychotic use for behavioural and psychological symptoms of dementia (BPSD) is controversial. Guidelines advise to reduce antipsychotics given the adverse effects and limited efficacy, to limit dose and treatment duration as well as to undertake discontinuation. METHODS: A pilot study with 40 hospitalised geriatric cognitively impaired patients, in which the effects of abrupt antipsychotic discontinuation were investigated, using neuropsychiatric inventory (NPI) scores before and one month after discontinuation. Withdrawal symptoms were monitored thrice a day with a checklist during five consecutive days. RESULTS: Participants (n = 40) had a mean age of 84 years (range 67-95) and 53% were male. The total mean baseline NPI score was 21 (SD 12) with predominantly behavioural rather than psychological disturbances. After abrupt discontinuation, mild withdrawal symptoms were observed in 72% of the patients, with frequencies of symptoms peaking on day 2 (53%) and day 3 (48%). After one month, 31 patients (85%) were still off antipsychotics and improved on the majority of NPI domains, with a total mean NPI score decreasing from 18 (SD 13) to 12 (SD 8, p = 0.003). In the relapse group, there was no deterioration associated with the abrupt discontinuation and subsequent resumption of therapy with a total mean NPI score decreasing from 31 (SD 12) at baseline to 27 (SD 8) at one-month follow-up (p = 0.345). CONCLUSION: Abrupt antipsychotic discontinuation appears to be feasible in older individuals with BPSD. Systematically performed discontinuation efforts in clinical practice are needed to differentiate between patients where antipsychotics have no added value and patients where the benefits outweigh the risks. PMID- 22928860 TI - Factors associated with satisfaction with prostate cancer care: results from Cancer of the Prostate Strategic Urologic Research Endeavor (CaPSURE). AB - OBJECTIVE: To evaluate the impact of demographic, clinical, treatment and patient reported parameters on satisfaction with prostate cancer care. Despite the significant worldwide impact of prostate cancer, few data are available specifically addressing satisfaction with treatment-related care. PATIENTS AND METHODS: CaPSURE comprises participants from 40 US sites who were monitored during and after their treatment course. Participants who were diagnosed with clinically localized prostate cancer after 1999 underwent radical prostatectomy, radiation therapy or primary androgen deprivation, and those who also completed the satisfaction questionnaire within 2 years of treatment were included in the present study. Satisfaction was measured using a validated instrument that assesses contact with providers, confidence in providers, communication skills, humanness and overall satisfaction. Multivariable linear regression analysis were performed to evaluate the independent relationships between demographic, clinical, treatment and patient-reported parameters and satisfaction. RESULTS: Of the 3056 participants, 1927 (63%) were treated with radical prostatectomy, 843 (28%) were treated with radiation therapy and 286 (9%) were treated with primary androgen deprivation. Multivariable analysis showed that multiple patient reported factors were independently associated with satisfaction, whereas clinical, demographic and treatment parameters were not. Baseline health-related quality of life, measured by the 36-item short-form health survey, baseline fear of cancer recurrence (all P < 0.01) and declines in the sexual (P = 0.03), urinary (P < 0.01) and bowel (P = 0.02) function domains of the University of California Los Angeles Prostate Cancer Index were all independently associated with satisfaction. Patient-reported outcomes were more strongly associated with satisfaction in the low-risk subgroup. CONCLUSIONS: Patient-reported factors such as health-related quality of life and fear of cancer recurrence are independently associated with satisfaction with care. Pretreatment parameters should be used to identify populations at-risk for dissatisfaction to allow for intervention and/or incorporation into treatment decision-making. PMID- 22928862 TI - High-throughput fluorescence-based early antibiogram determination using clinical Escherichia coli isolates as case study. AB - The objective of this study is to develop an antibiogram (AB) method superior to a disc diffusion method (DDM) with respect to rapidity, reliability, and accuracy especially in view of an increasing threat from multidrug resistance (MDR) of infectious bacteria. A high-throughput liquid-phase fluorescent antibiogram method capable of providing results within 6-8 hours has been developed. The AB method has been optimally designed for ease of operation, growth, and dye stability. This new method was more reliable than DDM in differentiating AB sensitivity as susceptible, intermediate, and resistant within 6-8 hours and providing evidence for efflux mechanism in the MDR phenotype. The superiority of this method even over the standard liquid turbidity method was evidenced by more accurate determination of intermediary resistance in a set of 23 clinical Escherichia coli strains against five common antibiotics. In view of the demand for the right choice of an antibiotic in short time, the newly developed AB method is clinically applicable and useful in the rational use of antibiotic and minimizing of MDR emergence. PMID- 22928863 TI - In vitro activity of minocycline alone and in combination with cefoperazone sulbactam against carbapenem-resistant Acinetobacter baumannii. AB - The aim of this study was to investigate the in vitro activity of minocycline combined with cefoperazone-sulbactam against carbapenem-resistant Acinetobacter baumannii (CRAB). A total of 53 nonduplicate CRAB were collected from inpatients of intensive care units in three hospitals in China from February 2009 to August 2011. Minimum inhibitory concentrations were determined by the broth microdilution method. The checkerboard method was used to determine whether combinations of the two agents act synergistically. Among the 53 A. baumannii, 64.2% of the isolates were susceptible to amikacin and 69.8% were susceptible to cefoperazone-sulbactam. More than 80% of isolates were resistant to the other agents and no isolates were found resistant to polymyxin B and minocycline. The combination of minocycline and cefoperazone-sulbactam demonstrated synergism in 39 isolates, partial synergism in 11 isolates, and indifference in 3 isolates. No antagonistic interactions were observed. Our study demonstrated that minocycline has good activity against CRAB and the combination of minocycline with cefoperazone-sulbactam had significant synergistic activity against these strains in vitro. The combination of minocycline and cefoperazone-sulbactam may be an alternative option for the treatment of infections caused by CRAB. PMID- 22928864 TI - 4alpha-phorbol 12,13-didecanoate activates cultured mouse dorsal root ganglia neurons independently of TRPV4. AB - BACKGROUND AND PURPOSE: The Ca(2+) -permeable cation channel TRPV4 is activated by mechanical disturbance of the cell membrane and is implicated in mechanical hyperalgesia. Nerve growth factor (NGF) is increased during inflammation and causes mechanical hyperalgesia. 4alpha-phorbol 12,13-didecanoate (4alphaPDD) has been described as a selective TRPV4 agonist. We investigated NGF-induced hyperalgesia in TRPV4 wild-type (+/+) and knockout (-/-) mice, and the increases in [Ca(2+) ](i) produced by 4alphaPDD in cultured mouse dorsal root ganglia neurons following exposure to NGF. EXPERIMENTAL APPROACH: Withdrawal thresholds to heat, von Frey hairs and pressure were measured in mice before and after systemic administration of NGF. Changes in intracellular Ca(2+) concentration were measured by ratiometric imaging with Fura-2 in cultured DRG and trigeminal ganglia (TG) neurons during perfusion of TRPV4 agonists. KEY RESULTS: Administration of NGF caused a significant sensitization to heat and von Frey stimuli in TRPV4 +/+ and -/- mice, but only TRPV4 +/+ mice showed sensitization to noxious pressure. 4alphaPDD stimulated a dose-dependent increase in [Ca(2+) ](i) in neurons from +/+ and -/- mice, with the proportion of responding neurons and magnitude of increase unaffected by the genotype. In contrast, the selective TRPV4 agonist GSK1016790A failed to stimulate an increase in intracellular Ca(2+) in cultured neurons. Responses to 4alphaPDD were unaffected by pretreatment with NGF. CONCLUSIONS AND IMPLICATIONS: TRPV4 contributes to mechanosensation in vivo, but there is little evidence for functional TRPV4 in cultured DRG and TG neurons. We conclude that 4alphaPDD activates these neurons independently of TRPV4, so it is not appropriate to refer to 4alphaPDD as a selective TRPV4 agonist. PMID- 22928865 TI - Validity and reliability of a self-report instrument to assess social support and physical environmental correlates of physical activity in adolescents. AB - BACKGROUND: The purpose of this study was to examine the internal consistency, test-retest reliability, construct validity and predictive validity of a new German self-report instrument to assess the influence of social support and the physical environment on physical activity in adolescents. METHODS: Based on theoretical consideration, the short scales on social support and physical environment were developed and cross-validated in two independent study samples of 9 to 17 year-old girls and boys. The longitudinal sample of Study I (n = 196) was recruited from a German comprehensive school, and subjects in this study completed the questionnaire twice with a between-test interval of seven days. Cronbach's alphas were computed to determine the internal consistency of the factors. Test-retest reliability of the latent factors was assessed using intra class coefficients. Factorial validity of the scales was assessed using principle components analysis. Construct validity was determined using a cross-validation technique by performing confirmatory factor analysis with the independent nationwide cross-sectional sample of Study II (n = 430). Correlations between factors and three measures of physical activity (objectively measured moderate-to vigorous physical activity (MVPA), self-reported habitual MVPA and self-reported recent MVPA) were calculated to determine the predictive validity of the instrument. RESULTS: Construct validity of the social support scale (two factors: parental support and peer support) and the physical environment scale (four factors: convenience, public recreation facilities, safety and private sport providers) was shown. Both scales had moderate test-retest reliability. The factors of the social support scale also had good internal consistency and predictive validity. Internal consistency and predictive validity of the physical environment scale were low to acceptable. CONCLUSIONS: The results of this study indicate moderate to good reliability and construct validity of the social support scale and physical environment scale. Predictive validity was only confirmed for the social support scale but not for the physical environment scale. Hence, it remains unclear if a person's physical environment has a direct or an indirect effect on physical activity behavior or a moderation function. PMID- 22928866 TI - Hypo-osmotic test in cat spermatozoa. AB - The hypo-osmotic (HOS) test has been used in other species as an indicator of the fertilising capacity of spermatozoa. The aims of this study were to assess the response of domestic cat spermatozoa to the hypo-osmotic test, to determine the type of solution, concentration and time of incubation needed to obtain a maximum percentage of swelling, to correlate the selected combination with the percentages of progressive motility and to evaluate whether dilution of the ejaculate alters the results. Incubation for 30 and 45 min in solutions of fructose and of citrate of 50 and 100 mOsmol kg-1 was evaluated. The highest percentage of swelling was obtained using the 50 mOsmol kg-1 solution, and no significant differences were observed between the times of exposure to the solutions. A positive correlation was observed between the percentage of individual progressive motility and the percentage of sperm swelling in a 50 mOsmol kg-1 fructose solution, with no significant differences being observed between raw and diluted semen samples. The results of this study suggest that the HOS test could be useful for evaluating membrane function in domestic cat spermatozoa, both in raw semen and in samples diluted in the EZ Mixin(r) commercial extender, and thus could be incorporated into routine semen evaluation protocols. PMID- 22928867 TI - Emission of nitrous oxide and dinitrogen by diverse earthworm families from Brazil and resolution of associated denitrifying and nitrate-dissimilating taxa. AB - The anoxic earthworm gut augments the activity of ingested microorganisms capable of anaerobiosis. Small earthworms (Lumbricidae) emit denitrification-derived N(2)O, whereas the large Octochaetus multiporus (Megascolecidae) does not. To examine this paradox, differently sized species of the families Glossoscolecidae (Rhinodrilus, Glossoscolex, Pontoscolex), Megascolecidae (Amynthas, Perionyx), Acanthodrilidae (Dichogaster), and Eudrilidae (Eudrilus) from Brazil were analyzed. Small species and the large Rhinodrilus alatus emitted N(2)O, whereas the large Glossoscolex paulistus did not, even though its gut could denitrify. N(2) and N(2)O were emitted concomitantly, and R. alatus emitted the highest amount of N(2). Denitrifiers and dissimilatory nitrate reducers were analyzed by barcoded amplicon pyrosequencing of narG, nirK, and nosZ. Gene sequences in gut and soil of the large G. paulistus were similar, whereas sequences in gut and soil of the small Amynthas gracilis were different and were also different compared with those of the gut and soil of G. paulistus. However, the denitrifying gut microbiota for both earthworms appeared to be soil-derived and dominated by Rhizobiales. The results demonstrated that (1) the emission of denitrification-derived N(2)O is widespread in different earthworm families, (2) large earthworms can also emit nitrogenous gases, and (3) ingested members of Rhizobiales are associated with this emission. PMID- 22928868 TI - Anxiolytic- and panicolytic-like effects of Neuropeptide S in the mouse elevated T-maze. AB - Neuropeptide S (NPS) regulates various biological functions by selectively activating the NPS receptor (NPSR). Recently, epidemiological studies revealed an association between NPSR single nucleotide polymorphisms and susceptibility to panic disorders. Here we investigated the effects of NPS in mice subjected to the elevated T maze (ETM), an assay which has been proposed to model anxiety and panic. Diazepam [1 mg/kg, intraperitoneally (i.p.)] elicited clear anxiolytic effects reducing the latency to emerge from the closed to the open (CO) arm without modifying the latencies from the open to the closed (OC) arm. By contrast, chronic fluoxetine (10 mg/kg i.p., once a day for 21 days) selectively increased OC latency, suggesting a panicolytic-like effect. NPS given intracerebroventricularly at 0.001-1 nmol elicited both anxiolytic- and panicolytic-like effects. However, although the NPS anxiolytic dose-response curve displayed the classical sigmoidal shape, the dose-response curve of the putative panicolytic-like effect was bell shaped with peak effect at 0.01 nmol. The behaviour of wild-type [NPSR(+/+)] and receptor knock out [NPSR(-/-)] mice in the ETM task was superimposable. NPS at 0.01 nmol elicited anxiolytic- and panicolytic-like effects in NPSR(+/+) but not in NPSR(-/-) mice. In conclusion, this study demonstrated that NPS, via selective activation of the NPSR, promotes both anxiolytic- and panicolytic-like actions in the mouse ETM. PMID- 22928869 TI - Familial amyloidosis with polyneuropathy associated with TTR Ser50Arg mutation. AB - BACKGROUND: The phenotypic heterogeneity of transthyretin amyloidosis (ATTR) familial polyneuropathy may be linked to the type of mutation and to the environmental factors. A gender difference in relation to the severity of the disease has been suspected. More than 100 different pathogenic variants of hereditary transthyretin (TTR) mutations have been reported. OBJECTIVE: To describe 32 patients with confirmed TTR Ser50Arg mutation from the same geographical origin. METHODS: Seven families with up to four affected generations underwent genetic testing and prospective clinical and laboratory evaluations. RESULTS: The mutation was confirmed in seven patients from different families with clinical symptoms compatible with ATTR amyloidosis, and in 25 (62%) of the 40 direct relatives tested. Of the 32 patients with positive test results, 18 (56%) were men. Only 5 (16%) subjects were disease-free at the time of the genetic test (mean age: 20, range: 18-30-year-old). The rest developed symptoms at a young age, between ages 36 and 41. Symptomatic, histologically positive patients were older than carriers and symptomatic patients without a confirmatory biopsy. The later generation displayed symptoms at a younger age. Initial manifestations in the 27 symptomatic patients were neuropathic in 19 (70%), gastrointestinal in 6 (22%) and autonomic in 1 (4%). Significant differences were demonstrated among genders, where men had a considerably worse outcome. CONCLUSION: ATTR Ser50Arg mutation was associated with an early onset, an unbalanced male to female ratio, a more aggressive course in males and possibly displayed anticipation. PMID- 22928870 TI - The role of the distal histidine in H2O2 activation and heme protection in both peroxidase and globin functions. AB - The distal histidine mutations of dehaloperoxidase-hemoglobin A (DHP A) to aspartate (H55D) and asparagine (H55N) have been prepared to study the role played by the distal histidine in both activation and protection against oxidation by radicals in heme proteins. The H55D and H55N mutants of DHP A have ~6-fold and ~11-fold lower peroxidase activities than wild type enzyme toward the oxidation of 2,4,6-trichlorophenol (TCP) to yield 2,6-dichloroquinone (DCQ) in the presence of H(2)O(2). The origin of the lower rate constants may be the solvent-exposed conformations of distal D55 and N55, which would have the dual effect of destabilizing the binding of H(2)O(2) to the heme iron, and of removing the acid-base catalyst necessary for the heterolytic O-O bond cleavage of heme bound H(2)O(2) (i.e., compound 0). The partial peroxidase activity of H55D can be explained if one considers that there are two conformations of the distal aspartate (open and closed) by analogy with the distal histidine. We hypothesize that the distal aspartate has an active conformation in the distal pocket (closed). Although the open form is observed in the low-temperature X-ray crystal structure of ferric H55D, the closed form is observed in the FTIR spectrum of the carbonmonoxy form of the H55D mutant. Consistent with this model, the H55D mutant also shows inhibition of TCP oxidation by 4-bromophenol (4-BP). Consistent with the protection hypothesis, compound ES, the tyrosyl radical-containing ferryl intermediate observed in WT DHP A, was not observed in H55D. PMID- 22928871 TI - Pyridinium-based fluororeceptors as practical chemosensors for hydrogen pyrophosphate (HP2O7(3-)) in semiaqueous and aqueous environments. AB - The pyridinium-based fluororeceptor 1 and the sensor bead 2 recognize hydrogen pyrophosphate effectively through the 'Indicator Displacement Assay' (IDA) technique over a series of other anions in aq CH(3)CN (CH(3)CN/H(2)O = 4:1, v/v, pH = 6.5). The sensor bead 2 is also capable of sensing the same anion selectively in pure water. PMID- 22928872 TI - Effects of exercise on kidney function among non-diabetic patients with hypertension and renal disease: randomized controlled trial. AB - BACKGROUND: Chronic kidney disease is an important public health threat. Such patients present high morbidity and mortality due to cardiovascular disease, with low quality of life and survival, and also high expenditure resulting from the treatment. Arterial hypertension is both a cause and a complication of kidney disease; also, arterial hypertension is a risk factor for cardiovascular disease among patients with kidney diseases. There is some evidence that exercise interventions may be beneficial to chronic kidney disease patients, but previous studies included only end-stage patients, i.e. those undergoing dialysis. This study aims to evaluate the effect of exercise on kidney function, quality of life and other risk factors for cardiovascular disease among non-diabetic chronic hypertensive kidney disease patients who are not undergoing dialysis. METHODS: The participants will be located through screening hypertensive patients attended within the public healthcare network in Pelotas, a city in south of Brazil. Eligible individuals will be those with glomerular filtration rate between 15 and 59 ml/min x 1.73 m(2). The randomization will be done in fixed-size blocks of six individuals such that 75 participants will be allocated to each group. At baseline, information on demographic, socioeconomic, behavioral, anthropometric, blood pressure and quality-of-life variables will be collected, and laboratory tests will be performed. The intervention will consist of three weekly physical exercise sessions lasting 60-75 minutes each, with a total duration of 16 weeks. The outcomes will be the kidney function progression rate, quality of life, blood pressure, lipid profile, hemoglobin level, ultrasensitive C-reactive protein level, and ankle-arm index. The patients in both groups (intervention and control) will be reassessed and compared partway through the study (8th week), at the end of the intervention (16th week) and in the 8th week after the end of the intervention. DISCUSSION: There is still a scarcity of data relating to the effect of physical exercise among the most numerous group of individuals with kidney disease, i.e. patients undergoing conservative treatment. In particular, there is a lack of randomized controlled studies. This study will help fill this gap. PMID- 22928873 TI - Evaluation of the retention force of double conical crowns used in combination with a galvanoforming and casting fabrication technique. AB - PURPOSE: The aim of this study was to measure the in vitro retention force of double conical crowns fabricated using primary galvanoforming and secondary casting techniques and those fabricated using primary casting and secondary galvanoforming techniques under simulated clinical conditions before and after a wear test. MATERIALS AND METHODS: Primary galvanoformed crowns (n = 10) with non noble secondary crowns (n = 10; group A) and primary non-noble crowns (n = 10) with secondary galvanoformed crowns (n = 10; group B) were fabricated. Each primary and secondary crown was embedded in acrylic resin and weighed with a digital balance. Retention forces were then measured using a universal testing device. To simulate wear, specimens were inserted and separated horizonatally 3285 times in wear equipment with artificial saliva. Retention forces and weights of the double crowns were then remeasured. Data were analyzed using paired t tests and Wilcoxon tests, and the groups were compared using Mann-Whitney U tests. RESULTS: In group A, the wear test had a significant influence on the retentive force (p < 0.05), but wear produced no significant difference in weight (p > 0.05). In group B, the wear test had a significant influence on the retentive force (p < 0.05), and wear produced a significant difference in weight (p < 0.05). CONCLUSIONS: The results of this study indicated that the use of different combinations of galvanoforming and casting techniques in the fabrication of conical crowns significantly affected retention force. PMID- 22928874 TI - Transient ischaemic attacks clinics provide equivalent and more efficient care than early in-hospital assessment. AB - BACKGROUND AND PURPOSE: Clinics for early management of transient ischaemic attacks (TIAs) have been developed in some stroke centres, resulting in reduced recurrence rates compared to appointment-based outpatient management, thus saving on hospitalization. We analysed the care process, recurrence rates and economic impact of the first year of work in our early-management TIA clinic and compared these with our previous in-hospital study protocols for low- and moderate-risk TIA patients. METHODS: This was a prospective evaluation of the management of low to moderate-risk TIA patients, comparing a new TIA clinic model (2010) with a previous hospitalization model (2009). Demographic data, vascular risk factor profiles, diagnostic test performance, secondary prevention measures, final aetiological diagnoses and cerebrovascular recurrences at 7 and 90 days were compared between in-hospital and TIA clinic assessed patients. We also carried out an economic comparison of the costs of each model's process. RESULTS: Two hundred and eleven low- to moderate-risk TIA patients were included, of whom 40.8% were hospitalized. There were no differences between the TIA clinic assessed and in-hospital assessed patients in terms of risk factor diagnosis and secondary prevention measures. The stroke recurrence rate (2.4% vs. 1.2%; P = 0.65) was low and similar for both groups (CI 95%, 0.214-20.436; P = 0.52). Cost per patient was ?393.28 for clinic versus ?1931.18 for in-hospital management. Outpatient management resulted in a 77.8% reduction in hospitalizations. CONCLUSION: Transient ischaemic attacks clinics are efficient for the early management of low- to moderate-risk TIA patients compared to in-hospital assessment, with no higher recurrence rates and at almost one-fifth the cost. PMID- 22928875 TI - Biology of Factor XIII and clinical manifestations of Factor XIII deficiency. AB - Factor XIII (FXIII) is activated by thrombin to form a transglutaminase (FXIIIa) that stabilizes clot formation by the cross-linking of fibrin monomers and antifibrinolytic proteins. Although rare, FXIII deficiency is characterized by variable bleeding manifestations depending on the magnitude of the deficiency. A congenital FXIII deficiency with levels less than 1% can be detected in children who present with prolonged bleeding from the umbilical stump as well as protracted bleeding after trauma. An acquired FXIII deficiency may occur in a number of diseases or clinical situations where FXIII levels and/or its activity are decreased. Patients may also develop a relative deficiency in FXIII as a result of hemorrhage or dilutional changes from transfusions during surgery or trauma and are at increased risk for postoperative bleeding. Genetic studies have identified a wide range of mutations that affect the activity of the FXIII protein but in lieu of molecular genetic analyses, FXIII deficiency can be identified by specific diagnostic assays that measure either the transglutaminase activity of the protein or the levels of the protein and its individual subunits. Replacement therapy has also been shown to increase FXIII levels and reduce bleeding symptoms in patients with congenital FXIII deficiency. This review presents recent findings on the biology of FXIII and the clinical manifestations observed among patients with congenital and acquired FXIII deficiencies. PMID- 22928878 TI - Transfer of tactile input from an artificial hand to the forearm: experiments in amputees and able-bodied volunteers. AB - PURPOSE: This study explores the possibilities of transferring peripheral tactile stimulations from an artificial hand to the forearm skin. METHOD: A tactile display applied to the forearm skin was used to transfer tactile input to the forearm from various locations on a hand displayed on a computer screen. Discernment of location, levels of pressure and a combination of the two in simulated functional grips was tested to quantify the participants' ability to accurately perceive the tactile stimulations presented. Ten participants (5 forearm amputees and 5 able-bodied volunteers) unfamiliar with the equipment participated in the three-stage experiments comprising a learning session with vision, a reinforced learning session without vision and a validation session without vision. RESULTS: The location discernment accuracy was high in both groups (75.2% and 89.6% respectively). The capacity to differentiate between three different levels of pressure was also high (91.7% and 98.1% respectively in the two groups). Recognition of simulated grip was slightly more difficult with the groups scoring 58.7% and 68.0% respectively for accuracy in the validation session. CONCLUSIONS: This study demonstrates that it is possible, following a brief training period, to transfer tactile input from an artificial hand to the forearm skin. The level of accuracy was lower for the more complex task, simulated grip recognition, possibly because this represents a more complex task requiring higher order brain functions. These results could form the basis for developing sensory feedback in hand prostheses. PMID- 22928876 TI - Pharmacophore-based virtual screening and biological evaluation of small molecule inhibitors for protein arginine methylation. AB - Protein arginine methyltransferases (PRMTs) are proved to play vital roles in chromatin remodeling, RNA metabolism, and signal transduction. Aberrant regulation of PRMT activity is associated with various pathological states such as cancer and cardiovascular disorders. Development and application of small molecule PRMT inhibitors will provide new avenues for therapeutic discovery. The combination of pharmacophore-based virtual screening methods with radioactive methylation assays provided six hits identified as inhibitors against the predominant arginine methyltransferase PRMT1 within micromolar potency. Two potent compounds, A9 and A36, exhibited the inhibitory effect by directly targeting substrate H4 other than PRMT1 and displayed even higher inhibition activity than the well-known PRMT inhibitors AMI-1. A9 significantly inhibits proliferation of castrate-resistant prostate cancer cells. Together, A9 may be a potential inhibitor against advanced hormone-independent cancers, and the work will provide clues for the future development of specific compounds that block the interaction of PRMTs with their targets. PMID- 22928879 TI - Probing why trypanosomes assemble atypical cytochrome c with an AxxCH haem binding motif instead of CxxCH. AB - Mitochondrial cytochromes c and c1 are core components of the respiratory chain of all oxygen-respiring eukaryotes. These proteins contain haem, covalently bound to the polypeptide in a catalysed post-translational modification. In all eukaryotes, except members of the protist phylum Euglenozoa, haem attachment is to the cysteine residues of a CxxCH haem-binding motif. In the Euglenozoa, which include medically relevant trypanosomatid parasites, haem attachment is to a single cysteine residue in an AxxCH haem-binding motif. Moreover, genes encoding known c-type cytochrome biogenesis machineries are all absent from trypanosomatid genomes, indicating the presence of a novel biosynthetic apparatus. In the present study, we investigate expression and maturation of cytochrome c with a typical CxxCH haem-binding motif in the trypanosomatids Crithidia fasciculata and Trypanosoma brucei. Haem became attached to both cysteine residues of the haem binding motif, indicating that, in contrast with previous hypotheses, nothing prevents formation of a CxxCH cytochrome c in euglenozoan mitochondria. The cytochrome variant was also able to replace the function of wild-type cytochrome c in T. brucei. However, the haem attachment to protein was not via the stereospecifically conserved linkage universally observed in natural c-type cytochromes, suggesting that the trypanosome cytochrome c biogenesis machinery recognized and processed only the wild-type single-cysteine haem-binding motif. Moreover, the presence of the CxxCH cytochrome c resulted in a fitness cost in respiration. The level of cytochrome c biogenesis in trypanosomatids was also found to be limited, with the cells operating at close to maximum capacity. PMID- 22928880 TI - Process attributes in bio-ontologies. AB - BACKGROUND: Biomedical processes can provide essential information about the (mal ) functioning of an organism and are thus frequently represented in biomedical terminologies and ontologies, including the GO Biological Process branch. These processes often need to be described and categorised in terms of their attributes, such as rates or regularities. The adequate representation of such process attributes has been a contentious issue in bio-ontologies recently; and domain ontologies have correspondingly developed ad hoc workarounds that compromise interoperability and logical consistency. RESULTS: We present a design pattern for the representation of process attributes that is compatible with upper ontology frameworks such as BFO and BioTop. Our solution rests on two key tenets: firstly, that many of the sorts of process attributes which are biomedically interesting can be characterised by the ways that repeated parts of such processes constitute, in combination, an overall process; secondly, that entities for which a full logical definition can be assigned do not need to be treated as primitive within a formal ontology framework. We apply this approach to the challenge of modelling and automatically classifying examples of normal and abnormal rates and patterns of heart beating processes, and discuss the expressivity required in the underlying ontology representation language. We provide full definitions for process attributes at increasing levels of domain complexity. CONCLUSIONS: We show that a logical definition of process attributes is feasible, though limited by the expressivity of DL languages so that the creation of primitives is still necessary. This finding may endorse current formal upper-ontology frameworks as a way of ensuring consistency, interoperability and clarity. PMID- 22928882 TI - Polybrominated diphenyl ethers (PBDEs): turning the corner in Great Lakes trout 1980-2009. AB - Lake trout and walleye composites were collected between 2004 and 2009 as part of the Great Lakes Fish Monitoring and Surveillance Program (GLFMSP) and analyzed for polybrominated diphenyl ethers (PBDEs). Yearly mean total PBDE concentrations (sum of congeners BDE-47, BDE-99, BDE-100, BDE-153, BDE-154) ranged from 44-192, 28-113, 50-107, 37-111, and 11-22 ng/g wet wt. for Lakes Michigan, Huron, Ontario, and Superior lake trout, and Lake Erie walleye, respectively. A 1980 2009 temporal record of PBDE concentrations in the Great Lakes' top predator fish (lake trout and walleye) was assembled by integrating previous GLFMSP data (1980 2003) with current results (2004-2009). Temporal profiles show obvious breakpoints between periods of PBDE accumulation and decline in trout for Lakes Huron, Michigan and Ontario with a significant (p < 0.0001 and r = 0.55, 0.72, and 0.51, respectively) decrease in concentration after 2000-2001. A similar transition was observed in Lake Superior for the nearshore site accompanied by a less significant decreasing trend (p = 0.016, r = 0.33), suggesting concentrations are declining very slowly or have leveled off. In contrast, Lake Erie walleye concentrations began leveling off in the late 1990s and no statistically significant trend (increasing or decreasing) has been observed in recent years. A decrease in the BDE-47/BDE-153 ratio was also recently observed, suggesting a transition to more highly brominated PBDEs is occurring in Great Lakes trout. This study provides region-wide evidence that PBDE concentrations are generally declining in Great Lakes trout, although there are clear exceptions to this trend. Results from this study reflect the positive impact of the 2004 PentaBDE ban on macro-scale aquatic freshwater ecosystems. PMID- 22928881 TI - A precystectomy decision model to predict pathological upstaging and oncological outcomes in clinical stage T2 bladder cancer. AB - OBJECTIVES: To categorize patients with clinical stage T2 bladder cancer into risk groups based on their potential for pathological upstaging and eventual oncological outcomes at cystectomy. To pre-emptively identify such patients who will be upstaged and have poor outcomes after cystectomy, aiming to better determine the ideal candidates for neoadjuvant chemotherapy. PATIENTS AND METHODS: A retrospective review was conducted of 1964 patients who underwent radical cystectomy for bladder cancer with intent to cure at the University of Southern California between 1971 and 2008. Neoadjuvant chemotherapy-naive patients with clinically organ-confined urothelial carcinoma invading bladder muscle (cT2N0M0) were included. Univariate analysis and multivariable decision tree modelling with cross-validation were employed to identify precystectomy variables that could predict pathological upstaging and poor oncological outcomes. RESULTS: A total of 948 patients met the inclusion criteria, of whom 512 (54%) patients were upstaged at cystectomy; upstaging was associated with a worse recurrence-free and overall survival (both P < 0.001). Age, presence of hydronephrosis, evidence of deep muscularis propria invasion and lymphovascular invasion on transurethral resection specimen, as well as tumour growth pattern and count, were significantly associated with upstaging. When these factors were included in a decision tree model, 70.6% of patients with hydronephrosis experienced upstaging and had the worst outcome (P < 0.001). In patients without hydronephrosis, tumour growth pattern was a second-tier discriminator (P < 0.001); in patients with non-papillary tumours, 71.7% of cases with evidence of deep muscularis propria involvement experienced upstaging compared to 53.8% of cases with no deep muscle involvement (P = 0.012), whereas, among patients with combined papillary and non-papillary features, 33% of cases aged <=65 years were upstaged compared to 47% of cases aged >65 years (P = 0.036). The cross-validated decision tree resulted in three risk groups with significantly varying probabilities of recurrence-free and overall survival (both with overall P < 0.001). CONCLUSIONS: Hydronephrosis, tumour growth pattern, deep muscle involvement and age can collectively identify patients with cT2N0M0 bladder cancer who have varying risks of pathological upstaging. Such categorization using a visually intuitive model can facilitate clinical decision-making with respect to neoadjuvant therapy in these patients. PMID- 22928883 TI - Safety and immunogenicity of bacterial and tobacco plant cell line derived recombinant native and mutant Escherichia coli heat-labile toxin in chickens. AB - The safety and immunogenicity of the mammalian mucosal adjuvants, Escherichia coli wild-type heat-labile holotoxin (LT) and E. coli mutant LT (LTA-K63/LTB), were examined in 1-day-old chicks and 10-day-old to 21-day-old broilers. Biologically active, E. coli recombinant wild-type LT and recombinant LTA-K63/LTB produced in a transgenic Nicotiana tabacum (NT-1) tobacco cell line (SLT102) were tested for safety and antigenicity following various routes of administration. Safety was assessed by clinical signs, body weight gain, gross organ pathology and wet organ weight, and histopathology. Antigenicity was assessed using LT-B specific serum IgG enzyme-linked immunosorbent assay. Parenteral administration of E. coli recombinant wild-type LT did not have any discernible effect on bird health and was well tolerated at levels up to 400 ug per dose. Recombinant, SLT102-derived mutant LT derived from SLT102 cells retained in vitro ganglioside binding and was safe and antigenic following repeated mucosal administration to birds. The highest systemic LT-B-specific IgG titres were detected in birds that received three on-feed doses of SLT102-derived mutant LT. Among the various SLT102-derived mutant LT preparations tested, whole, wet cells or whole cell lysates were the most antigenic. These results demonstrate for the first time that E. coli-derived recombinant, wild-type LT holotoxin is well tolerated following multiple administrations to young birds at body weight doses previously reported to be enteropathogenic and toxic in mammalian species. Moreover, these data also demonstrate the feasibility of using recombinant wild-type and mutant LT produced in transgenic NT-1 tobacco cells as safe and potent vaccine adjuvants in poultry. PMID- 22928884 TI - Nasopharyngeal suctioning does not produce a salivary cortisol reaction in preterm infants. AB - AIM: To investigate whether nasopharyngeal suctioning produces a physiological and behavioural stress reaction in preterm infants and if a possible reaction can be dampened by sweet solution. METHODS: Eleven preterm infants were randomly assigned to receive either 30% oral glucose or nothing prior to morning nasopharyngeal suctioning; the procedure was reversed in the afternoon. The study included a total of 44 samples from preterm infants evaluated with salivary cortisol, pain score (Visual Analogue Scale), heart rate, oxygen saturation and recovery time through the Newborn Individualized Developmental Care and Assessment Program. For reference, 44 samples from eleven full-term infants were evaluated for salivary cortisol. RESULTS: Regardless of whether or not preterm infants received glucose before nasopharyngeal suctioning, no statistically significant difference was found in salivary cortisol reactivity, pain score, heart rate, oxygen saturation or recovery time. Nor were any statistically significant differences between salivary cortisol baseline and response values found in full-term infants after nasopharyngeal suctioning. CONCLUSION: In the present setting, nasopharyngeal suctioning was not stressful enough to increase salivary cortisol or pain score. Oral glucose did not alter salivary cortisol levels. PMID- 22928885 TI - Evaluation of the embolic effect and degradability of gelatin microspheres and Gelpart particles. AB - PURPOSE: To evaluate the embolic effect and degradability of gelatin microspheres (GMS) and Gelpart particles (GPS) in dogs subjected to hepatic embolization. MATERIAL AND METHODS: We subjected 20 beagles to embolization of the hepatic artery (HA) and assessed the embolic effects of GMS measuring 500 MUm in dry and 1 mm in wet state and of 1-mm GPS, porous gelatin embolic particles. We obtained celiac angiographs before and immediately after embolization and two, 14, and 28 days later; the livers were histopathologically evaluated. Reperfusion of HA was assessed by inspecting the arterial branches. We checked the liver specimens for residual GMS, injury to surrounding tissues, and inflammatory changes, and investigated embolic formation in the HA. RESULTS: The mean amount of injected GMS and GPS was 15.5 and 14.5 mg, respectively. While none of the dogs manifested HA reperfusion two days post-embolization, there was angiographic evidence of complete reperfusion 28 days after embolization. In all dogs, histopathological study showed arterial inflammatory changes and injury of surrounding tissues irrespective of the embolization materials used. These findings were pronounced on day 28 in dogs injected with GMS. CONCLUSION: There was no difference in the embolic effects of GMS and GPS nor in their degradability in dogs subjected to hepatic embolization. PMID- 22928886 TI - Parsonage-Turner syndrome and a localised swelling around the extensor tendons of the hand: a clinical sign indicating increased risk of rupture of the tendon. AB - Two patients presented with intense pain in the shoulder followed by weakness and paralysis of muscles in the shoulder and arm, together with a peculiar swelling on the hand. The swelling seems to predispose to rupture of the extensor tendon. If this tumour is a regular finding in Parsonage-Turner syndrome, it may also help in making a definitive diagnosis. PMID- 22928887 TI - Field-scale labelling and activity quantification of methane-oxidizing bacteria in a landfill-cover soil. AB - Aerobic methane-oxidizing bacteria (MOB) play an important role in soils, mitigating emissions of the greenhouse gas methane (CH(4)) to the atmosphere. Here, we combined stable isotope probing on MOB-specific phospholipid fatty acids (PLFA-SIP) with field-based gas push-pull tests (GPPTs). This novel approach (SIP GPPT) was tested in a landfill-cover soil at four locations with different MOB activity. Potential oxidation rates derived from regular- and SIP-GPPTs agreed well and ranged from 0.2 to 52.8 mmol CH(4) (L soil air)(-1) day(-1). PLFA profiles of soil extracts mainly contained C(14) to C(18) fatty acids (FAs), with a dominance of C(16) FAs. Uptake of (13) C into MOB biomass during SIP-GPPTs was clearly indicated by increased delta(13)C values (up to c. 15000/00) of MOB characteristic FAs. In addition, (13)C incorporation increased with CH(4) oxidation rates. In general, FAs C(14:0) , C(16:1omega8), C(16:1omega7) and C(16:1omega6) (type I MOB) showed highest (13)C incorporation, while substantial (13)C incorporation into FAs C(18:1omega8) and C(18:1omega7) (type II MOB) was only observed at high-activity locations. Our findings demonstrate the applicability of the SIP-GPPT approach for in situ quantification of potential CH(4) oxidation rates and simultaneous labelling of active MOB, suggesting a dominance of type I MOB over type II MOB in the CH(4)-oxidizing community in this landfill-cover soil. PMID- 22928889 TI - Cyclic and linear NiO2: a multireference configuration interaction study. AB - Linear (ONiO) and triangular (Ni(O2))isomers of NiO2 are investigated by multiconfiguration self-consistent field (MCSCF) and multireference configuration interaction (MRCI) calculations. For ONiO, the ground electronic term is a 1Sigmag+ term. The lower-lying excited terms are 3Pig, 1Pig, and 5Piu at relative energies of 0.55, 0.95, and 1.20eV, respectively. For Ni(O2), the ground electronic term is a1A1 term with an energy of 1.53 eV with respect to the ONiO ground state. Lower-lying excited terms are 5B2, 5A1, and 3B2 at 0.58, 0.62, and 0.73 eV with respect to the 1A1 state, respectively.A transition structure between the ground states of both isomers has been located with an energy of 2.76 eV above the ONiO ground state. For the fragmentation Ni(O2) -> Ni + O2 the (electronic) reaction energy is estimated to 1.15 eV. The wave function based results demonstrate the failure of previous density functional investigations and emphasize the importance of a multireference treatment. PMID- 22928888 TI - Hydrogen sulphide-mediated vasodilatation involves the release of neurotransmitters from sensory nerves in pressurized mesenteric small arteries isolated from rats. AB - BACKGROUND AND PURPOSE: Hydrogen sulphide (H(2)S) is a gas that has recently been shown to have biological activity. In the majority of blood vessels studied so far, H(2)S has been shown to cause vasorelaxation, although contractile responses have been reported. In the present study, we have made a pharmacological assessment of the effects of H(2)S in mesenteric small arteries isolated from rats. EXPERIMENTAL APPROACH: Rat mesenteric small arteries were studied using pressure myography. In pressurised arteries, responses were obtained to the H(2)S donor, sodium hydrogen sulphide (NaHS), in the absence and presence of the NOS inhibitor L-NAME, raised extracellular potassium, the K(ATP) channel inhibitor glibenclamide, the Cl- channel blockers DIDS, NPPB and A9C, the TRPV1 receptor desensitizing agent, capsaicin, the CGRP antagonist, olcegepant, the TRPV1 channel blocker capsazepine and the TRPA1 channel blocker HC-030031. KEY RESULTS: NaHS produced a vasodilator response in rat mesenteric small arteries held at 90 mmHg. Responses to NaHS were not reproducible. Neither, glibenclamide nor, L-NAME inhibited responses to NaHS. DIDS abolished vasodilator responses to NaHS, but these were unaffected by the chloride channel blockers, NPPB and A9C. Responses to NaHS were attenuated after capsaicin pre-treatment, by a CGRP receptor antagonist and an inhibitor of TRPA1 channels. CONCLUSIONS AND IMPLICATIONS: In small arteries isolated from the rat mesentery, NaHS caused a vasodilatation. This response was not reproducible in vitro, since it was mediated by the release of sensory neurotransmitters in a capsaicin-like action. This release was mediated by a H(2)S-induced activation of TRPA1 channels. PMID- 22928890 TI - Insulin resistance in chronic hepatitis C: the search for effective drug treatment continues. PMID- 22928891 TI - Comparative effectiveness research in inflammatory bowel disease: prospects and challenges. PMID- 22928893 TI - Tenofovir disoproxil fumarate in the treatment of chronic hepatitis B. AB - The specific drugs available for chronic hepatitis B infection include standard and pegylated IFN-alpha, and nucleoside/nucleotide analogs that directly inhibit the reverse transcriptase. The main goal of current hepatitis B virus therapy is to achieve sustained suppression of viral replication to prevent the development of chronic liver disease, but favorable long-term tolerability and resistance profiles are also desirable. This article reviews the chemistry and the mechanisms of action of tenofovir disoproxil fumarate, but it also focuses on the related clinical trails designed to date, in which clinical efficacy has been analyzed attending to HBe antigen status. In addition, studies including patients that have been previously treated with lamivudine or adefovir are discussed. PMID- 22928894 TI - Rabeprazole for the treatment of acid-related disorders. AB - Proton pump inhibitors are widely used for the treatment of acid-related disorders. Rabeprazole is a potent and irreversible inhibitor of H(+)/K(+)-ATPase gastric pump, and it is indicated for the treatment of gastroesophageal reflux disease, Zollinger Ellison syndrome, duodenal and gastric ulcers and for the eradication of Helicobacter pylori in combination with antibiotics. Pharmacokinetic and pharmacodynamic data show that rabeprazole achieves a pronounced acid suppression from the first administration that is maintained with repeated use; this may translate into faster onset of symptom relief for patients, particularly suitable when the indication is for the on-demand long term maintenance of gastroesophageal reflux disease. Due to its predominantly nonenzymatic metabolism, rabeprazole has a lower potential for drug-drug interactions. The objective of this article is to update efficacy and safety data of rabeprazole in the treatment of acid-related disorders, following a previous review dated 2008. PMID- 22928895 TI - Helicobacter pylori: usefulness of an empirical fourth-line rifabutin-based regimen. AB - Helicobacter pylori represents the major cause of gastric cancer, gastric lymphoma and peptic ulcer diseases. In some cases, the infection persists even after three rounds of treatment. The evaluated article reports on the efficacy of an empirical multicenter, prospective fourth-line rescue study with rifabutin in patients with three consecutive eradication failures. A total of 100 patients (31% peptic ulcer and 69% functional dyspepsia) were included to receive a fourth line with rifabutin (150 mg twice daily [b.i.d.]), amoxicillin (1 g b.i.d.) and a proton-pump inhibitor (standard dose b.i.d.) for 10 days. The end point was H. pylori eradication, determined by (13)C-urea breath test 4-8 weeks after therapy. H. pylori eradication was achieved in approximately 50% of patients. Adverse events (mainly metallic taste, nausea and diarrhea) were reported in 30 patients. Thus, a fourth-line rifabutin-based rescue therapy constitutes a valid strategy after multiple previous H. pylori eradication failures with key antibiotics, such as clarithromycin, metronidazole, tetracycline and levofloxacin. PMID- 22928896 TI - Effectiveness of alpha-fetoprotein for hepatocellular carcinoma surveillance: the return of the living-dead? AB - The evaluated article assesses the effectiveness in clinical practice of surveillance with ultrasound (US) and alpha-fetoprotein (AFP) in patients at risk of developing hepatocellular carcinoma. After a median follow-up of 3.5 years, among the 442 enrolled patients with cirrhosis, 41 developed tumor (annual incidence, 2.8%). Twenty-three hepatocellular carcinomas were diagnosed at Barcelona Clinic Liver Cancer early stage (single tumor <5 cm or <=3 tumors each <3 cm). Two hundred and seventy one patients (61.3%) underwent 'consistent' (US done at least annually) surveillance, whereas 107 (24.2%) and 64 (14.5%) patients underwent 'inconsistent' and 'no surveillance', respectively. The per-patient sensitivity was 43.9% for US (58.1% excluding cases where US was inconsistently performed) and 65.9% for AFP >20 ng/ml. Specificity was 91.5% for US and 90.5% for AFP. The combination of the tests increased the sensitivity to 90.2%, with a small decrease in specificity (83.3%). In a real-world setting, the combination of US and AFP would be the most effective for hepatocellular carcinoma surveillance. PMID- 22928897 TI - Is the north to south gradient in inflammatory bowel disease a global phenomenon? AB - Inflammatory bowel diseases (IBDs), such as Crohn's disease and ulcerative colitis, are multifactorial diseases that result from an overly aggressive immune response towards an environmental trigger in a genetically susceptible host. Much has been learned about susceptibility genes; however, environmental triggers are still largely unknown. In the 1990s, a large study from Europe suggested a north south gradient regarding the incidence of IBD; however, this was never shown convincingly for the USA. In the present study, the authors used and extended data from the Nurses' Health Study I and II and were able to demonstrate that indeed the risk of developing IBD is significantly lower for the southern latitudes of the USA and did not depend on ancestry or lifestyle factors such as smoking. The authors speculate that an increased exposure to sunlight provides protection from IBD via the vitamin D pathway. PMID- 22928898 TI - Flexible endoscopic and surgical management of Zenker's diverticulum. AB - Zenker's diverticulum is an outpouching of the mucosa through the Killian's triangle. The etiology of Zenker's diverticulum is not well understood. It is thought to be due to the incoordination or incomplete relaxation of the cricopharyngeal muscle. Most patients are men who present with symptoms of dysphagia between the seventh and eighth decades of life. The diagnosis is made with a dynamic contrast swallowing study. Treatment options include open surgical diverticulectomy and diverticulopexy with myotomy or myotomy alone using flexible or rigid endoscopes. Rigid endoscopic treatment is currently the preferred initial choice for Zenker's diverticulum of any size. The flexible endoscopic technique is used when there is a high risk of general anesthesia, or neck extension is contraindicated. Some centers use flexible endoscopy as the initial treatment option. Due to a lack of prospective studies, the treatment choice should be tailored to the individual patient and local expertise. PMID- 22928899 TI - The race for mainstream gastrointestinal endoscopy: frontrunners. AB - In recent years, gastrointestinal endoscopy has evolved and branched out from a primary naked-eye diagnostic technique to a multitude of sophisticated investigative and therapeutic procedures. While many of the new endoscopic techniques are currently too complex or expensive to make it to mainstream clinical practice, others are already bringing major progress to the management of digestive diseases. In this review we will discuss a selected group of the emerging techniques and technologies used to increase the diagnostic yield in the colon and small intestine, including Third Eye(r) Retroscopes(r), colon capsule endoscopy, spiral enteroscopy and confocal laser endomicroscopy. We will also discuss over-the-scope clip devices, a relatively simple and inexpensive tool potentially capable of noninvasive closing intestinal perforations and allowing the removal of infiltrating tumors. PMID- 22928901 TI - Genomic variation-guided management in chronic hepatitis C. AB - In 2009, several different research groups simultaneously identified the polymorphisms close to IL28B gene as an important predictor of therapeutic response for chronic hepatitis C (CHC) patients receiving interferon-based treatment using approaches of genome-wide association studies. They also found that these genetic variations were strongly associated with the spontaneous viral clearance of hepatitis C virus (HCV) infection. Following these studies, ITPA gene variants were reported to affect ribavirin-induced anemia and therapeutic outcomes of CHC patients. All these lines of evidence usher in a new genomic era for the management of HCV infection. In this article, advances in recent genome wide association studies regarding HCV infection, and their impacts on the management of CHC patients will be reviewed. In addition, the clinical usefulness of genomic variations on the addition of direct antiviral agents to current standard of care will be discussed. PMID- 22928900 TI - Management of perihilar cholangiocarcinoma in the era of multimodal therapy. AB - Perihilar cholangiocarcinoma (CCA) is the second most common primary malignant tumor of the liver. In the USA, there are approximately 3000 cases of CCA diagnosed annually, with approximately 50-70% of these tumors arising at the hilar plate of the biliary tree. Risk factors include advanced age, male gender, primary sclerosing cholangitis, choledochal cysts, cholelithiasis, parasitic infection, inflammatory bowel disease, cirrhosis and chronic pancreatitis. Patients typically present with jaundice, abdominal pain, pruritus and weight loss. The mainstays of treatment include surgery, chemotherapy, radiation therapy and photodynamic therapy. Specific preoperative interventions for patients with perihilar CCA include endoscopic retrograde cholangiopancreatography, percutanteous transhepatic cholangiography and portal vein embolization. Surgical resection offers the only chance for curative therapy in perihilar CCA. R0 resection is of utmost importance and has been linked to improved survival. Major hepatic resection is needed to achieve both longitudinal and radial margins negative for tumor. Fractionated stereotactic body radiotherapy has shown promising results in CCA. Perihilar CCA typically presents with advanced disease, and many patients receive systemic therapy; however, the response to current regimens is limited. Orthotopic liver transplantation offers complete resection of locally advanced tumors in select patient groups. PMID- 22928902 TI - Clinical end points for developing pharmaceuticals to manage patients with a sporadic or genetic risk of colorectal cancer. AB - To reduce the morbidity and mortality from colorectal cancer (CRC), current clinical practice focuses on screening for early detection and polypectomy as a form of secondary prevention, complemented with surgical interventions when appropriate. No pharmaceutical agent is currently approved for use in clinical practice for the management of patients at risk for CRC. This article will review earlier attempts to develop pharmaceuticals for use in managing patients with a sporadic or genetic risk of CRC. It will also discuss therapeutic end points under evaluation in current efforts to develop drugs for treating CRC risk factors. PMID- 22928903 TI - Impact of treating dental caries on schoolchildren's anthropometric, dental, satisfaction and appetite outcomes: a randomized controlled trial. AB - BACKGROUND: There are no randomized controlled trials to assess the impact of treating dental caries on various aspects of children's health. This study was conducted to assess the impact of dental treatment of severe dental caries on children's weight, height and subjective health related outcomes, namely dental pain, satisfaction with teeth and smile, dental sepsis and child's appetite. METHODS: The study was a community-based, randomized, controlled trial in schoolchildren aged 6-7 years with untreated dental caries. Participants were randomly assigned to early (test) or regular (control) dental treatment. The primary outcome was Weight-for-age Z-score. Secondary outcomes were Height-for age and BMI-for-age Z-scores, dental pain, dental sepsis, satisfaction with teeth and child's appetite. RESULTS: 86 children were randomly assigned to test (42 children) and control (44) groups. Mean duration of follow-up was 34.8 (+/- 1.1) weeks. There were insignificant improvements in anthropometric outcomes between the groups after treatment of caries. However, treated children had significantly less pain experience (P = 0.006) (OR 0.09, [0.01-0.51]) and higher satisfaction with teeth (P = 0.001) (OR 9.91, [2.68-36.51]) compared to controls. Controls had significantly poorer appetites (P = 0.01) (OR 2.9, [1.24-6.82]) compared to treated children. All treated children were free of clinical dental sepsis whereas 20% (9 of 44) of controls who were free of sepsis at baseline had sepsis at follow-up. CONCLUSIONS: Although dental treatment did not significantly improve the anthropometric outcomes, it significantly improved the dental outcomes and children's satisfaction with teeth, smile and appetite. This is the first study to provide evidence that treatment of severe dental caries can improve children's appetite. TRIAL REGISTRATION: Effect of Dental Treatment on Children's Growth. Clinical Trial Gov ID# NCT01243866. PMID- 22928904 TI - Telomere length in reproduction. AB - Telomeres, noncoding hexameric tandem repeats located at the ends of chromosomes, maintain chromosome stability and genome integrity. These guanine-rich repeats are highly conserved during evolution, and their role is dependent on their length and structure. They have multiple functions, including regulating the reproductive lifespan by mediating synapsis and homologous recombination of the chromosomes. Short telomeres result in meiotic arrest, segregation abnormalities and dysjunction, which lead to an increased incidence of aneuploid germ cells. In addition, shortened telomeres in men result in apoptosis of germ cells, whereas, in women, they result in meiotic arrest. In somatic cells, telomere shortening occurs at each consecutive round of replication, which induces senescence in vitro and in vivo. However there is a 2-fold elongation of telomeres during spermatogenesis. Spermatozoa, are terminally differentiated cells, have longer telomeres than spermatogonia and pachytene spermatocytes. In addition to genetic factors, lifestyle factors and psychological stress also play crucial role in modulating telomere length. Because not much is known about its role in reproduction, we focused this review on the function, structure and length dynamics of the telomere in the reproductive process. PMID- 22928905 TI - Synthesis and fluorescence properties of thiazole-boron complexes bearing a beta ketoiminate ligand. AB - Novel fluorescent dyes, thiazole-boron complexes bearing beta-ketoiminate ligands, have been synthesized, and their fluorescence properties were investigated. The BF(2) complexes showed a pronounced aggregation-induced emission enhancement effect because of the restriction of C-Ph intramolecular rotation. The BPh(2) complexes showed higher fluorescence quantum yields than the corresponding BF(2) complexes, both in solution and in the solid state. PMID- 22928906 TI - Systemic AA amyloidosis in a patient with lung metastasis from renal cell carcinoma. AB - AA amyloidosis occurs in patients with high levels of serum amyloid A protein (SAA), which is produced by liver cells in response to signals from several pro inflammatory cytokines. Chronic inflammatory disease is a major cause of AA amyloidosis; however, malignant neoplasms are rarely reported to be associated with AA amyloidosis. We report herein a case of a solitary lung metastasis of renal cell carcinoma associated with systemic AA amyloidosis. Pathological specimens of the resected lung tumor demonstrated renal cell carcinoma, and the presence of IL-1beta, IL-6, and TNF-alpha in the lymphocytes and plasma cells surrounding the tumor cells, and AA amyloid in the vascular area, but not in metastatic clear cells. Four weeks after surgery, serum IL-6, SAA, and CRP levels normalized. Although this case is very rare, it is full of interesting suggestions about the pathogenesis of malignancy-related systemic amyloidosis. PMID- 22928907 TI - Massive somatic deafferentation and motor deefferentation of the lower part of the body impair its visual recognition: a psychophysical study of patients with spinal cord injury. AB - Embodied cognition theories postulate that perceiving and understanding the body states of other individuals are underpinned by the neural structures activated during first-hand experience of the same states. This suggests that one's own sensorimotor system may be used to identify the actions and sensations of others. Virtual and real brain lesion studies show that visual processing of body action and body form relies upon neural activity in the ventral premotor and the extrastriate body areas, respectively. We explored whether visual body perception may also be altered in the absence of damage to the above cortical regions by testing healthy controls and spinal cord injury (SCI) patients whose brain was unable to receive somatic information from and send motor commands to the lower limbs. Participants performed tasks investigating the ability to visually discriminate changes in the form or action of body parts affected by somatosensory and motor disconnection. SCI patients showed a specific, cross modal deficit in the visual recognition of the disconnected lower body parts. This deficit affected both body action and body form perception, hinting at a pervasive influence of ongoing body signals on the brain network dedicated to visual body processing. Testing SCI patients who did or did not practise sports allowed us to test the influence of motor practice on visual body recognition. We found better upper body action recognition in sport-practising SCI patients, indicating that motor practice is useful for maintaining visual representation of actions after deafferentation and deefferentation. This may be a potential resource to be exploited for rehabilitation. PMID- 22928909 TI - Analyses of recombinant activated factor VII treatments from clinical practice for rapid bleeding and acute pain control in haemophilia patients with inhibitors. PMID- 22928910 TI - Retrospective analysis of dental implants placed and restored by advanced prosthodontic residents. AB - PURPOSE: The purposes of this retrospective clinical review were to: (1) describe the demographics of implant patients, types of implant treatment and implant supported prostheses in an Advanced Education in Prosthodontic Program, (2) evaluate the survival rate of dental implants placed by prosthodontic residents from 2006 to 2008, and (3) analyze the relationship between resident year of training and implant survival rate. MATERIAL AND METHODS: All patients who received dental implants placed by prosthodontic residents from January 2006 to October of 2008 in the Advanced Prosthodontic Program at the University of Illinois at Chicago College of Dentistry were selected for this study. Age, gender, implant diameter, length, implant locations, surgical and restorative detail, and year of prosthodontic residency training were collected and analyzed. Life-table and Kaplan-Meier survival analyses were performed based on implants overall, locations, year of training, and use of a computer-generated surgical guide. A Logrank statistic was performed between implant survival and year of prosthodontic residency training, location, and use of computer-generated surgical guide (alpha= 0.05). RESULTS: Three hundred and six implants were placed, and of these, seven failed. Life-table and Kaplan-Meier analyses computed a cumulative survival rate (CSR) of 97% for overall implants and implants placed with a computer-generated surgical guide. No statistical difference was found in implant survival rates as a function of year of training (P= 0.85). CONCLUSION: Dental implants placed by prosthodontic residents had a CSR comparable to previously published studies by other specialties. The year of prosthodontic residency training and implant failure rate did not have any significant relationship. PMID- 22928908 TI - Thrombocytopenia and platelet transfusion in UK critical care: a multicenter observational study. AB - BACKGROUND: Platelet (PLT) transfusions are widely used, but few studies have described patterns of use in critical care. STUDY DESIGN AND METHODS: As part of a prospective multicenter observational study of all sequentially admitted patients to UK general intensive care units (ICUs) over 8 weeks, daily data were collected throughout admission on frequency of thrombocytopenia and use of PLT transfusions, in addition to clinical outcomes, including bleeding. RESULTS: There were 1923 admissions recruited across 29 ICUs for analysis (96.6% of all eligible admissions). The period prevalences of severe thrombocytopenia (<50 * 10(9) /L) for the entire ICU stay were 12.4% (234/1881) and 13.7% (263/1914) when the 24 hours before admission was also included. A total of 35.4% of patients who experienced severe thrombocytopenia died in the ICU. A total of 169 patients (9% of study population) received 534 units of transfused PLTs (median number of units per patient admission was 2; interquartile range, 1-3; maximum, 38). Pretransfusion PLT counts were more than 50 * 10(9) for 40% of PLT transfusions overall, and even when no clinically significant bleeding was recorded on the day of transfusion, the lowest recorded PLT count was more than 50 * 10(9) for 34% of transfusions. There was evidence of only modest increments in PLT count. CONCLUSION: Thrombocytopenia is common in critical care, but there is wide variation in PLT transfusion use. Patients commonly received PLT transfusions on days without clinically significant hemorrhage. The high prevalence of thrombocytopenia in the critically ill population and inconsistent patterns of PLT transfusions indicate the importance of improving the evidence base for PLT use. PMID- 22928911 TI - An insight to the dynamics of conserved water-mediated salt bridge interaction and interdomain recognition in hIMPDH isoforms. AB - Inosine monophosphate dehydrogenase (IMPDH) is involved in de novo biosynthesis pathway of guanosine nucleotide. Type II isoform of this enzyme is selectively upregulated in lymphocytes and chronic myelogenous leukemia (CML) cells, and is an excellent target for antileukemic agent. The molecular dynamics simulation results (15 ns) of three unliganded 1B3O, 1JCN, and 1JR1 structures have clearly revealed that IN, IC (N- and C-terminal of catalytic domains) and C1, C2 (cystathionine-beta-synthase-1 and 2) domains of IMPDH enzyme have been stabilized by six conserved water (center) mediated salt bridge interactions. These conserved water molecules could be involved in interdomain or intradomain recognition, intradomain coupling, and charge transfer processes. The binding propensity of cystathionine-beta-synthase domain to catalytic domain (through conserved water-mediated salt bridges) has provided a new insight to the biochemistry of IMPDH. Stereospecific interaction of IN with C2 domain through conserved water molecule (K109-W(II) 1-D215/D216) is observed to be unique in the simulated structure of hIMPDH-II. The geometrical/structural consequences and topological feature around the W(II) 1 water center may be utilized for isoform specific inhibitor design for CML cancer. An animated Interactive 3D Complement (I3DC) is available in Proteopedia at http://proteopedia.org/w/Journal :JBSD:1. PMID- 22928912 TI - Investigation of pyridine/propargyl bromide reaction and strong fluorescence enhancements of the resultant poly(propargyl pyridinium bromide). AB - Poly(propargyl pyridinium bromide), a kind of conjugated polyelectrolyte with polyacetylene as the backbone and pyridinium as side groups, was synthesized simply via reaction between pyridine and propargyl bromide under mild conditions. The resultant polymer was characterized by (1)H NMR, elemental analysis, FT-IR, and GPC-MALLS. An alkyne group was confirmed as the end group of the polymer chains by the alkyne/azide click chemistry, which reveals that the polymerization is terminated by the reaction between propargyl bromide and carbon anions. It is known that monosubstituted polyacetylenes reported have very weak fluorescence intensities, which limit their applications. As a monosubstituted polyacetylene, the freshly prepared poly(propargyl pyridinium bromide) also has a very weak fluorescence. However, we confirmed that addition of some anions to the polymer solution in DMF or DMSO leads to the fluorescence enhancements up to 25 times. Besides, heating the polymer solution at a temperature between 70 and 130 degrees C for longer than 0.5 h greatly enhanced the fluorescence intensity. The interaction with the anions or the heating enhances the effective exciton confinement within the conjugated backbone and thus results in the fluorescence enhancements. After the fluorescence enhancements, poly(propargyl pyridinium bromide) has relatively strong fluorescence emissions, which will make it promising in fluorescence-based applications. PMID- 22928913 TI - Long-term effects of cranial irradiation and intrathecal chemotherapy in treatment of childhood leukemia: a MEG study of power spectrum and correlated cognitive dysfunction. AB - BACKGROUND: Prophylaxis to prevent relapses in the central nervous system after childhood acute lymphoblastic leukemia (ALL) used to consist of both intrathecal chemotherapy (CT) and cranial irradiation (CRT). CRT was mostly abolished in the eighties because of its neurotoxicity, and replaced with more intensive intrathecal CT. In this study, a group of survivors treated with CRT before 1983 and another group treated without CRT thereafter are investigated 20-25 years later, giving a much stronger perspective on long-term quality of life than previous studies. The outcomes will help to better understand these groups' current needs and will aid in anticipating late effects of prophylactic CRT that is currently applied for other diseases. This study evaluates oscillatory neuronal activity in these long-term survivors. Power spectrum deviations are hypothesized to correlate with cognitive dysfunction. METHODS: Resting state eyes closed magnetoencephalography (MEG) recordings were obtained from 14 ALL survivors treated with CT + CRT, 18 treated with CT alone and 35 controls. Relative spectral power was calculated in the delta, theta, alpha1, alpha2, beta and gamma frequency bands. The Amsterdam Neuropsychological Tasks (ANT) program was used to assess cognition in the executive functions domain. MEG data and ANT scores were correlated. RESULTS: In the CT + CRT group, relative theta power was slightly increased (p = 0.069) and alpha2 power was significantly decreased (p = 0.006). The CT + CRT group performed worse on various cognitive tests. A deficiency in visuomotor accuracy, especially of the right hand, could be clearly associated with the deviating regional theta and alpha2 powers (0.471 < r < 0.697). A significant association between decreased regional alpha2 power and less attentional fluctuations was found for CT + CRT patients as well as controls (0.078 < r < 0.666). Patients treated with CT alone displayed a power spectrum similar to controls, except for a significantly increased level of left frontal alpha2 power (p = 0.030). CONCLUSIONS: The tendency towards global slowing of brain oscillatory activity, together with the fact that dementia has been reported as a late effect of CRT and the neuropsychological deficiencies currently present, suggest that the irradiated brain might be aging faster and could be at risk for early-onset dementia. The CT group showed no signs of early aging. PMID- 22928914 TI - Structure- and property-based design of aminooxazoline xanthenes as selective, orally efficacious, and CNS penetrable BACE inhibitors for the treatment of Alzheimer's disease. AB - A structure- and property-based drug design approach was employed to identify aminooxazoline xanthenes as potent and selective human beta-secretase inhibitors. These compounds exhibited good isolated enzyme, cell potency, and selectivity against the structurally related aspartyl protease cathepsin D. Our efforts resulted in the identification of a potent, orally bioavailable CNS penetrant compound that exhibited in vivo efficacy. A single oral dose of compound 11a resulted in a significant reduction of CNS Abeta40 in naive rats. PMID- 22928915 TI - Scheduled feeding alters the timing of the suprachiasmatic nucleus circadian clock in dexras1-deficient mice. AB - Restricted feeding (RF) schedules are potent zeitgebers capable of entraining metabolic and hormonal rhythms in peripheral oscillators in anticipation of food. Behaviorally, this manifests in the form of food anticipatory activity (FAA) in the hours preceding food availability. Circadian rhythms of FAA are thought to be controlled by a food-entrainable oscillator (FEO) outside of the suprachiasmatic nucleus (SCN), the central circadian pacemaker in mammals. Although evidence suggests that the FEO and the SCN are capable of interacting functionally under RF conditions, the genetic basis of these interactions remains to be defined. In this study, using dexras1-deficient (dexras1(-/-)) mice, the authors examined whether Dexras1, a modulator of multiple inputs to the SCN, plays a role in regulating the effects of RF on activity rhythms and gene expression in the SCN. Daytime RF under 12L:12D or constant darkness (DD) resulted in potentiated (but less stable) FAA expression in dexras1(-/-) mice compared with wild-type (WT) controls. Under these conditions, the magnitude and phase of the SCN-driven activity component were greatly perturbed in the mutants. Restoration to ad libitum (AL) feeding revealed a stable phase displacement of the SCN-driven activity component of dexras1(-/-) mice by ~2 h in advance of the expected time. RF in the late night/early morning induced a long-lasting increase in the period of the SCN-driven activity component in the mutants but not the WT. At the molecular level, daytime RF advanced the rhythm of PER1, PER2, and pERK expression in the mutant SCN without having any effect in the WT. Collectively, these results indicate that the absence of Dexras1 sensitizes the SCN to perturbations resulting from restricted feeding. PMID- 22928916 TI - The proximal C-terminus of alpha(1C) subunits is necessary for junctional membrane targeting of cardiac L-type calcium channels. AB - In cardiac myocytes, LTCCs (L-type calcium channels) form a functional signalling complex with ryanodine receptors at the JM (junctional membrane). Although the specific localization of LTCCs to the JM is critical for excitation-contraction coupling, their targeting mechanism is unclear. Transient transfection of GFP (green fluorescent protein)-alpha(1S) or GFP-alpha(1C), but not P/Q-type calcium channel alpha(1A), in dysgenic (alpha(1S)-null) GLT myotubes results in correct targeting of these LTCCs to the JMs and restoration of action-potential-induced Ca2+ transients. To identify the sequences of alpha(1C) responsible for JM targeting, we generated a range of alpha(1C)-alpha(1A) chimaeras, deletion mutants and alanine substitution mutants and studied their targeting properties in GLT myotubes. The results revealed that amino acids L(1681)QAGLRTL(1688) and P(1693)EIRRAIS(1700), predicted to form two adjacent alpha-helices in the proximal C-terminus, are necessary for the JM targeting of alpha(1C). The efficiency of restoration of action-potential-induced Ca2+ transients in GLT myotubes was significantly decreased by mutations in the targeting motif. JM targeting was not disrupted by the distal C-terminus of alpha(1C) which binds to the second alpha-helix. Therefore we have identified a new structural motif in the C-terminus of alpha(1C) that mediates the targeting of cardiac LTCCs to JMs independently of the interaction between proximal and distal C-termini of alpha(1C). PMID- 22928917 TI - Co action of CFTR and AQP1 increases permeability of peritoneal epithelial cells on estrogen-induced ovarian hyper stimulation syndrome. AB - BACKGROUND: Ovarian hyper stimulation syndrome (OHSS) is an iatrogenic complication associated with fertility drugs. It is characterized by increased vascular permeability and substantial fluid shift with accumulation in the body cavity. The pathogenesis of OHSS remains obscure, and no definitive treatments are currently available. RESULTS: Using western blot and short-circuit current (Isc) techniques, we investigate the potential coactions of analysis in cystic fibrosis transmembrane conductance regulator (CFTR) and aquaporin 1 (AQP1) on the hyper permeability of body cavity peritoneal epithelial cells in the pathogenesis of OHSS. The rats develop OHSS symptoms, with the up regulation of both CFTR and AQP1 expression and enhanced CFTR channel activity in peritoneal epithelial cells, can also be mimicked by administration of estrogen, alone in ovariectomized rats. Administration of progesterone suppresses CFTR activity, OHSS symptoms as well as CFTR and AQP1 expression. Besides, AQP1 inhibitor, HgCl(2), can suppress CFTR channel activity. Therefore, antisera against CFTR or AQP1 to OHSS animals may result in alleviation of the symptom. CONCLUSION: This study confirms the coactions of CFTR and AQP1 play a critical role in the development and progression of increased peritoneal epithelial permeability in severe OHSS. These findings may provide grounds for ameliorating assisted reproduction treatment strategy to reduce the risk of OHSS in in vitro fertilization (IVF). PMID- 22928918 TI - Sudden sensorineural hearing loss: a vascular cause? Analysis of prothrombotic risk factors in head and neck. AB - OBJECTIVE: This aim of this study was to determine the prevalence of thrombophilic risk factors in sudden sensorineural hearing loss, central retinal vein occlusion, and stroke associated with small vessel disease, with the purpose of investigating and reinforcing the vascular hypothesis in the pathogenesis of sudden sensorineural hearing loss. DESIGN: Case-control study. Genetic and acquired risk factors of these three groups were compared with healthy controls. STUDY SAMPLE: Forty-nine, 60, and 101 patients affected respectively by sudden sensorineural hearing loss, central retinal vein occlusion, or stroke associated with small vessel disease, enrolled during a three-year period were compared with 210 healthy controls. RESULTS: The frequency of hyperhomocysteinemia (homocysteine >= 15 MUmol/L) was higher in each disease group than in controls. A statically significant, albeit weak, correlation between the MTHFR C677T mutation and hyperhomocysteinemia was found in all three diseases. CONCLUSIONS: Hyperhomocysteinemia proved to be a risk factor for sudden sensorineural hearing loss. Based on these results, we propose to analyse homocysteine in sudden sensorineural hearing loss patients and, if its values are high, to evaluate the presence of MTHFR C677T mutation. PMID- 22928919 TI - Speech recognition in noise using bilateral open-fit hearing aids: the limited benefit of directional microphones and noise reduction. AB - OBJECTIVE: To investigate speech recognition performance in noise with bilateral open-fit hearing aids and as reference also with closed earmolds, in omnidirectional mode, directional mode, and directional mode in conjunction with noise reduction. DESIGN: A within-subject design with repeated measures across conditions was used. Speech recognition thresholds in noise were obtained for the different conditions. STUDY SAMPLE: Twenty adults without prior experience with hearing aids. All had symmetric sensorineural mild hearing loss in the lower frequencies and moderate to severe hearing loss in the higher frequencies. RESULTS: Speech recognition performance in noise was not significantly better with an omnidirectional microphone compared to unaided, whereas performance was significantly better with a directional microphone (1.6 dB with open fitting and 4.4 dB with closed earmold) compared to unaided. With open fitting, no significant additional advantage was obtained by combining the directional microphone with a noise reduction algorithm, but with closed earmolds a significant additional advantage of 0.8 dB was obtained. CONCLUSIONS: The significant, though limited, advantage of directional microphones and the absence of additional significant improvement by a noise reduction algorithm should be considered when fitting open-fit hearing aids. PMID- 22928920 TI - Paediatric conferences: only a profit making enterprise? PMID- 22928921 TI - Biohybrid glycopolymer capable of ionotropic gelation. AB - Ionotropic gelation is particularly appealing for the formation of hydrogels because it takes place under mild conditions, is not thermoreversible, and does not involve toxic chemicals. A well-known example is the gelation of alginate in the presence of calcium ions, which is at the base of numerous applications involving this polymer. In this study, alginate-derived oligosaccharides were converted into acrylamide- and methacrylamide-type macromonomers in two steps without resorting to protective group chemistry. They were then copolymerized with 2-hydroxyethylmethacrylamide in aqueous solution to yield high molar mass biohybrid glycopolymers containing between 25 and 52% by mass of oligosaccharide graft chains. A comparative kinetic study showed that both acrylamide- and methacrylamide-type macromonomers reacted since the early stages of the copolymerization, but that the mole fraction in the polymer was smaller than in the feed up to 50-60% conversion and increased markedly afterward. This effect was slighter for the methacrylamide-type macromonomer though. Copolymers carrying oligosaccharide chains with 16-20 repeating units were synthesized and used for a gelation experiment: When dialyzed against CaCl(2) 0.5 mol L(-1), the polymer carrying (1->4)-alpha-l-guluronan residues led to a soft isotropic self-standing transparent hydrogel, while the polymer carrying (1->4)-beta-d-mannuronan residues gave a loose opaque gel. This study demonstrates that alginate-extracted oligosaccharides and aqueous radical polymerization can be combined for the flexible design of biohybrid glycopolymers capable of ionotropic gelation under very mild conditions. PMID- 22928922 TI - Identification of antifungal natural products via Saccharomyces cerevisiae bioassay: insights into macrotetrolide drug spectrum, potency and mode of action. AB - Since current antifungal drugs have not kept pace with the escalating medical demands of fungal infections, new, effective medications are required. However, antifungal drug discovery is hindered by the evolutionary similarity of mammalian and fungal cells, which results in fungal drug targets having human homologs and drug non-selectivity. The group III hybrid histidine kinases (HHKs) are an attractive drug target since they are conserved in fungi and absent in mammals. We used a Saccharomyces cerevisiae reporter strain that conditionally expresses HHK to establish a high-throughput bioassay to screen microbial extracts natural products for antifungals. We identified macrotetrolides, a group of related ionophores thought to exhibit restricted antifungal activity. In addition to confirming the use of this bioassay for the discovery of antifungal natural products, we demonstrated broader, more potent fungistatic activity of the macrotetrolides against multiple Candida spp., Cryptococcus spp., and Candida albicans in biofilms. Macrotetrolides were also active in an animal model of C. albicans biofilm, but were found to have inconsistent activity against fluconazole-resistant C. albicans, with most isolates resistant to this natural product. The macrotetrolides do not directly target HHKs, but their selective activity against S. cerevisiae grown in galactose (regardless of Drk1 expression) revealed potential new insight into the role of ion transport in the mode of action of these promising antifungal compounds. Thus, this simple, high throughput bioassay permitted us to screen microbial extracts, identify natural products as antifungal drugs, and expand our understanding of the activity of macrotetrolides. PMID- 22928923 TI - Endemic paracoccidioidomycosis: relationship between clinical presentation and patients' demographic features. AB - Paracoccidioidomycosis (PCM) is a systemic fungal disease endemic to Latin America and characterized by two clinical presentations, i.e., patients develop either acute/subacute or chronic clinical manifestations. The differences in clinical presentations are mainly dependent on the host immune response, but may also be related to demographic characteristics of some patients. In this retrospective study, 1,219 PCM cases treated between 1970 and 2009 in a university medical center, located in southeastern Brazil, were analyzed according to their clinical and demographic features. The most affected anatomical sites were lungs (63.8%) and oral mucosa (50.0%), with increasing involvement of these sites in accord with the age of the patients. Generalized lymphadenopathy (28.1%) and skin lesions (29.6%) were more frequent on the first decades of life. Involvement of the larynx (16.1%), gut (7.5%), spleen (4.7%), central nervous system (3.4%), bones and joints (2.2%), and adrenal (2.1%) were also variable according to the age of the host. The acute/subacute form of the disease accounted for 26.4% of PCM cases and, on a multivariate analysis, was inversely associated with aging (OR = 0.8 per year, P < 0.001), and directly associated with female sex (OR = 7.2, P < 0.001), mixed black and white racial background (OR = 2.3, P < 0.001) or black skin color (OR = 4.6, P < 0.001). Based on these findings, we have shown that host immune response, as well as age, gender and ethnicity may influence the clinical presentation of PCM. PMID- 22928924 TI - Candida mesorugosa sp. nov., a novel yeast species similar to Candida rugosa, isolated from a tertiary hospital in Brazil. AB - Candida rugosa is a yeast species that is emerging as a causative agent of invasive infection, particularly in Latin America. Recently, C. pseudorugosa was proposed as a new species closely related to C. rugosa. We evaluated in this investigation the genetic heterogeneity within the C. rugosa species complex. All clinical isolates used in this study were identified phenotypically as C. rugosa but were genotypically different from the C. rugosa type, ATCC 10571. RAPD marker analysis revealed less than 83% similarity between our clinical isolates and the C. rugosa type strain. The D1/D2 region sequences of our clinical isolates showed 98% identity with C. rugosa but only 94-95% identity with C. pseudorugosa. The ITS rDNA sequences of the Brazilian isolates showed 91% identity with the C. rugosa ATCC 10571 ITS sequence. Network and Bayesian analyses of ITS and housekeeping gene sequences separated our clinical isolates into different branches from C. rugosa type strain. These differences are sufficient to reassign our isolates to a distinct species, named C. mesorugosa. PMID- 22928925 TI - Aspartyl proteinase, phospholipase, esterase and hemolysin activities of clinical isolates of the Candida parapsilosis species complex. AB - Candida parapsilosis is considered as an important emerging fungal pathogen and was recently found to be a complex that include three species, i.e., Candida parapsilosis sensu stricto, Candida orthopsilosis and Candida metapsilosis. The aim of this study was to determine the in vitro aspartyl proteinase, phospholipase, esterase and hemolysin activities of 65 clinical isolates of the C. parapsilosis complex, which had been previously identified by RFLP-BanI analysis. Of the enzymes evaluated, aspartyl proteinase was the least produced by the C. parapsilosis species complex. Phospholipase and esterase were strongly expressed by C. orthopsilosis (67% of isolates), while 10% and 13% of C. parapsilosis sensu stricto isolates were strong producers, respectively, of these two enzymes. In contrast, high production of both enzymes was not detected in C. metapsilosis. Hemolysin activity was significantly more abundant in C. orthopsilosis (87%) than C. parapsilosis sensu stricto (67%). Overall, C. orthopsilosis isolates were statistically associated with the production of hemolysins (P= 0.048) and phospholipases (P< 0.0001) compared to isolates of C. parapsilosis sensu stricto or C. metapsilosis. Furthermore, a statistical association was found between isolates recovered from blood and phospholipase production (P= 0.017). The distribution of isolates obtained from blood was 30% of C. parapsilosis sensu stricto, 67% of C. orthopsilosis and 20% of C. metapsilosis. PMID- 22928926 TI - Factors associated with satisfaction with prostate cancer care. PMID- 22928927 TI - Extended network thiocyanate- and tetracyanoethanide-based first-row transition metal complexes. AB - Linear chain thiocyanate complexes of M(NCS)(2)(OCMe(2))(2) (M = Fe, Mn, Cr) composition have been prepared and structurally, chemically, and magnetically characterized. Fe(NCS)(2)(OCMe(2))(2) exhibits metamagnetic-like behavior, and orders as an antiferromagnet at 6 K. The Mn and Cr compounds are antiferromagnets with T(c) of 30 and 50 K, respectively, with J/k(B) = -3.5 (-2.4 cm(-1)) and -9.9 K (-6.9 cm(-1)), respectively, when fit to one-dimensional (1-D) Fisher chain model (H = -2JS(i).S(j)). Co(NCS)(2) was prepared by a new synthetic route, and powder diffraction was used to determine its structure to be a two-dimensional (2 D) layer with MU(N,S,S)-NCS motif, and it is an antiferromagnet (T(c) = 22 K; theta = -33 K for T > 25 K). M(NCS)(2)(OCMe(2))(2) (M = Fe, Mn) and Co(NCS)(2) react with (NBu(4))(TCNE) in dichloromethane to form M(TCNE)[C(4)(CN)(8)](1/2), and in acetone to form M[C(4)(CN)(8)](OCMe(2))(2) (M = Fe, Mn, Co). These materials possess MU(4)-[C(4)(CN)(8)](2-) that form 2-D layered structural motifs, which exhibit weak antiferromagnetic coupling. Co(TCNE)[C(4)(CN)(8)](1/2) behaves as a paramagnet with strong antiferromagnetic coupling (theta = -50 K). PMID- 22928928 TI - Microbial community structure across fluid gradients in the Juan de Fuca Ridge hydrothermal system. AB - Physical and chemical gradients are dominant factors in shaping hydrothermal vent microbial ecology, where archaeal and bacterial habitats encompass a range between hot, reduced hydrothermal fluid and cold, oxidized seawater. To determine the impact of these fluid gradients on microbial communities inhabiting these systems, we surveyed bacterial and archaeal community structure among and between hydrothermal plumes, diffuse flow fluids, and background seawater in several hydrothermal vent sites on the Juan de Fuca Ridge using 16S rRNA gene diversity screening (clone libraries and terminal restriction length polymorphisms) and quantitative polymerase chain reaction methods. Community structure was similar between hydrothermal plumes and background seawater, where a number of taxa usually associated with low-oxygen zones were observed, whereas high-temperature diffuse fluids exhibited a distinct phylogenetic profile. SUP05 and Arctic96BD-19 sulfur-oxidizing bacteria were prevalent in all three mixing regimes where they exhibited overlapping but not identical abundance patterns. Taken together, these results indicate conserved patterns of redox-driven niche partitioning between hydrothermal mixing regimes and microbial communities associated with sinking particles and oxygen-deficient waters. Moreover, the prevalence of SUP05 and Arctic96BD-19 in plume and diffuse flow fluids indicates a more cosmopolitan role for these groups in the ecology and biogeochemistry of the dark ocean. PMID- 22928929 TI - Visuospatial memory in dyslexia: evidence for strategic deficits. AB - Impairments in working memory are suggested to be one of the defining characteristics of dyslexia, and deficits in verbal recall are well documented. However, the situation regarding visuospatial memory is less clear. In a widely used measure, the Corsi blocks task, sequences of visuospatial locations can be recalled forwards, in the order presented (CF), or backwards, in reverse order (CB). Previous research has suggested that, while CF draws on spatial-sequential resources, CB may load executive and distinctly visual processes. While people with dyslexia typically show no deficit on CF, CB is rarely presented. We present three studies which indicate a consistent dyslexic deficit on CB that can be ameliorated by visual strategy instructions. Our data suggest that, without instruction, people with dyslexia are unable to adopt an effective CB strategy and this is consistent with a deficit in executive function. These results have implications for our understanding of visuospatial memory in dyslexia, and also in terms of the administration of the Corsi task to special populations. PMID- 22928930 TI - Painful oral aphthae and myositis. PMID- 22928931 TI - Influencing factors on the NMP-22 urine assay: an experimental model. AB - BACKGROUND: The commercial NMP-22 urine assays for bladder cancer (BCa) detect nuclear mitotic apparatus protein 1 (NUMA1) using monoclonal antibodies. It remains unclear whether these assays are monitoring a tumor antigen or some other phenomenon associated with the disease state. In this study, we investigated the influence of urinary cellular and protein concentration, and hematuria on the performance of the NMP-22 tests in an experimental model. METHODS: Pooled urine from healthy subjects were spiked with varying concentrations of benign (UROtsa) cells, cancer cells (RT4, T24, KU-7 and UM-UC-14), whole blood or serum, prior to analysis with both NMP22(r) Bladder Cancer ELISA test and the NMP22(r) BladderChek(r) point-of-care test. RESULTS: Urines from control subjects were negative for NMP-22. The addition of whole blood at 50ul/10 ml, but not serum, resulted in a false-positive result. Furthermore, the addition of a high concentration of benign urothelial cells (10(6)) or the cell lysate from these cells (306 MUg protein) resulted in a false-positive result. High concentrations of pooled-cancer cells (10(6)) or cell lysate (30.6 MUg and above) resulted in a positive NMP-22 assay. Concordance between the NMP-22 ELISA assay and the NMP-22 point of care assay was >90%. CONCLUSIONS: Rather than detecting a specific tumor antigen, urinary NMP-22 assays may be measuring the cellularity or amount of cell turnover that may be introduced into the urine by a variety of conditions, including surface shedding from bladder tumors. The absence of significant urinary cellularity in some cases due to lesion characteristics or the timing of sampling may result in false-negative NMP-2 assays. PMID- 22928932 TI - Off-line Arc transcription in active ensembles during fear memory retrieval. AB - Neural activity and de novo protein synthesis during a rest period following memory retrieval in the amygdala is necessary for stabilization of reactivated fear memory. Arc/Arg3.1 (Arc) expression is regulated by neural activity and is a critical protein for memory reconsolidation. However, it remains unclear whether memory retrieval alters Arc transcription during subsequent rest. In this study, the populations of mouse lateral amygdala neurons that transcribe Arc during memory retrieval and at rest were detected using Arc cellular compartment analysis of temporal activity by fluorescence in situ hybridization (Arc catFISH). Results demonstrated that memory retrieval alters the composition of neuronal populations, which activate Arc transcription during subsequent rest. Approximately 50% of neurons that transcribe Arc at subsequent rest, transcribed Arc during memory retrieval, whereas only approximately 10% of neurons that transcribed Arc during a rest period prior to memory retrieval transcribe Arc during memory retrieval. In contrast, re-exposure to the chamber induced less preferential Arc transcription in latent inhibited mice that received shocks but recalled less conditioned fear. Taken together, these findings indicate that neuronal subpopulations activated during fear memory retrieval preferentially transcribe Arc during subsequent rest in the lateral amygdala. This preferential Arc transcription may contribute to memory reconsolidation. PMID- 22928933 TI - Transition-metal-free alpha-arylation of beta-keto amides via an interrupted insertion reaction of arynes. AB - Direct alpha-arylation reactions of secondary beta-keto amides with arynes, generated by fluoride-induced elimination of ortho-silyl aryltriflates, are described. The transformation proceeds via an interrupted insertion reaction of arynes and leads to densely functionalized aromatic compounds exhibiting a chiral 'all carbon' quaternary center under transition-metal-free conditions. An organocatalytic asymmetric version of the reaction also proved possible, affording the proof of concept that arynes can be involved in enantioselective transformations. PMID- 22928934 TI - Comparison of the semen analysis results obtained from two branded computer-aided sperm analysis systems. AB - The study evaluated the comparability of two branded computer-aided sperm analysis (CASA) systems commonly used in andrology laboratories in China. The same semen sample was analysed using two branded CASA systems (WLJY-9000 and CFT 9200) by one well-trained technician. Results of semen analysis obtained from two branded CASA systems were then compared. The accuracy of counting results of CASA systems was evaluated using latex bead solutions with known concentrations of (35 +/- 5) * 106 ml-1 and (18 +/- 2.5) * 106 ml-1. There were significant differences in all parameters (P < 0.01) except for LIN and WOB. The counting results of CFT 9200 were close to the standard solutions [(38.86 +/- 3.79) * 106 ml-1 and (19.03 +/- 1.99) * 106 ml-1], while those of WLJY-9000 were underestimated [(28.53 +/- 2.06) * 106 ml-1 and (14.62 +/- 0.95) * 106 ml-1]. But the coefficient of variation of WLJY-9000 was lower than that of CFT-9200 (7.22%, 6.50% vs. 9.82%, 10.46%). It is concluded that factors such as parameter settings and evaluation algorithms could significantly affect the results obtained from these two branded CASA systems. Great attention should also be paid to the quality control in semen analysis with CASA. PMID- 22928935 TI - Productivity losses from dental problems. PMID- 22928936 TI - Does chlorhexidine in different formulations interfere with the force of orthodontic elastics? AB - OBJECTIVE: To evaluate the effects of different concentrations of chlorhexidine on the decline in force of orthodontic elastics. MATERIALS AND METHODS: In a laboratory study, five groups of samples were tested, with one control group represented by distilled water (group 1) and four experimental groups: 0.12% manipulated chlorhexidine (group 2), 0.2% manipulated chlorhexidine (group 3), 0.12% chlorhexidine gluconate-based oral solution (0.12% Periogard; group 4), and 0.2% Cleanform mouthwash (formula and action; group 5). The test groups were submersed in artificial saliva at 37 degrees C. Templates were used and submerged in the chlorhexidine solutions for 30 seconds twice a day. Force was measured with a digital dynamometer at six different time intervals: 0, 1, 7, 14, 21, and 28 days. RESULTS: No statistical differences were found among the groups in the initial period, at 24 hours, and at 7 days (P > .05). There were statistical differences between groups 2 and 5 at 14 days of the experiment and between group 1 and the others at 28 days. In the initial period, the force was statistically higher than it was at any of the other periods of the experiment (P < .05). CONCLUSION: In the present study, chlorhexidine showed no significant influence on the force degradation of the chain elastics tested. PMID- 22928937 TI - Preparation of tantalum-based oxynitride nanosheets by exfoliation of a layered oxynitride, CsCa2Ta3O(10-x)N(y), and their photocatalytic activity. AB - Calcium tantalum oxynitride [Ca(2)Ta(3)O(9.7)N(0.2)](-) nanosheets were prepared by exfoliating a layered perovskite oxynitride (CsCa(2)Ta(3)O(9.7)N(0.2)) via proton exchange and two-step intercalation of ethylamine and tetrabutylammonium ions. Monolayer nanosheet was prepared by the above processes, although some bilayer or trilayer nanosheets were also produced. The [Ca(2)Ta(3)O(9.7)N(0.2)]( ) nanosheets exhibited photocatalytic activity for H(2) evolution from water under visible light irradiation. In contrast, CsCa(2)Ta(3)O(9.7)N(0.2) exhibited very low photocatalytic activity for H(2) evolution under the visible light irradiation, even when methanol was added to water as a sacrificial agent. The improved photocatalytic activity originates from the characteristics of nanosheets such as their molecular thickness and large surface area. Further, the Rh-loaded [Ca(2)Ta(3)O(9.7)N(0.2)](-) nanosheets restacked with protons exhibited photocatalytic activity for H(2) and O(2) evolution from pure water under UV light irradiation. The ratio of H(2)/O(2) evolved was around 3. The ratio of N/O in the catalyst remained the same after the photocatalytic reaction, signifying that there was no decomposition of the catalyst during the reaction. This indicates that the present N-doped nanosheet is stable in the photocatalytic reaction. PMID- 22928938 TI - Ion association in aqueous solutions probed through vibrational energy transfers among cation, anion, and water molecules. AB - KSCN and NH4SCN aqueous solutions were investigated with intermolecular vibrational energy transfer methods. In a KSCN/H2O (1/10 molar ratio) solution, 90% of the initial excitation of the CN stretch (~2066 cm(-1)) of the SCN(-) anion is transferred to the HOH bending mode (~1636 cm(-1)) of water molecules with an energy transfer time constant 3.1 ps. In a NH4SCN/H2O (1/10 molar ratio) solution, only 49% of the CN excitation flows to the water HOH bending mode with a time constant 6.3 ps. Most of the remaining CN excitation goes to the NH bending mode (~1460 cm(-1)) of the NH(+) cation with a time constant of 7.0 ps. The results indicate that about 50% of the energy transfer channel from the CN stretch to the HOH bending observed in the KSCN solution is overpowered by the NH4(+) cations in the NH4SCN/H2O solution. Ion concentration dependent measurements support this argument. According to the dipole/dipole approximation, the CN/OH energy transfer occurs most efficiently between SCN(-) anions and the water molecules closest to them. The experimental results therefore suggest that more than 50% of the water molecules closest to the SCN(-) anions are replaced by the NH4(+) cations in the NH4SCN/H2O (1/10 molar ratio) solution. The percentage is much larger than the NH4(+)/water ratio of 10%, indicating that the ion association between NH4(+) and SCN(-) is caused by the chemical nature of the solution rather than the statistical "forced contact" because of the high ion concentration. PMID- 22928939 TI - Elucidation by NMR solution of neurotensin in small unilamellar vesicle environment: molecular surveys for neurotensin receptor recognition. AB - Neurotensin (NT) is a tridecapeptide, hormone in the periphery and neurotransmitter in the brain. We used high-resolution nuclear magnetic resonance (NMR) to resolve the three-dimensional structure of NT in a small unilamellar vesicle (SUV) environment. We demonstrate that if the dynamic of the association dissociation processes of peptide to SUV binding is rapid enough, structural determination can be obtained by solution NMR experiments. Thus, according to the global dynamic of the system, SUVs seem to be an effective model to mimic biological membranes, especially since the lipid composition can be modified or sterols may be added to closely mimic the biological membranes studied. An animated Interactive 3D Complement (I3DC) is available in Proteopedia at http://proteopedia.org/w/Journal:JBSD:2. PMID- 22928940 TI - Cross-cultural validation of the revised temperament and character inventory in the Bulgarian language. AB - RATIONALE, AIMS AND OBJECTIVES: Health-care professions have long been considered prone to work-related stress, yet recent research in Bulgaria indicates alarmingly high levels of burnout. Cloninger's inventory is used to analyse and evaluate correlation between personality characteristics and degree of burnout syndrome manifestation among the risk categories of health-care professionals. The primary goal of this study was to test the conceptual validity and cross cultural applicability of the revised TCI (TCI-R), developed in the United States, in a culturally, socially and economically diverse setting. METHODS: Linguistic validation, test-retest studies, statistical and expert analyses were performed to assess cross-cultural applicability of the revised Cloninger's temperament and character inventory in Bulgarian, its reliability and internal consistency and construct validity. RESULTS: The overall internal consistency of TCI-R and its scales as well as the interscale and test-retest correlations prove that the translated version of the questionnaire is acceptable and cross culturally applicable for the purposes of studying organizational stress and burnout risk in health-care professionals. CONCLUSIONS: In general the cross cultural adaptation process, even if carried out in a rigorous way, does not always lead to the best target version and suggests it would be useful to develop new scales specific to each culture and, at the same time, to think about the trans-cultural adaptation. PMID- 22928941 TI - Recruitment of dynamic endothelial Ca2+ signals by the TRPA1 channel activator AITC in rat cerebral arteries. AB - OBJECTIVE: Stimulation of endothelial TRP channels, specifically TRPA1, promotes vasodilation of cerebral arteries through activation of Ca2+ -dependent effectors along the myoendothelial interface. However, presumed TRPA1-triggered endothelial Ca2+ signals have not been described. We investigated whether TRPA1 activation induces specific spatial and temporal changes in Ca2+ signals along the intima that correlates with incremental vasodilation. METHODS: Confocal imaging, immunofluorescence staining, and custom image analysis were employed. RESULTS: We found that endothelial cells of rat cerebral arteries exhibit widespread basal Ca2+ dynamics (44 +/- 6 events/minute from 26 +/- 3 distinct sites in a 3.6 * 10(4) MUm2 field). The TRPA1 activator AITC increased Ca2+ signals in a concentration-dependent manner, soliciting new events at distinct sites. Origination of these new events corresponded spatially with TRPA1 densities in IEL holes, and the events were prevented by the TRPA1 inhibitor HC-030031. Concentration-dependent expansion of Ca2+ events in response to AITC correlated precisely with dilation of pressurized cerebral arteries (p = 0.93 by F-test). Correspondingly, AITC caused rapid endothelium-dependent suppression of asynchronous Ca2+ waves in subintimal smooth muscle. CONCLUSIONS: Our findings indicate that factors that stimulate TRPA1 channels expand Ca2+ signal-effector coupling at discrete sites along the endothelium to evoke graded cerebral artery vasodilation. PMID- 22928942 TI - Thrombospondin-1-derived 4N1K peptide expression is negatively associated with malignant aggressiveness and prognosis in urothelial carcinoma of the upper urinary tract. AB - BACKGROUND: Thrombospondin (TSP) is a multi-functional protein that appears to have dual roles in cancer, that is, either as a promoter or a suppressor. 4N1K is a TSP-derived peptide that has been reported to be associated with neovascularity, cell survival, and invasion. There is a little information regarding its pathological roles in human cancer tissues. Our aim was to clarify clinical significance and prognostic value of 4N1K expression in patients with urothelial carcinoma of the upper urinary tract (UC-UUT). METHODS: We investigated 4N1K expression in 97 surgically excised, non-metastasized UC-UUT specimens and five normal tissues via immunohistochemistry. Microvessel density (MVD), lymph vessel density (LVD), cancer cell proliferation (PI), apoptotic index (AI), and matrix metalloproteinase (MMP)-9 expression was also determined. The relationships 4N1K expression and pT stage, grade, and prognosis were analysed. In addition, correlations with these cancer-related and TSP-related factors were also investigated. RESULTS: Strong and moderate 4N1K expression was found in normal urothelial tissues. Of the 97 specimens, 45 patients were positive for 4N1K expression, which was primarily located in the interstitial areas of the cancer tissue. 4N1K expression was negatively associated with pT stage (p = 0.003) and grade (p = 0.002). Survival analyses revealed that 4N1K is a predictor of metastasis-free (p = 0.036) and cause-specific survival (p = 0.009). 4N1K expression was closely associated with malignant behaviour, specifically MVD (p = 0.001), AI (p = 0.013), and MMP-9 expression (p = 0.036), but not PI and LVD, as determined via multivariate analysis models. CONCLUSIONS: 4N1K expression appears to be associated with cancer cell progression and survival in UC-UUT patients via the regulation of angiogenesis, apoptosis, and MMP-9 expression. There is a possibility that the 4N1K-peptide may be a useful marker and novel therapeutic target in patients with UC-UUT. PMID- 22928943 TI - Multiple stimulus presentation yields larger deficits in children with developmental dyslexia: a study with reading and RAN-type tasks. AB - In this study, we examined the effect of multiple versus single stimulus presentation in typically developing readers and children with developmental dyslexia. The tasks involved either reading single words or arrays of words or naming single or multiple colors and digits (rapid automatized naming or RAN). To be able to compare these sets of conditions, we recorded total response times (i.e., the time between stimulus onset and the end of the participant's vocal response) in all cases. The study included 43 typically developing readers and 25 children with dyslexia. Results indicate that typically developing readers have a clear advantage with multiple over single items on both RAN and reading tasks. The children with dyslexia showed a moderate advantage for multiple stimuli in naming colors and digits but presented the opposite pattern in reading. With regard to reading, the disproportionate impairment of the children with dyslexia in dealing with multiple arrays suggests difficulty in integrating the multiple subcomponents of the reading task over and above the basic nuclear deficit in decoding words. Regarding the RAN tasks, results confirm that the requirement of integrating multiple subcomponents may be critical in mediating the predictive value of these measures on reading. PMID- 22928944 TI - Insights into the structural determinants required for high-affinity binding of chiral cyclopropane-containing ligands to alpha4beta2-nicotinic acetylcholine receptors: an integrated approach to behaviorally active nicotinic ligands. AB - Structure-based drug design can potentially accelerate the development of new therapeutics. In this study, a cocrystal structure of the acetylcholine binding protein (AChBP) from Capitella teleta (Ct) in complex with a cyclopropane containing selective alpha4beta2-nicotinic acetylcholine receptor (nAChR) partial agonist (compound 5) was acquired. The structural determinants required for ligand binding obtained from this AChBP X-ray structure were used to refine a previous model of the human alpha4beta2-nAChR, thus possibly providing a better understanding of the structure of the human receptor. To validate the potential application of the structure of the Ct-AChBP in the engineering of new alpha4beta2-nAChR ligands, homology modeling methods, combined with in silico ADME calculations, were used to design analogues of compound 5. The most promising compound, 12, exhibited an improved metabolic stability in comparison to the parent compound 5 while retaining favorable pharmacological parameters together with appropriate behavioral end points in the rodent studies. PMID- 22928945 TI - The clinical effects of levosimendan are not attenuated by sulfonylureas. AB - OBJECTIVES: Levosimendan is an inodilator indicated for acute heart failure (AHF). Its vasodilatory and anti-ischemic effects are mediated by the opening of ATP-dependent potassium channels (K(ATP) channels). Diabetes mellitus is common in AHF patients and sulfonylureas are often prescribed. Sulfonylureas act by blocking the K(ATP) channels. An interaction between levosimendan and sulfonylureas has been shown in preclinical models and could be hypothesized in clinical practice. DESIGN: We produced a pooled analysis of six randomized levosimendan trials (in total of 3004 patients of which 1700 were treated with levosimendan and 226 both with levosimendan and sulfonylureas) with the aim to study the influence of concurrent sulfonylurea treatment to the levosimendan effects. Invasive and non-invasive hemodynamics, biomarkers (BNP), adverse events related to myocardial ischemia, and survival were evaluated. RESULTS: In our relatively small data set, we could not detect any clinically relevant interactions between the sulfonylureas and levosimendan. Similar decreases in systolic and diastolic blood pressure, pulmonary capillary wedge pressure and BNP, and similar survival and adverse event profiles were seen in sulfonylurea users and non-users exposed to levosimendan. CONCLUSIONS: Concomitant use of sulfonylureas with levosimendan does not attenuate the hemodynamic or other effects of levosimendan. PMID- 22928946 TI - Statement of retraction. PMID- 22928947 TI - Sex, cheating, and disgust: enhanced source memory for trait information that violates gender stereotypes. AB - The present study examines memory for social-exchange-relevant information. In Experiment 1 male and female faces were shown together with behaviour descriptions of cheating, altruistic, and neutral behaviour. Previous results have led to the hypothesis that people preferentially remember schema-atypical information. Given the common gender stereotype that women are kinder and less egoistic than men, this atypicality account would predict that source memory (that is, memory for the type of context to which a face was associated) should be enhanced for female cheaters in comparison to male cheaters. The results of Experiment 1 confirmed this hypothesis. Experiment 2 reveals that source memory for female faces associated with disgusting behaviours is enhanced in comparison to male faces associated with disgusting behaviours. Thus the atypicality effect generalises beyond social-exchange-relevant information, a result which is inconsistent with the assumption that the findings can be ascribed to a highly specific cheater detection module. PMID- 22928948 TI - A precystectomy decision model to predict pathological upstaging and oncological outcomes in clinical stage T2 bladder cancer. PMID- 22928949 TI - Persulfide formation on mitochondrial cysteine desulfurase: enzyme activation by a eukaryote-specific interacting protein and Fe-S cluster synthesis. AB - Cysteine desulfurases abstract sulfur from the substrate cysteine, generate a covalent persulfide on the active site cysteine of the enzyme, and then donate the persulfide sulfur to various recipients such as Fe-S clusters. In Saccharomyces cerevisiae, the Nfs1p protein is the only known cysteine desulfurase, and it forms a complex with Isd11p (Nfs1p.Isd11p). Both of these proteins are found primarily in mitochondria and both are essential for cell viability. In the present study we show, using the results of experiments with isolated mitochondria and purified proteins, that Isd11p is required for the cysteine desulfurase activity of Nfs1p. Whereas Nfs1p by itself was inactive, the Nfs1p.Isd11p complex formed persulfide and was active as a cysteine desulfurase. In the absence of Isd11p, Nfs1p was able to bind the substrate cysteine but failed to form a persulfide. Addition of Isd11p allowed Nfs1p with bound substrate to generate a covalent persulfide. We suggest that Isd11p induces an activating conformational change in Nfs1p to bring the bound substrate and the active site cysteine in proximity for persulfide formation. Thus mitochondrial Nfs1p is different from bacterial cysteine desulfurases that are active in the absence of accessory proteins. Isd11p may serve to regulate cysteine desulfurase activity in mitochondria. PMID- 22928950 TI - Lay people's and health professionals' views about breaking bad news to children. AB - BACKGROUND: Bad health news is difficult to communicate, especially when parents must give bad news to their children. METHODS: We had 170 lay persons, 33 nurses and six physicians in Toulouse, France, judge the appropriateness of the parents' behaviour in 64 scenarios of parents dealing with this problem. The scenarios were composed according to a four within-subject orthogonal design: child's age (4, 6, 8 or 10), severity of disease (lethal or worrisome but curable), child's concern or not about his illness and parents' decision about communicating the news (tell nothing, minimize, tell the truth or ask the physician to tell the truth). RESULTS: Cluster analysis revealed four clusters, labelled 'Always Tell the Truth' (33%, including a majority of doctors and nurses), 'Tell Nothing or Minimize' (16%, with an older average age), 'Tell the Truth Except in Cases of Incurable Illness' (22%) and 'Depends on Child's Characteristics' (29%). CONCLUSIONS: Physicians in training and in practice need to be aware that lay people--and likely parents as well--have diverse and complex opinions about when and how parents should give bad health news to their children. PMID- 22928952 TI - Lithium dihydroborate: first-principles structure prediction of LiBH2. AB - We report a first-principles structure prediction of the LiBH(2), which structures are modeled by using four formula units per unit cell without symmetry restrictions. The computational methodology combines a simulated annealing approach and density functional total energy calculations for crystalline solid structures. The predicted lowest energy structure shows the formation of linear anionic chains, (infinity)(1)[BH(2)], enthalpy of formation at 0 K equal to 90.07 kJ/mol. Ring structures, in particular with butterfly and planar square topologies, are found to be stable but well above the ground state by 20.26 and 12.92 kJ/mol, respectively. All convergent structures fall in the symmetry families monoclinic, tetragonal, and orthorhombic. For the representative structures of each family group, simulated X-ray diffraction patterns and infrared spectra are reported. PMID- 22928951 TI - Loss of SFRP1 promotes ductal branching in the murine mammary gland. AB - BACKGROUND: Secreted frizzled-related proteins (SFRPs) are a family of proteins that block the Wnt signaling pathway and loss of SFRP1 expression is found in breast cancer along with a multitude of other human cancers. Activated Wnt signaling leads to inappropriate mammary gland development and mammary tumorigenesis in mice. When SFRP1 is knocked down in immortalized non-malignant mammary epithelial cells, the cells exhibit a malignant phenotype which resembles the characteristics observed in metastatic breast cancer stem-like cells. However, the effects of SFRP1 loss on mammary gland development in vivo are yet to be elucidated. The work described here was initiated to investigate the role of SFRP1 in mammary gland development and whether SFRP1-/- mice exhibit changes in mammary gland morphology and cell signaling pathways shown to be associated with SFRP1 loss in vitro. RESULTS: 10 week old nulliparous SFRP1-/- mammary glands exhibited branching with clear lobulo-alveolar development, which normally only occurs in hormonally stimulated mid-pregnant wt mammary glands. Explant cultures of SFRP1-/- mammary glands display increased levels of a well known Wnt signaling target gene, Axin2. Histomorphologic evaluation of virgin glands revealed that by 10 weeks of age, the duct profile is markedly altered in SFRP1-/ mice showing a significantly higher density of ducts with distinct alveoli present throughout the mammary gland, and with focal ductal epithelial hyperplasia. These findings persist as the mice age and are evident at 23 weeks of age. Changes in gene expression, including c-Myc, TGFbeta-2, Wnt4, RANKL, and Rspo2 early in mammary gland development are consistent with the excessive hyper branching phenotype. Finally, we found that loss of SFRP1 significantly increases the number of mammary epithelial cells capable of mammosphere formation. CONCLUSIONS: Our study indicates that SFRP1 gene is critical for maintaining proper mammary gland development, and that reduced levels of SFRP1 results in hyperplastic lesions and its loss may be a critical event in cancer initiation. PMID- 22928953 TI - An evaluation of sirolimus in renal transplantation. AB - INTRODUCTION: Sirolimus is a powerful antiproliferative immunosuppressive drug approved for the prevention of kidney allograft rejection. By its unique mechanism of action, sirolimus provides a multitude of clinical potential and has been used effectively in different drug combinations. Extensive experience has been gained regarding the best timing of its application, side effect profile and potential benefits and limitations compared with other immunosuppressive drugs. AREAS COVERED: The authors evaluate the recent experience with sirolimus in kidney transplantation. Pivotal randomized controlled trials were used to provide an overview with special attention to pharmacokinetic and dynamic aspects of sirolimus, its current clinical use as well as perspectives for its future role. EXPERT OPINION: Sirolimus enriches the possibilities of immunosuppressive therapies after renal transplantation. Beneficial effects toward kidney function by allowing CNI sparing, lower incidence of malignancies and less viral infections have been suggested. Sirolimus should be used cautiously in de novo patients for reasons of wound healing. An early conversion to a sirolimus-based CNI-free regimen has shown promising results, whereas late conversion is more challenging. Finally, sirolimus-associated side effects are causing tolerability concerns and frequent discontinuations. Future research should aim to better define the therapeutic window and those patients most likely to benefit. PMID- 22928954 TI - Eruptive nevi in prostate cancer: is this a paraneoplastic phenomenon? PMID- 22928956 TI - Influence of dietary factors, age and nickel contact dermatitis on nickel excretion. AB - BACKGROUND: Nickel is a frequently detected cause of allergic contact dermatitis. Ingestion of nickel may lead to flares of nickel contact dermatitis. METHODS: We examined nickel excretion in the urine of 164 female patients with and without nickel contact dermatitis. The associations between age, atopic dermatitis, nickel contact dermatitis and nickel exposure through nutrition (e.g. dietary supplements) and by patch tests were investigated prospectively. Nickel was measured with atomic absorption spectrometry with two different standardized methods. RESULTS: A nickel detection limit of 0.2 ug/l was exceeded by all samples. The 95th percentiles of urine nickel concentration were 3.77 ug/l (age 18-30 years) and 3.98 ug/l (age 31-46 years). Bivariate analyses pointed to significantly increased nickel excretion with increasing age, ingestion of dietary supplements, drinking of stagnant tap water, and consumption of nickel rich food. In the multivariate analysis, age and dietary supplements remained significant predictors of high nickel excretion. A non-significant increase in the median concentration of nickel was observed after the administration of conventional nickel patch tests. Patients with atopic eczema showed urine nickel concentrations similar to those in non-atopic controls. CONCLUSIONS: The 95th percentile of nickel excretion in our study population markedly exceeded the actual reference value of 3 ug/l. Age and consumption of dietary supplements are the most important predictors. The use of stagnant tap water and consumption of nickel-rich food contribute to the total load. These factors should be explicitly mentioned when allergic patients on a low-nickel diet are counselled. In contrast, existing nickel contact sensitization was not more frequent in subjects with higher nickel excretion. Nickel patch testing may cause transient minor systemic nickel exposure. The findings of this study extend our understanding and management of factors associated with nickel allergy. PMID- 22928957 TI - Effect of temperature, cosolvent, and added drug on Pluronic-flurbiprofen micellization. AB - Structural changes in the micellization of Pluronics P103 and P123, as a function of temperature, cosolvent (ethanol, 10 v/v %), and the addition of the hydrophobic drug flurbiprofen, were investigated by SANS and tensiometry. Addition of ethanol increases the critical micellization concentration of the Pluronics (making the polymer more soluble), while increasing the repulsive interactions between the flurbiprofen-Pluronic spherical complexes. However, increasing temperature and addition of drug increases both the aggregation number and core radius and leads to a more dehydrated core. The addition of flurbiprofen to Pluronic P103 was also found to reduce the critical micellization temperature from between 15 and 20 degrees C to below 10 degrees C and at higher drug concentrations leads to an attractive interaction between micelles and eventually phase separation. PMID- 22928958 TI - Detection of increased gene copy number in DNA from dried blood spot samples allows efficient screening for Klinefelter syndrome. PMID- 22928955 TI - Coassembled cytotoxic and pegylated peptide amphiphiles form filamentous nanostructures with potent antitumor activity in models of breast cancer. AB - Self-assembled peptide amphiphiles (PAs) consisting of hydrophobic, hydvrogen bonding, and charged hydrophilic domains form cylindrical nanofibers in physiological conditions and allow for the presentation of a high density of bioactive epitopes on the nanofiber surface. We report here on the use of PAs to form multifunctional nanostructures with tumoricidal activity. The combination of a cationic, membrane-lytic PA coassembled with a serum-protective, pegylated PA was shown to self-assemble into nanofibers. Addition of the pegylated PA to the nanostructure substantially limited degradation of the cytolytic PA by the protease trypsin, with an 8-fold increase in the amount of intact PA observed after digestion. At the same time, addition of up to 50% pegylated PA to the nanofibers did not decrease the in vitro cytotoxicity of the cytolytic PA. Using a fluorescent tag covalently attached to PA nanofibers we were able to track the biodistribution in plasma and tissues of tumor-bearing mice over time after intraperitoneal administration of the nanoscale filaments. Using an orthotopic mouse xenograft model of breast cancer, systemic administration of the cytotoxic pegylated nanostructures significantly reduced tumor cell proliferation and overall tumor growth, demonstrating the potential of multifunctional PA nanostructures as versatile cancer therapeutics. PMID- 22928959 TI - Nickel-mediated N-arylation with arylboronic acids: an avenue to Chan-Lam coupling. AB - An efficient use of NiCl(2).6H(2)O, for the cross-coupling of arylboronic acids with various N-nucleophiles, has been demonstrated. The method is practical and offers an alternative to the corresponding Cu-mediated Chan-Lam process for the construction of the C-N bond. PMID- 22928960 TI - Does mentoring new peer reviewers improve review quality? A randomized trial. AB - BACKGROUND: Prior efforts to train medical journal peer reviewers have not improved subsequent review quality, although such interventions were general and brief. We hypothesized that a manuscript-specific and more extended intervention pairing new reviewers with high-quality senior reviewers as mentors would improve subsequent review quality. METHODS: Over a four-year period we randomly assigned all new reviewers for Annals of Emergency Medicine to receive our standard written informational materials alone, or these materials plus a new mentoring intervention. For this program we paired new reviewers with a high-quality senior reviewer for each of their first three manuscript reviews, and asked mentees to discuss their review with their mentor by email or phone. We then compared the quality of subsequent reviews between the control and intervention groups, using linear mixed effects models of the slopes of review quality scores over time. RESULTS: We studied 490 manuscript reviews, with similar baseline characteristics between the 24 mentees who completed the trial and the 22 control reviewers. Mean quality scores for the first 3 reviews on our 1 to 5 point scale were similar between control and mentee groups (3.4 versus 3.5), as were slopes of change of review scores (-0.229 versus -0.549) and all other secondary measures of reviewer performance. CONCLUSIONS: A structured training intervention of pairing newly recruited medical journal peer reviewers with senior reviewer mentors did not improve the quality of their subsequent reviews. PMID- 22928961 TI - Successful haploidentical PBSCT with subsequent T-cell addbacks in a boy with HyperIgM syndrome presenting as severe congenital neutropenia. AB - HIGM syndrome is a group of primary immunodeficiency disorders characterized by recurrent bacterial and opportunistic infections; it is also associated with normal to elevated serum IgM levels and a concomitant deficiency of IgG, IgA, and IgE. In this report, we give account of a boy with X-linked HIGM and a novel Y172C mutation within his CD40LG gene. He presented with severe neutropenia as the dominating symptom. His bone marrow showed maturation arrest at the promyelocyte/myelocyte stage, typical of congenital neutropenia. This boy suffered from life-threatening infections and required high doses of rhG-CSF, and a haploidentical PBSCT was also successfully performed, thus leading to reconstitution of CD40L expression on activated CD4+ T cells (as assessed with flow cytometry six months after the procedure). Two low-dose T-cell addbacks were required to re-establish full donor chimerism and clear CMV reactivation. The report demonstrates that in select cases, alternative donor allogeneic HSCT supported by DLI may be effective in correcting the defect in X-linked HIGM, and HSCT in HIGM children is not necessarily limited to matched sibling donor transplantation. PMID- 22928962 TI - Distinct neural processes in grapheme-colour synaesthetes and semantic controls. AB - In synaesthetes, stimulation of one sensory pathway provokes a sensory experience (e.g. a colour concurrent) in a different sensory modality or sub-modality. Results of synaesthetic Stroop and priming tests indicate that the perception of a colour concurrent interferes with the processing of a veridical colour in synaesthetes. We here examined the congruency between a stimulus' colour and the colour concurrent both in grapheme-colour synaesthetes and in non-synaesthetes trained on grapheme-colour associations. Electrophysiological (electroencephalogram) and behavioural measurements were collected during a priming task that included grapheme-grapheme and grapheme-colour patch pairs. To investigate covert bidirectional synaesthesia, an additional inverted colour patch-grapheme condition was included. Both groups of participants showed longer reaction time and more negative-going N300 and N400 event-related potential (ERP) components on incongruent trials. Whereas ERP effects in the non-synaesthetes were largely confined to the late cognitive components N300, P300 and N400, the synaesthetes also showed congruency-dependent modulation of the early sensory component N170. Our results suggest that early cognitive processes distinguish cross-modal synaesthetic perceptions from acquired associations. The involvement of both early- and late-stage cognitive components in bidirectional synaesthesia possibly indicates similar feature-binding mechanisms during processing of opposite flow directions of information, namely grapheme-colour and colour grapheme. PMID- 22928963 TI - Clinical protocol for punctuated 88% phenol peels in the treatment of photoaging: a histopathological study of three cases. PMID- 22928965 TI - Spatial distribution of N-cycling microbial communities showed complex patterns in constructed wetland sediments. AB - Constructed wetlands are used for biological treatment of wastewater from agricultural lands carrying pollutants such as nitrates. Nitrogen removal in wetlands occurs from direct assimilation by plants and through microbial nitrification and denitrification. We investigated the spatial distribution of N cycling microbial communities and genes involved in nitrification and denitrification in constructed wetland sediments receiving irrigation water. We used quantitative real-time PCR (qPCR) to characterize microbial communities. Geostatistical variance analysis was used to relate them with vegetation cover and biogeochemical sediment properties. The spatial distribution of the N-cycling microbial communities of sediments was heterogeneous and complex. Total communities of bacteria and crenarchaea showed different spatial distributions. Analysis of autocorrelation patterns through semivariance indicated a tendency towards a patchy distribution over scales around 10 m for genes involved in the nitrification and denitrification processes. In contrast, biogeochemical sediment properties showed diverse spatial distributions. While almost no patchiness was found for pH and moisture, patchiness at scales between 8 and 10 m was detected for carbon, nitrate and ammonia. Denitrification variables showed spatial autocorrelation at scales comparable to genes. However, denitrifying enzyme activity and potential N(2)O production showed a common spatial pattern, different from that of the N(2)O/(N(2)O + N(2)). PMID- 22928964 TI - Elimination of endoplasmic reticulum stress and cardiovascular, type 2 diabetic, and other metabolic diseases. AB - Multiple factors including unhealthy living habits influence the life-maintaining functions of the endoplasmic reticulum (ER) and induce ER stress and metabolic abnormalities. The ER responds to the disturbances by activating mechanisms that increase the capacity to eliminate ER stress. This article elucidates the effects of ER activation that eliminates both ER stress and associated cardiovascular, type 2 diabetic (DM2), and other metabolic diseases. ER-activating compounds eliminate ER stress by lowering elevated cholesterol, regress atherosclerosis, decrease cardiovascular mortality, reduce blood glucose and insulin, and, together with the normalization of glucose-insulin homeostasis, remove insulin resistance, pancreatic beta-cell failure, and DM2. A deficient cytochrome P450 activity in hepatic ER leads to cholesterol accumulation that induces stress and xanthoma formation, whereas P450-activating therapy up-regulates apolipoprotein AI and LDLR genes, down-regulates apolipoprotein B gene, and produces an antiatherogenic plasma lipoprotein profile. The ER activation reduces the stress also by eliminating hepatic fat and converting saturated fatty acids (FAs) to unsaturated FAs. Cognitive processes require gene expression modification, and preclinical studies indicate that ER-activating therapy improves cognition. Promotion of healthy lifestyle choices and indicated therapies are key factors in the prevention and elimination of ER stress and associated global health problems. PMID- 22928966 TI - High incidence of microsatellite instability and loss of heterozygosity in three loci in breast cancer patients receiving chemotherapy: a prospective study. AB - BACKGROUND: The aim of the study was to evaluate potential chemotherapy-induced microsatellite instability, loss of heterozygosity, loss of expression in mismatch repair proteins and associations with clinical findings in breast cancer patients, especially resistance to chemotherapy and/or development of other tumors in the four years following chemotherapy treatment. METHODS: A comprehensive study of chemotherapy-related effects with a follow-up period of 48 months post treatment was conducted. A total of 369 peripheral blood samples were collected from 123 de novo breast cancer patients. Microsatellite instability and loss of heterozygosity in five commonly used marker loci (including Tp53-Alu of the tumor suppressor gene TP53) were analyzed in blood samples. Sampling was conducted on three occasions; 4-5 weeks prior to the first chemotherapy session (pre-treatment), to serve as a baseline, followed by two consecutive draws at 12 weeks intervals from the first collection. Mismatch repair protein expression was evaluated in cancer tissues using immunohistochemistry for three mismatch-repair related proteins. RESULTS: A total of 70.7% of the patients showed microsatellite instability for at least one locus, including 18.6% marked as high-positive and 52.1% as low-positive; 35.8% showed loss of heterozygosity in addition to microsatellite instability, while 29.3% exhibited microsatellite stability. The following incidence rates for microsatellite instability and loss of heterozygosity were detected: 39.1% positive for Tp53-Alu, 31.1% for locus Mfd41, and 25.3% for locus Mfd28. A higher occurrence of loss of heterozygosity was noted with alleles 399 and 404 of Tp53-Alu. The mismatch repair protein expression analysis showed that the chemotherapy caused a loss of 29.3% in hMLH1 expression, and 18.7% and 25.2% loss in hMSH2 and P53 expression, respectively. A strong correlation between low or deficient hMSH2 protein expression and occurrence of mismatch repair/loss of heterozygosity events in Mfd41, Tp53-Alu, and Mfd28 was evident. A significant association between mismatch repair/loss of heterozygosity and incidence of secondary tumors was also established. CONCLUSION: Our results suggest that microsatellite instability, loss of heterozygosity, and deficiency in mismatch repair may serve as early prognostic factors for potential chemotherapy-related side effects in breast cancer patients. PMID- 22928967 TI - Inhibition of hypoxia inducible factor-2 transcription: isolation of active modulators from marine sponges. AB - Renal or kidney cancer accounts for about 3% of all cancer cases reported each year in the U.S. Molecular signatures that define the cancer, such as the loss of functional VHL, are found in both sporadic and familial cases of cancer. In clear cell renal cancer, the transcription factor HIF-2alpha has been shown to have a distinct role in tumorigenesis. Our laboratories developed a cell-based screen to identify modulators of HIF-2alpha. Screening of the NCI's Natural Product Extract Repository resulted in the identification of 10 sponge extracts, from which 12 compounds were isolated. The biological evaluation of these compounds will be discussed including evaluation of HIF-1alpha vs HIF-2alpha selectivity and the isolated compounds' effects on mRNA from several pathways regulated by HIF. PMID- 22928968 TI - Gating and conduction of nano-channel forming proteins: a computational approach. AB - Monitoring conformational changes in ion channels is essential to understand their gating mechanism. Here, we explore the structural dynamics of four outer membrane proteins with different structures and functions in the slowest nonzero modes of vibration. Normal mode analysis was performed on the modified elastic network model of channel in the membrane. According to our results, when membrane proteins were analyzed in the dominant mode, the composed pores, TolC and alpha hemolysin showed large motions at the intramembrane beta-barrel region while, in other porins, OmpA and OmpF, largest motions observed in the region of external flexible loops. A criterion based on equipartition theorem was used to measure the possible amplitude of vibration in channel forming proteins. The current approach complements theoretical and experimental techniques including HOLE, Molecular Dynamics (MD), and voltage clamp used to address the channel's structure and dynamics and provides the means to conduct a theoretical simultaneous study of the structure and function of the channel. An animated interactive 3D complement (I3DC) is available in Proteopedia at http://proteopedia.org/w/Journal:JBSD:3. PMID- 22928969 TI - Assembling wormlike micelles in tubular nanopores by tuning surfactant-wall interactions. AB - Threadlike molecular assemblies are excluded from narrow pores unless attractive interactions with the confining pore walls compensate for the loss of configurational entropy. Here we show that wormlike surfactant micelles can be assembled in the 8 nm tubular nanopores of SBA-15 silica by adjusting the surfactant-pore-wall interactions. The modulation of the interactions was achieved by coadsorption of a surface modifier that also provides control over the partitioning of wormlike aggregates between the bulk solution and the pore space. We anticipate that the concept of tuning the interactions with the pore wall will be applicable to a wide variety of self-assembling molecules and pores. PMID- 22928971 TI - The mechanism of oocyte activation influences the cell cycle-related genes expression during bovine preimplantation development. AB - The first cleavage divisions and preimplantation embryonic development are supported by mRNA and proteins synthesized and stored during oogenesis. Thus, mRNA molecules of maternal origin decrease and embryonic development becomes gradually dependent on expression of genetic information derived from the embryonic genome. However, it is still unclear what the role of the sperm cell is during this phase and whether the absence of the sperm cell during the artificial oocyte activation affects subsequent embryonic development. The objective of this study was to determine, in bovine embryos, changes in cell cycle-associated transcript levels (cyclin A, cyclin B, cyclin E, CDC2, CDK2, and CDK4) after oocyte activation in the presence or absence of the sperm cell. To evaluate that, in vitro-produced (IVP) and parthenogenetically activated (PA) embryos (2-4 cells (2-4C), 8-16 cells (8-16C) and blastocysts) were evaluated by real-time PCR. There was no difference in cleavage and blastocyst rates between IVP and PA groups. Transcript level was higher in oocytes than in IVP and PA embryos. Cleaved PA embryos showed higher expression of cyclin A, cyclin B, cyclin E, and CDK2 and lower expression of CDC2 when compared with that from the IVP group. At the time of activation, all transcripts were expressed less in PA than in IVP embryos, whereas at the blastocyst stage, almost all genes were expressed at a higher level in the PA group. These results suggest that in both groups there is an initial consumption of these transcripts in the early stages of embryonic development. Furthermore, 8-16C embryos seem to synthesize more cell cycle related genes than 2-4C embryos. However, in PA embryos, activation of the cell cycle genes seems to occur after the 8- to 16-cell stage, suggesting a failure in the activation process. PMID- 22928970 TI - Expression of innate immune response genes in liver and three types of adipose tissue in cloned pigs. AB - The pig has been proposed as a relevant model for human obesity-induced inflammation, and cloning may improve the applicability of this model. We tested the assumptions that cloning would reduce interindividual variation in gene expression of innate immune factors and that their expression would remain unaffected by the cloning process. We investigated the expression of 40 innate immune factors by high-throughput quantitative real-time PCR in samples from liver, abdominal subcutaneous adipose tissue (SAT), visceral adipose tissue (VAT), and neck SAT in cloned pigs compared to normal outbred pigs. The variation in gene expression was found to be similar for the two groups, and the expression of a small number of genes was significantly affected by cloning. In the VAT and abdominal SAT, six out of seven significantly differentially expressed genes were downregulated in the clones. In contrast, most differently expressed genes in both liver and neck SAT were upregulated (seven out of eight). Remarkably, acute phase proteins (APPs) dominated the upregulated genes in the liver, whereas APP expression was either unchanged or downregulated in abdominal SAT and VAT. The general conclusion from this work is that cloning leads to subtle changes in specific subsets of innate immune genes. Such changes, even if minor, may have phenotypic effects over time, e.g., in models of long-term inflammation related to obesity. PMID- 22928972 TI - Meanings and perceptions of patient-centeredness in social work, nursing and medicine: a comparative study. AB - Answering patients' evolving, more complex needs has been recognized as a main incentive for the development of interprofessional care. Thus, it is not surprising that patient-centered practice (PCP) has been adopted as a major outcome for interprofessional education. Nevertheless, little research has focused on how PCP is perceived across the professions. This study aimed to address this issue by adopting a phenomenological approach and interviewing three groups of professionals: social workers (n = 10), nurses (n = 10) and physicians (n = 8). All the participants worked in the same department (the General Internal Medicine department of a university affiliated hospital). Although the participants agreed on a core meaning of PCP as identifying, understanding and answering patients' needs, they used many dimensions to define PCP. Overall, the participants expressed value for PCP as a philosophy of care, but there was the sense of a hierarchy of patient-centeredness across the professions, in which both social work and nursing regarded themselves as more patient-centered than others. On their side, physicians seemed inclined to accept their lower position in this hierarchy. Gieryn's concept of boundary work is employed to help illuminate the nature of PCP within an interprofessional context. PMID- 22928973 TI - Outcomes of initially expectantly managed patients with low or intermediate risk screen-detected localized prostate cancer. AB - Study Type--Therapy (outcomes) Level of Evidence 2b. What's known on the subject? and What does the study add? Active surveillance aims to reduce overtreatment by selecting patients with low risk prostate cancer (PCa) based on favourable disease characteristics. However, most studies on active surveillance do not have long-term results available; in particular, data on patients with intermediate risk disease are lacking. Our findings demonstrate that withholding radical treatment in men with low or intermediate risk screen-detected localized PCa leads to a substantial delay or even avoidance of radical treatment in a majority of men. Favourable disease-specific outcomes confirm the feasibility of active surveillance for low risk PCa and also support a role for active surveillance in selected patients with intermediate risk PCa. OBJECTIVE: * To assess the longer term feasibility of active surveillance, we aimed to evaluate outcomes of patients with screen-detected localized prostate cancer (PCa) who initially elected to withhold radical treatment for either low or intermediate risk disease. PATIENTS AND METHODS: * All men underwent screening for PCa in the Rotterdam and Helsinki arms of the European Randomized Study of Screening for Prostate Cancer (ERSPC); eligible men were diagnosed with PCa prior to the establishment of the ERSPC-affiliated Prostate Cancer Research International: Active Surveillance (PRIAS) study (1994-2007) and were initially expectantly managed in the absence of a fixed follow-up protocol. * Low risk PCa was defined as clinical stage T1/T2, PSA <= 10 ng/mL, PSA density < 0.2 ng/mL/mL, Gleason <= 6 and maximum two positive biopsy cores, whereas PSA 10-20 ng/mL, Gleason score 7 and three positive biopsy cores were considered intermediate risk features. * Disease-specific, overall and treatment-free survival were analysed using the Kaplan-Meier and competing risks methods. RESULTS: * In all, 509 patients with PCa were eligible, of whom 381 were considered low risk and 128 intermediate risk. * During a median follow-up of 7.4 years, a total of 221 patients (43.4%) switched to deferred treatment after a median of 2.6 years. * The calculated 10 year disease-specific survival rates were 99.1% and 96.1% for low and intermediate risk patients, respectively (P = 0.44), and for overall survival 79.0% and 64.5%, respectively (P = 0.003). * Competing risks analysis showed similar results. CONCLUSIONS: * Withholding radical treatment in men with low to intermediate risk screen-detected PCa leads to a substantial delay or even avoidance of radical treatment and its potential side-effects in a majority of patients. * Disease-specific outcomes at 7.4 years of follow-up are favourable in low as well as intermediate risk patients. * This confirms the feasibility of active surveillance according to contemporary criteria, and also suggests a potential role for active surveillance in selected men with intermediate risk features. PMID- 22928975 TI - Paying the price works: increasing goal-state access cost improves problem solving and mitigates the effect of interruption. AB - The aim of this paper was to investigate whether it was possible to induce more internal planning in the four-disk Tower of Hanoi (ToH) in order not only to produce more efficient problem solving but also to make it more resistant to the negative effect of interruption. The theoretical frameworks of soft constraints and the memory for goals model underpinned Experiments 1 and 2. In both experiments, three goal-state access cost conditions were used: high (mouse movements and 2.5-s delay), medium (mouse movements) and low (goal state always available). In Experiment 1, more memory-based planning was induced by the high cost condition, which resulted in fewer moves to solution and the gradual development of an efficient subgoaling strategy, resulting in more perfect solutions. In Experiment 2, the same condition protected performance against a 10 s interruption irrespective of the interrupting task (blank screen, mental arithmetic, or three-disk ToH). The more memory-based planning strategy, induced by high access cost, presumably strengthened participants' goals during planning and problem solving, making them less susceptible to decay and interference from interruption. These novel results are discussed in the context of other recent studies. PMID- 22928976 TI - Thermal and light-induced spin switching dynamics in the 2D coordination network of {[Zn(1-x)Fe(x)(bbtr)3](ClO4)2}infinity: the role of cooperative effects. AB - The thermal spin transition, the photoexcitation, and the subsequent spin relaxation in the mixed crystal series of the covalently linked two-dimensional network {[Zn(1-x)Fe(x)(bbtr)(3)](ClO(4))(2)}(infinity) (x = 0.02-1, bbtr =1,4 di(1,2,3-triazol-1-yl)-butane) are discussed. In the neat compound, the thermal spin transition with a hysteresis of 13 K is accompanied by a crystallographic phase transition (Kusz, J.; Bronisz, R.; Zubko, M.; Bednarek, H. Chem. Eur. J.2011, 17, 6807). In contrast, the diluted crystals with x <= 0.1 stay essentially in the high-spin state down to low temperatures and show typical first order relaxation kinetics upon photoexcitation, and the structural phase transition is well separated from the spin transition. With increasing Fe(II) concentration, steeper thermal transitions and sigmoidal relaxation curves indicate increasingly important cooperative effects. Already at x = 0.38, the spin relaxation is governed by cooperative interactions between Fe(II) centers, and the crystallographic phase transition begins to influence the spin transition. The kinetic behavior of the thermal spin transition is reproduced within the framework of a dynamic mean-field model. PMID- 22928974 TI - Identification of a novel malonyl-CoA IC(50) for CPT-I: implications for predicting in vivo fatty acid oxidation rates. AB - Published values regarding the sensitivity (IC(50)) of CPT-I (carnitine palmitoyltransferase I) to M-CoA (malonyl-CoA) inhibition in isolated mitochondria are inconsistent with predicted in vivo rates of fatty acid oxidation. Therefore we have re-examined M-CoA inhibition kinetics under various P-CoA (palmitoyl-CoA) concentrations in both isolated mitochondria and PMFs (permeabilized muscle fibres). PMFs have an 18-fold higher IC(50) (0.61 compared with 0.034 MUM) in the presence of 25 MUM P-CoA and a 13-fold higher IC(50) (6.3 compared with 0.49 MUM) in the presence of 150 MUM P-CoA compared with isolated mitochondria. M-CoA inhibition kinetics determined in PMFs predicts that CPT-I activity is inhibited by 33% in resting muscle compared with >95% in isolated mitochondria. Additionally, the ability of M-CoA to inhibit CPT-I appears to be dependent on P-CoA concentration, as the relative inhibitory capacity of M-CoA is decreased with increasing P-CoA concentrations. Altogether, the use of PMFs appears to provide an M-CoA IC(50) that better reflects the predicted in vivo rates of fatty acid oxidation. These findings also demonstrate that the ratio of [P-CoA]/[M-CoA] is critical for regulating CPT-I activity and may partially rectify the in vivo disconnect between M-CoA content and CPT-I flux within the context of exercise and Type 2 diabetes. PMID- 22928978 TI - Molecular excited-state relaxation dynamics at the colloidal microparticle interface monitored with pump-probe second harmonic generation. AB - Time-resolved second harmonic generation is used to monitor the excited-state relaxation dynamics of molecules adsorbed to the surface of colloidal microparticles suspended in solution. The cationic organic dye, malachite green (MG), is adsorbed to the negatively charged surface of polystyrene sulfate microparticles in water. MG is photoexcited to the S1 excited state by a 615 nm pump pulse. The time-dependent change of the S0 ground-state depletion is probed by second harmonic generation of an 800 nm pulse as a function of pump-probe delay to obtain a lifetime of 5.7 +/- 0.4 ps. This excited-state lifetime is approximately three times longer than the corresponding lifetime at the air/water interface, showing the significant effect of the negatively charged surface on local friction, which is important in the energy relaxation of photoexcited MG. PMID- 22928977 TI - Regulation of multiple tip formation by caffeine in cellular slime molds. AB - BACKGROUND: The multicellular slug in Dictyostelium has a single tip that acts as an organising centre patterning the rest of the slug. High adenosine levels at the tip are believed to be responsible for this tip dominance and the adenosine antagonist, caffeine overrides this dominance promoting multiple tip formation. RESULTS: Caffeine induced multiple tip effect is conserved in all the Dictyostelids tested. Two key components of cAMP relay namely, cAMP phosphodiesterase (Pde4) and adenyl cyclase-A (AcaA) levels get reduced during secondary tip formation in Dictyostelium discoideum. Pharmacological inhibition of cAMP phosphodiesterase also resulted in multiple tips. Caffeine reduces cAMP levels by 16.4, 2.34, 4.71 and 6.30 folds, respectively in D. discoideum, D. aureostipes, D. minutum and Polysphondylium pallidum. We propose that altered cAMP levels, perturbed cAMP gradient and impaired signalling may be the critical factors for the origin of multiple tips in other Dictyostelids as well. In the presence of caffeine, slug cell movement gets impaired and restricted. The cell type specific markers, ecmA (prestalk) and pspA (prespore) cells are not equally contributing during additional tip formation. During additional tip emergence, prespore cells transdifferentiate to compensate the loss of prestalk cells. CONCLUSION: Caffeine decreases adenyl cyclase-A (AcaA) levels and as a consequence low cAMP is synthesised altering the gradient. Further if cAMP phosphodiesterase (Pde4) levels go down in the presence of caffeine, the cAMP gradient breaks down. When there is no cAMP gradient, directional movement is inhibited and might favour re-differentiation of prespore to prestalk cells. PMID- 22928979 TI - Researcher-decision-maker partnerships in health services research: practical challenges, guiding principles. AB - BACKGROUND: In health services research, there is a growing view that partnerships between researchers and decision-makers (i.e., collaborative research teams) will enhance the effective translation and use of research results into policy and practice. For this reason, there is an increasing expectation by health research funding agencies that health system managers, policy-makers, practitioners and clinicians will be members of funded research teams. While this view has merit to improve the uptake of research findings, the practical challenges of building and sustaining collaborative research teams with members from both inside and outside the research setting requires consideration. A small body of literature has discussed issues that may arise when conducting research in one's own setting; however, there is a lack of clear guidance to deal with practical challenges that may arise in research teams that include team members who have links with the organization/community being studied (i.e., are "insiders"). DISCUSSION: In this article, we discuss a researcher-decision-maker partnership that investigated practice in primary care networks in Alberta. Specifically, we report on processes to guide the role clarification of insider team members where research activities may pose potential risk to participants or the team members (e.g., access to raw data). SUMMARY: These guiding principles could provide a useful discussion point for researchers and decision-makers engaged in health services research. PMID- 22928980 TI - Phytate addition to soil induces changes in the abundance and expression of Bacillus beta-propeller phytase genes in the rhizosphere. AB - Phytate-mineralizing rhizobacteria (PMR) perform an essential function for the mineralization of organic phosphorus but little is known about their ecology in soils and rhizosphere. In this study, PCR-based methods were developed for detection and quantification of the Bacillus beta-propeller phytase (BPP) gene. Experiments were conducted to monitor the presence and persistence of a phytate mineralizing strain, Bacillus sp. MQH19, after inoculation of soil microcosms and within the rhizosphere. The occurrence of the BPP gene in natural pasture soils from Chilean Andisols was also examined. The results showed that the Bacillus BPP gene was readily detected in sterile and nonsterile microcosms, and that the quantitative PCR (qPCR) methods could be used to monitor changes in the abundance of the BPP gene over time. Our results also show that the addition of phytate to nonsterile soils induced the expression of the BPP gene in the rhizosphere of ryegrass and the BPP gene was detected in all pasture soils sampled. This study shows that phytate addition soils induced changes in the abundance and expression of Bacillus BPP to genes in the rhizosphere and demonstrates that Bacillus BPP gene is cosmopolitan in pasture soils from Chilean Andisols. PMID- 22928981 TI - The outcome of 9 years of consecutive patch testing with 4,4' diaminodiphenylmethane and 4,4'-diphenylmethane diisocyanate. AB - BACKGROUND: Two outbreaks of allergic contact dermatitis caused by isocyanates at two companies in southern Sweden initiated a research project focusing on contact allergy to isocyanates. Within the project, there was an interest in determining how often contact allergy to the most common isocyanate, diphenylmethane-4,4' diisocyanate (4,4'-MDI), occurred. OBJECTIVES: To determine and compare the occurrence of contact allergy to 4,4'-MDI, its corresponding amine 4,4' diaminodiphenylmethane (4,4'-MDA), and polymeric diphenylmethane diisocyanate (PMDI) in a Swedish and a Belgian study population. Patients and method. The study population consisted of 6190 consecutively patch tested dermatitis patients: 5690 patients from Malmo, Sweden, and 500 patients from Leuven, Belgium. Patch test results were analysed and compared. RESULTS: None of the Belgian patients reacted positively to 4,4'-MDI, but 5 Swedish patients did. Contact allergy to 4,4'-MDA was more common in the Belgian patients than in the Swedish patients: 3.6% and 0.9%, respectively. This could possibly be explained by the fact that the prevalence of p-phenylenediamine allergy was higher in the Belgian population. CONCLUSIONS: The prevalence of contact allergy to 4,4'-MDI, 4,4'-MDA and PMDI is not high enough to justify their inclusion in any baseline series. Isocyanate allergic individuals should be detected by aimed testing with an isocyanate series and work materials. PMID- 22928982 TI - 'That was helpful ... no one has talked to me about that before': Research participation as a therapeutic activity. AB - There is considerable interest in the various ethical problems associated with undertaking health and social science research. Participants in such research are often considered vulnerable because of their health status, social position, or dependence on others for health and welfare services. Researchers and ethics committees pay scrupulous attention to the identification and amelioration of risks to participants. Rarely are the benefits to participants of engaging in research highlighted or drawn to the attention of potential participants. Such potential benefits need to be considered by researchers and reviewers when considering the balance of benefits and harms associated with research projects. In this paper, we particularly consider the psychotherapeutic benefits of participation in research. PMID- 22928983 TI - A unique pathway for the 3-aminobutyrate starter unit from L-glutamate through beta-glutamate during biosynthesis of the 24-membered macrolactam antibiotic, incednine. AB - Incednine is a 24-membered macrolactam antibiotic produced by Streptomyces sp. ML694-90F3. A previous study demonstrated that its unique nitrogen-containing starter unit was derived from L-glutamate. To elucidate the missing link between L-glutamate and the starter unit, deuterium labeled amino acid feeding experiments were conducted. These experiments revealed that 3-[3 (2)H]aminobutyrate and beta-[2,2,4,4-(2)H(4)]glutamate were incorporated into the starter moiety. The results indicate that a novel decarboxylation of beta glutamate to give 3-aminobutyrate is involved in incednine biosynthesis. PMID- 22928984 TI - Correlation between Duffy blood group phenotype and breast cancer incidence. AB - BACKGROUND: Different ethnicities have different distribution of Duffy blood group (DBG) phenotypes and different breast cancer morbidity. A study in our lab demonstrated that Duffy antigen/receptor for chemokines (DARC, also known as DBGP, the Duffy protein phenotype), led to the inhibition of tumorigenesis. Therefore, we tested the hypothesis that DBGP is correlated with breast cancer occurrence. METHODS: DBGP proteins were examined by indirect antiglobulin testing with anti-FYa and anti-FYb antibodies. The phenotypes were classified into four groups according to the agglutination reactions: FYa + FYb+, FYa + FYb-, FYa-FYb + and FYa-FYb-. The phenotypes and pathological diagnosis of consecutively hospitalized female patients (n = 5,022) suffering from breast cancer at the Shanghai Cancer Hospital and Henan Province Cancer Hospital were investigated. The relationships between DBGP expression with breast cancer occurrence, axillary lymph status, histological subtype, tumor size pathological grade and overall survival were analyzed. RESULTS: The incidence of breast cancer was significantly different between FYa + FYb + (29.8%), FYa + FYb- (33.2%), FYa-FYb + (45.6%) and FYa-FYb- (59.1%; P = 0.001). Significant different numbers of breast cancer patients had metastases to the axillary lymph nodes in the FYa + FYb + group (25.1%), FYa + FYb- (36.9%), FYa-FYb + (41.0%) and FYa-FYb- (50.0%, (P = 0.005). There was a statistical significance (p = 0.022) of the overall survival difference between patients with difference phenotypes. No significant difference was observed in cancer size (t-test, p > 0.05), histological cancer type (Fisher's exact test, p > 0.05) or histological grade (Fisher's exact test, p > 0.05) between every each DBGP group. CONCLUSIONS: DBGP is correlated with breast cancer incidence and axillary lymph node metastasis and overall survival. Further investigations are required to determine the underlying mechanism of Duffy blood group phenotype on breast cancer risk. PMID- 22928985 TI - Benefits of off-campus education for students in the health sciences: a text mining analysis. AB - BACKGROUND: In Japan, few community-based approaches have been adopted in health care professional education, and the appropriate content for such approaches has not been clarified. In establishing community-based education for health-care professionals, clarification of its learning effects is required. A community based educational program was started in 2009 in the health sciences course at Gunma University, and one of the main elements in this program is conducting classes outside school. The purpose of this study was to investigate using text analysis methods how the off-campus program affects students. METHODS: In all, 116 self-assessment worksheets submitted by students after participating in the off-campus classes were decomposed into words. The extracted words were carefully selected from the perspective of contained meaning or content. With the selected terms, the relations to each word were analyzed by means of cluster analysis. RESULTS: Cluster analysis was used to select and divide 32 extracted words into four clusters: cluster 1-"actually/direct," "learn/watch/hear," "how," "experience/participation," "local residents," "atmosphere in community-based clinical care settings," "favorable," "communication/conversation," and "study"; cluster 2-"work of staff member" and "role"; cluster 3 "interaction/communication," "understanding," "feel," "significant/important/necessity," and "think"; and cluster 4-"community," "confusing," "enjoyable," "proactive," "knowledge," "academic knowledge," and "class." CONCLUSIONS: The students who participated in the program achieved different types of learning through the off-campus classes. They also had a positive impression of the community-based experience and interaction with the local residents, which is considered a favorable outcome. Off-campus programs could be a useful educational approach for students in health sciences. PMID- 22928986 TI - Amperometric noise at thin film band electrodes. AB - Background current noise is often a significant limitation when using constant potential amperometry for biosensor application such as amperometric recordings of transmitter release from single cells through exocytosis. In this paper, we fabricated thin-film electrodes of gold and conductive polymers and measured the current noise in physiological buffer solution for a wide range of different electrode areas. The noise measurements could be modeled by an analytical expression, representing the electrochemical cell as a resistor and capacitor in series. The studies revealed three domains; for electrodes with low capacitance, the amplifier noise dominated, for electrodes with large capacitances, the noise from the resistance of the electrochemical cell was dominant, while in the intermediate region, the current noise scaled with electrode capacitance. The experimental results and the model presented here can be used for choosing an electrode material and dimensions and when designing chip-based devices for low noise current measurements. PMID- 22928987 TI - Single-walled carbon nanotube growth from chiral carbon nanorings: prediction of chirality and diameter influence on growth rates. AB - Catalyst-free, chirality-controlled growth of chiral and zigzag single-walled carbon nanotubes (SWCNTs) from organic precursors is demonstrated using quantum chemical simulations. Growth of (4,3), (6,5), (6,1), (10,1) and (8,0) SWCNTs was induced by ethynyl radical (C(2)H) addition to organic precursors. These simulations show a strong dependence of the SWCNT growth rate on the chiral angle, theta. The SWCNT diameter however does not influence the SWCNT growth rate under these conditions. This agreement with a previously proposed screw dislocation-like model of transition metal-catalyzed SWCNT growth rates [Ding, F.; Proc. Natl. Acad. Sci. 2009, 106, 2506] indicates that the SWCNT growth rate is an intrinsic property of the SWCNT edge itself. Conversely, we predict that the rate of SWCNT growth via Diels-Alder cycloaddition of C(2)H(2) is strongly influenced by the diameter of the SWCNT. We therefore predict the existence of a maximum growth rate for an optimum diameter/chirality combination at a given C(2)H/C(2)H(2) ratio. We also find that the ability of a SWCNT to avoid defect formation during growth is an intrinsic quality of the SWCNT edge. PMID- 22928988 TI - The influence of different forms of early childcare on children's emotional and behavioural development at school entry. AB - BACKGROUND: Over the past few decades there has been a dramatic increase in maternal employment and, as a result, an increase in the use of non-maternal childcare in the early years. The purpose of this longitudinal study was to examine, in a large representative English sample, the influence of different forms of childcare on children's behavioural and emotional development around the age of school entry. METHODS: A sample of 991 families, originally recruited when the children were 3 months old, was assessed around school entry age at 51 months. The main outcome variable was the children's emotional and behavioural functioning, measured by questionnaire completed by both mothers and teachers. A range of repeated assessments were carried out at different time points, including direct observation of the quality of maternal caregiving and observations of the quality of non-parental care, and amount of time spent in different forms of care. RESULTS: The strongest and most consistent influences on behaviour and emotional problems were derived from the home, including lower socio-demographic status, poorer maternal caregiving, parental stress/maternal mental health problems, as well as child gender (being a boy). Non-parental childcare had small effects on child outcome. One finding that did emerge was that children who spent more time in group care, mainly nursery care, were more likely to have behavioural problems, particularly hyperactivity. CONCLUSIONS: These findings suggest that interventions to enhance children's emotional and behavioural development might best focus on supporting families and augmenting the quality of care in the home. PMID- 22928989 TI - beta-alanine supplementation improves YoYo intermittent recovery test performance. AB - BACKGROUND: beta-alanine supplementation has been shown to improve high-intensity exercise performance and capacity. However, the effects on intermittent exercise are less clear, with no effect shown on repeated sprint activity. The aim of this study was to investigate the effects of beta-alanine supplementation on YoYo Intermittent Recovery Test Level 2 (YoYo IR2) performance. METHODS: Seventeen amateur footballers were allocated to either a placebo (PLA; N = 8) or beta alanine (BA; N = 9) supplementation group, and performed the YoYo IR2 on two separate occasions, pre and post 12 weeks of supplementation during a competitive season. Specifically, players were supplemented from early to mid-season (PLA: N = 5; BA: N = 6) or mid- to the end of the season (PLA: N = 3; BA: N = 3). Data were analysed using a two factor ANOVA with Tukey post-hoc analyses. RESULTS: Pre supplementation scores were 1185 +/- 216 and 1093 +/- 148 m for PLA and BA, with no differences between groups (P = 0.41). YoYo performance was significantly improved for BA (+34.3%, P <= 0.001) but not PLA (-7.3%, P = 0.24) following supplementation. 2 of 8 (Early - Mid: 2 of 5; Mid - End: 0 of 3) players improved their YoYo scores in PLA (Range: -37.5 to + 14.7%) and 8 of 9 (Early - Mid: 6 of 6; Mid - End: 2 of 3) improved for BA (Range: +0.0 to +72.7%). CONCLUSIONS: 12 weeks of beta-alanine supplementation improved YoYo IR2 performance, likely due to an increased muscle buffering capacity resulting in an attenuation of the reduction in intracellular pH during high-intensity intermittent exercise. PMID- 22928990 TI - Bad milk, part 2: new-age doctrines that impeded breastfeeding. PMID- 22928991 TI - Dynamic sentinel node biopsy in penile cancer: initial experiences at a Swedish referral centre. AB - Study Type - Therapy (case series) Level of Evidence 4 What's known on the subject? and What does the study add? According to the current European Association of Urology Guidelines, dynamic sentinel node biopsy is the recommended approach to assess lymph node status in men with cN0 intermediate and high risk penile cancer. Nevertheless, most encouraging results derive from a limited number of studies. The present study shows a false-negative rate of 15%, comparable with or better than several previous studies. Nevertheless, the aim should be a false-negative rate of no more than 5%. We conclude that increased overall experience and the use of the complete modern dynamic sentinel node biopsy protocol are paramount to improve results. OBJECTIVE: * To evaluate the false-negative rate and complication rate of dynamic sentinel node biopsy (DSNB) in penile cancer. PATIENTS AND METHODS: * In this retrospective study, 58 unilaterally or bilaterally clinically lymph node negative (cN0) patients with penile cancer (57 squamous cell carcinomas and one malignant melanoma), scheduled for DSNB at the Orebro University Hospital, Sweden, between 1999 and 2011, were analysed. * Preoperative ultrasonography and fine-needle aspiration cytology of suspicious nodes were not introduced until 2008. * Patients were assessed by lymphoscintigraphy using (99m) technetium nanocolloid on the day before surgery and the dissection of sentinel nodes was aided by the lymphoscintigraphic images and intraoperative detection of radiotracer and patent blue dye. * The false negative rate and complication rate were calculated per groin. RESULTS: * Of the 58 patients, 32 (55%) underwent preoperative ultrasonography. * Two patients had positive fine-needle aspiration cytology and discontinued further DSNB protocol. Of the remaining 56 patients, all but one were bilaterally cN0 and hence 111 cN0 groins were assessed by lymphoscintigraphy. * In the 55 bilaterally cN0 patients, lymphoscintigraphy visualized a bilateral sentinel node in 34 (62%). * At surgery, all excised sentinel nodes were radioactive while 43% were additionally blue. In total, at least one sentinel node was harvested in 96 (86%) of the DSNB staged groins. * A positive sentinel node was found in 11 groins (bilaterally in three patients). During a median follow-up of 21 months, two false-negative cases emerged, producing a false-negative rate of 15%. Both false negative cases occurred during the first half of the study. The complication rate was 10%. The majority of complications were minor and transient. CONCLUSIONS: * DSNB is a minimally invasive staging tool in men with cN0 penile cancer, enabling early detection of metastatic disease and thus optimal care. * Our false negative rate of 15% is comparable or even favourable in comparison with several previous studies, but far from the 5% or less that we aim for. The complication rate found is somewhat higher than previously reported. * With increased overall experience and the continued use of the complete DSNB protocol, we believe our results will improve and the complication rate will decrease. PMID- 22928992 TI - Negative pressure therapy as palliative treatment for a colonic fistula. AB - Colonic fistulas in an open wound are always a challenge for colorectal surgeons, and this report provides a technique for the appropriate management of these cases. We communicate the use of a negative pressure dressing therapy as part of the palliative care for a patient following the development of an enterocutaneous fistula. The use of this therapy allowed us to keep the patient clean and comfortable during the last few days of his life. PMID- 22928993 TI - Controlling the chiral inversion reaction of the metallopeptide Ni-asparagine cysteine-cysteine with dioxygen. AB - Synthetically generated metallopeptides have the potential to serve a variety of roles in biotechnology applications, but the use of such systems is often hampered by the inability to control secondary reactions. We have previously reported that the Ni(II) complex of the tripeptide LLL-asparagine-cysteine cysteine, LLL-Ni(II)-NCC, undergoes metal-facilitated chiral inversion to dld Ni(II)-NCC, which increases the observed superoxide scavenging activity. However, the mechanism for this process remained unexplored. Electronic absorption and circular dichroism studies of the chiral inversion reaction of Ni(II)-NCC reveal a unique dependence on dioxygen. Specifically, in the absence of dioxygen, the chiral inversion is not observed, even at elevated pH, whereas the addition of O(2) initiates this reactivity and concomitantly generates superoxide. Scavenging experiments using acetaldehyde are indicative of the formation of carbanion intermediates, demonstrating that inversion takes place by deprotonation of the alpha carbons of Asn1 and Cys3. Together, these data are consistent with the chiral inversion being dependent on the formation of a Ni(III)-NCC intermediate from Ni(II)-NCC and O(2). The data further suggest that the anionic thiolate and amide ligands in Ni(II)-NCC inhibit Calpha-H deprotonation for the Ni(II) oxidation state, leading to a stable complex in the absence of O(2). Together, these results offer insights into the factors controlling reactivity in synthetic metallopeptides. PMID- 22928994 TI - GABA and glutamate receptors have different effects on excitability and are differentially regulated by calcium in spider mechanosensory neurons. AB - GABA and glutamate receptors belonging to the ligand-gated chloride-channel family are primary targets of insecticides and antiparasitics, so their molecular structure, pharmacology and biophysical properties have attracted significant attention. However, little is known about the physiological roles of these channels or how they regulate neuronal excitability and animal behavior. Mechanosensory neurons of VS-3 slit sensilla in the patella of the tropical wandering spider, Cupiennius salei, react to the GABA(A)-receptor agonists, GABA and muscimol, with depolarization and an increase in intracellular [Ca(2+)] and, during random noise stimulation, with a mixed inhibitory-excitatory response. We established that the GABA(A)-receptors in all VS-3 neurons are identical, but there are at least two types of glutamate receptors and some neurons do not respond to glutamate at all. Immunohistochemistry with antibodies against Drosophila inhibitory glutamate receptor (GluCls) alpha-subunit suggests that in addition to VS-3 neurons, these receptors may also be present in the efferent neurons surrounding the sensory neurons. Most VS-3 neurons were inhibited but not depolarized by glutamate during random stimulation, but some depolarized and had a similar excitatory-inhibitory response to glutamate as to muscimol. The membrane-permeable Ca(2+)-chelator BAPTA-AM abolished muscimol effects but potentiated glutamate effects, indicating that GABA and glutamate receptors are differentially modulated by Ca(2+), leading to diverse regulation of neuronal excitability. We hypothesize that this could be achieved by different Ca(2+) triggered phosphorylation processes at each receptor type. These findings are important for understanding the significance of Ca(2+)-mediated regulation of transmitter receptor molecules and its role in controlling excitability. PMID- 22928996 TI - Hyperthermophilic endoglucanase for in planta lignocellulose conversion. AB - BACKGROUND: The enzymatic conversion of lignocellulosic plant biomass into fermentable sugars is a crucial step in the sustainable and environmentally friendly production of biofuels. However, a major drawback of enzymes from mesophilic sources is their suboptimal activity under established pretreatment conditions, e.g. high temperatures, extreme pH values and high salt concentrations. Enzymes from extremophiles are better adapted to these conditions and could be produced by heterologous expression in microbes, or even directly in the plant biomass. RESULTS: Here we show that a cellulase gene (sso1354) isolated from the hyperthermophilic archaeon Sulfolobus solfataricus can be expressed in plants, and that the recombinant enzyme is biologically active and exhibits the same properties as the wild type form. Since the enzyme is inactive under normal plant growth conditions, this potentially allows its expression in plants without negative effects on growth and development, and subsequent heat-inducible activation. Furthermore we demonstrate that the recombinant enzyme acts in high concentrations of ionic liquids and can therefore degrade alpha-cellulose or even complex cell wall preparations under those pretreatment conditions. CONCLUSION: The hyperthermophilic endoglucanase SSO1354 with its unique features is an excellent tool for advanced biomass conversion. Here we demonstrate its expression in planta and the possibility for post harvest activation. Moreover the enzyme is suitable for combined pretreatment and hydrolysis applications. PMID- 22928995 TI - Chief nursing officers' perspectives on Medicare's hospital-acquired conditions non-payment policy: implications for policy design and implementation. AB - BACKGROUND: Preventable adverse events from hospital care are a common patient safety problem, often resulting in medical complications and additional costs. In 2008, Center for Medicare and Medicaid Services (CMS) implemented a policy, mandated by the Deficit Reduction Act of 2005, targeting a list of these 'reasonably' preventable hospital-acquired conditions (HACs) for reduced reimbursement. Extensive debate ensued about the potential adverse effects of the policy, but there was little discussion of its impact on hospitals' quality improvement (QI) activities. This study's goals were to understand organizational responses to the HAC policy, including internal and external influences that moderated the success or failure of QI efforts. METHODS: We employed a qualitative descriptive design. Representatives from 14 Nurses Improving Care of Health System Elders (NICHE) hospitals participated in semi-structured interviews addressing the impact of the HAC policy generally, and for two indicator conditions: central-line associated bloodstream infection (CLABSI) and catheter associated urinary tract infection (CAUTI). Within-case analysis identified the key components of each institution's response to the policy; across-case analysis identified themes. Exemplar cases were used to explicate findings. RESULTS: Interviewees reported that the HAC policy is one of many internal and external factors motivating hospitals to address HACs. They agreed the policy focused attention on prevention of HACs that had previously received fewer dedicated resources. The impact of the policy on prevention activities, barriers, and facilitators was condition-specific. CLABSI efforts were in place prior to the policy, whereas CAUTI efforts were less mature. Nearly all respondents noted that pressure ulcer detection and documentation became a larger focus stemming from the policy change. A major challenge was the determination of which conditions were 'hospital-acquired.' One opportunity arising from the policy has been the focus on nursing leadership in patient safety efforts. CONCLUSIONS: While the CMS's HAC policy was just one of many factors influencing QI efforts, it may have served the important role of drawing attention and resources to the targeted conditions-particularly those not previously in the spotlight. The translational research paradigm is helpful in the interpretation of the findings, illustrating how the policy can advance prevention efforts for HACs at earlier phases of research translation as well as pitfalls associated with earlier phase implementation. To maximize their impact, such policies should consider condition specific contextual factors influencing policy uptake and provide condition specific implementation support. PMID- 22928997 TI - Effects of gold nanoparticles on the stability of microbubbles. AB - Surfactant-coated microbubbles are utilized in a wide variety of applications, from wastewater purification to contrast agents in medical ultrasound imaging. In many of these applications, the stability of the microbubbles is crucial to their effectiveness. Controlling this, however, represents a considerable challenge. In this study, the potential for stabilizing microbubbles using solid nanoparticles adsorbed onto their surfaces was explored. A new theoretical model has been developed to describe the influence of interfacially adsorbed solid particles upon the dissolution of a gas bubble in a liquid. The aim of this work was to test experimentally the prediction of the model that the presence of the nanoparticles would inhibit gas diffusion and coalescence/disproportionation, thus increasing the life span of the bubbles. Near-monodisperse microbubbles (~100 MUm diameter) were prepared using a microfluidic device and coated with a surfactant, with and without the addition of a suspension of spherical gold nanoparticles (~15 nm diameter). The experimental results confirmed the theoretical predictions that as the surface concentration of gold nanoparticles increased the bubbles underwent negligible changes in their size and size distribution over a period of 30 days at the ambient temperature and pressure. Under the same conditions, bubbles coated with the same surfactant but no nanoparticles survived only a matter of hours. PMID- 22928999 TI - AbobotulinumtoxinA for reduction of glabellar lines in patients with skin of color: post hoc analysis of pooled clinical trial data. AB - BACKGROUND: A paucity of research exists on the safety and efficacy of aesthetic medicine products in patients with skin of color (SOC). OBJECTIVE: To compare the effectiveness and tolerability of abobotulinumtoxinA (BoNTA-ABO) for glabellar lines in a subpopulation of patients with SOC with that in white patients. MATERIALS AND METHODS: This post hoc analysis considered pooled safety data from six clinical trials from which were derived a safety population (n = 1,869 white, n = 472 SOC), an efficacy population for a comparison of fixed-dose BoNTA-ABO 50 U in white patients (n = 216) and patients with SOC (n = 117), and an efficacy population for a comparison of BoNTA-ABO adjusted to muscle mass in white (n = 555) and patients with SOC (n = 160). RESULTS: Adverse event rates were similar in white patients and patients with SOC. Onset of effect was similar in patients with SOC and white patients, but the response rate 30 days after treatment was greater in patients with SOC than in white patients. CONCLUSION: Tolerability and effectiveness of treatment BoNTA-ABO for glabellar lines was similar in patients with SOC and white patients. PMID- 22928998 TI - Probiotics, prebiotics infant formula use in preterm or low birth weight infants: a systematic review. AB - BACKGROUND: Previous reviews (2005 to 2009) on preterm infants given probiotics or prebiotics with breast milk or mixed feeds focused on prevention of Necrotizing Enterocolitis, sepsis and diarrhea. This review assessed if probiotics, prebiotics led to improved growth and clinical outcomes in formula fed preterm infants. METHODS: Cochrane methodology was followed using randomized controlled trials (RCTs) which compared preterm formula containing probiotic(s) or prebiotic(s) to conventional preterm formula in preterm infants. The mean difference (MD) and corresponding 95% confidence intervals (CI) were reported for continuous outcomes, risk ratio (RR) and corresponding 95% CI for dichotomous outcomes. Heterogeneity was assessed by visual inspection of forest plots and a chi2 test. An I2 test assessed inconsistencies across studies. I2> 50% represented substantial heterogeneity. RESULTS: Four probiotics studies (N=212), 4 prebiotics studies (N=126) were included. Probiotics: There were no significant differences in weight gain (MD 1.96, 95% CI: -2.64 to 6.56, 2 studies, n=34) or in maximal enteral feed (MD 35.20, 95% CI: -7.61 to 78.02, 2 studies, n=34), number of stools per day increased significantly in probiotic group (MD 1.60, 95% CI: 1.20 to 2.00, 1 study, n=20). Prebiotics: Galacto-oligosaccharide/Fructo oligosaccharide (GOS/FOS) yielded no significant difference in weight gain (MD 0.04, 95% CI: -2.65 to 2.73, 2 studies, n=50), GOS/FOS yielded no significant differences in length gain (MD 0.01, 95% CI: -0.03 to 0.04, 2 studies, n=50). There were no significant differences in head growth (MD -0.01, 95% CI: -0.02 to 0.00, 2 studies, n=76) or age at full enteral feed (MD -0.79, 95% CI: -2.20 to 0.61, 2 studies, n=86). Stool frequency increased significantly in prebiotic group (MD 0.80, 95% CI: 0.48 to 1.1, 2 studies, n=86). GOS/FOS and FOS yielded higher bifidobacteria counts in prebiotics group (MD 2.10, 95% CI: 0.96 to 3.24, n=27) and (MD 0.48, 95% CI: 0.28 to 0.68, n=56). CONCLUSIONS: There is not enough evidence to state that supplementation with probiotics or prebiotics results in improved growth and clinical outcomes in exclusively formula fed preterm infants. PMID- 22929000 TI - Doctor-patient communication in the e-health era. AB - The digital revolution will have a profound impact on how physicians and health care delivery organizations interact with patients and the community at-large. Over the coming decades, face-to-face patient/doctor contacts will become less common and exchanges between consumers and providers will increasingly be mediated by electronic devices.In highly developed health care systems like those in Israel, the United States, and Europe, most aspects of the health care and consumer health experience are becoming supported by a wide array of technology such as electronic and personal health records (EHRs and PHRs), biometric & telemedicine devices, and consumer-focused wireless and wired Internet applications.In an article in this issue, Peleg and Nazarenko report on a survey they fielded within Israel's largest integrated delivery system regarding patient views on the use of electronic communication with their doctors via direct-access mobile phones and e-mail. A previous complementary paper describes the parallel perspectives of the physician staff at the same organization. These two surveys offer useful insights to clinicians, managers, researchers, and policymakers on how best to integrate e-mail and direct-to-doctor mobile phones into their practice settings. These papers, along with several other recent Israeli studies on e-health, also provide an opportunity to step back and take stock of the dramatic impact that information & communication technology (ICT) and health information technology (HIT) will have on clinician/patient communication moving forward.The main goals of this commentary are to describe the scope of this issue and to offer a framework for understanding the potential impact that e-health tools will have on provider/patient communication. It will be essential that clinicians, managers, policymakers, and researchers gain an increased understanding of this trend so that health care systems around the globe can adapt, adopt, and embrace these rapidly evolving digital technologies. PMID- 22929001 TI - How much are we spending? The estimation of research expenditures on cardiovascular disease in Canada. AB - BACKGROUND: Cardiovascular disease (CVD) is a leading cause of death in Canada and is a priority area for medical research. The research funding landscape in Canada has changed quite a bit over the last few decades, as have funding levels. Our objective was to estimate the magnitude of expenditures on CVD research for the public and charitable (not-for profit) sectors in Canada between 1975 and 2005. METHODS: To estimate research expenditures for the public and charitable sectors, we compiled a complete list of granting agencies in Canada, contacted each agency and the Canadian Institutes of Health Research (CIHR), and extracted data from the organizations' annual reports and the Reference Lists of health research in Canada. Two independent reviewers scanned all grant and fellowship/scholarship titles (and summary/key words, when available) of all research projects funded to determine their inclusion in our analysis; only grants and fellowships/scholarships that focused on heart and peripheral vascular diseases were selected. RESULTS: Public/charitable sector funding increased 7.5 times, from close to $13 million (in constant dollars) in 1975 to almost $96 million (in constant dollars) in 2005 (base year). The Medical Research Council of Canada (MRCC)/CIHR and the Heart & Stroke Foundation of Canada have been the main founders of this type of research during our analysis period; the Alberta Heritage Foundation for Medical Research and the Fonds de la recherche en sante du Quebec have played major roles at the provincial level. The Indirect Costs Research Program and Canada Foundation for Innovation have played major roles in terms of funding in the last years of our analysis. CONCLUSION: Public/charitable funded research expenditures devoted to CVD have increased substantially over the last three decades. By international standards, the evidence suggests Canada spends less on health-related research than the UK and the US, at least in absolute terms. However, this may not be too problematic as Canada is likely to free-ride from research undertaken elsewhere. Understanding these past trends in research funding may provide decision makers with important information for planning future research efforts. Future work in this area should include the use of our coding methods to obtain estimates of funded research for other diseases in Canada. PMID- 22929002 TI - Are there universals of reading? We don't believe so. AB - There are universals of language; but is it also true, as the target article claims, that there are universals of reading? We believe there are no such universals, and invite others to refute our claim by providing a list of some universals of reading. If there are no universals of reading, there cannot be a universal model of reading. PMID- 22929003 TI - Writing systems: not optimal, but good enough. AB - Languages and writing systems result from satisfying multiple constraints related to learning, comprehension, production, and their biological bases. Orthographies are not optimal because these constraints often conflict, with further deviations due to accidents of history and geography. Things tend to even out because writing systems and the languages they represent exhibit systematic trade-offs between orthographic depth and morphological complexity. PMID- 22929004 TI - An injury awareness education program on outcomes of juvenile justice offenders in Western Australia: an economic analysis. AB - BACKGROUND: Injury is a major cause of mortality and morbidity of young people and the cost-effectiveness of many injury prevention programs remains uncertain. This study aimed to analyze the costs and benefits of an injury awareness education program, the P.A.R.T.Y. (Prevent Alcohol and Risk-related Trauma in Youth) program, for juvenile justice offenders in Western Australia. METHODS: Costs and benefits analysis based on effectiveness data from a linked-data cohort study on 225 juvenile justice offenders who were referred to the education program and 3434 who were not referred to the program between 2006 and 2011. RESULTS: During the study period, there were 8869 hospitalizations and 113 deaths due to violence or traffic-related injuries among those aged between 14 and 21 in Western Australia. The mean length of hospital stay was 4.6 days, a total of 320 patients (3.6%) needed an intensive care admission with an average length of stay of 6 days. The annual cost saved due to serious injury was $3,765 and the annual net cost of running this program was $33,735. The estimated cost per offence prevented, cost per serious injury avoided, and cost per undiscounted and discounted life year gained were $3,124, $42,169, $8,268 and $17,910, respectively. Increasing the frequency of the program from once per month to once per week would increase its cost-effectiveness substantially. CONCLUSIONS: The P.A.R.T.Y. injury education program involving real-life trauma scenarios was cost effective in reducing subsequent risk of committing violence or traffic-related offences, injuries, and death for juvenile justice offenders in Western Australia. PMID- 22929005 TI - Indehiscent sporangia enable the accumulation of local fern diversity at the Qinghai-Tibetan Plateau. AB - BACKGROUND: Indehiscent sporangia are reported for only a few of derived leptosporangiate ferns. Their evolution has been likely caused by conditions in which promotion of self-fertilization is an evolutionary advantageous strategy such as the colonization of isolated regions and responds to stressful habitat conditions. The Lepisorus clathratus complex provides the opportunity to test this hypothesis because these derived ferns include specimens with regular dehiscent and irregular indehiscent sporangia. The latter occurs preferably in well-defined regions in the Himalaya. Previous studies have shown evidence for multiple origins of indehiscent sporangia and the persistence of populations with indehiscent sporangia at extreme altitudinal ranges of the Qinghai-Tibetan Plateau (QTP). RESULTS: Independent phylogenetic relationships reconstructed using DNA sequences of the uniparentally inherited chloroplast genome and two low copy nuclear genes confirmed the hypothesis of multiple origins of indehiscent sporangia and the restriction of particular haplotypes to indehiscent sporangia populations in the Lhasa and Nyingchi regions of the QTP. In contrast, the Hengduan Mountains were characterized by high haplotype diversity and the occurrence of accessions with and without indehiscent sporangia. Evidence was found for polyploidy and reticulate evolution in this complex. The putative case of chloroplast capture in the Nyingchi populations provided further evidence for the promotion of isolated but persistent populations by indehiscent sporangia. CONCLUSIONS: The presented results confirmed the hypothesis that indehiscent sporangia promote the establishment of persistent population in different regions of the QTP. These results are consistent with the expectations of reproductive reassurance by promotion of self-fertilization that played a critical role in the assembly of populations in isolated locations and/or extreme habitats. PMID- 22929006 TI - Current immunity markers in insect ecological immunology: assumed trade-offs and methodological issues. AB - The field of ecological immunology currently relies on using a number of immune effectors or markers. These markers are usually used to infer ecological trade offs (via conflicts in resource allocation), though physiological nature of these markers remains elusive. Here, we review markers frequently used in insect evolutionary ecology research: cuticle darkening, haemocyte density, nodule/capsule formation, phagocytosis and encapsulation/melanization via use of nylon filaments and beads, phenoloxidase activity, nitric oxide production, lysozyme and antimicrobial peptide production. We also provide physiologically based information that may shed light on the probable trade-offs inferred when these markers are used. In addition, we provide a number of methodological suggestions to improve immune marker assessment. PMID- 22929007 TI - Social-cognitive correlates of fruit and vegetable consumption in minority and non-minority youth. AB - OBJECTIVE: Inadequate fruit and vegetable (FV) consumption signals a need for identifying predictors and correlates of intake, particularly in diverse adolescents. DESIGN: Participants completed an on-line assessment in early 2010. SETTING: Computer classrooms in 4 high schools. PARTICIPANTS: One hundred twenty two Caucasian and 125 minority (African American and Hispanic) high school students (mean age = 15.3 years, SD = 1.0) with parental consent. Response rate was 89%. VARIABLES MEASURED: Self-efficacy as measured by confidence in goal setting and decision making about healthful eating; perceived benefits and barriers to eating FVs; healthful eating-related social support; body esteem; and FV intake. ANALYSIS: t tests were used to examine group differences, and binary logistic regression analyses were conducted to explore the predictors of 5-A-Day FV consumption. RESULTS: Thirty-four percent of the non-minority group and 28% of the minority group reported eating 5 or more portions of FVs a day (P = .34). Self-efficacy and perceived benefits predicted consumption in minority participants, whereas barriers and social support were significant predictors in the non-minority group. CONCLUSIONS AND IMPLICATIONS: These findings suggest different variables predict consumption for minority and non-minority groups and that self-efficacy is an important variable to consider in dietary change programs for minority adolescents. PMID- 22929009 TI - Arthroscopic suture fixation for avulsion fractures in the tibial attachment of the posterior cruciate ligament. AB - PURPOSE: The purpose of the study was to highlight our surgical technique of arthroscopic suture fixation for acute tibial eminence posterior cruciate ligament (PCL) avulsion fractures, clinical and radiographic outcomes, and complication rates. METHODS: This prospective study enrolled patients who had undergone arthroscopic reduction and suture fixation by use of 4 No. 5 Ethibond sutures (Ethicon, Somerville, NJ) for image-proven displaced PCL attachment fractures of the tibial eminence with posterior knee instability of grade II or higher. The mean follow-up period was 36 months (range, 24 to 45 months). Follow up assessment included 3 different functional scores, KT-1000 arthrometry (MEDmetric, San Diego, CA), and radiographic evaluation. RESULTS: The mean preoperative Lysholm score in the 36 patients was 35 (range, 26 to 55); the mean postoperative Lysholm score was 95 (range, 80 to 100). The mean preinjury and preoperative Tegner scores in the 36 patients were 7.4 +/- 1.6 (range, 5 to 9) and 3.2 +/- 1.5 (range, 2 to 5), respectively. The mean postoperative Tegner score was 7.0 +/- 1.8 (range, 5 to 9). At the final follow-up, the International Knee Documentation Committee scores were observed to be normal (grade A) or nearly normal (grade B) in 33 patients (91.7%) and abnormal (grade C) in 3 patients (8.3%). All 36 fractures achieved union within 3 months. No significant complications such as arthrofibrosis, loss of initial fixation, or wound infection were noted. CONCLUSIONS: Treatment of tibial PCL avulsion fractures by arthroscopic suture fixation is a successful technique to restore tibial avulsion injuries of the PCL with well-documented radiographic healing, good clinical outcomes, and low complication rates. LEVEL OF EVIDENCE: Level IV, therapeutic case series. PMID- 22929010 TI - Bad milk, part 1: antique doctrines that impeded breastfeeding. PMID- 22929008 TI - Quantum dots: synthesis, bioapplications, and toxicity. AB - This review introduces quantum dots (QDs) and explores their properties, synthesis, applications, delivery systems in biology, and their toxicity. QDs are one of the first nanotechnologies to be integrated with the biological sciences and are widely anticipated to eventually find application in a number of commercial consumer and clinical products. They exhibit unique luminescence characteristics and electronic properties such as wide and continuous absorption spectra, narrow emission spectra, and high light stability. The application of QDs, as a new technology for biosystems, has been typically studied on mammalian cells. Due to the small structures of QDs, some physical properties such as optical and electron transport characteristics are quite different from those of the bulk materials. PMID- 22929011 TI - Epigenetic mechanisms regulate the prostaglandin E receptor 2 in breast cancer. AB - The increase in local oestrogen production seen in oestrogen receptor positive (ER+) breast cancers is driven by increased activity of the aromatase enzyme. CYP19A1, the encoding gene for aromatase, is often overexpressed in the oestrogen producing cells of the breast adipose fibroblasts (BAFs) surrounding an ER+ tumour, and the molecular processes underlying this upregulation is important in the development of breast-specific aromatase inhibitors for breast cancer therapy. Prostaglandin E2 (PGE2), a factor secreted by tumours, is known to stimulate CYP19A1 expression in human BAFs. The hormonal regulation of this process has been examined; however, what is less well understood is the emerging role of epigenetic mechanisms and how they modulate PGE2 signalling. This present study characterises the epigenetic processes underlying expression of the prostanoid receptor EP2 in the context of ER+ breast cancer. Sodium bisulphite sequencing of CpG methylation within the promoter region of EP2 revealed that an inverse correlation existed between methylation levels and relative EP2 expression in breast cancer cell lines MDA-MB-231, MCF7 and MCF10A but not in HS578t and T47D. Inhibition of DNA methylation with 5-aza-2'-deoxycytidine (5aza) and histone deacetylation with Trichostatin A (TSA) resulted in upregulation of EP2 mRNA in all cell lines with varying influences of each epigenetic process observed. Expression of EP2 was detected in human BAFs despite a natively methylated promoter, and this expression was further increased upon 5aza treatment. An examination of 3 triple negative, 3 ductal carcinoma in situ and 3 invasive ductal carcinoma samples revealed that there was no change in EP2 promoter methylation status between normal and cancer associated stroma, despite observed differences in relative mRNA levels. Although EP2 methylation status is inversely correlated to expression levels in established breast cancer cell lines, we could not identify that such a correlation existed in tumour-associated stroma cells. PMID- 22929012 TI - Unintentional poisoning in young children: does developmental stage predict the type of substance accessed and ingested? AB - BACKGROUND: When children aged 0-4 years are analysed together as a group for poisoning risk, important differences for smaller age intervals by medicinal and non-medicinal substances are masked. These differences have been attributed to child developmental stages but no studies have been conducted that examine the predictive value of child developmental stage for poisoning by substance type, using 3-month age intervals as a proxy for developmental stage and adjusting for the effect of sex, socio-economic status and remoteness of residence. METHODS: A population-based dataset of unintentional poisoning hospitalizations in children aged 0-4 years was used to predict the type of substance ingested. Associations between the type of substance and age, sex, socio-economic status and remoteness of residence were measured using multivariate logistic regression. RESULTS: Children aged 12-17 months had significantly higher odds of experiencing a non medicinal poisoning while children aged 24-41 months had significantly higher odds of experiencing a medicinal poisoning. Males and children from more disadvantaged and outer regional areas had higher odds of experiencing a non medicinal poisoning. CONCLUSIONS: Children aged 0-4 years differ in their stage of development and as a consequence, vary significantly in their ability to access their environment. Our results clearly show that odds of poisoning by medicinal substances compared with non-medicinal substances change as children age. This study provides evidence that child development predicts the type of substance accessed and ingested. PMID- 22929013 TI - The regulation and packaging of synaptic vesicles as related to recruitment within glutamatergic synapses. AB - The reserve pool (RP) and readily releasable pool (RRP) of synaptic vesicles within presynaptic nerve terminals, at crayfish and larval Drosophila neuromuscular junctions (NMJs), were examined for physiological differentiation into distinctly separate functional groups. These NMJs are glutamatergic and produce graded excitatory postsynaptic potentials (EPSPs). The packaging of glutamate was perturbed by blocking the vesicular glutamate transporter (VGlut) with bafilomycin A1. Various frequencies of motor nerve stimulation, exposure time, and concentration of bafilomycin A1 were examined. The low-output tonic opener NMJs in crayfish exposed to 4 MUM bafilomycin A1 and 20-Hz continuous stimulation decreased the EPSP amplitude to 50% in ~30 min with controls lasting 3h. After activity and bafilomycin A1-induced synaptic depression, the EPSPs were rapidly revitalized by serotonin (5-HT, 1 MUM) in the crayfish preparations. The 5-HT action can be blocked with a PLC inhibitor. We postulate 5-HT recruits unused vesicles from the RP. The perception is the RRP is selectively activated during rapid electrical stimulation (20 Hz) sparing the RP. When stimulation frequency is high (40 Hz) the RP is recruited to the RRP and dampens subsequent recruitment with 5-HT. The higher output synapses of the larval Drosophila NMJ when stimulated at 1 Hz or 5 Hz and exposed to 4 MUM of bafilomycin A1 showed a depression rate of 50% within ~10 min with controls lasting ~40 min. After low frequency depression and/or exposure to bafilomycin A1 a burst of higher frequency (10 Hz) can recruit vesicles from the RP to the RRP. PMID- 22929014 TI - Prognosis of breast cancer is associated with one-carbon metabolism related nutrients among Korean women. AB - BACKGROUND: The 5-year survival rate for breast cancer among Korean women has increased steadily; however, breast cancer remains the leading cause of cancer mortality among women. One-carbon metabolism, which requires an adequate supply of methyl group donors and B vitamins, may affect the prognosis of breast cancer. This aim of this study was to investigate the associations of dietary intake of vitamin B2, vitamin B6 and folate before diagnosis on the prognosis of breast cancer. METHODS: We assessed the dietary intake using a food frequency questionnaire with 980 women who were newly diagnosed and histopathologically confirmed to have primary breast cancer from hospitals in Korea, and 141 disease progression events occurred. Cox's proportional hazard regression models were used to estimate the hazard ratio (HR) and 95% confidence interval (95% CI) adjusting for age, education, recruitment sites, TNM stage, hormone status, nuclear grade and total calorie. RESULTS: There was no significant association between any one-carbon metabolism related nutrients (vitamin B2, B6 and folate) and the progression of breast cancer overall. However, one-carbon metabolism related nutrients were associated with disease progression in breast cancer patients stratified by subtypes. In ER + and/or PR + breast cancers, no association was observed; however, in ER-/PR- breast cancers, a high intake of vitamin B2 and folate statistically elevated the HR of breast cancer progression (HR = 2.28; 95% CI, 1.20-4.35, HR = 1.84; 95% CI, 1.02-3.32, respectively) compared to a low intake. This positive association between the ER/PR status and progression of the disease was profound when the nutrient intakes were categorized in a combined score (Pinteraction = 0.018). In ER-/PR- breast cancers, high combined scores were associated with a significantly poor DFS compared to those belonging to the low score group (HR = 3.84; 95% CI, 1.70 8.71). CONCLUSIONS: In conclusion, our results suggest that one-carbon related nutrients have a role in the prognosis of breast cancer depending on the ER/PR status. PMID- 22929015 TI - Primary care management for optimized antithrombotic treatment [PICANT]: study protocol for a cluster-randomized controlled trial. AB - BACKGROUND: Antithrombotic treatment is a continuous therapy that is often performed in general practice and requires careful safety management. The aim of this study is to investigate whether a best-practice model that applies major elements of case management and patient education, can improve antithrombotic management in primary healthcare in terms of reducing major thromboembolic and bleeding events. METHODS: This 24-month cluster-randomized trial will be performed with 690 adult patients from 46 practices. The trial intervention will be a complex intervention involving general practitioners, healthcare assistants, and patients with an indication for oral anticoagulation. To assess adherence to medication and symptoms in patients, as well as to detect complications early, healthcare assistants will be trained in case management and will use the Coagulation-Monitoring List (Co-MoL) to regularly monitor patients. Patients will receive information (leaflets and a video), treatment monitoring via the Co-MoL and be motivated to perform self-management. Patients in the control group will continue to receive treatment as usual from their general practitioners. The primary endpoint is the combined endpoint of all thromboembolic events requiring hospitalization and all major bleeding complications. Secondary endpoints are mortality, hospitalization, strokes, major bleeding and thromboembolic complications, severe treatment interactions, the number of adverse events, quality of anticoagulation, health-related quality of life, and costs. Further secondary objectives will be investigated to explain the mechanism by which the intervention is effective: patients' assessment of chronic illness care, self reported adherence to medication, general practitioners' and healthcare assistants' knowledge, and patients' knowledge and satisfaction with shared decision making. Practice recruitment is expected to take place between July and December 2012. Recruitment of eligible patients will start in July 2012. Assessment will occur at three time points: baseline and follow-up after 12 months and after 24 months. DISCUSSION: The efficacy and effectiveness of individual elements of the intervention, such as antithrombotic interventions, self-management concepts in orally anticoagulated patients, and the methodological tool of case management, have already been extensively demonstrated. This project foresees the combination of several proven instruments, as a result of which we expect to profit from a reduction in the major complications associated with antithrombotic treatment. PMID- 22929016 TI - Murine colon proteome and characterization of the protein pathways. AB - BACKGROUND: Most of the current proteomic researches focus on proteome alteration due to pathological disorders (i.e.: colorectal cancer) rather than normal healthy state when mentioning colon. As a result, there are lacks of information regarding normal whole tissue- colon proteome. RESULTS: We report here a detailed murine (mouse) whole tissue- colon protein reference dataset composed of 1237 confident protein (FDR < 2) with comprehensive insight on its peptide properties, cellular and subcellular localization, functional network GO annotation analysis, and its relative abundances. The presented dataset includes wide spectra of pI and Mw ranged from 3-12 and 4-600 KDa, respectively. Gravy index scoring predicted 19.5% membranous and 80.5% globularly located proteins. GO hierarchies and functional network analysis illustrated proteins function together with their relevance and implication of several candidates in malignancy such as Mitogen- activated protein kinase (Mapk8, 9) in colorectal cancer, Fibroblast growth factor receptor (Fgfr 2), Glutathione S-transferase (Gstp1) in prostate cancer, and Cell division control protein (Cdc42), Ras-related protein (Rac1,2) in pancreatic cancer. Protein abundances calculated with 3 different algorithms (NSAF, PAF and emPAI) provide a relative quantification under normal condition as guidance. CONCLUSIONS: This highly confidence colon proteome catalogue will not only serve as a useful reference for further experiments characterizing differentially expressed proteins induced from diseased conditions, but also will aid in better understanding the ontology and functional absorptive mechanism of the colon as well. PMID- 22929017 TI - The use of rehabilitation among patients with breast cancer: a retrospective longitudinal cohort study. AB - BACKGROUND: Breast cancer is the most common malignancy in women. Along with improvements in treatment, the number of women who survive breast cancer has increased. Rehabilitation can alleviate post-treatment side effects and maintain quality of life. This study aimed to explore the use of rehabilitation among a cohort of patients diagnosed with breast cancer. METHODS: A retrospective longitudinal cohort study was conducted using a National Health Insurance (NHI) research database in Taiwan. The study cohort consisted of 632 patients with breast cancer diagnosed in 2005. Their NHI claims over a period spanning 2005 through 2009 were analyzed. RESULTS: Overall, 39.6% of the cohort received rehabilitation therapy, with 9,691 rehabilitation visits claimed (an average of 38.8 visits per user). The prevalence of rehabilitation service use among the cohort was 16.5%, 13.3%, 13.0%, 13.3%, and 12.8% in the years 2005 through 2009, respectively. The average number of visits per rehabilitation user was 16.8, 25.0, 31.1, 24.2, and 23.8 in the years 2005 through 2009, respectively. Most rehabilitation therapy occurred as an outpatient service (96.0%). Physical therapy was the most commonly used form of rehabilitation (84.2%), followed by occupational therapy (15.4%). The most frequently recorded diagnoses were malignant neoplasm of the female breast, peripheral enthesopathies and allied syndromes, and osteoarthrosis and allied disorders. CONCLUSIONS: Only a small proportion of patients with breast cancer received rehabilitation therapy in the first five years after diagnosis. The average number of rehabilitation visits per user peaked in the third year after diagnosis. PMID- 22929018 TI - Trends in reproductive health in Israel: implications for environmental health policy. AB - Nearly two decades ago, researchers first reported that endocrine disrupting chemicals in the environment were affecting reproductive health in the general population. The purpose of this article is to examine the evidence of adverse reproductive health trends in Israel and to explore implications for environmental health policy in Israel. We reviewed studies and data in Israel regarding trends in reproductive health indices, specifically: breast and testis cancer, hypospadias, sperm quality, male factor infertility, and age at menarche. The data provide some evidence of adverse reproductive trends in the Israeli population: an increase in testicular cancer from 1990 to 2007, a decrease in age at menarche from 1986 to 2000, an increase in the prevalence of male factor infertility, and some evidence of decreasing sperm counts. However, we note that much of the evidence is limited.The policy implications of reported adverse reproductive health trends possibly related to environmental exposure have been radically different in Europe and the United States. In Europe, such reports led the Parliament of the European Community to adopt a resolution on endocrine disruptors, which emphasizes the application of the Precautionary Principle. U.S. Environmental Protection Agency policy is focused on screening chemicals for endocrine disrupting properties and does not specifically refer to the Precautionary Principle. To date, there has been no formal governmental policy or strategy in Israel regarding endocrine disrupting chemicals. Environmental health policy on endocrine disruptors requires integrating evidence on human reproductive health trends, evidence on adverse reproductive outcomes in wildlife and experimental systems, and data from biomonitoring studies. Despite gaps in evidence and current data, we support a precautionary approach to regulating potential endocrine disrupting chemicals and reducing public exposures, especially in sensitive groups such as children and pregnant women. PMID- 22929019 TI - A role for vimentin in Crohn disease. AB - Crohn disease (CD), one of the major chronic inflammatory bowel diseases, occurs anywhere in the gastrointestinal tract with discontinuous transmural inflammation. A number of studies have now demonstrated that genetic predisposition, environmental influences and a dysregulated immune response to the intestinal microflora are involved. Major CD susceptibility pathways uncovered through genome-wide association studies strongly implicate the innate immune response (NOD2), in addition to the more specific acquired T cell response (IL23R, ICOSLG) and autophagy (ATG16L1, IRGM). Examination of the disease associated microbiome, although complex, has identified several potentially contributory microorganisms, most notably adherent-invasive E.coli strains (AIEC), which have been isolated by independent investigators in both adult and pediatric CD patients. Here we discuss our recent finding that the type-III intermediate filament (IF) protein VIM/vimentin is a novel NOD2 interacting protein that regulates NOD2 activities including inflammatory NFKB1 signaling, autophagy and bacterial handling. PMID- 22929021 TI - An even more universal model of reading: various effects of orthography on dyslexias. AB - The properties of a specific orthography dictate the way people read it. We bring considerations from dyslexia to suggest that the claim can be extended further. First, the effect of orthographic neighborhood density can be extended beyond letter-position encoding and beyond the orthographic lexicon. Second, Hebrew and Arabic differ with respect to letter forms, and hence, in letter-position encoding. PMID- 22929020 TI - Mathematical modelling of the action potential of human embryonic stem cell derived cardiomyocytes. AB - BACKGROUND: Human embryonic stem cell derived cardiomyocytes (hESC-CMs) hold high potential for basic and applied cardiovascular research. The development of a reliable simulation platform able to mimic the functional properties of hESC-CMs would be of considerable value to perform preliminary test complementing in vitro experimentations. METHODS: We developed the first computational model of hESC-CM action potential by integrating our original electrophysiological recordings of transient-outward, funny, and sodium-calcium exchanger currents and data derived from literature on sodium, calcium and potassium currents in hESC-CMs. RESULTS: The model is able to reproduce basal electrophysiological properties of hESC-CMs at 15 40 days of differentiation (Early stage). Moreover, the model reproduces the modifications occurring through the transition from Early to Late developmental stage (50-110, days of differentiation). After simulated blockade of ionic channels and pumps of the sarcoplasmic reticulum, Ca2+ transient amplitude was decreased by 12% and 33% in Early and Late stage, respectively, suggesting a growing contribution of a functional reticulum during maturation. Finally, as a proof of concept, we tested the effects induced by prototypical channel blockers, namely E4031 and nickel, and their qualitative reproduction by the model. CONCLUSIONS: This study provides a novel modelling tool that may serve useful to investigate physiological properties of hESC-CMs. PMID- 22929022 TI - Genetic perspectives on the origin of clicks in Bantu languages from southwestern Zambia. AB - Some Bantu languages spoken in southwestern Zambia and neighboring regions of Botswana, Namibia, and Angola are characterized by the presence of click consonants, whereas their closest linguistic relatives lack such clicks. As clicks are a typical feature not of the Bantu language family, but of Khoisan languages, it is highly probable that the Bantu languages in question borrowed the clicks from Khoisan languages. In this paper, we combine complete mitochondrial genome sequences from a representative sample of populations from the Western Province of Zambia speaking Bantu languages with and without clicks, with fine-scaled analyses of Y-chromosomal single nucleotide polymorphisms and short tandem repeats to investigate the prehistoric contact that led to this borrowing of click consonants. Our results reveal complex population-specific histories, with female-biased admixture from Khoisan-speaking groups associated with the incorporation of click sounds in one Bantu-speaking population, while concomitant levels of potential Khoisan admixture did not result in sound change in another. Furthermore, the lack of sequence sharing between the Bantu-speaking groups from southwestern Zambia investigated here and extant Khoisan populations provides an indication that there must have been genetic substructure in the Khoisan-speaking indigenous groups of southern Africa that did not survive until the present or has been substantially reduced. PMID- 22929024 TI - A novel locus for autosomal dominant cone-rod dystrophy maps to chromosome 10q. AB - Here we report recruitment of a three-generation Romani (Gypsy) family with autosomal dominant cone-rod dystrophy (adCORD). Involvement of known adCORD genes was excluded by microsatellite (STR) genotyping and linkage analysis. Subsequently, two independent total-genome scans using STR markers and single nucleotide polymorphisms (SNPs) were performed. Haplotype analysis revealed a single 6.7-Mb novel locus between markers D10S1757 and D10S1782 linked to the disease phenotype on chromosome 10q26. Linkage analysis gave a maximum LOD score of 3.31 for five fully informative STR markers within the linked interval corresponding to the expected maximum in the family. Multipoint linkage analysis of SNP genotypes yielded a maximum parametric linkage score of 2.71 with markers located in the same chromosomal interval. There is no previously mapped CORD locus in this interval, and therefore the data reported here is novel and likely to identify a new gene that may eventually contribute to new knowledge on the pathogenesis of this condition. Sequencing of several candidate genes within the mapped interval led to negative findings in terms of the underlying molecular pathogenesis of the disease in the family. Analysis by comparative genomic hybridization excluded large chromosomal aberrations as causative of adCORD in the pedigree. PMID- 22929023 TI - Rare DNA copy number variants in cardiovascular malformations with extracardiac abnormalities. AB - Clinically significant cardiovascular malformations (CVMs) occur in 5-8 per 1000 live births. Recurrent copy number variations (CNVs) are among the known causes of syndromic CVMs, accounting for an important fraction of cases. We hypothesized that many additional rare CNVs also cause CVMs and can be detected in patients with CVMs plus extracardiac anomalies (ECAs). Through a genome-wide survey of 203 subjects with CVMs and ECAs, we identified 55 CNVs >50 kb in length that were not present in children without known cardiovascular defects (n=872). Sixteen unique CNVs overlapping these variants were found in an independent CVM plus ECA cohort (n=511), which were not observed in 2011 controls. The study identified 12/16 (75%) novel loci including non-recurrent de novo 16q24.3 loss (4/714) and de novo 2q31.3q32.1 loss encompassing PPP1R1C and PDE1A (2/714). The study also narrowed critical intervals in three well-recognized genomic disorders of CVM, such as the cat-eye syndrome region on 22q11.1, 8p23.1 loss encompassing GATA4 and SOX7 and 17p13.3-p13.2 loss. An analysis of protein-interaction databases shows that the rare inherited and de novo CNVs detected in the combined cohort are enriched for genes encoding proteins that are direct or indirect partners of proteins known to be required for normal cardiac development. Our findings implicate rare variants such as 16q24.3 loss and 2q31.3-q32.1 loss, and delineate regions within previously reported structural variants known to cause CVMs. PMID- 22929025 TI - A rare variant in the osteoarthritis-associated locus GDF5 is functional and reveals a site that can be manipulated to modulate GDF5 expression. AB - Osteoarthritis (OA) is a polygenic disease characterized by cartilage loss, with the single-nucleotide polymorphism (SNP) rs143383 (C/T) influencing OA susceptibility across a range of ethnic groups. The SNP resides within the 5'-UTR of the growth and differentiation factor 5 gene (GDF5), with the OA-associated T allele mediating reduced GDF5 expression. As GDF5 codes for a cartilage anabolic protein, this reduced expression may explain why the T-allele of rs143383 is an OA risk factor. Our deep sequencing of GDF5 identified a C/A transversion located -41 bp relative to the gene's transcription start site. This promoter variant is predicted to affect transcription factor binding and it may therefore highlight a regulatory site that could be exploited to manipulate GDF5 expression and alleviate the detrimental effect mediated by the T-allele of rs143383. Here, we describe our functional assessment of the -41 bp variant. Using reporter constructs we demonstrated that the transversion leads to increased gene expression to such a degree that the A-allele is able to compensate for the reduced expression mediated by the T-allele of rs143383. Using electrophoretic mobility shift assays we identified YY1 as a trans-acting factor that differentially binds to the alleles of the -41 bp variant, with more avid binding to allele A. Knockdown of YY1 led to a significant reduction in GDF5 expression, supporting YY1 as a GDF5 activator. In conclusion, we demonstrated that the -41 bp variant is functional and we have identified a regulatory region of GDF5 that can be exploited to overcome the OA genetic deficit mediated by the T-allele of rs143383. PMID- 22929026 TI - WikiGWA: an open platform for collecting and using genome-wide association results. AB - The number of discovered genetic variants from genome-wide association (GWA) studies (GWAS) has been growing rapidly. Centralized efforts such as the National Human Genome Research Institute's GWAS catalog provide regular updates and a convenient interface for quick lookup. However, the catalog entries are manually curated and rely on data from published articles. Other tools such as SNPedia (http://www.snpedia.com) collect published results regarding functional consequences of genetic variations. Here, we propose an approach that allows individual investigators to share their GWA results through an open platform. Unlike GWAS catalog or SNPedia, wikiGWA collects first-hand GWAS results and in a much larger scale. Investigators are not only able to post a much larger amount of results, but also post results from unpublished studies, which could alleviate publication bias and facilitate identification of weak signals. Our interface allows for flexible and fast queries, and the query results are formatted to work seamlessly with the LocusZoom program for visualization and annotation. We here describe wikiGWA, made publically available at http://www.wikiGWA.org. PMID- 22929027 TI - The frequency of an IL-18-associated haplotype in Africans. AB - Variation within the gene for the proinflammatory cytokine interleukin (IL)-18 has been associated with inter-individual differences in levels of free protein and disease risk. We investigated the frequency of function-associated IL18 gene haplotypes in an extensive sample (n=2357) of African populations from across the continent. A previously identified five tagging SNP (single-nucleotide polymorphism) haplotype (here designated hGTATA), known to be associated with lower levels of IL-18, was observed at a frequency of 27% in a British population of recent European ancestry, but was found at low frequency (<8%) or completely absent in African populations. Potentially protective variants may, as a consequence, be found at low frequency in African individuals and may confer a difference in disease risk. PMID- 22929028 TI - AKT1 fails to replicate as a longevity-associated gene in Danish and German nonagenarians and centenarians. AB - In addition to APOE and FOXO3, AKT1 has recently been suggested as a third consistent longevity gene, with variants in AKT1 found to be associated with human lifespan in two previous studies. Here, we evaluated AKT1 as a longevity associated gene across populations by attempting to replicate the previously identified variant rs3803304 as well as by analyzing six additional AKT1 single nucleotide polymorphisms, thus capturing more of the common variation in the gene. The study population was 2996 long-lived individuals (nonagenarians and centenarians) and 1840 younger controls of Danish and German ancestry. None of the seven SNPs tested were significantly associated with longevity in either a case-control or a longitudinal setting, although a supportive nominal indication of a disadvantageous effect of rs3803304 was found in a restricted group of Danish centenarian men. Overall, our results do not support AKT1 as a universal longevity-associated gene. PMID- 22929029 TI - Dilution of candidates: the case of iron-related genes in restless legs syndrome. AB - Restless legs syndrome (RLS) is a common multifactorial disease. Some genetic risk factors have been identified. RLS susceptibility also has been related to iron. We therefore asked whether known iron-related genes are candidates for association with RLS and, vice versa, whether known RLS-associated loci influence iron parameters in serum. RLS/control samples (n = 954/1814 in the discovery step, 735/736 in replication 1, and 736/735 in replication 2) were tested for association with SNPs located within 4 Mb intervals surrounding each gene from a list of 111 iron-related genes using a discovery threshold of P = 5 * 10(-4). Two population cohorts (KORA F3 and F4 with together n = 3447) were tested for association of six known RLS loci with iron, ferritin, transferrin, transferrin saturation, and soluble transferrin receptor. Results were negative. None of the candidate SNPs at the iron-related gene loci was confirmed significantly. An intronic SNP, rs2576036, of KATNAL2 at 18q21.1 was significant in the first (P = 0.00085) but not in the second replication step (joint nominal P-value = 0.044). Especially, rs1800652 (C282Y) in the HFE gene did not associate with RLS. Moreover, SNPs at the known RLS loci did not significantly affect serum iron parameters in the KORA cohorts. In conclusion, the correlation between RLS and iron parameters in serum may be weaker than assumed. Moreover, in a general power analysis, we show that genetic effects are diluted if they are transmitted via an intermediate trait to an end-phenotype. Sample size formulas are provided for small effect sizes. PMID- 22929030 TI - Connective tissue spectrum abnormalities associated with spontaneous cerebrospinal fluid leaks: a prospective study. AB - We aimed to assess the frequency of connective tissue abnormalities among patients with cerebrospinal fluid (CSF) leaks in a prospective study using a large cohort of patients. We enrolled a consecutive group of 50 patients, referred for consultation because of CSF leak. All patients have been carefully examined for the presence of connective tissue abnormalities, and based on findings, patients underwent genetic testing. Ancillary diagnostic studies included echocardiography, eye exam, and histopathological examinations of skin and dura biopsies in selected patients. We identified nine patients with heritable connective tissue disorders, including Marfan syndrome, Ehlers-Danlos syndrome and other unclassified forms. In seven patients, spontaneous CSF leak was the first noted manifestation of the genetic disorder. We conclude that spontaneous CSF leaks are associated with a spectrum of connective tissue abnormalities and may be the first noted clinical presentation of the genetic disorder. We propose that there is a clinical basis for considering spontaneous CSF leak as a clinical manifestation of heritable connective tissue disorders, and we suggest that patients with CSF leaks should be screened for connective tissue and vascular abnormalities. PMID- 22929032 TI - Endemic human blastomycosis in Quebec, Canada, 1988-2011. AB - Blastomycosis is a systemic fungal infection found in various parts of the world. A review of literature for Quebec, Canada revealed only few case reports with the most recent one dating back to 1993. However, whether Quebec represents an important endemic region for blastomycosis in North America is unknown. In this work we reviewed 158 cases of human blastomycosis documented in Quebec during 1988-2011 using microbiological records available from the provincial public health laboratory. The estimated annual incidence of blastomycosis in the province is was ~0.133 cases per 100 000 individuals with the highest rates of 0.79 and 0.46 cases per 100 000 recorded in South-eastern and South-western Quebec. Moreover, the annual incidence rate significantly increased over the past 20 years. This study for the first time establishes Quebec as an important endemic region for Blastomyces dermatitidis. PMID- 22929031 TI - Maternal ABCA1 genotype is associated with severity of Smith-Lemli-Opitz syndrome and with viability of patients homozygous for null mutations. AB - The Smith-Lemli-Opitz syndrome (SLOS [MIM 270400]) is an autosomal recessive malformation syndrome that shows a great variability with regard to severity. SLOS is caused by mutations in the Delta7sterol-reductase gene (DHCR7), which disrupt cholesterol biosynthesis. Phenotypic variability of the disease is already known to be associated with maternal apolipoprotein E (ApoE) genotype. The aim of this study was to detect additional modifiers of the SLOS phenotype. We examined the association of SLOS severity with variants in the genes for ApoC III, lecithin-cholesterol acyltransferase, cholesteryl-ester transfer protein, ATP-binding cassette transporter A1 (ABCA1), and methylene tetrahydrofolate reductase. Our study group included 59 SLOS patients, their mothers, and 49 of their fathers. In addition, we investigated whether ApoE and ABCA1 genotypes are associated with the viability of severe SLOS cases (n=21) caused by two null mutations in the DHCR7 gene. Maternal ABCA1 genotypes show a highly significant correlation with clinical severity in SLOS patients (P=0.007). The rare maternal p.1587Lys allele in the ABCA1 gene was associated with milder phenotypes. ANOVA analysis demonstrated an association of maternal ABCA1 genotypes with severity scores (logarithmised) of SLOS patients of P=0.004. Maternal ABCA1 explains 15.4% (R2) of severity of SLOS patients. There was no association between maternal ApoE genotype and survival of the SLOS fetus carrying two null mutations. Regarding ABCA1 p.Arg1587Lys in mothers of latter SLOS cases, a significant deviation from Hardy-Weinberg equilibrium (HWE) was observed (P=0.005). ABCA1 is an additional genetic modifier in SLOS. Modifying placental cholesterol transfer pathways may be an approach for prenatal therapy of SLOS. PMID- 22929033 TI - Oophorectomy: the debate between ovarian conservation and elective oophorectomy. AB - Ovarian cancer remains the fifth deadliest cancer among women because of its early asymptomatic nature and lack of efficacious screening methods, leading to frequent late-stage diagnosis. Elective oophorectomy is an option for women undergoing benign hysterectomy as a means of reducing their ovarian cancer risk. Benefits also include reduced risk of repeat surgical operation due to adnexal masses and reduced anxiety related to perceived risk of ovarian and breast cancer. The potential negative side effects of elective oophorectomy, such as decreased cognition and sexual function and increased risk of osteoporosis and cardiac mortality, offer support for ovarian conservation. The implications of this elective procedure and the possible consequences without it require physicians to review the pros and cons with patients in light of the patient's individual circumstances and ovarian cancer risk. PMID- 22929034 TI - Midlife women: symptoms associated with menopausal transition and early postmenopause and quality of life. AB - OBJECTIVE: The objectives of this study were to examine the effects of symptoms associated with the menopausal transition and early postmenopause on quality of life and to determine if there is a clustering of symptoms that has a larger effect on quality of life than individual symptoms. METHODS: This study used data from a cross-sectional study on women aged 45 to 60 years. Descriptive statistics and regression analyses were used to analyze the data. RESULTS: More than 60% of the participants reported three or more symptoms. The symptom clusters that had the highest impact on quality of life were sleep disturbances and vaginal dryness, which accounted for 9.7% of the variance in quality-of-life scores. A parsimonious model of individual symptoms, including sleep disturbances, fatigue, and anxiety, accounted for 16.7% of the variance in quality of life. This group of symptoms, not represented by a cluster, had the highest impact on quality of life. CONCLUSIONS: The symptoms found to most significantly affect quality of life are sleep disturbances, fatigue, and anxiety, suggesting that appropriate management of sleep disorders and anxiety may be beneficial to women undergoing the transition to postmenopause. Unanticipated clusters of symptoms point toward a unique symptom experience influenced by factors other than a decline in ovarian function. In this study, symptoms commonly associated with the menopausal transition and early postmenopause negatively affect quality of life; however, the results indicate that quality of life in midlife women is affected by these symptoms only to a small extent. PMID- 22929035 TI - Cross-cultural study: experience, understanding of menopause, and related therapies in Australian and Laotian women. AB - OBJECTIVE: The aim of this study was to investigate and compare symptom experiences, beliefs, attitudes, and understanding of menopause and menopausal therapies in Australian and Laotian women. METHODS: This was a cross-cultural, questionnaire-based study involving 108 women (56 Australian women and 52 Laotian women aged 40-65 y) attending outpatient clinics in Australia and Laos. Descriptive statistics and univariate analysis were conducted using Student's t test or Mann-Whitney U test, where appropriate. RESULTS: Psychological symptoms, depression, vasomotor symptoms, and sexual dysfunction were significantly higher in Australian women compared with Laotian women (P < 0.05). Australian women perceived the meaning of menopause as aging (57%), whereas most Laotian women reported not knowing what menopause meant to them (81%). Australian women's fears about menopause included weight gain (43%), aging (41%), and breast cancer (38%), whereas Laotian women reported not knowing about potential menopausal problems (85%). Exercise (55%), education and awareness (46%), and improving lifestyle (41%) were reported by Australian women as being effective in alleviating menopausal symptoms, with only 21% reporting not knowing what was effective compared with 83% of Laotian women. Many women reported not knowing the risks/benefits of hormonal therapies (50% of Australian women and 87% of Laotian women) and herbal therapies (79% of Australian women and 92% of Laotian women). General practitioners were the most common source of menopause information for both Australians (73%) and Laotians (67%). CONCLUSIONS: Sociocultural factors influence women's perception of menopause. Psychological symptoms, sexual dysfunction, and vasomotor symptoms are more commonly reported by Australian women than by Laotian women. Women have a limited understanding of the risks/benefits of menopausal therapies, and culturally appropriate education is needed. PMID- 22929036 TI - Disparity in menopausal hormone therapy use between women obstetrician gynecologists and women overall: are obstetrician gynecologists underserving their patients? PMID- 22929037 TI - Premenopausal antimullerian hormone concentration is associated with subsequent atherosclerosis. AB - OBJECTIVE: The aim of this study was to determine if premenopausal ovarian reserve is associated with susceptibility for atherosclerosis. METHODS: Female cynomolgus macaques (n = 66, women's equivalent age = 45 y) consumed an atherogenic diet for ~5 months before the measurement of a marker of ovarian reserve (antimullerian hormone [AMH]), plasma lipids, follicular phase estradiol, and body weight (BW). Monkeys were then ovariectomized (OVX; n = 17), remained premenopausal (n = 20), or were induced to have reduced ovarian reserve (ROR, n = 29). After 26 additional months consuming the diet, atherosclerosis measurements and risk variables were reassessed. RESULTS: No differences in baseline AMH, plasma lipids, BW, and estradiol or postdiet lipids and BW were observed among the groups subsequently assigned to the OVX, premenopausal control, or reduced ovarian reserve conditions. Postdiet measurements of atherosclerosis extent did not differ among the groups. However, analysis of plaque size by tertile of baseline AMH revealed that plaques were largest in monkeys that began the experiment with the lowest baseline AMH, followed by those in the middle and high tertiles (plaque extent: low AMH, 0.76 +/- 0.12 mm; mid AMH, 0.46 +/- 0.1 mm; high AMH, 0.34 +/- 0.08 mm; P = 0.02). Baseline AMH and plaque size were also correlated negatively (r = -0.31, P = 0.01). Plasma lipids were also correlated significantly with plaque extent (all P < 0.01) but not with AMH. CONCLUSIONS: We report for the first time an inverse relationship between a marker of ovarian reserve (AMH) and subsequent atherosclerosis risk. PMID- 22929038 TI - Initiating therapy with antidepressants after discontinuation of hormone therapy. AB - OBJECTIVE: This work aims to determine whether discontinuation of hormone therapy (HT) in perimenopausal and postmenopausal women is associated with an increased risk of initiating antidepressant therapy. METHODS: A population-based cohort study was conducted using data from the Swedish Prescribed Drug Register and the Total Population Register for the period July 2005 to June 2009. We included women aged 45 to 70 years who had used HT continuously for more than 6 months before July 2008. Women with previous use of antidepressants since July 2005 were excluded. We compared the incidence rates of initiating antidepressant therapy during HT and after withdrawal of HT. The women were followed from July 2008 until the first dispensing of antidepressants, restart of HT, migration, death, or end of the study period, whichever occurred first. Poisson regression analysis was used to estimate the incidence rate ratios adjusting for potential confounders (age, calendar time, duration of HT use, and number of HT prescriptions). RESULTS: Of the 101,911 women enrolled in the cohort, 39.8% discontinued HT during follow-up. Discontinuation of HT was associated with an increased risk of antidepressant use (incidence rate ratio, 1.24; 95% CI, 1.11 1.38). Women 65 years or older and women who had used HT for 3 years or more had the highest risk estimates, but effect modification by age and duration was not significant. CONCLUSIONS: We found a slightly increased risk in the use of antidepressant therapy after discontinuation of HT. PMID- 22929039 TI - Larval morphology, development and forensic importance of Synthesiomyia nudiseta (Diptera: Muscidae) in Europe: a rare species or just overlooked? AB - The muscid Synthesiomyia nudiseta (van der Wulp, 1883) is a species with forensic importance in tropical and subtropical regions of the world. This fly has recently been introduced into southern Europe and, until now, had not been recorded in forensic cases in this region. Here, morphology of all larval instars of S. nudiseta is documented in detail by using a combination of light and scanning electron microscopy. Literature data concerning larval morphology are revised and characters allowing identification from other forensically important Muscidae are listed. The life cycle of this species was studied at four constant temperatures: 15, 20, 25 and 30 degrees C. Total development varied between 46.50 +/- 0.97 days at 15 degrees C and 15.39 +/- 0.32 days at 30 degrees C. Moreover, we report this species breeding in human corpses, for the first time in Europe, in forensic cases from autopsies at the Anatomical Forensic Institute of Madrid and the Institute of Legal Medicine of Alicante, Spain. PMID- 22929041 TI - Sport-related concussion: a call for evidence and perspective amidst the alarms. PMID- 22929040 TI - Cyclin D3 coordinates the cell cycle during differentiation to regulate erythrocyte size and number. AB - Genome-wide association studies (GWASs) have identified a genetic variant of moderate effect size at 6p21.1 associated with erythrocyte traits in humans. We show that this variant affects an erythroid-specific enhancer of CCND3. A Ccnd3 knockout mouse phenocopies these erythroid phenotypes, with a dramatic increase in erythrocyte size and a concomitant decrease in erythrocyte number. By examining human and mouse primary erythroid cells, we demonstrate that the CCND3 gene product cyclin D3 regulates the number of cell divisions that erythroid precursors undergo during terminal differentiation, thereby controlling erythrocyte size and number. We illustrate how cell type-specific specialization can occur for general cell cycle components-a finding resulting from the biological follow-up of unbiased human genetic studies. PMID- 22929042 TI - Effectiveness of the SLICE program for youth concussion education. AB - OBJECTIVE: To analyze the effectiveness of the Sports Legacy Institute Community Educators (SLICE) curriculum for student-athletes on recognition and appropriate responses to concussions. DESIGN: Prospective cohort study, level II. SETTING: The SLICE concussion workshop. PARTICIPANTS: All students ranging from 9 to 18 years (n = 636) taking the SLICE concussion education program. INTERVENTION: The SLICE concussion education program featuring interactive demonstrations, discussion, and case studies of athletes delivered by medical students and others in health-related fields. MAIN OUTCOME MEASURES: Evaluations assessing knowledge of concussion recognition and appropriate response were administered before and after participating in the SLICE concussion education program. RESULTS: Students displayed significant improvements in absolute mean score on the concussion knowledge quiz between prepresentation and postpresentation (P < 0.0001). Significant improvements in mean score were observed among both male and female students within each age group. The proportion of students who passed the quiz increased from 34% prepresentation to 80% postpresentation (P < 0.0001). However, the percentage who passed the quiz postpresentation was significantly higher among female students compared with male students (P < 0.0001) and among students 13 years of age or older compared with students less than 13 years (P < 0.0001). Using multivariable logistic regression, we identified age group and gender as the most significant factors associated with passing the quiz postpresentation. CONCLUSION: The SLICE program promotes effective learning and knowledge about concussion recognition and response among students ranging from 9 to 18 years. Lessons from the SLICE program may be broadly applicable to youth concussion education. PMID- 22929043 TI - Head-first impact with head protrusion causes noncontiguous injuries of the cadaveric cervical spine. AB - OBJECTIVE: To simulate horizontally aligned head-first impacts with initial head protrusion using a human cadaveric neck model and to determine biomechanical responses, injuries, and injury severity. DESIGN: Head-first impacts with initial head protrusion were simulated at 2.4 m/s using a human cadaver neck model (n = 10) mounted horizontally to a torso-equivalent mass on a sled and carrying a surrogate head. Macroscopic neck injuries were determined, and ligamentous injuries were quantified using fluoroscopy and visual inspection after the impacts. Representative time-history responses for injured specimens were determined during impact using load cell data and analyses of high-speed video. SETTING: Biomechanics research laboratory. PARTICIPANTS: Cervical spines of 10 human cadavers. MAIN OUTCOME MEASURES: Injury severity at the middle and lower cervical spine was statistically compared using a 2-sample t test (P < 0.05). RESULTS: Neck buckling consisted of hyperflexion at C6/7 and C7/T1 and hyperextension at superior spinal levels. Noncontiguous neck injuries included forward dislocation at C7/T1, spinous process fracture and compression-extension injuries at the middle cervical spine, and atlas and odontoid fractures. Ligamentous injury severity at C7/T1 was significantly greater than at the middle cervical spine. CONCLUSIONS: Distinct injury mechanisms were observed throughout the neck, consisting of extension-compression and posterior shear at the upper and middle cervical spine and flexion-compression and anterior shear at C6/7 and C7/T1. Our experimental results highlight the importance of clinical awareness of potential noncontiguous cervical spine injuries due to head-first sports impacts. PMID- 22929044 TI - Correlation of preoperative MRI and MRA with arthroscopically proven articular cartilage lesions of the elbow. AB - OBJECTIVE: The purpose of this study was to evaluate the usefulness of magnetic resonance imaging (MRI) in detecting elbow articular cartilage injuries through comparison of preoperative MRI and magnetic resonance arthrography (MRA) with arthroscopic findings. DESIGN: Retrospective case analysis. SETTING: Tertiary care orthopedic private practice. PATIENTS: Consecutive series of 31 patients presenting with elbow pain and diagnosed at arthroscopy with articular cartilage defects of the elbow. All patients had a preoperative MRI or MRA using a 1.5 T magnet. INTERVENTIONS: Each patient had a systematic elbow arthroscopy, with careful inspection and recording of chondral injuries in 4 anatomical regions: capitellum, radius, trochlea, and ulna. Each MRI/MRA was then independently reviewed by 2 radiologists blinded to the arthroscopic findings. MAIN OUTCOME MEASURES: The sensitivity, specificity, negative predictive value, positive predictive value, and accuracy were calculated for MRI and MRI compared with arthroscopy as the gold standard, for each of the anatomical regions. RESULTS: The accuracy of MRI was 45% for chondral injuries of the radius, 65% for the capitellum, 20% for the ulna, and 30% for the trochlea. The accuracy of MRA was 45% for chondral injuries of the radius, 64% for the capitellum, 18% for the ulna, and 27% for the trochlea. CONCLUSION: We conclude that the ability of MRI and MRA using a 1.5 T magnet to detect articular cartilage lesions is limited. Neither MRI nor MRA demonstrates the intraarticular surface as accurately as direct visualization with the arthroscopy. This may be improved with the use of 3 T MRI. CLINICAL RELEVANCE: This study demonstrates that MRI and MRA with a 1.5 T magnet, as used in community practice, have limited ability to detect cartilage lesions of the elbow. PMID- 22929045 TI - Does static stretching reduce maximal muscle performance? A review. PMID- 22929046 TI - Two-year follow-up of injection with platelet-rich plasma versus corticosteroid for lateral epicondylitis. PMID- 22929047 TI - Diet and exercise for frail obese older adults. PMID- 22929049 TI - Nearly full-dense and fine-grained AZO:Y ceramics sintered from the corresponding nanoparticles. AB - Aluminum-doped zinc oxide ceramics with yttria doping (AZO:Y) ranging from 0 to 0.2 wt.% were fabricated by pressureless sintering yttria-modified nanoparticles in air at 1,300 degrees C. Scanning electron microscopy, energy-dispersive X-ray spectroscopy, X-ray diffraction analysis, a physical property measurement system, and a densimeter were employed to characterize the precursor nanoparticles and the sintered AZO ceramics. It was shown that a small amount of yttria doping can remarkably retard the growth of the as-received precursor nanoparticles, further improve the microstructure, refine the grain size, and enhance the density for the sintered ceramic. Increasing the yttria doping to 0.2 wt.%, the AZO:Y nanoparticles synthetized by a coprecipitation process have a nearly sphere shaped morphology and a mean particle diameter of 15.1 nm. Using the same amount of yttria, a fully dense AZO ceramic (99.98% of theoretical density) with a grain size of 2.2 MUm and a bulk resistivity of 4.6 * 10-3 Omega.cm can be achieved. This kind of AZO:Y ceramic has a potential to be used as a high-quality sputtering target to deposit ZnO-based transparent conductive films with better optical and electrical properties. PMID- 22929048 TI - FDG uptake correlates with recurrence and survival after treatment of unresectable stage III non-small cell lung cancer with high-dose proton therapy and chemotherapy. AB - BACKGROUND: We studied whether maximum standardized uptake values (SUV) from [18 F] PET/CT predict clinical outcome after concurrent proton/chemotherapy for stage III non-small cell lung cancer (NSCLC). METHODS: Eighty-four patients were treated prospectively with 74 Gy(RBE) proton therapy and concurrent chemotherapy. PET/CT scans were available before (SUV1) and within 6 months after (SUV2) treatment. The predictive value of clinical and PET/CT factors were analyzed with univariate and multivariate Cox regression models. RESULTS: Median survival time was 29.9 months. At 3 years, the local recurrence-free survival (LRFS) rate was 34.8%; distant metastasis-free survival (DMFS), 35.4%; progression-free survival (PFS), 31.2%; and overall survival (OS), 37.2%. Patients with SUV2 >=3.6 (the median) had high rates of LR (p = 0.021). Of 12 clinicopathologic features evaluated in univariate analysis, only KPS, SUV1, and SUV2 predicted LRFS, DMFS, PFS, and OS (p <0.05). Multivariate analysis showed that KPS (p = 0.025) and SUV2 (p = 0.017) were independently prognostic for LRFS and that SUV1, SUV2, and KPS were independently prognostic for DMFS, PFS, and OS (p <0.05). CONCLUSIONS: SUV2 predicted LRFS, and SUV1 and SUV2 predicted DMFS, PFS, and OS, in patients with stage III NSCLC treated with concurrent chemotherapy and high-dose proton therapy. PMID- 22929050 TI - Manipulation of autophagy by MIR375 generates antitumor effects in liver cancer. AB - The exploration into the roles of autophagy in tumorigenesis, either as tumor suppressor or tumor promoter, has led to a great increase in the knowledge of cancer development, progression and treatment. However, there is currently no consensus on how to manipulate autophagy to improve antitumor effects. In this study, we investigated the role of autophagy in established liver cancer cells in response to hypoxia. Hypoxia not only is the most pervasive microenvironmental stress in solid tumors but is also a canonical stimulus for autophagy. The involvement of dysregulated microRNAs in hypoxia-induced autophagy and their therapeutic potential in advanced liver cancer were examined. PMID- 22929052 TI - Endocrine disrupting chemicals and the growth of environmental health in Israel. AB - This commentary addresses the article by Berman, et al. on reproductive health trends in Israel potentially related to endocrine disrupting chemicals (EDCs) and on associated health policy decisions in Israel to prevent long-term effects from exposure to EDCs. There are intensive, ongoing research efforts in the US that will provide additional guidance on this issue in the future. The commentary also notes and commends the growing capacity and resources for environmental health work in government and academia in Israel. PMID- 22929051 TI - Characteristics of practitioners in a private managed behavioral health plan. AB - BACKGROUND: Little is known about the practitioners in managed behavioral healthcare organization (MBHO) networks who are treating mental and substance use disorders among privately insured patients in the United States. It is likely that the role of the private sector in treating behavioral health will increase due to the recent implementation of federal parity legislation and the inclusion of behavioral health as a required service in the insurance exchange plans created under healthcare reform. Further, the healthcare reform legislation has highlighted the need to ensure a qualified workforce in order to improve access to quality healthcare, and provides an additional focus on the behavioral health workforce. To expand understanding of treatment of mental and substance use disorders among privately insured patients, this study examines practitioner types, experience, specialized expertise, and demographics of in-network practitioners providing outpatient care in one large national MBHO. METHODS: Descriptive analyses used 2004 practitioner credentialing and other administrative data for one MBHO. The sample included 28,897 practitioners who submitted at least one outpatient claim in 2004. Chi-square and t-tests were used to compare findings across types of practitioners. RESULTS: About half of practitioners were female, 12% were bilingual, and mean age was 53, with significant variation by practitioner type. On average, practitioners report 15.3 years of experience (SD = 9.4), also with significant variation by practitioner type. Many practitioners reported specialized expertise, with about 40% reporting expertise for treating children and about 60% for treating adolescents. CONCLUSIONS: Overall, these results based on self-report indicate that the practitioner network in this large MBHO is experienced and has specialized training, but echo concerns about the aging of this workforce. These data should provide us with a baseline of practitioner characteristics as we enter an era that anticipates great change in the behavioral health workforce. PMID- 22929053 TI - Association of genetic variation in the NR1H4 gene, encoding the nuclear bile acid receptor FXR, with inflammatory bowel disease. AB - BACKGROUND: Pathogenesis of inflammatory bowel diseases (IBD), ulcerative colitis (UC) and Crohn's disease (CD), involves interaction between environmental factors and inappropriate immune responses in the intestine of genetically predisposed individuals. Bile acids and their nuclear receptor, FXR, regulate inflammatory responses and barrier function in the intestinal tract. METHODS: We studied the association of five variants (rs3863377, rs7138843, rs56163822, rs35724, rs10860603) of the NR1H4 gene encoding FXR with IBD. 1138 individuals (591 non IBD, 203 UC, 344 CD) were genotyped for five NR1H4 genetic variants with TaqMan SNP Genotyping Assays. RESULTS: We observed that the NR1H4 SNP rs3863377 is significantly less frequent in IBD cases than in non-IBD controls (allele frequencies: P = 0.004; wild-type vs. SNP carrier genotype frequencies: P = 0.008), whereas the variant rs56163822 is less prevalent in non-IBD controls (allele frequencies: P = 0.027; wild-type vs. SNP carrier genotype frequencies: P = 0.035). The global haplotype distribution between IBD and control patients was significantly different (P = 0.003). This also held true for the comparison between non-IBD and UC groups (P = 0.004), but not for the comparison between non IBD and CD groups (P = 0.079). CONCLUSIONS: We show that genetic variation in FXR is associated with IBD, further emphasizing the link between bile acid signaling and intestinal inflammation. PMID- 22929054 TI - In vitro antibiotic susceptibility testing of Brucella isolates from Egypt between 1999 and 2007 and evidence of probable rifampin resistance. AB - BACKGROUND: Brucellosis poses a significant public health problem in Mediterranean countries, including Egypt. Treatment of this disease is often empirical due to limited information on the antibiotic susceptibility profiles of Brucella spp. in this region of the world. The aim of this study was to determine the antibiotic susceptibility profiles of Brucella blood isolates in Egypt, a country endemic for brucellosis. METHODS: Brucella spp. isolates were identified from the blood cultures of acute febrile illness (AFI) patients presenting to a network of infectious disease hospitals from 1999-2007. Minimum inhibitory concentrations were determined for tetracycline, gentamicin, doxycycline, trimethoprim-sulfamethoxazole, streptomycin, ceftriaxone, ciprofloxacin and rifampin using the E-test. Interpretations were made according to Clinical and Laboratory Standards Institute (CLSI) guidelines. RESULTS: A total of 355 Brucella spp. isolates were analyzed. All were susceptible to tetracycline, doxycycline, trimethoprim-sulfamethoxazole, streptomycin and ciprofloxacin; probable resistance to rifampin and ceftriaxone was observed among 277 (64%) and 7 (2%) of the isolates, respectively. Percentages of isolates showing probable resistance to rifampin were significantly lower before 2001 than in the following years (7% vs. >81%, p < 0.01). CONCLUSIONS: Despite the high burden of brucellosis in Egypt and frequent empirical treatment, isolates have remained susceptible to the majority of tested antibiotics. However, this is the first report of high rates of probable resistance to rifampin among Brucella isolates from Egypt. Patients should be closely monitored while following standard treatment regimens. Continued surveillance, drug susceptibility studies and updated CLSI interpretive criteria are needed to monitor and update antibiotic prescribing policies for brucellosis. PMID- 22929055 TI - The use of cystometry in small rodents: a study of bladder chemosensation. AB - The lower urinary tract (LUT) functions as a dynamic reservoir that is able to store urine and to efficiently expel it at a convenient time. While storing urine, however, the bladder is exposed for prolonged periods to waste products. By acting as a tight barrier, the epithelial lining of the LUT, the urothelium, avoids re-absorption of harmful substances. Moreover, noxious chemicals stimulate the bladder's nociceptive innervation and initiate voiding contractions that expel the bladder's contents. Interestingly, the bladder's sensitivity to noxious chemicals has been used successfully in clinical practice, by intravesically infusing the TRPV1 agonist capsaicin to treat neurogenic bladder overactivity. This underscores the advantage of viewing the bladder as a chemosensory organ and prompts for further clinical research. However, ethical issues severely limit the possibilities to perform, in human subjects, the invasive measurements that are necessary to unravel the molecular bases of LUT clinical pharmacology. A way to overcome this limitation is the use of several animal models. Here we describe the implementation of cystometry in mice and rats, a technique that allows measuring the intravesical pressure in conditions of controlled bladder perfusion. After laparotomy, a catheter is implanted in the bladder dome and tunneled subcutaneously to the interscapular region. Then the bladder can be filled at a controlled rate, while the urethra is left free for micturition. During the repetitive cycles of filling and voiding, intravesical pressure can be measured via the implanted catheter. As such, the pressure changes can be quantified and analyzed. Moreover, simultaneous measurement of the voided volume allows distinguishing voiding contractions from non-voiding contractions. Importantly, due to the differences in micturition control between rodents and humans, cystometric measurements in these animals have only limited translational value. Nevertheless, they are quite instrumental in the study of bladder pathophysiology and pharmacology in experimental pre-clinical settings. Recent research using this technique has revealed the key role of novel molecular players in the mechano- and chemo-sensory properties of the bladder. PMID- 22929056 TI - Virus strategies for passing the nuclear envelope barrier. AB - Viruses that replicate in the nucleus need to pass the nuclear envelope barrier during infection. Research in recent years indicates that the nuclear envelope is a major hurdle for many viruses. This review describes strategies to overcome this obstacle developed by seven virus families: herpesviridae, adenoviridae, orthomyxoviridae, lentiviruses (which are part of retroviridae), Hepadnaviridae, parvoviridae and polyomaviridae. Most viruses use the canonical nuclear pore complex (NPC) in order to get their genome into the nucleus. Viral capsids that are larger than the nuclear pore disassemble before or during passing through the NPC, thus allowing genome nuclear entry. Surprisingly, increasing evidence suggest that parvoviruses and polyomaviruses may bypass the nuclear pore by trafficking directly through the nuclear membrane. Additional studies are required for better understanding these processes. Since nuclear entry emerges as the limiting step in infection for many viruses, it may serve as an ideal target for antiviral drug development. PMID- 22929057 TI - Towards a universal model of reading. AB - In the last decade, reading research has seen a paradigmatic shift. A new wave of computational models of orthographic processing that offer various forms of noisy position or context-sensitive coding have revolutionized the field of visual word recognition. The influx of such models stems mainly from consistent findings, coming mostly from European languages, regarding an apparent insensitivity of skilled readers to letter order. Underlying the current revolution is the theoretical assumption that the insensitivity of readers to letter order reflects the special way in which the human brain encodes the position of letters in printed words. The present article discusses the theoretical shortcomings and misconceptions of this approach to visual word recognition. A systematic review of data obtained from a variety of languages demonstrates that letter-order insensitivity is neither a general property of the cognitive system nor a property of the brain in encoding letters. Rather, it is a variant and idiosyncratic characteristic of some languages, mostly European, reflecting a strategy of optimizing encoding resources, given the specific structure of words. Since the main goal of reading research is to develop theories that describe the fundamental and invariant phenomena of reading across orthographies, an alternative approach to model visual word recognition is offered. The dimensions of a possible universal model of reading, which outlines the common cognitive operations involved in orthographic processing in all writing systems, are discussed. PMID- 22929059 TI - Visual word recognition models should also be constrained by knowledge about the visual system. AB - Frost's article advocates for universal models of reading and critiques recent models that concentrate in what has been described as "cracking the orthographic code." Although the challenge to develop models that can account for word recognition beyond Indo-European languages is welcomed, we argue that reading models should also be constrained by general principles of visual processing and object recognition. PMID- 22929058 TI - A population-based study of the epidemiology and clinical features of methicillin resistant Staphylococcus aureus infection in Pennsylvania, 2001-2010. AB - No U.S. general population-based study has characterized the epidemiology and risk factors, including skin and soft tissue infection (SSTI), for healthcare associated (HA) and community-associated (CA) methicillin-resistant Staphylococcus aureus (MRSA). We estimated the incidence of HA- and CA-MRSA and SSTI over a 9-year period using electronic health record data from the Geisinger Clinic in Pennsylvania. MRSA cases were frequency-matched to SSTI cases and controls in a nested case-control analysis. Logistic regression was used to assess risk factors, while accounting for antibiotic administration. We identified 1713 incident CA- and 1506 HA-MRSA cases and 78 216 SSTI cases. On average, from 2005 to 2009, the annual incidence of CA-MRSA increased by 34%, HA MRSA by 7%, and SSTI by 4%. Age, season, community socioeconomic deprivation, obesity, smoking, previous SSTI, and antibiotic administration were identified as independent risk factors for CA-MRSA. PMID- 22929060 TI - The paradox of vaginal examination practice during normal childbirth: Palestinian women's feelings, opinions, knowledge and experiences. AB - BACKGROUND: Vaginal examination (VE), is a frequent procedure during childbirth. It is the most accepted ways to assess progress during childbirth, but its repetition at short intervals has no value. Over years, VE continued to be plagued by a nature that implies negative feelings and experiences of women. The aim of this exploratory qualitative study was to explore women's feelings, opinions, knowledge and experiences of vaginal examinations (VE) during normal childbirth. METHODS: We interviewed 176 postpartum women using semi-structured questionnaire in a Palestinian public hospital in the oPt. Descriptive statistics were conducted; frequency counts and percentages for the quantitative questions. The association between the frequency of VE and age, parity, years of education, locale and the time of delivery was tested by Chi-squared and Fisher's Exact test. The open-ended qualitative questions were read line-by-line for the content and coded. The assigned codes for all responses were entered to the SPSS statistical software version 18. RESULTS: As compared with WHO recommendations, VE was conducted too frequently, and by too many providers during childbirth. The proportion of women who received a 'too high' frequency of VEs during childbirth was significantly larger in primipara as compared to multipara women (P = .037). 82% of women reported pain or severe pain and 68% reported discomfort during VE. Some women reported insensitive approaches of providers, insufficient means of privacy and no respect of dignity or humanity during the exam. CONCLUSIONS: Palestinian women are undergoing unnecessary and frequent VEs during childbirth, conducted by several different providers and suffer pain and discomfort un necessarily. PRACTICE IMPLICATIONS: Adhering to best evidence, VE during childbirth should be conducted only when necessary, and if possible, by the same provider. This will decrease the laboring women's unnecessary suffering from pain and discomfort. Providers should advocate for women's right to information, respect, dignity and privacy. PMID- 22929061 TI - The Consumer Quality index (CQ-index) in an accident and emergency department: development and first evaluation. AB - BACKGROUND: Assessment of patients' views are essential to provide a patient centred health service and to evaluating quality of care. As no standardized and validated system for measuring patients' experiences in accident and emergency departments existed, we have developed the Consumer Quality index for the accident and emergency department (CQI A&E). METHODS: Qualitative research has been undertaken to determine the content validity of the CQI A&E. In order to assess psychometric characteristics an 84-item questionnaire was sent to 653 patients who had attended a large A&E in the Netherlands. Also, fifty importance questions were added to determine relevance of the questions and for future calculations of improvement scores. Exploratory factor analysis was applied to detect the domains of the questionnaire. RESULTS: Survey data of 304 (47%) patients were used for the analysis. The first exploratory factor analysis resulted in three domains based on 13 items: 'Attitude of the healthcare professionals', 'Environment and impression of the A&E' and 'Respect for and explanation to the patient'. The first two had an acceptable internal consistency. The second analysis, included 24 items grouped into 5 domains: 'Attitude of the healthcare professionals', 'Information and explanation', 'Environment of the A&E','Leaving the A&E' and 'General information and rapidity of care'. All factors were internal consistent. According to the patients, the three most important aspects in healthcare performance in the A&E were: trust in the competence of the healthcare professionals, hygiene in the A&E and patients' health care expectations. In general, the highest improvement scores concerned patient information. CONCLUSIONS: The Consumer Quality index for the accident and emergency department measures patients' experiences of A&E healthcare performance. Preliminary psychometric characteristics are sufficient to justify further research into reliability and validity. PMID- 22929062 TI - Phase I-II study of hypofractionated simultaneous integrated boost using volumetric modulated arc therapy for adjuvant radiation therapy in breast cancer patients: a report of feasibility and early toxicity results in the first 50 treatments. AB - BACKGROUND: To report results in terms of feasibility and early toxicity of hypofractionated simultaneous integrated boost (SIB) approach with Volumetric Modulated Arc Therapy (VMAT) as adjuvant treatment after breast-conserving surgery. METHODS: Between September 2010 and May 2011, 50 consecutive patients presenting early-stage breast cancer were submitted to adjuvant radiotherapy with SIB-VMAT approach using RapidArc in our Institution (Istituto Clinico Humanitas ICH). Three out of 50 patients were irradiated bilaterally (53 tumours in 50 patients). All patients were enrolled in a phase I-II trial approved by the ICH ethical committee. All 50 patients enrolled in the study underwent VMAT-SIB technique to irradiate the whole breast with concomitant boost irradiation of the tumor bed. Doses to whole breast and surgical bed were 40.5 Gy and 48 Gy respectively, delivered in 15 fractions over 3 weeks. Skin toxicities were recorded during and after treatment according to RTOG acute radiation morbidity scoring criteria with a median follow-up of 12 months (range 8-16). Cosmetic outcomes were assessed as excellent/good or fair/poor. RESULTS: The median age of the population was 68 years (range 36-88). According to AJCC staging system, 38 breast lesions were classified as pT1, and 15 as pT2; 49 cases were assessed as N0 and 4 as N1. The maximum acute skin toxicity by the end of treatment was Grade 0 in 20/50 patients, Grade 1 in 32/50, Grade 2 in 0 and Grade 3 in 1/50 (one of the 3 cases of bilateral breast irradiation). No Grade 4 toxicities were observed. All Grade 1 toxicities had resolved within 3 weeks. No significant differences in cosmetic scores on baseline assessment vs. 3 months and 6 months after the treatment were observed: all patients were scored as excellent/good (50/50) compared with baseline; no fair/poor judgment was recorded. No other toxicities or local failures were recorded during follow-up. CONCLUSIONS: The 3 week course of postoperative radiation using VMAT with SIB showed to be feasible and was associated with acceptable acute skin toxicity profile. Long-term follow up data are needed to assess late toxicity and clinical outcomes. PMID- 22929063 TI - Epidemiology of anti-tuberculosis drug resistance patterns and trends in tuberculosis referral hospital in Addis Ababa, Ethiopia. AB - BACKGROUND: Drug-resistant TB has emerged as a major challenge facing TB prevention and control efforts. In Ethiopia, the extent/trend of drug resistance TB is not well known. The aim of this study was to determine the pattern and trend of resistance to first line anti-TB drugs among culture positive retreatment cases at St.Peter's TB Specialized Hospital. FINDINGS: A hospital based retrospective study was used to assess the pattern of anti-TB drug resistance among previously treated TB patients referred to St.Peter's TB Specialized Hospital from January 2004-December 2008 Gregorian calendar(GC) for better diagnosis and treatment. Among 376 culture positive for M. tuberculosis one hundred and two (27.1%) were susceptible to all of the four first line anti TB drugs -Isoniazid (INH), Rifampicin (RIF), Ethambutol (ETB) & Streptomycin (STM). While 274 (72.9%) were resistant to at least one drug. Any resistance to STM (67.3%) was found to be the most common and the prevalence of MDR-TB was 174 (46.3%). Trend in resistance rate among re-treatment cases from 2004 to 2008 showed a significant increase for any drug as well as for INH, RIF, and MDR resistance (P <0.05 for trend). CONCLUSIONS: There has been an increasing trend in drug resistance in recent years, particularly in retreatment cases. Therefore, establishing advanced diagnostic facilities for early detection of MDR-TB and expanding second line treatment center to treat MDR-TB patients and to prevent its transmission is recommended. PMID- 22929065 TI - Indoleamine 2,3-dioxygenase activation and depressive symptoms: results from the Young Finns Study. AB - OBJECTIVE: To examine whether the activation of indoleamine 2,3-dioxygenase (IDO), an enzyme involved in serotonin production, is associated with depressive symptoms. METHODS: The participants were 544 women and 442 men (aged 24-39 years) from the population-based Young Finns Study who participated in a medical examination in 2001 (including IDO and depression) and 2007 (follow-up assessment for depression). RESULTS: At baseline, IDO was associated with depressive symptoms (in the total cohort: B = 0.23, p < .001; women: B = 0.20, p = .007; men: B = 0.29, p = .002; p for interaction = .19). IDO at baseline was also associated with depressive symptoms at follow-up in women (B = 0.17, p = .03), which remained significant when adjusting for any of the biologic and behavioral risk factors. Adjusting for body mass index attenuated the association by 6%. In the final model including all baseline variables, none of the risk factors (except for baseline depressive symptoms) were associated with depressive symptoms at follow-up. CONCLUSIONS: These data suggest that IDO activity may be a risk factor for future depression especially in women. IDO-induced alterations in serotonergic function may offer one biologic explanation to the well-established associations between inflammation and depression. PMID- 22929064 TI - Somatoform pain: a developmental theory and translational research review. AB - Somatoform pain is a highly prevalent, debilitating condition and a tremendous public health problem. Effective treatments for somatoform pain are urgently needed. The etiology of this condition is, however, still unknown. On the basis of a review of recent basic and clinical research, we propose one potential mechanism of symptom formation in somatoform pain and a developmental theory of its pathogenesis. Emerging evidence from animal and human studies in developmental neurobiology, cognitive-affective neuroscience, psychoneuroimmunology, genetics, and epigenetics, as well as that from clinical and treatment studies on somatoform pain, points to the existence of a shared neural system that underlies physical and social pain. Research findings also show that nonoptimal early experiences interact with genetic predispositions to influence the development of this shared system and the ability to regulate it effectively. Interpersonal affect regulation between infant and caregiver is crucial for the optimal development of these brain circuits. The aberrant development of this shared neural system during infancy, childhood, and adolescence may therefore ultimately lead to an increased sensitivity to physical and social pain and to problems with their regulation in adulthood. The authors critically review translational research findings that support this theory and discuss its clinical and research implications. Specifically, the proposed theory and research review suggest that psychotherapeutic and/or pharmacological interventions that foster the development of affect regulation capacities in an interpersonal context will also serve to more effectively modulate aberrantly activated neural pain circuits and thus be of particular benefit for the treatment of somatoform pain. PMID- 22929066 TI - Endothelial cell senescence is associated with disrupted cell-cell junctions and increased monolayer permeability. AB - BACKGROUND: Cellular senescence is associated with cellular dysfunction and has been shown to occur in vivo in age-related cardiovascular diseases such as atherosclerosis. Atherogenesis is accompanied by intimal accumulation of LDL and increased extravasation of monocytes towards accumulated and oxidized LDL, suggesting an affected barrier function of vascular endothelial cells. Our objective was to study the effect of cellular senescence on the barrier function of non-senescent endothelial cells. METHODS: Human umbilical vein endothelial cells were cultured until senescence. Senescent cells were compared with non senescent cells and with co-cultures of non-senescent and senescent cells. Adherens junctions and tight junctions were studied. To assess the barrier function of various monolayers, assays to measure permeability for Lucifer Yellow (LY) and horseradish peroxidase (PO) were performed. RESULTS: The barrier function of monolayers comprising of senescent cells was compromised and coincided with a change in the distribution of junction proteins and a down regulation of occludin and claudin-5 expression. Furthermore, a decreased expression of occludin and claudin-5 was observed in co-cultures of non-senescent and senescent cells, not only between senescent cells but also along the entire periphery of non-senescent cells lining a senescent cell. CONCLUSIONS: Our findings show that the presence of senescent endothelial cells in a non-senescent monolayer disrupts tight junction morphology of surrounding young cells and increases the permeability of the monolayer for LY and PO. PMID- 22929067 TI - Ecological analysis of social risk factors for Rotavirus infections in Berlin, Germany, 2007-2009. AB - BACKGROUND: Socioeconomic factors are increasingly recognised as related to health inequalities in Germany and are also identified as important contributing factors for an increased risk of acquiring infections. The aim of the present study was to describe in an ecological analysis the impact of different social factors on the risk of acquiring infectious diseases in an urban setting. The specific outcome of interest was the distribution of Rotavirus infections, which are a leading cause of acute gastroenteritis among infants and also a burden in the elderly in Germany. The results may help to generate more specific hypothesis for infectious disease transmission. METHODS: We analysed the spatial distribution of hospitalized patients with Rotavirus infections in Berlin, Germany. The association between the small area incidence and different socio demographic and economic variables was investigated in order to identify spatial relations and risk factors. Our spatial analysis included 447 neighbourhood areas of similar population size in the city of Berlin. We included all laboratory confirmed cases of patients hospitalized due to Rotavirus infections and notified between 01/01/2007 and 31/12/2009. We excluded travel-associated and nosocomial infections. A spatial Bayesian Poisson regression model was used for the statistical analysis of incidences at neighbourhood level in relation to socio demographic variables. RESULTS: Altogether, 2,370 patients fulfilled the case definition. The disease mapping indicates a number of urban quarters to be highly affected by the disease. In the multivariable spatial regression model, two risk factors were identified for infants (<4 year olds): Rotavirus incidence increased by 4.95% for each additional percent of unemployed inhabitants in the neighbourhood (95% credibility interval (CI): 3.10%-6.74%) and by 0.53% for each additional percent of children attending day care in the neighbourhood (95% CI: 0.00%-1.06%). We found no evidence for an association with the proportion of foreign residents, population density, the residential quality of accommodations and resident changes in the neighbourhood. CONCLUSIONS: Neighbourhoods with a high unemployment rate and high day care attendance rate appear to be particularly affected by Rotavirus in the population of Berlin. Public health promotion programs should be developed for the affected areas. Due to the ecological study-design, risk pathways on an individual patient level remain to be elucidated. PMID- 22929068 TI - Got engagement? PMID- 22929069 TI - Let's get comfortable: preventing pressure ulcers. PMID- 22929070 TI - A day at the fair: updating nurse competencies. PMID- 22929071 TI - Leveraging the skills of APRNs to prevent HAIs. PMID- 22929072 TI - How mobile is your technology? PMID- 22929074 TI - Preparing exceptional leaders. PMID- 22929075 TI - The recipe for success? Invest in your team. PMID- 22929076 TI - Listen to your nurses! Improving work environments. PMID- 22929077 TI - Steering toward the future. PMID- 22929079 TI - Vimentin in upper gastrointestinal pathologies--letter. PMID- 22929081 TI - Current world literature. PMID- 22929080 TI - FRET microscopy for real-time monitoring of signaling events in live cells using unimolecular biosensors. AB - Forster resonance energy transfer (FRET) microscopy continues to gain increasing interest as a technique for real-time monitoring of biochemical and signaling events in live cells and tissues. Compared to classical biochemical methods, this novel technology is characterized by high temporal and spatial resolution. FRET experiments use various genetically-encoded biosensors which can be expressed and imaged over time in situ or in vivo. Typical biosensors can either report protein protein interactions by measuring FRET between a fluorophore-tagged pair of proteins or conformational changes in a single protein which harbors donor and acceptor fluorophores interconnected with a binding moiety for a molecule of interest. Bimolecular biosensors for protein-protein interactions include, for example, constructs designed to monitor G-protein activation in cells, while the unimolecular sensors measuring conformational changes are widely used to image second messengers such as calcium, cAMP, inositol phosphates and cGMP. Here we describe how to build a customized epifluorescence FRET imaging system from single commercially available components and how to control the whole setup using the Micro-Manager freeware. This simple but powerful instrument is designed for routine or more sophisticated FRET measurements in live cells. Acquired images are processed using self-written plug-ins to visualize changes in FRET ratio in real-time during any experiments before being stored in a graphics format compatible with the build-in ImageJ freeware used for subsequent data analysis. This low-cost system is characterized by high flexibility and can be successfully used to monitor various biochemical events and signaling molecules by a plethora of available FRET biosensors in live cells and tissues. As an example, we demonstrate how to use this imaging system to perform real-time monitoring of cAMP in live 293A cells upon stimulation with a beta-adrenergic receptor agonist and blocker. PMID- 22929083 TI - Nicotinic acetylcholine receptor signaling in atherogenesis. AB - Smoking is a major risk factor for the development of atherosclerosis, stroke and myocardial infarction. Cigarette smoke consists of a complex mixture of about 4000 compounds. Out of these, polycyclic hydrocarbons, tobacco-specific nitrosamines, oxidizing agents and carbon monoxide have been implicated in the development of atherosclerosis. Recent studies have shown that nicotine (the addictive component of cigarettes) binds to high affinity cell-surface receptors and accelerates the atherogenic process. These receptors are called nicotinic acetylcholine receptors (nAChRs) and are expressed ubiquitously in almost all cells existing in the blood vessels. The present review summarizes the pro atherogenic effects of nAChR ligands such as nicotine and tobacco nitrosamines. The contribution of different nAChR subunits in plaque growth, progression and neovascularization are discussed in detail. The signaling pathways underlying the actions of the nAChRs ligands in blood vessels are also described. Finally, the feasibility of nAChR ligands as therapeutic targets for atherosclerosis is summarized. We believe that the information presented in this review is relevant for atherosclerosis patients who are active smokers, exposed to environmental tobacco smoke or use nicotine patches or gums for smoking cessation. PMID- 22929084 TI - Can evolution provide perfectly optimal solutions for a universal model of reading? AB - Frost has given us good reason to question the universality of existing computational models of reading. Yet, he has not provided arguments showing that all languages share fundamental and invariant reading universals. His goal of outlining the blueprint principles for a universal model of reading is premature. Further, it is questionable whether natural evolution can provide the optimal solutions that Frost invokes. PMID- 22929085 TI - Emergence of extensively drug-resistant Acinetobacter baumannii complex over 10 years: nationwide data from the Taiwan Surveillance of Antimicrobial Resistance (TSAR) program. AB - BACKGROUND: Acinetobacter baumannii complex (ABC) has emerged as an important pathogen causing a variety of infections. Longitudinal multicenter surveillance data on ABC from different sources in Taiwan have not been published. Using data from the Taiwan Surveillance of Antimicrobial Resistance (TSAR) conducted biennially, we investigated the secular change in resistance of 1640 ABC from 2002 to 2010 (TSAR period III to VII) to different antimicrobial agents and identified factors associated with imipenem-resistant and extensively drug resistant ABC (IRABC and XDRABC). METHODS: Isolates were collected by TSAR from the same 26 hospitals located in all 4 regions of Taiwan. Minimum inhibitory concentrations (MIC) were determined by reference broth microdilution method. Isolates nonsusceptible to all tested aminoglycosides, fluoroquinolones, beta lactam, beta-lactam/beta-lactam inhibitors, and carbapenems were defined as extensively drug-resistant (XDR). Multivariate logistic regression analysis was performed to assess the relationship between predictor variables among patients with resistant ABC and patients with non-resistant ABC. RESULTS: The prevalence of IRABC increased from 3.4% in 2002 to 58.7% in 2010 (P < 0.001; odds ratio [OR], 2.138; 95% confidence interval [CI], 1.947 to 2.347) and that of XDRABC increased from 1.3% in 2002 to 41.0% in 2010 (P < 0.001; OR, 1.970; 95% CI, 1.773 2.189). The rates of non-susceptibility to other antimicrobial agents remained high (>55%) over the years with some fluctuations before and after TSAR V (2006) on some agents. Multivariate analysis revealed that recovery from elderly patients, origins other than blood, from ICU settings, or geographic regions are independent factors associated with IRABC and XDRABC. Although the prevalence of XDRABC increased in all four regions of Taiwan over the years, central Taiwan had higher prevalence of XDRABC starting in 2008. Susceptibility to polymyxin remained high (99.8%). CONCLUSIONS: This longitudinal multicenter surveillance program revealed significant increase and nationwide emergence of IRABC and XDRABC in Taiwan over the years. This study also identified factors associated with IRABC and XDRABC to help guide empirical therapy and at-risk groups requiring more intense interventional infection control measures with focused surveillance efforts. PMID- 22929087 TI - Change in retinal image contrast with age in eyes with transparent lenses. AB - PURPOSE: To compare and evaluate changes in the retinal image with age in Japanese adults with transparent crystalline lenses. SETTING: Shibuya-ku, Tokyo, Japan. DESIGN: Cross-sectional study. METHODS: The study comprised right eyes with corrected distance visual acuity better than 0.0 logMAR. A point-spread function analyzer (PSF-1000) was used to measure retinal image contrast with 3.0 mm pupils under maximum mydriasis. A wavefront analyzer (KR9000PW) was used to measure higher-order aberrations (HOAs) with 4.0 mm pupils. The lens transparency property was estimated by the backward light-scattering intensity of each layer of the lens and the optical distance (mm) photographed by an anterior segment analysis system (EAS-1000). The Pearson product-moment correlation (R(2)) was used for statistical analysis; the significance level was 5%. RESULTS: The study comprised 269 patients (mean age 39.7 years +/- 7.7 [SD]). The retinal image contrast degenerated significantly with age; the largest difference was seen with the 0.423 logMAR optotype, for which the decrease was 5.4% every decade. Backward light-scattering intensity (R(2) = 0.030, P<.01) and HOAs (R(2) = 0.032, P<.01) correlated negatively with retinal image contrast. CONCLUSION: Retinal image contrast in eyes with transparent lenses degenerated with age. The decrease was most prominent at the middle frequency domain and was due to the increase in HOAs and light-scattering intensity. PMID- 22929086 TI - Recruiting older men for geriatric suicide research. AB - BACKGROUND: Clinical research is required to develop and evaluate suicide prevention interventions in the elderly. However, there is insufficient information available about how to best recruit suicidal older adults for such research. This study evaluated the success and efficiency of five recruitment strategies for a clinical trial on the efficacy of cognitive therapy for suicidal older men. METHODS: For each strategy, the numbers of individuals approached, screened, and enrolled were calculated, and the expenses and time associated with each enrollment estimated. Men who were 60 years or older and who had a desire for suicide over the past month were eligible for the trial. RESULTS: Of 955 individuals considered for trial, 33 were enrolled. Most enrollments were sourced from the Veterans Affairs Behavioral Health Laboratory. Recruiting form this source was also the most time and cost efficient recruitment strategy in the study. CONCLUSIONS: Recruitment strategies are effective when they are based on collaborative relationships between researchers and providers, and utilize an existing infrastructure for involving patients in ongoing research opportunities. PMID- 22929088 TI - Management of intraoperative iris prolapse: stepwise practical approach. AB - Iris prolapse is not an uncommon occurrence during cataract surgery. It usually occurs through the main incision during hydrodissection and is commonly associated with floppy-iris syndrome; however, it can manifest in cases with no known predisposition and can occur at any stage during surgery. The mechanism is explained by the Bernoulli principle and its effect on iris position during the movement of fluid within the eye. Predisposing factors are iris configuration, anterior chamber depth, and position and architecture of the corneal tunnel. Strategies for prevention and management include the use of pharmacological agents, ophthalmic viscosurgical devices, and iris retractors. These strategies can be augmented by alteration and adaptation of the surgeon's technique. PMID- 22929089 TI - Cytomegalovirus seropositivity is associated with glucose regulation in the oldest old. Results from the Leiden 85-plus Study. AB - BACKGROUND: Cytomegalovirus (CMV) infection has been reported to contribute to the pathogenesis of type 1 diabetes and post-transplantation diabetes. However, CMV infection has not been evaluated as a possible risk factor for type 2 diabetes. Our aim was to investigate potential associations between CMV seropositivity, CMV IgG antibody level and glucose regulation in the oldest old. RESULTS: CMV seropositive subjects were more likely to have type 2 diabetes (17.2% vs 7.9%, p = 0.016), had a higher level of HbA1c (p = 0.014) and higher non-fasting glucose (p = 0.024) in the oldest olds. These associations remained significant after adjustment for possible confounders. CMV IgG antibody level was not significantly associated with glucose regulation (all p > 0.05). CONCLUSIONS: In the oldest old, CMV seropositivity is significantly associated with various indicators of glucose regulation. This finding suggests that CMV infection might be a risk factor for the development of type 2 diabetes in the elderly. PMID- 22929090 TI - Toxic misfolding of Arabidopsis cellulases in the secretory pathway of Pichia pastoris. AB - Plants produce a large number of cellulases that are either secreted or anchored in the plasma membrane where they likely function in various aspects of cellulose synthesis, modification and degradation during plant growth and development. Very few of these enzymes have been characterized in any detail, however. Here we attempted to produce two Arabidopsis modular cellulases, which contain a catalytic domain belonging to glycoside hydrolase family 9 (GH9) and a carbohydrate binding module (CBM), in the yeast Pichia pastoris. Neither of the intact modular enzymes was detectably produced, although the independently expressed GH9 catalytic domain of one enzyme was secreted when the protein was expressed at low temperature. Expression of intact and truncated cellulases at the standard temperature caused extensive cell lysis, with release of high concentrations of endogenous proteins into the culture medium. Cell lysis appeared to result from misfolding of cellulase proteins within the Pichia secretory pathway. The toxicity of these misfolded cellulases potentially could be exploited to derive host strains with enhanced capability to fold recombinant secretory proteins. PMID- 22929091 TI - Adherence: the goal to control asthma. AB - Asthma management requires adequate adherence to many recommendations, including therapy, monitoring of asthma control, avoidance of environmental triggers, and attending follow-up appointments. Poor adherence is common in patients with asthma and is often associated with increased health care use, morbidity, and mortality. Many determinants of poor adherence have been identified and should be addressed, but there is no clear profile of the nonadherent patient. Interventions to improve adherence therefore demand tailoring to the individual by including patient-specific education, addressing patient fears and misconceptions, monitoring adherence, and developing a shared decision process. PMID- 22929092 TI - Is the asthma epidemic still ascending? AB - Asthma is a phenotypically heterogeneous disorder of multifactorial origins that affects 300 million people suffering from asthma and more than 250,000 asthma related deaths each year. Although treatment for asthma has improved, its prevalence continues to increase, particularly in low and middle income countries, or in some ethnic groups in which prevalence was previously low. Observed spatio-temporal variations in the increased prevalence of asthma depend on exposure to environmental factors. Recently, several arguments are also in favor of the involvement of host susceptibility and stress in the observed increase of asthma prevalence. Further investigations are warranted to better understand mechanisms underlying asthma increase or stagnation. PMID- 22929094 TI - How to diagnose and phenotype asthma. AB - Asthma has been described as a chronic disease of the airways characterized by variable airflow obstruction, airway hyperresponsiveness, and airway inflammation. This review discusses the diagnosis and phenotyping of asthma, with a special emphasis on phenotyping based on the nature of cellular inflammation and radiological imaging and how this could be used to direct the treatment of asthma and, in the future, to apply specifically directed therapies to specific phenotypes. PMID- 22929093 TI - Genetics of asthma susceptibility and severity. AB - This article summarizes major findings in genome-wide studies of asthma susceptibility and severity. Two large meta-analyses identified four chromosomal regions which were consistently associated with development of asthma. Genes that are associated with asthma subphenotypes such as lung function, biomarker levels, and asthma therapeutic responses can provide insight into mechanisms of asthma severity and disease progression. Future genetic studies will incorporate sequencing in comprehensively phenotyped asthmatics to lead to the development of personalized therapy. PMID- 22929096 TI - Asthma: a chronic infectious disease? AB - There are increasing data to support the "hygiene" and "microbiota" hypotheses of a protective role of infections in modulating the risk of subsequent development of asthma. There is less evidence that respiratory infections can actually cause the development of asthma. There is some evidence that rhinovirus respiratory infections are associated with the development of asthma, particularly in childhood, whereas these infections in later life seem to have a weaker association with the development of asthma. The role of bacterial infections in chronic asthma remains unclear. This article reviews the available evidence indicating that asthma may be considered as a chronic infectious disease. PMID- 22929097 TI - Difficult childhood asthma: management and future. AB - Diagnosis and management of severe asthma implies the definition of different entities, that is, difficult asthma and refractory severe asthma, but also the different phenotypes included in the term refractory severe asthma. A complete evaluation by a physician expert in asthma is necessary, adapted for each child. Identification of mechanisms involved in different phenotypes in refractory severe asthma may improve the therapeutic approach. The quality of care and monitoring of children with severe asthma is as important as the prescription drug, and is also crucial for differentiating between severe asthma and difficult asthma, whereby expertise is required. PMID- 22929098 TI - Treating according to asthma control: does it work in real life? AB - Control-based asthma management has been incorporated in asthma guidelines for many years. This article reviews the evidence for its utility in adults, describes its strengths and limitations in real life, and proposes areas for further research, particularly about incorporation of future risk and identification of patients for whom phenotype-guided treatment would be effective and efficient. The strengths of control-based management include its simplicity and feasibility for primary care, and its limitations include the nonspecific nature of asthma symptoms, the complex role of beta(2)-agonist use, barriers to stepping down treatment, and the underlying assumptions about asthma pathophysiology and treatment responses. PMID- 22929099 TI - Occupational asthma: new deleterious agents at the workplace. AB - This article summarizes the main new categories of occupational agents responsible for causing occupational asthma, with and without a latency period reported in the last 10 years. It also reports examples of occupational agents for which the fabrication processing or use have influenced the outcome of occupational asthma. PMID- 22929095 TI - Biomarkers in asthma: a real hope to better manage asthma. AB - Diagnosis and treatment of asthma are currently based on assessment of patient symptoms and physiologic tests of airway reactivity. Research over the past decade has identified an array of biochemical and cellular biomarkers, which reflect the heterogeneous and multiple mechanistic pathways that may lead to asthma. These mechanistic biomarkers offer hope for optimal design of therapies targeting the specific pathways that lead to inflammation. This article provides an overview of blood, urine, and airway biomarkers; summarizes the pathologic pathways that they signify; and begins to describe the utility of biomarkers in the future care of patients with asthma. PMID- 22929100 TI - Corticosteroids: still at the frontline in asthma treatment? AB - Inhaled corticosteroids (ICS) have led to improved asthma control and reduced asthma mortality in the Western world. ICS are effective in combating T-helper type 2-driven inflammation featuring mast cell and eosinophilic airway infiltration. Their effect on innate immunity-driven neutrophilic inflammation is poor and their ability to prevent airway remodeling and accelerated lung decline is controversial. Although ICS remain pivotal drugs in asthma management, research is needed to find drugs complementary to the combination ICS/long-acting beta2-agonist in refractory asthma and perhaps a new class of drugs as a first line treatment in mild to moderate noneosinophilic asthma. PMID- 22929101 TI - Airway smooth muscle in asthma: just a target for bronchodilation? AB - Airway smooth muscle (ASM) has long been recognized as the main cell type responsible for bronchial hyperresponsiveness. It has, thus, been considered as a target for bronchodilation. In asthma, however, there is a complex relationship between ASM and inflammatory cells, such as mast cells and T lymphocytes. Moreover, the increased ASM mass in asthmatic airways is one of the key features of airway remodeling. This article aims to review the main concepts about the 3 possible roles of ASM in asthma: (1) contractile tone, (2) inflammatory response, and (3) remodeling. PMID- 22929103 TI - Severe asthma in adults: an orphan disease? AB - Severe asthma affects fewer than 10% of patients with asthma, is associated with a severe risk of death and disability, has a great impact on health and quality of life, and represents a huge cost to patients and society. Given the poor response to treatment and the side effects associated with medications for severe asthma, more efficient, cost-effective, and phenotype-specific medications are needed. Considering severe asthma as an orphan disease could encourage the pharmaceutical industry to stratify studies based on a more detailed characterization of study subjects at baseline, resulting in the development of novel therapeutic approaches. PMID- 22929102 TI - Resolution of inflammation in asthma. AB - The resolution of inflammation in healthy airways is an active process, with specialized mediators and cellular mechanisms enlisted to restore tissue homeostasis. This article focuses on recent discoveries of natural mediators derived from essential fatty acids, including omega-3 fatty acids, with anti inflammatory and pro-resolving. These pro-resolving mediators serve as agonists at specific receptors. Asthma is an incurable disease of chronic, nonresolving inflammation of the airways. While the biosynthesis of pro-resolving mediators occurs during asthma, defects in their production are associated with disease severity, suggesting that the pathobiology of asthma may result in part from impaired resolution of airway inflammation. PMID- 22929104 TI - Immunologic therapeutic interventions in asthma: impact on natural history. AB - The discovery of new pathobiological pathways involved in asthma chronicity and reliefs offers novel therapeutic avenues. Enhanced phenotyping criteria associated with simple biologic characterization allowed to test targeted interventions in selected patients. Long-term studies are de facto lacking but required to address their impact on the natural history of the disease. Here, the authors review all potential available therapeutics based on immunologic pathways involved in asthma pathophysiology during the last decade. PMID- 22929105 TI - Preface. Asthma. PMID- 22929106 TI - Flashing out or fleshing out? A developmental perspective on a universal model of reading. AB - The principles for universal reading models proposed by Frost correspond to developmental theories, in which neurocognitive constraints and cultural experiences shape development. We question his contention that Hebrew word identification is fundamentally about roots, excluding verbal and nominal word pattern morphemes; and we propose that readers use all information available in stimuli, adjusting for volume and usefulness. PMID- 22929107 TI - Burden of out-of-pocket expenditure for road traffic injuries in urban India. AB - BACKGROUND: Road traffic injuries (RTI) are an increasing public health problem in India where out-of-pocket (OOP) expenditures on health are among the highest in the world. We estimated the OOP expenses for RTI in a large city in India. METHODS: Information on medical and non-medical expenditure was documented for RTI cases of all ages that reported alive or dead to the emergency departments of two public hospitals and a large private hospital in Hyderabad. Differential risk of catastrophic OOP total expenditure (COPE-T) and medical expenditure (COPE-M), and distress financing was assessed for 723 RTI cases that arrived alive at the study hospitals with multiple logistic regression. Catastrophic expenditure was defined as expenditure > 25% of the RTI patient's annual household income. Variation in intensity of COPE-M in RTI was assessed using multiple classification analysis (MCA). RESULTS: The median OOP medical and non-medical expenditure was USD 169 and USD 163, respectively. The prevalence of COPE-M and COPE-T was 21.9% (95% CI 18.8-24.9) and 46% (95% CI 42-49.3), respectively. Only 22% had access to medical insurance. Being admitted to a private hospital (OR 5.2, 95% CI 2.7-9.9) and not having access to insurance (OR 3.8, 95% CI 1.9-7.6) were significantly associated with risk of having COPE - M. Similar results were seen for COPE - T. MCA analysis showed that the burden of OOP medical expenditure was mainly associated with in-patient days in hospital (Eta =0.191). Prevalence of distress financing was 69% (95% CI 65.5-72.3) with it being significantly higher for those reporting to the public hospitals (OR 2.8, 95% CI 1.7-4.6), those belonging to the lowest per capita annual household income quartile (OR 7.0, 95% CI 3.7-13.3), and for those without insurance access (OR 3.4, 95% CI 2.0 5.7). CONCLUSIONS: This paper has outlined the high burden of out-of-pocket medical and total expenditure associated with RTI in India. These data reinforce the need for implementing more effective financial protection mechanisms in India against the high out-of-pocket expenditure incurred on RTI. PMID- 22929108 TI - Lessons learned from war: a comprehensive review of the published experiences of the Iranian neurosurgeons during the Iraq-Iran conflict and review of the related literature. AB - BACKGROUND: This study sought to review the articles published by Iranian neurosurgeons regarding their experiences during the Iraq-Iran conflict and compare them with reports from other conflicts. METHODS: We searched databases (MEDLINE and 2 Iranian databases, namely IranMedex and Scientific Information Database, up to December 2011) and references for relevant studies. The search terms included Iran, Iraq, conflict, battle, war, traumatic aneurysm (TA), posttraumatic epilepsy (PTE), brain infection, penetrating head wound (PHW), cerebrospinal fluid (CSF) leakage, spine injury, and peripheral nerve injury. RESULTS: Twenty-eight articles were found that presented PHW, development of TA, infections, PTE, and peripheral nerve injuries. There were 2 different protocols for management of PHWs: radical surgery and minimal debridement protocol. The overall central nervous system infection rate was 10%. The cumulated incidence of TA was 6%. CONCLUSIONS: Conservative minimal debridement of the wounds is indicated in patients with small entrance wounds, or those with Glasgow Coma Scale score >= 8 and no progressive neurological deficit. To diagnose TA before rupture, angiography is indicated in patients who have shells or bone fragments pass through the crowded vasculature, or have large/delayed hematoma, or if the surgeon has high index of suspicion based on neuroimaging and early debridement surgery. Surgery in a well-equipped nearby hospital after quick and safe evacuation of the victims by trained salvaging ancillary groups and the administration of broad-spectrum antibiotics and proper antiepileptics decrease the morbidity and mortality of casualties after PHW in war situations. The biases of the case selection, data collection, and confounders, and decreasing biases by conducting blinded controlled clinical trials, are discussed. PMID- 22929109 TI - Multiple-day drainage when using bone morphogenic protein for long-segment thoracolumbar fusions is associated with low rates of wound complications. AB - BACKGROUND: Concerns over increased wound complication rates have been raised when bone morphogenic protein (BMP) is used as an adjunct for fusion in spinal surgery. This study evaluated 87 consecutive patients undergoing long-segment thoracolumbar spinal fusions with BMP to assess drain output and the rates of reoperation for infection or seroma. METHODS: Inclusion criteria included patients undergoing 4 or more levels of posterior instrumented thoracolumbar fusion, use of BMP, age >18 years, and a perioperative follow-up of >=60 days. Drain output, length of time of drainage, and need for reoperation for wound seroma or infection were reviewed. RESULTS: A total of 87 patients met inclusion criteria and had a mean age of 58.5 years (SD 16, range 20 to 81). The average number of levels instrumented and arthrodesed with BMP was 9.2 (SD 3.7; range 4 to 18), and the average dose of BMP used was 31.2 mg (SD 9.6, range 12 to 48) or 2.6 large sponges. Patients required drainage for a mean of 4.9 days (SD 1.3, range 3 to 9). The average total output was 1923 mL (SD 865, range 530 to 4310 mL). The wound infection rate was 2.3% (2 cases of deep wound infection that required reoperation). There was one (1.1%) hematoma, and one (1.1%) sterile seroma, both requiring evacuation. No other wound complications were noted. CONCLUSIONS: Use of BMP for long-segment posterior thoracolumbar fusions may be associated with significant drain output, requiring multiple days of drainage. However, when drained adequately, infections and seromas occur infrequently. PMID- 22929112 TI - Surgery for neurofibromatosis 2. AB - PURPOSE OF REVIEW: This study reviews the latest literature relating to the surgical treatment of otologic manifestations in patients with neurofibromatosis 2 (NF2). The emphasis is on vestibular and other schwannomas. We review surgical approaches, including hearing preservation and nonhearing preservation surgery, as well as outcomes, including hearing and facial nerve function. RECENT FINDINGS: Vestibular schwannomas in NF2 are difficult to manage because they are bilateral and may be aggressive. Depending on hearing status, tumor size and the presence or absence of compressive symptoms, these tumors can be managed by observation, radiotherapy or surgery. The goal is to maximize the years of useful hearing. Surgery may attempt to preserve hearing or aim for complete tumor resection and preservation of facial nerve function. SUMMARY: The natural history of vestibular schwannomas and other tumors in patients with NF2 is difficult to predict. The decision between observation and either medical or surgical intervention, as well as the choice of surgical procedure, depend on patient factors and preferences and on the experience of the treating center. PMID- 22929113 TI - Hearing preservation: microsurgery. AB - PURPOSE OF REVIEW: To evaluate the recent and significant contributions to the literature that examine hearing preservation outcomes and prognostic factors in vestibular schwannoma microsurgery. RECENT FINDINGS: Hearing preservation rates overall range considerably between 2 and 93% in recent studies. There are a number of factors that have been reported to be significant in the prediction of hearing preservation. Characteristics such as approach, results of preoperative neurophysiological testing, tumor size and nerve of origin have long been reported. A more recent contribution to the literature has included the association between MRI T2 signal in the fundus of the internal auditory canal and hearing preservation. This review provides a summary of some of the landmark studies in conjunction with more recent work detailing the prognostic factors for hearing preservation in the surgical management of vestibular schwannoma. SUMMARY: Hearing preservation in vestibular schwannoma surgery has undergone tremendous evolution over the past 50 years. In this review, we outline the prognostic factors that predict hearing preservation and describe recent contributions. PMID- 22929110 TI - Current status of boron neutron capture therapy of high grade gliomas and recurrent head and neck cancer. AB - Boron neutron capture therapy (BNCT) is a biochemically targeted radiotherapy based on the nuclear capture and fission reactions that occur when non radioactive boron-10, which is a constituent of natural elemental boron, is irradiated with low energy thermal neutrons to yield high linear energy transfer alpha particles and recoiling lithium-7 nuclei. Clinical interest in BNCT has focused primarily on the treatment of high grade gliomas, recurrent cancers of the head and neck region and either primary or metastatic melanoma. Neutron sources for BNCT currently have been limited to specially modified nuclear reactors, which are or until the recent Japanese natural disaster, were available in Japan, United States, Finland and several other European countries, Argentina and Taiwan. Accelerators producing epithermal neutron beams also could be used for BNCT and these are being developed in several countries. It is anticipated that the first Japanese accelerator will be available for therapeutic use in 2013. The major hurdle for the design and synthesis of boron delivery agents has been the requirement for selective tumor targeting to achieve boron concentrations in the range of 20 MUg/g. This would be sufficient to deliver therapeutic doses of radiation with minimal normal tissue toxicity. Two boron drugs have been used clinically, a dihydroxyboryl derivative of phenylalanine, referred to as boronophenylalanine or "BPA", and sodium borocaptate or "BSH" (Na2B12H11SH). In this report we will provide an overview of other boron delivery agents that currently are under evaluation, neutron sources in use or under development for BNCT, clinical dosimetry, treatment planning, and finally a summary of previous and on-going clinical studies for high grade gliomas and recurrent tumors of the head and neck region. Promising results have been obtained with both groups of patients but these outcomes must be more rigorously evaluated in larger, possibly randomized clinical trials. Finally, we will summarize the critical issues that must be addressed if BNCT is to become a more widely established clinical modality for the treatment of those malignancies for which there currently are no good treatment options. PMID- 22929111 TI - The role of Volatile Anesthetics in Cardioprotection: a systematic review. AB - This review evaluates the mechanism of volatile anesthetics as cardioprotective agents in both clinical and laboratory research and furthermore assesses possible cardiac side effects upon usage. Cardiac as well as non-cardiac surgery may evoke perioperative adverse events including: ischemia, diverse arrhythmias and reperfusion injury. As volatile anesthetics have cardiovascular effects that can lead to hypotension, clinicians may choose to administer alternative anesthetics to patients with coronary artery disease, particularly if the patient has severe preoperative ischemia or cardiovascular instability. Increasing preclinical evidence demonstrated that administration of inhaled anesthetics - before and during surgery - reduces the degree of ischemia and reperfusion injury to the heart. Recently, this preclinical data has been implemented clinically, and beneficial effects have been found in some studies of patients undergoing coronary artery bypass graft surgery. Administration of volatile anesthetic gases was protective for patients undergoing cardiac surgery through manipulation of the potassium ATP (KATP) channel, mitochondrial permeability transition pore (mPTP), reactive oxygen species (ROS) production, as well as through cytoprotective Akt and extracellular-signal kinases (ERK) pathways. However, as not all studies have demonstrated improved outcomes, the risks for undesirable hemodynamic effects must be weighed against the possible benefits of using volatile anesthetics as a means to provide cardiac protection in patients with coronary artery disease who are undergoing surgery. PMID- 22929114 TI - Management of tracheal stenosis. AB - PURPOSE OF REVIEW: The treatment for pediatric tracheal stenosis has evolved over the past 50 years. Open airway reconstruction has traditionally been the treatment of choice for this condition. Numerous recent publications now support the use of endoscopic techniques to both augment and sometimes replace open procedures. RECENT FINDINGS: During the past 12 months, a significant interest in expanding the role of airway dilation with balloons to manage airway stenoses has emerged. Development of novel airway stents, to include bioabsorbable products, holds promise to decrease the morbidity of stenting procedures. Continued improvement in preoperative imaging, in the form of virtual bronchoscopy, may someday replace airway endoscopy for planning purposes. Additionally, perioperative management strategies and the use of novel adjuvants have been introduced with a goal of improving outcomes in both endoscopic and open techniques through better control of granulation. Ultimately, advances in tissue engineering may provide yet another reconstructive option in the future. SUMMARY: Endoscopic techniques have an increasing role in the management of pediatric subglottic and tracheal stenosis. However, open airway reconstructive procedures are still required in cases of mature scar, high-grade stenosis, and long-segment stenosis. PMID- 22929115 TI - Effects of oropharyngeal surgery on velopharyngeal competence. AB - PURPOSE OF REVIEW: This article addresses the question of whether it is safe to perform pharyngeal surgery on children who are at risk for speech disorders. Patients with orofacial clefts or craniofacial disorders often have speech and resonance disorders that affect their understandability. They are also prone to develop sleep apnea or other diseases that affect Waldeyer's ring. RECENT FINDINGS: There is increasing recognition of sleep disordered breathing and obstructive sleep apnea syndrome (OSAS) in the group of children who have, or are at risk of developing, speech disorders. Often, these children have a dysfunctional velopharyngeal valve which results in velopharyngeal insufficiency (VPI) and unintelligible speech. There are also children, otherwise thought to be normal, who develop VPI after adenoidectomy or tonsillectomy. Greater knowledge of the causes for VPI has led to the strategies limiting the risk of speech disorders after tonsillectomy or adenoidectomy. SUMMARY: Children at risk for VPI who have OSAS may not experience deterioration of their speech understandability when a careful tonsillectomy with or without partial adenoidectomy is done. Coordination between the treating providers is paramount for successful outcomes for both the problems. PMID- 22929116 TI - 18F-FDG-PET/CT in initial staging and assessment of early response to chemotherapy of pediatric rhabdomyosarcomas. AB - PURPOSE: The objective of this retrospective study was to compare positron emission tomography/computed tomography using fluorine-18-fluorodeoxyglucose (18F FDG-PET/CT) and conventional imaging modalities (CIM) in initial staging and early assessment of response to chemotherapy in children and young adults treated for rhabdomyosarcoma (RMS). PATIENTS AND METHODS: At initial staging, 23 patients (9 months to 21 years) with histologically proven RMS underwent 18F-FDG-PET/CT in addition to CIM (MRI of the primary site, whole-body CT, and bone scintigraphy). After three courses of chemotherapy, 13 patients underwent 18F-FDG-PET/CT in addition to CIM. RECIST criteria and visual analysis of 18F-FDG uptake were used for assessment of response. The standard of reference was determined by an interdisciplinary tumor board on the basis of imaging material, histopathology, and follow-up data (median = 5 years). RESULTS: 18F-FDG-PET/CT sensitivity was superior to that of CIM for determination of lymph node involvement (100 vs. 75%) and detection of metastases (100 vs. 66%). 18F-FDG-PET/CT results changed therapeutic management in 13% of cases. After three courses of chemotherapy 18F FDG-PET/CT was able to detect 92% of objective responses compared with 84% by CIM. The rate of complete response was 69% with 18F-FDG-PET/CT compared with 8% with CIM. CONCLUSION: This study confirms that 18F-FDG-PET/CT reveals important additional information at initial staging of pediatric RMS, which suggests a superior prognostic value of 18F-FDG-PET/CT in early response to chemotherapy assessment. PMID- 22929117 TI - Endogenous growth hormone and insulin after interposition of a reversed jejunal segment in short bowel syndrome. An experimental study on pigs. AB - BACKGROUND: Interposition of a reversed jejunal loop in short bowel sydrome has previously been investigated in human along with animal models and seemed able to facilitate intestinal adaptation. However, it is unclear if growth hormone and insulin, well known for their implication in short bowel pathophysiology, intervene on this effect. FINDINGS: Porcine models were randomly allocated to two cohorts: (1) short bowel (SB) group (n = 8) and (2) short bowel reverse jejunal segment (SB-RS) group (n = 8). Amongst other parameters serum growth hormone and insulin were measured at baseline, as well as on postoperative day 30 and 60. CONCLUSION: Both endogenous hormones failed to demonstrate significant difference in respect to potential direct effect to mechanisms of enhanced intestinal adaptation in reversed group. PMID- 22929119 TI - Encapsulation and permeability characteristics of plasma polymerized hollow particles. AB - In this protocol, core-shell nanostructures are synthesized by plasma enhanced chemical vapor deposition. We produce an amorphous barrier by plasma polymerization of isopropanol on various solid substrates, including silica and potassium chloride. This versatile technique is used to treat nanoparticles and nanopowders with sizes ranging from 37 nm to 1 micron, by depositing films whose thickness can be anywhere from 1 nm to upwards of 100 nm. Dissolution of the core allows us to study the rate of permeation through the film. In these experiments, we determine the diffusion coefficient of KCl through the barrier film by coating KCL nanocrystals and subsequently monitoring the ionic conductivity of the coated particles suspended in water. The primary interest in this process is the encapsulation and delayed release of solutes. The thickness of the shell is one of the independent variables by which we control the rate of release. It has a strong effect on the rate of release, which increases from a six-hour release (shell thickness is 20 nm) to a long-term release over 30 days (shell thickness is 95 nm). The release profile shows a characteristic behavior: a fast release (35% of the final materials) during the first five minutes after the beginning of the dissolution, and a slower release till all of the core materials come out. PMID- 22929120 TI - Position-invariant letter identification is a key component of any universal model of reading. AB - A universal property of visual word identification is position-invariant letter identification, such that the letter "A" is coded in the same way in CAT and ACT. This should provide a fundamental constraint on theories of word identification, and, indeed, it inspired some of the theories that Frost has criticized. I show how the spatial coding scheme of Colin Davis (2010) can, in principle, account for contrasting transposed letter (TL) priming effects, and at the same time, position-invariant letter identification. PMID- 22929118 TI - Different gene expression profiles in normo- and dyslipidemic men after fish oil supplementation: results from a randomized controlled trial. AB - BACKGROUND: Epidemiological studies have suggested the benefits of omega-3 polyunsaturated fatty acids (n-3 PUFAs) on cardiovascular health, but only limited data are available describing n-3 PUFA regulated pathways in humans. The aim of this study was to investigate the effects of n-3 PUFA administration on whole genome expression profiles in the blood of normo- and dyslipidemic subjects. METHODS: Differentially expressed genes were detected after four hours, one week and twelve weeks of supplementation with either fish oil (FO) or corn oil in normo- and dyslipidemic men using whole genome microarrays. RESULTS: Independent of the oil, a significantly higher number of genes was regulated in dyslipidemic subjects compared to normolipidemic subjects. Pathway analyses discovered metabolisms dominantly affected by FO after twelve weeks of supplementation, including the lipid metabolism, immune system and cardiovascular diseases. Several pro-inflammatory genes, in particular, were down-regulated in dyslipidemic subjects, indicating the immune-modulatory and anti-inflammatory capability of FO and its bioactive FAs, eicosapentaenoic acid and docosahexaenoic acid. CONCLUSIONS: This is the first study showing significant differences in gene expression profiles between normo- and dyslipidemic men after FO supplementation. Further studies need to clarify the exact role of n-3 PUFAs in pathways and metabolisms which were identified as being regulated after FO supplementation in this study. TRIAL REGISTRATION: ClinicalTrials.gov (ID: NCT01089231). PMID- 22929121 TI - Guidelines for pathologic diagnosis of malignant mesothelioma: 2012 update of the consensus statement from the International Mesothelioma Interest Group. AB - CONTEXT: Malignant mesothelioma (MM) is an uncommon tumor that can be difficult to diagnose. OBJECTIVE: To provide updated practical guidelines for the pathologic diagnosis of MM. DATA SOURCES: Pathologists involved in the International Mesothelioma Interest Group and others with an interest in the field contributed to this update. Reference material includes peer-reviewed publications and textbooks. CONCLUSIONS: There was consensus opinion regarding (1) distinction of benign from malignant mesothelial proliferations (both epithelioid and spindle cell lesions), (2) cytologic diagnosis of MM, (3) key histologic features of pleural and peritoneal MM, (4) use of histochemical and immunohistochemical stains in the diagnosis and differential diagnosis of MM, (5) differentiation of epithelioid MM from various carcinomas (lung, breast, ovarian, and colonic adenocarcinomas, and squamous cell and renal cell carcinomas), (6) diagnosis of sarcomatoid mesothelioma, (7) use of molecular markers in the diagnosis of MM, (8) electron microscopy in the diagnosis of MM, and (9) some caveats and pitfalls in the diagnosis of MM. Immunohistochemical panels are integral to the diagnosis of MM, but the exact makeup of panels used is dependent on the differential diagnosis and on the antibodies available in a given laboratory. Immunohistochemical panels should contain both positive and negative markers. It is recommended that immunohistochemical markers have either sensitivity or specificity greater than 80% for the lesions in question. Interpretation of positivity generally should take into account the localization of the stain (eg, nuclear versus cytoplasmic) and the percentage of cells staining (>10% is suggested for cytoplasmic membranous markers). These guidelines are meant to be a practical reference for the pathologist. PMID- 22929122 TI - Differences between elderly voluntary and involuntary admitted psychiatric patients in Greece. AB - BACKGROUND: Involuntary psychiatric admission is a controversial issue with legislation varying from country to country. Research on elderly individuals being involuntary admitted has been limited. This study aims first at assessing whether elderly involuntary admitted patients (IAPs) differ with regard to demographic, psychopathological, and behavioral characteristics from voluntary admitted psychiatric patients (VAPs) and second to assess whether the former group should be treated in a different (special) way. METHODS: Forty IAPs were compared to 39 VAPs with regard to sociodemographic data, DSM-IV diagnosis, as well as behavioral issues recorded by the Patient-Staff Conflict Checklist - Shift Report (PSCC-SR). All patients were aged 60 years and over and were admitted in the psychiatric departments of four general hospitals in Athens. The study period lasted 12 months. RESULTS: VAPs were more likely to be suffering from mood disorders, while IAPs presented higher rates of delirium. From the 20 items of the PSCC-SR, differences were found only in two: IAPs presented more aggressive behavior during the first few days of admission whereas VAPs had committed recent suicide attempt just before admission. CONCLUSION: From the clinical point of view, IAPs presented with delirium and more aggressive behavior, whereas, the VAPs presented with higher rates of mood disorder and suicidality. However, from the medicolegal point of view, our findings lend support to the argument of either setting a limited time frame for involuntary admission in elderly patients, and/or allowing for elderly individuals with acute organic conditions to be treated against their will. PMID- 22929123 TI - Involvement of autophagy and mitochondrial dynamics in determining the fate and effects of irreparable mitochondrial DNA damage. AB - Mitochondrial DNA (mtDNA) is different in many ways from nuclear DNA. A key difference is that certain types of DNA damage are not repaired in the mitochondrial genome. What, then, is the fate of such damage? What are the effects? Both questions are important from a health perspective because irreparable mtDNA damage is caused by many common environmental stressors including ultraviolet C radiation (UVC). We found that UVC-induced mtDNA damage is removed slowly in the nematode Caenorhabditis elegans via a mechanism dependent on mitochondrial fusion, fission, and autophagy. However, knockdown or knockout of genes involved in these processes-many of which have homologs involved in human mitochondrial diseases-had very different effects on the organismal response to UVC. Reduced mitochondrial fission and autophagy caused no or small effects, while reduced mitochondrial fusion had dramatic effects. PMID- 22929124 TI - A study of the prevalence and risk factors leading to HIV infection among a sample of street children and youth of Kathmandu. AB - BACKGROUND: The true prevalence of HIV and other sexually transmitted diseases among street children in Nepal is virtually unknown while information on related behavioural risk factors in this population is non-existent. The risk of HIV infection among street children and adolescents may be especially high due to their marginalized social and economic conditions. This study was conducted to determine the prevalence of HIV infection among a sample of street children and youth of Kathmandu and to identify risk factors associated with HIV infection in this group.A sample of street children and youth was recruited based on the purposive sampling of ten streets in Kathmandu, Nepal, known to have a high density of street children and youth. A total of 251 street children (aged 11-16 years) and youth (aged 17-24 years) were enrolled, with informed consent, from November, 2008 through June, 2009. Most of the participants (95%) were male. Case status was determined by serological assessment of HIV status; data on risk factors were obtained using structured survey interviews. HIV prevalence and rates of a number of behavioural risk factors suspected to play a role in HIV transmission among street children and youth were determined, including unprotected sex, intravenous drug use, and other risky sex and substance use behaviours. RESULTS: Among the 251 children and youth, we found an overall HIV prevalence of 7.6%. As the sample size of females was small (n = 13) and the behavioural risk factors are likely to be quite different for boys and girls, we conducted separate analyses by gender. As our small sample of females is unlikely to be representative and lacks power for statistical testing, our report focuses on the results for the males surveyed.The strongest behavioural risk factor to emerge from this study was intravenous drug use; 30% of the male subjects were injecting drug users and 20% of those were HIV positive. Furthermore, frequency of drug injection was a highly significant predictor with a dose-response relationship; males reporting occasional injection drug use were nearly 9 times more likely to be HIV positive than never users, while weekly drug injectors had over 46 times the risk of non-users, controlling for exposure to group sex, the only other significant risk factor in the multivariate model. CONCLUSIONS: This sample of street children and youth of Kathmandu has a nearly 20-fold higher prevalence of HIV infection than the general population of Nepal (0.39%). The children and youth engage in number of high risk behaviours, including intravenous drug use, putting them at significant risk of contracting HIV and other sexually transmitted infections. PMID- 22929126 TI - Structures of amyloid fibrils formed by the prion protein derived peptides PrP(244-249) and PrP(245-250). AB - While the formation of amyloid fibrils from diverse peptide and protein sequences is well established, the molecular determinants of structure and assembly are not well understood. In particular, the relationship between amino acid sequence and the type of internal steric zipper packing adopted in amyloid fibrils has not been established. Here we report the structures of two cytotoxic amyloid peptides derived from the mammalian prion protein, PrP(244-249) and PrP(245-250), determined using solid state NMR. While the amino acid composition of these two hexapeptides is very similar (ISFLIF and SFLIFL), the intermolecular interactions that give rise to the intersheet packing within the fibrils differ significantly. PrP(245-250) adopts a class 1 steric zipper, with parallel sheets stacked in an antiparallel face to face arrangement, stabilized by N- to C-terminal salt bridges. PrP(244-249), by contrast, forms two different intersheet interfaces within amyloid fibrils, with parallel opposing sheets in either a face to face (class 3) or face to back (class 2) arrangement. The fibrils formed by this peptide are primarily stabilized by close packing of the hydrophobic side chains, with contributions from side-chain to backbone hydrogen bonding (class 2 only). Thus, the structures presented here provide new insight into the relationship between amino acid sequence and the types of interactions stabilizing amyloid fibrils. PMID- 22929125 TI - Molecular Modelling and Molecular Dynamics studies of GD1A, GD1B and their complexes with BoNT/B--perspectives in interaction and specificity. AB - The conformational property for the oligosaccharide structure of GD1A and GD1B in aqueous environment is studied by 10 ns Molecular Dynamics simulation using all atom model. Based on the trajectory analysis four conformational models are proposed for GD1A and one for GD1B. Direct and water mediated hydrogen bonding interactions plays a prominent role in stabilizing these conformational structures. The Molecular Modelling and 10 ns MD simulation of Botulinum Neuro Toxin/B-GD1A and BoNT/B-GD1B complex revealed that this toxin can interact with GD1A in the single binding mode and with GD1B in two binding modes. Least mobility is seen for GD1A in the binding pocket of BoNT/B. The GTSM comparison, pair interaction energy calculation, total energy calculation, MM/PBSA binding free energy calculation and RMSD predicts that GD1A is a better receptor for BoNT/B compared to GD1B. The internal NeuNAc1 tends to form more than 70% of hydrogen bonds with BoNT/B both in GD1A and GD1B, hence specifying this particular site as a crucial space for the therapeutic design that can restrict the pathogenic activity of BoNT/B. PMID- 22929127 TI - A taxonomy of nursing care organization models in hospitals. AB - BACKGROUND: Over the last decades, converging forces in hospital care, including cost-containment policies, rising healthcare demands and nursing shortages, have driven the search for new operational models of nursing care delivery that maximize the use of available nursing resources while ensuring safe, high-quality care. Little is known, however, about the distinctive features of these emergent nursing care models. This article contributes to filling this gap by presenting a theoretically and empirically grounded taxonomy of nursing care organization models in the context of acute care units in Quebec and comparing their distinctive features. METHODS: This study was based on a survey of 22 medical units in 11 acute care facilities in Quebec. Data collection methods included questionnaire, interviews, focus groups and administrative data census. The analytical procedures consisted of first generating unit profiles based on qualitative and quantitative data collected at the unit level, then applying hierarchical cluster analysis to the units' profile data. RESULTS: The study identified four models of nursing care organization: two professional models that draw mainly on registered nurses as professionals to deliver nursing services and reflect stronger support to nurses' professional practice, and two functional models that draw more significantly on licensed practical nurses (LPNs) and assistive staff (orderlies) to deliver nursing services and are characterized by registered nurses' perceptions that the practice environment is less supportive of their professional work. CONCLUSIONS: This study showed that medical units in acute care hospitals exhibit diverse staff mixes, patterns of skill use, work environment design, and support for innovation. The four models reflect not only distinct approaches to dealing with the numerous constraints in the nursing care environment, but also different degrees of approximations to an "ideal" nursing professional practice model described by some leaders in the contemporary nursing literature. While the two professional models appear closer to this ideal, the two functional models are farther removed. PMID- 22929128 TI - Recent outbreak of cutaneous anthrax in Bangladesh: clinico-demographic profile and treatment outcome of cases attended at Rajshahi Medical College Hospital. AB - BACKGROUND: Human cutaneous anthrax results from skin exposure to B. anthracis, primarily due to occupational exposure. Bangladesh has experienced a number of outbreaks of cutaneous anthrax in recent years. The last episode occurred from April to August, 2011 and created mass havoc due to its dreadful clinical outcome and socio-cultural consequences. We report here the clinico-demographic profile and treatment outcome of 15 cutaneous anthrax cases attended at the Dermatology Outpatient Department of Rajshahi Medical College Hospital, Bangladesh between April and August, 2011 with an aim to create awareness for early case detection and management. FINDINGS: Anthrax was suspected primarily based on cutaneous manifestations of typical non-tender ulcer with black eschar, with or without oedema, and a history of butchering, or dressing/washing of cattle/goat or their meat. Diagnosis was established by demonstration of large gram-positive rods, typically resembling B. anthracis under light microscope where possible and also by ascertaining therapeutic success. The mean age of cases was 21.4 years (ranging from 3 to 46 years), 7 (46.7%) being males and 8 (53.3%) females. The majority of cases were from lower middle socioeconomic status. Types of exposures included butchering (20%), contact with raw meat (46.7%), and live animals (33.3%). Malignant pustule was present in upper extremity, both extremities, face, and trunk at frequencies of 11 (73.3%), 2 (13.3%), 1 (6.7%) and 1 (6.7%) respectively. Eight (53.3%) patients presented with fever, 7 (46.7%) had localized oedema and 5 (33.3%) had regional lymphadenopathy. Anthrax was confirmed in 13 (86.7%) cases by demonstration of gram-positive rods. All cases were cured with 2 months oral ciprofloxacin combined with flucoxacillin for 2 weeks. CONCLUSIONS: We present the findings from this series of cases to reinforce the criteria for clinical diagnosis and to urge prompt therapeutic measures to treat cutaneous anthrax successfully to eliminate the unnecessary panic of anthrax. PMID- 22929129 TI - First results with the immediate reconstructive strategy for internal hardware exposure in non-united fractures of the distal third of the leg: case series and literature review. AB - BACKGROUND: Fractures of the distal third of the leg are increasingly common and are often handled by open reduction and internal fixation. Exposure and infection of internal hardware could occur, especially after high energy traumas, requiring hardware removal and delayed soft tissue reconstruction. Nevertheless immediate soft tissue reconstruction without internal hardware removal is still possible in selected patients. In this study the effectiveness and the complications of immediate soft tissue reconstruction without internal hardware removal is analyzed. METHODS: 13 patients, affected by internal hardware exposure in the distal leg, treated with immediate soft tissue reconstruction with pedicled flaps and hardware retention, are retrospectively analyzed, with special regard to flap survival and wound infection. RESULTS: Wound infection was observed in 10 cases before surgery and in 5 cases surgical debridement was necessary before reconstruction which was performed in a separate operative session. After reconstruction, wound dehiscence and infection occurred in 5 cases, and in 3 cases removal of internal hardware was necessary in order to achieve the complete healing of dehiscence. In one case the previous flap failed but prompt reconstruction with a sural fasciocutaneous flap was performed without hardware removal and without complications. Pre-operative infection and late reconstructive surgery are predictive for higher rates of post-operative complications (respectively p 0.018 and p 0.028). CONCLUSION: Our approach achieved full recovery in 53.8% of the treated cases after one-step surgery, therefore reducing hospitalization and allowing early mobilization. Controlled trials are needed to confirm the effectiveness of this strategy, although the present case series shows encouraging results. PMID- 22929130 TI - Pediatric prehospital evaluation of NYC respiratory arrest survival (PHENYCS). AB - OBJECTIVE: The objective of this study was to describe the demographics, epidemiology, and characteristics associated with survival of children younger than 18 years who had an out-of-hospital respiratory arrest (OOHRA) during a 1 year period in a large urban area. METHODS: A prospective observational cohort of consecutive children younger than 18 years with OOHRA cared for by the New York City 911 emergency medical services (EMS) system from April 12, 2002, to March 31, 2003. Following resuscitative efforts, data were collected from prehospital providers by trained paramedics using a previously validated telephone interview process. Data included Pediatric Utstein core measures and critical prehospital time intervals. Analyses used descriptive statistics and bivariate association with survival. RESULTS: Resuscitation was attempted on 109 OOHRAs during the study period. The median age was 7 years, 52% were male. Lay bystanders witnessed 56%. Most occurred at home (77%). Witnesses were family members in 59%. Bystander cardiopulmonary resuscitation (CPR) was performed in 31% of all respiratory arrests (RAs). A chronic medical condition existed in 28%. Median EMS response time was 4.4 minutes (range, 0-12 min). Overall survival was 79% to hospital discharge. Time interval to EMS arrival, witnessed arrest, bystander CPR, and ventilation method were not associated with survival. CONCLUSIONS: Most OOHRAs occurred at home, and bystander CPR occurred infrequently. The majority of children in OOHRA survived. Strategies to increase the rate of bystander CPR, especially by family members, are needed. Out-of-hospital RAs are a large proportion of all arrests in children. Future studies of pediatric arrest should include RA as well as cardiac arrest. PMID- 22929131 TI - Pediatric prehospital evaluation of NYC cardiac arrest survival (PHENYCS). AB - OBJECTIVES: The objective of this study was to describe the demographics of out of-hospital cardiac arrests (OOHCAs) in children younger than 18 years and characteristics associated with survival among these children in New York City (NYC). METHODS: A prospective observational cohort of all children younger than 18 years with OOHCA in NYC between April 1, 2002, and March 31, 2003. Data were collected from prehospital providers by trained paramedics utilizing a previously validated telephone interview process. Data included Pediatric Utstein core measures and critical prehospital time intervals. Analyses utilized descriptive statistics and bivariate association with survival. RESULTS: Resuscitation was attempted on 147 pediatric OOHCA patients in NYC during the study period; outcome data were collected on these patients. The median age was 2 years; most (58%) were male. The majority of arrests occurred at home (69%). Lay bystanders witnessed 33% of all OOHCA; 68% of witnesses were family members. Bystander cardiopulmonary resuscitation (CPR) was performed on 30% of children. Median emergency medical services response time was 3.6 minutes (range, 0.4-14.4 minutes). Initial rhythm was as follows: ventricular fibrillation, 2%; asystole, 50%; pulseless electrical activity, 9.5%; other rhythms, 11.6%; no rhythm recorded, 26%. Survival was 4% to hospital discharge and was present only among witnessed arrests (6/58 witnessed vs 0/70 unwitnessed, P < 0.05). CONCLUSIONS: Pediatric OOHCA survival rate is low. Witnessed arrest was the most important determinant of survival. Ventricular fibrillation was an uncommon rhythm measured by emergency medical services. The majority of arrests occurred at home. The rate of bystander CPR was low. Strategies to increase the rate of bystander CPR for children, especially by family members, are needed. PMID- 22929132 TI - The use of a modified pediatric early warning score to assess stability of pediatric patients during transport. AB - OBJECTIVE: Pediatric early warning scores (PEWSs) have been used effectively in limited patient care areas. Children's Transport, at Children's Healthcare of Atlanta, transports approximately 5000 children annually. In an effort to consistently assess patient acuity and the impact of our team's interventions, we instituted a modified "transport PEWS" (TPEWS). METHODS: The existing PEWS was modified to reflect the transport environment. A retrospective chart review was conducted of 100 consecutive children transported by Children's Transport in March 2009. Transport PEWS given during triage by the dispatch center (TPEWStri), TPEWS calculated at referring facility by the team (TPEWSref), and final TPEWS at the accepting institution (TPEWSacc) were compared. RESULTS: Eighty-six patients were transported by ground. The median age was 50.4 months. Sixty patients (60%) received some intervention from the transport team. Median TPEWSref was 3 (0-9) upon initial assessment, and TPEWSacc was 2 (0-9) on arrival at the accepting facility (P = 0.0001). Seventy-three percent (73/100) of patients were transported to the emergency room; 15 (15%) of 100 to the general inpatient area, and 12 (12%) of 100 to the intensive care unit. In addition, a triage TPEWS (TPEWStri) was calculated from information given from the referring facility in 59 of the 100 patients. A significant difference in TPEWStri and TPEWSref was noted (P = 0.0001). CONCLUSIONS: In this cohort of pediatric transport patients, TPEWS appears to be a helpful additional assessment tool. Transport PEWS may function as a tool for assessing severity of illness, hence optimizing transport dispatch and patient disposition. PMID- 22929133 TI - A comparison of resource utilization between emergency physicians and pediatric emergency physicians. AB - OBJECTIVES: Pediatric patients in the emergency department (ED) are typically seen either by general emergency physicians (EPs) or by pediatric emergency physicians (PEPs) who have completed either a fellowship in pediatric emergency medicine or both pediatric and emergency medicine residencies. This study evaluates admission rates, turnaround times, and test and medication utilization for EPs versus PEPs. METHODS: A retrospective chart analysis was conducted at an academic tertiary care hospital with a dedicated pediatric ED. When the pediatric ED is open (from noon to midnight), it is always staffed with dedicated pediatric nurses and residents. In our ED, the only variable is the attending physician, who can either be an EP or a PEP. All visits for patients younger than 18 years who presented during the time the pediatric ED was open from July 1, 2007, to June 30, 2010, were eligible for inclusion. Only patients seen by physicians who saw more than 400 patients during this period were included. Disposition outcomes for patients who were either admitted or discharged were compared between EPs and PEPs. Complete blood count, Chem 7, urinalysis, chest radiography ordering rates, and intravenous fluid and ondansetron administration were used as surrogates for general conclusions about test utilization. RESULTS: There were 13,347 patient visits eligible for inclusion, of which 8330 (62.4%) were seen by 2 PEPs, and 5017 (37.6%) were seen by 9 EPs. There was a difference in mean patient age (6.9 vs 7.1 years, P = 0.01), whereas sex (53.6% vs 53.9% male, P = 0.72), race (P = 0.13), acuity (mean Emergency Severity Index 3.35 vs 3.33, P = 0.99), and mode of arrival (10.6% vs 12.3% emergency medical services transport, P = 0.06) were not significantly different. Overall admission rates were similar (17.1% PEP vs 17.5% EP, P = 0.50), as were critical care admissions (2.9% PEP vs 2.7% EP of total admissions, P = 0.40). Turnaround times were significantly different (146.0 +/- 2.5 minutes PEP vs 149.7 +/- 3.2 minutes EP, P = 0.04). Ordering rates of Chem 7, urinalyses, chest radiographs, and ondansetron were lower by PEPs. CONCLUSIONS: In our pediatric ED, which represents a natural experiment where the type of physician is the only variable, PEPs and EPs have similar rates of admission to floor beds and critical care. Pediatric EPs are slightly faster at throughput and order fewer tests and medication. PMID- 22929134 TI - Conducted electrical weapon (TASER) use against minors: a shocking analysis. AB - OBJECTIVE: Conducted electrical weapons (CEWs) such as the TASER are often used by law enforcement (LE) personnel during suspect apprehension. Previous studies have reported an excellent safety profile and few adverse outcomes with CEW use in adults. We analyzed the safety and injury profile of CEWs when used during LE apprehension of children and adolescents, a potentially vulnerable population. METHODS: Consecutive CEW uses by LE officers against criminal suspects were tracked at 10 LE agencies and entered into a database as part of an ongoing multicenter injury surveillance program. All CEW uses against minors younger than 18 years were retrieved for analysis. Primary outcomes included the incidence and type of mild, moderate, and severe CEW-related injury, as assessed by physician reviewers in each case. Ultimate outcomes, suspect demographics, and circumstances surrounding LE involvement are reported secondarily. RESULTS: Of 2026 consecutive CEW uses, 100 (4.9%) were uses against minor suspects. Suspects ranged from 13 to 17 years, with a mean age of 16.1 (SD, 0.99) years (median, 16 years). There were no significant (moderate or severe) injuries reported (0%; 97.5% confidence interval, 0.0%-3.6%). Twenty suspects (20%; 95% confidence interval, 12.7%-29.1%) were noted to sustain 34 mild injuries. The majority of these injuries (67.6%) were expected superficial punctures from CEW probes. Other mild injuries included superficial abrasions and contusions in 7 cases (7%). CONCLUSIONS: None of the minor suspects studied sustained significant injury, and only 20% reported minor injuries, mostly from the expected probe puncture sites. These data suggest that adolescents are not at a substantially higher risk than adults for serious injuries after CEW use. PMID- 22929135 TI - Physician management of pediatric mental health patients in the emergency department: assessment, charting, and disposition. AB - OBJECTIVE: The focus of this study was to describe the clinical data that pediatric emergentologists recorded and how they were used in the mental health (MH) care of patients. METHODS: A structured chart review was conducted for all MH presentations to a pediatric emergency department in 2007. Three research assistants extracted clinical chart data and completed the Child and Adolescent Needs and Strengths Tool. RESULTS: The clinical records of 495 children and youth were reviewed. Emergentologists referred 124 (25.4%) for a psychiatric consult, and 46 (37%) of these patients were admitted to either an inpatient psychiatric or eating-disorders unit. Psychosis, suicide risk, eating disturbance, anxiety, and resistance to treatment predicted admission to the psychiatric inpatient unit or the eating-disorders unit. Of the 365 patients discharged back to the community, the majority (n = 189, 51.8%) were referred back to their family physician. For 117 patients (32%), there was no discharge documentation in the medical chart. Age, parent present, currently on medication, currently receiving counseling, depression, anxiety, and adjustment to trauma predicted provision of charted recommendation. CONCLUSIONS: This study revealed that the pediatric emergentologists' charting of MH patients is inconsistent and incomplete. Although recorded clinical data predicted psychiatric consultation and disposition for these patients, missing data were evident in a significant number of records. The results of the study point to a need to develop a more uniform approach to the collection and recording of clinical data for MH patients. PMID- 22929137 TI - Sonographic diagnosis of metaphyseal forearm fractures in children: a safe and applicable alternative to standard x-rays. AB - OBJECTIVE: Metaphyseal forearm fractures are very common in childhood. Radiography of the wrist is the standard diagnostic procedure. The aim of our study was to evaluate and confirm the safety and applicability of the ultrasound diagnostic procedure in comparison to x-ray diagnosis. METHODS: We investigated 76 patients aged between 1 and 14 years. After clinical assessment, patients with suspected forearm fractures first underwent ultrasound examination of the metaphyseal forearm followed by standard 2-view radiographs of the wrist. Ultrasound and radiographic findings were then compared, and sensitivity and specificity for ultrasound were calculated. RESULTS: Of 76 patients, we found 42 patients with 52 metaphyseal forearm fractures by x-rays. By ultrasound, we also diagnosed 52 fractures. All patients with no fractures were correctly diagnosed as well. Referring to x-ray, we calculated for ultrasound a sensitivity of 96.1% and a specificity of 97%. Comparing axis deviation of displaced fractures, we found a mean difference of 2.1 degrees between sonographic and x-ray values. CONCLUSIONS: We confirm that ultrasound is an applicable and safe alternative tool to x-rays in nondisplaced or excluded metaphyseal forearm fractures in children. PMID- 22929136 TI - Survey in the emergency department of parents' understanding of cough and cold medication use in children younger than 2 years. AB - OBJECTIVES: In August 2007, the Food and Drug Administration (FDA) released a public health advisory recommending that over-the-counter cough and cold medications (CCMs) not be used in children younger than 2 years. Our objective was to assess parents' awareness and understanding of the guidelines. METHODS: We surveyed caregivers of children younger than 2 years in the emergency department of an urban tertiary care military hospital where civilian patients are also treated. After completing the survey, caregivers received a handout explaining the FDA's recommendations. RESULTS: Our response rate was 99% (264/265). First time parents constituted 45% (114/251) of responders. Education level was high school, 21%; some college, 36%; and college graduate, 40%. Thirty-one percent (77/247) were aware of the FDA guidelines. Of these 77, 44 (57%) reported the guidelines indicated CCMs were not safe in children younger than 2 years, and 18 (23%) said CCMs have caused death. Twenty-six percent (68/264) did not give CCMs to their children younger than 2 years, and 40% of these reported it was because of learning about the guidelines; 63% (165/264) reported CCMs were effective, 11% ineffective, and 27% did not know. Fifty-seven percent (151/263) reported CCMs were safe, 12% unsafe, and 31% unsure. Twenty-two percent (31/143) planned to use or continue to use CCMs in their children, 34% did not, 23% not sure, and 21% only if their doctor advised it. CONCLUSIONS: The majority of caregivers were not aware of the FDA guidelines on CCM use in children younger than 2 years. Most thought CCMs were safe and effective. PMID- 22929138 TI - Intussusception: clinical presentations and imaging characteristics. AB - OBJECTIVE: The objectives of this study were to determine the prevalence of clinical findings associated with intussusception based on age and to evaluate the test characteristics of the presence of air in the ascending colon on abdominal radiographs and the effectiveness of ultrasound in diagnosing intussusception. METHODS: This was a retrospective cohort study via chart review at a tertiary care center from January 2002 to December 2008. All children, aged 0 to 17 years, were identified with intussusception by International Classification of Diseases, Ninth Revision diagnostic coding. Charts were reviewed for clinical signs and symptoms at presentation, and all diagnostic studies were retrieved. A pediatric radiologist reviewed all films and ultrasounds. RESULTS: A total of 219 patients were identified with intussusception. One hundred thirty-two (60%) of patients were male; 127 (60%) were younger than 1 year (median, 7 months), 59 (27%) were 13 to 35 months (median, 23 months), and 33 (15%) were 3 years or older (median, 5 years). Children younger than 12 months were more likely to present with emesis, irritability, and guaiac-positive or grossly bloody stools compared with children older than 12 months (P < 0.05). In children older than 12 months, abdominal pain was the most common symptom (>96%). Plain films were performed in 192 children, and of these, 163 (85%) had no air present in the ascending colon. Abdominal ultrasound was performed on 63 patients, with 58 (92%) having findings consistent with intussusception. CONCLUSIONS: Abdominal pain is the most common complaint in all ages for children presenting with intussusception. In children younger than 12 months, the strongest clinical predictors are emesis, irritability, and blood in the stool. For diagnosing intussusceptions, radiographs of the abdomen performed well, but ultrasound performed better, diagnosing intussusception in 92% of the cases. PMID- 22929139 TI - Bedside ultrasound education in pediatric emergency medicine fellowship programs in the United States. AB - OBJECTIVES: As the use of bedside ultrasound becomes more prevalent in pediatric emergency departments, the need for a national curriculum for fellows' training in pediatric emergency medicine (PEM) has increased. The objectives of this study were to describe the current state of bedside ultrasound education among existing PEM fellowship programs and to explore the interest in a national curriculum. METHODS: A 20-question survey was sent to all 57 PEM fellowship directors in the United States in February 2011. Weekly reminders were sent for 4 weeks. RESULTS: The response rate was 58% (33/57). Although 91% of respondents reported having an ultrasound machine available, only 16% reported an ultrasound curriculum designed specifically for PEM. Another 25% reported no curriculum, and 28% use a curriculum designed for general emergency medicine physicians. Most (>83%) directors thought an ultrasound curriculum for PEM fellows should include the focused assessment with sonography for trauma, bladder size assessment, soft tissue foreign body localization, skin and soft tissue infection evaluation, guidance for central and peripheral line insertion, and arthrocentesis. Some directors (40%-68%) thought that cardiac ultrasound, thoracic ultrasound, abdominal ultrasound, lumbar puncture guidance, fracture reduction, nerve blocks, and testicular ultrasounds should also be included. Forty-two percent plan to create a bedside ultrasound curriculum in the next 5 years, and 40% reported the lack of a national curriculum as a barrier to creating a curriculum. CONCLUSIONS: Bedside ultrasound use in pediatric emergency departments is very common, and PEM fellowship directors would welcome the development of a standard curriculum. PMID- 22929140 TI - Test characteristics of an automated age- and temperature-adjusted tachycardia alert in pediatric septic shock. AB - OBJECTIVES: This study aimed to create and analyze the performance of an automated triage tool alerting triage nursing staff and physicians to an abnormal heart rate consistent with septic shock in a pediatric emergency department. METHODS: A computerized best-practice alert (BPA) triage system corrected heart rate for temperature (5 beats per minute for each 1 degrees F above 100 degrees F or 9.6-10 beats per minute for each 1 degrees C > 36 degrees C) and alarmed on tachycardia. If patients appeared ill and/or had medical comorbidities predisposing them to sepsis, a "shock protocol" was activated. Sensitivity was calculated for patients clinically diagnosed with shock during the study period. RESULTS: During the study period (February to August 2010), the BPA was triggered in 4552 (11.5%) of 39,697 visits. Mean age was 5.4 years (range, 18 days to 18 years); 53% were female. The tool was 81% sensitive in identifying the 210 patients with shock. Missed patients were more likely to be previously healthy (odds ratio, 2.7; 95% confidence interval, 1.2-6.2), younger (5.7 vs 8.7 years, P = 0.004), and less likely to have a malignancy (odds ratio, 0.38; 95% confidence interval, 0.2-0.8). The tool was 89% specific; positive and negative predictive values were 4% and 99.9%, respectively. CONCLUSIONS: The BPA-automated sensitive triage tool, based solely on initial temperature and heart rate, led to the identification of most children with septic shock, even before clinical acumen and laboratory values were incorporated into the diagnostic algorithm. PMID- 22929141 TI - Capnometry as a predictor of admission in bronchiolitis. AB - OBJECTIVES: Bronchiolitis is a dynamic condition, and predicting clinical deterioration can be difficult. The objective of this study was to determine whether capnometry readings among bronchiolitic children admitted to the hospital are significantly different from those discharged from the emergency department. METHODS: We prospectively studied a convenience sample of children younger than 24 months with clinical bronchiolitis. A single end-tidal CO2 (ETCO2) reading was taken before treatment, and a clinical work of breathing score was assigned to each patient. Treating physicians and nurses were blinded to capnometry readings. The decision to admit was based on the judgment of the attending physician. Descriptive statistics and appropriate hypothesis testing were performed. A receiver operating characteristic curve was constructed for the association between admission and capnometry readings. The alpha was set at 0.05 for all comparisons. RESULTS: One hundred five children with bronchiolitis were included for study. Capnometry readings for admitted (mean, 32.6 mm Hg; 95% confidence interval [CI], 30.3-34.9 mm Hg) and discharged (mean 31.4 mm Hg; 95% CI 29.8-33.0 mm Hg) bronchiolitic children were not significantly different. Capnometry readings for low (mean, 31.7 mm Hg; 95% CI, 29.5-33.8 mm Hg), intermediate (mean, 32.1 mm Hg; 95% CI, 30.1-34.1 mm Hg), and high (mean, 30.5 mm Hg; 95% CI, 19.3 41.7 mm Hg) work of breathing (score) ranges were not significantly different. CONCLUSIONS: Capnometry readings are not useful in predicting admission for children younger than 2 years with clinical bronchiolitis. There are no significant differences in capnometry readings among bronchiolitic children with low, medium, and high work of breathing scores. PMID- 22929142 TI - Etomidate for short pediatric procedures in the emergency department. AB - OBJECTIVE: This study aimed to prospectively determine the etomidate dose associated with adequate sedation and few significant respiratory events for procedures of short duration in children. METHODS: This is a prospective cohort study in an urban pediatric emergency department of patients 4 to 18 years requiring sedation and analgesia for painful procedures of short duration. Patients received fentanyl 1 MUg/kg followed by intravenously administered etomidate 0.1 to 0.2 mg/kg as a loading dose. An additional dose of etomidate 0.1 mg/kg was intravenously administered if needed. The level of sedation was determined by The Children's Hospital of Wisconsin Sedation Score. The primary outcome was to determine the etomidate dose associated with an adequate level of sedation and procedural completion. RESULTS: Sixty patients were enrolled. The most frequent procedure was fracture reduction (50/60, 83.3%). Procedures were successfully completed for 59 (98.3%) of 60 patients. The initial dose of etomidate associated with adequate sedation was 0.2 mg/kg intravenously administered for 33 (66.7%) of 50 patients requiring fracture reduction and for 6 (60.0%) of 10 patients receiving a procedure other than fracture reduction. Respiratory depression was noted in 9 (16.4%) of 55 patients, and oxygen desaturation was noted in 23 (39.0%) of 59 patients. Of 58 patients, 21 (36.2%) experienced a respiratory adverse event requiring brief intervention including oxygen supplementation, stimulation, and/or airway repositioning. No patient experienced a significant adverse respiratory event, defined as positive pressure ventilation. Median time to discharge-ready was 21 minutes. CONCLUSIONS: For short-duration painful emergency department procedures, etomidate 0.2 mg/kg intravenously administered after fentanyl was associated with effective sedation, successful procedural completion, and readily managed respiratory adverse events in children. PMID- 22929143 TI - Accuracy of plain radiographs to exclude the diagnosis of intussusception. AB - OBJECTIVES: To prospectively determine the test characteristics of the 3-view abdominal radiograph to decrease the likelihood of ileocolic intussusception. METHODS: We conducted a prospective cross-sectional study of children aged 3 months to 3 years suspected of having intussusception at a children's hospital emergency department. Clinicians obtained supine, prone, and left lateral decubitus radiographs. We determined the presence or absence of intussusception by air enema, ultrasound, operative report, or clinical follow-up. A masked pediatric radiologist reviewed all radiographs. The criteria evaluated were whether air was visualized in the ascending colon on each view and in the transverse colon on the supine view. RESULTS: Nineteen (14.8%) of 128 patients had intussusception. Using air in the ascending colon on all 3 views as the diagnostic criteria, the test characteristics of the 3-view radiograph were sensitivity, 100% (95% confidence interval [CI], 79.1-100); specificity, 17.4% (95% CI, 11.1-26.1); negative predictive value, 100% (95% CI, 79.1-100); and likelihood ratio of a negative test, 0. When 2 or more of 3 views had air in the ascending colon, sensitivity decreased to 89.5% (95% CI, 75.7-100) and specificity improved to 45.0% (95% CI, 35.6-54.3). Air in the transverse colon had moderate sensitivity, 84.2% (95% CI, 67.8-100), but further improved specificity, 63.3% (95% CI, 54.2-72.4). CONCLUSIONS: The presence of air in the ascending colon on the 3-view abdominal radiograph can decrease the likelihood of or exclude intussusception. When clinical suspicion is low, the presence of specific criterion on a 3-view abdominal radiograph series may obviate the need for further studies. PMID- 22929144 TI - Factors associated with the interfacility transfer of the pediatric trauma patient: implications for prehospital triage. AB - OBJECTIVE: The goal of this study was to identify prehospital factors associated with increased likelihood of interfacility transfer of pediatric trauma patients. Such factors might serve as a basis for improvements in future field pediatric trauma triage guidelines. METHODS: This was a retrospective cohort study of children aged 12 years or younger with blunt, penetrating, or thermal injuries who were transported by ground emergency medical services from the scene to the emergency department of a Level I, II, or III trauma center within the Denver metropolitan area from January 1, 2000, to December 31, 2008. Characteristics predicting subsequent interfacility transfer to a pediatric trauma center (PTC) were assessed. RESULTS: A total of 1673 patients were included in the analysis. Variables hypothesized to be most commonly associated with interfacility transfer were age, sex, mechanism of injury, body region of injury, and Glasgow Coma Scale score. The cohort included 1079 males and 593 females. Logistic regression analysis yielded the following as significant predictors of transfer: younger age (odds ratio [OR], 1.19; 95% confidence interval [CI], 1.15-1.25), lower Glasgow Coma Scale score (OR, 1.08; 95% CI, 1.01-1.16), the presence of burns (OR, 37.52; 95% CI, 7.3-191.7), non-accidental trauma (OR, 6.09; 95% CI, 2.44-15.25), falls (OR, 1.62; 95% CI, 1.06-2.48), other motor vehicle-related incidents (OR, 2.37; 95% CI, 1.08-5.19), abdominal injury (OR, 5.39; 95% CI, 2.31-12.55), head/neck injury (OR, 7.89; 95% CI, 4.21-14.77), limb injury (OR, 5.31; 95% CI, 2.78 10.16), and multiple injuries (OR, 13.01; 95% CI, 5.0-33.8). CONCLUSIONS: Factors highly associated with transfer of an injured child from a non-PTC to a PTC included younger age, burns, non-accidental trauma, head/neck injury, and multiple injuries in younger children. Further investigation is warranted to determine whether these factors may have applicability in future improvements in field pediatric trauma patient triage guidelines. PMID- 22929145 TI - Gastrointestinal perforations in neonatal period: experience over 10 years. AB - AIM: This report describes our experience concerning gastrointestinal perforation due to necrotizing enterocolitis during a 10-year period. METHOD: The cases of 27 gastrointestinal perforations, which were treated in our hospital, were retrospectively reviewed. RESULTS: All patients were neonates and infants up to the age of 2 months. The study population consisted of 16 boys (59.3%) and 11 girls (40.7%). Twenty-one neonates (77.8%) were preterm, and the median gestational age was 28 weeks. Twenty-four cases (88.9%) of perforation underwent laparotomy. The overall mortality was 63%. Seventy-six percent of the preterm neonates and only 16.7% of the full-term neonates died. CONCLUSIONS: Gastrointestinal perforation is still connected with a high mortality rate, with necrotizing enterocolitis being the main cause of death. The neonates who did not undergo surgery all died. PMID- 22929146 TI - Effects of spermine NONOate and ATP on the thermal stability of hemoglobin. AB - BACKGROUND: Minor changes in protein structure induced by small organic and inorganic molecules can result in significant metabolic effects. The effects can be even more profound if the molecular players are chemically active and present in the cell in considerable amounts. The aim of our study was to investigate effects of a nitric oxide donor (spermine NONOate), ATP and sodium/potassium environment on the dynamics of thermal unfolding of human hemoglobin (Hb). The effect of these molecules was examined by means of circular dichroism spectrometry (CD) in the temperature range between 25 degrees C and 70 degrees C. The alpha-helical content of buffered hemoglobin samples (0.1 mg/ml) was estimated via ellipticity change measurements at a heating rate of 1 degrees C/min. RESULTS: Major results were: 1) spermine NONOate persistently decreased the hemoglobin unfolding temperature Tuirrespectively of the Na + /K + environment, 2) ATP instead increased the unfolding temperature by 3 degrees C in both sodium-based and potassium-based buffers and 3) mutual effects of ATP and NO were strongly influenced by particular buffer ionic compositions. Moreover, the presence of potassium facilitated a partial unfolding of alpha-helical structures even at room temperature. CONCLUSION: The obtained data might shed more light on molecular mechanisms and biophysics involved in the regulation of protein activity by small solutes in the cell. PMID- 22929147 TI - Flexible letter-position coding is unlikely to hold for morphologically rich languages. AB - We agree with Frost that flexible letter-position coding is unlikely to be a universal property of word recognition across different orthographies. We argue that it is particularly unlikely in morphologically rich languages like Finnish. We also argue that dual-route models are not overly flexible and that they are well equipped to adapt to the linguistic environment at hand. PMID- 22929148 TI - Informatics in radiology: development of a research PACS for analysis of functional imaging data in clinical research and clinical trials. AB - Picture archiving and communication systems (PACS) provide limited flexibility for the development of novel research methods. By contrast, the research model of data access is more flexible but has vulnerabilities in numerous areas. No single monolithic application can fulfill the diverse and rapidly changing needs of the clinical imaging research community. Instead, the focus should be on the interoperability of preexisting systems. To a large extent, this can be achieved by means of a unified interface for storing and retrieving data. The concept of a research PACS combines the advantages of the clinical and research models of data access while eliminating the disadvantages. A research PACS streamlines the data management process. Instead of a single software program, it consists of a confederation of independent applications brought together by the ability to store and retrieve data in a common database. A prototype research PACS has been developed that is based on the Extensible Neuroimaging Archive Toolkit (XNAT) in association with two new in-house tools: a data selection tool and a data archiving tool. By taking as an example the comparison of regions of interest in multifunctional liver data, it was demonstrated that this framework allows a number of in-house and open-source applications originally designed to work on a stand-alone basis to be integrated into a unified workflow, with minimal redevelopment effort. PMID- 22929149 TI - Informatics in radiology: web-based preliminary reporting system for radiology residents with PACS integration. AB - While on call, radiology residents review imaging studies and issue preliminary reports to referring clinicians. In the absence of an integrated reporting system at the training sites of the authors' institution, residents were typing and faxing preliminary reports. To partially automate the on-call resident workflow, a Web-based system for resident reporting was developed by using the free open source xAMP Web application framework and an open-source DICOM (Digital Imaging and Communications in Medicine) software toolkit, with the goals of reducing errors and lowering barriers to education. This reporting system integrates with the picture archiving and communication system to display a worklist of studies. Patient data are automatically entered in the preliminary report to prevent identification errors and simplify the report creation process. When the final report for a resident's on-call study is available, the reporting system queries the report broker for the final report, and then displays the preliminary report side by side with the final report, thus simplifying the review process and encouraging review of all of the resident's reports. The xAMP Web application framework should be considered for development of radiology department informatics projects owing to its zero cost, minimal hardware requirements, ease of programming, and large support community. PMID- 22929150 TI - Developing a universal model of reading necessitates cracking the orthographic code. AB - I argue, contra Frost, that when prime lexicality and target density are considered, it is not clear that there are fundamental differences between form priming effects in Semitic and European languages. Furthermore, identifying and naming printed words in these languages raises common theoretical problems. Solving these problems and developing a universal model of reading necessitates "cracking" the orthographic input code. PMID- 22929151 TI - Genome scanning for detecting adaptive genes along environmental gradients in the Japanese conifer, Cryptomeria japonica. AB - Local adaptation is important in evolutionary processes and speciation. We used multiple tests to identify several candidate genes that may be involved in local adaptation from 1026 loci in 14 natural populations of Cryptomeria japonica, the most economically important forestry tree in Japan. We also studied the relationships between genotypes and environmental variables to obtain information on the selective pressures acting on individual populations. Outlier loci were mapped onto a linkage map, and the positions of loci associated with specific environmental variables are considered. The outlier loci were not randomly distributed on the linkage map; linkage group 11 was identified as a genomic island of divergence. Three loci in this region were also associated with environmental variables such as mean annual temperature, daily maximum temperature, maximum snow depth, and so on. Outlier loci identified with high significance levels will be essential for conservation purposes and for future work on molecular breeding. PMID- 22929152 TI - Plio-Pleistocene history and phylogeography of Acacia senegal in dry woodlands and savannahs of sub-Saharan tropical Africa: evidence of early colonisation and recent range expansion. AB - Drylands are extensive across sub-Saharan Africa, socio-economically and ecologically important yet highly sensitive to environmental changes. Evolutionary history, as revealed by contemporary intraspecific genetic variation, can provide valuable insight into how species have responded to past environmental and population changes and guide strategies to promote resilience to future changes. The gum arabic tree (Acacia senegal) is an arid-adapted, morphologically diverse species native to the sub-Saharan drylands. We used variation in nuclear sequences (internal transcribed spacer (ITS)) and two types of chloroplast DNA (cpDNA) markers (PCR-RFLP, cpSSR) to study the phylogeography of the species with 293 individuals from 66 populations sampled across its natural range. cpDNA data showed high regional and rangewide haplotypic diversity (h(T(cpSSR))=0.903-0.948) and population differentiation (G(ST(RFLP))=0.700 0.782) with a phylogeographic pattern that indicated extensive historical gene flow via seed dispersal. Haplotypes were not restricted to any of the four varieties, but showed significant geographic structure (G(ST(cpSSR))=0.392; R(ST)=0.673; R(ST)>R(ST) (permuted)), with the major division separating East and Southern Africa populations from those in West and Central Africa. Phylogenetic analysis of ITS data indicated a more recent origin for the clade including West and Central African haplotypes, suggesting range expansion in this region, possibly during the Holocene humid period. In conjunction with paleobotanical evidence, our data suggest dispersal to West Africa, and across to the Arabian Peninsula and Indian subcontinent, from source populations located in the East African region during climate oscillations of the Plio-Pleistocene. PMID- 22929153 TI - Internalization of paramagnetic phosphatidylserine-containing liposomes by macrophages. AB - BACKGROUND: Inflammation plays an important role in many pathologies, including cardiovascular diseases, neurological conditions and oncology, and is considered an important predictor for disease progression and outcome. In vivo imaging of inflammatory cells will improve diagnosis and provide a read-out for therapy efficacy. Paramagnetic phosphatidylserine (PS)-containing liposomes were developed for magnetic resonance imaging (MRI) and confocal microscopy imaging of macrophages. These nanoparticles also provide a platform to combine imaging with targeted drug delivery. RESULTS: Incorporation of PS into liposomes did not affect liposomal size and morphology up to 12 mol% of PS. Liposomes containing 6 mol% of PS showed the highest uptake by murine macrophages, while only minor uptake was observed in endothelial cells. Uptake of liposomes containing 6 mol% of PS was dependent on the presence of Ca2+ and Mg2+. Furthermore, these 6 mol% PS-containing liposomes were mainly internalized into macrophages, whereas liposomes without PS only bound to the macrophage cell membrane. CONCLUSIONS: Paramagnetic liposomes containing 6 mol% of PS for MR imaging of macrophages have been developed. In vitro these liposomes showed specific internalization by macrophages. Therefore, these liposomes might be suitable for in vivo visualization of macrophage content and for (visualization of) targeted drug delivery to inflammatory cells. PMID- 22929154 TI - In vitro and in vivo evaluation of a preservative-free cationic emulsion of latanoprost in corneal wound healing models. AB - PURPOSE: Cationic emulsions (CEs), developed as vehicles for lipophilic drugs, have been shown to be safe and effective for the treatment of dry eye. The aim of this study was to investigate the effects of a preservative-free latanoprost 0.005% CE (latanoprost-CE) in in vitro and in vivo models of corneal wound healing. METHODS: An in vitro wound was made by scraping through a confluent layer of human corneal epithelial cells. Cytotoxicity, cell migration, and proliferation were analyzed after an exposure to phosphate-buffered saline, CE, latanoprost-CE, 0.02% benzalkonium chloride (0.02%BAK), and Xalatan (latanoprost). In vivo, the recovery and integrity of corneal wound healing were assessed in rat eyes instilled twice a day for 5 days with the above treatments after deepithelialization of the superior cornea. RESULTS: In vitro wound distances decreased at 2 and 24 hours for human corneal epithelial cells exposed to CE, latanoprost-CE, and phosphate-buffered saline, whereas they progressively increased for 0.02%BAK-treated and latanoprost-treated cells. The greater wound closure was associated with a higher number of Ki67-positive cells. In CE- and latanoprost-CE-treated rats, reepithelialization of the cornea was enhanced, restoring normal appearance and function. In contrast, 0.02%BAK or latanoprost delayed corneal healing, induced inflammation, and decreased MUC5-AC expression. CONCLUSIONS: Both models effectively evaluated the cytotoxicity and dynamic recovery of corneal wound healing, and their correlation supports the potential of the in vitro model as a reliable alternative to in vivo ocular toxicity tests. Both models demonstrated that in the face of corneal injury, CEs favored corneal healing, whereas BAK was deleterious. PMID- 22929155 TI - New approach for conjunctivochalasis using an argon green laser. AB - PURPOSE: To evaluate the effectiveness of conjunctivoplasty using an argon green laser in symptomatic patients with conjunctivochalasis (CCh). METHODS: Twenty nine eyes of 18 patients with various grades of CCh were included in this study. All the patients, who were refractory to the conventional therapy, were treated using an argon green laser. The ocular symptoms and signs, including the CCh grade, the tear Ocular Surface Disease Index, the breakup time, the Schirmer test, and the abnormal ocular surface findings, were evaluated preoperatively and postoperatively. RESULTS: The mean age of the patients was 69.1 +/- 8.4 years. The grade of CCh in 25 eyes (86%) decreased at 6 months after the laser conjunctivoplasty. When the grade reduction rates were calculated, the reduction rates of grades 1, 2, and 3 were 100%, 69%, and 48%, respectively. Most of the patients showed a significant symptomatic improvement, and the Ocular Surface Disease Index scores decreased from 0.41 to 0.22 (P < 0.001). The breakup time increased from 9.1 to 10.2 (P = 0.007), but the Schirmer test results did not show any differences after the surgery (P = 0.257). CONCLUSIONS: Conjunctivoplasty using an argon green laser is a simple and effective choice to treat symptomatic patients with CCh, especially in cases of mild-to-moderate grade CCh. PMID- 22929157 TI - Depiction of cavity formation in Terrien marginal degeneration by anterior segment optical coherence tomography. AB - PURPOSE: To evaluate detailed morphologic changes of Terrien marginal degeneration (TMD) using anterior segment optical coherence tomography (AS-OCT). METHODS: Two patients with TMD were examined by 1310-nm wavelength swept source optical coherence tomography, corneal topography, and slit-lamp microscopy. RESULTS: AS-OCT depicted corneal thinning with intact epithelial layer in the peripheral cornea of both patients. Moreover, AS-OCT images of both patients clearly showed cavity formation surrounded and enclosed by intact epithelial and endothelial layers in the thinned area. CONCLUSION: We demonstrate here the existence of cavity formation in the peripheral cornea with TMD. This observation suggests a possibility that corneal thinning in TMD is associated with cavity formation in the corneal stroma. AS-OCT is useful for the observation of detailed morphologic changes of diseased cornea. PMID- 22929156 TI - Co-isolation of Vahlkampfia and acanthamoeba in acanthamoeba-like keratitis in a Spanish population. AB - PURPOSE: To report the co-isolation incidence of Acanthamoeba and Vahlkampfia in amoebic keratitis from a tertiary care institution in Madrid, Spain. METHODS: In this retrospective case series, 7 eyes of 7 consecutive patients with culture proven or polymerase chain reaction-positive Acanthamoeba keratitis were seen at a tertiary care institution from January 2010 to April 2011, and their charts were reviewed. RESULTS: Two of 7 patients showed mixed Acanthamoeba and Vahlkampfia keratitis. Good clinical response to the treatment was strongly correlated with early diagnosis, whereas delayed diagnosis resulted in poor response to the treatment in single or mixed infection. CONCLUSIONS: Co-isolation of Vahlkampfia and Acanthamoeba in Acanthamoeba-like keratitis has recently been detected in our population. This finding should raise awareness of the existence of other amoeba different from Acanthamoeba causing keratitis. There are not enough cases yet to determine the impact of mixed amoebic keratitis in the prognosis of this disease. PMID- 22929158 TI - Bovine pericardium membrane (tutopatch) combined with solid platelet-rich plasma for the management of perforated corneal ulcers. AB - PURPOSE: To evaluate the use of a collagenous patch derived from bovine pericardium (Tutopatch) associated to a clot of autologous eye platelet-rich plasma (E-PRP) as a surgical alternative for the closure of perforated corneal ulcers. METHODS: A total of 6 patients with perforated corneal ulcers were treated. The Tutopatch was fixed to the conjunctiva with nylon stitches and then the E-PRP clot was placed on the corneal surface, underneath the patch. At the end of the procedure, a partial temporal tarsorrhaphy was done. Patients were observed daily for the following 10 days. RESULTS: In all cases, the corneal perforation was sealed. The bovine pericardium patch was present over the corneal surface until the tarsorrhaphy was opened. No evidence of infection or inflammation was detected. Digital tonometry confirmed acceptable ocular pressure in all cases from day 2 after the surgery. No patients reported pain, discomfort, or any subjective symptoms, and no complications were observed. The tarsorrhaphy was opened 2 to 3 weeks after the surgery, and the ocular surface was inspected without signs of leakage. The patients were followed up for 3 months with no evidence of relapses or perforations in 5 of them. CONCLUSION: The combined use of Tutopatch and E-PRP clot was found to be a safe and effective surgical technique for the closure of perforated corneal ulcers. This technique could be an alternative for the urgent management of perforated corneal ulcers although additional studies are needed to determine the technique's overall effectiveness. PMID- 22929159 TI - Refractive and visual outcomes of penetrating keratoplasty versus deep anterior lamellar keratoplasty with hydrodissection for treatment of keratoconus. AB - PURPOSE: To compare refractive and visual outcomes of penetrating keratoplasty (PKP) and deep anterior lamellar keratoplasty (DALK) with hydrodissection for keratoconus. METHODS: A review of medical records was performed to identify 69 subjects (77 eyes) who had undergone keratoplasty by a single surgeon. Inclusion criteria were as follows: no episodes of rejection, no adverse events or complications intraoperatively or postoperatively, a fairly normal rate of epithelialization within 2 weeks, and suture removal after 11 months. Eyes were categorized according to the procedure: 47 had undergone DALK with hydrodissection (DALK group) and 30 had undergone PKP (PKP group). A between group comparison was performed. RESULTS: Before suture removal, there was no statistical difference between groups in best-corrected visual acuity (BCVA) or refraction at 6 months (P > 0.05, all cases). The mean BCVA was 0.18 logarithm of the minimum angle of resolution for both groups at 12 months (just after suture removal) and 24 months postoperatively. The mean postoperative mean refractive spherical equivalents at 12 months and 2 years were -4.11 +/- 3.4 diopters (D) and -4.68 +/- 2.9 D, respectively, for the DALK group and -1.7 +/- 2.7 D and -1.1 +/- 3.6 D, respectively, for the PKP group. The DALK group was statistically more myopic at 12 and 24 months (P > 0.05, both cases). The mean refractive cylinders at 12 months and 2 years were 2.88 +/- 1.60 D and 3.18 +/- 1.70 D, respectively, for the DALK group and 2.80 +/- 1.6 D and 3.80 +/- 1.80 D, respectively, for the PKP group. The differences between groups were not statistically significant (P > 0.05, all comparisons). CONCLUSIONS: Long-term BCVA, mean refractive spherical equivalent, and mean refractive cylinder after DALK with hydrodissection were similar to those after PKP. PMID- 22929160 TI - Treatment of Acanthamoeba keratitis by corneal cross-linking. AB - PURPOSE: To evaluate the efficacy of corneal cross-linking (CXL; riboflavin/ultraviolet A) as a simple therapy for Acanthamoeba keratitis. METHODS: Twenty rabbits were systemically anesthetized and the stroma of their right corneas was inoculated with a suspension of Acanthamoeba. Rabbits were divided into 2 groups: one group was treated with corneal CXL 3 days after infection and the other did not receive any treatment (control). All eyes in both groups were examined before (days 0 and 3) and after (day 7) CXL treatment. On day 7, the eyes were enucleated; 18 corneal buttons (9 of each group) were sent for microbiological examination and 2 (1 of each group) for histopathologic examination. RESULTS: All animals developed Acanthamoeba keratitis. There was no statistically significant difference between groups before treatment (day 0, P = 1, and day 3, P = 0.684). The treated corneas had a higher score (3.48 +/- 0.30) at the time of enucleation compared with control corneas (2.60 +/- 0.26). This difference was statistically significant (P = 0.008). Microbiological analysis revealed that the treated corneas had a higher protozoal count (2.86 +/- 0.09) compared with the control corneas (2.18 +/- 0.07); this difference was statistically significant (P = 0.001). CONCLUSIONS: Treatment of Acanthamoeba keratitis by corneal CXL (riboflavin/ultraviolet A) did not prove effective in decreasing the intensity and severity of Acanthamoeba keratitis. PMID- 22929161 TI - An infant with pulmonary-cutaneous Sweet syndrome. AB - We report the case of a 31-day-old girl presenting with severe respiratory distress and cutaneous lesions from Sweet syndrome. Pulmonary symptoms unresponsive to antibiotics in patients with Sweet syndrome should raise suspicion for neutrophilic infiltration. PMID- 22929162 TI - Barriers to specialty care and specialty referral completion in the community health center setting. AB - OBJECTIVE: To assess the frequency of barriers to specialty care and to assess which barriers are associated with an incomplete specialty referral (not attending a specialty visit when referred by a primary care provider) among children seen in community health centers. STUDY DESIGN: Two months after their child's specialty referral, 341 parents completed telephone surveys assessing whether a specialty visit was completed and whether they experienced any of 10 barriers to care. Family/community barriers included difficulty leaving work, obtaining childcare, obtaining transportation, and inadequate insurance. Health care system barriers included getting appointments quickly, understanding doctors and nurses, communicating with doctors' offices, locating offices, accessing interpreters, and inconvenient office hours. We calculated barrier frequency and total barriers experienced. Using logistic regression, we assessed which barriers were associated with incomplete referral, and whether experiencing >= 4 barriers was associated with incomplete referral. RESULTS: A total of 22.9% of families experienced incomplete referral. 42.0% of families encountered 1 or more barriers. The most frequent barriers were difficulty leaving work, obtaining childcare, and obtaining transportation. On multivariate analysis, difficulty getting appointments quickly, difficulty finding doctors' offices, and inconvenient office hours were associated with incomplete referral. Families experiencing >= 4 barriers were more likely than those experiencing <= 3 barriers to have incomplete referral. CONCLUSION: Barriers to specialty care were common and associated with incomplete referral. Families experiencing many barriers had greater risk of incomplete referral. Improving family/community factors may increase satisfaction with specialty care; however, improving health system factors may be the best way to reduce incomplete referrals. PMID- 22929164 TI - A meta-analysis of the factor structure of the Geriatric Depression Scale (GDS): the effects of language. AB - BACKGROUND: Given the lack of consensus on the factor structure of the Geriatric Depression Scale (GDS), as well as the fact that the GDS factor structure appears to vary across diverse cultural and/or language groups, the present meta-analysis examined whether the factor structure of the GDS varies by language. METHODS: A total of 26 published studies using exploratory factor analysis (14,669 participants; 10 languages) were included in the meta-analysis. The factor structure of the GDS was assessed in the overall sample as well as in each language that had been examined in at least two different studies. RESULTS: The analysis of the full sample resulted in a four-factor structure, whereas analyses of the individual languages produced structures with 4 to 6 factors. The mean variable cosines between languages ranged from 0.612 to 0.839, suggesting that the different languages produced distinct factor structures. The three factors of dysphoria, social withdrawal-apathy-cognitive impairment, and positive mood were commonly observed across different languages. Of these, the positive mood factor was the most similar across the languages. CONCLUSIONS: These results provide strong evidence of language differences in the factor structure of the GDS. The findings suggest a need for researchers and clinicians to be careful when administering the GDS in different languages, as well as a need to take structural differences into account when interpreting results of the GDS. PMID- 22929163 TI - Structural, functional and molecular analysis of the effects of aging in the small intestine and colon of C57BL/6J mice. AB - BACKGROUND: By regulating digestion and absorption of nutrients and providing a barrier against the external environment the intestine provides a crucial contribution to the maintenance of health. To what extent aging-related changes in the intestinal system contribute to the functional decline associated with aging is still under debate. METHODS: Young (4 M) and old (21 M) male C57BL/6J mice were fed a control low-fat (10E%) or a high-fat diet (45E%) for 2 weeks. During the intervention gross energy intake and energy excretion in the feces were measured. After sacrifice the small and large intestine were isolated and the small intestine was divided in three equal parts. Swiss rolls were prepared of each of the isolated segments for histological analysis and the luminal content was isolated to examine alterations in the microflora with 16S rRNA Q PCR. Furthermore, mucosal scrapings were isolated from each segment to determine differential gene expression by microarray analysis and global DNA methylation by pyrosequencing. RESULTS: Digestible energy intake was similar between the two age groups on both the control and the high-fat diet. Microarray analysis on RNA from intestinal scrapings showed no marked changes in expression of genes involved in metabolic processes. Decreased expression of Cubilin was observed in the intestine of 21-month-old mice, which might contribute to aging-induced vitamin B12 deficiency. Furthermore, microarray data analysis revealed enhanced expression of a large number of genes involved in immune response and inflammation in the colon, but not in the small intestine of the 21-month-old mice. Aging-induced global hypomethylation was observed in the colon and the distal part of the small intestine, but not in the first two sections of the small intestine. CONCLUSION: In 21-month old mice the most pronounced effects of aging were observed in the colon, whereas very few changes were observed in the small intestine. PMID- 22929165 TI - Loss of function of hNav1.5 by a ZASP1 mutation associated with intraventricular conduction disturbances in left ventricular noncompaction. AB - BACKGROUND: Defects of cytoarchitectural proteins can cause left ventricular noncompaction, which is often associated with conduction system diseases. We have previously identified a p.D117N mutation in the LIM domain-binding protein 3 encoding Z-band alternatively spliced PDZ motif gene (ZASP) in a patient with left ventricular noncompaction and conduction disturbances. We sought to investigate the role of p.D117N mutation in the LBD3 NM_001080114.1 isoform (ZASP1-D117N) for the regulation of cardiac sodium channel (Na(v)1.5) that plays an important role in the cardiac conduction system. METHODS AND RESULTS: Effects of ZASP1-wild-type and ZASP1-D117N on Na(v)1.5 were studied in human embryonic kidney-293 cells and neonatal rat cardiomyocytes. Patch-clamp study demonstrated that ZASP1-D117N significantly attenuated I(Na) by 27% in human embryonic kidney 293 cells and by 32% in neonatal rat cardiomyocytes. In addition, ZASP1-D117N rightward shifted the voltage-dependent activation and inactivation in both systems. In silico simulation using Luo-Rudy phase 1 model demonstrated that altered Na(v)1.5 function can reduce cardiac conduction velocity by 28% compared with control. Pull-down assays showed that both wild-type and ZASP1-D117N can complex with Na(v)1.5 and telethonin/T-Cap, which required intact PDZ domains. Immunohistochemical staining in neonatal rat cardiomyocytes demonstrates that ZASP1-D117N did not significantly disturb the Z-line structure. Disruption of cytoskeletal networks with 5-iodonaphthalene-1-sulfonyl homopiperazine and cytochalasin D abolished the effects of ZASP1-D117N on Na(v)1.5. CONCLUSIONS: ZASP1 can form protein complex with telethonin/T-Cap and Na(v)1.5. The left ventricular noncompaction-specific ZASP1 mutation can cause loss of function of Na(v)1.5, without significant alteration of the cytoskeletal protein complex. Our study suggests that electric remodeling can occur in left ventricular noncompaction subject because of a direct effect of mutant ZASP on Na(v)1.5. PMID- 22929166 TI - MLEP: an R package for exploring the maximum likelihood estimates of penetrance parameters. AB - BACKGROUND: Linkage analysis is a useful tool for detecting genetic variants that regulate a trait of interest, especially genes associated with a given disease. Although penetrance parameters play an important role in determining gene location, they are assigned arbitrary values according to the researcher's intuition or as estimated by the maximum likelihood principle. Several methods exist by which to evaluate the maximum likelihood estimates of penetrance, although not all of these are supported by software packages and some are biased by marker genotype information, even when disease development is due solely to the genotype of a single allele. FINDINGS: Programs for exploring the maximum likelihood estimates of penetrance parameters were developed using the R statistical programming language supplemented by external C functions. The software returns a vector of polynomial coefficients of penetrance parameters, representing the likelihood of pedigree data. From the likelihood polynomial supplied by the proposed method, the likelihood value and its gradient can be precisely computed. To reduce the effect of the supplied dataset on the likelihood function, feasible parameter constraints can be introduced into maximum likelihood estimates, thus enabling flexible exploration of the penetrance estimates. An auxiliary program generates a perspective plot allowing visual validation of the model's convergence. The functions are collectively available as the MLEP R package. CONCLUSIONS: Linkage analysis using penetrance parameters estimated by the MLEP package enables feasible localization of a disease locus. This is shown through a simulation study and by demonstrating how the package is used to explore maximum likelihood estimates. Although the input dataset tends to bias the likelihood estimates, the method yields accurate results superior to the analysis using intuitive penetrance values for disease with low allele frequencies. MLEP is part of the Comprehensive R Archive Network and is freely available at http://cran.r project.org/web/packages/MLEP/index.html. PMID- 22929167 TI - Aortic mural thrombus in the normal or minimally atherosclerotic aorta. AB - BACKGROUND: Aortic mural thrombus in a nonaneurysmal minimally atherosclerotic or normal aorta is a rare clinical entity and an uncommon cause of peripheral arterial embolization. Both anticoagulation therapy and aortic surgery are commonly used as primary treatment, but there are no consensuses or clinical guidelines to outline the best management strategy for this unusual problem. This systematic review compares the outcomes of these different strategies for the treatment of aortic mural thrombus. METHODS: An extensive search of the literature was conducted, and all relevant publications were reviewed, with individual patient data pooled in this meta-analysis. The outcome variables included were persistence or recurrence of aortic thrombus, recurrence of peripheral embolization, mortality, and a composite end point of complications consisting of stroke, limb loss, and bowel resection. Chi-square test and logistic regression analysis were used to compare groups and to find any predictors of adverse outcome. RESULTS: Two hundred patients from 98 articles were considered. Of these, 112 patients received anticoagulation and 88 underwent aortic surgery as primary treatment. Smoking was more prevalent in the surgery group, but no other significant differences in demographics, comorbidities, or mode of presentation were seen between groups. The surgery group was more likely to have aortic thrombus located in the arch, but there were no differences in terms of the mobility or size of the thrombus between groups. Aortic thrombus persisted or recurred in 26.4% of the anticoagulation group and in 5.7% of the surgery group (P < 0.001). Recurrence of peripheral arterial embolization was seen in 25.7% of the anticoagulation group and 9.1% of the surgery group (P = 0.003). Mortality rates were similar at 6.2% and 5.7% for the anticoagulation group and the surgery group, respectively (P = 0.879). Complications were noted in 27% of the anticoagulation group and 17% of the surgery group (P = 0.07), and major limb amputation rates were 9% for the anticoagulation group and 2% for the surgery group (P = 0.004). Logistic regression analysis established thrombus location in the ascending aorta (odds ratio [OR]: 12.7; 95% confidence interval [CI]: 2.3-238.8) or arch (OR: 18.3; 95% CI: 2.6-376.7), mild atherosclerosis of the aortic wall (OR: 2.5; 95% CI: 1-6.4), and stroke presentation (OR: 11.8; 95% CI: 3.3-49.5) as important predictors of recurrence. CONCLUSIONS: The results of our meta-analysis seem to favor the surgical management of aortic mural thrombus in the normal or minimally diseased aorta. Anticoagulation as primary therapy is associated with a higher likelihood of recurrence, a trend toward a higher incidence of complications, and a higher incidence of limb loss. Aortic surgery should be considered as primary treatment, particularly for those patients at high risk for recurrence considered to be good operative candidates. PMID- 22929168 TI - Contemporary incidence and risk factors for carotid artery disease in patients referred for coronary artery bypass surgery. AB - BACKGROUND: In the past decade, there has been an increase in the amount of patients with medical co-morbidities referred for coronary artery bypass surgery (CABG). Significant carotid artery disease in patients undergoing CABG procedures increases the risk of neurological complications. We review the results of routine carotid screening in patients undergoing CABG to determine the contemporary incidence and risk factors for carotid artery disease. METHODS: Between 2008 through 2010, 673 patients were referred for isolated coronary artery bypass surgery at a single institution. Patients were identified through a systematic review of The Department of Cardiothoracic Surgery Society of Thoracic Surgery Outcomes Database. A retrospective analysis of prospectively collected demographic, clinical data and outcomes were performed. All patients with screening preoperative carotid duplex were reviewed. We defined the degree of carotid disease as: none to mild stenosis (<50%), moderate stenosis (50-69%), severe stenosis (70-99%). Multivariate analysis was performed to identify risk factors. RESULTS: 559 (83%) patients underwent screening preoperative carotid ultrasonography prior to CABG. The incidence of carotid artery disease (>50% stenosis) was 36% with 18% unilateral moderate disease, 10% bilateral moderate and 8% severe disease. Risk factors associated with carotid artery disease included: advanced age, renal failure, previous stroke, peripheral vascular disease, left main coronary artery disease, and previous myocardial infarction. CONCLUSIONS: There is a significant incidence of carotid artery stenosis in patients referred for CABG. Routine screening will identify patients with carotid artery disease and may reduce the risk of postoperative stroke. PMID- 22929169 TI - A novel walking speed estimation scheme and its application to treadmill control for gait rehabilitation. AB - BACKGROUND: Virtual reality (VR) technology along with treadmill training (TT) can effectively provide goal-oriented practice and promote improved motor learning in patients with neurological disorders. Moreover, the VR + TT scheme may enhance cognitive engagement for more effective gait rehabilitation and greater transfer to over ground walking. For this purpose, we developed an individualized treadmill controller with a novel speed estimation scheme using swing foot velocity, which can enable user-driven treadmill walking (UDW) to more closely simulate over ground walking (OGW) during treadmill training. OGW involves a cyclic acceleration-deceleration profile of pelvic velocity that contrasts with typical treadmill-driven walking (TDW), which constrains a person to walk at a preset constant speed. In this study, we investigated the effects of the proposed speed adaptation controller by analyzing the gait kinematics of UDW and TDW, which were compared to those of OGW at three pre-determined velocities. METHODS: Ten healthy subjects were asked to walk in each mode (TDW, UDW, and OGW) at three pre-determined speeds (0.5 m/s, 1.0 m/s, and 1.5 m/s) with real time feedback provided through visual displays. Temporal-spatial gait data and 3D pelvic kinematics were analyzed and comparisons were made between UDW on a treadmill, TDW, and OGW. RESULTS: The observed step length, cadence, and walk ratio defined as the ratio of stride length to cadence were not significantly different between UDW and TDW. Additionally, the average magnitude of pelvic acceleration peak values along the anterior-posterior direction for each step and the associated standard deviations (variability) were not significantly different between the two modalities. The differences between OGW and UDW and TDW were mainly in swing time and cadence, as have been reported previously. Also, step lengths between OGW and TDW were different for 0.5 m/s and 1.5 m/s gait velocities, and walk ratio between OGS and UDW was different for 1.0 m/s gait velocities. CONCLUSIONS: Our treadmill control scheme implements similar gait biomechanics of TDW, which has been used for repetitive gait training in a small and constrained space as well as controlled and safe environments. These results reveal that users can walk as stably during UDW as TDW and employ similar strategies to maintain walking speed in both UDW and TDW. Furthermore, since UDW can allow a user to actively participate in the virtual reality (VR) applications with variable walking velocity, it can induce more cognitive activities during the training with VR, which may enhance motor learning effects. PMID- 22929171 TI - HIV transmission to extremely low birth weight infants. AB - BACKGROUND: Prematurity increases the perinatal HIV transmission rate compared with term infants. There is sparse literature documenting the risk of transmission of HIV to extremely low birth weight (ELBW) infants. OBJECTIVE: To determine the risk of perinatal transmission of HIV to ELBW infants in a tertiary neonatal unit in South Africa. METHODS: A prospective database was maintained on all inborn ELBW infants over a 1-year period from March 2010 to February 2011. Survival and DNA HIV polymerase chain reaction results at 6 weeks were recorded. RESULTS: Of the 180 ELBW infants, 51 (28%) of these babies were HIV exposed. Of these 51 infants, 37 survived until 6 weeks of age. Polymerase chain reaction testing revealed 1 HIV-positive infant for a rate of 2.7% (95% confidence interval: 0.7-14.1%). Twenty-six (72%) of the 36 mothers received antiretroviral drugs, but only 16 (44%) had been treated for more than 1 month. CONCLUSIONS: The rate of HIV transmission in this cohort of ELBW infants is very low despite only 44% of the mothers receiving adequate antiretroviral drugs. We postulate that this is due to our high (89%) cesarean section rate, universal (100%) infant prophylactic antiretroviral drugs and the use of pasteurized breast milk. PMID- 22929172 TI - Potential intussusception risk versus benefits of rotavirus vaccination in the United States. AB - BACKGROUND: International data show a low-level increased risk of intussusception associated with rotavirus vaccination. Although US data have not documented a risk, we assumed a risk similar to international settings and compared potential vaccine-associated intussusception cases with benefits of prevention of rotavirus gastroenteritis by a fully implemented US rotavirus vaccine program. METHODS: To calculate excess intussusception cases, we used national data on vaccine coverage and baseline intussusception rates, and assumed a vaccine-associated intussusception relative risk of 5.3 (95% confidence interval [CI]: 3.0-9.3) in the first week after the first vaccine dose, the risk seen in international settings. We used postlicensure vaccine effectiveness data to calculate rotavirus disease burden averted. RESULTS: For a US birth cohort of 4.3 million infants, vaccine-associated intussusception could cause an excess 0.2 (range: 0.1-0.3) deaths, 45 (range: 21-86) hospitalizations and 13 (range: 6-25) cases managed in short-stay or emergency department settings. Vaccination would avert 14 (95% CI: 10-19) rotavirus-associated deaths, 53,444 (95% CI: 37,622-72,882) hospitalizations and 169,949 (95% CI: 118,161-238,630) emergency department visits. Summary benefit-risk ratios for death and hospitalization are 71:1 and 1093:1, respectively. CONCLUSIONS: The burden of severe rotavirus disease averted due to vaccination compared with the vaccine-associated intussusception events offers a side-by-side analysis of the benefits and potential risks. If an intussusception risk similar to that seen internationally exists in the United States, it is substantially exceeded by the benefits of rotavirus disease burden averted by vaccination. PMID- 22929173 TI - Association of maternal smoking during pregnancy with infant hospitalization and mortality due to infectious diseases. AB - BACKGROUND: Maternal smoking is associated with infant respiratory infections and with increased risk of low birth weight infants and preterm birth. This study assesses the association of maternal smoking during pregnancy with both respiratory and nonrespiratory infectious disease (ID) morbidity and mortality in infants. METHODS: We conducted 2 retrospective case-control analyses of infants born in Washington State from 1987 to 2004 using linked birth certificate, death certificate and hospital discharge records. One assessed morbidity--infants hospitalized due to IDs within 1 year of birth (47,404 cases/48,233 controls). The second assessed mortality--infants who died within 1 year due to IDs (627 cases/2730 controls). RESULTS: Maternal smoking was associated with both hospitalization (adjusted odds ratio [AOR] = 1.52; 95% confidence interval [CI]: 1.46, 1.58) and mortality (AOR = 1.51; 95% CI: 1.17, 1.96) due to any ID. In subgroup analyses, maternal smoking was associated with hospitalization due to a broad range of IDs including both respiratory (AOR = 1.69; 95% CI: 1.63, 1.76) and nonrespiratory IDs (AOR = 1.27; 95% CI: 1.20, 1.34). Further stratification by birth weight and gestational age did not appreciably change these estimates. In contrast, there was no association of maternal smoking with ID infant mortality when only low birth weight infants were considered. CONCLUSIONS: Maternal smoking was associated with a broad range of both respiratory and nonrespiratory ID outcomes. Despite attenuation of the mortality association among low birth weight infants, ID hospitalization was found to be independent of both birth weight and gestational age. These findings suggest that full-term infants of normal weight whose mothers smoked may suffer an increased risk of serious ID morbidity and mortality. PMID- 22929174 TI - Clinical characteristics of rotavirus diarrhea in hospitalized Romanian infants. AB - Clinical characteristics of rotavirus enteritis were evaluated by comparison with acute diarrhea of other etiologies. We reviewed the medical records of children (aged 0-12 months) admitted with acute diarrhea in our hospital between January and December 2011. Of the 839 patients, 49.3% had rotavirus diarrhea. The incidence of severe disease was significantly higher for rotavirus diarrhea (65.2%, P < 0.01) than for other types of diarrheal disease. PMID- 22929175 TI - Enhancing research capacity across healthcare and higher education sectors: development and evaluation of an integrated model. AB - BACKGROUND: With current policy in healthcare research, in the United Kingdom and internationally, focused on development of research excellence in individuals and teams, building capacity for implementation and translation of research is paramount among the professionals who use that research in daily practice. The judicious use of research outcomes and evaluation of best evidence and practice in healthcare is integrally linked to the research capacity and capabilities of the workforce. In addition to promoting high quality research, mechanisms for actively enhancing research capacity more generally must be in place to address the complexities that both undermine and facilitate this activity. METHODS: A comprehensive collaborative model for building research capacity in one health professional group, speech and language therapy, was developed in a region within the UK and is presented here. The North East of England and the strong research ethos of this profession in addressing complex interventions offered a fertile context for developing and implementing a model which integrated the healthcare and university sectors. Two key frameworks underpin this model. The first addresses the individual participants' potential trajectory from research consciousness to research participative to research active. The second embeds a model developed for general practitioners into a broader framework of practice academic partnership and knowledge and skills exchange, and considers external drivers and impacts on practice and patient outcomes as key elements. RESULTS AND DISCUSSION: The integration of practice and academia has been successful in building a culture of research activity within one healthcare profession in a region in the UK and has resulted, to date, in a series of research related outcomes. Understanding the key components of this partnership and the explicit strategies used has driven the implementation of the model and are discussed here. CONCLUSIONS: A strong, equitable collaboration between clinical and academic partners working towards a common outcome can enhance the use of research within the healthcare workforce and contribute actively to the research process. A set of propositions are specified to facilitate both transferability of this partnership model to other professional groups and clinical teams and evaluation of the model components. PMID- 22929176 TI - Lensfree on-chip tomographic microscopy employing multi-angle illumination and pixel super-resolution. AB - Tomographic imaging has been a widely used tool in medicine as it can provide three-dimensional (3D) structural information regarding objects of different size scales. In micrometer and millimeter scales, optical microscopy modalities find increasing use owing to the non-ionizing nature of visible light, and the availability of a rich set of illumination sources (such as lasers and light emitting-diodes) and detection elements (such as large format CCD and CMOS detector-arrays). Among the recently developed optical tomographic microscopy modalities, one can include optical coherence tomography, optical diffraction tomography, optical projection tomography and light-sheet microscopy. These platforms provide sectional imaging of cells, microorganisms and model animals such as C. elegans, zebrafish and mouse embryos. Existing 3D optical imagers generally have relatively bulky and complex architectures, limiting the availability of these equipments to advanced laboratories, and impeding their integration with lab-on-a-chip platforms and microfluidic chips. To provide an alternative tomographic microscope, we recently developed lensfree optical tomography (LOT) as a high-throughput, compact and cost-effective optical tomography modality. LOT discards the use of lenses and bulky optical components, and instead relies on multi-angle illumination and digital computation to achieve depth-resolved imaging of micro-objects over a large imaging volume. LOT can image biological specimen at a spatial resolution of <1 MUm x <1 MUm x <3 MUm in the x, y and z dimensions, respectively, over a large imaging volume of 15-100 mm(3), and can be particularly useful for lab-on-a-chip platforms. PMID- 22929177 TI - Orthographic consistency and parafoveal preview benefit: a resource-sharing account of language differences in processing of phonological and semantic codes. AB - Parafoveal preview benefit (PB) is an implicit measure of lexical activation in reading. PB has been demonstrated for orthographic and phonological but not for semantically related information in English. In contrast, semantic PB is obtained in German and Chinese. We propose that these language differences reveal differential resource demands and timing of phonological and semantic decoding in different orthographic systems. PMID- 22929178 TI - Effectiveness of rifaximin and fluoroquinolones in preventing travelers' diarrhea (TD): a systematic review and meta-analysis. AB - BACKGROUND: Recent developments related to a safe and effective nonabsorbable antibiotic, rifaximin, and identification of postinfectious irritable bowel syndrome as a frequent sequela call for a need to reconsider the value of primary prevention of traveler's diarrhea (TD) with antibiotics. METHODS: Randomized, placebo-controlled, double-blind studies evaluating the effectiveness and safety of rifaximin or a fluoroquinolone chemoprophylaxis against TD were pooled using a random effects model and assessed for heterogeneity. RESULTS: The nine studies (four rifaximin and five fluoroquinolone) included resulted in pooled relative risk estimates of 0.33 (95% CI = 0.24-0.45, I2 = 3.1%) and 0.12 (95% CI = 0.07 0.20, I2 =0.0%), respectively. Similar rates of treatment emergent adverse events were found between antibiotic and placebo groups. CONCLUSIONS: This meta-analysis supports the effectiveness of antibiotics in preventing TD. However, further studies that include prevention of secondary chronic health outcomes among travelers to different geographic regions, and a formal risk-benefit analysis for antibiotic chemoprophylaxis, are needed. PMID- 22929180 TI - Exogenous, TAP-independent lysosomal presentation of a respiratory syncytial virus CTL epitope. AB - Respiratory syncytial virus causes lower respiratory tract infections in infancy and old age, affecting also immunocompromised patients. The viral fusion protein is an important vaccine candidate eliciting antibody and cell-mediated immune responses. CD8(+) cytotoxic T lymphocytes (CTLs) are known to have a role in both lung pathology and viral clearance. In BALB/c mice, the fusion protein epitope F249-258 is presented to CTLs by the murine major histocompatibility complex (MHC) class I molecule K(d). In cells infected with recombinant vaccinia viruses encoding the fusion protein, F249-258 is presented by MHC class I molecules through pathways that are independent of the transporters associated with antigen processing (TAP). We have now found that F249-258 can be generated from non infectious virus from an exogenous source. Antigen processing follows a lysosomal pathway that appears to require autophagy. As a practical consequence, inactivated virus suffices for in vivo priming of virus-specific CTLs. PMID- 22929181 TI - Bringing development into a universal model of reading. AB - Reading development is integral to a universal model of reading. Developmental research can tell us which factors drive reading acquisition and which are the product of reading. Like adult research, developmental research needs to be contextualised within the language and writing system and it needs to include key cross-linguistic evaluations. This will create a universal model of reading development. PMID- 22929183 TI - Hippocampal and amygdala volumes in an older bipolar disorder sample. AB - BACKGROUND: Brain volumetric magnetic resonance imaging (MRI) studies of adult bipolar disorder samples, compared with healthy controls, have reported conflicting results in hippocampal and amygdala volumes. Among these, few have studied older bipolar samples, which would allow for examination of the effects of greater duration in mood episodes on brain volumes. The aim of this study was to compare hippocampal and amygdala volumes in older bipolar patients with controls. METHODS: High-resolution MRI scans were used to determine hippocampal and amygdala volumes that were manually traced using established protocols in 18 euthymic patients with DSM-IV bipolar I disorder (mean age 57 years) and 21 healthy controls (mean age 61 years). Analysis of covariance (ANCOVA) was used to explore group differences while controlling for intracranial volume (ICV), age, sex, and years of education. RESULTS: While gray matter, white matter, and cerebrospinal fluid volumes did not differ between the groups, bipolar disorder patients had smaller ICV (t = 2.54, p = 0.015). After correcting for ICV, the bipolar group had smaller hippocampal (left hippocampus F = 13.944, p = 0.001; right hippocampus F = 10.976, p = 0.002; total hippocampus F = 13.566; p = 0.001) and right amygdala (F = 13.317, p = 0.001) volumes. Total hippocampal volume was negatively associated with the duration of depressive (r = -0.636; p = 0.035) and manic (r = -0.659; p = 0.027) episodes, but not lithium use. Amygdala volumes were not associated with the duration of mood episodes. CONCLUSIONS: Older bipolar disorder patients had smaller hippocampal and amygdala volumes. That smaller hippocampal volume was associated with the duration of mood episodes may suggest a neuroprogressive course related to the severity of the disorder. PMID- 22929182 TI - The role of the gut hormone GLP-1 in the metabolic improvements caused by ileal transposition. AB - BACKGROUND: Bariatric surgery alters the gastrointestinal hormonal milieu leading to improved glucose homeostasis, though the mechanism leading to these changes is poorly understood. Ileal transposition (IT) is a procedure that is neither restrictive nor malabsorptive but nevertheless produces profound improvements in glucose regulation. Ileal transposition involves a short segment of distal ileum being transposed to the proximal jejunum in an isoperistaltic direction, thereby avoiding any gastric resection or intestinal bypass. METHODS: Diet-induced obese rats underwent either ileal transposition (IT) or Sham procedures. The Sham operated rats were pair-fed to the IT surgical group to control for the effects of reduced food intake. Body composition data were recorded at specific time points, and glucose tolerance tests were performed at 5 and 6 wk, both in the presence and absence of Exendin 9-39, a known glucose-like peptide 1 (GLP-1) receptor antagonist. A subset of naive rats were also maintained for comparison. RESULTS: IT and Sham operated rats had no differences in food intake and body weight, however, IT rats had a significant decrease in their body fat composition (P < 0.05). No difference existed in glucose tolerance when exposed to an intraperitoneal glucose load, however, IT rats showed markedly improved glucose tolerance when submitted to an oral glucose tolerance test (P < 0.001). Blocking GLP-1 receptors reversed these important improvements in rats with IT surgery. CONCLUSIONS: The present work recapitulates what is seen in rodents and humans that IT improves glucose tolerance and body composition. The present data provide compelling evidence that these improvements are a product of increased GLP-1 secretion that results from placing the key GLP-1 secreting cells closer to chyme coming from the stomach. Such data support the notion that rather than restriction or malabsorption, the underling molecular mechanisms that mediate the potent improvements produced by bariatric procedures involve increased activation of GLP-1 signaling. PMID- 22929184 TI - Development of the multi-attribute Adolescent Health Utility Measure (AHUM). AB - OBJECTIVE: Obtain utilities (preferences) for a generalizable set of health states experienced by older children and adolescents who receive therapy for chronic health conditions. METHODS: A health state classification system, the Adolescent Health Utility Measure (AHUM), was developed based on generic health status measures and input from children with Hunter syndrome and their caregivers. The AHUM contains six dimensions with 4-7 severity levels: self-care, pain, mobility, strenuous activities, self-image, and health perceptions. Using the time trade off (TTO) approach, a UK population sample provided utilities for 62 of 16,800 AHUM states. A mixed effects model was used to estimate utilities for the AHUM states. The AHUM was applied to trial NCT00069641 of idursulfase for Hunter syndrome and its extension (NCT00630747). RESULTS: Observations (i.e., utilities) totaled 3,744 (12*312 participants), with between 43 to 60 for each health state except for the best and worst states which had 312 observations. The mean utilities for the best and worst AHUM states were 0.99 and 0.41, respectively. The random effects model was statistically significant (p < 0.0001; adjusted R2 = 0.361; RMSE = 0.194). When AHUM utilities were applied to the idursulfase trial, mean utilities in the idursulfase weekly and placebo groups improved +0.087 and +0.006, respectively, from baseline to week 53. In the extension, when all patients received idursulfase, the utilities in the treatment group remained stable and the placebo group improved +0.039. DISCUSSION: The AHUM health state classification system may be used in future research to enable calculation of quality-adjust life expectancy for applicable health conditions. PMID- 22929186 TI - Assessing long-chain omega-3 polyunsaturated fatty acids: a tailored food frequency questionnaire is better. AB - OBJECTIVE: Polyunsaturated fatty acids (PUFAs), including the long-chain (LC) omega-3 PUFAs, are important for health. The aim was to assess if the Anti-Cancer Council of Victoria Dietary Questionnaire (ACC DQ) accurately determines PUFA intakes compared with the recently validated electronic PUFA food-frequency questionnaire (FFQ). METHODS: Forty-one study volunteers were recruited from the local Illawarra region of New South Wales, Australia. The method of triads was used to determine validity coefficients by comparing the ACC DQ intakes against a 3-d weighed food record and appropriate blood biomarkers (erythrocytes and plasma fatty acids). These validity coefficients were subsequently compared with previously published validity coefficients from the PUFA FFQ. RESULTS: Using erythrocytes as the biomarker, the electronic PUFA FFQ had much higher validity coefficients compared with the ACC DQ for eicosapentaenoic acid (0.92 versus 0.19), docosahexaenoic acid (0.69 versus 0.26), and total LC omega-3 PUFAs (0.78 versus 0.23), respectively, whereas omega-6 PUFAs were comparable. Using plasma as the biomarker, the electronic PUFA FFQ had much higher validity coefficients compared with the ACC DQ for alpha-linolenic acid (0.96 versus 0.49), eicosapentaenoic acid (0.87 versus 0.19), docosahexaenoic acid (0.64 versus 0.24), and total LC omega-3 PUFAs (0.73 versus 0.21), respectively, whereas omega 6 PUFAs were comparable. CONCLUSION: The validated electronic PUFA FFQ is better suited to determine omega-3 PUFA intakes than the ACC DQ. PMID- 22929185 TI - Specific-mutational patterns of p53 gene in bladder transitional cell carcinoma among a group of Iraqi patients exposed to war environmental hazards. AB - BACKGROUND: To unfold specific-mutational patterns in TP53 gene due to exposures to war environmental hazards and to detect the association of TP53 gene alteration with the depth of bladder cancer. METHODS: Twenty-nine bladder carcinomas were analyzed for TP53 alterations. PCR-single strand conformational polymorphism analysis, DNA sequencing and immunohistochemical analysis using monoclonal mouse anti-human p53 antibody (Clone DO-7) were employed. RESULTS: TP53 gene mutations occurred in 37.9% of the cases while TP53 overexpression occurred in 58.6%. Both of them were associated with deep invasive-tumors. Single mutations were seen in 63.6%, whereas only 27.3% have shown double mutations. Four mutations were frameshifted (30.8%); two of them showed insertion A after codon 244. There was no significant association between TP53 mutations and protein overexpression (P>0.05), while a significant association was observed between TP53 alterations and tumors progression (P <= 0.01). CONCLUSION: The infrequent TP53mutations, especially insertion A and 196 hotspot codon, may represent the specific-mutational patterns in bladder carcinoma among the Iraqi patients who were exposed to war environmental hazards. TP53 alteration associated with bladder cancer progression should be analyzed by both mutational and protein expression analysis. PMID- 22929187 TI - Re: more discrepancies around saturated fat and cardiovascular diseases. PMID- 22929188 TI - Fusion to a highly charged proteasomal retargeting sequence increases soluble cytoplasmic expression and efficacy of diverse anti-synuclein intrabodies. AB - Intrabodies can be powerful reagents to effect modulation of aberrant intracellular proteins that underlie a range of diseases. However, their cytoplasmic solubility can be limiting. We previously reported that overall charge and hydrophilicity can be combined to provide initial estimates of intracellular solubility, and that charge engineering via fusion can alter solubility properties experimentally. Additional studies showed that fusion of a proteasome-targeting PEST motif to the anti-huntingtin intrabody scFv-C4 can degrade mutant huntingtin proteins by directing them to the proteasome, while also increasing the negative charge. We now validate the generality of this approach with intrabodies against alpha-synuclein (alpha-syn), an important target in Parkinson disease. In this study, fusion of the PEST sequence to a set of four diverse, poorly soluble anti-alpha-syn intrabodies (D5E, 10H, D10 scFv, VH14 nanobody) significantly increased steady-state soluble intrabody protein levels in all cases, despite fusion with the PEST proteasomal-targeting signal. Furthermore, adding this PEST motif to the least soluble construct, VH14, significantly enhanced degradation of the target protein, alpha-syn~GFP. The intrabody-PEST fusion approach thus has dual advantages of potentially solubilizing intrabodies and enhancing their functionality in parallel. Empirical testing of intrabody-PEST fusions is recommended for enhancement of intrabody solubility from diverse sources. PMID- 22929190 TI - Assessment of risk factors associated with difficult intubation in prehospital emergency setting. PMID- 22929192 TI - The power of positive thinking. PMID- 22929189 TI - Inherited cobalamin malabsorption. Mutations in three genes reveal functional and ethnic patterns. AB - BACKGROUND: Inherited malabsorption of cobalamin (Cbl) causes hematological and neurological abnormalities that can be fatal. Three genes have been implicated in Cbl malabsorption; yet, only about 10% of ~400-500 reported cases have been molecularly studied to date. Recessive mutations in CUBN or AMN cause Imerslund Grasbeck Syndrome (IGS), while recessive mutations in GIF cause Intrinsic Factor Deficiency (IFD). IGS and IFD differ in that IGS usually presents with proteinuria, which is not observed in IFD. The genetic heterogeneity and numerous differential diagnoses make clinical assessment difficult. METHODS: We present a large genetic screening study of 154 families or patients with suspected hereditary Cbl malabsorption. Patients and their families have been accrued over a period spanning >12 years. Systematic genetic testing of the three genes CUBN, AMN, and GIF was accomplished using a combination of single strand conformation polymorphism and DNA and RNA sequencing. In addition, six genes that were contenders for a role in inherited Cbl malabsorption were studied in a subset of these patients. RESULTS: Our results revealed population-specific mutations, mutational hotspots, and functionally distinct regions in the three causal genes. We identified mutations in 126/154 unrelated cases (82%). Fifty-three of 126 cases (42%) were mutated in CUBN, 45/126 (36%) were mutated in AMN, and 28/126 (22%) had mutations in GIF. We found 26 undescribed mutations in CUBN, 19 in AMN, and 7 in GIF for a total of 52 novel defects described herein. We excluded six other candidate genes as culprits and concluded that additional genes might be involved. CONCLUSIONS: Cbl malabsorption is found worldwide and genetically complex. However, our results indicate that population-specific founder mutations are quite common. Consequently, targeted genetic testing has become feasible if ethnic ancestry is considered. These results will facilitate clinical and molecular genetic testing of Cbl malabsorption. Early diagnosis improves the lifelong care required by these patients and prevents potential neurological long term complications. This study provides the first comprehensive overview of the genetics that underlies the inherited Cbl malabsorption phenotype. PMID- 22929194 TI - Body dysmorphia and plastic surgery. AB - Body dysmorphic disorder is a mental disorder characterized by a preoccupation with some aspect of one's appearance. In cosmetic surgery, this preoccupation can be overlooked by practitioners resulting in a discrepancy between expected and realistic outcome. Identifying the characteristics of this disorder may be crucial to the practitioner-patient relationship in the plastic surgery setting. PMID- 22929196 TI - Communication between breast cancer patients and their physicians about breast related body image issues. AB - Breast cancer patients encounter body image changes throughout their diagnosis, treatment, and recovery from breast cancer. No prospective studies were identified investigating communication between physicians and breast cancer patients related to body image. This qualitative pilot study determines (1) how breast cancer patients prefer their physicians communicate regarding body image changes and (2) how comfortable physicians are in discussing body image issues with their patients. Data were collected from patients over 12 weeks through the breast evaluation questionnaire (BEQ), a valid and reliable instrument, and a qualitative questionnaire. Ten physicians completed a qualitative questionnaire. The data were analyzed using frequency analysis. Nearly 70% of the patients reported there was more the physician could do to improve patient comfort in discussing breast-related body image concerns. Honesty, openness, and directness were important to the patients. Thirty-three percent of the patients answered that their physicians should be honest, open, and direct while discussing these issues. On a five-point Likert scale (1 = very uncomfortable and 5 = very comfortable), the physicians most frequently answered a 4 when asked how comfortable they are speaking about breast-related body image issues; however, only four out of 10 always address the topic themselves during the patient's visit. These data suggest that patients want honesty, openness, and directness from their physicians during the discussion of breast-related body image issues. The physicians report they are comfortable speaking about breast-related body image issues; yet, they do not directly initiate the topic. PMID- 22929197 TI - Preventing postoperative nausea and vomiting: refresh your knowledge of how to recognize and respond to this common complication. AB - For surgical patients, postoperative nausea and vomiting (PONV) is one of the most undesired complications of anesthesia and surgery. PMID- 22929198 TI - Staying up to date on disinfection and sterilization techniques: brush up on AORN's recommendations for perioperative practice. AB - Preventing infection in surgical patients begins with cleaning, disinfecting, and sterilizing the medical instruments used during surgical and nonsurgical procedures. An estimated 71.9 million procedures are performed each year in the United States, so processing the instruments correctly is essential to minimize infection risk. The Joint Commission considers the following as infection prevention and control activities: Cleaning and performing low-level disinfection of medical supplies and devices and performing intermediate- and high-level disinfection and sterilization of medical equipment, devices, and supplies. Ongoing education about disinfection and sterilization techniques will improve your understanding of the implications of improper instrument handling. This article reviews the AORN practice recommendations for disinfection and sterilization so that you can better care for your patients during the perioperative and intraoperative periods. PMID- 22929199 TI - Permanent cosmetics. AB - Plastic surgery practices have become more accepting of the implantation of permanent cosmetics over the last few years. Many plastic surgery practices have added the implantation of permanent cosmetics into their offered services. Many clients who would not have considered having permanent cosmetics implanted because of having to go to a tattoo parlor are now having the procedures performed. The most popular procedures being performed are the implantation of permanent eyeliner followed by eyebrows and lip liner. Other implantations of permanent cosmetics are the full-lip applications, eye shadow application, cheek blush, and a beauty mark implantation. Micro pigmentation can be used for nipple coloration following reconstruction or camouflaging skin pigmentation problems due to trauma, birthmarks, cancer, etc. This article focuses on the use of micro pigmentation for the use of permanent cosmetics (WebMD, 2009). PMID- 22929200 TI - Scope of practice...standard of practice...standard of care...what is my/your obligation? AB - You are required by law, regulatory agencies, and ethical standards to deliver care within your scope of practice and to adhere to recognized standards of care while doing so. To comply with these mandates, you must also understand the scope of practice of those practitioners around you that comprise the plastic surgical team, as well as your responsibilities that flow therefrom. PMID- 22929201 TI - "Who moved my OR?". PMID- 22929202 TI - BRA Day and the plastic surgery nurse specialist. PMID- 22929203 TI - Weight changes and growth patterns following palatoplasty. PMID- 22929204 TI - The science behind sunscreens. AB - Exposure to ultraviolet light is a well-documented cause of immunosuppression, matrix degradation, premature facial aging, and skin cancer. Because sunscreens can limit ultraviolet-induced skin damage and production of matrix metalloproteinases, they are accepted as the most active and beneficial of antiaging products. Understanding the variety of ingredients available, and their individual advantages and disadvantages, will allow a clinician to make more informed recommendations regarding the use of sunscreens. PMID- 22929205 TI - Can the DermaClose device contribute to periwound tissue ischemia and necrosis: a case presentation and discussion? AB - The anterolateral thigh flaps allows for a large amount of vascularized skin and subcutaneous tissue for transfer as a locoregional flap or for microvascular free tissue transfer. In the settings of a large flap, primary closure of the donor site can be difficult. Multiple techniques, including the use of tissue expansion, can be used to assist with donor site closure. The DermaClose external tissue expander can be employed in such situations. We describe two cases with a unique use of the DermaClose system and postoperative complications. PMID- 22929206 TI - Universals of reading: developmental evidence for linguistic plausibility. AB - Children's reading and spelling errors show that orthographic learning involves complex interactions with phonology, morphology, and meaning throughout development. Even young children seek to make their visual word recognition strategies linguistically coherent. Orthographic knowledge gained through spelling affects reading, and vice versa. Developmental data support Frost's claim that letter-coding flexibility reflects the optimization of encoding resources in a highly developed system. PMID- 22929207 TI - In vitro inhibition of transmissible gastroenteritis coronavirus replication in swine testicular cells by short hairpin RNAs targeting the ORF 7 gene. AB - BACKGROUND: Transmissible gastroenteritis (TGE) is a highly contagious viral disease of swine, characterized by severe vomiting, diarrhea, and high mortality. Currently, the vaccines for it are only partially effective and no specific drug is available for treatment of TGE virus (TGEV) infection. RNA interference has been confirmed as a new approach for controlling viral infections. In this study, the inhibitory effect of short hairpin RNAs (shRNAs) targeting the ORF 7 gene of TGEV on virus replication was examined. RESULTS: Four theoretically effective sequences of TGEV ORF 7 gene were designed and selected for construction of shRNA expression plasmids. In the reporter assays, three of four shRNA expression plasmids were able to inhibit significantly the expression of ORF 7 gene and replication of TGEV, as shown by real-time quantitative RT-PCR analysis of viral ORF 7 and N genes and detection of virus titers (TCID50/ml). Stable swine testicular (ST) cells expressing the shRNAs were established. Observation of the cytopathic effect and apoptosis, as well as a cell proliferation assay demonstrated that the three shRNAs were capable of protecting ST cells against TGEV destruction, with high specificity and efficiency. CONCLUSIONS: Our results indicated that plasmid-transcribed shRNAs targeting the ORF 7 gene in the TGEV genome effectively inhibited expression of the viral target gene and viral replication in vitro. These findings provide evidence that the shRNAs have potential therapeutic application for treatment of TGE. PMID- 22929208 TI - Rectal hyposensitivity for non-noxious stimuli, postprandial hypersensitivity and its correlation with symptoms in complete spinal cord injury with neurogenic bowel dysfunction. AB - STUDY DESIGN: Prospective clinical study. OBJECTIVES: To assess fasting and postprandial (PP) perception of rectal distension and its correlation with symptoms in patients with spinal cord injury (SCI) and neurogenic bowel dysfunction compared to ten healthy subjects (HS). SETTING: Experimental Medicine and Motility Unit, Mexico General Hospital and National Institute of Rehabilitation. METHODS: Twenty patients with complete SCI at cervical, thoracic and lumbar levels [American Spinal Injury Association (ASIA) A] were studied. Rectal sensitivity was evaluated with a barostat. RESULTS: In SCI patients, while lower the rectal tone more time was used for defecate (R=0.50, P=0.048) and more PP episodes of fecal incontinence occur (R=0.54, P=0.030). The thresholds for non noxious stimuli of first (23.6 mmHg, CI 19.5-27.7) vs 14.0 (CI 10.9-17.1), P=0.004; gas (27.9 mmHg, CI 19.9-35.8) vs 17.9 mmHg (CI 14.25-21.69), P=0.02 and urge-to-defecate sensation (33.2 mmHg, CI 27.5-38.8) vs 22.4 mmHg (CI 17.9-26.9), P=0.01 were reported by SCI patients at higher pressure than HS, respectively. SCI patients reported PP pain sensation at a lower pressure than controls (27.8 mmHg, CI 21.5-34.2 vs 36.5 mmHg, CI 31.8-41.2), P=0.04. CONCLUSION: SCI patients preserve rectal sensation, present rectal hyposensitivity for non-noxious stimuli and PP hypersensitivity. Lower rectal tone was related to the time used for defecate and with fecal incontinence. The results suggest that an intact neural transmission between the spinal cord and higher centres is indispensable for noxious stimulus, but not for non-noxious stimuli. Also, barostat sensitivity studies can complement ASIA criteria to verify a complete injury. PMID- 22929209 TI - A within-trial cost-effectiveness analysis of primary care referral to a commercial provider for weight loss treatment, relative to standard care--an international randomised controlled trial. AB - BACKGROUND: Due to the high prevalence of overweight and obesity there is a need to identify cost-effective approaches for weight loss in primary care and community settings. OBJECTIVE: We evaluated the cost effectiveness of two weight loss programmes of 1-year duration, either standard care (SC) as defined by national guidelines, or a commercial provider (Weight Watchers) (CP). DESIGN: This analysis was based on a randomised controlled trial of 772 adults (87% female; age 47.4+/-12.9 years; body mass index 31.4+/-2.6 kg m(-2)) recruited by health professionals in primary care in Australia, United Kingdom and Germany. Both a health sector and societal perspective were adopted to calculate the cost per kilogram of weight loss and the ICER, expressed as the cost per quality adjusted life year (QALY). RESULTS: The cost per kilogram of weight loss was USD122, 90 and 180 for the CP in Australia, the United Kingdom and Germany, respectively. For SC the cost was USD138, 151 and 133, respectively. From a health-sector perspective, the ICER for the CP relative to SC was USD18 266, 12 100 and 40 933 for Australia, the United Kingdom and Germany, respectively. Corresponding societal ICER figures were USD31,663, 24,996 and 51,571. CONCLUSION: The CP was a cost-effective approach from a health funder and societal perspective. Despite participants in the CP group attending two to three times more meetings than the SC group, the CP was still cost effective even including these added patient travel costs. This study indicates that it is cost effective for general practitioners (GPs) to refer overweight and obese patients to a CP, which may be better value than expending public funds on GP visits to manage this problem. PMID- 22929211 TI - The associations between maternal pre-pregnancy body mass index or gestational weight change during pregnancy and body mass index of the child at 3 years of age. AB - OBJECTIVE: To estimate the associations between maternal pre-pregnancy body mass index (BMI) or gestational weight change (GWC) during pregnancy and offspring BMI at 3 years of age, while taking several pre-and postnatal factors into account. DESIGN: The Norwegian Mother and Child Cohort Study is a population-based pregnancy cohort study of women recruited from all geographical areas of Norway. SUBJECTS: The study includes 31 169 women enrolled between 2000 and 2009 through a postal invitation sent to women at 17-18 weeks of gestation. Data collected from 5898 of the fathers were included. MAIN OUTCOME MESURES: Offspring BMI at 3 years was the main outcome measured in this study. RESULTS: Mean maternal pre pregnancy BMI was 24.0 kg m(-2) (s.d. 4.1), mean GWC in the first 30 weeks of gestation was 9.0 kg (s.d. 4.1) and mean offspring BMI at 3 years of age was 16.1 kg m(-2) (s.d. 1.5). Both maternal pre-pregnancy BMI and GWC were positively associated with mean offspring BMI at 3 years of age. Pre-pregnancy BMI and GWC also interacted, and the strength of the interaction between these two factors was strongly associated with the increase in offspring BMI among mothers who gained the most weight during pregnancy and had the highest pre-pregnancy BMI. Our findings show that results could be biased by not including pre-pregnant paternal BMI. CONCLUSION(S): This large population-based study showed that both maternal pre-pregnancy BMI and GWC were positively associated with mean offspring BMI at 3 years of age. PMID- 22929212 TI - Beyond isolated word recognition. AB - In this commentary we concur with Frost's view of the centrality of universal principles in models of word identification. However, we argue that other processes in sentence comprehension also fundamentally constrain the nature of written word identification. Furthermore, these processes appear to be universal. We, therefore, argue that universality in word identification should not be considered in isolation, but instead in the context of other linguistic processes that occur during normal reading. PMID- 22929213 TI - Improved visualization of lung metastases at single cell resolution in mice by combined in-situ perfusion of lung tissue and X-Gal staining of lacZ-tagged tumor cells. AB - Metastasis is the main cause of death in the majority of cancer types and consequently a main focus in cancer research. However, the detection of micrometastases by radiologic imaging and the success in their therapeutic eradication remain limited. While animal models have proven to be invaluable tools for cancer research, the monitoring/visualization of micrometastases remains a challenge and inaccurate evaluation of metastatic spread in preclinical studies potentially leads to disappointing results in clinical trials. Consequently, there is great interest in refining the methods to finally allow reproducible and reliable detection of metastases down to the single cell level in normal tissue. The main focus therefore is on techniques, which allow the detection of tumor cells in vivo, like micro-computer tomography (micro-CT), positron emission tomography (PET), bioluminescence or fluorescence imaging. We are currently optimizing these techniques for in vivo monitoring of primary tumor growth and metastasis in different osteosarcoma models. Some of these techniques can also be used for ex vivo analysis of metastasis beside classical methods like qPCR, FACS or different types of histological staining. As a benchmark, we have established in the present study the stable transfection or transduction of tumor cells with the lacZ gene encoding the bacterial enzyme beta-galactosidase that metabolizes the chromogenic substrate 5-bromo-4-chloro-3-indolyl-beta-D galactopyranoside (X-Gal) to an insoluble indigo blue dye and allows highly sensitive and selective histochemical blue staining of tumor cells in mouse tissue ex vivo down to the single cell level as shown here. This is a low-cost and not equipment-intensive tool, which allows precise validation of metastasis in studies assessing new anticancer therapies. A limiting factor of X-gal staining is the low contrast to e.g. blood-related red staining of well vascularized tissues. In lung tissue this problem can be solved by in-situ lung perfusion, a technique that was recently established by Borsig et al. who perfused the lungs of mice under anesthesia to clear them from blood and to fix and embed them in-situ under inflation through the trachea. This method prevents also the collapse of the lung and thereby maintains the morphology of functional lung alveoli, which improves the quality of the tissue for histological analysis. In the present study, we describe a new protocol, which takes advantage of a combination of X-gal staining of lacZ-expressing tumor cells and in-situ perfusion and fixation of lung tissue. This refined protocol allows high sensitivity detection of single metastatic cells in the lung and enabled us in a recent study to detect "dormant" lung micrometastases in a mouse model, which was originally described to be non-metastatic. PMID- 22929214 TI - Patient-centered, comparative effectiveness of esophageal cancer screening: protocol for a comparative effectiveness research study to inform guidelines for evidence-based approach to screening and surveillance endoscopy. AB - BACKGROUND: The comparative effectiveness (CE) of endoscopic screening (versus no screening) for Barrett's esophagus (BE) in patients with GERD symptoms, or among different endoscopic surveillance strategies in patients with BE, for the early detection of esophageal adenocarcinoma (EA) is unknown. Furthermore, it is unclear if patients or providers have or will adopt any of these strategies (screening only, screening and surveillance, vs. none), irrespective of their effectiveness. Endoscopic screening and surveillance is expensive and can be risky. Therefore, it is imperative to establish the CE and acceptability about the risks and outcomes related to these practices to better inform expert recommendations and provider-patient decisions. METHODS/RESULTS: We propose a mixed methods study which will involve: (1) an analysis of secondary databases (VA and VA-Medicare linked datasets for 2004-09) to examine CE of endoscopic screening and surveillance in an observational study cohort (an estimated 680,000 patients with GERD; 25,000-30,000 with BE; and 3,000 with EA); (2) a structured electronic medical record (EMR) review on a national sample of patients using VA EMRs to verify all EA cases, identify cancer stage, cancer-targeted therapy, and validate the screening and surveillance endoscopy; and (3) qualitative in depth interviews with patients and providers to elicit preferences, norms, and behaviors to explain clinical contexts of these findings and address gaps arising from the CE study. CONCLUSION: This study will compare clinical strategies for detecting and monitoring BE, a pre-cancerous lesion. Additionally, by eliciting acceptability of these strategies for patients and providers, we will be able to propose effective and feasible strategies that are likely to be implemented in routine use. Findings will inform recommendations for clinical practice guidelines. Our innovative approach is consistent with the methodological standards of patient-centered outcomes research, and our findings will offer a significant contribution to the literature on cancer surveillance. PMID- 22929210 TI - Pharmacotherapy for childhood obesity: present and future prospects. AB - Pediatric obesity is a serious medical condition associated with significant comorbidities during childhood and adulthood. Lifestyle modifications are essential for treating children with obesity, yet many have insufficient response to improve health with behavioral approaches alone. This review summarizes the relatively sparse data on pharmacotherapy for pediatric obesity and presents information on obesity medications in development. Most previously studied medications demonstrated, at best, modest effects on body weight and obesity related conditions. It is to be hoped that the future will bring new drugs targeting specific obesity phenotypes that will allow clinicians to use etiology specific, and therefore more effective, anti-obesity therapies. PMID- 22929215 TI - Relative cost and outcomes in the intensive care unit of acute lung injury (ALI) due to pandemic influenza compared with other etiologies: a single-center study. AB - BACKGROUND: Critical illness due to 2009 H1N1 influenza has been characterized by respiratory complications, including acute lung injury (ALI) or acute respiratory distress syndrome (ARDS), and associated with high mortality. We studied the severity, outcomes, and hospital charges of patients with ALI/ARDS secondary to pandemic influenza A infection compared with ALI and ARDS from other etiologies. METHODS: A retrospective review was conducted that included patients admitted to the Cleveland Clinic MICU with ALI/ARDS and confirmed influenza A infection, and all patients admitted with ALI/ARDS from any other etiology from September 2009 to March 2010. An itemized list of individual hospital charges was obtained for each patient from the hospital billing office and organized by billing code into a database. Continuous data that were normally distributed are presented as the mean +/- SD and were analyzed by the Student's t test. The chi square and Fisher exact tests were used to evaluate differences in proportions between patient subgroups. Data that were not normally distributed were compared with the Wilcoxon rank-sum test. RESULTS: Forty-five patients were studied: 23 in the H1N1 group and 22 in the noninfluenza group. Mean +/- SD age was similar (44 +/- 13 and 51 +/- 17 years, respectively, p = 0.15). H1N1 patients had lower APACHE III scores (66 +/- 20 vs. 89 +/- 32, p = 0.015) and had higher Pplat and PEEP on days 1, 3, and 14. Hospital and ICU length of stay and duration of mechanical ventilation were comparable. SOFA scores over the first 2 weeks in the ICU indicate more severe organ failure in the noninfluenza group (p = 0.017). Hospital mortality was significantly higher in the noninfluenza group (77 vs. 39%, p = 0.016). The noninfluenza group tended to have higher overall charges, including significantly higher cost of blood products in the ICU. CONCLUSIONS: ALI/ARDS secondary to pandemic influenza infection is associated with more severe respiratory compromise but has lower overall acuity and better survival rates than ALI/ARDS due to other causes. Higher absolute charges in the noninfluenza group are likely due to underlying comorbid medical conditions. PMID- 22929216 TI - Species limits in the Andean toad genus Osornophryne (Bufonidae). AB - As Darwin observed, the differentiation among varieties, subspecies, and species seems, often times, arbitrary. Nowadays, however, novel tools provide the possibility of testing hypotheses of species. Using the Andean toad genus Osornophryne, we address the following questions: (1) How many species are within the genus? (2) Are morphological and molecular traits congruent when delimiting species? (3) Which morphological traits are the most divergent among species? We use recently developed methods for testing species boundaries and relationships using a multilocus data set consisting of two mitochondrial genes (12S, 16S; 1647bp aligned matrix), one exon (RAG-1; 923 aligned matrix), and one intron (RPL3Int5; 1410bp aligned matrix). As another line of evidence for species delimitation, we integrated analyses of 12 morphometric variables and 10 discrete traits commonly used in amphibian systematics. The molecular and morphological approaches support the validity of most of the described species in Osornophryne. We find, however, contradictory lines of evidence regarding the status of O. angel. Within O. guacamayo, we found a genetically divergent population that, we argue, represents a new species. We consider that O. bufoniformis represents a species complex that deserves further study. We highlight the importance of incorporating morphological data when delimiting species, especially for lineages that have a recent origin and have not achieved reciprocal monophyly in molecular phylogenies. Finally, the most divergent morphological traits among Osornophryne species are associated with locomotion (finger, toes and limbs) and feeding (head), suggesting an association between morphology and the ecological habits of the species. PMID- 22929218 TI - Surgical decortication as the first-line treatment for pleural empyema. AB - OBJECTIVE: The study objective was to evaluate the clinical outcomes of surgical decortication as the first line of treatment for pleural empyema. METHODS: We analyzed the medical records of 111 patients who presented with empyema and were treated with simple drainage or surgical decortication as the first line of treatment at Gangnam Severance Hospital, a tertiary referral medical center in Seoul, Korea. RESULTS: Of 111 patients with empyema, 27 underwent surgical decortication as the first intervention. Surgical decortication showed a better treatment success rate in all study subjects (96.3%, 26/27 patients) compared with simple drainage (58.3%, 49/84 patients; P < .0001 for method comparison). After propensity-scored matching, decortication resulted in a better outcome (95.0%, 19/20 patients) versus drainage (56.7%, 17/30 patients; P = .003). Surgical decortication as the first line of treatment for empyema was the best predictor of treatment success after adjustment for compounding factors (odds ratio, 14.529; 95% confidence interval, 1.715-123.074; P = .014). CONCLUSIONS: The first treatment choice for pleural empyema is a critical determinant of ultimate therapeutic success. After adjusting for confounding variables, surgical decortication is the optimal first treatment choice for advanced empyema. PMID- 22929219 TI - Discussion. PMID- 22929217 TI - Phylogenetic analysis of genome rearrangements among five mammalian orders. AB - Evolutionary relationships among placental mammalian orders have been controversial. Whole genome sequencing and new computational methods offer opportunities to resolve the relationships among 10 genomes belonging to the mammalian orders Primates, Rodentia, Carnivora, Perissodactyla and Artiodactyla. By application of the double cut and join distance metric, where gene order is the phylogenetic character, we computed genomic distances among the sampled mammalian genomes. With a marsupial outgroup, the gene order tree supported a topology in which Rodentia fell outside the cluster of Primates, Carnivora, Perissodactyla, and Artiodactyla. Results of breakpoint reuse rate and synteny block length analyses were consistent with the prediction of random breakage model, which provided a diagnostic test to support use of gene order as an appropriate phylogenetic character in this study. We discussed the influence of rate differences among lineages and other factors that may contribute to different resolutions of mammalian ordinal relationships by different methods of phylogenetic reconstruction. PMID- 22929220 TI - Very long-term results (up to 17 years) with the double-orifice mitral valve repair combined with ring annuloplasty for degenerative mitral regurgitation. AB - OBJECTIVE: The very long-term results of the double-orifice mitral valve repair are unknown. The aim of this study was to assess the late clinical and echocardiographic outcomes of this technique in patients with degenerative mitral regurgitation. METHODS: From 1993 to 2000, 174 patients with severe degenerative mitral regurgitation were treated with the double-orifice technique combined with ring annuloplasty. Mean age of patients was 52 +/- 12.8 years, New York Heart Association class I or II was present in 71% of the patients, atrial fibrillation in 17.2%, and preoperative left ventricular ejection fraction was 59.5% +/- 7.5%. Mitral regurgitation was due to anterior leaflet prolapse in 36 patients (20.6%), bileaflet prolapse in 128 (73.5%), and posterior leaflet prolapse in 10 patients (5.7%). RESULTS: There were no hospital deaths. At hospital discharge, mitral regurgitation was absent or mild in 169 patients (97.1%) and moderate (2+/4+) in 5 patients (2.8%). Mitral stenosis requiring reoperation was detected in 1 patient (0.6%). Clinical and echocardiographic follow-up was 97.1% complete (mean length, 11.5 +/- 2.53 years; median, 11.6 years; longest duration, 17.6 years). At 14 years, actuarial survival was 86.9% +/- 3.37%, freedom from cardiac death was 95.8% +/- 1.54%, and freedom from reoperation was 89.6 +/- 2.51%. At the last echocardiographic examination, recurrence of mitral regurgitation >=3+ was documented in 23 patients (23/169, 13.6%). Freedom from mitral regurgitation >=3+ at 14 years was 83.8% +/- 3.39%. The only predictor of recurrence of mitral regurgitation >=3+ was residual mitral regurgitation greater than mild at hospital discharge (hazard ratio, 5.7; 95% confidence interval, 1.6-20.6; P = .007). CONCLUSIONS: The double-orifice repair combined with ring annuloplasty provides very satisfactory long-term results in patients with degenerative mitral regurgitation in the setting of bileaflet and anterior leaflet prolapse. PMID- 22929221 TI - Predictors of hyperglycemia after cardiac surgery in nondiabetic patients. AB - OBJECTIVE: Postoperative hyperglycemia is associated with poor clinical outcomes in patients undergoing cardiac surgery. However, some experts consider hyperglycemia to be an epiphenomenon related to acute stress. We investigated whether preoperative patient characteristics can predict hyperglycemia after cardiac surgery in nondiabetic patients. METHODS: This is a retrospective study of nondiabetic patients undergoing cardiac surgery at a single center during the years 2004 to 2009. Hyperglycemia was defined as 2 consecutive blood glucose readings of 150 mg/dL or greater during the 72 hours after cardiac surgery. RESULTS: This study included 1453 patients with hyperglycemia and 2205 patients without hyperglycemia. Hyperglycemic patients were older, were more likely to be men, had higher body mass index, were more likely to be hypertensive and hypercholesterolemic, and had lower left ventricular ejection fractions; in addition, a greater proportion had a history of cardiovascular disease and renal failure. Multivariate logistic regression analysis showed age, gender, body mass index, preoperative serum creatinine, left ventricular ejection fraction, previous cardiac surgery, and preoperative cardiogenic shock to be independently associated with hyperglycemia (P < .05 for all). Hyperglycemic patients had more intraoperative and postoperative complications. CONCLUSIONS: Preoperative patient characteristics are associated with hyperglycemia after cardiac surgery. PMID- 22929222 TI - Pectus excavatum repair improves respiratory pump efficacy and cardiovascular function at exercise. PMID- 22929223 TI - Research incentive program for clinical surgical faculty associated with increases in research productivity. AB - OBJECTIVE: To develop a research productivity scoring program within an academic department of surgery that would help realign incentives to encourage and reward research. Although research is highly valued in the academic mission, financial incentives are generally aligned to reward clinical productivity. METHODS: A formula assigning points for publications and extramural grants was created and used to award a research incentive payment proportional to the research productivity score, beginning July 2007. Publication points reflect journal impact factor, author role, and manuscript type. Grant points reflect total funding and percentage of effort. Publication data were gathered from Web of Science/PubMed/Medline and grants data from the departmental grants office. An annual award is presented to the person with the greatest improvement. The research productivity score data after July 2007 were compared with control data for the 2 preceding years. A 33-question survey to 28 clinical faculty was conducted after the first year to measure satisfaction and solicit constructive feedback. RESULTS: The mean annual point scores increased from the preresearch productivity score to the postresearch productivity score academic years (2180 vs 3389, respectively, P = .08), with a significant change in the grant component score (272 vs 801, P = .03). Since research productivity score implementation, the operative case volumes increased 4.3% from 2006 to 2011. With a response rate of 89%, the survey indicated that 76% of the faculty wished to devote more time to research and 52% believed 1 or more research-related behaviors would change because of the research productivity score program. CONCLUSIONS: An objective, transparent research incentive program, through both monetary incentives and recognition, can stimulate productivity and was well-received by faculty. PMID- 22929224 TI - Sustainable sanitary landfills for neglected small cities in developing countries: the semi-mechanized trench method from Villanueva, Honduras. AB - Open dumping is the most common practice for the disposal of urban solid wastes in the least developed regions of Africa, Asia and Latin America. Sanitary landfill design and operation has traditionally focused on large cities, but cities with fewer than 50,000 in population can comprise from 6% to 45% of a given country's total population. These thousands of small cities cannot afford to operate a sanitary landfill in the way it is proposed for large cities, where heavy equipment is used to spread and compact the waste in daily cells, and then to excavate, transport and apply daily cover, and leachate is managed with collection and treatment systems. This paper presents an alternative approach for small cities, known as the semi-mechanized trench method, which was developed in Villanueva, Honduras. In the semi-mechanized trench method a hydraulic excavator is used for 1-3 days to dig a trench that will last at least a month before it is filled with waste. Trucks can easily unload their wastes into the trench, and the wastes compact naturally due to semi-aerobic biodegradation, after which the trenches are refilled and covered. The exposed surface area is minimal since only the top surface of the wastes is exposed, the remainder being covered by the sides and bottom of the trench. The surplus material from trench excavation can be valorized for use as engineering fill onsite or off. The landfill in Villanueva has operated for 15 years, using a total land area of approximately 11 ha for a population that grew from 23,000 to 48,000, with a land requirement of 0.2m(2)/person year, a cover to waste ratio of 0.2, and an estimated soil surplus of 298,000 m(3) that is valorized and used onsite. The landfill has been operated solely by the municipality with an operational cost in 2010 estimated at US$4.60 per ton. A modified water balance analysis at Villanueva shows negligible leachate generation from covered trenches and 700 m(3)/yr (60 m(3)/ha yr) from the two open trenches required for daily operation. If the site were an open dump, however, leachate generation is estimated to be 3900 m(3)/ha yr and contaminated runoff 5000 m(3)/ha yr. A simple model used to estimate dilution of generated leachate based on groundwater flow data and aquifer stratigraphy suggests that the leachate will be diluted by a factor of 0.01 in the aquifer. Leachate contaminants will not accumulate because the aquifer discharges to the Ulua River 2 km south of the landfill. While not suitable for all sites, the Villanueva method nevertheless serves as an excellent example of how a small city landfill with natural compaction of waste and attenuation of leachate can be sustainably operated. PMID- 22929225 TI - Clinical characteristics that distinguish eosinophilic organ infiltration from metastatic nodule development in cancer patients with eosinophilia. AB - BACKGROUND: When new space-occupying lesions are observed together with peripheral blood eosinophilia in patients diagnosed with cancer, the possibility of eosinophilic organ involvement should be differentiated from metastasis of primary cancer, since a misdiagnosis could lead to unnecessary chemotherapy. The aim of this study is to identify the clinical characteristics of eosinophilic organ involvement that distinguish it from distant metastasis in patients with primary cancer. METHODS: The medical records of 43 cancer patients who developed hepatic or pulmonary nodules with peripheral blood eosinophilia between January 2005 and February 2010 in the Asan Medical Center (Seoul) were reviewed. Eosinophilic infiltration and distant metastasis were identified on the basis of pathological findings and radiological features. Fisher's exact test, chi2 test or Mann-Whitney test were used for statistical analysis. RESULTS: In total, 33 patients (76%) were diagnosed with eosinophilic infiltration, 5 (12%) with cancer metastasis and 5 (12%) had undetermined diagnoses. Compared to the patients with metastases, the patients with eosinophilic infiltration were significantly more likely to have serology indicating a parasitic infection, a history of eating raw food, high serum levels of total IgE, normal liver function, normal C-reactive protein levels, a normal erythrocyte sedimentation rate, and fewer and smaller nodules. The most common underlying malignancy in the eosinophilic organ infiltration group was stomach cancer. Physicians tended to neglect the eosinophilia in patients with a history of cancer. CONCLUSIONS: Several clinical characteristics of eosinophilic organ infiltration distinguish it from cancer metastasis. Physicians should make greater efforts to determine the causes of organ involvement with peripheral blood eosinophilia, especially in cancer patients. PMID- 22929226 TI - The diagnosis and evaluation of dementia and mild cognitive impairment with emphasis on SPECT perfusion neuroimaging. AB - As the world population ages, the incidence of dementing illnesses will dramatically increase. The number of people afflicted with dementia is expected to quadruple in the next 50 years. Since the neuropathology of the dementias precedes clinical symptoms often by several years, earlier detection and intervention could be key steps to mitigating the progression and burden of these diseases. This review will explore methods of evaluating, differentiating, and diagnosing the multiple forms of dementia. Particular emphasis will be placed on the diagnosis of mild cognitive impairment-the precursor to dementia. Anatomical imaging; cerebrospinal fluid markers; functional neuroimaging, such as positron emission tomography and single photon emission tomography; and molecular imaging, such as amyloid marker imaging, will be assessed in terms of sensitivity and specificity. Cost will also be a consideration, as the growing population afflicted with dementia represents an increasingly large financial encumbrance to the healthcare systems of every nation. In the face of expensive new markers and limited availability of cyclotrons, single photon emission computer tomography (SPECT) provides relatively high sensitivity and specificity at a comparatively low overall cost. PMID- 22929227 TI - Regulation of nuclear envelope permeability in cell death and survival. AB - The nuclear pore complex (NPC) mediates macromolecular exchange between nucleus and cytoplasm. It is a regulated channel whose functional properties are modulated in response to the physiological status of the cell. Identifying the factors responsible for regulating NPC activity is crucial to understand how intracellular signaling cues are integrated at the level of this channel to control nucleocytoplasmic trafficking. For proteins lacking active translocation signals the NPC acts as a molecular sieve limiting passage across the nuclear envelope (NE) to proteins with a MW below ~40 kD. Here, we investigate how this permeability barrier is altered in paradigms of cell death and cell survival, i.e., apoptosis induction via staurosporine, and enhanced viability via overexpression of Bcl-2. We monitor dynamic changes of the NPC's size-exclusion limit for passive diffusion by confocal time-lapse microscopy of cells undergoing apoptosis, and use different diffusion markers to determine how Bcl-2 expression affects steady-state NE permeability. We show that staurosporine triggers an immediate and gradual leakiness of the NE preceding the appearance of apoptotic hallmarks. Bcl-2 expression leads to a constitutive increase in NE permeability, and its localization at the NE is sufficient for the effect, evincing a functional role for Bcl-2 at the nuclear membrane. In both settings, NPC leakiness correlates with reduced Ca2+ in internal stores, as demonstrated by fluorometric measurements of ER/NE Ca2+ levels. By comparing two cellular models with opposite outcome these data pinpoint ER/NE Ca2+ as a general and physiologically relevant regulator of the permeability barrier function of the NPC. PMID- 22929228 TI - ROCK-phosphorylated vimentin modifies mutant huntingtin aggregation via sequestration of IRBIT. AB - BACKGROUND: Huntington's Disease (HD) is a fatal hereditary neurodegenerative disease caused by the accumulation of mutant huntingtin protein (Htt) containing an expanded polyglutamine (polyQ) tract. Activation of the channel responsible for the inositol-induced Ca2+ release from ensoplasmic reticulum (ER), was found to contribute substantially to neurodegeneration in HD. Importantly, chemical and genetic inhibition of inositol 1,4,5-trisphosphate (IP3) receptor type 1 (IP3R1) has been shown to reduce mutant Htt aggregation. RESULTS: In this study, we propose a novel regulatory mechanism of IP3R1 activity by type III intermediate filament vimentin which sequesters the negative regulator of IP3R1, IRBIT, into perinuclear inclusions, and reduces its interaction with IP3R1 resulting in promotion of mutant Htt aggregation. Proteasome inhibitor MG132, which causes polyQ proteins accumulation and aggregation, enhanced the sequestration of IRBIT. Furthermore we found that IRBIT sequestration can be prevented by a rho kinase inhibitor, Y-27632. CONCLUSIONS: Our results suggest that vimentin represents a novel and additional target for the therapy of polyQ diseases. PMID- 22929229 TI - Selected imprinting of INS in the marsupial. AB - BACKGROUND: In marsupials, growth and development of the young occur postnatally, regulated by milk that changes in composition throughout the long lactation. To initiate lactation in mammals, there is an absolute requirement for insulin (INS), a gene known to be imprinted in the placenta. We therefore examined whether INS is imprinted in the mammary gland of the marsupial tammar wallaby (Macropus eugenii) and compared its expression with that of insulin-like growth factor 2 (IGF2). RESULTS: INS was expressed in the mammary gland and significantly increased, while IGF2 decreased, during established milk production. Insulin and IGF2 were both detected in the mammary gland macrophage cells during early lactation and in the alveolar cells later in lactation. Surprisingly, INS, which was thought only to be imprinted in the therian yolk sac, was imprinted and paternally expressed in the liver of the developing young, monoallelically expressed in the tammar mammary gland and biallelic in the stomach and intestine. The INS transcription start site used in the liver and mammary gland was differentially methylated. CONCLUSIONS: This is the first study to identify tissue-specific INS imprinting outside the yolk sac. These data suggest that there may be an advantage of selective monoallelic expression in the mammary gland and that this may influence the growth of the postnatal young. These results are not consistent with the parental conflict hypothesis, but instead provide support for the maternal-infant co-adaptation hypothesis. Thus, imprinting in the mammary gland maybe as critical for postnatal growth and development in mammals as genomic imprinting in the placenta is prenatally. PMID- 22929230 TI - Shadoo/PrP (Sprn(0/0) /Prnp(0/0) ) double knockout mice: more than zeroes. AB - Shadoo (Sho) is a brain glycoprotein with similarities to the unstructured region of PrP (C) . Frameshift alleles of the Sho gene, Sprn, are reported in variant Creutzfeldt-Jakob disease (vCJD) patients while Sprn mRNA knockdown in PrP-null (Prnp(0/0) ) embryos produces lethality, advancing Sho as the hypothetical PrP like "pi" protein. Also, Sho levels are reduced as misfolded PrP accumulates during prion infections. To penetrate these issues we created Sprn null alleles (Daude et al., Proc. Natl. Acad. Sci USA 2012; 109(23): 9035-40). Results from the challenge of Sprn null and TgSprn transgenic mice with rodent-adapted prions coalesce to define downregulation of Sho as a "tracer" for the formation of misfolded PrP. However, classical BSE and rodent-adapted BSE isolates may behave differently, as they do for other facets of the pathogenic process, and this intriguing variation warrants closer scrutiny. With regards to physiological function, double knockout mice (Sprn(0/0) /Prnp(0/0) ) mice survived to over 600 d of age. This suggests that Sho is not pi, or, given the accumulating data for many activities for PrP (C) , that the pi hypothesis invoking a discrete signaling pathway to maintain neuronal viability is no longer tenable. PMID- 22929231 TI - Ethylenediamine diacetate (EDDA) mediated synthesis of aurones under ultrasound: their evaluation as inhibitors of SIRT1. AB - An improved synthesis of functionalized aurones has been accomplished via the reaction of benzofuran-3(2H)-one with a range of benzaldehydes in the presence of a mild base EDDA under ultrasound. A number of aurones were synthesized (within 5 30min) and the molecular structure of a representative compound determined by single crystal X-ray diffraction study confirmed Z-geometry of the C-C double bond present within the molecule. Some of the compounds synthesized have shown SIRT1 inhibiting as well as anti proliferative properties against two cancer cell lines in vitro. Compound 3a [(Z)-2-(5-bromo-2-hydroxybenzylidene) benzofuran 3(2H)-one] was identified as a potent inhibitor of SIRT1 (IC(50)=1MUM) which showed a dose dependent increase in the acetylation of p53 resulting in induction of apoptosis. PMID- 22929232 TI - Synthesis and optimization of substituted furo[2,3-d]-pyrimidin-4-amines and 7H pyrrolo[2,3-d]pyrimidin-4-amines as ACK1 inhibitors. AB - Two classes of ACK1 inhibitors, 4,5,6-trisubstituted furo[2,3-d]pyrimidin4-amines and 4,5,6-trisubstituted 7H-pyrrolo[2,3-d]pyrimidin-4-amines, were discovered and evaluated as ACK1 inhibitors. Further structural refinement led to the identification of potent and selective dithiolane inhibitor 37. PMID- 22929233 TI - A focused sulfated glycoconjugate Ugi library for probing heparan sulfate-binding angiogenic growth factors. AB - A library of small molecule heparan sulfate (HS) mimetics was synthesized by employing the Ugi four-component condensation of d-mannopyranoside-derived isocyanides with formaldehyde as the carbonyl component and a selection of carboxylic acids and amines, followed by sulfonation. The library was used to probe the subtle differences surrounding the ionic binding sites of three HS binding angiogenic growth factors (FGF-1, FGF-2 and VEGF). Each compound features 3 or 4 sulfo groups which serve to anchor the ligand to the HS-binding site of the protein, with a diverse array of functionality in place extending from C-1 or C-6 to probe for adjacent favorable binding interactions. Selectivity of binding to these proteins was clearly observed and supported by molecular docking calculations. PMID- 22929235 TI - Increasing the time to expander-implant exchange after postmastectomy radiation therapy reduces expander-implant failure. AB - BACKGROUND: Increased rates of complications can occur when postmastectomy radiation therapy is required after immediate expander-implant breast reconstruction. The sequence and timing of tissue expansion and implant exchange with regard to postmastectomy radiation therapy may impact complication rates. METHODS: A prospectively maintained database of patients undergoing mastectomy and immediate reconstruction was queried for patients who underwent postmastectomy radiation therapy. The authors' protocol is to complete tissue expansion before radiation, irradiate the fully inflated expander, and then perform expander-implant exchange. Starting in 2009, the authors refined their protocol by increasing the time interval between completion of radiation therapy and expander-implant exchange from 3 months to 6 months as a strategy to reduce surgical complications. For analysis, patients were divided into two cohorts based on whether expander-implant exchange was performed less than 6 months or more than 6 months after radiation. The primary outcome was expander-implant failure, defined as device removal without concurrent replacement. RESULTS: Eighty-eight patients met selection criteria; 49 (55.7 percent) had expander implant exchange within 6 months of completing radiation therapy (mean, 3.4 months; range, 1.2 to 5.8 months), and the rest had at least a 6-month interval (mean, 8.6 months; range, 6.1 to 17.1 months). Risk factors for postoperative complications were equivalent between cohorts. Overall expander-implant failure was 15.9 percent; failure was significantly higher in the cohort with less than 6 months' time before exchange (22.4 percent versus 7.7 percent, p = 0.036). CONCLUSION: Delaying expander-implant exchange for at least 6 months after the completion of postmastectomy radiation therapy can significantly reduce expander implant failure. PMID- 22929234 TI - Influenza A(H1N1)pdm09 and flu response centres: characteristics of flu response centre staff in the West Midlands. AB - OBJECTIVE: To assess the operational experience and knowledge of staff who worked in the West Midlands Flu Response Centre (FRC) during the 'containment' phase of influenza A(H1N1)pdm09. STUDY DESIGN: Evaluation study. METHODS: Cross-sectional survey of staff who worked in the West Midlands FRC between 18 May 2009 and 10 July 2009 using an online self-administered questionnaire. The questionnaire included sections related to the respondents' FRC experience, knowledge about influenza A(H1N1)pdm09 and the containment phase. RESULTS: This study had a 51% (89/176) response rate. Of the respondents, 59% were female, 64% were of White ethnicity, 55% were clinicians, 46% were aged 25-44 years, and 67% had no previous call centre experience. A significant proportion (P < 0.001) of respondents believed that the FRC had made a positive contribution to the public health management of the containment phase. Nearly all respondents indicated that they were familiar with the terms 'pandemic flu' or 'influenza pandemic' (99%), understood the aim of the containment phase (90%), and knew the severity of the illness caused by the virus (97%). However, specific knowledge was lacking regarding a number of public health interventions, and overall knowledge scores for clinicians and non-clinicians were similar. CONCLUSION: This study is the first to report on the characteristics of FRC staff during the containment phase of influenza A(H1N1)pdm09 pandemic. Although overall, staff evaluation of the West Midlands FRC was very positive, a number of knowledge gaps were identified. This study provides valuable insights which can contribute to preparedness planning. PMID- 22929236 TI - A classification of clinical fat grafting: different problems, different solutions. AB - BACKGROUND: Fat grafting has reemerged from a highly variable procedure to a technique with vast reconstructive and cosmetic potential. Largely because of a more disciplined and scientific approach to fat grafting as a transplantation event, early adopters of fat transplantation have begun to approach fat grafting as a process, using sound surgical transplantation principles: recipient preparation, controlled donor harvest, time-efficient transplantation, and proper postoperative care. Despite these principles, different fat grafting techniques yield impressive clinical outcomes. METHODS: The essential variables of four types of fat grafting cases were identified and compared: harvesting, methods of cell processing, methods of transplantation, and management of the recipient site. RESULTS: Each case differed for most of the variables analyzed. The two clinical drivers that most impacted these differences were the volume demands of the recipient site and whether the recipient site was healthy tissue or pathologic tissue. After these two drivers, a matrix classification of small volume versus large-volume and regenerative versus nonregenerative cases yields four distinct categories. CONCLUSIONS: Not all fat grafting is the same. Fat grafting, once thought to be a simple technique with variable results, is a much more complex procedure with at least four definable subtypes. By defining the essential differences in the recipient site, the key driver in fat transplantation, the proper selection of technique can be best chosen. In fat transplantation, different problems require different solutions. PMID- 22929237 TI - Accelerated wound healing with topical application of complement C5. AB - BACKGROUND: Delayed-healing traumatic, surgical, and chronic wounds can be detrimental to patients and the health care system. The authors set out to investigate the effects of complement C5, a naturally occurring chemotactic cytokine, on wounds. METHODS: The authors examined the effects of complement C5 on the rat paired skin incision model. Each rat served as its own control where topical collagen was applied to one incision and 100 nM of C5 in collagen vehicle was applied to the other incision. Rats were killed on days 3 (n = 6), 7 (n = 6), and 28 (n = 5) after wounding. RESULTS: There was a statistically significant, 65 percent increase in maximum wound breaking strength with the topical application of C5 at day 3 (p < 0.01). The increase persisted to 14 percent at 7 days after wounding (p < 0.05). When compared with the sham group, the C5-treated wound strength increased by 83 percent at day 3 and 64 percent at day 7. There was no change in breaking strength at 28 days. Western blot analysis demonstrated a significant increase in collagen and fibronectin content in the C5-treated wounds. CONCLUSIONS: Topical application of C5 to skin wounds significantly increases wound healing maximum breaking strength as early as 3 days and up to 7 days after wounding. C5 accelerated wound healing by at least 4 days in the first week of wounding. This was correlated with an increase in vascular permeability, increased inflammatory cell recruitment, subsequent fibroblast migration, and increased collagen deposition. PMID- 22929238 TI - Decellularized tracheal matrix scaffold for tissue engineering. AB - BACKGROUND: A tracheal matrix scaffold decellularized by detergent-enzymatic treatment has been shown as a promising scaffold in tracheal tissue engineering. The objectives of this study were to evaluate the impact of this technique on tracheal extracellular matrix integrity and characterize the matrix environment for recellularization. METHODS: Brown Norway rat tracheae were decellularized using a modified detergent-enzymatic treatment. Antigenicity and cellularity were monitored during processing. Glycosaminoglycan content, histoarchitecture, and mechanical properties were also evaluated. Matrix compatibility was determined by cytotoxicity assay. Surface ultrastructure of the matrix and its interaction with seeded bone marrow stem cell-derived chondrocytes and tracheal epithelial cells were examined by scanning electron microscopy. RESULTS: Rat trachea treated with five detergent-enzymatic treatment cycles demonstrated complete elimination of antigenicity. Although there was a significant loss of glycosaminoglycan (t test, p < 0.01), histoarchitecture of tracheal cartilage and basement membrane was retained after decellularization. Stiffness decreased, but sufficient compressive strength was preserved to maintain lumen patency. The decellularized matrix showed good cell compatibility and favored adhesion and growth of chondrocytes and respiratory epithelial cells, as demonstrated by scanning electron microscopy. CONCLUSIONS: At the point of complete antigen removal, detergent enzymatic treatment altered tracheal extracellular matrix composition but preserved the major structure and adequate mechanical strength. The matrix provided a compatible and supportive environment for recellularization. PMID- 22929239 TI - External volume expansion increases subcutaneous thickness, cell proliferation, and vascular remodeling in a murine model. AB - BACKGROUND: Fat grafting is a powerful tool for soft-tissue reconstruction; however, the science behind recipient bed preparation has not been thoroughly explored. External volume expansion using suction before fat grafting has been used clinically to improve reliability and consistency of graft survival. The authors developed a murine model to investigate the underlying mechanism of external volume expansion. METHODS: The authors created an external volume expansion device using a soft-silicone dome connected to a vacuum source (25 mmHg) to treat the dorsum of mice, and the response was compared with treatment with an occlusive dressing. Treated areas were monitored with magnetic resonance imaging. Remodeling of microvasculature was studied with corrosion casting on day 7. Effects on tissue thickness, number of adipocytes, cell proliferation, and blood vessel density were analyzed at 28 days. RESULTS: Macroscopic analysis showed tissue swelling at sites treated with the external volume expansion device by 21 days, without skin damage. On day 28, external volume expansion increased the thickness of the subcutaneous fat layer twofold, consistent with magnetic resonance imaging observations. The proliferation rate in the subcutaneous layer of expansion-treated areas increased twofold, with a net 2.2-fold increase in number of adipocytes in columns; remodeling of the vessels network occurred, with reorientation and increase of vessel diameters shown by corrosion casting and 1.9 fold augmentation of vessels density. CONCLUSIONS: External volume expansion applied to mouse integument induces highly proliferative and vascularized subcutaneous tissue. Recipient-site preparation using external volume expansion devices may be a promising tool to enhance cell and tissue engraftment. PMID- 22929240 TI - Nasolabial rotation flaps based on the upper lateral lip subunit for superficial and large defects of the upper lateral lip. AB - BACKGROUND: Reconstruction of the defects of the upper lateral lip is still one of the most difficult challenges for plastic surgeons. No method specific to the superficial and larger defects of the upper lateral lip has been proposed before. Nasolabial rotation flaps based on the upper lateral lip subunit for superficial and large defects of the upper lateral lip are proposed. METHODS: In six patients reported here, rotation flaps shaped to replace the subunits of the upper lip were used to repair defects. Three men and three women presented with unilateral superficial, large defects (occupying 50 percent of an upper lip subunit). The defect and upper lateral lip ratio ranged from 50 to 100 percent (average, 65 percent) in this series. All lesions were partial-thickness. RESULT: Follow-up for all patients was 6 to 13 months (average, 6.8 months). No flap loss was noted. No patients had infection, hematoma, nerve injury, or secondary revision. The results were satisfactory. CONCLUSIONS: Nasolabial rotation flaps based on upper lateral lip subunits are reliable for reconstructing large, superficial defects of the upper lateral lip. Because they preserve the normal facial appearance with minimal donor-site morbidity, excellent aesthetic reconstructive results are easily achieved by appropriate patient selection and preoperative planning. PMID- 22929241 TI - Discussion: nasolabial rotation flaps based on the upper lateral lip subunit for superficial and large defects of the upper lateral lip. PMID- 22929242 TI - Epinephrine, norepinephrine, dobutamine, and dopexamine effects on free flap skin blood flow. AB - BACKGROUND: The optimal sympathomimetic drug to support blood pressure without adverse vasoconstriction of free flap circulation remains unknown. This study examined the effects of four agents (epinephrine, norepinephrine, dobutamine, and dopexamine) on free flaps following resection of head and neck cancer. METHODS: Twenty-four patients (25 data sets) were recruited into the study. Each patient received an infusion of the four drugs in a random order, with an intervening washout period between drugs, at four infusion rates. Continuous free flap skin blood flow monitoring was performed using laser Doppler velocimetry, with a second sensor on normal skin acting as a control. Global cardiovascular variables were monitored using the LiDCO Rapid Pulse Contour Analysis System (LiDCO Ltd., Cambridge, United Kingdom). RESULTS: Dose-dependent, increased free flap skin blood flow was observed with norepinephrine and dobutamine. Both dopexamine and epinephrine infusions decreased blood flow. Flap skin blood conductance decreased (vasoconstriction) with norepinephrine, but markedly less than in control tissue, so overall the flap skin blood flow increased with increasing arterial blood pressure. Dobutamine increased flap skin conductance, without significantly increasing blood pressure, and modestly increased flap blood flow. CONCLUSIONS: Both dobutamine and norepinephrine had beneficial effects on flap skin blood flow. The maximal improvement in flow occurred with norepinephrine, making it the optimal pressor to use in patients with hypotension after free flap surgery. PMID- 22929243 TI - Follicular isolation technique with de-epithelialization for eyebrow and eyelash reconstruction. AB - BACKGROUND: The eyebrow and eyelash are two major sites in facial hair transplantation. Different methods have been experienced for better results. Surgeons tend to use smaller grafts. The authors modified the follicular isolation technique and added de-epithelialization to reduce complications and improve outcomes. METHODS: Sixty patients were allocated to either the isolation group or the isolation plus de-epithelialization group. Some patients underwent both eyebrow and eyelash transplantation; therefore, 79 procedures were performed on 60 patients. Scar formation, number and percentage of surviving transplanted hairs, hair growth orientation, and satisfaction with outcome were reviewed at 6 months. RESULTS: The mean number of preserved transplanted hairs in eyebrow transplantation at follow-up was not significantly different between the two groups, but the mean percentage of preserved transplanted hairs was significantly higher in the isolation plus de-epithelialization group. In eyelash reconstruction, the mean number and percentage of surviving hairs were significantly higher in the isolation + de-epithelialization group than in the isolation-only group. The isolation + de-epithelialization group had more cases of normal hair growth direction in both eyebrow and eyelash transplantation cases, although the difference was statistically significant only in eyebrow reconstruction. CONCLUSIONS: This study showed that follicular isolation plus de epithelialization had better outcomes and fewer complications than did follicular isolation alone. This could be due to less need for suture in recipient sites, less risk for burying of epithelium of graft in the recipient site, less need for manipulation, lower graft volume, and less need for blood for survival and for removal of sweat glands. CLINICAL QUESTION/LEVEL OF EVIDENCE: : Therapeutic, II. PMID- 22929244 TI - Free flap take-back following postoperative microvascular compromise: predicting salvage versus failure. AB - BACKGROUND: The purpose of this study is twofold: (1) to stratify preoperative risk factors that predict successful free flap salvage and (2) to identify perioperative strategies that correlate with successful salvage. METHODS: A retrospective chart review was performed on all free flaps performed from January of 2005 to April of 2011. The time until salvage was defined as the end of the initial procedure until the initiation of the salvage attempt. The primary endpoint, successful salvage, was defined as any flap that did not result in total loss. RESULTS: A total of 2260 free flaps were reviewed, and 47 take-backs for delayed microvascular compromise were identified. Twenty-three of 47 flaps (49 percent) were salvaged. The mean time until take-back, presence of thrombophilia, and preoperative platelet counts were factors predictive of unsuccessful salvage. Preoperative platelet counts above 300 were associated with the lowest rates of salvage. Intraoperative maneuvers were examined, and surgeon experience (defined as >5 years in practice) was the only factor that was significant; however, intraoperative heparin anticoagulation and complete mechanical thrombectomy trended toward significance. The type of thrombolytic agent used was not found to result in a statistically significant difference. CONCLUSIONS: There is evidence to suggest that there may be preoperative factors predictive of flap salvage success, including thrombophilia and routine preoperative platelet values. Shorter time to take-back and surgeon experience may improve salvage, whereas intraoperative heparin anticoagulation and complete mechanical removal of the thrombus demonstrate preliminary evidence as effective intraoperative strategies. PMID- 22929245 TI - A paradigm shift for soft-tissue coverage of the zones of the abdominal wall using perforator flaps. AB - BACKGROUND: A team approach is essential to properly restore the integrity and function of the complete abdominal wall defect. If additional vascularized tissue coverage following this reconstruction is imperative, knowledge of all potential flap alternatives to achieve this goal becomes critical to ensure healing and reduce the risk of recurrent hernia. METHODS: A historical review of algorithms for the management of complex abdominal wall defects was undertaken. Numerous schemas have been suggested as guidelines for flap selection, if needed, and each was carefully scrutinized to determine its contemporary appropriateness. RESULTS: The method for closure of any abdominal wall defect depends on its size, depth, and location. Previous schemas divided the abdomen into subunits with an inventory of available flaps for each region. Traditionally, muscle or musculocutaneous flaps were most commonly suggested. With the advent of perforator flaps, a new set of options is available to augment the possibilities apropos to the specific abdomen zone. CONCLUSIONS: Complete restoration of even basic function of the abdominal wall requires an intact and contractile musculofascial supporting system. Any incisions or flaps that denervate functioning muscle should be avoided. Perforator flaps have proven to be another reasonable option with which to restore any skin deficiencies whether as pedicled or free flaps and, because by definition no muscle is ever included, maximum function preservation of the abdominal wall will also thereby be achieved. PMID- 22929246 TI - A Comparison of collateral sprouting of sensory and motor axons after end-to-side neurorrhaphy with and without the perineurial window. AB - BACKGROUND: Many experimental studies have confirmed collateral sprouting of axons after end-to-side neurorrhaphy and its possible clinical application. There is still controversy about how the surgical method should be carried out. The aim of the present study was to quantitatively evaluate collateral sprouting of motor and sensory axons after end-to-side neurorrhaphy with and without the perineurial window. METHODS: End-to-side neurorrhaphy of the distal stump of transected musculocutaneous nerve with intact ulnar nerve with or without a perineurial window was performed in a rat model. Collateral sprouts were quantitatively evaluated by counting of motor and sensory neurons following their retrograde labeling by Fluoro-Ruby and Fluoro-Emerald applied to the ulnar and musculocutaneous nerves, respectively. RESULTS: Our results show that significantly more motor and sensory axons sent their collateral branches into the recipient nerve in the group with a perineurial window. Some axons were injured during preparation of the perineurial window; the injured axons reinnervated directly into the recipient nerve to contribute to results of functional reinnervation. CONCLUSION: The authors conclude that it is necessary to create a perineurial window when using end-to-side neurorrhaphy in clinical practice, especially in brachial plexus reconstruction. PMID- 22929247 TI - Discussion: a comparison of collateral sprouting of sensory and motor axons after end-to-side neurorrhaphy with and without the perineurial window. PMID- 22929248 TI - Alveolar reconstruction in cleft patients: decreased morbidity and improved outcomes with supplemental demineralized bone matrix and cancellous allograft. AB - BACKGROUND: The safety and efficacy of supplemental allograft combined with iliac crest autograft as a treatment for cleft alveolus defects is poorly characterized. The authors report the safety and efficacy of supplemental demineralized bone matrix and cancellous allograft with iliac crest bone autograft in cleft alveolar bone defects. METHODS: A retrospective review of one institution's experience with cleft alveolar bone defects treated with traditional open iliac crest bone graft alone (group 1) or minimal access iliac crest bone graft plus demineralized bone matrix and cancellous allograft (group 2) was performed. All patients (n = 36) were treated with alveolar fistula repair with primary closure. RESULTS: Twenty-two patients [17 unilateral and five bilateral clefts (n = 27)] were treated in group 1 and 14 [six unilateral clefts and eight bilateral clefts (n = 22)] in group 2. The average operative time per alveolus was 147 minutes in group 1 and 111 minutes in group 2. Average engraftment (Enemark Scale) was 1.96 in group 1 and 1.20 in group 2. In group 1, canine eruption was complete in 71.4 percent, partial in 21.4 percent, and unerupted in 3.5 percent; in group 2, canine eruption was complete in 22 percent, partial in 55 percent, and unerupted in 18 percent. Bone graft extrusion occurred in six patients in group 1. There were no wound infections or deaths. CONCLUSIONS: The addition of supplemental demineralized bone matrix and cancellous allograft in cleft alveolar defects is safe and effective. The authors' allograft supplemental surgical technique is associated with low morbidity, shorter operative times, and higher rates of bone graft survival. PMID- 22929249 TI - Behavioral adjustment of toddler and preschool-aged children with single-suture craniosynostosis. AB - BACKGROUND: The purpose of this study was to confirm initial reports of elevated behavior problems in children with single-suture craniosynostosis, using multiple informants, longitudinal analyses, and a control group. The authors hypothesized that children with single-suture craniosynostosis would have higher levels of maladjustment than comparison children, particularly at the older age and in selected areas of previously observed vulnerability: attention and social adjustment. METHODS: The Child Behavior Checklist was completed by 436 mothers (219 with single-suture craniosynostosis) and 371 fathers (177 with single-suture craniosynostosis) when children were aged approximately 19 months, and by 361 mothers (175 with single-suture craniosynostosis) and 303 fathers (142 with single-suture craniosynostosis) when children were aged approximately 37 months. A minimum of one caregiver/teacher report was available for 169 of these children (74 with single-suture craniosynostosis) using the Caregiver-Teacher Report Form. RESULTS: Average Child Behavior Checklist/Caregiver-Teacher Report Form externalizing, internalizing, and total scores for all informants were consistently higher (worse) for children with single-suture craniosynostosis than for control group children, but most differences were small and statistically nonsignificant. No differences associated with suture site were found. At the oldest age point, both mothers and fathers (but not teachers) generated higher average scores for patients than for controls on scales measuring attention and social problems, with small to medium effect sizes (0.20 to 0.32). CONCLUSIONS: On average, toddlers/preschoolers with single-suture craniosynostosis show behavioral development that is largely indistinguishable from same-aged peers of similar socioeconomic background. The predictive significance of small group differences in attention and social adjustment will be assessed in a follow-up of this cohort at age 7. PMID- 22929250 TI - Dynamic abdominoplasty for the treatment of prune belly syndrome. AB - BACKGROUND: The deficient abdominal wall musculature associated with prune belly syndrome often results in numerous functional disabilities, including diminished cough, impaired bladder and bowel function, and poor posture and balance. Traditional abdominoplasties focus on static fascial excisions or plications. The authors sought to assess their preliminary experience with a new abdominoplasty technique that incorporates standard fascial tightening with bilateral pedicled rectus femoris muscle transfers. METHODS: This case series review included all patients treated with prune belly syndrome at the authors' center. Physical presentation, operative procedures, hospitalization, complications, and postoperative functional status were assessed, and a systematic analysis of published surgical series was performed. RESULTS: Over a 16-year period, the authors treated 13 patients with prune belly syndrome. All underwent standard "vest over pants" fascial plications, with 11 of 13 undergoing additional rectus femoris muscle transpositions at a mean age of 4 years (range, 12 months to 13 years). Hospitalization averaged 9.3 days, and the average follow-up was over 1.5 years. The authors identified three minor complications (chylous leak, fungal urinary tract infection, and partial umbilical necrosis), yielding a complication rate similar to those identified in our systematic analysis of published standard abdominoplasties. Postoperatively, all transposed muscles were palpably functional, one patient was successfully weaned off a ventilator, and all demonstrated improvements with balance and ambulation. CONCLUSION: The authors' preliminary review suggests that this new procedure, which supplements the standard prune belly abdominoplasty with bilateral rectus femoris transposition flaps, is not associated with substantially higher complication rates yet does appear to have the potential to provide functional improvements. PMID- 22929251 TI - Nasoalveolar molding in cleft care: is it efficacious? AB - In the era of evidence-based medicine, new treatment protocols and interventions should be routinely evaluated for their efficacy by reviewing the available evidence. In the cleft literature, nasoalveolar molding has garnered attention over the last decade as a new option for improving nasal form and symmetry before primary surgical repair. Systematic review of the evidence is, however, currently lacking. This review evaluates whether nasoalveolar molding can improve nasal symmetry and form toward the norm, as well as whether nasoalveolar molding demonstrates advantages over other protocols in achieving this goal. A literature search of five databases plus relevant reference lists retrieved 98 articles regarding nasoalveolar molding, 21 of which reported objective outcome measures of nasal symmetry and form, and six of which were able to be given evidence level ratings, all in the unilateral cleft population. Statistical analysis was not possible given the range of techniques and outcomes. Studies of bilateral cleft were not given evidence level ratings, given the inability to separate the effects of nasoalveolar molding from other primary nasal interventions in studies that would have otherwise been rated. In unilateral cleft lip-cleft palate, there was some evidence that nasoalveolar molding may improve nasal outcomes, though comparison with other techniques was limited. Despite a relative paucity of high level evidence, nasoalveolar molding appears to be a promising technique that deserves further study. PMID- 22929252 TI - Discussion: what motivates secondary rhinoplasty? A study of 150 consecutive patients. PMID- 22929253 TI - Endoscopic management of the difficult lower eyelid: a review of 300 cases. AB - BACKGROUND: The senior author's (H.S.B.) endoscopic brow and midface lift technique has a series of periorbital suture points. This study evaluated the efficacy of endoscopic treatment of the difficult lower eyelid and identifies the preoperative predictive patterns for additional suture placement and ancillary procedures within this population. METHODS: Patients who underwent endoscopic brow and midface lift performed by the senior author were stratified into categories of preoperative lower eyelid morphologies, including lower eyelid retraction, negative canthal tilt, negative vector orbit, exorbitism, and a deep tear trough. Intraoperative treatment and postoperative course were recorded and postoperative photographs were evaluated objectively. The data were analyzed to determine preoperative predictive patterns of endoscopic lower eyelid treatment. RESULTS: Three hundred patients who underwent an endoscopic brow and midface lift between 1999 and 2008 were included in the study, with an average follow-up of 1 year. Most patients were treated with endoscopic orbicularis oculi repositioning combined with midface elevation. Additional suture points were used in 12 percent, with preexisting scleral show being the most common indication for additional endoscopic suture placement. There were no cases of postoperative lower eyelid retraction. Skin resurfacing and volumetric filling were the most common revision procedures. CONCLUSIONS: The difficult lower eyelid can be treated effectively with endoscopic orbicularis repositioning and midface elevation. This technique preserves the innervation and continuity of the orbicularis oculi muscle, decreasing postoperative complications. Additional suture application is needed in only a minority of patients, and ancillary lower eyelid procedures can be performed safely in the same operative setting. PMID- 22929254 TI - Prospective study of lidocaine, bupivacaine, and epinephrine levels and blood loss in patients undergoing liposuction and abdominoplasty. AB - BACKGROUND: Bupivacaine levels have not been measured in cosmetic surgery patients to establish safety. Blood loss has been underestimated using the small volumes present in the aspirate. The proportion of wetting solution removed by liposuction has not been reliably ascertained. METHODS: To remedy these deficiencies, a prospective study was undertaken among 322 consecutive patients presenting for superwet ultrasonic liposuction and/or abdominoplasty, and other combined procedures, using infusions containing 0.05% lidocaine (liposuction) and/or 0.025% bupivacaine (abdominoplasty) with 1:500,000 epinephrine. Plasma levels of lidocaine, bupivacaine, and epinephrine were studied in a subset of 76 consecutive patients, including hourly intraoperative samples in 39 consecutive patients. Anesthetic levels were also measured in 12 consecutive patients during the 24-hour period after infusion. RESULTS: The maximum lidocaine dose was 3243 mg and the maximum level was 2.10 MUg/ml. The maximum bupivacaine dose was 550 mg and the maximum level was 0.81 MUg/ml. No clinical toxicity was encountered. Estimated blood loss from liposuction was 217.5 cc + 187 cc/liter of aspirate (r = 0.65). Abdominoplasty added 290 cc of blood loss, on average. The mean proportion of wetting solution removed by liposuction was 9.8 percent. CONCLUSIONS: Bupivacaine may be safely used in cosmetic surgery. A concentration of 1:500,000 epinephrine is safe and effective when administered as part of a wetting solution that is limited to less than 5 liters. Estimated blood loss is higher than previous estimates based on lipocrits. Combination procedures are safe. PMID- 22929255 TI - Discussion: prospective study of lidocaine, bupivacaine, and epinephrine levels and blood loss in patients undergoing liposuction and abdominoplasty. PMID- 22929256 TI - A simplified method for smile enhancement: botulinum toxin injection for gummy smile. AB - The authors studied and provided treatment to patients with the complaint of gummy smile. Between October of 2009 and January of 2011, 52 unaesthetic smiles were evaluated and treated with onabotulinum toxin A. Botulinum toxin injection was an effective treatment, with an average satisfaction level of 9.75 on a 10 point scale. The levator labii superioris alaeque nasi is the ideal muscle for injection, and lopsided smiles could be resolved also with onabotulinum toxin A asymmetric injection. Gummy smile treatment with onabotulinum toxin A into the levator labii superioris alaeque nasi muscle is an effective method, with minimum risk of complications and very high patient satisfaction. PMID- 22929260 TI - Retraction: Experiential learning in aesthetic surgery training: a quantitative comparison among surgical subspecialties. PMID- 22929257 TI - Misrepresentation of scholarly works by integrated plastic surgery applicants. AB - BACKGROUND: Many authors report alarming rates of false or questionable claims of scholarly achievement among residency applicants. The authors sought to further elucidate the authenticity of such inappropriate declarations by simultaneously conducting an investigation of a selected pool of integrated plastic surgery applicants. The authors' hypothesis is that the percentage of citations claimed by many authors to be false was erroneously high because of failure of an adequate search or prolonged time from submission to publication for many journals. METHODS: Applications received by the University of Michigan Integrated Plastic Surgery Residency Program for the 2008 National Residency Match Program match were reviewed 2 years after being submitted by the applicants. Scholarly works listed as published, accepted, or in-press, including journal articles, abstracts, and book chapters, were investigated. Those listed as submitted were excluded. An exhaustive search was conducted that included PubMed, Google Scholar, Ovid UM-MedSearch, hardcopy journals in the authors' medical library, and phone calls to regional societies. RESULTS: The authors' sample represented 63 percent of all integrated plastic surgery applicants for the 2008 National Residency Match Program, which included 102 applicants citing 342 scholarly works. Of these, 319 (93 percent) were verified. Of the remaining 23 citations, 15 (4 percent) by seven applicants (7 percent) were unverifiable, whereas eight (2 percent) by seven applicants were confirmed as misrepresentations. CONCLUSIONS: The majority (93 to 98 percent) of integrated plastic surgery applicants are truthful regarding scholarly achievement. Applicants should be given the benefit of the doubt and the opportunity to confirm their claims when we cannot. PMID- 22929261 TI - Retraction: Reconstructive surgery training: increased operative volume in plastic surgery residency programs. PMID- 22929263 TI - A microneurovascular TRAM flap does not compromise abdominal sensibility more than a conventional one. AB - BACKGROUND: Classic abdominoplasty for a transverse rectus abdominis musculocutaneous (TRAM) flap breast reconstruction impairs abdominal somatosensory function at the donor site. The aim of this study was to investigate whether the type of surgical procedure has an effect on somatosensory alterations of abdominal skin after TRAM flap breast reconstruction. METHODS: Sixty patients (mean +/- SD age, 50 +/- 6.0 years) who underwent microvascular TRAM flap breast reconstruction and 20 healthy subjects (control group; mean age, 46 +/- 6.7 years) participated in the study. Twenty patients had bilateral-nerve anastomosis, 20 had single-nerve anastomosis, and 20 underwent no nerve dissection for the TRAM flap. Clinical sensory examination and tactile and thermal quantitative sensory testing were performed and a patient questionnaire was administered at a mean of 2 to 4.5 years after surgery. RESULTS: All surgical techniques produced significant sensory impairment below the umbilicus, but there were no significant differences in total sensibility scores between the groups with single-nerve (mean sensibility score, 21.98 +/- 2.7) and double-nerve (mean sensibility score, 20.71 +/- 3.6) anastomosis of the TRAM flap. The best sensibility scores were found in the group with single-nerve dissection. Fifteen percent of patients complained of mild pain, and 13 percent felt occasional tactile hyperesthesia in their abdominal skin, mostly around the umbilicus and scars. CONCLUSIONS: In this study, unilateral or bilateral nerve dissection when preparing and lifting a TRAM flap did not seem to increase sensory alterations or postoperative pain in the abdominal donor site after breast reconstruction surgery. Cautious microneurovascular dissection techniques may even improve sensory recovery of the abdominal skin after TRAM flap breast reconstruction surgery. PMID- 22929264 TI - Relaxin-expressing adenovirus decreases collagen synthesis and up-regulates matrix metalloproteinase expression in keloid fibroblasts: in vitro experiments. AB - BACKGROUND: The hormone relaxin has been shown to affect the extracellular matrix by inhibiting collagen synthesis and expression in fibroblasts stimulated with a profibrotic agent. It also increases matrix metalloproteinase (MMP) expression. To investigate its effect on expression of collagen and MMPs in keloid fibroblasts and human dermal fibroblasts, the authors introduced a relaxin expressing adenovirus (dE1-RGD/lacZ/RLX) into a human dermal fibroblast cell line and keloid fibroblasts. METHODS: Both fibroblasts were infected with dE1 RGD/lacZ/RLX or control virus, and protein levels of relaxin and secreted transforming growth factor (TGF)-beta1 were assessed by enzyme-linked immunosorbent assay, and mRNA levels of collagen type I, collagen type III, MMP 1, and MMP-3 were assessed by real-time reverse-transcriptase polymerase chain reaction and enzyme-linked immunosorbent assay. Expression of Smad3 and phosphorylated Smad3 was also examined, and relaxin's effect on Smad2/3 complex localization was evaluated. RESULTS: When human dermal fibroblasts and keloid fibroblasts were transduced with dE1-RGD/lacZ/RLX or dE1-RGD/lacZ (control), mRNA expression of type I and type III collagen was markedly decreased by relaxin regardless of TGF-beta (10 ng/ml) treatment. Expression of Smad3 and phosphorylated Smad3 was reduced in keloid fibroblasts and decreased translocation of Smad 2/3 complex from cytosols to the nucleus of the human dermal fibroblasts with TGF-beta after dE1-RGD/lacZ/RLX transduction, suggesting that relaxin reduces collagen synthesis by blocking TGF-beta signaling. Analyses revealed that MMP-1 and MMP-3 expression were significantly increased in human dermal fibroblasts and keloid fibroblasts after dE1-RGD/lacZ/RLX transduction. CONCLUSION: These results suggest that the antifibrotic effect of relaxin expressing adenovirus may have therapeutic effects on keloids. PMID- 22929265 TI - A novel device for long bone osteodistraction: description of device and case series. AB - The purpose of this study was to present a novel intramedullary device (M-Bone; Phenix, Paris, France) that contains a mechanism for internal osteodistraction and bone transport in patients with segmental bone defects or limb length discrepancy after limb salvage operations. A total of five patients with primary bone tumors were enrolled in the study. After implantation, daily lengthening was performed in an outpatient setting either by the patient or with the help of a therapist, without the use of anesthesia. This unique device offers a totally new approach for the treatment of segmental bone defects or limb length discrepancy. It is designed to expand the remaining native bone by a magnetically activated drive system and induces new bone formation using osteodistraction and bone transport. PMID- 22929266 TI - Refinements in pollicization: a 30-year experience. AB - The thumb is a specialized organ with unique functions that cannot be replicated by any other digit. The most powerful technique for construction or reconstruction of a lost or missing thumb is index finger pollicization. In this article, the authors outline five technical refinements in this procedure that have evolved over the past 30 years in 313 cases. These refinements improve appearance and function, and include (1) modification of the incisions to produce a well-contoured web space, (2) metacarpal head positioning for optimal recreation of the carpal arch, (3) extrinsic tendon repositioning for improved pronation of the new thumb, (4) intrinsic tendon repositioning for maximal strength, and (5) thenar augmentation with an adipofascial flap in select cases for improved appearance. PMID- 22929267 TI - Early correction of septum JJ deformity in unilateral cleft lip-cleft palate. AB - BACKGROUND: The treatment of patients affected by unilateral cleft lip-cleft palate is based on a multistage procedure of surgical and nonsurgical treatments in accordance with the different types of deformity. Over time, the surgical approach for the correction of a nasal deformity in a cleft lip-cleft palate has changed notably and the protocol of treatment has evolved continuously. Not touching the cleft lip nose in the primary repair was dogmatic in the past, even though this meant severe functional, aesthetic, and psychological problems for the child. McComb reported a new technique for placement of the alar cartilage during lip repair. The positive results of this new approach proved that the early correction of the alar cartilage anomaly is essential for harmonious facial growth with stable results and without discomfort for the child. METHODS: The authors applied the same principles used for the treatment of the alar cartilage for correction of the septum deformity, introducing a primary rhinoseptoplasty during the cheiloplasty. The authors compared two groups: group A, which underwent septoplasty during cleft lip repair; and group B, which did not. RESULTS: After the anthropometric evaluation of the two groups, the authors observed better symmetry regarding nasal shape, correct growth of the nose, and a strong reduction of the nasal deformity in the patients who underwent primary JJ septum deformity correction. CONCLUSION: The authors can assume that, similar to the alar cartilage, the septum can be repositioned during the primary surgery, without causing growth anomaly, improving the morphologic/functional results. PMID- 22929268 TI - Classification of trigonocephaly in metopic synostosis. AB - BACKGROUND: The orbitofrontal deformity in metopic synostosis is recognized clinically but has not been quantitatively defined in a large patient population. The authors' purpose was to document the dysmorphology in metopic synostosis and define subtype gradations. METHODS: Demographic and computed tomographic information was recorded. Three-dimensional computed tomographic renderings were created digitally. Craniometric analysis was conducted for endocranial bifrontal angle, interzygomaticofrontal suture and interdacryon distance, and angle of orbital aperture to the midline. RESULTS: Thirty-five computed tomographic scans were analyzed: 25 affected infants (median age, 5 months) and 10 controls (median age, 6 months). The endocranial bifrontal angle ranged from 100 to 148 degrees in metopic patients and 134 to 160 degrees in controls. The metopic group was split into severe metopic (100 to 124 degrees) and moderate metopic (124 to 148 degrees) synostosis. The endocranial bifrontal angle was significantly different among severe metopic, moderate metopic, and control patients. Interzygomaticofrontal suture of the severe group was less than in both moderate (p = 0.0043) and control (p = 0.011) groups. Interdacryon distance was smaller in severe versus moderate (p = 0.0083) and control (p = 0.0002) groups. The orbital rim angle of the severe group was more acute than that in the moderate (p = 0.0106) and control (p = 0.0062) groups. Except for endocranial bifrontal angle, there was no difference between moderate metopic and control groups in any analysis. CONCLUSIONS: Metopic synostosis can be divided into two distinct severity indices. The severe group has significantly narrower orbitofrontal dimensions, whereas the moderate group does not differ from control. Characterization of trigonocephaly may shed light on the etiopathogenesis of disease. PMID- 22929269 TI - Nocturnal ultrasound measurements of optic nerve sheath diameter correlate with intracranial pressure in children with craniosynostosis. AB - Children with craniosynostosis are at risk for increased intracranial pressure, and additional possibilities to screen for increased intracranial pressure are required. The authors' aim was to use ultrasound measurements of the optic nerve sheath to understand and express the variability of intracranial pressure in syndromic craniosynostosis. Therefore, five pediatric patients with craniosynostosis underwent invasive 24-hour intracranial pressure monitoring and simultaneous optic nerve sheath measurements. In three patients, the intracranial pressure was abnormal, and during the second half of the night, the optic nerve sheath was increased in all three patients. The optic nerve sheath diameter changes during the night and is as dynamic as the intracranial pressure. To the best of their knowledge, the authors are the first to describe a real-time relationship of the optic nerve sheath with increased intracranial pressure in children. PMID- 22929270 TI - Discussion: nocturnal ultrasound measurements of optic nerve sheath diameter correlate with intracranial pressure in children with craniosynostosis. PMID- 22929271 TI - The virtual focus group: a modern methodology for facial attractiveness rating. AB - BACKGROUND: Traditional focus groups have been essential to facial aesthetics research. Although they are currently the criterion standard in acquiring facial attractiveness ratings, they retain many shortcomings. This study's objectives were twofold: to determine whether attractiveness scores obtained from a social network site correlate with those from the traditional focus group method; and to evaluate whether this methodology could be a superior tool in evaluating facial attractiveness. METHODS: Forty facial portraits were rated for attractiveness scores using three different subject recruitment methods: traditional live focus groups (n = 123 raters), Internet-based rating (n = 857 raters), and a novel method using a combination of focus groups and a social network site (i.e., Facebook) (n = 1775 raters). Each facial image was scored on a 10-point Likert scale. Regression analysis compared each approach to the traditional method. RESULTS: The methods varied in terms of data accrual time, rater demographics/ages, researcher's accessibility, necessity for subject incentives, researcher labor, and rater effort/accuracy. A strong correlation (0.922) existed between the online social network-based rating and focus group method. A minimum of 992 raters achieved stabilization of the attractiveness scores using social network-based rating. CONCLUSIONS: This study shows significant advantages to using a social network site-based method over both Internet-based rating and traditional focus groups for evaluating facial attractiveness. The main benefits include exponential increase in raters, minimized researcher time/labor, rater scores comparable to those of the focus group method, nonnecessity of rater monetary incentives, and selectable demographics/ages of raters. PMID- 22929272 TI - Stroke volume variation as a guide for fluid resuscitation in patients undergoing large-volume liposuction. AB - BACKGROUND: : The potential for fluid overload in large-volume liposuction is a source of serious concern. Fluid management in these patients is controversial and governed by various formulas that have been advanced by many authors. Basically, it is the ratio of what goes into the patient and what comes out. Central venous pressure has been used to monitor fluid therapy. Dynamic parameters, such as stroke volume and pulse pressure variation, are better predictors of volume responsiveness and are superior to static indicators, such as central venous pressure and pulmonary capillary wedge pressure. Stroke volume variation was used in this study to guide fluid resuscitation and compared with one guided by an intraoperative fluid ratio of 1.2 (i.e., Rohrich formula). METHODS: : Stroke volume variation was used as a guide for intraoperative fluid administration in 15 patients subjected to large-volume liposuction. In another 15 patients, fluid resuscitation was guided by an intraoperative fluid ratio of 1.2. The amounts of intravenous fluid administered in the groups were compared. RESULTS: : The mean amount of fluid infused was 561 +/- 181 ml in the stroke volume variation group and 2383 +/- 1208 ml in the intraoperative fluid ratio group. The intraoperative fluid ratio when calculated for the stroke volume variation group was 0.936 +/- 0.084. All patients maintained hemodynamic parameters (heart rate and systolic, diastolic, and mean blood pressure). Renal and metabolic indices remained within normal limits. CONCLUSION: : Stroke volume variation-guided fluid application could result in an appropriate amount of intravenous fluid use in patients undergoing large-volume liposuction. CLINICAL QUESTION/LEVEL OF EVIDENCE: : Therapeutic, II. PMID- 22929273 TI - Patient safety in plastic surgery. AB - LEARNING OBJECTIVES: After reading this article, the participant should be able to: 1. Recognize risk factors for venous thromboembolism and identify patients who would benefit from prophylactic anticoagulation; 2. Describe the effects of hypothermia in the perioperative period. 3. Understand the importance of blood pressure control in the plastic surgery patient. SUMMARY: This article provides a summary of important factors that contribute to improved patient safety in plastic surgery. The identification of patients and procedures that have an increased risk of complications enables the physician to carry out prophylactic measures to reduce the rate of these complications. Venous thromboembolism, hypothermia, bleeding diathesis, and perioperative hypertension are identifiable risks of plastic surgery, which can lead to significant morbidity and mortality. An evidence-based system and individual practice measures can help to decrease these risks. Thorough preoperative patient evaluation, detailed informed consent, and perioperative care delivered in a safe environment can contribute to improved safety in plastic surgery. PMID- 22929274 TI - Brava and autologous fat transfer is a safe and effective breast augmentation alternative: results of a 6-year, 81-patient, prospective multicenter study. PMID- 22929275 TI - Immediate tissue expander/implant breast reconstruction after salvage mastectomy for cancer recurrence following lumpectomy/irradiation. PMID- 22929277 TI - Response rates to the BREAST-Q are high in a routine practice setting. PMID- 22929279 TI - Discussion: The BREAST-Q: further validation in independent clinical trials. PMID- 22929281 TI - A retrospective photometric study of 82 published reports of mastopexy and breast reduction. PMID- 22929283 TI - Chest wall reconstruction with the perforator-plus thoracoabdominal flap. PMID- 22929285 TI - Digital photography in plastic surgery: the importance of standardization in the era of medicolegal issues. PMID- 22929287 TI - Leonardo da Vinci and Michelangelo: the eternal challenge. PMID- 22929288 TI - Anatomy of the epicanthal fold. PMID- 22929289 TI - Anatomical anomalies of alar cartilage. PMID- 22929290 TI - Discussion of preoperative indications and postoperative complications following laser-assisted lipolysis by non-plastic surgeons. PMID- 22929291 TI - Outcome of different timings of radiotherapy in implant-based breast reconstruction: clinical evidence of benefit using adipose-derived stem cells. PMID- 22929292 TI - Acellular dermis-assisted prosthetic breast reconstruction: mission accomplished? PMID- 22929293 TI - Our experience with autologous fat grafting for contour deformities of the reconstructed breast. PMID- 22929294 TI - What kind of breast implant do I have? The importance of the national breast implant registry. PMID- 22929295 TI - Mastotrainer: new training project for breast aesthetic and reconstructive surgery. PMID- 22929297 TI - Visual perceptual limitations on letter position uncertainty in reading. AB - Frost presents an explanatory theory of reading that generalizes across several languages, based on a revised role of orthographic coding. Perceptual and psychophysical evidence indicates a decay of letter position encoding as a function of the eccentricity of letters (crowding); this factor may account for some of the differences in the languages considered by Frost. PMID- 22929296 TI - Country specific comparison for profile of chlorinated, brominated and phosphate organic contaminants in indoor dust. Case study for Eastern Romania, 2010. AB - We have evaluated the levels and specific profiles of several organohalogenated contaminants, including organochlorine pesticides (OCPs), polychlorinated biphenyls (PCBs), and flame retardants (FRs), such as polybrominated diphenyl ethers (PBDEs), hexabromocyclododecanes (HBCDs), novel brominated FRs (NBFRs), and organophosphate FRs (OPFRs), in 47 indoor dust samples collected in 2010 from urban locations from Iasi, Eastern Romania. The dominant contaminants found in the samples were OPFRs (median sum OPFRs 7890 ng/g). Surprisingly, OCPs were also measured at high levels (median 1300 ng/g). Except for BDE 209 (median 275 ng/g), PBDEs were present in dust samples at relatively low levels (median sum PBDEs 8 ng/g). PCBs were also measured at low levels (median sum PCBs 35 ng/g), while NBFRs were only occasionally detected, showing a low usage in goods present on the Romanian market. The results of the present study evidence the existence of a multitude of chemical formulations in indoor dust. FRs are usually associated to human exposure via ingestion of dust, but other chemicals, such as OCPs, are not commonly reported in such matrix. Although OCPs were found at comparable levels with OPFRs in Romanian dust, OCPs possess a higher risk to human health due to their considerably lower reference dose (RfD) values. Indeed, the OCP exposure calculated for various intake scenarios was only 2-fold lower than the corresponding RfD. Therefore, the inclusion of OCPs as target chemicals in the indoor environment becomes important for countries where elevated levels in other environmental compartments have been previously shown. PMID- 22929298 TI - It is the outcome that counts! Damage to the ventromedial prefrontal cortex disrupts the integration of outcome and belief information for moral judgment. AB - Moral judgment involves considering not only the outcome of an action but also the intention with which it was pursued. Previous functional magnetic resonance imaging (fMRI) research has shown that integrating outcome and belief information for moral judgment relies on a brain network including temporo-parietal, precuneus, and medial prefrontal regions. Here, we investigated whether the ventromedial prefrontal cortex (vmPFC) plays a crucial role in this process. Patients with lesions in vmPFC (vmPFC patients), and brain-damaged and healthy controls considered scenarios in which the protagonist caused intentional harm (negative-outcome, negative-belief), accidental harm (negative-outcome, neutral belief), attempted harm (neutral-outcome, negative-belief), or no harm (neutral outcome, neutral-belief), and rated the moral permissibility of the protagonists' behavior. All groups responded similarly to scenarios involving intentional harm and no harm. vmPFC patients, however, judged attempted harm as more permissible, and accidental harm as less permissible, than the control groups. For vmPFC patients, outcome information, rather than belief information, shaped moral judgment. The results indicate that vmPFC is necessary for integrating outcome and belief information during moral reasoning. During moral judgment vmPFC may mediate intentions' understanding, and overriding of prepotent responses to salient outcomes. PMID- 22929300 TI - Management of thrombocytopenia in the ICU (pregnancy excluded). AB - Thrombocytopenia is a very frequent disorder in the intensive care unit. Many etiologies should be searched, and therapeutic approaches differ according to these different causes. However, no guideline exists regarding optimum practices for these situations in critically ill patients. We present recommendations for the management of thrombocytopenia in intensive care unit, excluding pregnancy, developed by an expert group of the French-Language Society of Intensive Care (Societe de Reanimation de Langue Francaise (SRLF), the French Language Group of Paediatric Intensive Care and Emergencies (GFRUP) and of the Haemostasis and Thrombosis Study Group (GEHT) of the French Society of Haematology (SFH). The recommendations cover six fields of application: definition, epidemiology, and prognosis; diagnostic approach; therapeutic aspects; thrombocytopenia and sepsis; iatrogenic thrombocytopenia, with a special focus on heparin-induced thrombocytopenia; and thrombotic microangiopathy. PMID- 22929299 TI - An in vitro co-infection model to study Plasmodium falciparum-HIV-1 interactions in human primary monocyte-derived immune cells. AB - Plasmodium falciparum, the causative agent of the deadliest form of malaria, and human immunodeficiency virus type-1 (HIV-1) are among the most important health problems worldwide, being responsible for a total of 4 million deaths annually. Due to their extensive overlap in developing regions, especially Sub-Saharan Africa, co-infections with malaria and HIV-1 are common, but the interplay between the two diseases is poorly understood. Epidemiological reports have suggested that malarial infection transiently enhances HIV-1 replication and increases HIV-1 viral load in co-infected individuals. Because this viremia stays high for several weeks after treatment with antimalarials, this phenomenon could have an impact on disease progression and transmission. The cellular immunological mechanisms behind these observations have been studied only scarcely. The few in vitro studies investigating the impact of malaria on HIV-1 have demonstrated that exposure to soluble malarial antigens can increase HIV-1 infection and reactivation in immune cells. However, these studies used whole cell extracts of P. falciparum schizont stage parasites and peripheral blood mononuclear cells (PBMC), making it hard to decipher which malarial component(s) was responsible for the observed effects and what the target host cells were. Recent work has demonstrated that exposure of immature monocyte-derived dendritic cells to the malarial pigment hemozoin increased their ability to transfer HIV-1 to CD4+ T cells, but that it decreased HIV-1 infection of macrophages(8). To shed light on this complex process, a systematic analysis of the interactions between the malaria parasite and HIV-1 in different relevant human primary cell populations is critically needed. Several techniques for investigating the impact of HIV-1 on the phagocytosis of micro-organisms and the effect of such pathogens on HIV-1 replication have been described. We here present a method to investigate the effects of P. falciparum-infected erythrocytes on the replication of HIV-1 in human primary monocyte-derived macrophages. The impact of parasite exposure on HIV-1 transcriptional/translational events is monitored by using single cycle pseudotyped viruses in which a luciferase reporter gene has replaced the Env gene while the effect on the quantity of virus released by the infected macrophages is determined by measuring the HIV-1 capsid protein p24 by ELISA in cell supernatants. PMID- 22929301 TI - Triple touch sperm immobilization vs. single touch sperm immobilization in ICSI - a randomised trial. AB - BACKGROUND: Although different techniques for sperm immobilization have been described, their value has not been assessed in an adequately powered randomized study. The aim of this study was to compare two types of sperm immobilization methods prior to ICSI and to test the hypothesis that triple touch immobilization (TTIm) would lead to a higher (5% -65% up to 70%) fertilization rate (FR) than single touch immobilization (STIm). METHODS: A total of 3056 metaphase II (MII) oocytes, from 290 patients, were randomly assigned to the STIm group (n = 1528 oocytes; 145 cycles) or to the TTIm group (n = 1528 oocytes; 138 cycles). A total of 1478 oocytes (STIm group) and 1476 oocytes (TTIm group) were used in the statistical analysis. The primary outcome variable was FR. Secondary outcome variables included: number of good quality embryos (GQE) on day 2 and day 3, implantation rate (IR) and implantation with foetal heart beat rate (FHB). Statistical analysis was done using the Fisher Exact test with a significance level of 0.05. RESULTS: The results showed no differences in FR between both groups. The proportion of good quality embryos on day 3, was significantly higher in the STIm group (37.5%) compared to the TTIm group (31.8%; p = 0.02). CONCLUSIONS: In this RCT, the hypothesis that the post-ICSI FR would be higher after TTIm than after STIm was not confirmed and the number of good quality embryos on day 3 was significantly lower in the TTIm group than in the STIm group. These data suggest that more 'aggressive' TTIm technique has no advantages compared to the STIm technique. PMID- 22929302 TI - Predictors of early and late enrollment in cardiac rehabilitation, among those referred, after acute myocardial infarction. AB - BACKGROUND: Cardiac rehabilitation (CR) after acute myocardial infarction (AMI) is a Class I recommendation. Although referral to CR after an AMI has recently become a performance measure, many patients may not participate. To illuminate potential barriers to participation, we examined the prevalence of, and patient related factors associated with, CR participation within 1 and 6 months after an AMI. METHODS AND RESULTS: We studied 2096 AMI patients enrolled from 19 US sites in the Prospective Registry Evaluating outcomes after Myocardial Infarction: Events and Recovery (PREMIER) registry. Analyses were limited to those patients referred for CR at the time of AMI hospitalization. A multivariable, conditional logistic regression model, stratified by hospital, was used to identify sociodemographic, comorbidity, and clinical factors independently associated with CR participation within 1 and 6 months of AMI hospital discharge. Only 29% (419/1450) and 48.25% (650/1347) of AMI patients who received referral for CR participated within 1 and 6 months after discharge, respectively. Women (odds ratio [OR], 0.61; 95% confidence interval [CI], 0.44-0.86), uninsured (OR, 0.39; 95% CI, 0.21-0.71), and patients with hypertension (OR, 0.58; 95% CI, 0.43-0.78) and peripheral arterial disease (OR, 0.43; 95% CI, 0.22-0.85) were less likely to participate at 1 month. At 6 months after AMI, older patients (OR, 0.85 for each 10-year increment; 95% CI, 0.74-0.97), smokers (OR, 0.59; 95% CI, 0.44-0.80), and patients with economic burden (OR, 0.56; 95% CI, 0.38-0.81) were less likely to participate. Caucasians (OR, 1.73; 95% CI, 1.16-2.58) and educated patients (OR, 1.81; 95% CI, 1.42-2.30) were more likely to participate at 6 months. Patients with previous percutaneous interventions were less likely to participate at both 1 and 6 months post-AMI. CONCLUSIONS: Among patients referred for CR post-AMI, participation remains low both at 1 and 6 months after AMI. Because CR is associated with beneficial changes in cardiovascular risk factors and better outcomes after AMI, more aggressive efforts are needed to increase CR participation after referral. PMID- 22929305 TI - The effect of optic asphericity on visual rehabilitation of corneal ectasia with a prosthetic device. AB - OBJECTIVES: To study the effect of optic asphericity on visual rehabilitation of corneal ectasia with a prosthetic device. METHODS: Subjects with corneal ectasia treated with a fluid-ventilated gas-permeable prosthetic device of diameter 18.0 19.0 mm, who had subjective improvement of good Snellen vision with introduction of optic asphericity, were studied. Best corrected Snellen visual acuity (BCVA) under standard illumination, high contrast visual acuity (HCVA), low contrast visual acuity (LCVA), and wavefront aberrations were measured in a sequence of devices that varied per patient only in presence or amount of ellipsoidal front surface optical eccentricity (FSE). RESULTS: Five eyes of 5 subjects were studied. (M:F = 3:2; Age: 20-76). Mean steepest SimK was 57.72+/-8.30 D. BCVA was >=20/30 in all eyes in all prosthetic devices, regardless of FSE. Although FSE improved BCVA, HCVA, and LCVA in each patient, no optimal amount could be identified in this small series. Asphericity in the form of 0.6 or 0.8 FSE improved HCVA, LCVA, or both in each patient. FSE was associated with a trend toward reduction of higher-order aberrations, particularly coma. CONCLUSIONS: Optic asphericity shows promise for optimization of vision in the rehabilitation of corneal ectasia with a prosthetic device. PMID- 22929303 TI - Therapeutic impact of follistatin-like 1 on myocardial ischemic injury in preclinical models. AB - BACKGROUND: Acute coronary syndrome is a leading cause of death in developed countries. Follistatin-like 1 (FSTL1) is a myocyte-derived secreted protein that is upregulated in the heart in response to ischemic insult. Here, we investigated the therapeutic impact of FSTL1 on acute cardiac injury in small and large preclinical animal models of ischemia/reperfusion and dissected its molecular mechanism. METHODS AND RESULTS: Administration of human FSTL1 protein significantly attenuated myocardial infarct size in a mouse or pig model of ischemia/reperfusion, which was associated with a reduction of apoptosis and inflammatory responses in the ischemic heart. Administration of FSTL1 enhanced the phosphorylation of AMP-activated protein kinase in the ischemia/reperfusion injured heart. In cultured cardiac myocytes, FSTL1 suppressed apoptosis in response to hypoxia/reoxygenation and lipopolysaccharide-stimulated expression of proinflammatory genes through its ability to activate AMP-activated protein kinase. Ischemia/reperfusion led to enhancement of bone morphogenetic protein-4 expression and Smad1/5/8 phosphorylation in the heart, and FSTL1 suppressed the increased phosphorylation of Smad1/5/8 in ischemic myocardium. Treating cardiac myocytes with FSTL1 abolished the bone morphogenetic protein-4-stimulated increase in apoptosis, Smad1/5/8 phosphorylation, and proinflammatory gene expression. In cultured macrophages, FSTL1 diminished lipopolysaccharide stimulated expression of proinflammatory genes via activation of AMP-activated protein kinase and abolished bone morphogenetic protein-4-dependent induction of proinflammatory mediators. CONCLUSIONS: Our data indicate that FSTL1 can prevent myocardial ischemia/reperfusion injury by inhibiting apoptosis and inflammatory response through modulation of AMP-activated protein kinase- and bone morphogenetic protein-4-dependent mechanisms, suggesting that FSTL1 could represent a novel therapeutic target for post-myocardial infarction, acute coronary syndrome. PMID- 22929306 TI - The role of crude saliva and purified salivary mucins in the inhibition of the Human Immunodeficiency Virus type 1. AB - BACKGROUND: Sub-Saharan Africa is the world's worst HIV-AIDS affected region. More interventions to manage this pandemic are urgently required. Transmission of the virus through an exchange of saliva is rarely known to occur. This project sought to verify statistically previous findings in our laboratory, that crude saliva from uninfected individuals together with its purified mucin components inhibited HIV-1, whilst mucins from infected saliva did not show this inhibition, in an in vitro assay. METHODS: Saliva was extracted in 4 M guanidinium hydrochloride and proteolytic inhibitors at pH 6.5, followed by the isolation of MUC5B and MUC7 by Sepharose 4B gel filtration and further purification of these mucins by density-gradient ultra-centrifugation in caesium chloride. Agarose gel electrophoresis, Western blotting and amino acid compositional analysis determined the size, purity and identity of the mucins. The inhibitory activity of crude saliva and purified MUC5B and MUC7, from HIV negative (n=20) and HIV positive (n=20) donors, was tested by their incubation with subtype C HIV-1 and subsequent infection of peripheral blood mononuclear cells (PBMCs). PCR was done on tandem repeat regions of MUC5B and MUC7 DNA to investigate whether any association existed between gene polymorphism and susceptibility to infection. RESULTS: There was an inter-individual variation in the amounts of MUC5B and MUC7 in saliva. In contrast to previous studies, crude saliva and purified mucins from both HIV negative and HIV positive individuals inhibited the infection of HIV-1 in an in vitro assay. DNA analysis of the tandem repeat regions of MUC5B and MUC7 revealed no difference between groups. CONCLUSIONS: Crude saliva and its mucins, MUC5B and MUC7, from both uninfected controls and HIV positive individuals inhibited HIV-1 in an in vitro assay. PMID- 22929307 TI - Explaining word recognition, reading, the universe, and beyond: a modest proposal. AB - Frost proposes a new agenda for reading research, whereby cross-linguistic experiments would uncover linguistic universals to be integrated within a universal theory of reading. We reveal the dangers of following such a call, and demonstrate the superiority of the very approach that Frost condemns. PMID- 22929308 TI - National health financing policy in Eritrea: a survey of preliminary considerations. AB - BACKGROUND: The 58th World Health Assembly and 56th WHO Regional Committee for Africa adopted resolutions urging Member States to ensure that health financing systems included a method for prepayment to foster financial risk sharing among the population and avoid catastrophic health-care expenditure. The Regional Committee asked countries to strengthen or develop comprehensive health financing policies. This paper presents the findings of a survey conducted among senior staff of selected Eritrean ministries and agencies to elicit views on some of the elements likely to be part of a national health financing policy. METHODS: This is a descriptive study. A questionnaire was prepared and sent to 19 senior staff (Directors) in the Ministry of Health, Labour Department, Civil Service Administration, Eritrean Confederation of Workers, National Insurance Corporation of Eritrea and Ministry of Local Government. The respondents were selected by the Ministry of Health as key informants. RESULTS: The key findings were as follows: the response rate was 84.2% (16/19); 37.5% (6/16) and 18.8% said that the vision of Eritrean National Health Financing Policy (NHFP) should include the phrases 'equitable and accessible quality health services' and 'improve efficiency or reduce waste' respectively; over 68% indicated that NHFP should include securing adequate funding, ensuring efficiency, ensuring equitable financial access, protection from financial catastrophe, and ensuring provider payment mechanisms create positive incentives to service providers; over 80% mentioned community participation, efficiency, transparency, country ownership, equity in access, and evidence-based decision making as core values of NHFP; over 62.5% confirmed that NHFP components should consist of stewardship (oversight), revenue collection, revenue pooling and risk management, resource allocation and purchasing of health services, health economics research, and development of human resources for health; over 68.8% indicated cost-sharing, taxation and social health insurance as preferred revenue collection mechanisms; and 68.75% indicated their preferred provider payment mechanism to be a global (lump sum) budget. CONCLUSION: This study succeeded in gathering the preliminary views of senior staff of selected Eritrean ministries and agencies regarding the likely elements of the NHFP, i.e. the vision, objectives, components, provider payment mechanisms, and health financing agency and its governance. In addition to stakeholder surveys, it would be helpful to inform the development of the NHFP with other pieces of evidence, including cost-effectiveness analysis of health services and interventions, financial feasibility analysis of financing options, a survey of the political and professional acceptability of financing options, national health accounts, and equity analyses. PMID- 22929309 TI - Epstein-barr virus infected gastric adenocarcinoma expresses latent and lytic viral transcripts and has a distinct human gene expression profile. AB - BACKGROUND: EBV DNA is found within the malignant cells of 10% of gastric cancers. Modern molecular technology facilitates identification of virus-related biochemical effects that could assist in early diagnosis and disease management. METHODS: In this study, RNA expression profiling was performed on 326 macrodissected paraffin-embedded tissues including 204 cancers and, when available, adjacent non-malignant mucosa. Nanostring nCounter probes targeted 96 RNAs (20 viral, 73 human, and 3 spiked RNAs). RESULTS: In 182 tissues with adequate housekeeper RNAs, distinct profiles were found in infected versus uninfected cancers, and in malignant versus adjacent benign mucosa. EBV-infected gastric cancers expressed nearly all of the 18 latent and lytic EBV RNAs in the test panel. Levels of EBER1 and EBER2 RNA were highest and were proportional to the quantity of EBV genomes as measured by Q-PCR. Among protein coding EBV RNAs, EBNA1 from the Q promoter and BRLF1 were highly expressed while EBNA2 levels were low positive in only 6/14 infected cancers. Concomitant upregulation of cellular factors implies that virus is not an innocent bystander but rather is linked to NFKB signaling (FCER2, TRAF1) and immune response (TNFSF9, CXCL11, IFITM1, FCRL3, MS4A1 and PLUNC), with PPARG expression implicating altered cellular metabolism. Compared to adjacent non-malignant mucosa, gastric cancers consistently expressed INHBA, SPP1, THY1, SERPINH1, CXCL1, FSCN1, PTGS2 (COX2), BBC3, ICAM1, TNFSF9, SULF1, SLC2A1, TYMS, three collagens, the cell proliferation markers MYC and PCNA, and EBV BLLF1 while they lacked CDH1 (E-cadherin), CLDN18, PTEN, SDC1 (CD138), GAST (gastrin) and its downstream effector CHGA (chromogranin). Compared to lymphoepithelioma-like carcinoma of the uterine cervix, gastric cancers expressed CLDN18, EPCAM, REG4, BBC3, OLFM4, PPARG, and CDH17 while they had diminished levels of IFITM1 and HIF1A. The druggable targets ERBB2 (Her2), MET, and the HIF pathway, as well as several other potential pharmacogenetic indicators (including EBV infection itself, as well as SPARC, TYMS, FCGR2B and REG4) were identified in some tumor specimens. CONCLUSION: This study shows how modern molecular technology applied to archival fixed tissues yields novel insights into viral oncogenesis that could be useful in managing affected patients. PMID- 22929311 TI - The hammock effect of wheelchair cushion covers: persistent redness over the ischial tuberosities in a patient with spinal cord injury - a case report. AB - We report a case of a 28-year-old man with a complete C5 level spinal cord injury who developed persistent redness over his ischial tuberosities due to his wheelchair cushion cover's hammock effect. He had purchased wheelchairs and cushions in 2004 and 2008. Persistent redness occurred over his ischial tuberosities when using the second cushion purchased in 2008. Pressure mapping did not detect any differences in pressure over the ischial tuberosities with different cushions. When comparing cushions without their covers, we noticed that the first cushion had a greater air volume than the second cushion. We exchanged the cushion covers to evaluate the hammock effect due to different covers. We found that the redness occurred at any time the second cushion cover was used. After the patient's family changed the top of the second cushion cover to a more elastic material, the redness resolved. As we were unable to detect the influence of the hammock effect using pressure mapping, it would be useful to develop an alternative method to evaluate this phenomenon. It would also be valuable to find a readily available solution for other patients experiencing this problem. PMID- 22929312 TI - Rapid screening of ASXL1, IDH1, IDH2, and c-CBL mutations in de novo acute myeloid leukemia by high-resolution melting. AB - Recently, many novel molecular abnormalities were found to be distinctly associated with acute myeloid leukemia (AML). However, their clinical relevance and prognostic implications are not well established. We developed a new combination of high-resolution melting assays on a LightCycler 480 and direct sequencing to detect somatic mutations of ASXL1 (exon 12), IDH1 (exon 4), IDH2 (exon 4), and c-CBL (exons 8 and 9) genes to know their incidence and prognostic effect in a cohort of 175 patients with de novo AML: 16 patients (9%) carried ASXL1 mutations, 16 patients had IDH variations (3% with IDH1(R132) and 6% with IDH2(R140)), and none had c-CBL mutations. Patients with ASXL1 mutations did not harbor IDH1, [corrected] or CEBPA mutations, and a combination of ASXL1 and IDH2 mutations was found only in one patient. In addition, we did not find IDH1 and FLT3 or CEBPA mutations concurrently or IDH2 with CEBPA. IDH1 and IDH2 mutations were mutually exclusive. Alternatively, NPM1 mutations were concurrently found with ASXL1, IDH1, or IDH2 with a variable incidence. Mutations were not significantly correlated with any of the clinical and biological features studied. High-resolution melting is a reliable, rapid, and efficient screening technique for mutation detection in AML. The incidence for the studied genes was in the range of those previously reported. We were unable to find an effect on the outcome. PMID- 22929310 TI - The peptide derived from the Ig-like domain of human herpesvirus 8 K1 protein induces death in hematological cancer cells. AB - BACKGROUND: Although significant progress has been made in the treatment of lymphomas, many lymphomas exhibit resistance to cell death, suggesting a defective Fas signaling, which remains poorly understood. We previously reported that cells expressing the K1 protein of human herpesvirus 8 (HHV-8) resist death through the complex formation of the Ig-like domain of K1 with Fas. Recently, we investigated whether peptides derived from the Ig-like domain of the K1 protein may affect cell death. METHODS: K1 positive and negative cell lines were incubated with the K1-derived peptides, and cell death (apoptotic and necrotic) was assessed by flow cytometry and LDH assay. Activation of caspases was assessed by fluorometric assay and flow cytometry. Fas receptor-independent, peptide mediated cell killing was tested in the Fas-resistant Daudi cell line and Jurkat cell clones deficient in caspase-8 and FADD functionality. Activation of TNF receptors I and II was blocked by pre-incubation with corresponding blocking antibodies. The effect of the K1 peptide in vivo was tested in a mouse xenograft model. RESULTS: We observed that the peptide S20-3 enhanced cell death in K1 positive BJAB cells and HHV-8 positive primary effusion lymphoma (PEL) cell lines. Similar effects of this peptide were observed in B-cell lymphoma and T lymphoblastic leukemia cells without K1 expression but not in normal human peripheral blood mononuclear cells. A single intratumoral injection of the S20-3 peptide decreased the growth of Jurkat xenografts in SCID mice. The mechanism of tumor cell death induced by the S20-3 peptide was associated with activation of caspases, but this activity was only partially inhibited by the pan-caspase inhibitor z-VAD. Furthermore, the K1 peptide also killed Fas-resistant Daudi cells, and this killing effect was inhibited by pre-incubation of cells with antibodies blocking TNFRI. CONCLUSION: Taken together, these findings indicate that the S20-3 peptide can selectively induce the death of malignant hematological cell lines by Fas- and/or TNFRI-dependent mechanisms, suggesting the K1-derived peptide or peptidomimetic may have promising therapeutic potential for the treatment of hematological cancers. PMID- 22929313 TI - Effects of adjuvants on the immune response of pigs after intradermal administration of antigen. AB - The ability of different adjuvants to enhance immune responses to intradermal (ID) immunisation with a model antigen was studied in pigs. Immune responses were evaluated with respect to the intensity of systemic and mucosal antibody formation, their isotype characterisation and rate of cell-mediated immunity. These findings were compared with the intensity of adverse local reactions. Six groups of piglets were immunised with keyhole limpet haemocyanin (KLH) antigen alone or in combination with aluminium hydroxide or selected oil-based adjuvants (complete and incomplete Freund's adjuvants, Montanide ISA 206 and Emulsigen). Systemic specific antibody responses were significantly increased following ID administration of antigen together with any of the adjuvants used. IgG antibody responses were most pronounced after the first administration of antigen, being stimulated with both Freund's and Montanide ISA 206 adjuvants. The oil adjuvants also enhanced the cell-mediated immune responses and the levels of local IgA antibodies in the respiratory mucosa. On the other hand, they elicited more pronounced adverse local reactions. PMID- 22929315 TI - Vitreomacular disorders: pathogenesis and treatment. PMID- 22929314 TI - Nucleotide sequencing and phylogenetic analysis of the 3' region of glycoprotein C gene of South American bovine herpesviruses 1 and 5. AB - We herein describe a molecular analysis based on the 3' region of the glycoprotein C gene of 45 bovine herpesvirus (BoHV) isolates from Brazil (n=41), Uruguay (n=2) and Argentina (n=2). Nucleotide (nt) sequencing and alignment of 333 nt revealed levels of similarity ranging from 99.1% to 100% among BoHV-1 sequences (n=12); 96.2-100% among BoHV-5 sequences (n=32); and 77.7-90.3% between BoHV-1 and BoHV-5 sequences. The phylogenetic tree reconstruction provided a clear distinction between BoHV-1 and BoHV-5, and BoHV-1 into subtypes BoHV-1.1 and BoHV-1.2. The isolate SV 453/93 (BoHV-1 associated with genital disease) could not be included within BoHV-1 subtypes since it presented a markedly distinct nt and amino acid (aa) deduced sequences. A transmembrane domain of 24 aa and the putative cytoplasmic tail of 8 aa were identified and mapped. These results indicate that this genome region represents a suitable target for phylogenetic subgrouping of BoHV-1 and BoHV-5 isolates and, perhaps, for understanding evolutionary relationships. PMID- 22929316 TI - Posterior vitreous detachment: evolution and role in macular disease. PMID- 22929317 TI - Brief overview of the molecular structure of normal and aging human vitreous. PMID- 22929318 TI - What we know (and do not know) about vitreoretinal adhesion. PMID- 22929319 TI - Vitreomacular traction syndrome. PMID- 22929320 TI - Pathology of epiretinal membrane, idiopathic macular hole, and vitreomacular traction syndrome. PMID- 22929321 TI - Controversies regarding internal limiting membrane peeling in idiopathic epiretinal membrane and macular hole. PMID- 22929322 TI - Myopic traction maculopathy: pathogenic mechanisms and surgical treatment. PMID- 22929323 TI - Role of vitreous in diabetic macular edema. PMID- 22929324 TI - Vitreomacular adhesion and neovascular age-related macular degeneration. PMID- 22929325 TI - Pharmacologic vitreolysis: rationale, potential indications, and promising agents. PMID- 22929326 TI - Ocriplasmin for pharmacologic vitreolysis. AB - The vitreous may play an important role in the pathogenesis of various retinal disorders. Pharmacologic vitreolysis uses intravitreal pharmacologic agents to provide liquefaction of the vitreous and complete vitreoretinal separation. Ocriplasmin, a genetically engineered version of plasmin, has been shown in clinical trials to be able to safely release vitreomacular adhesion and close Stage 2 macular holes in a significant number of patients. Advancements in the development of this safe and effective method of vitreolysis have provided an alternative, nonsurgical treatment option to physicians who manage these patients. A roundtable of clinical investigators convened to discuss and summarize recent progress in pharmacologic vitreolysis. Preclinical studies, and efficacy and safety data from controlled clinical trials of ocriplasmin were presented and discussed. Case studies were then presented to provide an opportunity for experts to reveal their specific thoughts regarding ocriplasmin for the treatment of vitreomacular adhesion and resulting vitreomacular traction and macular holes, based on their own interpretation of current clinical data and experience. PMID- 22929327 TI - Conclusion. PMID- 22929328 TI - Thru but not wisht: language, writing, and universal reading theory. AB - Languages may get the writing system they deserve or merely a writing system they can live with-adaption without optimization. A universal theory of reading reflects the general dependence of writing on language and the adaptations required by the demands of specific languages and their written forms. The theory also can be informed by research that addresses a specific language and orthography, gaining universality through demonstrating adaptations to language and writing input. PMID- 22929329 TI - Keep up the pace: declines in simple repetitive timing differentiate healthy aging from the earliest stages of Alzheimer's disease. AB - The current study examined whether healthy older adults (OA) and individuals at the earliest stages of dementia of the Alzheimer's type (DAT) differ from younger adults (YA) and from each other on a simple, extended continuous tapping task using intervals (500 ms, 1000 ms, and 1500 ms) thought to differentially engage attentional control systems. OA groups sped up their tapping at the slowest target rate compared to the YA; this pattern was magnified in the early stage DAT groups. Performance variability appeared especially sensitive to DAT-related changes, as reliable differences between healthy OA and very mild DAT individuals emerged for multiple tap rates. These differences are proposed to result from breakdowns in attentional control that disrupt error-correction processes and the ability to resolve discrepancies between internally-generated temporal expectancies and the external temporal demands of the repetitive timing task. PMID- 22929330 TI - Multi-modal imaging of angiogenesis in a nude rat model of breast cancer bone metastasis using magnetic resonance imaging, volumetric computed tomography and ultrasound. AB - Angiogenesis is an essential feature of cancer growth and metastasis formation. In bone metastasis, angiogenic factors are pivotal for tumor cell proliferation in the bone marrow cavity as well as for interaction of tumor and bone cells resulting in local bone destruction. Our aim was to develop a model of experimental bone metastasis that allows in vivo assessment of angiogenesis in skeletal lesions using non-invasive imaging techniques. For this purpose, we injected 10(5) MDA-MB-231 human breast cancer cells into the superficial epigastric artery, which precludes the growth of metastases in body areas other than the respective hind leg. Following 25-30 days after tumor cell inoculation, site-specific bone metastases develop, restricted to the distal femur, proximal tibia and proximal fibula. Morphological and functional aspects of angiogenesis can be investigated longitudinally in bone metastases using magnetic resonance imaging (MRI), volumetric computed tomography (VCT) and ultrasound (US). MRI displays morphologic information on the soft tissue part of bone metastases that is initially confined to the bone marrow cavity and subsequently exceeds cortical bone while progressing. Using dynamic contrast-enhanced MRI (DCE-MRI) functional data including regional blood volume, perfusion and vessel permeability can be obtained and quantified. Bone destruction is captured in high resolution using morphological VCT imaging. Complementary to MRI findings, osteolytic lesions can be located adjacent to sites of intramedullary tumor growth. After contrast agent application, VCT angiography reveals the macrovessel architecture in bone metastases in high resolution, and DCE-VCT enables insight in the microcirculation of these lesions. US is applicable to assess morphological and functional features from skeletal lesions due to local osteolysis of cortical bone. Using B-mode and Doppler techniques, structure and perfusion of the soft tissue metastases can be evaluated, respectively. DCE-US allows for real-time imaging of vascularization in bone metastases after injection of microbubbles. In conclusion, in a model of site-specific breast cancer bone metastases multi-modal imaging techniques including MRI, VCT and US offer complementary information on morphology and functional parameters of angiogenesis in these skeletal lesions. PMID- 22929331 TI - Pulmonary perifissural nodules on CT scans: rapid growth is not a predictor of malignancy. AB - PURPOSE: To assess the prevalence, natural course, and malignancy rate of perifissural nodules (PFNs) in smokers participating in a lung cancer screening trial. MATERIALS AND METHODS: As part of the ethics-committee approved Dutch Belgian Randomised Lung Cancer Multi-Slice Screening Trial (NELSON), computed tomography (CT) was used to screen 2994 current or former heavy smokers, aged 50 74 years, for lung cancer. CT was repeated after 1 and 3 years, with additional follow-up CT scans if necessary. All baseline CT scans were screened for nodules. Nodule volume was determined with automated volumetric analysis. Homogeneous solid nodules, attached to a fissure with a lentiform or triangular shape, were classified as PFNs. Nodules were considered benign if they did not grow during the total follow-up period or were proved to be benign in a follow-up by a pulmonologist. Prevalence, growth, and malignancy rate of PFNs were assessed. RESULTS: At baseline screening, 4026 nodules were detected in 1729 participants, and 19.7% (794 of 4026) of the nodules were classified as PFNs. The mean size of the PFNs was 4.4 mm (range: 2.8-10.6 mm) and the mean volume was 43 mm3 (range: 13-405 mm3). None of the PFNs were found to be malignant during follow-up. Between baseline and the first follow-up CT scan, 15.5% (123 of 794) were found to have grown, and 8.3% (66 of 794) had a volume doubling time of less than 400 days. One PFN was resected and proved to be a lymph node. CONCLUSION: PFNs are frequently found at CT scans for lung cancer. They can show growth rates in the range of malignant nodules, but none of the PFNs in the present study turned out to be malignant. Recognition of PFNs can reduce the number of follow-up examinations required for the workup of suspicious nodules. PMID- 22929332 TI - MR imaging-controlled transurethral ultrasound therapy for conformal treatment of prostate tissue: initial feasibility in humans. AB - PURPOSE: To evaluate the feasibility and safety of magnetic resonance (MR) imaging-controlled transurethral ultrasound therapy for prostate cancer in humans. MATERIALS AND METHODS: This pilot study was approved by the institutional review board and was performed in eight men (mean age, 60 years; range, 49-70 years) with localized prostate cancer (Gleason score<=7, prostate-specific antigen level #15 MUg/L) immediately before radical prostatectomy. All patients provided written informed consent. This phase 0 feasibility and safety study is the first evaluation in humans. Transurethral ultrasound therapy was performed with the patient under spinal anesthesia by using a clinical 1.5-T MR unit. Patients then underwent radical prostatectomy, and the resected gland was sliced in the plane of treatment to compare the MR imaging measurements with the pattern of thermal damage. The overall procedure time and coagulation rate were measured. In addition, the spatial targeting accuracy was evaluated, as was the thermal history along the thermal damage boundaries in the gland. RESULTS: The average procedure time was 3 hours, with 2 or fewer hours spent in the MR unit. The treatment was well tolerated by all patients, and a temperature uncertainty of less than 2 degrees C was observed in the treatments. The mean temperature and thermal dose measured along the boundary of thermal coagulation were 52.3 degrees C+/-2.1 and 3457 (cumulative equivalent minutes at 43 degrees C)+/-5580, respectively. The mean treatment rate was 0.5 mL/min, and a spatial targeting accuracy of -1.0 mm+/-2.6 was achieved. CONCLUSION: MR imaging-controlled transurethral ultrasound therapy is feasible, safe, and well tolerated. This technology could be an attractive approach for whole-gland or focal therapy. PMID- 22929333 TI - Liver: segment-specific analysis of B1 field homogeneity at 3.0-T MR imaging with single-source versus dual-source parallel radiofrequency excitation. AB - PURPOSE: To measure B1 field distribution in different liver segments with and without dual transmission and to quantify the contrast-to-noise ratio (CNR) between normal liver tissue and segmental venous vessels on standard clinical 3.0 T liver magnetic resonance (MR) images. MATERIALS AND METHODS: This prospective study was approved by the local ethics committee. All subjects gave written informed consent. Six patients with liver lesions and nine healthy volunteers were included. Average hepatic B1 field values in all Couinaud liver segments were assessed by using actual flip-angle imaging (first and second repetition times msec/echo time msec: 72, 192/2.2; transmission angle: 60 degrees ) for both single and dual transmission in a 3.0-T MR imaging unit that allowed both transmission modes. Additionally, two-dimensional T1-weighted gradient-echo (repetition time msec/echo time msec, 180/2.3; transmission angle, 55 degrees ) and T2-weighted single-shot fast spin-echo images (1501/80) were acquired. Average CNR between liver parenchyma and segmental veins were measured in each segment. Two-sided paired Student t tests were used for statistical evaluation. Two blinded radiologists independently identified lesions in images from acquisitions in both transmission modes. RESULTS: Mean flip angles achieved with conventional single transmission were 44%-53% of the nominal value in segments II IV and 67% and 63% of the nominal value in segments VI and VII, respectively, and were less than 77% in all segments. Mean actual flip angles measured for dual transmission were between 82% and 100% of the nominal value in all segments. T1 weighted single-transmission images exhibited areas of low B1 field strength with reduced image contrast. T2-weighted single-transmission images displayed significantly reduced signal intensity but nearly unchanged contrast weighting in these areas. On T1-weighted dual-transmission images, the two readers detected 22 and 14 additional lesions that they did not identify on the single-transmission images. On the dual-transmission T2-weighted images, they detected 11 and five additional lesions, respectively. CONCLUSION: Dual transmission can generate a B1 field with significantly improved homogeneity over all liver segments at a field strength of 3.0 T. PMID- 22929334 TI - Systolic myocardial dysfunction in patients with type 2 diabetes mellitus: identification at MR imaging with cine displacement encoding with stimulated echoes. AB - PURPOSE: To determine if cine displacement encoding with stimulated echoes (DENSE) can help to identify and determine the patterns of subclinical myocardial systolic dysfunction in patients with type 2 diabetes mellitus (DM) when compared with cine DENSE in control patients. MATERIALS AND METHODS: After obtaining approval from the institutional ethics committee and written informed consent from the patients, 37 patients with type 2 DM without overt heart disease and 23 age-matched control patients were prospectively included in the study. The patients underwent standard cine magnetic resonance (MR) imaging with two dimensional cine DENSE acquisitions. Circumferential (Ecc) and radial (Err) systolic strains were measured on short-axis views at basal, mid, and apical left ventricular levels. Longitudinal strain (Ell) was measured on four- and two chamber views. Statistical testing included the intraclass correlation coefficient and multiple linear regression analysis. RESULTS: The intraobserver intraclass correlation coefficient values were 0.85, 0.95, and 0.90, and the interobserver intraclass correlation coefficient values were 0.79, 0.91 and 0.80 for Ecc, Err, and Ell, respectively. The left ventricular ejection fraction was in the reference range and similar between the groups, and the patients with DM showed a decrease in Ecc (-14.4%+/-1.6 vs -17.0%+/-1.6, P<.001), Err (36.2%+/ 10.9 vs 44.4%+/-9.9, P=.006) and Ell (-12.9%+/-2.1 vs -15.5%+/-1.6, P<.001) compared with the control patients. Finally, DM was independently associated with Ecc (P<.001), Err (P=.05) and Ell (P=.01) after adjustment for age, sex, hypertension, body mass index, and left ventricular mass. CONCLUSION: Cine DENSE, a motion-encoding MR imaging technique for myocardial strain assessment with high spatial resolution, appears to be useful in the identification of subclinical myocardial dysfunction in patients with DM. PMID- 22929335 TI - Repeat biopsy for mutational analysis of non-small cell lung cancers resistant to previous chemotherapy: adequacy and complications. AB - PURPOSE: To evaluate the feasibility and safety of repeat biopsy for mutational analysis in patients with non-small cell lung cancer (NSCLC) who have a resistance history to previous chemotherapy. MATERIALS AND METHODS: This prospective study was institutional review board approved, and written informed consent was obtained from all patients. Of 126 patients referred for repeat biopsy (hereafter, rebiopsy) with NSCLC that was resistant to conventional chemotherapy or epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors, 94 patients (31 men, 63 women; mean age +/- standard deviation, 57 years +/- 10.3) were selected for rebiopsy. Thirty-two patients were excluded for several reasons after strict review of the chest computed tomography (CT) images. Percutaneous transthoracic lung biopsy was performed with C-arm cone-beam CT guidance. The technical success rates for the rebiopsy and the adequacy rates of specimens for mutational analysis were evaluated. Any biopsy-related complications were recorded. RESULTS: The technical success rate for biopsy was 100%. In 75 (80%) of 94 patients, specimens were adequate for mutational analysis. Of 75 specimens, 35 were tested for EGFR mutation, 34 for anaplastic lymphoma kinase gene (ALK) rearrangement, and six for both. The results were positive for EGFR-sensitizing mutation (exon 19 or 21) in 20, for EGFR T790M mutation in five, and for ALK rearrangement in 11. Postprocedural complications occurred in 13 (14%) of 94 patients. CONCLUSION: When performed by employing rigorous CT criteria, rebiopsies for the mutational analysis of NSCLCs treated previously with chemotherapy are feasible in all patients and are adequate in approximately four-fifths of patients referred for gene analysis, with acceptable rates of complications. PMID- 22929336 TI - To seek perfection or not? That is the question. PMID- 22929337 TI - Affect and state dysregulation as moderators of the relationship between childhood sexual abuse and nonsuicidal self-injury. AB - Nonsuicidal self-injury (NSSI) is a significant problem in both clinical and nonclinical populations. Affect and state dysregulation are frequently observed in survivors of childhood sexual abuse and in those who engage in NSSI. Both have been found to predict NSSI, and affect regulation has also been modeled as a mediator of NSSI. This study extends present research by modeling both affect and state dysregulation as moderators of NSSI. The findings are discussed as an extension of the tension reduction theory and within a conceptualization of posttraumatic stress disorder (PTSD) as an asymmetry of the approach-avoidance neurophysiological system. PMID- 22929338 TI - Militarized sexual violence in South Kivu, Democratic Republic of Congo. AB - Eastern DRC has been the site of a protracted conflict in which sexual violence has been a defining feature. The method used was a retrospective registry-based study of sexual violence survivors presenting to Panzi Hospital between 2004 and 2008. This analysis aimed to describe the patterns of sexual violence described by survivors and to analyze perpetrator profiles. As regards results, a total of 4,311 records were analyzed. Perpetrators in this data set were identified as follows: (a) 6% were civilians; (b) 52% were armed combatants; and (c) 42% were simply identified as "assailant(s)" with no further identifying information. Those identified simply as "assailants" perpetrated patterns of sexual violence that were similar to those of armed combatants, suggesting that this group included a large number of armed combatants. Civilian assailants perpetrated a pattern of sexual violence that was distinct from armed combatants. Conclusions are as follows: These data suggest that a high proportion of sexual assaults in South Kivu are perpetrated by armed combatants. Protection of women in South Kivu will require new strategies that take into account the unique nature of sexual violence in DRC. Engaging with local communities, the UN and other aid organizations is necessary to create new context-appropriate protection programs. PMID- 22929339 TI - A preliminary investigation of the influence of subjective norms and relationship commitment on stages of change in female intimate partner violence victims. AB - Intimate partner violence (IPV) against women is a prevalent and serious problem throughout the world, causing devastating mental and physical health problems for victims. Recent research has begun to focus on factors that may influence women's decisions to stay or leave their abusive partners, as interventions for batterers has only resulted in minimal success in reducing IPV. Therefore, this study preliminarily examined the influence of women's perceptions of their social network members' subjective norms and their relationship commitment on stages of change to end an abusive relationship among a community sample of female IPV victims (N = 84). Results showed that subjective norms and women's relationship commitment were associated with women's stages of change. Relationship commitment did not mediate the relation between subjective norms and stages of change. These findings indicate that a number of factors contribute to women's stay/leave decision-making process, and close social network members could be included in interventions designed to keep women safe. PMID- 22929340 TI - School factors as moderators of the relationship between physical child abuse and pathways of antisocial behavior. AB - Physical child abuse is a predictor of antisocial behavior in adolescence and adulthood. Few studies have investigated factors that moderate the risk of physical child abuse for later occurring outcomes, including antisocial behavior. This analysis uses data from the Lehigh Longitudinal Study to investigate the prediction of antisocial behavior from physical child abuse and the buffering role of 3 school-related factors (i.e., school commitment, school dropout, and IQ), which are hypothesized to change the course of antisocial behavior from childhood into the adult years. Results show an association between physical child abuse and early antisocial behavior. Early antisocial behavior predicts antisocial behavior in adolescence, and that, in turn, predicts antisocial behavior in adulthood. Child IQ moderated the relationship between child physical abuse and antisocial behavior in childhood. However, no other moderation effects were observed. Limitations and implications for future research and prevention are discussed. PMID- 22929341 TI - Effect of type and severity of intimate partner violence on women's health and service use: findings from a primary care trial of women afraid of their partners. AB - Intimate partner violence (IPV) has major affects on women's wellbeing. There has been limited investigation of the association between type and severity of IPV and health outcomes. This article describes socio-demographic characteristics, experiences of abuse, health, safety, and use of services in women enrolled in the Women's Evaluation of Abuse and Violence Care (WEAVE) project. We explored associations between type and severity of abuse and women's health, quality of life, and help seeking. Women (aged 16-50 years) attending 52 Australian general practices, reporting fear of partners in last 12 months were mailed a survey between June 2008 and May 2010. Response rate was 70.5% (272/386). In the last 12 months, one third (33.0%) experienced Severe Combined Abuse, 26.2% Physical and Emotional Abuse, 26.6% Emotional Abuse and/or Harassment only, 2.7% Physical Abuse only and 12.4% scored negative on the Composite Abuse Scale. A total of 31.6% of participants reported poor or fair health and 67.9% poor social support. In the last year, one third had seen a psychologist (36.6%) or had 5 or more general practitioner visits (34.3%); 14.7% contacted IPV services; and 24.4% had made a safety plan. Compared to other abuse groups, women with Severe Combined Abuse had poor quality of life and mental health, despite using more medications, counseling, and IPV services and were more likely to have days out of role because of emotional issues. In summary, women who were fearful of partners in the last year, have poor mental health and quality of life, attend health care services frequently, and domestic violence services infrequently. Those women experiencing severe combined physical, emotional, and sexual abuse have poorer quality of life and mental health than women experiencing other abuse types. Health practitioners should take a history of type and severity of abuse for women with mental health issues to assist access to appropriate specialist support. PMID- 22929342 TI - "That's so gay": heterosexual male undergraduates and the perpetuation of sexual orientation microagressions on campus. AB - "That's so gay," a popular expression on campuses, is a sexual orientation microaggression that can contribute to a hostile environment for lesbian, gay, and bisexual (LGB) students. Using data from a campus climate survey conducted at a large urban university, we investigated use of the phrase among heterosexual male undergraduates who are emerging adults (18-25 years). Multiple regression analysis suggested that saying the phrase is positively associated with hearing peers say it and with holding negative perceptions of feminine men, whereas having LGB acquaintances was negatively associated with use of this expression. We offer practice and policy recommendations for curbing its use, thereby enhancing campus climate. PMID- 22929343 TI - Posttraumatic stress disorder symptoms: a mechanism in the relationship between early sexual victimization and incapacitated/drug-or-alcohol-facilitated and forcible rape. AB - Sexual assault occurring when the victim is unable to consent or resist due to the use or administration of alcohol or drugs (i.e., incapacitated/drug-or alcohol facilitated rape; IR/DAFR) is a particularly prevalent form of victimization experienced by college women. By definition, substance use precedes IR/DAFR; however, few studies have examined other potential risk factors for IR/DAFR that may be unique from those associated with forcible rape (FR; i.e., sexual assault occurring due to threats or physical restraint). The present investigation tested a model of risk for IR/DAFR and FR suggesting that child or adolescent sexual abuse (CASA) leads to posttraumatic stress disorder (PTSD) symptoms, which in turn increase the likelihood of IR/DAFR, but not FR. Results revealed full mediation for PTSD hyperarousal symptoms in the pathway between CASA and IR/DAFR, and partial mediation for hyperarousal symptoms in the pathway between CASA and FR. Theoretical and clinical implications are discussed. PMID- 22929344 TI - Rural Australian women's legal help seeking for intimate partner violence: women intimate partner violence victim survivors' perceptions of criminal justice support services. AB - Intimate partner violence (IPV) is a widespread, ongoing, and complex global social problem, whose victims continue to be largely women. Women often prefer to rely on friends and family for IPV help, yet when informal support is unavailable they remain hesitant to contact formal services, particularly legal support for many reasons. This study applies a sociological lens by framing the IPV and legal help-seeking experiences of rural Australian women gained from 36 in-depth face to-face interviews as socially contextualized interactions. Findings reveal police and court responses reflect broader social inequalities and rurality exacerbates concerns such as anonymity and lack of service. Cultural differences and power imbalances between survivors and formal support providers are manifested to inform future research seeking to improve survivors' willingness to engage and satisfaction with formal services. Finally, the important role police and the criminal justice system play in de-stigmatizing IPV and legitimating its unacceptability is argued a crucial, yet unrecognized, key to social change. PMID- 22929345 TI - Canadian mock juror attitudes and decisions in domestic violence cases involving asian and white interracial and intraracial couples. AB - This study manipulated the race of the defendant and the victim (White/White, White/Asian, Asian/Asian, and Asian/White) in a domestic violence case to examine the potential prejudicial impact of race on juror decision making. A total of 181 undergraduate students read a trial transcript involving an allegation of spousal abuse in which defendant and victim race were manipulated using photographs. They then provided a verdict and confidence rating, a sentence, and responsibility attributions, and completed various scales measuring attitudes toward wife abuse and women. Findings revealed that female jurors were harsher toward the defendant than were male jurors. When controlling for attitudes toward Asians, jurors found the defendant guilty more often in cases involving interracial couples, as compared to same-race couples. Path analyses revealed various factors and attitudes involved in domestic violence trial outcomes. Findings contribute to the scarce literature on legal proceedings involving Asians, particularly in domestic violence cases. Outcomes also provide a model for relevant factors and characteristics of jurors in domestic violence cases. Roadblocks inherent in jury research are also discussed. PMID- 22929346 TI - The experiences of parents who report youth bullying victimization to school officials. AB - Current research offers a limited understanding of parental experiences when reporting bullying to school officials. This research examines the experiences of middle-school parents as they took steps to protect their bullied youth. The qualitative tradition of interpretive phenomenology was used to provide in-depth analysis of the phenomena. A criterion-based, purposeful sample of 11 parents was interviewed face-to-face with subsequent phone call follow-ups. Interviews were taped, transcribed, and coded. MAX qda software was used for data coding. In analyzing the interviews, paradigm cases, themes, and patterns were identified. Three parent stages were found: discovering, reporting, and living with the aftermath. In the discovery stage, parents reported using advice-giving in hopes of protecting their youth. As parents noticed negative psychosocial symptoms in their youth escalate, they shifted their focus to reporting the bullying to school officials. All but one parent experienced ongoing resistance from school officials in fully engaging the bullying problem. In the aftermath, 10 of the 11 parents were left with two choices: remove their youth from the school or let the victimization continue. One paradigm case illustrates how a school official met parental expectations of protection. This study highlights a parental sense of ambiguity of school officials' roles and procedures related to school reporting and intervention. The results of this study have implications in the development and use of school-wide bullying protocols and parental advocacy. PMID- 22929347 TI - Intimate partner violence and welfare participation: a longitudinal causal analysis. AB - This longitudinal study examined the temporal-ordered causal relationship between intimate partner violence (IPV), five mental disorders (depression, generalized anxiety disorder, social phobia, panic attack, posttraumatic stress disorder [PTSD]), alcohol abuse/dependence, drug abuse/dependence, treatment seeking (from physician, counselor, and self-help group), employment, child support, and welfare participation. It was a secondary data analysis of records of 571 women; the records were extracted from the study "Violence Against Women and the Role of Welfare Reform" (VAWRWR). Results from generalized estimating equations (GEE) showed that experiencing controlling behaviors reduced likelihood of welfare participation whereas experiencing physical abuse increased it. Significant impact on welfare participation was wielded by panic attack, drug abuse/dependence, and employment; treatment seeking and child support made no significant impact. The study found no significant mediating effect wielded by panic attack, drug abuse/dependence, employment, or child support on welfare participation's relationship to controlling behaviors or physically abusive behaviors experienced. Implications for intervention are discussed. PMID- 22929348 TI - The impact of different types of intimate partner violence on the mental and physical health of women in different ethnic groups. AB - Intimate partner violence, including threats, stalking, emotional, physical, and sexual assault by a spouse or partner, has significant influences on the well being of women of all racial and social backgrounds. This study of a nationally representative sample of women from varying racial and ethnic groups examined specific types of violent acts on health and well-being. An association between intimate partner violence and poor physical and mental health was found. Types of partner violence also had different associations with the well-being of women of different racial and ethnic backgrounds. Social and demographic factors played an important role in moderating women's outcomes. Suggestions for future studies are discussed. PMID- 22929349 TI - Fathers' emotional awareness and children's empathy and externalizing problems: the role of intimate partner violence. AB - Emerging evidence suggests that fathers, more so than mothers, socialize emotions in a gender-stereotyped manner. Gender-stereotyped emotion socialization may be particularly pronounced in men perpetrating intimate partner violence (IPV), and may be detrimental to child adjustment, particularly for boys. This study explored the relation between fathers' socialization of children's emotions and child adjustment in families where IPV is present. We hypothesized that in families where there is IPV, fathers' awareness of their children's sadness and fear will be associated with negative child outcomes. Participants were 74 families recruited for a longitudinal study. Interview and questionnaire measures were used to assess IPV and fathers' emotional awareness when children were 5 years old. Child adjustment was measured when children were 16 years old. Results suggested that in families where there is IPV, fathers who were more aware of their children's fear had children who showed lower levels of empathy and higher levels of externalizing problems than children whose fathers were less aware of their fear, specifically for boys. Results are discussed in terms of gender socialization in families where there is IPV. PMID- 22929350 TI - Introduction. Information technology. PMID- 22929351 TI - Decision support in dermatology and medicine: history and recent developments. AB - This article is focused on diagnostic decision support tools and will provide a brief history of clinical decision support (CDS), examine the components of CDS and its associated terminology, and discuss recent developments in the use and application of CDS systems, particularly in the field of dermatology. For this article, we use CDS to mean an interactive system allowing input of patient specific information and providing customized medical knowledge-based results via automated reasoning, for example, a set of rules and/or an underlying logic, and associations. PMID- 22929352 TI - Special requirements for electronic health records in dermatology. AB - Government incentives and mandates to increase the meaningful use of electronic health records (EHR), with subsequent disincentives by Medicare, have made a significant push for dermatologists to adopt this technology into their practices. EHRs were originally developed for primary care physicians; however, owing to the unique features of dermatology, specialty-specific systems are a must. In this article, we discuss the special needs of dermatologists when choosing an EHR system. PMID- 22929353 TI - YouTube and the expanding role of videos in dermatologic surgery education. AB - Video is an excellent medium for medical education, both for clinicians and for the public. YouTube has emerged as one of the largest sources of freely accessible content. It is our intent to provide a preliminary discussion of the growing role of videos in medical education, sources of this video content, and the format of surgical video content on YouTube. Additionally, we will highlight the limitations and pitfalls that clinicians and the public should be aware of when viewing online video content. Several sources of both patient- and clinician directed videos are easily accessible from the Internet and DVDs today. Medical professionals, students, and patients now have mobiles and instantaneous access to a growing collection of video content. A brief list of online video sources to view and learn dermatologic surgical techniques is provided. Given the increasing ease of creating and posting high-quality video content, this list will continue to grow, providing dermatologic surgeons with an ever-increasing wealth of visual knowledge. Although YouTube is a dominant source of publicly accessible videos, clinicians and consumers should be aware of the source and intent of the video content before accepting the content. Although it is easy to post content on YouTube, it is difficult to verify sources and the credentials of the people posting the videos. Therefore, the viewer should filter content with a discerning eye, embracing the concept of caveat emptor--or buyer beware. PMID- 22929354 TI - Social media in dermatology: moving to Web 2.0. AB - Patient use of social media platforms for accessing medical information has accelerated in parallel with overall use of the Internet. Dermatologists must keep pace with our patients' use of these media through either passive or active means are outlined in detail for 4 specific social media outlets. A 5-step plan for active engagement in social media applications is presented. Implications for medical professionalism, Health Insurance Portability and Accountability Act compliance, and crisis management are discussed. PMID- 22929355 TI - Mobile applications for dermatology. AB - The number of available mobile applications has increased by 500% over the past 3 years. Searching for useful dermatology applications may be overwhelming. The following summary may help both advanced and budding dermatologists select useful programs. PMID- 22929356 TI - Dermatology resources on the internet. AB - Both patients and medical professionals are increasingly accessing the Internet for health information. Today's Web enables features that facilitate information sharing in a social and collaborative manner, thus transforming the way we access data and communicate with our patients and colleagues. The visual nature of the field of dermatology lends itself to the use of the Internet for reference and educational purposes. To generate a list of Web sites commonly used by academic dermatologists, the authors polled the Accreditation Council for Graduate Medical Education Dermatology Program Directors for their top 3 Web resources. The purpose of this article is to identify resources used by dermatologists as well as patients and examine factors that can influence Internet search results. Concerns regarding professionalism in the era of social media are also explored. As the volume of health information on the Internet continues to increase, it is essential for physicians to be aware of what is available in cyberspace. Reference and learning tools for the physician, learning and support tools for the patient, and physician Internet presence are key aspects of modern dermatology practice. PMID- 22929357 TI - Clinical photography in the dermatology practice. AB - Photography has been accepted for decades as a standard means for documenting dermatologic conditions and as an adjunct to their treatment, in both medical practice and research. The emergence of low-cost easy-to-use digital imaging systems has made good-quality photography more accessible to practitioners, while providing improved functionality in the clinical environment. Primary concerns are controlling lighting and positioning to provide a clear record of the patients skin condition and maintaining consistency over time to assure meaningful comparison of clinical end points. PMID- 22929358 TI - Expanding the role of the iPad and tablet devices to cosmetic patient consultations. AB - The iPad is a useful reference tool for patient education in cosmetic consultations. In this article, we plan to (1) discuss how the iPad can be implemented and used by patients and physicians in consultations, (2) compare the advantages and disadvantages of the iPad with other forms of technology, (3) discuss the optimal way of using the iPad for patient care, (4) see how this tool complies with privacy regulations, and (5) look at other uses of the iPad in the patient care setting. There has been positive feedback from both patients and physicians regarding the addition of the tablet computer during consultations. In addition to showing patients pictures of cosmetic procedures, the iPad also has various multimedia capabilities such as videos and drawing tools that are useful in optimizing patient satisfaction, increasing clinical efficacy, and improving the overall patient experience. PMID- 22929359 TI - Apolipoprotein E, amyloid-beta clearance and therapeutic opportunities in Alzheimer's disease. AB - Alzheimer's disease (AD) is a progressive neurodegenerative disease characterised by extracellular amyloid-beta (Abeta) and intraneuronal tau protein brain pathologies. The most significant risk factor for non-familial AD is the presence of the E4 isoform of the cholesterol transporter apolipoprotein E (apoE). Despite extensive basic research, the exact role of apoE in disease aetiology remains unclear. Correspondingly, therapeutic targeting of apoE in AD is at an early preclinical stage. In this review, I discuss the key interactions of apoE and Abeta pathology, the current progress of preclinical animal models and the caveats of existing therapeutic approaches targeting apoE. Finally, novel Alzheimer's genetics and Abeta-independent disease mechanisms are highlighted. PMID- 22929360 TI - A method to localize RF B1 field in high-field magnetic resonance imaging systems. AB - In high-field magnetic resonance imaging (MRI) systems, B0 fields of 7 and 9.4 T, the RF field shows greater inhomogeneity compared to clinical MRI systems with B0 fields of 1.5 and 3.0 T. In multichannel RF coils, the magnitude and phase of the input to each coil element can be controlled independently to reduce the nonuniformity of the RF field. The convex optimization technique has been used to obtain the optimum excitation parameters with iterative solutions for homogeneity in a selected region of interest. The pseudoinverse method has also been used to find a solution. The simulation results for 9.4- and 7-T MRI systems are discussed in detail for the head model. Variation of the simulation results in a 9.4-T system with the number of RF coil elements for different positions of the regions of interest in a spherical phantom are also discussed. Experimental results were obtained in a phantom in the 9.4-T system and are compared to the simulation results and the specific absorption rate has been evaluated. PMID- 22929361 TI - Theoretical analysis and experimental evaluation of laser-induced interstitial thermotherapy in ex vivo porcine pancreas. AB - Laser-induced interstitial thermotherapy (LITT) has been recently applied to pancreas in animal models for ablation purpose. Assessment of thermal effects due to the laser-pancreatic tissue interaction is a critical factor in validating the procedure feasibility and safety. A mathematical model based on bioheat equation and its experimental assessment was developed. The LITT procedure was performed on 40 ex vivo porcine pancreases, with an Nd:YAG (1064 nm) energy of 1000 J and power from 1.5 up to 10 W conveyed by a quartz optical fiber with 300 MUm diameter. Six fiber Bragg grating sensors have been utilized to measure temperature distribution as a function of time at fixed distances from the applicator tip within pancreas undergoing LITT. Simulations and experiments show temperature variations Delta T steeply decreasing with distance from the applicator at higher power values: at 6 W, ?T > 40 degrees C at 5 mm and Delta T is approximately equal to 5 degrees C at 10 mm. Delta T nonlinearly increases with power close to the applicator. Ablated and coagulated tissue volumes have also been measured and experimental results agree with theoretical ones. Despite the absence of data in the current literature on pancreas optical parameters, the model allowed a quite good prediction of thermal effects. The prediction of LITT effects on pancreas is necessary to assess laser dosimetry. PMID- 22929362 TI - An echo state neural network for QRST cancellation during atrial fibrillation. AB - A novel method for QRST cancellation during atrial fibrillation (AF) is introduced for use in recordings with two or more leads. The method is based on an echo state neural network which estimates the time-varying, nonlinear transfer function between two leads, one lead with atrial activity and another lead without, for the purpose of canceling ventricular activity. The network has different sets of weights that define the input, hidden, and output layers, of which only the output set is adapted for every new sample to be processed. The performance is evaluated on ECG signals, with simulated f-waves added, by determining the root mean square error between the true f-wave signal and the estimated signal, as well as by evaluating the dominant AF frequency. When compared to average beat subtraction (ABS), being the most widely used method for QRST cancellation, the performance is found to be significantly better with an error reduction factor of 0.24-0.43, depending on f-wave amplitude. The estimates of dominant AF frequency are considerably more accurate for all f-wave amplitudes than the AF estimates based on ABS. The novel method is particularly well suited for implementation in mobile health systems where monitoring of AF during extended time periods is of interest. PMID- 22929363 TI - ECG analysis using multiple instance learning for myocardial infarction detection. AB - This paper presents a useful technique for totally automatic detection of myocardial infarction from patients' ECGs. Due to the large number of heartbeats constituting an ECG and the high cost of having all the heartbeats manually labeled, supervised learning techniques have achieved limited success in ECG classification. In this paper, we first discuss the rationale for applying multiple instance learning (MIL) to automated ECG classification and then propose a new MIL strategy called latent topic MIL, by which ECGs are mapped into a topic space defined by a number of topics identified over all the unlabeled training heartbeats and support vector machine is directly applied to the ECG-level topic vectors. Our experimental results on real ECG datasets from the PTB diagnostic database demonstrate that, compared with existing MIL and supervised learning algorithms, the proposed algorithm is able to automatically detect ECGs with myocardial ischemia without labeling any heartbeats. Moreover, it improves classification quality in terms of both sensitivity and specificity. PMID- 22929364 TI - A real-time electrical impedance sensing biopsy needle. AB - Diagnostic confirmation of cancer in solid organs is based on biopsy findings. In a standard 12-core prostate biopsy protocol, conventional biopsy needles sample only 0.95% (~0.228 cm3) of a typical 24-cm3 prostate gland. The primary objective of this study was to enhance the sensitivity of standard biopsy protocol by gauging electrical properties of tissue simultaneously with tissue extraction for histopathology analysis. A conventional biopsy (Bx) needle was instrumented with an electrical impedance spectroscopy (EIS) sensor to interrogate the tissue volume surrounding the needle tip. The EIS-Bx device was evaluated in a series of saline bath and ex vivo porcine experiments. It was found to sense a volume of 0.286 cm3 of tissue around the needle tip. EIS measurements were recorded from three ex vivo human prostates using the device, and the extracted biopsy cores were histologically assessed. Prostate conductivity sigma ranged from 0.179 to 0.3310 S/m for benign tissues and 0.0746 to 0.0837 S/m for malignant tissues at frequencies ranging from 1 to 100 kHz. Relative permittivity epsilon(r) ranged from 2.10*106 to 2.9 * 104 for benign and 6.63*105 to 5.3 * 103 for cancer tissues over the same frequency range. Both are found to be significantly higher in normal prostate tissues than in malignant tissue (p < 0.00001). PMID- 22929365 TI - STAR development and protocol comparison. AB - Accurate glycemic control (AGC) is difficult due to excessive hypoglycemia risk. Stochastic TARgeted (STAR) glycemic control forecasts changes in insulin sensitivity to calculate a range of glycemic outcomes for an insulin intervention, creating a risk framework to improve safety and performance. An improved, simplified STAR framework was developed to reduce light hypoglycemia and clinical effort, while improving nutrition rates and performance. Blood glucose (BG) levels are targeted to 80-145 mg/dL, using insulin and nutrition control for 1-3 h interventions. Insulin changes are limited to +3U/h and nutrition to +/-30% of goal rate (minimum 30%). All targets and rate change limits are clinically specified and generalizable. Clinically validated virtual trials were run on using clinical data from 371 patients (39841 h) from the Specialized Relative Insulin and Nutrition Tables (SPRINT) cohort. Cohort and per patient results are compared to clinical SPRINT data, and virtual trials of three published protocols. Performance was measured as time within glycemic bands, and safety by patients with severe (BG < 40 mg/dL) and mild (%BG < 72 mg/dL) hypoglycemia. Pilot trial results from the first ten patients (1486 h) are included to support the in-silico findings. In both virtual and clinical trials, mild hypoglycemia was below 2% versus 4% for SPRINT. Severe hypoglycemia was reduced from 14 (SPRINT) to 6 (STAR), and 0 in the pilot trial. AGC was tighter than both SPRINT clinical data and in-silico comparison protocols, with 91% BG within the specified target (80-145 mg/dL) in virtual trials and 89.4% in pilot trials. Clinical effort (measurements) was reduced from 16.2/day to 11.8/day (13.5/day in pilot trials). This STAR framework provides safe AGC with significant reductions in hypoglycemia and clinical effort due to stochastic forecasting of patient variation-a unique risk-based approach. Initial pilot trials validate the in-silico design methods and resulting protocol, all of which can be generalized to suit any given clinical environment. PMID- 22929366 TI - Estimation of muscular fatigue under electromyostimulation using CWT. AB - The aim of this study is to investigate muscular fatigue and to propose a new fatigue index based on the continuous wavelet transform (CWT) which is compared to the standard fatigue indexes from literature. Fatigue indexes are all based on the electrical activity of muscles [electromyogram (EMG)] acquired during an electrically stimulated contraction thanks to two modules (electromyostimulation + electromyography recording) that can analyze EMG signals in real time during electromyostimulation. The extracted parameters are compared with each other and their sensitivity to noise is studied. The effect of truncation of M waves is then investigated, enlightening the robustness of the index obtained using CWT. PMID- 22929367 TI - Comparison study of intraoperative surface acquisition methods for surgical navigation. AB - Soft-tissue image-guided interventions often require the digitization of organ surfaces for providing correspondence from medical images to the physical patient in the operating room. In this paper, the effect of several inexpensive surface acquisition techniques on target registration error and surface registration error (SRE) for soft tissue is investigated. A systematic approach is provided to compare image-to-physical registrations using three different methods of organ spatial digitization: 1) a tracked laser-range scanner (LRS), 2) a tracked pointer, and 3) a tracked conoscopic holography sensor (called a conoprobe). For each digitization method, surfaces of phantoms and biological tissues were acquired and registered to CT image volume counterparts. A comparison among these alignments demonstrated that registration errors were statistically smaller with the conoprobe than the tracked pointer and LRS (p<0.01). In all acquisitions, the conoprobe outperformed the LRS and tracked pointer: for example, the arithmetic means of the SRE over all data acquisitions with a porcine liver were 1.73 +/- 0.77 mm, 3.25 +/- 0.78 mm, and 4.44 +/- 1.19 mm for the conoprobe, LRS, and tracked pointer, respectively. In a cadaveric kidney specimen, the arithmetic means of the SRE over all trials of the conoprobe and tracked pointer were 1.50 +/- 0.50 mm and 3.51 +/- 0.82 mm, respectively. Our results suggest that tissue displacements due to contact force and attempts to maintain contact with tissue, compromise registrations that are dependent on data acquired from a tracked surgical instrument and we provide an alternative method (tracked conoscopic holography) of digitizing surfaces for clinical usage. The tracked conoscopic holography device outperforms LRS acquisitions with respect to registration accuracy. PMID- 22929368 TI - Retinal vascular tree reconstruction with anatomical realism. AB - Motivated by the goals of automatically extracting vessel segments and constructing retinal vascular trees with anatomical realism, this paper presents and analyses an algorithm that combines vessel segmentation and grouping of the extracted vessel segments. The proposed method aims to restore the topology of the vascular trees with anatomical realism for clinical studies and diagnosis of retinal vascular diseases, which manifest abnormalities in either venous and/or arterial vascular systems. Vessel segments are grouped using extended Kalman filter which takes into account continuities in curvature, width, and intensity changes at the bifurcation or crossover point. At a junction, the proposed method applies the minimum-cost matching algorithm to resolve the conflict in grouping due to error in tracing. The system was trained with 20 images from the DRIVE dataset, and tested using the remaining 20 images. The dataset contained a mixture of normal and pathological images. In addition, six pathological fluorescein angiogram sequences were also included in this study. The results were compared against the groundtruth images provided by a physician, achieving average success rates of 88.79% and 90.09%, respectively. PMID- 22929370 TI - A new furaquinocin derivative, JBIR-136, from Streptomyces sp. 4963H2. PMID- 22929369 TI - A brief review on dengue molecular virology, diagnosis, treatment and prevalence in Pakistan. AB - Dengue virus infection is a serious health problem infecting 2.5 billion people worldwide. Dengue is now endemic in more than 100 countries, including Pakistan. Each year hundreds of people get infected with dengue in Pakistan. Currently, there is no vaccine available for the prevention of Dengue virus infection due to four viral serotypes. Dengue infection can cause death of patients in its most severity, meanwhile many antiviral compounds are being tested against dengue virus infection to eradicate this disease but still there is a need to develop an efficient, low-cost and safe vaccine that can target all the four serotypes of dengue virus. This review summarizes dengue molecular virology, important drug targets, prevalence in Pakistan, diagnosis, treatment and medicinal plant inhibitors against dengue. PMID- 22929371 TI - Use of back-scatter electron signals to visualise cell/nanowires interactions in vitro and in vivo; frustrated phagocytosis of long fibres in macrophages and compartmentalisation in mesothelial cells in vivo. AB - BACKGROUND: Frustrated phagocytosis has been stated as an important factor in the initiation of an inflammatory response after fibre exposure. The length of fibrous structures has been linked to the potential of fibres to induce adverse health effects for at least 40 years. However, we only recently reported for the first time the threshold length for fibre-induced inflammation in the pleural space and we implicated frustrated phagocytosis in the pro-inflammatory effects of long fibres. This study extends the examination of the threshold value for frustrated phagocytosis using well-defined length classes of silver nanowires (AgNW) ranging from 3-28 MUm and describes in detail the morphology of frustrated phagocytosis using a novel technique and also describes compartmentalisation of fibres in the pleural space. METHODS: A novel technique, backscatter scanning electron microscopy (BSE) was used to study frustrated phagocytosis since it provides high-contrast detection of nanowires, allowing clear discrimination between the nanofibres and other cellular features. A human monocyte-derived macrophage cell line THP-1 was used to investigate cell-nanowire interaction in vitro and the parietal pleura, the site of fibre retention after inhalation exposure was chosen to visualise the cell- fibre interaction in vivo after direct pleural installation of AgNWs. RESULTS: The length cut-off value for frustrated phagocytosis differs in vitro and in vivo. While in vitro frustrated phagocytosis could be observed with fibres>=14 MUm, in vivo studies showed incomplete uptake at a fibre length of >=10 MUm. Recently we showed that inflammation in the pleural space after intrapleural injection of the same nanofibre panel occurs at a length of >=5 MUm. This onset of inflammation does not correlate with the onset of frustrated phagocytosis as shown in this study, leading to the conclusion that intermediate length fibres fully enclosed within macrophages as well as frustrated phagocytosis are associated with a pro-inflammatory state in the pleural space. We further showed that fibres compartmentalise in the mesothelial cells at the parietal pleura as well as in inflammatory cells in the pleural space. CONCLUSION: BSE is a useful way to clearly distinguish between fibres that are, or are not, membrane-bounded. Using this method we were able to show differences in the threshold length at which frustrated phagocytosis occurred between in vitro and in vivo models. Visualising nanowires in the pleura demonstrated at least 2 compartments--in leukocyte aggregations and in the mesothelium--which may have consequences for long term pathology in the pleural space including mesothelioma. PMID- 22929374 TI - Positive relationships that support elder health and well-being are grounded in midlife/adolescent family. AB - Family is potentially a major support system for people of all ages. It can become particularly important for elders. On the basis of a 25-year longitudinal study, this article explores the contributions of family system functioning at parents' midlife to elderly parents' physical and mental health. Findings support the significant influence of the quality of the midlife/adolescent family life cycle stage on later life relationships between elderly parents and their adult children. Positive relationships with their adult children were important for both elderly parents' well-being. Frequency of contact with children was important for fathers-both for their well-being and for their physical health. PMID- 22929375 TI - Intensity of grandparent caregiving and life satisfaction among rural Chinese older adults: a longitudinal study using latent difference score analysis. AB - This study examined how life satisfaction and grandparent caregiving intensity changed over time among rural Chinese older adults, and whether there was a leading predictor between grandparent caregiving intensity and life satisfaction. Using 4 waves of data from the Well-being of Elderly in Anhui Province of China (N = 1704), we applied latent difference score analysis to explore this relationship. Results indicated that grandparent caregiving intensity decreased and life satisfaction increased over time. There was a lagged effect between grandparent caregiving intensity and life satisfaction, and life satisfaction demonstrated a leading prediction role between these 2 variables. This study confirmed the potentially rewarding aspect of grandparent caregiving, which may lead to greater life satisfaction. The results also revealed that psychological well-being among grandparents is very important for performing activities, such as caregiving. PMID- 22929376 TI - Perceived discrimination and social networks among older African Americans and Caribbean blacks. AB - The relationship between perceived discrimination and depressive symptoms among older black American populations is poorly understood. Although a small number of studies have examined the relationship between stress and social support, few have examined the association between perceived discrimination, social networks, and depressive symptoms among a representative sample of older racial and ethnic groups. This study examines (a) the relationship between sociodemographic factors, perceived discrimination and depressive symptoms and (b) social networks as a potential moderator in the perceived discrimination and depressive symptom relationship between 2 groups of older black Americans. This was a cross sectional study using data from the National Survey of American Life with a sample of older African Americans (N = 837) and Caribbean blacks (N = 271). Depressive symptoms were assessed using the 12-item Center for Epidemiological Studies Depression scale. Linear regression analyses were used to predict depressive symptoms. The relationship between perceived discrimination and depressive symptoms was significant in both groups. Social networks contributed as a protective factor for depressive symptoms for both groups. However, there was no significant moderation effect. Results suggest that regardless of ethnic affiliation, the experience of perceived discrimination is similar in both groups and is a risk factor for depressive symptoms. Future research is needed in this area to better understand the associations between sociodemographic factors, perceived discrimination, social networks, and their impact on depressive symptoms. PMID- 22929377 TI - Homophily and health behavior in social networks of older adults. AB - A common network phenomenon, homophily, involves developing relationships with others who are similar to you. The intent of this study was to determine if older adults' health behaviors were shared within social networks. We interviewed older adults from low-income senior housing (egos) on egocentric social network characteristics and key health behaviors for themselves and for named social ties (alters). Findings suggest strong effects for homophily, especially for those who smoked and were physically inactive. Public health interventions for older adults should consider the influence that social relationships have on personal health behaviors. Network-based interventions may be required. PMID- 22929378 TI - Exploring the use of social network analysis to measure social integration among older adults in assisted living. AB - Social integration is measured by a variety of social network indicators each with limitations in its ability to produce a complete picture of the variety and scope of interactions of older adults receiving long-term services and supports. The purpose of this study was to develop and evaluate the feasibility of collecting sociocentric (whole network) data among older adults in one assisted living neighborhood. The sociocentric approach is required to conduct social network analysis. Applying social network analysis is an innovative way to measure different facets of social integration among residents. Sociocentric data are presented for 12 residents. Network visualization or sociograms are used to illustrate the level of social integration among residents and between residents and staff. Measures of network centrality are reported to illustrate the number of personal connections and cohesion. The use of resident photographs helped residents with cognitive impairment to nominate individuals with whom they interacted. The sociocentric approach to data collection is feasible and allows researchers to measure levels and different aspects of social integration in assisted living environments. Residents with mild to moderate cognitive impairment were able to participate with the aid of resident and staff photographs. This approach is sensitive to capturing routine day-to-day interactions between residents and assisted living staff members that are often not reported in person-centered networks. This study contributes to the foundation for larger more representative studies of entire assisted living organizations that could in the future inform interventions aimed at improving social integration and cohesion among recipients of long-term services and supports. PMID- 22929379 TI - Staff interaction strategies that optimize delivery of transitional care in a skilled nursing facility: a multiple case study. AB - After hospitalization, more than 1.5 million older adults each year receive postacute care in skilled nursing facilities (SNFs). Transitional care services, designed to prepare older SNF patients (and their family caregivers) for their transitions from an SNF to home, have rarely been studied. Thus, we conducted a longitudinal, multiple case study of transitional care provided in an SNF to explore the care processes and staff interaction strategies that SNF staff members used to optimize delivery of transitional care. Using qualitative data from 89 interviews, 118 field observations, and 70 chart, or document reviews, we observed that transitional care services were not solely formalized processes, but rather were embedded in the interactions among older adult patients, their family caregivers, and members of interdisciplinary care teams. We found, moreover, that staff member interactions with patients and family caregivers increased the capacity of patient care teams for optimizing patient-centered care, information exchange, and coordination of transitional care. PMID- 22929380 TI - Linking employed caregivers' perceptions of long-term community services with health care legislation. AB - Many Americans experience the daily struggle of combining employment with long term caregiving of an older adult in their family. This study examined factors affecting employed informal caregivers use and nonuse of long-term community services and the influence on their employment. Using a mixed-methods approach, the study had a convenience sample of 50 employed informal caregivers. Three major factors were identified as facilitating the use of long-term community care services, whereas 9 others were described as barriers. The study participants also suggested 12 changes in long-term community services that could have allowed them to continue both employment and informal caregiving. Information from this study may help advance the discussion regarding the linkage of employed informal caregivers' needs, perceptions of community support services, and their employment. PMID- 22929381 TI - Priorities for action in a rural older adults study. AB - This article reports the findings from a recent study of older adults in the rural southwestern United States and discusses practice and research implications. The aim of the study was to analyze health disparities and strengths in the contexts of rurality, aging, a depressed economy, and limited health resources. Identified themes needing action included sustained access to prescriptions, transportation solutions for older adults in isolated communities, inadequate access to care, poor infrastructure and coordination of services, scarce assisted living and in-home care for frail older adults, and barriers related to culture, language, and economics. PMID- 22929382 TI - Delayed Plasmodium falciparum clearance following artesunate-mefloquine combination therapy in Thailand, 1997-2007. AB - BACKGROUND: There is concern that artesunate resistance is developing in Southeast Asia. The purpose of this study is to investigate the prevalence of parasitaemia in the few days following treatment with artesunate-mefloquine (AM), which is an indirect measure of decreased artesunate susceptibility. METHODS: This is a retrospective analysis of 31 therapeutic efficacy studies involving 1,327 patients treated with AM conducted by the Thai National Malaria Control Programme from 1997-2007. RESULTS: The prevalence of patients with parasitaemia on day 2 was higher in the east compared to the west (east: 20%, west: 9%, OR 2.47, 95% CI: 1.77, 3.45). In addition, the prevalence of day-2 parasitaemia increased over time (OR for each year = 1.10, 95% CI: 1.03, 1.19). After controlling for initial parasitaemia and age, year and region remained important determinants of day-2 parasitaemia (OR for region = 3.98, 95%CI 2.63, 6.00; OR for year = 1.28, 95%CI: 1.17, 1.39). The presence of parasitaemia on day 2 and day 3 were specific, but not sensitive predictors of treatment failure. DISCUSSION: Delayed resolution of parasitaemia after AM treatment increased in eastern Thailand between 1997 and 2007, which may be an early manifestation of decreased artesunate susceptibility. However, clinical and parasitological treatment failure after 28 days (which is related to both mefloquine and artesunate decreased susceptibility) is not changing over time. The presence of parasitaemia on day 2 is a poor indicator of AM 28-day treatment failure. PMID- 22929383 TI - Direct 4-D PET list mode parametric reconstruction with a novel EM algorithm. AB - The production of images of kinetic parameters is often the ultimate goal of positron emission tomography (PET) imaging. The indirect method of PET parametric imaging, also called the frame-based method (FM), is performed by fitting the time-activity curve (TAC) for each voxel with an appropriate compartment model after image reconstruction. The indirect method is simple and easily implemented, however, it usually leads to some loss of accuracy or precision, due to the use of two separate steps. This paper presents a direct 4-D method for producing 3-D images of kinetic parameters from list mode PET data. In this application, the TAC for each voxel is described by a one-tissue compartment model (1T). Extending previous EM algorithms, a new spatiotemporal complete data space was introduced to optimize the maximum likelihood function. This leads to a straightforward closed-form parametric image update equation. This method was implemented by extending the current list mode platform MOLAR to produce a parametric algorithm PMOLAR-1T. Using an ordered subset approach, qualitative and quantitative evaluations were performed using 2-D (x, t) and 4-D (x, y, z, t) simulated list mode data based on brain receptor tracers and also with a human brain study. Comparisons with the indirect method showed that the proposed direct method can lead to accurate estimation of the parametric image values with reduced variance, especially at low count levels. In the 2-D test, the direct method showed similar bias to the frame-based method but with variance reduction of 23%-60%. In the 4-D test, bias values of both methods were no more than 4% and the direct method had lower variability (coefficient of variation reduction of 0%-64% compared to the frame-based method) at the normal count level. The direct method had a larger reduction in variability (27%-81%) and lower bias (1%-5% for 4-D and 1%-19% for FM) at low count levels. The results in the human brain study are similar with PMOLAR-1T showing lower noise than FM. PMID- 22929384 TI - Registration of 3D ultrasound through an air-tissue boundary. AB - In this study we evaluated a new method for registering three-dimensional ultrasound (3DUS) data to external coordinate systems. First, 3DUS was registered to the stereo endoscope of a da Vinci Surgical System by placing a registration tool against an air-tissue boundary so that the 3DUS could image ultrasound fiducials while the stereo endoscope could image camera markers on the same tool. The common points were used to solve the registration between the 3DUS and camera coordinate systems. The target registration error (TRE) when imaging through a PVC tissue phantom ranged from 3.85 1.76 mm to 1.82 1.03 mm using one to four registration tool positions. TRE when imaging through an ex-vivo liver tissue sample ranged from 2.36 1.01 mm to 1.51 0.70 mm using one to four registration tool positions. Second, using a similar method, 3DUS was registered to the kinematic coordinate system of a da Vinci Surgical System by using the da Vinci surgical manipulators to identify common points on an air-tissue boundary. TRE when imaging through a PVC tissue phantom was 0.95 0.38 mm. This registration method is simpler and potentially more accurate than methods using commercial motion tracking systems. This method may be useful in the future in augmented reality systems for laparoscopic and robotic-assisted surgery. PMID- 22929385 TI - Consideration of the linguistic characteristics of letters makes the universal model of reading more universal. AB - We suggest that the linguistic characteristics of letters also need to be considered to fully understand how a reader processes printed words. For example, studies in Korean showed that unambiguity in the assignment of letters to their appropriate onset, vowel, or coda slot is one of the main sources of the letter transposition effect. Indeed, the cognitive system that processes Korean is tuned to the structure of the Korean writing system. PMID- 22929386 TI - The mediating role of loneliness in the relation between social engagement and depressive symptoms among older Korean Americans: do men and women differ? AB - OBJECTIVES: This study conceptualized loneliness as a mediator in the relation between social engagement and depressive symptoms and explored gender differences in the mediation model. Various indices of social engagement were considered including living arrangement, social network, and activity participation. METHOD: Using data from 674 community-dwelling Korean American older adults, we first examined the mediation effect of loneliness in the relation between each of 3 indices of social engagement (not living alone, social network, and activity participation) and depressive symptoms. Subsequently, gender differences in the mediation model were examined. RESULTS: As hypothesized, loneliness was found to mediate the relation between each of the indices of social engagement and depressive symptoms in both men and women. We also observed gender differences in the strength of mediating effects; the effect of living alone was more likely to be mediated by loneliness among men, whereas women showed greater levels of mediation in the models with social network and activity participation. DISCUSSION: Our findings suggest that loneliness may explain the mechanism by which deficits in social engagement exerts its effect on depressive symptoms and that gender differences should be considered in interventions targeting social engagement for mental health promotion. PMID- 22929388 TI - Friend or foe? Age moderates time-course specific responsiveness to trustworthiness cues. AB - OBJECTIVES: There is growing evidence of a greater focus on positive relative to negative information in older adulthood. Up to date, the age-related positivity effect in affective processing has been only investigated with respect to explicit emotional cues. Thus, the purpose of this study was to investigate whether similar age-related differences would be observed in reference to subtler cues, such as emotionally suggestive structural facial characteristics. METHOD: We used a gaze following paradigm and investigated the temporal dynamics of responding to facial trustworthiness cues in younger and older adults. RESULTS: Both age groups provided similar trustworthiness evaluations. Nonetheless, under responding conditions that allowed for volitional modulatory influences (600 ms), older (but not younger) adults with superior cognitive resources showed more gaze following in response to trustworthy than to untrustworthy looking faces. CONCLUSIONS: This study provided initial evidence that the age-related positivity effect in affective processing extends to subtle emotional cues, generally interpreted as being reflective of socially relevant personality traits. Implications for aging theories of motivated cognition and developmental changes in reliance on superficial affective cues are discussed. PMID- 22929387 TI - Relationship between age and promotion orientation depends on perceived older worker stereotypes. AB - OBJECTIVES: Research has consistently revealed a negative relationship between chronological age and promotion orientation, that is, the motivational orientation toward approaching possible gains. In addition, experimental research has demonstrated that activating positive self-relevant stereotypes (e.g., for men, the stereotype that men are good at math) can stimulate increases in promotion orientation. Integrating and applying this research to the work context, we hypothesized that the relationship between age and promotion orientation would depend on employees' perceptions of the stereotype of older workers in their work context, such that there would be no negative relationship between age and promotion orientation when individuals perceive a more positive older worker stereotype. METHOD: We analyzed the relationships between age, perceived older worker stereotype (POWS), and promotion orientation using a sample of working adults (N = 337) aged 19-64 years. RESULTS: Results revealed a significant age by POWS interaction such that there was a negative relationship between age and promotion orientation when POWS was less positive. However, there was no relationship between age and promotion orientation when POWS was more positive. DISCUSSION: Results suggest that the negative relationship between age and promotion orientation depends on contextual factors such as POWS. PMID- 22929390 TI - Age-related differences in social economic decision making: the ultimatum game. AB - OBJECTIVES: Despite recognition of the increasing influence of emotion on decision making with age, there are few studies that have assessed older adults' financial choices in a socioemotional context. Thus, social economic decision making between same- versus other-aged partners was assessed. METHOD: Young (n = 35) and older (n = 34) adults participated in two Ultimatum Games. In the first, they proposed divisions of money between themselves and future young and older participants. In the second, they accepted or rejected fair and unfair divisions of money proposed by past young and older participants. Lastly, participants reported their anger in response to the offers that were proposed to them in the second game. RESULTS: In the first game, older participants divided the money more generously than did young participants. In the second game, young, but not older, participants rejected more unfair offers proposed by young relative to older adults. However, both participant age groups reported being angrier at unfair offers proposed by young adults compared with when receiving the same offer from an older adult. DISCUSSION: These findings are discussed in the context of evidence for improved anger regulation and increased prosocial behavior with age. PMID- 22929389 TI - Modeling learning and memory using verbal learning tests: results from ACTIVE. AB - OBJECTIVE: To investigate the influence of memory training on initial recall and learning. METHOD: The Advanced Cognitive Training for Independent and Vital Elderly study of community-dwelling adults older than age 65 (n = 1,401). We decomposed trial-level recall in the Auditory Verbal Learning Test (AVLT) and Hopkins Verbal Learning Test (HVLT) into initial recall and learning across trials using latent growth models. RESULTS: Trial-level increases in words recalled in the AVLT and HVLT at each follow-up visit followed an approximately logarithmic shape. Over the 5-year study period, memory training was associated with slower decline in Trial 1 AVLT recall (Cohen's d = 0.35, p = .03) and steep pre- and posttraining acceleration in learning (d = 1.56, p < .001). Findings were replicated using the HVLT (decline in initial recall, d = 0.60, p = .01; pre and posttraining acceleration in learning, d = 3.10, p < .001). Because of the immediate training boost, the memory-trained group had a higher level of recall than the control group through the end of the 5-year study period despite faster decline in learning. DISCUSSION: This study contributes to the understanding of the mechanisms by which training benefits memory and expands current knowledge by reporting long-term changes in initial recall and learning, as measured from growth models and by characterization of the impact of memory training on these components. Results reveal that memory training delays the worsening of memory span and boosts learning. PMID- 22929391 TI - Interference from previous distraction disrupts older adults' memory. AB - OBJECTIVES: Previously relevant information can disrupt the ability of older adults to remember new information. Here, the researchers examined whether prior irrelevant information, or distraction, can also interfere with older adults' memory for new information. METHOD: Younger and older adults first completed a 1 back task on pictures that were superimposed with distracting words. After a delay, participants learned picture-word paired associates and memory was tested using picture-cued recall. In 1 condition (high interference), some pairs included pictures from the 1-back task now paired with new words. In a low interference condition, the transfer list used all new items. RESULTS: Older adults had substantially lower cued-recall performance in the high- compared with the low-interference condition. In contrast, younger adults' performance did not vary across conditions. DISCUSSION: These findings suggest that even never relevant information from the past can disrupt older adults' memory for new associations. PMID- 22929392 TI - Insomnia symptoms, nightmares, and suicidal ideation in older adults. AB - OBJECTIVES: Prior research has found that insomnia symptoms and nightmares are associated with suicidal ideation, suicide attempts, and death by suicide. However, to the best of our knowledge, no research has examined the relation between insomnia symptoms, nightmares, and suicidal ideation in older adults. The current project aimed to fill this void by investigating the relation between insomnia symptoms, nightmares, and suicidal ideation in an older adult sample. METHOD: The study utilized a cross-sectional design. The sample consisted of 81 older adult patients (age >= 65 years) recruited from a family medicine clinic. The participants were asked to complete surveys about their sleep, symptoms of depression, and suicidal ideation. RESULTS: Insomnia symptoms, but not nightmares, were significantly related to suicidal ideation. In addition, insomnia symptoms were related to suicidal ideation independent of nightmares. Furthermore, the relation between insomnia symptoms and suicidal ideation was mediated by depressive symptoms. DISCUSSION: These findings have implications for the identification and treatment of suicidal ideation in older adults. PMID- 22929393 TI - Age differences in trust: an investigation across 38 countries. AB - OBJECTIVE: Population aging is a global challenge in the 21st century. As social relationships contribute significantly to older adults' well-being and trust lays the foundation of constructive social interactions, it is theoretically and practically significant to examine age differences in trust in a worldwide sample. METHOD: The current study examined age differences in generalized trust and trust toward family members, friends, neighbors, and strangers, using data from the World Value Survey based on 57,497 individuals from 38 countries. RESULTS: Age was positively related to generalized trust and trust toward the four target groups across the 38 countries. Age differences in trust toward friends, neighbors, and strangers were also moderated by contextual factors (i.e., income inequality, developing status, and individualism). DISCUSSION: The results suggest that, across countries, enhancing trust toward others may be one mechanism through which older adults maintain emotional connectedness with others. Future studies are encouraged to investigate the mechanism underlying the age differences in trust. PMID- 22929394 TI - Benefits of physical exercise training on cognition and quality of life in frail older adults. AB - OBJECTIVES: Frailty is a state of vulnerability associated with increased risks of fall, hospitalization, cognitive deficits, and psychological distress. Studies with healthy senior suggest that physical exercise can help improve cognition and quality of life. Whether frail older adults can show such benefits remains to be documented. METHOD: A total of 83 participants aged 61-89 years were assigned to an exercise-training group (3 times a week for 12 weeks) or a control group (waiting list). Frailty was determined by a complete geriatric examination using specific criteria. Pre- and post-test measures assessed physical capacity, cognitive performance, and quality of life. RESULTS: Compared with controls, the intervention group showed significant improvement in physical capacity (functional capacities and physical endurance), cognitive performance (executive functions, processing speed, and working memory), and quality of life (global quality of life, leisure activities, physical capacity, social/family relationships, and physical health). Benefits were overall equivalent between frail and nonfrail participants. DISCUSSION: Physical exercise training leads to improved cognitive functioning and psychological well-being in frail older adults. PMID- 22929396 TI - Does social activity decrease risk for institutionalization and mortality in older people? AB - OBJECTIVES: Social inactivity predicts adverse health events, but less is known about how different dimensions of social activity are related to health. The aim of this study was to investigate collective (e.g., cultural and organizational activities) and productive (e.g., helping others) social activity as predictors of risk for mortality and institutionalization in old age. METHOD: A total of 1,181 community-living people aged 65-84 years at baseline were interviewed face to face as part of the Evergreen project, in Jyvaskyla, Finland in 1988. Time to institutionalization and mortality were analyzed in separate models for proportional hazard regression on mortality and competing risks analysis on institutionalization and mortality. RESULTS: At follow-up, approximately 17 years later, 22% of persons were institutionalized and 71% had died. When sociodemographics, health, functioning, and intensity of physical activity were controlled for, collective social activity reduced risk for mortality and initially for institutionalization although this latter effect diminished over time. DISCUSSION: Collective social activity may be associated with a reduced risk for mortality and institutionalization in older people. Further studies on the mechanisms underlying the association between social activity and health are needed. PMID- 22929395 TI - The relationship between computer experience and computerized cognitive test performance among older adults. AB - OBJECTIVE: This study compared the relationship between computer experience and performance on computerized cognitive tests and a traditional paper-and-pencil cognitive test in a sample of older adults (N = 634). METHOD: Participants completed computer experience and computer attitudes questionnaires, three computerized cognitive tests (Useful Field of View (UFOV) Test, Road Sign Test, and Stroop task) and a paper-and-pencil cognitive measure (Trail Making Test). Multivariate analysis of covariance was used to examine differences in cognitive performance across the four measures between those with and without computer experience after adjusting for confounding variables. RESULTS: Although computer experience had a significant main effect across all cognitive measures, the effect sizes were similar. After controlling for computer attitudes, the relationship between computer experience and UFOV was fully attenuated. DISCUSSION: Findings suggest that computer experience is not uniquely related to performance on computerized cognitive measures compared with paper-and-pencil measures. Because the relationship between computer experience and UFOV was fully attenuated by computer attitudes, this may imply that motivational factors are more influential to UFOV performance than computer experience. Our findings support the hypothesis that computer use is related to cognitive performance, and this relationship is not stronger for computerized cognitive measures. Implications and directions for future research are provided. PMID- 22929397 TI - Accumulated financial strain and women's health over three decades. AB - OBJECTIVE: Drawing from cumulative inequality theory, this research examines how accumulated financial strain affects women's self-rated health in middle and later life. METHOD: Using data from the National Longitudinal Survey of Mature Women (1967-2003), we employ random-coefficient growth curve models to examine whether recurring financial strain influences women's health, above and beyond several measures of objective social status. Predicted probabilities of poor health were estimated by the frequency of financial strain. RESULTS: Financial strain is associated with rapid declines in women's health during middle and later life, especially for those women who reported recurrent strain. Changes in household income and household wealth were also associated with women's health but did not eliminate the effects due to accumulated financial strain. DISCUSSION: Accumulated financial strain has long-term effects on women's health during middle and later life. The findings demonstrate the importance of measuring life course exposure to stressors in studies of health trajectories. PMID- 22929398 TI - Gambling behavior and problems among older adults: a systematic review of empirical studies. AB - OBJECTIVES: With the rapid aging of the population and the increased availability of gambling facilities over the past three decades, older adults may gamble more and may be increasingly at risk for problem gambling (PG) or pathological gambling disorder (PGD). To facilitate a better understanding of gambling behavior among older adults that will inform preventive strategies, this article systematically examined empirical studies on issues related to older adults' gambling. METHOD: This article reviewed 75 empirical studies including data on the distribution and determinants of PG and PGD and the outcomes of gambling. RESULTS: This review used the broad term of "disordered gambling" as a means to explain a continuum of problems caused by PG and PGD. The analyses covered seven topics concerning older adults' gambling behaviors: Participation rates for gambling, prevalence rates of disordered gambling, motivation for initially beginning to gamble, risk and protective factors for disordered gambling, and negative and positive health outcomes from gambling. DISCUSSION: Based on research gaps identified in the review, this article proposes six recommendations for future studies focusing on well-being of older adults who gamble, research method issues, and taking into account older adults' inspirations and adjustment to the aging process in the 21st century. PMID- 22929399 TI - Differences in self-reported physical limitation among older women and men in Ismailia, Egypt. AB - OBJECTIVES: This study explores the reasons for gender differences in self reported physical limitation among older adults in Ismailia, Egypt. METHOD: 435 women and 448 men, 50 years and older in Ismailia, Egypt, participated in a social survey and tests of physical performance. Ordered logit models were estimated to compare unadjusted gender differences in reported disability with these differences adjusted sequentially for (a) age and objective measures of physical performance, (b) self-reported morbidities and health care use, and (c) social and economic attributes. RESULTS: Compared with men, women more often reported higher levels of limitation in activities of daily living (ADLs), upper extremity range of motion (ROM), and lower-extremity gross mobility (GM). Adjusting for age and objective measures of physical performance, women and men had similar odds of self-reporting difficulty with ADLs. With sequential adjustments for the remaining variables, women maintained significantly higher odds of self-reported difficulty with upper-extremity ROM and lower-extremity GM. DISCUSSION: Cross-culturally, gender differences in self-reported disability may arise from objective and subjective perceptions of disability. Collectively, these results and those from prior studies in Bangladesh and the United States suggest that gender gaps in self-reported physical limitation may be associated with the degree of gender equality in society. PMID- 22929400 TI - Family caregiver involvement for long-term care residents at the end of life. AB - OBJECTIVES: To examine family caregiver involvement for long-term care (LTC) residents during the last month of life. Researchers examined direct (personal care and meals) and indirect (management and monitoring) types of caregiver involvement and the relationship between the type of involvement and predisposing, enabling, and need characteristics. Researchers also examined whether the frequency of involvement changed during the end-of-life (EOL) period. METHOD: Researchers used an expanded version of Andersen's Behavioral Model to conceptualize predictors of family involvement for 438 residents in 125 residential care/assisted living and nursing home settings. Bivariate and multivariate analyses examined relationships among variables. RESULTS: More than one-half of family caregivers monitored, managed care and assisted with meals, and 40% assisted with personal care tasks. The enabling characteristic of days visited and the need characteristic of caregiver role strain were related to each of the 4 types of involvement. However, the other correlates were distinct to the type of involvement. DISCUSSION: Families are involved in EOL care in LTC settings. Higher role strain is related to more involvement in each of the 4 types of involvement, suggesting that whether involvement is by desire, perceived need, or both, there is cause to more critically examine the family caregiver's desired role and need for support. PMID- 22929401 TI - Upregulation of Hsp90-beta and annexin A1 correlates with poor survival and lymphatic metastasis in lung cancer patients. AB - BACKGROUND: Hsp90-beta and annexin A1 were investigated as prognostic factors because of their apparent association with tumorigenesis. However, the effect of Hsp90-beta and annexin A1 in lung cancer remains poorly understood. The expressions of Hsp90-beta and annexin A1 in lung cancer and normal lung specimens were examined, and the relationships with respect to the clinico-pathological features and patient survival in lung cancer were analyzed. METHODS: The expression levels of Hsp90-beta and annexin A1 were examined using immunohistochemistry, in-situ hybridization, and Western blot. RESULTS: Lung cancer tissues exhibited higher expression levels of Hsp90-beta and annexin A1 than the normal tissues (p < 0.05), and the expression levels of the markers were significantly associated with the pathological grade and lymphatic invasion of lung cancer (p < 0.05). Moreover, the upregulation of Hsp90-beta and annexin A1 correlated with decreased survival (p < 0.05). CONCLUSION: The upregulation of Hsp90-beta and annexin A1 were associated with poor post-surgical survival time and lymphatic metastasis of lung cancer patients. Moreover, the high expression of the markers was an independent predictor of poor outcomes. PMID- 22929402 TI - Modification of the protocol for selective adrenal venous sampling results in both a significant increase in the accuracy and necessity of the procedure in the management of patients with primary hyperaldosteronism. AB - BACKGROUND: Adrenal venous sampling (AVS) is used in the work-up of primary hyperaldosteronism (PA) to distinguish unilateral PA from bilateral adrenal hyperplasia. In 2006, we reported that only 44% of AVS had biochemical evidence of bilateral adrenal vein cannulation (BAVC). Critical appraisal of our practice resulted in a protocol change. This study examined the impact of this new protocol on both the technical success rate and its influence on management of PA. METHODS: Since 2006, all patients with biochemically documented PA referred to either a single endocrine surgeon or endocrine specialist underwent AVS. Successful BAVC was defined as an adrenal vein to inferior vena cava/cortisol ratio of >3:1. Lateralization was defined as an aldosterone:cortisol ratio >3 times the unaffected side. RESULTS: Of the 86 AVS performed on 84 patients with PA, 82 had BAVC (95%). AVS altered the management in 26 of 84 (31%) patients. Despite clear unilateral findings on imaging in 45 patients, AVS demonstrated bilateral adrenal hyperplasia. in 10 and contralateral disease in 3. AVS confirmed unilateral PA in 5 patients with equivocal <1 cm nodules. In 4 of 25 patients with normal adrenal glands, AVS demonstrated lateralization. AVS demonstrated unilateral PA in 4 of 9 patients in whom imaging suggested bilateral adrenal hyperplasia. CONCLUSION: Our new AVS protocol resulted in a marked improvement in BAVC. AVS influenced management in a third of patients with PA. Surgical decision-making cannot be made solely on the basis of cross-sectional imaging. PMID- 22929403 TI - Renal transplant status in patients undergoing colorectal surgery: is immunosuppression safer than kidney disease? AB - BACKGROUND: It is unknown how colorectal surgical outcomes in recipients of renal transplants (TXP) compare to the outcomes in patients with chronic kidney disease (CKD) and end-stage renal disease (ESRD). METHODS: Data from the Nationwide Inpatient Sample for 2004 to 2008 were reviewed. International Classification of Diseases (ICD-9) codes identified patients undergoing colorectal surgery who were stratified as having no kidney disease, CKD, ESRD, or TXP. The effects of renal status on mortality, length of hospital stay, and hospital costs were determined. RESULTS: A total of 171,133 patients were identified; 162,986 had no kidney disease, 3,686 had CKD, 1,296 had ESRD, and 3,765 had had TXP. The odds of death after surgery were 43% more likely for patients with CKD, 82% more likely for TXP, and 240% more likely for those with ESRD. TXP resulted in an additional length of hospital stay of 3.4 days, compared to 3.2 days for those with ESRD, and 1.1 days for those with CKD (P < .0001). CKD added $4,223 in additional costs, TXP added $8,213, and ESRD added $12,821 (P < .0001). TXP demonstrated odds of mortality between those of CKD and ESRD for cardiovascular complications (OR 2.47). Pulmonary complications resulted in the highest odds of mortality for TXP (OR 6.3). CONCLUSION: After TXP, patients undergoing colorectal surgery have mortality and costs between those of patients with CKD and ESRD, with pulmonary complications remaining high mortality events. PMID- 22929405 TI - Rethinking phonological theories of reading. AB - One key insight of Frost's target article is that morphology has priority over phonology in writing and in cognitive processing. I argue that this insight raises challenges for theories that put phonology at the heart of the reading process. Instead, it highlights the potential importance of a morphemically based visual pathway to meaning in this process. PMID- 22929404 TI - A scoring system for the prognosis and treatment of malignant bowel obstruction. AB - BACKGROUND: Malignant bowel obstruction is a common result of end-stage abdominal cancer that is a treatment dilemma for many physicians. Little has been reported predicting outcomes or determining the role of surgical intervention. We sought to review our experience with surgical and nonsurgical management of malignant bowel obstruction to identify predictors of 30-day mortality and of who would most likely benefit from surgical intervention. METHODS: A chart review of 523 patients treated between 2000 and 2007 with malignant bowel obstruction were evaluated for factors present at admission to determine return to oral intake, 30 day mortality, and overall survival. Propensity score matching was used to homogenize patients treated with and without surgery to identify those who would benefit most from operative intervention. RESULTS: Radiographic evidence of large bowel obstruction was predictive of return to oral intake. Hypoalbuminemia and radiographic evidence of ascites or carcinomatosis were all predictive of increased 30-day mortality and overall survival. A nomogram of 5 identified risk factors correlated with increased 30-day mortality independent of therapy. Patients with large bowel or partial small bowel obstruction benefited most from surgery. A second nomogram was created from 4 identified risk factors that revealed which patients with complete small bowel obstruction might benefit from surgery. CONCLUSION: Two nomograms were created that may guide decisions in the care of patients with malignant bowel obstruction. These nomograms are able to predict 30-day mortality and who may benefit from surgery for small bowel obstruction. PMID- 22929406 TI - Reduced valproic acid serum concentrations due to drug interactions with carbapenem antibiotics: overview of 6 cases. AB - BACKGROUND: The plasma concentrations of valproic acid (VPA) are known to decrease during the concomitant administration of carbapenem antibiotics, such as meropenem, imipenem, and ertapenem. This study summarizes 6 cases of drug-drug interactions between VPA and carbapenem antibiotics. METHODS: To investigate the onset and severity of the reductions in the concentration of VPA in patients with or without the coadministration of carbapenem antibiotics, the authors performed a retrospective evaluation of therapeutic drug monitoring (TDM) reports that described a decrease in the serum concentrations of VPA during the concomitant use of carbapenem antibiotics from January 2008 to December 2010 in the Seoul National University Hospital. The evaluated TDM reports included 6 cases. The decrement ratio of the VPA serum concentration was calculated from the TDM reports, and the change in the half-life of the VPA was also estimated. RESULTS: Six cases presented with changes in the VPA serum concentration before and after the administration of carbapenem antibiotics. (Three cases were treated with meropenem, 2 were treated with ertapenem, and 1 was treated with imipenem.) The VPA concentrations reduced by (mean +/- SD) 88.7 +/- 5.3% (3 cases of meropenem), 74.0 +/- 9.8% (2 cases of ertapenem), and 73.3% (1 case of imipenem), respectively, and the half-life of VPA reduced by 80.1 +/- 9.0%, 64.4 +/- 24.2%, and 50.6%, respectively. CONCLUSION: The interaction between VPA and carbapenem antibiotics caused decreases in the VPA serum concentrations; the extent of this decrease was greater in the meropenem-treated patients than in the imipenem treated or ertapenem-treated cases. Because the therapeutic effect of VPA depends on its serum concentration, it should be recognized that there may be a loss of seizure control in patients using VPA with carbapenem antibiotics. PMID- 22929408 TI - A puzzling case of increased serum clozapine levels in a patient with inflammation and infection. AB - A 23-year old male with a history of schizophrenia treated with clozapine 900 mg/d was admitted to the hospital for a gastrointestinal infection. The trough serum concentration of clozapine at admission was 9074 nmole/L, that is, almost 4 fold the upper limit of the reference range. The patients did not report any adverse effects of clozapine. The clozapine concentration 1 month earlier had been 1919 nmole/L, which is well within the reference range. There seems to be 2 different mechanisms explaining the increase in clozapine levels in this patient. First, a downregulation of CYP enzyme activities, which primarily seems to be mediated by interleukin-6, takes place during infection and inflammation. Second, the concentration of the acute phase protein alpha1-acid glycoprotein (AGP; orosomucoid) increases during infection and inflammation. As approximately 95% of clozapine is bound to AGP, the concentration of clozapine will increase in parallel with the increase in AGP. A therapeutic drug monitoring analysis measures the total drug concentration (ie, the concentration of unbound plus plasma protein bound drug), whereas the concentration of free drug exerts its pharmacological effects. Thus, this second mechanism will, in contrast to the first mechanism, not affect the clinical effect of clozapine. Although the patient was also treated with ciprofloxacin, which has been reported to inhibit the metabolism of clozapine, the clozapine levels did not further increase. This case illustrates the complex interrelationship between serum levels of clozapine and an intercurrent infection treated with potentially interacting antibiotics. PMID- 22929407 TI - Population pharmacokinetic modeling of risperidone and 9-hydroxyrisperidone to estimate CYP2D6 subpopulations in children and adolescents. AB - AIM: The study aims were to characterize risperidone and (+/-)-9 hydroxyrisperidone pharmacokinetic (PK) variability in children and adolescents and to evaluate covariate effects on PK parameters. METHODS: Steady-state samples were drawn at predose, 1, 2, 4, and 7 hours postdose; cytochrome P450 2D6 (CYP2D6) genotypes were available for 28 subjects. A nonlinear mixed-effects model (NONMEM) modeled the PKs of risperidone and (+/-)-9-hydroxyrisperidone; covariates included age, weight, sex, and CYP2D6 phenotype. The model included 497 observations [risperidone (n = 163), (+) and (-)-9-hydroxyrisperidone (n = 334)] from 45 subjects aged 3-18.3 (mean 9.6 +/- 3.7) years, weighing 16.8-110 (43 +/- 20.2) kg. RESULTS: A 1-compartment mixture model described risperidone and (+/-)-9-hydroxyrisperidone clearances for 3 CYP2D6 metabolizer subpopulations: extensive, intermediate, and poor. Weight significantly affected (+/-)-9-hydroxyrisperidone clearance. Clearance estimates in the mixture model were poor metabolizer 9.38 L/h, intermediate metabolizer 29.2 L/h, and extensive metabolizer 37.4 L/h. CONCLUSION: Active moiety [risperidone plus (+/-)-9 hydroxyrisperidone] PK variability and the covariate effects were better explained with the addition of metabolite PK parameters. This model may aid the development of individualized risperidone dosing regimens in children and adolescents. PMID- 22929409 TI - Increased cyclosporin a sensitivity in vivo in pediatric renal transplant recipients compared with adults. AB - BACKGROUND: Developmental regulation of the pharmacodynamics of cyclosporin A (CsA) has been suggested by in vitro studies. However, these results have not yet been reproduced in the complexity of an in vivo immune system, because reliable biomarkers of CsA effects have not been available. METHODS: Gene expression of interleukin-2 (IL-2), interferon (IFN)-gamma, and granulocyte macrophage colony stimulating factor (GM-CSF) in peripheral blood from stable pediatric (N = 31) and adult renal transplant recipients (N = 153) (age range 6.5-78 years) was measured by quantitative real-time polymerase chain reaction before (C0) and 2 hours (C2) after oral CsA intake. To control for the effect of varying CsA concentrations, an index was calculated as a measure of individual CsA sensitivity. RESULTS: The CsA sensitivity of IL-2 gene expression in pediatric patients was 3.9% higher than in middle-aged adults and 5.2% higher than in seniors, indicating stronger immunosuppression at a given CsA blood concentration in younger patients. For the entire patient cohort, there was a statistically significant inverse correlation between the CsA sensitivity of IL-2 and chronological age (r = 0.142, P < 0.0001). Also, the CsA sensitivity of IFN-gamma (r = 0.131, P < 0.0001) and GM-CSF (r = 0.036, P < 0.01) were inversely correlated with chronological age. Multiple linear regression analysis revealed that age was a highly significant (P = 0.0027) independent predictor for residual gene expression of IL-2, but not of IFN-gamma and GM-CSF. CONCLUSIONS: An increased sensitivity of IL-2 to suppression by CsA was found in pediatric renal transplant recipients in vivo compared with adults. Hence, there seems to be an effect of human development on CsA pharmacodynamics, which, besides the effect of age on pharmacokinetics, should also be considered for the design of treatment regimens of CsA and potentially other calcineurin inhibitors in the pediatric patient population. PMID- 22929410 TI - Differential expression of pro-inflammatory cytokines in intra-epithelial T cells between trachea and bronchi distinguishes severity of COPD. AB - Measuring T-cell production of intracellular cytokines by flow cytometry enables specific monitoring of airway inflammation and response to therapies in chronic lung diseases including chronic obstructive pulmonary disease (COPD). We have previously shown that T cells in the airways of ex- and current- smoker COPD patients and healthy smokers produce increased T-cell pro-inflammatory cytokines IFNgamma and TNFalpha versus healthy controls. However, we could not differentiate between COPD groups and smokers due to a high degree of inter patient variability. To address this limitation, we hypothesized that intraepithelial T cells obtained from brushings of trachea may serve as an ideal intra-patient control compared with cells obtained from left and right bronchi. Production of intracellular cytokines by intraepithelial T-cells obtained from trachea and right and left bronchi from 26 individuals with COPD (16 with GOLD I and 10 with GOLD II-III disease), 11 healthy controls and 8 smokers was measured by flow cytometry. There was a significant increase in intraepithelial T-cell IFNgamma and TNFalpha in both right and left bronchi of GOLD II-III COPD patients compared to cells obtained from the trachea. There were no changes in T cell pro inflammatory cytokines between the bronchi and trachea from control subjects, GOLD I COPD patients or healthy smokers. There was a significant negative correlation between increased intraepithelial IFNgamma and TNFalpha in bronchial brushing T-cells compared with tracheal T-cells, and compared with FEV1. Monitoring intracellular intra-epithelial T-cell cytokine production in bronchial brushings using autologous tracheal brushings as controls provides improves the sensitivity of the technique. Therapeutic targeting of these pro-inflammatory cytokines and assessing the effects of drugs on immune reactivity has the potential to reduce lung inflammation caused by intra-epithelial T cells in COPD. PMID- 22929411 TI - Cytokine profiles of patients with enterohemorrhagic Escherichia coli O111 induced hemolytic-uremic syndrome. AB - Proinflammatory cytokines are related to the pathogenesis of enterohemorrhagic Escherichia coli (EHEC) infection and hemolytic-uremic syndrome (HUS). We assessed the kinetics of the release of cytokines such as neopterin, interleukin (IL)-6, IL-8 and tumour necrosis factor (TNF)-alpha and the soluble forms of type I and II TNF receptors during EHEC O111-induced HUS (EHEC O111/HUS). Fourteen patients with EHEC O111/HUS were enrolled in this study. Serum concentrations of all cytokines other than TNF-alpha were significantly elevated in patients with severe HUS compared with those in patients with mild HUS. Although serum concentrations of TNF-alpha were not significantly higher in patients with severe HUS, most patients with acute encephalopathy showed elevated TNF-alpha levels. Serum concentrations of these cytokines rapidly and markedly increased, and massive hypercytokinaemia developed 1 day before the diagnosis of HUS in patients with severe HUS. Changes in the number of white blood cells and concentration of serum lactate dehydrogenase were significantly larger between the onset of hemorrhagic colitis and the time of the diagnosis of HUS in patients with severe HUS compared with those in patients with mild HUS. Proinflammatory cytokines play an important role in the pathogenesis of EHEC infection and development of severe complications, including HUS and encephalopathy. Monitoring the cytokine profile may be useful for assessing disease activity of EHEC O111 infections. PMID- 22929412 TI - An optimized procedure for fluorescence-activated cell sorting (FACS) isolation of autonomic neural progenitors from visceral organs of fetal mice. AB - During development neural crest (NC)-derived neuronal progenitors migrate away from the neural tube to form autonomic ganglia in visceral organs like the intestine and lower urinary tract. Both during development and in mature tissues these cells are often widely dispersed throughout tissues so that isolation of discrete populations using methods like laser capture micro-dissection is difficult. They can however be directly visualized by expression of fluorescent reporters driven from regulatory regions of neuron-specific genes like Tyrosine hydroxylase (TH). We describe a method optimized for high yields of viable TH+ neuronal progenitors from fetal mouse visceral tissues, including intestine and lower urogenital tract (LUT), based on dissociation and fluorescence-activated cell sorting (FACS). The Th gene encodes the rate-limiting enzyme for production of catecholamines. Enteric neuronal progenitors begin to express TH during their migration in the fetal intestine and TH is also present in a subset of adult pelvic ganglia neurons . The first appearance of this lineage and the distribution of these neurons in other aspects of the LUT, and their isolation has not been described. Neuronal progenitors expressing TH can be readily visualized by expression of EGFP in mice carrying the transgene construct Tg(Th EGFP)DJ76Gsat/Mmnc. We imaged expression of this transgene in fetal mice to document the distribution of TH+ cells in the developing LUT at 15.5 days post coitus (dpc), designating the morning of plug detection as 0.5 dpc, and observed that a subset of neuronal progenitors in the coalescing pelvic ganglia express EGFP. To isolate LUT TH+ neuronal progenitors, we optimized methods that were initially used to purify neural crest stem cells from fetal mouse intestine. Prior efforts to isolate NC-derived populations relied upon digestion with a cocktail of collagenase and trypsin to obtain cell suspensions for flow cytometry. In our hands these methods produced cell suspensions from the LUT with relatively low viability. Given the already low incidence of neuronal progenitors in fetal LUT tissues, we set out to optimize dissociation methods such that cell survival in the final dissociates would be increased. We determined that gentle dissociation in Accumax (Innovative Cell Technologies, Inc), manual filtering, and flow sorting at low pressures allowed us to achieve consistently greater survival (>70% of total cells) with subsequent yields of neuronal progenitors sufficient for downstream analysis. The method we describe can be broadly applied to isolate a variety of neuronal populations from either fetal or adult murine tissues. PMID- 22929413 TI - CADLIVE optimizer: web-based parameter estimation for dynamic models. AB - Computer simulation has been an important technique to capture the dynamics of biochemical networks. In most networks, however, few kinetic parameters have been measured in vivo because of experimental complexity. We develop a kinetic parameter estimation system, named the CADLIVE Optimizer, which comprises genetic algorithms-based solvers with a graphical user interface. This optimizer is integrated into the CADLIVE Dynamic Simulator to attain efficient simulation for dynamic models. PMID- 22929414 TI - Core functions for the public health nutrition workforce in Europe: a consensus study. AB - OBJECTIVE: To assess and develop a consensus among a European panel of public health nutrition workforce stakeholders (academics and employers) regarding core functions required for effective public health nutrition practice. DESIGN: A modified Delphi study involving data from two rounds of questionnaires administered among a panel of public health nutrition workforce stakeholders. SETTING: Europe. SUBJECTS: A panel of fifty-three public health nutrition development stakeholders, including thirty-three academics and twenty employers, sampled from eighteen European countries. RESULTS: Panellists rated 50 % (19/38) of the initially listed functions as core (i.e. without which public health capacity is limited), using a majority cut-off (>50 %). Out of the nineteen core functions seven were categorised under the heading Intervention management, emphasising high agreement on the importance of managing interventions in public health nutrition work. Only one of the identified core public health nutrition functions was rated differently between academics and employers, suggesting consistent identification of core functions between stakeholder groups. CONCLUSIONS: This consensus on core functions of the public health nutrition workforce in Europe can be used to promote a consistent understanding of the role and value of public health nutritionists as a discrete disciplinary sub-specialty of the public health workforce. The convergence of opinions of academics and employers, as well as comparison with previous international studies, indicates that there is a set of core public health nutrition functions transferable between countries that can be used as a benchmark to guide further development of the public health nutrition workforce in Europe. PMID- 22929415 TI - Vitrification of in vitro produced bovine embryos: effect of embryonic block and developmental kinetics. AB - In order to investigate whether the kinetics and stage of embryo development affect cryosurvival of in vitro produced bovine embryos, cleaved embryos were categorized in six groups based on their developmental kinetics regarding the stage of embryonic block in bovine (8-16 cell stage): I and II--early (day 2) and late (day 3) 5-8 cell, III and IV--early (day 3) and late (day 4) 8-16 cell, and V and VI--early (day 4) and late (day 5) morula. The cryosurvival and developmental competence of these embryos were compared with each other and also with the corresponding control groups. The potential of 5-8 cell stage embryos to survive vitrification and further develop towards blastocyst stage was significantly lower than vitrified and un-vitrified 8-16 cell and morula stage embryos. These results suggest that, the survival rate and potential of embryos to develop towards blastocyst stage might be affected by the kinetic of the embryo development. Moreover, the results of this study indicated that the optimal stages of early embryo vitrification are post-embryonic block. PMID- 22929416 TI - The importance of teaching and learning moments. PMID- 22929417 TI - Lengthening residency training and the need for debt relief. PMID- 22929419 TI - Reimagining the behavioral and social sciences in medical education. PMID- 22929422 TI - Easier said than done. PMID- 22929424 TI - Commentary: our heads touch: telling and listening to stories of self. AB - This commentary reflects on the first decade of the Teaching and Learning Moments (TLM) feature of Academic Medicine. The author places the feature within the context of a growing movement within health care to improve reflective practice through the practice of reflective writing and reading. As an example of the opportunity these reflective activities afford, the author depicts a seminar in which students and faculty from four health sciences schools learn together about culture, illness, and health care. The participants find that their own capacity to examine and write about aspects of their own lived experience contributes to their understanding of patients. The seminar has been a meaningful adventure for these students and clinicians, as the TLM feature has been for its authors and readers. Meeting on the grounds of stories of patients and of themselves, readers and writers demonstrate for themselves how their source of commitment to health is to be found very deep within the self. As a dividend, these moments of teaching and learning provide what is needed to become members of effective health care teams. PMID- 22929425 TI - Commentary: two kinds of intelligence. AB - This commentary is a celebration of the 10th anniversary of the Academic Medicine feature Teaching and Learning Moments. The authors reflect that the moments highlighted in these columns are everyday moments in every medical school, in every residency program, in every clinic, in every hospital. These moments become extraordinary and personally transformative only when we pay attention. The invitation to honor these moments and value our subjective experiences is an invitation to integrity, to unite "soul" and "role." Yet the power of these narratives is not truly unleashed until they are discussed in community. In conversation, these personal narratives or "stories of self" have the potential to find common cause with the stories of others and become "stories of us." Through conversation that is rooted in a particular time and place, these stories of self and stories of us are linked to a "story of now." And these public narratives have the power to catalyze movements for change. PMID- 22929426 TI - Commentary: educating the present and future health care workforce to provide care to populations. AB - The crisis of the rising cost of health care in the United States is stimulating major changes in the way care is being delivered. New models such as patient centered medical homes and accountable care organizations are being developed with the expectation that health care professionals will address and improve the health of populations. Electronic health records and interprofessional teams will be critical to achieving the goal of better health. It is now time to bring together educators and clinicians at academic health centers, public health educators and practitioners, along with researchers, representatives from the health care delivery and financing systems, and community partners to reengineer health professions education to prepare health professions students for the health care system of the future. PMID- 22929428 TI - Medicine and the arts. Annie John: [excerpt] by Jamaica Kincaid. Commentary. PMID- 22929430 TI - Physicianship amongst physicians-in-training. PMID- 22929431 TI - The global health curriculum of Weill Cornell Medical College: how one school developed a global health program. AB - Since 2009, a multidisciplinary team at Weill Cornell Medical College (WCMC) has collaborated to create a comprehensive, elective global health curriculum (GHC) for medical students. Increasing student interest sparked the development of this program, which has grown from ad hoc lectures and dispersed international electives into a comprehensive four-year elective pathway with over 100 hours of training, including three courses, two international experiences, a preceptorship with a clinician working with underserved populations in New York City, and regular lectures and seminars by visiting global health leaders. Student and administrative enthusiasm has been strong: In academic years 2009, 2010, and 2011, over half of the first-year students (173 of 311)participated in some aspect of the GHC, and 18% (55 of 311) completed all first-year program requirements.The authors cite the student-driven nature of GHC as a major factor in its success and rapid growth. Also important was the foundation previously established by WCMC global health faculty, the serendipitous timing of the GHC's development in the midst of curricular reform and review, as well as the presence of a full-time, nonclinical Global Health Fellow who served as a program coordinator. Given the enormous expansion of medical student interest in global health training throughout the United States and Canada over the past decade, the authors hope that medical schools developing similar programs will find the experience at Weill Cornell informative and helpful. PMID- 22929432 TI - AM last page: Hospice and Palliative Medicine (HPM). PMID- 22929433 TI - Tumour morphology of early-onset breast cancers predicts breast cancer risk for first-degree relatives: the Australian Breast Cancer Family Registry. AB - INTRODUCTION: We hypothesised that breast cancer risk for relatives of women with early-onset breast cancer could be predicted by tumour morphological features. METHODS: We studied female first-degree relatives of a population-based sample of 452 index cases with a first primary invasive breast cancer diagnosed before the age of 40 years. For the index cases, a standardised tumour morphology review had been conducted for all; estrogen (ER) and progesterone receptor (PR) status was available for 401 (89%), and 77 (17%) had a high-risk mutation in a breast cancer susceptibility gene or methylation of the BRCA1 promoter region in peripheral blood DNA. We calculated standardised incidence ratios (SIR) by comparing the number of mothers and sisters with breast cancer with the number expected based on Australian incidence rates specific for age and year of birth. RESULTS: Using Cox proportional hazards modelling, absence of extensive sclerosis, extensive intraductal carcinoma, absence of acinar and glandular growth patterns, and the presence of trabecular and lobular growth patterns were independent predictors with between a 1.8- and 3.1-fold increased risk for relatives (all P <0.02). Excluding index cases with known genetic predisposition or BRCA1 promoter methylation, absence of extensive sclerosis, circumscribed growth, extensive intraductal carcinoma and lobular growth pattern were independent predictors with between a 2.0- and 3.3-fold increased risk for relatives (all P <0.02). Relatives of the 128 (34%) index cases with none of these four features were at population risk (SIR = 1.03, 95% CI = 0.57 to 1.85) while relatives of the 37 (10%) index cases with two or more features were at high risk (SIR = 5.18, 95% CI = 3.22 to 8.33). CONCLUSIONS: This wide variation in risks for relatives based on tumour characteristics could be of clinical value, help discover new breast cancer susceptibility genes and be an advance on the current clinical practice of using ER and PR as pathology-based predictors of familial and possibly genetic risks. PMID- 22929434 TI - Impact of a population based intervention to increase the adoption of multiple physical activity practices in centre based childcare services: a quasi experimental, effectiveness study. AB - BACKGROUND: There is considerable scope to improve the delivery of practices that increase the physical activity of children in centre based childcare services. Few studies have reported the effectiveness of interventions to address this, particularly at a population level. The primary aim of this study was to describe the impact of an intervention to increase the adoption of multiple policies and practices to promote physical activity in centre based childcare services. METHODS: A quasi experimental study was conducted in centre based childcare services (n =228) in New South Wales (NSW), Australia and involved a three month intervention to increase the adoption of eight practices within childcare services that have been suggested to promote child physical activity. Intervention strategies to support the adoption of practices included staff training, resources, incentives, follow-up support and performance monitoring and feedback. Randomly selected childcare services in the remainder of NSW acted as a comparison group (n = 164) and did not receive the intervention but may have been exposed to a concurrent NSW government healthy eating and physical activity initiative. Self reported information on physical activity policies, fundamental movement skills sessions, structured physical activity opportunities, staff involvement in active play and provision of verbal prompts to encourage physical activity, small screen recreation opportunities, sedentary time, and staff trained in physical activity were collected by telephone survey with childcare service managers at baseline and 18 months later. RESULTS: Compared with the comparison area, the study found significantly greater increases in the prevalence of intervention services with a written physical activity policy, with policy referring to placing limits on small screen recreation, and with staff trained in physical activity. In addition, non-significant trends towards a greater increase in the proportion of intervention services conducting daily fundamental movement skill sessions, and such services having a physical activity policy supporting physical activity training for staff were also evident. CONCLUSION: The intervention was effective in improving a number of centre based childcare service policies and practices associated with promoting child physical activity. Adoption of a broader range of practices may require more intensive and prolonged intervention support. PMID- 22929435 TI - Link Between and Comparison and Combination of Zhang Neural Network and Quasi Newton BFGS Method for Time-Varying Quadratic Minimization. AB - Since 2001, a novel type of recurrent neural network called Zhang neural network (ZNN) has been proposed, investigated, and exploited for solving online time varying problems in a variety of scientific and engineering fields. In this paper, three discrete-time ZNN models are first proposed to solve the problem of time-varying quadratic minimization (TVQM). Such discrete-time ZNN models exploit methodologically the time derivatives of time-varying coefficients and the inverse of the time-varying coefficient matrix. To eliminate explicit matrix inversion operation, the quasi-Newton BFGS method is introduced, which approximates effectively the inverse of the Hessian matrix; thus, three discrete time ZNN models combined with the quasi-Newton BFGS method (named ZNN-BFGS) are proposed and investigated for TVQM. In addition, according to the criterion of whether the time-derivative information of time-varying coefficients is explicitly known/used or not, these proposed discrete-time models are classified into three categories: 1) models with time-derivative information known (i.e., ZNN-K and ZNN-BFGS-K models), 2) models with time-derivative information unknown (i.e., ZNN-U and ZNN-BFGS-U models), and 3) simplified models without using time derivative information (i.e., ZNN-S and ZNN-BFGS-S models). The well-known gradient-based neural network is also developed to handle TVQM for comparison with the proposed ZNN and ZNN-BFGS models. Illustrative examples are provided and analyzed to substantiate the efficacy of these proposed models for TVQM. PMID- 22929436 TI - Automated core-penumbra quantification in neonatal ischemic brain injury. AB - Neonatal hypoxic-ischemic brain injury (HII) and arterial ischemic stroke (AIS) result in irreversibly injured (core) and salvageable (penumbral) tissue regions. Identification and reliable quantification of salvageable tissue is pivotal to any effective and safe intervention. Magnetic resonance imaging (MRI) is the current standard to distinguish core from penumbra using diffusion-perfusion mismatch (DPM). However, subtle MR signal variations between core-penumbral regions make their visual delineation difficult. We hypothesized that computational analysis of MRI data provides a more accurate assessment of core and penumbral tissue evolution in HII/AIS. We used two neonatal rat-pup models of HII/AIS (unilateral and global hypoxic-ischemia) and clinical data sets from neonates with AIS to test our noninvasive, automated computational approach, Hierarchical Region Splitting (HRS), to detect and quantify ischemic core penumbra using only a single MRI modality (T2- or diffusion-weighted imaging, T2WI/DWI). We also validated our approach by comparing core-penumbral images (from HRS) to DPM with immunohistochemical validation of HII tissues. Our translational and clinical data results showed that HRS could accurately and reliably distinguish the ischemic core from penumbra and their spatiotemporal evolution, which may aid in the vetting and execution of effective therapeutic interventions as well as patient selection. PMID- 22929437 TI - Glucagon-like peptide-1 decreases intracerebral glucose content by activating hexokinase and changing glucose clearance during hyperglycemia. AB - Type 2 diabetes and hyperglycemia with the resulting increase of glucose concentrations in the brain impair the outcome of ischemic stroke, and may increase the risk of developing Alzheimer's disease (AD). Reports indicate that glucagon-like peptide-1 (GLP-1) may be neuroprotective in models of AD and stroke: Although the mechanism is unclear, glucose homeostasis appears to be important. We conducted a randomized, double-blinded, placebo-controlled crossover study in nine healthy males. Positron emission tomography was used to determine the effect of GLP-1 on cerebral glucose transport and metabolism during a hyperglycemic clamp with (18)fluoro-deoxy-glucose as tracer. Glucagon-like peptide-1 lowered brain glucose (P=0.023) in all regions. The cerebral metabolic rate for glucose was increased everywhere (P=0.039) but not to the same extent in all regions (P=0.022). The unidirectional glucose transfer across the blood-brain barrier remained unchanged (P=0.099) in all regions, while the unidirectional clearance and the phosphorylation rate increased (P=0.013 and 0.017), leading to increased net clearance of the glucose tracer (P=0.006). We show that GLP-1 plays a role in a regulatory mechanism involved in the actions of GLUT1 and glucose metabolism: GLP-1 ensures less fluctuation of brain glucose levels in response to alterations in plasma glucose, which may prove to be neuroprotective during hyperglycemia. PMID- 22929438 TI - Statins and cerebral hemodynamics. AB - HMG-CoA reductase inhibitors (statins) are associated with improved stroke outcome. This observation has been attributed in part to the palliative effect of statins on cerebral hemodynamics and cerebral autoregulation (CA), which are mediated mainly through the upregulation of endothelium nitric oxide synthase (eNOS). Several animal studies indicate that statin pretreatment enhances cerebral blood flow after ischemic stroke, although this finding is not further supported in clinical settings. Cerebral vasomotor reactivity, however, is significantly improved after long-term statin administration in most patients with severe small vessel disease, aneurysmal subarachnoid hemorrhage, or impaired baseline CA. PMID- 22929439 TI - Energy demand of synaptic transmission at the hippocampal Schaffer-collateral synapse. AB - Neuroenergetic models of synaptic transmission predicted that energy demand is highest for action potentials (APs) and postsynaptic ion fluxes, whereas the presynaptic contribution is rather small. Here, we addressed the question of energy consumption at Schaffer-collateral synapses. We monitored stimulus-induced changes in extracellular potassium, sodium, and calcium concentration while recording partial oxygen pressure (pO(2)) and NAD(P)H fluorescence. Blockade of postsynaptic receptors reduced ion fluxes as well as pO(2) and NAD(P)H transients by ~50%. Additional blockade of transmitter release further reduced Na(+), K(+), and pO(2) transients by ~30% without altering presynaptic APs, indicating considerable contribution of Ca(2+)-removal, transmitter and vesicle turnover to energy consumption. PMID- 22929440 TI - alphaCaMKII is differentially regulated in brain regions that exhibit differing sensitivities to ischemia and excitotoxicity. AB - Different brain regions exhibit differing sensitivities to ischemia/excitotoxicity. Whether these differences are due to perfusion or intrinsic factors has not been established. Herein, we found no apparent association between sensitivity to ischemia/excitotoxicity and the level of expression or basal phosphorylation of calcium/calmodulin-stimulated protein kinase II (alphaCaMKII) or glutamate receptors. However, we demonstrated significant differences in CaMKII-mediated responses after ischemia/excitotoxic stimulation in striatum and cortex. In vivo ischemia and in vitro excitotoxic stimulation produced more rapid phosphorylation of Thr253-alphaCaMKII in striatum compared with cortex, but equal rates of Thr286-alphaCaMKII phosphorylation. Phosphorylation by CaMKII of Ser831-GluA1 and Ser1303-GluN2B occurred more rapidly in striatum than in cortex after either stimulus. The differences between brain regions in CaMKII activation and its effects were not accounted for by differences in the expression of alphaCaMKII, glutamate receptors, or density of synapses. These results implicate intrinsic tissue differences in Thr253 alphaCaMKII phosphorylation in the differential sensitivities of brain regions to ischemia/excitotoxicity. PMID- 22929441 TI - In-vivo measurement of LDOPA uptake, dopamine reserve and turnover in the rat brain using [18F]FDOPA PET. AB - Longitudinal measurements of dopamine (DA) uptake and turnover in transgenic rodents may be critical when developing disease-modifying therapies for Parkinson's disease (PD). We demonstrate methodology for such measurements using [(18)F]fluoro-3,4-dihydroxyphenyl-L-alanine ([(18)F]FDOPA) positron emission tomography (PET). The method was applied to 6-hydroxydopamine lesioned rats, providing the first PET-derived estimates of DA turnover for this species. Control (n=4) and unilaterally lesioned (n=11) rats were imaged multiple times. Kinetic modeling was performed using extended Patlak, incorporating a k(loss) term for metabolite washout, and modified Logan methods. Dopaminergic terminal loss was measured via [(11)C]-(+)-dihydrotetrabenazine (DTBZ) PET. Clear striatal [(18)F]FDOPA uptake was observed. In the lesioned striatum the effective DA turnover increased, shown by a reduced effective distribution volume ratio (EDVR) for [(18)F]FDOPA. Effective distribution volume ratio correlated (r>0.9) with the [(11)C]DTBZ binding potential (BP(ND)). The uptake and trapping rate (k(ref)) decreased after lesioning, but relatively less so than [(11)C]DTBZ BP(ND). For normal controls, striatal estimates were k(ref)=0.037+/-0.005 per minute, EDVR=1.07+/-0.22 and k(loss)=0.024+/-0.003 per minute (30 minutes turnover half time), with repeatability (coefficient of variation) <=11%. [(18)F]fluoro-3,4 dihydroxyphenyl-L-alanine PET enables measurements of DA turnover in the rat, which is useful for developing novel therapies for PD. PMID- 22929443 TI - Anomalous diffusion of brain metabolites evidenced by diffusion-weighted magnetic resonance spectroscopy in vivo. AB - Translational displacement of molecules within cells is a key process in cellular biology. Molecular motion potentially depends on many factors, including active transport, cytosol viscosity and molecular crowding, tortuosity resulting from cytoskeleton and organelles, and restriction barriers. However, the relative contribution of these factors to molecular motion in the cytoplasm remains poorly understood. In this work, we designed an original diffusion-weighted magnetic resonance spectroscopy strategy to probe molecular motion at subcellular scales in vivo. This led to the first observation of anomalous diffusion, that is, dependence of the apparent diffusion coefficient (ADC) on the diffusion time, for endogenous intracellular metabolites in the brain. The observed increase of the ADC at short diffusion time yields evidence that metabolite motion is characteristic of hindered random diffusion rather than active transport, for time scales up to the dozen milliseconds. Armed with this knowledge, data modeling based on geometrically constrained diffusion was performed. Results suggest that metabolite diffusion occurs in a low-viscosity cytosol hindered by ~2-MUm structures, which is consistent with known intracellular organization. PMID- 22929445 TI - The ophthalmology surgical competency assessment rubric for strabismus surgery. AB - PURPOSE: To produce an internationally valid tool to assess skill in performing strabismus surgery. METHODS: A panel of 7 content experts adapted a previously published tool for assessing phacoemulsification by using a modified Dreyfus scale of skill acquisition and providing behavioral descriptors for each level of skill in each category. The tools were then reviewed by 12 international content experts for their constructive comments. The main outcome measure was a consensus of the experts on the final rubric. RESULTS: Experts' comments were incorporated, establishing face and content validity. CONCLUSIONS: The tool (Ophthalmology Surgical Competency Assessment Rubric for Strabismus Surgery (ICO-OSCAR: strabismus) has face and content validity. It can be used globally to assess strabismus surgical skill. Reliability and predictive validity are yet to be determined. PMID- 22929442 TI - Drug transport across the blood-brain barrier. AB - The blood-brain barrier (BBB) prevents the brain uptake of most pharmaceuticals. This property arises from the epithelial-like tight junctions within the brain capillary endothelium. The BBB is anatomically and functionally distinct from the blood-cerebrospinal fluid barrier at the choroid plexus. Certain small molecule drugs may cross the BBB via lipid-mediated free diffusion, providing the drug has a molecular weight <400 Da and forms <8 hydrogen bonds. These chemical properties are lacking in the majority of small molecule drugs, and all large molecule drugs. Nevertheless, drugs can be reengineered for BBB transport, based on the knowledge of the endogenous transport systems within the BBB. Small molecule drugs can be synthesized that access carrier-mediated transport (CMT) systems within the BBB. Large molecule drugs can be reengineered with molecular Trojan horse delivery systems to access receptor-mediated transport (RMT) systems within the BBB. Peptide and antisense radiopharmaceuticals are made brain-penetrating with the combined use of RMT-based delivery systems and avidin-biotin technology. Knowledge on the endogenous CMT and RMT systems expressed at the BBB enable new solutions to the problem of BBB drug transport. PMID- 22929446 TI - Oblique muscle surgery for treatment of nystagmus with head tilt. AB - BACKGROUND: Patients with nystagmus may adopt an abnormal head posture if they have a null zone in eccentric gaze. These patients uncommonly present with torticollis due to a null zone when the head is tilted. We describe the results of surgery on the oblique muscles to improve the abnormal head posture in this condition. METHODS: This was a retrospective review of patients who had head tilts due to null zones of nystagmus. Surgery consisted of an anterior 50% tenectomy of the superior oblique tendon on one side and recession of the inferior oblique muscle to a position 6 mm posterior to the insertion of the inferior rectus muscle on the contralateral side. The patients' clinical histories and outcomes were reviewed. RESULTS: Six patients underwent the procedure. Of these, four had infantile nystagmus syndrome and two were born prematurely and had histories of intraventricular hemorrhages. Five of the patients had previous Kestenbaum surgery that corrected the horizontal component of their abnormal head postures. Age at time of surgery for the head tilt ranged from 3 to 13 years. Postoperative follow-up ranged from 1.5 to 3 years. The preoperative head tilts ranged from 25 degrees to 45 degrees (mean, 39 degrees ). The postoperative improvement ranged from 20 degrees to 40 degrees (mean, 28 degrees ). One of the patients with a history of intraventricular hemorrhage required additional surgery for strabismus unrelated to nystagmus. CONCLUSIONS: Anterior tenectomy of the superior oblique tendon combined with contralateral recession of the inferior oblique muscle improved head tilts related to a null zone of nystagmus. PMID- 22929447 TI - Mini-plication to treat small-angle strabismus: A minimally invasive procedure. AB - BACKGROUND: Mini-plication is a new rectus muscle tightening procedure for the correction of small-angle strabismus that can be performed under topical anesthesia. The purpose of this study was to report the outcomes of mini-rectus muscle plication. METHODS: We retrospectively reviewed the medical records of patients who underwent mini-plication. In this procedure, 6-0 polyglactin 910 suture was secured to the central 3 to 4 mm of the muscle belly 5 mm posterior to the insertion and was then passed through the sclera just anterior to the muscle insertion to plicate the central portion of the muscle. This differs from the standard procedure, in which the entire width of the muscle is plicated. Two groups were analyzed: those who underwent mini-plication alone and those who underwent mini-plication after prior antagonist muscle-weakening surgery. RESULTS: Our review identified nine patients aged 5 to 78 years. Topical anesthesia was used for all adults, who experienced no local or systemic complications. Mini-plication reduced vertical and horizontal deviations an average (+/- SD) of 6.7(Delta) +/- 3.5(Delta). The mini-plication-only group (3 patients) had an average postoperative correction of 5.5(Delta) +/- 2.6(Delta); the prior surgery group (6 patients), an average of 9(Delta) +/- 2.7(Delta). Diplopia was noted in 50% of the adults preoperatively and none postoperatively. All patients experienced a decrease in strabismus, with an average outcome of <5(Delta) of postoperative deviation. CONCLUSIONS: Mini-plication, which can be performed under topical anesthesia, corrected small deviations and was especially useful for adult strabismus patients with diplopia. PMID- 22929448 TI - Augmented Hummelsheim procedure to treat complete abducens nerve palsy. AB - BACKGROUND: Horizontal strabismus due to a weak rectus muscle can be treated with an augmented Hummelsheim procedure, in which both vertical rectus muscle tendons are split, resected by 4 mm, and reattached to the sclera adjacent to the weak rectus muscle. Compared with vertical rectus transposition, the procedure spares two ciliary vessels and does not require placement of augmentation sutures. In this study, we evaluated binocular alignment and ocular motility in patients with abducens nerve palsy treated with an augmented Hummelsheim procedure. METHODS: The medical records of consecutive patients with complete abducens nerve palsy who underwent the augmented Hummelsheim procedure, usually combined with medial rectus muscle recession, were retrospectively reviewed. Binocular alignment, ocular motility, and complications were analyzed. RESULTS: Ten patients (age range, 12-57 years) met inclusion criteria for the study, of whom 9 of 10 had simultaneous medial rectus recession. Follow-up ranged from 1 week to 24 months. The augmented Hummelsheim procedure improved esotropia from 43(Delta) +/- 5(Delta) preoperatively to 6(Delta) +/- 7(Delta) postoperatively (P < 0.0001) and reduced abduction deficits from -4 to -3 (P < 0.0001). One patient with coexisting oculomotor nerve palsy developed consecutive exotropia; 2 had induced vertical deviations. There were no cases of anterior segment ischemia. CONCLUSIONS: The augmented Hummelsheim procedure combined with medial rectus muscle recession reduced mean primary position esotropia and improved abduction in patients with complete abducens nerve palsy. PMID- 22929449 TI - The efficacy of superior oblique Z-tenotomy in the treatment of overdepression in adduction (superior oblique overaction). AB - INTRODUCTION: To evaluate the efficacy of superior oblique Z-tenotomy in the treatment of overdepression in adduction (superior oblique overaction) with respect to collapse of A-pattern strabismus and normalization of versions. METHODS: The medical records of patients who underwent bilateral superior oblique Z-tenotomy for mild to moderate overdepression in adduction and A-pattern strabismus between June 2004 and August 2010 were retrospectively reviewed. Surgical indications included mild to moderate overdepression in adduction (+2 to 3) and an A pattern of 10(Delta) to 40(Delta) between upgaze and downgaze. A monopolar electrode microdissection needle was used to make two tenotomies, 60% to 80% in width and 8 mm apart, perpendicular to the axes of the tendon in opposite directions. Surgical success included a postoperative A pattern of <=10(Delta) and overdepression in adduction of <=1. RESULTS: A total of 20 patients (mean age, 9.8 years; age range, 3-34) underwent bilateral superior oblique Z-tenotomy during the study period: 2 patients (10%) with esotropia and 18 with exotropia (90%). Average decrease in pattern was 16(Delta) (range, 0(Delta)-32.5(Delta)). Success rate for pattern collapse was 78%, with resolution of overdepression in adduction of 90%. CONCLUSIONS: Z-tenotomy of the superior oblique tendon collapsed A-pattern strabismus and normalized versions. PMID- 22929450 TI - Effects of sequential injections of hepatocyte growth factor and insulin-like growth factor-I on adult rabbit extraocular muscle. AB - PURPOSE: To determine whether hepatocyte growth factor (HGF) and insulin-like growth factor-I (IGF-I) have synergistic effects in promoting extraocular muscle fiber growth and force generation. METHODS: A superior rectus muscle of adult rabbits was treated with either a single injection of HGF or sequential injections of HGF followed 1 week later by IGF-I. One week after HGF alone and 1 week after the IGF-I injection, the superior rectus muscles from treated and control orbits were examined for alterations in force generation as well as changes in myofiber size. RESULTS: Injection of HGF alone did not result in changes to muscle force, specific tension, or myofiber cross-sectional area; however, it did result in a significant increase in numbers of satellite cells. Sequential injection of HGF and IGF-I resulted in significantly increased force, specific tension, and myofiber cross-sectional areas as well as increased numbers of satellite cells. CONCLUSIONS: Preinjection with HGF augments the treatment effect of IGF-I. This synergistic effect is likely a result of HGF-induced activation of satellite cells and should allow a reduction in IGF-I dosing required to produce a given increase in extraocular muscle force generation. PMID- 22929451 TI - A randomized controlled trial to determine the lowest effective dose for adequate mydriasis in premature infants. AB - PURPOSE: To compare the mydriatic efficacy of different numbers of eye drops for retinal examination of premature infants. METHODS: This pilot study enrolled preterm infants born at <32 weeks' gestational age who were scheduled for retinopathy of prematurity screening examinations. In all study group assignments, the right (treatment reference group) eye received 3 eye drops per current neonatal intensive care unit protocol, whereas the left (test) eye was randomized at each examination to receive either: 0, 1, or 2 drops. Pupils were dilated with the use of a cyclopentolate 0.2% and phenylephrine 1% ophthalmic solution. Pupil size (in mm) was measured by a single examiner at 0 (baseline), 45, 90, and 120 minutes after instillation. Retinal examination occurred at the first opportunity to adequately visualize the peripheral retina. Comparison of the means was calculated using paired t test, t test, or analysis of variance, as appropriate. RESULTS: A total of 64 eye examinations were performed on 15 enrolled infants (mean gestational age, 28.7 +/- 2.6 weeks, 53% white; 40% male). No significant differences existed in mean pupil size between the 1-, 2- and 3 drop groups at baseline, 90 minutes, and 120 minutes. All 1-drop group eyes could be examined by 90 minutes. The 0-drop group maintained baseline size. CONCLUSIONS: Effective mydriasis was achieved in the test eye with 1 or 2 drops and was sustained to 120 minutes. Therefore, retinal examinations could be completed by 90 minutes in most infants with the use of 1 drop. A larger study is needed to determine the effect of iris color and severity of ROP on these findings. PMID- 22929452 TI - Ocular manifestations of cobalamin C type methylmalonic aciduria with homocystinuria. AB - PURPOSE: To report the ocular complications of cobalamin-C type methylmalonic aciduria with homocystinuria (cblC) in a large consecutive series of patients. METHODS: Medical records of patients with genetically diagnosed cblC disease from Mount Sinai Medical Center, New York, and Hopital Necker, Paris, France, were reviewed. All patients with the diagnosis of cblC seen after January 2008 at Mount Sinai and January 1998 at Hopital Necker were included. RESULTS: A total of 9 cases are reported. Age at initial ocular examination ranged from 3.5 months to 10 years of age. All 9 patients had early-onset disease, with manifestation of disease presenting prior to 1 year of age. Two patients had definitive optic nerve pallor. All patients had retinal findings ranging from peripheral pigmentary retinal changes to central macular atrophy with Bull's eye lesions. Optical coherence tomography was performed on one child and showed retinal thinning in the area of the bull's eye lesions. Electroretinography was performed in 6 of the 9 patients, three of whom showed decreased scotopic and photopic responses. The other three patients had normal responses on electroretinography. CONCLUSIONS: Ocular findings in patients with cblC are variable. All patients in the study exhibited early-onset disease and had noteworthy ophthalmic findings. To the best of our knowledge, this is the first study in the literature correlating optical coherence tomography findings with fundus findings in cblC. PMID- 22929453 TI - Visual acuity outcomes in pediatric glaucomas. AB - PURPOSE: To evaluate and compare the visual acuity prognosis in the various pediatric glaucoma subtypes and to determine risk factors for vision loss. METHODS: The medical records of pediatric glaucoma patients from 2000 to 2010 at Children's Hospital of Philadelphia were retrospectively reviewed. Visual acuities, surgeries, glaucoma subtype, and etiology of vision impairment were recorded. Univariate and multivariate analyses were performed to determine the risk factors for visual impairment. RESULTS: A total of 133 eyes (36.8% primary congenital glaucoma, 28.6% aphakic glaucoma, 12.0% glaucoma associated with anterior segment dysgenesis, 12.0% Sturge-Weber glaucoma) of 88 patients were included. At last follow-up (median length, 5 years), 46.6% eyes achieved excellent (>=20/70) visual acuity. Of the glaucoma subtypes, primary congenital glaucoma conferred the best visual prognosis, with 69.4% eyes with excellent (>=20/70) visual acuity at final follow-up. Factors most associated with visual impairment (<20/200) were unilateral disease, multiple surgeries, poor vision at diagnosis, and other ocular comorbidities. The most common primary etiology for vision impairment was amblyopia (54.9%). CONCLUSIONS: Patients with glaucoma early in life appear to have a better visual acuity prognosis than previously reported, with those with primary congenital glaucoma faring better than other glaucoma subtypes. Recognition of risk factors for visual impairment can better guide clinical management and counseling of patients. PMID- 22929454 TI - Asymptomatic atrophy of the temporal median raphe of the retina associated with cerebral vasculopathy in homozygous sickle cell disease. AB - A 13-year-old girl with homozygous sickle cell disease was referred for vision loss in her left eye of 1 year's duration. Clinical findings were consistent with a past retinal arterial occlusion. In the asymptomatic right eye, spectral domain optical coherence tomography showed a severe atrophy of the inner retinal layers of the temporal median raphe; a significant internal carotid stenosis was also present. We hypothesize that specific atrophy of the retinal temporal median raphe resulted from chronic ischemia. The inner layers of the retina are vascularized by terminal vessels and the median raphe can therefore be regarded as a junction territory; its atrophy may represent an ocular equivalent of a silent border zone cerebral infarct. PMID- 22929455 TI - Quantitative characterization of growth rate of an incidental deep dermoid cyst in a child using sequential magnetic resonance imaging. AB - When orbital lesions are discovered incidentally, some have advocated observation given the slow-growing nature of deep dermoids; however, little has been published regarding the true growth potential of these tumors. We describe a case of an incidental deep orbital dermoid cyst in a 7.5-month-old girl with retinoblastoma. The cyst was monitored with five sequential magnetic resonance imaging studies of the orbit over 23 months with careful documentation of growth. The cyst was surgically removed without complication, and histopathology confirmed the diagnosis of dermoid cyst. This case represents the first published quantitative measurement of dermoid growth potential and highlights the need for close early monitoring in incidentally discovered cases. PMID- 22929456 TI - Chronic myeloid leukemia presenting with bilateral central retinal vein occlusion and massive retinal infiltrates. AB - Visual impairment as the initial symptom of leukemia, especially chronic myeloid leukemia, is rare, occurring in approximately 3% of all leukemias in children. We describe the case of a 14-year-old boy with vision loss attributable to bilateral central retinal vein occlusion and massive retinal infiltrates. Bone marrow biopsy demonstrated the BCR-ABL translocation, and the patient was diagnosed with chronic myeloid leukemia. A major cytogenetic remission was achieved 6 months after initiation of therapy. PMID- 22929457 TI - Bilateral maculopathy associated with Pierre Robin sequence. AB - Pierre Robin sequence has been associated with a number of ocular complications, including myopia, strabismus, Mobius syndrome, nasolacrimal duct obstruction, glaucoma, cataract, microphthalmos, coloboma of choroid, and retinal detachment. We report a 10-day-old boy who presented with micrognathia, glossoptosis, and cleft palate as well as multiple congenital anomalies. Ophthalmic examination was notable for bilateral maculopathy, with focal areas of retinal and retinal pigment epithelial atrophy. The association of Pierre Robin sequence and maculopathy has been reported only twice previously. PMID- 22929458 TI - Scaling-up from an implementation trial to state-wide coverage: results from the preliminary Melbourne Diabetes Prevention Study. AB - BACKGROUND: The successful Greater Green Triangle Diabetes Prevention Program (GGT DPP), a small implementation trial, has been scaled-up to the Victorian state-wide 'Life!' programme with over 10,000 individuals enrolled. The Melbourne Diabetes Prevention Study (MDPS) is an evaluation of the translation from the GGT DPP to the Life! programme. We report results from the preliminary phase (pMDPS) of this evaluation. METHODS: The pMDPS is a randomised controlled trial with 92 individuals aged 50 to 75 at high risk of developing type 2 diabetes randomised to Life! or usual care. Intervention consisted of six structured 90-minute group sessions: five fortnightly sessions and the final session at 8 months. Participants underwent anthropometric and laboratory tests at baseline and 12 months, and provided self-reported psychosocial, dietary, and physical activity measures. Intervention group participants additionally underwent these tests at 3 months. Paired t tests were used to analyse within-group changes over time. Chi square tests were used to analyse differences between groups in goals met at 12 months. Differences between groups for changes over time were tested with generalised estimating equations and analysis of covariance. RESULTS: Intervention participants significantly improved at 12 months in mean body mass index (-0.98 kg/m(2), standard error (SE) = 0.26), weight (-2.65 kg, SE = 0.72), waist circumference (-7.45 cm, SE = 1.15), and systolic blood pressure (-3.18 mmHg, SE = 1.26), increased high-density lipoprotein-cholesterol (0.07 mmol/l, SE = 0.03), reduced energy from total (-2.00%, SE = 0.78) and saturated fat (-1.54%, SE = 0.41), and increased fibre intake (1.98 g/1,000 kcal energy, SE = 0.47). In controls, oral glucose at 2 hours deteriorated (0.59 mmol/l, SE = 0.27). Only waist circumference reduced significantly (-4.02 cm, SE = 0.95).Intervention participants significantly outperformed controls over 12 months for body mass index and fibre intake. After baseline adjustment, they also showed greater weight loss and reduced saturated fat versus total energy intake.At least 5% weight loss was achieved by 32% of intervention participants versus 0% controls. CONCLUSIONS: pMDPS results indicate that scaling-up from implementation trial to state-wide programme is possible. The system design for Life! was fit for purpose of scaling-up from efficacy to effectiveness. TRIAL REGISTRATION: Australian and New Zealand Clinical Trials Registry ACTRN12609000507280. PMID- 22929460 TI - No reason to expect "reading universals". AB - Writing systems encode linguistic information in diverse ways, relying on cognitive procedures that are likely to be general purpose rather than specific to reading. Optimality in reading for meaning is achieved via the entire communicative act, involving, when the need arises, syntax, nonlinguistic context, and selective attention. PMID- 22929461 TI - Optical tracking-based model surgery for orthognathic surgical planning using a quantifying evaluation method. AB - Traditional cephalometry with a cast-mounted articulator is a useful and well established tool for orthognathic surgery 7 planning. However, 2-D planning with dental casts cannot provide 8 comprehensive information on facial bone conditions, especially 9 with regards to symmetry. To plan and predict postsurgical facial 10 symmetry and occlusions, this paper uses an optical navigation system to track the movement of the upper and lower dental models 12 in model surgery. The corresponding movement and the new position of the jawbones are demonstrated in the computer and the 14 symmetry status can be evaluated. Surgical splints can be fabricated from the virtual models and used in surgery. The procedure 16 provides more realistic predictions, which can assist surgeons to 17 better control postsurgical facial harmony. PMID- 22929459 TI - Variation in apoptosis mechanisms employed by malaria parasites: the roles of inducers, dose dependence and parasite stages. AB - BACKGROUND: Plasmodium berghei ookinetes exhibit an apoptotic phenotype when developing within the mosquito midgut lumen or when cultured in vitro. Markers of apoptosis increase when they are exposed to nitric oxide or reactive oxygen species but high concentrations of hydrogen peroxide cause death without observable signs of apoptosis. Chloroquine and other drugs have been used to induce apoptosis in erythrocytic stages of Plasmodium falciparum and to formulate a putative pathway involving cysteine protease activation and mitochondrial membrane permeabilization; initiated, at least in the case of chloroquine, after its accumulation in the digestive vacuole causes leakage of the vacuole contents. The lack of a digestive vacuole in ookinetes prompted the investigation of the effect of chloroquine and staurosporine on this stage of the life cycle. Finally, the suggestion that apoptosis may have evolved as a strategy employed by ookinetes to increase the fitness of surviving parasites was explored by determining whether increasing the ecological triggers parasite density and nutrient depletion induced apoptosis. METHODS: Ookinetes were grown in culture then either exposed to hydrogen peroxide, chloroquine or staurosporine, or incubated at different densities and in different media. The proportion of ookinetes displaying positive markers for apoptosis in treated samples was compared with controls and results were analyzed using analysis of variance followed by a Turkey's test, or a Kruskal-Wallis test as appropriate. RESULTS: Hydrogen peroxide below 50 MUM triggered apoptosis but cell membranes were rapidly compromised by higher concentrations, and the mode of death could not be defined. Both chloroquine and staurosporine cause a significant increase in ookinetes with condensed chromatin, caspase-like activity and, in the case of chloroquine, phosphatidylserine translocation and DNA fragmentation (not investigated for staurosporine). However, mitochondrial membrane potential remained intact. No relationship between ookinete density and apoptosis was detected but nutrient depletion significantly increased the proportion of ookinetes with chromatin condensation in four hours. CONCLUSIONS: It is proposed that both a mitochondrial and an amitochondrial apoptotic pathway may be involved, dependent upon the trigger that induces apoptosis, and that pathways may differ between erythrocytic stages and ookinetes, or between rodent and human malaria parasites. PMID- 22929462 TI - QT variability index changes with severity of cardiovascular autonomic neuropathy. AB - Cardiovascular autonomic neuropathy (CAN) has been frequently postulated to increase susceptibility to ventricular arrhythmias and sudden cardiac death in diabetic patients. The relation between the progression of CAN in diabetes and ventricular repolarization remains to be fully described. Therefore, this study examined QT interval variability and heart rate interbeat variability to identify any alterations of cardiac repolarization in diabetic patients in relation to severity of CAN. Seventy control participants without (CAN-) and 74 patients with CAN (CAN+) were enrolled in this study. Among 74 CAN + patients, 62 are early CAN + (eCAN +) , and 12 are definite CAN + (dCAN +) according to autonomic nervous system function tests as described by Ewing. The results showed that the QT variability index (QTVI) was significantly higher and positive in the dCAN + (0.51 +/-1.32) group than in the eCAN + (-0.39 +/-0.91) and CAN - (-0.54 +/ 0.72) groups. The QT variability to heart-rate variability ratio provides a measure of the balance between QT and heart interbeat variability. QTVI was more sensitive in identifying disease progression at all stages. Our study supports the hypothesis that QTVI could be used as a clinical test to identify early CAN and as a marker of CAN progression in diabetic patients and may help physicians in determining the best therapeutic strategy for these patients. PMID- 22929463 TI - Knowledge discovery in medical systems using differential diagnosis, LAMSTAR & k NN. AB - Medical data is an ever-growing source of information generated from the hospitals in the form of patient records. When mined properly the information hidden in these records is a huge resource bank for medical research. As of now, this data is mostly used only for clinical work. This data often contains hidden patterns and relationships, that can lead to better diagnosis, better medicines, better treatment and overall, a platform to better understand the mechanisms governing almost all aspects of the medical domain. Unfortunately, discovery of these hidden patterns and relationships often goes unexploited. However there is on-going research in medical diagnosis which can predict the diseases of the heart, lungs and various tumours based on the past data collected from the patients.They are mostly limited to domain specific systems that predict diseases restricted to their area of operation like heart, brain and various other domains. These are not applicable to the whole medical dataset. The system proposed in this paper uses this vast storage of information so that diagnosis based on this historical data can be made. It focuses on computing the probability of occurrence of a particular ailment from the medical data by mining it using a unique algorithm which increases accuracy of such diagnosis by combining the key points of Neural Networks, Large Memory Storage and Retrieval (LAMSTAR), k-NN and Differential Diagnosis all integrated into one single algorithm. The system uses a Service-Oriented Architecture wherein the system components of diagnosis, information portal and other miscellaneous services are provided.This algorithm can be used in solving a few common problems that are encountered in automated diagnosis these days, which include: diagnosis of multiple diseases showing similar symptoms, diagnosis of a person suffering from multiple diseases, receiving faster and more accurate second opinion and faster identification of trends present in the medical records. PMID- 22929464 TI - A service-oriented distributed semantic mediator: integrating multiscale biomedical information. AB - Biomedical research continuously generates large amounts of heterogeneous and multimodal data spread over multiple data sources. These data, if appropriately shared and exploited, could dramatically improve the research practice itself, and ultimately the quality of health care delivered. This paper presents DISMED (DIstributed Semantic MEDiator), an open source semantic mediator that provides a unified view of a federated environment of multiscale biomedical data sources. DISMED is a Web-based software application to query and retrieve information distributed over a set of registered data sources, using semantic technologies. It also offers a userfriendly interface specifically designed to simplify the usage of these technologies by non-expert users. Although the architecture of the software mediator is generic and domain independent, in the context of this paper, DISMED has been evaluated for managing biomedical environments and facilitating research with respect to the handling of scientific data distributed in multiple heterogeneous data sources. As part of this contribution, a quantitative evaluation framework has been developed. It consist of a benchmarking scenario and the definition of five realistic use-cases. This framework, created entirely with public datasets, has been used to compare the performance of DISMED against other available mediators. It is also available to the scientific community in order to evaluate progress in the domain of semantic mediation, in a systematic and comparable manner. The results show an average improvement in the execution time by DISMED of 55% compared to the second best alternative in four out of the five use-cases of the experimental evaluation. PMID- 22929465 TI - Christopher S. Potten, 1940-2012. PMID- 22929466 TI - The MCART Consortium animal models series. AB - The single, overarching goal of the National Institute of Allergy and Infectious Diseases (NIAID)-sponsored Consortium, Medical Countermeasures Against Radiological Threats (MCART), is the development of medical countermeasures (MCM) to treat the key sequelae of the acute radiation syndrome (ARS) and the delayed effects of acute radiation exposure (DEARE). In addition, a parallel goal is to evaluate the toxicity and efficacy of decorporating agents that will reduce the whole-body burden of internalized radionuclides. MCM must be developed within the criteria of the U.S. Food and Drug Administration's (FDA) "animal rule" (AR) and the subsequent Guidance document for animal models that addresses essential elements to demonstrate efficacy under the animal rule; .The FDA AR underscores the requisite design and conduct of validated animal models as paramount in defining the regulatory pathway to licensure of MCM to treat personnel exposed to potentially lethal doses of radiation that define the major sequelae of the ARS and DEARE. PMID- 22929467 TI - Establishing a murine model of the hematopoietic syndrome of the acute radiation syndrome. AB - The authors have developed a murine model of the Hematopoietic Syndrome of the Acute Radiation Syndrome (H-ARS) for efficacy testing of medical countermeasures (MCM) against radiation according to the FDA Animal Rule. Ten- to 12-wk-old male and female C57BL/6 mice were exposed to the LD50/30-LD70/30 dose of total body irradiation (TBI, (137)Cs, 0.62-0.67 Gy min(-1)) in the morning hours when mice were determined to be most radiosensitive, and they were assessed for 30-d survival and mean survival time (MST). Antibiotics were delivered in drinking water on days 4-30 post-TBI at a concentration based on the amount of water that lethally-irradiated mice were found to consume. The fluoroquinolones, ciprofloxacin and levofloxacin, as well as the tetracycline doxycycline, and aminoglycoside neomycin, all significantly increased MST of decedent mice, while ciprofloxacin (p = 0.061) and doxycycline + neomycin (p = 0.005) showed at least some efficacy to increase 30-d survival. Blood sampling (30 MUL/mouse every fifth day) was found to negatively impact 30-d survival. Histopathology of tissues harvested from nonmoribund mice showed expected effects of lethal irradiation, while moribund mice were largely septicemic with a preponderance of enteric organisms. Kinetics of loss and recovery of peripheral blood cells in untreated mice and those treated with two MCM, granulocyte-colony stimulating factor and Amifostine further characterized and validated this model for use in screening studies and pivotal efficacy studies of candidate MCM for licensure to treat irradiated individuals suffering from H-ARS. PMID- 22929468 TI - Long-term hematopoietic stem cell damage in a murine model of the hematopoietic syndrome of the acute radiation syndrome. AB - Residual bone marrow damage (RBMD) persists for years following exposure to radiation and is believed to be due to decreased self-renewal potential of radiation-damaged hematopoietic stem cells (HSC). Current literature has examined primarily sublethal doses of radiation and time points within a few months of exposure. In this study, the authors examined RBMD in mice surviving lethal doses of total body ionizing irradiation (TBI) in a murine model of the Hematopoietic Syndrome of the Acute Radiation Syndrome (H-ARS). Survivors were analyzed at various time points up to 19 mo post-TBI for hematopoietic function. The competitive bone marrow (BM) repopulating potential of 150 purified c-Kit+ Sca-1+ lineage- CD150+ cells (KSLCD150+) remained severely deficient throughout the study compared to KSLCD150+ cells from non-TBI age-matched controls. The minimal engraftment from these TBI HSCs is predominantly myeloid, with minimal production of lymphocytes both in vitro and in vivo. All classes of blood cells as well as BM cellularity were significantly decreased in TBI mice, especially at later time points as mice aged. Primitive BM hematopoietic cells (KSLCD150+) displayed significantly increased cell cycling in TBI mice at all time points, which may be a physiological attempt to maintain HSC numbers in the post-irradiation state. Taken together, these data suggest that the increased cycling among primitive hematopoietic cells in survivors of lethal radiation may contribute to long-term HSC exhaustion and subsequent RBMD, exacerbated by the added insult of aging at later time points. PMID- 22929469 TI - A nonhuman primate model of the hematopoietic acute radiation syndrome plus medical management. AB - The development of medical countermeasures against the hematopoietic subsyndrome of the acute radiation syndrome requires well characterized and validated animal models. The model must define the radiation dose- and time-dependent relationships for mortality and major signs of morbidity to include other organ damage that may contribute to morbidity and mortality. Herein, the authors define these parameters for a nonhuman primate exposed to total body radiation and administered medical management. A blinded, randomized study (n = 48 rhesus macaques) determined the lethal dose-response relationship using bilateral 6 MV linear accelerator photon radiation to doses in the range of 7.20 to 8.90 Gy at 0.80 Gy min(-1). Following irradiation, animals were monitored for complete bloodcounts, body weight, temperature, diarrhea, and hydration status for 60 d. Animals were administered medical management consisting of intravenous fluids, prophylactic antibiotics, blood transfusions, anti-diarrheals, analgesics, and nutrition. The primary endpoint was survival at 60 d post-irradiation; secondary endpoints included hematopoietic-related parameters, number of transfusions, incidence of documented infection, febrile neutropenia, severity of diarrhea, mean survival time of decedents, and tissue histology. The study defined an LD30/60 of 7.06 Gy, LD50/60 of 7.52 Gy, and an LD70/60 of 7.99 Gy with a relatively steep slope of 1.13 probits per linear dose. This study establishes a rhesus macaque model of the hematopoietic acute radiation syndrome and shows the marked effect of medical management on increased survival and overall mean survival time for decedents. Furthermore, following a nuclear terrorist event, medical management may be the only treatment administered at its optimal schedule. PMID- 22929470 TI - The acute gastrointestinal subsyndrome of the acute radiation syndrome: a rhesus macaque model. AB - The development of medical countermeasures against the acute gastrointestinal subsyndrome of the acute radiation syndrome in humans requires well characterized and validated animal models. These models must adhere to the criteria of the U.S. Food and Drug Administration's Animal Rule and consider the natural history and clinical context of the human radiation response and treatment in the nuclear terrorist scenario. The models must define the radiation dose- and time-dependent relationships for mortality and major signs of morbidity, including concurrent damage in other organs, such as the bone marrow, that may contribute to the overall mortality and morbidity. There are no such models of the gastrointestinal syndrome in response to total-body irradiation in the nonhuman primate. Herein, these parameters are defined for the rhesus macaque exposed to potentially lethal doses of radiation and administered medical management. Rhesus macaques (n = 69) were exposed bilaterally to 6 MV linear accelerator-derived photon total body irradiation to midline tissue (thorax) doses ranging from 10.0 to 14.0 Gy at 0.80 Gy min(-1). Following irradiation, all animals were administered supportive care consisting of fluids, anti-emetics, anti-diarrheal medication, antibiotics, blood transfusions, analgesics, and nutrition. The primary endpoint was survival at 15 d post-irradiation. Secondary endpoints included indices of dehydration, diarrhea, weight loss, hematological parameters, cellular histology of the small and large intestine, and mean survival time of decedents. Mortality within the 15 d in vivo study defined the acute gastrointestinal syndrome and provided an LD30/15 of 10.76 Gy, LD50/15 of 11.33 Gy, and an LD70/15 of 11.90 Gy. Intestinal crypt and villus loss were dose- and time-dependent with an apparent nadir 7 d post-irradiation and recovery noted thereafter. Severe myelosuppression and thrombocytopenia were noted in all animals, requiring the administration of antibiotics and blood transfusions. The model defines the dose response relationship and time course of acute gastrointestinal syndrome-induced morbidity and mortality in the rhesus macaque. PMID- 22929472 TI - A preclinical rodent model of radiation-induced lung injury for medical countermeasure screening in accordance with the FDA animal rule. AB - The purpose of preclinical murine model development is to establish that the pathophysiological outcome of the rodent model of radiation-induced lung injury is sufficiently representative of the anticipated pulmonary response in the human population. This objective is based on concerns that the C57BL/6J strain may not be the most appropriate preclinical model of lethal radiation lung injury in humans. In this study, the authors assessed this issue by evaluating the relationship between morbidity (pulmonary function, histopathologic damage) and mortality among three strains of mice: C57BL/6J, CBA/J, and C57L/J. These different strains display variations in latency and phenotypic expression of radiation-induced lung damage. By comparing the response of each strain to the human pulmonary response, an appropriate animal model(s) of human radiation induced pulmonary injury was established. Observations in the C57L/J and CBA/J murine models can be extrapolated to the human lung for evaluation of the mechanisms of action of radiation as well as future efficacy testing and approving agents that fall under the "Animal Rule" of the U.S. Food and Drug Administration (FDA) (21 CFR Parts 314 and 601). PMID- 22929473 TI - Biokinetics of systemically distributed 60Co in the rat: an experimental model useful in evaluating medical countermeasures for internal contamination. AB - LBERI, a member of the Medical Countermeasures to Radiologic Threats (MCART) consortium funded by NIAID, was tasked to develop biokinetic models for the distribution of radionuclide threats using the most likely routes of incorporation in both small and large animals. In this paper, the biokinetics of systemically administered soluble (60)Co have been examined. Male and female jugular-vein-catheterized (JVC) F344 rats received intravenous (IV) doses of 11.2 kBq of (60)CoCl2. The distribution of the radiocobalt was followed for 28 d with tissue sampling done at 1 and 4 h, and at 1, 2, 4, 8, 16, and 28 d. Urine and feces were collected daily. Tissues and excreta were analyzed by gamma pulse height analysis. Within 8 d, 93% of the cobalt was eliminated from the body, primarily though urine. The highest tissue burdens were found in the liver, gastrointestinal (GI) tract, and muscle shortly after administration. These tissues cleared quickly, so that by the conclusion of the 28-d study, less than 3% of the injected dose remained in the body. The results are comparable to published literature values for tissue content of (60)Co and for excretion patterns up to 30 d after injection. These results will provide the data needed to construct a biokinetic model for the unperturbed biokinetics of (60)Co in rats, which will subsequently be used to evaluate the impact of administered decorporating agents on organ radiation doses. The animal model described in this paper is representative of that used for other routes of radionuclide administration, such as inhalation, ingestion, and wound contamination, that have been studied at LBERI in support of the MCART and NIAID programs. PMID- 22929474 TI - Software for empirical building of biokinetic models for normal and decorporation affected data. AB - This paper describes software ("RATDOSE") developed to analyze data from animal experiments investigating the efficacy of chelating agents. An empirical model building approach is used where, starting from the simplest model structures, one minimizes chi(2) by varying transfer rates in the model. Model complexity is increased as needed until the minimum attained value of chi(2) per data point decreases to about 1. This approach requires careful treatment of data uncertainties and independent checks of data self-consistency. The biokinetic models can include second-order kinetics to describe the chelation chemical reaction. The radiation dose to the animal is also calculated using S quantities specific for the animal, although the tissue weighting factors used to calculate the effective dose are those for the human. PMID- 22929471 TI - The prolonged gastrointestinal syndrome in rhesus macaques: the relationship between gastrointestinal, hematopoietic, and delayed multi-organ sequelae following acute, potentially lethal, partial-body irradiation. AB - The dose response relationship for the acute gastrointestinal syndrome following total-body irradiation prevents analysis of the full recovery and damage to the gastrointestinal system, since all animals succumb to the subsequent 100% lethal hematopoietic syndrome. A partial-body irradiation model with 5% bone marrow sparing was established to investigate the prolonged effects of high-dose radiation on the gastrointestinal system, as well as the concomitant hematopoietic syndrome and other multi-organ injury including the lung. Herein, cellular and clinical parameters link acute and delayed coincident sequelae to radiation dose and time course post-exposure. Male rhesus Macaca mulatta were exposed to partial-body irradiation with 5% bone marrow (tibiae, ankles, feet) sparing using 6 MV linear accelerator photons at a dose rate of 0.80 Gy min(-1) to midline tissue (thorax) doses in the exposure range of 9.0 to 12.5 Gy. Following irradiation, all animals were monitored for multiple organ-specific parameters for 180 d. Animals were administered medical management including administration of intravenous fluids, antiemetics, prophylactic antibiotics, blood transfusions, antidiarrheals, supplemental nutrition, and analgesics. The primary endpoint was survival at 15, 60, or 180 d post-exposure. Secondary endpoints included evaluation of dehydration, diarrhea, hematologic parameters, respiratory distress, histology of small and large intestine, lung radiographs, and mean survival time of decedents. Dose- and time-dependent mortality defined several organ-specific sequelae, with LD50/15 of 11.95 Gy, LD50/60 of 11.01 Gy, and LD50/180 of 9.73 Gy for respective acute gastrointestinal, combined hematopoietic and gastrointestinal, and multi-organ delayed injury to include the lung. This model allows analysis of concomitant multi-organ sequelae, thus providing a link between acute and delayed radiation effects. Specific and multi organ medical countermeasures can be assessed for efficacy and interaction during the concomitant evolution of acute and delayed key organ-specific subsyndromes. PMID- 22929476 TI - Health Physics Society prospectus. PMID- 22929478 TI - Eigenspace-based minimum variance beamformer combined with Wiener postfilter for medical ultrasound imaging. AB - In this paper, a new beamformer which combines the eigenspace-based minimum variance (ESBMV) beamformer with the Wiener postfilter is proposed for medical ultrasound imaging. The primary goal of this work is to further improve the medical ultrasound imaging quality on the basis of the ESBMV beamformer. In this method, we optimize the ESBMV weights with a Wiener postfilter. With the optimization of the Wiener postfilter, the output power of the new beamformer becomes closer to the actual signal power at the imaging point than the ESBMV beamformer. Different from the ordinary Wiener postfilter, the output signal and noise power needed in calculating the Wiener postfilter are estimated respectively by the orthogonal signal subspace and noise subspace constructed from the eigenstructure of the sample covariance matrix. We demonstrate the performance of the new beamformer when resolving point scatterers and cyst phantom using both simulated data and experimental data and compare it with the delay-and-sum (DAS), the minimum variance (MV) and the ESBMV beamformer. We use the full width at half maximum (FWHM) and the peak-side-lobe level (PSL) to quantify the performance of imaging resolution and the contrast ratio (CR) to quantify the performance of imaging contrast. The FWHM of the new beamformer is only 15%, 50% and 50% of those of the DAS, MV and ESBMV beamformer, while the PSL is 127.2dB, 115dB and 60dB lower. What is more, an improvement of 239.8%, 232.5% and 32.9% in CR using simulated data and an improvement of 814%, 1410.7% and 86.7% in CR using experimental data are achieved compared to the DAS, MV and ESBMV beamformer respectively. In addition, the effect of the sound speed error is investigated by artificially overestimating the speed used in calculating the propagation delay and the results show that the new beamformer provides better robustness against the sound speed errors. Therefore, the proposed beamformer offers a better performance than the DAS, MV and ESBMV beamformer, showing its potential in medical ultrasound imaging. PMID- 22929479 TI - Combining performance and outcome indicators can be used in a standardized way: a pilot study of two multidisciplinary, full-scale major aircraft exercises. AB - BACKGROUND: Disaster medicine is a fairly young scientific discipline and there is a need for the development of new methods for evaluation and research. This includes full-scale disaster exercisers. A standardized concept on how to evaluate these exercises, could lead to easier identification of pitfalls caused by system-errors in the organization. The aim of this study was to demonstrate the feasibility of using a combination of performance and outcome indicators so that results can be compared in standardized full-scale exercises. METHODS: Two multidisciplinary, full-scale exercises were studied in 2008 and 2010. The panorama had the same setup. Sets of performance indicators combined with indicators for unfavorable patient outcome were recorded in predesigned templates. Evaluators, all trained in a standardized way at a national disaster medicine centre, scored the results on predetermined locations; at the scene, at hospital and at the regional command and control. RESULTS: All data regarding the performance indicators of the participants during the exercises were obtained as well as all data regarding indicators for patient outcome. Both exercises could therefore be compared regarding performance (processes) as well as outcome indicators. The data from the performance indicators during the exercises showed higher scores for the prehospital command in the second exercise 15 points and 3 points respectively. Results from the outcome indicators, patient survival and patient complications, demonstrated a higher number of preventable deaths and a lower number of preventable complications in the exercise 2010. In the exercise 2008 the number of preventable deaths was lower and the number of preventable complications was higher. CONCLUSIONS: Standardized multidisciplinary, full-scale exercises in different settings can be conducted and evaluated with performance indicators combined with outcome indicators enabling results from exercises to be compared. If exercises are performed in a standardized way, results may serve as a basis for lessons learned. Future use of the same concept using the combination of performance indicators and patient outcome indicators may demonstrate new and important evidence that could lead to new and better knowledge that also may be applied during real incidents. PMID- 22929480 TI - Double-differential recording and AGC using microcontrolled variable gain ASIC. AB - Low-power wearable recording of biopotentials requires acquisition front-ends with high common-mode rejection for interference suppression and adjustable gain to provide an optimum signal range to a cascading analogue-to-digital stage. A microcontroller operated double-differential (DD) recording setup and automatic gain control circuit (AGC) are discussed which reject common-mode interference and provide tunable gain, thus compensating for imbalance and variation in electrode interface impedance. Custom-designed variable gain amplifiers (ASIC) are used as part of the recording setup. The circuit gain and balance is set by the timing of microcontroller generated clock signals. Measured results are presented which confirm that improved common-mode rejection is achieved compared to a single differential amplifier in the presence of input network imbalance. Practical measured examples further validate gain control suitable for biopotential recording and power-line rejection for wearable ECG and EMG recording. The prototype front-end consumes 318 MUW including amplifiers and microcontroller. PMID- 22929481 TI - Synthesis, identification, and antibacterial activity of new sulfonamide nanoparticles. AB - Nanoparticles of sulfonamide are prepared by the reaction of a benzenesulfonyl chloride with ammonia or an amine in acetonitrile solvent. The ultrasonic treatment was applied for preparation of nanoparticles. The produced sulfonamide nanoparticles were characterized by X-ray diffraction (XRD), infrared spectroscopy (IR), transmission electron microscope (TEM), scanning electron microscope (SEM), and other techniques. The antibacterial activities of sulfonamide nanoparticles derivatives tested against microorganism and compared with bulk forms (non-nano) conditions. The antibacterial activities of synthesized compounds were studied against two Gram-negative bacteria, Escherichia coli, Klebsiella pneumoniae, and two Gram-positive species, Staphylococcus aureus and Bacillus subtilis. These compounds antifungal activities have been studied against, Candida albicans, Aspergillus flavus, Aspergillus nigar. PMID- 22929482 TI - Remember why we went into this field in the first place... PMID- 22929483 TI - The etiology of pneumoperitoneum in the 21st century. AB - BACKGROUND: We sought to determine the origin of free intraperitoneal air in this era of diminishing prevalence of peptic ulcer disease and imaging studies. In addition, we attempted to stratify the origin of free air by the size of the air collection. METHODS: We queried our hospital database for "pneumoperitoneum" from 2005 to 2007 and for proven gastrointestinal perforation from 2000 to 2007. Massive amount of free air was defined as any air pocket greater than 10.0 cm. RESULTS: Among patients with free air, the predominant causes were perforated viscus (41%) and postoperative (<8 days) residual air (37%). For patients with visceral perforation, only 45% had free air on imaging studies, and for these patients, the predominant cause was peptic ulcer (16%), diverticulitis (16%), trauma (14%), malignancy (14%), bowel ischemia (10%), appendicitis (6%), and endoscopy (4%). The likelihood that free air was identified on an imaging study by lesion was 72% for perforated peptic ulcer, 57% for perforated diverticulitis, but only 8% for perforated appendicitis. The origin of massive free air was equally likely to be gastroduodenal, small bowel, or colonic perforation. CONCLUSION: The cause of free air when surgical pathology is the source has substantially changed from previous reports. LEVEL OF EVIDENCE: Epidemiologic study, level IV. PMID- 22929484 TI - Placement of intracranial pressure monitors by non-neurosurgeons: excellent outcomes can be achieved. AB - BACKGROUND: Traumatic brain injury remains one of the most prevalent and costly injuries encountered within the discipline of trauma and represents a leading cause of morbidity and mortality within our society. The purpose of this study was to compare the safety of intracranial pressure (ICP) monitor placement by general surgery residents and neurosurgeons. METHODS: A retrospective chart review of all trauma patients requiring ICP monitor placement at an American College of Surgeons-verified Level 1 trauma center during a 10-year period was performed. Comparison of demographic variables, injury severity, intracranial injuries, incidence of ICP monitor-related complications, and outcomes were made between general surgery residents, trauma surgeons, and neurosurgeons. RESULTS: There were 546 patients included in the study. The average age of the cohort was 37.6 years, with an average hospital length of stay being 16.0 days and an Injury Severity Score of 27.7. Mechanisms of injury varied, but 58.8% was a result of motor vehicle and motorcycle collisions, and an additional 19.2% was a result of falls. No significant difference was found in terms of procedure-related complications between subgroups, including intracranial hemorrhage, infection, malfunctions, dislodgment, or death. CONCLUSION: Our results demonstrate that the placement of ICP monitors may be performed safely by both neurosurgeons and non neurosurgeons. This procedure should thus be considered a core skill for trauma surgeons and surgical residents alike, thereby allowing initiation of prompt medical treatment in both rural areas and trauma centers with inadequate neurosurgeon or fellow coverage. LEVEL OF EVIDENCE: Therapeutic study, level IV. PMID- 22929485 TI - Pediatric trauma centers: correlation of ACS-verified trauma centers with CDC statewide pediatric mortality rates. AB - BACKGROUND: Research on the impact of pediatric trauma centers (PTCs) on mortality has been conflicting, most likely owing to differing methodologies. Using a population-based approach, we assessed whether American College of Surgeons (ACS)-verified trauma centers are associated with reduced overall state pediatric injury mortality rates. METHODS: A population-based study of state pediatric injury mortality rates (per 100,000 children <= 18 years) using data for 2008 from Centers for Disease Control and Prevention-National Center for Injury Prevention and Control. The availability of verified PTCs (vPTCs) and ACS verified adult trauma centers in each state was determined and compared with mortality rates using regression, adjusting for injury mortality covariates. Correlation of mortality with type of trauma centers available was determined. The mortality versus number of PTCs per pediatric population was also examined. RESULTS: vPTCs were present in 36% of states, including 24% of states with Level I vPTCs. The mean (SD) pediatric injury mortality for the 32 states without a vPTC was 20.6 (6.6) per 100,000 children 18 years or younger. Presence and higher verification level of vPTC within a state correlated with decreasing pediatric injury mortality (p(unadjusted)= 0.005; p(adjusted) = 0.004). Mortality was 37% lower among states with only Level I vPTCs (12.9 [2.2]). Mortality was inversely correlated with the number of Level I vPTCs (p(unadjusted) = 0.006; p(adjusted) = 0.06) and lowest for states with two Level I vPTCs (11.8 [1.7]). Higher ratios of Level I vPTCs per population correlated with lower mortality rates (beta = -3.53, p = 0.003). CONCLUSION: The findings highlight a correlation between state pediatric injury mortality rates and presence of ACS-verified Level I PTCs. LEVEL OF EVIDENCE: Prognostic study, level IV. PMID- 22929486 TI - Evidence-based guidelines are equivalent to a liberal computed tomography scan protocol for initial patient evaluation but are associated with decreased computed tomography scan use, cost, and radiation exposure. AB - BACKGROUND: We hypothesized that trauma patient evaluations using evidence-based treatment guidelines (evidence-based group [EBG]), which include serial examinations and limited computed tomography (CT) scans in an established trauma center, would be associated with equivalent outcomes but with decreased CT scan usage, decreased cost, and less radiation exposure compared with a liberal CT scan approach (conventional group [CONV]). METHODS: Fifteen evidence-based treatment guidelines were developed using published literature and in collaboration with other institutional departments. These were implemented on July 1, 2010. Prospectively collected data during a 4-month period were compared with a similar period in 2008 when CONV was used. RESULTS: In 2010 (EBG), there were 611 patients compared with 612 in 2008 (CONV). Their average Injury Severity Score was 11.93 versus 8.77 (p < 0.0001), and the total CT scans were 757 and 1194, respectively (p < 0.001). The average APACHE II and hospital length of stay did not significantly vary. No missed or delayed injuries were identified. Estimated CT scan charges were $1,842,534 versus $2,935,024. The average number of scans per patient were 1.2 (EBG) versus 1.9 (CONV). Regarding radiation dosimetry, the estimated average computed tomography dose index (CTDI) per patient were 36.7 versus 53.31 mGy, and the estimated average dose-length product per patient were 889.91 versus 1364.11 mGy.cm. CONCLUSION: EBG, including serial examinations, provided equivalent diagnostic data to CONV for initial workup but reduced CT scan usage, CT scan charges, and average radiation exposure per patient. This strategy may be beneficial in institutions where serial monitoring can be assiduously provided. LEVEL OF EVIDENCE: Case management study, level IV. PMID- 22929487 TI - "Blush" on trauma computed tomography: not as bad as we think! AB - INTRODUCTION: Intravenous contrast extravasation (IVCE) on a trauma computed tomography has been quoted as a reason for intervention (angiographic embolization or operation). The new-generation computed tomographic (CT) scanners identify IVCE with increasing frequency. We hypothesized that most IVCEs do not require an intervention. METHODS: This study was a retrospective evaluation of trauma patients with IVCE on abdomen or pelvis CT scan (January 2005-December 2009). Along with demographic and hemodynamic variables, the following characteristics of IVCE were examined as potential risk factors for intervention: maximal dimension, small (<= 1.5 cm) versus large (>1.5 cm), contained versus free, and single versus multiple and location. RESULTS: Sixty-nine patients with 81 IVCEs were identified: 48 IVCEs occurred in intra-abdominal solid organs, 18 IVCEs in the pelvic retroperitoneal space, and 15 IVCEs in the soft tissues or other locations. Thirty patients (43.5%) were managed without an intervention, and 39 patients (56.5%) required either an immediate (30 patients) or a delayed (9 patients) intervention. Multivariate analysis identified three independent predictors of an intervention: an admission systolic blood pressure of 100 mm Hg or lower, a large ICVE, and an Abbreviated Injury Score of the abdomen of 3 or higher. If all three independent predictors were present, 100% of patients received an intervention. CONCLUSION: Nearly half of IVCEs on CT scan did not require an intervention. A hypotension at admission, a severe abdominal trauma, and a blush diameter of 1.5 cm or greater predicted the need for intervention. LEVEL OF EVIDENCE: Therapeutic study, level IV; prognostic study, level III. PMID- 22929488 TI - Dead men tell no tales: analysis of the use of autopsy reports in trauma system performance improvement activities. AB - PURPOSE: To analyze the influence and use of autopsy report review on preventability judgments as part of trauma system performance improvement activities. METHODS: All cases trauma fatalities occurring across one state within 1 year were reviewed. Preventability judgments were first analyzed by multidisciplinary panel consensus without benefit of autopsy report. Deaths were then reanalyzed after the panel was provided with autopsy findings. Changes in panel determinations of preventability and cause of death were noted. RESULTS: A total of 434 cases were reviewed, autopsies were performed in 240 (55%) patients. Autopsy rate was 83% for prehospital deaths (PHDs) and 37% for hospital deaths (HDs). A complete examination (CA) was performed in 166 (69%) cases, and 74 (31%) cases were limited internal or external examinations only (NCA). Of autopsies performed on HD, 60% were CA versus 75% in PHD. Autopsy review changed preventability determination in four cases (1%). All changes were from nonpreventable to possibly preventable. For all patients with autopsy, the panel felt that the autopsy should have been of sufficient quality to analyze the cause of death in 83%. The autopsy was felt to actually establish a specific cause of death in 70% of all patients with autopsy, 71% in patients with NCA, and 74% in patients with CA. The autopsy changed the panel's preautopsy review-determination cause of death in 31% of all patients with autopsy (37% in the CA group; 13% in the NCA group). For PHD, autopsy changed the panel-determination cause of death in 44% and in 13% for HD. CONCLUSION: Review of autopsy reports adds little to the trauma performance improvement process. It does not significantly change death review panel determinations. It may, perhaps, be most useful in PHD. Ardent initiatives to expend resources on autopsy performance and acquisition of autopsy reports in all patients with trauma is unwarranted. PMID- 22929489 TI - Full-scale regional exercises: closing the gaps in disaster preparedness. AB - BACKGROUND: Man-made (9/11) and natural (Hurricane Katrina) disasters have enlightened the medical community regarding the importance of disaster preparedness. In response to Joint Commission requirements, medical centers should have established protocols in place to respond to such events. We examined a full-scale regional exercise (FSRE) to identify gaps in logistics and operations during a simulated mass casualty incident. METHODS: A multiagency, multijurisdictional, multidisciplinary exercise (FSRE) included 16 area hospitals and one American College of Surgeons-verified Level I trauma center (TC). The scenario simulated a train derailment and chemical spill 20 miles from the TC using 281 moulaged volunteers. Third-party contracted evaluators assessed each hospital in five areas: communications, command structure, decontamination, staffing, and patient tracking. Further analysis examined logistic and operational deficiencies. RESULTS: None of the 16 hospitals were compliant in all five areas. Mean hospital compliance was 1.9 (+/- 0.9 SD) areas. One hospital, unable to participate because of an air conditioner outage, was deemed 0% compliant. The most common deficiency was communications (15 of 16 hospitals [94%]; State Medical Asset Resource Tracking Tool system deficiencies, lack of working knowledge of Voice Interoperability Plan for Emergency Responders radio system) followed by deficient decontamination in 12 (75%). Other deficiencies included inadequate staffing based on predetermined protocols in 10 hospitals (63%), suboptimal command structure in 9 (56%), and patient tracking deficiencies in 5 (31%). An additional 11 operational and 5 logistic failures were identified. The TC showed an appropriate command structure but was deficient in four of five categories, with understaffing and a decontamination leak into the emergency department, which required diversion of 70 patients. CONCLUSION: Communication remains a significant gap in the mass casualty scenario 10 years after 9/11. Our findings demonstrate that tabletop exercises are inadequate to expose operational and logistic gaps in disaster response. FSREs should be routinely performed to adequately prepare for catastrophic events. PMID- 22929490 TI - Creation of an emergency surgery service concentrates resident training in general surgical procedures. AB - INTRODUCTION: Emergency general surgery (EGS) is increasingly being provided by academic trauma surgeons in an acute care surgery model. Our tertiary care hospital recently changed from a model where all staff surgeons (private, subspecialty academic, and trauma academic) were assigned EGS call to one in which an emergency surgery service (ESS), staffed by academic trauma faculty, cares for all EGS patients. In the previous model, many surgeries were "not covered" by residents because of work-hour restrictions, conflicting needs, or private surgeon preference. The ESS was separate from the trauma service. We hypothesize that by creating a separate ESS, residents can accumulate needed and concentrated operative experience in a well-supervised academic environment. METHODS: A prospectively accrued EGS database was retrospectively queried for the 18-month period: July 2010 to June 2011. The Accreditation Council for Graduate Medical Education (ACGME) databases were queried for operative numbers for our residency program and for national resident data for 2 years before and after creating the ESS. The ACGME operative requirements were tabulated from online sources. ACGME requirements were compared with surgical cases performed. RESULTS: During the 18-month period, 816 ESS operations were performed. Of these, 307 (38%) were laparoscopy. Laparoscopic cholecystectomy and appendectomy were most common (138 and 145, respectively) plus 24 additional laparoscopic surgeries. Each resident performed, on average, 34 basic laparoscopic cases during their 2 month rotation, which is 56% of their ACGME basic laparoscopic requirement. A diverse mixture of 70 other general surgical operations was recorded for the remaining 509 surgical cases, including reoperative surgery, complex laparoscopy, multispecialty procedures, and seldom-performed operations such as surgery for perforated ulcer disease. Before the ESS, the classes of 2008 and 2009 reported that only 48% and 50% of cases were performed at the main academic institution, respectively. This improved for the classes of 2010 and 2011 to 63% and 68%, respectively, after ESS creation. CONCLUSION: An ESS rotation is becoming essential in large teaching hospitals by helping to fulfill ACGME requirements and by providing emergent general surgical skills an efficient and well supervised academic environment. Movement toward concentrating EGS on a single service can enhance resident education and may decrease the need to supplement certain aspects of general surgery education with away rotations. PMID- 22929491 TI - Do we glow? Evaluation of trauma team work habits and radiation exposure. AB - BACKGROUND: Health care workers' potential exposure to ionizing radiation has increased. Annual radiation exposure limit for the general public per US Nuclear Regulatory Commission is 100 mrem (1 mSv). The whole-body annual occupational radiation exposure limit is 5,000 mrem (50 mSv). Studies have been done to evaluate patient radiation exposure. To date, there has been no study to evaluate the radiation exposure of trauma team members or evaluate their behaviors and attitudes. METHODS: Forty primary providers (residents, physician assistants) rotating on the trauma service at an American College of Surgeons Level 1 trauma center participated. Dosimeters were worn by participants, and the radiation doses were measured monthly. A survey detailing the frequency of involvement in radiographic studies, use of protective equipment, and knowledge of education programs was completed monthly. RESULTS: The range of radiation measured was 1 mrem to 56 mrem, with an average effective dose of 10 mrem per month. Thirty-two (80%) of 40 reported daily exposure to x-rays and 28 (70%) of 40 to computed tomographic scans. Thirty-four (85%) of 40 reported that they never or seldom wore lead apron in trauma bay as opposed to 1 (3%) of 40 who failed to wear it during fluoroscopy. Twenty (50%) reported that an apron was not available, while 20 (50%) reported that it was too hot or did not fit. Thirty-nine (97%) of 40 reported that they received training in radiation safety. CONCLUSION: Despite inconsistent use of protective equipment by resident staff, the actual radiation exposure remains low. Hospitals should be sure lead aprons and collars are available. Additional education concerning the availability of programs during pregnancy is needed. LEVEL OF EVIDENCE: Epidemiologic study, level III. PMID- 22929492 TI - Are general surgeons behind the curve when it comes to disaster preparedness training? A survey of general surgery and emergency medicine trainees in the United States by the Eastern Association for the Surgery for Trauma Committee on Disaster Preparedness. AB - PURPOSE: We think that general surgeons are underprepared to respond to mass casualty disasters. Preparedness education is required in emergency medicine (EM) residencies, yet such requirements are not mandated for general surgery (GS) training programs. We hypothesize that EM residents receive more training, consider themselves better prepared, and are more comfortable responding to disaster events than are GS residents. METHODS: From February to May 2009, the Eastern Association for the Surgery of Trauma-Committee on Disaster Preparedness conducted a Web-based survey cataloging training and preparedness levels in both GS and EM residents. Approximately 3000 surveys were sent. Chi-squared, logistic regression, and basic statistical analyses were performed with SAS. RESULTS: Eight hindered forty-eight responses were obtained, GS residents represented 60.6% of respondents with 39% EM residents, and four residents did not respond with their specialty (0.4%). We found significant disparities in formal training, perceived preparedness, and comfort levels between resident groups. Experience in real-life disaster response had a significant positive effect on comfort level in all injury categories in both groups (odds ratio, 1.3-4.3, p < 0.005). CONCLUSION: This survey confirms that EM residents have more disaster-related training than GS residents. The data suggest that for both groups, comfort and confidence in treating victims were not associated with training but seemed related to previous real-life disaster experience. Given wide variations in the relationship between training and comfort levels and the constraints imposed by the 80-hour workweek, it is critical that we identify and implement the most effective means of training for all residents. PMID- 22929493 TI - Is low-molecular-weight heparin safe for venous thromboembolism prophylaxis in patients with traumatic brain injury? A Western Trauma Association multicenter study. AB - BACKGROUND: Venous thromboembolism (VTE) is a significant risk in trauma patients. Although low-molecular weight heparin (LMWH) is effective in VTE prophylaxis, its use for patients with traumatic intracranial hemorrhage remains controversial. The purpose of this study was to evaluate the safety of LMWH for VTE prophylaxis in blunt intracranial injury. METHODS: We conducted a retrospective multicenter study of LMWH chemoprophylaxis on patients with intracranial hemorrhage caused by blunt trauma. Patients with brain Abbreviated Injury Scale score of 3 or higher, age 18 years or older, and at least one repeated head computed tomographic scan were included. Patients with previous VTE; on preinjury anticoagulation; hospitalized for less than 48 hours; on heparin for VTE prophylaxis; or required emergent thoracic, abdominal, or vascular surgery at admission were excluded. Patients were divided into two groups: those who received LMWH and those who did not. The primary outcome was progression of intracranial hemorrhage on repeated head computed tomographic scan. RESULTS: The study included 1,215 patients, of which 220 patients (18.1%) received LMWH and 995 (81.9%) did not. Hemorrhage progression occurred in 239 of 995 control subjects and 93 of 220 LMWH patients (24% vs. 42%, p < 0.001). Hemorrhage progression occurred in 32 patients after initiating LMWH (14.5%). Nine of these patients (4.1%) required neurosurgical intervention for hemorrhage progression. CONCLUSION: Patients receiving LMWH were at higher risk for hemorrhage progression. We were unable to demonstrate safety of LMWH for VTE prophylaxis in patients with brain injury. The risk of using LMWH may exceed its benefit. LEVEL OF EVIDENCE: Therapeutic study, level IV. PMID- 22929494 TI - Negative-pressure wound therapy for critically ill adults with open abdominal wounds: a systematic review. AB - BACKGROUND: Open abdominal management with negative-pressure wound therapy (NPWT) is increasingly used for critically ill trauma and surgery patients. We sought to determine the comparative efficacy and safety of NPWT versus alternate temporary abdominal closure (TAC) techniques in critically ill adults with open abdominal wounds. METHODS: We conducted a systematic review of published and unpublished comparative studies. We searched MEDLINE, PubMed, EMBASE, Scopus, Web of Science, the Cochrane Database, the Center for Reviews and Dissemination, clinical trials registries, and bibliographies of included articles. Two authors independently abstracted data on study design, methodological quality, patient characteristics, and outcomes. RESULTS: Among 2,715 citations identified, 2 randomized controlled trials and 9 cohort studies (3 prospective/6 retrospective) met inclusion criteria. Methodological quality of included prospective studies was moderate. One randomized controlled trial observed an improved fascial closure rate (relative risk [RR], 2.4; 95% confidence interval [CI], 1.0-5.3) and length of hospital stay after addition of retention sutured sequential fascial closure to the Kinetic Concepts Inc. (KCI) vacuum-assisted closure (VAC). Another reported a trend toward enhanced fascial closure using the KCI VAC versus Barker's vacuum pack (RR, 2.6; 95% CI, 0.95-7.1). A prospective cohort study observed improved mortality (RR, 0.48; 95% CI, 0.25-0.92) and fascial closure (RR, 1.5; 95% CI, 1.1 2.0) for patients who received the ABThera versus Barker's vacuum pack. Another noted a reduced arterial lactate, intra-abdominal pressure, and hospital stay for those fitted with the KCI VAC versus Bogota bag. Most included retrospective studies exhibited low methodological quality and reported no mortality or fascial closure benefit for NPWT. CONCLUSION: Limited prospective comparative data suggests that NPWT versus alternate TAC techniques may be linked with improved outcomes. However, the clinical heterogeneity and quality of available studies preclude definitive conclusions regarding the preferential use of NPWT over alternate TAC techniques. LEVEL OF EVIDENCE: Systematic review, level III. PMID- 22929495 TI - Ultraviolet C light for Acinetobacter baumannii wound infections in mice: potential use for battlefield wound decontamination? AB - BACKGROUND: Since the beginning of the conflicts in the Middle East, US Army physicians have noted a high rate of multidrug-resistant Acinetobacter baumannii infections among US soldiers wounded and initially treated in Iraq. In this study, we investigated the use of ultraviolet C (UVC) light for prevention of multidrug-resistant A. baumannii wound infections using mouse models. METHODS: Partial-thickness skin abrasions and full-thickness burns in mice were infected with a multidrug-resistant A. baumannii isolate recovered from a wounded US soldier deployed to Iraq. The luxCDABE operon, which was contained in plasmid pMF 385, was cloned into the A. baumannii strain. This allowed real-time monitoring of the extent of infection in mice using bioluminescence imaging. UVC light was delivered to the mouse wounds at 30 minutes after the inoculation of A. baumannii. Groups of infected mouse wounds without being exposed to UVC served as the controls. RESULTS: In vitro studies demonstrated that A. baumannii cells were inactivated at UVC exposures much lower than those needed for a similar effect on mammalian cells. It was observed in animal studies that UVC (3.24 J/cm(2) for abrasions and 2.59 J/cm(2) for burns) significantly reduced the bacterial burdens in UVC-treated wounds by approximately 10-fold compared with nontreated controls (p = 0.004 for abrasions, p = 0.019 for burns). DNA lesions were observed by immunofluorescence in mouse skin abrasions immediately after a UVC exposure of 3.24 J/cm(2); however, the lesions were extensively repaired within 72 hours. CONCLUSION: These results suggested that UVC may be useful in preventing combat related wound infections. PMID- 22929496 TI - Restrictive fluid resuscitation in combination with damage control resuscitation: time for adaptation. AB - BACKGROUND: Damage control resuscitation (DCR) conveys a survival advantage in patients with severe hemorrhage. The role of restrictive fluid resuscitation (RFR) when used in combination with DCR has not been elucidated. We hypothesize that RFR, when used with DCR, conveys an overall survival benefit for patients with severe hemorrhage. METHODS: This is a retrospective analysis from January 2007 to May 2011 at a Level I trauma center. Inclusion criteria included penetrating torso injuries, systolic blood pressure less than or equal to 90 mm Hg, and managed with DCR and damage control surgery (DCS). There were two groups according to the quantity of fluid before DCS: (1) standard fluid resuscitation (SFR) greater than or equal to 150 mL of crystalloid; (2) RFR less than 150 mL of crystalloid. Demographics and outcomes were analyzed. RESULTS: Three hundred seven patients were included. Before DCS, 132 (43%) received less than 150 mL of crystalloids, grouped under RFR; and 175 (57%) received greater than or equal to 150 mL of crystalloids, grouped under SFR. Demographics and initial clinical characteristics were similar between the study groups. Compared with the SFR group, RFR patients received less fluid preoperatively (129 mL vs. 2,757 mL; p < 0.001), exhibited a lower intraoperative mortality (9% vs. 32%; p < 0.001), and had a shorter hospital length of stay (13 vs. 18 days; p = 0.02). Patients in the SFR group had a lower trauma intensive care unit mortality (5 vs. 12%; p = 0.03) but exhibited a higher overall mortality. Patients receiving RFR demonstrated a survival benefit, with an odds ratio for mortality of 0.69 (95% confidence interval, 0.37-0.91). CONCLUSION: To the best of our knowledge, this is the first civilian study that analyzes the impact of RFR in patients managed with DCR. Its use in conjunction with DCR for hypotensive trauma patients with penetrating injuries to the torso conveys an overall and early intraoperative survival benefit. LEVEL OF EVIDENCE: Therapeutic study, level IV. PMID- 22929497 TI - A prospective evaluation of the use of routine repeat cranial CT scans in patients with intracranial hemorrhage and GCS score of 13 to 15. AB - BACKGROUND: Scheduled repeat head computed tomography after mild traumatic brain injury has been shown to have limited use for predicting the need for an intervention. We hypothesized that repeat computed tomography in persons with intracranial hemorrhage and a Glasgow Coma Scale (GCS) score of 13 to 15, without clinical progression of neurologic symptoms, does not impact the need for neurosurgical intervention or discharge GCS scores. METHODS: This prospective cohort study followed all patients presenting to our urban Level I trauma center with intracranial hemorrhage and a GCS score of 13 to 15 from February 2010 to December 2010. Subjects were divided into two groups: those in whom repeat CT scans were performed routinely (ROUTINE) and those in whom they were performed selectively (SELECTIVE) based on changes in clinical examination. CT scanning decisions were made at the discretion of the neurosurgical service attending physician. RESULTS: One hundred forty-five patients met the inclusion criteria (ROUTINE, n = 92; SELECTIVE, n = 53). Group demographics, including age, sex, and presenting GCS score were not significantly different. Of SELECTIVE patients, six (11%) required a repeat head computed tomography for a neurologic change, with one having a radiographic progression of hemorrhage (16%) versus 26 (28%) of 92 in the ROUTINE group showing a radiographic progression. No patient in either group required medical or neurosurgical intervention based on repeat scan. The number of CT scans performed differed between the two groups (three scans in ROUTINE vs. one scan in SELECTIVE, p < 0.001), as did the intensive care unit (2 days vs. 1 day, p < 0.001) and hospital (5 days vs. 2 days, p < 0.001) lengths of stay. Discharge GCS score was similar for both groups (15 vs. 15, p = 0.37). One death occurred in the SELECTIVE group, unrelated to intracranial findings. The negative predictive value of a repeat CT scan leading to neurosurgical intervention with no change in clinical examination was 100% for both groups. CONCLUSION: A practice of selective repeat head CT scans in patients with traumatic brain injury admitted with a GCS score of 13 to 15 decreases use of the test and is associated with decreased hospital length of stay, without impacting discharge GCS scores. LEVEL OF EVIDENCE: Diagnostic study, level II. PMID- 22929498 TI - Trauma caused by falling objects at construction sites. AB - BACKGROUND: Workplace-related injuries carry a significant health care challenge. The state of Qatar is developing rapidly, with much construction and an expanding industrial work force. This study aimed to assess the incidence and social impact of work-related injuries requiring hospitalization caused by falling objects at the construction sites. METHODS: We performed a prospective study for all admissions, which resulted from falling objects between January 2008 and June 2010 at the only trauma center in the state of Qatar. Data were analyzed, and outcomes were described (mortality, length of hospital stay, and safety measures). RESULTS: Of the total injured patients (N = 4,302) admitted between January 2008 and June 2010, 185 (4%) had injuries caused purely by falling objects. Patients' mean age was 29 years, and 97% of the patients were men. All injuries occurred at construction sites. Most patients (86%) were brought by ambulance, and the reminder was brought by private vehicles. After initial evaluation and resuscitation, 120 patients (65%) were found to have a single system injury, and 65 (35%) had multisystem injury. Operative interventions were required in 50% of the patients. Mean length of hospital stay varied from 6.5 days for single-system injuries to 19 days for multisystem injuries. Safety devices were used in 32 patients (17.3%). All of the 16 mortality cases (8.6%) were reported in multiple injuries. CONCLUSION: Traumatic injury caused by falling object represents a significant problem in a rapidly developing country. Many of these injuries could be prevented by following established safety guidelines. LEVEL OF EVIDENCE: Epidemiologic study, level III. PMID- 22929499 TI - Accuracy of prehospital diagnosis and triage of a Swiss helicopter emergency medical service. AB - BACKGROUND: Helicopter emergency medical services (HEMSs) have become a standard element of modern prehospital emergency medicine. This study determines the percentage of injured HEMS patients whose injuries were correctly recognized by HEMS physicians. METHODS: A retrospective level III evidence prognostic study using data from the largest Swiss HEMS, REGA (Rettungsflugwacht/Guarde Aerienne), on adult patients with trauma transported to a Level I trauma center (January 2006-December 2007). National Advisory Committee on Aeronautics (NACA) scores and the Injury Severity Score (ISS) were assessed to identify severely injured patients. Injured body regions diagnosed by REGA physicians were compared with emergency department discharge diagnoses. RESULTS: Four hundred thirty-three patients were analyzed. Median age was 42.1 years (interquartile range, 25.5 57.9). Three hundred twenty-three (74.6%) were men. Patients were severely injured, with an in-hospital NACA score of 4 or higher in 88.7% of patients and median ISS of 13. REGA physicians correctly recognized injuries to the head in 92.9%, to the femur in 90.5%, and to the tibia/fibula in 83.8% of patients. Injuries to these body regions were overdiagnosed in less than 30%. Abdominal injuries were missed in 56.1%, pelvic injuries in 51.8%, spinal injuries in 40.1%, and chest injuries in 31.2% of patients. CONCLUSION: This study shows that patients are adequately triaged by REGA physicians reflected by a NACA score 4 or higher in 88.7% of patients and a median ISS of 13. However, recognition of injured body regions seems to be challenging in the prehospital setting. Prospective studies on specific training of HEMS physicians for recognition of these injuries (e.g., portable ultrasonography, telemedicine) might help in the future. LEVEL OF EVIDENCE: Prognostic study, level III. PMID- 22929500 TI - The mortality risk from motor vehicle injuries in California has increased during the last decade. AB - BACKGROUND: Organized trauma systems and trauma centers are thought to improve trauma outcomes. It is clear that injured patients who receive care in trauma centers have survival advantages. However, large regions of California still do not have access to trauma centers. Many injured patients in California continue to receive their care in nontrauma center hospitals. The purpose of this study was to compare outcomes in California counties with and without trauma centers. In addition, we wished to query the efficacy of the current statewide trauma system by asking whether mortality after motor vehicle trauma in California has improved during the last decade. METHODS: We performed a retrospective outcome study. The California highway patrol provided data from all motor vehicle crashes (MVCs) and mortality during the years 1999 to 2008 for the 58 counties in California. Percent fatality was calculated as the number of motor vehicle fatalities divided by the number of injuries. Data were analyzed to compare outcomes in counties with and without trauma centers. Furthermore, demographic data were studied to analyze the relationship of population and hospital density on mortality. RESULTS: Mortality was significantly lower in counties with trauma centers. Low population and hospital density independently correlated with increased mortality. Injury mortality rates after MVCs increased during the decade both in counties with and without trauma centers. CONCLUSION: Overall, the presence of a trauma center improved the chances of survival after an MVC in California counties. However, mortality rates after injuries increased during the decade both in counties with and without trauma centers. Future efforts to improve outcomes for injured patients in California will require new approaches, which must include improving both access to trauma centers and the care provided in nontrauma center hospitals. LEVEL OF EVIDENCE: Epidemiologic study, level III. PMID- 22929501 TI - Pediatric penetrating trauma: the epidemic continues. AB - BACKGROUND: Pediatric penetrating injuries plague inner cities. Based on our clinical observations, we hypothesized that pediatric penetrating trauma (PPT) is increasing with the major increase occurring in communities with lower socioeconomic status. METHODS: We retrospectively reviewed the trauma databases between 2000 and 2009 of the three major trauma centers in Alameda and San Francisco counties. Patients with PPT aged 16 years or younger were included. Demographics, Injury Severity Score, probability of survival, and length of hospital stay were collected. Median family incomes (MFI) were obtained from US Census data. RESULTS: We identified 598 patients with PPT: 432 gunshot wounds (GSWs), 141 stabbings, and 25 other. The rate of PPT increased by 138% from 2000 to 2009 (p = 0.003). The mean (SEM) age of the patients was 13.8 (0.1) years, which did not change during the study period (p = 0.12). The incidence of single GSW to the head increased from 3% to 7% (p = 0.01) and carried a 63% mortality rate. Blacks and Hispanics sustained 82.5% of PPT. The MFI of PPT victims was $39,209. PPT was more prevalent in zip codes with an MFI below the Bay Area MFI of $68,954, (mean [SEM], 8.0 [1.5] victims per zip code below MFI vs. 1.9 [0.3] victims per zip code above MFI; p = < 0.001). CONCLUSION: PPT in the Bay Area increased during the last decade, and the increased PPT was associated with lower MFIs. Black and Hispanic children experienced the greatest proportion of penetrating injuries and had the lowest MFIs. The prevalence of single GSW to the head is increasing, which may suggest a deliberate attempt to fatally injure these children. LEVELS OF EVIDENCE: Prognostic study, level II. PMID- 22929502 TI - Effect of penetrating and blunt ocular trauma on the outcome of traumatic cataract in children in northern India. AB - BACKGROUND: We studied the demographic profile and outcome of traumatic cataract after penetrating and blunt ocular trauma in children in northern India. METHODS: We reviewed the medical records of children with penetrating and blunt ocular trauma associated with traumatic cataract who underwent cataract surgery with posterior chamber intraocular lens implantation and having more than 1 year follow up. We evaluated the demographic characteristics and visual outcome in the affected eye. RESULTS: Of the 100 children (100 eyes), 65 were penetrating trauma and 35 were blunt trauma. The common modes of injury in the penetrating group were wooden splinters in 30.8% and bow and arrow in 15.4%. Fire crackers and trauma during play with ball were seen in 34% and 11.4% of blunt eye trauma, respectively. The age ranged from 1 to 14 years (mean, 7.8 years) in the penetrating trauma and 2 to 15 years (mean, 8.3 years) in the blunt trauma group. The best corrected visual acuity of 20/40 or better was achieved in 57.6% eyes in penetrating group compared with 71.4% in the blunt trauma group. Visually significant posterior capsular opacification developed in 32.3% eyes in penetrating group and 28.6% eyes in blunt trauma group. Glaucoma was diagnosed in 4.6% eyes in penetrating group and 8.6% in blunt trauma group. CONCLUSION: Eye injuries with traumatic cataract are associated with significant visual impairment. There were more children with penetrating eye injuries as compared with blunt trauma. Cataract surgery with intraocular lens implantation is a preferred method for visual rehabilitation in these children. LEVEL OF EVIDENCE: Epidemiologic study, level IV. PMID- 22929503 TI - Computed tomography-based Three-Column Classification in tibial plateau fractures: introduction of its utility and assessment of its reproducibility. AB - BACKGROUND: The purpose of our study is to introduce a new Three-Column Classification for tibial plateau fractures and evaluate its reproducibility and reliability. METHODS: From December 2004 to December 2006, 278 consecutive patients with tibial plateau fractures were treated operatively at the Department of Orthopedics and Trauma III in Shanghai Sixth People's Hospital. Computed tomography (CT) and three-dimensional reconstruction were preformed for each patient before open reduction and internal fixation. The approaches were instructed by the Three-Column Classification. To test the reproducibility of the Three-Column Classification, the interobserver and intraobserver reliability of this classification system compared with that of the Schatzker Classification was investigated by four observers. RESULTS: Fourteen cases could not be classified by Schatzker Classification. Meanwhile, all cases could be classified by the Three-Column Classification. Using plain radiographs, the mean kappa values for interobserver reliability using Schatzker Classification systems were 0.567 (range, 0.513-0.589), representing "moderate agreement," whereas the mean kappa values were 0.766 (range, 0.706-0.890), representing "substantial agreement" by the use of the Three-Column Classification based on the CT scan. The mean kappa values for intraobserver reliability using Schatzker Classification and the Three Column Classification based on the CT scan were 0.758 (range, 0.691-0.854) and 0.810 (range, 0.745-0.918), respectively, representing "substantial agreement." CONCLUSION: The Three-Column Classification demonstrates a higher interobserver reliability and can be used as a supplement to the conventional Schatzker Classification, especially in the complex and posterior comminuted tibial plateau fractures. Furthermore, the Three-Column Classification is clinically relevant and, to some degree, can instruct the surgeon in preoperative planning. LEVEL OF EVIDENCE: Diagnostic study, level III. PMID- 22929505 TI - Advanced operative techniques in the management of complex liver injury. PMID- 22929506 TI - Overcoming challenges of endovascular treatment of complex subclavian and axillary artery injuries in hypotensive patients. PMID- 22929504 TI - Development of posttraumatic empyema in patients with retained hemothorax: results of a prospective, observational AAST study. AB - BACKGROUND: The natural history of retained hemothorax (RH), in particular factors contributing to the subsequent development of empyema, is not well known. The intent of our study was to establish the modern incidence of empyema among patients with trauma and RH and identify the independent predictors for development of this complication. METHODS: An American Association for the Surgery of Trauma multicenter prospective observational trial was conducted, enrolling patients with placement of a thoracostomy tube within 24 hours of trauma admission, and subsequent development of RH was confirmed on computed tomography of the chest. Demographics, interventions, and outcomes were analyzed. Logistic regression analysis was used to identify the independent predictors for the development of empyema. RESULTS: Among 328 patients with posttraumatic RH from the 20 participating centers, overall incidence of empyema was 26.8% (n = 88). On regression analysis, the presence of rib fractures (adjusted odds ratio [OR], 2.3; 95% confidence interval [CI], 1.3-4.1; p = 0.006), Injury Severity Score of 25 or higher (adjusted OR, 2.4; 95% CI, 1.3-4.4; p = 0.005), and the need for any additional therapeutic intervention (adjusted OR, 28.8; 95% CI, 6.6 125.5; p < 0.001) were found to be independent predictors for the development of empyema for patients with posttraumatic RH. Patients with empyema also had a significantly longer adjusted intensive care unit stay (adjusted mean difference, 4.1; 95% CI, 1.3-6.9; p = 0.008) and hospital stay (adjusted mean difference, 7.9; 95% CI, -12.7 to -3.2; p = 0.01). CONCLUSION: Among patients with trauma and posttraumatic RH, the incidence of empyema was 26.8%. Independent predictors of empyema development after posttraumatic RH included the presence of rib fractures, Injury Severity Score of 25 or higher, and the need for additional interventions to evacuate retained blood from the thorax. Our findings highlight the need to minimize the risk associated with subsequent thoracic procedures among patients with critical illness and RH, through selection of the most optimal procedure for initial evacuation. LEVEL OF EVIDENCE: Prognostic study, level III. PMID- 22929507 TI - Impact of prehospital mode of transport after severe injuries: reevaluation of results. PMID- 22929508 TI - Specificity of desaturation during air transport. PMID- 22929509 TI - Is bougie-aided cricothyrotomy really "extremely fast and safe" in the morbidly obese patient? PMID- 22929510 TI - Percutaneous tracheostomy: let's play it safe. PMID- 22929512 TI - Shock index: a simple clinical parameter for mortality risk assessment in trauma? PMID- 22929514 TI - Torso gunshot wounds: special considerations regarding asymptomatic gunshot related spinal injuries. PMID- 22929518 TI - Phono-morpho-orthographic construal: the view from spelling. AB - A spelling model which has evolved in the parallel universe of spelling research resonates with Frost's reading model. Like reading, spelling cannot be based solely on phonology or orthography, but should accommodate all linguistic facets. The cognitive domain of spelling does not take place at the level of single grapheme or phoneme or syllable, but rather, at the lexical level. PMID- 22929515 TI - Expression of HMGB1 and RAGE in rat and human brains after traumatic brain injury. PMID- 22929519 TI - Human neuroendocrine tumor cell lines as a three-dimensional model for the study of human neuroendocrine tumor therapy. AB - Neuroendocrine tumors (NETs) are rare tumors, with an incidence of two per 100, 000 individuals per year, and they account for 0.5% of all human malignancies. Other than surgery for the minority of patients who present with localized disease, there is little or no survival benefit of systemic therapy. Therefore, there is a great need to better understand the biology of NETs, and in particular define new therapeutic targets for patients with nonresectable or metastatic neuroendocrine tumors. 3D cell culture is becoming a popular method for drug screening due to its relevance in modeling the in vivo tumor tissue organization and microenvironment. The 3D multicellular spheroids could provide valuable information in a more timely and less expensive manner than directly proceeding from 2D cell culture experiments to animal (murine) models. To facilitate the discovery of new therapeutics for NET patients, we have developed an in vitro 3D multicellular spheroids model using the human NET cell lines. The NET cells are plated in a non-adhesive agarose-coated 24-well plate and incubated under physiological conditions (5% CO2, 37 degrees C) with a very slow agitation for 16-24 hr after plating. The cells form multicellular spheroids starting on the 3(rd) or 4(th) day. The spheroids become more spherical by the 6(th) day, at which point the drug treatments are initiated. The efficacy of the drug treatments on the NET spheroids is monitored based on the morphology, shape and size of the spheroids with a phase-contrast light microscope. The size of the spheroids is estimated automatically using a custom-developed MATLAB program based on an active contour algorithm. Further, we demonstrate a simple method to process the HistoGel embedding on these 3D spheroids, allowing the use of standard histological and immunohistochemical techniques. This is the first report on generating 3D spheroids using NET cell lines to examine the effect of therapeutic drugs. We have also performed histology on these 3D spheroids, and displayed an example of a single drug's effect on growth and proliferation of the NET spheroids. Our results support that the NET spheroids are valuable for further studies of NET biology and drug development. PMID- 22929520 TI - Results of a psychosomatic training program in China, Vietnam and Laos: successful cross-cultural transfer of a postgraduate training program for medical doctors. AB - BACKGROUND: With the "ASIA-LINK" program, the European Community has supported the development and implementation of a curriculum of postgraduate psychosomatic training for medical doctors in China, Vietnam and Laos. Currently, these three countries are undergoing great social, economic and cultural changes. The associated psychosocial stress has led to increases in psychological and psychosomatic problems, as well as disorders for which no adequate medical or psychological care is available, even in cities. Health care in these three countries is characterized by the coexistence of Western medicine and traditional medicine. Psychological and psychosomatic disorders and problems are insufficiently recognized and treated, and there is a need for biopsychosocially orientated medical care. Little is known about the transferability of Western oriented psychosomatic training programs in the Southeast Asian cultural context. METHODS: The curriculum was developed and implemented in three steps: 1) an experimental phase to build a future teacher group; 2) a joint training program for future teachers and German teachers; and 3) training by Asian trainers that was supervised by German teachers. The didactic elements included live patient interviews, lectures, communication skills training and Balint groups. The training was evaluated using questionnaires for the participants and interviews of the German teachers and the future teachers. RESULTS: Regional training centers were formed in China (Shanghai), Vietnam (Ho Chi Minh City and Hue) and Laos (Vientiane). A total of 200 physicians completed the training, and 30 physicians acquired the status of future teacher. The acceptance of the training was high, and feelings of competence increased during the courses. The interactive training methods were greatly appreciated, with the skills training and self-experience ranked as the most important topics. Adaptations to the cultural background of the participants were necessary for the topics of "breaking bad news," the handling of negative emotions, discontinuities in participation, the hierarchical doctor-patient relationship, culture-specific syndromes and language barriers. In addition to practical skills for daily clinical practice, the participants wanted to learn more about didactic teaching methods. Half a year after the completion of the training program, the participants stated that the program had a great impact on their daily medical practice. CONCLUSIONS: The training in psychosomatic medicine for postgraduate medical doctors resulted in a positive response and is an important step in addressing the barriers in providing psychosomatic primary care. The transferability of western concepts should be tested locally, and adaptations should be undertaken where necessary. The revised curriculum forms the basis of training in psychosomatic medicine and psychotherapy for medical students and postgraduate doctors in China, Vietnam and Laos. PMID- 22929521 TI - Identification of a Wilms' tumor 1-derived immunogenic CD4(+) T-cell epitope that is recognized in the context of common Caucasian HLA-DR haplotypes. PMID- 22929523 TI - Describing compassionate care: the burn survivor's perspective. AB - Compassion is vital in burn care. Its delivery could be considered a professional duty and a characteristic of care that affects patient satisfaction. However, the description of compassionate care is underexplored in the burn care literature. This study investigates the concept of compassionate care and how it is described from the perspective of the burn survivor. A qualitative design with two focus groups at the Phoenix Society for Burn Survivors' World Burn Congress was used to examine views of compassionate care directly through 31 burn survivors' accounts to better understand the concept and its delivery within the context of burn care. Discussions were recorded and transcripts were analyzed for prominent themes and descriptive components. Participants were primarily Caucasian (77%), female (60%), with an average age of 47.6 years and an average TBSA burn of approximately 49% sustained approximately 12 years ago. Qualitative data analysis yielded primary themes of: 1) respect the person (subthemes were: establishing an empathic connection, restoring control through choice, providing individualized care, and going above and beyond), 2) communication (subthemes: interpersonal and informational), and 3) provision of competent care. The three primary themes were components of compassionate care; it was not defined by a single characteristic, behavior, or skill but might be best understood as the convergence of the three themes. Implications of findings and barriers to the provision of compassionate care are also discussed. PMID- 22929522 TI - Analysis of NUP98/NSD1 translocations in adult AML and MDS patients. PMID- 22929524 TI - A ten-year review of lower extremity burns in diabetics: small burns that lead to major problems. AB - Diabetes mellitus with its resulting neurovascular changes may lead to an increased risk of burns and impaired wound healing. The purpose of this article is to review 10 years of experience with foot and lower leg burns in patients with diabetes at a single adult burn center. Patients with lower extremity burns and diabetes mellitus, between May 1999 and December 2009, were identified in the Trauma Registry of the American College of Surgeons database, and their charts were reviewed for data related to their outcomes. Sixty-eight diabetic patients, 87% male, with a mean age of 54 years, sustained foot or lower extremity burns with 37 having burns resulting from insensate feet. The pathogenesis included walking on a hot or very cold surface (8), soaking feet in hot water (22), warming feet on or near something hot such as a heater (13), or spilling hot water (7). The majority of patients were taking insulin (59.6%) or oral hyperglycemic medications (34.6%). Blood sugar levels were not well controlled (mean glucose, 215.8 mg/dl; mean hemoglobin A1c, 9.08%). Renal disease was common with admission serum blood urea nitrogen (27.5 mg/dl) and creatinine (2.21 mg/dl), and 13 were on dialysis preinjury. Cardiovascular problems were common with 39 (57%) having hypertension or cardiac disease, 3 having peripheral vascular disease, and 9, previous amputations. The mean burn size was 4.2% TBSA (range, 0.5-15%) with 57% being full thickness. Despite the small burn, the mean length of stay was 15.2 days (range, 1-95), with 5.65 days per 1% TBSA. Inability to heal these wounds was evident in 19 patients requiring readmission (one required 10 operative procedures). At least one patient sustained more than one burn. There were 62 complications with 30 episodes of infection (cellulitis, 28; osteomyelitis, 4; deep plantar infections, 2; ruptured Achilles tendon, 1) and 3 deaths. Eleven patients needed amputations (7 below-knee amputations, 4 transmetatarsal amputations, and 20 toe amputations) with several needing revisions or higher amputations. Patients with diabetes have an increased risk for lower extremity complications, but the risk of burns is not well known. The majority of lower extremity burns result from intentional exposure to sources of heat without recognition for the risk of burns. Once a burn occurs, morbidity and cost to the patient and society are severe. Prevention programs should be initiated to make diabetic patients and their doctors aware of the significant risk for burns. PMID- 22929525 TI - Recurrent toxic epidermal necrolysis secondary to iopromide contrast. AB - We present the case report of a patient with three episodes of Stevens-Johnson syndrome/toxic epidermal necrolysis attributed to the monomeric, nonionic, intravenous contrast iopromide. All three episodes required inpatient management, with the last two episodes being referred to the burn unit. Recurrence was the result of misattribution of an antibiotic as the inciting agent in the first two episodes. PMID- 22929526 TI - Hemodynamic responses to dexmedetomidine in critically injured intubated pediatric burned patients: a preliminary study. AB - Because of ineffectiveness and tolerance to benzodiazepines and opioids developing with time, drugs acting via other receptor systems (eg, alpha-2 agonists) have been advocated in burn patients to improve sedation and analgesia. This study in severely burned pediatric subjects examined the hemodynamic consequences of dexmedetomidine (Dex) administration. Eight intubated patients with >=20 to 79% TBSA burns were studied between 7 and 35 days after injury. After baseline measurements of mean arterial blood pressure and heart rhythm were taken, each patient received a 1.0 ug/kg bolus of Dex followed by an ascending dose infusion protocol (0.7-2.5 ug/kg/hr), with each dose administered for 15 minutes. There was significant hypotension (27+/-7.5%, average drop in mean arterial pressure [MAP] +/- SD), and a decrease in heart rate (HR; 19% +/- 7, average drop in HR +/- SD). The average HR decreased from 146 beats per minute to 120. No bradycardia (HR < 60) or heart blocks were observed. In three patients, the MAP decreased to <50mm Hg with the bolus dose of Dex. Of the remaining five patients, three patients completed the study receiving the highest infusion dose of Dex (2.5 ug/kg/hr), whereas in 2 patients the infusion part of the study was begun, but the study was stopped due to persistent hypotension (MAP < 50mm Hg). These observations indicate that a bolus dose of Dex (1.0 ug/kg for 10 minutes) and high infusion rates may require fluid resuscitation or vasopressor support to maintain normotension in critically injured pediatric burn patients. PMID- 22929527 TI - The use of Emla(r) cream to remove staples from skin-grafted areas. PMID- 22929528 TI - Eczema in full-thickness skin graft. PMID- 22929529 TI - Comminuted scapular fracture from electric injury: an unusual cause. PMID- 22929530 TI - Severe rhabdomyolysis without renal injury associated with lightning strike. AB - Lightning strikes cause injuries in multiple systems and organs. Early recognition of lightning injury syndromes and anticipation of harmful complications can improve outcomes for these patients. The author has presented a case report of a patient who was struck by lightning and exhibited extensive soft tissue injury with myoglobinuria. He was treated with delayed fasciotomy and had evidence of severe muscle injury with markedly elevated creatine kinase levels that gradually improved with aggressive fluid infusion. The patient did not require alkalinization of urine, mannitol, or dialysis, and his renal function remained normal. PMID- 22929531 TI - A new diagnostic approach for Turkish speaking populations DAWBA Turkish Version. AB - Aims. Turkey has the youngest population in Europe with about 25 million people aged below 19 years and Turkish-speaking people comprise the biggest migrant group in Europe with 2.5 million people dispersed in different countries, but conducting epidemiologic surveys on Turkish people is challenging due to the lack of a suitable diagnostic tool. The Development and Well-Being Assessment (DAWBA) is one of the most widely used diagnostic interviews in child and adolescent psychiatry. In this study, we aimed at translating the DAWBA into Turkish and then examined its validity and reliability. Methods. The validity of the Turkish version was examined in clinical (n = 50) and community (n = 104) samples. The interrater reliability was also evaluated on 20 cases. Results. The translation method used in the study achieved semantic, conceptual, content, technical, item and criterion equivalence between the Turkish and original forms. The validity of the Turkish DAWBA was good or excellent for different diagnostic categories (kappa: 0.43-0.84); the interrater reliability was also excellent (kappa: 0.85 1). Conclusions. The Turkish DAWBA may be useful for future prevalence studies in Turkey. European clinicians and researchers who work with Turkish-speaking families can use the online Turkish DAWBA to gather structured information from Turkish-speaking informants and review the answers in their own language. PMID- 22929532 TI - Primary cutaneous CD30+ lymphoproliferative disorder successfully treated by etretinate. PMID- 22929534 TI - Associations of body mass index and insulin resistance with leptin, adiponectin, and the leptin-to-adiponectin ratio across ethnic groups: the Multi-Ethnic Study of Atherosclerosis (MESA). AB - PURPOSE: Associations of adiponectin and leptin and their ratio with body mass index (BMI) and homeostasis model assessment of insulin resistance (HOMA-IR) have been investigated in different ethnic groups but variability in both assays and statistical methods have made cross-study comparisons difficult. We examined associations among these variables across four ethnic groups in a single study. METHODS: Adiponectin and leptin were measured in a subset of participants from the Multi-Ethnic Study of Atherosclerosis study. We calculated associations (using both partial correlations and adjusted linear regression) in each ethnic group and then compared the magnitude of these associations across groups. RESULTS: After we excluded individuals with type 2 diabetes, there were 714 white, 219 Chinese, 332 African-American, and 405 Hispanic subjects in the study sample. Associations of BMI with adiponectin and leptin differed significantly (P < .05) across the ethnic groups in regression analyses, whereas associations of HOMA-IR with adiponectin and leptin did not differ across ethnic groups. The leptin-to-adiponectin ratio was not associated with a greater amount of adiposity or HOMA-IR variance than leptin or adiponectin in any ethnic group. CONCLUSIONS: Given the consistency of HOMA-IR and adipokine associations, the differing means of adiponectin and leptin across ethnic groups may help to explain ethnic differences in mean insulin resistance. PMID- 22929533 TI - Integrated next-generation sequencing of 16S rDNA and metaproteomics differentiate the healthy urine microbiome from asymptomatic bacteriuria in neuropathic bladder associated with spinal cord injury. AB - BACKGROUND: Clinical dogma is that healthy urine is sterile and the presence of bacteria with an inflammatory response is indicative of urinary tract infection (UTI). Asymptomatic bacteriuria (ABU) represents the state in which bacteria are present but the inflammatory response is negligible. Differentiating ABU from UTI is diagnostically challenging, but critical because overtreatment of ABU can perpetuate antimicrobial resistance while undertreatment of UTI can result in increased morbidity and mortality. In this study, we describe key characteristics of the healthy and ABU urine microbiomes utilizing 16S rRNA gene (16S rDNA) sequencing and metaproteomics, with the future goal of utilizing this information to personalize the treatment of UTI based on key individual characteristics. METHODS: A cross-sectional study of 26 healthy controls and 27 healthy subjects at risk for ABU due to spinal cord injury-related neuropathic bladder (NB) was conducted. Of the 27 subjects with NB, 8 voided normally, 8 utilized intermittent catheterization, and 11 utilized indwelling Foley urethral catheterization for bladder drainage. Urine was obtained by clean catch in voiders, or directly from the catheter in subjects utilizing catheters. Urinalysis, urine culture and 16S rDNA sequencing were performed on all samples, with metaproteomic analysis performed on a subsample. RESULTS: A total of 589454 quality-filtered 16S rDNA sequence reads were processed through a NextGen 16S rDNA analysis pipeline. Urine microbiomes differ by normal bladder function vs. NB, gender, type of bladder catheter utilized, and duration of NB. The top ten bacterial taxa showing the most relative abundance and change among samples were Lactobacillales, Enterobacteriales, Actinomycetales, Bacillales, Clostridiales, Bacteroidales, Burkholderiales, Pseudomonadales, Bifidobacteriales and Coriobacteriales. Metaproteomics confirmed the 16S rDNA results, and functional human protein pathogen interactions were noted in subjects where host defenses were initiated. CONCLUSIONS: Counter to clinical belief, healthy urine is not sterile. The healthy urine microbiome is characterized by a preponderance of Lactobacillales in women and Corynebacterium in men. The presence and duration of NB and method of urinary catheterization alter the healthy urine microbiome. An integrated approach of 16S rDNA sequencing with metaproteomics improves our understanding of healthy urine and facilitates a more personalized approach to prevention and treatment of infection. PMID- 22929535 TI - Adiposity measures as predictors of long-term physical disability. AB - OBJECTIVE: To compare the predictive value of a variety of adiposity measures for the risk of disability. DESIGN/SETTING: This study used 14-year follow-up of the Melbourne Collaborative Cohort Study (n = 7142). Adiposity measures were collected at baseline and disability measures for 5 self-care activities and mobility were collected at follow-up (2003-2007). METHODS: Logistic regression was used to analyze the association between each adiposity measure (body mass index [BMI], waist circumference [WC], hip circumference, waist-to-hip ratio, fat mass, fat free mass, and percentage fat and disability. Area under the receiver operating curve ranking and comparison between nested models were used to determine the best predictor of disability. RESULTS: For men and women, the odds for disability increased with increasing adiposity. In men, BMI was the most predictive adiposity measure for all types of disability. In women, 2 adiposity measures (BMI and WC) predicted overall and mobility disability better than only one measure, with hip circumference the single best predictor for self-care disability. CONCLUSIONS: BMI and WC predicted disability well in men and women. Identifying individuals at high risk of future disability through simple measures of adiposity will be essential if we are to adequately cater for our ageing population. PMID- 22929536 TI - The diagnostic value of the stump impingement reflex sign for determining anterior cruciate ligament stump impingement as a cause of knee locking. AB - BACKGROUND: The stump impingement reflex is a subtle bounce to the knee thought to be caused by hamstring contraction when the knee is brought into extension and the torn ACL stump impinges between the distal femur and the tibial plateau. We have studied the diagnostic value of this sign. FINDINGS: From Feb 2008-Feb 2009, we audited 30 patients who underwent urgent arthroscopy for acutely locked knees. The presence of the stump impingement reflex prior to surgery was compared with the intra-operative findings. The diagnostic values of the stump impingement sign were found to be: Sensitivity 58%, Specificity 81%, Positive predictive value 70%, Negative predictive value 72% and Accuracy 71%. CONCLUSIONS: We believe that the stump impingement reflex is a specific sign for ACL stump impingement as a cause of knee locking. We recommend close inspection for this sign when examining locked knees. PMID- 22929537 TI - Genetic variation in histidine rich proteins among Indian Plasmodium falciparum population: possible cause of variable sensitivity of malaria rapid diagnostic tests. AB - BACKGROUND: Rapid diagnostic tests (RDTs) have revolutionized the diagnosis of malaria. Among the various factors affecting RDTs sensitivity is genetic variation of the antigen used. The genetic variation in PfHRP2 and PfHRP3 proteins was studied among the Indian Plasmodium falciparum isolates. METHODS: One hundred and forty isolates of P. falciparum were collected from six geographical regions of India. Target genes encoding PfHRP2 and PfHRP3 antigens were sequenced to study genetic polymorphism. Minimum detection limit giving a positive rapid diagnostic test was also determined. RESULTS: Extensive variations were observed in amino acid repeat types of PfHRP2 and PfHRP3. PfHRP2 exhibited more polymorphism than PfHRP3. Significant relation was observed between type 2 and type 7 repeats and RDT detection rate as higher number of these repeats showed better sensitivity with RDTs. CONCLUSION: The results provide insights into the genetic diversity of Pfhrp2 and Pfhrp3 genes among Indian P. falciparum population and its relation to RDT sensitivity. PMID- 22929538 TI - A novel tylophorine analog NK-007 ameliorates colitis through inhibition of innate immune response. AB - In this study, we synthesized (+/-)-tylophorine malate (NK-007), an analog of tylophorine (DCB3503), and analyzed its anti-inflammatory effect in vivo using a dextran sulfate sodium (DSS)-induced colitis model and an acetic acid-induced colitis model. As indicated by disease activity index (DAI) and degree of macroscopic colonic damage, NK-007 can significantly suppress colitis. To delineate the underlying mechanism, we have explored the influence of NK-007 on the production of TNF-alpha by murine primary bone marrow-derived dendritic cells (BMDCs) as well as monocyte/macrophage cell line Raw 264.7 triggered by lipopolysaccharide (LPS). For both types of innate immune cells, NK-007 showed a potent TNF-alpha inhibitory effect, and has in addition reduced the expression of IL-12 in BMDCs. Moreover, Raw cells treated with NK-007 also showed decreased phosphorylation of NF-kappaB, which may explain the protective immune-regulatory effect of NK-007 for experimental colitis. PMID- 22929539 TI - Bradykinin promotes Toll like receptor-4 expression in human gingival fibroblasts. AB - Bacterial infections are a potent mechanism for enzymatic generation of kinins such as bradykinin (BK), a universal mediator for inducing inflammatory reaction by associating with the B2 receptor and stimulating liberation of arachidonic acid and synthesis of prostaglandin E2 (PGE2). In this study we evaluate the role of bradykinin in regulating the expression of TLR4 receptor in human gingival fibroblasts. We examine the ability of bradykinin to modulate inflammatory response of human gingival fibroblasts to Gram-negative components and evaluated the role of Toll-like receptors (TLR)-4 in the co-operation between bradykinin and bacterial pathogens. We show that treatment with bradykinin promotes TLR4 receptor expression in human gingival fibroblasts (HGF) and amplifies inflammatory responses to the bacterial components of Gram-negative bacteria. The TLR4 expression induced by bradykinin was blocked with Hoe 140, a B2R antagonist. When HGF cells were incubated with BK resulted of an increased in cyclooxygenase 2 (COX-2) expression and prostaglandin E2 synthesis. Bradykinin and lipopolysaccharide, a specific TLR4 ligand stimulated COX-2 expression. In other series of experiments we found that ERK, phosphatidylinositol-3 kinase, protein kinase C and NFkB are involved in BK promoted-increased in TLR4 expression. The results demonstrate that bradykinin up-regulates the expression of TLR4 and promotes an additive increase in inflammatory responses to lipopolysaccharides. PMID- 22929541 TI - What and where is the word? AB - Examples from Chinese, Thai, and Finnish illustrate why researchers cannot always be confident about the precise nature of the word unit. Understanding ambiguities regarding where a word begins and ends, and how to model word recognition when many derivations of a word are possible, is essential for universal theories of reading applied to both developing and expert readers. PMID- 22929540 TI - Transcriptional profiling of long non-coding RNAs and novel transcribed regions across a diverse panel of archived human cancers. AB - BACKGROUND: Molecular characterization of tumors has been critical for identifying important genes in cancer biology and for improving tumor classification and diagnosis. Long non-coding RNAs, as a new, relatively unstudied class of transcripts, provide a rich opportunity to identify both functional drivers and cancer-type-specific biomarkers. However, despite the potential importance of long non-coding RNAs to the cancer field, no comprehensive survey of long non-coding RNA expression across various cancers has been reported. RESULTS: We performed a sequencing-based transcriptional survey of both known long non-coding RNAs and novel intergenic transcripts across a panel of 64 archival tumor samples comprising 17 diagnostic subtypes of adenocarcinomas, squamous cell carcinomas and sarcomas. We identified hundreds of transcripts from among the known 1,065 long non-coding RNAs surveyed that showed variability in transcript levels between the tumor types and are therefore potential biomarker candidates. We discovered 1,071 novel intergenic transcribed regions and demonstrate that these show similar patterns of variability between tumor types. We found that many of these differentially expressed cancer transcripts are also expressed in normal tissues. One such novel transcript specifically expressed in breast tissue was further evaluated using RNA in situ hybridization on a panel of breast tumors. It was shown to correlate with low tumor grade and estrogen receptor expression, thereby representing a potentially important new breast cancer biomarker. CONCLUSIONS: This study provides the first large survey of long non-coding RNA expression within a panel of solid cancers and also identifies a number of novel transcribed regions differentially expressed across distinct cancer types that represent candidate biomarkers for future research. PMID- 22929543 TI - The limitations of the reverse-engineering approach to cognitive modeling. AB - Frost's critique reveals the limitations of the reverse-engineering approach to cognitive modeling--the style of psychological explanation in which a stipulated internal organization (in the form of a computational mechanism) explains a relatively narrow set of phenomena. An alternative is to view organization as both the explanation for some phenomena and a phenomenon to be explained. This move poses new and interesting theoretical challenges for theories of word reading. PMID- 22929545 TI - Methods for assessment of health outcomes in children with burn injury: the Multi Center Benchmarking Study. AB - BACKGROUND: The Multi-Center Benchmarking Study (MCBS) is an innovative program giving a new paradigm for monitoring health outcomes in children and adolescents with burn injuries. METHODS: This article presents the methodologies for conducting a multicenter long-term cohort study of 1,140 children and adolescents with small to large burn injuries followed from the acute burn discharge at four burn centers for up to 4 years. The components for this project include a broad and rich range of patient-centered health assessments tailored to children with burn injury, an infrastructure for obtaining relevant clinical data, and patient centered questionnaire data based on validated Shriners Hospitals for Children/American Burn Association Burn Outcomes Questionnaire (BOQ) and Short Form Psychosocial Questionnaire, aged 0 years to 18 years. Recovery curves are described for analysis of complex data with repeated measures that are based on mixed models and generalized estimating equations, with adjustments for clinical characteristics. RESULTS: Accrual rates are as high as 93%, and follow-up rates of completion are 65%. Recovery curves for selected BOQ domains (upper extremity function, patient compliance, and parental concern) are presented for those children and adolescents aged 5 years to 18 years using the rich cohort of data from the MCBS. Results suggest that the BOQ is sensitive and responsive to capturing differences in the rate and levels of change over time. CONCLUSION: The methods implemented in the MCBS are a useful model for conducting large multicenter studies to track the clinical and quality of life of children with burn injuries. PMID- 22929544 TI - The American Burn Association/Shriners Hospitals for Children Burn Outcomes Program: a progress report at 15 years. AB - The American Burn Association and the Shriners Hospitals for Children Outcomes Program has been in development for more than 15 years. Many of the tools and important findings are described in this special issue of The Journal of Trauma. This unique program in outcomes research introduces a model for outcome assessments from the patient-centered perspective with a cohort of 1,140 children with burn injury after hospitalization for up to 4 years. The findings represent a fundamental contribution to the field of burn care for monitoring outcomes from the perspective of the parent or child/adolescent. The Multi-Center Benchmarking Study of four burn centers serve as a model for collecting empiric scientific data on the variation and the expected trajectories of recovery in the most important domains of patient outcomes and can inform clinical decisions and the conduct of health service research. The dramatic progress in survival of children with severe burn injury and other advances in burn management can now move into a new phase of understanding the most cost-effective components of this care. PMID- 22929546 TI - The effects of facial burns on health outcomes in children aged 5 to 18 years. AB - BACKGROUND: There are many potential long-term effects of facial burns in children and young adults. We evaluated the outcomes of children and young adults with and without facial burns with respect to physical, psychological, and social domains of health-related quality of life (HRQoL). In addition, we examined the role of sex and socioeconomic status on HRQoL in these patients. METHODS: Parents of children aged from 5 to 18 years with burn injury completed the American Burn Association/Shriners Hospitals for Children Burn Outcomes Questionnaire when survival was ensured at their original burn center admission and at regular 6 month intervals during the first 2 years and annually up to 4 years after their acute care discharge. Generalized estimating equations with mixed models were used to evaluate the course of recovery with risk adjustments for time since burn, presence of facial burns, and clinical and other sociodemographic characteristics. RESULTS: Patients with facial burns paralleled the recovery of patients without facial burns, but their mean scores remained lower during the 4 years, with the lowest scores in the domains of appearance, emotional health, and parental concern. Teenagers had improved recovery rates when compared with younger children. Males scored lower with respect to family disruption but recovered at faster rates than females over time, and parents with higher education scored lower for parental concern during the 4 years of follow-up. CONCLUSION: Psychosocial concerns predominate in the recovery of children who sustain facial burns and are significantly greater than those observed in children in whom the face is not involved by burn injury. PMID- 22929547 TI - Impact of hand burns on health-related quality of life in children younger than 5 years. AB - BACKGROUND: The purpose of this multicenter study was to evaluate the impact of hand burn injury in preschool children younger than 5 years on health-related quality of life, including both physical and psychosocial function, in the 5 years after burn injury. METHODS: This prospective case series assessed children younger than 5 years admitted to four pediatric burn centers. Each child's family completed the American Burn Association/Shriners Hospitals for Children Burn Outcome Questionnaire (BOQ), a validated and reliable assessment tool, which measures the physical and psychosocial functioning of the child with burn injury ages 0 year to 5 years, at baseline, 3, 6, 12, 18, 24, 36, and 48 months after discharge. Multivariate models controlling for sociodemographic and clinical characteristics were developed, and recovery curves were generated for the time since burn using generalized estimating equations with random effects. RESULTS: A cohort of 438 patients was followed up prospectively. Mean (SD) patient age was 2.2 (1.2) years, mean (SD) total body surface area (TBSA) was 28% (22.4%), and 19% had inhalation injury. Children with hand burns had lower scores in most of the areas tested, with the most pronounced and significant differences were in fine motor function, gross motor function, and appearance. These findings applied to both small (<20% TBSA) and large (>=20% TBSA) burns. The most profound impact of hand burns was noted in fine and gross motor function during the 4 years of follow-up. CONCLUSION: Children with hand burns have significantly worse outcomes than do children with burns in other areas. PMID- 22929548 TI - The effect of family characteristics on the recovery of burn injuries in children. AB - BACKGROUND: Interactions between family members and characteristics of family life and function may affect a child's recovery from burn injury. We prospectively examined the relationship between family characteristics and physical and psychosocial recovery from burns. METHODS: The families of 399 burned children aged 5 years to 18 years admitted to one of four Shriners Hospitals for Children for management of acute burns completed the Family Environment Scale within 7 days of admission and then the American Burn Association/Shriners Hospitals for Children Burn Outcome Questionnaire (BOQ) at baseline, 3, 6, 12, 18, 24, 36, and 48 months. Generalized estimating equations with random effects for the time since burn were used to track recovery of the BOQ patient-centered domains associated with baseline family characteristics during the course of the study. RESULTS: The children had a mean age of 11 years and burn size of 32% total body surface area burned. Higher Family Environment Scale scores in cohesion, independence, organization, and active recreational orientation were associated with significantly better rates of recovery in multiple BOQ domains of health-related quality of life. Higher scores in conflict and achievement orientation predicted statistically significant impaired recovery. Higher expressiveness predicted greater difficulty with school reentry. CONCLUSION: Family characteristics affect the recovery of children after serious burns. Some of these may be amenable to focused anticipatory family interventions to help optimize outcomes. In particular, those characteristics that impair school reentry should be targeted. PMID- 22929549 TI - Adolescent survivors of burn injuries and their parents' perceptions of recovery outcomes: do they agree or disagree? AB - BACKGROUND: This study analyzed the concordance of parent and child in assessing the progress of child and adolescent survivors of burn injuries using health outcomes. METHODS: The American Burn Association/Shriners Hospitals for Children Burn Outcomes Questionnaire (BOQ) was completed by 355 pairs of parents and their 11- to 18-year-old adolescents who experienced a burn injury. These patients completed BOQ child/parent questionnaire pairs at four regional pediatric burn care centers nationally during the first 4 years postburn. The BOQ includes 12 scales that range from physical to emotional health. Predicted recovery curves for each scale (dependent variable) were obtained from generalized linear models, with the independent variables the logarithmic transformation of the time since burn and parent/child as the principal indicator. Covariates included sociodemographics and clinical severity. RESULTS: Mean differences between the parent and adolescent scale scores were small, with few insignificant exceptions. Most of the recovery curves over time for the parent and the adolescent were undifferentiated, except for the outcome of appearance where the adolescent rating was better than that of the parent (p < 0.01) and itch was judged as worse than that of the parent (p < 0.01). School reentry was rated higher by the adolescent initially (p < 0.001), but after 18 months, it was rated higher by the parent (p = 0.012). CONCLUSION: Analysis of the BOQ completed by adolescents and their parents reveal similar estimates of recovery following the burn injury. These results suggest that the adolescent's reported outcomes can be used interchangeably with the parent's assessments, with the exception of appearance, itch, and school reentry, where there are some differences. PMID- 22929550 TI - Test performance characteristics of a case-finding psychosocial questionnaire for children with burn injuries and their families. AB - BACKGROUND: The Long-Form Psychosocial Questionnaire (LFPQ) includes full versions of the Child Stress Reaction Checklist, the Family Environment Scale, and the Parenting Stress Index. Condensed versions of these measures were used to create a Short-Form Psychosocial Questionnaire (SFPQ) that could be used as an indicator of child well-being and specific areas of child, parent, and family functioning in children aged 0 years to 18 years with burn injury. METHODS: Parents of 830 children aged 0 years to 18 years with acute burn injury from the Shriners Hospitals for Children Multi-Center Benchmarking Study completed the LFPQ at baseline and follow-up visits up to 48 months at four major burn centers. The internal consistency reliability and variability of the LFPQ explained by the SFPQ for each of the measures were calculated. The construct validity of the SFPQ measures was determined by factor analysis. The magnitude of the change for the SFPQ measures during 48 months of follow-up was examined. RESULTS: The internal consistency reliability of the short-form measures ranged from 0.62 to 0.90. The variability of the long-form measures explained by the short-form measures was 61% for the Child Stress Reaction Checklist (average of six long-form scales), 60% for the Family Environment Scale (conflict), and 90% for the Parenting Stress Index (average of 13 scales). Factor analysis supported the construct validity of the model for the short-form measures. The magnitude of change for the short-form measures showed clinical improvement for 48 months. CONCLUSION: The SFPQ is both a reliable and valid assessment for evaluating the psychosocial functioning of children following burn injuries. PMID- 22929551 TI - Measuring the cost of care for children with acute burn injury. AB - BACKGROUND: There have been few studies on costs of burn treatment. Furthermore, quantifying the actual cost of care at the patient level is hindered by anomalies of our insurance system. This article presents a practical method for determining the cost of caring for pediatric burn patients, using a cohort of patients from the Multi-Center Benchmarking Study at the Shriners Hospitals for Children-Boston and allows an estimate of resource use that may be linked to need or to best practices, without the confounding variable of inconsistent billing practices. METHODS: We estimated the cost of hospitalization for a cohort of 230 pediatric patients who sustained burn injuries. In a simulation of billing patterns of all US hospitals between 2001 and 2009, we applied Shriners Hospitals for Children use data to two external sources of cost information. For the hospital component of costs, we used the Healthcare Cost and Utilization Project Kid's Inpatient Database, and for the physician component of costs, we used the Medicare fee schedule. RESULTS: Patients had a mean of 1.9 hospitalizations over 3 to 4 years. The mean total cost of hospitalization was $83,535 per patient, and the median total cost was $16,331 in 2006 dollars. CONCLUSION: This is the first effort to estimate the early hospital costs of caring for children and young adults with burns in specialty hospitals and to establish a referent for quantifying the cost of caring for patients with acute burns. It lays the groundwork for studies relating costs of specific interventions to their effects on patient-centered outcomes. PMID- 22929552 TI - Chemoselective modification of viral surfaces via bioorthogonal click chemistry. AB - The modification of virus particles has received a significant amount of attention for its tremendous potential for impacting gene therapy, oncolytic applications and vaccine development. Current approaches to modifying viral surfaces, which are mostly genetics-based, often suffer from attenuation of virus production, infectivity and cellular transduction. Using chemoselective click chemistry, we have developed a straightforward alternative approach which sidesteps these issues while remaining both highly flexible and accessible. The goal of this protocol is to demonstrate the effectiveness of using bioorthogonal click chemistry to modify the surface of adenovirus type 5 particles. This two step process can be used both therapeutically or analytically, as it allows for chemoselective ligation of targeting molecules, dyes or other molecules of interest onto proteins pre-labeled with azide tags. The three major advantages of this method are that (1) metabolic labeling demonstrates little to no impact on viral fitness, (2) a wide array of effector ligands can be utilized, and (3) it is remarkably fast, reliable and easy to access. In the first step of this procedure, adenovirus particles are produced bearing either azidohomoalanine (Aha, a methionine surrogate) or the unnatural sugar O-linked N azidoacetylglucosamine (O-GlcNAz), both of which contain the azide (-N3) functional group. After purification of the azide-modified virus particles, an alkyne probe containing the fluorescent TAMRA moiety is ligated in a chemoselective manner to the pre-labeled proteins or glycoproteins. Finally, an SDS-PAGE analysis is performed to demonstrate the successful ligation of the probe onto the viral capsid proteins. Aha incorporation is shown to label all viral capsid proteins (Hexon, Penton and Fiber), while O-GlcNAz incorporation results in labeling of Fiber only. In this evolving field, multiple methods for azide-alkyne ligation have been successfully developed; however only the two we have found to be most convenient are demonstrated herein - strain-promoted azide alkyne cycloaddition (SPAAC) and copper-catalyzed azide-alkyne cycloaddition (CuAAC) under deoxygenated atmosphere. PMID- 22929554 TI - Radon and thoron doses in kindergartens and elementary schools. AB - Exposing the Raduet Rn-Tn solid-state nuclear track detectors, radon (Rn: (222)Rn) and thoron (Tn: (220)Rn) activity concentrations have been measured in 7 kindergartens and 18 elementary schools in Slovenia. Diurnal variations of both gases were monitored using a Rad7 device. The Rn concentration was in the range from 145 to 794 Bq m(-3) in kindergartens and from 70 to 770 Bq m(-3) in schools, and the Tn concentration was in the range from 21 to 73 Bq m(-3) in kindergartens and from 4 to 91 Bq m(-3) in schools. The Tn versus Rn concentration ratio varied from 0.02 to 0.83. Monthly effective doses due to radon and its decay products ranged from 109 to 600 MUSv month(-1) in kindergartens and from 21 to 232 MUSv month(-1) in schools, and those due to thoron and its decay products ranged from 3.8 to 13.3 MUSv month(-1) in kindergartens and from 0.29 to 6.62 MUSv month(-1) in schools. The contribution of thoron to the total effective dose was from 1.3 to 11 % in kindergartens and from 0.4 to 17 % in schools. PMID- 22929555 TI - Optimisation of performance for computed radiography in the West of Scotland. AB - This paper describes experiences in the introduction of computed radiography systems to hospitals within the West of Scotland. Setting of automatic exposure control levels has enabled dose-area product values to be maintained at 160 cGy cm2 for lumbar spine antero-posterior (AP), 250 cGy cm2 for lumbar spine lateral, 210 cGy cm2 for pelvis AP and 260 cGy cm2 for abdomen AP. The study looks at dose levels achieved after 8 y in use and compares the dose levels found from surveys undertaken in 2007 and in 2010. The effects of raising tube potentials on image quality in terms of details and on contrast-to-noise ratio (CNR) were assessed. The results showed that CNR details seen in test images at tube potentials of 85 90 kV did not differ significantly from those with lower potentials and gave lower entrance surface doses. PMID- 22929542 TI - Rationale, study design, and analysis plan of the Alveolar Recruitment for ARDS Trial (ART): study protocol for a randomized controlled trial. AB - BACKGROUND: Acute respiratory distress syndrome (ARDS) is associated with high in hospital mortality. Alveolar recruitment followed by ventilation at optimal titrated PEEP may reduce ventilator-induced lung injury and improve oxygenation in patients with ARDS, but the effects on mortality and other clinical outcomes remain unknown. This article reports the rationale, study design, and analysis plan of the Alveolar Recruitment for ARDS Trial (ART). METHODS/DESIGN: ART is a pragmatic, multicenter, randomized (concealed), controlled trial, which aims to determine if maximum stepwise alveolar recruitment associated with PEEP titration is able to increase 28-day survival in patients with ARDS compared to conventional treatment (ARDSNet strategy). We will enroll adult patients with ARDS of less than 72 h duration. The intervention group will receive an alveolar recruitment maneuver, with stepwise increases of PEEP achieving 45 cmH2O and peak pressure of 60 cmH2O, followed by ventilation with optimal PEEP titrated according to the static compliance of the respiratory system. In the control group, mechanical ventilation will follow a conventional protocol (ARDSNet). In both groups, we will use controlled volume mode with low tidal volumes (4 to 6 mL/kg of predicted body weight) and targeting plateau pressure <=30 cmH2O. The primary outcome is 28-day survival, and the secondary outcomes are: length of ICU stay; length of hospital stay; pneumothorax requiring chest tube during first 7 days; barotrauma during first 7 days; mechanical ventilation-free days from days 1 to 28; ICU, in-hospital, and 6-month survival. ART is an event-guided trial planned to last until 520 events (deaths within 28 days) are observed. These events allow detection of a hazard ratio of 0.75, with 90% power and two-tailed type I error of 5%. All analysis will follow the intention-to-treat principle. DISCUSSION: If the ART strategy with maximum recruitment and PEEP titration improves 28-day survival, this will represent a notable advance to the care of ARDS patients. Conversely, if the ART strategy is similar or inferior to the current evidence-based strategy (ARDSNet), this should also change current practice as many institutions routinely employ recruitment maneuvers and set PEEP levels according to some titration method. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01374022. PMID- 22929556 TI - Deposition-based passive monitors for assigning radon, thoron inhalation doses for epidemiological studies. AB - The International Commission on Radiological Protection dose limits for radiation protection have been based on linearly extrapolating the high-dose risk coefficients obtained from the Japanese A bomb survivor data to low doses. The validity of these extrapolations has been questioned from time to time. To overcome this, epidemiological studies have been undertaken across the world on populations chronically exposed to low-radiation levels. In the past decade, the results of these studies have yielded widely differing, and sometimes, contradictory, conclusions. While recent residential radon studies have shown statistically significant radon risks at low doses, high-level natural radiation (HLNR) studies in China and India have not shown any low-dose risks. Similar is the case of a congenital malformation study conducted among the HLNR area populations in Kerala, India. It is thus necessary to make efforts at overcoming the uncertainties in epidemiological studies. In the context of HLNR studies, assigning radon and thoron doses has largely been an area of considerable uncertainty. Conventionally, dosimetry is carried out using radon concentration measurements, and doses have been assigned using assumed equilibrium factors for the progeny species. Gas-based dose assignment is somewhat inadequate due to variations in equilibrium factors and possibly due to significant thoron. In this context, passive, deposition-based progeny dosimetry appears to be a promising alternative method to assess inhalation doses directly. It has been deployed in various parts of India, including HBRAs and countries in Europe. This presentation discusses the method, the results obtained and their relevance to dose assignment in Indian epidemiological studies. PMID- 22929553 TI - Detecting microRNAs of high influence on protein functional interaction networks: a prostate cancer case study. AB - BACKGROUND: The use of biological molecular network information for diagnostic and prognostic purposes and elucidation of molecular disease mechanism is a key objective in systems biomedicine. The network of regulatory miRNA-target and functional protein interactions is a rich source of information to elucidate the function and the prognostic value of miRNAs in cancer. The objective of this study is to identify miRNAs that have high influence on target protein complexes in prostate cancer as a case study. This could provide biomarkers or therapeutic targets relevant for prostate cancer treatment. RESULTS: Our findings demonstrate that a miRNA's functional role can be explained by its target protein connectivity within a physical and functional interaction network. To detect miRNAs with high influence on target protein modules, we integrated miRNA and mRNA expression profiles with a sequence based miRNA-target network and human functional and physical protein interactions (FPI). miRNAs with high influence on target protein complexes play a role in prostate cancer progression and are promising diagnostic or prognostic biomarkers. We uncovered several miRNA regulated protein modules which were enriched in focal adhesion and prostate cancer genes. Several miRNAs such as miR-96, miR-182, and miR-143 demonstrated high influence on their target protein complexes and could explain most of the gene expression changes in our analyzed prostate cancer data set. CONCLUSIONS: We describe a novel method to identify active miRNA-target modules relevant to prostate cancer progression and outcome. miRNAs with high influence on protein networks are valuable biomarkers that can be used in clinical investigations for prostate cancer treatment. PMID- 22929557 TI - Restriction periods for carers, comforters and members of the public in the treatment of hyperthyroidism. AB - People treated for hyperthyroidism are normally outpatients who pose a potential radiological risk to some members of the public. In this study, measurements of the uptake in 30 patients were used to estimate the values of the activity of 131I in the whole body of patients, AWB, by using a model of two compartments. Restriction periods to be followed by patients for different values of the administered activity of 131I were calculated. To perform calculations, the following were used: the curve obtained for AWB; the value of the dose rate at one metre from patients after the administration of the treatment; and the estimated time that carers, comforters and members of the public will spend at certain distances from patients. Results show that protection from radiation for carers, comforters and members of the public related to patients treated for hyperthyroidism can become a cumbersome matter as patients may have to follow very long restriction periods. PMID- 22929558 TI - Sorption-desorption characteristics of uranium, cesium and strontium in typical podzol soils from Ukraine. AB - Sorption-desorption behaviour of uranium (U), cesium (Cs) and strontium (Sr) was examined by quantification of the solid-liquid distribution coefficients (K(d)) using batch method in typical podzol soils from Ukraine. The effect of different physico-chemical parameters of soil on K(d) values has been discussed. Sorption reversibility has been tested by single extraction test. U shows reversible sorption and there was no isotopic fractionation observed with a known isotopic U composition using as tracer. Cs sorption mostly occurred in an irreversible manner. The clay content and exchangeable potassium in soil play an important role in Cs fixation. Sr adsorption is observed to be reversible and mainly controlled by cation exchange and shows highest mobility in the soil-water system. The K(d) values are found in the decreasing order U (log K(d) ~ 2-3) > Cs (log K(d) ~ 2) > Sr (log K(d) ~ 1). PMID- 22929559 TI - Human immunodeficiency virus and the gastrointestinal immune system: does highly active antiretroviral therapy restore gut immunity? AB - While only partial immune reconstitution in gut-associated lymphoid tissue typically occurs following initiation of highly active antiretroviral therapy (HAART) in human immunodeficiency virus (HIV) infection, near-complete immune reconstitution has occasionally been described. This review highlights findings from studies examining the effects of HAART and the timing of its initiation on gastrointestinal (GI) CD4+ T-cell recovery. Its effects on specific CD4+ T-cell subtypes, CD8+ T cells, natural killer cells, and immunoglobulins are also described. Finally, the ability of HAART to restore the intestinal epithelial barrier and lymphatic tissue architecture and reduce microbial translocation is addressed. Determining whether HAART has the ability to prevent permanent GI immune damage when commenced in acute HIV infection has implications for the optimal timing of HAART initiation. PMID- 22929562 TI - Effects of magnetic ion exchange pretreatment on low pressure membrane filtration of natural surface water. AB - Magnetic ion exchange (MIEX) pretreatment has been increasingly employed by water treatment plants for removal of dissolved organic carbon (DOC). In this study, the effects of MIEX pretreatment on low pressure membrane filtration of natural surface water were investigated under different feedwater qualities, membrane properties, and MIEX dosing conditions. Regardless of feedwater DOC, moderate decrease in the total and hydraulically irreversible fouling was observed for a polyvinylidene fluoride (PVDF) microfiltration membrane and a polyethersulfone ultrafiltration (UF) membrane after MIEX pretreatment, which was coincident with moderate removals of high molecular weight DOC in the feedwaters. Comparatively, the fouling of a PVDF UF membrane did not decrease after MIEX pretreatment, revealing the impact of membrane properties on membrane fouling in the presence of MIEX pretreatment. Reuse of virgin or regenerated MIEX resulted in similar membrane fouling as observed with single use of the virgin MIEX. The level of DOC removal by MIEX was similar to the removal of MS2 bacteriophage spiked in the feedwater, suggesting a potential similarity in the removal of organic and microbial particles. In conclusion, MIEX pretreatment was effective for DOC removal, but less effective in controlling short-term membrane fouling or removing viruses. PMID- 22929560 TI - Molecular organization of the mucins and glycocalyx underlying mucus transport over mucosal surfaces of the airways. AB - Mucus, with its burden of inspired particulates and pathogens, is cleared from mucosal surfaces of the airways by cilia beating within the periciliary layer (PCL). The PCL is held to be "watery" and free of mucus by thixotropic-like forces arising from beating cilia. With radii of gyration ~250 nm, however, polymeric mucins should reptate readily into the PCL, so we assessed the glycocalyx for barrier functions. The PCL stained negative for MUC5AC and MUC5B, but it was positive for keratan sulfate (KS), a glycosaminoglycan commonly associated with glycoconjugates. Shotgun proteomics showed KS-rich fractions from mucus containing abundant tethered mucins, MUC1, MUC4, and MUC16, but no proteoglycans. Immuno-histology by light and electron microscopy localized MUC1 to microvilli, MUC4 and MUC20 to cilia, and MUC16 to goblet cells. Electron and atomic force microscopy revealed molecular lengths of 190-1,500 nm for tethered mucins, and a finely textured glycocalyx matrix filling interciliary spaces. Adenoviral particles were excluded from glycocalyx of the microvilli, whereas the smaller adenoassociated virus penetrated, but were trapped within. Hence, tethered mucins organized as a space-filling glycocalyx function as a selective barrier for the PCL, broadening their role in innate lung defense and offering new molecular targets for conventional and gene therapies. PMID- 22929563 TI - Effect of matrix metalloproteinase and their inhibitors on atrial myocardial structural remodeling. AB - AIMS: To explore the expression of matrix metalloproteinase and tissue inhibitor of metalloproteinase of atrial myocardial structure of rheumatic and coronary heart disease. METHODS: Fifty patients with rheumatic heart disease (RHD) undergoing artificial mitral valve replacement surgery were selected: 20 with sinus rhythm and 30 with atrial fibrillation. Another 40 patients with coronary artery disease (CAD) undergoing coronary artery bypass surgery were selected: 22 with myocardial infarction (MI) and 18 with unstable angina. During thoractomy, samples of the right auricle were taken and immunohistochemical staining and fluorescence quantitative PCR were performed to test matrix metalloproteinase (MMP) 1, MMP-3, MMP-7, MMP-9, tissue inhibitor of metalloproteinase (TIMP) 1, TIMP-2, TIMP-3 and TIMP-4 expression of the samples. RESULTS: In RHD, the left and right atrial diameters of the atrial fibrillation group were significantly larger than those of the sinus rhythm group (P < 0.01), but there was no significant difference between the left ventricular diastolic diameter and the left ventricular ejection. The immunohistochemical staining and real-time (RT) PCR show that the expression of MMP-3, MMP-7, MMP-9, TIMP-1, TIMP-2, TIMP-3 and TIMP-4 were significantly increased in the atrial fibrillation group compared with the sinus rhythm group (all P < 0.01). The difference in MMP-1 of the two groups was not statistically significant. In CAD patients, the left and right atrial diameters and left ventricular diameter of the MI group were significantly larger than those of the unstable angina group (P < 0.01), but the left ventricular ejection fraction was obviously lower than that of the unstable angina group (P < 0.05). Immunohistochemical staining and RT-PCR show that the expression of MMP-3, MMP-9, TIMP-1 TIMP-2, TIMP-3, TIMP-4 were significantly increased in MI group compared with the unstable angina (P < 0.01, P < 0.01, P < 0.05, P < 0.05, P < 0.01 and P < 0.01, respectively). CONCLUSION: The expression of MMPs and TIMPs increased in RHD patients and MI patients. Regulating the expression and activity of MMPs and TIMPs may be an important clinical treatment and method to prevent, and even reverse, atrial remodeling. PMID- 22929564 TI - The importance of training in echocardiography: a validation study using pocket echocardiography. AB - AIMS: To investigate the training effect in echocardiography by using recent hand held ultrasound scanners (HANDs). METHODS: In this prospective study, 320 consecutive patients were scanned with HAND by an inexperienced ultrasonographer over a period of 8 weeks. Imaging studies were compared with high-end echocardiography as gold standard. Segmental endocardial border delineation was scored to describe image quality. Assessment of left ventricular dimensions, regional/global left ventricular function and grading of valve disease were compared. RESULTS: A significant reduction in examination duration, improvement in image quality, substantial agreement in functional assessment (kappa > 0.61, P < 0.01) and wall motion scoring (kappa=0.67, P < 0.01) could be observed over time. The correlation in left ventricular measurements was excellent (r > 0.98, P < 0.01). The detection of valve diseases and pericardial effusions was sufficient, but the grading only moderate (kappa < 0.6). CONCLUSION: Well grounded training in echocardiography leads to a rapid improvement in image acquisition and interpretation over a period of a few weeks. Basic diagnostic findings could be interpreted with high accuracy after short training. Interpretation of complex findings remained difficult. The time needed to carry out an examination using pocket echocardiography could not be reduced to less than 3-4 min per patient. New educational concepts are warranted. PMID- 22929561 TI - Ancient T-independence of mucosal IgX/A: gut microbiota unaffected by larval thymectomy in Xenopus laevis. AB - Many studies address the influence of the gut microbiome on the immune system, but few dissect the effect of T cells on gut microbiota and mucosal responses. We have employed larval thymectomy in Xenopus to study the gut microbiota with and without the influence of T lymphocytes. Pyrosequencing of 16S ribosomal RNA genes was used to assess the relative abundance of bacterial groups present in the stomach, small and large intestine. Clostridiaceae was the most abundant family throughout the gut, while Bacteroidaceae, Enterobacteriaceae, and Flavobacteriaceae also were well represented. Unifrac analysis revealed no differences in microbiota distribution between thymectomized and unoperated frogs. This is consistent with immunization data showing that levels of the mucosal immunoglobulin IgX are not altered significantly by thymectomy. This study in Xenopus represents the oldest organisms that exhibit class switch to a mucosal isotype and is relevant to mammalian immunology, as IgA appears to have evolved from IgX based upon phylogeny, genomic synteny, and function. PMID- 22929565 TI - Pulse pressure and mild cognitive impairment. AB - OBJECTIVE: Patients with suboptimal blood pressure (BP) control may remain with an elevated cardiovascular risk and risk for cognitive impairment. Pulse pressure (PP) assessed with ambulatory BP monitoring (ABPM) or self-measurement so far has been an underestimated risk factor for target organ damage. METHODS: One hundred and forty-eight patients were screened: 51 men (34.5%) and 97 women (65.5%), mean age 64.16 +/- 11.18 years and a mean hypertension history of 13.1 +/- 11.05 years. We gathered full medical and hypertension history, physical examination, laboratory screening and ambulatory blood pressure monitoring. Neuropsychological profile was assessed with tests (NPTs): Mini Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA). RESULTS: Regression analysis found a correlation between day and night PP and NPT results. Mann-Whitney Test (alpha less than 0.05) was used to find a significant difference (P = 0.02 for MMSE) in the mean values of the NPT results between the groups with PP more than 50 and PP 50 mmHg or less. The result was not age dependent. There was also a significant difference between mean values of day-PP (P = 0.01) and night-PP (P = 0.02) between patients with cognitive impairment and those without (respectively more than 55 mmHg and less than 55 mmHg). CONCLUSION: Elevated PP during the day, the night or with self-measurement is correlated with cognitive impairment. It is a marker of large artery stiffness and target organ damage not only in the very elderly, but also in younger individuals (mean age 64.16 years). PMID- 22929566 TI - From intraplaque haemorrhages to plaque vulnerability: biological consequences of intraplaque haemorrhages. AB - Intraplaque hemorrhages are mainly related to inward neoangiogenesis, initiated from the adventitia by lipid-dependent outwardly convected signals, and by the immaturity of these neovessels, allowing leaks and hemorrhages. Repeated intraplaque hemorrhages play a major role in the evolution of thrombotic occlusive disease, similar to the role of intraluminal thrombus in the progression of abdominal aortic aneurysm toward rupture. Red blood cells (RBCs) are an important source of unesterified cholesterol, because their membranes are particularly cholesterol rich. This unesterified cholesterol is rapidly organized in cholesterol crystals, highly toxic for cell and membranes. Oxidized cholesterol and LDL provoke the irreversible covalent aggregation of proteins, including hemoglobin, forming ceroids, which are also highly toxic. Hemoglobin play a major role of prooxydant molecules in this context, by its ability to release heme and iron, the main catalyser of oxidative reaction. In the context of type 2 diabetes, the oxidative potential of intraplaque-free hemoglobin play a predominant role in the progression of atherothrombotic disease toward clinical expression. Associated to RBC, intraplaque hemorrhages convey leukocyte, mainly neutrophils in human, and plasma zymogen that are the main source of proteases, including coagulation proteases, activation of the fibrinolytique system, release of leukocyte serine proteases and cathepsins and activation of MMPs. These proteases concentrate in the hemorrhagic/necrotic core rendered plaque highly vulnerable. An adaptive immune response takes place in the adventitia, in regard of hemorrhagic plaques, in relation to outwardly convected oxidized or proteolyzed neoantigens, and chemokinic signals. Finally, intraplaque hemorrhages and thrombi are the site of weak pathogen entrapment, which promote all these oxydative and proteolytic phenomenons. PMID- 22929567 TI - Successful management of a huge thrombus in coronary aneurysmatic dilatation after failed mechanical thrombectomy during acute myocardial infarction. AB - The benefit of the routine application of aspiration thrombectomy in primary percutaneous coronary intervention (PPCI) is now well established. The optimal management of patients who have 'failed' thrombectomy, characterized by a large residual thrombus burden after repeated mechanical thrombectomy, however, is not known. We report a case of failed aspiration thrombectomy in a 55-year-old man who was admitted to our institution with chest pain non-ST-elevation myocardial infarction due to a huge nonocclusive thrombus in an aneurysmatic segment of the left anterior descending coronary artery. Aspiration thrombectomy did little to reduce thrombus load and so the patient was treated with unfractioned heparin infusion and warfarin. Repeat coronary angiography at 7 days revealed complete thrombus resolution with thrombolysis in myocardial infarction grade 3 anterograde flow.This case demonstrates the potential for appropriate anticoagulation therapy as a treatment option for the management of patients following failed thrombectomy in PPCI. PMID- 22929568 TI - Randomized trial of standard versus ClearWay-infused abciximab and thrombectomy in myocardial infarction: rationale and design of the COCTAIL II study. AB - BACKGROUND: Patients with ST-elevation myocardial infarction (STEMI) are at substantial risk of suboptimal procedural results and late adverse events. Angiography and optical coherence tomography (OCT) studies have identified residual coronary thrombus and microcirculatory injury as potential culprits for these adverse outcomes. We hypothesized that coronary thrombectomy and local infusion of glycoprotein IIb/IIIa inhibitors by means of a dedicated infusion device can synergistically improve results of percutaneous coronary intervention (PCI) for STEMI, as appraised by OCT. METHODS: A total of 128 patients with STEMI will be randomized, to one of the following: abciximab infusion with the ClearWay coronary catheter (C), standard abciximab infusion (A), thrombectomy followed by abciximab infusion with the ClearWay catheter (T+C), or thrombectomy followed by standard abciximab infusion (T+A). The primary objective is to demonstrate that abciximab infusion with the ClearWay catheter with or without manual thrombus aspiration (groups C or T+C) will result in a significant reduction of intrastent thrombus formations when compared with intravenous or intracoronary abciximab with or without thrombectomy (groups A or T+A). The primary endpoint will be the number of cross-sections with thrombus area more than 10% immediately after stent implantation as assessed with OCT. Additional angiographic, ECG and clinical endpoints will be collected and adjudicated. CONCLUSION: This trial will provide important mechanistic insights on the most appropriate invasive treatment strategy for patients with STEMI and significant thrombus burden, by exploiting its factorial design and reliance on sensitive OCT endpoints. PMID- 22929569 TI - Enterococcus septicemia due to a pacemaker lead infection. AB - Pacemaker lead infections are rare but potentially life threatening. We report the case of an 80-year-old pacemaker-dependent female patient with complete heart block, who presented with subfebrile temperatures and chills due to a pacemaker lead infection by Enterococcus faecalis. PMID- 22929571 TI - [Cheating in scientific articles]. PMID- 22929570 TI - Nectin like-5 overexpression correlates with the malignant phenotype in cutaneous melanoma. AB - NECL-5 is involved in regulating cell-cell junctions, in cooperation with cadherins, integrins and platelet-derived growth factor receptor, that are essential for intercellular communication. Its role in malignant transformation was previously described. It has been reported that transformation of melanocytes is associated with altered expression of adhesion molecules suggesting the potential involment of NECL-5 in melanoma development and prognosis. To shed light on this issue, the expression and the role of NECL-5 in melanoma tissues was investigated by bioinformatic and molecular approaches. NECL-5 was up regulated both at the mRNA and the protein levels in WM35, M14 and A375 cell lines compared with normal melanocytes. A subsequent analysis in primary and metastatic melanoma specimens confirmed "in vitro" findings. NECL-5 overexpression was observed in 53 of 59 (89.8%) and 12 of 12 (100%), primary melanoma and melanoma metastasis, respectively; while, low expression of NECL-5 was detected in 12 of 20 (60%) benign nevi. A significant correlation of NECL-5 overexpression was observed with most of known negative melanoma prognostic factors, including lymph-node involvement (P = 0.009) and thickness (P = 0.004). Intriguingly, by analyzing the large series of melanoma samples in the Xu dataset, we identified the transcription factor YY1 among genes positively correlated with NECL-5 (r = 0.5). The concordant computational and experimental data of the present study indicate that the extent of NECL-5 expression correlates with melanoma progression. PMID- 22929572 TI - [Generic prescription should be evaluated as new way of prescription in Denmark]. PMID- 22929573 TI - [Medical mistakes due to generic substitution]. AB - Generic substitution is a major cause of medical mistakes in the general population. Danish legislation obligates pharmacies to substitute prescribed medicine with the cheapest equivalent formulation, despite variations in product name, packaging, shape and colour. Consequently, medical mistakes occur. Scientific evidence on the consequences of generic substitution is sparse. Call upon fellow health workers to report medical mistakes to the national entities and scientific peers, in order to increase awareness and scientific evidence about the problem. PMID- 22929574 TI - [Uncertain whether weight-reducing diet lowers the risk of early death in hypertensive patients]. AB - The Cochrane review "Long-term effects of weight-reducing diets in hypertensive patients" fails to evaluate the primary outcomes of mortality and morbidity. It is uncertain whether weight loss in general reduces the risk of cardiovascular disease and death as the relation between intentional weight loss and mortality is biased by reverse causation. Weight loss is a potent risk factor of weight regain and weight cycling is associated to early death. Recommendations on weight loss should be individualized and focused on promotion of a healthy and active lifestyle rather than counting kilos. PMID- 22929575 TI - [A procalcitonin-guided algorithm for pneumonia may reduce antibiotic use and treatment duration]. AB - Reduction of antimicrobial resistance in microorganisms is imperative. Pneumonia is important in this matter because of its high incidence, subjective diagnostic criteria, and variations in aetiology. Research has focused on the use of a procalcitonin-guided algorithm for antimicrobial stewardship with promising reductions in antibiotic use and treatment duration, but more research is needed in order to draw a final conclusion. Lack of objective diagnostic criteria, methodological challenges in research, a future focus on primary care, and the need for a cost-benefit analysis should be considered. PMID- 22929576 TI - [Sublingual immunotherapy in children with grass pollen induced allergic rhinoconjunctivitis]. AB - Specific immunotherapy is the only current treatment that may modify the disease process in allergic rhinoconjunctivitis. Recent studies have evidenced that sublingual administration of grass extract tablets is an efficacious, safe and convenient form of specific immunotherapy in children with grass pollen induced allergic rhinoconjunctivitis. It is recommended that daily treatment is initiated four months before the pollen season begins and continued through three years, though paediatric studies of long-term and potential asthma and allergy prevention effects are still awaited. PMID- 22929577 TI - [Information campaigns can reduce unnecessary prolonged time of thirst in elective surgical patients]. AB - This prospective study was aimed at identifying the time of thirst above the recommended two hours after repeated information campaigns. Elective surgical patients >= 15 years of age were eligible to answer the questionnaire in four different periods between which information campaigns were carried out. A total of 765 patients were included. The median time of thirst was reduced from 6.5 hours to 3.0 hours (p < 0.0001) over a two-year period. Repeated interventions were found to be necessary to reduce the period of thirst to the recommended two hours for elective surgical patients. PMID- 22929578 TI - [Charcots arthropathy causing hypoparathyroid hypercalcaemia]. AB - A 45-year-old woman with type 2 diabetes and multiple diabetic complications was diagnosed with hypoparathyroid hypercalcaemia. The bone scintigraphy showed Charcots arthropathy. Blood tests, computer tomography and mammography did not give any indication of malignancy, vitamin-D intoxication nor hyperthyroidism. Charcots arthropathy is not a recognized cause of hypoparathyroid hypercalcaemia, but the mechanism might be increased boneresorption. We recommend that Charcots arthropathy is considered a cause of hypoparathyroid hypercalcaemia in patients with diabetic neuropathy. PMID- 22929579 TI - [Fungal infection secondary to treatment of Escherichia coli in a critically ill patient]. AB - The incidence of nosocomial fungal infections has increased over the past 20 years. Candida albicans is the most commonly involved pathogen. Concurrently, the number of non-albicans species with decreased susceptibility to commonly used antifungal agents has increased significantly. Invasive candidiasis is associated with significant morbidity and mortality. We present a case of unusually massive infection with a number of different Candida species, which caused severe prolonged infection in a critically ill patient. PMID- 22929580 TI - [Endometriosis as a cause of pneumothorax]. AB - A young woman, who had formerly been diagnosed with endometriosis, was admitted to hospital with five incidents of right-sided spontaneous pneumothorax. Despite two thoracoscopic operations the pneumothorax reoccurred. The third operation revealed histologically verified endometriotic tissue of the diaphragm causing diaphragmatic fenestrations. It was concluded that the patient suffered from catamenial pneumothorax, where transdiaphragmatic passage of air from the cervix through the peritoneum during the menstruation period is believed to cause pneumothorax. PMID- 22929581 TI - [Neck pain in children can be caused by a retropharyngeal abscess]. AB - A six-year-old boy presented with fever, neck pain, and ear pain. Within days, the motility of his neck limited, his temperature rose, and blood samples showed signs of infection. On suspicion of cervical spondylodiscitis, a bone scintigraphy was performed, but gave negative results. A magnetic resonance imaging of the neck area showed results, which led to the diagnosis of a retropharyngeal abscess. This case is a reminder that retropharyngeal abscess poses a diagnostic challenge for the physician, and that the prognosis is potentially serious. PMID- 22929582 TI - Health disparities in the genomic era: the case for diversifying ethnic representation. AB - A report on the meeting 'Why we can't wait: conference to eliminate health disparities in genomic medicine', Miami, Florida, USA, 31 May to 1 June 2012. PMID- 22929583 TI - Biologic resurfacing of the glenoid with meniscal allograft: long-term results with minimum 2-year follow-up. AB - BACKGROUND: There is a lack of consensus in treating glenohumeral arthritis in younger patients. Hemiarthroplasty has historically been favored because of complications associated with total shoulder arthroplasty. Biologic resurfacing of the glenoid has been investigated as a potential treatment that would decrease glenoid erosion and pain, the major complications of hemiarthroplasty. MATERIALS AND METHODS: We report on 19 shoulders treated with meniscal allograft glenoid resurfacing and shoulder hemiarthroplasty. All patients were followed up for a minimum of 2 years postoperatively (mean, 4.25 years) with Disabilities of the Arm, Shoulder and Hand (DASH), Simple Shoulder Test (SST), and visual analog scale (VAS) scores. In addition, we compared the outcomes related to preoperative concentric versus eccentric glenoid wear. RESULTS: At final follow-up, the mean score for the DASH questionnaire was 28; SST, 8; and VAS, 3.5. Whereas the eccentric wear group (DASH score, 19.4; SST score, 9.1; VAS score, 2.5) exhibited better shoulder function and pain scores compared with the concentric wear group (DASH score, 37.6; SST score, 8.4; VAS score, 4.1), the difference was not statistically significant (P = .098, P = .647, and P = .198, respectively). There were 6 complications (32%), all resulting in repeat surgery. Three patients underwent total shoulder arthroplasty and one shoulder had revision hemiarthroplasty, whereas synovectomy was performed in another shoulder. The sixth patient underwent lysis of adhesions and capsular release. DISCUSSION: With long-term follow-up, we have observed that biologic resurfacing of the glenoid with meniscal allograft exhibits inconsistent results and high complication rates. Strong consideration should be given to performing total shoulder arthroplasty in patients in whom all conservative treatment options have failed. PMID- 22929584 TI - Coracoid graft dimensions after harvesting for the open Latarjet procedure. AB - BACKGROUND: Recent studies have reported the theoretic amount of coracoid graft available for harvesting with the Latarjet procedure. Our aim was to investigate the actual dimensions of coracoid grafts harvested using a standardized technique. We also hoped to confirm previous recommendations regarding placement of the inferior glenoid drill hole to avoid lateral overhang of the graft. MATERIALS AND METHODS: Intraoperative measurements were taken after coracoid graft harvesting and preparation during the Latarjet procedure. Specifically, we measured the length of coracoid, thickness of coracoid, distance from the inferior drill hole to the lateral margin of the graft, distance between drill holes, width at the level of the superior drill hole, and width at the level of the inferior drill hole. RESULTS: Data were collected from 76 Latarjet procedures (67 men, 9 women). Patients were an average age of 28.7 years (range 16-67 years). Mean measurements were length of coracoid graft, 26.4 +/- 2.9 mm; thickness, 9.3 +/- 1.4 mm; distance from the edge of the inferior drill hole to the lateral margin of the graft, 5.7 +/- 1.1 mm; distance between drill holes, 7.8 +/- 1.9 mm; width at the level of the superior drill hole, 14.1 +/- 1.8 mm; and width at the level of the inferior drill hole, 13.3 +/- 1.8 mm. CONCLUSIONS: Using a standardized surgical technique that does not violate the coracoclavicular ligaments, a coracoid graft greater than 25 mm can routinely be harvested for the Latarjet procedure. The inferior glenoid drill hole should typically be placed at least 7 mm from the glenoid margin to avoid lateral overhang. PMID- 22929585 TI - Contribution of medullary raphe to control of coughing--codeine trials in cat. AB - In order to determine if a codeine-sensitive control system for cough exists in the medullary raphe four microinjections of codeine (3.3 and 16.5 mM; 36.6+/-0.7 nl 1.5 and 3 mm rostral to the obex at the depths 1.5 and 3 mm; the total dose 1.12+/-0.3 nmol, 9 animals) were performed on pentobarbitone anesthetized spontaneously breathing cats. Amplitudes of abdominal muscle EMG moving averages during mechanically induced tracheobronchial cough decreased by 18% compared to control coughs (p<0.05). The duration between maxima of cough diaphragm and abdominal muscle EMG discharge, cough expiratory phase duration and period of relative motor quiescence between coughs were increased (all p<0.05). Cough number, other cough parameters, and cardiorespiratory characteristics were not altered significantly. Control microinjections of artificial cerebro-spinal fluid had no effect on coughing. Codeine sensitive neurons involved in the generation or modulation of motor pattern of tracheobronchial cough are located in the medullary midline raphe nuclei; however, their contribution to codeine induced cough suppression is limited. PMID- 22929586 TI - Tracking the impact of translational research in psychiatry: state of the art and perspectives. AB - Personalized treatments have become a primary goal in translational psychiatric research. They include the identification of neural circuits associated with psychiatric disorders and definition of treatment according to individual characteristics. Many new tools and technologies have been developed but further efforts are required to provide clues on how these scientific advances in psychiatry may be translated into more effective therapeutic approaches. Obstacles to the progress of translational psychiatry also involve numerous scientific, financial, ethical, logistics and regulatory aspects. Also, the goal of DSM-5 to expand "signs and symptoms" classification to incorporate biological measures may help the development of new multifactorial and dimensional models able to better understand the pathophysiology of psychiatric disorders and develop improved treatments. Finally, a better understanding on the significant response variability, cognitive functioning, role of comorbidities and treatment resistant cases are critical for the development of prevention and intervention strategies that are more effective. PMID- 22929587 TI - Trends in availability and prices of subsidized ACT over the first year of the AMFm: evidence from remote regions of Tanzania. AB - BACKGROUND: The Affordable Medicines Facility for malaria (AMFm) is a pilot supra national subsidy program that aims to increase access and affordability of artemisinin combination therapy (ACT) in public sector clinics and private retail shops. It is unclear to what extent the AMFm model will translate into wide scale availability and price reductions in ACT, particularly for rural, remote areas where disparities in access to medicines often exist. This study is the first to rigorously examine the availability and price of subsidized ACT during the first year of the AMFm, measured through retail audits in remote regions of Tanzania. METHODS: Periodic retail audits of Accredited Drug Dispensing Outlets (ADDOs) were conducted in two remote regions of Tanzania (Mtwara and Rukwa). Temporal and spatial variation in ACT availability and pricing were explored. A composite measure of ADDO remoteness, using variables, such as distance to suppliers and towns, altitude and population density, was used to explore whether ACT availability and price vary systematically with remoteness. RESULTS: Between February 2011 and January 2012, the fraction of ADDOs stocking AMFm-ACT increased from 25% to 88% in Mtwara and from 3% to 62% in Rukwa. Availability was widespread, though diffusion throughout the region was achieved more quickly in Mtwara. No significant relationship was found between ACT availability and remoteness. Adult doses of AMFm-ACT were much more widely available than any other age/weight band. Average prices fell from 1529 TZS (1.03 USD) to 1272 TZS (0.81 USD) over the study period, with prices in Rukwa higher than Mtwara. The government recommended retail price for AMFm- ACT is 1,000 TZS ($0.64 USD). The median retail ACT price in the final round of data collection was 1,000 TZS. CONCLUSIONS: The AMFm led to large increases in availability of low priced ACT in Tanzania, with no significant variation in availability based on remoteness. Availability did remain lower and prices remained higher in Rukwa, which is a more remote region overall. Low availability of child and adolescent ACT doses could be due in part to lower quantities of non-adult packs imported into Tanzania. Future research will explore whether increased availability and affordability persists and whether it translates into higher ACT use in Tanzania. PMID- 22929589 TI - Effect of juvenile hormone analog, methoprene on H-fibroin regulation during the last instar larval development of Corcyra cephalonica. AB - Juvenile hormone (JH) and 20-hydroxyecdysone (20E), co-ordinately orchestrate insect growth and development. The process of silk synthesis and secretion in lepidopteran insects is known to be under hormonal control. However, the role of JH in this process has not been demonstrated hitherto. The present study is aimed to elucidate the role of JH in H-fibroin regulation in Corcyra cephalonica, a serious lepidopteran pest. Reiterated amino acid stretches and the large molecular weight of H-fibroin render its cloning and characterization cumbersome. To address this, a commercially synthesized short amino acid peptide conjugated with a carrier protein was used to generate antibodies against the N-terminal region of H-fibroin. ELISA and immunoblot experiments demonstrated the sensitivity and specificity of antibody. Further, immunohistochemical analyses revealed the antibody's cross-reactivity with H-fibroins of C. cephalonica and Bombyx mori in the silk gland lumen. Quantitative RT-PCR and Western blot analysis demonstrated the tissue-specificity and developmental expression of H fibroin. Hormonal studies revealed that JH alone does not alter the expression of H-fibroin. However, in the presence 20E, JH reverses the declined expression caused by 20E administration to normal levels. This study provides molecular evidence for the regulation of H-fibroin by the cumulative action of JH and 20E. PMID- 22929588 TI - Relationship between seasonal cold acclimatization and mtDNA haplogroup in Japanese. AB - BACKGROUND: The purpose of this study was to elucidate the interaction between mtDNA haplogroup and seasonal variation that contributes to cold adaptation. METHODS: There were 15 subjects (seven haplotype D subjects and eight haplotype non-D subjects). In summer and winter, the subjects were placed in an environment where the ambient temperature dropped from 27 degrees C to 10 degrees C in 30 minutes. After that, they were exposed to cold for 60 minutes. RESULTS: In summer, the decrease in rectal temperature and increase in oxygen consumption was smaller and cold tolerance was higher in the haplotype non-D group than in the haplotype D group. In winter, no significant differences were seen in rectal temperature or oxygen consumption, but the respiratory exchange ratio decreased in the haplotype D group. CONCLUSIONS: The results of the present study suggest that haplogroup D subjects are a group that changes energy metabolism more, and there appears to be a relationship between differences in cold adaptability and mtDNA polymorphism within the population. Moreover, group differences in cold adaptability seen in summer may decrease in winter due to supplementation by seasonal cold acclimatization. PMID- 22929590 TI - Orthographic processing is universal; it's what you do with it that's different. AB - We agree with Frost that the variety of orthographies in the world's languages complicates the task of "cracking the orthographic code." Frost suggests that orthographic processing must therefore differ between orthographies. We suggest that the same basic orthographic processes are applied to all languages. Where languages differ is in what the reader must do with the results of orthographic processing. PMID- 22929591 TI - Stochastic Boolean networks: an efficient approach to modeling gene regulatory networks. AB - BACKGROUND: Various computational models have been of interest due to their use in the modelling of gene regulatory networks (GRNs). As a logical model, probabilistic Boolean networks (PBNs) consider molecular and genetic noise, so the study of PBNs provides significant insights into the understanding of the dynamics of GRNs. This will ultimately lead to advances in developing therapeutic methods that intervene in the process of disease development and progression. The applications of PBNs, however, are hindered by the complexities involved in the computation of the state transition matrix and the steady-state distribution of a PBN. For a PBN with n genes and N Boolean networks, the complexity to compute the state transition matrix is O(nN22n) or O(nN2n) for a sparse matrix. RESULTS: This paper presents a novel implementation of PBNs based on the notions of stochastic logic and stochastic computation. This stochastic implementation of a PBN is referred to as a stochastic Boolean network (SBN). An SBN provides an accurate and efficient simulation of a PBN without and with random gene perturbation. The state transition matrix is computed in an SBN with a complexity of O(nL2n), where L is a factor related to the stochastic sequence length. Since the minimum sequence length required for obtaining an evaluation accuracy approximately increases in a polynomial order with the number of genes, n, and the number of Boolean networks, N, usually increases exponentially with n, L is typically smaller than N, especially in a network with a large number of genes. Hence, the computational efficiency of an SBN is primarily limited by the number of genes, but not directly by the total possible number of Boolean networks. Furthermore, a time-frame expanded SBN enables an efficient analysis of the steady-state distribution of a PBN. These findings are supported by the simulation results of a simplified p53 network, several randomly generated networks and a network inferred from a T cell immune response dataset. An SBN can also implement the function of an asynchronous PBN and is potentially useful in a hybrid approach in combination with a continuous or single-molecule level stochastic model. CONCLUSIONS: Stochastic Boolean networks (SBNs) are proposed as an efficient approach to modelling gene regulatory networks (GRNs). The SBN approach is able to recover biologically-proven regulatory behaviours, such as the oscillatory dynamics of the p53-Mdm2 network and the dynamic attractors in a T cell immune response network. The proposed approach can further predict the network dynamics when the genes are under perturbation, thus providing biologically meaningful insights for a better understanding of the dynamics of GRNs. The algorithms and methods described in this paper have been implemented in Matlab packages, which are attached as Additional files. PMID- 22929592 TI - Equity of access to kidney transplantation: to what extent should international guidelines differ? PMID- 22929593 TI - Charcot neuroarthropathy after simultaneous pancreas-kidney transplant. AB - BACKGROUND: Immunosuppressive regimen is associated with several metabolic adverse effects. Bone loss and fractures are frequent after transplantation and involve multifactorial mechanisms. METHODS: A retrospective analysis of 130 patients submitted to simultaneous pancreas-kidney transplantation (SPKT) and an identification of risk factors involved in de novo Charcot neuroarthropathy by multivariate analysis were used; P<0.05 was considered significant. RESULTS: Charcot neuroarthropathy was diagnosed in 4.6% of SPKT recipients during the first year. Cumulative glucocorticoid doses (daily dose plus methylprednisolone pulse) during the first 6 months both adjusted to body weight (>78 mg/kg) and not adjusted to body weight were associated with Charcot neuroarthropathy (P=0.001 and P<0.0001, respectively). Age, gender, race, time on dialysis, time of diabetes history, and posttransplantation hyperparathyroidism were not related to Charcot neuroarthropathy after SPKT. CONCLUSIONS: Glucocorticoids are the main risk factors for de novo Charcot neuroarthropathy after SPKT. Protocols including glucocorticoid avoidance or minimization should be considered. PMID- 22929594 TI - Long-term tolerance to kidney allografts after induced rejection of donor hematopoietic chimerism in a preclinical canine model. AB - BACKGROUND: Allogeneic hematopoietic cell transplantation provides a reliable method for inducing tolerance toward solid organ grafts. However, this procedure can result in graft-versus-host disease, thereby limiting its application. Here, we test the hypothesis that mixed chimerism can be intentionally reverted to host hematopoiesis without rejection of a kidney graft. METHODS: Recipient dogs were given 2-Gy total-body irradiation (TBI) before and a short course of immunosuppression after marrow infusion from dog leukocyte antigen-identical littermates. All dogs achieved stable mixed chimerism. After a mean of 20 weeks, one cohort of dogs received kidney transplants from their respective marrow donors. Subsequently, recipients were reconditioned with 2-Gy TBI and given autologous granulocyte colony-stimulating factor-mobilized leukocytes (recipient leukocyte infusion [RLI]) that had been collected before marrow transplantation. RESULTS: Dogs receiving a second TBI and RLI without a kidney transplant rejected their donor hematopoietic graft within 3 weeks. Dogs that received kidney grafts, followed by a second TBI and RLI, rejected their marrow graft without rejecting their transplanted kidneys for periods greater than 1 year. CONCLUSION: Mixed chimerism may be clinically reverted to 100% recipient without rejection of a kidney allograft. This finding may have application toward minimizing the risk of graft-versus-host disease in solid organ transplantation patients given hematopoietic cell transplantation from human leukocyte antigen-identical donors. PMID- 22929595 TI - High transplant rates of highly sensitized recipients with virtual crossmatching in kidney paired donation. AB - BACKGROUND: In kidney paired donation (KPD), flexibility in the allocation of incompatible pairs is required if a critical mass of pairs to efficiently find matches cannot be reached. METHODS: In the Australian KPD program, virtual crossmatch is used for the allocation of suitable donors to registered recipients. Matching is based on acceptable mismatches, and donors are excluded from matching to recipients with donor-specific antibodies (DSAs) greater than 2000 mean fluorescence intensity (MFI). Match and transplant rates in the first year of the program were reviewed with respect to recipient and donor characteristics, including blood group distribution, level of recipient's sensitization, and postallocation crossmatches. RESULTS: Four quarterly match runs were performed, which included 53 pairs and 2 altruistic donors. Human leukocyte antigen incompatibility accounted for 90% of the listed pairs. In the second run, the DSA threshold was increased to greater than 8000 MFI, because no matches were found with standard allocation. Optional ABO-incompatible matching was introduced from run 3. Matches were identified in 37 (70%) patients, of whom 92% had a negative crossmatch with their matched donor. Crossmatch positive results were found only in recipients with DSAs greater than 2000 MFI in the second run. In 4 cases immunological reasons and in 4 cases other reasons resulted in breakdown of chains and 17 patients not progressing to transplantation. Eventually, 20 (38%) patients received a KPD transplant, and 35% of these had a calculated panel-reactive antibody greater than 90%. CONCLUSIONS: KPD using virtual crossmatch is a valid and effective solution for patients with immunologically incompatible donors even in the context of highly sensitized recipients. PMID- 22929596 TI - Frost and fogs, or sunny skies? Orthography, reading, and misplaced optimalism. AB - I argue that the study of variability rather than invariance should head the reading research agenda, and that strong claims of orthographic "optimality" are unwarranted. I also expand briefly on Frost's assertion that an efficient orthography must represent sound and meaning, by considering writing systems as dual-purpose devices that must provide decipherability for novice readers and automatizability for the expert. PMID- 22929597 TI - Modeling socially anhedonic syndromes: genetic and pharmacological manipulation of opioid neurotransmission in mice. AB - Social anhedonia, or the diminished capacity to experience pleasure and reward from social affiliation, is a major symptom of different psychiatric disorders, including some forms of infantile autism and schizophrenia spectrum disorders. The brain opioid hypothesis of social attachment is a promising model for achieving insights into how neurobiological and developmental factors contribute to the regulation of social reward. In this study, genetic knocking-out and naltrexone (NTRX) treatment during the first 4 days of life were used to disrupt opioid neurotransmission in mouse pups and their attachment relationships with the mother. Both permanent (genetic) and transient (pharmacological) manipulations of opioid neurotransmission exerted long-term effects on social affiliation. When juveniles, both MU-opioid receptor knockout mice and NTRX treated pups showed reduced interest in peers and no preference for socially rewarding environment. These results demonstrate that sociability in juvenile mice is highly dependent on the establishment during infancy of a positive affective relationship with their mothers and that opioid neurotransmission has a major role in the regulation of social hedonic capacity. If the validity of this animal model will be confirmed by future research, translational studies focusing on the interaction between early experience and opioid neurotransmission could provide useful insights for identifying endophenotypes of human psychiatric disorders associated with social anhedonia. PMID- 22929598 TI - Study protocol of a mixed-methods evaluation of a cluster randomized trial to improve the safety of NSAID and antiplatelet prescribing: data-driven quality improvement in primary care. AB - BACKGROUND: Trials of complex interventions are criticized for being 'black box', so the UK Medical Research Council recommends carrying out a process evaluation to explain the trial findings. We believe it is good practice to pre-specify and publish process evaluation protocols to set standards and minimize bias. Unlike protocols for trials, little guidance or standards exist for the reporting of process evaluations. This paper presents the mixed-method process evaluation protocol of a cluster randomized trial, drawing on a framework designed by the authors. METHODS/DESIGN: This mixed-method evaluation is based on four research questions and maps data collection to a logic model of how the data-driven quality improvement in primary care (DQIP) intervention is expected to work. Data collection will be predominately by qualitative case studies in eight to ten of the trial practices, focus groups with patients affected by the intervention and quantitative analysis of routine practice data, trial outcome and questionnaire data and data from the DQIP intervention. DISCUSSION: We believe that pre specifying the intentions of a process evaluation can help to minimize bias arising from potentially misleading post-hoc analysis. We recognize it is also important to retain flexibility to examine the unexpected and the unintended. From that perspective, a mixed-methods evaluation allows the combination of exploratory and flexible qualitative work, and more pre-specified quantitative analysis, with each method contributing to the design, implementation and interpretation of the other.As well as strengthening the study the authors hope to stimulate discussion among their academic colleagues about publishing protocols for evaluations of randomized trials of complex interventions. DATA DRIVEN QUALITY IMPROVEMENT IN PRIMARY CARE TRIAL REGISTRATION: ClinicalTrials.gov: NCT01425502. PMID- 22929599 TI - Will recent murder charges filed against physicians for opioid-related deaths affect pain management? PMID- 22929600 TI - Kangaroo care and behavioral and physiologic pain responses in very-low-birth weight twins: a case study. AB - The purpose of this case study was to describe pain responses in three study conditions: longer (30 minutes) kangaroo care (KC) before and throughout heel stick (KC30), shorter (15 minutes) KC before and throughout heel stick (KC15), and incubator care throughout heel stick (IC) in 28-week gestational age twins. Pain responses were measured by crying time, Preterm Infant Pain Profile (PIPP), and heart rate variability indexes, including low-frequency power (LF, representing sympathetic activity), high-frequency power (HF, parasympathetic activity), and LF/HF ratio (sympathetic-parasympathetic balance). Both twins cried more and had higher PIPP pain scores and tachycardia during heel stick in the IC condition. Infant B had an incident of apnea and tachycardia by the end of the heel stick and a bradycardia episode during recovery in the IC condition. The twins had lower LF/HF ratios (better autonomic nervous system balance) during recovery in both longer and shorter KC conditions compared with the IC condition. Infant B had difficulty returning to LF/HF ratio baseline level after the painful procedure in the IC condition. These data suggest that both longer and shorter KC before and throughout painful procedures can be helpful in reducing behavioral and physiologic pain responses in preterm infants. PMID- 22929601 TI - Effectiveness of oral sucrose for pain management in infants during immunizations. AB - This study examined the effects of oral sucrose as an analgesic agent during routine immunization for infants at 2, 4, and 6 months of age. A sample of 113 healthy infants were recruited from three ambulatory clinics and randomly assigned to one of three treatment groups. Infants were given 2 mL orally of either 50% sucrose, 75% sucrose, or sterile water 2 minutes before administration of immunizations. No significant difference was found among the different age groups with the different treatments for pain as measured with the FLACC scores and crying time. Consolability factors are felt to have some influence. PMID- 22929602 TI - Postoperative pain: acupuncture versus percutaneous electrical nerve stimulation. AB - The purpose of this study was to examine the effect of traditional acupuncture compared with acupuncture with percutaneous electrical nerve stimulation (PENS) on postoperative surgical pain relief in gynecologic oncology patients. Twenty postoperative gynecologic oncology patients were randomly assigned into the two groups, and the intervention was initiated within 24 hours after surgery. The patients in each group received four treatments in the subsequent 48 hours, with 12 hours between each treatment. Either traditional acupuncture needles or acupuncture needles with a pulsed electric current were applied to stimulate the area of points Sp6 and Sp8 near the saphenous nerve. Pain measurement instruments included a visual analog scale and the McGill Pain Questionnaire. Although the PENS treatment group demonstrated a consistent decrease in pain with each treatment application compared with the traditional acupuncture group, after 48 hours both groups experienced equivalent pain relief. PMID- 22929603 TI - Biobehavioral measures for pain in the pediatric patient. AB - Pain is a complex biobehavioral phenomenon. The quantification of pain involves the incorporation of many factors, including physiologic, behavioral, and psychologic factors. Recognition of pain relies heavily on the expression of the patient as well as the interpretation of the caregiver. There are many studies published on biobehavioral pain assessment tools, such as neuroimaging, neuromuscular, biomarker, and behavioral pain assessment scales. These tools present a clinical challenge to appropriately assess and manage pain in the noncommunicative pediatric patients, such as infants, preverbal toddlers, and intubated and/or unconscious or cognitively impaired patients. Pain is a combination of physiologic, behavioral, and psychologic interactions. Any tool that incorporates the measurement of only one of those domains is inherently incomplete in the assessment of pain. Therefore, the purpose of this literature review was to provide a comprehensive overview of these biobehavioral pain assessment tools used in pain assessment in the noncommunicative pediatric population. PMID- 22929606 TI - The influence of juggling on mental rotation performance in children with spina bifida. AB - This study examined the influence of juggling training on mental rotation ability in children with spina bifida. Children between the ages of 8 and 12 solved a chronometric mental rotation test. Half of the children received juggling training (EG) over an 8 week time period; the other half did not receive training (CG). Afterwards, all participants completed the mental rotation test again. Children of the EG showed a significant decrease in reaction time and an increase in mental rotation speed compared to the control group. This indicates that juggling improves the rotation in the mental rotation process in children with spina bifida. PMID- 22929604 TI - American Society for Pain Management nursing position statement: pain management in patients with substance use disorders. AB - The American Society for Pain Management Nursing (ASPMN) has updated its position statement on managing pain in patients with substance use disorders. This position statement is endorsed by the International Nurses Society on Addictions (IntNSA) and includes clinical practice recommendations based on current evidence. It is the position of ASPMN and IntNSA that every patient with pain, including those with substance use disorders, has the right to be treated with dignity, respect, and high-quality pain assessment and management. Failure to identify and treat the concurrent conditions of pain and substance use disorders will compromise the ability to treat either condition effectively. Barriers to caring for these patients include stigmatization, misconceptions, and limited access to providers skilled in these two categories of disorders. Topics addressed in this position statement include the scope of substance use and related disorders, conceptual models of addiction, ethical considerations, addiction risk stratification, and clinical recommendations. PMID- 22929607 TI - Stress sensitive healthy females show less left amygdala activation in response to withdrawal-related visual stimuli under passive viewing conditions. AB - The amygdalae are key players in the processing of a variety of emotional stimuli. Especially aversive visual stimuli have been reported to attract attention and activate the amygdalae. However, as it has been argued that passively viewing withdrawal-related images could attenuate instead of activate amygdalae neuronal responses, its role under passive viewing conditions remains unclear. Furthermore, because individual sensitivity to stress reactions has been shown to modulate amygdalae processing, the aim of the current event-related fMRI study was to investigate whether individual differences in stress proneness could influence amygdala responses while passively viewing withdrawal and approach related visual images. We presented 14 healthy female subjects with a random sequence of images of happy 'healthy' baby faces (approach-related) and baby faces disfigured by severe dermatological conditions (withdrawal-related). No instructions were given other than to watch the images attentively. We integrated individual perceived stress (PSS) scores in our analysis. The processing of withdrawal-related pictures resulted in less left amygdala activity in females scoring higher on perceived stress. Our findings suggest that stress-sensitive healthy females are less able to fully attend to withdrawal-related visual material and in essence avoid exposure to such images in an effort to reduce strong psychophysiological responses. Although the relatively small number of participants limits drawing firm conclusions, we suggest that in passive viewing emotional brain imaging paradigms, individual information on stress proneness should be included in the interpretation of amygdala neuronal processes. PMID- 22929608 TI - Primary aldosteronism: evidence against a second epidemic. AB - Primary aldosteronism is widely held to be the most common cause of identifiable (secondary) hypertension, reported to be present in 6-10% of all hypertensive patients. This belief reflects the widespread use of the aldosterone-to-renin ratio (ARR) as a screening test. Unfortunately, the ARR is often wrong, leading to even more expensive testing that is also often misleading but that may then lead to potentially harmful additional measures. This review provides evidence that referral bias has markedly inflated the estimates of this condition and recommends a much less aggressive approach to the diagnosis of this condition based on more limited testing and the use of mineralocorticoid receptor antagonists in the treatment of most hypertensive patients. PMID- 22929609 TI - Ultimately we are in furious agreement. PMID- 22929610 TI - Angiotensin-converting enzyme inhibitor/angiotensin II receptor blockers and pneumonia risk among stroke patients. AB - OBJECTIVE: To investigate the effect of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers on pneumonia hospitalization in patients with stroke history in Taiwan. METHODS: We conducted a case-crossover study using the National Health Insurance Research Database in Taiwan during the period from 1998 to 2007. Patients who had stroke history and were subsequently admitted for pneumonia were enrolled for analysis. The status of exposure to angiotensin converting enzyme inhibitors and angiotensin II receptor blockers 1-30 days prior to admission (case period) was compared to that during 91-120 days and 181-210 days before admission (control periods) for each patient. Conditional logistic regression was used to estimate the odds ratio (OR) and 95% confidence interval (95% CI) for the association between pneumonia and use of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers. RESULTS: In this study, 13 832 patients with incident pneumonia from the stroke patient population were enrolled. After adjustment for time-varying confounding factors, angiotensin converting enzyme inhibitor use was associated with a decreased pneumonia risk (OR 0.70; 95% CI 0.68-0.87) and a significant dose-response relationship (P < 0.01). The pneumonia risk associated with angiotensin II receptor blockers use was not significant (OR 1.02; 95% CI 0.87-1.19). CONCLUSIONS: Our study revealed a significant protective effect with dose-response relationship of angiotensin converting enzyme inhibitor use on hospitalization for pneumonia among stroke patients. Further studies to confirm the protective effect of angiotensin converting enzyme inhibitor use on pneumonia risk are warranted. PMID- 22929611 TI - Meal-induced blood pressure variation and cardiovascular mortality in ambulatory hypertensive elderly patients: preliminary results. AB - OBJECTIVES: This prospective cohort study was designed to investigate the prevalence and the prognostic value of postprandial hypotension (PPH) in ambulatory hypertensive elderly patients without overt heart diseases, an issue that has never been evaluated so far. METHODS: All patients consecutively referred to our cardiologic clinic in the period from January 2005 to August 2009, were enrolled in the study and underwent a 24-h ambulatory arterial blood pressure monitoring (ABPM). PPH has been defined as a decrease in SBP of 20 mmHg within 2 h after a meal. RESULTS: Four hundred and one patients were enrolled (mean age 77.7 +/- 11 years, males 47.7%). Hypertension was not adequately controlled in 290 (72.3%) patients. PPH was found in 292 of 401 (72.8%) patients. A value of 10 mmHg or higher of SD SBP was predictive of PPH, with a sensitivity and specificity of 87 and 57%, respectively. At each meal, patients with higher SBP readings before meal had the greatest decrease in SBP (P < 0.001). During the follow-up, 34 patients died for cardiovascular causes. Breakfast BP variation was the most predictive variable of cardiovascular mortality (B = 0.020, P = 0.04, HR 1.020, IC 1.001-1.040). CONCLUSION: In our population, PPH was common. A diurnal standard deviation of SBP of 10 mmHg or higher was suggestive of its presence. ABPM identified breakfast BP decrease as a possible new risk factor for cardiovascular mortality. PMID- 22929612 TI - Membranoproliferative glomerulonephritis associated with influenza A infection. AB - A 24-year-old man with normal renal function developed influenza A with subsequent onset of hematuria, proteinuria, hypocomplementemia, hypertension and acute kidney injury. Renal biopsy showed mesangial hypercellularity, intratubular red blood cell casts, mesangial immunoglobulin M and C3 deposition, arterial C3 and C1q deposition, and foot process effacement most consistent with membranoproliferative glomerulonephritis. Six months after presentation, all manifestations of the glomerulonephritis resolved. We report the only documented case of membranoproliferative glomerulonephritis associated with influenza A is reported. PMID- 22929613 TI - Reversible renal glycosuria in acute interstitial nephritis. AB - Renal glycosuria is defined as the excretion of glucose in urine in a normoglycemic state. It results from renal tubular dysfunction or immaturity of tubular function in the newborn. Etiologically, renal glycosuria is of 3 types benign renal glycosuria, glycosuria with diabetes mellitus (including gestational diabetes) and tubular defects (Fanconi syndrome). Prognosis of benign renal glycosuria is excellent and reversible. Acute interstitial nephritis (AIN) is one of the main causes of acute renal failure and may often result in tubular dysfunction. In this study, the authors report the occurrence of AIN with acute renal failure that contributed to reversible renal glycosuria. The glycosuria observed in the patient of this study was an isolated tubular defect, with no phosphaturia, aminoaciduria or bicarbonaturia. Such a presentation is very rare in adults and has not been previously reported. These findings confirm that AIN with acute renal failure can cause an isolated tubular defect with benign reversible glycosuria in an adult. PMID- 22929614 TI - Prevalence and prevalence trends of transfusion transmissible infections among blood donors at four Chinese regional blood centers between 2000 and 2010. AB - BACKGROUND: In China, high prevalence of HBV and HCV parallels with the growing epidemic of syphilis and HIV in the general population poses a great threat to blood safety. This study investigated the prevalence of serologic markers for transfusion transmissible infections (TTIs) among four Chinese blood centers. METHODS: We examined whole blood donations collected from January 2000 through December 2010 at four Chinese blood centers. Post-donation testing of TTIs (HIV, HBV, HCV and syphilis) were conducted using two different enzyme-linked immunosorbent assay kits for each seromarker. The prevalence of serologic markers for TTIs (%) was calculated and additional analysis was conducted to examine donor characteristics associated with positive TTIs serology. RESULTS: Of the 4,366,283 donations, 60% were from first-time donors and 40% were from repeated donors. The overall prevalence of HIV, HBsAg, HCV and syphilis was 0.08%, 0.86%, 0.51% and 0.47%, respectively. The prevalence profile of TTIs varied among different blood centers and appeared at relatively high levels. Overall, the prevalence of HBsAg and HCV demonstrated a decline trend among four blood centers, while the prevalence of HIV and syphilis displayed three different trends: constantly steady, continually increasing and declining among different centers. CONCLUSIONS: This study reflects the risk of TTIs has been greatly reduced in China, but blood transfusion remains an ongoing risk factor for the spread of blood-borne infections, and further work and improvements are needed to strengthen both safety and availability of blood in China. PMID- 22929615 TI - Inferring transcriptional and microRNA-mediated regulatory programs in glioblastoma. AB - Large-scale cancer genomics projects are profiling hundreds of tumors at multiple molecular layers, including copy number, mRNA and miRNA expression, but the mechanistic relationships between these layers are often excluded from computational models. We developed a supervised learning framework for integrating molecular profiles with regulatory sequence information to reveal regulatory programs in cancer, including miRNA-mediated regulation. We applied our approach to 320 glioblastoma profiles and identified key miRNAs and transcription factors as common or subtype-specific drivers of expression changes. We confirmed that predicted gene expression signatures for proneural subtype regulators were consistent with in vivo expression changes in a PDGF driven mouse model. We tested two predicted proneural drivers, miR-124 and miR 132, both underexpressed in proneural tumors, by overexpression in neurospheres and observed a partial reversal of corresponding tumor expression changes. Computationally dissecting the role of miRNAs in cancer may ultimately lead to small RNA therapeutics tailored to subtype or individual. PMID- 22929616 TI - Systems-based analysis of Arabidopsis leaf growth reveals adaptation to water deficit. AB - Leaves have a central role in plant energy capture and carbon conversion and therefore must continuously adapt their development to prevailing environmental conditions. To reveal the dynamic systems behaviour of leaf development, we profiled Arabidopsis leaf number six in depth at four different growth stages, at both the end-of-day and end-of-night, in plants growing in two controlled experimental conditions: short-day conditions with optimal soil water content and constant reduced soil water conditions. We found that the lower soil water potential led to reduced, but prolonged, growth and an adaptation at the molecular level without a drought stress response. Clustering of the protein and transcript data using a decision tree revealed different patterns in abundance changes across the growth stages and between end-of-day and end-of-night that are linked to specific biological functions. Correlations between protein and transcript levels depend on the time-of-day and also on protein localisation and function. Surprisingly, only very few of >1700 quantified proteins showed diurnal abundance fluctuations, despite strong fluctuations at the transcript level. PMID- 22929618 TI - Perceptual uncertainty is a property of the cognitive system. AB - We qualify Frost's proposals regarding letter-position coding in visual word recognition and the universal model of reading. First, we show that perceptual uncertainty regarding letter position is not tied to European languages-instead it is a general property of the cognitive system. Second, we argue that a universal model of reading should incorporate a developmental view of the reading process. PMID- 22929617 TI - Dynamics of protein noise can distinguish between alternate sources of gene expression variability. AB - Within individual cells, two molecular processes have been implicated as sources of noise in gene expression: (i) Poisson fluctuations in mRNA abundance arising from random birth and death of individual mRNA transcripts or (ii) promoter fluctuations arising from stochastic promoter transitions between different transcriptional states. Steady-state measurements of variance in protein levels are insufficient to discriminate between these two mechanisms, and mRNA single molecule fluorescence in situ hybridization (smFISH) is challenging when cellular mRNA concentrations are high. Here, we present a perturbation method that discriminates mRNA birth/death fluctuations from promoter fluctuations by measuring transient changes in protein variance and that can operate in the regime of high molecular numbers. Conceptually, the method exploits the fact that transcriptional blockage results in more rapid increases in protein variability when mRNA birth/death fluctuations dominate over promoter fluctuations. We experimentally demonstrate the utility of this perturbation approach in the HIV-1 model system. Our results support promoter fluctuations as the primary noise source in HIV-1 expression. This study illustrates a relatively simple method that complements mRNA smFISH hybridization and can be used with existing GFP tagged libraries to include or exclude alternate sources of noise in gene expression. PMID- 22929619 TI - CardioNet: a human metabolic network suited for the study of cardiomyocyte metabolism. AB - BACKGROUND: Availability of oxygen and nutrients in the coronary circulation is a crucial determinant of cardiac performance. Nutrient composition of coronary blood may significantly vary in specific physiological and pathological conditions, for example, administration of special diets, long-term starvation, physical exercise or diabetes. Quantitative analysis of cardiac metabolism from a systems biology perspective may help to a better understanding of the relationship between nutrient supply and efficiency of metabolic processes required for an adequate cardiac output. RESULTS: Here we present CardioNet, the first large-scale reconstruction of the metabolic network of the human cardiomyocyte comprising 1793 metabolic reactions, including 560 transport processes in six compartments. We use flux-balance analysis to demonstrate the capability of the network to accomplish a set of 368 metabolic functions required for maintaining the structural and functional integrity of the cell. Taking the maintenance of ATP, biosynthesis of ceramide, cardiolipin and further important phospholipids as examples, we analyse how a changed supply of glucose, lactate, fatty acids and ketone bodies may influence the efficiency of these essential processes. CONCLUSIONS: CardioNet is a functionally validated metabolic network of the human cardiomyocyte that enables theorectical studies of cellular metabolic processes crucial for the accomplishment of an adequate cardiac output. PMID- 22929620 TI - Clinical and pathological characteristics of giant cell angioblastoma: a case report. AB - Giant cell angioblastoma (GCAB) is an extremely rare soft tissue tumor of early childhood and only five cases have been described to date. As such the clinical, pathological, and prognostic features are poorly defined. We prensent here a new case of GCAB in bone of a child aged 4-years old. The lesion was composed of dense and loose cell regions. The dense regions were characterized by nodular, linear, and plexiform aggregates of oval- to spindle-shaped tumor cells around small vascular channels and interspersed with large mononuclear cells and multinucleate giant cells. The loose cell areas were characterized by distributed fibroblasts and abundant myxoid matrix, which diminished with patient age. Infiltrative growth was observed in some areas. Oval-to-spindle cells showed positivity for Vimentin, CD31 and CD34 staining, and partial positivity for smooth muscle actin. Mononuclear cells and multinucleate giant cells showed Vimentin and CD68 positivity. Seventeen months after thorough curettage of the lesion, a local recurrence was found. Based upon the clinical, histological and immunohistochemical findings, infiltrate condition, and prognosis, we classified GCAB into two subtypes. Type I does not infiltrate surrounding tissues and has good prognosis. Type II infiltrates the surrounding tissues, relapses earlier, and has worse prognosis. This report augments the limited GCAB literature to promote our understanding and guide therapy of this rare disease. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/6699811297488137. PMID- 22929621 TI - Artemisinin resistance containment project in Thailand. II: Responses to mefloquine-artesunate combination therapy among falciparum malaria patients in provinces bordering Cambodia. AB - BACKGROUND: The area along the Thai-Cambodian border is considered an epicenter of anti-malarial drug resistance. Recently, parasite resistance to artemisinin based therapies has been reported in the area. The artemisinin resistance containment project was initiated in November 2008, with the aim to limit resistant parasites and eliminate malaria in this region. This study describes the response to artemisinin-based therapy among falciparum malaria patients in the area, using data from the malaria surveillance programmed under the containment project. METHODS: The study was conducted in seven provinces of Thailand along the Thai-Cambodian border. Data of Plasmodium falciparum-positive patients during January 2009 to December 2011 were obtained from the electronic malaria information system (eMIS) Web-based reporting system. All P. falciparum cases were followed for 42 days, as the routine case follow-up protocol. The demographic characteristics of the patients were described. Statistical analysis was performed to determine the cure rate of the current standard anti-malarial drug regimen--mefloquine-artesunate combination therapy (MAS). The proportion of patients who remained parasite-positive at each follow-up day was calculated. In addition, factors related to the delayed parasite clearance on day-3 post treatment, were explored. RESULTS: A total of 1,709 P. falciparum-positive cases were reported during the study period. Almost 70% of falciparum cases received MAS therapy (n = 1,174). The majority of cases were males, aged between 31 and 50 years. The overall MAS cure rate was > 90% over the three-year period. Almost all patients were able to clear the parasite within 7 to 14 days post-treatment. Approximately 14% of patients undergoing MAS remained parasite-positive on day-3. Delayed parasite clearance was not significantly associated with patient gender, age, or citizenship. However, delayed parasite clearance varied across the study area. CONCLUSION: Anti-malarial drug-resistant parasites should be closely monitored in the area along the Thai-Cambodian border. Although the MAS cure rate in this study area was above 90%, an increasing trend of treatment failure has been reported in neighboring parts. Effective malaria surveillance is an important component to monitor drug-resistance in the malaria containment project. PMID- 22929623 TI - Towards a universal neurobiological architecture for learning to read. AB - Letter-position tolerance varies across languages. This observation suggests that the neural code for letter strings may also be subtly different. Although language-specific models remain useful, we should endeavor to develop a universal model of reading acquisition which incorporates crucial neurobiological constraints. Such a model, through a progressive internalization of phonological and lexical regularities, could perhaps converge onto the language-specific properties outlined by Frost. PMID- 22929624 TI - Computational genomics-proteomics and Phylogeny analysis of twenty one mycobacterial genomes (Tuberculosis & non Tuberculosis strains). AB - BACKGROUND: The genus Mycobacterium comprises different species, among them the most contagious and infectious bacteria. The members of the complex Mycobacterium tuberculosis are the most virulent microorganisms that have killed human and other mammals since millennia. Additionally, with the many different mycobacterial sequences available, there is a crucial need for the visualization and the simplification of their data. In this present study, we aim to highlight a comparative genome, proteome and phylogeny analysis between twenty-one mycobacterial (Tuberculosis and non tuberculosis) strains using a set of computational and bioinformatics tools (Pan and Core genome plotting, BLAST matrix and phylogeny analysis). RESULTS: Considerably the result of pan and core genome Plotting demonstrated that less than 1250 Mycobacterium gene families are conserved across all species, and a total set of about 20,000 gene families within the Mycobacterium pan-genome of twenty one mycobacterial genomes.Viewing the BLAST matrix a high similarity was found among the species of the complex Mycobacterium tuberculosis and less conservation is found with other slow growing pathogenic mycobacteria.Phylogeny analysis based on both protein conservation, as well as rRNA clearly resolve known relationships between slow growing mycobacteria. CONCLUSION: Mycobacteria include important pathogenic species for human and animals and the Mycobacterium tuberculosis complex is the most cause of death of the humankind. The comparative genome analysis could provide a new insight for better controlling and preventing these diseases. PMID- 22929625 TI - Mean field mutation dynamics and the continuous Luria-Delbruck distribution. AB - The Luria-Delbruck mutation model has a long history and has been mathematically formulated in several different ways. Here we tackle the problem in the case of a continuous distribution using some mathematical tools from nonlinear statistical physics. Starting from the classical formulations we derive the corresponding differential models and show that under a suitable mean field scaling they correspond to generalized Fokker-Planck equations for the mutants distribution whose solutions are given by the corresponding Luria-Delbruck distribution. Numerical results confirming the theoretical analysis are also presented. PMID- 22929626 TI - Antimicrobial activity of geranium oil against clinical strains of Staphylococcus aureus. AB - The aim of this work was to investigate the antibacterial properties of geranium oil obtained from Pelargonium graveolens Ait. (family Geraniaceae), against one standard S. aureus strain ATCC 433000 and seventy clinical S. aureus strains. The agar dilution method was used for assessment of bacterial growth inhibition at various concentrations of geranium oil. Susceptibility testing of the clinical strains to antibiotics was carried out using the disk-diffusion and E-test methods. The results of our experiment showed that the oil from P. graveolens has strong activity against all of the clinical S. aureus isolates-including multidrug resistant strains, MRSA strains and MLS(B)-positive strains-exhibiting MIC values of 0.25-2.50 MUL/mL. PMID- 22929622 TI - A lesson for cancer research: placental microarray gene analysis in preeclampsia. AB - Tumor progression and pregnancy share many common features, such as immune tolerance and invasion. The invasion of trophoblasts in the placenta into the uterine wall is essential for fetal development, and is thus precisely regulated. Its deregulation has been implicated in preeclampsia, a leading cause for maternal and perinatal mortality and morbidity. Pathogenesis of preeclampsia remains to be defined. Microarray-based gene profiling has been widely used for identifying genes responsible for preeclampsia. In this review, we have summarized the recent data from the microarray studies with preeclamptic placentas. Despite the complex of gene signatures, suggestive of the heterogeneity of preeclampsia, these studies identified a number of differentially expressed genes associated with preeclampsia. Interestingly, most of them have been reported to be tightly involved in tumor progression. We have discussed these interesting genes and analyzed their potential molecular functions in preeclampsia, compared with their roles in malignancy development. Further investigations are warranted to explore the involvement in molecular network of each identified gene, which may provide not only novel strategies for prevention and therapy for preeclampsia but also a better understanding of cancer cells. The trophoblastic cells, with their capacity for proliferation and differentiation, apoptosis and survival, migration, angiogenesis and immune modulation by exploiting similar molecular pathways, make them a compelling model for cancer research. PMID- 22929627 TI - Associated factors for uterine prolapse. AB - BACKGROUND: Uterine prolapsed is a significant public health problem in Nepal. METHODS: The study was conducted in 50 women having second and third degree of uterus prolapse who were admitted in Dhulikhel Hospital for vaginal hysterectomy. A total 200 individual were taken as a control groups who were OPD attendants of Dhulikhel hospital without any sign or had no any sign and symptom of uterus prolapse . Data were collected by structured and semi-structured questionnaires and analysis done by using z test. RESULTS: The occurrence of uterus prolapse had significant difference among ethnicity (p value-<0.001), level of education (p value-<0.001) and occupation of respondents (p value-0.0000). There was no significant difference in the age at birth of first child between the groups (p value 0.138). Parity, gravida and age of the last child birth (p value-.040, .025, 003 respectively) comprised of significant differences. There was significant difference between duration of rest after delivery (zalpha=16.53), days of household work started (zalpha 14.24) and days of heavy load lifting started (zalpha 7.96) in case and control. CONCLUSIONS: The finding shows significant factors for uterus prolapse were parity, gravida and age at last birth and work after delivery. Therefore civil society and concerned authority should work to raise awareness on the preventive measure of uterus prolapsed. PMID- 22929628 TI - Evaluation of nurse providers of comprehensive abortion care using MVA in Nepal. AB - BACKGROUND: Although Nepal's maternal mortality ratio has fallen over the past decade, unsafe abortion remains a leading cause of maternal morbidity and mortality. A key strategy for improving access to safe abortion services is to train mid-level providers such as nurses in comprehensive abortion care (CAC). The Family Health Division of the Nepal Ministry of Health trained an initial cohort of 96 nurses to provide first trimester CAC services using manual vacuum aspiration (MVA) between September 2006 and July 2009. This study evaluates the acceptability and quality of CAC services provided by trained nurses in Nepal. METHODS: Five assessments were used to evaluate post-training service provision on CAC: facility logbooks registry, nurse provider interviews, facility assessments, facility manager interviews and procedure observation checklists. Ninety-two nurses from 50 facilities participated in the evaluation. Descriptive statistics are reported. RESULTS: Overall, 5,600 women received CAC services from 42 facilities where nurses were providing services between June 2009 and April 2010. Complications were experienced by 68 surgical abortion clients (1.6%) and 12 medical abortion clients (1.2%). All nurses reported that clients were happy to receive care from them, and 67% of facility managers reported that clients preferred nurse providers over physicians or had no preference. Facility managers and nurses reported a need for additional support, including further training and improved drug and equipment supply. CONCLUSIONS: Trained nurses provide high quality CAC services in Nepal. Additional support in the form of facilitative supervision and training should be considered to strengthen CAC service provision. PMID- 22929629 TI - Comparison of Misoprostol versus Dinoprostone for pre-induction cervical ripening at-term. AB - BACKGROUND: The purpose of this study was to compare the efficacy and safety of 25 MUg Misoprostol vs. 0.5 mg Dinoprostone for pre-labour ripening of the cervix at-term. METHODS: Nullipara or Para one women with unfavourable cervices after 37 completed weeks with live foetuses were randomized to received either 25 MUg intravaginal Misoprostol or 0.5 mg intracervical Dinoprostone. The doses were repeated after 6 hrs if the Bishop Score was less than 6. In cases, in which cervical ripening was not reached even after two doses of ripening agents, oxytocin induction was started at least 6 hours apart. Insertion delivery interval (IDI), complications and pregnancy outcome associated with the use of drugs were compared. RESULTS: Two hundred women--100 in each group were evaluated. Comparatively more women (62% vs. 58%) in the Misoprostol group achieved cervical ripening (BS>=6) after one dose. The mean IDI was significantly shorter (3.91 hrs) in the Misoprostol group. The difference was marked more among the multipara at 5.72 hrs, mean difference (p=0.045). In the Misoprostol group 76.92% delivered within 24 hrs whereas, only 70.4% in the Dinoprostone group. Vaginal deliveries were achieved more in the Misoprostol group (78% vs. 71%). No significant differences found in terms of intrapartum complications and foetal outcome. Meconium stained liquor was found more in the Dinoprostone group (23% vs. 32%). CONCLUSIONS: A 25 MUg dose of Misoprostol is superior in promoting cervical ripening, significantly shortened the insertion delivery interval. It is safe and effective for cervical ripening when applied in the hospital setting with close monitoring. PMID- 22929630 TI - Comparative study of sensitivity of rapid diagnostic (hexagon) test with calculated malarial parasitic density in peripheral blood. AB - BACKGROUND: Different diagnostic test kits are used for rapid diagnosis of malaria. Most are based on antigen detection (pLDH, Pan Aldolase, HRP-2). In context of Nepal the diagnostic reliability and sensitivity of these tests is unknown. Hexagon Malaria CombiTM is one of the most commonly used test kit in Nepal for rapid diagnosis of malaria. The aim of the present study is to evaluate the sensitivity of the Hexagon malaria Combi test in comparison with parasitic density by microscopy technique. METHODS: A Cross sectional prospective study was conducted in three districts of Nepal from September to November 2009. Blood samples were collected from the suspected cases of malaria. Thick and thin smear were prepared from all the samples and Giemsa stain was done. Simultaneously RDT (hexagon) for malaria was done. When RDT was found to be positive, blood was serially diluted in 6 tubes as 1:2, 1:4, 1:8, 1:16, 1:32 and 1:64. RDT was done on diluted blood till RDT test gave negative result. Parasitic density was calculated for undiluted and diluted blood samples and sensitivity of RDT in various parasitic densities was calculated. RESULTS: Hexagon malaria combi test is sensitive (86%) when malarial parasitic density is >500/MUl. Sensitivity was found to be directly related to parasitic density. Its sensitivity is very low (2.9%) when parasitic density is less than 500/ MUl. CONCLUSIONS: The sensitivity of rapid diagnostic test (hexagon Combi test detecting malarial pLDH antigen) is high only if the parasitic density is more than 500/MUl. PMID- 22929631 TI - Intestinal parasitic infection among school children. AB - BACKGROUND: Intestinal parasitosis is a major public health problem of developing countries, children being major victims. Higher prevalence has been reported among school children, mostly in hilly regions of Nepal. This study aims at assessing prevalence of intestinal parasitosis among school children of a school in a border town of Nepal and the associated factors. METHODS: Fecal samples from the students were examined by direct smear technique and result was correlated with their socioeconomic status and hygienic behavior. The chi-square test was used for analytical assessment. RESULTS: The prevalence rate was 13.9%, girls being highly infected (19.1%) than boys (10.3%) (P>0.05). Entamoeba histolytica (36.0%) was the commonest parasite followed by A. lumbricoides (28.0%). The highest positive rate was found among children of 5 years and less age (29.2%) and least among those above 12 years (5.3%) (P>0.05). Those from family size 5 and less than 5 were least infected (10.5%). Children of illiterate parents (16.7%) and farmers (17.1%) were more infected than literate ones and non-farmers (P>0.05). 8.7% of positive children had multi-parasitic infection. Children drinking untreated water (15.0%) were more infected than those drinking treated water (5.5%) (P>0.05). CONCLUSIONS: Intestinal parasitic infection was found among 17% school children. Awareness on infectious diseases, improving hygiene, and application of supportive programs for parents to elevate socioeconomic conditions may reduce the burden of infection. PMID- 22929632 TI - Antibiotic susceptibility of organisms causing urinary tract infection in patients presenting to a teaching hospital. AB - BACKGROUND: Urinary tract infections (UTI) are common. It causes severe morbidity and mortality, and it is important to know the causative organisms in the hospital and community for optimum management of UTI. METHODS: This is a prospective hospital based study to identify the organisms causing UTI and their antibiotic susceptibility. Consecutive patients presenting with symptoms of UTI had their clean catch midstream urine analysed. Antibiotic susceptibility was tested by Kirby-Bauer's disc diffusion method as described by National Committee for Clinical Laboratory Services (NCCLS) guidelines. RESULTS: Out of 1726 patients, 549 (31.8%) showed bacterial growth. Escherichia coli was most common (72.5%), followed by Klebsiella pneumoniae (11.3%), Staphylococcus aureus (3.1%), coagulase negative Staphylococcal species (2.7%) and others (10.1%). There was a female dominance of 3.2:1 compared to males, except in the 61 and above age range. Infections were most common in young adults (21-30 years). The most effective antibiotic was Nitrofurantoin followed by Norfloxacin, Ciprofloxacin and Ofloxacin. Some isolates were resistant to Norfloxacin, Ampicillin, Cotrimoxazole and Ciprofloxacin. CONCLUSIONS: The most common causative organism for UTI was Escherichia coli, and the best first line antibiotic was Nitrofurantoin. Organisms are developing resistance to antibiotics such as Norfloxacin, Ampicillin and Ciprofloxacin. PMID- 22929633 TI - Early feeding and discontinuation of intravenous fluid after laparoscopic cholecystectomy. AB - BACKGROUND: Common practice at most centers in the country is to continue intravenous (i.v.) fluid till morning round next day following laparoscopic cholecystectomy (LC), assess patient and gradually allow oral diet. However this seems unnecessary in view of fast recovery after minimal invasive LC. The aim of this study was to observe the prospects and assess the acceptability, safety and benefit of early oral feeding and discontinuing i.v. fluid after LC. METHODS: This cross-sectional observational study was carried out prospectively from Oct 1, 2009 to Sep 31, 2010 at Patan Hospital, a university teaching hospital. All elective LC patients were included. Oral liquid was introduced after four hours and i.v. fluid was stopped after six hr of LC. I.v. cannula was kept locked in situ. Vomiting, abdomen distension and reasons for continuation or resumption of i.v. fluids were recorded. RESULTS: During one year period 294 LC patients fulfilled study criteria. Average age was 40.8 years. Female accounted for 78.2%. Oral fluid was started in average of 5.5 hrs in 97%. In 3% (9/294) i.v. was continued. Postoperative nausea and vomiting was observed in 25.9% (76/294), of which 6.6% (5/76) required i.v.. There was no untoward affect after i.v. fluid was stopped. CONCLUSIONS: Early oral feeding and discontinuing of intravenous fluid in laparoscopic cholecystectomy is safe, economic and well accepted by patients, family and nursing staff in Patan hospital. PMID- 22929634 TI - Prevalence of pulmonary tuberculosis among HIV infected persons in Pokhara, Nepal. AB - BACKGROUND: Tuberculosis (TB) is a major public health problem in Nepal. HIV co infection has further added a serious challenge to control TB. An early diagnosis and treatment of TB in HIV infected individuals can help reduce not only the morbidity and mortality associated in this high risk group but also to control the TB burden in Nepal. METHODS: Clinical and bacteriological examination for pulmonary TB was carried out in 184 HIV positive persons from the community in Pokhara. Questionnaire was used to screen for symptoms and collect participants' demographic information and potential risk factors for TB. RESULTS: Eighty (43.5%) sero-positive participants were young adult (21-30 years), followed by 71 (38.6%) middle aged (31-40 years) persons. Eleven participants were found to have Mycobacterium tuberculosis in their sputum, giving an overall prevalence of tuberculosis of 5.97%. All 11 cases were detected by Acid Fast Bacilli (AFB) culture, of which only three cases were detected by direct microscopy of AFB stained sputum smear. The majority of TB/HIV patients were asymptomatic with low AFB smear positivity. No significant association was found between TB and risk factors like ARV status, common clinical features of tuberculosis and smoking habit. However, significant association was found between the alcohol consumption and TB (X2=4.11, p<0.05). CONCLUSIONS: High prevalence of tuberculosis (5.97%) was found among HIV infected persons. Alcohol consumption was associated with the development of tuberculosis. Majority of the studied subjects were asymptomatic for common signs and symptoms of TB. Weight loss was observed in 43% of the studied subjects followed by chest pain (39.2%), loss of appetite (34.8%), fever (34.8%) and night sweat (26.1%). Only 27% of the TB cases were found to be smear positive. PMID- 22929635 TI - Status of pathology professionals. AB - BACKGROUND: The status of basic, general and specialist workforces in pathology services in Nepal needs to be defined and explored for better pathology services. The objective of the study was to find out the status of laboratory medicine professionals (pathology workforces) and the regulation of ethics and limitations of the different level of workforces. METHODS: A cross-sectional descriptive study was conducted by observing and taking interview with the head of the clinical private institutions from August 2008 to January 2009. A total of 373 private pathology laboratories and the workforces working over there were included in the study. RESULTS: The workforces heading private pathology services showed that 153 (41%) of laboratories were headed by laboratory assistant, 79 (21%) by laboratory technician, 90 (24%) by (medical technologist) pathology officer, 30 (8%) by histocytopathologist and 21 (6%) by non pathology professionals. Officer level Pathology workforce (eligible to work independently) was 113 (30%) whereas 260 (70%) of laboratories had no such workforces. Intermediate level Pathology workforce (eligible to work dependently and for some investigation independently) was 34% (127/373) where as 66% (246/373) of laboratories were lacking such workforces. Specialist level (MD/M. Sc) workforces in histocytopathology, clinical microbiology and cytopatholgy & hematology were 43 (11%), 10 (3%) and 3 (1%) respectively. CONCLUSIONS: The workforces heading the private laboratories were not according to the norms of good laboratory practices. The workforces had crossed their limitations and ethical barrier in performing pathological investigations which did not abide by the rules and regulations made by respective councils of Nepal by pathology workforces. There was intervention of non medical/clinical workforce in laboratory services especially in microbiology and biochemistry. PMID- 22929636 TI - Study of haemodynamic and endocrine stress responses following carbon dioxide pneumoperitonium. AB - BACKGROUND: The aim of the study is to investigate the effect of oral gabapentin or clonidine versus placebo premedication on haemodynamic and endocrine responses in patients of American Society of Anesthesiology (ASA) physical status I and II undergoing laparoscopic cholecystectomy. METHODS: This was a randomized prospective double-blinded comparative study of 75 ASA I and II patients with three groups: clonidine, gabapentin and placebo group having 25 patients in each. They were randomly allocated to receive 600 mg oral gabapentin or clonidine 150 mcg one hour prior to induction of anesthesia and a placebo group. Hemodynamic parameters were recorded before pneumoperitonium (PP) and every 5 minutes till 35 minutes of post PP. Blood samples for serum glucose and cortisol were collected before PP and 10 mins after PP. The investigators were blinded to what the patients received. RESULTS: With similar demographic profiles and baseline haemodynamics in three groups (p>0.05) significant rise in haemodynamic parameters were observed in placebo group at different time points before and following PP where as those parameters remained stable in gabapentin and clonidine group (p<0.05). The serum cortisol level was high in placebo group before PP than in two other groups, p<0.05. The same marker measured at 10th minute after PP was significantly higher in placebo group than that in clonidine or gabapentin group, p<0.05. CONCLUSIONS: Oral clonidine or gabapentin premedication offers intraoperative haemodynamic stability in laparoscopic cholecystectomy. When serum cortisol is taken as a stress marker, gabapentin group exhibited significant attenuation of stress of PP, p<0.05. PMID- 22929638 TI - Obstetric and perinatal outcome of teenage pregnancy. AB - BACKGROUND: Adolescents are at higher risk during childbirth than women between 20 to 25 years. Adolescent childbearing initiates a syndrome of failure: failure to complete one's education; failure in limiting family size; failure to establish a vocation and become independent. This study was done to find out the obstetric and perinatal outcome of teenage pregnancy along with factors contributing to teenage pregnancy. METHODS: A prospective, cross sectional study was carried out in College of Medical Sciences Teaching Hospital (CMSTH), Bharatpur during the period for two years from September 2008 to August 2010. Pregnant girls <=19 years admitted to labour ward were taken for the study. Cases planned for abortion and MTP were also taken. RESULTS: One hundred cases of pregnant teenagers were admitted in CMSTH during a period of two years. Incidence was 6.85%. In our study, most of the teenagers were unbooked, from low socioeconomic status and with no or inadequate education. They had little knowledge about contraception and less number of teenagers used temporary means of contraception. Because of our social custom of early marriage, most of the teenage mothers were married. All these factors were correlated with teenage pregnancy in present study. CONCLUSIONS: This study failed to show any statistically significant difference in the incidence of anaemia, LBW babies, preterm delivery, hypertensive disorder of pregnancy, mode of delivery in different ages of teenage mothers. However, there was significant difference in the incidence of perinatal death in different ages of teenage mothers indicating that perinatal deaths were more in younger teenagers. PMID- 22929637 TI - External validation of prognostic model of one-year mortality in patients requiring prolonged mechanical ventilation. AB - BACKGROUND: External validation of prognostic model for one-year mortality in patients ventilated for 21 days or more. A measure that identifies patients who are at high risk of mortality after prolonged ventilation will help physicians communicate prognoses to patients or surrogate decision makers. Our objective was to validate a prognostic model developed by Carson et al in a different setting. METHODS: An observational study was conducted from September 2002 to September 2007 in 30 beds Medical/Surgical Intensive Care Unit (ICU) at Mercy Fitzgerald Hospital (MFH) and 20 beds Medical/Surgical ICU at Mercy Philadelphia Hospital (MPH). One hundred and fifty medical and surgical patients requiring mechanical ventilation after acute illness for at least 21 days after initial intubation were enrolled. RESULTS: One year mortality was 45.4%. Area under the receiver operating characteristic curve for three month mortality was 0.90 and for one year mortality was 0.92. For identifying patients who had >=90% risk of death at 3 month had sensitivity of 40% and specificity of 95% and risk of death at 1 year had sensitivity of 70% and specificity of 99%. Four predictive variables, requirement of vasopressors, hemodalysis, platelet count <= 150 x 10 9/L and age >=50 yrs can be used as a simple prognostic score that clearly identifies low risk patients and high-risk patients. CONCLUSIONS: Simple clinical variables measured on day 21 of mechanical ventilation can identify patients at highest and lowest risk of death from prolonged mechanical ventilation. PMID- 22929639 TI - Histopathologic study of chronic antral gastritis. AB - BACKGROUND: Gastritis has a broad histopathologic and topographical spectrum and leads to different patterns of disease. The introduction of the Sydney system made it possible to grade histological parameters, identify topographic distribution and provide etiological information which would help to generate reproducible and clincally useful diagnoses. The aim of this study was to determine the prevalence of Helicobacter pylori in non-ulcer dyspepsia, duodenal ulcer and gastric ulcer; and to assess the histopathologic features associated with chronic gastritis. METHODS: Gastric antral biopsy specimens from 200 patients were examined for the prevalence of H. pylori, and were classified and graded histologically. RESULTS: The overall colonization rate of H. pylori was 44%. The colonization rates were 85%, 67% and 41% in patients with duodenal ulcer, gastric ulcer and non-ulcer dyspepsia respectively. There was not much difference between the degree of atrophy and intestinal metaplasia in H. pylori positive and negative cases. CONCLUSIONS: Helicobacter gastritis is the commonest type of gastritis present in patients presenting with dyspeptic symptoms. It is more common in patients presenting with duodenal ulcer. Adequate sampling is a must for accurate diagnosis of H. pylori colonization. PMID- 22929640 TI - Percutaneous K wire fixation of fifth metacarpal neck fracture--new and simple technique. AB - BACKGROUND: Isolated fractures of metacarpals and phalanges are the commonest injuries affected upper extremity, which constitute about 10% of skeletal fractures in general. Fifth metacarpal (boxer's fractures) being the most common. The objective of this study was to investigate the outcome of treatment of the displaced neck and sub-capital fractures of the fifth metacarpal by percutaneous K wire fixation. METHODS: An observational study was conducted in the department of orthopedics Patan hospital as an outpatient procedure from January 2010 to January 2012. All adult patients with unilateral fracture of neck of fifth metacarpal bone were included. Whose physis was open, having previous hand injury or diseases causing deformity or impaired hand function and when fracture was more than 7 days old, were excluded from the study. RESULTS: Twenty eight of 35 patients obtained anatomic reduction, and 7 patients had 2/3 apposition of bone end and no rotational deformity. Follow-up was available for only 30 patients. The follow-up time was up to 12 weeks. The head/shaft angle of the fifth metacarpal was 60.60 degrees +/-9.39 degrees preoperatively, and 14.20 degrees +/ 7.32 degrees postoperatively, and 15.60 degrees +/-6.95 degrees in 12 weeks postoperatively. The difference between preoperative and postoperative angles was highly significant. The range of motion of the metacarpal joint was 86.73 degrees +/-6.13 degrees postoperatively, which was not significantly different compared with that of uninjured side which was 90.93 degrees +/-3.18. The difference between preoperative and postoperative angles was highly significant. The range of motion of the metacarpal joint was not significantly different compared with that of uninjured side. The average union time was 5.46 weeks +/-1.22. CONCLUSIONS: This method under consideration does not disturb the fracture site itself, the Kirschner wire being introduced in retrograde fashion makes it easier to correctly place the wire, which gives reasonably stable fixation, gives excellent results in a high proportion of selected cases. Local anesthesia is an added advantage. PMID- 22929641 TI - An unusual experience with ureterorenoscopy: a case report. AB - A 42 years lady was reported. Patient was worked up and was found to have stone in the upper third of the right ureter. She underwent a session of Extracorporeal Shock Wave Lithotripsy (ESWL) but the stone was too hard to fragment in a single session. She then underwent ureterorenoscopy (URS) the next day. The ureteric orifice was very tight for negotiation of ureterorenoscope due to tight ureteric stricture. We finally managed to negotiate beyond the stricture up to the level of stone impaction. However, during withdrawal of the scope, nearly the whole length of the ureter was avulsed out along with the latter. Immediate exploration of the abdomen was performed and we found complete avulsion of the entire length of the ureter. We performed an ileal transposition to bridge the gap formed after avulsion of ureter. PMID- 22929642 TI - Atypical presentation of the broken heart syndrome associated with chronic anxiety. AB - The "broken heart syndrome", or Takotsubo cardiomyopathy, is an acute cause of transient left ventricular systolic dysfunction characterized by abrupt onset of chest symptoms, ECG changes and a mild rise in myocardial enzymes mimicking acute myocardial infarction. This condition is more common in postmenopausal women and is typically preceded by an intense emotional or physical stress or an acute illness. A higher prevalence of anxiety disorders in patients with this syndrome have also been reported recently. Apical ballooning with left ventricular akinesis or dyskinesis of distal one-third to two-thirds of the left ventricle in cardiac catheterization and absence of significant coronary obstruction is this hallmark of this condition. However, various morphologic variants with different ventricular region involvement have been reported including "an atypical variant" where the left ventricular hypokinesia is restricted to the midventricular segment without involvement of the apex. Here we present a case of 56-year-old female with a history of chronic anxiety who presented with retrosternal chest pain after her partner threatened to leave her. Her EKG showed diffuse T-wave changes with prolonged QT intervals. She also had modest elevation of cardiac enzymes. PMID- 22929643 TI - Dyselectrolytemias after single dose of pamidronate administration. AB - Bisphosphonate such as pamidronate initially described for the treatment of neoplastic hypercalcemia, currently is being used off label to treat sever hypercalcemia of any etiology. Multiple dyselectrolytemias are a potential adverse effect of this drug, and are considered infrequent. We describe a case of transient electrolyte abnormalities after single dose of 60 mg intravenous pamidronate. PMID- 22929644 TI - Environmental assessment of a territory: an overview of existing tools and methods. AB - In order to reduce our environmental impact, methods for environmental assessment of human activities are urgently needed. In particular in the case of assessment of land planning scenarios, there is presently no consensual and widely adopted method although it is strongly required by the European Directive (2001/42/EC) on Strategic Environmental Assessment. However, different kinds of tools and methods are available such as human and environmental risk assessment, the ecological footprint, material flow analysis, substance flow analysis, physical input-output table, ecological network analysis, exergy, emergy or life cycle assessment. This review proposes a discussion on these tools and methods specifically applied to territories. After the meaning of territory is clarified, these approaches are presented and analyzed based on "key features" such as formalization, system modeling, inventoried flows, indicators provided and usability. This comparison highlights the strengths and weaknesses of each tool. It also emphasizes that the approach of life cycle assessment could provide a relevant framework for the environmental assessment of territories as it is the only method which can avoid burden shifting between life cycle stages, environmental impacts and territories. PMID- 22929645 TI - Preventing central line-associated bloodstream infections. PMID- 22929646 TI - A road map to Translational Medicine in Qatar and a model for the world. AB - Translational Medicine (TM) in Qatar is part of a concerted effort of the Qatari medical and scientific leadership supported by a strong political will by Qatari authorities to deliver world-class health care to Qatari residents while participating in the worldwide quest to bridge the gap between bench-to-bedside to-community. TM programs should embrace the Qatar National vision for research to become an international hub of excellence in research and development, based on intellectual merit, contributing to global knowledge and adhering to international standards, to innovate by translating new and original ideas into useful applications, to be inclusive at the national and international level, to build and maintain a competitive and diversified economy and ultimately improve the health and well-being of the Qatar's population. Although this writing focuses on Qatar, we hope that the thoughts expressed here may be of broader use for the development of any TM program particularly in regions where an established academic community surrounded by a rich research infrastructure and/or a vibrant biotechnology enterprise is not already present. PMID- 22929647 TI - The prognostic value of schizontaemia in imported Plasmodium falciparum malaria. AB - BACKGROUND: In Plasmodium falciparum infection, peripheral parasite counts do not always correlate well with the sequestered parasite burden. As erythrocytes parasitized with mature trophozoites and schizonts have a high tendency to adhere to the microvascular endothelium, they are often absent in peripheral blood samples. The appearance of schizonts in peripheral blood smears is thought to be a marker of high sequestered parasite burden and severe disease. In the present study, the value of schizontaemia as an early marker for severe disease in non immune individuals with imported malaria was evaluated. METHODS: All patients in the Rotterdam Malaria Cohort diagnosed with P. falciparum malaria between 1 January 1999 and 1 January 2012 were included. Thick and thin blood films were examined for the presence of schizontaemia. The occurrence of WHO defined severe malaria was the primary endpoint. The diagnostic performance of schizontaemia was compared with previously evaluated biomarkers C-reactive protein and lactate. RESULTS: Schizonts were present on admission in 49 of 401 (12.2%) patients. Patients with schizontaemia were more likely to present with severe malaria, a more complicated course and had longer duration of admission in hospital. Schizontaemia had a specificity of 0.95, a sensitivity of 0.53, a negative predictive value of 0.92 and a positive predictive value of 0.67 for severe malaria. The presence of schizonts was an independent predictor for severe malaria. CONCLUSION: Absence of schizonts was found to be a specific marker for exclusion of severe malaria. Presence of schizonts on admission was associated with a high positive predictive value for severe malaria. This may be of help to identify patients who are at risk of a more severe course than would be expected when considering peripheral parasitaemia alone. PMID- 22929648 TI - After-hours coverage of various radiologic subspecialties and its impact on the fourth-year radiology residency curriculum. AB - RATIONALE AND OBJECTIVE: The modification of the initial radiology board exam series has as a concerted aim the promotion of subspecialization. Yet, in practice, fellowship-trained radiologists may be assigned to off-hours work in other diagnostic areas. The purpose of this study is to chart the prevalence of after-hour work among the various subspecialties in radiology and to relate those findings to the pertinence of a fourth-year training curriculum devoted to only one imaging discipline. MATERIALS AND METHODS: A questionnaire was sent to members of Society of Chairs of Academic Radiology Departments and to directors of the 50 largest American private radiology practices requesting that they list after-hours coverage obligations of their various subspecialists. RESULTS: Academic and private practice response rates were 40.8% (42 of 103) and 42% (21 of 50), respectively. In academic practice, 80% of neuroradiologists, 93% of interventional radiologists, and 84% of pediatric radiologists were not assigned after-hour coverage in other subspecialties. In private practice groups, only 24% of neuroradiologists, 48% of interventional radiologists, and 33% of pediatric radiologists were free of these duties. For other subspecialists, the likelihood of after-hours assignments to other disciplines was not so discrepant between academic and private practices. CONCLUSION: Residents pursuing an academic career in neuroradiology, interventional radiology, or pediatric radiology could benefit from a full fourth-year experience in their area of subspecialty, whereas a more variegated curriculum would be more suitable for other specialists independent of practice type. PMID- 22929649 TI - Breast milk expression among formally employed women in urban and rural Malaysia: A qualitative study. AB - BACKGROUND: Many women are unable to practice exclusive breastfeeding because they are separated from their infants while working. Expressing their breast milk helps them to continue breastfeeding. This study explores the perception and experiences related to the feasibility, acceptability and safety of breast milk expression among formally employed women in Kelantan, Malaysia. METHODS: A qualitative method using in-depth interviews was conducted from December 2008 to December 2009 among Malay women from urban and rural areas. A snowball sampling method was used to recruit the informants, and the interviews, which were facilitated by an interview guide, were audio-recorded and transcribed verbatim. Thematic analysis was conducted, with construction of codes and themes from each interview. RESULTS: Analysis of the interviews with 20 informants identified three themes related to breast milk expression. The themes were as follows: (i) lack of feasibility of expressing breast milk, (ii) negative feelings about expressing breast milk, and (iii) doubts about the safety and hygiene of expressed breast milk. The informants who did not practice exclusive breastfeeding believed that expressing their breast milk was not feasible, commonly because they felt there were not enough facilities for them. They also had negative feelings such as embarrassment. The safety and hygiene of the expressed breast milk was also their main concern. CONCLUSION: More practical and focused education, as well as provision of facilities, is needed for women to effectively and safely express and store their breast milk. The issue of inadequate milk production should be emphasized, especially by encouraging them to express their breast milk as a way to improve milk production. PMID- 22929650 TI - New bactericide derived from Isatin for treating oilfield reinjection water. AB - Isatin, an extract from Strobilanthes cusia (Nees) Kuntze, was the base for synthesizing derivatives that were screened for antibacterial activity against oilfield water-borne bacteria. The bacterial groups are sulfate reducing, iron and total. The derivatives were characterized by spectrums and they showed good to moderate activity against sulfate reducing bacteria. PMID- 22929651 TI - Ultrasound time-reversal MUSIC imaging of extended targets. AB - Ultrasound time-reversal imaging with multiple signal classification (TR-MUSIC) can produce images with subwavelength spatial resolution when the targets are point scatterers. In this experimental study, we evaluate the performance of the TR-MUSIC algorithm when the interrogated medium contains extended targets that cannot be considered as point scatterers, i.e., the size of the targets is on the order of the ultrasound wavelength or larger. We construct four tissue-mimicking phantoms, each of which contains glass spheres of a given size. We show that the quality of the phantom images obtained using the TR-MUSIC algorithm decreases with increasing sphere size. However, significant improvement is achieved when the image plane is divided into subregions, where each subregion is imaged separately. In this method, the TR-MUSIC calculations are performed on the windowed backscattered signals originating from each subregion. Our study demonstrates that the TR-MUSIC algorithm with time windowing can accurately locate extended targets but cannot provide the shape and reflectivity of the targets. We scan an inhomogeneous commercial tissue-mimicking phantom using an investigational synthetic-aperture ultrasound system, and show that the TR-MUSIC algorithm is capable of detecting small targets with high spatial resolution in inhomogeneous media. PMID- 22929653 TI - Assessment of early hepatic echinococcus multilocularis infection in rats with real-time contrast-enhanced ultrasonography. AB - The aim of this study was to demonstrate characteristic imaging and accurate evaluation of blood perfusion in early stage of hepatic alveolar echinococcosis (HAE) by contrast-enhanced ultrasonography (CEUS). The early stage of experimentally induced secondary HAE in 45 rats was studied. Thirty-six HAE lesions in 33 rats, confirmed by pathologic examination, were examined by ultrasound (US), color Doppler flow imaging (CDFI) and then CEUS. Thirty-three lesions were found in 30 rats by US, and 30 lesions were detected in 27 rats by CEUS. The sensitivity of US and CEUS was 92% (95% CI 76%-98%) and 82% (95% CI 65% 93%), respectively. US imaging characteristics were categorized into four types: hyperechoic spot (type 1, 45.5%, 15/33), granular hyperechoic spots (type 2, 12.1%, 4/33), hyperechoic lesion (type 3, 30.3%, 10/33) and mixed pattern (type 4, 12.1%, 4/33). CDFI failed to detect blood flow signals in any lesions. CEUS results for 30 lesions showed ring enhancement in the peripheral area during the arterial phase and no filling effect in either the portal or the delayed phase (46.7%, 14/30); ring enhancement combined with central septa enhancement during the arterial phase and portal venous phase (46.7, 14/30), and no enhancement (6.6%, 2/30). The enhanced area, confirmed by pathologic examination, was an inflammatory reaction belt surrounding the lesion. The results of this study suggest that US, with high sensitivity, can be used as a screening method for early HAE lesions in the animal model, while CEUS can be used for displaying the peripheral blood perfusion and vesicle structure. PMID- 22929652 TI - Stability of echogenic liposomes as a blood pool ultrasound contrast agent in a physiologic flow phantom. AB - Echogenic liposomes (ELIP) are multifunctional ultrasound contrast agents (UCAs) with a lipid shell encapsulating both air and an aqueous core. ELIP are being developed for molecular imaging and image-guided therapeutic delivery. Stability of the echogenicity of ELIP in physiologic conditions is crucial to their successful translation to clinical use. In this study, we determined the effects of the surrounding media's dissolved air concentration, temperature transition and hydrodynamic pressure on the echogenicity of a chemically modified formulation of ELIP to promote stability and echogenicity. ELIP samples were diluted in porcine plasma or whole blood and pumped through a pulsatile flow system with adjustable hydrodynamic pressures and temperature. B-mode images were acquired using a clinical diagnostic scanner every 5 s for a total duration of 75 s. Echogenicity in porcine plasma was assessed as a function of total dissolved gas saturation. ELIP were added to plasma at room temperature (22 degrees C) or body temperature (37 degrees C) and pumped through a system maintained at 22 degrees C or 37 degrees C to study the effect of temperature transitions on ELIP echogenicity. Echogenicity at normotensive (120/80 mmHg) and hypertensive pressures (145/90 mmHg) was measured. ELIP were echogenic in plasma and whole blood at body temperature under normotensive to hypertensive pressures. Warming of samples from room temperature to body temperature did not alter echogenicity. However, in plasma cooled rapidly from body temperature to room temperature or in degassed plasma, ELIP lost echogenicity within 20 s at 120/80 mmHg. The stability of echogenicity of a modified ELIP formulation was determined in vitro at body temperature, physiologic gas concentration and throughout the physiologic pressure range. However, proper care should be taken to ensure that ELIP are not cooled rapidly from body temperature to room temperature as they will lose their echogenic properties. Further in vivo investigations will be needed to evaluate the optimal usage of ELIP as blood pool contrast agents. PMID- 22929654 TI - Disruption of splenic circulation using microbubble-enhanced ultrasound and prothrombin: a preliminary study. AB - The spleen is a solid organ in which splenomegaly frequently develops and to which abdominal blunt trauma occurs. In this study, we demonstrated the potential therapeutic effect of microbubble-enhanced ultrasound (MEUS) combined with prothrombin to disrupt splenic circulation. A high-pressure-amplitude therapeutic ultrasound (TUS) device was used to treat 36 surgically exposed spleens in healthy New Zealand rabbits. Eighteen spleens were treated with either MEUS (n = 9) or MEUS combined with prothrombin (n = 9). The other 18 spleens were treated with TUS only or sham ultrasound exposure and served as the controls. The TUS was operated at a frequency of 831 kHz and a peak negative pressure of 4.8 MPa. Prothrombin was administered intravenously at 20 IU/kg. Contrast-enhanced ultrasound (CEUS) and acoustic quantification were performed to assess splenic blood perfusion. We found significant blood perfusion slowdown and drop-off in the MEUS-treated spleens. The peak intensity dropped from 20.2 +/- 2.70 dB to 11.6 +/- 4.58 dB immediately after treatment. The spleens treated with the combination of MEUS and prothrombin showed consistently poor perfusion within 1 h. In histologic examination of the MEUS-treated spleens, we found significant dilatation of splenic sinuses, hemorrhage, interstitial edema and thrombosis. This study demonstrated that the vascular effects induced by microbubble enhanced, high-pressure ultrasound can slow down or block blood perfusion in the rabbit spleen. Prothrombin helps to enhance and extend the effects for up to 1 h. PMID- 22929655 TI - Estimating the delivery efficiency of drug-loaded microbubbles in cancer cells with ultrasound and bioluminescence imaging. AB - The application of drug-loaded microbubbles (MBs) in combination with ultrasound (US), which results in an increase in capillary permeability at the site of US sonication-induced MB destruction, may be an efficient method of localized drug delivery. This study investigated the mechanism underlying the US-mediated release of luciferin-loaded MBs through the blood vessels to targeted cells using an in vivo bioluminescence imaging (BLI) system. The luciferin-loaded MBs comprised an albumin shell with a diameter of 1234 +/- 394 nm (mean +/- SD) and contained 2.48 * 109 bubbles/mL; within each MB, the concentration of encapsulated luciferin was 1.48 * 10-10 mg/bubble. The loading efficiency of luciferin in MBs was only about 19.8%, while maintaining both the bioluminescence and acoustic properties. In vitro and in vivo BLI experiments were performed to evaluate the US-mediated release of luciferin-loaded MBs. For in vitro results, the increase in light emission of luciferin-loaded albumin-shelled MBs after destruction via US sonication (6.24 +/- 0.72 * 107 photons/s) was significantly higher than that in the luciferin-loaded albumin-shelled MBs (3.11 +/- 0.33 * 107 photons/s) (p < 0.05). The efficiency of the US-mediated release of luciferin loaded MBs in 4T1-luc2 tumor-bearing mice was also estimated. The signal intensity of the tumor with US destruction at 3 W/cm2 for 30 s was significantly higher than without US destruction at 3 (p = 0.025), 5 (p = 0.013), 7 (p = 0.012) and 10 (p = 0.032) min after injecting luciferin-loaded albumin-shelled MBs. The delivery efficiency was, thus, improved with US-mediated release, allowing reduction of the total injection dose of luciferin. PMID- 22929656 TI - Impact of preconditioning pulse on lesion formation during high-intensity focused ultrasound histotripsy. AB - Therapeutic applications with high-intensity focused ultrasound (HIFU) fall into two classifications-one using thermal effect for coagulation or ablation while generally avoiding cavitation and the other using cavitation-mediated mechanical effects while suppressing heating. Representative of the latter, histotripsy uses HIFU at low duty factor to create energetic bubble clouds inside tissue to liquefy a region and has the advantages in real-time monitoring and lesion fidelity to treatment planning. We explored the impact of a preconditioning/heating pulse on histotripsy lesion formation in porcine muscle samples. During sonication, a targeted square region 9 mm wide (lateral to the focal plane) was scanned in a raster pattern with a step size of 0.75 mm. The 20 s exposure at each treatment location consisted of a 5-s duration preconditioning burst at spatial-peak intensities from 0-1386 W/cm2 followed by 5000 tone bursts at high intensity (with spatial-peak pulse-average intensity of 47.34 kW/cm2, spatial-peak temporal-average intensity of 284 W/cm2, peak compressional pressure of 102 MPa and peak rarefactional pressure of 17 MPa). The temperature increase for all exposures was measured using a thermal imager immediately after each exposure. Lesion volume increased with increasing amplitude of the preconditioning pulse until coagulation was observed, but lesion width/area did not change significantly with the amplitude. In addition, the lesion dimensions became smaller when the global tissue temperature was raised before applying the histotripsy pulsing sequence. Therefore, the benefit of the preconditioning pulse was not caused by global heating. PMID- 22929657 TI - Vision, development, and bilingualism are fundamental in the quest for a universal model of visual word recognition and reading. AB - We agree with many of the principles proposed by Frost but highlight crucial caveats and report research findings that challenge several assertions made in the target article. We discuss the roles that visual processing, development, and bilingualism play in visual word recognition and reading. These are overlooked in all current models, but are fundamental to any universal model of reading. PMID- 22929658 TI - Intravenous mesenchymal stem cells prevented rejection of allogeneic corneal transplants by aborting the early inflammatory response. AB - Mesenchymal stem/progenitor cells (MSCs) were reported to enhance the survival of cellular and organ transplants. However, their mode of action was not established. We here used a mouse model of corneal allotransplantation and demonstrated that peri-transplant intravenous (i.v.) infusion of human MSCs (hMSCs) decreased the early surgically induced inflammation and reduced the activation of antigen-presenting cells (APCs) in the cornea and draining lymph nodes (DLNs). Subsequently, immune rejection was decreased, and allograft survival was prolonged. Quantitative assays for human GAPDH revealed that <10 hMSCs out of 1 * 10(6) injected cells were recovered in the cornea 10 hours to 28 days after i.v. infusion. Most of hMSCs were trapped in lungs where they were activated to increase expression of the gene for a multifunctional anti inflammatory protein tumor necrosis factor-alpha stimulated gene/protein 6 (TSG 6). i.v. hMSCs with a knockdown of TSG-6 did not suppress the early inflammation and failed to prolong the allograft survival. Also, i.v. infusion of recombinant TSG-6 reproduced the effects of hMSCs. Results suggest that hMSCs improve the survival of corneal allografts without engraftment and primarily by secreting TSG 6 that acts by aborting early inflammatory responses. The same mechanism may explain previous reports that MSCs decrease rejection of other organ transplants. PMID- 22929659 TI - IFN-gamma-induced iNOS expression in mouse regulatory macrophages prolongs allograft survival in fully immunocompetent recipients. AB - Mouse monocytes exposed to macrophage colony-stimulating factor (M-CSF) and interferon-gamma (IFN-gamma) were driven to a novel suppressor phenotype. These regulatory macrophages (M regs) expressed markers distinguishing them from M0-, M1-, and M2-polarized macrophages and monocyte-derived dendritic cells (DCs). M regs completely suppressed polyclonal T cell proliferation through an inducible nitric oxide synthase (iNOS)-dependent mechanism. Additionally, M regs eliminated cocultured T cells in an allospecific fashion. In a heterotopic heart transplant model, a single intravenous administration of 5 * 10(6) donor-strain M regs before transplantation significantly prolonged allograft survival in fully immunocompetent recipients using both the stringent C3H-to-BALB/c (32.6 +/- 4.5 versus 8.7 +/- 0.2 days) and B6-to-BALB/c (31.1 +/- 12 versus 9.7 +/- 0.4 days) strain combinations. Nos2-deficient M regs did not prolong allograft survival, proving that M reg function in vivo is iNOS-dependent and mediated by living cells. M regs were detectable for at least 2 weeks postinfusion in allogeneic recipients. In their origin, development, phenotypic relationship with other in vitro-derived macrophages and functions, there are solid grounds to assert a near equivalence of mouse and human M regs. It is concluded that mouse M regs represent a novel, phenotypically distinct subset of suppressor macrophages. Clinical applications of M reg therapy as an adjunct immunosuppressive therapy are currently being investigated within The ONE Study. PMID- 22929660 TI - Cerebral infusion of AAV9 vector-encoding non-self proteins can elicit cell mediated immune responses. AB - There is considerable interest in the use of adeno-associated virus serotype 9 (AAV9) for neurological gene therapy partly because of its ability to cross the blood-brain barrier to transduce astrocytes and neurons. This raises the possibility that AAV9 might also transduce antigen-presenting cells (APC) in the brain and provoke an adaptive immune response. We tested this hypothesis by infusing AAV9 vectors encoding foreign antigens, namely human aromatic L-amino acid decarboxylase (hAADC) and green fluorescent protein (GFP), into rat brain parenchyma. Over ensuing weeks, both vectors elicited a prominent inflammation in transduced brain regions associated with upregulation of MHC II in glia and associated lymphocytic infiltration. Transduction of either thalamus or striatum with AAV9-hAADC evinced a significant loss of neurons and induction of anti-hAADC antibodies. We conclude that AAV9 transduces APC in the brain and, depending on the immunogenicity of the transgene, can provoke a full immune response that mediates significant brain pathology. We emphasize, however, that these observations do not preclude the use of AAV serotypes that can transduce APC. However, it does potentially complicate preclinical toxicology studies in which non-self proteins are expressed at a level sufficient to trigger cell-mediated and humoral immune responses. PMID- 22929661 TI - Multimechanistic tumor targeted oncolytic virus overcomes resistance in brain tumors. AB - Only a subset of cancer patients inoculated with oncolytic herpes simplex virus (oHSV) type-1 has shown objective response in phase 1 and 2 clinical trials. This has raised speculations whether resistance of tumor cells to oHSV therapy may be a limiting factor. In this study, we have identified established and patient derived primary glioblastoma multiforme (GBM) stem cell lines (GSC) resistant to oHSV and also to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) that has recently shown promise in preclinical and initial clinical studies. We created a recombinant oHSV bearing a secretable TRAIL (oHSV-TRAIL) and hypothesized that oHSV-TRAIL could be used as a cancer therapeutic to target a broad spectrum of resistant tumors in a mechanism-based manner. Using the identified resistant GBM lines, we show that oHSV-TRAIL downregulates extracellular signal-regulated protein kinase (ERK)-mitogen-activated protein kinase (MAPK) and upregulates c-Jun N-terminal kinase (JNK) and p38-MAPK signaling, which primes resistant GBM cells to apoptosis via activation of caspase-8, -9, and -3. We further show that oHSV-TRAIL inhibits tumor growth and invasiveness and increases survival of mice bearing resistant intracerebral tumors without affecting the normal tissues. This study sheds new light on the mechanism by which oHSV and TRAIL function in concert to overcome therapeutic resistance, and provides an oncolytic virus based platform to target a broad spectrum of different cancer types. PMID- 22929662 TI - Ad5:Ad48 hexon hypervariable region substitutions lead to toxicity and increased inflammatory responses following intravenous delivery. AB - The development of adenoviral vectors for intravascular (i.v.) delivery will require improvements to their in vivo safety and efficacy. The hypervariable regions (HVRs) of the Ad5 hexon are a target for neutralizing antibodies, but also interact with factor X (FX), facilitating hepatocyte transduction. Ad48, a species D adenovirus, does not bind FX and has low seroprevalence. Therefore, it has been suggested that Ad5HVR48(1-7), a hexon-chimeric vector featuring the seven HVRs from Ad48, should display advantageous properties for gene therapy, by evading pre-existing Ad5 immunity and blocking FX interactions. We investigated the in vivo biodistribution of Ad5, Ad5HVR48(1-7), and Ad48 following i.v. delivery. Ad5HVR48(1-7) displayed reduced hepatocyte transduction and accumulation in Kupffer cells (KCs), but triggered a robust proinflammatory response, even at relatively low doses of vector. We detected elevated serum transaminases (48 hours) and increased numbers of periportal CD11b(+)/Gr-1(+) cells in the livers of Ad5HVR48(1-7)-treated animals following i.v., but not intramuscular (i.m.), delivery. In contrast, Ad48 did not elevate transaminases or result in the accumulation of CD11b(+)/Gr-1(+) cells. Collectively, these findings suggest that substantial hexon modifications can lead to unexpected properties which cannot be predicted from parental viruses. Therefore, refined mutations may be preferential for the successful development of targeted vector systems which require i.v. administration. PMID- 22929663 TI - Giving theories of reading a sporting chance. AB - The search for a universal theory of reading is misguided. Instead, theories should articulate general principles of neural computation that interact with language-specific learning environments to explain the full diversity of observed reading-related phenomena across the world's languages. PMID- 22929664 TI - Cell-free collagen-based scaffolds used for making blood vessels in cardiovascular surgery. AB - The present article deals with the technology of obtaining decellularized cell free collagen-based scaffolds from arterial vessels and surgical assessment of the possibility of experimentally implanting them into the blood system of laboratory animals for experimental purposes. The study was performed on arterial vessels (n=60) and fragments of the human internal thoracic artery (n=20). Described herein is a method of obtaining a connective-tissue matrix of a blood vessel by means of vessel's perfusion for 2-3 hours with detergent solutions. Cell-free collagen-based conduits were implanted to a total of ten dogs. After the operation, the blood flow remained functional. The anastomoses established turned out to be leak-proof and the acellular vessels were able to withstand the haemodynamic load of the arterial blood flow. PMID- 22929665 TI - [Peculiarities of arterial lesions in patients with critical ischaemia on the background of diabetic foot syndrome]. AB - The authors investigated peculiarities of occlusive and stenotic arterial lesions influencing the pattern of revascularization in patients presenting with a neuroischaemic form of diabetic foot syndrome. We examined a total of 106 patients with a neuroischaemic form of diabetic foot syndrome and undergoing treatment at the City Municipal Centre for Diabetic Foot in the City of Minsk. In order to visualize the arteries in 82 (77.4%) cases we used contrast-enhanced angiography, in 16 (15.1%) cases - CT angiography, and in 8 (7.5%) cases a combination of the both methods was used. The overwhelming majority of patients were found to have distal occlusion with lesions of three and two crural arteries. Standard approaches made it possible to perform revascularization only in 46 (43.9%) patients in the examined group. A promising trend of improving rendering care for patients with a neuroischaemic form of diabetic foot syndrome and decreasing the rate of high amputations consists in thrther development and implementation of hybrid technologies of limb revascularization, as well as adequate material and technical provision of such interventions. PMID- 22929666 TI - [Comparative analysis of arterial bioprostheses with various antithrombotic modification]. AB - The present study was aimed at comparing the results of remote patency ol arterial bioprosthcses "KemAngioprosthesis" in infrainguinal position with various antithromhotic modifi cation. We analyzed the outcomes in a total of 133 patients who were subdivided into two groups: Group I (n=91) underwent implantation of hioprostheses with antithrombotic modifi calion by non fractionated heparin. and Group II (n=42) received prostheses treated with low molecular-weight heparin "Clexane". Patients of the both groups underwent comprehensive analysis of the haemostatic system, blood plasma lipid spectrum, as well as duplex scanning of the prosthesis. 39 (42.9%) Group I patients and 6 (13.6%) Group II patients were found to have developed thromboses. Besides, 14 (I5.4%) Group I patients were diagnosed as hawing restenosis of the anastomosis site, with this complication observed in 3 (7.3%) Group II patients. The results of the analysis demonstrated better remote patency of bioprostheses with antithromhotic modifi cation by low-molecular-weight heparin "Clexane". Dynamic follow up of the patients made it possible to carry out timely correction of medicamentous therapy, as well as at early stages to reveal restenosis of anastomoses followed by endovascular correction. PMID- 22929667 TI - [Neuroprotective effect of ischemic postconditioning and remote preconditioning. Prospective of clinical use]. AB - Ischemic postconditioning enhances brain and spinal cord tolerance to ischemia and reperfusion. There are no clinical data on the neuroprotective effect of postconditioning. It was established that foregoing effect of ischemic postconditioning depended upon an activation of PKCs, ERK, Akt kinases and a decrease in the activity of JNK kinase. Superoxide dismutase, Bax, Bal-2 and HSP proteins may be the end effector of postconditioning. Postconditioning phenomenon is mimicked by norepinephrine, diazoxide, sevoflurane, isoflurane and propofol. It is unknown before whether these pharmacological agents prevent brain reperfusion injury in human. Remote preconditioning improves brain and spinal cord tolerance to ischemic and reperfusion damages. There are no data on the neuroprotective effect of remote preconditioning in human at ischemic insult. The endogenous cannabinoids, reactive oxygen species are triggers of remote preconditioning. The neuroprotective effect of preconditioning at distance is depended on the activation of p38, ERK kinases and is attributed to enhancement of HSP-70 protein synthesis. PMID- 22929668 TI - [Prevention of ischemic stroke in patients with asymptomatic lesions of carotid arteries]. AB - Based on the data from both Russian and foreign literature, analysed herein are the methods of surgical and medicamentous prevention of ischaemic stroke in patients presenting with asymptomatic lesions of carotid arteries. This is followed by discussing haemodynamic parameters of the blood flow in the carotid arteries and their effect on cerebrovascular symptomatology. Also presented herein are the data concerning efficacy of different modalities of antithrombocytic therapy, followed by presenting own results regarding surgical management for stenoses and pathological kinking of carotid arteries in the patient cohort concerned. PMID- 22929669 TI - [Microcirculation blood flow of the upper extremities in patients with coronary artery disease combined with non-insulin dependent diabetes mellitus]. AB - The work was aimed at assessing the possibilities of the microcirculatory blood flow (MBF) of the upper extremities in patients suffering from coronary artery disease (CAD), as well as in patients with CAD accompanied by type 2 diabetes mellitus (NIDDM) by means of laser Doppler flowmetry (LDF) using functional tests. The obtained findings of the study demonstrated that that the lowest reserve capabilities of the MBF were observed in the group of patients with CAD and NIDDM, and this group considerably more often versus patients with CAD without NIDDM showed decreased collateral reserve and low compensatory capabilities of the microcirculatory bed of the upper limbs. PMID- 22929670 TI - [Comparative characteristics of new PTFE vascular patches in experiment]. AB - Presented herein are the findings of a comparative experimental study of 64 novel patches made of porous polytctrafluoroethylene (PTFE). The PTFE explants with various number of technological layers were examined both in vitro and in vivo. The authors performed plasty of the canine aorta with explants followed by morphological assessment of the tissues with PTFE at various terms of follow up. Based on the results obtained during intraoperative assessment of the patches' properties and histological examination thereof, we selected better patches for plasty of the aorta and major arteries to be implemented into clinical practice. PMID- 22929671 TI - [Computed tomography and CT angiography in diagnosis of acute disorders impairment of mesenteric circulation]. AB - Presented herein is the first experience in using two instrumental methods (remote contrast- free computed tomography and CT angiography) in a total of twenty-one patients suspected of having acute mesenteric ischaemia. Contrast-free computed tomography allowed of making a correct diagnosis of acute mesenteric ischaemia in 6 of 7 patients (with sensitivity of 85.7% and specificity amounting to 90%). Thrombosis of mesenteric vessels was revealed in all cases on CT angiography, with both sensitivity and specificity of the method equalling 100%. Also described herein is the incidence rate of various CT signs of intestinal lesions depending on aetiology and the stage of the disease. Minimally invasive nature, high spatial resolution of these two methods, high sensitivity and specificity make it possible to recommend them as the first step for instrumental diagnosis of acute mesenteric ischaemia. PMID- 22929672 TI - [Comparative characteristics of revealing hibernated myocardium by means of perfusion and metabolic scintigraphy]. AB - OBJECTIVE: comparative assessment of the informative value of the methods of perfusion and metabolic single-photon emission computed tomography (SPECT) in detecting the hibernated myocardium. MATERIALS AND METHODS: the study included a total of twenty six patients diagnosed with coronary artery disease (CAD). Of these, there were 24 men and 2 women, mean age 52.0+/-7.0 years. All the patients in order to detect the viable myocardium were subjected to perfusion scintigraphy of the myocardium with (99)mTc-technitrile ("Diamed", Russia) at rest and in a combination with the nitroglycerine test, as well as metabolic scintigraphy of the myocardium with (123)I-labelled beta-methyl-rho-iodophenyl pentadecanic acid (BMIPP). RESULTS: the studies showed that sensitivity of myocardial scintigraphy with (99)mTc-technitrile on the background of the nitroglycerine test amounted to 89%, with specificity of 85% and diagnostic accuracy of 86%. While calculating the diagnostic significance of SPECT with (123)I-BMIPP, in turned out that the method's sensitivity amounted to 94%, specificity to 87%, and diagnostic accuracy to 91%. CONCLUSION: perfusion scintigraphy of the myocardium on the background of the nitroglycerine test and scintigraphic assessment of metabolism of fatty acids are highly informative tests for revealing viable portions of the ischemic myocardium, with the diagnostic parameters of SPECT with (123)I-BMIPP being slightly superior to those of perfusion scintigraphy with (99)mTc-technitrile on the background of sublingual administration of nitroglycerine. PMID- 22929673 TI - [Endografting of a true aneurysm of the internal carotid artery]. AB - Aneurysms of the internal carotid artery are a rarely encountered nosological entity, with only sporadic clinical cases being reported in both Russian and foreign literature. In the majority of instances, this pathology is removed by means of prosthetic repair of the internal carotid artery. However, recent trends are toward increased use of endovascular endografting. Described in the article is a case of an internal carotid artery aneurysm successfully treated by a self opening stent graft. PMID- 22929674 TI - [Endovascular balloon angioplasty of a stenotic lesion of autovenous bypass grafts in the infrainguinal position]. AB - Analysed in the article are the results of dynamic follow up of autovenous bypass grafts in the infrainguinal position. About 80% of patients were operated on for lower limb critical ischaemia. Remote patency of the bypass grafts amounted to 68%. Also presented herein are the outcomes of balloon angioplasty of the bypass grafts (30 interventions) in both immediate and remote periods. Primary success was achieved in 94% of cases. The early stage (30 days) was characterized by two thromboses of the bypass graft, and the remote period showed eleven restenoses. Two limb amputations were performed. The role of endovascular correction of bypass graft stenoses in order to save the limb is determined. PMID- 22929675 TI - [Lower limb vein thrombosis in dynamics of acute impairments of cerebral circulation]. AB - The present work was aimed at studying the state of the inferior vena cava system according to the findings of duplex scanning in dynamics of acute cerebral circulation impairments (ACCI). Amongst 100 patients with ACCI, lower limb vein deep thrombosis (LLVDT) was revealed in 57% of cases. The incidence of LLVDT in patients with intracerebral haemorrhage was higher than in those with ischaemic stroke, however there were no statistically significant differences between the type of ACCI (p=0.06) and subtypes of ischaemic stroke (atherothrombotic, ceardioembolic) (p = 0.68). The main risk factors for LLVDT are the presence of pronounced motion deficit in the extremities, induced by the underlying disease (p=0.02) and immobilization. In the overwhelming majority of patients (81%) thrombosis localized isolatedly in the crural veins. Ascending thrombosis and the development of a floating thrombus were represented mainly on the side of motility deficit in the extremities. We have confirmed a strong association between positive dynamics in the neurological status of patients and frequency of recanalization of thrombi (p=0.043). Ultrasonographic examination of lower limb veins in dynamics of ACCI is an important component of preventive and therapeutic process. PMID- 22929676 TI - [State of crural perforating veins after sclerosurgical interventions for lower limb varicose disease]. AB - Analysed herein are the findings obtained by comprehensive examination of 106 patients presenting with grade C3 chronic venous insufficiency according to the CEAP classification. Localization, intensity and extent of refluxes of blood in the venous system of the affected extremity were determined by means of ultrasonographic angioscanning. Based on the obtained results, the patients were subdivided into two groups. Group One was composed of 87 (82.1%) patients found to have their perforant venous insufficiency caused by superficial hypervolemia due to sharply pronounced varicosity of superficial veins. Group Two comprised 19 (17.9%) patients who had developed perforant insufficiency secondary to superficial and deep blood refluxes. In 82 (77.3%) Group One patients, the scope of the operations was limited to elimination of the superficial blood reflux, with only five (4.7%) patients at the second stage of management had their perforant blood reflux removed. Group Two patients were subjected to single-stage removal of both superficial and perforant blood refluxes. Excellent therapeutic outcomes were observed in 49.1% of cases, with good and satisfactory results obtained in 41.5% and 9.4% of patients, respectively. PMID- 22929677 TI - [On advisability of perioperative phleboprotection in endovascular treatment of lower in varicose disease: first initial results of the decision study]. AB - Presented in the article are the results of the DECISION multicenter study dedicated io assessment of efficacy and feasibility of using the phlebotropbic drug detralex in the perioperative period in patients undergoing endovascular treatment of lower limb varicose discase. The study comprised a total of 230 patients presenting with chronic venous disease. (CVD) C2-4s according the CEAP classification, each of these had not less than three CVD- related symptoms. All patients were randomly assigned to the Study Group (126 people) and the Control Group (104 subjects). The Study Group patients 2 weeks prior to endovascular treatment and during 4 weeks thereafter took the phlebotrophic drug detralex at a standard daily dose of 1,000 mg. The Control Group patients received conventional compression thernpy using compression bandages or medicinal knitted fabric. The findings of the statistically processed results in the both groups demonstrated a significant decrease in the CVD severity score according to the VCSS scale and an increase in the quality of life parameters according to the disease-specilic questionnaire CIVIQ-14. While so doing, more pronounced dynamics was observed in patients taking detralex during the perioperative period. Besides, there was synergism between the results of the endovascular intervention and therapeutic effects from detralex. Based on the findings obtained in the present study, the authors made a conclusion on feasibility of using the drug detralex as an agent for nonspecific pharmacological protection in endovascular treatment of varicose disease. PMID- 22929678 TI - [Modern methods of comprehensive management of patients with varicose disease relapsing after surgical interventions]. AB - Despite progress achieved by Russian phlebology in diagnosis and treatment of lower-limb varicose disease, the latter remains the most commonly encountered pathology of the vascular bed. Treatment for varicose disease includes a series of unsolved as yet problems, the main of which being a relapse of varicose disease after surgical interventions. The authors share herein their experience gained in using comprehensive methods while managing varicose disease relapses, also describing the technique of the procedures performed and analysing certain technical variants thereof. PMID- 22929679 TI - [Efficacy of ANTISTAX in treatment of postmastectomic oedema of the upper limb]. AB - Analysed herein are the results of two-year treatment with Antistax of 50 female patients presenting with early stages of upper limb lymphedema (the 'preclinical' stage of 'transient' oedemas, mild-oedema stage). The control group consisted of patients who due to various circumstances received no regular treatment with agents decreasing limb oedema, including diuretics. The obtained results demonstrated undoubted efficacy of Antistax administered at early stages of postmastectomic lymphedema. Preventive administration of the agent makes it possible to delay and in the majority of cases to also prevent the development of lymphedema. Administration of Antistax in a combination with physiotherapeutic treatment makes it possible both in the first and second stages of the disease to preserve the cosmetic and functional state of the upper limb. PMID- 22929680 TI - [Remote results of open interventions in treatment of abdominal aortic aneurysms]. AB - Analysed herein are the results of treating a total of 471 patients operated on at the Department of Surgical Treatment for Arterial Pathology of the Research Centre of Cardiovascular Surgery named after A. N. Bakulev under the Russian Academy of Medical Sciences for an aneurysm of the infrarenal portion of the abdominal aorta. Complicated forms of AAA were observed in 71 (15.1%) patients. Of these, 13 patients were admitted presenting with a clinical picture of aortic rupture, 56 patients with aortic wall tear (according to ultrasound and/or MSCH findings), and two patients had break of the inferior vena cava. The most frequently encountered accompanying diseases were as follows: CAD noted in 367 (78.2%) patients. Valvular heart defects were revealed in 68 (14.4%) patients. Atherosclerotic alterations of the ascending aorta were diagnosed in 97 (20.6%) patients, and an ascending aortic aneurysm in 14 (2.8%) patients. Operations on the heart were performed in 45 (19.1%) patients. Mitral valve plasty was carried out in 7 patients, and 11 patients had a history of prior interventions on the aortic root and ascending aorta (Bentall-De Bono operation in 3 patients, Carbol operation in 3 patients). 32 patients underwent reconstructive operations on coronary arteries. Transmyocardial laser revascularization of the myocardium was carried out in 4 patients. Endovascular interventions were performed in 32 (6.8%) patients (stenting or transluminal balloon angioplasty of coronary arteries). All patients underwent AAA resection with prosthetic repair. The mentioned operations were combined with the following simultaneous interventions: aortocoronary bypass grafting performed in 31 cases, carotid endarterectomy in 27 cases, and plasty of renal arteries was carried out in 48 patients. Complications in the immediate postoperative period were observed in 79 (16.8%) patients. Hospital mortality amounted to 11 (2.3%) patients. The cumulative survival rate after 1, 5 and 10 years after surgery amounted to 93%, 81% and 44%, respectively, in a complicated course amounting to 91%, 79% and 16%, respectively. The obtained findings of the study demonstrated that the results of the AAA resection should be regarded as fairly good. The main factors influencing the quality of life and surgical outcomes in abdominal aortic aneurysms are as follows: CAD, arterial hypertension, and chronic cerebrovascular diseases. In patients without accompanying diseases, the criteria of quality of life after surgery approximate to those in a healthy population. PMID- 22929681 TI - [Left anterior descending bypass grafting from the anterolateral minitorakotomy]. AB - Current efficient methods of open revascularization in patients with multivessel coronary artery lesions are associated with a certain amount of general and local complications depending on traumatic interventions, bypass, manipulation on the ascending aorta. Minimally Invasive Direct Coronary Artery Bypass Grafting (MIDCAB) allows to avoid certain perioperative risk factors and appears to be a promising myocardial revascularization model in isolated lesion of left anterior descending (LAD) and multivessel lesions, applying combines percutaneous intervention (PCI). PMID- 22929682 TI - [Comparison of remote results outcomes of stenting and eversion endarterectomy from internal carotid arteries]. AB - Presented in the article are comparative results of carotid angioplasty with stenting (CAS) and eversion carotid endarterectomy (ECEA) in the remote period of follow up. The study included a total of 92 patients. Of these, 33 were subjected to CAS (Group I) and 59 underwent a total of 63 ECEAs (Group II). Depending upon the presence or absence of symptoms of cerebrovascular insufficiency (CVI), as well as based on assessment of risk factors for surgical intervention, the patients were subdivided into four subgroups: a) low-risk asymptomatic b) low risk symptomatic, c) high-risk asymptomatic and d) high-risk symptomatic. We followed up remote results in 31 Group I patients (94%) up to 70 months (mean period of follow up amounted to 25+/-17 months), and in 36 Group II patients up to for up to 65 months (mean duration of the follow up amounting to 37+/-20 months). There was no statistically significant difference (P >0.05) between subgroups of patients along such parameters as severe or mild stroke, myocardial infarction, stroke-related death, or myocardial infarction related death. CAS and ECEA are equally highly efficient techniques of preventing acute cerebral circulation impairments in the remote period of follow up in patients of both high and low risk of surgical intervention. PMID- 22929683 TI - On the terms to perform minor amputations for chronic critical lower limb ischaemia after successful vascular reconstruction. AB - Assessed herein are the results of treating a total of 119 patients presenting with chronic critical ischaemia of the lower extremities accompanied by necrosis of distal portions of the foot. All patients underwent various successful operations of lower-limb revascularization, followed by evaluating the terms of healing of the wounds on the foot after necrectomy and minor amputations. A conclusion was made that after successful limb revascularization for critical ischaemia in patients with atherosclerosis accompanied by coagulative necrosis, performing minor amputations and necrectomies should be delayed. PMID- 22929684 TI - [Hybrid operations in multilevel lesions of lower-limb arteries]. AB - Reflected in the article is experience in treating a total of 24 patients suffering from lower limb chronic ischaemia and diagnosed as having concomitant lesions of the aortofemoral and femoropopliteal segments, with a total of 24 hybrid operations performed. Of these, nineteen interventions consisted of implanting a stent graft into iliac arteries and revascularization of the femoropopliteal segment, whereas the remaining five cases included balloon angioplasty of the iliac artery with revascularization of the femoropopliteal segment. Good immediate outcomes were obtained in 23 patients. The ankle-brachial index increased averagely from 0.38 to 0.88. The remote outcomes (from 12 months to 5 years) were followed up in fifteen patients. Cumulative patency of the bypass grafts after 1, 3 and 5 years amounted to 78%, 41.5% and 41.5%, respectively. The cumulative survival rates after 1, 3 and 5 years equalled 90.8%, 76.2% and 76.2%, respectively. All extremities were eventually spared, with the long-term limb salvage rate thus amounting to 100%. PMID- 22929685 TI - [Stagewise bilateral stenting of vertebral arteries in a patient with occlusion of both internal carotid arteries]. AB - The authors describe herein a case report concerning stagewise endovascular treatment of a 69-year-old male patient presenting with occlusion of the right and left internal carotid arteries admitted to Clinical Hospital No 1 of the RF President's Affairs Administration with the following diagnosis: atherosclerotic occlusion of carotid arteries, arterial hypertension, chronic bronchitis, chronic prostatitis, and a history of multiple episodes of unconsciousness. Duplex scanning and angiography of the brachiocephalic arteries revealed occlusion of the both internal carotid arteries, as well as pronounced narrowing of the ostium of the right and left vertebral arteries supplying blood to all portions of the brain. Computed tomography revealed no signs of endured stroke. The first stage consisted in stenting of critical stenosis of the left vertebral artery ostium, followed by stenting of the right vertebral artery ostium performed 2 weeks after (with implanting drug-covered stents "Promus" in both cases). The patient was discharged home in a satisfactory condition. PMID- 22929686 TI - [A rare case of surgical management of a patient with thoracic aortic aneurysm]. AB - Described in the article is a clinical case of successful surgical management of a male patient diagnosed with a syphilitic-origin aneurysm of the thoracic aorta isthmus, complicated by an aortopulmonary fistula. Also presented herein are the clinical pattern, findings of examination, and treatment policy. This is followed by a detailed description of both the course of the surgical intervention and outcomes obtained. PMID- 22929687 TI - [Substantiation of an adequate scope of diagnostic methods and surgical procedures in patients with diabetic foot syndrome]. AB - Analysed herein are the results of treating a total of 154 patients presenting with diabetes mellitus and pyo-necrotic alterations in the lower limbs. Duration of diabetes prior to the development of necrotic complications averagely amounted to 15 years, in 76 patients of the Study Group we determined the species-specific composition of the pathogens, the number of microbial bodies in 1 gram of necrotic tissues as well as the state of cellular and humoral immunity, and the complex of therapeutic measures was supplemented by cytokine therapy: Operative treatment in 78 patients of the control group consisted of various-scope necrectomies and open management of the wounds. The operative procedures in the Study Group patients included revascularizing operations, as well as secondary surgical debridement of the wounds with placing sutures. In the control group, the limb salvage rate amounted to 57.7% (29 of 78) and that in the Study Group to 88.15% (67 of 76). In the first group, we performed a total of 29 (37.17%) major amputations and 4 (5.25%) in the study group. Conclusion was made on advantages of a comprehensive approach while assessing all impairments in the body of duibetic patients and adequate therapeutic policy aimed at re-establishing blood flow, removal of the purulent focus and decrease of tissue infectedness, correction of the immune status, as well as application of novel methods of treatment and drug therapy. PMID- 22929688 TI - Letter from the editor: what's your trauma intelligence quotient? PMID- 22929689 TI - Letter from the guest editor: imaging of trauma. PMID- 22929690 TI - Imaging of blunt cerebrovascular injuries. PMID- 22929691 TI - Computed tomographic imaging in head and neck trauma: what the radiologist needs to know. PMID- 22929692 TI - Multidetector computed tomography of spinal fractures. PMID- 22929693 TI - Evaluation of thoracic vascular trauma with multidetector computed tomography. PMID- 22929694 TI - Multidetector computed tomography of blunt hepatic and splenic trauma: pearls and pitfalls. PMID- 22929695 TI - Multidetector computed tomography of pancreatic, small bowel, and mesenteric traumas. PMID- 22929696 TI - Multidetector computed tomography of penetrating abdominal trauma. PMID- 22929697 TI - Real-time quantification of antibody-short interfering RNA conjugate in serum by antigen capture reverse transcription-polymerase chain reaction. AB - Short interfering RNA (siRNA) has therapeutic potential. However, efficient delivery is a formidable task. To facilitate delivery of siRNA into cells, we covalently conjugated siRNA to antibodies that bind to cell surface proteins and internalize. Understanding how these antibody-siRNA conjugates function in vivo requires pharmacokinetic analysis. Thus, we developed a simple real-time antigen capture reverse transcription-polymerase chain reaction (RT-PCR) assay to detect intact antibody-siRNA conjugates. Biotinylated antigen bound to streptavidin coated PCR tubes was used to capture antibody-siRNA conjugate. The captured antibody-siRNA conjugate was then reverse-transcribed in the same tube, avoiding a sample transfer step. This reproducible assay had a wide standard curve range of 0.029 to 480ng/ml and could detect as low as 0.58ng/ml antibody-siRNA conjugates in mouse serum. The presence of unconjugated antibody that could be generated from siRNA degradation in vivo did not affect the assay as long as the total antibody concentration in the antigen capture step did not exceed 480ng/ml. Using this assay, we observed a more rapid decrease in serum antibody-siRNA conjugate concentrations than the total antibody concentrations in mice dosed with antibody-siRNA conjugates, suggesting loss of siRNA from the antibody. This assay is useful for optimizing antibody-siRNA and likely aptamer-siRNA conjugates to improve pharmacokinetics and aid siRNA delivery. PMID- 22929699 TI - Comparison of Stain-Free gels with traditional immunoblot loading control methodology. AB - Loading controls are necessary for semiquantitative Western blotting to compensate for loading errors. Loading control methods include the reprobing of membranes with an antibody against a constitutively expressed protein or staining the membrane with a total protein stain. We compared the loading control performance of recently released Stain-Free (SF) gels with Sypro Ruby (SR) and reprobing using beta-actin. SF gels demonstrated superior performance in that they were faster, required fewer steps and consumables, and allowed the quality of electrophoresis and Western transfer to be assessed before committing to costly and time-consuming Western blots. PMID- 22929698 TI - Zeptomole detection of DNA nanoparticles by single-molecule fluorescence with magnetic field-directed localization. AB - Single-molecule fluorescence methods offer the promise of ultrasensitive detection of biomolecules, but the passive immobilization methods commonly employed require analyte concentrations in the picomolar range. Here, we demonstrate that superparamagnetic Fe(3)O(4) nanoparticles (NPs) can be used with an external magnetic field as a simple strategy to enhance the immobilization efficiency and thereby decrease the detection limit. Inorganic NPs functionalized with streptavidin were bound to biotinylated single-stranded DNA oligonucleotides, which were in turn annealed to complementary oligonucleotides labeled with a Cy3 fluorescent dye. Using an external magnetic field, the superparamagnetic nanoparticles were localized to a specific region within the flow chamber surface. From the single-molecule fluorescence time traces, single step photobleaching indicated that the surface-immobilized NPs were primarily bound with a single Cy3-labeled oligonucleotide. This strategy gave a concentration detection limit for the Cy3-labeled oligonucleotide of 100aM, 3000 fold lower than that from an analogous strategy with passive immobilization. With a sample volume of 25MUl, this method achieved a mole detection limit of approximately 2.5zmol (~1500 molecules). Together, the results support that idea that single-molecule fluorescence methods could be used for biological applications such as detection and measurements of nucleic acids from biological or clinical samples without polymerase chain reaction amplification. PMID- 22929700 TI - Comparison of bidirectional and bicistronic inducible systems for coexpression of connexin genes and fluorescent reporters. AB - Gene expression studies often require inducible coexpression of both a gene of interest and a reporter gene. Fusion of fluorescent reporters can, however, modify protein structure and function. We have generated inducible expression systems for two connexin genes: Cx30 and Cx43. It has been reported recently that reporter fusion to connexins can modify their function. Therefore, we compared two methods of independent reporter coexpression and examined colocalization with induced connexin expression. Identical levels of connexin expression were observed for both the bidirectional and bicistronic expression systems. In contrast, however, reporter gene expression by the bidirectional promoter provided brighter average fluorescent pixel intensity than expression of a reporter gene in a bicistronic transcript. Moreover, as a result of this difference in reporter expression, bidirectional expression systems provided equal or better colocalization between the connexins and reporter gene fluorescence. The results of our study indicate that bidirectional reporter expression provides a robust indicator of transfection and gene expression and, therefore, may favor the use of bidirectional over bicistronic reporters in the design of expression systems where the gene of interest, such as a connexin gene, contains translational motifs or long intronic regions. PMID- 22929701 TI - Analysis of evolutionary patterns of genes in Campylobacter jejuni and C. coli. AB - BACKGROUND: The thermophilic Campylobacter jejuni and Campylobacter coli are considered weakly clonal populations where incongruences between genetic markers are assumed to be due to random horizontal transfer of genomic DNA. In order to investigate the population genetics structure we extracted a set of 1180 core gene families (CGF) from 27 sequenced genomes of C. jejuni and C. coli. We adopted a principal component analysis (PCA) on the normalized evolutionary distances in order to reveal any patterns in the evolutionary signals contained within the various CGFs. RESULTS: The analysis indicates that the conserved genes in Campylobacter show at least two, possibly five, distinct patterns of evolutionary signals, seen as clusters in the score-space of our PCA. The dominant underlying factor separating the core genes is the ability to distinguish C. jejuni from C. coli. The genes in the clusters outside the main gene group have a strong tendency of being chromosomal neighbors, which is natural if they share a common evolutionary history. Also, the most distinct cluster outside the main group is enriched with genes under positive selection and displays larger than average recombination rates. CONCLUSIONS: The Campylobacter genomes investigated here show that subsets of conserved genes differ from each other in a more systematic way than expected by random horizontal transfer, and is consistent with differences in selection pressure acting on different genes. These findings are indications of a population of bacteria characterized by genomes with a mixture of evolutionary patterns. PMID- 22929702 TI - Early enteral feeding in intestinal anastomosis. AB - BACKGROUND: Routine practice after major GI surgery has been to keep patient nil per oral till the return of bowel sound with a belief that this will prevent post operative nausea and vomiting and protect the anastomotic site where as the trend has been changing to encourage enteral feeding as soon as possible as various studies has shown early enteral feeding to be beneficial in terms of nutritional, immunological aspect and for faster recovery of patient. METHODS: Patients undergoing major elective GI surgery in department of Surgery, Kathmandu Medical college Teaching Hospital who were given early enteral feeding (within 24 hrs of operation) were studied prospectively and were compared retrospectively with historical control who underwent similar procedure. RESULTS: Early enteral feeding in patient undergoing major G.I surgery showed early return of bowel movement, decreased ICU and hospital stay with a significant reduction in postoperative cost. CONCLUSIONS: Early enteral feeding promotes faster recovery while reducing hospital stay and treatment cost in patient undergoing major GI surgery. PMID- 22929703 TI - Allergic fungal rhinosinusitis in chronic rhinosinusitis. AB - BACKGROUND: Rhinosinusitis is the inflammation of nasal and paranasal sinus mucosa and is associated with mucosal alteration ranging from inflammatory thickening or gross nasal polyp formation.The main objective of this study is to determine the prevalence of allergic fungal rhino sinusitis among the patients having chronic rhino sinusitis with or without polyps who under goes functional endoscopic sinus surgery. METHODS: The patient with chronic rhinosinusitis with or without polyp who FESS were studied. Surgical specimens were sent for mycology and histopathological analysis for identification of fungus. RESULTS: Headache 41(82%) and nasal block 45(90%) were the commonest clinical presentation. Out of 50 patients, fungal elements were detected by KOH in 8(16%) of cases and histopathological examination in 11(22%) of cases. CONCLUSIONS: Allergic Fungal Rhinosinusitisis a common disorder in patients with chronic rhinosinusitis, it need different specific tests for the diagnosis, a more specific diagnostic tests are fungus culture, and IgE to fungal antigen and skin test are needed for definite diagnosis. PMID- 22929704 TI - Laparoscopic primary repair of common bile duct: does the suture size matter. AB - BACKGROUND: Laparoscopic common bile duct exploration and primary closure is being popular method of management for common bile duct stone. As the standard method of procedure is yet to be established, we have compared the outcome of using different size suture for the closure of choledochotomy wound. METHODS: Prospective cross-sectional study was conducted where patients were categorized in two groups. Those with 3-0 suture were grouped "A" and those with 5-0 in"B". Outcome regarding the suturing time, cost, postoperative bile leak and hospital stay were compared between two groups. RESULTS: Total 42 cases were included, twenty-one in each group. Mean age in group A is 38.6yrs and in group B is 44.24yrs. The sex ratio is comparable. Mean time taken for suturing is almost same (34.4 mins Vs 32.6 mins). The Post-operative bile leak is significantly for shorter duration in 5-0 group than 3-0 group. But there is no difference in overall hospital stay. CONCLUSIONS: Post-operative bile leak is significantly less when common bile duct is sutured with thinner needle and suture. This does not increase the cost, does not prolong the operating time and is not associated with other complications. Although the overall hospital stay is same. Further large scale study is needed. PMID- 22929705 TI - Diagnostic accuracy of fine needle aspiration cytology in thyroid swellings. AB - BACKGROUND: Proper management of the disease depends upon accurate diagnosis. Fine Needle Aspiration Cytology has become the investigation of choice because of its high accuracy, simplicity, minimal-invasiveness, quick result and reliability. METHODS: All the patients with thyroid disease, irrespective of age and gender, who underwent thyroid were studied. These patients had their fine needle aspiration Cytology was done in our centre. Detailed history, physical examination, routine investigations, radiological investigations (including CT scans when needed), hormonal assay, (T3, T4, TSH ), ultrasound of neck and FNAC were done. Pre- operative fine needle aspiration results were compared with histopathology results of operated specimen and then analyzed statistically to assess the sensitivity, specificity and accuracy of the result. RESULTS: There were total of 51 patients. Age ranges from 21 to 62 years. The study duration was from May 2006 to February 2011. Out of 51 patients, 82.35% (n=42) were females and 17.64% (n=9) were males. In 43 patients, FNAC showed benign lesions, of which 40 were true negative (TN) and three false negative (FN), which on histopathology reported malignancy. Remaining eight cases were diagnosed as malignancy on histopathology of which seven cases were true positive (TP), one case of false positive (FP) was detected in our study. Over all Sensitivity was 70% and specificity was 97.5% and accuracy of FNAC was 92.1%. CONCLUSIONS: FNAC should be performed in all cases of thyroid nodules because of its high sensitivity and specificity to differentiate benign from malignant lesions and counsel the patient as well as plan surgery accordingly. Expenditure, time and the hassle of revision surgery is minimized by the pre operative FNAC report. PMID- 22929706 TI - Management of liver abscess at teaching hospital. AB - BACKGROUND: A current assessment of liver abscesses should allow for better understanding of the pathogenesis of the disease and improve the effectiveness of diagnosis and treatment. Amoebic liver abscess occurs more commonly than the pyogenic liver abscess on a worldwide basis. The purpose of the study is to investigate the clinical presentation and management option for liver abscess. METHODS: A prospective observational study was conducted from January 2007 to December 2010, in Kathmandu Medical College Teaching Hospital. We recorded and analyzed the clinical presentations, diagnostic modalities, treatment programmes of all liver abscesses. RESULTS: Liver abscess was more common in males, 24(85.7%) males and 4(14.3%) females, occurring more frequently in right lobe of liver. Most patients presented with nonspecific clinical and biochemical features. Twenty (71.4%) patients presented with chills & rigors. Five patients (17.8%) presented jaundice and none had transaminases raised but 15(56.3%) had raised alkaline phospahatases. Eight (28.5%) patients were treated with antibiotics alone. USG guided drainage was done in 12(42.8%) patients and 6(21.4%) required surgical exploration with laparoscopic deroofing in 2(7.1%) patients. The largest size was 1100cc.with right lobe predominance in 20(76.9%) patients and single lobe involvement in 22(78.4%) patients. Six (21.4%) patients had multiple liver lobes involved. Three (7.1%) patients had ruptured liver abscess and 3(7.1%) had right sided pleural effusion. Seventeen (60.7%) patients were diagnosed have amoebic liver abscess. Ten (35.7%) patients were found to have pyogenic liver abscess. One (3.5%) had tuberculosis. CONCLUSIONS: Liver abscess requires a high degree of suspicion for early diagnosis. When appropriate therapy in the form of antibiotics in combination with percutaneous drainage or surgery is administered the mortality is very low. However, significant morbidity is still a problem in old debilitated persons with other core morbidities. PMID- 22929707 TI - Semirigid ureteroscopy with pneumatic lithotripsy for ureteral stone. AB - BACKGROUND: Ureteral stones present with acute loin to groin pain. The objective of this study is to find out the outcome and safety of semi-rigid ureterscopy with pneumatic lithotripsy for treatment of ureteral stones of >30 mm(2) and to assess the impact of size and location on stone free (SF) rate. METHODS: Total 110 patients with isolated ureteral stone size>30 mm(2) were included in this study and treated with pneumatic lithotripsy using 8/9.8 Fr. Semi-rigid ureteroscope (Stiema Germany). Stones were fragmented into 2-3 mm particles and removed. Outcome parameters assessed at 3 months follow up were stone free rate(SF),Efficiency Quotient (EQ), and impact of stone size and site on SF/EQ was also analyzed. Similarly, patient demographics, procedures, patient related parameters and complications were also noted. RESULTS: The overall SF rate at 3 months follow up was 69.33% and efficient Quotient (EQ) 52.52%. The SF/EQ for upper, middle and lower third of ureteral stone was 55/37.67, 61/43.57, 92/84.40 respectively (P-value< 0.001). The SF for stone size 30-110 mm(2) and >110 mm(2) was 78% and 67% respectively. There were no major complications seen. Overall minor complication rate was 5.45 % (minor ureteral perforations-5, urinoma formation 1). CONCLUSIONS: Semi-rigid ureteroscopy with pneumatic lithotripsy is a safe, simple and effective procedure for ureteral stones with excellent success rate for distal ureteral stones. The stone free rate and EQ are statistically significant (P value<0.001) between upper, middle and lower ureteral stones. Stone size has a direct impact on the SF rate and EQ. PMID- 22929708 TI - Factors for abortion seeking among women attending health facilities. AB - BACKGROUND: Unsafe abortion contributes to high maternal mortality in the country which is 281 per 100,000 live births. In line with the expansion of safe abortion services to all 75 districts, it was time for us to look into the depths of the determinants that lead women to seek abortion. METHODS: A cross-sectional descriptive study was conducted in three centers providing safe abortion services in Kathmandu valley, viz. Paropakar Maternity and Women's Hospital, Marie Stopes International (MSI), Nepal, at SatDobato and Tribhuvan University Teaching Hospital (TUTH) from 16th July to 31st August 2009. A total of 450 respondents were interviewed, out of them 270 (60%) were from public centers and 180 (40%) from INGO run centers. RESULTS: It was observed that 32% of the respondents were in the group of 25-29 years;more than a third (34.9%) of the respondents was pregnant for the third time;58% were using some kind of contraceptive prior to this pregnancy and 90.4% showed a desire to use some kind of contraceptive after the abortion. The main reasons cited for termination were completed desired family size and mistiming and 101 (22.4%) had a history of previous induced abortion. CONCLUSIONS: There was a significant association between the uses of contraceptive methods prior to the index pregnancy in women who had sought previous induced abortion and it was also seen that women having previous termination had completed their desired family size of two and the age of the last child was above five. PMID- 22929709 TI - Intestinal parasitic infection among school age children. AB - BACKGROUND: World Health Organization estimates one-fourth of world's population harbors one or more intestinal parasites. Intestinal parasites are among the most common infections of school age children causing-nutritional deficiency, chronic dysentery, rectal prolapse, poor weight gains, retarded growth and mental retardation. METHODS: The stool samples were collected from school going children and examined for intestinal parasite by normal saline wet mount, formalin ether sedimentation technique was performed for the concentration. RESULTS: Among 360 school age students, the prevalence of intestinal parasite was found 40%. Among the positive cases of which 60% were female. It was observed that the rate of parasitic infection among positive cases, Newar was 35(36.84%), Chettri 31(32.97%) and Brahmin and others 29(33.72%) respectively. The study detects an association between intestinal parasitic infection and drinking tape water. CONCLUSIONS: The findings of this study showed that intestinal parasitic infections remain prevalent in the study area. The high prevalence of parasitic infections seems directly related to the unhygienic living conditions. This strongly indicates a need for intervention measures likely-to take up sustained health education, provision of safe drinking water and improvement in environmental sanitation and to provide the school student with health education. PMID- 22929710 TI - Thyroid dysfunction and its effect in serum lipids. AB - BACKGROUND: Thyroid hormones are involved in regulation of lipid and lipoprotein metabolism; therefore, thyroid dysfunctions induce significant change in lipid levels. This study was conducted to study the prevalence of thyroid dysfunction and to observe the relationship between hypothyroidism and hyperthyroidism in lipid profile. METHODS: The study group comprised of 567 patients. 100 subjects with normal thyroid profile and no history of any chronic diseases were taken as control group. Serum free triiodothyroxine (fT3), free thyroxine (fT4),thyroid stimulating hormone (TSH), Total cholesterol, low density lipoprotein (LDL) cholesterol, high density lipoprotein (HDL) cholesterol and Triglycerides were estimated in these patients and the results were analyzed using SPSS 11.5. RESULTS: Out of 567 sera tested, 146 (25.75%) had thyroid dysfunction. Total cholesterol and LDL-cholesterol was significantly raised in hypothyroidism. However, there was no significant association among lipid levels in hyperthyroid and control group. CONCLUSIONS: Lipid profile was significantly raised in hypothyroid patients thereby, indicating the need for monitoring of lipid levels in patients with thyroid dysfunction to avoid the risk of cardiovascular diseases. PMID- 22929711 TI - Biliary complications after laparoscopic cholecystectomy. AB - BACKGROUND: The reported prevalence of biliary tract disruption following laparoscopic cholecystectomy has ranged from 0% to 7% in early reports. Bile leaks are the most common biliary complication of laparoscopic cholecystectomy. METHODS: Total 530 patients who had undergone laparoscopic cholecystectomy from January 2004 to November 2006 at Kathmandu Medical College Teaching Hospital were studied for biliary complications after laparoscopic cholecystectomy. RESULTS: We reviewed 500 laparoscopic cholecystectomies performed at our institution and found 13 cases of bile extravasation and/or biloma formation and/or bile duct injuries (prevalence, 2.6%). One bile duct transection was acutely recognized and treated with hepaticojejunostomy. Three lateral bile duct injuries were also acutely recognized, two of them were managed with primary repair of CBD without T tube and the other was managed with repair and T-tube drainage. Two patients had postoperative generalized biliary peritonitis, one of whom was undergone exploratory laparotomy and found to have lateral injury on CBD which was managed with repair and T-tube drainage, whereas the other was undergone diagnostic laparoscopy with clipping of duct of Lushka. Two patients presented within seven days with biloma, one was treated with percutaneous drainage alone, the other treated with percutanous drainage was found to be complete transection of CBD on subsequent ERCP and managed with late hepaticojejunostomy. One patient with continued bile leak from surgical drainage tube for more than one week was managed with ERCP, diagnosed to be bile leak from duct of Lushka, managed by sphincterotomy and bile duct stenting. One patient presented with obstructive jaundice 6 months after laparoscopic cholecystectomy was found to have Bismuth type II bile duct stricture and was undergone hepaticojejunostomy. The remaining three had bile leak from surgical drainage which resolved within one week without further complication. CONCLUSIONS: Laparoscopic cholecystectomy appears to be associated with a higher incidence of bile duct injury than previous reports of open cholecystectomy. Possible explanations include variant anatomy plus failure to obtain an operative cholangiogram, inadequate dissection, injudicious use of cautery or clip placement, inherent limitations of the procedure, or the learning curve associated with a new technology. PMID- 22929712 TI - Knowledge, behavior and attitude towards sexually transmitted infections and acquired immunodeficiency syndrome of adolescent students. AB - BACKGROUND: Adolescence is a period of great physical, mental and emotional turmoil within teenagers. The objective of the study was to assess the knowledge of, attitude to and behaviour towards STI and AIDS among adolescence. METHODS: Four randomly selected higher secondary school from students of class XI and XII were included after taking their verbal consent. A pre-designed and pre-tested questionnaire was given to all the participants of the school. In order to get correct answers, specific questions were explained to the students with the help of their class teachers. RESULTS: The results were encouraging with the majority (94.16%) have heard about STIs and HIV/AIDS. Teachers (100%), Newspaper/magazine (90%) and Television (78.33%) were the main informational source about disease. Respondents correctly identified that unsafe sexual contact (86.66%) as major mode of transmission of AIDS and more than 90% of students regarded the use of condoms as the true preventive method for the disease. Among those respondents 6% were sexually active and their partners were either sex worker (71%) or friends (29%). CONCLUSIONS: The student's attitude towards disease was positive and most of the adolescent wished inclusion of sex education in their text book from secondary level school's curriculum. PMID- 22929713 TI - Histomorphological spetrum of breast lesions. AB - BACKGROUND: Cancer of the breast is the second most common cause of cancer in women. Mass in the breast, whether benign or malignant is a cause of anxiety to the patients and the family members. All breast lumps are considered to be carcinomas until proved otherwise and are the causes of concern both for the patient and surgeon. METHODS: This is a retrospective study conducted in Kathmandu Model Hospital for a total duration of three years from August 2007 to August 2010. RESULTS: 114 sample of breast tissue sent for histopathology were studied. Peak incidence of benign lesion was in between 21-30 years and malignant lesions in between 31-50 years. No breast lesions were seen in the first decade of life. Cancer of the breast was seen in 12.28% of cases. Fibroadenoma and fibrocystic disease were the commonest benign lesion and infiltrating ductal carcinoma was the commonest malignant lesion. Specimens from 10 male breasts were received. Gynaecomastia was the most common lesion encountered in males. Infiltrating ductal carcinoma was seen in a 70 year old male. CONCLUSIONS: Breast cancer is one of the commonest causes of breast lump particularly in women and is growing public health problem in Nepal. PMID- 22929714 TI - A five years review intra-operative cholangiogram. AB - BACKGROUND: Intra-operative cholangiogram is often performed to detect concurrent common bile duct stones in cholecystectomy patients. Routine cholangiogram add to cost and exposes patients to unnecessary exploration of common bile duct due to frequent false positive results. Thus, there is need of better indicators for cholangiogram in order to minimize unnecessary procedure and its morbidity. METHODS: A retrospective analysis of patients undergoing intra-operative cholangiogram during open or laparoscopic cholecystectomy was done at Patan Hospital from Oct 1, 2005 to Sep 31, 2009. Indications and outcome of cholangiogram were analyzed together with findings of common bile duct exploration. RESULTS: A total of 68 (2.8%, 68/2400) intra-operative cholangiogram were done in 2400 cholecystectomy patients during five years period. Eight (11.8%, 8/68) patients had abnormal findings. Two (3%, 2/68) patients with abnormal cholangiogram had stones in common bile duct. There was no mortality in this series. CONCLUSIONS: Existing indications of intra-operative cholangiogram detects only small percentage of patients with bile duct stones and has high false positive results. This unnecessarily increases bile duct exploration, cost and morbidity. Thus, there is need to redefine indications for intra-operative cholangiogram. PMID- 22929715 TI - Magnetic resonance neuroimaging in patient with complain of seizure. AB - BACKGROUND: MRI is the preferred modality to investigate seizure as diagnostic yield is higher and more specific due to its varied applications. Total of 160 brain MR images of patients suffering from seizure during one year period was evaluated. All seizure cases underwent specific protocol for imaging that targeted hippocampal/mesial temporal lobe imaging. METHODS: A cross sectional study of 160 MRI brain images was performed in patients with the main complaint of seizure within one-year period. The percentage distribution of abnormalities was calculated separately for pediatric and adult groups with Excel software. RESULTS: The total diagnostic yield of abnormal cases ranged from 53% to 55%. In pediatric group major abnormalities found were hippocampal sclerosis 4 (21%) 'T2 hyperintense foci in various distributions' 4 (21%), and cortical atrophy 4 (21%) where as major abnormalities found in adults were space occupying lesions 19 (27%), ischemia/infarcts 11 (16.2%), granulomatous lesions 8 (11%). CONCLUSIONS: Lesions that are better detected in MRI include hippocampal sclerosis and T2 hyperintensities that form the bulk of abnormalities in the pediatric category. Majority of abnormalities in the adult category like space occupying lesions can be easily picked up by CT whereas refractory seizure, cases with EEG findings suggesting TLE, suspected stroke should preferably undergo MRI brain imaging as it is much more sensitive in detecting these pathological substrates. PMID- 22929716 TI - Fitting ordinal regression analysis to anthropometric data. AB - BACKGROUND: National level surveys on nutritional status since 1975 to 2006 in Nepal do not indicate the satisfying level of nutrition. Nepal demographic and health survey 2006 uncover that the percent prevalence for underweight and wasted children of under five years of age are 39% and 13% and 49 % of the under five children are stunted. Understanding the factors that affect the nutrition of children is essential. Some studies in other countries show wealth index, size at birth and education as significant contributors. This analysis analyze the factors associated with nutritional status among children of under five years of age. METHODS: This study was cross sectional which used secondary data of the Demographic and Health Survey, 2006 conducted in Nepal. STATA 9, SPSS 13 and SPSS 17 are used for analysis. In this analysis, the outcome variables namely stunting, underweight and wasting are in ordered form. Hence ordinal regression is considered as suitable method. RESULTS: Ordinal regression well suit the data to model nutritional status through different predictors in case of underweight and wasting however stunting model fails to satisfy the assumption behind ordinal regression. Hence for stunting, model with constraints imposed to certain variables is formed. CONCLUSIONS: Underweight is seen significantly less in households with high wealth index, among children of big and average size at birth and among educated women. Education, wealth index and size at birth are found important factors affecting wasting among children. Wealth index and education of mothers are significantly affecting for stunting among children. PMID- 22929717 TI - Role of CaCO3 alone and CaCO3 plus vitamin D3 in terms of calcium phosphorus product in chronic kidney diseases. AB - BACKGROUND: CaCO3 alone and CaCO3 plus vitamin D3 metabolites are commonly prescribed in CKD patients. The objective of this study is to analyze the changes in Ca x P product, calcium level and phosphorus level in CKD patients receiving calcium carbonate alone and calcium carbonate with vitamin D3 in combination. METHODS: A prospective, cross sectional study among CKD patients under maintenance hemodialysis two times a week were studied over a period of one year. The patients were divided into two groups receiving oral CaCO3 alone and CaCO3 plus vitamin D3 once a day. The patients were followed for 1 month and result of Ca x P product was analyzed accordingly. RESULTS: Mean decrease of Ca x P product in CaCO3 group is (50.42+/-8.85 to 47 +/-6.63) in one month, p value =0.001(0.6 5) and CI- 95%. There is also significant reduction of phosphorus level in CaCO3 group than CaCO3 plus vitamin D3 group. Mean decrease in phosphorus in CaCO3 group is (5.51+/-0.76 to 5.17+/- 0.05) in one month. P value =0.01(0.14-0.53) and CI 95%. CONCLUSIONS: There is a significant decrease in Ca x P product and phosphorus level was observed in CKD patients taking CaCO3 alone. PMID- 22929718 TI - Public health impacts of climate change in Nepal. AB - Climate change is a global issue in this century which has challenged the survival of living creatures affecting the life supporting systems of the earth: atmosphere, hydrosphere and lithosphere. Scientists have reached in a consensus that climate change is happening. The anthropogenic emission of greenhouse gases is responsible for global warming and therefore climate change. Climate change may directly or indirectly affect human health through a range of pathways related to temperature and precipitation. The aim of this article is to share knowledge on how climate change can affect public health in Nepal based on scientific evidence from global studies and experience gained locally. In this review attempt has been made to critically analyze the scientific studies as well as policy documents of Nepalese Government and shed light on public health impact of climate change in the context of Nepal. Detailed scientific study is recommended to discern impact of climate change on public health problems in Nepal. PMID- 22929719 TI - Unusual cause of severe knee pain. AB - MRI is the preferred modality to investigate seizure as diagnostic yield is higher and more specific due to its varied applications. Total of 160 brain MR images of patients suffering from seizure during one year period was evaluated. All seizure cases underwent specific protocol for imaging that targeted hippocampal/mesial temporal lobe imaging. PMID- 22929720 TI - Van Gogh syndrome. AB - Self injury is the intentional and direct injury to self that include bite, burn, ulceration and head banging. These injuries are rarely fatal and are usually not suicidal in nature. This behavior is common among adolescents, psychiatric patients and in females. Bipolar disorder, drug abuse and metabolic syndromes like LeschNyhan and Munchausen's syndrome are often associated with this disorder. Repetitive self mutilation is termed the Van Gogh syndrome after the famous painter who cut off his ear and gave it to a prostitute. We describe two such cases of self mutilation in schizophrenic patients. PMID- 22929721 TI - Setting up an Emergency Medicine training program. AB - MRI is the preferred modality to investigate seizure as diagnostic yield is higher and more specific due to its varied applications. Total of 160 brain MR images of patients suffering from seizure during one year period was evaluated. All seizure cases underwent specific protocol for imaging that targeted hippocampal/mesial temporal lobe imaging. PMID- 22929722 TI - Scenario of health camps in Nepal. AB - It has become a rising trend in Nepal to conduct health camps. This article tries to give an overview about the direction to which this aspect of community based service is going to and also points out a few pros and cons related to this. A couple of issues has also been raised like; ethical issues, lack of governing bodies and a lack of national policy, unavailability of data upon health camps and so forth. Above all, this article tries to clarify the importance of conducting health camps in a country like ours and if properly conducted this has a balanced benefit to all. PMID- 22929723 TI - Health impacts and research ethics in female trafficking. AB - Female trafficking is a social and public health problem, associated with physical and sexual abuse, psychological trauma, injuries from violence, sexually transmitted infections, adverse reproductive outcomes and substance misuse. It faces several challenges ranging from the hidden nature of the problem to ethical and human rights issues. The objectives of this paper are to analyze health impact of trafficking; ethical and research issues and anti-trafficking strategies in the Nepalese context. We collected published and unpublished data assessing the public health, ethical burden and research needs from different sources. Trafficked female involved in sex-industry that face grave situation as depicted and it might a reservoir of sexually transmitted diseases. Ethical issues related to survey of assessing the burden are difficult to carry out. The best ways to prevent and control these problems are to enhance anti- trafficking laws and raise awareness, empower and mobilize females and establish organizational capacity. PMID- 22929724 TI - Health care executives be physician or non-physician: qualification in health care management is crucial. PMID- 22929725 TI - Catastrophic Kawasaki disease unresponsive to IVIG in a 3-month-old infant: a diagnostic and therapeutic challenge. AB - The present report describes the severe evolution of Kawasaki disease in a three month-old infant. The ailment was initially atypical in its presentation, with the patient exhibiting only persistent fever in association with a progressive lethargy and maculopapular rash on the face, trunk and limbs erroneously diagnosed as roseola infantum. On the 10th day of the condition, mainly due to the unexplained persistence of fever, the infant was admitted to a local hospital. The typical features of KD appeared only on the 14th day of illness with the relapse of the maculopapular rash in association with non-purulent conjunctivitis; dry, reddish and fissured lips; tongue with reddish and hypertrophic papillae; erythema and edema of the palms and soles. During the following days, the ailment rapidly evolved to a catastrophic clinical picture characterized by generalized vasculitis, splenic infarction, pulmonary thrombosis, giant right and left coronary aneurysms, dilatation of common and internal iliac arteries and progressive ischemia of the distal third of the feet resulting in necrotic lesions of both halluces. Appropriate therapy was initiated, but repeated administration of intravenous immunoglobulin G (IVIG) followed by three days of administration of methylprednisolone did not abate the intense inflammatory activity. The remission of inflammation and regression of vascular lesions were only achieved during the following five weeks after the introduction of methotrexate associated with etanercept. The report of this case aims to draw attention to severe forms of KD that exhibit an unfavorable evolution and can be extremely refractory to the conventional therapy. PMID- 22929727 TI - Beware the horns of the mandible! PMID- 22929726 TI - Electroencephalographic and hypnotic recoveries after brief and prolonged infusions of etomidate and optimized soft etomidate analogs. AB - BACKGROUND: Methoxycarbonyl etomidate is the prototypical soft etomidate analog. Because it has relatively low potency and is extremely rapidly metabolized, large quantities must be infused to maintain hypnosis. Consequently with prolonged infusion, metabolite reaches sufficient concentrations to delay recovery. Dimethyl-methoxycarbonyl metomidate (DMMM) and cyclopropyl-methoxycarbonyl metomidate (CPMM) are methoxycarbonyl etomidate analogs with higher potencies and slower clearance. Because of these properties, we hypothesized that dosing would be lower and electroencephalographic and hypnotic recoveries would be faster - and less context-sensitive - with DMMM or CPMM versus methoxycarbonyl etomidate or etomidate. METHODS: Etomidate, DMMM, and CPMM where infused into rats (n = 6 per group) for either 5 min or 120 min. After infusion termination, electroencephalographic and hypnotic recovery times were measured. The immobilizing ED50 infusion rates were determined using a tail clamp assay. RESULTS: Upon terminating 5-min infusions, electroencephalographic and hypnotic recovery times were not different among hypnotics. However, upon terminating 120 min infusions, recovery times varied significantly with respective values (mean +/- SD) 48 +/- 13 min and 31 +/- 6.5 min (etomidate), 17 +/- 7.0 min and 14 +/- 3.4 min (DMMM), and 4.5 +/- 1.1 min and 4.2 +/- 1.6 min (CPMM). The immobilizing ED50 infusion rates were (mean +/- SD) 0.19 +/- 0.03 mg . kg . min (etomidate), 0.60 +/- 0.12 mg . kg . min (DMMM), and 0.89 +/- 0.18 mg . kg . min (CPMM). CONCLUSIONS: Electroencephalographic and hypnotic recoveries following prolonged infusions of DMMM and CPMM are faster than those following methoxycarbonyl etomidate or etomidate. In the case of CPMM infusion, recovery times are 4 min and context-insensitive. PMID- 22929728 TI - The problem with amnesia. PMID- 22929729 TI - Metabolomic profiling of children's brains undergoing general anesthesia with sevoflurane and propofol. AB - BACKGROUND: We recently applied proton magnetic resonance spectroscopy (HMRS) to investigate metabolic consequences of general anesthesia in the rodent brain, and discovered that isoflurane anesthesia was characterized by higher concentrations of lactate, glutamate, and glucose in comparison with propofol. We hypothesized that the metabolomic differences between an inhalant and intravenous anesthetic observed in the rodent brain could be reproduced in the human brain. METHODS: HMRS-based metabolomic profiling was applied to characterize the cerebral metabolic status of 59 children undergoing magnetic resonance imaging during anesthesia with either sevoflurane or propofol. HMRS scans were acquired in the parietal cortex after approximately 60 min of anesthesia. Upon emergence the children were assessed using the pediatric anesthesia emergence delirium scale. RESULTS: With sevoflurane anesthesia, the metabolic signature consisted of higher concentrations of lactate and glucose compared with children anesthetized with propofol. Further, a correlation and stepwise regression analysis performed on emergence delirium scores in relation to the metabolic status revealed that lactate and glucose correlated positively and total creatine negatively with the emergence delirium score. CONCLUSIONS: Our results demonstrating higher glucose and lactate with sevoflurane in the human brain compared with propofol could reflect greater neuronal activity with sevofluane resulting in enhanced glutamate neurotransmitter cycling, increased glycolysis, and lactate shuttling from astrocytes to neurons or mitochondrial dysfunction. Further, the association between emergence delirium and lactate suggests that anesthesia-induced enhanced cortical activity in the unconscious state may interfere with rapid return to "coherent" brain connectivity patterns required for normal cognition upon emergence of anesthesia. PMID- 22929731 TI - Acquired neuromuscular weakness and early mobilization in the intensive care unit. AB - Survival from critical illness has improved in recent years, leading to increased attention to the sequelae of such illness. Neuromuscular weakness in the intensive care unit (ICU) is common, persistent, and has significant public health implications. The differential diagnosis of weakness in the ICU is extensive and includes critical illness neuromyopathy. Prolonged immobility and bedrest lead to catabolism and muscle atrophy, and are associated with critical illness neuromyopathy and ICU-acquired weakness. Early mobilization therapy has been advocated as a mechanism to prevent ICU-acquired weakness. Early mobilization is safe and feasible in most ICU patients, and improves outcomes. Implementation of early mobilization therapy requires changes in ICU culture, including decreased sedation and bedrest. Various technologies exist to increase compliance with early mobilization programs. Drugs targeting muscle pathways to decrease atrophy and muscle-wasting are in development. Additional research on early mobilization in the ICU is needed. PMID- 22929730 TI - Event-related functional magnetic resonance imaging of a low dose of dexmedetomidine that impairs long-term memory. AB - BACKGROUND: Work suggests the amnesia from dexmedetomidine (an alpha2-adrenergic agonist) is caused by a failure of information to be encoded into long-term memory and that dexmedetomidine might differentially affect memory for emotionally arousing material. We investigated these issues in humans using event related neuroimaging to reveal alterations in brain activity and subsequent memory effects associated with drug exposure. METHODS: Forty-eight healthy volunteers received a computer-controlled infusion of either placebo or low-dose dexmedetomidine (target = 0.15 ng/ml plasma) during neuroimaging while they viewed and rated 80 emotionally arousing (e.g., graphic war wound) and 80 nonarousing neutral (e.g., cup) pictures for emotional arousal content. Long-term picture memory was tested 4 days later without neuroimaging. Imaging data were analyzed for drug effects, emotional processing differences, and memory-related changes with statistical parametric mapping-8. RESULTS: Dexmedetomidine impaired overall (mean +/- SEM) picture memory (placebo: 0.58 +/- 0.03 vs. dexmedetomidine: 0.45 +/- 0.03, P = 0.001), but did not differentially modulate memory as a function of item arousal. Arousing pictures were better remembered for both groups. Dexmedetomidine had regionally heterogeneous effects on brain activity, primarily decreasing it in the cortex and increasing it in thalamic and posterior hippocampal regions. Nevertheless, a single subsequent memory effect for item memory common to both groups was identified only in the left hippocampus/amygdala. Much of this effect was found to be larger for the placebo than dexmedetomidine group. CONCLUSION: Dexmedetomidine impaired long-term picture memory, but did not disproportionately block memory for emotionally arousing items. The memory impairment on dexmedetomidine corresponds with a weakened hippocampal subsequent memory effect. PMID- 22929732 TI - Superiority of desflurane over sevoflurane and isoflurane in the presence of pressure-overload right ventricle hypertrophy in rats. AB - BACKGROUND: Pulmonary hypertension and associated pressure-overload right ventricular (RV) hypertrophy represent a tremendous challenge for the anesthesiologist, as optimal perioperative management is mandatory. However, the ideal anesthetic agent remains unknown because scientific evidence is lacking. METHODS: Twenty-eight rats were randomly assigned to a control or a monocrotaline group (60 mg kg). Four weeks later, animals were anesthetized, instrumented with a RV conductance catheter, and underwent well-controlled dose-responses to isoflurane, desflurane, and sevoflurane inhalation (minimum alveolar concentrations 0.5, 1.0, 1.5). RESULTS: Compared with controls, rats injected with monocrotaline presented with RV hypertrophy, increased afterload, and contractility, without change in cardiac output. The ratio of pressures in the right over the left circulation increased. The halogenated volatiles differently altered hemodynamics. Sevoflurane reduced RV contractility (more than 50%) and the right over left pressures ratio increased (from 0.41 +/- 0.08 [SD] to 0.82 +/ 0.14; P < 0.0001) secondary to profound concomitant systemic vasodilation, demonstrating a critical pressure gradient between right and left circulations. Despite significantly higher RV systolic pressures and afterload, desflurane decreased RV contractility much less (<10%; P < 0.0001 vs. sevoflurane) and maintained the right over left pressures ratio at more favorable values (0.47 +/- 0.07; P < 0.0001 vs. sevoflurane). Isoflurane presented intermediate effects. CONCLUSION: In the presence of pressure-overload RV hypertrophy, hemodynamics are better preserved under desflurane inhalation, whereas sevoflurane-and to a lesser extent isoflurane-cause large discrepancies on the left and right circulations, raising the right over left pressures ratio to critical levels despite a conserved cardiac output. PMID- 22929733 TI - A novel mechanism for sevoflurane preconditioning-induced neuroprotection. PMID- 22929734 TI - Sevoflurane anesthesia does not impair acquisition learning or memory in the Morris water maze in young adult and aged rats. AB - BACKGROUND: Sevoflurane has been found to increase apoptosis and pathologic markers associated with Alzheimer disease, provoking concern over their potential contribution to postoperative cognitive dysfunction. METHODS: The effects of anesthesia with 1 minimum alveolar concentration of sevoflurane for 4 h or sham exposure on cognition were investigated in young adult and aged (20-24 months) rats at 1, 4, and 12 weeks postexposure. Spatial reference memory acquisition and retention were tested in the Morris water maze task. Latency to locate the hidden platform and swim speed were determined and compared between treatments. RESULTS: Sevoflurane anesthesia significantly reduced latency to find the hidden platform in both young adult (n = 10 per treatment, P < 0.0001) and aged rats (n = 7 per treatment, P < 0.0001) when tested 1 week after exposure. In young rats only, this improved acquisition learning was maintained at 4 (P = 0.003) but not at 12 weeks postexposure (P = 0.061). There were no differences in swim speed or in open field exploration between groups (no confounding effects of stress or locomotion). Retention memory measured using probe trials was not affected by exposure to sevoflurane in young adult or aged rats. CONCLUSION: Sevoflurane anesthesia did not impair acquisition learning and retention memory in young adult or aged rats. PMID- 22929735 TI - Activation of canonical notch signaling pathway is involved in the ischemic tolerance induced by sevoflurane preconditioning in mice. AB - BACKGROUND: A wealth of evidence has demonstrated that sevoflurane preconditioning induces brain ischemic tolerance, but the mechanism remains poorly understood. This study was designed to investigate the role of canonical Notch signaling in the neuroprotection induced by sevoflurane preconditioning in a mouse model. METHODS: C57BL/6 mice were pretreated with 1-h sevoflurane exposure at a dose of 2.5% for 5 consecutive days. Twenty-four hours after the last exposure, all mice were subjected to focal cerebral ischemia by right middle cerebral artery occlusion for 60 min. Neurobehavioral scores, brain infarct volumes, and cellular apoptosis were determined at 72 h after reperfusion (n = 10 per group). The activation of Notch signaling was evaluated (n = 5 per group), and its role in ischemic tolerance was assessed by intraperitoneal administration of gamma-secretase inhibitor DAPT (100 mg/kg, n = 10 per group) and conditional Notch-RBP-J knockout technique (n = 8 per group). RESULTS: Sevoflurane preconditioning reduced brain infarct volumes (42.5%), improved neurologic outcomes (P < 0.01 vs. control), and attenuated neuronal cell apoptosis (cells positive for terminal deoxynucleotidyl transferase-mediated 2'-deoxyuridine 5' triphosphate nick-end labeling reduced to 21.2%). The expression of Notch1 intracellular domain (1.35 folds) and the transcriptions of Hes1 (1.95 times) and Hes5 (1.48 times) were up-regulated. DAPT augmented the brain infarcts (1.64 fold) and decreased neurologic scores (P = 0.43 vs. sevoflurane) in sevoflurane preconditioned mice. Brain infarct volumes, neurobehavioral scores, and apoptotic cell numbers showed no significance between Notch knockout mice with sevoflurane preconditioning and wild-type mice without preconditioning. CONCLUSIONS: Sevoflurane preconditioning-induced protective effects against transient cerebral ischemic injuries are mediated by the activation of canonical Notch signaling pathway in mice. PMID- 22929736 TI - Modifying methoxycarbonyl etomidate inter-ester spacer optimizes in vitro metabolic stability and in vivo hypnotic potency and duration of action. AB - BACKGROUND: Methoxycarbonyl etomidate is the prototypical very rapidly metabolized etomidate analog. Initial studies suggest that it may be too short acting for many clinical uses. We hypothesized that its duration of action could be lengthened and clinical utility broadened by incorporating specific aliphatic groups into the molecule to sterically protect its ester moiety from esterase catalyzed hydrolysis. To test this hypothesis, we developed a series of methoxycarbonyl etomidate analogs (spacer-linked etomidate esters) containing various aliphatic-protecting groups and spacer lengths. METHODS: Spacer-linked etomidate esters were synthesized and their hypnotic potencies and durations of action following bolus administration were measured in rats using a loss-of righting reflexes assay. Octanol:water partition coefficients and metabolic half lives in pooled rat blood were determined chromatographically. RESULTS: All spacer-linked etomidate esters produced hypnosis rapidly and in a dose-dependent manner. ED50s for loss of righting reflexes ranged from 0.69 +/- 0.04 mg/kg for cyclopropyl-methoxycarbonyl metomidate to 11.1 +/- 0.8 mg/kg for methoxycarbonyl metomidate. The slope of a plot of the duration of loss of righting reflexes versus the logarithm of the dose ranged 12-fold among spacer-linked etomidate esters, implying widely varying brain clearance rates. The in vitro metabolic half-lives of these compounds in rat blood varied by more than two orders of magnitude and were diastereometrically selective. CONCLUSIONS: We created 13 new analogs of methoxycarbonyl etomidate and identified two that have significantly higher potency and potentially address the too-brief duration of action for methoxycarbonyl etomidate. This work may provide a blueprint for optimizing the pharmacological properties of other soft drugs. PMID- 22929737 TI - Avoiding subarachnoid or intravascular injection of local anesthetics: a single test dose. PMID- 22929738 TI - Macromolecular capillary leakage is involved in the onset of anaphylactic hypotension. AB - BACKGROUND: The role of the hypovolemic component secondary to the microcirculatory changes in the onset of inaugural anaphylactic hypotension remains debated. We investigated the microcirculatory permeability in a model of anaphylactic shock using a fluorescence confocal microscopy imaging system. METHODS: Ovalbumin-sensitized anesthetized Brown Norway rats were randomly allocated into two groups (n = 6/group): control and anaphylaxis, respectively induced by intravenous saline or ovalbumin at time 0 (T0). The mesentery was surgically exposed. Macromolecular fluorescein isothiocyanate-dextran was intravenously injected (T0-5min) allowing in vivo visualization of the mesenteric microvascular network by fluorescence microscopy. After a period of stabilization of the contrast agent concentration, a 5-s movie was recorded to obtain baseline signal intensity. Following T0, 5-s movies were recorded every 30 s for 30 min. Capillary leakage of fluorescein isothiocyanate-dextran was assessed in interstitium and compared between groups. Data are expressed as mean +/- SD. RESULTS: Following anaphylactic shock onset, an early, progressive, and global signal intensity increase over time was detected in the interstitium. Mean index leakage differed between control and anaphylaxis (respectively 20 +/- 11 vs. 170 +/- 127%; P < 0.0001), starting at 2 min after shock onset and progressively increasing. Index leakage correlated with the drop in arterial blood pressure until T0 + 10 min (r = -0.75, P = 0.0001). CONCLUSIONS: During anaphylaxis, interstitial capillary leakage occurs within minutes after shock onset. Compared with controls, the mesenteric microcirculation showed at least 8-fold-increased macromolecular capillary leakage. The inflammation-induced microcirculatory changes with subsequent intravascular fluid transfer might be involved in the onset of the inaugural hypotension during anaphylactic shock. PMID- 22929739 TI - Microwave torrefaction of rice straw and Pennisetum. AB - Microwave torrefaction of rice straw and pennisetum was researched in this article. Higher microwave power levels contributed to higher heating rate and reaction temperature, and thus produced the torrefied biomass with higher heating value and lower H/C and O/C ratios. Kinetic parameters were determined with good coefficients of determination, so the microwave torrefaction of biomass might be very close to first-order reaction. Only 150W microwave power levels and 10min processing time were needed to meet about 70% mass yield and 80% energy yield for torrefied biomass. The energy density of torrefied biomass was about 14% higher than that of raw biomass. The byproducts (liquid and gas) possessed about 30% mass and 20% energy of raw biomass, and they can be seen as energy sources for heat or electricity. Microwave torrefaction of biomass could be a competitive technology to employ the least energy and to retain the most bioenergy. PMID- 22929740 TI - A fermentation strategy for producing docosahexaenoic acid in Aurantiochytrium limacinum SR21 and increasing C22:6 proportions in total fatty acid. AB - During the fermentation process, dissolved oxygen values and carbon-to-nitrogen ratios are critical factors influencing DHA productivity. This study employed an intermittent oxygen feeding method to maintain a 50% dissolved oxygen level and produced a dissolved oxygen fluctuation environment to facilitate both Aurantiochytrium limacinum SR21 growth and lipid accumulation. Study results indicated that at a 1.25 C:N ratio and medium composition of 100gL(-1) glycerol, 40gL(-1) yeast extract, and 40gL(-1) peptone, A. limacinum SR21 achieved biomass at 61.76gL(-1), lipid content at 65.2%, DHA concentration at 20.3gL(-1), and DHA productivity at 122.62mgL(-1)h(-1), this result were better than most similar researches. Dissolved oxygen fluctuation environment also altered the fatty acid composition of A. limacinum SR21. In the late period of the fermentation process, C16:0 fatty acid ratios decreased significantly to below 5%, and C22:6 fatty acid ratios increased to 70%. PMID- 22929741 TI - Comparison of electrogenic capabilities of microbial fuel cell with different light power on algae grown cathode. AB - Electricity generation capabilities of microbial fuel cell with different light power on algae grown cathode were compared. Results showed that microbial fuel cell with 6 and 12W power of light always produced higher voltage and power density than with 18 and 26W. Similarly, microbial fuel cell with 6 and 12W of light power always displayed higher Coulombic efficiency and specific power than the one with 18 and 26W. The results also showed that microbial fuel cell with covered anodic chamber always displayed higher voltage, power density, Coulombic efficiency and specific power than the one without covered anodic chamber. Binary quadratic equations can be used to express the relationships between the light power and the voltage, power density, Coulombic efficiency and specific power. Although lower power of light on algae grown cathode and covering anodic chamber will increase system's electricity production, they will not significantly reduce its internal resistance. PMID- 22929742 TI - Enhancing the hydrolysis and acidification of steam-exploded cornstalks by intermittent pH adjustment with an enriched microbial community. AB - Intermittent pH adjustment was used to increase the degradation rate of steam exploded cornstalks (SEC) and the production of organic acids by an enriched microbial community. The results showed that the degradation rate of SEC was as high as 75% and not affected by the intermittent pH adjustment within the range of 7.0-9.0. However, the total concentration of major water soluble metabolites (acetate and propionate) were increased with pH enhancement, showing the results of 1.86gL(-1) for pH 7.0, 2.04gL(-1) for pH 8.0 and 3.32gL(-1) for pH 9.0 after 84h of fermentation. Based on 16s rDNA analysis by denaturing gradient gel electrophoresis (DGGE), different strains were dominant due to pH shift by intermittent adjustment, which would consequently cause the change in fermentation pattern. Intermittent pH adjustment was considered to be a useful way to enhance bioconversion potentiality of lignocellulose. PMID- 22929743 TI - [Dutch military casualties of the war in Afghanistan--quality of life and level of participation after rehabilitation]. AB - OBJECTIVE: To describe the distribution of injuries and the quality of life and functioning at activity and participation level of rehabilitated Dutch military personnel who were wounded during the mission to Afghanistan. DESIGN: Retrospective, descriptive. METHOD: The study population consisted of military war casualties who followed multidisciplinary rehabilitation treatment for injuries sustained in combat in Afghanistan. Distribution and degree of injuries were classified according to the 'Abbreviated Injury Scale' (AIS) and the 'Injury Severity Score' (ISS). Quality of life and functional disabilities were assessed with a semi-structured interview, and the following questionnaires: EuroQol-5D with an extra dimension 'cognition' (EQ-6D), the 'Assessment of Life Habits' shortened version 3.0 (LIFE-H 3.0) and the 'Lower Extremity Functional Scale'(LEFS). Coping style was assessed with the Cognitive Emotion Regulation Questionnaire' (CERQ). RESULTS: A total of 48 servicemen cooperated. A total of 248 injuries; 54% of which affected the extremities. In 9 victims an amputation of the lower extremity was performed; 4 of them had to have a double amputation. 31 servicemen were still receiving specialist medical care at the time of the interview. 39 servicemen had to adjust their career plans. The mean quality of life, measured by EQ-5D, had an index score of 0.72 (Dutch population norm: 0.88). The mean score on the LEFS was 58 (maximum score 80). Changes in mobility and occupation appeared to be predictive factors for quality of life. CONCLUSION: The quality of life and functional level of Dutch military personnel who were injured in combat in Afghanistan seemed to be lower than in the general population after 2.3 years. For a large part this could be explained by the level of mobility and occupation. PMID- 22929744 TI - [A woman with hepatomegaly]. AB - A 32-year-old woman was referred because of hepatomegaly of unknown cause. CT and MRI images of the abdomen showed a markedly enlarged right liver lobe extending into the pelvis. A diagnosis of hepatomegaly due to a Riedel's lobe was made. PMID- 22929745 TI - [A marine with acute dyspnea]. AB - A 29-year-old male marine presented with acute dyspnea and abdominal discomfort. The complaints were caused by a diaphragmatic rupture with an intrathoracic stomach and spleen probably due to an explosion during a military mission a year earlier. Subsequent operative intervention was initiated. PMID- 22929746 TI - [Pregnant women with psychiatric illness are able to stop smoking]. AB - Smoking during pregnancy is associated with neonatal complications and health problems later in life. However, about 10% of the pregnant women in the Netherlands smoke and those with a psychiatric illness smoke even more frequently. Although giving up smoking may be more difficult for these women, it does not lead to an increase of psychiatric symptoms. We present two patients who smoked during pregnancy. A 28-year-old female started smoking again during her first pregnancy when her depression relapsed. We advised a higher dose of medication and with her midwife's support she gave up smoking. A 35-year-old female, suffering from posttraumatic stress disorder, had an increase of symptoms during her second pregnancy. She resumed smoking to feel more relaxed. Treatment with bupropion and an online support program helped her to give up smoking. We advise that every smoking pregnant woman with psychiatric problems be treated concurrently for the psychiatric illness and for smoking. PMID- 22929747 TI - [Moleschott and materialism]. AB - Jacques Moleschott (1822-1893), born into a Dutch Roman Catholic family, attended secondary school in Cleve (Germany). There he became captivated by Hegelian philosophy and lost his faith. After medical studies in Heidelberg and a brief spell as physician in Utrecht, where he struck up a life-long friendship with the physiologists Franciscus Donders (1818-1889) and Izaak van Deen (1805-1869), he returned to Heidelberg as lecturer in physiology. In his textbooks and particularly in his book for the general public, 'The circulation of life' (in German), he attested to a strict physicochemical view of biological phenomena, in opposition to contemporary notions of vitalism and teleology. When the atheistic implications had caused a conflict with the authorities in Baden, he moved as professor of physiology to Zurich (1854) and subsequently to the emerging nation of Italy, as professor in Turin (1861) and finally in Rome (1878), where he became a senator. PMID- 22929748 TI - [West Nile virus poliomyelitis after a holiday in Egypt]. AB - BACKGROUND: Due to the worldwide near-extinction of poliovirus infections an acute presentation of poliomyelitis in the Netherlands has become extremely rare. However, in the differential diagnosis of such a disease presentation other pathogens need to be considered as well. CASE DESCRIPTION: A 44-year-old female presented with fever and a flaccid paresis of the left leg, following a holiday in Egypt. The laboratory investigation demonstrated an acute West Nile virus (WNV) infection, after which the diagnosis 'WNV poliomyelitis' was made. CONCLUSION: WNV poliomyelitis is a rare neurological complication of an infection with the WNV. The areas in Europe where WNV transmission to humans occurs are expanding. In the future, the number of neurological disorders caused by WNV is likely to increase, also in the Netherlands. PMID- 22929749 TI - [Multidisciplinary guideline 'Recognition and treatment of chronic pain in vulnerable elderly people']. AB - Chronic pain in vulnerable elderly people is still poorly recognized and treated, both at home and in hospitals and care and nursing homes. Vulnerable elderly people experience and express pain differently to relatively healthy adults, especially when they suffer from cognitive impairment or specific conditions. Determining the nature and severity of the pain requires the use of pain assessment instruments that have been validated for use in vulnerable elderly people. Effective treatment of pain demands careful diagnosis and pharmacological and non-pharmacological interventions that have proven effectiveness in vulnerable elderly people. The combination of multiple morbidity and poly pharmacy increases the chance of side-effects and complications. In addition, the pharmacokinetic and pharmacodynamic characteristics of many drugs are different in vulnerable elderly people. The advice is to start with a lower dose of pain medication and gradually build up a level on the basis of pain relief and side effects ('start low, go slow!'). PMID- 22929750 TI - [Summary of the NHG Standard 'Preconception care']. AB - Preconception care is part is the primary care by general practitioners and midwives in the Netherlands. The Dutch College of General Practitioners' (NHG) practice guideline 'Preconception care' gives the general practitioner guidelines for assisting couples to be well informed and in the best possible health before conception. The guideline advises general practitioners to be alert for prescription of chronic medication to women wishing to have a child and informs couples wishing to have a child of the availability of a preconception consultation. The general practitioner should review which interventions are necessary in women with chronic disorders. A thorough medical family history is required for the man as well as the woman. Their employment situation and conditions also need to be reviewed. In the case of desire for a child, folic acid is advised. In addition, the practitioner should give advice concerning stopping smoking, healthy weight and avoidance of alcohol use during pregnancy. Implementation of the guideline is especially important for the less educated and for immigrants, as these groups have less healthy lifestyle habits and less knowledge of risk factors in pregnancy. PMID- 22929751 TI - [Choosing the correct benzodiazepine: mechanism of action and pharmacokinetics]. AB - There is a discrepancy between the recommendation for caution and daily practice in the prescription of benzodiazepines. Although there is heterogeneity in the registered indications, all benzodiazepine agonists have almost the same mechanism of action. There are, however, substantial pharmacokinetic differences between individual benzodiazepine agonists. During short-term use of benzodiazepines, the elimination half-life is no measure of duration of action. Benzodiazepine lipophilicity determines the speed of action. If a rapid effect is desired, for instance in acute anxiety or agitation, then regarding oral medication the use of a lipophilic benzodiazepine such as diazepam is a rational choice. An accumulation factor can be used to estimate benzodiazepine accumulation during chronic use. In theory, accumulation does not occur with once daily dosage of benzodiazepines that have an elimination half-life markedly shorter than 24 h, such as oxazepam, temazepam, and lorazepam. PMID- 22929752 TI - [Useful guideline for treatment of pain in vulnerable elderly people]. AB - Forty to fifty percent of elderly people (> 70 years of age) appear to have pain that interferes with daily life. The frail elderly, described as elderly people who are vulnerable, mostly chronically ill, with physical, and psychological, as well as social, and communicative disabilities, are often inadequately treated for pain. This interdisciplinary guideline aims to improve recognition and treatment of chronic pain in frail elderly patients and is therefore very useful in clinical practice. Interventional, minimally invasive pain treatment is not described in this guideline, although for a number of pain syndromes this could be an evidence-based potential treatment. PMID- 22929753 TI - [Necrotic bladder following radiotherapy for cervical carcinoma]. AB - BACKGROUND: In contrast to proctitis, vaginitis and acute radiation cystitis are late complications of pelvic radiation therapy, rare, more severe and irreversible. CASE DESCRIPTION: A 66-year-old patient presented with progressive renal failure ten years after radiotherapy for carcinoma of the cervix. Ultrasound investigation revealed a bilateral hydroutereronefrosis (grade 4), with narrowing of the ureterovesical junctions and a diffuse thickening of the urinary bladder wall. Biopsy of the bladder wall showed extended necrosis. The diagnosis was a necrotic bladder with bilateral ureteral stenosis without local symptoms. Lifelong renal urinary drainage was indicated. CONCLUSION: Late obstructive urological complications, such as bladder necrosis and urethral obstruction, are rare following radiotherapy for cervical carcinoma. Ultrasound follow-up can contribute to the early detection of these complications and intervention can prevent further loss of renal function; however, this would not be cost-effective because of the low incidence rate and because these complications appear in the long term. PMID- 22929754 TI - [Osteomyelitis of the talus in a limping child]. AB - BACKGROUND: Haematogenous osteomyelitis of the talus is a rare cause of limping in children. Due to the slow onset and atypical pattern of symptoms, it is difficult to diagnose. This can result in delays in the provision of adequate treatment. CASE DESCRIPTION: A 3-year old girl was examined in the outpatient ward for pain in the right leg and limping. A diagnosis of coxitis fugax was suspected initially. Supplemental laboratory testing, conventional roentgenograms and bone scintigraphy however, showed a haematogenous osteomyelitis of the talus. The patient was treated with flucloxacillin. She was symptom-free four months after the first outpatient visit, with full recovery of function in her right ankle and foot. CONCLUSION: Haematogenous osteomyelitis of the talus is rare in children. The diagnosis is often missed because symptoms are often subtle in the early phase. It is important to choose imaging techniques carefully because treatment with antibiotics is sufficient when this type of osteomyelitis is detected at an early stage. PMID- 22929755 TI - [Injured soldiers and their quality of life]. AB - This is a commentary on the article entitled 'Dutch military casualties of the war in Afghanistan - Quality of life and level of participation after rehabilitation' by de Kruijff and colleagues, published in the Dutch Journal of Medicine (Nederlands Tijdschrift voor Geneeskunde, NTvG). The article addresses a very relevant issue: the impact of war injuries on a wounded soldier's recovery, quality of life and level of participation after rehabilitation. The choice was made to compare soldiers wounded during their mission in Uruzgan with the Dutch general trauma population by means of the 'Injury Severity Score' (ISS) and the 'Abbreviated Injury Scale' (AIS) score. As mechanisms of trauma in the military setting (e.g. war injuries such as blast and penetrating trauma; blunt trauma in civilians), their resulting injuries and their psychological context differ strongly from those encountered in the Dutch general population, the question arises whether such a comparison is the optimal choice. We encourage the authors to follow up on this study and in doing so, to correct for type of injury and to integrate findings from the military-psychology field of expertise into the outcome. PMID- 22929756 TI - The study of orthographic processing has broadened research in visual word recognition. AB - Interest in orthographic processing reflects an expansion, not constriction, of the scope of research in visual word recognition (VWR). Transposition effects are merely one aspect of investigations into orthographic encoding, while open bigrams can accommodate differences across languages. The target article's inaccurate characterization of the study of orthographic processing is not conducive to the advancement of VWR research. PMID- 22929757 TI - Portable bacterial identification system based on elastic light scatter patterns. AB - BACKGROUND: Conventional diagnosis and identification of bacteria requires shipment of samples to a laboratory for genetic and biochemical analysis. This process can take days and imposes significant delay to action in situations where timely intervention can save lives and reduce associated costs. To enable faster response to an outbreak, a low-cost, small-footprint, portable microbial identification instrument using forward scatterometry has been developed. RESULTS: This device, weighing 9 lb and measuring 12 * 6 * 10.5 in., utilizes elastic light scatter (ELS) patterns to accurately capture bacterial colony characteristics and delivers the classification results via wireless access. The overall system consists of two CCD cameras, one rotational and one translational stage, and a 635-nm laser diode. Various software algorithms such as Hough transform, 2-D geometric moments, and the traveling salesman problem (TSP) have been implemented to provide colony count and circularity, centering process, and minimized travel time among colonies. CONCLUSIONS: Experiments were conducted with four bacteria genera using pure and mixed plate and as proof of principle a field test was conducted in four different locations where the average classification rate ranged between 95 and 100%. PMID- 22929758 TI - High-resolution manometry correlates of ineffective esophageal motility. AB - OBJECTIVES: There are currently no criteria for ineffective esophageal motility (IEM) and ineffective swallow (IES) in esophageal pressure topography (EPT). Our aims were to use high-resolution manometry metrics to define IEM within the Chicago Classification and to determine the distal contractile integral (DCI) threshold for IES. METHODS: The EPT of 150 patients with either dysphagia or reflux symptoms were reviewed. Peristaltic function in EPT was defined by the Chicago Classification; the corresponding conventional line tracing (CLT) were reviewed separately. Generalized linear mixed models were used to find thresholds for DCI corresponding to traditionally determined IES and failed swallows. An external validation sample was used to confirm these thresholds. RESULTS: In terms of swallow subtypes, IES in CLT were a mixture of normal, weak, and failed peristalsis in EPT. A DCI of 450 mm Hg-s-cm was determined to be optimal in predicting IES. In the validation sample, the threshold of 450 mm Hg-s-cm showed strong agreement with CLT determination of IES (positive percent agreement 83%, negative percent agreement 90%). The patient diagnostic level agreement between CLT and EPT was good (78.6% positive percent agreement and 63.9% negative percent agreement), with negative agreement increasing to 92.0% if proximal breaks were excluded. CONCLUSIONS: The manometric correlate of IEM in EPT is a mixture of failed swallows and weak swallows with breaks in the middle/distal troughs. A DCI value <450 mm Hg-s-cm can be used to predict IES previously defined in CLT. IEM can be defined by >5 swallows with weak/failed peristalsis or with a DCI <450 mm Hg-s-cm. PMID- 22929759 TI - Prevalence of symptoms meeting criteria for irritable bowel syndrome in inflammatory bowel disease: systematic review and meta-analysis. AB - OBJECTIVES: Symptoms compatible with irritable bowel syndrome (IBS) may co-exist in patients with inflammatory bowel disease (IBD), presenting a clinical dilemma for physicians. We conducted a systematic review and meta-analysis to examine this issue. METHODS: MEDLINE, EMBASE, and EMBASE Classic were searched (through February 2012) to identify cross-sectional surveys or case-control studies reporting the prevalence of symptoms meeting diagnostic criteria for IBS in >=50 unselected adult IBD patients. The number of individuals with symptoms meeting criteria for IBS was extracted for each study, and pooled prevalence and odds ratios (ORs), with 95% confidence intervals (CIs), were calculated. RESULTS: The search identified 3,045 articles. Thirteen studies, containing 1,703 patients, were eligible. The pooled prevalence for IBS in all IBD patients was 39% (95% CI 30-48%), with an OR compared with controls of 4.89 (95% CI 3.43-6.98). In IBD patients in remission, the OR was 4.39 (95% CI 2.24-8.61). For IBD patients with active disease, the pooled prevalence of IBS was 44%, compared with 35% in those felt to be in remission (OR 3.89; 95% CI 2.71-5.59). The prevalence in patients with Crohn's disease (CD) was higher than in those with ulcerative colitis (UC; 46 vs. 36%, OR 1.62; 95% CI 1.21-2.18). CONCLUSIONS: Symptoms compatible with IBS were significantly higher in patients with IBD compared with non-IBD controls, even among those felt to be in remission. IBS-type symptoms were also significantly more common in CD than in UC patients, and in those with active disease. Management strategies for IBD patients with symptoms suggestive of IBS are required. PMID- 22929760 TI - Alcohol and tobacco lower the age of presentation in sporadic pancreatic cancer in a dose-dependent manner: a multicenter study. AB - OBJECTIVES: The objective of this study was to examine the association between tobacco and alcohol dose and type and the age of onset of pancreatic adenocarcinoma (PancCa). METHODS: Prospective data from the Pancreatic Cancer Collaborative Registry were used to examine the association between age of onset and variables of interest including: gender, race, birth country, educational status, family history of PancCa, diabetes status, and tobacco and alcohol use. Statistical analysis included logistic and linear regression, Cox proportional hazard regression, and time-to-event analysis. RESULTS: The median age to diagnosis for PancCa was 66.3 years (95% confidence intervals (CIs), 64.5-68.0). Males were more likely than females to be smokers (77% vs. 69%, P=0.0002) and heavy alcohol and beer consumers (19% vs. 6%, 34% vs. 19%, P<0.0001). In univariate analysis for effects on PancCa presentation age, the following were significant: gender, alcohol and tobacco use (amount, status and type), family history of PancCa, and body mass index. Both alcohol and tobacco had dose dependent effects. In multivariate analysis, alcohol status and dose were independently associated with increased risk for earlier PancCa onset with greatest risk occurring in heavy drinkers (HR 1.62, 95% CI 1.04-2.54). Smoking status had the highest risk for earlier onset pancreatic cancer with a HR of 2.69 (95% CI, 1.97-3.68) for active smokers and independent effects for dose (P=0.019). The deleterious effects for alcohol and tobacco appear to resolve after 10 years of abstinence. CONCLUSIONS: Alcohol and tobacco use are associated with a dose-related increased risk for earlier age of onset of PancCa. Although beer drinkers develop pancreatic cancer at an earlier age than nondrinkers, alcohol type did not have a significant effect after controlling for alcohol dose. PMID- 22929761 TI - Long-acting reversible contraceptive methods for adolescents with chronic medical problems. AB - Adolescents with chronic medical problems are just as at-risk for unintended pregnancy as their healthy counterparts, but pregnancy in these adolescents can carry greater health risks. The objective of this article is to provide an overview of the United States Medical Eligibility Criteria for Contraceptive Use, the concept of contraceptive effectiveness, and a risk-benefit algorithm. Together these tools provide an evidence-based and clinically sound method of providing contraception to adolescents with chronic medical problems. Three cases of adolescents with chronic medical problems are used to illustrate this approach. To best avoid the complicated problem of a teenager with a chronic medical problem becoming pregnant, LARC should be considered as first-line contraception. In most cases, LARC methods are safe to prescribe, and preferable to less effective methods. PMID- 22929762 TI - Gynecologic and reproductive health concerns of adolescents using selected psychotropic medications. AB - Psychiatric disorders are common in adolescent girls and may require chronic therapies with psychotropic medications. Antipsychotic medications and mood stabilizers have been increasingly prescribed to and widely used by adolescents for a variety of both "on" an "off" label indications. Studies on the safety and monitoring of these medications in adolescent girls have shown important potential for gynecologic and reproductive adverse effects. The objective of this article is to review the mechanisms for and management of menstrual disorders mediated by hyperprolactinemia associated with antipsychotic medications, hypothyroidism associated with lithium and quetiapine, and the independent association of polycystic ovary syndrome (PCOS) in girls using valproic acid. Beyond their susceptibility to these disruptions in the menstrual cycle, adolescent girls with psychiatric illness also have increased sexual risk behaviors. These behaviors makes it all the more important to review teratogenicity and clinically relevant contraceptive drug interactions in adolescent girls using these psychotropic medications. PMID- 22929763 TI - DNA translocation of ATP-dependent chromatin remodeling factors revealed by high resolution optical tweezers. AB - ATP-dependent chromatin remodeling complexes (remodelers) use the energy of ATP hydrolysis to regulate chromatin structures by repositioning and reconfiguring nucleosomes. Ensemble experiments have suggested that remodeler ATPases are DNA translocases, molecular motors capable of processively moving along DNA. This concept of DNA translocation has become a foundation for understanding the molecular mechanisms of ATP-dependent chromatin remodeling and its biological functions. However, quantitative characterizations of DNA translocation by representative remodelers are rare. Furthermore, it is unclear how a unified theory of chromatin remodeling is built upon this foundation. To address these problems, high-resolution optical tweezers have been applied to investigate remodeler translocation on bare DNA and nucleosomal DNA substrates at a single molecule level. Our strategy is to hold two ends of a single DNA molecule and measure remodeler translocation by detecting the end-to-end extension and tension changes of the DNA molecule in response to chromatin remodeling. These single molecule assays can reveal detailed kinetics of remodeler translocation, including velocity, processivity, stall force, pauses, direction changes, and even step size. Here we describe instruments, reagents, sample preparations, and detailed protocols for the single-molecule experiments. We show that optical tweezer force microscopy is a powerful and friendly tool for studies of chromatin structures and remodeling. PMID- 22929764 TI - Unzipping single DNA molecules to study nucleosome structure and dynamics. AB - DNA unzipping is a powerful tool to study protein-DNA interactions at the single molecule level. In this chapter, we provide a detailed and practical guide to performing this technique with an optical trap, using nucleosome studies as an example. We detail protocols for preparing an unzipping template, constructing and calibrating the instrument, and acquiring, processing, and analyzing unzipping data. We also summarize major results from utilization of this technique for the studies of nucleosome structure, dynamics, positioning, and remodeling. PMID- 22929765 TI - Monitoring conformational dynamics with single-molecule fluorescence energy transfer: applications in nucleosome remodeling. AB - Due to its ability to track distance changes within individual molecules or molecular complexes on the nanometer scale and in real time, single-molecule fluorescence resonance energy transfer (single-molecule FRET) is a powerful tool to tackle a wide range of important biological questions. Using our recently developed single-molecule FRET assay to monitor nucleosome translocation as an illustrative example, we describe here in detail how to set up, carry out, and analyze single-molecule FRET experiments that provide time-dependent information on biomolecular processes. PMID- 22929766 TI - 4C technology: protocols and data analysis. AB - Chromosome conformation capture (3C) technology and its genome-wide derivatives have revolutionized our knowledge on chromatin folding and nuclear organization. 4C-seq Technology combines 3C principles with high-throughput sequencing (4C-seq) to enable for unbiased genome-wide screens for DNA contacts made by single genomic sites of interest. Here, we discuss in detail the design, application, and data analysis of 4C-seq experiments. Based on many hundreds of different 4C seq experiments, we define criteria to assess data quality and show how different restriction enzymes and cross-linking conditions affect results. We describe in detail the mapping strategy of 4C-seq reads and show advanced strategies for data analysis. PMID- 22929767 TI - A Torrent of data: mapping chromatin organization using 5C and high-throughput sequencing. AB - The study of three-dimensional genome organization is an exciting research area, which has benefited from the rapid development of high-resolution molecular mapping techniques over the past decade. These methods are derived from the chromosome conformation capture (3C) technique and are each aimed at improving some aspect of 3C. All 3C technologies use formaldehyde fixation and proximity based ligation to capture chromatin contacts in cell populations and consider in vivo spatial proximity more or less inversely proportional to the frequency of measured interactions. The 3C-carbon copy (5C) method is among the most quantitative of these approaches. 5C is extremely robust and can be used to study chromatin organization at various scales. Here, we present a modified 5C analysis protocol adapted for sequencing with an Ion Torrent Personal Genome MachineTM (PGMTM). We explain how Torrent 5C libraries are produced and sequenced. We also describe the statistical and computational methods we developed to normalize and analyze raw Torrent 5C sequence data. The Torrent 5C protocol should facilitate the study of in vivo chromatin architecture at high resolution because it benefits from high accuracy, greater speed, low running costs, and the flexibility of in-house next-generation sequencing. PMID- 22929768 TI - Genome-wide mapping of nucleosomes in yeast using paired-end sequencing. AB - The DNA of eukaryotic cells is packaged into chromatin by histone proteins, which play a central role in regulating access to genetic information. The nucleosome core is the basic structural unit of chromatin: it is composed of an octamer of the four major core histones (two molecules each of H2A, H2B, H3, and H4), around which are wrapped ~1.75 negative superhelical turns of DNA, a total of 145-147bp. Nucleosome cores are regularly spaced along the DNA in vivo, separated by linker DNA. Nucleosomes are compact structures capable of blocking access to the DNA that they contain. For example, they may prevent the binding of transcription factors to their cognate sites. It is therefore very important to obtain quantitative information on the positions of nucleosomes with respect to regulatory regions in vivo. The advent of high-throughput sequencing methods has revolutionized this field. We describe the use and advantages of paired-end sequencing to map nucleosomal DNA obtained by micrococcal nuclease digestion of budding yeast nuclei. This approach provides high-quality genome-wide nucleosome occupancy and position maps. PMID- 22929769 TI - Measuring genome-wide nucleosome turnover using CATCH-IT. AB - The dynamic interplay between DNA-binding proteins and nucleosomes underlies essential nuclear processes such as transcription, replication, and DNA repair. Manifestations of this interplay include the assembly, eviction, and replacement of nucleosomes. Hence, measurements of nucleosome turnover kinetics can lead to insights into the regulation of dynamic chromatin processes. In this chapter, we describe a genome-wide method for measuring nucleosome turnover that uses metabolic labeling followed by capture of newly synthesized histones, which we have termed Covalent Attachment of Tagged Histones to Capture and Identify Turnover (CATCH-IT). Although CATCH-IT can be used with any genome-wide mapping procedure, high-resolution profiling is attainable using paired-end sequencing of native chromatin. Our protocol also includes an efficient Solexa DNA sequencing library preparation protocol that can be used for single base-pair resolution mapping of both nucleosome and subnucleosomal particles. We not only describe the use of these protocols in the context of a Drosophila cell line but also provide the necessary changes for adaptation to other model systems. PMID- 22929771 TI - Genome-wide in vitro reconstitution of yeast chromatin with in vivo-like nucleosome positioning. AB - Recent genome-wide mapping of nucleosome positions revealed that well-positioned nucleosomes are pervasive across eukaryotic genomes, especially in important regulatory regions such as promoters or origins of replication. As nucleosomes impede access to DNA, their positioning is a primary mode of genome regulation. In vivo studies, especially in yeast, shed some light on factors involved in nucleosome positioning, but there is an urgent need for a complementary biochemical approach in order to confirm their direct roles, identify missing factors, and study their mechanisms. Here we describe a method that allows the genome-wide in vitro reconstitution of nucleosomes with very in vivo-like positions by a combination of salt gradient dialysis reconstitution, yeast whole cell extracts, and ATP. This system provides a starting point and positive control for the biochemical dissection of nucleosome positioning mechanisms. PMID- 22929772 TI - Genome-wide mapping of nucleosome positions in yeast using high-resolution MNase ChIP-Seq. AB - Eukaryotic DNA is packaged into chromatin where nucleosomes form the basic building unit. Knowing the precise positions of nucleosomes is important because they determine the accessibility of underlying regulatory DNA sequences. Here we describe a detailed method to map on a genomic scale the locations of nucleosomes with very high resolution. Micrococcal nuclease (MNase) digestion followed by chromatin immunoprecipitation and facilitated library construction for deep sequencing provides a simple and accurate map of nucleosome positions. PMID- 22929773 TI - Preparation of Drosophila tissue culture cells from different stages of the cell cycle for chromatin immunoprecipitation using centrifugal counterflow elutriation and fluorescence-activated cell sorting. AB - Many nuclear proteins alter their localization during the cell cycle. This includes proteins which regulate and execute cell cycle events and proteins involved in transcription and DNA repair. The core components of chromatin, the histone proteins, also change their modification state through the cell cycle. Chromatin immunoprecipitation (ChIP) makes it possible to localize chromatin associated proteins to specific sequences in the genome and has revolutionized studies of transcription. Fewer studies have used ChIP to analyze protein localization or modification at specific stages in the cell cycle. This is in part because these studies require isolation of pure populations of cells at each stage of the cell cycle, which is challenging for many cell types. However, the ability to carry out ChIP from cells at specific stages in the cell cycle in some systems has revealed cell cycle regulation of chromatin localization, and cell cycle stage-specific functions and modification of chromatin proteins, providing incentive to pursue these experiments. This chapter presents protocols for isolating Drosophila S2 cells from all phases of the cell cycle using centrifugal elutriation and fluorescent-activated cell sorting. These cells are suitable for ChIP analysis. PMID- 22929770 TI - DNA methyltransferase accessibility protocol for individual templates by deep sequencing. AB - A single-molecule probe of chromatin structure can uncover dynamic chromatin states and rare epigenetic variants of biological importance that bulk measures of chromatin structure miss. In bisulfite genomic sequencing, each sequenced clone records the methylation status of multiple sites on an individual molecule of DNA. An exogenous DNA methyltransferase can thus be used to image nucleosomes and other protein-DNA complexes. In this chapter, we describe the adaptation of this technique, termed Methylation Accessibility Protocol for individual templates, to modern high-throughput sequencing, which both simplifies the workflow and extends its utility. PMID- 22929774 TI - Genome-wide polyadenylation site mapping. AB - Alternative polyadenylation site usage gives rise to variation in 3' ends of transcripts in diverse organisms ranging from yeast to human. Accurate mapping of polyadenylation sites of transcripts is of major biological importance, since the length of the 3'UTR can have a strong influence on transcript stability, localization, and translation. However, reads generated using total mRNA sequencing mostly lack the very 3' end of transcripts. Here, we present a method that allows simultaneous analysis of alternative 3' ends and transcriptome dynamics at high throughput. By using transcripts produced in vitro, the high precision of end mapping during the protocol can be controlled. This method is illustrated here for budding yeast. However, this method can be applied to any natural or artificially polyadenylated RNA. PMID- 22929775 TI - Genome-wide mapping of nucleosome occupancy, histone modifications, and gene expression using next-generation sequencing technology. AB - Gene transcription can be regulated through alteration of chromatin structure, such as changes in nucleosome positioning and histone-modification patterns. Recent development of techniques based on the next-generation sequencing technology has allowed high-resolution analysis of genome-wide distribution of these chromatin features. In this chapter, we describe in detail the protocols of ChIP-Seq and MNase-Seq, which have been developed to detect the genome-wide profiles of transcription factor binding, histone modifications, and nucleosome occupancy. We also describe RNA-Seq protocols used to map global gene expression profiles. PMID- 22929776 TI - A chemical approach to mapping nucleosomes at base pair resolution in yeast. AB - Most eukaryotic DNA exists in DNA-protein complexes known as nucleosomes. The exact locations of nucleosomes along the genome play a critical role in chromosome functions and gene regulation. However, the current methods for nucleosome mapping do not provide the necessary accuracy to identify the precise nucleosome locations. Here we describe a new experimental approach that directly maps nucleosome center locations in vivo genome-wide at single base pair resolution. PMID- 22929777 TI - Nucleosomes, histones & chromatin part B. Preface. PMID- 22929778 TI - Identification of the functional binding pocket for compounds targeting small conductance Ca2+-activated potassium channels. AB - Small- and intermediate-conductance Ca(2+)-activated potassium channels, activated by Ca(2+)-bound calmodulin, have an important role in regulating membrane excitability. These channels are also linked to clinical abnormalities. A tremendous amount of effort has been devoted to developing small molecule compounds targeting these channels. However, these compounds often suffer from low potency and lack of selectivity, hindering their potential for clinical use. A key contributing factor is the lack of knowledge of the binding site(s) for these compounds. Here we demonstrate by X-ray crystallography that the binding pocket for the compounds of the 1-ethyl-2-benzimidazolinone (1-EBIO) class is located at the calmodulin-channel interface. We show that, based on structure data and molecular docking, mutations of the channel can effectively change the potency of these compounds. Our results provide insight into the molecular nature of the binding pocket and its contribution to the potency and selectivity of the compounds of the 1-EBIO class. PMID- 22929779 TI - Controlled rotation of the F1-ATPase reveals differential and continuous binding changes for ATP synthesis. AB - F(1)-ATPase is an ATP-driven rotary molecular motor that synthesizes ATP when rotated in reverse. To elucidate the mechanism of ATP synthesis, we imaged binding and release of fluorescently labelled ADP and ATP while rotating the motor in either direction by magnets. Here we report the binding and release rates for each of the three catalytic sites for 360 degrees of the rotary angle. We show that the rates do not significantly depend on the rotary direction, indicating ATP synthesis by direct reversal of the hydrolysis-driven rotation. ADP and ATP are discriminated in angle-dependent binding, but not in release. Phosphate blocks ATP binding at angles where ADP binding is essential for ATP synthesis. In synthesis rotation, the affinity for ADP increases by >10(4), followed by a shift to high ATP affinity, and finally the affinity for ATP decreases by >10(4). All these angular changes are gradual, implicating tight coupling between the rotor angle and site affinities. PMID- 22929780 TI - Charge stripe order near the surface of 12-percent doped La2-xSrxCuO4. AB - A collective order of spin and charge degrees of freedom into stripes has been predicted to be a possible ground state of hole-doped CuO(2) planes, which are the building blocks of high-temperature superconductors. In fact, stripe-like spin and charge order has been observed in various layered cuprate systems. For the prototypical high-temperature superconductor La(2-x)Sr(x)CuO(4), no charge stripe signal has been found so far, but several indications for a proximity to their formation. Here we report the observation of a pronounced charge-stripe signal in the near surface region of 12-percent doped La(2-x)Sr(x)CuO(4). We conclude that this compound is sufficiently close to charge stripe formation that small perturbations or reduced dimensionality near the surface can stabilize this order. Our finding of different phases in the bulk and near the surface of La(2 x)Sr(x)CuO(4) should be relevant for the interpretation of data from surface sensitive probes, which are widely used for La(2-x)Sr(x)CuO(4) and similar systems. PMID- 22929781 TI - Optical separation of mechanical strain from charge doping in graphene. AB - Because of its superior stretchability, graphene exhibits rich structural deformation behaviours and its strain engineering has proven useful in modifying its electronic and magnetic properties. Despite the strain-sensitivity of the Raman G and 2D modes, the optical characterization of the native strain in graphene on silica substrates has been hampered by excess charges interfering with both modes. Here we show that the effects of strain and charges can be optically separated from each other by correlation analysis of the two modes, enabling simple quantification of both. Graphene with in-plane strain randomly occurring between -0.2% and 0.4% undergoes modest compression (-0.3%) and significant hole doping on thermal treatments. This study suggests that substrate mediated mechanical strain is a ubiquitous phenomenon in two-dimensional materials. The proposed analysis will be of great use in characterizing graphene based materials and devices. PMID- 22929782 TI - Hygro-responsive membranes for effective oil-water separation. AB - There is a critical need for new energy-efficient solutions to separate oil-water mixtures, especially those stabilized by surfactants. Traditional membrane-based separation technologies are energy-intensive and limited, either by fouling or by the inability of a single membrane to separate all types of oil-water mixtures. Here we report membranes with hygro-responsive surfaces, which are both superhydrophilic and superoleophobic, in air and under water. Our membranes can separate, for the first time, a range of different oil-water mixtures in a single unit operation, with >99.9% separation efficiency, by using the difference in capillary forces acting on the two phases. Our separation methodology is solely gravity-driven and consequently is expected to be highly energy-efficient. We anticipate that our separation methodology will have numerous applications, including the clean-up of oil spills, wastewater treatment, fuel purification and the separation of commercially relevant emulsions. PMID- 22929783 TI - Programmable multimode quantum networks. AB - Entanglement between large numbers of quantum modes is the quintessential resource for future technologies such as the quantum internet. Conventionally, the generation of multimode entanglement in optics requires complex layouts of beamsplitters and phase shifters in order to transform the input modes into entangled modes. Here we report the highly versatile and efficient generation of various multimode entangled states with the ability to switch between different linear optics networks in real time. By defining our modes to be combinations of different spatial regions of one beam, we may use just one pair of multi-pixel detectors in order to measure multiple entangled modes. We programme virtual networks that are fully equivalent to the physical linear optics networks they are emulating. We present results for N=2 up to N=8 entangled modes here, including N=2, 3, 4 cluster states. Our approach introduces the highly sought after attributes of flexibility and scalability to multimode entanglement. PMID- 22929784 TI - Exploiting multimode waveguides for pure fibre-based imaging. AB - There has been an immense drive in modern microscopy towards miniaturization and fibre-based technology. This has been necessitated by the need to access hostile or difficult environments in situ and in vivo. Strategies to date have included the use of specialist fibres and miniaturized scanning systems accompanied by ingenious microfabricated lenses. Here we present a novel approach for this field by utilizing disordered light within a standard multimode optical fibre for lensless microscopy and optical mode conversion. We demonstrate the modalities of bright- and dark-field imaging and scanning fluorescence microscopy at acquisition rates that allow observation of dynamic processes such as Brownian motion of mesoscopic particles. Furthermore, we show how such control can realize a new form of mode converter and generate various types of advanced light fields such as propagation-invariant beams and optical vortices. These may be useful for future fibre-based implementations of super-resolution or light-sheet microscopy. PMID- 22929785 TI - Direct dynamic imaging of non-adiabatic spin torque effects. AB - Spin-transfer torques offer great promise for the development of spin-based devices. The effects of spin-transfer torques are typically analysed in terms of adiabatic and non-adiabatic contributions. Currently, a comprehensive interpretation of the non-adiabatic term remains elusive, with suggestions that it may arise from universal effects related to dissipation processes in spin dynamics, while other studies indicate a strong influence from the symmetry of magnetization gradients. Here we show that enhanced magnetic imaging under dynamic excitation can be used to differentiate between non-adiabatic spin-torque and extraneous influences. We combine Lorentz microscopy with gigahertz excitations to map the orbit of a magnetic vortex core with <5 nm resolution. Imaging of the gyrotropic motion reveals subtle changes in the ellipticity, amplitude and tilt of the orbit as the vortex is driven through resonance, providing a robust method to determine the non-adiabatic spin torque parameter beta=0.15+/-0.02 with unprecedented precision, independent of external effects. PMID- 22929786 TI - Optical detection of a single rare-earth ion in a crystal. AB - Rare-earth-doped laser materials show strong prospects for quantum information storage and processing, as well as for biological imaging, due to their high-Q 4f<->4f optical transitions. However, the inability to optically detect single rare-earth dopants has prevented these materials from reaching their full potential. Here we detect a single photostable Pr(3+) ion in yttrium aluminium garnet nanocrystals with high contrast photon antibunching by using optical upconversion of the excited state population of the 4f<->4f optical transition into ultraviolet fluorescence. We also demonstrate on-demand creation of Pr(3+) ions in a bulk yttrium aluminium garnet crystal by patterned ion implantation. Finally, we show generation of local nanophotonic structures and cell death due to photochemical effects caused by upconverted ultraviolet fluorescence of praseodymium-doped yttrium aluminium garnet in the surrounding environment. Our study demonstrates versatile use of rare-earth atomic-size ultraviolet emitters for nanoengineering and biotechnological applications. PMID- 22929787 TI - Rotational dynamics of cargos at pauses during axonal transport. AB - Direct visualization of axonal transport in live neurons is essential for our understanding of the neuronal functions and the working mechanisms of microtubule based motor proteins. Here we use the high-speed single particle orientation and rotational tracking technique to directly visualize the rotational dynamics of cargos in both active directional transport and pausing stages of axonal transport, with a temporal resolution of 2 ms. Both long and short pauses are imaged, and the correlations between the pause duration, the rotational behaviour of the cargo at the pause, and the moving direction after the pause are established. Furthermore, the rotational dynamics leading to switching tracks are visualized in detail. These first-time observations of cargo's rotational dynamics provide new insights on how kinesin and dynein motors take the cargo through the alternating stages of active directional transport and pause. PMID- 22929788 TI - Biocompatibility of a genetically encoded calcium indicator in a transgenic mouse model. AB - Engineering efforts of genetically encoded calcium indicators predominantly focused on enhancing fluorescence changes, but how indicator expression affects the physiology of host organisms is often overlooked. Here, we demonstrate biocompatibility and widespread functional expression of the genetically encoded calcium indicator TN-XXL in a transgenic mouse model. To validate the model and characterize potential effects of indicator expression we assessed both indicator function and a variety of host parameters, such as anatomy, physiology, behaviour and gene expression profiles in these mice. We also demonstrate the usefulness of primary cells and organ explants prepared from these mice for imaging applications. Although we find mild signatures of indicator expression that may be further reduced in future sensor generations, the 'green' indicator mice generated provide a well-characterized resource of primary cells and tissues for in vitro and in vivo calcium imaging applications. PMID- 22929789 TI - Active learning framework with iterative clustering for bioimage classification. AB - Advances in imaging systems have yielded a flood of images into the research field. A semi-automated facility can reduce the laborious task of classifying this large number of images. Here we report the development of a novel framework, CARTA (Clustering-Aided Rapid Training Agent), applicable to bioimage classification that facilitates annotation and selection of features. CARTA comprises an active learning algorithm combined with a genetic algorithm and self organizing map. The framework provides an easy and interactive annotation method and accurate classification. The CARTA framework enables classification of subcellular localization, mitotic phases and discrimination of apoptosis in images of plant and human cells with an accuracy level greater than or equal to annotators. CARTA can be applied to classification of magnetic resonance imaging of cancer cells or multicolour time-course images after surgery. Furthermore, CARTA can support development of customized features for classification, high throughput phenotyping and application of various classification schemes dependent on the user's purpose. PMID- 22929791 TI - The self-reported health and productivity burden of autoimmune disorders at a major self-insured employer. AB - OBJECTIVES: Examine the self-reported health and productivity burden of three autoimmune disorders: rheumatoid arthritis, psoriasis, and inflammatory bowel disease. METHODS: A 2009 representative survey of a major employer's US workforce, with two approaches for disease identification: (1) self-report and (2) self-report replicated by claims-based International Classification of Diseases, 9th Revision (ICD-9), codes. RESULTS: Self-reported prevalence: rheumatoid arthritis, 4.2%; psoriasis, 3.0%; inflammatory bowel disease, 1.2%. Psoriasis and inflammatory bowel disease replicated rheumatoid arthritis' pattern of health and productivity effects though not as strongly. The three autoimmune disorders combined significantly affected health at all severity levels. They also significantly affected productivity at higher severity but not at no symptom/lower severity levels. CONCLUSIONS: When employees with autoimmune disorders with lower severity/no symptoms do not progress to higher severity, their work performance remains on par with healthy employees. Autoimmune disorders' high impact/low prevalence offers much promise for lowering costs through benefit design. PMID- 22929790 TI - Imaging enzyme-triggered self-assembly of small molecules inside live cells. AB - Self-assembly of small molecules in water to form nanofibres, besides generating sophisticated biomaterials, promises a simple system inside cells for regulating cellular processes. But lack of a convenient approach for studying the self assembly of small molecules inside cells hinders the development of such systems. Here we report a method to image enzyme-triggered self-assembly of small molecules inside live cells. After linking a fluorophore to a self-assembly motif to make a precursor, we confirmed by (31)P NMR and rheology that enzyme-triggered conversion of the precursor to a hydrogelator results in the formation of a hydrogel via self-assembly. The imaging contrast conferred by the nanofibres of the hydrogelators allowed the evaluation of intracellular self-assembly, the dynamics and the localization of the nanofibres of the hydrogelators in live cells. This approach explores supramolecular chemistry inside cells and may lead to new insights, processes or materials at the interface of chemistry and biology. PMID- 22929792 TI - Managing the burden of chronic obstructive pulmonary disease on workforce health and productivity: upping a leading employer's game. AB - OBJECTIVE: To develop new evidence for advancing a leading employer's capacity to manage the burden of chronic obstructive pulmonary disease (COPD). METHODS: Retrospective analyses of an integrated database tracking active employees (n = 19,989) from 2001-2009. Tests on 29 measures of direct/indirect costs and drivers examined unique disease burden and impact over time. RESULTS: The costs of COPD exceeded workforce-wide costs by wide margins in 2001-2002. Direct costs linked to the disease rose in 2008-2009; whereas, its indirect costs dropped sharply. Differences between yet-to-be-diagnosed versus diagnosed and newly diagnosed versus established diagnosed groups were directionally consistent on driver and cost measures in 2001-2002. In 2008-2009, these comparisons were similarly consistent on indirect measures but not direct measures. Medication use helped to explain the inconsistencies. DISCUSSION: New action on COPD-oriented unit price escalation, prevention, and medical management concerns raised by these results could strengthen an already exemplary health and productivity program. PMID- 22929793 TI - Sleep, fatigue, recovery, and depression after change in work time control: a one year follow-up study. AB - OBJECTIVE: We examined how change in work time control was associated with sleep and health 1 year later. METHODS: Work time control, sleep, fatigue, recovery, and depression were assessed at baseline (T1) and at follow-up (T2) for 2382 daytime workers. The change in work time control from T1 to T2 was classified into four groups: low to low, low to high, high to low, and high to high. RESULTS: A repeated-measures analysis of covariance showed significant decreases in the frequency of insomnia symptoms and depressive symptoms from T1 to T2 for the low to high group, which were similar to the high to high group. Significantly lower fatigue was found for these two groups at T2. CONCLUSION: An increase in work time control, in addition to its stable high level, may produce beneficial effects upon sleep and health. PMID- 22929794 TI - Incidence and cost of depression after occupational injury. AB - OBJECTIVES: We examined if injured workers were more likely than noninjured workers to be treated for depression after an occupational injury and estimated the cost paid by group medical insurance. METHOD: Nearly 367,900 injured and noninjured workers were drawn from the 2005 Thomson Reuters MarketScan data. Descriptive, logistic, and two-part model regression analyses were used. RESULTS: The odds of injured workers being treated for depression within the study period were 45% higher than those of noninjured workers (95% confidence interval, 1.17 1.78). The unconditional average cost of outpatient depression treatment was 63% higher for injured workers than for noninjured workers. CONCLUSIONS: Injured workers were more likely than noninjured workers to suffer from depression during the study period. Consequently, additional costs are incurred for treating injured workers' depression; these costs were not covered by the workers' compensation system. PMID- 22929795 TI - Work environment and psychosocial factors affecting physical activity among Taiwanese information technology professionals: a structural equation modeling approach. AB - OBJECTIVE: To examine the relationships among work environment, psychosocial factors, and physical activity (PA) among information technology (IT) professionals. METHODS: This was a cross-sectional survey of 576 IT professionals from three IT companies in Taiwan. Structural equation modeling was used to test a theoretically supported model using social cognitive theory, incorporating variables from the demand-control model. RESULTS: Higher levels of PA were positively associated with supportive workplace environments, positive outcome expectations, and self-efficacy for PA. Self-efficacy partially mediated the effects of supportive workplace environments on PA. Job strain had an indirect effect on PA through self-efficacy. The final model accounted for 31% of the variance in PA. CONCLUSIONS: Work environment and psychosocial factors are both important. Workplace PA interventions directed toward individuals' self-efficacy and outcome expectations in the context of supportive environments may be useful. PMID- 22929796 TI - Perceived job insecurity and health: the Michigan Recession and Recovery Study. AB - OBJECTIVE: To examine the association between perceived job insecurity in the next 12 months and current health with a sample representing working-aged employed adults in southeast Michigan in late 2009/early 2010 (n, 440 to 443). METHODS: Logistic regression was used to compare the health of participants who perceived job insecurity with those who did not, with adjustments for objective employment problems and social characteristics. RESULTS: Insecure workers were more likely to report fair or poor self-rated health (odds ratio [OR], 2.68; 95% confidence interval [CI], 1.14 to 6.32), symptoms suggesting major or minor depression (OR, 6.76; 95% CI, 3.34 to 13.3), and anxiety attacks (OR, 3.73; 95% CI, 1.40 to 9.97), even after correction for confounding factors. CONCLUSION: This study provides evidence that perceived job insecurity may be linked to health even among those who avoided unemployment in the late-2000s recession. PMID- 22929797 TI - The comparative value of various employer-sponsored influenza vaccination clinics. AB - OBJECTIVE: Many US firms offer influenza vaccination clinics to prevent lost productivity due to influenza. Strategies to promote and offer vaccination differ, and the economic value of the strategies is unknown. METHODS: Decision analytic modeling and Monte Carlo probabilistic sensitivity analyses estimated the one-season cost-consequences of three types of influenza clinics (trivalent inactivated influenza vaccine only, vaccine choice [trivalent inactivated influenza or intranasal {live attenuated influenza} vaccine], or vaccine choice plus incentive) in firms of 50 and 250 employees, from the employer's perspective. RESULTS: On-site influenza vaccination was generally cost-saving over no vaccination. For the scenario of vaccine effectiveness of 70% and intermediate transmissibility, the incremental costs per employee for a firm of 50 employees were -$6.41 (ie, cost savings) for inactivated vaccine only versus no vaccination, -$1.48 for vaccine choice versus inactivated vaccine, and $1.84 for vaccine choice plus incentive versus vaccine choice. Clinics offering a choice of vaccines were slightly less costly under many scenarios. Generally, incremental costs were lower (1) in larger firms; (2) when influenza was assumed to be more contagious; and (3) when vaccine effectiveness was assumed to be higher. CONCLUSION: Employer-sponsored influenza vaccination clinics are generally cost-saving. PMID- 22929798 TI - Attenuation of oxidative stress-induced vascular endothelial dysfunction by thymoquinone. AB - This study aimed to assess the effects of thymoquinone (TQ) on pyrogallol-induced endothelial dysfunction in isolated rabbit aorta. The protective effects of TQ were examined by incubating aortic rings in TQ concomitant with pyrogallol. The results revealed that pyrogallol produced significant enhancement of phenylephrine-induced contraction and impairment of acetylcholine-induced relaxation. Pyrogallol caused a significant increase in lipid peroxidation and reduction in the level of superoxide dismutase and reduced glutathione in the aortic homogenates. In addition, pyrogallol produced a significant decrease in nitrite/nitrate concentrations (NOx), constitutive nitric oxide synthase (cNOS) activity and an increase in inducible nitric oxide synthase (iNOS) activity in the aortic homogenates. These changes were counteracted by TQ co-incubation as TQ attenuated pyrogallol-induced impairment in vascular reactivity in a dose dependent manner. Furthermore, TQ showed potent antioxidant activity as well as causing a significant increase in NOx and cNOS activity, and depression in iNOS activity. These results suggest that TQ can protect against pyrogallol-induced endothelial dysfunction which probably results from its potent antioxidant capacity that leads to an increase in NO production as well as its ability to enhance the generation and bioavailability of NO. PMID- 22929799 TI - The antigen-binding fragment of anti-double-stranded DNA IgG enhances F-actin formation in mesangial cells by binding to alpha-actinin-4. AB - Anti-double-stranded DNA (dsDNA) IgG causes renal damage in patients with lupus nephritis by cross-reacting with multiple autoantigens, including alpha-actinin 4, in mesangial cells (MCs). However, how the cross-reactions play a role in mesangial phenotypic abnormalities is not well understood. Here, we investigated the effects of the fragment antigen-binding (Fab) of anti-dsDNA IgG3 on the biochemical properties of alpha-actinin-4. Experiments revealed that anti-dsDNA Fab specifically binds to alpha-actinin-4, but not G-actin. The binding by anti dsDNA Fab sequentially increases the positive charge of alpha-actinin-4 and inhibits the affinity of alpha-actinin-4 to calcium ions. By the low shear viscosity and a co-sedimentation assay, we found that the alpha-actinin-4-induced F-actin gelation improves when anti-dsDNA Fab is added. However, the Fab control has no such effect on F-actin gelation. Furthermore, the in vitro cultured MCs exhibit higher F-actin expression and transforming growth factor-beta1 synthesis after the incubation with anti-dsDNA Fab. Therefore, our results indicated that anti-dsDNA Fab may enhance F-actin formation by the proprietary modification of alpha-actinin-4, which could partially explain the myofibroblast-like phenotype of MCs in anti-dsDNA-positive lupus nephritis. PMID- 22929800 TI - Cardiac remodeling in rats with renal failure shows interventricular differences. AB - Chronic renal failure (CRF) is associated with an increased incidence of cardiovascular diseases. Intensive research revealed a number of alterations in the heart during CRF; however, possible interventricular differences in CRF induced cardiac remodeling have so far not been addressed. CRF was induced by two stage surgical 5/6 nephrectomy (NX) in male Wistar rats. Cellular hypertrophy was quantified using immunohistological morphometric analysis. Contraction force and membrane potential were recorded in left and right ventricle papillary muscles with an isometric force transducer and high-resistance glass microelectrodes. Hypertrophy was present in the left ventricle (LV) of NX animals, but not in the right ventricle (RV) of NX animals, as documented by both ventricle/body weight ratios and cellular morphometric analysis of the cross-sectional area of myocytes. The contraction force was reduced in the LV of NX animals but increased in the RV of NX animals compared with sham-operated rats. Rest potentiation of contraction force was relatively more pronounced in the LV of NX rats. Fifty percent substitution of extracellular sodium with lithium significantly increased the contraction force only in the LV of NX animals. Action potential durations were shortened in both ventricles of CRF animals. Cardiac structural and contractile remodeling in CRF shows significant interventricular differences. CRF induces hypertrophy of the LV but not of the RV. LV hypertrophy was associated with a reduction of contraction force, whereas in the RV, the contraction force was enhanced. Partial recovery of contractile function of the LV by rest potentiation or lithium substitution indicates a role of the Na(+)/Ca(2+) exchanger in this phenomenon. PMID- 22929801 TI - Providing cell phone numbers and e-mail addresses to patients: The patient's perspective, a cross sectional study. AB - BACKGROUND: Today patients can consult with their treating physician by cell phone or e-mail. These means of communication enhance the quality of medical care and increase patient satisfaction, but they can also impinge on physicians' free time and their patient schedule while at work. The objective of this study is to assess the attitudes and practice of patients on obtaining the cell phone number or e-mail address of their physician for the purpose of medical consultation. METHODS: Personal interviews with patients, 18 years of age or above, selected by random sampling from the roster of adults insured by Clalit Health Services, Southern Division. The total response rate was 41%. The questionnaire included questions on the attitude and practice of patients towards obtaining their physician's cell phone number or e-mail address. Comparisons were performed using Chi-square tests to analyze statistically significant differences of categorical variables. Two-tailed p values less than 0.05 were considered statistically significant, with a power of 0.8. RESULTS: The study sample included 200 patients with a mean age of 46.6 +/- 17.1, of whom 110 were women (55%). Ninety-three (46.5%) responded that they would be very interested in obtaining their physician's cell phone number, and an additional 83 (41.5%) would not object to obtaining it. Of the 171 patients (85.5%) who had e-mail addresses, 25 (14.6%) said they would be very interested in obtaining their physician's e-mail address, 85 (49.7%) said they would not object to getting it, and 61 (35.7%) were not interested. In practice only one patient had requested the physician's e-mail address and none actually had it. CONCLUSIONS: Patients favored cell phones over e-mail for consulting with their treating physicians. With new technologies such as cell phones and e-mail in common use, it is important to determine how they can be best used and how they should be integrated into the flow of clinical practice. PMID- 22929802 TI - Prognostic significance of promoter DNA methylation in patients with childhood neuroblastoma. AB - PURPOSE: To characterize the clinical significance of promoter methylation in a cohort of primary neuroblastoma tumors and investigate the association between DNA methylation and clinical outcome. EXPERIMENTAL DESIGN: A customized Illumina GoldenGate methylation assay was used to assess methylation status of 96 CpG sites within 48 candidate genes in primary neuroblastoma tumors obtained from 131 children diagnosed in Australia. Genes were selected on the basis of previous reports of altered DNA methylation in embryonal cancers. Levels of DNA methylation were validated in a subset of 48 patient samples using combined bisulfite restriction analysis (CoBRA) and bisulfite sequencing. A Cox proportional hazards model was used to investigate the association between promoter hypermethylation and the risk of relapse/death within 5 years of diagnosis, while adjusting for known prognostic factors including MYCN amplification, age, and stage at diagnosis. RESULTS: Levels of promoter methylation of DNAJC15, neurotrophic tyrosine kinase receptor 1 or TrkA (NTRK1), and tumor necrosis factor receptor superfamily, member 10D (TNFRSF10D), were higher in older patients at diagnosis (P < 0.01), whereas higher levels of methylation of DNAJC15, NTRK1, and PYCARD were observed in patients with MYCN amplification (P < 0.001). In multivariate analysis, hypermethylation of folate hydrolase (FOLH1), myogenic differentiation-1 (MYOD1), and thrombospondin-1 (THBS1) remained significant independent predictors of poorer clinical outcome after adjusting for known prognostic factors (P <= 0.017). Moreover, more than 30% of patients displayed hypermethylation in 2 genes or more and were at least 2 times more likely to relapse or die (HR = 2.72, 95% confidence interval = 1.55 4.78, P = 0.001), independent of MYCN status, age, and stage at diagnosis. CONCLUSIONS: Our findings highlight the potential use of methylation profiling to identify additional prognostic markers and detect new therapeutic targets for selected patient subsets. PMID- 22929804 TI - New strategies in sarcoma therapy: linking biology and novel agents. AB - The ability to better interrogate the genetic state of a given cancer is giving rise to a new paradigm in cancer therapeutics in which the specific genetic alterations that give rise to the cancer inform the therapeutic decision-making for that specific patient. Sarcomas of soft tissue and bone represent model diseases that underscore this paradigm. However, many barriers prevent linkage of one of the 75 or more different types of sarcoma to novel therapeutic agents. In the present perspective, the authors outline key therapeutic opportunities and hurdles in clinical sarcoma research, focusing on specific examples of sarcomas that are on the verge of new breakthroughs, as well as those in which promise has not lived up to expectations. Focused clinical trial design, ideally with several biomarker or histology-specific arms, is one means to be simultaneously parsimonious and inclusive. PMID- 22929803 TI - Carfilzomib and ONX 0912 inhibit cell survival and tumor growth of head and neck cancer and their activities are enhanced by suppression of Mcl-1 or autophagy. AB - PURPOSE: Carfilzomib is a selective, irreversible inhibitor of the chymotrypsin like activity of the proteasome and is undergoing clinical evaluation in myeloma. ONX 0912 (oprozomib) is an orally bioavailable derivative. The activities of carfilzomib and ONX 0912 against solid tumor malignancies are less well understood. We investigated the impact and mechanisms of action of carfilzomib and ONX 0912 in preclinical models of head and neck squamous cell carcinoma (HNSCC). EXPERIMENTAL DESIGN: The effects of carfilzomib and ONX 0912 on HNSCC cell survival and xenograft tumor growth were evaluated. The impact and mechanisms of both agents on apoptosis and autophagy induction were also investigated. The contribution of the unfolded protein response (UPR) to autophagy induction and the role of autophagy in attenuating HNSCC cell death were determined. RESULTS: Carfilzomib and ONX 0912 potently induced apoptosis in HNSCC cell lines via upregulation of pro-apoptotic Bik. Upregulation of Mcl-1 by these agents served to dampen their efficacies. Carfilzomib and ONX 0912 also induced autophagy, mediated, in part, by activation of the UPR pathway involving upregulation of ATF4 transcription factor. Autophagy induction served a prosurvival role. Oral administration of ONX 0912 inhibited the growth of HNSCC xenograft tumors in a dose-dependent manner. CONCLUSIONS: These results show that carfilzomib and ONX 0912 are potently active against HNSCC cells, and the activities of these agents can be enhanced via suppression of Mcl-1 or inhibition of autophagy. Oral ONX 0912 exhibits in vivo activity against HNSCC tumors and may represent a useful therapeutic agent for this malignancy. PMID- 22929805 TI - Sorafenib inhibits hypoxia-inducible factor-1alpha synthesis: implications for antiangiogenic activity in hepatocellular carcinoma. AB - PURPOSE: The overexpression of hypoxia-inducible factor 1alpha (HIF-1alpha) is a common finding in hepatocellular carcinoma (HCC), and it leads to angiogenesis and poor prognosis. Sorafenib, a multikinase inhibitor, has shown significant improvement in survival in patients with advanced HCC in clinical trials. However, the mechanisms that account for the antiangiogenic efficiency of sorafenib have not been fully elucidated. The present study aims to explore the effect of sorafenib on HIF-1alpha expression and activation in HCC cells and xenografts. EXPERIMENTAL DESIGN: HCC cells and xenografts were treated with sorafenib or vehicles. Western blotting and quantitative PCR array were used to determine protein and mRNA expression, respectively. HIF-1alpha activity, de novo protein synthesis, and VEGF secretions were determined using assay kits. RESULTS: Sorafenib dose dependently decreased the hypoxia-induced accumulation and activation of HIF-1alpha protein. Further analysis revealed that such reduction of HIF-1alpha was associated with the inhibition of HIF-1alpha protein synthesis rather than the promotion of HIF-1alpha protein degradation or the reduction of HIF-1alpha mRNA. Moreover, the phosphorylation levels of mTOR, extracellular signal-regulated kinase (ERK), p70S6K, RP-S6, 4E-BP1, and eIF4E were significantly suppressed by sorafenib. In vivo studies further confirmed the inhibitory effect of sorafenib on the expression of HIF-1alpha and VEGF proteins, leading to a decrease in tumor vascularization and growth of the xenografts. CONCLUSIONS: Sorafenib-mediated inhibition of HIF-1alpha synthesis is associated with previously undefined pathways in which mTOR/p70S6K/4E-BP1 and ERK phosphorylation are downregulated. Our preclinical data expand our understanding of sorafenib's antiangiogenic mechanism of action by inhibiting HIF-1alpha and VEGF protein expression. PMID- 22929807 TI - The case of the neglected alphasyllabary: orthographic processing in Devanagari. AB - We applaud Ram Frost for highlighting the need for multicultural perspectives while developing universal models of visual word recognition. We second Frost's proposal that factors like lexical morphology should be incorporated besides purely orthographic features in modeling word recognition. In support, we provide fresh evidence from Hindi (written in Devanagari), an example of hitherto under represented alphasyllabic orthographies, in which flexible encoding of aksara (character) position is constrained by the morphological structure of words. PMID- 22929806 TI - CCT244747 is a novel potent and selective CHK1 inhibitor with oral efficacy alone and in combination with genotoxic anticancer drugs. AB - PURPOSE: Many tumors exhibit defective cell-cycle checkpoint control and increased replicative stress. CHK1 is critically involved in the DNA damage response and maintenance of replication fork stability. We have therefore discovered a novel potent, highly selective, orally active ATP-competitive CHK1 inhibitor, CCT244747, and present its preclinical pharmacology and therapeutic activity. EXPERIMENTAL DESIGN: Cellular CHK1 activity was assessed using an ELISA assay, and cytotoxicity a SRB assay. Biomarker modulation was measured using immunoblotting, and cell-cycle effects by flow cytometry analysis. Single-agent oral CCT244747 antitumor activity was evaluated in a MYCN-driven transgenic mouse model of neuroblastoma by MRI and in genotoxic combinations in human tumor xenografts by growth delay. RESULTS: CCT244747 inhibited cellular CHK1 activity (IC(50) 29-170 nmol/L), significantly enhanced the cytotoxicity of several anticancer drugs, and abrogated drug-induced S and G(2) arrest in multiple tumor cell lines. Biomarkers of CHK1 (pS296 CHK1) activity and cell-cycle inactivity (pY15 CDK1) were induced by genotoxics and inhibited by CCT244747 both in vitro and in vivo, producing enhanced DNA damage and apoptosis. Active tumor concentrations of CCT244747 were obtained following oral administration. The antitumor activity of both gemcitabine and irinotecan were significantly enhanced by CCT244747 in several human tumor xenografts, giving concomitant biomarker modulation indicative of CHK1 inhibition. CCT244747 also showed marked antitumor activity as a single agent in a MYCN-driven neuroblastoma. CONCLUSION: CCT244747 represents the first structural disclosure of a highly selective, orally active CHK1 inhibitor and warrants further evaluation alone or combined with genotoxic anticancer therapies. PMID- 22929808 TI - Combined blockade of programmed death-1 and activation of CD137 increase responses of human liver T cells against HBV, but not HCV. AB - BACKGROUND & AIMS: In patients with chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) infections, antiviral functions of T cells are impaired; these might be increased by blocking T-cell co-inhibitory pathways, such as preventing interaction between the receptor programmed death (PD)-1 and its ligand, PD-L1. We attempted to optimize the restoration of T-cell functions in patients with chronic HBV or HCV infection with a combination of reagents that block PD-1 interaction with PD-L1 and stimulate T-cell signaling via CD137, a member of the tumor necrosis factor-receptor family. METHODS: We assessed the effects of CD137 stimulation (via CD137L), alone or in combination with antibodies that block PD-1 interaction with PD-L1 (anti-PD-L1), on proliferation and production of interferon-gamma and interleukin-2 by intrahepatic and peripheral T cells from patients with chronic HBV or HCV infection. We also analyzed expression of different co-stimulatory molecules on virus-specific CD8+ and forkhead box P3+CD4+ cells by flow cytometry. RESULTS: Incubation of intrahepatic T cells with CD137L and anti-PD-L1 increased their responses to HBV, but not HCV. However, HCV specific T cells isolated from peripheral blood were sensitive to these reagents. Virus-specific T cells from some, but not all patients, had increased responses to anti-PD-L1 when CD137L was added because in some cases the combination of anti PD-L1 and CD137L overstimulated T cells, leading to their inhibition. Intrahepatic HBV- and HCV-specific CD8+ T cells had different costimulatory profiles; liver cells from patients with chronic HBV infection had a higher proportion of forkhead box P3+ regulatory T cells, with higher levels of PD-1, compared with liver cells from patients with chronic HCV infection. CONCLUSIONS: A combination of reagents that prevent interaction between PD-1 and its ligand and activate CD137 signaling increase responses of intrahepatic HBV-specific T cells and circulating HCV-specific T cells. This strategy might be developed to increase T-cell responses to these viruses in patients with chronic hepatitis B or C, and tailoring the dose of CD137L administered will help optimize results. PMID- 22929809 TI - Obesity-related metabolic dysfunction in dogs: a comparison with human metabolic syndrome. AB - BACKGROUND: Recently, metabolic syndrome (MS) has gained attention in human metabolic medicine given its associations with development of type 2 diabetes mellitus and cardiovascular disease. Canine obesity is associated with the development of insulin resistance, dyslipidaemia, and mild hypertension, but the authors are not aware of any existing studies examining the existence or prevalence of MS in obese dogs.Thirty-five obese dogs were assessed before and after weight loss (median percentage loss 29%, range 10-44%). The diagnostic criteria of the International Diabetes Federation were modified in order to define canine obesity-related metabolic dysfunction (ORMD), which included a measure of adiposity (using a 9-point body condition score [BCS]), systolic blood pressure, fasting plasma cholesterol, plasma triglyceride, and fasting plasma glucose. By way of comparison, total body fat mass was measured by dual-energy X ray absorptiometry, whilst total adiponectin, fasting insulin, and high sensitivity C-reactive protein (hsCRP) were measured using validated assays. RESULTS: Systolic blood pressure (P = 0.008), cholesterol (P = 0.003), triglyceride (P = 0.018), and fasting insulin (P < 0.001) all decreased after weight loss, whilst plasma total adiponectin increased (P = 0.001). However, hsCRP did not change with weight loss. Prior to weight loss, 7 dogs were defined as having ORMD, and there was no difference in total fat mass between these dogs and those who did not meet the criteria for ORMD. However, plasma adiponectin concentration was less (P = 0.031), and plasma insulin concentration was greater (P = 0.030) in ORMD dogs. CONCLUSIONS: In this study, approximately 20% of obese dogs suffer from ORMD, and this is characterized by hypoadiponectinaemia and hyperinsulinaemia. These studies can form the basis of further investigations to determine path genetic mechanisms and the health significance for dogs, in terms of disease associations and outcomes of weight loss. PMID- 22929810 TI - High-throughput sorting of mosquito larvae for laboratory studies and for future vector control interventions. AB - BACKGROUND: Mosquito transgenesis offers new promises for the genetic control of vector-borne infectious diseases such as malaria and dengue fever. Genetic control strategies require the release of large number of male mosquitoes into field populations, whether they are based on the use of sterile males (sterile insect technique, SIT) or on introducing genetic traits conferring refractoriness to disease transmission (population replacement). However, the current absence of high-throughput techniques for sorting different mosquito populations impairs the application of these control measures. METHODS: A method was developed to generate large mosquito populations of the desired sex and genotype. This method combines flow cytometry and the use of Anopheles gambiae transgenic lines that differentially express fluorescent markers in males and females. RESULTS: Fluorescence-assisted sorting allowed single-step isolation of homozygous transgenic mosquitoes from a mixed population. This method was also used to select wild-type males only with high efficiency and accuracy, a highly desirable tool for genetic control strategies where the release of transgenic individuals may be problematic. Importantly, sorted males showed normal mating ability compared to their unsorted brothers. CONCLUSIONS: The developed method will greatly facilitate both laboratory studies of mosquito vectorial capacity requiring high-throughput approaches and future field interventions in the fight against infectious disease vectors. PMID- 22929811 TI - Non-retinotopic feature processing in the absence of retinotopic spatial layout and the construction of perceptual space from motion. AB - The spatial representation of a visual scene in the early visual system is well known. The optics of the eye map the three-dimensional environment onto two dimensional images on the retina. These retinotopic representations are preserved in the early visual system. Retinotopic representations and processing are among the most prevalent concepts in visual neuroscience. However, it has long been known that a retinotopic representation of the stimulus is neither sufficient nor necessary for perception. Saccadic Stimulus Presentation Paradigm and the Ternus Pikler displays have been used to investigate non-retinotopic processes with and without eye movements, respectively. However, neither of these paradigms eliminates the retinotopic representation of the spatial layout of the stimulus. Here, we investigated how stimulus features are processed in the absence of a retinotopic layout and in the presence of retinotopic conflict. We used anorthoscopic viewing (slit viewing) and pitted a retinotopic feature-processing hypothesis against a non-retinotopic feature-processing hypothesis. Our results support the predictions of the non-retinotopic feature-processing hypothesis and demonstrate the ability of the visual system to operate non-retinotopically at a fine feature processing level in the absence of a retinotopic spatial layout. Our results suggest that perceptual space is actively constructed from the perceptual dimension of motion. The implications of these findings for normal ecological viewing conditions are discussed. PMID- 22929812 TI - Active search for multiple targets is inefficient. AB - This study examines saccade strategy in a novel task where observers actively search a display to find multiple targets in a limited time. Theory predicts that the relative merit of different saccade strategies depends on the prior probability of the target at a location: when the target prior is low and multiple-target trials are rare, making a saccade to the most likely target location is close to the optimal strategy, but when the target prior is high and multiple-target trials are frequent, selecting uncertain locations is more informative. The prior probability of the target was varied from 0.17 to 0.67 to determine whether observers adjusted their saccades strategies to maximize information. Observers actively searched a noisy display with six potential target locations. Each location had an independent probability of a target, so the number of targets in a trial ranged from 0 to 6. For all target priors ranging from low to high, a trial-by-trial analysis of saccade strategy indicated that observers made saccades to the most likely target location more often than the most uncertain location. Fixating likely locations is efficient only when multiple targets are rare, as in the case of a low target prior, or in the case of the more standard single-target search task. Yet it is the preferred saccade strategy in all our conditions, even when multiple targets are frequent. These findings indicate that humans are far from ideal searchers in multiple-target search. PMID- 22929813 TI - Hybrid stage I palliation for hypo-plastic left heart condition without a hybrid suite: suggestions for developing nations. AB - Cardiac hybrid procedures are performed in modern, spacious, and highly equipped hybrid suites in developed countries. Organizing such expensive suites in countries with an emerging economy is difficult from both a financial and logistics point of view. We share our experience of safely performing a Hybrid stage I palliation procedure for Aortic atresia with ventricular septal defect on a 2-month-old infant weighing 3.35 kg using minimal resources in a conventional catheterization laboratory. PMID- 22929814 TI - Definitive therapy for hypoplastic left heart syndrome - Indian scenario. PMID- 22929815 TI - CYP2C19*2/ABCB1-C3435T polymorphism and risk of cardiovascular events in coronary artery disease patients on clopidogrel: is clinical testing helpful? AB - BACKGROUND: Studies evaluating CYP2C19*2 and ABCB1-C3435T polymorphisms have shown conflicting results. We performed this meta-analysis to evaluate role of clinical testing for these polymorphisms in CAD patients on clopidogrel. METHODS: 19,601 patients from 14 trials were analyzed. The endpoints were major adverse cardiovascular events (MACE), cardiovascular (CV) death, stent thrombosis (ST), myocardial infarction (MI), stroke and major bleeding. Combined relative risks (RR) with 95% confidence intervals (CI) were computed for each outcome by using standard methods of meta-analysis and test parameters were computed. RESULTS: CYP2C19*2 polymorphism was associated with higher risk of MACE [RR: 1.28, CI: 1.06-1.54; p=0.009], CV death [RR: 3.21, CI: 1.65-6.23; p=0.001], MI [RR: 1.36, CI: 1.12-1.65; p=0.002], ST [RR: 2.41, CI: 1.69-3.41; p<0.001]. No difference was seen in major bleeding events [RR: 1.02, CI: 0.86-1.20; p=0.83]. Subgroup analysis showed similar results for elective PCI [RR: 1.34, CI: 1.01-1.76; p=0.03], and PCI with DES [RR: 1.53, CI: 1.029-1.269; p=0.03]. CYP2C19*2 polymorphism has very low sensitivity (28-58%), specificity (71-73%), positive predictive value (3-10%) but good negative predictive value (92-99%). ABCB1 C3435T polymorphism analysis revealed similar MACE [RR: 1.13, CI: 0.99-1.29; p=0.06], ST [RR: 0.88, CI: 0.52-1.47; p=0.63] and major bleeding [RR: 1.04, CI: 0.87-1.25; p=0.62] in both groups. CONCLUSION: In CAD patients on clopidogrel therapy, CYP2C19*2 polymorphism is associated with significantly increased adverse cardiovascular events. However, due to the low positive predictive value, routine genetic testing cannot be recommended at present. PMID- 22929816 TI - Clopidogrel resistance - a clear problem with an unclear solution. PMID- 22929817 TI - Study of cardiovascular risk factors among tertiary hospital employees and their families. AB - BACKGROUND: The aim of the present study was to estimate the prevalence of cardiovascular risk factors among administrative employees working at a tertiary hospital (All India Institute of Medical Sciences, New Delhi) and their families. METHODS AND RESULTS: A cross-sectional survey was conducted among a total of 453 individuals aged 30 years and above. The mean age of the study group was 43.3 +/- 9.5 years. There was a high prevalence of major cardiovascular risk factors - current smoking 58 (12.8%), tobacco consumption 26 (5.7%), family history of coronary artery disease 79 (17.4%), diabetes mellitus 25 (5.8%), hypertension 94 (20.7%), hypercholesterolemia 110 (25.7%), hypertriglyceridemia 148 (34.5%), physical inactivity 180 (39.7%), body mass index >=23 kg/m(2) 350 (77.3%), central obesity 201 (80.1%) of males and 163 (80.7%) of females, inadequate fruit and vegetable consumption 387 (85.4%), heavy drinking 12 (2.6%), and stress 58 (12.7%). CONCLUSION: This indicates an urgent need to initiate a comprehensive health promotion and cardiovascular disease prevention programme at workplace and community level. PMID- 22929818 TI - Coronary heart disease and risk factors in India - on the brink of an epidemic? PMID- 22929819 TI - Recent trends in reperfusion in ST elevation myocardial infarction in a South Indian tier-3 city. AB - AIMS: In India, larger proportions of patients with ACS present with STEMI. We sought to study the recent trends of reperfusion in patients of acute STEMI. METHODS AND RESULTS: 1905 patients presenting with acute STEMI enrolled. 1636 (86%) received some form of reperfusion therapy. Streptokinase, 1235 (65%) patients, was the most common mode of reperfusion therapy used followed by primary PCI (205, 10.7%) and tenecteplase (196, 10%). 269 (14%) did not receive any form of reperfusion therapy, the most common reason being late presentation in 230 (85.7%). Patients presenting with STEMI increased from 297 to 446 comparing first and last half-year of study period. The PCI and tenecteplase numbers increased from 19 to 68 and 27 to 97 respectively. CONCLUSION: There was 20% increase in STEMI every year. Younger patients are least likely to receive primary PCI or tenecteplase. 1 in 8 patients of STEMI did not receive any form of reperfusion therapy. PMID- 22929820 TI - Prevalence of isolated diastolic hypertension and associated risk factors among adults in Kanpur, India. AB - BACKGROUND: Isolated diastolic hypertension (IDH) is a largely unrecognized subtype of hypertension, more commonly seen in the younger age group. AIMS: (1) To determine the prevalence of IDH in the adult population of Kanpur district. (2) To study the associated risk factors of IDH. METHODS: A community-based cross sectional study was conducted in 801 subjects, aged 20 years and above, using multistage stratified random sampling technique. RESULTS: The prevalence of IDH was 4.5%, which was 6.2% in men and 3.1% in women. A significant proportion of IDH was seen in the 40-49 years age group. Multivariate logistic regression analysis of the associated risk factors showed that gender, physical activity and BMI were significantly associated with IDH. CONCLUSION: Isolated diastolic hypertension is an emerging problem in developing countries. IDH is more common among men, sedentary individuals and those with a higher BMI. PMID- 22929821 TI - Red cell distribution width, inflammatory markers and cardiorespiratory fitness: results from the National Health and Nutrition Examination Survey. AB - AIMS: Cardiorespiratory fitness is an important predictor of cardiovascular morbidity and mortality. Both red cell distribution width (RDW) and inflammatory markers like C-reactive protein (CRP) have been shown to predict adverse outcomes in patients with heart disease. METHODS: We utilized pooled data from NHANES 1999 2004 to assess cardiorespiratory fitness in healthy adults 12-49 years old using submaximal exercise. The primary outcome was the estimated maximal oxygen uptake (VO2max). Low fitness was defined as VO2max < 20th percentile of age- and gender based reference category. RESULTS: In our study, we estimated 21.2% of individuals had low fitness. Elevated RDW (>13%) was encountered in 20.4% subjects with low fitness as compared to 14.0% subjects in the control group (p < 0.001). Similarly, elevated CRP (>0.5 mg/dL) was found among 17.4% subjects with low fitness as compared to 12.4% subjects in the control group (p < 0.001). Adjusted analysis demonstrated a dose-response relationship between low cardiorespiratory fitness and increasing RDW or CRP. CONCLUSION: In a large representative database of general US population, we observed a significant association between elevated RDW and elevated CRP with low cardiorespiratory fitness. PMID- 22929822 TI - Corsair microcatheter for retrograde coronary chronic total occlusion recanalization: early experience outside the realm of dedicated recanalization specialists. AB - OBJECTIVE: To determine the extent to which use of the Corsair microcatheter (CM, Asahi Intecc Co., Japan) improves procedural outcomes when an experienced operator who is not a dedicated recanalization specialist attempts retrograde chronic total occlusion (CTO) recanalization through collateral channels during percutaneous coronary intervention. BACKGROUND: The recently introduced CM has improved success rates of retrograde CTO recanalization to nearly 100% in the hands of dedicated coronary recanalization specialists; however, the impact the CM has on the results of non-specialist operators attempting retrograde CTO recanalization is not known. METHODS: A non-specialist operator attempted CM assisted recanalization in seven consecutive CTO cases requiring retrograde recanalization. The results obtained were compared with those achieved by the same operator in eleven consecutive retrograde CTO recanalization procedures during the last 2 years before the CM became available. RESULTS: CM-assisted retrograde CTO recanalization was successful in 6 of 7 cases (86%), but failed in one case attempted through a tortuous epicardial collateral; there were no complications. In contrast, during the 2 years before the CM became available, retrograde CTO recanalization was successful in only 3 of 11 attempted cases (27%), and was associated with significant morbidity. Lesions in the two groups were comparable in terms of technical difficulty and procedural risk. CONCLUSIONS: The non-specialist operator's retrograde CTO recanalization results improve significantly when using the CM. Given the effectiveness and safety of CM assisted retrograde CTO recanalization, operators should be less aggressive with anterograde recanalization attempts, and should switch to the retrograde approach earlier and more often. PMID- 22929823 TI - Our experience of coronary angiography with and without heparin. AB - AIM: Coronary angiography is usually done with heparin. Our aim is to see whether it can be done without heparin through femoral route and its effect on local complications. METHOD: We have studied 3780 patients from 2006 to 2010 using standard dose Heparin (5000 units), low dose heparin (2000 units) and no heparin. We have compared safety and complications in these three groups. RESULTS: Local complications were lowest in no heparin group. Blood transfusion requirements and surgical interventions were lowest in no heparin group. Thrombosis rate did not increase in no heparin group. CONCLUSION: Coronary angiography can be done safely without heparin through femoral route. PMID- 22929824 TI - Depression and the heart. AB - Cardio Vascular disease (CVD) as well as depression are both highly prevalent disorders and both of them cause a significant decrease in quality of life and increase the economic burden for the patient. Depressed individuals are more likely to develop angina, fatal or non-fatal myocardial infarction, than those who are not depressed. Over the past decade, evidence has accumulated to suggest that depression may be a risk factor for cardiac mortality in patients with established coronary artery disease (CAD). The 'vicious cycle' linking CVD to major depression and depression to CVD, deserves greater attention from both cardio-vascular and psychiatric investigators.(1). PMID- 22929825 TI - Posterior mitral leaflet aneurysm - a rare cause of mitral regurgitation. AB - Posterior mitral leaflet aneurysm is a very rare complication of infective endocarditis. A 28-year-old athlete got admitted with fever, congestive heart failure and multi-organ dysfunction syndrome. The echocardiogram showed large aneurysm of the posterior mitral leaflet with severe mitral regurgitation. Patient succumbed to refractory heart failure. PMID- 22929826 TI - Brugada pattern masquerading as ST-segment elevation myocardial infarction in flecainide toxicity. AB - Flecainide (a class 1c antiarrhythmic) produces a dose-dependent decrease in intracardiac conduction. Its well known common electrocardiographic effects are prolongation of PR and QT intervals and the QRS complex duration. We report a case of flecainide toxicity in an elderly female who presented with a type 1 Brugada pattern who essentially had a previously normal ECG pattern on therapeutic dose of flecainide therapy. The case describes a rare electrocardiographic abnormality induced by flecainide toxicity which otherwise could be easily misinterpreted as a ST-segment elevation myocardial infarction (STEMI) without lack of expertise and high clinical suspicion. PMID- 22929827 TI - Late survival in Ellis-van Creveld syndrome - a case report. AB - Ellis-van Creveld syndrome (EVC) is an autosomal recessive disorder characterized by chondrodystrophy, polydactyly, ectodermal dysplasia, and cardiac anomalies. Acromelic shortening of upper and lower limbs, genu valgum, multiple frenula, deformed teeth, short ribs and narrow thorax and congenital heart diseases complete the picture. The patients with the syndrome rarely survive into adulthood. Here, we report a lady with EVC presenting for the first time in middle age. PMID- 22929830 TI - Left atrial spindle cell sarcoma - case report. AB - Primary spindle cell sarcoma of the left atrium is an extremely rare tumour. Surgical excision is the mainstay of treatment since it responds poorly to chemotherapy or radiotherapy. In spite of all the treatment, the prognosis remains poor due to inadvertent delay in diagnosis, few therapeutic options and propensity to metastasize. We present a 47-year-old male who underwent a surgical excision of a left atrial mass in February 2010. It was proved to be a high-grade spindle cell sarcoma on histopathology. He presented again in October 2010 with recurrence of the tumour for which he was re-operated. However, the tumour recurred again within one month, to which the patient succumbed. PMID- 22929828 TI - Tetralogy of Fallot with restrictive ventricular septal defect by accessory tricuspid leaflet tissue. AB - In tetralogy of Fallot septal defect is usually large because of malalignment of outlet septum, restrictive defect has been reported rarely. We present a case of tetralogy of Fallot with accessory tricuspid leaflet tissue restricting ventricular septal defect. The report includes echocardiographic and catheter images of this rare presentation of tetralogy of Fallot. PMID- 22929831 TI - "Add-on pacing lead": an effective and safe alternative to lead replacement in ICD pacing failure. AB - Despite recent advances in implantable cardioverter defibrillator (ICD) technology, the long-term reliability of ICD leads remains a significant problem. Lead failures constitute a major risk for patients with an implantable cardioverter defibrillator. There is no clear consensus on treatment strategy of ICD lead failure and decision should be individualized. We report a pacing dependent elderly male with ICD lead pacing failure secondary to insulation break resulting in recurrent syncope. We emphasize the technique of "Add-on pacing lead implantation" could be an effective and alternative to ICD lead replacement. PMID- 22929832 TI - Different transcatheter strategies for aortic coarctation associated with patent ductus arteriosus. AB - BACKGROUND: Older patients with combination of aortic coarctation and large patent ductus arteriosus can be managed with transcatheter interventions. The strategies depend on anatomy of coarctation and size of ductus arteriosus. METHODS: We present three different patients with this combination. The anatomic factors like isthmic hypoplasia, dilatation of post coarctation descending aorta and size of ductus arteriosus were noted. RESULTS: Patients with isthmic hypoplasia needed stent angioplasty of the coarctation. If there is no dilatation of post coarctation aorta, a single covered stent excluded the ductus arteriosus and relieved the coarctation gradients. Dilated post coarctation aorta precluded a covered stent and warranted closure of duct with occluder device and stent angioplasty of coarctation. When there is a good sized aortic isthmus in a discrete membranous coarctation, device closure of the duct and balloon aortoplasty was successful. CONCLUSIONS: In coarctation with patent ductus arteriosus associated with good sized aortic isthmus, closure of duct with duct occluder device and balloon aortoplasty would correct the lesions. If there is isthmic hypoplasia, device closure of the duct and stenting of the coarctation is needed. Covered stent is a reasonable alternative only in presence of non dilated descending aorta. PMID- 22929833 TI - Wide-complex tachycardia: what is the diagnosis? PMID- 22929834 TI - Angiographic and echocardiographic imaging of secondaries in pericardium. PMID- 22929836 TI - Detection of nitric oxide and superoxide radical anion by electron paramagnetic resonance spectroscopy from cells using spin traps. AB - Reactive nitrogen/oxygen species (ROS/RNS) at low concentrations play an important role in regulating cell function, signaling, and immune response but in unregulated concentrations are detrimental to cell viability. While living systems have evolved with endogenous and dietary antioxidant defense mechanisms to regulate ROS generation, ROS are produced continuously as natural by-products of normal metabolism of oxygen and can cause oxidative damage to biomolecules resulting in loss of protein function, DNA cleavage, or lipid peroxidation, and ultimately to oxidative stress leading to cell injury or death. Superoxide radical anion (O2*-) is the major precursor of some of the most highly oxidizing species known to exist in biological systems such as peroxynitrite and hydroxyl radical. The generation of O2*- signals the first sign of oxidative burst, and therefore, its detection and/or sequestration in biological systems is important. In this demonstration, O2*- was generated from polymorphonuclear neutrophils (PMNs). Through chemotactic stimulation with phorbol-12-myristate-13-acetate (PMA), PMN generates O2*- via activation of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. Nitric oxide (NO) synthase which comes in three isoforms, as inducible-, neuronal- and endothelial-NOS, or iNOS, nNOS or eNOS, respectively, catalyzes the conversion of L- arginine to L-citrulline, using NADPH to produce NO. Here, we generated NO from endothelial cells. Under oxidative stress conditions, eNOS for example can switch from producing NO to O2* in a process called uncoupling, which is believed to be caused by oxidation of heme or the co-factor, tetrahydrobiopterin (BH4). There are only few reliable methods for the detection of free radicals in biological systems but are limited by specificity and sensitivity. Spin trapping is commonly used for the identification of free radicals and involves the addition reaction of a radical to a spin trap forming a persistent spin adduct which can be detected by electron paramagnetic resonance (EPR) spectroscopy. The various radical adducts exhibit distinctive spectrum which can be used to identify the radicals being generated and can provide a wealth of information about the nature and kinetics of radical production. The cyclic nitrones, 5,5-dimethyl-pyrroline-N-oxide, DMPO, the phosphoryl-substituted DEPMPO, and the ester-substituted, EMPO and BMPO, have been widely employed as spin traps--the latter spin traps exhibiting longer half lives for O2*- adduct. Iron (II)-N-methyl-D-glucamine dithiocarbamate, Fe(MGD)2 is commonly used to trap NO due to high rate of adduct formation and the high stability of the spin adduct. PMID- 22929837 TI - State of maternal, newborn and child health programmes in Nepal: what may a continuum of care model mean for more effective and efficient service delivery? AB - The cost-effective interventions exist across the continuum of maternal to child survival at each level of the health system that can contribute to achieve the Millennium Development Goals 4 and 5. However, implementation inefficiency, low coverage and equity gaps along this continuum remain a serious challenge to Nepal's efforts to achieve these goals. This paper proposes a continuum of care model; discusses the readiness of policy and programs to provide high impact interventions across the continuum; identifies existing gaps in MNCHN programs; and recommends policy and program actions to improve coverage, equity, effectiveness and efficiency along the continuum of MNCHN service delivery in Nepal. The literature review includes systematic desk review, followed by discussions and deliberations amongst a group of professionals and MNCH experts in Nepal. Within the government health system in Nepal, a continuum of care approach is feasible, as policies and plans exist to ensure an integrated approach across the maternal to child care continuum. However, health programs largely remain vertically oriented. Achieving integration across the maternal to child continuum of care remains a challenge at each level of health system. An integrated system of program management for maternal, newborn and child health would be a feasible solution to enable an efficient and effective delivery of intervention packages. A collaborative and partnership approach to strengthen health systems, building managerial capacity, improving governance and engaging the private and civil sectors remains vital to achieve effective coverage and improve equity across the continuum of care. PMID- 22929839 TI - Developing community-based intervention strategies and package to save newborns in Nepal. AB - In Nepal, the proportion of under 5 deaths that are neonatal (0-28 days) has been increasing in the last decade, due to faster declines in infant and child mortality than in neonatal mortality. This trend is likely due to a focus on maternal and child survival programs that did not adequately address newborn health needs. Policy and actions to save newborn lives resulted from increased attention to newborn deaths in 2001, culminating in the endorsement of the National Neonatal Health Strategy in 2004, a milestone that established newborn health and survival as a national priority. Operationalization of the National Neonatal Health Strategy took place in 2007 with the development of the Community Based Newborn Care Package (CB-NCP). This paper describes how national stakeholders used global, regional and in-country research and policies to develop the CB-NCP, thus outlining key ingredients to make newborn health programming a reality in Nepal. A technical working group was constituted to review existing evidence on interventions to improve newborn survival, develop a tool to prioritize neonatal interventions, and conduct program learning visits to identify key components appropriate to the Nepal context that should be included in the Community Based Integrated Newborn Care Package. The group identified interventions based on the evidence of impact on newborn survival, potential mechanisms within the existing health system to deliver the interventions, and linkages with existing programs and different tiers of the health system. Not only was Nepal one of the first countries in south-east Asia where government adopted a national strategy to reduce neonatal deaths, but it was also one of the first to endorse a package of neonatal interventions for pilot testing and scaling up through existing community-based health systems that provide basic health services throughout the country. CB-NCP was designed to be gradually scaled up throughout the country by integration with Safe Motherhood and Child survival programs that are currently operating at scale. Under Ministry of health and Population leadership, a network of academia, professional bodies and partners developed a common vision for improving newborn health and survival, and launched district-level pilot programs to demonstrate and learn how newborn health interventions could be effectively and efficiently delivered and scaled up in Nepal. PMID- 22929838 TI - Community participation and mobilization in community-based maternal, newborn and child health programmes in Nepal. AB - A number of studies on community mobilization for maternal and newborn health have demonstrated that community participation is of profound importance in the delivery of community based survival interventions for mother, newborn and children and a cost effective way to reduce mortality. However, the lessons learnt from the efficacy trials have not been tested within the health systems. Nepal is well known for its public health programmes and wide successes in campaign based interventions as a result of active involvement of volunteers and organizations based in the community. This paper analyzes the degree of community participation and mobilization in community-based maternal, newborn and child health programmes and its potential implication in acceleration towards achieving Millennium Development Goals 4 and 5. The study is based on analysis of the existing national community based maternal, neonatal and child health programmes in terms of degree of community mobilization and participation for ownership and sustainability of programmes. Furthermore, a qualitative assessment was carried out to assess the level of engagement of community structures in community based maternal, newborn and child health programme. None of the national community based maternal, newborn and child health programmes used the community action cycle approach and there was minimal level of involvement of community networks. The mother's groups had been least engaged in identifying and solving the maternal, newborn and child health problems and Female community health volunteer were engaged in delivering messages at household level and not through the mother's groups. Though the Community Action Cycle was studied in Nepal and it was found effective to achieve the objectives, getting its lessons into practice to design community health programs were lacking. The mother's groups need to be revitalized to ensure their active participation in identifying, analyzing and agreeing on steps to solve the problems related to maternal, neonatal and child health so that care seeking and utilization of health services will be further enhanced. The national strategies need to explore the possibilities of incorporating the community action cycle frame into its programmes, test the frame and ensure its implementation in the National community based programs in order to improve health outcomes of mother, newborn and children. PMID- 22929840 TI - Fitting Community Based Newborn Care Package into the health systems of Nepal. AB - Community-based strategies for delivering effective newborn interventions are an essential step to avert newborn death, in settings where the health facilities are unable to effectively deliver the interventions and reach their population. Effective implementation of community-based interventions as a large scale program and within the existing health system depends on the appropriate design and planning, monitoring and support systems. This article provides an overview of implementation design of Community-Based Newborn Care Package (CB-NCP) program, its setup within the health system, and early results of the implementation from one of the pilot districts. The evaluation of CB-NCP in one of the pilot districts shows significant improvement in antenatal, intrapartum and post natal care. The implementation design of the CB-NCP has six different health system management functions: i) district planning and orientation, ii) training/human resource development, iii) monitoring and evaluation, iv) logistics and supply chain management, v) communication strategy, and vi) pay for performance. The CB-NCP program embraced the existing system of monitoring with some additional components for the pilot phase to test implementation feasibility, and aligns with existing safe motherhood and child health programs. Though CB-NCP interventions are proven independently in different local and global contexts, they are piloted in 10 districts as a "package" within the national health system settings of Nepal. PMID- 22929841 TI - Effectiveness and efficiency of Aama Surakshya Karyakram in terms of barriers in accessing maternal health services in Nepal. AB - BACKGROUND: The Family Health Division along with the MoHP developed a policy that recommended provision of incentives to all delivering mother by removing the parity condition and termed Safe Delivery Incentive Programme (SDIP) to make it more appropriate. The SDIP was branded as AamaSurakshyaKaryakram (ASK). The main objective of the study was to find out the effectiveness and efficiency of AamaSurakshyaKaryakram to address barrier in accessing maternal health services in Nepal. METHODS: An exploratory and cross sectional descriptive study was conducted by quantitative and qualitative tools and techniques. To provide comprehensive coverage, five districts have been selected representing four development (eastern, central, western and far-western) and three (mountain, hill and flat) ecological region were selected. RESULTS: Out of 47 exit client interviews conducted in this study, 51 percent were done in Sunsari, followed by Sarlahi (17%), Dadeldhura (17%), and Arghakhanchi (15%). Most of these mothers (94%) delivered their children in the hospitals, and rest (6%) in PHCCs. Sixty percent mothers were in the age group of 20-25 years, while 45 percent were from Tarai/Madhesi group followed by Brahmins/Chhetries group (34%). Total 70% mothers were found to be literate. 55% mothers were found to be visiting health facilities during labour pain. 2% mothers were visiting heath facilities before labour pain started. Rest mothers were visiting health facilities after one or two days of labour pain. Total 70% mothers were able to reach the health facility within 60 minutes, while 13 percent mothers were able to reach the facility more than 3 hours, and 17% were in between. All mothers who visited PHCCs were able to reach the facility within 60 minutes while analyzing health facility-wise. CONCLUSIONS: Mothers delivered at home as they were not well prepared to go to health facility. Lack of transportation facility hindered for institutional delivery. None of them figured out that there was a provision of transport incentive; they only knew that there was a cash payment, but they didn't know exactly for what specific purpose mothers were receiving such payments. Ask found to be effective and efficient in order to address barriers occurring inside the health facility and financial barrier except geo-graphical barrier in accessing maternal health services in Nepal. PMID- 22929842 TI - Assessment of medical and health institutions registered as research centres in Nepal. AB - BACKGROUND: There were several reports in the various mass media regarding misuse of the word "research" by various organization and it has been argued that putting the word "Research" in any agency's name made easier to get the various medical from abroad without paying or paying minimum or discounted government tax than others. The objectives of the study was to find out the status Medical and Health institutions designated as Research Centres in Nepal. METHODS: A cross sectional prospective study was carried in medical and health institutions of Nepal. Data regarding the registration of institutions/organizations having the word "research" in its name were collected from concerned registered organizations. Formative evaluation method was adopted in which information were added continuously, organized systematically and analysed periodically during the evaluation period. RESULTS: There were altogether 370 health related research centers registered in MoI and CDO at the district level till 31 December 2010. These research centers were located in 33 districts of Nepal. Among these there were 65 (82%) health facilities and 305 (18%) NGOs designated as research centers. The region wise the range of number of research centers among five regions was 4 to 283. The highest number of research centers level. The highest number of research centers was found in Kathmandu district. Out of 370 research centers, 85 research centers (72 from among health facility related research centers and 13 from among NGO related research centers) were selected randomly for evaluation purpose, which represented 23 percent of sample selection. The sample selection was not less than 20 percent in each category of research centers. One fifth research centers were found to conduct health related research progam. Among which majority (more than 50%) of NGO related research centers was found to conduct health research. There were few (14%) health facility related research centers that actually conducted health related research program. The study also shows that majority 73 (86%) of the research centers didn't start the research yet. CONCLUSIONS: Forty percent of the research centers in Nepal didn't know the actual reason for putting the word "research" into their signboard. A regulation has to be made to safeguard and maintain the integrity of research in Nepal. PMID- 22929843 TI - Nerve stimulation under ultrasound guidance expedites onset of axillary brachial plexus block. AB - BACKGROUND: Axillary block is popular technique in upper extremity surgery. Nerve stimulation is used for location of nerves to provide effective blockade. The advent of ultrasound imaging technique in regional anaesthesia has increased the accuracy of needle placement and local anaesthetic deposition around the nerve. The aim of this study is to find out if the nerve stimulation technique with ultrasound guidance has advantages over sole nerve stimulation technique. The outcome measures studied were onset of sensory and motor block, procedure time, number of skin puncture, vascular puncture and paresthesia during nerve stimulation. METHODS: This is a prospective randomized comparative study conducted in KMCTH from June 2009 to March 2010 on patients of American Society of Anaesthesiologist I and II requiring upper arm surgery under axillary block. The study comprised of two groups: ultrasound with nerve stimulation group (n=35) and nerve stimulation group (n=35). 24 ml of Bupivacaine 0.5% with injection Dexamethasone 4 mg was used to block the individual four nerves with 6 ml of the local anaesthetic solution per nerve namely ulnar, radial, median and musculocutaneous. The data were recorded by blinded observer. In case of partial block or block failure, the patients were supplemented with Fentanyl or subjected to laryngeal mask placement. RESULTS: Demographic characteristics (age, weight) in either group were similar (p>0.05). The male and female ratio (M: F) in ultrasound with nerve stimulation group was 12:16. The ratio was 18:17 in nerve stimulation group. The onset of complete sensory block was earlier and the onset of motor block was faster in ultrasound with nerve stimulation group than in sole nerve stimulation group (p=0.001). Ultrasound guidance decreased the number of skin puncture during the nerve stimulation, p= 0.02. The incidence of paresthesia was encountered during nerve location (14%), which could be minimized using ultrasound (7%). The success rate of the block was 93% with ultrasound assistance. The procedure time was not different in both techniques. The surgery duration was not significant statistically in either of the group, p=0.715. CONCLUSIONS: This study showed that the onset of sensory and motor block was faster with ultrasound assistance nerve stimulation. Complications can be decreased with the use of ultrasound in axillary block. PMID- 22929844 TI - Analysis of perinatal deaths and ascertaining perinatal mortality trend in a hospital. AB - BACKGROUND: Perinatal mortality rate is very high in developing countries including Nepal. Analyzing perinatal deaths help in identifying preventable factors thus help in reducing it. Analysis of causes of perinatal deaths over a period in a hospital will help to identify the perinatal mortality trend and preventable factors thus help in taking corrective measures to reduce the perinatal mortality rate. The aim of the study is to analyse perinatal deaths and ascertain perinatal mortality trend of Kathmandu Medical College Teaching hospital in the last 8 year period. METHODS: Stillbirths and early neonatal deaths from 2002 to 2011 are collected from the register book of the labour room, special care baby unit and operation theatre of the hospital. Perinatal mortality rate and extended perinatal mortality rates are calculated and perinatal deaths were classified according to Wigglesworth's classification. Trend of Perinatal and Extended Perinatal mortality rates, stillbirth rates and early neonatal death rates among 5 perinatal death audits of the hospital were compared. RESULTS: In the first perinatal death audit (Oct '02-Sept '03) perinatal mortality rate (PMR) was recorded as 30.7 per 1000 births and extended perinatal mortality rate (EPMR) as 47.9 per 1000 births, where as in the fifth perinatal death audit (Apr '10-Mar '11) PMR was recorded as 14.4 per 1000 births and EPMR as 19.6 per 1000 births. In Wigglesworth's classification, in the first perinatal death audit, most of the perinatal deaths were in group IV (41%) reflecting more asphyxial deaths however in fifth audit, group III mortality (41%) was highest indicating death of low birth weight or preterm babies. In the first audit, stillbirth rate (SBR) excluding <1 kg was 18.1 per 1000 births and early neonatal deaths (ENND) excluding <1 kg was 12.9 per 1000 live births. In the fifth audit, SBR (excluding <1 kg) and ENND rate (excluding <1 kg) were 7.1 per 1000 births and 7.2 per 1000 live births respectively reflecting declining trend of both SBR and ENND rate in the hospital. CONCLUSIONS: Distinct declining trend in PMR, EPMR, SBR and ENND rates at KMCTH were noted. As asphyxial deaths have been reduced significantly, more intensive efforts are needed to prevent premature births with care of preterm and very low birth weight babies. PMID- 22929846 TI - Risk factors associated with low birth weight. AB - BACKGROUND: Babies with a birth weight of less than 2500 grams, irrespective of the period of their gestation are termed as Low Birth Weight (LBW) babies. Despite consistent efforts to improve the quality of maternal and child health, more than twenty million low birth-weight (LBW) babies are born every year throughout the world. Though, the health situation of Nepal has improved substantially over the years, the low birth-weight (LBW) rate still high. The present study was to explore the effects of various maternal risk factors associated with low birth-weight of institutionally delivered newborns. METHODS: A cross sectional hospital based study was conducted in Obstetrics and Gynaecology ward of Janakpur Zonal Hospital, Janakpur, Nepal from December 2009 to January 2010. Altogether 306 respondents were taken and respondents were mothers who have delivered newborns in hospital. RESULTS: A total of 1426 birth occurred during the study period (December 2009 to January 2010), of which 306 met the study criteria. Among which 66 (21.56%) were low birth weight (LBW) and 240 were normal birth weight (NBW). Overall mean birth weight was found to be 2.75 +/- 0.639 kg. Out of total 21.56% newborns were weighing less than 2.50 kg and mean birth weight was 1.96 +/- 0.409 kg. The study also shows that majority 73 (86%) of the research centers didn't start the research yet. CONCLUSIONS: This study suggests that there are several factors interplaying which lead to LBW babies. Socio-demographic factors (maternal age, educational level and economic status) and antenatal care are more important. PMID- 22929845 TI - Factors affecting retention of child health card in a rural area. AB - BACKGROUND: The child health card is a tool used by Health Management Information System in Nepal. It contains records on immunization, vitamin A and a weight-for age growth chart. The objective of this study was to identify the magnitude of and the factors affecting retention of child health card. METHODS: A cross sectional descriptive design using quantitative methodology was applied. Divyapuri VDC was selected purposively and simple random sampling was applied to obtain a sample of 282 households with children between one to 36 months. Information was collected by interview with mothers of one to 36 months children and by observation of child health cards. Descriptive analysis was performed to assess the magnitude of retention of child health card. Then, bivariate analysis was performed; odds ratio and corresponding 95% confidence interval were used to test the significance of association. Logistic regression model was used for control of confounding. RESULTS: Only 41% of the mothers produced child health card at the time of survey. For about 7% respondents, child health card was not issued and only 45% of the respondents who were issued child health card have retained it. Younger age group of the child, mothers living nearer to health facility, mothers with knowledge on use of child health card for recording immunization and recording growth monitoring; and mothers who were explained child health card by health worker were found significantly higher odds of retaining it. CONCLUSIONS: The retention of child health card was low in the study area. Health workers should be trained to educate mothers on retention and use of child health cards. PMID- 22929847 TI - Lower urinary tract infection and bacterial colonization in patient with double J ureteral stent. AB - BACKGROUND: The aim of this study is to investigate the bacteriology of urinary tract infection associated with indwelling DJ stent. METHODS: A total of 60 patients were included and 14 lost during follow up. Study period was for 6 months carried out in the department of surgery, Kathmandu Medical College. Prophylactic antibiotic was given at the time of intervention. Mid stream urine samples for routine and culture were sent before intervention. Urine samples during DJ removal and DJ tip cultures were also sent. All patients were "stented" during the various open and endourolgical procedures. Patients were clinically followed for a period till the DJ was removed. Statistical Package for Scientific Study (SPSS) 11, Chi square Test was used for statistical analysis. RESULTS: A total of 46 cases were included. Mean age in years was 35.70 (10-78 years). Male were 22 and female 24. Eleven patients (23.91%) had stent placed less than 30 days and 35 patients (76.08%) had it for equal or more than 30 days. DJ indwelling time was in between 12-86 days. Bacterial colonies were found in 28.3% (13 of 46) of the urine samples and 30.4% (14 of 46) from the tip of the DJ stent segment. Of the pathogens identified, E. coli was found to be the most common. An increased stent colonization rate was associated with implantation time, female sex. On urine culture 70.21% had no growth, 14.89% E. coli, 4.25% Klebsiella, Actinobacter, 2.12% E. coli/kleb, multiple org, psuedomonas. Ten patients (21.7%) had positive urine culture before stent insertion. Thirteen patients (28.3%) were shown to have positive urine culture on stent removal. Fourteen patients (30.4%) had positive DJ stent culture. CONCLUSIONS: Positive urine culture and positive DJ tip cultures had strong correlation. Longer duration of placement of stent showed stent colonization. The commonest pathogen was E. coli. PMID- 22929848 TI - Clinicopathological profile of patients with abdominal tuberculosis. AB - BACKGROUND: Tuberculosis (TB) is not a uncommon problem throughout the world particularly in the developing countries like Nepal, India and Bangladesh. Abdominal Tuberculosis accounts for nearly 2% of tuberculosis worldwide. The aim of this study was to evaluate the clinicopathological profile with the help of other investigations in the diagnosis of patients with abdominal TB and their response to anti-tubercular therapy. This was a prospective cross-sectional study conducted in the department of Gastroenterology, Bangabandhu Sheikh Mujib Medical University (BSMMU), Dhaka during the period of October 2002 to June 2009. METHODS: Total 53 patients with abdominal TB diagnosed on the basis of clinical profile and supported investigation data like gross morphological findings at endoscopy, colonoscopy, diagnostic laparoscopy , laparotomy or histologically proven caseating granulomas were selected for this study. Detailed demographic, clinical profile, investigations and treatment response were recorded properly in a predesigned data collection sheet which were analyzed and compared with other studies. RESULTS: Out of the 53 patients, 33 were males and 20 females with age ranging 16-70 (Mean 30.01+/-11.7) years. Abdominal pain was the most common presenting symptom in 47 (88.68%), fever in 45 (84.9%) and weight loss in 37 (69.81%) cases. Anemia was found in 41 (77.36%), cachexia 40 (75.47%), ascites 20 (37.74%), palpable abdominal mass in 14 (26.42%) and features of intestinal obstruction in 5 (9.43%) cases. Five patients had positive family history of TB and five had past history of pulmonary TB. The diagnosis of abdominal TB was confirmed microscopically in 5 (9.43%), histopathologically in 31 (58.49%) and the remaining 17 (32.07%) cases were diagnosed by a positive response to anti-TB therapy. According to site of involvement, 31 (58.51%), patients had intestinal TB, 9 (16.98%) had peritoneal TB and disseminated TB in 20 (37.74%) of the case. Twenty seven patients were given 3 drugs regimen for 12 months and 26 patients received 4 drugs regimen for 9 months under close supervision. By 9 months of therapy 51 patients become symptom free and no pathological findings were observed thereafter at follow up visits after 6 months. Response was not satisfactory in two patients and subsequent follow up investigation revealed to have crohn's disease rather than TB and none of them died. CONCLUSIONS: Abdominal TB is an important clinical entity having varied mode of clinical presentation. So the diagnosis of abdominal TB is difficult and careful approach to the patients and supportive investigation data are necessary to make the final diagnosis. Neither clinical features, laboratory, radiological and Endoscopic methods nor bacteriological and histopathological findings by themselves provide a gold standard in the diagnosis of abdominal TB. In this series of abdominal TB, intestinal TB was the most frequent clinical type and the common presenting symptoms were abdominal pain, fever and weight loss. If diagnosed early, it can be treated successfully with anti-TB drugs. PMID- 22929849 TI - Perceived risk of cigarette smoking among college students. AB - BACKGROUND: Many studies have indicated that the young adults (18-24 years) were not fully aware of health consequences of cigarette smoking. The objective of the study is to determine the prevalence of cigarette smoking among college students and to assess how they perceive the risks of cigarette smoking. METHODS: A cross sectional study was carried out in Kathmandu valley during mid February and March 2011. This study comprises 340 students from seven private public health colleges of Kathmandu valley. The anonymous question contains information on demographic characteristics, smoking habits, and smoking related risk perception. Data was analyzed by both descriptive and inferential statistics including logistic regression with the help of Microsoft Excel 2007 and SPSS 11.5 version. RESULTS: Overall prevalence rate of ever smokers was 33% and about 16% were current smokers. Non-smokers were about 3 times more likely than smokers to report that smoking one to five cigarettes per day was harmful (aOR = 2.60; 95% CI: 1.34 5.05). Similarly, Non Smokers were 2 times more likely to belief the statement that people get addicted to tobacco as to cocaine or heroin (aOR = 2.27; 95%CI: 1.33-4.57). Nearly one fifth of smokers and non-smokers believed that smoking on a weekend or a couple of days a week was harmful, and there was no significant difference between two groups (P>0.05). CONCLUSIONS: The study reveals the smoker students were less aware of risks of cigarette smoking and its health consequences. Thus there is a need to promote effective anti-smoking messages focusing effects of each cigarette they smoke. PMID- 22929850 TI - Molecular screening of major bacterial enteropathogens in human stool samples from diarrhoeal outbreak sites. AB - BACKGROUND: V. cholera types have been implicated often in a number of occasions in diarrhoeal outbreaks in Nepal. The recent outbreak in Far Western Nepal, 2009, was also attributed primarily to V. cholera. Molecular tools were used for the first time on some of the samples from the outbreak to screen for major pathogens present in those samples. METHODS: A commercial multiplex PCR kit based bacterial enteropathogen screening assessment was carried out on 33 human stool samples from areas of a diarrhoeal outbreak in Nepal. A total of 10 pathogenic bacterial strains at the genus level were targeted using primers provided by the manufacturer. RESULTS: Bacterial pathogens were detected in 23 samples (69.7%). Vibrio species was detected at an overall frequency of 36.4% followed by Aeromonas spp (33.3%) and Shigella spp (15.2%) along with Verocytotoxin producing E. coli (VTEC) family (15.2%). The frequency of singly occurring pathogen in all samples was 18.2% with most of the bacterial pathogens detected in combination with other pathogens at a frequency of 60.6%. The study also shows that majority 73 (86%) of the research centers didn't start the research yet. CONCLUSIONS: This first ever molecular screening study shows that bacterial screening is indeed possible in diarrhoeal samples. The results obtained from this study will enable monitoring of future such outbreaks using similar techniques. PMID- 22929851 TI - Postoperative complications of septal quilting and BIPP packing following septoplasty. AB - BACKGROUND: Septoplasty is one of the most common surgeries in otorhinolaryngology. After septal surgery nasal packing is usually done to prevent complications like haemorrhage, septal haematoma. However it is associated with many postoperative complications such as pain, hypoxia, dryness in throat, headache, epiphora, vestibular stenosis, crusting, synaechiae, secondary infection etc. In order to prevent these complications quilting has been developed. No study has been done in our country to compare the postoperative complications after septoplasty. METHODS: This study was carried out to compare postoperative crusting, oedema, synaechia and infection in patients who underwent septal quilting and BIPP packing following septoplasty from August 2008 to July 2011 in the Department of ENT-Head and Neck Surgery, Tribhuvan University Teaching Hospital, Maharajgunj, Kathmandu, Nepal. RESULTS: There were 44 patients in quilting and 41 patients in BIPP packing group. Out of 44 patients of quilting group, crusting occurred in 3 patients, oedema in 4 patients, synechia in 1 patient and infection in 3 patients. Out of 41 patients of BIPP packing group, 9 patients had crusting, oedema was present in 7 patients, 6 patients had synaechia and 5 patients had infection. Crusting and synaechia was found to be statistically significant while oedema and infection was not significant between two groups. CONCLUSIONS: Complications like excessive crusting, oedema, synaechia and infection can be minimized by quilting suture following septoplasty. PMID- 22929852 TI - Altemeier rectosigmoidectomy for strangulated rectal prolapse. AB - A 70 year old gentleman presented in the emergency department of Tribhuvan University Teaching Hospital, Kathmandu, Nepal with strangulated complete rectal prolapse. After complete evaluation and necessary investigations, patient underwent Altemeier perineal rectosigmoidectomy and had an uneventful recovery. This case report tries to highlight the importance of Altemeier procedure as the only option for managing rectal prolapse when patients present with incarceration or strangulation of the prolapsed rectum with very good outcome. PMID- 22929853 TI - Late presentations of congenital diaphragmatic hernia. AB - The occurrence of congenital diaphragmatic hernia in adults is rare and misleading even to experienced clinicians. In contrast to neonatal diaphragmatic hernias, most of the adult patients present with vague gastrointestinal and respiratory symptoms mimicking other diseases. Hence high index of suspicion is required. When a diagnosis is established, it must be promptly treated surgically in order to avoid complications such as strangulation or bowel perforation. We present two cases of diaphragmatic hernia which were being managed as pulmonary pathologies. PMID- 22929854 TI - Health system through the eyes of a doctor from rural Nepal. AB - Its almost 30 years of declaration of Alma-Ata for primary healthcare policy the health system in Nepal still facing shortage of trained medical doctors and health professionals reaching remote and rural part of the country to provide quality health services. There are number of issues such as financial or non financial incentives, professional advancements, educational opportunities and workplace environment. Healthcare delivery system in Nepal is failing to meet the healthcare need of the general public and needs discussion and revision. However, despite of so many challenges more doctors are willing to work in the remote and rural Nepal. The government has to come out with effective planning and policy regarding health system and human resource for health. In this context, an attempt has been made for a analytical perspective from a medical doctor point of view to highlight some of the pertinent local and policy related issues to improve Health System in Nepal. PMID- 22929855 TI - Medical practice in the peripheral health centers in Nepal. AB - The Ministry of Health and Population has implemented a compulsory two year service contract in government health facilities for all the scholarship holders of the Ministry of Education. Doctors are now being deployed to all hospitals and primary health centers of the country. Prior to 2005 it was very difficult to send doctors to the peripheral part, and now they wish to go more remote area due to the privilege given to the National Academy of Medical Sciences Post Graduate Entrance Examination, which help them get MD/MS seat. However, there are more challenges due to weak health system and failure to implement established rule and regulation. This paper highlights the outcry of a doctor working in the remote part of the country. PMID- 22929856 TI - Imaging biomarker dynamics in an intracranial murine glioma study of radiation and antiangiogenic therapy. AB - PURPOSE: There is a growing need for noninvasive biomarkers to guide individualized spatiotemporal delivery of radiation therapy (RT) and antiangiogenic (AA) therapy for brain tumors. This study explored early biomarkers of response to RT and the AA agent sunitinib (SU), in a murine intracranial glioma model, using serial magnetic resonance imaging (MRI). METHODS AND MATERIALS: Mice with MRI-visible tumors were stratified by tumor size into 4 therapy arms: control, RT, SU, and SU plus RT (SURT). Single-fraction conformal RT was delivered using MRI and on-line cone beam computed tomography (CT) guidance. Serial MR images (T2-weighted, diffusion, dynamic contrast-enhanced and gadolinium-enhanced T1-weighted scans) were acquired biweekly to evaluate tumor volume, apparent diffusion coefficient (ADC), and tumor perfusion and permeability responses (K(trans), K(ep)). RESULTS: Mice in all treatment arms survived longer than those in control, with a median survival of 35 days for SURT (P<.0001) and 30 days for RT (P=.009) and SU (P=.01) mice vs 26 days for control mice. At Day 3, ADC rise was greater with RT than without (P=.002). Sunitinib treatment reduced tumor perfusion/permeability values with mean K(trans) reduction of 27.6% for SU (P=.04) and 26.3% for SURT (P=.04) mice and mean K(ep) reduction of 38.1% for SU (P=.01) and 27.3% for SURT (P=.02) mice. The magnitude of individual mouse ADC responses at Days 3 and 7 correlated with subsequent tumor growth rate R values of -0.878 (P=.002) and -0.80 (P=.01), respectively. CONCLUSIONS: Early quantitative changes in diffusion and perfusion MRI measures reflect treatment responses soon after starting therapy and thereby raise the potential for these imaging biomarkers to guide adaptive and potentially individualized therapy approaches in the future. PMID- 22929857 TI - CXC receptor 1 and 2 and neutrophil elastase inhibitors alter radiation-induced lung disease in the mouse. AB - PURPOSE: We previously reported increased numbers of neutrophils to be associated with the development of the radiation-induced lung responses of alveolitis (pneumonitis) and fibrosis in mice. In the present study we investigated whether CXC receptor 1 and 2 antagonism with DF2156A, a small molecule inhibitor of neutrophil chemotaxis, or the neutrophil elastase inhibitor sivelestat decreases the lung response to irradiation. METHODS AND MATERIALS: KK/HIJ mice received 14 Gy whole-thorax irradiation, and a subset of them received drug treatment 3 times per week from the day of irradiation until they were killed because of respiratory distress symptoms. RESULTS: Irradiated mice receiving sivelestat survived 18% longer than did mice receiving radiation alone (73 vs 60 days for female mice, 91 vs 79 days for male mice), whereas postirradiation survival times did not differ between the group of mice receiving DF2156A and the radiation-only group. The numbers of neutrophils in lung tissue and in bronchoalveolar lavage fluid did not differ among groups of irradiated mice, but they significantly exceeded the levels in unirradiated control mice. The extent of alveolitis, assessed histologically, did not differ between irradiated mice treated with either drug and those receiving radiation alone, when assessed at the end of the experiment, but it was significantly reduced, as were the neutrophil measures, in sivelestat-treated mice at the common kill time of 60 days after irradiation. Mice treated with radiation and DF2156A developed significantly less fibrosis than did mice receiving radiation alone, and this difference was associated with decreased expression of interleukin-13 in lung tissue. CONCLUSIONS: We conclude that neutrophil elastase inhibition affects alveolitis and prolongs survival, whereas CXCR1/2 antagonism reduces radiation-induced fibrotic lung disease in mice without affecting the onset of distress. PMID- 22929858 TI - Clinical and dosimetric predictors of radiation pneumonitis in a large series of patients treated with stereotactic body radiation therapy to the lung. AB - PURPOSE: To report clinical and dosimetric factors predictive of radiation pneumonitis (RP) in patients receiving lung stereotactic body radiation therapy (SBRT) from a series of 240 patients. METHODS AND MATERIALS: Of the 297 isocenters treating 263 patients, 240 patients (n=263 isocenters) had evaluable information regarding RP. Age, gender, current smoking status and pack-years, O2 use, Charlson Comorbidity Index, prior lung radiation therapy (yes/no), dose/fractionation, V5, V13, V20, Vprescription, mean lung dose, planning target volume (PTV), total lung volume, and PTV/lung volume ratio were recorded. RESULTS: Twenty-nine patients (11.0%) developed symptomatic pneumonitis (26 grade 2, 3 grade 3). The mean V20 was 6.5% (range, 0.4%-20.2%), and the average mean lung dose was 5.03 Gy (0.547-12.2 Gy). In univariable analysis female gender (P=.0257) and Charlson Comorbidity index (P=.0366) were significantly predictive of RP. Among dosimetric parameters, V5 (P=.0186), V13 (P=.0438), and Vprescription (where dose=60 Gy) (P=.0128) were significant. There was only a trend toward significance for V20 (P=.0610). Planning target volume/normal lung volume ratio was highly significant (P=.0024). In multivariable analysis the clinical factors of female gender, pack-years smoking, and larger gross internal tumor volume and PTV were predictive (P=.0094, .0312, .0364, and .052, respectively), but no dosimetric factors were significant. CONCLUSIONS: Rate of symptomatic RP was 11%. Our mean lung dose was <600 cGy in most cases and V20<10%. In univariable analysis, dosimetric factors were predictive, while tumor size (or tumor/lung volume ratio) played a role in multivariable and univariable and analysis, respectively. PMID- 22929860 TI - Long-term changes in pulmonary function after incidental lung irradiation for breast cancer: a prospective study with 7-year follow-up. AB - PURPOSE: To evaluate late pulmonary function changes after incidental pulmonary irradiation for breast cancer. METHODS AND MATERIALS: Forty-three consecutive female patients diagnosed with breast carcinoma and treated with postoperative radiation therapy (RT) at the same dose (50 Gy) and fractionation (2 Gy/fraction, 5 days/week) were enrolled. Pulmonary function tests (PFT) and ventilation/perfusion scans were performed before RT and 6, 12, 24, and 84 months afterward. RESULTS: Forty-one patients, mean age 55 years, were eligible for the analysis. No differences were found in the baseline PFT values for age, smoking status and previous chemotherapy; women undergoing mastectomy showed baseline spirometric PFT values lower than did women treated with conservative surgery. The mean pulmonary dose was 10.9 Gy, being higher in women who also received lymph node RT (15.8 vs 8.6, P<.01). Only 1 patient experienced symptomatic pneumonitis. All PFT values showed a reduction at 6 months. From then on, the forced vital capacity and forced expiratory volume in 1 second began their recovery until reaching, and even exceeding, their baseline values at 7 years. Diffusing capacity of the lungs for carbon monoxide and ventilation/perfusion scans continued to reduce for 24 months and then partially recovered their baseline values (-3.5%, -3.8%, and -5.5%, respectively). Only the percentage difference at 7 years in the ventilation scan correlated with the dosimetric parameters studied. Other variables, such as age, smoking status, previous chemotherapy, and concomitant tamoxifen showed no significant relation with changes in PFT (DeltaPFT) values at 7 years. CONCLUSIONS: The study of reproducible subclinical parameters, such as PFT values, shows how their figures decrease in the first 2 years but practically recover their baseline values in the long term. The extent of the reduction in PFT values was small, and there was no clear association with several dosimetric and clinical parameters. PMID- 22929859 TI - High-dose-rate interstitial brachytherapy as monotherapy for clinically localized prostate cancer: treatment evolution and mature results. AB - PURPOSE: To report the clinical outcome of high-dose-rate (HDR) interstitial (IRT) brachytherapy (BRT) as sole treatment (monotherapy) for clinically localized prostate cancer. METHODS AND MATERIALS: Between January 2002 and December 2009, 718 consecutive patients with clinically localized prostate cancer were treated with transrectal ultrasound (TRUS)-guided HDR monotherapy. Three treatment protocols were applied; 141 patients received 38.0 Gy using one implant in 4 fractions of 9.5 Gy with computed tomography-based treatment planning; 351 patients received 38.0 Gy in 4 fractions of 9.5 Gy, using 2 implants (2 weeks apart) and intraoperative TRUS real-time treatment planning; and 226 patients received 34.5 Gy, using 3 single-fraction implants of 11.5 Gy (3 weeks apart) and intraoperative TRUS real-time treatment planning. Biochemical failure was defined according to the Phoenix consensus, and toxicity was evaluated using Common Toxicity Criteria for Adverse Events version 3. RESULTS: The median follow-up time was 52.8 months. The 36-, 60-, and 96-month biochemical control and metastasis-free survival rates for the entire cohort were 97%, 94%, and 90% and 99%, 98%, and 97%, respectively. Toxicity was scored per event, with 5.4% acute grade 3 genitourinary and 0.2% acute grade 3 gastrointestinal toxicity. Late grade 3 genitourinary and gastrointestinal toxicities were 3.5% and 1.6%, respectively. Two patients developed grade 4 incontinence. No other instance of grade 4 or greater acute or late toxicity was reported. CONCLUSION: Our results confirm IRT-HDR-BRT is safe and effective as monotherapy for clinically localized prostate cancer. PMID- 22929861 TI - Individualized 3D reconstruction of normal tissue dose for patients with long term follow-up: a step toward understanding dose risk for late toxicity. AB - PURPOSE: Understanding the relationship between normal tissue dose and delayed radiation toxicity is an important component of developing more effective radiation therapy. Late outcome data are generally available only for patients who have undergone 2-dimensional (2D) treatment plans. The purpose of this study was to evaluate the accuracy of 3D normal tissue dosimetry derived from reconstructed 2D treatment plans in Hodgkin's lymphoma (HL) patients. METHODS AND MATERIALS: Three-dimensional lung, heart, and breast volumes were reconstructed from 2D planning radiographs for HL patients who received mediastinal radiation therapy. For each organ, a reference 3D organ was modified with patient-specific structural information, using deformable image processing software. Radiation therapy plans were reconstructed by applying treatment parameters obtained from patient records to the reconstructed 3D volumes. For each reconstructed organ mean dose (Dmean) and volumes covered by at least 5 Gy (V5) and 20 Gy (V20) were calculated. This process was performed for 15 patients who had both 2D and 3D planning data available to compare the reconstructed normal tissue doses with those derived from the primary CT planning data and also for 10 historically treated patients with only 2D imaging available. RESULTS: For patients with 3D planning data, the normal tissue doses could be reconstructed accurately using 2D planning data. Median differences in Dmean between reconstructed and actual plans were 0.18 Gy (lungs), -0.15 Gy (heart), and 0.30 Gy (breasts). Median difference in V5 and V20 were less than 2% for each organ. Reconstructed 3D dosimetry was substantially higher in historical mantle-field treatments than contemporary involved-field mediastinal treatments: average Dmean values were 15.2 Gy vs 10.6 Gy (lungs), 27.0 Gy vs 14.3 Gy (heart), and 8.0 Gy vs 3.2 Gy (breasts). CONCLUSIONS: Three-dimensional reconstruction of absorbed dose to organs at risk can be estimated accurately many years after exposure by using limited 2D data. Compared to contemporary involved-field treatments, normal tissue doses were significantly higher in historical mantle-field treatments. These methods build capacity to quantify the relationship between 3D normal tissue dose and observed late effects. PMID- 22929863 TI - Electrocatalytic oxidation of hydrogen peroxide on a platinum electrode in the imitation of oxidative drug metabolism of lidocaine. AB - Electrochemistry in combination with mass spectrometry has shown promise as a versatile technique not only in the analytical assessment of oxidative drug metabolism, but also for small-scale synthesis of drug metabolites. However, electrochemistry is generally limited to reactions initiated by direct electron transfer. In the case of substituted-aromatic compounds, oxidation proceeds through a Wheland-type intermediate where resonance stabilization of the positive charge determines the regioselectivity of the anodic substitution reaction, and hence limits the extent of generating drug metabolites in comparison with in vivo oxygen insertion reactions. In this study, we show that the electrocatalytic oxidation of hydrogen peroxide on a platinum electrode generates reactive oxygen species, presumably surface-bound platinum-oxo species, which are capable of oxygen insertion reactions in analogy to oxo-ferryl radical cations in the active site of Cytochrome P450. Electrochemical oxidation of lidocaine at constant potential in the presence of hydrogen peroxide produces both 3- and 4 hydroxylidocaine, suggesting reaction via an arene oxide rather than a Wheland type intermediate. No benzylic hydroxylation was observed, thus freely diffusing radicals do not appear to be present. The results of the present study extend the possibilities of electrochemical imitation of oxidative drug metabolism to oxygen insertion reactions. PMID- 22929862 TI - A 10-year analysis of American Society For Radiation Oncology Junior Faculty Career Development Awards. AB - PURPOSE: Between 2000 and 2010, the American Society for Radiation Oncology (ASTRO) awarded 22 Junior Faculty Career Development Awards (JFA) totaling $4.4 million. This study aimed to evaluate the impact of these awards on the grantees' career development, including current position, publications, and subsequent independent grant funding. METHODS: Each awardee was requested via email and telephone to provide an updated curriculum vitae, a National Institutes of Health (NIH) biosketch, and information regarding current position of employment. Twenty one of the 22 JFA recipients complied. Reported grant funding was extracted from each candidate's CV, and the amounts of NIH grants obtained were confirmed via NIH REPORTER. Reported publications were confirmed via PubMed. RESULTS: All survey respondents (21 of 21) have remained in academic positions. Subsequent aggregate grant funding totaled more than $25 million (range, $0-$4.1 million), 5.9 times the initial investment. NIH grant funding totaled almost $15 million, 3 times the initial investment. Awardees have published an average of 34.6 publications (range, 0-123) for an overall rate of 4.5 papers/year (range, 1-11). CONCLUSIONS: ASTRO JFAs over the past decade have been strongly associated with grantees remaining in academic positions, success in attracting private and NIH grants, and publication productivity. In an era of dwindling federal research funding, the support provided by the ASTRO JFA may be especially helpful to support the research careers of promising junior faculty members. PMID- 22929864 TI - Use of cetyltrimethylammonium bromide as a simple probe for rapid determination of emodin by resonance light scattering technique. AB - A new resonance light scattering (RLS) method for emodin determination with cationic surfactant cetyltrimethylammonium bromide (CTAB) as probe has been developed. In Britton-Robinson buffer (pH 6.5) medium, emodin reacted with cationic surfactant CTAB and formed the emodin-CTAB complex. The complex aggregated together through hydrophobic forces and causing great enhancement of RLS signals with the maximum peak located at about 350 nm. The enhanced RLS intensities were found to be proportional to the concentration of emodin in the range of 0.54-9.72 MUg ml(-1) with the detection limit (3sigma) of 10.3 ng ml( 1). In this work, the characteristics of RLS, absorption, fluorescence spectra of the system were studied. The optimum reaction condition and the influencing factors on the RLS signal were investigated in detail. The proposed method was applied to the analysis of emodin in synthetic samples and human urine with satisfactory results. Furthermore, the forms of the substances under the experimental condition and the mechanism of the reaction were discussed in detail. PMID- 22929865 TI - Beyond one-way streets: the interaction of phonology, morphology, and culture with orthography. AB - Frost's claim that universal models of reading require linguistically diverse data is relevant and justified. We support it with evidence demonstrating the extent of the bias towards some Indo-European languages and alphabetic scripts in scientific literature. However, some of his examples are incorrect, and he neglects the complex interaction of writing system and language structure with history and cultural environment. PMID- 22929867 TI - The neurodevelopmental hypothesis of schizophrenia: convergent clues from epidemiology and neuropathology. AB - The neurodevelopmental hypothesis of schizophrenia suggests that the disruption of early brain development increases the risk of later developing schizophrenia. This hypothesis focuses attention on critical periods of early brain development. From an epidemiologic perspective, various prenatal and perinatal risk factors have been linked to schizophrenia, including exposures related to infection, nutrition, and obstetric complications. From a genetic perspective, candidate genes have also been linked to altered brain development. In recent decades evidence from neuropathology has provided support for the neurodevelopmental hypothesis. Animal models involving early life exposures have been linked to changes in these same brain systems, providing convergent evidence for this long standing hypothesis. PMID- 22929866 TI - The nosology of schizophrenia: toward DSM-5 and ICD-11. AB - Although dementia praecox or schizophrenia has been considered a unique disease entity for more than a century, definitions and boundaries have changed and its precise cause and pathophysiology remain elusive. Despite uncertain validity, the construct of schizophrenia conveys useful clinical and etiopathophysiologic information. Revisions of the Diagnostic and Statistical Manual of Mental Disorders and the International Classification of Diseases seek to incorporate new information about schizophrenia and include elimination of subtypes, addition of psychopathological dimensions, elimination of special treatment of Schneiderian "first-rank" symptoms, better delineation of schizoaffective disorder, and addition of a new category of "attenuated psychosis syndrome". PMID- 22929868 TI - Predicting risk and the emergence of schizophrenia. AB - This article gives an overview of genetic and environmental risk factors for schizophrenia. The presence of certain molecular, biological, and psychosocial factors at certain points in the life span, has been linked to later development of schizophrenia. All need to be considered in the context of schizophrenia as a lifelong brain disorder. Research interest in schizophrenia is shifting to late childhood/early adolescence for screening and preventative measures. This article discusses those environmental risk factors for schizophrenia for which there is the largest evidence base. PMID- 22929870 TI - Can structural neuroimaging be used to define phenotypes and course of schizophrenia? AB - This article examines whether structural neuroimaging measures have been found to predict outcome in schizophrenia and whether changes in neuroimaging measures have been found to correlate with poor outcome in the disorder. Overall, there is little compelling evidence that structural neuroimaging measures in either first episode or chronic patients predict future outcome. Progressive brain changes might reflect a neuroimaging phenotype associated with a worse course of the disorder. At the same time, there are many fruitful avenues that future research could take in an attempt to better predict future outcome or to identify specific imaging phenotypes associated with outcome. PMID- 22929869 TI - Is early intervention for psychosis feasible and effective? AB - Services that provide comprehensive, early intervention (EI) have shown promise in improving long-term outcomes in schizophrenia. This article reviews the rationale and salient concepts relevant to understanding the growing EI literature. A selective review of studies evaluating the effectiveness of integrated EI is followed by a discussion of feasibility, especially in the US context. Finally, the authors present a framework that seeks to integrate activities traditionally categorized and separated as discovery and implementation. This framework is offered as a way to advance both goals. PMID- 22929871 TI - Reliable biomarkers and predictors of schizophrenia and its treatment. AB - Biomarkers are chemical and physiologic parameters that can provide reliable and predictive information about the course and treatment of a given illness. Biomarkers are being increasingly sought after in other medical conditions, and in some instances (eg, breast cancer therapy) are beginning to be incorporated into clinical decision making. There is a confluence of research investigating potential biomarkers for schizophrenia. This article reviews early progress and strategies for evaluating biomarkers, as well as how this approach can advance the treatment of schizophrenia toward personalized medicine. PMID- 22929874 TI - Peers and peer-led interventions for people with schizophrenia. AB - This article provides a snapshot of the nature, guiding philosophy, and empiric status of interventions for people with schizophrenia that go beyond traditional psychopharmacological and psychosocial treatments to include peer-led interventions. The authors discuss the nature and principles of peer-led interventions for people with schizophrenia and the types of peer-led interventions along with evidence of their effectiveness in fostering the recovery of people with schizophrenia and other severe mental illnesses. Focus is on 3 types of peer-led interventions: (1) mutual support/self-help, (2) consumer operated services, and (3) peer support services. PMID- 22929875 TI - Homelessness in schizophrenia. AB - The impact of mental illness, comorbid substance abuse, and medication nonadherence, coupled with disjointed psychiatric and social services, conspires to a disproportionately high rate of psychiatric disorders among people who are homeless in the United States. This article reviews the prevalence of homeless among the mentally ill as well as the prevalence of mental illness among the homeless and details barriers in access to care and the solutions that have been attempted. The need and solutions to introduce a new generation of physicians and allied health care workers to the unique health care needs of the homeless population are highlighted. PMID- 22929876 TI - Internet-based interventions for psychosis: a sneak-peek into the future. AB - The Internet and mobile technologies are becoming ubiquitous. However, the potential of these technologies to support people with psychosis has been unexplored and the development of innovative e-based interventions is overdue. Research suggests the acceptability and effectiveness of such interventions in psychosis. Internet-based technologies have the potential to transform psychosis treatment by enhancing the accessibility of evidence-based interventions, fostering engagement with mental health services, and maintaining treatment benefits over the long term. This article reviews the current evidence on Internet-based interventions for psychosis, including potential benefits, risks, and future challenges. Recommendations are proposed for developing future online interventions for psychosis. PMID- 22929873 TI - Cognitive enhancement in schizophrenia: pharmacological and cognitive remediation approaches. AB - This article discusses the measurement of cognition in schizophrenia, its role as a determinant of disability, and treatment efforts to date, including pharmacological and behavioral interventions as well as effective treatments that lead to improved outcomes. The measurement of functioning when patients with schizophrenia receive treatment in the office is addressed. The review focuses on new developments in the creation and adoption of a consensus method for the assessment of cognitive functioning in treatment studies, on the increased appreciation for assessment of functional skills in the prediction of everyday outcomes, and on developments in the basic neuroscience of cognition. PMID- 22929872 TI - Antipsychotic polypharmacy: a comprehensive evaluation of relevant correlates of a long-standing clinical practice. AB - Antipsychotic polypharmacy (APP) is common in the treatment of schizophrenia spectrum disorders. The literature indicates that APP is related to patient, illness, and treatment variables that are proxy measures for greater illness acuity, severity, complexity, and chronicity. The largely unknown relative risks and benefits of APP need to be weighed against the known risks and benefits of clozapine for treatment-resistant patients. To inform evidence-based clinical practice, controlled, high-quality antipsychotic combination and discontinuation trials are necessary to determine the effectiveness, safety, and role of APP in the management of severely ill patients with insufficient response to antipsychotic monotherapy. PMID- 22929877 TI - Early diagnosis and intervention in schizophrenia. PMID- 22929878 TI - Complexity and multifractality of neuronal noise in mouse and human hippocampal epileptiform dynamics. AB - Fractal methods offer an invaluable means of investigating turbulent nonlinearity in non-stationary biomedical recordings from the brain. Here, we investigate properties of complexity (i.e. the correlation dimension, maximum Lyapunov exponent, 1/f(gamma) noise and approximate entropy) and multifractality in background neuronal noise-like activity underlying epileptiform transitions recorded at the intracellular and local network scales from two in vitro models: the whole-intact mouse hippocampus and lesional human hippocampal slices. Our results show evidence for reduced dynamical complexity and multifractal signal features following transition to the ictal epileptiform state. These findings suggest that pathological breakdown in multifractal complexity coincides with loss of signal variability or heterogeneity, consistent with an unhealthy ictal state that is far from the equilibrium of turbulent yet healthy fractal dynamics in the brain. Thus, it appears that background noise-like activity successfully captures complex and multifractal signal features that may, at least in part, be used to classify and identify brain state transitions in the healthy and epileptic brain, offering potential promise for therapeutic neuromodulatory strategies for afflicted patients suffering from epilepsy and other related neurological disorders. PMID- 22929879 TI - Tumour basement membrane laminin expression predicts outcome following curative resection of pancreatic head cancer. AB - BACKGROUND: Although widely fragmented BMs have been associated with adverse outcome in several cancer types, comparatively little is known with respect to its effect on the prognosis of pancreatic cancer. The aim of the current study was therefore to determine the prognostic value of tumour basement membrane (BM) continuity in two anatomically closely related, however, prognostically different tumours, pancreatic head- and periampullary cancer. METHODS: Tumour BM continuity was determined by immunohistochemical staining of its two major components, laminin and collagen type IV. Associations were made with recurrence free survival (RFS), cancer-specific survival (CSS), overall survival (OS) and conventional prognostic factors. RESULTS: Fifty-nine and 61% of pancreatic head and periampullary tumours, respectively, showed limited BM laminin expression. Whereas 43% and 41% of pancreatic head and periampullary cancers, respectively, showed limited BM collagen type IV expression. Limited BM laminin was associated with poor outcome following curative resection of pancreatic head cancer (P=0.034, 0.013 and 0.017 for RFS, CSS and OS, respectively). Two and a half times as many patients with >= 25% BM laminin were recurrence free and alive 5 years following resection compared with those with limited BM laminin. Although staining patterns of both BM components were weakly correlated with each other, BM collagen type IV expression was not significantly associated with outcome in either tumour type. CONCLUSION: Discontinuous BMs, determined by laminin expression, are associated with poor outcome following curative resection of pancreatic head cancer. PMID- 22929880 TI - Genomic Grade Index predicts postoperative clinical outcome of GIST. AB - BACKGROUND: Prognosis of localised gastrointestinal stromal tumour (GIST) is heterogeneous, notably for patients with AFIP intermediate or high risk of relapse, who are candidates to adjuvant imatinib. We hypothesised that gene expression profiles might improve the prognostication and help to refine the indications for imatinib. METHODS: We collected gene expression and histoclinical data of 146 pre-treatment localised GIST samples treated with surgery alone. We searched for a gene expression signature (GES) predictive for relapse-free survival (RFS) and compared its performances to that of three published prognostic proliferation-based GES (Genomic Grade Index (GGI), 16-Kinase, and CINSARC) and AFIP classification. We also analysed a data set from 28 patients with advanced GIST treated with neo-adjuvant imatinib. RESULTS: We identified a 275-gene GES (gene expression signature) predictive of RFS in a learning set and validated its robustness in an independent set. However, the GGI outperformed its prognostic performances, and those of the two other signatures and the AFIP intermediate-risk classification in two independent tests sets in uni- and multivariate analyses. Importantly, GGI could split the AFIP intermediate/high risk samples into two groups with different RFS. Genomic Grade Index 'high-risk' tumours were more proliferative and genetically unstable than 'low-risk' tumours, and more sensitive to imatinib. CONCLUSION: GGI refines the prediction of RFS in localised GIST and might help tailor adjuvant imatinib. PMID- 22929881 TI - Whole sentinel lymph node analysis by a molecular assay predicts axillary node status in breast cancer. AB - BACKGROUND: The one-step nucleic acid amplification (OSNA) assay is a rapid procedure for the detection of lymph node (LN) metastases using molecular biological techniques. The aim of this study was to assess the reliability of the whole sentinel lymph node (SLN) analysis by the OSNA assay as a predictor of non SLN metastases. METHODS: Consecutive 742 patients with breast cancer were enroled in the study. The association of non-SLN or >=4 LN metastases with clinicopathological variables was investigated using multivariate logistic analysis. RESULTS: In total, 130 patients with a positive SLN who underwent complete axillary LN dissection were investigated. The frequency of non-SLN metastases in patients who were OSNA+ and ++ was 19.3% and 53.4%, respectively, and that in patients with >=4 LN metastases who were OSNA+ and ++ was 7.0% and 27.4%, respectively. The cytokeratin 19 (CK19) mRNA copy number (>=5.0 * 10(3); OSNA++) in the SLN was the most significant predictors of non-SLN metastases (P=0.003). The CK19 mRNA copy number (>=1.0 * 10(5)) in the SLN was the only independent predictor of >=4 LN metastases (P=0.014). CONCLUSION: Whole SLN analysis using the OSNA assay could become a valuable method for predicting non SLN and >=4 LN metastases. PMID- 22929882 TI - Curcumin-cyclodextrin complexes potentiate gemcitabine effects in an orthotopic mouse model of lung cancer. AB - BACKGROUND: Overall clinical outcome for advanced lung cancer remains very disappointing despite recent advances in treatment. Curcumin has been reported as potentially active against cancer. METHODS: Owing to poor curcumin solubility, we have used cyclodextrins (CD) as an excipient allowing a considerable increase of aqueous solubility and bioavailability of curcumin. The effects of solubilised curcumin have been evaluated in cell cultures as well as in an in vivo orthotopic lung tumour mouse model. RESULTS: Cell proliferation was reduced while apoptosis rates were increased when lung epithelial tumour cells were cultured in the presence of curcumin-CD complexes. For in vivo experiments, cells were grafted into lungs of C57Bl/6 mice treated by an oral administration of a non-soluble form of curcumin, CDs alone or curcumin-CD complexes, combined or not with gemcitabine. The size of orthotopically implanted lung tumours was reduced upon curcumin complex administration as compared with treatments with placebo or non solubilised curcumin. Moreover, curcumin potentiated the gemcitabine-mediated antitumour effects. CONCLUSION: Our data demonstrate that curcumin, when given orally in a CD-solubilised form, reduces lung tumour size in vivo. In vitro experiments show impaired tumour cell proliferation and increased cell apoptosis. Moreover, our data underline a potential additive effect of curcumin with gemcitabine thus providing an efficient therapeutic option for antilung cancer therapy. PMID- 22929883 TI - WNT/beta-catenin pathway activation in Myc immortalised cerebellar progenitor cells inhibits neuronal differentiation and generates tumours resembling medulloblastoma. AB - BACKGROUND: Medulloblastoma is the most common malignant childhood brain tumour. Aberrant activation of the WNT/beta-catenin pathway occurs in approximately 25% of medulloblastomas. However, its role in medulloblastoma pathogenesis is not understood. METHODS: We have developed a model of WNT/beta-catenin pathway activated medulloblastoma. Pathway activation was induced in a Myc immortalised cerebellar progenitor cell line through stable expression of Wnt1. In vitro and in vivo analysis was undertaken to understand the effect of pathway activation and identify the potential cell of origin. RESULTS: Tumours that histologically resembled classical medulloblastoma formed in vivo using cells overexpressing Wnt1, but not with the control cell line. Wnt1 overexpression inhibited neuronal differentiation in vitro, suggesting WNT/beta-catenin pathway activation prevents cells terminally differentiating, maintaining them in a more 'stem-like' state. Analysis of cerebellar progenitor cell markers demonstrated the cell line resembled cells from the cerebellar ventricular zone. CONCLUSION: We have developed a cell line with the means of orthotopically modelling WNT/beta-catenin pathway-activated medulloblastoma. We provide evidence of the role pathway activation is playing in tumour pathogenesis and suggest medulloblastomas can arise from cells other than granule cell progenitors. This cell line is a valuable resource to further understand the role of pathway activation in tumorigenesis and for investigation of targeted therapies. PMID- 22929884 TI - Dose banding as an alternative to body surface area-based dosing of chemotherapeutic agents. AB - BACKGROUND: Dose banding is a recently suggested dosing method that uses predefined ranges (bands) of body surface area (BSA) to calculate each patient's dose by using a single BSA-value per band. Thus, drugs with sufficient long-term stability can be prepared in advance. The main advantages of dose banding are to reduce patient waiting time and improve pharmacy capacity planning; additional benefits include reduced medication errors, reduced drug wastage, and prospective quality control. This study compares dose banding with individual BSA dosing and fixed dose according to pharmacokinetic criteria. METHODS: Three BSA bands were defined: BSA<1.7 m(2), 1.7 m(2)<= BSA<1.9 m(2), BSA >= 1.9 m(2) and each patient dose was calculated based on a unique BSA-value per band (1.55, 1.80, and 2.05 m(2), respectively). By using individual clearance values of six drugs (cisplatin, docetaxel, paclitaxel, doxorubicin, irinotecan, and topotecan) from 1012 adult cancer patients in total, the AUCs corresponding to three dosing methods (BSA dosing, dose banding, and fixed dose) were compared with a target AUC for each drug. RESULTS: For all six drugs, the per cent variation in individual dose obtained with dose banding compared with BSA dosing ranged between -14% and +22%, and distribution of AUC values was very similar with both dosing methods. In terms of reaching the target AUC, there was no significant difference in precision between dose banding and BSA dosing, except for paclitaxel (32.0% vs 30.7%, respectively; P<0.05). However, precision was significantly better for BSA dosing compared with fixed dose for four out of six drugs. CONCLUSION: For the studied drugs, implementation of dose banding should be considered as it entails no significant increase in interindividual plasma exposure. PMID- 22929885 TI - Quantitative relationship between silica exposure and lung cancer mortality in German uranium miners, 1946-2003. AB - BACKGROUND: In 1996 and 2009, the International Agency for Research on Cancer classified silica as carcinogenic to humans. The exposure-response relationship between silica and lung cancer risk, however, is still debated. Data from the German uranium miner cohort study were used to further investigate this relationship. METHODS: The cohort includes 58677 workers with individual information on occupational exposure to crystalline silica in mg m(-3)-years and the potential confounders radon and arsenic based on a detailed job-exposure matrix. In the follow-up period 1946-2003, 2995 miners died from lung cancer. Internal Poisson regression with stratification by age and calendar year was used to estimate the excess relative risk (ERR) per dust-year. Several models including linear, linear quadratic and spline functions were applied. Detailed adjustment for cumulative radon and arsenic exposure was performed. RESULTS: A piecewise linear spline function with a knot at 10 mg m(-3)-years provided the best model fit. After full adjustment for radon and arsenic no increase in risk <10 mg m(-3)-years was observed. Fixing the parameter estimate of the ERR in this range at 0 provided the best model fit with an ERR of 0.061 (95% confidence interval: 0.039, 0.083) >10 mg m(-3)-years. CONCLUSION: The study confirms a positive exposure-response relationship between silica and lung cancer, particularly for high exposures. PMID- 22929886 TI - MicroRNA profiling of diagnostic needle aspirates from patients with pancreatic cancer. AB - BACKGROUND: A major challenge to the development of biomarkers for pancreatic cancer (PC) is the small amount of tissue obtained at the time of diagnosis. Single-gene analyses may not reliably predict biology of PC because of its complex molecular makeup. MicroRNA (miRNA) profiling may provide a more informative molecular interrogation of tumours. The primary objective of this study was to determine the feasibility of performing miRNA arrays and quantitative real-time PCR (qRT-PCR) from archival formalin-fixed paraffin embedded (FFPE) cell blocks obtained from fine-needle aspirates (FNAs) that is the commonest diagnostic procedure for suspected PC. METHODS: MicroRNA expression profiling was performed on FFPE from FNA of suspicious pancreatic masses. Subjects included those who had a pathological diagnosis of pancreatic adenocarcinoma and others with a non-malignant pancreatic histology. Exiqon assay was used to quantify miRNA levels and qRT-PCR was used to validate abnormal expression of selected miRNAs. RESULTS: A total of 29 and 15 subjects had pancreatic adenocarcinoma and no evidence of cancer, respectively. The RNA yields per patient varied from 25 to 100 ng. Profiling demonstrated deregulation of over 228 miRNAs in pancreatic adenocarcinoma of which the top 7 were further validated by qRT-PCR. The expression of let-7c, let-7f, and miR-200c were significantly reduced in most patients whereas the expression of miR-486-5p and miR-451 were significantly elevated in all pancreas cancer patients. MicroRNAs let-7d and miR 423-5p was either downregulated or upregulated with a significant inter individual variation in their expression. CONCLUSION: This study demonstrated the feasibility of using archival FFPE cell blocks from FNAs to establish RNA-based molecular signatures unique to pancreatic adenocarcinoma with potential applications in clinical trials for risk stratification, patient selection, and target validation. PMID- 22929887 TI - Human responses against HER-2-positive cancer cells in human immune system engrafted mice. AB - BACKGROUND: Human immune system (HIS)-engrafted mice are new tools to investigate human immune responses. Here, we used HIS mice to study human immune responses against human HER-2-positive cancer cells and their ability to control tumour growth and metastasis. METHODS: BALB/c Rag2(-/-), Il2rg(-/-) mice were engrafted with CD34(+) or CD133(+) human cord blood hematopoietic stem cells (HSC) and vaccinated with human HER-2-positive cancer cells SK-OV-3 combined to human IL 12. RESULTS: Both CD34(+) or CD133(+) human HSC gave long-term engraftment and differentiation, both in peripheral blood and in lymphoid organs, and production of human antibodies. Vaccinated mice produced specific anti-HER-2 human IgG. An s.c. SK-OV-3 challenge was significantly inhibited (but not abolished) in both vaccinated and non-vaccinated HIS mice. Tumours were heavily infiltrated with human and murine cells, mice showed NK cells and production of human interferon gamma, that could contribute to tumour growth inhibition. Vaccinated HIS mice showed significantly inhibited lung metastases when compared with non-vaccinated HIS mice and to non-HIS mice, along with higher levels of tumour-infiltrating human dendritic cells. CONCLUSION: Anti-HER-2 responses were elicited through an adjuvanted allogeneic cancer cell vaccine in HIS mice. Human immune responses elicited in HIS mice effectively inhibited lung metastases. PMID- 22929888 TI - Ovarian cancer and menopausal hormone therapy in the NIH-AARP diet and health study. AB - BACKGROUND: Women using unopposed estrogens during menopause are at increased risk of ovarian cancer. It is uncertain whether oestrogen plus progestin therapy exerts similar effects. METHODS: We evaluated menopausal hormone use and incident ovarian cancer (n=426) in 92601 post-menopausal women enrolled in the National Institutes of Health-AARP (NIH-AARP) Diet and Health Study. Participants were administered questionnaires in 1996-1997 and followed through 2006. Hazard rate ratios (RR) and 95% confidence intervals (CIs) were estimated using Cox regression. RESULTS: Increased risks were associated with long duration (10+ years) use of unopposed oestrogen (RR 2.15, 95% CI: 1.30-3.57 among women with a hysterectomy) and oestrogen plus progestin (RR 1.68, 95% CI: 1.13-2.49 among women with intact uteri) therapy. Similar risks were associated with progestins that were used sequentially (<15 days progestin per month) (RR 1.60, 95% CI: 1.10 2.33) or continuously (>25 days progestin per month) (RR 1.43, 95% CI: 1.032 2.01; P-value for heterogeneity=0.63). CONCLUSION: Our findings suggest that long duration use of both unopposed estrogens and oestrogen plus progestins are associated with increased risks of ovarian cancer, and that risk associated with oestrogen plus progestin use does not vary by regimen (sequential or continuous). PMID- 22929889 TI - Tissue factor expression in the metaplasia-adenoma-carcinoma sequence of gastric cancer in a European population. AB - BACKGROUND: Tissue factor (TF), which has a role in normal tissue haemostasis, was reported to be aberrantly expressed, associated with higher microvascular density and a poor prognosis in intestinal-type gastric adenocarcinoma in the Japanese population. This is the first study to look at the relationship of TF and the metaplasia-adenoma-carcinoma sequence (MACS) of gastric cancer in a European population. METHODS: The expression of TF was examined immunohistochemically in 191 gastric tissue samples: (13: normal; 18: intestinal metaplasia; 160: gastric adenocarcinoma) from the European population. RESULTS: TF was not expressed in normal gastric mucosal cells. A strong intensity of staining was found in intestinal metaplasia cells but in 2 of 18 samples. TF expression increased with advancing stage of gastric cancer (P<0.0001, Jonckheere's test for ordered medians). Stage 3-4 gastric cancers preferentially expressed TF (34%, P=0.04). In comparison with the Japanese study, TF was not expressed at a higher level in intestinal vs diffuse-type gastric cancers and expression had 'no prognostic' significance. CONCLUSION: TF may be involved in tumour progression along the MACS of gastric cancer in the European population and is shown to start in precancerous lesions. However, clinical features may differ due to differences in biological features in the two populations, as reflected by differences in TF expression profile. PMID- 22929891 TI - Phase I oncology trials incorporating patient choice of dose. AB - BACKGROUND: Patients recruited in phase I oncology trials are often treated at doses lower than the maximum tolerated dose (MTD), and therefore may not receive the most efficacious dose available, despite their expectations to the contrary. This report investigates the consequences of allowing a patient choice of dose within a common dose-escalation scheme. METHODS: Trials using the continual reassessment method of dose escalation are simulated, with a modification of the rules to allow patients to choose a higher dose if they wish. The effect of allowing this choice is assessed in terms of probability of toxicity and probability of being treated at the MTD or higher. RESULTS: The simulations show that allowing a patient choice of dose reduces the proportions of patients treated at doses lower than the MTD, and has little impact on the overall probability of correct identification of the MTD. CONCLUSION: The results illustrate the principle that a choice of dose can be offered to patients in such trials without compromising the overall properties of the study. PMID- 22929890 TI - miRNA-214 modulates radiotherapy response of non-small cell lung cancer cells through regulation of p38MAPK, apoptosis and senescence. AB - BACKGROUND: Radio- and chemotherapy (RT/CT) resistance hampers success in combating small and non-small cell lung cancers (SCLC/NSCLC). The underlying molecular mechanisms of RT/CT resistance of LCs are multifactorial and have been understood in part hitherto. miRNAs, key regulators of mRNAs, are well-recognised oncomirs; however, their role in regulating RT response remains poorly understood. METHODS: Six human NSCLC and five SCLC cell lines with different SF2 values were investigated. Using microarray we examined whether expression of miRNAs is linked to the RT resistance of NSCLCs or SCLCs. Obtained data were validated by quantitative real-time PCR. Apoptosis and senescence were analysed using siRNA transfection, western blot and flow cytometry. RESULTS: miRNA-21, miRNA-1827, miRNA-214, miRNA-339-5p, miRNA-625, miRNA-768-3p, miRNA-523-3p, miRNA 1227, miRNA-324-5p, miRNA-423-3p, miRNA-1301 and miRNA-1249 are differentially expressed in LC cells. miRNA-214 is upregulated in RT-resistant NSCLC cells relative to radiosensitive counterparts. Considering miRNA-214 as a putative regulator of RT resistance, we demonstrate that knockdown of miRNA-214 in radioresistant NSCLCs sensitised them to RT by stimulation of senescence. Consistently, overexpression of miRNA-214 in radiosensitive NSCLCs protected against RT-induced apoptosis. Protection was mediated by p38MAPK, as downregulation of this kinase could reverse the miRNA-214 overexpression-induced resistance of NSCLC cells. CONCLUSION: miRNA profiling of LC revealed putative RT resistance signalling circuits, which might help in sensitisation of LC to RT. PMID- 22929892 TI - Hydrodynamic performance of a prototype bioprosthetic valve derived from the pulmonary valve of Phoca groenlandica. AB - Biological valves offer significant advantages over mechanical valves, and for this reason, we studied the possibility of using a new animal source such as that of Phoca groenlandica. Four aortic and four pulmonary leaflets were cut radially and their uniaxial tensile testing was evaluated. Three prototype pulmonary valves of Phoca groenlandica preserved in buffered glutaraldehyde solution 0.625% at pH 7.4 were mounted on a 19, 21, and 27 mm novel support system (stent) with heart shape commissural posts covered with polytetrafluoroethylene. The valves were tested in a steady flow system, the peak pressure gradients (PPGs) were measured, and the effective orifice areas (EOAs) were calculated for the flows of 3, 4, 5, 6, and 8 L/min. There were five different measurements for each flow variant. Aortic and pulmonary leaflets present no statistically significant difference in failure strength (p = 0.93). The PPGs across the valves for the flow of 3, 4, 5, 6, and 8 L/min for all three tested valves were low and the corresponding calculated EOAs were large. The new bioprosthetic valve derived from the pulmonary valve of Phoca groenlandica mounted on this novel support system presented a satisfactory hydrodynamic performance in a steady flow system. More research is needed before it can be considered suitable for human cardiac valve replacement. PMID- 22929893 TI - Identifying hemodialysis catheter recirculation using effective ionic dialysance. AB - Vascular catheter use for dialysis remains highly prevalent, however, it is frequently adversely affected by access recirculation (AR). We previously reported the utility of effective ionic dialysance (EID)/blood flow rate (Qb) ratio in identifying significant (>5%) AR in arteriovenous (AV) fistulas (Mohan et al ASAIO J 56:427-433, 2010). We present data from 58 patients, receiving hemodialysis via venous catheters (85% tunneled cuffed catheters) who underwent intermittent monitoring for AR with the saline dilution technique (Transonic HD02 monitor) and had EID and Qb measurements from Diascan biosensor in the Gambro Phoenix dialysis machine available. Among the 193 hemodialysis sessions studied, 74 instances of significant access recirculation (sAR) were identified. A higher incidence of sAR occurred with temporary catheters and catheters in the femoral vein. We report a significant correlation between the EID/Qb ratio and AR in addition to demonstrating the predictive utility of the ratio for identifying dysfunction catheters with sAR (area under the receiver operator characteristic curve of 0.86 with a sensitivity of 79% and a specificity of 76% at an EID/Qb ratio of <= 0.60). Our data demonstrate the utility of the EID/Qb ratio as an indicator of sAR in dialysis catheters albeit at a different threshold than that seen with AV fistulae. PMID- 22929894 TI - The influence of device position on the flow within the Penn State 12 cc pediatric ventricular assist device. AB - Ventricular assist devices are a commonly used heart failure therapy for adult patients as bridge-to-transplant or bridge-to-recovery tools. The application of adult ventricular assist devices in pediatric patients has led to increased thrombotic events. Therefore, we have been developing a pediatric ventricular assist device (PVAD), the Penn State 12 cc PVAD. It is designed for patients with a body weight of 5-15 kg and has a stroke volume of 12 cc. Clot formation is the major concern. It is correlated to the coagulability of blood, the blood contacting materials and the fluid dynamics within the system. The intent is for the PVAD to be a long term therapy. Therefore, the system may be oriented in different positions according to the patient's behavior. This study evaluates for the first time the impact of position on the flow patterns within the Penn State 12 cc PVAD, which may help to improve the PVAD design concerning chamber and ports geometries. The fluid dynamics are visualized by particle image velocimetry. The evaluation is based on inlet jet behavior and calculated wall shear rates. Vertical and horizontal model orientations are compared, both with a beat rate of 75, outlet pressures of 90/60 mm Hg and a flow rate of 1.3 l/min. The results show a significant change of the inlet jet behavior and the development of a rotational flow pattern. Vertically, the inlet jet is strong along the wall. It initiates a rotational flow pattern with a wandering axis of rotation. In contrast, the horizontal model orientation results show a weaker inlet jet along the wall with a nearly constant center of rotation location, which can be correlated to a higher risk of thrombotic events. In addition, high speed videography illustrates differences in the diaphragm motion during diastole. Diaphragm opening trajectories measurements determine no significant impact of the density of the blood analog fluids. Hence, the results correlate to human blood. PMID- 22929895 TI - Long-term tolerance of airway silicone stent in patients with post-tuberculosis tracheobronchial stenosis. AB - Surgery is a well-recognized modality of treatment for benign tracheobronchial stenosis. However, in some benign disease groups, such as tuberculosis, sarcoidosis, war gas exposure, and inhalation burns, multiplicity of involvement or long length of stenosed segment heightens surgical challenge. We investigated the outcomes and long-term tolerability of the Natural stent (N-stent) in such patients with post-tuberculosis tracheobronchial stenosis. A retrospective review was done for 17 patients who underwent silicone stenting (N-stent) for post tuberculosis tracheobronchial stenosis during January 2000-December 2003 but needed persistent stent placement and still require the stent. Significant increase in the ratio of forced expiratory volume in 1 second (FEV1) to forced vital capacity (FVC), expressed as FEV1%, as well as in forced percentual vital capacity (FVC%) (Delta24% and Delta11%, respectively) in the short term and sustained increase in the FEV1% and FVC% (Delta26.5% and Delta16.5%, respectively) in the long term were noted at a median (range) interval of 1 (0.5 72) month and 72 (12-114) months, respectively, along with symptomatic relief. No procedure-related death occurred. Stent-related late complications included granulation tissue formation (76%), migration (70%), and mucostasis (17%). The median duration for which N-stents were tolerated was 7.9 (range, 3-11) years. N stents are well-tolerated for a prolonged period. Stent-related complications occur, but are easily managed. These results might carry medical implications for those who have airway lesions difficult to correct surgically. PMID- 22929896 TI - Growing experience with extracorporeal membrane oxygenation as a bridge to lung transplantation. AB - Extracorporeal membrane oxygenation (ECMO) is rarely used as a bridge to lung transplantation (BTT) because of its associated morbidity and mortality. However, recent advancements in perfusion technology and critical care have revived interest in this application of ECMO. We retrospectively reviewed our utilization of ECMO as BTT and evaluated our early and midterm results. Nineteen patients were placed on ECMO with the intent to transplant of which 14 (74%) were successfully transplanted. Early and midterm survival of transplanted patients was 75% (1 year) and 63% (3 years), respectively, with the most favorable results observed in interstitial lung disease patients supported in the venovenous configuration. Extracorporeal membrane oxygenation-bridged transplant survival rates were equivalent to nonbridged recipients, but early morbidity and mortality are high and the failure to bridge to transplant is significant. Overall, successfully bridged patients can derive a tangible benefit, albeit with considerable consumption of resources. PMID- 22929897 TI - Subclavian artery cannulation for venoarterial extracorporeal membrane oxygenation. AB - Femoral artery cannulation for venoarterial extracorporeal membrane oxygenation (ECMO) can be associated with ischemic and neurologic complications. The subclavian artery offers an alternative cannulation site, which is helpful in patients with peripheral vascular disease, in those who have sustained pelvic trauma, or when ambulation is anticipated. This is a single-institution review of 20 adults who were placed on venoarterial ECMO using subclavian arterial cannulation over a 2 year period. Technical success with subclavian venoarterial ECMO was 100%. Median ECMO time was 168 hours (2.4-720 hours). Sufficient flows (median 4.24 L/min), oxygenation (median postcannulation PaO2 315 mm Hg), and ventricular unloading confirmed with intraoperative transesophageal echocardiogram were achieved in all patients. Seventy-five percent of patients were decannulated, 50% were extubated, and 45% were discharged. Seven patients (35%) had an entirely upper body ECMO configuration with the internal jugular vein serving as the venous drainage site. Complications included arterial cannula site hematoma and infection, as well as ipsilateral arm swelling. Each required conversion to femoral artery cannulation. There were no ischemic or neurologic complications. Patients with acute cardiopulmonary failure can safely be placed on subclavian venoarterial ECMO for prolonged periods with full flows, adequate oxygenation, and sufficient ventricular unloading. PMID- 22929898 TI - Racial differences in patients with left ventricular assist devices. AB - We examined clinical outcomes based on ethnicity in patients undergoing left ventricular assist device (LVAD) implantation. We hypothesized that treatment in a specialized, comprehensive heart failure program results in similar survival between African Americans and whites. We retrospectively reviewed patient data implanted with HeartMate II (HM-II) LVAD over 2 years. There were 79 patients: 34 (43%) whites, 33 (42%) African Americans, and 12 (15%) patients belonging to other ethnicities there was no difference in demographics. The etiology of cardiomyopathy was more commonly ischemic in white patients compared to nonischemic in African American patients (p = 0.01). The mean left ventricular ejection fraction was 22.21 +/- 10.66% in African American patients and 15.21 +/- 5.54% in white patients (p = 0.008). The left ventricular end-diastolic (p = 0.06) and end-systolic (p = 0.03) diameters were greater in white patients compared to African American patients. Hypertension was seen in 79% of African American patients compared to 56% in white patients (p = 0.07). Survival by Kaplan-Meier analysis revealed an unadjusted survival advantage in African American patients (p = 0.04 by log-rank test), but this survival advantage was lost in multivariable Cox regression analysis after adjustment for other covariates. There was no difference in readmissions (p = 0.36). In patients with advanced heart failure undergoing HM-II LVAD implantation, African American patients had a similar survival and no difference in readmissions when compared with white patients despite significant differences in baseline clinical characteristics. PMID- 22929899 TI - Hemodynamic simulation study of a novel intra-aorta left ventricular assist device. AB - The intra-aorta pump proposed here is a novel left ventricular assist device (LVAD). The mathematic model and the in vitro experiment demonstrate that the pump can satisfy the demand of human blood perfusion. However, the implantation of LVAD will change the fluid distribution or even generate a far-reaching influence on the aorta. At present, the characteristics of endaortic hemodynamics under the support of intra-aorta pump are still unclear. In this article, a computational fluid dynamics study based on a finite-element method was performed for the aorta under the support of intra-aorta pump. To explore the hemodynamic influence of intra-aorta pump on aorta, fully coupled fluid-solid interaction simulation was used in this study. From the flow profiles, we observed that the maximum disturbed flow and nonuniform flow existed within the aortic arch and the branches of the aortic arch. Flow waveforms at the inlets of aortas were derived from the lumped parameter model that we proposed in our previous study. The results demonstrated that the intra-aorta pump increased the blood flow in the aorta to normal physiologic conditions, but decreased the pulsatility of the flow and pressure. The pulsatility index changed from 2,540 to 1,370. The pressure gradient (PG) for heart failure conditions was 18.88 mm Hg/m vs. 25.51 mm Hg/m for normal physiologic conditions; for intra-aorta pump assist conditions, normal PG value could not be regained. Furthermore, our experimental results showed that the wall shear stress (WSS) of aorta under heart failure and normal physiologic conditions were 1.5 and 6.3 dynes/cm, respectively. The intra-aorta pump increased the WSS value from 1.5 to 4.1 dynes/cm. PMID- 22929900 TI - Extracorporeal membrane oxygenation as a bridge to lung transplantation. PMID- 22929901 TI - Signalling through mechanical inputs: a coordinated process. AB - There is growing awareness that mechanical forces - in parallel to electrical or chemical inputs - have a central role in driving development and influencing the outcome of many diseases. However, we still have an incomplete understanding of how such forces function in coordination with each other and with other signalling inputs in vivo. Mechanical forces, which are generated throughout the organism, can produce signals through force-sensitive processes. Here, we first explore the mechanisms through which forces can be generated and the cellular responses to forces by discussing several examples from animal development. We then go on to examine the mechanotransduction-induced signalling processes that have been identified in vivo. Finally, we discuss what is known about the specificity of the responses to different forces, the mechanisms that might stabilize cells in response to such forces, and the crosstalk between mechanical forces and chemical signalling. Where known, we mention kinetic parameters that characterize forces and their responses. The multi-layered regulatory control of force generation, force response and force adaptation should be viewed as a well integrated aspect in the greater biological signalling systems. PMID- 22929902 TI - Retraction. Mitochondrial dysfunction and HIF1alpha stabilization in inflammation. PMID- 22929904 TI - Synthesis, growth, structural, optical, spectral, thermal and mechanical studies of 4-methoxy 4-nitrostilbene (MONS): a new organic nonlinear optical single crystal. AB - 4-Methoxy 4-nitrostilbene (MONS), a new organic nonlinear optical material has been synthesized. Based on the solubility data good quality single crystal with dimensions up to 38*11*3 mm(3) has been grown by slow evaporation method using ethyl methyl ketone (MEK) as a solvent. Powder XRD confirms the crystalline property and also the diffraction planes have been indexed. The lattice parameters for the grown MONS crystals were determined by using single crystal X ray diffraction analysis and it reveals that the crystal lattice system is triclinic. The crystalline perfection of the grown crystals has been analysed by high resolution X-ray diffraction (HRXRD) rocking curve measurements. Fourier transform infrared (FTIR) spectrum for powdered MONS sample confirms the functional groups present in the grown crystal. The UV-vis absorption spectrum has been recorded in the range of 190-1100 nm and the cut off wavelength 499 nm has been determined. The optical constants of MONS have been determined through UV-vis-NIR spectroscopy. The MONS crystals were further subjected to other characterizations. i.e., (1)H NMR, TG/DTA, photoluminescence and microhardness test. The Kurtz and Perry powder technique confirms the NLO property of the grown crystal and the SHG efficiency of MONS was found to be 1.55* greater than that of KDP crystal. PMID- 22929905 TI - DFT, FT-Raman, FT-IR, HOMO-LUMO and NBO studies of 4-Methylmorpholine. AB - The experimental FT-IR (4000-400 cm(-1)) and FT-Raman (3500-100 cm(-1)) spectra of 4-Methylmorpholine were recorded. The observed bands were interpreted with the aid of normal coordinate analysis and force field calculations based on density functional theory (DFT) using B3LYP functional theory (DFT) using B3LYP functional with 6-311+G and 6-3++G basis sets. The complete assignments were performed on the basis of the potential energy distribution (PED) of the vibrational modes, calculated with scaled quantum mechanical (SQM) method. The molecular structure and vibrational frequencies, infrared intensities and Raman scattering actives have been calculated frequency showed the best agreement with experimental results. The formation of the hydrogen bond was investigated using NBO calculations. The calculated HOMO and LUMO energies show that charge transfer occur within the molecule. The dipolemoment (MU) and polarizability (alpha), anisotropy polarizability (Deltaalpha) and first hyperpolarizability (beta(total)) of the molecule have been reported. PMID- 22929906 TI - Electrocardiographic electrode misplacement, misconnection, and artifact. AB - BACKGROUND: Electrocardiograms (ECGs) are performed by humans, and thus are subject to human error. An underappreciated source of electrocardiographic abnormality is electrode misconnection, both limb and precordial, and improper placement, which is principally an issue with the precordial electrodes due to anatomic variation. Patterns of abnormality exist; recognition allows the emergency physician to avoid mistaking the resulting electrocardiographic findings for true pathology. OBJECTIVES: The purpose of this clinical review is to describe the patterns of electrocardiographic electrode reversal, misplacement, and artifact and thus make them recognizable to the Emergency Physician. DISCUSSION: Common limb electrode reversals feature distinctive patterns manifesting as unexpected morphologic and frontal plane axis changes in the QRS complexes in the limb and augmented leads. Precordial electrode misplacement (improper positioning of the electrodes on the chest) is common and may mimic a pseudoinfarction pattern, or ST-segment/T-wave changes, which must be recognized as the result of the misplacement rather than true cardiac ischemia. Precordial electrode reversal should be suspected when the normal R/S wave amplitude transition is violated. Electrocardiographic artifact must be distinguished from dysrhythmia to avoid a potentially hazardous progression to unnecessary diagnostics and therapeutics. CONCLUSIONS: The hallmarks of electrode misconnection, misplacement, and electrocardiographic artifact can be easily mastered by the Emergency Physician; recognition of these findings can positively impact patient care by avoiding unnecessary intervention secondary to misattribution of findings on the 12-lead ECG to cardiac pathology. PMID- 22929907 TI - Theories of reading should predict reading speed. AB - Reading speed matters in most real-world contexts, and it is a robust and easy aspect of reading to measure. Theories of reading should account for speed. PMID- 22929908 TI - Running just to stand still. PMID- 22929909 TI - Shaping barrels: activity moves NG2+ glia. PMID- 22929910 TI - Bursting for exploration. PMID- 22929911 TI - Target practice: HDAC inhibitors for schizophrenia. PMID- 22929912 TI - The value of competition in the rat race. PMID- 22929915 TI - Novel microsatellite DNA markers indicate strict parthenogenesis and few genotypes in the invasive willow sawfly Nematus oligospilus. AB - Invasive organisms can have major impacts on the environment. Some invasive organisms are parthenogenetic in their invasive range and, therefore, exist as a number of asexual lineages (=clones). Determining the reproductive mode of invasive species has important implications for understanding the evolutionary genetics of such species, more especially, for management-relevant traits. The willow sawfly Nematus oligospilus Forster (Hymenoptera: Tenthredinidae) has been introduced unintentionally into several countries in the Southern Hemisphere where it has subsequently become invasive. To assess the population expansion, reproductive mode and host-plant relationships of this insect, microsatellite markers were developed and applied to natural populations sampled from the native and expanded range, along with sequencing of the cytochrome-oxidase I mitochondrial DNA (mtDNA) region. Other tenthredinids across a spectrum of taxonomic similarity to N. oligospilus and having a range of life strategies were also tested. Strict parthenogenesis was apparent within invasive N. oligospilus populations throughout the Southern Hemisphere, which comprised only a small number of genotypes. Sequences of mtDNA were identical for all individuals tested in the invasive range. The microsatellite markers were used successfully in several sawfly species, especially Nematus spp. and other genera of the Nematini tribe, with the degree of success inversely related to genetic divergence as estimated from COI sequences. The confirmation of parthenogenetic reproduction in N. oligospilus and the fact that it has a very limited pool of genotypes have important implications for understanding and managing this species and its biology, including in terms of phenotypic diversity, host relationships, implications for spread and future adaptive change. It would appear to be an excellent model study system for understanding evolution of invasive parthenogens that diverge without sexual reproduction and genetic recombination. PMID- 22929916 TI - Bone metastasis in breast cancer: the story of RANK-ligand. AB - The primary cellular mechanism responsible for osteolytic bone metastases is osteoclastic activation. Preclinical models have shown that breast cancer cells can produce parathyroid hormone-related protein (PTHrP), and other osteolytic molecules, which stimulate excessive osteoclastic bone resorption and establishment of osteolytic lesions. It has been shown that PTHrP by itself cannot directly induce osteoclastic activation, but it mediates its effect through the transactivation of RANK-ligand (RANKL) gene on stromal and osteoblastic cells. Accordingly RANKL up-regulation has been considered as a prerequisite in virtually all conditions of cancer induced bone destruction. Hence, therapeutic targeting of RANKL seems to be a rational approach to treat or even to prevent the process of bone metastases. In this review, we will focus on the unique patho-physiological aspects related to the evolution of bone metastases in breast cancer, emphasizing the pivotal role of RANKL and some other key molecules in osteoclastic bone resorption. We will discuss the therapeutic interventions using bisphosphonates and RANKL inhibitors in patients with bone metastases and the outcome of this novel approach. PMID- 22929913 TI - Decision-making in the adolescent brain. AB - Adolescence is characterized by making risky decisions. Early lesion and neuroimaging studies in adults pointed to the ventromedial prefrontal cortex and related structures as having a key role in decision-making. More recent studies have fractionated decision-making processes into its various components, including the representation of value, response selection (including inter temporal choice and cognitive control), associative learning, and affective and social aspects. These different aspects of decision-making have been the focus of investigation in recent studies of the adolescent brain. Evidence points to a dissociation between the relatively slow, linear development of impulse control and response inhibition during adolescence versus the nonlinear development of the reward system, which is often hyper-responsive to rewards in adolescence. This suggests that decision-making in adolescence may be particularly modulated by emotion and social factors, for example, when adolescents are with peers or in other affective ('hot') contexts. PMID- 22929917 TI - Association of folate intake, dietary habits, smoking and COX-2 promotor -765G>C polymorphism with K-ras mutation in patients with colorectal cancer. AB - BACKGROUND: Understanding the role of environmental and molecular influences on the nature and rate of K-ras mutations in colorectal neoplasms is crucial. COX-2 polymorphisms -765G>C may play a role in carcinogenic processes in combination with specific life-style conditions or dependent on the racial composition of a particular population. If mutational events play an important role in colorectal carcinogenesis sequence, one can hypothesize that modification of these events by life-style or other factors would be a useful prevention strategy. AIM OF WORK: To explore the association between K-ras mutation and potential variables known or suspected to be related to the risk of colorectal cancer (CRC) as well as determining the possible modulating effect of the COX-2 polymorphism, -765G>C. SUBJECTS AND METHODS: The study was conducted on 80 patients with colorectal cancer from Tropical Medicine and Gastrointestinal Tract endoscopy Departments and those attending clinic of the National Cancer Institute, Cairo University during the period extending from April 2009 to March 2010. Full history taking with emphasis on the risk factors of interest, namely age, sex, family history, smoking and dietary history. Serum CEA and CA19-9, RBCs folic acid and occult blood in stool were done to all samples. K-ras protooncogene mutation at codon 12 (exon 1) and cyclooxygenase 2 (COX-2) -765G>C polymorphism were determined by PCR RFLP. RESULTS: The K-ras mutation was positive in 23 (28.7%) patients. COX-2 polymorphism revealed GG in 62.5%, GC in 26.2 % and CC genotype was found in 11.3 % of cases. The mean red blood cell folic acid level was lower in the K-ras positive group (100.96+/-51.3 ng/ml) than the negative group (216.6+/-166.4 ng/ml), (P<0.01). Higher folate levels were found in males than females (median=173 ng/ml and 85 ng/ml; respectively, P=0.002) with adjusted odds ratio (OR) of 0.984. Only, the RBCs folate (P=0.0018) followed by gender (P=0.036) contributed significantly in the discrimination between patients prone to develop K-ras mutation and those who are not. CONCLUSION: RBC folic acid was significantly deficient in CRC (colorectal cancer) patients with K-ras mutations in comparison with CRC patients free of the mutations, suggesting that folic acid may be a risk factor for K-ras mutation development. PMID- 22929918 TI - Epstein-Barr virus and breast cancer: epidemiological and molecular study on Egyptian and Iraqi women. AB - BACKGROUND AND PURPOSE: The role of Epstein-Barr virus (EBV) in breast carcinogenesis is still controversial. Unraveling this relationship is potentially important for better understanding of breast cancer etiology, early detection and possibly prevention of breast cancer. The aim of the current study is to unravel the association between EBV and primary invasive breast cancer (PIBC) in two different Arab populations (Egyptian and Iraqi women). PATIENTS AND METHODS: The study was done on paraffin-embedded tissues of 40 Egyptian and 50 Iraqi patients with PIBC in addition to 20 normal breast tissues as controls for each group. Both controls and neoplastic tissues were assessed for the expression of EBV genes and proteins (EBNA-1, LMP-1, and EBER) as well as CD21 marker by immunohistochemistry (IHC), in situ hybridization (ISH) and PCR techniques. RESULTS: Our gold standard for EBV reactivity in breast cancer cases was positivity of both EBNA1 by PCR and EBER by in situ hybridization. EBV was detected in 18/40 (45%) and 14/50 (28%) of Egyptian and Iraqi women; respectively where p=0.073, compared to 0/20 (0%) of their control groups (p<0.05). Regarding the association between EBV positivity and tumor grade, there was not any statistical significant difference between EBV presence and tumor grade in both populations where p=0.860 and p=0.976 and the calculated rank biserial correlation coefficient was 0.114 and 0.269 for Egyptian and Iraqi women respectively. CONCLUSION: Our findings show that EBV might act as a promoter for the development of PIBC and it might contribute to increased tumor aggressiveness in Egyptian and Iraqi patients. PMID- 22929919 TI - Does fasting during Ramadan trigger non-adherence to oral hormonal therapy in breast cancer patients? AB - PURPOSE: To estimate the effect of fasting during Ramadan (the ninth lunar month) on adherence to oral hormonal therapies (OHT) among breast cancer (BC) patients. PATIENTS AND METHODS: During Ramadan 2010, 139 BC patients were interviewed at the Egyptian National Cancer Institute. They were asked about fasting as well as intake of OHT in Ramadan and in the preceding month. RESULTS: The median age was 50years and most patients were postmenopausal with good performance status and non-metastatic disease. The median number of fasting days was 18% and 93% of patients were fasting 80% or more of Ramadan. Tamoxifen and aromatase inhibitors were used in 64% and 36%, respectively. Adherence to OHT during Ramadan and its preceding month were 94.2% and 95.7%, respectively (p=0.77). In univariate analysis, non-adherence prior to Ramadan and shorter duration of OHT were predictors of non-adherence during Ramadan (P<0.001, 0.003, respectively). Fasting, age, performance status, presence of metastases and type of hormonal therapy were not good predictors of adherence. CONCLUSIONS: While most of patients receiving OHT for BC are fasting during Ramadan, this does not negatively impact compliance with treatment. PMID- 22929920 TI - Hypofractionated conformal irradiation of patients with malignant glioma. AB - PURPOSE: The aim of the study is to evaluate the effect of a conformal irradiation in short fractionation scheme of 49.5Gy in 15 fractions in an overall time of 3 weeks, in terms of overall survival (OAS) and progression free survival (PFS) rates in brain glioma patients. PATIENTS AND METHODS: A prospective study was conducted on 54 brain glioma patients and was carried out in the Radiation Oncology Department, South Egypt Cancer Institute, Assiut University during the period from April 2006 till June 2009. Patients were treated by hypofractionated conformal irradiation (49.5 Gy/15 fractions/3 weeks). RESULTS: The median follow up was 23 months (range: 9-39 months). Two-year OAS and PFS rates were 68% and 60%, respectively. In univariate analysis, age >50 years, poor performance status [Karnofasky score of >=40-<=70%], poor neuroperformance status of score III, high grade tumor [glioblastoma multiforme], and biopsy were all associated with statistically significant reduction in OAS and PFS rates. Multivariate analysis, showed that age >50 years and glioblastoma pathology were the only independent prognostic factors that were associated with poor OAS (p=0.003 and p=0.004, respectively), and PFS (p=0.027 and p=0.011, respectively). CONCLUSION: Hypofractionated conformal radiotherapy was as effective as the conventional radiotherapy, with time sparing for patients, and for radiation oncology centers. Hypofractionated radiotherapy may be considered the radiotherapy regimen of choice in clinical practice for patients with gliomas. PMID- 22929921 TI - The validity of immunocytochemical expression of cyclin D1 in fine needle aspiration cytology of breast carcinoma. AB - PURPOSE: The aim of this work is to study the validity of cyclin D1 expression, a cell cycle regulatory protein, on (fine needle aspiration cytology) FNAC samples in patients with breast carcinoma using immunostaining technique. PATIENT AND METHODS: This is a study done on 70 patients with primary breast carcinoma, presented to Cytology Unit, Pathology Department, National Cancer Institute, Cairo University. They underwent preoperative FNAC and diagnosed as breast carcinoma. The cytologic and tissue section slides were subjected to cyclin D1 immunocytochemical staining. Only the nuclear immunoreactivity for cyclin D1 was considered specific. The rate of concordance, and discordance, and kappa value were calculated. Relation between cytologic expression of cyclin D1 and different clinicopathologic parameters was evaluated. RESULTS: Cyclin D1 immunocytochemical expression was observed in 53/70 cases (75.7%) in cytologic smears. In histologic sections of the corresponding cases, cyclin D1was detected in 48/70 cases (68.6%). The concordance rate of cyclin D1 expression in the FNA and histologic sections was 87.1% while the discordance rate was 12.9%. Kappa showed a value of 0.65. A statistically significant relation was found between cyclin D1 immunocytochemical expression and hormonal status as well as nuclear grade. CONCLUSION: Cyclin D1 immunocytochemical expression can be performed successfully on cytologic samples with a high concordance rate and agreement with histologic results. This can help in determining tumor biology, and plan for patients' treatment. The marker showed a significant relation with hormone receptor status and nuclear grade. PMID- 22929922 TI - Real-time monitoring of ligand-receptor interactions with fluorescence resonance energy transfer. AB - FRET is a process whereby energy is non-radiatively transferred from an excited donor molecule to a ground-state acceptor molecule through long-range dipole dipole interactions. In the present sensing assay, we utilize an interesting property of PDA: blue-shift in the UV-Vis electronic absorption spectrum of PDA (Figure 1) after an analyte interacts with receptors attached to PDA. This shift in the PDA absorption spectrum provides changes in the spectral overlap (J) between PDA (acceptor) and rhodamine (donor) that leads to changes in the FRET efficiency. Thus, the interactions between analyte (ligand) and receptors are detected through FRET between donor fluorophores and PDA. In particular, we show the sensing of a model protein molecule streptavidin. We also demonstrate the covalent-binding of bovine serum albumin (BSA) to the liposome surface with FRET mechanism. These interactions between the bilayer liposomes and protein molecules can be sensed in real-time. The proposed method is a general method for sensing small chemical and large biochemical molecules. Since fluorescence is intrinsically more sensitive than colorimetry, the detection limit of the assay can be in sub-nanomolar range or lower. Further, PDA can act as a universal acceptor in FRET, which means that multiple sensors can be developed with PDA (acceptor) functionalized with donors and different receptors attached on the surface of PDA liposomes. PMID- 22929923 TI - The 1200 patients project: creating a new medical model system for clinical implementation of pharmacogenomics. AB - The paradigm of individualized drug therapy based on genetics is an ideal that is now potentially possible. However, translation of pharmacogenomics into practice has encountered barriers such as limited availability and the high cost of genetic testing, the delays involved, disagreements about interpretation of results, and even lack of understanding about pharmacogenomics in general. We describe our institutional pharmacogenomics-implementation project, "The 1200 Patients Project," a model designed to overcome these barriers and facilitate the availability of pharmacogenomic information for personalized prescribing. PMID- 22929924 TI - A new feature extraction method for signal classification applied to cord dorsum potential detection. AB - In the spinal cord of the anesthetized cat, spontaneous cord dorsum potentials (CDPs) appear synchronously along the lumbo-sacral segments. These CDPs have different shapes and magnitudes. Previous work has indicated that some CDPs appear to be specially associated with the activation of spinal pathways that lead to primary afferent depolarization and presynaptic inhibition. Visual detection and classification of these CDPs provides relevant information on the functional organization of the neural networks involved in the control of sensory information and allows the characterization of the changes produced by acute nerve and spinal lesions. We now present a novel feature extraction approach for signal classification, applied to CDP detection. The method is based on an intuitive procedure. We first remove by convolution the noise from the CDPs recorded in each given spinal segment. Then, we assign a coefficient for each main local maximum of the signal using its amplitude and distance to the most important maximum of the signal. These coefficients will be the input for the subsequent classification algorithm. In particular, we employ gradient boosting classification trees. This combination of approaches allows a faster and more accurate discrimination of CDPs than is obtained by other methods. PMID- 22929926 TI - Phenol degradation under visible light irradiation in the continuous system of photocatalysis and sonolysis. AB - The combination of photocatalysis under visible light irradiation and sonolysis in the continuous system has been used to degrade an aqueous solution of phenol. ZnFe(2)O(4)/TiO(2)-GAC was employed as the photocatalysts which were obtained by sol-gel process and characterized by spectroscopic X-ray diffraction (XRD), scanning electron microscopy with energy dispersive X-ray microanalyses (SEM-EDX) and Brunauer-Emmett-Teller sorptometer (BET). It was observed that the rates of phenol degradation were affected by the initial pH value of phenol solution, salt addition, gas supplying and the recycling times of the recovered photocatalyst. The kinetic law for the phenol degradation can be apparently expressed as the first-order with respect to the concentration of phenol. Degradation of phenol solution in the continuous system, i.e., photocatalysis and sonolysis has synergistic effect in comparison with the photocatalytic reaction and sonolysis, respectively. PMID- 22929925 TI - Using psychological theory to inform methods to optimize the implementation of a hand hygiene intervention. AB - BACKGROUND: Careful hand hygiene (HH) is the single most important factor in preventing the transmission of infections to patients, but compliance is difficult to achieve and maintain. A lack of understanding of the processes involved in changing staff behaviour may contribute to the failure to achieve success. The purpose of this study was to identify nurses' and administrators' perceived barriers and facilitators to current HH practices and the implementation of a new electronic monitoring technology for HH. METHODS: Ten key informant interviews (three administrators and seven nurses) were conducted to explore barriers and facilitators related to HH and the impact of the new technology on outcomes. The semi structured interviews were based on the Theoretical Domains Framework by Michie et al. and conducted prior to intervention implementation. Data were explored using an inductive qualitative analysis approach. Data between administrators and nurses were compared. RESULTS: In 9 of the 12 domains, nurses and administrators differed in their responses. Administrators believed that nurses have insufficient knowledge and skills to perform HH, whereas the nurses were confident they had the required knowledge and skills. Nurses focused on immediate consequences, whereas administrators highlighted long-term outcomes of the system. Nurses concentrated foremost on their personal safety and their families' safety as a source of motivation to perform HH, whereas administrators identified professional commitment, incentives, and goal setting. Administrators stated that the staff do not have the decision processes in place to judge whether HH is necessary or not. They also highlighted the positive aspects of teams as a social influence, whereas nurses were not interested in group conformity or being compared to others. Nurses described the importance of individual feedback and self-monitoring in order to increase their performance, whereas administrators reported different views. CONCLUSIONS: This study highlights the benefits of using a structured approach based on psychological theory to inform an implementation plan for a behavior change intervention. This work is an essential step towards systematically identifying factors affecting nurses' behaviour associated with HH. PMID- 22929927 TI - Wetting and reaction promoted by ultrasound between sapphire and liquid Al-12Si alloy. AB - Ultrasonic-assisted wetting between sapphire bulks and liquid Al-12Si alloy in an atmospheric environment at 620 degrees C is carried out in this study. Complete, rather than partial, wetting and joining can be achieved with the aid of ultrasound. Growth of epitaxial alumina on sapphire bulks is promoted dramatically during ultrasonic-assisted wetting comparing to that during hot dipping without ultrasound. XRD results show that the epitaxial alumina is non crystalline. This indicates that the temperature on the surface of the sapphire substrate is not more than 1200 degrees C even though the collapse of acoustic cavitation bubbles could theoretically produce extremely high temperature. The bonding force at the interface between the Al-Si alloy and sapphire is strengthened because of the epitaxial alumina. The interfacial shear strength of sapphire/Al-Si alloy can reach as high as 60-65 MPa. The fracture morphology shows that cracks initiated at the interface between Si grains and the epitaxial alumina on sapphire. This result is especially useful for the joining of metals and ceramics. PMID- 22929928 TI - Creaming enhancement in a liter scale ultrasonic reactor at selected transducer configurations and frequencies. AB - Recent research has shown that high frequency ultrasound (0.4-3 MHz), can enhance milkfat separation in small scale systems able to treat only a few milliliters of sample. In this work, the effect of ultrasonic standing waves on milkfat creaming was studied in a 6L reactor and the influence of different frequencies and transducer configurations in direct contact with the fluid was investigated. A recombined coarse milk emulsion with fat globules stained with oil-red-O dye was selected for the separation trials. Runs were performed with one or two transducers placed in vertical (parallel or perpendicular) and horizontal positions (at the reactor base) at 0.4, 1 and/or 2 MHz (specific energy 8.5 +/- 0.6 kJ/kg per transducer). Creaming behavior was assessed by measuring the thickness of the separated cream layer. Other methods supporting this assessment included the measurement of fat content, backscattering, particle size distribution, and microscopy of samples taken at the bottom and top of the reactor. Most efficient creaming was found after treatment at 0.4 MHz in single and double vertical transducer configurations. Among these configurations, a higher separation rate was obtained when sonicating at 0.4 MHz in a vertical perpendicular double transducer setup. The horizontal transducer configuration promoted creaming at 2 MHz only. Fat globule size increase was observed when creaming occurred. This research highlights the potential for enhanced separation of milkfat in larger scale systems from selected transducer configurations in contact with a dairy emulsion, or emulsion splitting in general. PMID- 22929929 TI - A better exam. PMID- 22929930 TI - [Do we need yet another cancer plan?]. PMID- 22929934 TI - [Last chance for effective antibiotics?]. PMID- 22929935 TI - [A time plan for better forensic psychiatry]. PMID- 22929936 TI - [Maximum expected heart rate]. PMID- 22929937 TI - [Vaccination Research running on empty]. PMID- 22929938 TI - [Research ethics, truth and love]. PMID- 22929939 TI - [Physicians inspired the olympic games]. PMID- 22929940 TI - Red blood cell transfusion at Ulleval University Hospital--indications, consumption and blood group immunisation. AB - BACKGROUND: Knowledge of clinical transfusion practice should be improved to ensure that therapy is optimally effective, to avoid waste of resources and to ensure a safe supply of blood. MATERIAL AND METHOD: All patients who received a transfusion of red blood cell concentrate at Ulleval University Hospital in two 14-day periods in 2003 were included. Diagnoses, haemoglobin values and intervention codes were recorded from the patient records for which consent to access had been given. Blood samples were taken from consenting survivors to be tested for blood group immunisation. RESULTS: 348 patients were included. The median age was 62.8 years. They were given 1,162 concentrates in 471 transfusion episodes, of which 373 (79 %) consisted of one or two concentrates. As at 1 February 2009, 181 patients (52 %) were registered as having died. Access was possible to the records of 218 patients. The primary diagnosis was cancer for 76 patients (35 %), injuries for 36 (17 %) and cardiovascular disease for 34 (16 %). The transfusion was given to 89 (41 %) of patients in connection with a surgical intervention during the period covered by the patient records. A note about the transfusion was lacking in 46 (21 %) of the records. Transfusions were given to 52 patients whose haemoglobin concentration was above a threshold level of >= 8 g/100 ml (43 % of the patients). Blood group immunisation was found in one (3 %) of 38 survivors. INTERPRETATION: Red blood cell transfusion is most commonly given to elderly patients with chronic disorders and uncertain long-term prognoses. The clinical documentation is not infrequently incomplete. There is probably scope for a reduction in consumption if indications are based more on established scientific evidence and well-defined transfusion protocols. Blood group immunisation is not a frequent complication. PMID- 22929941 TI - Diagnosis of dementia--automatic quantification of brain structures. AB - BACKGROUND: The aim of the present study was to examine the usefulness of a fully automatic quantification of brain structures by means of magnetic resonance imaging (MRI) for diagnosing dementia of the Alzheimer's type (DAT). MATERIAL AND METHOD: MRI scans of the brains of 122 patients, referred to a memory clinic, were analysed using Neuroquant(r) software, which quantifies the volume of various brain structures. Clinical diagnoses were made by two doctors without knowledge of the MRI results. We performed Receiver Operating Characteristic analyses and calculated the area under the curve (AUC). A value of 1 means that all ill patients have been diagnosed as diseased and no patient has been falsely diagnosed as diseased. RESULTS: The mean age of the patients was 67.2 years (SD 10.5 years), 60 % were men, 63 had DAT, 24 had another type of dementia, 25 had mild cognitive impairment (MCI) and ten had subjective cognitive impairment (SCI). In the comparison between DAT patients and patients with SCI or MCI, seven of eleven volumes were significantly larger than AUC 0.5. Positive and negative likelihood ratios were less than 5 and more than 0.2, respectively, for the best limit values of the volumes. Apart from the cerebellum (AUC 0.67), none of the brain structures was significantly different from AUC 0.5 in patients with dementia conditions other than dementia Alzheimer's type. INTERPRETATION: MRI scans with Neuroquant analyses cannot be used alone to distinguish between persons with dementia of Alzheimer's type and persons without dementia. PMID- 22929942 TI - [Glioma-associated epilepsy]. AB - BACKGROUND: Epileptic seizures are a common symptom in patients with primary brain tumours of the glioma type. The paper presents a discussion of epileptogenesis, choice of medication and follow-up of these patients. METHOD: The article is based on a search in PubMed and selection of articles based on the authors' discretionary judgement and clinical experience with this patient group. RESULTS: Epileptic seizures are a common symptom of glioma, particularly the low grade types. The background to glioma-associated epilepsy is multifactorial, and the molecular biological characteristics of the tumour probably play a central part in the epileptogenesis. Effective treatment of epileptic seizures is of great importance to the quality of life of the glioma patient. Seizure frequency and the effectiveness of anti-epileptic treatment vary, and some patients require treatment with several anti-epileptic drugs. Surgical and oncological treatment of the tumour will also often reduce the frequency of seizures. CONCLUSION: As a general rule, antiepileptics without enzyme-inducing properties and with low protein-binding should be preferred for glioma patients. This will reduce the risk of interactions with chemotherapy or steroid therapy. Patients with brain tumours are particularly vulnerable to the effects on wakefulness, moods and cognition, and this should be borne in mind in the choice of medication and in follow-up. Haematological status should be monitored particularly closely when there is concomitant use of chemotherapy and antiepileptic drugs that may affect the bone marrow function. PMID- 22929943 TI - Cerebral venous thrombosis with venous infarction. PMID- 22929945 TI - [Problems with dizziness]. PMID- 22929944 TI - [A man with debilitating orthostatic hypotension]. PMID- 22929946 TI - [Two men who acquired acute respiratory symptoms while working at a water treatment plant]. PMID- 22929947 TI - [Of harm and of benefit]. PMID- 22929948 TI - Knowledge, leadership and quality in the medical school curriculum. PMID- 22929949 TI - [American medical education]. PMID- 22929952 TI - [LIS and LUS]. PMID- 22929953 TI - [From stud.med. to medical student]. PMID- 22929956 TI - Slow force response and auto-regulation of contractility in heterogeneous myocardium. AB - Classically, the slow force response (SFR) of myocardium refers to slowly developing changes in cardiac muscle contractility induced by external mechanical stimuli, e.g. sustained stretch. We present evidence for an intra-myocardial SFR (SFR(IM)), caused by the internal mechanical interactions of muscle segments in heterogeneous myocardium. Here we study isometric contractions of a pair of end to-end connected functionally heterogeneous cardiac muscles (an in-series muscle duplex). Duplex elements can be either biological muscles (BM), virtual muscles (VM), or a hybrid combination of BM and VM. The VM implements an Ekaterinburg Oxford mathematical model accounting for the ionic and myofilament mechanisms of excitation-contraction coupling in cardiomyocytes. SFR(IM) is expressed in gradual changes in the overall duplex force and in the individual contractility of each muscle, induced by cyclic auxotonic deformations of coupled muscles. The muscle that undergoes predominant cyclic shortening shows force enhancement upon return to its isometric state in isolation, whereas average cyclic lengthening may decrease the individual muscle contractility. The mechanical responses are accompanied with slow and opposite changes in the shape and duration of both the action potential and Ca2+ transient in the cardiomyocytes of interacting muscles. Using the mathematical model we found that the contractility changes in interacting muscles follow the alterations in the sarcoplasmic reticulum loading in cardiomyocytes which result from the length-dependent Ca2+ activation of myofilaments and intracellular mechano-electrical feedback. The SFR(IM) phenomena unravel an important mechanism of cardiac functional auto-regulation applicable to the heart in norm and pathology, especially to hearts with severe electrical and/or mechanical dyssynchrony. PMID- 22929957 TI - Immunohistochemical localization of T-lymphocyte subsets in the developing lymphoid tissues of the tammar wallaby (Macropus eugenii). AB - Research into marsupial adaptive immunity during ontogeny has been hampered by the lack of antibodies that react to marsupial immunological cell populations. In this study, newly synthesised polyclonal antibodies to the T cell marker, CD8, have been developed and used to investigate the ontogeny and distribution of this T cell population in the tammar wallaby. Immunohistochemical analysis indicated that the distribution of the CD8 lymphocytes in the lymphoid tissues of tammar neonates during the first 144 days of pouch life was similar to that of the eutherian mammals. However, CD8alpha(+) lymphocytes were observed in the intestines of tammar neonates prior to their first appearance in the cervical thymus, an observation that has not been found in eutherians. A dual labelling immunohistochemical approach was used for the indirect demonstration of CD4 and enabled the simultaneous detection in the tammar wallaby tissues of the two major T-lymphocyte populations, CD4 and CD8 that are associated with adaptive immunity. As in eutherian mammals, CD4(+) cells were the predominant T cell lymphocyte subset observed in the spleen while in the nodal tissues, an age-related decrease in the CD4(+)/CD8(+) ratio was noted. These antibodies provide a new immunological tool to study the role of T cell subsets in marsupial immunity and disease pathogenesis studies. PMID- 22929959 TI - Experimental and theoretical studies on pyrene-grafted polyoxometalate hybrid. AB - A novel pyrene covalently-attached polyoxometalate (POM) hybrid has been synthesized and fully characterized. The attractive electronic and photophysical properties of pyrene derivatives make the hybrid promising for studying and understanding electron transfer mechanisms in organic-functionalized POMs. The hybrid has an electronic absorption at 450 nm, indicating that there is a strong electronic interaction between the organic pyreneimido group and inorganic hexamolybdate cluster. The electron transfer mechanism of the as-prepared hybrid is illuminated via the combined studies of theoretical calculations and transient absorption spectroscopy. Time-dependent density functional theory studies revealed that the strong electronic absorption at the visible region mainly comes from the optically allowed pi-pi* transitions of the pyreneimido component (S(0) to S(2) transition). The electron transfer process from the excited pyreneimido moiety to the inorganic POM cluster is at the time scale of ~700 fs, which could be ascribed to the internal conversion of singlet excited states from S(2) state to S(1) state. This study provided a clear understanding of the mechanism governing the electron transfer process in organoimido derivatives of POMs. This result might offer a new route for the design of new charge transfer hybrid clusters of organic functionalized POMs and crucial guidance for their applications in optical and electrical devices. PMID- 22929960 TI - High frequency in the delay in primary tooth loss in X-linked chronic granulomatous disease. PMID- 22929963 TI - 'Cutoff point for selenium deficiency'. PMID- 22929964 TI - Neural effects of green tea extract on dorsolateral prefrontal cortex. AB - BACKGROUND/OBJECTIVES: Green tea is being recognized as a beverage with potential benefits for human health and cognitive functions. In vivo studies provide preliminary evidence that green tea intake may have a positive role in improving effects on cognitive functions. We aimed to examine the neural effects of green tea extract on brain activation in humans. SUBJECTS/METHODS: Functional magnetic resonance imaging was recorded while 12 healthy volunteers performed a working memory task following administration of 250 or 500 ml of a milk whey based green tea containing soft drink or milk whey based soft drink without green tea as control in a double-blind, controlled repeated measures within-subject design with counterbalanced order of substance administration. A whole-brain analysis with a cluster-level threshold of P<0.001 (unadjusted) was followed by an a priori-defined region of interest (ROI) analysis of the dorsolateral prefrontal cortex (DLPFC) including a cluster-level threshold of P<0.05 and family-wise error (FWE) adjustment for multiple comparisons. RESULTS: Whole-brain analyses revealed no significant effects after correction for multiple comparisons (FWE P<0.05). Using a ROI approach, green tea extract increased activation in the DLPFC relative to a control condition (FWE P<0.001). This neural effect was related to green tea dosage. Green tea extract was not associated with any significant attenuation in regional activation relative to control condition. CONCLUSIONS: These data suggest that green tea extract may modulate brain activity in the DLPFC, a key area that mediates working memory processing in the human brain. Moreover, this is the first neuroimaging study implicating that functional neuroimaging methods provide a means of examining how green tea extract acts on the brain. PMID- 22929965 TI - Adaptable pulmonary artery band for late arterial switch procedure in transposition of the great arteries. AB - BACKGROUND: In late-diagnosed transposition of the great arteries (TGA), the left ventricle (LV) involutes as it pumps against low resistance and needs retraining by applying a pulmonary artery band (PAB) in preparation for an arterial switch operation. We report our experience with a telemetrically adaptable band compared with classic banding. METHODS: Ten patients underwent retraining of the LV, 4 patients with an adaptable band and progressive weekly tightening of the band (group 1) and 6 patients with a traditional band (group 2). RESULTS: Mean weight and age at pulmonary band placement was 5.8+/-2.36 kg and 11.7+/-11.1 months for group 1 and 5.0+/-2.3 kg and 6.4+/-7.6 months for group 2. Time between palliation and switch procedure was 4.2 months in both groups. Group 1 showed an initial mean pulmonary gradient of 25.5+/-4.43 mm Hg with a 5% closure of the device. The mean gradient increased with progressive closure to 63.5+/-9.8 mm Hg at the time of the arterial switch operation. There were no reinterventions or deaths in this group. In group 2, the mean pulmonary gradient increased with growth from 49+/-21.4 mm Hg to 68.4+/-7.86 mm Hg at the time of the switch procedure. However, 4 of these patients required reoperations during retraining: 2 needed 1 reoperation and 2 needed 2 reoperations. Two patients died-1 after banding and 1 after the switch operation. CONCLUSIONS: Retraining of the LV by the adaptable device allows precise control of the tightening, avoids repetitive operations, and diminishes morbidity. PMID- 22929966 TI - Primary microglia isolation from mixed glial cell cultures of neonatal rat brain tissue. AB - Microglia account for approximately 12% of the total cellular population in the mammalian brain. While neurons and astrocytes are considered the major cell types of the nervous system, microglia play a significant role in normal brain physiology by monitoring tissue for debris and pathogens and maintaining homeostasis in the parenchyma via phagocytic activity. Microglia are activated during a number of injury and disease conditions, including neurodegenerative disease, traumatic brain injury, and nervous system infection. Under these activating conditions, microglia increase their phagocytic activity, undergo morpohological and proliferative change, and actively secrete reactive oxygen and nitrogen species, pro-inflammatory chemokines and cytokines, often activating a paracrine or autocrine loop. As these microglial responses contribute to disease pathogenesis in neurological conditions, research focused on microglia is warranted. Due to the cellular heterogeneity of the brain, it is technically difficult to obtain sufficient microglial sample material with high purity during in vivo experiments. Current research on the neuroprotective and neurotoxic functions of microglia require a routine technical method to consistently generate pure and healthy microglia with sufficient yield for study. We present, in text and video, a protocol to isolate pure primary microglia from mixed glia cultures for a variety of downstream applications. Briefly, this technique utilizes dissociated brain tissue from neonatal rat pups to produce mixed glial cell cultures. After the mixed glial cultures reach confluency, primary microglia are mechanically isolated from the culture by a brief duration of shaking. The microglia are then plated at high purity for experimental study. The principle and protocol of this methodology have been described in the literature. Additionally, alternate methodologies to isolate primary microglia are well described. Homogenized brain tissue may be separated by density gradient centrifugation to yield primary microglia. However, the centrifugation is of moderate length (45 min) and may cause cellular damage and activation, as well as, cause enriched microglia and other cellular populations. Another protocol has been utilized to isolate primary microglia in a variety of organisms by prolonged (16 hr) shaking while in culture. After shaking, the media supernatant is centrifuged to isolate microglia. This longer two-step isolation method may also perturb microglial function and activation. We chiefly utilize the following microglia isolation protocol in our laboratory for a number of reasons: (1) primary microglia simulate in vivo biology more faithfully than immortalized rodent microglia cell lines, (2) nominal mechanical disruption minimizes potential cellular dysfunction or activation, and (3) sufficient yield can be obtained without passage of the mixed glial cell cultures. It is important to note that this protocol uses brain tissue from neonatal rat pups to isolate microglia and that using older rats to isolate microglia can significantly impact the yield, activation status, and functional properties of isolated microglia. There is evidence that aging is linked with microglia dysfunction, increased neuroinflammation and neurodegenerative pathologies, so previous studies have used ex vivo adult microglia to better understand the role of microglia in neurodegenerative diseases where aging is important parameter. However, ex vivo microglia cannot be kept in culture for prolonged periods of time. Therefore, while this protocol extends the life of primary microglia in culture, it should be noted that the microglia behave differently from adult microglia and in vitro studies should be carefully considered when translated to an in vivo setting. PMID- 22929967 TI - Diclofenac delays micropore closure following microneedle treatment in human subjects. AB - Drugs absorbed poorly through the skin are commonly delivered via injection with a hypodermic needle, which is painful and increases the risk of transmitting infectious diseases. Microneedles (MNs) selectively and painlessly permeabilize the outermost skin layer, allowing otherwise skin-impermeable drugs to cross the skin through micron-sized pores and reach therapeutic concentrations. However, rapid healing of the micropores prevents further drug delivery, blunting the clinical utility of this unique transdermal technique. We present the first human study demonstrating that micropore lifetime can be extended following MN treatment. Subjects received one-time MN treatment and daily topical application of diclofenac sodium. Micropore closure was measured with impedance spectroscopy, and area under the admittance-time curve (AUC) was calculated. AUC was significantly higher at MN+diclofenac sodium sites vs. placebo, suggesting slower rates of micropore healing. Colorimetry measurements confirmed the absence of local erythema and irritation. This mechanistic human proof-of-concept study demonstrates that micropore lifetime can be prolonged with simple topical administration of a non-specific cyclooxygenase inhibitor, suggesting the involvement of subclinical inflammation in micropore healing. These results will allow for longer patch wear time with MN-enhanced delivery, thus increasing patient compliance and expanding the transdermal field to a wider variety of clinical conditions. PMID- 22929968 TI - Precocious sexual signalling and mating in Anastrepha fraterculus (Diptera: Tephritidae) sterile males achieved through juvenile hormone treatment and protein supplements. AB - Sexual maturation of Anastrepha fraterculus is a long process. Methoprene (a mimic of juvenile hormone) considerably reduces the time for sexual maturation in males. However, in other Anastrepha species, this effect depends on protein intake at the adult stage. Here, we evaluated the mating competitiveness of sterile laboratory males and females that were treated with methoprene (either the pupal or adult stage) and were kept under different regimes of adult food, which varied in the protein source and the sugar:protein ratio. Experiments were carried out under semi-natural conditions, where laboratory flies competed over copulations with sexually mature wild flies. Sterile, methoprene-treated males that reached sexual maturity earlier (six days old), displayed the same lekking behaviour, attractiveness to females and mating competitiveness as mature wild males. This effect depended on protein intake. Diets containing sugar and hydrolyzed yeast allowed sterile males to compete with wild males (even at a low concentration of protein), while brewer's yeast failed to do so even at a higher concentration. Sugar only fed males were unable to achieve significant numbers of copulations. Methoprene did not increase the readiness to mate of six-day-old sterile females. Long pre-copulatory periods create an additional cost to the management of fruit fly pests through the sterile insect technique (SIT). Our findings suggest that methoprene treatment will increase SIT effectiveness against A. fraterculus when coupled with a diet fortified with protein. Additionally, methoprene acts as a physiological sexing method, allowing the release of mature males and immature females and hence increasing SIT efficiency. PMID- 22929969 TI - Non-invasive breath analysis of pulmonary nodules. AB - INTRODUCTION: The search for non-invasive diagnostic methods of lung cancer (LC) has led to new avenues of research, including the exploration of the exhaled breath. Previous studies have shown that LC can, in principle, be detected through exhaled-breath analysis. This study evaluated the potential of exhaled breath analysis for the distinction of benign and malignant pulmonary nodules (PNs). METHODS: Breath samples were taken from 72 patients with PNs in a prospective trial. Profiles of volatile organic compounds were determined by (1) gas chromatography/mass spectrometry (GC-MS) combined with solid-phase microextraction and (2) a chemical nanoarray. RESULTS: Fifty-three PNs were malignant and 19 were benign with similar smoking histories and comorbidities. Nodule size (mean +/- SD) was 2.7 +/- 1.7 versus 1.6 +/- 1.3 cm (p = 0.004), respectively. Within the malignant group, 47 were non-small-cell lung cancer and six were small-cell lung cancer. Thirty patients had early-stage disease and 23 had advanced disease. Gas chromatography/mass spectrometry analysis identified a significantly higher concentration of 1-octene in the breath of LC, and the nanoarray distinguished significantly between benign versus malignant PNs (p < 0.0001; accuracy 88 +/- 3%), between adeno- and squamous-cell carcinomas [LINE SEPARATOR](p < 0.0001; 88 +/- 3%) and between early stage and advanced disease (p < 0.0001; 88 +/- 2%). CONCLUSIONS: In this pilot study, breath analysis discriminated benign from malignant PNs in a high-risk cohort based on LC-related volatile organic compound profiles. Furthermore, it discriminated adeno- and squamous-cell carcinoma and between early versus advanced disease. Further studies are required to validate this noninvasive approach, using a larger cohort of patients with PNs detected by computed tomography. PMID- 22929970 TI - Dietary polyphenol-derived protection against neurotoxic beta-amyloid protein: from molecular to clinical. AB - Polyphenolic compounds derived mainly from plant products have demonstrated neuroprotective properties in a number of experimental settings. Such protective effects have often been ascribed to antioxidant capacity, but specific augmentation of other cellular defences and direct interactions with neurotoxic proteins have also been demonstrated. With an emphasis on neurodegenerative conditions, such as Alzheimer's disease, we highlight recent findings on the neuroprotection ascribed to bioactive polyphenols capable of directly interfering with the Alzheimer's disease hallmark toxic beta-amyloid protein (Abeta), thereby inhibiting fibril and aggregate formation. This includes compounds such as the green tea polyphenol (-)-epigallocatechin-3-gallate (EGCG) and the phytoalexin resveratrol. Targeted studies on the biomolecular interactions between dietary polyphenolics and Abeta have not only improved our understanding of the pathogenic role of beta-amyloid, but also offer fundamentally novel treatment options for Alzheimer's disease and potentially other amyloidoses. PMID- 22929971 TI - HS-173, a novel phosphatidylinositol 3-kinase (PI3K) inhibitor, has anti-tumor activity through promoting apoptosis and inhibiting angiogenesis. AB - We synthesized a novel imidazopyridine analogue, a PI3Kalpha inhibitor HS-173 and investigated anti-cancer capacity in human cancer cells. HS-173 inhibited the PI3K signaling pathway, and showed anti-proliferative effects on cancer cells. Also, HS-173 induced cell cycle arrest at the G(2)/M phase and apoptosis. In addition, HS-173 decreased the expression HIF-1alpha and VEGF which play an important role in angiogenesis. This effect was confirmed by the suppression of tube formation and migration assay in vitro. Furthermore, HS-173 diminished blood vessel formation in the Matrigel plug assay in mice. Therefore, HS-173 is considered as a novel drug candidate to treat cancer patients. PMID- 22929972 TI - Impact of FLT3 ITD/NPM1 mutation status in adult patients with acute myelocytic leukemia autografted in first remission. PMID- 22929973 TI - High frequencies of SF3B1 and JAK2 mutations in refractory anemia with ring sideroblasts associated with marked thrombocytosis strengthen the assignment to the category of myelodysplastic/myeloproliferative neoplasms. PMID- 22929974 TI - Recent trends in survival of adult patients with acute leukemia: overall improvements, but persistent and partly increasing disparity in survival of patients from minority groups. AB - The survival of younger patients with acute leukemia has improved in the early 21(st) century, but it is unknown whether people of all ethnic and racial backgrounds have benefited equally. Using cancer registry data from the Surveillance, Epidemiology and End Results Program, we assessed trends in 5-year relative survival for patients aged 15 years or more with acute lymphoblastic leukemia and acute myeloblastic leukemia divided by racial and ethnic group, including non-Hispanic whites, African-Americans, Hispanics, and Asian-Pacific Islanders in the 1990s and the early 21(st) century. Modeled period analysis was used to obtain the most up-to-date estimates of survival. Overall, the 5-year survival increased from 31.6% in 1997-2002 to 39.0% in 2003-2008 for patients with acute lymphoblastic leukemia and from 15.5% in 1991-1996 to 22.5% in 2003 2008 for those with acute myeloblastic leukemia. Nevertheless, among patients with acute lymphoblastic leukemia, age-adjusted 5-year relative survival rates remained lower for African-Americans and Hispanics than for non-Hispanic whites. Among patients with acute myeloblastic leukemia, the increase in survival was greatest (from 32.6% in 1991-1996 to 47.1% in 2003-2008) for younger patients (15 54 years), and was more pronounced for non-Hispanic whites (+16.4% units) than for other patients (+10.8% units). Increases in survival are observed in all ethnic or racial groups. Nevertheless, among patients with acute leukemias, disparities in survival persist between non-Hispanic white people and people of other ethnic or racial groups. Disparities are increasing in younger patients with acute myeloblastic leukemia. Improvements in access to treatment, especially for minority patients, may improve outcomes. PMID- 22929975 TI - Serial assessment of suspected myelodysplastic syndromes: significance of flow cytometric findings validated by cytomorphology, cytogenetics, and molecular genetics. AB - The significance of flow cytometry indicating myelodysplasia without proof of myelodysplasia by cytomorphology remains to be clarified. We evaluated follow-up analyses in 142 patients analyzed in parallel by flow cytometry, cytomorphology and cytogenetics for suspected myelodysplasia without proof of myelodysplasia by cytomorphology. At initial assessment, flow cytometry indicated myelodysplasia in 64 of 142 (45.1%) patients. In 9 of 142 (6.3%) patients, cytogenetics revealed aberrant karyotypes at first evaluation that were found in 5 of 64 (7.8%) patients rated with myelodysplasia by flow cytometry. The remaining 133 patients without proof of myelodysplasia by cytomorphology and with normal karyotype underwent follow-up analyses that confirmed myelodysplasia by cytomorphology, cytogenetics or molecular genetics in 47 (35.3%) after a median interval of nine months (range 1-53 months). As far as initial flow cytometry results are concerned, this applied to 30 of 59 (50.1%) with myelodysplasia, 10 of 42 (23.8%) with "possible myelodysplasia" (minor antigen aberrancies only) and 7 of 32 (21.9%) without myelodysplasia (P=0.004). Notably, in these latter 7 patients, flow cytometry results changed at follow up to "possible myelodysplasia" (n=4) and "myelodysplasia" (n=2). These data argue in favor of including flow cytometry along with cytomorphology, cytogenetics and molecular genetics to diagnose myelodysplasia, and suggest a closer monitoring of patients with myelodysplasia typical aberrant antigen expression found by flow cytometry. PMID- 22929976 TI - Correlation of clinical response and response duration with miR-145 induction by lenalidomide in CD34(+) cells from patients with del(5q) myelodysplastic syndrome. AB - We examined whether lenalidomide exposure up-regulates miRNAs and mRNAs, previously shown to play a role in the disease phenotype of del(5q) myelodysplastic syndrome, in pre-treatment CD34(+) marrow cells. We hypothesized that increased expression would predict for clinical response. Changes in miR 143, miR-145, miR-146a, miR-146b, miR-378, miR-584, SPARC and RPS14 were examined in del(5q) (n=10) and non-del(5q) (n=18) myelodysplastic syndrome patient samples. Significantly increased expression of miR-143 (1.8-fold and 1.5-fold in del(5q) and non-del(5q), respectively), and miR-145 (1.9-fold and 1.6-fold in del(5q) and non-del(5q), respectively) was observed. In the del(5q) myelodysplastic syndrome cohort, transfusion independence correlated with a 1.3 fold or more increase in miR-145 expression and response over 12 months correlated with a 1.5-fold or more increase. Knockdown of miR-143 and miR-145 in cord blood CD34(+) cells resulted in increased erythroid progenitor activity. Lenalidomide selectively abrogated progenitor activity in cells depleted of miR 143 and miR-145 supporting a key role for miR-143/145 in the sensitivity to lenalidomide of del(5q) myelodysplastic syndrome patients. PMID- 22929977 TI - Genetic modification of human T lymphocytes for the treatment of hematologic malignancies. AB - Modern chemotherapy regimens and supportive care have produced remarkable improvements in the overall survival of patients with hematologic malignancies. However, the development of targeted small molecules, monoclonal antibodies, and biological therapies that demonstrate greater efficacy and lower toxicity remains highly desirable in hematology, and oncology in general. In the context of biological therapies, T-lymphocyte based treatments have enormous potential. Donor lymphocyte infusion in patients relapsed after allogeneic hematopoietic stem cell transplant pioneered the concept that T lymphocytes can effectively control tumor growth, and this was then followed by the development of cell culture strategies to generate T lymphocytes with selective activity against tumor cells. Over the past decade, it has become clear that the adoptive transfer of ex vivo expanded antigen-specific cytotoxic T lymphocytes promotes sustained antitumor effects in patients with virus-associated lymphomas, such as Epstein Barr virus related post-transplant lymphomas and Hodgkin's lymphomas. Because of this compelling clinical evidence and the concomitant development of methodologies for robust gene transfer to human T lymphocytes, the field has rapidly evolved, offering new opportunities to extend T-cell based therapies. This review summarizes the most recent biological and clinical developments using genetically manipulated T cells for the treatment of hematologic malignancies. PMID- 22929978 TI - B-lymphopoiesis is stopped by mobilizing doses of G-CSF and is rescued by overexpression of the anti-apoptotic protein Bcl2. AB - Osteoblasts are necessary to B lymphopoiesis and mobilizing doses of G-CSF or cyclophosphamide inhibit osteoblasts, whereas AMD3100/Plerixafor does not. However, the effect of these mobilizing agents on B lymphopoiesis has not been reported. Mice (wild-type, knocked-out for TNF-alpha and TRAIL, or over expressing Bcl-2) were mobilized with G-CSF, cyclophosphamide, or AMD3100. Bone marrow, blood, spleen and lymph node content in B cells was measured. G-CSF stopped medullar B lymphopoiesis with concomitant loss of B-cell colony-forming units, pre-pro-B, pro-B, pre-B and mature B cells and increased B-cell apoptosis by an indirect mechanism. Overexpression of the anti-apoptotic protein Bcl2 in transgenic mice rescued B-cell colony forming units and pre-pro-B cells in the marrow, and prevented loss of all B cells in marrow, blood and spleen. Blockade of endogenous soluble TNF-alpha with Etanercept, or combined deletion of the TNF alpha and TRAIL genes did not prevent B lymphopoiesis arrest in response to G CSF. Unlike G-CSF, treatments with cyclophosphamide or AMD3100 did not suppress B lymphopoiesis but caused instead robust B-cell mobilization. G-CSF, cyclophosphamide and AMD3100 have distinct effects on B lymphopoiesis and B-cell mobilization with: 1) G-CSF inhibiting medullar B lymphopoiesis without mobilizing B cells in a mechanism distinct from the TNF-alpha-mediated loss of B lymphopoiesis observed during inflammation or viral infections; 2) CYP mobilizing B cells but blocking their maturation; and 3) AMD3100 mobilizing B cells without affecting B lymphopoiesis. These results suggest that blood mobilized with these three agents may have distinct immune properties. PMID- 22929979 TI - Platelet factor 4 induces cell apoptosis by inhibition of STAT3 via up-regulation of SOCS3 expression in multiple myeloma. AB - Platelet factor 4 (PF4) is an angiostatic chemokine that suppresses tumor growth and metastasis. We previously revealed frequent transcriptional silencing of PF4 in multiple myeloma, but the functional roles of this chemokine are still unknown. We studied the apoptotic effects of PF4 on myeloma cell lines and primary myeloma in vitro, and investigated the involved signaling pathway. The in vivo effects were also studied using a mouse model. PF4 not only suppressed myeloma-associated angiogenesis, but also inhibited growth and induced apoptosis in myeloma cells. We found that PF4 negatively regulated STAT3 and concordantly inhibited constitutive and interleukin-6-induced phosphorylation of STAT3, and down-regulated the expression of STAT3 target genes (Mcl-1, survivin and VEGF). Overexpression of constitutively activated STAT3 could rescue PF4-induced apoptotic effects. Furthermore, we found that PF4 induced the expression of SOCS3, a STAT3 inhibitor, and gene silencing of SOCS3 abolished its ability to inhibit STAT3 activation, suggesting a critical role of SOCS3 in PF4-induced STAT3 inhibition. Knockdown of LRP1, a putative PF4 receptor, could also abolish PF4-induced apoptosis and STAT3 inhibition. Finally, the tumor growth inhibitory effect of PF4 was confirmed by in vivo mouse models. Immunostaining of rabbit bone xenografts from PF4-treated mice showed induction of apoptosis of myeloma cells and inhibition of angiogenesis, which was associated with suppression of STAT3 activity. Together, our preclinical data indicate that PF4 may be a potential new targeting agent for the treatment of myeloma. PMID- 22929981 TI - A high level of fatigue among long-term survivors of non-Hodgkin's lymphoma: results from the longitudinal population-based PROFILES registry in the south of the Netherlands. AB - The course of fatigue and quality of life in survivors of non-Hodgkin's lymphoma is unknown. The aims of this study were, therefore, to assess fatigue and quality of life in patients with non-Hodgkin's lymphoma following primary treatment, compare fatigue and quality of life in these patients with those of an age- and sex matched normative population to assess the severity of concerns and identify associations with fatigue of survivors who remained fatigued. The population based Eindhoven Cancer Registry was used to select all patients diagnosed with non-Hodgkin's lymphoma from 1999-2009. The European Organization for Research and Treatment of Cancer Quality of Life Questionnaire and the Fatigue Assessment Scale were completed once by 824 survivors of non-Hodgkin's lymphoma (80% response rate); 434 survivors completed these questionnaires again 1 year later. Survivors of non-Hodgkin's lymphoma reported more clinically relevant fatigue up till 10 years post-diagnosis compared to a normative population (P<0.001). Mean fatigue scores remained fairly stable over time (T1: x=28, SD=26; T2: x=30, SD=27, P=0.14): 22-28% of survivors reported deterioration, 19-23% reported improvement and 44-54% reported constant fatigue. Survivors who reported constant fatigue were more often diagnosed with stage IV disease and had more comorbid diseases. They were additionally more often female and divorced. Having comorbidities and being without a partner were also associated with constant fatigue in the normative population. In conclusion, six out of every ten responding non-Hodgkin's lymphoma survivors reported a high level of fatigue up till 10 years after diagnosis. Mean fatigue scores remained stable over time and survivors reporting constant fatigue more often had stage IV disease at diagnosis and comorbidities. PMID- 22929980 TI - Patients with diffuse large B-cell lymphoma of germinal center origin with BCL2 translocations have poor outcome, irrespective of MYC status: a report from an International DLBCL rituximab-CHOP Consortium Program Study. AB - Diffuse large B-cell lymphoma can be classified by gene expression profiling into germinal center and activated B-cell subtypes with different prognoses after rituximab-CHOP. The importance of previously recognized prognostic markers, such as Bcl-2 protein expression and BCL2 gene abnormalities, has been questioned in the new therapeutic era. We analyzed Bcl-2 protein expression, and BCL2 and MYC gene abnormalities by interphase fluorescence in situ hybridization in 327 patients with de novo disease treated with rituximab-CHOP. Isolated BCL2 and MYC rearrangements were not predictive of outcome in our patients as a whole, but only in those with the germinal center subtype of lymphoma. The prognostic relevance of isolated MYC rearrangements was weaker than that of BCL2 isolated translocations, but was probably limited by the rarity of the rearrangements. Seven of eight patients with double hit lymphoma had the germinal center subtype with poor outcome. The germinal center subtype patients with isolated BCL2 translocations had significantly worse outcome than the patients without BCL2 rearrangements (P=0.0002), and their outcome was similar to that of patients with the activated B-cell subtype (P=0.30), but not as bad as the outcome of patients with double hit lymphoma (P<0.0001). Bcl-2 protein overexpression was associated with inferior outcome in patients with germinal center subtype lymphoma, but multivariate analysis showed that this was dependent on BCL2 translocations. The gene expression profiling of patients with BCL2 rearrangements was unique, showing activation of pathways that were silent in the negative counterpart. BCL2 translocated germinal center subtype patients have worse prognosis after rituximab-CHOP, irrespective of MYC status, but the presence of combined gene breaks significantly overcomes the prognostic relevance of isolated lesions. PMID- 22929982 TI - Ongoing graft-versus-host disease is a risk factor for azoospermia after allogeneic hematopoietic stem cell transplantation: a survey of the Late Effects Working Party of the European Group for Blood and Marrow Transplantation. AB - The aim of this study was to assess the degree of spermatogenesis defects in sperm analysis in long-term male survivors after allogeneic hematopoietic stem cell transplantation in order to identify the risk factors related to potential infertility after hematopoietic stem cell transplantation and to provide data on longitudinal sperm recovery after hematopoietic stem cell transplantation. Here, the Late Effects Working Party of the European Group for Blood and Marrow Transplantation reports data of sperm analysis from 224 males who underwent hematopoietic stem cell transplantation. Median time between transplantation and sperm analysis was 63 months (8-275 months). At last sperm analysis, presence of any degree of spermatozoa was reported in 70 (31%) and complete azoospermia in 154 (69%) patients. In multivariate analysis, being conditioned with total body irradiation (RR 7.1; 95% CI: 3.4-14.8) and age over 25 years at transplantation (RR 2.4; 95% CI: 1.09-5.2) were significantly associated with higher risk for azoospermia. In patients not conditioned with total body irradiation, ongoing chronic graft-versus-host disease is the main adverse factor for sperm recovery (RR of 3.11; 95% CI: 1.02-9.47; P=0.045). Already established risk factors, such as total body irradiation and age older than 25 years at hematopoietic stem cell transplantation, were seen to be the most relevant adverse risk factor for sperm production after hematopoietic stem cell transplantation. Furthermore, for the first time, ongoing graft-versus-host disease has been shown to be the most relevant adverse factor for sperm recovery, particularly in patients conditioned without total body irradiation. We also introduce a useful scoring system to predict the probability of male long-term survivors' azoospermia. PMID- 22929983 TI - Cytogenetic profiles in multiple myeloma and monoclonal gammopathy of undetermined significance: a study in highly purified aberrant plasma cells. AB - Cytogenetic studies in clonal plasma cell disorders have mainly been done in whole bone marrow or CD138(+) microbead-enriched plasma cells and suggest that recurrent immunoglobulin heavy chain translocations - e.g. t(4;14) -are primary oncogenetic events. The aim of this study was to determine cytogenetic patterns of highly purified aberrant plasma cells (median purity >= 98%) in different clonal plasma cell disorders. We analyzed aberrant plasma cells from 208 patients with multiple myeloma (n=148) and monoclonal gammopathy of undetermined significance (n=60) for the presence of del(13q14), del(17p13) and t(14q32) using multicolor interphase fluorescence in situ hybridization. Additionally, immunoglobulin heavy chain gene arrangements were analyzed and complementarity determining region 3 was sequenced in a subset of patients and combined multicolor interphase fluorescence in situ hybridization/immunofluorescent protein staining analyses were performed in selected cases to confirm clonality and cytogenetic findings. At diagnosis, 96% of cases with multiple myeloma versus 77% of monoclonal gammopathy of undetermined significance cases showed at least one cytogenetic alteration and/or hyperdiploidy. The cytogenetic heterogeneity of individual cases reflected coexistence of cytogenetically-defined aberrant plasma cell clones, and led to the assumption that karyotypic alterations were acquired stepwise. Cases of multiple myeloma and monoclonal gammopathy of undetermined significance frequently showed different but related cytogenetic profiles when other cytogenetic alterations such as deletions/gains of the immunoglobulin heavy chain or the fibroblast growth factor receptor 3 were additionally considered. Interestingly, in 24% of multiple myeloma versus 62% of monoclonal gammopathy of undetermined significance patients with an immunoglobulin heavy chain translocation, aberrant plasma cells with and without t(14q32) coexisted in the same patient. Our data suggest that recurrent immunoglobulin heavy chain translocations might be absent in the primordial plasma cell clone in a significant proportion of patients with clonal plasma cell disorders carrying these cytogenetic alterations. PMID- 22929985 TI - Proposal for halogen atom transfer mechanism for Ullmann O-arylation of phenols with aryl halides. AB - A systematic theoretical study on reaction mechanisms for copper(I)-catalyzed C-O coupling of phenols with aryl bromides is reported herein. Through evaluation of the relative concentrations of possible copper species in reaction solution and reactivity study of these copper species with aryl halides in the context of several commonly proposed mechanisms for copper(I)-catalyzed Ullmann reactions, we propose that the active copper catalyst should be a neutral (L)Cu(I)-OAr (L denotes an ancillary ligand; OAr denotes an aryloxide ligand) species in nonpolar solvent and Cu(OAr)(2)(-) anion in highly polar solvent. In the reaction solution, these two kinds of copper species should be in equilibrium, the direction of which is highly dependent on the polarity of the solvent. For both kinds of copper species, a halogen atom transfer mechanism is favored where an initial halogen atom transfer from phenyl bromide to the Cu(I) center occurs, resulting in the formation of Cu(II)(OAr)(Br) and a phenyl radical. Subsequent rapid attack of this phenyl radical to the aryloxide ligand bound to copper(II) would yield the coupling product and Cu(I)(Br) species, which can be readily converted to the active Cu(I)-OAr species in the presence of phenols and base. Other mechanisms such as oxidative addition, single electron transfer and sigma bond metathesis mechanisms all possess activation barriers which are too high, rendering them kinetically unfavorable. Electronic effects on phenol rings reveal that electron-donating substituents accelerate the coupling of (phen)Cu(I)(OAr) with aryl halides whereas electron-withdrawing substituents lead to much higher activation barriers, which is consistent with experimental findings and thus lends further support for such a halogen atom transfer mechanism. In view of the widely accepted oxidative addition/reductive elimination mechanism for analogous copper(I)-catalyzed coupling of N-nucleophiles with aryl halides, our results here highlight that the reaction mechanism of copper(I)-catalyzed Ullmann reactions is highly dependent on the nature of the nucleophile and different kinds of nucleophiles can be involved in different mechanisms. PMID- 22929984 TI - Small heat shock protein AgsA: an effective stabilizer of enzyme activities. AB - A small heat shock protein, AgsA, possesses chaperone activity that can reduce the amount of heat-aggregated protein in vivo, and suppress the aggregation of chemical- and heat-denatured proteins in vitro. Therefore, we examined the ability of AgsA to stabilize the activity of several enzymes by using this chaperone activity. We observed that AgsA can stabilize the enzymatic activities of Renilla (Renilla reniformis) luciferase, firefly (Photinus pyralis) luciferase, and beta-galactosidase, and showed comparable or greater stabilization of these enzymes than bovine serum albumin (BSA), a well-known stabilizer of enzyme activities. In particular, AgsA revealed better stabilization of Renilla luciferase and beta-galactosidase than BSA under disulfide bond-reducing conditions with dithiothreitol. In addition, AgsA also increased the enzymatic performance of beta-galactosidase and various restriction enzymes to a comparable or greater extent than BSA. These data indicate that AgsA may be useful as a general stabilizer of enzyme activities. PMID- 22929987 TI - Chromatin: a model for nucleosome positioning. PMID- 22929988 TI - Epigenomics: dissecting the roles of Pol V. PMID- 22929989 TI - Validation of the anti-bacteremic efficacy of an essential oil rinse in a Brazilian population: a cross-over study. AB - This cross-over study was conducted to assess the germ-killing efficacy of an essential oil mouthrinse (EOM) by determining the blood levels of microorganisms associated with induced bacteremia and investigating the prevalence of this event in Brazilians with mild-to-moderate gingivitis. Thirty four (31.19%) subjects positive for bacteremia induced by chewing a ration of apple were enrolled out of 109 screened subjects (50 males and 59 females). A difference of at least 10 colony forming units between the pre- and post-insult blood samples was defined as a positive result. For the following two weeks patients underwent a toothbrush plus fluoride dentifrice normalization period, and were then scheduled for the Phase I protocol as follows. At baseline I, subjects were instructed to chew a new apple ration, had new blood samples taken before and after this oral stimulus, and were randomly assigned to an experimental essential oil (n = 17) or placebo (P) mouthrinse (n = 17) treatment for 2 weeks. These procedures were repeated at the end of Phase I and then followed by a two-week wash-out period (tooth brushing with fluoride dentifrice). Bacteremia was again induced at baseline and at the end of Phase II, when subjects were crossed-over to the other EOM or placebo groups. Bacterial count differences between baseline and 2-week post-treatment (EOM versus P) in the blood samples collected were assessed by analysis of covariance. Mean aerobic counts decreased by 45.8%, whereas mean anaerobic counts decreased by 63.3% after EOM treatment. After the P treatment, aerobic bacteria increased by 28.4% and anaerobic bacteria decreased by 18.5%. This study validated this novel methodology and showed that the germ-killing action of EOM significantly reduced bacteremia. PMID- 22929990 TI - Biomedical nanomaterials for imaging-guided cancer therapy. AB - To date, even though various kinds of nanomaterials have been evaluated over the years in order to develop effective cancer therapy, there is still significant challenges in the improvement of the capabilities of nano-carriers. Developing a new theranostic nanomedicine platform for imaging-guided, visualized cancer therapy is currently a promising way to enhance therapeutic efficiency and reduce side effects. Firstly, conventional imaging technologies are reviewed with their advantages and disadvantages, respectively. Then, advanced biomedical materials for multimodal imaging are illustrated in detail, including representative examples for various dual-modalities and triple-modalities. Besides conventional cancer treatment (chemotherapy, radiotherapy), current biomaterials are also summarized for novel cancer therapy based on hyperthermia, photothermal, photodynamic effects, and clinical imaging-guided surgery. In conclusion, biomedical materials for imaging-guided therapy are becoming one of the mainstream treatments for cancer in the future. It is hoped that this review might provide new impetus to understand nanotechnology and nanomaterials employed for imaging-guided cancer therapy. PMID- 22929991 TI - Sarcopenia: pharmacology of today and tomorrow. AB - Sarcopenia remains largely undiagnosed and undertreated because of the lack of a universally accepted definition, effective ways to measure it, and identification of the outcomes that should guide treatment efficacy. An ever-growing number of clinicians and researchers along with funding and regulatory agencies have gradually recognized that sarcopenia is a human condition that requires both prevention and treatment. In this article, we review sarcopenia and its common and less known pharmacological treatments, attempt to define sarcopenia in its broader context, and present some new ideas for potential future treatment for this devastating condition. PMID- 22929992 TI - Using electronic health care records for drug safety signal detection: a comparative evaluation of statistical methods. AB - BACKGROUND: Drug safety monitoring relies primarily on spontaneous reporting, but electronic health care record databases offer a possible alternative for the detection of adverse drug reactions (ADRs). OBJECTIVES: To evaluate the relative performance of different statistical methods for detecting drug-adverse event associations in electronic health care record data representing potential ADRs. RESEARCH DESIGN: Data from 7 databases across 3 countries in Europe comprising over 20 million subjects were used to compute the relative risk estimates for drug-event pairs using 10 different methods, including those developed for spontaneous reporting systems, cohort methods such as the longitudinal gamma poisson shrinker, and case-based methods such as case-control. The newly developed method "longitudinal evaluation of observational profiles of adverse events related to drugs" (LEOPARD) was used to remove associations likely caused by protopathic bias. Data from the different databases were combined by pooling of data, and by meta-analysis for random effects. A reference standard of known ADRs and negative controls was created to evaluate the performance of the method. MEASURES: The area under the curve of the receiver operator characteristic curve was calculated for each method, both with and without LEOPARD filtering. RESULTS: The highest area under the curve (0.83) was achieved by the combination of either longitudinal gamma poisson shrinker or case-control with LEOPARD filtering, but the performance between methods differed little. LEOPARD increased the overall performance, but flagged several known ADRs as caused by protopathic bias. CONCLUSIONS: Combinations of methods demonstrate good performance in distinguishing known ADRs from negative controls, and we assume that these could also be used to detect new drug safety signals. PMID- 22929993 TI - Systematic review of comorbidity indices for administrative data. AB - BACKGROUND: Adjustment for comorbidities is common in performance benchmarking and risk prediction. Despite the exponential upsurge in the number of articles citing or comparing Charlson, Elixhauser, and their variants, no systematic review has been conducted on studies comparing comorbidity measures in use with administrative data. We present a systematic review of these multiple comparison studies and introduce a new meta-analytical approach to identify the best performing comorbidity measures/indices for short-term (inpatient + <= 30 d) and long-term (outpatient+>30 d) mortality. METHODS: Articles up to March 18, 2011 were searched based on our predefined terms. The bibliography of the chosen articles and the relevant reviews were also searched and reviewed. Multiple comparisons between comorbidity measures/indices were split into all possible pairs. We used the hypergeometric test and confidence intervals for proportions to identify the comparators with significantly superior/inferior performance for short-term and long-term mortality. In addition, useful information such as the influence of lookback periods was extracted and reported. RESULTS: Out of 1312 retrieved articles, 54 articles were eligible. The Deyo variant of Charlson was the most commonly referred comparator followed by the Elixhauser measure. Compared with baseline variables such as age and sex, comorbidity adjustment methods seem to better predict long-term than short-term mortality and Elixhauser seems to be the best predictor for this outcome. For short-term mortality, however, recalibration giving empirical weights seems more important than the choice of comorbidity measure. CONCLUSIONS: The performance of a given comorbidity measure depends on the patient group and outcome. In general, the Elixhauser index seems the best so far, particularly for mortality beyond 30 days, although several newer, more inclusive measures are promising. PMID- 22929994 TI - Thirty-day, all-cause readmissions for elderly patients who have an injury related inpatient stay. AB - BACKGROUND: Policymakers are exploring ways to reduce readmission rates. Much attention has been given to readmissions for conditions such as heart failure, acute myocardial infarction, and pneumonia, but little attention has been given to readmissions of patients with injury-related index admissions. METHODS: This analysis is a retrospective cohort study of elderly persons who are admitted to a community hospital for a principal diagnosis of injury. We use 2006 Healthcare Cost and Utilization Project State Inpatient Databases and State Emergency Department Databases from 11 States. With logistic regression we identify factors associated with a 30-day, all-cause inpatient readmission. Factors include: patient characteristics, injury characteristics, clinical experiences during the hospital stay, and hospital characteristics. RESULTS: About 1 in 7 elderly patients with an injury-related admission were readmitted in 30 days (13.7%). We found that severe injuries had higher predicted readmission rates. Patients receiving transfusions, experiencing a Patient Safety Indicator event, and with infections had higher readmission rates. Patients discharged to nursing homes or home health care had higher readmission rates compared with patients discharged to the community. CONCLUSIONS: This study expands evidence for the influence of injury characteristics on readmission rates. It also provides evidence about hospital experiences that affect readmissions. These findings suggest that a focus on preventing complications during the hospital stay may help reduce hospital-specific readmissions for patients with injury-related conditions. It also suggests that a strategy to reduce readmission rates should not only focus on hospitals but also nursing homes and home health care. PMID- 22929995 TI - Effectiveness of an electronic health record-based intervention to improve follow up of abnormal pathology results: a retrospective record analysis. AB - BACKGROUND AND OBJECTIVE: On March 11, 2009, the Veterans Health Administration (VA) implemented an electronic health record (EHR)-based intervention that required all pathology results to be transmitted to ordering providers by mandatory automated notifications. We examined the impact of this intervention on improving follow-up of abnormal outpatient pathology results. RESEARCH DESIGN AND SUBJECTS: We extracted pathology reports from the EHR of 2 VA sites. From 16,738 preintervention and 17,305 postintervention reports between 09/01/2008 and 09/30/2009, we randomly selected about 5% and evaluated follow-up outcomes using a standardized chart review instrument. Documented responses to the alerted report (eg, ordering follow-up tests or referrals, notifying patients, and prescribing/changing treatment) were recorded. MEASURES: Primary outcome measures included proportion of timely follow-up responses (within 30 d) and median time to direct response for abnormal reports. RESULTS: Of 816 preintervention and 798 postintervention reports reviewed, 666 (81.6%) and 688 (86.2%) were abnormal. Overall, there was no apparent intervention effect on timely follow-up (69% vs. 67.1%; P=0.4) or median time to direct response (8 vs. 8 d; P=0.7). However, logistic regression uncovered a significant intervention effect (preintervention odds ratio, 0.7; 95% confidence interval, 0.5-1.0) after accounting for site specific differences in follow-up, with a lower likelihood of timely follow-up at one site (odds ratio, 0.4; 95% confidence interval, 0.2-0.7). CONCLUSIONS: An electronic intervention to improve test result follow-up at 2 VA institutions using the same EHR was found effective only after accounting for certain local contextual factors. Aggregating the effect of EHR interventions across different institutions and EHRs without controlling for contextual factors might underestimate their potential benefits. PMID- 22929996 TI - Structural insight into receptor-selectivity for lurasidone. AB - Lurasidone is a novel antipsychotic agent with high affinity for dopamine D(2), 5 hydroxyltryptamine 5-HT(2A), and 5-HT(7) receptors. Lurasidone has negligible affinity for histamine H(1) and muscarinic M(1) receptors, which are thought to contribute to side effects such as weight gain, sedation, and worsening of cognitive deficits. Our interests focus on why lurasidone has such high selectivity for only a part of these aminergic G-protein coupled receptors (GPCRs) and the different binding profile from ziprasidone, which has the same benzisothiazolylpiperazine moiety as lurasidone. In order to address these issues, we constructed structural models of lurasidone-GPCR complexes by homology modeling of receptors, exhaustive docking of ligand, and molecular dynamics simulation-based refinement of complexes. This computational study gave reliable structural models for D(2), 5-HT(2A), and 5-HT(7), which had overall structural complementarities with a salt bridge anchor at the center of the lurasidone molecule, but not for H(1) and M(1) owing to steric hindrance between the norbornane-2,3-dicarboximide and/or cyclohexane part of lurasidone and both receptors. By comparison with the structural models of olanzapine-GPCRs and ziprasidone-GPCRs constructed using the same computational protocols, it was suggested that the bulkiness of the norbornane-2,3-dicarboximide part and the rigidity and the bulkiness of the cyclohexyl linker gave lurasidone high selectivity for the desired aminergic GPCRs. Finally, this structural insight was validated by a binding experiment of the novel benzisothiazolylpiperazine derivatives. This knowledge on the structural mechanism behind the receptor selectivity should help to design new antipsychotic agents with preferable binding profiles, and the established computational protocols realize virtual screening and structure-based drug design for other central nervous system drugs with desired selectivity for multiple targets. PMID- 22929997 TI - ROCK inhibition with Y27632 promotes the proliferation and cell cycle progression of cultured astrocyte from spinal cord. AB - Rho-associated Kinase (ROCK) has been identified as an important regulator of proliferation and cell cycle progression in a number of cell types. Although its effects on astrocyte proliferation have not been well characterized, ROCK has been reported to play important roles in gap junction formation, morphology, and migration of astrocytes. In the present study, our aim was to investigate the effect of ROCK inhibition by [(+)-(R)-trans-4-(1-aminoethyl)-N-(4-pyridyl) cyclohexanecarboxamide dihydrochloride] (Y27632) on proliferation and DNA synthesis in cultured astrocytes from rat spinal cord and the possible mechanism involved. Western blots showed that treatment of astrocytes with Y27632 increased their expression of cyclin D1, CDK4, and cyclin E, thereby causing cell cycle progression. Furthermore, Y27632-induced astrocyte proliferation was mediated through the extracellular-signal-regulated kinase signaling cascade. These results indicate the importance of ROCK in astrocyte proliferation. PMID- 22929998 TI - Multimodal mechanisms of food creaminess sensation. AB - In this work, the sensory creaminess of a set of four viscosity-matched fluid foods (single cream, evaporated milk, corn starch solution, and corn starch solution containing long chain free fatty acids) was tested by a panel of 16 assessors via controlled sensation mechanisms of smell only, taste only, taste and tactile, and integrated multimodal. It was found that all sensation channels were able to discriminate between creamy and non-creamy foods, but only the multimodal method gave creaminess ratings in agreement with the samples' fat content. Results from this study show that the presence of long chain free fatty acids has no influence on creaminess perception. It is certain that food creaminess is not a primary sensory property but an integrated sensory perception (or sensory experience) derived from combined sensations of visual, olfactory, gustatory, and tactile cues. Creamy colour, milky flavour, and smooth texture are probably the most important sensory features of food creaminess. PMID- 22929999 TI - Development of a therapeutically important radiation induced promoter. AB - Radio-genetic therapy is a combination of radiation therapy and gene therapy that may solve some of the problems associated with conventional radiotherapy. A promoter responsive to radiation was obtained from a promoter library composed of DNA fragments created by linking the TATA box signal to randomly combined binding sequences of transcription factors that are reactive to radiation. Each promoter connected to the luciferase gene, was evaluated by luciferase expression enhancement in transfected cells after X-ray irradiation. The reactivity of the best promoter was improved by the random introduction of point mutations and the resultant promoter showed more than a 20-fold enhancement of the luciferase expression after X-ray irradiation at 10 Gy. The expression of downstream genes was also enhanced in stably transfected cells not only by X-rays but also by proton beam irradiation; and either enhancement was attenuated when an anti oxidant was added, thus suggesting the involvement of oxidative stress in the promoter activation. Constructed promoters were also activated in tumors grown in mice. In addition, cell killing with the fcy::fur gene (a suicide gene converting 5-fluorocytosin to highly toxic 5-fluorouracil) increased dose-dependently with 5 fluorocytosin only after X-ray irradiation in vitro. These results suggest that promoters obtained through this method could be used for possible clinical applications. PMID- 22930000 TI - [When case studies must replace lacking evidence]. PMID- 22930001 TI - [Research on aging. Abstracts of the transnational and translational joint Gerontology and Geriatric Congress. September 12-15, 2012. Bonn, Germany]. PMID- 22930002 TI - Establishment and characterization of immortalized human hepatocyte cell line for applications in bioartificial livers. AB - An immortalized human hepatocyte cell line, HepLi5, was established via transfection of Simian virus 40 large T antigen (SV40 LT) into primary human hepatocytes. The morphologic and functional characteristics of HepLi5 cells were evaluated. The expression of SV40 LT in HepLi5 cells was detected by reverse transcription-PCR (RT-PCR) and western blotting. mRNA expression of liver enriched genes, including glutamine synthetase, albumin, and cytochrome P450 was detected via RT-PCR in HepLi5 cells. Activity of CYP1A2, one of the drug metabolizing P450 enzymes, was detected. Subcutaneous injection of HepLi5 cells into nude mice did not induce tumors within 3 months. Short Tandem Repeat results confirmed the authenticity of the cell line. Clinical-grade quantities of HepLi5 cells could be harvested using large-scale culture in roller bottles after which their cellular function was significantly enhanced. Therefore, the immortalized HepLi5 cells are a suitable cell source for applications in bioartificial livers. PMID- 22930003 TI - Financial distress and depressive symptoms among African American women: identifying financial priorities and needs and why it matters for mental health. AB - Prior research found that financial hardship or distress is one of the most important underlying factors for depression/depressive symptoms, yet factors that contribute to financial distress remain unexplored or unaddressed. Given this, the goals of the present study were (1) to examine the relationship between perceived financial distress and depressive symptoms, and (2) to identify financial priorities and needs that may contribute to financial distress. Surveys from 111 African American women, ages 18-44, who reside in Allegheny County, PA, were used to gather demographic information and measures of depressive symptoms and financial distress/financial well-being. Correlation and regression analyses revealed that perceived financial distress was significantly associated with levels of depressive symptoms. To assess financial priorities and needs, responses to two open-ended questions were analyzed and coded for common themes: "Imagine you won a $10,000 prize in a local lottery. What would you do with this money?" and "What kinds of programs or other help would be beneficial to you during times of financial difficulties?" The highest five priorities identified by the participants were paying bills and debt, saving, purchasing a home or making home repairs, and/or helping others. The participant's perceived needs during times of financial difficulty included tangible assistance and/or financial education. The findings from this study can be used to create new and/or enhance existing programs, services, and/or interventions that focus on the identified financial priorities and needs. Collaborative efforts among professionals in different disciplines are also needed, as ways to manage and alleviate financial distress should be considered and discussed when addressing the mental health of African American women. PMID- 22930004 TI - Endometrial gene expression in the early luteal phase is impacted by mode of triggering final oocyte maturation in recFSH stimulated and GnRH antagonist co treated IVF cycles. AB - STUDY QUESTION: Do differences in endometrial gene expression exist after ovarian stimulation with four different regimens of triggering final oocyte maturation and luteal phase support in the same patient? SUMMARY ANSWER: Significant differences in the expression of genes involved in receptivity and early implantation were seen between the four protocols. WHAT IS KNOWN ALREADY: GnRH agonist triggering is an alternative to hCG triggering in GnRH antagonist co treated cycles, resulting in an elimination of early ovarian hyperstimulation syndrome. Whereas previous studies have revealed a low ongoing clinical pregnancy rate after GnRH agonist trigger due to a high early pregnancy loss rate, despite supplementation with the standard luteal phase support, more recent studies, employing a 'modified' luteal phase support including a bolus of 1500 IU hCG on the day of oocyte aspiration, have reported ongoing pregnancy rates similar to those seen after hCG triggering. STUDY DESIGN, SIZE DURATION: A prospective randomized study was performed in four oocyte donors recruited from an oocyte donation program during the period 2010-2011. PARTICIPANTS, MATERIALS, SETTING, METHODS: Four oocyte donors in a university IVF center each prospectively underwent four consecutive stimulation protocols, with different modes of triggering final oocyte maturation and a different luteal phase support, followed by endometrial biopsy on Day 5 after oocyte retrieval. The following protocols were used: (A) 10 000 IU hCG and standard luteal phase support, (B) GnRH agonist (triptorelin 0.2 mg), followed by 1500 IU hCG 35 h after triggering final oocyte maturation, and standard luteal phase support, (C) GnRH agonist (triptorelin 0.2 mg) and standard luteal phase support and (D) GnRH agonist (triptorelin 0.2 mg) without luteal phase support. Microarray data analysis was performed with GeneSpring GX 11.5 (RMA algorithm). Pathway and network analysis was performed with the gene ontology software Ingenuity Pathways Analysis (Ingenuity(r) Systems, www.ingenuity.com, Redwood City, CA, USA). Samples were grouped and background intensity values were removed (cutoff at the lowest 20th percentile). A one-way ANOVA test (P< 0.05) was performed with Benjamini-Hochberg multiple testing correction. MAIN RESULTS: Significant differences were seen in endometrial gene expression, related to the type of ovulation trigger and luteal phase support. However, the endometrial gene expression after the GnRH agonist trigger and a modified luteal phase support (B) was similar to the pattern seen after the hCG trigger (A). LIMITATIONS, REASONS FOR CAUTION: The study was performed in four oocyte donors only; however, it is a strength of the study that the same donor underwent four consecutive stimulation protocols within 1 year to avoid inter-individual variations. WIDER IMPLICATIONS OF THE FINDINGS: These endometrial gene-expression findings support the clinical reports of a non significant difference in live birth rates between the GnRH agonist trigger and the hCG trigger, when the GnRH agonist trigger is followed by a bolus of 1500 IU hCG at 35 h post trigger in addition to the standard luteal phase support. STUDY FUNDING/ COMPETING INTERESTS: This study was supported by an un-restricted research grant by MSD Belgium. TRIAL REGISTRATION NUMBER: EudraCT number 2009 009429-26, protocol number 997 (P06034). PMID- 22930005 TI - Structural, spectroscopic, and electrochemical properties of nonheme Fe(II) hydroquinonate complexes: synthetic models of hydroquinone dioxygenases. AB - Using the tris(3,5-diphenylpyrazol-1-yl)borate ((Ph2)Tp) supporting ligand, a series of mono- and dinuclear ferrous complexes containing hydroquinonate (HQate) ligands have been prepared and structurally characterized with X-ray crystallography. The monoiron(II) complexes serve as faithful mimics of the substrate-bound form of hydroquinone dioxygenases (HQDOs) - a family of nonheme Fe enzymes that catalyze the oxidative cleavage of 1,4-dihydroxybenzene units. Reflecting the variety of HQDO substrates, the synthetic complexes feature both mono- and bidentate HQate ligands. The bidentate HQates cleanly provide five coordinate, high-spin Fe(II) complexes with the general formula [Fe((Ph2)Tp)(HL(X))] (1X), where HL(X) is a HQate(1-) ligand substituted at the 2 position with a benzimidazolyl (1A), acetyl (1B and 1C), or methoxy (1D) group. In contrast, the monodentate ligand 2,6-dimethylhydroquinone (H(2)L(F)) exhibited a greater tendency to bridge between two Fe(II) centers, resulting in formation of [Fe(2)((Ph2)Tp)(2)(MU-L(F))(MeCN)].[2F(MeCN)]. However, addition of one equivalent of "free" pyrazole ((Ph2)pz) ligand provided the mononuclear complex, [Fe((Ph2)Tp)(HL(F))((Ph2)pz)].[1F((Ph2)pz)], which is stabilized by an intramolecular hydrogen bond between the HL(F) and (Ph2)pz donors. Complex 1F((Ph2)pz) represents the first crystallographically-characterized example of a monoiron complex bound to an untethered HQate ligand. The geometric and electronic structures of the Fe/HQate complexes were further probed with spectroscopic (UV-vis absorption, (1)H NMR) and electrochemical methods. Cyclic voltammograms of complexes in the 1X series revealed an Fe-based oxidation between 0 and -300 mV (vs. Fc(+/0)), in addition to irreversible oxidation(s) of the HQate ligand at higher potentials. The one-electron oxidized species (1X(OX)) were examined with UV-vis absorption and electron paramagnetic resonance (EPR) spectroscopies. PMID- 22930007 TI - Peripheral vision benefits spatial learning by guiding eye movements. AB - The loss of peripheral vision impairs spatial learning and navigation. However, the mechanisms underlying these impairments remain poorly understood. One advantage of having peripheral vision is that objects in an environment are easily detected and readily foveated via eye movements. The present study examined this potential benefit of peripheral vision by investigating whether competent performance in spatial learning requires effective eye movements. In Experiment 1, participants learned room-sized spatial layouts with or without restriction on direct eye movements to objects. Eye movements were restricted by having participants view the objects through small apertures in front of their eyes. Results showed that impeding effective eye movements made subsequent retrieval of spatial memory slower and less accurate. The small apertures also occluded much of the environmental surroundings, but the importance of this kind of occlusion was ruled out in Experiment 2 by showing that participants exhibited intact learning of the same spatial layouts when luminescent objects were viewed in an otherwise dark room. Together, these findings suggest that one of the roles of peripheral vision in spatial learning is to guide eye movements, highlighting the importance of spatial information derived from eye movements for learning environmental layouts. PMID- 22930008 TI - Asymmetric [3 + 2] annulation of N-protected isatins with but-3-yn-2-one catalyzed by DIOP: facile creation of enantioenriched spiro[furan-2,3'-indoline] 2',4(5H)-dione. AB - DIOP catalyzed highly enantioselective [3 + 2] annulation of N-protected isatins with but-3-yn-2-one has been disclosed, allowing the synthesis of enantioenriched spiro[furan-2,3'-indoline]-2',4(5H)-dione in moderate yields along with good to high enantioselectivities under mild conditions. PMID- 22930009 TI - Let's Brazilianize science! PMID- 22930010 TI - Diabesity: the 'Achilles Heel' of our modernized society. PMID- 22930011 TI - Results: "now it is the time for these sun-tanned people to show their worth". PMID- 22930012 TI - What is the best approach for patients at high risk for colorectal cancer? PMID- 22930013 TI - Does the use of DuraSeal in head and spinal surgeries reduce the risk of cerebrospinal fluid leaks and complications when compared to conventional methods of dura mater closure? PMID- 22930014 TI - Intestinal intussusception. PMID- 22930015 TI - Acute diverticulitis in a patient with intestinal malrotation. PMID- 22930016 TI - Home-based nutritional therapy. PMID- 22930018 TI - Index of health development: conceptualization and reflections on its need. AB - This article aimed to review the concept of social indices by focusing on their practical use and need in the health setting. For this purpose, the initial consideration was how these indices are defined, their possible use, and the importance they have as a means of depicting the real world. Thus, a wide concept of health, consistent with the current view, was adopted. Health was further described within international and national settings, emphasizing indicators that can be employed to estimate health problems in the population were highlighted. Finally, as no specific social index describing health in a Brazilian setting has been developed, the need to rely on the Health Development Index was indicated. This index will serve as a tool for managers, inspection agents, and the general population to follow-up the developments reached and the shortcomings that should be addressed to ensure a better health status for the majority of the population. PMID- 22930019 TI - Treatment of symptomatic vertebrobasilar artery stenosis with stent-assistant angioplasty in the elderly. AB - OBJECTIVE: To study the efficacy, safety, and feasibility of stent-assistant angioplasty (SAA) in the treatment of symptomatic vertebrobasilar artery stenosis in the elderly. METHODS: SAA was performed in 26 elderly patients with symptomatic vertebrobasilar artery stenosis. The success rate, perioperative complications, and long-term effectiveness were evaluated. RESULTS: A total of 29 balloon expandable stents were implanted in these patients. The success ratio was 100%. The degree of stenosis decreased from 81.3 +/- 8.8% to 3.7 +/- 3.6% (p < 0.01). Complications were absent during the perioperative period. Follow-up was performed for seven to 36 months (median: 21.9 months). Two patients developed the recurrent symptoms of vertebrobasilar artery stenosis, and no cerebral ischemic events were noted in the remaining patients, suggesting a favorable outcome. CONCLUSION: SAA is a safe and effective strategy for the treatment of symptomatic vertebrobasilar artery stenosis in the elderly. PMID- 22930020 TI - Analysis of extrinsic and intrinsic factors that predispose elderly individuals to fall. AB - OBJECTIVE: In a sample of elderly individuals from Porto Alegre - RS, Brazil, to analyze the intrinsic and extrinsic factors that predispose them to the risk of falls and fractures. METHODS: The study included a random sample of 267 elderly individuals, to whom two balance tests were applied: the Functional Reach Test (FRT) and the Timed Up and Go Test (TUG). The elderly also answered a questionnaire (13 questions divided into four categories) on sociodemographic and health factors. RESULTS: Elderly individuals from both genders (76.8% women), aged between 60 and 90 years (mean = 70.22 years, SD = +/- 7.30 years) participated in the study. A statistically significant association (p < 0.05) was found between age, self-perception of eyesight, type of dwelling, last monthly income, and the FRT; the same was found between age range, self-rated health (p < 0.001) and the TUG. CONCLUSION: It was identified that, in the sample of elderly individuals living in Porto Alegre - RS, Brazil, the intrinsic factors that predispose to the risk of falls and fractures are older age, poor self-perception of eyesight, and poor selfrated health; the extrinsic factors are type of dwelling (living in a house) and a monthly income < one minimum wage. PMID- 22930021 TI - Factors associated with nutritional status of the elderly in two regions of Brazil. AB - OBJECTIVE: To verify the association of nutritional status with sociodemographic factors, lifestyle, and health status in elderly individuals from two cities in different regions of Brazil. METHODS: Cross-sectional epidemiological home-based study, involving 477 and 316 elderly individuals (>= 60 years) from the towns of Antonio Carlos (AC-SC) and Lafaiete Coutinho (LC-BA), respectively. Nutritional status was verified using the body mass index (BMI). Explanatory variables in the study were gender, age, level of schooling, living arrangements, lifelong occupation, smoking status, alcohol consumption, time spent sitting, hypertension, diabetes, osteoarthritis, respiratory diseases, and medications. Logistic regression analyses were used (crude and adjusted). RESULTS: Underweight (BMI < 22.0 kg/m(2)) was more frequent among the elderly from LC-BA (28.9% vs. 8.2%), and overweight (BMI > 27.0 kg/m(2)) was more prevalent among individuals from AC-SC (52.8% vs. 28.2%). In AC-SC, underweight was positively associated with older age (>= 75 years) and smoking, and inversely associated with longer periods spent sitting (>= 6 hrs/day). Overweight was positively associated with longer periods spent sitting, hypertension, and arthritis, and inversely associated with older age, male gender, working in rural areas, and alcohol consumption. In LC-BA, no explanatory variable was associated with underweight. Overweight was positively associated with hypertension, and inversely associated with individuals aged >= 75 years, and with living alone. CONCLUSION: Underweight was more prevalent in LC-BA and overweight was more prevalent in AC-SC. Factors associated with nutritional status are specific to each municipality. PMID- 22930022 TI - Potentially inappropriate medications in elderly. AB - OBJECTIVE: To compare PRISCUS with Beers-Fick in detecting potentially inappropriate medication (PIMs) in elderly at their first outpatient geriatric visit. METHODS: Retrospective medical record analysis by PRISCUS and Beers-Fick adapted to Brazilian pharmacopoeia, comparing the finding of PIMs at the first outpatient geriatric visit by both criteria. RESULTS: Cases had mean age of 77.4 +/- 7.7 years (64 females and 36 males), and mean consumption of 3.9 +/- 2.5 drugs. This study found statistical significance for the numbers of women using benzodiazepines and men using salicylates. The mean was 0.5 +/- 0.7 PIMs/patient by Beers-Fick criteria and 0.7 +/- 0.8 PIMs/patient by PRISCUS. Medications most often reported by Beers-Fick criteria were: benzodiazepines, methyldopa and ergot derived drugs. Medications most often reported by PRISCUS criteria were: benzodiazepines, antihypertensive drugs, and tricyclic antidepressants. No statistical significance was found when the number of elderly patients with PIMs was compared between both criteria. Statistical significance was found (PRISCUS versus Beers-Fick) for the consumption of long acting benzodiazepines and laxatives. Both criteria do not include drugs such as vitamins, herbal medications, and eye drops, reported by a percentage of cases. CONCLUSION: Both criteria are useful to prevent PIMs in the elderly, with PRISCUS being more updated and comprehensive, but they are not complete for the Brazilian outpatient reality. PMID- 22930023 TI - Prevalence of excessive daytime sleepiness and associated factors in women aged 35-49 years from the "Pindamonhangaba Health Project" (PROSAPIN). AB - OBJECTIVE: To estimate the prevalence of excessive daytime sleepiness (EDS) and to identify associated factors in women aged 35 to 49 years from the "Pindamonhangaba Health Project" (PROSAPIN). METHODS: This was a cross-sectional observational study of 372 women aged 35 to 49 years, randomly selected from the Family Health Strategy (FHS) program of the city of Pindamonhangaba, SP, Brazil, where the "Pindamonhangaba Health Project" (PROSAPIN) is being developed. EDS was assessed through interviews using the Epworth Sleepiness Scale and the associated factors through questions that investigated sociodemographic characteristics, gynecological history, presence of comorbidities, lifestyle, sleep routine, and use of drugs capable of altering the state of alertness; anthropometric variables were also measured. The prevalence of EDS was estimated with a 95% confidence interval (95% CI) and the associated factors were identified through a multiple logistic regression model performed with the Stata software, release 10.0. RESULTS: EDS prevalence was 18.5% (95% CI: 14.7-22.9) and the associated factors were: profession related to domestic services (OR = 2.2, 95% CI: 1.1-4.3), physical activity level above the mean of the study population (OR = 1.9, 95% CI: 1.1-3.4), and presence of features suggestive of anxiety (OR = 1.9, 95% CI: 1.1 3.4). CONCLUSION: The prevalence of EDS in women aged 35-49 years from PROSAPIN was high and associated with sociodemographic characteristics, presence of comorbidities, and lifestyle. PMID- 22930024 TI - Maternal obesity in high-risk pregnancies and postpartum infectious complications. AB - OBJECTIVE: To analyze the association between maternal obesity and postnatal infectious complications in high-risk pregnancies. METHODS: Prospective study from August 2009 through August 2010 with the following inclusion criteria: women up to the 5(th) postpartum day; age >= 18 years; high-risk pregnancy; singleton pregnancy with live fetus at labor onset; delivery at the institution; maternal weight measured on day of delivery. The nutritional status in late pregnancy was assessed by the body mass index (BMI), with the application of the Atalah et al. curve. Patients were graded as underweight, adequate weight, overweight, or obese. Postpartum complications investigated during the hospital stay and 30 days post-discharge were: surgical wound infection and/or secretion, urinary infection, postpartum infection, fever, hospitalization, antibiotic use, and composite morbidity (at least one of the complications mentioned). RESULTS: 374 puerperal women were included, graded according to the final BMI as: underweight (n = 54, 14.4%); adequate weight (n = 126, 33.7%); overweight (n = 105, 28.1%); and obese (n = 89, 23.8%). Maternal obesity was shown to have a significant association with the following postpartum complications: surgical wound infection (16.7%, p = 0.042), urinary infection (9.0%, p = 0.004), antibiotic use (12.3%, p < 0.001), and composite morbidity (25.6%, p = 0.016). By applying the logistic regression model, obesity in late pregnancy was found to be an independent variable regardless of the composite morbidity predicted (OR: 2.09; 95% CI: 1.15 3.80, p = 0.015). CONCLUSION: Maternal obesity during late pregnancy in high-risk patients is independently associated with postpartum infectious complications, which demonstrates the need for a closer follow-up of maternal weight gain in these pregnancies. PMID- 22930025 TI - Neonatal screening for congenital adrenal hyperplasia. AB - OBJECTIVE: The effectiveness of neonatal screening for reducing morbimortality in children with congenital adrenal hyperplasia (CAH) is the main justification for its implementation. One of the challenges for its implementation is to determine the cutoff value for laboratory measurement of 17-hydroxyprogesterone (17OHP) with appropriate cost-effectiveness. This study identified factors affecting the results of the pilot project of newborn screening for CAH, performed in the state of Minas Gerais, Brazil. METHODS: Neonatal screening performed between September, 2007 and May, 2008, with 17OHP measurements performed in blood samples taken from the heel (filter paper), on the 5(th) day of life, processed by the UMELISA 17-OH Progesterona NEONATAL((r)) method. The cutoff value was 80 and 160 nmol/L for healthy children or not, respectively. RESULTS: The incidence of CAH was 1:19,939 in 159,415 children screened. The 99(th) percentile (p99) of 17OHP in the first sample was 108 nmol/L. In 13,298 newborns whose weight had been reported, the p99 of 17OHP were, respectively: 344 nmol/L for weight < 1,500 g; 260 nmol/L for weight between 1,500 and 1,999 g; 221 nmol/L for weight between 2,000 and 2,499 g; 109 nmol/L for weight >= 2,500g. The rate of recall for medical consultation was 0.31%. The test sensitivity was 100%, specificity was 99.6%, and the positive predictive value was 2.2%. By adjusting the cutoff values of 17OHP to 110 nmol/L and 220 nmol/L, a 76% decrease in consultation referrals was projected. CONCLUSION: The use of 17OHP cutoff values, considering birth weight, was a cost effective measure to reduce false positives. The results of this pilot study suggest that screening for CAH might benefit the pediatric population. PMID- 22930026 TI - Domestic violence against children and adolescents: a challenge. AB - OBJECTIVE: To study children and adolescents victims of domestic violence treated at the Referenced Pediatric Emergency Unit of the Hospital de Clinicas of the Universidade Estadual de Campinas and its specialized outpatient clinic between January 2003 and December 2007, emphasizing sexual abuse. METHODS: The variables gender, age, origin, and classification were studied. For victims of sexual abuse, the following variables were also studied: type of abuse (rape), location (domestic/urban), duration (acute/chronic), perpetrator (known, incestuous), alterations at medical examination, notification to child protection agencies, and antiretroviral medication and serology (HIV, syphilis, hepatitis B and C). Patients were divided into two groups according to the type of abuse and type of perpertrator and they were associated with gender, age, and duration. For the comparison, chi-squared or Fisher's exact test were performed (significance p < 0.05), as well as raw prevalence odds ratio. RESULTS: Of the total cases of abuse (551), neglect (33.9%) and sexual abuse (31.9%) predominated; the victims were female in 55.9% of the cases, and 50% were up to 5 years of age. Of the sexual abuse cases (95), 80% were female, and 58.9% were between 5 and 10 years of age. Rape was observed in 39% and indecent assault in 59.6%; 72.6% occurred in the domestic area, 81.1% by known perpetrator; 31.6% were incestuous, 47.4% were chronic, and 76.5% had no clinical alterations. 81.1% were referred to child protection agencies. Antiretroviral medication was prescribed to 49.1% of patients, and serological tests (HIV in 46 [48.4%], syphilis in 42 [44.2%], hepatitis B in 44 [46.3%] and hepatitis C in 45 [47.4%]%), all of which were negative, were more frequent in rape victims (p = 0.00). There was an association between rape and age (10 and 15 years, p = 0.01) and between incestuous perpetrator and chronic duration (p = 0.01). CONCLUSION: Although this study does not reflect reality, it can be used as a warning to pediatricians. PMID- 22930027 TI - Evaluation of the prevalence and nutritional and social determinants of overweight in a population of schoolchildren: a cross-sectional analysis of 5,037 children. AB - OBJECTIVE: To evaluate the prevalence and nutritional and social determinants of overweight in a population of schoolchildren in Southern Brazil. METHODS: Cross sectional descriptive study of 5,037 children of both genders, between 6 and 10.9 years of age, from public and private schools of Maringa, Parana, Brazil. Evaluation of factors associated with excess weight (overweight and obesity) included gender, age, school type, socioeconomic level, education of the head of the family, eating habits, and means of commuting to school. After univariate analysis (Fisher's exact test), we adjusted a logistic regression model and used Wald's test for decision-making (p < 0.05). RESULTS: The mean age was 8.7 +/- 1.3 years, with 52.8% females; 79.1% of the students attended public school and 54.6% had families of socioeconomic class A or B. Regarding nutritional status, 24% of children were overweight (7% obesity, 17% overweight). Being male, attending a private school, and having a head of the family with over four years of education were significantly associated with excess weight. In relation to food, inadequate intake of carbohydrates was associated with a 48% greater chance of overweight/obesity (p < 0.001; OR: 1.48; 95% CI: 1.25-1.76). CONCLUSION: The prevalence of overweight found in this study is approximate to that reported in national studies. Its association with gender and inadequate food intake indicates that these factors should be considered in initiatives aimed at preventive measures in childhood. PMID- 22930028 TI - The burden of dengue: Jundiai, Brazil - January 2010. AB - OBJECTIVE: To study the antibody prevalence against dengue in the municipality of Jundiai, Sao Paulo, Brazil, due to the low number of official confirmed autochthonous cases. METHODS: A serological study on dengue infection was conducted during January 2010 and previous reports on dengue and entomological surveillance during that period were reviewed. RESULTS: A prevalence of 7.8% IgG positive (68:876) was found. Furthermore, based on the detection of IgM antibodies in five samples, it was observed that the incidence of dengue in the city at the time of the survey contrasts with the absence of notifications by local health authorities over the same period of time. CONCLUSION: These results highlight the discrepancies between the actual and the detected number of dengue infections, possibly due to significant numbers of asymptomatic infections aggravated by difficulties with dengue clinical diagnosis. PMID- 22930029 TI - Mood swings in patients with Crohn's disease: incidence and associated factors. AB - OBJECTIVE: To assess the incidence of mood swings (MS) and possible associated factors in patients with Crohn's disease (CD). METHODS: Prospective longitudinal study of 50 patients (60% females; mean age 40.6 years) with a diagnosis of CD over a 16-month follow-up. Clinical activity was assessed by the CD activity index. Psychological status self-report tools (Beck Depression Inventory and the anxiety subscale of the Hospital Anxiety and Depression Scale) were used for mood disorder diagnosis. The tools were applied at baseline and at four-month intervals thereafter. RESULTS: The inflammatory phenotype was the most common (86%); 36% had a previous history of surgery related to CD; 82% were in clinical remission at baseline. MS occurred in 58% of patients; 28% had progression of depression and/or anxiety symptoms from baseline normal mood, and 30% had baseline depressive and/or anxious mood normalized. In 38% of patients with MS, no change in the disease clinical activity could be found (p = 0.015), whereas 20% had a change in CD activity. Female gender and absence of previous surgery related to CD complications were associated with higher MS incidence (p = 0.04 for both). CONCLUSION: In this study, a high MS incidence (58%) was found in patients with CD. Female gender and absence of previous surgery from CD complications were associated with a higher MS incidence. Periodic psychological assessment could be useful to detect and approach MS in patients with CD. PMID- 22930030 TI - Jaccoud arthropathy in systemic lupus erythematosus: clinical and serological findings. AB - OBJECTIVE: To study the prevalence of Jaccoud arthropathy (JA) in a sample of local systemic lupus erythematosus (SLE) patients and its clinical and serological associations. METHODS: 308 SLE patients from a single university center for the last two years were interviewed and examined. The presence of JA was searched for according to the JA index. After this, charts were reviewed for clinical and serological profile. RESULTS: The studied sample was composed by 94.5% females and 5.5% males with mean age of 38.08 +/- 12.04 years and mean disease duration of 29.68 +/- 11.63 years. A JA prevalence of 6.1% was found in this sample. There was a positive association of JA presence with arthritis complaints (p = 0.001) and a negative association with renal involvement (p = 0.028). Patients with JA had higher positivity for anti-dsDNA (p = 0.022). CONCLUSION: Despite the positive association of JA with arthritis and anti-dsDNA, there was a negative association with nephritis. This could suggest that JA patients belong with a SLE subset with a better prognosis. PMID- 22930031 TI - Molecular features of sexual steroids on cartilage and bone. AB - In Brazil, the increase in the reported cases of degenerative diseases of articular cartilage is 20% per year, meaning that 200,000 Brazilians develop degenerative joint diseases every year, which have a negative impact on bone mass. This study shows evidence that hormone production of sexual steroids (estrogens, progestogens, and androgens) have an influence on cartilage quality, as well as on bone mass. Therefore, this review aimed to analyze literature data on the molecular and genic action of sexual steroids on hyaline cartilage and bone physiology, as well as osteoarthritis interference on the quality of these structures. PMID- 22930032 TI - Diagnostic methods in sepsis: the need of speed. AB - OBJECTIVE: Sepsis is a common condition encountered in hospital environments. There is no effective treatment for sepsis, and it remains an important cause of death at intensive care units. This study aimed to discuss some methods that are available in clinics, and tests that have been recently developed for the diagnosis of sepsis. METHODS: A systematic review was performed through the analysis of the following descriptors: sepsis, diagnostic methods, biological markers, and cytokines. RESULTS: The deleterious effects of sepsis are caused by an imbalance between the invasiveness of the pathogen and the ability of the host to mount an effective immune response. Consequently, the host's immune surveillance fails to eliminate the pathogen, allowing it to spread. Moreover, there is a pro-inflammatory mediator release, inappropriate activation of the coagulation and complement cascades, leading to dysfunction of multiple organs and systems. The difficulty achieve total recovery of the patient is explainable. There is an increased incidence of sepsis worldwide due to factors such as aging population, larger number of surgeries, and number of microorganisms resistant to existing antibiotics. CONCLUSION: The search for new diagnostic markers associated with increased risk of sepsis development and molecules that can be correlated to certain steps of sepsis is becoming necessary. This would allow for earlier diagnosis, facilitate patient prognosis characterization, and prediction of possible evolution of each case. All other markers are regrettably constrained to research units. PMID- 22930033 TI - Perioperative cardiovascular evaluation: heads or tails? AB - When dealing with surgical patients, a perioperative evaluation is essential to anticipate complications and institute measures to reduce the risks. Several algorithms and exams have been used to identify postoperative cardiovascular events, which account for more than 50% of perioperative mortality. However, they are far from ideal. Some of these algorithms and exams were proposed before important advances in cardiology, at a time when pharmacological risk reduction strategies for surgical patients were not available. New biomarkers and exams, such as C-reactive protein, brain natriuretic peptide, and multislice computed tomography have been used in cardiology and have provided important prognostic information. The ankle-brachial index is another significant marker of atherosclerosis. However, specific information regarding the perioperative context of all these methods is still needed. The objective of this article is to evaluate cardiovascular risk prediction models after noncardiac surgery. PMID- 22930034 TI - Cis-trans isomerism in diphenoxido bridged dicopper complexes: role of crystallized water to stabilize the cis isomer, variation in magnetic properties and conversion of both into a trinuclear species. AB - The trans-[Cu(2)L(2)Cl(2)] (1), and cis-[Cu(2)L(2)Cl(2)].H(2)O (2) isomers of a diphenoxido bridged Cu(2)O(2) core have been synthesized using a tridentate reduced Schiff base ligand 2-[(2-dimethylamino-ethylamino)-methyl]-phenol. The geometry around Cu(II) is intermediate between square pyramid and trigonal bipyramid (Addison parameter, tau = 0.463) in 1 but nearly square pyramidal (tau = 0.049) in 2. The chloride ions are coordinated to Cu(II) and are trans oriented in 1 but cis oriented in 2. Both isomers have been optimized using density functional theory (DFT) calculations and it is found that the trans isomer is 7.2 kcal mol(-1) more favorable than the cis isomer. However, the hydrogen bonding interaction of crystallized water molecule with chloride ions compensates for the energy difference and stabilizes the cis isomer. Both complexes have been converted to a very rare phenoxido-azido bridged trinuclear species, [Cu(3)L(2)(MU(1,1)-N(3))(2)(H(2)O)(2)(ClO(4))(2)] (3) which has also been characterized structurally. All the complexes are antiferromagnetically coupled but the magnitude of the coupling constants are significantly different (J = 156.60, -652.31, and -31.54 cm(-1) for 1, 2, 3 and respectively). Density functional theory (DFT) calculations have also been performed to gain further insight into the qualitative theoretical interpretation on the overall magnetic behavior of the complexes. PMID- 22930035 TI - Mechanism of the protective action of taurine in toxin and drug induced organ pathophysiology and diabetic complications: a review. AB - Taurine (2-aminoethanesulfonic acid), a conditionally essential amino acid, is found in large concentrations in all mammalian tissues and is particularly abundant in aquatic foods. Taurine exhibits membrane stabilizing, osmoregulatory and cytoprotective effects, antioxidative properties, regulates intracellular Ca(2+) concentration, modulates ion movement and neurotransmitters, reduce the levels of pro-inflammatory cytokines in various organs and controls blood pressure. Recently, emerging evidence from the literature shows the effectiveness of taurine as a protective agent against several environmental toxins and drug induced multiple organ injuries as the outcome of hepatotoxicity, nephrotoxicity, neurotoxicity, testicular toxicity and cardiotoxicity in several animal models. Besides, taurine is also effective in combating diabetes and its associated complications, including cardiomyopathy, nephropathy, neuropathy, retinopathy and atherosclerosis. These beneficial effects appear to be due to the multiple actions of taurine on cellular functions. This review summarizes the mechanism of the prophylactic role of taurine against several environmental toxins and drug induced organ pathophysiology and diabetes. PMID- 22930036 TI - Schizophrenia is primed for an increased expression of depression through activation of immuno-inflammatory, oxidative and nitrosative stress, and tryptophan catabolite pathways. AB - Schizophrenia and depression are two common and debilitating psychiatric conditions. Up to 61% of schizophrenic patients have comorbid clinical depression, often undiagnosed. Both share significant overlaps in underlying biological processes, which are relevant to the course and treatment of both conditions. Shared processes include changes in cell-mediated immune and inflammatory pathways, e.g. increased levels of pro-inflammatory cytokines and a Th1 response; activation of oxidative and nitrosative stress (O&NS) pathways, e.g. increased lipid peroxidation, damage to proteins and DNA; decreased antioxidant levels, e.g. lowered coenzyme Q10, vitamin E, glutathione and melatonin levels; autoimmune responses; and activation of the tryptophan catabolite (TRYCAT) pathway through induction of indoleamine-2,3-dioxygenase. Both show cognitive and neurostructural evidence of a neuroprogressive process. Here we review the interlinked nature of these biological processes, suggesting that schizophrenia is immunologically primed for an increased expression of depression. Such a conceptualization explains, and incorporates, many of the current perspectives on the nature of schizophrenia and depression, and has implications for the nature of classification and treatment of both disorders. An early developmental etiology to schizophrenia, driven by maternal infection, with subsequent impact on offspring immuno-inflammatory responses, creates alterations in the immune pathways, which although priming for depression, also differentiates the two disorders. PMID- 22930037 TI - A thermodynamic perspective of the metastability of holey sheets: the role of curvature. AB - Producing nanostructures with high surface area that are stable is important to accomplish sustained use of catalytic materials in practical settings. Avoiding the processes of ripening and sintering that typically hinder stability has long been recognized as a significant challenge and much research is focused on addressing these issues. In this article, we investigate a Pt nanostructure-a holey nanosheet-that exhibits high surface area and stability. The findings from lattice gas simulations produce a stability diagram that relates a critical hole diameter to sheet thickness. The stability is now addressed from a thermodynamic point of view, and, in particular, the crucial role of curvature is considered. We find that the stability of certain sized holes is due to the near zero mean curvature of the surface of the holes and of the surrounding flat sheet. Molecular dynamics simulations of Pt (using an embedded atom potential) are reported for small nanoclusters and model holes in sheets to illustrate the strong effects of curvature on thermodynamic properties such as the lowering of melting and surface melting temperatures. PMID- 22930038 TI - Fluorescent properties and resonance energy transfer of 3,4-bis(2,4 difluorophenyl)-maleimide. AB - A fluorescent compound 3,4-bis(2,4-difluorophenyl)-maleimide from the 3,4-diaryl substituted maleimides was synthesized and determined to have a Stokes shift of 140 nm (lambda(abs) 341 nm, lambda(em) 481 nm), a high fluorescent quantum yield (Phi(fl) 0.61) and an extinction coefficient epsilon((340)) of 48 400 M(-1) cm( 1) in dichloromethane. For the first time we demonstrated the successful implementation of a 3,4-diaryl-substituted maleimide molecule as a donor component in FRET experiments. PMID- 22930039 TI - Parasite, vectors and reservoirs as determinants of tegumentary leishmaniasis. PMID- 22930040 TI - Ecological aspects of the sandfly fauna (Diptera, Psychodidae) in an American cutaneous leishmaniasis endemic area under the influence of hydroelectric plants in Paranapanema river, State of Parana, Brazil. AB - INTRODUCTION: An epidemiological study was undertaken to identify determinant factors in the occurrence of American cutaneous leishmaniasis in areas under the influence of hydroelectric plants in Paranapanema river, State of Parana, Brazil. The ecological aspects of the phlebotomine fauna were investigated. METHODS: Sandflies were sampled with automatic light traps from February 2004 to June 2006 at 25 sites in the urban and rural areas of Itambaraca, and in Porto Almeida and Sao Joaquim do Pontal. RESULTS: A total of 3,187 sandflies of 15 species were captured. Nyssomyia neivai predominated (34.4%), followed by Pintomyia pessoai (32.6%), Migonemyia migonei (11.6%), Nyssomyia whitmani (8.8%), and Pintomyia fischeri (2.7%), all implicated in the transmission of Leishmania. Males predominated for Ny. neivai, and females for the other vector species, with significant statistical differences (p < 0.001). Nyssomyia neivai, Pi. pessoai, Ny. whitmani, Brumptomyia brumpti, Mg. migonei, and Pi. fischeri presented the highest values for the Standardized Species Abundance Index (SSAI). The highest frequencies and diversities were found in the preserved forest in Porto Almeida, followed by forests with degradation in Sao Joaquim do Pontal and Vila Rural. CONCLUSIONS: Sandflies were captured in all localities, with the five vectors predominating. Ny. neivai had its highest frequencies in nearby peridomestic environments and Pi. pessoai in areas of preserved forests. The highest SSAI values of Ny. neivai and Pi. pessoai reflect their wider dispersion and higher frequencies compared with other species, which seems to indicate that these two species may be transmitting leishmaniasis in the area. PMID- 22930041 TI - Liver fibrosis progression in HIV/hepatitis C virus coinfected patients with normal aminotransferases levels. AB - INTRODUCTION: Approximately 30% of hepatitis C virus (HCV) monoinfected patients present persistently normal alanine aminotransferase (ALT) levels. Most of these patients have a slow progression of liver fibrosis. Studies have demonstrated the rate of liver fibrosis progression in hepatitis C virus-human immunodeficiency virus (HCV-HIV) coinfected patients is faster than in patients infected only by HCV. Few studies have evaluated the histological features of chronic hepatitis C in HIV-infected patients with normal ALT levels. METHODS: HCV-HIV coinfected patients (HCV-RNA and anti-HIV positive) with known time of HCV infection (intravenous drugs users) were selected. Patients with hepatitis B surface antigen (HBsAg) positive or hepatitis C treatment before liver biopsy were excluded. Patients were considered to have a normal ALT levels if they had at least 3 normal determinations in the previous 6 months prior to liver biopsy. All patients were submitted to liver biopsy and METAVIR scale was used. RESULTS: Of 50 studied patients 40 (80%) were males. All patients were treated with antiretroviral therapy. The ALT levels were normal in 13 (26%) patients. HCV-HIV co-infected patients with normal ALT levels had presented means of the liver fibrosis stages (0.77+/-0.44 versus 1.86+/-1.38; p<0.001) periportal inflammatory activity (0.62+/-0.77 versus 2.24+/-1.35; p<0.001) and liver fibrosis progression rate (0.058+/-0.043 fibrosis unit/year versus 0.118+/-0.102 fibrosis unit/year) significantly lower as compared to those with elevated ALT. CONCLUSIONS: HCV-HIV coinfected patients with persistently normal ALTs showed slower progression of liver fibrosis. In these patients the development of liver cirrhosis is improbable. PMID- 22930042 TI - Biological, behavioral, and socioeconomic factors associated with death from AIDS in Brasilia, Brazil, in 2007. AB - INTRODUCTION: In the jurisdiction of Brasilia, Brazil, significant reductions in mortality rates and lethality resulting from acquired immunodeficiency syndrome (AIDS) were observed shortly after the introduction of highly active antiretroviral therapy. In recent years, however, the decline of these rates has not been as significant. Non-adherence to treatment and delayed diagnosis appear to be the main factors that increase the risk of death from AIDS. Behavioral, socioeconomic, and biological factors could also be associated with increased risk of death due to AIDS. This study aimed to identify which of these factors were associated with deaths from AIDS in Brasilia. METHODS: A case-control study was undertaken using the data recorded in the Information System of Notifiable Diseases. Cases consisted of AIDS deaths occurring in 2007, residing in Brasilia, and over 12 years of age. Controls consisted of AIDS patients who did not die until December 31 2007, also residing in Brasilia, and over 12 years of age. For each group, frequency and proportion tables for the variables were prepared. The statistical association of each factor in isolation with the occurrence of the deaths was verified through a model of multivariate analysis using logistic regression. RESULTS: The factors that were associated with an increased risk of death were intravenous drug use, age 50 years or more, and residing in a region whose residents have low per capita income. CONCLUSIONS: We identified factors associated with death due to AIDS that can guide health planning. PMID- 22930043 TI - Molecular epidemiology of hepatitis B virus among the indigenous population of the Curuca and Itaquai Rivers, Javari Valley, State of Amazonas, Brazil. AB - INTRODUCTION: Hepatitis B virus (HBV) infection is one of the most serious public health problems in the world. In Brazil, HBV endemicity is heterogeneous, with the highest disease prevalence in the North region. METHODS: A total of 180 samples were analyzed and subjected to polymerase chain reaction (PCR) and semi nested PCR of the HBV S-gene, with the aim of determining the prevalence of HBV DNA (deoxyribonucleic acid) in indigenous groups inhabiting the areas near the Curuca and Itaquai Rivers in the Javari Valley, State of Amazonas, Brazil. RESULTS: The prevalence of the HBV-DNA S-gene was 51.1% (92/180). The analysis found 18 of 49 (36.7%) samples from the Marubo tribe, 68 of 125 (54.4%) from the Kanamary, and 6 of 6 (100%) from other ethnic groups to be PCR positive. There was no statistically significant difference in gender at 5% (p=0.889). Indigenous people with positive PCR for HBV-DNA had a lower median age (p<0.001) of 23 years. There was no statistical difference found in relation to sources of contamination or clinical aspects with the PCR results, except for fever (p<0.001). The high prevalence of HBV-DNA of 75% (15/20) in pregnant women (p=0.009) demonstrates an association with vertical transmission. CONCLUSIONS: The results confirm the high prevalence of HBV-DNA in the Javari Valley, making it important to devise strategies for control and more effective prevention in combating the spread of HBV. PMID- 22930044 TI - Hepatitis B virus infection in a population exposed to occupational hazards: firefighters of a metropolitan region in central Brazil. AB - INTRODUCTION: By the nature of their activities, firefighters are exposed to a high risk of contracting hepatitis B virus (HBV) as most of the Fire Brigade occurrences in Campo Grande, State of Mato Grosso do Sul (MS), Brazil, are related to the rescue of victims of traffic accidents and the transportation of clinical and psychiatric emergencies. The aim of this study was to investigate the seroepidemiological profile of HBV infection in firefighters from the City of Campo Grande, central Brazil. METHODS: The research involved 308 firefighters. After giving written consent, they were interviewed and blood was collected for the detection of HBsAg, anti-HBs and total anti-HBc of enzyme-linked immunosorbent assays (ELISA). RESULTS: The participants had an average of 36.4 years of age (SD +/- 6.5), being 89.9% male. Blood tests revealed 6.5% of seropositivity for hepatitis B (HB) infection (n=20), and 1% for HbsAg. Isolated anti-HBs markers, indicative of vaccine immunity, were found in 66.9% of the participants and 28.2% were susceptible to infection. With regard to risk factors for HB infection, multivariate regression analysis showed a statistically significant association with length of service; and prevalence was higher in individuals with over 20 years of service. CONCLUSIONS: The prevalence of HB found among the firefighters was low and length of time in the profession was found to be a risk factor. Non-occupational risk factors did not influence the occurrence of HB infection in the population studied. PMID- 22930045 TI - Rifampicin fails to eradicate mature biofilm formed by methicillin-resistant Staphylococcus aureus. AB - INTRODUCTION: Antimicrobial activity on biofilms depends on their molecular size, positive charges, permeability coefficient, and bactericidal activity. Vancomycin is the primary choice for methicillin-resistant Staphylococcus aureus (MRSA) infection treatment; rifampicin has interesting antibiofilm properties, but its effectivity remains poorly defined. METHODS: Rifampicin activity alone and in combination with vancomycin against biofilm-forming MRSA was investigated, using a twofold serial broth microtiter method, biofilm challenge, and bacterial count recovery. RESULTS: Minimal inhibitory concentration (MIC) and minimal bactericidal concentration for vancomycin and rifampicin ranged from 0.5 to 1mg/l and 0.008 to 4mg/l, and from 1 to 4mg/l and 0.06 to 32mg/l, respectively. Mature biofilms were submitted to rifampicin and vancomycin exposure, and minimum biofilm eradication concentration ranged from 64 to 32,000 folds and from 32 to 512 folds higher than those for planktonic cells, respectively. Vancomycin (15mg/l) in combination with rifampicin at 6 dilutions higher each isolate MIC did not reach in vitro biofilm eradication but showed biofilm inhibitory capacity (1.43 and 0.56log10 CFU/ml reduction for weak and strong biofilm producers, respectively; p<0.05). CONCLUSIONS: In our setting, rifampicin alone failed to effectively kill biofilm-forming MRSA, demonstrating stronger inability to eradicate mature biofilm compared with vancomycin. PMID- 22930046 TI - In vitro action of antiparasitic drugs, especially artesunate, against Toxoplasma gondii. AB - INTRODUCTION: Toxoplasmosis is usually a benign infection, except in the event of ocular, central nervous system (CNS), or congenital disease and particularly when the patient is immunocompromised. Treatment consists of drugs that frequently cause adverse effects; thus, newer, more effective drugs are needed. In this study, the possible activity of artesunate, a drug successfully being used for the treatment of malaria, on Toxoplasma gondii growth in cell culture is evaluated and compared with the action of drugs that are already being used against this parasite. METHODS: LLC-MK2 cells were cultivated in RPMI medium, kept in disposable plastic bottles, and incubated at 36oC with 5% CO2. Tachyzoites of the RH strain were used. The following drugs were tested: artesunate, cotrimoxazole, pentamidine, pyrimethamine, quinine, and trimethoprim. The effects of these drugs on tachyzoites and LLC-MK2 cells were analyzed using nonlinear regression analysis with Prism 3.0 software. RESULTS: Artesunate showed a mean tachyzoite inhibitory concentration (IC50) of 0.075uM and an LLC MK2 toxicity of 2.003uM. Pyrimethamine was effective at an IC50 of 0.482uM and a toxicity of 11.178uM. Trimethoprim alone was effective against the in vitro parasite. Cotrimoxazole also was effective against the parasite but at higher concentrations than those observed for artesunate and pyrimethamine. Pentamidine and quinine had no inhibitory effect over tachyzoites. CONCLUSIONS: Artesunate is proven in vitro to be a useful alternative for the treatment of toxoplasmosis, implying a subsequent in vivo effect and suggesting the mechanism of this drug against the parasite. PMID- 22930047 TI - Antigens of worms and eggs showed a differentiated detection of specific IgG according to the time of Schistosoma mansoni infection in mice. AB - INTRODUCTION: The correlation between the immunological assay and the antibody titer can offer a tool for the experimental analysis of different phases of the disease. METHODS: Two simple immunological assays for Schistosoma mansoni in mice sera samples based on specific IgG detection for worms soluble antigens and eggs soluble antigens were standardized and evaluated in our laboratory. Fifty mice were used in negative and positive groups and the results obtained by enzyme linked immunosorbent assays (ELISA) assays were compared with the number of worms counted and the IgG titers at different times of infection. RESULTS: Data showed that ELISA using adult worm antigens (ELISA-SWAP) presented a satisfactory correlation between the absorbance value of IgG titers and the individual number of worms counted after perfusion technique (R2=0.62). In addition, ELISA-SWAP differentially detected positive samples with 30 and 60 days post infection (p=0.011 and 0.003, respectively), whereas ELISA using egg antigens (ELISA-SEA) detected samples after 140 days (p=0.03). CONCLUSIONS: These data show that the use of different antigens in immunological methods can be used as potential tools for the analysis of the chronological evolution of S. mansoni infection in murine schistosomiasis. Correlations with human schistosomiasis are discussed. PMID- 22930048 TI - Increased detection of schistosomiasis with Kato-Katz and SWAP-IgG-ELISA in a Northeastern Brazil low-intensity transmission area. AB - INTRODUCTION: The laboratory diagnosis of schistosomiasis is based mainly on the detection of parasite eggs in stool samples through the Kato-Katz (KK) technique, reading one slide by test. However, a widely known limitation of parasitological methods is reduced sensitivity, particularly in low endemic areas. METHODS: To increase sensitivity, we conducted further slide readings from the same stool sample using the parasitological method associated with a serological test. We used the KK method (three slides) and the IgG anti-Schistosoma mansoni-enzyme linked immunosorbent assay (ELISA) technique to diagnose schistosomiasis in low endemic areas in the Brazilian State of Ceara. Fecal samples and sera from 250 individuals were analyzed. RESULTS: Sixteen percent and 47.2% of samples were positive in parasitological tests and serological tests, respectively. Parasitological methods showed that 32 (80%) individuals tested positive on the first slide, 6 (15%) on the second slide, and 2 (5%) on the third. The performance of the ELISA test in the diagnosis, using the KK method as diagnostic reference, showed a negative predictive value of 100%, with specificity and positive predictive values of 62.8% and 33.9%, respectively. CONCLUSIONS: In this study, the increase from one to three slides analyzed per sample using the KK technique was shown to be a useful procedure for increasing the diagnostic sensitivity of this technique. PMID- 22930049 TI - Development of cognitive abilities of children infected with helminths through health education. AB - INTRODUCTION: The aim of this study was to evaluate the effect of health education in learning and cognitive development of children infected, previously treated in an endemic area for helminthiasis. METHODS: It is a longitudinal, experimental, with random allocation of participants. The study included 87 children of both sexes enrolled in the school hall of Maranhao, State of Minas Gerais, Brazil, and divided into two groups: intervention and control. Initially the children were submitted to the parasitological fecal examination for infection diagnosis and, when positive, they were treated. For the data collection, a structured questionnaire and the psychological tests Raven, Wisc III and DAP III were applied, before and after the educational intervention. For the group comparison, the Mann Whitney test was used, and established significance level of 5%. RESULTS: It was found that previously infected children who received the educational intervention, children showed higher performance than the control group in strutured questionnaire (p<0.05). CONCLUSIONS: It is acceptable to suppose the positive influence and the importance in the use of educational interventions in the cognitive recovery and learning of children previously treated with anthelmintics. PMID- 22930050 TI - Rotavirus genotyping in gastroenteritis cases of an infantile population from Western Brazilian Amazonia. AB - INTRODUCTION: During the period from 2000 to 2002, 79 rotavirus-positive stool samples were collected from children presenting diarrhea in the Western Brazilian Amazon. METHODS: Molecular characterization of the G and P genotypes was performed using RT-PCR and electropherotyping analysis by polyacrylamide gel electrophoresis. RESULTS: A total of 59 samples were confirmed as group A rotavirus. A long electrophoretic profile was exhibited by the G1P[8], G3P[8], and G4P[8] genotypes. The G1P[8] genotype was found in greater proportion. The short electropherotype was exhibited only by G2 genotype strains. CONCLUSIONS: The proportion of the rotavirus genotypes observed was not different from that in other areas of Brazil. This study is the first genotyping of rotavirus in the Western Brazilian Amazon. PMID- 22930051 TI - Comparative evaluation of adverse effects in the use of powder trivalent antivenom and liquid antivenoms in Bothrops snake bites. AB - INTRODUCTION: Snake bite, a problem in public health, generally occurs where there is no electric power. METHODS: A comparative clinical study was conducted with 102 victims of Bothrops snake bite, from the state of Amazonas, Brazil; 58 victims were treated with liofilizated trivalent antivenom serum (SATL) and 44 victims treated with liquid bivalent and monovalent antivenom serum (SAMBL). RESULTS: 17% (10/58) of patients presented adverse effects with the SATL and 25% (11/44) with the SAMBL. CONCLUSIONS: There was no statistic difference in number of adverse effects between the two types of snake bite antivenom. PMID- 22930052 TI - Epidemiology of malaria in the municipality of Cruzeiro do Sul, State of Acre, Brazil, in 2010: uses of a control chart at the local level. AB - INTRODUCTION: This study describes the uses of a control chart in the malaria surveillance at the local level, signaling whether there is a need to intensify or adapt control measures. METHODS: The districts of Cruzeiro do Sul (n=14), State of Acre, Brazil, were classified into three groups: I) those with an incidence lower than expected; II) those with an incidence within the expected range; and III) those with an epidemic. RESULTS: Thirteen of the fourteen districts had outbreaks of malaria at some point in 2010, and six districts showed persistent malaria epidemic throughout the year. CONCLUSIONS: The control chart may help the malaria control at the local level. PMID- 22930053 TI - Primary multidrug-resistant tuberculosis and its control implications in the State of Amazonas, Brazil: report of 3 cases. AB - The occurrence of tuberculosis with first-line multidrug resistance leads to the use of alternative medications, often at higher costs, longer treatment periods, and greater clinical complexity. Here, we report 3 patients with multidrug resistant tuberculosis. One patient with human immunodeficiency virus died before the sensitivity test was performed. The early diagnosis of multidrug-resistant tuberculosis and appropriate treatment should be priorities of the National Tuberculosis Control Program in order to break the chain of transmission. In addition, the possibility of substituting the proportion method with more modern and faster techniques should be urgently evaluated. PMID- 22930054 TI - Tick paralysis cases in Argentina. AB - Tick paralysis (TP) occurs worldwide and is caused by a neurotoxin secreted by engorged female ticks that affects the peripheral and central nervous system. The clinical manifestations range from mild or nonspecific symptoms to manifestations similar to Guillain-Barre syndrome, bulbar involvement, and death in 10% of the patients. The diagnosis of TP is clinical. To our knowledge, there are no formal reports of TP in humans in South America, although clusters of TP among hunting dogs in Argentina have been identified recently. In this paper, clinical features of two cases of TP occurring during 1994 in Jujuy Province, Argentina, are described. PMID- 22930055 TI - Actinomycosis affecting the spinal cord: a case report. AB - Actinomycosis is a rare, chronic, suppurative, granulomatous infection caused by a group of gram-positive anaerobic bacteria belonging to the natural flora of the oral cavity and gastrointestinal and urogenital tracts. It may involve several organs. This case study refers to pulmonary actinomycosis with chest wall involvement and cord compression in a 29-year-old male who presented with fever, cough, hemoptysis, neck pain, and paresis and plegia of the lower limbs of 5 month duration. PMID- 22930056 TI - Detection of clusters of leprosy cases among Guarani Indians in the southern region of the State of Rio de Janeiro, Brazil. PMID- 22930057 TI - Oral chronic hyperplastic candidiasis associated with juvenile dermatomyositis. PMID- 22930059 TI - Stabilization of secondary structure elements by specific combinations of hydrophilic and hydrophobic amino acid residues is more important for proteins encoded by GC-poor genes. AB - Stabilization of secondary structure elements by specific combinations of hydrophobic and hydrophilic amino acids has been studied by the way of analysis of pentapeptide fragments from twelve partial bacterial proteomes. PDB files describing structures of proteins from species with extremely high and low genomic GC-content, as well as with average G + C were included in the study. Amino acid residues in 78,009 pentapeptides from alpha helices, beta strands and coil regions were classified into hydrophobic and hydrophilic ones. The common propensity scale for 32 possible combinations of hydrophobic and hydrophilic amino acid residues in pentapeptide has been created: specific pentapeptides for helix, sheet and coil were described. The usage of pentapeptides preferably forming alpha helices is decreasing in alpha helices of partial bacterial proteomes with the increase of the average genomic GC-content in first and second codon positions. The usage of pentapeptides preferably forming beta strands is increasing in coil regions and in helices of partial bacterial proteomes with the growth of the average genomic GC-content in first and second codon positions. Due to these circumstances the probability of coil-sheet and helix-sheet transitions should be increased in proteins encoded by GC-rich genes making them prone to form amyloid in certain conditions. Possible causes of the described fact that importance of alpha helix and coil stabilization by specific combinations of hydrophobic and hydrophilic amino acids is growing with the decrease of genomic GC-content have been discussed. PMID- 22930060 TI - Ultrafast electron transfer in riboflavin binding protein in macromolecular crowding of nano-sized micelle. AB - In this contribution, we have studied the dynamics of electron transfer (ET) of a flavoprotein to the bound cofactor, an important metabolic process, in a model molecular/macromolecular crowding environments. Vitamin B(2) (riboflavin, Rf) and riboflavin binding protein (RBP) are used as model cofactor and flavoprotein, respectively. An anionic surfactant sodium dodecyl sulfate (SDS) is considered to be model crowding agent. A systematic study on the ET dynamics in various SDS concentration, ranging from below critical micellar concentration (CMC), where the surfactants remain as monomeric form to above CMC, where the surfactants self assemble to form nanoscopic micelle, explores the dynamics of ET in the model molecular and macromolecular crowding environments. With energy selective excitation in picosecond-resolved studies, we have followed temporal quenching of the tryptophan residue of the protein and Rf in the RBP-Rf complex in various degrees of molecular/macromolecular crowding. The structural integrity of the protein (secondary and tertiary structures) and the vitamin binding capacity of RBP have been investigated using various techniques including UV-Vis, circular dichroism (CD) spectroscopy and dynamic light scattering (DLS) studies in the crowding environments. Our finding suggests that the effect of molecular/macromolecular crowding could have major implication in the intra protein ET dynamics in cellular environments. PMID- 22930061 TI - Black rice extract extends the lifespan of fruit flies. AB - Black rice is rich in anthocyanin antioxidants. The present study investigated the lifespan-prolonging activity of black rice extracts (BREs) and its effect on gene expressions of CuZnSOD (SOD1), MnSOD (SOD2), catalase (CAT), methuselah (Mth) and Rpn11 involved in the antioxidant system and ageing of fruit flies. The OR wild type fly was maintained on a control diet or two experimental diets containing 10 mg ml(-1) BRE (BRE10) or 30 mg ml(-1) BRE (BRE30). Results demonstrated that BRE30 could prolong the mean lifespan of fruit flies by 14%, accompanied with up-regulation of mRNA SOD1, SOD2, CAT and Rpn11, and with down regulation of Mth. It was also found that BRE30 could attenuate the paraquat induced neurodegeneration in OR wild type flies accompanied by up-regulation of SOD1, SOD2, CAT and Rpn11. In addition, BRE30 supplementation increased the survival time of OR wild type flies and Alzheimer transgenic flies Abeta42 33769 with chronic exposure to paraquat. It was concluded that BREs could extend the lifespan of fruit flies, most likely by regulating the genes of SOD1, SOD2, CAT, Mth and Rpn11 at the transcriptional level. PMID- 22930062 TI - Estrogen receptor alpha/beta-cofactor motif interactions; interplay of tyrosine 537/488 phosphorylation and LXXLL motifs. AB - The Estrogen Receptors ERalpha and ERbeta bind cofactor proteins via short LXXLL motifs. The exact regulation and selectivity of these interactions remains an open question and the role of post-translational modifications (PTMs) is virtually unexplored. Here, we designed an X(7)-LXXLL-X(7) T7 phage display library and screened this against four ER protein constructs: the 'naked' ERalpha and ERbeta Ligand Binding Domains (LBDs) and the tyrosine phosphorylated ERalpha (pY537) and ERbeta (pY488) LBDs. The site-selective tyrosine phosphorylated protein constructs were obtained via a protein semi-synthesis approach. Phage display screening yielded preferential sets of peptides. LXXLL peptides with a low pI/acidic C-terminus prefer binding to the naked ERbeta over the phosphorylated ERbeta analogue and ERalpha constructs. Peptides with a high pI/basic C-terminus show the opposite behaviour. These findings not only show regulation of the ERbeta-cofactor interaction via tyrosine phosphorylation, but also suggest that ERbeta and its tyrosine 488 phosphorylation play crucial roles in modulating interactions of coactivators to ERalpha since the natural Steroid Receptor Coactivators (SRCs) feature LXXLL motifs with acidic C-termini, while the repressor protein RIP140 features LXXLL motifs with basic C-termini. This insight provides explanation for ER transcriptional activity and can lead to more focussed targeting of the ER-coactivator interaction. PMID- 22930064 TI - Telemetry capsule for measuring contractile motion in the small intestine. AB - The aim of this study was to develop a capsule which can measure contractions in the small intestine. Currently available methods cause discomfort to the patient while taking measurements; with the development of a telemetry capsule that can measure contractions, patients can avoid pain and continue with ordinary activities while the information is automatically collected from the external receiver. In order to develop the contraction force measuring capsule, various types of silicone transducers were designed and implemented to measure the contraction pressure in the small intestine. The minimum resolution of the implemented transducer was 0.05 mbar, which was small enough to measure contractions. The transducer was assembled with telemetry modules and packaged as a capsule (Phi13 * L25 mm) that had a similar size to a commercial capsule endoscope. In order to verify the function of the capsule, in vitro experiments were conducted and contractile motion was measured as 16.6 cycles per minute (CPM). PMID- 22930063 TI - [Vascular grafts as access for hemodialysis]. AB - Prosthetic arteriovenous grafts have an inferior patency rate and greater morbidity than those with autogenous vessels and are therefore considered as secondary or tertiary vascular access for hemodialysis in patients with fatigued or unsuitable superficial arm veins. Prior access planning in accordance of patient characteristics, careful operative procedure and appropriate revision of complications can ensure long-term functioning of a vascular access using a large variety of possible prosthetic conduits. Arteriovenous grafts remain essential in vascular access surgery and their role may be increasing with higher comorbidities of patients and should be preferred to tunnelled cuffed catheters. This article reviews the indications, alternative configurations and characteristics of arteriovenous grafts. PMID- 22930065 TI - [Bitemporal scalp necrosis : a very rare manifestation of giant cell arteritis]. AB - A 71-year-old woman developed progressive spreading of bitemporal scalp necrosis within 4 weeks accompanied by headaches, myalgia of the shoulder girdle and muscle weakness that had started a few months previously. No additional diseases were reported. The suspected temporal giant cell arteritis could be confirmed by temporal artery biopsy. Therapy with glucocorticoids led to a rapid resolution of clinical symptoms and was tapered over 18 months. Recovery of the scalp necrosis emerged following second intention healing and split-skin transplantation of necrotic areas after successful wound conditioning. The case study demonstrates a rare and serious complication of temporal arteritis which is often accompanied by a poor prognosis. PMID- 22930066 TI - [Early arthritis : no advantage of an early aggressive therapy in the first 2 years]. PMID- 22930067 TI - Hydrogenation properties of KSi and NaSi Zintl phases. AB - The recently reported KSi-KSiH(3) system can store 4.3 wt% of hydrogen reversibly with slow kinetics of several hours for complete absorption at 373 K and complete desorption at 473 K. From the kinetics measured at different temperatures, the Arrhenius plots give activation energies (E(a)) of 56.0 +/- 5.7 kJ mol(-1) and 121 +/- 17 kJ mol(-1) for the absorption and desorption processes, respectively. Ball-milling with 10 wt% of carbon strongly improves the kinetics of the system, i.e. specifically the initial rate of absorption becomes about one order of magnitude faster than that of pristine KSi. However, this fast absorption causes a disproportionation into KH and K(8)Si(46), instead of forming the KSiH(3) hydride from a slow absorption. This disproportionation, due to the formation of stable KH, leads to a total loss of reversibility. In a similar situation, when the pristine Zintl NaSi phase absorbs hydrogen, it likewise disproportionates into NaH and Na(8)Si(46), indicating a very poorly reversible reaction. PMID- 22930068 TI - Synthesis, characterization, DFT studies and catalytic activities of manganese(II) complex with 1,4-bis(2,2':6,2''-terpyridin-4'-yl) benzene. AB - A new di-manganese complex with "back-to-back" 1,4-bis(2,2':6,2''-terpyridin-4' yl) benzene ligation has been synthesized and characterised by a variety of techniques. The back-to-back ligation presents a novel new mononuclear manganese catalytic centre that functions as a heterogeneous catalysis for the evolution of oxygen in the presence of an exogenous oxidant. We discuss the synthesis and spectroscopic characterizations of this complex and propose a mechanism for oxygen evolution activity of the compound in the presence of oxone. The di manganese complex also shows efficient and selective catalytic oxidation of sulfides in the presence of H(2)O(2). Density functional theory calculations were used to assess the structural optimization of the complex and a proposed reaction pathway with oxone. The calculations show that middle benzene ring is distorted respect to both of metallic centers, and this in turn leads to negligible resonance of electrons between two sides of complex. The calculations also indicate the unpaired electron located on oxyl-ligand emphasizes the radical mechanism of water oxidation for the system. PMID- 22930069 TI - Mycobacterium chelonae hand infection following ferret bite. AB - We present a case of hand infection caused by Mycobacterium chelonae. The patient was a 58-year-old woman with Type II diabetes mellitus and stage 4 chronic kidney disease. The infection occurred following a ferret bite and had not responded to oral antibiotics in the primary care setting. She developed signs of pyogenic flexor tenosynovitis of the index and middle fingers of her left hand. Laboratory parameters showed high C-reactive protein, raised erythrocyte sedimentation rate and leucocytosis. Ultrasound imaging confirmed the clinical diagnosis. Plain radiographs showed no osseous involvement. The infection was treated with surgical debridement and broad spectrum parenteral antibiotics. The intra operative tissue specimens were initially negative on aerobic and anaerobic cultures. Following transient improvement of her inflammatory parameters and clinical signs, she developed a recurrence with added features of osteomyelitis of the index and middle finger metacarpal heads on repeat radiographs. A revision surgical debridement of the flexor tenosynovitis and osteomyelitis with specific long-term antibiotic cover has led to resolution of the infection. Extended cultures of the tissue specimens at the regional laboratory confirmed the causative organism to be M. chelonae. To our knowledge, this is the first reported case of M. chelonae infection resulting from a ferret bite. This case reminds us of the need for a high index of suspicion for infection with uncommon pathogens following animal bites, especially in patients with altered immune status. PMID- 22930070 TI - Highly selective carbon dioxide adsorption in a water-stable indium-organic framework material. AB - A metal-organic framework, with chiral 4(1) In(OH)(CO(2))(2) helix chains, exhibits a high CO(2) uptake under ambient conditions and outstanding selective separations of CO(2) from CH(4) or N(2). Its high stability toward humidity or even boiling water is confirmed by PXRD method. PMID- 22930071 TI - Synthesis of vitamin D3 derivatives with nitrogen-linked substituents at A-ring C 2 and evaluation of their vitamin D receptor-mediated transcriptional activity. AB - Binding of a series of novel 1alpha,25-dihydroxyvitamin D(3) (1,25-VD(3)) derivatives, having a nitrogen-linked substituent at the 2alpha- or 2beta position of the A-ring (2-N-substituted compounds), with the vitamin D receptor (VDR) was investigated by means of computational docking studies. Selected compounds were synthesized by coupling A-ring synthons and/or with CD-ring bearing bromomethylene under Trost's conditions. The 2alpha- and 2beta stereoisomers of the A-ring synthons were synthesized from l-serine () as a single chiral source by installing vinyl and propargyl groups at opposite ends of the molecule. The activity of the obtained compounds was evaluated by means of a luciferase-based VDR transcriptional activity assay in NIH3T3 cells. Relatively small substituents incorporating a hydrogen-bonding donor, i.e., NHAc and NHMs, were effective for eliciting VDR transcriptional activity, and 2beta-NHMs-1,25 VD(3) () showed the highest activity, being more potent than 1,25-VD(3). Derivatives with bulky substituents were inactive. These new insights into the structure-activity relationships of 1,25-VD(3) derivatives may be helpful in separating the various biological activities of 1,25-VD(3) and in generating novel therapeutic drug candidates. PMID- 22930072 TI - Evaluation of the influence of whole and defatted flaxseed on satiety, glucose, and leptin levels of women in the late postoperative stage of bariatric surgery. AB - BACKGROUND: Satiety decline is one of the factors that are involved in weight regain in the postoperative period of bariatric surgery. Nutrients such as long chain n-3 polyunsaturated fatty acid and fibers could assist in food intake control by increasing satiety. Flaxseed is a source of these nutrients, and its consumption could help with possible glycemic control and increased satiety. The aim of this study was to evaluate the influence of whole flaxseed and defatted flaxseed on satiety, postprandial blood glucose, and leptin in post-bariatric women. METHODS: A single-blind crossover and randomized study was performed with 18 women in the late postoperative of Roux-en-Y gastric bypass (RYGBP). All women received three test meals containing whole flaxseed, defatted flaxseed, and placebo with 1 week of washout. Satiety was evaluated by a Visual Analog Scale during the fasting period; immediately after ingestion; and 60, 120, and 180 min after meals. RESULTS: There was no difference between test meals for the variables of hunger, satisfaction, fullness, and desire to eat. The basal and postprandial glucose and leptin levels did not differ between the test meals. The intake of defatted flaxseed and placebo muffins resulted in reduced postprandial blood glucose. Postprandial leptin was higher than the baseline (p = 0.02); however, only defatted flaxseed showed increased postprandial leptin levels (p = 0.044). CONCLUSIONS: Whole flaxseed and defatted flaxseed did not promote satiety in women in the late postoperative of RYGBP. However, the test meals with a lower fat content increased the serum leptin levels. PMID- 22930074 TI - Frequency of adjustments and weight loss after laparoscopic adjustable gastric banding. AB - Laparoscopic adjustable gastric banding is an effective procedure for weight loss. Long-term follow-up and band adjustments are crucial to achieve sustained weight loss, but the optimal frequency is unknown. We compare the weight loss of two patient groups adjusted at different frequencies. A 24-month analysis was conducted to 280 patients (156 from an academic center and 124 from an outpatient surgery center). Each center's patients were stratified into 6-month groups according to the length of follow-up. These groups were compared between the settings for average adjustments per month and percent excess weight loss (%EWL). Patient subgroup 0-6 months had 0.6 adjustments/month (adj/mo) and 18.3% EWL at AC compared to 0.7 adj/mo and 19.1% EWL at OC. Subgroup 6-12 months had 0.4 adj/mo and 27.2% EWL at AC compared to 0.5 adj/mo and 33.4% EWL at OC. Subgroup 12-18 months had 0.3 adj/mo and 25.3% EWL at AC compared to 0.5 adj/mo and 45.6% EWL at OC. Subgroup 18-24 months had 0.3 adj/mo and 30.9% EWL at AC compared to 0.3 adj/mo and 42.2% EWL at OC. Analysis of variance crossing 6-month groups with facility produced significant effects for groups (F = 15.52, df = 4.290, p < 0.001), center (F = 14.28, df = 1.290, p < 0.001), and the center-by-group interaction (F = 3.01, df = 4.290, p < 0.02). Our data suggest that more frequent adjustments result in increased EWL, but optimal frequency remains unknown. We believe that the difference noted between the clinics stems from accessibility to adjustments. Additional data, such as %EWL at smaller monthly intervals and the point of diminishing results, should be investigated in future studies. PMID- 22930073 TI - Do postoperative psychotherapeutic interventions and support groups influence weight loss following bariatric surgery? A systematic review and meta-analysis of randomized and nonrandomized trials. AB - Bariatric surgery is currently considered the most effective treatment of severe obesity, but considerable individual variations in weight loss results have been reported. We therefore conducted a systematic review and meta-analysis of studies investigating the effect of psychotherapeutic interventions and support groups on weight loss following bariatric surgery. A literature search was conducted in the databases PubMed and PsycINFO, identifying nine eligible studies reporting results of the effect of psychotherapeutic interventions and support groups on weight loss following bariatric surgery. The results revealed a statistically significant overall effect of both psychotherapeutic interventions and support groups on weight loss (pooled effect size correlation (ESr) = 0.18; p < 0.0001). When comparing the effect sizes of psychotherapeutic interventions and support groups, no difference was found (p = 0.51). Higher quality studies had smaller effect sizes (0.16) than studies with low quality scores (0.22), but the difference did not reach statistical significance (p = 0.26). Patients attending psychotherapeutic interventions or support groups in combination with bariatric surgery appeared to experience greater weight loss results than patients treated with bariatric surgery only. However, research in this area is characterized by a lack of methodological rigor, and it is recommended that future study designs include randomization and active attention control conditions. PMID- 22930075 TI - Palladium complexes derived from N,N-bidentate NH-iminophosphorane ligands: synthesis and use as catalysts in the Sonogashira reaction. AB - The addition of primary amines to the C=C bond of diphenylalkenyl iminophosphoranes yielded a new subtype of N,N-bidentate ligands bearing N=P(V)-C C-NH backbones. These donor ligands reacted with PdCl(2)(COD) to give the corresponding sigmaN,sigmaN-palladium complexes containing secondary amino groups, bearing an intrinsically chiral nitrogen atom, and iminophosphorane units. These new complexes have been fully characterized by the use of spectroscopic techniques and X-ray crystallography. The comparison of the data extracted from their solution NMR spectra with their solid state structures demonstrated the conformational stability of their six-membered chelate ring and also the configurational stability of the chiral nitrogen atom, thus ruling out an arm-off racemization process. The addition of the chiral, racemic alpha methylbenzylamine to the prochiral P-alkenyl iminophosphoranes yielded mixtures of the two expected diasteroisomeric ligands in low diastereoisomeric ratios. One of these mixtures was resolved into their components, each one in turn giving rise to a pair of diasteromeric palladium complexes epimeric at the amino nitrogen atom. One selected example of the new complexes efficiently catalyzes the copper- and amine-free Sonogashira reaction of aryl halides with acetylenes. PMID- 22930076 TI - Academic medicine: a training gap. PMID- 22930077 TI - Sulcus vocalis. PMID- 22930078 TI - Endoscopic view of secretion transport in the maxillary sinus following a long term inferior meatal antrostomy. PMID- 22930079 TI - Avoiding misdiagnosis in venous malformation of the parotid. PMID- 22930080 TI - Massive Zenker diverticulum. PMID- 22930081 TI - Comparison of transient and distortion-product otoacoustic emissions during the luteal and follicular phases of the menstrual cycle. AB - We conducted a study to examine cochlear activity in women with a naturally occurring menstrual cycle by measuring transient otoacoustic emissions (TOAEs) and distortion-product otoacoustic emissions (DPOAEs). Our study population was made up of 11 women aged 20 to 40 years (mean: 35.6) who were not taking a contraceptive medication or hormone therapy. Measurements of TOAEs and DPOAEs were made during both the follicular phase and the luteal phase of the menstrual cycle. We found no statistically significant difference in any of the TOAE amplitude values between the two phases. Although a sharp decrease at the 0.75 kHz frequency was seen in DPOAEs during both phases, none of the amplitude values in the tested frequencies were significantly different between the two phases. The absence of TOAE and DPOAE amplitude changes suggests that it is unnecessary to take into account the phase of the menstrual cycle when interpreting the results of otoacoustic emissions testing. PMID- 22930082 TI - Prediction of stapes footplate thickness based on the level of hearing loss in otosclerosis. AB - During surgical treatment of a patient with otosclerosis, the probability of success depends in large part on the extent of the surgeon's experience. Therefore, predicting the preoperative severity of disease may help determine the choice of surgeon based on how experienced the surgeon should be. We conducted a study to evaluate the relationship between hearing thresholds and footplate thickness in otosclerosis patients who underwent stapes surgery. We used a qualitative method for measuring footplate thickness that was based on the simplicity or difficulty of opening the footplate. Our study population was divided into two groups; group 1 was made up of 66 patients whose footplates were easily opened with low pressure or with repeated motions by hand, and group 2 was made up of 14 patients whose footplate was either opened by drilling or not opened because it had been obliterated. We found that the patients in group 2, who had more severe disease, had significantly higher air- and bone-conduction thresholds than did the patients in group 1. According to our findings, otosclerotic patients with high air- and bone-conduction thresholds generally have more severe disease and thus require a more experienced surgeon. PMID- 22930083 TI - Bipolar microdebrider may reduce intraoperative blood loss and operating time during nasal polyp surgery. AB - Bleeding during endoscopic sinus surgery (ESS) can interrupt the flow of the procedure and increase the risk of complications. Advances in microdebrider design now allow for bleeding to be controlled by bipolar energy during the suctioning and shaving of polyps. We conducted a retrospective study to examine the effects of this technology on blood loss and operating times during ESS for chronic rhinosinusitis with nasal polyps (CRS+P). Our patient population was made up of 80 patients who had undergone ESS for CRS+P by the same surgeon from January 2007 through May 2008. All surgeries were performed with either the PK diego bipolar microdebrider (Gyrus ACMI, ENT Division; Bartlett, Tenn.) or a standard microdebrider. There were 40 patients in each group. The PK group was made up of 23 males and 17 females, aged 14 to 66 years (mean: 43.1), and the control group included 21 males and 19 females, aged 17 to 71 years (mean: 43.1); there were no statistically significant differences between the two groups in terms of sex and age. In addition to demographic data, the charts were reviewed for comorbidities and operative variables; the latter included blood loss, operating room (OR) time, and complications. The preoperative treatment and anesthesia protocols were similar for all patients, and all patients demonstrated a similar disease burden on imaging (mean Harvard CT stage: 3.12 for the PK group and 3.15 for the controls; p > 0.05). We found that during ESS, the PK group experienced significantly less intraoperative blood loss than did the controls (means: 86.0 and 123.0 ml, respectively; p = 0.015). In addition, the PK device was associated with significantly shorter OR times (means: 88.9 and 101.4 min, respectively; p = 0.026). There were no complications in either group. We conclude that using a microdebrider with bipolar capabilities during ESS may offer the advantages of less blood loss and shorter operating times in patients with nasal polyps. PMID- 22930084 TI - Utility of preoperative hematologic screening for pediatric adenotonsillectomy. AB - We conducted a 3-year retrospective study to examine the results of preoperative hematologic screening, the incidence of postoperative bleeding, and the possible relationship between the two factors in patients who had undergone tonsillectomy with or without adenoidectomy. Our study population was made up of 875 patients- 441 boys and 434 girls, aged 2 to 18 years (mean: 7.52 +/- 4.25)--who had been treated at our institution from January 2004 through December 2006. In addition to demographic data, we compiled information on each patient's medical and surgical history, personal and family history of abnormal bleeding, indication for tonsillectomy, and preoperative hematologic screening results. The latter included determinations of the prothrombin time, activated partial thromboplastin time, international normalized ratio (INR), and platelet count. A total of 748 patients (85.5%) had normal findings on preoperative hematologic screening, and 127 (14.5%) had at least one abnormality. Postoperatively, hemorrhagic complications occurred in 31 children (3.5%)--in 22 of the 748 patients with normal screening results (2.9%) and in 9 of the 127 with a screening abnormality (7.1%); the difference between the two groups was statistically significant (p = 0.041). The abnormalities in the latter group consisted of an elevated INR but no otherwise identifiable coagulopathy. Another 14 patients with an abnormal screening result (11.0%) were found to have at least one coagulopathy that was newly diagnosed during our preoperative evaluation; they were treated perioperatively, and none bled postoperatively. Of 21 patients who had a personal or family history of abnormal bleeding, 5 (23.8%) were found to have a coagulopathy, but none bled following surgery. In conclusion, we found that preoperative hematologic screening identified patients with undiagnosed coagulopathies, and with appropriate treatment our surgeons were able to prevent some bleeding events in these patients. Our finding that patients with a mildly elevated INR had a higher incidence of postoperative hemorrhage warrants further study. PMID- 22930085 TI - Hyoid suspension surgery with UPPP for the treatment of hypopharyngeal airway obstruction in obstructive sleep apnea. AB - We report our experience with hyoid suspension surgery in patients with obstructive sleep apnea (OSA) diagnosed on the basis of polysomnographic criteria. We conducted a prospective, observational study of 20 patients--18 males and 2 females, aged 15 to 52 years (mean: 42.1)--who were treated at our tertiary care center. All patients underwent hyoid suspension surgery and uvulopalatopharyngoplasty (UPPP) in a single session. Postoperative success was defined as either (1) a reduction in the apnea-hypopnea index (AHI) from 20 or higher to less than 20 or (2) a reduction in AHI of at least 50%. Postoperative follow-up polysomnography indicated that surgery was successful in 18 of 20 patients (90%). No important complications were observed. We conclude that hyoid suspension surgery is an effective procedure with low morbidity for the treatment of OSA in selected patients with hypopharyngeal obstruction. We believe it is a good option for those patients who will not or cannot tolerate therapy with continuous positive airway pressure. PMID- 22930086 TI - Management of head and neck paragangliomas: a series of 9 cases and review of the literature. AB - We conducted a retrospective study of the long-term functional results of surgery for head and neck paragangliomas. Our study population was made up of 9 patients- 4 men and 5 women, aged 22 to 59 years (mean: 46.6; median: 51)--who had undergone surgical excision of a head and neck paraganglioma from January 2002 through December 2006 in the ENT Department at Pugliese-Ciaccio Hospital in Catanzaro, Italy. Of the 9 paragangliomas, 4 were carotid body tumors, 2 were glomus tympanicum tumors, and 3 were glomus vagale tumors. None of the cases was bilateral or hereditary. Complete tumor resection was achieved in 8 patients; in the remaining patient, a small amount of intradural residual vagus nerve paraganglioma had to be left in situ. The internal carotid artery was preserved in all 4 resections of carotid body tumors. There was only 1 case of postoperative lower cranial nerve deficits, which occurred in a patient with a carotid body tumor. Follow-up ranged from 12 to 53 months (mean: 37.2; median: 36), and no recurrences were documented. Our small sample showed that surgical treatment of head and neck paragangliomas provided excellent tumor control with low postoperative morbidity, even in patients with large tumors. A wait-and-scan policy may be more appropriate for patients at an advanced age or who are otherwise at high surgical risk, as well as for those whose tumors have recurred following radiotherapy. PMID- 22930087 TI - Topical mitomycin C application before myringotomy and ventilation tube insertion: does it affect the final outcome? AB - Previous animal studies have shown that the topical application of mitomycin C is safe and effective in prolonging the patency of myringotomy openings in ears that have not received a ventilation tube. We conducted a randomized, controlled study in humans to determine if this treatment would make a difference in outcomes when a ventilation tube is inserted. To that end, we prospectively studied a group of patients with resistant otitis media with effusion who underwent bilateral myringotomy and ventilation tube insertion. Our original study population was made up of 55 children aged 2 to 12 years; 15 of these patients were lost to follow-up, leaving us with 40 patients and 80 ears. Each patient served as his or her own control, as mitomycin C was applied to the tympanic membrane on one side just prior to myringotomy creation and normal saline was applied to the other side. Our main outcomes measures were the duration of tube placement (i.e., the length of time before extrusion of the tube) and the incidence of other early and late postoperative complications. We found no statistically significant difference between the mitomycin C-treated ears and the control ears in any of these parameters. We conclude that the use of mitomycin C prior to myringotomy and ventilation tube insertion is not worthwhile. PMID- 22930088 TI - A comparison of unilevel and multilevel surgery in obstructive sleep apnea syndrome. AB - We conducted a retrospective study of 35 adults who had undergone tongue base suspension in addition to other surgery for the treatment of obstructive sleep apnea syndrome (OSAS). Our goal was to determine the most effective surgical approach by comparing these patients' preoperative apnea-hypopnea index (AHI) with their postoperative scores at 6 months. The 35 patients were divided into three groups based on a preoperative assessment of their level of airway obstruction; the assessment included a determination of AHI and endoscopic findings during the MUller maneuver. Patients in group 1 (n = 9) exhibited unilevel obstruction, and they were treated with lateral pharyngoplasty; patients in group 2 (n = 13) also had unilevel obstruction, and they underwent Z palatoplasty; patients in group 3 (n = 13) had multilevel obstruction, and they underwent combined surgery. Postoperatively, all three groups exhibited statistically significant improvements in AHI, but we determined that of the three approaches, multilevel surgery was significantly more effective (p < 0.001). PMID- 22930089 TI - Angiofollicular lymphoid hyperplasia (Castleman disease) presenting as an isolated neck mass. AB - Castleman disease is a relatively uncommon lymphoproliferative disorder. A presentation as an isolated lesion in the neck is extremely rare. We report the case of a 26-year-old man who presented with a 4-month history of an enlarging right neck mass that was identified as Castleman disease on excisional biopsy. The biopsy was curative. In localized forms of Castleman disease, excisional biopsy is both diagnostic and curative. However, in multicentric forms, additional treatment is required. PMID- 22930090 TI - Extramedullary plasmacytoma of the true vocal fold. AB - We report a rare case of extramedullary plasmacytoma (EMP) of the true vocal fold. Our patient, a 62-year-old woman, presented with dysphonia. On workup, fiberoptic laryngoscopy detected a lesion arising from the anterior half of her left true vocal fold. No evidence of other pathology was noted. The patient underwent radical radiotherapy, and the lesion resolved. Follow-up revealed no sign of recurrence. A type of myeloma, EMP is rare, especially in the larynx. To the best of our knowledge, our patient represents the sixth case of glottic EMP to be reported in the literature. PMID- 22930091 TI - Interhemispheric subdural abscess: a rare complication of atticoantral ear disease. AB - A 14-year-old girl who had been experiencing ear discharge for the previous 3 years was referred to a tertiary care center for management of a 3-day history of severe headache and vomiting. Otolaryngologic examination revealed the presence of an atticoantral type of ear disease on the left side. Computed tomography detected an interhemispheric subdural abscess that had originated on the left side. The patient was initially treated with antibiotics, and she later underwent a mastoidectomy to clear the ear disease. She recovered without complications. Subdural empyema is the rarest complication of otitis media, and it is very rarely seen in an interhemispheric setting. PMID- 22930092 TI - Paraganglioma of the palatine tonsil. AB - Paragangliomas of the head and neck are rare. We describe the case of an 11-year old girl who presented with an enlarged right palatine tonsil (grade 4). After a bilateral tonsillectomy, microscopic examination of the right tonsillar tissue revealed well-formed nests of polygonal epithelial cells separated by a collagenous stroma. The tumor cell nuclei were centrally placed and featured finely clumped chromatin and moderate anisonucleosis. Occasional mitotic figures were present. No necrosis was seen. An immunohistochemical staining panel showed no label for keratin, epithelial membrane antigen, HMB-45, or Melan-A; there was a strong label of tumor cells with chromogranin A, synaptophysin, and neuron specific enolase. The S-100 protein label was strongly positive in the surrounding stromal cells and weakly positive in the polygonal tumor cells. Given the classic histology and the immunohistochemical staining profile, the diagnosis of paraganglioma was made. At 7 months postoperatively, the patient exhibited no evidence of recurrence or metastasis. To the best of our knowledge, no case of a paraganglioma of the palatine tonsil has been previously described in the literature. PMID- 22930093 TI - Serum levels of advanced oxidation protein products in response to allergen exposure in allergic rhinitis. AB - Patients with asthma, allergic rhinitis, or atopic dermatitis experience increased oxidative stress. We conducted a prospective study to examine the levels of advanced oxidation protein products (AOPPs) as an indicator of oxidative stress in 97 patients with allergic rhinitis who were followed in our clinic during a 3.5-month period. Of these 97 patients, 51 were treated with subcutaneous immunotherapy (SCIT), and 46 did not receive any treatment until the study was concluded. In each patient, allergic rhinitis and allergic sensitization were documented by the history, the findings on clinical examination, and the results of blood and skin-prick tests. Blood samples from each patient were analyzed to determine AOPP levels. We found that the mean serum AOPP level was significantly higher in the SCIT group than in the non-SCIT group (258.55 vs. 163.83 umol/L; p = 0.0015). We conclude that as a known indicator of protein oxidation, the serum AOPP level is a marker of increased oxidative stress in response to allergen exposure in allergic rhinitis. PMID- 22930094 TI - Intradermal melanocytic nevus of the external auditory canal. PMID- 22930095 TI - An adjustable implant for nasal valve dysfunction: a 3-year experience. AB - A 3-year, single-center, prospective study was undertaken to measure the effect and long-term results of using the Monarch Nasal Implant to surgically correct nasal valve dysfunction. Thirty-nine patients were implanted, with follow-up lasting 36 months for 9 of the patients. Implant effectiveness and maintenance of effectiveness were determined through acoustic rhinomanometry and a subjective patient questionnaire. Rhinomanometry studies and patient questionnaires revealed a significant initial improvement in internal nasal valve areas and patient symptoms; the improvements were maintained or had even increased at 36 months. The cosmetic changes were acceptable to the patients. The Monarch Nasal Implant provides a consistent and lasting correction of nasal valve dysfunction with minimal drawbacks when properly used. PMID- 22930096 TI - Microsieve lab-chip device for rapid enumeration and fluorescence in situ hybridization of circulating tumor cells. AB - Herein we present a lab-chip device for highly efficient and rapid detection of circulating tumor cells (CTCs) from whole blood samples. The device utilizes a microfabricated silicon microsieve with a densely packed pore array (10(5) pores per device) to rapidly separate tumor cells from whole blood, utilizing the size and deformability differences between the CTCs and normal blood cells. The whole process, including tumor cell capture, antibody staining, removal of unwanted contaminants and immunofluorescence imaging, was performed directly on the microsieve within an integrated microfluidic unit, interconnected to a peristaltic pump for fluid regulation and a fluorescence microscope for cell counting. The latter was equipped with a dedicated digital image processing program which was developed to automatically categorize the captured cells based on the immunofluorescence images. A high recovery rate of >80% was achieved with defined numbers of MCF-7 and HepG2 cancer cells spiked into human whole blood and filtered at a rapid flow rate of 1 mL min(-1). The device was further validated with blood drawn from various cancer patients (8 samples). The whole process, from sample input to result, was completed in 1.5 h. In addition, we have also successfully demonstrated on-microsieve fluorescence in situ hybridization for single cell molecular analysis. This simple method has great potential to supplant existing complex CTC detection schemes for cancer metastasis analysis. PMID- 22930097 TI - Facile synthesis and up-conversion properties of monodisperse rare earth fluoride nanocrystals. AB - Monodisperse rare earth (RE) fluoride colloidal nanocrystals (NCs) including REF(3) (RE = La, Pr, Nd), NaREF(4) (RE = Sm-Ho, Y) and Na(5)RE(9)F(32) (RE = Er, Yb, Lu) have been successfully synthesized by a facile one-step method using oleic acid as surfactant and 1-octadecene as solvent. The phase, morphology, size, and photoluminescence properties of as-synthesized NCs were well investigated by X-ray diffraction (XRD), transmission electron microscopy (TEM) and high-resolution transmission electron microscopy (HRTEM), Fourier transform infrared spectroscopy (FT-IR), and photoluminescence (PL) spectra. The results reveal that the as-synthesized NCs consist of monodisperse colloidal NCs with narrow size distribution, which can easily disperse in non-polar cyclohexane solvent. The as-prepared NCs exhibit a rich variety of morphologies and different crystal phases (hexagonal or cubic), which may be related to the inherent natures of different rare earth ions. The possible formation mechanism of NCs with diverse architectures has been presented. In addition, representative Yb/Er, Yb/Tm, or Yb/Ho co-doped NaGdF(4) and Na(5)Lu(9)F(32) NCs exhibit intensive multicolor up-conversion (UC) luminescence under a single 980 nm NIR excitation, displaying potential applications in bioimaging and therapy. Moreover, transparent and UC fluorescent NCs-polydimethylsiloxane (PDMS) composites with regular dimensions were also prepared by an in situ polymerization route. PMID- 22930098 TI - [Aneurysm inflammation: a hot spot?]. PMID- 22930099 TI - Association of angiotensin-converting enzyme insertion/deletion gene polymorphism with susceptibility of minimal change nephrotic syndrome in Asians: a meta analysis. PMID- 22930100 TI - Re: ALTITUDE study. PMID- 22930101 TI - Dual RAAS suppression: recent developments and implications in light of the ALTITUDE study. PMID- 22930102 TI - Proprioception, laxity, muscle strength and activity limitations in early symptomatic knee osteoarthritis: results from the CHECK cohort. AB - OBJECTIVE: To establish whether proprioception and varus-valgus laxity moderate the association between muscle strength and activity limitations in patients with early symptomatic knee osteoarthritis. DESIGN: A cross-sectional study. SUBJECTS: A sample of 151 participants with early symptomatic knee osteoarthritis from the Cohort Hip and Cohort Knee study. METHODS: Regression analyses were performed to establish the associations between muscle strength, proprioception (knee joint motion detection threshold in the anterior--posterior direction), varus-valgus laxity and activity limitations (self-reported and performance-based). Interaction terms were used to establish whether proprioception and laxity moderated the association between muscle strength and activity limitations. RESULTS: Proprioception moderated the association between muscle strength and activity limitations: the negative association between muscle strength and activity limitations was stronger in participants with poor proprioception than in participants with accurate proprioception (performance-based activity limitations p = 0.02; self-reported activity limitations p = 0.08). The interaction between muscle strength and varus-valgus laxity was not significantly associated with activity limitations. CONCLUSION: The results of the present study support the theory that in the absence of adequate proprioceptive input, lower muscle strength affects a patient's level of activities to a greater degree than in the presence of adequate proprioceptive input. PMID- 22930104 TI - [Rheumatology - current and future treatment of inflammatory and non-inflammatory musculoskeletal diseases in Germany. An assessment by the board of the German Society for Rheumatology]. PMID- 22930105 TI - [Neurology and rheumatology]. PMID- 22930106 TI - [Neurological manifestations of vasculitis and primary central nervous system vasculitis]. AB - Neurologic complications of vasculitis occur frequently in the form of either peripheral neuropathy or manifestations within the central nervous system (CNS). Primary vasculitis of the CNS is characterized by central nervous system manifestations only with no evidence of systemic disease manifestations. Large vessel vasculitis is particularly associated with central nervous system complications, such as ischemic cerebral infarcts whereas medium size, e.g. polyarteritis nodosa and small vessel vasculitis, e.g. antineutrophil cytoplasmic antibodies (ANCA)-associated vasculitis manifest with peripheral neuropathies and central nervous system complications. The same also holds true for Behcet's disease which affects both large, medium and small sized arteries and veins. Due to the severity of nervous system manifestations a highly potent immunosuppressive therapy (e.g. cyclophosphamide and glucocorticoids) is usually required for remission induction. Virus-associated vasculitis (e.g. hepatitis C associated cryoglobulinemic vasculitis) should receive antiviral therapy as first line treatment. Chronic damage is frequent in spite of swift initiation of immunosuppressive treatment. PMID- 22930107 TI - [Neurological manifestations in connective tissue disease]. AB - In connective tissue diseases, especially systemic lupus erythematosus and Sjogren's syndrome, diverse neurological symptoms and syndromes involving both the central and peripheral nervous system can occur at any stage of the disease. The pathogenesis is diverse. Prevalence figures in the literature vary considerably and the causal relationships are often uncertain. Very often connective tissue diseases must be considered in the differential diagnosis of conditions manifesting with unclear neurological symptoms. Both rheumatologists and neurologists should be familiar with the main neurological signs, symptoms and complications of connective tissue diseases and should recognize the importance of diagnostic testing. PMID- 22930108 TI - [Nervous system side effects of disease modifying treatments of rheumatoid arthritis]. AB - Antirheumatic medication is of crucial importance within the treatment concept of chronic inflammatory disorders. Side effects may affect various organ systems, among which are neurologic manifestations. If patients have comorbidities involving the nervous system this should be taken into consideration before choosing an individual immunosuppressant or immunomodulatory compound, as any worsening of the underlying neurologic disease should be avoided. In this article, relevant neurologic disorders will be described with respect to the clinical manifestations, differential diagnosis and treatment. In the second part, pharmaceuticals and biologicals which are frequently used as part of an antirheumatic regimen are discussed with respect to the potential to induce side effects specifically related to the nervous system. PMID- 22930109 TI - [Biologicals for children and adolescents in the treatment of rheumatic diseases]. AB - Following pharmacolegal measures several biologic agents have been tested in children and adolescents with rheumatic diseases, mainly juvenile idiopathic arthritis (JIA), in controlled trials and have been introduced into treatment algorithms. This was achieved by international research cooperation and after introduction of well-defined criteria for disease entities, disease activity, improvement and deterioration. Etanercept, adalimumab, abatacept, tocilizumab and canakinumab have obtained limited licenses. Etanercept is the longest available biologic agent. Etanercept or adalimumab are the treatment of choice when methotrexate is not sufficient or toxic in children with polyarthritis. Tocilizumab is given to patients with systemic JIA when glucocorticoids fail or become toxic. These and other biologic agents including anakinra and rituximab are effectively applied also off label; however, there is a lack of long-term studies. These drugs should be prescribed only by pediatric rheumatologists. PMID- 22930114 TI - Raman spectroscopic detection of sub-picomolar DNA by coupling silver catalyzed silver deposition with circular strand-replacement polymerization on magnetic nanoparticles. AB - A novel strategy of dual signal amplification was developed using circular strand replacement DNA polymerization with a molecular beacon as a switch and silver enhancement on magnetic nanoparticles for the specific Raman spectroscopic detection of DNA down to the sub-picomolar level. PMID- 22930111 TI - [Systematic literature research for S1 guidelines on sequential medical treatment of rheumatoid arthritis]. AB - BACKGROUND: On behalf of the German association of Rheumatology national experts developed guidelines for the medical treatment of rheumatoid arthritis (RA) based on the EULAR recommendations for the management of RA published in 2010. Current evidence was provided with an update of the systematic literature review (SLR). The methods and results of the SLR are presented in this article. MATERIALS AND METHODS: An update of the EULAR SLR for the medical treatment of RA was performed from January 2009 to August 2011. The SLR assessed all controlled studies dealing with the outcome in clinical aspects, function and structure of disease modifying treatment of RA. RESULTS: Out of 6,869 screened publications, 138 articles and 56 abstracts were considered in the development of the German guidelines on the treatment of RA. A modified set of recommendations was approved in a consensus of national experts. CONCLUSION: A systematic literature research provided current evidence for the German recommendations on the sequential medical treatment of RA. PMID- 22930110 TI - [German 2012 guidelines for the sequential medical treatment of rheumatoid arthritis. Adapted EULAR recommendations and updated treatment algorithm]. AB - Following the EULAR recommendations published in 2010 German guidelines for the medical treatment of rheumatoid arthritis were developed based on an update of the systematic literature search and expert consensus. Methotrexate is the standard treatment option at the time of diagnosis, preferably in combination with low dose glucocorticoids. Combined disease-modifying antirheumatic drugs (DMARD) therapy should be considered in patients not responding within 12 weeks. Treatment with biologicals should be initiated in patients with persistent high activity no later than 6 months after conventional treatment and in exceptional situations (e.g. early destruction or unfavorable prognosis) even earlier. If treatment with biologicals remains ineffective, changing to another biological is recommended after 3-6 months. In cases of long-standing remission a controlled reduction of medical treatment can be considered. PMID- 22930115 TI - Prasugrel versus high dose clopidogrel to overcome early high on clopidogrel platelet reactivity in patients with ST elevation myocardial infarction. AB - OBJECTIVE: There is a paucity of data regarding the early effectiveness of the proposed 600 mg clopidogrel loading dose (LD) on platelet reactivity (PR) in ST elevation myocardial infarction (STEMI) patients. If high on-treatment platelet reactivity (HTPR) is present, prasugrel reloading and subsequent maintenance dose (MD), might offer faster and stronger platelet inhibition than high clopidogrel MD. METHODS: In 93 STEMI patients treated by primary percutaneous coronary intervention we assessed PR using the VerifyNow P2Y12 platelet function test, 2 h following 600 mg LD of clopidogrel. All the 60 (64.5 %) patients exhibiting HTPR (defined as PR >= 235 P2Y12 reaction units), were randomized to 1 of 2 therapeutic strategies: reloading with prasugrel 60 mg/10 mg MD or high (150 mg) clopidogrel MD. RESULTS: The primary endpoint of PR at 24 h post randomization was lower in the prasugrel compared to the clopidogrel group (51.3, 25.7-77.0 versus 242.4, 215.8-268.9 P2Y12 reaction units, least square estimates, 95 % confidence intervals, p < 0.001). PR at 2 h and 5 days post randomization was lower in the prasugrel compared to the clopidogrel group (117.2, 70.9-163.4 and 101.6, 70.1-133.2 least square mean difference, 95 % confidence intervals, p < 0.001 for both). At all the time points of PR assessment, HTPR rates were lower in prasugrel than in clopidogrel group. CONCLUSIONS: HTPR is commonly observed early post 600 mg clopidogrel LD in STEMI patients. In this case, prasugrel 60 mg LD/10 mg MD provides faster and stronger platelet inhibition than a high clopidogrel MD regimen. PMID- 22930116 TI - Mourning Dr Welby. PMID- 22930118 TI - A sustainable family medicine academic workforce: a study of Pennsylvania residency faculty. AB - BACKGROUND AND OBJECTIVES: This study determined the demographic and practice characteristics of current Pennsylvania family medicine residency faculty. METHODS: Surveys were sent electronically to program directors to distribute to their faculty members. Participants were surveyed for age, race, gender, current and completed residency training program, fellowship completion, practice track, and current practice characteristics. RESULTS: Survey response rate represented 35.3% of residency faculty in Pennsylvania. The majority represented full-time faculty (83.7%), were male (53.8%), were Caucasian (84.8%), did not enter their faculty position following residency (65.9%), had completed their residency training in Pennsylvania (57.9%), and did not complete a fellowship. While most faculty have continued inpatient and outpatient care, less than half participate in other surveyed elements of comprehensive family medicine care. CONCLUSIONS: The environment within academic family medicine and changing cultures have created a shift that the future of academic practice may need to depend on new graduates. Current demographics suggest a poorly diverse faculty with private practice experience and limited full-spectrum mentors that may have contributed to family medicine's difficulties within the academic marketplace. Creating a strong primary care workforce demands ensuring a sustainable faculty. PMID- 22930117 TI - Preparation for practice in family medicine: before and after duty hours. AB - BACKGROUND AND OBJECTIVES: In July of 2003, the Accreditation Council for Graduate Medical Education (ACGME) adopted requirements limiting the duty hours of resident physicians. The impact of these restrictions on education and patient care activities is not clear. The purpose of this study is to examine the perception of graduates of family medicine residency programs immediately prior to and following implementation of duty hours regarding preparedness to practice and board certification status, as well as current patient care activities. METHODS: Surveys of graduates of family medicine residency programs in South Carolina were conducted. Preparation for practice and professional activities of program graduates prior to (1999--2003) and following (2005--2009) implementation of duty hours were compared. RESULTS: Response rates were 54.4% and 53.1%, respectively. No significant differences by survey years in the average age, gender, or race was noted. Recent graduates felt as well prepared for practice in most curricular areas except surgery (OR=0.50 [0.27, 0.91]) and performed similar procedures with the following exceptions: central line placement (OR=0.32 [0.11, 0.95]), flexible sigmoidoscopy (OR=0.12 [0.02, 0.80]), ICU care (OR=0.39 [0.22, 0.70]), and ventilator management (OR=0.54 [0.29, 0.99]). Higher proportion of recent graduates do not take after hours call (22.3% versus 8.6%). Similarly, fewer recent graduates care for patients in nursing homes (22.0% versus 44.9%) and hospitals (46.2% versus 68.0%). CONCLUSIONS: Implementation of resident duty hours appears to have little overall association with self-reported preparedness for practice. An association was noted in the patient care services and procedures performed. PMID- 22930119 TI - Four years of training in family medicine: implications for residency redesign. AB - BACKGROUND AND OBJECTIVES: In light of the ongoing consideration for extending the length of residency education in family medicine in the United States, this paper reports the findings from a retrospective, qualitative study of six family physicians that elected to extend their residency training from 3 to 4 years. METHODS: Each participant completed a written questionnaire and a structured personal interview focusing on various aspects of career development resulting from the additional year of training. The authors independently evaluated these interviews to identify major themes. RESULTS: All the participants were found to have been involved in teaching medicine, valued a more flexible and expanded curriculum, and appreciated their individualized curricula-based on their respective career interests. Given the opportunity, each would opt again for a fourth year of training. There were mixed opinions as to whether the fourth year should be required of all family medicine residents. Other perceived benefits reported were: a better opportunity to find a personally satisfactory practice, additional time for gaining clarity about career plans, and a higher beginning salary as a result of the additional skills and experiences gained. CONCLUSIONS: This study of mid-career physicians supports that a fourth-year (PGY4) curriculum in family medicine may enhance subsequent career satisfaction. Further studies of residents in other PGY4 training programs are necessary to assess outcomes comparing our findings as well as guide the discipline's leaders in residency redesign. PMID- 22930120 TI - Association between alcohol screening scores and diabetic self-care behaviors. AB - BACKGROUND AND OBJECTIVES: Alcohol misuse is associated with poor adherence to recommended self-care behaviors, which are critical for diabetes management. This study investigated whether scores on a validated brief alcohol misuse screen are associated with diabetes self-care. METHODS: Male outpatients (n=3,930) from seven Veterans Affairs sites returned the Alcohol Use Disorders Identification Test-Consumption (AUDIT-C) alcohol screen on mailed surveys and indicated they had diabetes. Patients were divided into five alcohol screening groups: no past year alcohol use (AUDIT-C 0), low-level alcohol use (AUDIT-C 1-3); and mild (AUDIT-C 4-5), moderate (AUDIT-C 6-7), and severe (AUDIT-C 8-12) misuse. Outcomes included self-report of monitoring blood glucose, maintaining normal blood glucose levels, inspecting feet, following a meal plan, not smoking, and laboratory data indicating that glycosylated hemoglobin A1c (HbA1c) had been tested in the past year. For each group, the proportion of patients adherent to each behavior were estimated from logistic regression models adjusted for demographics, comorbidity, and depressive symptoms. RESULTS: Patients who did not drink were most likely to report adherence to self-care behaviors, except for past-year HbA1c testing. Compared to patients who did not drink, patients with AUDIT-C scores ?6 were significantly less likely to report maintaining normal blood glucose levels (eg, AUDIT-C 6-7 44% versus AUDIT-C 0 59%) or following a meal plan (48% versus 58%), and were more likely to smoke (71% abstained versus 85%) in adjusted analyses. CONCLUSIONS: Results of this study indicate that higher alcohol screening scores are associated with poorer diabetes self-care. PMID- 22930121 TI - Variation in refill protocols and procedures in a family medicine residency network. AB - BACKGROUND AND OBJECTIVES: Efficient and accurate medication refill authorization is an integral service provided by family physicians and an essential skill to teach family medicine residents. The goal of this study was to examine the variation in medication refill protocols, procedures, and resources in family medicine residency practices across a five-state region as a background for development of best practices. METHODS: Structured telephone interviews with a key informant at each of 11 clinical practices in a five-state (Washington, Wyoming, Alaska, Montana, and Idaho) family medicine residency network focused on refill protocols and procedures, which personnel have authorization authority, and other factors related to refill protocols and medication prescribing curriculum. Key themes were abstracted from interview notes. RESULTS: There was marked variation in refill protocols and procedures across the clinical sites. While all practices were able to identify their refill procedure, no two practices' procedures were the same, and only 36.4% had a formal written protocol that could be identified by the key informant. All of the practices with formal protocols routinely reviewed medical records before authorizing refills (100%, four/four) compared to less than half of those without formal protocols (42.9%, three/seven). Practices with formal protocols (75.0%) also transferred refill requests between staff prior to authorization more than those without formal protocols (57.1%). CONCLUSIONS: Refill protocols and procedures were highly variable across these family medicine residency program practices. Surprisingly, formal written refill protocols were uncommon. Further research to identify best practices in medication refill procedures associated with safety outcomes is warranted. PMID- 22930122 TI - Impact of quality improvement training during residency on current practice. AB - BACKGROUND AND OBJECTIVES: Quality improvement (QI) has become an integral aspect of family medicine residency training. This study examines whether QI training during residency is associated with the integration of QI activities into practice following graduation. METHODS: A confidential survey was delivered to South Carolina Area Health Education Consortium (SC AHEC)-associated family medicine residency program graduates from 2005--2009. The survey evaluated QI training during residency, as well as the following QI activities in current practice: periodic patient care data review, patient care registries, specific QI projects, disease-specific QI activities, National Committee on Quality Assurance (NCQA) Recognition, having staff QI leaders, and participation in a Practice based Research Network (PBRN). Proportions were compared using chi-square tests. Stepwise logistic regressions were performed to identify variables predictive of specific QI activities in practice. RESULTS: The response rate was 51.3% (n=136). Most participants received QI training (75.8%) and currently participated in at least one QI activity (87.1%). PBRN involvement and having staff QI leaders was associated with involvement in all other QI activities. QI training was associated with periodic patient care data review (odds ratio (OR)=3.32; 95% confidence interval (CI)=1.26--8.78) and performing specific QI projects (OR=3.17; 95% CI=1.09--9.23). CONCLUSIONS: QI training during residency is associated with involvement in specific QI activities following graduation. Further, participation in a PBRN or having staff QI leaders is also associated with involvement in QI activities. Further evaluation of residency QI curricula is warranted to identify effective strategies that positively impact future practice. PMID- 22930123 TI - Advanced directives and code status documentation in an academic practice. AB - BACKGROUND AND OBJECTIVES: Although advance directives (AD) allow patients a voice during their end-of-life care, less than 20% of US individuals have one. We investigated how physicians, both attendings and residents, of the Sioux Falls Family Medicine Residency Program (SFFMRP) were addressing AD and code status with our geriatric population, which has an increased need for advance directive implementation secondary to declining health. METHODS: We used a retrospective design, in which a random sampling of charts was performed. The setting was the SFFMRP and associated facilities Participants included a chart review of 121 patients over age 65 seen by a SFFMRP physician within the past year. Percentages were calculated looking at overall outcomes, living situation, age, and resident versus attending involvement. Statistical significance was evaluated using Chi square analysis. RESULTS: Overall, 44% of all individuals examined had an advanced directive (80.6% of nursing home (NH) patients, 76% of assisted living (AL) patients, and 21% of independent living patients). Evaluating code status, 55% of all individuals had a known code status (100% of NH patients, 92% of AL patients, and 25% of independent living patients). No significant difference was found when comparing attending versus resident physicians' patient groups. CONCLUSIONS: SFFMRP geriatric patients are more likely than the national population to have an AD, but more than half of patients still have no known documentation in place. The living situation of a patient significantly affects whether an AD or known code status is present, indicating that focus should be placed on independent living patients completing these documents. PMID- 22930124 TI - Is exposure to a student-run clinic associated with future primary care practice? AB - BACKGROUND AND OBJECTIVES: The number of student-run clinics has increased in recent years, but student outcomes from participation are largely unknown. This study explored whether or not there is an association between presence of a student-run clinic at a medical school and future practice of medical school graduates in a primary care specialty. METHODS: A 2005 survey of all student-run clinics associated with medical schools was supplemented by direct survey of schools missing from this dataset. We used multiple linear regression to test associations between presence of a student-run clinic and current primary care practice, using specialty designation in the American Medical Association Physician Masterfile and controlling for medical school confounders (urban versus rural, private versus public, and absence versus presence of family medicine department.) RESULTS: In 2005, 72 medical schools had at least one student-run clinic, and 43 schools did not (93.5% response rate). After controlling for confounders, the correlation coefficient between presence of student run clinic in 2005 and current primary care practice is -0.0122. CONCLUSIONS: We found no association between having a student-run clinic in 2005 at a medical school and proportion of its graduates who currently practice primary care. Since there are considerable limitations of an institution-based study, it may be useful to study specialty choice for individual students who participate in student-run clinics, given that prior research has shown longitudinal educational experience with underserved population is associated with increased likelihood of choosing primary care careers. PMID- 22930126 TI - A guru at grand rounds. PMID- 22930125 TI - Lessons. PMID- 22930127 TI - Overcoming barriers to interprofessional education: the example of the joint position statement of the Physician Assistant Education Association and the Society of Teachers of Family Medicine. PMID- 22930128 TI - Spontaneous diaphragm rupture associated with vaginal delivery. AB - Spontaneous rupture of the diaphragm associated with vaginal delivery is a rare occurrence, but has high rates of morbidity and mortality. Herein, we present a first uncomplicated case of spontaneous rupture of the diaphragm associated with vaginal delivery, which was treated successfully with surgery via a thoracotomy. PMID- 22930129 TI - 1,3-Dipolar cycloaddition of unstabilised azomethine ylides by Lewis base catalysis. AB - Lewis base catalysed 1,3-dipolar cycloaddition between alpha,beta-unsaturated acyl fluorides and N-[(trimethylsilyl)methyl]amino ethers has been achieved using 1 mol% DMAP. Competition experiments and (19)F-NMR studies indicate that the cycloaddition occurs preferentially between the alpha,beta-unsaturated acyl fluoride and the unstabilised azomethine ylide. In addition, an enantioselective variant, using chiral isothiourea catalysts, has been achieved with 14% ee. PMID- 22930130 TI - The prevalence of metal-based drugs as therapeutic or diagnostic agents: beyond platinum. AB - Metal complexes and metal salts have a wide range of medicinal applications and are extensively administered to patients or purchased over the counter as a matter of routine. The abundance and variety of non-platinum metal complexes, which are approved for use as therapeutic or diagnostic agents, are highlighted. Current insights into the mechanism of action or indeed lack thereof of a selection of metallodrugs are discussed. Ultimately this perspective seeks to inspire chemists to tackle new challenges and raise awareness of opportunities in the area of inorganic therapeutic and diagnostic medicine. PMID- 22930131 TI - Synthesis, characterization, DNA binding and cleavage, BSA interaction and anticancer activity of dinuclear zinc complexes. AB - Three new zinc(II) complexes: [Zn(2)(L(1))(2)Cl(2)](ClO(4))(2).C(2)H(5)OH (1) and [ZnL(2)X(4)].2CH(3)CN (X = Br for 2, Cl for 3), utilizing two new and interrelated di-nucleating polypyridyl ligands (L(1), L(2)), have been synthesized and characterized by using various physico-chemical techniques. The interactions of three complexes with CT-DNA have been explored by using absorption, emission and CD spectral methods, which reveal that three complexes bind to CT-DNA by partial intercalation binding modes. Notably, in the presence of H(2)O(2) as a revulsant or an activator, the cleavage abilities of all complexes are obviously enhanced. The hydrolytic mechanism was demonstrated by adding standard radical scavengers and anaerobic reaction. Further, the protein binding ability has been monitored by quenching of tryptophan emission in the presence of complexes using BSA as a model protein. The quenching mechanisms of BSA by the complexes are static procedures. In addition, the in vitro cytotoxicity of the complexes on three human tumor cells lines (HeLa, MCF-7 and RL952) and the apoptosis-inducing activity of were assessed by MTT, Clonogenic assay, Hoechst 33342 staining, Cell cycle and Annexin V binding experiments. PMID- 22930132 TI - Genetic mapping of a major dominant gene for resistance to Ralstonia solanacearum in eggplant. AB - Resistance of eggplant against Ralstonia solanacearum phylotype I strains was assessed in a F(6) population of recombinant inbred lines (RILs) derived from a intra-specific cross between S. melongena MM738 (susceptible) and AG91-25 (resistant). Resistance traits were determined as disease score, percentage of wilted plants, and stem-based bacterial colonization index, as assessed in greenhouse experiments conducted in Reunion Island, France. The AG91-25 resistance was highly efficient toward strains CMR134, PSS366 and GMI1000, but only partial toward the highly virulent strain PSS4. The partial resistance found against PSS4 was overcome under high inoculation pressure, with heritability estimates from 0.28 to 0.53, depending on the traits and season. A genetic map was built with 119 AFLP, SSR and SRAP markers positioned on 18 linkage groups (LG), for a total length of 884 cM, and used for quantitative trait loci (QTL) analysis. A major dominant gene, named ERs1, controlled the resistance to strains CMR134, PSS366, and GMI1000. Against strain PSS4, this gene was not detected, but a significant QTL involved in delay of disease progress was detected on another LG. The possible use of the major resistance gene ERs1 in marker-assisted selection and the prospects offered for academic studies of a possible gene for gene system controlling resistance to bacterial wilt in solanaceous plants are discussed. PMID- 22930133 TI - Genetic ablation of PI3Kgamma results in defective IL-17RA signalling in T lymphocytes and increased IL-17 levels. AB - The signalling molecule PI3Kgamma has been reported to play a key role in the immune system and the inflammatory response. In particular, it facilitates the migration of haemato-poietic cells to the site of inflammation. In this study, we reveal a novel role for PI3Kgamma in the regulation of the pro-inflammatory cytokine IL-17. Loss of PI3Kgamma or expression of a catalytically inactive mutant of PI3Kgamma in mice led to increased IL-17 production both in vitro and in vivo in response to various stimuli. The kinetic profile was unaltered from WT cells, with no effect on proliferation or other cytokines. Elevated levels of IL 17 were not due to an aberrant expansion of IL-17-producing cells. Furthermore, we also identified an increase in IL-17RA expression on PI3Kgamma(-/-) CD4(+) T cells, yet these cells exhibited impaired PI3K-dependent signalling in response to IL-17A, and subsequent NF-kappaB phosphorylation. In vivo, instillation of recombinant IL-17 into the airways of mice lacking PI3Kgamma signalling also resulted in reduced phosphorylation of Akt. Cell influx in response to IL-17 was also reduced in PI3Kgamma(-/-) lungs. These data demonstrate PI3Kgamma-dependent signalling downstream of IL-17RA, which plays a pivotal role in regulating IL-17 production in T cells. PMID- 22930134 TI - On-chip latex agglutination immunoassay readout by electrochemical impedance spectroscopy. AB - We describe a new class of impedance-based lab-on-chip immunosensors in which the immunoagglutination of latex is monitored by electrochemical impedance spectroscopy (EIS). Antibody-coated latex microspheres agglutinated in the presence of target antigens are precipitated from solution between interdigitated microsized electrodes on a chip. Impedance spectra are reproducibly measured in the 0.1-1 MHz frequency range within several minutes and are shown to be dependent on the aggregate morphology and the sedimentation rates of the agglutinated particles. An equivalent circuit model of the system suggests that the impedance is governed primarily by the electric double layer interactions close to the electrode surface. The effects of sedimentation time, particle type, particle size, and concentration are characterized. The readout method holds promise for developing sensitive miniaturized sensors for rapid immunotesting. PMID- 22930135 TI - Theory of pulsed Reaction Yield Detected Magnetic Resonance. AB - We propose pulse sequences for Reaction Yield Detected Magnetic Resonance (RYDMR), which are based on refocusing the zero-quantum coherences in radical pairs by non-selective microwave pulses and using the population of a radical pair singlet spin state as an observable. The new experiments are analogues of existing EPR experiments such as the primary echo, Carr-Purcell, ESEEM, stimulated echo and Mims ENDOR. All pulse sequences are supported by analytical results and numerical calculations. The pulse sequences can be used for more efficient and highly detailed characterization of intermediates of chemical reactions and charge carriers in organic semiconductors. PMID- 22930136 TI - [Analysis of sustained attention in patients with Parkinson's disease being treated with dopamine precursors]. AB - INTRODUCTION: Parkinson's disease (PD) is a degenerative disorder with a predominance of motor symptoms at the beginning. However, cognitive symptoms, such as executive functions, visuo-spatial abilities, language or attention, could be also impaired in an early phase of this disease. AIM: We analyzed the attentional deficits in patients with a moderate PD. In addition, we studied the performance of participants for a on and off periods of levodopa in plasma. SUBJECTS AND METHODS: Parkinson group: 20 patients with moderates PD (according to Hoehn & Yahr scale) were used. CONTROL GROUP: 14 healthy participants. Both groups performed a sustained attention test based on oddball task. RESULTS. The percentage of correct responses of the control group was significantly higher than of the PD group. There were no significant differences between the on and off periods in the PD group. CONCLUSIONS: Moderate PD patients showed an impairment of the ability to maintain attention. In addition, they displayed a deficit to adjust flexibly their behaviors to the environmental requirements. This attentional disability could be explained by the progressive dopamine depletion associated with the development of areas affected by PD. PMID- 22930137 TI - [Feasibility of a telemedicine support system for diagnosing dementia in primary care]. AB - INTRODUCTION: The Computerised Support System for the Diagnosis of Dementia in Primary Care (SISDDAP, in Spanish) is an asynchronous telemedicine programme that establishes protocols for the screening and diagnosis of dementia, thereby enabling primary care (PC) and specialised care (SC) professionals to reach shared diagnoses of dementia. AIMS: To determine the feasibility and degree of implementation of an asynchronous telemedicine programme and to evaluate the rate of agreement between the cognitive and functional measures taken by professionals from two different levels of healthcare. PATIENTS AND METHODS: The study examines the use of the SISDDAP programme by professionals from four basic areas of healthcare (BAH) in which the programme was introduced on a voluntary basis. The absolute and relative frequency of use of the SISDDAP programme and the number of variables registered were calculated, together with the intra-class correlation coefficient among the scores obtained by PC and SC professionals on the different psychometric instruments, including the SISDDAP diagnostic module (Mini-Mental State Examination, Blessed Dementia Rating Scale and Patient Health Questionnaire 9). RESULTS: The four BAH that incorporated the SISDDAP referred 215 (45.3%) applications via the telemedicine programme, and 82.2% of these applications had a maximum of two data items missing. The intra-class correlation coefficient was above 0.70 among all the instruments evaluated. CONCLUSIONS: The SISDDAP is an asynchronous telemedicine programme that is well accepted among PC professionals. After suitable training, the level of agreement among the psychometric instruments is acceptable. PMID- 22930138 TI - [Hemicrania continua: characteristics and therapeutic experience in a series of 36 patients]. AB - INTRODUCTION: Hemicrania continua is characterised by a continuous unilateral pain, which frequently gets worse in association with autonomic symptoms. It is probably little known and underdiagnosed. Its diagnosis requires a response to indomethacin, which is not always well tolerated. AIMS: We report a series of 36 cases of hemicrania continua that were treated in the headache service of a tertiary hospital. We analyse their demographic and clinical features and the therapeutic alternatives to indomethacin. PATIENTS AND METHODS: Between January 2008 and April 2012, 36 patients (28 females, eight males) were diagnosed with hemicrania continua from among 1800 (2%) who were treated in that service. RESULTS: The age of onset was 46.3 +/- 18.4 years. In four patients (11.1%) there were pain remissions that lasted over three months. The baseline pain was chiefly oppressive or burning with an intensity of 5.2 +/- 1.4 on the verbal analogue scale. Exacerbations lasted 32.3 +/- 26.1 minutes, were of a predominantly stabbing nature with an intensity of 8.3 +/- 1.4, and in 69.4% of cases were accompanied by autonomic symptoms. Altogether 16.7% of the patients did not tolerate indomethacin beyond an indotest and 50% did so with side effects. In 13 cases at least one anaesthetic blockade was performed in the supraorbital or the greater occipital nerve or a trochlear injection of corticoids was carried out with a full response in 53.8% and a partial response in 38.5%. CONCLUSIONS: Hemicrania continua is not an infrequent diagnosis in a headache clinic and, because it is a treatable condition, further knowledge on the subject is needed. Anaesthetic blockades of the supraorbital or greater occipital nerves or a trochlear injection of corticoids are the therapeutic options that must be taken into consideration when indomethacin is not well tolerated. PMID- 22930139 TI - [Intracranial tuberculoma mimicking malignant tumour]. AB - INTRODUCTION: Tuberculous involvement of the central nervous system is uncommon in western countries. Brain tuberculoma is a granulomatous inflammatory process than in rare occasions can simulate a malignant neoplasm. CASE REPORT: A 81-year old man regarding symptoms of several weeks of evolution of numbness affecting upper limb and right face. The neuroimaging studies showed a left parietal lesion suggestive of a primary malignant tumor. A stereotactic biopsy was performed and the pathological examination showed a brain tuberculoma. The patient was treated with anti-tuberculous drugs. CONCLUSIONS: Parenchymal central nervous system tuberculosis are rare in our medio and may present as a space-occupying lesion with complex neuroimaging morphology suggesting a malignant neoplasm. Definitive diagnosis was performed with neuropathological studies or with the demonstration of acid-fast bacilli in the tuberculoma. PMID- 22930140 TI - [Severe asymptomatic carotid stenosis: a neurological perspective]. AB - Asymptomatic carotid stenosis is a relatively frequent pathology, although when considering the possibility of managing it surgically, there is still an important amount of disagreement concerning the criteria to be taken into account. This study conducts a broad examination of the condition, from its concept and epidemiology to the studies that triggered the boom in its surgical treatment during the nineties. The research also reviews the tools available for a better selection of cases that could potentially benefit most from surgery, the presence of silent brain lesions, the severity of the stenosis, its progression, the characteristics of the plaque, colaterality and vasoreactivity studies, the detection of micro-emboli, the presence of risk factors independently associated to the symptomatic conversion of the stenosis, and other elements that have recently been reported either clinically or experimentally. Finally, the article outlines the current state of the surgical technique and the advances being made in its pharmacological treatment. This review is not intended to be a set of clinical practice guidelines, but to offer a global integrating overview of the management of high-grade asymptomatic carotid stenosis. PMID- 22930141 TI - [New therapeutic approaches in the treatment of neglect: transcranial magnetic stimulation]. AB - AIM: To highlight the effectiveness of transcranial magnetic stimulation (TMS) as therapeutic tool in rehabilitation of neglect. DEVELOPMENT: The therapeutic benefits of TMS in different neurological disorders, such as epilepsy, Parkinson's disease, stroke or dementias, are increasingly evident. For many years clinical research has been conducted to develop new and effective rehabilitation strategies for neglect, being repetitive transcranial stimulation an important tool in this regard. The positive outcomes of treatment of neglect based on noninvasive brain stimulation have been demonstrated by several researchers. So, TMS should be, at least, considered as a therapeutic intervention adjuvant to conventional approaches. CONCLUSIONS: Although the evidence for considering TMS as a new therapeutic tool is still scarce, as therapeutic applications of TMS are a subject of recent study, the findings so far are encouraging. Further research is essential to know the real TMS potential in the rehabilitation of neglect in particular, and of neurological diseases in general. PMID- 22930142 TI - [From the vegetative state to unresponsive wakefulness: a historical review]. AB - INTRODUCTION: Over the last few decades, the terminology, diagnostic techniques and treatment of patients with altered levels of consciousness have varied considerably. At the same time, the percentage of patients in this clinical situation has undergone a marked increase. AIMS: The purpose of this study is to present a historical review of the different terms that have been used in the medical literature to describe patients with altered states of consciousness. The article also includes the different diagnostic criteria utilised by research groups that have focused their attention on this population. DEVELOPMENT: The concept of 'vegetative state', a term coined back in the sixties, has since been transformed and replaced by other terms with a less negative connotation, such as 'unresponsive wakefulness syndrome'. In parallel, new clinical categories (minimally conscious state or minimally conscious plus) have appeared since it has been acknowledged that there are patients with a low level of consciousness but who nevertheless show signs that are consistent with interaction with the environment by means of unmistakeably voluntary behaviours in response to orders or gestures. CONCLUSIONS: The wide spectrum of signs and symptoms shown by patients with altered levels of consciousness reflects the clinical and neuropathological heterogeneity of these states. The current tendency is to describe the state clinically, adding the aetiology and the date of the event that caused the clinical picture. This article focuses on the context of an effort made by the scientific community to highlight the needs of this growing population. PMID- 22930144 TI - [Guillain-Barre syndrome: an unusual saltatory-type variant in the paediatric age]. PMID- 22930145 TI - [Extra-hospital stroke care]. PMID- 22930148 TI - Low-dose magnesium sulphate in the control of eclamptic fits: a randomized controlled trial. AB - CONTEXT: Magnesium sulphate is now the gold standard for the control of eclamptic fits. The place of low-dose magnesium sulphate for the control of eclamptic seizures is yet to be determined. OBJECTIVES: To determine the effectiveness of low-dose magnesium sulphate in controlling eclamptic fits. STUDY DESIGN: Randomized controlled trial comparing low-dose with standardized dosing regimen. SETTING: Labour Unit of the department of Obstetrics and Gynecology Federal Medical Centre Azare, north-eastern Nigeria. PROTOCOL: Thirty-nine patients randomized into the low-dose regimen group received 9 g loading dose (4 g iv and 5 g im) and im maintenance of 2.5 g four hourly for 24 h post-delivery or post last fit, while the 33 patients in the standard dose regimen group received loading dose of 14 g followed by im maintenance dose of 5 g four hourly. In both study groups, 2 g iv of magnesium sulphate is given for breakthrough fits and 10 ml of 10 % calcium gluconate (slowly iv) was administered in the event of toxicity. Outcome measures include recurrent fits, mode of delivery, mean Apgar Score at 5 min, perinatal death, maternal complications including death. RESULT: The mean age of the 72 patients was 22.3 +/- 5.4 years and 60 % were primigravidas. Intrapartum eclampsia was encountered in 44 % of the patients followed by antepartum eclampsia (26 %). Overall 4.2 % recurrent convulsion rate was documented and it is not different among the study groups. There were also no differences in both foetal and maternal outcomes in the two study groups. CONCLUSION: The effectiveness of low-dose regimen of magnesium sulphate appeared comparable to the 'standard dose regimen'. Low-dose regimen may guarantee more safety and in an environment (such as ours) where cost is an important determinant of accessibility to qualitative health services, it is certainly attractive. More studies are needed to establish the place of low-dose regimen of magnesium sulphate in the management of eclampsia. PMID- 22930149 TI - Does obesity compromise ovarian reserve markers? A clinician's perspective. AB - OBJECTIVE: The aim of the study was to ascertain if increasing body mass index (BMI) adversely affects ovarian reserve among infertile women of Asian origin undergoing in vitro fertilization (IVF). MATERIALS AND METHODS: This prospective study on 183 women was carried out in the infertility clinic of All India Institute of Medical Sciences, New Delhi, India. Blood hormonal assay in all patients including follicle-stimulating hormone (FSH), luteinizing hormone (LH) and inhibin B was performed on day 2/3 of a spontaneous cycle. A transvaginal ultrasonographic examination on day 2-5 of the menstrual cycle was done for antral follicle count (AFC) and ovarian volume. A correlation between BMI and ovarian reserve parameters like FSH, LH, inhibin B, antral follicle count and ovarian volume was noted. RESULTS: Age was comparable in the three BMI groups. The mean duration of infertility was 8.38 years. Compared to the normal weight, the overweight and obese women had a statistically significantly low inhibin B (p < 0.0259). The AFC when taken together on both sides was not statistically significant between the groups; however, the overweight and obese women had a significantly low AFC (p < 0.0129) on the right side. CONCLUSION: Incorporating anti-mullerian hormone, a newer marker for ovarian reserve, may benefit these obese infertile women. Further work is required to elucidate the mechanisms underlying the effect of obesity on inhibin B as a marker of ovarian reserve in infertile women. The best marker to check the ovarian reserve is perhaps the woman's performance during an IVF cycle. However, considering the psychological and financial stress of the procedure, it may seem wise to consider counseling of obese women on their expected performance in the first cycle of IVF through such studies. PMID- 22930150 TI - Uterine perforation with omentum incarceration after dilatation and evacuation/curettage. PMID- 22930151 TI - Comparative study between VEGF-A and CA-125 in diagnosis and follow-up of advanced endometriosis after conservative laparoscopic surgery. AB - OBJECTIVE: To evaluate the role of serum level of VEGF-A in comparison to CA-125 in diagnosis and follow-up of patients with advanced endometriosis after conservative laparoscopic surgery. METHODS: A prospective randomized case-control study was performed on patients referred for laparoscopy complaining of unexplained primary infertility with or without chronic pelvic pain. Thirty patients with advanced endometriosis; stage III-IV were included (study group), another 30 women without endometriosis or any other medical conditions were settled as a control group. Pre-operative blood samples were collected from study and control cases. Post-operative blood samples were collected from 25 treated patients in the follicular phase of the third menstrual cycle; 5 cases were drop outs. Serum level of cancer antigen-125 (CA-125) and vascular endothelial growth factor (VEGF-A) were assayed by using enzyme linked immunosorbent assay (ELISA) kit. RESULTS: There was a statistically significant difference in serum CA-125 and VEGF-A level in patients with advanced endometriosis before conservative laparoscopic surgery and those without endometriosis (p < 0.001) and after conservative laparoscopic surgery (p < 0.001). High sensitivity (93.3 %), specificity (96.7 %) and accuracy (95.0 %) of VEGF-A assay than in CA-125 distinguishing between patients with endometriosis from those without endometriosis; CA-125 has 70.0 %sensitivity, 90.0 % specificity and 85.0 % accuracy. Percentage of decrease of VEGF-A level after operation was higher than that of CA-125 (45.9 vs. 25.8 %) p < 0.001, respectively. CONCLUSION: The use of VEGF-A for diagnosis of advanced endometriosis at cut-off 680 pg/ml and for follow-up is better than CA-125. PMID- 22930152 TI - The redox effect of the [1,2-(NH)2C6H4]2- ligand in the formation of transition metal compounds. AB - Reactions of the [1,2-(NH)(2)C(6)H(4)](2-) dianion (LH(2)(2-)) with Cp(2)M(II) (M = V, Mn) lead to complete or partial oxidation of the metals (M), giving the V(III) compound [(eta(5)-Cp)(LH(2))(2)VV(LH(2))](-)[Li(THF)(4)](+) (1) and Mn(II)(4)Mn(III)(2) oxo cage [Mn(6)(LH(2))(6)(MU(6)-O)(THF)(4)] (2). PMID- 22930153 TI - Physical examination, magnetic resonance image, and electrodiagnostic study in patients with lumbosacral disc herniation or spinal stenosis. AB - OBJECTIVE: To compare the clinical implications of electro-diagnostic study with those of magnetic resonance imaging in patients with lumbosacral intervertebral herniated disc or spinal stenosis. DESIGN: Retrospective study of clinical data. PATIENTS: Patients with lumbosacral intervertebral herniated disc or spinal stenosis, diagnosed by clinical assessment and magnetic resonance imaging (MRI), were selected. A total of 753 patients (437 with lumbosacral intervertebral herniated disc and 316 with spinal stenosis) were included in the study. METHODS: Clinical data for electrodiagnostic study (EDX)and MRI were compared and the sensitivity and specificity of these studies were evaluated. Among all subjects, 267 had radiculopathy on EDX (EDX (+)) and 486 no radiculopathy (EDX(-)). Furthermore, 391 had root compression on MRI (MRI (+)) and 362 no root compression on MRI (MRI (-)). RESULTS: Patients with radioculopathy on EDX (+) showed a significantly higher visual analogue scale score for radiating pain and a higher Oswestry Disability Index than those with negative findings by EDX (-) in the total subjects group and the lumbosacral intervertebral herniated disc subgroup, and there was a trend toward higher Oswestry Disability Index in the spinal stenosis subgroup. Although patients with radioculopathy on root compression on MRI (+) also had a higher visual analogue scale for radiating pain than patients with negative findings by MRI (-) in the total subjects group and the lumbosacral intervertebral herniated disc subgroup, no significant difference was seen in the Oswestry Disability Index. EDX revealed a significant correlation with muscle weakness in the total subjects group and the lumbosacral intervertebral herniated disc subgroup, and trends toward muscle weakness in the spinal stenosis subgroup, whereas there was no such significant correlation for MRI findings in any group. Electrodiagnostic study had a higher specificity in terms of physical examination data than MRI, in spite of its lower sensitivity. CONCLUSION: Electrodiagnostic study was significantly more correlated with clinical data, especially leg muscle weakness and functional status, and showed a higher specificity than MRI in patients with lumbosacral intervertebral herniated disc or spinal stenosis. PMID- 22930154 TI - A simple route for synthesis of PbSe nanocrystals: shape control by ligand and reaction time. AB - The shape controlled synthesis of high quality colloidal lead selenide (PbSe) nanocrystals (NCs) was achieved through a simple solvothermal process. By using oleic acid (OA) as a ligand and activating agent for the Pb precursor, the evolution of the NCs from nanospheres to nanoflowers and finally to nanocubes was achieved by increasing the reaction time. Further, the shape variation from nanospheres to polyhedrons was readily realized through the increase of OA concentration in the stock solution. More interestingly, the change of the anion ligand was proven to be a facile method to control the structure and size of the nanoflowers. The X-ray diffraction and TEM analysis demonstrated the cubic rock salt structure of the synthesized PbSe NCs. Accompanied by comprehensive analytics, the discussion on the possible mechanisms for the shape evolution was provided. PMID- 22930155 TI - Naming abilities in low-proficiency second language learners. AB - Difficulties in second language (L2) learning are often associated with recognizable learning difficulties in native language (L1), such as in dyslexia. However, some individuals have low L2 proficiency but intact L1 reading skills. These L2 learners experience frequent tip-of-the-tongue states while naming in L1, which indicates that they have a weakness in retrieval of phonological codes of words. The authors hypothesized that if naming ability is shared across languages, this difficulty would reemerge in L2 naming, which was tested using the tip-of-the-tongue experimental paradigm. Consistent with this hypothesis, low proficiency L2 learners (n = 15) reported more tip-of-the-tongue states, more frequently mispronounced correctly retrieved words, and benefited less from phonological cuing compared to high-proficiency L2 learners (n = 23). It is notable that low-proficiency L2 learners performed worse than individuals with dyslexia (n = 16) on some of these measures, despite the same level of L2 proficiency. These results indicate that L2 naming difficulties of low proficiency L2 learners are a manifestation not merely of their low L2 proficiency but rather of a general weakness in phonological word form retrieval, which is shared across languages. More broadly, the study provides further evidence for the existence of a distinct profile of cognitive weaknesses characteristic of the behavioral phenotype of low-proficiency L2 learners. PMID- 22930156 TI - Non-interpenetrated IRMOF-8: synthesis, activation, and gas sorption. AB - The synthesis and successful activation of IRMOF-8 (Zn(4)O(ndc)(3), ndc = naphthalene-2,6-dicarboxylate) is presented. Room temperature synthesis effectively suppresses interpenetration. Although conventional activation under reduced pressure leads to structural collapse, activation by flowing supercritical CO(2) yields a guest-free material with a BET surface area of 4461 m(2) g(-1). PMID- 22930157 TI - The impact of tobacco use on preterm premature rupture of the membranes. AB - OBJECTIVE: To determine if tobacco use increases the incidence of preterm premature rupture of the membranes (pPROM) or alters perinatal outcomes after pPROM. STUDY DESIGN: This is a secondary analysis of the databases of three completed Eunice Kennedy Shriver National Institute of Child Health and Human Development-supported Maternal Fetal Medicine Units Network studies. Self reported tobacco exposure data was obtained. Its relationship with the incidence of pPROM and associated neonatal outcome measures were assessed. RESULTS: There was no difference in the incidence of pPROM when comparing nonsmokers to those using tobacco. Although a trend was seen between the incidence of pPROM and the amount smoked, this did not reach statistical significance. Among the patients with pPROM, the use of tobacco was not associated with an increase in perinatal morbidity. CONCLUSION: Our data do not support a significant relationship between tobacco use and pPROM. PMID- 22930158 TI - Optimisation of BACE1 inhibition of tripartite structures by modification of membrane anchors, spacers and pharmacophores - development of potential agents for the treatment of Alzheimer's disease. AB - Systematic variation of membrane anchor, spacer and pharmacophore building blocks leads to an optimisation of the inhibitory effect of tripartite structures towards BACE1-induced cleavage of the amyloid precursor protein (APP). PMID- 22930159 TI - Medical causation and expert testimony: allergists at this intersection of medicine and law. AB - Clinical practice always necessitates proper diagnosis and correct treatment. For most clinical fields, determining the cause of the illness is irrelevant to the intervention. An oncologist, for example, has no need to explore the "cause" of the patient's lymphoma. Allergists, by contrast, have tools and the need to examine the relevant allergen which is the putative "cause" of the patient's allergic symptomatology. In the context of a legal claim, the "cause" of the symptoms or disorder is central, because it determines financial responsibility. However, in the case of an allergic disorder and identified allergen, a claim requires more. Whose allergen? Where did it come from? These are crucial questions that must be answered. This paper explores the approaches to causal assessment which are important for the clinical allergist as he/she navigates the interface between clinical practice and legal proceedings. Its purpose is to help the allergist understand that interface, and to be prepared to enter an unfamiliar legal arena. PMID- 22930160 TI - 3-D imaging and illustration of the perfusive mouse islet sympathetic innervation and its remodelling in injury. AB - AIMS/HYPOTHESIS: Sympathetic nerves influence islet hormone levels in the circulation. Insights into islet sympathetic innervation and its remodelling in diabetes may impact future therapeutics. However, standard immunohistochemistry and microtome-based microscopy cannot provide an integral view of the islet neurovascular complex. We prepared transparent islet specimens to investigate the spatial relationship between sympathetic nerves, blood vessels and islet cells in normal, streptozotocin-injected and non-obese diabetic mouse models. METHODS: Cardiac perfusion of fluorescent lectin was used to label pancreatic blood vessels. Tyrosine hydroxylase and nuclear staining were used to reveal islet sympathetic innervation and microstructure. Optical clearing (i.e. use of immersion solution to reduce scattering) was applied to enable 3-dimensional confocal microscopy of islets to visualise the sympathetic neurovascular complex in space. RESULTS: Unlike previously reported morphology, we observed perfusive intra-islet, perivascular sympathetic innervation, in addition to peri-islet contacts of sympathetic nerves with alpha cells and sympathetic fibres encircling the adjacent arterioles. The intra-islet axons became markedly prominent in streptozotocin-injected mice (2 weeks after injection). In non-obese diabetic mice, lymphocytic infiltration remodelled the peri-islet sympathetic axons in early insulitis. CONCLUSIONS/INTERPRETATION: We have established an imaging approach to reveal the spatial features of mouse islet sympathetic innervation. The neurovascular complex and sympathetic nerve-alpha cell contact suggest that sympathetic nerves modulate islet hormone secretion through blood vessels, in addition to acting directly on alpha cells. In islet injuries, sympathetic nerves undergo different remodelling in response to different pathophysiological cues. PMID- 22930163 TI - Hydrogen interaction with the anatase TiO2(101) surface. AB - The interaction of atomic hydrogen with the majority (101) surface of anatase TiO(2) is studied using density functional theory calculations both with a standard semi-local functional and with the inclusion of on-site Coulomb repulsion terms. We investigate the energetics of different adsorption configurations at surface and subsurface sites and different coverages, from low to one monolayer, as well as diffusion pathways among the different sites and recombinative H(2) desorption barriers. While H(2) desorption is the energetically most favorable process, the diffusion of H into the subsurface is found to be at least equally favorable kinetically. It is further shown that subsurface oxygen vacancies on reduced anatase are favorable adsorption sites for hydrogen atoms. PMID- 22930162 TI - A novel mixed valent Cu(II)-Cu(I) 2D framework made of a hydrazone and MU-SCN bridged metallacyclic loops cross-linked by MU3-SCN chains. AB - A mixed valent copper complex [Cu(II)Cu(I)(L)(MU-SCN)(MU(3)-SCN)](n) (LH = N' ((pyridin-2-yl)methylene)acetohydrazide) has been synthesized and characterized. It is a unique example of a 2D mixed valent Cu(II)-Cu(I) interlinked molecular assembly with a very unusual bridging property of the hydrazone ligand. An extraordinary in situ partial Cu(II)-> Cu(I) reduction is observed in this system at room temperature. PMID- 22930161 TI - (Pro)renin receptor is associated with angiogenic activity in proliferative diabetic retinopathy. AB - AIMS/HYPOTHESIS: The renin-angiotensin system (RAS) potentially has a role in the development of end-organ damage, and tissue RAS activation has been suggested as a risk factor for diabetic retinopathy. We have recently shown significant involvement of (pro)renin receptor ([P]RR) in retinal inflammation in a rodent model of early diabetes. In this study we aim to elucidate the (P)RR-associated pathogenesis of fibrovascular proliferation, a late-stage angiogenic complication in human diabetic retinopathy. METHODS: Vitreous fluids from 23 eyes of patients with proliferative diabetic retinopathy (PDR) and 16 eyes of controls with non diabetic, idiopathic macular diseases (macular hole and epiretinal membrane) were collected. Protein levels of soluble (P)RR were measured by ELISA, and immunofluorescence was performed to assess the localisation of (P)RR and related molecules in fibrovascular tissues from PDR eyes. RESULTS: (P)RR immunoreactivity was detected in neovascular endothelial cells, colocalised with prorenin, phosphorylated extracellular signal-regulated kinase (ERK) and vascular endothelial growth factor (VEGF). Prorenin application to human retinal microvascular endothelial cells significantly upregulated mRNA expression of VEGF, especially the VEGF165 isoform, which was abolished by (P)RR or ERK signalling blockade. Proteases known to cleave (P)RR, including furin, were positive in endothelial cells in fibrovascular tissues. Protein levels of soluble (P)RR in vitreous fluids were higher in PDR eyes than in non-diabetic control eyes, and correlated significantly with vitreous prorenin and VEGF levels and the vascular density of fibrovascular tissues. CONCLUSIONS/INTERPRETATION: Our data using human samples provide the first evidence that (P)RR is associated with angiogenic activity in PDR. PMID- 22930164 TI - Inertial microfluidics in parallel channels for high-throughput applications. AB - Passive particle focusing based on inertial microfluidics was recently introduced as a high-throughput alternative to active focusing methods that require an external force-field to manipulate particles. In this study, we introduce inertial microfluidics in flows through straight, multiple parallel channels. The scalable, single inlet and two outlet, parallel channel system is enabled by a novel, high-density 3D PDMS microchannel manufacturing technology, mediated via a targeted inhibition of PDMS polymerization. Using single channels, we first demonstrate how randomly distributed particles can be focused into the centre position of the channel in flows through low aspect ratio channels and can be effectively fractionated. As a proof of principle, continuous focusing and filtration of 10 MUm particles from a suspension mixture using 4- and 16-parallel channel devices with a single inlet and two outlets are demonstrated. A filtration efficiency of 95-97% was achieved at throughputs several orders of magnitude higher than previously shown for flows through straight channels. The scalable and low-footprint focusing device requiring neither external force fields nor mechanical parts to operate is readily applicable for high-throughput focusing and filtration applications as a stand-alone device or integrated with lab-on-a-chip systems. PMID- 22930165 TI - Low back pain among caregivers of spinal cord injured patients. AB - OBJECTIVE: To evaluate the prevalence of low back pain among caregivers of patients with spinal cord injury and to investigate the risk factors for LBP among this population. DESIGN: A cross-sectional study. SUBJECTS: A total of 100 spinal cord injured patients and their caregivers, and 87 healthy control subjects. METHODS: Caregivers and control subjects completed a questionnaire about demographic characteristics and low back pain. Pain was evaluated using a visual analogue scale and the Oswestry Disability Index. Duration, severity and level of spinal cord injury, and functional level were recorded. RESULTS: The prevalence of low back pain was higher among caregivers than among the control group. Visual analogue scale scores of caregivers with low back pain were higher than those of the control group, whereas there was no significant difference in the Oswestry Disability Index score. There was a significant correlation between low back pain and level, severity and duration of injury. Prevalence of low back pain was higher among caregivers of patients with low functional scores. CONCLUSION: Low back pain is common among caregivers of patients with spinal cord injury and is associated with duration of injury, level of injury, severity of injury, and functional level of the patient. PMID- 22930166 TI - "Peak tracking chip" for label-free optical detection of bio-molecular interaction and bulk sensing. AB - A novel imaging method for bulk refractive index sensing or label-free bio molecular interaction sensing is presented. This method is based on specially designed "Peak tracking chip" (PTC) involving "tracks" of adjacent resonant waveguide gratings (RWG) "micropads" with slowly evolving resonance position. Using a simple camera the spatial information robustly retrieves the diffraction efficiency, which in turn transduces either the refractive index of the liquids on the tracks or the effective thickness of an immobilized biological layer. Our intrinsically multiplex chip combines tunability and versatility advantages of dielectric guided wave biochips without the need of costly hyperspectral instrumentation. The current success of surface plasmon imaging techniques suggests that our chip proposal could leverage an untapped potential to routinely extend such techniques in a convenient and sturdy optical configuration toward, for instance for large analytes detection. PTC design and fabrication are discussed with challenging process to control micropads properties by varying their period (step of 2 nm) or their duty cycle through the groove width (steps of 4 nm). Through monochromatic imaging of our PTC, we present experimental demonstration of bulk index sensing on the range [1.33-1.47] and of surface biomolecule detection of molecular weight 30 kDa in aqueous solution using different surface densities. A sensitivity of the order of 10(-5) RIU for bulk detection and a sensitivity of the order of ~10 pg mm(-2) for label-free surface detection are expected, therefore opening a large range of application of our chip based imaging technique. Exploiting and chip design, we expect as well our chip to open new direction for multispectral studies through imaging. PMID- 22930167 TI - Distribution of trivalent metal cations in alumino-/gallogermanate zeolites with JST topology. AB - A series of zeolitic alumino- and gallogermanate compounds, |M(II)(en)(3)|[M(III)(2)Ge(4)O(12)] (M(II) = Ni, Co, Zn; M(III) = Al, Ga; en = ethylenediamine), has been synthesized using in situ formed [M(II)(en)(3)](2+) cations as the structure-directing agents. These zeolitic compounds exhibit the same JST framework topology which is built exclusively of 3-rings. Their structures were determined by single-crystal X-ray diffraction. The frameworks of these compounds are constructed from M(III)- and Ge-centred tetrahedra. According to inductively coupled plasma (ICP) analyses, the ratios of M(III)/Ge are 1/2 in all these compounds. The resulting negative charges in these frameworks are compensated by extra-framework [M(II)(en)(3)](2+) cations. Single crystal structural analyses show that there are two crystallographically distinct atom sites for M(3+). According to the ICP results and the unique structural feature of JST, the most reasonable distribution of M(3+) cations in these structures was deduced. PMID- 22930169 TI - Noninvasive ventilation for weaning in hypoxemic respiratory failure: not ready for prime time. PMID- 22930171 TI - Intralesional steroid injection to prevent stricture after endoscopic submucosal dissection for esophageal cancer: a controlled prospective study. AB - BACKGROUND AND STUDY AIMS: The frequency of stricture after endoscopic submucosal dissection (ESD) for esophageal squamous cell carcinoma with a mucosal defect involving more than three-quarters of the circumference is 70% - 90%. Stricture decreases quality of life and requires multiple endoscopic balloon dilation (EBD) sessions. We investigated the efficacy and safety of a single session of intralesional steroid injections to prevent post-ESD stricture. PATIENTS AND METHODS: We conducted a prospective study on 30 patients with esophageal squamous cell carcinoma treated by ESD, who had a more than three-quarter but less than whole circumferential defect. A single session of intralesional steroid injections was undertaken immediately after ESD. Esophagogastroduodenoscopy was performed whenever patients reported dysphagia and 2 months after ESD in patients without dysphagia. Results were compared with a historical control group of 29 patients who underwent ESD without intralesional steroid injection. The primary endpoint was the post-ESD stricture rate. Secondary endpoints were the number of EBD sessions and the complication rate. RESULTS: Compared with the historical control group, the study group had a significantly lower stricture rate (10%, 3/30 patients vs. 66%, 19/29 patients; P < 0.0001) and a lower number of EBD sessions (median 0, range 0 - 2 vs. median 2, range 0 - 15; P < 0.0001). The study group had a complication rate of 7 % (2 /30 patients), comprising a submucosal tear in one patient and bleeding in another, which were not a direct result of EBD. CONCLUSIONS: A single session of intralesional steroid injections showed promising results for the prevention of stricture after ESD for esophageal cancer. PMID- 22930172 TI - Endoscopic submucosal dissection for duodenal tumors: a single-center experience. AB - The indications for endoscopic submucosal dissection (ESD) for duodenal tumors have not yet been established. We reviewed our experience of ESD performed for duodenal tumors. We analyzed the data of a total of 13 patients with 14 duodenal lesions (excluding papillary lesions) comprising 2 early cancers, 5 adenomas, and 7 neuroendocrine tumors, who were treated by ESD between 2005 and 2011. The mean tumor diameter was 12.7 +/- 14.8 mm. En bloc resection was achieved in 85.7% of the cases. The procedure time was 89.1 +/- 64.6 minutes. Intraoperative perforation occurred in three cases. The mean length of postoperative hospitalization was 8.4 +/- 2.4 days. Because ESD for duodenal lesions was associated with a higher incidence of perforation than ESD for lesions in other locations (stomach, esophagus, and colon) reported previously, its use for duodenal lesions should be considered with caution. PMID- 22930170 TI - Transcriptional profiling identifies genes induced by hepatocyte-derived extracellular matrix in metastatic human colorectal cancer cell lines. AB - The milieu of the liver, and in particular hepatocyte-derived extracellular matrix (hECM), is a critical factor regulating development of liver metastases of colorectal cancer (CRC) cells. The present study has investigated genes altered by hECM in CRC cells and particularly by heparan sulfate chains of hepatocyte proteoglycans. Gene profiling analysis shows that after 2 days on hECM, 226 genes are up-regulated more than 2-fold in strongly metastatic SM cells, including genes involved in growth arrest and apoptosis, signal transduction, cell migration, proliferation, communication and angiogenesis, with activation of the erbB signaling network and p53 effectors. Genes down-regulated by hECM include genes involved in lipogenesis and the S phase of the cell cycle. Further studies exploring the kinetics of gene expression after 4 and 7 days culture on hECM show induction of EGF family members and of stem cell markers. In particular, hECM, but not collagen, increases mRNA expression of HB-EGF and colon stem cell marker leucine-rich repeat-containing G protein-coupled receptor 5 (LGR5). Expression of these genes is not induced by hECM depleted of the heparan sulfate chains of proteoglycans. Lastly, a specific cell population positive for cancer stem cell (CSC) markers LGR5, epCAM and CD133, but negative for CD44, appears after 7 days culture on hECM, a population which is reduced by 50 % in cells grown on heparan sulfated-depleted hECM. Collectively, the data suggest that hECM induces growth factors and receptors regulating proliferation of metastatic CRC in the liver and offers a growth advantage for specific populations expressing CSC markers. PMID- 22930173 TI - Colorectal polypectomy during insertion and withdrawal or only during withdrawal? A randomized controlled trial. AB - BACKGROUND AND STUDY AIMS: Removal of colorectal polyps is routinely performed during withdrawal of the endoscope. However, polyps detected during insertion of the colonoscope may be missed at withdrawal. We aimed to evaluate whether polypectomy during both insertion and withdrawal increases polyp detection and removal rates compared with polypectomy at withdrawal only, and to assess the duration of both approaches. PATIENTS AND METHODS: Patients were included into the study when the first polyp was detected, and randomized into two groups; in group A, polyps <= 10 mm in diameter were removed during insertion and withdrawal of the colonoscope, while in group B, these polyps were removed at withdrawal only. Main outcome measures were duration of colonoscopy, number of polyps detected during insertion but not recovered during withdrawal, technical ease, patient discomfort, and complications. RESULTS: 150 patients were randomized to group A and 151 to group B. Mean (+/- standard deviation [SD]) duration of colonoscopy did not differ between the groups (30.8 +/- 15.6 min [A] vs. 28.5 +/- 13.8 min [B], P = 0.176). In group A 387 polyps (mean 2.58 per colonoscopy) were detected and removed compared with 389 polyps detected (mean 2.58 per colonoscopy) in group B of which 376 were removed (13 polyps were missed, mean size [SD] 3.2 [1.3] mm; 7.3 % of patients). Patient tolerance was similar in the two groups. CONCLUSIONS: Removal of polyps <= 10 mm during withdrawal only is associated with a considerable polyp miss rate. We therefore recommend that these polyps are removed during both insertion and withdrawal. PMID- 22930174 TI - Validity of insertion depth measurement in double-balloon endoscopy. AB - BACKGROUND AND STUDY AIMS: In double-balloon enteroscopy (DBE) the use of a reliable and practical method to calculate the insertion depth of the endoscope could help to improve diagnosis accuracy and optimize the effort and cost of the technique. The objectives of this work were to compare and evaluate two methods of estimating the insertion depth and to obtain a descriptive model capable of representing the exploration dynamics and efficiency in terms of advanced distance and time. METHODS: Oral DBE was performed in 25 pigs. Insertion depth was calculated during the procedure by: 1) estimation of time and distance for each push and pull cycle during progression; and 2) estimation of distance during withdrawal. At the maximum insertion depth a tattoo was placed, and the observed measures for the two methods were compared with the distance between the pylorus and the mark after euthanasia and necropsy of the animals 1 week after DBE. RESULTS: The average insertion depth during progression, withdrawal, and after necropsy was 324.92 cm, 317.23 cm, and 342.05 cm, respectively (P Anova = 0.72). The Pearson correlation coefficient (r > 0.85; P < 0.001) and paired Brand - Altman plots demonstrated high agreement between progression and necropsy (0.03 % difference) and between withdrawal and necropsy (6.9 % difference). The exploration dynamics and efficiency in terms of advanced distance per cycle and time fitted to potential and logarithmic regression models, respectively. CONCLUSIONS: Measurement of insertion depth in vivo was validated in the porcine model during progression and withdrawal. Estimation during progression was more accurate and allowed exploration dynamics and efficiency to be plotted, which might be used as approximate reference values for humans. PMID- 22930175 TI - Nurse endoscopists perform colonoscopies according to the international standard and with high patient satisfaction. AB - BACKGROUND AND STUDY AIMS: Colonoscopy is increasingly performed by nurse endoscopists. We aimed to assess the endoscopic quality and patient experience of these procedures. PATIENTS AND METHODS: This prospective multicenter study analyzed 100 consecutive colonoscopies each for 10 trained nurse endoscopists with respect to endoscopic quality and patient experience. Colonoscopies were performed under the supervision of a gastroenterologist, using the techniques and protocols of the participating hospitals. Patient experience was assessed using a questionnaire. RESULTS: Most nurse endoscopists were female (90 %; median age 43 [range 35 - 49]). Before the start of the study, they had performed a median of 528 colonoscopies (range 208 - 2103). For the 1000 patients, mean age was 56 +/- 15 years; 55 % were women; and 96 % were in class I or II according to the American Society of Anesthesiologists' physical status classification system. Colonoscopies were performed for screening or surveillance in 42 %; for symptomatic indications in 58 % of patients. The unassisted cecal intubation rate was 94 %; the mean withdrawal time was 10 +/- 5 minutes. The adenoma detection rate was 26.7 %. In 229 of the colonoscopies (23 %), the nurse endoscopists required assistance from the supervising gastroenterologist. The complication rate was 0.2 %: one perforation and one cardiopulmonary complication. The questionnaire was completed by 734 /1000 patients (73 %) and of these 694 /734 (95 %) were satisfied with the endoscopic procedure. Among the respondents 530 /734 (72 %) had no specific preference for a physician or nurse endoscopist, whereas 113 /734 (15 %) preferred a physician endoscopist, and 91 /734 (12 %) preferred a nurse endoscopist. CONCLUSION: The nurse endoscopists performed colonoscopies according to the internationally recognized quality standards and with high patient satisfaction. PMID- 22930176 TI - A randomized head-to-head study of small-bowel imaging comparing MiroCam and EndoCapsule. AB - BACKGROUND AND STUDY AIMS: The MiroCam is a new video capsule device offering a higher frame rate and a longer battery life-expectancy. We aimed to quantify its clinical impact and performed a randomized head-to-head comparison with the EndoCapsule device with respect to the rate of complete small-bowel examinations, diagnostic yield in the small bowel, and capsule transit time. PATIENTS AND METHODS: Patients referred for video capsule endoscopy because of obscure gastrointestinal bleeding, chronic diarrhea, and anemia of unknown origin were randomly assigned to swallow either the MiroCam first, followed by the EndoCapsule 2 hours later, or vice versa. All videos were analyzed by two independent investigators. RESULTS: A total of 50 patients (median age 61, range 21-84) were included. Complete small-bowel examination was achieved in 48/50 patients using the MiroCam and 45/50 using the EndoCapsule (96% vs. 90%, odds ratio [OR] 2.67, 95% confidence interval [CI] 0.49-14.45; P=0.38). There was diagnostic yield in the small bowel for 25/50 patients using the MiroCam and 24/50 using the EndoCapsule (50% vs. 48%, OR 1.08, 95%CI 0.49-2.37; P>0.99). However, the findings were concordant in 68% only (kappa = 0.50). The combined diagnostic yield was 58%. Even solitary findings had a relevant clinical impact during a 6-month follow-up. CONCLUSION: In this direct comparison the MiroCam and EndoCapsule devices were not statistically different with regard to their rates of complete small-bowel examinations or diagnostic yield. Their moderate concordance, mainly caused by missed pathological findings, which affected both devices, needs consideration in clinical practice. PMID- 22930177 TI - A combined experimental and DFT/TDDFT investigation of structural, electronic, and pH-induced tuning of photophysical and redox properties of osmium(II) mixed chelates derived from imidazole-4,5-dicarboxylic acid and 2,2'-bipyridine. AB - Experimental results coupled with computational studies were utilized to investigate the structural and electronic properties of mixed-ligand monometallic osmium(II) complexes of composition [(bipy)(2)Os(H(2)Imdc)](+) (1(+)), the N-H deprotonated form [(bipy)(2)Os(HImdc)] (1), and the COOH deprotonated form [(bipy)(2)Os(Imdc)](-) (1(-)), where H(3)Imdc = imidazole-4,5-dicarboxylic acid and bipy = 2,2'-bipyridine. The X-ray crystal structures of [(bipy)(2)Os(H(2)Imdc)](+) (1(+)) and [(bipy)(2)Os(HImdc)] (1) have been determined, which showed that compound 1(+) crystallizes in a monoclinic form with the space group P2(1)/c, while 1 is obtained in a triclinic form with the space group P1[combining macron]. The optimized geometrical parameters for the complexes computed both in the gas phase and in solution are reported and compared with the available X-ray data. The influence of pH on the photophysical and redox properties of the complexes has been thoroughly investigated. As compared to protonated complex (1(+)), which undergoes reversible oxidation at 0.50 V (vs. Ag/AgCl) in acetonitrile, the redox potential of the fully deprotonated complex (1(-)) is shifted to a much lower value, 0.16 V. The proton coupled redox activity of 1(+) has been studied over the pH range 2-12 in an acetonitrile-water (3 : 2) medium. From the pH versus E(1/2) profile, the equilibrium constants of the complex species in the protonated/deprotonated forms and the metal ion in +2/+3 oxidation states have been determined. Using these values the bond dissociation free energies for the imidazole N-H and COOH bonds have also been estimated. The pK(a) values for 1(+) in the +2 state have also been determined spectrophotometrically. Substantial red shifts in the MLCT bands and the large shift in the E(1/2) value to a less positive potential that occur on deprotonation are energetically correlated. Density functional theory (DFT) and time-dependent DFT (TD-DFT) studies provide insight into the nature of the ground and excited states, with resulting detailed assignments of the orbitals involved in the absorption and emission transitions. PMID- 22930178 TI - Rationale behind survivin inhibition as a potential therapeutic strategy in head and neck carcinoma too. PMID- 22930179 TI - Chemical signals of past climate and environment from polar ice cores and firn air. AB - Chemical and isotopic records obtained from polar ice cores have provided some of the most iconic datasets in Earth system science. Here, I discuss how the different records are formed in the ice sheets, emphasising in particular the contrast between chemistry held in the snow/ice phase, and that which is trapped in air bubbles. Air diffusing slowly through the upper firn layers of the ice sheet can also be sampled in large volumes to give more recent historical information on atmospheric composition. The chemical and geophysical issues that have to be solved to interpret ice core data in terms of atmospheric composition and emission changes are also highlighted. Ice cores and firn air have provided particularly strong evidence about recent changes (last few decades to centuries), including otherwise inaccessible data on increases in compounds that are active as greenhouse gases or as agents of stratospheric depletion. On longer timescales (up to 800,000 years in Antarctica), ice cores reveal major changes in biogeochemical cycling, which acted as feedbacks on the very major changes in climate between glacial and interglacial periods. PMID- 22930180 TI - Systematic characterization of feature dimensions and closing pressures for microfluidic valves produced via photoresist reflow. AB - Multilayer soft lithography (MSL) provides a convenient and low-cost method for fabricating poly(dimethyl siloxane) (PDMS) microfluidic devices with on-chip valves for automated and precise control of fluid flow. MSL casting molds for flow channels typically incorporate small patches of rounded positive photoresist at valve locations to achieve the rounded cross-sectional profile required for these valves to function properly. Despite the importance of these rounded features for device performance, a comprehensive characterization of how the rounding process affects feature dimensions and closing pressures has been lacking. Here, we measure valve dimensions both before and after rounding and closing pressures for 120 different valve widths and lengths at post-rounding heights between 15 and 84 MUm, for a total of 1200 different geometries spanning a wide range of useful sizes. We find that valve height and width after rounding depend strongly on valve aspect ratios, with these effects becoming more pronounced for taller and narrower features. Based on the measured data, we provide a simple fitted model and an online tool for estimating the pre-rounding dimensions needed to achieve desired post-rounding dimensions. We also find that valve closing pressures are well explained by modelling valve membranes in a manner analogous to a suspension bridge, shedding new light on device physics and providing a practical model for estimating closing pressures during device design. PMID- 22930182 TI - Quantum chemical characterization of the mechanism of a supported cobalt-based water oxidation catalyst. AB - Quantum chemical modeling is employed to elucidate the catalytic cycle of a recently described supported cobalt compound that catalyzes water oxidation. Key features of the catalytic cycle include a supporting corrole that is rendered non innocent early in the oxidation process and a pendant carboxylate moiety that functions as a general base to further activate a water molecule that nucleophilically attacks a reactive metal oxo functionality. Fluorination of the supporting corrole appears both to modulate the electrophilicity of the metal-oxo fragment and to mitigate decomposition reactions that might otherwise be expected for a corrole radical cation. PMID- 22930181 TI - Copper catalysed azide-alkyne cycloaddition (CuAAC) in liquid ammonia. AB - Copper(I) catalysed azide-alkyne cycloaddition reactions (CuAAC) occur smoothly in liquid ammonia (LNH(3)) at room temperature to give exclusively 1,4 substituted 1,2,3-triazoles with excellent yields (up to 99%). The CuAAC reactions in liquid ammonia require relatively small amounts of copper(I) catalyst (0.5 mole%) compared with that in conventional solvents. The product can be obtained conveniently by simply evaporation of ammonia, indicating its potential application in industry. The rate of the CuAAC reaction in liquid ammonia shows a second order dependence on the copper(I) concentration and the reaction occurs only with terminal alkynes. Deuterium exchange experiments with phenyl acetylene-d(1) show that the acidity of the alkyne is increased at least 1000-fold with catalytic amounts of copper(I) in liquid ammonia. The mechanism of the CuAAC reaction in liquid ammonia is discussed. PMID- 22930184 TI - Frequent relapse and irradiation strategy in primary cutaneous diffuse large B cell lymphoma, leg-type. PMID- 22930183 TI - T cells induced by recombinant chimpanzee adenovirus alone and in prime-boost regimens decrease chimeric EcoHIV/NDK challenge virus load. AB - The popularity of nonreplicating adenoviruses of chimpanzee origin (ChAdVs) as vectors for subunit vaccines is on the rise. This is mainly for their excellent safety and impressive immunogenicity observed in human studies to date. Here, we recloned the chimpanzee adenovirus sero type 68 (ChAdV-68), also designated SAdV 25 and AdC68, genome and demonstrated its straightforward genetic manipulation facilitated by the use of bacterial artificial chromosome recombineering. To generate the ChAdV68.GagB vaccine, the HIV-1 consensus clade B Gag-derived Tg was inserted into the E1 region. In part confirming previous observations, the ChAdV68.GagB vaccine alone and in heterologous prime-boost regimens with plasmid DNA- and modified vaccinia virus Ankara (MVA)-vectored vaccines induced robust polyfunctional HIV-1-specific CD8(+) and CD4(+) T-cell responses with a gut homing phenotype. Importantly, we showed that when a single epitope is expressed as an immunodominant CD8(+) T-cell determinant, responses elicited by ChAdV68.GagB alone and in combination lowered surrogate challenge EcoHIV/NDK (where EcoHIV is chimeric ecotropic HIV) virus load in mice both at the peak T cell frequencies 2 weeks after vaccination and 16 weeks later indicating development of protective effector memory. These results parallel the immunogenicity of similar vaccine regimens in macaques and an ongoing phase I/IIa trial in humans, and support further development of vaccines vectored by ChAdVs. PMID- 22930185 TI - Seasonal variability of chlorophyll-a and oceanographic conditions in Sabah waters in relation to Asian monsoon--a remote sensing study. AB - A study was conducted to investigate the influence of Asian monsoon on chlorophyll-a (Chl-a) content in Sabah waters and to identify the related oceanographic conditions that caused phytoplankton blooms at the eastern and western coasts of Sabah, Malaysia. A series of remote sensing measurements including surface Chl-a, sea surface temperature, sea surface height anomaly, wind speed, wind stress curl, and Ekman pumping were analyzed to study the oceanographic conditions that lead to large-scale nutrients enrichment in the surface layer. The results showed that the Chl-a content increased at the northwest coast from December to April due to strong northeasterly wind and coastal upwelling in Kota Kinabalu water. The southwest coast (Labuan water) maintained high concentrations throughout the year due to the effect of Padas River discharge during the rainy season and the changing direction of Baram River plume during the northeast monsoon (NEM). However, with the continuous supply of nutrients from the upwelling area, the high Chl-a batches were maintained at the offshore water off Labuan for a longer time during NEM. On the other side, the northeast coast illustrated a high Chl-a in Sandakan water during NEM, whereas the northern tip off Kudat did not show a pronounced change throughout the year. The southeast coast (Tawau water) was highly influenced by the direction of the surface water transport between the Sulu and Sulawesi Seas and the prevailing surface currents. The study demonstrates the presence of seasonal phytoplankton blooms in Sabah waters which will aid in forecasting the possible biological response and could further assist in marine resource managements. PMID- 22930186 TI - Petroleum pollution in mangrove forests sediments from Qeshm Island and Khamir Port-Persian Gulf, Iran. AB - The concentrations of total polycyclic aromatic hydrocarbons (PAHs) and 22 individual PAH compounds in 42 surface sediments collected from the mangrove forest of Qeshm Island and Khamir Port (Persian Gulf) were analyzed. PAHs concentrations ranged from 259 to 5,376 ng g(-1) dry weight with mean and median values of 1,585 and 1,146 ng g(-1), respectively. The mangrove sediments had higher percentages of lower molecular weight PAHs and the PAH profiles were dominated by naphthalene. Ratio values of specific PAH compounds were calculated to evaluate the possible source of PAH contamination. This ratios suggesting that the mangrove sediments have a petrogenic input of PAHs. Sediment quality guidelines were conducted to assess the toxicity of PAH compounds. The levels of total PAHs at all of stations except one station, namely Q6, were below the effects range low. Also, concentrations of naphthalene in some stations exceeded the effects range median. PMID- 22930187 TI - Evaluation of honeys and bee products quality based on their mineral composition using multivariate techniques. AB - The aim of this investigation was to estimate honeys and bee products quality in view of their mineral composition using multivariate techniques. Fourteen elements (Ca, Mg, K, Na, P, Co, Mn, Fe, Cr, Ni, Zn, Cu, Cd, and Pb) were determined in 66 honeys and bee products from different places of Poland and Europe and various botanical origins. The total metals contents were analyzed by flame atomic absorption spectrometry using deuterium-background correction after wet digestion with nitric acid in an automatic microwave digestion system. Phosphorus was determined in the form of phosphomolybdate by a spectrophotometric method. Reliability of the procedure was checked by analysis of the certified reference materials tea (NCS DC 73351) and cabbage (IAEA-359). The analytical data indicated a good level of quality of honeys, especially with regard to the concentration of toxic trace elements, such as Cd and Pb. Results were submitted to multivariate analysis, including such techniques as factor and cluster analyses in order to evaluate the existence of data patterns and the possibility of classification of honeys from different botanical origins according to their mineral content. The nine metals determined were considered as chemical descriptors of each sample. There was a significant influence of the botanical and geographical provenance as well as technological processing on the elemental composition of honeys. PMID- 22930188 TI - The problem of using fixed-area subsampling methods to estimate macroinvertebrate richness: a case study with Neotropical stream data. AB - Subsampling has been widely applied in the laboratory to process freshwater macroinvertebrate samples. Currently, many governmental agencies and research groups apply the fixed-count approach, targeting a number of individuals per sample, and at the same time keeping track of the number of quadrats (fraction of the sample) processed. However, fixed-area methods are still in use. The objective of this paper was to evaluate the reliability of macroinvertebrate taxonomic richness estimates developed from processing a standard number of subsampling quadrats (i.e., fixed-area approaches). We used a dataset from 18 tropical stream sites experiencing three different levels of human disturbance (most-, intermediate-, and least-disturbed). With 12 quadrats processed (half the sample), the collection curves started to stabilize, and for more than half of the sites studied, it was possible to sample at least 80 % of the total taxonomic richness of the sample. However, we observed that the minimum number of quadrats to achieve 80 % of taxonomic richness was strongly negatively correlated with the number of individuals collected in each site: the fewer the individuals in a sample, the greater the processed proportion of that sample needed to represent it properly. Thus our results indicate that for any given areal subsampling effort (any fixed fraction of the sample), samples with different numbers of individuals will be represented differently in terms of the proportion of the total number of taxa of the whole samples, those with greater numbers being overestimated and those with fewer numbers being underestimated. Therefore, we do not recommend the use of fixed-area subsampling methods alone if the main purpose is to measure and analyze taxonomic richness; instead, we encourage researchers to use fixed-count approaches for this purpose. PMID- 22930189 TI - Factors affecting metribuzin retention in Algerian soils and assessment of the risks of contamination. AB - Metribuzin is a widely used herbicide around the world but it could lead to soil and water contamination. Metribuzin retention on a silty-clay agricultural soil of Algeria was studied in laboratory batch experiments to assess the contamination risk of the groundwater. Factors conditioning the fate of metribuzin were investigated: soil nature, metribuzin formulation, NPK fertilizer, and soil pH. Freundlich sorption isotherms gave the coefficients K F between 1.2 and 4.9 and 1/n a between 0.52 and 0.93. The adsorption is directly dependent on organic and clay soil contents. Formulated metribuzin (Metriphar) reduces the adsorption (K F = 1.25) compared to pure metribuzin (K F = 2.81). The addition of an NPK fertilizer decreases the soil pH (6.67 for the soil without fertilizer and 5.86 for 2 % of fertilizer) and increases metribuzin adsorption (K F is 4.83 for 2 % of fertilizer). The pH effect on the adsorption is corroborated in experiments changing the soil pH between 5 (K F is 4.17) and 8 (K F is 1.57) under controlled conditions. Desorption isotherms show a hysteresis and only 30 to 40 % of the initially adsorbed metribuzin is released. The estimated GUS index is >= 2.8 for a DT50 >= 30 days. K F values and the hysteresis show that metribuzin is little but strongly retained on the soil. Formulated metribuzin and addition of fertilizer affect the retention. However, the GUS index indicates a high mobility and a significant risk of leaching. The most appropriate risk management measure would be an important increase in organic matter content of the soil by addition of organic amendments. PMID- 22930190 TI - A novel electrochemical biosensor for highly selective detection of protease biomarker from Bacillus licheniformis with D-amino acid containing peptide. AB - A simple, selective and sensitive electrochemical biosensor has been developed to detect protease biomarker from Bacillus licheniformis, a recognized model of the biochemical warfare agent Bacillus anthracis. In this assay, the biosensor is constructed using a d-amine acid containing substrate peptide via self-assembly of cysteine residual at the C-terminal. A biotin modifier is labelled at the N terminal of the substrate peptide. This enables sensitive electrochemical detection of the intact substrate peptide using a streptavidin-conjugated alkaline phosphatase, which catalyzes the conversion of electrochemically inactive 1-naphthyl phosphate into electrochemically active phenol. In the presence of the protease biomarker, the peptide is cleaved, and the biotin moiety is removed away from the electrode surface, which results in a decreased electrochemical signal corresponding to the concentration of the protease biomarker. This electrochemical biosensor is simple, sensitive and cost effective. The introduction of d-amino acids into the peptide substrate enables high species selectivity and eliminates the steps for enzyme isolation and purification. Under optimized conditions, the protease can be determined in the concentration range from 0.5 to 100 MUg mL(-1) with a detection limit to 0.16 MUg mL(-1). PMID- 22930192 TI - Effect of muscle preserved on tendon graft on intra-articular healing in anterior cruciate ligament reconstruction. AB - PURPOSE: The aim of this study was to determine the impact on intra-articular healing of muscle tissue retained on tendon grafts used for anterior cruciate ligament (ACL) reconstruction. METHODS: In an animal study on 40 New Zealand rabbits, a semi-tendon/semi-muscle graft (SSG) and a total tendon graft (TTG) were individually harvested from the Achilles tendons in each animal. After transecting the ACLs in both knees of each rabbit, SSG and TTG were randomly used on bilateral sides of the knee for ACL reconstruction. After 2, 4, and 8 weeks, functional scoring, gross observations, and histological evaluations of the repaired knees were performed (each time point; n = 10). Biomechanical testing was conducted on remaining animals at 8 weeks (n = 10). RESULTS: At 2, 4, and 8 weeks after surgery, there were no statistically significant differences in functional scores between the SSG group and TTG group (n.s.). As healing progressed, skeletal muscle on the SSG was gradually absorbed with a corresponding decrease in graft diameter, compared to TTG, at each time point (P < 0.001). However, healing and incorporation of the intra-articular graft in the SSG were more apparent than those in the TTG, based on histology. The vascularity and cellularity in the center of the sample were significantly greater in the SSG group than the TTG group at all the time points (P < 0.01). At 8 weeks, the SSG group's ultimate failure load, yield load, and elongation at failure were significantly less than for the TTG group (P < 0.01). There were no significant differences in stiffness between the two groups with biomechanical testing (n.s.). CONCLUSION: Results of this study indicate that muscle left on tendon grafts promotes intra-articular healing and remodeling of the graft in a rabbit model. However, excessive amounts of retained skeletal muscle weaken tendon graft's strength for ACL reconstruction. Preserving small amounts of muscle on tendon grafts is feasible for improving the biological success of ACL reconstruction in humans. PMID- 22930193 TI - Treatment and evolution of grade III acromioclavicular dislocations in soccer players. AB - PURPOSE: To evaluate postoperative functional results in soccer players diagnosed with acute grade III acromioclavicular dislocation, stabilized with clavicular hook plate. METHODS: Between 2006 and 2010, 11 soccer players were diagnosed with acute acromioclavicular dislocation. Mean age was 22.9 years. The clavicular hook plate was used for stabilization. The follow-up was 4 years (2-6 years). RESULTS: Constant score showed 82 % excellent results and 18 % good functional results. Average pain measured with VAS was 1.8 (+/-0.59) mm out of 10. We did not report any complication within the process. CONCLUSIONS: Use of the clavicular hook plate is considered adequate for the treatment of acute acromioclavicular dislocation in soccer players, allowing a quick return to sports. LEVEL OF EVIDENCE: Retrospective case series, Level IV. PMID- 22930194 TI - Restoration of sagittal and transverse plane proprioception following anatomic double-bundle ACL reconstruction. AB - PURPOSE: To investigate the restoration of knee proprioception after anatomic double-bundle ACL reconstruction. METHODS: Eleven subjects who underwent anatomic double-bundle ACL reconstruction (12.5-15 months following surgery) and eleven healthy control subjects participated in the study. Sagittal and transverse plane threshold to detect passive motion (TTDPM) were assessed utilizing a customized isokinetic dynamometer by passively rotating the tibia about a fixed femur in both the sagittal plane and transverse plane at 0.25 degrees /s until the subject signalled recognition of movement and movement direction. Based on the normality assumption, either dependent t test or Wilcoxon test was utilized to determine whether significant differences were present between the ACL-reconstructed and the uninjured contralateral limbs. Independent t test or Mann-Whitney test was utilized to compare between the ACL-reconstructed/uninjured contralateral and the external control limbs. RESULTS: There were no significant differences in TTDPM measurement in eleven out of twelve comparisons between the ACL-reconstructed and the uninjured contralateral/external control limbs. The only statistical significant difference was found on TTDPM towards internal rotation direction from the externally rotated-test position between the ACL-reconstructed and the uninjured contralateral limbs (p = 0.01). CONCLUSIONS: Based on a small sample of eleven subjects, the current results indicate a restoration of both sagittal and transverse plane TTDPM following the anatomic double-bundle ACL reconstruction. LEVEL OF EVIDENCE: III. PMID- 22930195 TI - [Integrative and personalized health care--requirements for a timely health-care system]. AB - In medical and public debates, the concept "personalized" or "individualized" medicine (PM) is increasingly used for the orientation of medicine towards individual genetic, molecular and biological characteristics. However, this tunnel view neglects that the human "person" or "individual" encompasses more than just the molecular and biological side, and that patients increasingly call for a more holistic and more person-centred form of health care. Therefore the authors propose to extend the concept of PM in the framework of an integrative health-care concept, so that with respect to a modern and patient-centred health care system not only the biological, but also the relevant psychological, mental, social, cultural, spiritual, and economic aspects of the human individual are accounted for in health care. The Faculty of Health of Witten/Herdecke University proposes the term "integrative and personalised health care" for such a holistic form of PM. PMID- 22930196 TI - [Improved opportunities for the identification of people with a migrant background for mortality research using the example of Bremen]. AB - BACKGROUND: 19.6% of Germany's population has a "migrant" background. Comprehensive epidemiological research on health and health development of this large, heterogeneous and increasingly important population group in Germany is still deficient. There is a lack of results on mortality and morbidity, particularly concerning chronic diseases and disease processes. OBJECTIVE: The aim of this paper is to combine and to compare already applied methods with new methodological approaches for determining the vital status and the mortality of immigrants from Turkey and the former Soviet Union. METHODS: For this purpose we used data from the state of Bremen (666 709 residents, last update 2010). We examined 2 methodological aspects: (i) possibilities for identifying immigrant background in the data of residents' registration office with different methods (onomastic, toponomastic, etc.) and (ii) opportunities for record linkage of the obtained data with the Bremen mortality index. RESULTS: Immigrants from Turkey and the former Soviet Union were successfully identified in databases of the residents' registration office by a combination of different methods. The combination of different methodological approaches proved to be considerably better than using one method only. Through the application of a name-based algorithm we found that Turkish immigrants comprise 6.9% of the total population living in Bremen. By combining the variables "citizenship" and "country of birth" the total population proportion of immigrants from the former Soviet Union was found to be 5%. We also identified the deceased immigrant population in Bremen. The information obtained from residents' registration office could be successfully linked by death register number with the data of the Bremen mortality index. This information can be used in further detailed mortality analyses. CONCLUSION: The results of this analysis show the existing opportunities to consider the heterogeneity of the German population in mortality research, especially by means of combination of different methods to identify the immigrant background. PMID- 22930197 TI - Long-term efficacy and safety of arsenic trioxide for first-line treatment of elderly patients with newly diagnosed acute promyelocytic leukemia. AB - BACKGROUND: The prognosis of acute promyelocytic leukemia (APL) in the elderly is poorer than that of younger patients after treatment with all-trans retinoic acid plus chemotherapy, which is the current standard therapy for APL. A significantly higher mortality during consolidation therapy was found, which is mainly due to deaths from sepsis following chemotherapy-induced myelosuppression. METHODS: A total of 33 patients aged 60 years or older with de novo APL were treated with single-agent arsenic trioxide (ATO) for remission induction and postremission therapy. The postremission therapy continued for up to 4 years. RESULTS: Twenty nine patients (87.9%) achieved a hematologic complete remission, and the most common adverse event during remission induction was leukocytosis (63.6%). Definite differentiation syndrome was observed in 5 patients. Nonhematologic adverse events were all manageable and reversible. Twenty-eight patients proceeded to postremission therapy. Adverse effects during postremission therapy were mild, transient, and no treatment was required. No patients died from ATO related toxicities. With a median follow-up of 99 months, the 10-year cumulative incidence of relapse, overall survival, disease-free survival, and cause-specific survival were 10.3%, 69.3%, 64.8%, and 84.8%, respectively, which are comparable with those in the younger APL partners. No significant risks for development of chronic arsenicosis or second malignancy were observed during the follow-up period. CONCLUSIONS: The results indicate that the single-agent ATO regimen is safe and effective with long-term durable remission, and could be used as first line treatment for elderly patients with de novo APL. PMID- 22930198 TI - Microfluidic photoelectrocatalytic reactors for water purification with an integrated visible-light source. AB - This paper reports experimental studies using the photoelectrocatalytic effect to eliminate a fundamental limit of photocatalysis - the recombination of photo excited electrons and holes. The fabricated reactor has a planar reaction chamber (10 * 10 * 0.1 mm(3)), formed by a blank indium tin oxide glass slide, an epoxy spacer and a BiVO(4)-coated indium tin oxide glass substrate. A blue light emitting diode panel (emission area 10 * 10 mm(2)) is mounted on the cover for uniform illumination of the reaction chamber. In the experiment, positive and negative bias potentials were applied across the reaction chamber to suppress the electron/hole recombination and to select either the hole-driven or electron driven oxidation pathway. The negative bias always exhibits higher performance. It is observed that under -1.8 V the degradation rate is independent of the residence time, showing that the accompanying electrolysis can solve the oxygen deficiency problem. The synergistic effect of photocatalysis and electrocatalysis is observed to reach its maximum under the bias potential of +/- 1.5 V. The photoelectrocatalytic microreactor shows high stability and may be scaled up for high-performance water purification. PMID- 22930199 TI - Pulmonary inflammation in mice with collagen-induced arthritis is conditioned by complete Freund's adjuvant and regulated by endogenous IFN-gamma. AB - Following immunization with collagen II (CII) in complete Freund's adjuvant (CFA), DBA/1 mice develop arthritis of major joints. This collagen-induced arthritis (CIA) is used as a model for rheumatoid arthritis (RA) in man. Inflammatory changes in lung tissue commonly occur in RA. However, evidence for pulmonary inflammation in CIA is scarce and ambiguous. Here, we demonstrate pulmonary inflammation accompanying CIA in wild-type DBA/1 mice. In IFN-gamma receptor-deficient (IFN-gammaR KO) mice, inflammation was more frequent and more severe. Injection of CFA only (without CII) proved to be as efficient in eliciting pulmonary inflammation as immunization with CFA + CII, though being less effective in causing arthritis. Significant correlation in severity between joint and pulmonary involvement could not be demonstrated. Macroscopic, microscopic, and functional characteristics of pulmonary inflammation in the mice resembled those seen in human RA. Increased inflammation in IFN-gammaR KO mice was accompanied by augmented expression of various cytokines and chemokines, as measured by RT-PCR on affected tissue. Treatment with a TNF-alpha inhibitor ameliorated lung pathology. We conclude that CIA in DBA/1 mice is accompanied by pulmonary inflammation. Although both disease processes are kept in check by endogenous IFN-gamma, lack of strict parallelism indicates that overlap in their pathogeneses is partial. PMID- 22930201 TI - Daylight photodynamic therapy in private practice in Switzerland: gain without pain. PMID- 22930202 TI - Unified approach to catechin hetero-oligomers: first total synthesis of trimer EZ EG-CA isolated from Ziziphus jujuba. AB - A catechin hetero-trimer isolated from Ziziphus jujuba has been synthesized. Among three constituent monomers, (-)-epiafzelechin and (-)-epigallocatechin were prepared by de novo synthesis. Trimer formation relied on the unified approach to oligomers based on the bromo-capping and the orthogonal activation, reaching the reported structure of the natural product. PMID- 22930203 TI - Ethylene polymerization by 2-iminopyridylnickel halide complexes: synthesis, characterization and catalytic influence of the benzhydryl group. AB - A series of 2-(2-benzhydrylbenzenamino)pyridine ligands (L1-L13) was synthesized and used as bidentate N^N ligands with nickel halides to afford the corresponding nickel dihalide complexes L(2)Ni(2)Cl(4) C1-C13 and L(2)NiBr(2) D1-D13. All ligands and complexes were characterized by IR and NMR spectroscopy, and by elemental analysis. The molecular structures of the representative complexes C1.2CH(3)OH, C5.2H(2)O, D4, D7 and D9 were confirmed by single-crystal X-ray diffraction studies. Upon activation with either methylaluminoxane (MAO) or ethylaluminium sesquichloride (Et(3)Al(2)Cl(3), EASC), these nickel pre-catalysts exhibited high activities (up to the range of 10(7) g mol(-1) (Ni) h(-1)) towards ethylene polymerization, producing branched polyethylenes with narrow polydispersity. PMID- 22930204 TI - Diet and fatty acid pattern among patients with SLE: associations with disease activity, blood lipids and atherosclerosis. AB - OBJECTIVE: As atherosclerosis is increased in systemic lupus erythematosus (SLE) we compared dietary habits in patients with SLE with controls, and in the patients studied associations of diet components, especially fatty acids (FAs), with disease activity, serum lipids and carotid plaque presence. METHODS: In all 114 patients with SLE and 122 age- and sex-matched population-based controls answered a food frequency questionnaire (FFQ). Subcutaneous abdominal fat cell aspiration was analysed as to FA content and plaque occurrence was determined by B-mode ultrasound. RESULTS: The total diet energy intake did not differ between patients and controls. However, the patients with SLE reported a higher intake of carbohydrate, lower fibre intake and lower intake of omega-3 and omega-6, than controls (p < 0.05). In the patients, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in adipose tissue (AT) correlated negatively with disease activity (SLEDAI), r = -0.36, p = < 0.001 and r = -0.33, p = < 0.001, respectively. AT omega-3 was further positively associated with serum apoA1, r = 0.29, p = 0.004, whereas AT omega-6 showed a negative association, r = -0.21, p = 0.040. These FAs also had opposite associations with plaque presence, EPA and were DHA negative, r = -0.32, p = 0.002 and r = -0.33, p = 0.001, respectively, and omega-6 positive, r = 0.22, p = 0.027. The carbohydrate intake was positively correlated to AT omega-6, r = 0.38, p < 0.001, and negatively with serum apoA1, r = -0.27, p = 0.005. CONCLUSION: The macronutrient dietary pattern is different in SLE as compared with controls. The low intake of omega-3 and high intake of carbohydrate among patients with SLE appear to be associated with worse disease activity, adverse serum lipids and plaque presence. PMID- 22930205 TI - Catastrophic antiphospholipid syndrome triggered by fulminant disseminated herpes simplex infection in a patient with systemic lupus erythematosus. AB - Infections are considered one of the most common causes of morbidity and mortality in patients with systemic lupus erythematosus (SLE), and occasionally can trigger a catastrophic antiphospholipid syndrome (APS). We describe a 22-year old SLE patient with lupus nephritis under immunosuppressant therapy and asymptomatic carrier of antiphospholipid antibodies, who was admitted with tonsillitis and acute hepatitis, developing multiorgan failure in a few hours. Postmortem examination revealed hepatic necrosis, tonsillitis, pharyngitis and uterine cervicitis caused by herpes simplex virus (HSV) together with microthrombosis in lungs and glomerular arterioles, suggesting the diagnosis of fulminant HSV disseminated infection and catastrophic APS. PMID- 22930206 TI - Pure cutaneous lupus erythematosus in a population of African descent in French Guiana: a retrospective population-based description. AB - The objective of this study was to examine the characteristics of cutaneous lupus erythematosus, excluding systemic lupus erythematosus (SLE), in patients of African descent. Indeed, since the description of subacute cutaneous lupus erythematosus (SCLE), which had been included in chronic cutaneous lupus erythematosus (CCLE), there has been no description of the disease in black patients. In 2000, we performed a retrospective epidemiological study by querying multiple sources to identify all patients with lupus in French Guiana--a part of France in South America having western living conditions, free healthcare and 157,000 inhabitants, most of whom are of African origin. We found 45 patients with pure cutaneous lupus, which included CCLE (mostly discoid), SCLE and bullous lupus. The disease characteristics of these patients exhibited few differences compared with those of the Caucasian patients cited in the literature. However, the age of onset for our patients of African descent was younger than that of Caucasian patients. In contrast to the race-related differences reported for SLE, we found no major differences in terms of demographic, clinical and biological presentation between this cohort of pure cutaneous lupus erythematosus patients of African origin and Caucasian patients with similar forms of lupus. PMID- 22930207 TI - Understanding the redox behaviour of PbCrO4 and its application in selective hydrogen combustion. AB - The performance of PbCrO(4) during reduction/oxidation cycles has been studied over the temperature range 673-873 K. During thermal treatment in an inert atmosphere, PbCrO(4) is stable up to 773 K. At higher temperatures, it decomposes rapidly and irreversibly to Pb(2)(CrO(4))O. Moreover, the redox cycling of Pb(2)(CrO(4))O is also irreversible at 873 K when the reduction semi-reaction is prolonged beyond 3 min. Taking a standard 2 min cyclic treatment, we demonstrate that the surface reduction/oxidation of Pb(2)(CrO(4))O is exothermic between 773 873 K. In contrast, the redox cycling of PbCrO(4) is endothermic at 673 K. These findings demonstrate for the first time the potential of Pb(2)(CrO(4))O as a solid oxygen reservoir for the oxidative dehydrogenation of alkanes; especially at T >= 773 K, where H(2) oxidation by Pb(2)(CrO(4))O is exothermic. Preliminary kinetic studies suggest that Pb(2)(CrO(4))O reduction and oxidation both proceed through a "3D diffusion of the reacting front" mechanism. Our results open up opportunities for developing energy-efficient oxidative dehydrogenation routes to commercially important olefins. PMID- 22930209 TI - Rubeotic glaucoma and what else should be worried about? PMID- 22930210 TI - Do plain radiographs correlate with CT for imaging of cam-type femoroacetabular impingement? AB - BACKGROUND: Three-dimensional imaging (CT and MRI) is the gold standard for detecting femoral head-neck junction malformations in femoroacetabular impingement, yet plain radiographs are used for initial diagnostic evaluation. It is unclear, however, whether the plain radiographs accurately reflect the findings on three-dimensional imaging. QUESTIONS/PURPOSES: We therefore: (1) investigated the correlation of alpha angle measurements on plain radiographs and radial reformats of CT scans; (2) determined which radiographic views are most sensitive and specific in detecting head-neck deformities present on CT scans; and (3) determined if specific radiographic views correlated with specific locations on the radial oblique CT scan. METHODS: We retrospectively reviewed 41 surgical patients with preoperative CT scans (radial oblique reformats) and plain radiographs (AP pelvis, 45 degrees Dunn, frog lateral, and crosstable lateral). Alpha angles were measured on plain radiographs and CT reformats. RESULTS: The complete radiographic series was 86% to 90% sensitive in detecting abnormal alpha angles on CT. The maximum alpha angle on plain radiographs was greater than that of CT reformats in 61% of cases. Exclusion of the crosstable lateral did not affect the sensitivity (86%-88%). The Dunn view was most sensitive (71%-80%). The frog lateral showed the best specificity (91%-100%). Substantial correlations (intraclass correlation coefficients, 0.64-0.75) between radiograph and radial oblique CT position were observed, including AP/12:00 (superior), Dunn/1:00 (anterolateral), frog/3:00 (anterior), and crosstable/3:00 (anterior). CONCLUSIONS: For diagnostic and treatment purposes, a three-view radiographic hip series (AP pelvis, 45 degrees Dunn, and frog lateral) effectively characterizes femoral head-neck junction malformations. LEVEL OF EVIDENCE: Level II, diagnostic study. See Guidelines for Authors for a complete description of levels of evidence. PMID- 22930211 TI - The 2012 Otto Aufranc Award: The interpretation of metal ion levels in unilateral and bilateral hip resurfacing. AB - BACKGROUND: The interpretation of metal ion concentrations and their role in clinical management of patients with metal-on-metal implants is still controversial. QUESTIONS/PURPOSES: We questioned whether patients undergoing hip resurfacing with no clinical problems could be differentiated from those with clinical (pain, loss of function) and/or radiographic (component malpositioning, migration, bone loss), problems based on metal ion levels, and if there was a threshold metal level that predicted the need for clinical intervention. Furthermore, we asked if patient and implant factors differed between these functional groups. METHODS: We retrospectively identified 453 unilateral and 139 bilateral patients with ion measurements at minimum followup of 12 months (mean, 4.3 years; range, 1-12.9 years). Patients were designated as well functioning or poorly functioning based on strict criteria. The acceptable upper levels within the well-functioning group were determined from the 75th percentile plus 1.5* interquartile range. The sensitivity and specificity of these levels to predict clinical problems were calculated. RESULTS: Well-functioning group ions were lower than the poorly functioning group ion levels. The acceptable upper levels were: chromium (Cr) 4.6 MUg/L, cobalt (Co) 4.0 MUg/L unilateral and Cr 7.4 MUg/L, Co 5.0 MUg/L bilateral. The specificity of these levels in predicting poor function was high (95%) and sensitivity was low (25%). There were more males in the well-functioning group and more females and smaller femoral components in the poorly functioning group. CONCLUSIONS: Metal levels higher than these proposed safe upper limits can predict problems with metal-on-metal resurfacings and are important parameters in the management of at-risk patients. LEVEL OF EVIDENCE: Level II, diagnostic study. See Guidelines for Authors for a complete description of levels of evidence. PMID- 22930212 TI - Immediate postoperative radiographs after shoulder arthroplasty are often poor quality and do not alter care. AB - BACKGROUND: It is technically difficult to obtain high-quality, postoperative shoulder radiographs immediately after surgery. Further, poor-quality radiographs may be unlikely to change clinical practice or improve patient outcomes. We therefore questioned the value of routine postoperative radiographs after shoulder arthroplasty. QUESTIONS/PURPOSES: We asked whether (1) postanesthesia care unit (PACU) radiographs can reasonably serve as a baseline for future studies; and (2) routine PACU radiographs change clinical care. (3) We also determined the charges associated with routine PACU radiographs and formal radiographic interpretation of these images. METHODS: We retrospectively compared the radiographs of 283 patients who had shoulder arthroplasties (Group 1) who underwent PACU radiographs with those of 241 patients (Group 2) who had their first postoperative radiographs at a later date. Radiographs were compared for quality, ability to serve as a baseline, and their influence on clinical course. Orthopaedic evaluation of each radiograph and the radiographic report were compared and charges were analyzed. RESULTS: All images in Group 1 were single view radiographs (88% internal rotation), most were underpenetrated (71%); no images changed postoperative management or were considered adequate to serve as a baseline. Group 2 radiographs were multiview radiographs, and 83% were deemed adequate to serve as baseline radiographs. Radiographic interpretation of immediate postoperative radiographs did not change the clinical course or treatment. The charges billed from radiographic evaluation in this study were $64,524 for Group 1. CONCLUSIONS: Routine PACU radiographs, in the absence of a specific indication, may result in poor-quality images. Elimination of these radiographs and radiographic interpretation after shoulder arthroplasty may reduce charges without changing clinical care. LEVEL OF EVIDENCE: Level III, diagnostic study. See Guidelines for Authors for a complete description of levels of evidence. PMID- 22930213 TI - Measuring outcomes in urogynecological surgery: "perspective is everything". AB - Over 10 years have passed since the first US National Institutes of Health consensus panel considered the standardization of definitions of pelvic floor conditions and the criteria utilized for reporting pelvic floor research study outcomes. The literature is replete with pelvic floor outcome studies; however, a consistent standardized approach to the evaluation of patients and characterization of outcomes is still needed. The purpose of this overview is to describe how the use of outcome measures has evolved over time and to attempt to help readers utilize the best measures for their clinical and research needs. PMID- 22930214 TI - Laparoscopic sacrocolpopexy versus transvaginal mesh for recurrent pelvic organ prolapse. AB - Both expert surgeons agree with the following: (1) Surgical mesh, whether placed laparoscopically or transvaginally, is indicated for pelvic floor reconstruction in cases involving recurrent advanced pelvic organ prolapse. (2) Procedural expertise and experience gained from performing a high volume of cases is fundamentally necessary. Knowledge of outcomes and complications from an individual surgeon's audit of cases is also needed when discussing the risks and benefits of procedures and alternatives. Yet controversy still exists on how best to teach new surgical techniques and optimal ways to efficiently track outcomes, including subjective and objective cure of prolapse as well as perioperative complications. A mesh registry will be useful in providing data needed for surgeons. Cost factors are also a consideration since laparoscopic and especially robotic surgical mesh procedures are generally more costly than transvaginal mesh kits when operative time, extra instrumentation and length of stay are included. Long-term outcomes, particularly for transvaginal mesh procedures, are lacking. In conclusion, all surgery poses risks; however, patients should be made aware of the pros and cons of various routes of surgery as well as the potential risks and benefits of using mesh. Surgeons should provide patients with honest information about their own experience implanting mesh and also their experience dealing with mesh-related complications. PMID- 22930215 TI - Effects of propiverine hydrochloride, an anticholinergic agent, on urethral continence mechanisms and plasma catecholamine concentration in rats. AB - INTRODUCTION AND HYPOTHESIS: Anticholinergics are used to treat overactive bladder. Anticholinergic agents such as propiverine hydrochloride reportedly increase plasma catecholamine levels in rats. It is also known that active urethral closure mechanisms prevents stress urinary incontinence (SUI), which is enhanced by central and peripheral noradrenergic system activation. Therefore, we examined the influence of propiverine hydrochloride on urethral anti-incontinence function in rats. METHODS: Adult female rats were divided into propiverine and vehicle-treated groups. The propiverine group was given propiverine orally once a day for 2 weeks, after which urethral function and plasma concentrations of catecholamine (dopamine, norepinephrine, epinephrine) were tested. RESULTS: Urethral baseline pressure measured by a microtransducer-tipped urethral catheter and leak-point pressure during passive intravesical pressure elevation were significantly increased in the propiverine group compared with the vehicle group. Plasma norepinephrine and epinephrine levels in the propiverine group were also significantly increased. CONCLUSIONS: Propiverine treatment that increases plasma catecholamine levels could contribute to improvement of SUI conditions by increasing urethral resistance. PMID- 22930216 TI - Lower exposure rates of partially absorbable mesh compared to nonabsorbable mesh for cystocele treatment: 3-year follow-up of a prospective randomized trial. AB - INTRODUCTION AND HYPOTHESIS: In surgery for pelvic organ prolapse (POP) the use of alloplastic meshes has become common. Among possible complications, mesh exposure is the most frequent problem. It is hypothesized that exposure rates are correlated to mesh weight and the amount of foreign material. Therefore, we conducted a prospective open-label randomized multicenter trial comparing a conventional polypropylene mesh (PP) with a partially absorbable polypropylene mesh (PA) for cystocele treatment. METHODS: A total of 200 patients with POP > stage I were randomized either to a conventional or a partially absorbable mesh. Exposure rates were observed after 3, 12, and 36 months and correlated to mesh material, patient characteristics, intraoperative data, and treatment centers. Furthermore, management of mesh exposure, satisfaction with surgery, and postoperative pain were evaluated. RESULTS: At all follow-up intervals mesh exposure rate was smaller in the group of the partially absorbable mesh (3 months PP 11.3 % vs PA 3.2 %, p=0.0492; 12 months 6.6 % vs 6.3 %; 36 months 7.5 % vs 3.4 %). Over the course of time, mesh exposure was observed in 27 patients, with surgical intervention necessary in 11 patients. The rate of recurrent POP was higher (p>0.05) in patients with the partially absorbable mesh. The majority of patients were fully satisfied with the operation (52.8 %) and had no pelvic floor pain (67.5 %). CONCLUSION: In this prospective, randomized trial with a long-term follow-up there was a low exposure rate in both treatment groups with a trend toward fewer exposures in the group of the partially absorbable mesh. PMID- 22930217 TI - Population based trends in procedures following sling surgery for urinary incontinence. AB - INTRODUCTION AND HYPOTHESIS: To investigate practice patterns and variation associated with sling removal/revision and urethrolysis on a population level. METHODS: We used CPT 4 codes and the State Ambulatory Surgery Database (SASD) to identify all ambulatory procedures for sling removal/revision and urethrolysis from 2004 to 2009 in Florida. Next, we calculated adjusted rates for these procedures and measured regional variation in rates at the level of the Hospital Service Area (HSA). RESULTS: During this time period, rates of secondary procedures following slings more than doubled from 3.2 per 100,000 to 6.5 per 100,000 population (p<0.001). There was a large amount of regional variation, with rates of these procedures varying more than 5-fold across HSAs. Regions that placed more slings did not necessarily have higher rates of secondary procedures following sling placement. CONCLUSIONS: The large amount of variability in rates of secondary procedures following slings signifies considerable uncertainty about the indications for these procedures. Further research is warranted to better explain potential sources for this variation in order to improve the quality of care surrounding midurethral sling placement and the recognition and treatment of its complications. PMID- 22930219 TI - Effects of exercise on S-IGA and URS in postmenopausal women. AB - 32 postmenopausal women were randomized to a 16-week home-based walking program or control group. Before and after the intervention, each subject completed a graded maximal treadmill test to establish VO(2)max and resting saliva was collected to determine levels of salivary immunoglobulin A. The 16-week walking program resulted in an increase in VO(2)max (+10.4%; p<0.01). Repeated measures ANOVA revealed a marked increase in the resting secretion rate of salivary immunoglobulin A (+37.4%; p<0.05) in the exercise group following training. Independent of study group, both before and after the intervention, the secretion rate of salivary immunoglobulin A ( - 32.3%) and saliva flow rate (- 29.3%) were reduced following acute maximal exercise (p<0.05). Weekly upper respiratory symptomatology logs revealed that the number of incidences of upper respiratory symptoms throughout the intervention period were the same and the duration per incidence (control: 5.3+/-1.5 days; exercise: 6.3+/-2.2 days) were similar between study groups. These findings in postmenopausal women support that the secretion rate of salivary immunoglobulin A and saliva flow rate are reduced immediately following maximal exercise. Moreover, a 16-week moderate intense walking program can increase the secretion of salivary immunoglobulin A without affecting upper respiratory symptomatology. PMID- 22930220 TI - Expression of aldehyde dehydrogenase 1 as a marker of mammary stem cells in benign and malignant breast lesions of Ghanaian women. AB - BACKGROUND: Breast cancers that are negative for the estrogen receptor (ER), the progesterone receptor (PR), and the HER2 (human epidermal growth factor receptor 2) marker are more prevalent among African women, and the biologically aggressive nature of these triple-negative breast cancers (TNBCs) may be attributed to their mammary stem cell features. Little is known about expression of the mammary stem cell marker aldehyde dehydrogenase 1 (ALDH1) in African women. Novel data are reported regarding ALDH1 expression in benign and cancerous breast tissue of Ghanaian women. METHODS: Formalin-fixed, paraffin-embedded specimens were transported from the Komfo Anoyke Teaching Hospital in Kumasi, Ghana to the University of Michigan for centralized histopathology study. Expression of ER, PR, HER2, and ALDH1 was assessed by immunohistochemistry. ALDH1 staining was further characterized by its presence in stromal versus epithelial and/or tumor components of tissue. RESULTS: A total of 173 women contributed to this study: 69 with benign breast conditions, mean age 24 years, and 104 with breast cancer, mean age 49 years. The proportion of benign breast conditions expressing stromal ALDH1 (n = 40, 58%) was significantly higher than those with cancer (n = 44, 42.3%) (P = .043). Among the cancers, TNBC had the highest prevalence of ALDH1 expression, either in stroma or in epithelial cells. More than 2-fold higher likelihood of ALDH1 expression was observed in TNBC cases compared with other breast cancer subtypes (odds ratio = 2.38, 95% confidence interval 1.03-5.52, P = .042). CONCLUSIONS: ALDH1 expression was higher in stromal components of benign compared with cancerous lesions. Of the ER-, PR-, and HER2-defined subtypes of breast cancer, expression of ALDH1 was highest in TNBC. PMID- 22930221 TI - Strong and sustained effector function of memory- versus naive-derived T cells upon T-cell receptor RNA transfer: implications for cellular therapy. AB - Current protocols used to select CMV-specific T cells for adoptive immunotherapy focus on virus-specific memory T cells from seropositive donors. However, this strategy is not feasible in patients undergoing allogeneic haematopoietic stem cell transplantation (HSCT) from CMV-seronegative donors. Here, we redirected T cells of CMV-seronegative donors with a human genetically engineered TCR recognizing an HLA-A*0201-binding peptide epitope of CMVpp65. To facilitate clinical translation of this approach, we used a non-viral expression system based on in vitro transcribed RNA and electroporation. Although memory and naive derived T-cell subsets were both efficiently transfected by TCR-RNA, memory derived T cells showed much stronger levels of HLA-A*0201-restricted cytolytic activity to CMV-infected fibroblasts and maintained acquired function for 5-10 days. In addition to redirection of CD8(+) cytotoxic T cells, TCR-RNA transfection was capable of redirecting CD4(+) T cells into potent Ag-specific Th cells that efficiently triggered maturation of DCs. Our data suggest that memory rather than naive-derived T cells are the preferred subset for transient TCR expression by RNA electroporation, providing more efficient and sustained virus-specific CD4(+) and CD8(+) T-cell function. CMV TCR-RNA may represent a suitable therapeutic 'off-the-shelf' reagent to be used in severe CMV infections of HSCT patients when endogenous CMV-specific T-cell immunity is insufficient. PMID- 22930222 TI - Sudden onset of severe anemia in a patient with cystic fibrosis. PMID- 22930223 TI - Commentary. Re: Sudden onset of severe anemia in a patient with cystic fibrosis. PMID- 22930224 TI - Commentary. Re: Sudden onset of severe anemia in a patient with cystic fibrosis. PMID- 22930225 TI - Peter Wilding. PMID- 22930226 TI - A 62-year-old woman with a 6-month history of jaundice. PMID- 22930227 TI - Multiplexing the Raman way. PMID- 22930230 TI - Pablo Picasso and the universe of art. PMID- 22930231 TI - Polymerization-based signal amplification under ambient conditions with thirty five second reaction times. AB - Although polymerization-based amplification (PBA) has demonstrated promise as an inexpensive technique for use in molecular diagnostics, oxygen inhibition of radical photopolymerization has hindered its implementation in point-of-care devices. The addition of 0.3-0.7 MUM eosin to an aqueous acrylate monomer solution containing a tertiary amine allows an interfacial polymerization reaction to proceed in air only near regions of a test surface where additional eosin initiators coupled to proteins have been localized as a function of molecular recognition events. The dose of light required for the reaction is inversely related to eosin concentration. This system achieves sensitivities comparable to those reported for inert gas-purged systems and requires significantly shorter reaction times. We provide several comparisons of this system with other implementations of polymerization-based amplification. PMID- 22930233 TI - Field-induced slow magnetic relaxation in chiral seven-coordinated mononuclear lanthanide complexes. AB - Four couples of enantiomerically pure chiral seven-coordinated mononuclear lanthanide complexes, [(L(OEt))Dy((R,R)-Salphen)](2).3H(2)O (1, L(OEt) = [(Cp)Co(P(O)(OEt)(2))(3)], Cp = cyclopentadiene, Salphen = N,N'-1,2 diphenylethylenebis(salicylideneiminato) dianion), [(L(OEt))Dy((S,S) Salphen)](2).3H(2)O (2), [(L(OEt))Dy((R,R)-5-Cl-Salcy)].CH(3)OH.1/8H(2)O (3, Salcy = N,N'-(1,2-cyclohexanediylethylene)bis(salicylideneiminato) dianion), [(L(OEt))Dy((S,S)-5-Cl-Salcy)].CH(3)OH.1/8H(2)O (4), [(L(OEt))Tb((R,R)-5-Cl Salcy)].CH(3)OH.1/8H(2)O (5), [(L(OEt))Tb((S,S)-5-Cl-Salcy)].CH(3)OH.1/8H(2)O (6), [(L(OEt))Ho((R,R)-5-Cl-Salcy)].CH(3)OH.1/8H(2)O (7) and [(L(OEt))Ho((S,S)-5 Cl-Salcy)].CH(3)OH.1/8H(2)O (8), have been successfully synthesized by using tetradentate chiral salen-type ligands and the Klaui's tripodal ligand of L(OEt). Structural analyses reveal that all compounds have a typical double-decker sandwich structure, and the Ln(iii) ions exhibit a rare seven-coordinated mode, situating in a distorted monocapped triangular prism polyhedron. Circular dichroism (CD) spectra confirm the enantiomeric nature of the optically active complexes and demonstrate that the chirality is successfully transferred from the ligand to the coordination environment of the Ln(iii) ions. Field-induced slow relaxation of the magnetization is observed for complexes 1-4, suggesting that they can be rare chiral single-ion magnets (SIMs) based on the seven-coordinated lanthanide ions. PMID- 22930234 TI - Despondency among HIV-positive older men and women in Uganda. AB - Forty people over 60 years of age took part in longitudinal research over the course of a year on the impact of the HIV epidemic in southern Uganda. In this paper we focus mainly on the data from 26 of the 40 who were HIV-positive. While we observed that feelings of depression were frequently experienced by many of the people in our study, the state of 'being depressed' was not constant. Participants regularly expressed economic frustration (because of a lack of money to buy food and other commodities including sugar and soap); medical problems (including those related to HIV) as well as old age, the burden of dependents (including concerns about school fees for grandchildren), feelings of sadness and isolation, and a lack of support from others, as well as stigma, whether real or perceived. However, while worries, sorrow and despondent thoughts were reported in many of the interviews across the study, moods fluctuated moving from happiness and hope, to sadness and despair, from month to month. Concerns regarding the psychological wellbeing amongst older people, including those living with HIV and older carers in Uganda deserve greater attention. PMID- 22930236 TI - [Chronic central serous chorioretinopathy (cCSC): differential diagnosis to choroidal neovascularisation (CNV) secondary to age-related macular degeneration (AMD)]. AB - Central neurosensory detachments (NSD) with time-dependent height constitute a disease called central serous chorioretinopathy (CSC), if not arising from uveitis, choroidal neovascularisations (CNV) or leaking retinal vessels. In 10 % of these patients, CSC develops into a chronic disease with recurrent NSD, atrophy of photoreceptors and severe drop in visual acuity. This review article summarises recent progress in understanding this disease and its appearance in funduscopy, FLA, ICG, OCT, autofluorescence as well as its progress, therapy and possible development into secondary CNV. The provided examples illustrate the progression of acute CSC into chronic CSC and with CNV over years. The different appearance of polypoidal choroidal vasculopathy (PCV) in ICG and some of the signs of atypical chronic CSC are discussed. To distinguish between cCSC and wet AMD--both exhibiting leakage in FLA--typical signs are helpful, e.g., "gravitational tracks", retinal precipitates and missing drusen. However, in small lesions, it may be difficult or almost impossible to ensure the correct diagnosis of the underlying disease. The same holds for occult and classic secondary CNV in cCSC vs. CNV in AMD, where photodynamic therapy (PDT) can be successful only in cCSC-CNV and in cCSC without CNV. Corticosteroids often lead to further impairment, even in cases of atypical cCSC, when frequently misdiagnosed as uveitis. As a duration of NSD of more than 4 months is suspected to induce an impairment of photoreceptors, regular examinations are necessary not only in chronic CSC but also after acute CSC (as this form can develop into chronic CSC), while effective therapies are available to resolve the NSD (PDT, anti-VEGF). PMID- 22930235 TI - Catalytic asymmetric synthesis of butane diacetal-protected (4S,5S) dihydroxycyclohexen-1-one and use in natural product synthesis. AB - Due to the lack of availability of unnatural (+)-quinic acid as a starting material, a 6-step synthesis of butane diacetal-protected (4S,5S) dihydroxycyclohexen-1-one (formally derived from (+)-quinic acid) has been devised. The key catalytic asymmetric step involves a chiral Co-salen-catalysed epoxide ring-opening reaction. (4S,5S)-Dihydroxycyclohexen-1-one was utilised in the synthesis of two cyclohexenone natural products isolated from the mycelia of Lasiodiplodia theobromae. PMID- 22930237 TI - Carbon/carbon nanocomposites fabricated by base catalyzed twin polymerization of a Si-spiro compound on graphite sheets. AB - Defect-free microporous carbon layers on graphite can be produced by DABCO catalyzed twin polymerization of 2,2'-spirobi[4H-1,3,2-benzodioxasiline] in a slurry polymerization and subsequent thermal transformation of the resulting phenolic resin into carbon. PMID- 22930239 TI - Changes in short-term health-related quality of life in women undergoing gynecologic oncologic laparotomy: an associated factor analysis. AB - PURPOSE: The primary purpose of this study is to evaluate health-related quality of life (HR-QOL) of gynecologic cancer patients undergoing laparotomy. METHODS: Women who underwent laparotomy by gynecologic cancer completed the European Organization for Research and Treatment of Cancer (EORTC) Quality of life questionnaires (QLQ-C30 and QLQ-OV28) presurgery and at 1 month. RESULTS: Of the 181 women studied between January 2007 and March 2008, 116 women (64.1%) had ovarian cancer, 27 (14.9%) had cervical cancer, and 29 (16.0%) had endometrial cancer. By 1 month post-surgery, there was a significant decrease in HR-QOL on the global, abdominal/gastrointestinal (GI) score, body image, chemotherapy side effects, and other single items of the OV28 questionnaire, as well as on physical, role and social functioning, fatigue, nausea and vomiting, pain, insomnia, constipation, appetite loss, and financial difficulties items on C30 questionnaires. Emotional functioning on C30 questionnaires was significantly improved 1 month after surgery. The majority of these items persisted 1 month after surgery only in patients with ovarian cancer. Abdominal/GI score on OV28 questionnaires as well as role and physical functioning on C30 questionnaires were significantly lower between baseline and postsurgical HR-QOL in women with other gynecologic malignancies. CONCLUSION: The results suggest a significant impact of HR-QOL among gynecologic cancer patients 1 month after laparotomy, particularly among those with ovarian cancer. PMID- 22930240 TI - Improved adherence with PTH(1-84) in an extension trial for 24 months results in enhanced BMD gains in the treatment of postmenopausal women with osteoporosis. AB - The purpose of this study is to examine the effect of PTH(1-84) treatment over 24 months followed by 12 months discontinuation on BMD, bone turnover markers, fractures and the impact of adherence on efficacy. INTRODUCTION: There is limited information about the effect of PTH(1-84) after 18 months and limited data about the impact of compliance on response to anabolic therapy. METHODS: Seven hundred and eighty-one subjects who received active PTH(1-84) in the Treatment of Osteoporosis with Parathyroid hormone trial for approximately 18 months were entered into a 6-month open-label extension. Thereafter, they were followed for 12 additional months after discontinuation of treatment. Endpoints examined included changes in BMD and biochemical markers. RESULTS: PTH(1-84) treatment over 24 months increased BMD at the lumbar spine by 6.8% above baseline (p<0.05).The total corresponding BMD increases at the hip and femoral neck were 1.1 and 2.2% above baseline. Larger increases in spine BMD were observed in participants with >=80% adherence to daily injections of PTH(1-84) (8.3% in adherent vs 4.9% in poorly adherent patients). Total hip BMD gains were 1.7% in adherent vs 0.6% in poorly adherent participants. Markers of bone turnover (BSAP and NTx) peaked 6 months after starting PTH(1-84) treatment and declined slowly but remained above baseline at 24 months. After discontinuation of PTH(1-84) treatment (at 24 months), bone turnover markers returned to near baseline levels by 30 months. The adherent group sustained significantly fewer fractures than the poorly adherent group. CONCLUSIONS: PTH(1-84) treatment over 24 months results in continued increases in lumbar spine BMD. Adherence to treatment with PTH(1-84) for up to 24 months is also associated with greater efficacy. PMID- 22930241 TI - Quality of fracture risk assessment in post-fracture care in Ontario, Canada. AB - As fracture risk assessment is a basis for treatment decisions, accurate risk assessments on bone mineral density (BMD) reports are important. Over 50 % of sampled BMD reports for Ontarians with fracture histories underestimated fracture risk by a single category. Risk assessments in Ontario may not accurately inform treatment recommendations. INTRODUCTION: The shifting emphasis on fracture risk assessment as a basis for treatment recommendations highlights the importance of ensuring that accurate fracture risk assessments are present on reading specialists' BMD reports. This study seeks to determine the accuracy of fracture risk assessments on a sample of BMD reports from 2008 for individuals with a history of fracture and produced by a broad cross section of Ontario's imaging laboratories. METHODS: Forty-eight BMD reports for individuals with documented history of fragility fracture were collected as part of a cluster randomized trial. To compute fracture risk, risk factors, and BMD T-scores from reports were abstracted using a standardized template and compared to the assessments on the reports. Cohen's kappa was used to score agreement between the research team and the reading specialists. RESULTS: The weighted kappa was 0.21, indicating agreement to be at the margin of "poor to fair." More than 50 % of the time, reported fracture risks did not reflect fracture history and were therefore underestimated by a single category. Over 30 % of the reports containing a "low" fracture risk assessment were assessed as "moderate" fracture risk by the research team, given fracture history. Over 20 % of the reports with a "moderate" fracture risk were assessed as "high" by the research team, given fracture history. CONCLUSIONS: This study highlights the high prevalence of fracture risk assessments that are underestimated. This has implications in terms of fracture risk categorization that can negatively affect subsequent follow-up care and treatment recommendations. PMID- 22930242 TI - Life-course evidence of birth weight effects on bone mass: systematic review and meta-analysis. AB - A systematic review of the literature was performed in July 2011. Original papers based on longitudinal studies measuring spine, femoral neck, or total body bone mass by DXA were included (n = 17). Birth weight was positively associated with bone mass among children. The association was unclear among adolescents and weak among adults. This study aims to evaluate the association between birth weight and bone mass in future ages through a systematic review of literature and meta analysis. A systematic review of the literature was performed in July 2011 in Medline, Web of Science and LILACS bases using key terms: ("birth size" OR "birth weight" OR birthweight OR prematurity OR premature OR "gestational age") AND (osteoporosis OR "bone mass" OR "bone density" OR "bone mineral density" OR "bone mineral content" OR "bone area") AND (longitudinal OR cohort). Original papers based on longitudinal studies measuring lumbar spine, femoral neck or total body bone mass by dual-emission X-ray absorptiometry (DXA) were included. A meta analysis was performed using birth weight and bone mass density and/or content as continuous variables and adjusted for current height and/or weight. A total of 218 articles were retrieved from which 17 were selected and grouped into three categories according to age: studies with children; with adolescents and young adults, and studies with adults (older than 25). Five papers were included in the meta-analysis. Positive association between birth weight and bone mass was clear among children, unclear among adolescents, and weak among adults. The effect on bone mass content was stronger than those on body mass density regardless of age. Birth weight influences positively bone health in later life. Preventive health policies dealing with early-life modifiable risk factors, as birth weight, should be encouraged to attain an optimal peak bone mass as an strategy to decrease osteoporosis in the elderly. PMID- 22930243 TI - Recommendations for including multiple symptoms as endpoints in cancer clinical trials: a report from the ASCPRO (Assessing the Symptoms of Cancer Using Patient Reported Outcomes) Multisymptom Task Force. AB - The multiple symptoms arising from cancer and its treatment impose significant distress for patients. However, in clinical research, there is no agreed-upon way of assessing and presenting the effects of treatment on multiple symptoms, as either individual scores or a composite score. The ASCPRO (Assessing the Symptoms of Cancer Using Patient-Reported Outcomes) Multisymptom Task Force was established to make recommendations about measuring multiple symptoms as outcomes in cancer clinical trials. The Multisymptom Task Force addressed how to choose the symptoms to be assessed and how multiple individual symptom scores or composite scores of several symptoms might be used as clinical trial outcomes. Consensus was reached on a definition of a multisymptom outcome, the problem of source attribution, and the need for a hypothesis-driven conceptual framework to measure multisymptom outcomes. Validated single-item and multi-item measures currently available or that can be easily generated for oncology use were deemed sufficient for measuring multiple symptoms. The relative value of a composite score versus a set of individual symptom scores was discussed, along with issues in developing and deploying such a composite measure. The results indicated that more research on combining scores of different symptoms is needed. Symptom data should be a required component of cancer clinical trials. Patient-reported symptoms provide a unique patient perspective on treatment benefit and risk that goes beyond clinician-reported adverse events. A representation of changes in multiple symptoms would clarify the impact of treatment and enhance the interpretation of cancer clinical trials for clinicians, patients, and those who make health care policy. PMID- 22930244 TI - Increased red cell turnover in a line of CD22-deficient mice is caused by Gpi1c: a model for hereditary haemolytic anaemia. AB - CD22, an inhibitory co-receptor of the BCR, has been identified as a potential candidate gene for the development of autoimmune haemolytic anaemia in mice. In this study, we have examined Cd22(tm1Msn) CD22-deficient mice and identified an increase in RBC turnover and stress erythropoiesis, which might be consistent with haemolysis. We then, however, eliminated CD22 deficiency as the cause of accelerated RBC turnover and established that enhanced RBC turnover occurs independently of B cells and anti-RBC autoanti-bodies. Accelerated RBC turnover in this particular strain of CD22-deficient mice is red cell intrinsic and appears to be the consequence of a defective allele of glucose phosphate isomerase, Gpi1(c). This form of Gpi1 was originally derived from wild mice and results in a substantial reduction in enzyme activity. We have identified the polymorphism that causes impaired catalytic activity in the Gpi1(c) allele, and biochemically confirmed an approximate 75% reduction of GPI1 activity in Cd22(-/ ) RBCs. The Cd22(-/-).Gpi1(c) congenic mouse provides a novel animal model of GPI1-deficiency, which is one of the most common causes of chronic non spherocytic haemolytic anaemia in humans. PMID- 22930245 TI - Optofluidic microsystems with integrated vertical one-dimensional photonic crystals for chemical analysis. AB - In this work, we report all-silicon, integrated optofluidic microsystems (OFMs) fabricated by electrochemical micromachining (ECM) technology, in which high aspect-ratio (HAR) photonic crystal (PhC) devices (i.e. micromirrors, optical cavities) are integrated by one-etching-step, together with microfluidic reservoirs/channels, for the infiltration of liquids in the PhC air gaps, and with fiber grooves for alignment/positioning of readout optical fibers in front of the PhC, on the same silicon die. This has not previously been reported in the literature, and opens up new ground in, though not limited to, the optofluidics field, due to the low-cost and high-flexibility of the ECM technology that allows optofluidic microsystem fabrication to be performed in any lab. Optofluidic characterization of PhC-OFMs by both capillary-action and pressure-driven operations is carried out through the measurement of the reflectivity spectra of HAR-PhCs upon injection of liquids featuring different refractive index values in the HAR-PhC air gaps, by using readout optical fibers positioned in the on-chip fiber grooves. High sensitivity and good limit of detection of PhC-OFMs are obtained for both capillary-action and pressure-driven operations. A best sensitivity value of 670 nm/RIU and a worst-case limit of detection of the order of 10(-3) RIU are measured, the former being comparable to state-of-the-art integrated refractive index sensors and the latter being limited by constraints of the experimental setup. The proof of concept about the biosensing potential of PhC-OFMs is given by successfully carrying out a sandwich assay based on antigen antibody interactions for the detection of the C-reactive protein (CRP) at a concentration value of 10 mg L(-1), which represents the boundary level between physiological and pathological conditions. PMID- 22930247 TI - Common pathophysiological mechanisms involved in luteal phase deficiency and polycystic ovary syndrome. Impact on fertility. AB - Luteal phase deficiency (LPD) is a consequence of the corpus luteum (CL) inability to produce and preserve adequate levels of progesterone. This is clinically manifested by short menstrual cycles and infertility. Abnormal follicular development, defects in neo-angiogenesis or inadequate steroidogenesis in the lutein cells of the CL have been implicated in CL dysfunction and LPD. LPD and polycystic ovary syndrome (PCOS) are independent disorders sharing common pathophysiological profiles. Factors such as hyperinsulinemia, AMH excess, and defects in angiogenesis of CL are at the origin of both LPD and PCOS. In PCOS ovulatory cycles, infertility could result from dysfunctional CL. The aim of this review was to investigate common mechanisms of infertility in CL dysfunction and PCOS. PMID- 22930249 TI - Impairment of ribosomal subunit synthesis in aminoglycoside-treated ribonuclease mutants of Escherichia coli. AB - The bacterial ribosome is an important target for many antimicrobial agents. Aminoglycoside antibiotics bind to both 30S and 50S ribosomal subunits, inhibiting translation and subunit formation. During ribosomal subunit biogenesis, ribonucleases (RNases) play an important role in rRNA processing. E. coli cells deficient for specific processing RNases are predicted to have an increased sensitivity to neomycin and paromomycin. Four RNase mutant strains showed an increased growth sensitivity to both aminoglycoside antibiotics. E. coli strains deficient for the rRNA processing enzymes RNase III, RNase E, RNase G or RNase PH showed significantly reduced subunit amounts after antibiotic treatment. A substantial increase in a 16S RNA precursor molecule was observed as well. Ribosomal RNA turnover was stimulated, and an enhancement of 16S and 23S rRNA fragmentation was detected in E. coli cells deficient for these enzymes. This work indicates that bacterial RNases may be novel antimicrobial targets. PMID- 22930251 TI - A novel copper-catalyzed reductive coupling of N-tosylhydrazones with H phosphorus oxides. AB - We report here a novel C(sp(3))-P bonds formation via copper-catalyzed reductive coupling of N-tosylhydrazones with H-phosphorus oxides. A variety of aliphatic and aromatic substrates bearing electron-rich and electron-deficient substituents affords phosphine oxide derivatives with moderate to good yields. This work suggests a new transformation of aldehydes/ketones via N-tosylhydrazones to organophosphorus compounds. PMID- 22930254 TI - Toxic epidermal necrolysis with some features of acute generalized exanthematous pustulosis. PMID- 22930253 TI - Randomized controlled trial of maintaining quality of life during radiotherapy for advanced cancer. AB - BACKGROUND: Psychosocial interventions often address only 1 domain of quality of life (QOL), are offered to patients with early-stage cancer, do not include the caregiver, and are delivered after cancer treatment has been completed. METHODS: In the current randomized controlled trial, 131 patients with advanced cancer who received radiotherapy and their caregivers were randomly assigned to either a 6 session, structured, multidisciplinary intervention arm or a standard care arm. The average age of the patients was 58 years, the majority were male (63%), and tumor types varied (gastrointestinal [37%], brain [22%], head and neck [16%], lung [13%], and other [12%]). The six 90-minute sessions addressed the 5 domains of QOL: cognitive, physical, emotional, social, and spiritual. The in-person intervention was followed by 10 brief telephone counseling sessions that took place over the next 6 months. RESULTS: Of the 117 patients who completed the study, overall QOL (assessed by Functional Assessment of Cancer Therapy-General [FACT-G]) at week 4 was significantly higher in the intervention group (n = 54) compared with the standard arm control group (n = 63) (75.2 vs 68.7; P = .02). The 10 brief telephone contacts did not appear to impact QOL because at week 27 the groups had identical QOL (means of 77.6 and 77.7, respectively). There was no effect of the intervention noted on caregiver QOL. CONCLUSIONS: Participating in a 6-session multidisciplinary intervention was found to be effective in maintaining the QOL of patients with advanced cancer who were actively receiving radiotherapy. The QOL and symptom burden of this population is striking, making it important to identify effective QOL strategies to implement in conjunction with cancer care. PMID- 22930255 TI - Elevated levels of survivin and livin mRNA in bronchial aspirates as markers to support the diagnosis of lung cancer. AB - Survivin and livin are two members of the inhibitor of apoptosis gene family, which have been found to be expressed in many human cancer tissues. But their expression could not be detected in normal adult tissue. The aim of our study was to evaluate the diagnostic role of survivin and livin mRNA expression in the bronchial aspirates of patients with lung cancer. Seventy lung cancer patients and 26 benign lung disease patients participated in our study. The bronchial aspirates (bronchial wash or bronchoalveolar lavage fluids) obtained during bronchoscopy. Survivin and livin mRNA were determined by reverse transcriptase polymerase chain reaction. Receiver operating characteristic (ROC) curve was used to analyze diagnostic performance of the two markers. Survivin and livin mRNA levels in patients with lung cancer were significantly higher than in those with benign lung disease (p < 0.001 and p = 0.001, respectively). In lung cancer patients, specimens taken from cancerous bronchi had significantly higher levels of survivin and livin mRNA than specimens from the mirror side bronchi in the same patients (p < 0.001 and p = 0.001, respectively). The best cutoff values of survivin and livin were selected according to ROC curves. The survivin mRNA expression in bronchial aspirates had sensitivity and specificity of 83 and 96% for diagnosis of lung cancer. Livin mRNA detection in bronchial aspirates showed 63% sensitivity and 92% specificity. Our findings suggest that survivin and livin mRNA detection in bronchial aspirates may be valuable diagnostic marker for the early diagnosis of lung cancer. PMID- 22930257 TI - Molecular and electronic structures and photophysical properties of quadruply bonded dimetal complexes (M = Mo or W) supported by trans-arylethynylcarboxylate ligands where aryl = p-tolyl or 9-anthrancenyl. AB - From the reactions between M(2)(T(i)PB)(4), where T(i)PB = 2,4,6 triisopropylbenzoate and M = Mo or W, in toluene and each of the respective carboxylic acids (2 equiv) the quadruply MM bonded compounds trans M(2)(T(i)PB)(2)(O(2)C-C=C-Ar)(2) have been prepared where Ar = p-tolyl and M = Mo, , and M = W, , and Ar = 9-anthracenyl, where M = Mo, 2a, and M = W, 2b. Single crystal X-ray crystallographic studies of 1a and 2b confirmed the trans substitution pattern about the Mo(2)(4+) unit and the centrosymmetric molecules have structural features that indicate extensive Lpi-Mo(2)delta-Lpi conjugation involving the arylethynylcarboxylates. The compounds are intensely colored as a result of the HOMO -> LUMO, metal delta-to-ligand pi* charge transfer (1)MLCT transition: 1a (orange), 1b (red), 2a (blue) and 2b(green). The compounds 1a, 2a, 1b and 2b have been characterized by UV-Vis-NIR absorption and emission spectroscopy, cyclic voltammetry, femtosecond (fs) and nanosecond (ns) transient absorption spectroscopy and by fs time-resolved infrared spectroscopy in the region of nu(C=C), nu(CO(2)) and from 1400-1000 cm(-1). Aided by density functional theory, (DFT) and time dependent DFT, the electronic structures of the ground state and the S(1) and T(1) states are described. The molybdenum compounds have short lived (1)MLCT states, 1a ~ 5.0 ps and 2a ~ 10.5 ps, that undergo intersystem crossing to long lived (3)MoModeltadelta* states: 1a ~ 101 MUs and 2a ~ 83 MUs. The tungsten complexes show interesting time-resolved infrared spectra in the nu(C=C) region when compared with their ground state. Compound 1b shows nu(C=C) at 1975 cm(-1) for the (1)MLCT state which decays with tau ~ 0.7 ps to nu(C=C) at 2000 cm(-1) for the (3)MLCT state. For 2b the (1)MLCT is characterized by nu(C=C) at 2150 cm(-1), tau ~ 19 ps, and a very broad absorption with a maximum ~1970 cm(-1) which is proposed to arise from a low energy electronic transition. The (3)MLCT state for shows no evidence of nu(C=C) and is suggested to have an electron localized principally on the anthracenyl portion of the ligand, a proposal that finds support from the nature of triplet transient absorption spectrum of 2b. PMID- 22930258 TI - Droplet sensing by measuring the capacitance between coplanar electrodes in a digital microfluidic system. AB - In this paper, we report a novel method of droplet sensing in a two-plate digital microfluidic system (DMS) based on coplanar capacitance measurement. The total capacitance between the two adjacent electrodes on the lower plate depends on the position of the droplet. Both numerical and experimental results show that the capacitance is maximal at the midpoint between two electrodes. The value of maximum capacitance increases with the volume of the droplet. Further, the measured capacitance is a function of the gaps between the electrodes as well as the plates. This new method of droplet sensing adds to the functionality of DMSs by allowing single plate measurement. PMID- 22930256 TI - Use of combination chemotherapy for treatment of granulomatous and lymphocytic interstitial lung disease (GLILD) in patients with common variable immunodeficiency (CVID). AB - PURPOSE: A subset of patients with common variable immunodeficiency (CVID) develops granulomatous and lymphocytic interstitial lung disease (GLILD), a restrictive lung disease associated with early mortality. The optimal therapy for GLILD is unknown. This study was undertaken to see if rituximab and azathioprine (combination chemotherapy) would improve pulmonary function and/or radiographic abnormalities in patients with CVID and GLILD. METHODS: A retrospective chart review of patients with CVID and GLILD who were treated with combination chemotherapy was performed. Complete pulmonary function tests (PFTs) and high resolution computed tomography (HRCT) scans of the chest were done prior to therapy and >6 months later. HRCT scans of the chest were blinded, randomized, and scored independently (in pairs) by two radiologists. The differences between pre- and post-treatment HRCT scores and PFT parameters were analyzed. RESULTS: Seven patients with CVID and GLILD met inclusion criteria. Post-treatment increases were noted in both FEV1 (p=0.034) and FVC (p=0.043). HRCT scans of the chest demonstrated improvement in total score (p=0.018), pulmonary consolidations (p=0.041), ground-glass opacities (p=0.020) nodular opacities (p=0.024), and both the presence and extent of bronchial wall thickening (p=0.014, 0.026 respectively). No significant chemotherapy-related complications occurred. CONCLUSIONS: Combination chemotherapy improved pulmonary function and decreased radiographic abnormalities in patients with CVID and GLILD. PMID- 22930260 TI - Giant amyloid goiter in Crohn's disease. AB - Crohn's disease is one of the causes of secondary amyloidosis, which can lead to amyloid infiltration of the thyroid gland. It is essential to follow strict controls to prevent the appearance of a large amyloid goiter. Two patients with amyloid goiter secondary to Crohn's disease, with a large adipose tissue component and who required surgical treatment, were studied. Both surgical interventions were difficult because of the fragility of the thyroid tissue. A patient with Crohn's disease and secondary amyloidosis could begin to develop amyloid goiter. This is usually fast growing and commonly causes compressive symptoms, although in some cases it only grows in the neck with no evidence of these symptoms. When surgery is indicated, patients should be remitted to hospitals with experienced endocrine surgeons, given that there is a high risk of developing complications. PMID- 22930261 TI - Is race associated with morbidity and mortality after hospital discharge among neonates undergoing heart surgery? AB - This study aimed to characterize the impact of race on morbidity and mortality after hospital discharge from neonatal congenital heart surgery. A retrospective chart review examined all the neonates who underwent neonatal heart surgery from January 2005 to June 2006 at The Children's Hospital of Philadelphia. After risk adjustment for the type of surgery using the Risk Adjustment for Congenital Heart Surgery 1 (RACHS-1) method, the association of race with mortality after hospital discharge was assessed using Fisher's exact test for statistical analysis. A cross-sectional telephone survey of surviving patients also was conducted to examine the association of race and social factors with adverse events (admissions or reinterventions). Mortality status was known for 201 of the 217 patients screened. The mortality rate after discharge was 8 %, with a higher mortality rate for nonwhite patients (14 %) than for white patients (4 %) (p = 0.01). After risk adjustment, this effect was limited to nonwhite patients with less complex heart disease (RACHS-1 categories 1-3; 17 vs 2 %, respectively; p = 0.01). The survey completion rate was 54 %. In this cohort, race also was independently associated with adverse events among patients with less complex heart disease (RACHS-1 categories 1-3; nonwhites 53 % vs whites 25 %; p = 0.046). Among the patients with less complex heart disease, the nonwhite patients had a significantly higher risk of morbidity and mortality after hospital discharge than the white patients. PMID- 22930263 TI - The structural role of the carrier protein--active controller or passive carrier. AB - Common to all FASs, PKSs and NRPSs is a remarkable component, the acyl or peptidyl carrier protein (A/PCP). These take the form of small individual proteins in type II systems or discrete folded domains in the multi-domain type I systems and are characterized by a fold consisting of three major alpha-helices and between 60-100 amino acids. This protein is central to these biosynthetic systems and it must bind and transport a wide variety of functionalized ligands as well as mediate numerous protein-protein interactions, all of which contribute to efficient enzyme turnover. This review covers the structural and biochemical characterization of carrier proteins, as well as assessing their interactions with different ligands, and other synthase components. Finally, their role as an emerging tool in biotechnology is discussed. PMID- 22930264 TI - Paired-pulse facilitation of multivesicular release and intersynaptic spillover of glutamate at rat cerebellar granule cell-interneurone synapses. AB - A simple form of presynaptic plasticity, paired-pulse facilitation (PPF), has been explained as a transient increase in the probability of vesicular release. Using the whole-cell patch-clamp technique to record synaptic activity in rat cerebellar slices, we found different forms of presynaptically originated short term plasticity during glutamatergic excitatory neurotransmission from granule cells (GCs) to molecular-layer interneurones (INs). Paired-pulse activation of GC axons at short intervals (30-100 ms) elicited not only a facilitation in the peak amplitude (PPF(amp)), but also a prolongation in the decay-time constant (PPP(decay)) of the EPSCs recorded from INs. The results of pharmacological tests and kinetics analyses suggest that the mechanisms underlying the respective types of short-term plasticity were different. PPF(amp) was elicited by a transient increase in the number of released vesicles. On the other hand, PPP(decay) was caused not only by delayed release as has been reported but also by extrasynaptic spillover of the GC transmitter and the subsequent intersynaptic pooling. Both PPF(amp) and PPP(decay) closely rely on repetitive-activation-induced multivesicular release. Using a dynamic clamp technique, we further examined the physiological significance of different presynaptic plasticity, and found that PPF(amp) and PPP(decay) can differentially encode and process neuronal information by influencing the total synaptic charge transferred to postsynaptic INs to reflect activation frequency of the presynaptic GCs. PMID- 22930265 TI - Homeostatic metaplasticity of corticospinal excitatory and intracortical inhibitory neural circuits in human motor cortex. AB - Homeostatic metaplasticity, a fundamental principle for maintaining overall synaptic weight in the physiological range in neuronal networks, was demonstrated at the cellular and systems level predominantly for excitatory synaptic neurotransmission. Although inhibitory networks are crucial for regulating excitability, it is largely unknown to what extent homeostatic metaplasticity of inhibition also exists. Here, we employed intermittent and continuous transcranial magnetic theta burst stimulation (iTBS, cTBS) of the primary motor cortex in healthy subjects for induction of long-term potentiation (LTP)-like and long-term depression (LTD)-like plasticity. We studied metaplasticity by testing the interactions of priming TBS with LTP/LTD-like plasticity induced by subsequent test TBS. Changes in excitatory neurotransmission were measured by the input-output curve of motor-evoked potentials (IO-MEP), and changes in GABA(A)ergic inhibitory neurotransmission by the IO of short-interval intracortical inhibition (IO-SICI, four conditioning stimulus intensities of 70 100% active motor threshold, interstimulus interval 2.0 ms). Non-primed iTBS increased IO-MEP, while non-primed cTBS decreased IO-MEP. Pairing of identical protocols (iTBSiTBS, cTBScTBS) resulted in suppression of the non-primed TBS effects on IO-MEP, and pairing of different protocols (cTBSiTBS, iTBScTBS) enhanced the test TBS effects on IO-MEP. While non-primed TBS did not result in significant changes of IO-SICI, iTBSiTBS resulted in IO-SICI decrease, and cTBScTBS in IO-SICI increase compared with the non-primed conditions. The changes in SICI induced by priming TBS correlated with the changes in MEP induced by subsequent test TBS. Findings demonstrate that plasticity in both excitatory and inhibitory circuits in the human motor cortex are regulated by homeostatic metaplasticity, and that priming effects on inhibition contribute to the homeostatic regulation of metaplasticity in excitatory circuits. PMID- 22930266 TI - Adverse cardiac remodelling in spontaneously hypertensive rats: acceleration by high aerobic exercise intensity. AB - In the present study it was hypothesized that voluntary aerobic exercise favours a pro-fibrotic phenotype and promotes adverse remodelling in hearts from spontaneously hypertensive rats (SHRs) in an angiotensin II-dependent manner. To test this, female SHRs at the age of 1 year were started to perform free running wheel exercise. Captopril was used to inhibit the renin-angiotensin system (RAS). Normotensive rats and SHRs kept in regular cages were used as sedentary controls. Training intensity, expressed as mean running velocity, was positively correlated with the left ventricular mRNA expression of TGF-beta(1), collagen-III and biglycan but negatively correlated with the ratio of sarcoplasmic reticulum Ca(2+)-ATPase (SERCA)2a to Na(+)-Ca(2+) exchanger (NCX). A pro-fibrotic phenotype was verified by Picrosirius red staining. Sixty-seven per cent of SHRs performing free running wheel exercise died either spontaneously or had to be killed during a 6 month follow-up. In the presence of captopril, aerobic exercise did not show a similar positive correlation between training intensity and the expression of fibrotic markers. Moreover, in SHRs receiving captopril and performing free running wheel exercise, a training intensity-dependent reverse remodelling of the SERCA2a-to-NCX ratio was observed. None of these rats died spontaneously or had to be killed. In captopril-treated SHRs performing exercise, expression of mRNA for decorin, a natural inhibitor of TGF-beta(1), was up-regulated. Despite these differences between SHR-training groups with and without captopril, positive training effects (lower resting heart rate and no progression of hypertension) were found in both groups. In conclusion, high aerobic exercise induces an angiotensin II-dependent adverse remodelling in chronic pressure overloaded hearts. However, high physical activity can potentially induce reverse remodelling in the presence of RAS inhibition. PMID- 22930267 TI - Size-dependent heterogeneity of contractile Ca2+ sensitization in rat arterial smooth muscle. AB - Each segment along arterial vessels adapts to different circumstances, including blood pressure and sympathetic innervation. PKC and Rho-associated kinase (ROCK) Ca(2+)-sensitizing pathways leading to myosin phosphatase inhibition are critically involved in alpha(1)-adrenoceptor-mediated vascular smooth muscle contraction in distinctive time-dependent manners. We tested whether the amplitude and time course of each pathway varies dynamically between arterial segments. Using pharmacological approaches, we determined the time-dependent roles of Ca(2+) release, Ca(2+) influx, PKC and ROCK in alpha(1)-agonist-induced contraction and phosphorylation of key proteins in denuded rat small mesenteric artery, midsized caudal artery and thoracic aorta. SR Ca(2+) release and voltage dependent Ca(2+) influx were essential for the initial rising and late sustained phases, respectively, of phenylephrine-induced contraction, regardless of arterial size. In small mesenteric arteries, alpha(1A)-subtype-specific antagonists and inhibitors of PKC, but not ROCK, markedly reduced the initial and late phases of contraction in a non-additive manner and suppressed phosphorylation of myosin light chain (MLC) and CPI-17, but not myosin targeting subunit of myosin light chain phosphatase (MYPT1). In aorta, an alpha(1D) specific antagonist reduced both the initial and late phases of contraction with a significant decrease in MLC but not CPI-17 or MYPT1 phosphorylation. ROCK inhibitors, but not PKC inhibitors, suppressed the sustained phase of contraction with a decrease in MLC and MYPT1 phosphorylation in the aorta. The effect of ROCK inhibitors was additive with the alpha(1D)-antagonist. The results for midsized arteries were intermediate. Thus, the PKC-CPI-17 Ca(2+)-sensitizing pathway, which is dependent on PKC subtype and a Ca(2+)-handling mechanism, and is downstream of alpha(1A) receptors, plays a major role in alpha(1)-agonist-induced contraction of small resistance arteries in the splanchnic vascular beds. The effect of PKC and ROCK increases and decreases, respectively, with decreasing arterial size. PMID- 22930268 TI - Intracellular BK(Ca) (iBK(Ca)) channels. AB - The large conductance calcium- and voltage-activated potassium channel (BK(Ca)) is widely expressed at the plasma membrane. This channel is involved in a variety of fundamental cellular functions including excitability, smooth muscle contractility, and Ca(2+) homeostasis, as well as in pathological situations like proinflammatory responses in rheumatoid arthritis, and cancer cell proliferation. Immunochemical, biochemical and pharmacological studies from over a decade have intermittently shown the presence of BK(Ca) in intracellular organelles. To date, intracellular BK(Ca) (iBK(Ca)) has been localized in the mitochondria, endoplasmic reticulum, nucleus and Golgi apparatus but its functional role remains largely unknown except for the mitochondrial BK(Ca) whose opening is thought to play a role in protecting the heart from ischaemic injury. In the nucleus, pharmacology suggests a role in regulating nuclear Ca(2+), membrane potential and eNOS expression. Establishing the molecular correlates of iBK(Ca), the mechanisms defining iBK(Ca) organelle-specific targeting, and their modulation are challenging questions. This review summarizes iBK(Ca) channels, their possible functions, and efforts to identify their molecular correlates. PMID- 22930269 TI - Maternal corticosterone regulates nutrient allocation to fetal growth in mice. AB - Stresses during pregnancy that increase maternal glucocorticoids reduce birth weight in several species. However, the role of natural glucocorticoids in the mother in fetal acquisition of nutrients for growth remains unknown. This study aimed to determine whether fetal growth was reduced as a consequence of altered amino acid supply when mice were given corticosterone in their drinking water for 5 day periods in mid to late pregnancy (day, D, 11-16 or D14-19). Compared to controls drinking tap water, fetal weight was always reduced by corticosterone. At D16, corticosterone had no effect on materno-fetal transfer of [(14)C]methylaminoisobutyric acid (MeAIB), although placental MeAIB accumulation and expression of the Slc38a1 and Slc38a2 transporters were increased. However, at D19, 3 days after treatment ended, materno-fetal transfer of MeAIB was increased by 37% (P < 0.04). During treatment at D19, placental accumulation and materno-fetal transfer of MeAIB were reduced by 40% (P < 0.01), although expression of Slc38a1 was again elevated. Permanent reductions in placental vascularity occurred during the earlier but not the later period of treatment. Placental Hsd11b2 expression, which regulates feto-placental glucocorticoid bioavailability, was also affected by treatment at D19 only. Maternal corticosterone concentrations inversely correlated with materno-fetal MeAIB clearance and fetal weight at D19 but not D16. On D19, weight gain of the maternal carcass was normal during corticosterone treatment but reduced in those mice treated from D11 to D16, in which corticosterone levels were lowest. Maternal corticosterone is, therefore, a physiological regulator of the amino acid supply for fetal growth via actions on placental phenotype. PMID- 22930270 TI - Inactivating ion channels augment robustness of subthreshold intrinsic response dynamics to parametric variability in hippocampal model neurons. AB - Voltage-gated ion channels play a critical role in regulating neuronal intrinsic response dynamics (IRD). Here, we computationally analysed the roles of the two inactivating subthreshold conductances (A and T), individually and in various combinations with the non-inactivating h conductance, in regulating several physiological IRD measurements in the theta frequency range. We found that the independent presence of a T conductance, unlike that of an h conductance, was unable to sustain an inductive phase lead in the theta frequency range, despite its ability to mediate theta frequency resonance. The A conductance, on the other hand, when expressed independently, acted in a manner similar to a leak conductance with reference to most IRD measurements. Next, analysing the impact of pair-wise coexpression of these channels, we found that the coexpression of the h and T conductances augmented the range of parameters over which they sustained resonance and inductive phase lead. Additionally, coexpression of the A conductance with the h or the T conductance elicited changes in IRD measurements that were similar to those obtained with the expression of a leak conductance with a resonating conductance. Finally, to understand the global sensitivity of IRD measurements to all parameters associated with models expressing all three channels, we generated 100,000 neuronal models, each built with a unique set of parametric values. We categorized valid models among these by matching their IRD measurements with experimental counterparts, and found that functionally similar models could be achieved even when underlying parameters displayed tremendous variability and exhibited weak pair-wise correlations. Our results suggest that the three prominent subthreshold conductances contribute differently to intrinsic excitability and to phase coding. We postulate that the differential expression and activity-dependent plasticity of these conductances contribute to robustness of subthreshold IRD, whereby response homeostasis is achieved by recruiting several non-unique combinations of these channel parameters. PMID- 22930271 TI - Activation of IGF-2R stimulates cardiomyocyte hypertrophy in the late gestation sheep fetus. AB - In vitro studies using rat and fetal sheep cardiomyocytes indicate that, in addition to its role as a clearance receptor, the insulin-like growth factor 2 receptor (IGF-2R) can induce cardiomyocyte hypertrophy. In the present study, we have determined the effect of specific activation of the IGF-2R in the heart of the late gestation fetus on cardiomyocyte development. Leu(27)IGF-2, an IGF-2R agonist, was infused into the fetal left circumflex coronary artery for 4 days beginning at 128.1 +/- 0.4 days gestation. Ewes were humanely killed at 132.2 +/- 1.2 days gestation (term, 150 days). Fetuses were delivered and hearts dissected to isolate the cardiomyocytes and to collect and snap-freeze tissue. Leu(27)IGF-2 infusion into the left circumflex coronary artery of fetal sheep increased the area of binucleated cardiomyocytes in the left, but not the right, ventricle. However, this infusion of Leu(27)IGF-2 did not change fetal weight, heart weight, blood pressure, blood gases or cardiomyocyte proliferation/binucleation. The increase in cardiomyocyte size in the Leu(27)IGF-2-infused group was associated with increased expression of proteins in the Galphas, but not the Galphaq, signalling pathway. We concluded that infusion of Leu(27)IGF-2 into the left circumflex coronary artery causes cardiac IGF-2R activation in the left ventricle of the heart, and this stimulates cardiomyocyte hypertrophy in a Galphas dependent manner. PMID- 22930272 TI - Neurogliaform cells of amygdala: a source of slow phasic inhibition in the basolateral complex. AB - Synaptic inhibition in the amygdala actively participates in processing emotional information. To improve the understanding of interneurons in amygdala networks it is necessary to characterize the GABAergic cell types, their connectivity and physiological roles. We used a mouse line expressing a green fluorescent protein (GFP) under the neuropeptide Y (NPY) promoter. Paired recordings between presynaptic NPY-GFP-expressing (+) cells and postsynaptic principal neurons (PNs) of the basolateral amygdala (BLA) were performed. The NPY-GFP+ neurons displayed small somata and short dendrites embedded in a cloud of highly arborized axon, suggesting a neurogliaform cell (NGFC) type. We discovered that a NPY-GFP+ cell evoked a GABA(A) receptor-mediated slow inhibitory postsynaptic current (IPSC) in a PN and an autaptic IPSC. The slow kinetics of these IPSCs was likely caused by the low concentration and spillover of extracellular GABA. We also report that NGFCs of the BLA fired action potentials phase-locked to hippocampal theta oscillations in anaesthetized rats. When this firing was re-played in NPY+-NGFCs in vitro, it evoked a transient depression of the IPSCs. Presynaptic GABA(B) receptors and functional depletion of synaptic vesicles determined this short term plasticity. Synaptic contacts made by recorded NGFCs showed close appositions, and rarely identifiable classical synaptic structures. Thus, we report here a novel interneuron type of the amygdala that generates volume transmission of GABA. The peculiar functional mode of NGFCs makes them unique amongst all GABAergic cell types of the amygdala identified so far. PMID- 22930273 TI - Synaptic integration in dendrites: exceptional need for speed. AB - Some neurons in the mammalian auditory system are able to detect and report the coincident firing of inputs with remarkable temporal precision. A strong, low voltage-activated potassium conductance (g(KL)) at the cell body and dendrites gives these neurons sensitivity to the rate of depolarization by EPSPs, allowing neurons to assess the coincidence of the rising slopes of unitary EPSPs. Two groups of neurons in the brain stem, octopus cells in the posteroventral cochlear nucleus and principal cells of the medial superior olive (MSO), extract acoustic information by assessing coincident firing of their inputs over a submillisecond timescale and convey that information at rates of up to 1000 spikes s(-1). Octopus cells detect the coincident activation of groups of auditory nerve fibres by broadband transient sounds, compensating for the travelling wave delay by dendritic filtering, while MSO neurons detect coincident activation of similarly tuned neurons from each of the two ears through separate dendritic tufts. Each makes use of filtering that is introduced by the spatial distribution of inputs on dendrites. PMID- 22930274 TI - Zinc induces long-term upregulation of T-type calcium current in hippocampal neurons in vivo. AB - Extracellular zinc can induce numerous acute and persistent physiological and toxic effects in neurons by acting at their plasma membrane or intracellularly following permeation or uptake into them. Zinc acutely and reversibly blocks T type voltage-gated calcium current (I(CaT)), but the long-term effect of zinc on this current has not been studied. Because chemically induced status epilepticus (SE) results in the release of zinc into the extracellular space, as well as in a long-lasting increase in I(CaT) in CA1 pyramidal cells, we hypothesized that zinc may play a causative role in I(CaT) upregulation. We tested this hypothesis by monitoring for 18 days the effects of zinc and ibotenic acid (a neurotoxic agent serving as control for zinc), injected into the right lateral ventricle, on I(CaT) in rat CA1 pyramidal cells. Both zinc and ibotenic acid caused marked hippocampal lesions on the side of injection, but only minor damage to contralateral hippocampi. Zinc, but not ibotenic acid, caused upregulation of a nickel-sensitive I(CaT) in a subset of contralateral CA1 pyramidal cells, appearing 2 days after injection and lasting for about 2 weeks thereafter. In contrast, acute application of zinc to CA1 pyramidal cells promptly blocked I(CaT). These data indicate that extracellular zinc has a dual effect on I(CaT), blocking it acutely while causing its long-term upregulation. Through the latter effect, zinc may regulate the intrinsic excitability of principal neurons, particularly in pathological conditions associated with enhanced release of zinc, such as SE. PMID- 22930276 TI - Predicting the drug interaction potential of AMG 853, a dual antagonist of the D prostanoid and chemoattractant receptor-homologous molecule expressed on T helper 2 cells receptors. AB - 2-(4-(4-(tert-Butylcarbamoyl)-2-(2-chloro-4-cyclopropylphenylsulfonamido)phenoxy) 5-chloro-2-fluorophenyl)acetic acid (AMG 853) is an orally bioavailable and potent dual antagonist of the D-prostanoid and chemoattractant receptor homologous molecule expressed on T helper 2 cells receptors. The drug interaction potential of AMG 853, both as a victim and a perpetrator, was investigated using in vitro, in silico, and in vivo methodologies. Experiments in human liver microsomes (HLM) and recombinant enzymes identified CYP2C8, CYP2J2, and CYP3A as well as multiple UDP-glucuronosyltransferase isoforms as being responsible for the metabolic clearance of AMG 853. With use of HLM and selective probe substrates, both AMG 853 and its acyl glucuronide metabolite (M1) were shown to be inhibitors of CYP2C8. AMG 853 and M1 did not inhibit any of the other cytochrome P450 isoforms tested, and AMG 853 exhibited minimal enzyme induction properties in human hepatocytes cultures. In light of the in vitro findings, modeling and simulation approaches were used to examine the potential for ketoconazole (a CYP3A inhibitor) to inhibit the metabolism of AMG 853 as well as for AMG 853 to inhibit the metabolism of paclitaxel, rosiglitazone, and montelukast, commonly used substrates of CYP2C8. A weak and clinically insignificant drug interaction (area under the drug concentration-time curve (AUC)(i)/AUC <2) was predicted between ketoconazole and AMG 853. No drug interactions were predicted for AMG 853 and paclitaxel, rosiglitazone, or montelukast. Finally, administration of AMG 853 to healthy human subjects in clinical trials in the presence or absence of ketoconazole confirmed that AMG 853 is unlikely to be involved in clinically significant drug interactions. PMID- 22930275 TI - Physical exercise reduces cardiac defects in type 2 spinal muscular atrophy-like mice. AB - Spinal muscular atrophy (SMA), the leading genetic cause of death in infants worldwide, is due to the misexpression of the survival of motor neuron protein, causing death of motor neurons. Several clinical symptoms suggested that, in addition to motor neurons, the autonomic nervous systems could be implicated in the cardiac function alterations observed in patienst with SMA. These alterations were also found in a severe SMA mouse model, including bradycardia and a reduction of sympathetic innervation, both associated with autonomic imbalance. In the present study, we investigate the extent of autonomic dysfunction and the effects of a running-based exercise on the altered cardiorespiratory function in type 2 SMA-like mice. We observed that the SMA induced: (1) a dramatic alteration of intrinsic cardiac conduction associated with bradycardia; (2) a severe cardiomyopathy associated with extensive ventricular fibrosis; and (3) a delay in cardiac muscle maturation associated with contractile protein expression defects. Furthermore, our data indicate that the sympathetic system is not only functioning, but also likely contributes to alleviate the bradycardia and the arrhythmia in SMA-like mice. Moreover, physical exercise provides many benefits, including the reduction of cardiac protein expression defect, the reduction of fibrosis, the increase in cardiac electrical conduction velocity, and the drastic reduction in bradycardia and arrhythmias resulting in the partial restoration of the cardiac function in these mice. Thus, modulating the cardiorespiratory function in SMA could represent a new target for improving supportive care and for developing new pharmacological and non-pharmacological interventions that would most certainly include physical exercise. PMID- 22930277 TI - Assessment of intestinal availability of various drugs in the oral absorption process using portal vein-cannulated rats. AB - To understand the rate-limiting process of oral drug absorption, not only total bioavailability (F) but also intestinal (F(a) . F(g)) and hepatic (F(h)) availability after oral administration should be evaluated. Usually, F(a) . F(g) of drug is calculated from pharmacokinetic parameters after intravenous and oral administration. This approach is influenced markedly by the estimated value of F(h), which varies with the hepatic blood flow used in the calculations. In this study, portal vein-cannulated rats were used to calculate the F(a) . F(g) of drugs from a single oral dosing experiment without data from intravenous injection. Portal vein-cannulated rats were prepared by a new operative method that enables stable portal vein blood flow. This surgery had no effects on hepatic blood flow and metabolic activity. Our method for calculating F(a) . F(g) was validated by determining both portal and systemic plasma concentration profiles of various drugs possessing different pharmacokinetic properties after oral administration to the portal vein-cannulated rats. Simulation of portal and systemic plasma concentrations by physiologically based pharmacokinetic modeling indicated that the balance of the absorption rate constant (k(a)) and elimination rate constant (k(e)) resulted in different patterns in portal and systemic plasma concentration-time profiles. This study is expected to provide a new experimental animal model that enables identification of the factors that limit oral bioavailability and to provide pharmacokinetic information on the oral absorption process of drugs during drug discovery. PMID- 22930278 TI - [Management and prognosis of patients with squamous cell carcinomas of the nasal cavity and the paranasal sinuses]. AB - Squamous cell carcinomas (SCC) of the nasal cavity and the paranasal sinuses are a very rare and poorly understood tumor entity. To date, no consistent management strategy exists. The purpose of our study was to demonstrate our therapeutic strategy and to correlate clinicopathological features with clinical follow-up data.45 patients with primarily resected SCC of the nasal cavity (n=35) and the paranasal sinuses (n=10) between 1994 and 2010 were reviewed retrospectively (mean follow-up period 2.6 years; range 0.3 to 14.9 years).Tumors of the nasal cavity were diagnosed at an early stage (97% T1 and T2) whereas tumors of the parasinuses were found at an advanced stage (90% T3 and T4). Lymph node metastases were only found 2 patients. 13 patients (29%) had a local tumor progress, 2 patients showed lymph node metastases and 4 patients had distant metastases in follow up. The prognosis of tumors of the nasal cavitiy or the paranasal sinuses was bad (31% 5-year overall survival) especially by patients with a relapse.Reconstructive surgery was performed after 12 months, when early local relapse could be excluded. There was no positive correlation between clinicopathological features and survival data.The prognosis of tumors of the nasal cavity and paranasal sinuses depends mainly on the control of local tumor growth. Modern strategies of surgical treatment in combination with radiotherapy need to be implemented in an effort to achieve continuous tumor-free survival. PMID- 22930279 TI - IL-20, IL-21 and p40: potential biomarkers of treatment response for ustekinumab. AB - Although biological drugs in psoriasis treatment show clinical efficacy, there are still a proportion of patients in whom little treatment response is obtained. The aim of this study was to identify molecular biomarkers for treatment response and to investigate the molecular effects of ustekinumab treatment of psoriasis. The mRNA expression of various genes in skin biopsies was analysed by quantitative polymerase chain reaction (qPCR). At baseline, there was no significant clinical difference be-tween responders and non-responders. Ten patients were clinical responders, with a mean baseline Psoriasis Area and Severity Index (PASI) score of 15.4 and a mean percentage improvement of 89.6%. No significant reduction in PASI during treatment was seen among the 5 non responders. In the responder group, ustekinumab therapy reduced the mRNA expression of the majority of the studied genes in lesional psoriatic skin. IL 20, IL-21 and p40 mRNA expression in lesional psoriatic skin at baseline were significantly upregulated by factors of 2.7, 2.4 and 2.3, respectively, among non responders compared with responders. The mRNA levels of p40, IL-20 and IL-21 at baseline may serve as potential predictors of treatment response to ustekinumab treatment. PMID- 22930280 TI - Rapid synthesis of substituted pyrrolines and pyrrolidines by nucleophilic ring closure at activated oximes. AB - Substituted pyrrolines are available by ring closure initiated by direct nucleophilic attack of stabilized enolates at the nitrogen of oximes activated with a leaving group, in a process which effectively out-competes the more usual Beckmann rearrangement. Subsequent reduction provides diastereoselective access to the corresponding pyrrolidines. This provides a rapid route to saturated heterocyclic systems from readily available precursors. PMID- 22930281 TI - Prognostic value of ventricular wall fluorescence during 5-aminolevulinic-guided surgery for glioblastoma. AB - BACKGROUND: The meaning of the ventricular wall fluorescence during 5 aminolevulinic (5-ALA)-guided surgery in patients with glioblastoma (GBM) is still unknown. The authors studied the association between ventricle fluorescence, clinical outcome and survival, and described the histopathological findings of selective biopsies from the ventricular wall. METHODS: One hundred and forty patients diagnosed of GBM underwent fluorescence-guided surgery (FGS); 65 of them were naive GBM and ventricle fluorescence during surgery was annotated prospectively. Selective biopsies were collected from the ventricular wall when possible. Clinical and radiological data were registered, including age, Karnofsky Performance Scale (KPS) score, presence of hydrocephalus, overall survival (OS), tumour volume and location (periventricular vs non periventricular) and leptomeningeal dissemination. RESULTS: During FGS the ventricle wall was opened just when the tumour was periventricular in the preoperative MRI (45 out of 65). In 28 of them (60 %) the fluorescence extended far away from the site of opening, while in 17 it ended just in the few millimetres around the tumour. All four patients who developed hydrocephalus had periventricular tumours and the ventricle wall had been opened during surgery. Statistically significant differences were seen in OS according to periventricular location (15 m vs 33 m, P = 0.008 log rank). However, there was not significant relationship between ventricle fluorescence and hydrocephalus (P = 0.75), nor survival (14 m vs 15.5 m, P = 0.64). CONCLUSIONS: Preoperative MRI predicts if the ventricle will be opened using the 5-ALA fluorescence, according to tumour location. It does not predict, however if the ventricle wall is going to be fluorescent or not. The fluorescence of the ventricle wall is not a predictor for complications or survival. Periventricular tumour location is an independent bad prognostic factor in GBM. PMID- 22930282 TI - The subthalamic nucleus at 7.0 Tesla: evaluation of sequence and orientation for deep-brain stimulation. AB - BACKGROUND: Deep-brain stimulation (DBS) of the subthalamic nucleus (STN) is an accepted neurosurgical technique for the treatment of medication-resistant Parkinson's disease and other neurological disorders. The accurate targeting of the STN is facilitated by precise and reliable identification in pre-stereotactic magnetic resonance imaging (MRI). The aim of the study was to compare and evaluate different promising MRI methods at 7.0 T for the pre-stereotactic visualisation of the STN METHODS: MRI (T2-turbo spin-echo [TSE], T1-gradient echo [GRE], fast low-angle shot [FLASH] two-dimensional [2D] T2* and susceptibility weighted imaging [SWI]) was performed in nine healthy volunteers. Delineation and image quality for the STN were independently evaluated by two neuroradiologists using a six-point grading system. Inter-rater reliability, contrast-to-noise ratios (CNRs) and signal-to-noise ratios (SNRs) for the STN were calculated. For the anatomical validation, the coronal FLASH 2D T2* images were co-registered with a stereotactic atlas (Schaltenbrand-Wahren). RESULTS: The STN was clearly and reliably visualised in FLASH 2D T2* imaging (particularly coronal view), with a sharp delineation between the STN, the substantia nigra and the zona incerta. No major artefacts in the STN were observed in any of the sequences. FLASH 2D T2* and SWI images offered significantly higher CNR for the STN compared with T2-TSE. The co-registration of the coronal FLASH 2D T2* images with the stereotactic atlas affirmed the correct localisation of the STN in all cases. CONCLUSION: The STN is best and reliably visualised in FLASH 2D T2* imaging (particularly coronal orientation) at 7.0-T MRI. PMID- 22930284 TI - Dietary health behaviors of women living in high rise dwellings: a case study of an urban community in Malaysia. AB - Diet-related non-communicable disease (DR-NCD) occurrence is a serious problem amongst Malaysian women and urbanization is probably a challenge to their achieving the nutritional environment conducive to healthy eating. This case study aimed to determine diet quality of an urban community using women respondents from high rise dwellings in Kuala Lumpur. The sample consisted of 135 households and a healthy eating index (HEI) scale was used to evaluate the women's diet quality. A total of 128 women (Malays = 45, Chinese = 56, Indian = 27) participated. Total HEI score was significantly different (P < 0.05) within ethnicity (Indians = 75.7 +/- 8.1 0.05) regardless of ethnicity. Income strata (rho = 0.159, P = 0.048) and eating out frequency (rho = -0.149, P = 0.046) also independently affected HEI scores. Income negatively correlated with sodium restriction score (rho = -0.294, P = 0.001) but positively with cereals (rho = 0.181; P = 0.025), fruits (rho = 0.178; P = 0.022), dairy products (rho = 0.198; P = 0.013) and food variety (rho = 0.219, P = 0.007). Decreased vegetable intake (rho = -0.320; P < 0.001) and sodium excess (rho = -0.135, P = 0.065) were associated with eating out frequency and poor HEI scores. This case study suggests health promotion for DR-NCD prevention is needed at the community level to improve diet quality of urban women. PMID- 22930285 TI - The inhibition of iridium-promoted water oxidation catalysis (WOC) by cucurbit[n]urils. AB - A series of iridacycles bearing pi-bonded moieties of variable electron withdrawing capabilities were tested for their ability to promote water oxidation catalysis (WOC) in the presence of high loading in a sacrificial oxidant, under conditions chosen for optimal dioxygen production. This report shows that none of these complexes performs differently than monometallic iridacycles and that the pi-bonded moiety does not affect the overall rate of O(2) production. Furthermore, it is shown that cucurbituril macrocycles significantly inhibit the production of dioxygen independently of the nature of the Cp*Ir(III)-based catalyst used to perform WOC. Theoretical first-principles based DFT-D3 investigations including a complete treatment of solvation with COSMO and COSMO RS treatments supported by ITC analyses suggest that concealment of the catalyst by curcurbit[7]uril could occur by non-covalent interaction of the Cp*Ir moiety in the hydrophobic pocket of the cavitand. For other cavitands of smaller inner cavity diameter, inclusion may not be the main mode of inhibition. Assuming the intervention of the putative Ir(IV)-oxyl biradical of a Cp*Ir(IV)(O)(H(2)O)(2) species like suggested by many authors, inhibition of WOC by inclusion would probably result from unfavourable coulombic interactions between water and the inclusion complex. PMID- 22930283 TI - BRAF mutation is associated with early stage disease and improved outcome in patients with low-grade serous ovarian cancer. AB - BACKGROUND: Low-grade serous (LGS) ovarian cancer is a chemoresistant disease that accounts for 10% of serous ovarian cancers. Prior studies have reported that 28% to 35% of serous borderline (SB)/LGS ovarian tumors harbor a BRAF mutation, suggesting that BRAF inhibitors may be a rational therapeutic approach for this disease. In the current study, the authors sought to determine whether BRAF or KRAS mutation status was associated with disease stage and/or histology in patients with SB and LGS ovarian cancer. METHODS: Genetic profiles were constructed for 75 SB and LGS ovarian tumors to determine BRAF and KRAS mutation status. The incidence and identity of BRAF and KRAS mutations were defined, and the results were correlated with disease stage, response to treatment, and overall survival. RESULTS: Of 75 samples examined, 56 tumors (75%) had SB histology, and 19 tumors (25%) had LGS histology. Fifty-seven percent of tumors harbored either a KRAS mutation (n = 17) or a BRAF mutation (a valine-to glutamate substitution at residue 600 [V600E]; n = 26). The BRAF V600E mutation was associated significantly with early disease stage (stage I/II; P < .001) and SB histology (P = .002). KRAS mutations were not associated significantly with disease stage or histology. Of the 22 patients (29%) who required chemotherapy, 20 had tumors with wild-type KRAS/BRAF, 2 had KRAS mutant tumors, and none had tumors that harbored a BRAF mutation. All patients with BRAF tumors remained alive at a median follow-up of 3.6 years (range, 1.9-129.3 months). CONCLUSIONS: V600E BRAF mutations were present in 35% of patients who had SB/LGS ovarian cancers. The presence of the BRAF V600E mutation in SB/LGS ovarian cancer was associated with early stage disease and improved prognosis. The authors concluded that patients with SB/LGS ovarian cancer who require systemic therapy are unlikely to have BRAF mutant tumors. PMID- 22930286 TI - A cyanide-bridged trinuclear Fe(II)-Ru(II)-Fe(II) complex with three stable states: synthesis, crystal structures, electronic couplings and magnetic properties. AB - Treatment of trans-(Ph-tpy)Ru(PPh(3))(CN)(2) (Ph-tpy = 4'-phenyl-2,2':6',2'' terpyridine, PPh(3) = triphenylphosphine) with 2 equiv of Cp(dppe)Fe(NCCH(3))Br (dppe = bis(diphenylphosphino)ethane) in the presence of NH(4)PF(6) produced a trinuclear cyanide-bridged complex, trans-[Cp(dppe)Fe(CN)(Ph tpy)Ru(PPh(3))(CN)Fe(dppe)Cp][PF(6)](2) (1[PF(6)](2)). Its one-electron oxidation product (1[PF(6)](3)) and two-electron-oxidation product (1[PF(6)](4)) were obtained by oxidation with (Cp)(2)FePF(6) and AgPF(6), respectively. Firstly, the crystal structures of the cyanide-bridged complexes with three stable states were fully characterized. The reversible electrochemistry measurement of 1(2)(+) shows the presence of a long range intervalence interaction between the external iron centres. Both 1(3)(+) and 1(4)(+) were considered to be Class II mixed valence complexes according to the classification of Robin and Day. Magnetic analysis indicated the presence of a moderately strong antiferromagnetic coupling between the two remote Fe(III) ions across the Fe-NC-Ru-CN-Fe array in 1(4)(+). This proves that the Ru(II)-dicyano complex is a bridging ligand that can transmit electro- and magneto-communication. PMID- 22930287 TI - Sexual coercion prior to imprisonment: prevalence, demographic and behavioural correlates. AB - Little is known about experiences of sexual coercion among prisoners prior to incarceration. Prisoner populations are routinely excluded from national surveys of sexual health which also tend to under-represent marginalized groups. We surveyed 2351 randomly selected men and women, aged 18-64 years, in New South Wales and Queensland prisons who participated in a computer-assisted telephone interview. Around 60% of women and 14% of men self-reported having been sexually coerced prior to incarceration, with 60% of these experiences occurring before the age of 16 years. Factors independently associated with a self-reported history of sexual coercion were: homosexual and bisexual identity, being unable to work, separated marital status, higher level of education (among women), having been paid for sex, a past sexually transmissible infection (among men), drug use (among women) and a history of mental health problems. Prior sexual coercion was associated with unwanted sexual contact and physical assault while in prison. The high prevalence of sexual coercion reported by prisoners and its association with a range of factors indicates a need for a greater acknowledgement of the potential consequences of this within the criminal justice system. This could entail providing counselling and support services within the correctional setting. PMID- 22930288 TI - Missed opportunities for identifying primary HIV within genitourinary medical/HIV services. AB - To assess the ability of three genitourinary medical centres to clinically identify primary HIV infection (PHI). Cases of recently acquired HIV infection, identified using the Health Protection Agency (HPA) avidity assay on all HIV diagnoses from January to August 2009, were investigated by case-note review. Sixty-four individuals were identified as PHI using the HPA avidity assay. Of 64 individuals, 31 (48%) were identified clinically. Imperial College identified 8/26 (31%), Guys and St Thomas' 15/27 (56%) and Brighton 8/11 (73%). Clinical suspicion of PHI was associated with reported unprotected anal intercourse (P = 0.017), seroconversion symptoms (P = 0.0004), a negative HIV test within six months (P = 0.024) and avidity assay result availability (P = 0.0169). Seventy percent of PHI cases missed had a documented risk factor. Thirty-five percent of those clinically identified with PHI were documented as informed of the associated enhanced infectivity. Suspicion of PHI was low despite documented risk factors and recent HIV-negative antibody tests. Counselling to prevent onward transmission was suboptimal. PMID- 22930289 TI - Access to genitourinary medicine clinics: how long does it take to book an appointment by telephone? AB - A unique feature of genitourinary (GU) medicine clinics is that patients can book appointments themselves. The aim of this study was to assess how long it takes and the barriers that exist when making an appointment in a UK GU medicine clinic. Male and female researchers recorded the number of attempts needed to make a successful contact, how the call was dealt with, and the time taken for the call to be initially answered and then completed; 72% (479/666) of the telephone contacts were answered on the first attempt (range: 1-17). The median length of the total call was one minute 51 seconds (range: 15 seconds to eight minutes, six seconds) but male callers took a mean of 40 seconds longer to complete a call (P < 0.001), reflecting additional and often intrusive questions they were asked compared with female researchers. Care should be taken to ensure that the first point of contact with a clinic is favourable as it reflects on how an entire service may be perceived. PMID- 22930290 TI - A dedicated clinic for HIV-positive individuals over 50 years of age: a multidisciplinary experience. AB - The HIV-infected population is ageing. Issues including polypharmacy and co morbidities led us to develop a dedicated clinic for HIV-infected individuals over 50. We describe our service evaluation after two years. The over 50 clinic commenced in January 2009. The team comprises a registrar, consultant, nurse practitioner and is supported by a pharmacist and mental health services. Patients undergo a full medication and drug interactions review, neurocognitive assessment, adherence self-assessment and investigations including therapeutic drug monitoring (TDM), coronary artery calcium scores (CACS) and bone mineral density. Over two years of activity, 150 patients attended the service. Median (range) age was 58 (50-88), all were on combined antiretroviral therapy and 38% (57/150) were on >=3 non-HIV drugs. CACS was high (>90th centile) in 14%. Thirty eight percent had osteopaenia and 18% had osteoporosis requiring treatment. Thirteen out of 125 men had an increased prostate specific antigen, four were diagnosed with prostate cancer. Drug interaction, TDM and neurocognitive assessments were useful for several patients. Asymptomatic patients over 50 in long-term follow-up had new pathologies detected through targeted screening. The clinic has improved general practitioner (GP) liaison and facilitated closer working relationships with other specialties. Patients have reacted positively to the clinic, particularly as many do not routinely access their GP. PMID- 22930291 TI - Sexually transmitted infections and sexual behaviour among youth clients of hotel based female sex workers in Dhaka, Bangladesh. AB - A cross-sectional study was conducted among youth clients of hotel-based female sex workers (YCHBFSWs) in nine randomly selected hotels in Bangladesh to examine sexual-risk behaviour, condom use and determinants of condom use in last sex, knowledge of HIV, sexually transmitted infection (STI) prevalence and STI care seeking behaviour. A prestructured questionnaire was used to collect sociodemographic, behavioural, clinical information; urine specimens (before sex) and blood were collected for diagnosis of Neisseria gonorrhoeae, Chlamydia trachomatis, Trichomonas vaginalis, syphilis and herpes simplex virus 2 (HSV2) infection. One thousand and thirteen participants were enroled in the study. Approximately half of them reported visiting female sex workers (FSWs) at least once a month and 25% visited FSWs at least once a week. Only 12% of participants reported regular condom use. The prevalence of N. gonorrhoeae, C. trachomatis, T. vaginalis, syphilis and HSV2 was 2.2%, 3.9%, 7.2%, 2.6% and 12.9%, respectively. Only 15.3% of the YCHBFSW sought STI care in the past year. Negotiation of condom use with FSWs was the main determinant (odds ratio = 17.95) for condom use at last sex. Male clients of FSWs, including YCHBFSW, are an important bridge population for HIV transmission in Bangladesh and HIV interventions should be designed and implemented for them. PMID- 22930292 TI - HIV-1 and herpes simplex virus type-2 genital shedding among co-infected women using self-collected swabs in Chiang Rai, Thailand. AB - We analysed 528 genital self-collected swabs (SCS) from 67 HIV-1 and herpes simplex virus type-2 (HSV-2) co-infected women collected during the placebo month of a randomized crossover clinical trial of suppressive acyclovir in Chiang Rai, Thailand. In this first longitudinal study of HIV-1 and HSV-2 co-infected women using genital SCS specimens, we found frequent mucosal HIV-1 shedding. Overall, 372 (70%) swabs had detectable HIV-1 RNA with median HIV-1 viral load of 2.61 log(10) copies/swab. We found no statistically significant association between detectable HIV-1 RNA and HSV-2 DNA in the same SCS specimen (adjusted odds ratio [aOR] 1.40; 95% confidence intervals [CI], 0.78-2.60, P = 0.25). Only baseline HIV-1 plasma viral load was independently associated with genital HIV-1 RNA shedding (aOR, 7.6; 95% CI, 3.3-17.2, P < 0.0001). SCS may be useful for future HIV-1 and HSV-2 studies because this method allows for frequent genital sampling, and inclusion of genital sites other than the cervix. PMID- 22930293 TI - Rescreening for abnormal vaginal flora in pregnancy and re-treating with clindamycin vaginal cream significantly increases cure and improvement rates. AB - We investigated 199 pregnant women with bacterial vaginosis (BV) who received clindamycin vaginal cream (CVC) for three days and compared with 205 women treated with placebo. The vaginal flora was assessed at each visit. At the second visit, 71% in the CVC group were cured/improved, compared with 12% in the placebo group (P < 0.001). At visit 3 about 90% who responded to initial CVC treatment were still cured/improved. Of women who initially failed to respond to CVC and were given an additional seven-day course, 33% were cured/improved by the third visit, compared with 15% who failed to respond to placebo initially and were given a further seven-day course (P = 0.02). By visit 4, half the women in the CVC group who received additional treatment remained cured/improved, compared with 26% who had additional placebo (P = 0.004). In the CVC group, a change from abnormal to normal rose from 71% (visit 2) to 76% (visit 3) and 79% (visit 4). A similar trend was seen in women who received placebo but the proportions were significantly lower (12%, 24% and 33%, respectively). There is value in rescreening and re-treating women who remain BV-positive after initial clindamycin treatment. PMID- 22930294 TI - High HIV vulnerability of ethnic minorities after a trans-Asian highway construction in remote northern Laos. AB - From 2004 to 2008 a new Asian highway was constructed through remote multiethnic areas of north Laos linking a low with higher HIV prevalence areas in bordering Thailand and China. We assessed the HIV vulnerability in four minority villages alongside the new road in Luang Namtha Province using structured interviews and voluntary counselling and testing (VCT) for HIV. Of 470 villagers aged 15-49 years old, 47.0% did not know any ways of HIV transmission yet 82.1% reported sexual contacts. Median age at first sex was 17.5 years. Sex of never-married 15 24 years old was associated with higher age (P = 0.002) and ethnicity (P = 0.013; Hmong odds ratio [OR] 7.27); 61.9% (86/139) used no condom at last non-cohabitant sex, especially women (OR 17.7, P < 0.001) and older villagers (P = 0.001). No HIV-infection was detected among villagers who received VCT in 2006 (924 of 933) and 2008 (538 of 1249). Nonetheless our findings reveal an alarming vulnerability for HIV among ethnic minorities alongside the new highway, and further culturally adapted prevention efforts are warranted. PMID- 22930296 TI - Bacterial vaginosis is conducive to the persistence of HPV infection. AB - We investigated the effects of bacterial vaginosis (BV) on the outcomes of high risk human papillomavirus infection (HR-HPV). BV was diagnosed on Papanicolaou stained cytology slides of 707 HPV-positive patients. HR-HPV DNA expression was analysed using the Hybrid Capture II (HC-II) assay. Of the 707 HR-HPV-positive female patients, 298 (42.1%) exhibited clearance of HR-HPV. The remaining 409 patients had persistent HR-HPV infection. The persistent HR-HPV group and the clearing group had similar rates of BV at the beginning of the study. At the end of the study, the persistent HR-HPV group had a BV prevalence of 11.2% while the clearing group had a significant lower BV prevalence of 5.0%. A decreased clearance of HPV was found in women with current BV, compared with women without BV. Furthermore, the natural history of HPV was not affected by the HPV viral load or the BV prevalence at the beginning of the study (P > 0.05). Bacterial vaginosis appears conducive to the persistence of HPV infection. PMID- 22930295 TI - Cumulative exposure to stimulants and immune function outcomes among HIV-positive and HIV-negative men in the Multicenter AIDS Cohort Study. AB - We examined associations between stimulant use (methamphetamine and cocaine) and other substances (nicotine, marijuana, alcohol and inhaled nitrites) with immune function biomarkers among HIV-seropositive (HIV +) men taking highly active antiretroviral therapy (ART) and HIV-seronegative (HIV-) men in the Multicenter AIDS Cohort Study. Among HIV + men, cumulative adherence to ART (4.07, 95% confidence interval [CI]: 3.52, 4.71, per 10 years of adherent ART use), and recent cohort enrolment (1.38; 95% CI: 1.24, 1.55) were multiplicatively associated with increase in CD4+/CD8+ ratios. Cumulative use of methamphetamine (0.93; 95% CI: 0.88, 0.98, per 10 use-years), cocaine (0.93; 95% CI: 0.89, 0.96, per 10 use-years) and cumulative medical visits (0.99; 95% CI: 0.98, 0.99, per 10 visit-years), each showed small negative associations with CD4+/CD8+ ratios. Among HIV- men, cumulative medical visits (0.996; 95% CI: 0.993, 0.999), cumulative number of male sexual partners (0.999; 95% CI: 0.998, 0.9998, per 10 partner-years) and cigarette pack-years (1.10; 95% CI: 1.02, 1.18, per 10 pack years) were associated with CD4+/CD8+ ratios over the same period. ART adherence is associated with a positive immune function independent of stimulant use, underscoring the influence of ART on immune health for HIV+ men who engage in stimulant use. PMID- 22930297 TI - Screening for hazardous alcohol consumption in a sexual health clinic: a service evaluation. AB - On the basis of National Institute for Health and Clinical Excellence (NICE) guidance we conducted a survey in a sexual health clinic to assess acceptability of an alcohol screening questionnaire, rates of hazardous drinking and success of referral to a specialist alcohol service (Aquarius). Seventy-two percent of patients accepted the offer of screening, of whom 34% were hazardous drinkers; 2.6% consented to referral to Aquarius but failed to attend. We estimate the cost range to screen and deliver a five-minute brief intervention at L3.62-L9.19 per case. Opportunistic alcohol screening identifies high rates of hazardous drinkers and is acceptable to patients, but onward referral by untrained staff to an external specialist alcohol service is unsatisfactory to patients. Research into the cost-effectiveness of screening and delivery of brief interventions within sexual health clinics is required. PMID- 22930298 TI - STIFCompetency: development and evaluation of a new clinical training and assessment programme in sexual health for primary care health professionals. AB - UK sexual health services are shifting from hospital-based clinics into primary care, creating a need for high quality clinical sexual health training for non specialists. Here we describe development, evaluation and costing of a new competency-based training programme, the Sexually Transmitted Infection (STI) Foundation Competency (STIFCompetency) programme, based on the Department of Health's toolkit for delivering more specialized sexual health in primary care. We used an action research paradigm with two iterative cycles. Evaluation was to Kirkpatrick's third level with triangulation of results between trainers and trainees, and different methods, including portfolio evaluation, nominal group technique process, semi-structured interviews, Likert questionnaires and chlamydia testing rates. All 13 primary care clinicians completed the training successfully (median 20 hours) and rated STIFCompetency highly. Trainers needed to reduce their clinical workload to accommodate the training. Average cost per trainee was L1125, reflecting the need for direct observation of competence across a wide range of clinical skills. PMID- 22930299 TI - An audit of chaperone use for intimate examinations in an integrated sexual health clinic. AB - We performed an audit at the Edinburgh Chalmers Sexual Health Centre to examine if the use and documentation of chaperones complies with the guidance set out by the General Medical Council (GMC) and other regulatory bodies. The case-notes of patients seen in the non-specialist, morning clinics over a one-week period were studied. Only 20 of the 104 genital examinations undertaken were recorded as chaperoned. Only in five of the unchaperoned examinations was it documented that a chaperone was declined. Thus, a total of 24% patients had documentation regarding the presence of a chaperone or the offer of one. However, these results show that our department is certainly lacking in documentation of this, if not the use of chaperones itself. This falls short of the GMC guidance for good practice: primarily in place not only to protect patients from harm, but also to safeguard clinicians against false accusations of impropriety. PMID- 22930300 TI - Trends in attendances to genitourinary medicine services by older women. AB - We sought to analyse reasons for attendance of older women (defined as aged 46 years and over) to genitourinary (GU) medicine services at two UK clinics. We used KC60 coding data to count new episode attendances by year from 1998 to 2008 and to further dissect reason for attendance in 2827 new episodes during 2003 2008. The total number of new episodes of attendance in older women increased from 167 in 1998 to 701 in 2008. Within this overall increase, there was a stable proportion of acute sexually transmitted infections (STIs) over time, alongside significant increases in the proportion of women requesting STI screening and HIV testing and those attending GU medicine for other reasons, such as dermatological or gynaecological complaints. In our clinic population it was encouraging to see that older women increasingly use GU medicine services for STI screening and HIV testing. Services may need to adapt to older women's specific health-care needs. PMID- 22930301 TI - Primary syphilitic chancre on the upper arm in an HIV-1-infected patient. AB - A 32-year-old HIV-infected man presented with an ulcerating skin lesion with indurated borders on the upper right arm. Both dark-field microscopy and syphilis serology confirmed the diagnosis of primary syphilis. Extragenital syphilitic chancres are uncommon but nevertheless have to be kept in mind as they often delay diagnosis. PMID- 22930302 TI - A case of lues maligna in an AIDS patient. AB - Lues maligna is a severe and rare manifestation of syphilis, also known as malignant syphilis or ulceronodular syphilis and mostly occurring in patients with HIV infection. In this report, we present a case of lues maligna in an AIDS patient. Our report shows the typical clinical features of lues maligna and the important association between lues maligna and HIV/AIDS. Although the clinical manifestations of lues maligna are complicated and severe, the response to the therapy of penicillin is excellent. PMID- 22930303 TI - Luetic lymphadenopathy despite negative serology. AB - Laboratory tests can be misleading for the diagnosis of syphilis and false negative results are possible, but it is rare for both treponemal and non treponemal tests to prove negative in different stages of the disease. We report on a case of luetic lymphadenopathy, diagnosed by histological examination and supported by immunohistochemical staining for Treponema pallidum, in the absence of skin lesions and positive serology. This case reminds us of how syphilis may present in many different clinical forms and that it should not be excluded only on the basis of negative serological tests. This patient's negative serology was probably due to inadequate initial antibiotic therapy. Given the current widespread use of antibiotics, greater consideration is warranted of the extent to which serological test results are modified by non-specific antibiotic therapies. PMID- 22930304 TI - Favourable outcome of progressive multifocal leukoencephalopathy with mefloquine treatment in combination with antiretroviral therapy in an HIV-infected patient. AB - A 33-year-old man who developed progressive multifocal leukoencephalopathy (PML) with HIV infection is reported. The patient exhibited rapid decline in neurological status after initiation of antiretroviral therapy (ART), which was attributed to the PML-immune re-constitution inflammatory syndrome. Following the administration of mefloquine in combination with ART, the patient's neurological status improved substantially. This case suggests that further investigation of the use of mefloquine might be warranted for treatment of PML in HIV-infected patients. PMID- 22930305 TI - HIV prevalence and underreporting of men who have sex with men in Beijing. PMID- 22930306 TI - Screening for alcohol use disorders and alcohol related brief interventions in a genitourinary medicine clinic. PMID- 22930307 TI - Metronidazole treatment for acute phase amoebic liver abscess in patients co infected with HIV. AB - Metronidazole is the drug of choice for invasive amoebiasis; however, it is not known whether its dose or duration require modification in HIV infection when treating invasive amoebiasis. Seven HIV-positive patients with acute phase amoebic liver abscess were treated with daily oral administration of 1500 mg of metronidazole for 10 days. None of the patients required abscess drainage, and metronidazole was effective in all patients without serious side-effects. The CD4 cell count or HIV viral load did not appear to influence the efficacy of metronidazole therapy. PMID- 22930308 TI - Knowledge and attitudes of physicians in private practice towards HIV/AIDS in Mashhad, Iran. AB - Being responsible for providing care for HIV/AIDS in a society, physicians should be knowledgeable and have favourable attitudes. We designed a cross-sectional study to assess knowledge and attitudes towards HIV/AIDS of private practicing physicians in Mashhad, Iran. A total of 346 general practitioners and specialists completed anonymous self-administered questionnaires with response rate of 91.1%. For knowledge questions, the mean proportion of correct responses was 53.5% (+/ 13.2). Misconceptions about HIV transmission were the main areas of insufficient knowledge. Surprisingly only 20% knew how to manage a patient who had experienced sexual contact with an HIV-positive partner. While 84% disagreed that 'HIV infected individuals deserved to catch infection' owing to high-risk behaviours, 38% sympathized less with people who were infected via extramarital sex. It seems that knowledge and attitudes towards HIV/AIDS among the studied physicians is not favourable and is an area that requires attention to enable effective management of the disease in Iran. PMID- 22930309 TI - Prevalence of hepatitis in early syphilis among an HIV cohort. AB - To investigate the prevalence of syphilitic hepatitis among a group of HIV infected patients we performed a cross-sectional observational study of consecutive HIV-infected patients with early syphilis attending University Hospital Birmingham between 1 January 2005 and 31 August 2008. The AIDS Clinical Trials Group grading for abnormal liver enzymes was used to identify hepatitis. A total of 62 HIV-infected patients were diagnosed with early syphilis during the study period. Twelve (19.3%) of them demonstrated abnormal liver enzymes consistent with syphilitic hepatitis involving raised levels of alanine aminotransferase, aspartate transaminase, alkaline phosphatase or gamma-glutamyl transferase (GGT). Grade 3 hepatotoxicity was observed among five patients. None of the patients with syphilitic hepatitis had grade IV hepatitis or abnormal bilirubin levels. Liver biopsy was not carried out in any of the patients, and following completion of treatment of syphilis all abnormal liver enzymes returned to normal levels after a median of 16 weeks. Exclusion of syphilis must be considered when investigating hepatic disease in HIV-infected patients. PMID- 22930310 TI - The prevalence of six species of Mycoplasmataceae in an HIV/AIDS population in Jiangsu Province, China. AB - This study employed culture and polymerase chain reaction (PCR) to examine the prevalence of Ureaplasma urealyticum, Mycoplasma hominis, Mycoplasma genitalium, Mycoplasma fermentans, Mycoplasma penetrans and Mycoplasma pirum in 210 HIV/AIDS patients, 455 sexually transmitted infection (STI) clinic attendees and 245 healthy volunteers from first-void urine specimens for men and endocervical swabs for women. U. urealyticum and M. hominis were detected in 107 (51.0%) and 69 (32.9%) patients in the HIV/AIDS group. At least one of the other four organisms was detected in 34 (16.2%) HIV/AIDS patients, 29 (6.4%) STI clinic attendees and six (2.5%) healthy volunteers. This study showed that U. urealyticum, M. hominis and M. fermentans were significantly more prevalent in HIV/AIDS patients, as were other mycoplasmas. Our results suggest a possible role for co-infection. PMID- 22930311 TI - Validity of reported Medicare Part D enrollment in the Medical Expenditure Panel Survey. AB - The authors validate reported Part D coverage in the Medical Expenditure Panel Survey (MEPS) and assess the impact of misreporting on descriptive and behavioral analyses. MEPS participants with Medicare coverage during 2006 to 2007 were matched to Medicare administrative data. A summary measure of Part D coverage based on several questions has substantial validity (kappa = .70) and an agreement rate of 85.1%. Some beneficiaries confused Part D and private drug coverage, leading to both under- and overreported Part D coverage. Accuracy varies little by sociodemographic group. Standard regression models of the determinants of Part D enrollment were estimated with both MEPS-based and administrative data-based measures of Part D enrollment. In this analysis, the signs of the marginal effects were the same, the magnitudes were similar, and mostly the same variables had statistically significant effects in both regressions. Thus, behavioral analyses are largely unaffected by misreporting. PMID- 22930312 TI - Improving the effectiveness of health care innovation implementation: middle managers as change agents. AB - The rate of successful health care innovation implementation is dismal. Middle managers have a potentially important yet poorly understood role in health care innovation implementation. This study used self-administered surveys and interviews of middle managers in health centers that implemented an innovation to reduce health disparities to address the questions: Does middle managers' commitment to health care innovation implementation influence implementation effectiveness? If so, in what ways does their commitment influence implementation effectiveness? Although quantitative survey data analysis results suggest a weak relationship, qualitative interview data analysis results indicate that middle managers' commitment influences implementation effectiveness when middle managers are proactive. Scholars should account for middle managers' influence in implementation research, and health care executives may promote implementation effectiveness by hiring proactive middle managers and creating climates in which proactivity is rewarded, supported, and expected. PMID- 22930313 TI - Health care experiences of Hispanics in new and traditional U.S. destinations. AB - Over the past 15 years, striking new settlement patterns have emerged that have brought about unprecedented geographic dispersion in the population of approximately 45 million Hispanics in the United States. In this study, the authors compare the health care experiences of working age U.S.-born Mexican Americans and Mexican immigrants living in new and traditional Hispanic destinations. They use a geocoded version of the Medical Expenditure Panel Survey Household Component linked to contextual data from secondary sources. They characterize destinations as new or traditional using information on the percentage of the population that was Hispanic in 1990 and the growth in percent Hispanic between 1990 and 2000. The authors find that, compared with living in destinations with a well-established Hispanic presence, U.S.-born Mexican Americans living in new destinations have less favorable health care outcomes, including a greater probability of having an unmet need for or delay in receiving medical care and reduced satisfaction with care. PMID- 22930314 TI - Changes in 5-HT1A receptor expression in the oculomotor nucleus in a rat model of post-traumatic stress disorder. AB - Post-traumatic stress disorder (PTSD) is an anxiety disorder that develops after exposure to a life-threatening traumatic experience. Mental disorder appears after the traumatic stress incident and affects the movement of the eye muscle dominated by the oculomotor nucleus, an important nuclear group of the brainstem. It has been reported that dysfunction of the neurotransmitter 5-hydroxytryptamine (5-HT) can lead to the instability of the internal environment in response to stress and plays an important role in the pathology of PTSD and that the 5-HT1A receptor (5-HT1AR) is critically involved in regulating mood and anxiety levels. In this study, the 5-HT1AR expression in the oculomotor nucleus was examined in rats with single-prolonged stress (SPS), a well established post-traumatic stress disorder animal model. Our results show that the expression of 5-HT1AR in the oculomotor nucleus neurons gradually increased 1, 4, and 7 days after exposure to SPS in comparison to the normal control group, measured by immunohistochemistry, western blotting, and reverse transcription polymerase chain reaction (RT-PCR). The expression of 5-HT1AR reached its peak 7 days after the SPS exposure and then decreased 14 days after. There is also a change in the ultrastructure in the oculomotor nucleus neuron upon SPS treatment which was observed by transmission electron microscopy. These results suggest that SPS can induce a change of the 5 HT1AR expression in the oculomotor nucleus, which may be one of the molecular mechanisms that lead to PTSD. PMID- 22930315 TI - Open-cell recording of action potentials using active electrode arrays. AB - The investigation of complex communication in cellular networks requires superior measurement tools than those available to date. Electrode arrays integrated onto silicon electronics are increasingly used to measure the electrical activity of cells in an automated and highly parallelized fashion, but they are restricted to recording extracellular potentials. Here, we report on an array of TiN electrodes built using standard silicon electronics for intracellular action potential recording. Intracellular access, possible at each of the 16 384 electrodes on the chip, was accomplished by local membrane electroporation using electrical stimulation with subcellular, micrometer-sized electrodes. Access to the cell interior was transient and could be tuned in duration by adapting the electroporation protocol. Intracellular sensing was found to be minimally invasive in the short and long-term, allowing consecutive intracellular recordings from the same cell over the course of days. Finally, we applied this method to investigate the effect of an ion channel blocker on cardiac electrical activity. This technique opens the door to massively parallel, long-term intracellular recording for fundamental electrophysiology and drug screening. PMID- 22930317 TI - The interrelation between mechanical characteristics of contracting muscle, cross bridge internal structure, and the mechanism of chemomechanical energy transduction. AB - The cross-bridge working stroke is regarded as a continuous (without jumps) change of myosin head internal state under the action of a force exerted within the nucleotide-binding site. Involvement of a concept of continuous cross-bridge conformation enables discussion of the nature of the force propelling muscle, and the Coulomb repulsion of like-charged adenosine triphosphate (ATP) fragments ADP(2-) and P (i) (2-) can quite naturally be considered as the source of this force. Two entirely different types of working stroke termination are considered. Along with the fluctuation mechanism, which controls the working stroke duration t (w) at isometric contraction, another interrupt mechanism is initially taken into account. It is triggered when the lever arm shift amounts to the maximal value S ~ 11 nm, the back door opens, and P(i) crashes out. As a result, t (w) becomes inversely proportional to the velocity v of sliding filaments t (w) ~ S/v for a wide range of values of v. Principal features of the experimentally observed dependences of force, efficiency, and rate of heat production on velocity and ATP concentration can then be reproduced by fitting a single parameter: the velocity-independent time span t (r) between the termination of the last and beginning of the next working stroke. v becomes the principal variable of the model, and the muscle force changes under external load are determined by variations in v rather than in the tension of filaments. The Boltzmann equation for an ensemble of cross-bridges is obtained, and some collective effects are discussed. PMID- 22930318 TI - Effective control of recalcitrant pruritus by bevacizumab: a possible role for vascular endothelial growth factor in chronic itch? AB - Prurigo is a difficult to treat condition characterized by severe pruritus presenting with chronic secondary scratch lesions. We report here a dramatic improvement in pruritus in a patient with prurigo simplex who was being treated with bevacizumab, a monoclonal vascular endothelial growth factor (VEGF) antibody. On the basis of the increased VEGF expression measured in the skin of this patient, serum levels of VEGF were subsequently analysed in 27 consecutive patients with prurigo and 19 healthy controls. VEGF levels were significantly increased in the serum of patients with prurigo. Moreover, VEGF concentrations correlated with physician-assessed disease activity. Based on these observations, we speculate that VEGF is involved in the pathophysiology of prurigo. PMID- 22930321 TI - Highly heteroselective ring-opening polymerization of racemic lactide initiated by divalent ytterbium complexes bearing amino bis(phenolate) ligands. AB - Polymerization of racemic lactide initiated by divalent ytterbium complexes supported by either dimethylamino-amino bis(phenolate) or methoxy-amino bis(phenolate) ligands proceeds rapidly at room temperature in a living fashion to give heterotactic polylactide with the racemic enchainment of monomer units P(r) ranging from 0.97-0.99. PMID- 22930322 TI - Natural product 'legal highs'. AB - The last five years have seen a dramatic increase in the global popularity of 'Legal Highs', often referred to as Novel Psychoactive Substances (NPS). These materials are single chemicals, plant or fungal materials or their extracts, which may be purchased and possessed without legal restriction in certain countries. The single chemical entity drugs are often closely structurally related to existing controlled drugs of abuse from, for example, the amphetamine (phenethylamine), cannabinoid-mimetic or tryptamine classes, whereas the natural products are from plant or fungal materials that have a long history of pharmacognosy. These natural product legal highs are by their very nature highly chemically complex, and in the clear majority of cases, chemical studies were conducted some considerable time ago. Their pharmacology and toxicology generally focuses on the major active principles with few studies detailing the potentially highly complicated and multiple effects of their extracts. This complexity, coupled with the inherent natural product variability of plant and fungal species, adds a further dimension to the potential harms associated with natural product legal high use. This review encompasses the most popular current legal highs and describes their basic chemistry, usage and preparation, pharmacology, toxicology and discusses the issues surrounding the complexity of these materials, and how this can impact on the evaluation of their harms. PMID- 22930324 TI - Synthesis, structures, and magnetic properties of four copper compounds with 2,2' dinitrobiphenyl-4,4'-dicarboxylate. AB - Four copper(II) coordination polymers of 2,2'-dinitrobiphenyl-4,4'-dicarboxylic acid (H(2)dnbpdc), with or without 4,4'-bipyridyl (bipy) as co-ligand, were synthesized under hydrothermal conditions and characterized crystallographically and magnetically. They are formulated as [Cu(2)(dnbpdc)(OH)(2)](n) (1), [Cu(Hdnbpdc)(2)(bipy)](n).2nH(2)O (2), [Cu(2)(dnbpdc)(2)(bipy)(H(2)O)(2)](n).2nH(2)O (3) and [Cu(3)(dnbpdc)(2)(bipy)(OH)(2)(H(2)O)](n).nH(2)O (4). Compound 1 exhibits a 2D coordination network, in which infinite [Cu(MU-OH)(MU-COO)](n) chains are linked by the backbones of the dnbpdc(2-) ligands. Magnetic studies indicated antiferromagnetic coupling through the mixed hydroxo and carboxylate bridges between Cu(II) ions. In 2, mononuclear Cu(II) centers are linked by Hdnbpdc(-) and bipy ligands into 2D grid-like layers. Compound 3 also consists of 2D grid like coordination layers, which however are based on aqua-bridged Cu(2)(MU OH(2))(2) units. Magnetic studies showed that the magnetic coupling through the double aqua bridges is antiferromagnetic. Compound 4 exhibits a 3D framework in which [Cu(OH)(COO)](n) chains are linked by bipy and dnbpdc(2-) ligands. The chain has a complicated bridging network involving MU(3)-OH, MU(2)-OH and MU-COO, and magnetic studies revealed overall antiferromagnetic interactions within the chain. PMID- 22930323 TI - Predictive classification of individual magnetic resonance imaging scans from children and adolescents. AB - Neuroimaging techniques are increasingly being explored as potential tools for clinical prediction in psychiatry. There are a wide range of approaches which can be applied to make individual predictions for various aspects of disorders such as diagnostic status, symptom severity scores, identification of patients at risk of developing disorders and estimation of the likelihood of response to treatment. This selective review highlights a popular group of pattern recognition techniques, support vector machines (SVMs) for use with structural magnetic resonance imaging scans. First, however, we outline various practical issues, limitations and techniques which need to be considered before SVM's can be applied. We begin with a discussion on the practicalities of scanning children and adolescent participants and the importance of acquiring high quality images. Scan processing required for inter-subject comparisons is then discussed. We then briefly discuss feature selection and other considerations when applying pattern recognition techniques. Finally, SVMs are described and various studies highlighted to indicate the potential of these techniques for child and adolescent psychiatric research. PMID- 22930325 TI - [Analysis of image acquisition, post-processing and documentation in adolescents with spine injuries - comparison before and after referral to a university hospital]. AB - PURPOSE: Systematic evaluation of imaging situation and standards in acute spinal injuries of adolescents. MATERIALS AND METHODS: Retrospective analysis of imaging studies of transferred adolescents with spinal injuries and survey of transferring hospitals (TH) with respect to the availability of modalities and radiological expertise and post-processing and documentation of CT studies were performed. Repetitions of imaging studies and cumulative effective dose (CED) were noted. RESULTS: 33 of 43 patients (77 %) treated in our hospital (MA 17.2 years, 52 % male) and 25 of 32 TH (78 %) were evaluated. 24-hr availability of conventional radiography and CT was present in 96 % and 92 % of TH, whereas MRI was available in only 36 %. In 64 % of TH, imaging expertise was guaranteed by an on-staff radiologist. During off-hours radiological service was provided on an on call basis in 56 % of TH. Neuroradiologic and pediatric radiology expertise was not available in 44 % and 60 % of TH, respectively. CT imaging including post processing and documentation matched our standards in 36 % and 32 % of cases. The repetition rate of CT studies was 39 % (CED 116.08 mSv). CONCLUSION: With frequent CT repetitions, two-thirds of re-examined patients revealed a different clinical estimation of trauma severity and insufficient CT quality as possible causes for re-examination. A standardization of initial clinical evaluation and CT imaging could possibly reduce the need for repeat examinations. PMID- 22930327 TI - Monitoring of vegetation impact due to trampling on Cadillac Mountain summit using high spatial resolution remote sensing data sets. AB - Cadillac Mountain--the highest peak along the eastern seaboard of the United States--is a major tourist destination in Acadia National Park, Maine. Managing vegetation impact due to trampling on the Cadillac Mountain summit is extremely challenging because of the large number of visitors and the general open nature of landscape in this fragile subalpine environmental setting. Since 2000, more intensive management strategies--based on placing physical barriers and educational messages for visitors--have been employed to protect threatened vegetation, decrease vegetation impact, and enhance vegetation recovery in the vicinity of the summit loop trail. The primary purpose of this study was to evaluate the effect of the management strategies employed. For this purpose, vegetation cover changes between 2001 and 2007 were detected using multispectral high spatial resolution remote sensing data sets. A normalized difference vegetation index was employed to identify the rates of increase and decrease in the vegetation areas. Three buffering distances (30, 60, and 90 m) from the edges of the trail were used to define multiple spatial extents of the site, and the same spatial extents were employed at a nearby control site that had no visitors. No significant differences were detected between the mean rates of vegetation increase and decrease at the experimental site compared with a nearby control site in the case of a small spatial scale (<=30 m) comparison (in all cases P > 0.05). However, in the medium (<=60 m) and large (<=90 m) spatial scales, the rates of increased vegetation were significantly greater and rates of decreased vegetation significantly lower at the experimental site compared with the control site (in all cases P < 0.001). Research implications are explored that relate to the spatial extent of the radial patterns of impact of trampling on vegetation at the site level. Management implications are explored in terms of the spatial strategies used to decrease the impact of trampling on vegetation. PMID- 22930328 TI - Editorial: structural aspects of biosynthesis themed issue. PMID- 22930330 TI - Temperature dependent measurements reveal similarities between muscle and non muscle myosin motility. AB - We examined the temperature dependence of muscle and non-muscle myosin (heavy meromyosin, HMM) with in vitro motility and actin-activated ATPase assays. Our results indicate that myosin V (MV) has a temperature dependence that is similar in both ATPase and motility assays. We demonstrate that skeletal muscle myosin (SK), smooth muscle myosin (SM), and non-muscle myosin IIA (NM) have different temperature dependence in ATPase compared to in vitro motility assays. In the class II myosins we examined (SK, SM, and NM) the rate-limiting step in ATPase assays is thought to be attachment to actin or phosphate release, while for in vitro motility assays it is controversial. In MV the rate-limiting step for both in vitro motility and ATPase assays is known to be ADP release. Consequently, in MV the temperature dependence of the ADP release rate constant is similar to the temperature dependence of in vitro motility. Interestingly, the temperature dependence of the ADP release rate constant of SM and NM was shifted toward the in vitro motility temperature dependence. Our results suggest that the rate limiting step in SK, SM, and NM may shift from attachment-limited in solution to detachment limited in the in vitro motility assay. Internal strain within the myosin molecule or by neighboring myosin motors may slow ADP release which becomes rate-limiting in the in vitro motility assay. Within this small subset of myosins examined, the in vitro sliding velocity correlates reasonably well with actin-activated ATPase activity, which was suggested by the original study by Barany (J Gen Physiol 50:197-218, 1967). PMID- 22930332 TI - An economic appraisal of using source separation of human urine to contain and treat endocrine disrupters in the USA. AB - Elevated concentrations of estrogens in natural waters pose a significant threat to public health and aquatic ecosystems. Both natural (estrone, 17beta-estradiol and estriol) and synthetic (17alpha ethynylestradiol) estrogens, ubiquitous in wastewater effluents and receiving waters, have been shown to affect the endocrine system of human and aquatic life. The effects vary from cancer to sex reversals at levels as low as parts per trillion in sensitive organisms. Separation of urine, which constitutes only about 1% of domestic sewage and contains nearly all of the excreted estrogens, potentially offers an energy efficient way to contain and then treat these chemicals. With a capital expense of $2100 and operation and maintenance costs of $69 per year for a urine diverting toilet system, a family in the USA can realize estimated savings of $101 per year in energy, water, and nutrients and a decrease of 100 kg in greenhouse gas emissions. To remove 99% of estrogenicity in discharged waters would require approximately 12 kW h per year using continuous electrodialysis followed by ozonation (O(3)) of source separated urine. To achieve the same results by adding O(3) treatment after activated sludge at existing municipal wastewater treatment plants would require 23 kW h per year. From an energy standpoint it makes sense to practice source separation and treatment of urine to limit estrogen discharges into the environment. PMID- 22930331 TI - Structural dynamics of muscle protein phosphorylation. AB - We have used site-directed spectroscopic probes to detect structural changes, motions, and interactions due to phosphorylation of proteins involved in the regulation of muscle contraction and relaxation. Protein crystal structures provide static snapshots that provide clues to the conformations that are sampled dynamically by proteins in the cellular environment. Our site-directed spectroscopic experiments, combined with computational simulations, extend these studies into functional assemblies in solution, and reveal details of protein regions that are too dynamic or disordered for crystallographic approaches. Here, we discuss phosphorylation-mediated structural transitions in the smooth muscle myosin regulatory light chain, the striated muscle accessory protein myosin binding protein-C, and the cardiac membrane Ca(2+) pump modulator phospholamban. In each of these systems, phosphorylation near the N terminus of the regulatory protein relieves an inhibitory interaction between the phosphoprotein and its regulatory target. Several additional unifying themes emerge from our studies: (a) The effect of phosphorylation is not to change the affinity of the phosphoprotein for its regulated binding partner, but to change the structure of the bound complex without dissociation. (b) Phosphorylation induces transitions between order and dynamic disorder. (c) Structural states are only loosely coupled to phosphorylation; i.e., complete phosphorylation induces dramatic functional effects with only a partial shift in the equilibrium between ordered and disordered structural states. These studies, which offer atomic-resolution insight into the structural and functional dynamics of these phosphoproteins, were inspired in part by the ground-breaking work in this field by Michael and Kate Barany. PMID- 22930333 TI - Electrode-free picoinjection of microfluidic drops. AB - Existing methods for injecting reagents into drops utilize metal electrodes integrated into the microfluidic chip, adding cumbersome and error-prone steps to the fabrication process. Here, we introduce a method that uses the injection fluid itself as an electrode by exploiting dissolved electrolytes in the solution. This obviates the need for metal electrodes and reduces fabrication time and complexity while also affording precise control of the injected reagent volumes. PMID- 22930334 TI - Ring splitting of azetidin-2-ones via radical anions. AB - The radical anions of azetidin-2-ones, generated by UV-irradiation in the presence of triethylamine, undergo ring-splitting via N-C4 or C3-C4 bond breaking, leading to open-chain amides. This reactivity diverges from that found for the neutral excited states, which is characterised by alpha-cleavage. The preference for beta-cleavage is supported by DFT theoretical calculations on the energy barriers associated with the involved transition states. Thus, injection of one electron into the azetidin-2-one moiety constitutes a complementary activation strategy which may be exploited to produce new chemistry. PMID- 22930335 TI - Verbalizing extremes of the visual analogue scale for pruritus: a consensus statement. PMID- 22930336 TI - Structure and luminescence behaviour of as-synthesized, calcined, and restored MgAlEu-LDH with high crystallinity. AB - Highly crystalline Eu(3+)-incorporated MgAl layered double hydroxides (LDHs) were synthesized by the homogeneous precipitation method. For the crystals as prepared, after their calcination from 200-1000 degrees C, and, further, after restoration in a Na(2)CO(3) solution, the structural and luminescent changes were investigated for the first time. Eu(3+) ions with a coordination number of, probably, 8, were incorporated into the hydrotalcite layer, which led to a basal spacing (d(basal)) increase, microstrain formation, and crystalline morphology imperfections, while retaining the original lattice symmetry, R3[combining macron]m. In the deconstruction process due to calcination, the Eu(3+) ions restrained the formation of the spinel phase from the layered double oxide (LDO), but did not significantly change the memory effect, by which LDOs can convert to LDHs during the hydration process. For the reversible phase transformation between LDH and LDO, the morphology observation revealed that, in addition to the formation of pores on the surface, nano-slabs were formed, especially for the restored crystals. A layered phase with a d(basal) of 5.8 A, due to bridging bidentate carbonates with the hydrotalcite layer, was formed in the calcination process at low temperature (300 degrees C) before the formation of LDO, but could not be restored to a large spacing. Typical (5)D(0) -> (7)F(J) (J = 0-4) transitions of Eu(3+) at 579, 593, 615, 653, and 698 nm were observed in the photoluminescence spectra and the intensity of the dominating 615 nm band decreased with the LDH deconstruction and the formation of free water, and then increased with the formation of LDOs in the calcination process, and vice versa in the reconstruction process. The Eu(3+) ions had a probable 9- or 10 coordination mode in addition to the probable 8-coordination mode as the spinel phase appeared. PMID- 22930337 TI - Malnutrition may worsen the prognosis of critically ill children with hyperglycemia and hypoglycemia. AB - OBJECTIVES: To determine whether hyperglycemia and hypoglycemia are associated with higher mortality, longer length of intensive care unit (ICU) stay, and fewer ventilator-free days in critically ill children while taking into account the clinical severity and nutrition status. PATIENTS AND METHODS: A prospective observational cohort study was conducted on 221 children admitted to the ICU. Blood glucose levels were analyzed in the first 72 hours. Potential exposure variables for adverse prognosis included hyperglycemia (blood glucose >150 mg/dL), hypoglycemia (blood glucose <=60 mg/dL), age <1 year, sex, nutrition status, the revised Pediatric Index of Mortality (PIM 2), and the Pediatric Logistic Organ Dysfunction (PELOD). RESULTS: Of the patients, 47.1% were malnourished. Controlling for nutrition status, both hyperglycemia and hypoglycemia increased the risk of mortality in the malnourished patients compared with the well-nourished ones. Adjusting for clinical severity, the odds ratio of mortality was higher in malnourished patients with hyperglycemia (odds ratio [OR], 3.98; 95% confidence interval [CI], 1.14-13.94; P = .03), whereas no significant associations were detected in the well-nourished patients. After controlling for nutrition status, hypoglycemia was associated with longer length of ICU stay (OR, 6.5; 95% CI, 1.30-32.57; P < .01) and fewer ventilator-free days (OR, 4.11; 95% CI, 1.26-13.40; P < .01) only in the malnourished group of patients. CONCLUSIONS: Compared with the well nourished, malnourished patients with hyperglycemia are at a greater risk of mortality, independent of clinical severity. Hypoglycemia was shown to be associated with mortality, longer length of ICU stay, and fewer ventilator-free days only in malnourished patients. PMID- 22930338 TI - Residual antibiotics disrupt meat fermentation and increase risk of infection. AB - Fermented sausages, although presumed safe for consumption, sometimes cause serious bacterial infections in humans that may be deadly. Not much is known about why and when this is the case. We tested the hypothesis that residual veterinary antibiotics in meat can disrupt the fermentation process, giving pathogenic bacteria a chance to survive and multiply. We found that six commercially available starter cultures were susceptible to commonly used antibiotics, namely, oxytetracycline, penicillin, and erythromycin. In meat, statutorily tolerable levels of oxytetracycline and erythromycin inhibited fermentation performance of three and five of the six starter cultures, respectively. In model sausages, the disruption of meat fermentation enhanced survival of the pathogens Escherichia coli O157:H7 and Salmonella enterica serovar Typhimurium compared to successful fermentations. Our work reveals an overlooked risk associated with the presence of veterinary drugs in meat. IMPORTANCE: Antibiotics have for a long time been used as growth promoters in farm animals, and while they are banned as such in Europe, their clinical use in farm animals still accounts for the majority of consumption. Here, we examined how acceptable levels of antibiotics in meat influence fermentation. Our results show that commonly used bacterial starter cultures are sensitive to residual antibiotics at or near statutorily tolerable levels, and as a result, processed sausages may indeed contain high levels of pathogens. Our findings provide a possible explanation for outbreaks and disease cases associated with consumption of fermented sausages and offer yet another argument for limiting the use of antimicrobials in farm animals. PMID- 22930340 TI - Parent-reported sleep-disordered breathing symptoms early in life predict childhood behavioural problems at age 4 and 7 years. PMID- 22930339 TI - Comparative genomics of early-diverging Brucella strains reveals a novel lipopolysaccharide biosynthesis pathway. AB - Brucella species are Gram-negative bacteria that infect mammals. Recently, two unusual strains (Brucella inopinata BO1(T) and B. inopinata-like BO2) have been isolated from human patients, and their similarity to some atypical brucellae isolated from Australian native rodent species was noted. Here we present a phylogenomic analysis of the draft genome sequences of BO1(T) and BO2 and of the Australian rodent strains 83-13 and NF2653 that shows that they form two groups well separated from the other sequenced Brucella spp. Several important differences were noted. Both BO1(T) and BO2 did not agglutinate significantly when live or inactivated cells were exposed to monospecific A and M antisera against O-side chain sugars composed of N-formyl-perosamine. While BO1(T) maintained the genes required to synthesize a typical Brucella O-antigen, BO2 lacked many of these genes but still produced a smooth LPS (lipopolysaccharide). Most missing genes were found in the wbk region involved in O-antigen synthesis in classic smooth Brucella spp. In their place, BO2 carries four genes that other bacteria use for making a rhamnose-based O-antigen. Electrophoretic, immunoblot, and chemical analyses showed that BO2 carries an antigenically different O antigen made of repeating hexose-rich oligosaccharide units that made the LPS water-soluble, which contrasts with the homopolymeric O-antigen of other smooth brucellae that have a phenol-soluble LPS. The results demonstrate the existence of a group of early-diverging brucellae with traits that depart significantly from those of the Brucella species described thus far. IMPORTANCE: This report examines differences between genomes from four new Brucella strains and those from the classic Brucella spp. Our results show that the four new strains are outliers with respect to the previously known Brucella strains and yet are part of the genus, forming two new clades. The analysis revealed important information about the evolution and survival mechanisms of Brucella species, helping reshape our knowledge of this important zoonotic pathogen. One discovery of special importance is that one of the strains, BO2, produces an O-antigen distinct from any that has been seen in any other Brucella isolates to date. PMID- 22930341 TI - Appointment and medication non-adherence is associated with increased mortality in insulin-treated type 2 diabetes. PMID- 22930343 TI - Nonhemostatic adverse effects of anticoagulants and antiplatelet agents. AB - The topic of adverse effects of drugs is now receiving due attention in both the lay and medical communities. For drugs of the coagulation disorder class, such as anticoagulants and antiplatelet agents, the obvious adverse effects are bleeding from a dose too high and thrombosis from a dose too low. However, these drugs have other potential adverse effects that are not directly related to blood coagulation, yet cannot be dismissed due to their medical importance. There has been a recent advancement of several new drugs in this category and this number will soon grow as more drugs are reaching the end of their clinical trials. This article will discuss the nonhemostatic adverse effects of anticoagulants and antiplatelet drugs. As the adverse effects of bleeding and thrombosis will be excluded, this article will be in contrast to the typical discussions on the anticoagulant and antiplatelet drug classes. PMID- 22930342 TI - Viral dynamics model with CTL immune response incorporating antiretroviral therapy. AB - We present two HIV models that include the CTL immune response, antiretroviral therapy and a full logistic growth term for uninfected CD4+ T-cells. The difference between the two models lies in the inclusion or omission of a loss term in the free virus equation. We obtain critical conditions for the existence of one, two or three steady states, and analyze the stability of these steady states. Through numerical simulation we find substantial differences in the reproduction numbers and the behaviour at the infected steady state between the two models, for certain parameter sets. We explore the effect of varying the combination drug efficacy on model behaviour, and the possibility of reconstituting the CTL immune response through antiretroviral therapy. Furthermore, we employ Latin hypercube sampling to investigate the existence of multiple infected equilibria. PMID- 22930344 TI - Investigation of effects of terpene skin penetration enhancers on stability and biological activity of lysozyme. AB - The transport of proteins through skin can be facilitated potentially by using terpenes as chemical enhancers. However, we do not know about the effects of these enhancers on the stability and biological activity of proteins which is crucial for the development of safe and efficient formulations. Therefore, this project investigated the effects of terpene-based skin penetration enhancers which are reported as nontoxic to the skin (e.g., limonene, p-cymene, geraniol, farnesol, eugenol, menthol, terpineol, carveol, carvone, fenchone, and verbenone), on the conformational stability and biological activity of a model protein lysozyme. Terpene (5% v/v) was added to lysozyme solution and kept for 24 h (the time normally a transdermal patch remains) for investigating conformational stability profiles and biological activity. Fourier transform infrared spectrophotometer was used to analyze different secondary structures, e.g., alpha-helix, beta-sheet, beta-turn, and random coil. Conformational changes were also monitored by differential scanning calorimeter by determining midpoint transition temperature (Tm) and calorimetric enthalpy (DeltaH). Biological activity of lysozyme was determined by measuring decrease in A (450) when it was added to a suspension of Micrococcus lysodeikticus. The results of this study indicate that terpenes 9, 10, and 11 (carvone, L-fenchone, and L-verbenone) decreased conformational stability and biological activity of lysozyme significantly (p < 0.05) less than other terpenes used in this study. It is concluded that smaller terpenes containing ketones with low lipophilicity (log K (ow) ~2.00) would be optimal for preserving conformational stability and biological activity of lysozyme in a transdermal formulation containing terpene as permeation enhancer. PMID- 22930345 TI - Sexually transmitted penile amoebiasis in Iran: a case series. AB - OBJECTIVES: Four cases of penile amoebiasis (PA) presenting as genital ulceration seen among men who practiced unprotected insertive anal intercourse in Tehran are described. METHODS: PA was confirmed by observation of motile trophozoites of Entamoeba histolytica from lesions examined by wet mount microscopy. RESULTS: Ulcers were solitary, painful, irregular, discharging and increasing in size. Three heterosexuals and one bisexual had practised insertive anal intercourse in the 2 weeks before diagnosis. Bilateral inguinal lymphadenitis occurred in one case. Direct examination of lesions was positive for the presence of amoebic trophozoites. Complete resolution occurred after treatment with oral metronidazole 800 mg three times daily for 7-10 days. CONCLUSIONS: Clinicians need to be aware of cutaneous amoebiasis in sexually active men who practice unprotected insertive anal sex where intestinal amoebiasis is endemic. Wet mount microscopy is a rapid and useful diagnostic test. PMID- 22930346 TI - External infections contribute minimally to HIV incidence among HIV sero discordant couples in sub-Saharan Africa. AB - OBJECTIVE: Recent randomised clinical trials among stable HIV sero-discordant couples (SDCs) in sub-Saharan Africa (SSA) have reported that about 20-30% of new HIV infections are acquired from external sexual partners, rather than transmitted from the infected to the uninfected partner within the couple. The aim of this study is to examine whether, and to what extent, these findings are generalisable to SDCs in the wider population in SSA. METHODS: A mathematical model was constructed to calculate the fraction of new HIV-1 infections among SDCs that are due to sources external to the couple. The model was parameterised using empirical and population-based data for 20 countries in SSA. Uncertainty and sensitivity analyses were also conducted. RESULTS: The contribution of external infections among SDCs was generally modest, but it varied widely across SSA. In low HIV prevalence countries (<= 3.0%), it ranged from 0.6-2.9%. In intermediate prevalence countries (3.0-18.0%), it ranged from 4.9-11.7%. In Swaziland and Lesotho, the world's most-intense epidemics, sizable levels of 27.9% and 27.3% were found, respectively. CONCLUSIONS: In most countries in SSA, nearly all HIV acquisitions by the uninfected partners in SDCs appear to be due to transmissions from the HIV infected partners in the SDCs. The contribution of externally acquired infections varies with HIV population prevalence, but rarely exceeds 10% in the majority of countries. Only in hyperendemic HIV epidemics the contribution of external infections is substantial and may reach the levels reported in recent randomised clinical trials involving SDCs. PMID- 22930349 TI - The "periodic table" of di-2-pyridyl ketone: vanadium complexes. AB - The reactions of V(IV) sources and di-2-pyridyl ketone have led to V(IV)(2), V(V)(2) and V(V)(4) complexes with interesting structures and properties. PMID- 22930347 TI - The HPV vaccine: a comparison of focus groups conducted in South Africa and Ohio Appalachia. AB - Worldwide, cervical cancer is one of the leading causes of morbidity and mortality among women. Even though women in developing countries account for approximately 85 % of the cervical cancer cases and deaths, disparities in cervical cancer rates are also documented in developed countries like the United States (U.S.). Recently, formative research conducted in the U.S. and developing countries like South Africa have sought to gain a better understanding of the knowledge, beliefs, and attitudes about cervical cancer prevention, HPV, and the acceptance of the HPV vaccine. This study compares findings from two independent focus group studies. One study was conducted in a segregated township in Johannesburg, South Africa (n = 24) and the other study was conducted in Ohio Appalachia (n = 19). The following seven themes emerged during the discussions from both studies: HPV and cervical cancer; health decision making; parent-child communication; healthy children; HPV vaccine costs; sexual abuse; and HPV vaccine education. Findings from both studies indicate the importance of the role of mothers and grandmothers in the health care decision-making process for children and a lack of awareness of HPV and its association with cervical cancer. While there was interest in the HPV vaccine, participants voiced concern about the vaccine's cost and side effects. Some participants expressed concern that receipt of the HPV vaccine may initiate adolescent sexual behavior. However, other participants suggested that the HPV vaccine may protect young women who may experience sexual abuse. The importance of developing culturally appropriate educational materials and programs about cervical cancer prevention and the HPV vaccine were expressed by participants in both countries. PMID- 22930350 TI - Using Py-GC/MS to fingerprint additives associated with paper mill effluent toxicity episodes. AB - Understanding the cause of effluent toxicity is an important requirement for its prevention, remediation and return to compliance. One component of the strategy entails identification and fingerprinting of additives or components in additives that may be the cause of the toxicity episodes. A number of additives used in pulp and papermaking are polymeric compounds that are suspect in effluent toxicity. Their analysis and detection is difficult as they are not amenable to analysis by normal techniques applicable to mill effluents such as gas chromatography. Py-GC/MS is a powerful analytical technique that can be used to fingerprint these additives. The presence of the additives is confirmed by fingerprint pyrograms of the additives (or components in the formulations of the additives) in conjunction with mass spectrometry. The technique has been used to fingerprint and quantify polymeric additives associated with mill effluent toxicity episodes. PMID- 22930353 TI - Determining phase diagrams of gas-liquid systems using a microfluidic PVT. AB - A novel microfluidic device designed for analyzing phase diagrams of gas-liquid systems (PVT or pressure-volume-temperature measurements) is described. The method mimics the phase transition of a reservoir fluid as it travels through the wellbore from the formation to the surface. The device consists of a long serpentine microchannel etched in a silicon substrate. The local pressure inside the channel is measured using membrane-based optical pressure sensors positioned along the channel. Geometrical restrictions are placed along the microchannel in order to nucleate bubbles when nucleation conditions are met, thus preventing the development of a supersaturation state in the channel. We point out that a local equilibrium state between gas and liquid phases is achieved, which implies that equilibrium properties can be directly measured on the chip. We analyze different mixtures of hydrocarbon systems and, consistently with the preceding analysis, obtain excellent agreement between our technique and conventional measurements. From a practical viewpoint (important for the relevance of the technology), we observe that the measurement time of thermodynamic properties of gas-liquid systems is reduced from hours to minutes with the present device without compromising the measurement accuracy. PMID- 22930352 TI - Generalized and naevoid epidermolytic ichthyosis in Denmark: clinical and mutational findings. AB - A Danish-Swedish collaboration was established to identify and classify a Danish cohort of patients with epidermolytic ichthyosis, also known as epidermolytic hyperkeratosis. Patients were recruited from 5 dermatology departments in Denmark, and data were obtained using a structured questionnaire and a systematic examination together with photographs, histopathological descriptions and blood samples for mutational analysis. Sixteen patients from 12 families with generalized or naevoid epidermolytic ichthyosis and ichthyosis bullosa of Siemens were identified. Five families had mutations in K1 and 6 families had mutations in K10. Nine patients had been treated with systemic retinoids (etretinate, acitretin, isotretinoin or alitretinoin), but only 3 patients had acceptable treatment responses and chose to continue therapy. In conclusion epidermolytic ichthyosis is a rare disease with a prevalence of approximately 1 in 350,000 in Denmark and a high percentage of de novo mutations (75%). We identified 4 novel disease-causing mutations. PMID- 22930354 TI - Photoinduced protein modifications by methylene blue and naproxen. AB - HPLC and emission spectroscopy were used to investigate UVA photosensitization of methylene blue (MB) or naproxen (NAP) towards bovine serum albumin (BSA). In addition, time resolved singlet oxygen measurements were carried out. The most stable drug : protein adducts stoichiometry of MB-BSA (1 : 1) and NAP-BSA (9 : 1) were verified by means of binding constant determination. UVA photosensitization of MB or NAP on BSA was studied by monitoring tryptophan (Trp) residue integrity. The sensitized photodegradation of the BSA resulted in different degrees of Trp damage. Thus, protein damage was determined by quantitative measurements of the different Trp (photo)-products. Indeed, many of these Trp derivatives are diagnostic for the photosensitization mechanism and some of them, for the first time in this work, were obtained by UVA photosensitization in proteins. The analysis of quantum yields of the photoproduct distribution allowed to weigh up the type I/II contribution to the UVA photosensitization mechanism. As expected, additional experiments in deuterated solvent resulted in an increase of the photodegradation quantum yields for those species where a singlet oxygen mechanism was involved. The UVA mediated generation of these Trp derivatives is consistent with the occurrence of singlet oxygen formation (almost dominant in MB), and photoionization (significant in NAP) within the protein matrix. Additional experiments at lower NAP concentration, as well as with human serum albumin (which differs for Trp content and, partially, localization), support further the molecular mechanism of photosensitization proposed. The results obtained in the case of this more complex system are in agreement with the free Trp model, even if, in almost all cases, the Trp photoproduct formation quantum yields are lower, due to the higher number of sensitization targets in the proteins. PMID- 22930355 TI - Sequence selectivity of azinomycin B in DNA alkylation and cross-linking: a QM/MM study. AB - Azinomycin B--a well-known antitumor drug--forms cross-links with DNA through alkylation of purine bases and blocks tumor cell growth. This reaction has been modeled using the ONIOM (B3LYP/6-31+g(d):UFF) method to understand the mechanism and sequence selectivity. ONIOM results have been checked for reliability by comparing them with full quantum mechanics calculations for selected paths. Calculations reveal that, among the purine bases, guanine is more reactive and is alkylated by aziridine ring through the C10 position, followed by alkylation of the epoxide ring through the C21 position of Azinomycin B. While the mono alkylation is controlled kinetically, bis-alkylation is controlled thermodynamically. Solvent effects were included using polarized-continuum-model calculations and no significant change from gas phase results was observed. PMID- 22930357 TI - Within-city contrasts in PM composition and sources and their relationship with nitrogen oxides. AB - The present work is part of the INMA (INfancia y Medio Ambiente -'Environment and Childhood') project, which aims at assessing the adverse effects of exposure to air pollution during pregnancy and early in life. The present study was performed in the city of Sabadell (Northeast Spain) at three sampling sites covering different traffic characteristics, during two times of the year. It assesses time and spatial variations of PM(2.5) concentrations, chemical components and source contributions, as well as gaseous pollutants. Furthermore, a cross-correlation analysis of PM components and source contributions with gaseous pollutants used as a proxy for exposure assessment is carried out. Our data show the influence of traffic emissions in the Sabadell area. The main PM sources identified by Positive Matrix Factorisation (PMF) were similar between the two seasons: mineral source (traffic-induced resuspension, demolition/construction and natural background), secondary sulphate (higher in summer), secondary nitrate (only during winter), industrial, and road traffic, which was the main contributor to PM(2.5) at two of the sites. The correlation of concentrations of nitrogen oxides was especially strong with those of elemental carbon (EC). The relatively weaker correlations with organic carbon (OC) in summer are attributed to the variable formation of secondary OC. Strong correlations between concentration of nitrogen oxides and PM(2.5) road traffic contributions obtained from source apportionment analysis were seen at all sites. Therefore, under the studied urban environment, nitrogen oxides can be used as a proxy for the exposure to road traffic contribution to PM(2.5); the use of NO(x) concentrations being preferred, with NO and NO(2) as second and third options, respectively. PMID- 22930358 TI - Please register here. PMID- 22930356 TI - Interpretation of multi-detector computed tomography images before dissection may allow detection of vascular anomalies: a postmortem study of anomalous origin of the right subclavian artery and the right vertebral artery. AB - The Graduate School of Medicine at Chiba University is planning to introduce computed tomography (CT) images of donated cadavers to the gross anatomy laboratory. Here we describe an anomaly of the right subclavian artery that was detected by interpretation of CT images prior to dissection. The anomaly was verified to be the right subclavian artery, as the last branch of the aortic arch, by subsequent dissection of the cadaver. We also identified an anomalous origin of the right vertebral artery by dissection. This anomaly was also visible on CT images, although it had not been recognized in the first interpretation of the CT images. Our results suggest that branching anomalies of arteries with a diameter of >1 cm are detectable on CT images even without the injection of contrast medium. We also discuss the utility of interpreting CT images prior to dissection as a means by which medical students can gain a better understanding of human body during the gross anatomy laboratory. PMID- 22930359 TI - Indication and structures and management of transcatheter aortic valve implantation: a review of the literature. AB - BACKGROUND: Transcatheter aortic valve implantation (TAVI) is a new treatment option for patients with severe symptomatic aortic stenosis. Despite a lack of scientific evidence for a benefit of the procedure compared with surgical valve replacement or repair as the current gold standard and pending questions about safety and long-term results, a continuous and remarkable increase of its application in Germany can be observed. METHODS: In a systematic research, publications suitable for the deduction of criteria for indication and structural and process standards were identified. RESULTS: No appropriate studies exist to define scientifically sound criteria for indication and structural and process standards for TAVI. Two randomized controlled trials give hints for potential patient selection criteria. However, several interdisciplinary position statements of the most relevant scientific societies in Europe and North America provide recommendations for indication criteria and minimum structural and process requirements. TAVI should be used only in patients with contraindications for open surgery or highest perioperative risk. Multidisciplinary heart teams comprising at least one cardiac surgeon and one cardiologist are mandatory for patient selection and performance of TAVI. Structural equipment to carry out immediate open heart surgery is mandatory. Most recommendations require performing TAVI only in hospitals with a cardiac surgery unit. Participation in a registry is recommended. CONCLUSION: Currently, TAVI should be restricted to patients with severe symptomatic aortic valve stenosis and contraindications against open heart surgery or maximum perioperative risk. The surgical risk should be assessed by a multidisciplinary team. The procedure should be performed by interdisciplinary heart teams in hospitals with a cardiac surgery unit. PMID- 22930360 TI - Gamete donation in France: the future of the anonymity doctrine. AB - In France, since the approval of the first bioethics laws in 1994, the principle of the anonymity of sperm donors has prevailed. This choice is regularly challenged, namely by children who have been conceived under these conditions and have now reached adulthood. In this paper, we will briefly describe the reasons that led practitioners of assisted reproduction to endorse the anonymity principle in 1994. Secondly, we will elaborate on the reasons why this principle is becoming so controversial today. Finally, we shall examine two possible outcomes of the debate, highlighting their respective legitimacy as well as their consequences, as far as the rights of children, the notion of the family, and medical practice are concerned. PMID- 22930361 TI - A study of enzymatic activity in cell cultures via the analysis of volatile biomarkers. AB - Aldehyde dehydrogenase (ALDH) enzymes are responsible for the metabolism of aldehydes, including acetaldehyde (AA), and are linked to disease. We describe a method to study ALDH activity in cell cultures involving the measurement of AA concentrations in the gas/vapour phase. This has been achieved using selected ion flow tube mass spectrometry (SIFT-MS), developed for the rapid quantification of trace gases in humid media. Human cells of the hepG2 hepatocellular carcinoma cell line and primary bone marrow-derived mesenchymal stem cells (hMSCs) depleted AA from the culture media, but the application of ALDH inhibitors diethylaminobenzaldehyde (DEAB) and disulfiram (DSF), suppressed this depletion or in some cases resulted in elevated AA concentrations. Further, the cells were shown to reduce the dimethyl sulphoxide (DMSO) to dimethyl sulphide, which is mediated by methionine sulfoxide reductase A (MsrA) enzymes. Interestingly, this process was also inhibited by DEAB and DSF. The results of this study indicate that SIFT-MS gas phase analysis could be applied to the study of volatile metabolites of intracellular enzyme reactions, this having potential utility in disease research and drug discovery. PMID- 22930362 TI - Photodegradation of E2 in the presence of natural montmorillonite and the iron complexing agent ethylenediamine-N,N'-disuccinic acid. AB - In this work, the photochemical degradation process of 17beta-estradiol (E2) in a suspension of natural montmorillonite (NM) has been studied. The addition of the iron complexing agent ethylenediamine-N,N'-disuccinic acid (EDDS) to the suspension was investigated and compared with the system without EDDS. The effects of the main physicochemical parameters (pH, EDDS, oxygen and NM concentrations) on E2 degradation in NM suspensions were also investigated. In order to better understand the photochemical process, experiments were carried out in the presence of 2-propanol. In general, the photochemical efficiency of the E2 degradation is better in EDDS-NM suspensions than in NM suspensions, especially at higher pH. This work demonstrated that the NM-EDDS system is an interesting and valuable research area and could be considered as a promising photochemical system for wastewater treatment. PMID- 22930363 TI - Immunogenicity to biologics: mechanisms, prediction and reduction. AB - Currently, there is a significant rise in the development and clinical use of a unique class of pharmaceuticals termed as Biopharmaceuticals or Biologics, in the management of a range of disease conditions with, remarkable therapeutic benefits. However, there is an equally growing concern regarding development of adverse effects like immunogenicity in the form of anti-drug antibodies (ADA) production and hypersensitivity. Immunogenicity to biologics represents a significant hurdle in the continuing therapy of patients in a number of disease settings. Efforts focussed on the identification of factors that contribute towards the onset of immunogenic response to biologics have led to reductions in the incidence of immunogenicity. An in-depth understanding of the cellular and molecular mechanism underpinning immunogenic responses will likely improve the safety profile of biologics. This review addresses the mechanistic basis of ADA generation to biologics, with emphasis on the role of antigen processing and presentation in this process. The article also addresses the potential contribution of complement system in augmenting or modulating this response. Identifying specific factors that influences processing and presentation of biologic-derived antigens in different genotype and disease background may offer additional options for intervention in the immunogenic process and consequently, the management of immunogenicity to biologics. PMID- 22930365 TI - Size-dependent melting behavior of iron nanoparticles by replica exchange molecular dynamics. AB - Using the replica-exchange molecular dynamics method (REMD), we have investigated the size dependence of the melting behavior of iron nanoparticles. Comparing to conventional molecular dynamics (MD), the REMD method is found to be very efficient in determining the melting point by avoiding superheating and undercooling phenomena. With accurate determination of the melting point, we find that the melting temperature does not follow linearly with the inverse of size. By incorporating the size dependent thickness of surface liquid layer which is observed in our simulation, we propose a revised liquid skin melting model to describe the size dependent melting temperature. PMID- 22930364 TI - Characterization of a heavy-ion induced white flower mutant of allotetraploid Nicotiana tabacum. AB - KEY MESSAGE : We characterized a white flower mutant of allotetraploid N. tabacum as a DFR-deficient mutant; one copy of DFR has a cultivar-specific frameshift, while the other was deleted by heavy-ion irradiation. In most plants, white flowered mutants have some kind of deficiency or defect in their anthocyanin biosynthetic pathway. Nicotiana tabacum normally has pink petals, in which cyanidin is the main colored anthocyanidin. When a relevant gene in the cyanidin biosynthetic pathway is mutated, the petals show a white color. Previously, we generated white-flowered mutants of N. tabacum by heavy-ion irradiation, which is accepted as an effective mutagen. In this study, we determined which gene was responsible for the white-flowered phenotype of one of these mutants, cv. Xanthi white flower 1 (xwf1). Southern blot analysis using a DNA fragment of the dihydroflavonol 4-reductase (DFR) gene as a probe showed that the xwf1 mutant lacked signals that were present in wild-type genomic DNAs. Sequence analysis demonstrated that one copy of the DFR gene (NtDFR2) was absent from the genome of the xwf1 mutant. The other copy of the DFR gene (NtDFR1) contained a single-base deletion resulting in a frameshift mutation, which is a spontaneous mutation in cv. Xanthi. Introduction of NtDFR2 cDNA into the petal limbs of xwf1 by particle bombardment resulted in production of the pink-colored cells, whereas introduction of NtDFR1 cDNA did not. These results indicate that xwf1 is a DFR deficient mutant. One copy of NtDFR1 harbors a spontaneous frameshift mutation, while the other copy of NtDFR2 was deleted by heavy-ion beam irradiation. PMID- 22930366 TI - Novel PANK2 gene mutations in two Chinese siblings with atypical pantothenate kinase-associated neurodegeneration. AB - Pantothenate kinase-associated neurodegeneration (PKAN) is an autosomal-recessive disorder characterized by neurodegeneration and iron accumulation in the brain. Classic and atypical PKAN are distinguished on the basis of age at onset and disease progression. PANK2, localized on chromosome20p13, is confirmed as the responsible gene. We report two Chinese siblings with atypical PKAN, who had a 26 and 24-year disease course, respectively. Brain MRI scans of the two siblings showed the specific "eye of the tiger" sign. Genetic analysis identified novel compound heterozygous mutations (IVS1-2 A>T, c.T1130C) in PANK2 gene, which were confirmed to be deleterious. We verify the clinical heterogeneity even in siblings with identical genotype and expand the gene mutation pool for PKAN. PMID- 22930368 TI - Identification, emotional reactions, and perceived threat to persons with Alzheimer's disease. AB - BACKGROUND/RATIONALE: The identification of Alzheimer's Disease (AD), the emotional reactions, and the perceived threat to AD were compared across 3 Greek samples: 147 primary care health professionals (PCHPs), 74 health and social service graduate students, and 99 laypersons. Within the group of PCHPs, physicians, nurses, and social workers were compared. The factors associated with emotional reactions were examined. Finally, the Emotional Reactions Scale's (ERS) latent structure was validated. METHODS: The participants were asked to identify the disease of a vignette, respond to the ERS and in 3 indices of perceived threat. RESULTS: The PCHPs identified AD equally accurate to laypersons. Students and laypersons reported the most intense emotions. Social workers perceived higher consequences than physicians and nurses. Age, personal experience, education, and perceived concern predicted emotional reactions. CONCLUSIONS: Findings underscore the importance of implementing education and training actions to increase AD identification, reduce negative emotions, and further advance care for patients. PMID- 22930369 TI - Do you want to convince me or to be understood?: preference-consistent information sharing and its motivational determinants. AB - In two experiments, we provide evidence for a fundamental discussion asymmetry, namely, preference-consistent information sharing. Despite being in a dyadic situation requiring open information exchange and being given no incentive to do so, participants communicated more information that supported their individually preferred decision alternative than information that contradicted it. Preference consistent information sharing was not caused by biased recall and occurred in written as well as in face-to-face communication. Moreover, we tested whether preference-consistent information sharing was influenced by statements by bogus discussion partners indicating that they held a congruent versus incongruent preference to the participants' preference and that they understood versus did not understand the participants' preference. We found that when partners stated that they understood the participants' preference, subsequent preference consistent information sharing was considerably reduced. This indicates that a motivation to be understood by others might be an important driving force underlying preference-consistent information sharing. PMID- 22930370 TI - Distinguishing autonomous and directive forms of goal support: their effects on goal progress, relationship quality, and subjective well-being. AB - Three studies examined the relations of autonomy support and directive support to goal progress over 3 months. Autonomy support was defined in terms of empathic perspective-taking, whereas directive support was defined in terms of the provision of positive guidance. Results from Study 1 revealed that autonomy support between romantic partners was significantly positively related to goal progress over 3 months, and that the beneficial effect of autonomy support was mediated by enhanced autonomous goal motivation. Study 2 involved female friend dyads and extended the goal progress results to include both self-reports and reports by peers. Study 3 showed that autonomy support similarly promoted progress at vicarious goals. Across three studies, autonomy support was also significantly associated with improved relationship quality and subjective well being. Directive support was marginally associated with better goal progress across the three studies and unrelated to relationship quality or well-being. PMID- 22930371 TI - Occlusion of left main coronary artery during percutaneous coronary intervention for chronic total occlusion of left circumflex artery with retrograde approach. AB - The retrograde approach, a new technique of percutaneous coronary intervention (PCI) for chronic total occlusion (CTO), allows coronary interventionalists to improve the success rate. However, this technique occasionally has serious complications. We report a case with the occlusion of left main coronary artery (LMCA) during PCI for CTO in the proximal LCX with retrograde approach because of backward spiral dissection formed by retrograde wire. We could perform bail-out stenting for LMCA. In PCI for CTO in the proximal site of left coronary artery with retrograde approach, we should keep in mind a backward dissection to LMCA formed by retrograde wire. PMID- 22930372 TI - Deep seating of 5 Fr. guiding catheter across the stenosis with 5 in 7 method was effective for severely calcified lesion. AB - A 57-year-old male with end stage renal disease underwent coronary angiography (CAG). The CAG revealed two vessel disease with severe calcification. A week after the percutaneous coronary intervention (PCI) to the left anterior descending coronary artery (LAD), we performed PCI to the right coronary artery (RCA). Because of the calcification, no devices could be crossed. We then performed 5 in 7 method using Heartrail ST01, and inserted it across the stenosis, with dilatation balloon at the distal RCA as anchoring. Finally we managed to implant two stents. We report that 5 in 7 method and deep seating of 5 Fr. guiding catheter were effective for the severely calcified lesion. PMID- 22930373 TI - Flame retardants in eggs of American kestrels and European starlings from southern Lake Ontario region (North America). AB - While a number of studies have extensively investigated flame retardant (FR) contamination in aquatic ecosystems from the Laurentian Great Lakes basin, there remains a dearth of information for terrestrial ecosystems. In the current study, American kestrels (Falco sparverius) (AMKE) and European starlings (Sturnus vulgaris) (EUST) that are terrestrial ecosystem consumers, and from the southern Lake Ontario regions, were investigated as potential terrestrial bio-monitoring species. Egg homogenates were screened for sixteen PBDE congeners and nineteen non-PBDE FRs of established or emerging environmental importance. PBDE congeners dominated the FR burdens in eggs of AMKE and EUST, with total concentrations ranging from 3.4 to 39.8 (median: 13.5) and 1.5 to 117 (median: 4.9) ng g(-1) wet weight (ww), respectively. Although the production and application of the Firemaster FF-1 (a commercial hexabromobiphenyl PBB mixture) has been discontinued for over four decades, its major component, 2,2',4,4',5,5' hexabromobiphenyl (BB-153), was still frequently detected in AMKE and EUST eggs. Two isomers of the chlorinated FR Dechlorane plus (DP) were mostly detected in eggs collected from Niagara-on-the-Lake in the western portion of Lake Ontario, approximately 15 km from the only North American DP manufacturing site, clearly reflecting point source influences. FR comparisons in eggs from AMKE, EUST and Great Lakes herring gulls revealed species-specific contamination burdens and PBDE congener profiles, likely due to influences from trophic levels and PBDE congener-specific bioaccumulation and biomagnification capacities in terrestrial versus aquatic food chains. Insectivorous birds (e.g. great tit) and relatives of AMKE have also been used as bio-monitoring tools in European and Asian regions, allowing investigation of spatial distribution patterns on a more international scale. AMKE and EUST have also been used as model species for laboratory evaluation of FR toxic effects in birds. Therefore, AMKE and EUST are deemed valuable bio-monitoring species for investigating FR contamination in terrestrial ecosystems. PMID- 22930374 TI - Mutation screening in the mitochondrial D-loop region of tumoral and non-tumoral breast cancer in Iranian patients. AB - The mitochondrial DNA (mtDNA) mutations in mitochondrial coding and non coding regions seem to be important in carcinogenesis. The aim of this investigation was to evaluate coding region (mt-tRNA(Phe) and tRNA(Pro)) and non-coding sequence, mitochondrial displacement loop (mtDNA D-loop), in the cancerous and non cancerous lesions of Iranian patients with breast cancer (BC). Genomic DNA was extracted from 50 breast tumors and surrounding normal tissue pairs as well as from 50 unrelated normal breast tissues from Iranian Kurdish population. Subsequently, PCR amplification was performed using specific primers, and then PCR products were subjected to direct sequencing. 41 genetic variants were identified in mtDNA D-loop among tumoral and non-tumoral tissues but not in tRNA(Phe) and tRNA(Pro) sequences. Our findings indicated that C182T, 194insT, 285insA and 16342delT were just found in BC tumors whereas 302insC, C309T and C16069T found in both tumors and surrounding normal tissues. Although our findings showed that the observed genetic variations were not restricted to breast cancer tissues, some genetic changes were found only in BC tumors. Our results, in agreement with the evidence from earlier studies, confirm that the mtDNA genetic alterations might be implicated in tumor initiation, progression and development. PMID- 22930375 TI - Influence of chemotherapy on the lipid peroxidation and antioxidant status in patients with acute myeloid leukemia. AB - Chemotherapeutic agents used in patients with cancer cause to generate the enormous amounts of free radicals associated with cell injury. In this study we assess the effects of chemotherapy regimen on oxidant/antioxidant status in patients with acute myeloid leukemia (AML). 38 newly diagnosed patients with acute myeloid leukemia were recruited in this study. All patients received cytarabine and daunorubicin as chemotherapy regimen. Plasma levels of malondialdehyde (MDA), total antioxidant status (TAS), and the levels of erythrocyte activity of superoxide dismutase (SOD) and glutathione peroxidase (GPx) were determined before chemotherapy and 14 days after chemotherapy with cytarabine and daunorubicin. Plasma MDA concentrations increased significantly (from 2.68 +/- 0.89 nmol/L to 3.14 +/- 1.29 nmol/L) during the 14 days post chemotherapy period (P=0.04). Plasma TAS concentrations changed with chemotherapy from 1.09 +/- 0.15 mmol/L to 1.02 +/- 0.14 mmol/L with P=0.005. Erythrocyte SOD and GPX activity decreased overtime from 1157.24 +/- 543.61 U/g Hb to 984.01 +/- 419.09 U/g Hb (P=0.04) and 46.96 +/- 13.70 U/g Hb to 41.40 +/- 6.44 U/g Hb (P=0.02) respectively. We report here that there is an increase in malondialdehyde levels and a decrease in the levels of antioxidant enzymes and total antioxidant status. This suggests that chemotherapy causes these changes as a result of enormous production of reactive oxygen species in the patients with AML. Antioxidant supplementation must be approached with caution because of the probability of reduction the therapeutic efficacy of these cytotoxic drugs. PMID- 22930376 TI - Frozen section as a diagnostic test for major salivary gland tumors. AB - Major salivary gland tumors are uncommon and the exact nature of these tumors is not obvious. This study was carried out to compare the histological results of intraoperative frozen sections against those of permanent reports for major salivary glands masses. One hundred thirty-nine patients with major salivary gland masses who were candidates for surgery underwent an intraoperative frozen section biopsy. A permanent histological examination was then performed for definite diagnosis and its result was compared with that of the frozen section. Sensitivity, specificity, accuracy and the positive and negative predictive values were analyzed. The frozen section had 98.4% sensitivity, 87% specificity, 97.1% accuracy, 98.4% positive predictive value and 87% negative predictive value in differentiating between non-neoplastic and neoplastic lesions. In addition, the frozen section's identification of a mass as either benign or malignant showed 98% sensitivity, 100% specificity, 99.2% accuracy, 100% positive predictive value and 99% negative predictive value. Based on the current study's findings, it can be suggested that the frozen section is considerably accurate in the diagnosis of malignant versus benign lesions of major salivary glands, regardless of the exact histopathological type of the malignant tumors. PMID- 22930377 TI - Late sequelae of hip septic arthritis in children. AB - Septic arthritis of the hip in children has multiple sequelae and may result in severe disability. Significant morbidity can be prevented by early recognition and treatment. The authors reviewed 13 children with 14 hips with sequelae of septic arthritis of the hip. All of children had history of hip septic arthritis before age of 4 years. Six were male subjects, and 7 were female subjects. We evaluated the history, clinical findings and radiographs of all children who had been treated at the Imam Khomeini hospital between 1986 and 2001 for septic arthritis of the hip. Final results of operations in patients include range of motion, presence or absence pain, joint stability, limb-length discrepancy were assessed. Three hips had mild pain in usual daily activities and one patient with cerebral palsy experienced hip instability. Most of patients (80%) had flexion contracture about 10-15 degrees .Final results showed average limb length discrepancy was about 2.8 cm. Septic arthritis of the hip in children may result in a spectrum of residual problems and the significant complications can be averted by early detection and treatment. Treatment in younger age cause better outcome. PMID- 22930378 TI - When is the best time for voiding cystourethrogram in urinary tract infection of children? AB - This study was conducted to investigate whether the length of the interval between a urinary tract infection and the performance of the voiding cystourethrogram influences the presence or severity of vesicoureteral reflux (VUR). In this study 161 children with first episode of urinary tract infection were evaluated. Depending on time of performance of voiding cystourethrogram (VCUG), patients divided into two groups: early (within the first 7 days following treatment) and late (during second week or thereafter of the start of treatment). The prevalence and severity of vesicoureteral reflux in both groups were compared. Out of 161 patients, the early and late groups consisted of 75 and 86 patients, respectively. The prevalence of vesicouretral reflux in the early and late groups was 25.3% and 30.2%, respectively. No significant difference was observed between two groups regarding prevalence (P=0.598) and severity (P=0.379) of vesicoureteral reflux. This study showed that the prevalence and severity of VUR is not affected by timing of VCUG. Therefore, it is recommended that in children with urinary tract infection, VCUG should be done following negative urine culture as soon as possible. PMID- 22930379 TI - Intraventricular hemorrhage in premature infants and its association with pneumothorax. AB - Intraventricular hemorrhage (IVH) is one of the major causes of the cerebral palsy and mental retardation. Prevention and early management of these neurologic developmental problems will require determining the perinatal risk factors associated with this clinical entity. Pneumothorax increase the risk of IVH, and cause of pneumothorax has an important effect in severity of IVH. This is a prospective cross sectional study in 2010. This study includes 150 preterm neonates. Cranial ultrasound was performed in all neonates in age 3, 7, 30, 60, just after pneumothorax and every 2 week until chest tube discontinuation. Then prevalence of IVH and pneumothorax was calculated in preterm infant and severity of IVH was investigated before and after development of pneumothorax, and this comparison was divided by different causes of pneumothorax with SPSS version 11.5. Prevalence of IVH and pneumothorax in preterm infants were 30% and 10% respectively. Pneumothorax was not a risk factor of IVH (P>0.05), but prevalence of pneumothorax caused by RDS was a risk factor of development of IVH (P=0.01). Also pneumothorax in patients with birth weight less than 1000 g and gestational age less than 28 week was a risk factor of IVH pneumothorax (P=0.008, P=0.01 respectively). Our study discusses the differences in previous studies about association of pneumothorax and IVH. Also we suggest the hypothesis that lack of cerebral autoregulation in neonates with gestational age less than 28 week can cause IVH development after hypotension induces by pneumothorax. PMID- 22930380 TI - Preservation of thoracic kyphosis is critical to maintain lumbar lordosis in the surgical treatment of adolescent idiopathic scoliosis. AB - Restoration of the sagittal alignment is one of the fundamental goals in scoliosis correction surgery. Having an increase in popularity of segmental spinal instrumentation, thoracic kyphosis (TK) is often sacrificed to achieve frontal and axial plane correction. Patients with a Lenke type 1 deformity underwent selective thoracic fusion (lowest instrumented vertebra of T12 or L1) using corrective segmental spinal instrumentation (Hook-Rod) and were followed up for 2 years. They were evaluated before and after operation for coronal and sagittal alignments using standing anteroposterior and lateral radiographs. There were 63 patients (21 male, 42 female) with a mean age of 15.8 +/- 2.1 years included to this study. TK reduction had significant correlation (P<=0.001) with lumbar lordosis (LL) decrease at preoperative (r=0.47), immediately postoperative (r=0.37) and at 2-year follow-up (r=0.5). The decrease in LL after 2-years was less than decrease in TK (4.5 +/- 8.5 vs 6 +/- 10, respectively). PMID- 22930381 TI - Prevalence of vitamin D deficiency and rickets in children with cholestasis in Iran. AB - This study was aimed to determine prevalence of vitamin D deficiency and rickets in children with cholestatic liver diseases. Forty eight children with established cholestatic liver disease who referred to gastrointestinal clinic of Children Medical Center (Tehran, Iran) between April 2010 and March 2011 were enrolled in a cross-sectional study. Laboratory analysis including calcium, phosphate, albumin, total and direct bilirubin, aminotransferases, alkalinephosphatase (ALP), prothrombin time (PT), parathyroid hormone (PTH), total protein determined by routine laboratory techniques. Mean age of participants was 299.1 +/- 676.8 days (range 2-3600 days) whereas twenty one were female (43.8%) and 27 (56.3%) were male. Twenty two (45.8%) had evidences of rickets in X-ray evaluation. Three children with rickets and two with normal X ray had vitamin D deficiency while ten in rickets group and 16 in normal group had vitamin D insufficiency. The main underlying diseases were anatomical biliary atresia in cases with rickets and idiopathic in other group. Rickets and vitamin D deficiency should be considered in chronic cholestatic children. PMID- 22930382 TI - Bacterial analysis of peri-implantitis and chronic periodontitis in Iranian subjects. AB - Chronic periodontitis (CP) and peri-implantitis (PI) are multifactorial diseases of tooth and implant supporting apparatus. Bacterial invasion and consequent host immune response seem to play a role in relevant pathogenesis. The structural differences between tooth and implant pose preferential biofilm colonization. This study was aimed to compare the prevalence of bacteria in CP and PI. Clinical and radiographic examination performed over 69 individuals referred to Shahid Beheshti Dental School (Tehran, Iran) and four groups categorized: CP (n=22), HP (n=21), PI (n=13) and HI (n=13). The mean age was 45.6 years, 55% of participants were female and 45% were male. Bacterial samples were collected by paper point method and transferred to Institute of Odontology, University of Gothenburg (Gothenburg, Sweden) for checkerboard DNA-DNA hybridization. Kruskal-Wallis and Mann-Whitney U tests were used to compare distribution of bacteria in four groups. Significant differences were observed for T. forsythia, P. intermedia, C. rectus, P. endodontic, P. gingivalis, T. denticola and P. tannerae (P<0.05). The most prevalent bacteria in CP and PI were T. forsythia and P. gingivalis, respectively. In conclusion, bacterial prevalence differs significantly between tooth and implant. The most prevalent bacteria in Iranian subpopulation do not necessarily bear a resemblance to other populations. The type of implant surface may influence the biofilm. Other studies should be conducted to corroborate these findings. PMID- 22930383 TI - Changes in 4-year antimicrobial resistance pattern of gram-positive bacteria at the main referral teaching hospital, Tehran, Iran. AB - Infectious diseases are one of the most common causes of morbidity and mortality and the spread of resistant microorganisms is playing a significant role in this regard. The purpose of this study was to assess the trend in antimicrobial resistance of gram-positive bacteria at the main referral teaching hospital in Tehran during a 4-year period. All patients' biological isolates such as blood, urine, wound drainage, synovial fluid, sputum, and cerebrospinal fluid sent to the central laboratory of the hospital from 2007 to 2010 for identification and subsequently, antimicrobial susceptibility testing by Kirby-Bauer disc diffusion method were considered. All isolates (100%) of S. aureus were sensitive to vancomycin and linezolid and resistant to amoxicillin. The rate of S. aureus resistance to oxacillin increased from 60.78% in 2007 to 72% in 2010. All isolates of Streptococci in 2007 and 2008 were sensitive to vancomycin; while, 3.33% and 4.76% of Streptococci isolates were reported to be vancomycin-resistant in 2009 and 2010, respectively. Enterococci isolated from the entire specimens were identified to be sensitive to teicoplanin and linezolid and resistant to cloxacillin and oxacillin. The rates of Enterococci sensitivity to vancomycin were 90.91%, 81.25%, 86.67%, and 93.3% in 2007, 2008, 2009, and 2010, respectively. Changes of antibiotics sensitivity against g positive pathogens were significant during four years in this study. To minimize the spread of resistant gram positive pathogens, periodic and regular surveillance of antimicrobial resistance pattern is highly recommended. PMID- 22930384 TI - The first study of patient safety culture in Iranian primary health centers. AB - Although the error in health care has received attention recently, patient safety culture in health centers has been relatively neglected. To measure the patient safety culture in primary health centers. A cross-sectional study, utilizing the modified version of the Hospital Survey on Patient Safety Culture (HSOPSC) developed by the Agency for Healthcare Research and Quality (AHRQ) and a demographic questionnaire. Healthcare staffs from health centers were participated in the survey. The patient safety culture score including subscores on 11 dimensions and 39 items; patient safety grade and number of events reported. The overall positive response rate of patient safety culture was 57 +/- 16.8 (CI (95)55%-59%). The dimensions that received higher positive response rate were "Teamwork across units of health center", "Teamwork within units", "Head of center support for patient safety". The lowest percentage of positive responses was "Non punitive response to error". There were no relationship between working years and patients safely culture score. Similarly, no relationship was found between professional, gender and total patients safely culture score. Statistical analysis showed discrepancies between Iranian health centers and the US hospitals in three dimensions. For improving patient safety culture in health centers, it is necessary to have enough staff and establish an environment to be open and fair with staff which helps report errors spontaneously and without any fear. The findings of this study could be used to measure changes in patient safety culture over the time. PMID- 22930385 TI - Associations between skin diseases and quality of life: a comparison of psoriasis, vitiligo, and alopecia areata. AB - The goal of this study was to compare depression and quality of life in three auto immune diseases: psoriasis, vitiligo, and alopecia areata. From January 2009 until January 2010, 300 patients (100 with alopecia areata, 100 with psoriasis and 100 with vitiligo) who were randomly selected (by simple random selection) from outpatient clinic of Razi Hospital (Center of Skin Diseases of Tehran University of Medical Sciences) were asked to answer to Beck Depression Inventory (BDI), SF-36 and Dermatology Life Quality Index (DLQI) questionnaires. DLQI scores were significantly higher in psoriasis cases than others (12.8 +/- 6.1, P<0.0001) and SF-36 score were significantly lower (59.8 +/- 19.5, P=0.007), both indicating poor quality of life. Significant correlation was found between DLQI and BDI in all disease groups (r=0.44, P<0.001). BDI scores were the highest in psoriasis group but this difference was not significant (P=0.2). Based on these results, dermatologists should consider psychological aspects of autoimmune skin diseases. PMID- 22930386 TI - Nurses opinion on the attributes of polypharmacy in patient safety. AB - Nurses play a functional role in preventing drug related problems. They need to be aware of the dangers of polypharmacy while reviewing patient medications. We studied the nurses' opinion on the diverse effects of polypharmacy in the hospital setting. Nurses working in a tertiary care teaching hospital participated in this cross-sectional study, conducted over 3 months, by responding to a self-administered questionnaire. Chi-square test was used to analyze association between socio-demographic characteristics and items in the study. A value of P<0.05 was considered statistically significant. Increased drug interactions scored the highest (98.1%), followed by increased adverse drug effects (81.9%), and increase in financial burden (69.5%) among the negative effects of polypharmacy. 61% of the respondents felt that polypharmacy increased therapeutic effect in polypathology. No difference was observed in the opinion between male and female nurses or among varying nursing experience. Nurses with 5 10 years of experience opined increase in non-compliance to prescribed medication regimen and increase in financial burden also as negative attributes. Nurses pointed out both positive and negative implications of polypharmacy. Training programs such as continuing nursing education and workshops can be planned to translate this knowledge into practice in their routine nursing practice. PMID- 22930387 TI - Sleep-related eating disorder: a case report of a progressed night eating syndrome. AB - Night eating syndrome is a common disorder in eating behaviors that occurs in close relation to the night time sleep cycle. Although eating disorders are common in society, night eating syndrome has been left neglected by health care professionals. In this report we present a case of eating disorder that exhibits some novel features of night eating syndrome. Our case was a progressed type of eating disorder which may increase awareness among physicians about sleep-related eating disorders. PMID- 22930388 TI - Use of personalized molecular biomarkers in the clinical care of adults with glioblastomas. AB - This study was conducted to assess the current pattern of use and the impact of available molecular predictive and prognostic biomarkers on clinical care in patients with glioblastoma (GBM). An online questionnaire consisting of 15 questions about the frequency of use and clinical utility of tissue-based molecular tests was distributed to 1,053 members of the Neuro-Oncology Community in the United States. A total of 320 responses (30.4 %) were collected. 73 respondents who did not see GBM patients were excluded from analysis. MGMT promoter methylation testing (MGMT-meth) was the most commonly requested (37.2; 95 % CI, 31-44), followed by EGFR amplification (22.7; 95 % CI, 18-28), co deletion of 1p/19q (22.3 %), EGFR expression (21.5 %), P53 mutation (19.8 %), PTEN mutation or deletion (17.4 %), EGFRvIII mutation (12.1 %), IDH1/2 mutation (12.1 %), PDGFR (4.5 %), and PIK3CA (0.8 %). The perceived utility of these studies was variable between participants. A small percentage of respondents felt that any of the studies were "always" or "almost always" helpful in clinical decision making (MGMT-meth 10.9 %; range, 0-13.8 %), but more frequently "never" or "almost never" helpful (MGMT-meth 25.9 %; range, 25-54.7 %). 26.7 % reported not to routinely order any of these studies. Although molecular markers are frequently ordered for patients with GBM, only a minority of clinicians ordering these tests report that the results influence clinical decision-making. Molecular markers that are likely to affect patient care should be ordered with the goal to maximize benefit for patients and to avoid non-actionable results and additional costs. PMID- 22930389 TI - Giant cell myocarditis. Diagnosis and treatment. AB - Giant cell myocarditis (GCM) usually presents as acute dilated cardiomyopathy that does not improve with guideline-based treatments. Ventricular tachycardia and heart block occur in a substantial number of patients. Diagnosis by endomyocardial biopsy can allow for the addition of immunosuppressive therapy and timely use of mechanical circulatory support when indicated. Recent studies suggest that the ventricular arrhythmias in GCM may be mediated by a cytokine induced change in desmosomal protein expression. Genomic and proteomic studies suggest that the regulation of inflammatory pathways differs in GCM from lymphocytic myocarditis. Transplantation remains an effective therapy despite a 20-25% risk of GCM recurrence in the allograft. Recurrence in the native heart occurs up to 8 years after initial diagnosis. The long-term management of GCM patients, who initially recover, is not known and highlights the need for continuing multicenter collaborative clinical investigations. PMID- 22930391 TI - Tirofiban in Takotsubo cardiomyopathy. Atypical broken heart syndrome with extremely fast recovery: a case report. AB - Takotsubo cardiomyopathy, also known as broken heart syndrome, is similar to acute coronary syndrome. The absence of significant stenosis on coronary angiography and spontaneous improvement of ventricular akinesia are very important features that distinguish this syndrome from acute coronary syndromes. Despite the fact that ST segment elevations are typically encountered, atypical presentation without ECG changes should be kept in mind. We herein report the case of a 61-year-old woman who presented with mid-apical left ventricular akinesia resolving within 24 h. PMID- 22930390 TI - Remodelling and adverse remodelling in CAD. AB - Remodelling is the adaptive or maladaptive response to cardiac overload or injury resulting in changes of size and function of the heart. The final pathway of maladaptive or adverse cardiac remodelling is the evolution of heart failure or sudden cardiac death. In coronary artery disease, ischemic injury leads to changes in the cellular and extra-cellular architecture of the infarcted and non infarcted region resulting in cavity enlargement and loss of contractility of the entire heart. During the last three decades, potential therapeutic concepts have been established and reversal of adverse remodelling could be demonstrated in up to end-stage disease. A further understanding of the underlying cellular, extracellular, molecular and genetic alterations in ischemic remodelling should reveal other promising targets for prevention and reversal of remodelling. PMID- 22930393 TI - Photocatalytic activity of NH4F-doped TiO2 modified by noble metal nanoparticle deposition. AB - The effect of noble metal (Pt and Au) nanoparticle photodeposition on a series of NH4F-doped TiO2 photocatalysts calcined at 700 degrees C was investigated both in a thermodynamically down-hill reaction, i.e. the degradation of formic acid in aqueous suspension, and in an up-hill reaction, i.e. hydrogen production from methanol-water vapour mixtures. All photocatalysts were characterized by BET, XRD, UV-vis absorption and HRTEM analysis. Intriguing synergistic effects of simultaneous bulk and surface TiO2 modification were evidenced in both photocatalytic reactions, which can be interpreted in relation to the structural features of the materials. On one hand NH4F doping guarantees that the most active TiO2 anatase phase is stabilised up to high calcination temperature, ensuring high crystallinity and good photoinduced charge carriers production, on the other hand noble metal nanoparticles contribute in increasing the separation of photoproduced charge carriers, resulting in enhanced photocatalytic performances of the surface- and bulk-modified photocatalyst systems. PMID- 22930392 TI - Loss of miR-101 expression promotes Wnt/beta-catenin signalling pathway activation and malignancy in colon cancer cells. AB - Colorectal cancer (CRC) is the second leading cause of cancer-related mortality in Western countries. Although the aberrant expression of several microRNAs (oncomiRs) is associated with CRC progression, the molecular mechanisms of this phenomenon are still under investigation. Here we show that miR-101 expression is differentially impaired in CRC specimens, depending on tumour grade. miR-101 re expression suppresses cell growth in 3D, hypoxic survival and invasive potential in CRC cells showing low levels of miR-101. Additionally, we provide molecular evidence of a bidirectional regulatory mechanism between miR-101 expression and important CRC pro-malignant features, such as inflammation, activation of the Wnt/beta-catenin signalling pathway and epithelial-mesenchymal transition (EMT). We then propose that up-regulated miR-101 may function as a tumour suppressor in CRC and that its pharmacological restoration might hamper the aggressive behaviour of CRC in vivo. MiR-101 expression may also represent a cancer biomarker for CRC diagnosis and prognosis. PMID- 22930394 TI - Silica cross-linked nanoparticles encapsulating fluorescent conjugated dyes for energy transfer-based white light emission and porphyrin sensing. AB - This work demonstrated that water-soluble fluorescent hybrid materials can be successfully synthesized by use of silica cross-linked micellar nanoparticles (SCMNPs) as scaffolds to encapsulate fluorescent conjugated dyes for pH sensing, porphyrin sensing and tunable colour emission. Three dyes were separately encapsulated inside SCMNPs (short to dye-SCMNPs). Each of the dye-SCMNPs indicated longer lifetime in water than that of free dye dissolved in organic solvent. The 7-(hexadecyloxy) coumarin-3-ethylformate (HCE) encapsulated inside SCMNPs (HCE-SCMNPs) exhibited fluorescence quenching by pH change in aqueous media. Furthermore, it was confirmed that the radiative and nonradiative energy transfer processes both occurred between HCE-SCMNPs and tetraphenyl-porphyrin (TPP), which were used to synthesize the water-soluble TPP sensor. Significantly, HCE-SCMNPs doped with 5,12-dicotyl-quinacridone (8CQA) and TPP showed water soluble white light emission (CIE (0.29, 0.34)) upon singlet excitation of 376 nm due to colour adjustment of 8CQA and energy transfer from HCE (donor) to TPP (acceptor). PMID- 22930395 TI - Intronic promoters and their noncoding transcripts: a new source of cancer associated genes. AB - Recent studies of mammalian genomes suggest that alternative promoters are associated with various disorders, including cancer. Here we present an intronic promoter of the murine proteinase 3 gene, which drives the expression of an alternative mRNA in intron 2 of the prtn3 gene. The proximal promoter sequences were identified and a series of promoter deletion constructs were used to identify the sequence elements that are required for basal promoter activity. Expression of the homeobox transcription factor CUX1 p75 isoform was found to suppress the activity of the alternative PR3 promoter. Data base analyses, multiple alignments and expression data showed that the intronic PR3 promoter is active in leukemia and other tumor cells as well as in mouse embryo, male mammary gland and bone marrow. In the spleen, the transcript is exclusively expressed by Gr-1(int) /CD11b(+) cells, which are also known as myeloid-derived suppressor cells (MDSCs). In humans, an alternative transcript of the PR3-gene could be detected in the bone marrow and in various cancer cell lines but not in primary leukemia cells, suggesting a species-overarching function of this kind of promoter. Therefore, the alternative PR3 promoter and its mRNA may be useful tools to investigate the fate of hematopoietic stem cells. PMID- 22930396 TI - In vitro measurement of drug efficiency index to aid early lead optimization. AB - The concepts of drug efficiency (D(eff) ) and Drug Efficiency Index (DEI) have been recently introduced as useful parameters to optimize the absorption, distribution, metabolism, elimination/excretion, and toxicity properties and in vivo efficacy potential of molecules during lead optimization and at pre-clinical stages. The available free drug concentration relative to dose depends on the compound's bioavailability, clearance, and the nonspecific binding to proteins and phospholipids. In this paper, we have demonstrated, using the data of over 115 known drug molecules, that the nonspecific binding can be determined in vitro very efficiently using biomimetic high-performance liquid chromatography measurements. DEI can therefore be estimated from in vitro measurements. The data show that high in vitro DEI values can be associated with lower efficacious dose. A strategy is described of how to use the DEI parameter during early lead optimization. An example is given to highlight the advantages of optimizing on DEI value rather than on potency alone. In order to facilitate the in silico compound design, correlation between in vitro DEI and in silico ligand efficiency parameters such as ligand lipophilicity efficiency has been revealed, suggesting the potential use of these efficiency-related parameters across lead optimization. PMID- 22930397 TI - Synthesis, crystal structure and magnetism of new salicylamidoxime-based hexanuclear manganese(III) single-molecule magnets. AB - Salicylamidoxime was used to synthesize 13 new polynuclear Mn(III) complexes. We present the crystallographic structures, the magnetic susceptibility and the magnetization measurements of eight of them (1-8) with the general formula [Mn(6)O(2)(H(2)N-sao)(6)(L)(2)(solvent)(4-6)] (L = carboxylate, chloride, 2 cyanophenolate; solvent = H(2)O, MeOH, EtOH, py). These complexes consist of two trinuclear {Mn(III)(3)(MU(3)-O)(H(2)N-sao)(3)}(+) cationic units linked together via two oximate and two phenolate oxygen atoms. All behave as single-molecule magnets, with the spin ground state varying from 4 to 12 and anisotropy energy barriers from 24 to 86 K, the latter being as high as the present record barrier in the Mn(6) complexes. DFT calculations were performed to compute the exchange magnetic coupling constants J between the metallic ions and to provide an orbital interpretation of exchange. Our results are in line with previously reported results with the parent salicylaldoxime derivatives. The Mn-N-O-Mn torsion angle appears as the main parameter controlling the J values. The critical angle where the exchange coupling between two Mn(III) switches from antiferromagnetic to ferromagnetic is 27 degrees , less than the one found in related complexes with salicylaldoxime (30 degrees ). We propose a structural classification of the {Mn(6)} complexes in four classes depending on the coordination of the axial carboxylate. The work points out the structural flexibility of such systems, their sensitivity to solvent effects and their ability to achieve high anisotropy energy barriers by simple desolvation. PMID- 22930398 TI - 1,1'-Bis(diphenylphosphino)ferrocene in functional molecular materials. AB - The bidentate ligand 1,1'-bis(diphenylphosphino)ferrocene (dppf) is a widely used component in catalytic systems and its role in this capacity has been expertly reviewed elsewhere. The focus of this Perspective is the increasing use of dppf in the synthesis and matrix of 21st century materials. The ferrocene core imparts fine control to catalytic C-C and C-X coupling reactions used to manufacture a range of functional macromolecules from tailored dyes and OLED components to precisely engineered conducting polymers and thermoplastics. This ligand's limited flexibility resembles a ball and socket joint with simultaneous rotation and constrained perpendicular freedom. This uniquely restricted range of movement stabilizes a diverse array of ground and transition states for these important transition metal catalysed coupling reactions. It may also contribute desirable mechanical or electronic functionality as a bridging or chelating component in a coordination array, metallocycle or larger supramolecular assembly. The ferrocene offers steric bulk and crystallinity to these materials aiding chemical stability and ease of handing. It's oxidizability assists characterization and may be tailored to provide or complement photo- or electroactivity. Dppf containing materials have been designed with diverse functions from cooperative luminescence to host-guest complexation. It is likely that this ubiquitous lab companion will increasingly find its way into the fabric or processing of future functional molecular materials. PMID- 22930399 TI - Validation of terminal peptide of procollagen III for the detection and assessment of nonalcoholic steatohepatitis in patients with nonalcoholic fatty liver disease. AB - Liver biopsy is the reference standard for the detection of nonalcoholic steatohepatitis (NASH) within nonalcoholic fatty liver disease (NAFLD). The aim of this study was to identify a biomarker of NASH in patients without significant fibrosis. In all, 172 patients from two centers with biopsy-proven NAFLD were included in this study. Eighty-four patients from a single center were included as a derivation cohort and 88 patients from a second center were included as a validation cohort. Serum samples were tested for candidate markers of fibrosis and inflammation alongside hematological and biochemical markers. Among patients without advanced fibrosis, terminal peptide of procollagen III (PIIINP) was the only marker found to be associated with a histological diagnosis of NASH in both cohorts. PIIINP also correlated with the total NAFLD activity score (NAS) and its constituent components (P < 0.001). Area under receiver operating characteristic curve (AUROC) for PIIINP in discriminating between NASH and simple steatosis (SS) was 0.77-0.82 in patients with F0-2 fibrosis and 0.82-0.84 in patients with F0-3 fibrosis. PIIINP was elevated in patients with advanced fibrosis, the overwhelming majority of whom had NASH. When incorporating patients with all degrees of fibrosis from both cohorts, PIIINP was able to discriminate between patients with SS and those with NASH or advanced fibrosis with AUROC 0.85-0.87. CONCLUSION: PIIINP discriminates between SS and NASH or advanced fibrosis. The use of a single biomarker in this context will be of clinical utility in detecting the minority of patients with NAFLD who have NASH or advanced fibrosis related to NASH. PMID- 22930400 TI - Age- and behaviour-related changes in the expression of biogenic amine receptor genes in the antennae of honey bees (Apis mellifera). AB - We recently identified changes in amine-receptor gene expression in the antennae of the honey bee that correlate with shifts in the behavioural responsiveness of worker bees towards queen mandibular pheromone. Here we examine whether variations in expression of amine-receptor genes are related to age and/or to behavioural state. Colonies with a normal age structure were used to collect bees of different ages, as well as pollen foragers of unknown age. Single- and double cohort colonies were established also to generate nurses and pollen foragers of the same age. Amdop1 was the only gene examined that showed no significant change in expression levels across the age groups tested. However, expression of this gene was significantly higher in 6-day-old nurses than in pollen foragers of the same age. Levels of expression of Amdop2 were very variable, particularly during the first week of adult life, and showed no correlation with nursing or foraging behaviour. Amdop3 and Amtyr1 expression levels changed dramatically with age. Interestingly, Amtyr1 expression was significantly higher in 15-day-old pollen foragers than in same-age nurses, whereas the opposite was true for Amoa1. While Amoa1 expression in the antennae was lower in 6- and 15-day-old pollen foragers than in nurses of the same age, differences in gene expression levels between nurses and pollen foragers could not be detected in 22-day-old bees. Our data show dynamic modulation of gene expression in the antennae of worker bees and suggest a peripheral role for biogenic amines in regulating behavioural plasticity in the honey bee. PMID- 22930401 TI - Continuous stochastic detection of amino acid enantiomers with a protein nanopore. PMID- 22930403 TI - Curcuminoids exert glucose-lowering effect in type 2 diabetes by decreasing serum free fatty acids: a double-blind, placebo-controlled trial. AB - SCOPE: We previously found that curcuminoids decreased blood glucose and improved insulin resistance by reducing serum free fatty acids (FFAs) and increasing fatty acid oxidation in skeletal muscle of diabetic rats. This study was to investigate whether curcuminoids have beneficial effects on type 2 diabetic patients, and its possible mechanisms. METHODS AND RESULTS: Overweight/obese type 2 diabetic patients (BMI >= 24.0; fasting blood glucose >= 7.0 mmol/L or postprandial blood glucose >=11.1 mmol/L) were randomly assigned to curcuminoids (300 mg/day) or placebo for 3 months. Bodyweight, glycosylated hemoglobin A1c (HbA1c ,% ), serum fasting glucose, FFAs, lipids, and lipoprotein lipase (LPL) were determined. A total of 100 patients (curcuminoids, n = 50; placebo, n = 50) completed the trial. Curcuminoids supplementation significantly decreased fasting blood glucose (p < 0.01), HbA1c (p = 0.031), and insulin resistance index (HOMA-IR) (p < 0.01) in type 2 diabetic patients. Curcuminoids also led to a significant decrease in serum total FFAs (p < 0.01), triglycerides (P = 0.018), an increase in LPL activity (p < 0.01). CONCLUSION: These findings suggest a glucose-lowering effect of curcuminoids in type 2 diabetes, which is partially due to decrease in serum FFAs, which may result from promoting fatty acid oxidation and utilization. PMID- 22930404 TI - Psychosocial features associated with lifetime comorbidity of major depression and anxiety disorders among a community sample of mid-life women: the SWAN mental health study. AB - BACKGROUND: In clinical samples, comorbidity between depressive and anxiety disorders is associated with greater symptom severity and elevated suicide risk. Less is known, however, regarding the long-term psychosocial impact that a lifetime history of both major depressive disorder (MDD) and one or more anxiety disorders has in community samples. This report evaluates clinical, psychological, social, and stress-related characteristics associated with a lifetime history of MDD and anxiety. METHODS: Data from 915 women aged 42-52 who were recruited as part of the the Study of Women's Health across the Nation (SWAN) Mental Health Study were used to examine clinical and psychosocial features across groups of women with a lifetime history of MDD alone, anxiety alone, both MDD and anxiety, or neither MDD nor anxiety. RESULTS: As compared with women with a history of either MDD or anxiety alone, women with a comorbid history were more likely to report recurrent MDD, multiple and more severe lifetime anxiety disorders, greater depressive and anxiety symptoms, diminished social support, and more past-year distressing life events. Exploratory analyses indicated that women with a comorbid history also report more childhood abuse/neglect and diminished self-esteem, as compared with women with a history of either disorder alone. CONCLUSIONS: Midlife women with a comorbid history that includes both MDD and anxiety disorders report diminished social support, more symptomatic distress, and a more severe and recurrent psychiatric history. Future research is needed to clarify the biological and psychosocial risk factors associated with this comorobid profile, and to develop targeted interventions for this at-risk group. Depression and Anxiety 00:1-8, 2012. (c) 2012 Wiley Periodicals, Inc. PMID- 22930406 TI - Is diabetes a risk factor for central venous access port-related bloodstream infection in oncological patients? AB - It was a dogma that patients with diabetes mellitus (DM) are at increased risk of infection or death associated with an infection. However, in cancer patients, this has not been well investigated. The aim was to investigate whether diabetic patients with cancer are at high risk of central venous access port (CVAP) related bloodstream infection (BSI), and to analyse mortality after CVAP-BSI. A total of 17 patients with type 1 DM (T1DM), 66 with type 2 DM (T2DM) and 307 non diabetic patients were included. Each patient was followed up until the first late CVAP-BSI or for a maximum for 1 year in the absence of a CVAP-BSI. Fifty three CVAP-BSIs occurred in 66,528 catheter-days. The cumulative incidence of CVAP-BSI was not higher in T1DM (5.9 %; p = 0.17) and T2DM (19.7 %; p = 0.70) compared with the non-diabetic patients (12.7 %). However, in patients with CVAP BSI, the 1-month crude mortality rate was higher in DM patients (42.9 % vs. 15.4 %; p = 0.04), whereas the mortality in patients without CVAP-BSI was similar in both groups of patients (19.8 % vs. 17.1 %; p = 0.58). Of the 12 deaths that occurred within 1 month of CVAP-BSI, 16.66 % was attributable to CVAP-BSI. The predictive factor of 1-month mortality was DM (p = 0.04). Parenteral nutrition (PN) was independently associated with CVAP-BSI in diabetic patients (p = 0.001). In this study, diabetes did not increase the risk of CVAP-BSI, but mortality was higher in diabetic patients who had a CVAP-BSI. This suggests, in addition to medical treatment, CVAP should be withdrawn after infection onset. PMID- 22930408 TI - First isolation and characterization of genomic SSR markers for the giant red shrimp Aristaeomorpha foliacea (Risso, 1827). AB - Fourteen microsatellite markers were isolated from the giant red shrimp Aristaeomorpha foliacea (Risso, 1827) using the FIASCO protocol (fast isolation by AFLP of sequences containing repeats). Polymorphism was assessed in 30 individuals from two localities of the western Mediterranean basin (N = 20 from Sardinia and N = 10 from Sicily); nine loci showed polymorphism with 2 to 19 alleles per locus (average: 8.9). Polymorphic information content ranged from 0.36 to 0.91, and the observed and expected heterozygosities ranged from 0.50 to 0.97 and from 0.47 to 0.93, respectively. Two loci showed significant deviation from Hardy-Weinberg equilibrium, and evidence of linkage disequilibrium was found for only one locus pair. These loci are the first to be characterized in A. foliacea and could be effective tools for the investigation of genetic diversity, population structure, and demographic connectivity, useful information for the management of this important commercial resource. PMID- 22930407 TI - Human herpes virus co-infection is associated with mortality in HIV-negative patients with Pneumocystis jirovecii pneumonia. AB - The purpose of this investigation was to characterize the management and prognosis of severe Pneumocystis jirovecii pneumonia (PJP) in human immunodeficiency virus (HIV)-negative patients. An observational cohort study of HIV-negative adults with PJP documented by bronchoalveolar lavage (BAL) through Gomori-Grocott staining or immunofluorescence, admitted to one intensive care unit (ICU) for acute respiratory failure, was undertaken. From 1990 to 2010, 70 patients (24 females, 46 males) were included, with a mean age of 58.6 +/- 18.3 years. The mean Simplified Acute Physiology Score (SAPS)-II was 36.9 +/- 20.4. Underlying conditions included hematologic malignancies (n = 21), vasculitis (n = 13), and solid tumors (n = 13). Most patients were receiving systemic corticosteroids (n = 63) and cytotoxic drugs (n = 51). Not a single patient received trimethoprim-sulfamethoxazole as PJP prophylaxis. Endotracheal intubation (ETI) was required in 42 patients (60.0 %), including 38 with acute respiratory distress syndrome (ARDS). In-ICU mortality was 52.9 % overall, reaching 80.9 % and 86.8 %, respectively, for patients who required ETI and for patients with ARDS. In the univariate analysis, in-ICU mortality was associated with SAPS-II (p = 0.0131), ARDS (p < 0.0001), shock (p < 0.0001), and herpes simplex virus (HSV) or cytomegalovirus (CMV) on BAL (p = 0.0031). In the multivariate analysis, only ARDS was associated with in-ICU mortality (odds ratio [OR] 23.4 [4.5-121.9], p < 0.0001). PJP in non-HIV patients remains a serious disease with high in-hospital mortality. Pulmonary co-infection with HSV or CMV may contribute to fatal outcome. PMID- 22930402 TI - Augmented generation of protein fragments during wakefulness as the molecular cause of sleep: a hypothesis. AB - Despite extensive understanding of sleep regulation, the molecular-level cause and function of sleep are unknown. I suggest that they originate in individual neurons and stem from increased production of protein fragments during wakefulness. These fragments are transient parts of protein complexes in which the fragments were generated. Neuronal Ca2+ fluxes are higher during wakefulness than during sleep. Subunits of transmembrane channels and other proteins are cleaved by Ca2+-activated calpains and by other nonprocessive proteases, including caspases and secretases. In the proposed concept, termed the fragment generation (FG) hypothesis, sleep is a state during which the production of fragments is decreased (owing to lower Ca2+ transients) while fragment-destroying pathways are upregulated. These changes facilitate the elimination of fragments and the remodeling of protein complexes in which the fragments resided. The FG hypothesis posits that a proteolytic cleavage, which produces two fragments, can have both deleterious effects and fitness-increasing functions. This (previously not considered) dichotomy can explain both the conservation of cleavage sites in proteins and the evolutionary persistence of sleep, because sleep would counteract deleterious aspects of protein fragments. The FG hypothesis leads to new explanations of sleep phenomena, including a longer sleep after sleep deprivation. Studies in the 1970s showed that ethanol-induced sleep in mice can be strikingly prolonged by intracerebroventricular injections of either Ca2+ alone or Ca2+ and its ionophore (Erickson et al., Science 1978;199:1219-1221; Harris, Pharmacol Biochem Behav 1979;10:527-534; Erickson et al., Pharmacol Biochem Behav 1980;12:651-656). These results, which were never interpreted in connection to protein fragments or the function of sleep, may be accounted for by the FG hypothesis about molecular causation of sleep. PMID- 22930409 TI - Comparative analyses of genetic/epigenetic diversities and structures in a wild barley species (Hordeum brevisubulatum) using MSAP, SSAP and AFLP. AB - We analyzed genetic diversity and population genetic structure of four artificial populations of wild barley (Hordeum brevisubulatum); 96 plants collected from the Songnen Prairie in northeastern China were analyzed using amplified fragment length polymorphism (AFLP), specific-sequence amplified polymorphism (SSAP) and methylation-sensitive amplified polymorphism (MSAP) markers. Indices of (epi-)genetic diversity, (epi-)genetic distance, gene flow, genotype frequency, cluster analysis, PCA analysis and AMOVA analysis generated from MSAP, AFLP and SSAP markers had the same trend. We found a high level of correlation in the artificial populations between MSAP, SSAP and AFLP markers by the Mantel test (r > 0.8). This is incongruent with previous findings showing that there is virtually no correlation between DNA methylation polymorphism and classical genetic variation; the high level of genetic polymorphism could be a result of epigenetic regulation. We compared our results with data from natural populations. The population diversity of the artificial populations was lower. However, different from what was found using AFLP and SSAP, based on MSAP results the methylation polymorphism of the artificial populations was not significantly reduced. This leads us to suggest that the DNA methylation pattern change in H. brevisubulatum populations is not only related to DNA sequence variation, but is also regulated by other controlling systems. PMID- 22930410 TI - Glutamate-ammonia ligase and reduction of G0 population in PANC-1 cells. AB - In our previous study, we screened and isolated genes that were up-regulated after partial pancreatectomy using transcriptomic analysis and glutamate-ammonia ligase (GLUL) was selected for further study based on its effect on differentiation and proliferation. In the immunohistochemical analysis, GLUL was highly up-regulated in the acinar cells and the ductal cells in the pancreas damaged through partial pancreatectomy. Overexpression of GLUL enhanced the proliferation of PANC-1 cells and INS-1 cells. GLUL overexpression shifted the major population of PANC-1 cells from the G0/G1 phase to G2/M phase. In the double thymidine blocking analysis, similar cycle duration was observed between mock cells and GLUL-overexpressing cells while GLUL-overexpressing cells were partially resistant to thymidine blocking. In the FACS analysis of cells stained with Pyronin Y and Hoechst 33342, GLUL-overexpressing cells showed lower population of cells in the G0-quiescent phase than mock cells (5-12%). In addition, GLUL-overexpressing cells had high activation levels of AKT, ERK1/2, JNK, PCNA, c-FOS, and P70S6K in PANC-1 cells. Taken together, these results suggest that GLUL contributes to pancreatic regeneration. PMID- 22930411 TI - Facilitatory effects of an auditory warning stimulus in a visual location identification task and a visual shape identification task. AB - The occurrence of a weak auditory warning stimulus increases the speed of the response to a subsequent visual target stimulus that must be identified. This facilitatory effect has been attributed to the temporal expectancy automatically induced by the warning stimulus. It has not been determined whether this results from a modulation of the stimulus identification process, the response selection process or both. The present study examined these possibilities. A group of 12 young adults performed a reaction time location identification task and another group of 12 young adults performed a reaction time shape identification task. A visual target stimulus was presented 1850 to 2350 ms plus a fixed interval (50, 100, 200, 400, 800, or 1600 ms, depending on the block) after the appearance of a fixation point, on its left or right side, above or below a virtual horizontal line passing through it. In half of the trials, a weak auditory warning stimulus (S1) appeared 50, 100, 200, 400, 800, or 1600 ms (according to the block) before the target stimulus (S2). Twelve trials were run for each condition. The S1 produced a facilitatory effect for the 200, 400, 800, and 1600 ms stimulus onset asynchronies (SOA) in the case of the side stimulus-response (S-R) corresponding condition, and for the 100 and 400 ms SOA in the case of the side S-R non corresponding condition. Since these two conditions differ mainly by their response selection requirements, it is reasonable to conclude that automatic temporal expectancy influences the response selection process. PMID- 22930412 TI - Relationships between dendritic morphology, spatial distribution and firing patterns in rat layer 1 neurons. AB - The cortical layer 1 contains mainly small interneurons, which have traditionally been classified according to their axonal morphology. The dendritic morphology of these cells, however, has received little attention and remains ill defined. Very little is known about how the dendritic morphology and spatial distribution of these cells may relate to functional neuronal properties. We used biocytin labeling and whole cell patch clamp recordings, associated with digital reconstruction and quantitative morphological analysis, to assess correlations between dendritic morphology, spatial distribution and membrane properties of rat layer 1 neurons. A total of 106 cells were recorded, labeled and subjected to morphological analysis. Based on the quantitative patterns of their dendritic arbor, cells were divided into four major morphotypes: horizontal, radial, ascendant, and descendant cells. Descendant cells exhibited a highly distinct spatial distribution in relation to other morphotypes, suggesting that they may have a distinct function in these cortical circuits. A significant difference was also found in the distribution of firing patterns between each morphotype and between the neuronal populations of each sublayer. Passive membrane properties were, however, statistically homogeneous among all subgroups. We speculate that the differences observed in active membrane properties might be related to differences in the synaptic input of specific types of afferent fibers and to differences in the computational roles of each morphotype in layer 1 circuits. Our findings provide new insights into dendritic morphology and neuronal spatial distribution in layer 1 circuits, indicating that variations in these properties may be correlated with distinct physiological functions. PMID- 22930413 TI - Resistance exercise improves hippocampus-dependent memory. AB - It has been demonstrated that resistance exercise improves cognitive functions in humans. Thus, an animal model that mimics this phenomenon can be an important tool for studying the underlying neurophysiological mechanisms. Here, we tested if an animal model for resistance exercise was able to improve the performance in a hippocampus-dependent memory task. In addition, we also evaluated the level of insulin-like growth factor 1/insulin growth factor receptor (IGF-1/IGF-1R), which plays pleiotropic roles in the nervous system. Adult male Wistar rats were divided into three groups (N = 10 for each group): control, SHAM, and resistance exercise (RES). The RES group was submitted to 8 weeks of progressive resistance exercise in a vertical ladder apparatus, while the SHAM group was left in the same apparatus without exercising. Analysis of a cross-sectional area of the flexor digitorum longus muscle indicated that this training period was sufficient to cause muscle fiber hypertrophy. In a step-through passive avoidance task (PA), the RES group presented a longer latency than the other groups on the test day. We also observed an increase of 43 and 94% for systemic and hippocampal IGF-1 concentration, respectively, in the RES group compared to the others. A positive correlation was established between PA performance and systemic IGF-1 (r = 0.46, P < 0.05). Taken together, our data indicate that resistance exercise improves the hippocampus-dependent memory task with a concomitant increase of IGF-1 level in the rat model. This model can be further explored to better understand the effects of resistance exercise on brain functions. PMID- 22930415 TI - Quantum dot applications endowing novelty to analytical proteomics. AB - This review surveys all the state-of-art applications of quantum dots (QDs) in conventional and modern analytical methods in proteomic studies. A brief introduction of QDs and their properties is initially presented followed by outlining the application of QDs in fluorescence, MS, imaging, and cancer-based proteomics. The in-depth application of QDs in MALDI-MS and surface assisted laser desorption/ionization-MS has been elaborately discussed, summarizing the speculated mechanism behind the protein-QDs interactions during QD matrix applications leading to enhanced detection sensitivity. PMID- 22930414 TI - Single nucleotide polymorphisms of ADH1B, ADH1C and ALDH2 genes and esophageal cancer: a population-based case-control study in China. AB - Alcohol drinking is a major risk factor for esophageal cancer (EC) and the metabolism of ethanol has been suggested to play an important role in esophageal carcinogenesis. Epidemiologic studies, including genomewide association studies (GWAS), have identified single nucleotide polymorphisms (SNPs) in alcohol dehydrogenases (ADHs) and aldehyde dehydrogenases (ALDHs) to be associated with EC. Using a population-based case-control study with 858 EC cases and 1,081 controls conducted in Jiangsu Province, China, we aimed to provide further information on the association of ADH1B (rs1229984), ADH1C (rs698) and ALDH2 (rs671) polymorphisms with EC in a Chinese population. Results showed that ADH1B (rs1229984) was associated with EC with odds ratios (ORs) of 1.34 [95% confidence interval (CI): 1.08-1.66] for G-allele carriers compared to A/A homozygotes. No heterogeneity was detected on this association across different strata of alcohol drinking and tobacco smoking. Statistical interaction between ALDH2 (rs671) and alcohol drinking on EC susceptibility in both additive and multiplicative scales was observed. Compared to G/G homozygotes, A-allele carriers were positively associated with EC among moderate/heavy drinkers (OR = 1.64, 95% CI: 1.12-2.40) and inversely associated with EC among never/light drinks (OR = 0.75, 95% CI: 0.54-1.03). In addition, statistical interaction between ALDH2 and ADH1B polymorphisms on EC susceptibility among never/light drinkers was indicated. We did not observe association of ADH1C polymorphism with EC. In conclusion, our findings indicated that ADH1B (rs1229984) was associated with EC independent of alcohol drinking and tobacco smoking status and alcohol drinking interacted with ALDH2 (rs671) on EC susceptibility in this high-risk Chinese population. PMID- 22930416 TI - Evidence-based information on the clinical use of neurofeedback for ADHD. AB - Neurofeedback (NF) is a training to enhance self-regulatory capacity over brain activity patterns and consequently over brain mental states. Recent findings suggest that NF is a promising alternative for the treatment of attention deficit/hyperactivity disorder (ADHD). We comprehensively reviewed literature searching for studies on the effectiveness and specificity of NF for the treatment of ADHD. In addition, clinically informative evidence-based data are discussed. We found 3 systematic review on the use of NF for ADHD and 6 randomized controlled trials that have not been included in these reviews. Most nonrandomized controlled trials found positive results with medium-to-large effect sizes, but the evidence for effectiveness are less robust when only randomized controlled studies are considered. The direct comparison of NF and sham-NF in 3 published studies have found no group differences, nevertheless methodological caveats, such as the quality of the training protocol used, sample size, and sample selection may have contributed to the negative results. Further data on specificity comes from electrophysiological studies reporting that NF effectively changes brain activity patterns. No safety issues have emerged from clinical trials and NF seems to be well tolerated and accepted. Follow-up studies support long-term effects of NF. Currently there is no available data to guide clinicians on the predictors of response to NF and on optimal treatment protocol. In conclusion, NF is a valid option for the treatment for ADHD, but further evidence is required to guide its use. PMID- 22930418 TI - Upconversion nanoparticles for sensitive and in-depth detection of Cu2+ ions. AB - Detection of Cu(2+) ions and study of their subcellular distribution in physiological processes are of considerable significance because of their potential environmental and biological applications. Some fluorescence based sensors have been developed for selective detection of Cu(2+) ions, based on organic fluorescent probes that specifically bind to Cu(2+) ions. However, these sensors are not suitable for detection in biological samples due to the short penetration depth of UV/visible light used to excite the fluorescent probes. The use of near-infrared (NIR) light can afford penetration depths of an order of magnitude greater than that of visible light, however, a material that can convert NIR light to visible light is required. A facile method has been developed for in-depth detection of Cu(2+) ions based on fluorescence upconversion. A mesoporous silica shell is coated on upconversion nanoparticles (UCNPs) and a Cu(2+) ion sensitive fluorescent probe, rhodamine B hydrazide, is incorporated into the mesoporous silica. Upon excitation by a NIR light, the UCNPs emit visible light to excite the Cu(2+)-sensitive fluorescent probe. Because of the unique optical properties of UCNPs and their ability to convert NIR light to visible light, this is a feasible method for sensitive and in-depth detection of Cu(2+) ions in a complex biological or environmental sample due to the low autofluorescence and the high penetration depth of NIR light. PMID- 22930417 TI - Reaction time variability in ADHD: a review. AB - For the past decade, intra-individual variability in reaction times on computerized tasks has become a central focus of cognitive research on Attention Deficit/Hyperactivity Disorder (ADHD). Numerous studies document increased reaction time variability among children and adults with ADHD, relative to typically developing controls. However, direct comparisons with other disorders with heightened reaction time variability are virtually nonexistent, despite their potential to inform our understanding of the phenomenon. A growing literature examines the sensitivity of reaction time variability to theoretically and clinically relevant manipulations. There is strong evidence that stimulus treatment reduces reaction time variability during a range of cognitive tasks, but the literature is mixed regarding the impact of motivational incentives and variation in stimulus event rate. Most studies of reaction time variability implicitly assume that heightened reaction time variability reflects occasional lapses in attention, and the dominant neurophysiological interpretation suggests this variability is linked to intrusions of task-negative brain network activity during task performance. Work examining the behavioral and neurophysiological correlates of reaction time variability provides some support for these hypotheses, but considerably more work is needed in this area. Finally, because conclusions from each of domains reviewed are limited by the wide range of measures used to measure reaction time variability, this review highlights the need for increased attention to the cognitive and motivational context in which variability is assessed and recommends that future work always supplement macro level variability indices with metrics that isolate particular components of reaction time variability. PMID- 22930419 TI - Terrestrial activity in pitheciins (Cacajao, Chiropotes, and Pithecia). AB - Neotropical monkeys of the genera Cacajao, Chiropotes, and Pithecia (Pitheciidae) are considered to be highly arboreal, spending most of their time feeding and traveling in the upper canopy. Until now, the use of terrestrial substrates has not been analyzed in detail in this group. Here, we review the frequency of terrestrial use among pitheciin taxa to determine the ecological and social conditions that might lead to such behavior. We collated published and unpublished data from 14 taxa in the three genera. Data were gleaned from 53 published studies (including five on multiple pitheciin genera) and personal communications of unpublished data distributed across 31 localities. Terrestrial activity was reported in 61% of Pithecia field studies (11 of 18), in 34% of Chiropotes studies (10 of 29), and 36% of Cacajao studies (4 of 11). Within Pithecia, terrestrial behavior was more frequently reported in smaller species (e.g. P. pithecia) that are vertical clingers and leapers and make extensive use of the understory than in in the larger bodied canopy dwellers of the western Amazon (e.g. P. irrorata). Terrestrial behavior in Pithecia also occurred more frequently and lasted longer than in Cacajao or Chiropotes. An apparent association was found between flooded habitats and terrestrial activity and there is evidence of the development of a "local pattern" of terrestrial use in some populations. Seasonal fruit availability also may stimulate terrestrial behavior. Individuals also descended to the ground when visiting mineral licks, escaping predators, and responding to accidents such as a dropped infant. Overall, the results of this review emphasize that terrestrial use is rare among the pitheciins in general and is usually associated with the exploitation of specific resources or habitat types. PMID- 22930421 TI - Role of the ribosomal protein L27 revealed by single-molecule FRET study. AB - The ribosome is a ribozyme. However, in bacterial ribosomes, the N-terminus of L27 is located within the peptidyl transfer center. The roles of this protein in real time remain unclear. We present single-molecule fluorescence resonance energy transfer (FRET) studies of tRNA dynamics at the peptidyl transfer center in ribosomes containing either wild type (WT) L27, or L27 mutants with A2H3, A2H3K4 or nine N-terminal residues removed. Removing L27's first three N-terminal residues or mutating a single residue, K4, reduces the formation of a stable peptidyl tRNA after translocation. These results imply that L27 stabilizes the peptidyl tRNA and residue K4 contributes significantly to the stabilization. PMID- 22930422 TI - Graphene: an emerging electronic material. AB - Graphene, a single layer of carbon atoms in a honeycomb lattice, offers a number of fundamentally superior qualities that make it a promising material for a wide range of applications, particularly in electronic devices. Its unique form factor and exceptional physical properties have the potential to enable an entirely new generation of technologies beyond the limits of conventional materials. The extraordinarily high carrier mobility and saturation velocity can enable a fast switching speed for radio-frequency analog circuits. Unadulterated graphene is a semi-metal, incapable of a true off-state, which typically precludes its applications in digital logic electronics without bandgap engineering. The versatility of graphene-based devices goes beyond conventional transistor circuits and includes flexible and transparent electronics, optoelectronics, sensors, electromechanical systems, and energy technologies. Many challenges remain before this relatively new material becomes commercially viable, but laboratory prototypes have already shown the numerous advantages and novel functionality that graphene provides. PMID- 22930423 TI - Bioimpedance imaging: an overview of potential clinical applications. AB - Electrical Impedance Tomography (EIT) is an imaging technique based on multiple bio impedance measurements to produce a map (image) of impedance or changes in impedance across a region. Its origins lay in geophysics where it is still used to today. This review highlights potential clinical applications of EIT. Beginning with a brief overview of the underlying principles behind the modality, it describes the background research leading towards the development of the application of EIT for monitoring pulmonary function, detecting and localising tumours and monitoring brain function. PMID- 22930424 TI - Evaluation of drug supersaturation by thermodynamic and kinetic approaches for the prediction of oral absorbability in amorphous pharmaceuticals. AB - Supersaturation behavior of model drugs, danazol, griseofulvin, itraconazole, vemurafenib, and ER-34122, was analyzed by both thermodynamic and kinetic approaches to better understand the absorption characteristics of amorphous pharmaceuticals. For each amorphous drug, the extent of supersaturation during in vitro dissolution was proved to be similar to that in vivo, which was estimated from relative bioavailability data. The theoretical limit of supersaturation was thermodynamically calculated from several thermal properties and water sorption isotherms of amorphous solids. in vitro and in vivo supersaturation of amorphous vemurafenib was thermodynamically controlled and was in good agreement with the theoretical limit. On the contrary, the supersaturation ratio of the other four drugs was highly overestimated by the thermodynamic calculation. However, it was satisfactorily explained by considering supersaturation stability, which indicated how long supersaturation can be maintained without crystal nucleation. Supersaturation stability was evaluated by measuring the induction time for crystal nucleation kinetically. Concomitant use of thermodynamic and kinetic approaches is, therefore, invaluable in evaluating supersaturation behavior of amorphous materials and assessing development potential of poorly water-soluble drugs. PMID- 22930425 TI - More technology, better learning resources, better learning? Lessons from adopting virtual microscopy in undergraduate medical education. AB - The adoption of virtual microscopy at the University of Turku, Finland, created a unique real-world laboratory for exploring ways of reforming the learning environment. The purpose of this study was to evaluate the students' reactions and the impact of a set of measures designed to boost an experimental group's understanding of abnormal histology through an emphasis on knowledge of normal cells and tissues. The set of measures included (1) digital resources to review normal structures and an entrance examination for enforcement, (2) digital course slides highlighting normal and abnormal tissues, and (3) self-diagnostic quizzes. The performance of historical controls was used as a baseline, as previous students had never been exposed to the above-mentioned measures. The students' understanding of normal histology was assessed in the beginning of the module to determine the impact of the first set of measures, whereas that of abnormal histology was assessed at the end of the module to determine the impact of the whole set of measures. The students' reactions to the instructional measures were assessed by course evaluation data. Additionally, four students were interviewed. Results confirmed that the experimental group significantly outperformed the historical controls in understanding normal histology. The students held favorable opinions on the idea of emphasizing normal structures. However, with regards to abnormal histology, the historical controls outperformed the experimental group. In conclusion, allowing students access to high-quality digitized materials and boosting prerequisite skills are clearly not sufficient to boost final competence. Instead, the solution may lie in making students externally accountable for their learning throughout their training. PMID- 22930426 TI - Regulation of ATG6/Beclin-1 homologs by abiotic stresses and hormones in rice (Oryza sativa L.). AB - Autophagy, a complex and conserved mechanism, serving as a defense response in all eukaryotic organisms, is regulated by several proteins, among which ATG proteins are the most important due to their involvement in autophagosome formation. ATG6/Beclin-1 proteins, reported to be essential for autophagosome formation and assigned as a conserved domain, were subjected to database searches. We found three homologs in the rice (Oryza sativa) genome. A phylogeny tree was constructed to establish their across species relationship, which divided them into three distinct groups; two for plants, i.e., monocots and dicots, and one for animals. Evolutionary study of this family by critical amino acid conservation analysis revealed significant functional divergence. The finding of important stress-related cis-acting elements in the promoter region of rice ATG6 genes demonstrated their involvement in abiotic stress responses. Furthermore, expression profiling of rice ATG6 genes based on microarray data, as well as by semi-quantitative RT-PCR showed differential expression when subjected to different stresses suggesting the involvement of OsATG6 genes in abiotic stresses (heat, cold and drought) and hormone (abscisic acid) responses. Analysis of co-expressed genes showed that most of them annotated to DNA repair pathways and proteolysis, etc. Collectively, these results suggest the involvement of OsATG6 genes in different stresses, and provide a basis for further functional studies to investigate the biological mechanism of action of these genes under abiotic stresses. PMID- 22930427 TI - A missense mutant of the PPAR-gamma gene associated with carcass and meat quality traits in Chinese cattle breeds. AB - The peroxisome proliferator-activated receptor gamma (PPAR-gamma) is a key molecule in adipocyte differentitation; it transactivates multiple target genes in lipid metabolic pathways. Using PCR-SSCP and DNA sequencing, we evaluated a potential association of an SNP (72472 G>T in exon7) of the bovine PPAR-gamma gene with carcass and meat quality traits in 660 individuals from five Chinese indigenous cattle breeds, Qinchuan (QC), Luxi (LX), Nanyang (NY), Jiaxian (JX), and Xianan (XN). This 72472 G>T mutation identified a missense mutation, Q448H. Two alleles were named C and D. Allele frequencies of PPAR-gamma-C/D in the five breeds were 0.7815/0.2185, 0.9/0.1, 0.7442/0.2558, 0.7051/0.2949, and 0.8333/0.1667 for QC, NY, JX, LX, and XN, respectively. Except for the XN breed, all breeds were in Hardy-Weinberg equilibrium at this locus. The polymorphism information content was low for NY and XN (0.16 and 0.24, respectively), while it was moderately high for QC, JX, and LX (0.28, 0.31 and 0.33, respectively). Correlation analysis showed significant association of this missense mutation with carcass length, backfat thickness and water holding capacity in the QC breed. Animals with the genotype CD had significantly greater carcass length than those with genotypes CC and DD, while animals with genotype CC had significantly greater backfat thickness than those with genotypes CD and DD. Animals with genotype CC had lower water holding capacity than those with the genotypes CD and DD. In conclusion, this locus is a candidate for a major quantitative trait locus affecting production traits and could be used for beef breeding selection. PMID- 22930428 TI - Changes in inflorescence protein during advanced stages of floret development in Buchloe dactyloides (Poaceae). AB - Buffalograss, Buchloe dactyloides, is a dioecious species native to the Great Plains of North America. The florets at the early stages of development possess both gynoecium and androecium organ primordia but later become unisexual. Very little is known about the proteomic changes that occur when the florets change from hermaphroditism to unisexuality. We compared the protein composition of florets at the hermaphroditic stage with that at the unisexual stage. The development stage of the floret was determined by stereomicroscopic observation. Two-dimensional gel electrophoresis was used to separate the proteins extracted from female and male inflorescences. Stage- specific protein maps, with an average of about 400 spots per map, were analyzed with the protein analysis software. Eighteen spots were found to be differentially expressed between the hermaphrodite and unisexual stages. Of these, 12 were present at both stages but with a different expression value. Four specific spots appeared at the hermaphrodite stage and disappeared at the unisexual stage. Two specific protein spots were associated with female and male floret differentiation. One appears to be associated with contabescence in the female floret and the final protein appears to lead to the abortion of gynoecium in the male floret. The MALDI TOF/TOF technique was used for peptide mass fingerprinting of the differentially expressed proteins and the MASCOT software was used to search the protein database. However, only two protein spots were identified from the database. These were aldolase1 and Os05g0574400 (similar to malate dehydrogenase). This type of proteomic study can help to identify novel protein products and determine the mechanisms involved in the floral sex differentiation process in buffalo grass. PMID- 22930429 TI - Optimization of dengue virus genome assembling using GSFLX 454 pyrosequencing data: evaluation of assembling strategies. AB - Currently assembling genomes without reference is one of the most important challenges for bioinformaticists all over the world in an attempt to characterize new organisms. The current study has used two dengue virus type 4 (DENV-4) strains recently isolated in Brazil, which have its genomes sequenced using the GSFLX 454 sequencer (Roche, Life Science) by the pyrosequencing method. The GSFLX 454 data were used for testing different genome assembling strategies. We described a pipeline that was able to recover more than 96% of the sequenced genome in a single run and could be helpful for further assembly attempts of other DENV genomes, as well as other RNA virus-like genomes. PMID- 22930430 TI - Analysis of the role of hMLH1 hypermethylation and microsatellite instability in meningioma progression. AB - We investigated a possible role of hMLH1 hypermethylation and microsatellite instability in meningioma progression. Fifty meningomas were examined for methylation of hMLH1 using a methylation-specific PCR; 43 of them were analyzed for microsatellite instability using nine microsatellite markers. Loss of heterozygosity on chromosome 22q was detected using two markers. Two atypical meningiomas showed microsatellite instability at four loci; one was methylated on hMLH1 and the other was unmethylated. Nine meningiomas were found to have methylated hMLH1; the frequencies in the different grades of meningioma were one of 20, two of 16, and six of 14, respectively. We concluded that the methylation status of hMLH1 is associated with the meningioma grade but not with microsatellite instability. Loss of heterozygosity was detected in 22 cases in at least one marker. The frequency of loss of heterozygosity increased with meningioma grade, but the tendency was not significant. The correlation between loss of heterozygosity and methylation of the hMLH1 gene was also not significant. We conclude that hypermethylation of the promoter of hMLH1 is an epigenetic change in meningiomas and is associated with the tumor grade, while microsatellite instability is an uncommon event in meningiomas. PMID- 22930431 TI - Dynamic QTL analysis for fruit lycopene content and total soluble solid content in a Solanum lycopersicum x S. pimpinellifolium cross. AB - Fruit lycopene content and total soluble solid content are important factors determining fruit quality of tomatoes; however, the dynamic quantitative trait loci (QTL) controlling lycopene and soluble solid content have not been well studied. We mapped the chromosomal regions controlling these traits in different periods in F(2:3) families derived from a cross between the domestic and wild tomato species Solanum lycopersicum and S. pimpinellifolium. Fifteen QTLs for lycopene and soluble solid content and other related traits analyzed at three different fruit ripening stages were detected with a composite interval mapping method. These QTLs explained 7-33% of the individual phenotypic variation. QTLs detected in the color-changing period were different from those detected in the other two periods. On chromosome 1, the soluble solid content QTL was located in the same region during the color-changing and full-ripe periods. On chromosome 4, the same QTL for lycopene content was found during the color-changing and full ripe periods. The QTL for lycopene content on chromosome 4 co-located with the QTL for soluble solid content during the full-ripe period. Co-location of lycopene content QTL and soluble solid content QTLs may be due to pleiotropic effects of a single gene or a cluster of genes via physiological relationships among traits. On chromosome 9, the same two QTLs for lycopene content at two different fruit ripening periods may reflect genes controlling lycopene content that are always expressed in tomato fruit development. PMID- 22930432 TI - Eucalyptus growth promotion by endophytic Bacillus spp. AB - Clonal eucalyptus plantings have increased in recent years; however, some clones with high production characteristics have vegetative propagation problems because of weak root and aerial development. Endophytic microorganisms live inside healthy plants without causing any damage to their hosts and can be beneficial, acting as plant growth promoters. We isolated endophytic bacteria from eucalyptus plants and evaluated their potential in plant growth promotion of clonal plantlets of Eucalyptus urophylla x E. grandis, known as the hybrid, E. urograndis. Eighteen isolates of E. urograndis, clone 4622, were tested for plant growth promotion using the same clone. These isolates were also evaluated for indole acetic acid production and their potential for nitrogen fixation and phosphate solubilization. The isolates were identified by partial sequencing of 16S rRNA. Bacillus subtilis was the most prevalent species. Several Bacillus species, including B. licheniformis and B. subtilis, were found for the first time as endophytes of eucalyptus. Bacillus sp strain EUCB 10 significantly increased the growth of the root and aerial parts of eucalyptus plantlets under greenhouse conditions, during the summer and winter seasons. PMID- 22930433 TI - Association of single nucleotide polymorphisms in the bovine leptin and leptin receptor genes with growth and ultrasound carcass traits in Nellore cattle. AB - Given the important role of leptin in metabolism, we looked for a possible association of leptin and leptin receptor polymorphisms with carcass and growth traits in Nellore cattle. We examined associations of leptin and leptin receptor SNPs with ultrasound carcass (longissimus dorsi muscle area (ribeye area), backfat thickness and rump fat thickness and growth traits (weaning weight adjusted to 210 days of age, yearling weight adjusted to 550 days of age, weight gain of weaning to yearling and scrotal circumference adjusted to 550 days of age) of 2162 Bos primigenius indicus (Nellore) animals. Allele and genotypic frequencies were calculated for each marker. Allele substitution, additive and dominance effects of the polymorphisms were also evaluated. Some alleles of the molecular markers had low frequencies, lower than 1%, in the sample analyzed, although the same polymorphisms described for B. p. taurus cattle were found. Due to very low allelic frequencies, the E2JW, A59V and UASMS2 markers were not included in the analysis, because they were almost fixed. E2FB was found to be significantly associated with weight gain, ribeye area and backfat thickness. The promoter region markers, C963T and UASMS1, were also found to be significantly associated with ribeye area. T945M was significantly associated with weight gain. We conclude that the leptin and receptor gene markers would be useful for marker-assisted selection. PMID- 22930434 TI - Characterization of nine transferred SSR markers in the tropical tree species Enterolobium contortisiliquum (Fabaceae). AB - Transfer of molecular markers is widely used in conservation genetic studies. We investigated the transferability of simple sequence repeat (SSR) markers developed for Enterolobium cyclocarpum to E. contortisiliquum, a tropical tree widely distributed in dry forests. A set of 9 evaluated SSR markers were amplified in E. contortisiliquum and the degree of polymorphism was assessed in 8 trees sampled from each of 5 populations from central Brazil. All loci were polymorphic and the mean number of alleles for all loci was 6. In addition, all pairs of SSR markers were in linkage equilibrium. For most loci, the observed heterozygosity was higher than the expected heterozygosity under Hardy-Weinberg equilibrium, with fixation indices not significantly different from zero. The combined probability of paternity exclusion was high and the probability of identity was very low. We conclude that these SSR markers developed for E. cyclocarpum are applicable for genetic studies of E. contortisiliquum. PMID- 22930435 TI - Mapping of AFLP loci linked to tolerance to cowpea golden mosaic virus. AB - AFLP markers combined with the bulk segregant analysis methodology was used for the identification of molecular markers associated with the cowpea golden mosaic virus (CGMV) resistance gene in 286 F(2) cowpea plants derived from the cross IT97K-499-35 x Canapu T16. Segregation data in the F(2) population demonstrated that tolerance to CGMV is controlled by a single dominant gene. Among the 196 combinations of AFLP primers tested, which generated approximately 3800 amplicons, three markers linked to the CGMV resistance gene were identified: E.AAC/M.CCC(515) at 4.3 cM, E.AGG/M.CTT(280) at 14.2 cM and E.AAA/M.CAG(352) at 16.8 cM, with 50.4, 24.4, and 28.7 LOD scores, respectively; the former two markers flank the CGMV loci. These markers could be used for the development of 'sequence characterized amplified region' type markers or for greater saturation of this region, to increase the precision of assisted selection for the development of cowpea strains tolerant to CGMV. PMID- 22930436 TI - Oxidative stress proteins as an indicator of a low quality of eucalyptus clones for the pulp and paper industry. AB - Eucalyptus is a genus widely cultivated in many tropical and subtropical regions of the world as one of the main sources of raw materials for the pulp and paper industry. Identification of clones and selection of genotypes with desirable agronomic characteristics would be useful. We assessed eucalyptus full-sibs that varied in wood quality, using a combination of two-dimensional gel electrophoresis and mass spectrometry to identify differentially expressed proteins as candidates for quality markers. Thirty-one differently expressed proteins were identified, including three proteins of clone X1, four of clone X2, and 12 each of clones X3 and X4. These proteins are involved in various biological processes, including polyphosphate biosynthesis, catalytic activity, nucleotide excision repair, cellular metabolic processes, cell redox homeostasis, response to salt stress, response to temperature, oxidation and reduction processes, cellular water homeostasis, and protein phosphorylation. In the cambial region of each clone, the proteins ketol-acid reductoisomerase, uncharacterized protein MG428, receptor-like serine/threonine-protein kinase and a heat shock protein were found in larger quantities in clone X4 than in clone X1. These proteins are known to be related to protection against oxidative stress and biosynthesis of lignin. A high buildup of proteins involved in response to stress in the cambial region of eucalyptus would indicate clones with undesirable characteristics for use in the pulp and paper industry. PMID- 22930437 TI - Genetic characterization and evaluation of anthropogenic impacts on genetic patterns in cultured and wild populations of mussels (Mytilus galloprovincialis) from Greece. AB - Despite the great commercial and economic importance of mussels, Mytilus galloprovincialis (Bivalvia, Mollusca) in Greece, little information is available concerning their population genetic structure. We used RAPD markers to examine genetic differentiation and potential impact of aquaculture practices and other anthropogenic activities on the genetic structure of two cultivated and eight wild mussel populations collected from one Turkish and nine Greek coast sites. Five random decamer primers were chosen, among 34 tested, for the analysis of 433 individuals. Eighty-eight bands (genetic loci) were scored, all of which were polymorphic. No indication of reduced genetic variability was observed in the cultured populations. In contrast, a loss in genetic diversity was observed in populations from two localities (Canakkale and Kalochori) that are heavily polluted by chemical contaminants. FST analyses and exact tests revealed significant heterogeneity among M. galloprovincialis population samples, although their genetic divergence seemed to be independent of geographic distances. Anthropogenic activities, i.e., marine pollution and transplantation of mussels, appear to have played an important role in shaping patterns of genetic diversity and differentiation among Greek M. galloprovincialis populations. PMID- 22930438 TI - Short noncoding DNA fragment improve efficiencies of in vivo electroporation mediated gene transfer. AB - BACKGROUND: A major obstacle to the application of gene therapy methods in experimental and clinical practice is the lack of safe and efficient gene delivery systems. Electroporation has been shown to an effective physical delivery method. A variety of factors have been shown to affect the electroporation-mediated gene delivery efficiency. In the present study, we assessed the usefulness of noncoding short-fragment DNA (sf-DNA) for facilitating electroporation-mediated gene transfer. METHODS: The plasmid pGL3-control encoding firefly luciferase was injected into tissues together with or without sf DNA. Immediately after injection, the tissues were electroporated and the level of luciferase activity was assessed 24 h later. Different types of DNA fragments with different molecular weights, structures and doses were compared. The transfection efficiencies of sf-DNA-mediated electroporation in different tissues or with different electric field strengths were examined. RESULTS: Plasmid DNA formulated with 300-bp sf-DNA resulted in a significant improvement in electroporation-mediated gene transfer efficiency. The effect is dose-dependent and is also affected by DNA fragment length and structure. It was useful for intramuscular electroporation application, as well as intratumoral application with various pulse voltage parameters. CONCLUSIONS: The data obtained in the present study indicate that sf-DNA can be used as a helper molecule to improve electroporation-mediated gene transfection efficiency. PMID- 22930439 TI - NYVAC immunization induces polyfunctional HIV-specific T-cell responses in chronically-infected, ART-treated HIV patients. AB - We report the results of the Theravac-01 phase I trial, which was conducted to evaluate the safety and immunogenicity of a poxvirus-based vector, NYVAC, expressing Gag, Pol, Nef, and Env from an HIV clade B isolate. NYVAC-B vaccine was injected intra-muscularly into ten HIV-infected patients successfully treated with antiretroviral therapy, twice on day 0 and again at week 4. Safety and immunogenicity were monitored for 48 weeks. HIV-specific T-cell responses following immunization were quantitatively analyzed using an IFN-gamma ELISPOT assay and qualitatively characterized for their functional profile (including multiple cytokines secretion plus cytotoxic and proliferation capacity) by polychromatic flow cytometry. Our results indicate that the NYVAC-B vaccine is safe and highly immunogenic, as indicated by increased HIV-specific T-cell responses in virtually all vaccinees. Interestingly, both an expansion of preexisting T-cell responses, and the appearance of newly detected HIV-specific CD4(+) and CD8(+) T-cell responses were observed. Furthermore, immunization mostly induced an increase in Gag-specific T-cell responses. In conclusion, NYVAC B immunization induces broad, vigorous, and polyfunctional HIV-specific T-cell responses, suggesting that poxvirus-based vaccine regimens may be instrumental in the therapeutic HIV vaccine field. PMID- 22930440 TI - Secondary ion mass spectrometry imaging of molecular distributions in cultured neurons and their processes: comparative analysis of sample preparation. AB - Neurons often exhibit a complex chemical distribution and topography; therefore, sample preparation protocols that preserve structures ranging from relatively large cell somata to small neurites and growth cones are important factors in secondary ion mass spectrometry (SIMS) imaging studies. Here, SIMS was used to investigate the subcellular localization of lipids and lipophilic species in neurons from Aplysia californica. Using individual neurons cultured on silicon wafers, we compared and optimized several SIMS sampling approaches. After an initial step to remove the high salt culturing media, formaldehyde, paraformaldehyde, and glycerol, and various combinations thereof, were tested for their ability to achieve cell stabilization during and after the removal of extracellular media. These treatments improved the preservation of cellular morphology as visualized with SIMS imaging. For analytes >250 Da, coating the cell surface with a 3.2 nm-thick gold layer increased the ion intensity; multiple analytes previously not observed or observed at low abundance were detected, including intact cholesterol and vitamin E molecular ions. However, once a sample was coated, many of the lower molecular mass (<200 Da) analyte signals were suppressed. The optimum approach depended on the analyte being studied; the approaches evaluated included rinsing with water and cell stabilization with glycerol and 4 % paraformaldehyde. The sample preparation methods described here enhance SIMS imaging of processes of individual cultured neurons over a broad mass range with enhanced image contrast. PMID- 22930441 TI - Metabolism and permeability of curcumin in cultured Caco-2 cells. AB - SCOPE: Curcumin (CUR) and its major metabolite hexahydro-CUR were studied in Caco 2 cells and in the Caco-2 Millicell(r) system in vitro to simulate their in vivo intestinal metabolism and absorption in humans. METHODS AND RESULTS: Analysis of the incubation medium and cell lysate showed that Caco-2 cells reduce CUR to hexahydro-CUR and octahydro-CUR, and conjugate CUR and its reductive metabolites with glucuronic acid and sulfate. Using the Caco-2 Millicell(r) system, an efficient transfer of the conjugates into the basolateral, but not the apical, compartment was observed after apical administration. Likewise, hexahydro-CUR was reduced to octahydro-CUR, and glucuronide and sulfate conjugates almost exclusively permeated to the basolateral side. The apparent permeability coefficients (Papp values) of CUR, hexahydro-CUR and their metabolites were determined and found to be extremely low for unchanged CUR, but somewhat higher for hexahydro-CUR and the conjugated metabolites. CONCLUSION: The results of this study clearly show that the systemic bioavailability of CUR from the intestine after oral intake must be expected to be virtually zero. Reductive and conjugated metabolites, formed from CUR in the intestine, exhibit moderate absorption. Thus, any biological effects elicited by CUR in tissues other than the gastrointestinal tract are likely due to CUR metabolites. PMID- 22930442 TI - Anatomy of hallux valgus in rheumatoid arthritis: radiographic analysis using a two-dimensional coordinate system. AB - OBJECTIVE: The purpose of this study is to compare the anatomy of rheumatoid hallux valgus with that of idiopathic hallux valgus from the standpoint of joint preserving surgery. METHODS: One hundred forty-eight feet of 81 rheumatoid patients were included. Feet with idiopathic hallux valgus and normal feet were compared as controls. Weight-bearing dorsoplantar radiographs of the feet were taken of each patient. A two-dimensional coordinate system was defined on the radiographic image, and 19 anatomic points of the forefoot were measured. RESULTS: In rheumatoid hallux valgus, the first metatarsal head shifted medially as hallux valgus angle increased, which was similar to the deformity of idiopathic hallux valgus. Proximal deviation of the tips of the lesser toes, caused by clawing and dislocations of the metatarsophalangeal joints, occurred in rheumatoid hallux valgus. Specifically the tips of the second toes in rheumatoid hallux valgus were located more proximally than those in idiopathic hallux valgus irrespective of the severity of hallux valgus. CONCLUSIONS: Corrective osteotomy of the first metatarsal is a reasonable procedure for rheumatoid hallux valgus. Additionally, correction of the second toe deformity to make a stable lateral support on the hallux may be another important factor for successful joint preserving surgery. PMID- 22930443 TI - Observation of two types of magnetization relaxation in a weakly correlated antiferromagnetic chain of Mn(III)2 single-molecule magnets. AB - A Mn(III)(2)Fe(II) chain with a [-Mn(III)-(O(Ph))(2)-Mn(III)-ON-Fe(II)-NO-] repeat unit was synthesized via the assembling reaction of Mn(III) salen-type dimers and Fe(II) pyridyloximate complexes, where the -(O(Ph))- and -ON- bridges represent a biphenolate bridge and an oximate bridge, respectively. The bulky counter anions, BPh(4)(-), which surround the chain to form a zeolite-like brick wall, successfully isolate the chains from a magnetic point of view. This compound is isostructural with Mn(2)Ni-BPh(4), which is an SCM with S(T) = 3 (H. Miyasaka, A. Saitoh, M. Yamashita and R. Clerac, Dalton Trans., 2008, 2422). Because the Fe(II) unit is diamagnetic, the Mn(III) dimer, which has the potential to be a single-molecule magnet (SMM), is nearly magnetically isolated, although a weak antiferromagnetic interaction with J/k(B)~-0.1 K is perturbed between the Mn(III) dimers with S(T) = 4 via the Fe(II) unit. Ac susceptibility data shows that two types of relaxation of the magnetization are present, which are attributed to SMM and chain relaxations. PMID- 22930444 TI - FOXO3a/p27kip1 expression and essential role after acute spinal cord injury in adult rat. AB - FOXO3a (Forkhead Class box O3a), as an important direct target of the phosphatidylinositol 3-kinase (PI3K)/protein B (Akt) pathway, which regulates the cell survival and the cell-cycle progression. Recent reports showed that FOXO3a could inhibit cell-cycle progression at the G1/S transition by controlling transcription of the cyclin-dependent kinase inhibitor p27(kip1) , which is also a key regulator of the mammalian neurogenesis. To elucidate the expression and role of FOXO3a in nervous system lesion and repair, we performed an acute spinal cord contusion injury (SCI) model in adult rats, which showed a temporal-spatial expression pattern of FOXO3a. Temporally, FOXO3a protein level significantly reduced day 3 after injury, and following FOXO3a down-regulation, p27(kip1) protein and mRNA levels were also decreased after injury. Spatially, decreased levels of FOXO3a and p27(kip1) were predominant in astrocytes, which were regenerating axons and largely proliferated after injury. Furthermore in vitro, Western blot analysis, RT-PCR, and immunofluorescence staining analysis demonstrated the relationship between FOXO3a and p27(kip1) in primary astrocytes. FOXO3a modulated the cell cycle by transcriptional regulation of p27(kip1) in astrocytes. Administration of the PI3K pharmacological inhibitor LY294002 abrogated this effect by regulating FOXO3a and p27(kip1) expression and subcellular localization. These results suggest that decreased levels of FOXO3a and p27(kip1) in spinal cord are involved in axonal regeneration and the proliferation of glial cells after SCI. PMID- 22930445 TI - Trajectory of isoelectric focusing from gels to capillaries to immobilized gradients in capillaries. AB - This review presents the need for replacing gels in 2D separations for proteomics, where speed, high-throughput, and the ability to characterize trace level proteins or small samples are the current desires. The theme of the review is isoelectric focusing, which is a valuable tool because it pre-concentrates proteins in addition to separating with high peak capacity. The review traces the technological progress from gel IEF to CIEF to packed capillaries with immobilized gradients for CIEF. Multiple capillary techniques are progressing toward meeting the current desires, providing extremely high sensitivity with regard to concentration and to small samples, integrated automation, and high peak capacity from multiple dimensions of separation. Capillaries with immobilized pH gradients for CIEF are emerging, which will alleviate interference from ampholytes and improve reproducibility in separation times when this valuable technique can be used as one of the dimensions. PMID- 22930447 TI - Assessing the differential affinity of small molecules for noncanonical DNA structures. AB - The targeting of higher-order DNA structures has been thoroughly developed with G quadruplex DNA but not with other structures like branched DNA (also known as DNA junctions). Because these alternative higher-order DNA architectures might be of high biological relevance, we implemented a high-throughput version of the FRET melting assay that enabled us to map the interactions of a candidate with four different DNA structures (duplex- and quadruplex DNA, three- and four-way junctions) in a rapid and reliable manner. We also introduce a novel index, the BONDS (branched and other noncanonical DNA selectivity) index, to conveniently quantify this differential affinity. PMID- 22930449 TI - Author's reply to: "Prognostic value of cetuximab related skintoxicity in metastatic colorectal cancer patients and its correlation with parameters of the EGFR signal transduction pathway: results from a randomized trial of the GERMAN AIO CRC Study Group". PMID- 22930448 TI - A TFIIIA-type zinc finger protein confers multiple abiotic stress tolerances in transgenic rice (Oryza sativa L.). AB - The TFIIIA-type zinc finger transcription factors are involved in plant development and abiotic stress responses. Most TFIIIA-type zinc finger proteins are transcription repressors due to existence of an EAR-motif in their amino acid sequences. In this work, we found that ZFP182, a TFIIIA-type zinc finger protein, forms a homodimer in the nucleus and exhibits trans-activation activity in yeast cells. The deletion analysis indicated that a Leu-rich region at C-terminus is required for the trans-activation. Overexpression of ZFP182 significantly enhanced multiple abiotic stress tolerances, including salt, cold and drought tolerances in transgenic rice. Overexpression of ZFP182 promotes accumulation of compatible osmolytes, such as free proline and soluble sugars, in transgenic rice. ZFP182 activates the expression of OsP5CS encoding pyrroline-5-carboxylate synthetase and OsLEA3 under stress conditions, while OsDREB1A and OsDREB1B were regulated by ZFP182 under both normal and stress conditions. Interestingly, site directed mutagenesis assay showed that DRE-like elements in ZFP182 promoter are involved in dehydration-induced expression of ZFP182. The yeast two-hybrid assay revealed that ZFP182 interacted with several ribosomal proteins including ZIURP1, an ubiquitin fused to ribosomal protein L40. The in vivo and in vitro interactions of ZFP182 and ZIURP1 were further confirmed by bimolecular fluorescence complementation and His pull-down assays. Our studies provide new clues in the understanding of the mechanisms for TFIIIA-type zinc finger transcription factor mediated stress tolerance and a candidate gene for improving stress tolerance in crops. PMID- 22930450 TI - Comparison of the structures and stabilities of coiled-coil proteins containing hexafluoroleucine and t-butylalanine provides insight into the stabilizing effects of highly fluorinated amino acid side-chains. AB - Highly fluorinated analogs of hydrophobic amino acids are well known to increase the stability of proteins toward thermal unfolding and chemical denaturation, but there is very little data on the structural consequences of fluorination. We have determined the structures and folding energies of three variants of a de novo designed 4-helix bundle protein whose hydrophobic cores contain either hexafluoroleucine (hFLeu) or t-butylalanine (tBAla). Although the buried hydrophobic surface area is the same for all three proteins, the incorporation of tBAla causes a rearrangement of the core packing, resulting in the formation of a destabilizing hydrophobic cavity at the center of the protein. In contrast, incorporation of hFLeu, causes no changes in core packing with respect to the structure of the nonfluorinated parent protein which contains only leucine in the core. These results support the idea that fluorinated residues are especially effective at stabilizing proteins because they closely mimic the shape of the natural residues they replace while increasing buried hydrophobic surface area. PMID- 22930451 TI - Folate-modified gold nanoclusters as near-infrared fluorescent probes for tumor imaging and therapy. AB - Ultra-small gold nanoclusters (Au NCs) are highly promising materials for tumor imaging and therapy because of their low toxicity, intrinsic fluorescence, and the availability of multifunctional groups for covalent linkage of diverse bioactive molecules. Au NCs stabilized by bovine serum albumin (BSA) were prepared via an improved "green" synthetic routine. To ameliorate the selective affinity of Au NCs for high folate receptor (FR) expressing tumors, folic acid (FA) was immobilized on the surface of Au NCs. Subsequently, a near-infrared (NIR) fluorescent dye MPA was conjugated with Au-FA NCs for in vitro and in vivo fluorescence imaging. Similarly, Doxorubicin (DOX), a widely used clinical anticancer drug, was also conjugated to the folate-modified Au NCs to form a prodrug (Au-FA-DOX). Cellular and in vivo acute toxicity studies demonstrated the low toxicity of the Au-FA-MPA to normal cells and tissues. Additionally, in vitro and in vivo study of the dynamic behavior and targeting ability of Au-FA-MPA to different tumors validated the high selective affinity of Au-FA-MPA to FR positive tumors. With regard to the Au-FA-DOX, high anti-tumor activity was displayed by this pro-drug due to the FR mediated uptake. Herein, all of the results supported the potential of using ligand-modified Au NCs for tumor imaging and targeted therapy. PMID- 22930453 TI - Body temperature and physical activity correlates of the menstrual cycle in Chacma Baboons (Papio hamadryas ursinus). AB - We investigated the temporal relationship between abdominal temperature, physical activity, perineal swelling, and urinary progesterone and estradiol concentrations over the menstrual cycle in unrestrained captive baboons. Using a miniature temperature-sensitive data logger surgically implanted in the abdominal cavity and an activity data logger implanted subcutaneously on the trunk, we measured, continuously over 6 months at 10-min intervals, abdominal temperature and physical activity patterns in four female adult baboons Papio hamadryas ursinus (12.9-19.9 kg), in cages in an indoor animal facility (22-25 degrees C). We monitored menstrual bleeding and perineal swelling changes, and measured urinary progesterone and estradiol concentrations, daily for up to 6 months, to ascertain the stage and length of the menstrual cycle. The menstrual cycle was 36 +/- 2 days (mean +/- SD) long and the baboons exhibited cyclic changes in perineal swellings, abdominal temperature, physical activity, urinary progesterone, and estradiol concentrations over the cycle. Mean 24-hr abdominal temperature during the luteal phase was significantly higher than during the periovulatory phase (ANOVA, F((2, 9)) = 4.7; P = 0.04), but not different to that during the proliferative phase. Physical activity followed a similar pattern, with mean 24-hr physical activity almost twice as high in the luteal than in the periovulatory phase (ANOVA, P = 0.58; F((2, 12)) = 5.8). We have characterized correlates of the menstrual cycle in baboons and shown, for the first time, a rhythm of physical activity and abdominal temperature over the menstrual cycle, with a nadir of temperature and activity at ovulation. PMID- 22930452 TI - Decreased STAT5 phosphorylation and GATA-3 expression in NOX2-deficient T cells: role in T helper development. AB - Absence of phagocyte NADPH oxidase (NOX2) activity causes chronic granulomatous disease (CGD), a primary immunodeficiency characterized by recurrent bacterial infections. In contrast to this innate immune deficit, CGD patients and animal models display a predisposition toward autoimmune disease and enhanced response to Helicobacter pylori and influenza virus infection. These data imply an altered, perhaps augmented, adaptive immune response in CGD. As previous data demonstrated functional NOX2 expression in T cells, our goal here was to determine if NOX2-deficient T cells are inherently altered in their responses. Activation of purified naive CD4(+) T cells from NOX2-deficient mice led to augmented IFN-gamma and diminished IL-4 production and an increased ratio of expression of the T(H)1-specific transcription factor T-bet versus the T(H)2 specfic transcription factor GATA-3, consistent with a T(H)1 skewing of naive T cells. Selective inhibition of TCR-induced STAT5 phosphorylation was identified as a potential mechanism for skewed T helper differentiation. Exposure to antioxidants inhibited, while pro-oxidants augmented T(H)2 cytokine secretion and STAT5 phosphorylation, supporting the redox dependence of these signaling changes. These data suggest that TCR-induced ROS generation from NOX2 activation can regulate the adaptive immune response in a T-cell-inherent fashion, and propose a possible role for redox signaling in T helper differentiation. PMID- 22930454 TI - Lithographically encoded polymer microtaggant using high-capacity and error correctable QR code for anti-counterfeiting of drugs. AB - A QR-coded microtaggant for the anti-counterfeiting of drugs is proposed that can provide high capacity and error-correction capability. It is fabricated lithographically in a microfluidic channel with special consideration of the island patterns in the QR Code. The microtaggant is incorporated in the drug capsule ("on-dose authentication") and can be read by a simple smartphone QR Code reader application when removed from the capsule and washed free of drug. PMID- 22930455 TI - Rapid casein quantification in milk powder with aggregation induced emission character of tetraphenylethene derivative. AB - A casein assay has been developed with aggregation induced emission character of BSPOTPE, which is a derivative of tetraphenylethene (TPE). The method exhibits a wide dynamic range of detection for casein from 10 MUg ml(-1) to 5000 MUg ml(-1), and a good linear range from 20 MUg ml(-1) to 1250 MUg ml(-1). With sample pretreatment procedures, we can detect the casein in skimmed and full milk powder, avoiding the interferences from other components and illegal additives in milk. PMID- 22930456 TI - What is an objective structured practical examination in anatomy? AB - Assessing teaching-learning outcomes in anatomical knowledge is a complex task that requires the evaluation of multiple domains: theoretical, practical, and clinical knowledge. In general, theoretical knowledge is tested by a written examination system constituted by multiple choice questions (MCQs) and/or short answer questions (SAQ). The assessment of practical knowledge (three-dimensional anatomical concepts) involves oral, spot, or objective structured practical examinations (OSPE). Finally, the application of anatomical knowledge to patients is tested mainly through objective structured clinical examinations (OSCE). The major focus of this study is the OSPE. Although many schools challenge students using this tool in practical examinations in the early phase of the curriculum, the true meaning of OSPE is frequently forgotten and it becomes, in reality, a spot examination. This article, for the first time, describes how the concept of the OSPE has evolved and is currently being used to assess the practical domain of anatomical knowledge in a problem-based curriculum at Alfaisal University College of Medicine. In addition, it describes the main differences from the spot examination, which is normally used in traditional medical curricula. The authors believe that the OSPE remains the most efficient tool to assess the practical aspects of anatomical knowledge in a system where basic knowledge is integrated with the clinical or functional part of anatomy. However, this contention only holds true if the OSPE process revolves around structured objectives. PMID- 22930457 TI - Animal tales: observations of the emotions in American experimental psychology, 1890-1940. AB - In nineteenth-century science, the emotions played a crucial role in explaining the social behavior of animals and human beings. Beginning in the 1890s, however, the first American psychologists, resolutely parsimonious in method, dismissed affective experience as intellectually imprecise. Yet in practice, feelings continued to influence at least one research setting: animal experiments. Laboratory reports, although focused on learning, became a repository of informal observations about the animals' temperaments and moods. When American psychologists began to reexamine the emotions between the world wars, they drew on this empirical legacy in animal studies. They also devised a conceptual approach to emotion consistent with their expectation of experimental precision. PMID- 22930459 TI - Surgical ablation of atrial fibrillation after the PRAGUE-12 study: more questions than answers. PMID- 22930458 TI - Comparison of cardiac surgery with left atrial surgical ablation vs. cardiac surgery without atrial ablation in patients with coronary and/or valvular heart disease plus atrial fibrillation: final results of the PRAGUE-12 randomized multicentre study. AB - AIMS: Surgical ablation procedure can restore sinus rhythm (SR) in patients with atrial fibrillation (AF) undergoing cardiac surgery. However, it is not known whether it has any impact on long-term clinical outcomes. METHODS AND RESULTS: This multicentre study randomized 224 patients with AF scheduled for valve and/or coronary surgery: group A (left atrial surgical ablation, n = 117) vs. group B (no ablation, n = 107). The primary efficacy outcome was the SR presence (without any AF episode) during a 24 h electrocardiogram (ECG) after 1 year. The primary safety outcome was the combined endpoint of death/myocardial infarction/stroke/renal failure at 30 days. A Holter-ECG after 1 year revealed SR in 60.2% of group A patients vs. 35.5% in group B (P = 0.002). The combined safety endpoint at 30 days occurred in 10.3% (group A) vs. 14.7% (group B, P = 0.411). All-cause 1-year mortality was 16.2% (A) vs. 17.4% (B, P = 0.800). Stroke occurred in 2.7% (A) vs. 4.3% (B) patients (P = 0.319). No difference (A vs. B) in SR was found among patients with paroxysmal (61.9 vs. 58.3%) or persistent (72 vs. 50%) AF, but ablation significantly increased SR prevalence in patients with longstanding persistent AF (53.2 vs. 13.9%, P < 0.001). CONCLUSION: Surgical ablation improves the likelihood of SR presence post-operatively without increasing peri-operative complications. However, the higher prevalence of SR did not translate to improved clinical outcomes at 1 year. Further follow-ups (e.g. 5 year) are warranted to show any potential clinical benefit which might occur later. PMID- 22930460 TI - Earthquakes: another cause of heart failure? PMID- 22930461 TI - The Great East Japan Earthquake Disaster and cardiovascular diseases. AB - AIMS: While previous studies reported a short-term increase in individual cardiovascular disease (CVD) after great earthquakes, mid-term occurrences of all types of CVDs after great earthquakes are unknown. We addressed this important issue in our experience with the Great East Japan Earthquake (11 March 2011). METHODS AND RESULTS: We retrospectively examined the impact of the Earthquake on the occurrences of CVDs and pneumonia by comparing the ambulance records made by doctors in our Miyagi Prefecture, the centre of the disaster area, during the periods of 2008-11 (n = 124,152). The weekly occurrences of CVDs, including heart failure (HF), acute coronary syndrome (ACS), stroke, cardiopulmonary arrest (CPA), and pneumonia were all significantly increased after the Earthquake compared with the previous 3 years. The occurrences of ACS and CPA showed the rapid increase followed by a sharp decline, whereas those of HF and pneumonia showed a prolonged increase for more than 6 weeks and those of stroke and CPA showed a second peak after the largest aftershock (7 April 2011). Furthermore, the occurrence of CPA was increased in the first 24 h after the Earthquake, followed by other diseases later on. These increases were independent of age, sex, or residence area (seacoast vs. inland). CONCLUSION: These results indicate that the occurrences of all types of CVDs and pneumonia were increased in somewhat different time courses after the Earthquake, including the first observation of the marked and prolonged increase in HF, emphasizing the importance of intensive medical management of all types of CVDs after great earthquakes. PMID- 22930463 TI - Interferometric silicon biochips for label and label-free DNA and protein microarrays. AB - Protein and DNA microarrays hold the promise to revolutionize the field of molecular diagnostics. Traditional microarray applications employ labeled detection strategies based on the use of fluorescent and chemiluminescent secondary antibodies. However, the development of high throughput, sensitive, label-free detection techniques is attracting attention as they do not require labeled reactants and provide quantitative information on binding kinetics. In this article, we will provide an overview of the recent author's work in label and label-free sensing platforms employing silicon/silicon oxide (Si/SiO(2)) substrates for interferometric and/or fluorescence detection of microarrays. The review will focus on applications of Si/SiO(2) with controlled oxide layers to (i) enhance the fluorescence intensity by optical interferences, (ii) quantify with sub-nanometer accuracy the axial locations of fluorophore-labeled probes tethered to the surface, and (iii) detect protein-protein interactions label free. Different methods of biofunctionalization of the sensing surface will be discussed. In particular, organosilanization reactions for monodimensional coatings and polymeric coatings will be extensively reviewed. Finally, the importance of calibration of protein microarrays through the dual use of labeled and label-free detection schemes on the same chip will be illustrated. PMID- 22930464 TI - Prognostic value of cetuximab-related skin toxicity in metastatic colorectal cancer patients and its correlation with parameters of the epidermal growth factor receptor signal transduction pathway: results from a randomized trial of the GERMAN AIO CRC Study Group. PMID- 22930465 TI - Electrochemical fabrication and properties of highly ordered Fe-doped TiO2 nanotubes. AB - Highly-ordered Fe-doped TiO(2) nanotubes (TiO(2)nts) were fabricated by anodization of co-sputtered Ti-Fe thin films in a glycerol electrolyte containing NH(4)F. The as-sputtered Ti-Fe thin films correspond to a solid solution of Ti and Fe according to X-ray diffraction. The Fe-doped TiO(2)nts were studied in terms of composition, morphology and structure. The characterization included scanning electron microscopy, energy-dispersive X-ray spectroscopy, X-ray diffraction, UV/Vis spectroscopy, X-ray photoelectron spectroscopy and Mott Schottky analysis. As a result of the Fe doping, an indirect bandgap of 3.0 eV was estimated using Tauc's plot, and this substantial red-shift extends its photoresponse to visible light. From the Mott-Schottky analysis, the flat-band potential (E(fb)) and the charge carrier concentration (N(D)) were determined to be -0.95 V vs Ag/AgCl and 5.0*10(19) cm(-3) respectively for the Fe-doped TiO(2)nts, whilst for the undoped TiO(2)nts, E(fb) of -0.85 V vs Ag/AgCl and N(D) of 6.5*10(19) cm(-3) were obtained. PMID- 22930466 TI - Genetic diversity and population structure of the endangered Namaqua Afrikaner sheep. AB - The Namaqua Afrikaner is an endangered sheep breed indigenous to South Africa, primarily used in smallholder farming systems. Genetic characterization is essential for the breed's conservation and utilization. In this study, a genetic characterization was performed on 144 Namaqua Afrikaner sheep kept at the Karakul Experimental Station (KES), Carnarvon Experimental Station (CES), and a private farm Welgeluk (WGK) using 22 microsatellite markers. The mean number of alleles observed was low (3.7 for KES, 3.9 for CES, and 4.2 for WGK). Expected heterozygosity values across loci ranged between 46 % for WGK, 48 % for KES, and 55 % for CES, indicating low to moderate genetic variation. The analysis of molecular variance revealed that 89.5 % of the genetic variation was due to differences within populations. The population structure confirmed the differentiation of three clusters with high relationships between the CES and WGK populations. In the population structure comparison with Pedi and South African Mutton Merino sheep, limited hybridization between the Namaqua Afrikaner sheep and both of these breeds was observed. The results of this study will serve as a reference for genetic management and conservation of Namaqua Afrikaner sheep. PMID- 22930467 TI - Pulse inversion chirp coded tissue harmonic imaging (PI-CTHI) of Zebrafish heart using high frame rate ultrasound biomicroscopy. AB - This paper reports a pulse inversion chirp coded tissue harmonic imaging (PI CTHI) method for visualizing small animal hearts that provides fine spatial resolution at a high frame rate without sacrificing the echo signal to noise ratio (eSNR). A 40 MHz lithium niobate (LiNbO(3)) single element transducer is employed to evaluate the performance of PI-CTHI by scanning tungsten wire targets, spherical anechoic voids, and zebrafish hearts. The wire phantom results show that PI-CTHI improves the eSNR by 4 dB from that of conventional pulse inversion tissue harmonic imaging (PI-THI), while still maintaining a spatial resolution of 88 and 110 MUm in the axial and lateral directions, respectively. The range side lobe level of PI-CTHI is 11 dB lower than that of band-pass filtered CTHI (or F-CTHI). In the anechoic sphere phantom study, the contrast-to noise ratio of PI-CTHI is found to be 2.7, indicating a 34% enhancement over conventional PI-THI. Due to such improved eSNR and contrast resolution, blood clots in zebrafish hearts can be readily visualized throughout heart regeneration after 20% of the ventricle is removed. Disappearance of the clots in the early stages of the regeneration has been observed for 7 days without sacrificing the fish. PMID- 22930468 TI - Milk protein and fat play different roles in affecting the bioavailability and the antioxidant activity of jujube juice phenolics in rats. AB - SCOPE: In this study, we intend to clarify the role that milk proteins and fat may play in affecting the bioavailability and the antioxidant activity of jujube juice phenolics. METHODS AND RESULTS: Three milk preparations-skimmed milk, milk fat, and whole milk were produced to represent milk protein, milk fat, and milk protein and fat together, respectively. The bioavailability of phenolics and the rat plasma antioxidant capacity were measured for 8 h after the consumption of jujube juice with and without milk preparations. The addition of skimmed milk to jujube juice resulted in significant changes in the plasma kinetics profile of phenolics, rather than affecting the overall absorption. Milk fat did not interact with jujube juice phenolics. However, when jujube juice was ingested with whole milk, a significant reduction of the bioavailability of phenolics and the maximum increase in plasma antioxidant capacity was observed. Moreover, a consistent increase in the median diameters of the emulsions indicated the formation of complexes of proteins, fat, and phenolics during digestion. CONCLUSION: The present study suggests that when ingested with jujube juice, milk proteins and fat play different roles in affecting the bioavailability and the antioxidant activity of jujube juice phenolics. PMID- 22930469 TI - Constitutive Akt1 signals attenuate B-cell receptor signaling and proliferation, but enhance B-cell migration and effector function. AB - Ligation of the BCR induces a complex signaling network that involves activation of Akt, a family of serine/threonine protein kinases associated with B-cell development, proliferation, and tumor formation. Here, we analyzed the effect of enhanced Akt1 signals on B-cell maturation and function. Unexpectedly, we found that peripheral B cells overexpressing Akt1 were less responsive to BCR stimuli. This correlated with a decrease in Ca(2+) -mobilization and proliferation, in an impaired activation of Erk1/2 and mammalian target of rapamycin (mTOR) kinases and poor mobilization of NFATc1 and NF-kappaB/p65 factors. In contrast, activation of STAT5 and migration of B cells toward the chemokine SDF1alpha was found to be enhanced. Akt1 Tg mice showed an altered maturation of peritoneal and splenic B1 B cells and an enhanced production of IgG1 and IgG3 upon immunization with the T-cell independent Ag TNP-Ficoll. Furthermore, mice homo-zygous for Tg Akt1 showed a severe block in the maturation of B-cell precursors in BM and a strong enrichment of plasma cells in spleen. Altogether, our data reveal that enhanced Akt1 signals modify BCR signaling strength and, thereby, B-cell development and effector function. PMID- 22930470 TI - Estimation of secondary endpoints in two-stage phase II oncology trials. AB - In the development of a new treatment in oncology, phase II trials play a key role. On the basis of the data obtained during phase II, it is decided whether the treatment should be studied further. Therefore, the decision to be made on the basis of the data of a phase II trial must be as accurate as possible. For ethical and economic reasons, phase II trials are usually performed with a planned interim analysis. Furthermore, the decision about stopping or continuing the study is usually based on a short-term outcome like tumor response, whereas secondary endpoints comprise stable disease, progressive disease, toxicity, and/or overall survival. The data obtained in a phase II trial are often analyzed and interpreted by applying the maximum likelihood estimator (MLE) without taking into account the sequential nature of the trial. However, this approach provides biased results and may therefore lead to wrong conclusions. Whereas unbiased estimators for two-stage designs have been derived for the primary endpoint, such estimators are currently not available for secondary endpoints. We present uniformly minimum variance unbiased estimators (UMVUE) for secondary endpoints in two-stage designs that allow stopping for futility (and efficacy). We compare the mean squared error of the UMVUE and the MLE and investigate the efficiency of the UMVUE. A clinical trial example illustrates the application. PMID- 22930471 TI - In situ growth of a ZnO nanowire network within a TiO(2) nanoparticle film for enhanced dye-sensitized solar cell performance. AB - ZnO nanowire networks featuring excellent charge transport and light scattering properties are grown in situ within TiO(2) films. The resultant TiO(2) /ZnO composites, used as photoanodes, remarkably enhance the overall conversion efficiency of dye-sensitized solar cells (DSSCs) by 26.9%, compared to that of benchmark TiO(2) films. PMID- 22930472 TI - Role of fibroblast growth factor signaling in vascular formation and maintenance: orchestrating signaling networks as an integrated system. AB - The vascular system has begun to be perceived as a dynamic organ actively controlling a wide variety of physiological processes. The structural and functional integrity of blood vessels, regulated by signaling activities finely modulating cell-cell and cell-matrix interactions, is crucial for vessel physiology, as well as basic functionality of the tissue. Throughout the process of new vessel formation, while blood vessels are actively reorganized and remodeled with migration and proliferation of vascular cells, maintenance of vascular barrier function is essentially important. These conflicting properties, i.e., dynamic cellular mobilization and maintenance of barrier integrity, are simultaneously achieved through the interaction of highly organized signaling networks governing coordinated cell-cell interplay. Recent evidence suggests that the fibroblast growth factor (FGF) system plays a regulatory role in several physiological conditions in the vascular system. In this article, we will attempt to summarize current knowledge in order to understand the mechanism of this coordination and evaluate the pivotal role of FGF signaling in integrating a diverse range of signaling events in vascular growth and maintenance. PMID- 22930473 TI - In search of the kingdom: the social gospel, settlement sociology, and the science of reform in America's progressive era. AB - This critical narrative history examines the development of sociology in the United States during what has come to be labeled as the Progressive Era, roughly the years from the 1890s to World War I. Despite the label, this era was defined as much by social problems associated with industrialization, urbanization, and immigration as by the growth of its cities and the wealth of its capitalists. We explore the roots of American sociology in the transition of protestant theology from Calvinism to its reformation in the social gospel, the simultaneous development of settlement houses, and the "creation" of sociology as the science of reform. PMID- 22930475 TI - Terminal galactose residues on transferrin are increased in midlife adults compared to young adults. AB - Humans undergo biological ageing at different rates. This associates with functional decline in a number of physiological systems and increasing incidence of age-related pathologies. The discovery of robust biomarkers of ageing could be used to identify early divergence from a path of healthy ageing towards age related disease. In the present study, we undertook proteomic analysis of plasma from healthy young men (mean age = 21.4 +/- 1.5 years) and healthy midlife men (mean age = 57.0 +/- 1.6 years). We identified 12 spots including transferrin, complement C3b and transthyretin that differed in abundance between the age groups. Transferrin spots showed an acidic pI shift in older males. Sandwich ELISAs were used to investigate the changes further. C3b levels were below the level of detection by ELISA and plasma concentrations of total transferrin or transthyretin were not different between the age groups studied here. However, analysis of transferrin N-glycan structures showed an increase in terminal galactose residues in older men, suggesting that the loss of terminal N-acetyl neuraminic acid residues contributes to the more acid pI of transferrin spots observed with age. Terminal galactosylation of transferrin may be a biomarker of healthy ageing and is now under investigation in the MARK-AGE study. PMID- 22930474 TI - Mechanical stress and ATP synthesis are coupled by mitochondrial oxidants in articular cartilage. AB - Metabolic adaptation of articular cartilage under joint loading is evident and matrix synthesis seems to be critically tied to ATP. Chondrocytes utilize the glycolytic pathway for energy requirements but seem to require mitochondrial reactive oxygen species (ROS) to sustain ATP synthesis. The role of ROS in regulating ATP reserves under a mechanically active environment is not clear. It is believed that physiological strains cause deformation of the mitochondria, potentially releasing ROS for energy production. We hypothesized that mechanical loading stimulates ATP synthesis via mitochondrial release of ROS. Bovine osteochondral explants were dynamically loaded at 0.5 Hz with amplitude of 0.25 MPa for 1 h. Cartilage response to mechanical loading was assessed by imaging with dihydroethidium (ROS indicator) and a Luciferase-based ATP assay. Electron transport inhibitor rotenone and mitochondrial ROS scavenger MitoQ significantly suppressed mechanically induced ROS production and ATP synthesis. Our findings indicate that mitochondrial ROS are produced as a result of physiological mechanical strains. Taken together with our previous findings of ROS involvement in blunt impact injuries, mitochondrial ROS are important contributors to cartilage metabolic adaptation and their precise role in the pathogenesis of osteoarthritis warrants further investigation. PMID- 22930476 TI - N,N-dimethylformamide: a multipurpose building block. AB - Often used as a common solvent for chemical reations and utilized widely in industry as a reagent, N,N-dimethylformamide (DMF) has played an important role in organic synthesis for a long time. Numerous highly useful articles and reviews discussing its utilizations have been published. With a focus on the performance of DMF as a multipurpose precursor for various units in numerous reactions, this Minireview summarizes recent developments in the employment of DMF in the fields of formylation, aminocarbonylation, amination, amidation, and cyanation, as well as its reaction with arynes. PMID- 22930477 TI - The Depression Anxiety Stress Scales-21 (DASS-21): further examination of dimensions, scale reliability, and correlates. AB - OBJECTIVES: We conducted two studies to examine the dimensions, internal consistency reliability estimates, and potential correlates of the Depression Anxiety Stress Scales-21 (DASS-21; Lovibond & Lovibond, 1995). METHOD: Participants in Study 1 included 887 undergraduate students (363 men and 524 women, aged 18 to 35 years; mean [M] age = 19.46, standard deviation [SD] = 2.17) recruited from two public universities to assess the specificity of the individual DASS-21 items and to evaluate estimates of internal consistency reliability. Participants in a follow-up study (Study 2) included 410 students (168 men and 242 women, aged 18 to 47 years; M age = 19.65, SD = 2.88) recruited from the same universities to further assess factorial validity and to evaluate potential correlates of the original DASS-21 total and scale scores. RESULTS: Item bifactor and confirmatory factor analyses revealed that a general factor accounted for the greatest proportion of common variance in the DASS-21 item scores (Study 1). In Study 2, the fit statistics showed good fit for the bifactor model. In addition, the DASS-21 total scale score correlated more highly with scores on a measure of mixed depression and anxiety than with scores on the proposed specific scales of depression or anxiety. Coefficient omega estimates for the DASS-21 scale scores were good. CONCLUSIONS: Further investigations of the bifactor structure and psychometric properties of the DASS-21, specifically its incremental and discriminant validity, using known clinical groups are needed. PMID- 22930478 TI - Low-temperature solid-state microwave reduction of graphene oxide for transparent electrically conductive coatings on flexible polydimethylsiloxane (PDMS). AB - Microwaves (MWs) are applied to initialize deoxygenation of graphene oxide (GO) in the solid state and at low temperatures (~165 degrees C). The Fourier transform infrared (FTIR) spectra of MW-reduced graphene oxide (rGO) show a significantly reduced concentration of oxygen-containing functional groups, such as carboxyl, hydroxyl and carbonyl. X-ray photoelectron spectra confirm that microwaves can promote deoxygenation of GO at relatively low temperatures. Raman spectra and TGA measurements indicate that the defect level of GO significantly decreases during the isothermal solid-state MW-reduction process at low temperatures, corresponding to an efficient recovery of the fine graphene lattice structure. Based on both deoxygenation and defect-level reduction, the resurgence of interconnected graphene-like domains contributes to a low sheet resistance (~7.9*10(4) Omega per square) of the MW-reduced GO on SiO(2) -coated Si substrates with an optical transparency of 92.7 % at ~547 nm after MW reduction, indicating the ultrahigh efficiency of MW in GO reduction. Moreover, the low temperature solid-state MW reduction is also applied in preparing flexible transparent conductive coatings on polydimethylsiloxane (PDMS) substrates. UV/Vis measurements indicate that the transparency of the thus-prepared MW-reduced GO coatings on PDMS substrates ranges from 34 to 96 %. Correspondingly, the sheet resistance of the coating ranges from 10(5) to 10(9) Omega per square, indicating that MW reduction of GO is promising for the convenient low-temperature preparation of transparent conductors on flexible polymeric substrates. PMID- 22930479 TI - Blood biomarkers of methylation in Down syndrome and metabolic simulations using a mathematical model. AB - SCOPE: The study tests the metabolites of the methylation cycle in individuals with Down syndrome (DS) and applies a mathematical model in order to change this cycle by nutritional factors. METHODS AND RESULTS: We measured concentrations of the metabolites related to the methylation cycle in the blood of 35 young individuals with DS and 47 controls of comparable age. Moreover, we applied a mathematical model to learn more about the regulation of the methylation cycle in DS. Concentrations of cystathionine, cysteine, betaine, choline, dimethylglycine, S-adenosylhomocysteine (SAH), S-adenosylmethionine (SAM), and holotranscobalamin were significantly higher in DS compared to the controls. The median SAM/SAH ratio was lower in DS and that of methionine and reduced glutathione did not differ significantly between the groups. The mathematical model showed that enhanced methionine turnover and accelerated Hcy-remethylation might explain the shift in the methylation cycle in DS. CONCLUSION: In addition to the DS-related excess of cystathionine beta synthase (CBS) activity, increases in the activities of MS and betaine homocysteine methyl transferase, and in methionine input were necessary to account for the changes in metabolite levels observed in DS. A low methionine diet might offer a perspective for reversing the metabolic imbalance in DS, but this awaits clinical investigations. PMID- 22930480 TI - The more basic isoform of eEF1A relates to tumour cell phenotype and is modulated by hyper-proliferative/differentiating stimuli in normal lymphocytes and CCRF-CEM T-lymphoblasts. AB - The elongation factor 1A proteins (eEF1A1/A2) are known to play a role in tumours. We previously found that a more basic isoform of eEF1A (MBI-eEF1A) is present in the cytoskeletal/nuclear-enriched extracts of CCRF-CEM T-lymphoblasts but not in those of normal lymphocytes. To obtain deeper knowledge about MBI eEF1A biology, we investigate from which of the eEF1A proteins, eEF1A1 or eEF1A2, MBI-eEF1A originates and the possibility that its appearance can be modulated by the differentiated or proliferative cell status. CCRF-CEM T-lymphoblasts and normal lymphocytes were cultured with or without differentiation/pro proliferative stimuli (Phorbol 12-Myristate 13-Acetate (PMA) alone or the combination of phytohaemagglutinin (PHA) with PMA, respectively), and the presence of MBI-eEF1A evaluated together with that of the eEF1A1/A2 mRNAs. Our data indicate that the MBI-eEF1A may derive from eEF1A1 as eEF1A2 is not expressed in CCRF-CEM and normal lymphocytes. Moreover, MBI-eEF1A is inducible in normal lymphocytes upon hyper-proliferative stimuli application; in CCRF-CEM, its presence can be abrogated by PMA-induced differentiation. Finally, MBI-eEF1A may have a functional role in hyper-proliferating/tumour cells as its disappearance reduces the growth of CCRF-CEM and that of PHA/PMA-stimulated lymphocytes. The presented data suggest that MBI-eEF1A may be related to oncogenic cell phenotype, rising the possibility to use MBI-eEF1A as target for novel therapeutic strategies. PMID- 22930481 TI - Analytic results on the bias due to nondifferential misclassification of a binary mediator. AB - Consider a study in which the effect of a binary exposure on an outcome operates partly through a binary mediator but measurement of the mediator is nondifferentially misclassified. Suppose that an investigator wishes to estimate the direct and indirect effects of the exposure on the outcome. In this paper, the authors describe a mathematical correspondence between the empirical expressions for the natural direct effect and the effect of exposure among the unexposed standardized by a binary confounder. They then exploit this correspondence to prove that the direction of the bias due to nondifferential measurement error in estimating the natural direct and indirect effects is to overestimate the natural direct effect and underestimate the natural indirect effect. PMID- 22930482 TI - A quantitative approach for assessing significant improvements in elite sprint performance: has IGF-1 entered the arena? AB - The introduction of doping substances and methods in sports triggers noticeable effects on physical performance in metric sports. Here, we use time series analysis to investigate the recent development in male and female elite sprinting performance. Time series displaying the average of the world's top 20 athletes were analyzed employing polynomial spline functions and moving averages. Outstanding changes in performance over time were statistically analyzed by Welch's t-test and by Cohen's measurements of effect. For validation we exemplarily show that our analysis is capable of indicating the effect of the introduction of in- and out-of-competition doping testing on women's shot put as well as the effects of the market introduction of erythropoietin (EPO) and the introduction of EPO and continuous erythropoiesis receptor activator (CERA) testing on 5000 m top 20 male performances. Time series analysis for 100 m men reveals a highly significant (p < 0.001) drop by more than 0.1 s from 2006 to 2011 with a large effect size of 0.952. This is roughly half of the effect size that can be found for the development of the 5000 m performance during the introduction of EPO between 1991 and 1996. While the men's 200 m sprinting performance shows a similar development, the women's 100 m and 200 m sprinting performances only show some minor abnormalities. We will discuss here why the striking sex-specific improvement in sprinting performance is indicative for a novel, very effective doping procedure with insulin-like growth factor-1 (IGF-1) being the primary candidate explaining the observed effects. PMID- 22930483 TI - Solution-processable molecular cage micropores for hierarchically porous materials. AB - Macroscopic inorganic porous beads are imbibed with a "porous molecular additive" by simple solution processing techniques, resulting in controllable loading and increased surface area. The porous additive consists of soluble organic cage molecules that precipitate as microporous crystals when solutions of opposite chirality are mixed. PMID- 22930484 TI - Cochlear nerve deficiency in children with CHARGE syndrome. AB - OBJECTIVES/HYPOTHESIS: To describe cochlear nerve deficiency and abnormalities of the internal auditory canal (IAC) associated with CHARGE (coloboma, heart defects, atresia choanae, retardation of growth and/or development, genital hypoplasia, and ear anomalies and/or deafness) syndrome. STUDY DESIGN: Case series. METHODS: In a tertiary children's hospital, children with CHARGE syndrome were evaluated between 2006 and 2009. Morphology of the inner ear, IAC, and cochlear nerves was evaluated along with auditory-evoked brainstem response results. RESULTS: Of the 17 patients with CHARGE diagnosis, 14 ears demonstrated profound sensorineural hearing loss (SNHL). The remaining ears had conductive hearing loss, mixed hearing loss, or mild to moderate SNHL. Computed tomography (CT) evaluation was refused in one case and delayed in one case due to parental decision. Of 30 ears evaluated with CT, 28 (93%) had substantial abnormalities of the inner ear including hypoplasia or aplasia of the semicircular canals and abnormalities of the cochlea and vestibule. CT evaluation revealed cochlear aperture narrowing or occlusion in 16 ears, one of which had normal hearing. The eight most recent patients with profound SNHL (six bilateral SNHL, two unilateral) underwent magnetic resonance imaging (MRI) of the IAC, and 13 of 14 ears with SNHL were noted to have absent or deficient cochlear nerves. CT scans in two ears with profound SNHL revealed normal cochlear apertures. CONCLUSIONS: The dysmorphic inner ear is well described in CHARGE patients; however, cochlear nerve deficiency has not been considered a common etiology for SNHL in these patients. Because of the implications of cochlear nerve deficiency in therapeutic decision making (i.e., cochlear implantation), MRI evaluation of the eighth nerve should be considered in CHARGE patients with profound SNHL. PMID- 22930485 TI - pH-responsive luminescent lanthanide-functionalized gold nanoparticles with "on off" ytterbium switchable near-infrared emission. PMID- 22930486 TI - Surfaces resistant to fouling from biological fluids: towards bioactive surfaces for real applications. AB - The fouling from four human body fluids - blood plasma, cerebrospinal fluid, urine and saliva - and four animal fluids - foetal bovine and calf sera, egg and milk - relevant to human and veterinary medicine, immunology, biology and diagnostics is assessed on antifouling SAMs and on polymer brushes of oligo(ethylene glycol) methacrylate, 2-hydroxyethyl methacrylate, carboxybetaine acrylamide and N-(2-hydroxypropyl)methacrylamide synthesized via ATRP. While important deposits from the all biofluids are observed on SAMs, a superior resistance is achieved on polymer brushes. Importantly, only poly(CBAA) and poly(HPMA) are capable of resisting the fouling from the most challenging media, blood plasma and eggs. PMID- 22930487 TI - Effects of standard glucocorticoid replacement therapies on subjective well being: a randomized, double-blind, crossover study in patients with secondary adrenal insufficiency. AB - OBJECTIVE: For secondary adrenal insufficiency (SAI), established biochemical parameters for dosage control are lacking and no optimal substitution dosage and daily distribution have been determined yet. Therefore, in clinical practice, the individual total dose is often adjusted based on patients' subjective well-being. DESIGN: Effects of three standard glucocorticoid replacement regimens on psychological variables were assessed in patients with SAI based on a randomized double-blind study design. METHODS: SAI patients (n=18) were treated with three different established glucocorticoid replacement regimens in a randomized, double blind, crossover study (treatment A, hydrocortisone 10 mg-placebo-5 mg-placebo; treatment B, hydrocortisone 10 mg-5 mg-placebo-5 mg; and treatment C, prednisone 5 mg-placebo-placebo-placebo). Following each 4-week replacement regimen, quality of life (SF-36) and emotional distress (brief symptom inventory (BSI)) were assessed along with diurnal changes in current well-being (Bf-S) and alertness (Stanford Sleepiness Scale (SSS)) using validated questionnaires, and additionally compared with patient (patients with pituitary disease and adrenal sufficiency) and healthy control groups. RESULTS: SAI patients showed improvements in physical quality of life (i.e. SF-36 physical function, P<0.05; physical role function, P<0.05) and current well-being (at 1800 h, P<0.05) under treatment A (hydrocortisone 10-0-5-0 mg) compared with the other replacement regimens. Quality of life and current well-being were significantly impaired compared with healthy controls but did not differ from patient controls. CONCLUSIONS: Although the observed improvements in psychological parameters were comparatively small, our results indicate beneficial effects of a 10-0-5-0 mg hydrocortisone replacement regimen. Nevertheless, treatment effects were insufficient to restore subjective health compared with healthy controls, indicating the need for improved replacement regimens and supportive psychosocial interventions in SAI patients. PMID- 22930488 TI - Etomidate in the emergency management of hypercortisolemia. AB - We describe a protocol for etomidate infusion for the emergency management of hypercortisolemia. Etomidate is commenced at 2.5 mg/h and titrated subsequently according to cortisol levels. It is well tolerated without any sedative effects and can be administered safely via peripheral access for use in the general ward setting. PMID- 22930489 TI - Laparoscopic and robotic distal gastrectomy for gastrointestinal stromal tumour: case report. AB - BACKGROUND: Gastrointestinal stromal tumours (GISTs) are the most common mesenchymal tumours of the digestive tract. The most frequent site of occurrence is the stomach. Due to the high potential for malignancy of GIST, resection should be the first-line treatment. Minimally invasive surgery may be used for surgical resection of GISTs. METHODS: We describe a case of laparoscopic and robotic distal gastrectomy in a patient with diagnosis of GIST in the gastric antrum. Laparoscopy was useful for dissection and a da Vinci robot was used for Roux-en-Y reconstruction. RESULTS: The postoperative course was uneventful. CONCLUSIONS: Minimally invasive surgery offers benefits compared to open surgery, and laparoscopic and robot-assisted gastrectomy for the treatment of GIST could be technically feasible and safe because of the advantageous movements provided by the robotic arms. PMID- 22930490 TI - Diet supplementation with donkey milk upregulates liver mitochondrial uncoupling, reduces energy efficiency and improves antioxidant and antiinflammatory defences in rats. AB - Dietary PUFA, mainly those of the n-3 family, are known to play essential roles in the maintenance of energy balance and in the reduction of body fat deposition through the upregulation of mitochondrial uncoupling that is the main source of reactive oxygen species. We hypothesized that rat supplementation with raw donkey's milk (DM), characterized by low-fat content and higher n3:n6 ratio, may affect energy balance, lipid metabolism, and prooxidant status as compared to animals treated with cow's milk. In the present study, the effects of drinking raw DM (for 4 weeks) on energy balance, lipid metabolism, antiinflammatory, and antioxidant/detoxifying defences was compared to that produced by rat intake of an iso-energetic amount of raw cow's milk. The hypolipidemic effect produced by DM paralleled with the enhanced mitochondrial activity/proton leakage and with the increased activity or expression of mitochondrial markers namely, carnitine palmitoyl transferase and uncoupling protein 2. The association of decreased energy efficiency with reduced proinflammatory signs (TNF-alpha and LPS levels) with the significant increase antioxidant (total thiols) and detoxifying enzyme activities (glutathione-S-transferase NADH quinone oxidoreductase) in DM-treated animals, indicated that beneficial effects were attributable, at least in part, to the activation of nuclear factor 2 erythroid-related factor 2 pathway. PMID- 22930491 TI - Effects of participation in a mindfulness program for veterans with posttraumatic stress disorder: a randomized controlled pilot study. AB - OBJECTIVE: To assess outcomes associated with Mindfulness-Based Stress Reduction (MBSR) for veterans with PTSD. METHODS: Forty-seven veterans with posttraumatic stress disorder (PTSD; 37 male, 32 Caucasian) were randomized to treatment as usual (TAU; n = 22), or MBSR plus TAU (n = 25). PTSD, depression, and mental health-related quality of life (HRQOL) were assessed at baseline, posttreatment, and 4-month follow-up. Standardized effect sizes and the proportion with clinically meaningful changes in outcomes were calculated. RESULTS: Intention-to treat analyses found no reliable effects of MBSR on PTSD or depression. Mental HRQOL improved posttreatment but there was no reliable effect at 4 months. At 4 month follow-up, more veterans randomized to MBSR had clinically meaningful change in mental HRQOL, and in both mental HRQOL and PTSD symptoms. Completer analyses (>= 4 classes attended) showed medium to large between group effect sizes for depression, mental HRQOL, and mindfulness skills. CONCLUSIONS: Additional studies are warranted to assess MBSR for veterans with PTSD. PMID- 22930492 TI - Relationships between perceived diagnostic disclosure, patient characteristics, psychological distress and illness perceptions in Indian cancer patients. AB - OBJECTIVE: Non-disclosure of a cancer diagnosis is a common practice in many Asian cultures where family-based medical decision making is the norm. The present study sought to compare Indian cancer patients who were aware versus unaware of their cancer diagnosis on a range of patient characteristics, levels of psychological distress and illness perceptions. METHODS: A sample of 329 Indian cancer patients were interviewed about their understanding of their illness (to assess awareness of a cancer diagnosis) and administered the following measures: the modified Rotterdam Symptom Checklist, the Hospital Anxiety and Depression Scale, and the Brief Illness Perceptions Questionnaire. Demographic and medical details were also obtained. RESULTS: Over half of the sample (54.1%) was unaware of their cancer diagnosis. A logistic regression analysis predicting perceived diagnostic disclosure indicated that awareness of a cancer diagnosis was associated with being involved in medical decisions, receiving multiple treatments, longer treatment durations, greater perceived understanding of one's illness (illness coherence) and citing a cause for one's illness. CONCLUSIONS: The results highlight the importance of the context in which decisions about the patient's illness are made (e.g. by whom) as well as illness perceptions relating to patients' understanding of their illness. PMID- 22930493 TI - Vitamin D and Parkinson's disease. AB - Parkinson's disease (PD) is the second most common form of neurodegeneration among the elderly population. PD is clinically characterized by tremors, rigidity, slowness of movement, and postural imbalance. Interestingly, a significant association has been demonstrated between PD and low levels of vitamin D in the serum, and vitamin D supplement appears to have a beneficial clinical effect on PD. Genetic studies have provided the opportunity to determine which proteins link vitamin D to PD pathology, e.g., Nurr1 gene, toll-like receptor, gene related to lipid disorders, vascular endothelial factor, tyrosine hydroxylase, and angiogenin. Vitamin D also exerts its effects on cancer through nongenomic factors, e.g., bacillus Calmette-Guerin vaccination, interleukin-10, Wntbeta-catenin signaling pathways, mitogen-activated protein kinase pathways, and the reduced form of the nicotinamide adenine dinucleotide phosphate. In conclusion, vitamin D might have a beneficial role in PD. Calcitriol is best used for PD because it is the active form of the vitamin D(3) metabolite and modulates inflammatory cytokine expression. Further investigation with calcitriol in PD is needed. PMID- 22930494 TI - Single crystals of 5,5'-Bis(4'-methoxybiphenyl-4-yl)-2,2'-bithiophene for organic laser media. AB - Room temperature lasing was stably observed in air from an orthorhombic crystal of 5,5'-bis(4'-methoxybiphenyl-4-yl)-2,2'-bithiophene (BP2T-OMe). A pair of parallel {110} facets of the single crystal acted as effective Fabry-Perot mirrors. This prominent lasing is based on high group refractive index (3.5) and Q factor (4500) of the orthorhombic crystal resonator indicating a promising potential of BP2T-OMe for organic laser media. PMID- 22930495 TI - Circulation of HIV-1 subtype A within the subtype C HIV-1 epidemic in Tamil Nadu, India. AB - The HIV-1 epidemic in India is caused mainly by subtype C viruses that are transmitted sexually and by injecting drug use. The state of Tamil Nadu in Southern India has an HIV-1 median prevalence of 16.8% among injecting drug users, 6.6% in men who have sex with men, and 4.6% in female sex workers. In the rural district of Namakkal, a prevalence >3% was detected among antenatal women. The goal of this study was to determine the HIV-1 molecular epidemiology in Tamil Nadu. Blood samples were collected from 40 high-risk HIV-seropositive individuals from Chennai and Namakkal. HIV-1 subtype was determined by envelope nucleotide sequencing. Among the samples studied, 85% were subtype C, however, a cluster of subtype A samples (12.5%) and one subtype E recombinant form CRF01_AE (close to the Thailand strains) were detected. The average genetic distance of subtype C samples from Chennai and Namakkal were 9.44 +/- 0.77% and 11.8 +/- 0.7%, respectively indicating an evolved epidemic. This pilot study confirmed that subtype C was predominant in these regions but an outbreak of subtype A was detected in Namakkal. These results stress the importance of periodic monitoring of circulating HIV-1 subtypes in South India. PMID- 22930496 TI - Prevalence of transmitted HIV-1 drug resistance among female sex workers and men who have sex with men in El Salvador, Central America. AB - Transmitted drug resistance has important implications for the successful use and management of therapy among persons infected with HIV. We estimated the prevalence of transmitted drug resistance in 145 samples from female sex workers (n = 47) and men who have sex with men (n = 98) in El Salvador. Samples were collected during March to September 2008, using a respondent driven sampling. The HIV-1 pol gene was sequenced to identify drug resistance mutations and transmitted drug resistance was scored as recommended by World Health Organization. Specimens were classified as recent or established infections using the Immunoglobulin G-Capture BED-Enzyme Immunoassay. The overall prevalence of transmitted drug resistance was 9.4% (95% CI: 4.7-16.1%), and was 5.9% for non nucleoside reverse transcriptase inhibitors, 4.2% for nucleoside reverse transcriptase inhibitors, and 0.8% for protease inhibitors. Transmitted drug resistance prevalence was 10.3% (95% CI: 2.8-24.2%) among female sex workers, and 9.0% (95% CI: 3.6-17.6%) among men who have sex with men. Nineteen patients were classified as having recent infection (16.2%, 95% CI: 10.1-24.2%), while 98 patients (83.8%, 95% CI: 75.8-89.9%) were classified as having established infections. Transmitted drug resistance among recent and established infections was similar at 10.5% and 9.2%, respectively. This study shows that the prevalence of transmitted drug resistance is moderate among female sex workers and men who have sex with men in El Salvador. These results highlight the importance of transmitted drug resistance surveillance in a representative sample of recently infected patients following the World Health Organization guidelines. PMID- 22930498 TI - Increased circulation of hepatitis A virus genotype IIIA over the last decade in St Petersburg, Russia. AB - The current study, covering the period 2004-2009, is a part of long-term monitoring for hepatitis A virus (HAV) strains circulating in St Petersburg, Russia. The HAV RNA was isolated directly from the sera of hepatitis A patients and RT-PCR was carried out using primer pairs for VP1/2A and VP1 genomic regions. PCR products were sequenced and 324 nucleotides from VP1/2A and 332 from the VP1 region were used for phylogenetic analysis. The results show that the IA subtype was the most common circulating subtype during the follow-up period, as found in the previous study: almost 90% of the isolated HAV strains belonged to the IA subtype. The large hepatitis A food-borne outbreak in St Petersburg in 2005 was caused by HAV IA. However, the proportion of HAV isolates belonging to subtype IIIA significantly increased in the period 2001-2009 (7.9%) compared to the period 1997-2000 (none found). The subtype IIIA was first found in St Petersburg in 2001 among a group of intravenous drug users. The increase in its circulation during the decade suggests that this previously unusual genotype has been permanently introduced into the general population of St Petersburg. These results indicate the usefulness of molecular epidemiological methods for studying changes in the circulation of HAV strains. PMID- 22930497 TI - IL28B polymorphism is not associated with HCV protease diversity in patients co infected with HIV and HCV treated with pegylated interferon and ribavirin. AB - Recent studies have demonstrated that IL28B polymorphisms predict therapeutic responses in chronic hepatitis C virus (HCV)-treated patients; however, the effect on HCV viral diversity, particularly on the HCV protease gene, is not clear. This study sought to evaluate the effect of IL28B polymorphisms on HCV diversity at NS3/4 protease region, which may influence therapeutic response to an HCV protease inhibitor based regimen. Twenty-two patients co-infected with HIV and HCV genotype 1, treatment-naive on stable HIV antiretroviral therapy initiating interferon-based treatment were evaluated. Plasma HCV NS3 gene diversity was analyzed by clonal analysis at baseline and end of treatment. IL28B (rs12979860) genotypes were tested for associations with virologic outcomes and diversity parameters. There was similar baseline NS3 diversity in patients with CC (favorable) genotype compared to those with CT/TT (unfavorable) genotypes. There was no significant association between IL28B genotype and baseline NS3 nucleotide p-distance, dS-dN, amino acid p-distance, or nucleotide changes. Among patients without a sustained virologic response, between baseline and follow-up there was a significant trend towards decreased diversity after treatment among patients with favorable genotype, which was not observed in unfavorable genotypes. In patients treated with peginterferon/ribavirin therapy, IL28B polymorphism was not associated with enhanced NS3 diversity at baseline. Among non-SVR patients with the less favorable genotype, there was no change in diversity after treatment. This suggests that IL28B genotype is unlikely to have a negative impact on subsequent HCV PI efficacy in patients co-infected with HIV and HCV patients who have previously failed HCV therapy. PMID- 22930499 TI - Does genotype predict response to treatment in children infected with hepatitis B perinatally? AB - HBV genotype may correlate with outcome and treatment response. Genotype has been compared with treatment response in children infected perinatally with hepatitis B following treatment with oral antiviral drugs (lamivudine or adefovir) or interferon (IFN) alone and with prednisolone priming (Pred/IFN). All children who took part in clinical trials in this unit since 1990 were included. Hepatitis B genotypes were determined by direct sequencing or using a commercial line probe assay (InnoLipa). Sixty-five children were included; 20 were treated with IFN; 19 with Pred/IFN; 22 with lamivudine and 7 with adefovir, some took part in more than one treatment study. 63 out of 65 children were clearly typed into single genotypes; 16, 7, 3, and 37 typing as A, B, C, and D respectively. The majority of South-Asian children had genotype D and European and Afro-Caribbean children were more likely to have genotype A. Treatment response (seroconversion from HBeAg to Anti-HBe) was better in children with genotypes A [n = 16] and D [n = 37] (55.5% and 48.7%), compared to those with B [n = 7] and C [n = 3] (12.5% and 0%) for all treatments. The response to interferon alone was better in children with genotype A compared to D (50% and 36%), but prednisolone priming improved the response so that there was no difference between genotypes A and D (66.7% and 70%). Assessment of genotype in children pre-treatment may provide a guide to potential response. The response to treatment by genotype should be evaluated in future clinical trials in children. PMID- 22930500 TI - The distribution of hepatitis B virus genotypes in Thailand. AB - Phylogenetic analysis was performed on hepatitis B virus (HBV) strains obtained from 86 hepatitis B surface antigen (HBsAg) positive donors from Thailand originating throughout the country. Based on the S gene, 87.5% of strains were of genotype C while 10.5% were of genotype B, with all genotype B strains obtained from patients originating from the central or the south Thailand. No genotype B strains were found in the north of Thailand. Surprisingly, one patient was infected with a genotype H strain while another patient was infected with a genotype G strain. Complete genome sequencing and recombination analysis identified the latter as being a genotype G and C2 recombinant with the breakpoint around nucleotide position 700. The origin of the genotype G fragment was not identifiable while the genotype C2 fragment most likely came from strains circulating in Laos or Malaysia. The performance of different HBsAg diagnostic kits and HBV nucleic acid amplification technology (NAT) was evaluated. The genotype H and G/C2 recombination did not interfere with HBV detection. PMID- 22930501 TI - Unexpected distribution of hepatitis B genotypes in patients with kidney disease: comparison with immunocompetent subjects. AB - Hepatitis B virus (HBV) infection has a high prevalence among hemodialysis and renal transplant patients. Data regarding genotype distribution in these populations are scarce and are still under investigation. The aim of this study was to evaluate the distribution of HBV genotypes in end-stage renal disease (ESRD)-patients and renal transplant patients and to compare with the distribution observed in immunocompetent patients from the same geographic region. From a population of 213 patients evaluated initially, 120 patients with detectable HBV-DNA were included in the study and submitted to genotype determination by amplification of S gene by nested PCR followed by sequencing method. Among 41 hemodialysis patients the most frequent genotype was D (83%), followed by genotype A (10%), C (5%), and F (2%). Genotype D was also the most prevalent (73%) among 33 renal transplant patients, followed by genotype A (18%), F (6%), and B (3%). This distribution was similar in these two groups of patients and for the comparative analysis they were considered in the kidney disease group. Compared to immunocompetents, patients with kidney disease (ESRD and renal transplant patients) showed a distinct distribution, with a higher prevalence of genotype D (78% vs. 17%, P < 0.001) whereas genotype A was the most prevalent among immunocompetent patients (70% vs. 14%, P < 0.001). In conclusion, the higher frequency of genotype A in immunocompetent patients and of genotype D in patients with renal disease suggest a higher capacity of environmental transmission or a better adaptability of this genotype in patients with a different pattern of immunologic response. PMID- 22930502 TI - Emergence of lamivudine resistance hepatitis B virus mutations in pregnant women infected with HBV and HIV receiving antiretroviral prophylaxis for the prevention of mother-to-infant transmission in Malawi. AB - HIV/HBV co-infection is highly prevalent in sub-Saharan Africa. The aim of this study was to determine if the use of triple combination lamivudine-containing prophylaxis for the prevention of mother-to-infant HIV transmission was associated with the emergence of lamivudine HBV mutations. The study included 21 pregnant co-infected women in Malawi who received either zidovudine or stavudine plus lamivudine and nevirapine from week 25 of gestation until 6 months after delivery or indefinitely if they met the criteria for treatment (CD4+ <350/mm(3)). HBV-DNA was determined using the Roche COBAS assay. Resistance mutations were assessed by the Trugene assay (Siemens Diagnostics). At baseline 33% of the women were HBeAg positive and had HBV-DNA > 10(4) IU/ml. Median CD4 count was 237 cells/mm(3) and median HIV-RNA was 3.8 log(10) copies/ml. After a median of 259 days of treatment, HBV-DNA was detectable in 9 out of 21 patients (42.8%). In three cases the HBV-DNA level was >10(4) IU/ml. Resistance mutations (M204I in five cases and L180M + M204I/V in one case) were present in 6 (28.6%) patients. Women with a resistant virus had significantly higher baseline HBV-DNA levels than those not developing resistance (1.1 * 10(7) IU/ml vs. 20.8 IU/ml, P = 0.022). Levels of ALT and AST were higher in women with resistant viruses compared to those retaining a wild-type virus. A high rate of lamivudine resistance was seen in this cohort of pregnant women. Follow-up of these patients will clarify if the presence of resistance has a significant impact on liver disease. PMID- 22930503 TI - Clinical characteristics and chronicity of acute hepatitis B induced by lamivudine-resistant strains. AB - Whether resistant hepatitis B virus (HBV) strains are transmissible and can lead to chronic infection remains to be studied. The aim of this study was to investigate the clinical characteristics of patients with acute hepatitis B caused by lamivudine (LAM)-resistant strains. Sera were collected from 234 Chinese patients with acute hepatitis B. LAM-resistance mutations were identified by direct polymerase chain reaction (PCR) sequencing. LAM-resistant HBV variants were detected in 11 of the 234 (4.7%) patients. Among these patients, six harbored the rtM204I mutation, two harbored the rtL180M + rtM204I mutations, one harbored the rtM204I + rtM204V mutations, one harbored the rtL80I + rtM204I mutations, and one harbored the rtV173L + rtL180M + rtM204V mutations. Three patients were infected with genotype B HBV and eight patients were infected with genotype C HBV. Two patients infected with viruses with LAM-resistance mutations developed severe acute hepatitis. One patient developed chronic hepatitis B. This patient was infected with genotype C HBV that had LAM-resistance mutations (rtL180M + rtM204I). The patient was diagnosed with an occult hepatitis B virus infection based on the presence of HBV DNA in the liver and the absence of detectable hepatitis B surface antigen (HBsAg) in the serum. LAM-resistant HBV strains in China are transmissible, can cause acute hepatitis B, and can even progress to chronic infection in China. PMID- 22930504 TI - Hepatitis B e antigen predicts delayed reduction of HBV DNA without viral breakthrough with adefovir dipivoxil and lamivudine: a 5-year study of patients with hepatitis B with lamivudine resistance. AB - To clarify the factors associated with delayed reduction of HBV DNA during combination treatment with adefovir dipivoxil (ADV) and lamivudine (LAM) for patients with LAM-resistant hepatitis B virus (HBV), factors including patient characteristics, viral mutations, and drug metabolism were investigated during a 5-year observation period. Delayed reduction of HBV DNA was defined as delayed viral response of detectable HBV DNA after 3 years of combination therapy. Of 67 consecutive patients, 47 attained undetectable HBV DNA after 3 years of combination therapy, and the mean therapeutic duration was 5 years (range: 3.0 8.4 years). The patients with delayed viral response had high levels of HBV DNA and HBe antigen, while those with negative or low levels of HBe antigen were also negative for HBV DNA, even if they had high levels of HBV DNA. In the multivariate analysis with the proportional hazards model, a high baseline level of HBe antigen was negatively associated with viral decline to an undetectable level (P = 0.013). A higher baseline of HBe antigen corresponded to a lower annual decline in HBV DNA (R = -0.38, P = 0.004). No patients showed ADV resistant mutations in the HBV reverse transcriptase region. Trough concentrations of LAM and ADV showed no clear associations with viral response. HBe antigen levels at the initiation of therapy, and reductions in these levels during therapy are predictive of the therapeutic response to combination therapy with ADV and LAM for patients with LAM-resistant HBV. PMID- 22930505 TI - Hepatitis C virus: the role of molecular mimicry in response to interferon treatment. AB - Chronic hepatitis C virus (HCV) infection is one of the major causes of chronic liver disease worldwide. In order for HCV to persist, the virus must escape immune recognition or inhibit the host immune response. The NS5A protein contains the interferon sensitivity-determining region (ISDR) and is able to repress dsRNA dependent protein kinase (PKR) thus influencing the response to interferon (IFN) therapy. Patients who respond to IFN therapy have stronger antibody reactivity against the NS5A compared to IFN non-responders. Therefore, given the possible role for the ISDR in IFN resistance and differential antibody reactivity, it is possible that variation in ISDR may be involved in viral immune escape and development of persistent HCV infection employing aspects of host mimicry. In this study, pre-treatment samples obtained from HCV infected patients were used to investigate the effect of different NS5A ISDR variants on the IFN antiviral response and their involvement in immune evasion. The NS5A was identified as a homologue of the variable region of immunoglobulins (Ig). The IFN resistant genotypes had higher levels of similarity to Ig compared to IFN sensitive genotypes. Expression of NS5A-6003 (HCV genotype 1b) and NS5A-6074 (HCV genotype 2a) was able to rescue vesicular stomatitis virus (VSV) from IFN inhibition and restore luciferase activity. A correlation between Ig-like NS5A structure and also antibody response with the outcome of IFN treatment was observed. PMID- 22930506 TI - Hepatitis C virus infection of human cytotrophoblasts cultured in vitro. AB - Hepatitis C virus (HCV) infection in the uterus is a significant path of vertical HCV transmission. Some studies consider vertical HCV transmission in the uterus as the result of maternal blood leakage into infant blood, whereas others theorize that HCV is transmitted by the mother to the infant through cells constituting the placenta barrier. Although trophoblasts play an important role in the placenta barrier, no definitive evidence has been presented to prove that cytotrophoblasts can be infected with HCV. The current study investigated whether or not these can be infected with HCV by conducting an experiment, in which cultured human cytotrophoblasts were infected with HCV in vitro. The results were analyzed using reverse transcription polymerase chain reaction (RT-PCR), ultrastructural characteristic changes under an electron microscope, and immunoelectron microscopy. HCV RNA in the supernatant of the cultured medium of the infected group was intermittently detected during the 16-day incubation period using RT-PCR. Under an electron microscope, the ultrastructures of infected human cytotrophoblasts were markedly different from normal cells, demonstrating lysosomal hyperplasia, rough endoplasmic reticulum, decreased lipid droplets, presence of vacuoles, and the appearance of HCV-like particles. Using immunoelectron microscopy, HCV-like particles conjoined with golden granules were also observed. Based on the data, the current study concludes that HCV infects a human cytotrophoblast cultured in vitro; moreover, its ultrastructure changes dramatically upon infection. PMID- 22930507 TI - Association of IL28B genotype and viral response of hepatitis C virus genotype 2 to interferon plus ribavirin combination therapy. AB - The impacts of IL28B genotype to treatment response of hepatitis C virus (HCV) genotype 2 are still not clear. A total of 381 consecutive Japanese patients infected with HCV genotype 2, who could complete combination therapy with interferon (IFN) plus ribavirin for 24 weeks, were evaluated to investigate pretreatment predictors. Patients, who could not achieve sustained virological response at the first course of 24-week IFN plus ribavirin, were recruited into the study protocol of total 48-week IFN plus ribavirin. In 24-week regimen, rates of sustained virological response and rapid virological response were 82% and 50%, respectively. There were no significant differences in rates of sustained virological response and rapid virological response, according to IL28B genotype. Multivariate analysis identified younger age, higher level of albumin, absence of past history of IFN, and lower level of viremia as significant determinants of sustained virological response. As significant or marginal significant determinants of non-sustained virological response regardless of rapid virological response, multivariate analysis identified IL28B rs8099917 genotype TG + GG and lower level of albumin. In 48-week regimen to 10 patients of non sustained virological response at the first course of 24-week regimen, sustained virological response rates were 70%. All of six patients, with IL28B TT and relapse at the first course of 24-week regimen, could achieve sustained virological response, but two patients with IL28B TG could not achieve sustained virological response. In conclusion, the present results suggest that IL28B genotype might partly affect viral response of HCV genotype 2 to combination therapy. PMID- 22930508 TI - Dried blood spot samples: optimization of commercial EIAs for hepatitis C antibody detection and stability under different storage conditions. AB - This study was undertaken to optimize and compare the efficiency of two commercial EIAs for anti-HCV detection (HCV Ab Radim, Pomezzia, Italy and ETI-AB HCVK-4 DiaSorin, Vercelli, Italy), in dried blood spot (DBS) samples. The long term stability of anti-HCV on DBS samples stored at three environmental conditions was also evaluated at: 2-8 degrees C, 20-25 degrees C, and -20 degrees C. Paired DBS and serum samples were obtained from individuals with or without anti-HCV. The type of elution buffer, sample and conjugate volume, sample incubation time and cut-off values were evaluated. For both EIAs, a larger sample volume was used, and the cut-off value determined by the manufacturer was employed for Radim EIA; however, ROC curve analysis was used for the DiaSorin EIA. The sensitivity and specificity of Radim EIA on DBS were 97.5% and 99.5%, respectively, and of DiaSorin EIA were 88.9% and 98.9%, respectively. Accurate results were obtained for a period of 117 days using DBS samples stored at all storage conditions, but storage at -20 degrees C resulted in the lowest variation among the absorbance values. Both EIAs demonstrated the same limit of detection (until dilution of 1:10(4) with estimated viral load of 3.1 * 10(-1) UI/ml), but the Radim EIA was associated with the best performance because a low coefficient of variation was observed in the repetition and reproducibility studies. In conclusion, commercial EIAs can be optimized for anti-HCV detection in DBS samples that are extremely stable at different conditions for more than 100 days. PMID- 22930509 TI - Hepatitis C virus infection among drug addicts in Italy. AB - There is a lack of updated nationwide records regarding hepatitis C virus (HCV) infection among drug addicts in Italy. The prevalence and characteristics of HCV infection in a national sample of drug addicts in Italy were determined. Five hundred forty-three drug addicts (mean age 35.3 years, 85.1% males), selected from 25 Italian Centers for Substance Dependence were enrolled to be evaluated for anti-HCV, HCV-RNA, HCV genotype, HBV markers, anti-HDV, and anti-HIV during the period of April-November 2009. Anti-HCV prevalence was 63.9%. HCV-RNA was detected in 68.3% of patients positive for anti-HCV. Genotypes 1 and 3 prevailed (49.3% and 39.7%, respectively). However, 9.3% of the subjects had genotype 4, a rate over threefold higher than the one observed in 1996 among drug addicts in central Italy. Needle sharing was the strongest independent predictor of the likelihood to contract an HCV infection (OR 8.9; 95% CI: 5.0-16.0). Only 19.3% of subjects received antiviral treatment for HCV. The prevalence of HBsAg and HIV positivity was 2.8% and 3.1%, respectively. The pattern of HBV markers showed that nearly one-third of subjects had been vaccinated, while 42.3% were negative for any marker of HCV. The prevalence of HCV infection is high among drug addicts in Italy. The incidence of Genotype 4 is increasing and this may lead to the spreading of the disease to the general population in the near future. Efforts should be made to improve the rate of antiviral treatment for drug addicts with HCV infection and vaccination against hepatitis B. PMID- 22930510 TI - Hepatitis C virus genotype 4d in Southern Italy: reconstruction of its origin and spread by a phylodynamic analysis. AB - Hepatitis C Virus (HCV) genotype 4 predominates in Middle East and Central Africa countries. Recently, it has become also prevalent in Southern European countries where it is thought to have been introduced through immigration and the movement of intravenous drug users. In Italy, the prevalence of genotype 4 is particularly high (4.5%) in Southern regions, such as Calabria, and reaches values of 8.4% in specific areas where there appears to be endemic circulation of this genotype. In the present study, the phylogeny of HCV subtype 4d isolated from 19 Italian patients in Calabria was investigated by analysing a fragment of the NS5B viral genomic region. A Bayesian coalescent-based framework was used to estimate origin and spread of the HCV 4d in this area. The mean evolutionary rate HCV 4d NS5B sequences was estimated using a dataset of sequences sampled at known times and a relaxed clock constant model that best fitted the data. By using a Bayesian coalescent method, the Italian 4d isolates collected in Calabria were found to share a common ancestor with reference 4d isolates whose origin was traced back to 1940s. The genotype 4d epidemic in Southern Italy was maintained in a steady non-expanding phase until the late 1970s after that it grew exponentially up to 1990s probably sustained by the vast increase of unsafe blood transfusions and the spread of illicit intravenous drug users. PMID- 22930511 TI - Identification and characterization of a monoclonal antibody recognizing the linear epitope RVADVI on VP1 protein of enterovirus 71. AB - Several large outbreaks of hand-foot-mouth disease (HFMD) have occurred in the Asian-Pacific region since 1997, with Enterovirus 71 (EV71) and/or Coxsackievirus A16 (CAV16) as the main causative agents. Despite the close genetic relationship between the two viruses, only EV71 is associated with severe clinical manifestations and deaths. Effective antiviral treatment and vaccines are not available. High-quality monoclonal antibodies (mAbs) are necessary to improve the accuracy of the diagnosis of EV71. In this study, a mAb (designated 1D9) was generated using EV71 C5 strain virus particles as immunogens. Examined by indirect immunofluorescence assay (IFA) and Western blotting, 1D9 detected successfully all 11 subgenotypes of EV71 and showed no cross-reactivity to the four selected subgenogroups of Coxsackieviruses CAV4, CAV6, CAV10, and CAV16. A linear motif, R(3) VADVI(8), which is located at the N-terminus of the EV71 VP1 protein, was identified as the minimal binding region of 1D9. Alignment and comparison of the 1D9-defined epitope sequence against the listed sequences in the NCBI EV71 database indicated that this epitope R(3) VADVI(8) was highly conserved among EV71 strains, while no significant similarity was observed when blasted against the Coxsackieviruses. This suggests that the mAb 1D9 may be useful for the development of a cost-effective and accurate method for surveillance and early differentiation of EV71 from CAV16 infection. PMID- 22930513 TI - HPV persistence and its oncogenic role in prostate tumors. AB - HPV has carcinogenic effects at several anatomical sites in women and men. Whether the presence of HPV in the genitourinary tract of men is associated with a higher prostate cancer risk has been a matter of research for a long-time and the results are still not fully conclusive. Similarly, the question of the reservoir of HPV infection in men is not clearly resolved. HPV DNA presence and types were evaluated by means of polymerase chain reaction in the tissue of 146 patients with benign prostate hyperplasia and prostate cancer. HPV-specific antibodies were analyzed by enzyme-linked immunosorbent assay in the sera of all patients and 172 controls. In addition, 256 biopsies taken from non-tumorous tissues were analyzed. No statistically significant differences were observed in HPV DNA prevalence between patients with benign prostate hyperplasia (2%) and patients with prostatic cancer (2%; P = 1.000). The seropositivity rates did not differ significantly between groups of subjects except for antibodies against HPV 6 VLPs which were found more often in prostate cancer patients (adjusted P = 0.018). Similarly, no difference in the seroprevalence rates for HPV 16 E6 and/or E7 oncoproteins between groups of patients and healthy controls was detected. The overall HPV prevalence in 256 healthy tissue samples was 4%. The results indicate that HPV infection is not associated with prostate oncogenesis in men. However, they imply that multiple tissues of the male genitourinary tract may be important reservoirs for the transmission of some HPV types. PMID- 22930512 TI - Type-specific human papillomavirus distribution in invasive cervical carcinomas in Paraguay. A study of 432 cases. AB - Cervical carcinoma is the most common malignant tumor among woman in Paraguay. Cytological screening programs have not been successful and a plan for human papillomavirus (HPV) based-screening program and/or vaccination is under evaluation. This study aimed to identify the contribution of HPV genotypes in invasive cervical cancer in Paraguay to provide essential background data to guide and assess the introduction and impact of new preventive strategies based on HPV. Four hundred thirty two histologically confirmed cases (1960-2004) were analyzed. HPV detection in paraffin blocks was performed at the Catalan Institute of Oncology using PCR with SPF-10 broad spectrum primers followed by DNA enzyme immunoassay and genotyping with a reverse hybridization line probe analysis. The majority of cases were squamous cell carcinoma (92.8%). Mean patients age was 48 years old. HPV DNA was detected in 73.1% of the cases and single infections were predominant (97.8%). The most common HPV single types were 16, 18, 45, 33, 31, 52, 35, and 39. 73.1% of HPV positive cases had an HPV 16, 18 as single infection. HPV16 was frequent in SCC whereas HPV 18 and 45 were prevalent in glandular tumors. Significant decrease of HPV 16 with age groups (P-trend = 0.022) and increase in other HPV types (P-trend > 0.001) were observed. The potential impact of HPV 16 and 18 for a vaccination program was 73.1%. The study provide a profile of the HPV situation in the country, with robust clinical, pathological and virological data which would permit a better cervical cancer screening and vaccination programs. PMID- 22930514 TI - A universal influenza A and B duplex real-time RT-PCR assay. AB - A high throughput universal influenza A and B duplex real-time RT-PCR was developed to meet effectively the heightened surveillance and diagnostic needs essential in managing influenza infections and outbreaks. Primers and probes, designed to target highly conserved regions of the matrix protein of influenza A and the nucleoprotein of influenza B, were optimized using the high-throughput LightCycler 480 II system. Analytical sensitivity and specificity were characterized using RNA transcripts diluted serially, archived non-influenza respiratory viruses, and proficiency test samples. Eighty-nine clinical samples were tested in parallel against existing influenza A and B monoplex assays. Once validated, the duplex assay was applied prospectively on 2,458 clinical specimens that were later subtyped. In April 2011, the emergence of an influenza B variant necessitated the inclusion of an additional modified probe for influenza B and revalidation of the revised protocol. The lower detection limits of the assay were 50 copies/PCR. There was no cross-reactivity against any non-influenza respiratory virus and all proficiency testing materials were identified correctly. The parallel testing revealed a 98.9% overall agreement. Routine application of the assay revealed high sensitivity and specificity for the detection of influenza A/H1N1/2009, A/H3N2 and influenza B. Assay C(q) values correlated well between the pre- and post-revision protocols for influenza A (r(2) = 0.998) and B (r(2) = 0.999). The revised protocol detected three additional novel influenza B variant cases in 200 specimens reported previously as influenza B negative. This in-house assay offers a highly sensitive and specific option for laboratories seeking to expand their influenza testing capacity. PMID- 22930515 TI - Molecular and phylogenetic analyses of human Parvovirus B19 isolated from Brazilian patients with sickle cell disease and beta-thalassemia major and healthy blood donors. AB - Human Parvovirus B19 (B19V) is a recognized cause of life-threatening conditions among patients with hemoglobinopathies. This study investigates B19V infection in patients with sickle cell disease and beta-thalassemia using different experimental approaches. A total of 183 individuals (144 with sickle cell disease and 39 with beta-thalassemia major) and 100 healthy blood donors were examined for B19V using anti-B19V IgG enzyme immunoassay, quantitative PCR, DNA sequencing, and phylogenetic analysis. Viremia was documented in 18.6% of patients and 1% of donors, and was generally characterized by low viral load (VL); however, acute infections were also observed. Anti-B19V IgG was detected in 65.9% of patients with sickle cell disease and in 60% of donors, whereas the patients with thalassemia exhibited relatively low seroreactivity. The seroprevalence varied among the different age groups. In patients, it progressively increased with age, whereas in donors it reached a plateau. Based on partial NS1 fragments, all isolates detected were classified as subgenotype 1A with a tendency to elicit genetically complex infections. Interestingly, quasispecies occurred in the plasma of not only patients but also donors with even higher heterogeneity. The partial NS1 sequence examined did not exhibit positive selection. Quantitation of B19V with a conservative probe is a technically and practically useful approach. The extensive spread of B19V subgenotype 1A in patients and donors and its recent introduction into the countryside of the Sao Paulo State, Brazil were demonstrated; however, it is difficult to establish a relationship between viral sequences and the clinical outcomes of the infection. PMID- 22930516 TI - Phylogenetic analysis of rubella virus strains during an outbreak in Sao Paulo, 2007-2008. AB - Rubella virus (RV) is an important human pathogen that causes rubella, an acute contagious disease. It also causes severe birth defects collectively known as congenital rubella syndrome when infection occurs during the first trimester of pregnancy. Here, we present the phylogenetic analysis of RV that circulated in Sao Paulo during the 2007-2008 outbreak. Samples collected from patients diagnosed with rubella were isolated in cell culture and sequenced. RV RNA was obtained from samples or RV-infected cell cultures and amplified by reverse transcriptase-polymerase chain reaction. Sequences were assigned to genotypes by phylogenetic analysis using RV reference sequences. Seventeen sequences were analyzed, and three genotypes were identified: 1a, 1G, and 2B. Genotypes 1a and 1G, which were isolated in 2007, were responsible for sporadic rubella cases in Sao Paulo. Thereafter, in late 2007, the epidemiological conditions changed, resulting in a large RV outbreak with the clear dominance of genotype 2B. The results of this study provide new approaches for monitoring the progress of elimination of rubella from Sao Paulo, Brazil. PMID- 22930517 TI - Molecular characterization of varicella-zoster virus clinical isolates from 2006 to 2008 in a tertiary care hospital, Dublin, Ireland, using different genotyping methods. AB - Varicella-zoster virus (VZV), a herpesvirus, is a ubiquitous organism that causes considerable morbidity worldwide and can cause severe complications on reactivation. Phylogenetic analysis was performed on 19 clinical VZV isolates (16 zoster and 3 varicella) found in Ireland, between December 2006 and November 2008, in order to determine whether previously reported viral heterogeneity was still present and whether viral recombination was evident. Open reading-frames (ORFs) from genes 1, 21, 50, and 54, were sequenced. Clades 1, 2, 3, and 5 were identified. Four putative recombinant isolates were detected (three clade 3/1 and one clade 5/3/1). Further sequencing and examination of ORF 22 and 21/50, did not elucidate the putative recombinant genotypes further. These two previously published genotyping schemes were examined in light of the new consensus genotyping scheme proposed in 2010. Remarkable VZV heterogeneity remains prevalent in Ireland. This is the first evidence of putative VZV recombination found in Ireland. PMID- 22930518 TI - Review: Viral infections and mechanisms of thrombosis and bleeding. AB - Viral infections are associated with coagulation disorders. All aspects of the coagulation cascade, primary hemostasis, coagulation, and fibrinolysis, can be affected. As a consequence, thrombosis and disseminated intravascular coagulation, hemorrhage, or both, may occur. Investigation of coagulation disorders as a consequence of different viral infections have not been performed uniformly. Common pathways are therefore not fully elucidated. In many severe viral infections there is no treatment other than supportive measures. A better understanding of the pathophysiology behind the association of viral infections and coagulation disorders is crucial for developing therapeutic strategies. This is of special importance in case of severe complications, such as those seen in hemorrhagic viral infections, the incidence of which is increasing worldwide. To date, only a few promising targets have been discovered, meaning the implementation in a clinical context is still hampered. This review discusses non hemorrhagic and hemorrhagic viruses for which sufficient data on the association with hemostasis and related clinical features is available. This will enable clinicians to interpret research data and place them into a perspective. PMID- 22930519 TI - Alkali-metal-promoted Pt/TiO2 opens a more efficient pathway to formaldehyde oxidation at ambient temperatures. PMID- 22930520 TI - Production of human cytochrome P450 2D6 drug metabolites with recombinant microbes--a comparative study. AB - The processes of drug development require efficient strategies to produce the respective drug metabolites, which are often difficult to obtain. Biotransformations employing recombinant microorganisms as whole-cell biocatalysts have become an attractive alternative to the chemical syntheses of such metabolites. For the first time, the potential of four different microbial systems expressing the human cytochrome P450 2D6 (CYP2D6), which is one of the most important drug-metabolizing enzymes, were compared and evaluated for such applications. The microbial host Pichia pastoris was the most efficient at expressing CYP2D6. Without additional over-expression of chaperons, the achieved yield of CYP2D6 was the highest of microbial hosts reported so far. Therefore, the system described in this study outperformed the previously reported expression of the N-terminally modified enzyme. It was also shown that the activities of the whole-cell conversions of bufuralol in recombinant P. pastoris were significantly higher than the Escherichia coli catalyst, which expressed the same unmodified gene. PMID- 22930521 TI - Evolutional and functional analysis of a serine protease in Spodoptera litura. AB - Spodoptera litura is a threatening agricultural insect in tropical and subtropical areas and accounts for tremendous annual crop losses. As seen in virtually all insect species, serine proteases (SPs) are crucial to S. litura. The expression pattern of SPs from the midgut of S. litura was studied through expressed sequence tags (ESTs) analysis. One of SP (SlSP1) was chosen for detailed study, because the expression of the gene was midgut and larvae specific. SlSP1 was conducted as a model of its evolution, structure, and potential binding activity with corresponding substrates. SlSP1 is composed of 255 amino acids including a signal peptide at N-terminal followed by a putative activation peptide and the mature protein along with five putative phosphorylation sites, three disulphide bridges, and two N-glycosylation positions. At least nine conserved motifs were obtained in multiple sequence alignments. Some conserved residues, such as the catalytic triad His84, Asp127, and Ser229 as well as six cysteines at position 66, 82, 194, 211, 223, and 247, were examined. After homology modeling and molecular dynamics simulation, the resultant three-dimensional (3D) structure of SlSP1 was docked with the substrates 2PTC-Arg and 2PTC-Lys, respectively. Molecular Mechanic/Poisson Boltzmann surface area analysis was applied to anticipate optimal binding mode and crucial active sites of this enzyme. The residues Trp28, Gly187, Aso188, Arg249, Ile250, Lys246, and Lys278 are crucial for the substrate binding and molecule process. This information can be used in logical design of SPs inhibitors. New inhibitors may be a basis for development of a new pest control technology. PMID- 22930522 TI - Inter-endothelial transport of microvectors using cellular shuttles and tunneling nanotubes. AB - New insights into the intra- and intercellular trafficking of drug delivery particles challenges the dogma of particles as static intracellular depots for sustained drug release. Recent discoveries in the cell-to-cell transfer of cellular constituents, including proteins, organelles, and microparticles sheds light on new ways to propagate signals and therapeutics. While beneficial for the dispersion of therapeutics at sites of pathologies, propagation of biological entities advancing disease states is less desirable. Mechanisms are presented for the transfer of porous silicon microparticles between cells. Direct cell-to-cell transfer of microparticles by means of membrane adhesion or using membrane extensions known as tunneling nanotubes is presented. Cellular relays, or shuttle cells, are also shown to mediate the transfer of microparticles between cells. These microparticle-transfer events appear to be stimulated by environmental cues, introducing a new paradigm of environmentally triggered propagation of cellular signals and rapid dispersion of particle-delivered therapeutics. The opportunity to use microparticles to study cellular transfer events and biological triggers that induce these events may aid in the discovery of therapeutics that limit the spread of disease. PMID- 22930523 TI - Whole mount nuclear fluorescent imaging: convenient documentation of embryo morphology. AB - Here, we describe a relatively inexpensive and easy method to produce high quality images that reveal fine topological details of vertebrate embryonic structures. The method relies on nuclear staining of whole mount embryos in combination with confocal microscopy or conventional wide field fluorescent microscopy. In cases where confocal microscopy is used in combination with whole mount nuclear staining, the resulting embryo images can rival the clarity and resolution of images produced by scanning electron microscopy (SEM). The fluorescent nuclear staining may be performed with a variety of cell permeable nuclear dyes, enabling the technique to be performed with multiple standard microscope/illumination or confocal/laser systems. The method may be used to document morphology of embryos of a variety of organisms, as well as individual organs and tissues. Nuclear stain imaging imposes minimal impact on embryonic specimens, enabling imaged specimens to be utilized for additional assays. PMID- 22930524 TI - Brain-derived neurotrophic factor exerts antinociceptive effects by reducing excitability of colon-projecting dorsal root ganglion neurons in the colorectal distention-evoked visceral pain model. AB - The mechanism underlying visceral pain is still largely unclear. Recently, much attention has focused on a potential modulatory role of brain-derived neurotrophic factor (BDNF) in visceral pain. In the present study, we investigated the expression of BDNF in dorsal root ganglia (DRG) primary sensory neurons and its role in a colorectal distention (CRD)-induced model of visceral pain. Results obtained from enzyme-linked immunosorbant assay (ELISA) revealed that BDNF protein was upregulated after CRD. An abdominal withdrawal reflex (AWR) assay confirmed that BDNF played an antinociceptive role in this model. Application of BDNF directly to DRG neurons decreased their hypersensitivity when evoked by CRD. Pretreatment with k252a partially blocked the effect of BDNF. These findings suggest that BDNF might be a novel analgesic agent for the treatment of visceral pain. PMID- 22930525 TI - Fatty streak assessed by optical coherence tomography: early atherosclerosis detection. PMID- 22930526 TI - Hierarchically structured superoleophobic surfaces with ultralow contact angle hysteresis. AB - Hierarchically structured, superoleophobic surfaces are demonstrated that display one of the lowest contact angle hysteresis values ever reported - even with extremely low-surface-tension liquids such as n-heptane. Consequently, these surfaces allow, for the first time, even ~2 MUL n-heptane droplets to bounce and roll-off at tilt angles. <= 2 degrees . PMID- 22930527 TI - Universal screening of cholesterol in children. AB - Atherosclerosis begins in childhood, and these early lesions are related to cardiovascular risk factors, including non-high-density lipoprotein cholesterol (HDL-C). Genetic disorders of lipid metabolism, principally familial hypercholesterolemia, have a high frequency in the population (about 1:300 1:500), and cause cardiovascular morbidity beginning in the third decade of life. The current obesity epidemic in children has worsened cardiovascular risk status. Cardiovascular risk factors present in youth often track into adulthood and are more predictive of future subclinical atherosclerosis than risk factors measured in young adulthood. Further, modification of risk factors beginning in childhood and young adulthood can lead to restoration to normal or improvement in measures of subclinical atherosclerosis measures both in those with genetic dyslipidemias and those with dyslipidemia secondary to obesity. Prior recommended selective lipid screening strategies based on family history or presence of other cardiovascular risk factors have failed to capture many with genetic dyslipidemia. Medium-term clinical trials of statin therapy for inherited dyslipidemias are safe and effective in lowering low-density lipoprotein cholesterol (LDL-C). Cholesterol screening in childhood is necessary to prevent cardiovascular morbidity in those with genetic dyslipidemias and to increase awareness of the need for behavioral intervention in those with multiple cardiovascular risk factors, often a result of the obesity epidemic. PMID- 22930528 TI - A mechanically controlled indicator displacement assay. PMID- 22930529 TI - Structural analyses of mannose pentasaccharide of high mannose type oligosaccharides by 1D and 2D NMR spectroscopy. AB - NMR spectroscopy is a very important and useful method for the structural analysis of oligosaccharides, despite its low sensitivity. We first applied conventional measuring methods, 2D DQF COSY, (1)H-(13)C HSQC, and (1)H-(13)C HMBC, and also the Double Pulsed Field Gradient Spin Echo (DPFGSE)-TOCSY and DPFGSE-NOESY/ROESY techniques to analyze a branched mannose pentasaccharide as a model of high mannose type N-glycans in natural abundance. The NMR spectra of the model compound are very complex and difficult to analyze owing to overlapping signals. The superior selective irradiation capability of the DPFGSE technique is useful for fine structural and conformational analyses of such complex oligosaccharides. We here introduce a novel technique called DPFGSE-Double Selective Population Transfer (SPT)-Difference and DPFGSE-NOE/ROE-SPT-Difference spectroscopy. The DPFGSE-Double-SPT-Difference method involves irradiation of two peaks from one proton and the subtraction of higher and lower peaks from each spectrum. The DPFGSE-NOE/ROE-SPT-Difference method involves the transfer of the magnetization polarized by NOE/ROE from the nuclei to the spin-coupled nuclei through scalar spin-spin interaction using the SPT method. Even if the signals in the NMR spectra overlap, each signal can be accurately assigned. In particular, DPFGSE-NOE/ROE-SPT-Difference is very useful for identifying sugar connectivity. PMID- 22930530 TI - Gene network analysis leads to functional validation of pathways linked to cancer cell growth and survival. AB - Hepatocellular carcinoma (HCC) represents one of the most frequently diagnosed human cancers; however, there are currently few treatment alternatives to surgical resection. In this study we performed bioinformatic analysis of previously published transcriptomic data in order to characterize liver specific networks, including biological functions, signaling pathways and transcription factors, potentially dysregulated in HCC. By incorporating specific signaling inhibitors into real-time proliferation assays using HepG2 cells, we then validated these in silico results. We found that G protein subunits Gi/G0, protein kinase C, Mek1/2, and Erk1/2 (P42/44), JAK1, PPARA and NFkappaB p65 subunit were the major signaling molecules required for survival and proliferation of human HCC cell lines. We also found that these pathways regulate the expression of key hepatic transcription factors involved in cell differentiation, such as CEBPA, EGR1, FOXM1 and PPARs. By combining bioinformatic and functional analyses, major signaling pathways related to tumorigenicity in HCC are revealed, thereby elucidating potential targets for drug therapies. PMID- 22930531 TI - Dual-responsive breakdown of nanostructures with high doxorubicin payload for apoptotic anticancer therapy. AB - Self-assembled nanoaggregates co-encapsulating doxorubicin (DOX) and oligonucleotide are prepared for dual-responsive breakdown of the nanostructure with complete disappearance characteristics. Four-arm poly(ethylene glycol) is co conjugated with DOX and anti-bcl-2 oligonucleotide with reducible linkers and acid-cleavable linkers, respectively. The conjugate is hydrophobically self assembled into nanoaggregates in aqueous solution. Elemental scanning of the nanoaggregates reveals their core-shell structure with DOX and oligonucleotide located at the core and the shell, respectively. The tracking of size modulation suggests the complete disappearance of the particles under reducing conditions and the liberation of oligonucleotide at low pH, which is confirmed by dynamic light scattering and electron microscopy. The release of DOX and oligonucleotide is controlled by the pH and the reducing potential of the medium, and most of the drug and DNA are released in 24 h. The released fractions are analyzed by reversed-phase chromatography, which indicates facile cleavage of DOX and oligonucleotide from the carriers. The nanoaggregates with both DOX and oligonucleotide show the lowest IC(50) value when a cytotoxicity assay is performed against A549 cells. Apoptosis assay also confirms that cells treated with the nanoaggregates having both DOX and oligonucleotide show higher fluorescence intensity of antiapoptotic antibody than native DOX. PMID- 22930532 TI - Abusive supervision and workload demands from supervisors: exploring two types of supervisor-related stressors and their association with strain. AB - Our study aimed to identify two types of stressors from supervisors: abusive supervision (AS) and workload demands from supervisors (WDS). AS reflects the relationship dimension of supervisor-related stressors, and WDS reflects the task dimension of supervisor-related stressors. In Study 1, we attempted to distinguish between AS and WDS. The results of confirmatory factor analysis showed that AS and WDS are two distinct dimensions of supervisor-related stressors. In Study 2, we utilized job demands-resources model and investigated whether AS and WDS can uniquely predict subordinates' emotional exhaustion (EE). We also explored whether perceived job characteristics (PJCs) have differential moderating effects on the relationships between the two dimensions of supervisor related stressors (AS and WDS) and EE. Consistent with our predictions, the results showed that both AS and WDS have incremental predictive effects on EE after controlling for the effect of the other. The results also revealed that PJCs weaken the WDS-EE relationship, not the AS-EE relationship. We discussed the theoretical and practical implications at the end. PMID- 22930533 TI - Increased blood viscosity and red blood cell aggregation in a patient with sickle cell anemia and smoldering myeloma. PMID- 22930534 TI - Iptycene-based fluorescent sensors for nitroaromatics and TNT. AB - Small-molecule fluorescent sensors (1-5) for the recognition of nitroaromatic compounds, such as 2,4-dinitrotoluene and the explosive TNT, were obtained by using a three-step dehydrohalogenation cycloaddition protocol. The interaction of the receptors and nitroaromatics was studied both in solution and in the solid state by using fluorescence spectroscopy and X-ray crystallography, respectively. It is shown that the iptycene receptors 1-5 provide a cavity suitable for binding nitroaromatic compounds in an edge-to-face mode, rather than simple ring-stacking interactions. The results obtained inspired us to develop an inexpensive, reliable and robust sensor for vapour detection of explosives. Polymer nanofibres are particularly suitable for the production of such TNT sensors as they accelerate the mass exchange between the polymer and the vapours of TNT. Quenching of the sensors took place within 1 min compared to 10 min for a glass slide assay. Hence, the sensor performance can be improved by optimising the matrix material and morphology without resynthesising the sensor moieties. PMID- 22930535 TI - Detection of AMP-activated protein kinase alpha1 by isoelectric focusing in sera of patients with metabolic diseases. AB - The aim of this study is to determine by isoelectric focusing the level of AMPKalpha1, an energy sensor, in sera of patients who are in energy-demanding situation. After Western blotting, detection was performed with specific antibodies against AMPKalpha and its phosphorylated form. To evaluate the effect of weight loss on AMPK, sera from 24 patients were collected before and after intragastric balloon insertion over a 16-week follow-up period. Compared to baseline, all patients showed postoperatively an increase of AMPK. Patients with ischemic heart, with inflammatory bowel disease, with chronic undernutrition or with hepatic diseases were examined. Compared to control subjects, the majority of them showed a significant increase of AMPK. These results suggest that serum AMPK may have a potential for diagnosis of several metabolic diseases. However, this has to be confirmed by further studies with additional biomarkers and with more specific techniques. PMID- 22930536 TI - Umpolung of fluoroform by C-F bond activation: direct difluoromethylation of lithium enolates. PMID- 22930537 TI - Critical role of plasma corticosteroid-binding-globulin during stress to promote glucocorticoid delivery to the brain: impact on memory retrieval. AB - We aimed at demonstrating that corticosteroid binding globulin (CBG), a plasma glycoprotein binding glucocorticoids with high affinity in blood, endorses a major role under stress conditions by regulating free glucocorticoid access to the brain and thereby influences glucocorticoid-dependent behaviors. Hence, we compared CBG-deficient mice (Cbg-/-) and their controls (Cbg+/+) in a specific memory task, i.e. the delayed alternation behavior, requiring memory retrieval both under stress and nonstress conditions and previously shown to be dependent on hippocampal glucocorticoid levels. Our results evidence that Cbg-/- mice, unlike controls, remain insensitive to stress applied before memory retrieval. Furthermore, under stress conditions, we observed a blunted surge of corticosterone (CORT) in plasma and no free CORT rise in the hippocampus of Cbg-/ . Moreover, intrahippocampal infusion of CORT through implanted cannulae was used to mimic stress CORT rise before memory retrieval. This infusion of CORT reproduced memory retrieval impairments in Cbg-/- as in Cbg+/+ controls. Finally, we provide evidence that Cbg-/- mice exhibit a normal adrenal response to stress and ACTH. Given that CBG deficiency is known to markedly impact on CORT clearance from plasma, our current article demonstrates that Cbg-/- insensitivity in memory retrieval after stress results from the blunted CORT response due to increased CORT clearance. Overall, our data suggest that the impact of CBG genetic deficiency on various behavioral patterns reported previously stems from a smaller CORT reservoir in blood. Inasmuch as CBG discloses interindividual variations, such a parameter ought to be taken into account when studying stress induced glucocorticoid action in brain. PMID- 22930538 TI - NMR characterisation of structure in solvates and polymorphs of formoterol fumarate. AB - The solid-state structures of two polymorphs and two alcoholates (ethanol and isopropanol) of formoterol fumarate have been investigated by a combination of NMR techniques. First-principles shielding computations are combined with NMR data to successfully relate peaks to their crystallographic positions for the solvates, including atoms that are in equivalent molecular positions. The uncharacterised structure of the asolvate form C is found to contain a single formoterol ion and half a fumarate ion in its asymmetric unit. HETCOR experiments for the ethanolate and form C allow proton chemical shifts to be determined and give improved (13)C resolution for the former compound. Desolvation of the solvates to form C has been monitored under the conditions of the NMR experiment. Differential rates of phenylene ring flipping are observed in the different forms. Carbon-13 relaxation times and (2)H NMR are used to probe dynamics of the fumarate ion. PMID- 22930539 TI - Distance-mediated plasmonic dimers for reusable colorimetric switches: a measurable peak shift of more than 60 nm. AB - The first reconfigurable colorimetric DNA switches based on target DNA binding are reported. This DNA binding actuates a change in the interparticle distance between gold nanoparticle dimers. A significant spectral shift of 68 nm is achievable from on-off switching. The reconfigurability is possible owing to thiol and EDC-imidazole coupling which anchors the DNA linkers to the nanoparticles. The huge spectral shift allows the unaided eye to observe single target biomolecular binding event in real time under a darkfield microscope. The limit-of-detection for target molecules in PBS and human serum are 10(-13) M and 10(-11) M respectively. An improved fabrication strategy via asymmetric functionalization is also described, assisted by solid phase synthesis which minimizes the formation of trimers and multimers. PMID- 22930540 TI - Stress and coping mediate relationships between contingent and global self-esteem and alcohol-related problems among college drinkers. AB - This study examined the hypotheses that contingent self-esteem would be positively associated with alcohol-related problems and that global self-esteem would be negatively associated with such problems. It also examined the hypothesis that high stress and maladaptive coping would mediate these relationships. A sample of college students (n = 399) who were predominantly Hispanic (89%) completed measures of global and contingent self-esteem; stress and coping; and alcohol-related problems. Correlational and latent variable analyses indicated that contingent self-esteem positively related to alcohol related problems, with maladaptive coping mediating this relationship. In contrast, global self-esteem negatively related to such problems, a relationship that was also mediated by maladaptive coping and stress. Overall, the results highlight the potentially harmful consequences of contingent self-worth and the adaptive nature of non-contingent self-esteem. They also demonstrate the important role that coping plays in mediating self-esteem's associations with alcohol-related problems. PMID- 22930541 TI - The male copulatory system of European pea crabs (crustacea, brachyura, pinnotheridae). AB - The male copulatory system of the European pinnotherid species Pinnotheres pisum, Pinnotheres pectunculi, and Nepinnotheres pinnotheres was investigated by gross morphology, scanning electron microscopy, histological methods, and confocal laser scanning microscopy. The brachyuran copulatory system is consistently formed by paired penes and two pairs of abdominal appendages, the gonopods, functioning in sperm transfer. In pinnotherids, the long first gonopods transfer the sperm mass into the female ducts. The first gonopod has the ejaculatory canal inside that opens both basally and distally. The second gonopod is solid, short, and conical. During copulation, the penis and the second gonopod are inserted into the basal lumen of the first gonopod. While the penis injects the sperm mass, the second gonopod functions in the transport of spermatozoa inside the ejaculatory canal toward its distal opening. The second gonopod is adapted for the sealing of the tubular system in the first gonopod by its specific shape and the ability to swell. Longitudinal cuticle foldings of the second gonopod hook into structures inside the first gonopod. The second gonopod can interact with the penis during copulation by a flexible flap separating the lumina in which the second gonopod and the penis are inserted. PMID- 22930542 TI - Pharmacist-initiated intervention trial in osteoarthritis: a multidisciplinary intervention for knee osteoarthritis. AB - OBJECTIVE: Knee osteoarthritis (OA) is a commonly undiagnosed condition and care is often not provided. Pharmacists are uniquely placed for launching a multidisciplinary intervention for knee OA. METHODS: We performed a cluster randomized controlled trial with pharmacies providing either intervention care or usual care (14 and 18 pharmacies, respectively). The intervention included a validated knee OA screening questionnaire, education, pain medication management, physiotherapy-guided exercise, and communication with the primary care physician. Usual care consisted of an educational pamphlet. The primary outcome was the pass rate on the Arthritis Foundation's quality indicators for OA. Secondary outcomes included the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), the Lower Extremity Function Scale (LEFS), the Paper Adaptive Test-5D (PAT-5D), and the Health Utilities Index Mark 3 (HUI3). RESULTS: One hundred thirty-nine patients were assigned to the control (n = 66) and intervention (n = 73) groups. There were no differences between the groups in baseline measures. The overall quality indicator pass rate was significantly higher in the intervention arm compared to the control arm (difference of 45.2%; 95% confidence interval 34.5, 55.9). Significant improvements were observed for the intervention care group as compared to the usual care group in the WOMAC global, pain, and function scores at 3 and 6 months (all P < 0.01); the PAT-5D daily activity scores at 3 and 6 months (both P < 0.05); the PAT-5D pain scores at 6 months (P = 0.05); the HUI3 single-attribute pain scores at 3 and 6 months (all P < 0.05); and the LEFS scores at 6 months (P < 0.05). CONCLUSION: Pharmacists can launch a multidisciplinary intervention to identify knee OA cases, improve the utilization of treatments, and improve function, pain, and quality of life. PMID- 22930543 TI - Ectopic expression of Fgf3 leads to aberrant lineage segregation in the mouse parthenote preimplantation embryos. AB - BACKGROUND: Parthenogenetic mammalian embryos were reported to die in utero no later than the 25-somite stage due to abnormal development of both embryonic and extraembryonic lineages. Interestingly, it has been shown that parthenogenetic ICM cells tend to differentiate more into primitive endoderm cells and less into epiblast and ES cells. Hence we are interested in studying the molecular mechanisms underlying lineage defects of parthenotes. RESULTS: We found that parthenote inner cell masses (ICMs) contained decreased numbers of Sox2(+) /Nanog(+) epiblast cells but increased numbers of Gata4(+) primitive endoderm cells, indicating an unusual lineage segregation. We demonstrate for the first time that the increased Gata4 level in parthenotes may be explained by the strong up-regulation of Fgf3 and Fgfr2 phosphorylation. Inhibition of Fgfr2 activation by SU5402 in parthenotes restored normal Nanog and Gata4 levels without affecting Fgf3, indicating that Fgf3 is upstream of Fgfr2 activation. In parthenote trophectoderm, we detected normal Cdx2 but ectopic Gata4 expression and reduced Elf5 and Tbr2(Eomes) levels. CONCLUSIONS: Taken together, our work provides for the first time the insight into the molecular mechanisms of the developmental defects of parthenogenetic embryos in both the trophectoderm and ICM. PMID- 22930544 TI - Atomic contributions from spin-orbit coupling to 29Si NMR chemical shifts in metallasilatrane complexes. AB - New members of a novel class of metallasilatrane complexes [X-Si-(MU-mt)(4)-M-Y], with M=Ni, Pd, Pt, X=F, Cl, Y=Cl, Br, I, and mt=2-mercapto-1-methylimidazolide, have been synthesized and characterized structurally by X-ray diffraction and by (29)Si solid-state NMR. Spin-orbit (SO) effects on the (29)Si chemical shifts induced by the metal, by the sulfur atoms in the ligand, and by heavy halide ligands Y=Cl, Br, I were investigated with the help of relativistic density functional calculations. Operators used in the calculations were constructed such that SO coupling can selectively be switched off for certain atoms. The unexpectedly large SO effects on the (29)Si shielding in the Ni complex with X=Y=Cl reported recently originate directly from the Ni atom, not from other moderately heavy atoms in the complex. With respect to Pd, SO effects are amplified for Ni owing to its smaller ligand-field splitting, despite the smaller nuclear charge. In the X=Cl, Y=Cl, Br, I series of complexes the Y ligand strongly modulates the (29)Si shift by amplifying or suppressing the metal SO effects. The pronounced delocalization of the partially covalent M<-Y bond plays an important role in modulating the (29)Si shielding. We also demonstrate an influence from the X ligand on the (29)Si SO shielding contributions originating at Y. The NMR spectra for [X-Si-(MU-mt)(4)-M-Y] must be interpreted mainly based on electronic and relativistic effects, rather than structural differences between the complexes. The results highlight the sometimes unintuitive role of SO coupling in NMR spectra of complexes containing heavy atoms. PMID- 22930546 TI - Enantioseparation of alpha-hydroxy acids by chiral ligand exchange CE with a dual central metal ion system. AB - Using two kinds of central metal ions in a background electrolyte, ligand exchange CE was investigated for the simultaneous enantioseparation of dl-malic, dl-tartaric, and dl-isocitric acids. Ligand exchange CE with 100 mM d-quinic acid as a chiral selector ligand and 10 mM Cu(II) ion as a central metal ion could enantioseparate dl-tartaric acid but not dl-malic acid or dl-isocitric acid. A dual central metal ion system containing 0.5 mM Al(III) ion in addition to 10 mM Cu(II) ion in the background electrolyte enabled the simultaneous enantioseparation of the three alpha-hydroxy acids. These results suggest that the use of a dual central metal ion system can be useful for enantioseparation by ligand exchange CE. PMID- 22930547 TI - A selective fluorescent probe for carbon monoxide imaging in living cells. PMID- 22930548 TI - HMBC-1,1-ADEQUATE via generalized indirect covariance: a high sensitivity alternative to n,1-ADEQUATE. AB - 1,1-ADEQUATE and the related long-range 1,n- and n,1-ADEQUATE variants were developed to provide an unequivocal means of establishing (2)J(CH) and the equivalent of (n)J(CH) correlations where n = 3,4. Whereas the 1,1- and 1,n ADEQUATE experiments have two simultaneous evolution periods that refocus the chemical shift and afford net single quantum evolution for the carbon spins, the n,1-variant has a single evolution period that leaves the carbon spin to be observed at the double quantum frequency. The n,1-ADEQUATE experiment begins with an HMBC-type (n)J(CH) magnetization transfer, which leads to inherently lower sensitivity than the 1,1- and 1,n-ADEQUATE experiments that begin with a (1)J(CH) transfer. These attributes, in tandem, serve to render the n,1-ADEQUATE experiment less generally applicable and more difficult to interpret than the 1,n ADEQUATE experiment, which can in principle afford the same structural information. Unsymmetrical and generalized indirect covariance processing methods can complement and enhance the structural information encoded in combinations of experiments e.g. HSQC-1,1- or -1,n-ADEQUATE. Another benefit is that covariance processing methods offer the possibility of mathematically combining a higher sensitivity 2D NMR spectrum with for example 1,1- or 1,n-ADEQUATE to improve access to the information content of lower sensitivity congeners. The covariance spectrum also provides a significant enhancement in the F(1) digital resolution. The combination of HMBC and 1,1-ADEQUATE spectra is shown here using strychnine as a model compound to derive structural information inherent to an n,1-ADEQUATE spectrum with higher sensitivity and in a more convenient to interpret single quantum presentation. PMID- 22930549 TI - Reproductive performance and early postnatal development in interleukin (IL)-13 deficient mice. AB - OBJECTIVE: The purpose of this study was to assess the effect of interleukin (IL) 13 deficiency on fertility and reproductive performance of adult mice and on morphological and behavioral development of the offspring. METHODS: Wild-type and homozygous IL-13-deficient (KO) mice were grouped by genotype, and male and female mice were mated within each group. Adult (F(0) ) mice were evaluated for reproductive performance, and development was assessed in F(1) fetuses on gestation day 18, and in F(1) pups to postnatal day 35. RESULTS: In F(0) males, there were no differences in the number of males that mated or impregnated females, or in total sperm count or sperm motility, between the wild-type and KO groups. In F(0) females, there were no observed genotype-related differences in fertility, length of gestation, number of viable fetuses per litter, or viability of offspring. There were no differences in embryo-fetal development (external/palate, skeletal, visceral) of the F(1) fetuses between genotypes. Similarly, IL-13 deficiency had no impact on any postnatal parameters assessed including reflex, sexual maturation, learning, and memory. CONCLUSIONS: IL-13 deficiency had no observed effect on reproductive performance or morphological and behavioral development in mice. PMID- 22930550 TI - Inhibition of bacterial dihydrofolate reductase by 6-alkyl-2,4 diaminopyrimidines. AB - (+/-)-6-Alkyl-2,4-diaminopyrimidine-based inhibitors of bacterial dihydrofolate reductase (DHFR) have been prepared and evaluated for biological potency against Bacillus anthracis and Staphylococcus aureus. Biological studies revealed attenuated activity relative to earlier structures lacking substitution at C6 of the diaminopyrimidine moiety, though minimum inhibitory concentration (MIC) values are in the 0.125-8 MUg mL(-1) range for both organisms. This effect was rationalized from three- dimensional X-ray structure studies that indicate the presence of a side pocket containing two water molecules adjacent to the main binding pocket. Because of the hydrophobic nature of the substitutions at C6, the main interactions are with protein residues Leu 20 and Leu 28. These interactions lead to a minor conformational change in the protein, which opens the pocket containing these water molecules such that it becomes continuous with the main binding pocket. These water molecules are reported to play a critical role in the catalytic reaction, highlighting a new area for inhibitor expansion within the limited architectural variation at the catalytic site of bacterial DHFR. PMID- 22930552 TI - Achieving ultrahigh concentrations of fluorescent single-walled carbon nanotubes using small-molecule viscosity modifiers. AB - Surfactant dispersion is a well-established method for stabilizing individual single-walled carbon nanotubes in aqueous solutions. However, achieving high concentrations of individually dispersed nanotubes with this technique has proven challenging. Here it is demonstrated that the introduction of viscosity-enhancing compounds such as sucrose can increase the maximum concentration of surfactant dispersed single-walled carbon nanotubes by more than a factor of 100 while still retaining the optical properties of individual nanotubes. When these solutions are used as inks for methods such as inkjet printing, they retain their fluorescent properties even after the ink has dried. PMID- 22930551 TI - Morphology of the Daphnia nervous system: a comparative study on Daphnia pulex, Daphnia lumholtzi, and Daphnia longicephala. AB - The freshwater crustacean Daphnia is well known for its phenotypic plasticity, in which environmental cues are perceived by the nervous system and transformed into phenotypic adaptations beneficial under current conditions. Critical knowledge regarding the distribution and localization of neuronal antigens or neurotransmitters and differentially expressed proteins is sparse. Here, we applied immunohistochemical and histological-staining methods in combination with confocal laser scanning microscopy on whole mount preparations in Daphnia pulex, Daphnia longicephala, and Daphnialumholtzi. We document the nervous system, elements of the sensory system, and cell clusters with secretory characteristics in the Daphnia head. This is the first report on the nervous system of the species D.longicephala and D.lumholtzi. The methods established in this investigation will help to foster research on specific neuronal mechanisms in this rapidly advancing model system of life science research. PMID- 22930553 TI - Global posterior prevalence is unique to vertebrates: a dance to the music of time? AB - We reach the conclusion that posterior prevalence, a collinear property considered important for Hox complex function, is so far unique, in a global form, to vertebrates. Why is this? We suspect this is because posterior prevalence is explicitly connected to the vertebrate form of Hox temporal collinearity, which is central to axial patterning. PMID- 22930554 TI - Exceptional crystallization diversity and solid-state conversions of Cd(II) coordination frameworks with 5-bromonicotinate directed by solvent media. AB - A series of nine coordination polymers {[Cd(L)(2)(solvent)(x)](solvent)(y)}(n) have been prepared from Cd(NO(3))(2) and 5-bromonicotinic acid (HL) in different solvents through a layered diffusion method. By using CH(3)OH/H(2)O at different volume ratios of 1:1 and 1:3, a one-dimensional (1D) coordination species (1a) and a three-dimensional (3D) (3,6)-connected framework (2a.g(1)) can be obtained. A similar self-assembly process in C(2)H(5)OH/H(2)O or H(2)O/1,4-dioxane gives 2a.g(2) or 2a.g(3), which are isomorphic to 2a.g(1) but with different lattice solvents. Replacement of the mixed solvents with DMF/H(2)O (v/v 1:1 or 1:3) also gives a 1D chain complex (1b) or a 3D microporous framework (2b.g(1)). Similarly, MOF 2b.g(2) can be assembled from CH(3)CN/H(2)O as an isomorphic solvate of 2b.g(1). Significantly, the 3D MOF families of 2a.g(n) and 2b.g(n) are supramolecular isomers even though they are topologically equivalent. Also, if a mixture of CH(3)OH/CH(2)Cl(2) (v/v 1:1 or 3:1) is used, a pair of distinct MOFs (3a.g) and (3b) are generated as pseudo-polymorphs that show a two-dimensional (2D) sheet and a 3D coordination framework, respectively. Furthermore, mutual solvent-induced conversions were realized between 1a and 1b and between 2a.g(1), 2a.g(2), and 2a.g(3) following the size-dependent rule of the solvent. These results are of great significance in recognizing the solvent effect upon coordination assemblies and their crystal transformations. PMID- 22930555 TI - Sodium desoxycholate-assisted capillary electrochromatography with methacrylate ester-based monolithic column on fast separation and determination of coumarin analogs in Angelica dahurica extract. AB - A rapid and sensitive CEC method with methacrylate ester-based monolithic column has been developed for separation and determination of five coumarins (byakangelicin, oxypeucedanin hydrate, xanthotoxol, 5-hydroxy-8-methoxypsoralen and bergapten) in Angelica dahurica extract. Surfactant sodium desoxycholate (SDC) was introduced into the mobile phase as the pseudostationary to dynamically increase the selectivity of analytes instead of increasing the hydrophobicity of stationary phase. In addition, other factors, pH of phosphate buffer, ACN content and applied voltage, for instance, have also an obvious effect on the resolution but little on the retention time. Satisfactory separation of these five coumarins was achieved within 6 min under a 30:70 v/v ACN-buffer containing 20 mM sodium dihydrogen phosphate (NaH(2) PO(4) ) and 0.25 mM SDC at pH 2.51. The RSDs of intraday and interday for relative peak areas were less than 3.0% and 4.7%, respectively; and the recoveries were between 87.5% and 95.0%. The LODs were lower than 0.15 MUg/mL and the LOQs were lower than 0.30 MUg/mL, respectively, while calibration curves showed a good linearity (r(2) > 0.9979). Finally, five target coumarins from the crude extracts of A. dahurica were separated, purified, and concentrated by D-101 macroporous resin, and were successfully separated and quantitatively determined within 6 min. PMID- 22930556 TI - A highly reactive and sinter-resistant catalytic system based on platinum nanoparticles embedded in the inner surfaces of CeO2 hollow fibers. PMID- 22930557 TI - Levels of select PCB and PBDE congeners in human postmortem brain reveal possible environmental involvement in 15q11-q13 duplication autism spectrum disorder. AB - Persistent organic pollutants (POPs), including polychlorinated biphenyls (PCBs) and polybrominated diphenylethers (PBDEs) that bioaccumulate in lipid-rich tissues are of concern as developmental neurotoxicants. Epigenetic mechanisms such as DNA methylation act at the interface of genetic and environmental factors implicated in autism-spectrum disorders. The relationship between POP levels and DNA methylation patterns in individuals with and without neurodevelopmental disorders has not been previously investigated. In this study, a total of 107 human frozen postmortem brain samples were analyzed for eight PCBs and seven PBDEs by GC-micro electron capture detector and GC/MS using negative chemical ionization. Human brain samples were grouped as neurotypical controls (n = 43), neurodevelopmental disorders with known genetic basis (n = 32, including Down, Rett, Prader-Willi, Angelman, and 15q11-q13 duplication syndromes), and autism of unknown etiology (n = 32). Unexpectedly, PCB 95 was significantly higher in the genetic neurodevelopmental group, but not idiopathic autism, as compared to neurotypical controls. Interestingly, samples with detectable PCB 95 levels were almost exclusively those with maternal 15q11-q13 duplication (Dup15q) or deletion in Prader-Willi syndrome. When sorted by birth year, Dup15q samples represented five out of six of genetic neurodevelopmental samples born after the 1976 PCB ban exhibiting detectable PCB 95 levels. Dup15q was the strongest predictor of PCB 95 exposure over age, gender, or year of birth. Dup15q brain showed lower levels of repetitive DNA methylation measured by LINE-1 pyrosequencing, but methylation levels were confounded by year of birth. These results demonstrate a novel paradigm by which specific POPs may predispose to genetic copy number variation of 15q11-q13. PMID- 22930559 TI - Trp53 inactivation leads to earlier phaeochromocytoma formation in pten knockout mice. AB - Phaeochromocytomas (PCCs) are benign neuroendocrine tumours of the adrenal medulla. Approximately 10% of PCC patients develop metastases, but this frequency is much higher in specific subtypes of patients. The reliable diagnosis of malignant PCC can only be made after identification of a metastasis. To study the effect of Trp53 inactivation on PCC pathogenesis in Pten KO mice, we investigated the adrenals of a large cohort of mice with conditional monoallelic and biallelic inactivation of Trp53 and Pten. The adrenal weights were determined for all mice, and in a proportion of these mice, immunohistochemistry for tyrosine hydroxylase and dopamine beta-hydroxylase was performed on the adrenals and corresponding lungs. Finally, comparative genomic hybridization (CGH) was performed. The histological and immunohistochemical results confirmed that the adrenal tumours were PCCs. Inactivation of one or both alleles of Trp53 resulted in earlier tumour occurrence in the Pten(loxP/loxP) mice as well as in the Pten(loxP/+) mice. In addition, lung metastases were found in up to 67% of mice. The CGH results showed that the most frequent genomic alterations were loss of chromosome 19 (86%) and gain of chromosome 15 (71%). In this study, we have shown that Pten/Trp53 KO mice showed metastatic PCC at high frequency and primary tumours occurred at younger ages in mice with Trp53 inactivation. Therefore, the present model appears to be a suitable model that might allow the preclinical study of new therapeutics for these tumours. PMID- 22930560 TI - Structure-activity relationships of a novel group of large-conductance Ca(2+) activated K(+) (BK) channel modulators: the GoSlo-SR family. AB - Opening up ion channels: We synthesised a series of anthraquinone analogues, called the GoSlo-SR family. Their effects on bladder smooth muscle BK channels were examined and, as shown, shifted voltage dependent activation >-100 mV (at 10 MUM). They were more efficacious than NS11021 and could provide a new scaffold for the design of efficacious BK openers. PMID- 22930561 TI - Object discrimination reversal as a method to assess cognitive impairment in nonhuman primate enhanced pre- and postnatal developmental (ePPND) studies: statistical power analysis. AB - An important aspect of the enhanced pre- and postnatal developmental (ePPND) toxicity study in nonhuman primates (NHP) is that it combines in utero and postnatal assessments in a single study. However, it is unclear if NHP ePPND studies are suitable to perform all of the evaluations incorporated into rodent PPND studies. To understand the value of including cognitive assessment in a NHP ePPND toxicity study, we performed a power analysis of object discrimination reversal task data using a modified Wisconsin General Testing Apparatus (ODR WGTA) from two NHP ePPND studies. ODR-WGTA endpoints evaluated were days to learning and to first reversal, and number of reversals. With alpha = 0.05 and a one-sided t-test, a sample of seven provided 80% power to predict a 100% increase in all three of the ODR-WGTA endpoints; a sample of 25 provided 80% power to predict a 50% increase. Similar power analyses were performed with data from the Cincinnati Water Maze (CWM) and passive avoidance tests from three rat PPND toxicity studies. Groups of 5 and 15 in the CWM and passive avoidance test, respectively, provided 80% power to detect a 100% change. While the power of the CWM is not far superior to the NHP ODR-WGTA, a clear advantage is the routine use of larger sample size, with a group of 20 rats the CWM provides ~90% power to detect a 50% change. Due to the limitations on the number of animals, the ODR WGTA may not be suitable for assessing cognitive impairment in NHP ePPND studies. PMID- 22930558 TI - The reactive stroma microenvironment and prostate cancer progression. AB - Reactive stroma initiates during early prostate cancer development and coevolves with prostate cancer progression. Previous studies have defined the key markers of reactive stroma and have established that reactive stroma biology influences prostate tumorigenesis and progression. The stem/progenitor cells of origin and the mechanisms that regulate their recruitment and activation to myofibroblasts or carcinoma-associated fibroblasts are essentially unknown. Key regulatory factors have been identified, including transforming growth factor beta, interleukin-8, fibroblast growth factors, connective tissue growth factor, wingless homologs-Wnts, and stromal cell-derived factor-1, among others. The biology of reactive stroma in cancer is similar to the more predictable biology of the stroma compartment during wound repair at sites where the epithelial barrier function is breached and a stromal response is generated. The coevolution of reactive stroma and the biology of how reactive stroma-carcinoma interactions regulate cancer progression and metastasis are targets for new therapeutic approaches. Such approaches are strategically designed to inhibit cancer progression by uncoupling the reactive stroma niche. PMID- 22930562 TI - Carbodiimides in the synthesis of enamino- and alpha-aminophosphonates as peptidomimetics of analgesic/antiinflammatory and anticancer agents. AB - Carbodiimide that was generated from the condensation reaction of iminophosphorane with phenylisocyanate was allowed to react with different phosphorus nucleophiles. Thus, the in situ resulted heterocumulene reacted with dialkylhydrogenphosphonates in tetrahydrofuran (THF)/FeCl(3) /H(2) O system to give fused pyrrole- (~14%) and pyrimidinephosphonates (~57%). On the other hand, with tris-(dialkyl)aminophosphines, the reaction afforded the corresponding hexaalkylphosphinic diamides as a water-sensitive fine powder, quite stable for a few days in a desiccator. When a protonating agent was present in the reaction medium, the reaction was markedly accelerated leading to the formation of the phosphamides. Next, some saturated and unsaturated Horner-Emmons reagents were applied in situ to the same carbodiimide to obtain more phosphorylated N heterocycles. The analgesic and antiinflammatory activities of the newly synthesized compounds were investigated and showed significant activities. Finally, we further estimated the antitumor activity of five new phosphonates against four carcinoma cell lines. PMID- 22930563 TI - Development of a cloud point extraction method for the determination of phenolic compounds in environmental water samples coupled with high-performance liquid chromatography. AB - A method based on ultrasound-assisted cloud point extraction (CPE) was developed for the determination of phenolic compounds in water samples by high-performance liquid chromatography coupled with diode array detection (DAD) (HPLC-DAD). A nonionic surfactant, Tergitol 15-S-7, was chosen as the surfactant. The parameters affecting the CPE efficiency, such as Tergitol 15-S-7 concentration, salt concentration, extraction temperature, incubation time, centrifugation time, ultrasonic time, sample pH, and dilution solvent were systematically evaluated and optimized. Under the optimum experimental conditions, the linear regression coefficients of the standard curves were greater than 0.9986 and the limits of detection were in the range of 1.7-6.0 MUg/L. The method was shown to be reproducible and reliable with intraday and interday relative standard deviations lower than 4.0 and 5.8%, respectively. The recoveries for the addition of different concentrations of phenolic compounds to water samples were in the range of 81.1-109.4%. PMID- 22930564 TI - Fast olefin metathesis at low catalyst loading. AB - Reactions of the Grubbs 3rd generation complexes [RuCl(2)(NHC)(Ind)(Py)] (N heterocyclic carbene (NHC)=1,3-bis(2,4,6-trimethylphenylimidazolin)-2-ylidene (SIMes), 1,3-bis(2,6-diisopropylphenylimidazolin)-2-ylidene (SIPr), or 1,3 bis(2,6-diisopropylphenylimidazol)-2-ylidene (IPr); Ind=3-phenylindenylid-1-ene, Py=pyridine) with 2-ethenyl-N-alkylaniline (alkyl=Me, Et) result in the formation of the new N-Grubbs-Hoveyda-type complexes 5 (NHC=SIMes, alkyl=Me), 6 (SIMes, Et), 7 (IPr, Me), 8 (SIPr, Me), and 9 (SIPr, Et) with N-chelating benzylidene ligands in yields of 50-75 %. Compared to their respective, conventional, O Grubbs-Hoveyda complexes, the new complexes are characterized by fast catalyst activation, which translates into fast and efficient ring-closing metathesis (RCM) reactivity. Catalyst loadings of 15-150 ppm (0.0015-0.015 mol %) are sufficient for the conversion of a wide range of diolefinic substrates into the respective RCM products after 15 min at 50 degrees C in toluene; compounds 8 and 9 are the most catalytically active complexes. The use of complex 8 in RCM reactions enables the formation of N-protected 2,5-dihydropyrroles with turnover numbers (TONs) of up to 58,000 and turnover frequencies (TOFs) of up to 232,000 h(-1); the use of the N-protected 1,2,3,6-tetrahydropyridines proceeds with TONs of up to 37,000 and TOFs of up to 147,000 h(-1); and the use of the N-protected 2,3,6,7-tetrahydroazepines proceeds with TONs of up to 19,000 and TOFs of up to 76,000 h(-1), with yields for these reactions ranging from 83-92 %. PMID- 22930565 TI - Comparative spatiotemporal analysis of Hox gene expression in early stages of intermediate mesoderm formation. AB - BACKGROUND: Hox genes are key players in AP patterning of the vertebrate body plan and are necessary for organogenesis. Several studies provide evidence for the role Hox genes play during kidney development and especially regarding metanephros initiation and formation. However, the role Hox genes play during early stages of kidney development is largely unknown. A recent study in our lab revealed the role Hoxb4 plays in conferring the competence of intermediate mesodermal cells to respond to kidney inductive signals and express early kidney regulators. RESULTS: As a first step in understanding the role Hox genes play in setting the formation of the pronephros morphogenetic field and the expression of early regulators of kidney development, we studied in detail the expression pattern of 10 Hox genes in relation to the 6th somite axial level, the anterior sharp border of the kidney field. Despite the idea of spatial co-linearity as exemplified in the Hox gene expression pattern in late developmental stages, a very dynamic spatio-temporal expression of these genes was found in early stages. CONCLUSIONS: Since mesodermal patterning occurs at gastrula stages, the relevance of a "Hox code" at early stages is questioned in this study. PMID- 22930566 TI - Continuous symmetry analyses: C(nv) and D(n) measures of molecules, complexes, and proteins. AB - The continuous symmetry methodology has been developed to provide a quantitative estimation for the degree of a selected symmetry point-group in a molecular structure. Previous developed measures included the C(S), C(n), S(n) (including C(i)) symmetries, several polyhedral symmetries, and the related chirality measure. Motivated by the abundance and importance of C(nv) symmetry in many key molecules and by the abundance of D(n) symmetry in many organometallic complexes and in many protein clusters, measures for these symmetries, based on the general definition of the continuous symmetry measure, were developed. Detailed description of the derivation of the measures, along with plenty of examples for their application, is provided. PMID- 22930567 TI - "Self-immolative" spacer for uncaging with fluorescence reporting. PMID- 22930568 TI - High order interactions of xenobiotic metabolizing genes and P53 codon 72 polymorphisms in acute leukemia. AB - Polymorphisms in xenobiotic metabolizing genes are associated with altered metabolism of carcinogens in acute leukemia (AL). This study applied two data mining approaches to explore potential interactions among P53 and xenobiotic metabolizing genes in 230 AL patients [131 acute myeloid leukemia (AML) and 99 acute lymphoblastic leukemia (ALL)] and 199 controls. Individually, none of the genotypes showed significant associations with AML risk. However, in ALL the CYP1A12A TC genotype was associated with increased risk (OR = 2.02; 95% CI = 1.14 3.58; P = 0.01), whereas the GSTM1 null genotype imparted reduced risk (OR = 0.55; 95% CI = 0.31-0.96; P = 0.03). In classification and regression tree analysis, combinations of GSTM1 present, CYP1A12C AA or GG, EPHX1 exon3 TC, and EPHX1 exon4 AA or GG genotype strongly enhanced the risk of AML (OR = 5.89; 95% CI = 1.40-26.62; P = 0.01). In ALL, combinations of CYP1A12A TT, P53 GG or CC and GSTP1 AG genotypes conferred the highest risk (OR = 4.19; 95% CI = 1.45-12.25; P = 0.004). In multifactor dimensionality reduction analysis, a four locus model (GSTP1, P53, EPHX1 exon3, and CYP1A12A) was the best predictor model for ALL risk. The association between this model and ALL risk remained true even at low prior probabilities of 0.01% (false positive report probability = 0.05). Interaction entropy interpretations of the best model of ALL revealed that two way interactions were mostly synergistic. These results suggest that high order gene-gene interactions play an important role in AL risk. PMID- 22930569 TI - A call for a fresh new look at the plasma proteome. AB - Serum and plasma from which serum is derived represent a substantial challenge for proteomics due to their complexity. A landmark plasma proteome study was initiated a decade ago by the Human Proteome Organization (HUPO) that had as an objective to examine the capabilities of existing technologies. Given the advances in proteomics and the continued interest in the plasma proteome, it would timely reassess the depth and breadth of analysis of plasma that can be achieved with current methodology and instrumentation. A collaborative project to define the plasma proteome and its variation, with a plan to build a plasma proteome database would be timely. PMID- 22930570 TI - Analysis of herpes simplex virus type I nuclear particles by flow cytometry. AB - Flow cytometry has been instrumental to characterize cell populations and examine their inner molecules and processes. In most instances, whole cells are analyzed, and hence, particle size is not an issue. Viruses are 2-3 orders of magnitude smaller than cells so flow cytometry has typically been used to study viral markers within whole infected cells. However, the ability to separate and purify viral particles representing different maturation stages within a viral life cycle would be a useful tool to analyze them in details and characterize the host proteins they associate with. Herpes simplex virus Type 1 is a 250 nm enveloped DNA virus that replicates in the nucleus where it assembles new viral particles called capsids. These capsids eventually travel to the cell surface and are modified along the way, producing several intermediate particles. In the nucleus, three types of stable nonenveloped 125 nm nuclear capsids exist that differ in protein composition and genome content. This includes so-called nuclear C-capsids that are the precursors of mature extracellular virions. We report that we can apply flow cytometry to sort these nuclear C-capsid intermediates by labeling the viral genome with Syto 13, a fluorescent marker that binds to nucleic acids. This is the first time flow cytometry has been used not only to detect but also to purify an intracellular viral maturation intermediate. This opens new research avenues in virology to study capsid assembly, maturation and egress, analyze mutant phenotypes, and define host factors associated with specific viral intermediates. PMID- 22930571 TI - Anti-inflammatory activities of isorhamnetin-3-O-galactoside against HMGB1 induced inflammatory responses in both HUVECs and CLP-induced septic mice. AB - High mobility group box 1 (HMGB1) protein is a crucial nuclear cytokine that elicits severe vascular inflammatory diseases. Oenanthe javanica (water dropwort) extract has anti-arrhythmic, neuroprotective and anti-diabetic activity. However, isorhamnetin-3-O-galactoside (I3G), an active compound from O. javanica, is not researched well for its biological activity. Here, we investigated the anti inflammatory activities of I3G by monitoring the effects of I3G on the lipopolysaccharide (LPS) or cecal ligation and puncture (CLP)-mediated release of HMGB1 and HMGB1 or CLP-mediated modulation of inflammatory responses. I3G potently inhibited the release of HMGB1 and down-regulated HMGB1-dependent inflammatory responses in human endothelial cells. I3G also inhibited HMGB1 mediated hyperpermeability and leukocyte migration in mice. Further studies revealed that I3G suppressed the production of tumor necrosis factor-alpha and activation of nuclear factor-kappaB by HMGB1. In addition, I3G reduced CLP induced HMGB1 release and sepsis-related mortality. Given these results, I3G should be viewed as a candidate therapeutic agent for the treatment of severe vascular inflammatory diseases such as sepsis or septic shock via inhibition of the HMGB1 signaling pathway. PMID- 22930572 TI - Synthesis of a library of fluorescent 2-aryl-3-trifluoromethylnaphthofurans from naphthols by using a sequential pummerer-annulation/cross-coupling strategy and their photophysical properties. AB - A library of 2-aryl-3-trifluoromethylnaphthofurans was synthesized with high efficiency from simple naphthols. In this synthesis, the Pummerer-type annulation of naphthols with 3-(2,2,2-trifluoroethylidene)-2,4-dithiapentane 2-oxide was followed by a cross-coupling of the resulting 2-methylthio-3 trifluoromethylnaphthofurans with a variety of arylzinc reagents. A palladium complex, Pd-PEPPSI-IPr, was the most efficient catalyst for the arylation step, which represents the first cross-coupling of aryl sulfides by using an N heterocyclic-carbene-ligated palladium complex. This library consists of new pi expanded molecules, all of which are fluorescent in the solid state as well as in solution. Their photophysical properties, such as absorption and emission, fluorescence quantum yields, and fluorescence lifetimes, were thoroughly investigated. This library was also useful to identify acidochromic molecules. PMID- 22930573 TI - Sequential extraction of inorganic arsenic compounds and methyl arsenate in human urine using mixed-mode monolithic silica spin column coupled with gas chromatography-mass spectrometry. AB - A sequential analytical method was developed for the detection of arsenite, arsenate, and methylarsenate in human urine by gas chromatography-mass spectrometry (GC-MS). The combination of a derivatization of trivalent arsenic compounds by 2,3-dithio-1-propanol (British antilewisite; BAL) and a reduction of pentavalent arsenic compounds (arsenate and methylarsenate) were accomplished to carry out the analysis of arsenic compounds in urine. The arsenic derivatives obtained using BAL were extracted in a stepwise manner using a monolithic spin column and analyzed by GC-MS. A linear curve was observed for concentrations of arsenic compounds of 2.0 to 200 ng/mL, where the correlation coefficients of calibration curves were greater than 0.996 (for a signal-to-noise (S/N) ratio >10). The detection limits were 1 ng/mL (S/N > 3). Recoveries of the targets in urine were in the range 91.9-106.5%, and RSDs of the intra- and interday assay for urine samples containing 5, 50, and 150 ng/mL of arsenic compounds varied between 2.95 and 13.4%. The results from real samples obtained from a patient suspected of having ingested As containing medications using this proposed method were in good agreement with those obtained using high-performance liquid chromatography with inductively coupled plasma mass spectrometry. PMID- 22930574 TI - Lens regenerates by means of similar processes and timeline in adults and larvae of the newt Cynops pyrrhogaster. AB - BACKGROUND: It is widely accepted that juvenile animals can regenerate faster than adults. For example, in the case of lens regeneration of the newt Cynops pyrrhogaster, larvae and adults require approximately 30 and 80 days for completion of lens regeneration, respectively. However, when we carefully observed lens regeneration in C. pyrrhogaster at the cellular level using molecular markers in the present study, we found that lens regeneration during the larval stage proceeded at similar speed and by means of similar steps to those in adults. RESULTS: We could not find any drastic difference between regeneration at these two stages, except that the size of the eyes was very different. CONCLUSIONS: Our observations suggested that larvae could regenerate a lens of the original size within a shorter time than adults because the larval lens was smaller than the adult lens, but the speed of regeneration was not faster in larvae. In addition, by repeatedly observing the regeneration in one individual transgenic newt that expressed fluorescence specifically in lens fiber cells in vivo and comparing the regeneration process at the embryonic, larval, and postmetamorphosis stages, we confirmed that the regeneration speed was the same at each of these stages in the same individual. PMID- 22930575 TI - In vivo imaging of photoreceptor disruption associated with age-related macular degeneration: A pilot study. AB - BACKGROUND AND OBJECTIVE: Age-related macular degeneration is one of the leading causes of vision loss in the developed world. As the disease progresses, the central part of the retina, called the macula, is compromised leading to a disruption of both structure and visual function. In this study, we investigate the disruption of macular photoreceptor cells in vivo as a function of disease stage in patients with the dry form of age-related macular degeneration AMD. MATERIALS AND METHODS: An investigational confocal Adaptive Optics Scanning Laser Ophthalmoscope (AO-SLO) was used to obtain high resolution images of the macular photoreceptor mosaic in patients previously diagnosed with AMD. Four patients were selected as representative cases, comprising each of the four clinical stages of AMD progression. RESULTS: AO-SLO imaging revealed slight disruption in the photoreceptor mosaic in early stage AMD due to focal drusen formation and identified several small drusen deposits that were not observed with standard clinical imaging techniques. An increase in photoreceptor disruption was visualized within the macula in direct correlation with the stage of AMD progression leading to a decrease in visual acuity. Large coalescent drusen and areas of geographic atrophy in advanced stage dry AMD exhibited a significant decrease in visible photoreceptor density. Significant decrease in photoreceptor counts (~35-50%) were observed when comparing earlier stages of AMD progression (Categories I and II) to later stages of the disease (Categories III and IV). CONCLUSIONS: This study demonstrates the capabilities of adaptive optics retinal imaging to monitor disruption of individual photoreceptor cells as a function of disease progression yielding valuable diagnostic findings in early stage AMD beyond what can be learned about the health of photoreceptors using conventional retinal imaging techniques. Lasers Surg. Med. 44: 603-610, 2012. (c) 2012 Wiley Periodicals, Inc. PMID- 22930576 TI - Rational design of a palladium-catalyzed C(sp)-C(sp) cross-coupling reaction inspired by kinetic studies. PMID- 22930577 TI - Characterization of unstable microsatellites in mice: no evidence for germline mutation induction following gamma-radiation exposure. AB - Large tandem repeat DNA loci such as expanded simple tandem repeats and minisatellites are efficient markers for detecting germline mutations; however, mutation detection using these loci can be imprecise and difficult to standardize across labs. Short-tandem repeats, such as microsatellites, offer more precise and high-throughput mutation detection, but germline mutation induction at these loci has not yet been studied in model organisms such as mice. In this study, we used microsatellite enrichment and large-scale DNA sequencing of several closely related inbred mouse lines to identify a panel of 19 polymorphic microsatellites with potentially high spontaneous mutation frequencies. We used this panel and four additional loci from other sources to quantify spontaneous mutation frequency in pedigrees of outbred Swiss-Webster mice. In addition, we also examined mutation induction in families in which sires were treated with acute doses of either 0.5 Gy or 1.0 Gy gamma-irradiation to spermatogonial stem cells. Per locus mutation frequencies ranged from 0 to 5.03 * 10(-3). Considering only the 11 loci with mutations, the mutation frequencies were: control 2.78 * 10(-3), 0.5 Gy 4.09 * 10(-3), and 1.0 Gy 1.82 * 10(-3). There were no statistically significant changes in mutation frequencies among treatment groups. Our study provides the first direct quantification of microsatellite mutation frequency in the mouse germline, but shows no evidence for mutation induction at pre-meiotic male germ cells following acute gamma-irradiation. Further work using the panel is needed to examine mutation induction at different doses of radiation, exposure durations, and stages during spermatogenesis. PMID- 22930578 TI - Serum proteome profiling of pancreatitis using recombinant antibody microarrays reveals disease-associated biomarker signatures. AB - PURPOSE: Pancreatitis is an inflammatory state of the pancreas, for which high performing serological biomarkers are lacking. The aim of the present study was to evaluate the use of affinity proteomics for identifying potential markers of disease and stratifying pancreatitis subtypes. EXPERIMENTAL DESIGN: High-content, recombinant antibody microarrays were applied for serum protein expression profiling of 113 serum samples from patients with chronic, acute, and autoimmune pancreatitis, as well as healthy controls. The sample groups were compared using supervised classification based on support vector machine analysis. RESULTS: This discovery study showed that pancreatitis subtypes could be discriminated with high accuracy. Using unfiltered data, the individual subtypes, as well as the combined pancreatitis cohort, were distinguished from healthy controls with high AUC values (0.96-1.00). Moreover, characteristic protein patterns and AUC values in the range of 0.69-0.95 were observed for the individual pancreatitis entities when compared to each other, and to all other samples combined. CONCLUSIONS AND CLINICAL RELEVANCE: This study demonstrated the potential of the antibody microarray approach for stratification of pancreatitis. Distinct candidate multiplex serum biomarker signatures for chronic, acute, and autoimmune pancreatitis were defined, which could enhance our fundamental knowledge of the underlying molecular mechanisms, and potentially lead to improved diagnosis. PMID- 22930579 TI - Type 2 diabetes mellitus impairs the maturation of endothelial progenitor cells and increases the number of circulating endothelial cells in peripheral blood. AB - Type 2 diabetes mellitus (T2DM) is associated with endothelial dysfunction, which leads to vascular complications. Endothelial progenitor cells (EPCs) are thought to be a subset of cells derived from the bone marrow that play a crucial role in the neovascularization of ischemic tissue and in the maintenance of endothelial cell integrity. In contrast, circulating endothelial cells (CECs) are of endothelial origin and become detached from the intima of blood vessels in response to pathological stimuli. The study investigated the effects of T2DM on subpopulations of EPCs and CECs in peripheral blood, as compared with the effects on unacylated (UAG) and acylated (AG) ghrelin levels, which have been shown recently to play an important role in endothelial dysfunction associated with diabetes. Using the high-performance flow cytometer FACSCanto, and UAG/AG ghrelin enzyme immunoassay kits, we analyzed whole peripheral blood samples from: (i) diabetic patients with a history of disease of less than 1 year and no clinical evidence of angiopathy, (ii) diabetic patients with long-standing disease with vascular complications, and (iii) healthy donors. We found that T2DM did not affect bone-marrow mobilization, but it altered the UAG/AG profile and decreased the number of highly differentiated EPCs (late EPCs) greatly. In addition, T2DM increased the number of CECs, together with the number of activated CECs. Our results suggest that: (i) the endothelial damage could be due mainly to altered maturation/commitment of EPCs, rather than a simple decrease in their production in the bone marrow; and (ii) EPC subpopulations and ghrelin levels could be useful markers to assess endothelial damage in diabetes. PMID- 22930580 TI - Ruthenium-catalyzed oxidative coupling/cyclization of isoquinolones with alkynes through C-H/N-H activation: mechanism study and synthesis of dibenzo[a,g]quinolizin-8-one derivatives. AB - The mechanism of [{RuCl(2)(p-cymene)}(2)]-catalyzed oxidative annulations of isoquinolones with alkynes was investigated in detail. The first step is an acetate-assisted C-H bond activation process to form cyclometalated compounds. Subsequent mono-alkyne insertion of the Ru-C bonds of the cyclometalated compounds then takes place. Finally, oxidative coupling of the C-N bond of the insertion compounds occurs to afford Ru(0) sandwich complexes that undergo oxidation to regenerate the catalytically active Ru(II) complex with the copper oxidant and release the desired dibenzo[a,g]quinolizin-8-one derivatives. All of the relevant intermediates were fully characterized and determined by single crystal X-ray diffraction analysis. The [{RuCl(2)(p-cymene)}(2)]-catalyzed C-H bond functionalization of isoquinolones with alkynes to synthesize dibenzo[a,g]quinolizin-8-one derivatives through C-H/N-H activation was also demonstrated. PMID- 22930581 TI - Vertical inhibition of the PI3K/Akt/mTOR pathway for the treatment of osteoarthritis. AB - Osteoarthritis is characterized by degenerative alterations of articular cartilage including both the degradation of extracellular matrix and the death of chondrocytes. The PI3K/Akt pathway has been demonstrated to involve in both processes. Inhibition of its downstream target NF-kB reduces the degradation of extracellular matrix via decreased production of matrix metalloproteinases while inhibition of mTOR increased autophagy to reduce chondrocyte death. However, mTOR feedback inhibits the activity of the PI3K/Akt pathway and inhibition of mTOR could result in increased activity of the PI3K/Akt/NF-kB pathway. We proposed that the use of dual inhibitors of PI3K and mTOR could be a promising approach to more efficiently inhibit the PI3K/Akt pathway than rapamycin or PI3K inhibitor alone and produce better treatment outcome. PMID- 22930582 TI - Highly efficient organosuperbase-catalyzed Mannich-type reactions of sulfonylimidates with imines: successful use of aliphatic imines as substrates and a unique reaction mechanism. PMID- 22930583 TI - Astrocytes as a regulated source of retinoic acid for the brain. AB - Retinaldehyde dehydrogenases (RALDH) catalyze the synthesis of the regulatory factor retinoic acid (RA). Cultured astrocytes express several of the RALDH enzyme family, and it has been assumed that this can be extrapolated to astrocytes in vivo. However, this study finds that few astrocytes in the rodent brain express detectable RALDH enzymes, and only when these cells are grown in culture are these enzymes upregulated. Factors controlling the expression of the RALDHs in cultured astrocytes were explored to determine possible reasons for differences between in vitro versus in vivo expression. Retinoids were found to feedback to suppress several of the RALDHs, and physiological levels of retinoids may be one route by which astrocytic RALDHs are maintained at low levels. In the case of RALDH2, in vivo reduction of vitamin A levels in rats resulted in an increase in astrocyte RALDH2 expression in the hippocampus. Other factors though are likely to control RALDH expression. A shift in astrocytic RALDH subcellular localization is a potential mechanism for regulating RA signaling. Under conditions of vitamin A deficiency, RALDH2 protein moved from the cytoplasm to the nucleus where it may synthesize RA at the site of the nuclear RA receptors. Similarly, in conditions of oxidative stress RALDH1 and RALDH2 moved from the cytoplasm to a predominantly nuclear position. Thus, the RALDHs have been revealed to be dynamic in their expression in astrocytes where they may maintain retinoid homeostasis in the brain. PMID- 22930584 TI - Stepwise isolation of human peripheral erythrocytes, T lymphocytes, and monocytes for blood cell proteomics. AB - PURPOSE: Density gradient centrifugation and magnetic- or fluorescence-activated cell sorting are common and robust techniques for the isolation of different types of blood cells. In this article, we give detailed description of a stepwise application of these methods as one isolation strategy for enrichment of different cell types from one blood sample. EXPERIMENTAL DESIGN: The workflow targeted erythrocytes, monocytes, and T lymphocytes. Pancoll(r) density gradient centrifugation was used together with subsequent MACSTM isolation. Purity of monocytes and T lymphocytes was controlled by fluorescence-activated cell sorting analysis, and cells were used for carrier-ampholine-based 2D-PAGE to confirm compatibility of the procedure to standard proteomic applications. RESULTS: Gradient centrifugation resulted in an average of 125 MUL of packed erythrocytes per milliliter blood. MACSTM sorting reached purities of 90 +/- 2% (monocytes) and 93 +/- 2% (T lymphocytes), with an average yield of 12 * 10(4) monocytes or T lymphocytes. 2D-PAGE of isolated cells showed well-separated spot patterns. CONCLUSIONS AND CLINICAL RELEVANCE: A combined isolation holds substantial advantages especially in clinical studies, as it allows for the comparison of findings not only between individuals, but also between different cell types derived from one donor. Our approach ensured high reproducibility, yields, and purities of cells as required for reliable proteome analysis. PMID- 22930585 TI - Flow cytometric cell-based assay to preselect antibody constructs for radionuclide conjugation. AB - Radiolabeled antibodies (Abs) are an attractive tool for targeting and delivering particle emitters for therapy or imaging applications. The labeling of Abs with metal radionuclides requires chelating agents and can cause loss of binding to their ligands. The aim of the present approach was to design an easy-handling flow cytometric cell-based assay to evaluate Ab-binding capacity of conjugates of the therapeutic Ab Cetuximab and to verify the most promising candidate in a competitive radioactive binding experiment. The final setup for flow cytometric assessment of cellular binding capacities of epidermal growth factor receptor (EGFR)/ErbB1-directed Ab conjugates is based on (a) the selection of a robust cell line model (b) the definition of nonsaturated staining concentrations for the unconjugated reference Ab Cetuximab plus implementation of a reasonable isotype control, and (c) the calculation of relative Ab affinities based on the flow cytometric data. Two (FaDu, SAS) out of the three cell lines with different total and cell surface expression levels of EGFR turned out to be adequate models but the application of one cell line was sufficient to estimate reduced binding capacities of conjugates relative to Cetuximab. Only 1/11 conjugate Abs exhibited a fluorescence signal comparable to unconjugated Cetuximab and was applied for radiolabeling with Yttrium-90. Unaltered binding affinity of this conjugate was proven in a competitive radioactive Ab-binding study. We conclude that the flow cytometric assay is reliable and that the relative binding capacity of Cetuximab is neither affected by covalent modification with CHX-A"-DTPA (N-[(R)-2-Amino-3 (p-isothiocyanato-phenyl) propyl]-trans-(S,S)-cyclohexane-1,2-diamine N,N,N',N",N"-pentaacetic acid) with a final chelator-to-Ab ratio of 5 nor by subsequent radiolabeling. [(90)Y]Y-CHX-A"-DTPA-Cetuximab thus qualifies for preclinical treatment testing as a prerequisite for therapeutic application. PMID- 22930587 TI - Influence of sequential modifications and carbohydrate variations in synthetic AFGP analogues on conformation and antifreeze activity. AB - Certain Arctic and Antarctic ectotherm species have developed strategies for survival under low temperature conditions that, among others, consist of antifreeze glycopeptides (AFGP). AFGP form a class of biological antifreeze agents that exhibit the ability to inhibit ice growth in vitro and in vivo and, hence, enable life at temperatures below the freezing point. AFGP usually consist of a varying number of (Ala-Ala-Thr)(n) units (n=4-55) with the disaccharide beta D-galactosyl-(1->3)-alpha-N-acetyl-D-galactosamine glycosidically attached to every threonine side chain hydroxyl group. AFGP have been shown to adopt polyproline II helical conformation. Although this pattern is highly conserved among different species, microheterogeneity concerning the amino acid composition usually occurs; for example, alanine is occasionally replaced by proline in smaller AFGP. The influence of minor and major sequence mutations on conformation and antifreeze activity of AFGP analogues was investigated by replacement of alanine by proline and glycosylated threonine by glycosylated hydroxyproline. The target compounds were prepared by using microwave-enhanced solid phase peptide synthesis. Furthermore, artificial analogues were obtained by copper-catalyzed azide-alkyne cycloaddition (CuAAC): propargyl glycosides were treated with polyproline helix II-forming peptides comprising (Pro-Azp-Pro)(n) units (n=2-4) that contained 4-azidoproline (Azp). The conformations of all analogues were examined by circular dichroism (CD). In addition, microphysical analysis was performed to provide information on their inhibitory effect on ice recrystallization. PMID- 22930586 TI - Comprehensive timeline of mesodermal development in the quail small intestine. AB - BACKGROUND: To generate the mature intestine, splanchnic mesoderm diversifies into six different tissue layers each with multiple cell types through concurrent and complex morphogenetic events. Hindering the progress of research in the field is the lack of a detailed description of the fundamental morphological changes that constitute development of the intestinal mesoderm. RESULTS: We used immunofluorescence and morphometric analyses of wild-type and Tg(tie1:H2B-eYFP) quail embryos to establish a comprehensive timeline of mesodermal development in the avian intestine. The following landmark features were analyzed from appearance of the intestinal primordium through generation of the definitive structure: radial compartment formation, basement membrane dynamics, mesothelial differentiation, mesenchymal expansion and growth patterns, smooth muscle differentiation, and maturation of the vasculature. In this way, structural relationships between mesodermal components were identified over time. CONCLUSIONS: This integrated analysis presents a roadmap for investigators and clinicians to evaluate diverse experimental data obtained at individual stages of intestinal development within the longitudinal context of intestinal morphogenesis. PMID- 22930588 TI - Role of bombesin receptor activated protein in the antigen presentation by human bronchial epithelial cells. AB - Bombesin receptor activated protein (BRAP) was identified in a bacterial two hybrid screen for proteins interacting with bombesin receptor subtype-3 (BRS-3). We found that BRAP is widely expressed in the airway epithelium of human lungs and may play a role during the stress response of lung epithelium. In this work, we explored the potential roles of BRAP in the antigen presenting function of human bronchial epithelial cells (HBECs). Overexpression of a BRAP recombinant protein in a human bronchial epithelial cell line resulted in a reduction of FITC OVA uptake by HBECs, which indicated that the antigen uptake ability is inhibited. The analysis of the protein expression of surface molecules including B7 homologs and the major histocompactability complex (MHC) class II molecules showed that the expression levels of HLA-DR and B7DC increased while the levels of B7-H1 and B7.2 decreased. Since those surface molecules are all related to antigen presenting process, the altered expression pattern of those molecules provides further evidence showing that BRAP overexpression leads to a change in antigen presenting function of HBECs. Moreover, overexpression of BRAP in HBECs caused a decrease of co-cultured lymphocytes proliferation and a changed pattern of cytokines produced by lymphocytes in the presence of FITC-OVA, which indicated that changes in the maturation pattern and functions of co-cultured lymphocytes were induced by BRAP overexpression. Overall, our results suggested that overexpression of BRAP may play a role during the antigen presenting process of bronchial epithelium by inhibiting the antigen uptake ability of bronchial epithelial cells. PMID- 22930589 TI - Enforced planarity: a strategy for stable boron-containing pi-conjugated materials. PMID- 22930590 TI - An epithelial tissue in Dictyostelium challenges the traditional origin of metazoan multicellularity. AB - We hypothesize that aspects of animal multicellularity originated before the divergence of metazoans from fungi and social amoebae. Polarized epithelial tissues are a defining feature of metazoans and contribute to the diversity of animal body plans. The recent finding of a polarized epithelium in the non metazoan social amoeba Dictyostelium discoideum demonstrates that epithelial tissue is not a unique feature of metazoans, and challenges the traditional paradigm that multicellularity evolved independently in social amoebae and metazoans. An alternative view, presented here, is that the common ancestor of social amoebae, fungi, and animals spent a portion of its life cycle in a multicellular state and possessed molecular machinery necessary for forming an epithelial tissue. Some descendants of this ancestor retained multicellularity, while others reverted to unicellularity. This hypothesis makes testable predictions regarding tissue organization in close relatives of metazoans and provides a novel conceptual framework for studies of early animal evolution. PMID- 22930591 TI - Multicolor flow cytometry analysis of the proliferations of T-lymphocyte subsets in vitro by EdU incorporation. AB - EdU (5-ethynyl-2'-deoxyuridine) incorporation has proved advantageous in the studies of cell kinetics, DNA synthesis, and cellular proliferation in vitro and in vivo compared to [(3) H]thymidine incorporation and BrdU (5-bromo-2' deoxyuridine) incorporation. Here, we describe a method that combines EdU incorporation and immunostaining with flow cytometric analysis to detect the proliferations of T lymphocyte subsets in vitro and optimized the assay's conditions. We found that the number of EdU(+) cells were associated with EdU concentration, incubation time, and the volume of Click reaction solution, the best EdU concentration 10-50 MUM, the optimal incubation time 8-12 h and the proper volume of Click volume 100 MUl for labeling 1 * 10(6) lymphocytes. Fixation was better to be performed before permeabilization, not together with. Furthermore, the permeabilization detergent reagent, PBS with 0.05% saponin was better than Tris buffer saline (TBS) with 0.1% Triton X-100. In addition, sufficient wash with PBS with 0.05% saponin has no influence on the staining of EdU(+) cells. Also, the lymphocytes incorporating EdU could be stored at 4 degrees C, -80 degrees C, and in liquid nitrogen up to 21 days. The present study will aid in optimization of flow cytometry assay to detect the proliferations of T cell subsets by EdU incorporation and the labeling of cell surface antigens. PMID- 22930592 TI - Plasma proteomics can discriminate isolated early from dual responses in asthmatic individuals undergoing an allergen inhalation challenge. AB - PURPOSE: This proteomics study was designed to determine the utility of iTRAQ MALDI-TOF/TOF technology to compare plasma samples from carefully phenotyped mild, atopic asthma subjects undergoing allergen inhalation challenge. EXPERIMENTAL DESIGN: Eight adult subjects with mild, allergic asthma (four early responders (ERs) and four dual responders (DRs)) participated in the allergen inhalation challenge. Blood samples were collected prior to and 2 h after the inhalation challenge. Sixteen plasma samples (two per subject), technical replicates, and pooled controls were analyzed using iTRAQ. Technical validation was performed using LC-MRM/MS. Moderated robust regression was used to determine differentially expressed proteins. RESULTS: Although this study did not show significant differences between pre- and post-challenge samples, discriminant analysis indicated that certain proteins responded differentially to allergen challenge with respect to responder type. At pre-challenge, fibronectin was significantly elevated in DRs compared to ERs and remained significant in the multiple reaction monitoring validation. CONCLUSIONS AND CLINICAL RELEVANCE: This proof of principle demonstration has shown that iTRAQ can uncover differences in the human plasma proteome between two endotypes of asthma and merits further application of iTRAQ to larger cohorts of asthma and other respiratory diseases. PMID- 22930594 TI - Organocatalytic enantioselective one-pot four-component ugi-type multicomponent reaction for the synthesis of epoxy-tetrahydropyrrolo[3,4-b]pyridin-5-ones. AB - Enantioselective multicomponent reaction: in the presence of a catalytic amount of chiral BINOL-derived phosphoric acid (TRIP), the reaction of an alpha isocyanoacetate 1, an aldehyde 2, and an aniline 3, followed by addition of a toluene solution of alpha,beta-unsaturated acyl chloride 4 afforded the oxa bridged tricycle 5 in excellent yield, diastereoselectivity, and enantioselectivity. Six chemical bonds, five stereogenic centers, and three cycles were formed in this one-pot four-component reaction. PMID- 22930593 TI - A loss-of-function variant in the human histidyl-tRNA synthetase (HARS) gene is neurotoxic in vivo. AB - Aminoacyl-tRNA synthetases (ARSs) are ubiquitously expressed enzymes responsible for ligating amino acids to cognate tRNA molecules. Mutations in four genes encoding an ARS have been implicated in inherited peripheral neuropathy with an axonal pathology, suggesting that all ARS genes are relevant candidates for disease in patients with related phenotypes. Here, we present results from a mutation screen of the histidyl-tRNA synthetase (HARS) gene in a large cohort of patients with peripheral neuropathy. These efforts revealed a rare missense variant (c.410G>A/p.Arg137Gln) that resides at a highly conserved amino acid, represents a loss-of-function allele when evaluated in yeast complementation assays, and is toxic to neurons when expressed in a worm model. In addition to the patient with peripheral neuropathy, p.Arg137Gln HARS was detected in three individuals by genome-wide exome sequencing. These findings suggest that HARS is the fifth ARS locus associated with axonal peripheral neuropathy. Implications for identifying ARS alleles in human populations and assessing them for a role in neurodegenerative phenotypes are discussed. PMID- 22930595 TI - Human Wharton's jelly stem cell conditioned medium and cell-free lysate inhibit human osteosarcoma and mammary carcinoma cell growth in vitro and in xenograft mice. AB - Human Wharton's jelly stem cells (hWJSCs) were shown to inhibit the growth of human mammary carcinomas. It is not known whether cell-free secretions or lysates of hWJSCs do the same on different cancers. They may be less controversial than cells to regulatory bodies for clinical application. We examined the influence of hWJSC conditioned medium (hWJSC-CM) and cell-free lysate (hWJSC-CL) on two osteosarcoma cell lines (MG-63, SKES-1) in vitro and on human mammary carcinomas in immunodeficient mice. When exposed to hWJSC-CL, increased vacuolations in MG 63 and increased membrane fragmentation in SKES-1 cells were observed, with greater cell death in SKES-1. Exposure of SKES-1 and MG-63 cells to hWJSC-CL showed significant decreases in cell proliferation of 46.48 +/- 6.66% and 24.32 +/- 5.67% respectively compared to controls. MG-63 and SKES-1 cells were annexin V-FITC positive and SKES-1 TUNEL positive following treatment with hWJSC-CM and hWJSC-CL. MG-63 cells were positive and SKES-1 cells negative for anti-BECLIN-1 and anti-LC3B following treatment with hWJSC-CM and hWJSC-CL. RT-PCR showed that the pro-apoptotic BAX gene and the autophagy-related ATG-5 and BECLIN-1 genes were up-regulated while the anti-apoptotic BCL2 and SURVIVIN genes were down regulated in MG-63 and SKES-1 cells treated with hWJSC-CM and hWJSC-CL. Injections of hWJSCs and hWJSC-CM into mammary carcinomas in immunodeficient mice resulted in decreased tumor sizes and weights of 24.86 +/- 6.05% to 37.03 +/- 5.91% and 47.14 +/- 7.36% to 55.09 +/- 5.87% respectively at 6 weeks compared to controls. hWJSC-CM and hWJSC-CL inhibit mammary carcinoma and osteosarcoma cells via apoptosis and autophagy. PMID- 22930596 TI - The risk of pulmonary embolism and deep vein thrombosis in rheumatoid arthritis: a UK population-based outpatient cohort study. AB - BACKGROUND: Recent hospital-based studies have suggested a sixfold increased risk of pulmonary embolism (PE) in rheumatoid arthritis (RA) in the year following admission. We evaluated the risk of PE and deep vein thrombosis (DVT) and associated time trend among RA patients (84.5% without a history of hospitalisation during the past year) derived from the general population. METHODS: We conducted a cohort study using an electronic medical records database representative of the UK general population, collected from 1986 to 2010. Primary definitions of the RA cohort (exposure) and PE/DVT outcomes required physician diagnoses followed by corresponding treatments. We estimated relative risks (RRs) of PE and DVT compared with a matched non-RA comparison cohort, adjusting for age, sex, smoking, body mass index, comorbidities and hospitalisations. RESULTS: Among 9589 individuals with RA (69% female, mean age of 58 years), 82 developed PE and 110 developed DVT (incidence rates, 1.5 and 2.1 per 1000 person-years). Compared with non-RA individuals (N=95 776), the age-, sex- and entry-time matched RRs were 2.23 (95% CI 1.75 to 2.86) for PE and 2.20 (CI 1.78 to 2.71) for DVT. Adjusting for other covariates, the corresponding RRs were 2.16 (CI 1.68 to 2.79) and 2.16 (CI 1.74 to 2.69). The time-specific RRs for PE were 3.27, 1.88 and 2.35 for follow-up times of <1 year, 1-4.9 years, and >=5 years, and corresponding RRs for DVT were 3.16, 1.82 and 2.32. CONCLUSIONS: This population based study indicates an increased risk of PE and DVT in RA, supporting increased monitoring of venous-thromboembolic complications and risk factors in RA, regardless of hospitalisation. PMID- 22930597 TI - Long-term safety of rituximab in patients with rheumatic diseases and chronic or resolved hepatitis B virus infection. PMID- 22930598 TI - Thermally assisted photonic inversion of supramolecular handedness. AB - Spiraling into control: A photoresponsive supramolecular assembly demonstrates that light, along with heating (Delta) and cooling (), can cause chiral communication between molecules. This effect leads to bias in the helicity of the complex, causing a reversible switching of macroscopic handedness, as shown by a reversal of sign of the circularly polarized luminescence (CPL) that is emitted. PMID- 22930599 TI - Control of osteogenesis by the canonical Wnt and BMP pathways in vivo: cooperation and antagonism between the canonical Wnt and BMP pathways as cells differentiate from osteochondroprogenitors to osteoblasts and osteocytes. AB - Although many regulators of skeletogenesis have been functionally characterized, one current challenge is to integrate this information into regulatory networks. Here, we discuss how the canonical Wnt and Smad-dependent BMP pathways interact together and play antagonistic or cooperative roles at different steps of osteogenesis, in the context of the developing vertebrate embryo. Early on, BMP signaling specifies multipotent mesenchymal cells into osteochondroprogenitors. In turn, the function of Wnt signaling is to drive these osteochondroprogenitors towards an osteoblastic fate. Subsequently, both pathways promote osteoblast differentiation, albeit with notable mechanistic differences. In osteocytes, the ultimate stage of osteogenic differentiation, the Wnt and BMP pathways exert opposite effects on the control of bone resorption by osteoclasts. We describe how the dynamic molecular wiring of the canonical Wnt and Smad-dependent BMP signaling into the skeletal cell genetic programme is critical for the generation of bone-specific cell types during development. PMID- 22930601 TI - Harmonisation of laboratory testing. PMID- 22930600 TI - Aging and Family Life: A Decade Review. AB - In this review, we summarize and critically evaluate the major empirical, conceptual, and theoretical directions that studies of aging families have taken during the first decade of the 21st century. The field has benefited from an expanded perspective based on four overarching themes: (a) complexity in emotional relations, (b) diversity in family structures and households, (c) interdependence of family roles and functions, and (d) patterns and outcomes of caregiving. Although research on aging families has advanced theory and applied innovative statistical techniques, the literature has fallen short in fully representing diverse populations and in applying the broadest set of methodological tools available. We discuss these and other frontier areas of scholarship in light of the aging of baby boomers and their families. PMID- 22930602 TI - Quality indicators to detect pre-analytical errors in laboratory testing. AB - Pre-analytical steps, the major source of mistakes in laboratory diagnostics, arise during patient preparation, sample collection, sample transportation, sample preparation, and sample storage. However, while it has been reported that the pre-analytical phase is error-prone, only recently has it been demonstrated that most errors occur in the 'pre-pre-analytical phase'. This comprises the initial procedures of the testing process performed by healthcare personnel outside the laboratory walls and outside the direct control of the clinical laboratory. Quality indicators (QIs) should therefore cover all steps in the pre analytical phase, from test requesting to sample storage. In the present paper, the state-of-the-art of QIs in laboratory testing is described. The focus is on the experience of a working group of the International Federation of Clinical Chemistry and Laboratory Medicine (IFCC) in developing a model of QIs, 16 of which concern the pre-analytical phase. PMID- 22930603 TI - The Approach to Pathology Harmony in the UK. PMID- 22930604 TI - Harmonisation of Measurement Procedures: how do we get it done? AB - Clinical laboratory measurement results must be comparable among different measurement procedures, different locations and different times in order to be used appropriately for identifying and managing disease conditions. Harmonisation in the broad sense is the overall process of achieving comparability of results among clinical laboratory measurement procedures that measure the same measurand. The term standardisation is used when comparable results among measurement procedures are based on calibration traceability to SI using a reference measurement procedure of the highest available order. When there is no higher order reference measurement procedure available, and it is unlikely that one can be developed, the term harmonisation refers to any process for achieving comparable results among measurement procedures for an individual measurand.This review explains calibration traceability and focuses on the principles of harmonisation for those measurands for which a reference measurement procedure does not exist. We discuss the value of harmonisation, the importance of commutable reference materials, the barriers to harmonisation that exist today, and conclude with a discussion of a current global effort to improve the state of harmonisation. PMID- 22930605 TI - Harmonisation of growth hormone assays in australasia. PMID- 22930606 TI - The Australian pathology units and terminology standardisation project - an overview. PMID- 22930607 TI - Coding for pathology tests - strengths and weaknesses. AB - Laboratory professionals will increasingly find themselves called upon to assist with the coding of pathology test requests and reported results in the era of the e-Health Record (EHR). EHR users from outside pathology, including patients and clinicians, will expect seamless integration of pathology services, and question variations in test nomenclature, units, reference intervals, and interpretive comments. Scientists and pathologists will need to be ready to work with colleagues outside their traditional scientific disciplines, along with IT and terminology experts, to resolve illogical historical variations, highlight differences that might endanger patient safety, and help lay the foundations for evolving e-health systems that enhance healthcare without eroding the interpretive value of pathology reports from different laboratories. An overview of medical terminologies and Australasian eHealth harmonisation programs is also provided. PMID- 22930608 TI - The new zealand approach to harmonised reference intervals. PMID- 22930609 TI - Guest editorial. PMID- 22930610 TI - Breast conservation in locally advanced breast cancer. AB - Absence of breast cancer screening in India, lack of awareness in rural population, social inhibitions and poor socioeconomic status leads to a situation where a large proportion of women in India are still presenting with locally advanced breast cancer (LABC) at the time of initial diagnosis, although, there are relatively more of early stage cases detected in the metros and urban areas than maybe a decade ago. With advances in care and introduction of newer chemotherapeutic agents, it has now become feasible to offer neoadjuvant therapy with effective tumor downsizing, thus making it possible to even consider breast conservation surgery in select patients with locally advanced and unresectable disease at presentation. With reports suggesting apparent safety of the procedure, breast conservation treatment after chemotherapy is now being offered as routine care in most major centers for selective women with LABC. Multimodality therapy is the standard of care with neoadjuvant systemic therapy for all women with LABC. PMID- 22930611 TI - The magnitude of cancer breast in India: a summary. AB - Cancer of breast has emerged as the leading site of cancer in most urban populations of India. For the year 2007, there have been an estimated 82,000 new cases of cancer Breast in India. It is rapidly replacing cancer of cervix as the most important leading site of cancer among women. The data collected over the years from five urban population based cancer registries namely Bangalore, Bhopal, Chennai, Delhi and Mumbai, under the network of National Cancer Registry Programme (NCRP) have shown a statistical rising trend in the incidence rate of breast cancer. In hospital-based cancer registries, cancer of the breast is the leading site of cancer in Mumbai and Thiruvananthapuram, second leading site in Bangalore, Dibrugarh and Chennai. Cancer of breast constitutes 14.3 to 30.0% of all cancers in women in these HBCRs. The report on 'Development of an Atlas of Cancer in India' showed that Chandigarh (39.5), North Goa (36.8), Aizawl (36.2) and Panchkula (34.6) had the higher microscopic incidence rates of breast cancer compared to that seen in Delhi PBCR that had the highest rate among all PBCRs. PMID- 22930612 TI - Sentinel lymph node biopsy in breast cancer: the node to recovery. AB - The widespread adoption of sentinel lymph node biopsy to stage the axilla has led to decrease in arm and shoulder morbidity. Sentinel lymph node biopsy is suitable for patients with clinically/radiologically node negative invasive breast cancer and selected patients with DCIS (those with clinical/radiological mass or extensive lesions requiring mastectomy). The combined isotope-blue dye injection technique gives the best results. We inject the isotope intra-dermally preoperatively and blue dye dye subdermally after anesthetic induction into the tumour quadrant peri-areolar tissue. Lymphoscintiscan is not necessary but is useful during the learning phase. Sentinel node biopsy can be performed through a small transverse or vertical axillary incision (~3 cm) appropriately placed to allow axillary lymph node clearance if needed. PMID- 22930613 TI - Gene profiling in breast cancer. AB - Breast cancer is a heterogenous disease which shows a great variation in presentation and response to treatment. Currently, the most commonly used prognostic criteria are patient age, tumor size, lymph node status, tumor grade and hormone receptor status. These are however not very accurate. This is partly explained by the fact that they do not demonstrate the inherent genetic variability of breast cancer, which determines the aggressive nature and metastatic potential of the disease. Recent advances in molecular biology have demonstrated that breast cancer is not a single disease. The new diagnostic and prognostic tests based on molecular biology methods have helped identify molecular subtypes of breast cancer that are sensitive to chemotherapy and others that are resistant. This could provide valuable critical information and predict which patients would really benefit from chemo and/or hormonal therapy. Molecular biology will become increasingly important in clinical decision making and as the understanding of molecular processes within cancer cells grow, new targets for therapy will be discovered. PMID- 22930614 TI - Role of aromatase inhibitors in the upfront adjuvant hormonal therapy of postmenopausal patients with breast cancer. AB - Tamoxifen has been considered for several decades as the standard upfront hormonal therapy for patients with endocrine-sensitive early breast cancer. The efficacy and favorable toxicity profiles of third-generation aromatase inhibitors (AIs), anastrozole, letrozole and exemestane, in advanced disease led to their development in early breast cancer. Recent trial results consistently showed the superiority of AIs over tamoxifen in using the two following therapeutic approaches: either the upfront strategy (randomization of newly diagnosed patients: tamoxifen for 5 years vu AI for 5 years) or the sequencial strategy (randomization of newly diagnosed patients: tamoxifen (2-3 years) followed by AI or the inverse for a total of 5 years vs upfront AI for 5 years).Despite some common characteristics, a body of evidence on AIs suggests some specific differences between the three agents in terms of efficacy as well as toxicity profiles. Thus, these hormonal agents may not be considered interchangeable in clinical practice. This review will explore available results from AIs trials and will try to define their present role in the upfront adjuvant management of postmenopausal patients with breast cancer. PMID- 22930616 TI - Is estrogen receptor study useful in prognostication of breast cancer patients in India? AB - BACKGROUND: To assess the validity of estrogen receptor (ER) status of breast tumor as a prognostic marker in clinical practice in the Indian perspective. MATERIALS AND METHODS: Sixty-three patients of breast cancer attending breast clinic IPGMER, Kolkata were included in this study. All patients underwent surgery. Metastatic status and tumor were done. Immunohistochemistry was also used for further analysis. RESULTS: Statistically we have proved that advancing course of the disease, there is a tendency of the tumors to become hormone insensitive. CONCLUSIONS: ER has a strong prognostic importance in early breast cancer and can play a major role in optimizing treatment modalities in node negative early breast cancer. PMID- 22930615 TI - Value of frozen section and primary tumor factors in determining sentinel lymph node spread in early breast carcinoma. AB - INTRODUCTION: Sentinel lymph node biopsy (SLNB) is the standard of care to assess the metastasis in breast carcinoma. Accuracy of intraoperative frozen section examination to evaluate SLN in detecting metastasis is important as it determines the further management of axilla. Primary tumor characteristics determining the metastasis to the lymph node will help in predicting the probability of spread and to determine the nature of disease. It also helps in refining selection of patients for SLNB. We evaluated all these criteria on Indian patients for the better management. MATERIALS AND METHODS: Between January 2005 and April 2009, 114 consecutive patients of all age group of both sex, with cytology or biopsy proven carcinoma breast, clinical stage T1/T2 N0 M0 at Manipal Comprehensive Cancer Center, Manipal Hospital, Bangalore were subjected to SLNB and introperative frozen examination. First 75 cases had complete axillary clearance irrespective of SLNB result and subsequently, positive cases underwent axillary lymph node dissection (ALND). Age of the patient and primary tumor characteristics like size, grade, lymphovascular invasion (LVI), perineural invasion, ER/PR status, Her2-neu status and histological sub-types were evaluated for predicting the SLN metastasis. Feasibility of SLNB in previously treated patient is also evaluated. RESULTS: The age of the patient ranged from 23 to 87 years and its association with SLN spread is not significant. Frozen section examination had accuracy of 97.37% in determining metastatic sentinel node with sensitivity of 96.15% and specificity of 100% with value P < 0.001. SLN remained significant indicator of the status of rest of axilla with value P < 0.001. Primary tumor characteristics like histological subtypes, grade (P = 0.353), ER/PR status (P = 0.839), Her2-neu status (P =0.296) were not significantly associated with SLN metastasis. Size of the primary tumor (P = 0.002), LVI (P < 0.001), perineural invasion (P = 0.084+) were significant factors determining the SLN metastasis. SLNB evaluation had no false negative values in previously treated breast. CONCLUSION: SLNB is a valuable method of determining the axillary nodal metastasis. Intraoperative frozen section examination is highly ac-curate in detecting nodal metastasis. Primary tumor characteristics like size, LVI and perineural invasion are significant in predicting SLN metastasis. SLNB remains an important method of predicting axillary metastasis even in previously treated breast carcinomas. PMID- 22930617 TI - Expression of E-Cadherin in breast carcinomas and its association with other biological markers - a prospective study. AB - CONTEXT: E-cadherin (E-CD) is an important cell adhesion molecule in normal epithelial cells and has been shown to be an invasion tumor suppressor gene. MATERIALS AND METHODS: Various clinicopathological parameters like age, family history, tumor stage, histological grade, lymph node status and other biological markers were also analyzed. Present study reveals E-CD expression in 65 cases of breast cancer including 41 (63%) cases of pure infiltrating ductal carcinoma (IDC), 11 (16.9%) of pure infiltrating lobular carcinoma (ILC); another 10 (15.3%) of mixed ductal/lobular type, and remaining 3 (4.6%) miscellaneous types. RESULTS: Negative E-CD expression was noticed more in advancing age groups (P = 0.01). About 59.2% cases showing negative E-CD expression had family history of breast and/or other cancers. E-CD expression was found significantly higher in cases of pure IDC (55.5%) than in pure ILC cases (18.1%) (P = 0.04). Eleven (68.7%) of the total 16 high-grade IDC cases, revealed negative expression. Both cases of comedo carcinoma revealed negative expression. Three (30%) out of 10 mixed cases revealed negative expression in both ductal and lobular areas, while in remaining 7 cases, positvity was seen in ductal areas only. Invasive cribriform and medullary carcinoma revealed a stronger expression, while negative staining was observed in sweat gland carcinoma. E-CD re-expression was noticed in lymph node tumor deposits. A direct association of E-CD expression with ER expression and an inverse association with that of p53 were also observed (P = 0.001), (P = 0.04). CONCLUSIONS: E-CD expression is useful, but limited, in differentiating IDCs from ILCS. Its negative expression correlates with certain poor prognostic parameters reflecting its use as a marker for invasive cancers. It re-expresses at metastatic sites. PMID- 22930618 TI - Long-term outcomes after ROLL lumpectomy. AB - BACKGROUND: Occult breast lesions are being successfully targeted by means of Radioactive-guided Occult Lesion Localization (ROLL). Several reports demonstrate suitability of ROLL technique to excise non-palpable breast lesions with immediate advantages. AIM: Evaluation of long-term outcomes after ROLL guided lumpectomy for early breast cancer. MATERIALS AND METHODS A CONSECUTIVE SERIES OF NON PALPABLE EARLY INVASIVE BREAST CANCERS EXCISED WITH ROLL (151 PTS; DECEMBER 2002#ENTITYSTARTX02013;JUNE 2006) WERE FOLLOWED UP FOR LONG-TERM OUTCOMES, I.E. LOCAL AND/OR SYSTEMIC RECURRENCE. OUR FOLLOW-UP PROTOCOL INCLUDED 6 MONTHLY PHYSICIAN ADMINISTERED CLINICAL EXAMINATIONS AND 18 MONTHLY IMAGING, I.E. MAMMOGRAM. BONE SCAN, LIVER AND BRAIN IMAGING WERE REQUESTED ON CLINICAL NEED. CLINICAL AND/OR RADIOLOGICAL SUSPICIOUS LESIONS FOR LOCAL RECURRENCE WERE CONFIRMED PATHOLOGICALLY: RESULTS: The median follow-up was 46 months with all patients having a minimum 22 months follow-up. 3/151 local recurrences occurred (1.98%). CONCLUSIONS: Long-term outcomes, i.e. local recurrence of invasive breast cancer excised with ROLL guidance compares well with existing localization techniques. PMID- 22930619 TI - Sentinel lymph node mapping in early breast cancer - Our experience. AB - BACKGROUND: The axillary lymph node status is the most important determinant of prognosis in patients with breast cancer. Sentinel lymph node (SLN) biopsy is a safe alternative for axillary clearance with an equal efficacy limiting the morbidity caused by axillary clearance. PATIENT AND METHODS: From May 1996 till September 2009, 523 clinically node negative, early breast cancer patients attending our clinic at All India Institute of Medical Sciences were included in the study. They underwent sentinel lymph node biopsy by either combined technique or blue dye alone. All patients irrespective of the axillary status underwent axillary lymph node dissection (ALND). RESULTS: Of 523 patients, 267 underwent combined technique of sentinel node mapping and 256 underwent blue dye technique alone. The identification rate of sentinel lymph node was 94.3% (253/267) for combined technique and 87.8% (225/256) for blue dye alone. Of 523 patients SLN was identified in 478 patients. The identification rate was 91.3%. The sensitivity = 91.5% (141/154), false negative = 8.4% (13/154), negative predictive value = 96.14% (324/337), and accuracy being 97.2% (465/478). CONCLUSION: Sentinel node mapping is a simple and safe technique of identifying the axillary node involvement. Sentinel lymph node biopsy is associated with less arm oedema and shoulder morbidity compared to ALND. However, the results of long term effects of sentinel node approach on tumor recurrence or patient survival are awaited. PMID- 22930620 TI - Axillary lymph node dissection for sentinel lymph node micrometastases may be safely omitted in early-stage breast cancer patients: long-term outcomes of a prospective study. AB - OBJECTIVES: To evaluate the long-term disease-free and overall survival of patients with sentinel lymph node (SLN) micrometastases, in whom a completion axillary lymph node dissection (ALND) was systematically omitted. BACKGROUND: The use of step sectioning and immunohistochemistry for SLN analysis results in a more accurate histopathologic examination and a higher detection rate of micrometastases. However, the clinical relevance and therapeutic implications of SLN micrometastases remain a matter of debate. METHODS: In this prospective study, 236 SLN biopsies were performed in 234 consecutive early-stage breast cancer patients (T1, T2 <= 3 cm, cN0 M0) between 1998 and 2002. The SLN were examined by step sectioning and stained with hematoxylin and eosin and immunohistochemistry. None of the patients with negative SLN or SLN micrometastases (International Union Against Cancer classification, >0.2 to <= 2 mm) underwent a completion ALND or radiation to the axilla. Long-term overall and disease-free survivals were compared between patients with negative SLN and those with SLN micrometastases by log rank tests. RESULTS: The SLN was negative in 55% of patients (123 of 224). SLN micrometastases were detected in 27 patients (27 of 224, 12%). After a median followup of 77 months (range, 24-106 months), neither locoregional recurrences nor distant metastases occurred in any of the 27 patients with SLN micrometastases. There were no statistically significant differences for overall (P = 0.656), locoregional (P = 0.174), and axillary and distant disease-free survival (P = 0.15) between patients with negative SLN and SLN micrometastases. CONCLUSIONS: This analysis of unselected patients provides evidence that a completion level I and II ALND may be safely omitted in early stage breast cancer patients with SLN micrometastases. PMID- 22930621 TI - Ratio between positive lymph nodes and total excised axillary lymph nodes as an independent prognostic factor for overall survival in patients with nonmetastatic lymph node-positive breast cancer. AB - BACKGROUND: The status of the axillary lymph nodes in nonmetastatic lymph node positive breast cancer (BC) patients remains the single most important determinant of overall survival (OS). Although the absolute number of nodes involved with cancer is important for prognosis, the role of the total number of excised nodes has received less emphasis. Thus, several studies have focused on the utility of the axillary lymph node ratio (ALNR) as an independent prognostic indicator of OS. However, most studies suffered from shortcomings, such as including patients who received neoadjuvant therapy or failing to consider the use of adjuvant therapy and tumor receptor status in their analysis. METHODS: We conducted a single-center retrospective review of 669 patients with nonmetastatic lymph nodepositive BC. Data collected included patient demographics; breast cancer risk factors; tumor size, histopathological, receptor, and lymph node status; and treatment modalities used. Patients were subdivided into four groups according to ALNR value (<0.25, 0.25-0.49, 0.50-0.74, 0.75-1.00). Study parameters were compared at the univariate and multivariate levels for their effect on OS. RESULTS: On univariate analysis, both the absolute number of positive lymph nodes and the ALNR were significant predictors of OS. On multivariate analysis, only the ALNR remained an independent predictor of OS, with a 2.5-fold increased risk of dying at an ALNR of ?0.25. CONCLUSIONS: Our study demonstrates that ALNR is a stronger factor in predicting OS than the absolute number of positive axillary lymph nodes. PMID- 22930622 TI - Breast cancer presenting as parotid tumour - first reported case in literature. AB - Breast cancer presenting as parotid tumour is very rare. This is the first reported case in which parotid tumour was the presenting complaint of the patient. Since the patient was estrogen and progesterone receptor positive - was put on hormone therapy and responded well. PMID- 22930623 TI - Update on role of chemotherapy in head and neck squamous cell cancer. AB - Head and neck squamous cell cancer (HNSCC) is most commonly a tobacco-related disease, affecting nearly 600,000 people worldwide each year. For decades, HNSCC has been treated successfully with multimodality treatments including, surgery, radiation, and chemotherapy, though the 'perfect' treatment paradigm remains elusive. This review will discuss a number of clinical trials, comparing various combinations of chemotherapy and the settings in which they are most successful. Promising research and recent data on the combination of cytotoxic chemotherapy with new biological agents indicate chemotherapy plays a critical role in treatment of HNSCC and will only continue to improve. PMID- 22930625 TI - Current concepts in the management of primary hyperparathyroidism. AB - Primary hyperparathyroidism is the commonest cause of hypercalcemia in the ambulatory setting. Widespread use of routine laboratory screening has resulted in a large number of patients presenting with subclinical disease. In truly asymptomatic patients, consensus guidelines have been developed to determine which patients need definitive treatment. The most common pathologic finding is parathyroid adenoma, followed by hyperplasia, double adenomas and parathyroid carcinoma. The mainstay of treatment is surgery. While there is still an important role for four gland exploration and evaluation, there is now considerable interest in a more focused surgical approach. This paradigm shift is based on localizing studies that combine sestamibi scanning with anatomic imaging, most commonly ultrasound scanning. A range of minimally invasive approaches have been developed to treat parathyroid adenomas, including unilateral and single gland explorations as well as a number of different endoscopic techniques. Intra-operative rapid parathormone assay has replaced histologic examination as a more effective method to confirm the adequacy of surgery in most cases. Functional localization and exploration using a gamma probe has also been described. The management of patients with persistent or recurrent hyperparathyroidism is difficult and requires a multidisciplinary approach. PMID- 22930626 TI - Novel flaps for head and neck reconstruction. AB - The head and neck region is important both functionally and aesthetically and its reconstruction poses a formidable challenge for plastic surgeons. A perforator flap is a flap of skin or subcutaneous tissue supplied by a vessel that perforates the deep fascia to gain access to flap. With improvement in our knowledge of the anatomy of blood supply to the skin, the perforator flaps have opened a whole new horizon for the plastic surgeon to choose flaps with better function and cosmesis. The locally available perforators enable flaps to be designed with excellent match in tissue characteristics. Perforator flaps limit donor site morbidity and as they are islanded complete insetting is possible in a single stage. The principal perforator flaps such as facial artery perforator flap, platysma flap and its variant the submental flap and supra-clavicular artery flap used in the head and neck reconstruction are discussed. The more commonly used flaps are the free radial artery forearm flap and the anterolateral thigh flap while the novel ones are the thoracodorsal artery perforator flap, medial sural artery perforator flap and the toe-web flap for commissure reconstruction. The indications, reach and drawbacks of these flaps have been discussed in this review. PMID- 22930627 TI - Management of lateral skull base tumours. AB - Lateral skull base tumours arise from overlying skin, parotid, temporal bone, mandible, muscle or the vasculature and they spread in midst of important neurovascular structures. This makes their diagnosis and management challenging. These tumours are primarily dealt with surgery which can be extensive, functionally disabling and cosmetically disfiguring. Tumour biology, involvement of the internal carotid artery and cranial nerves play key roles in management of these tumours. This review will focus on management of common tumours afflicting the lateral skull base. PMID- 22930624 TI - Parotid carcinoma: Current diagnostic workup and treatment. AB - In this review we present recent progress in diagnostic workup, prognostic evaluation, treatment options and resulting outcomes. Whenever possible, complete resection remains the mainstay of treatment. Sacrifice of facial nerve branches is reserved for the clinically or electromyographically dysfunctioning facial nerve. Clinical or radiological neck disease demands combined surgery and radiotherapy. Treatment of the N0 neck is indicated for advanced stage-high grade tumors but the question remains unanswered whether this should be surgical or radiotherapeutic elective treatment. Surgery alone will cure low stage, low grade tumors, that show no additional negative prognostic factors following adequate resection. In all other tumors postoperative radiotherapy will improve locoregional control. This approach results in good locoregional control, in a way that distant metastasis remains the typical presentation of treatment failure. In this setting, the results of systemic treatment today remain limited, but a huge effort in the molecular biology field has been done to introduce targeted therapy into this domain of head and neck cancer. Disease control remains variable within the patient population. This variation can increasingly be predicted by systems that incorporate the combined information of multivariately identified and quantified prognostic factors into an individualized prognosis for the parotid carcinoma patient. PMID- 22930629 TI - Prosthetic voice rehabilitation after total laryngectomy. AB - Loss of voice is a major concern after total laryngectomy. Tracheo-esophageal prosthesis was described in 1980 by Blom and Singer as a method of postlaryngectomy voice rehabilitation. Since then it has seen many phases of developments. Now it has evolved into highly effective method with success rates more than 90% and better quality of voice than other modalities. It also gives good quality of life and voice related quality of life. Though it is associated with some complications, they are easy to manage. All these have made tracheo esophageal prosthesis the 'Gold Standard' of post-laryngectomy voice rehabilitation. PMID- 22930628 TI - Anterior skull base surgery. AB - The basic principle of anterior skull base surgery is to provide adequate exposure to enable three dimensional resection of skull base tumors. Negative surgical margins, which is within the control of surgeon, is the principle prognostic factor in anterior skull base tumors. Open skull base approaches is the standard of care for malignant anterior skull base tumors. Benign lesions may be resected by alternate minimally invasive approaches. Advances in anterior skull base surgery, in particular the facial translocation approaches allows wide exposure of the tumors with minimal retraction of the brain. The outcome of anterior skull base tumors have steadily increased over the years with disease free survival comparable to other malignant neoplasm of the head and neck region. This review described various surgical approaches and pertaining anatomy and pathology of anterior skull base tumors. PMID- 22930631 TI - Periorbital fascia, its significance in total maxillectomy. AB - In the surgical management of T3-T4 carcinoma of the maxillary antrum, involvement of the roof and/or erosion of the orbital floor, raises the possibility of the sacrifice of the orbital contents. While it is evident that the eyeball has to be sacrificed in the presence of gross disease, the indications when it can be preserved are not clear. Radiological assessment requires a minimum thickness of 4mm of the tissue. Standard anatomical texts describe the bony orbital floor and the orbital periosteum. In 1998 this author for the first time described a distinct fascial layer which encapsulates the orbital fat and termed it Periorbital Fascia. The purpose of this article is to draw attention to this anatomical structure and discuss the precise indications when the eyeball may be sacrificed or preserved. The conclusions are based on the experience with eighty two total maxillectomies for cancer performed over a period of 30 years. In the opinion of this author the following conclusions can be drawn. First, the orbital fat does not rest on the orbital periosteum as shown in anatomical texts, but is enclosed in a thin independent fascial layer termed the periorbital fascia. Secondly, in the event of malignant disease eroding the orbital roof, what is crucial is to know whether the orbital periosteum is involved and to know as to whether the disease process has reached the orbital surface of the periosteum. In case the disease is limited to the under surface of the orbital periosteum, the eyeball may still be preserved by a careful dissection between the periosteum and the periorbital fascia. PMID- 22930630 TI - Management of thyroid cancers. AB - Thyroid cancers cover a large spectrum of disease with diametrically opposite prognosis. At one end of the spectrum we have the well differentiated cancers which carry an excellent prognosis, while at the other end there is anaplastic cancer with high mortality rates and dismal prognosis. Management of thyroid cancers still has some controversial issues due to lack of randomized controlled trials. Extent of surgery, extent of neck dissection, role of radioiodine treatment and thyroid stimulating hormone suppression are still debatable. In this review, we highlight these controversial issues and give guidelines for the management and follow up of patients with thyroid cancer. PMID- 22930633 TI - Newer imaging techniques in head and neck cancer. AB - Computerized tomography (CT), Magnetic Resonance Imaging form the backbone of head and neck cancer imaging. This review describes the role of newer functional imaging techniques like diffusion weighted MR imaging and perfusion imaging in head and neck cancers. A review of the current role of PET-CT in head and neck tumors is also included in this article. PMID- 22930632 TI - IMRT and IGRT in head and neck cancer: Have we delivered what we promised? AB - Intensity-modulated radiation therapy (IMRT) is a revolutionary new paradigm that aims at improving the therapeutic ratio by increasing the dosegradient between target tissues and surrounding normal structures thereby offering probability of better loco-regional control with decreased risk of complications. IMRT is relatively intolerant to set-up uncertainties, warranting periodic image guidance, making Image-Guided Radiation Therapy (IGRT) a natural corollary to IMRT. There are several challenges associated with the planning, delivery, and quality assurance of the IMRT and IGRT processes that must be addressed to realize the full potential of such exciting and promising technology. Given the complexities involved, it is quite intuitive to understand that IMRT and IGRT are resource-intensive, demanding increased labor, rigour, and expenses too. Other disadvantages associated with high-precision techniques include potentially increased risk of marginal failures, decreased dose homogeneity, and an increase in total body dose with increased risk of secondary carcinogenesis. The aim of this review is to define the role of IMRT and IGRT in contemporary head and neck oncologic practice through a critical appraisal of pertinent literature. Despite relatively short follow-up and limited clinical outcomes data, the weight of evidence suggests that loco-regional control is not inferior (either comparable or even better) and toxicity lesser with IMRT resulting in potentially improved quality-of-life, prompting the widespread adoption of such technology in community practice. Ongoing clinical trials in head and neck IMRT are currently addressing issues to optimize the IMRT process, adopting functional imaging for dose-painting, and incorporating adaptive re-planning strategies to further improve outcomes. PMID- 22930634 TI - Endoscopic v/s conventional approach to sino-nasal tumours - What's the debate? AB - In the past two decades nasal endoscopy has advanced technologically to offer us magnified vision and better illumination along with better instrumentation. Surgery has traditionally been via the transfacial approaches such as lateral rhinotomy or the Weber Fergueson incision. For disease extension into the skull base traditional approach is a transfrontal craniotomy via either the bicoronal incision or the subcranial Raveh's approach. A combined access via the cranium from above and the transfacial access from below aids in encompassing the tumour all around. Transnasal access is a natural trajectory which leads us directly onto the tumour. The endoscope alone or with the microscope has been utilised to improve the magnification and illumination to aid in tumour removal. Minimal access to the Sinonasal and anterior skull base tumours is proven to be possible and feasible. We now have an additional armamentarium to our existing approaches in management of these tumours. We have to be judicious and see which approach can remove the disease completely maintaining the quality of life of the patient. PMID- 22930635 TI - Minimal access surgery - thyroid and parathyroid. AB - The concept of surgical invasiveness cannot be limited to the length or to the site of the skin incision. It must be extended to all structures dissected during the procedure. Therefore, MIT or MIP should properly be defined as operations through a short and discrete incision that permits direct access to the thyroid or parathyroid gland, resulting in a focused dissection.Parathyroid glands are particularly suitable for minimally invasive surgery as most parathyroid tumors are small and benign. MIP are performed through a limited or discrete incision when compared to classic open transverse cervical incision and are targeted on one specific parathyroid gland. The concept of these limited explorations is based on the fact that 85% of patients will have single-gland disease. MIP must be proposed only for patients with sporadic hyperparathyroidism in whom a single adenoma has been clearly localized by preoperative imaging studies.The minimal access approaches to the thyroid gland may be broadly classified into three groups: the mini-open lateral approach via a small incision, minimally invasive video-assisted thyroidectomy via the midline and various endoscopic techniques. Endoscopic extracervical approaches have the main advantage of leaving no scar in the neck but cannot reasonably be described as minimally invasive as they require more dissection than conventional open surgery.Initially the indications for MIT were a solitary thyroid nodule of less than 3 cm in diameter in an otherwise normal gland. Today, MIT are also proposed in patients with small nodular goiters, Graves's diseases and low risk papillary thyroid cancers. Some concern remains about the radicality of MIT in this latter group but preliminary results are comparable to those of conventional surgery both in terms of I-131 uptake and serum thyroglobuline levels.Demonstrating the advantages of MIT and MIP over conventional surgery is not easy. Main complications, such as nerve injury, hypoparathyroidism, or hemorrhage, are the same as in conventional surgery. Several studies comparing conventional surgery with minimally invasive techniques using a cervical access have shown a diminution of postoperative pain, and better cosmetic results with minimally invasive techniques. MIP and MIT seem overall to be an advance but only randomized studies will demonstrate the real benefit. PMID- 22930637 TI - A molecular imaging analysis of Cx43 association with Cdo during skeletal myoblast differentiation. AB - Cell-to-cell contacts are crucial for cell differentiation. The promyogenic cell surface protein, Cdo, functions as a component of multiprotein clusters to mediate cell adhesion signaling. Connexin 43, the main connexin forming gap junctions, also plays a key role in myogenesis. At least part of its effects is independent of the intercellular channel function, but the mechanisms underlying are unknown. Here, using multiple optical approaches, we provided the first evidence that Cx43 physically interacts with Cdo to form dynamic complexes during myoblast differentiation, offering clues for considering this interaction a structural basis of the channel-independent function of Cx43. PMID- 22930636 TI - Transoral resection of laryngeal and hypopharyngeal cancers. AB - The advent of transoral microlaryngoscopic laser surgery is making a significant impact on treatment decisions in the management of early squamous cancers of the larynx and the hypopharynx. It has, to a great extent replaced the conventional open partial laryngectomy procedures. Moreover many cancers of the larynx or the hypopharynx that were earlier being treated with radiation therapy are now resected transorally with the CO(2) laser. This article focuses on the progress of transoral laser microsurgery in the management of early larygopharyngeal cancers. PMID- 22930638 TI - The first case of cutaneous infection with Mycobacterium parascrofulaceum. AB - The authors present the first, to the best of their knowledge, reported case of cutaneous infection caused by Mycobacterium parascrofulaceum. A 42-year-old woman presented with asymptomatic reddish papules, nodules, plaques, and patches on the right side of her face and on her forehead that had persisted for 5 years, with the lesions gradually increasing in size over that time. No previous intervening medical treatment had been applied. No history or evidence of immunosuppression was found. A skin biopsy was performed for routine histological examination. Samples of lesioned skin were inoculated on Lowenstein-Jensen medium to determine the presence of acid-fast bacilli. Ziehl-Neelsen staining was used to confirm the presence of the organism. In vitro drug susceptibility testing was conducted using the microtiter plate method. Mycobacterium was identified by polymerase chain reaction-restriction fragment length polymorphism analysis and sequencing of the hsp65 and 16S rDNA genes. Cultures for aerobic and anaerobic bacteria, as well as fungus, were also conducted. Routine histopathology revealed granulomatous changes without caseation. Ziehl-Neelsen staining showed that the organisms in both the lesions and the cultures were acid-fast bacilli. The cultured colonies were grown in Lowenstein-Jensen medium and incubated at two different temperatures (32 degrees C and 37 degrees C) for 2-3 weeks, developing pigmentation both in the dark and in the light. In vitro drug susceptibility tests showed that the organism was sensitive to clarithromycin and moxifloxacin. Polymerase chain reaction-restriction fragment length polymorphism analysis and sequencing of the hsp65 and 16S rDNA genes confirmed that the isolated organisms were M. parascrofulaceum. Fungal and other standard bacterial cultures were negative. In conclusion, identification and diagnosis of nontuberculous mycobacteria should be performed promptly to obtain better prognoses. Empirical treatments may be feasible, and drug susceptibility tests are important. PMID- 22930639 TI - Disparity in risk factor pattern in premature versus late-onset coronary artery disease: a survey of 15,381 patients. AB - BACKGROUND: There are few data available regarding the specificity and modifiability of major cardiovascular (CV) risk factors in patients with premature versus (vs) late-onset coronary artery disease (CAD). This study was designed to analyze and compare these risk factors. PATIENTS AND METHODS: Data from 15,381 consecutive patients (mean age, 62.3 +/- 11.7 years; female, 33.8%) hospitalized with CAD were collected from a large-scale registry (Transparency Registry to Objectify Guideline-Oriented Risk Factor Management) and analyzed. The patients were divided into two groups, depending on age at inclusion: group 1 patients (n = 5725; mean age, 50.5 +/- 7.2 years) were males aged < 55 years and females aged < 65 years; group 2 patients (n = 9656; mean age, 69.4 +/- 7.4 years) were males aged > 55 years and females aged > 65 years and had a low density lipoprotein cholesterol level of >100 mg/dL on admission to cardiac rehabilitation. Besides the conventional risk factors, lipoprotein(a) concentrations and glucose tolerance were measured facultatively. Univariate (chi square test) and multivariate logistic regression models were used. RESULTS: Cigarette smoking (group 1 at 31.5% vs group 2 at 9.4%; P < 0.001), family history of CAD (group 1 at 43.6% vs group 2 at 26.5%; P < 0.001), and dyslipidemia (group 1 at 92.7% vs group 2 at 91.8%; P < 0.001) were dominant risk factors in the younger group. Arterial hypertension (group 1 at 71.4% vs group 2 at 87.0%; P < 0.001) and diabetes (group 1 at 23.5% vs group 2 at 30.1%; P < 0.001) were dominant risk factors in the older group. Impaired glucose tolerance and diabetes were less frequent in the younger group (P(trend) = 0.038), and identical lipoprotein(a) concentration levels of >30 mg/dL were found in both groups (8.0%; P = 0.810). Modification of lipid profile and blood pressure was more effective in the younger group (low-density lipoprotein cholesterol < 100 mg/dL: group 1 at 66.3% vs group 2 at 61.1%; systolic blood pressure < 140 mmHg: group 1 at 91.7% vs group 2 at 83.0%; P < 0.001). CONCLUSION: CV risk factors differ markedly between premature and non-premature CAD. Cardiac rehabilitation provides an opportunity to reinforce secondary prevention after acute coronary syndrome. PMID- 22930640 TI - Measurement of imatinib uptake by flow cytometry. AB - One of the essential parameters of targeted therapy efficiency in cancer treatment is the amount of drug reaching the therapeutic target area. Imatinib (IM) was the first specifically targeted drug to be developed and has revolutionized the treatment of patients with chronic myeloid leukemia (CML). To evaluate cellular uptake of IM, we developed a method based on the chemical structure of the molecule and using the natural UV fluorescence that we quantified by flow cytometry. In two CML cell lines, we obtained a satisfactory relationship between intracellular IM (ICIM) levels and media concentrations, and we found a strong correlation between ICIM at 1 h and IM efficacy at 24 h, demonstrating that ICIM at 1 h might be a relevant predictive parameter of cell sensitivity. Our method was more sensitive than the standard physicochemical method. We applied our method to primary cells and found cell morphology dependent IM accumulation. Moreover, in CML cells from patients at diagnosis, IM accumulation was heterogeneous. In all cases, ICIM at the single-cell level was much higher than in culture media arguing in favor of a predominantly active uptake process. We developed a simple method directly applicable to primary cells that has shown two major advantages: only a small number of cells are required, and cell subsets can be identified according to morphological criteria and/or the presence of particular antigenic sites. This method provides a new tool to assess CML cell sensitivity to IM, and ICIM levels in native CML cells could be used to monitor therapeutic response. PMID- 22930641 TI - Safety profiles of current antiangiogenic therapies for metastatic colorectal cancer. AB - The biological agents approved for the treatment of patients with metastatic colorectal cancer - bevacizumab, a monoclonal antibody that targets vascular endothelial growth factor A, along with cetuximab and panitumumab, two monoclonal antibodies that target the epidermal growth factor receptor - are associated with a number of adverse events that range in severity from relatively mild to potentially life threatening. Hypertension, thromboembolic events, proteinuria, bleeding, and gastrointestinal perforation have all been associated with bevacizumab, while dermatologic toxicities are common with cetuximab and panitumumab. Hypersensitivity reactions and hypomagnesemia are also a concern with cetuximab and panitumumab. The frequency of these adverse events in randomized clinical trials is reviewed, and recommendations for managing these events in patients undergoing treatment for metastatic colorectal cancer are provided. PMID- 22930642 TI - Separation of two cytotoxic saponins from the roots of Adenophora triphylla var. japonica by high-speed counter-current chromatography. AB - INTRODUCTION: The roots of Adenophorae species have been reported to exhibit anti obese, anti-oxidant, anti-cancer, and anti-bacterial activities. However, there has been no single report regarding the preparative isolation and biological activities of the chemical components from Adenophora triphylla. OBJECTIVE: To develop an efficient method for the determination of the active fraction from the methanol extract from the roots of Adenophora triphylla and for the preparative isolation and purification of target compounds having cytotoxicity on carcinoma cells from the active fraction by high-speed counter-current chromatography (HSCCC). METHODS: The Plant (5 kg, dry weight) was extracted with methanol. Three hundred grams of the dried methanol extract (885 g) were fractionated by open column chromatography with a stepwise gradient of water-methanol. Preparative isolation of bioactive components was performed by HSCCC with a two-phase solvent system composed of ethyl acetate-n-butanol-0.2% trifluoroacetic acid in water (5:5:10, v/v). The cytotoxicity of column fractions and isolated compounds was evaluated by 2-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromide assay. RESULTS: The 70% MeOH column fraction showed inhibitory effects against three human carcinoma cells A549, AGS and HepG2. Two saponins were separated from 400 mg of the active fraction by HSCCC. After further purification with solid phase extraction column, 25 mg of peak fraction 1 and 20 mg of peak fraction 2 were obtained. Their structures were identified by 1H-NMR, 13C-NMR, Fourier transform infrared, fast atom bombardment-MS and electrospray ionisation-MS/MS. They exhibited strong cytotoxic effects against three cancer cells. CONCLUSION: Two cytotoxic saponins were isolated for the first time from the roots of Adenophora triphylla by HSCCC. PMID- 22930643 TI - Emotions in eating disorders: changes of anger control after an emotion-focused day hospital treatment. AB - OBJECTIVE: Emotional states are key elements of eating disorders (EDs), with anger and aggressiveness playing an important role. This study aimed to investigate anger features in ED patients before and after an intensive day hospital (DH) specifically focused on emotions. METHOD: Forty-one ED patients were admitted to our DH, which specifically includes emotion-focused activities. They completed self-reported questionnaires at the beginning and after the intervention: Eating Disorders Inventory-2, State-Trait Anger Expression Inventory (STAXI) and Beck Depression Inventory (BDI). RESULTS: Anger Control (Axcon) subscale of STAXI decreased significantly, and both BDI and body mass index - in case of underweight patients - significantly improved after completion of DH. Axcon decrease correlated with BMI improvement. The majority of individuals showing good outcome reported also a significant improvement in Axcon levels. DISCUSSION: This study provided preliminary data about the effectiveness mainly in anger coping - of an emotion-focused DH. PMID- 22930644 TI - High-resolution ultra-high mass spectrometry: increasing the m/z range of protein analysis. AB - The proof of principle for high-resolution TOF mass analysis spanning the entire range of intact singly charged proteins has recently been demonstrated. The centers of the isotope distributions of individual proteins in a complex distribution can be defined to within 0.5 Da or better up to 200 kDa with internal calibration. This achievement will have an enormous effect on the process of routine protein analysis over the next few years as the technology mainstreams. The greatest obstacle to high-resolution in the ultra-high mass range (m/z > 20 000) is the expansion-induced kinetic energy (KE) and its spread. The solution to this problem is to trap the ions in a buffer gas so that the motion of the ions can be completely defined by the applied fields. If this can accomplished without mass dependence, then any ion, regardless of size, can be mass analyzed with high resolution. This article discusses the methodology that we used to capture atmosphere sampled singly charged proteins in vacuum at a point just before they enter the mass analyzer to completely eliminate the expansion-induced KE. We then used digitally created quadrupole waveforms to inject the ions into the mass analyzer in a well-collimated plug with a controlled amount of KE. Trapping the ions to remove the expansion-induced KE and then electrodynamically manipulating the ions are the key steps to high resolution mass analysis at any value of m/z. The impact of this technology will be discussed. PMID- 22930645 TI - Predictive value of CD4 cell count nadir on long-term mortality in HIV-positive patients in Uganda. AB - OBJECTIVE: Although international guidelines recommend initiating antiretroviral therapy (ART) when a patient's CD4 cell count is <=350 cells/MUL, most patients in resource-limited settings present with much lower CD4 cell counts. The lowest level that their CD4 cell count reaches, the nadir, may have long-term consequences in terms of mortality. We examined this health state in a large cohort of HIV+ patients in Uganda. DESIGN: This was an observational study of HIV patients in Uganda aged 14 years or older, who were enrolled in 10 major clinics across Uganda. METHODS: We assessed the CD4 nadir of patients, using their CD4 cell count at initiation of ART, stratified into categories (,50, 50-99, 100-149, 150-249, 250+ cells/MUL). We constructed Kaplan-Meier curves to assess the differences in survivorship for patients left-censored at 1 year and 2 years after treatment initiation. We used Cox proportional hazards regression to model the associations between CD4 nadir and mortality. We adjusted mortality for loss to-follow-up. RESULTS: Of 22,315 patients, 20,129 patients had greater than 1 year of treatment follow-up. Among these patients, 327 (1.6%) died and 444 (2.2%) were lost to follow-up. After left-censoring at one year, relative to lowest CD4 strata, patients with higher CD4 counts had significantly lower rates of mortality (CD4 150-249, hazard ratio [HR] 0.60, 95% confidence interval [CI]: 0.45-0.82, P = 0.001; 250+, HR 0.66, 95% CI, 0.44-1.00, P = -0.05). Male sex, older age, and duration of time on ART were independently associated with mortality. When left-censoring at 2 years, CD4 nadir was no longer statistically significantly associated with mortality. CONCLUSION: After surviving for 1 year on ART, a CD4 nadir was strongly predictive of longer-term mortality among patients in Uganda. This should argue for efforts to increase engagement with patients to ensure a higher CD4 nadir at initiation of treatment. PMID- 22930646 TI - Cosmic chirality both true and false. AB - The discrete symmetries of parity P, time reversal T, and charge conjugation C may be used to characterize the properties of chiral systems. It is well known that parity violation infiltrates into ordinary matter via an interaction between the nucleons and electrons, mediated by the Z(0) particle, that lifts the degeneracy of the mirror-image enantiomers of a chiral molecule. Being odd under P but even under T, this P-violating interaction exhibits true chirality and so may induce absolute enantioselection under all circumstances. It has been suggested that CP violation may also infiltrate into ordinary matter via a P-odd, T-odd interaction mediated by the (as yet undetected) axion. This CP-violating interaction exhibits false chirality and so may induce absolute enantioselection in processes far from equilibrium. Both true and false cosmic chirality should be considered together as possible sources of homochirality in the molecules of life. PMID- 22930647 TI - Liver repercussions of defective gut surveillance. PMID- 22930648 TI - A world checklist of Onychophora (velvet worms), with notes on nomenclature and status of names. AB - Currently, the number of valid species of Onychophora is uncertain. To facilitate taxonomic work on this understudied animal group, we present an updated checklist for the two extant onychophoran subgroups, Peripatidae and Peripatopsidae, along with an assessment of the status of each species. According to our study, 82 species of Peripatidae and 115 species of Peripatopsidae have been described thus far. However, among these 197 species, 20 are nomina dubia due to major taxonomic inconsistencies. Apart from nomina dubia, many of the valid species also require revision, in particular representatives of Paraperipatus within the Peripatopsidae, and nearly all species of Peripatidae. In addition to extant representatives, the record of unambiguous fossils includes three species with uncertain relationship to the extant taxa. For all species, we provide a list of synonyms, information on types and type localities, as well as remarks on taxonomic and nomenclatural problems and misspellings. According to recent evidence of high endemism and cryptic speciation among the Peripatidae and Peripatopsidae, previous synonyms are revised. Putative mutations, subspecies and variations are either raised to the species status or synonymised with corresponding taxa. In our revised checklist, we follow the rules and recommendations of the International Code of Zoological Nomenclature to clarify previous inconsistencies. PMID- 22930649 TI - A review of the genus Raveniola (Araneae, Nemesiidae) in China, with notes on allied genera and description of four new species from Yunnan. AB - The Chinese representatives of Raveniola Zonstein, 1987 are currently recognized to comprise seven species. Four new species - Raveniola montanasp. n. (??), Raveniola shangrilasp. n. (?), Raveniola songisp. n. (?) and Raveniola yunnanensissp. n. (?) - are described from the highlands of Yunnan Province, China. According to some characters (shape of the palpus, palpal tibia and tibia I in males) they can be placed together with Raveniola hebeinica Zhu, Zhang & Zhang, 1999 and with Raveniola guangxi (Raven & Schwendinger, 1995), comb. n., transferred here from Sinopesa Raven & Schwendinger, 1995. The current generic position of Raveniola xizangensis (Hu & Li, 1987) is confirmed. Other Chinese nemesiids referred previously to Raveniola are transferred to Sinopesa: Sinopesa chinensis (Kulczynski, 1901), comb. n., Sinopesa sinensis (Zhu & Mao, 1983), comb. n. and Sinopesa chengbuensis (Xu & Yun, 2002), comb. n. The relationships between these Asian genera and their relations to Afrotropical nemesiids are discussed. PMID- 22930651 TI - Expression pattern of Boule in dairy goat testis and its function in promoting the meiosis in male germline stem cells (mGSCs). AB - Boule is a conserved gene in meiosis, which encodes RNA binding protein required for spermatocyte meiosis. Deletion of Boule was found to block meiosis in spermatogenesis, which contributes to infertility. Up to date, the expression and function of Boule in the goat testis are not known. The objectives of this study were to investigate the expression pattern of Boule in dairy goat testis and their function in male germline stem cells (mGSCs). The results first revealed that the expression level of Boule in adult testes was significantly higher than younger and immature goats, and azoospermia and male intersex testis. Over expression of Boule promoted the expression of meiosis-related genes in dairy goat mGSCs. The expression of Stra8 was up-regulated by over-expression of Boule analyzed by Western blotting and Luciferase reporter assay. While, Cdc25a, the downstream regulator of Boule, was found not to affect the expression of Stra8, and our data illustrated that Cdc25a did not regulate meiosis via Stra8. The expression of Stra8 and Boule was up-regulated by RA induction. Taken together, results suggest the Boule plays an important role in dairy goat spermatogenesis and that over-expression of Boule may promote spermatogenesis and meiosis in dairy goat. PMID- 22930650 TI - Towards a comprehensive picture of the genetic landscape of complex traits. AB - The formation of phenotypic traits, such as biomass production, tumor volume and viral abundance, undergoes a complex process in which interactions between genes and developmental stimuli take place at each level of biological organization from cells to organisms. Traditional studies emphasize the impact of genes by directly linking DNA-based markers with static phenotypic values. Functional mapping, derived to detect genes that control developmental processes using growth equations, has proven powerful for addressing questions about the roles of genes in development. By treating phenotypic formation as a cohesive system using differential equations, a different approach-systems mapping-dissects the system into interconnected elements and then map genes that determine a web of interactions among these elements, facilitating our understanding of the genetic machineries for phenotypic development. Here, we argue that genetic mapping can play a more important role in studying the genotype-phenotype relationship by filling the gaps in the biochemical and regulatory process from DNA to end-point phenotype. We describe a new framework, named network mapping, to study the genetic architecture of complex traits by integrating the regulatory networks that cause a high-order phenotype. Network mapping makes use of a system of differential equations to quantify the rule by which transcriptional, proteomic and metabolomic components interact with each other to organize into a functional whole. The synthesis of functional mapping, systems mapping and network mapping provides a novel avenue to decipher a comprehensive picture of the genetic landscape of complex phenotypes that underlie economically and biomedically important traits. PMID- 22930652 TI - A doubly axially chiral phosphoric acid catalyst for the asymmetric tandem oxyfluorination of enamides. PMID- 22930653 TI - Laser-driven beam lines for delivering intensity modulated radiation therapy with particle beams. AB - Laser-accelerated particles are a promising option for radiation therapy of cancer by potentially combining a compact, cost-efficient treatment unit with the physical advantages of charged particle beams. To design such a treatment unit we consider different dose delivery schemes and analyze the necessary devices in the required particle beam line for each case. Furthermore, we point out that laser driven treatment units may be ideal tools for motion adaptation during radiotherapy. Reasons for this are the potential of a flexible gantry and the time structure of the beam with high particle numbers in ultrashort bunches. One challenge that needs to be addressed is the secondary radiation produced in several beam line elements. PMID- 22930654 TI - The effect of exercise absence on affect and body dissatisfaction as moderated by obligatory exercise beliefs and eating disordered beliefs and behaviors. AB - AIM: Research suggests that exercise absence is frequently associated with greater guilt and negative affect, particularly when obligatory exercise beliefs and eating disordered psychopathology are considered. Two separate studies used ecological momentary assessment (EMA) to examine differences in mood on exercise and non-exercise days and the moderating impact of obligatory exercise beliefs and eating disordered beliefs and behaviors. METHOD: Both studies recruited female university students who endorsed frequent exercise behavior and study two also recruited based on level of eating disordered psychopathology. Participants completed the Obligatory Exercise Questionnaire at baseline and EMA measures of affect and exercise behavior for approximately one week. Study two participants also completed measures of body dissatisfaction and cognitions. RESULTS: Results of study one suggest that obligation to exercise appears to have a greater impact on general level of affect than does exercise absence or the interaction of these two. In addition, in study two, eating disorder symptomatology was significantly associated with affect and cognition while exercise absence and obligatory exercise beliefs were not. CONCLUSIONS: The present studies suggest that the absence of exercise is not associated with significant changes in affect or cognitions. However, obligation to exercise and eating disorder symptomatology do impact affect and cognitions. PMID- 22930655 TI - Curcumin attenuates testicular damage, apoptotic germ cell death, and oxidative stress in streptozotocin-induced diabetic rats. AB - SCOPE: The present study was designed to examine the protective and antioxidative effects of curcumin (Cur) on streptozotocin (STZ) induced testicular damage, apoptotic germ cell death, and oxidative stress. METHODS AND RESULTS: Diabetes was induced by a single intraperitoneal injection of STZ (50 mg/kg). The rats in the Cur-treated group were given Cur (100 mg/kg) once a day intragastrik for 8 weeks starting 3 days prior to STZ injection. Cur treatment significantly decreased the elevated tissue malondialdehyde levels and increased the reduced superoxide dismutase, and glutathione peroxidase enzyme activities in testis tissues samples. The Cur-treated rats in the diabetic group showed an improved histological appearance and serum testosterone levels. Our data indicate a significant reduction in the activity of in situ identification of apoptosis using terminal dUTP nick end-labeling and there was a rise in the expression of proliferating cell nuclear antigen in testis tissues of Cur-treated rats in the diabetic group. CONCLUSION: These results demonstrate that Cur attenuated testicular damage in diabetic rats by decreasing oxidative stress. PMID- 22930656 TI - The more it is needed, the less it is wanted: attitudes toward face-to-face intervention among depressed patients undergoing online treatment. AB - Many individuals suffering from depression do not actively seek treatment. Self help strategies represent low-threshold treatment options that are particularly relevant for milder cases. The present study addressed two important issues: (1) we examined depressed individuals' motives and attitudes that may represent barriers to face-to-face treatment; (2) we examined if the participation in an online treatment program facilitates or compromises their willingness to undergo face-to-face treatment. We recruited 210 participants with depression for a trial on the efficacy of an online treatment program for depression. Participants were randomly allocated either to a self-help treatment (Deprexis) or to a wait-list control group. All participants filled out a newly developed 42-item questionnaire called Psychotherapy Expectations, Concerns, and Hopes Inventory (PECHI). The scale measures attitudes toward face-to-face treatment and was administered at baseline and 8 weeks later. Principal component analysis of the PECHI revealed five dimensions: hope for symptomatic improvement, fear of poor alliance with the therapist, skill acquisition, skepticism and resentment of psychotherapy, and self-stigma. Attitudes toward treatment were stable over time and neither modulated by group status nor by self-reported or objective symptom decline. Correlation analyses revealed that current levels of depression and well being were potent predictors of attitudes toward treatment, suggesting that when the patient feels more depressed, doubts about the effectiveness of therapy emerge more strongly. To conclude, results suggest that Deprexis neither promotes nor reduces negative attitudes toward psychotherapy, nor does it increase barriers to enter face-to-face treatments. An alarming paradox emerged: when a depressed person is in greatest need of help, motivation to seek face-to-face treatment is lowest. PMID- 22930657 TI - Current perspectives on skeletal health and cancer progression across the disease continuum in breast cancer-the role of bisphosphonates. AB - Pre-clinical and clinical evidence suggest that bisphosphonates inhibit both bone resorption and cancer progression. New and updated analyses from several large, controlled studies in pre- and post-menopausal women with early stage breast cancer (BC) suggest that addition of bisphosphonates improves cancer-related outcomes, particularly in patients with a 'low-estrogen environment'. Further, preliminary clinical data suggest that bisphosphonate therapy may reduce circulating tumour cell numbers (a negative prognostic indicator of disease-free and overall survival) in patients with advanced/metastatic disease. These new findings warrant reconsideration of the therapeutic role of bisphosphonates in BC. PMID- 22930658 TI - Qualitative and semi-quantitative analysis of phenolics in Eucalyptus globulus leaves by high-performance liquid chromatography coupled with diode array detection and electrospray ionisation mass spectrometry. AB - INTRODUCTION: Eucalyptus species are widely cultivated in Mediterranean regions. Moreover, plants of this family have been utilized for medicinal purposes. A number of studies have been devoted to the identification of eucalypt phenolics, all of them have focused on specific families of compounds, and no exhaustive profiling has been reported in leaves of this plant. OBJECTIVE: To develop methods that allows the identification and quantification of different classes of phenolics in Eucalyptus globulus leaf. METHODOLOGY: Acetonic extract was fractionated by chromatography on a Sephadex LH-20 column using consecutive elution with ethanol, methanol and aqueous acetone (60%). High-performance liquid chromatography coupled with diode array detection and electrospray ionization mass spectrometry (HPLC-DAD-ESI/MS) were applied to determine the structure of different compounds. Quantities were evaluated from peak areas in the HPLC profile, using external calibration curves. RESULTS: Fractionation of acetonic extract yielded three fractions: F1, F2 and F3. In total 39 phenolic compounds are detected. Among them: 16 hydrolyzable tannins, 3 terpenyl derivatives, 12 ellagic acid derivatives, 5 flavonols, 2 hydroxybenzoic acids and 1 formylated phloroglucinol. 26 compounds described in this study have not previously detected in leaves of this plant and this is the first report of quercetin 3-O-beta galactoside-6"-O-gallate and cypellogin A and B, in E. globulus plant. Quantitatively, ellagic acid derivatives and sideroxylonal A or B are largely predominant. CONCLUSION: Fractionation of crude extract by chromatography on Sephadex LH-20 was efficient to separate different molecular weight compounds. HPLC-DAD-ESI/MS enabled detection of gallotannin, ellagitannin and flavonol derivatives, in leaves of E. globulus. PMID- 22930659 TI - Proteomic profiling of high glucose primed monocytes identifies cyclophilin A as a potential secretory marker of inflammation in type 2 diabetes. AB - Hyperglycemia is widely recognized to be a potent stimulator of monocyte activity, which is a crucial event in the pathogenesis of atherosclerosis. We analyzed the monocyte proteome for potential markers that would enhance the ability to screen for early inflammatory status in Type 2 diabetes mellitus (T2DM), using proteomic technologies. Monocytic cells (THP-1) were primed with high glucose (HG), their protein profiles were analyzed using 2DE and the downregulated differentially expressed spots were identified using MALDI TOF/MS. We selected five proteins that were secretory in function with the help of bioinformatic programs. A predominantly downregulated protein identified as cyclophilin A (sequence coverage 98%) was further validated by immunoblotting experiments. The cellular mRNA levels of cyclophilin A in various HG-primed cells were studied using qRT-PCR assays and it was observed to decrease in a dose dependent manner. LC-ESI-MS was used to identify this protein in the conditioned media of HG-primed cells and confirmed by Western blotting as well as ELISA. Cyclophilin A was also detected in the plasma of patients with diabetes. We conclude that cyclophilin A is secreted by monocytes in response to HG. Given the paracrine and autocrine actions of cyclophilin A, the secreted immunophilin could be significant for progression of atherosclerosis in type 2 diabetes. Our study also provides evidence that analysis of monocyte secretome is a viable strategy for identifying candidate plasma markers in diabetes. PMID- 22930660 TI - A subset of papillary thyroid carcinomas contain KRAS mutant subpopulations at levels above normal thyroid. AB - The molecular pathogenesis of papillary thyroid carcinoma (PTC) is largely attributed to chromosomal rearrangements and point mutations in genes within the MAPK pathway (i.e., BRAF and RAS). Despite KRAS being the 6th most frequently mutated gene for all cancers, the reported frequency in thyroid cancer is only 2%. This may be due, in part, to the use of insensitive mutation detection methods such as DNA sequencing. Therefore, using the sensitive and quantitative ACB-PCR approach, we quantified KRAS codon 12 GGT -> GAT and GGT -> GTT mutant fraction (MF) in 20 normal thyroid tissues, 17 primary PTC, 2 metastatic PTC, and 1 anaplastic thyroid carcinoma. We observed measurable levels of KRAS codon 12 GAT or GTT mutation in all normal thyroid tissues. For PTCs, 29.4% and 35.3% had KRAS codon 12 GAT and GTT MF above the 95% upper confidence interval for the corresponding MFs in normal thyroid. The highest observed KRAS codon 12 GTT MFs were associated with tumors with follicular characteristics and relatively high levels of tumor necrosis. The results indicate KRAS mutant subpopulations are present in a large number of thyroid tumors, a fact previously unrecognized. The presence of KRAS mutation may indicate a tumor with an aggressive phenotype, thus directing the course of clinical treatment. PMID- 22930661 TI - Model of Abnormal Chromophore-Protein Interaction for E181K Rhodopsin Mutation: Computer Molecular Dynamics Study. AB - The interaction of the 11-cis-retinal chromophore with the surrounding amino acid residues in the chromophore center of the rhodopsin protein has been investigated for the E181K mutant form using molecular dynamics simulation. A comparative analysis of the arrangement of the amino acid residues in the chromophore center has been performed for both wild (native) and mutant rhodopsins. It is shown that for the E181K mutant rhodopsin there is no proper binding of 11-cis-retinal with the surrounding amino acid residues. The distortion of the conformation states in the mutant rhodopsin molecule takes place in both the chromophore center and cytoplasmic domain. Our simulations suggest that a stable covalent linkage of 11 cis-retinal with the protein part (viz. opsin) of the rhodopsin molecule will not form. This, on the other hand, implies that the protein's active site in the cytoplasmic domain, which is responsible for the G-protein binding (so-called transducin), may not be completely blocked.Based on our molecular simulation data, we discuss the possible correlation between retinitis pigmentosa pathogenesis and the structural and functional properties of the rhodopsin protein. PMID- 22930663 TI - LIGHT regulates the adipogenic differentiation of mesenchymal stem cells. AB - LIGHT is a cytokine belonging to the TNF family. This cytokine has been extensively defined in its role on T-cell regulation and dendritic cell maturation. It also exhibits the role in liver regeneration. We recently identified its role in regulation of hematopoietic stem cell differentiation. However, the question whether this cytokine regulates mesenchymal stem cells (MSCs) proliferation and/or differentiation remains unknown. In this study, we observed that MSCs express LT-betaR but not HVEM. PCR analysis show LIGHT mRNA is undectable in MSCs. LIGHT did promote neither MSCs proliferation nor migration. However, LIGHT promoted MSCs differentiation into adipocyte which was confirmed by Oil Red O Staining Assay. Since either MSCs or adipocytes are the major cell population in bone marrow niche, we then suggest that LIGHT regulate bone marrow niche, such as MSCs differentiation. PMID- 22930662 TI - Water Soluble Vitamin E Administration in Wistar Rats with Non-alcoholic Fatty Liver Disease. AB - OBJECTIVE: A diet rich in fat is associated with hepatic fat deposition [steatosis; non-alcoholic fatty liver disease (NAFLD)]. The exact cause of NAFLD however, is still unknown. The aim of this study was to assess the effect of a water-soluble formulation of vitamin E on a dietary-induced-NAFLD animal model. METHODS: Adult male Wistar rats (n=20) were allocated to 2 groups: Controls (Group A, n=6), which received a standard chow diet for 24 weeks and a High Cholesterol group (HC: n=14), which received a standard chow diet enriched with cholesterol for the first 14 weeks of the experiment (t(1)). At t(1), the HC group was divided into: Group HC(B), which received a high-saturated-fat/high cholesterol (HSF/HCH) diet and Group HC(C), which followed the same HSF/HCH diet but was also administered water soluble vitamin E (10 IU/kg body weight/day), for 10 more weeks. RESULTS: At the end of the study, group HC(C) exhibited significantly lower mean total cholesterol (T-CHOL) than group HC(B) (p<0.001). No significant differences were observed between HC(C) and Control groups in blood glucose and serum lipid concentrations. Liver Function Tests did not vary between all groups at the end of the study. Animals in group HC(B) exhibited higher SGOT at the end of the study compared with the beginning of the study (p<0.05). Group HC(B) exhibited the highest scores in steatosis, and grading (according to the NAFLD scoring system) in the histopathological analysis (p<=0.001 in all cases). CONCLUSIONS: Vitamin E seems to exert a hypolipidemic and hepatoprotective role in the presence of a HSF/HCH atherogenic diet in a rat model. PMID- 22930664 TI - Photoswitchable exciton coupling in merocyanine-diarylethene multi-chromophore hydrogen-bonded complexes. PMID- 22930665 TI - Current aspects on oral squamous cell carcinoma. AB - Oral squamous cell carcinoma is the most common malignant epithelial neoplasm affecting the oral cavity. This article overviews the essential points of oral squamous cell carcinoma, highlighting its risk and genomic factors, the potential malignant disorders and the therapeutic approaches. It also emphasizes the importance of the early diagnosis. PMID- 22930666 TI - Applications of ultrasensitive wavelength-modulated differential photothermal radiometry to noninvasive glucose detection in blood serum. AB - Wavelength-Modulated Differential Laser Photothermal Radiometry (WM-DPTR) has been designed for noninvasive glucose measurements in the mid-infrared (MIR) range. Glucose measurements in human blood serum in the physiological range (20 320 mg/dl) with predicted error <10.3 mg/dl demonstrated high sensitivity and accuracy to meet wide clinical detection requirements, ranging from hypoglycemia to hyperglycemia. The glucose sensitivity and specificity of WM-DPTR stem from the subtraction of the simultaneously measured signals from two excitation laser beams at wavelengths near the peak and the baseline of the strongest interference free glucose absorption band in the MIR range. It was found that the serum glucose sensitivity and measurement precision strongly depend on the tunability and stability of the intensity ratio and the phase shift of the two laser beams. This level of accuracy was favorably compared to other MIR techniques. WM-DPTR has shown excellent potential to be developed into a clinically viable noninvasive glucose biosensor. PMID- 22930667 TI - Few adverse reactions to metal on metal articulation in total hip arthroplasty in a review study on 358 consecutive cases with 1 to 5 years follow-up. AB - The aim of the present study was to determine the frequency of adverse reaction to metal on metal total hip arthroplasty using a M2a-38 articulation and a Magnum articulation, (Biomet Warsaw, Indiana).All patients who had received a Metal on Metal bearing prosthesis, in two centres in Copenhagen, were asked to complete a questionnaire about groin pain. Patients with self-reported groin pain, 68/314, underwent a physical examination and had Co and Cr ion levels measured in full blood samples. Fifty patients also had a CT scan performed.The present study found one patient with bilateral arthroplasty, who had an adverse reaction on one side. In addition the study showed that females had higher values of Co and Cr, and that younger patient reported groin pain more often.The conclusion of this study is that the number of adverse reactions is low, despite the time of observation being relatively short, no high frequency of adverse reactions to this prosthesis is expected. PMID- 22930668 TI - Partially overlapping substrate specificities of staphylococcal group A sortases. AB - Sortases catalyze the covalent attachment of proteins with a C-terminal LPxTG motif to the cell walls of Gram-positive bacteria. Here, we show that deletion of the srtA genes of Staphylococcus aureus and Staphylococcus epidermidis resulted in the dislocation of several LPxTG proteins from the cell wall to the growth medium. Nevertheless, proteomics and Western blotting analyses revealed that substantial amounts of the identified proteins remained cell wall bound through noncovalent interactions. The protein dislocation phenotypes of srtA mutants of S. aureus and S. epidermidis were reverted by ectopic expression of srtA genes of either species. Interestingly, S. epidermidis contains a second sortase A, which was previously annotated as ''SrtC.'' Ectopic expression of this SrtC in srtA mutant cells reverted the dislocation of some, but not all, cell wall associated proteins. Similarly, defects in biofilm formation were reverted by ectopic expression of SrtC in some, but not all, tested srtA mutant strains. Finally, overexpression of SrtA resulted in increased levels of biofilm formation in some tested strains. Taken together, these findings show that the substrate specificities of SrtA and SrtC overlap partially, and that sortase levels may be limiting for biofilm formation in some staphylococci. PMID- 22930669 TI - Is 1 Hz rTMS Always Inhibitory in Healthy Individuals? AB - 1 Hz repetitive Transcranial Magnetic Stimulation (rTMS) is considered to have an inhibitory effect in healthy people because it suppresses the excitability of the motor or visual cortex that is expressed as an increase in the motor or the phosphene threshold (PT), respectively. However, the underlying mechanisms and the brain structures involved in the action of rTMS are still unknown. In this study we used two sessions of simultaneous TMS-functional magnetic resonance imaging (fMRI), one before and one after, 15 minutes of 1Hz rTMS to map changes in brain function associated with the reduction in cortical excitability of the primary visual cortex induced by 1 Hz rTMS, when TMS was applied on the occipital area of healthy volunteers. Two groups were evaluated, one group composed of people that can see phosphenes, and another of those lacking this perception. The inhibitory effect, induced by the 1 Hz rTMS, was observed through the increase of the PT, in the first group, but did not lead to a global reduction in brain activation, instead, showed change in the activation pattern before and after rTMS. Conversely, for the second group, changes in brain activation were observed just in few brain areas, suggesting that the effect of 1 Hz rTMS might not be inhibitory for everyone and that the concept of inhibitory/excitatory effect of rTMS may need to be revised. PMID- 22930670 TI - Vertical distribution of microbial communities in a perennially stratified Arctic lake with saline, anoxic bottom waters. AB - Meromictic lakes are useful biogeochemical models because of their stratified chemical gradients and separation of redox reactions down the water column. Perennially ice-covered meromictic lakes are particularly stable, with long term constancy in their density profiles. Here we sampled Lake A, a deep meromictic lake at latitude 83 degrees N in High Arctic Canada. Sampling was before (May) and after (August) an unusual ice-out event during the warm 2008 summer. We determined the bacterial and archaeal community composition by high-throughput 16S rRNA gene tag-pyrosequencing. Both prokaryote communities were stratified by depth and the Bacteria differed between dates, indicating locally driven selection processes. We matched taxa to known taxon-specific biogeochemical functions and found a close correspondence between the depth of functional specialists and chemical gradients. These results indicate a rich microbial diversity despite the extreme location, with pronounced vertical structure in taxonomic and potential functional composition, and with community shifts during ice-out. PMID- 22930671 TI - Quantum navigation and ranking in complex networks. AB - Complex networks are formal frameworks capturing the interdependencies between the elements of large systems and databases. This formalism allows to use network navigation methods to rank the importance that each constituent has on the global organization of the system. A key example is Pagerank navigation which is at the core of the most used search engine of the World Wide Web. Inspired in this classical algorithm, we define a quantum navigation method providing a unique ranking of the elements of a network. We analyze the convergence of quantum navigation to the stationary rank of networks and show that quantumness decreases the number of navigation steps before convergence. In addition, we show that quantum navigation allows to solve degeneracies found in classical ranks. By implementing the quantum algorithm in real networks, we confirm these improvements and show that quantum coherence unveils new hierarchical features about the global organization of complex systems. PMID- 22930673 TI - Photograph-aided assessment of clutter in hoarding disorder: is a picture worth a thousand words? AB - BACKGROUND: Clutter impeding the normal use of living spaces is a landmark feature of hoarding disorder (HD) but can also be present in other conditions. The assessment of clutter ideally requires home visits, although such assessments are sometimes not feasible. This study examined whether photographs from patients' homes can assist in the diagnostic process. METHODS: Thirty-two professionals with experience with hoarding cases were shown pictures from the inside of 10 houses and asked to decide whether the house belonged to a person with HD, a person with obsessive compulsive disorder (OCD), or a healthy collector. Participants also rated different features of the room appearing in each picture (overall amount of possessions, tidiness, functionality, number of different classes of items, and cleanliness). RESULTS: Sensitivity for the HD and collectors' pictures was high, whereas sensitivity for the OCD pictures was substantially lower. Specificity was high for all groups. Rooms belonging to HD individuals were rated as significantly more cluttered, more untidy, less functional, containing a higher number of different classes of items, and being less clean than the rooms from the remaining groups. CONCLUSIONS: Photographs may be used to assist clinicians in determining the presence of clinically significant levels of clutter in the event a home visit is not feasible. Although differential diagnosis will usually not be possible from photographs alone, examination of certain characteristics of the environment might provide useful diagnostic clues. Combined with a thorough psychopathological interview, the use of photographs may increase the clinician's confidence in the diagnosis of HD. PMID- 22930674 TI - Testing multiple variance components in linear mixed-effects models. AB - Testing zero variance components is one of the most challenging problems in the context of linear mixed-effects (LME) models. The usual asymptotic chi-square distribution of the likelihood ratio and score statistics under this null hypothesis is incorrect because the null is on the boundary of the parameter space. During the last two decades many tests have been proposed to overcome this difficulty, but these tests cannot be easily applied for testing multiple variance components, especially for testing a subset of them. We instead introduce a simple test statistic based on the variance least square estimator of variance components. With this comes a permutation procedure to approximate its finite sample distribution. The proposed test covers testing multiple variance components and any subset of them in LME models. Interestingly, our method does not depend on the distribution of the random effects and errors except for their mean and variance. We show, via simulations, that the proposed test has good operating characteristics with respect to Type I error and power. We conclude with an application of our process using real data from a study of the association of hyperglycemia and relative hyperinsulinemia. PMID- 22930672 TI - Control of adaptive immune responses by Staphylococcus aureus through IL-10, PD L1, and TLR2. AB - Microbes induce innate immune responses in hosts. It is critical to know how different microbes control adaptive responses through innate pathways. The impact of gram-positive bacteria on the innate and adaptive responses is unclear. Herein we report that Staphylococcus aureus induces IL-10, Th17-inducing cytokines IL-6 and IL-23, chemokines, and regulates dendritic cell markers. S. aureus inhibits T cell IL-2 responses through modulation of HLA-DR, CD86 and PD-L1. IFN-gamma, Src kinase inhibitors, or TLR2 antibodies prevented the down-modulation of HLA-DR by S. aureus. Our data demonstrate that innate TLR signaling induces multi dimensional inhibition of adaptive immune responses, which may contribute to the lack of protective immunity to bacteria or microbe tolerance. IL-10 and PD-L1 antagonists may boost immunity to vaccines for S. aureus and other microbes. PMID- 22930675 TI - Scarce vaccine supplies in an influenza pandemic should not be distributed randomly: reply to McLachlan. AB - In a recent paper, Hugh McLachlan argues from a deontological perspective that the most ethical means of distributing scarce supplies of an effective vaccine in the context of an influenza pandemic would be via an equal lottery. I argue that, even if one accepts McLachlan's ethical theory, it does not follow that one should accept the vaccine lottery. McLachlan's argument relies upon two suppressed premises which, I maintain, one need not accept; and it misconstrues vaccination programmes as clinical interventions targeted solely at protecting the health of vaccinated individuals, rather than as public health interventions targeted at protecting the health of the population as a whole. PMID- 22930676 TI - Is prostitution harmful? AB - A common argument against prostitution states that selling sex is harmful because it involves selling something deeply personal and emotional. More and more of us, however, believe that sexual encounters need not be deeply personal and emotional in order to be acceptable--we believe in the acceptability of casual sex. In this paper I argue that if casual sex is acceptable, then we have few or no reasons to reject prostitution. I do so by first examining nine influential arguments to the contrary. These arguments purport to pin down the alleged additional harm brought about by prostitution (compared to just casual sex) by appealing to various aspects of its practice, such as its psychology, physiology, economics and social meaning. For each argument I explain why it is unconvincing. I then weight the costs against the benefits of prostitution, and argue that, in sum, prostitution is no more harmful than a long line of occupations that we commonly accept without hesitation. PMID- 22930677 TI - Not robots: children's perspectives on authenticity, moral agency and stimulant drug treatments. AB - In this article, I examine children's reported experiences with stimulant drug treatments for attention deficit hyperactivity disorder in light of bioethical arguments about the potential threats of psychotropic drugs to authenticity and moral agency. Drawing on a study that involved over 150 families in the USA and the UK, I show that children are able to report threats to authenticity, but that the majority of children are not concerned with such threats. On balance, children report that stimulants improve their capacity for moral agency, and they associate this capacity with an ability to meet normative expectations. I argue that although under certain conditions stimulant drug treatment may increase the risk of a threat to authenticity, there are ways to minimise this risk and to maximise the benefits of stimulant drug treatment. Medical professionals in particular should help children to flourish with stimulant drug treatments, in good and in bad conditions. PMID- 22930678 TI - Abortion and regret. AB - The article considers three theses about postabortion regret which seek to illustrate its pertinence to reasoning about abortion, and which are often deployed, either explicitly or implicitly, to dissuade women out of that reproductive choice. The first is that postabortion regret renders an abortion morally unjustified. The second is that that a relatively high incidence of postabortion regret-compared with a lower incidence of postnatal regret in the relevant comparator field-is good evidence for the moral impermissibility of abortion choice. The third is that high rates of postabortion regret suggest that abortion is not the most prudent or welfare-maximising choice for the woman concerned. All three theses argue for the compellingness of knowledge about postabortion regret in moral and practical reasoning about abortion, especially from the pregnant woman's point of view. This article argues that all three theses are flawed. In particular, it seeks to remind readers that feelings of regret directed at past decisions are often decoupled from the fact of the matter about their moral or rational justification. Moreover, certain features of reproductive decisions in particular make regret an especially unsuitable yardstick for actual justification in this context, and even less epistemically reliable as evidence for a lack of justification than it may be in other fields of decision-making. The implication is that rates of postabortion regret, even if they can be presumed to be higher than rates of postnatal regret, are not as pertinent to moral and practical reasoning about abortion as is sometimes suggested. PMID- 22930679 TI - Elements of human dignity in healthcare settings: the importance of the patient's perspective. PMID- 22930680 TI - Editorial note on 'abortion and regret'. PMID- 22930681 TI - Comparison of aqueous concentrations of angiogenic and inflammatory cytokines in diabetic macular oedema and macular oedema due to branch retinal vein occlusion. AB - AIMS: The involvement of cytokines in the aqueous humour is important in the development and progression of diabetic macular oedema (DMO) and macular oedema (MO) due to branch retinal vein occlusion (BRVO-MO). In this study, the concentrations of cytokines in the aqueous humour of eyes with DMO and BRVO-MO were measured and compared. METHODS: Prospective, observational case series. Aqueous samples were obtained from 18 eyes with DMO (DMO group), 12 eyes with BRVO-MO (BRVO-MO group), and 16 normal eyes (control group). The aqueous levels of cytokines, including interleukin (IL)-2, IL-5, IL-6, IL-8, IL-12p70, IL-13, monocytochemotactic protein-1 (MCP-1), macrophage inflammatory protein-1alpha (MIP-1alpha), platelet-derived growth factor-AA (PDGF)-AA, transforming growth factor-alpha (TGF-alpha), interferon-gamma (IFN-gamma), epidermal growth factor, fibroblast growth factor 2 (FGF2) and vascular endothelial growth factor (VEGF), were measured. RESULTS: The aqueous levels of IL-8, MCP-1, PDGF-AA and VEGF were higher, and IL-13 was lower in the DMO group compared with the control group. The aqueous levels of IL-8 and VEGF were higher in the BRVO-MO group than in the control group. Compared with the IL-6 and MCP-1 levels in the BRVO-MO group, those levels were significantly higher in the DMO group. Correlation analyses revealed that IL-8 was positively and IFN-gamma was negatively correlated with the severity of MO in the DMO group. In the BRVO-MO group, IL-8 and was positively correlated with severity of MO and retinal ischaemia. CONCLUSIONS: DMO and BRVO-MO may differ in terms of pathogenesis because the cytokine concentrations in the aqueous humour differ. The results suggest that the inflammatory reaction may be more activated in DMO than in BRVO-MO, and ischaemic insult may play a central role in the development of BRVO-MO. PMID- 22930683 TI - The Tour de France: an updated physiological review. AB - From its initial inception in 1903 as a race premised on a publicity stunt to sell newspapers, the Tour de France had grown and evolved over time to become one of the most difficult and heralded sporting events in the world. Though sporting science and the Tour paralleled each other, it was not until the midlate 1980s, and especially the midlate 1990s (with the use of heart-rate monitors) that the 2 began to unify and grow together. The purpose of this brief review is to summarize what is currently known of the physiological demands of the Tour de France, as well as of the main physiological profile of Tour de France competitors. PMID- 22930682 TI - Variations in the nature of behavioral experience can differentially alter the consequences of developmental exposures to lead, prenatal stress, and the combination. AB - Behavioral experience (BE) can critically influence later behavior and brain function, but the central nervous system (CNS) consequences of most developmental neurotoxicants are examined in the absence of any such context. We previously demonstrated marked differences in neurotransmitter changes produced by developmental lead (Pb) exposure +/- prenatal stress (PS) depending upon whether or not rats had been given BE (Cory-Slechta, D. A., Virgolini, M. B., Rossi George, A., Weston, D., and Thiruchelvam, M. (2009). The current study examined the hypothesis that the nature of the BE itself would be a critical determinant of outcome in mice that had been continually exposed to 0 or 100 ppm Pb acetate in drinking water alone or in combination with prenatal restraint stress. Half of the offspring in each of the four resulting groups/gender were exposed to positively reinforced (food-rewarded Fixed Interval schedule-controlled behavior) or negatively reinforced (inescapable forced swim) BE. Brain monoamines and amino acids differed significantly in relation to BE, even in control animals, as did the trajectory of effects of Pb +/- PS, particularly in frontal cortex, hippocampus (both genders), and midbrain (males). In males, Pb +/- PS-related changes in neurotransmitters correlated with behavioral performance. These findings suggest that CNS consequences of developmental toxicants studied in the absence of a broader spectrum of BEs may not necessarily be predictive of human outcomes. Evaluating the role of specific BEs as a modulator of neurodevelopmental insults offers the opportunity to determine what specific BEs may ameliorate the associated impacts and can assist in establishing underlying neurobiological mechanisms. PMID- 22930689 TI - Comparison of the 45-second/15-second intermittent running field test and the continuous treadmill test. AB - PURPOSES: To compare the physiological responses and maximal aerobic running velocity (MAV) during an incremental intermittent (45-s run/15-s rest) field test (45-15FIT) vs an incremental continuous treadmill test (TR) and to demonstrate that the MAV obtained during 45-15FIT (MAV45-15) was relevant to elicit a high percentage of maximal oxygen uptake (VO2max) during a 30-s/30-s intermittent training session. METHODS: Oxygen uptake (VO2), heart rate (HR), and lactate concentration ([La]) were measured in 20 subjects during 2 maximal incremental tests and four 15-min intermittent tests. The time spent above 90% and 95% VO2max (t90% and t95% VO2max, respectively) was determined. RESULTS: Maximal physiological parameters were similar during the 45-15FIT and TR tests (VO2max 58.6+/-5.9 mL.kg(-1).min(-1) for TR vs 58.5+/-7.0 mL.kg(-1).min(-1) for 45-15FIT; HRmax 200+/-8 beats/min for TR vs 201+/-7 beats/min for 45-15FIT). MAV45-15 was significantly (P<.001) greater than MAVTR (17.7+/-1.1 vs 15.6+/-1.4 km/h). t90% and t95% VO2max during the 30-s/30-s performed at MAVTR were significantly (P<.01) lower than during the 30-s/30-s performed at MAV45-15. Similar VO2 during intermittent tests performed at MAV45-15 and at MAVTR can be obtained by reducing the recovery time or using active recovery. CONCLUSIONS: The results suggested that the 45-15FIT is an accurate field test to determine VO2max and that MAV45-15 can be used during high-intensity intermittent training such as 30-s runs interspersed with 30-s rests (30-s/30-s) to elicit a high percentage of VO2max. PMID- 22930690 TI - Repeated-sprint ability: where are we? AB - Repeated-sprint ability (RSA) is now well accepted as an important fitness component in team-sport performance. It is broadly described as the ability to perform repeated short (~3-4 s, 20-30 m) sprints with only brief (~10-30 s) recovery between bouts. Over the past 25 y a plethora of RSA tests have been trialed and reported in the literature. These range from a single set of ~6-10 short sprints, departing every 20-30 s, to team-sport game simulations involving repeating cycles of walk-jog-stride-sprint movements over 45-90 min. Such a wide range of RSA tests has not assisted the synthesis of research findings in this area, and questions remain regarding the optimal methods of training to best improve RSA. In addition, how RSA test scores relate to player "work rate," match performance, or both requires further investigation to improve the application of RSA testing and training to elite team-sport athletes. PMID- 22930691 TI - Overexpression of the DMP1 C-terminal fragment stimulates FGF23 and exacerbates the hypophosphatemic rickets phenotype in Hyp mice. AB - Dentin matrix protein-1 (DMP1) or phosphate-regulating gene with homologies to endopeptidases on the X chromosome (PHEX) inactivation results in elevation of the phosphaturic hormone fibroblast growth factor (FGF)-23, leading to hypophosphatemia, aberrant vitamin D metabolism, and rickets/osteomalacia. Compound mutant Phex-deficient Hyp and Dmp1(ko) mice exhibit nonadditive phenotypes, suggesting that DMP1 and PHEX may have interdependent effects to regulate FGF23 and bone mineralization. To determine the relative importance of DMP1 and PHEX in regulating FGF23 and mineralization, we tested whether the transgenic expression of full-length [Dmp1(Tg(full-length))] or C-terminal Dmp1 [Dmp1(Tg(57kDa))] could rescue the phenotype of Hyp mice. We found that Dmp1(ko) and Hyp mice have similar phenotypes characterized by decreased cortical bone mineral density (-35% vs. wild type, P < 0.05) and increased serum FGF23 levels (~12-fold vs. wild type, P < 0.05). This was significantly corrected by the overexpression of either the full-length or the C-terminal transgene in Dmp1(ko) mice. However, neither of the transgenes rescued the Hyp mice phenotype. Hyp/Dmp1(Tg(full-length)) and Hyp mice were similar, but Hyp/Dmp1(Tg(57 kDa)) mice exhibited worsening of osteomalacia (-20% cortical bone mineral density) in association with increased serum FGF23 levels (+2-fold) compared with Hyp mice. Bone FGF23 mRNA expression was decreased and a 2-fold increase in the ratio of the full-length/degraded circulating FGF23 was observed, indicating that degradation of FGF23 was impaired in Hyp/Dmp1(Tg(57 kDa)) mice. The paradoxical effects of the C-terminal Dmp1 transgene were observed in Hyp/Dmp1(Tg(57 kDa)) but not in Dmp1(Tg(57 kDa)) mice expressing a functional PHEX. These findings indicate a functional interaction between PHEX and DMP1 to regulate bone mineralization and circulating FGF23 levels and for the first time demonstrate effects of the C-terminal DMP1 to regulate FGF23 degradation. PMID- 22930694 TI - Effects of Olympic-style taekwondo kicks on an instrumented head-form and resultant injury measures. AB - OBJECTIVE: The objective of this study was to assess the effect of taekwondo kicks and peak foot velocity (FVEL) on resultant head linear acceleration (RLA), head injury criterion (HIC15) and head velocity (HVEL). METHODS: Each subject (n=12) randomly performed five repetitions of the turning kick (TK), clench axe kick (CA), front leg axe kick, jump back kick (JB) and jump spinning hook kick (JH) at the average standing head height for competitors in their weight division. A Hybrid II Crash Test Dummy head was fitted with a protective taekwondo helmet and instrumented with a triaxial accelerometer and fixed to a height-adjustable frame. Resultant head linear acceleration, HVEL, FVEL data were captured and processed using Qualysis Track Manager. RESULTS: The TK (130.11 +/- 51.67 g) produced a higher RLA than the CA (54.95 +/- 20.08 g, p<0.001, d=1.84) and a higher HIC15 than the JH (672.74 +/- 540.89 vs 300.19 +/- 144.35, p<0.001, ES=0.97). There was no difference in HVEL of the TK (4.73 +/- 1.67 m/s) and that of the JB (4.43 +/- 0.78 m/s; p=0.977, ES<0.01). CONCLUSIONS: The TK is of concern because it is the most common technique and cause of concussion in taekwondo. Future studies should aim to understand rotational accelerations of the head. PMID- 22930692 TI - Minireview: applications of next-generation sequencing on studies of nuclear receptor regulation and function. AB - Next-generation sequencing technologies have expanded the experimental possibilities for studying the genome-wide regulation of transcription by nuclear receptors, their collaborating transcription factors, and coregulators. These technologies allow investigators to obtain abundance and DNA sequence information in a single experiment. In this review, we highlight proven and potential uses of next-generation sequencing in the study of gene regulation by nuclear receptors. We also provide suggestions on how to effectively leverage this technology in a collaborative environment. PMID- 22930695 TI - Topical glyceryl trinitrate treatment of chronic patellar tendinopathy: a randomised, double-blind, placebo-controlled clinical trial. AB - OBJECTIVES: To assess if continuous topical glyceryl trinitrate (GTN) treatment improves outcome in patients with chronic patellar tendinopathy when compared with eccentric training alone. METHODS: Randomised double-blind, placebo controlled clinical trial comparing a 12-week programme of using a GTN or placebo patch in combination with eccentric squats on a decline board. Measurements were performed at baseline, 6, 12 and 24 weeks. Primary outcome measure was the Victorian Institute of Sports Assessment-Patella (VISA-P) questionnaire. Secondary outcome measures were patient satisfaction and pain scores during sports. Generalised estimated equation was used to analyse the treatment, time and treatment*time effect. Analyses were performed following the intention-to treat principle. RESULTS: VISA-P scores for both groups improved over the study period to 75.0+/-16.2 and 80.7+/-22.1 at 24 weeks. Results showed a significant effect for time (p<0.01) but no effect for treatment*time (p=0.80). Mean Visual Analogue Scores pain scores during sports for both groups increased over the study period to 6.6+/-3 and 7.8+/-3.1. Results showed a significant effect for time (p<0.01) but no effect for treatment*time (p=0.38). Patient satisfaction showed no difference between GTN and placebo groups (p=0.25) after 24 weeks, but did show a significant difference over time (p=0.01). Three patients in the GTN group reported some rash. CONCLUSION: It seems that continuous topical GTN treatment in addition to an eccentric exercise programme does not improve clinical outcome compared to placebo patches and an eccentric exercise programme in patients with chronic patellar tendinopathy. PMID- 22930697 TI - Contribution of brain imaging to the understanding of gait disorders in Alzheimer's disease: a systematic review. AB - Although gait disorders are common in Alzheimer's disease (AD), determining which brain structures and related lesions are specifically involved is a goal yet to be reached. Our objective was to systematically review all published data that examined associations between gait disorders and brain imaging in AD. Of 486 selected studies, 4 observational studies met the selection criteria. The number of participants ranged from 2 to 61 community dwellers (29%-100% female) with prodromal or dementia-stage AD. Quantitative gait disorders (ie, slower gait velocity explained by shorter stride length) were associated with white matter lesions, mainly in the medial frontal lobes and basal ganglia. The nigrostriatal dopamine system was unaffected. Qualitative gait disorders (ie, higher stride length variability) correlated with lower hippocampal volume and function. Gait disorders in AD could be explained by a high burden of age-related subcortical hyperintensities on the frontal-subcortical circuits (nonspecific) together with hippocampal atrophy and hypometabolism (specific). PMID- 22930698 TI - The effects of evacuation on nursing home residents with dementia. AB - BACKGROUND: In response to the hurricane-related deaths of nursing home residents, there has been a steady increase in the number of facilities that evacuate under storm threat. This study examined the effects of evacuation during Hurricane Gustav on residents who were cognitively impaired. METHODS: Nursing homes in counties located in the path of Hurricane Gustav were identified. The Minimum Data Set resident assessment files were merged with the Centers for Medicare enrollment file to determine date of death for residents in identified facilities. Difference-in-differences analyses were conducted adjusting for residents' demographic characteristics and acuity. RESULTS: The dataset included 21,255 residents living in 119 at risk nursing homes over three years of observation. Relative to the two years before the storm, there was a 2.8 percent increase in death at 30 days and a 3.9 percent increase in death at 90 days for residents with severe dementia who evacuated for Hurricane Gustav, controlling for resident demographics and acuity. CONCLUSIONS: The findings of this research reveal the deleterious effects of evacuation on residents with severe dementia. Interventions need to be developed and tested to determine the best methods for protecting this at risk population when there are no other options than to evacuate the facility. PMID- 22930699 TI - Subgroup analysis of US and non-US patients in a global study of high-dose donepezil (23 mg) in moderate and severe Alzheimer's disease. AB - To better understand responses in the large number of US-based patients included in a global trial of donepezil 23 mg/d versus 10 mg/d for moderate-to-severe Alzheimer's disease (AD), post hoc exploratory analyses were performed to assess the efficacy and safety in US and non-US (rest of the world [RoW]) patient subgroups. In both subgroups, donepezil 23 mg/d was associated with significantly greater cognitive benefits than donepezil 10 mg/d. Significant global function benefits of donepezil 23 mg/d over 10 mg/d were also observed in the US subgroup only. Compared with RoW patients, US patients had relatively more severe AD, had been treated with donepezil 10 mg/d for longer periods prior to the start of the study, and a higher proportion took concomitant memantine. In both subgroups, donepezil had acceptable tolerability; overall incidence of treatment-emergent adverse events was higher in patients receiving donepezil 23 mg/d compared with donepezil 10 mg/d. PMID- 22930700 TI - Stage-specific gender differences in cognitive and neuropsychiatric manifestations of vascular dementia. AB - Studies on gender differences in the clinical manifestations of vascular dementia (VaD) are still lacking. In the present study, gender comparisons of cognitive and neuropsychiatric profiles were conducted separately for mild and moderate-to severe VaD in a total of 467 patients with VaD. There were no significant gender differences in cognitive manifestations, except that females performed better on immediate verbal recall than males in mild stage. Women were more likely to exhibit delusions (15.5% vs 7.4%), hallucinations (9.5% vs 3.4%), and depression (43.1% vs 27.3%) in mild stage. The predominance of male patients was observed in apathy at moderate-to-severe stage (50.5% vs 34.8%). To conclude, gender differences existed in neuropsychiatric symptoms of VaD and were especially pronounced in mild stage. Delusions, hallucinations, and depression were more prevalent in females in mild VaD, with the male predominance only in apathy in the later stage. PMID- 22930702 TI - Impact of missing data on phylogenies inferred from empirical phylogenomic data sets. AB - Progress in sequencing technology allows researchers to assemble ever-larger supermatrices for phylogenomic inference. However, current phylogenomic studies often rest on patchy data sets, with some having 80% missing (or ambiguous) data or more. Though early simulations had suggested that missing data per se do not harm phylogenetic inference when using sufficiently large data sets, Lemmon et al. (Lemmon AR, Brown JM, Stanger-Hall K, Lemmon EM. 2009. The effect of ambiguous data on phylogenetic estimates obtained by maximum likelihood and Bayesian inference. Syst Biol. 58:130-145.) have recently cast doubt on this consensus in a study based on the introduction of parsimony-uninformative incomplete characters. In this work, we empirically reassess the issue of missing data in phylogenomics while exploring possible interactions with the model of sequence evolution. First, we note that parsimony-uninformative incomplete characters are actually informative in a probabilistic framework. A reanalysis of Lemmon's data set with this in mind gives a very different interpretation of their results and shows that some of their conclusions may be unfounded. Second, we investigate the effect of the progressive introduction of missing data in a complete supermatrix (126 genes * 39 species) capable of resolving animal relationships. These analyses demonstrate that missing data perturb phylogenetic inference slightly beyond the expected decrease in resolving power. In particular, they exacerbate systematic errors by reducing the number of species effectively available for the detection of multiple substitutions. Consequently, large sparse supermatrices are more sensitive to phylogenetic artifacts than smaller but less incomplete data sets, which argue for experimental designs aimed at collecting a modest number (~50) of highly covered genes. Our results further confirm that including incomplete yet short-branch taxa (i.e., slowly evolving species or close outgroups) can help to eschew artifacts, as predicted by simulations. Finally, it appears that selecting an adequate model of sequence evolution (e.g., the site-heterogeneous CAT model instead of the site-homogeneous WAG model) is more beneficial to phylogenetic accuracy than reducing the level of missing data. PMID- 22930704 TI - Rising litigation does not mean falling standards. PMID- 22930705 TI - Lower circumcision rates mean higher health costs, US study says. PMID- 22930703 TI - Effect of systemic steroids on post-tonsillectomy bleeding and reinterventions: systematic review and meta-analysis of randomised controlled trials. AB - OBJECTIVE: To evaluate the risk of postoperative bleeding and reintervention with the use of systemic steroids in patients undergoing tonsillectomy. DESIGN: Systematic review and meta-analysis of randomised controlled trials. DATA SOURCES: Medline, Embase, Cochrane Library, Scopus, Web of Science, Intute, Biosis, OpenSIGLE, National Technical Information Service, and Google Scholar were searched. References from reviews identified in the search and from included studies were scanned. REVIEW METHODS: Randomised controlled trials comparing the administration of systemic steroids during tonsillectomy with any other comparator were eligible. Primary outcome was postoperative bleeding. Secondary outcomes were the rate of admission for a bleeding episode, reintervention for a bleeding episode, blood transfusion, and mortality. RESULTS: Of 1387 citations identified, 29 randomised controlled trials (n=2674) met all eligibility criteria. Seven studies presented a low risk of bias, but none was specifically designed to systematically identify postoperative bleeding. Administration of systemic steroids did not significantly increase the incidence of post tonsillectomy bleeding (29 studies, n=2674 patients, odds ratio 0.96 (95% confidence interval 0.66 to 1.40), I²=0%). We observed a significant increase in the incidence of operative reinterventions for bleeding episodes in patients who received systemic steroids (12, n=1178, 2.27 (1.03 to 4.99), I²=0%). No deaths were reported. Sensitivity analyses were consistent with the findings. CONCLUSIONS: Although systemic steroids do not appear to increase bleeding events after tonsillectomy, their use is associated with a raised incidence of operative reinterventions for bleeding episodes, which may be related to increased severity of bleeding events. Systemic steroids should be used with caution, and the risks and benefits weighed, for the prevention of postoperative nausea and vomiting after tonsillectomy before further research is performed to clarify their condition of use. PMID- 22930706 TI - Implementing the patient-centered medical home model for chronic disease care in small medical practices: practice group characteristics and physician understanding. AB - Strengthening primary care may improve health outcomes and restrain spending. The patient-centered medical home (PCMH) model is endorsed as a tool to achieve this. Early evaluations in large group practices demonstrate improvements in some health outcomes. Evidence is lacking from small medical practices that deliver the majority of primary health care. This was a national survey of 200 physicians that explored perceptions of PCMH. There was considerable interest in adoption of the model; however, providing PCMH care was seen as an extension of traditional roles that requires additional reimbursement. No differentiation was made among a variety of payment models to do this. All joint principle components of the model were identified as important: extending access and information technology were the most contentious. There was consensus that PCMH might improve the quality of primary care; however, tension between wider societal benefits and rising costs for individual practices was a challenge to implementation. PMID- 22930707 TI - Delivering influenza vaccine to high-risk adults: subspecialty physician practices. AB - Influenza is responsible for significant morbidity and mortality in the United States. Despite long-standing national recommendations, only 47% of adults with a high-risk condition received the influenza vaccine in 2009-2010. Subspecialty practices provide a significant portion of ambulatory care visits for high-risk adults and understanding their role in the immunization infrastructure may increase immunization rates, decrease public health burden, and reduce influenza associated disease. A cross-sectional survey of cardiology, pulmonology, and obstetrics/gynecology practices was conducted to assess influenza vaccination practices, plans, patient acceptance, frustrations, and reasons for not vaccinating. It was found that 51% of respondents planned to vaccinate patients. Plans differed significantly by practice type. Practices that do not vaccinate generally recommend vaccination and refer patients to public health clinics, primary care, and pharmacies. Administrative and patient-related barriers affected most practices, but practices that vaccinate were able to overcome these barriers. Improvements in vaccination may be addressed by adapting practice support services for subspecialty practices. PMID- 22930708 TI - The ERCP quality network: a pilot study of benchmarking practice and performance. AB - There is increasing interest in the quality of endoscopic practice and in documenting it. Endoscopic retrograde cholangiopancreatography (ERCP) is the most complex and risky procedure performed regularly by gastroenterologists. The goal was to test the acceptability and functioning of a voluntary system for individual endoscopists to report details of their ERCP cases and to compare them with unidentified peers. Participants were compared by site of practice, procedure complexity, volumes, durations, and selected technical success rates. There was no independent audit. A total of 63 endoscopists in the United States entered data on 18 182 procedures over 3 years. Results in academic and community practices were similar, but there were significant and expected differences in the complexity of practice and key quality metrics between endoscopists performing more than and fewer than 100 cases per year. The study provided useful data on variations in ERCP practice in the United States and will assist in planning the development of national projects in this field. PMID- 22930709 TI - Chronic caffeine intake in adult rat inhibits carotid body sensitization produced by chronic sustained hypoxia but maintains intact chemoreflex output. AB - Sustained hypoxia produces a carotid body (CB) sensitization, known as acclimatization, which leads to an increase in carotid sinus nerve (CSN) activity and ensuing hyperventilation greater than expected from the prevailing partial pressure of oxygen. Whether sustained hypoxia is physiological (high altitude) or pathological (lung disease), acclimatization has a homeostatic implication because it tends to minimize hypoxia. Caffeine, the most commonly ingested psychoactive drug and a nonselective adenosine receptor antagonist, alters CB function and ventilatory responses when administered acutely. Our aim was to investigate the effect of chronic caffeine intake on CB function and acclimatization using four groups of rats: normoxic, caffeine-treated normoxic, chronically hypoxic (12% O2, 15 days), and caffeine-treated chronically hypoxic rats. Caffeine was administered in drinking water (1 mg/ml). Caffeine ameliorated ventilatory responses to acute hypoxia in normoxic animals without altering the output of the CB (CSN neural activity). Caffeine-treated chronically hypoxic rats exhibited a decrease in the CSN response to acute hypoxia tests but maintained ventilation compared with chronically hypoxic animals. The findings related to CSN neural activity combined with the ventilatory responses indicate that caffeine alters central integration of the CB input to increase the gain of the chemoreflex and that caffeine abolishes CB acclimatization. The putative mechanisms involved in sensitization and its loss were investigated: expression of adenosine receptors in CB (A(2B)) was down-regulated and that in petrosal ganglion (A(2A)) was up-regulated in caffeine-treated chronically hypoxic rats; both adenosine and dopamine release from CB chemoreceptor cells was increased in chronic hypoxia and in caffeine-treated chronic hypoxia groups. PMID- 22930710 TI - Small molecule allosteric modulation of the glucagon-like Peptide-1 receptor enhances the insulinotropic effect of oxyntomodulin. AB - Identifying novel mechanisms to enhance glucagon-like peptide-1 (GLP-1) receptor signaling may enable nascent medicinal chemistry strategies with the aim of developing new orally available therapeutic agents for the treatment of type 2 diabetes mellitus. Therefore, we tested the hypothesis that selectively modulating the low-affinity GLP-1 receptor agonist, oxyntomodulin, would improve the insulin secretory properties of this naturally occurring hormone to provide a rationale for pursuing an unexplored therapeutic approach. Signal transduction and competition binding studies were used to investigate oxyntomodulin activity on the GLP-1 receptor in the presence of the small molecule GLP-1 receptor modulator, 4-(3-benzyloxyphenyl)-2-ethylsulfinyl-6-(trifluoromethyl)pyrimidine (BETP). In vivo, the intravenous glucose tolerance test characterized oxyntomodulin-induced insulin secretion in animals administered the small molecule. BETP increased oxyntomodulin binding affinity for the GLP-1 receptor and enhanced oxyntomodulin-mediated GLP-1 receptor signaling as measured by activation of the alpha subunit of heterotrimeric G protein and cAMP accumulation. In addition, oxyntomodulin-induced insulin secretion was enhanced in the presence of the compound. BETP was pharmacologically characterized to induce biased signaling by oxyntomodulin. These studies demonstrate that small molecules targeting the GLP-1 receptor can increase binding and receptor activation of the endogenous peptide oxyntomodulin. The biased signaling engendered by BETP suggests that GLP-1 receptor mobilization of cAMP is the critical insulinotropic signaling event. Because of the unique metabolic properties of oxyntomodulin, identifying molecules that enhance its activity should be pursued to assess the efficacy and safety of this novel mechanism. PMID- 22930711 TI - Identification of structural motifs critical for epstein-barr virus-induced molecule 2 function and homology modeling of the ligand docking site. AB - Epstein-Barr virus-induced molecule 2 (EBI2) (also known as G-protein-coupled receptor 183) is a G-protein-coupled receptor (GPCR) that is best known for its role in B cell migration and localization. Our recent deorphanization effort led to the discovery of 7alpha,25-dihydroxycholesterol (7alpha,25-OHC) as the endogenous ligand for EBI2, which provides a tool for mechanistic studies of EBI2 function. Because EBI2 is the first GPCR known to bind and to be activated by an oxysterol, the goal of this study was to understand the molecular and structural bases for its ligand-dependent activation; this was achieved by identifying structural moieties in EBI2 or in 7alpha,25-OHC that might affect receptor-ligand interactions. By using a series of chemically related OHC analogs, we demonstrated that all three hydroxyl groups in 7alpha,25-OHC contributed to ligand-induced activation of the receptor. To determine the location and composition of the ligand binding domain in EBI2, we used a site-directed mutagenesis approach and generated mutant receptors with single amino acid substitutions at selected positions of interest. Biochemical and pharmacological profiling of these mutant receptors allowed for structure-function analyses and revealed critical motifs that likely interact with 7alpha,25-OHC. By using a hybrid beta(2)-adrenergic receptor-C-X-C chemokine receptor type 4 structure as a template, we created a homology model for EBI2 and optimized the docking of 7alpha,25-OHC into the putative ligand binding site, so that the hydroxyl groups interact with residues Arg87, Asn114, and Glu183. This model of ligand docking yields important structural insight into the molecular mechanisms mediating EBI2 function and may facilitate future efforts to design novel therapeutic agents that target EBI2. PMID- 22930712 TI - German ethics council backs religious circumcision if specific conditions met. PMID- 22930713 TI - Outbreaks among travellers linked to almost twofold rise in measles cases. PMID- 22930714 TI - Court case adjourned after diagnosis of persistent vegetative state changes. PMID- 22930715 TI - Anorexic woman cannot be force fed, judge rules. PMID- 22930716 TI - Trusts required to show they are providing NICE approved treatments. PMID- 22930717 TI - 2012 EHRA/HRS expert consensus statement on cardiac resynchronization therapy in heart failure: implant and follow-up recommendations and management. PMID- 22930718 TI - Approach to cardiac resyncronization therapy. AB - AIMS: The purpose of this EP Wire is to compare indications, techniques, implant strategy, and follow-up regarding cardiac resynchronization therapy (CRT) in several countries across Europe. METHODS AND RESULTS: Forty-one centres, members of the EHRA-EP Research Network, responded to this survey and completed the questions. Thirty-two per cent of the responding centres always use CRT in heart failure (HF) patients with New York Heart Association functional class II and QRS width >120 ms, and 55% of the responding centres demand additional criteria when indicating CRT, most often QRS width >150 ms (49%) and echocardiographic criteria of asynchrony (34%). Only 10% of centres indicate CRT in all HF patients with QRS >120 ms and right bundle branch block, and 51% demand additional criteria, most frequently echocardiographic asynchrony parameters. The vast majority of centres also indicate CRT in patients with atrial fibrillation and standard criteria for CRT. In 24% of the centres, biventricular pacemaker (CRT-P) is implanted in all situations, unless there is an indication for secondary prevention of sudden cardiac death, while 10% always choose to implant a biventricular defibrillator (CRT-D). There are no clear evidence-based recommendations concerning the implant procedure and follow-up in patients treated with CRT; therefore, the chosen strategies vary widely from one centre to another. CONCLUSION: This EP Wire survey shows a wide variation not only as far as CRT indications are concerned, but especially in techniques, implant strategy, and follow-up across the European countries. PMID- 22930719 TI - Do lipids retard the evaporation of the tear fluid? AB - PURPOSE: We examined in vitro the potential evaporation-retarding effect of the tear film lipid layer (TFLL). The artificial TFLL compositions used here were based on the present knowledge of TFLL composition. METHODS: A custom-built system was developed to measure evaporation rates at 35 degrees C. Lipids were applied to an air-water interface, and the evaporation rate through the lipid layer was defined as water loss from the interface. A thick layer of olive oil and a monolayer of long-chain alcohol were used as controls. The artificial TFLLs were composed of 1 to 4 lipid species: polar phosphatidylcholine (PC), nonpolar cholesteryl ester, triglycerides, and wax ester (WE). Brewster angle microscopy (BAM) and interfacial shear rheometry (ISR) were used to assess the lateral structure and shear stress response of the lipid layers, respectively. RESULTS: Olive oil and long-chain alcohol decreased evaporation by 54% and 45%, respectively. The PC monolayer and the four-component mixtures did not retard evaporation. WE was the most important evaporation-retardant TFLL lipid (~20% decrease). In PC/WE mixtures, an ~90% proportion of WE was required for evaporation retardation. Based on BAM and ISR, WE resulted in more condensed layers than the non-retardant layers. CONCLUSIONS: Highly condensed, solid-like lipid layers, such as those containing high proportions of WEs, are evaporation retardant. In multi-component lipid layers, the evaporation-retardant interactions between carbon chains decrease and, therefore, these lipid layers do not retard evaporation. PMID- 22930720 TI - Cytokines and chemokines in the vitreous fluid of eyes with uveal melanoma. AB - PURPOSE: In uveal melanoma, both tumor size and an inflammatory phenotype have been shown to correlate with a poor clinical prognosis. The purpose of this study was to identify whether inflammatory cytokines were present in the vitreous of eyes with uveal melanoma and to determine whether the vitreal concentration of cytokines correlated with prognostic variables such as tumor dimensions and immune cell infiltrate. METHODS: Vitreous was acquired from patients with uveal melanoma (n = 33) and from control eyes with no known ocular conditions (n = 9), and analyzed using a 27-plex cytokine bead array. Immunofluorescence testing was performed to determine the presence of macrophages, CD4(+), CD8(+), and Foxp3(+) regulatory T cells (T(regs)). RESULTS: Compared with control eyes, eyes with uveal melanoma demonstrated higher vitreal concentrations of many cytokines and chemokines, including IL-6, IL-8, IP-10, MCP-1, MIP-1alpha, MIP-1beta, TNF-alpha, and RANTES. IL-1ra was decreased in the vitreous of tumor-bearing eyes compared with controls. Tumor prominence positively correlated with several cytokines, including IL-6, IL-8, IP-10, MCP-1, MIP-1alpha, MIP-1beta, TNF-alpha, RANTES, GCSF, IFN-gamma, and VEGF. IL-6 and IP-10 were found to positively correlate with increasing regulatory T-cell infiltrate and IL-6 alone positively correlated with macrophage infiltration. CONCLUSIONS: Eyes with uveal melanoma contain higher vitreal concentrations of several inflammatory cytokines and chemokines that correlate predominantly with increasing tumor size; elevations in certain cytokines and chemokines also correlate with the presence of immune cell infiltrate. PMID- 22930721 TI - Association of genetic variants on 8p21 and 4q12 with age-related macular degeneration in Asian populations. AB - PURPOSE: To evaluate the association of genetic variants at chromosomes 8p21 and 4q12 with the risk of developing AMD and its two main subtypes, choroidal neovascular membrane (CNV) and polypoidal choroidal vasculopathy (PCV), in Asian populations. METHODS: The study population comprised 2360 patients with neovascular AMD (1013 typical AMD-CNV and 1282 PCV), and 3598 controls from four independent cohorts, two of Japanese (n = 4859) and two of Chinese (n = 1099) ethnicity. We performed a meta-analysis in case-control studies of two reported single nucleotide polymorphisms (SNPs) (rs13278062 at TNFRSF10A-LOC389641 on 8p21 and rs1713985 at REST-C4orf14-POLR2B-IGFBP7 on 4q12) by using logistic regression analysis adjusted for age and sex. Subgroup analysis by CNV and PCV subtypes were performed to evaluate the significance of these two variants. RESULTS: The reported association between rs13278062 at 8p21 and neovascular AMD was replicated in this population (P = 1.12 * 10(-4), odds ratio [OR] = 0.79, 95% confidence interval [CI] = 0.70-0.89). However, there was no association of rs1713985 at 4q12 with neovascular AMD, or its two subtypes, typical AMD-CNV and PCV (all P > 0.05). The study sample size had a statistical power of greater than 99% to detect an association of a risk allele with AMD with an OR of 1.30, as reported in the original study of rs1713985 and AMD. CONCLUSIONS: The present results did not replicate the reported association between rs1713985 at 4q12 and neovascular AMD. However, we confirmed the association between rs13278062 at 8p21 and neovascular AMD in Asian populations. PMID- 22930722 TI - Activation of the alternative complement pathway in vitreous is controlled by genetics in age-related macular degeneration. AB - PURPOSE: To determine if the progression of age-related macular degeneration (AMD) is associated with complement activation in the eye. METHODS: Immunohistochemistry and ELISAs were used to determine the distribution, concentration, and activation of the alternative pathway complement proteases factor B (FB) and factor D (FD) and the central complement protein C3 in genotyped human postmortem donor eyes graded as having no or minimal drusen (category 1; controls), large drusen (category 3), and large drusen with advanced AMD (category 4). RESULTS: C3, FB, and FD were present in vitreous and Bruch's membrane choroid (BM/C) interface of the macula of eyes in all tested AMD severity categories (n = 100). C3, FB, and FD were predominantly located to the choroidal vasculature and Bruch's membrane and, together with the serum proteins transferrin and albumin, elevated in BM/C extracts of category 4 eyes (n = 23) compared with category 1 eyes (n = 24). A significant increase in FB activation was found only in vitreous of category 4 eyes (n = 23) compared with category 1 eyes (n = 25). Genetic variants of complement factor H (CFH), C3, C2, and FB associated with increased risk of AMD were correlated with alternative pathway complement activation in vitreous, but not with complement proteins in BM/C protein extracts. CONCLUSIONS: Increased activation of the alternative complement pathway in vitreous was controlled by disease stage and genetic variation in the complement pathway, supporting a role for complement activation in AMD disease pathogenesis. PMID- 22930723 TI - eNOS overexpression exacerbates vascular closure in the obliterative phase of OIR and increases angiogenic drive in the subsequent proliferative stage. AB - PURPOSE: In ischemic retinopathies, the misdirection of reparative angiogenesis away from the hypoxic retina leads to pathologic neovascularization. Thus, therapeutic strategies that reverse this trend would be extremely beneficial. Nitric oxide (NO) produced by endothelial nitric oxide synthase (eNOS) is an important mediator of vascular endothelial growth factor (VEGF) function facilitating vascular growth and maturation. However, in addition to NO, eNOS can also produce superoxide (O(2)(-)), exacerbating pathology. Here, our aim was to investigate the effect of eNOS overexpression on vascular closure and subsequent recovery of the ischemic retina. METHODS: Mice overexpressing eNOS-GFP were subjected to oxygen-induced retinopathy (OIR) and changes in retinal vascularization quantified. Background angiogenic drive was assessed during vascular development and in aortic rings. NOS activity was measured by Griess assay or conversion of radiolabeled arginine to citrulline, nitrotyrosine (NT), and superoxide by immunolabeling and dihydroethidium fluorescence and VEGF by ELISA. RESULTS: In response to hyperoxia, enhanced eNOS expression led to increased NOS-derived superoxide and dysfunctional NO production, NT accumulation, and exacerbated vessel closure associated with tetrahydrobiopterin (BH4) insufficiency. Despite worse vaso-obliteration, eNOS overexpression resulted in elevated hypoxia-induced angiogenic drive, independent of VEGF production. This correlated with increased vascular branching similar to that observed in isolated aortas and during development. Enhanced recovery was also associated with neovascular tuft formation, which showed defective NO production and increased eNOS-derived superoxide and NT levels. CONCLUSIONS: In hyperoxia, reduced BH4 bioavailability causes overexpressed eNOS to become dysfunctional, exacerbating vaso-obliteration. In the proliferative phase, however, eNOS has important prorepair functions enhancing angiogenic growth potential and recovery in ischemia. PMID- 22930724 TI - Stimulus-specific pupil dynamics measured in birds (Gallus gallus domesticus) in vivo with ultrahigh resolution optical coherence tomography. AB - PURPOSE: To demonstrate the ability of high speed, ultrahigh-resolution optical coherence tomography (UHR-OCT) to measure and characterize in vivo visual stimulus-specific pupil dynamics in birds. METHODS: Ten two-week old White Leghorn (Gallus gallus domesticus) chickens were imaged in this study. The chickens were dark-adapted for 1 hour and anesthetized with 2% isoflurane prior to the imaging procedure. Blue, green, and red single flash visual stimuli of 7 ms duration were used to evoke pupillary responses. UHR-OCT cross-sectional images of the pupil were acquired prior, during, and for several seconds after the visual stimuli onset. Images were processed with a novel custom automatic algorithm, designed to determine the pupil diameter changes over time. RESULTS: Results from this study show that the pupillary constriction begins with the onset of the visual stimuli; however, maximum pupil constriction occurs ~150 ms later. No statistically significant variation in the timing of the maximum pupillary constriction was observed for stimuli of different colors. However, significant variation was observed in the maximum pupil constriction amplitudes, between red-green and red-blue stimuli, but not between blue-green stimuli. Furthermore, the magnitude of the maximum pupil constriction decreased monotonically with time under isoflurane anesthesia. CONCLUSIONS: We demonstrated, for the first time, measurements of visually evoked pupillary dynamics in animals using high speed UHR-OCT. The results suggest dependence of the pupillary dynamics on the color of the visual stimulus, and adverse effects of isoflurane anesthesia on the visually evoked pupillary responses in chickens. PMID- 22930725 TI - Visual search with image modification in age-related macular degeneration. AB - PURPOSE: AMD results in loss of central vision and a dependence on low-resolution peripheral vision. While many image enhancement techniques have been proposed, there is a lack of quantitative comparison of the effectiveness of enhancement. We developed a natural visual search task that uses patients' eye movements as a quantitative and functional measure of the efficacy of image modification. METHODS: Eye movements of 17 patients (mean age = 77 years) with AMD were recorded while they searched for target objects in natural images. Eight different image modification methods were implemented and included manipulations of local image or edge contrast, color, and crowding. In a subsequent task, patients ranked their preference of the image modifications. RESULTS: Within individual participants, there was no significant difference in search duration or accuracy across eight different image manipulations. When data were collapsed across all image modifications, a multivariate model identified six significant predictors for normalized search duration including scotoma size and acuity, as well as interactions among scotoma size, age, acuity, and contrast (P < 0.05). Additionally, an analysis of image statistics showed no correlation with search performance across all image modifications. Rank ordering of enhancement methods based on participants' preference revealed a trend that participants preferred the least modified images (P < 0.05). CONCLUSIONS: There was no quantitative effect of image modification on search performance. A better understanding of low and high-level components of visual search in natural scenes is necessary to improve future attempts at image enhancement for low vision patients. Different search tasks may require alternative image modifications to improve patient functioning and performance. PMID- 22930726 TI - In vivo analysis of vectors involved in pupil constriction in Chinese subjects with angle closure. AB - PURPOSE: To evaluate the acceleration of pupil constriction (APC) in response to illumination using video anterior segment optical coherence tomography (AS-OCT) in angle closure and normal eyes. METHODS: This was an observational study of 342 Chinese subjects. Iris and angle changes in response to illumination were captured with real-time video recordings of AS-OCT and analyzed frame by frame. APC was calculated using a quadratic function, fitting pupil diameter to a time series. APC was divided into two vector components: acceleration of pupil block (APB) acting perpendicular to the lens surface and acceleration of iris stretch (AIS) acting toward the iris root. RESULTS: Of 342 eligible patients, 306 (89.5%) were available for analysis; of whom 136 (41.7%) had angle closure. After adjusting for age, sex, baseline pupil diameter, and iris thickness, APC was significantly lower in angle closure eyes (0.61 mm/s(2)) than in open-angle eyes (0.90 mm/s(2)) (P < 0.0001) as was AIS (0.58 mm/s(2) vs. 0.89 mm/s(2)) (P < 0.001). APB was significantly higher in angle closure eyes compared to open-angle eyes (0.14 mm/s(2) vs. 0.09 mm/s(2)) (P < 0.001). After adjusting for age and sex in logistic regression, the magnitude and direction of all vector parameters were significantly associated with presence of angle closure. CONCLUSIONS: Angle closure eyes have smaller AIS and larger APB in response to illumination as measured using AS-OCT videography. This shows that, comparatively, the iris of angle closure eyes stretches less and develops a more convex configuration in response to illumination. PMID- 22930727 TI - Involvement of periostin in regression of hyaloidvascular system during ocular development. AB - PURPOSE: A timely regression of the hyaloid vascular system (HVS) is required for the normal ocular development. Although macrophages have a critical role in this process, the exact mechanism remains undetermined. Periostin is a matricellular protein involved in tissue and vascular remodeling. The purpose of our study was to determine whether periostin is involved in the HVS regression. METHODS: We used wild type (WT) and periostin knockout (KO) mice. Indocyanine green angiography and immunohistochemistry with isolectin B4 were used to evaluate the HVS regression. TUNEL-labeling was used to quantify the number of apoptotic hyaloid vascular endothelial cells. F4/80 and Iba-1 staining was performed to determine the number and location of macrophages in the vitreous. The location of periostin also was investigated by immunohistochemistry. To determine the functional role of periostin, the degree of adhesion of human monocytes to fibronectin was measured by an adhesion assay. RESULTS: The HVS regression and peak in the number of TUNEL-positive apoptotic endothelial cells were delayed in periostin KO mice. The number of F4/80 positive cells in the vitreous was higher in periostin KO mice. Only a small number of Iba-1-positive cells near the hyaloid vessels was co-stained with periostin, and peripheral blood monocytes were not stained with periostin. Adhesion assay showed that periostin increased the degree of attachment of monocytes to fibronectin. CONCLUSIONS: These results suggest that periostin, which is secreted by the intraocular macrophages, enhances the HVS regression by intensifying the adhesion of macrophages to hyaloid vessels. PMID- 22930729 TI - Genome-wide DNA methylation events in TMPRSS2-ERG fusion-negative prostate cancers implicate an EZH2-dependent mechanism with miR-26a hypermethylation. AB - Prostate cancer is the second most common cancer among men worldwide. Alterations in the DNA methylation pattern can be one of the leading causes for prostate cancer formation. This study is the first high-throughput sequencing study investigating genome-wide DNA methylation patterns in a large cohort of 51 tumor and 53 benign prostate samples using methylated DNA immunoprecipitation sequencing. Comparative analyses identified more than 147,000 cancer-associated epigenetic alterations. In addition, global methylation patterns show significant differences based on the TMPRSS2-ERG rearrangement status. We propose the hypermethylation of miR-26a as an alternative pathway of ERG rearrangement independent EZH2 activation. The observed increase in differential methylation events in fusion-negative tumors can explain the tumorigenic process in the absence of genomic rearrangements. SIGNIFICANCE: In contrast to TMPRSS2-ERG rearranged tumors, the pathomechanism for gene fusion-negative tumors is completely unclear. Using a sequencing-based approach, our work uncovers significant global epigenetic alterations in TMPRSS2-ERG gene fusion-negative tumors and provides a mechanistic explanation for the tumor formation process. PMID- 22930728 TI - Thrombospondin-1 (TSP1)-null and TSP2-null mice exhibit lower intraocular pressures. AB - PURPOSE: Thrombospondin-1 (TSP1) and TSP2 are matricellular proteins that have been shown to regulate cytoskeleton, cell adhesion, and extracellular matrix remodeling. Both TSP1 and TSP2 are found in the trabecular meshwork (TM). In cadaver eyes with primary open-angle glaucoma (POAG), TSP1 is increased in one third of patients. We hypothesized that TSP1 and TSP2 participate in the regulation of intraocular pressure (IOP). Methods. IOPs of TSP1-null, TSP2-null mice, and their corresponding wild-type (WT) mice were measured using a commercial rebound tonometer. Fluorophotometric measurements assessed aqueous turnover. Central corneal thickness (CCT) was measured by optical coherence tomography. Iridocorneal angles were examined using light microscopy (LM), immunofluorescence (IF), and transmission electron microscopy (TEM). RESULTS: Average IOPs of TSP1-null and TSP2-null mice were 10% and 7% less than that of the corresponding WT mice, respectively. CCTs were 6.5% less in TSP1-null mice (P < 0.05) and 1.1% less in TSP2-null mice (P > 0.05). Fluorophotometric measurements suggest that aqueous turnover rates in TSP1-null and TSP2-null mice are greater than those of WT mice. LM of the TSP1-null and TSP2-null iridocorneal angles reveals morphology, which is indistinguishable from that of their corresponding WTs. IF revealed possible concurrent underexpression of TSP2 in TSP1-null mice and of TSP1 in TSP2-null mice. TEM revealed larger collagen fibril diameters in TSP1-null and TSP2-null mice compared with WTs. CONCLUSIONS: TSP1 null and TSP2-null mice have lower IOPs than their WT counterparts. The rate of aqueous turnover suggests that the mechanism is enhanced outflow facility. An alteration in the extracellular matrix may contribute to this finding. PMID- 22930730 TI - Targeting the EWSR1-FLI1 oncogene-induced protein kinase PKC-beta abolishes ewing sarcoma growth. AB - Ewing sarcoma is a rare but aggressive disease most common in young adults. This cancer is driven by a unique chimeric fusion oncogene but targeted strategies have been elusive. Here we report the identification of the protein kinase PKC beta (PRKCB) as a disease-specific druggable target for treatment of Ewing sarcoma. We found that transcriptional activation of PRKCB was directly regulated by the chimeric fusion oncogene EWSR1-FLI1 that drives this cancer. PRKCB phosphorylated histone H3T6 to permit global maintenance of H3K4 trimethylation at a variety of gene promoters. PRKCB loss induced apoptosis in vitro and prevented tumor growth in vivo. Gene expression profiling revealed a strong overlap between genes modulated by EWSR1-FLI1 and PRKCB in regulating crucial signaling pathways. Taken together, our findings offer a preclinical proof-of concept for PRKCB as a promising therapeutic target in Ewing sarcoma. PMID- 22930732 TI - The Medicago truncatula sucrose transporter family: characterization and implication of key members in carbon partitioning towards arbuscular mycorrhizal fungi. AB - We identified de novo sucrose transporter (SUT) genes involved in long-distance transport of sucrose from photosynthetic source leaves towards sink organs in the model leguminous species Medicago truncatula. The identification and functional analysis of sugar transporters provide key information on mechanisms that underlie carbon partitioning in plant-microorganism interactions. In that way, full-length sequences of the M. truncatula SUT (MtSUT) family were retrieved and biochemical characterization of MtSUT members was performed by heterologous expression in yeast. The MtSUT family now comprises six genes which distribute among Dicotyledonous clades. MtSUT1-1 and MtSUT4-1 are key members in regard to their expression profiles in source leaves and sink roots and were characterized as functional H(+)/sucrose transporters. Physiological and molecular responses to phosphorus supply and inoculation by the arbuscular mycorrhizal fungus (AMF) Glomus intraradices was studied by gene expression and sugar quantification analyses. Sucrose represents the main sugar transport form in M. truncatula and the expression profiles of MtSUT1-1, MtSUT2, and MtSUT4-1 highlight a fine-tuning regulation for beneficial sugar fluxes towards the fungal symbiont. Taken together, these results suggest distinct functions for proteins from the SUT1, SUT2, and SUT4 clades in plant and in biotrophic interactions. PMID- 22930731 TI - A LIM domain protein from tobacco involved in actin-bundling and histone gene transcription. AB - The two LIM domain-containing proteins from plants (LIMs) typically exhibit a dual cytoplasmic-nuclear distribution, suggesting that, in addition to their previously described roles in actin cytoskeleton organization, they participate in nuclear processes. Using a south-western blot-based screen aimed at identifying factors that bind to plant histone gene promoters, we isolated a positive clone containing the tobacco LIM protein WLIM2 (NtWLIM2) cDNA. Using both green fluorescent protein (GFP) fusion- and immunology-based strategies, we provide clear evidence that NtWLIM2 localizes to the actin cytoskeleton, the nucleus, and the nucleolus. Interestingly, the disruption of the actin cytoskeleton by latrunculin B significantly increases NtWLIM2 nuclear fraction, pinpointing a possible novel cytoskeletal-nuclear crosstalk. Biochemical and electron microscopy experiments reveal the ability of NtWLIM2 to directly bind to actin filaments and to crosslink the latter into thick actin bundles. Electrophoretic mobility shift assays show that NtWLIM2 specifically binds to the conserved octameric cis-elements (Oct) of the Arabidopsis histone H4A748 gene promoter and that this binding largely relies on both LIM domains. Importantly, reporter-based experiments conducted in Arabidopsis and tobacco protoplasts confirm the ability of NtWLIM2 to bind to and activate the H4A748 gene promoter in live cells. Expression studies indicate the constitutive presence of NtWLIM2 mRNA and NtWLIM2 protein during tobacco BY-2 cell proliferation and cell cycle progression, suggesting a role of NtWLIM2 in the activation of basal histone gene expression. Interestingly, both live cell and in vitro data support NtWLIM2 di/oligomerization. We propose that NtWLIM2 functions as an actin-stabilizing protein, which, upon cytoskeleton remodeling, shuttles to the nucleus in order to modify gene expression. PMID- 22930733 TI - New insights into nested long terminal repeat retrotransposons in Brassica species. AB - Long terminal repeat (LTR) retrotransposons, one of the foremost types of transposons, continually change or modify gene function and reorganize the genome through bursts of dramatic proliferation. Many LTR-TEs preferentially insert within other LTR-TEs, but the cause and evolutionary significance of these nested LTR-TEs are not well understood. In this study, a total of 1.52Gb of Brassica sequence containing 2020 bacterial artificial chromosomes (BACs) was scanned, and six bacterial artificial chromosome (BAC) clones with extremely nested LTR-TEs (LTR-TEs density: 7.24/kb) were selected for further analysis. The majority of the LTR-TEs in four of the six BACs were found to be derived from the rapid proliferation of retrotransposons originating within the BAC regions, with only a few LTR-TEs originating from the proliferation and insertion of retrotransposons from outside the BAC regions approximately 5-23Mya. LTR-TEs also preferably inserted into TA-rich repeat regions. Gene prediction by Genescan identified 207 genes in the 0.84Mb of total BAC sequences. Only a few genes (3/207) could be matched to the Brassica expressed sequence tag (EST) database, indicating that most genes were inactive after retrotransposon insertion. Five of the six BACs were putatively centromeric. Hence, nested LTR-TEs in centromere regions are rapidly duplicated, repeatedly inserted, and act to suppress activity of genes and to reshuffle the structure of the centromeric sequences. Our results suggest that LTR-TEs burst and proliferate on a local scale to create nested LTR-TE regions, and that these nested LTR-TEs play a role in the formation of centromeres. PMID- 22930734 TI - Activated expression of WRKY57 confers drought tolerance in Arabidopsis. AB - Drought is one of the most serious environmental factors that limit the productivity of agricultural crops worldwide. However, the mechanism underlying drought tolerance in plants is unclear. WRKY transcription factors are known to function in adaptation to abiotic stresses. By screening a pool of WRKY associated T-DNA insertion mutants, we isolated a gain-of-function mutant, acquired drought tolerance (adt), showing improved drought tolerance. Under drought stress conditions, adt accumulated higher levels of ABA than wild-type plants. Stomatal aperture analysis indicated that adt was more sensitive to ABA than wild-type plants. Molecular genetic analysis revealed that a T-DNA insertion in adt led to activated expression of a WRKY gene that encodes the WRKR57 protein. Constitutive expression of WRKY57 also conferred similar drought tolerance. Consistently with the high ABA content and enhanced drought tolerance, three stress-responsive genes (RD29A, NCED3, and ABA3) were up-regulated in adt. ChIP assays demonstrated that WRKY57 can directly bind the W-box of RD29A and NCED3 promoter sequences. In addition, during ABA treatment, seed germination and early seedling growth of adt were inhibited, whereas, under high osmotic conditions, adt showed a higher seed germination frequency. In summary, our results suggested that the activated expression of WRKY57 improved drought tolerance of Arabidopsis by elevation of ABA levels. Establishment of the functions of WRKY57 will enable improvement of plant drought tolerance through gene manipulation approaches. PMID- 22930735 TI - Contribution of genomics to gene discovery in plant abiotic stress responses. PMID- 22930736 TI - CLE and RGF family peptide hormone signaling in plant development. PMID- 22930737 TI - Effects of magnetic stray fields from a 7 tesla MRI scanner on neurocognition: a double-blind randomised crossover study. AB - OBJECTIVE: This study characterises neurocognitive domains that are affected by movement-induced time-varying magnetic fields (TVMF) within a static magnetic stray field (SMF) of a 7 Tesla (T) MRI scanner. METHODS: Using a double-blind randomised crossover design, 31 healthy volunteers were tested in a sham (0 T), low (0.5 T) and high (1.0 T) SMF exposure condition. Standardised head movements were made before every neurocognitive task to induce TVMF. RESULTS: Of the six tested neurocognitive domains, we demonstrated that attention and concentration were negatively affected when exposed to TVMF within an SMF (varying from 5.0% to 21.1% per Tesla exposure, p<0.05), particular in situations were high working memory performance was required. In addition, visuospatial orientation was affected after exposure (46.7% per Tesla exposure, p=0.05). CONCLUSION: Neurocognitive functioning is modulated when exposed to movement-induced TVMF within an SMF of a 7 T MRI scanner. Domains that were affected include attention/concentration and visuospatial orientation. Further studies are needed to better understand the mechanisms and possible practical safety and health implications of these acute neurocognitive effects. PMID- 22930740 TI - Work-related factors and early retirement intention: a study of the Danish eldercare sector. AB - BACKGROUND: Western countries are experiencing an ageing and shrinking workforce in the eldercare sector. This study investigated whether 12 different work related factors are associated with early retirement intentions of employees in the Danish eldercare sector. We tested whether three hypotheses explained the increase of early retirement intention: (i) high job demands (four factors) and low resources (four factors); (ii) low job attitude (three factors); and (iii) high physical strain (one factor). METHODS: We included 2444 employees (aged 45 57 years) from two waves (T1 and T2) from a prospective study. Multinomial logistic regression models showed whether 12 work-related factors (T1) were associated with early retirement intention (T2); very early retirement intention and early retirement intention vs. normal retirement intention. RESULTS: Only 14% of the participants wished to retire at the normal retirement age (65 years or older). High physical strain [hypothesis (iii)] and low and normal affective organizational commitment [hypothesis (ii)] were associated with very early retirement intention. None of the other work-related factors associated with early retirement intention. CONCLUSIONS: Future interventions should focus on reducing physical strain and increase or maintain affective organizational commitment among employees in the eldercare sector to postpone retirement. PMID- 22930738 TI - Genomic analysis of sleep deprivation reveals translational regulation in the hippocampus. AB - Sleep deprivation is a common problem of considerable health and economic impact in today's society. Sleep loss is associated with deleterious effects on cognitive functions such as memory and has a high comorbidity with many neurodegenerative and neuropsychiatric disorders. Therefore, it is crucial to understand the molecular basis of the effect of sleep deprivation in the brain. In this study, we combined genome-wide and traditional molecular biological approaches to determine the cellular and molecular impacts of sleep deprivation in the mouse hippocampus, a brain area crucial for many forms of memory. Microarray analysis examining the effects of 5 h of sleep deprivation on gene expression in the mouse hippocampus found 533 genes with altered expression. Bioinformatic analysis revealed that a prominent effect of sleep deprivation was to downregulate translation, potentially mediated through components of the insulin signaling pathway such as the mammalian target of rapamycin (mTOR), a key regulator of protein synthesis. Consistent with this analysis, sleep deprivation reduced levels of total and phosphorylated mTOR, and levels returned to baseline after 2.5 h of recovery sleep. Our findings represent the first genome-wide analysis of the effects of sleep deprivation on the mouse hippocampus, and they suggest that the detrimental effects of sleep deprivation may be mediated by reductions in protein synthesis via downregulation of mTOR. Because protein synthesis and mTOR activation are required for long-term memory formation, our study improves our understanding of the molecular mechanisms underlying the memory impairments induced by sleep deprivation. PMID- 22930739 TI - Quantitative proteomic analysis reveals novel mitochondrial targets of estrogen deficiency in the aged female rat heart. AB - The incidence of myocardial infarction rises sharply at menopause, implicating a potential role for estrogen (E(2)) loss in age-related increases in ischemic injury. We aimed to identify quantitative changes to the cardiac mitochondrial proteome of aging females, based on the hypothesis that E(2) deficiency exacerbates age-dependent disruptions in mitochondrial proteins. Mitochondria isolated from left ventricles of adult (6 mo) and aged (24 mo) F344 ovary-intact or ovariectomized (OVX) rats were labeled with 8plex isobaric tags for relative and absolute quantification (iTRAQ; n = 5-6/group). Groups studied were adult, adult OVX, aged, and aged OVX. In vivo coronary artery ligation and in vitro mitochondrial respiration studies were also performed in a subset of rats. We identified 965 proteins across groups and significant directional changes in 67 proteins of aged and/or aged OVX; 32 proteins were unique to aged OVX. Notably, only six proteins were similarly altered in adult OVX (voltage-dependent ion channel 1, adenine nucleotide translocator 1, cytochrome c oxidase subunits VIIc and VIc, catalase, and myosin binding protein C). Proteins affected by aging were primarily related to cellular metabolism, oxidative stress, and cell death. The largest change occurred in monoamine oxidase-A (MAO-A), a source of oxidative stress. While acute MAO-A inhibition induced mild uncoupling in aged mitochondria, reductions in infarct size were not observed. Age-dependent alterations in mitochondrial signaling indicate a highly selective myocardial response to E(2) deficiency. The combined proteomic and functional approaches described here offer possibility of new protein targets for experimentation and therapeutic intervention in the aged female population. PMID- 22930741 TI - Hearing loss and risk of early retirement. The HUNT study. AB - BACKGROUND: We explore the possible consequences of measured hearing impairment (HI) and perceived hearing difficulties for early retirement in a large population-based study. Furthermore, we study whether having a part-time position was associated with measured HI and perceived hearing difficulties in the same population. METHODS: This study included 25,740 persons from the Nord-Trondelag Health Study (HUNT) aged 20-54 years at baseline in HUNT1 (1984-1986) who also participated in the follow up, HUNT2, including a hearing examination 11 years later. Logistic regression analysis was conducted for men and women separately and in two age strata. Effects of low-, middle- and high-frequency hearing levels were explored, adjusting for each other. Further adjustment was made for socio economic class and general health in HUNT1. RESULTS: The risk of early retirement increased with degree of loss of low-frequency hearing in young and middle-aged men and middle-aged women. The middle-aged men and women experiencing hearing disability had an increased risk of early retirement. Degree of hearing level was not associated with part-time work, but in middle-aged men, awareness of having a hearing loss was associated with part-time employment. CONCLUSIONS: Degree of low frequency hearing loss was associated with early retirement but not with part time work. Perceived hearing disability increased the risk of early retirement in middle-aged men and women and also the risk of part-time work in middle-aged men. PMID- 22930742 TI - Peer victimization and subjective health among students reporting disability or chronic illness in 11 Western countries. AB - BACKGROUND: To compare the strength of the association between peer victimization at school and subjective health according to the disability or chronic illness (D/CI) status of students across countries. METHODS: This study used data from 55 030 students aged 11, 13 and 15 years from 11 countries participating in the 2005 06 Health Behaviour in School-aged Children survey. Self-completed questionnaires were administered in classrooms. Multivariate models of logistic regression (controlled for confounding factors and countries) were used to investigate differences in the association between peer victimization and poor subjective health according to the D/CI status. RESULTS: Overall, 13.5% of the students reported having been bullied at least two or three times a month. The percentage of victims was significantly higher among those reporting D/CI than among others in all countries studied. Victims of bullying were more likely to report poor self-rated health, low life satisfaction and multiple health complaints. However, there were no differences in the associations between peer victimization and subjective health indicators according to the D/CI status. CONCLUSIONS: In all countries studied, students reporting D/CI were more likely to report being victims of bullying. Victims of bullying reported more negative subjective health outcomes regardless of their D/CI status. Although inclusive education is currently a major topic of educational policies in most countries, additional efforts should be made to improve the quality of the integration of students with D/CI. PMID- 22930743 TI - Health impact assessment in Europe--current dilemmas and challenges. PMID- 22930744 TI - Psychosocial factors in GP work: the effects of taking a GP position or leaving GP work. AB - BACKGROUND: We examined the effects of leaving public sector general practitioner (GP) work and of taking a GP position on changes in work-related psychosocial factors, such as time pressure, patient-related stress, distress and work interference with family. In addition, we examined whether changes in time pressure and patient-related stress mediated the association of employment change with changes of distress and work interference with family. METHODS: Participants were 1705 Finnish physicians (60% women) who responded to surveys in 2006 and 2010. Analyses of covariance were conducted to examine the effect of employment change to outcome changes adjusted for gender, age and response format. Mediational effects were tested following the procedures outlined by Baron and Kenny. RESULTS: Employment change was significantly associated with all the outcomes. Leaving public sector GP work was associated with substantially decreased time pressure, patient-related stress, distress and work interference with family. In contrast, taking a position as a public sector GP was associated with an increase in these factors. Mediation tests suggested that the associations of employment change with distress change and work interference with family change were partially explained by the changes in time pressure and patient-related stress. CONCLUSIONS: Our results showed that leaving public sector GP work is associated with favourable outcomes, whereas taking a GP position in the public sector is associated with adverse effects. Primary health care organizations should pay more attention to the working conditions of their GPs, in particular, to time pressure and patient-related stress. PMID- 22930745 TI - Unemployment at a young age and later sickness absence, disability pension and death in native Swedes and immigrants. AB - BACKGROUND: Youth unemployment is an increasing problem for societies around the world. Research has revealed negative health effects of unemployment, and this longitudinal register-based cohort study examined the relationship between unemployment and later sickness absence, disability pension and death among youth in Sweden. METHOD: The study group of 199,623 individuals comprised all immigrants born between 1968 and 1972 who immigrated before 1990 (25,607) and a random sample of native Swedes in the same age-range (174,016). The baseline year was 1992, and the follow-up period was from 1993 to 2007. Subjects with unemployment benefit in 1990-91, disability pension in 1990-92, severe disorders leading to hospitalization in 1990-92 and subjects who emigrated during follow-up were excluded. RESULTS: Those who were unemployed in 1992 had elevated risk of >=60 days of sickness absence (OR 1.02-1.49), disability pension (HR 1.08-1.62) and all except native Swedish women had elevated risk of death (HR 1.01-1.65) during follow-up compared with non-unemployed individuals. The risk of future sickness absence increased with the length of unemployment in 1992 (OR 1.06 1.54), and the risk of sickness absence increased over time. A larger part of the immigrant cohort was unemployed at baseline than native Swedes. Selection to unemployment by less healthy subjects may explain part of the association between unemployment and the studied outcomes. CONCLUSION: Unemployment at an early age may influence the future health of the individual. To a society it may lead to increased burdens on the welfare system and productivity loss for many years. PMID- 22930746 TI - Which health data for Europe? PMID- 22930747 TI - Genome-wide methylation screen in low-grade breast cancer identifies novel epigenetically altered genes as potential biomarkers for tumor diagnosis. AB - Aberrant DNA methylation constitutes a well-established epigenetic marker for breast cancer. Changes in methylation early in cancer development may be clinically relevant for cancer detection and prognosis-based therapeutic decisions. In the present study, a combination of methyl-CpG immunoprecipitation (MCIp) and human CpG island (CGI) arrays was applied to compare genome-wide DNA methylation profiles in 10 low-grade in situ and invasive breast cancers against 10 normal breast samples. In total, 214 CGIs were found to be hypermethylated in >=6 of 10 tumors. Functional term enrichment analyses revealed an overrepresentation of homeobox genes and genes involved in transcription and regulation of transcription. Significant hypermethylation of 11 selected genes in tumor vs. normal tissue was validated in two independent sample sets (45 tumors and 11 controls, 43 tumors and 8 controls) using quantitative EpiTyper technology. In tumors, median methylation levels of BCAN, HOXD1, KCTD8, KLF11, NXPH1, POU4F1, SIM1, and TCF7L1 were >=30% higher than in normal samples, representing potential biomarkers for tumor diagnosis. Using the 90th percentile of methylation levels in normal tissue as cutoff value, 62-92% of in situ samples (n=13), 72-97% of invasive samples from the first validation set (n=32), and 86 100% of invasive samples from the second validation set (n=43) were classified as hypermethylated. Hypermethylation of KLF11 and SIM1 might also be associated with increased risk of developing metastases. In summary, early methylation changes are frequent in the low-grade pathway of breast cancer and may be useful in the development of differential diagnostic and possibly also prognostic markers. PMID- 22930748 TI - Arabidopsis ECERIFERUM2 is a component of the fatty acid elongation machinery required for fatty acid extension to exceptional lengths. AB - Primary aerial surfaces of land plants are coated by a lipidic cuticle, which forms a barrier against transpirational water loss and protects the plant from diverse stresses. Four enzymes of a fatty acid elongase complex are required for the synthesis of very-long-chain fatty acid (VLCFA) precursors of cuticular waxes. Fatty acid elongase substrate specificity is determined by a condensing enzyme that catalyzes the first reaction carried out by the complex. In Arabidopsis (Arabidopsis thaliana), characterized condensing enzymes involved in wax synthesis can only elongate VLCFAs up to 28 carbons (C28) in length, despite the predominance of C29 to C31 monomers in Arabidopsis stem wax. This suggests additional proteins are required for elongation beyond C28. The wax-deficient mutant eceriferum2 (cer2) lacks waxes longer than C28, implying that CER2, a putative BAHD acyltransferase, is required for C28 elongation. Here, we characterize the cer2 mutant and demonstrate that green fluorescent protein tagged CER2 localizes to the endoplasmic reticulum, the site of VLCFA biosynthesis. We use site-directed mutagenesis to show that the classification of CER2 as a BAHD acyltransferase based on sequence homology does not fit with CER2 catalytic activity. Finally, we provide evidence for the function of CER2 in C28 elongation by an assay in yeast (Saccharomyces cerevisiae). PMID- 22930749 TI - Carbon deprivation-driven transcriptome reprogramming in detached developmentally arresting Arabidopsis inflorescences. AB - Senescence is genetically controlled and activated in mature tissues during aging. However, immature plant tissues also display senescence-like symptoms when continuously exposed to adverse energy-depleting conditions. We used detached dark-held immature inflorescences of Arabidopsis (Arabidopsis thaliana) to understand the metabolic reprogramming occurring in immature tissues transitioning from rapid growth to precocious senescence. Macroscopic growth of the detached inflorescences rapidly ceased upon placement in water in the dark at 21 degrees C. Inflorescences were completely degreened by 120 h of dark incubation and by 24 h had already lost 24% of their chlorophyll and 34% of their protein content. Comparative transcriptome profiling at 24 h revealed that inflorescence response at 24 h had a large carbon-deprivation component. Genes that positively regulate developmental senescence (ARABIDOPSIS NAC DOMAIN CONTAINING PROTEIN92) and shade-avoidance syndrome (PHYTOCHROME INTERACTING FACTOR4 [PIF4] and PIF5) were up-regulated within 24 h. Mutations in these genes delayed degreening of the inflorescences. Their up-regulation was suppressed in dark-held inflorescences by glucose treatment, which promoted macroscopic growth and development and inhibited degreening of the inflorescences. Detached inflorescences held in the dark for 4 d were still able to reinitiate development to produce siliques upon being brought out to the light, indicating that the transcriptional reprogramming at 24 h was adaptive and reversible. Our results suggest that the response of detached immature tissues to dark storage involves interactions between carbohydrate status sensing and light deprivation signaling and that the dark-adaptive response of the tissues appears to utilize some of the same key regulators as developmental senescence. PMID- 22930750 TI - Hypoxia-inducible factor-1 (HIF-1) but not HIF-2 is essential for hypoxic induction of collagen prolyl 4-hydroxylases in primary newborn mouse epiphyseal growth plate chondrocytes. AB - Hypoxia-inducible factors (HIFs) are the master regulators of hypoxia-responsive genes. They play a critical role in the survival, development, and differentiation of chondrocytes in the avascular hypoxic fetal growth plate, which is rich in extracellular matrix (ECM) and in its main component, collagens. Several genes involved in the synthesis, maintenance, and degradation of ECM are regulated by HIFs. Collagen prolyl 4-hydroxylases (C-P4Hs) are key enzymes in collagen synthesis because the resulting 4-hydroxyprolines are necessary for the stability of all collagen molecules. The vertebrate C-P4Hs are alpha(2)beta(2) tetramers with three isoforms of the catalytic alpha subunit, yielding C-P4Hs of types I-III. C-P4H-I is the main form in most cells, but C-P4H-II is the major form in chondrocytes. We postulated here that post-translational modification of collagens, particularly 4-hydroxylation of proline residues, could be one of the modalities by which HIF regulates the adaptive responses of chondrocytes in fetal growth plates. To address this hypothesis, we used primary epiphyseal growth plate chondrocytes isolated from newborn mice with conditionally inactivated genes for HIF-1alpha, HIF-2alpha, or the von Hippel-Lindau protein. The data obtained showed that C-P4H alpha(I) and alpha(II) mRNA levels were increased in hypoxic chondrocytes in a manner dependent on HIF-1 but not on HIF-2. Furthermore, the increases in the C-P4H mRNA levels were associated with both increased amounts of the C-P4H tetramers and augmented C-P4H activity in hypoxia. The hypoxia inducibility of the C-P4H isoenzymes is thus likely to ensure sufficient C-P4H activity for collagen synthesis occurring in chondrocytes in a hypoxic environment. PMID- 22930751 TI - The claudin Megatrachea protein complex. AB - Claudins are integral transmembrane components of the tight junctions forming trans-epithelial barriers in many organs, such as the nervous system, lung, and epidermis. In Drosophila three claudins have been identified that are required for forming the tight junctions analogous structure, the septate junctions (SJs). The lack of claudins results in a disruption of SJ integrity leading to a breakdown of the trans-epithelial barrier and to disturbed epithelial morphogenesis. However, little is known about claudin partners for transport mechanisms and membrane organization. Here we present a comprehensive analysis of the claudin proteome in Drosophila by combining biochemical and physiological approaches. Using specific antibodies against the claudin Megatrachea for immunoprecipitation and mass spectrometry, we identified 142 proteins associated with Megatrachea in embryos. The Megatrachea interacting proteins were analyzed in vivo by tissue-specific knockdown of the corresponding genes using RNA interference. We identified known and novel putative SJ components, such as the gene product of CG3921. Furthermore, our data suggest that the control of secretion processes specific to SJs and dependent on Sec61p may involve Megatrachea interaction with Sec61 subunits. Also, our findings suggest that clathrin-coated vesicles may regulate Megatrachea turnover at the plasma membrane similar to human claudins. As claudins are conserved both in structure and function, our findings offer novel candidate proteins involved in the claudin interactome of vertebrates and invertebrates. PMID- 22930752 TI - Automating single subunit counting of membrane proteins in mammalian cells. AB - Elucidating subunit stoichiometry of neurotransmitter receptors is preferably carried out in a mammalian expression system where the rules of native protein assembly are strictly obeyed. Although successful in Xenopus oocytes, single subunit counting, manually counting photobleaching steps of GFP-tagged subunits, has been hindered in mammalian cells by high background fluorescence, poor control of expression, and low GFP maturation efficiency. Here, we present a fully automated single-molecule fluorescence counting method that separates tagged proteins on the plasma membrane from background fluorescence and contaminant proteins in the cytosol or the endoplasmic reticulum and determines the protein stoichiometry. Lower GFP maturation rates observed in cells cultured at 37 degrees C were partly offset using a monomeric version of superfolder GFP. We were able to correctly identify the stoichiometry of GluK2 and alpha1 glycine receptors. Our approach permits the elucidation of stoichiometry for a wide variety of plasma membrane proteins in mammalian cells with any commercially available TIRF microscope. PMID- 22930753 TI - Probing the structural basis of Zn2+ regulation of the epithelial Na+ channel. AB - Extracellular Zn(2+) activates the epithelial Na(+) channel (ENaC) by relieving Na(+) self-inhibition. However, a biphasic Zn(2+) dose response was observed, suggesting that Zn(2+) has dual effects on the channel (i.e. activating and inhibitory). To investigate the structural basis for this biphasic effect of Zn(2+), we examined the effects of mutating the 10 extracellular His residues of mouse gammaENaC. Four mutations within the finger subdomain (gammaH193A, gammaH200A, gammaH202A, and gammaH239A) significantly reduced the maximal Zn(2+) activation of the channel. Whereas gammaH193A, gammaH200A, and gammaH202A reduced the apparent affinity of the Zn(2+) activating site, gammaH239A diminished Na(+) self-inhibition and thus concealed the activating effects of Zn(2+). Mutation of a His residue within the palm subdomain (gammaH88A) abolished the low-affinity Zn(2+) inhibitory effect. Based on structural homology with acid-sensing ion channel 1, gammaAsp(516) was predicted to be in close proximity to gammaHis(88). Ala substitution of the residue (gammaD516A) blunted the inhibitory effect of Zn(2+). Our results suggest that external Zn(2+) regulates ENaC activity by binding to multiple extracellular sites within the gamma-subunit, including (i) a high-affinity stimulatory site within the finger subdomain involving His(193), His(200), and His(202) and (ii) a low-affinity Zn(2+) inhibitory site within the palm subdomain that includes His(88) and Asp(516). PMID- 22930754 TI - The prion protein preference of sporadic Creutzfeldt-Jakob disease subtypes. AB - Sporadic Creutzfeldt-Jakob disease (CJD) is the most prevalent manifestation of the transmissible spongiform encephalopathies or prion diseases affecting humans. The disease encompasses a spectrum of clinical phenotypes that have been correlated with molecular subtypes that are characterized by the molecular mass of the protease-resistant fragment of the disease-related conformation of the prion protein and a polymorphism at codon 129 of the gene encoding the prion protein. A cell-free assay of prion protein misfolding was used to investigate the ability of these sporadic CJD molecular subtypes to propagate using brain derived sources of the cellular prion protein (PrP(C)). This study confirmed the presence of three distinct sporadic CJD molecular subtypes with PrP(C) substrate requirements that reflected their codon 129 associations in vivo. However, the ability of a sporadic CJD molecular subtype to use a specific PrP(C) substrate was not determined solely by codon 129 as the efficiency of prion propagation was also influenced by the composition of the brain tissue from which the PrP(C) substrate was sourced, thus indicating that nuances in PrP(C) or additional factors may determine sporadic CJD subtype. The results of this study will aid in the design of diagnostic assays that can detect prion disease across the diversity of sporadic CJD subtypes. PMID- 22930755 TI - Human synovial lubricin expresses sialyl Lewis x determinant and has L-selectin ligand activity. AB - Lubricin (or proteoglycan 4 (PRG4)) is an abundant mucin-like glycoprotein in synovial fluid (SF) and a major component responsible for joint lubrication. In this study, it was shown that O-linked core 2 oligosaccharides (Galbeta1 3(GlcNAcbeta1-6)GalNAcalpha1-Thr/Ser) on lubricin isolated from rheumatoid arthritis SF contained both sulfate and fucose residues, and SF lubricin was capable of binding to recombinant L-selectin in a glycosylation-dependent manner. Using resting human polymorphonuclear granulocytes (PMN) from peripheral blood, confocal microscopy showed that lubricin coated circulating PMN and that it partly co-localized with L-selectin expressed by these cells. In agreement with this, activation-induced shedding of L-selectin also mediated decreased lubricin binding to PMN. It was also found that PMN recruited to inflamed synovial area and fluid in rheumatoid arthritis patients kept a coat of lubricin. These observations suggest that lubricin is able to bind to PMN via an L-selectin dependent and -independent manner and may play a role in PMN-mediated inflammation. PMID- 22930756 TI - Structure of a proteasome Pba1-Pba2 complex: implications for proteasome assembly, activation, and biological function. AB - The 20S proteasome is an essential, 28-subunit protease that sequesters proteolytic sites within a central chamber, thereby repressing substrate degradation until proteasome activators open the entrance/exit gate. Two established activators, Blm10 and PAN/19S, induce gate opening by binding to the pockets between proteasome alpha-subunits using C-terminal HbYX (hydrophobic tyrosine-any residue) motifs. Equivalent HbYX motifs have been identified in Pba1 and Pba2, which function in proteasome assembly. Here, we demonstrate that Pba1 Pba2 proteins form a stable heterodimer that utilizes its HbYX motifs to bind mature 20S proteasomes in vitro and that the Pba1-Pba2 HbYX motifs are important for a physiological function of proteasomes, the maintenance of mitochondrial function. Other factors that contribute to proteasome assembly or function also act in the maintenance of mitochondrial function and display complex genetic interactions with one another, possibly revealing an unexpected pathway of mitochondrial regulation involving the Pba1-Pba2 proteasome interaction. Our determination of a proteasome Pba1-Pba2 crystal structure reveals a Pba1 HbYX interaction that is superimposable with those of known activators, a Pba2 HbYX interaction that is different from those reported previously, and a gate structure that is disrupted but not sufficiently open to allow entry of even small peptides. These findings extend understanding of proteasome interactions with HbYX motifs and suggest multiple roles for Pba1-Pba2 interactions throughout proteasome assembly and function. PMID- 22930757 TI - Suppressor of fused (Sufu) mediates the effect of parathyroid hormone-like hormone (Pthlh) on chondrocyte differentiation in the growth plate. AB - Growth plate chondrocytes undergo a coordinated process of differentiation, regulating long bone growth. Parathyroid hormone-like hormone (Pthlh) inhibits hypertrophic differentiation in the growth plate chondrocytes and reduces Hedgehog (Hh) signaling. In mice lacking the Hh mediator Suppressor of fused (Sufu), Pthlh treatment resulted in the up-regulation of Hh activity and an increased number of hypertrophic chondrocytes. Furthermore, Pthlh increased Sufu protein levels, and in chondrocytes lacking Sufu, it was unable to process Hh regulated Gli transcription factors. Pthlh regulates chondrocyte differentiation and Gli activity in a Sufu-dependent manner, with Sufu acting as a molecular switch in its regulation of differentiation. PMID- 22930758 TI - Variable region identical immunoglobulins differing in isotype express different paratopes. AB - The finding that the antibody (Ab) constant (C) region can influence fine specificity suggests that isotype switching contributes to the generation of Ab diversity and idiotype restriction. Despite the centrality of this observation for diverse immunological effects such as vaccine responses, isotype-restricted antibody responses, and the origin of primary and secondary responses, the molecular mechanism(s) responsible for this phenomenon are not understood. In this study, we have taken a novel approach to the problem by probing the paratope with (15)N label peptide mimetics followed by NMR spectroscopy and fluorescence emission spectroscopy. Specifically, we have explored the hypothesis that the C region imposes conformational constraints on the variable (V) region to affect paratope structure in a V region identical IgG(1), IgG(2a), IgG(2b), and IgG(3) mAbs. The results reveal isotype-related differences in fluorescence emission spectroscopy and temperature-related differences in binding and cleavage of a peptide mimetic. We conclude that the C region can modify the V region structure to alter the Ab paratope, thus providing an explanation for how isotype can affect Ab specificity. PMID- 22930759 TI - Thyroid hormone receptor isoform-specific modification by small ubiquitin-like modifier (SUMO) modulates thyroid hormone-dependent gene regulation. AB - Thyroid hormone receptor (TR) alpha and beta mediate thyroid hormone action at target tissues. TR isoforms have specific roles in development and in adult tissues. The mechanisms underlying TR isoform-specific action, however, are not well understood. We demonstrate that posttranslational modification of TR by conjugation of small SUMO to TRalpha and TRbeta plays an important role in triiodothyronine (T3) action and TR isoform specificity. TRalpha was sumoylated at lysines 283 and 389, and TRbeta at lysines 50, 146, and 443. Sumoylation of TRbeta was ligand-dependent, and sumoylation of TRalpha was ligand-independent. TRalpha-SUMO conjugation utilized the E3 ligase PIASxbeta and TRbeta-SUMO conjugation utilized predominantly PIAS1. SUMO1 and SUMO3 conjugation to TR was important for T3-dependent gene regulation, as demonstrated in transient transfection assay and studies of endogenous gene regulation. The functional role of SUMO1 and SUMO3 in T3 induction in transient expression assays was closely matched to the pattern of TR and cofactor recruitment to thyroid hormone response elements (TREs) as determined by ChIP assays. SUMO1 was required for the T3 induced recruitment of the co-activator CREB-binding protein (CBP) and release of nuclear receptor co-repressor (NCoR) on a TRE but had no significant effect on TR DNA binding. SUMO1 was required for T3-mediated recruitment of NCoR and release of CBP from the TSHbeta-negative TRE. SUMO3 was required for T3-stimulated TR binding to the TSHbeta-negative TRE and recruitment of NCoR. These findings demonstrate that conjugation of SUMO to TR has a TR-isoform preference and is important for T3-dependent gene induction and repression. PMID- 22930761 TI - Progress in global health. PMID- 22930760 TI - The evolution of intron size in amniotes: a role for powered flight? AB - Intronic DNA is a major component of eukaryotic genes and genomes and can be subject to selective constraint and have functions in gene regulation. Intron size is of particular interest given that it is thought to be the target of a variety of evolutionary forces and has been suggested to be linked ultimately to various phenotypic traits, such as powered flight. Using whole-genome analyses and comparative approaches that account for phylogenetic nonindependence, we examined interspecific variation in intron size variation in three data sets encompassing from 12 to 30 amniotes genomes and allowing for different levels of genome coverage. In addition to confirming that intron size is negatively associated with intron position and correlates with genome size, we found that on average mammals have longer introns than birds and nonavian reptiles, a trend that is correlated with the proliferation of repetitive elements in mammals. Two independent comparisons between flying and nonflying sister groups both showed a reduction of intron size in volant species, supporting an association between powered flight, or possibly the high metabolic rates associated with flight, and reduced intron/genome size. Small intron size in volant lineages is less easily explained as a neutral consequence of large effective population size. In conclusion, we found that the evolution of intron size in amniotes appears to be non-neutral, is correlated with genome size, and is likely influenced by powered flight and associated high metabolic rates. PMID- 22930762 TI - Islands, disasters, and public health. PMID- 22930763 TI - Color me appreciative. PMID- 22930764 TI - His way or no way: an interview with Dr John Beumer III by Neal Garrett. PMID- 22930765 TI - A systematic review of all-ceramic crowns: clinical fracture rates in relation to restored tooth type. AB - PURPOSE: The objective of this systematic review was to evaluate the clinical fracture incidence of tooth-supported all-ceramic crowns according to restored tooth type. MATERIALS AND METHODS: An electronic search of clinical trials published in English and Chinese was performed using four databases (Medline/PubMed, EMBASE, Cochrane Library, and the Chinese Biomedical Literature Database) from 1990 to 2011 and complemented by an additional manual search. The annual core and veneer fracture rates of various tooth types were estimated and compared using Poisson regression. Moreover, the 5-year cumulative incidence was calculated. RESULTS: Of 5,600 titles and abstracts retrieved, 37 publications were included, with a follow-up period that ranged from 36 to 97 months. Based on the calculated results, all-ceramic crowns demonstrated an acceptable overall 5 year fracture rate of 4.4% irrespective of the materials used. Molar crowns (8.1%) showed a significantly higher 5-year fracture rate than premolar crowns (3.0%), and the difference between anterior (3.0%) and posterior crowns (5.4%) also achieved significance. Fractures were classified as either core or veneer fractures. Core fracture rates were calculated as having a 5-year incidence of 2.5%, and a significantly higher core fracture rate was found in the posterior region (3.9%). The overall 5-year incidence of veneer fracture was 3.0%, and no clear difference was found between restored tooth types, with incidences of 2.0%, 2.5%, 1.0%, and 3.0% for incisor, canine, premolar, and molar crowns, respectively. CONCLUSIONS: Within the limitations of this study, current dental ceramic materials demonstrated acceptable 5-year core and veneer fracture incidences when used for tooth-supported single crowns in both anterior and posterior segments. A higher fracture tendency for posterior crowns was the trend for all-ceramic crowns, while molar crowns showed a significantly higher fracture rate than premolar crowns. Moreover, it is recommended that randomized controlled trials with large sample sizes be undertaken to obtain more definitive results. PMID- 22930766 TI - A four-year prospective clinical evaluation of zirconia and metal-ceramic posterior fixed dental prostheses. AB - PURPOSE: The aim of this study was to compare the survival rates and biologic and technical complications of three-unit metal-ceramic posterior fixed dental prostheses (FDPs) with those obtained with zirconia frameworks. MATERIALS AND METHODS: Thirty-seven patients in need of 40 three-unit posterior FDPs were included in this study. The FDPs were randomly assigned to 20 zirconia and 20 metal-ceramic restorations. Abutment preparation guidelines consisted of a 1-mm wide circumferential chamfer, axial reduction of 1 mm, and occlusal reduction of 1.5 to 2 mm. At baseline and 1, 2, 3, and 4 years after cementation, success of both types of restorations was evaluated. The restorations were assessed using the California Dental Association's assessment system. Periodontal parameters were assessed by determining the Plaque Index (PI), Gingival Index (GI), Marginal Index (MI), and pocket depth of the abutment and control teeth. Statistical analysis was performed by applying Wilcoxon rank sum and Wilcoxon signed-rank tests. RESULTS: Patients were examined after a mean observation period of 50 +/- 2.4 months. The survival rates for metal-ceramic and zirconia restorations were 100% and 95%, respectively. One biologic complication in a zirconia FDP was observed at the 3-year follow-up. No fractures of the zirconia or metal frameworks were observed. Restorations from both groups were assessed as satisfactory. Minor chipping of the veneering ceramic was observed in 2 zirconia FDPs after 4 years. No significant differences were observed between abutment and contralateral teeth for either type of restoration or within the groups with regard to PI, GI, and pocket depth. CONCLUSION: Zirconia-based FDPs demonstrated a similar survival rate to metal-ceramic FDPs after medium-term clinical use. PMID- 22930767 TI - Aggressive external root resorption of the entire dentition accompanied by osteolysis: a case report. AB - A healthy Caucasian male lost all of his teeth because of aggressive cervical, apical, and lateral root resorption over a period of 11 years. Microscopically, there was no sign of reparative cementum apposition, but cell-rich fibrous connective tissue filling the deep resorptions was seen. The resorbed teeth were surrounded by fibro-osseous tissue of osteolytic appearance, as noted during radiologic examination. Radiography showed the osteolytic processes to regress dramatically with the removal or loss of teeth. No underlying systemic or local factor was identified. In spite of endodontic and surgical treatment, none of the resorptions went into remission. PMID- 22930768 TI - Comparison of primary stability of straight-walled and tapered implants using an insertion torque device. AB - PURPOSE: Implant geometry has a major impact on insertion torque values and primary stability, and bone engagement during implant insertion differs according to implant morphology. Primary stability of straight-walled and tapered implants was compared using insertion torque monitoring. MATERIALS AND METHODS: A total of 57 implants (36 straight-walled OSSEOTITE and 21 tapered OSSEOTITE NT) were inserted in 20 patients. Implant torque values and insertion times were recorded, and the data were processed and interpolated to determine torque as a function of time. RESULTS: Tapered implants required less insertion time and a higher insertion torque than straight-walled implants; this provided better primary stability, although the success rate was 86% for tapered and 100% for straight walled implants. CONCLUSIONS: Tapered implants showed better primary stability than straight-walled implants but had a lower success rate. The authors suggest that in low-density bone, in which only a thin dense cortical layer can contribute to primary stability, a higher insertion torque can lead to the destruction of peri-implant bone, compromising osseointegration. PMID- 22930769 TI - Influence of length of occlusal support on masticatory function of free-end removable partial dentures. AB - PURPOSE: The aim of this study was to determine the influence of occlusal support length (OSL) of free-end removable partial dentures (RPDs) on masticatory function. MATERIALS AND METHODS: Twenty-three subjects (mean age: 55.2 +/- 8.4 years) who were edentulous in the maxilla and classified as Kennedy Class I in the mandible were selected. Subjects received new maxillary complete dentures and mandibular RPDs. Five OSL conditions were determined by RPD artificial tooth wear: full occlusal support (L1, control), OSL to first molar (L2), OSL to second premolar (L3), OSL to first premolar (L4), and absence of occlusal support (L5). Masticatory performance and efficiency were evaluated using the sieve method. Chewing rate was defined as the number of masticatory cycles per minute. Bolus selection opportunities and bolus breakage function were evaluated using the one chew method. Qualitative and quantitative measurements of masticatory cycle patterns were recorded kinesiographically. Data were analyzed using repeated measures analysis of variance and Friedman and Fisher exact tests (alpha = .05). RESULTS: Masticatory performance and efficiency decreased (P < .05) from L1 (5.46 +/- 0.64 mm and 51.21% +/- 19.44%, respectively) to L5 (6.24 +/- 0.44 mm and 24.50% +/- 15.98%, respectively). Chewing rate was higher for L4 than L1 (P < .05). Bolus selection chances and bolus breakage function decreased as OSL was reduced (P < .05); however, there were no differences in masticatory cycle pattern among the OSL conditions (P > .05). CONCLUSION: Reduction of OSL altered masticatory function, thereby decreasing masticatory performance and efficiency resulting from a lower capacity to select and break down food. PMID- 22930770 TI - A 5-year retrospective study of cobalt-chromium-based single crowns inserted in a private practice. AB - The aim of this retrospective study was to evaluate the clinical performance of cobalt-chromium (Co-Cr) single crowns. Ninety restorations were placed in 55 patients, and follow-up examinations were performed annually for 5 years. Six patients (8 crowns) were regarded as dropouts. During the follow-up period, 15 (17%) crowns/abutment teeth experienced some type of complication; 8 (9%) of these were regarded as failures. The cumulative survival rate was estimated at 90.3% over 5 years, though only 3 (3%) crowns had complications that could be related to the crown material. The results suggest that Co-Cr single crowns are a promising alternative to other alloys used in fixed prosthodontics. PMID- 22930771 TI - Patients' expectations of and satisfaction with implant-supported fixed partial dentures and single crowns. AB - PURPOSE: Patient variables and expectations may influence patients' evaluations of treatment outcomes, which are essential to the success of therapy. The main objective of this study was to compare patients' expectations before and satisfaction after receiving implant-supported fixed partial dentures (FPDs) and single crowns. A secondary objective was to evaluate other variables that may affect patient satisfaction. MATERIALS AND METHODS: The sample comprised 52 volunteers (mean age: 51.2 +/- 10.6 years) who had received implant-supported FPDs (n = 25) and single crowns (n = 27). A visual analog scale (VAS) was used to assess their expectations before and satisfaction after therapy with regard to mastication, esthetics, comfort, and phonetics. Patients also completed a questionnaire concerning other variables involved in the treatment and their evaluation of their clinician's conduct. RESULTS: Patient expectations before treatment were higher than satisfaction after treatment, but this difference was significant only for esthetics in patients who had received implant-supported FPDs. Negative correlations were found between satisfaction and age and between number of absent teeth and number of post delivery adjustments, but only for implant-supported FPDs. A positive relationship was found for the majority of questions concerning patients' evaluations of clinician conduct and VAS scores. CONCLUSION: Patients' evaluation of clinician conduct appears to be an important factor that influences their expectations before and satisfaction after receiving implant-supported FPDs and single crowns. PMID- 22930772 TI - Patient attendance in a recall program after prosthodontic rehabilitation: a 5 year follow-up. AB - PURPOSE: This study evaluated the recall attendance and maintenance for a patient population after prosthodontic treatment in undergraduate student courses. MATERIALS AND METHODS: Four hundred ninety-three patients who received fixed restorations (FRs; crowns or fixed partial dentures) or removable partial dentures (RPDs; conical crown-retained or precision attachment-retained dental prostheses) were included in a recall program. The number of patients attending regularly scheduled follow-up visits every 6 months was recorded. On the basis of the complexity of the performed treatment, all follow-up interventions were assigned to the categories minimal, moderate, or extensive. RESULTS: After 60 months, a cumulative follow-up attendance rate between 63% (RPD) and 74% (FR) was evident and not gender related. Altogether, 399 patients (193 FR, 206 RPD) regularly attended the follow-up visits. Between 61.9% (RPD) and 93.8% (FR) of these patients did not need any extensive treatment; however, only 19.2% (RPD) to 85.6% (FR) did not need any moderate or extensive treatment between follow-up visits. CONCLUSIONS: Patients treated with FRs showed a higher recall attendance than patients treated with RPDs. Further, patients with RPDs needed more extensive and moderate treatments than patients with FRs. This difference should be taken into consideration during prosthetic planning and patient consultation. PMID- 22930773 TI - Computed tomographic evaluation of the effects of mandibular advancement devices on pharyngeal dimension changes in patients with obstructive sleep apnea. AB - PURPOSE: The aims of this study were to evaluate the effect of a mandibular advancement device on oropharyngeal dimension in patients with obstructive sleep apnea (OSA) and reveal the predominate site of changes produced by mandibular advancement using computed tomography (CT). MATERIALS AND METHODS: CT scans of 20 patients diagnosed with OSA were taken with and without the appliance. Three dimensional changes in pharyngeal shape measured on cross-sectional CT images during two respiratory cycles after oral appliance insertion were estimated at five vertical levels using three variables: (1) lateral dimension, (2) anteroposterior dimension, and (3) cross-sectional area. Various parameters related to severity of OSA such as snoring volume, frequency, duration, and episodes; breathing pauses; oxygen saturation; Epworth Sleepiness Scale (ESS) score; and Apnea Hypopnea Index (AHI) score underwent comparative evaluation subjectively and objectively. Data were analyzed using the Student t test for parametric analysis. RESULTS: A significant increase in the lateral and anteroposterior dimension of the pharyngeal lumen was observed at all five levels, but the mean change was greatest at the retroglossal level and smallest at the hypopharyngral level in both the lateral and anteroposterior dimensions. The cross-sectional area at all levels appeared to increase significantly, and apnea indices improved significantly. A significant decrease in snoring volume, snoring frequency, breathing pauses, snoring duration, snoring episodes, ESS score, and AHI score and a significant increase in oxygen saturation were found after treatment with the mandibular advancement device. CONCLUSION: Within the limitations of this study, CT was shown to be useful in evaluating treatment efficacy in subjects with OSA. PMID- 22930774 TI - Alternative procedure to improve the stability of mandibular complete dentures: a modified neutral zone technique. AB - The aim of this report is to describe an alternative technique to record the neutral zone. An acrylic resin base with posterior occlusal rims was applied using a thermoplastic denture adhesive. After being worn for 2 days, the base was transferred into an acrylic resin complete denture. Most patients reported an improvement in denture stability and a reduction of pressure sores. This procedure seems to be helpful to improve denture function, especially in the mandible, in patients who cannot be treated with implants. However, because of its complexity, this neutral zone technique cannot be recommended for routine clinical use. PMID- 22930775 TI - Aging effects of fiber post surface treatment with nonthermal plasma. AB - The purpose of this study was to observe the aging effects of post surface treatment with nonthermal plasma using air or helium mixed with 2% oxygen as the working gas. Two groups of fiber posts were treated with one of the nonthermal plasmas. Both groups were further divided into four subgroups, each receiving an air exposure time of 0, 1, 12, or 24 hours before being bonded with composite resin cement. The microtensile bond strength of each subgroup was measured. The results showed that the improvement in bond strength disappeared when fiber posts were exposed to air for 1 hour or longer after being treated with plasma. PMID- 22930776 TI - Effects of implant angulation, material selection, and impression technique on impression accuracy: a preliminary laboratory study. AB - The aim of this preliminary laboratory study was to evaluate the effects of 5- and 25-degree implant angulations in simulated clinical casts on an impression's accuracy when using different impression materials and tray selections. A convenience sample of each implant angulation group was selected for both open and closed trays in combination with one polyether and two polyvinyl siloxane impression materials. The influence of material and technique appeared to be significant for both 5- and 25-degree angulations (P < .05), and increased angulation tended to decrease impression accuracy. The open-tray technique was more accurate with highly nonaxially oriented implants for the small sample size investigated. PMID- 22930777 TI - Feasibility of Attachment Based Family Therapy for depressed clinic-referred Norwegian adolescents. AB - Several studies have earned Attachment Based Family Therapy (ABFT) the designation of a promising empirically supported treatment for adolescents with depression. This study evaluated the feasibility of importing ABFT into a hospital-based outpatient clinic in Norway. This article documents the challenges of initiating and conducting research in a real world clinical setting and training staff therapists. It also reports on outcomes of a pilot randomized clinical trial. Implementation barriers rapidly emerged in relation to hospital administration, infrastructure development, and therapists. Despite these barriers, 20 clinic-referred adolescents were randomly assigned to ABFT (n= 11) or to Treatment as Usual (TAU) (n= 9). Adolescents in ABFT showed significantly better symptom reduction compared to adolescents in TAU with an effect size of 1.08. While preliminary, this study suggests that Norwegian clinical staff therapists could be engaged in learning and delivering ABFT, and in producing promising treatment results. The importance of institutional support for dissemination research is highlighted. PMID- 22930778 TI - Effectiveness of a breath-actuated nebulizer device on asthma care in the pediatric emergency department. AB - The breath-actuated nebulizer (BAN) is a new respiratory device to deliver short acting beta-agonists to patients with asthma exacerbations. This pediatric convenience sample experimental study compares the BAN with conventional nebulizers and demonstrates that the BAN allows for shorter treatment times to achieve improved clinical asthma scores with less albuterol, shorter emergency department length of stay, and fewer hospitalizations. PMID- 22930779 TI - A Harry Potter fan. PMID- 22930780 TI - Intentional use of testosterone by a father to stimulate penis growth in an infant. PMID- 22930781 TI - Obesity in pediatric specialty clinics: an underestimated comorbidity. AB - OBJECTIVES: (a) To examine the prevalence of obesity across 31 subspecialties in a tertiary care children's hospital and (b) to examine the percentage of obesity specified diagnosis codes used for obese patient visits. METHODS: We analyzed 48 479 youth aged 2 to 18 years in 31 outpatient subspecialty clinics at Seattle Children's Hospital between 2005 and 2007. Body mass index (BMI) percentiles were determined by age- and gender-adjusted BMI calculated from height/weight obtained at clinic visits. For obese patients, the percentage of diagnoses coded as obesity-specific (278.11, 278.01, 272.02, 783.1) were determined by evaluation of standard diagnostic codes. RESULTS: Twenty-two of the 31 clinics had patient obesity rates greater than 15%. Analysis of International Classification of Diseases, 9th Revision, codes for obese patient visits as defined by BMI revealed only 2 clinics used obesity-specific codes for >5% of all diagnoses. CONCLUSIONS: Given the prevalence of obesity across all subspecialties, more recognition and resources are needed to screen, diagnosis, and provide coordinated services for healthy weight management. PMID- 22930782 TI - Pigment epithelium-derived factor (PEDF) varies with body composition and insulin resistance in healthy young people. AB - CONTEXT: Pigment epithelium-derived factor (PEDF) was recently implicated as a metabolic regulatory protein because plasma concentration was increased in obese or insulin resistant adults. To our knowledge, circulating PEDF values in children have not been reported. Because PEDF is a predictor of metabolic health in adults, it may have a similar impact on metabolic profiles in children. OBJECTIVE: The objective of the study was to determine whether PEDF in normal weight (NW) and overweight/obese (OW) children and young adults varies with age, sex, or body composition or is associated with clinical markers of metabolic disease. SETTING: Volunteers were tested at the University of Oklahoma Health Sciences Center. PARTICIPANTS: Ninety-one NW (8-30 yr old) and 105 OW (8-35 yr old) males and females participated in the study. MAIN OUTCOME MEASURES: Body composition, blood pressure, arterial compliance, fasting plasma PEDF, glucose, insulin, (used for homeostasis model assessment of insulin resistance), triglycerides, cholesterol (total, low density lipoprotein, and high density lipoprotein), and C-reactive protein. RESULTS: PEDF was 60% higher in the OW vs. NW participants but did not differ between males and females. PEDF was positively correlated with body mass, body mass index, fat and lean mass, fasting insulin, and homeostasis model assessment of insulin resistance in both the NW and OW groups. Multiple regression models revealed that fat and lean mass were significant predictors of circulating PEDF levels independent of age, sex, and body mass index category. CONCLUSIONS: Plasma PEDF is elevated in OW youth and is positively associated with insulin resistance. These findings suggest that PEDF may play a role in the development of cardiometabolic dysfunction in youth. PMID- 22930783 TI - Excess mortality in hyperthyroidism: the influence of preexisting comorbidity and genetic confounding: a danish nationwide register-based cohort study of twins and singletons. AB - CONTEXT: Hyperthyroidism is associated with severe comorbidity, such as stroke, and seems to confer increased mortality. However, it is unknown whether this increased mortality is explained by hyperthyroidism per se, comorbidity, and/or genetic confounding. OBJECTIVE: The objective of the study was to investigate whether hyperthyroidism is associated with an increased mortality and, if so, whether the association is influenced by comorbidity and/or genetic confounding. METHODS: This was an observational cohort study using record-linkage data from nationwide Danish health registers. We identified 4850 singletons and 926 twins from same-sex pairs diagnosed with hyperthyroidism. Each case was matched with four controls for age and gender. The Charlson score was calculated from discharge diagnoses on an individual level to measure comorbidity. Cases and controls were followed up for a mean of 10 yr (range 0-31 yr), and the hazard ratio (HR) for mortality was calculated using Cox regression analyses. RESULTS: In singletons there was a significantly higher mortality in individuals diagnosed with hyperthyroidism than in controls [HR 1.37; 95% confidence interval (CI) 1.30 1.46]. This persisted after adjustment for preexisting comorbidity (HR 1,28; 95% CI 1.21-1.36). In twin pairs discordant for hyperthyroidism (625 pairs), the twin with hyperthyroidism had an increased mortality compared with the corresponding cotwin (HR 1.43; 95% CI 1.09-1.88). However, this was found only in dizygotic pairs (HR 1.80; 95% CI 1.27-2.55) but not in monozygotic pairs (HR 0.95; 95% CI 0.60-1.50). CONCLUSIONS: Hyperthyroidism is associated with an increased mortality independent of preexisting comorbidity. The study of twin pairs discordant for hyperthyroidism suggests that genetic confounding influences the association between hyperthyroidism and mortality. PMID- 22930784 TI - Estradiol, tamoxifen, and flaxseed alter IL-1beta and IL-1Ra levels in normal human breast tissue in vivo. AB - INTRODUCTION: Sex steroid exposure increases the risk of breast cancer by unclear mechanisms. Diet modifications may be one breast cancer prevention strategy. The proinflammatory cytokine family of IL-1 is implicated in cancer progression. IL 1Ra is an endogenous inhibitor of the proinflammatory IL-1alpha and IL-1beta. OBJECTIVE: The objective of this study was to elucidate whether estrogen, tamoxifen, and/or diet modification altered IL-1 levels in normal human breast tissue. DESIGN AND METHODS: Microdialysis was performed in healthy women under various hormone exposures, tamoxifen therapy, and diet modifications and in breast cancers of women before surgery. Breast tissue biopsies from reduction mammoplasties were cultured. RESULTS: We show a significant positive correlation between estradiol and in vivo levels of IL-1beta in breast tissue and abdominal sc fat, whereas IL-1Ra exhibited a significant negative correlation with estradiol in breast tissue. Tamoxifen or a dietary addition of 25 g flaxseed per day resulted in significantly increased levels of IL-1Ra in the breast. These results were confirmed in ex vivo culture of breast biopsies. Immunohistochemistry of the biopsies did not reveal any changes in cellular content of the IL-1s, suggesting that mainly the secreted levels were affected. In breast cancer patients, intratumoral levels of IL-1beta were significantly higher compared with normal adjacent breast tissue. CONCLUSION: IL-1 may be under the control of estrogen in vivo and may be attenuated by antiestrogen therapy and diet modifications. The increased IL-1beta in breast cancers of women strongly suggests IL-1 as a potential therapeutic target in breast cancer treatment and prevention. PMID- 22930785 TI - Prediction of occult central lymph node metastasis in papillary thyroid carcinoma by preoperative BRAF analysis using fine-needle aspiration biopsy: a prospective study. AB - CONTEXT: Few reports have determined whether preoperative detection of the BRAF V600E mutation in fine-needle aspiration biopsy (FNAB) may influence determination of surgical extent such as prophylactic central lymph node dissection (CLND) in patients with papillary thyroid carcinoma (PTC). OBJECTIVES: Our objectives were to investigate whether preoperative BRAF analysis may assist determination of surgical extent, including prophylactic CLND with variable clinicopathological risk factors for central lymph node metastasis, in patients with PTC and clinically node-negative neck. PATIENTS AND METHODS: From July 2009 to May 2011, we prospectively enrolled 148 PTC patients with clinically node negative neck who received a total thyroidectomy and prophylactic CLND. BRAF mutation by pyrosequencing was tested on preoperative FNAB specimens. The relationships between occult central lymph node metastasis and preoperative BRAF mutation or clinicopathological factors were analyzed. Additionally, we assessed the associations between preoperative BRAF mutation status and various clinicopathological characteristics of PTC revealed postoperatively. RESULTS: The prevalence of the BRAF V600E mutation was 53.4%, and the rate of occult central lymph node metastasis was 25.7%. Multivariate analysis showed that tumor size over 1 cm [P = 0.006; odds ratio (OR) = 3.559], perithyroidal invasion (P = 0.023; OR = 2.893), and preoperative positive BRAF mutation (P = 0.029; OR = 2.727) were independent risk factors for the presence of occult central lymph node metastasis. BRAF mutation examined in FNAB specimens, compared with the wild type allele, strongly predicted perithyroidal invasion (48 vs. 29%; P = 0.017), extracapsular spread (65 vs. 45%; P = 0.017), occult central lymph node metastasis (35 vs. 15%; P = 0.004), and advanced TNM stage (44 vs. 28%; P = 0.035). In the multivariate analysis, patients with preoperative positive BRAF mutation were significantly more likely (P = 0.023; OR = 2.848) to have occult central lymph node metastasis. CONCLUSION: Preoperative BRAF analysis by FNAB and primary tumor size based on ultrasonography may assist in predicting occult central lymph node metastasis in patients with PTC and clinically node-negative neck. PMID- 22930786 TI - Soluble human leukocyte antigen-g and its insertion/deletion polymorphism in papillary thyroid carcinoma: novel potential biomarkers of disease? AB - INTRODUCTION: Human leukocyte antigen-G (HLA-G), a nonclassical major histocompatibility complex class I antigen, plays a pivotal role in immune tolerance and a paradoxical role in cancers. AIMS: Our aims were to evaluate plasma soluble HLA-G (sHLA-G) concentrations and the 14-bp insertion/deletion polymorphism of the HLA-G gene in patients with papillary thyroid carcinoma (PTC) or Hashimoto's thyroiditis (HT) and to assess the possible association of these parameters with PTC aggressiveness. METHODS: Samples for the analysis of sHLA-G and +14/-14-bp HLA-G polymorphism were obtained from 121 patients with HT and 183 with PTC; 245 gender- and age-matched healthy subjects served as controls. PTC histopathological aggressiveness was defined according to the last American Thyroid Association guidelines. RESULTS: Positive serum antithyroid antibody titers were observed in 22% of PTC patients and lymphocyte infiltration of thyroid parenchyma at histological examination in 21%, whereas both circulating and histological autoimmunity was detectable in 12% of PTC patients. No differences in the +14/-14-bp polymorphism frequencies were observed between the study groups. The prevalence of detectable sHLA-G was lower in healthy controls (52%) as compared with both HT (57%) and PTC (62%) patients. By stratifying the study groups according to sHLA-G level of positive subjects, significantly higher plasma sHLA-G values in PTC (42.9 +/- 3.3 ng/ml; P = 0.002) and HT patients (49.1 +/- 2.6 ng/ml; P < 0.002) as compared with healthy controls (8.5 +/- 1.8 ng/ml) were obtained. Moreover, PTC patients with detectable plasma sHLA-G levels showed a higher aggressive behavior (P < 0.04) than those without. CONCLUSIONS: Although confirming the frequent association between PTC and chronic autoimmune thyroiditis, these data suggest that elevated circulating sHLA-G levels, besides an important signal of alterations of immune homeostasis, may be considered a potential, novel marker of PTC histopathological aggressiveness at diagnosis. Additional studies are needed to confirm the actual role and clinical relevance of the HLA-G complex in PTC development and progression. PMID- 22930787 TI - Evaluation of the Duration of Action and Comparative Effectiveness of Lisdexamfetamine Dimesylate and Behavioral Treatment in Youth With ADHD in a Quasi-Naturalistic Setting. AB - OBJECTIVE: This study compared the relative effects of three treatment conditions: long-acting stimulant medication (MED), behavior modification, and medication/behavioral treatments combined (COM) in children with ADHD. METHOD: A total of 25 children, aged 6 to 12 years, received the three treatment conditions during a 7-week Summer Treatment Program in an alternating treatments design. Counselors completed behavioral ratings from 0.5 to 12.5 hr post dose, and parents completed nighttime ratings. RESULTS: Ratings for SKAMP (Swanson, Kotkin, Agler, M-Flynn, and Pelham) and for following instructions indicated COM and MED improved symptoms over BEH treatment beginning 3 hr post dose (p = .008), with ratings maintained 12.5 hr post dose (p = .001 and .006). Results for frustration tolerance indicated significant improvement in all three conditions until 9 hr post dose. CONCLUSION: MED and COM separated from BEH at 3 hr post dose, and sustained benefit was observed across the day for two of three measures. BEH appears to have an additive effect, extending the duration of frustration tolerance. PMID- 22930788 TI - Anxiety in college students With ADHD: relationship to cognitive functioning. AB - OBJECTIVE: This study sought to explore how anxiety impacts college students with ADHD, especially with regard to cognitive functioning. METHOD: 473 college students with ADHD and a control group of 200 college students without ADHD completed self-report measures of anxiety, ADHD symptomatology and tests of cognitive functioning. RESULTS: Students with ADHD reported significantly more anxiety than students without ADHD. Within the ADHD group, the relationship between anxiety and inattention was similar to the relationship between anxiety and hyperactivity/impulsivity. Students with ADHD reported more anxiety with regard to academics compared to life-in-general. There were no gender differences for anxiety; however, freshman indicated more anxiety than upper-classmen. Anxiety and inattention were found to interact such that students with low levels of inattention but high levels of anxiety performed better on tasks of cognitive ability. CONCLUSION: Anxiety in college students with ADHD can take many forms, and interventions require a multi-focused approach. There may be some positive aspects to anxiety. PMID- 22930789 TI - Does Comorbid Disruptive Behavior Modify the Effects of Atomoxetine on ADHD Symptoms as Measured by a Continuous Performance Test and a Motion Tracking Device? AB - OBJECTIVE: To compare the reduction of ADHD symptoms under atomoxetine in patients with and without comorbid oppositional defiant disorder (ODD) or conduct disorder (CD) using a computer-based continuous performance test (cb-CPT) combined with an infrared motion tracking (MT) device. METHOD: Secondary analysis of a placebo-controlled study in ADHD patients (6-12 years old) treated with atomoxetine (target dose: 1.2 mg/kg per day). Cb-CPT/MT scores were analyzed using ANCOVA (last observation carried forward [LOCF]). RESULTS: The data (N = 125) suggested a more pronounced atomoxetine effect in the group with comorbid ODD/CD as measured by all cb-CPT/MT parameters except for "normalized variation of reaction time" (nVRT). CONCLUSION: The results showed that atomoxetine reduced ADHD severity as measured by cb-CPT and MT parameters regardless of whether comorbid ODD/CD was present. The treatment effect of atomoxetine on hyperactivity appears to be more pronounced in the subgroup of patients with comorbid ODD/CD than in the subgroup without this comorbidity. PMID- 22930790 TI - ADHD Rate in Obese Women With Binge Eating and Bulimic Behaviors From a Weight Loss Clinic. AB - OBJECTIVE: Few studies have demonstrated a possible association between ADHD and obesity in adults. The aim of this study was to investigate the prevalence of ADHD in a sample of obese women seeking treatment, and its relations with binge eating and bulimic behaviors. METHOD: We performed a cross-sectional study in a clinical sample of one hundred fifty-five women, with a mean age of 38.9 (+10.7) years and a mean body mass index (BMI) of 39.2 (+5.29). Participants were evaluated with semistructured interviews and completed self-report psychiatric rating scales. RESULTS: The rate of ADHD in the sample was of 28.3%. The presence of ADHD was significantly correlated with more severe binge eating, bulimic behaviors, and depressive symptomatology. CONCLUSION: Similar to previous studies, a higher than expected rate of ADHD was observed among obese women. ADHD in obese individuals may be a risk factor for greater severity of disordered eating patterns. PMID- 22930791 TI - Intratask Variability As a Correlate for DRD4 and SLC6A3 Variants: A Pilot Study in ADHD. AB - Behavioral variability may be an ADHD key feature. Currently used ex Gaussian/Fast Fourier Transform analyses characterize general distribution and oscillatory/rhythmic components of performance but are unable to demonstrate slow cumulative changes over entire tasks. OBJECTIVE: To explore how performance of ADHD children and unaffected sibs gradually evolves in relation to genetic variants linked to ADHD. METHOD: A total of 40 kids (20 ADHD-discordant sib pairs) between 8 and 13 years resolved a visual Go/NoGo with 10% NoGo probability. Variable number tandem repeats (VNTRs) at DRD4 and SLC6A3 were identified following standard protocols. Performance changes were assessed by linear/logistic mixed-effect models. RESULTS: Models exploring SLC6A3 effects demonstrated less accentuated increments of response time (RT) (p = .046) and cumulative increments in the correct responses to "NoGo" (p = .00027) in 10R/10R participants. Models for DRD4 showed faster decline of correct responses to "Go" (p = .0078) in 2R/7R carriers. CONCLUSION: Dynamical analysis of attention/inhibition measures may unravel new correlates to DRD4 and SLC6A3 variants. PMID- 22930792 TI - The relationships among ADHD, self-esteem, and test anxiety in young adults. AB - OBJECTIVE: The comorbidity of adult ADHD with test anxiety (TA) has not been previously reported. This comorbidity can potentially affect clinical and academic interventions among individuals with ADHD. The present study investigated the relationships among ADHD, self-esteem, and three subscales of TA among young adults: Cognitive Obstruction, Social Derogation, and Tenseness. METHOD: A total of 25 female participants diagnosed with ADHD and 30 female controls without ADHD of comparable age and education completed an Online Continuous Performance Test, an ADHD questionnaire, a self-esteem inventory, and a TA questionnaire. RESULTS: Participants with ADHD exhibited significantly higher levels of TA on all three subscales and lower levels of self-esteem compared with controls. Self-esteem served as a partial mediator between ADHD and cognitive obstruction TA and as a full mediator between ADHD and social derogation TA, but had no mediation effect in the relationships between ADHD and tenseness TA. CONCLUSION: The findings of this study suggest that TA, well known to affect success on tests, is correlated with ADHD. Therefore, interventions for ADHD should include components aimed at reducing TA. PMID- 22930793 TI - The prevalence and clinicopathological profile of IgM nephropathy in children with steroid-resistant nephrotic syndrome at a single centre in Pakistan. AB - BACKGROUND: There is little information on the clinicopathological characteristics of IgM nephropathy (IgMN) in paediatric steroid-resistant nephrotic syndrome (SRNS) and its response to calcineurin inhibitors (CNI). MATERIAL AND METHODS: This study was conducted at Sindh Institute of Urology and Transplantation, from January 2009 to August 2011. All SRNS children who received renal biopsies were included. Relevant data were compared among minimal change disease (MCD) and IgMN. The response to CNI was analysed in detail in IgMN by groups (group 1: complete or partial remission; group 2: no response). RESULTS: The frequency of IgMN in 147 children with SRNS was 13.6%. Compared with MCD, there was a male preponderance in IgMN. Blood urea and serum creatinine both at presentation and at last follow-up were significantly higher in IgMN. Regarding subgroups of IgMN, systolic blood pressure (SBP), blood urea and serum creatinine were significantly higher in group 2 at presentation, while at last follow-up, SBP, diastolic blood pressure and proteinuria were higher in group 2. The prevalence and degree of mesangial proliferation, global glomerulosclerosis, interstitial fibrosis and tubular atrophy were significantly higher in group 2. CONCLUSIONS: IgMN is a common cause of paediatric SRNS and is significantly different from MCD. There is also a significant difference in clinical and laboratory parameters among responders and non-responders to CNI in IgMN. PMID- 22930794 TI - Choosing sides: HIV health care practices among shared populations of HIV positive Latinos living near the US-Mexico border. AB - BACKGROUND: We compared HIV-positive patients receiving care in the border cities of San Diego, United States, with Tijuana, Mexico. METHODS: Participants were HIV positive Latinos (n = 233) receiving antiretroviral therapy (ART) from San Diego Tijuana clinics (2009-2010). Logistic regression identified correlates of receiving HIV care in San Diego versus Tijuana. RESULTS: Those with their most recent HIV visit in San Diego (59%) were more likely to be older, have at least a high school education, and were less likely to have been deported than those with last visits in Tijuana. Despite reporting better patient-provider relationships and less HIV-related stigma than those with visits in Tijuana, San Diego patients were twice as likely to make unsupervised changes in their ART regimen. CONCLUSIONS: We observed poorer relative adherence among HIV-positive Latinos receiving care in San Diego, despite reports of good clinical relationships. Further study is needed to ascertain underlying reasons to avoid ART-related resistance. PMID- 22930795 TI - Thalidomide-associated thrombosis in the treatment of HIV-associated severe aphthous disease: a case report and review of the literature. AB - Venous thrombosis is a well-described complication of thalidomide therapy in patients with multiple myeloma (MM). However, an association between thalidomide use and thrombosis in HIV-positive patients has not been previously described. We present the case of a 48-year-old HIV-positive man who developed a deep venous thrombosis while on thalidomide for the treatment of severe aphthous ulcers. We review the management of severe aphthous disease and the potential adverse effects of thalidomide therapy. We examine the association between thalidomide and thrombosis in patients with MM and discuss how the same relationship may or may not exist in HIV-positive patients. Although the strength of the association between thalidomide use and thrombosis in HIV-positive patients being treated for aphthous disease remains unclear, HIV providers should be aware of the potential risk of thrombosis in all patients receiving thalidomide. PMID- 22930796 TI - Once-daily nevirapine XR: a brief overview of the safety and efficacy of a new formulation. AB - Nevirapine (NVP) was the first nonnucleoside reverse transcriptase inhibitor (NNRTI) approved by the US Food and Drug Administration (FDA) in 1996, for the treatment of HIV infection. Current treatment guidelines include NVP as a component of a recommended alternative NNRTI regimen, which may be the preferred regimen for patients with established cardiovascular risk factors since NVP has minimal untoward effects on serum lipids. Two randomized and controlled clinical trials established the noninferior virologic efficacy of twice-daily NVP versus ritonavir-boosted atazanavir (ATV/r), a protease inhibitor with limited effects on serum lipids, each drug on a background regimen of once-daily (QD) tenofovir (TDF)/emtricitabine (FTC). An extended-release (XR) formulation of NVP was developed since QD dosing and reduced pill burdens have been shown to improve regimen adherence. This formulation (Viramune XR 400 mg) was recently FDA approved based on the results of 2 randomized, controlled clinical trials. The XR formulation will provide additional treatment options for patients who may benefit from NVP-based regimens. PMID- 22930797 TI - The intubated patient with mediastinal disease--a role for esophageal access using the endobronchial ultrasound bronchoscope. AB - Ultrasound-guided transbronchial needle aspiration using the bronchoscope with a dedicated curvilinear probe has emerged as a primary tool for the investigation of mediastinal pathology. Recently, the utility of this scope has been expanded to include access via the esophagus. In this case series, we describe a role for esophageal ultrasound using the endobronchial ultrasound bronchoscope in the diagnostic evaluation of critically ill/intubated patients with mediastinal disease. Esophageal access with the ultrasound bronchoscope allows the pulmonologist to diagnose mediastinal disease in the intubated patient with minimal risk. PMID- 22930798 TI - Retraction. "Immunohistochemical prognostic markers in diffuse large B-cell lymphoma: validation of tissue microarray as a prerequisite for broad clinical applications (a study from the Lunenburg Lymphoma Biomarker Consortium)" (J Clin Pathol 2009;62:128-38;doi:10.1136/jcp.2008.057257). AB - The Journal of Clinical Pathology wishes to inform its readers of the authors' retraction of the following article for redundancy. The original article by D de Jong, W Xie, Rosenwald, M Chhanabhai, P Gaulard,W Klapper, A Lee, B Sander, C Thorns,E Campo, T Molina, A Hagenbeek,S Horning, A Lister, J Raemaekers, G Salles, R D Gascoyne and E Weller entitled "Immunohistochemical prognostic markersi n diffuse large B-cell lymphoma: validation of tissue microarray as a prerequisite for broad clinical applications (a study from the Lunenburg Lymphoma Biomarker Consortium)" (J Clin Pathol 2009;62:128-38;doi:10.1136/jcp.2008.057257) published online on 15 September 2008, contained substantial overlap in text, data, and conclusions compared with a previous article with the same title published in Journal of Clinical Oncology on 1 March 2007 by Daphne de Jong, Andreas Rosenwald, Mukesh Chhanabhai, Philippe Gaulard,Wolfram Klapper, Abigail Lee, Birgitta Sander, Christoph Thorns, Elias Campo, Thierry Molina, Andrew Norton, Anton Hagenbeek, Sandra Horning, Andrew Lister, John Raemaekers, Randy D Gascoyne, Gilles Salles and Edie Weller (doi:10.1200/JCO.2006.09.4490). In addition, the authors did not cite the Journal of Clinical Oncology article in the paper published in Journal of Clinical Pathology. PMID- 22930799 TI - Association of objectively measured physical activity with established and novel cardiovascular biomarkers in elderly subjects: every step counts. AB - OBJECTIVE: To analyse the relationship between objectively measured daily walking duration and cardiovascular biomarkers of inflammation, cardiac dysfunction and renal impairment. METHODS: Between March 2009 and April 2010, physical activity was assessed in 1253 community-dwelling individuals living in Germany aged >=65 years (57% men) over 1 week using a thigh-worn accelerometer. C reactive protein (CRP), white blood cells (WBC), N-terminal pro-brain natriuretic peptide, high sensitive troponin T (hsTnT), creatinine (Cr) and cystatin C (CysC) were also measured. Least-square means of daily walking duration were calculated for quartiles of each biomarker adjusted for sex, age, pre-existing cardiovascular disease and smoking status. RESULTS: After adjustment for covariates, statistically significant linear associations with walking duration were observed for WBC, hsTnT, Cr and CysC. CRP quartiles 1 and 2 showed no significant difference followed by a significant inverse dose-response relationship. A similar pattern, but less pronounced, was seen for N-terminal pro-brain natriuretic peptide. Mean differences between the first two quartiles of CRP and its fourth quartile were 17 min. Between categories 1 (more beneficial) and 4 of WBC, hsTnT, Cr and CysC the differences were 15, 12, 23 and 20 min, respectively. CONCLUSION: Increased walking duration is associated with a more favourable profile of cardiovascular biomarkers in elderly subjects. PMID- 22930800 TI - Of receptors, channels, and watching the red cell center lose hold. PMID- 22930801 TI - Fitting K(V) potassium channels into the PIP(2) puzzle: Hille group connects dots between illustrious HH groups. PMID- 22930802 TI - Structural changes during HCN channel gating defined by high affinity metal bridges. AB - Hyperpolarization-activated cyclic nucleotide-sensitive nonselective cation (HCN) channels are activated by membrane hyperpolarization, in contrast to the vast majority of other voltage-gated channels that are activated by depolarization. The structural basis for this unique characteristic of HCN channels is unknown. Interactions between the S4-S5 linker and post-S6/C-linker region have been implicated previously in the gating mechanism of HCN channels. We therefore introduced pairs of cysteines into these regions within the sea urchin HCN channel and performed a Cd(2+)-bridging scan to resolve their spatial relationship. We show that high affinity metal bridges between the S4-S5 linker and post-S6/C-linker region can induce either a lock-open or lock-closed phenotype, depending on the position of the bridged cysteine pair. This suggests that interactions between these regions can occur in both the open and closed states, and that these regions move relative to each other during gating. Concatenated constructs reveal that interactions of the S4-S5 linker and post S6/C-linker can occur between neighboring subunits. A structural model based on these interactions suggests a mechanism for HCN channel gating. We propose that during voltage-dependent activation the voltage sensors, together with the S4-S5 linkers, drive movement of the lower ends of the S5 helices around the central axis of the channel. This facilitates a movement of the pore-lining S6 helices, which results in opening of the channel. This mechanism may underlie the unique voltage dependence of HCN channel gating. PMID- 22930803 TI - Tuning of EAG K(+) channel inactivation: molecular determinants of amplification by mutations and a small molecule. AB - Ether-a-go-go (EAG) and EAG-related gene (ERG) K(+) channels are close homologues but differ markedly in their gating properties. ERG1 channels are characterized by rapid and extensive C-type inactivation, whereas mammalian EAG1 channels were previously considered noninactivating. Here, we show that human EAG1 channels exhibit an intrinsic voltage-dependent slow inactivation that is markedly enhanced in rate and extent by 1-10 uM 3-nitro-N-(4-phenoxyphenyl) benzamide, or ICA105574 (ICA). This compound was previously reported to have the opposite effect on ERG1 channels, causing an increase in current magnitude by inhibition of C-type inactivation. The voltage dependence of 2 uM ICA-induced inhibition of EAG1 current was half-maximal at -73 mV, 62 mV negative to the half-point for channel activation. This finding suggests that current inhibition by the drug is mediated by enhanced inactivation and not open-channel block, where the voltage half-points for current inhibition and channel activation are predicted to overlap, as we demonstrate for clofilium and astemizole. The mutation Y464A in the S6 segment also induced inactivation of EAG1, with a time course and voltage dependence similar to that caused by 2 uM ICA. Several Markov models were investigated to describe gating effects induced by multiple concentrations of the drug and the Y464A mutation. Models with the smallest fit error required both closed- and open-state inactivation. Unlike typical C-type inactivation, the rate of Y464A- and ICA-induced inactivation was not decreased by external tetraethylammonium or elevated [K(+)](e). EAG1 channel inactivation introduced by Y464A was prevented by additional mutation of a nearby residue located in the S5 segment (F359A) or pore helix (L434A), suggesting a tripartite molecular model where interactions between single residues in S5, S6, and the pore helix modulate inactivation of EAG1 channels. PMID- 22930804 TI - The contribution of hydrophobic residues in the pore-forming region of the ryanodine receptor channel to block by large tetraalkylammonium cations and Shaker B inactivation peptides. AB - Although no high-resolution structural information is available for the ryanodine receptor (RyR) channel pore-forming region (PFR), molecular modeling has revealed broad structural similarities between this region and the equivalent region of K(+) channels. This study predicts that, as is the case in K(+) channels, RyR has a cytosolic vestibule lined with predominantly hydrophobic residues of transmembrane helices (TM10). In K(+) channels, this vestibule is the binding site for blocking tetraalkylammonium (TAA) cations and Shaker B inactivation peptides (ShBPs), which are stabilized by hydrophobic interactions involving specific residues of the lining helices. We have tested the hypothesis that the cytosolic vestibule of RyR fulfils a similar role and that TAAs and ShBPs are stabilized by hydrophobic interactions with residues of TM10. Both TAAs and ShBPs block RyR from the cytosolic side of the channel. By varying the composition of TAAs and ShBPs, we demonstrate that the affinity of both species is determined by their hydrophobicity, with variations reflecting alterations in the dissociation rate of the bound blockers. We investigated the role of TM10 residues of RyR by monitoring block by TAAs and ShBPs in channels in which the hydrophobicity of individual TM10 residues was lowered by alanine substitution. Although substitutions changed the kinetics of TAA interaction, they produced no significant changes in ShBP kinetics, indicating the absence of specific hydrophobic sites of interactions between RyR and these peptides. Our investigations (a) provide significant new information on both the mechanisms and structural components of the RyR PFR involved in block by TAAs and ShBPs, (b) highlight important differences in the mechanisms and structures determining TAA and ShBP block in RyR and K(+) channels, and (c) demonstrate that although the PFRs of these channels contain analogous structural components, significant differences in structure determine the distinct ion-handling properties of the two species of channel. PMID- 22930805 TI - Modulation of innate host factors by Mycobacterium avium complex in human macrophages includes interleukin 17. AB - BACKGROUND: Although opportunistic infections due to Mycobacterium avium complex (MAC) have been less common since the introduction of highly active antiretroviral therapy, globally, human immunodeficiency virus-1 (HIV-1)-positive patients remain predisposed to these infections. Absence of a properly functioning acquired immune response allows MAC persistence within macrophages localized in lymph nodes coinfected with HIV and MAC. Although a deficiency in interferon gamma appears to play a part in the ability of MAC to deflect the macrophage-associated antimicrobial attack, questions about this process remain. Our study examines the ability of MAC to regulate interleukin 17 (IL-17), a proinflammatory cytokine involved in host cell recruitment. METHODS: Coinfected lymph nodes were examined for IL-17 by immunohistochemical analysis. In vitro, macrophages exposed to mycobacteria were evaluated for transcription activities, proteins, and signaling pathways responsible for IL-17 expression. Infected macrophages were also analyzed for expression of interleukin 21 (IL-21) and negative regulators of immune responses. RESULTS: Infection of macrophages triggered synthesis of IL-17, correlating with IL-17 expression by macrophages in coinfected lymph nodes. Infected macrophages exposed to exogenous IL-17 expressed CXCL10, which favors recruitment of new macrophages as targets for infection. Blockade of nuclear factor kappa-light-chain-enhancer of activated B cells and mitogen-activated protein kinase pathways suppressed mycobacteria-induced IL-17 expression. MAC triggered expression of IL-21, IRF4, and STAT3 genes related to IL-17 regulation, as well as expression of the negative immunoregulators CD274(PD L1) and suppressors of cytokine signaling. CONCLUSIONS: MAC-infected macrophages can provide an alternative source for IL-17 that favors accumulation of new targets for perpetuating bacterial and viral infection while suppressing host antimicrobial immune responses. PMID- 22930806 TI - Diversity of individual dynamic patterns of emergence of resistance to quinolones in Escherichia coli from the fecal flora of healthy volunteers exposed to ciprofloxacin. AB - BACKGROUND: Emergence of quinolone-resistant Escherichia coli (QREC) is an increasing clinical challenge mostly originating in fecal microbiota. The dynamics of the emergence of QREC in feces from individuals exposed to ciprofloxacin is unknown. METHODS: A total of 48 healthy volunteers received oral ciprofloxacin for 14 days. Fecal specimens were collected on days 0, 8, 14, and 42. Subpopulations of QREC were detected on selective agar, genetically characterized, and compared with quinolone-susceptible E. coli (QSEC) strains collected on different days. RESULTS: On day 42, 34 subjects carried QSEC, and 14 carried QREC. Of the 14 who carried QREC, 9 carried quinolone-susceptible E. coli on day 0, 1 carried E. coli with a lower level of quinolone resistance on day 0, and 4 carried E. coli with similar levels of resistance and RAPD-genotypes on days 0 and 42. No plasmid acquisition and no selection of resistant mutants from the initial microbiota was evidenced in any case. CONCLUSIONS: In QREC emerging under ciprofloxacin pressure in the fecal microbiota, no proof of selection of quinolone-resistant mutants from the initial microbiota was evidenced, suggesting that QREC strains on day 42 were either present at undetectable levels in the initial microbiota or that exogenous acquisition of QREC strains occurred. Clinical Trials Registration. NCT00190151. PMID- 22930807 TI - Permeases of the sap transporter are required for cathelicidin resistance and virulence of Haemophilus ducreyi in humans. AB - BACKGROUND: Haemophilus ducreyi encounters several classes of antimicrobial peptides (APs) in vivo and utilizes the sensitive-to-antimicrobial-peptides (Sap) transporter as one mechanism of AP resistance. A mutant lacking the periplasmic solute-binding component, SapA, was somewhat more sensitive to the cathelicidin LL-37 than the parent strain and was partially attenuated for virulence. The partial attenuation led us to question whether the transporter is fully abrogated in the sapA mutant. METHODS: We generated a nonpolar sapBC mutant, which lacks both inner membrane permeases of the Sap transporter, and tested the mutant for virulence in human volunteers. In vitro, we compared LL-37 resistance phenotypes of the sapBC and sapA mutants. RESULTS: Unlike the sapA mutant, the sapBC mutant was fully attenuated for virulence in human volunteers. In vitro, the sapBC mutant exhibited significantly greater sensitivity than the sapA mutant to killing by LL-37. Similar to the sapA mutant, the sapBC mutant did not affect H. ducreyi's resistance to human defensins. CONCLUSIONS: Compared with the sapA mutant, the sapBC mutant exhibited greater attenuation in vivo, which directly correlated with increased sensitivity to LL-37 in vitro. These results strongly suggest that the SapBC channel retains activity when SapA is removed. PMID- 22930809 TI - The glutamic acid decarboxylase system of the new species Brucella microti contributes to its acid resistance and to oral infection of mice. AB - BACKGROUND: Genome analysis indicated that the new species Brucella microti possesses a potentially functional glutamate decarboxylase (GAD) system involved in extreme acid resistance in several foodborne bacteria. The contribution of this system in adaptation of B. microti to an acidic environment, including the intracellular vacuole and stomach, was investigated. RESULTS: B. microti was GAD positive and able to export its product, gamma-aminobutyrate, to the extracellular medium. The resistance of B. microti to acid stress (pH 2.5) was glutamate dependent. Mutants affected in the GAD system lost this resistance, demonstrating its direct involvement in survival under these conditions. The reciprocal heterologous complementation of mutants with the GAD systems of Escherichia coli or B. microti confirmed conserved functions in both bacterial species. A gad mutant was not attenuated during infection of macrophages, where Brucella resides in an acidified vacuole at a pH of 4-4.5 during the early phase of macrophage infection, but GAD contributed to the survival of B. microti in a murine model following oral infection. CONCLUSIONS: This work provides first evidence that the GAD system might play an essential role in the resistance of an environment-borne, pathogenic Brucella species to extreme acid shock and during passage through the host stomach following oral infection. PMID- 22930810 TI - Gastrointestinal bacteria will have its way. PMID- 22930808 TI - Epidemiological dynamics and phylogeography of influenza virus in southern China. AB - BACKGROUND: Understanding the epidemiological dynamics of influenza virus is central to surveillance and vaccine strain selection. It has been suggested that tropical and subtropical regions represent the global source of influenza epidemics. However, our understanding of the epidemiological dynamics of influenza virus in these regions is limited by a relative lack of long-term data. METHODS: We analyzed epidemiological and virological data on influenza recorded over a period of 15 years from the metropolitan city of Shenzhen in subtropical southern China. We used wavelet analysis to determine the periodicity of influenza epidemics and molecular phylogeographic analysis to investigate the role of Shenzhen and southern China in the global evolution of influenza virus. RESULTS: We show that southern China is unlikely to represent an epicenter of global influenza activity, because activity in Shenzhen is characterized by significant annual cycles, multiple viral introductions every year, limited persistence across epidemic seasons, and viruses that generally are not positioned on the trunk of the global influenza virus phylogeny. CONCLUSIONS: We propose that novel influenza viruses emerge and evolve in multiple geographic localities and that the global evolution of influenza virus is complex and does not simply originate from a southern Chinese epicenter. PMID- 22930811 TI - Mass spectrometry images acylcarnitines, phosphatidylcholines, and sphingomyelin in MDA-MB-231 breast tumor models. AB - The lipid compositions of different breast tumor microenvironments are largely unknown due to limitations in lipid imaging techniques. Imaging lipid distributions would enhance our understanding of processes occurring inside growing tumors, such as cancer cell proliferation, invasion, and metastasis. Recent developments in MALDI mass spectrometry imaging (MSI) enable rapid and specific detection of lipids directly from thin tissue sections. In this study, we performed multimodal imaging of acylcarnitines, phosphatidylcholines (PC), a lysophosphatidylcholine (LPC), and a sphingomyelin (SM) from different microenvironments of breast tumor xenograft models, which carried tdTomato red fluorescent protein as a hypoxia-response element-driven reporter gene. The MSI molecular lipid images revealed spatially heterogeneous lipid distributions within tumor tissue. Four of the most-abundant lipid species, namely PC(16:0/16:0), PC(16:0/18:1), PC(18:1/18:1), and PC(18:0/18:1), were localized in viable tumor regions, whereas LPC(16:0/0:0) was detected in necrotic tumor regions. We identified a heterogeneous distribution of palmitoylcarnitine, stearoylcarnitine, PC(16:0/22:1), and SM(d18:1/16:0) sodium adduct, which colocalized primarily with hypoxic tumor regions. For the first time, we have applied a multimodal imaging approach that has combined optical imaging and MALDI MSI with ion mobility separation to spatially localize and structurally identify acylcarnitines and a variety of lipid species present in breast tumor xenograft models. PMID- 22930812 TI - Effect of fenofibrate and atorvastatin on VLDL apoE metabolism in men with the metabolic syndrome. AB - We examined the effects of fenofibrate and atorvastatin on very low density lipoprotein (VLDL) apolipoprotein (apo)E metabolism in the metabolic syndrome (MetS). We studied 11 MetS men in a randomized, double-blind, crossover trial. VLDL-apoE kinetics were examined using stable isotope methods and compartmental modeling. Compared with placebo, fenofibrate (200 mg/day) and atorvastatin (40 mg/day) decreased plasma apoE concentrations (P < 0.05). Fenofibrate decreased VLDL-apoE concentration and production rate (PR) and increased VLDL-apoE fractional catabolic rate (FCR) compared with placebo (P < 0.05). Compared with placebo, atorvastatin decreased VLDL-apoE concentration and increased VLDL-apoE FCR (P < 0.05). Fenofibrate and atorvastatin had comparable effects on VLDL-apoE concentration. The increase in VLDL-apoE FCR with fenofibrate was 22% less than that with atorvastatin (P < 0.01). With fenofibrate, the change in VLDL-apoE concentration was positively correlated with change in VLDL-apoB concentration, and negatively correlated with change in VLDL-apoB FCR. In MetS, fenofibrate and atorvastatin decreased plasma apoE concentrations. Fenofibrate decreased VLDL apoE concentration by lowering VLDL-apoE production and increasing VLDL-apoE catabolism. By contrast, atorvastatin decreased VLDL-apoE concentration chiefly by increasing VLDL-apoE catabolism. Our study provides new insights into the mechanisms of action of two different lipid-lowering therapies on VLDL-apoE metabolism in MetS. PMID- 22930813 TI - Nicotinic acid inhibits hepatic APOA gene expression: studies in humans and in transgenic mice. AB - Elevated plasma lipoprotein(a) (LPA) levels are recognized as an independent risk factor for cardiovascular diseases. Our knowledge on LPA metabolism is incomplete, which makes it difficult to develop LPA-lowering medications. Nicotinic acid (NA) is the main drug recommended for the treatment of patients with increased plasma LPA concentrations. The mechanism of NA in lowering LPA is virtually unknown. To study this mechanism, we treated transgenic (tg) APOA mice with NA and measured plasma APOA and hepatic mRNA levels. In addition, mouse and human primary hepatocytes were incubated with NA, and the expression of APOA was followed. Feeding 1% NA reduced plasma APOA and hepatic expression of APOA in tg APOA mice. Experiments with cultured human and mouse primary hepatocytes in addition to reporter assays performed in HepG2 cells revealed that NA suppresses APOA transcription. The region between -1446 and -857 of the human APOA promoter harboring several cAMP response element binding sites conferred the negative effect of NA. In accordance, cAMP stimulated APOA transcription, and NA reduced hepatic cAMP levels. It is suggested that cAMP signaling might be involved in reducing APOA transcription, which leads to the lowering of plasma LPA. PMID- 22930814 TI - Is psycho-physical stress a risk factor for stroke? A case-control study. AB - BACKGROUND: Chronic stress is associated with cardiovascular diseases, but the link with stroke has not been well established. Stress is influenced by life style habits, personality type and anxiety levels. We sought to evaluate psycho physical stress as a risk factor for stroke, while assessing gender influences. METHODS: Case-control study. cases: patients (n=150) aged 18-65, admitted consecutively to our Stroke Unit with the diagnosis of incident stroke. CONTROLS: (n=300) neighbours (paired with case +/-5 years) recruited from the census registry. STUDY VARIABLES: socio-demographic characteristics, vascular risk factors, psychophysical scales of H&R (Holmes & Rahe questionnaire of life events), ERCTA (recall scale of type A behaviour), SF12 (QoL scale), GHQ28 (general health questionnaire). Statistical analyses included conditional multiple logistic regression models. RESULTS: Mean age was 53.8 years (SD: 9.3). Compared with controls, and following adjustment for confounding variables, significant associations between stroke and stress were: H&R values >150 OR=3.84 (95% CI 1.91 to 7.70, p<0.001); ERCTA (values >24) OR=2.23 (95% CI 1.19 to 4.18, p=0.012); mental SF12 (values >50) OR=0.73 (95% CI 0.39 to 1.37, p=0.330); psychological SF12 (values >50) OR=0.66 (95% CI 0.33 to 1.30, p=0.229), male gender OR=9.33 (95% CI 4.53 to 19.22, p<0.001), high consumption of energy providing beverages OR=2.63 (95% CI 1.30 to 5.31, p=0.007), current smoker OR=2.08 (95% CI 1.01 to 4.27, p=0.046), ex-smoker OR=2.35 (95% CI 1.07 to 5.12, p=0.032), cardiac arrhythmia OR=3.18 (95% CI 1.19 to 8.51, p=0.022) and Epworth scale (>=9) OR=2.83 (95% CI 1.03 to 7.78, p=0.044). CONCLUSIONS: Compared with healthy age-matched individuals, stressful habits and type A behaviour are associated with high risk of stroke. This association is not modified by gender. PMID- 22930815 TI - Quantitative determination of apoptosis of pancreatic beta-cells in a murine model of type 1 diabetes mellitus. AB - Type 1 diabetes mellitus is characterized by a significant deficit in pancreatic beta-cell mass, presumably caused by beta-cell apoptosis. We investigated the incidence of beta-cell apoptosis in streptozotocin-treated mice and nonobese diabetic (NOD) mice with (99m)Tc-annexin A5. METHODS: Vehicle-treated mice, streptozotocin-treated mice, and NOD mice at the ages of 5, 9, 16, and 20 wk (5-8 mice per group) were injected with (99m)Tc-annexin A5 and sacrificed 6 h later for autoradiography, and the regional (99m)Tc-annexin A5 level in the pancreas was evaluated. Pancreatic islets were identified by insulin immunohistochemical staining, and apoptotic cells were determined by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) staining. The (99m)Tc-annexin A5 level in pancreatic islets was expressed as the percentage injected dose per area of pancreatic islets and normalized by animal body weight (%ID * 10(6)/mm(2)/kg). The level of apoptotic cells in pancreatic islets was expressed as the number of TUNEL-positive cells per area of pancreatic islets (cells/mm(2)). RESULTS: The (99m)Tc-annexin A5 accumulation level was significantly higher (2.5 +/- 0.7 vs. 0.7 +/- 0.1 %ID * 10(6)/mm(2)/kg, P < 0.05) and the number of TUNEL-positive cells was significantly higher (1,170 +/- 535 vs. 5 +/- 6 cells/mm(2), P < 0.05) in the pancreatic islets of the streptozotocin treated mice than in those of the vehicle-treated mice. The (99m)Tc-annexin A5 accumulation level was significantly higher (1.1 +/- 0.4 vs. 0.5 +/- 0.1 %ID * 10(6)/mm(2)/kg, P < 0.05) and the number of TUNEL-positive cells was significantly higher (152 +/- 82 vs. 4 +/- 9 cells/mm(2), P < 0.05) in the pancreatic islets of 16-wk-old NOD mice than in those of 5-wk-old NOD mice. In addition, the level of (99m)Tc-annexin A5 correlated with the number of TUNEL positive cells in the pancreatic islets of the streptozotocin-treated mice (r = 0.821, P < 0.001) and NOD mice (r = 0.721, P < 0.001). CONCLUSION: There is significant islet cell apoptosis with (99m)Tc-annexin A5 accumulation in the pancreas of both streptozotocin and NOD mice. PMID- 22930817 TI - Resolving conflict in eutherian mammal phylogeny using phylogenomics and the multispecies coalescent model. AB - The reconstruction of the Tree of Life has relied almost entirely on concatenation methods, which do not accommodate gene tree heterogeneity, a property that simulations and theory have identified as a likely cause of incongruent phylogenies. However, this incongruence has not yet been demonstrated in empirical studies. Several key relationships among eutherian mammals remain controversial and conflicting among previous studies, including the root of eutherian tree and the relationships within Euarchontoglires and Laurasiatheria. Both bayesian and maximum-likelihood analysis of genome-wide data of 447 nuclear genes from 37 species show that concatenation methods indeed yield strong incongruence in the phylogeny of eutherian mammals, as revealed by subsampling analyses of loci and taxa, which produced strongly conflicting topologies. In contrast, the coalescent methods, which accommodate gene tree heterogeneity, yield a phylogeny that is robust to variable gene and taxon sampling and is congruent with geographic data. The data also demonstrate that incomplete lineage sorting, a major source of gene tree heterogeneity, is relevant to deep-level phylogenies, such as those among eutherian mammals. Our results firmly place the eutherian root between Atlantogenata and Boreoeutheria and support ungulate polyphyly and a sister-group relationship between Scandentia and Primates. This study demonstrates that the incongruence introduced by concatenation methods is a major cause of long-standing uncertainty in the phylogeny of eutherian mammals, and the same may apply to other clades. Our analyses suggest that such incongruence can be resolved using phylogenomic data and coalescent methods that deal explicitly with gene tree heterogeneity. PMID- 22930818 TI - Dynamics of the L-fucose/H+ symporter revealed by fluorescence spectroscopy. AB - FucP of Escherichia coli catalyzes L-fucose/H(+) symport, and a crystal structure in an outward-facing conformation has been reported. However, nothing is known about FucP conformational dynamics. Here, we show that addition of L-fucose to purified FucP in detergent induces ~20% quenching of Trp fluorescence in a concentration-dependent manner without a shift in lambda(max). Quenching is essentially abolished when both Trp38 and Trp278, which are positioned on opposing faces of the outward-facing cavity walls, are replaced with Tyr or Phe, and reduced quenching is observed when either Trp is mutated. Therefore, both Trp residues are involved in the phenomenon. Furthermore, replacement of either Trp38 or Trp278, predominantly Trp38, causes decreased quenching, decreased apparent affinity for L-fucose, and significant inhibition of active L-fucose transport, indicating that the two residues are likely involved directly in sugar binding. It is proposed that sugar binding induces a conformational change in which the outward-facing cavity in FucP closes, thereby bringing Trp38 and Trp278 into close proximity around the bound sugar to form an "occluded" intermediate. The location of these two Trp residues provides a unique method for analyzing structural dynamics in FucP. PMID- 22930819 TI - Structural insights into the editing of germ-line-encoded interactions between T cell receptor and MHC class II by Valpha CDR3. AB - The conserved diagonal docking mode observed in structures of T-cell receptors (TCRs) bound to peptide-MHC ligands is believed to reflect coevolution of TCR and MHC genes. This coevolution is supported by the conservation of certain interactions between the germ-line-encoded complementarity-determining region (CDR)1 and CDR2 loops of TCR and MHC. However, the rules governing these interactions are not straightforward, even when the same variable (V) region recognizes the same MHC molecule. Here, we demonstrate that the somatically generated CDR3 loops can markedly alter evolutionarily selected contacts between TCR and MHC ("CDR3 editing"). To understand CDR3 editing at the atomic level, we determined the structure of a human melanoma-specific TCR (G4) bound to the MHC class II molecule HLA-DR1 and an epitope from mutant triose phosphate isomerase (mutTPI). A comparison of the G4-mutTPI-DR1 complex with a complex involving a TCR (E8) that uses the same Valpha region to recognize the same mutTPI-DR1 ligand as G4 revealed that CDR1alpha adopts markedly different conformations in the two TCRs, resulting in an almost entirely different set of contacts with MHC. Based on the structures of unbound G4 and E8, the distinct conformations of CDR1alpha in these TCRs are not induced by binding to mutTPI-DR1 but result from differences in the length and sequence of CDR3alpha that are transmitted to CDR1alpha. The editing of germ-line-encoded TCR-MHC interactions by CDR3 demonstrates that these interactions possess sufficient intrinsic flexibility to accommodate large structural variations in CDR3 and, consequently, in the TCR binding site. PMID- 22930821 TI - Maternal effects can inflate rate of adaptation to captivity. PMID- 22930820 TI - Antibodies and IL-3 support helminth-induced basophil expansion. AB - Basophils are powerful mediators of Th2 immunity and are present in increased numbers during allergic inflammation and helminth infection. Despite their ability to potentiate Th2 immunity the mechanisms regulating basophil development remain largely unknown. We have found a unique role for isotype-switched antibodies in promoting helminth-induced basophil production following infection of mice with Heligmosomoides polygyrus bakeri or Nippostrongylus brasiliensis. H. polygyrus bakeri-induced basophil expansion was found to occur within the bone marrow, and to a lesser extent the spleen, and was IL-3 dependent. IL-3 was largely produced by CD4(+)CD49b(+)NK1.1(-) effector T cells at these sites, and required the IL-4Ralpha chain. However, antibody-deficient mice exhibited defective basophil mobilization despite intact T-cell IL-3 production, and supplementation of mice with immune serum could promote basophilia independently of required IL-4Ralpha signaling. Helminth-induced eosinophilia was not affected by the deficiency in isotype-switched antibodies, suggesting a direct effect on basophils rather than through priming of Th2 responses. Although normal type 2 immunity occurred in the basopenic mice following primary infection with H. polygyrus bakeri, parasite rejection following challenge infection was impaired. These data reveal a role for isotype-switched antibodies in promoting basophil expansion and effector function following helminth infection. PMID- 22930822 TI - Will identification of a prostate cancer stem cell lead to its cure? PMID- 22930823 TI - New technologies and techniques for laparoscopic partial nephrectomy. PMID- 22930824 TI - The quest for quantitative microscopy. AB - With the aid of informatics, microscopy is in the midst of a crucial evolution into a more quantitative and powerful technique. PMID- 22930825 TI - Points of view: Representing genomic structural variation. PMID- 22930826 TI - FDA treads carefully with PrEP. PMID- 22930827 TI - Chlamydia: a much underestimated STI. PMID- 22930828 TI - Secrets of RNA granules. PMID- 22930829 TI - DNA nanoLEGOlogy. PMID- 22930830 TI - Sorting out epigenetic states. PMID- 22930832 TI - Taming stem cell heterogeneity. PMID- 22930831 TI - Shaping the waves. PMID- 22930833 TI - The sixth base and counting. PMID- 22930834 TI - NIH Image to ImageJ: 25 years of image analysis. AB - For the past 25 years NIH Image and ImageJ software have been pioneers as open tools for the analysis of scientific images. We discuss the origins, challenges and solutions of these two programs, and how their history can serve to advise and inform other software projects. PMID- 22930836 TI - Blood type study sheds light on biology of pancreatic cancer. PMID- 22930835 TI - Georgetown researcher: two or more drinks a day may increase pancreatic cancer risk. PMID- 22930837 TI - Synthetic gene circuit allows precise dosing of gene expression. PMID- 22930838 TI - UCLA launches urologic oncology institute to develop leading-edge therapies. PMID- 22930840 TI - Abstracts of the 42nd Annual ESDR (European Society for Dermatological Research) Meeting. September 7-10, 2012. Venice, Italy. PMID- 22930839 TI - Effects of Streptococcus thermophilus TH-4 on intestinal mucositis induced by the chemotherapeutic agent 5-Fluorouracil (5-FU). AB - Beneficial bacteria (probiotics) and probiotic-derived factors have the potential to ameliorate disorders of the intestine. The aim of this study was to compare live Streptococcus thermophilus TH-4 (TH-4), dead TH-4 and TH-4 supernatant in rats treated with 5-Fluorouracil. Rats were randomly allocated to five treatment groups (n = 8-10): Saline + Water; 5-FU + Skim Milk; 5-FU+ Live TH-4; 5-FU + Supernatant TH-4; and 5-FU + Dead TH-4.5-FU (150 mg.kg-1) was administered by a single intraperitoneal injection on day zero; animals were killed on day four. Treatments were administered daily from days -2 to +3 via oro-gastric gavage. Metabolic parameters were measured daily. Blood was obtained by cardiac puncture, and intestinal tissues removed for quantitative and qualitative histological assessment, including: villus height and area; crypt depth and area, mitotic count and crypt fission;biochemical determination of sucrase and myeloperoxidase (MPO)activity; and disease severity scoring. One-way ANOVA statistical analyses were conducted for the majority of outcome measures. Live TH-4 significantly reduced disease severity score by 13% (p< 0.05), and partially normalized mitotic counts compared with 5-FU + Skim Milk controls. Live and Supernatant TH-4 reduced crypt fission by 69% and 48% (p < 0.05), respectively, compared to 5-FU + Skim Milk controls. No significant differences (p > 0.05) in the occurrence of bacteraemia were evident across all groups. Live TH-4 partially normalized mitotic count and histological severity score in 5-FU treated rats. The inhibitory effect of live TH-4 and TH-4 Supernatant on crypt fission suggests therapeutic utility in the prevention of disorders characterized by increased crypt fission,such as colorectal carcinoma. PMID- 22930841 TI - Abstracts of the 4th Australian Lung Cancer Conference (ALCC). Adelaide, Australia. August 23-25, 2012. PMID- 22930842 TI - 2010: the emergency medical services literature in review. AB - Emergency physicians, specialists, and primary care doctors across the health care delivery spectrum remain actively engaged in the provision of medical oversight for emergency medical services (EMS) systems, a vital link in the medical continuum of care. Practicing emergency physicians, regardless of their level of formal EMS training, interface with EMS system components and providers on a regular basis. It is important to remain aware of trends and practice patterns that have the potential to affect the care of emergency patients. PubMed was used to find articles for this review. The authors included EMS articles from 2010 felt applicable to all emergency physicians that fit the general topics discussed in this review. Some key articles from 2009 were also included. Case series were generally excluded. The selection is by no means an attempt to single out the best research articles. Like a single 12-lead electrocardiographic (ECG) tracing, this review represents a "snapshot" of current discussions in the EMS community. Prehospital medicine is a dynamic discipline, and its practice patterns are not identical to those found in a hospital emergency department (ED). The purpose of this literature review is to familiarize emergency physicians with some of the ongoing discussions in the prehospital literature. PMID- 22930843 TI - A patient with short term memory problems and ataxia. PMID- 22930844 TI - Rapid neurological deterioration in a patient with hepatitis A infection. PMID- 22930845 TI - 'This chimp will kick your ass at memory games - but how the hell does he do it?'. AB - Extraordinary evidence generates extraordinary claims. I discuss the remarkable memory skills of chimpanzees tested in the Kyoto Primate Laboratory, and suggest a novel - but deflationary - hypothesis to explain them. Could the chimpanzees, who have been highly trained to learn the sequence of Arabic numerals, have developed number-colour synaesthesia? PMID- 22930847 TI - Teaching the world to listen. PMID- 22930846 TI - Abstracts of the 2010 Joint Annual Meeting of the American Association for Cancer Education, the European Association for Cancer Education and the Cancer Patient Education Network. San Diego, California, USA. October 25-27, 2010. PMID- 22930848 TI - The generous words of heredity. PMID- 22930849 TI - Nothing to hide, something to gain? how the US Sunshine Act may effect Canadian doctors. PMID- 22930850 TI - [Life in balance]. PMID- 22930851 TI - [Healthy and motivated into retirement]. PMID- 22930852 TI - [Pointed, sharp and fragile]. PMID- 22930853 TI - [Treating back, skin and soul well]. PMID- 22930854 TI - [Increasing the attractiveness of education]. PMID- 22930855 TI - [Managing ethnic diversity]. PMID- 22930856 TI - [Opening the door to foreign lifestyles]. PMID- 22930857 TI - [Systemizing and standardizing]. PMID- 22930858 TI - [Tai Chi in rheumatoid arthritis]. PMID- 22930859 TI - [Managing public announcements skillfully]. PMID- 22930860 TI - [The art of motivating]. PMID- 22930861 TI - [Nursing under the Mallorca sun]. PMID- 22930862 TI - [Data security is a primary condition for treatment success]. PMID- 22930863 TI - [Alcohol, nicotine and sleep deprivation]. PMID- 22930864 TI - ["Scientific evidence not considered"]. PMID- 22930865 TI - [Premature aging in human immunodeficiency virus (HIV) infected patients: detection, pathophysiological mechanisms and management]. AB - Most patients diagnosed with human immunodeficiency virus (HIV) infection now receive effective treatment. However, as the HIV-infected population gets older, manifestations of aging is starting to emerge 10-15 years earlier than in the general population, such as cardiovascular disease, osteoporosis, neurocognitive disorders, metabolic complications, and kidney and liver failure. Clinical studies suggest that the pathophysiology of this premature aging may be multifactorial. In addition to residual HIV infection, immune activation (leading to immunodeficiency) and some antiretrovirals might contribute to low-grade systemic inflammation that could drive tissue senescence and provoke degenerative and proliferative disorders. Management of these patients involves lifestyle modifications and switching from first-generation antiretrovirals towards less toxic drugs. Antiinflammatory treatment could be considered for at-risk patients. PMID- 22930866 TI - [Extracorporeal life support for treating cardiac arrest]. AB - Percutaneous extracorporeal life support (ECLS) is now widespread for treating acute cardiac failure. ECLS has been used for treating in-hospital and out of hospital cardiac arrests. A systematic review of literature was performed in order to assess the results. Nine studies of in-hospital cardiac arrests were published between 2003 and January 31, 2011. They included 724 patients, 208 of which survived without significant neurological sequelae (28.7 %). In the other patients, the initial disease and the consequences of low flow brought multiorgan failure, or ECLS resulted in haemorrhage and ischaemia. Low flow lasted between 42 and 105 min (mean 54min). ECLS was used after out of hospital cardiac arrests in 3 studies published between 2008 and January 31, 2011. They included 110 patients of which only 6 survived (4.4 %) despite strict inclusion criteria. Low flow lasted between 60 and 120 min (mean 98 min.) According to these results the use of ECLS should be encouraged after in-hospital cardiac arrest and training in cardiorespiratory resuscitation should be improved in global population and health professionals. PMID- 22930867 TI - [Are nanoparticles a new class of environmental toxin?]. AB - In view of the toxic properties of nanoparticles, the authorities require them to be specifically identified and labeled This is in keeping with the spirit of the REACH legislation, which aims to protect consumers from products with inadequately documented risks for human health and the environment. However, the presence of natural nanoparticles in the environment must also be taken into account, together with the fact that, in any mixture of particles, the presence of a fraction of nanometer-sized particles cannot be ruled out, owing to the laws of statistical distribution. Moreover, while all toxic nanoparticles generate oxidative stress, their properties are not due solely to their size but also to their shape, surface texture and composition. Thus, nanoparticle toxicity should be considered specifically for each substance or group of substances, and the notion of intentional manufacture of nano-sized particles should be included in the impact assessment. The conditions of nanoparticle concentration/dilution and persistence, especially in water and sewage sludge, exemplified by silver and titanium oxide, suggest that nanoparticle behavior in the environment should be monitored. PMID- 22930868 TI - [The death of Ignatius Loyola]. AB - A recent examination of a bilioportal fistula led us to suspect a link between this case and the death of Ignatius of Loyola. Realdo Colombo, professor of anatomy, eviscerated Ignatius prior to his embalming In his book De re anatomica, published in 1559, he wrote that he extracted stones from the portal vein of the venerable Ignatius. Before his death, Ignatius suffered from epigastric pain and fever (Monumenta historica societatis Jesu). Colombo latin text is difficult to interpret and the data are meager. Other possible causes of Ignatius' death include gastroduodenal ulcer, tuberculosis and hyperparathyroidism, but despite of rarity bilioportal fistula is the best guess. PMID- 22930869 TI - Hospitalists--too much baggage to travel? PMID- 22930870 TI - Measuring and costing delayed discharges: conceptual and methodological challenges. PMID- 22930871 TI - #ClinMed: What have social media got to do with medicine? PMID- 22930872 TI - Patient need at the heart of workforce planning: the use of supply and demand analysis in a large teaching hospital's acute medical unit. AB - Timely medical assessment is integral to the safety and quality of healthcare delivery in acute medicine. Medical staff are an expensive resource. This study aimed to develop a modelling system that facilitated efficient workforce planning according to patient need on the acute medical unit. A realistic 24-hour 'supply' of junior doctors was calculated by adjusting the theoretical numbers on the rota for leave allowances, natural breaks and other ward duties by a combination of direct observation of working practice and junior doctor interviews. 'Demand' was analysed using detailed admission data. Supply and demand were then integrated with data from a survey of the time spent on the process of clerking and assessment of medical admissions. A robust modelling system that predicted the number of unclerked patients was developed. The utility of the model was assessed by demonstrating the impact of a regulation-compliant redesign of the rota using existing staff and by predicting the most efficient use of an additional shift. This simple modelling system has the potential to enhance quality of care and efficiency by linking workforce planning to patient need. PMID- 22930873 TI - Inpatient care: should the general physician now take charge? AB - In an ageing population, patients are living longer with one or more chronic disease, and with acute illnesses increasingly extending outside the boundaries of a single medical specialty. Therefore, is it time for the general physician to take charge? PMID- 22930874 TI - In-depth analysis of delays to patient discharge: a metropolitan teaching hospital experience. AB - Delayed patient discharge will likely exacerbate bed shortages. This study prospectively determined the frequency, causes and potential cost implications of delays for 83 consecutive patients, who were inpatients for a total of 888 days. 65% of patients experienced delay whilst awaiting a service. 48% of patients experienced delays that extended their discharge date. Discharge delays accounted for 21% of the cohort's inpatient stay, at an estimated cost of 565 sterling pounds per patient; 77% of these hold-ups resulted from delays in the provision of social and therapy requirements. Discharge delays are costly for hospitals and depressing for patients. Investment is required to enable health and social-care professionals to work more closely to improve the patient journey. PMID- 22930875 TI - Compliance with NICE guidance on the use of anti-TNFalpha agents in ankylosing spondylitis: an east and west Midlands regional audit. AB - Here we report on an audit performed to examine compliance with National Institute for Health and Clinical Excellence (NICE) guidelines for the use of anti-tumour necrosis factor alpha (anti-TNFalpha) in treating patients with ankylosing spondylitis (AS). Data from 17 rheumatology centres across the Midlands were collected prospectively from patients with AS attending outpatient clinics and retrospectively in patients receiving anti-TNFalpha but not attending outpatient clinics during the audit. In total, 80% of the 416 patients for whom data were collected were male. Of the 238 patients recruited prospectively, 41% were receiving anti-TNFalpha. Reviewing all patients on anti-TNFalpha (N=275), pre-treatment assessments 12 weeks apart were documented in 55% of patients. After anti-TNFalpha treatment had started, regular 12-weekly assessments occurred in 46% of patients. Therefore, compliance with NICE guidance was found to vary among centres. Based on our audit, clinical capacity, and clinical or patient choice might be influencing the suboptimal adherence seen in assessment timing suggested by NICE guidelines relating to the use of anti-TNFalpha in treating patients with AS. PMID- 22930876 TI - Acute kidney injury: top ten tips. AB - Acute kidney injury (AKI) is associated with increased patient morbidity and mortality, and represents a significant financial burden for the NHS. The National Confidential Enquiry into Patient Outcomes and Death (NCEPOD)'s report, Adding insult to injury, demonstrated that only 50% of patients who died from AKI received good care and 30% of patients had predictable and avoidable AKI. It is therefore essential to identify patients at risk of AKI early and to treat patients who develop it promptly. This article proposes how this may be achieved by highlighting ten top tips that describe the points along the patient pathway where it is possible to intervene and prevent or treat AKI. The tips emphasise the importance of good basic medical care and the need for engagement with patients, healthcare professionals and hospital processes. The implementation of these tips in hospitals across the UK could potentially improve patient outcomes and reduce associated costs. PMID- 22930877 TI - Hyperparathyroidism in chronic kidney disease: complexities within the commonplace. AB - Secondary hyperparathyroidism in patients with chronic kidney disease (CKD) is common and usually caused by associated metabolic abnormalities, in particular, hypocalcaemia and hyperphosphataemia. Nevertheless, other causes of hyperparathyroidism can exist concurrently with CKD, challenging diagnostic interpretation and therapeutic intervention. We present four cases of hyperparathyroidism in patients with CKD that highlight some of these dilemmas. PMID- 22930878 TI - Developing a higher specialist training programme in renal medicine in the era of competence-based training. AB - Renal specialty medical training in the UK was reformed in August 2007, with an emphasis placed on competency-based training and the publication of a new curriculum and assessment blueprint. This model of training places additional time demands on both trainees and trainers, with implications for job planning and service delivery. We evaluated the resource requirements and impact on service delivery of implementing a high-quality training programme in renal medicine. Each trainee maintained a portfolio containing details of workplace based assessments. The change in educational environment led to improved trainee satisfaction. The mean total consultant time involved in implementing the training programme was 0.7 programmed activities (PAs) per trainee per week in the first year, which decreased to 0.5 PAs per trainee per week in the second year. This pilot study indicates that it is possible to integrate successful and high-quality specialty training in a busy clinical environment. The model outlined could form a template for postgraduate specialist training delivery in a variety of medical specialties. PMID- 22930879 TI - The role of the specialty training committee. AB - Many medical (and other) trainees will have heard mention during their training years of the specialty training committee (STC) relevant to their chosen medical specialty and might even be aware of some of the trainer members who sit on this committee. However, there is a perception that, equally, many trainees have no clear understanding of the roles and functions of STCs in relation to their training and, furthermore, the relation of their STC to its local deanery. This might also extend to consultant educational trainers who are less involved in the broader provision of postgraduate medical training (although, ideally this should not be the case). Here, I provide a brief guide to the role of STCs in training and their relation to their local deanery. PMID- 22930880 TI - The role of the training programme director. PMID- 22930881 TI - Austerity: a failed experiment on the people of Europe. AB - Many governments in Europe, either of their own volition or at the behest of the international financial institutions, have adopted stringent austerity policies in response to the financial crisis. By contrast, the USA launched a financial stimulus. The results of these experiments are now clear: the American economy is growing and those European countries adopting austerity, including the UK, Ireland, Greece, Portugal and Spain, are stagnating and struggling to repay rising debts. An initial recovery in the UK was halted once austerity measures hit. However, austerity has been not only an economic failure, but also a health failure, with increasing numbers of suicides and, where cuts in health budgets are being imposed, increasing numbers of people being unable to access care. Yet their stories remain largely untold. Here, we argue that there is an alternative to austerity, but that ideology is triumphing over evidence. Our paper was written to contribute to discussions among health policy leaders in Europe that will take place at the 15th European Health Forum at Gastein in October 2012, as its theme 'Crisis and Opportunity - Health in an Age of Austerity'. PMID- 22930882 TI - Managing respiratory problems in athletes. AB - Respiratory problems are common in athletes of all abilities and can significantly impact upon their health and performance. In this article, we provide an overview of respiratory physiology in athletes. We also discuss the assessment and management of common clinical respiratory conditions as they pertain to athletes, including airways disease, respiratory tract infection and pneumothorax. We focus on providing a pragmatic approach and highlight important caveats for the physician treating respiratory conditions in this highly specific population. PMID- 22930883 TI - Drug therapy of inflammatory arthritis. AB - Inflammatory arthritis involves a diverse range of conditions in which an uncontrolled immune response occurs. A number of advances in assessment, diagnosis and treatment have been made in recent years. Drug therapies used in inflammatory arthritis aim to reduce symptoms and suppress inflammation, joint damage and disability. In rheumatoid arthritis (RA), immunosuppression is used in almost all patients, with an emphasis on early aggressive treatment to achieve clinical remission. This approach is less successful in spondylarthropathies, for which non-steroidal anti-inflammatory drugs remain first-line therapy. The use of biologic therapies has increased dramatically across a range of indications and has resulted in improved outcomes for patients. These agents are associated with an increased risk of infection, particularly tuberculosis in patients receiving tumour necrosis factor inhibitors. Alternative biologics have entered clinical practice for RA in recent years, and clinical trials using these agents, as well as novel non-biologic therapies, are in progress for RA and other conditions. PMID- 22930884 TI - Nuclear medicine functional imaging of the brain. PMID- 22930885 TI - PET/CT in oncology. PMID- 22930886 TI - Nuclear cardiology. PMID- 22930887 TI - Nuclear medicine imaging of neuroendocrine tumours. PMID- 22930888 TI - Molecular radiotherapy. PMID- 22930889 TI - Ulcerative colitis presenting as pyrexia of unknown origin (PUO) without bowel symptoms. PMID- 22930890 TI - Simultaneous myocardial infarction and ischaemic stroke secondary to paradoxical emboli through a patent foramen ovale. PMID- 22930891 TI - A medical classic: Liza of Lambeth. PMID- 22930892 TI - Early warning scores and chronic respiratory disease. PMID- 22930893 TI - Interventional procedures: physician involvement enhances clinical coding. PMID- 22930894 TI - Rocket scientists need not apply. PMID- 22930895 TI - An unusual cause of bleeding in an elderly patient. PMID- 22930896 TI - Cardiology day case unit: the way to manage chronic cardiovascular conditions cost-effectively in future. PMID- 22930897 TI - Smoking: keeping the joint alight. PMID- 22930898 TI - Is it time to replace the bleeper system with smart phones? PMID- 22930899 TI - The essentials of leadership. PMID- 22930901 TI - The advantage of being organized. PMID- 22930900 TI - Staffing challenges and military commitments. PMID- 22930902 TI - Enhancing the success of a dental practice through patient satisfaction. AB - After careful case planning and communication, this case presented a great result for the patient who was pleased to no longer consider herself as having a villainous smile (Figures 7 and 8, page 17). With successful teamwork and planning, the dental auxiliary is able to help determine the outcome of a successful treatment plan. Listening to patients' desires helps to map out a plan of action to exceed the expectations ofpatients, which allows the potential for referrals and future growth for the practice. PMID- 22930904 TI - Should parents of pediatric patients be permitted in the operatory? PMID- 22930903 TI - What a good supply rep does. PMID- 22930905 TI - Deployed dental assistant soldier lives the Army value. PMID- 22930906 TI - "Be proud to be a nurse in the health service". PMID- 22930907 TI - Nurse retirement plan faces review. PMID- 22930908 TI - "We must learn from the cultural failings at mid staffs". PMID- 22930909 TI - "Celebrate the pioneering move to raise education status". PMID- 22930910 TI - Breastfeeding: how to increase prevalence. AB - Increasing breastfeeding prevalence is essential to reduce health inequalities and improve health outcomes for all mothers and babies. Evidence-based services need to be commissioned and developed in line with UNICEF's Baby Friendly Initiative Seven Point Plan, to ensure positive outcomes for breastfeeding. Support services offered early in the neonatal period can increase prevalence at 6-8 weeks of age and encourage longer-term breastfeeding, recommended by the World Health Organization and Department of Health. This article describes how an early intervention infant feeding service successfully supported mothers to continue breastfeeding and increased prevalence. PMID- 22930911 TI - Challenges and issues in managing hepatitis C. AB - Hepatitis C virus infection is the most common chronic bloodborne infection in the world. Injecting drug users are most at risk of infection in the UK and other industrialised countries but this group remains hard to reach. This article discusses the epidemiology, diagnosis and treatment of HCV, including new treatment strategies. It also explores and gives advice for general nurses. PMID- 22930912 TI - Hepatitis C awareness among South Asians. AB - This article describes a project that worked to raise awareness of hepatitis C virus (HCV) in the South Asian community. The aim was to encourage people to come forward for testing and to reduce the incidence of liver disease in this group. Health education talks were given within the community and two GP practices offered support. Seventy four people came forward for HCV testing, three of whom were HCV positive and were referred for antiviral treatment. PMID- 22930913 TI - The breast start for mums. PMID- 22930914 TI - How to restore pride in nursing. PMID- 22930915 TI - Mental health. PMID- 22930916 TI - The challenges that Clinical Commissioning Groups must address to provide improved care to mental health service users. PMID- 22930917 TI - Still kicking. PMID- 22930918 TI - Working on it. PMID- 22930919 TI - A little soul. PMID- 22930920 TI - The importance of being busy. PMID- 22930921 TI - Resources may not be pointed in the right direction. PMID- 22930922 TI - The aim of joined-up services should not be disregarded. PMID- 22930923 TI - Prevalence of suicide among children and young people. PMID- 22930924 TI - Making a name for dementia: a national challenge. PMID- 22930925 TI - How mental health services will fare in the reforms of health and social care services. PMID- 22930926 TI - Good news: coffee and chocolate are good for your physical and mental health. PMID- 22930927 TI - Co-operation and negotiation are key to a good journey through mental health services. PMID- 22930928 TI - One good turn deserves another: the link between altruistic behaviour an mental wellbein. PMID- 22930929 TI - From service users to associates. PMID- 22930930 TI - Looking at ordinary people's tales of living with their mental illness. Interview by Dan Parton. PMID- 22930931 TI - [Croatian guidelines for the management of pancreatic exocrine insufficiency]. AB - Pancreatic exocrine insufficiency is a major consequence of pancreatic diseases (e. g. chronic pancreatitis and cystic fibrosis), extrapancreatic diseases like celiac disease and Crohn's disease, and gastrointestinal and pancreatic surgical resections. Recognition of this entity is highly relevant to avoid malnutrition related morbidity and mortality. The main clinical consequence of PEI is fat maldigestion and malabsorption, resulting in steatorrhoea. Pancreatic exocrine function should be assessed by measuring levels of faecal elastase-1. Pancreatic enzyme replacement therapy is the mainstay of treatment for PEI. Administration of enzymes in form of enteric-coated minimicrospheres avoids acid-mediated lipase inactivation and ensures gastric emptying of enzymes in parallel with nutrients. In adults, the initial recommended dose of pancreatic enzymes is 25.000 units of lipase per meal, titrating up to a maximum of 80000 units of lipase per meal. Large meals require 25.000 - 80.000 units of lipase per meal while snacks require 10.000 - 40.000 units of lipase per meal. Oral pancreatic enzymes should be taken with meals to ensure adequate mixing with the chyme. Adjunct therapy with acid suppressing agents may be useful in patients who continue to experience symptoms of PEI despite high-dose enzyme therapy. Patients with PEI should be encouraged to consume small, frequent meals and to abstain from alcohol. Dietary fat restriction is not recommended for patients with PEI. PMID- 22930932 TI - [Comparative urinary bactericidal activity of oral antibiotics against gram positive pathogens]. AB - In routine bacteriological laboratories the antibacterial activity of antibiotics is determined by in vitro testing, usually by disk-diffusion test. However, in vitro testing does not always reflect antibacterial efficiency of antibiotics in vivo. In this investigation, the urine samples obtained in a single oral dose pharmacokinetic study were examined for their bactericidal activity against a range of relevant Gram-positive urinary tract pathogens. Urinary bactericidal activity of linezolid had been previously compared with ciprofloxacin but not with other oral antibiotics such as beta-lactams. Linezolid showed satisfactory urinary bactericidal titres throughout the whole testing period against all Gram positive cocci. Fluoroquinolones displayed high and persisting levels of urinary bactericidal activity against staphylococci, but their activity against enterococci was weaker. According to the results of ex-vivo testing amoxycillin could be recommended only for infections caused by E. faecalis. Amoxycillin combined with clavulanic acid can be considered as a therapeutic option for infections caused by S. saprophyticus and E. faecalis. Older cephalosporins had high titres only against S. saprophyticus. Their drawback is a short elimination half-time in urine resulting in rapid decrease of urinary bactericidal titers during dosing interval. Furthermore, they do not show activity against enterococci due to their intrinsic resistance to cephalosporins. PMID- 22930933 TI - [The efficacy of the fixed drug combination dorzolamide 2%/timolol 0.5% in patients with primary open angle glaucoma]. AB - The aim was to investigate the effectiveness of the fixed drug combination dorzolamide 2%/timolol 0.5% as monotherapy, substitutive and as adjunctive therapy in patients with primary open angle glaucoma. 130 patients were divided in three different study groups and treated by the combination dorzolamide 2%/timolol 0.5% as monotherapy, substitutive therapy and additional therapy. After three months using fixed combination dorzolamide 2%/timolol 0.5%, the mean IOP decreased by 5.6 mmHg. After prescribing substitutive therapy with fixed drug combination dorzolamide 2%/timolol 0.5% for 3 months, the intraocular preassure increased by 0.13 mmHg. Three months after the treatment with fixed combination dorzolamide 2%/timolol 0.5% as an additional antiglaucomatous drug, we have noticed a decrease of the mean IOP of 3.28 mmHg. Itching and soarness were reported by 43% patients. In conclusion, glaucoma drug therapy with fixed drug combination dorzolamide 2%/timolol 0.5% achieves effective lowering of intraocular preassure levels as monotherapy or as adjunctive therapy. As a substitutive therapy, the combination had the same IOP lowering effect. Simple drug administration and good drug tolerance indicate the effectiveness of the same drug. PMID- 22930934 TI - [Breast cancer metastases to the stomach and colon: two case reports]. AB - Summary. Breast cancer has a high potential for metastasis, usually to the lungs, bones, liver and lymph nodes. Metastases in the holow organs of the digestive system are rare and mainly affectes the stomach and colon. They are characterized by very different clinical and radiological manifestations. We have warned that the initial unrecognized breast cancer can appear as a primary tumor of the stomach and colon, and onlya histopathological analysis reveales that it is a metastatic breast cancer. Metastases to the stomach or intestine involve deep layer of the mucosa and pathohistological findings of standard biopsy sample can be falsely negative, despite positive imaging technique (abdominal ultrasound and MSCT, endoscopic ultrasound) that indicate the tumor process. That's,why we emphasize the importance of endoscopic mucosal resection in the detection of malignant process of deeper layers of the gastric mucosa and deep intestinal mucosal biopsies with postoperative analysis of its walls. PMID- 22930935 TI - [Virology diagnosis of re-emergent infections: dengue virus]. AB - Dengue is acute viral disease transmitted to humans by Aedes mosquitoes (Ae. aegypti, Ae. albopictus). Dengue virus belongs to the family Flaviviridae, genus Flavivirus. There are four dengue virus serotypes (1-4) which are maintained endemically. The disease is endemic in tropical and subtropical areas between latitudes 35 degrees N and 35 degrees S. Infections may be asymptomatic or may produce a wide spectrum of diseases: non-specific febrile illness, dengue fever, dengue haemorrhagic fever or dengue shock syndrome. For the first time in Croatia, Ae. albopictus was registered in Zagreb in October 2004. In autumn 2005, additional records of Ae. albopictus presence were made in many places along the Adriatic coast. During 2007, two cases of imported dengue fever were reported in Croatia, after which similar imported cases appeared continually. In August 2010, the first autochthonous case of dengue fever was recorded on the peninsula Peljesac. Though Croatia is not endemic for dengue, the existence of a corresponding vector and a latent threat by imported dengue cases demand state-of the-art and timely diagnostics. The most commonly used methods in laboratory diagnosis of dengue infections involve detection of viral RNA, antigen detection and serologic methods (detection of antibodies). PMID- 22930936 TI - [Allergic reactions to food]. AB - Food allergy is common disease that affects 11-26 million people in Europe. The incidence is estimated to be greater in children (5-8%) than the in adults (1 3%). Currently, the mechanisms of food allergy are not well characterized. There are a lot of open questions, for example: "Why do some individuals develop allergy to food? Why is some food more allergenic than other? Why do some children become tolerant?" Recognition of food allergy is largely based on symptoms and in a number of cases its recognition can be difficult. The spectrum of food allergy consists of a variety of different clinical presentations, and can range from chronic gastrointestinal symptoms to severe, life threatening, and anaphylactic reactions. The diagnosis of food allergy is mostly limited by the lack of reliable in vitro tests, especially for non-IgE mediated diseases. Currently, there is no safe and efficient treatment for food allergy, and the treatment relies on avoidance diets, that significantly affect the quality of life of allergic patients. PMID- 22930937 TI - [Allergic reactions to vaccines]. AB - Allergic reactions after vaccination are very rare. Even if the vaccine is not clearly the cause of possible side effects, including possible allergic reactions occurring after vaccine administration, they should be reported to the appropriate authorized body. Allergic reaction occuring to other vaccine components are more likely than to the active agent, for instance to gelatine, egg protein, chicken protein, dextran, thimerosal, antimicrobials, etc. All patients with suspected allergy to vaccine components should be evaluated by an allergist. Immediate-type allergy skin testing should be performed in patients who appear to have had an allergic reaction after vaccination. This testing should help confirm that the reaction was IgE mediated and identify the responsible vaccine component. If the skin test result is negative, it is extremely unlikely that the patient will develop an allergic reaction and the patient can be vaccinated. In patients with suggestive history and positive skin tests results to vaccine components, the clinician can consider administering the alternative vaccine or the same vaccine in graded doses while observing the patient. Mild local reactions, fever, and other constitutional symptoms after vaccinations are not contraindications to subsequent doses. PMID- 22930938 TI - [Transradial approach in interventional cardiology: "quod licet femoralisti, non licet radialisti"]. AB - Transradial approach has been used in invasive cardiology since 1989 and since 1995 for PCI. Croatia is late in using this technique for about one whole decade. The advantage of transradial approach over femoral approach are serious local complications of (2.6-2.8%), more frequent with modem therapy (7.4%), occasionally requiring surgical repair (2.4%). Major adverse cardiovascular events are significantly more occurring with femoral (3.8-6.55%) compared to transradial approach (2.5-3.7%), while in the MORTAL study total mortality is higher as well. Patients prefer transradial approach due to it being less painful and uncomfortable, and also because of greater mobility after the procedure. Time spent for patient care by nurses is shortened by half than what it used to be, and the final savings per patient is $290. An unfavorable aspect of transradial approach is clinically insignificant radial artery occlusion (0.6%-1.4%), as well as higher radiation exposure, for 12% in practice. Procedural time is similar, but it could take up to 3 minutes longer. Access site crossover is more often with transradial (4.7-7.6%), compared to femoral procedure (1.4-2.0%), but PCI failure is independent of approach. All unfavorable aspects are diminishing with experience of a cardiologist. Now, some of the Croatian centers, such as General Hospital Zadar, use transradial approach in 67% of catheterizations, 64% of PCI, and 38% of all primary PCIs. PMID- 22930939 TI - [The lower Neretva basin as a pathological topos: press reports and politicization of the memories of the age of cholera in 1886]. AB - The lower Neretva basin as a space that has undergone historical transformation into a myth of a pathological topos has been analyzed. Starting from the fact that temporality is essential for understanding of the elements that partake in conceptualization of a myth, we have analyzed the state of this area as it was during its exposure to an epidemic of cholera in 1886. There is evidence that at this time exactly a step forward was made in comprehension of the etiology of the disease, which resulted in the change of centuries-long concepts of the Neretva basin as an unhealthy area. In this paper the Neretva basin was understood and presented as a field of unfolding of all kinds of transformations, a habitat exposed to manifold social arrangements, lushly documented in newspapers and other printed material. The arguments about the natural disaster in these texts are ethically and politically coloured, which to a large extent corresponds to the vocabulary of current print media on similar occasions. Thus, the area of the Neretva basin imposes itself as a multilayered anthropological concept, a multi semantic ecologically and socially constituted reality, within which history functions as a valuable source of knowledge pliable to contemporary usage. PMID- 22930940 TI - [Our experience in vulvar reconstruction after radical and hemivulvectomy]. PMID- 22930941 TI - [Infrared thermography]. PMID- 22930943 TI - Rapid progress in digital dentistry thanks to computer technology. PMID- 22930942 TI - [Is sufficient evidence for rutine, non-selective use of prostate-specific antigen (PSA) in prostate cancer screening or selective use in specific subgroups?]. PMID- 22930944 TI - Possibilities and limitations of implant placement by virtual planning data and surgical guide templates. AB - The use of computer-aided surgical systems for dental implant bed preparation and implant placement results in an average precision within 1 mm of implant position and within 5 degrees of deviation for implant inclination. The accuracy of axis and implant position is significantly more precise with the three-dimensional surgical guide than with the free-hand method. The three-dimensional assessment of the restorative goal (radiopaque simulation of prosthesis with scanning template) allows virtual planning of implants, which enables optimized positioning of implants with surgical guide templates in oral surgery. If there is a clear indication for three-dimensional diagnostics, it should always be checked whether the data can be used as planning data for a surgical guide template, otherwise the chance for guided surgery remains unused. Since uncertainties still exist despite the use of a drilling template, it is recommended that the minimum safety distance from adjacent structures be maintained. The successful use of surgical guide templates requires comprehensive knowledge of and experience in using three-dimensional information for the virtual planning of implant position. PMID- 22930945 TI - InLab and Cerec Connect: virtual contacts in maximum intercuspation compared with original contacts--an in vitro study. AB - PURPOSE: The aim of this in-vitro study was to evaluate the accuracy of inLab and Cerec Connect software in simulating the maximum intercuspal contacts in comparison to the real situation on the respective gypsum casts. MATERIALS AND METHODS: Ten pairs of maxillary and mandibular casts were mounted in articulators in maximum intercuspal position. The contacts of the gypsum casts were marked and digital photographs of the mandibular casts were taken. Digital impressions of arches were made using two different software packages; inLab (Version 3.83) and Cerec Connect (Version 3.83) using the Cerec Acquisition Center. The intercuspal position of the teeth was captured by buccal images. Screenshots of the virtual casts showing the occlusal contacts were saved. The digital photographs of the contacts of the cast and the screenshots of the occlusal contacts were superimposed using an image processing program. The number of contacts of the virtual mandibular models that were identical with the contacts of the gypsum casts were determined and calculated as percentages in relation to the gypsum cast contacts, which were set as 100%. The null hypothesis tested was that the Cerec connect software delivers contacts that are closer to the real situation than contacts created with the inLab software. RESULTS: Cerec Connect showed a median percentage of 41.6% and Inlab a median percentage of 31.9%. The Wilcoxon test revealed statistically significant differences between the inLab software and Cerec Connect. Especially at the contra-lateral side of that side where the virtual buccal registration was done, the contacts showed the greatest deviations from the original. CONCLUSION: Cerec Connect more precisely virtually simulated the real contacts than did inLab when scanning full-arch dentitions. PMID- 22930946 TI - Quality assurance in digital dental radiography--justification and dose reduction in dental and maxillofacial radiology. AB - OBJECTIVE: To evaluate the implementation of quality assurance requirements for digital dental radiography in routine clinical practice. The results should be discussed by radiation protection authorities in the context of the relevant legal requirements and current debates on radiation protection. MATERIALS AND METHODS: Two hundred digital dental radiographs were randomly selected from the digital database of the Department of Dentistry's Dental and Maxillofacial Surgery Clinic, Ulm University, and evaluated for various aspects of image quality and compliance with radiographic documentation requirements. The dental films were prepared by different radiology assistants (RAs) using one of two digital intraoral radiographic systems: Sirona Heliodent DS, 60 kV, focal spot size: 0.7 mm (group A) or KaVo Gendex 765 DC, 65 kV, focal spot size: 0.4 mm (group B). RESULTS: Radiographic justification was documented in 70.5% of cases, and the radiographic findings in 76.5%. Both variables were documented in the patient records as well as in the software in 14% of cases. Clinical documentation of the required information (name of the responsible dentist and radiology assistant, date, patient name, department, tube voltage, tube current, exposure time, type of radiograph, film size, department and serial number of the dental radiograph) was 100% complete in all cases. Moreover, the department certified according to DIN ISO 9001:2008 specifications demonstrated complete clinical documentation of radiographic justifications and radiographic findings. The entire dentition was visible on 83% of the digital films. The visible area corresponded to the target region on 85.7% of the digital dental radiographs. Seven to 8.5% of the images were classified as "hypometric" or "hypermetric". CONCLUSIONS: This study indicates that improvements in radiology training and continuing education fordentists and dental staff performing x-ray examinations are needed to ensure consistent high quality of digital dental radiography. Implementation of internal radiological quality assurance programs, as required by public law in Germany since 2010 (SGB V), would appear prudent. PMID- 22930947 TI - Cerec Guide: rapid and streamlined manufacture of surgical guides in dental practice. PMID- 22930948 TI - Cerec reconstruction of a hemisected mandibular molar: method and case report. AB - Hemisection of mandibular molars is a viable method of preserving periodontally or endodontically compromised teeth or roots. This paper describes a simple chairside CAD/CAM method of fabricating a cantilever crown for a hemisected molar. The technique is illustrated by a clinical case, which was treated according to this protocol and was followed-up over 2.5 years. Given careful patient selection and strict recall intervals, the introduced method represents a conservative and cost-effective treatment modality for high-quality ceramic reconstructions of root-resected teeth. In addition, other treatment options such as implantation or prosthesis, which would represent therapeutic and prosthetic endpoints, can be postponed. PMID- 22930949 TI - Potential of 3D guided implantology. PMID- 22930951 TI - Early starts, long commutes and pride at being Olympics nurses. PMID- 22930950 TI - Health secretary intervenes over NMC's proposed fee increase. PMID- 22930952 TI - Trust may face court action over decision to halve mileage rates. PMID- 22930953 TI - NHS pension scheme access should be extended, says review co-chair. PMID- 22930954 TI - Get the culture of the organisation right, and good care will follow. PMID- 22930955 TI - Look to the future. AB - Research into Parkinson's has been held back by the difficulty of setting up clinical trials, with fewer than one in ten people with the condition taking part. Fox Trial Finders is a scheme that enables people with Parkinson's to find and take part in suitable trials. PMID- 22930956 TI - Championing women. AB - A 'small but significant' number of midwives choose to be members of the RCN. Their interests are represented by Carmel Bagness, a midwife, educator and policy adviser who is forging a role at the college that encompasses wider women's health issues. PMID- 22930957 TI - Healing in an uprising. AB - British nurse Karen Graham was working at a hospital for oil workers in Tripoli when the uprising against the Gaddafi government began. She stayed on to care for people injured in the conflict. She was awarded an MBE, and has made her home in Libya. PMID- 22930958 TI - Exercise caution. AB - A recent study into the effects of structured physical exercise for people diagnosed with depression claimed that it did not help. The findings attracted huge media coverage that may have made it harder to persuade patients with depression to take exercise. PMID- 22930959 TI - Maintaining oral health after stroke. AB - Oral care is essential to maintain oral health and prevent complications such as tooth loss, gingivitis and periodontitis. Poor oral hygiene in dependent, hospitalised patients could lead to serious complications such as chest infection, pneumonia, poor nutritional intake and increased length of hospital stay. Patients who have had a stroke may have physical and cognitive problems that make them dependent on others for their personal care, including oral care. It is essential that nurses and carers understand why maintaining oral hygiene is important following stroke and the consequences of poor oral care. PMID- 22930960 TI - Bariatric surgery: nutritional considerations for patients. AB - Nutritional deficiencies are common in patients who are obese and therefore individuals considering bariatric surgery may require dietary supplementation with multivitamins and minerals before surgery. Nutritional deficiencies following bariatric surgery are often proportional to the degree of malabsorption created by the surgical procedure or the extent of weight loss. Eating habits often contribute to nutritional deficiencies, so appropriate dietary and lifestyle counselling are essential following bariatric procedures to ensure appropriate macronutrient and micronutrient status. Nutritional supplementation following bariatric surgery commonly includes calcium with vitamin D, iron and vitamin B12 in addition to a daily multivitamin and mineral tablet. Although general guidelines exist, individual monitoring and tailoring are frequently required. This article provides an update of guidelines regarding the most common nutritional concerns and myths surrounding bariatric surgery. PMID- 22930961 TI - Key principles in assessing students' practice-based learning. AB - Assessing student learning in the practice setting is one of the most sophisticated and complex forms of evaluation undertaken by registered nurses. The Nursing and Midwifery Council sets standards relating to learning and assessment in practice, focusing on professional values, communication and interpersonal skills, nursing practice, decision making, leadership, management and teamworking. Assessment needs to include evaluation of skill (technical, psychomotor and interpersonal), attitudes and insights, and reasoning. As assessment of student learning is conducted in the practice setting, risks have to be managed, and targets and service standards met. Therefore, it is understandable that mentors may express doubts about their ability to assess student learning rigorously and fairly. It is particularly challenging for mentors to state confidently what represents a demonstration of learning and competence when asked to decide whether a student is fit to practise. PMID- 22930962 TI - Promoting hydration. PMID- 22930963 TI - A view from the top. PMID- 22930964 TI - Prevention is better than cure. PMID- 22930966 TI - Improving medication safety: a simple way to start. PMID- 22930965 TI - Safe from the start. PMID- 22930967 TI - Rectal exam: a necessary part of the physical exam. PMID- 22930968 TI - Illinois Supreme Court rules non-economic damages cap unconstitutional. PMID- 22930969 TI - Do-it-yourself intensive care. PMID- 22930970 TI - MSMS reimbursement advocate tackles tough billing troubles--for free. PMID- 22930971 TI - Physician extenders: shared benefits, shared risks. PMID- 22930972 TI - The H1N1 initiative: County Medical Society takes the lead. PMID- 22930973 TI - A community-based physician recruitment model. PMID- 22930974 TI - Bioethics in ordinary and extraordinary times. PMID- 22930975 TI - Training programs consider part-time residency options. PMID- 22930976 TI - Lancet retracts study linking autism to MMR vaccine. PMID- 22930977 TI - Home is where the heart is. PMID- 22930978 TI - [Baby coming--Women and pregnancy in veterinary medicine]. PMID- 22930979 TI - [From paper mill to ground beef mill]. PMID- 22930980 TI - [Journal for veterinary medicine gets a new profile]. PMID- 22930981 TI - [Trends from the GD monitoring]. PMID- 22930982 TI - Atypical myopathy: a review and description of the outbreak in the Netherlands during autumn 2009 and spring 2010. AB - This article reviews the literature on equine atypical myopathy (AM), an acute, severe rhabdomyolysis that occurs in horses at pasture. The prevalence, mortality, clinical signs, pathology, potential aetiology, typical aspects, diagnosis, treatment, and prognosis are described. Horse management, characteristic weather conditions, and possible preventive measures are also discussed. In addition, the characteristics of 54 highly probable or confirmed cases of equine AM occurring between autumn 2009 (27 cases) and spring 2010 (27 cases) in the Netherlands are described. Of the 54 affected horses, nineteen were mares, eleven geldings, and eight stallions; the sex of the other sixteen horses was not recorded. The mortality rate (74.5%) was in the same range as that reported in earlier studies. Many cases were reported at about the same time. Thirty-five horses had been pastured near maple trees, and in fifteen cases the maple trees were known to be infected with the fungus Rhytisma acerinum. PMID- 22930984 TI - [Herpesvirus in eel characterized for the first time]. PMID- 22930983 TI - Exploratory trial to determine the efficacy of the PYthon and the PYthon Magnum slow-release insecticide ear tags for the control of midges (Culicoides spp.), attacking sheep and cattle and flies attacking cattle. AB - This study investigated the prophylactic action of the chemical combination zeta cypermethrin and piperonyl butoxide, administered by means of slow-release insecticide-impregnated ear tags, against biting midges (Culicoides spp) attacking sheep and against midges, horn flies (Haematobia irritant), stable flies (Stomoxys calcitrans), and houseflies (Musca domestica) attacking cattle. Treated sheep and cattle were protected 100 percent against blood-feeding midges for two months and there was a clear reduction in the number of midges collected from treated animals. Three days after the ear tags were attached to cattle, the number of horn flies on the cattle was reduced to practically zero and remained at a low level until the end of the trial (day 85). There was also a strong reduction in the numbers of stable flies and houseflies counted. PMID- 22930985 TI - [The abattoir is not the end: animal byproducts]. PMID- 22930986 TI - [Reference: animal lameness is not always the same]. PMID- 22930987 TI - [Mission and vision: not a luxury but a necessity]. PMID- 22930988 TI - [New standard methods in testing antibiotic sensitivity]. PMID- 22930989 TI - [Weapons in the veterinary clinic: rules and conditions]. PMID- 22930990 TI - [Stricter rules for antibiotics in all sectors]. PMID- 22930991 TI - [Dutch pioneers in Portugal]. PMID- 22930992 TI - [The veterinarian and ritual slaughter]. PMID- 22930993 TI - [Identical lectures for veterinarians and their assistants]. PMID- 22930994 TI - "Say it...near the flower shop": further evidence of the effect of flowers on mating. AB - For millennia, flowers have been used to convey romance. In this study, 18-25 year-old women (N = 600) walking alone in a shopping mall were approached by an attractive 20-year-old male-confederate who solicited them for their phone number. The women were solicited as they were walking in the area of a flower shop, a cake shop, or a women's shoes shop. It was found that women agreed more favorably to the confederate's courtship solicitation when solicited in the area of the flower shop. Positive mood induced by exposure to flowers was used to explain these results. PMID- 22930995 TI - Benevolent sexist beliefs predict perceptions of speakers and recipients of a term of endearment. AB - This study examined how endorsement of benevolent sexist ideologies predicts perceptions of requesters who use a term of endearment and of the female addressees who comply with their requests. Undergraduate women who previously completed the Benevolent Sexism Scale as part of the Ambivalent Sexism Inventory were randomly assigned to one of four groups. They watched one of four videos in which a female addressee responded to a request that either included or did not include the term of endearment "hon"; the requester was either male or female. Participants then rated both actors' social likeability. Among participants who watched a woman respond to a female requester who addressed her with the term "hon," benevolent sexism scores predicted liking for the female responder and disliking of the female requester. Findings reflect the dissatisfaction of women who are high in benevolent sexism with women who act outside of traditional gender role expectations. PMID- 22930996 TI - Shame and guilt--do they really differ in their focus of evaluation? Wanting to change the self and behavior in response to ingroup immorality. AB - Shame and guilt are often theorized to differ on a self versus behavior focus. However, we propose that this is not true when taking a group perspective. In our field study, 196 communal participants were confronted with historical ingroup immorality. Results showed that participants who were old enough to have understood what happened in that time-period felt more guilt and shame than did those who were too young. Partly due to their ingroup anger, shame motivated an intention to change the ingroup self and behavior. In contrast, partly due to personal anger, guilt motivated an intention to change personal self and behavior. This suggests that the distinction between shame and guilt are not as clear-cut as previous research have assumed. PMID- 22930997 TI - Perceptions of personal sex discrimination: the role of belief in a just world and situational ambiguity. AB - The roles of belief in a just world (BJW) and discrimination against ones' group in perceptions of personal discrimination were examined. Female participants (n = 63) were personally discriminated against in a laboratory setting. We manipulated whether the experimenter appeared to discriminate against other participants, which presumably made the presence of personal discrimination less ambiguous, or did not appear to discriminate against others, which presumably made personal discrimination more ambiguous. In the no group discrimination condition, but not in the group discrimination condition, participants' perceptions of being personally discriminated against depended on individual differences in BJW: Women with a strong BJW perceived less personal discrimination than those with a weak BJW. Also, strong BJW women in the group discrimination condition perceived less personal discrimination than strong BJW women in the no group discrimination condition. PMID- 22930998 TI - Every cloud has a silver lining: positive effects of deviant coworkers. AB - Drawing on the labeling perspective of deviance, we investigate employee reactions to coworkers perceived as deviants. We look at two positive effects for employees in the presence of a deviant coworker. First, in comparison to a deviant individual, other employees can draw more positive conclusions about themselves; and second, a deviant can be informative about organizational norms, thereby improving employee role clarity. We also examine individual and situational moderators. For the purpose of the study, we developed a measure of the presence of a deviant. The hypothesized relationships were tested in two large samples using multiple regression analyses. The results revealed that in the presence of a deviant coworker, employees reported enhanced self-evaluation. The presence of a deviant coworker was associated with better role clarity only for employees with more interdependent jobs. We also discuss practical implications of the findings and future research directions. PMID- 22930999 TI - Trait expectancies and stereotype expectancies affect person memory similarly in a jury context. AB - This experiment, a simulated trial study, examined whether trait expectancies and stereotype expectancies similarly affected memory for expectancy-relevant behaviors. Participants read a description of a defendant, which was followed by testimony that induced a trait or stereotype expectancy. After viewing the evidence items and giving a guilt judgment, the participants were asked to recall as many of the evidence items as they could and to complete a thought listing measure. The results showed that, when overtly applied to the defendant, trait expectancies and stereotype expectancies had similar effects, producing incongruity effects on recall. Additional analyses examining the participants' post-hoc reports of the thoughts that they had as they processed the behaviors provided little evidence that subjects attempted to reconcile items or attempted to reconcile the items with the expectancy. PMID- 22931000 TI - Ego depletion increases risk-taking. AB - We investigated how the availability of self-control resources affects risk taking inclinations and behaviors. We proposed that risk-taking often occurs from suboptimal decision processes and heuristic information processing (e.g., when a smoker suppresses or neglects information about the health risks of smoking). Research revealed that depleted self-regulation resources are associated with reduced intellectual performance and reduced abilities to regulate spontaneous and automatic responses (e.g., control aggressive responses in the face of frustration). The present studies transferred these ideas to the area of risk taking. We propose that risk-taking is increased when individuals find themselves in a state of reduced cognitive self-control resources (ego-depletion). Four studies supported these ideas. In Study 1, ego-depleted participants reported higher levels of sensation seeking than non-depleted participants. In Study 2, ego-depleted participants showed higher levels of risk-tolerance in critical road traffic situations than non-depleted participants. In Study 3, we ruled out two alternative explanations for these results: neither cognitive load nor feelings of anger mediated the effect of ego-depletion on risk-taking. Finally, Study 4 clarified the underlying psychological process: ego-depleted participants feel more cognitively exhausted than non-depleted participants and thus are more willing to take risks. Discussion focuses on the theoretical and practical implications of these findings. PMID- 22931001 TI - Flying the unfriendly skies? The role of forgiveness and race in the experience of racial microaggressions. AB - Because even subtle forms of racial discrimination can damage well-being, identifying individual differences that shape this stress process is important. Dispositional forgiveness has been shown to influence how people perceive and react to interpersonal transgressions, yet its role in the context of racial discrimination has not received much research attention. In the current study, participants completed an initial measure of dispositional forgiveness and then considered a scenario that could be deemed racially discriminatory. Next, participants' perceptions of the scenario, negative affect, and cognitive performance were assessed. Dispositional forgiveness predicted all three outcomes such that more forgiving individuals were less likely to view the event as racially discriminatory and showed lower negative affect and greater cognitive performance after reading the scenario. Moreover, race moderated these relationships such that forgiveness played a more beneficial role for ethnic minorities than for whites. PMID- 22931002 TI - "That's so gay!" Priming the general negative usage of the word gay increases implicit anti-gay bias. AB - One of the most recent uses of the term gay is to refer to things as negative in general, detached from explicit reference to gay individuals. Research has shown that exposure to explicitly homonegative speech can increase anti-gay bias; however, the effect of more ambivalent homonegative speech on implicit attitudes has not yet been explored. Despite the conscious disassociation between both meanings of the word, given previous studies on priming and automaticity, an association was expected at an automatic level. Therefore, this study investigated the effect of priming the general negative usage of gay on participants' implicit attitudes towards gay individuals, as measured by the Implicit Association Test. Results revealed that exposure to the general negative usage of gay increased implicit anti-gay bias. PMID- 22931003 TI - Friendship, perceived mattering and happiness: a study of American and Turkish college students. AB - Although it is well established that friendship is a consistent correlate of happiness, less is known about how friendship experiences might promote happiness. The current investigation addressed this gap by testing a mediational model proposing that perceived mattering explains the association of friendship quality with happiness among college students in Turkey and the United States. An alternative model suggesting friendship quality as the mediator was also tested to enhance confidence in the proposed model. SEM analyses revealed that perceived mattering mediated the association of friendship with happiness only in the American sample. In the Turkish sample, friendship quality mediated the association between mattering and happiness. Findings highlight the importance of cross-cultural research and suggest that the underlying processes and psychological mechanisms related to the friendship-happiness link might be different in different cultures. PMID- 22931004 TI - Words as environmental cues: the effect of the word "loving" on compliance to a blood donation request. AB - In a field setting, students (N = 3600) on different campus locations were solicited to give blood during a special one-day drive. Solicitations were made through face-to-face interactions. The solicitors wore a white T-shirt with different inscriptions: no inscription, Loving = Helping, Donating = Helping. Results showed that, when compared to the no inscription condition, the number of donors increased when the solicitor-confederates wore the T-shirt Loving = Helping whereas no effect was found when the confederates wore the T-shirt Donating = Helping. The activation spreading theory is used to explain these results. The practical application of these results for blood donation drives and other health-related fundraising events is explored. PMID- 22931005 TI - Mediating role of coping in the dispositional optimism-posttraumatic growth relation in breast cancer patients. AB - The aim of the present study was to examine if coping strategies mediate dispositional optimism-posttraumatic growth relation in postoperative breast cancer patients. The data were collected from 90 patients in two hospitals. Regression analyses revealed that problem-focused coping fully mediated dispositional optimism-posttraumatic growth relation, but emotion-focused coping did not. That is, postoperative breast cancer patients who were optimistic were more likely to use problem-focused coping strategies that, in turn, led to the development of posttraumatic growth. The findings were congruent with the literature in which problem-focused coping was mostly highlighted as compared to emotion-focused coping, and in which optimism and problem-focused coping relationship was emphasized in the path of posttraumatic growth. PMID- 22931006 TI - Incremental validity of person-organization fit over the Big Five personality measures. AB - Few studies have provided the validity evidence of a measure of objective person organization fit (P-O fit) as a selection tool. The present study used a concurrent validation design to examine the criterion-related validity and the incremental validity of a P-O fit measure beyond the validity of the Big Five personality test for predicting job performance (task performance and organizational citizenship behavior) and employee commitment (organizational commitment and supervisory commitment) for a group of high-tech professional employees in Taiwan. Results showed that P-O fit predicted the contextual component of overall job performance and was significantly related to two types of employee commitment. Moreover, P-O fit had an incremental validity beyond that of the personality measures for predicting some of our outcome variables. PMID- 22931007 TI - Self-serving bias effects on job analysis ratings. AB - The purpose of this study was to investigate whether worker-oriented job analysis importance ratings were influenced by subject matter experts' (SME) standing (as measured by self-rated performance) on a competency. This type of relationship (whereby SMEs indicate that the traits they have are important for successful job performance) is an example of the self-serving bias (which is widely described in the social cognition literature and rarely described in the industrial/organizational psychology literature). An archival dataset covering 57 clerical and technical occupations with 26,682 participants was used. Support was found for the relationship between self-rated performance and importance ratings. Significant relationships (typically in the .30s) were observed for all 31 competencies that were studied. Controls were taken to account for common method bias and differences in the competencies required for each of the 57 occupations. Past research has demonstrated the effects of the self-serving bias on personality-based job analysis ratings. This study was the first to extend these findings to traditional job analysis, which covers other competencies in addition to personality. In addition, this study is the first to use operational field data instead of laboratory data. PMID- 22931008 TI - Optimal experience among teachers: new insights into the work paradox. AB - Several studies highlighted that individuals perceive work as an opportunity for flow or optimal experience, but not as desirable and pleasant. This finding was defined as the work paradox. The present study addressed this issue among teachers from the perspective of self-determination theory, investigating work related intrinsic and extrinsic motivation, as well as autonomous and controlled behavior regulation. In Study 1, 14 teachers were longitudinally monitored with Experience Sampling Method for one work week. In Study 2, 184 teachers were administered Flow Questionnaire and Work Preference Inventory, respectively investigating opportunities for optimal experience, and motivational orientations at work. Results showed that work-related optimal experiences were associated with both autonomous regulation and with controlled regulation. Moreover, teachers reported both intrinsic and extrinsic motivation at work, with a prevailing intrinsic orientation. Findings provide novel insights on the work paradox, and suggestions for teachers' well-being promotion. PMID- 22931009 TI - Finding Canada's healthcare equilibrium. AB - Economic equilibrium, in which demand for health services is in balance with supply, is an elusive phenomenon in advanced healthcare systems worldwide, yet some countries have come closer to economic stasis than Canada. In 2008, the Euro Canada Health Consumer Index ranked Canada 30th out of 30 countries studied for value for money. Wait times were Canada's weakest spot, and, in terms of system design, context, and economics, there was clear evidence that Canada's healthcare system was out of equilibrium. Canadians can learn from Austria. If Canada expects better value for its healthcare dollar, then cost drivers need to be addressed in a design overhaul. Only then will Canada approach equilibrium. PMID- 22931010 TI - The complexities of governing in a social media world. AB - The complexity of governing has increased with the Internet's introduction of social media. Boards need to be aware of social media impact upon external stakeholder relations, as well as legal responsibilities within the organization. This paper outlines the various implications of social media that a board needs to consider. A governance framework is used to help put the issues in perspective. The conclusion is that boards need to take social media seriously and ensure that their organization has a social media risk mitigation strategy for external communications, as well as eDiscovery. Various other strategies and tactics are suggested to help boards address the challenge. PMID- 22931011 TI - Procurement change in Canada: an opportunity for improving system performance. AB - The Canadian healthcare system is undergoing restructuring of how goods and services are purchased. A conference "Navigating Hospital and Health System Procurement" was organized by MEDEC and the Canadian College of Health Leaders to examine the issues. This paper describes the implications and opportunities these changes present for healthcare policy, regulation, practice, and the supplier marketplace. PMID- 22931012 TI - The contribution of work environment to nurses' assessments of the quality of patient care. AB - The quality of patient care was found to be significantly correlated with work environment measures in a quasi-experimental study in the Saskatoon Health Region. Since first line supervisors face multiple pressures in organizing the work of their units, they need to be supported by senior leadership for continuity in instilling a common purpose and shared values to the patient care staff. The role of supervision and leadership is crucial in strategically managing the human, financial and technical resources in our healthcare system, especially when such resources are likely to remain limited. PMID- 22931013 TI - Integrating research and education into clinical practice: the multi-organ transplant student research training program. AB - Given the increased student interest in health research and the need to implement health research initiatives, the Multi-Organ Transplant Student Research Training Program provides student trainees with the opportunity to contribute to health research initiatives in transplant care. Program quality initiatives achieved include the development of a clinical research database, knowledge exchange, performance measurement tools, and health research projects. The program promotes collaboration between academic and healthcare institutions to integrate research and education into clinical practice. PMID- 22931014 TI - Leaders and emotional intelligence: a view from those who follow. AB - Abstract-Boyatzis and Goleman state that Emotional Intelligence (EI) "is an important predictor of success." In their book Primal Leadership, they refer to "the leadership competencies of emotional intelligence: how leaders handle themselves and their relationships." The leadership exercises reported here examined the practices of effective and ineffective leaders as identified by individuals who have worked under such leaders (ie, followers/subordinates). We sought to ascertain to what extent these practices are related to EI. The 2-year data from these leadership exercises show the strong relationships between perceived leadership effectiveness and emotionally intelligent leadership practices as observed by leaders' followers. For example, whether considering the practices that made effective leaders effective or the practices that ineffective leaders needed to adopt or significantly improve upon (in the eyes of subordinates), these practices were almost exclusively related to EI. These findings are supported in the EI literature, as is the strength of subordinates' assessments in predicting leadership effectiveness. PMID- 22931015 TI - The ethics of disclosure of patient safety incidents. PMID- 22931016 TI - There we go again! PMID- 22931017 TI - The debate over health care rationing: Deja vu all over again? AB - Health care rationing has been a source of contentious debate in the United States for nearly 30 years. Because rationing is bewildering to many Americans, persistent myths about "death panels" and critical health care decisions to be made by faceless bureaucrats abound, instilling fear about health care reform and cost containment measures aimed at slowing spending growth. This paper retrospectively reviews the policy literature on health care rationing over the past quarter century, examines alternative definitions and classification schemes, traces the evolution of the debate, and explores ways in which rationing may be made more rational, transparent, and equitable in the future allocation of scarce health care resources. PMID- 22931018 TI - Employment-based health benefits: recent trends and future outlook. AB - The employment-based health benefits system established its roots many years ago. It was during World War II that many more employers began to offer health benefits. Recently, however, both the percentage of workers with employment-based health benefits and the comprehensiveness of such coverage have been declining. This paper examines recent trends in employment-based health benefits. It also considers the likely future of this important workplace benefit in light of shifts from defined benefit to defined contribution models of employee benefits and with regard to the implementation of health reform. PMID- 22931019 TI - Why employers will continue to provide health insurance: the impact of the Affordable Care Act. AB - The Congressional Budget Office, the Rand Corporation, and the Urban Institute have estimated that the Patient Protection and Affordable Care Act (ACA) will leave employer-sponsored coverage largely intact; in contrast, some economists and benefit consultants argue that the ACA encourages employers to drop coverage, thereby making both their workers and their firms better off (a "win-win" situation). This analysis shows that no such "win-win" situation exists and that employer-sponsored insurance will remain the primary source of coverage for most workers. Analysis of three issues-the terms of the ACA, worker characteristics, and the fundamental economics of competitive markets-supports this conclusion. PMID- 22931020 TI - How should risk adjustment data be collected? AB - Risk adjustment has broad general application and is a key part of the Patient Protection and Affordable Care Act (ACA). Yet, little has been written on how data required to support risk adjustment should be collected. This paper offers analytical support for a distributed approach, in which insurers retain possession of claims but pass on summary statistics to the risk adjustment authority as needed. It shows that distributed approaches function as well as or better than centralized ones-where insurers submit raw claims data to the risk adjustment authority-in terms of the goals of risk adjustment. In particular, it shows how distributed data analysis can be used to calibrate risk adjustment models and calculate payments, both in theory and in practice--drawing on the experience of distributed models in other contexts. In addition, it explains how distributed methods support other goals of the ACA, and can support projects requiring data aggregation more generally. It concludes that states should seriously consider distributed methods to implement their risk adjustment programs. PMID- 22931021 TI - The financial repercussions of new work-limiting health conditions for older workers. AB - This analysis used propensity score matching to construct a comparison sample that is observationally similar at baseline interview to older workers who later experience the onset of a medical condition that limits their ability to work. Using these matched onset and comparison samples, we studied trajectories in earnings and income around onset of the work limitation. Earnings two years after onset for the work-limitation group were 50% lower and poverty rates were nearly double. Income from unemployment insurance, workers' compensation, and retirement and disability benefits offset only a small amount of the earnings declines, resulting in decreased overall household income after onset of the work-limiting condition. PMID- 22931022 TI - The relationship between hospital market competition, evidence-based performance measures, and mortality for chronic heart failure. AB - Using data from the Joint Commission's ORYX initiative and the Medicare Provider Analysis and Review file from 2003 to 2006, this study employed a fixed-effects approach to examine the relationship between hospital market competition, evidence-based performance measures, and short-term mortality at seven days, 30 days, 90 days, and one year for patients with chronic heart failure. We found that, on average, higher adherence with most of the Joint Commission's heart failure performance measures was not associated with lower mortality; the level of market competition also was not associated with any differences in mortality. However, higher adherence with the discharge instructions and left ventricular function assessment indicators at the 80th and 90th percentiles of the mortality distribution was associated with incrementally lower mortality rates. These findings suggest that targeting evidence-based processes of care might have a stronger impact in improving patient outcomes. PMID- 22931023 TI - John Sperry: a CPA among physicians. PMID- 22931024 TI - 5 ways to reduce variation. PMID- 22931025 TI - An improved accrual: reducing medical malpractice year-end adjustments. AB - Healthcare organizations can improve their year-end malpractice insurance accruals by taking the following steps: Maintain productive communication. Match accrual and accounting policies. Adjust amount of credit to own historical loss experience. Request more frequent analysis. Obtain a second opinion. PMID- 22931026 TI - Leveraging EHR investments through medical device connectivity. AB - There are two primary factors for analyzing the cost of medical device integration: the total cost of ownership and gains in clinician efficiency. When calculating the long-term total cost of ownership, hospitals should consider the original acquisition cost, ongoing support costs, and also look at the incremental cost of adding a new device. In determining clinical efficiency, recent analyses show that medical device integration alleviates the initial negative impact of implementing an electronic health record and improves clinician efficiency by reducing clinicians' overall documentation activities. PMID- 22931027 TI - Integration without employment. AB - Three models for hospital-physician alignment may offer hospitals for which large scale physician employment is not practical the best means to prepare for payment changes under accountable care: Comanagement arrangements Clinical joint ventures Professional services agreements with performance incentives. PMID- 22931028 TI - Navigating the road ahead: lessons from a pioneer ACO. AB - Genesys PHO in Flint, Mich., is one of 32 ACOs participating in the Pioneer ACO Model initiative administered by the CMS. Genesys PHO' experience suggests that successful ACOs will invest physicians with decision power and focus on strengthening the physician-patient relationship, restoring patients' trust in physicians, and allocating the right human resources to the effort. Organizations that are considering an ACO strategy should evaluate the risk structures of their proposed contracts and their provider groups' willingness to accept the contractual level of risk. PMID- 22931029 TI - 5 pillars of clinical integration. AB - Implementing an effective clinical integration program requires deliberate investment of time and resources in five key areas: Physician leadership, Physician-led care management, Quality monitoring, Patient information and data sharing, Payer engagement. PMID- 22931030 TI - After the Supreme Court decision: what's next for reform. AB - A Republican sweep in the November elections could lead to repeal of most of the Affordable Care Act, to be replaced with legislation to achieve limited coverage expansion. A Romney victory and split Congress would likely result in Republicans using their administrative authority to modify or disrupt implementation of the act, with provisions altered or repealed where bipartisan agreement exists. An Obama victory and split Congress would likely result in continued implementation of the act but with a delay to some elements. PMID- 22931031 TI - Building data-driven trust with physicians. AB - Steps healthcare finance executives should take to develop a data-driven, transparent approach to working with physicians should include the following: Show the assumptions behind the data. Explain the rationale or methodology behind the assumptions and be sure there are no flaws in how conclusions are drawn from the data sets. Explain why the metrics used are representative of the physician's practice. Account for all data gaps in metrics or benchmarks, but explain how the data represent the best option for going forward. PMID- 22931032 TI - Back to basics: 5 ways to pick low-hanging fruit. AB - Five areas of potential cost reduction related to labor and the supply chain are: Overtime actual to budget biweekly analysis, Overtime actual trend (to budget) analysis, Overtime actual total individual employee costs Actual monthly supply chain expenses compared with budget by chart of accounts code and detail analysis, Actual monthly analysis by individual vendor and detail analysis. PMID- 22931033 TI - Moving from CFO to COO. AB - Strategies for positioning yourself for the role of COO or chief administrative officer include the following: Learn more than just the financial aspects of running a hospital or health system. Cultivate deep self awareness of your attributes as a leader. Find ways to accelerate innovation in your organization. Take a fresh look at issues that are continuing challenges for your organization. PMID- 22931034 TI - Focusing on white space to improve patient throughput. AB - When designing a new patient care process or modifying an existing one, healthcare leaders should: Set specific goals for frontline staff, Move beyond gathering and discussing data to acting on the data, Issue data reports frequently, Prepare to take advantage of success, Do not expect a silver bullet. PMID- 22931035 TI - Reducing healthcare costs through better chronic disease management. PMID- 22931036 TI - The value proposition: 4 lessons from failing quality programs. PMID- 22931038 TI - Hospitals invest less in updates, renovations, and expansions. PMID- 22931037 TI - What would you do? Which initiatives should a health system pursue in a highly competitive market? PMID- 22931039 TI - Frequency of estrogen receptor (ER)-negative, progesterone receptor (PR) negative, and HER2-negative invasive breast cancer, the so-called triple-negative phenotype: a population-based study from Trentino, North East Italy. AB - OBJECTIVE: Triple negative breast carcinomas (TNT) are infiltrating breast carcinomas (BC) with negative oestrogen receptor (ER), progesterone receptor (PgR) and human epidermal growth factor receptor 2 (HER-2) expression, and are associated with frequent BRCA1/BRCA2 mutations. The aim of the present study is to analyze the frequency and distribution of TNT in our population where a breast cancer screening program for women aged between 50 and 69 years is effective since 2001 with 85% accrual. METHODS: We investigated the records of 2112 consecutive BC and 153 interval BC (i.e. BC detected in the screened negative women in the interval between screening rounds). Tumours with complete negative expression of ER, PgR and Her2 were considered TNT; tumours with negative ER and PgR status and faint Her2 expression (score 1) were considered as possible TNT (pTNT). RESULTS: We identified 82 (3.8%) TNT and 20 (0.9%) pTNT in the series of 2112 consecutive BC and 7 TNT and 1 pTNT (5.2%) in the series of 153 interval BC. In the consecutive series, TNT/ pTNT were observed in 6.5% patients below 50 years and in 4.3% of patients above 50 years. A high proliferation rate (Ki-67 labelling > 36%) was observed in 87.8% of TNT (median labelling 56.3%) and in 60% of pTNT (median labelling 48.4%). CONCLUSIONS: Since TNT/pTNT occurring in women < 50 years is a criterion for selecting patients whom genetic counselling and BRCA1 testing should be offered, our study is of help in foreseeing the workload of the Unit of Medical Genetics and the Laboratory of Molecular Pathology. PMID- 22931040 TI - Oncocytic papillary renal cell carcinoma: potential pitfall in small enucleation. AB - OBJECTIVE: We describe an emerging entity, recently recognized as a pitfall in the diagnostic practice among eosinophilic renal cell tumours. METHODS: A 60-year old male underwent enucleation of a 1.2 cm nodule. Immunohistochemistry and FISH analysis were performed. RESULTS: Histology revealed a neoplasm composed of large cells with eosinophilic cytoplasm, Fuhrman grade 3, arranged in papillae. At the immunohistochemical level, cells showed positivity for AMACR and CD10. Fluorescence in situ hybridization (FISH) demonstrated gains of chromosomes 7 and 17 and loss of Y. A diagnosis of oncocytic papillary renal cell carcinoma was made. CONCLUSIONS: The distinction between renal oncocytoma and oncocytic papillary renal cell carcinoma is of substantial importance because of their different behaviour and prognosis, since the latter has malignant potential. Although the available evidence supporting tumour enucleation as the surgical treatment for renal cortical tumours < or = 4 cm, due to aforementioned clinicopathological features such tumours need to be evaluated using appropriate immunophenotypical and cytogenetic analyses. PMID- 22931041 TI - Clear cell papillary renal cell carcinoma with characteristic morphology and immunohistochemical staining pattern. AB - Clear cell papillary renal cell carcinoma is newly-defined entity initially believed to be associated with end stage renal disease. We report a rare case of this neoplasm in a 70-year-old female patient with no known history of end-stage renal disease who presented with haematuria lasting several days. After initial workup, a computed tomography (CT) scan was performed and revealed a cystic mass in the right kidney. Material obtained by fine needle aspiration (FNA) biopsy of the mass was felt to be suspicious for renal cell carcinoma. The patient subsequently underwent right nephrectomy, and the lesional tissue was examined microscopically. A 2.3 cm in greatest dimension cystic space circumscribed by a fibrous wall was surfaced by a single layer of bland cuboidal cells with abundant clear cytoplasm. The solid component of the tumour consisted of branching papillae with delicate fibrovascular cores and uniformly lined by cells similar to those of the inner wall of the cyst. Some of the fibrovascular cores were markedly expanded by a myxoid-appearing substance, but no foamy cells were appreciated. Immunohistochemically, the neoplastic cells were diffusely immunoreactive with cytokeratin 7 (CK7), epithelial membrane antigen (EMA), high molecular weight cytokeratin (HMWCK) and vimentin. Neoplastic cells were only focally immunoreactive with CD10, and were negative for both p63 and alpha methylacyl-CoA racemase (AMACR) (P504S). The cytomorphological features and immunohistochemical staining pattern of this tumour was consistent with that of clear cell papillary renal cell carcinoma (CCPRCC), as described by Gobbo et al. PMID- 22931042 TI - Idiopathic granulomatous mastitis mimicking breast cancer: report of two cases. AB - Idiopathic granulomatous mastitis is a rare inflammatory breast disease of unknown aetiology that is frequently mistaken for breast carcinoma both clinically and mammographically. In this paper, the authors report two cases of idiopathic granulomatous mastitis that occurred in two parous women aged 38 and 45 years. Clinically, both patients presented with a tender palpable lump in the left breast. Mammography showed an poorly-defined mass in both patients with microcalcification in the first case and skin retraction in the second case. Breast lumpectomy was performed in both patients. Histological examination of the surgical specimen revealed non-caseating granulomas confined to breast lobules. Special staining for fungi and tuberculosis were all negative. Correct diagnosis ofidiopathic granulomatous mastitis requires the exclusion of malignancy, other granulomatous disease and infectious aetiologies. Histopathologic examination remains the gold standard for diagnosis. This disease is rare, and therefore the optimum treatment protocol is still being established. PMID- 22931043 TI - Grafting polymer brushes on biomimetic structural surfaces for anti-algae fouling and foul release. AB - Sylgard-184 silicone elastomer negative replica and resorcinol-formaldehyde (RF) positive replica were made by biomimicking the patterns of natural Trifolium and three other kinds of leaves using the micromolding lithography. An effective antifouling (AF) polymer, poly(3-sulfopropyl methacrylate) (PSPMA), was then grafted on these replica surfaces via the surface-initiated atom transfer radical polymerization (SI-ATRP). The AF property of the modified biomimetic surfaces was tested via the settlement assay with two microalgae in different sizes, and their fouling-release (FR) property was evaluated by the removal assay. The results indicate that the structure of microspines on Trifolium leaf can inhibit settlement of microalgae and facilitate the cell release. The AF property was improved by modification with PSPMA brushes. PMID- 22931044 TI - Probing the mechanism of Baylis-Hillman reaction in ionic liquids. AB - The kinetic data for a Baylis-Hillman reaction in certain ionic liquids possessing ethylsulfate anion [EtSO(4)](-) demonstrate that the rate determining step (RDS) is second order in aldehyde, but first order in acrylate and DABCO. This observation is similar to the one made by McQuade et al., who carried out this reaction in an aprotic polar solvent like DMSO. However, this is in contrast to the general observation that RDS is first order in aldehyde, acrylate, and DABCO in organic solvents. PMID- 22931045 TI - Facile synthesis of surfactant-free Au cluster/graphene hybrids for high performance oxygen reduction reaction. AB - Non-Pt noble metal clusters like Au clusters are believed to be promising high performance catalysts for the oxygen reduction reaction (ORR) at the cathode of fuel cells, but they still suffer big problems during the catalysis reactions, such as a large amount of the capping agents being on the surface and easy occurrence of dissolution and aggregation. To overcome these obstacles, here, we present a novel and general strategy to grow ultrafine Au clusters and other metal (Pt, Pd) clusters on the reduced graphene oxide (rGO) sheets without any additional protecting molecule or reductant. Compared with the currently generally adopted nanocatalysts, including commercial Pt/C, rGO sheets, Au nanoparticle/rGO hybrids, and thiol-capped Au clusters of the same sizes, the as synthesized Au cluster/rGO hybrids display an impressive eletrocatalytic performance toward ORR, for instance, high onset potential, superior methanol tolerance, and excellent stability. PMID- 22931046 TI - Species dynamics alter community diversity-biomass stability relationships. AB - The relationship between community diversity and biomass variability remains a crucial ecological topic, with positive, negative and neutral diversity-stability relationships reported from empirical studies. Theory highlights the relative importance of Species-Species or Species-Environment interactions in driving diversity-stability patterns. Much previous work is based on an assumption of identical (stable) species-level dynamics. We studied ecosystem models incorporating stable, cyclic and more complex species-level dynamics, with either linear or non-linear density dependence, within a locally stable community framework. Species composition varies with increasing diversity, interacting with the correlation of species' environmental responses to drive either positive or negative diversity-stability patterns, which theory based on communities with only stable species-level dynamics fails to predict. Including different dynamics points to new mechanisms that drive the full range of diversity-biomass stability relationships in empirical systems where a wider range of dynamical behaviours are important. PMID- 22931047 TI - Combined use of synchrotron radiation based micro-X-ray fluorescence, micro-X-ray diffraction, micro-X-ray absorption near-edge, and micro-fourier transform infrared spectroscopies for revealing an alternative degradation pathway of the pigment cadmium yellow in a painting by Van Gogh. AB - Over the past years a number of studies have described the instability of the pigment cadmium yellow (CdS). In a previous paper we have shown how cadmium sulfide on paintings by James Ensor oxidizes to CdSO(4).H(2)O. The degradation process gives rise to the fading of the bright yellow color and the formation of disfiguring white crystals that are present on the paint surface in approximately 50 MUm sized globular agglomerations. Here, we study cadmium yellow in the painting "Flowers in a blue vase" by Vincent van Gogh. This painting differs from the Ensor case in the fact that (a) a varnish was superimposed onto the degraded paint surface and (b) the CdS paint area is entirely covered with an opaque crust. The latter obscures the yellow color completely and thus presents a seemingly more advanced state of degradation. Analysis of a cross-sectioned and a crushed sample by combining scanning microscopic X-ray diffraction (MU-XRD), microscopic X-ray absorption near-edge spectroscopy (MU-XANES), microscopic X-ray fluorescence (MU-XRF) based chemical state mapping and scanning microscopic Fourier transform infrared (MU-FT-IR) spectrometry allowed unravelling the complex alteration pathway. Although no crystalline CdSO(4) compounds were identified on the Van Gogh paint samples, we conclude that the observed degradation was initially caused by oxidation of the original CdS pigment, similar as for the previous Ensor case. However, due to the presence of an overlying varnish containing lead-based driers and oxalate ions, secondary reactions took place. In particular, it appears that upon the photoinduced oxidation of its sulfidic counterion, the Cd(2+) ions reprecipitated at the paint/varnish interface after having formed a complex with oxalate ions that themselves are considered to be degradation products of the resin and/or oil in the varnish. The SO(4)(2-) anions, for their part, found a suitable reaction partner in Pb(2+) ions stemming from a dissolved lead-based siccative that was added to the varnish to promote its drying. The resulting opaque anglesite compound in the varnish, in combination with the underlying CdC(2)O(4) layer at the paint/varnish interface, account for the orange-gray crust that is disfiguring the painting on a macroscopic level. In this way, the results presented in this paper demonstrate how, through a judicious combined use of several microanalytical methods with speciation capabilities, many new insights can be obtained from two minute, but highly complex and heterogeneous paint samples. PMID- 22931048 TI - The toxic effect of opioid analgesics on human sperm motility in vitro. AB - Opioid analgesics are the most common therapeutic analgesic for acute pain. In this study, the toxicological and pharmacological features of a group of opioid analgesics were characterized by the motility of human sperm. Aliquots of sperm were incubated with various concentrations of opioid analgesics in vitro. Computer-assisted sperm analysis was used to assess sperm motility at 15 minutes, 2 hours, and 4 hours after drug addition to the medium. Butorphanol and dezocine showed marked reduction of motility after incubation with sperm for 15 minutes. Butorphanol was more effective than dezocine in immobilizing sperm. Other opioids studied, such as fentanyl, alfentanil, and sufentanil, showed only partial inhibitory activity. Based on the data reported herein, we have found that butorphanol and dezocine exert a sperm-immobilizing effect. However, fentanyl, alfentanil, and sufentanil exhibit only partial inhibition of sperm motility. Given the increasing use of opioids and their potential effect on sperm motility, these findings are greatly relevant to male reproductive health. PMID- 22931049 TI - Antibodies against polyethylene glycol in healthy subjects and in patients treated with PEG-conjugated agents. AB - In contrast to the accepted general assumption that polyethylene glycol (PEG) is non-immunogenic and non-antigenic, animal studies clearly showed that uricase, ovalbumin and some other PEGylated agents can elicit antibody formation against PEG (anti-PEG). In humans, anti-PEG may limit therapeutic efficacy and/or reduce tolerance of PEG-asparaginase (PEG-ASNase) in patients with acute lymphoblastic leukemia and of pegloticase in patients with chronic gout, but did not impair hyposensitization of allergic patients with mPEG-modified ragweed extract or honeybee venom or the response to PEG-IFN in patients with hepatitis C. Of major importance is the recent finding of a 22 - 25% occurrence of anti-PEG in healthy blood donors, compared with a very low 0.2% occurrence two decades earlier. This increase may be due to an improvement of the limit of detection of antibodies during the years and to greater exposure to PEG and PEG-containing compounds in cosmetics, pharmaceuticals and processed food products. These results raise obvious concerns regarding the efficacy of PEG-conjugated drugs for a subset of patients. To address these concerns, the immunogenicity and antigenicity of approved PEGylated compounds should be carefully examined in humans. With all these data in hand, patients should be pre-screened and monitored for anti-PEG prior to and throughout a course of treatment with a PEGylated compound. Finally, protein conjugates with the poorly immunogenic hydroxy-PEG sequence or other hydrophilic polymers are in early phases of development and may represent an alternative to immunogenic PEGylated proteins. PMID- 22931050 TI - Successful treatment of a left ventricular assist device infection with daptomycin non-susceptible methicillin-resistant Staphylococcus aureus: case report and review of the literature. AB - Recipients of left ventricular assist devices (LVADs) are highly susceptible to the development of infections with multidrug-resistant (MDR) organisms. We describe the case of a patient with an LVAD who developed a device-related, daptomycin non-susceptible, methicillin-resistant Staphylococcus aureus infection, highlighting this patient population as highly vulnerable to the development of such antimicrobial resistance. This report includes a thorough review of the literature on the mechanisms of development of daptomycin non susceptibility and suggests ways to prevent its emergence. We also provide and underscore the appropriate guidelines to abide by when attempting to control infections with such resistant isolates. This case also demonstrates the importance of definitive treatment with LVAD removal and transplantation as a component of appropriate management of invasive LVAD infections. In addition, we suggest that even infections with MDR organisms may not adversely affect post transplant outcomes. PMID- 22931051 TI - Acral lentiginous melanoma of the toe treated using Mohs surgery with sparing of the digit and subsequent reconstruction using split-thickness skin graft. PMID- 22931053 TI - Social exclusion and myiasis of the upper lip in a Brazilian rural resident. AB - CONTEXT: People living in rural or remote Brazil, as in other sub-tropical or tropical nations, are vulnerable to infections that would not normally occur in urban areas or wealthier nations. Brazil is a geographically extensive nation, historically marked by vast socioeconomic inequalities. Approximately 16% of the population live in rural areas. ISSUE: This clinical case report demonstrates the vulnerability of rural residents who are underserved by Brazil's 'universal' public healthcare system, despite social and economic challenges that increase their risk for disease. Myiasis (especially oral myiasis) is a rare health condition in humans caused by fly larvae. Oral myiasis usually appears in periodontal pockets and open wounds, such as after dental extractions. It is associated with poverty, lack of access to health care, and very poor overall health status. While myiasis has a worldwide distribution, it is particularly associated with the tropical and sub-tropical regions of North and South America. LESSONS LEARNED: This article describes a rare case of myiasis in the upper lip of a rural male patient. The case report demonstrate that rural and remote residents can be socially excluded from the benefits of technology and biomedicine, making them vulnerable to rare infections. PMID- 22931052 TI - Prevalence of KRAS, BRAF, and PIK3CA somatic mutations in patients with colorectal carcinoma may vary in the same population: clues from Sardinia. AB - BACKGROUND: Role of KRAS, BRAF and PIK3CA mutations in pathogenesis of colorectal cancer (CRC) has been recently investigated worldwide. In this population-based study, we evaluated the incidence rates and distribution of such somatic mutations in genetically isolated population from Sardinia. METHODS: From April 2009 to July 2011, formalin-fixed paraffin-embedded tissues (N = 478) were prospectively collected from Sardinian CRC patients at clinics across the entire island. Genomic DNA was isolated from tissue sections and screened for mutations in KRAS, BRAF, and PIK3CA genes by automated DNA sequencing. RESULTS: Overall, KRAS tumour mutation rate was 30% (145/478 positive cases). Distribution of mutation carriers was surprisingly different within the island: 87/204 (43%) in North Sardinia vs. 58/274 (21%) in Middle-South Sardinia (p<0.001). Among 384 CRC cases whose DNA was available, only one (0.3%) patient carried a mutation in BRAF gene; PIK3CA was found mutated in 67 (17%) patients. A significant inverse distribution of PIK3CA mutation rates was observed within Sardinian population: 19/183 (10%) cases from northern vs. 48/201 (24%) cases from central-southern island (p<0.001). This heterogeneity in frequencies of KRAS/PIK3CA somatic mutations is consistent with already-reported discrepancies in distribution of germline mutations for other malignancies within Sardinian population. Preliminary clinical evaluation of 118 KRAS wild-type patients undergoing anti EGFR-based treatment indicated lack of role for PIK3CA in predicting response to therapy. CONCLUSIONS: Our findings support the hypothesis that differences in patients' origins and related genetic backgrounds may contribute to even determine the incidence rate of somatic mutations in candidate cancer genes. PMID- 22931054 TI - Structural insight into how Pseudomonas aeruginosa peptidoglycanhydrolase Tse1 and its immunity protein Tsi1 function. AB - Tse1 (Tse is type VI secretion exported), an effector protein produced by Pseudomonas aeruginosa, is an amidase that hydrolyses the gamma-D-glutamyl-DAP (gamma-D-glutamyl-L-meso-diaminopimelic acid) linkage of the peptide bridge of peptidoglycan. P. aeruginosa injects Tse1 into the periplasm of recipient cells, degrading their peptidoglycan, thereby helping itself to compete with other bacteria. Meanwhile, to protect itself from injury by Tse1, P. aeruginosa expresses the cognate immunity protein Tsi1 (Tsi is type VI secretion immunity) in its own periplasm to inactivate Tse1. In the present paper, we report the crystal structures of Tse1 and the Tse1-(6-148)-Tsi1-(20-end) complex at 1.4 A and 1.6 A (1 A=0.1 nm) resolutions respectively. The Tse1 structure adopts a classical papain-like alpha+beta fold. A cysteine-histidine catalytic diad is identified in the reaction centre of Tse1 by structural comparison and mutagenesis studies. Tsi1 binds Tse1 tightly. The HI loop (middle finger tip) from Tsi1 inserts into the large pocket of the Y-shaped groove on the surface of Tse1, and CD, EF, JK and LM loops (thumb, index finger, ring finger and little finger tips) interact with Tse1, thus blocking the binding of enzyme to peptidoglycan. The catalytic and inhibition mechanisms provide new insights into how P. aeruginosa competes with others and protects itself. PMID- 22931055 TI - Preparation of aggregation-resistant biocompatible superparamagnetic noncovalent hybrid multilayer hollow microspheres for controlled drug release. AB - Biocompatible superparamagnetic polyelectrolyte hybrid hollow microspheres ((CS/Fe(3)O(4)-CA)(3)-CS-NH-CH(2)-PEG) were successfully prepared by PEGylation of multilayered polyelectrolyte hybrid shell encapsulated polystyrene sulfonate (PSS) microsphere templates fabricated by the layer-by-layer self-assembly of chitosan (CS) and citrate modified ferroferric oxide magnetic nanoparticles (Fe(3)O(4)-CA), after etching the templates by dialysis. Their hollow structure with diameter of about 200 nm was confirmed by TEM analysis. The pH and ionic strength responsive properties were retained after the PEGylation of the hollow microspheres. Furthermore, their biocompatibility and stability against aggregation and fusion in media with high ionic strength were distinctly improved. A typical anti-inflammatory drug, ibuprofen, was used for drug loading, and the release behaviors of ibuprofen in a simulated body fluid (SBF) were studied. The results indicate that the biocompatible superparamagnetic polyelectrolyte hybrid hollow microspheres ((CS/Fe(3)O(4)-CA)(3)-CS-NH-CH(2)-PEG) have a high drug loading capacity and favorable release property for ibuprofen; thus, they are very promising for application in drug delivery. PMID- 22931057 TI - Respiratory syncytial virus (RSV) pneumonia in a southern muriqui (Brachyteles arachnoides). AB - BACKGROUND: An adult male Brachyteles arachanoides, kept in captivity since 1990, was found dead without apparent clinical evidence. METHODS: Necropsy report, histopathology, immunohistochemistry, and ultrastructural examination were conducted. RESULTS: Pulmonary syncytial cells were positive for respiratory syncytial virus (RSV), and ultrastructural examination revealed viral particles inside macrophages compatible with the Paramyxoviridae family. CONCLUSIONS: Muriquis are susceptible to RSV pneumonia followed by respiratory distress syndrome and death. PMID- 22931056 TI - Methicillin-resistant Staphylococcus pseudintermedius in Sweden. AB - Staphylococcus pseudintermedius is an opportunistic pathogen that is one of the most frequent causes of infections in dogs. In Europe, there are increasing reports of methicillin-resistant S. pseudintermedius (MRSP), and in Sweden, MRSP has also been more frequently isolated during recent years. However, there is limited knowledge regarding the epidemiology and genetic relationship among the Swedish isolates. This study therefore investigated the genetic relationship of MRSP isolated from companion animals in Sweden. In the study, MRSP isolates taken in the period January 2008-June 2010 from a total of 226 dogs and cats were characterized by spa typing, pulsed-field gel electrophoresis, and antimicrobial susceptibility testing. In addition, the geographical distribution of the isolates based on year of isolation and genetic typing was determined using a geographical information system. One multiresistant clonal lineage dominated among Swedish MRSP isolates, corresponding to the European winning lineage ST71-J t02-SCCmec II-III. Furthermore, the geographical dissemination of MRSP corresponded to areas with high dog densities, centered on the three major cities in Sweden where the largest animal hospitals are situated. PMID- 22931059 TI - How suitable is the measurement of take-off forces for detection of sticking during direct compression of various ibuprofen tablet formulations? AB - Sticking of tablet formulations to punch surfaces is one of the most common problems observed during tablet manufacture. An inline method proposed for detection of sticking during compression is the measurement of take-off forces, which occur when tablets are detached from the lower punch surface. It has been postulated that the tablet take-off force is a direct indicator of the sticking tendency of a tablet formulation. In the present study, the take-off forces measured during direct compression of sticking ibuprofen tablet formulations were evaluated and compared to the sticking extent of these tablets quantified by HPLC analysis of ibuprofen. As expected, sticking to the lower punch was increased with an increase of the ibuprofen content in the investigated tablet formulations. However, data obtained from take-off force measurements did not correlate with the quantified amount of sticking. Although pronounced sticking was observed, the measured tablet take-off forces remained low even at high drug contents. These results indicate that the tablet take-off force is not a direct indicator of the sticking tendency of ibuprofen tablet formulations. It is suggested that the evaluation of take-off force data requires a differentiated approach. A new interpretation of take-off force data is presented in this paper. PMID- 22931060 TI - Ano-cathodophilic biofilm catalyzes both anodic carbon oxidation and cathodic denitrification. AB - Biocathodic denitrification using bioelectrochemical systems (BES) have shown promise for both wastewater and groundwater treatment. Typically, these systems involve anodic carbon oxidation and cathodic denitrification catalyzed by two electroactive biofilms located separately at an anode and a cathode. However, process efficiencies are often limited by pH drifts in the respective electrode biofilms: acidification (pH <5.5) in the bioanode and basification (pH >8.5) in the biocathode. Here, we describe for the first time a single electroactive biofilm that acts as a bioanode and a biocathode, alternately catalyzing anodic acetate oxidation (Coulombic efficiency (CE) 85.3%) and cathodic denitrification (CE 87.3%) (-400 mV Ag/AgCl). Our results indicate that the ano-cathodophilic biofilm denitrified autotrophically using the electrode (-200 to -600 mV Ag/AgCl) as a direct electron donor. Further, the alkalinity produced from cathodic denitrification partially (19%) neutralized the acidity of the anodic reaction. Switching the electrode potential to temporarily favor either an anodic or cathodic reaction may represent a unique method for removing carbon and nitrate from contaminated liquors. This study offers new insights into the development of sustainable BES-based nutrient removal processes. PMID- 22931058 TI - Assessing the utility of an anti-malarial pharmacokinetic-pharmacodynamic model for aiding drug clinical development. AB - BACKGROUND: Mechanistic within-host models relating blood anti-malarial drug concentrations with the parasite-time profile help in assessing dosing schedules and partner drugs for new anti-malarial treatments. A comprehensive simulation study to assess the utility of a stage-specific pharmacokinetic-pharmacodynamic (PK-PD) model for predicting within-host parasite response was performed. METHODS: Three anti-malarial combination therapies were selected: artesunate mefloquine, dihydroartemisinin-piperaquine, and artemether-lumefantrine. The PK PD model included parameters to represent the concentration-time profiles of both drugs, the initial parasite burden and distribution across the parasite life cycle, and the parasite multiplication factor due to asexual reproduction. The model also included the maximal killing rate of each drug, and the blood drug concentration associated with half of that killing effect (in vivo EC50), derived from the in vitro IC50, the extent of binding to 0.5% Albumax present in the in vitro testing media, and the drugs plasma protein binding and whole blood to plasma partitioning ratio. All stochastic simulations were performed using a Latin-Hypercube-Sampling approach. RESULTS: The simulations demonstrated that the proportion of patients cured was highly sensitive to the in vivo EC50 and the maximal killing rate of the partner drug co-administered with the artemisinin derivative. The in vivo EC50 values that corresponded to on average 95% of patients cured were much higher than the adjusted values derived from the in vitro IC50. The proportion clinically cured was not strongly influenced by changes in the parameters defining the age distribution of the initial parasite burden (mean age of 4 to 16 hours) and the parasite multiplication factor every life cycle (ranging from 8 to 12 fold/cycle). The median parasite clearance times, however, lengthened as the standard deviation of the initial parasite burden increased (i.e. the infection became more asynchronous). CONCLUSIONS: This simulation study demonstrates that the PD effect predicted from in vitro growth inhibition assays does not accord well with the PD effect of the anti-malarials observed within the patient. This simulation-based PK-PD modelling approach should not be considered as a replacement to conducting clinical trials but instead as a decision tool to improve the design of a clinical trial during drug development. PMID- 22931061 TI - Novel SLC9A6 mutations in two families with Christianson syndrome. PMID- 22931062 TI - The simple fool's guide to population genomics via RNA-Seq: an introduction to high-throughput sequencing data analysis. AB - High-throughput sequencing technologies are currently revolutionizing the field of biology and medicine, yet bioinformatic challenges in analysing very large data sets have slowed the adoption of these technologies by the community of population biologists. We introduce the 'Simple Fool's Guide to Population Genomics via RNA-seq' (SFG), a document intended to serve as an easy-to-follow protocol, walking a user through one example of high-throughput sequencing data analysis of nonmodel organisms. It is by no means an exhaustive protocol, but rather serves as an introduction to the bioinformatic methods used in population genomics, enabling a user to gain familiarity with basic analysis steps. The SFG consists of two parts. This document summarizes the steps needed and lays out the basic themes for each and a simple approach to follow. The second document is the full SFG, publicly available at http://sfg.stanford.edu, that includes detailed protocols for data processing and analysis, along with a repository of custom made scripts and sample files. Steps included in the SFG range from tissue collection to de novo assembly, blast annotation, alignment, gene expression, functional enrichment, SNP detection, principal components and F(ST) outlier analyses. Although the technical aspects of population genomics are changing very quickly, our hope is that this document will help population biologists with little to no background in high-throughput sequencing and bioinformatics to more quickly adopt these new techniques. PMID- 22931063 TI - Ubiquitin carboxy-terminal hydrolase L1 (UCH-L1) is increased in cerebrospinal fluid and plasma of patients after epileptic seizure. AB - BACKGROUND: Clinical and experimental studies have demonstrated that seizures can cause molecular and cellular responses resulting in neuronal damage. At present, there are no valid tests for assessing organic damage to the brain associated with seizure. The aim of this study was to investigate cerebrospinal fluid (CSF) and plasma concentrations of Ubiquitin carboxy-terminal hydrolase L1 (UCH-L1), a sensitive indicator of acute injury to brain neurons, in patients with tonic clonic or partial secondarily generalized seizures due to various etiologies. METHODS: CSF and plasma concentrations of UCH-L1 were assessed in 52 patients within 48 hours after epileptic seizure and in 19 controls using ELISA assays. RESULTS: CSF obtained within 48 hours after seizure or status epilepticus (SE) presented significantly higher levels of UCH-L1 compared to controls (p = 0.008). Plasma UCH-L1 concentrations were negatively correlated with time to sample withdrawal. An analysis conducted using only the first 12 hours post-seizure revealed significant differences between concentrations of UCH-L1 in plasma and controls (p = 0.025). CSF and plasma concentrations were strongly correlated with age in patients with seizure, but not in control patients. Plasma UCH-L1 levels were also significantly higher in patients after recurrent seizures (n = 4) than in those after one or two seizures (p = 0.013 and p = 0.024, respectively). CONCLUSION: Our results suggest that determining levels of neuronal proteins may provide valuable information on the assessment of brain damage following seizure. These data might allow clinicians to make more accurate therapeutic decisions, to identify patients at risk of progression and, ultimately, to provide new opportunities for monitoring therapy and targeted therapeutic interventions. PMID- 22931064 TI - Early left atrial mechanics and volume abnormalities in subjects with prehypertension: a real time three-dimensional echocardiography study. AB - The aim of this study was to evaluate left atrial (LA) volume and mechanical functions by real time three-dimensional echocardiography (RT3DE) in prehypertensive subjects. The study included 54 (34 male and 20 female) prehypertensive subjects and 36 (14 male and 22 female) healthy control subjects. Transthoracic echocardiography and RT3DE were performed in all patients. Interventricular septum thickness and isovolumetric relaxation time were significantly higher in prehypertensives than in controls (10.7 +/- 0.7 vs. 10.1 +/- 0.8 P = 0.001 and 89.9 +/- 10 vs. 82.4 +/- 11 P = 0.002, respectively). LA maximum volume, volume before atrial contraction, total and active stroke volume, total and active emptying fractions, expansion index, and LA max volume index were significantly higher in prehypertensives when compared with controls (P < 0.0001 for all). However, the passive emptying fraction was significantly lower in prehypertensives than controls (45.7 +/- 5.6 vs. 48.6 +/- 4.1, P = 0.006), and the minimum LA volume between the two groups was similar. The main finding of this study was that although LA volume and LA active systolic functions were significantly increased in prehypertensive people, there was a reduction in passive LA systolic functions. These parameters may be important in showing hemodynamic and structural changes in cardiac tissue caused by prehypertension. PMID- 22931065 TI - Private rural health providers in Haryana, India: profile and practices. AB - INTRODUCTION: Despite a widespread public health system, the private healthcare sector is the major provider of health care in rural India. This study describes the profile and medical practices of private rural health providers (PRHPs) in rural Haryana, India. METHODS: A cross-sectional study was conducted among PRHPs practicing in the villages of Comprehensive Rural Health Services Project (CRHSP) at Ballabgarh block located in the Faridabad district of Haryana State. The CRHSP is an Intensive Field Practice Area (IFPA) of the Centre for Community Medicine, All India Institute of Medical Sciences, New Delhi. RESULTS: Eighty PRHPs participated in this study (response rate 93%). The majority (96%) did not possess a qualification in any formal system of medicine. Half of the PRHPs had a separate space (private area) for the examination of patients. Almost all had stethoscopes, thermometers and blood pressure apparatus. The PRHPs were involved in a wide range of practices, such as dispensing medicines (98.7%), providing injections (98.7%) and intravenous fluids (98.7%), and conducting minor surgery (78.5%). Dumping biomedical waste was a common practice among these practitioners. Some PRHPs (8.7%) were involved in national health programs. CONCLUSIONS: Unqualified PRHPs provide substantial outpatient healthcare services in rural Ballabgarh, India. Their biomedical waste disposal practices are inadequate. There is a need for training in waste disposal practices and monitoring of safe injection techniques among PRHPs. Consideration should be given to utilising PRHPs in important public health programs such as disease surveillance. PMID- 22931066 TI - Esophageal telocytes and hybrid morphologies. AB - TCs (telocytes) are actually defined as stromal cells with specific long and thin prolongations, called Tp (telopodes). They have been positively identified in various tissues and we now report their presence in the esophagus. These cells were identified by TEM (transmission electron microscopy) in esophageal samples of Wistar rats (n = 5) occurring beneath the basal epithelial layer, in submucosa, closely related to smooth and striated muscular fibres, as also in the adventitia. They are closely related to mast cells, macrophages and microvessels. Hybrid morphologies of stromal cells processes were found: cytoplasmic processes continued distally in a telopodial fashion. Telopodes alone may not be sufficient, however, for a safe diagnosis of TCs in TEM. A larger set of specific standards (such as the telopodial emergence, and the size of the cell body and telopodes) should be considered to differentiate TCs from various species of fibroblasts. The morphological and ultrastructural features should distinguish between TCs and interstitial cells of Cajal in the digestive tract. PMID- 22931067 TI - Advancing American Indian/Alaska Native substance abuse research. PMID- 22931068 TI - Advancing American Indian and Alaska Native substance abuse research: current science and future directions. AB - American Indians and Alaska Natives (AI/AN) have disproportionately high rates of substance abuse yet there is little empirical research addressing this significant public health problem. This paper is an introduction to a special issue that includes cutting edge science in this research area. We identify several areas that require consideration in this field and indicate how the papers in the special issue address these gaps. These overarching areas of need, which should be considered in any substantive research, include attention to heterogeneity within the population, research that has tangible health benefits, continued work on research methods and strategies, increased focus on strength based and community oriented approaches, and the need for strong research partnerships. The special issue marks a major step forward for AI/AN substance abuse research. However, articles also highlight where more work is need to improve public health in AI/AN communities by addressing identified gap areas. PMID- 22931069 TI - Epidemiology and etiology of substance use among American Indians and Alaska Natives: risk, protection, and implications for prevention. AB - BACKGROUND: The epidemiology and etiology of substance use and disorder in American Indian and Alaska Native (AI/AN) communities have received increasing attention over the past 25 years and accumulating evidence provides important insights into substance use patterns in these populations. OBJECTIVES AND METHODS: We provide a descriptive sketch of the AI/AN population in the United States today, present a brief review of the literature on the epidemiology and etiology of substance use within these populations, and discuss key implications of this literature for prevention efforts. CONCLUSIONS AND SCIENTIFIC SIGNIFICANCE: Patterns of alcohol use and abuse in AI/AN populations are complex and vary across cultural groups, but alcohol clearly impacts both physical health and mental health within these communities. Tobacco use - and associated health consequences - is typically higher in these populations than among other US groups, although significant variation across Native communities is apparent here as with alcohol. Evidence regarding drug use and disorder is less extensive and thus less conclusive, but evidence demonstrates higher rates of use as well. Etiological explanations for substance use and disorder cut across individual characteristics (e.g., genetics) or experiences (e.g., exposure to trauma), to social contexts (e.g., family disruption), and to cultural factors (e.g., historical trauma). Protective factors likely cut across these multiple levels as well and deserve more focused attention for informing prevention efforts. The development of effective prevention strategies, built through collaboration between researchers and Native communities, drawing from the wisdom of both, is a high priority. PMID- 22931070 TI - Patterns of substance use initiation among young adolescents in a Northern Plains American Indian tribe. AB - BACKGROUND: Substantial evidence documents problematic substance use in Northern Plains American Indian communities. Studies suggest that disparities can be traced to disproportionate rates of early substance use, but most evidence comes from the retrospective reports of adults or older adolescents. OBJECTIVE: To use a prospective longitudinal design to examine substance use initiation patterns as they emerge among young American Indian adolescents. METHODS: Four waves of data were collected across three consecutive school years from middle school students on a Northern Plains reservation (N = 450). Discrete-time survival analyses were used to estimate risks of initiation of cigarettes, alcohol, and marijuana from age 10 to 13. RESULTS: Risk for cigarette initiation was relatively high at age 10 and stable until age 13. Marijuana risk was low at age 10 but increased sharply by age 12. Alcohol initiation lagged, not surpassing risk for cigarette initiation until age 13 and remaining below risk for marijuana initiation throughout middle school. Hazards for girls trended higher than those for boys across all substances, but differences did not reach significance. CONCLUSION: Initiation patterns among these American Indian adolescents differed from patterns reported in other US groups, particularly with respect to deviation from the sequence characterized the initiation of marijuana before alcohol that is predicted by the gateway theory. SCIENTIFIC SIGNIFICANCE: Findings suggest that prevention efforts with youth in this community should begin early with a primary focus on marijuana use. They also suggest the importance of examining sequences of substance initiation among youth in other American Indian communities. PMID- 22931071 TI - ADH and ALDH polymorphisms and alcohol dependence in Mexican and Native Americans. AB - BACKGROUND: Ethanol is primarily metabolized in the liver by two rate-limiting reactions: conversion of ethanol to acetaldehyde by alcohol dehydrogenase (ADH) and subsequent conversion of acetaldehyde to acetate by aldehyde dehydrogenase (ALDH). ADH and ALDH exist in multiple isozymes that differ in their kinetic properties. Notably, polymorphisms within the genes that encode for these isozymes vary in their allele frequencies between ethnic groups, and thus, they have been considered as candidate genes that may differentially influence risk for the development of alcohol dependence across ethnic groups. OBJECTIVES AND METHODS: Associations between alcohol dependence and polymorphisms in ADH1B, ADH1C, and ALDH2 were compared in a community sample of Native Americans (n 791) living on reservations and Mexican Americans (n 391) living within the same county. RESULTS: Two Mexican Americans and no Native Americans possessed one ALDH2*2 allele. Presence of at least one ADH1B*2 allele was found in 7% of the Native Americans and 13% of the Mexican Americans, but was only associated with protection against alcohol dependence in the Mexican Americans. Presence of at least one ADH1B*3 allele was found in 4% of the Native Americans and 2% of the Mexican Americans, but was associated with protection against alcohol dependence only in the Native Americans. No associations between alcohol dependence and polymorphisms in ADH1C were found. CONCLUSIONS AND SCIENTIFIC SIGNIFICANCE: Polymorphisms in ADH1B are protective against alcoholism in these two populations; however, these findings do not explain the high prevalence of alcoholism in these populations. PMID- 22931072 TI - Fatherhood roles and drug use among young American Indian men. AB - BACKGROUND: High rates of substance abuse among young American Indian (AI) fathers pose multigenerational challenges for AI families and communities. OBJECTIVE: The objective of this study was to describe substance use patterns among young AI fathers and examine the intersection of substance use with men's fatherhood roles and responsibilities. METHODS: As part of a home-visiting intervention trial for AI teen mothers and their children, in 2010 we conducted a descriptive study of fatherhood and substance use on three southwestern reservations. Substance use and parenting data were collected from n = 87 male partners of adolescent mothers using audio computer-assisted self-interviews. RESULTS: Male partners were on average 22.9 years old, primarily living with their children (93%), unmarried (87%), and unemployed (70%). Lifetime substance use was high: 80% reported alcohol; 78% marijuana; 34% methamphetamines; 31% crack/cocaine; and 16% reported drinking binge in the past 6 months. Substance use was associated with history of alcohol abuse among participants' fathers (but not mothers); participants' poor relationships with their own fathers; unemployment status; and low involvement in child care. CONCLUSION: Drug and alcohol abuse may be obstructing ideal fatherhood roles among multiple generations of AI males. SCIENTIFIC SIGNIFICANCE: Targeting drug prevention among young AI men during early fatherhood may provide special opportunity to reduce substance use and improve parenting. Intergenerational approaches may hold special promise. PMID- 22931073 TI - Understanding the relationship between substance use and self-injury in American Indian youth. AB - BACKGROUND: American Indian communities compared to other US populations are challenged by the largest health disparities in substance abuse and suicidal behavior among youth ages 15-24. OBJECTIVES: This article examines the co occurrence of substance use and self-injury among reservation-based youth in the US. METHODS: White Mountain Apache tribal leaders and Johns Hopkins University formed a partnership to address self-injury and substance abuse among Apache youth. Data on suicide (deaths, attempts, ideation), non-suicidal self-injury, and substance use were analyzed from the White Mountain Apache tribally mandated self-injury surveillance registry from 2007 to 2010, including 567 validated incidents from 352 individuals aged 15-24 years. Findings regarding characteristics of co-occurrence - including differences in the type of self-harm behavior, gender, and reported reasons for the act - were interpreted through a community-based participatory research process. RESULTS: From 2007 to 2010, 64% (n = 7/11) of Apache youth ages 15-24 were "drunk or high" at the time of suicide death with data missing for 2/11 deaths; 75.7% (n = 118/156) were "drunk or high" during suicide attempt; 49.4% (n = 83/168) during suicidal ideation; and 49.4% (81/166) during non-suicidal self-injury. Co-occurrence of substance use was higher for more lethal acts and among males. CONCLUSION: High rates of co occurring self-injury and substance use within this population highlight the importance of research to understand relationships between these behaviors to design preemptive and integrated interventions. SCIENTIFIC SIGNIFICANCE: Tribal specific and culturally informed data on the co-occurrence of self-injury and substance use hold promise for reducing the combined toll of years of productive life lost among American Indian youth. PMID- 22931074 TI - Exploring binge drinking and drug use among American Indians: data from adolescent focus groups. AB - BACKGROUND: Risk factors for binge substance use and non-suicidal self-injury (NSSI) are similar, suggesting the importance of exploring how binge substance use and self-injury interrelate. OBJECTIVES: To gain insight from a sample of American Indian (AI) adolescents regarding how binge drinking and drug use function in their lives, including as overlapping forms of self-injury, and to identify community-based ideas for dual prevention strategies. METHODS: A total of N = 58 White Mountain Apache (Apache) adolescents participated in ten mixed gender (n = 33 males, 55.9%) focus group discussions. Results were interpreted and categorized by Apache researchers and compared to Nock's behavioral model of NSSI. RESULTS: Participants reported substance use most commonly with "family" and "friends," "at a house," or "around the community." Substance use was not confined to a particular time of day, and often occurred "at school." Commonly endorsed reasons fell into two main categories: "to avoid problems" or "to reduce negative feelings," versus "to be cool" or "to feel part of a group." All adolescents but one thought that some youths use substances excessively as a way to harm/injure themselves (n = 25 responses). Prevention approaches included encouraging healthy relationships, teaching about consequences of use, providing alternative recreation, and changing/enforcing laws on the reservation. CONCLUSION: Tribal-specific data support the idea that binge substance use sometimes functions as a form of self-injury. Home/school environments are critical prevention settings, in addition to improved law enforcement and increased recreation. SCIENTIFIC SIGNIFICANCE: Understanding possible shared root causes and functions of binge substance use and self-injury may advance integrated prevention approaches. PMID- 22931075 TI - Advantages of stress process approaches for measuring historical trauma. AB - Despite growing attention to historical trauma (HT) as a key mechanism for documented Indigenous health disparities like alcohol abuse, the complexities of conceptualizing and measuring HT-related constructs have limited empirical tests of these relationships. In this article, we review the current evidence surrounding one HT measure: the Historical Loss Scale. In addition, we provide examples of the benefits of treating historical cultural losses as stressors within sociological and Indigenous stress process models of health. PMID- 22931076 TI - Indian boarding school experience, substance use, and mental health among urban two-spirit American Indian/Alaska natives. AB - BACKGROUND: Systematic efforts of assimilation removed many Native children from their tribal communities and placed in non-Indian-run residential schools. OBJECTIVES: To explore substance use and mental health concerns among a community based sample of 447 urban two-spirit American Indian/Alaska Native adults who had attended boarding school as children and/or who were raised by someone who attended boarding school. METHOD: Eighty-two respondents who had attended Indian boarding school as children were compared to respondents with no history of boarding school with respect to mental health and substance use. RESULTS: Former boarding school attendees reported higher rates of current illicit drug use and living with alcohol use disorder, and were significantly more likely to have attempted suicide and experienced suicidal thoughts in their lifetime compared to non-attendees. About 39% of the sample had been raised by someone who attended boarding school. People raised by boarding school attendees were significantly more likely to have a general anxiety disorder, experience posttraumatic stress disorder symptoms, and have suicidal thoughts in their lifetime compared to others. PMID- 22931077 TI - Substance abuse prevention in American Indian and Alaska Native communities. AB - In this article we review three categories of American Indian/Alaska Native (AIAN) substance abuse prevention programs: (1) published empirical trials; (2) promising programs published and unpublished that are in the process of development and that have the potential for empirical trials; and (3) examples of innovative grassroots programs that originate at the local level and may have promise for further development. AIAN communities are taking more and more independent control of substance abuse prevention. We point out that European American prevention scientists are largely unaware of the numerous grassroots prevention work going on in AIAN communities and urge a paradigm shift from adapting European American prevention science "best practices" to creating cultural "best practices" by working from inside AIAN communities. PMID- 22931078 TI - A review of evidence-based approaches for reduction of alcohol consumption in Native women who are pregnant or of reproductive age. AB - BACKGROUND: Fetal alcohol spectrum disorders (FASDs) are the leading preventable cause of developmental disabilities in the United States and likely throughout the world. FASDs can be prevented by avoiding alcohol use during pregnancy; however, efforts to prevent risky alcohol consumption in women of childbearing potential have not been universally successful. OBJECTIVES: Data suggest that successful interventions may require tailoring methods to meet the needs of specific populations and cultures. Key findings of interventions previously tested among American Indian and Alaskan Native (AI/AN) women who are or may become pregnant, data gaps, and promising ongoing interventions are reviewed. METHODS: A systematic review of the current literature on empirically based interventions among AI/AN women was conducted. Selected alternative approaches currently being tested in AI/AN settings are also described. RESULTS: Similar to findings among other populations of women in the United States, a number of interventions have been implemented; however, only a small number have measured results. Approaches have included standard interventions involving hospitalization, inpatient, or outpatient care; wellness education; traditional approaches; and case management for high-risk women. An ongoing Screening, Brief Intervention, and Referral to Treatment (SBIRT) protocol comparing the effectiveness of a web-based culturally adapted tool, or a peer health educator model to standard clinical practice is described. CONCLUSION: Translation of successful interventions from other settings to AI/AN populations holds promise. SCIENTIFIC SIGNIFICANCE: FASDs represent a significant health issue with high personal and societal costs. Improvement of interventions to prevent prenatal alcohol consumption in specific populations, including AI/AN women, is a critical public health need. PMID- 22931079 TI - Community partnership to affect substance abuse among Native American adolescents. AB - BACKGROUND: Substance abuse is one of the nation's primary health concerns. Native American youth experience higher rates of substance abuse than other youth. There is little empirical evidence that exists concerning the use of culturally-based interventions among Native American adolescents. OBJECTIVES: This study used a community-based participatory research approach to develop and evaluate an innovative school-based cultural intervention targeting substance abuse among a Native American adolescent population. METHODS: A two-condition quasi-experimental study design was used to compare the Cherokee Talking Circle (CTC) culturally-based intervention condition (n = 92) with the Be A Winner Standard Education (SE) condition (n = 87). Data were collected at pre intervention, immediate post-intervention, and 90-day post-intervention using the Cherokee Self-Reliance Questionnaire, Global Assessment of Individual Needs - Quick, and Written Stories of Stress measures. RESULTS: Significant improvements were found among all measurement outcomes for the CTC culturally-based intervention. CONCLUSIONS: The data provide evidence that a Native American adolescent culturally-based intervention was significantly more effective for the reduction of substance abuse and related problems than a noncultural-based intervention. SCIENTIFIC SIGNIFICANCE: This study suggests that cultural considerations may enhance the degree to which specific interventions address substance abuse problems among Native American adolescents. PMID- 22931080 TI - Implementing a reward and reminder underage drinking prevention program in convenience stores near Southern California American Indian reservations. AB - BACKGROUND: Underage drinking is associated with a number of social and public health consequences. Preventing access to alcohol is one approach to reducing underage drinking. OBJECTIVES: This study assesses the efficacy of a culturally tailored "reward and reminder" program aimed at reducing convenience store alcohol sales to youth living on or near nine American Indian reservations. METHODS: First, tribal council proclamations were sought to support underage drinking prevention, including reward and reminder efforts. Then, decoys (volunteers over 21 years of age but judged to look younger) attempted to purchase alcohol without identification. Clerks who asked for identification were given "rewards" (gift cards and congratulatory letters), whereas clerks who did not were given "reminders" of the law regarding sales to minors. Following an initial baseline of 12 purchase attempts, three repeated reward and reminder visits were made to 13 convenience stores selling alcohol within 10 miles of the reservations (n = 51 total attempts). RESULTS: Five of nine tribal councils passed resolutions in support of the program. The baseline sales rate without requesting ID was 33%. Similarly, 38% of stores in the first reward and reminder visit round failed to request identification. However, in the following two reward and reminder rounds, 0% of the stores failed to request identification. CONCLUSIONS: These results indicate that environmental community-level underage drinking prevention strategies to reduce alcohol sales near rural reservations are feasible and can be effective. SCIENTIFIC SIGNIFICANCE: Environmental prevention strategies within reservation communities support integrated supply and demand reduction models for reducing underage drinking. PMID- 22931083 TI - Review of substance use disorder treatment research in Indian country: future directions to strive toward health equity. AB - BACKGROUND: American Indians and Alaska Natives (AI/ANs) have disproportionately high rates of substance use disorders (SUDs). Effective treatment can help to reduce these disparities. OBJECTIVE: To review and summarize the AI/AN SUD treatment research literature. METHODS: The literature between 1965 and 2011 was reviewed to identify AI/AN SUD treatment articles. RESULTS: Twenty-four unique studies were identified. Earlier treatment research focused on clinical ratings of improvement; later studies employed formal assessment measures. Poor outcomes were attributed to psychosocial factors. Where treatment outcomes appeared to be similar to comparison samples, interpretation was hampered by methodological concerns. CONCLUSIONS: The research has improved across the decades, as has the inclusion of cultural adaptations. Future research should examine factors that influence treatment effectiveness and improve retention to bolster confidence in findings. SCIENTIFIC SIGNIFICANCE: AI/ANs experience SUD-related health disparities. Understanding what factors contribute to positive treatment outcomes can help to address these disparities. PMID- 22931081 TI - Umyuangcaryaraq "Reflecting": multidimensional assessment of reflective processes on the consequences of alcohol use among rural Yup'ik Alaska Native youth. AB - BACKGROUND AND AIMS: Concerns in some settings regarding the accuracy and ethics of employing direct questions about alcohol use suggest need for alternative assessment approaches with youth. Umyuangcaryaraq is a Yup'ik Alaska Native word meaning "Reflecting." OBJECTIVES: The Reflective Processes Scale was developed as a youth measure tapping awareness and thinking over potential negative consequences of alcohol misuse as a protective factor that includes cultural elements often shared by many other Alaska Native and American Indian cultures. This study assessed multidimensional structure, item functioning, and validity. METHODS: Responses from 284 rural Alaska Native youth allowed bifactor analysis to assess structure, estimates of location and discrimination parameters, and convergent and discriminant validity. RESULTS: A bifactor model of the scale items with three content factors provided excellent fit to observed data. Item response theory analysis suggested a binary response format as optimal. Evidence of convergent and discriminant validity was established. CONCLUSION: The measure provides an assessment of reflective processes about alcohol that Alaska Native youth engage in when thinking about reasons not to drink. SCIENTIFIC SIGNIFICANCE: The concept of reflective processes has potential to extend understandings of cultural variation in mindfulness, alcohol expectancies research, and culturally mediated protective factors in Alaska Native and American Indian youth. PMID- 22931084 TI - Indigenous traditional knowledge and substance abuse treatment outcomes: the problem of efficacy evaluation. AB - BACKGROUND: In the field of substance abuse treatment, American Indian and Alaska Native (AI/AN) communities have routinely incorporated ceremonial practices as one important component in the promotion of recovery and healing. The beneficial effects of such practices are frequently described as plainly apparent by community-based advocates, providers, and professionals alike. In the present era of evidence-based substance abuse intervention, however, indigenous integration of such practices raises questions pertaining to the systematic evaluation of treatment efficacy. OBJECTIVES: The focus of this article is outcome evaluation. Although intervention outcome researchers recognize the randomized controlled trial as the "gold standard" against which claims of treatment efficacy are measured, AI/AN efficacy assertions grounded in indigenous traditional knowledge (ITK) reflect different concerns that have emerged in non-Western historical contexts. The interface between scientific and indigenous "ways of knowing" is explored here relative to efficacy claims about substance abuse treatment. METHODS: Distinguishing features of both scientific knowing and ITK are summarized and compared. RESULTS: ITK has been described as personal and experiential, reflecting the primacy of autonomous individual knowing. In contrast, intervention scientists are skeptical of personal inference as a basis for efficacy evaluation. The evident divergence between these epistemic paradigms can result in potentially contradictory claims. CONCLUSION: Proper appraisal of the status and relevance of ITK for determining treatment efficacy requires further exploration of these marginalized approaches to knowledge. SCIENTIFIC SIGNIFICANCE: Intervention scientists who work in AI/AN communities should remain open to the legitimacy and role of ITKs in investigations of substance abuse treatment. PMID- 22931082 TI - Patterns of protective factors in an intervention for the prevention of suicide and alcohol abuse with Yup'ik Alaska Native youth. AB - BACKGROUND: Community-based participatory research (CBPR) with American Indian and Alaska Native communities creates distinct interventions, complicating cross setting comparisons. OBJECTIVE: The objective of this study is to develop a method for quantifying intervention exposure in CBPR interventions that differ in their forms across communities, permitting multi-site evaluation. METHODS: Attendance data from 195 youth from three Yup'ik communities were coded for the specific protective factor exposure of each youth, based on information from the intervention manual. The coded attendance data were then submitted to latent class analysis to obtain participation patterns. RESULTS: Five patterns of exposure to protective factors were obtained: Internal, External, Limits, Community/family, and Low Protection. Patterns differed significantly by community and youth age. CONCLUSION: Standardizing interventions by the functions an intervention serves (protective factors promoted) instead of their forms or components (specific activities) can assist in refining CBPR interventions and evaluating effects in culturally distinct settings. PMID- 22931085 TI - American Indians with substance use disorders: treatment needs and comorbid conditions. AB - BACKGROUND: American Indians and Alaska Natives (AI/ANs) experience significant disparities in health status and access to care. Furthermore, only limited data are available on substance use, mental health disorders, and treatment needs for this population. Addressing such disparities and developing culturally relevant, effective interventions for AI/AN communities require participatory research. OBJECTIVES AND METHODS: The Western States Node of the National Institute on Drug Abuse Clinical Trials Network partnered with two American Indian substance abuse treatment programs: an urban health center and a reservation-based program to assess client characteristics, drug use patterns, and treatment needs. Data collected by staff members at the respective programs from urban (n = 74) and reservation (n = 121) clients were compared. Additional sub-analysis examined patients reporting regular opioid use and mood disorders. RESULTS: Findings indicate that urban clients were more likely to report employment problems, polysubstance use, and a history of abuse. Reservation-based clients reported having more severe medical problems and a greater prevalence of psychiatric problems. Clients who were regular opioid users were more likely to report having a chronic medical condition, suicidal thoughts, suicide attempts, polysubstance abuse, and IV drug use. Clients who reported a history of depression had twice as many lifetime hospitalizations and more than five times as many days with medical problems. CONCLUSIONS: Findings from this project provide information about the patterns of substance abuse and the importance of comprehensive assessments of trauma and comorbid conditions. Results point to the need for integrative coordinated care and auxiliary services for AI/AN clients seeking treatment for substance use disorders. PMID- 22931086 TI - Utilizing drumming for American Indians/Alaska Natives with substance use disorders: a focus group study. AB - BACKGROUND: Drumming has been utilized among American Indian/Alaska Native (AI/AN) tribes for centuries to promote healing and self-expression. Drum Assisted Recovery Therapy for Native Americans (DARTNA), currently under development, is a substance abuse treatment utilizing drumming as a core component. OBJECTIVES: Focus groups were conducted to assist in the development of the DARTNA protocol. Feedback obtained from these focus groups will inform a subsequent pretest of DARTNA and an empirical study analyzing its effectiveness. METHODS: Three focus groups were conducted among AIs/ANs with substance use disorders (n = 6), substance abuse treatment providers (n = 8), and a community advisory board (n = 4) to solicit feedback prior to a pretest of the DARTNA protocol. RESULTS: Overall, participants indicated that DARTNA could be beneficial for AIs/ANs with substance use disorders. Four overarching conceptual themes emerged across the focus groups: (1) benefits of drumming, (2) importance of a culture-based focus, (3) addressing gender roles in drumming activities, and (4) providing a foundation of common AI/AN traditions. CONCLUSIONS: The DARTNA protocol is a potentially beneficial and culturally appropriate substance abuse treatment strategy for AIs/ANs. In order to optimize the potential benefits of a substance abuse treatment protocol utilizing drumming for AIs/ANs, adequate attention to tribal diversity and gender roles is needed. SCIENTIFIC SIGNIFICANCE: Due to the shortage of substance abuse treatments utilizing traditional healing activities for AIs/ANs, including drumming, results from this study provide an opportunity to develop an intervention that may meet the unique treatment needs of AIs/ANs. PMID- 22931087 TI - Substance use, treatment admissions, and recovery trends in diverse Washington State tribal communities. AB - BACKGROUND: Qualitative and quantitative data and participatory research approaches might be most valid and effective for assessing substance use/abuse and related trends in American Indian and Alaska Native (AIAN) communities. METHOD: Twenty-nine federally recognized AIAN tribes in Washington (WA) State were invited to participate in Health Directors (HD) interviews and State treatment admissions data analyses. Ten Tribal HD (or designees) from across WA participated in 30-60-minute qualitative interviews. State treatment admissions data from 2002 to 2008 were analyzed for those who identified with one of 11 participating AIAN communities to explore admission rates by primary drug compared to non-AIANs. Those who entered treatment and belonged to one of the 11 participating tribes (n = 4851) represented 16% of admissions for those who reported a tribal affiliation. RESULTS: Interviewees reported that prescription drugs, alcohol, and marijuana are primary community concerns, each presenting similar and distinct challenges. Additionally, community health is tied to access to resources, services, and culturally appropriate and effective interventions. Treatment data results were consistent with interviewee-reported substance use/abuse trends, with alcohol as the primary drug for 56% of AIAN adults compared to 46% of non-AIAN, and other opiates as second most common for AIAN adults in 2008 with 15% of admissions. LIMITATIONS: Findings are limited to those tribal communities/community members who agreed to participate. CONCLUSION: Analyses suggest that some diverse AIAN communities in WA State share similar substance use/abuse, treatment, and recovery trends and continuing needs. SCIENTIFIC SIGNIFICANCE: Appropriate and effective research with AIAN communities requires respectful and flexible approaches. PMID- 22931088 TI - A framework for conducting a national study of substance abuse treatment programs serving American Indian and Alaska native communities. AB - BACKGROUND: Because of their broad geographic distribution, diverse ownership and operation, and funding instability, it is a challenge to develop a framework for studying substance abuse treatment programs serving American Indian and Alaska Native communities at a national level. This is further complicated by the historic reluctance of American Indian and Alaska Native communities to participate in research. OBJECTIVES AND METHODS: We developed a framework for studying these substance abuse treatment programs (n ~ 293) at a national level as part of a study of attitudes toward, and use of, evidence-based treatments among substance abuse treatment programs serving AI/AN communities with the goal of assuring participation of a broad array of programs and the communities that they serve. RESULTS: Because of the complexities of identifying specific substance abuse treatment programs, the sampling framework divides these programs into strata based on the American Indian and Alaska Native communities that they serve: (1) the 20 largest tribes (by population); (2) urban AI/AN clinics; (3) Alaska Native Health Corporations; (4) other Tribes; and (5) other regional programs unaffiliated with a specific AI/AN community. In addition, the recruitment framework was designed to be sensitive to likely concerns about participating in research. CONCLUSION AND SCIENTIFIC SIGNIFICANCE: This systematic approach for studying substance abuse and other clinical programs serving AI/AN communities assures the participation of diverse AI/AN programs and communities and may be useful in designing similar national studies. PMID- 22931089 TI - TLR2 and TLR4 activation induces p38 MAPK-dependent phosphorylation of S6 kinase 1 in C2C12 myotubes. AB - Toll-like receptors 2 (TLR2) and 4 (TLR4) are present in the plasma membrane of skeletal muscle cells where their functions remain incompletely resolved. They can bind various extracellular ligands, such as FSL-1, lipopolysaccharide (LPS) and/or palmitic acid (PA). We have investigated the link between PA, TLR2/4 and ribosomal S6 kinase 1 (S6K1) in C2C12 myotubes. Incubation with agonists of either TLR2 or TLR4, and with a high concentration of PA, increased S6K1 phosphorylation. Canonical upstream kinases of S6K1, protein kinase B (PKB) and mammalian target of rapamycin complex 1 (mTORC1), were regulated in the opposite way by PA, indicating that these kinases were probably not involved. By using the SB202190 inhibitor, p38 MAPK (mitogen-activated protein kinase) was found to be a key mediator of PA-induced phosphorylation of S6K1. Downregulation of either tlr2 or tlr4 gene expression by small interfering RNAs prevented the activation of both p38 MAPK and S6K1 by FSL-1, LPS or PA. Thus TLR2 and TLR4 agonists can increase the level of S6K1 phosphorylation in a p38 MAPK-dependent way in C2C12 myotubes. As PA induced the same intracellular signalling, a novel atypical pathway for PA is induced at the cellular membrane level and results in a higher phosphorylation state of S6K1. PMID- 22931090 TI - Improved efficiency of organic/inorganic hybrid near-infrared light upconverter by device optimization. AB - An organic/inorganic hybrid up-conversion device was demonstrated in this work, which can convert near-infrared light (NIR) to visible green at high conversion efficiency. The upconverter was fabricated by integrating an In(0.12)Ga(0.88)As/GaAs multiquantum wells (MQWs) photodetector (PD) with an organic light emitting diode (OLED). The up-conversion efficiency of 4.0 W/W % was obtained at 20 V under NIR illumination of 1 mW/mm(2) at room temperature by optimizing the structure of the PD unit and adding MoO(3) doped perylene-3,4,9,10 tetracarboxylic dianhydride (PTCDA) as interfacial layer of OLED. Meanwhile, the green light output induced by NIR achieved 6050 cd/m(2), which proves that the organic/inorganic hybrid upconverter an excellent candidate that can be applied in light converter field. PMID- 22931091 TI - From sample processing to quantification: a full electrochemical approach for neutral analyte derivatization, capillary electrophoresis separation, and contactless conductivity detection. AB - A thin-layer electrochemical flow cell coupled to capillary electrophoresis with contactless conductivity detection (EC-CE-C(4)D) was applied for the first time to the derivatization and quantification of neutral species using aliphatic alcohols as model compounds. The simultaneous electrooxidation of four alcohols (ethanol, 1-propanol, 1-butanol, and 1-pentanol) to the corresponding carboxylates was carried out on a platinum working electrode in acid medium. The derivatization step required 1 min at 1.6 V vs. Ag/AgCl under stopped flow conditions, which was preceded by a 10 s activation at 0 V. The solution close to the electrode surface was then hydrodynamically injected into the capillary, and a 2.5 min electrophoretic separation was carried out. The fully automated flow system operated at a frequency of 12 analyses per hour. Simultaneous determination of the four alcohols presented detection limits of about 5 * 10(-5) mol L(-1). As a practical application with a complex matrix, ethanol concentrations were determined in diluted pale lager beer and in nonalcoholic beer. No statistically significant difference was observed between the EC-CE C(4)D and gas chromatography with flame ionization detection (GC-FID) results for these samples. The derivatization efficiency remained constant over several hours of continuous operation with lager beer samples (n = 40). PMID- 22931092 TI - Long-term hydrogen peroxide exposure potentiates anoikis resistance and anchorage independent growth in lung carcinoma cells. AB - Hydrogen peroxide (H2O2) is upregulated in tumour microenvironments and may contribute to effects on metastatic cancer cells. This study demonstrates that treatment of lung carcinoma and melanoma cells with H2O2 for 14 days results in an induction of anoikis resistance and growth in an anchorage-independent condition. H2O2 exposure increased the Cav-1 (caveolin-1) level through an increase of Cav-1 mRNA with minimal effect on protein degradation. Upregulation of Cav-1 induced anoikis resistance and facilitated growth in a detached manner. The findings show a novel role of hydrogen peroxide in the regulation of metastatic potential of cancer cells. PMID- 22931093 TI - Hydrogen-bonding partner of the proton-conducting histidine in the influenza M2 proton channel revealed from 1H chemical shifts. AB - The influenza M2 protein conducts protons through a critical histidine (His) residue, His37. Whether His37 only interacts with water to relay protons into the virion or whether a low-barrier hydrogen bond (LBHB) also exists between the histidines to stabilize charges before proton conduction is actively debated. To address this question, we have measured the imidazole (1)H(N) chemical shifts of His37 at different temperatures and pH using 2D (15)N-(1)H correlation solid state NMR. At low temperature, the H(N) chemical shifts are 8-15 ppm at all pH values, indicating that the His37 side chain forms conventional hydrogen bonds (H bonds) instead of LBHBs. At ambient temperature, the dynamically averaged H(N) chemical shifts are 4.8 ppm, indicating that the H-bonding partner of the imidazole is water instead of another histidine in the tetrameric channel. These data show that His37 forms H-bonds only to water, with regular strength, thus supporting the His-water proton exchange model and ruling out the low-barrier H bonded dimer model. PMID- 22931094 TI - Comparing procyanidins in selected Vaccinium species by UHPLC-MS(2) with regard to authenticity and health effects. AB - Cranberry procyanidins have been associated with an effect against urinary tract infections (UTI) for decades, and European health claims are requested. This study compares the procyanidin profiles and concentrations of American cranberry ( Vaccinium macrocarpon Ait.), European cranberry ( Vaccinium oxycoccus L.), and lingonberry ( Vaccinium vitis-idaea L.) analyzed using ultrahigh-performance liquid chromatoraphy coupled to a triple-quadrupole mass spectrometer with electrospray interface (UHPLC-MS(2)). Concentrations of A-type trimers, procyanidin A2, catechin, epicatechin, and B-type dimers and trimers have been evaluated and compared for the first time in the three berries. The data clearly show remarkable differences in the procyanidin profiles and concentrations, especially the lack of A-type trimers in V. oxycoccus; thus, the effectiveness against UTI may vary among the Vaccinium species. These differences can be used to prove authenticity. PMID- 22931095 TI - Quick installation of a 1,4-difunctionality via regioselective nickel-catalyzed reductive coupling of ynoates and aldehydes. AB - The development of efficient methods for the synthesis of molecules with 1,4 difunctionalities has been a dire need of the synthetic community. In this work, intermolecular reductive coupling of ynoates and aldehydes (in the presence of a silane) has been accomplished for the first time using catalytic amounts of Ni(COD)(2), an N-heterocyclic carbene ligand, and PPh(3). High regioselectivity has been demonstrated for the multicomponent coupling reactions, and more than a dozen invaluable silyl-protected gamma-hydroxy-alpha,beta-enoates have been synthesized. This methodology provides a quick entry to many other 1,4 difunctional compounds and oxygen-containing five-membered rings. The intermediacy of metallacycles in the catalytic process has been established by deuterium-labeling experiments. PMID- 22931096 TI - Two-dimensional carbon-coated graphene/metal oxide hybrids for enhanced lithium storage. AB - Metal oxides (MOs) have been widely investigated as promising high-capacity anode material for lithium ion batteries, but they usually exhibit poor cycling stability and rate performance due to the huge volume change induced by the alloying reaction with lithium. In this article, we present a double protection strategy by fabricating a two-dimensional (2D) core-shell nanostructure to improve the electrochemical performance of metal oxides in lithium storage. The 2D core-shell architecture is constructed by confining the well-defined graphene based metal oxides nanosheets (G@MO) within carbon layers. The resulting 2D carbon-coated graphene/metal oxides nanosheets (G@MO@C) inherit the advantages of graphene, which possesses high electrical conductivity, large aspect ratio, and thin feature. Furthermore, the carbon shells can tackle the deformation of MO nanoparticles while keeping the overall electrode highly conductive and active in lithium storage. As the result, the produced G@MO@C hybrids exhibit outstanding reversible capacity and excellent rate performance for lithium storage (G@SnO(2)@C, 800 mAh g(-1) at the rate of 200 mA g(-1) after 100 cycles; G@Fe(3)O(4)@C, 920 mAh g(-1) at the rate of 200 mA g(-1) after 100 cycles). PMID- 22931097 TI - General practitioners' awareness of their own drug prescribing profiles after postal feedback and outreach visits. AB - BACKGROUND: General practice accounts for the vast majority of drug prescribing in the Nordic countries. Various methods have been used to promote rational drug prescribing. Awareness of own prescribing profile may be a first crucial step in the quality assessment and improvement process. AIM OF THE STUDY: To analyse awareness among general practitioners of their drug prescribing profile during two outreach visits one year apart. METHODS: All 94 practices with a total of 166 general practitioners in the former Storstrom County, Denmark, were invited to participate in a project launching outreach visits led by a general practitioner; 88 practices with 160 general practitioners agreed to participate. RESULTS: During the first round of outreach visits the general practitioners were asked to rate their own prescribing level of 13 major drug groups as being in the lowest 25%, the middle 26%-74%, or the highest 25% of the distribution across all 88 practices. The result was better than chance (chi-square = 337, 4 df, r = 0.37, both P < 0.0001). After the assessment a one-hour discussion on rational drug prescribing was held. One year later a new round of outreach visits was held. This time the assessment accuracy was generally greatly improved (chi-square = 724, 4 df, r = 0.48, both P < 0.0001). The main determinants for the improved accuracy during the second round were high accuracy during the first round, and the number of general practitioners in the practice. CONCLUSIONS: General practitioners' awareness of their prescribing volumes was substantially improved by a single outreach visit with discussion on rational drug prescribing. PMID- 22931098 TI - Underweight and overweight men have greater exercise-induced dyspnoea than normal weight men. AB - INTRODUCTION: Persons with high or low body mass index (BMI), involved in clinical or mechanistic trials involving exercise testing, might estimate dyspnoea differently from persons with a normal BMI. AIMS: Our objective was to investigate the relationship between BMI and dyspnoea during exercise in normal subjects with varying BMI. MATERIAL AND METHODS: A total of 37 subjects undertook progressive exercise testing. Subjects were divided into three groups: underweight (UW), normal weight (NW), and overweight (OW). Dyspnoea was estimated using the visual analogue scale (VAS). Spirometry, maximum voluntary ventilation (MVV), and respiratory muscle strength (RMS) were measured. RESULTS AND DISCUSSION: The intercept of the VAS/ventilation relationship was significantly higher in NW subjects compared to UW (P = 0.029) and OW subjects (P = 0.040). Relative to the OW group, FVC (P = 0.020), FEV(1) (P = 0.024), MVV (P = 0.019), and RMS (P = 0.003) were significantly decreased in the UW group. The greater levels of dyspnoea in UW subjects could possibly be due to decreased RMS. Healthy persons should aim to achieve an optimum BMI range to have the lowest exercise induced dyspnoea. PMID- 22931100 TI - Synthesis of functionalized materials using aryloxo-organometallic compounds toward spinel-like MM'2O4 (M = Ba2+, Sr2+; M' = In3+, Al3+) double oxides. AB - The predesigned single-source precursors [Ba{(MU-ddbfo)(2)InMe(2)}(2)] (1), [Me(2)In(MU-ddbfo)](2) (2), [Sr{(MU-ddbfo)(2)AlMe(2)}(2)] (4), and [Me(2)Al(MU ddbfo)](2) (5) (ddbfoH = 2,3-dihydro-2,2-dimethylbenzofuran-7-ol) for spinel-like double oxides and group 13 oxide materials were prepared via the direct reaction of the homoleptic aryloxide [M(ddbfoH)(4)](ddbfo)(2).ddbfoH (M = Ba(2+), Sr(2+) (3)) and InMe(3) or AlMe(3) in toluene. In all of the reactions, there was an organometallic-driven abstraction of the OH protons from the 7-benzofuranols in the Ba(2+) and Sr(2+) cation sphere. All compounds were characterized by elemental analysis, (1)H NMR, and FT-IR spectroscopy. In addition, the molecular structures of 1, 2, and 3 were determined by single-crystal X-ray diffraction. The oxide products derived from the compounds mentioned above were studied using elemental analysis, Raman spectroscopy, X-ray powder diffraction, and scanning and transmission electron microscopy equipped with an energy-dispersive spectrometer. Moreover, their specific surface area and mesopore size distribution were evaluated using nitrogen porosimetry. Preliminary investigations of the Eu-doped SrAl(2)O(4) and In(2)O(3) phosphors revealed that the oxides obtained could be considered as matrices for lanthanide ions. PMID- 22931099 TI - Low BRMS1 expression promotes nasopharyngeal carcinoma metastasis in vitro and in vivo and is associated with poor patient survival. AB - BACKGROUND: Breast cancer metastasis suppressor 1 (BRMS1) is a metastasis suppressor gene. This study aimed to investigate the impact of BRMS1 on metastasis in nasopharyngeal carcinoma (NPC) and to evaluate the prognostic significance of BRMS1 in NPC patients. METHODS: BRMS1 expression was examined in NPC cell lines using quantitative reverse transcription-polymerase chain reaction and Western blotting. NPC cells stably expressing BRMS1 were used to perform wound healing and invasion assays in vitro and a murine xenograft assay in vivo. Immunohistochemical staining was performed in 274 paraffin-embedded NPC specimens divided into a training set (n = 120) and a testing set (n = 154). RESULTS: BRMS1 expression was down-regulated in NPC cell lines. Overexpression of BRMS1 significantly reversed the metastatic phenotype of NPC cells in vitro and in vivo. Importantly, low BRMS1 expression was associated with poor distant metastasis-free survival (DMFS, P < 0.001) and poor overall survival (OS, P < 0.001) in the training set; these results were validated in the testing set and overall patient population. Cox regression analysis demonstrated that low BRMS1 expression was an independent prognostic factor for DMFS and OS in NPC. CONCLUSIONS: Low expression of the metastasis suppressor BRMS1 may be an independent prognostic factor for poor prognosis in NPC patients. PMID- 22931101 TI - Successful treatment of monomorphic primary central nervous system post transplantation lymphoproliferative disorder 5 years after kidney transplantation. AB - A 31-year-old man underwent living-related kidney transplantation in 2004 as a consequence of primary focal segmental glomerulosclerosis (FSGS). Four years after the transplantation, we confirmed nephrotic syndrome caused by recurrent FSGS. We performed plasmapheresis and low-density lipoprotein adsorption. We also combined steroid therapy with a reduction in the dose of tacrolimus and an increased dose of mycophenolate mofetil. The nephrotic syndrome improved dramatically with this combined therapeutic approach. However, 10 months after these treatments, he revisited our hospital because of altered consciousness. We detected multiple tumor masses in his brain that were ring enhanced on contrast magnetic resonance imaging. Consequently, we suspected primary central nervous system post-transplantation lymphoproliferative disorder (CNS-PTLD). We performed a craniotomy to biopsy the brain tumors. The biopsy specimen showed Epstein-Barr virus-associated diffuse large B-cell lymphoma. There is no definitive treatment for CNS-PTLD. Therefore, we treated the primary CNS-PTLD successfully with whole brain radiation and discontinuation of immunosuppression therapy. PMID- 22931102 TI - Pharmacokinetics and pharmacodynamics of phase II drug metabolizing/antioxidant enzymes gene response by anticancer agent sulforaphane in rat lymphocytes. AB - This study assesses the pharmacokinetics (PK) and pharmacodynamics (PD) of Nrf2 mediated increased expression of phase II drug metabolizing enzymes (DME) and antioxidant enzymes which represents an important component of cancer chemoprevention in rat lymphocytes following intravenous (iv) administration of an anticancer phytochemical sulforaphane (SFN). SFN was administered intravenously to four groups of male Sprague-Dawley JVC rats each group comprising four animals. Blood samples were drawn at selected time points. Plasma were obtained from half of each of the blood samples and analyzed using a validated LC-MS/MS method. Lymphocytes were collected from the remaining blood samples using Ficoll-Paque Plus centrifuge medium. Lymphocyte RNAs were extracted and converted to cDNA, quantitative real-time PCR analyses were performed, and fold changes were calculated against those at time zero for the relative expression of Nrf2-target genes of phase II DME/antioxidant enzymes. PK-PD modeling was conducted based on Jusko's indirect response model (IDR) using GastroPlus and bootstrap method. SFN plasma concentration declined biexponentially and the pharmacokinetic parameters were generated. Rat lymphocyte mRNA expression levels showed no change for GSTM1, SOD, NF-kappaB, UGT1A1, or UGT1A6. Moderate increases (2-5-fold) over the time zero were seen for HO-1, Nrf2, and NQO1, and significant increases (>5-fold) for GSTT1, GPx1, and Maf. PK PD analyses using GastroPlus and the bootstrap method provided reasonable fitting for the PK and PD profiles and parameter estimates. Our present study shows that SFN could induce Nrf2-mediated phase II DME/antioxidant mRNA expression for NQO1, GSTT1, Nrf2, GPx, Maf, and HO-1 in rat lymphocytes after iv administration, suggesting that Nrf2-mediated mRNA expression in lymphocytes may serve as surrogate biomarkers. The PK-PD IDR model simultaneously linking the plasma concentrations of SFN and the PD response of lymphocyte mRNA expression is valuable for quantitating Nrf2-mediated effects of SFN. This study may provide a conceptual framework for future clinical PK-PD studies of dietary cancer chemopreventive agents in human. PMID- 22931103 TI - Phytotoxic secondary metabolites and peptides produced by plant pathogenic Dothideomycete fungi. AB - Many necrotrophic plant pathogenic fungi belonging to the class of Dothideomycetes produce phytotoxic metabolites and peptides that are usually required for pathogenicity. Phytotoxins that affect a broad range of plant species are known as non-host-specific toxins (non-HSTs), whereas HSTs affect only a particular plant species or more often genotypes of that species. For pathogens producing HSTs, pathogenicity and host specificity are largely defined by the ability to produce the toxin, while plant susceptibility is dependent on the presence of the toxin target. Non-HSTs are not the main determinants of pathogenicity but contribute to virulence of the producing pathogen. Dothideomycetes are remarkable for the production of toxins, particularly HSTs because they are the only fungal species known so far to produce them. The synthesis, regulation, and mechanisms of action of the most important HSTs and non-HSTs will be discussed. Studies on the mode of action of HSTs have highlighted the induction of programed cell death (PCD) as an important mechanism. We discuss HST-induced PCD and the plant hypersensitive response upon recognition of avirulence factors that share common pathways. In this respect, although nucleotide-binding-site-leucine-rich repeat types of resistance proteins mediate resistance against biotrophs, they can also contribute to susceptibility toward necrotrophs. PMID- 22931104 TI - Thoracoabdominoplasty with umbilicoplasty for Cantrell's syndrome. AB - Cantrell et al. described a syndrome with five anomalies characterised by defects of the abdominal wall, lower sternum, anterior diaphragm, diaphragmatic pericardium, and heart. Because most of the children who survived could not have the thoracoabdominal wall adequately reconstructed at the initial operation, ventral herniation is often the result and they have to live with the danger of direct trauma to the unprotected heart. It therefore becomes important protect the unguarded heart while improving the appearance of the thoracoabdominal region. The reconstruction of the lower sternum has rarely been reported. We describe four such patients, three of whom had a thoracoabdominoplasty and umbilicoplasty using autologous rib cartilage and rectus muscles. All these children had solidly reconstructed sternums, and their abdominal appearances are excellent. PMID- 22931105 TI - Patients' satisfaction with immediate breast reconstruction with a latissimus dorsi musculocutaneous flap. AB - Immediate breast reconstruction with a latissimus dorsi musculocutaneous (LDM) flap is still not much reported, particularly in studies of patients' views. The aim of this study was to assess the level of patients' satisfaction with the technique. All patients (n = 257) who had had a mastectomy and immediate breast reconstruction with a LDM flap at a single hospital between January 1999 and December 2005 were identified, and 196 patients free of recurrence were included. The operations were done by the same surgical team in a standard manner. Clinical data, technical details, and outcome were collected prospectively. To assess the patients' degree of satisfaction with the aesthetic results in relation to clinical characteristics and treatment, a study-specific questionnaire and a visual analogue scale were sent to 196 patients; 178 forms were completed and returned. To analyse general satisfaction and aesthetic results we used the Mann Whitney, Kruskal-Wallis, chi square, or Fisher's exact test, as appropriate. The median reconstruction follow-up period was 34 months. Patients who were 51 years or older at the time of reconstruction were less likely to opt for immediate breast reconstruction with LDM flap than younger patients. Patients who were divorced and those who had postoperative complications were less likely to be satisfied. One hundred and sixty-four patients (92%) were satisfied, and 161 (90%) said they would recommend the reconstruction. The median satisfaction score was 9 (range 1-10, mean 8.5). The technique provided satisfactory immediate breast reconstruction according to the patients' evaluation. PMID- 22931106 TI - Immediate breast reconstruction: a retrospective study with emphasis on complications and risk factors. AB - The use of skin-sparing mastectomy (SSM) with immediate reconstruction is preferred, as it has cosmetic and psychological advantages, and comprises one operation. We retrospectively reviewed the complication rate after SSM and immediate reconstruction with implants in 141 consecutive patients with 208 reconstructions. Risk factors were related to both patients and the procedure. The overall morbidity was 42/208 (20%) with one or more minor or major complications including epidermolysis, skin necrosis, or infection. The overall explantation rate was 26/208 (13%). Smoking was a significant risk factor for infection and explantation, and tended to increase risk of necrosis (p = 0.05). Preoperative radiation did not increase the risk of explantation. Age above the median of 44 (range 25-67) years implied a significantly increased risk of epidermolysis, infection, and explantation. Women who had a one-stage procedure with implantation of fixed-sized implant experienced explantation four times more often than women who had a two-stage procedure with tissue expander (p = 0.001). In conclusion, SSM with immediate reconstruction yields a low complication rate when patients are carefully selected. SSM with immediate reconstruction should be done for younger women who have had no previous radiation. Patients should stop smoking to ensure optimal outcome. PMID- 22931108 TI - Medical student research output in a developing country: where has all the research gone? PMID- 22931107 TI - Ready to Use Therapeutic Foods (RUTF) improves undernutrition among ART-treated, HIV-positive children in Dar es Salaam, Tanzania. AB - BACKGROUND: HIV/AIDS is associated with an increased burden of undernutrition among children even under antiretroviral therapy (ART). To treat undernutrition, WHO endorsed the use of Ready to Use Therapeutic Foods (RUTF) that can reduce case fatality and undernutrition among ART-naive HIV-positive children. However, its effects are not studied among ART-treated, HIV-positive children. Therefore, we examined the association between RUTF use with underweight, wasting, and stunting statuses among ART-treated HIV-positive children in Dar es Salaam, Tanzania. METHODS: This cross-sectional study was conducted from September October 2010. The target population was 219 ART-treated, HIV-positive children and the same number of their caregivers. We used questionnaires to measure socio economic factors, food security, RUTF-use, and ART-duration. Our outcome variables were underweight, wasting, and stunting statuses. RESULTS: Of 219 ART treated, HIV-positive children, 140 (63.9%) had received RUTF intervention prior to the interview. The percentages of underweight and wasting among non-RUTF receivers were 12.4% and 16.5%; whereas those of RUTF-receivers were 3.0% (P = 0.006) and 2.8% (P = 0.001), respectively. RUTF-receivers were less likely to have underweight (Adjusted Odd Ratio (AOR) =0.19, CI: 0.04, 0.78), and wasting (AOR = 0.24, CI: 0.07, 0.81), compared to non RUTF-receivers. Among RUTF receivers, children treated for at least four months (n = 84) were less likely to have underweight (P = 0.049), wasting (P = 0.049) and stunting (P < 0.001). CONCLUSIONS: Among HIV-positive children under ART, the provision of RUTF for at least four months was associated with low proportions of undernutrition status. RUTF has a potential to improve undernutrition among HIV-positive children under ART in the clinical settings in Dar es Salaam, Tanzania. PMID- 22931109 TI - A new spin on vertical integration. PMID- 22931110 TI - Teaching complementary and alternative medicine. PMID- 22931111 TI - Clerkships do not improve recognition of patient hazards by advanced medical students during chart review. PMID- 22931112 TI - Direct characterization of native chemical ligation of peptides on silicon nanowires. AB - We describe the site-specific and chemoselective immobilization of peptides on hydrogen-terminated silicon nanowires (SiNWs) using native chemical ligation (NCL) (i.e., the reaction of a thioester group with a cysteine moiety to give a stable amide bond). The SiNWs investigated in this work were grown via a vapor liquid-solid mechanism and functionalized with a thioester moiety. The immobilization of the peptides on the SiNWs was demonstrated by synthesizing peptides with an N-terminal cysteine residue and labeled with tetramethylrhodamine or trifluoromethyl groups that were detected by fluorescence and X-ray photoelectron spectroscopy, respectively. The peptides labeled with tetramethylrhodamine or trifluoromethyl groups for fluorescence or X-ray photoelectron spectroscopy (XPS) detection studies were synthesized with an N terminal cysteine residue. N-Terminal seryl peptides and carboxy-terminated SiNWs were used as controls to demonstrate the chemoselectivity of the peptide immobilization. PMID- 22931113 TI - Five new CRF07_BC near full-length sequences isolated from Sichuan, China. AB - The main heroine traffic from Yunnan province to the Xinjiang Autonomous Region is believed to initiate the transmission of CRF07_BC which is the predominant strain in intravenous drug users (IDUs) in China. However, the great distances between Yunnan and Xinjiang lead to an unclear and elusive diffusion process of CRF07_BC due to the absence of an important middle site such as Sichuan province. Moreover, in recent years the rapidly increasing infection rate among IDUs in the Liangshan region of Sichuan made it necessary to characterize the genetic character of the circulating strain of Sichuan IDUs. In this study, we characterized the genetic character of seven newly isolated CRF07_BC genomes (five from Sichuan and two from Xinjiang) and analyzed the transmission linkage among strains from IDUs in different regions. By conducting Markov chain Monte Carlo (MCMC) analysis and reconstruction of neighbor-joining trees and maximum likelihood trees, our results revealed the genetic variation and important role of Sichuan-derived CRF07_BC strains during the transmission of CRF07_BC. PMID- 22931114 TI - Premature activation of the HIV RNase H drives the virus into suicide: a novel microbicide? AB - Sexual transmission of HIV is the major cause of spread of HIV in Africa and the Third World and is an unmet medical need. Recently, microbicides have attracted attention because they allow females to protect themselves and their offspring. We are exploiting one of the four retroviral enzymes, the ribonuclease H, RNase H, as a novel approach for a microbicide. It is the only enzyme of HIV not yet targeted by antiretroviral therapy. The enzyme is linked to the reverse transcriptase (RT) and hydrolyzes the RNA moiety of RNA-DNA hybrids. The RNase H is located inside virus particles and normally functions during viral replication inside cells. Here we show that activating the RNase H prematurely inside the virus particles destroys the viral genome and abrogates viral infectivity. The antiviral compound consists of a synthetic oligodeoxynucleotide (ODN), which creates an artificial RNA-DNA hybrid substrate for the RNase H inside the particle. The compound was analyzed in mouse models including humanized SCID mice and the vagina of mice. Infection was reduced up to 1000-fold or could be completely prevented. The compound is suitable as microbicide or to prevent mother-to-child transmission. PMID- 22931115 TI - Superior hybrid cathode material containing lithium-excess layered material and graphene for lithium-ion batteries. AB - Graphene-wrapped lithium-excess layered hybrid materials (Li(2)MnO(3).LiMO(2), M = Mn, Ni, Co, hereafter abbreviated as LMNCO) have been synthesized and investigated as cathode materials for lithium-ion batteries. Cyclic voltammetry measurement shows a significant reduction of the reaction overpotential in benefit of the graphene conducting framework. The electrochemical impedance spectroscopy results reveal that the graphene can greatly reduce the cell resistance, especially the charge transfer resistance. Our investigation demonstrates that the graphene conducting framework can efficiently alleviate the polarization of pristine LMNCO material leading to an outstanding enhancement in cell performance and cycling stability. The superior electrochemical properties support the fine hybrid structure design by enwrapping active materials in graphene nanosheets for high-capacity and high-rate cathode materials. PMID- 22931116 TI - Changes in the oligomerization potential of the division inhibitor UgtP co ordinate Bacillus subtilis cell size with nutrient availability. AB - How cells co-ordinate size with growth and development is a major, unresolved question in cell biology. In previous work we identified the glucosyltransferase UgtP as a division inhibitor responsible for increasing the size of Bacillus subtilis cells under nutrient-rich conditions. In nutrient-rich medium, UgtP is distributed more or less uniformly throughout the cytoplasm and concentrated at the cell poles and/or the cytokinetic ring. Under these conditions, UgtP interacts directly with FtsZ to inhibit division and increase cell size. Conversely, under nutrient-poor conditions, UgtP is sequestered away from FtsZ in punctate foci, and division proceeds unimpeded resulting in a reduction in average cell size. Here we report that nutrient-dependent changes in UgtP's oligomerization potential serve as a molecular rheostat to precisely co-ordinate B. subtilis cell size with nutrient availability. Our data indicate UgtP interacts with itself and the essential cell division protein FtsZ in a high affinity manner influenced in part by UDP glucose, an intracellular proxy for nutrient availability. These findings support a model in which UDP-glc-dependent changes in UgtP's oligomerization potential shift the equilibrium between UgtP*UgtP and UgtP*FtsZ, fine-tuning the amount of FtsZ available for assembly into the cytokinetic ring and with it cell size. PMID- 22931118 TI - Correlation between myocardial dysfunction and perfusion impairment in diabetic rats with velocity vector imaging and myocardial contrast echocardiography. AB - The purpose of this study was to investigate whether myocardial systolic dysfunction and perfusion impairment occur in diabetic rats, and to assess their relationship using velocity vector imaging (VVI) and myocardial contrast echocardiography (MCE). Forty-six rats were randomly divided into either control or the diabetes mellitus (DM) groups. DM was induced by intraperitoneal administration of streptozotocin. Twelve weeks later, 39 survival rats underwent VVI and MCE in short-axis view at the middle level of the left ventricle, both at rest and after dipyridamole stress. VVI-derived contractile parameters included peak systolic velocity (Vs ), circumferential strain (epsilonc ), strain rate (SRc ), and their reserves. MCE-derived perfusion parameters consisted of myocardial blood flow (MBF) and myocardial flow reserve (MFR). At rest, SRc in the DM group was significantly lower than in the control group, Vs , epsilonc , and MBF did not differ significantly between groups. After dipyridamole stress, all VVI parameters and their reserves in the DM group were significantly lower than those in the control group, MBF and MFR were substantially lower than those in the control group, too. Meanwhile, significant correlations between VVI parameter reserves and MFR were observed in the DM group. Both myocardial systolic function and perfusion were impaired in DM rats. Decreased MFR could be an important contributor to the reduction in myocardial contractile reserve. PMID- 22931117 TI - Association of gastroesophageal reflux disease with asthma control. AB - Gastroesophageal reflux disease (GERD) may make asthma difficult to control and may be a potential risk factor for frequent asthma exacerbations, but the mechanisms of the relationship between GERD and not well-controlled asthma remain unclear. The aim of this study was to explore the association of GERD with asthma control in adults. Patients with asthma were consecutively recruited, and Asthma Control Test (ACT) and Reflux Diagnostic Questionnaire scores were determined. The patients were categorized into not well-controlled asthma and well-controlled asthma groups according to the ACT score. Univariate and multivariate logistic regression analyses were performed to evaluate the relationship between GERD and not well-controlled asthma. Seven hundred and sixty-eight patients with asthma were enrolled. The mean ACT score was 18.2 +/- 3.6, and there were 161 (21.0%) patients with not well-controlled asthma. The Reflux Diagnostic Questionnaire score was 10.5 +/- 4.7, and 212 (27.6%) patients were complicated by GERD. Multivariate logistic regression analyses revealed the independent association of GERD with not well-controlled asthma (odds ratio, 3.12; 95% confidence interval, 1.53-4.88) after other established contributors to asthma control were adjusted. In conclusion, there is an association of GERD with not well-controlled asthma, independent of other potential contributors to asthma control. PMID- 22931119 TI - Two-fold modification of the phenyl substituent in phenylphosphonic acid monoester monoamides. AB - Phenylphosphonic acid ethyl ester N,N-diethylamide was subjected to a double modification of its phenyl substituent through directed ortho-metalation followed by dearomatization of the aryl substituent under Birch reduction conditions. Application of the same methodology to a diastereomerically pure phenylphosphonic acid monoester monoamide led to the formation of P-stereogenic cyclohexadienyl phosphonic acid derivatives. The method offers a simple and efficient modification of phenyl substituent in organophosphorus compounds. PMID- 22931120 TI - Ultrafast photoinduced electron transfer between an incarcerated donor and a free acceptor in aqueous solution. AB - Supramolecular photoinduced electron transfer dynamics between coumarin 153 (C153) and 4,4'-dimethyl viologen dichloride (MV(2+)) across the molecular barrier of a host molecule, octa acid (OA), has been investigated with femtosecond time resolution. The ultrafast electron transfer from C153 to MV(2+) followed excitation with 150 fs laser pulses at a wavelength of 390 nm despite the fact that C153 was incarcerated within an OA(2) capsule. As a result, the photoexcited coumarin did not show any of the typical relaxation dynamics that is usually observed in free solution. Instead, the excited electron was transferred across the molecular wall of the capsuleplex within 20 ps. Likewise, the lifetime of the charge transfer state was short (724 ps), and electron back-transfer reestablished the ground state of the system within 1 ns, showing strong electronic coupling among the excited electron donor, host, and acceptor. When the donor was encapsulated into the host molecule, the electron transfer process showed significantly accelerated dynamics and essentially no solvent relaxation compared with that in free solution. The study was also extended to N methylpyridinium iodide as the acceptor with similar results. PMID- 22931122 TI - Proteomic approach based on MALDI-TOF MS to detect powdered milk in fresh cow's milk. AB - Milk and cheese are expensive foodstuffs, and their consumption is spread among the population because of their high nutritional value; for this reason they are often subjected to adulterations. Among the common illegal practices, the addition of powdered derivatives seems very difficult to detect because the adulterant materials have almost the same chemical composition of liquid milk. However, the high temperatures (180-200 degrees C) used for milk powder production could imply the occurrence of some protein modifications (e.g., glycation, lactosylation, oxidation, deamidation, dehydration). The modified proteins or peptides could then be used as markers for the presence of powdered milk. In this work, matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS) was employed to analyze tryptic digests relevant to samples of raw liquid (without heat treatment), commercial liquid, and powdered cow's milk. Samples were subjected to two-dimensional gel electrophoresis (2-DE); differences among liquid and powder milk were detected at this stage and eventually confirmed by MALDI analysis of the in gel digested proteins. Some diagnostic peptides of powdered milk, attributed to modified whey proteins and/or caseins, were identified. Then, a faster procedure was optimized, consisting of the separation of caseins from milk whey and the subsequent in solution digestion of the two fractions, with the advantage of obtaining almost the same information in a limited amount of time. Finally, analyses were carried out with the fast procedure on liquid milk samples adulterated with powdered milk at different percentages, and diagnostic peptides were detected down to 1% of adulteration level. PMID- 22931123 TI - Microcollection of gases in a capillary tube: preservation of spatial and temporal resolution. AB - Researchers at the National Oceanic and Atmospheric Administration (NOAA) have recently developed and reported a novel air collection device for measuring vertical profiles of trace gases in the atmosphere, which has been applied to carbon dioxide and methane so far. The device consists of a long stainless steel tube that is prefilled with calibrated gas and allowed to ascend on a weather balloon. During ascent, the device is evacuated as it equilibrates with the decreasing atmospheric pressure. During descent, the tube is filled with atmospheric gas in an ordered manner. The diffusion rate inside the tube is slow enough that the collected gas remains ordered. Here is reported a miniaturization of the device described above, in which the stainless steel tube is replaced with Hydroguard fused silica tubing (0.53 mm * 30 m) and two lightweight valves having a total mass of less than 28 g. This micro-AirCore device was deployed on the SwRI-developed unmanned SkyWisp glider. Profiling of carbon dioxide in the atmosphere proceeded via mass spectrometric detection. A laboratory-based validation system was used for evaluating the micro-AirCore function, including accuracy and precision, for carbon dioxide. The diffusion profiles of carbon dioxide, argon, oxygen, and methane were also investigated. Overall, the micro AirCore demonstrated an accuracy error of 2% ((12)CO(2)) and minimal diffusion over a period of 16 h (peak width increased by a factor of 1.6). Even after 63 h, mixing of the gases inside the tube was not complete. A triplet of micro-AirCores was deployed on the SkyWisp glider yielding a relative standard deviation of 0.08%, or 0.3 ppm, for CO(2). The profile collected resulted in observation of the boundary layer with elevated CO(2) levels, a region in the free troposphere with relatively constant CO(2) mole fraction, and a gradual decrease in CO(2) above 10,000 m. This microdevice has broad applications extending beyond vertical profiling. Fitting the device with a metering device could enable horizontal collection of gases. PMID- 22931121 TI - Profiling anti-cyclic citrullinated peptide antibodies in patients with juvenile idiopathic arthritis. AB - BACKGROUND: Anti-citrullinated protein/peptide antibodies (ACPA), have high specificity for rheumatoid arthritis (RA). Some children with juvenile idiopathic arthritis (JIA), phenotypically resemble RA and test positive for rheumatoid factor (RF) a characteristic biomarker of RA. We investigated the prevalence of ACPA and its relationship to other serologic markers associated with RA in a well characterized JIA cohort. METHODS: Cases were 334 children with JIA, 30 of whom had RF + polyarticular JIA. Sera from all cases and 50 healthy pediatric controls were investigated by ELISA at a single time point for anti-cyclic citrullinated peptide (anti-CCP) IgG, RF IgM, IgA and IgG, anti-RA33 IgG, and antinuclear antibodies (ANA). Comparisons between cases and controls were made using Chi square or Fisher exact tests and T-tests. RESULTS: The prevalence of RF was 8% among controls, and 12% among cases (ns). The prevalence of ACPA was 2% in controls and 14.3% in cases (OR 8.2, p <0.01). Children who were ACPA-positive and RF-negative (n = 23) had a significantly earlier onset-age (4.6 years vs. 12.1 years, p <0.00001) and had fewer HLA-DRB1 shared epitope alleles than those positive for both RF and ACPA (n = 25). Prevalence of anti-RA33 was not different between cases and controls. CONCLUSIONS: ACPAs are detectable in 14% of children with JIA. Children with positive ACPA but negative RF are frequent, and may define a distinct subset of children with JIA. ACPA testing should be included in the classification of JIA. PMID- 22931124 TI - Inhibition of proliferation and induction of G1-phase cell-cycle arrest by dFMGEN, a novel genistein derivative, in lung carcinoma A549 cells. AB - Genistein (GEN) is a molecule of great interest as a potent chemopreventive agent against atherosclerosis and cancer. However, the bioavailability of GEN is very low in vivo. Our previous study showed that a GEN derivative, 7-difluoromethyl 5,4'-dimethoxygenistein (dFMGEN) has a better bioavailability than GEN in vivo. In this study, we further evaluated the efficacy of dFMGEN as a candidate for cancer therapy. We demonstrated that dFMGEN treatment decreased the viability of A549 cells in a concentration- and time-dependent manner and induced cell-cycle arrest at the G(1) phase. G(1) phase arrest was correlated with a significant reduction of Cdk4 and cyclin D1 protein level. Further studies showed that cyclin dependent kinase (Cdk)4 and cyclin D1 protein-level decrease was caused by Cdk inhibitors p15, p21, and p27 level increase, and decreased protein level directly suppressed Rb protein phosphorylation and E2F-1 expression, then cell-cycle progression was arrested. Finally, we also found that dFMGEN has a dosage effect in suppressing tumor growth in vivo, and that dFMGEN was well tolerated by animals. In summary, our results suggest that dFMGEN has therapeutic potential for the treatment of human lung cancer. PMID- 22931125 TI - Whole exome sequencing identifies a novel DFNA9 mutation, C162Y. AB - We report the genetic analysis of a Chinese family with autosomal dominant non syndromic progressive sensorineural hearing loss. Taking advantage of next generation high-throughput DNA sequencing technology, we combined whole exome capture sequencing with Sanger direct sequencing. A novel missense mutation in the coagulation factor C homolog (COCH) gene was identified in a consanguineous Chinese family. This missense mutation in the seventh exon (c.889G>A; p.C162Y) of COCH is most probably a disease-causing mutation and it segregates with the disease. The mutation is not found in the single nucleotide polymorphism (SNP) database, the yhSNP database, the 1000 genomes SNP database or in matching normal controls. It is the first reported autosomal dominant nonsyndromic sensorineural deafness 9 (DFNA9) mutation outside the limulus factor C, cochlin and late gestation lung protein and von Willebrand factor 2 domain, i.e. the first reported DFNA9 mutation in the intervening domain of cochlin, encoded by the COCH gene. In the future, we will focus on functional studies of this mutation. PMID- 22931127 TI - Electronic spectra of cycl[3.3.2]azine and related compounds: solvent effect on vibronic couplings. AB - Quantitative ab initio calculations are presented for the ultraviolet-visible peaks of cycl[3.2.2]azine and its mono- and dibenzannulated polycyclic compounds at the multistate CASPT2 (MS-CASPT2) level of theory, with 11 nm deviation from the experimental S0 -> S1 absorption. The electrophilic substitution reactions of cycl[3.2.2]azine, benzo[a]/[g]annulated cycl[3.2.2]azines, and 6 dimethylamino[2.2.3]cyclazine-1-carboxylates with 3-cyano-4-methylthiomaleimide gave the corresponding functionalized cycl[3.2.2]azine derivatives, which exhibited the absorption maxima around 510-630 nm. The first intense peaks were investigated by means of time-dependent density functional theory (TD-DFT). These peaks were systematically underevaluated by ~50 nm, within the acceptable accuracies of TD-DFT. Furthermore, we calculated vibronic coupling constants of the electronic excited states of cycl[3.2.2]azine and simulated absorption spectra both in vacuo and in ethanol. The solvent effect is found to enhance oscillator strengths and vibronic couplings. This is because the solvent effect gives rise to changes in the electron density difference on the phenyl ring, and in turn, the intensified overlap between the electron density difference and the potential derivative in the phenyl ring leads to enhanced vibronic couplings in ethanol. PMID- 22931126 TI - Interspecies modulation of bacterial development through iron competition and siderophore piracy. AB - While soil-dwelling actinomycetes are renowned for secreting natural products, little is known about the roles of these molecules in mediating actinomycete interactions. In a previous co-culture screen, we found that one actinomycete, Amycolatopsis sp. AA4, inhibited aerial hyphae formation in adjacent colonies of Streptomyces coelicolor. A siderophore, amychelin, mediated this developmental arrest. Here we present genetic evidence that confirms the role of the amc locus in the production of amychelin and in the inhibition of S. coelicolor development. We further characterize the Amycolatopsis sp. AA4 - S. coelicolor interaction by examining expression of developmental and iron acquisition genes over time in co-culture. Manipulation of iron availability and/or growth near Amycolatopsis sp. AA4 led to alterations in expression of the critical developmental gene bldN, and other key downstream genes in the S. coelicolor transcriptional cascade. In Amycolatopsis sp. AA4, siderophore genes were downregulated when grown near S. coelicolor, leading us to find that deferrioxamine E, produced by S. coelicolor, could be readily utilized by Amycolatopsis sp. AA4. Collectively these results suggest that competition for iron via siderophore piracy and species-specific siderophores can alter patterns of gene expression and morphological differentiation during actinomycete interactions. PMID- 22931128 TI - Validation of digital photographs, as a tool in 24-h recall, for the improvement of dietary assessment among rural populations in developing countries. AB - BACKGROUND: Improvement of traditional methods for dietary assessment is necessary, especially in rural areas where it is more difficult to succeed with self-reporting methods. This study presents and validates a method for improving accuracy when measuring food and nutrient intake of individuals in rural areas. It is called the "Food photography 24-h recall method" (FP 24-hR) and is a modified 24-h recall with the addition of a digital food photography record and a photo atlas. METHODS: The study was carried out in a rural area in the tropical region of Bolivia; 45 women participated. Validation of the method was made by comparing it with a reference method, the Weighed Food Record (WFR). During the FP 24-hR, digital photographs were taken by the subjects of all food consumed during a day and a 24-h recall questionnaire was conducted by an interviewer. An estimate of the amount of food consumed was made using a photo atlas and the photographs taken by the subjects. For validation, comparison was made between the calculations, by both methods, of the levels of food, and nutrient, intake. RESULTS: The comparison was made in 10 food categories; most of which were somewhat underestimated from -2.3% (cassava) to -6.8% (rice), except for beverages (+1.6%) and leafy vegetables (+8.7%), which were overestimated. Spearman's correlation coefficients were highly significant (r from 0.75 for eggs to 0.98 for potato and cassava). Nutrient intakes calculated with data from both methods showed small differences from -0.90% (vitamin C) to -5.98% (fat). Although all nutrients were somewhat underestimated, Pearson's coefficients are high (>0.93 for all) and statistically significant. Bland Altman analysis showed that differences between both methods were random and did not exhibit any systematic bias over levels of food and nutrient intake, with acceptable 95% limits of agreement. CONCLUSION: The FP 24-hR exhibits acceptable differences when compared with a WFR, digital photos are useful as a memory aid for the subjects during 24-h recall and as an estimation tool. The method is suitable for assessing dietary intake among rural populations in developing countries. PMID- 22931129 TI - Risk of significant cytopenias after treatment with tocilizumab in systemic juvenile arthritis patients with a history of macrophage activation syndrome. AB - Tocilizumab (TCZ) is the first FDA- approved treatment for systemic juvenile idiopathic arthritis (sJIA). We report 3 cases of cytopenias in children with sJIA treated with TCZ. Two of the children who developed significant cytopenias shortly after initiation of TCZ had a history of macrophage activation syndrome. We raise the possibility that patients with a tendency towards MAS have an increased risk of developing cytopenias when treated with tocilizumab. PMID- 22931130 TI - Hypocrellin-loaded gold nanocages with high two-photon efficiency for photothermal/photodynamic cancer therapy in vitro. AB - A new bioconjugate nanostructure was constructed by using photosensitizer incorporated mixed lipid-coated gold nanocages for two-photon photothermal/photodynamic cancer therapy in vitro with high efficiency. Scanning electron microscopic and transmission electron microscopic images reveal that the precursors and bioconjugate nanostructure as-prepared are narrowly dispersed and possess uniform morphologies. The relevant energy dispersion X-ray analysis and UV-vis spectra indicate that the bioconjugate nanostructure above was assembled successfully and has a strong absorption in the near-infrared region. Fluorescence and electronic spin resonance results show that the gold nanocage in the bioconjugate nanostructure can dramatically quench the photosensitizer and inhibit the production of singlet oxygen, which is supposed to alleviate the photosensitizers' unwanted side effects originating from their nontargeted distribution. We have demonstrated that as the nanocomplex is internalized by cancer cells, under two-photon illumination, photodynamic anticancer treatment is dramatically enhanced by the photothermal effect. PMID- 22931131 TI - Stereocontrolled solid-phase synthesis of phosphorothioate oligoribonucleotides using 2'-O-(2-cyanoethoxymethyl)-nucleoside 3'-O-oxazaphospholidine monomers. AB - A method for the synthesis of P-stereodefined phosphorothioate oligoribonucleotides (PS-ORNs) was developed. PS-ORNs of mixed sequence (up to 12mers) were successfully synthesized by this method with sufficient coupling efficiency (94-99%) and diastereoselectivity (>=98:2). The coupling efficiency was greatly improved by the use of 2-cyanoethoxymethyl (CEM) groups in place of the conventional TBS groups for the 2'-O-protection of nucleoside 3'-O oxazaphospholidine monomers. The resultant diastereopure PS-ORNs allowed us to clearly demonstrate that an ORN containing an all-(Rp)-PS-backbone stabilizes its duplex with the complementary ORN, whereas its all-(Sp)-counterpart has a destabilizing effect. PMID- 22931133 TI - Comparison of modified Kessler and Yotsumoto-Dona suture: a biomechanical study on porcine tendons. AB - There is a need for a strong suture technique that allows early active mobilisation after repair of flexor tendons, but the best method has not yet been found. The aim of this study was to compare the modified Kessler suture biomechanically with a newer, two-strand suture. Eighteen porcine tendons were cut and repaired according to either the grasping modified Kessler suture or the combined side-locking loop technique (Yotsumoto) and interlocking horizontal mattress suture (Dona). The specimens were tested linearly to failure. The 2 mm gap force, yield force, ultimate force, stiffness, energy to yield, and energy to failure were all significantly higher (p value = 0.005, 0.003, <0.001, 0.001, 0.004, and 0.001, respectively) in the Yotsumoto-Dona group (median values (IQR): 30.9 (28.1-39.5) N, 82.7 (64.9-114.1) N, 82.7 (76.6-114.1) N, 12.5 (10-14.5) N/mm, 0.45 (0.2-0.5) J, and 0.45 (0.35-0.5) J) than in the modified Kessler group (25.8 (12.2-28.1) N, 35 (24.6-54.4) N, 50.9 (34.4-55.1) N, 7 (5.8-91) N/mm, 0.09 (0.06-0.18) J, and 0.21 (0.18-0.28) J). All Yotsumoto-Dona specimens had a yield force exceeding 35 N, while in the Kessler group only four did. The early yielding rate was 6/9 and 2/9 in the modified Kessler and the Yotsumoto-Dona groups, respectively (p = 0.15). Most of the core sutures failed by breakage, but three Yotsumoto knots loosened. All the simple running and six of the Dona epitendinous sutures failed predominantly by pulling-out, and by breakage at the intersections in three of the latter. The relatively easy two-strand Yotsumoto Dona suture is likely to withstand the loads of active finger flexion, whereas the modified Kessler suture is probably not. PMID- 22931132 TI - Small bowel obstruction caused by inflammatory cytomegalovirus tumor in a renal transplant recipient: report of a rare case and review of the literature. AB - Cytomegalovirus (CMV) infection in renal transplant recipients can present as asymptomatic viremia or CMV syndrome or, in more severe cases, as tissue-invasive disease. CMV enteritis, a common manifestation of CMV invasive disease, usually presents with fever, abdominal pain, anorexia, nausea, and diarrhea, and can be rarely complicated by colon perforation, hemorrhage, or megacolon. CMV infection occurs primarily in the first 6 months post transplantation, when immunosuppression is more intense. We describe the case of a female renal transplant recipient with small bowel obstruction caused by CMV disease 7 years post renal transplantation. The patient presented with diarrhea and abdominal pain. Because of elevated CMV viral load, she was initially treated with antiviral therapy with transient response. Endoscopy and imaging tests showed obstruction of the terminal ileum and, subsequently, the patient underwent exploratory laparotomy when a right hemicolectomy was performed. Biopsy results confirmed the diagnosis of CMV enteritis. Epidemiologic characteristics, clinical presentation, diagnostic workup, therapeutic options, and morbidity-mortality rates of CMV infection/disease, in renal transplant recipients, are reviewed. PMID- 22931134 TI - Reduction of the opposite breast in patients with a breast reconstructed with an implant: validity of the inverted "T", superior pedicle technique, with an inferiorly-based dermal adipose flap. AB - We reviewed 28 cases of breasts reconstructed with implants and reduction mammaplasty on the other side for symmetry, with the aim of assessing the stability and aesthetic result in the reduced breasts five years postoperatively. An inverted "T", superior pedicle technique, with an inferiorly-based dermal adipose flap was used in patients who did not have overstretched Cooper's ligaments. At the 5-year follow-up, the sternal notch-to-nipple and inframammary fold-to-nipple distances were measured and the degree of ptosis was evaluated (Regnault's classification). The patients recorded their satisfaction using a verbal numerical rating scale (1-5). The patients' photographs were also sent to 12 plastic surgeons for aesthetic assessment of the reduced breasts (same verbal numerical rating scale). The comparison of the preoperative and postoperative measurements and degrees of ptosis showed reasonable stability at least during a 5-year period. The patients' mean rating of the aesthetic result was 4.3, more than good, and the surgeons' mean rating was 3.4, more than satisfactory. PMID- 22931135 TI - Modified Millard's technique in operations for unilateral cleft lip. AB - Many approaches have been described, but the rotation-advancement technique described by Millard remains one of the most popular repair techniques for correction of cleft lip. The technique described here is a modified method that can be used in primary cleft surgery but also for secondary correction, using the same incision with a small modification in design. Thirty-two patients were followed up for two years, all of whom had good postoperative results without secondary correction. The modification provides rotation and elongation of the lip where it is needed. This technique can be useful for all aspects of secondary cleft lip correction, but is also useful in primary surgery when the cleft side is too short. PMID- 22931136 TI - Morphological assessment of early axonal regeneration in end-to-side nerve coaptation models. AB - Histological changes were observed in peripheral nerves following end-to-side nerve coaptation to determine the effects of perineurial opening and deliberate donor nerve injury during surgery. Twenty rats were randomised into four groups as follows: group 1, end-to-side nerve coaptation without perineurial opening; group 2, end-to-side nerve coaptation with simple perineurial opening; group 3, end-to-side nerve coaptation with partial crush injury after perineurial opening; group 4, end-to-side nerve coaptation with partial neurotomy after perineurial opening. Seven days after coaptation of the musculocutaneous (recipient) nerve to the ulnar (donor) nerve, the nerves were immunohistochemically analysed using antibodies against neurofilament-H (RT97) and phosphorylated GAP-43 (p-GAP-43). The former labels all axons, including regenerating axons and degenerated axonal debris, while the latter only labels regenerating axons. Results demonstrated no regenerating nerves in the recipient nerve of group 1. In group 2, because nerve herniation from the perineurial opening partially injured donor nerve fibres, some regenerating axons extended proximally and distally along the partially injured fibres in the donor nerve; some of these regenerating axons also extended into the recipient nerve via the perineurial opening. In groups 3 and 4, thin regenerating axons were more prominent in recipient and donor nerves compared with group 2. Statistical evaluation revealed increased efficacy of perineurial opening and deliberate donor nerve injury in end-to-side nerve coaptation, suggesting that partial nerve fibre herniation with partial axonotmesis or neurotomesis was important for effective axonal regeneration in end-to-side nerve coaptation. PMID- 22931137 TI - Effect of glutamate side chain length on intrahelical glutamate-lysine ion pairing interactions. AB - Ion pairing interactions between oppositely charged amino acids are important for protein structure stability. Despite the apparent electrostatic nature of these interactions, the charged amino acids Lys, Arg, Glu, and Asp have a different number of hydrophobic methylenes linking the charged functionality to the backbone. To investigate the effect of Glu (and Asp) side chain length on ion pairing interactions, a series of 36 monomeric alpha-helical peptides containing Zbb-Xaa (i, i+3), (i, i+4), and (i, i+5) (Zbb = Aad, Glu, Asp; Xaa = Lys, Orn, Dab, Dap) sequence patterns were studied by circular dichroism (CD) spectroscopy at pH 7 and 2. Peptides with Glu and Aad exhibited similar helicity and pH dependence, whereas peptides with Asp behaved distinctly different. The side chain interaction energetics were derived from the CD data using the nesting block method coupled with modified Lifson-Roig theory. At pH 7, no Zbb-Xaa (i, i+5) interaction was observed, regardless of side chain length (consistent with the helix geometry). Interestingly, only Lys was capable of supporting Zbb-Xaa (i, i+3) interactions, whereas any Xaa side chain length supported Zbb-Xaa (i, i+4) interactions. In particular, the magnitude of both Zbb(-)-Lys (i, i+4) and Zbb(-)-Orn (i, i+4) interaction energies followed the trend Asp > Glu > Aad. Side chain conformational analysis by molecular mechanics calculations showed that the Zbb-Xaa (i, i+3) interactions involved the chi(1) dihedral combination (g+, g+) for the i and i+3 residues, whereas the Zbb-Xaa (i, i+4) interactions were supported by the chi(1) dihedral combination (t, g+) for the i and i+4 residues. These calculated low energy conformers were consistent with conformations of intrahelical Asp-Lys and Glu-Lys salt bridges in a nonredundant protein structure database. These results suggest that Asp and Glu provide natural variation, and lengthening the Glu side chain further to Aad does not furnish additional characteristics that Glu cannot supply. PMID- 22931138 TI - Effect of sertraline on [Ca2+](i) and viability of human MG63 osteosarcoma cells. AB - The antidepressant, sertraline, has been shown to have diverse in vitro effects. This study examined whether sertraline altered [Ca(2+)](i) in MG63 human osteosarcoma cells by using fura-2 as a Ca(2+)-sensitive fluorescent dye. At 50 200 uM, sertraline induced a [Ca(2+)](i) rise in a concentration-dependent manner. Ca(2+) response was decreased by removing extracellular Ca(2+), suggesting that Ca(2+) entry and release contributed to the [Ca(2+)](i) signal. Sertraline-induced Ca(2+) entry was inhibited by nifedipine, La(3+), Gd(3+), and SK&F96365. When extracellular Ca(2+) was removed, pretreatment with the endoplasmic reticulum (ER) Ca(2+) pump inhibitor, thapsigargin, or 2,5-di-tert butylhydroquinone (BHQ) abolished the sertraline-evoked [Ca(2+)](i) rise. Incubation with sertraline also abolished the thapsigargin or BHQ-induced [Ca(2+)](i) rise. Inhibition of phospholipase C (PLC) with U73122 abolished the sertraline-induced [Ca(2+)](i) rise. At 20-30 uM, overnight treatment with sertraline killed cells in a concentration-dependent manner. The cytotoxic effect of sertraline was not reversed by chelating cytosolic Ca(2+) with 1,2-bis(2 aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (BAPTA). Annexin V/propidium iodide staining data demonstrate that sertraline (30 uM) evoked apoptosis. Sertraline (20 and 30 uM) also increased levels of reactive oxygen species. Together, in human osteosarcoma cells, sertraline evoked a [Ca(2+)](i) rise by inducing PLC-dependent Ca(2+) release from the ER and Ca(2+) entry by L-type Ca(2+) channels and store-operated Ca(2+) channels. Sertraline induced cell death that may involve apoptosis by mitochondrial pathways. PMID- 22931139 TI - Construct validation of progress testing to measure knowledge and visual skills in radiology. AB - BACKGROUND: The Dutch Radiology Progress Test (DRPT) monitors the acquisition of knowledge and visual skills of radiology residents in the Netherlands. AIM: We aimed to evaluate the quality of progress testing in postgraduate radiology training by studying the reliability of the DRPT and finding an indication for its construct validity. We expected that knowledge would increase rapidly in the first years of residency, leveling-off in later years, to allow for the development of visual skills. We hypothesized that scores on the DRPT reflect this pattern. METHODS: Internal consistencies were estimated with Cronbach's alpha. Performance increase over program years were tested using one-way analysis of variance. RESULTS: Data were available for 498 residents (2281 test results). Reliabilities were around Cronbach's alpha 0.90. There was a significant difference in the mean test results between the first three years of residency. After the fourth year no significant increase in test scores on knowledge could be measured on eight tests. The same pattern occurred for scores on visual skills. However, visual skills scores tend to increase more sharply than knowledge scores. CONCLUSION: We found support for the reliability and construct validity of the DRPT. However, assessment on visual skill development needs further exploration. PMID- 22931140 TI - Simple maths of 'task-based learning (TBL)' in Acute Medicine TBL = effective learning + timely completion of tasks + productivity. PMID- 22931141 TI - Workplace-based assessments in surgery: are we heading in the wrong direction? PMID- 22931142 TI - Learn to walk before you run--my 'case for change'. PMID- 22931143 TI - Evaluation of clinical teaching in general practice using the Maastricht Clinical Teaching Questionnaire. PMID- 22931144 TI - E-learning = inequity in learning? PMID- 22931145 TI - A corrective approach to doctors' illegible handwriting: a pilot course in Italy. PMID- 22931146 TI - The impact of tobacco cessation training of medical students on their attitude towards smoking. PMID- 22931147 TI - Reflective writing in medical education. AB - BACKGROUND: The teaching of reflection and the use of reflective writing assignments is commonplace in medical school education. There is a preponderance of research in medical education, which appraises and discusses new ways of teaching reflection. AIMS: Students often complain about having to write about their experience with that patient. This work explores some of the reasoning between the variability of student acceptance of reflection in medical education. METHODS: The method is based on available literature as well as a personal perspective regarding reflective writing in medical education. RESULTS: Reflection is a skill that requires teaching and practice. It is within the explicit process of teaching reflection in medical education that reflective learners can be developed. CONCLUSIONS: Reflection includes the take-home lesson from patient encounters. Its use can help learners become better physicians in terms of medical and humanistic effectiveness and support personal growth. PMID- 22931148 TI - Let's be clear on the proper place of photographs in teaching dermatology. PMID- 22931149 TI - Online testing from Google DocsTM to enhance teaching of core topics in critical care: a pilot study. AB - BACKGROUND: Recent evidence suggests that retrieval practice, or learning by testing, may lead to more effective knowledge retention than standard educational techniques. AIM: The purpose of this pilot project was to document successful teaching of evidence-based guidelines in critical care by augmenting interactive problem-based teaching sessions with online pre- and post-testing. METHODS: We used a free, internet-based document collaboration system (Google DocsTM) 1 to develop and share pre-tests and pre-session teaching files with the fellows. At the teaching sessions the pre-tests were reviewed interactively, and additional case-based questions were presented. One week after the sessions, the fellows were sent a post-test and a post-session survey. Results of the pre- and post tests as well as the post-session surveys were tabulated by the document collaboration system. RESULTS: The mean score was 54.6% (SD = 21.4%) on the pre tests and 87.0% (SD = 15.8%) on the post-tests (p < 0.01). On a scale of 1-10, the median ratings given by the fellows were 9.5 (IQR = 9-10) for utility of the teaching sessions, 9 for utility of the test questions (IQR = 9-10), and 10 (IQR = 9-10) for utility of the teaching files. CONCLUSION: Google DocsTM can be successfully used to integrate retrieval practice into the teaching of evidence based guidelines in critical care. PMID- 22931150 TI - Re: Jackson et al. - Medical education: time to go back to school. PMID- 22931151 TI - Towards widening access to medicine. PMID- 22931152 TI - Barriers faced by medical students interested in research. PMID- 22931153 TI - Identification of Mammalian orthoreovirus type 3 in Italian bats. AB - Summary This study describes the isolation and molecular characterization of Mammalian orthoreovirus (MRV) in microbats. Faecal samples and dead individuals available from rehabilitation centres or collected from known roost sites were virologically tested. In total, 112 carcasses of bats found dead, and 44 faecal samples were analysed. Nineteen viral strains were isolated by in vitro cell culture from faecal and tissue samples of different bat species (Pipistrellus khulii, Tadarida teniotis, Rhinolophus hipposideros and Vespertilio murinus), and they were morphologically identified as reoviruses by negative staining electron microscopy observation. The definitive assignment of all isolates to MRV was confirmed by RT-PCR assays targeting the L1 gene. Through a multiplex RT-PCR assay targeting the S1 gene, we typed 15 of 19 isolates as MRV type 3. Partial L1 (416 bp) and complete S1 (1416 bp) sequences of the isolates were analysed and compared with those of reference strains obtained from GenBank, belonging to the three serotypes. Molecular analysis of the S1 gene revealed that the amino acid residues associated with neurotropism (198-204NLAIRLP, 249I, 350D and 419E) were highly conserved among the Italian bat strains. These results suggest that potentially neurotropic MRV type 3 strains are widespread among Italian bats. Furthermore, the identification of MRV type 3 in bat species such as Pipistrellus Khulii, which is common in urban areas and known for its close contact with humans, underlines the need for vigilance. PMID- 22931154 TI - Hydrodynamics of capillary imbibition under nanoconfinement. AB - Understanding fluid flow in nanoconfined geometries is crucial for a broad range of scientific problems relevant to the behavior of porous materials in biology, nanotechnology, and the built environment. Because of the dominant importance of surface effects at the nanoscale, long-standing assumptions that are valid for macroscopic systems must be revisited when modeling nanoconfined fluids, because boundary conditions and the confined behavior of liquids are challenging to discern from experiments. To address this issue, here we present a novel coarse grained model that combines parameters calibrated for water with a dissipative particle dynamics thermostat for the purpose of investigating hydrodynamics under confinement at scales exceeding current capabilities with all-atomistic simulations. Conditions pertaining to slip boundary conditions and confinement emerge naturally from particle interactions, with no need for assumptions a priori. The model is used to systematically investigate the imbibition dynamics of water into cylindrical nanopores of different diameters. Interestingly, we find that the dynamic contact angle depends on the size of the nanopore in a way that cannot be explained through a relationship between contact line velocity and dynamic contact angle, suggesting nonlocal effects of the flow field may be important. Additionally, a size-dependent characteristic time scale for imbibition is found, which could be useful for the interpretation of experiments and design of novel nanofluidic devices. We present the first systematic study that explains how contact angle dynamics and imbibition dynamics vary with nanopore radius. Our modeling approach lays the foundation for broader investigations on the dynamics of fluids in nanoporous materials in conjunction with experimental efforts. PMID- 22931155 TI - Young African American perceptions of substance use in rural eastern Arkansas communities. AB - This study examined barriers to substance abuse treatment through focus group interviews of African American youth in three rural, eastern Arkansas counties in the Mississippi Delta region. Participants in the study included adolescents with a current or prior history of substance use, non-substance using adolescents acquainted with other substance users, and adolescents who initiated substance use during adolescence (N = 41). Grand tour and subsequent probe questions elicited multiple themes regarding rural adolescent substance use, treatment decisions, and preferences. Adolescents' perceptions of substance use indicate that treatment or prevention programs will need to address multiple dimensions, ranging from individual to community-wide factors. PMID- 22931156 TI - Alcohol use of African Americans and Whites from ages 9-20: descriptive results from a longitudinal study. AB - African American and White youth (N = 405) were assessed annually for 8 years, providing alcohol use data spanning from ages 9-20 years. Alcohol use increased with age, as did binge drinking, drunkenness, peer alcohol use, and ease of obtaining alcohol. At younger ages, the usual alcoholic drink was wine; other drinks were preferred at older ages. Fewer African Americans than Whites reported alcohol use, binge drinking, drunkenness, peer alcohol use, and encouragement of alcohol. These results support and extend previous findings and suggest that contextual influences may help explain alcohol use differences and similarities between African American and White youth. PMID- 22931157 TI - The influence of linguistic acculturation and parental monitoring on the substance use of Mexican-heritage adolescents in predominantly Mexican enclaves of the Southwest US. AB - This study presents the results of an assessment of 377 Mexican heritage 7th grade adolescents attending middle school in Arizona. The students answered questions concerning personal substance use, linguistic acculturation and parental monitoring. Linguistic acculturation in general did not predict substance use, while greater perceived parental monitoring significantly predicted a lesser likelihood to use substances for both boys and girls. There was a significant acculturation by parental monitoring interaction for every use of alcohol for boys, with parent monitoring effects being more pronounced in reducing alcohol use among highly acculturated boys. Results are discussed in terms of how acculturation impacts family processes and the drug use behaviors of Mexican heritage adolescents living in predominantly Mexican enclaves. PMID- 22931158 TI - Perceptions of family caring and its impact on peer associations and drug involvement among rural dwelling African American and White adolescents. AB - The purpose of this study was to investigate the premise that adolescent perceptions of family caring are a precipitating source of substance use deterrence. More specifically, this study examined the role of family caring on communication of substance use harm and sanctions of use and the effect of these on peer substance involvement and individual use outcomes. A sample of rural dwelling African American and White 7th and 8th grade students (N = 1780) was assessed through self-report. It was anticipated that family caring would be positively related to harm communication and sanctions of use, and that these would be negatively related to peer substance involvement and individual use. Results suggest that family caring was positively linked to harm communication and sanctions of use, and that these were both negatively related to peer substance involvement and individual use. Several significant race differences were noted, which suggest differential associations between some variables. Results are discussed in terms of these race differences, as well as in terms of rural residency. PMID- 22931159 TI - Alcohol use and cigarette smoking during pregnancy among American Indians/Alaska Natives. AB - Previous research states that American Indian/Alaska Native pregnant women exhibit high rates of alcohol use and smoking. The current study uses the National Survey of Drug Use and Health (2005-2009) to update and expand on this literature. Results reveal lower rates of alcohol use and, with compositional controls, lower rates of smoking for American Indian/Alaska Native pregnant women compared with pregnant women of other racial/ethnic groups. These findings support social-structural explanations of substance use among American Indian/Alaska Native pregnant women and refute commonly offered cultural arguments that alcohol use and smoking reflect something that is "uniquely Indian." PMID- 22931161 TI - Seizure recurrence and remission after switching antiepileptic drugs. AB - PURPOSE: Studies of seizure outcome in patients undergoing serial antiepileptic drug trials have all been uncontrolled, with no account made for the spontaneous changes in disease state that could confound the elucidation of drug effects. In addition, no study has ever looked at outcome following antiepileptic drug switch in seizure-free patients, despite the fact that this is done routinely in clinical practice. We aimed to address both of these issues using a matched case cohort design. METHODS: We followed patients taking phenytoin or carbamazepine in monotherapy for focal epilepsy who were being crossed over to a newer agent as part of studies on the metabolic effects of anticonvulsant therapy. Many had been seizure-free but were being switched nonetheless due to side effects or concerns about long-term adverse consequences. Each patient was matched with two controls of the same seizure status who were taking anticonvulsant monotherapy and whose drug was not switched. Seizure freedom over the ensuing 6 months was the primary end point. KEY FINDINGS: There were 43 cases and 86 matched controls. Twenty three patients (cases) had been seizure-free on their old drug; 5 (21.7%) had seizure recurrence after drug switch compared to 2 (4.3%) of 46 matched controls. Twenty patients (cases) were having seizures on their old drug; 6 (30%) entered remission after drug switch, compared to 8 of 40 matched controls (20%). The two groups differed at baseline in number of anticonvulsants previously failed, which was the most important factor for prognosis. After statistical adjustment to account for this, seizure-free patients had 6.53 times higher odds of seizure recurrence if switched to a new drug (95% confidence interval [CI] 1.02-61.19; p = 0.06). Non-seizure-free patients had 1.66 times higher odds of remission if they remained on the same drug compared to switching, although this was not significant (95% CI 0.36-8.42; p = 0.532). Neither dose changes, nor drug mechanism, nor duration of seizure freedom had any bearing upon the results. SIGNIFICANCE: Although the large majority of seizure-free patients remain so when switched to another agent, about one sixth have a recurrence attributable to the change. Conversely, our study design provides the first evidence to suggest that most improvements in drug-resistant patients are likely due to spontaneous remissions, not new drug introductions. These findings have conflicting implications for two competing models of comparative antiepileptic drug efficacy, which will require further study to elaborate. PMID- 22931163 TI - Molybdenum(VI) dioxo complexes employing Schiff base ligands with an intramolecular donor for highly selective olefin epoxidation. AB - Reaction of [MoO(2)(eta(2)-tBu(2)pz)(2)] with Schiff base ligands HL(X) (X = 1-5) gave molybdenum(VI) dioxo complexes of the type cis-[MoO(2)(L(X))(2)] as yellow to light brown solids in moderate to good yields. All ligands coordinate via its phenolic O atom and the imine N atom in a bidentate manner to the metal center. The third donor atom (R(2) = OMe or NMe(2)) in the side chain in complexes 1-4 is not involved in coordination and remains pendant. This was confirmed by X-ray diffraction analyses of complexes 1 and 3. Complexes 1, 3, and 5 exist as a mixture of two isomers in solution, whereas complexes 2 and 4 with sterically less demanding substituents on the aromatics only show one isomer in solution. All complexes are active catalysts in the epoxidation of various internal and terminal alkenes, and epoxides in moderate to good yields with high selectivities are obtained. In the challenging epoxidation of styrene, complexes 1 and 2 prove to be very active and selective. The selectivity seems to be influenced by the pendant donor arm, as complex 5 without additional donor in the side chain is less selective. Experiments prove that the addition of n-butyl methyl ether as intermolecular donor per se has no influence on the selectivity. The basic conditions induced by the NMe(2) groups in complexes 3 and 4 lead to lower activity. PMID- 22931162 TI - Comparative study on the in vitro cytotoxicity of linear, dendritic, and hyperbranched polylysine analogues. AB - Lysine-based polycations are widely used as nonviral carriers for gene delivery. This manuscript reports the results of a comparative study on the in vitro cytotoxicity of a library of three structural polylysine variants, namely, linear polylysine (LPL), dendritic polylysine (DPL), and hyperbranched polylysine (HBPL). The aim of this study was to identify possible effects of polymer molecular weight and architecture on both immediate and delayed cytotoxicity and also to provide a mechanistic understanding for possible differences. Acute cytotoxicities were evaluated using cell viability assays with CHO DG44 cells. At comparable molecular weights, the EC(50) values for the LPL analogues were ~5-250 times higher as compared to the DPL and HBPL samples. For low molecular weight polycations, osmotic shock was found to be an important contributor to immediate cell death, whereas for the higher molecular weight analogues, direct cell membrane disruption was identified to play a role. Delayed cytotoxicity (>=3 h) was assessed by identifying several of the hallmark events that characterize apoptosis, including phosphatidyl serine translocation, mitochondrial membrane depolarization, cytoplasmic cytochrome C release, and caspase 3 activation. At comparable molecular weights, apoptosis was found to be more pronounced for DPL and HBPL as compared to LPL. This difference was ascribed to the fact that LPL is completely enzymatically degradable, in contrast to DPL and HBPL, which also contain epsilon-peptidic bonds and are only partially degradable. Because their toxicity profiles are similar, HBPL is an interesting (i.e., synthetically easily accessible and inexpensive) alternative to DPL for the nonviral delivery of DNA. PMID- 22931164 TI - Association between serum total antioxidant status and coronary microvascular functions in patients with SLE. AB - Mortality from cardiovascular disease has been found to be increased in patients with systemic lupus erythematosus (SLE). Coronary flow reserve (CFR) measurement is used both to assess epicardial coronary arteries and to examine the integrity of coronary microvascular circulation. Oxidative stress, enhancing modification of plasma lipids, is also associated with atherosclerotic events in lupus patients. Impairment of CFR and TAS has been shown to be an early manifestation of coronary atherosclerosis. Forty patients with SLE and 33 healthy volunteers were included in this study. Echocardiographic examination included left ventricular myocardial velocity measurements and coronary flow reserve (CFR) measurement. Serum total antioxidant status levels (TAS) also were measured using TAS kit. Lateral myocardial early peak velocity (Em) and lateral Em/Am ratio did not differ between the groups, but lateral myocardial atrial peak velocity (Am) was significantly higher in SLE group than the control group. Baseline coronary diastolic peak flow velocity (DPFV) of left anterior descending was similar in both the groups. However, hyperemic DPFV and CFR (2.50 +/- 0.42 vs. 3.09 +/- 0.45, P < 0.0001) were significantly lower in the SLE group than in the control group. CFR significantly and inversely correlated with CRP and significantly correlated with TAS. Subclinical coronary microvascular dysfunction can occur in SLE patients without traditional cardiovascular risk factors, probably associated with underlying inflammation and impairment of TAS. PMID- 22931166 TI - Uncertain benefits estimates for reductions in fine particle concentrations. AB - The Environmental Protection Agency's (EPA's) estimates of the benefits of improved air quality, especially from reduced mortality associated with reductions in fine particle concentrations, constitute the largest category of benefits from all federal regulation over the last decade. EPA develops such estimates, however, using an approach little changed since a 2002 report by the National Research Council (NRC), which was critical of EPA's methods and recommended a more comprehensive uncertainty analysis incorporating probability distributions for major sources of uncertainty. Consistent with the NRC's 2002 recommendations, we explore alternative assumptions and probability distributions for the major variables used to calculate the value of mortality benefits. For metropolitan Philadelphia, we show that uncertainty in air quality improvements and in baseline mortality have only modest effects on the distribution of estimated benefits. We analyze the effects of alternative assumptions regarding the value of reducing mortality risk, whether the toxicity is above or below the average for fine particles, and whether there is a threshold in the concentration response relationship, and show these assumptions all have large effects on the distribution of benefits. PMID- 22931167 TI - Deprotonation of p-hydroxybenzoic acid: does electrospray ionization sample solution or gas-phase structures? AB - Despite the simplicity of the molecule, the site of single deprotonation of p hydroxybenzoic acid upon electrospray ionization (ESI) has recently formed a subject of debate in this journal. By means of NMR experiments in solution and gas-phase studies employing ion-mobility mass spectrometry (IM-MS), the apparent controversy is resolved. It is shown that irrespective of the solvent the carboxylate tautomer is preferred in solution, while the opposite holds true for isolated ions in the gas phase. The tautomer distribution sampled in the gas phase very much depends on the actual solvent used in ESI, the pH value, as well as the total concentration. Moreover, the occurrence of gas-phase reactions in the course of the ESI process influences the tautomer ratio. Implications for correlations between ESI mass spectra and solution-phase chemistry are discussed. PMID- 22931165 TI - The T-box transcription factor Brachyury regulates epithelial-mesenchymal transition in association with cancer stem-like cells in adenoid cystic carcinoma cells. AB - BACKGROUND: The high frequencies of recurrence and distant metastasis of adenoid cystic carcinoma (AdCC) emphasize the need to better understand the biological factors associated with these outcomes. To analyze the mechanisms of AdCC metastasis, we established the green fluorescence protein (GFP)-transfected subline ACCS-GFP from the AdCC parental cell line and the metastatic ACCS-M GFP line from an in vivo metastasis model. METHODS: Using these cell lines, we investigated the involvement of the epithelial-mesenchymal transition (EMT) and cancer stem cell (CSCs) in AdCC metastasis by real-time RT-PCR for EMT related genes and stem cell markers. Characteristics of CSCs were also analyzed by sphere forming ability and tumorigenicity. Short hairpin RNA (shRNA) silencing of target gene was also performed. RESULTS: ACCS-M GFP demonstrated characteristics of EMT and additionally displayed sphere-forming ability and high expression of EMT related genes (Snail, Twist1, Twist2, Slug, zinc finger E-box binding homeobox 1 and 2 [Zeb1 and Zeb2], glycogen synthase kinase 3 beta [Gsk3beta and transforming growth factor beta 2 [Tgf-beta2]), stem cell markers (Nodal, Lefty, Oct-4, Pax6, Rex1, and Nanog), and differentiation markers (sex determining region Y [Sox2], Brachyury, and alpha fetoprotein [Afp]). These observations suggest that ACCS-M GFP shows the characteristics of CSCs and CSCs may be involved in the EMT of AdCC. Surprisingly, shRNA silencing of the T-box transcription factor Brachyury (also a differentiation marker) resulted in downregulation of the EMT and stem cell markers. In addition, sphere-forming ability, EMT characteristics, and tumorigenicity were simultaneously lost. Brachyury expression in clinical samples of AdCC was extremely high and closely related to EMT. This finding suggests that regulation of EMT by Brachyury in clinical AdCC may parallel that observed in vitro in this study. CONCLUSIONS: The use of a single cell line is a limitation of this study. However, parallel data from in vitro and clinical samples suggest the possibility that EMT is directly linked to CSCs and that Brachyury is a regulator of EMT and CSCs. PMID- 22931168 TI - Selectivity control in synergistic liquid-liquid anion exchange of univalent anions via structure-specific cooperativity between quaternary ammonium cations and anion receptors. AB - Two anion receptors enhance liquid-liquid anion exchange when added to quaternary alkylammonium chloride anion exchangers, but with a striking dependence on the structure of the alkylammonium cation that suggests a supramolecular cooperative effect. Two anion receptors were investigated, meso-octamethylcalix[4]pyrrole (C4P) and the bisthiourea tweezer 1,1'-(propane-1,3-diyl)bis(3-(4-sec butylphenyl)thiourea (BTU). Whereas synergism is comparatively weak when either methyltri(C(8,10))alkylammonium chloride (Aliquat 336) or tetraheptylammonium chloride is used with the BTU receptor, synergism between C4P and Aliquat 336 is so pronounced that anion exchange prefers chloride over more extractable nitrate and trifluoroacetate, effectively overcoming the ubiquitous Hofmeister bias. A thermochemical analysis of synergistic anion exchange has been provided for the first time, resulting in the estimation of binding constants for C4P with the ion pairs of A336(+) with Cl(-), Br(-), OAc(F3)(-), NO(3)(-), and I(-). PMID- 22931169 TI - Elastic stiffness and filler size effect of covalently grafted nanosilica polyimide composites: molecular dynamics study. AB - The filler size-dependent elastic stiffness of nanosilica (alpha-quartz) reinforced polyimide(s-BPDA/1,3,4-APB) composites under the same volume fraction and grafting ratio conditions was investigated via molecular dynamics(MD) simulations. To enhance the interfacial load transfer efficiency, we treated the surface oxygen atoms of the silica nanoparticle with additional silicon atoms attached by a propyl group to which the aromatic hydrocarbon in the polyimide is directly grafted. As the radius of the embedded nanoparticle increases, the Young's and shear moduli gradually decrease, showing a prominent filler size effect. At the same time, the moduli of the nanocomposites increase as the grafting ratio increases. The contribution of different nanoparticles to the filler size dependency in elastic stiffness of the nanocomposites can be elucidated by comparing the normalized adhesive interaction energy between the particle and matrix which exhibits prominent filler size dependency. Because of the immobilization of the matrix polymer in the vicinity of the nanoparticles, which was confirmed by the self-diffusion coefficient, the highly grafted interface is found to bring about a greater reinforcing effect than the ungrafted interface. PMID- 22931170 TI - Simultaneous boosting of source and sink capacities doubles tuber starch yield of potato plants. AB - An important goal in biotechnological research is to improve the yield of crop plants. Here, we genetically modified simultaneously source and sink capacities in potato (Solanum tuberosum cv. Desiree) plants to improve starch yield. Source capacity was increased by mesophyll-specific overexpression of a pyrophosphatase or, alternatively, by antisense expression of the ADP-glucose pyrophosphorylase in leaves. Both approaches make use of re-routing photoassimilates to sink organs at the expense of leaf starch accumulation. Simultaneous increase in sink capacity was accomplished by overexpression of two plastidic metabolite translocators, that is, a glucose 6-phosphate/phosphate translocator and an adenylate translocator in tubers. Employing such a 'pull' approach, we have previously shown that potato starch content and yield can be increased when sink strength is elevated. In the current biotechnological approach, we successfully enhanced source and sink capacities by a combination of 'pull' and 'push' approaches using two different attempts. A doubling in tuber starch yield was achieved. This successful approach might be transferable to other crop plants in the future. PMID- 22931171 TI - Multiresidue pesticide analysis of dried botanical dietary supplements using an automated dispersive SPE cleanup for QuEChERS and high-performance liquid chromatography-tandem mass spectrometry. AB - An automated dispersive solid phase extraction (dSPE) cleanup procedure as part of the Quick, Easy, Cheap, Effective, Rugged, and Safe (QuEChERS) method, coupled with liquid chromatography-tandem mass spectrometry using electrospray ionization in positive mode, was used for the simultaneous analysis of 236 pesticides in three dried powdered botanical dietary supplements (ginseng, saw palmetto, and gingko biloba). The procedure involved extraction of the dried powdered botanical samples with salt-out acetonitrile/water extraction using anhydrous magnesium sulfate and sodium chloride, followed by an automated dSPE cleanup using a mixture of octadodecyl- (C18) and primary-secondary amine (PSA)-linked silica sorbents and anhydrous MgSO4 and online LC-MS/MS analysis. Dynamic multiple reaction monitoring (DMRM) based on the collection of two precursor-to-product ion transitions with their retention time windows was used for all of the targeted pesticides and the internal standard. Matrix-matched calibration standards were used for quantitation, and standard calibration curves showed linearity (r(2) > 0.99) across a concentration range of 0.2-400 ng/mL for the majority of the 236 pesticides evaluated in the three botanical matrices. Mean recoveries (average %RSD, n = 4) were 91 (6), 93 (4), 96 (3), and 99 (3)% for ginseng, 101 (9), 98 (6), 99 (4), and 102 (3)% for gingko biloba, and 100 (9), 98 (6), 96 (4), and 96 (3)% for saw palmetto at fortification concentrations of 25, 100, 250, and 500 MUg/kg, respectively. The geometric mean matrix-dependent instrument detection limits were 0.17, 0.09, and 0.14 MUg/kg on the basis of the studies of 236 pesticides tested in ginseng roots, gingko biloba leaves, and saw palmetto berries, respectively. The method was used to analyze incurred ginseng samples that contained thermally labile pesticides with a concentration range of 2-200 MUg/kg, indicating different classes of pesticides are being applied to these botanicals other than the traditional pesticides that are commonly used and analyzed by gas chromatography techniques. The method demonstrates the use of an automated cleanup procedure and the LC-MS/MS detection of multiple pesticide residues in dried, powdered botanical dietary supplements. PMID- 22931172 TI - Alcohol-impaired driving in the United States: contributors to the problem and effective countermeasures. AB - OBJECTIVE: To review the effectiveness of current countermeasures in alcohol impaired driving. METHOD: This article provides an overview of the contributors to the alcohol-impaired driving problem in the United States and reviews the effectiveness of alcohol-impaired driving countermeasures. RESULTS: Many effective countermeasures have been used during the past few decades both to deter drivers from driving when they are over the legal limit for alcohol and to discourage driving while intoxicated (DWI) offenders from reoffending once they have been caught and convicted. In recent years, greater attention has been given to the problem of "hardcore" drinking drivers, a term coined to refer to those who repeatedly drive with high blood alcohol concentrations and are resistant to changing their behavior. Although such individuals are a legitimate target for attention, focusing predominantly on this group will result in missed opportunities to address a large portion of alcohol-impaired driving crashes. This article provides a review of the primary countermeasures that have been used to reduce alcohol-impaired driving and summarizes evidence for their effectiveness. It asks the question of where, in an environment of limited resources, attention should be focused. CONCLUSIONS: General deterrent approaches, such as frequent and highly publicized sobriety checkpoints, have the greatest potential to save lives and should be the mainstay of state and local efforts. Specific deterrent approaches, aimed at deterring DWI offenders from reoffending, such as alcohol ignition interlocks, should be applied to all apprehended drivers, whatever their drinking history. Evidence suggests that they could benefit from them. In the future, advanced in-vehicle technologies that would prevent vehicles from being driven when their drivers are over the legal limit may hold the key to drastically reducing the alcohol-impaired driving problem. PMID- 22931173 TI - Automatic imitation of risky behavior: a study of simulated driving in China. AB - OBJECTIVE: Imitation of risky behaviors among drivers is a potentially dangerous threat to driving safety but is infrequently discussed in the existing literature. To enrich the understanding of drivers' imitation behaviors on the road, 2 experiments were designed for a simulated traffic environment. METHODS: Safe and risky behaviors were demonstrated by model vehicles separately in the 2 experiments, and imitation behaviors of the participants were observed and analyzed. RESULTS: From experiment 1 it was found that the following distance of participants (measured in time headway) was affected by the distance demonstrated by other vehicles on the road. The influence was stronger when the speed was low, and the participants imitated both risky and safe behavior models. When the speed was high, the participants tended to only learn safe behaviors. In experiment 2, when approaching yellow lights, it was examined whether a driver's decision (pass or stop) would be affected by the behavior of another vehicle (the model vehicle), which was designed to either pass through or stop at the intersection. When the model vehicle ran the yellow light, 65 percent of the participants did the same, even though they were 30 m behind the model vehicle. In contrast, if the model vehicle stopped at the intersection, only 25 percent of the participants decided to pass. CONCLUSIONS: It was found that both novice and experienced participants had the tendency to imitate what they saw but were rarely aware of the influence by other drivers in both scenarios. PMID- 22931174 TI - Cognitive skills underlying driving in patients discharged following self poisoning with central nervous system depressant drugs. AB - BACKGROUND: Central nervous system-depressant (CNS-Ds) drugs can impair cognitive functions and driving. They are also the most common drugs taken in overdose in hospital-treated episodes of self-poisoning. In Australia most of these patients are discharged within 48 h, while they still have possible subclinical drug effects. We aimed to determine whether patients treated for self-poisoning with CNS-Ds are impaired in the Trail-Making Test (TMT, parts A and B), a neuropsychological test that is known to correlate with driving performance. METHODS: This study was a conducted from November 2008 to April 2011 in a referral center for poisonings in New South Wales, Australia. One hundred seven patients discharged from the clinical toxicology unit following treatment for self-poisoning of CNS-Ds (benzodiazepines, atypical antipsychotics, or opioids) and a control group of 68 discharged following self-poisoning of non-CNS depressant drugs (acetaminophen or nonsedating antidepressants) were tested with the TMT (parts A and B). Due to the known association of impaired TMT with driving impairment and increased risk of traffic accidents, performance less than the 10th percentile for age was defined as significant impairment in each part of the TMT. The odds ratio (OR) for impairment in each part was calculated in multivariate logistic regression (MLR) models adjusted for gender, education, IQ, and the presence of a major psychiatric illness. A secondary MLR analysis was conducted only for those patients (78 CNS-D and 54 control group participants) who were directly discharged home, after excluding those who were transferred for further psychiatric care. RESULTS: The odds of impairment in the CNS-D group was 2.8 times that of the control group on the TMT-A (38 [35.5%] vs. 11 [16.2%]: adjusted OR = 2.76, 95% confidence interval [CI]: 1.28-5.97), and 4.6 times on the TMT-B (67 [62.6%] vs. 22 [32.4%]: adjusted OR = 4.63, 95% CI: 2.06-10.42). The results were similar in the subgroup of patients discharged home, and the odds of impairment in the CNS-D group was 3.3 times that of the control group on the TMT-A (25 [32.1%] vs. 7 [13.0%]: adjusted OR = 3.30, 95% CI: 1.28-8.52), and 3.6 times on the TMT-B (46 [59.0%] vs. 17 [31.5%]: adjusted OR = 3.64, 95% CI: 1.44-9.20). TMT-B impairment in the CNS-D group remained significant even after adjusting for TMT-A performance. CONCLUSIONS: Patients with CNS-D overdose may have significant impairment in cognitive skills underlying driving at the time of discharge from hospitals. Clinicians should warn these patients that their driving skills might still be impaired, even if they are considered clinically recovered and advise them not to drive during the first 1 to 2 days following discharge. PMID- 22931175 TI - Factors affecting accident severity inside and outside urban areas in Greece. AB - OBJECTIVES: This research aims to identify and analyze the factors affecting accident severity through a macroscopic analysis, with a focus on the comparison between inside and outside urban areas. Disaggregate road accident data for Greece for the year 2008 were used. METHODS: Two models were developed, one for inside and one for outside urban areas. Because the dependent variable had 2 categories, killed/severely injured (KSI) and slightly injured (SI), the binary logistic regression analysis was selected. Furthermore, this research aims to estimate the probability of fatality/severe injury versus slight injury as well as to calculate the odds ratios (relative probabilities) for various road accident configurations. The Hosmer and Lemeshow statistic and other diagnostic tests were conducted in order to assess the goodness-of-fit of the model. RESULTS: From the application of the models, it appears that inside urban areas 3 types of collisions (sideswipe, rear-end, with fixed object/parked car), as well as involvement of motorcycles, bicycles, buses, 2 age groups (18-30 and older than 60 years old), time of accident, and location of the accident, seem to affect accident severity. Outside urban areas, 4 types of collisions (head-on, rear-end, side, sideswipe), weather conditions, time of accident, one age group (older than 60 years old), and involvement of motorcycles and buses were found to be significant. CONCLUSIONS: Factors affecting road accident severity only inside urban areas include young driver age, bicycles, intersections, and collision with fixed objects, whereas factors affecting severity only outside urban areas are weather conditions and head-on and side collisions, demonstrating the particular road users and traffic situations that should be focused on for road safety interventions for the 2 different types of networks (inside and outside urban areas). The methodology and the results of this research may provide a promising tool to prioritize programs and measures to improve road safety in Greece and worldwide. PMID- 22931176 TI - Both texting and eating are associated with impaired simulated driving performance. AB - OBJECTIVE: Distracted driving is a known contributor to traffic accidents, and many states have banned texting while driving. However, little is known about the potential accident risk of other common activities while driving, such as eating. The objective of the current study was to examine the adverse impact of eating/drinking behavior relative to texting and nondistracted behaviors on a simulated driving task. METHODS: A total of 186 participants were recruited from undergraduate psychology courses over 2 semesters at Kent State University. We utilized the Kent Multidimensional Assessment Driving Simulation (K-MADS) to compare simulated driving performance among participants randomly assigned to texting (N = 45), eating (N = 45), and control (N = 96) conditions. Multivariate analyses of variance (MANOVA) were conducted to examine between-group differences on simulated driving indices. RESULTS: MANOVA analyses indicated that groups differed in simulated driving performance, F(14, 366) = 7.70, P < .001. Both texting and eating produced impaired driving performance relative to controls, though these behaviors had approximately equal effect. Specifically, both texting and eating groups had more collisions, pedestrian strikes, and center line crossings than controls. In addition, the texting group had more road edge excursions than either eating or control participants and the eating group missed more stop signs than controls. CONCLUSIONS: These findings suggest that both texting and eating are associated with poorer simulated driving performance. Future work is needed to determine whether these findings generalize to real world driving and the development of strategies to reduce distracted driving. PMID- 22931177 TI - Gasoline prices and traffic crashes in Alabama, 1999-2009. AB - OBJECTIVE: The price of gasoline has been found to be negatively associated with traffic crashes in a limited number of studies. However, most of the studies have focused either on fatal crashes only or on all crashes but measured over a very short time period. In this study, we examine gasoline price effects on all traffic crashes by demographic groups in the state of Alabama from 1999 to 2009. METHODS: Using negative binomial regression techniques to examine monthly data from 1999 to 2009 in the state of Alabama, we estimate the effects of changes in gasoline price on changes in automobile crashes. We also examine how these effects differ by age group (16-20, 21-25, 26-30, 31-64, and 65+), gender (male and female), and race/ethnicity (non-Hispanic white, non-Hispanic black, and Hispanic). RESULTS: The results show that gasoline prices have both short-term and long-term effects on reducing total traffic crashes and crashes of each age, gender, and race/ethnicity group (except Hispanic due to data limitations). The short-term and long-term effects are not statistically different for each individual demographic group. Gasoline prices have a stronger effect in reducing crashes involving drivers aged 16 to 20 than crashes involving drivers aged 31 to 64 and 65+ in the short term; the effects, however, are not statistically different across other demographic groups. CONCLUSIONS: Although gasoline price increases are not favored, our findings show that gasoline price increases (or decreases) are associated with reductions (or increases) in the incidence of traffic crashes. If gasoline prices had remained at the 1999 level of $1.41 from 1999 to 2009, applying the estimated elasticities would result in a predicted increase in total crashes of 169,492 (or 11.3%) from the actual number of crashes. If decision makers wish to reduce traffic crashes, increasing gasoline taxes is a possible option-however, doing so would increase travel costs and lead to equity concerns. These findings may help to shape transportation safety planning and policy making. PMID- 22931178 TI - Risky driving and the perception of motorcycle accident causes among Chinese motorcyclists in Hong Kong. AB - OBJECTIVE: The primary purposes of this study were to explore the relationship between risk-taking acts while driving motorcycles and perceived causes of motorcycle accidents, as well as their contribution to active involvement in traffic accidents among Chinese motorcyclists in Hong Kong. Active involvement means the riders was likely at fault for the crash. METHODS: A total of 774 motorcyclists were recruited, of whom 292 had been involved in active motorcycle accident in the previous 3 years. All were asked to fill in a questionnaire, which was developed to assess their risk-taking acts while driving a motorcycle and perception of motorcycle accident causes. RESULTS: The results of the study revealed 3 dimensions of accident causes, namely, driving-related, environment related, and belief-related causes. These motorcycle accident causes were correlated with risk-taking acts while driving a motorcycle. A multivariate logistic regression analysis showed that risk-taking acts while driving motorcycles (adjusted odds ratio [OR]: 1.036, 95% confidence interval [CI]: 1.020 1.052), perception of driving-related cause (adjusted OR: 0.941, 95% CI: 0.916 0.967), and belief-related cause (adjusted OR: 1.134, 95% CI: 1.088-1.182) were significant factors contributing to involvement in active traffic accidents by motorcycle riders after controlling for concurrent demographic variables. CONCLUSIONS: The study highlights that perceived causes of motorcycle accidents are multidimensional, including those areas related to driving, the environment, and beliefs. It substantiates previous studies that a higher degree of driving related risk perception is related to a lower degree of risk-taking acts while driving. Further research is needed to understand why belief-related causes, sometimes called superstitions, lead riders to believe that it is beyond their ability to affect accident causation and prevention. PMID- 22931179 TI - Bicyclist fatalities involving heavy goods vehicles: gender differences in risk perception, behavioral choices, and training. AB - OBJECTIVES: Females are typically involved in fewer collisions when pedal cycling than males. However, female cyclists appear to be overrepresented in the number of fatal collisions involving heavy goods vehicles (HGVs). These collisions often involve cyclists passing HGVs on the side furthest from the HGV driver (nearside). It is hypothesized that this pattern of fatalities may be partly due to differences in how males and females perceive the risk associated with various cycling maneuvers. It is also hypothesized that this difference may be overcome with advanced training. METHODS: 4,596 UK cyclists completed an online questionnaire in which they reported their level of cycle training and rated the risk they perceived to be associated with various cycling maneuvers, the likelihood that they would engage in them, and history of collision involvement. RESULTS: Females perceived a slightly greater level of risk to be associated with cycling. However, males differentiated between the risks involved in nearside and offside overtaking to a greater extent than females. Risk perception was significantly correlated with the reported likelihood that participants would engage in risky maneuvers such as overtaking on the nearside and also with past collision prevalence. Advanced cycling training was correlated with higher levels of perceived risk associated with overtaking on the nearside; however, basic cycle training was not. CONCLUSIONS: Cyclists who do not correctly differentiate between the risks associated with nearside and offside overtaking may be more at risk of being involved in HGV-related collisions. Advanced cycling training is linked to more accurate risk perception. To reduce fatalities, public awareness campaigns should focus on the increased risk of nearside overtaking and encourage cyclists to take advanced training. PMID- 22931180 TI - Biomechanical response targets for physical and computational models of the pediatric trunk. AB - OBJECTIVES: This paper quantifies pediatric thoracoabdominal response to belt loading to guide the scaling of existing adult response data and to assess the validity of a juvenile porcine abdominal model for application to the development of physical and computational models of the human child. METHODS: Table-top belt loading experiments were performed on 6, 7, and 15 year-old pediatric post-mortem human subjects (PMHS). Response targets are reported for diagonal belt and distributed loading of the anterior thorax and for horizontal belt loading of the abdomen. RESULTS: The pediatric PMHS exhibited abdominal response similar to the swine, including the degree of rate sensitivity. The thoraces of the PMHS were as stiff as, or slightly more stiff than, published adult corridors. CONCLUSIONS: An assessment of age-related changes in thoracic stiffness suggests that the effective stiffness of the chest increases through the fourth decade of life and then decreases, resulting in stiffness values similar for children and elderly adults. PMID- 22931181 TI - Effects of vehicle impact velocity, vehicle front-end shapes on pedestrian injury risk. AB - OBJECTIVE: This study aimed at investigating the effects of vehicle impact velocity, vehicle front-end shape, and pedestrian size on injury risk to pedestrians in collisions with passenger vehicles with various frontal shapes. METHOD: A series of parametric studies was carried out using 2 total human model for safety (THUMS) pedestrian models (177 and 165 cm) and 4 vehicle finite element (FE) models with different front-end shapes (medium-size sedan, minicar, one-box vehicle, and sport utility vehicle [SUV]). The effects of the impact velocity on pedestrian injury risk were analyzed at velocities of 20, 30, 40, and 50 km/h. The dynamic response of the pedestrian was investigated, and the injury risk to the head, chest, pelvis, and lower extremities was compared in terms of the injury parameters head injury criteria (HIC), chest deflection, and von Mises stress distribution of the rib cage, pelvis force, and bending moment diagram of the lower extremities. RESULT: Vehicle impact velocity has the most significant influence on injury severity for adult pedestrians. All injury parameters can be reduced in severity by decreasing vehicle impact velocities. The head and lower extremities are at greater risk of injury in medium-size sedan and SUV collisions. The chest injury risk was particularly high in one-box vehicle impacts. The fracture risk of the pelvis was also high in one-box vehicle and SUV collisions. In minicar collisions, the injury risk was the smallest if the head did not make contact with the A-pillar. CONCLUSION: The vehicle impact velocity and vehicle front-end shape are 2 dominant factors that influence the pedestrian kinematics and injury severity. A significant reduction of all injuries can be achieved for all vehicle types when the vehicle impact velocity is less than 30 km/h. Vehicle designs consisting of a short front-end and a wide windshield area can protect pedestrians from fatalities. The results also could be valuable in the design of a pedestrian-friendly vehicle front-end shape. [Supplementary materials are available for this article. Go to the publisher's online edition of Traffic Injury Prevention for the following free supplemental resource: Head impact conditions and injury parameters in four-type vehicle collisions and validation result of the finite element model of one-box vehicle and minicar. ]. PMID- 22931182 TI - Investigation of motorcyclist cervical spine trauma using HUMOS model. AB - OBJECTIVE: With 16 percent of the total road user fatalities, motorcyclists represent the second highest rate of road fatalities in France after car occupants. Regarding road accidents, a large proportion of trauma was on the lower cervical spine. According to different clinical studies, it is postulated that the cervical spine fragility areas are located on the upper and lower cervical spine. In motorcycle crashes, impact conditions occur on the head segment with various orientations and impact directions, leading to a combination of rotations and compression. Hence, motorcyclist vulnerability was investigated considering many impact conditions. METHOD: Using the human model for safety (HUMOS), a finite element model, this work aims to provide an evaluation of the cervical spine weaknesses based on an evaluation of injury mechanisms. This evaluation consisted of defining 2 injury risk factors (joint injury and bone fracture) using a design of experiment including various velocities, impact directions, and impact orientations. RESULTS: The results confirmed previously reported clinical and epidemiological work on the fragility of the lower cervical spine and the upper cervical spine segments. Joint injuries appeared before bone fractures on both the upper and lower cervical spine. Bone fracture risk was greater on the lower cervical spine than on the upper cervical spine. The compression induced by a high impact angle was identified as an important injury severity factor. It significantly increased the injury incidence for both joint injuries and bone fractures. It also induced a shift in injury location from the lower to the upper cervical spine. The impact velocity exhibited a linear relationship with injury risks and severity. It also shifted the bone fracture risk from the lower to upper spinal segments. PMID- 22931183 TI - Investigating cervical muscle response and head kinematics during right, left, frontal and rear-seated perturbations. AB - OBJECTIVE: Whiplash research has largely focused on rear collisions because they account for the majority of whiplash injuries. The purpose of this study was to evaluate the effects of 4 perturbation directions (anterior, posterior, right, and left) on muscle activity and head kinematics to provide insight into the whiplash mechanism of injury. METHODS: The effects of 4 perturbation directions induced by a parallel robotic platform, with peak acceleration of 8.50 m/s2, were analyzed on 10 subjects. Surface electromyography (EMG) measures were collected from the sternocleidomastoid (SCM), trapezius, and splenius capitus muscles. Kinematics of the head, thorax, and head relative to thorax were also measured. RESULTS: We observed stereotypic responses for kinematics and SCM EMG for the various perturbation directions; the trapezius and splenius capitus muscles showed amplitudes that were less than 5 percent maximum voluntary contraction (MVC). Rear perturbations elicited the smallest onset latencies for the SCM (30 ms) and kinematic variables and greatest linear head center of mass (COM) accelerations. Frontal perturbations resulted in an average SCM onset latency of 143 ms and demonstrated the greatest magnitude of head translations and rotations relative to the thorax. Left and right perturbations demonstrated similar kinematics and SCM onset latencies (55 and 65 ms, respectively). CONCLUSIONS: Compared to frontal, left, and right directions, rear perturbations showed smaller SCM onset latencies, greater SCM amplitudes, and larger head accelerations, relating to a greater potential for injury. We suggest that the greater contact area and stiffness of the seatback, in the posterior direction, compared to restrictions in other directions, led to increased peak head accelerations and shorter SCM onset latencies. PMID- 22931184 TI - The influence of substrate in determining the band gap of metallic carbon nanotubes. AB - We report a detailed comparison of ultraclean suspended and on-substrate carbon nanotubes (CNTs) in order to quantify the effect of the substrate interaction on the effective band gap of metallic nanotubes. Here, individual CNTs are grown across two sets of electrodes, resulting in one segment of the nanotube that is suspended across a trench and the other segment supported on the substrate. The suspended segment shows a significant change in the conductance (DeltaG/G = 0.84) with applied gate voltage, which is attributed to a small band gap. The on substrate segment, however, only shows a change in the measured conductance of DeltaG/G = 0.11. A Landauer model is used to fit the low bias conductance of these devices. From these fits, the band gaps in the suspended region range from 75 to 100 meV but are only 5-14.3 meV when the nanotube is in contact with the substrate. The decreased band gap is attributed to localized doping caused by trapped charges in the substrate that result in inhomogeneous broadening of the Fermi energy, which in turn limits the ability to modulate the conductance. PMID- 22931185 TI - Deep-cavity cavitand octa acid as a hydrogen donor: photofunctionalization with nitrenes generated from azidoadamantanes. AB - 1-azidoadamantane and 2-azidoadamantane form a 1:1 complex with hosts octa acid (OA) and cucurbit[7]uril (CB7) in water. Isothermal titration calorimetric measurements suggest these complexes to be very stable in aqueous solution. The complexes have been characterized by (1)H NMR in solution and by ESI-MS in gas phase. In both phases, the complexes are stable. Irradiation of these complexes (lambda > 280 nm) results in nitrenes via the loss of nitrogen from the guest azidoadamantanes. The behavior of nitrenes within OA differs from that in solution. Nitrenes included within octa acid attack one of the four tertiary benzylic hydrogens present at the lower interior part of OA. While in solution intramolecular insertion is preferred, within OA intermolecular C-H insertion seems to be the choice. When azidoadamantanes included in CB7 were irradiated (lambda > 280 nm) the same products as in solution resulted but the host held them tightly. Displacement of the product required the use of a higher binding guest. In this case, no intermolecular C-H insertion occurred. Difference in reactivity between OA and CB7 is the result of the location of hydrogens; in OA they are in the interior of the cavity where the nitrene is generated, and in CB7 they are at the exterior. Reactivity of nitrenes within OA is different from that of carbenes that do not react with the host. PMID- 22931186 TI - Clinical pharmacology of etoposide in children undergoing autologous stem cell transplantation for various solid tumours. AB - 1. The population pharmacokinetics of high-dose etoposide was studied in a group of young children and adolescents. 2. Twenty-six children and adolescent were administered high-dose etoposide as a continuous infusion over 24 h. Etoposide plasma concentration-time data was modelled using NONMEM(r) 7. The effect of age, weight, serum creatinine (SCr), and gender on pharmacokinetic parameters (CL and V(d)) were determined by a nonlinear mixed effect model. 3. The pharmacokinetics of etoposide based on BSA dosing was best described with a 1-compartment structural model which was parameterised in terms of clearance (CL) and volume of distribution (V(d)). An exponential error model was used to explain intersubject variability and a proportional error model was used to describe residual or intrapatient variability. The final model parameter estimates for the typical (normalised to 70 kg) values of CL and V(d) were 2.31 L/hr and 17.5 L, respectively. The CL and V(d) allometrically increased with weight with the power of 3/4 and 1, respectively. After accounting for weight dependence using the allometric scaling, age, serum creatinine, and gender did not have any influence on model parameters. 4. The results of this children and adolescent population pharmacokinetic study indicates that etoposide pharmacokinetics were influenced by body weight on an allometric basis. The pharmacokinetic parameters CL and V(d) increased with increasing weight similar to BSA. PMID- 22931187 TI - Disposition and metabolism of [14C]PTZ601 in healthy volunteers. AB - 1. Six healthy male subjects were given a single dose of 500 mg of [14C]PTZ601 (mean radioactivity 79.2 MUCi) by intravenous (IV) infusion over 1 h, and observed for 5 days post-dose during which pharmacokinetic (PK) samples were collected. Plasma PTZ601 concentrations and metabolite identification were determined using LC-MS/MS; PK parameters were estimated by non-compartmental analysis. Excretion and mass balance were determined with liquid scintillation analysis and metabolites profiling was characterized by HPLC online radiochemical detection. 2. The disposition of PTZ601 was best described by a fast absorption, followed by a biphasic elimination phase. Peak PTZ601 plasma concentrations were reached within 0.5-1 h. The mean elimination half-life was 1.6 h and clearance was 13 L/h. 3. Recovery of the radioactivity dose was complete (mean 92%). The main route of excretion (parent and metabolites) was the renal route, as urine accounted for 69-77%, while feces only 13-22%, of the total radioactivity. 4. The majority of the drug was excreted in urine as multiple open ring metabolites: M17.3 (oxidative ring-opened product) and M22.2 (di cysteine conjugate of 17.3); unchanged PTZ601 in urine contributed to 15% of radioactivity. The major metabolites detected in plasma were M17.3, M12.8 (acetylated M17.3), M22.2, and M41.4 (methylated M17.3). 5. PTZ601 was well tolerated. PMID- 22931189 TI - Intramolecular interactions versus hydration effects on p-guanidinoethyl-phenol structure and pKa values. AB - We analyze the structure, hydration, and pK(a) values of p-guanidinoethyl-phenol through a combined experimental and theoretical study. These issues are relevant to understand the mechanism of action of the tetrameric form, the antibacterial compound tetra-p-guanidinoethyl-calix[4]arene (Cx1). The investigated system can also be useful to model other pharmaceutical drugs bearing a guanidine function in the vicinity of an ionizable group and the effect of arginine on the pK(a) of vicinal ionizable residues (in particular tyrosine) in peptides. The p guanidinoethyl-phenol monomer (mCx1) has two ionizable groups. One important particularity of this system is that it exhibits high molecular flexibility that potentially leads to enhanced stabilization in folded structures by direct, strong Coulombic interactions between the ionizable groups. The first pK(a) corresponding to ionization of the -OH group has experimentally been shown to be only slightly different from usual values in substituted phenols. However, because of short-range Coulombic interactions, the role of intramolecular interactions and solvation effects on the acidities of this compound is expected to be important and it has been analyzed here on the basis of theoretical calculations. We use a discrete-continuum solvation model together with quantum mechanical calculations at the B3LYP level of theory and the extended 6 311+G(2df,2p) basis set. Both intra- and intermolecular effects are very large (~70 kcal/mol) but exhibit an almost perfect compensation, thus explaining that the actual pK(a) of mCx1 is close to free phenol. The same compensation of environmental effects applies to the second pK(a) that concerns the guanidinium group. Such a pK(a) could not be determined experimentally with standard titration techniques and in fact the theoretical study predicts a value of 14.2, that is, one unit above the pK(a) of the parent ethyl-guanidinium molecule. PMID- 22931188 TI - Food group intake patterns and nutrient intake vary across low-income Hispanic and African American preschool children in Atlanta: a cross sectional study. AB - BACKGROUND: The food group intake patterns of low income Hispanic and African American preschool children are not well documented. The aim of this study was to perform a food group intake analysis of low income minority preschool children and evaluate how macronutrient and micronutrient intake compares to Dietary Reference Intakes (DRI). METHODS: A cross sectional study design using three-day food diaries analyzed by dietary analysis software (Nutrient Database System for Research) was used. Children were recruited from well-child clinics at Children's Healthcare of Atlanta at Hughes Spalding and North Dekalb Grady Satellite Clinic, Atlanta, GA. Low-income, African American and Hispanic preschool age children (n = 291) were enrolled. A total of 105 completed and returned the 3-day food diaries. Chi-squared tests were used to assess demographic variables. The mean percentage of intake per day of specific food groups and sub-groups were obtained (servings of given food group/total daily servings). Food intake data and proportion of children meeting DRIs for macro- and micronutrients were stratified by race/ethnicity, nutritional status, and caloric intake, and were compared using t-tests. Regression models controlling for age, BMI and sex were obtained to assess the effect of total caloric intake upon the proportional intake of each studied food group. RESULTS: The mean age of African American children was 2.24 +/- 1.07 years and Hispanic children 2.84 +/- 1.12 years. African Americans consumed more kcal/kg/day than Hispanics (124.7 +/- 51 vs. 96.9 +/- 33, p < 0.05). Hispanics consumed more fruits (22.0 +/- 10.7% vs. 14.7 +/- 13.7%, p < 0.05), while African Americans consumed more grains (25.7 +/- 7.8% vs. 18.1 +/- 6.4%, p < 0.05), meats (20.7 +/- 9.0% vs. 15.4 +/- 6.1%, p < 0.05), fats (9.8 +/- 5.4% vs. 7.0 +/- 5.8%, p < 0.05), sweet drinks (58.7 +/- 17.1% vs. 41.3 +/- 14.8%, p < 0.05) and low-fat dairy products (39.5 +/- 19.3% vs. 28.9 +/- 12.6%, p < 0.05). Among Hispanics, the proportional intake of fruits, fats and grains varied by total caloric intake, while no difference by total caloric intake was found for the dietary patterns of African Americans. Micronutrient intake also differed significantly between African American and Hispanic children. CONCLUSIONS: Food group intake patterns among low-income children differ by ethnic group. There is a need for more research to guide program design and target nutritional interventions for this population. PMID- 22931191 TI - Behaviour of silver nanoparticles and silver ions in an in vitro human gastrointestinal digestion model. AB - Oral ingestion is an important exposure route for silver nanoparticles (AgNPs), but their fate during gastrointestinal digestion is unknown. This was studied for 60 nm AgNPs and silver ions (AgNO3) using in vitro human digestion model. Samples after saliva, gastric and intestinal digestion were analysed with SP-ICPMS, DLS and SEM-EDX. In presence of proteins, after gastric digestion the number of particles dropped significantly, to rise back to original values after the intestinal digestion. SEM-EDX revealed that reduction in number of particles was caused by their clustering. These clusters were composed of AgNPs and chlorine. During intestinal digestion, these clusters disintegrated back into single 60 nm AgNPs. The authors conclude that these AgNPs under physiological conditions can reach the intestinal wall in their initial size and composition. Importantly, intestinal digestion of AgNO3 in presence of proteins resulted in particle formation. These nanoparticles (of 20-30 nm) were composed of silver, sulphur and chlorine. PMID- 22931192 TI - The Medich giant platelet syndrome: two new cases. AB - Hypogranular platelet disorders in human subjects are relatively rare. They include the gray platelet syndrome, alphadelta storage pool deficiency, the Hermansky-Pudlak syndrome, and the white platelet syndrome. Perhaps the rarest of them all is the Medich giant platelet disorder. No additional cases of this condition have been reported since description of the first case in 2004. This study describes two children with thrombocytopenia and giant, hypogranular platelets found shortly after birth. Electron microscopic study of their platelets revealed sheets of membrane wrapped into tubes resembling scrolls. The scroll-like structures were open at both ends and often filled with glycogen particles. The abnormal structures are identical to those found in the initial case. As a result, the disorder can now be referred to as the Medich giant platelet syndrome. PMID- 22931193 TI - Streptococcus pneumoniae R6 interspecies transformation: genetic analysis of penicillin resistance determinants and genome-wide recombination events. AB - Interspecies gene transfer has been implicated as the major driving force for the evolution of penicillin resistance in Streptococcus pneumoniae. Genomic alterations of S. pneumoniae R6 introduced during four successive transformations with DNA of the high-level penicillin-resistant Streptococcus mitis B6 with beta lactam selection have now been determined and the contribution of genes to high resistance levels was analysed genetically. Essential for high level resistance to penicillins of the transformant CCCB was the combination of murM(B) (6) and the 3' region of pbp2b(B) (6) . Sequences of both genes were detected in clinical isolates of S. pneumoniae, confirming the participation of S. mitis in the global gene pool of beta-lactam resistance determinants. The S. mitis PBP1b gene which contains an authentic stop codon within the transpeptidase domain is now shown to contribute only marginal to resistance, but it is possible that the presence of its transglycosylase domain is important in the context of cognate PBPs. The genome sequence of CCCB revealed 36 recombination events, including deletion and acquisition of genes and repeat elements. A total of 78 genes were affected representing 67 kb or 3.3% of the genome, documenting extensive alterations scattered throughout the genome. PMID- 22931194 TI - Reinforcement of polyether polyurethane with dopamine-modified clay: the role of interfacial hydrogen bonding. AB - Dopamine-modified clay (D-clay) was successfully dispersed into polyether polyurethane (PU) by solvent blending. It is found that the incorporation of D clay into PU gives rise to significant improvements in mechanical properties, including initial modulus, tensile strength, and ultimate elongation, at a very low clay loading. The large reinforcement could be attributed to the hydrogen bonds between the hard segments of PU and stiff D-clay layers that lead to more effective interfacial stress transfer between the polymer and D-clay. Besides, the interactions between D-clay and PU are also stronger than those between Cloisite 30B organoclay and the PU chains. Consequently, at a similar clay loading, the PU/D-clay nanocomposite has much higher storage modulus than the PU/organoclay nanocomposite at elevated temperatures. PMID- 22931195 TI - Biosynthesis, natural sources, dietary intake, pharmacokinetic properties, and biological activities of hydroxycinnamic acids. AB - Hydroxycinnamic acids are the most widely distributed phenolic acids in plants. Broadly speaking, they can be defined as compounds derived from cinnamic acid. They are present at high concentrations in many food products, including fruits, vegetables, tea, cocoa, and wine. A diet rich in hydroxycinnamic acids is thought to be associated with beneficial health effects such as a reduced risk of cardiovascular disease. The impact of hydroxycinnamic acids on health depends on their intake and pharmacokinetic properties. This review discusses their chemistry, biosynthesis, natural sources, dietary intake, and pharmacokinetic properties. PMID- 22931196 TI - Activation of hydrogen and hydrogenation catalysis by a borenium cation. AB - The readily prepared borenium salt [(IiPr(2))(BC(8)H(14))][B(C(6)F(5))(4)] (2) [IiPr(2) = C(3)H(2)(NiPr)(2)] is shown to activate H(2) heterolytically in the presence of tBu(3)P. Compound 2 also acts as a catalyst for the metal-free hydrogenation of imines and enamines at room temperature. PMID- 22931197 TI - Poly(ethyleneglycol)-b-poly(epsilon-caprolactone-co-gamma-hydroxyl-epsilon- caprolactone) bearing pendant hydroxyl groups as nanocarriers for doxorubicin delivery. AB - A novel biodegradable amphiphilic diblock copolymer methoxy poly(ethylene glycol) b-poly(epsilon-caprolactone-co-gamma-hydroxyl-epsilon-caprolactone) (mPEG-b-P(CL co-HCL)) bearing pendant hydroxyl groups on the PCL block was prepared. The hydroxyl groups were formed through the reduction of ketones by sodium borohydride without protection and deprotection. The obtained polymers were well characterized by (1)H NMR, Fourier transform infrared (FT-IR), gel permeation chromatography (GPC), differential scanning calorimetry (DSC), X-ray diffraction (XRD), and contact angle measurement. mPEG-b-P(CL-co-HCL) could self-assemble into stable nanoparticles (NPs) with critical micellar concentrations (CMC) of 6.3 * 10(-4) ~ 8.1 * 10(-4) mg/mL. The NPs prepared from mPEG-b-P(CL-co-HCL) were spherical in shape with diameters about 100 to 140 nm. The hydrophobic doxorubicin (DOX) was chosen as a drug model and successfully encapsulated into the NPs. The encapsulation efficiency and release kinetics of DOX were investigated. The results indicated that the introduction of hydroxyl groups onto the core-forming block could decrease the hydrophobicity of copolymers, thus improving the storage stability of NPs in aqueous solution. Moreover, higher loading capacity and slower in vitro release of DOX were observed, which was due to the hydrogen-bonding formation between DOX and hydroxyl groups. Meanwhile, the MTT assay demonstrated that the blank NPs were biocompatible to HepG2 cell,s while free DOX and DOX-loaded NPs showed significant cytotoxicity against the cells. Moreover, Compared to the free DOX, the DOX-loaded NPs were more efficiently internalized by HepG2 cells. In sum, the introduction of hydroxyl groups on the polyester block in mPEG-b-P(CL-co-HCL) exhibited great potentials for modifications in the stability, drug solubilization, and release properties of NPs. PMID- 22931198 TI - Diagnosis of celiac artery in-stent thrombosis by transesophageal echocardiography. AB - We present a case of a 70-year-old woman with severe peripheral arterial disease presenting with celiac artery in-stent thrombosis diagnosed by transesophageal echocardiography (TEE). Routine assessment of the visceral arteries is not performed in most TEE studies. A review of the literature shows that the celiac and superior mesenteric arteries can be successfully visualized during transgastric views of the abdominal aorta. We propose that two-dimensional and color Doppler echocardiography have several intrinsic advantages over computed tomography, magnetic resonance angiography and catheterization when assessing aortic and visceral arterial pathology. PMID- 22931199 TI - DNA cruciform arms nucleate through a correlated but asynchronous cooperative mechanism. AB - Inverted repeat (IR) sequences in DNA can form noncanonical cruciform structures to relieve torsional stress. We use Monte Carlo simulations of a recently developed coarse-grained model of DNA to demonstrate that the nucleation of a cruciform can proceed through a cooperative mechanism. First, a twist-induced denaturation bubble must diffuse so that its midpoint is near the center of symmetry of the IR sequence. Second, bubble fluctuations must be large enough to allow one of the arms to form a small number of hairpin bonds. Once the first arm is partially formed, the second arm can rapidly grow to a similar size. Because bubbles can twist back on themselves, they need considerably fewer bases to resolve torsional stress than the final cruciform state does. The initially stabilized cruciform therefore continues to grow, which typically proceeds synchronously, reminiscent of the S-type mechanism of cruciform formation. By using umbrella sampling techniques, we calculate, for different temperatures and superhelical densities, the free energy as a function of the number of bonds in each cruciform arm along the correlated but asynchronous nucleation pathways we observed in direct simulations. PMID- 22931200 TI - Long-term skeletal and dental effects and treatment timing for functional appliances in Class II malocclusion. AB - OBJECTIVE: To analyze the long-term skeletal and dentoalveolar effects and to evaluate treatment timing of Class II treatment with functional appliances followed by fixed appliances. MATERIALS AND METHODS: A group of 40 patients (22 females and 18 males) with Class II malocclusion consecutively treated either with a Bionator or an Activator followed by fixed appliances was compared with a control group of 20 subjects (9 females and 11 males) with untreated Class II malocclusion. Lateral cephalograms were available at the start of treatment (mean age 10 years), end of treatment with functional appliances (mean age 12 years), and long-term observation (mean age 18.6 years). The treated sample also was divided into two groups according to skeletal maturity. The early-treatment group was composed of 20 subjects (12 females and 8 males) treated before puberty, while the late-treatment group included 20 subjects (10 females and 10 males) treated at puberty. Statistical comparisons were performed with analysis of variance followed by Tukey's post hoc tests. RESULTS: Significant long-term mandibular changes (Co-Gn) in the treated group (3.6 mm over the controls) were associated with improvements in the skeletal sagittal intermaxillary relationship, overjet, and molar relationship (~3.0-3.5 mm). Treatment during the pubertal peak was able to produce significantly greater increases in total mandibular length (4.3 mm) and mandibular ramus height (3.1 mm) associated with a significant advancement of the bony chin (3.9 mm) when compared with treatment before puberty. CONCLUSION: Treatment of Class II malocclusion with functional appliances appears to be more effective at puberty. PMID- 22931201 TI - Measurement of mini-implant stability using resonance frequency analysis. AB - OBJECTIVE: To investigate whether resonance frequency analysis (RFA) is suitable to measure orthodontic mini-implant stability. Implant size significantly affects the level of resonance frequency. Regarding the operating mode of RFA, it has to be proven whether the resonance frequency of mini-implants in bone fits the range of frequency emitted by the Osstell ISQ device. MATERIAL AND METHODS: For this purpose the SmartPegs in the Osstell ISQ device were modified to fit with the inner screw thread of orthodontic mini-implants, and 110 mini-implants were inserted into porcine pelvic bone. RFA was performed parallel and perpendicular to the run of superficial bone fibers. A suitability test, Periotest, was also performed in the same directions. Compacta thickness was measured using cone-beam computed tomography. Correlation tests and linear regression analysis were carried out between the three methods. RESULTS: The RFA showed a mean Implant Stability Quotient value of 36.36 +/- 2.67, and the Periotest mean value was 2.10 +/- 1.17. The differences between the two directions of measurement were statistically significant (P > .001) for RFA and the Periotest. There was a high correlation between RFA and the Periotest (r = -0.90) and between RFA and compacta thickness (r = 0.71). The comparison between the Periotest and compacta thickness showed a correlation coefficient of r = -0.64. CONCLUSION: The present results suggest that RFA is feasible as a measurement method for orthodontic mini-implant stability. As a consequence, it could be used for clinical evaluation of current stability and allow stability-related loading of mini-implants to reduce the failure rate. PMID- 22931202 TI - The impact of intronic single nucleotide polymorphisms and ethnic diversity for studies on the obesity gene FTO. AB - In 2007, the first common genetic variants were identified, which undoubtedly affect our susceptibility to obesity. These variants are located in the fat mass and obesity-associated gene FTO. Since then, over 50 loci for common obesity have been identified. As the research on these loci is still at an early stage, there is a great need to review, for clarification purposes, the current research on FTO, as this is likely to influence future studies. Based on the current knowledge, FTO seems to be directly involved in the regulation of energy intake, but there is an urgent need for the identification of regulatory polymorphisms. Thus, herein, we discuss current knowledge and highlight putative functional regions in FTO based on published data and computer-based analysis. PMID- 22931203 TI - Surface electrostatic immobilization of thin layers of water on silver halide. Experimental and calculated infrared spectrum of cyclic trimer of water and a ponderal isotope effect. AB - Evaporation of water on a planar AgX surface leads to a strongly bound monolayer for which IR spectra display the marker peaks for modest numbers of oligomers. From 700-1800 spectra for each isotopomer, H(2)O(16) and H(2)O(18), a pair was selected with moderate intensity at 1616 cm(-1) (a peak reported for the cyclic trimer of water) from the monolayer portion of the experiment. Every selected spectrum had lesser peaks for other oligomers. The sum of a spectroscopic pair reveals the vibrational spectra of the cyclic trimers of H(2)O(16) and H(2)O(18). All fundamentals in the mid-IR are seen including the bending, OH stretching, and intramolecular H-bonding regions, the last never previously recognized. The relative prevalence of cyclic trimer can be attributed to the "low" water concentration on the surface. In addition, a ponderal effect leads to higher concentrations of cyclic trimer in the H(2)O(18) spectra than in the H(2)O(16) spectra and allows observation of combination bands in the H(2)O(18) spectra, representing a new type of isotope effect. The spectroscopic results for the two water isotopomers are much more extensive than those obtained through matrix isolation. Remarkably complete spectra of the cyclic trimer are obtained for the first time, especially for H(2)O(18). DFT calculations with the cyclic trimer on a simplified model for the AgCl surface yield spectra consistent with the experimental spectrum. The technique can be extended to other oligomers of water and many other OH compounds. PMID- 22931204 TI - Synthesis of quinoline dicarboxylic esters as biocompatible fluorescent tags. AB - A series of dicarboxylic quinoline derivatives bearing electron-releasing or withdrawing substituents have been synthesized using mono- or/and biphasic methodologies. By controlling the regioselectivity of addition into our electrophilic intermediate, we also characterized by which mechanism the Doebner Miller cyclization step occurred. As anticipated, electron-releasing substituents induce a red shift of the low-energy absorption allowing excitation in the visible region. In addition, by playing on the strength and position of the electron-releasing substituents, chromophore having interesting fluorescent properties such as large Stoke shifts, good fluorescent quantum yields, emission in the visible green-yellow region and reasonable two-photon absorption in the NIR region have been obtained. These small-size fluorophores, which can be made water-soluble and have been shown to be non-toxic, can be hetero- and/or polyfunctionalized and thus represent promising key units for fluorescence-based physiological experiments with low background interactions. PMID- 22931205 TI - Formulation development and statistical optimization of chronotherapeutic tablets of indometacin. AB - Chronotherapeutic drug delivery offers a new approach in the pharmacologic interventions design for the effective treatment in the diseases which follows circadian rhythm. In the present study chronotherapeutic tablets of indometacin was designed to match the timing of rheumatoid arthritis treatment with the intrinsic illness timing. The developed chronotherapeutic delivery system consists of a core tablet containing the active ingredient along with osmogents and other excipients, which was coated with a swellable polymer, hydroxyl propyl methyl cellulose by compression coating technique. The time controlled release was achieved by coating the entire system with a combination of pH-independent polymer, Eudragit RS 100 and Eudragit RL 100 (1:1). The optimization technique using Box-Behnken design was employed for the selection of the ideal formula. The optimization procedure was validated, and the observed value of the ideal batch was found to be similar with the predicted values within 5% of predicted error. The formulation when administered at bed time starts releasing the drug after a lag time of 4 h and provides sufficient plasma concentration after 6 h of normal sleep. Thus, the tablets can be successfully used for the chronotherapeutic drug delivery of indometacin in the treatment of rheumatoid arthritis. PMID- 22931206 TI - Algorithm development for corticosteroid management in systemic juvenile idiopathic arthritis trial using consensus methodology. AB - BACKGROUND: The management of background corticosteroid therapy in rheumatology clinical trials poses a major challenge. We describe the consensus methodology used to design an algorithm to standardize changes in corticosteroid dosing during the Randomized Placebo Phase Study of Rilonacept in Systemic Juvenile Idiopathic Arthritis Trial (RAPPORT). METHODS: The 20 RAPPORT site principal investigators (PIs) and 4 topic specialists constituted an expert panel that participated in the consensus process. The panel used a modified Delphi Method consisting of an on-line questionnaire, followed by a one day face-to-face consensus conference. Consensus was defined as >= 75% agreement. For items deemed essential but when consensus on critical values was not achieved, simple majority vote drove the final decision. RESULTS: The panel identified criteria for initiating or increasing corticosteroids. These included the presence or development of anemia, myocarditis, pericarditis, pleuritis, peritonitis, and either complete or incomplete macrophage activation syndrome (MAS). The panel also identified criteria for tapering corticosteroids which included absence of fever for >= 3 days in the previous week, absence of poor physical functioning, and seven laboratory criteria. A tapering schedule was also defined. CONCLUSION: The expert panel established consensus regarding corticosteroid management and an algorithm for steroid dosing that was well accepted and used by RAPPORT investigators. Developed specifically for the RAPPORT trial, further study of the algorithm is needed before recommendation for more general clinical use. PMID- 22931207 TI - Axial-stressed piezoresistive nanobeam for ultrahigh chemomechanical sensitivity to molecular adsorption. AB - This study proposes nanothickness piezoresistive double-clamped beams that are used in a double-side adsorbing mode. The axially stressed clamped beam exhibits continually increasing sensitivity as it is thinned down to nanoscale, and the thinning is theoretically without limitation. Sensing experiments to part-per million levels of trimethylamine vapor well verify the proposal. A 93 nm thick beam sensor exhibits higher than 1 order of magnitude sensitivity compared to typical piezoresistive cantilever sensors, and its chemomechanical sensing resolution is comparable with that obtained by the off-cantilever optical detection method. With the nanobeam, a surprisingly ultrahigh sensitivity to surface molecular self-assembly induced surface stress is also obtained that is about 150 times higher than that obtained from a conventional cantilever. With additional advantages of elimination of single-sided adsorption induced bimetallic effect noise, tinier size, and easier fabrication, the ultrasensitive nanothick beam sensors show promise to replace the state-of-the-art piezoresistive cantilevers for bio/chemical nanomechanical detection. PMID- 22931208 TI - Comparison of different sampling strategies and laboratory methods for the detection of C. jejuni and C. coli from broiler flocks at primary production. AB - The objective of the study was to evaluate the performance of different combinations of sample type, transport medium and culture methods for the recovery of Campylobacter jejuni and C. coli from broiler flocks at primary production. Boot swabs moistened with one of four different transport media [maximum recovery diluent (n=120), Exeter broth (EX) (n=120), buffered peptone water (n=120) and modified semi-solid Cary-Blair (n=120)], caecal samples (n=40) and faecal samples (n=120) from 40 broiler flocks were compared and sensitivity estimates obtained using a Bayesian model. Samples were cultured onto mCCDA before and after enrichment in EX and incubated microaerobically at 41.5 degrees C. Campylobacter suspect colonies were identified to the species level by multiplex PCR. Results from the Bayesian model indicated that boot swabs after enrichment had higher sensitivity (90-94%) than caecal contents before or after enrichment (84% and 89%, respectively) and faecal samples after enrichment (82%) for the detection of Campylobacter spp., although these differences were not statistically significant. Enrichment significantly increased the sensitivity of boot swab and caecal samples for detection of Campylobacter spp. and C. jejuni, respectively. However, the enrichment of caecal samples resulted in a significant decrease in the sensitivity of these samples for detection of C. coli. There was much greater variation in the sensitivity estimates of the methods for detecting C. coli than for C. jejuni, and the ranking of methods was different between the two species. Boot swabs gave the best sensitivity values for detection of C. jejuni, and enrichment culture of faecal samples was the most sensitive method for detection of C. coli. PMID- 22931210 TI - Testing for minimal consciousness in complex partial and generalized tonic-clonic seizures. AB - Impaired consciousness in epilepsy has a major negative impact on quality of life. Prior work suggests that complex partial seizures (CPS) and generalized tonic-clonic seizures (GTCS), which both cause loss of consciousness, affect similar frontoparietal networks. Milder involvement in CPS than in GTCS may spare some simple behavioral responses, resembling the minimally conscious state. However, this difference in responses has not been rigorously tested previously. During video-electroencephalography (EEG) monitoring, we administered a standardized prospective testing battery including responses to questions and commands, as well as tests for reaching/grasping a ball and visual tracking in 27 CPS (in 14 patients) and 7 GTCS (in six patients). Behavioral results were analyzed in the ictal and postictal periods based on video review. During both CPS and GTCS, patients were unable to respond to questions or commands. However, during CPS, patients often retained minimally conscious ball grasping and visual tracking responses. Patients were able to successfully grasp a ball in 60% or to visually track in 58% of CPS, and could carry out both activities in 52% of CPS. In contrast, during GTCS, preserved ball grasp (10%), visual tracking (11%), or both (7%), were all significantly less than in CPS. Postictal ball grasping and visual tracking were also somewhat better following CPS than GTCS. These findings suggest that impaired consciousness in CPS is more similar to minimally conscious state than to coma. Further work may elucidate the specific brain networks underlying relatively spared functions in CPS, ultimately leading to improved treatments aimed at preventing impaired consciousness. PMID- 22931209 TI - miRNA-21 is developmentally regulated in mouse brain and is co-expressed with SOX2 in glioma. AB - BACKGROUND: MicroRNAs (miRNAs) and their role during tumor development have been studied in great detail during the last decade, albeit their expression pattern and regulation during normal development are however not so well established. Previous studies have shown that miRNAs are differentially expressed in solid human tumors. Platelet-derived growth factor (PDGF) signaling is known to be involved in normal development of the brain as well as in malignant primary brain tumors, gliomas, but the complete mechanism is still lacking. We decided to investigate the expression of the oncogenic miR-21 during normal mouse development and glioma, focusing on PDGF signaling as a potential regulator of miR-21. METHODS: We generated mouse glioma using the RCAS/tv-a system for driving PDGF-BB expression in a cell-specific manner. Expression of miR-21 in mouse cell cultures and mouse brain were assessed using Northern blot analysis and in situ hybridization. Immunohistochemistry and Western blot analysis were used to investigate SOX2 expression. LNA-modified siRNA was used for irreversible depletion of miR-21. For inhibition of PDGF signaling Gleevec (imatinib mesylate), Rapamycin and U0126, as well as siRNA were used. Statistical significance was calculated using double-sided unpaired Student's t-test. RESULTS: We identified miR-21 to be highly expressed during embryonic and newborn brain development followed by a gradual decrease until undetectable at postnatal day 7 (P7), this pattern correlated with SOX2 expression. Furthermore, miR-21 and SOX2 showed up-regulation and overlapping expression pattern in RCAS/tv-a generated mouse brain tumor specimens. Upon irreversible depletion of miR-21 the expression of SOX2 was strongly diminished in both mouse primary glioma cultures and human glioma cell lines. Interestingly, in normal fibroblasts the expression of miR-21 was induced by PDGF-BB, and inhibition of PDGF signaling in mouse glioma primary cultures resulted in suppression of miR-21 suggesting that miR-21 is indeed regulated by PDGF signaling. CONCLUSIONS: Our data show that miR-21 and SOX2 are tightly regulated already during embryogenesis and define a distinct population with putative tumor cell of origin characteristics. Furthermore, we believe that miR-21 is a mediator of PDGF-driven brain tumors, which suggests miR 21 as a promising target for treatment of glioma. PMID- 22931211 TI - beta-Secretase (BACE1) inhibitory property of loganin isolated from Corni fructus. AB - In the course of searching for anti-dementia agents from natural products, loganin isolated from EtOAc fraction of Corni fructus possessed specific inhibitory activity against beta-secretase (BACE1) with 9.2 * 10-5 M and K(i) value of 5.5 * 10-5 M. Loganin exhibited less inhibitory activity to alpha secretase (TACE) and other serine proteases exhibiting that it was a relatively specific inhibitor of BACE1. These novel findings suggest that loganin may be used to attenuate the progression and/or prevention of Alzheimer's disease. PMID- 22931212 TI - Elucidation of the mechanism of ribose conjugation in a pyrazole-containing compound in rodent liver. AB - 1. Here we report on the mechanism of ribose conjugation, through NADH as a cofactor, of a pyrazole-containing compound (PT). Incubation of PT in rat liver microsomes supplemented with NADP+/H, NAD+/H, and beta-nicotinamide mononucleotide (NMN) resulted in complete conjugation to the adenine dinucleotide phosphate conjugate (ADP-C), adenine dinucleotide conjugate (AD-C), and 5 phosphoribose conjugate (Rib-C1), respectively. In hepatocytes, PT predominantly formed three ribose conjugates: Rib-C1, the ribose conjugate (Rib-C2), and the carboxylic acid of Rib-C2 (Rib-C3). 2. Phosphatase inhibitors were added to hepatocyte incubations. AD-C was detected in this reaction, which suggests that one of the major pathways for the formation of the ribose conjugates is through NAD+/H. When AD-C was incubated with phosphatase, Rib-C1 and Rib-C2 formed. 3. To understand the in vivo relevance of this metabolic pathway, rats were dosed with PT and Rib-C2 was found in the urine. 4. Structure-activity relationship shows that replacement of the distal thiazole group in the PT to a phenyl group abolishes this conjugation. Three amino acid residues in the active site preferentially interact with the sulfur atom in the thiazole of PT. 5. In summary, PT forms direct AD-C in hepatocytes, which is further hydrolyzed by phosphatase to give ribose conjugates. PMID- 22931213 TI - Update on hydrocodone metabolites in rats and dogs aided with a semi-automatic software for metabolite identification Mass-MetaSite. AB - 1. There has been a lack of in vivo metabolite profiling update of hydrocodone since the original report on species differences was published in 1978. As such, the mechanism for its analgesic activity in different species has been ambiguous. To address safety concern from regulatory agencies, hydrocodone metabolite profiles in rats and dogs are updated herein aided by a newly developed software, Mass-MetaSite. 2. Samples collected from rats and dogs dosed orally with hydrocodone were analyzed with reversed phase liquid chromatography coupled with LTQ-Orbitrap. The exact mass measurement data collected with data-dependent acquisition methodology were analyzed both traditionally, using Xcalibur Qual Browser and MetWorks, and by Mass-MetaSite. 3. Profiling of hydrocodone metabolites in rat and dog plasma reflected previously reported species differences in circulating metabolites. While hydrocodone mainly underwent O demethylation and ketone reduction in rats forming hydromorphone and reduced hydromorphone, which were then subsequently cleared via glucuronide conjugation, hydrocodone in dogs was cleared predominantly by N-demethylation and N-oxidation. 4. Given the success ratio of metabolite detection offered by Mass-MetaSite, the software will be able to aid chemists in early identification of drug metabolites from complex biomatrices. PMID- 22931214 TI - Series of mixed uranyl-lanthanide (Ce, Nd) organic coordination polymers with aromatic polycarboxylates linkers. AB - Three series of mixed uranyl-lanthanide (Ce or Nd) carboxylate coordination polymers have been successfully synthesized by means of a hydrothermal route using either conventional or microwave heating methods. These compounds have been prepared from mixtures of uranyl nitrate, lanthanide nitrate together with phthalic acid (1,2), pyromellitic acid (3,4), or mellitic acid (5,6) in aqueous solution. The X-ray diffraction (XRD) single-crystal revealed that the phthalate complex (UO(2))(4)O(2)Ln(H(2)O)(7)(1,2-bdc)(4).NH(4).xH(2)O (Ln = Ce(1), Nd(2); x = 1 for 1, x = 0 for 2), is based on the connection of tetranuclear uranyl centered building blocks linked to discrete monomeric units LnO(2)(H(2)O)(7) via the organic species to generate infinite chains, intercalated by free ammonium cations. The pyromellitate phase (UO(2))(3)Ln(2)(H(2)O)(12)(btec)(3).5H(2)O (Ce(3), Nd(4)) contains layers of monomeric uranyl-centered hexagonal and pentagonal bipyramids linked via the carboxylate arms of the organic molecules. The three-dimensionality of the structure is ensured by the connection of remaining free carboxylate groups with isolated monomeric units LnO(2)(H(2)O)(7). The network of the third series (UO(2))(2)(OH)Ln(H(2)O)(7)(mel).5H(2)O (Ce(5), Nd(6)) is built up from dinuclear uranyl units forming layers through connection with the mellitate ligands, which are further linked to each other through discrete monomers LnO(3)(H(2)O)(6). The thermal decomposition of the various coordination complexes led to the formation of mixed uranium-lanthanide oxide, with the fluorite-type structure at 1500 degrees C (for 1, 2) or 1400 degrees C for 3-6. Expected U/Ln ratio from the crystal structures were observed for compounds 1-6. PMID- 22931215 TI - Impact of poroelasticity of intraluminal thrombus on wall stress of abdominal aortic aneurysms. AB - BACKGROUND: The predictions of stress fields in Abdominal Aortic Aneurysm (AAA) depend on constitutive descriptions of the aneurysm wall and the Intra-luminal Thrombus (ILT). ILT is a porous diluted structure (biphasic solid-fluid material) and its impact on AAA biomechanics is controversially discussed in the literature. Specifically, pressure measurements showed that the ILT cannot protect the wall from the arterial pressure, while other (numerical and experimental) studies showed that at the same time it reduces the stress in the wall. METHOD: To explore this phenomenon further a poroelastic description of the ILT was integrated in Finite Element (FE) Models of the AAA. The AAA model was loaded by a pressure step and a cyclic pressure wave and their transition into wall tension was investigated. To this end ILT's permeability was varied within a microstructurally motivated range. RESULTS: The two-phase model verified that the ILT transmits the entire mean arterial pressure to the wall while, at the same time, it significantly reduces the stress in the wall. The predicted mean stress in the AAA wall was insensitive to the permeability of the ILT and coincided with the results of AAA models using a single-phase ILT description. CONCLUSION: At steady state, the biphasic ILT behaves like a single-phase material in an AAA model. Consequently, computational efficient FE single-phase models, as they have been exclusively used in the past, accurately predict the wall stress in AAA models. PMID- 22931216 TI - Impact of tumor-associated macrophages on invasive ductal carcinoma of the pancreas head. AB - Tumor-associated macrophages (TAMs) are candidate histological factors in invasive ductal carcinoma (IDC) of the pancreas. Tumor-associated macrophages can be affected by cancer-related inflammation and pancreatitis and interact with important invasive behavior in a recurrent manner in pancreatic IDC. These features may help elucidate the aggressiveness of pancreatic IDC. The aim of this study was to characterize TAMs in pancreatic IDC in comparison with chronic pancreatitis (CP) and to reveal TAM-related factors and the clinical impact of TAMs. CD68 (a pan-macrophage marker) and CD204 (an M2 macrophage marker) immunohistochemistry was carried out in pancreas head specimens from 107 IDC cases and 11 CP cases. Immunopositive cell areas were calculated at the periphery and center of the tumor. The distributions of macrophages in IDC and CP and the relationship between TAMs and histological tumor factors, survival, and recurrence were evaluated. Macrophages were more frequently observed in the lesion periphery than the center in IDC and CP. The density of macrophages was elevated in IDC compared to CP. Dense M2 macrophages at the tumor periphery were frequently seen in large tumors and showed an independent impact on overall survival and disease-free time. Early recurrence in the liver or the local manipulated area was associated with high accumulation of peripheral M2 macrophages. More M2 macrophages were seen in IDC than in CP in both the periphery and the center. High numbers of peripheral M2 macrophages were associated with large tumor size, early recurrence in the liver, local recurrence, and shortened survival time in patients with pancreatic IDC. PMID- 22931217 TI - Elucidation of the multiple roles of CheD in Bacillus subtilis chemotaxis. AB - Chemotaxis by Bacillus subtilis requires the CheD protein for proper function. In a cheD mutant when McpB was the sole chemoreceptor in B. subtilis, chemotaxis to asparagine was quite good. When McpC was the sole chemoreceptor in a cheD mutant, chemotaxis to proline was very poor. The reason for the difference between the chemoreceptors is because CheD deamidates Q609 in McpC and does not deamidate McpB. When mcpC-Q609E is expressed as the sole chemoreceptor in a cheD background, chemotaxis is almost fully restored. Concomitantly, in vitro McpC activates the CheA kinase poorly, whereas McpC-Q609E activates it much more. Moreover, CheD, which activates chemoreceptors, binds better to McpC-Q609E compared with unmodified McpC. Using hydroxyl radical susceptibility in the presence or absence of CheD, the most likely sites of CheD binding were the modification sites where CheD, CheB and CheR carry out their catalytic activities. Thus, CheD appears to have two separate roles in B. subtilis chemotaxis - to bind to chemoreceptors to activate them as part of the CheC/CheD/CheYp adaptation system and to deamidate selected residues to activate the chemoreceptors and enable them to mediate amino acid chemotaxis. PMID- 22931218 TI - SWEET--where are we heading with international type 1 diabetes registries? PMID- 22931219 TI - Heterogeneity in the systems of pediatric diabetes care across the European Union. AB - BACKGROUND: It is known that the systems of pediatric diabetes care differ across the member states of the European Union (EU). The aim of this project was to characterize some of the main differences among the national systems. METHODS: Data were collected using two questionnaires. The first one was distributed among leading centers of pediatric diabetes (one per country) with the aim of establishing an overview of the systems, national policies, quality control (QC) and financing of pediatric diabetes care. Responses were received from all 27 EU countries. The second questionnaire was widely disseminated among all 354 International Society for Pediatric and Adolescent Diabetes members with a domicile in an EU country; it included questions related to individual pediatric diabetes centers. A total of 108 datasets were collected and processed from healthcare professionals who were treating more than 29 000 children and adolescents with diabetes. Data on the reimbursement policies were verified by representatives of the pharmaceutical and medical device companies. RESULTS: The collected data reflect the situation in 2009. There was a notable heterogeneity among the systems for provision of pediatric diabetes care across the EU. Only 20/27 EU countries had a pediatric diabetes register. Nineteen countries had officially recognized centers for pediatric diabetes, but only nine of them had defined criteria for becoming such a center. A system for QC of pediatric diabetes at the national level was reported in 7/26 countries. Reimbursement for treatment varied significantly across the EU, potentially causing inequalities in access to modern technologies. CONCLUSIONS: The collected data help develop strategies toward improving equity and access to modern pediatric diabetes care across Europe. PMID- 22931220 TI - Harmonize care to optimize outcome in children and adolescents with diabetes mellitus: treatment recommendations in Europe. AB - OBJECTIVE: Identify and evaluate current treatment recommendations in Europe for the care of children with diabetes in view of the European Union (EU) recommendations for Reference Centers. METHODS: A questionnaire was sent in 2008 to representatives of all EU countries and Norway, all known to be actively involved in pediatric diabetes care. Participants were asked whether specific guidelines were recommended and applied in their countries; when possible, they were invited to forward their national guidelines. As a second step, we evaluated the guideline mostly used in relationship to the recommendations of the EU. RESULTS: Information was obtained from all EU countries (including Scotland and Norway). National guidelines, as available, were forwarded for review. A 15/29 reported to use the International Society for Pediatric and Adolescent Diabetes (ISPAD) Clinical Practice Consensus Guidelines (CPCG), whereas 10 reported using national guidelines. These national guidelines were partly based on and/or compatible with ISPAD guidelines, but in most cases were far less detailed. The size and presentation differed (web based, booklet, page or chapter in adult guidelines). In four countries, no specific guidelines were used. As ISPAD CPCG were used most frequently, its content was evaluated within the EU Centres of Reference recommendations and minor changes were made in agreement with the ISPAD editor. DISCUSSION: Differences between guidelines may influence surveillance and quality of care in pediatric diabetes within Europe. Although a majority of countries is using or at least mentioning the ISPAD CPCG, their implementation as EU standard needs further endorsement. As language difficulties may hamper its implementation on a wider scale, further translation of the ISPAD guidelines should be endorsed to render it accessible to all healthcare professionals. With respect to the content, some changes were then made in agreement with the editors, adjusting them to the European context. For European Reference Centers, some further guidance on research may be included. Once implemented on an EU wide level, benchmarking of carefully defined robust quality of care and quality of life indicators will allow us to improve these guidelines on a regular basis ensuring an evidence-based care for all children with diabetes. PMID- 22931221 TI - Recommendations for age-appropriate education of children and adolescents with diabetes and their parents in the European Union. AB - Education is the keystone of diabetes care, and structured self-management education is the key to a successful outcome. Existing guidelines provide comprehensive guidance on the various aspects of education and offer general and organizational principles of education, detailed curricula at different ages and stages of diabetes, and recommendations on models, methods, and tools to attain educative objectives. The International Society for Pediatric and Adolescent Diabetes guidelines give the most elaborate and detailed descriptions and recommendations on the practice of education, which other national guidelines address on specific aspects of education and care. The aim of the work package on education developed by Better Control in Paediatric and Adolescent Diabetes in the European Union: Working to Create Centers of Reference (SWEET) project was not to generate new guidelines but to evaluate how the existing guidelines were implemented in some pediatric diabetes reference centers. The SWEET members have completed a questionnaire that elaborates on the many aspects of delivery of education. This survey highlights a profound diversity of practices across centers in Europe, in terms of organization as well as the practices and the content of initial and continuing education. A toolbox is being developed within SWEET to facilitate exchanges on all aspects of education and to establish a process of validation of materials, tools, written structured age-adjusted programs, and evaluation procedures for the education of children and adolescents with diabetes. PMID- 22931222 TI - Good practice recommendations on paediatric training programmes for health care professionals in the EU. AB - Part of the SWEET Project: EU (European Union), Better Control in Paediatric and Adolescent Diabetes: Working to Create Centres of Reference, was specifically to examine the training of health care professionals (HCPs) across the EU. Several types of information were collected during 2009, and these included a literature search, workshops of the SWEET members, examination of the data collected by the Hvidore Study Group and the Diabetes Attitudes, Wishes, and Needs (DAWN) Youth initiative, and a questionnaire distributed to SWEET members and professional colleagues who cared for children and young people (CYP) with diabetes. It was clear from the information collected that there was no European or global consensus either on a curriculum for the training of the paediatric diabetes multidisciplinary team (MDT) or individual professions in paediatric diabetes. A minority of countries had well-established training but, for the majority, there was little standardisation or accreditation. Moreover, most countries did not have available courses for training the diabetes MDT and training was not mandatory. Of the courses that were available more were accredited for doctors and nurses but fewer for the other professions. As a consequence, the majority of HCP posts in paediatric diabetes do not demand prior experience in the specialty. Standardised accredited training and continuous professional development (CPD) opportunities are severely limited. The SWEET Project supports a standardised, accredited approach to training and CPD of the MDT and for individual professions. As a consequence, a curriculum for the training of the MDT was developed, and this is now ready for implementation. PMID- 22931224 TI - A pediatric diabetes toolbox for creating centres of reference. AB - INTRODUCTION: ISPAD guidelines recommend age appropriate diabetes education concepts for young patients and their families as well as tools for nutritional management, psychosocial assessment, and psychological advice but their implementation in Europe is presently unknown. METHODS: On the basis of a structured survey among the European SWEET members information on established tools and programs in national languages were analyzed using an extensive literature and desk search. These were differentiated according to five age groups and five target groups (young people with diabetes, parents, and other close relations, carers in school and nursery, and healthcare professionals). RESULTS: Responses and original tools were received from 11 SWEET countries reflecting the European status in 2011. More or less structured information for parents, close relations, and carers in school or nursery are available in all 11 participating countries. However, only two countries followed the recommendations of having published a structured, curriculum lead, and evaluated program for different age-groups and carers. One of these was evaluated nationwide and funded by the respective National Health Care System after accreditation. In addition a huge variety of creative tools, e.g., booklets, leaflets, games, videos, and material for educating children of different age-groups and their parents are available - but most of them are not linked to a structured education program. CONCLUSIONS: Harmonizing and integrating these materials into quality assured structured holistic national education programs will be an important future task for the ongoing SWEET project. A comprehensive European diabetes educational toolbox is aimed to be published and continuously updated on the SWEET website. PMID- 22931225 TI - Criteria for Centers of Reference for pediatric diabetes--a European perspective. AB - 'SWEET' is an acronym standing for 'Better control in pediatric and adolescent diabeteS: Working to crEate CEnTers of Reference (CORs)' and is based on a partnership of established national and European diabetes organizations such as International Diabetes Federation, Federation of European Nurses in Diabetes, and Primary Care Diabetes Europe (PCDE, www.sweet-project.eu). A three-level classification of centers has been put forward. In addition to centers for local care, SWEET collaborating centers on their way to being a COR have been defined. Peer-audited CORs with a continuous electronic documentation of at least 150 pediatric patients with diabetes treated by a multidisciplinary team based on the International Society for Pediatric and Adolescent Diabetes (ISPAD) Clinical Practice recommendations have been created in 12 European countries. In 2011, they cared for between 150 to more than 700 youth with diabetes with an average hemoglobin A1c between 7.6 and 9.2%. Although these clinics should not be regarded as representative for the whole country, the acknowledgment as COR includes a common objective of targets and guidelines as well as recognition of expertise in treatment and education at the center. In a first step, the SWEET Online platform allows 12 countries using 11 languages to connect to one unified diabetes database. Aggregate data are de-identified and exported for longitudinal health and economic data analysis. Through their network, the CORs wish to obtain political influence on a national and international level and to facilitate dissemination of new approaches and techniques. The SWEET project hopes to extend from the initial group of centers within countries, throughout Europe, and beyond with the help of the ISPAD network. PMID- 22931223 TI - Technical solution for data collection, data safety and data privacy legislation: experiences from the SWEET study. AB - BACKGROUND: One of the most important tasks of the SWEET study is benchmarking the data collected. Information on the occurrence of the disease of diabetes, the treatment, and their outcomes in children from the different member states of European Union (EU) is crucial. How the collection of data is realized is essential, concerning both the technical issues and the results. The creation of SWEET Centers of Reference (CoR), all over Europe will be facilitated by the access to safe data collection, where legal aspects and privacy are ascertained. OBJECTIVE: To describe the rationale for- and the technical procedure in the data collection implementation, in the SWEET study. SUBJECTS: Selected data on all patients treated at SWEET CoR are collected. METHODS: The SWEET project data collection and management system, consists of modular components for data collection, online data interchange, and a database for statistical analysis. CONCLUSION: The SWEET study and the organization of CoR aims for the goal of offering an updated, secure, and continuous evaluation of diabetes treatment regimens for all children with diabetes in Europe. To support this goal, an appropriate and secure data management system as described in this paper has been created. PMID- 22931226 TI - Ultracold molecules formed by photoassociation: heteronuclear dimers, inelastic collisions, and interactions with ultrashort laser pulses. PMID- 22931228 TI - What business are we in? The emergence of health as the business of health care. PMID- 22931227 TI - A benzobisimidazolium-based fluorescent and colorimetric chemosensor for CO2. AB - A new sensor for the fluorescent and colorimetric detection of CO(2) is described. The system utilizes fluoride to activate a tetrapropyl benzobisimidazolium salt and operates in the absence of an exogenous base. On the basis of spectroscopic and theoretical analyses, the mode of action of the present system is ascribed to the fluoride-induced formation of an N-heterocyclic carbene intermediate that reacts with CO(2) to form an imidazolium carboxylate. PMID- 22931229 TI - The risk of proliferative retinopathy in siblings with Type 1 diabetes. AB - AIMS: The siblings first affected by Type 1 diabetes (probands) within a sibship have been shown to have a lower age at onset of Type 1 diabetes compared with their later-affected siblings. The aim of the present study was to investigate whether this difference affects the long-term risk of proliferative diabetic retinopathy. METHODS: A cohort of 396 siblings with Type 1 diabetes in 188 sibships was drawn from a larger Finnish Diabetic Nephropathy Study population (4800 patients). Ophthalmic records were obtained for 369/396 (93%) patients. Retinopathy was graded based on fundus photographs and/or repeated ophthalmoscopies. RESULTS: The median age at onset of Type 1 diabetes was 8.4 (interquartile range 4.2-13.3) years in probands and 16.9 (interquartile range 10.2-27.8) years in later-affected siblings (P < 0.001). Proliferative retinopathy was diagnosed in 115/369 (31%) patients. The cumulative incidence estimates for proliferative retinopathy, accounting for the competing risk of death, were 21% (95% CI 15-27) in probands and 26% (95% CI 19-35) in later affected siblings at 20 years of diabetes duration, and the respective 30 years' incidences were 37% (95% CI 29-45) and 53% (95% CI 40-64), (P = 0.05, Gray's test). The risk of proliferative retinopathy, adjusted for conventional risk factors, age at onset and sibship size, was higher in later-affected siblings [hazard ratio 1.75 (95% CI 1.13-2.75), P = 0.01] compared with their probands. CONCLUSION: The siblings first affected by Type 1 diabetes had a better long-term prognosis with regards to development of proliferative retinopathy compared with their later-affected siblings. PMID- 22931230 TI - Photoluminescence enhancement in CdS quantum dots by thermal annealing. AB - The photoluminescence behavior of CdS quantum dots in initial growth stage was studied in connection with an annealing process. Compared to the as-synthesized CdS quantum dots (quantum efficiency ? 1%), the heat-treated sample showed enhanced luminescence properties (quantum efficiency ? 29%) with a narrow band edge emission. The simple annealing process diminished the accumulated defect states within the nanoparticles and thereby reduced the nonradiative recombination, which was confirmed by diffraction, absorption, and time-resolved photoluminescence. Consequently, the highly luminescent and defect-free nanoparticles were obtained by a facile and straightforward process. PMID- 22931231 TI - Physicochemical characterization of a low-molecular-weight fructooligosaccharide from Chinese Cangshan garlic (Allium sativum L.). AB - A novel low-molecular-weight fructooligosaccharide (LMWF) from garlic ( Allium sativum ) was isolated and identified. The structure and physicochemical properties of the LMWF were determined by chemical and spectroscopic methods, size-exclusion chromatography, atomic force microscopy (AFM), dynamic rheometry, and differential scanning calorimetry (DSC). The results showed that the LMWF was a neo-ketose with a molecular weight of 1770 Da. The LMWF had a (2,1)-linked beta D-Fruf backbone with (2,6)-linked beta-D-Fruf side chains, and it was mainly composed of fructose. The branch degree was 18.1%, and the intrinsic viscosity was 3.06 mL/g. The spherical particles of the LMWF were observed by AFM, and their size was relatively uniform. With an increase in the water content, the peak temperature (T(p)), onset temperature (T(o)), and endset temperature (T(c)) increased, while the gelatinization enthalpy (DeltaH(gel)) decreased. The LMWF was more stable at a water content of 10%. PMID- 22931232 TI - Oligofluorenes as polymeric model compounds for providing insight into the triplets of ketone and ketylimine derivatives. AB - A series of oligofluorenes ranging between one and three repeating units were prepared as structurally well-defined representative models of polyfluorenes. The photophysics of the oligofluorene models were investigated both by laser flash photolysis and steady-state fluorescence. The effects of the ketone and ketylimine functional groups in the 9-position on the photophysical properties, notably the triplet quantum yield (Phi(TT)) by intersystem crossing and the absolute fluorescence quantum yields (Phi(fl)), were investigated. The singlet depletion method was used to determine both the Phi(TT) and molar absorption coefficients of the observed triplets (epsilon(TT)). Meanwhile, the absolute Phi(fl) were determined using an integrating sphere. It was found that both the ketone and ketylimine substituents and the degree of oligomerization contributed to quenching the oligofluorene fluorescence. For example, the Phi(fl) was quenched 5-fold with the ketylimine and ketone substituents for the bifluorenyl derivatives compared to their corresponding 9,9-dihexyl bifluorenyl counterparts. Meanwhile, the Phi(fl) quenching increased 14 times with the trifluorenyl ketone and ketylimine derivatives. Measured Phi(TT) values ranged between 22 and 43% for the difluorenyl derivatives with epsilon(TT) on the order of 13 000 cm(-1) M(-1). The Phi(TT) decreased to <10% concomitant with doubling of the epsilon(TT) when the degree of oligomerization was increased to 3. A new fluorescence emission at 545 nm formed at low temperatures for the ketone and ketylimine oligofluorene derivatives. The emission intensity was dependent on the temperature, and it disappeared at room temperature. PMID- 22931233 TI - Downregulation of platelet activation markers during long-term immobilization. AB - Immobilization and sedentary lifestyle are risk factors for venous thromboembolism and cardiovascular disease, yet little is known about platelet function during long-term physical inactivity. Our aim was to investigate platelet activation markers and their coupling to standardized immobilization: platelet-derived growth factor (PDGF-BB) and P-selectin. We studied 15 healthy females participating in the Women International Space simulation for Exploration study. Following a 20-day ambulatory control period, the subjects underwent 60 days of bed rest in head-down tilt position (-6 degrees ) 24 hours a day, finalized by 20 days of recovery. The subjects were randomized into two groups during bed rest: a control group (n = 8) that remained physically inactive and an exercise group (n = 7) that participated in both supine resistance and aerobic exercise training. Blood samples for the analysis of platelet activation markers were collected at baseline (5 days before bed rest), after 44 days of bed rest and 8 days into the recovery period. Compared to baseline, the levels of P selectin and PDGF-BB decreased after bed rest (by 55%, p = 0.01 and 73%, p < 0.03, respectively) and remained decreased in the recovery period (by 76%, p < 0.001 and 78%, p < 0.02, respectively, compared to baseline). Platelet count (baseline value for the exercise group 260 000/ul +/- 34 000 and baseline value for the control group 210 000/ul +/- 30 000) did not change during the bed rest study (two-way repeated measurements ANOVA, p = ns). There were no statistical differences between the physically inactive and the exercise group. During long term immobilization, a known risk factor for thrombosis, the levels of P-selectin and PDGF-BB decreased. Our findings indicate downregulation of platelet activation during immobilization. PMID- 22931235 TI - Hydrophobic attraction between silanated silica surfaces in the absence of bridging bubbles. AB - The interaction forces between silanated silica surfaces on which there were neither nanobubbles nor a gas phase were measured using colloidal probe atomic force microscopy (AFM). To obtain hydrophobic surfaces without attached nanobubbles, an aqueous solution was introduced between the surfaces after an exchange process involving several solvents. In the approaching force curves obtained, an attractive force was observed from a distance of 10-25 nm, indicating the existence of an additional attractive force stronger than the van der Waals attraction. In the retracting force curves, a strong adhesion force was observed, and the value of this force was comparable to that of the capillary bridging force. The data clearly showed that although the bridging of nanobubbles is responsible for long-range hydrophobic attraction, there also exists an additional attractive force larger than the van der Waals attraction between hydrophobic surfaces without nanobubbles. Both the ionic strength and the temperature of the solution had little influence on the force. The possible origin of the force is discussed on the basis of the obtained results. PMID- 22931234 TI - Isotope effects suggest a stepwise mechanism for berberine bridge enzyme. AB - The flavoprotein Berberine Bridge Enzyme (BBE) catalyzes the regioselective oxidative cyclization of (S)-reticuline to (S)-scoulerine in an alkaloid biosynthetic pathway. A series of solvent and substrate deuterium kinetic isotope effect studies were conducted to discriminate between a concerted mechanism, in which deprotonation of the substrate phenol occurs before or during the transfer of a hydride from the substrate to the flavin cofactor and substrate cyclization, and a stepwise mechanism, in which hydride transfer results in the formation of a methylene iminium ion intermediate that is subsequently cyclized. The substrate deuterium isotope effect of 3.5 on k(red), the rate constant for flavin reduction, is pH-independent, indicating that C-H bond cleavage is rate-limiting during flavin reduction. Solvent isotope effects on k(red) are equal to 1 for both wild-type BBE and the E417Q mutant, indicating that solvent exchangeable protons are not in flight during or before flavin reduction, thus eliminating a fully concerted mechanism as a possibility for catalysis by BBE. An intermediate was not detected by rapid chemical quench or continuous-flow mass spectrometry experiments, indicating that it must be short-lived. PMID- 22931237 TI - Quartz resonator for simultaneously measuring changes in the mass and electrical resistance of a polyaniline film. AB - A novel quartz resonator was developed to measure, simultaneously, changes in the mass and electrical resistance of a polyaniline film during the absorption of water vapor. Interdigitated gold electrodes were vacuum-deposited on the sensing surfaces of the quartz crystals, and polyaniline films were drop-cast on the electrodes used to measure the changes in the electrical resistance. Two symmetric semicircular gold electrodes were deposited on the bottom surface of the quartz crystal. These electrodes were used to measure the changes in the mass of absorbed water based on the changes in the resonance frequency. The simultaneous measurements of mass and electrical resistance shed light on the interactions between the water vapor and the polyaniline film. The resonator was exposed to various organic gases, including ethanol, acetone, or chloroform, and each gas was found to produce characteristic changes in the normalized electrical resistance. PMID- 22931238 TI - Three-dimensional optical trapping and manipulation of single silver nanowires. AB - We report the first experimental realization of all-optical trapping and manipulation of plasmonic nanowires in three dimensions. The optical beam used for trapping is the Fourier transform of a linearly polarized Bessel beam (termed FT-Bessel). The extended depth of focus of this beam enables the use of a retroreflection geometry to cancel radiation pressure in the beam propagation direction, making it possible to trap highly scattering and absorbing silver nanowires. Individual silver nanowires with lengths of several micrometers can be positioned by the trapping beam with a precision better than 100 nm and are oriented by the polarization of the trapping light with a precision of approximately 1 degrees . Multiple nanowires can be trapped simultaneously in spatially separated maxima of the trapping field. Since trapping in the interferometric FT-Bessel potential is robust in bulk solution and near surfaces, it will enable the controlled assembly of metal nanowires into plasmonic nanostructures. PMID- 22931236 TI - Rapid compensatory changes in the expression of EAAT-3 and GAT-1 transporters during seizures in cells of the CA1 and dentate gyrus. AB - BACKGROUND: Epilepsy is a neurological disorder produced by an imbalance between excitatory and inhibitory neurotransmission, in which transporters of both glutamate and GABA have been implicated. Hence, at different times after local administration of the convulsive drug 4-aminopyridine (4-AP) we analyzed the expression of EAAT-3 and GAT-1 transporter proteins in cells of the CA1 and dentate gyrus. METHODS: Dual immunofluorescence was used to detect the co localization of transporters and a neuronal marker. In parallel, EEG recordings were performed and convulsive behavior was rated using a modified Racine Scale. RESULTS: By 60 min after 4-AP injection, EAAT-3/NeuN co-labelling had increased in dentate granule cells and decreased in CA1 pyramidal cells. In the latter, this decrease persisted for up to 180 min after 4-AP administration. In both the DG and CA1, the number of GAT-1 labeled cells increased 60 min after 4-AP administration, although by 180 min GAT-1 labeled cells decreased in the DG alone. The increase in EAAT-3/NeuN colabelling in DG was correlated with maximum epileptiform activity and convulsive behavior. CONCLUSIONS: These findings suggest that a compensatory mechanism exists to protect against acute seizures induced by 4-AP, whereby EAAT-3/NeuN cells is rapidly up regulated in order to enhance the removal of glutamate from the extrasynaptic space, and attenuating seizure activity. PMID- 22931239 TI - Characterization of in vitro metabolites of CP 47,497, a synthetic cannabinoid, in human liver microsomes by LC-MS/MS. AB - CP 47,497, a potent cannabinoid receptor type 1 agonist, is the main active ingredient in the herbal mixture "Spice" sold in European countries. The illegal use of "Spice" for its psychoactive effects has become a social issue. In this study, the in vitro metabolism of CP 47,497 was investigated in human liver microsomes to characterize the metabolic fate of CP 47,497. CP 47,497 was incubated with human liver microsomes, and the reaction mixture was analyzed using liquid chromatography-tandem mass spectrometry. A total of eight metabolites were detected in human liver microsomes and structurally characterized based on mass spectral data. The main metabolic pathways involved hydroxylations or oxygenations. The identified metabolites were mono-oxygenated metabolites (M1 and M4), mono-hydroxylated metabolites (M3, M5, M6, M7, and M8), and a di-oxygenated metabolite (M2). The detection of these metabolites could confirm the presence of CP 47,497 in biological samples; therefore, collectively, they would be excellent indicators of "Spice" drug abuse. PMID- 22931241 TI - Retrospective evaluation of vacuum-assisted peritoneal drainage for the treatment of septic peritonitis in dogs and cats: 8 cases (2003-2010). AB - OBJECTIVE: To describe the use of vacuum-assisted peritoneal drainage (VAPD) in dogs and cats with septic peritonitis. DESIGN: Retrospective descriptive study. SETTING: University Veterinary Teaching Hospital. ANIMALS: Six dogs and 2 cats with septic peritonitis. INTERVENTIONS: Application of VAPD after abdominal exploration. MEASUREMENTS: Pre- and post-operative physical and clinicopathologic data, surgical findings, treatment, VAPD fluid production, outcome, and survival are reported. MAIN RESULTS: Eight nonconsecutive cases of septic peritonitis, consisting of 6 dogs and 2 cats, were treated surgically and had VAPD applied post-operatively. The mean duration of clinical signs prior to surgical intervention was 4 +/- 3 days. VAPD therapy was applied for a mean of 2 +/- 1.1 days and collected a median of 27 mL/kg/d of abdominal effusate. The median time in hospital was 5 days and abdominal closure was completed in 5 of the 8 patients. All specimens collected at surgery cultured positive for bacteria, most commonly Enterococcus spp. The peritoneum of 4 animals was cultured at the time of abdominal closure; 1 was negative and 3 were positive for Escherichia coli, Enterococcus spp. or gram-positive cocci. Cultures before and after surgery differed in 2 patients. Hypoproteinemia was present in all patients postoperatively. Three patients were considered survivors, all of which were dogs. Five patients died or were euthanized due to cardiopulmonary arrest (n = 3), pyothorax (n = 1), and acute, severe, septic peritonitis (n = 1). CONCLUSIONS: VAPD is available for maintaining abdominal drainage for the treatment of septic peritonitis after surgical intervention; however, similar to open abdominal drainage and closed suction drainage, nosocomial infection and hypoproteinemia remain challenges in the treatment of septic peritonitis. PMID- 22931240 TI - Benefits of early systemic antibiotics in localized aggressive periodontitis: a retrospective study. AB - BACKGROUND: Treatment of localized aggressive periodontitis (LAP) may include systemic antibiotics, yet it is unclear at what stage of treatment planning antibiotics are most effective. AIM: This retrospective analysis compared immediate versus delayed antibiotic therapy on clinical parameters and gingival crevicular fluid (GCF) inflammatory mediators. MATERIAL AND METHODS: At baseline, 3 months and 6 months after treatment, clinical parameters [probing depth (PD), clinical attachment level (CAL), bleeding on probing (BoP) and plaque] and GCF were collected from LAP participants, who received a 7-day antibiotic regimen immediately (ImA) or 3 months following (DelA) mechanical therapy. RESULTS: Although both groups presented significant CAL reductions at 6 months, only ImA resulted in a reduction in mean PD at both 3 and 6 months, along with reductions in CAL and BoP at 3 months following therapy. In addition, GCF mediators were higher in DelA group at 3 months post mechanical treatment, but were significantly reduced 6 months following antibiotic therapy. CONCLUSIONS: ImA and DelA regimens were both effective in improving CAL by 6 months post therapy. However, ImA allowed for better improvement in overall clinical parameters early in the course of treatment, concomitant with lower levels of inflammatory mediators within the GCF. PMID- 22931242 TI - GNAS1 (Galphas) gene T393C polymorphism and renal cell carcinoma risk in a North Indian population: a case-control study. AB - AIM: Heterotrimeric G protein alpha-subunit Galphas is required for activation of adenylyl cyclase and generation of cyclic adenosine monophosphate (cAMP) in cells and plays a key role in multiple signal transduction pathways, linked to proapoptotic processes in cancer cells. This study investigated whether Galphas gene polymorphism was associated with increased renal cell carcinoma (RCC) risk in the North Indian population. In the present study, genotyping of GNAS1 gene in 196 RCC cases and 250 healthy controls was performed via polymerase chain reaction-restriction fragment length polymorphism. RESULTS: The frequency of homozygous genotype CC was 29.6%, heterozygous TC was 51.5%, and homozygous TT was 18.9% in cases, whereas in controls it was 16.8%, 50.8%, and 32.4%, respectively; thus, there was a significant difference between the two groups (p=0.0001) in the univariate model. Further, multivariate analysis also demonstrated significant association of CC genotype with RCC risk (p=0.002). The high-risk genotype CC of GNAS1 gene showed threefold increase in risk to RCC relative to the TT genotype (unadjusted odds ratio [OR]=3.023, 95% confidence interval [CI]: 1.734-5.270). Whereas multivariate analysis showed a twofold increase in RCC risk among the CC genotype compared with the TT genotype (adjusted OR=2.181, 95% CI: 1.344-3.538). The C allele frequency was found to be significantly higher in RCC patients (55.3%) than in controls (42.2%) as compared with the T allele frequency that was 44.64% in RCC cases and 57.8% in controls. Moreover, patients with the CC genotype showed the worst prognosis in terms of the highest frequency of individuals having higher stages of RCC, but did not show any association with histological grade. CONCLUSION: Our results suggest that a T393C SNP could be considered as a genetic marker implicated in the pathogenesis of RCC. PMID- 22931243 TI - SNaPshot Assay in Quantitative Detection of Allelic Nondisjunction in Down Syndrome. AB - AIM: We wished to identify markers associated with allelic nondisjunction in nuclear families with Down syndrome (DS) offspring. Since the GRIK1 and GARS-AIRS GART genes, mapping to chromosome 21q22.1, may be informative in this regard, we genotyped four single-nucleotide polymorphisms [30952599(A/G) rs363484; 30924733(A/G) rs363506; 34901423(A/G) rs2834235; 34877070(A/G) rs7283354] present in these genes using the SNaPshot(TM) assay protocol. RESULTS: We have reported 30952599(A/G)-rs363484 to be monomorphic in our sample population. Genotyping revealed 35/65 families to be informative for 34877070(A/G)-rs7283354 (GARS-AIRS GART), whereas only 25/65 and 11/65 are informative for 34901423(A/G)-rs2834235 (GARS-AIRS-GART) and 30924733(A/G)-rs363506 (GRIK1) polymorphisms, respectively. The parent- and stage-of-origin of nondisjunction could be traced in 48/65 families using at least one polymorphic marker. A single trio provided internal validation for assignment of the parent- and stage-of-origin of nondisjunction whereby the nondisjoining alleles were independently identified as G-rs363506, G rs2834235, and G-rs7283354, respectively. An enhanced ratio of meiosis-I to meiosis-II errors during maternal or paternal meioses accounts for allelic nondisjunction. CONCLUSIONS: The SNaPshot assay is quantitative and permits multiplexing for detection of allelic nondisjunction. Inclusion of additional informative chromosome 21-specific markers may aid rapid aneuploidy detection, screening, and prenatal counseling of parents at risk of having babies with DS. PMID- 22931244 TI - The effect of direct-to-consumer genetic tests on anticipated affect and health seeking behaviors: a pilot survey. AB - PURPOSE: Numerous websites offer direct-to-consumer (DTC) genetic testing, yet it is unknown how individuals will react to genetic risk profiles online. The objective of this study was to determine the feasibility of using a web-based survey and conjoint methods to elicit individuals' interpretations of genetic risk profiles by their anticipated worry/anxiousness and health-seeking behaviors. METHODS: A web-based survey was developed using conjoint methods. Each survey presented 12 hypothetical genetic risk profiles describing genetic test results for four diseases. Test results were characterized by the type of disease (eight diseases), individual risk (five levels), and research confidence (three levels). After each profile, four questions were asked regarding anticipated worry and health-seeking behaviors. Probabilities of response outcomes based on attribute levels were estimated from logistic regression models, adjusting for covariates. RESULTS: Overall, 319 participants (69%) completed 3828 unique genetic risk profiles. Across all profiles, most participants anticipated making doctor's appointments (63%), lifestyle changes (57%), and accessing screening (57%); 40% anticipated feeling more worried and anxious. Higher levels of disease risk were significantly associated with affirmative responses. CONCLUSION: Conjoint methods may be used to elicit reactions to genetic information online. Preliminary results suggest that genetic information may increase worry/anxiousness and health-seeking behaviors among consumers of DTC tests. Further research is planned to determine the appropriateness of these affects and behaviors. PMID- 22931245 TI - Growth inhibition and chemosensitization of human carcinoma cells by human serum albumin-coated liposomal antisense oligodeoxyribonucleotide against bcl-2. AB - Previous study has shown human serum albumin (HSA) coated liposomes can deliver bcl-2 antisense oligodeoxyribonucleotide (ODN) into KB carcinoma cells, and decrease bcl-2 mRNA and protein expression level. In the current study, cell growth inhibition and chemosensitization of KB cells were evaluated. Liposomes composed of dimethyldioctadecyl ammonium bromide/egg phosphatidylcholine/alpha tocopheryl polyethylene glycol 1000 succinate (58:40:2 molar ratio) complexed with bcl-2 antisense ODN and coated with HSA were examined for cell growth inhibition and sensitization to a commonly used chemotherapeutic drug, doxorubicin. HSA-coated liposome-ODN complexes effectively inhibited cell growth in the range of ODN concentration of 0.45-7.2 uM. Upon posttreatment with doxorubicin, the cytotoxicity was further significantly increased compared to the ODN complexes alone. The cytotoxicity was dependent on antisense ODN concentration, incubation time and doxorubicin concentration, and relatively independent on HSA concentration. This study suggests that HSA-coated liposomes are effective delivery vehicles for antisense ODN with potential therapeutic application and can be effectively combined with doxorubicin. PMID- 22931247 TI - Molecular interaction of Rifabutin on model lung surfactant monolayers. AB - Tuberculosis is one of the most relevant problems for global health care. The design of new drugs against tuberculosis is aimed at maximizing impact against the disease, as well as minimizing the toxicological effect on the lung surfactant. In this work, the antituberculosis drug Rifabutin is studied in combination with phospholipid Langmuir monolayers as models of the lung surfactant monolayer. The zwitterionic 1,2-dipalmitoyl-sn-glycero-3 phosphocholine (DPPC) and the anionic 1,2-dipalmitoyl-sn-glycero-3-phospho-(1' rac-glycerol) (DPPG) were used as model phospholipids. A combination of in situ experimental techniques of Brewster angle microscopy, polarization-modulated infrared reflection-absorption spectroscopy, and UV-vis reflection spectroscopy with computer simulations has been used. The interactions between Rifabutin and the DPPC and DPPG Langmuir monolayers were described as the formation of an inclusion complex. The phospholipid-Rifabutin inclusion complex prevents the penetration of the Rifabutin into the alkyl chain region of the phospholipids, leading to a disruption of the monolayer structure and a possible toxicological effect. PMID- 22931246 TI - Tumor microvasculature with endothelial fenestrations in VHL null clear cell renal cell carcinomas as a potent target of anti-angiogenic therapy. AB - Vascular endothelial growth factor (VEGF)-targeted therapies show significant antitumor effects for advanced clear cell renal cell carcinomas (CC-RCCs). Previous studies using VEGF inhibitors in mice models revealed that VEGF dependent capillaries were characterized by the existence of endothelial fenestrations (EFs). In this study, we revealed that capillaries with abundant EFs did exist, particularly in CC-RCCs harboring VHL mutation. This finding was recapitulated in mice xenograft models, in which tumors from VHL null cells showed more abundant EFs compared to those from VHL wild-type cells. Importantly, treatment with bevacizumab resulted in a significant decrease of tumor size established from VHL null cells. Additionally, a significant reduction of EFs and microvessel density was observed in VHL null tumors. Indeed, xenograft from 786 O/mock (pRC3) cells developed four times more abundant EFs than that from 786 O/VHL (WT8). However, introduction of the constitutively active form of hypoxia inducible factor (HIF)-2alpha to WT8 cells failed to either augment the number of EFs or restore the sensitivity to bevacizumab in mice xenograft, irrespective of the equivalent production of VEGF to 786-O/mock cells. These results indicated that HIF-2alpha independent factors also play significant roles in the development of abundant EFs. In fact, several angiogenesis-related genes including CCL2 were upregulated in 786-O cells in a HIF-2alpha independent manner. Treatment with CCL2 neutralizing antibody caused significant reduction of capillaries with EFs in 786-O xenograft, indicating that they were also sensitive to CCL2 inhibition as well as VEGF. Collectively, these results strongly indicated that capillaries with distinctive phenotype developed in VHL null CC RCCs are potent targets for anti-angiogenic therapy. PMID- 22931248 TI - Derivation and characterization of matched cell lines from primary and recurrent serous ovarian cancer. AB - BACKGROUND: Cell line models have proven to be effective tools to investigate a variety of ovarian cancer features. Due to the limited number of cell lines, particularly of the serous subtype, the heterogeneity of the disease, and the lack of cell lines that model disease progression, there is a need to further develop cell line resources available for research. This study describes nine cell lines derived from three ovarian cancer cases that were established at initial diagnosis and at subsequent relapse after chemotherapy. METHODS: The cell lines from three women diagnosed with high-grade serous ovarian cancer (1369, 2295 and 3133) were derived from solid tumor (TOV) and ascites (OV), at specific time points at diagnosis and relapse (R). Primary treatment was a combination of paclitaxel/carboplatin (1369, 3133), or cisplatin/topotecan (2295). Second line treatment included doxorubicin, gemcitabine and topotecan. In addition to molecular characterization (p53, HER2), the cell lines were characterized based on cell growth characteristics including spheroid growth, migration potential, and anchorage independence. The in vivo tumorigenicity potential of the cell lines was measured. Response to paclitaxel and carboplatin was assessed using a clonogenic assay. RESULTS: All cell lines had either a nonsense or missense TP53 mutations. The ability to form compact spheroids or aggregates was observed in six of nine cell lines. Limited ability for migration and anchorage independence was observed. The OV3133(R) cell line, formed tumors at subcutaneous sites in SCID mice. Based on IC50 values and dose response curves, there was clear evidence of acquired resistance to carboplatin for TOV2295(R) and OV2295(R2) cell lines. CONCLUSION: The study identified nine new high-grade serous ovarian cancer cell lines, derived before and after chemotherapy that provides a unique resource for investigating the evolution of this common histopathological subtype of ovarian cancer. PMID- 22931249 TI - User fee exemptions and equity in access to caesarean sections: an analysis of patient survey data in Mali. AB - INTRODUCTION: Little rigorous evidence exists on how health service utilization varies across socioeconomic groups after a user fee exemption policy has been implemented, and the evidence that does exist is mixed. In this paper, we estimate the distribution of caesarean section deliveries across socioeconomic groups following Mali's implementation of a fee exemption policy for caesareans in 2005. METHODS: We conducted a patient survey in 2010 to collect socioeconomic data from 2,477 women who had caesareans in a representative sample of 25 facilities across all regions of Mali. We used these data along with data from the most recent Demographic and Health Survey to construct a wealth index and classify women into population-based wealth groupings. We compared the wealth distribution of women delivering via caesarean section to that of a nationally representative sample of women giving birth. RESULTS: We found that wealthier women make up a disproportionate share of those having free caesareans, five years after implementation of the fee exemption policy. Women in the richest two quintiles accounted for 58 percent of all caesareans, while women in the poorest two quintiles accounted for 27 percent of all caesareans. Fewer women in the poorest two-fifths of the population are receiving caesareans than what we would expect given their share in the population of women giving birth. CONCLUSIONS: While fee exemptions remove important financial barriers to accessing priority maternal health services, they are insufficient to ensure equal access among wealth groups. PMID- 22931252 TI - An inclusion complex of hexamolybdate inside a supramolecular cage and its structural conversion. AB - A self-assembled cage compound consisting of four concave ligands and two square planar-coordinated Pd(II) ions was found to quantitatively encapsulate a hexamolybdate dianion [Mo(6)O(19)](2-) in solution. The addition of 1 equiv more of [Mo(6)O(19)](2-) to the inclusion complex resulted in the formation of a precipitate from which single crystals were grown. X-ray analysis showed that a structural conversion had taken place upon crystallization: one hexamolybdate anion was found to be wrapped in a chiral, cyclic arrangement of three ligands in the absence of any Pd(II) ions to give a compound of the formula {[Mo(6)O(19)](2 )@(ligand)(3)+2H(+)}. We postulate the stabilization of this arrangement by attractive C-H...O and CF(3)-pyridine interactions. PMID- 22931250 TI - Microcolony formation by the opportunistic pathogen Pseudomonas aeruginosa requires pyruvate and pyruvate fermentation. AB - A hallmark of the biofilm architecture is the presence of microcolonies. However, little is known about the underlying mechanisms governing microcolony formation. In the pathogen Pseudomonas aeruginosa, microcolony formation is dependent on the two-component regulator MifR, with mifR mutant biofilms exhibiting an overall thin structure lacking microcolonies, and overexpression of mifR resulting in hyper-microcolony formation. Using global transcriptomic and proteomic approaches, we demonstrate that microcolony formation is associated with stressful, oxygen-limiting but electron-rich conditions, as indicated by the activation of stress response mechanisms and anaerobic and fermentative processes, in particular pyruvate fermentation. Inactivation of genes involved in pyruvate utilization including uspK, acnA and ldhA abrogated microcolony formation in a manner similar to mifR inactivation. Moreover, depletion of pyruvate from the growth medium impaired biofilm and microcolony formation, while addition of pyruvate significantly increased microcolony formation. Addition of pyruvate to or expression of mifR in lactate dehydrogenase (ldhA) mutant biofilms did not restore microcolony formation, while addition of pyruvate partly restored microcolony formation in mifR mutant biofilms. In contrast, expression of ldhA in mifR::Mar fully restored microcolony formation by this mutant strain. Our findings indicate the fermentative utilization of pyruvate to be a microcolony specific adaptation of the P. aeruginosa biofilm environment. PMID- 22931253 TI - Why GPCRs behave differently in cubic and lamellar lipidic mesophases. AB - Recent successes in the crystallographic determination of structures of transmembrane proteins in the G protein-coupled receptor (GPCR) family have established the lipidic cubic phase (LCP) environment as the medium of choice for growing structure-grade crystals by the method termed "in meso". The understanding of in meso crystallogenesis is currently at a descriptive level. To enable an eventual quantitative, energy-based description of the nucleation and crystallization mechanism, we have examined the properties of the lipidic cubic phase system and the dynamics of the GPCR rhodopsin reconstituted into the LCP with coarse-grained molecular dynamics simulations with the Martini force-field. Quantifying the differences in the hydrophobic/hydrophilic exposure of the GPCR to lipids in the cubic and lamellar phases, we found that the highly curved geometry of the cubic phase provides more efficient shielding of the protein from unfavorable hydrophobic exposure, which leads to a lesser hydrophobic mismatch and less unfavorable hydrophobic-hydrophilic interactions between the protein and lipid-water interface in the LCP, compared to the lamellar phase. Since hydrophobic mismatch is considered a driving force for oligomerization, the differences in exposure mismatch energies between the LCP and the lamellar structures suggest that the latter provide a more favorable setting in which GPCRs can oligomerize as a prelude to nucleation and crystal growth. These new findings lay the foundation for future investigations of in meso crystallization mechanisms related to the transition from the LCP to the lamellar phase and studies aimed at an improved rational approach for generating structure-quality crystals of membrane proteins. PMID- 22931251 TI - Grp1-associated scaffold protein (GRASP) is a regulator of the ADP ribosylation factor 6 (Arf6)-dependent membrane trafficking pathway. AB - GRASP interacts with Grp1 (general receptor for phosphoinositides 1; cytohesin 3), which catalyses nucleotide exchange on and activation of Arf6 (ADP ribosylation factor-6). Arf6 is a low-molecular-mass GTPase that regulates key aspects of endocytic recycling pathways. Overexpressed GRASP accumulated in the juxtanuclear ERC (endocytic recycling compartment). GRASP co-localized with a constitutively inactive mutant of Arf6 in the ERC such that it was reversed by expression of wild-type Grp1. Co-expression of GRASP and Grp1 promoted membrane ruffling, a cellular hallmark of Arf6 activation. GRASP accumulation in ERC was found to block recycling of the MHC-I (major histocompatibility complex-I), which is trafficked by the Arf6-dependent pathway. In contrast, overexpression of GRASP had no effect on the recycling of transferrin receptors, which are trafficked by a clathrin-dependent pathway. The findings suggest that GRASP regulates the non clathrin/Arf6-dependent, plasma membrane recycling and signalling pathways. PMID- 22931254 TI - Comparison of plain vertebral X-ray and dual-energy X-ray absorptiometry for the identification of older women for fracture prevention in primary care. AB - BACKGROUND: Recently, the dual-energy X-ray absorptiometry (DXA) diagnostic cut off (T-score) for Australian Pharmaceutical Benefits Scheme (PBS) supported primary fracture prevention therapy with alendronate for older women (>70 years) has been changed from -3.0 to -2.5. AIM: To examine the impact of the expanded criteria for PBS-supported fracture prevention therapy in older women on case finding and cost. METHODS: One thousand, nine hundred and eighty-three women, median age 76 years, not previously known to have low bone mineral density by DXA or a vertebral fracture underwent DXA scanning and a thoracolumbar X-ray. A woman was considered eligible for fracture prevention therapy if she had a T-score <= 2.5 at the femoral neck and/or the lumbar vertebrae (two to four) or at least one vertebral fracture of >=20% deformity. RESULTS: Seven hundred and forty-six women (37.6%) met the new criteria as a case for PBS-subsidised fracture prevention therapy. Four hundred and thirty-one (21.7%) had a T-score <=-2.5 on DXA compared with 10.6% (n = 210) with a T-score <=-3.0. Four hundred and eighty-three (24.4%) had at least one vertebral fracture. Only 8.5% (n = 168) had both a T-score <= 2.5 and a prevalent vertebral fracture. The cost per case found by DXA equated to $460 compared with $398 for screening by thoracolumbar X-ray. CONCLUSIONS: The use of either DXA or X-ray will identify approximately two-thirds of women aged 70 years and over who would be eligible for fracture prevention. The use of X-ray would identify a marginally larger number of women and at lower financial cost but involve substantially greater radiation exposure. PMID- 22931255 TI - The effects of porosity on optical properties of semiconductor chalcogenide films obtained by the chemical bath deposition. AB - This paper is dedicated to study the thin polycrystalline films of semiconductor chalcogenide materials (CdS, CdSe, and PbS) obtained by ammonia-free chemical bath deposition. The obtained material is of polycrystalline nature with crystallite of a size that, from a general point of view, should not result in any noticeable quantum confinement. Nevertheless, we were able to observe blueshift of the fundamental absorption edge and reduced refractive index in comparison with the corresponding bulk materials. Both effects are attributed to the material porosity which is a typical feature of chemical bath deposition technique. The blueshift is caused by quantum confinement in pores, whereas the refractive index variation is the evident result of the density reduction. Quantum mechanical description of the nanopores in semiconductor is given based on the application of even mirror boundary conditions for the solution of the Schrodinger equation; the results of calculations give a reasonable explanation of the experimental data. PMID- 22931256 TI - Brain amyloid imaging--FDA approval of florbetapir F18 injection. PMID- 22931257 TI - From sick care to health care--reengineering prevention into the U.S. system. PMID- 22931258 TI - The developing vision of primary care. PMID- 22931259 TI - Intermittent androgen suppression for rising PSA level after radiotherapy. AB - BACKGROUND: Intermittent androgen deprivation for prostate-specific antigen (PSA) elevation after radiotherapy may improve quality of life and delay hormone resistance. We assessed overall survival with intermittent versus continuous androgen deprivation in a noninferiority randomized trial. METHODS: We enrolled patients with a PSA level greater than 3 ng per milliliter more than 1 year after primary or salvage radiotherapy for localized prostate cancer. Intermittent treatment was provided in 8-month cycles, with nontreatment periods determined according to the PSA level. The primary end point was overall survival. Secondary end points included quality of life, time to castration-resistant disease, and duration of nontreatment intervals. RESULTS: Of 1386 enrolled patients, 690 were randomly assigned to intermittent therapy and 696 to continuous therapy. Median follow-up was 6.9 years. There were no significant between-group differences in adverse events. In the intermittent-therapy group, full testosterone recovery occurred in 35% of patients, and testosterone recovery to the trial-entry threshold occurred in 79%. Intermittent therapy provided potential benefits with respect to physical function, fatigue, urinary problems, hot flashes, libido, and erectile function. There were 268 deaths in the intermittent-therapy group and 256 in the continuous-therapy group. Median overall survival was 8.8 years in the intermittent-therapy group versus 9.1 years in the continuous-therapy group (hazard ratio for death, 1.02; 95% confidence interval, 0.86 to 1.21). The estimated 7-year cumulative rates of disease-related death were 18% and 15% in the two groups, respectively (P=0.24). CONCLUSIONS: Intermittent androgen deprivation was noninferior to continuous therapy with respect to overall survival. Some quality-of-life factors improved with intermittent therapy. (Funded by the Canadian Cancer Society Research Institute and others; ClinicalTrials.gov number, NCT00003653.). PMID- 22931260 TI - Somatic HIF2A gain-of-function mutations in paraganglioma with polycythemia. AB - Hypoxia-inducible factors are transcription factors controlling energy, iron metabolism, erythropoiesis, and development. When these proteins are dysregulated, they contribute to tumorigenesis and cancer progression. However, mutations in genes encoding alpha subunits of hypoxia-inducible factors (HIF alpha) have not previously been identified in any cancer. Here we report two novel somatic gain-of-function mutations in the gene encoding hypoxia-inducible factor 2alpha (HIF2A) in two patients, one presenting with paraganglioma and the other with paraganglioma and somatostatinoma, both of whom had polycythemia. The two mutations were associated with increased HIF-2alpha activity and increased protein half-life. PMID- 22931261 TI - Tuberculosis, drug resistance, and the history of modern medicine. PMID- 22931262 TI - Images in clinical medicine. Burton's Line. PMID- 22931263 TI - Clinical problem-solving. The eyes have it. PMID- 22931264 TI - Androgen deprivation--continuous, intermittent, or none at all? PMID- 22931265 TI - Targeting the skeletal muscle-metabolism axis in prostate-cancer therapy. PMID- 22931267 TI - Drotrecogin alfa (activated) in septic shock. PMID- 22931268 TI - Drotrecogin alfa (activated) in septic shock. PMID- 22931270 TI - Vismodegib in advanced basal-cell carcinoma. PMID- 22931271 TI - Vismodegib in advanced basal-cell carcinoma. PMID- 22931273 TI - Nighttime intensivist staffing. PMID- 22931274 TI - Nighttime intensivist staffing. PMID- 22931275 TI - Nighttime intensivist staffing. PMID- 22931277 TI - Guillain-Barre syndrome. PMID- 22931278 TI - Guillain-Barre syndrome. PMID- 22931279 TI - Guillain-Barre syndrome. PMID- 22931280 TI - IVIG--a hemolytic culprit. PMID- 22931284 TI - Images in clinical medicine. Corneal dendrites. PMID- 22931285 TI - Comparative genomics guided discovery of two missing archaeal enzyme families involved in the biosynthesis of the pterin moiety of tetrahydromethanopterin and tetrahydrofolate. AB - C-1 carriers are essential cofactors in all domains of life, and in Archaea, these can be derivatives of tetrahydromethanopterin (H(4)-MPT) or tetrahydrofolate (H(4)-folate). Their synthesis requires 6-hydroxymethyl-7,8 dihydropterin diphosphate (6-HMDP) as the precursor, but the nature of pathways that lead to its formation were unknown until the recent discovery of the GTP cyclohydrolase IB/MptA family that catalyzes the first step, the conversion of GTP to dihydroneopterin 2',3'-cyclic phosphate or 7,8-dihydroneopterin triphosphate [El Yacoubi, B.; et al. (2006) J. Biol. Chem., 281, 37586-37593 and Grochowski, L. L.; et al. (2007) Biochemistry46, 6658-6667]. Using a combination of comparative genomics analyses, heterologous complementation tests, and in vitro assays, we show that the archaeal protein families COG2098 and COG1634 specify two of the missing 6-HMDP synthesis enzymes. Members of the COG2098 family catalyze the formation of 6-hydroxymethyl-7,8-dihydropterin from 7,8 dihydroneopterin, while members of the COG1634 family catalyze the formation of 6 HMDP from 6-hydroxymethyl-7,8-dihydropterin. The discovery of these missing genes solves a long-standing mystery and provides novel examples of convergent evolutions where proteins of dissimilar architectures perform the same biochemical function. PMID- 22931286 TI - Graphene nanomesh as highly sensitive chemiresistor gas sensor. AB - Graphene is a one atom thick carbon allotrope with all surface atoms that has attracted significant attention as a promising material as the conduction channel of a field-effect transistor and chemical field-effect transistor sensors. However, the zero bandgap of semimetal graphene still limits its application for these devices. In this work, ethanol-chemical vapor deposition (CVD) of a grown p type semiconducting large-area monolayer graphene film was patterned into a nanomesh by the combination of nanosphere lithography and reactive ion etching and evaluated as a field-effect transistor and chemiresistor gas sensors. The resulting neck-width of the synthesized nanomesh was about ~20 nm and was comprised of the gap between polystyrene (PS) spheres that was formed during the reactive ion etching (RIE) process. The neck-width and the periodicities of the graphene nanomesh (GNM) could be easily controlled depending on the duration/power of the RIE and the size of the PS nanospheres. The fabricated GNM transistor device exhibited promising electronic properties featuring a high drive current and an I(ON)/I(OFF) ratio of about 6, significantly higher than its film counterpart. Similarly, when applied as a chemiresistor gas sensor at room temperature, the graphene nanomesh sensor showed excellent sensitivity toward NO(2) and NH(3), significantly higher than their film counterparts. The ethanol based graphene nanomesh sensors exhibited sensitivities of about 4.32%/ppm in NO(2) and 0.71%/ppm in NH(3) with limits of detection of 15 and 160 ppb, respectively. Our demonstrated studies on controlling the neck width of the nanomesh would lead to further improvement of graphene-based transistors and sensors. PMID- 22931287 TI - Obtaining optical purity for product diols in enzyme-catalyzed epoxide hydrolysis: contributions from changes in both enantio- and regioselectivity. AB - Enzyme variants of the plant epoxide hydrolase StEH1 displaying improved stereoselectivities in the catalyzed hydrolysis of (2,3-epoxypropyl)benzene were generated by directed evolution. The evolution was driven by iterative saturation mutagenesis in combination with enzyme activity screenings where product chirality was the decisive selection criterion. Analysis of the underlying causes of the increased diol product ratios revealed two major contributing factors: increased enantioselectivity for the corresponding epoxide enantiomer(s) and, in some cases, a concomitant change in regioselectivity in the catalyzed epoxide ring-opening half-reaction. Thus, variant enzymes that catalyzed the hydrolysis of racemic (2,3-epoxypropyl)benzene into the R-diol product in an enantioconvergent manner were isolated. PMID- 22931288 TI - Cbl proteins in platelet activation. AB - Platelets play a fundamental role in hemostasis. Their functional responses have to be tightly controlled as any disturbance may lead to bleeding disorders or thrombosis. It is thus important to clearly identify and understand the signaling mechanisms involved in platelet function. An important role of c-Cbl and Cbl-b ubiquitin ligases in platelet functional responses and in hematological malignancies has been recently described. Cbl proteins perform negative and positive regulation of several signaling pathways in platelets. In this review, we explore the role of Cbl proteins in platelet functional responses. PMID- 22931289 TI - Relation of kinetic energy to contact wounds of the head by centerfire rifles and shotgun slugs. AB - Wounds of high-energy centerfire rifles and shotguns represent distinctive injuries of forensic importance. Previous studies of contact wounds have shown variability in the potential of these weapons to produce bursting wounds of the head. The present study analyzed contact head wounds owing to 26 centerfire rifles and nine shotgun slugs and compared them with respect to weapon, ammunition, entry wound site, and projectile kinetic energy. The bursting effect, defined for this study as disruption of at least 50% of the head, occurred in 25/35 of cases and was related to kinetic energy. Bursting was associated with energies <2700 ft-lbs in 12/22 cases and energies >2700 ft-lbs in 13/13 cases. The volume of gunpowder gas injected into the wound was considered as contributing to the bursting phenomenon. There was no relation of bursting to the specific entrance wound site, type of ammunition, or projectile fragmentation. PMID- 22931290 TI - Alternating current electrokinetic properties of gold-coated microspheres. AB - We present dielectrophoresis (DEP) and electrorotation (ROT) measurements of gold coated polystyrene microspheres as a function of frequency and for several electrolyte conductivities. Particle rotation was counterfield with a maximum rotation rate observed at a single characteristic frequency. Negative DEP was observed for frequencies lower than this characteristic frequency and positive DEP for signal frequencies higher than this. These experimental observations are in agreement with predictions for the force and torque on the induced dipole of a perfectly polarizable metal sphere. We present a theoretical model for this case, and good agreement is found for both ROT and DEP measurements if we take into account the viscous friction for a spherical particle near a wall. From the characteristic frequency for rotation, we obtain the capacitance of the electrical double layer at the electrolyte-particle interface. Remarkably, no effect of induced charge electroosmosis around the particles can be inferred from DEP measurements. PMID- 22931292 TI - Peri-implant marginal bone level: a systematic review and meta-analysis of studies comparing platform switching versus conventionally restored implants. AB - AIM: To systematically review the literature to compare implant survival (IS) and marginal bone loss (MBL) around platform-switched (PS) versus conventionally restored platform-matching dental implants. MATERIAL AND METHODS: Randomized, controlled human clinical trials (RCTs) comparing IS and MBL in PS and conventionally restored implants, with 12 months of follow-up and at least 10 implants were identified through electronic and manual search. Review and meta analysis were performed according to PRISMA statement. Risk ratio (RR) for implant failure and mean difference (MD) for MBL, with 95% confidence interval (CI) were calculated. Sources of heterogeneity among studies were also investigated by subgroup analyses. RESULTS: Ten RCTs involving 435 subjects and 993 implants contributed to this review. The cumulative estimated implant success rate revealed no statistically significant difference between the two groups. At a patient level, a smaller amount of MBL [MD -0.55 mm, 95%CI (-0.86; -0.24), p = 0.0006] was noted around PS implants. Subgroup analyses performed at implant level suggested less MBL when platform switching showed a larger mismatching. CONCLUSION: PS technique appeared to be useful in limiting bone resorption. Nevertheless, these data should be interpreted cautiously as significant heterogeneity and possible publication bias were noted. Further research is needed to identify the factors most associated with successful outcomes. PMID- 22931291 TI - Roles of microRNAs in atherosclerosis and restenosis. AB - Atherosclerosis is commonly appreciated to represent a chronic inflammatory response of the vascular wall, and its complications cause high mortality in patients. Angioplasty with stent replacement is commonly performed in patients with atherosclerotic disease. However, the restenosis usually has a high incidence rate in angioplasty patients. Although the pathophysiological mechanisms underlying atherosclerosis and restenosis have been well established, new signaling molecules that control the progress of these pathologies have continuously been discovered. MicroRNAs (miRs) have recently emerged as a novel class of gene regulators that work via transcriptional degradation and translational inhibition or activation. Over 30% of genes in the cell can be directly regulated by miRs. Thus, miRs are recognized as crucial regulators in normal development, physiology and pathogenesis. Alterations of miR expression profiles have been revealed in diverse vascular diseases. A variety of functions of vascular cells, such as cell differentiation, contraction, migration, proliferation and inflammation that are involved in angiogenesis, neointimal formation and lipid metabolism underlying various vascular diseases, have been found to be regulated by miRs. This review summarizes current research progress and knowledge on the roles of miRs in regulating vascular cell function in atherosclerosis and restenosis. These discoveries are expected to present opportunities for clinical diagnostic and therapeutic approaches in vascular diseases resulting from atherosclerosis and restenosis. PMID- 22931293 TI - Comparison of the transcutaneous bilirubinometers BiliCheck and Minolta JM-103 in preterm neonates. AB - AIM: To investigate the trueness and uncertainty of two transcutaneous bilirubinometers BiliCheck and Minolta JM-103 in preterm infants; establish cut off values for the transcutaneous bilirubin (TcB) level, indicating the need for total serum bilirubin (TsB) measurement; and estimate how many blood samples could be saved. METHODS: In 133 neonates with gestational ages 28(+0) -34(+6) weeks, 239 measurements of TcB by BiliCheck (TcB(B)) and JM-103 (TcB(M)) and of TsB were performed. RESULTS: Median TsB of the first samples was 160 (range, 53 293) MUmol/L, whereas median TcB(B) was 12 MUmol/L (8%) lower and TcB(M) 67 MUmol/L (40%) lower. TcB(B) underestimated TsB for TsB >=180MUmol/L. All TcB(M) values, except one, underestimated TsB. The underestimation increased with increasing TsB. Multiple regression analysis showed that post-natal age and ethnicity were confounding factors for TcB(M); none were found for TcB(B). The uncertainty was the same for the two instruments. By using cut-off values of 70% of the phototherapy limit for TcB(B) and 35% for TcB(M), the sensitivity of the screening would be 95% and 97%, and 36% and 24% of the blood samples could be saved, respectively. CONCLUSION: TcB determined with JM-103 gave values much lower than those obtained with BiliCheck. The underestimation of TsB increased with increasing concentrations. By using transcutaneous bilirubinometers in preterm neonates, 24-36% of the blood samples could be saved. PMID- 22931294 TI - Autocatalytic replication and homochirality in biopolymers: is homochirality a requirement of life or a result of it? AB - A key step in the origin of life is the establishment of autocatalytic cycles controlled by biopolymer catalysts. These catalysts (either ribozymes or proteins) are composed of homochiral monomers. Homochirality in living systems is maintained because biopolymers are asymmetric in their catalysis and synthesize molecules of their own handedness. Asymmetric autocatalysis is also possible with small molecules, as demonstrated by the Soai reaction, but it is rare. As far as we know, single nucleotides and amino acids are not autocatalytic. The observation that organic molecules in meteorites can have an enantiomeric excess of a few percent suggests that the prebiotic mixture may have had a partial chiral bias that was caused by external physical influences. Here, we consider the way that such a partial prebiotic bias would influence the origin of ribozymes in an RNA world scenario. We have previously shown how a transition to a living state can occur in a model for RNA polymerization. Here, we add chirality to the problem by considering simultaneous synthesis and polymerization of left- and right-handed monomers. The two chemical synthesis rates may be equal or unequal, due to physical or chemical effects prior to the origin of life. We determine the stationary states of this reaction system. The nonliving state is racemic, or slightly biased. There are two living states that are almost completely homochiral, whether or not the nonliving state is biased. It is a feature of our model that, for some regions of parameter space, living and nonliving states are both found to be stable under the same conditions. The origin of life therefore involves a stochastic transition between the nonliving and living states. Our model extends previous theories by treating the origin of life and the origin of chirality as aspects of the same model. PMID- 22931295 TI - Polychlorinated biphenyl exposure, diabetes and endogenous hormones: a cross sectional study in men previously employed at a capacitor manufacturing plant. AB - BACKGROUND: Studies have shown associations of diabetes and endogenous hormones with exposure to a wide variety of organochlorines. We have previously reported positive associations of polychlorinated biphenyls (PCBs) and inverse associations of selected steroid hormones with diabetes in postmenopausal women previously employed in a capacitor manufacturing plant. METHODS: This paper examines associations of PCBs with diabetes and endogenous hormones in 63 men previously employed at the same plant who in 1996 underwent surveys of their exposure and medical history and collection of bloods and urine for measurements of PCBs, lipids, liver function, hematologic markers and endogenous hormones. RESULTS: PCB exposure was positively associated with diabetes and age and inversely associated with thyroid stimulating hormone and triiodothyronine uptake. History of diabetes was significantly related to total PCBs and all PCB functional groupings, but not to quarters worked and job score, after control for potential confounders. None of the exposures were related to insulin resistance (HOMA-IR) in non-diabetic men. CONCLUSIONS: Associations of PCBs with specific endogenous hormones differ in some respects from previous findings in postmenopausal women employed at the capacitor plant. Results from this study, however, do confirm previous reports relating PCB exposure to diabetes and suggest that these associations are not mediated by measured endogenous hormones. PMID- 22931296 TI - Diagnosing postural tachycardia syndrome: comparison of tilt testing compared with standing haemodynamics. AB - POTS (postural tachycardia syndrome) is characterized by an increased heart rate (DeltaHR) of >=30 bpm (beats/min) with symptoms related to upright posture. Active stand (STAND) and passive head-up tilt (TILT) produce different physiological responses. We hypothesized these different responses would affect the ability of individuals to achieve the POTS HR increase criterion. Patients with POTS (n=15) and healthy controls (n=15) underwent 30 min of tilt and stand testing. DeltaHR values were analysed at 5 min intervals. ROC (receiver operating characteristic) analysis was performed to determine optimal cut point values of DeltaHR for both tilt and stand. Tilt produced larger DeltaHR than stand for all 5 min intervals from 5 min (38+/-3 bpm compared with 33+/-3 bpm; P=0.03) to 30 min (51+/-3 bpm compared with 38+/-3 bpm; P<0.001). Sn (sensitivity) of the 30 bpm criterion was similar for all tests (TILT10=93%, STAND10=87%, TILT30=100%, and STAND30=93%). Sp (specificity) of the 30 bpm criterion was less at both 10 and 30 min for tilt (TILT10=40%, TILT30=20%) than stand (STAND10=67%, STAND30=53%). The optimal DeltaHR to discriminate POTS at 10 min were 38 bpm (TILT) and 29 bpm (STAND), and at 30 min were 47 bpm (TILT) and 34 bpm (STAND). Orthostatic tachycardia was greater for tilt (with lower Sp for POTS diagnosis) than stand at 10 and 30 min. The 30 bpm DeltaHR criterion is not suitable for 30 min tilt. Diagnosis of POTS should consider orthostatic intolerance criteria and not be based solely on orthostatic tachycardia regardless of test used. PMID- 22931298 TI - Are people who inject performance and image-enhancing drugs an increasing population of Needle and Syringe Program attendees? PMID- 22931297 TI - Site-specific measurement of water dynamics in the substrate pocket of ketosteroid isomerase using time-resolved vibrational spectroscopy. AB - Little is known about the reorganization capacity of water molecules at the active sites of enzymes and how this couples to the catalytic reaction. Here, we study the dynamics of water molecules at the active site of a highly proficient enzyme, Delta(5)-3-ketosteroid isomerase (KSI), during a light-activated mimic of its catalytic cycle. Photoexcitation of a nitrile-containing photoacid, coumarin183 (C183), mimics the change in charge density that occurs at the active site of KSI during the first step of the catalytic reaction. The nitrile of C183 is exposed to water when bound to the KSI active site, and we used time-resolved vibrational spectroscopy as a site-specific probe to study the solvation dynamics of water molecules in the vicinity of the nitrile. We observed that water molecules at the active site of KSI are highly rigid, during the light-activated catalytic cycle, compared to the solvation dynamics observed in bulk water. On the basis of this result, we hypothesize that rigid water dipoles at the active site might help in the maintenance of the preorganized electrostatic environment required for efficient catalysis. The results also demonstrate the utility of nitrile probes in measuring the dynamics of local (H-bonded) water molecules in contrast to the commonly used fluorescence methods which measure the average behavior of primary and subsequent spheres of solvation. PMID- 22931299 TI - Interplay of F-H...F hydrogen bonds and P...N pnicogen bonds. AB - Ab initio MP2/aug'-cc-pVTZ calculations have been carried out to investigate the influence of F-H...F hydrogen bonds on the P...N pnicogen bond in complexes nFH:(H2FP:NFH2) for n = 1-2, and a selected complex with n = 3. The NBO analysis indicates that the N(lp) -> P-Fsigma* charge-transfer transition has a much greater stabilizing effect than the P(lp) -> N-Fsigma* transition. When hydrogen bonding occurs at P-F, charge transfer associated with the pnicogen bond and the hydrogen bond are in the same direction but are in opposite directions when hydrogen bonding occurs at N-F. As a result, the formation of F-H...F hydrogen bonds at P-F leads to shorter P...N distances, increased strength of P...N bonds, and synergistic energetic effects; hydrogen bonding at N-F has opposite effects. (31)P and (15)N chemical shieldings do not correlate with charges on P and N, respectively, but (31)P shieldings correlate quadratically with the P-N distance. (1p)J(P-N) coupling constants do not correlate with the intermolecular P-N distance. However, when hydrogen bonding occurs only at P-F, (1p)J(P-N) decreases in absolute value as the P-N distance decreases, thereby approaching (1)J(P-N) for H2P-NH2. However, the P...N bond in 3FH:(H2FP:NFH2) has little covalent character, unlike the P...P bond in the corresponding complex 3FH:(PH2F)2. PMID- 22931300 TI - Preclinical strategy to reduce clinical hepatotoxicity using in vitro bioactivation data for >200 compounds. AB - Drug-induced liver injury is the most common cause of market withdrawal of pharmaceuticals, and thus, there is considerable need for better prediction models for DILI early in drug discovery. We present a study involving 223 marketed drugs (51% associated with clinical hepatotoxicity; 49% non-hepatotoxic) to assess the concordance of in vitro bioactivation data with clinical hepatotoxicity and have used these data to develop a decision tree to help reduce late-stage candidate attrition. Data to assess P450 metabolism-dependent inhibition (MDI) for all common drug-metabolizing P450 enzymes were generated for 179 of these compounds, GSH adduct data generated for 190 compounds, covalent binding data obtained for 53 compounds, and clinical dose data obtained for all compounds. Individual data for all 223 compounds are presented here and interrogated to determine what level of an alert to consider termination of a compound. The analysis showed that 76% of drugs with a daily dose of <100 mg were non-hepatotoxic (p < 0.0001). Drugs with a daily dose of >=100 mg or with GSH adduct formation, marked P450 MDI, or covalent binding >=200 pmol eq/mg protein tended to be hepatotoxic (~ 65% in each case). Combining dose with each bioactivation assay increased this association significantly (80-100%, p < 0.0001). These analyses were then used to develop the decision tree and the tree tested using 196 of the compounds with sufficient data (49% hepatotoxic; 51% non hepatotoxic). The results of these outcome analyses demonstrated the utility of the tree in selectively terminating hepatotoxic compounds early; 45% of the hepatotoxic compounds evaluated using the tree were recommended for termination before candidate selection, whereas only 10% of the non-hepatotoxic compounds were recommended for termination. An independent set of 10 GSK compounds with known clinical hepatotoxicity status were also assessed using the tree, with similar results. PMID- 22931301 TI - Amphiphilic polyaspartamide copolymer-based micelles for rivastigmine delivery to neuronal cells. AB - A novel polysorbate-80 (PS(80))-attached amphiphilic copolymer comprising a hydrophilic alpha,beta-poly(N-2-hydroxyethyl)-D,L-aspartamide (PHEA) backbone and hydrophobic squalenyl-C(17) (Sq(17)) portions was synthesized and characterized; the formation of polymeric micelles was also evaluated. Rivastigmine free-base (Riv), a hydrophobic drug employed to treat Alzheimer's disease, was chosen as model drug to investigate micelle's ability to incorporate hydrophobic molecules and target them to neuronal cells. Micelle formation was studied through analyses including fluorescence spectroscopy and 2D (1)H-NMR NOESY experiments. Finally, the capacity of Riv-loaded micelles, versus free drug, to penetrate mouse neuroblastoma cells (Neuro2a) was evaluated. 2D (1)H-NMR NOESY experiments demonstrated that the PHEA-EDA-Sq(17)-PS(80) copolymer self-assembles into micelle structures in water, with a micelle core formed by hydrophobic interaction between Sq(17) alkyl chains. Fluorescence probe studies revealed the CAC of PHEA-EDA-Sq(17)-PS(80) micelles, which was 0.25 mg mL(-1). The micelles obtained had a nanometric hydrodynamic diameter with narrow size distribution and negative surface charge. The PHEA-EDA-Sq(17)-PS(80) micelles incorporated a large amount of Riv, and the system maintained the stability of Riv after incubation in human plasma. An in vitro biological assay evidenced no cytotoxic effects of either empty or loaded micelles on the neuronal cell lines tested. Moreover, the micelles are internalized by neuroblastoma cell lines with drug uptake depending on the micelles concentration. PMID- 22931302 TI - The European Principles of Haemophilia Care: a pilot investigation of adherence to the principles in Europe. AB - In 2008 the 10 Principles of Haemophilia Care were outlined to provide a benchmark for haemophilia treatment. The EHTSB performed a survey to establish to what extent the Principles of Haemophilia Care were being applied throughout Europe. In total, 21 centres from 14 countries (France, UK, Germany, Switzerland, Sweden, Norway, the Netherlands, Belgium, Poland, Portugal, Slovakia, Spain, Greece and Italy), were surveyed. A central organization of haemophilia care (principle 1) was present in 79%, and a central patient registry in 57% (principle 2). National haemophilia care decision-making was performed by clinicians, ministries and patient organizations (principle 4). All had designated comprehensive care centres (CCC--principle 3), responsible the majority of severe patients, but in 36% some patients were treated outside CCC/haemophilia treatment centres (HTC)s. Clotting factor concentrates were available everywhere, without dosing restraints (principle 5), including recombinant products in 86% of countries. Prophylactic treatment was available for all children but not for all adults (principle 7). Immune tolerance was available in all countries (principle 9). Home treatment was supported and taught by all centres (principle 6). At centre level, 86% had 24-h laboratory facilities and all participated in education and research (principle 10). An experienced haematologist was available at all centres, a paediatrician in 47%, and prompt out of hours review was available in all (principle 8). The Principles of Haemophilia Care were generally applied throughout Europe. Some aspects of centralization, national organization of care, use of registries, formal paediatric care and prophylaxis for adults may be improved. PMID- 22931303 TI - Assessment of acute moderate hyperglycemia on traditional and thromboelastometry coagulation parameters in healthy adult horses. AB - OBJECTIVE: To determine whether experimentally induced acute moderate hyperglycemia is associated with coagulation activation in healthy adult horses. DESIGN: Prospective experimental study. SETTING: University veterinary teaching hospital. ANIMALS: Six healthy adult horses. INTERVENTIONS: Hyperglycemia (10.0 13.3 mmol/L [180-240 mg/dL]) was induced and maintained for 6 hours using a hyperglycemic clamp technique. Blood glucose concentrations were assessed using a point of care (POC) glucometer at 10- and 20-minute intervals throughout the hyperglycemic clamp procedure. Platelet count, fibrinogen concentration, prothrombin time (PT), activated partial thromboplastin time (aPTT), thrombin antithrombin complex level (TAT), and thromboelastometry (TEM) were determined before and after jugular catheter placement, prior to glucose administration, and at 3 and 6 hours of sustained hyperglycemia. Data were analyzed by repeated measures analysis of variance with significance defined as P < 0.05. MEASUREMENTS AND MAIN RESULTS: All horses maintained blood glucose concentration >10.0 mmol/L (>180 mg/dL) throughout the duration of the hyperglycemic clamp with a mean concentration of 11.9 +/- 0.3 mmol/L [216 +/- 6 mg/dL] as measured by the POC glucometer. No significant difference was found for any evaluated parameter associated with sustained hyperglycemia. Intravenous catheter placement resulted in a significant increase in mean TAT (0.8 +/- 0.3 MUg/L pre-catheter, 2.3 +/- 0.8 MUg/L post-catheter; P = 0.008). CONCLUSIONS: Acute, moderate hyperglycemia in healthy adult horses does not have a detectable effect on coagulation based on evaluated parameters. Jugular catheter placement results in a transient increase in thrombin generation as determined by increased TAT concentrations. PMID- 22931305 TI - Opportunity of spinel ferrite materials in nonvolatile memory device applications based on their resistive switching performances. AB - The opportunity of spinel ferrites in nonvolatile memory device applications has been demonstrated by the resistive switching performance characteristics of a Pt/NiFe(2)O(4)/Pt structure, such as low operating voltage, high device yield, long retention time (up to 10(5) s), and good endurance (up to 2.2 * 10(4) cycles). The dominant conduction mechanisms are Ohmic conduction in the low resistance state and in the lower-voltage region of the high-resistance state and Schottky emission in the higher-voltage region of the high-resistance state. On the basis of measurements of the temperature dependence of the resistances and magnetic properties in different resistance states, we explain the physical mechanism of resistive switching of Pt/NiFe(2)O(4)/Pt devices using the model of formation and rupture of conducting filaments by considering the thermal effect of oxygen vacancies and changes in the valences of cations due to the redox effect. PMID- 22931304 TI - Hospitalised neonates in Estonia commonly receive potentially harmful excipients. AB - BACKGROUND: Information on the neonatal exposure to excipients is limited. Our aim was to describe the extent of excipient intake by Estonian neonates; to classify the excipients according to potential neonatal toxicity and thereby to measure the extent of exposure of neonates to potentially harmful excipients. METHODS: A prospective cohort study that recorded all medicines prescribed to patients aged below 28 days admitted to Tartu University Hospital from 01.02 01.08 2008 and to Tallinn Children's Hospital from 01.02- 01.08 2009 was conducted. Excipients were identified from Summaries of Product Characteristics and classified according to toxicity following a literature review. RESULTS: 1961 prescriptions comprising 107 medicines were written for 348/490 neonates admitted. A total of 123 excipients were found in 1620 (83%) prescriptions and 93 (87%) medicines. 47 (38%) of these excipients were classified as potentially or known to be harmful to neonates. Most neonates (97%) received at least one medicine (median number 2) with potentially or known to be harmful excipient. Parabens were the most commonly used known to be harmful excipients and sodium metabisulphite the most commonly used potentially harmful excipient, received by 343 (99%) and 297 (85%) of treated neonates, respectively. CONCLUSIONS: Hospitalised neonates in Estonia are commonly receiving a wide range of excipients with their medication. Quantitative information about excipients should be made available to pharmacists and neonatologists helping them to take into account excipient issues when selecting medicines and to monitor for adverse effects if administration of medicines containing excipients is unavoidable. PMID- 22931306 TI - Towards on-chip time-resolved thermal mapping with micro-/nanosensor arrays. AB - In recent years, thin-film thermocouple (TFTC) array emerged as a versatile candidate in micro-/nanoscale local temperature sensing for its high resolution, passive working mode, and easy fabrication. However, some key issues need to be taken into consideration before real instrumentation and industrial applications of TFTC array. In this work, we will demonstrate that TFTC array can be highly scalable from micrometers to nanometers and that there are potential applications of TFTC array in integrated circuits, including time-resolvable two-dimensional thermal mapping and tracing the heat source of a device. Some potential problems and relevant solutions from a view of industrial applications will be discussed in terms of material selection, multiplexer reading, pattern designing, and cold junction compensation. We show that the TFTC array is a powerful tool for research fields such as chip thermal management, lab-on-a-chip, and other novel electrical, optical, or thermal devices. PMID- 22931307 TI - Telerheumatology: an idea whose time has come. AB - Australia is a vast country with one-third of the population living outside capital cities. Providing specialist rheumatologist services to regional, rural and remote Australians has generally required expensive and time-consuming travel for the patient and/or specialist. As a result, access to specialist care for remote Australians is poor. Rheumatoid arthritis is a common disease, but like many rheumatic diseases, it is complex to treat. Time-dependent joint damage and disability occur unless best evidence care is implemented. The relatively poor access to rheumatologist care allotted to nonmetropolitan Australians therefore represents a significant cause of potentially preventable disability in Australia. Telehealth has the potential to improve access to specialist rheumatologists for patients with rheumatoid arthritis and other rheumatic diseases, thereby decreasing the burden of disability caused by these diseases. Advances in videoconferencing technology, the national broadband rollout and recent Federal government financial incentives have led to a heightened interest in exploring the use of this technology in Australian rheumatology practice. This review summarises the current evidence base, outlines telehealth's strengths and weaknesses in managing rheumatic disease, and discusses the technological, medicolegal and financial aspects of this model of care. A mixed model offering both face-to-face and virtual consultations appears to be the best option, as it can overcome the barriers to accessing care posed by distance while also mitigating the risks of virtual consultation. PMID- 22931308 TI - Ball milling synthesis of silica nanoparticle from rice husk ash for drug delivery application. AB - Silica nanoparticles were synthesized from rice husk ash at room temperature by using high energy planetary ball mill. The milling time and mill rotational speed were varied in four levels. The morphology of the synthesized powders was investigated by the FE-SEM and TEM image as well as XRD patterns. The results have revealed that the nano-sized amorphous silica particles are formed after about 6 h ball milling and they are spherical in shape. The average particle size of the silica powders is found to be around 70 nm which decreases with increasing ball milling time or mill rotational speed. The as-synthesized silica nanoparticles were subsequently employed as drug carrier to investigate in vitro release behavior of Penicillin-G in simulated body fluid. UV-Vis spectroscopy was used to determine the amount of Penicillin-G released from the carrier. Penicillin-G release profile from silica nanoparticles exhibited a delayed release effect. PMID- 22931309 TI - Structure-based drug design for dopamine D3 receptor. AB - D2-like receptors are members of dopamine receptors, including dopamine D2 receptor (D2R), dopamine D3 receptor (D3R), and dopamine D4 receptor (D4R), which modulate behavior, cognition, and emotion. D2-like receptors are critical targets for drug development. Particularly, D3R has been identified as a therapeutic target for antipsychotic and anti-parkinsonian drugs. Recently, the crystal structure of D3R was reported. Here we summarize the available active compounds for D3R and the structure-activity relationships (SAR) studies of them. This provides lead templates for further chemical modification. We describe the structure features of the recent crystal structure of D3R and its difference from other G protein-coupled receptors (GPCRs). We provide the recognition mechanism of the inhibitors of D3R (molecular docking results and molecular dynamics results), which illustrates the interaction between the inhibitors and critical residues of D3R. Finally, we summarize the outlook of drug development for D3R. Our study provides useful information for developing high selective, high potent antagonists and agonists of D3R. PMID- 22931311 TI - Abstracts of the XXIXth Congress of the International Academy of Pathology. September 30-October 5, 2012. Cape Town, South Africa. PMID- 22931310 TI - ZnO nanoparticles-catalyzed cyclocondensation reaction of arylmethylidenepyruvic acids with 6-aminouracils. AB - A new, efficient, and solvent-free cyclocondensation reaction of arylmethylidenepyruvic acids with 6- aminouracils is presented that uses a catalytic amount of ZnO nanoparticles (ZnO Nps) as a recyclable catalyst at 70 degrees C. This protocol has the advantages of high yields (91-98%), easy work up, very short reaction time (2 h), and using environmentally friendly procedure. PMID- 22931312 TI - Homozygosity for a mutation in the CYP11B2 gene in an infant with congenital corticosterone methyl oxidase deficiency type II. AB - Isolated aldosterone synthase deficiency can be the source of life-threatening salt wasting and failure to thrive in infancy. We studied an infant with failure to thrive and persistent hyponatremia despite oral sodium supplementation. Initial analyses revealed highly elevated plasma renin but normal values of plasma aldosterone. The biochemical diagnosis of corticosterone methyl oxidase deficiency type II was established by multisteroid analysis, revealing a pathognomonic pattern with a highly elevated ratio of 18-OH-corticosterone to aldosterone. This reflects an enzymatic defect in the aldosterone synthase that is responsible for the terminal steps in the aldosterone biosynthesis. Molecular genetic analysis supported the diagnosis revealing homozygosity for a pathogenic c.554C>T (p.T185I) variation in exon 3 of the CYP11B2 gene encoding aldosterone synthase. Homozygosity for two other polymorphic variations c.504C>T (p.F168F) and c.518A>G (p.K173R) were identified as well. Treatment with fludrocortisone resulted in catch-up growth. Discontinuation of treatment at the age of 9 years was later possible without any clinical or biochemical deterioration. CONCLUSIONS: Isolated deficiency in aldosterone biosynthesis should be considered in neonates and infants with failure to thrive and salt wasting. Normal levels of plasma aldosterone compared with highly elevated levels of plasma renin indicate an impaired aldosterone biosynthesis and suggest the disorder. Recognition of its existence is important as fludrocortisone replacement therapy effectively normalizes sodium balance and growth. PMID- 22931313 TI - Diversity oriented synthesis of pyran based polyfunctional stereogenic macrocyles and their conformational studies. AB - A new approach to synthesize a homologous series of 14-, 15-, and 16-membered drug-like, macrocyclic glycoconjugates involving TBAHS promoted azide-propenone intramolecular cycloaddition in designed C-glycopyranosyl butenones from a simple sugar d-glucose and d-mannose is reported. PMID- 22931314 TI - HLA-C-dependent prevention of leukemia relapse by donor activating KIR2DS1. AB - BACKGROUND: Of the cancers treated with allogeneic hematopoietic stem-cell transplantation (HSCT), acute myeloid leukemia (AML) is most sensitive to natural killer (NK)-cell reactivity. The activating killer-cell immunoglobulin-like receptor (KIR) 2DS1 has ligand specificity for HLA-C2 antigens and activates NK cells in an HLA-dependent manner. Donor-derived NK reactivity controlled by KIR2DS1 and HLA could have beneficial effects in patients with AML who undergo allogeneic HSCT. METHODS: We assessed clinical data, HLA genotyping results, and donor cell lines or genomic DNA for 1277 patients with AML who had received hematopoietic stem-cell transplants from unrelated donors matched for HLA-A, B, C, DR, and DQ or with a single mismatch. We performed donor KIR genotyping and evaluated the clinical effect of donor KIR genotype and donor and recipient HLA genotypes. RESULTS: Patients with AML who received allografts from donors who were positive for KIR2DS1 had a lower rate of relapse than those with allografts from donors who were negative for KIR2DS1 (26.5% vs. 32.5%; hazard ratio, 0.76; 95% confidence interval [CI], 0.61 to 0.96; P=0.02). Of allografts from donors with KIR2DS1, those from donors who were homozygous or heterozygous for HLA-C1 antigens could mediate this antileukemic effect, whereas those from donors who were homozygous for HLA-C2 did not provide any advantage (24.9% with homozygosity or heterozygosity for HLA-C1 vs. 37.3% with homozygosity for HLA-C2; hazard ratio, 0.46; 95% CI, 0.28 to 0.75; P=0.002). Recipients of KIR2DS1-positive allografts mismatched for a single HLA-C locus had a lower relapse rate than recipients of KIR2DS1-negative allografts with a mismatch at the same locus (17.1% vs. 35.6%; hazard ratio, 0.40; 95% CI, 0.20 to 0.78; P=0.007). KIR3DS1, in positive genetic linkage disequilibrium with KIR2DS1, had no effect on leukemia relapse but was associated with decreased mortality (60.1%, vs. 66.9% without KIR3DS1; hazard ratio, 0.83; 95% CI, 0.71 to 0.96; P=0.01). CONCLUSIONS: Activating KIR genes from donors were associated with distinct outcomes of allogeneic HSCT for AML. Donor KIR2DS1 appeared to provide protection against relapse in an HLA-C-dependent manner, and donor KIR3DS1 was associated with reduced mortality. (Funded by the National Institutes of Health and others.). PMID- 22931316 TI - MYD88 L265P somatic mutation in Waldenstrom's macroglobulinemia. AB - BACKGROUND: Waldenstrom's macroglobulinemia is an incurable, IgM-secreting lymphoplasmacytic lymphoma (LPL). The underlying mutation in this disorder has not been delineated. METHODS: We performed whole-genome sequencing of bone marrow LPL cells in 30 patients with Waldenstrom's macroglobulinemia, with paired normal tissue and tumor-tissue sequencing in 10 patients. Sanger sequencing was used to validate the findings in samples from an expanded cohort of patients with LPL, those with other B-cell disorders that have some of the same features as LPL, and healthy donors. RESULTS: Among the patients with Waldenstrom's macroglobulinemia, a somatic variant (T->C) in LPL cells was identified at position 38182641 at 3p22.2 in the samples from all 10 patients with paired tissue samples and in 17 of 20 samples from patients with unpaired samples. This variant predicted an amino acid change (L265P) in MYD88, a mutation that triggers IRAK-mediated NF kappaB signaling. Sanger sequencing identified MYD88 L265P in tumor samples from 49 of 54 patients with Waldenstrom's macroglobulinemia and in 3 of 3 patients with non-IgM-secreting LPL (91% of all patients with LPL). MYD88 L265P was absent in paired normal tissue samples from patients with Waldenstrom's macroglobulinemia or non-IgM LPL and in B cells from healthy donors and was absent or rarely expressed in samples from patients with multiple myeloma, marginal-zone lymphoma, or IgM monoclonal gammopathy of unknown significance. Inhibition of MYD88 signaling reduced IkappaBalpha and NF-kappaB p65 phosphorylation, as well as NF-kappaB nuclear staining, in Waldenstrom's macroglobulinemia cells expressing MYD88 L265P. Somatic variants in ARID1A in 5 of 30 patients (17%), leading to a premature stop or frameshift, were also identified and were associated with an increased disease burden. In addition, 2 of 3 patients with Waldenstrom's macroglobulinemia who had wild-type MYD88 had somatic variants in MLL2. CONCLUSIONS: MYD88 L265P is a commonly recurring mutation in patients with Waldenstrom's macroglobulinemia that can be useful in differentiating Waldenstrom's macroglobulinemia and non-IgM LPL from B-cell disorders that have some of the same features. (Funded by the Peter and Helen Bing Foundation and others.). PMID- 22931317 TI - A new phlebovirus associated with severe febrile illness in Missouri. AB - Two men from northwestern Missouri independently presented to a medical facility with fever, fatigue, diarrhea, thrombocytopenia, and leukopenia, and both had been bitten by ticks 5 to 7 days before the onset of illness. Ehrlichia chaffeensis was suspected as the causal agent but was not found on serologic analysis, polymerase-chain-reaction (PCR) assay, or cell culture. Electron microscopy revealed viruses consistent with members of the Bunyaviridae family. Next-generation sequencing and phylogenetic analysis identified the viruses as novel members of the phlebovirus genus. Although Koch's postulates have not been completely fulfilled, we believe that this phlebovirus, which is novel in the Americas, is the cause of this clinical syndrome. PMID- 22931318 TI - Clinical practice. Infections of cardiovascular implantable electronic devices. PMID- 22931319 TI - Images in clinical medicine. Cerebral air embolism. PMID- 22931320 TI - Case records of the Massachusetts General Hospital. Case 27-2012. A 60-year-old woman with painful muscle spasms and hyperreflexia. PMID- 22931321 TI - Lifelong management of amyloid-beta metabolism to prevent Alzheimer's disease. PMID- 22931322 TI - Control of acute myeloid leukemia relapse--dance between KIRs and HLA. PMID- 22931324 TI - Prednisone, azathioprine, and N-acetylcysteine for pulmonary fibrosis. PMID- 22931325 TI - Prednisone, azathioprine, and N-acetylcysteine for pulmonary fibrosis. PMID- 22931326 TI - Prednisone, azathioprine, and N-acetylcysteine for pulmonary fibrosis. PMID- 22931328 TI - Natalizumab-associated progressive multifocal leukoencephalopathy. PMID- 22931329 TI - Natalizumab-associated progressive multifocal leukoencephalopathy. PMID- 22931331 TI - Preoperative chemoradiotherapy for esophageal cancer. PMID- 22931315 TI - Effects of clopidogrel added to aspirin in patients with recent lacunar stroke. AB - BACKGROUND: Lacunar infarcts are a frequent type of stroke caused mainly by cerebral small-vessel disease. The effectiveness of antiplatelet therapy for secondary prevention has not been defined. METHODS: We conducted a double-blind, multicenter trial involving 3020 patients with recent symptomatic lacunar infarcts identified by magnetic resonance imaging. Patients were randomly assigned to receive 75 mg of clopidogrel or placebo daily; patients in both groups received 325 mg of aspirin daily. The primary outcome was any recurrent stroke, including ischemic stroke and intracranial hemorrhage. RESULTS: The participants had a mean age of 63 years, and 63% were men. After a mean follow-up of 3.4 years, the risk of recurrent stroke was not significantly reduced with aspirin and clopidogrel (dual antiplatelet therapy) (125 strokes; rate, 2.5% per year) as compared with aspirin alone (138 strokes, 2.7% per year) (hazard ratio, 0.92; 95% confidence interval [CI], 0.72 to 1.16), nor was the risk of recurrent ischemic stroke (hazard ratio, 0.82; 95% CI, 0.63 to 1.09) or disabling or fatal stroke (hazard ratio, 1.06; 95% CI, 0.69 to 1.64). The risk of major hemorrhage was almost doubled with dual antiplatelet therapy (105 hemorrhages, 2.1% per year) as compared with aspirin alone (56, 1.1% per year) (hazard ratio, 1.97; 95% CI, 1.41 to 2.71; P<0.001). Among classifiable recurrent ischemic strokes, 71% (133 of 187) were lacunar strokes. All-cause mortality was increased among patients assigned to receive dual antiplatelet therapy (77 deaths in the group receiving aspirin alone vs. 113 in the group receiving dual antiplatelet therapy) (hazard ratio, 1.52; 95% CI, 1.14 to 2.04; P=0.004); this difference was not accounted for by fatal hemorrhages (9 in the group receiving dual antiplatelet therapy vs. 4 in the group receiving aspirin alone). CONCLUSIONS: Among patients with recent lacunar strokes, the addition of clopidogrel to aspirin did not significantly reduce the risk of recurrent stroke and did significantly increase the risk of bleeding and death. (Funded by the National Institute of Neurological Disorders and Stroke and others; SPS3 ClinicalTrials.gov number, NCT00059306.). PMID- 22931332 TI - Preoperative chemoradiotherapy for esophageal cancer. PMID- 22931333 TI - Preoperative chemoradiotherapy for esophageal cancer. PMID- 22931335 TI - Reproductive technologies and the risk of birth defects. PMID- 22931336 TI - Reproductive technologies and the risk of birth defects. PMID- 22931338 TI - Anti-CD20 antibody therapy for B-cell lymphomas. PMID- 22931339 TI - Anti-CD20 antibody therapy for B-cell lymphomas. PMID- 22931340 TI - Anti-CD20 antibody therapy for B-cell lymphomas. PMID- 22931341 TI - Acute hepatic necrosis and ischemic limb necrosis. PMID- 22931345 TI - Images in clinical medicine. Voluntary nystagmus. PMID- 22931346 TI - Structure and magnetism of Sr3Co2O4Cl2--an electronically driven lattice distortion in an oxychloride containing square planar Co(II) centers. AB - Topochemical reduction of Sr(3)Co(2)O(5)Cl(2) with NaH at 200 degrees C yields Sr(3)Co(2)O(4)Cl(2), a phase consisting of infinite double sheets of corner linked Co(II)O(4) square planes stacked with SrCl rocksalt layers. At 298 K, the structure of Sr(3)Co(2)O(4)Cl(2) is described in the tetragonal space group I4/mmm [a = 4.007(1) A, c = 22.282(1) A]; however, on cooling below 200 K, the structure undergoes a lattice distortion to adopt a structure with orthorhombic symmetry in space group Immm [a = 3.9757(5) A, b = 4.0294(5) A, and c = 22.147(3) A at 5 K]. The structural distortion can be considered Jahn-Teller-like as it lifts the orbital degeneracy of the square planar, d(7), Co(II) centers, demonstrating a strong coupling between the electronic configuration and the structural lattice of this oxychloride phase. On cooling below 50 K, Sr(3)Co(2)O(4)Cl(2) adopts a canted antiferromagnetically ordered state. All magnetization data show that the local cobalt moment is much greater than would be expected for a simple spin-only S = 3/2 center, indicating a strong orbital contribution to the magnetic behavior. PMID- 22931347 TI - Access to ultralarge-pore ordered mesoporous materials through selection of surfactant/swelling-agent micellar templates. AB - The surfactant-micelle-templating method has revolutionized the synthesis of high surface-area materials with mesopores (diameter 2-50 nm) that have well-defined shapes and sizes. One of the major benefits of this method is the ability to tailor the pore size by manipulating the size of the templating micelles. The uniform pores typically form ordered arrays. Although the choice of surfactant can tune the size of the micelles, it is more convenient to use a single surfactant and tailor the micelle size by adding a swelling agent. Unfortunately, the swelling agent tends to induce disorder or heterogeneity in the resulting structures, which can make this approach difficult to implement. We hypothesized that the swelling agents that are moderately solubilized within the micelles of a particular surfactant could generate well-defined micelle-templated structures with significantly enlarged pores. Using this idea, we could judiciously select candidate swelling agents from families of compounds whose extent of solubilization in the surfactant micelles systematically changes with variations in the compound structure. Alkyl-substituted benzenes proved very useful as swelling agents, because their extent of solubilization in micelles of common Pluronic surfactants (EO(m)PO(n)EO(m); EO = ethylene oxide, PO = propylene oxide) significantly increases as the number or size of alkyl substituents decreases. On the basis of these principles, we identified 1,3,5-triisopropylbenzene and cyclohexane as swelling agents for the synthesis of ultralarge-pore SBA-15 silica (pore diameter up to 26 nm) and organosilicas with 2-D hexagonal structures of cylindrical mesopores. Moreover, we used xylene, ethylbenzene, and toluene as swelling agents for the synthesis of large-pore (pore diameter up to 37 nm) face centered cubic silicas and organosilicas with spherical mesopores. During the early stages of the synthesis, the entrances to large cylindrical and spherical mesopores of these materials were much smaller than the inner pore diameter. Therefore we can often use calcination at sufficiently high temperatures (400-950 degrees C) to produce closed-pore silicas. Using hydrothermal treatments, we can obtain materials with large pore entrance sizes. In Pluronic-templated synthesis, we observed the propensity for formation of single-micelle-templated nanoparticles as the ratio of the framework precursor to surfactant decreased, and this process afforded organosilica nanotubes and uniform hollow spheres with inner diameters up to ~21 nm. Consequently, the adjustment of variables in the micelle-templated synthesis allows researchers to tailor the pore size and connectivity and to form either periodic pore arrays or individual nanoparticles. PMID- 22931348 TI - Effects of a cell-imprinted poly(dimethylsiloxane) surface on the cellular activities of MG63 osteoblast-like cells: preparation of a patterned surface, surface characterization, and bone mineralization. AB - To understand the relationship between surface patterns and cellular activities, various types of pattern models have been investigated. In this study, we suggest a new surface pattern model, which replicates proliferated cells. We used osteoblast-like cells (MG63) as a target cell pattern and constructed various cell-imprinted surfaces using an electric field assisted casting method for different culturing times (4 h and 7 and 14 days). On the basis of scanning electron microscopy images and three-dimensional topographical optical images, we acquired the cells' unique patterns and used them for replicating patterned substrates. We then cultured MG63 cells in the patterned surfaces for 7 and 14 days to observe various cellular activities, cell viability, alkaline phosphatase (ALP) activity, and mineralization. Higher cellular activities were observed on the roughened surface as compared with the smooth surface. In particular, we obtained the most appropriate roughness value (R(a) = 702 +/- 87 nm) from proliferated cells cultured over 14 days. On the basis of these findings, we demonstrate a new biomimical surface model that enhances cellular activities at the cell-substrate interface. PMID- 22931349 TI - Concentration-dependent structural transitions of human telomeric DNA sequences. AB - Oligodeoxyribonucleotides (ODNs) that have four repeats of the human telomeric sequence d(TTAGGG)(n) can assume multiple monomolecular G-quadruplex topologies. These are determined by the cation species present, the bases at the 5' or 3' end, and the sample preparation technique. In this work, we report our studies of the concentration dependence of the circular dichroism (CD) and the vibrational modes probed by Raman scattering of three previously characterized monomolecular G-quadruplexes: H-Tel, d[5'-A(GGGTTA)(3)GGG-3']; hybrid-1, d[5' AAA(GGGTTA)(3)GGGAA-3']; and hybrid-2, d[5'-TTA(GGGTTA)(3)GGGTT-3']. At high (millimolar) ODN concentrations, we observed a transformation of the CD spectrum of H-Tel, with a relaxation time on the order of 10 h. Analysis of the kinetics of this process is consistent with the formation of an aggregated complex of folded H-Tel monomers. Upon dilution, the aggregates dissociate rapidly, yielding spectra identical to those of monomeric H-Tel. Both hybrid sequences undergo a similar transition under high-salt (1 M) conditions. The measurements suggest that for these ODN concentrations, which are typically used in high-resolution spectroscopies, the monomolecular G-quadruplex structures undergo a transition to multimolecular structures at room temperature. Guided by our findings, we propose that the terminal bases of the hybrid-1 and hybrid-2 ODNs impede the formation of these aggregates; however, in solutions containing 1 M salt, the hybrid oligonucleotides aggregate. PMID- 22931350 TI - Proteomic analysis of 'Zaosu' pear (Pyrus bretschneideri Rehd.) and its red skin bud mutation. AB - BACKGROUND: Breeding for strong red skin color is an important objective of the pear breeding program. There are few reports of proteome research in green skin pear and its red skin bud mutation. The manuscript at hand is one of the first studies dealing with 2D-PAGE-based analysis of pear fruits and leaves, establishing a suitable sample preparation and testing different 2D-PAGE protocols. Therefore, it may grant a basis for further studies on the pear proteome being the studies main goal. A proteomic analysis was conducted on leaves and fruits of 'Zaosu' pear (Pyrus bretschneideri Rehd.) and its red skin bud mutation in order to reveal their genetic differences in the protein level. RESULTS: In the present study, the optimized two-dimensional (2-D) gel electrophoresis system of pear leaf and fruit was set up, and applied to analyze the leaves and fruit protein. The interesting peptide fragments were determined using 4800 Plus MALDI TOF/TOFTM Analyzer mass spectrometer, and the sequence obtained was blasted in NCBInr to identify the differentially-expressed protein. In the 1.5-fold differently-expressed proteins between 'Zaosu' pear and its mutant, 10 out of 35 proteins in fruit and 12 out of 24 ones in leaves were identified successfully. Among the 22 identified proteins, 7 protein spots were related to photosynthesis and energy metabolism; 4 were associated with environmental stress; 4 with disease defense; 2 with amino acid metabolism; 2 with cytoskeleton; 1 with antioxidant function; 1 with calcium metabolism; and 1 with unknown function. Moreover, related physiological index, such as chlorophyll content, Rubisco content and polyphone oxidase activity, were different between 'Zaosu' pear and its mutant. CONCLUSION: A 2-D gel electrophoresis system of pear leaves and fruits was established, which was suitable for the analysis of proteome comparison. To the best of our knowledge, we have performed the first analysis of the proteomic changes in leaves and fruits of 'Zaosu' pear and its red skin bud mutation. Our study provides important information on the use of proteomic methods for studying protein regulation of 'Zaosu' pear and its red skin bud mutation. PMID- 22931351 TI - A novel forged image detection method using the characteristics of interpolation. AB - Development of digital image-editing programs has enabled us to be widely exposed to forged digital images surrounding us. Such forged images have been dispersed through the Internet, newspaper articles, and magazines, and in particular, the information contained in these unverified images happened to be regarded as true. As a result, the forged images provided wrong information for individuals and society, thus sometimes creating social issues. In order to solve such problems, this study was aimed to suggest the methods of identifying the veracity of forged images. In this way, it suggested re-interpolation algorithm. Namely, the study re-interpolated in identical arbitrary values both the interpolated and un interpolated regions based on the interpolation used a lot in forged, confirmed discrete fourier transform (DFT) characteristics of these two regions, and embodied a detection map for the final forged images, using the subtraction value between two regions in DFT characteristics. PMID- 22931353 TI - Sample transport by pneumatic tube system alters results of multiple electrode aggregometry but not rotational thromboelastometry. AB - Pneumatic tube systems (PTS) present a convenient way for blood sample transport in medical facilities. Associated preanalytical interference in various tests is largely unknown. Implementing point-of-care coagulation management at our institution, we investigated multiple electrode aggregometry (MEA) and rotational thromboelastometry (ROTEM) after PTS transportation. Whole blood samples from patients undergoing general or trauma surgery were analysed by MEA after collection (baseline, '0 * PTS') and sent on a predefined PTS track (n = 12). MEA was repeated after samples travelled the track 4 ('4 * PTS'), 8 ('8 * PTS') and 12 times ('12 * PTS') and compared with stationary controls analysed at the same time. Samples for ROTEM (n = 6) were analysed after collection and travelling the track 12 times. An acceleration detector recorded g-forces on the PTS track. At '0 * PTS' no significant differences in MEA results were detected. Values were significantly lower for transported samples compared with controls ('4 * PTS' to '12 * PTS', p < 0.001). Furthermore, MEA results of PTS samples were significantly decreased for '4 * PTS' to '12 * PTS' compared to baseline (p < 0.001). Except for the clotting time in EXTEM PTS transport did not significantly alter results for investigated ROTEM parameters, compared with baseline and stationary controls. Acceleration detector readout revealed alternating g-forces between -6.3 and +5.9 during transport. PTS transport caused invalid results in MEA while only one ROTEM parameter was found to be affected in this study. Variable acceleration during transport provides a potential reason for platelet activation. The authors recommend sample transport by hand or the device to be placed patient-side when MEA is performed. PMID- 22931352 TI - Daidzein induces neuritogenesis in DRG neuronal cultures. AB - BACKGROUND: Daidzein, a phytoestrogen found in isoflavone, is known to exert neurotrophic and neuroprotective effects on the nervous system. Using primary rat dorsal root ganglion (DRG) neuronal cultures, we have examined the potential neurite outgrowth effect of daidzein. METHODS: Dissociated dorsal root ganglia (DRG) cultures were used to study the signaling mechanism of daidzein-induced neuritogenesis by immunocytochemistry and Western blotting. RESULTS: In response to daidzein treatment, DRG neurons showed a significant increase in total neurite length and in tip number per neuron. The neuritogenic effect of daidzein was significantly hampered by specific blockers for Src, protein kinase C delta (PKCdelta) and mitogen-activated protein kinase/extracellular signal-regulated kinase kinases (MEK/ERK), but not by those for estrogen receptor (ER). Moreover, daidzein induced phosphorylation of Src, PKCdelta and ERK. The activation of PKCdelta by daidzein was attenuated in the presence of a Src kinase inhibitor, and that of ERK by daidzein was diminished in the presence of either a Src or PKCdelta inhibitor. CONCLUSION: Daidzein may stimulate neurite outgrowth of DRG neurons depending on Src kinase, PKCdelta and ERK signaling pathway. PMID- 22931354 TI - An unusual aneurysm of a basilar perforating artery presenting with a subarachnoid haemorrhage. AB - A 65-year-old man had a perimesencephalic subarachnoid haemorrhage with normal angiography initially. After a rebleed 5 days later, a repeat angiogram revealed a pea-like aneurysm a short distance behind and below the basilar bifurcation. It was not amenable to endovascular treatment and the feeding vessel was coagulated and divided at open surgery via a sub temporal approach. He developed a right hemiparesis and dysphasia, from which he slowly recovered. Basilar perforating artery aneurysms are extremely rare, with only 4 previous cases reported. PMID- 22931356 TI - Transient complete lower facial nerve palsy after craniotomy for aneurysm clipping. AB - We present the case of a 41-year old female who developed a complete facial nerve palsy after an interhemispheric approach for clipping of a distal anterior cerebral artery aneurysm. Work-up revealed that she had developed acute parotitis during surgery, possibly from obstruction of the parotid duct by the tracheal tube. PMID- 22931355 TI - Air travel after intracranial surgery: a survey of advice given to patients by consultant neurosurgeons in the UK. AB - OBJECTIVE: Air travel following intracranial surgery is considered to be associated with a risk of tension pneumocephalus. However, the likelihood of it is currently undetermined in the literature. We decided to establish if there was any consensus amongst UK neurosurgeons with regard to advice given to patients. METHODS: A questionnaire was approved by the Scientific Meeting Committee of the Society of British Neurological Surgeons (SBNS) and then distributed to all current practicing Consultant Neurosurgeons in the UK via e-mail. RESULTS: 61/66 responders advised patients not to fly for a period of time postoperatively. 35/61 of these neurosurgeons advised a fixed post-operative timescale against flying irrespective of the nature of surgery. The remaining 26/61 advised patients with complex surgical procedures against flying for a longer period. However, the timescales advised by different surgeons in both categories varied between <2 weeks and >8 weeks. Pneumocephalus was the main concern for air travel (42/61) and 17/61 precluded flying due to concerns regarding complications away from home. 3/61 were concerned with deep vein thrombosis. CT scans were obtained prior to discharge by 11/61 of these neurosurgeons. 5/66 neurosurgeons did not advise patients against flying and their advice was independent of the type of surgery. Only one of these 5 neurosurgeons obtained a pre-discharge CT scan. CONCLUSION: Clinical practice varies widely due to a lack of clear evidence, standards or guidelines. Should the SBNS be producing national guidelines to standardise the advice given to patients? PMID- 22931357 TI - Traumatic intracranial prolapse of eye ball - a case report. AB - We report a rare condition in a child where the skull fracture was associated with prolapse of orbital contents into anterior cranial fossa. CT scan findings are very much pathognomonic. This patient was operated, orbital contents have been relocated and orbital roof was reconstructed, but vision could not be restored. PMID- 22931358 TI - Corticospinal tractography as a prognosticator for motor improvement after brainstem cavernoma resection. AB - Given their highly eloquent location, surgical morbidity of brainstem cavernomas (BSCs) remain significant. Currently, there are no clinical factors or imaging techniques that can reliably predict post-operative motor improvement. Diffusion tensor imaging (DTI) might have some prognostic value. We present a case supporting the use of DTI as predictor of motor recovery following brainstem surgery. PMID- 22931359 TI - Comparison of activity level among patients with chronic liver disease. AB - PURPOSE: To determine whether self-reported maximal and daily activity levels are impaired among patients with nonalcoholic fatty liver disease (NAFLD), hepatitis C (HCV) and hepatitis B (HBV). METHODS: Clinicodemographic, diagnostic, self report and standard laboratory data were obtained. Univariate, multivariate and regression analyses were performed comparing group maximal (Maximum Activity Score [MAS]) and daily activity scores (Adjusted Activity Score [AAS]), adjusted for age and gender. RESULTS: Two hundred twenty-two patients completed activity level self-reports (mean age [52.4 +/- 10.0 years], BMI [28.3 +/- 6.58], 31.2% NAFLD, 48.3% HCV, 20.3% HBV). On multivariate analysis, significantly higher MAS (p < 0.05) and AAS in HBV patients correlated with absence of cirrhosis, younger age, male gender (higher MAS) and lower BMI (higher AAS). Lowest activity levels were found primarily in obese patients (p < 0.009). Compared with population norms, NAFLD and HCV cohorts scored mildly disabled on MAS; the HBV cohort scored low normal. Mild disability on AAS was observed in patients with HBV; moderate disability in those with NAFLD, HCV. CONCLUSIONS: All groups had significantly lower activity levels than population norms. Nonobese patients showed significantly less disability than obese patients. Patients with NAFLD and HCV are likely to have lower levels than those with HBV without cirrhosis. This presents an additional risk factor for disability and mortality. IMPLICATIONS FOR REHABILITATION: * Hepatitis B (HBV), hepatitis C (HCV), and nonalcoholic fatty liver disease (NAFLD) patients had significantly lower activity levels than expected for their age and gender, as measured by the Human Activity Profile (HAP). * Overweight and normal weight chronic liver disease (CLD) patients showed significantly less disability than obese chronic liver disease patients. * Patients with NAFLD and HCV are likely to participate in low levels of activity that require fewer metabolic equivalents for completion, adding an additional risk factor for disability and mortality. * Targeting low activity level in CLD patients, and decreasing BMI below the obesity threshold, may reduce disability and risk of mortality. PMID- 22931360 TI - Diagnostic accuracy of multidetector computed tomography in the detection of left atrial/left atrial appendage thrombus: a meta-analysis. AB - BACKGROUND AND OBJECTIVE: The current results on the diagnostic accuracy of multidetector computed tomography (MDCT) in the detection of left atrial/left atrial appendage (LA/LAA) thrombus are conflicting. AIM: The aim of the present study was to determine the diagnostic accuracy of MDCT in LA/LAA thrombus with meta-analysis. METHODS: We searched for studies in PubMed, Embase and Cochrane library prior to May 2012 evaluating the accuracy of MDCT in detecting LA/LAA thrombus. Primary results were summarised using a random-effects model or a fixed effects model. Receiver operating characteristic curves were used to summarise overall diagnosis accuracy. Metaregression and subgroup analysis were used to explore the potential sources of heterogeneity. RESULTS: A total of 10 studies with 1313 subjects was included in this meta-analysis. The summary estimates of sensitivity, specificity, positive likelihood ratio, negative likelihood ratio, diagnostic odds ratio and the area under cure of overall analysis were 0.84, 0.93, 9.32, 0.21, 50.84 and 0.951, respectively, but all with significant heterogeneity (P < 0.01). Meta-regression and subgroup analysis showed that using electrocardiogram (ECG)-gating technique was a source of heterogeneity (P = 0.022); studies using ECG-gating technique had a higher summary sensitivity than studies with non-gating technique (0.97 vs 0.33). CONCLUSION: Our results suggest that MDCT is a potentially useful technique in the diagnosis of LA/LAA thrombus, especially when ECG gating is applied. PMID- 22931361 TI - Design of efficient thermally activated delayed fluorescence materials for pure blue organic light emitting diodes. AB - Efficient thermally activated delayed fluorescence (TADF) has been characterized for a carbazole/sulfone derivative in both solutions and doped films. A pure blue organic light emitting diode (OLED) based on this compound demonstrates a very high external quantum efficiency (EQE) of nearly 10% at low current density. Because TADF only occurs in a bipolar system where donor and acceptor centered (3)pipi* states are close to or higher than the triplet intramolecular charge transfer ((3)CT) state, control of the pi-conjugation length of both donor and acceptor is considered to be as important as breaking the pi-conjugation between them in blue TADF material design. PMID- 22931364 TI - Mechanisms of toxicity of amorphous silica nanoparticles on human lung submucosal cells in vitro: protective effects of fisetin. AB - There is growing evidence that amorphous silica nanoparticles (SiO2-NP) can cause an inflammatory response in the lung. We studied in vitro the effects of exposing human lung submucosal cells to SiO2-NP of various sizes (10, 150, and 500 nm) for 2-24 h. Cell survival, reactive oxygen species (ROS), malondialdehyde (MDA) levels, cytokine production, inflammatory gene expression, and genotoxicity were measured after exposure of Calu-3 cells to 10SiO2-NP in the presence or absence of the flavanoid fisetin and an antioxidant enzyme catalase. The exposure of Calu 3 cells to 10SiO2-NP resulted in (1) increased cytotoxicity and cell death in a time- and concentration-dependent manner, with a lethal concentration (LC50) of 9.7 MUg/mL after 24 h; (2) enhanced gene expression of interleukin (IL)-6, IL-8, and matrix metalloproteinase-9; (3) a significant correlation between increases in MDA and cytotoxicity at 18 h; (4) ROS production; (5) IL-6 and IL-8 release; and (6) up-regulation of the pro-apoptotic genes, p53 and caspase-3. Cell death and inflammatory reactions were attenuated by fisetin and catalase. We observed that 150- and 500SiO2-NP exerted no toxic effects on Calu-3 cells. In conclusion, the nanotoxicity of amorphous 10SiO2-NP on submucosal cells is associated with inflammation, the release of ROS leading to apoptosis, and decreased cell survival. The nanotoxic effects of 10SiO2-NP can be decreased by fisetin and catalase treatment, implicating oxidative stress in this injury. PMID- 22931363 TI - Potential risk of HIV transmission in barbering practice in Ethiopia: from public health and microbiological perspectives. AB - BACKGROUND: HIV and other blood borne infections can be transmitted through the use of improperly sterilized and disinfected sharp equipments. METHODS: A cross sectional study was conducted from January to June, 2010 to assess the potential risk of HIV transmission in barbering practice in Ethiopia from public health and microbiological perspectives. Barbers in barbershop were interviewed using pre designed questionnaires and check lists were used to evaluate barbering practice. Microbiological data from tips of the sharpener before and after the barbering was collected and processed as per the standard procedure. RESULTS: One hundred and twenty three barbering sessions and barbers were observed in which 106 (86.2%) were males. Ninety six (78%) of the respondents knew that HIV could be transmitted by sharing non-sterile sharp instruments. Among the total participants 59 (48%) had the correct knowledge of what sterilization mean and 111 (94.1%) of them believed its importance in their work place. Barbers had a mean knowledge score of 6 +/- 1.5 out of a score of 10 regarding sterilization and disinfection as well as in the transmission of HIV in their work place. Three (2.5%) barbers were disagreed that unsterilized blade can transmit skin diseases and 26 (21.3%) of them believed disinfection is enough to avoid microbes from sharp objects. Ninety two (76.7%) barbers were using sterilization in their establishment. According to Likert scaling almost all sterilization and disinfection procedures were riskily practiced and respondents had poor level of knowledge. No significant association was found to influence the decontamination and sterilization of barbering equipments except monthly income, pre and post colony count of microbes identified. The isolation of normal skin flora in the pre-and post-sterilization and disinfectant procedures and less average percent colony reduction showed that sterilization and disinfectant practices in barbershop were generally poor that proofed proper sterilization and/or disinfection techniques were unfavorable. CONCLUSION: This study has revealed the presence of potential risk of HIV and other blood borne disease transmission among the barbers of the study areas. Thus continuous and intensified public health strategies on health education, training, supervision and monitoring are needed to facilitate the adoption of effective methods of sterilization and/or disinfection. PMID- 22931362 TI - Integrase-deficient lentiviral vectors mediate efficient gene transfer to human vascular smooth muscle cells with minimal genotoxic risk. AB - We have previously shown that injury-induced neointima formation was rescued by adenoviral-Nogo-B gene delivery. Integrase-competent lentiviral vectors (ICLV) are efficient at gene delivery to vascular cells but present a risk of insertional mutagenesis. Conversely, integrase-deficient lentiviral vectors (IDLV) offer additional benefits through reduced mutagenesis risk, but this has not been evaluated in the context of vascular gene transfer. Here, we have investigated the performance and genetic safety of both counterparts in primary human vascular smooth muscle cells (VSMC) and compared gene transfer efficiency and assessed the genotoxic potential of ICLVs and IDLVs based on their integration frequency and insertional profile in the human genome. Expression of enhanced green fluorescent protein (eGFP) mediated by IDLVs (IDLV-eGFP) demonstrated efficient transgene expression in VSMCs. IDLV gene transfer of Nogo B mediated efficient overexpression of Nogo-B in VSMCs, leading to phenotypic effects on VSMC migration and proliferation, similar to its ICLV version and unlike its eGFP control and uninfected VSMCs. Large-scale integration site analyses in VSMCs indicated that IDLV-mediated gene transfer gave rise to a very low frequency of genomic integration compared to ICLVs, revealing a close-to random genomic distribution in VSMCs. This study demonstrates for the first time the potential of IDLVs for safe and efficient vascular gene transfer. PMID- 22931365 TI - Organization of T-shaped facial amphiphiles at the air/water interface studied by infrared reflection absorption spectroscopy. AB - We studied the behavior of monolayers at the air/water interface of T-shaped facial amphiphiles which show liquid-crystalline mesophases in the bulk. The compounds are composed of a rigid p-terphenyl core (TP) with two terminal hydrophobic ether linked alkyl chains of equal length and one facial hydrophilic tri(ethylene oxide) chain with a carboxylic acid end group. Due to their amphiphilic nature they form stable Langmuir films at the air/water interface. Depending on the alkyl chain length they show markedly different compression isotherms. We used infrared reflection absorption spectroscopy (IRRAS) to study the changes in molecular organization of the TP films upon compression. We could retrieve information on layer thickness, alkyl chain crystallization, and the orientation of the TP cores within the films. Films of TPs with long (16 carbon atoms: TP 16/3) and short (10 carbon atoms: TP 10/3) alkyl chains were compared. Compression of TP 16/3 leads to crystallization of the terminal alkyl chains, whereas the alkyl chains of TP 10/3 stay fluid over the complete compression range. TP 10/3 shows an extended plateau in the compression isotherm which is due to a layering transition. The mechanism of this layering transition is discussed. Special attention was paid to the question of whether a so-called roll-over collapse occurs during compression. From the beginning to the end of the plateau, the layer thickness is increased from 15 to 38 A and the orientation of the TP cores changes from parallel to the water surface to isotropic. We conclude that the plateau in the compression isotherm reflects the transition of a TP monolayer to a TP multilayer. The monolayer consists of a sublayer of well-organized TP cores underneath a sublayer of fluid alkyl chains whereas the multilayer consists of a well oriented bottom layer and a disordered top layer. Our findings do not support the model of a roll-over collapse. This study demonstrates how the IRRA band intensity of OH or OD stretching vibrations can be used to retrieve information about layer thickness and refractive indices of the film and how multicomponent IRRA bands can be fitted to retrieve information about the orientation of molecules within the monolayer. PMID- 22931366 TI - Patients' family satisfaction with needs met at the medical intensive care unit. AB - AIMS: The current study investigated the perceived importance and the perceived met needs of family members in the medical intensive care unit and assessed family members' satisfaction with needs met. BACKGROUND: Studies conducted throughout the world over the past 30 years indicate that family needs are still neglected. Unmet needs of family members of patients in the intensive care unit lead to dissatisfaction with care. DESIGN: A cross-sectional study. METHOD: A total of 70 family members of critically ill patients were included in this study conducted in a medical intensive care unit in Israel between October 2007 September 2008, using a structured interview. Three outcomes measured by the Family Satisfaction in the Intensive Care Unit Inventory were regressed separately for baseline variables and family needs met subscales as measured by the Critical Care Family Needs Inventory. Multivariate linear regression analysis was used to detect factors that could have predicted each outcome. FINDINGS: The results showed differences between the perceived importance and the perceived met needs of family members. Satisfaction with care was positively related to meeting all needs domains except the information need. However, satisfaction with information and decision-making was related only to meeting information and emotional support needs. CONCLUSION: Continued unmet needs of family members of intensive care unit patients have a negative impact on family satisfaction. Only sweeping changes in clinical practice will succeed in meeting the unmet needs of patients' families. PMID- 22931367 TI - Stress and stressors in the clinical environment: a comparative study of fourth year student nurses and newly qualified general nurses in Ireland. AB - AIMS AND OBJECTIVES: To measure and compare the perceived levels of job-related stress and stressors of newly qualified nurses and fourth-year student nurses in the clinical environment and to explore the participants' views on stress and stressors. BACKGROUND: Stress in the nursing workplace has significant consequences for the person, the patient and the organisation, such as psychological and physical health deterioration and impaired professional practice. To address this problem, stress and stressors need to be measured and identified. DESIGN: This study used a cross-sectional survey design and self reporting questionnaires to measure and compare levels of stress in both groups. Convenience sampling involved all newly qualified nurses (n = 120) and fourth year student nurses (n = 128) in Dublin North-East region in Ireland. METHODS: The instrument used was 'The Nursing Stress Scale' (Gray-Toft & Anderson 1981, Journal of Behavioral Assessment 3, 11-23). Descriptive, qualitative analysis was conducted on an open-ended question. Data were obtained from newly qualified nurses (n = 31) and fourth-year student nurses (n = 40) in six acute hospital sites. RESULTS: Levels of perceived stress and stressors were high in both groups. Themes identified from the responses to the open question by both groups included excessive workload, difficult working relationships and unmet clinical learning needs. Student nurses also reported the combination of academic demands with clinical placement as a major stressor. There was no significant difference between each group. CONCLUSION: Stress continues to be a problem for nurses in the clinical setting. Excessive workload requires urgent attention by hospital managers in view of widespread retention difficulties. Themes identified could provide a framework for possible interventions for improving the clinical environment for nurses. RELEVANCE TO CLINICAL PRACTICE: These results can help stakeholders in nurse education and practice to develop interventions to reduce stress for both groups and to ease the transition from student to graduate nurse. PMID- 22931368 TI - Acute renal failure in Congolese children: a tertiary institution experience. AB - AIM: Published data on acute renal failure in children from the Democratic Republic of Congo are rare. The objective of this study was to review clinical manifestations, aetiologies and outcome in hospitalized children with acute renal failure. METHODS: A retrospective study at Pediatric Nephrology Unit of University Hospital of Kinshasa was carried out. RESULTS: Fifty-six children with acute renal failure were eligible. There were 31 boys (55.4%) and 25 girls (44.6%) with a sex ratio of 1.24. The median age was 6.7 years (range 1-13 years). Fever (80.3%), oligo-anuria (73.2%), jaundice (67.9%) were the common clinical presentation. Blackwater fever (42.8%) was the leading cause of Acute Renal Failure. The incidence of severe dehydration because of gastroenteritis was low (5.3%). Around 12.5% of patients' misused herbal plants. Acute Peritoneal Dialysis was indicated in 15/56 children and only performed in four patients. Fourteen children (25%) died. CONCLUSION: A wide spectrum of features was seen in hospitalized Acute Renal Failure children and limited access to Acute Peritoneal Dialysis remained an important mortality risk factor. PMID- 22931369 TI - Silica nanoparticles functionalized via click chemistry and ATRP for enrichment of Pb(II) ion. AB - Silica nanoparticles have been functionalized by click chemistry and atom transfer radical polymerization (ATRP) simultaneously. First, the silanized silica nanoparticles were modified with bromine end group, and then the azide group was grafted onto the surface via covalent coupling. 3-Bromopropyl propiolate was synthesized, and then the synthesized materials were used to react with azide-modified silica nanoparticles via copper-mediated click chemistry and bromine surface-initiated ATRP. Transmission electron microscopy, Fourier transform infrared spectroscopy, X-ray photoelectron spectroscopy, and thermogravimetric analysis were performed to characterize the functionalized silica nanoparticles. We investigated the enrichment efficiency of bare silica and poly(ethylene glycol) methacrylate (PEGMA)-functionalized silica nanoparticles in Pb(II) aqueous solution. The results demonstrated that PEGMA functionalized silica nanoparticles can enrich Pb(II) more quickly than pristine silica nanoparticles within 1 h. PMID- 22931370 TI - Molecular defects in the factor X gene caused by novel heterozygous mutations IVS5+1G>A and Asp409del. AB - Factor X (FX) deficiency is a rare autosomal-recessive bleeding disorder caused by diverse mutations in the F10 gene. To investigate the molecular basis of severe FX deficiency in a mildly hemorrhagic patient, variants of the F10 gene were detected by sequencing. A missense mutation was analysed by in vitro expression and modelling analysis, and a splice mutation using ectopic transcript analysis. The levels of activity of FX (FX:C) were <1% in both intrinsic and extrinsic pathway assays and 1.71% in chromogenic assay, the level of FX antigen (FX:Ag) was 53.36% in the proband. Two novel heterozygous mutations (IVS5+1G>A and Asp409del) were identified in the F10 gene. Ectopic transcript expression combined with informative marker (heterozygous Asp409del) analysis of the splice mutation (IVS5+1G>A) revealed and confirmed that the transcript from the mutated allele was absent, likely caused by the nonsense-mediated mRNA decay pathway. In vitro expression analysis showed that the Asp409del mutant led to a loss of enzymatic activity rather than impaired expression. Molecular modelling analysis confirmed that the Asp409del mutant dramatically altered the conformation of the 185-189 loop and impaired binding of the loop to sodium ions (Na(+) ), diminishing the enzymatic activity of FXa. This is the first report to clarify the molecular mechanisms of two naturally occurring F10 gene variants that cause severe FX deficiency. PMID- 22931371 TI - Efficient synthesis of gamma-lactones via gold-catalyzed tandem cycloisomerization/oxidation. AB - A novel Au-catalyzed tandem cycloisomerization/oxidation of homopropargyl alcohols was developed. Various gamma-lactones can be accessed readily by utilizing this strategy. Notably, the mechanism of this reaction is distinctively different from the related Ru-catalyzed reactions where the ruthenium vinylidene intermediate was proposed. PMID- 22931373 TI - Picosecond rotational interconversion adjacent to a C?O bond studied by two dimensional infrared spectroscopy. AB - Molecular conformations around the C?O group of carbonyl compounds like ketones and aldehydes play an important role in determining their reaction properties in solutions, including reaction rate, mechanism, steric structure, and chirality of products. Investigating different rotational conformers and their rapid exchange at room temperature will provide information on the rotational barrier and insights into how different rotamers may contribute to fundamental reactions in chemistry. We applied two-dimensional infrared (2D IR) spectroscopy and polarization-dependent IR transient grating technique to the study of 4,4 dimethyl-2-pentanone in CCl(4). Spectroscopic evidence showed that the internal rotation around the single carbon-carbon bond adjacent to the C?O group takes place on a picosecond time scale. DFT calculations suggested the presence of three different rotational conformations, one eclipsed and two staggered forms. Spectral simulation utilized the stochastic Liouville equation with a three-state jump model and incorporated the polarization factors that take into account the different direction of transition dipole moment in the three rotamers. The effects of the intramolecular vibrational energy redistribution process on the waiting time dependence of the 2D absorptive spectra were also included. Through comprehensive simulation of the observed spectral features, the exchange time constants between the three rotamers were determined: 5.4 ps from the eclipsed to staggered forms and 1.7 ps for the reverse direction. PMID- 22931372 TI - The N-terminus and the chain-length determination domain play a role in the length of the isoprenoid product of the bifunctional Toxoplasma gondii farnesyl diphosphate synthase. AB - Toxoplasma gondii possesses a bifunctional farnesyl diphosphate (FPP)/geranylgeranyl diphosphate (GGPP) synthase (TgFPPS) that synthesizes C(15) and C(20) isoprenoid diphosphates from isopentenyl diphosphate (IPP) and dimethylallyl diphosphate (DMAPP). This enzyme has a unique arrangement of the fourth and fifth amino acid upstream from the first aspartic rich motif (FARM) where the fourth amino acid is aromatic and the fifth is a cysteine. We mutated these amino acids, converting the enzyme to an absolute FPPS by changing the cysteine to a tyrosine. The enzyme could be converted to an absolute GGPPS by changing both the fourth and fifth amino acids to alanines. We also constructed four mutated TgFPPSs whose regions around the first aspartate rich motif were replaced with the corresponding regions of FPP synthases from Arabidopsis thaliana or Saccharomyces cerevisiae or with the corresponding regions of GGPP synthases from Homo sapiens or S. cerevisiae. We determined that the presence of a cysteine at the fifth position is essential for the TgFPPS bifunctionality. We also found that the length of the N-terminal domain plays a role in determining the specificity and the length of the isoprenoid product. Phylogenetic analysis supports the grouping of this enzyme with other type I FPPSs, but the biochemical data indicate that TgFPPS has unique characteristics that differentiate it from mammalian FPPSs and GGPPSs and is therefore an important drug target. PMID- 22931374 TI - Stability of serotonin-selective antidepressants in sterile and decomposing liver tissue. AB - It is well established that bacteria are capable of degrading selected drugs during decomposition. The aim of this study was to investigate the stability of several serotonin-selective reuptake inhibitor antidepressants and venlafaxine during putrefaction in porcine liver macerate inoculated with porcine cecal contents rich in bacteria. Blank liver matrices, sterile liver macerates, and sterile aqueous controls were included with the experiment performed for 57 days at 20 degrees C under anaerobic conditions. A liquid chromatography/mass spectrometry method was developed for quantitative determination of the drugs investigated in both sterile and decomposed liver matrices. The method was found to encounter matrix effects not detected during the validation stage. Citalopram, paroxetine, sertraline, venlafaxine, and fluoxetine were found to be stable under the experimental conditions; however, fluvoxamine was found to be decreased by c. 50% over 57 days in bacterially inoculated liver macerate. This study suggests that fluvoxamine concentrations in cases with evidence of decomposition/putrefaction should be interpreted with extra caution. PMID- 22931375 TI - A review of the efficacy, safety, and cost-effectiveness of COX-2 inhibitors for Africa and the Middle East region. AB - Despite an increasingly sophisticated understanding of pain mechanisms, acute and chronic pain remain undertreated throughout the world. This situation reflects the large gap that exists between evidence and practice in pain management and is typified by inappropriate use of nonsteroidal anti-inflammatory drugs (NSAIDs). The scientific evidence around these drugs continues to expand at a high rate, yet physicians are often unaware of best practice. To address this gap among physicians in Africa and the Middle East, an Expert Panel meeting was convened with representatives from the region. The principal objective of the meeting was to review the latest guidelines on the management of acute and chronic pain and to review the efficacy, safety, and cost-effectiveness of cyclooxygenase-2 (COX 2) inhibitors in these settings. The main outcome of this review process was a number of consensus statements concerning the definitions of acute and chronic pain, and the efficacy, safety and cost-effectiveness of traditional nonselective NSAIDs (nsNSAIDs) and selective COX-2 inhibitors (coxibs). The panel agreed that nsNSAIDs and coxibs are effective analgesics with similar efficacy for acute pain; for chronic musculoskeletal pain, NSAIDs are significantly more effective than either placebo or paracetamol. Coxibs offer important safety advantages over nsNSAIDs, including gastrointestinal safety and preservation of platelet function; notably, the cardiovascular safety of coxibs has been the subject of much recent debate. Furthermore, the panel agreed there is substantial evidence to indicate that cost savings can be achieved by using celecoxib in patients at moderate to high risk of gastrointestinal adverse events, even in countries with moderate healthcare expenditures. PMID- 22931376 TI - Sequence-specific nucleic acid detection from binary pore conductance measurement. AB - We describe a platform for sequence-specific nucleic acid (NA) detection utilizing a micropipet tapered to a 2 MUm diameter pore and 3 MUm diameter polystyrene beads to which uncharged peptide nucleic acid (PNA) probe molecules have been conjugated. As the target NAs hybridize to the complementary PNA-beads, the beads acquire negative charge and become electrophoretically mobile. An applied electric field guides these NA-PNA-beads toward the pipet tip, which they obstruct, leading to an indefinite, electrically detectable, partial blockade of the pore. In the presence of noncomplementary NA, even to the level of single base mismatch, permanent pore blockade is not seen. We show application of this platform to detection of the anthrax lethal factor sequence. PMID- 22931378 TI - Condensation on superhydrophobic surfaces: the role of local energy barriers and structure length scale. AB - Water condensation on surfaces is a ubiquitous phase-change process that plays a crucial role in nature and across a range of industrial applications, including energy production, desalination, and environmental control. Nanotechnology has created opportunities to manipulate this process through the precise control of surface structure and chemistry, thus enabling the biomimicry of natural surfaces, such as the leaves of certain plant species, to realize superhydrophobic condensation. However, this "bottom-up" wetting process is inadequately described using typical global thermodynamic analyses and remains poorly understood. In this work, we elucidate, through imaging experiments on surfaces with structure length scales ranging from 100 nm to 10 MUm and wetting physics, how local energy barriers are essential to understand non-equilibrium condensed droplet morphologies and demonstrate that overcoming these barriers via nucleation-mediated droplet-droplet interactions leads to the emergence of wetting states not predicted by scale-invariant global thermodynamic analysis. This mechanistic understanding offers insight into the role of surface-structure length scale, provides a quantitative basis for designing surfaces optimized for condensation in engineered systems, and promises insight into ice formation on surfaces that initiates with the condensation of subcooled water. PMID- 22931377 TI - Transcriptome profiling in conifers and the PiceaGenExpress database show patterns of diversification within gene families and interspecific conservation in vascular gene expression. AB - BACKGROUND: Conifers have very large genomes (13 to 30 Gigabases) that are mostly uncharacterized although extensive cDNA resources have recently become available. This report presents a global overview of transcriptome variation in a conifer tree and documents conservation and diversity of gene expression patterns among major vegetative tissues. RESULTS: An oligonucleotide microarray was developed from Picea glauca and P. sitchensis cDNA datasets. It represents 23,853 unique genes and was shown to be suitable for transcriptome profiling in several species. A comparison of secondary xylem and phelloderm tissues showed that preferential expression in these vascular tissues was highly conserved among Picea spp. RNA-Sequencing strongly confirmed tissue preferential expression and provided a robust validation of the microarray design. A small database of transcription profiles called PiceaGenExpress was developed from over 150 hybridizations spanning eight major tissue types. In total, transcripts were detected for 92% of the genes on the microarray, in at least one tissue. Non annotated genes were predominantly expressed at low levels in fewer tissues than genes of known or predicted function. Diversity of expression within gene families may be rapidly assessed from PiceaGenExpress. In conifer trees, dehydrins and late embryogenesis abundant (LEA) osmotic regulation proteins occur in large gene families compared to angiosperms. Strong contrasts and low diversity was observed in the dehydrin family, while diverse patterns suggested a greater degree of diversification among LEAs. CONCLUSION: Together, the oligonucleotide microarray and the PiceaGenExpress database represent the first resource of this kind for gymnosperm plants. The spruce transcriptome analysis reported here is expected to accelerate genetic studies in the large and important group comprised of conifer trees. PMID- 22931379 TI - A concise review of the efficacy of stereotactic radiosurgery in the management of melanoma and renal cell carcinoma brain metastases. AB - Melanoma and renal cell carcinoma have a well-documented tendency to develop metastases to the brain. Treating these lesions has traditionally been problematic, because chemotherapy has difficulty crossing the blood brain barrier and whole brain radiation therapy (WBRT) is a relatively ineffective treatment against these radioresistant tumor histologies. In recent years, stereotactic radiosurgery (SRS) has emerged as an effective and minimally-invasive treatment modality for irradiating either single or multiple intracranial structures in one clinical treatment setting. For this reason, we conducted a review of modern literature analyzing the efficacy of SRS in the management of patients with melanoma and renal cell carcinoma brain metastases. In our analysis we found SRS to be a safe, effective and attractive treatment modality for managing radioresistant brain metastases and highlighted the need for randomized trials comparing WBRT alone vs. SRS alone vs. WBRT plus SRS in treating patients with radioresistant brain metastases. PMID- 22931380 TI - Microgradient-heaters as tools for high-throughput experimentation. AB - A microgradient-heater (MGH) was developed, and its feasibility as a tool for high-throughput materials science experimentation was tested. The MGH is derived from microhot plate (MHP) systems and allows combinatorial thermal processing on the micronano scale. The temperature gradient is adjustable by the substrate material. For an Au-coated MGH membrane a temperature drop from 605 to 100 degrees C was measured over a distance of 965 MUm, resulting in an average temperature change of 0.52 K/MUm. As a proof of principle, we demonstrate the feasibility of MGHs on the example of a chemical vapor deposition (CVD) process. The achieved results show discontinuous changes in surface morphology within a continuous TiO2 film. Furthermore the MGH can be used to get insights into the energetic relations of film growth processes, giving it the potential for microcalorimetry measurements. PMID- 22931381 TI - Detection of complement-fixing and non-fixing antibodies specific for endothelial precursor cells and lymphocytes using flow cytometry. AB - Donor human leukocyte antigen (HLA)-specific antibodies (Abs) with the ability to activate complement are associated with an increased risk of early Ab-mediated rejection (AMR) of kidney allografts. In recent years, also non-HLA Abs-binding endothelial cells have been shown to elicit early AMR. Donor-specific anti endothelial cell Abs escape detection in the pre-transplant evaluation if only lymphocytes are used as target cells in crossmatch tests. We addressed whether endothelial precursor cells (EPCs) could be used for detection of complement fixing as well as non-fixing Abs and if complement factor and immunoglobulin G (IgG) deposition on co-purified T and B cells correlated to the outcome of the T- and B-cell complement-dependent cytotoxicity assay. Deposition of complement factors C3c and C3d, but not C1q nor C4d, were detected on EPCs and lymphocytes upon incubation with HLA Ab-positive sera. There was a correlation between the amount of C3c deposition and IgG binding on EPCs (R(2) = 0.71, P = 0.0012) and T cells (R(2) = 0.74, P = 0.0006) but not for B cells (R(2) = 0.34, P = 0.059). The specificity and sensitivity for C3d deposition on endothelial precursor cell crossmatch (EPCXM) T cells vs the T complement-dependent cytotoxicity (CDC) assay were 69% and 72%, respectively. The EPCXM B-cell C3d assay had considerably lower sensitivity (39%) than the B CDC assay. Altogether, this novel assay based on the detection of complements factors on EPCs and lymphocytes by flow cytometry may widen the diagnostic repertoire and thereby improve the clinical management of patients undergoing kidney transplantation. PMID- 22931382 TI - Assessing and comparing the total antioxidant capacity of commercial beverages: application to beers, wines, waters and soft drinks using TRAP, TEAC and FRAP methods. AB - This work measures and tries to compare the Antioxidant Capacity (AC) of 50 commercial beverages of different kinds: 6 wines, 12 beers, 18 soft drinks and 14 flavoured waters. Because there is no reference procedure established for this purpose, three different optical methods were used to analyse these samples: Total Radical trapping Antioxidant Parameter (TRAP), Trolox Equivalent Antioxidant Capacity (TEAC) and Ferric ion Reducing Antioxidant Parameter (FRAP). These methods differ on the chemical background and nature of redox system. The TRAP method involves the transfer of hydrogen atoms while TEAC and FRAP involves electron transfer reactions. The AC was also assessed against three antioxidants of reference, Ascorbic acid (AA), Gallic acid (GA) and 6-hydroxy-2,5,7,8 tetramethyl- 2-carboxylic acid (Trolox). The results obtained were analyzed statistically. Anova one-way tests were applied to all results and suggested that methods and standards exhibited significant statistical differences. The possible effect of sample features in the AC, such as gas, flavours, food colouring, sweeteners, acidity regulators, preservatives, stabilizers, vitamins, juice percentage, alcohol percentage, antioxidants and the colour was also investigated. The AC levels seemed to change with brand, kind of antioxidants added, and kind of flavour, depending on the sample. In general, higher ACs were obtained for FRAP as method, and beer for kind of sample, and the standard expressing the smaller AC values was GA. PMID- 22931383 TI - Reliability and validity of perceived self-efficacy in wheeled mobility scale among elite wheelchair-dependent athletes with a spinal cord injury. AB - PURPOSE: To study the reliability and validity of the perceived self-efficacy in wheeled mobility scale among elite athletes with a spinal cord injury (SCI). METHOD: During the Beijing Paralympics, 79 participants with SCI completed the SCI Exercise Self-Efficacy Scale (ESES), the revised Self-Efficacy in Wheeled Mobility scale (SEWM) and the perceived wheeled mobility (WM) at present Visual Analog Scale (VAS). Sample included athletes from 18 countries and subcategorized by gender, lesion level/completeness and type of sports. Reliability and concurrent validity were determined. RESULTS: SEWM Cronbach's alpha was 0.905. High internal consistency was confirmed in Split-half correlation coefficient (r = 0.87). Validity was supported by significant correlations between SWEM and ESES total scores (r = 0.64, p < 0.05), and between SEWM and WM VAS scores (r = 0.60; p < 0.001). Subgroups analyses showed that athletes with tetraplegia showed significantly lower WM self-efficacy levels than those with paraplegia. There was a significant difference in perceived WM self-efficacy between athletes who participated in dynamic wheelchair sports and those who participated in non wheelchair sports (p < 0.03). CONCLUSIONS: The SEWM is a reliable and valid scale among Paralympic athletes with SCI. Findings confirmed a significantly higher perception of self-efficacy in WM among athletes who participated in dynamic wheelchair sports. IMPLICATIONS FOR REHABILITATION: * Increased self-efficacy in wheeled mobility (WM) may encourage wheelchair users with spinal cord injury (SCI) to approach, persist, and persevere at WM related tasks that were previously avoided. * The perceived self-efficacy in WM scale (SEWM), which is available on-line in five different languages, may find clinical applications for people with SCI in different countries. * The SEWM can be applied to the assessment of progress in WM levels during the acute rehabilitation phase, and also in structured WM workshops conducted after discharge from the hospital. PMID- 22931384 TI - Whether or not the association of MPV with coronary collateral development is independent of hs-CRP level? PMID- 22931385 TI - Potential biomarkers in gallbladder cancer: present status and future directions. AB - CONTEXT: Carcinoma of the gallbladder (GBC) is the most common biliary tree cancer in the world. Beside gallstones, no specific risk factors for GBC are currently established. Several published studies have identified various prognostic gene expression markers in GBC. OBJECTIVE: The present article reviewed published studies on gene expression biomarkers and gallbladder cancer susceptibility. METHODS: We searched the PubMed, Medline, and Embase databases using the search terms "Gallbladder", "cancer/carcinoma", "expression", "genes", "proteins", and "biomarker" updated until June 2012 and limited to English language papers. The online searching was accompanied by checking reference lists from the identified articles for potentially eligible original reports. RESULTS: Potential GBC biomarkers identified by different studies were summarized. CONCLUSION: To infer, the present article highlights a few potential biomarkers in GBC. However, none of the markers identified so far are effective as a routine screening test in GBC. PMID- 22931386 TI - Screening and management of renal disease in human immunodeficiency virus infected patients in Australia. AB - BACKGROUND: Renal disease has become one of the most important comorbidities observed in the human immunodeficiency virus (HIV)-infected patient cohort. Data are lacking on the current screening and management of renal disease in patients with HIV. We evaluated HIV-infected Australian adults in primary care to determine current practices. METHODS: This prospective, multicentre observational study included two rounds of data collection; the first was followed by an educational programme. Outcomes included screening for renal disease; management of risk factors for kidney disease and other comorbidities associated with renal disease. RESULTS: Fifty-three general practitioners participated with 733 patients enrolled. Most were male (94%); almost 40% were 41-50 years of age, and 6% and 84% were receiving antiretroviral therapy. Comorbidities were common; 19% had hypertension, 5% were diabetic, 32% were dyslipidaemic, and 40% were smokers. Estimated glomerular filtration rate was commonly measured in both rounds of data collection (96% vs 95%). Proteinuria was assessed less frequently; this improved after education (48% vs 71%). Almost 10% of patients tested had proteinuria on urinalysis. Of the 45 patients (6%) with renal impairment (estimated glomerular filtration rate <60 mL/min), none was referred for assessment by a renal specialist. CONCLUSIONS: This large observational study provides important information on renal disease in HIV-infected patients, an area with a paucity of clinical data. Current screening and management practices fall short of suggested guidelines. Failure to refer patients to specialists is a major deficiency. Improvements with education suggest the need to promote awareness of guidelines in primary care doctors. PMID- 22931387 TI - Chemical characterization of latent fingerprints by matrix-assisted laser desorption ionization, time-of-flight secondary ion mass spectrometry, mega electron volt secondary mass spectrometry, gas chromatography/mass spectrometry, X-ray photoelectron spectroscopy, and attenuated total reflection Fourier transform infrared spectroscopic imaging: an intercomparison. AB - The first analytical intercomparison of fingerprint residue using equivalent samples of latent fingerprint residue and characterized by a suite of relevant techniques is presented. This work has never been undertaken, presumably due to the perishable nature of fingerprint residue, the lack of fingerprint standards, and the intradonor variability, which impacts sample reproducibility. For the first time, time-of-flight secondary ion mass spectrometry, high-energy secondary ion mass spectrometry, and X-ray photoelectron spectroscopy are used to target endogenous compounds in fingerprints and a method is presented for establishing their relative abundance in fingerprint residue. Comparison of the newer techniques with the more established gas chromatography/mass spectrometry and attenuated total reflection Fourier transform infrared spectroscopic imaging shows good agreement between the methods, with each method detecting repeatable differences between the donors, with the exception of matrix-assisted laser desorption ionization, for which quantitative analysis has not yet been established. We further comment on the sensitivity, selectivity, and practicability of each of the methods for use in future police casework or academic research. PMID- 22931388 TI - New insights into HLA-G and inflammatory diseases. AB - Human leucocyte antigen-G (HLA-G) is a non-classical HLA class I molecule with an important role at the fetus-maternal interface, preventing fetus recognition and abortion. The role of HLA-G as an immune-modulatory and anti-inflammatory molecule has led to investigate its role in pathological conditions. In these years, HLA-G has been shown to have an important implication in inflammatory pathologies. The focus of this review is to up-date the scientific knowledge on the expression of HLA-G molecules in inflammatory conditions. PMID- 22931389 TI - Toll-like receptors and their role in renal pathologies. AB - Toll-like receptors (TLRs) are the first identified and best studied family of pattern recognition receptors. Expressed in immunocytes, TLRs initiate innate immune responses and concurrently shape the subsequent adaptive immune response. They are sensors of both pathogens, through the exogenous pathogen-associated molecular patterns (PAMPs), and tissue injury, through the endogenous danger associated molecular patterns (DAMPs). In addition to immunocytes, TLRs are widely distributed in various cell types, including renal cells where they contribute significantly to various pathologies. In particular, many experimental and emerging clinical data indicate that TLRs are involved in the pathogenesis of urinary tract infections, sepsis-induced renal failure, kidney ischemia/reperfusion injury, idiopathic or systemic autoimmunity-induced glomerulonephritis and ultimately is renal fibrosis, which leads to end-stage renal disease. This review summarizes the present data about the important role TLRs play in the above kidney diseases focusing on the specific role of PAMPs versus DAMPs and of local versus systemic TLR activation. PMID- 22931390 TI - Comparing model performance for survival prediction using total Glasgow Coma Scale and its components in traumatic brain injury. AB - The Glasgow Coma Scale (GCS) score is used in clinical practice for patient assessment and communication among clinicians and also in outcome prediction models such as the Trauma and Injury Severity Score (TRIS). The objective of this study is to determine which GCS subscore is best associated with outcome, taking time of assessment into account. Records of patients with brain injury who presented after 1989 were extracted from the Trauma Audit and Research Network (TARN) database. Using logistic regression, a baseline model was derived with age, Injury Severity Score (ISS), and year of injury as covariates and survival at discharge as the dependent variable. Total GCS, its subscores, and their combinations at various time points were separately added to the baseline model to compare their effect on model performance. The dataset contained 21,657 cases. The total GCS score at scene and its subscores had significantly lower predictive power compared with those recorded on arrival at the Emergency Department (ED) (scene total GCS: Area Under the Curve-AUC: 0.89; 95% confidence interval [CI]: 0.89-0.90) and Nagelkerke R(2) of 0.55, admission total GCS: AUC of 0.91; 95% CI: 0.91-0.91, and Nagelkerke R(2) of 0.59). Eye and verbal subscores had significantly lower performances compared with total GCS, motor subscore, and various combinations of subscores. Motor subscore and total GCS appeared to have similar predictive performance (admission total and motor GCS both had AUC of 0.91 (95% CI: 0.91-0.92) and Nagelkerke R(2) of 0.59 and 0.58, respectively). Motor subscore contains most of the predictive power of the total score. GCS on arrival is a significantly better predictor of outcome than that recorded at scene. PMID- 22931391 TI - Differences between clinical specialist and advanced practitioner clinical practice, leadership, and research roles, responsibilities, and perceived outcomes (the SCAPE study). AB - AIM: To report a study designed comparing the roles, responsibilities, and perceived outcomes of Clinical Nurse Specialists, Clinical Midwife Specialists, and Advanced Nurse Practitioners in Ireland. BACKGROUND: A clinical career pathway that encompasses progression from staff nurse or midwife through clinical specialist to advanced practitioner level was introduced in Ireland in 2000. Such roles are common internationally, but little evaluation has been conducted and few comparisons have been made between roles. DESIGN: A mixed-method case-study design was used. METHODS: Following Research Ethics Committee Approval, data were collected in 2009-2010, using non-participant observation (92 hours) of 23 Clinical Specialists and Advanced Practitioners, interviews with 21 clinicians and 13 Directors of Nursing or Midwifery. A survey was completed by 154 service users. RESULTS: A clear difference was seen between Clinical Specialist and Advanced Practitioners, with advanced practice roles providing improved service delivery, greater clinical and professional leadership, increased research, and a clear governance and accreditation structure. Clinical Midwife Specialists were rated at a similar level to Advanced Nurse Practitioners for certain aspects and rated more highly for 'continuity of care and carer'. CONCLUSION: Advanced Practitioners do give a higher level of care, particularly at a strategic level. Existing Clinical Specialists should therefore be encouraged to develop their skills and education to achieve advanced practice level and more specialist and advanced practice posts should be instituted. PMID- 22931392 TI - Predictive value of readiness, importance, and confidence in ability to change drinking and smoking. AB - BACKGROUND: Visual analog scales (VAS) are sometimes used to assess change constructs that are often considered critical for change. AIMS OF STUDY: 1.) To determine the association of readiness to change, importance of changing and confidence in ability to change alcohol and tobacco use at baseline with the risk for drinking (more than 21 drinks per week/6 drinks or more on a single occasion more than once per month) and smoking (one or more cigarettes per day) six months later. 2.) To determine the association of readiness, importance and confidence with alcohol (number of drinks/week, number of binge drinking episodes/month) and tobacco (number of cigarettes/day) use at six months. METHODS: This is a secondary analysis of data from a multi-substance brief intervention randomized trial. A sample of 461 Swiss young men was analyzed as a prospective cohort. Participants were assessed at baseline and six months later on alcohol and tobacco use, and at baseline on readiness to change, importance of changing and confidence in ability to change constructs, using visual analog scales ranging from 1-10 for drinking and smoking behaviors. Regression models controlling for receipt of brief intervention were employed for each change construct. The lowest level (1-4) of each scale was the reference group that was compared to the medium (5-7) and high (8-10) levels. RESULTS: Among the 377 subjects reporting unhealthy alcohol use at baseline, mean (SD) readiness, importance and confidence to change drinking scores were 3.9 (3.0), 2.7 (2.2) and 7.2 (3.0), respectively. At follow up, 108 (29%) reported no unhealthy alcohol use. Readiness was not associated with being risk-free at follow-up, but high importance (OR 2.94; 1.15, 7.50) and high confidence (OR 2.88; 1.46, 5.68) were. Among the 255 smokers at baseline, mean readiness, importance and confidence to change smoking scores were 4.6 (2.6), 5.3 (2.6) and 5.9 (2.7), respectively. At follow-up, 13% (33) reported no longer smoking. Neither readiness nor importance was associated with being a non smoker, whereas high confidence (OR 3.29; 1.12, 9.62) was. CONCLUSIONS: High confidence in ability to change was associated with favorable outcomes for both drinking and smoking, whereas high importance was associated only with a favorable drinking outcome. This study points to the value of confidence as an important predictor of successful change for both drinking and smoking, and shows the value of importance in predicting successful changes in alcohol use. TRIAL REGISTRATION NUMBER: ISRCTN78822107. PMID- 22931393 TI - BMS-708,163 targets presenilin and lacks notch-sparing activity. AB - The "Notch-sparing" gamma-secretase inhibitor (GSI) BMS-708,163 (Avagacestat) is currently in phase II clinical trials for Alzheimer's disease. Unlike previously failed GSIs, BMS-708,163 is considered to be a promising drug candidate because of its reported Notch-sparing activity for the inhibition of Abeta production over Notch cleavage. We now report that BMS-708,163 binds directly to the presenilin-1 N-terminal fragment and that binding can be challenged by other pan GSIs, but not by gamma-secretase modulators. Furthermore, BMS-708,163 blocks the binding of four different active site-directed GSI photoaffinity probes. We therefore report that this compound acts as a nonselective gamma-secretase inhibitor. PMID- 22931394 TI - Comparison of application times for ice packs used to relieve perineal pain after normal birth: a randomised clinical trial. AB - AIMS AND OBJECTIVES: To compare the effect of an ice pack applied for 10, 15 and 20 minutes to relieve perineal pain after birth. BACKGROUND: Perineal pain after vaginal birth, with or without vaginal trauma, is one of the most common morbidities reported for postnatal women. Cryotherapy has been used in postpartum period to relieve perineal pain and investigated in several studies. However, cryotherapy treatment protocols in perineal care vary widely regarding temperature, frequency and duration of the application. DESIGN: A controlled trial, randomised for two groups and with a third group as a historical control. METHOD: The intervention was carried out in a maternity hospital in Sao Paulo, Brazil. The study population consisted of three groups of 38 women who used an ice pack on the perineum, in a single application: group A-10 minutes; group B-15 minutes; group C-20 minutes (historical control from another clinical trial). Participants' perineal pain magnitude was evaluated through a numerical scale (0 10), at four different points: before the cryotherapy; immediately after and at 20 and 40 minutes after cryotherapy. RESULTS: After application of the ice pack, there was no statistical difference when comparing the perineal pain among groups in the second, third and fourth evaluations. Most of the postnatal women reported pain relief, with 72.8% reporting a decrease in pain >50%; 21.9% reported a decrease between 30-50%. All postnatal women subjected to cryotherapy were favourable to the procedure. CONCLUSION: There is no difference in pain scores following ice pack application in three different times (10, 15 and 20 minutes) in women who report moderate or intense perineal pain after normal delivery. RELEVANCE FOR CLINICAL PRACTICE: Ice treatment is safe, and application times of 10 or 15 minutes are as beneficial as an application time of 20 minutes to relieve perineal pain. PMID- 22931395 TI - Are hydrodynamic interactions important in the kinetics of hydrophobic collapse? AB - We study the kinetics of assembly of two plates of varying hydrophobicity, including cases where drying occurs and water strongly solvates the plate surfaces. The potential of mean force and molecular-scale hydrodynamics are computed from molecular dynamics simulations in explicit solvent as a function of particle separation. In agreement with our recent work on nanospheres [J. Phys. Chem. B 2012,116, 378-389], regions of high friction are found to be engendered by large and slow solvent fluctuations. These slow fluctuations can be due to either drying or confinement. The mean first passage times for assembly are computed by means of molecular dynamics simulations in explicit solvent and by Brownian dynamics simulations along the reaction path. Brownian dynamics makes use of the potential of mean force and hydrodynamic profile that we determined. Surprisingly, we find reasonable agreement between full-scale molecular dynamics and Brownian dynamics, despite the role of slow solvent relaxation in the assembly process. We found that molecular-scale hydrodynamic interactions are essential in describing the kinetics of assembly. PMID- 22931396 TI - Identification of CpG islands in DNA sequences using statistically optimal null filters. AB - : CpG dinucleotide clusters also referred to as CpG islands (CGIs) are usually located in the promoter regions of genes in a deoxyribonucleic acid (DNA) sequence. CGIs play a crucial role in gene expression and cell differentiation, as such, they are normally used as gene markers. The earlier CGI identification methods used the rich CpG dinucleotide content in CGIs, as a characteristic measure to identify the locations of CGIs. The fact, that the probability of nucleotide G following nucleotide C in a CGI is greater as compared to a non-CGI, is employed by some of the recent methods. These methods use the difference in transition probabilities between subsequent nucleotides to distinguish between a CGI from a non-CGI. These transition probabilities vary with the data being analyzed and several of them have been reported in the literature sometimes leading to contradictory results. In this article, we propose a new and efficient scheme for identification of CGIs using statistically optimal null filters. We formulate a new CGI identification characteristic to reliably and efficiently identify CGIs in a given DNA sequence which is devoid of any ambiguities. Our proposed scheme combines maximum signal-to-noise ratio and least squares optimization criteria to estimate the CGI identification characteristic in the DNA sequence. The proposed scheme is tested on a number of DNA sequences taken from human chromosomes 21 and 22, and proved to be highly reliable as well as efficient in identifying the CGIs. PMID- 22931397 TI - Multi-resistant Staphylococcus pseudintermedius: a wake-up call in our approach to bacterial infection. PMID- 22931398 TI - Lack of associations between ultrasonographic appearance of parenchymal lesions of the canine liver and histological diagnosis. AB - OBJECTIVE: To assess if there are any ultrasonographic features that may enable tentative diagnosis of hepatic parenchymal disease. METHODS: Records of 371 dogs that had abdominal ultrasonography and abnormal liver on biopsy or necropsy were reviewed. RESULTS: Histological diagnoses were hepatitis (n=77), nodular hyperplasia (n=47), vacuolar change (n=45), fibrosis (n=32), primary hepatic carcinoma (n=30), lymphoma (n=28), metastatic neoplasia (n=27), necrosis (n=21), lipidosis (n=17), haemangiosarcoma (n=13), round cell tumour (n=9), hepatocellular adenoma (n=8), degenerative change (n=6), steroid hepatopathy (n=7) and extramedullary haematopoiesis (n=4). The most prevalent ultrasonographic features were multifocal lesions (63% livers with haemangiosarcoma and 43% livers with hepatocellular carcinoma), diffuse lesions (71% livers with steroid hepatopathy, 44% livers with fibrosis and 40% livers with vacuolar hepatopathy), hyperechoic lesions (71% livers with steroid hepatopathy, 41% livers with lipidosis and 38% livers with fibrosis), heterogeneous lesions (62% livers with haemangiosarcoma), hepatomegaly (43% livers with steroid hepatopathy) and peritoneal fluid (62% livers with haemangiosarcoma). Target lesions were associated with malignancy in 67% instances. Marked variability in ultrasonographic appearance of lesions was observed for all diagnoses, and no statistically significant associations between ultrasonographic appearance and diagnosis were found. CLINICAL SIGNIFICANCE: Histological examination remains essential for diagnosis of canine hepatic disease. PMID- 22931399 TI - Intentional marginal excision of canine limb soft tissue sarcomas followed by radiotherapy. AB - OBJECTIVES: To evaluate the outcome in a group of dogs treated with postoperative radiotherapy following intentional marginal excision of soft tissue sarcomas from their limbs and to assess parameters for prognostic significance. METHOD: Patients that had had intentional marginal excision of limb soft tissue sarcomas followed by radiotherapy were selected. A coarse fractionated protocol of four once weekly 8 to 9 Gy by 4 MV x-rays was used. The time to local recurrence was determined. Tumour grade, size, site, number of surgeries, surgeon and time from last surgery to radiotherapy were evaluated as potential prognostic indicators. RESULTS: Fifty-six cases were included. Minor surgical complications occurred in four patients (7%). Tumour recurred locally in 10 dogs (18%). Fourteen dogs died from tumour-related causes (25%). From Cox proportional hazard analysis time from surgery to radiotherapy was the only predictor of tumour recurrence (P=0.039); hazard ratio 8.63. Delaying radiotherapy beyond 4 weeks was associated with improved outcomes. Three dogs developed serious but non-life-threatening local complications; wound dehiscence, self-trauma and osteonecrosis of underlying bone. CLINICAL SIGNIFICANCE: Intentional marginal excision followed by hypofractionated radiotherapy is a viable option for canine limb soft tissue sarcomas, providing good long-term clinical outcomes and low morbidity. PMID- 22931400 TI - Dietary hyperthyroidism in dogs. AB - OBJECTIVES: Evaluation of dogs with elevated plasma thyroxine concentration fed raw food before and after changing the diet. METHOD: Between 2006 and 2011 all dogs presented with an elevated plasma thyroxine concentration and a dietary history of feeding raw food were included. Thyroxine (reference interval: 19.3 to 51.5 nmol/L) and in many cases also thyroid-stimulating hormone concentrations (reference interval: <0.30 ng/mL) were measured initially and after changing the diet. RESULTS: Twelve dogs were presented with a median age of five years. The median plasma thyroxine concentration was 156.1 (range of 79.7 to 391.9) nmol/L; in six dogs, thyroid-stimulating hormone concentration was measured and was <0.03 ng/mL in five dogs and 0.05 ng/mL in one dog. Six dogs showed clinical signs such as weight loss, aggressiveness, tachycardia, panting and restlessness while six dogs had no clinical signs. After changing the diet eight dogs were examined: thyroxine concentration normalised in all dogs and clinical signs resolved. CLINICAL SIGNIFICANCE: Dietary hyperthyroidism can be seen in dogs on a raw meat diet or fed fresh or dried gullets. Increased plasma thyroxine concentration in a dog, either with or without signs of hyperthyroidism, should prompt the veterinarian to obtain a thorough dietary history. PMID- 22931402 TI - Au20 nanocluster protected by hemilabile phosphines. AB - A novel phosphine-protected Au(20) nanocluster was isolated through the reduction of Au(PPhpy(2))Cl by NaBH(4) (PPhpy(2) = bis(2-pyridyl)-phenylphosphine). Its composition was determined to be [Au(20)(PPhpy(2))(10)Cl(4)]Cl(2), and single crystal X-ray structural analysis revealed that the Au(20) core can be viewed as being generated from the fusion of two Au(11) clusters via sharing two vertices. Optical absorption spectroscopy indicated this Au(20) has a large HOMO-LUMO gap (E(g) ~ 2.24 eV). This is the first example of a ligand-protected gold nanocluster with a core generated from incomplete icosahedral Au(11) building units. PMID- 22931401 TI - Total synthesis of incarviditone and incarvilleatone. AB - The total synthesis of the racemic natural products (+/-)-incarviditone and (+/-) incarvilleatone has been accomplished in three steps via biomimetic dimerization of (+/-)-rengyolone. Homochiral dimerization of (+/-)-rengyolone affords (+/-) incarviditone through a domino oxa-Michael/Michael sequence. Heterochiral dimerization, involving a domino oxa-Michael/Michael/aldol reaction sequence, affords (+/-)-incarvilleatone. Single-crystal X-ray analysis of a derivative of (+/-)-incarviditone has resulted in revision of the originally proposed structure. PMID- 22931403 TI - Aggregation of modified celluloses in aqueous solution: transition from methylcellulose to hydroxypropylmethylcellulose solution properties induced by a low-molecular-weight oxyethylene additive. AB - Temperature effects on the viscosity and aggregation behavior of aqueous solutions of three different cellulose ethers--methylcellulose (MC), hydroxypropylmethylcellulose (HPMC), and ethyl(hydroxyethyl)cellulose (EHEC)- were investigated using viscosity and dynamic light scattering measurements as well as cryo-TEM. In all cases, increasing temperature reduces the solvent quality of water, which induces aggregation. It was found that the aggregation rate followed the order EHEC > HPMC > MC, suggesting that cellulose ethers containing some bulky and partially hydrophilic substituents assemble into large aggregates more readly than methylcellulose. This finding is discussed in terms of the organization of the structures formed by the different cellulose ethers. The temperature-dependent association behavior of cellulose ethers was also investigated in a novel way by adding diethyleneglycolmonobutylether (BDG) to methylcellulose aqueous solutions. When the concentration of BDG was at and above 5 wt %, methylcellulose adopted HPMC-like solution behavior. In particular, a transition temperature where the viscosity was decreasing, prior to increasing at higher temperatures, appeared, and the aggregation rate increased. This observation is rationalized by the ability of amphiphilic BDG to accumulate at nonpolar interfaces and thus also to associate with hydrophobic regions of methylcellulose. In effect, BDG is suggested to act as a physisorbed hydrophilic and bulky substituent inducing constraints on aggregation similar to those of the chemically attached hydroxypropyl groups in HPMC and oligo(ethyleneoxide) chains in EHEC. PMID- 22931404 TI - Needs, priorities, and desired rehabilitation outcomes of family members of young adults who have had a stroke: findings from a phenomenological study. AB - PURPOSE: This study explored the experience of stroke from the perspective of family members of young adults who have had a stroke. Gaining understanding of the short, medium and long-term needs and desired rehabilitation outcomes of family members assisted identification of appropriate family-centred multidisciplinary rehabilitation interventions. METHOD: A qualitative approach based on Merleau-Ponty's existential phenomenology enabled exploration of family members' experience of stroke. Eleven family members, including parents, spouses, children and siblings, participated in 24 interviews over 2 years. A subsequent iterative process of critical reflection was used to identify family-centred needs, priorities and associated rehabilitation outcomes. RESULTS: Within a thematic framework, family members' experience was conceptualised as Disruption of Temporal Being. Against this overarching theme or (back)ground, figural themes were identified: Uncertainty, Disrupted and Altered Relationships, and Situatedness. In addition, sixteen short, medium and long-term effects of stroke were identified along with associated family-centred needs and rehabilitation outcomes. CONCLUSION: An empathetic understanding of the experience of stroke from the perspective of family members, combined with research evidence and professional expertise enables the multidisciplinary rehabilitation team to deliver tailored interventions based on identified needs and priorities, and negotiation of mutually agreed goals. IMPLICATIONS FOR REHABILITATION: * Following stroke in a young adult, families' needs, priorities and associated rehabilitation outcomes change over time; rehabilitation services should reflect this dynamic process. * To deliver family-centred care, rehabilitation professionals need to develop a deeper understanding of the experience of families affected by stroke, gained from qualitative research findings and from their own reflective practice. * Gaining understanding of the experience of family members of young adults who have had a stroke will enable health professionals to consider how they may improve practice and enhance service provision to ensure delivery of effective, family-centred interventions. * The table of family-centred needs and outcomes can be used by members of the multidisciplinary stroke rehabilitation team in conjunction with their own knowledge, experience and resources to inform family-centred practice. PMID- 22931405 TI - Gender disparity of living donor renal transplantation in East China. AB - Gender disparity among living kidney donors is common world wide, which demonstrates different social and economic problems in different countries. However, few data are available for China. Therefore, we retrospectively analyzed all 139 living donor renal transplants performed in our center between 2003 and 2010. The annual number of living donor renal transplants increased from six to 26 cases per year during the observation period. Among them, 69.2% of all kidney donors were females, whereas 79.5% of the recipients were male. The average age of recipients was 34.1 +/- 7.6 yr and 94% (110/117) were younger than 44 yr. In contrast, 53% (62/117) of all donors were "middle-aged" (45-59 yr) with an average donor age of 47.8 +/- 9.2 yr. The first-degree relatives accounted for the majority of the donor pool, as the most common donor-recipient combination consisted of mother to son. In conclusion, there was a male and young preponderance among recipients, and a female and middle-aged one among donors of living kidney transplants in our transplant center, which might be related to socio-cultural as well as economic factors. PMID- 22931406 TI - Mechanism of fluctuation in shear force applied to buttocks during reclining of back support on wheelchair. AB - PURPOSE: The purpose of this study was to investigate the mechanism of the fluctuation in the shear force applied to the buttocks. METHOD: The subjects were 11 healthy adult men without leg or trunk diseases. The amount of force applied to the buttocks was measured by using a force plate, and a pressure and shear force sensor was used to measure the timing of the force applied to the back support. RESULTS: The average value of the shear force applied to the buttocks was 9.4 +/- 2.4 (%BW) in the initial upright position (IUP), 9.3 +/- 1.2 (%BW) in the fully reclined position (FRP), and 15.0 +/- 2.9 (%BW) in the returning to an upright position (RUP). Significant differences appeared between the RUP and the other positions. CONCLUSIONS: The results of this study suggested that the adjustment of the axes of rotation of the back support and trunk-pelvis and the release of the remaining shear force after the back support is reclined are important for the prevention of decubitus ulcers. PMID- 22931408 TI - A quantitative study of the environmental effects on the optical response of gold nanorods. AB - The effects of the dielectric environment on the optical extinction spectra of gold nanorods were quantitatively studied using individual bare and silica-coated nanorods. The dispersion and amplitude of their extinction cross-section, dominated by absorption for the investigated sizes, were measured using spatial modulation spectroscopy (SMS). The experimental results were compared to calculations from a numerical model that included environmental features present in the measurements and the morphology and size of the corresponding nanorods measured by transmission electron microscopy. The combination of these experimental and theoretical tools permits a detailed interpretation of the optical properties of the individual nanorods. The measured optical extinction spectra and the extinction cross-section amplitudes were well reproduced by the numerical model for silica-coated gold nanorods, for which the silica shell provides a controlled environment. In contrast, additional environmental factors had to be assumed in the model for bare nanorods, stressing the importance of controlling and characterizing the experimental conditions when measuring the optical response of bare surface-deposited single metal nanoparticles. PMID- 22931409 TI - Laparoscopic injury of the obturator nerve during fertility-sparing procedure for cervical cancer. AB - BACKGROUND: Intraoperative injury of the obturator nerve has rarely been reported in patients with gynecological malignancies undergoing extensive radical surgeries. Irreversible damage of this nerve causes thigh paresthesia and claudication. Intraoperative repair may be done by end-to-end anastomosis or grafting when achieving tension-free anastomosis is not possible. CASE PRESENTATION: A 28-year-old woman with stage IB cervical cancer underwent fertility-sparing surgery, including conization and bilateral pelvic lymphadenectomy. The left obturator nerve was damaged intraoperatively during pelvic dissection. CONCLUSION: Immediate laparoscopic repair was successful and there was no functional deficit in the left thigh for six months postoperatively. PMID- 22931407 TI - HLA-B*15:02 is associated with anemia in patients with chronic hepatitis C treated with pegylated interferon-alpha and ribavirin. AB - To investigate the relationship between human leukocyte antigen (HLA) class I and II alleles and treatment-induced anemia in chronic hepatitis C (CHC) patients receiving combination therapy with pegylated interferon-alpha (PEG-IFN-alpha) and ribavirin (RBV). One hundred six naive CHC patients (59 females and 47 males; mean age, 53.08 years) who underwent combination treatment were enrolled. The patients were considered positive for hemoglobin (Hb)-related side effects if the Hb concentrations dropped below 10 g/dl during PEG-IFN-alpha plus RBV treatment. The HLA-A, -B, -C, -DR, and -DQ loci were investigated by sequence-based genotyping. The effects of the clinical characteristics, virologic variables, and the HLA alleles on treatment-induced anemia were evaluated by a logistic regression analysis. Forty patients (37.7%) had Hb levels below 10 g/dl during the treatment course. Low baseline Hb levels and an advanced liver fibrosis stage were associated with decreases in Hb levels to below 10 g/dl. The occurrence of treatment-related anemia (Hb < 10 g/dl) was significantly associated with HLA B*15:02 as shown by multivariate analysis (adjusted odds ratio, 8.13; 95% confidence interval: 1.19-55.70; P-value after Holm's procedure, 0.03). HLA B*15:02 is associated with treatment-induced anemia in Taiwanese CHC patients receiving combination therapy with PEG-IFN-alpha plus RBV. PMID- 22931410 TI - Interacting effect of BDNF Val66Met polymorphism and stressful life events on adolescent depression. AB - There is a strong etiological link between brain-derived neurotrophic factor and depression, but the neurocellular mechanisms and gene-environment interactions remain obscure. This study investigated whether one functional polymorphism in the brain-derived neurotrophic factor gene (BDNF Val66Met) modulates the influence of stressful life events on adolescent depressive symptoms. A total of 780 pairs of ethnic Han Chinese adolescent twins, 11-17 years of age, were randomly assigned to one of two subgroups (twin1 and twin2). All subjects were genotyped as Val/Val, Val/Met or Met/Met, and assessed for depressive symptoms using the Children's Depression Inventory. The level of environmental stress was estimated by the frequency of stressful life events using the Life Events Checklist. The frequency of stressful life events was significantly correlated with depressive symptoms (twin1: beta = 0.21, P = 0.01; twin2: beta = 0.27, P < 0.01), but there was no significant main effect of the BDNF Val66Met genotype on depressive symptoms. In both subgroups, however, the interaction between the BDNF Val66Met genotype and stressful life event frequency was significant (twin1: beta = 0.19, P = 0.01; twin2: beta = 0.15, P = 0.04); individuals with one or two Val alleles demonstrated a greater susceptibility to both the detrimental effects of higher stress and the beneficial effects of lower stress compared to the Met/Met genotype. These findings support the 'differential-susceptibility' hypothesis, whereby the BDNF Val allele modulates the influence of environmental stress on depression by enhancing the neuroplastic response to all life events. PMID- 22931413 TI - New insight into p-glycoprotein as a drug target. AB - Multidrug resistance (MDR) of cancer tissue is a phenomenon in which cancer cells exhibit reduced sensitivity to a large group of unrelated drugs with different mechanisms of pharmacological activity. Mechanisms that reduce cell sensitivity to damage induced by a variety of chemicals were found to be caused by diverse, albeit well-defined, phenotypic alterations. The molecular basis of MDR commonly involves overexpression of the plasma membrane drug efflux pump - P-glycoprotein (P-gp). This glycoprotein is an ABCB1 member of the ABC transporter family. Cells that develop MDR of this type express massive amounts of P-gp that can induce a drug resistance of more than 100 times higher than normal cells to several drugs, which are substrates of P-gp. Expression of P-gp could be inherent to cancer cells with regard to the specialized tissues from which the cells originated. This is often designated as intrinsic Pgp- mediated MDR. However, overexpression of P-gp may be induced by selection and/or adaptation of cells during exposure to anticancer drugs; this particular example is known as acquired P-gp-mediated MDR. Drugs that are potential inducers of P-gp are often substrates of this transporter. However, several substances that have been proven to not be transportable by P-gp (such as cisplatin or alltrans retinoic acid) could induce minor improvements in P-gp overexpression. It is generally accepted that the drug efflux activity of Pgp is a major cause of reduced cell sensitivity to several compounds. However, P-gp may have side effects that are independent of its drug efflux activity. Several authors have described a direct influence of P-gp on the function of proteins involved in regulatory pathways, including apoptotic progression (such as p53, caspase-3 and Pokemon). Moreover, alterations of cell regulatory pathways, including protein expression, glycosylation and phosphorylation, have been demonstrated in cells overexpressing P-gp, which may consequently induce changes in cell sensitivity to substances that are not P-gp substrates or modulators. We recently reported that P-gppositive L1210 cells exhibit reduced sensitivity to cisplatin, concanavalin A, thapsigargin and tunicamycin. Thus, P-gp-mediated MDR represents a more complex process than was expected, and the unintended effects of P-gp overexpression should be considered when describing this phenotype. The present review aims to provide the most current informations about P-gp-mediated MDR while paying particular attention to the possible dual function of this protein as a drug efflux pump and a regulatory protein that influences diverse cell processes. From a clinical standpoint, overexpression of P-gp in cancer cells represents a real obstacle to effective chemotherapy for malignant diseases. Therefore, this protein should be considered as a viable target for pharmaceutical design. PMID- 22931411 TI - Selected approaches for rational drug design and high throughput screening to identify anti-cancer molecules. AB - Structure-based modeling combined with rational drug design, and high throughput screening approaches offer significant potential for identifying and developing lead compounds with therapeutic potential. The present review focuses on these two approaches using explicit examples based on specific derivatives of Gossypol generated through rational design and applications of a cancer-specificpromoter derived from Progression Elevated Gene-3. The Gossypol derivative Sabutoclax (BI 97C1) displays potent anti-tumor activity against a diverse spectrum of human tumors. The model of the docked structure of Gossypol bound to Bcl-XL provided a virtual structure-activity-relationship where appropriate modifications were predicted on a rational basis. These structure-based studies led to the isolation of Sabutoclax, an optically pure isomer of Apogossypol displaying superior efficacy and reduced toxicity. These studies illustrate the power of combining structure-based modeling with rational design to predict appropriate derivatives of lead compounds to be empirically tested and evaluated for bioactivity. Another approach to cancer drug discovery utilizes a cancer-specific promoter as readouts of the transformed state. The promoter region of Progression Elevated Gene-3 is such a promoter with cancer-specific activity. The specificity of this promoter has been exploited as a means of constructing cancer terminator viruses that selectively kill cancer cells and as a systemic imaging modality that specifically visualizes in vivo cancer growth with no background from normal tissues. Screening of small molecule inhibitors that suppress the Progression Elevated Gene-3-promoter may provide relevant lead compounds for cancer therapy that can be combined with further structure-based approaches leading to the development of novel compounds for cancer therapy. PMID- 22931414 TI - Synthesis and anticancer properties of a novel bis-intercalator. AB - A series of naphthalene diimide (ND)-based mono-, bis-, and tris-intercalators are synthesized and evaluated for their anticancer activities. All compounds show anticancer activities in the micromolar range. Among them the bis-intercalator is the most promising. Experimental results indicate that (i) target compounds intercalate DNA and (ii) the bis-intercalator with the optimal linker shows considerably more affinity to DNA than corresponding mono-and tris-intercalators. Spectroscopic measurements indicate that the ND groups bind to the double stranded DNA (ds-DNA) in a classical threading intercalation mode, while the cationic linker reinforces the intercalation via electrostatic interaction with ds-DNA. In vitro cytotoxicity of the bis-intercalator towards a number of cancer cells, such as C6, HeLa, and MDA-435S, is tested and compared to that of normal cells. Attractive anticancer activity is observed with the bisintercalator, which provides a new lead in the anticancer drug design strategy. PMID- 22931412 TI - Epigenetic mechanisms underlying diet-sourced compounds in the prevention and treatment of gastrointestinal cancer. AB - The development of colon cancer, the third most diagnosed cancer and third leading cause of cancer deaths in the United States, can be influenced by genetic predispositions and environmental exposures. As 80% of colon cancer cases are sporadic in nature, much interest lies in determining risk factors that may foster its development, as well as identifying compounds that could inhibit colon cancer development or halt progression. A major risk factor for sporadic colon cancer is a high fat, Western diet which has been linked to a cancer-prone, pro inflammatory state. Cultures which place an emphasis on fresh fruits and vegetables demonstrate lower colon cancer incidences. Diet not only has the potential to encourage colon cancer development, but recent evidence demonstrates that certain dietary natural products can halt colon cancer development and progression via epigenetic regulation. Epigenetic dysregulation may contribute to inflammation-driven diseases, such as cancer, and can lead to the inappropriate silencing of genes necessary to inhibit cancer development. Natural compounds have shown the ability to reverse epigenetic dysregulation in in vitro and in vivo models. As current allopathic medicines aimed at reversing epigenetic silencing are accompanied with the risk of toxicity and side effects, much interest lies in being able to harness the disease preventing properties in natural products. Here, we discuss the epidemiology of colon cancer, describe the need for natural approaches to inhibit disease development and highlight natural products which have been shown to inhibit gastrointestinal cancer initiation and progression in vitro or in vivo through epigenetic modulation. PMID- 22931415 TI - Human skin-derived fibroblasts acquire in vitro anti-tumor potential after priming with Paclitaxel. AB - The main goal in cancer chemotherapy is to drive the drug into the tumor microenvironment to kill as many cancer cells as possible while producing the lowest collateral toxicity. Previously, we have shown that human bone marrow derived mesenchymal stromal cells (hBM-MSCs) exposed to Paclitaxel (PTX) were able to uptake and subsequently release the drug in the culture medium. PTX primed hBM-MSCs (hBM-MSCsPTX) located in the vicinity of cancer cells produced a strong inhibition of tumor cell growth both in vitro and in vivo. To expand these observations, in the present study we exposed human skin derived fibroblasts (hSDFs) to 2,000 ng/ml of PTX and then tested both cells and their conditioned medium (CM) in vitro for their capacity to inhibit the proliferation of human tumor cell lines (MOLT-4, DU-145, U87-MG, SH-SY5Y(+) and LAN-5). We found that hSDFs primed with PTX (hSDFsPTX) were able to uptake and subsequently release PTX in a time dependent manner. hSDFsPTX-derived CM(hSDFsPTX-CM) from 1:4 to 1:10 dilutions produced a significant (p < 0.05) in vitro tumor growth inhibition. hSDFsPTX co-cultured with leukemia cells at 1:1 to 1:10 ratio, completely inhibited cells growth whereas no inhibition was induced by normal hSDFs cells. Our results demonstrate for the first time that hSDFs can be loaded in vitro with PTX and thus can acquire a potent anti-tumor activity. Since hSDFs can be easily isolated from skin biopsies without any particular pain and discomfort to donor patients, we conclude that hSDFs may represent a valid cell type option for carrying and delivering anti-cancer drugs. PMID- 22931416 TI - A natural anticancer agent thaspine targets human topoisomerase IB. AB - The different steps of the topoisomerase I catalytic cycle have been analyzed in the presence of the plant alkaloid thaspine (1- (2-(Dimethylamino)ethyl)-3,8 dimethoxychromeno[5,4,3-cde]chromene-5,10-dione), known to induce apoptosis in colon carcinoma cells. The experiments indicate that thaspine inhibits both the cleavage and the religation steps of the enzyme reaction. The inhibition is reversible and the effect is enhanced upon pre-incubation. Molecular docking simulations of thaspine over topoisomerase I, in the presence or absence of the DNA substrate, show that thaspine, when interacting with the enzyme alone in the closed or in the open state, can bind in proximity of the active residues preventing the cleavage reaction, whilst when docked with the enzyme-DNA cleavable complex intercalates between the DNA bases in a way similar to that found for camptothecin, explaining its religation inhibition. These results unequivocally demonstrate that thaspine targets human topoisomerase I . PMID- 22931417 TI - Quinones derived from plant secondary metabolites as anti-cancer agents. AB - Quinones are plant-derived secondary metabolites that present some anti proliferation and anti-metastasis effects in various cancer types both in vitro and in vivo. This review focuses on the anti-cancer prospects of plant-derived quinones, namely, aloe-emodin, juglone, beta-lapachol, plumbagin, shikonin, and thymoquinone. We intend to summarize their anti-cancer effects and investigate the mechanism of actions to promote the research and development of anti-cancer agents from quinones. PMID- 22931418 TI - NADPH Oxidases NOXs and DUOXs as putative targets for cancer therapy. AB - Reactive oxygen species (ROS) form a class of molecules with both positive and negative impacts on cellular health. Negatively, ROS may react with cellular constituents including proteins, lipids, and DNA to generate an array of oxidative lesions. These lesions may compromise genome stability which is critical for long-term cellular homeostasis and healthy progeny. Paradoxically, ROS also function as strong signalling molecules that mediate various growth related responses, so their presence is also essential for cellular metabolism. While ROS are generated in an unregulated manner by physical stresses such as exposure to ionizing radiation and biochemical malfunctions such as mitochondrial leakage, cells also contain the NADPH oxidases NOXs and DUOXs, which specifically generate ROS in a wide variety of tissues. While the NOXs/DUOXs may be involved in maintaining optimal cellular redox levels, there is also accumulating evidence that NADPH oxidases-derived ROS may elevate the risk for genomic instability and cancer. Cancer cells may produce high levels of ROS, and in some cases, the source of these ROS has been linked to NOX/DUOX deregulation as reported for prostate cancer (NOX1 and NOX5), melanoma and glioblastoma (NOX4) among others. In addition, recent studies reveal that targeting NADPH oxidases with NOXs inhibitors may impair tumor growth in vivo; indicating that these proteins may be useful targets in future clinical strategies to fight cancer. This review provides an overview of the current knowledge concerning these enzymes, their roles in cancer, and their potential as targets in future cancer therapies. PMID- 22931419 TI - Endocrine therapy resistance: current status, possible mechanisms and overcoming strategies. AB - Endocrine therapy has developed rapidly and become most effective and clearly target form of adjuvant therapy for hormone sensitive breast cancer. Adjuvant endocrine therapy for breast cancer can be given after surgery or radiotherapy, and also prior, or subsequent to chemotherapy. Current commonly used drugs for adjuvant endocrine therapy can be divided into following three classes: selective estrogen receptor modulators (SERMs), aromatase inhibitors (AIs) and selective estrogen receptor down-regulators (SERDs). Unfortunately, tumor cells may develop resistance to endocrine therapy, which become a major obstacle limiting the success of breast cancer treatment. The complicated crosstalk, both genomic and nongenomic, between estrogen receptor and growth factors was considered to be a crucial factor contributing to endocrine resistance. However, the progression of resistance to endocrine therapy supposes to be a progressive, step-wise procedure and the underlying mechanism remains unclear. In this review, we would summarize the possible biology and molecular mechanisms that underlie endocrine resistance, and also some novel strategies to overcoming this issue. PMID- 22931420 TI - Histone deacetylase inhibitors as potential therapeutic agents for the treatment of malignant mesothelioma. AB - Histone deacetylase inhibitors (HDACIs) represent one of the most promising, recently developed classes of anticancer agents already approved by the U.S. FDA. The effectiveness of these new drugs has currently being explored in a variety of cancer cell lines, in vitro, animal models, in vivo, as well as in clinical trials. Malignant mesothelioma (MM) is a rare aggressive malignancy with a median overall survival of 12 months when the current chemotherapy regimen, cisplatin pemetrexed, is applied. This disappointing overall survival has encouraged the experimental use of novel pharmaceutical agents, including HDACIs. In this aspect, the present review is aimed to summarize the existing data regarding the potential utility of HDACIs as therapeutic targets for the treatment of MM. Taking into consideration the research investigations so far, both in vitro and in vivo studies have documented encouraging results. Promising results are also being expected by ongoing clinical trials that concern combination of chemotherapy with HDACIs against MM. PMID- 22931421 TI - Azidothymidine is effective against human multiple myeloma: a new use for an old drug? AB - Azidothymidine (AZT) is an antiretroviral drug that affects cell proliferation, apoptosis, and the NF-kappaB pathway. As multiple myeloma (MM) presents with constitutive activation of NF-kappaB, we analyzed the effect of AZT on human MM cell lines. We evaluated the cytotoxic effect of AZT in human MM cell lines sensitive (8226/S) or resistant to doxorubicin (8226/DX5) and human T cell lymphoblast-like cells, uterine sarcoma cells, and HUVEC using MTT assay. Cytotoxicity was also evaluated in vivo in nude mice xenografted with 8226/S tumor. The effect of AZT on the expression of genes involved in cell proliferation, apoptosis, angiogenesis, and the NF-kappaB pathway was analyzed in the xenografts using real-time polymerase chain reaction. AZT was effective against both 8226/S and 8226/DX5 cells in a dose and time-dependent manner (p = 0.02) in vitro and promoted cell cycle arrest in S phase in these cells. The tumor volume was lower in mice treated with AZT compared to untreated mice (p = 0.0003). AZT down-regulated the pro-proliferative genes encoding AKT1, MYC, STAT1, MAPK8, MAPK9, CCL-3, Bcl-3, and cyclin D2; pro-angiogenenic genes encoding VEGF and IL8; and genes involved in cell adhesion (ICAM1 and FN1) and the NF kappaB pathway. AZT up-regulated the expression of tumor suppressor gene FOXP1 and the pro-apoptotic genes encoding BID, Bcl-10, and caspase-8. Thus, we demonstrated the cytotoxic effect of AZT in human MM cell lines for the first time. Our data may provide the rationale for future clinical trials of AZT for treating MM. PMID- 22931422 TI - Coevolution between simple sequence repeats (SSRs) and virus genome size. AB - BACKGROUND: Relationship between the level of repetitiveness in genomic sequence and genome size has been investigated by making use of complete prokaryotic and eukaryotic genomes, but relevant studies have been rarely made in virus genomes. RESULTS: In this study, a total of 257 viruses were examined, which cover 90% of genera. The results showed that simple sequence repeats (SSRs) is strongly, positively and significantly correlated with genome size. Certain repeat class is distributed in a certain range of genome sequence length. Mono-, di- and tri- repeats are widely distributed in all virus genomes, tetra- SSRs as a common component consist in genomes which more than 100 kb in size; in the range of genome < 100 kb, genomes containing penta- and hexa- SSRs are not more than 50%. Principal components analysis (PCA) indicated that dinucleotide repeat affects the differences of SSRs most strongly among virus genomes. Results showed that SSRs tend to accumulate in larger virus genomes; and the longer genome sequence, the longer repeat units. CONCLUSIONS: We conducted this research standing on the height of the whole virus. We concluded that genome size is an important factor in affecting the occurrence of SSRs; hosts are also responsible for the variances of SSRs content to a certain degree. PMID- 22931423 TI - Transient improvement in sensorimotor conversion during post-anoxic encephalopathy with bilateral medial temporal ischemia. AB - We report the case of a patient with sensorimotor conversion that improved transiently during post-anoxic medial temporal ischemia inducing anterograde and retrograde amnesia. Symptoms reappeared in parallel with mnesic recovery. This case raises a hypothesis concerning the role of hippocampi and amygdalae, which are involved in emotionally-associated memory. The amnesia may have modified the patient's "self," giving her a "distant" point of view. Another hypothesis is that cerebral anoxic stress may have "reset" the cerebral network that controls behavior. These findings give clues about the mechanisms of somatoform disorder and highlight the possibility of specific therapeutic strategies to induce cognitive reappraisal of emotionally-associated experiences. PMID- 22931425 TI - Fully atomistic simulations of the response of silica nanoparticle coatings to alkane solvents. AB - Molecular dynamics simulations are used to study the effect of passivating ligands of varying lengths grafted to a nanoparticle and placed in various alkane solvents. Average height and density profiles for methyl-terminated alkoxylsilane ligands (-O-Si(OH)(2)(CH(2))(n)CH(3), with n = 9, 17, and 35) attached to a 5-nm diameter amorphous silica nanoparticle with coverages of between 1.0 and 3.0 chains/nm(2) are presented for explicitly modeled, short-chain hydrocarbon solvents and for implicit good and poor solvents. Three linear solvents, C(10)H(22) (decane), C(24)H(50), and C(48)H(96), and a branched solvent, squalene, were studied. An implicit poor solvent captured the effect of the longest chain length solvent at lower temperatures, while its temperature dependence was similar to that of the branched solvent squalene. In contrast, an implicit good solvent produced coating structures that were far more extended than those found in any of the explicit solvents tested and showed little dependence on temperature. Coatings equilibrated in explicit solvents were more compact in longer-chain solvents because of autophobic dewetting. Changes in the coating density profiles were more pronounced as the solvent chain length was increased from decane to C(24)H(50) than from C(24)H(50) to C(48)H(98) for all coatings. The response of coatings in squalene was not significantly different from that of the linear chain of equal mass. Significant interpenetration of the solvent chains with the brush coating was observed only for the shortest grafted chains in decane. In all cases, the methyl terminal group was not confined to the coating edge but was found throughout the entire coating volume, from the core to the outermost shell. Increasing the temperature from 300 to 500 K led to greater average brush heights, but the dependence was weak. PMID- 22931424 TI - Caseload of general surgeons working in a rural hospital with outreach practice. AB - BACKGROUND: There is little published data regarding the caseloads of general surgeons working in rural Australia conducting outreach services as part of their practice. It remains difficult to attract and retain surgeons in rural Australia. This study aims to describe the workload of surgeons working in a rural centre with outreach practices in order to determine the required skills mix for prospective surgeons. METHODS: A retrospective review of surgical procedures carried out by two surgeons over 5 years working from a base in Wangaratta, Victoria, with outreach services to Benalla, Bright and Mansfield was undertaken. Data were extracted from surgeon records using Medicare Benefits Schedule item numbers. RESULTS: A total of 18 029 procedures were performed over 5 years, with 15% of these performed in peripheral hospitals as part of an outreach service. A full range of general surgical procedures were undertaken, with endoscopies accounting for 32% of procedures. In addition, vascular procedures and emergency craniotomies were also performed. The majority of procedures undertaken at peripheral centres were minor procedures, with only two laparotomies performed at these centres over 5 years. CONCLUSION: General surgeons working in rural centres are required to have broad skills and be able to undertake a large number of procedures. Trainees should be encouraged to consider rural practice, and those who are interested should consider the needs of the community in which they intend to practice. Outreach work to surrounding communities can be rewarding for both the surgeon and the community. PMID- 22931427 TI - 15N-labeled full-length apolipoprotein E4 as an internal standard for mass spectrometry quantification of apolipoprotein E isoforms. AB - Apolipoprotein E isoforms (apoE2, apoE3, and apoE4) affect the likelihood of developing Alzheimer's disease (AD), with the apoE4 isoform being a major risk factor. However, the underlying mechanism remains to be determined. ApoE isoforms vary by a single amino acid change, and it is a challenge to distinguish them on the protein level. We developed a mass spectrometry-based quantitative method utilizing (15)N-labeled full-length apoE4 ((15)N-apoE4) as an internal standard to quantify concentrations of the specific apoE4 isoform and total apoE. The measurements were performed on control and severe AD samples from human postmortem brain in a single experimental run with a single internal standard, (15)N-apoE4. By subtracting apoE4 from total apoE, the concentration of apoE2 or apoE3 for individuals possessing epsilon2/epsilon4 or epsilon3/epsilon4 alleles can be assessed. Moreover, using the full-length (15)N-apoE4 standard for the set of samples with pure epsilon2/epsilon2, epsilon3/epsilon3, or epsilon4/epsilon4 genotypes makes possible comparison of changes that occur in individual apoE2, apoE3, or apoE4 isoforms, respectively. Overall, using this method, it is possible to study the differences between apoE isoform functions on the protein level and therefore to understand the underlying biological mechanism by which apoE alters AD susceptibility. PMID- 22931429 TI - Enuresis - children's predictions of their treatment's progress and outcomes. AB - AIMS AND OBJECTIVES: To investigate how nurses can use children's ability to predict treatment outcomes as a possible feature contributing to successful therapeutic processes targeting enuresis. BACKGROUND: Prediction of outcomes was viewed both as a self-efficacy component or belief (based on self-efficacy theory), and also as a skill for actually influencing change. DESIGN: The study was conducted in a mental health community center, located in a large city in central Israel, which was well known for treatment of children with enuresis. For the purpose of the study, the children and their parents completed three questionnaires and underwent training to maintain bedwetting records. METHODS: The study compared three groups of children aged 8-14 years who: made predictions only at baseline (n = 32), predicted progress every week during treatment (n = 38), or did not use prediction at all (n = 31). RESULTS: Findings pinpointed the role of practice in improving predictions. Children who predicted weekly showed the highest congruence with outcomes. RELEVANCE TO CLINICAL PRACTICE: Based on self-efficacy, skills acquisition, and learning and training in the change process, nurses may help children overcome enuresis. PMID- 22931428 TI - Italy SimSmoke: the effect of tobacco control policies on smoking prevalence and smoking attributable deaths in Italy. AB - BACKGROUND: While Italy has implemented some tobacco control policies over the last few decades, which resulted in a decreased smoking prevalence, there is still considerable scope to strengthen tobacco control policies consistent with the World Health Organization (WHO) policy guidelines. The present study aims to evaluate the effect of past and project the effect of future tobacco control policies on smoking prevalence and associated premature mortality in Italy. METHODS: To assess, individually and in combination, the effect of seven types of policies, we used the SimSmoke simulation model of tobacco control policy. The model uses population, smoking rates and tobacco control policy data for Italy. RESULTS: Significant reductions of smoking prevalence and premature mortality can be achieved through tobacco price increases, high intensity media campaigns, comprehensive cessation treatment program, strong health warnings, stricter smoke free air regulations and advertising bans, and youth access laws. With a comprehensive approach, the smoking prevalence can be decreased by as much as 12% soon after the policies are in place, increasing to a 30% reduction in the next twenty years and a 34% reduction by 30 years in 2040. Without effective tobacco control policies, a total of almost 300 thousand lives will be prematurely lost due to smoking by the year 2040. CONCLUSION: Besides presenting the benefits of a comprehensive tobacco control strategy, the model helps identify information gaps in surveillance and evaluation schemes that will promote the effectiveness of future tobacco control policy in Italy. PMID- 22931430 TI - Structural interactions dictate the kinetics of macrophage migration inhibitory factor inhibition by different cancer-preventive isothiocyanates. AB - Regulation of cellular processes by dietary nutrients is known to affect the likelihood of cancer development. One class of cancer-preventive nutrients, isothiocyanates (ITCs), derived from the consumption of cruciferous vegetables, is known to have various effects on cellular biochemistry. One target of ITCs is macrophage migration inhibitory factor (MIF), a widely expressed protein with known inflammatory, pro-tumorigenic, pro-angiogenic, and anti-apoptotic properties. MIF is covalently inhibited by a variety of ITCs, which in part may explain how they exert their cancer-preventive effects. We report the crystallographic structures of human MIF bound to phenethylisothiocyanate and to l-sulforaphane (dietary isothiocyanates derived from watercress and broccoli, respectively) and correlate structural features of these two isothiocyanates with their second-order rate constants for MIF inactivation. We also characterize changes in the MIF structure using nuclear magnetic resonance heteronuclear single-quantum coherence spectra of these complexes and observe many changes at the subunit interface. While a number of chemical shifts do not change, many of those that change do not have features similar in magnitude or direction for the two isothiocyanates. The difference in the binding modes of these two ITCs provides a means of using structure-activity relationships to reveal insights into MIF biological interactions. The results of this study provide a framework for the development of therapeutics that target MIF. PMID- 22931431 TI - Method for the efficient synthesis of highly-substituted oxetan- and azetidin-, dihydrofuran- and pyrrolidin-3-ones and its application to the synthesis of (+/-) pseudodeflectusin. AB - Highly substituted four- and five-membered heterocycles were prepared starting with O,P- and N,P-acetals by using a one-pot method involving base induced cyclization and a Horner-Wadsworth-Emmons (HWE) olefination reaction. Divergent synthesis of various heterocycles was achieved by using this method and transformations of the alkenyl group in the products of these processes were exemplified. Finally, a short and efficient synthesis of (+/-)-pseudodeflectusin based on the new methodology was achieved. PMID- 22931432 TI - Gene expression indicates a zone of heterocyst differentiation within the thallus of the cyanolichen Pseudocyphellaria crocata. AB - Development of the symbiotic association in the bipartite lichen Pseudocyphellaria crocata was investigated by characterizing two regions of the thallus. Thallus organization was examined using microscopy. A HIP1-based differential display technique was modified for use on Nostoc strains, including lichenized strains. Northern hybridization and quantitative real-time polymerase chain reaction were used to confirm differential display results, and determine expression levels of key cyanobacterial genes. Photosystem II yield across the thallus was measured using pulse-amplitude modulated fluorescence. Microscopy revealed structural differences in the thallus margins compared with the centre and identified putative heterocysts in both regions. Differential display identified altered transcript levels in both Nostoc punctiforme and a lichenized Nostoc strain. Transcript abundance of cox2, atpA, and ribA was increased in the thallus margin compared with the centre. Expression of cox2 is heterocyst specific and expression of other heterocyst-specific genes (hetR and nifK) was elevated in the margin, whereas, expression of psbB and PSII yield were not. Structural organization of the thallus margin differed from the centre. Both regions contained putative heterocysts but gene expression data indicated increased heterocyst differentiation in the margins where photosystem II yield was decreased. This is consistent with a zone of heterocyst differentiation within the thallus margin. PMID- 22931434 TI - Predictors of mobility in community-dwelling women aged 85 and older. AB - PURPOSE: To describe changes in mobility measured with the Timed Up and Go test (TUG) from baseline to follow-up 9 years later, and to examine which of the demographic, physical performance and health variables measured at baseline were predictors of the TUG at follow-up in a sample of women aged 85 or older. METHOD: This prospective cohort study included 113 community-dwelling women with a baseline mean age of 79.5 years. TUG was measured at baseline and at follow-up. The following baseline measurements were used as predictors: demographics, step climbing ability, functional reach, and health. RESULTS: At follow-up 110 women had decline in the TUG. Mean TUG scores at baseline and at follow-up were 6.7 s (SD = 1.3) and 13.2 s (SD = 6.8) respectively. Higher age, higher BMI, poorer results on; functional reach, step-climbing and self-rated health were independent predictors of poorer TUG at the 9-year follow-up. Exhibiting sufficient strength to climb a step of 40 cm or more protected significantly against mobility decline. Improving balance measured by the functional reach test by 1 cm lowered the probability of major mobility decline by 7%. CONCLUSIONS: Our results suggest that to decrease the risk of mobility decline focus should be on strength, balance and nutrition. IMPLICATIONS FOR REHABILITATION: * A great reduction in mobility, measured with the Timed Up and Go was observed at the 9 year followup. Thirty-nine percent of the community dwelling women aged 85 and above scored below average for their age group and are at risk for adverse outcomes. * The amendable baseline predictors of poorer Timed Up and Go at 9-year follow-up were: higher BMI, poor step climbing capacity and poor balance. Exhibiting sufficient muscle strength and muscle power to climb a step of 40 cm or higher protected significantly against mobility decline. Improving balance measured by the functional reach test by 1 cm lowered the probability of mobility decline by 7%. * To decrease the risk for mobility decline, exercise programmes should focus on muscle strength and balance. PMID- 22931433 TI - Intracranial hemorrhage in adult patients with hematological malignancies. AB - BACKGROUND: Clinical characteristics and outcomes of intracranial hemorrhage (ICH) among adult patients with various hematological malignancies are limited. METHODS: A total of 2,574 adult patients diagnosed with hematological malignancies admitted to a single university hospital were enrolled into this study between 2001 and 2010. The clinical characteristics, image reports and outcomes were retrospectively analyzed. RESULTS: A total of 72 patients (48 men and 24 women) with a median age of 56 (range 18 to 86) had an ICH. The overall ICH incidence was 2.8% among adult patients with hematological malignancies. The incidence of ICH was higher in acute myeloid leukemia (AML) patients than in patients with other hematological malignancies (6.3% vs 1.1%, P = 0.001). ICH was more common among patients with central nervous system (CNS) involvement of lymphoma than among patients with CNS involved acute leukemia (P <0.001). Sites of ICH occurrence included the cerebral cortex (60 patients, 83%), basal ganglia (13 patients, 18%), cerebellum (10 patients, 14%), and brainstem (5 patients, 7%). A total of 33 patients (46%) had multifocal hemorrhages. In all, 56 patients (77%) had intraparenchymal hemorrhage, 22 patients (31%) had subdural hemorrhage, 15 patients (21%) had subarachnoid hemorrhage (SAH), and 3 patients (4%) had epidural hemorrhage. A total of 22 patients had 2 or more types of ICH. In all, 46 (64%) patients died of ICH within 30 days of diagnosis, irrespective of the type of hematological malignancy. Multivariate analysis revealed three independent prognostic factors: prolonged prothrombin time (P = 0.008), SAH (P = 0.021), and multifocal cerebral hemorrhage (P = 0.026). CONCLUSIONS: The incidence of ICH in patients with AML is higher than patients with other hematological malignancies. But in those with intracranial malignant disease, patients with CNS involved lymphoma were more prone to ICH than patients with CNS involved acute leukemia. Mortality was similar regardless of the type of hematological malignancy. Neuroimaging studies of the location and type of ICH could assist with prognosis prediction for patients with hematological malignancies. PMID- 22931435 TI - Graphene polyimide nanocomposites; thermal, mechanical, and high-temperature shape memory effects. AB - Flexible graphene polyimide nanocomposites (0.1-4 wt %) with superior mechanical properties over those of neat polyimide resin have been prepared by solution blending. Imide moieties were grafted to amine-functionalized graphene using a step-by-step condensation and thermal imidization method. The imide functionalized graphene exhibited excellent compatibility with N-methyl-2 pyrrolidone. The dynamic storage moduli of the graphene polyimide nanocomposites increased linearly with increasing graphene content for both unmodified graphene and imidized graphene. Moduli of the imidized graphene nanocomposites were 25-30% higher than those of unmodified graphene nanocomposites. Both neat polyimide and polyimide nanocomposites exhibited shape memory effects with a triggering temperature of 230 degrees C. where addition of graphene improved the recovery rate. Addition of graphene improved thermal stability of the polyimide nanocomposites for both graphene and modified graphene. PMID- 22931436 TI - Minimizing the risk of intrusion: a grounded theory of intimate partner violence disclosure in emergency departments. AB - AIMS: To report a study of processes used by women to disclose intimate partner violence to healthcare professionals in urban emergency department settings. BACKGROUND: Women seek emergency care for impairment related to intimate partner violence yet face barriers non-judgmental and supportive care. DESIGN: A two phase sequential explanatory mixed methods study. METHODS: The study was conducted in Ontario, Canada (May 2006-December 2007). In a sub-analysis of quantitative data with 1182 participants, 15% of women patients reported intimate partner violence, but only 2% disclosed to a healthcare professional. To understand these results, grounded theory with 19 participants was completed. RESULTS/FINDINGS: Participants identified that the basic social problem was the violence 'being found out' by healthcare professionals while receiving care. To address this problem, women undertook a process to minimize intrusion including: deciding to seek care, evaluating the level of trust with the presenting healthcare professional, and establishing personal readiness to disclose. The trajectory of this process was different for each participant with some negotiating all phases leading to violence disclosure. The length of time it took for participants to move through each phase varied across all participants. Common to all participants was the anticipation and the actual experience of intrusion and its influence on women's willingness to disclose intimate partner violence. CONCLUSION: The results suggest nurses may be able to facilitate disclosure of intimate partner violence through limiting intrusion. This can include assessment in a private setting, and fewer professionals who interact with the client. PMID- 22931437 TI - TRPV6 and Calbindin-D9k-expression and localization in the bovine uterus and placenta during pregnancy. AB - BACKGROUND: Transient receptor potential channel type 6 (TRPV6) and Calbindin-D9k (CaBP-9k) are involved in the active calcium (Ca2+) transport mechanism in many tissues including placenta and uterus, suggesting a role in the establishment and maintenance of pregnancy. Moreover, TRPV6 and CaBP-9k seem to support the materno fetal Ca2+ transport that is crucial for fetal Ca2+ homeostasis, bone growth and development. However, it is unknown if these proteins are also involved in the aetiology of pathologies associated with parturition in cows, such as retained fetal membranes (RFM). The aim of the current study was to create an expression profile of uterine and placentomal TRPV6 and CaBP-9k mRNAs and proteins during pregnancy and postpartum in cows with and without fetal membrane release. METHODS: Uteri and placentomes of 27 cows in different stages of pregnancy and placentomes of cows with and without RFM were collected. Protein and mRNA expression of TRPV6 and CaBP-9k was investigated by real-time PCR, immunohistochemistry and Western blot. RESULTS: In the uterine endometrium, highest TRPV6 and CaBP-9k expression was found in the last trimester of pregnancy, with a particular increase of protein in the glandular epithelium. In the placentomes, a gradual increase in TRPV6 mRNA was detectable towards parturition, while protein expression did not change significantly. Placentomal CaBP-9k expression did not change significantly throughout pregnancy but immunohistochemistry revealed an increase in staining intensity in the maternal crypt epithelium. Immunohistochemical, stronger placental CaBP-9k signals were seen in animals with RFM compared to animals with an undisturbed fetal membrane release, while protein levels, measured by Western blot analyses did not change significantly. CONCLUSIONS: The results of the present study demonstrate a dynamic expression of TRPV6 and CaBP-9k during pregnancy in the bovine uterine endometrium and placentomes, suggesting a functional role for these proteins in Ca2+ metabolism during pregnancy. The temporal and spatial expression patterns indicate that TRPV6 and CaBP-9k may be involved in materno-fetal Ca2+ transport, mainly through an interplacentomal transport, and that both proteins may participate in physiological processes that are crucial for fetal and placental development. However, neither TRPV6 nor CaBP-9k seem to be causative in the retention of fetal membranes. PMID- 22931438 TI - HLA-matched family hematopoetic stem cell transplantation in children with beta thalassemia major: the experience of the Turkish Pediatric Bone Marrow Transplantation Group. AB - From January 1991 to June 2009, 245 children with beta thalassemia major who underwent their first allogeneic HSCT in Turkey and who were followed for a minimum of one yr post-transplantation were enrolled this study. The median age of the patients was 6.6 yr old (range, 1-22 yr). The distribution of Pesaro risk class I, II, and III categories was 41, 130, and 63 children, respectively. The median serum ferritin level was 2203 ng/mL. Eighty-eight patients received bone marrow (BM) stem cells; 137, peripheral blood (PB) stem cells; and 20, cord blood (CB) stem cells. The donors were HLA-matched siblings or parents. Median engraftment times were shorter in PBSCT patients compared with the BMT group (p < 0.001). Grade II-IV acute GvHD was observed in 33 children (13.5%), while cGvHD was observed in 28 patients (12.5%), eight of whom had the extensive form. Thalassemic reconstitution was observed in 43 (17%) of the transplant patients. Post-transplant aplasia occurred in three patients, and the TRM rate was 7.75%. Seventeen patients were lost after 100 days. The thalassemia-free survival and OS rates were 68% (95% CI, 61.8-74.2) and 85.0% (95% CI, 80.2-89.8), respectively. We believe that this study is important because it is the first multicenter national data for children with beta thalassemia major receiving HSCT. PMID- 22931439 TI - Linear time relational prototype based learning. AB - Prototype based learning offers an intuitive interface to inspect large quantities of electronic data in supervised or unsupervised settings. Recently, many techniques have been extended to data described by general dissimilarities rather than Euclidean vectors, so-called relational data settings. Unlike the Euclidean counterparts, the techniques have quadratic time complexity due to the underlying quadratic dissimilarity matrix. Thus, they are infeasible already for medium sized data sets. The contribution of this article is twofold: On the one hand we propose a novel supervised prototype based classification technique for dissimilarity data based on popular learning vector quantization (LVQ), on the other hand we transfer a linear time approximation technique, the Nystrom approximation, to this algorithm and an unsupervised counterpart, the relational generative topographic mapping (GTM). This way, linear time and space methods result. We evaluate the techniques on three examples from the biomedical domain. PMID- 22931440 TI - Biodegradable and nontoxic nanogels as nonviral gene delivery systems. AB - The development of polymeric systems with tailored properties as nonviral gene carriers continues to be a challenging and exciting field of research. We report here the synthesis and characterization of biodegradable, temperature- and pH sensitive carbohydrate-based cationic nanogels as effective gene delivery carriers to Hep G2 cells. The temperature-sensitive property of the nanogels allows their facile complexation of DNA, while the pH-sensitive property allows the degradation of nanogels followed by the release of plasmid in the endosome. The nanogels are synthesized via reversible addition-fragmentation chain transfer polymerization (RAFT) technique and are evaluated for their DNA condensation efficacy. The gene delivery efficacies of these nanogels are subsequently studied and it is found that these cationic glyconanogels can serve as potent gene delivery vectors in hepatocytes. It is found that the gene delivery efficacies of this system are similar to that of branched poly(ethyleneimine), which is used as a positive control. Moreover, these nanogels show desirable properties for systemic applications including low toxicity and degradation in acidic environment. PMID- 22931441 TI - Children's physiological and emotional reactions to witnessing bullying predict bystander intervention. AB - Study goals were to explore whether children clustered into groups based on reactions to witnessing bullying and to examine whether these reactions predicted bullying intervention. Seventy-nine children (M = 10.80 years) watched bullying videos in the laboratory while their heart rate (HR) was measured, and they self reported on negative emotion after each video. Bullying intervention was assessed by school peers. Two groups emerged based on reactions to the bullying videos: The Emotional group (43% of children) displayed HR acceleration and reported high negative emotion, whereas the Unemotional group (57% of children) showed HR deceleration and reported low negative emotion. Group membership predicted bullying intervention, with peers reporting that Emotional children were more likely to stop a bully than Unemotional children. PMID- 22931442 TI - Synthesis and pharmacological evaluation of novel 4-alkyl-5-thien-2'-yl pyrazole carboxamides. AB - The synthesis of three series of novel 4-alkyl-5-(5'-chlorothiophen-2'-yl) pyrazole-3-carbamoyl analogues of rimonabant with affinity for the CB1 cannabinoid receptor subtype is reported. Amongst the novel derivatives, compounds 21j, 22a, 22c, and 22f showed affinity values expressed as Ki ranging from 5.5 to 9.0 nM. Derivative 23e revealed a good CB1 affinity (K(i) = 11.7 nM) and the highest CB1 selectivity of the whole series (K(i)CB2/K(i)CB1 = 384.6). These new compounds appeared to be able to pass the blood brain barrier and to counteract the activity of cannabinoid agonist. According to the results of mice vas deferens assays, as in the case of rimonabant, derivatives 21a, 22a, and 22b showed inverse agonist activity. In contrast, as a preliminary result to be confirmed, compound 23a exhibited neutral antagonist profile. According to the data obtained through an acute animal model, selected compounds 21a, 22a, and 23a evidenced the capability to significantly reduce food intake. At specific conditions, the effect of the novel compounds were higher than that induced by rimonabant. Amongst the novel CB1 antagonist compounds, 23a may represent a useful candidate agent for the treatment of obesity and its metabolic complications, with reduced side effects relative to those instead observed with rimonabant. PMID- 22931443 TI - Nanomedicine: the future for advancing medicine and neuroscience. PMID- 22931444 TI - Protein nanotechnology for the new design and development of biocrystals and biosensors. PMID- 22931445 TI - News & views in ... Nanomedicine. PMID- 22931446 TI - Interview: from traditional polymer science to nanomedicine: the interplay between disciplines to drive innovation. PMID- 22931447 TI - Company profile: NanoSight: delivering practical solutions for biological nanotechnology. PMID- 22931448 TI - Nanobiotechnology-based strategies for crossing the blood-brain barrier. AB - The blood-brain barrier (BBB) is meant to protect the brain from noxious agents; however, it also significantly hinders the delivery of therapeutics to the brain. Several strategies have been employed to deliver drugs across this barrier and some of these may do structural damage to the BBB by forcibly opening it to allow the uncontrolled passage of drugs. The ideal method for transporting drugs across the BBB should be controlled and should not damage the barrier. Among the various approaches that are available, nanobiotechnology-based delivery methods provide the best prospects for achieving this ideal. This review describes various nanoparticle (NP)-based methods used for drug delivery to the brain and the known underlying mechanisms. Some strategies require multifunctional NPs combining controlled passage across the BBB with targeted delivery of the therapeutic cargo to the intended site of action in the brain. An important application of nanobiotechnology is to facilitate the delivery of drugs and biological therapeutics for brain tumors across the BBB. Although there are currently some limitations and concerns for the potential neurotoxicity of NPs, the future prospects for NP-based therapeutic delivery to the brain are excellent. PMID- 22931449 TI - Tailoring polymeric micelles to optimize delivery to solid tumors. AB - Block copolymer micelles have shown great potential in drug delivery systems, not only for overcoming the drawbacks of small agents such as water insolubility and wide distribution in normal tissues, but also for avoiding traditional nanoparticle formulation shortcomings, including in vivo instability and fast clearance from the blood. However, for translating micellar formulations to clinical practice, it is essential to overcome the many in vivo obstacles. Surmounting these barriers strongly depends on micellar physicochemical properties, which can be further optimized by the unique physiological aspects of solid tumors such as low pH, high temperature and the presence of abnormal vessels. Herein, based on the Flory parameter and scaling theory, the fundamental mechanisms and correlations in vitro/in vivo between self assembly, drug loading and release, stability, intracellular delivery and in vivo distribution, as well as micellar composition, size and microstructural tailoring are systematically revisited. The methods for enhancing micellar performance in solid tumors were consequently proposed through well-defined core-corona structure tailoring. PMID- 22931450 TI - Nanotechnology in therapeutics: a focus on nanoparticles as a drug delivery system. AB - Continuing improvement in the pharmacological and therapeutic properties of drugs is driving the revolution in novel drug delivery systems. In fact, a wide spectrum of therapeutic nanocarriers has been extensively investigated to address this emerging need. Accordingly, this article will review recent developments in the use of nanoparticles as drug delivery systems to treat a wide variety of diseases. Finally, we will introduce challenges and future nanotechnology strategies to overcome limitations in this field. PMID- 22931452 TI - Generation and genetic engineering of human induced pluripotent stem cells using designed zinc finger nucleases. AB - Zinc finger nucleases (ZFNs) have become powerful tools to deliver a targeted double-strand break at a pre-determined chromosomal locus in order to insert an exogenous transgene by homology-directed repair. ZFN-mediated gene targeting was used to generate both single-allele chemokine (C-C motif) receptor 5 (CCR5) modified human induced pluripotent stem cells (hiPSCs) and biallele CCR5-modified hiPSCs from human lung fibroblasts (IMR90 cells) and human primary cord blood mononuclear cells (CBMNCs) by site-specific insertion of stem cell transcription factor genes flanked by LoxP sites into the endogenous CCR5 locus. The Oct4 and Sox2 reprogramming factors, in combination with valproic acid, induced reprogramming of human lung fibroblasts to form CCR5-modified hiPSCs, while 5 factors, Oct4/Sox2/Klf4/Lin28/Nanog, induced reprogramming of CBMNCs. Subsequent Cre recombinase treatment of the CCR5-modified IMR90 hiPSCs resulted in the removal of the Oct4 and Sox2 transgenes. Further genetic engineering of the single-allele CCR5-modified IMR90 hiPSCs was achieved by site-specific addition of the large CFTR transcription unit to the remaining CCR5 wild-type allele, using CCR5-specific ZFNs and a donor construct containing tdTomato and CFTR transgenes flanked by CCR5 homology arms. CFTR was expressed efficiently from the endogenous CCR5 locus of the CCR5-modified tdTomato/CFTR hiPSCs. These results suggest that it might be feasible to use ZFN-evoked strategies to (1) generate precisely targeted genetically well-defined patient-specific hiPSCs, and (2) then to reshape their function by targeted addition and expression of therapeutic genes from the CCR5 chromosomal locus for autologous cell-based transgene correction therapy to treat various recessive monogenic human diseases in the future. PMID- 22931453 TI - Surgical outcomes of hepatocellular carcinoma originating from caudate lobe. AB - BACKGROUND: Caudate resection for hepatocellular carcinoma (HCC) remains a challenging procedure. This study aimed to assess the surgical outcomes of HCC originating from caudate lobe. METHODS: Twenty-three patients with HCC in the caudate lobe who received surgical treatment were retrospectively reviewed. RESULTS: Surgical procedures included 13 isolated caudatectomy (56.5%) and 10 combined caudatectomy (43.5%). Eight patients (34.7%) experienced post-operative complications. Mortality was nil. The 1-, 3- and 5-year overall survival rates after surgery were 90.1%, 60% and 37%, respectively. Isolated caudatectomy was associated with less frequent tumours located in paracaval portion, longer operative time, longer vascular occlusion time and more blood loss than combined caudatectomy (P < 0.05). CONCLUSION: Surgical resection is feasible and beneficial for patients with HCC in the caudate lobe. If liver functional reserve is sufficient, combined caudatectomy is preferred. PMID- 22931454 TI - Both projection and commissural pathways are disrupted in individuals with chronic stroke: investigating microstructural white matter correlates of motor recovery. AB - BACKGROUND: Complete recovery of motor function after stroke is rare with deficits persisting into the chronic phase of recovery. Diffusion tensor imaging (DTI) can evaluate relationships between white matter microstructure and motor function after stroke. The objective of this investigation was to characterize microstructural fiber integrity of motor and sensory regions of the corpus callosum (CC) and descending motor outputs of the posterior limb of the internal capsule (PLIC) in individuals with chronic stroke and evaluate the relationships between white matter integrity and motor function. RESULTS: Standardized measures of upper extremity motor function were measured in thirteen individuals with chronic stroke. Manual dexterity was assessed in thirteen healthy age-matched control participants. DTI scans were completed for each participant. Fractional anisotropy (FA) of a cross-section of sensory and motor regions of the CC and the PLIC bilaterally were quantified. Multivariate analysis of variance evaluated differences between stroke and healthy groups. Correlational analyses were conducted for measures of motor function and FA. The stroke group exhibited reduced FA in the sensory (p = 0.001) region of the CC, contra- (p = 0.032) and ipsilesional (p = 0.001) PLIC, but not the motor region of the CC (p = 0.236). In the stroke group, significant correlations between contralesional PLIC FA and level of physical impairment (p = 0.005), grip strength (p = 0.006) and hand dexterity (p = 0.036) were observed. CONCLUSIONS: Microstructural status of the sensory region of the CC is reduced in chronic stroke. Future work is needed to explore relationships between callosal sensorimotor fiber integrity and interhemispheric interactions post-stroke. In addition, contralesional primary motor output tract integrity is uniquely and closely associated with multiple dimensions of motor recovery in the chronic phase of stroke suggesting it may be an important biomarker of overall motor recovery. PMID- 22931455 TI - Formation of pH-sensitive cationic liposomes from a binary mixture of monoalkylated primary amine and cholesterol. AB - It has been shown that mixtures of monoalkylated amphiphiles and sterols can form liquid-ordered (lo) lamellar phases. These bilayers can be extruded using conventional methods to obtain large unilamellar vesicles (LUVs) that have very low permeability and a specific response to a given stimulus. For example, pH variations can trigger the release from LUVs formed with palmitic acid and sterols. In the present work, the possibility to form non phospholipid liposomes with mixtures of stearylamine (SA) and cholesterol (Chol) was investigated. The phase behavior of these mixtures was characterized by differential scanning calorimetry, infrared, and (2)H NMR spectroscopy. It is found that this particular mixture can form a lo lamellar phase that is pH-sensitive as the system undergoes a transition from a lo phase to a solid state when pH is increased from 5.5 to 12. LUVs have been successfully extruded from equimolar SA/Chol mixtures. Release experiments as a function of time revealed the relatively low permeability of these systems. The fact that the stability of these liposomes is pH dependent implies that these LUVs display an interesting potential as new cationic carriers for pH-triggered release. This is the first report of non phospholipid liposomes with high sterol content combining an overall positive charge and pH-sensitivity. PMID- 22931456 TI - Guidelines for preventing urinary retention and bladder damage during hospital care. AB - AIMS AND OBJECTIVES: To develop evidence-based guidelines for adult patients in order to prevent urinary retention and to minimise bladder damage and urinary tract infection. BACKGROUND: Urinary retention causing bladder damage is a well known complication in patients during hospital care. The most common treatment for urinary retention is an indwelling urinary catheter, which causes 80% of hospital-acquired urinary tract infections. Appropriate use of bladder ultrasonography can reduce the rate of bladder damage as well as the need to use an indwelling urinary catheter. It can also lead to a decrease in the rate of urinary tract infections, a lower risk of spread of multiresistant Gram-negative bacteria, and lower hospital costs. DESIGN: An expert group was established, and a literature review was performed. METHODS: On the basis of literature findings and consensus in the expert group, guidelines for clinical situations were constructed. RESULTS: The main points of the guidelines are the following: identification of risk factors for urinary retention, managing patients at risk of urinary retention, strategies for patients with urinary retention and patient documentation and information. CONCLUSION: Using literature review and consensus technique based on a multiprofessional group of experts, evidence-based guidelines have been developed. Although consensus was reached, there are parts of the guidelines where the knowledge is weak. RELEVANCE TO CLINICAL PRACTICE: These guidelines are designed to be easy to use in clinical work and could be an important step towards minimising bladder damage and hospital-acquired urinary tract infections and their serious consequences, such as bacteraemia and the spread of multidrug-resistant bacteria in hospitals. PMID- 22931457 TI - Using formative research to develop the healthy eating component of the CHANGE! school-based curriculum intervention. AB - BACKGROUND: Childhood obesity is a significant public health concern. Many intervention studies have attempted to combat childhood obesity, often in the absence of formative or preparatory work. This study describes the healthy eating component of the formative phase of the Children's Health Activity and Nutrition: Get Educated! (CHANGE!) project. The aim of the present study was to gather qualitative focus group and interview data regarding healthy eating particularly in relation to enabling and influencing factors, barriers and knowledge in children and adults (parents and teachers) from schools within the CHANGE! programme to provide population-specific evidence to inform the subsequent intervention design. METHODS: Semi-structured focus group interviews were conducted with children, parents and teachers across 11 primary schools in the Wigan borough of North West England. Sixty children (N = 24 boys), 33 parents (N = 4 male) and 10 teachers (N = 4 male) participated in the study. Interview questions were structured around the PRECEDE phases of the PRECEDE-PROCEED model. Interviews were transcribed verbatim and analysed using the pen-profiling technique. RESULTS: The pen-profiles revealed that children's knowledge of healthy eating was generally good, specifically many children were aware that fruit and vegetable consumption was 'healthy' (N = 46). Adults' knowledge was also good, including restricting fatty foods, promoting fruit and vegetable intake, and maintaining a balanced diet. The important role parents play in children's eating behaviours and food intake was evident. The emerging themes relating to barriers to healthy eating showed that external drivers such as advertising, the preferred sensory experience of "unhealthy" foods, and food being used as a reward may play a role in preventing healthy eating. CONCLUSIONS: Data suggest that; knowledge related to diet composition was not a barrier per se to healthy eating, and education showing how to translate knowledge into behavior or action is required. The key themes that emerged through the focus groups and pen-profiling data analysis technique will be used to inform and tailor the healthy eating component of the CHANGE! intervention study. TRIAL REGISTRATION: Current Controlled Trials ISRCTN03863885 PMID- 22931458 TI - Femtomolar inhibitors bind to 5'-methylthioadenosine nucleosidases with favorable enthalpy and entropy. AB - 5'-Methylthioadenosine/S-adenosylhomocysteine nucleosidase (MTAN) catalyzes the hydrolytic cleavage of adenine from methylthioadenosine (MTA). Inhibitor design and synthesis informed by transition state analysis have developed femtomolar inhibitors for MTANs, among the most powerful known noncovalent enzyme inhibitors. Thermodynamic analyses of the inhibitor binding reveals a combination of highly favorable contributions from enthalpic (-24.7 to -4.0 kcal mol(-1)) and entropic (-10.0 to 6.4 kcal mol(-1)) interactions. Inhibitor binding to similar MTANs from different bacterial species gave distinct energetic contributions from similar catalytic sites. Thus, binding of four transition state analogues to EcMTAN and SeMTAN is driven primarily by enthalpy, while binding to VcMTAN is driven primarily by entropy. Human MTA phosphorylase (hMTAP) has a transition state structure closely related to that of the bacterial MTANs, and it binds tightly to some of the same transition state analogues. However, the thermodynamic signature of binding of an inhibitor to hMTAP differs completely from that with MTANs. We conclude that factors other than first-sphere catalytic residue contacts contribute to binding of inhibitors because the thermodynamic signature differs between bacterial species of the same enzyme. PMID- 22931460 TI - RuHCl(CO)(PPh3)3-catalyzed alpha-alkylation of ketones with primary alcohols. AB - The alpha-alkylation reaction of ketones with primary alcohols to give alpha alkylated ketones was achieved using RuHCl(CO)(PPh(3))(3) as a catalyst in the presence of Cs(2)CO(3) as a base. This reaction proceeds via an aldol condensation of ketones with aldehydes, formed via transfer dehydrogenation of alcohols, to give alpha,beta-unsaturated ketones, which then undergo transfer hydrogenation with primary alcohols to give alpha-alkylated ketones and aldehydes, the latter of which participate in the next catalytic cycle. While the reaction of aliphatic primary alcohols was sluggish compared with that of benzylic alcohols, a catalytic amount of 1,10-phenanthroline was found to promote the alkylation dramatically. PMID- 22931459 TI - Biomechanical assessment of balance and posture in subjects with ankylosing spondylitis. AB - BACKGROUND: Ankylosing spondylitis is a major chronic rheumatic disease that predominantly affects axial joints, determining a rigid spine from the occiput to the sacrum. The dorsal hyperkyphosis may induce the patients to stand in a stooped position with consequent restriction in patients' daily living activities. The aim of this study was to develop a method for quantitatively and objectively assessing both balance and posture and their mutual relationship in ankylosing spondylitis subjects. METHODS: The data of 12 healthy and 12 ankylosing spondylitis subjects (treated with anti-TNF-alpha stabilized), with a mean age of 51.42 and 49.42 years; mean BMI of 23.08 and 25.44 kg/m(2) were collected. Subjects underwent a morphological examination of the spinal mobility by means of a pocket compass needle goniometer, together with an evaluation of both spinal and hip mobility (Bath Ankylosing Spondylitis Metrology Index), and disease activity (Bath Ankylosing Spondylitis Disease Activity Index). Quantitative evaluation of kinematics and balance were performed through a six cameras stereophotogrammetric system and a force plate. Kinematic models together with a test for evaluating balance in different eye level conditions were developed. Head protrusion, trunk flexion-extension, pelvic tilt, hip-knee-ankle flexion-extension were evaluated during Romberg Test, together with centre of pressure parameters. RESULTS: Each subject was able to accomplish the required task. Subjects' were comparable for demographic parameters. A significant increment was observed in ankylosing spondylitis subjects for knee joint angle with the target placed at each eye level on both sides (p < 0.042). When considering the pelvic tilt angle a statistically significant reduction was found with the target placed respectively at 10 degrees (p = 0.034) and at 30 degrees (p = 0.019) less than eye level. Furthermore in ankylosing spondylitis subjects both hip (p = 0.048) and ankle (p = 0.029) joints angles differs significantly. When considering the posturographic parameters significant differences were observed for ellipse, center of pressure path and mean velocity (p < 0.04). Goniometric evaluation revealed significant increment of thoracic kyphosis reduction of cervical and lumbar range of motion compared to healthy subjects. CONCLUSIONS: Our findings confirm the need to investigate both balance and posture in ankylosing spondylitis subjects. This methodology could help clinicians to plan rehabilitation treatments. PMID- 22931462 TI - Bacterial pathogen surface plasmon resonance biosensor advanced by long range surface plasmons and magnetic nanoparticle assays. AB - A new approach to surface plasmon resonance (SPR) biosensors for rapid and highly sensitive detection of bacterial pathogens is reported. It is based on the spectroscopy of grating-coupled long-range surface plasmons (LRSPs) combined with magnetic nanoparticle (MNP) assay. The interrogation of LRSPs allows increasing the biosensor figure of merit (FOM), and the employment of MNPs further enhances the sensor response by a fast delivery of the analyte to the sensor surface and through the amplified refractive index changes associated with the capture of target analyte. This amplification strategy is particularly attractive for detection of large analytes that diffuse slowly from the analyzed sample to the sensor surface. The potential of the presented approach is demonstrated in a model experiment in which Escherichia coli O157:H7 was detected at concentrations as low as 50 cfu mL(-1), 4 orders of magnitude better than the limit of detection achieved by regular grating-coupled SPR with direct detection format. PMID- 22931461 TI - MicroR828 regulates lignin and H2O2 accumulation in sweet potato on wounding. AB - MicroRNAs (miRNAs) are small noncoding RNAs which post-transcriptionally regulate gene expression by directing mRNA cleavage or translational inhibition. miRNAs play multiple roles in the growth, development and stress responses in plants. However, little is known of the wounding-responsive miRNAs and their regulation. Here, we investigated the expression patterns of microR828 (miR828) on wounding in sweet potato (Ipomoea batatas cv Tainung 57). The expression of miR828 was only detected in leaves, and was induced by wounding rather than by ethylene, hydrogen peroxide (H2O2), methyl jasmonate or nitric oxide (NO). Moreover, cyclic guanosine monophosphate (cGMP) was necessary for miR828 accumulation in leaves on wounding. Two miR828 target candidates, named IbMYB and IbTLD, were obtained by cDNA cloning, and their mRNA cleavage caused by miR828 was confirmed by cleavage site mapping, agro-infiltration and transgenics studies. The reduction in IbMYB and IbTLD expression coincided with the induction of miR828, demonstrating that IbMYB and IbTLD might be miR828 targets. Furthermore, transgenic sweet potato overexpressing miR828 precursor affected lignin and H2O2 contents. These results showed that cGMP could regulate wounding-responsive miR828, which repressed the expression of IbMYB and IbTLD. Subsequently, lignin and H2O2 were accumulated to participate in defense mechanisms. PMID- 22931464 TI - CD147/EMMPRIN: an effective therapeutic target for hepatocellular carcinoma. AB - Hepatocellular carcinoma (HCC) is characterized by high resistance to conventional systemic therapies, rapid progression, easy metastasis and frequent recurrence. There is therefore an urgent requirement to develop novel systemic agents which specifically target hepatoma-associated antigen in the tumors of HCC patients. CD147, a transmembrane glycoprotein, is highly expressed by HCC cells and is strongly associated with HCC progression and prognosis. CD147 in HCC cells modulates HCC growth, promotes invasion and metastasis by stimulating adjacent fibroblasts and HCC cells to produce elevated levels of several extracellular matrix metalloproteinases (MMPs) in the HCC microenvironment. It is also involved in HCC angiogenesis and multidrug resistance (MDR). Clinical progress has been made in HCC treatment using CD147-directed monoclonal antibodies. Here, we give an overview of the literature regarding the molecular features and expression of CD147 in human HCC tissues. We specifically focus on the role of CD147 in HCC invasion and metastasis, as well as in angiogenesis and multidrug resistance. In addition, advances in therapeutic strategies targeting HCC CD147 are summarized. PMID- 22931463 TI - Instrument translation and initial psychometric evaluation of the Chinese version of the Self-Management of Type 1 Diabetes for Adolescents scale. AB - AIM: To translate the validated measure, Self-Management of Type 1 Diabetes in Adolescents, into the Mandarin Chinese language and to test the psychometric properties of the Chinese version. BACKGROUND: Although research on self management of Type 1 diabetes has been increasing over the past 20 years, few health-related instruments have been available in the Chinese language for youth with Type 1 diabetes. DESIGN: A two-phase design was used in this study, including instrument translation and psychometric testing. METHODS: The instrument translation, from October 2008-April 2009, included three steps: forward translation, back translation, and comparison of versions via Translation Validity Index - with multiple rounds, group discussion, and achievement of consensus at each step. Psychometric properties of the Chinese version Schilling's Self-Management of Type 1 Diabetes for Adolescents scale was assessed in a convenience sample of 136 Chinese youth (ages 8-19) with Type 1 diabetes between June 2009-August 2009. RESULTS: The internal consistency and test-retest reliabilities indicated generally good consistency and temporal stability of the Chinese version. Evidence of construct validity and criterion-related validity was obtained via correlations of subscales with established measures of diabetes adherence and quality of life and also with haemoglobin A1c. Results from hypothesis testing also supported construct validity. CONCLUSION: The Chinese version of Self-Management of Type 1 Diabetes for Adolescents scale is sound and will facilitate cross-cultural studies, while also enabling nurses to monitor and enhance the diabetes self-management of Chinese youth with Type 1 diabetes. PMID- 22931465 TI - Humoral immunity is involved in the development of pericentral fibrosis after pediatric live donor liver transplantation. AB - Although LT can be successful for treating end-stage liver disease in children, some patients develop fibrosis around the central vein area (PCF). This raises the possibility that PCF could lead to later cirrhosis and graft failure. Here, we report a retrospective immunohistochemical study of 28 patients who received a live donor liver transplant. We assessed the incidence and etiology of PCF using CD3, CD20, HLA-DR, and C4d-specific antibodies. Histological evidence of PCF was found in 13 cases (46.4%), of which 11 (84.6%) had experienced ACR and/or CP events post-transplant. Immunohistochemical evaluation revealed significantly stronger staining with these antibodies in the central vein area in PCF, especially for CD20 and C4d. This implies humoral immunopathology and suggests involvement of humoral immunity in the development of PCF. These results further imply that suppression of cellular immunity alone is insufficient to prevent PCF. We therefore suggest that suppression of both humoral and cellular immunity in combination would be required for prevention of PCF. PMID- 22931467 TI - Abstracts of the 22nd IUBMB & 37th FEBS Congress. Seville, Spain. September 4-9, 2012. PMID- 22931466 TI - Does maternal employment following childbirth support or inhibit low-income children's long-term development? AB - This study assessed whether previous findings linking early maternal employment to lower cognitive and behavioral skills among middle-class and White children generalized to other groups. Using a representative sample of urban, low-income, predominantly African American and Hispanic families (n = 444), ordinary least squares regression and propensity score matching models assessed links between maternal employment in the 2 years after childbearing and children's functioning at age 7. Children whose mothers were employed early, particularly in their first 8 months, showed enhanced socioemotional functioning compared to peers whose mothers remained nonemployed. Protective associations emerged for both part-time and full-time employment, and were driven by African American children, with neutral effects for Hispanics. Informal home-based child care also heightened positive links. PMID- 22931468 TI - Strengthening management and leadership practices to increase health-service delivery in Kenya: an evidence-based approach. AB - BACKGROUND: The purpose of the study was to test the hypothesis that strengthening health systems, through improved leadership and management skills of health teams, can contribute to an increase in health-service delivery outcomes. The study was conducted in six provinces in the Republic of Kenya. METHODS: The study used a non-randomized design comparing measures of key service delivery indicators addressed by health teams receiving leadership and management training (the intervention) against measures in comparison areas not receiving the intervention. Measurements were taken at three time periods: baseline, endline, and approximately six months post intervention. At the district level, health-service coverage was computed. At the facility level, the percentage change in the number of client visits was computed. The t-test was used to test for significance. RESULTS: Results showed significant increases in health-service coverage at the district level (p = <0.05) in the intervention teams compared to the comparison teams. Similarly, there were significant increases in the number of client visits at the facility level in the intervention group versus comparison facilities (P < 0.05). CONCLUSIONS: Strengthening the leadership and management skills of health teams, through team-based approaches focused on selected challenges, contributed to improved health service delivery outcomes and these improvements were sustained at least for six months. PMID- 22931469 TI - Copper(II)-catalyzed dehydrogenative cross-coupling between two azoles. AB - The copper(II)-catalyzed dehydrogenative coupling between two different azoles for the preparation of unsymmetrical biazoles has been developed. The current catalytic system can effectively control the chemoselectivity for heterocoupling over homocoupling. PMID- 22931471 TI - Reversible, non-plaque-induced loss of osseointegration of successfully loaded dental implants. AB - OBJECTIVES: Excess loading has been often cited as a reason for the failure of dental implants or bone loss post-osseointegration. The available data from animal studies have failed to show a clear role for excessive loading in the loss of osseointegration. The present case documentations aimed at providing a deeper insight into the medium- to long-term influence of occlusal loading on osseointegrated implants, and describe the clinical manifestations of such pathology. MATERIAL AND METHODS: Two cases of loss of osseointegration are documented with single implants in the posterior maxilla. Implant mobility was in both cases the first and only sign of pathology, with the absence of plaque induced inflammation and marginal bone loss. RESULTS: Re-osseointegration of the implants was achieved after the removal of the prosthetic reconstruction. CONCLUSIONS: The two cases reported that the loss of osseointegration in the absence of plaque-induced peri-implant inflammation is possible, although the clinical manifestations were very different to these of peri-implantitis. Once the occlusal loading was withdrawn, re-osseointegration was clinically confirmed in a period of 6-8 months. PMID- 22931472 TI - Identification of less lipophilic riminophenazine derivatives for the treatment of drug-resistant tuberculosis. AB - Clofazimine (CFZ), a member of the riminophenazine class, has been studied in clinical trials for the treatment of multidrug-resistant tuberculosis (MDR-TB). CFZ has several side effects which can be attributed to its extremely high lipophilicity. A series of novel riminophenazine analogues bearing a C-2 pyridyl substituent was designed and synthesized with the goal of maintaining potent activity against Mycobacterium tuberculosis (M. tuberculosis) while improving upon its safety profile by lowering the lipophilicity. All compounds were evaluated for their in vitro activity and cytotoxicity. The results demonstrated that many new compounds had potent activity against M. tuberculosis with MICs of less than 0.03 MUg/mL and low cytotoxicity with IC(50) values greater than 64 MUg/mL. Some compounds were tested for in vivo efficacy against MDR-TB in an experimental mouse infection model. Two compounds demonstrated equivalent or better efficacy than CFZ in this model with significantly reduced skin discoloration potential. PMID- 22931470 TI - Ex vivo reconstitution of arterial endothelium by embryonic stem cell-derived endothelial progenitor cells in baboons. AB - There is an increasing need for an animal model that can be used to translate basic research into clinical therapy. We documented the differentiation and functional competence of embryonic stem cell (ESC)-derived endothelial cells in baboons. Baboon angioblasts were sequentially differentiated from embryoid body cultures for 9 days in an angioblast differentiation medium with varying concentrations of BMP-4, FLT-3 ligand, stem cell factor, thrombopoietin, basic fibroblast growth factor (FGF), vascular endothelial growth factor (VEGF), and knockout serum replacement. Real-time polymerase chain reaction results showed that ESC-derived angioblasts downregulated NANOG and OCT3/4, upregulated T brachyury and GATA2, and moderately expressed CD34; they did not express CD144, TEK, or VWF, and varied in levels of CD31 expression. Several populations of putative angioblasts appeared 3 days and 9 days after differentiation, as identified by flow cytometry. Angioblasts at this stage exhibited dual paths of differentiation toward hematopoietic and vascular fates. To examine whether derived angioblasts could reconstitute the endothelium, we built an ex vivo culture system and seeded fluorescently labeled angioblast cultures onto a denuded segment of the femoral artery. We found that the seeded cells were able to grow into the endothelium on the interior surface of denuded artery segments within 5 days after seeding. After 14 days of ex vivo culture, the transplanted cells expressed CD31, an endothelial marker. The control arteries, seeded with vehicle only, did not harbor cells with endothelial markers. We conclude that ESC derived angioblasts are promising therapeutic agents for repairing damaged vasculature, and that the baboon model will be vital for optimizing therapies for human clinical studies. PMID- 22931473 TI - Quality-of-life assessment in the treatment of iatrogenic bile duct injuries: hepaticojejunostomy versus end-to-end biliary reconstructions. AB - BACKGROUND: Assessment and comparison of quality of life (QOL) in patients treated for iatrogenic bile duct injuries (IBDI) with Roux-en-Y hepaticojejunostomy (HJ) or end-to-end ductal anastomosis (EE). METHODS: The Medical Outcomes Study Short Form 36v2 (SF-36v2) Health Survey and the Karnofsky score were used. Comparative analysis of QOL was performed in 41 patients following reconstructive surgery for IBDI between 1990 and 2005: 22 - HJ and 21 - EE. RESULTS: Seven of eight values were comparable in both analysed groups: role physical, bodily pain, general health, vitality, social functioning, role emotional and mental health index. Physical functioning was significantly better in patients following EE (P = 0.04). Physical component summary (P = 0.11) and mental component summary (P = 0.92) in both groups were comparable. QOL according to the Karnofsky scale was comparable in both groups (P = 0.294). CONCLUSIONS: Physical functioning was significantly better in patients after EE. Other values of QOF according to the SF-36v2 and the Karnofsky score were comparable in both groups. PMID- 22931475 TI - Innovations in nurse practitioner education. PMID- 22931476 TI - The use of simulation with advanced practice nursing students. AB - PURPOSE: To review use of simulation in the education of advanced practice nurses and to describe an innovative simulation program for family nurse practitioner (NP) students. DATA SOURCES: The literature was reviewed using MEDLINE and CINAHL searches for descriptions of simulation programs for advanced practice nursing (APN) students. A description of a simulation program in a family NP program was provided. CONCLUSIONS: The literature on the use of simulation in primary care APN programs is scant, but simulation seems to represent an active learning strategy that would be of benefit to primary care APN students in increasing knowledge and confidence about the management of clinical situations. Students can also work with faculty to create simulation experiences based on the knowledge of their own learning needs and expertise in specialty areas of nursing. IMPLICATIONS FOR PRACTICE: More information about the use of simulation programs for APN students is needed along with more information about educational outcomes. PMID- 22931477 TI - Design and initial evaluation of a virtual pediatric primary care clinic in Second Life((r)). AB - PURPOSE: To present an example of an innovative educational strategy using a theoretical framework for the design and evaluation of a virtual world simulation for family nurse practitioner (FNP) students. DATA SOURCES: The example arises from a primary care pediatric clinic developed for FNP students in Second Life((r)) to supplement experiences in clinical practice sites. The simulation uses a case-based interactive format. The educational strategy is based on constructivist learning theory and experiential learning principles. Report of initial prototype testing of faculty and FNP students is reported. CONCLUSIONS: Virtual-world simulations have the potential to provide a safe environment for students to practice clinical decision making for pediatric patients. However, attention to the context, pedagogy, learner, and the capabilities of the technology is essential to provide a quality educational experience. IMPLICATIONS FOR PRACTICE: Preparation of FNP students can include quality educational experiences in a virtual world when guided by a theoretical framework. PMID- 22931478 TI - Growing an innovative faculty-driven management team in a distance-delivery NP education program: thinking outside the box to meet the nursing education and health needs of northern British Columbia, Canada. AB - PURPOSE: The purpose of this article is to describe how one university in northern British Columbia (BC) dealt with the issues of nurse practitioner (NP) program administration in light of its geographic context. DATA SOURCES: Reflections of the management team during the first 2 years of implementation of the faculty-driven approach. CONCLUSIONS: Our experience reflects family NP (FNP) faculty shortages internationally, the challenge of attracting qualified candidates to centers outside the urban mainstream in today's competitive academic job market, as well as the need to develop NP faculty capacity in BC, Canada. The team management approach evolved organically, based on program need, available human resources, and the culture of the faculty. The team approach for program leadership and coordination is a good fit for this NP program. IMPLICATIONS FOR PRACTICE: Implementing the team management approach has allowed the continuation of an NP program situated in a northern Canadian community that is consistent with the program's unique focus in preparing NPs to practice in often-underserved northern, rural, remote, and Aboriginal settings. While the approach provides for continuation of a quality program, it also ensures the availability of graduates well prepared to take up practice challenges in rural and northern communities. PMID- 22931474 TI - Community-based interventions for enhancing access to or consumption of fruit and vegetables among five to 18-year olds: a scoping review. AB - BACKGROUND: Low fruit and vegetable ( FV) consumption is a key risk factor for morbidity and mortality. Consumption of FV is limited by a lack of access to FV. Enhanced understanding of interventions and their impact on both access to and consumption of FV can provide guidance to public health decision-makers. The purpose of this scoping review is to identify and map literature that has evaluated effects of community-based interventions designed to increase FV access or consumption among five to 18-year olds. METHODS: The search included 21 electronic bibliographic databases, grey literature, targeted organization websites, and 15 key journals for relevant studies published up to May 2011. Retrieved citations were screened in duplicate for relevance. Data extracted from included studies covered: year, country, study design, target audience, intervention setting, intervention strategies, interventionists, and reported outcomes. RESULTS: The search located 19,607 unique citations. Full text relevance screening was conducted on 1,908 studies. The final 289 unique studies included 30 knowledge syntheses, 27 randomized controlled trials, 55 quasi experimental studies, 113 cluster controlled studies, 60 before-after studies, one mixed method study, and three controlled time series studies. Of these studies, 46 included access outcomes and 278 included consumption outcomes. In terms of target population, 110 studies focused on five to seven year olds, 175 targeted eight to 10 year olds, 192 targeted 11 to 14 year olds, 73 targeted 15 to 18 year olds, 55 targeted parents, and 30 targeted teachers, other service providers, or the general public. The most common intervention locations included schools, communities or community centres, and homes. Most studies implemented multi-faceted intervention strategies to increase FV access or consumption. CONCLUSIONS: While consumption measures were commonly reported, this review identified a small yet important subset of literature examining access to FV. This is a critically important issue since consumption is contingent upon access. Future research should examine the impact of interventions on direct outcome measures of FV access and a focused systematic review that examines these interventions is also needed. In addition, research on interventions in low- and middle-income countries is warranted based on a limited existing knowledge base. PMID- 22931479 TI - Blending technology in teaching advanced health assessment in a family nurse practitioner program: using personal digital assistants in a simulation laboratory. AB - PURPOSE: This article describes the development and implementation of integrated use of personal handheld devices (personal digital assistants, PDAs) and high fidelity simulation in an advanced health assessment course in a graduate family nurse practitioner (NP) program. A teaching tool was developed that can be utilized as a template for clinical case scenarios blending these separate technologies. DATA SOURCES: Review of the evidence-based literature, including peer-reviewed articles and reviews. CONCLUSIONS: Blending the technologies of high-fidelity simulation and handheld devices (PDAs) provided a positive learning experience for graduate NP students in a teaching laboratory setting. Combining both technologies in clinical case scenarios offered a more real-world learning experience, with a focus on point-of-care service and integration of interview and physical assessment skills with existing standards of care and external clinical resources. Faculty modeling and advance training with PDA technology was crucial to success. IMPLICATIONS FOR PRACTICE: Faculty developed a general template tool and systems-based clinical scenarios integrating PDA and high fidelity simulation. Faculty observations, the general template tool, and one scenario example are included in this article. PMID- 22931480 TI - Evaluation of the clinical hour requirement and attainment of core clinical competencies by nurse practitioner students. AB - PURPOSE: The purpose of this study was to analyze the national practice of fulfilling 500 clinical hours as a requirement for graduation from nurse practitioner (NP) programs at the master's level and to compare this standard to a comprehensive approach of evaluating attainment of clinical competencies. DATA SOURCES: The National Organization of NP Faculties (NONPF) and specialty accreditation bodies publications were used for references to clinical hour and core competency requirements for graduation from NP programs. Data from one university from student documentation on a commercial electronic tracking system were also analyzed. CONCLUSIONS: Data analysis revealed that the 500 clinical hours correlated to populations, skills performed, required levels of decision making, and expected diagnoses. However, assurance that these clinical hour requirements translated to exposure to all core competencies for entry into practice could not be established. IMPLICATIONS FOR PRACTICE: A more comprehensive approach to the evaluation of student core competencies by implementing one or more performance-based assessments, such as case-based evaluations, simulations, or objective structured clinical examinations (OSCEs), as a strategic part of NP evaluation prior to graduation is proposed. This change is viewed as critical to the continued success of NP programs as master's level education transitions to direct BS to DNP educational preparation for advanced nursing practice. PMID- 22931481 TI - Clarifying, affirming, and preserving the nurse in nurse practitioner education and practice. AB - PURPOSE: This work responds to the need for maintaining an ethic of care in the face of increased demands for cost effectiveness and efficiency. Findings are presented from a qualitative study describing how nurse practitioner (NP) faculty teach NP students about holistic nursing dimensions of NP practice. DATA RESOURCES: Data collection consisted of face to face or telephone interviews with 24 experienced NP faculty members teaching in 22 NP programs across the country. Data were analyzed using the interpretive phenomenological approach. Aspects of scientific merit were addressed through reviewing transcripts for accuracy, consensual validation sessions, and member checking. CONCLUSIONS: The most common approaches used for teaching holistic nursing dimensions of NP practice were role modeling and sharing narratives of actual cases. Other approaches included: incorporation of holistic complementary diagnoses along with medical diagnoses into assessments, use of case scenarios and standardized patients, a rite of passage ceremony, and an entire narrative curriculum. IMPLICATIONS FOR PRACTICE: NP faculty advocate incorporating a holistic mind-body-spirit perspective into assessment and intervention and broadening the diagnostic process to include complementary components of nursing and medicine. Findings have implications for teaching/learning, curriculum planning, and evaluation as NP programs transition from the master's to the doctoral level. PMID- 22931482 TI - Perivascular mesenchymal progenitors in human fetal and adult liver. AB - The presence of mesenchymal stem cells (MSCs) has been described in various organs. Pericytes possess a multilineage differentiation potential and have been suggested to be one of the developmental sources for MSCs. In human liver, pericytes have not been defined. Here, we describe the identification, purification, and characterization of pericytes in human adult and fetal liver. Flow cytometry sorting revealed that human adult and fetal liver contains 0.56%+/ 0.81% and 0.45%+/-0.39% of CD146(+)CD45(-)CD56(-)CD34(-) pericytes, respectively. Of these, 41% (adult) and 30% (fetal) were alkaline phosphatase-positive (ALP(+)). In situ, pericytes were localized around periportal blood vessels and were positive for NG2 and vimentin. Purified pericytes could be cultured extensively and had low population doubling times. Immunofluorescence of cultures demonstrated that cells were positive for pericyte and mesenchymal cell markers CD146, NG2, CD90, CD140b, and vimentin, and negative for endothelial, hematopoietic, stellate, muscle, or liver epithelial cell markers von Willebrand factor, CD31, CD34, CD45, CD144, CD326, CK19, albumin, alpha-fetoprotein, CYP3A7, glial fibrillary acid protein, MYF5, and Pax7 by gene expression; myogenin and alpha-smooth muscle actin expression were variable. Fluorescence-activated cell sorting analysis of cultures confirmed surface expression of CD146, CD73, CD90, CD10, CD13, CD44, CD105, and ALP and absence of human leukocyte antigen-DR. In vitro differentiation assays demonstrated that cells possessed robust osteogenic and myogenic, but low adipogenic and low chondrogenic differentiation potentials. In functional in vitro assays, cells had typical mesenchymal strong migratory and invasive activity. In conclusion, human adult and fetal livers harbor pericytes that are similar to those found in other organs and are distinct from hepatic stellate cells. PMID- 22931483 TI - A randomized controlled trial of the effects of listening to non-commercial music on quality of nocturnal sleep and relaxation indices in patients in medical intensive care unit. AB - AIM: The purpose was to examine the effects of non-commercial music on quality of sleep and relaxation indices, including heart rate, mean arterial pressure, and respiratory rate in patients in intensive care units. BACKGROUND: There is currently insufficient scientific knowledge for the effects of music on quality of sleep in critically ill patients. DESIGN: A randomized controlled trial. METHODS: Between January-December 2010, 28 patients aged 39-78 years were randomly assigned to music and control groups. Participants in the music groups listened to non-commercial music for 45 minutes at nocturnal sleep time. In the control group, participants slept with no music. Participants were assessed using vital signs monitors, standardized questionnaire, and polysomnography. Polysomnography sleep was recorded for the first 2 hours of the nocturnal sleep. General estimating equation was applied to analyse data. FINDINGS: Participants in the music group had shorter stage N2 sleep and longer stage N3 sleep in the first 2 hours of the nocturnal sleep and improved self-reported sleep quality, compared with those in the control group. The music group patients also had significantly lower heart rates than those in the control group. The intensive care units patients experienced fragmented sleep with a high frequency of awakenings and severe reduction in random eye movement sleep during the first 2 hours of the nocturnal sleep. CONCLUSION: The findings provided evidence for nurses to use soothing music as a research-based nursing intervention for intensive care unit patients' sleep improvement. PMID- 22931485 TI - Site-dependent donation/backdonation charge transfer at the CoPc/Ag(111) interface. AB - The organic/metal interface formed upon adsorption of cobalt(II) phthalocyanine (CoPc) molecules on a flat Ag(111) single crystal was investigated using a combination of scanning tunneling microscopy (STM) and photoemission spectroscopy (PES). A flat-lying molecular adsorption with the pi conjugated phthalocyanine ligand parallel to the substrate was found to lead to an effective molecule substrate coupling which governs a template-guided molecular growth. A voltage polarity dependence at the cobalt ion site was emphasized and correlated with the Co 2p core level spectra evolution which sustains an interface-confined reduction effect of the cobalt oxidation state. The formation of interface dipoles was observed via monitoring the changes in the work function (WF) upon deposition. The observations are discussed on the basis of a site-dependent donation/backdonation charge transfer at the molecule-substrate interface. PMID- 22931484 TI - From mechanical force to RhoA activation. AB - Throughout their lives, all cells constantly experience and respond to various mechanical forces. These frequently originate externally but can also arise internally as a result of the contractile actin cytoskeleton. Mechanical forces trigger multiple signaling pathways. Several converge and result in the activation of the GTPase RhoA. In this review, we focus on the pathways by which mechanical force leads to RhoA regulation, especially when force is transmitted via cell adhesion molecules that mediate either cell-matrix or cell-cell interactions. We discuss both the upstream signaling events that lead to activation of RhoA and the downstream consequences of this pathway. These include not only cytoskeletal reorganization and, in a positive feedback loop, increased myosin-generated contraction but also profound effects on gene expression and differentiation. PMID- 22931486 TI - CYP98A22, a phenolic ester 3'-hydroxylase specialized in the synthesis of chlorogenic acid, as a new tool for enhancing the furanocoumarin concentration in Ruta graveolens. AB - BACKGROUND: Furanocoumarins are molecules with proven therapeutic properties and are produced in only a small number of medicinal plant species such as Ruta graveolens. In vivo, these molecules play a protective role against phytophageous insect attack. Furanocoumarins are members of the phenylpropanoids family, and their biosynthetic pathway is initiated from p-coumaroyl coA. The enzymes belonging to the CYP98A cytochrome P450 family have been widely described as being aromatic meta-hydroxylases of various substrates, such as p-coumaroyl ester derivatives, and are involved in the synthesis of coumarins such as scopoletin. In furanocoumarin-producing plants, these enzymes catalyze the step directly downstream of the junction with the furanocoumarin biosynthetic pathway and might indirectly impact their synthesis. RESULTS: In this work, we describe the cloning and functional characterization of the first CYP98A encoding gene isolated from R. graveolens. Using Nicotiana benthamiana as a heterologous expression system, we have demonstrated that this enzyme adds a 3-OH to p-coumaroyl ester derivatives but is more efficient to convert p-coumaroyl quinate into chlorogenic acid than to metabolize p-coumaroyl shikimate. Plants exposed to UV-B stress showed an enhanced expression level of the corresponding gene. The R. graveolens cyp98a22 open reading frame and the orthologous Arabidopsis thaliana cyp98a3 open reading frame were overexpressed in stable transgenic Ruta plants. Both plant series were analyzed for their production of scopoletin and furanocoumarin. A detailed analysis indicates that both genes enhance the production of furanocoumarins but that CYP98A22, unlike CYP98A3, doesn't affect the synthesis of scopoletin. CONCLUSIONS: The overexpression of CYP98A22 positively impacts the concentration of furanocoumarins in R. graveolens. This gene is therefore a valuable tool to engineer plants with improved therapeutical values that might also be more resistant to phytophageous insects. PMID- 22931487 TI - Data preprocessing method for liquid chromatography-mass spectrometry based metabolomics. AB - A set of data preprocessing algorithms for peak detection and peak list alignment are reported for analysis of liquid chromatography-mass spectrometry (LC-MS) based metabolomics data. For spectrum deconvolution, peak picking is achieved at the selected ion chromatogram (XIC) level. To estimate and remove the noise in XICs, each XIC is first segmented into several peak groups based on the continuity of scan number, and the noise level is estimated by all the XIC signals, except the regions potentially with presence of metabolite ion peaks. After removing noise, the peaks of molecular ions are detected using both the first and the second derivatives, followed by an efficient exponentially modified Gaussian-based peak deconvolution method for peak fitting. A two-stage alignment algorithm is also developed, where the retention times of all peaks are first transferred into the z-score domain and the peaks are aligned based on the measure of their mixture scores after retention time correction using a partial linear regression. Analysis of a set of spike-in LC-MS data from three groups of samples containing 16 metabolite standards mixed with metabolite extract from mouse livers demonstrates that the developed data preprocessing method performs better than two of the existing popular data analysis packages, MZmine2.6 and XCMS(2), for peak picking, peak list alignment, and quantification. PMID- 22931488 TI - Self-reported gait unsteadiness in mildly impaired neurological patients: an objective assessment through statistical gait analysis. AB - BACKGROUND: Self-reported gait unsteadiness is often a problem in neurological patients without any clinical evidence of ataxia, because it leads to reduced activity and limitations in function. However, in the literature there are only a few papers that address this disorder. The aim of this study is to identify objectively subclinical abnormal gait strategies in these patients. METHODS: Eleven patients affected by self-reported unsteadiness during gait (4 TBI and 7 MS) and ten healthy subjects underwent gait analysis while walking back and forth on a 15-m long corridor. Time-distance parameters, ankle sagittal motion, and muscular activity during gait were acquired by a wearable gait analysis system (Step32, DemItalia, Italy) on a high number of successive strides in the same walk and statistically processed. Both self-selected gait speed and high speed were tested under relatively unconstrained conditions. Non-parametric statistical analysis (Mann-Whitney, Wilcoxon tests) was carried out on the means of the data of the two examined groups. RESULTS: The main findings, with data adjusted for velocity of progression, show that increased double support and reduced velocity of progression are the main parameters to discriminate patients with self reported unsteadiness from healthy controls. Muscular intervals of activation showed a significant increase in the activity duration of the Rectus Femoris and Tibialis Anterior in patients with respect to the control group at high speed. CONCLUSIONS: Patients with a subjective sensation of instability, not clinically documented, walk with altered strategies, especially at high gait speed. This is thought to depend on the mechanisms of postural control and coordination. The gait anomalies detected might explain the symptoms reported by the patients and allow for a more focused treatment design. The wearable gait analysis system used for long distance statistical walking assessment was able to detect subtle differences in functional performance monitoring, otherwise not detectable by common clinical examinations. PMID- 22931489 TI - Buthionine sulfoximine and 1,25-dihydroxyvitamin D induce apoptosis in breast cancer cells via induction of reactive oxygen species. AB - Calcitriol or 1,25(OH)(2)D(3) is a negative growth regulator of breast cancer cells. The aim of this study was to determine whether L-buthionine-S,R sulfoximine, a glutathione-depleting drug, modifies the antiproliferative effects of 1,25(OH)(2)D(3) on MCF-7 cells. For comparison, we included studies in MCF-7 cells selected for vitamin D resistance and in human mammary epithelial cells transformed with SV40 and ras. Our data indicate that L-buthionine-S,R sulfoximine enhances the growth inhibition of 1,25(OH)(2)D(3) in all transformed breast cell lines. This effect is mediated by ROS leading to apoptosis. In conclusion, BSO alters redox state and sensitizes breast cancer cells to 1,25(OH)(2)D(3)-mediated apoptosis. PMID- 22931490 TI - Subcutaneous IgG replacement after pediatric SCT. AB - Hypogammaglobulinemia is common after pediatric SCT and IgG replacement is recommended. Some children will have a prolonged hypogammaglobulinemia but may have poor venous access which impedes further iv IgG replacement. In primary antibody deficiencies, sc IgG replacement, performed by parents at home, has been shown to be efficient and to improve life quality. In this study prolonged hypogammaglobulinemia post-SCT was observed in 58 of 158 (37%) children transplanted 2003-2010. Iv IgG (n = 46) and sc IgG (n = 12) replacement was compared and in 32 of 35 surviving children, it was possible to assess family attitudes to the treatment. There was no significant difference in numbers of patients reaching IgG >=4 g/L (64-96%) or IgG trough levels between the two groups. However, the levels were less variable in the sc IgG group. Side effects associated with the IgG replacement occurred more frequently in the iv IgG group (67.4% vs. 16.7%, p = 0.003). The frequency of clinical infections was equal in the groups. No family in the sc IgG group desired change of route of administration in contrast to the iv IgG group. To conclude, sc IgG replacement is a convenient and safe alternative to iv IgG replacement which should be offered to children undergoing SCT. PMID- 22931491 TI - Prediction of allergenic proteins by means of the concept of Chou's pseudo amino acid composition and a machine learning approach. AB - Because of the importance of proteins in inducing allergenic reactions, the ability of predicting their potential allergenicity has become an important issue. Bioinformatics presents valuable tools for analyzing allergens and these complementary approaches can help traditional techniques to study allergens. This work proposes a computational method for predicting the allergenic proteins. The prediction was performed using pseudo-amino acid composition (PseAAC) and Support Vector Machines (SVMs). The predictor efficiency was evaluated by fivefold cross validation. The overall prediction accuracies and Matthew's correlation coefficient (MCC) obtained by this method were 91.19% and 0.82, respectively. Furthermore, the minimum Redundancy and Maximum Relevance (mRMR) feature selection method was utilized for measuring the effect and power of each feature. Interestingly, in our study all six characters (hydrophobicity, hydrophilicity, side chain mass, pK1, pK2 and pI) are present among the 10 higher ranked features obtained from the mRMR feature selection method. PMID- 22931492 TI - Quantitative structure-activity relationship study of aromatic inhibitors against rat lens aldose reductase activity using variable selections. AB - A quantitative structure-activity relationship (QSAR) study of aromatic inhibitors against aldose reductase (AR) activity was performed using variable selection from stepwise multiple linear regression (MLR) and genetic algorithm (GA)-MLR. As a result of variable selection, stepwise MLR and GA-MLR gave the same results with one, two, three and five descriptors and different results with four and six descriptors. GA-MLR produced higher values and was better in explanatory and predictive power than stepwise MLR in four variables. AR activity (pIC50) of aromatic derivatives was expressed with acceptable explanatory (74.6 81.2%) and predictive power (68.8-74.4%) in models 3 and 4. The resulting models with the given descriptors illustrate that hydrophobic and electrostatic interactions play a significant role in inhibition of AR activity. This study suggests that the QSAR models can be used as guidelines to predict improved aldose reductase inhibitory activity and to obtain reliable predictions in structurally diverse compounds. PMID- 22931493 TI - Synthesis of benzopyran linked pyrrolo[2,1-c][1,4]benzodiazepines as DNA-binding and potential anticancer agents. AB - A series of twelve benzopyran linked pyrrolo[2,1-c][1,4]benzodiazepines (PBDs) have been synthesized. They exhibit significant DNA-binding activity and excellent cytotoxic activity against various human cancer cell lines. PMID- 22931494 TI - Synthesis and ABCG2 inhibitory activity of novel fumitremorgin C analogs- specificity and structure activity correlations. AB - The Ko family of fumitremorgin C analogs are potent and selective ABCG2 inhibitors. However, the most potent Ko compounds carry an ester linkage in their side-chain that makes them chemically and metabolically less stable. We have synthesized 16 tricyclic and 28 tetracyclic novel analogs devoid of ester linkages and tested them for ABCG2 inhibition potency and specificity. Unlike in the tricyclic analog group, potent ABCG2 inhibitory compounds were found among the tetracyclic analogs. The most potent compounds carried the 3S,6S,12aS configuration. We observed a marked stereospecificity as compounds with the 3S,6S,12aS configuration were at least 18-fold more potent inhibitors than their diastereoisomeric pairs with a 3S,6R,12aS configuration. This stereospecificity was not observed in ABCB1 and ABCC1 inhibition. Therefore, a single chiral center confers specificity for ABCG2 over ABCB1 and ABCC1. This is quite unexpected considering the large multivalent drug binding site these transporters harbor. PMID- 22931495 TI - Design, synthesis, and biological evaluation of potent photoaffinity probes of oleanolic acid. AB - To study the target proteins of oleanolic acid, a series of novel photoaffinity probes were designed and synthesized. Their affinity for the target proteins was evaluated in an enzyme inhibition assay against glycogen phosphorylase, a known target protein of oleanolic acid. Among these compounds, probe 2 exhibited the most potent activity with an IC50 value of 5.98 MUM, which was about 2.5-fold more potent than its parent compound oleanolic acid. The results showed that the synthesized photoaffinity probes retained the binding affinity for their target proteins, and might be used as powerful tools to fish out the target proteins of oleanolic acid. PMID- 22931496 TI - CoMFA and CoMSIA 3D QSAR models for a series of some condensed thieno[2,3 d]pyrimidin-4(3H)-ones with antihistaminic (H1) activity. AB - Comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) studies were carried out for a series of thienopyrimidines, novel Histamine H1 receptor antagonists. Various models were generated. The best predictive CoMFA model gave significant correlation coefficients (cross-validated r2 (q2) = 0.514, non-cross-validated r2 = 0.925), showing the influence of steric and electrostatic fields. Likewise, the best predictive CoMSIA model gave cross-validated r2 (q2) = 0.541, non-cross-validated r2 = 0.862, eliciting the influence of steric, electrostatic, hydrophobic and hydrogen bond acceptor fields. The generated models were externally validated and well correlated with calculated (predicted) and experimental inhibitory concentration (IC50) values, using test sets. The analysis of the contour maps of both CoMFA and CoMSIA models offer important structural insight for designing novel and more active Histamine H1 receptor antagonists prior to their synthesis. PMID- 22931497 TI - Significant genetic and phenotypic changes arising from clonal growth of a single spore of an arbuscular mycorrhizal fungus over multiple generations. AB - Arbuscular mycorrhizal fungi (AMF) are highly successful plant symbionts. They reproduce clonally producing multinucleate spores. It has been suggested that some AMF harbor genetically different nuclei. However, recent advances in sequencing the Glomus irregulare genome have indicated very low within-fungus polymorphism. We tested the null hypothesis that, with no genetic differences among nuclei, no significant genetic or phenotypic variation would occur among clonal single spore lines generated from one initial AMF spore. Furthermore, no additional variation would be expected in the following generations of single spore lines. Genetic diversity contained in one initial spore repeatedly gave rise to genetically different variants of the fungus with novel phenotypes. The genetic changes represented quantitative changes in allele frequencies, most probably as a result of changes in the frequency of genetic variation partitioned on different nuclei. The genetic and phenotypic variation is remarkable, given that it arose repeatedly from one clonal individual. Our results highlight the dynamic nature of AMF genetics. Even though within-fungus genetic variation is low, some is probably partitioned among nuclei and potentially causes changes in the phenotype. Our results are important for understanding AMF genetics, as well as for researchers and biotechnologists hoping to use AMF genetic diversity for the improvement of AMF inoculum. PMID- 22931498 TI - Potassium Boc-protected secondary aminomethyltrifluoroborates: synthesis and Suzuki-Miyaura cross-coupling reactions. AB - Seven potassium Boc-protected secondary aminomethyltrifluoroborates were prepared in a standardized two-step process. The Suzuki-Miyaura cross-coupling reaction was studied with this new class of nucleophiles, and a large variety of aryl and hetaryl chlorides provided the desired products in good to excellent yields, thereby allowing easy access to secondary aminomethyl substructures. PMID- 22931499 TI - Insights into bone marrow-derived mesenchymal stem cells safety for cutaneous repair and regeneration. AB - Wound healing involves the orchestration of a complex process of interactions between numerous types of cell, components of extracellular matrix and signalling molecules following injury, which is usually a highly successful biological course to reconstruct the integrity of the skin. Nevertheless, when skin is severely damaged, the injured skin is limited in its ability to repair itself and possibly results in the hypertrophic scars or so-called keloids, and non healing wound or ulcer. Bone marrow-derived mesenchymal stem cells (BM-MSCs) are being clinically explored as a promising therapy in the field of tissue repair and regeneration. However, potential risks associated with these cell-based therapies remain uncertain. The aim of this review is to summarise the safety issues accompanying the administration of BM-MSCs for acute or chronic skin repair and regeneration. More importantly, this review highlights the requirement for fundamental research to improve future clinical application of these strategies, as well as for regulatory authorities to establish clinical criteria to identify the qualitative requirements for the manufacture process of cells products, which will ensure the manufacture process of the best benefit-to-risk ratio of cell based therapy for the patients. PMID- 22931500 TI - Nanostructured lipid carriers system: recent advances in drug delivery. AB - Nanostructured lipid carrier (NLC) is second generation smarter drug carrier system having solid matrix at room temperature. This carrier system is made up of physiological, biodegradable and biocompatible lipid materials and surfactants and is accepted by regulatory authorities for application in different drug delivery systems. The availability of many products in the market in short span of time reveals the success story of this delivery system. Since the introduction of the first product, around 30 NLC preparations are commercially available. NLC exhibit superior advantages over other colloidal carriers viz., nanoemulsions, polymeric nanoparticles, liposomes, SLN etc. and thus, have been explored to more extent in pharmaceutical technology. The whole set of unique advantages such as enhanced drug loading capacity, prevention of drug expulsion, leads to more flexibility for modulation of drug release and makes NLC versatile delivery system for various routes of administration. The present review gives insights on the definitions and characterization of NLC as colloidal carriers including the production techniques and suitable formulations. This review paper also highlights the importance of NLC in pharmaceutical applications for the various routes of drug delivery viz., topical, oral, pulmonary, ocular and parenteral administration and its future perspective as a pharmaceutical carrier. PMID- 22931503 TI - Abstracts of the 11th Asian Congress of Urology of the Urological Association of Asia. August 22-26, 2012. Pattaya, Thailand. PMID- 22931501 TI - The african health profession regulatory collaborative for nurses and midwives. AB - BACKGROUND: More than thirty-five sub-Saharan African countries have severe health workforce shortages. Many also struggle with a mismatch between the knowledge and competencies of health professionals and the needs of the populations they serve. Addressing these workforce challenges requires collaboration among health and education stakeholders and reform of health worker regulations. Health professional regulatory bodies, such as nursing and midwifery councils, have the mandate to reform regulations yet often do not have the resources or expertise to do so. In 2011, the United States of America Centers for Disease Control and Prevention began a four-year initiative to increase the collaboration among national stakeholders and help strengthen the capacity of health professional regulatory bodies to reform national regulatory frameworks. The initiative is called the African Health Regulatory Collaborative for Nurses and Midwives. This article describes the African Health Regulatory Collaborative for Nurses and Midwives and discusses its importance in implementing and sustaining national, regional, and global workforce initiatives. DISCUSSION: The African Health Profession Regulatory Collaborative for Nurses and Midwives convenes leaders responsible for regulation from 14 countries in East, Central and Southern Africa. It provides a high profile, south-to-south collaboration to assist countries in implementing joint approaches to problems affecting the health workforce. Implemented in partnership with Emory University, the Commonwealth Secretariat, and the East, Central and Southern African College of Nursing, this initiative also supports four to five countries per year in implementing locally-designed regulation improvement projects. Over time, the African Health Regulatory Collaborative for Nurses and Midwives will help to increase the regulatory capacity of health professional organizations and ultimately improve regulation and professional standards in this region of Africa. The African Health Regulatory Collaborative for Nurses and Midwives will measure the progress of country projects and conduct an annual evaluation of the initiative's regional impact, thereby contributing to the global evidence base of health workforce interventions. CONCLUSION: The African Health Regulatory Collaborative for Nurses and Midwives is designed to address priority needs in health workforce development and improve regulation of the health workforce. This model may assist others countries and regions facing similar workforce challenges. PMID- 22931504 TI - Use of outcome events in surgical trials: a systematic review. AB - BACKGROUND: Surgical trials sometimes fail to clearly identify the primary outcome events of interest. This results in trials that are diffuse and difficult to interpret. OBJECTIVE: The objective of this study was to systematically review the use of outcome events in surgical trials. DATA SOURCES: Surgical trials published between 1 January 2007 and 30 June 2010 in 26 peer-reviewed journals representing a wide range of specialty interests were used in this study. REVIEW METHODS: Copies of all potentially relevant articles were scrutinized to identify the admissible surgical trials. Two investigators experienced in health research methods used a standardized form to extract discrete information (i.e. it was an 'identifying and counting' exercise that did not require subjective evaluations). All forms were double-checked. RESULTS: Twenty-four per cent (130 out of 531) of the trials failed to declare the primary outcome events - 11% (56 out of 531) of the trials indicated the primary outcome events in the abstract, but not in the body of the article. The compliant trials used a median of three primary outcome events (interquartile range: 2-5, absolute range: 1-17), and a median of 19 statistical comparisons (interquartile range: 9-32, absolute range: 1-130). Only 2% (11 out of 531) of the trials made an adjustment for the multiple testing of statistical significance (9 of these trials declared a single primary outcome event). Composite outcome events appeared in 9% (48 out of 531) of the trials and these studies contained a median of 24 statistical comparisons. CONCLUSIONS: Many surgical trials fail to clearly define the specific outcome events of interest, and this is often accompanied by a subversive number of statistical comparisons. PMID- 22931505 TI - Chemokine receptor antagonists. PMID- 22931506 TI - High vitamin D status in younger individuals is associated with low circulating thyrotropin. AB - BACKGROUND: Vitamin D is an immunomodulator and may affect autoimmune thyroid diseases. Vitamin D has also been shown to influence thyrocytes directly by attenuating thyrotropin (TSH)-stimulated iodide uptake and cell growth. However, it is unclear how vitamin D status is related to TSH at the population level. The goal of the present study was to investigate the relationship between vitamin D status and TSH levels according to thyroid autoantibodies in a population-based health survey in Thailand. METHODS: A total of 2582 adults, aged 15-98 years, were randomly selected according to the geographical region from the Thailand 4th National Health Examination Survey sample. By study design, the sexes were equally represented. Serum levels of 25-hydroxyvitamin D [25(OH)D], TSH, the thyroid peroxidase antibody (TPOAb), and the thyroglobulin antibody (TgAb) were measured in all subjects. RESULTS: The mean age was 55.0+/-0.4 (SE) years. In subjects positive for serum TgAb, serum TSH levels were higher, whereas total serum 25(OH)D levels were lower. In addition, the prevalence of vitamin D insufficiency in TgAb-positive subjects was significantly higher than that observed in TPOAb- and TgAb-negative subjects, whether based on cutoff values of 20 or 30 ng/mL: 8.3% vs. 5.6%, p<0.05; or 47.6% vs. 42.0%, p<0.05, respectively. However, vitamin D status was not associated with positive TPOAb and/or TgAb after controlling for sex and age. To explore the probable interaction between vitamin D status and age on serum TSH, analyses were performed according to age tertiles; it was found that higher 25(OH)D levels were independently associated with lower TSH, but only in subjects in the lowest age tertile. CONCLUSIONS: This population-based study showed that high vitamin D status in younger individuals is associated with low circulating TSH. PMID- 22931507 TI - Redox switching of heteropolyanions entrapped in polypyrrole films investigated by ac electrogravimetry. AB - In this work, the global kinetics and the exchange of protons and free solvent at the film/electrolyte interface were investigated when a PPy film doped with HPA (heteropolyanions) is polarized. The ionic and electronic transfers for the PPy HPA system are fast because the determined values of the resistances are relatively low (a few ohms). Depending on the applied potential, the global kinetics is controlled by both the ionic and electronic transfers. The transport effects were neglected here because the prepared films were very thin. Protons play an important role in charge compensation whatever the imposed potential on the PPy-HPA film. This phenomenon results from the acidic-basic properties of the SiMo(12)O(40)(4-) reduced species. A small quantity of water was also shown to be involved in the film reaction process. PMID- 22931508 TI - Child/adolescent abuse and suicidal behavior: are they sex related? AB - The association between childhood and adolescent abuse and suicidal behavior, and the possible contribution of abuse to sex differences in non lethal suicidal behavior, was investigated. Data were extracted from the Israel-based component of the WHO World Mental Health Survey (Kessler & Utsun, 2008a). Increased risk for ideation, plan, and suicidal attempt were associated with childhood abuse, and increased risk for attempt was associated also with abuse at adolescence. No associations with sex or sex by abuse interactions were observed. The higher frequency of childhood abuse among women could account in part for their higher rates of suicidal attempts as compared to men. PMID- 22931509 TI - Rapid core measure improvement through a "business case for quality". AB - Incentives to improve performance are emerging as revenue or financial penalties are linked to the measured quality of service provided. The HCA "Getting to Green" program was designed to rapidly increase core measure performance scores. Program components included (1) the "business case for quality"-increased awareness of how quality drives financial performance; (2) continuous communication of clinical and financial performance data; and (3) evidence-based clinical protocols, incentives, and tools for process improvement. Improvement was measured by comparing systemwide rates of adherence to national quality measures for heart failure (HF), acute myocardial infarction (AMI), pneumonia (PN), and surgical care (SCIP) to rates from all facilities reporting to the Centers for Medicare and Medicaid Services (CMS). As of the second quarter of 2011, 70% of HCA total measure set composite scores were at or above the 90th percentile of CMS scores. A test of differences in regression coefficients between the CMS national average and the HCA average revealed significant differences for AMI (p = .001), HF (p = .012), PN (p < .001), and SCIP (p = .015). This program demonstrated that presentation of the financial implications of quality, transparency in performance data, and clearly defined goals could cultivate the desire to use improvement tools and resources to raise performance. PMID- 22931510 TI - Garlic extracts prevent oxidative stress, hypertrophy and apoptosis in cardiomyocytes: a role for nitric oxide and hydrogen sulfide. AB - BACKGROUND: In ancient times, plants were recognized for their medicinal properties. Later, the arrival of synthetic drugs pushed it to the backstage. However, from being merely used for food, plants are now been widely explored for their therapeutic value. The current study explores the potential of skin and flesh extracts from a hard-necked Rocambole variety of purple garlic in preventing cardiomyocyte hypertrophy and cell death. METHODS: Norepinephrine (NE) was used to induce hypertrophy in adult rat cardiomyocytes pretreated with garlic skin and flesh extracts. Cell death was measured as ratio of rod to round shaped cardiomyocytes. Fluorescent probes were used to measure apoptosis and oxidative stress in cardiomyocytes treated with and without extracts and NE. Pharmacological blockade of nitric oxide (NO) and hydrogen sulfide (H2S) were used to elucidate the mechanism of action of garlic extracts. Garlic extract samples were also tested for alliin and allicin concentrations. RESULTS: Exposure of cardiomyocytes to NE induced an increase in cell size and cell death; this increase was significantly prevented upon treatment with garlic skin and flesh extracts. Norepinephrine increased apoptosis and oxidative stress in cardiomyocytes which was prevented upon pretreatment with skin and flesh extracts; NO, and H2S blockers significantly inhibited this beneficial effect. Allicin and alliin concentration were significantly higher in garlic flesh extract when compared to the skin extract. CONCLUSION: These results suggest that both skin and flesh garlic extracts are effective in preventing NE induced cardiomyocyte hypertrophy and cell death. Reduction in oxidative stress may also play an important role in the anti-hypertrophic and anti-apoptotic properties of garlic extracts. These beneficial effects may in part be mediated by NO and H2S. PMID- 22931511 TI - Lactose repressor experimental folding landscape: fundamental functional unit and tetramer folding mechanisms. AB - The fundamental principles that govern monomer folding are believed to be congruent with those of protein oligomers. However, the effects of protein assembly during the folding reaction can result in a series of complex transitions that are considerably more challenging to deconvolute. Here we developed the experimental protein folding mechanism for the lactose repressor (LacI), for both the dimeric and the tetrameric states, using equilibrium unfolding and kinetic experiments, and by leveraging the previously reported monomer folding landscape. Reaction details for LacI oligomers were observed by way of circular dichroism, intrinsic fluorescence, and Forster resonance energy transfer (FRET) and as a function of protein concentration. In general, the dimer and tetramer are four-phase folding reactions in which the first three transitions are tantamount to the folding of constituent monomers. The final reaction phase of the LacI dimer can be attributed to protein assembly, based on the concentration dependence of the observed folding rates and intermolecular FRET measurements. Unlike the dimer, the latter reaction phase of the LacI tetramer is not dependent on protein concentration, likely because of a strong tethering of the monomers, which simplifies the folding reaction by eliminating an explicit protein assembly phase. Finally, folding of the LacI dimer and tetramer was assessed in the presence of polyethylene glycol to rule out inert molecular crowding as the driving force for the protein folding reaction; in addition, these data provide insight into the folding mechanism in vivo. PMID- 22931512 TI - DFT and experimental exploration of the mechanism of InCl3-catalyzed type II cycloisomerization of 1,6-enynes: identifying InCl2(+) as the catalytic species and answering why nonconjugated dienes are generated. AB - InCl(3) and other In(III) species have been widely applied as catalysts in many reactions. However, what are the real catalytic species of these reactions? Through DFT calculations and experimental investigation of the mechanism and regioselectivity of InCl(3)-catalyzed cycloisomerization reactions of 1,6-enynes (here all discussed 1,6-enynes are ene-internal-alkyne molecules), we propose that the catalytic species of this reaction is the in situ generated InCl(2)(+). Further electrospray ionization high-resolution mass spectroscopy (ESI-HRMS) supported the existence of InCl(2)(+) in acetonitrile solution. This finding of InCl(2)(+) as the catalytic species suggests that other reactions catalyzed by In(III) species could also have cationic In(III) species as the real catalysts. DFT calculations revealed that the catalytic cycle of the cycloisomerization of 1,6-enynes catalyzed by InCl(3) starts from InCl(2)(+) coordination to the alkyne of the substrate, generating a vinyl cation. Then nonclassical cyclopropanation of the vinyl cation to the alkene part of the substrate gives a homoallylic cation, which undergoes a novel homoallylic cation rearrangement involving a [1,3]-carbon shift to give the more stable homoallylic cation 15. Finally InCl(2)(+) cation coordination assisted nonconjugated [1,2]-hydride shifts deliver the final nonconjugated diene products. The preference of generating nonconjugated dienes instead of conjugated dienes in the cycloisomerization reaction is mainly due to two reasons: coordination of the InCl(2)(+) to the alkene part in [1,2]-H shift transition states disfavors the conjugated [1,2]-H shifts that generate cations adjacent to the positively charged alkene, and coordination of InCl(2)(+) to the nonconjugated diene product is stronger than coordination to the conjugated diene, making nonconjugated [1,2]-H shift transition states lower in energy than conjugated [1,2]-H shift transition states, on the basis of the Hammond postulate. DFT calculations predicted that the conjugated [1,2]-H shifts could become favored if the electron-donating methyl substituent in the alkyne moiety of the 1,6-enyne is replaced by a H atom. This prediction of producing a conjugated diene has been verified experimentally. Rationalization about why type II rather than type I products were obtained using InCl(3) as the catalyst in the cycloisomerization of 1,6-enynes has also been investigated computationally. PMID- 22931513 TI - Comparative mapping in the Fagaceae and beyond with EST-SSRs. AB - BACKGROUND: Genetic markers and linkage mapping are basic prerequisites for comparative genetic analyses, QTL detection and map-based cloning. A large number of mapping populations have been developed for oak, but few gene-based markers are available for constructing integrated genetic linkage maps and comparing gene order and QTL location across related species. RESULTS: We developed a set of 573 expressed sequence tag-derived simple sequence repeats (EST-SSRs) and located 397 markers (EST-SSRs and genomic SSRs) on the 12 oak chromosomes (2n = 2x = 24) on the basis of Mendelian segregation patterns in 5 full-sib mapping pedigrees of two species: Quercus robur (pedunculate oak) and Quercus petraea (sessile oak). Consensus maps for the two species were constructed and aligned. They showed a high degree of macrosynteny between these two sympatric European oaks. We assessed the transferability of EST-SSRs to other Fagaceae genera and a subset of these markers was mapped in Castanea sativa, the European chestnut. Reasonably high levels of macrosynteny were observed between oak and chestnut. We also obtained diversity statistics for a subset of EST-SSRs, to support further population genetic analyses with gene-based markers. Finally, based on the orthologous relationships between the oak, Arabidopsis, grape, poplar, Medicago, and soybean genomes and the paralogous relationships between the 12 oak chromosomes, we propose an evolutionary scenario of the 12 oak chromosomes from the eudicot ancestral karyotype. CONCLUSIONS: This study provides map locations for a large set of EST-SSRs in two oak species of recognized biological importance in natural ecosystems. This first step toward the construction of a gene-based linkage map will facilitate the assignment of future genome scaffolds to pseudo-chromosomes. This study also provides an indication of the potential utility of new gene-based markers for population genetics and comparative mapping within and beyond the Fagaceae. PMID- 22931515 TI - Habitat filtering and niche differentiation jointly explain species relative abundance within grassland communities along fertility and disturbance gradients. AB - Deterministic niche-based processes have been proposed to explain species relative abundance within communities but lead to different predictions: habitat filtering (HF) predicts dominant species to exhibit similar traits while niche differentiation (ND) requires that species have dissimilar traits to coexist. Using a multiple trait-based approach, we evaluated the relative roles of HF and ND in determining species abundances in productive grasslands. Four dimensions of the functional niche of 12 co-occurring grass species were identified using 28 plant functional traits. Using this description of the species niche, we investigated patterns of functional similarity and dissimilarity and linked them to abundance in randomly assembled six-species communities subjected to fertilization/disturbance treatments. Our results suggest that HF and ND jointly determined species abundance by acting on contrasting niche dimensions. The effect of HF decreased relative to ND with increasing disturbance and decreasing fertilization. Dominant species exhibited similar traits in communities whereas dissimilarity favored the coexistence of rare species with dominants by decreasing inter-specific competition. This stabilizing effect on diversity was suggested by a negative relationship between species over-yielding and relative abundance. We discuss the importance of considering independent dimensions of functional niche to better understand species abundance and coexistence within communities. PMID- 22931516 TI - Dithranol as a MALDI matrix for tissue imaging of lipids by Fourier transform ion cyclotron resonance mass spectrometry. AB - To fill the unmet need for improved matrixes for matrix-assisted laser desorption ionization (MALDI) tissue imaging of small molecules, dithranol (DT)--a matrix mainly used for the analysis of synthetic polymers--was evaluated for detection of lipids in rat liver and bovine calf lens, using MALDI Fourier transform ion cyclotron resonance mass spectrometry (FTICR MS). The use of DT resulted in better detection of endogenous lipids than did two other commonly used matrixes, alpha-cyano-4-hydroxycinnamic acid (CHCA) and 2,5-dihydroxybenzoic acid (DHB), with >70 lipid entities (including phosphatidylcholines, phosphatidylethanolamines, sphingomyelins, phosphatidylserines, phosphatidylglycerol, phosphatidic acids, ceramide phosphates, sterol lipids, acyl carnitines, and glycerides) being detected in rat liver and bovine lens tissue sections, using positive-ion detection. Using saturated DT in chloroform/methanol (2:1, v/v), with 1% formic acid in the final mixture, 57 lipid entities were successfully imaged from bovine calf lens, with clear and distinct distribution patterns. In a section across the lens equatorial plane, all compounds showed concentric distributions around the lens nucleus and most showed specific abundance changes, which correlated with lens fiber cell age. As a novel finding, palmitoylcarnitine and oleoylcarnitine were found uniquely localized to the younger lens fiber cell cortex region. This work demonstrates the potential of DT as a new matrix for tissue imaging by MALDI-FTICR MS. PMID- 22931514 TI - Bluetongue virus non-structural protein 1 is a positive regulator of viral protein synthesis. AB - BACKGROUND: Bluetongue virus (BTV) is a double-stranded RNA (dsRNA) virus of the Reoviridae family, which encodes its genes in ten linear dsRNA segments. BTV mRNAs are synthesised by the viral RNA-dependent RNA polymerase (RdRp) as exact plus sense copies of the genome segments. Infection of mammalian cells with BTV rapidly replaces cellular protein synthesis with viral protein synthesis, but the regulation of viral gene expression in the Orbivirus genus has not been investigated. RESULTS: Using an mRNA reporter system based on genome segment 10 of BTV fused with GFP we identify the protein characteristic of this genus, non structural protein 1 (NS1) as sufficient to upregulate translation. The wider applicability of this phenomenon among the viral genes is demonstrated using the untranslated regions (UTRs) of BTV genome segments flanking the quantifiable Renilla luciferase ORF in chimeric mRNAs. The UTRs of viral mRNAs are shown to be determinants of the amount of protein synthesised, with the pre-expression of NS1 increasing the quantity in each case. The increased expression induced by pre expression of NS1 is confirmed in virus infected cells by generating a replicating virus which expresses the reporter fused with genome segment 10, using reverse genetics. Moreover, NS1-mediated upregulation of expression is restricted to mRNAs which lack the cellular 3' poly(A) sequence identifying the 3' end as a necessary determinant in specifically increasing the translation of viral mRNA in the presence of cellular mRNA. CONCLUSIONS: NS1 is identified as a positive regulator of viral protein synthesis. We propose a model of translational regulation where NS1 upregulates the synthesis of viral proteins, including itself, and creates a positive feedback loop of NS1 expression, which rapidly increases the expression of all the viral proteins. The efficient translation of viral reporter mRNAs among cellular mRNAs can account for the observed replacement of cellular protein synthesis with viral protein synthesis during infection. PMID- 22931517 TI - First global forum on education on organ donation and transplantation for schools. AB - The Transplantation Society, in collaboration with the Canadian Society of Transplantation, organized a forum on education on ODT for schools. The forum included participants from around the world, school boards, and representatives from different religions. Participants presented on their countries' experience in the area of education on ODT. Working groups discussed about technologies for education, principles for sharing of resources globally, and relationships between education, and health authorities and non-governmental organizations. The forum concluded with a discussion about how to best help existing programs and those wishing to start educational programs on ODT. PMID- 22931518 TI - Understanding oligonucleotide-templated nanocrystals: growth mechanisms and surface properties. AB - We describe studies of nanoparticle synthesis using oligonucleotides as capping ligands. The oligonucleotides nucleate, grow, and stabilize near-infrared fluorescent, approximately uniform PbS nanocrystals in an aqueous environment. The properties of the resulting particles strongly depend upon the sequences as well as synthesis conditions. Fourier Transform infrared measurements suggest that functional groups on the nucleobases such as carbonyl and amine moieties are responsible for surface passivation, while the phosphate backbone is strained to accommodate nucleobase bonding, preventing irreversible aggregation and thereby stabilizing the colloids. Our theoretical model indicates that oligonucleotide mediated particle growth relies on the chemical reactivity of the oligonucleotide ligands that saturate dangling bonds of growing clusters, and favorable sequences are those that have the highest surface reactivity with growing particles. The oligonucleotide template approach is facile and versatile, offering a route to produce a range of material compositions for other chalcogenide semiconductor quantum dots and metal oxide nanoparticles. PMID- 22931519 TI - Developing new drugs for diabetes and cardiometabolic disorders: a changing paradigm. PMID- 22931520 TI - Will abuse-deterrent formulations of opioid analgesics be successful in achieving their purpose? AB - During the last 2 decades, there has been a dramatic increase in the use of strong opioids for chronic non-cancer pain. This increase has been accompanied by a steep increase in abuse, misuse, and both fatal and non-fatal overdoses involving prescription opioids. The situation is already alarming in the US. Prescription opioid-related harm is a complex, multifactorial issue that requires a multifaceted solution. In this respect, formulations of opioid analgesics designed to resist or deter abuse may be a useful component of a comprehensive opioid risk minimization programme. Such formulations have or are being developed. Abuse-resistant opioids include those that use some kind of physical barrier to prevent tampering with the formulation. Abuse-deterrent opioids are not necessarily resistant to tampering, but contain substances that are designed to make the formulation less attractive to abusers. This article focuses on two products intended to deter abuse that were reviewed by the US Food and Drug Administration (FDA). The first (Embeda(r)) consists of extended-release morphine with sequestered naltrexone, an opioid antagonist that is released if the tablet is compromised by chewing or crushing. Although Embeda(r) exhibited abuse deterrent features, its label warns that it can be abused in a manner similar to other opioid agonists. Furthermore, tampering with Embeda(r) will result in the release of naltrexone, which may precipitate withdrawal in opioid-tolerant individuals. In March 2011, all dosage forms of Embeda(r) were recalled because the product failed to meet routine stability standards, and its return date to the market is currently unknown. The second product (Acurox(r)) was intended to be both tamper resistant and abuse deterrent. It consisted of an immediate release oxycodone tablet with subtherapeutic niacin as an aversive agent and used a gel-forming ingredient designed to inhibit inhalation and prevent extraction of the drug for injection. The new drug application for Acurox(r) was rejected in 2010 by the FDA because of concerns about the potential abuse-deterrent benefits of niacin. While acknowledging that no one formulation can be expected to deter all types of opioid-abusive behaviours and no product is likely to be abuse proof in the hands of clear and determined abusers, the reductions in abuse these new products would provide may be an incremental step towards safer prescription opioids. PMID- 22931521 TI - New oral anticoagulants: a review of the literature with particular emphasis on patients with impaired renal function. AB - Oral anticoagulant therapy (OAT) is widely used to prevent and treat thromboembolic events. Traditionally, warfarin has been the drug of choice and, indeed, this drug is effective and provides a more than 60% reduction in stroke risk in patients with atrial fibrillation. However, OAT entails an increased bleeding risk, and management of this is challenging. Among other things, new oral anticoagulant drugs offer fixed dosing, more predictable pharmacokinetics and fewer interactions with drugs and food. Moreover, these drugs seem to provide an improved benefit-risk ratio with respect to thromboembolic events and bleeding complications in a broad patient population. The new drugs differ from traditional OAT with respect to their mechanism of action and pharmacokinetics, especially with respect to elimination through the kidneys. These drugs may potentially cause bleeding complications in patients with reduced drug excretion due to impaired renal function. Dabigatran etexilate and rivaroxaban carry the highest risk due to a high degree of renal excretion, whereas the risk for apixaban, edoxaban and betrixaban seems lower. Pharmacokinetic studies and data from clinical studies have provided information on how to guide dosing in patients with renal impairment. However, the risk of drug accumulation and bleeding may be amplified by several drug-drug interactions. This article provides a review of the literature on the pharmacology of new anticoagulant drugs with particular focus on the impact of impaired renal function. PMID- 22931523 TI - Cationic niosomes composed of spermine-based cationic lipids mediate high gene transfection efficiency. AB - Non-ionic surfactant-based vesicles (niosomes) composed of non-ionic surfactants (i.e., Tween and Span) and cholesterol were formulated, and their turbidity and particle size assayed. The most appropriate niosomes formulation was mixed with novel synthesized spermine-based cationic lipids to prepare cationic niosomes that could act as gene carriers. Factors affecting gene transfection and cell viability including differences in the acyl chain length (C14, C16 and C18) of cationic lipids and the weight ratio of niosomes to DNA were evaluated on a human cervical carcinoma cell line (HeLa cells) using pDNA encoding green fluorescent protein (pEGFP-C2). The morphology, size and charge of the niosomes were also characterized, and a gel retardation assay to determine complex formation was performed. The results revealed that the transfection efficiency of the Span 20 niosomes was the highest for the spermine-C14 formulation and decreased as follows: spermine-C14 > spermine-C16 > spermine-C18. In addition to the highest transfection efficiency, there was also no serum effect on transfection efficiency of the spermine-C14 niosomes at a weight ratio of 10. This formulation was safe in vitro and had good physical stability for at least 1 month at 4 degrees C. In conclusion, the cationic niosomes may constitute a good alternative carrier for gene transfection. PMID- 22931524 TI - Mitochondrion-toxic drugs given to patients with mitochondrial psychoses. PMID- 22931522 TI - Reduced-antigen, combined diphtheria, tetanus and acellular pertussis vaccine, adsorbed (Boostrix(r)): a review of its properties and use as a single-dose booster immunization. AB - Reduced-antigen, combined diphtheria, tetanus and three-component acellular pertussis vaccine (Tdap; Boostrix(r)) is indicated for booster vaccination against diphtheria, tetanus and pertussis in individuals from age four years onwards in Europe and from age 10 years onwards in the US. Compared with infant formulations used for primary vaccination, Tdap contains reduced quantities (10 50%) of all toxoids and antigens, which are adsorbed to either <=0.39 mg/dose (US licensed formulation) or 0.5 mg/dose (rest-of-world formulation) of aluminium adjuvant. The reduced antigen content is designed to avoid the increasing reactogenicity historically seen with the fourth and fifth doses of infant vaccine. This article reviews the immunogenicity, protective efficacy and reactogenicity of Tdap booster administered to children, adolescents and adults, including those aged >=65 years. In clinical trials, a single booster dose of Tdap induced seroprotective levels of antibodies to diphtheria and tetanus toxoids in virtually all children and adolescents, and in a high proportion of adults and elderly individuals at approximately 1 month post-vaccination irrespective of their vaccination history. In all age groups, seropositivity rates for antibodies against pertussis antigens were >=90% (including in unvaccinated adolescents), and booster response rates were high. Tdap was safely co-administered with other common vaccines without significantly affecting the immune responses. The immunogenicity and reactogenicity profiles of booster doses of Tdap were generally similar to those of infant diphtheria-tetanus-whole-cell pertussis vaccine and infant diphtheria-tetanus-acellular pertussis vaccine in children aged 4-6 years, and infant diphtheria-tetanus vaccine in older children. In adolescents and adults, the immunogenicity and reactogenicity of Tdap were generally similar to those of reduced-antigen diphtheria-tetanus vaccine, reduced antigen diphtheria-tetanus-five-component acellular pertussis vaccine and reduced antigen acellular pertussis vaccine. Therefore, Tdap is suitable as a booster in place of these vaccines, including tetanus toxoid vaccine in the management of tetanus-prone wounds in adults. The quantity of aluminium adjuvant in Tdap did not markedly affect the immunogenicity or reactogenicity of the vaccine. Seropositivity rates for antibodies against pertussis toxin had begun to decline by 5 years after a booster dose of Tdap in adolescents/adults, and a subsequent booster dose 10 years later was generally as immunogenic as the initial booster and was well tolerated. Tdap was safe and well tolerated in all age groups. Local injection-site reactions were the most common adverse events. Most adverse events were of mild or moderate intensity and transient; there were few serious vaccination-related adverse events. Thus, Tdap is highly immunogenic, with low reactogenicity, in all age groups and appears suitable for targeted and/or repeat Tdap boosters in children, adolescents, adults and elderly individuals as part of immunization strategies that may prove beneficial in further limiting the burden of pertussis. PMID- 22931525 TI - Use of a risk assessment method to improve the safety of negative pressure wound therapy. AB - To conduct a risk analysis of the negative pressure wound therapy (NPWT) care process and to improve the safety of NPWT, a working group of nurses, hospital pharmacists, physicians and hospital managers performed a risk analysis for the process of NPWT care. The failure modes, effects and criticality analysis (FMECA) method was used for this analysis. Failure modes and their consequences were defined and classified as a function of their criticality to identify priority actions for improvement. By contrast to classical FMECA, the criticality index (CI) of each consequence was calculated by multiplying occurrence, severity and detection scores. We identified 13 failure modes, leading to 20 different consequences. The CI of consequences was initially 712, falling to 357 after corrective measures were implemented. The major improvements proposed included the establishment of 6-monthly training cycles for nurses, physicians and surgeons and the introduction of computerised prescription for NPWT. The FMECA method also made it possible to prioritise actions as a function of the criticality ranking of consequences and was easily understood and used by the working group. This study is, to our knowledge, the first to use the FMECA method to improve the safety of NPWT. PMID- 22931526 TI - Benzodeazaoxaflavins as sirtuin inhibitors with antiproliferative properties in cancer stem cells. AB - Inhibition of sirtuins has recently been proposed as a promising anticancer strategy. Some of the new benzodeazaoxaflavins (2a, 2b, and 2d) here reported as SIRT1/2 inhibitors were endowed with pro-apoptotic properties in human U937 leukemia cells and, most importantly, together with the prototype MC2141 (1) displayed antiproliferative effects in cancer stem cells from patients with colorectal carcinoma and glioblastoma multiforme, known to be highly tumorigenic, resistant to conventional cancer chemotherapy, and responsible, at least in part, for cancer relapse or recurrence. PMID- 22931527 TI - Biological and Medicinal Significance of Purines. AB - This article outlines the biological significance of one of the most important heterocycles, the purines. An attempt has been made to cover most of the physiologically as well as medicinally important compounds containing the purine derivatives. Purines are the drug molecules, which possess a variety of biological and medicinal significance. PMID- 22931528 TI - Histamine H3 receptor function and ligands: recent developments. AB - Histamine H3 receptors are found mostly in central nervous system involved in the regulation of release of various neurotransmitters in brain. They have been implicated in diverse potential therapeutic applications such as sleep-wake disorders, attention-deficient hyperactivity disorder, epilepsy, cognitive impairment and obesity. This review is an attempt to elucidate the function of H3 receptors and their role in various CNS disorders. Also, it is aimed at collating the information on efforts of various medicinal chemists to synthesize the H3 receptor agonists and antagonists in single article. PMID- 22931529 TI - Ezogabine: development and role in the management of epileptic seizures. AB - Epilepsy which is a diverse set of complex neurological disorders comprised of seizures affecting more than 50 million people worldwide among which 90 % are from developing countries. The aim of current antiepileptic therapy is to control the seizures with minimal side effects and improve the patients' quality of life. Near by about 20 medications are approved by Food and Drug Administration among which only five to six are widely used for the treatment of epileptic seizures. Ezogabine (D-23129) is a recently approved antiepileptic drug approved by USFDA for adjunctive therapy of partial onset seizures. It was developed by Valeant Pharmaceuticals and Glaxosmithkline in 2011 for the management of partial onset seizures. The drug has shown unique mechanism of action among other antiepileptic drugs by facilitating potassium channel current in nerve growth factor differentiated PC12 cells. It also promotes membrane repolarisation and thus opposes rapid repetitive discharges. The drug is quickly absorbed and reaches maximum plasma concentration between 0.5 hour and 2 hours after a single oral dose also showing a moderately high bioavailability, volume of distribution and a terminal half life of 8 to 11 hours. It is metabolized via glucuronidation and acetylation. The various adverse effects found with the drug were related to central nervous system and appeared to be dose related like drowsiness, dizziness, vertigo and confusion etc. All these parameters make it superior from other available drugs for the management of epileptic seizures. The present review describes the development; medicinal chemistry; mechanism of action, pharmacokinetics and pharmacodynamics of Ezogabine. Further the review put forwards the indispensible role of this drug for antiepileptic treatment. PMID- 22931530 TI - alpha-Amino-alpha'-halomethylketones: synthetic methodologies and pharmaceutical applications as serine and cysteine protease inhibitors. AB - alpha-Amino-alpha'-halomethylketones are interesting scaffolds bearing (at least) two sequential electrophilic carbons that by interacting with the nucleophilic moieties of several enzymes, represent the ideal candidates for in vivo and in vitro inhibition studies. In this work a summary of their use as optimal inhibitors of physiologically relevant serine and cysteine proteases is given with a particular emphasis on recently established SAR studies. A brief survey of the most relevant synthetic processes for their obtainment and the importance they possess in synthetic medicinal chemistry is reported. PMID- 22931531 TI - The effect of polyphenol consumption on blood pressure. AB - Several observational and intervention studies have found an inverse association between the risk of cardiovascular disease and the consumption of polyphenol-rich foods and beverages such as cocoa, fruit and vegetables, tea, virgin olive oil and wine. We present here an overview of the latest research on the beneficial effect of dietary polyphenols on blood pressure, focusing on the development of urine biomarkers for an accurate estimation of polyphenol intake. Total polyphenols (TP) excreted in spot urine samples have been successfully used as a biomarker of the consumption, bioavailability and accumulation of TP in a cross sectional clinical trial. In addition, we describe how the vasoprotective effect of dietary polyphenols has been related to their ability to increase endothelial synthesis of nitric oxide (NO) and endothelium-derived hyperpolarizing factor (EDHF)-mediated responses. PMID- 22931532 TI - Anthracyclines still prove effective in anticancer therapy. AB - Present-day is developing in many fields. Many pathological processes are better understood, including carcinogenesis. Consequently, the failure of pharmacotherapy aimed at cancerous diseases is becoming explainable. At the same time, new anticancer drugs continue to be introduced. Anthracycline antibiotics are a well-known and widely used group of anticancer drugs. However, in addition to their efficiency they demonstrate severe side effects compounded by the appearance of resistant cells. Therefore, the search for new anthracycline derivatives with improved pharmacodynamic properties and fewer adverse effects is in progress, delivering promising results. PMID- 22931534 TI - Ghrelin in obesity, physiological and pharmacological considerations. AB - The aim of this review is to summarize the physiological and pharmacological aspects of ghrelin. Obesity can be defined as an excess of body fat and is associated with significant disturbances in metabolic and endocrine function. Obesity has become a worldwide epidemic. In obesity there is a decreased growth hormone (GH) secretion, and the altered somatotroph secretion in obesity is functional. Ghrelin is a peptide that has a unique structure with 28 amino-acids and an n-octanoyl ester at its third serine residue, which is essential for its potent stimulatory activity on somatotroph secretion. The pathophysiological mechanism responsible for GH hyposecretion in obesity is probably multifactorial, and there is probably a defect in ghrelin secretion. Ghrelin is the only known circulating orexigenic factor, and has been found to be reduced in obese humans. Ghrelin levels in blood decrease during periods of feeding. Due to its orexigenic and metabolic effects, ghrelin has a potential benefit in antagonizing protein breakdown and weight loss in catabolic conditions such as cancer cachexia, renal and cardiac disease, and age-related frailty. Theoretically ghrelin receptor antagonists could be employed as anti-obesity drugs, blocking the orexigenic signal. By blocking the constitutive receptor activity, inverse agonists of the ghrelin receptor may lower the set-point for hunger, and could be used for the treatment of obesity. In summary, ghrelin secretion is reduced in obesity, and could be partly responsible for GH hyposecretion in obesity, ghrelin antagonist or partial inverse agonists should be considered for the treatment of obesity. PMID- 22931535 TI - Adhesion of osteoblasts to a vertically aligned TiO2 nanotube surface. AB - The adhesion of cells to vertically aligned TiO2 nanotubes is reviewed. The attraction between a negatively charged nanotube surface and a negatively charged osteoblast is facilitated by charged protein-mediators like proteins with a quadrupolar internal charge distribution, fibronectin and vitronectin. It is shown that adhesion and spreading of osteoblasts on vertically aligned TiO2 nanotube surfaces depend on the diameter of the nanotubes. Apparently, a small diameter nanotube surface has on average more sharp convex edges per unit area than a large one, leading to stronger binding affinity on its surface. PMID- 22931533 TI - Cholinergic modulation by opioid receptor ligands: potential application to Alzheimer's disease. AB - Morphinans have a storied history in medicinal chemistry as pain management drugs but have received attention as modulators of cholinergic signaling for the treatment of Alzheimer's Disease (AD). Galantamine is a reversible, competitive acetylcholinesterase (AChE) inhibitor and allosteric potentiating ligand of nicotinic acetylcholine receptors (nAChR-APL) that shares many common structural elements with morphinan-based opioids. The structurally diverse opioids codeine and eseroline, like galantamine, are also nAChR-APL that have greatly diminished affinity for AChE, representing potential lead compounds for selective nAChR-APL development. In accordance with the emerging repurposing trend of evaluating known compounds for novel pharmacological activity, ongoing research on augmentation of cholinergic signaling that has been aided by the use of opioids will be reviewed. PMID- 22931536 TI - Budgeting based on need: a model to determine sub-national allocation of resources for health services in Indonesia. AB - BACKGROUND: Allocating national resources to regions based on need is a key policy issue in most health systems. Many systems utilise proxy measures of need as the basis for allocation formulae. Increasingly these are underpinned by complex statistical methods to separate need from supplier induced utilisation. Assessment of need is then used to allocate existing global budgets to geographic areas. Many low and middle income countries are beginning to use formula methods for funding however these attempts are often hampered by a lack of information on utilisation, relative needs and whether the budgets allocated bear any relationship to cost. An alternative is to develop bottom-up estimates of the cost of providing for local need. This method is viable where public funding is focused on a relatively small number of targeted services. We describe a bottom up approach to developing a formula for the allocation of resources. The method is illustrated in the context of the state minimum service package mandated to be provided by the Indonesian public health system. METHODS: A standardised costing methodology was developed that is sensitive to the main expected drivers of local cost variation including demographic structure, epidemiology and location. Essential package costing is often undertaken at a country level. It is less usual to utilise the methods across different parts of a country in a way that takes account of variation in population needs and location. Costing was based on best clinical practice in Indonesia and province specific data on distribution and costs of facilities. The resulting model was used to estimate essential package costs in a representative district in each province of the country. FINDINGS: Substantial differences in the costs of providing basic services ranging from USD 15 in urban Yogyakarta to USD 48 in sparsely populated North Maluku. These costs are driven largely by the structure of the population, particularly numbers of births, infants and children and also key diseases with high cost/prevalence and variation, most notably the level of malnutrition. The approach to resource allocation was implemented using existing data sources and permitted the rapid construction of a needs based formula that is highly specific to the package mandated across the country. Refinement could focus more on resources required to finance demand side costs and expansion of the service package to include priority non-communicable services. PMID- 22931538 TI - Structural phases of ordered FePc-nanochains self-assembled on Au(110). AB - Iron-phthalocyanine molecules deposited on the Au(110) reconstructed channels assemble into one-dimensional molecular chains, whose spatial distribution evolves into different structural phases at increasing molecular density. The plasticity of the Au channels first induces an ordered phase with a 5*5 symmetry, followed by a second long-range ordered structure composed by denser chains with a 5*7 periodicity with respect to the bare Au surface, as observed in the low energy electron-diffraction (LEED) and grazing incidence X-ray diffraction (GIXRD) patterns. The geometry of the FePc molecular assemblies in the Au nanorails is determined by scanning tunneling microscopy (STM). For the 5*7 phases, the GIXRD analysis identifies a "4-3" rows profile along the [001] direction in the Au surface and an on-top FePc adsorption site, further confirmed by density functional theory (DFT) calculations. The latter also reveals the electronic mixing of the interface states. The chain assembly is driven by the molecule-molecule interaction and the chains interact with the Au nanorails via the central metal atom, while the chain-chain distance in the different structural phases is primarily driven by the plasticity of the Au surface. PMID- 22931537 TI - Development of the patient approach and views toward healthcare communication (PAV-COM) measure among older adults. AB - BACKGROUND: This study examines the psychometric properties of 9 items on the Patient Activation component of the Medicare Current Beneficiary Survey (MCBS) that assess how patients approach and communicate with their physicians. The MCBS is a nationally representative, cross-sectional survey of Medicare beneficiaries. METHODS: We analyzed MCBS data collected in 2002 and 2005 from 15,165 adults aged 65 and older. Exploratory factor analysis was conducted using maximum likelihood to estimate a polychoric correlation matrix on the 2002 data, and confirmatory factor analysis was performed using the 2005 data. RESULTS: Exploratory factor analysis of the 2002 data showed a 2-factor solution: approach to interactions (5 items) and views about physician's healthcare communication (6 items). Findings were confirmed using the 2005 data. Items were combined to form the Patient Approach and Views toward Healthcare Communication (PAV-COM) scale (range 1 to 100; Cronbach's alpha of 0.75, and item-rest correlations between 0.33 and 0.54). Higher PAV-COM scores were associated with greater fulfillment of preventive health behaviors such as vaccinations and cancer screenings. CONCLUSIONS: The PAV COM measure is a valid tool for assessing patient approaches and views toward communication with physicians. This measure can be used to evaluate interventions to improve patient participation during healthcare encounters. PMID- 22931539 TI - Atrial septal occluder device embolization to an iliac artery: a case highlighting the utility of three-dimensional transesophageal echocardiography during percutaneous closure. AB - Percutaneous closure of secundum atrial defects has become an accepted treatment in part because it is minimally invasive and relatively low risk. Despite recent advances in implantation technique and device improvements, complications occur. Here, we report a case of device embolization during percutaneous repair of an atrial septal defect (ASD) with multiple fenestrations. We highlight the value of using live/real time three-dimensional transesophageal echocardiography to help plan the percutaneous procedure and detect complications. PMID- 22931540 TI - Quality review of an adverse incident reporting system and root cause analysis of serious adverse surgical incidents in a teaching hospital of Scotland. AB - BACKGROUND: A significant proportion of surgical patients are unintentionally harmed during their hospital stay. Root Cause Analysis (RCA) aims to determine the aetiology of adverse incidents that lead to patient harm and produce a series of recommendations, which would minimise the risk of recurrence of similar events, if appropriately applied to clinical practice. A review of the quality of the adverse incident reporting system and the RCA of serious adverse incidents at the Department of Surgery of Ninewells hospital, in Dundee, United Kingdom was performed. METHODS: The Adverse Incident Management (AIM) database of the Department of Surgery of Ninewells Hospital was retrospectively reviewed. Details of all serious (red, sentinel) incidents recorded between May 2004 and December 2009, including the RCA reports and outcomes, where applicable, were reviewed. Additional related information was gathered by interviewing the involved members of staff. RESULTS: The total number of reported surgical incidents was 3142, of which 81 (2.58%) cases had been reported as red or sentinel. 19 of the 81 incidents (23.4%) had been inappropriately reported as red. In 31 reports (38.2%) vital information with regards to the details of the adverse incidents had not been recorded. In 12 cases (14.8%) the description of incidents was of poor quality. RCA was performed for 47 cases (58%) and only 12 cases (15%) received recommendations aiming to improve clinical practice. CONCLUSION: The results of our study demonstrate the need for improvement in the quality of incident reporting. There are enormous benefits to be gained by this time and resource consuming process, however appropriate staff training on the use of this system is a pre-requisite. Furthermore, sufficient support and resources are required for the implementation of RCA recommendations in clinical practice. PMID- 22931541 TI - Neospora caninum infection in dogs from Southern Romania: coproparasitological study and serological follow-up. AB - Neospora caninum is an important cause of bovine abortion worldwide for which dogs are the definitive host. The present study was aimed at investigating the exposure to N. caninum infection based on lifestyle categories of dogs from southern Romania. For this purpose, randomly selected rural and urban dogs were examined for fecal N. caninum -like oocysts and were serologically tested for the presence of anti- N. caninum IgG antibodies. Of the 386 dog fecal samples, N. caninum -like oocysts were found in 19 (4.9%; 95% CI = 2.89-7.59) as follows: rural guard dogs (4/41; 9.8%), cattle farm dogs (6/118; 5.1%), and stray dogs (9/192; 4.7%) (P > 0.05). None of the 35 urban guard dogs was positive. Serum samples (n = 84) from all of the 19 N. caninum -like oocysts-positive dogs and another 65 randomly selected canines (15 cattle farm dogs, 21 rural guard dogs, and 29 strays) were tested by indirect fluorescent antibody test (IFAT). None of these dogs exhibited any symptoms of clinical neosporosis. However, IgG antibodies against N. caninum were detected in 17/84 (20.2%) (P < 0.05) serum samples. The highest prevalence was registered in cattle farm dogs (38.1%) followed by strays (18.4%) and rural guard dogs (8.0%). The seropositivity to N. caninum increased significantly with age (P < 0.05), reaching 66.7% in dogs >10 yr of age, suggesting post-natal exposure to N. caninum is the predominant mechanism of N. caninum recruitment. PMID- 22931542 TI - Testing the metabolic theory of ecology. AB - The metabolic theory of ecology (MTE) predicts the effects of body size and temperature on metabolism through considerations of vascular distribution networks and biochemical kinetics. MTE has also been extended to characterise processes from cellular to global levels. MTE has generated both enthusiasm and controversy across a broad range of research areas. However, most efforts that claim to validate or invalidate MTE have focused on testing predictions. We argue that critical evaluation of MTE also requires strong tests of both its theoretical foundations and simplifying assumptions. To this end, we synthesise available information and find that MTE's original derivations require additional assumptions to obtain the full scope of attendant predictions. Moreover, although some of MTE's simplifying assumptions are well supported by data, others are inconsistent with empirical tests and even more remain untested. Further, although many predictions are empirically supported on average, work remains to explain the often large variability in data. We suggest that greater effort be focused on evaluating MTE's underlying theory and simplifying assumptions to help delineate the scope of MTE, generate new theory and shed light on fundamental aspects of biological form and function. PMID- 22931543 TI - Mothers, minds, and maternal response. PMID- 22931544 TI - DNase-mediated single-cycle selection of aptamers for proteins blotted on a membrane. AB - We describe a single-cycle DNA aptamer selection strategy that is able to obtain high affinity aptamers (K(d) of sub-nM) directly from a protein blotted on membrane. The key to the success of this strategy is the unique use of DNase I digestion to remove unwanted ssDNA from the membrane, leaving only the strongest bound aptamers. A crude Hepatitis B virus core protein (HBcAg) was separated using polyacrylamide gel electrophoresis (PAGE) and electro-blotted onto a polyvinylidene fluoride (PVDF) membrane. The membrane strip containing HBcAg and a second membrane strip containing human serum proteins were coincubated with a ssDNA library consisting of ~10 copies each of 10(15) random sequences. Unbound and weakly bound sequences were efficiently removed from the membrane containing HBcAg using DNase I digestion and gradient wash with urea buffers. The remaining ssDNA bound to the target consisted of approximately 500 molecules, from which two aptamers with high affinity (K(d) ~100 and 200 pM) were identified. This technique can be potentially used for selection of aptamers directly from multiple proteins that are separated by gel electrophoresis from a biological mixture. PMID- 22931545 TI - BVOC emission from Populus * canadensis saplings in response to acute UV-A radiation. AB - Hybrid poplar (Populus * canadensis) saplings were subjected to acute ultraviolet A (UV-A) irradiation (30 W m(-2) , ambient treatment, 60, 90 and 120 W m(-2) of UV-A irradiance) to determine the effects on photosynthesis and biogenic volatile organic compound (BVOC) emissions in two different short-term experiments (i.e. sequential increase in UV-A irradiance and UV-A intensity-response relationships). Both intensity-response experiments showed that the UV-A ambient treatment did not affect photosynthesis and BVOC emissions. Whereas exposition at 60, 90 and 120 W m(-2) of UV-A (first experiment), increasingly inhibited photosynthesis. This increasing inhibition was also detected by decreasing trends of both photochemical reflectance index (PRI) and fluorescence yield. Isoprene emission resulted to be very sensitive to increasing UV-A irradiances. Methanol was also very sensitive to high UV-A radiation, suggesting the occurrence of strong damages of cellular structures. The second experiment, which was performed both in the middle of July and repeated towards the end of the summer, showed a temporal variations in the UV-A intensity-response relationships. In fact, there were no longer significant differences in photosynthesis, PRI and isoprene emission in response to high UV-A radiation toward the end of the summer season. The adaxial flavonoid level increased significantly over the period monitored, resulting 85% higher toward the end of the summer than during the middle of the summer. This dramatic increase in the adaxial flavonoids may have played a protective role against UV-A radiation by shielding leaves. Our findings add to the understanding of physiological processes involved in plant response to UV radiation. PMID- 22931546 TI - Oxidation of alpha-trifluoromethyl alcohols using a recyclable oxoammonium salt. AB - A simple, mild method for the oxidation of alpha-trifluoromethyl alcohols to trifluoromethyl ketones (TFMKs) using the oxoammonium salt 4-acetylamino-2,2,6,6 tetramethylpiperidine-1-oxoammonium tetrafluoroborate (1) is described. Under basic conditions, oxidation proceeds rapidly and affords good to excellent yields of TFMKs, without concomitant formation of the hydrate. The byproduct of the oxidation, 4-acetylamino-2,2,6,6-tetramethyl-1-piperidinyloxy (1c), is easily recovered and can be conveniently reoxidized to regenerate the oxoammonium salt. PMID- 22931547 TI - The fate of bone marrow-derived cells carrying a Polycystic Kidney Disease mutation in the genetically normal kidney. AB - BACKGROUND: Polycystic Kidney Disease (PKD) is a genetic condition in which dedifferentiated and highly proliferative epithelial cells form renal cysts and is frequently treated by renal transplantation. Studies have reported that bone marrow-derived cells give rise to renal epithelial cells, particularly following renal injury as often occurs during transplantation. This raises the possibility that bone marrow-derived cells from a PKD-afflicted recipient could populate a transplanted kidney and express a disease phenotype. However, for reasons that are not clear the reoccurrence of PKD has not been reported in a genetically normal renal graft. We used a mouse model to examine whether PKD mutant bone marrow-derived cells are capable of expressing a disease phenotype in the kidney. METHODS: Wild type female mice were transplanted with bone marrow from male mice homozygous for a PKD-causing mutation and subjected to renal injury. Y chromosome positive, bone marrow-derived cells in the kidney were assessed for epithelial markers. RESULTS: Mutant bone marrow-derived cells were present in the kidney. Some mutant cells were within the bounds of the tubule or duct, but none demonstrated convincing evidence of an epithelial phenotype. CONCLUSIONS: Bone marrow-derived cells appear incapable of giving rise to genuine epithelial cells and this is the most likely reason cysts do not reoccur in kidneys transplanted into PKD patients. PMID- 22931548 TI - Safety of liposuction of the neck using tumescent local anesthesia: experience in 320 cases. AB - BACKGROUND: Liposuction of the neck has become a popular, minimally invasive technique for fat reduction and skin tightening. OBJECTIVES: To evaluate the safety of neck liposuction in a large series of patients. METHODS: Between 2003 and 2011, 320 patients underwent liposuction of the neck. Complications were recorded, and all patients were followed up after 8 weeks. RESULTS: There were no serious complications. Four patients required closer follow-up because of hematoma (n = 1), transient mandibular nerve inflammation (n = 2), and globus pharyngeus (n = 1). CONCLUSION: Liposuction of the neck with tumescent local anesthesia requires a higher amount of patient monitoring than liposuction of the body. In the hands of an experienced surgeon, it is a safe method rendering excellent aesthetic results. PMID- 22931550 TI - Prevalence of asthma in Portugal - The Portuguese National Asthma Survey. AB - BACKGROUND: Asthma is a frequent chronic respiratory disease in both children and adults. However, few data on asthma prevalence are available in Portugal. The Portuguese National Asthma Survey is the first nationwide study that uses standardized methods. We aimed to estimate the prevalence of current asthma in the Portuguese population and to assess the association between 'Current asthma' and comorbidities such as upper airways disease. METHODS: A cross-sectional, population-based, telephone interview survey including all municipalities of Portugal was undertaken. Participants were randomly selected to answer a questionnaire based on the Portuguese version of the GA2LEN survey. 'Current asthma' was defined as self-reported lifetime asthma and at least one of 3 symptoms in the last 12 months: wheezing, waking with breathlessness or having an asthma attack. RESULTS: Data were obtained for 6 003 respondents, with mean age of 38.9 (95%CI 38.2-39.6) years and 57.3% females. In the Portuguese population, the prevalence of 'Current asthma' was 6.8% (95%CI 6.0-7.7) and of 'Lifetime asthma' was 10.5% (95%CI 9.5-11.6) Using GA2LEN definition for asthma, our prevalence estimate was 7.8% (95%CI 7.0-8.8). Rhinitis had a strong association with asthma (Adjusted OR 3.87, 95%CI 2.90-5.18) and the association between upper airway diseases and asthma was stronger in patients with both rhinitis and sinusitis (Adjusted OR 13.93, 95%CI 6.60-29.44). CONCLUSIONS: Current asthma affects 695 000 Portuguese, with a prevalence of 6.8%. People who reported both rhinitis and sinusitis had the highest risk of having asthma. PMID- 22931551 TI - How many times can parvovirus B19-related anemia recur in solid organ transplant recipients? AB - Parvovirus B19 (PB19) infection is known to cause acute erythroblastopenia mediated anemia in solid organ transplant (SOT) recipients. Intravenous immunoglobulins (IVIg) and the decrease of immunosuppression level are supposed to induce a long-term remission, although no consensus exists about the dose and the schedule of IVIg administrations. However, a few reports have shown that PB19 related anemia can recur despite this treatment, with a maximum of 3 recurrences reported. In this report, we describe in detail the cases of 2 kidney recipients with PB19 infection. They experienced, respectively, 9 and 7 PB19-related anemia recurrences. Immunosuppression level was decreased and IVIg were administered at each recurrence followed by a transitory normalization of hemoglobin level and a decrease of serum PB19 viral load. Episodes were separated by several months. These patients raise an original therapeutic management question about a frequent viral infection in SOT recipients. One patient is currently receiving IVIg every 3 months as a secondary prophylaxis without recurrence to date. These 2 case reports are followed by a review of the literature. PMID- 22931549 TI - Particulate matter air pollution disrupts endothelial cell barrier via calpain mediated tight junction protein degradation. AB - BACKGROUND: Exposure to particulate matter (PM) is a significant risk factor for increased cardiopulmonary morbidity and mortality. The mechanism of PM-mediated pathophysiology remains unknown. However, PM is proinflammatory to the endothelium and increases vascular permeability in vitro and in vivo via ROS generation. OBJECTIVES: We explored the role of tight junction proteins as targets for PM-induced loss of lung endothelial cell (EC) barrier integrity and enhanced cardiopulmonary dysfunction. METHODS: Changes in human lung EC monolayer permeability were assessed by Transendothelial Electrical Resistance (TER) in response to PM challenge (collected from Ft. McHenry Tunnel, Baltimore, MD, particle size >0.1 MUm). Biochemical assessment of ROS generation and Ca2+ mobilization were also measured. RESULTS: PM exposure induced tight junction protein Zona occludens-1 (ZO-1) relocation from the cell periphery, which was accompanied by significant reductions in ZO-1 protein levels but not in adherens junction proteins (VE-cadherin and beta-catenin). N-acetyl-cysteine (NAC, 5 mM) reduced PM-induced ROS generation in ECs, which further prevented TER decreases and atteneuated ZO-1 degradation. PM also mediated intracellular calcium mobilization via the transient receptor potential cation channel M2 (TRPM2), in a ROS-dependent manner with subsequent activation of the Ca2+-dependent protease calpain. PM-activated calpain is responsible for ZO-1 degradation and EC barrier disruption. Overexpression of ZO-1 attenuated PM-induced endothelial barrier disruption and vascular hyperpermeability in vivo and in vitro. CONCLUSIONS: These results demonstrate that PM induces marked increases in vascular permeability via ROS-mediated calcium leakage via activated TRPM2, and via ZO-1 degradation by activated calpain. These findings support a novel mechanism for PM induced lung damage and adverse cardiovascular outcomes. PMID- 22931552 TI - DeloRes trial: study protocol for a randomized trial comparing two standardized surgical approaches in rectal prolapse - Delorme's procedure versus resection rectopexy. AB - BACKGROUND: More than 100 surgical approaches to treat rectal prolapse have been described. These can be done through the perineum or transabdominally. Delorme's procedure is the most frequently used perineal, resection rectopexy the most commonly used abdominal procedure. Recurrences seem more common after perineal compared to abdominal techniques, but the latter may carry a higher risk of peri- and postoperative morbidity and mortality. METHODS/DESIGN: DeloRes is a randomized, controlled, observer-blinded multicenter trial with two parallel groups. Patients with a full-thickness rectal prolapse (third degree prolapse), considered eligible for both operative methods are included. The primary outcome is time to recurrence of full-thickness rectal prolapse during the 24 months following primary surgery. Secondary endpoints are time to and incidence of recurrence of full-thickness rectal prolapse during the 5-year follow-up, duration of surgery, morbidity, hospital stay, quality of life, constipation, and fecal incontinence. A meta-analysis was done on the basis of the available data on recurrence rates from 17 publications comprising 1,140 patients. Based on the results of a meta-analysis it is assumed that the recurrence rate after 2 years is 20% for Delorme's procedure and 5% for resection rectopexy. Considering a rate of lost to follow-up without recurrence of 30% a total of 130 patients (2 x 65 patients) was calculated as an adequate sample size to assure a power of 80% for the confirmatory analysis. DISCUSSION: The DeloRes Trial will clarify which procedure results in a smaller recurrence rate but also give information on how morbidity and functional results compare. TRIAL REGISTRATION: German Clinical Trial Number DRKS00000482. PMID- 22931553 TI - Predictors of left ventricular remodeling after aortic valve replacement in pediatric patients with isolated aortic regurgitation. AB - OBJECTIVE: To identify the risk factors that could predict postoperative outcome after aortic valve replacement in pediatric patients with isolated aortic regurgitation (AR). BACKGROUND: There is controversy regarding the appropriate timing of surgery in asymptomatic or minimally symptomatic patients with isolated AR. In the pediatric age group, there are limited studies in this regard and most of them are on combined aortic valve stenosis and regurgitation. METHODS: All patients with biventricular physiology and morphologic left ventricle (LV) who underwent aortic valve surgery for AR from January 1988 to July 2010 were included in the study. Demographic, clinical, and echocardiographic data were collected at presurgical visit, early postoperative, 1 year, and most recent follow-up. RESULTS: Among 53 patients (36 males), 18 had LV end-diastolic diameter (LVEDD) z-score >4 standard deviation (SD) (group I) and 35 had LVEDD <4 SD (group II). Forty-one had long-term follow-up. Mean age at surgery was 11.6 +/ 5.9 years; mean follow-up was 6.9 +/- 5.6 years. Preoperative LVEDD >4 SD predicted persistent LV dilation (>2 SD) at early post-op (P < .05) and 1 year follow-up (P = .09). Preoperative decreased LV function (fractional shortening <28%) was the only significant predictor of persistent LV dysfunction at most recent follow-up and requirement for repeat interventions (P < .01). Most have reduction of LV dimensions in the immediate postoperative period to normal limits. CONCLUSION: In children with AR, preoperative LV dysfunction and extreme LV dilation (>4 SD) are significant predictors of incomplete LV remodeling or persistent LV dysfunction. PMID- 22931554 TI - Genetic susceptibility to sickness absence is similar among women and men: findings from a Swedish twin cohort. AB - Previous studies of risk factors for sickness absence (SA) focus primarily on psychosocial and work environmental exposures. The aim of this study was to investigate the relative contribution of genetic influences on SA among women and men. The population-based study sample of Swedish twins (34,547) included 13,743 twin pairs of known zygosity, 3,495 monozygotic, 5,073 same-sexed dizygotic, and 5,175 opposite sexed. The point prevalence of long-term SA (>=15 days) in each zygosity and sex group was calculated. The risk of SA was estimated as an odds ratio (OR) with 95% confidence intervals (CI) where the odds for twins on SA to have a co-twin on SA was compared to the OR for SA in twins whose co-twin were not sickness absent. Intrapair correlations and probandwise concordance rates were calculated and standard biometrical genetic model-fitting methods were used to estimate the heritability of SA. The prevalence of SA was 8.8% (women 10.7%; men 6.5%). Intrapair similarity was higher among monozygotic than dizygotic twin pairs. The best-fitting model showed no sex differences in genetic effects or variance components contributing to SA. The heritability estimate was 36% (95% CI: 35-40%). Results suggest genetic contribution to the variation of SA and that environmental factors have an important role, for women and men. As SA seem to be influenced by genetic factors, future studies of associations between risk factors and SA should consider this potentially confounding effect. PMID- 22931555 TI - The 14th Congress of the International Society for Twin Studies: selected highlights. PMID- 22931558 TI - Influence of fermentation conditions on the surface properties and adhesion of Lactobacillus rhamnosus GG. AB - BACKGROUND: The surface properties of probiotic bacteria influence to a large extent their interactions within the gut ecosystem. There is limited amount of information on the effect of the production process on the surface properties of probiotic lactobacilli in relation to the mechanisms of their adhesion to the gastrointestinal mucosa. The aim of this work was to investigate the effect of the fermentation pH and temperature on the surface properties and adhesion ability to Caco-2 cells of the probiotic strain Lactobacillus rhamnosus GG. RESULTS: The cells were grown at pH 5, 5.5, 6 (temperature 37 degrees C) and at pH 6.5 (temperature 25 degrees C, 30 degrees C and 37 degrees C), and their surfaces analysed by X-ray photoelectron spectrometry (XPS), Fourier transform infrared spectroscopy (FT-IR) and gel-based proteomics. The results indicated that for all the fermentation conditions, with the exception of pH 5, a higher nitrogen to carbon ratio and a lower phosphate content was observed at the surface of the bacteria, which resulted in a lower surface hydrophobicity and reduced adhesion levels to Caco-2 cells as compared to the control fermentation (pH 6.5, 37 degrees C). A number of adhesive proteins, which have been suggested in previous published works to take part in the adhesion of bacteria to the human gastrointestinal tract, were identified by proteomic analysis, with no significant differences between samples however. CONCLUSIONS: The temperature and the pH of the fermentation influenced the surface composition, hydrophobicity and the levels of adhesion of L. rhamnosus GG to Caco-2 cells. It was deduced from the data that a protein rich surface reduced the adhesion ability of the cells. PMID- 22931559 TI - Synchronous spontaneous cerebrospinal fluid leaks in the nose and ear. AB - OBJECTIVE: The majority of spontaneous cerebrospinal fluid leaks occur at the anterior skull base; few cases at the temporal bone have been described. There have been no previous reports of synchronous leaks at the anterior skull base and temporal bone in the same patient. METHODS: Case report and brief review of management of spontaneous cerebrospinal fluid leaks in the nose and ear. CASE REPORT: A 34-year-old, pregnant woman presented with watery nasal discharge and unilateral middle-ear effusion. The nasal and ear secretions both proved to be cerebrospinal fluid. Radiological imaging showed defects in both the ethmoid roof and the mastoid roof (middle cranial fossa). These defects were surgically closed using duraplasties. CONCLUSION: A literature review indicated that this is the first reported case of synchronous spontaneous cerebrospinal fluid leaks via the anterior skull base and temporal bone. PMID- 22931560 TI - Does a focus on universals represent a new trend in word recognition? AB - Comparisons across languages have long been a means to investigate universal properties of the cognitive system. Although differences between languages may be salient, it is the underlying similarities that have advanced our understanding of language processing. Frost is not unique in emphasizing that the interaction among linguistic codes reinforces the inadequacy of constructing a model of word recognition where orthographic processes operate in isolation. PMID- 22931561 TI - bla(OXA-181)-positive Klebsiella pneumoniae, Singapore. PMID- 22931562 TI - Hospitalizations associated with disseminated coccidioidomycosis, Arizona and California, USA. AB - We analyzed hospitalization databases from Arizona and California for disseminated coccidioidomycosis-associated hospitalizations among immunocompetent persons. Racial/ethnic disease ratios were characterized by a higher incidence of hospitalization among blacks compared with other groups. This finding suggests that HIV infection, AIDS, and primary immune conditions are not a major factor in this disparity. PMID- 22931564 TI - [The etiopathogenesis of oral lichen planus: current status and future strategy]. PMID- 22931563 TI - Finding biomarkers in non-model species: literature mining of transcription factors involved in bovine embryo development. AB - BACKGROUND: Since processes in well-known model organisms have specific features different from those in Bos taurus, the organism under study, a good way to describe gene regulation in ruminant embryos would be a species-specific consideration of closely related species to cattle, sheep and pig. However, as highlighted by a recent report, gene dictionaries in pig are smaller than in cattle, bringing a risk to reduce the gene resources to be mined (and so for sheep dictionaries). Bioinformatics approaches that allow an integration of available information on gene function in model organisms, taking into account their specificity, are thus needed. Besides these closely related and biologically relevant species, there is indeed much more knowledge of (i) trophoblast proliferation and differentiation or (ii) embryogenesis in human and mouse species, which provides opportunities for reconstructing proliferation and/or differentiation processes in other mammalian embryos, including ruminants. The necessary knowledge can be obtained partly from (i) stem cell or cancer research to supply useful information on molecular agents or molecular interactions at work in cell proliferation and (ii) mouse embryogenesis to supply useful information on embryo differentiation. However, the total number of publications for all these topics and species is great and their manual processing would be tedious and time consuming. This is why we used text mining for automated text analysis and automated knowledge extraction. To evaluate the quality of this "mining", we took advantage of studies that reported gene expression profiles during the elongation of bovine embryos and defined a list of transcription factors (or TF, n = 64) that we used as biological "gold standard". When successful, the "mining" approach would identify them all, as well as novel ones. METHODS: To gain knowledge on molecular-genetic regulations in a non model organism, we offer an approach based on literature-mining and score arrangement of data from model organisms. This approach was applied to identify novel transcription factors during bovine blastocyst elongation, a process that is not observed in rodents and primates. As a result, searching through human and mouse corpuses, we identified numerous bovine homologs, among which 11 to 14% of transcription factors including the gold standard TF as well as novel TF potentially important to gene regulation in ruminant embryo development. The scripts of the workflow are written in Perl and available on demand. They require data input coming from all various databases for any kind of biological issue once the data has been prepared according to keywords for the studied topic and species; we can provide data sample to illustrate the use and functionality of the workflow. RESULTS: To do so, we created a workflow that allowed the pipeline processing of literature data and biological data, extracted from Web of Science (WoS) or PubMed but also from Gene Expression Omnibus (GEO), Gene Ontology (GO), Uniprot, HomoloGene, TcoF-DB and TFe (TF encyclopedia). First, the human and mouse homologs of the bovine proteins were selected, filtered by text corpora and arranged by score functions. The score functions were based on the gene name frequencies in corpora. Then, transcription factors were identified using TcoF-DB and double-checked using TFe to characterise TF groups and families. Thus, among a search space of 18,670 bovine homologs, 489 were identified as transcription factors. Among them, 243 were absent from the high-throughput data available at the time of the study. They thus stand so far for putative TF acting during bovine embryo elongation, but might be retrieved from a recent RNA sequencing dataset (Mamo et al. , 2012). Beyond the 246 TF that appeared expressed in bovine elongating tissues, we restricted our interpretation to those occurring within a list of 50 top-ranked genes. Among the transcription factors identified therein, half belonged to the gold standard (ASCL2, c-FOS, ETS2, GATA3, HAND1) and half did not (ESR1, HES1, ID2, NANOG, PHB2, TP53, STAT3). CONCLUSIONS: A workflow providing search for transcription factors acting in bovine elongation was developed. The model assumed that proteins sharing the same protein domains in closely related species had the same protein functionalities, even if they were differently regulated among species or involved in somewhat different pathways. Under this assumption, we merged the information on different mammalian species from different databases (literature and biology) and proposed 489 TF as potential participants of embryo proliferation and differentiation, with (i) a recall of 95% with regard to a biological gold standard defined in 2011 and (ii) an extension of more than 3 times the gold standard of TF detected so far in elongating tissues. The working capacity of the workflow was supported by the manual expertise of the biologists on the results. The workflow can serve as a new kind of bioinformatics tool to work on fused data sources and can thus be useful in studies of a wide range of biological processes. PMID- 22931565 TI - [Oral lichen planus: syndrome differentiation and types of traditional Chinese medicine and treatment of integrative medicine]. PMID- 22931566 TI - [Advance and prospect for the diagnosis and management of lichen planus]. PMID- 22931567 TI - [Guidelines for diagnosis and treatment of oral lichen planus (draft)]. PMID- 22931568 TI - [Guidelines for the diagnosis and management of recurrent aphthous ulcers (draft)]. PMID- 22931569 TI - [Discussion of guidelines for diagnosis and treatment of oral lichen planus]. PMID- 22931570 TI - [A consensus on guidelines for the diagnosis and management of recurrent aphthous ulcers]. PMID- 22931571 TI - [Clinicopathological characteristics of malignant transformation in 85 cases of oral leukoplakia]. AB - OBJECTIVE: To investigate the histological features of oral leukoplakia which underwent malignant transformation and its correlation with the clinical manifestation. METHODS: A total of 1832 cases of oral leukoplakia were reviewed and the clinicopathological characteristics of malignant transformation were analyzed. RESULTS: Malignant transformation occurred in 85 cases (4.6%) of the 1832 cases. Thirty cases (2.1%) of 1404 cases with simple epithelial hyperplasia had malignant transformation. Fifty-five cases (12.9%) in 428 cases with epithelial dysplasia were transformed to malignancy, especially in the cases with moderate or severe dysplasia, in which the ratio of malignant transformation was higher than in the cases with simple epithelial hyperplasia (P < 0.005). Clinical parameters associated with an increased risk of malignant transformation were female gender and epithelial dysplasia was more often seen in non-homogenous leukoplakias than in homogenous (P < 0.005). CONCLUSIONS: Non-dysplastic leukoplakia may become malignant. Epithelial dysplasia was associated with an increased risk of malignant transformation. Leukoplakia in female may be at a higher risk for malignant transformation. PMID- 22931572 TI - [Clinical evaluation of computer-navigated surgery in correcting unilateral delayed zygomatic fractures]. AB - OBJECTIVE: To compare the efficacy of computer-navigated surgery and the 3-D skull models and guide plates for the treatment of unilateral delayed zygomatic fractures. METHODS: Eleven patients with unilateral delayed zygomatic fractures were treated by computer-navigated surgery (test group) and another 12 patients were treated by 3-D skull models and guide plates as the control group. Quality of reduction was assessed by examination of postoperative axial CT scans through zygomatic arch, the malar prominence and the width of zygomatic arch were measured in both groups. RESULTS: The difference between bilateral malar prominence was (0.94 +/- 0.73) mm in the test group and (1.88 +/- 1.82) mm in the control group, there was no significant difference between the two groups (P > 0.05). The difference between bilateral width of zygomatic arch was (0.77 +/- 0.51) mm in the test group, less than (3.00 +/- 1.81) mm in the control group (P < 0.05). Excessive malar prominence was observed in 6 cases (6/11) in the test group and in 7 cases (7/12) in the control group, whereas malar depression was observed in 5 cases (5/11) in the test group and in 5 cases (5/12) in the control group. Overcorrection of the width of zygomatic arch was observed in 6 cases (6/11) in the test group and in 12 cases (12/12) in the control group, whereas under correction was observed in 5 cases (5/11) in the test group and in 0 cases (0/12) in the control group. CONCLUSIONS: In the treatment of unilateral delayed zygomatic fractures, symmetry of malar prominence can be achieved by application of computer-navigated surgery or the 3-D skull models and guide plates. Symmetry of the width of zygomatic arch achieved with the computer-navigated surgery is better than that achieved with 3-D skull models and guide plates. PMID- 22931573 TI - [Assessment of velopharyngeal status of postoperative cleft palate patients in silent mode by visual analog scale]. AB - OBJECTIVE: To evaluate the velopharyngeal status of cleft palate patients after operation in silent mode by visual analog scale. METHODS: A total of 82 patients with cleft lip and palate after operation were examined by nasopharyngeal fiber endoscopy with 11 voice samples. The velopharyngeal status was evaluated by three experienced experts using qualitative method and visual analog scale (VAS) method in silent mode. The Spearman correlation relationship was analyzed between VAS value and qualitative grade. The VAS value range of 10 non-nasal consonant voice samples was divided according to qualitative classification. RESULTS: VAS values could accurately reflect the outcome of the qualitative classification. The poorer the velopharyngeal status was, the lower the VAS value, and vice versa. The whole effectiveness of value range was greater than 70%. CONCLUSIONS: VAS values can accurately reflect the outcome of the qualitative classification about velopharyngeal function, and VAS value grading velopharyngeal status is reliable. This study proposed VAS values range standards for different velopharyngeal qualitative classification. PMID- 22931574 TI - [Classification and clinical characteristics of masticatory myospasm]. AB - OBJECTIVE: To determine the classification of masticatory myospasm by analyzing characteristics of clinical appearances. METHODS: Thirty-six cases of masticatory myospasm from 2000 to 2010 were included. The clinical data of these patients were analyzed, including patient information, patient history, clinical characteristics, severity and the frequency of myospasmodic movement, electromyogram (EMG), and the efficacy of botulinum toxin injection treatment. RESULTS: There were 11 males and 25 females, aged from 15 to 71. According to the clinical manifestation and EMG findings, patients could be divided into two groups: 18 cases were classified as jaw closing type which involved masseter and/or temporalis muscles presenting as trismus and acute pain, the other 18 cases were jaw opening type which involved lateral pterygoid muscles complaining difficulty in jaw closing and teeth clenching. The jaw closing type was often seen in patients of 20 to 50 years old, the jaw opening was frequently seen in patients over 50 years old. Jaw closing type was attacked intermittently and unilaterally, but jaw opening was often attacked continually and bilaterally. The rating scale of the severity of spasmodic movement was not different between the two types, but the frequency of spasmodic attack was much higher for jaw opening type (P < 0.05). The EMG of jaw closing type was classified into persistent, rhythmic and irregular type. The EMG of jaw opening type was classified into spontaneous and exercise-induced type. Twelve cases were treated by botulinum toxin injection that could significantly relieve symptoms. CONCLUSIONS: Masticatory myospasm can be classified into jaw closing and jaw opening types. Jaw closing type involves masseter and/or temporalis muscles and jaw opening type involves lateral pterygoid muscles. Botulinum toxin injection was the most effective therapy for the masticatory myospasm. PMID- 22931575 TI - [Comparative adaptation of crowns of selective laser melting and wax-lost-casting method]. AB - OBJECTIVE: To investigate the marginal adaptation of crowns fabricated by selective laser melting (SLM) and wax-lost-casting method, so as to provide an experimental basis for clinic. METHODS: Co-Cr alloy full crown were fabricated by SLM and wax-lost-casting for 24 samples in each group. All crowns were cemented with zinc phosphate cement and cut along longitudinal axis by line cutting machine. The gap between crown tissue surface and die was measured by 6-point measuring method with scanning electron microscope (SEM). The marginal adaptation of crowns fabricated by SLM and wax-lost-casting were compared statistically. RESULTS: The gap between SLM crowns were (36.51 +/- 2.94), (49.36 +/- 3.31), (56.48 +/- 3.35), (42.20 +/- 3.60) um, and wax-lost-casting crowns were (68.86 +/ 5.41), (58.86 +/- 6.10), (70.62 +/- 5.79), (69.90 +/- 6.00) um. There were significant difference between two groups (P < 0.05). CONCLUSIONS: Co-Cr alloy full crown fabricated by wax-lost-casting method and SLM method provide acceptable marginal adaptation in clinic, and the marginal adaptation of SLM is better than that of wax-lost-casting method. PMID- 22931576 TI - [Effect of four different types of base metal alloy crown on the expression of prostaglandin E2 and cyclo-oxygenase-2 by human gingival fibroblast]. AB - OBJECTIVE: To investigate the effect of alloy leaching liquor of four different types of base metal alloy on the expression of prostaglandin E(2) (PGE(2)) and cyclo-oxygenase-2(COX-2) by human gingival fibroblast(HGF) in vitro. METHODS: Ni Cr, Co-Cr, pure Ti and Au ceramic alloys were incubated in Dulbecco's modified Eagle's medium (DMEM) to prepare alloy leaching liquor, and then added in HGF medium. DMEM was prepared as negative control. Aliquots were taken from exposed media after 1, 6, 12, 24 h. Assays for PGE(2) were carried out by enzyme-linked immunosorbent assay (ELISA). RESULTS: In 6, 12, 24 h, the expression of PGE(2) in Ni-Cr and Co-Cr alloy groups (Ni-Cr: 45.568 +/- 0.926, 60.538 +/- 0.988, 73.754 +/- 0.507; Co-Cr: 40.496 +/- 0.693, 53.216 +/- 0.327, 65.470 +/- 1.086) were significantly higher than those in other experimental groups (Ti: 31.564 +/- 0.719, 31.998 +/- 0.856, 32.066 +/- 0.513; Au alloy: 31.540 +/- 0.821, 31.136 +/- 0.518, 31.340 +/- 0.443) and control group (31.122 +/- 0.642, 31.230 +/- 0.634, 30.980 +/- 0.746) (P < 0.05). No significant difference were found in the expression of PGE(2) among pure Ti, Au alloy groups and the control group (P > 0.05). Immunofluorescence showed dark and uniform COX-2 stain in Ni-Cr and Co-Cr alloy groups, while in pure Ti group, Au alloy group, and negative control group shallow and uneven distribution of COX-2 stain were observed. CONCLUSIONS: Our findings suggested that pure Ti and Au alloy did not cause elevated PGE(2) and COX-2 release from HGF. However, Ni-Cr and Co-Cr alloy caused increase in PGE(2) and COX-2 levels. PMID- 22931577 TI - [A dynamic finite element analysis of stress distribution in bone tissue surrounding solely or splinted implant-borne fixed partial denture]. AB - OBJECTIVE: To study the distribution patterns of stresses induced in bone tissue surrounding solely and splinted implants under dynamic loads. METHODS: Three dimensional finite-element models were created of two 765 sections of the mandible with solely or splinted implants embedded in. Vertical and oblique dynamic loads were applied in a circle of mastication (0.875 s). The stress distribution was analyzed to study the biomechanical behavior of bone tissue surrounding solely or splinted implants. RESULTS: As loading on the solely implant 5, the maximum von Mises value in the surrounding bone tissue under oblique loads at 0.300 s was 4.2 times as much as that under vertical loads at 0.150 s. Meanwhile, as coincidently loading on the splinted implants, the maximum von Mises value at 0.300 s was 1.2 times as much as that at 0.150 s. As loading on the solely implant 5, the maximum stress value was 48.393 MPa at 0.300 s. As separately loading on the splinted implant 5, the maximum stress value of the whole model was 9.541 MPa in the same loading course, and the maximum stress was located at the distal cervical of the indirectly loaded implant 7. When loading on the pontic, the stress in bone tissue surrounding implant 7 was more than that of implant 5. CONCLUSIONS: Stress in the bone-interface of the splinted implants is evenly distributed at the cervical level, which may also reduce disadvantages from oblique loads. PMID- 22931578 TI - [Studies on the saliva adsorption and the salivary film property on the hydroxyapatite surface]. AB - OBJECTIVE: To evaluate the thickness and viscoelasticity of whole saliva (WS), parotid saliva (PS) and submandibular/sublingual gland saliva (SMSLS) film adsorption on the hydroxyapatite (HA) surface. METHODS: Ultra-thin layer of HA nanocrystals was coated on the dissipation TiO(2) sensor of gold quartz crystal microbalance using electrophoretic deposition technique. The thickness of the HA layer was measured by the ellipsometer, and element analysis was conducted using X-ray photoelectron spectroscopy. Atomic force microscopy and scanning electron microscope were used to observe its morphology. The in-situ adsorption thickness, the shear elastic modulus and the shear viscosity of salivary layers (WS, PS and SMSLS) on HA surfaces were investigated. The statistical data were analysed by an one-way ANOVA analysis followed by a SNK-q test. RESULTS: The results show that the HA layer was a plate-like morphology with 1.53 +/- 0.12 in Ca/P molar ratio, (19.1 +/- 0.9) nm in the thickness and (6.5 +/- 1.6) nm in the roughness. The thickness of salivary film was SMSLS [(21.84 +/- 1.25) nm] > WS[(17.91 +/- 1.35) nm] > PS [(14.30 +/- 1.03 nm) (P < 0.05). The shear elastic modulus of salivary film was PS [(0.61 +/- 0.01) MPa] > SMSLS [(0.31 +/- 0.09) MPa] and WS [(0.25 +/- 0.03) MPa] (P < 0.05). The trend of the shear viscosity was opposite to one of thickness. CONCLUSIONS: The characteristics of saliva adsorption on HA surface suggest that the thicker, softer and more hydrated properties for the SMSLS and WS films are likely to afford a stronger lubrication to protect oral surfaces from wear and dehydration. The viscoelasticity of the PS film is probably related to the retention covering the oral cavity. PMID- 22931579 TI - [Progress of electric-current-assisted technique on dentin bonding]. PMID- 22931580 TI - Accelerated immunoassays based on magnetic particle dynamics in a rotating capillary tube with stationary magnetic field. AB - A rapid and simple magnetic particle-based immunoassay has been demonstrated in a capillary mixing system. Antibody-coated micrometer size superparamagnetic polystyrene (SPP) particles were used in an assay for rabbit IgG in a sandwich (noncompetitive) format. The kinetics of the assay was compared between a plate based system and a single capillary tube. The interaction between the antigen (R IgG) and the antibody (anti-R-IgG) that was carried by the SPP particles in a rotating capillary was tested under a stationary magnetic field. Competing magnetic and viscous drag forces helped to enhance the interaction between the analyte and the capture antibodies on the particles. The dimensionless Mason number (Mn) was employed to characterize the magnetic particle dynamics; a previously determined critical Mason number (Mn(c)) was employed as a guide to the appropriate experimental conditions of magnetic field strength and rotational speed of the capillary. The advantage of the rotating capillary system included a short assay time and a reduced reactive volume (20 MUL). The results show that the immunoassay kinetics were improved by the formation of chains of the SPP particles for the conditions that corresponded to the critical Mason number. PMID- 22931581 TI - Ultrasound imaging for the rheumatologist XL. Sonographic assessment of the hip in rheumatoid arthritis patients. AB - OBJECTIVES: The aim of the present study was to correlate clinical and laboratory data with those obtained by ultrasound (US) evaluation of the hip in a cohort of patients with rheumatoid arthritis (RA). METHODS: Fifty-two RA patients attending the Rheumatology Departments involved in the present study were enrolled. Demographic (age, gender), clinical (body mass index, disease duration, treatments, history or current hip pain, tenderness by internal or external hip rotation or palpation of the greater trochanteric region), laboratory (erythrosedimentation rate, C-reactive protein, rheumatoid factor and antibodies anti-citrullinated peptides) and clinimetric data (disease activity score 28 - DAS28, Health Assessment Questionnaire - HAQ, Lequesne index) were collected. All patients underwent an US examination of both hips according to international guidelines. RESULTS: A total of 100 hips were scanned in 52 patients with RA. Approximately half of the patients reported a history of hip pain, one fourth complained of current pain, and the physical examination (internal and/or external rotation and palpation of the greater trochanteric region) evocated pain up to 19% and 22% of the patients, respectively. US examination found signs of hip joint abnormalities in 42% of the patients; US changes indicative of hip joint inflammation and damage were detected respectively in 24% and 32% of the cases. No patient presented power Doppler signal in the hip joint. A significant correlation between US pathological findings at hip level was found with clinical data (current pain and evocated pain by internal or external hip rotation). Furthermore, US cartilage lesion correlated with age of the patient, and US bone erosions with the disease duration. No correlation was found between the sonographic assessment and laboratory data, DAS 28, and Lequesne index. CONCLUSIONS: US abnormalities at hip joint level obtained in the present study correlated with clinical findings, while no correlation was found with DAS28 or laboratory data. Further investigations are encouraged to clarify the US additional value at hip level in patients with RA. PMID- 22931582 TI - Influenza A H1N1/2009 vaccine in juvenile dermatomyositis: reduced immunogenicity in patients under immunosuppressive therapy. AB - OBJECTIVES: The aim of the present paper is to assess the influence of demographic, muscle enzymes, JDM scores and treatment on non-adjuvanted influenza A H1N1/2009 vaccine immunogenicity in juvenile dermatomyositis (JDM) patients. METHODS: Thirty JDM patients and 81 healthy age-matched controls were vaccinated. All participants were evaluated pre- and 21 days post-vaccination and serology for anti-H1N1 was performed by haemagglutination inhibition assay. Muscle enzymes, JDM scores and treatment were evaluated before and after vaccination. Adverse events were reported. RESULTS: After immunisation, seroconversion rates were significantly lower in JDM patients compared to age-matched controls (86.7 vs. 97.5%, p=0.044), whereas seroprotection (p=0.121), geometric mean titres (GMT) (p=0.992) and factor increase (FI) in GMT (p=0.827) were similar in both groups. Clinical and laboratorial evaluations revealed that JDM scores and muscle enzymes remained stable throughout the study (p>0.05). A higher frequency of chronic course was observed in non-seroconverted compared to seroconverted (100% vs. 27%, p=0.012). Regarding treatment, a lower rate of seroconversion was observed in patients under prednisone>20mg/day (50% vs. 4%, p=0.039), and in those treated with a combination of prednisone, methotrexate and cyclosporine (50% vs. 4%, p=0.039). Local and systemic vaccine adverse events were mild and similar in patients and controls (p>0.05). CONCLUSIONS: This study identified that chronic course and immunosuppressive therapy are the major factors hampering seroconversion in JDM, suggesting that a specific protocol may be required for this subgroup of patients. In spite of that, a single dose of non-adjuvanted influenza A/H1N1 2009 vaccine was generally seroprotective in this disease with no evident deleterious effect in disease itself (ClinicalTrials.gov, no. NCT01151644). PMID- 22931583 TI - Guillain-Barre syndrome following adalimumab treatment. PMID- 22931585 TI - Increased immune reactivity towards human hsp60 in patients with primary Sjogren's syndrome is associated with increased cytokine levels and glandular inflammation. PMID- 22931584 TI - A case of resistant adult-onset periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis (PFAPA) syndrome responsive to anakinra. PMID- 22931586 TI - Mikulicz's disease: a long-term follow-up case report. PMID- 22931588 TI - The effects of oncostatin M on trophoblast cells: influence on matrix metalloproteinases-2 and -9, and invasion activity. AB - Oncostatin M (OSM), a cytokine of the interleukin-6 (IL-6) family, can either promote or inhibit cell growth in various normal and tumor cells and is expressed in rheumatoid arthritis, multiple sclerosis, multiple myeloma, and other inflammatory conditions. We investigated one of the possible mechanisms involved in trophoblast invasion using the human placental cell line derived from first trimester extravillous trophoblasts (HTR8SVneo): modulation of matrix metalloproteinase (MMP)-2 and -9 expression and enzymatic activity. And we addressed also the effects of exogenous OSM on the in vitro invasion activity of HTR8SVneo cells. We found that OSM enhanced the constitutive RNA and protein expressions of MMP-2 and MMP-9 in HTR8SVneo cell lines. Also, OSM treatment increased significantly the enzymatic activity of MMP-2 on gelatin zymography. The effects OSM on enzymatic activity of MMP-9 was not significant. We found that OSM increased invasion activities of HTR8SVneo cells in time-dependent and dose dependent manners. This study suggests that OSM enhances invasion activities of extravillous trophoblasts during the first trimester through the increased enzyme activity of gelatinases, especially MMP-2. PMID- 22931589 TI - Diethyldithiocarbamate complex with copper: the mechanism of action in cancer cells. AB - The idea of "repurposing" of existing drugs provides an effective way to develop and identify new therapies. Disulfiram (Antabuse), a drug commonly used for the treatment of alcoholism, shows promising anticancer activity in both preclinical and clinical studies. In the human body, disulfiram is rapidly converted to its reduced metabolite, diethyldithiocarbamate. If copper ions are available, a bis(diethyldithiocarbamate)-copper(II) complex is formed. Disulfiram's selective anticancer activity is attributed to the copper(II) complex's ability to inhibit the cellular proteasome. It is assumed that the complex inhibits the proteasome by a mechanism that is distinct to the clinically used drug bortezomib, targeting the 19S rather than the 20S proteasome. This difference could be explained by inhibition of the JAMM domain of the POH1 subunit within the lid of the 19S proteasome. PMID- 22931590 TI - Dithiocarbamate complexes as radiopharmaceuticals for medical imaging. AB - Over the past 30 years dithiocarbamate ligands have found application in radiopharmaceutical metal-ligand complexes to image a range of disease states. The vast majority of research and applications, and the widest range of complex structures, have involved radionuclides of technetium and rhenium. Considering the extent of coordination chemistry of dithiocarbamate ligands described elsewhere in this issue, the extent of radiopharmaceutical application with metallic radionuclides is surprisingly narrow. Here we summarise the types of radiopharmaceutical complexes studied and the uses, and potential uses, to which they have been put in nuclear medicine. PMID- 22931592 TI - Metal-dithiocarbamate complexes: chemistry and biological activity. AB - Dithiocarbamates are highly versatile mono-anionic chelating ligands which form stable complexes with all the transition elements and also the majority of main group, lanthanide and actinide elements. They are easily prepared from primary or secondary amines and depending upon the nature of the cation can show good solubility in water or organic solvents. They are related to the thiuram disulfides by a one-electron redox process (followed by dimerisation via sulfur sulfur bond formation) which is easily carried out upon addition of iodide or ferric salts. Dithiocarbamates are lipophilic and generally bind to metals in a symmetrical chelate fashion but examples of other coordination modes are known, the monodentate and anisobidentate modes being most prevalent. They are planar sterically non-demanding ligands which can be electronically tuned by judicious choice of substituents. They stabilize metals in a wide range of oxidation states, this being attributed to the existence of soft dithiocarbamate and hard thioureide resonance forms, the latter formally resulting from delocalization of the nitrogen lone pair onto the sulfurs, and consequently their complexes tend to have a rich electrochemistry. Tetraethyl thiuramdisulfide (disulfiram or antabuse) has been used as a drug since the 1950s but it is only recently that dithiocarbamate complexes have been explored within the medicinal domain. Over the past two decades anti-cancer activity has been noted for gold and copper complexes, technetium and copper complexes have been used in PET-imaging, dithiocarbamates have been used to treat acute cadmium poisoning and copper complexes also have been investigated as SOD inhibitors. PMID- 22931591 TI - Dithiocarbamate-based coordination compounds as potent proteasome inhibitors in human cancer cells. AB - Dithiocarbamates are a class of metal-chelating compounds with various applications in medicine. They have been used for the treatment of bacterial and fungal infections, possible treatment of AIDS, and most recently cancer. Their anti-tumor effects can in part be attributed to their ability to complex tumor cellular copper, leading to binding to and inhibition of the proteasome and in turn initiating tumor cell-specific apoptosis. Current chemotherapeutic agents are highly toxic and therefore their efficacy in the eradication of tumors is greatly limited. As a result many scientists have joined the quest for novel targeted therapies in hopes of reducing toxicity while maximizing potency and proteasome inhibition has become an attractive therapy in this regard. Here we discuss the origins, mechanism, and evolution of dithiocarbamates as potent proteasome inhibitors and therefore anti-cancer agents. PMID- 22931593 TI - Noble metal-dithiocarbamates precious allies in the fight against cancer. AB - To date, cisplatin and its analogs are among the most effective chemotherapeutic agents for cancer treatment. However, high systemic toxicity and the propensity for patients to develop tumor resistance remain the main challenges in the clinical application. Therefore, the discovery and development of novel active chemotherapeutic agents are largely needed and the research of new metal-based anticancer drugs continues to be a very active international field. In this review paper we aim to give a detailed overview on our research work devoted to the design of novel dithiocarbamato complexes with different noble metals (such as palladium, platinum, copper, ruthenium and gold), which have gained considerable interest in both the development and the treatment of cancer. In particular, we summarize the results of the metal complexes achieved so far, focusing on the gold(III) compounds, that show outstanding in vitro and in vivo antitumor properties and reduced, or even no, systemic and renal toxicity, compared to the reference drug cisplatin. PMID- 22931594 TI - [Diclofenac inhibits Kv1.3 and Kir2.1 expressions in human macrophages and affects the membrane potential and foam cell formation]. AB - OBJECTIVE: To investigate the effect of diclofenac on the expression of Kv1.3 and Kir2.1 channels in human macrophages and the membrane potential and foaming process of the macrophages. METHODS: The effect of diclofenac on the expression of Kv1.3 and Kir2.1 channels in cultured human monocyte-derived macrophages was investigated using real-time RT-PCR and Western blotting, and its effect on the membrane potential was analyzed with optical mapping of the membrane potential with voltage-sensitive dyes. The ratio of cholesterol ester (CE) in the macrophages following intake of oxidized low-density lipoprotein (OxLDL) was analyzed by an enzymatic fluorometric method. RESULTS: The expression of Kv1.3 and Kir2.1 channels in the macrophages were down-regulated by diclofenac (1.5 umol/L and 15 umol/L). Compared with those in the control group, Kv1.3 mRNA expression was reduced by over 80% and 90% (P<0.05), and Kir2.1 mRNA by over 20% and 30% (P>0.05), respectively; both their protein expression was reduced by over 10% and 60% with a dose- dependent effect (P<0.05). Diclofenac at the two doses dose-dependently reduced the surface fluorescence intensity of the macrophage, and the membrane potential was decreased by 28% and 54%, respectively (P<0.05). Incubation of the macrophages with 30 mg/L OxLDL for 60 h caused an obvious enlargement of the cell volume and deposition of numerous lipid granules in cytoplasm, resulting also in a CE/TC ratio over 50% (P<0.05). Diclofenac at 1.5 and 15 umol/L both significantly decreased the CE/TC ratio to (23.624?3.34)% and (13.601?2.916)% (P<0.05), respectively, but this effect did not show a dose response relationship (P>0.05). CONCLUSION: Diclofenac can significant down regulate the expression of Kv1.3 and Kir2.1 channels in human macrophages, lower their membrane potential and inhibit the process of foam cell formation. PMID- 22931595 TI - [Oral bioavailability and intestinal disposition of dehydroandrographolide in rats]. AB - OBJECTIVE: Dehydroandrographolide (DP) from Andrographis paniculata (Burm. F.) Nees is a potential anticancer agent. This study aimed to investigate the oral bioavailability and intestinal disposition of DP to provide useful information for the development of DP as a new candidate anticancer drug. METHODS: The pharmacokinetics of DP was evaluated in rats, and its intestinal disposition was determined using cultured Caco-2 cells and a single-pass rat intestinal perfusion model. RESULTS: The oral bioavailability of DP was 11.92% in rats. The apparent permeability coefficient (P(app)) of DP from the basolateral side (B) to the apical side (A) (5.37*10(-5) cm/s) of the Caco-2 model was roughly equal to that from A to B (4.56*10(-5) cm/s), suggesting no involvement of the efflux transporter(s). In the perfusion model, no significant difference was found in the effective permeability (P*(eff)) of DP between the 4 segments of the intestine. No significant metabolism of DP was detected in the intestinal perfusates. The amount of DP found in the bile was only about 0.1% of the absorbed amount. The P*(eff) and bile amounts of DP were not significantly increased by P-glycoprotein (P-gp) inhibitor or breast cancer resistant protein (BCRP) inhibitor (P>0.05). CONCLUSION: The bioavailability of DP was 11.92% in rats. DP has good absorption and metabolism stability in the intestine. The efflux transporters such as P-gp and BCRP do not participate in DP transport. PMID- 22931596 TI - [Construction of personalized full-length fully human mammalian display antibody library for children with systemic lupus erythematosus]. AB - OBJECTIVE: To construct a personalized full-length fully human antibody mammalian display library for children with systemic lupus erythematosus (SLE). METHODS: The total RNA was isolated from the PBMCs of SLE children. The heavy chain variable region and kappa light chain (VH and LCkappa) of the antibody genes were amplified by RT-PCR and inserted into the pDGB-HC-TM vector separately to construct the heavy chain and light chain libraries. The library DNAs were transfected into 293T cells and the expression of full-length fully human antibody on the surface of 293T cells was analyzed by flow cytometry. RESULTS: Using 0.8 ug total RNA as the template, the VH and LCkappa were amplified and the full-length fully human antibody mammalian display library was constructed. The VH and LCkappa gene libraries had a size of 9.4*10(4) and 8.4*10(4), respectively. Sequence analysis of 10 clones randomly selected from the VH and LCkappa gene libraries each showed that 8 heavy chain clones and 7 light chain clones contained correct open reading frames, and flow cytometry demonstrated that all the 15 clones express full-length antibodies on 293T cell surfaces. 293T cells co-transfected with the VH and LCkappa gene libraries expressed the full length antibodies on the cell surface. CONCLUSION: The personalized full-length fully human antibody library for SLE children constructed allows display of the full-length antibodies on mammalian cell surfaces, thus providing a valuable platform for analyzing the autoantibodies, their etiological role, and their clinical implications in SLE. PMID- 22931597 TI - [Establishment of a human embryonic stem cell line with stable beta-catenin silencing by shRNA lentivirus]. AB - OBJECTIVE: To establish a human embryonic stem cell line with stably beta-catenin gene silencing by lentivirus-mediated shRNA interference. METHODS: PLKO.1-puro beta-catenin vector, a lentivirus plasmid expressing beta-catenin shRNA, was packaged into 293FT cells. Human embryonic stem cells were infected with the lentivirus and the cell clones stably expressing beta-catenin shRNA were selected by puromycin, with the uninfected cells and cells infected with the empty vector as the control. Real-time RT-PCR was used to evaluate the efficiency of beta catenin knocked down; beta-catenin and OCT4 protein expression in the infected cells was examined using immunofluorescence assay. RESULTS: Infection with beta catenin-specific shRNA lentivirus resulted in stable interference of beta-catenin expression in human embryonic stem cells, which showed a beta-catenin mRNA expression of only 1% of that in the uninfected cells. Infection with the empty vector produced no obvious effect on beta-catenin expression compared to the uninfected cells. In the cells infected with beta-catenin shRNA lentivirus, beta catenin protein expression was almost undetectable in immunofluorescence assay, while OCT4 was still expressed after the interference. CONCLUSION: Lentiviral vector-delivered shRNA results in effective and stable beta-catenin gene silencing in human embryonic stem cells. PMID- 22931598 TI - [Small interfering RNA-mediated Nrf2 gene knockdown enhances hirsutanols A induced cytotoxicity in cancer cells]. AB - OBJECTIVE: To investigate the effect of Nrf2 gene knockdown on hirsutanols A induced cytotoxicity in cancer cells. METHODS: The changes in the cell viability following treatment with different concentrations of hirsutanols A was detected by MTT assay, and the generation of reactive oxygen species (ROS) was assayed using flow cytometry. AnnexinV-FITC apoptosis kit was used to detect the cell apoptosis. Nrf2 protein expression in HepG2 and SW480 cells transfected with the siRNA targeting Nrf2 was analyzed with Western blotting. RESULTS: At the concentrations of 1.25, 2.5, 5, 10, 20 and 40 umol/L, hirsutanols A obviously inhibited the cell proliferation of human liver cancer HepG2 and colon cancer SW480 cells in a concentration-dependent manner. The levels of hydrogen peroxide increased rapidly after hirsutanols A treatment in both HepG2 (30 umol/L) and SW480 (15 umol/L) cells. Hirsutanols A also induced apoptosis of the two cells. Pretreatment with 5 mmol/L NAC totally inhibited apoptosis and ROS accumulation in the two cells induced by hirsutanols A. Transfection of HepG2 and SW480 cells with the siRNA caused a significant reduction in Nrf2 protein expression, which resulted in an increased sensitivity of the cells to hirsutanols A. CONCLUSION: Hirsutanols A can induce apoptosis in HepG2 and SW480 cells by promoting ROS production and up-regulating Nrf2 expression. Nrf2 knockdown by siRNA can increase the sensitivity of the cancer cells to hirsutanols A in vitro. PMID- 22931599 TI - [Construction of has-microRNA-338-3p lentiviral vector and verification of its target gene]. AB - OBJECTIVE: To construct a lentiviral expression vector of has-miR-338-3p and verify its target gene. METHODS: The pre-miR-338-3p was synthesized and inserted into pLV-THM, and the recombinant plasmid pLV-THM-miR-338-3p was confirmed by restriction endonuclease analysis and DNA sequencing. 293T cells were co transfected with the lentiviral vector pLV-THM-miR-338-3p, psPAX2 and pMD2.G, and the supernatant containing the lentivirus particles was harvested to determine the virus titer and used to infect SW-620 cells. Flow cytometry was employed for sorting the GFP-positive cells. The expression of miR-338-3p was determined using real-time RT-PCR and the expression of SMO protein was detected with Western blotting in the infected SW-620 cells. The invasiveness of the infected SW-620 cells was assessed using Transwell assay. RESULTS: Restriction enzyme digestion and DNA sequencing demonstrated successful construction of the lentiviral vector pLV-THM-miR-338-3p. SW-620 cells infected with pLV-THM-miR-338-3p showed a significantly increased expression of miR-338-3p, and the overexpression of miR 338-3p suppressed the expression of SMO protein and the invasiveness of the cells. CONCLUSION: The successful construction of the lentiviral vector pLV-THM miR-338-3p and the establishment of a SW-620 cell line with miR-338-3p overexpression provide the basis for further study of the molecular function of miR-338-3p in colorectal carcinoma. MiR-338-3p can suppress SMO gene expression to inhibit the invasiveness of colorectal carcinoma cells. PMID- 22931600 TI - [BRCA1 inhibits progesterone-induced proliferation and migration of breast cancer cells]. AB - OBJECTIVE: To study the effect of BRCA1 in regulating the proliferation and migration of breast cancer cells stimulated by progesterone. METHODS: Breast cancer MCF-7 and T-47D cell were transfected with a vector containing the coding sequence of BRCA1 (pFlag-CMV2-BRCA1 wt) to induce BRCA1 overexpression or with the empty vector (control). The cells were then stimulated with progesterone, and the cell proliferation and migration were observed using MTT assay and wound healing assay, respectively. The proliferation and migration of MCF-7 cells were also observed following transfection with a small interfering RNA (siRNA) for BRCA1 knockdown or with a scrambled siRNA prior to progesterone stimulation. RESULTS: Transfection with the empty vector and with pFlag-CMV2-BRCA1 wt prior to progesterone stimulation caused significantly different proliferation rates in MCF-7 cells [(114.4?6.0)% vs (82.1?3.2)%, P<0.05] and in T-47D cells [(111.3?4.3)% vs (84.2?3.5)%, P<0.05], resulting also in significantly different cell migration rates (55.9% vs 15.8% in MCF-7 cells and 44.83% vs 10.43% in T-47D cells). Compared to the scrambled siRNA, BRCA1 siRNA transfection prior to progesterone stimulation significantly increased the proliferation rates [(114.4?3.05)% vs (125.3?4.0)%, P<0.05] and migration rate (39.2% vs 69.08%) of MCF-7 cells. The progesterone antagonist RU468 could antagonize the effects of BRCA1 knockdown in enhancing progesterone-stimulated MCF-7 cell proliferation and migration. CONCLUSION: A decreased BRCA1 expression can enhance progesterone stimulated tumor cell proliferation and migration in sporadic breast cancer. PMID- 22931601 TI - [Expression of thyroid transcription factor-1 and vimentin in neonatal mice with bronchopulmonary dysplasia]. AB - OBJECTIVE: To investigate the expressions of thyroid transcription factor-1 (TTF 1), the type II alveolar epithelial cells (AECII)-specific marker, and vimentin, the fibroblast-specific marker, in the lungs of neonatal mice with bronchopulmonary dysplasia (BPD) and explore the pathogenesis of BPD. METHODS: Neonatal mice were exposed to hyperoxia to induce BPD, and pathological changes in the lung tissues were examined. At 3, 7, 14 and 21 days after the exposure, the protein and mRNA expressions of TTF-1 and vimentin were detected by double labeled immunofluorescence assay and real-time PCR, respectively. RESULTS: Compared with the neonatal mice exposed in normal air, those with hyperoxic exposure showed developmental disorders and collagen deposition in the lung tissues. The protein expression of TTF-1 decreased while vimentin expression increased in the lung tissues, where their co-expression was observed at 14 and 21 days after the exposure. TTF-1 mRNA expression decreased markedly (P<0.05) and vimentin mRNA increased significantly in the lung tissues at 21 days after hyperoxic exposure of the mice (P<0.05). CONCLUSION: Hyperoxia-induced transition of AECII to fibroblasts may play an important role in pulmonary fibrosis in neonatal mice with BPD. PMID- 22931602 TI - [Safety of three-dimensional technique in patients undergoing complicated hepatectomy]. AB - OBJECTIVE: To assess the value of abdominal three-dimensional medical image visualization system (MI-3DVS) in assisting complicated hepatectomy. METHODS: Twenty-four patients undergoing complicated hepatectomy for hepatic carcinoma or hepatic focal nodular hyperplasia were enrolled in this study. Three-dimensional models of the organs, vessels and tumors were reconstructed with MI-3DVS, and virtual operations were carried out to assess the feasibility of hepatectomy. The diameter of the liver tumors, intraoperative blood loss and transfusion, complications, in-hospital mortality rate, and one-year survival rate were analyzed in these cases. RESULTS: The operations were safely completed in all the cases without perioperative deaths. The mean diameter of liver tumor was 9.8?4.3 cm, and the median volumes of intraoperative blood loss and transfusion were 800 ml and 600 ml, respectively, with a blood transfusion rate of 91.7% (22/24). The incidence of complications was 29.2% (7/24), and the one-year survival rate was 37.5%. CONCLUSION: Three-dimensional techniques such as volumetric analysis and risk evaluation of residual liver blood supply and drainage can increase the accuracy of surgical planning and improve the safety of complicated hepatectomy. PMID- 22931603 TI - [Quantitative assessment of left ventricular systolic dyssynchrony in relation to systolic function by real-time three-dimensional echocardiography-derived regional systolic dyssynchrony index in chronic heart failure patients]. AB - OBJECTIVE: To quantitatively assess the left ventricular systolic dyssynchrony in patients with chronic heart failure based on the regional systolic dyssynchrony index (R-SDI) derived from real-time three-dimensional echocardiography (RT-3DE), and investigate the relation between R-SDI and the left ventricular systolic function. METHODS: Forty-two patients with chronic heart failure (LVEF<50%) were classified into severe dysfunction group (group A, LVEF<40%) and mild dysfunction group (group B, LVEF>=40%), with 33 healthy subjects as the control group (LVEF>50%). RT-3DE was performed for each subject to obtain the left volume-time curves and the 16, 12, and 6 segment R-SDI. The value of R-SDI in assessing left ventricular systolic dyssynchrony and its correlation with LVEF were analyzed. RESULTS: The 16, 12, and 6R-SDI were significantly higher in the chronic heart failure group than in the control group (P<0.01). The R-SDI of group A was significantly greater than those of group B in the chronic heart failure patients (P<0.01), and 16R-SDI, 12R-SDI, and 6R-SDI were inversely correlated with LVEF of the patients (r=-0.843, -0.840, and -0.841, respectively, P<0.01). CONCLUSIONS: R SDI can be used to assess the left ventricular mechanic systolic dyssynchrony, and the degree of the dyssynchrony is inversely correlated with LVEF. RT-3DE can serve as a valuable modality for quantitative evaluation of left ventricular dyssynchrony in chronic heart failure patients. PMID- 22931604 TI - [Screening of proteins regulated by CCDC19 gene in nasopharyngeal carcinoma using proteomics technology]. AB - OBJECTIVE: To screen the proteins under regulation by the candidate tumor suppressor gene CCDC19 using proteomics technology in nasopharyngeal carcinoma (NPC). METHODS: The cellular proteins were extracted from 3D8 NPC cells with CCDC19 overexpression and the control C6 NPC cells. Two-dimensional (2D) gel electrophoresis was employed to compare the protein expression profiles between these two cells, and the differential proteins were identified using peptide mass fingerprinting and database searching. Real-time PCR and Western blotting were used to validate the expression levels of the differential proteins. RESULTS: Matrix-assisted laser desorption/time of flight showed that 3 differential proteins, namely FASN, CTSD and PGK1, were down-regulated by -3.28, -1.64, and 6.97 folds, respectively, which were confirmed by real-time PCR and Western blotting. CONCLUSION: FASN, CTSD and PGK1 are probably the target proteins regulated by CCDC19 in NPC. PMID- 22931605 TI - [Hydrogen peroxide induces high mobility group box 1 release in human bronchial epithelial cells]. AB - OBJECTIVE: To investigate the effect of hydrogen dioxide (H(2)O(2)) on the release and translocation of high mobility group box 1 release (HMGB1) from normal human bronchiolar epithelial cells (HBE). METHODS: MTT assay was used to assess the viability of HBE135-E6E7 cells exposed to different concentrations of H(2)O(2). The expression and location of HMGB1 in the cytoplasm, nuclei and culture medium of the exposed cells were determined using Western blotting and immunofluorescence assay. RESULTS: Exposure to 125 ummol/L H(2)O(2) did not obviously affect the cell viability. At the concentration of 250 ummol/L, H(2)O(2) significantly decreased the cell viability (P<0.05), but significant cell death occurred only after exposure to 400 ummol/L H(2)O(2) (P=0.000). Compared with the control cells, the cells exposed to 12.5, 125 and 250 ummol/L H(2)O(2) for 24 h showed significantly increased levels of HMGB1 in the culture medium (P<0.05), and exposure to 125 ummol/L H(2)O(2) for 12 and 24 h also caused significantly increased HMGB1 level (P<0.05). Exposure to 125 ummol/L H(2)O(2) for 24 h significantly increased HMGB1 expression in the cytoplasm but decreased its expression in the nucleus. HMGB1 translocation from the nuclei to the cytoplasm and to the plasmalemma occurred after 125 ummol/L H(2)O(2) exposure for 12 h and 24 h, respectively. CONCLUSION: H(2)O(2) can induce HMGB1 translocation and release in human bronchial epithelial cells, suggesting the involvement of HMGB1 in airway oxidative stress in chronic inflammatory diseases such as asthma and COPD. PMID- 22931606 TI - [Spironolactone inhibits hepatic sinusoid angiogenesis in rats with hepatic fibrosis]. AB - OBJECTIVE: To investigate the inhibitory effects of spironolactone against hepatic sinusoid angiogenesis in rats with hepatic fibrosis. METHODS: Twenty-four male Wistar rats were randomly divided into sham-operated group, bile duct ligation (BDL) group, and BDL+SP group in which the rats received daily spironolactone injection (20 mg/kg) the day after BDL. Four weeks after the operation, the rats were sacrificed for examination of liver histology using Masson staining and the expression of vascular endothelial growth factor A (VEGF A) mRNA in the liver using real-time quantitative PCR. Immunohistochemistry was used to detect the expression of von Willebrand factor (vWF) in the hepatic tissues. RESULTS: Spironolactone significantly inhibited liver fibrogenesis in rats after BDL (METAVIR liver fibrosis scores 2.84?0.44 vs 19.73?3.54, P=0.00). Real-time PCR and immunohistochemistry showed that compared with BDL group, spironolactone treatment significantly inhibited the expression of VEGF-A mRNA (0.71?0.12 vs 1.75?0.15, P=0.00) and vWF (1.15?0.09 vs 3.08?0.17, P=0.00) in the liver. The expression of VEGF-A mRNA was highly correlated with the expression of vWF (r=0.890, P=0.000). CONCLUSION: Spironolactone can inhibit hepatic sinusoid angiogenesis in rats with BDL-induced hepatic fibrosis by inhibiting the expression of VEGF-A. PMID- 22931607 TI - [Changes of cholinergic nerves and tumor necrosis factor-alpha in doxorubicin induced rat failing heart]. AB - OBJECTIVE: To investigate the changes of cholinergic nerves in doxorubicin (DOX) induced rat failing heart and tumor necrosis factor-alpha (TNF-alpha) in the heart tissue and serum. METHODS: Adult Sprague-Dawley rats were randomized into control (n=10) and DOX-induced chronic heart failure (CHF) groups (n=15), and in the latter group, the rats were given intraperitoneal injections of 2.5 mg/kg DOX once a week for 6 weeks, with a total cumulative dose of 15 mg/kg. The control rats were injected with normal saline (1 ml/week). Karnovsky-Roots histochemical staining combined with point counting was used to demonstrate the distribution of cholinergic nerves in the heart. The expression levels of TNF-alpha in the heart tissue and serum were determined with ELISA. RESULTS: Positively stained cholinergic nerves were found in all the rat hearts in the two groups, but in CHF group, the point counts of cholinergic nerves were significantly lower than that of the control group (P<0.01). Compared with the control rats, those with DOX induced CHF showed elevated levels of TNF-alpha both in the heart tissue and in the serum (P<0.01). CONCLUSION: In rats with DOX-induced CHF, the parasympathetic nervous system is down-regulated in the failing heart, and the diminished cholinergic anti-inflammatory pathway may play an important role in the progression of CHF. PMID- 22931608 TI - [Imaging features of urinary dysfunction associated with ketamine abuse]. AB - OBJECTIVE: To summarize the imaging features of urinary dysfunction associated with ketamine abuse (KAUD) for imaging diagnosis of KAUD. METHODS: We analyzed the imaging findings in 45 patients with KAUD, all having a history of ketamine abuse and presenting with severe lower urinary tract symptoms. The patients underwent imaging examinations with ultrasonography (n=45), X-ray (n=38), computed tomography (n=28), magnetic resonance imaging (n=10) or single photon emission computed tomography (n=25), and the results were classified and evaluated to identify the common imaging findings. RESULTS: The imaging changes of KAUD were found primarily in the urinary and biliary system. The most common imaging characteristics included thickening of the bladder wall, contracture and decreased functional volume of the bladder, dilation of the ureter and hydronephrosis, stricture of the upper ureter, renal impairment, dilation of the biliary system, and inflammation or swelling of the adjacent organs and lymph nodes CONCLUSION: KAUD presents with typical imaging changes. Radiologists should be aware of KAUD if the typical imaging features are detected, especially in cases with a history of ketamine abuse. PMID- 22931609 TI - [A novel method for studying nuclear localization signal-mediated nuclear translocation]. AB - OBJECTIVE: To establish a new method for studying the mechanism of nuclear localization signal (NLS)-mediated nuclear translocation in living cells. METHODS: The cells were treated with 67 mg/L 3-[(3 Cholamidopropyl)dimethylammonio]propanesulfonate (CHAPS), followed by incubation with 1 g/L wheat germ agglutinin (WGA), and their effects on interferon- gamma (IFN-gamma)-induced nuclear translocation of signal transducer and activator of transcription 1 (STAT1) were observed. RESULTS: Treatment with CHAPS alone had no effect on IFN-gamma-induced nuclear translocation of STAT1, while this process was blocked by further WGA incubation. CONCLUSION: We established a new, simple but effective method for studying the mechanism of NLS-mediated nuclear translocation in living cells by perforating the cell membrane with CHAPS treatment. PMID- 22931610 TI - [An improved method for primary culture of mouse pulmonary microvascular endothelial cells]. AB - OBJECTIVE: To establish an improved method for culturing primary mouse pulmonary microvascular endothelial cells (PMVECs). METHODS: An improved tissue block adherent culture method was used to isolate and culture the PMVECs from C57 mice. The cultured cells were identified by factor VIII-related antigen and CD31 antigen, and the growth of cells cultured using the improved method and the conventional method was compared. RESULTS: The cultured primary pulmonary microvascular endothelial cells showed a short fusiform or round morphology, and the cell monolayer displayed a cobble stone-like appearance. The cultured cells were positive for VIII-related antigen and CD31 antigen. The cell growth was accelerated in the cell cultures with the improved method compared with that in conventional cell cultures. CONCLUSION: The improved culture method allows more efficient acquisition of primary mouse PMVECs of a greater purity. PMID- 22931611 TI - [Value of blood inflammatory markers in the diagnosis of acute appendicitis in children]. AB - OBJECTIVE: To investigate the value of serum inflammatory markers in the diagnosis of acute appendicitis (AA) in children. METHODS: Blood samples were collected from 51 children with AA and 16 children with nonsurgical abdominal pain (NSAP) to examine white blood cell count (WBC), serum C-reactive protein (CRP), interleukin-6, and tumor necrosis factor-alpha (TNF-alpha). RESULTS: WBC count, CRP, IL-6 and TNF-alpha increased significantly in children with severe AA (phlegmonous or gangrenous, and perforated appendicitis). ROC curves showed that IL-6 or TNF-alpha had a greater contribution than WBC count to the diagnosis of severe appendicitis. CONCLUSION: IL-6 and TNF-alpha can provide complementary information to assist the clinical decision of emergency operation for children with AA. PMID- 22931612 TI - [Peripheral dendritic cell subsets and changes in plasma monocyte chemoattractant protein 1 in patients with coronary heart disease]. AB - OBJECTIVE: To assess the association between peripheral blood dendritic cells subtype distribution and plasma monocyte chemoattractant protein 1 (MCP-1) concentration in patients with coronary heart disease (CHD). METHODS: Sixty consecutive CHD patients admitted in our department during the period from November, 2010 to December, 2011 were enrolled, including 10 with stable angina pectoris (SAP), 25 with unstable angina pectoris (UAP), and 25 with acute myocardial infarction (AMI), with 28 healthy volunteers as normal controls. All the subjects underwent routine tests and coronary angiography. The percentages of peripheral blood myeloid dendritic cells (mDCs) and plasma cell-like dendritic cells (pDCs) in peripheral blood mononuclear cells were detected by flow cytometry, and plasma MCP-1 levels were detected using enzyme-linked immunosorbent assay. RESULTS: The percentage and absolute quantity of mDCs and pDCs were significantly lower in AMI and UAP groups than in the normal control and SAP groups (P<0.001). In the CHD patients, the plasma MCP-1 level was significantly higher than that in the normal control group (P<0.001) with an inverse correlation with the percentage of peripheral mDCs. CONCLUSION: MCP-1 may promote the migration of mDCs into atherosclerotic plaques and mediate the local immune and inflammatory responses to aggravate plaque instability in CHD patients. PMID- 22931613 TI - [Effect of livin gene suppression by genistein on apoptosis, cell cycle and proliferation of malignant melanoma LiBr cells]. AB - OBJECTIVE: To observe the effect of livin gene suppression by genistein on apoptosis, cell cycle and proliferation of malignant melanoma LiBr cells. METHODS: RT-PCR was used to detect the expression of livin mRNA in LiBr cells 48 h after treatment with 40 umol/L genistein. Flow cytometry with annexin V-FITC/PI double staining was employed to detect cell apoptosis, and the caspase-3 protein expression in the cells following genistein treatment was assayed using Western blotting. The changes in the cell cycle and proliferation of the cells after genistein treatment were examined with flow cytometry with PI staining and MTT colorimetric assay, respectively. RESULTS: Genistein can suppress the expression of Livin Gene (87.94% with 40 umol/L genistein) and induce the apoptosis of LiBr effectively, both in the early and late phases (27.87?5.38% and 11.87?3.86% respectively). LiBr cells in phase G(0)/G(1) increases notably(G(0)/G(1)=72.11?5.89%,S=14.53?3.47%,G(2)/M=12.36?2.64%). Genistein significantly reduced caspase-3 protein expression and inhibit cell proliferation. CONCLUSION: Genistein can suppress Livin Gene expression, induce LiBr cell apoptosis, hinder cell generation cycle, restrain cell proliferation. PMID- 22931614 TI - [Clarithromycin combined with tanshinone for rhinosinusal and laryngeal radiation injury in patients with nasopharyngeal carcinoma after radiotherapy]. AB - OBJECTIVE: To evaluate the therapeutic effect of clarithromycin combined with tanshinone in the treatment of rhinosinusal and laryngeal radiation injury induced by radiotherapy in patients with nasopharyngeal carcinoma (NPC). METHODS: A total of 255 NPC patients with rhinosinusal and laryngeal radiation injury following radiotherapy were randomized into 3 groups for treatment with clarithromycin (group A, n=69), tanshinone (group B, n=69), and clarithromycin + tanshinone (group C, n=69), and the clinical outcomes of the patients were evaluated. RESULTS: In all the 3 groups the patients responded favorably to the treatments and showed obvious improvements (P<0.05). The therapeutic effects were similar between groups A and B (P>0.05), but the patients in group C showed the most obvious improvements (P<0.05). CONCLUSIONS: Clarithromycin combined with tanshinone can be an effective regimen for treatment of rhinosinusal and laryngeal radiation injury induced by radiotherapy in NPC patients. PMID- 22931615 TI - [Association of serum transforming growth factor-beta1 with radiation injury and survival of patients with early-stage nasopharyngeal carcinoma]. AB - OBJECTIVE: To observe the changes in serum transforming growth factor-beta1 (TGF beta1) in patients with early-stage nasopharyngeal carcinoma (NPC) after radiotherapy and explore the correlation of serum TGF-beta1 with radiation injury and disease-free survival. METHODS: The average serum TGF-beta1 level (50.2?3.2 ng/ml) determined from 32 healthy volunteers was used as the standard value for NPC patients in this trial. Fifty-seven patients with early-stage (T1-2N0-1M0) NPC without prior treatment were divided into two groups with serum TGF-beta1 level before treatment lower than or equal to the standard value (group A, 29 cases) and a level beyond the standard value (group B, 28 cases). Serum TGF-beta1 level was determined in all the patients before, during and after the radiotherapy to evaluate the radiation injury and therapeutic effect. RESULTS: The serum TGF-beta1 level before radiotherapy was significantly lower in group A than in group B (35.4?1.4 vs 58.8?1.0 ng/ml, P<0.05). After radiotherapy, acute radiation mucositis and skin reaction was significantly severer in group B (P<0.05). The serum TGF-beta1 level before radiotherapy was significantly higher in patients with grade 3 acute radiation mucositis and skin reaction than in those with injuries below grade 3 (54.0?2.2 vs 42.0?2.3 ng/ml and 54.3?2.4 vs 43.4?2.2 ng/ml, P<0.05). The two groups showed no significant differences in the locoregional failure rate (3.4% vs 7.1%), distant metastasis rate (3.4% vs 10.8%) or disease-free survival (P>0.05). CONCLUSIONS: Radiotherapy can significantly decrease serum TGF-beta1 level in early NPC patients. Serum TGF-beta1 level before radiotherapy can help predict the degree of acute radiation mucositis and skin reaction, but shows no correlation with disease-free survival of early-stage NPC patients. PMID- 22931616 TI - [Structural and functional changes of the carotid artery and their relationship with subclinical inflammation in patients with H-type hypertension]. AB - OBJECTIVE: To investigate the changes in the structure and function of the carotid artery and their relationship with subclinical inflammation in patients with H-type hypertension. METHODS: Sixty patients with H-type hypertension and 49 with non-H-type hypertension were enrolled in this study, with 20 healthy volunteers as the control group. All the subjects underwent color Doppler ultrasound examination of the carotid artery, and their blood levels of hyper sensitive C-reactive protein (hs-CRP), fibrinogen (FIB), and tumor necrosis factor-alpha (TNF-alpha) were measured to investigate the correlation between the structural and functional changes of the carotid artery and the inflammatory factors. RESULTS: No significant difference was found in the blood pressure level between the H-type and non-H-type hypertension groups (136.0?10.1 vs 131.9?7.0 mmHg for systolic blood pressure, P>0.05; 80.9?8.9 vs 73.2?7.9 mmHg for diastolic pressure, P>0.05). The intima-media thickness, distensibility of the common carotid artery, carotid artery stiffness, and blood homocysteine level all showed significant differences between patients with H-type and non-H-type hypertension (1.52?0.08 vs 1.09?0.06 mm, 0.23?0.14 mmHg(-1)*100 vs 0.46?0.14 mmHg(-1)*100, and 15.37?5.89 vs 8.19?4.53 umol/L, respectively, P<0.05). The H-type hypertensive patients showed significantly higher hs-CRP, FIB, and TNF-alpha levels than the non-H-type hypertensive patients, and these inflammatory factors were positively correlated with the structural and functional changes of the carotid artery. CONCLUSION: The patients with H-type hypertension are more likely to have carotid artery structure and function impairments, which closely correlate with the subclinical inflammatory factors. These changes might be attributed to the synergism of subclinical inflammation and hyperhomocysteinemia, for which active intervention may prove beneficial. PMID- 22931617 TI - [Expressions of orotate phosphoribosyltransferase in colorectal carcinoma and its correlations with toxicities of chemotherapy]. AB - OBJECTIVE: To investigate the expression of orotate phosphoribosyltransferase (OPRT) in colorectal carcinoma and analyze its correlations with the toxicities of chemotherapy. METHODS: The expression of OPRT mRNA was detected using RT-PCR in colorectal carcinoma tissues and paired adjacent normal tissues from 58 patients receiving FOLFOX6 regimen chemotherapy. The toxicities of the chemotherapy were recorded, and the correlations between OPRT mRNA expression and the toxicities were analyzed. RESULTS: OPRT mRNA expression was significantly higher in the tumor tissues than in the corresponding normal tissues (P=0.001), but OPRT expression in the tumor tissues was not correlated with the toxicities of the chemotherapy (P>0.05). OPRT level in the normal tissues showed a significant positive correlation with the occurrence of diarrhea in these cases (P=0.013). CONCLUSION: OPRT expression in colorectal carcinoma tissues is not correlated with the toxicities of 5-FU-based regimen, but OPRT expression in the normal tissues can help predict the toxicities associated with 5-FU. PMID- 22931618 TI - [Exendin-4 ameliorates high glucose- and TNF-alpha-induced vascular endothelial cell damage by inhibiting p38 MAPK and NF-kappaB p65 translocation]. AB - OBJECTIVE: To investigate the protective effects of exendin-4 on vascular endothelial cells and explore the possible mechanism. METHODS: Human umbilical vascular endothelial cells (HUVECs) were cultured in the presence of high glucose and tumor necrosis factor-alpha (TNF-alpha, 10 ng/ml) with or without exendin-4. The level of nitric oxide (NO) in the cell culture supernatant was measured using a nitrate reductase method. The expression of intercellular adhesion molecule-1 (ICAM-1) mRNA was measured by real-time PCR, and nuclear factor-kappaB (NF kappaB) p65 translocation was detected using immunofluorescence assay. Western blotting was employed to measure the expression of p38 MAPK protein in the treated cells. RESULTS: In the presence of high glucose and TNF-alpha, treatment of cells with exendin-4 did not obviously affect the cellular synthesis of NO, but significantly down-regulated the expression of ICAM-1 mRNA (P<0.01). The nuclear fluorescence intensity of NF-kappaB p65 and the expression level of p38 MAPK protein in the cells were significantly lowered by exendin-4 treatment (P<0.01). CONCLUSION: Exendin-4 ameliorates high glucose- and TNF-alpha-induced HUVEC-12 cell damage by inhibiting the expression of p38 MAPK protein and translocation of NF-kappaB p65. PMID- 22931619 TI - [Protein kinase A signaling pathway participates in high glucose-induced inhibition of G6PD activity and respiratory burst dysfunction in THP-1 cells]. AB - OBJECTIVE: To observe the changes in glucose 6-phosphate dehydrogenase (G6PD) activity, cAMP and respiratory burst function in THP-1 cells exposed to high glucose and identify the possible signaling pathways to mediate these changes. METHODS: THP-1 cells were treated with high glucose, high glucose plus the PKA inhibitor (PKI), or normal glucose plus Forskolin. The changes in the G6PD activity and cAMP in the exposed cells were assayed using the spectrophotometric method, and the reactive oxygen species (ROS) content in the cell culture was determined using the fluorescent probe DCFH-DA. Western blotting was employed to examine the expression of phosphorylated p47(phox) in the cells. RESULTS: Compared with the normal control cells, the cells exposed to high glucose and to normal glucose and Forskolin showed a significantly lowered G6PD activity, ROS content and expression of phosphorylated p47(phox), but with a increased cAMP content (P<0.01). High glucose exposure in the presence of PKI caused no significant changes in G6PD activity, ROS level, phosphorylated p47(phox) or cAMP compared to those in the normal control cells (P>0.01). CONCLUSION: High glucose causes inhibition of G6PD activity in THP-1 cells via activation of PKA and thus leads to respiratory burst dysfunction, which is the probable mechanism underlying the lowered leucocyte function and susceptibility to infections in diabetic patients. PMID- 22931620 TI - [Effect of perioperative intestinal probiotics on intestinal flora and immune function in patients with colorectal cancer]. AB - OBJECTIVE: To investigate the effect of perioperative application of intestinal probiotics to substitute oral intestinal antimicrobial agents on intestinal flora and immune function in surgical patients with colorectal cancer. METHODS: Sixty patients with colorectal cancer undergoing elective laparoscopic radical surgery were randomized to receive preoperative bowel preparation using oral intestinal antimicrobial agents (n=20) or using oral intestinal probiotics (Jinshuangqi Tablets, 2.0 g, 3 times daily) since the fifth day before the operation and at 24 h after the operation for 7 consecutive days. Upon admission and 7 days after the operation, fecal samples and fasting peripheral venous blood were collected from the patients to examine the intestinal flora and serum levels of interleukin-2 (IL-2), IgA, IgG, and IgM, NK cell activity, T lymphocytes subsets CD3(+), CD4(+), CD8(+) and CD4(+)/CD8(+) ratio. RESULTS: At 7 days after the operation, the patients receiving probiotics showed significantly increased counts of intestinal Bifidobacterium, Lactobacillus, and Enterococcus (P<0.05) and significantly lowered counts of Escherichia coli and Staphylococcus aureus (P<0.05). The serum levels of IL-2, IgA, IgG and IgM as well as CD4(+) cell percentage all increased significantly in probiotics group compared with those in patients with conventional intestinal preparation (P<0.05). CONCLUSIONS: Perioperative application of intestinal probiotics to replace preoperative oral intestinal antimicrobial agents can effectively correct intestinal flora imbalance and improve the immune function of surgical patients with colorectal cancer. PMID- 22931621 TI - [Application of tube gastrostomy in radical cystectomy with ileal conduit: a retrospective, comparative study]. AB - OBJECTIVE: To evaluate the clinical results of tube gastrostomy in radical cystectomy and ileal conduit. METHODS: We retrospectively analyzed the data of 98 patients undergoing radical cystectomy and ileal conduit between March 2007 and February 2010. According to postoperative gastrointestinal decompression methods, the patients were divided into nasogastric decompression group (n=50) and tube gastrostomy group (n=48), and the gastrointestinal recovery time, surgical complications and hospital stay were compared between them. RESULTS: No statistical difference was found in gastrointestinal recovery time, hospital stay, or surgical complications between the two groups, but the incidence of pulmonary infection was significantly lower in tube gastrostomy group than in nasogastric decompression group (P<0.05). CONCLUSION: Tube gastrostomy is an easy, safe and effective means for gastric decompression after radical cystectomy with ileal conduit, especially suitable for elderly patients and those with potential pulmonary disorder. PMID- 22931622 TI - [Slow anti-epileptic drug taper protocol in video-EEG monitoring for presurgical evaluation of epilepsy]. AB - OBJECTIVE: To evaluate the efficacy and safety of slow anti-epileptic drug (AED) taper protocol and a rescue benzodiazepine protocol in video electroencephalography (video-EEG) monitoring for presurgical evaluation of epilepsy. METHODS: Sixty-two of 109 patients with refractory focal epilepsy underwent pre-surgical video-EEG monitoring with a slow AEDs taper protocol and a rescue benzodiazepine protocol. Seizures were recorded by video-EEG in 56 patients. The time to the first seizure, duration of monitoring, incidence of 4-h and 24-h seizure clustering, secondarily generalized tonic-clonic seizures (sGTCS), status epilepticus, falls and cardiac asystole were evaluated. RESULTS: A total of 191 seizures were recorded in the 56 cases, and the diagnostic efficiency of video-EEG was 90.3%. The mean time to the first seizure was 2.4 days and the time to conclude video-EEG monitoring averaged 6.8 days. Eight (12.9%) patients had 4-h clusters and 24 (38.7%) had 24-h clusters. Seizure clusters were more frequent in extra temporal epilepsy than in temporal lobe epilepsy. While 19 sGTCS were recorded in 15 patients (26.8%), status epilepticus did not occur and no seizure was complicated by cardiac asystole. Epileptic falls with no significant injuries occurred in 4 patients. CONCLUSION: Seizure clustering is common during presurgical video-EEG monitoring, but serious adverse events are rare with a slow AED tapering and a rescue benzodiazepine protocols. These two protocols are effective and save in presurgical video-EEG monitoring for refractory focal epilepsy. PMID- 22931623 TI - [Dosimetric study of postoperative 3-dimensional conformal radiotherapy and coplanar decile intensity-modulated radiotherapy for cervical cancer]. AB - OBJECTIVE: To compare the difference of the dose distribution in clinical target volume and organ at risk (OAR) between coplanar decile field intensity-modulated radiotherapy (IMRT) and conventional three-dimensional conformal radiotherapy (3D CRT) for postoperative radiotherapy of cervical cancer. METHODS: Ten postoperative patients with cervical cancer were selected randomly to undergo CT scan and planning target volume (PTV) and OAR contouring. 3D-CRT and coplanar decile IMRT planning was performed for each patient with a prescribed dose of 50 Gy. The homogeneity index (HI), conformity index (CI), maximum dose, minimum dose, mean dose of PTV, and irradiated volume of OARs were calculated and the results were compared. RESULTS: 5-field IMRT, 7-field IMRT and 9-field IMRT plans had a significant better conformity index (CI) of PTV compared with 3D-CRT (P<0.05) . Compared with 3D-CRT plans , V30, V40, and V50 of the bladder, V50 of the small bowel, and V30, V40, and V50 of the rectum in the coplanar decile IMRT plans were all significantly reduced (P<0.05) but showed no significant differences among the IMRT plans (P>0.05). CONCLUSION: Coplanar decile IMRT plans is superior to 3D-CRT plan in terms of the conformity index (CI) of the PTV and sparing the bladder, rectum and small bowel. Seven-field and 9-field IMRT do not warrant more benefits than 5-field IMRT, and the latter can significantly reduce the treatment time and costs. PMID- 22931624 TI - [Cutaneous and subcutaneous phaeohyphomycosis caused by Exophiala jeanselmei after renal transplantation: a case report]. AB - OBJECTIVE: We report a case of cutaneous and subcutaneous phaeohyphomycosis caused by Exophiala jeanselmei after renal transplantation in Guangdong. A 66 year-old man who had a renal transplantation 6 years ago was admitted in October 2011 for the presence of 16 nodules (0.5-1.5 cm) found on his right middle finger, wrist and forearm for 5 months. Microscopic examination of the purulent exudate showed segmented and branched brown mycelium, and tissue biopsy and PAS staining showed fungal hyphae. The isolate was processed for morphological identification and molecular sequence analysis. A black colony was found after culture of the isolate on SDA at 26 degrees Celsius;, and small culture identified the isolate as Exophiala jeanselmei. ITS sequence analysis of the isolate showed a 100% homology with Exophiala jeanselmei. E-test strip was used in drug sensitivity test, and the isolate was sensitive to amphotericin B, voriconazole, itraconazole and fluconazole, but resistant to 5-flucytosine and caspofungin. Good response was obtained with surgical intervention, local injection and systemic antifungal treatment. PMID- 22931625 TI - [Effect of hydrogen inhalation on p38 MAPK activation in rats with lipopolysaccharide- induced acute lung injury]. AB - OBJECTIVE: To investigate the effect of hydrogen inhalation on lipopolysaccharide (LPS)-induced acute lung injury (ALI) and the underlying molecular mechanisms. METHODS: Thirty-two male SD rats were randomly divided into 4 groups (n=8), namely the normal saline group (SA), saline with 2% hydrogen gas inhalation group (SH group), ALI group, and ALI with hydrogen inhalation group (LH group). In the two ALI groups, ALI was induced by intraperitoneal injection of 15 mg/kg LPS. Treatments with inhalation of 2% hydrogen gas for 6 h was administered after the injection of LPS or saline. The concentrations of tumor necrosis factor-alpha (TNF-alpha) in the lung tissue and serum were examined with ELISA. The expression of p38 MAPK in the lung tissue was detected by Western blotting.. RESULTS: Hydrogen inhalation decreased the expression of p-p38 MAPK in the lung tissue, and significantly reduced TNF-alpha content in the lung tissue and serum of rats with ALI. CONCLUSION: Hydrogen inhalation can decrease the expression of TNF alpha in the lung tissue and serum, and this effect may be related with reduced p38 MAPK expression and inhibition of p38 MAPK activation. PMID- 22931626 TI - [Microsurgical management of intracranial giant aneurysms]. AB - OBJECTIVE: To study the surgical timing, strategy and outcome of intracranial giant aneurysms. METHODS: The clinical and surgical data of 15 cases of intracranial giant aneurysms treated between January, 2001 and January, 2010 were analyzed. Aneurysm clipping was performed in 8 cases, aneurysm trapping with extracranial-intracranial (EC-IC) bypass in 1 case, parent artery occlusion with EC-IC bypass using great saphenous vein graft in 3 cases, aneurysm resection with aneurysm wall suture in 1 case, and exclusive aneurysm trapping in 2 cases. RESULTS: Deaths occurred in 2 (13%) of the cases. Good surgical outcomes were achieved in 12 cases (80%), and poor outcome was found in 1 case (7%) after the surgery. CONCLUSION: Individualized surgical planning is suggested for microsurgical management of intracranial giant aneurysms, and the operation should be performed by surgeons having sufficient microsurgical experience and capable of vessel reconstruction. PMID- 22931627 TI - [Effect of epidural analgesia on the duration of labor stages and delivery outcome]. AB - OBJECTIVE: To assess the effect of epidural analgesia on the duration of labor stages and the delivery outcome. METHODS: This prospective study was conducted in 328 nulliparous term parturients presenting for delivery in December 1 to 31, 2011. The parturients were assigned into epidural analgesia group (n=162) and control group (n=166) according to their request when no contraindications were present. The stage I, stage II, and total duration of labor, volume blood loss, oxytocin use, delivery mode, and neonatal outcomes were compared between the two groups. RESULTS: In epidural analgesia group, the duration of stage I and stage II labor and the total duration of labor was 497.9?168.4 min, 54.3?43.8 min, and 522.1?178.9 min, respectively, significantly longer than those in the control group (404.2?156.0 min, 31.5?19.8 min, and 435.8?159.2 min, respectively, P<=0.05). No significant difference was found between the two groups in the rates of oxytocin use, emergency cesarean section, instrumental delivery, meconium stained amniotic fluid, and low Apgar scores (P>=0.05). CONCLUSION: Epidural analgesia prolongs the labor duration, especially the second stage of labor, but it does not increase the incidences of emergency cesarean section or instrumental delivery or cause adverse effect on the neonatal outcome, and is therefore safe for pain relief in labor. PMID- 22931628 TI - [Effect of extubation time of indwelling urinary catheters on postoperative recovery after cesarean section]. AB - OBJECTIVE: To study the effect of extubation time of indwelling urinary catheters on postoperative recovery after cesarean section. METHODS: A total of 138 parturients undergoing elective cesarean delivery were randomized into experimental group and control group to have the urinary catheters removed at 6-8 h and 24 h after cesarean section, respectively. RESULTS: Compared with the control group, the experimental group showed significantly decreased incidences of urinary tract infection and urethral irritation (P<0.05), with also a significantly increased rate of autonomous urination and a higher degree of comfort (P<0.05) after removing the catheter. CONCLUSION: A shortened indwelling time of urinary catheters can promote postoperative recovery after cesarean section. PMID- 22931629 TI - Biofilm production in oral Candida isolates from HIV-positive individuals from Pune, India. AB - Biofilm formation is implicated as a potential virulence factor in Candida species and carries important clinical repercussions because of their increased resistance to antifungal treatment, ability to withstand host defences and to serve as a reservoir for continuing infections. The present study was undertaken to determine the biofilm production among oral Candida isolates from HIV-positive and HIV-negative individuals from Pune, India. Biofilm formation was determined using the spectrophotometric or microtitre plate method in 182 Candida isolates, of which 154 were from HIV-positive and 28 were from HIV-negative individuals. A total of 63.2% of the Candida isolates were biofilm producers. Significantly increased biofilm forming abilities both qualitatively as well as quantitatively were observed in Candida isolates from HIV-positive individuals (66.2%) compared to isolates from HIV-negative ones (46.4%), (P- 0.041). Eighty-one (59.6%) C. albicans isolates and 34 (73.9%) non -C. albicans Candida (NCAC) showed biofilm positivity. The NCAC showed significantly greater intensity of biofilm formation compared to the C. albicans, P- 0.032. Our results thus show the enhanced biofilm forming abilities of oral Candida isolates from HIV-infected individuals compared to HIV-uninfected ones and highlight the important role played by biofilm formation in the pathogenesis of NCAC isolates. PMID- 22931630 TI - The added-up albumin enhances the diuretic effect of furosemide in patients with hypoalbuminemic chronic kidney disease: a randomized controlled study. AB - BACKGROUND: Chronic kidney disease (CKD) with edema is a common clinical problem resulting from defects in water and solute excretion. Furosemide is the drug of choice for treatment. In theory, good perfusion and albumin are required for the furosemide to be secreted at the tubular lumen. Thus, in the situation of low glomerular filtration rate (GFR) and hypoalbuminemia, the efficacy of furosemide alone might be limited. There has been no study to validate the effectiveness of the combination of furosemide and albumin in this condition. METHODS: We conducted a randomized controlled crossover study to compare the efficacy of diuretics between furosemide alone and the combination of furosemide plus albumin in stable hypoalbuminemic CKD patients by measuring urine output and sodium. The baseline urine output/sodium at 6 and 24 hours were recorded. The increment of urine output/sodium after treatment at 6 and 24 hours were calculated by using post-treatment minus baseline urine output/sodium at the corresponding period. RESULTS: Twenty-four CKD patients (GFR = 31.0 +/- 13.8 mL/min) with hypoalbuminemia (2.98 +/- 0.30 g/dL) were enrolled. At 6 hours, there were significant differences in the increment of urine volume (0.47 +/- 0.40 vs 0.67 +/- 0.31 L, P < 0.02) and urine sodium (37.5 +/- 29.3 vs 55.0 +/- 26.7 mEq, P < 0.01) between treatment with furosemide alone and with furosemide plus albumin. However, at 24 hours, there were no significant differences in the increment of urine volume (0.49 +/- 0.47 vs 0.59 +/- 0.50 L, P = 0.46) and urine sodium (65.3 +/- 47.5 vs 76.1 +/- 50.1 mEq, P = 0.32) between the two groups. CONCLUSION: The combination of furosemide and albumin has a superior short-term efficacy over furosemide alone in enhancing water and sodium diuresis in hypoalbuminemic CKD patients. TRIAL REGISTRATION: The Australian New Zealand Clinical Trials Registration (ANZCTR12611000480987). PMID- 22931631 TI - NK/T-cell lymphoma of bilateral adrenal glands in a patient with pyothorax. AB - Primary lymphoma of adrenal glands is rare, and non-B-cell lymphoma associated with pyothorax is also very rare. Here we report the first autopsy case of non-B cell lymphoma in bilateral adrenal glands of a 79-year-old woman with pyothorax who had an aggressive clinical course. Immunohistochemically, tumor cells showed CD3+, CD45RO+, CD5-, CD7-, CD4-, CD8-, CD10-, CD20-, CD30-, CD79a-, CD138-, CD56 , granzyme B-, TIA-1+ and ALK-. In addition, tumor cells were strongly EBER1 positive by in situ hybridization. In genomic DNA of tumor cells, T-cell receptor rearrangements were not detected by southern blotting. We finally diagnosed this case as extranodal NK/T-cell lymphoma (nasal type). Virtual slides: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/8050621197741854. PMID- 22931632 TI - [Clinical significance of CD34(+)CD38(+) and CD34(+)CD38(low/-) subgroups in bone marrow of patients with B lymphoblastic leukemia]. AB - This study was purpose to investigate the biological characteristics of B lymphoblastic leukemia (B-ALL) between CD34 positive CD38 positive (CD34(+)CD38(+)) and CD34(+)CD38(low/-) subgroups and their clinical significance. Immunophenotyping of B cells in bone marrow of 54 patients with newly diagnosed CD34(+)B-ALL were analyzed by 4 color multiparametric flow cytometry (FCM). According to the different expression of CD38, the newly diagnosed patients with B-ALL were divided into two groups: CD34(+)CD38(+) subgroup and CD34(+)CD38(low/-) subgroup. BCR-ABL, TEL-AML1 fusion genes and WT1 gene were detected by real time RT-PCR simultaneously. After chemotherapy, minimal residual disease (MRD) was monitored by one tube of 7 color FCM. The average follow-up time was 12 months (range 1 - 28), the average follow-up interval was 2 months (range 1 - 5). The results showed that there was no significant differences such as WBC, Plt count and Hb level between the two groups at diagnosis, the positive rate of BCR-ABL, TEL-AML1 and WT1 gene was also no significantly different. After clinical complete remission (CR), MRD positive (MDR(+)) case rates were 28.57% (10/35) in CD34(+)CD38(+) subgroup and 68.42% (13/19) in CD34(+)CD38(low/-) subgroup (P < 0.01). The relapse rate between the two groups was 5.71% (2/35) in CD34(+)CD38(+) subgroup (relapse time at 94 and 245 d respectively) and 36.84% (7/19) in CD34(+)CD38(low/-) group [median relapse time was 263 d (range 46 - 468), P < 0.01]. The age distribution was analyzed in these two subgroups (> 16 or <= 16 years old), there was 8 (8/35) adult patients (> 16 years old) in CD34(+)CD38(+)group and 10 (10/19) adult patients in CD34(+)CD38(low/-) group (P < 0.05). It is concluded that CD34(+)CD38(low/-) phenotype is more often presented in adult patients and the CD34(+)CD38(low/-) patients with B-ALL are more likely to have MRD(+)and relapse after treatment. PMID- 22931633 TI - [Immunophenotypic analysis of leukemia promyelocytes in 71 patients with acute promyelocytic leukemia]. AB - This study was purpose to investigate the immunophenotype of leukemia promyelocytes (LP) and its significance through retrospective analysis of LP immunophenotype and data in new diagnosis of patients with acute promyelocytic leukemia (APL). The immunophenotype of leukemia cells in 71 APL patients was analyzed by means of 6 color immunotyping. The results indicated that MPO, CD33 and CD13 were consistently expressed in leukemia cells of all APL cases with highest average percentages (> 88%) of positive cells among all studied markers. CD117 was found to be positive in 50.7%, and its average percentage of positive cells was 52.5%. Leukemia cells in about 10% cases expressed CD15 weakly, and its average percentage of positive cells was 42.5%. CD34 and HLA-DR showed decreased expressions in a small number of cases and were negative in the others. CD2 and CD56 were weakly expressed in nearly 25% APL cases, and the average percentage of positive cells were 39.3% and 42.3%, respectively. Thereby, it is of the opinion that the typical immunophenotype is characterized by MPO(+)CD13(+)CD33(+)CD117(+/ )CD15(+/-)CD34(-)HLA-DR(-) in APL. CD2 and CD56 were expressed significantly higher in CD34(+) or HLA-DR(+) group (including CD34(+) HLA-DR(+), CD34(+) HLA DR(-) and CD34(-)HLA-DR(+)) than in CD34(-) and HLA-DR(-) group. Significant differences were also found in WBC and platelet counts, percentage of peripheral blood leukemic promyelocytes and the expression of CD13 among CD15 < 10%, 10% < CD15 < 20% and CD15 > 20% groups. It is concluded that the APL has a characteristic immunophenotypic profile, flow cytometric immunophenotyping may be considered as a useful tool for rapid recognition of APL and also may be considered to have an important significance for analysing origin of leukemic cells and clinical outcome of patients. PMID- 22931634 TI - [Expression characteristics of isoforms of Ikaros and Helios in patients with leukemia and their mechanism]. AB - This study was aimed to investigate the expression characteristics of two transcriptional factors in Ikaros family, Ikaros and Helios isoforms and their mechanism, as well as their correlation with clinical parameters, which play important roles in transcriptional regulation of hematopoiesis. Expression of Ikaros and Helios isoforms in a total of 163 patients with leukemia and correlations between Ikaros and Helios isoforms were analyzed by PCR. The results showed that different expression patters of Ikaros and Helios isoforms existed in leukemia patients, that is, Ikaros isoform (Ik-6) was predominantly expressed in acute lymphoblastic leukemia (ALL) with BCR/ABL fusion gene, while Helios isoform (He-i) was overexpressed in T-cell ALL patients. The results of cloning and sequencing demonstrated that the isoforms of Ikaros and Helios had different genetic alterations. The statistical correlation between these two isoforms not was found in this study, although interaction between Ikaros and Helios has been reported. It is concluded that although Ikaros and Helios belong to the same family with similar structure of zinc fingers, their isoforms have different expression profile, specific genetic alterations, and different clinical relevance in patients with leukemia. The connection and interaction between Ik-6 and He-i needs further research. PMID- 22931635 TI - [Direct contact with bone stromal HS-5 cells reduces the sensitivity of HEL to drugs]. AB - This study was proposed to investigate the sensitivity and resistence of HEL cells co-cultured with bone marrow stromal HS-5 cells to chemotherapeutic drugs. HEL cells were cultured in direct contact with HS-5 cells for 6, 12, and 24 h. Cell Counting Kit-8 (CCK-8) was used to determine the sensitivity of HEL cell to cytarabine, methotrexate, VP16, and daunomycin. Cell cycle distribution was determined by using flow cytometry. Real-time RT-PCR was performed to detect the transcription levels of p19, p21, p27, MDR1, ABCG2 and bcl-2. Western blot was performed to determine the protein levels of p-Akt(Ser473), p-glycogen synthase kinase 3beta (p-GSK3beta(Ser9)), p-signal transducer and activator of transcription (p-STAT3(Tyr705)), Bcl-2, cleaved-Notch1(V1754), and Hes1. The results showed that chemo-sensitivity of HEL cells was remarkably reduced when co cultured with HS-5 cells. HEL cells were arrested in the G(0)/G(1) phase after co culture for 24 h. Transcription of p21 was significantly up-regulated at 6 h. Transcription of p19 decreased at 12 h and returned to baseline at 24 h. No significant changes in the mRNA expression of other genes were found. The expressions of p-Akt(Ser473), p-GSK3beta(Ser9), cleaved-Notch1(V1754) and Bcl-2 proteins were significantly up-regulated in HEL cells, and Hes1 protein was significantly down-regulated. There was no change in p-STAT3(Tyr705) expression. It is concluded that the direct contact with HS-5 cells can reduce the chemo sensitivity of HEL cells. PMID- 22931636 TI - [Morphologic diagnosis and onset characteristics of acute leukemia: a retrospective analysis of 233 cases in 10 years]. AB - The objective of this study was to evaluate the value of morphologic diagnosis for acute leukemia (AL), to explore the relation of morphologic diagnosis with immunology, cytogenetics and molecular biology diagnosis of AL and to analyze the onset characteristics of AL in 10 years. The samples of bone marrow and peripheral blood from 233 newly diagnosed cases of AL were collected during 2001 2011 years; the morphologic examination and immunologic, cytogenetic and molecular biologic examination (ICM) were carried out, the consistency of morphologic diagnosis with ICM diagnosis was compared, the onset characteristics of AL was analyzed. The results showed that: (1) the consistent rate of immunology, cytogenetics, molecular biology diagnosis with morphologic diagnosis was 84.3%. The order of consistent rat was AUL, M0 < M1 < HAL < M4 < M2 < M3 < M5 < ALL < M6, M7, AP; (2) Misdiagnosis always occurred among AUL, M0, M1, ALL and HAL or among M2a, M3v, M4 and M5. (3) In 233 cases, the highest ratio of blast was observed in M1 (92.5%), while the lowest ratio of blast was observed in M2 (49.5%). (4) AL occurred more frequently in males than that in female (147:86). (5) AL occurred in patients aged from 1 to 88 years. The median age was 41.5 for AUL, 40.8 for M0, 43.4 for M1, 46.3 for M2, 33.8 for M3, 42.6 for M4, 48.8 for M5, 77.3 for M6, 2.5 for M7, 65.0 for AP, 29.1 for ALL and 40.3 for HAL. (6) The number of patients in the later five years (139 cases) was significantly greater than that in the first five years (94 cases), especially the patients with M1, M2, M3, M4, and M5. It is concluded that morphologic diagnosis has important clinical value in the MICM diagnosis of AL. Attaching importance to the confusing cell morphology and onset characteristics of AL can improve the diagnostic accuracy. PMID- 22931637 TI - [Effect of mPGES-1 inhibitor MK886 on apoptosis and drug resistance of HL-60/A cells]. AB - This study was aimed to investigate the effect of MK886, a mPGES-1 inhibitor, on apoptosis and drug resistance of leukemia HL-60/A cell line. Expression of mPGES 1 was assayed by QT-PCR and Western blot. The effect of MK886 on HL-60/A cell proliferation was assayed by CCK-8 method, and flow cytometry was used to detect cell apoptosis. The expression of Akt and P-Akt was detected by Western blot. PGE2 was measured by ELISA. Effect of MK886 (10 umol/L) on the chemotherapeutic sensitivity of HL-60/A cells and expression of mdr-1 mRNA and P170 protein were investigated too. The results indicated the expression of mPGES-1 was higher in HL-60/A cells. MK886 inhibited HL-60/A cell proliferation and induced apoptosis in a time- and concentration-dependent manner. Expression of mPGES-1 and P-Akt and synthesis of PGE2 decreased significantly. MK886 reduced expression of mdr-1 and P170 protein and enhanced the sensitivity of HL-60/A cells to chemotherapeutic drugs. It is concluded that MK886 can inhibit HL-60/A cell proliferation, induce apoptosis and enhance sensitivity to chemotherapeutic drugs, the mechanism of which possibly associates to down-regulation of mPGES 1/PGE2 synthesis, reduction P-Akt expression and decreasing mdr-1 and P170 protein expression. PMID- 22931638 TI - [Effect of knocking down eEF1A1 gene on proliferation and apoptosis in Jurkat cells and its mechanisms]. AB - This study was purposed to investigate the effect of knocking down eukaryotic elongation factor 1A1 (eEF1A1) gene on the proliferation and apoptosis in human acute T lymphocytic leukemia (T-ALL) cell line Jurkat and explore its mechanism. The eEF1A1 mRNA and protein expressions of Jurkat cells and 3 healthy adult peripheral blood mononuclear cells (PBMNC) were detected by real time PCR and Western blot, respectively. eEF1A1-shRNA lentivirus was constructed through molecular biological method, and was used to transfect Jurkat cells. Then, cell eEF1A1 mRNA and protein expressions were detected by real time PCR and Western blot, respectively. Cell proliferation, apoptosis and cycle were detected by MTT method, Annexin V-APC labeling and DNA ploidy analysis, respectively. Cell related protein expressions of phosphatidylinositol-3-kinase (PI3K)/serine/threonine kinase (Akt) signaling pathway were detected by Western blot. The results showed that eEF1A1 mRNA and protein expression levels of Jurkat cells were significantly higher than that of healthy adult PBMNC, respectively (P < 0.01, P < 0.05). eEF1A1 mRNA and protein expressions of Jurkat cells were significantly knocked down by constructing eEF1A1-shRNA lentivirus. Compared to negative control group (transfected with negative control-shRNA lentivirus), cell proliferation in eEF1A1-shRNA group was significantly inhibited, cell apoptosis was remarkably induced, cell cycle was blocked in G(0)/G(1) phase, and the expression levels of p-Akt (Ser 473), nuclear factor kappa B (NF-kappaB), p-NF kappaB (Ser 468), mammalian target of rapamycin (mTOR) and p-mTOR (Ser 2448) proteins were significantly reduced. It is concluded that eEF1A1 may be a putative oncoprotein in T-ALL cells. Knocking down eEF1A1 gene has noticeable effects on the proliferation inhibition and apoptosis induction of Jurkat cells, which may be mediated by the down-regulation of PI3K/Akt/NF-kappaB and PI3K/Akt/mTOR signaling pathway. PMID- 22931639 TI - [Leukemia SH-1 cells purged by ZnPcH(1)-based photodynamic therapy]. AB - The objective of this study was to investigate the effect of a novel Zinc phthalocyanine (ZnPcH(1)) based photodynamic therapy (PDT) on acute monocytic leukemia cell lines SHI-1 and its mechanism, so as to provide theory basis for bone marrow purging in vitro for patients with leukemia. The killing effect of ZnPcH(1)-PDT on SHI-1 cells were assessed by MTT method; the SHI-1 cell death patterns were analyzed by AO/EB fluorescence staining, TdT-mediated dUTP nick end labeling (TUNEL), DNA ploidy analysis, and Annexin V-FITC/PI double staining.Cell mixture was established by integrating SHI-1 cells with normal bone marrow MNC (by 1:100-1:10 000). Purging effect of ZnPcH(1)-PDT against SHI-1 mixed into normal MNC was assessed by analyzing the expression of fusion gene MLL/AF6 mRNA using nested RT-PCR. The results showed that ZnPcH(1)-PDT could effectively inhibit SHI-1 cell proliferation in dose-dependent manner, and ZnPcH(1)-PDT could induce cell apoptosis in time-dependent manner. 0.5 umol/L ZnPcH(1)-PDT could completely photoinactivated kill SHI-1 cells in the simulated remission bone marrow. It concluded that ZnPcH(1)-PDT may be a effective and convenient promising purging technique for leukemia. PMID- 22931640 TI - [Molecular mechanism of HL-60 cell apoptosis induced by baicalin]. AB - This study was aimed to investigate the effect of baicalin on proliferation and apoptosis of HL-60 cells and its mechanism. Cell proliferation was assayed by using Cell Counting Kit-8. The morphological changes of HL-60 cells were examined by light microscopy and nucleolus morphological changes were observed by fluorescent microscopy after Hoechst 33342 staining. The early cell apoptosis was detected by using flow cytometry with Annexin V-FITC/PI double staining. The expression of caspase-3, caspase-9, Bcl-2 and Bax mRNA was detected by RT-PCR and Western blot assay was carried out to examine Bax, Bcl-2, caspase-8 and cleaved caspase-3 expression. The results showed that Baicalin inhibited the proliferation of HL-60 cells in a time- and concentration-dependent manner. HL-60 cells exhibited typical morphological features (for example, cell shrinkage, membrane blebbing and formation of apoptotic bodies). Cell apoptosis in early stage could be detected, the expression of caspase-3, caspase-9 and Bax mRNA was obviously up-regulated, while the Bcl-2 expression down-regulated, and accordingly Bcl-2/Bax ratio decreased. Such results were consistent with the expression of these proteins. In addition, the expression of cleaved caspase-8 protein was induced significantly after treated with baicalin. It is concluded that baicalin can significantly inhibit the proliferation of HL-60 cells and induce the apoptosis of HL-60 cells, which may occur through decreasing Bcl-2/Bax ratio by intrinsic pathway and through extrinsic pathway. It suggests that baicalin may be a promising drug for the therapy of acute myeloid leukemia. PMID- 22931641 TI - [Establishment and application of a novel method for detecting MLL fusion genes of acute leukemia]. AB - This study was aimed to establish an efficient method to detect 10 common MLL fusion genes in patients with acute leukemia. Firstly, the relevant references and databases were searched to thoroughly investigate all fusion breakpoints; the primers and probes were designed according to nearly all the involved fusion types of gene. Then the multiplex real-time PCR system was established and optimized by using the established 16 positive plasmids and negative cell lines. Finally, the detection system was clinically evaluated by means of collected 54 samples of leukemia. The results indicated that the established detection system could efficiently detect all positive plasmids with sensibility to 10 copies. Four kinds of fusion gene types such as MLL-AF4, MLL-AF9, MLL-AF10, MLL-ELL could be detected in 54 samples, the sequencing of positive samples showed consistency of sequencing results with detection results. It is concluded that a novel multiplex real-time PCR detection method is established which can detect 10 common MLL fusion genes covering about 90% of the cases harboring MLL fusions. This method is fast, sensitive, specific and reliable, and should be an useful clinical tool for identification and management of leukemia patients with MLL fusions. PMID- 22931642 TI - [Significance and application value of multiparameter flow cytometry for differentiation of immunophenotype in chronic myelomonocytic leukemia, myelodysplastic syndrome and acute monocytic leukemia]. AB - This study was purposed to analyse the immunophenotypic characteristics of chronic myelomonocytic leukemia (CMML), myelodysplastic syndromes (MDS) and acute monocytic leukemia (AML-M5b) by using multiparameter flow cytometry, and to explore its significance in diagnosis and differential diagnosis. The immunophenotypic characteristics of bone marrow samples from 14 CMML patients, 48 MDS patients, 46 AML-M5b patients and 18 normal persons were analyzed and compared by multiparametric flow cytometry. The results showed that the ratio of monocytes in CMML patients was obviously higher than that in MDS, AML-M5b patients and normal persons (P < 0.05), but there was no statistically significant difference between bone marrow samples of MDS and AML-M5b patients as well as normal persons. The ratio of blast cells in MDS patients was obviously higher than that in normal persons (P < 0.05), but did not show significant difference as compared with CMML patients. The ratio of mature granulocytes in AML-M5b patients was obviously lower than that in CMML and MDS patients as well as normal person bone marrow (P < 0.05). Certain differences of CD45/SSC characteristics in MDS, AML-M5b and CMML patients were found in comparison with normal persons. The abnormal expression of CD2, CD56, and CD14 tailing phenomenon were observed in CMML patients in comparison with bone marrow samples of MDS, AML M5b and normal persons (P < 0.05). Lack and decrease of CD15 expression in MDS and CMML patients was significant different from AML-M5b and normal persons marrow, abnormal expression rate of CD15 in CMML patients was higher than that in MDS patients (P < 0.05), the CD13/CD11b/CD16 abnormal expression of granulocytes was seen in both CMML and MDS patients, but there was no statistically significant difference between them. Other antigens showed abnormality of varying degrees, but did not have any statistical significance. It is concluded that MDS, CMML and AML-M5b displayed a certain degree of similarity, and also possess their own immunophenotype characteristics. Comprehensive analysis of immunophenotype by multiparameter flow cytometry may be important for differential diagnosis among CMML, MDS and AML-M5b. High percentage of monocytes, abnormal coexpression of CD2, CD56 and CD14 tailing phenomenon, lack or decrease of CD15 as well as abnormal expression of CD13/CD11b/CD16 in granulocytes may play important roles in diagnosis of CMML. PMID- 22931643 TI - [Effects of hyperbaric oxygenation combined with As(2)O(3) on proliferation of K562 cells and associated mechanism]. AB - This study was aimed to explore the effects of hyperbaric oxygenation (HBO) alone or combined with As(2)O(3) on proliferation, apoptosis and expression of HIF-1a, VEGF, caspase-3 mRNA of K562 cells, and the molecular mechanism of As(2)O(3) enhancing the anti-leukemic effect of HBO so as to provide a scientific basis for clinical treatment of chronic myeloid leukemia. The effects of drugs on proliferation of K562 cells was assayed by MTT method, the apoptosis rate of K562 cells was detected by flow cytometry with Annexin V/PI double staining, the expressions of HIF-1a, VEGF, caspase-3 mRNA of K562 cells were determined by real time quantitative PCR. The results showed that as compared with As(2)O(3) alone, HBO combined with As(2)O(3) could increase inhibitory rate of K562 cell proliferation, and enhance apoptotic effect, obviously down-regulate expressions of HIF-1a and VEGF mRNA, up-regulate expression of caspase-3 mRNA. The effect of HBO combined with As(2)O(3) was higher then effect of As(2)O(3) alone, and their effects were synergistic (P < 0.05). It is concluded that HBO combined with As(2)O(3) can increase the expression of caspase 3 mRNA and decrease the expression of HIF-1a and VEGF mRNA, which may be one of molecular mechanisms underlying their synergistic antileukemia efficacy. PMID- 22931644 TI - [CML cell apoptosis induced by AMN107 combined with heme oxygenase-1 inhibitor]. AB - This study was aimed to investigate the effect of AMN107 (nilotinib) combined with heme oxygenase-1 (HO-1) inhibitor zinc protoporphyrin IX (ZnPPIX) on chronic myeloid leukemia (CML) cells and its mechanism. Proliferative rate of cells treated with AMN107 (10 umol/L) and ZnPPIX (10 umol/L) alone or both for different time was observed by MTT and trypan blue methods; the expression of HO 1 in the control group, ZnPPIX (10 umol/L) group, AMN107 (10 umol/L) group, AMN107 (10 umol/L) combined with ZnPPIX (10 umol/L) group was evaluated by semi quantitative RT-PCR and Western blot at 48 h. Cell apoptosis was detected by flow cytometry with Annexin V/PI double staining at 48 h. The results showed that the strongest inhibition of cell proliferation was detected in combined group, and in a time-dependent manner; the expression level of HO-1 was lowest in combined group; the cell apoptosis rates were (11.38 +/- 0.02)%, (17.44 +/- 0.08)%, (39.81 +/- 0.07)% and (56.46 +/- 0.19)% in the control group, ZnPPIX group, AMN107 group, AMN107 combined with ZnPPIX group at 48 h respectively. It is concluded that the second-generation tyrosine kinase inhibitor AMN107 can induce the apoptosis in CML cells. Inhibition of HO-1 expression can enhance the killing effect of AMN107 on CML cells, which provides experimental evidence to further improve the clinical efficacy of CML treatment. PMID- 22931645 TI - [Influence of polypeptide extract from scorpion venom on PI3K and p-Akt signaling protein expression and cell proliferation of K562 cells]. AB - This study was aimed to investigate the effect of polypeptide extract from scorpion venom (PESV) on PI3K, p-Akt signal protein regulating K562 cell apoptosis and its mechanism. The K562 cells were cultured with PESV for different time, the cell growth curve was determined by MTT method, the levels of PI3K and p-Akt proteins were detected by Western blot. The results showed that as compared with control group, the apoptosis rate of K562 cells treated with PESV increased, the levels of PI3K and p-Akt expression decreased. It is concluded that the PESV inhibits the proliferation and promotes the apoptosis of K562 cells probably through suppressing the expression of PI3K and p-Akt signal proteins. PMID- 22931646 TI - [Thiopurine S-methyltransferase gene sequence analysis of ALL children severely intolerant to 6-mercaptopurine]. AB - This study was aimed to analyze the thiopurine S-methyltransferase (TPMT) gene sequence in acute lymphoblastic leukemia (ALL) children severely intolerant to 6 mercaptopurine (6-MP) and to investigate the causes resulting in tolerance difference to 6-MP in ALL children so as to provide evidence for safe and rational use of 6-MP. The adverse reactions of drug was evaluated in ALL children treated with BCH-2003-ALL chemotherapeutic protocol during 2004-10-1 to 2007-9-30 according to NCI-CTC V2.0. The TPMT gene sequences of ALL children with 3-4 grade of severe toxicity during the maintenance therapy were analyzed by PCR and direct DNA sequencing. To assure the accuracy of sequencing, the 738 bp fragment of coding region in TPMT gene (NM_000367) was divided into 3 subfragments and bidirectionally sequenced. The results indicated that among 133 ALL children, 61 were severely intolerant to 6-MP. The direct DNA sequencing showed that among 59 patients (excluding 2 cases without RNA samples), the simple myelotoxicity was found in 37 cases, hepato-myelotoxicity was observed in 9 cases, hepatotoxicity along appeared in 12 cases, 1 case showed skin rash. Out of 59 ALL children, the C474T mutation was found in 57 cases, with mutation rate 96.6%, including 21 cases with heterozygous mutation and 36 cases with homozygosis mutation. The TPMT gene sequencing of 10 cases tolerant to 6-MP indicated that C474T mutation was detected in 8 cases which was homozygous mutation. It is concluded that the C474T mutation in 738 bp fragment of coding region in TPMT gene is very frequent, but it is not related with tolerance to 6-MP, suggesting that severe intolerance to 6 MP in ALL children may be not related with the mutation of coding region in TPMT gene. PMID- 22931647 TI - [Effect of astragalus polysaccharide on sensitivity of leukemic cell line HL-60 to NK cell cytotoxicity and its mechanism]. AB - The objective of this study was to explore the effect of astragalus polysaccharide (APS) on sensitivity of leukemic cell line HL-60 to NK cell cytotoxicity and its mechanism. The cytotoxicities of NK cells against HL-60 cells were analyzed by LDH releasing assay at different effect-to-target cell ratios (E:T) before and after treated with APS. The gene expression of MHC class I chain-related (MICA) in HL-60 cells before and after APS treatment was assayed with RT-PCR. Protein expression of MICA in HL-60 cells was assayed by flow cytometry before and after treated by APS. The results showed that after treated with APS 15 mg/ml for 48 h, the cytotoxicities of NK cells against HL-60 cells enhanced at different effect-to-target (P < 0.05), and the gene and protein expressions in MICA of HL-60 cells were up-regulated (P < 0.05). It is concluded that the APS can obviously up-regulate the expression of MICA in HL-60 cells, thus enhance sensitivity of HL-60 cells to cytotoxicity of NK cells. PMID- 22931648 TI - [Effects of IAT and MAT chemotherapeutic regimens in patients with refractory or relapsed acute myeloid leukemia]. AB - The aim of this study was to investigate effects of IAT and MAT chemotherapeutic regimens treating patients with refractory and relapsed acute myeloid leukemia (AML). 99 patients with refractory and relapsed AML received IAT regimen or MAT regimen as study objects were retrospectively analyzed (56 patients with refractory AML and 43 patients with relapsed AML). Among of them, 28 patients were treated with IAT regimen, and 71 patients received with MAT regimen. The results showed that in 2 groups mentioned above the OR was 65.7%, CR was 49.5%, PR was 16.2%; in IAT group the OR was 64.3%, CR was 46.4%; in MAT group the OR was 66.2%, CR was 50.7%, no statistical difference was found between these 2 groups; The 2 years overall survival was 25% in IAT group and 15.5% in MAT group. Serious infection in IAT and MAT regime groups was 25% and 9.9%, respectively. It is concluded that both IAT and MAT regimens are effective methods for inducing CR in patients with refractory of relapsed AML. IAT and MAT regimens can be used in treatment of the refractory or relapsed MAL patients who were not respond to other regimen. PMID- 22931649 TI - [AG490 inhibits the proliferation of K562 and down-regulates protein phosphatase PHLPP expression]. AB - This study was aimed to investigate the effect of AG490, a JAK2 inhibitor, on expression of PHLPP and p-Akt in K562. K562 cells were treated with different concentrations of AG490. The proliferation of K562 cells was examined by WST-1 assay and apoptosis of K562 cells was detected by flow cytometry with Annexin V FITC/PI double staining. The expressions of PHLPP, phosphorate-Akt (p-Akt) and total Akt protein were detected by Western blot. The results indicated that AG490 inhibited the proliferation of K562 cells in concentration-and time-dependent manners, with the IC(50) 338.0 umol/L in 48 h. AG490 100 umol/L also induced apoptosis of K562 cells in a time-dependent manner. AG490 100 umol/L time dependently down-regulated the protein expression of p-Akt and PHLPP, but without significant effect on expression of total Akt. It is concluded that AG490 can inhibit proliferation and induce apoptosis of K562 cells through down-regulation of p-Akt expression, but inhibiting efficacy of AG490 on K562 proliferation also may be limited due to the down-regulation of p-Akt regulatory protein PHLPP expression. PMID- 22931650 TI - [Effect of chidamide on human B lymphoma cell lines and its mechanisms]. AB - This study was aimed to explore the effects of histone deacetylase inhibitor chidamide on the proliferation, apoptosis of B lymphoma cell lines Raji (Burkitt lymphoma), Maver and Z-138 (mantle cell lymphoma) and its mechanisms. Three B lymphoma cell lines were cultured in vitro with different concentrations of chidamide for different time. The cell proliferation was determined by CCK-8 method; the cell apoptosis and mitochondrial membrane potential were analyzed by flow cytometry; the protein levels of histone H3/H4 acetylation in cells and the activity of caspase-3 were detected by Western blot. The results showed that chidamide inhibited the proliferation of 3 B lymphoma cell lines in time- and concentration-dependent manners, especially in Z-138 cell line earlier and faster; chidamide could induce cell apoptosis and decline of mitochondrial membrane potential, which was more sensitive in Maver and Z-138 cells than that in Raji cells. Chidamide could elevate the histone H3/H4 acetylation level in 3 B lymphoma cell lines and the activity of caspase-3 in Maver and Z-138 cells. It is concluded that chidamide can inhibit proliferation of B lymphoma cell lines and promote cell apoptosis, the increase of histone H3/H4 acetylation induced by chidamide, triggering of mitochondrial pathway and activation of caspase-3 may be considered as possible mechanisms. PMID- 22931651 TI - [Construction of a lentiviral vector carrying TRAIL gene and its infection efficiency to lymphoma cells in vitro]. AB - This study was purposed to construct a lentiviral vector carrying the TNF-related apoptosis-inducing ligand (TRAIL) gene and investigate its infection efficiency to several lymphoma cells lines. A pGM-T-TRAIL vector was constructed by inserting the cDNA segment derived from TRAIL mRNA into the cloning vector pGM-T, which was then inserted into the lentiviral vector pWPI. The recombinant lentiviral vector plenti-TRAIL was produced by transfecting 293T cells with pWPI TRAIL, packaging plasmid Delta8.2, and envelope plasmid pCMV-VSVG and then harvested from the culture supernatant. Infection efficiency was measured in several lymphoma cell lines by live cell GFP fluorescence, while TRAIL expression was assessed by RT-PCR and Western blot. The results showed that the enzyme cut identification and sequencing demonstrated the successful construction of both pGM-T-TRAIL and pWPI-TRAIL. The results of testing drop showed that the concentration of the restructured lentiviral plenti-TRAIL reached 10(9) IU/ml. Comparison of infection efficiency revealed that YTS cells were more likely to be infected than DOHH2 or Jurkat cells (P < 0.05). Finally, RT-PCR and Western blot showed that lymphoma cells infected with plenti-TRAIL were able to efficiently express the TRAIL mRNA and protein. It is concluded that the lentiviral vector pWPI-TRAIL is successfully constructed and the recombinant lentiviral plenti TRAIL is manufactured. The plenti-TRAIL vector is able to infect several lymphoma cell lines, and the infected lymphoma cells can effectively express TRAIL genes. PMID- 22931652 TI - [Detection of antigen-receptor gene rearrangement clonality for diagnosis of lymphoma]. AB - This study was aimed to investigate the significance of detecting the antigen receptor gene rearrangement clonality in the diagnosis of lymphoma. Paraffin embedding and HE staining of samples from 31 patients with lymphomas were performed for morphologic observation by light microscope. Immunophenotype was analyzed by the immunohistochemistry (IHC) method. The clonality of antigen receptor gene rearrangement was detected by BIOMED-2 Assay Kit. The results showed that among the 31 cases, 12 cases were suspected to be T-cell lymphoma, 1 case was suspected to be T-cell reactive hyperplasia, and 16 cases were suspected to be B-cell lymphoma, 2 cases were B-cell reactive hyperplasia. The detection results showed that the positivity of Ig gene rearrangement clonality was 94.44% (17/18), the positivity of TCR gene rearrangement clonality was 92.31% (12/13), the other two cases were negative. Finally, 12 cases were diagnosed to be T-cell lymphoma and 17 cases were B-cell lymphoma. The other two cases were reactive lymphoid proliferations. And the positivity rate in the 31 patients with lymphomas was 93%. It is concluded that the detection of antigen-receptor gene rearrangement clonality is a useful assistant method in the diagnosis of lymphoma. PMID- 22931653 TI - [Efficacy of chemotherapy as a first-line treatment in patients with ocular adnexal MALT lymphoma]. AB - The aim of this study was to analyze the efficacy of first-line chemotherapy in treating patients with ocular adnexal extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT). Eight consecutive newly diagnosed ocular adnexal MALT lymphoma patients were treated with chemotherapy, in which 3 patients in stage IE were treated with a combination of cyclophosphamide, vincristine and prednisolone (COP) or cyclophosphamide, adriamycin, vincristine, and prednisolone (CHOP), 5 patients in stage IV were treated with COP/CHOP in combination with rituximab. The results showed that chemotherapy resulted in an overall response rate of 100%, 3 patients in stage IE were in partial remission (PR), 5 patients in stage IV were in complete remission (CR). After a median follow-up of 21 months, 3 patients in stage IE were still in PR status, 5 patients in stage IV were still in CR status, and no relapses or disease progression were observed. It is concluded that the first-line chemotherapy has been confirmed to be effective and well tolerated in patients with localized ocular adnexal MALT lymphoma. Rituximab combined with chemotherapy can increase remission rate, it is feasible option as first-line treatment for ocular adnexal MALT lymphoma. PMID- 22931654 TI - [Cytogenetic abnormality of chromosome 13q14 in 112 patients with multiple myeloma detected by using LSI-RB1 and LSI-D13S319 probes]. AB - Chromosome 13q14 deletion is one of the most common cytogenetic abnormalities in multiple myeloma (MM). LSI (locus-specific identification)-RB1 (13q14.1-14.2 region) and LSI-D13S319 (13q14.3 region) probes are usually used to detect 13q14 deletion. The aims of this study was to compare the incidence of chromosome 13q14.1-14.2 and 13q14.3 deletion and to detect 13q14 deletion size and number of involved cells in MM patients. The chromosome 13q14 region was detected by fluorescence in situ hybridization using probes LSI-RB1 and LSI-D13S319 in plasma cells of 112 MM patients. The results showed that 47.3% (53 out of 112) MM patients had both LSI-RB1 and LSI-D13S319 13q14 deletion (cut-off value: 7%), and the deletion rates detected by probes LSI-RB1 and LSI-D13S319 were accordant. The positive rates of 13q14 deletion were 46.4% and 47.3% respectively when the cut off level was increased to 20%, and the corresponding rate was 98%. MM patients carrying 13q14 deletion showed 18% - 98% (median value: 72.5%) and 22% - 98.5% (median value: 76.5%) of deleted nuclei involving the RB1 and the D13S319 locus (P = 0.38). There were 67.9% (36 out of 53) and 66% (35 out of 53) cases carrying > 65% of 13q14.1-14.2 and 13q14.3 deleted nuclei as high proportion deletion patients, respectively (P = 0.188). The positive rate of the high proportion deletion patients had still no difference between LSI-RB1 and LSI-D13S319 groups when the cut-off value was defined as 85% (P = 0.439). In conclusion, in this cohort of 112 MM patients, there was no significant difference between the LSI RB1and LSI-D13S319 probes to detect 13q14 deletion. Both LSI-RB1 and LSI-D13S319 probes can be selected to detect 13q14 deletion in MM patients. All the 53 MM patients with 13q14 deletion had deletions of 13q14.1-14.2 and 13q14.3 regions, which is a large deletion as one of the important characters in MM patients with 13q14 deletion. PMID- 22931655 TI - [Effect of DAPT on proliferation and apoptosis of human multiple myeloma cell line RPMI8226]. AB - The aim of this study was to explore the effect of DAPT (N-[N-(3,5 difluorophenacetyl)-L-alanyl]-S-phenylglycinet-butyl ester) on proliferation in vitro of human multiple myeloma cell line RPMI8226 and its underlying mechanism. The proliferation of RPMI8226 cells was detected by CCK-8 method; flow cytometry was employed to assay the cell apoptosis rate;the expressions of Notch1 and Hes1 proteins were detected by Western blot. The results indicated that the proliferation of human RPMI8226 cells significantly decreased after treatment with DAPT 0.5 - 5.0 umol/L for 24 - 72 h (P < 0.05) in a concentration- and time dependent manner. DAPT significantly induced apoptosis of RPMI8226 cells (P < 0.05). The expressions of Notch1 and Hes1 proteins were gradually downregulated with the increase of DAPT concentration. It is concluded that the DAPT can inhibit the proliferation of RPMI8226 cells, which may be related with the down regulation of the protein expression of Notchl and Hes1. PMID- 22931656 TI - [Screening of prognostic factors and comparing of staging systems of multiple myeloma]. AB - This study was aimed to investigate the clinical features and laboratory data of 56 patients with multiple myeloma (MM), find the potential prognostic factors and compare Durie Salmon staging system with International Staging System for patients classification. The median survival time was calculated by the Kaplan Meier, and survival curves were compared using the Log-Rank test. Potential prognostic factors were evaluated by univariate and multivariate analyses. Bivariate correlation of Durie Salmon staging system with International Staging System were analyzed. The results showed that the median survival time of the patients was 42.7 months. Prognostic factors identified as adversely affecting survival included low levels of hemoglobin, platelet, serum albumin, high levels of lactate dehydrogenase, creatinine, C-reactive, serum beta2-microglobulin and high proportion of plasma cells in bone marrow. Among them, only hemoglobin level had independent prognostic value in MM. Durie Salmon staging system significantly correlated with International Staging System. In DS staging system, significant survival differences were found between patients in stages I and III, but statistically significant survival differences were observed among the all three stages in International Staging System. It is concluded that hemoglobin, platelet, serum albumin, lactate dehydrogenase, creatinine, C-reactive, beta2 microglobulin and the number of plasma cells in bone marrow have clinical value for evaluating the prognosis of MM patients. International Staging System can significantly distinguish three clinical stages of MM patients. PMID- 22931657 TI - [Serum level of IL-17 in patients with multiple myeloma and its clinical significance]. AB - This study was purposed to detect the serum concentrations of interleukin-17 (IL 17) in patients with multiple myeloma (MM), and to investigate its clinical significance. the serum IL-17 levels in 33 patients with MM and 20 normal control subjects were quantified by using double antibody sandwich ELISA, and serum beta2 microglobulin (beta2-MG) levels were detected by radioimmunoassay. The results showed that the serum concentrations of IL-17 and beta2-MG in patients with MM were significantly higher than those in the control group (P < 0.001), the serum concentrations of IL-17 and beta2-MG in active stage were significantly higher than those in stable stage (P < 0.05), the serum concentrations of IL-17 and beta2-MG were significantly higher in stage III than that in stage II according to International Staging System (ISS) (P < 0.05), the serum IL-17 and beta2-MG levels were significantly correlated (r = 0.690, P < 0.05). It is concluded that the serum IL-17 level correlates with active/stable stages of MM and staging of MM, IL-17 may play an important role in development stage and prognosis of this disease. PMID- 22931658 TI - [Application of multiplex nested RT-PCR to detecting 10 fusion genes related with MLL gene in myelodysplastic syndrome]. AB - This study was aimed to investigate the clinical value of multiplex nested reverse transcription PCR (RT-PCR) in detecting MLL-related fusion genes in myelodysplastic syndrome (MDS). Ten MLL-related genes (dupMLL, MLL-ELL, MLL-ENL, MLL-AF6, MLL-AF9, MLL-AF10, MLL-AF17, MLL-CBP, MLL-AF1P, MLL-AF1Q) in 221 MDS cases were detected by multiplex nested RT-PCR. The results indicated that 20 patients were detected with positive result among 221 patients and the positive rate was 9.05%. The number of the positive cases and positive rates of the above mentioned 10 fusion genes were in order: 7 (3.16%), 2 (0.9%), 1 (0.45%), 1 (0.45%), 2 (0.9%), 2 (0.9%), 1 (0.45%), 2 (0.9%), 1 (0.45%), 1 (10.45%). It is concluded that the multiplex nested RT-PCR has been confirmed to be able to detect 10 fusion genes in MDS patients, which can provide important evidences for assessing diagnosis and treatment, and give related necessary information about minimal residual disease and its prognosis. PMID- 22931659 TI - [Detection of tissue factor-positive microparticles and its clinical significance in the haemostatic disorder]. AB - Objective of this study was to detect the level of tissue factor-positive microparticles (TF(+)MP) by flow cytometry (FCM) and to analyze its clinical significance in the haemostatic disorder. TF(+) MP was detected by FCM using antibody CD142-PE in 25 cases of acute promyelocytic leukemia (APL), 20 cases of hemostatic diseases and 20 healthy adults as controls. The differences of TF(+) MP between various groups were determined. The results showed that the level of TF(+) MP in the patients with thrombotic complications was significantly higher than that in the healthy adults (P < 0.05). The TF(+) MP level was higher in the patient with APL than that in the healthy adults, especially in course before therapy (P < 0.01), but the difference was not statistically significant in the patient with APL after therapy and the healthy adults. Among these patient with APL, the level of TF(+) MP in the 18 patients who complicated with disseminated intravascular coagulation (DIC) was also higher than that in the healthy adults (P < 0.05), but the level of TF(+) MP in the other 7 patients who did not complicate with DIC was similar before and after treatment. It is concluded that the method of TF(+) MP detection by FCM is feasible and simple, it is useful for the diagnosis of thrombotic disorder, and helps evaluation for the prognosis of APL patient. PMID- 22931660 TI - [Clinical therapeutic efficacy of rituximab for relapsed and refractory idiopathic thrombocytopenic purpura]. AB - The aim of this study was to evaluate the effect of rituximab treatments for refractory and relapsed idiopathic thrombocytopenic purpura (ITP). 18 patients with refractory and relapsed ITP who received 22 courses of rituximab treatments from January 2007 to December 2010 were analyzed retrospectively. Rituximab was given at a dose of 375 mg/m(2) intravenously weekly for a continuous 4 weeks. The results indicated that responses were achieved in 15 of 22 (68%) courses, out of which complete responses were achieved in 10 of 22 (45%) courses, partial and minimal responses were achieved in 5 of 22 (23%) courses, and no responses were achieved in 7 of 22 (32%) courses. The median time of response was 3 weeks (1 - 17 weeks) from the start of treatment and median duration of response was 13 weeks (1 week - 42 months). The responses were mostly short-sustained and follow up median time was 20 months (1 - 52 months). The responses of 8 patients (36%) sustained for over 6 months, 6 patients (27%) sustained for over 1 year, and 4 patients also showed sustained response at last visit of follow-up. Previous splenectomy resulted in a poor response (P = 0.037). Patients who failed in rituximab treatment and prior received multiple treatments including splenectomy, had a poor response to further therapies. It is concluded that rituximab is well tolerated by patients and is useful in some patients with relapsed and refractory ITP, however, only about 20% patients can achieve sustained remissions. The patients who failed in rituximab treatment has a poor response to further treatment. PMID- 22931661 TI - [Effect of high dose dexamethasone on function and TLR-9 mRNA expression of plasmacytoid dendritic cells in patients with immune thrombocytopenic purpura]. AB - This study was purposed to investigate the effect of high-dose dexamethasone (DXM) on function and Toll like receptor 9 (TLR-9) expression of plasmacytoid dendritic cells (pDC) in peripheral blood of patients with immune thrombocytopenic purpura (ITP). 15 newly diagnosed patients with ITP received high dose DXM at single daily doses of 40 mg for 4 consecutive days. The peripheral blood plasmacytoid dendritic cells from 13 remission patients and 15 normal controls were separated by immunomagnetic beads and then induced by CpG OND2216. 24 h later, the levels of IFN-alpha, IL-6 and TNF-alpha in the supernatant were detected by enzyme linked immunosorbent assay (ELISA). The expression of TLR9 mRNA of pDC was detected by real-time quantitative PCR. The results indicated that the levels of IFN-alpha, IL-6 and TNF-alpha produced by pDC in ITP patients were significantly higher than those in normal controls (P < 0.05). After high dose DXM treatment, the levels of IFN-alpha, IL-6 and TNF-alpha decreased without significant difference compared with normal controls (P > 0.05). The expression of TLR9 mRNA in pDC of untreated patients was significantly higher than that in control group (P < 0.05), and significantly reduced after treatment without difference from that in control group (P > 0.05). It is concluded that pDC may play an important role in ITP by their TLR9 and secreted cytokines; dexamethasone may down regulate the expression of TLR9, inhibit pDC function, and thus play a therapeutic role. PMID- 22931662 TI - [Correlation analysis of thrombin-activatable fibrinolysis inhibitor single nucleotide polymorphism with venous thromboembolism]. AB - This study was aimed to explore the change of single nucleotide polymorphism (SNP) of thrombin-activatable fibrinolysis inhibitor (TAFI) and its correlation of 2 sites (505a/g, 1040c/t) in its gene-coding region with venous thromboembolism (VTE). The genotype distribution of TAFI in 80 patients with VTE and 80 normal controls was detected by allele-specific PCR. The results showed that the distribution of each genotype of 505a/g polymorphism was not significantly different between the VTE and control groups (P > 0.05). However, t allele frequency of 1040c/t in VTE group decreased significantly as compared with the control group (40% vs 53.75%, P < 0.05), mainly due to the decrease of the proportion of tt homozygous in VTE group. It is concluded that obvious relationship is found between the polymorphism of 1040c/t in TAFI gene and VTE patients. t allele genotype may paly a protective role in VTE. The polymorphism of TAFI 505a/g may be not associated with VTE. PMID- 22931663 TI - [Impact of disease status on outcomes of allogeneic hematopoietic stem cell transplantation in patients with refractory and relapsed acute myeloid leukemia]. AB - The study was aimed to evaluate the impact of disease status on the outcomes of allogeneic hematopoietic stem cell transplantation (allo-HSCT) in patients with refractory and relapsed acute myeloid leukemia (AML). 32 patients with refractory and relapsed AML received allo-HSCT after myeloablative conditioning regimen, including 17 patients in no-remission (NR) and 15 patients in complete remission (CR) at the time of transplant. Treatment related adverse events, relapse rate and leukemia free survival (LFS) were analyzed. The results showed that the parameters of sex, age, cytogenetic risk and transplant procedures were comparable between the two groups. 30 patients had successful engraftment, except one had graft failure and one died from severe veno-occlusive disease in the NR group. The incidences of aGVHD in NR group and CR group were 47.1% (8 patients) and 33.5% (5 patients) respectively. Out of comparable patients, 5 from 9 patients in NR group developed with cGVHD, and 4 from 11 patients in CR group were subjected to cGVHD. There were no statistic difference in incidences of aGVHD and cGVHD between two group. Compa-red with CR group, NR group had a higher treatment-related mortality (29.4% vs 14.3%, P = 0.392) and relapse rate (42.9% vs 26.7% P = 0.300), but there was no significant difference. With a median follow-up of 13 (1 - 124) months, 6 patients remained alive in both of the two groups, and the 2 year LFS of them were parallel (35.3% vs 40.0%, P = 0.267). Among these 32 patients, overall survival (OS) was better in patients with age < 35 years (P = 0.044) and with the appearance of cGVHD (P = 0.046). It is concluded that allo-HSCT is an effective salvage therapy for patients with refractory and relapsed AML, and the overall outcome seems unrelated to the disease status (NR or CR) before transplantation. As such, for refractory and relapsed AML patients in non-remission, performance of allo-HSCT to achieve long term survival is feasible. PMID- 22931664 TI - [Clinical analysis of haploidentical or unrelated donor hematopoietic stem cell transplantation for patients with severe aplastic anemia]. AB - Objective of this study was to evaluate the efficacy and safety of haploidentical or unrelated donor hematopoietic stem cell transplantation (HSCT) for patients with severe aplastic anemia (SAA). Twenty patients with SAA received allogeneic HSCT from haploidentical or unrelated donors (14 from haploidentical donors and 6 from unrelated donors) from November 2005 to May 2011. Conditioning regimen consisted of fludarabine (FLU), cyclophosphamide (Cy) and anti-thymocyte immunoglobulin (ATG). The patients were administrated with G-CSF-primed bone marrow and mobilized peripheral blood as grafts from haploidentical donor or only mobilized peripheral blood from the unrelated donor. The results showed that the median time of neutrophil and platelet engraftment were 14 (11 - 20) d and 17 (13 - 31) d respectively. All patients who achieved engraftment had complete hematologic recovery with complete donor chimerism, except for two patients who developed graft failure in 2 months after transplantation. Four cases developed acute grade IIGVHD. The chronic GVHD occurred in 7 of the 16 evaluable cases (6 limited, 1 extensive). 14 patients got disease-free survival with follow-up to January 2012. The disease-free survival rate was 68.9%. It is concluded that the haploidentical or unrelated donor hematopoietic stem cell transplantation may become a viable therapeutic option for severe aplastic anemia patients who lack suitable human leukocyte antigen-matched donors and fail immunosuppressive therapy. PMID- 22931665 TI - [Prophylactic effect of TLR5 agonist flagellin on acute graft versus host disease after allogeneic hematopoietic stem cell transplantation and its mechanism]. AB - This study was aimed to investigate the prophylactic effect of Toll like receptor (TLR)5 agonist flagellin on acute graft versus host disease (aGVHD) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) and its possible mechanism. The animal model with allo-HSCT aGVHD was established by using purebred mice (male mouse C57BL/6 as donor, female mouse BALB/c as recipient) with complete-unidentical major histocompatibility antigen. The recipient mice were randomly divided into 3 groups: group 1 in which mice were injected with high purity (95%) flagellin before and after allo-HSCT respectively, group 2 in which mice received allo-HSCT without injection of flagellin, group 3 in which mice were radiated alone. The aGVHD features of mice in group 1 and 2 were observed and compared. The results showed that the typical symptoms of aGVHD appeared in transplanted mice. The death peak of mice in group 2 appeared at day 4-5 after transplantation. The aGVHD symptoms were obviously alleviated and the mean survival time was prolonged significantly in mice group 1 as compared with mice in group 2 (P < 0.05). The comparison of WBC count in peripheral blood of mice in 3 groups before transplantation showed no significant difference (P > 0.05), while WBC count of mice in group 1 and 2 showed the significant difference at days 14 and 21 after transplantation (P < 0.05). The pathological appearances of aGVHD in mice of group 1 were obviously reduced as compared with mice in group 2. The flow cytometric detection of Treg cell/CD4(+) T cell levels at different time before and after transplantation demonstrated that the Treg cell level in mice of group 1 at weeks 2-4 after transplantation significantly increased as compared with mice in group 2 (P < 0.05). It is concluded that flagellin can effectively prevent the aGVHD occurrence after allo-HSCT, reduce the symptoms and pathological changes of aGVHD, obviously prolong mean survival time of mice in group 1. The mechanism of flagellin effect may be associated to increase of Treg cell level in mice after allo-HSCT. PMID- 22931666 TI - [Clinical analysis of cytomegalovirus infection after allogeneic hematopoietic stem cell transplantation]. AB - The objective of this study was to explore the incidence and therapeutic efficacy of cytomegalovirus (CMV) infection after allogeneic hematopoietic stem cell transplantation (allo-HSCT). The clinical data of 140 patients undergoing allo HSCT in our department of hematology from 2010-01 to 2012-01 were retrospectively analyzed. The results showed that the incidence of CMV infection was 4.3% (48/140), the time for the first detection of positive CMV-DNA was at day 45 (33 to 68) after allo-HSCT, and the CMV quantitative range was 1.25*10(3) - 5.5*10(6). There were 2 cases of CMV-related interstitial pneumonia and 5 cases of hemorrhagic bladder inflammation. A total of 65 patients suffered from graft versus host disease (GVHD), in which 32 cases (49.2%) were accompanied with CMV infection, CMV-DNA negative in patients treated with ganciclovir, foscarnet sodium anti-CMV was at day 45 (33 to 68) with the effective rate of 100%. 12 patients with CMV infection were accompanied with transient neutropenia and thrombocytopenia. It is concluded that after allo-HSCT the CMV infection occurs frequently. The patients with GVHD have a higher incidence of CMV infection. Ganciclovir and foscarnet sodium are reliable to be used for treatment of CMV infection with fewer adverse reactions. PMID- 22931667 TI - [Supportive effects of conditioned culture media of human umbilical cord mesenchymal stem cells on hematopoiesis in vitro]. AB - This study was aimed to explore whether the conditioned culture medium of human umbilical cord-derived mesenchymal stem cells (hUC-MSC) has supportive effects on hematopoiesis in vitro. hUC-MSC were cultured in 75 cm(2) culture flasks at a concentration of 2*10(6) cells per flask. After 48 h, the conditioned culture medium was harvested. CD34(+) cells were isolated with the human cord blood CD34 positive selection kit. The CD34(+) cells were plated in three different culture systems: the culture supernatant from hUC-MSC added into incomplete methylcellulose without recombinant human cytokines as conditioned culture medium; the complete methylcellulose medium with recombinant human cytokines as positive control medium; incomplete methylcellulose adding DMEM/F12 with 10% FBS instead of conditioned culture medium as the negative control medium. After 14 days of culture, colonies containing >= 50 cells were scored and types of colonies were classified under inverted microscope. The immunophenotypes of cells which were collected from the colonies were detected by flow cytometry. The results showed that conditioned culture medium of hUC-MSC supported the differentiation of CD34(+) cells into CFU-G (47.67 +/- 0.58), CFU-GM (48.67 +/- 4.73) and CFU-M (3.00 +/- 2.00) in vitro, while the CFU-E, BFU-E or CFU-GEMM were absent. Comparatively, in the positive control medium all kinds of CFU were observed. Interestingly, the percentage of CD45(+)cells of CFU in conditioned culture medium (97.43 +/- 2.15)% was more than CD45(+)cells in positive control medium (39.69 +/- 0.96)% (P < 0.05). It is concluded that the conditioned culture medium of hUC-MSC has been confirmed to have ability to support hematopoiesis separately in vitro. Besides, it enhances the differentiation of CD34(+) cells into myeloid cells except cells of erythroid lineage. PMID- 22931668 TI - [Effects of tumor necrosis factor-alpha on immunoregulatory activities of mesenchymal stem cells in vitro and in vivo]. AB - Mesenchymal stem cells (MSC) are characterized by their potent immuno-regulatory activity, however our previous data have shown that MSC have no therapeutic effects on collagen-induced arthritis (CIA). To further clarify the complexity, the effects of tumor necrosis factor-alpha (TNF-alpha) on the in vitro and in vivo immunoregulatory activity of MSC were investigated in this study, as TNF alpha is recognized as the key factor in the development of rheumatoid arthritis. The nuclear translocation of the inflammation-associated factor NF-kappaB was observed after human umbilical cord MSC were treated with TNF-alpha and the cell proliferation status was assessed by MTT test. The inhibitory effects of MSC or TNF-alpha-treated MSC on the mixed lymphocyte reaction, in which Wistar rat spleen mononuclear cells were served as the responders and the splenocytes from SD rat spleens as the stimulators, were also determined by the MTT test. Further, the therapeutic potentials of MSC or TNF-alpha-treated MSC were observed in a Wistar rat CIA model. The results showed that NF-kappaB translocated into the nuclei promptly after TNF-alpha treatment, though TNF-alpha had little effect on the MSC proliferation. MSC, whether pre-stimulated by TNF-alpha or not and when different doses were tested, exhibited obviously inhibitory effects on the proliferation of the lymphocytes (P < 0.001 for all groups tested), while MSC treated by TNF-alpha displayed more potent suppression especially when low density were used. Unexpectedly, the infiltration of inflammatory cells into the involved knees was aggravated by cell treatment and the pathological scores were significantly higher than those of controls (P < 0.05). It is concluded that the TNF-alpha exhibits different effects on immune regulation activity of MSC, and its underlying mechanism needs to further investigate. PMID- 22931670 TI - [Effect of sphingosine 1-phosphate/sphingosine 1-phosphate receptor signal pathway on function of neutrophils]. AB - The aim of this study was to examine the priming effect of sphingosine 1 phosphate (S1P) on fMLP-activated neutrophils, mainly to detect the neutrophil respiratory burst products, and to investigate the signaling pathway involved in S1P activity. Flow cytometry was used to evaluate the new isolated neutrophil; the superoxide anion output was detected indirectly by cytochrome C reduction in respiratory burst; the dihydro-rhodamine 123 was used to detect the intensity of respiratory burst; the signal transduction pathways of neutrophil respiratory burst were explored by Western blot. The results showed that after pretreated with S1P, the level of superoxide anion released by fMLP-activated neutrophils significantly increased; the Rhodamine 123 mean fluorescence intensity in S1P primed fMLP-activated neutrophils group was significantly higher than that in fMLP treatment group; PI3K and Akt proteins involved in the signal pathway of neutrophil respiratory burst. It is concluded that S1P is a new priming reagent, which primes respiratory burst of fMLP-activated neutrophils; this signal pathway may be that S1P interacts with its receptor, activates PI3K, then activates Akt transmitting signals through NADPH oxidase, finally results in the respiratory burst. PMID- 22931669 TI - [Propagation of prdm1 gene knockout mouse and its genotype identification]. AB - This study was aimed to propagate and identify the prdm1 gene-knockout mice, so as to lay the foundation for studying Blimp-1 protein. Two kinds of transgenic homozygous mice with B6.prdm1(flox/flox) and B6.Lck-Cre were feed and propagated; after successful propagating, the first passage mice were obtained; after the first passage mice were copulated once again, the genotypes were obtained as follows: B6. prdm1(wild/wild). Lck-Cre, B6. prdm1(wild/wild), B6.prdm1(flox/flox). Lck-Cre, B6.prdm1(flox/wild). Lck-Cre, B6.prdm1(flox/flox), B6. prdm1(flox/wild). The genomic DNA of second passage mice was extracted, the Cre and loxp gene fragments were amplified by PCR, then the size of Cre and loxp genomic DNA were detected by agarose gel electrophoresis. The mice with B6.prdm1(flow/flox). Lek-Cre were used as conditionally prdm1-knockout mice, B6.prdm1(flox/wild). Lck-Cre mice, B6.prdm1(flox/flox) and B6 mice were used as controls. The spleen T lymphocytes and B lymphocytes were sorted by using magnetic beads, the blimp-1 target protein was identified by Western blot. The results showed that the two transgenic homozygous mice had the ability to reproduce, and the separation ratio of second passage mice generated from propagation of their offspring cach other meet Mendelian laws, and the prdm1 gene knockout mice also could successfully obtained. It is concluded that the application of Cre-loxp system may successfully obtain plentiful prdm1 gene knockout mice. PMID- 22931671 TI - [Therapeutic effect of rmIL-12 combined with G-CSF on acute radiation sickness produced by gamma-ray irradiation in mice]. AB - The aim of this study is to observe the therapeutic effect of recombinant murine interleukin 12 (rmIL-12) combining with granulocyte colony stimulating factor (G CSF) on mice irradiated by gamma-rays. 56 BALB/c mice were totally irradiated by 6.0 Gy of (60)Co gamma-ray and randomly divided into irradiation control group, rmIL-12 treatment group, G-CSF treatment group and combination therapy (rmIL-12 plus G-CSF) group. rmIL-12 20 ug/kg was administrated intraperitoneally at 1 h following irradiation, and was administrated every 3 days after irradiation for 4 times in rmIL-12 treatment group. G-CSF 100 ug/kg was administrated subcutaneously the 2 h following irradiation for 14 d in G-CSF treatment group. The dose and method of rmIL-12 and G-CSF in combination therapy group were same as in rmIL-12 group and G-CSF group. The general status of mice were observed twice a day, the changes in body weight, peripheral blood cell (WBC and Plt) counts were examined once every three days, bone marrow cells were collected to perform colony cultivation on day 14 and 28 after irradiation. The results showed that WBC count recovery time in combination therapy group was significantly earlier than that of the control group (7 d vs 11 d), WBC count recovery velocity in the combination therapy group was no significant different from that of the G CSF treatment group. Combined therapy significantly promoted Plt count recovery, resulting in less profound nadirs (16.5% vs 8.1%, P < 0.01) and rapid recovery to normal levels (11 d vs 14 d), Plt count recovery velocity in the combination therapy group was no significant different from that of the rmIL-12 treatment group. Culture of bone marrow cells in semi-solid medium also demonstrated that combination of rmIL-12 and G-CSF could stimulate bone marrow cells to form more CFU-GM and CFU-Mix than those of the irradiation control group in vitro on day 14 and 28 after irradiation (P < 0.05). It is concluded that the combination of rmIL 12 and G-CSF can significantly accelerate the recovery of hematopoietic function in mice with acute radiation sickness. PMID- 22931672 TI - [Clinical study of intravenous injecting itraconazole as empirical antifungal therapy for patients with hematological malignancies]. AB - This study was purposed to investigate the efficacy and safety of intravenous injecting itraconazole (ITCZ) as empirical antifungal therapy in the patients with hematological malignancies. According to recommendation in IDSA guidebook, the patients suffered from fever during neutropenia and inefficacy of treatment using broad-spectrum antibiotics for 4 days should receive intravenous injection of ITCZ as empirical antifungal therapy. The results showed that the overall clinical response rate to ITCZ injection was 62.9% (22/35), and the success rate of achieving composite endpoints was 54.3% (19/35). Mild adverse reactions were observed in 6 patients (17.1%). The injection of ITCZ was stopped in 2 patents (5.7%) due to adverse reaction. Further analysis revealed that the response rate was higher in patients with fever prior to the start of ITCZ within five days than beyond five days (P = 0.031). The response rate was higher in patients with possible invasive fungus infection (IFI) than that in patients with probable and confirmed IFI (P = 0.002). The prophylactic antifungal treatment during neutropenia displayed no significant influence on efficacy of empirical antifungal therapy with itraconazole (P = 0.054). It is concluded that the good efficacy and safety of empirical ITCZ injection for hematological malignancies patients is efficient and safe. PMID- 22931673 TI - [Investigation of family pedigree rare blood group of JK(a-b-) phenotype]. AB - The purpose of this study was to find the rare individual JK(a-b-) phenotype of proband family and explore its molecular mechanism and the genetic background, in order to provide base for searching compatible donor to blood transfusion of the individuals with rare JK(a-b-) phenotype. Urea lysis test was used to screen the JK(a-b-) phenotype and results were confirmed with serological method. The genotypes were detected with PCR-SSP. The 4-11 exons and their flanking intron regions of JK gene were amplified and sequenced. The results showed that her elder brother has a same phenotype JK(a-b-) and genotypes JK(a)/JK(b) with proband. The phenotype and genotypes of their parent is JK (a+b-) and JK(a)/JK(b), respectively; and the younger sister's is JK (a+b-) and JK(a)/JK(a). Acceptor site of intron 5 3' g > a mutation was detected in proband and her elder brother, which may cause the JK(a-b-) phenotype of proband and her elder brother. There is g/a and a at this site in their parent and younger sister, respectively. Additionally, the SNP (ncbi:rs8090908) a > g at nt-99 in intron 3 was found in proband and her elder brother, it needs to be explored whether the SNP is related to JK(a-b-) phenotype. This SNP was not found in their parent and younger sister. This JK(a-b-) phenotype abides by the rule of dominant inheritance in the family, suggesting that there is higher probability to find homology phenotype and genotype by investigating in their family, especially in their siblings. PMID- 22931674 TI - [Identification of a novel HLA allele, HLA-B*35:03:07, by sequencing-based typing]. AB - This study was purposed to analyze and identify a novel HLA allele in Chinese population. A new HLA-B allele which is closely related to HLA-B*35:03:01 was initially detected by PCR-SSOP, then DNA sequencing was performed to identify the difference between the novel allele and HLA-B*35:03:01 allele. The result showed that the sequence of the new allele was different from all other known sequence. It differs from the closest matching HLA-B*35:03:01 by a single substitution at position 387 C->G in exon 3, no resulting in amino acid change. It is concluded that this allele is a novel one and has been officially named B*35:03:07 by the WHO Nomenclature Committee. PMID- 22931675 TI - [Roles of microRNAs in lymphocytopoiesis and lymphoid malignancies - review]. AB - microRNAs (miRNAs) are small molecular non-coding RNA with 21-25 nucleotides in a variety of eukaryotic systems, and regulate gene expression at the post transcriptional level by degrading or translational repressing target messenger RNA (mRNA). Many studies have showed the roles of miRNAs in normal lymphocytopoiesis, giving an interpretative key to the aberrant expression observed in human lymphoid malignancies. The recent advances of understanding the roles of miRNAs in lymphoid malignancies show that miRNAs as tumoral biomarkers can effectively be used for diagnosis, prognosis, and prediction of response to therapy. This review focuses the roles of miRNA in development and differentiation of lymphocytes and the relation of miRNA to lymphoid malignancies. PMID- 22931676 TI - [Recent advances of molecular mechanisms influencing prognosis of myelodysplastic syndrome - review]. AB - Myelodysplastic syndrome (MDS) is clonal disorder of hematopoiesis characterized by inefficient hematopoiesis, peripheral blood cytopenias, aberrant differentiation, and risk of progression to acute myeloid leukemia. Although specific karyotypic abnormalities have been found to link to MDS for decades, more recent findings have demonstrated the importance of mutations within individual genes. The recent molecular abnormalities found in MDS include following gene mutation such as TET2, TP53, RUNX1, ASXL1, IDH1/IDH2, EZH2 and RAS. In this review, the recent advances of prognostic molecular markers of MDS and their biological and clinical significance are summarized. PMID- 22931677 TI - [Research progress on necroptosis regulation mechanism and its clinical relevance]. AB - Necroptosis is a caspase-independent programmed cell death, its regulation, induction and blocking mechanism are a complex process involving in a series of molecular expression and regulation. The studies found that the necroptosis is not only involved in the physiological regulation mechanism, but also directly correlated to the occurrence, development and final outcome of some necrotic diseases, such as neurodegenerative diseases, ischemic disease, inflammation and viral infection. Moreover, the studies on multidrug-resistant tumor cell line demonstrated that necroptotic induction agents possess excellent "broad-spectrum" to escape the multidrug resistance. Therefore, exploration of the signaling pathways, physical characteristics, clinical relevance of necroptosis may provide new prospects for molecular target therapy and drug discovery of tumours. This review summarizes the research progress on possible regulation mechanism of necroptosis, physiologic characteristics and relation of necroptosis with clinical diseases and multi-drug resistance. PMID- 22931678 TI - [Research advances of hepcidin expression and its regulation mechanism]. AB - Hepcidin can regulate cell irons' efflux transport. The expression of hepcidin can be influenced by the body signals (such as serum ferritin and erythropoietin levels) as well as inflammation, hypoxia and other disease states. These stimulus activate the signaling pathway of BMP-the SMAD, the JAK-STAT and HIF1 through the liver parenchymal cell surface type I transmembrane glycoprotein of HFE, transferrin receptor 1, 2, hepcidin regulatory proteins, thereby changing the hepcidin gene transcription, regulating the expression levels of hepcidin. However, the molecular mechanism that regulate hepcidin expression is unclear. From the signal factors that affect hepcidin expression and signaling pathways involved in its expression, the latest research progress on regulatory mechanism of hepcidin are summarized. PMID- 22931679 TI - [NK cell surface receptors and their research progress - review]. AB - Natural killer (NK) cells are important immune cells in human body, which occupy an important place in adoptive immunotherapy for patients with malignancies due to their capacity of killing tumor cells without MHC limitation, as well as separating graft versus leukemia (GVL) and graft versus host disease (GVHD). Recent studies showed that different kinds of NK cell-surface receptors have been found, which transmit inhibiting signals or activating signals, the balance between them determines the functional status of NK cells. Researchers have focused on the study of NK cell-surface receptors recently in order to improve application of NK cells for adoptive immunotherapy. This review summaries the current advancement about NK cell-surface receptors and their clinical significance. PMID- 22931680 TI - [Action mechanism of lenalidomide in hematological malignancies - review]. AB - Immunomodulatory drug lenalidomide is a synthetic compound derived by modifying the chemical structure of thalidomide to improve its potency and reduce its side effects. Lenalidomide is a 4-amino-glutamyl analogue of thalidomide that has emerged as a drug with activity against various hematological and solid malignancies. It is approved by FDA in USA for clinical use in myelodysplastic syndromes with deletion of chromosome 5q and multiple myeloma. Studies have shown that lenalidomide exert anti-tumor activity probably by various mechanisms in hematologic malignancies, such as immunomodulation, anti-angiogenesis and effects on signal transduction. In this article, the progresses of study on these problems are reviewed. PMID- 22931681 TI - [The research progress on Langerhans cell tumor - review]. AB - Langerhans cell tumor is a kind of tumor that originates from Langerhans cells (LC) and maintain their specific phenotype profile and ultrastructural features. Based on cell morphology, immunohistochemical and ultrastructural characteristics, Langerhans cell tumor has two main subcategories: Langerhans cell histiocytosis (LCH) and Langerhans cell sarcoma (LCS). LCH is a benign clonal proliferative disease of the LC, whereas LCS is an extremely rare neoplastic proliferation of Langerhans cells with overtly malignant cytologic features and spreads aggressively, which is considered to be a high level malignant type of LCH. Both LCH and LCS can involved various tissues and organs and have complex and diverse clinical manifestation, which cause different severity. The diagnosis depends on histopathological morphology and immunohistochemistry; the electron microscopy was used to assists diagnosis when necessary. The treatment includes surgery, chemotherapy, radiotherapy, immunotherapy and hematopoietic stem cell transplantation, etc, but lack of generally accepted optimal treatment options currently, individualized treatment is needed. The prognosis of LCH is primarily related to the number of damaged organ, while LCS has a poor overall prognosis as its invasion and rapid progress. This article reviews the pathogenesis, clinical manifestations, diagnosis, treatment and prognosis of both LCH and LCS. PMID- 22931682 TI - DNA barcoding a regional fauna: Irish solitary bees. AB - As the globally dominant group of pollinators, bees provide a key ecosystem service for natural and agricultural landscapes. Their corresponding global decline thus poses an important threat to plant populations and the ecosystems they support. Bee conservation requires rapid and effective tools to identify and delineate species. Here, we apply DNA barcoding to Irish solitary bees as the first step towards a DNA barcode library for European solitary bees. Using the standard barcoding sequence, we were able to identify 51 of 55 species. Potential problems included a suite of species in the genus Andrena, which were recalcitrant to sequencing, mitochondrial heteroplasmy and parasitic flies, which led to the production of erroneous sequences from DNA extracts. DNA barcoding enabled the assignment of morphologically unidentifiable females of the parasitic genus Sphecodes to their nominal taxa. It also enabled correction of the Irish bee list for morphologically inaccurately identified specimens. However, the standard COI barcode was unable to differentiate the recently diverged taxa Sphecodes ferruginatus and S. hyalinatus. Overall, our results show that DNA barcoding provides an excellent identification tool for Irish solitary bees and should be rolled out to provide a database for solitary bees globally. PMID- 22931683 TI - Drugs for kids: good or bad? PMID- 22931684 TI - Antidepressant medication to treat anxiety in patients with bipolar disorder. PMID- 22931685 TI - Heat shock 70 kDa protein 5/glucose-regulated protein 78 "AMP"ing up autophagy. AB - Breast cancer is one of the most prevalent cancers in women, with more than 240,000 new cases reported in the United States in 2011. Classification of breast cancer based upon hormone and growth factor receptor profiling shows that approximately 70% of all breast cancers express estrogen receptor-alpha. Thus, drugs that either block estrogen biosynthesis (aromatase inhibitors like Letrozole), or compete with estrogen for estrogen receptor (ER) binding (selective ER modulators including tamoxifen; TAM) and/or cause ER degradation (selective estrogen receptor downregulators such as fulvestrant), are among the most prescribed targeted therapeutics for breast cancer. However, overall clinical benefit from the use of these drugs is often limited by resistance; ER+ breast cancers either fail to respond to endocrine therapies initially (de novo resistance), or they respond and then lose sensitivity over time (acquired resistance). While several preclinical studies postulate how antiestrogen resistance occurs, for the most part, the molecular mechanism(s) of resistance is unknown. PMID- 22931686 TI - The complete mitochondrial genome of the melon fly Bactrocera cucurbitae (Diptera: Tephritidae). AB - The mitochondrial genome of Bactrocera cucurbitae, a representative of the Tephritid family, was completely sequenced for the first time. The B. cucurbitae genome is a double-stranded circular molecule of 15,825 bp long, including the entire set of the 37 genes. The 72.9% A+T content and 0.047 AT-skew are within the range of the known dipteran genomes. Comparative analyses showed that dipteran mitochondrial protein-coding genes present complex evolutionary patterns. Some of the codon families were strongly biased towards J-strand. The mitochondrial ATP8 of B. cucurbitae exhibited a faster substitution rate than other genes. Cox1 is the slowest evolving protein and could be considered as a potential phylogenetic marker. PMID- 22931687 TI - Reemerging Sudan Ebola virus disease in Uganda, 2011. AB - Two large outbreaks of Ebola hemorrhagic fever occurred in Uganda in 2000 and 2007. In May 2011, we identified a single case of Sudan Ebola virus disease in Luwero District. The establishment of a permanent in-country laboratory and cooperation between international public health entities facilitated rapid outbreak response and control activities. PMID- 22931688 TI - An automated framework for hypotheses generation using literature. AB - BACKGROUND: In bio-medicine, exploratory studies and hypothesis generation often begin with researching existing literature to identify a set of factors and their association with diseases, phenotypes, or biological processes. Many scientists are overwhelmed by the sheer volume of literature on a disease when they plan to generate a new hypothesis or study a biological phenomenon. The situation is even worse for junior investigators who often find it difficult to formulate new hypotheses or, more importantly, corroborate if their hypothesis is consistent with existing literature. It is a daunting task to be abreast with so much being published and also remember all combinations of direct and indirect associations. Fortunately there is a growing trend of using literature mining and knowledge discovery tools in biomedical research. However, there is still a large gap between the huge amount of effort and resources invested in disease research and the little effort in harvesting the published knowledge. The proposed hypothesis generation framework (HGF) finds "crisp semantic associations" among entities of interest - that is a step towards bridging such gaps. METHODOLOGY: The proposed HGF shares similar end goals like the SWAN but are more holistic in nature and was designed and implemented using scalable and efficient computational models of disease-disease interaction. The integration of mapping ontologies with latent semantic analysis is critical in capturing domain specific direct and indirect "crisp" associations, and making assertions about entities (such as disease X is associated with a set of factors Z). RESULTS: Pilot studies were performed using two diseases. A comparative analysis of the computed "associations" and "assertions" with curated expert knowledge was performed to validate the results. It was observed that the HGF is able to capture "crisp" direct and indirect associations, and provide knowledge discovery on demand. CONCLUSIONS: The proposed framework is fast, efficient, and robust in generating new hypotheses to identify factors associated with a disease. A full integrated Web service application is being developed for wide dissemination of the HGF. A large-scale study by the domain experts and associated researchers is underway to validate the associations and assertions computed by the HGF. PMID- 22931689 TI - The use of natalizumab for treatment of MS: do the risks still outweigh the gains? PMID- 22931690 TI - Surgical resection and glioblastoma: molecular profiling and safety. PMID- 22931691 TI - Could we do better in the administration of "justice" to neurological patients? PMID- 22931692 TI - Technology in caring for traumatic brain injury: does what make sense really do? PMID- 22931693 TI - Mixed dementia in clinical trials of Alzheimer's disease. PMID- 22931694 TI - Stroke genetics and the Chinese population. PMID- 22931695 TI - A new therapeutic target for the treatment of multiple sclerosis. PMID- 22931696 TI - Intracranial pressure monitors in traumatic brain injury: a systematic review. AB - We conducted a systematic review to examine the relationship between intracranial pressure monitors (ICP) monitors and mortality in traumatic brain injury (TBI). We systematically searched for articles that met the following criteria: (1) adults patients, (2) TBI, (3) use of an ICP monitor, (4) point estimate for mortality with ICP monitoring (5) adjustment for potential confounders. Six observational studies were identified with 11,371 patients. There was marked between-study heterogeneity that precluded a pooled analysis. Patients with ICP monitors had different clinical characteristics and received more ICP targeted therapy in the ICU. Four studies found no significant relationship between ICP monitoring and survival, while the other two studies demonstrated conflicting results. Significant confounding by indication in observational studies limits the examination of isolated TBI interventions. More research should focus on interventions that affect TBI careplan systems. Further research is needed to identify which subset of severe TBI patients may benefit from ICP monitoring. PMID- 22931697 TI - The diagnosis and management of Piriformis Syndrome: myths and facts. AB - Piriformis Syndrome (PS) is an uncommon, controversial neuromuscular disorder that is presumed to be a compression neuropathy of the sciatic nerve at the level of the piriformis muscle (PM). The diagnosis is hampered by a lack of agreed upon clinical criteria and a lack of definitive investigations such as imaging or electrodiagnostic testing. Treatment has focused on stretching, physical therapies, local injections, including botulinum toxin, and surgical management. This article explores the various sources of controversy surrounding piriformis syndrome including diagnosis, investigation and management. We conclude with a proposal for diagnostic criteria which include signs and symptoms, imaging, and response to therapeutic injections. PMID- 22931698 TI - Immunomodulation in adult epilepsy: the role of IVIG. AB - Much of the research for intravenous immunoglobulins (IVIG) use in epilepsy has focused on childhood epilepsies and the results have been inconclusive. As evidence for inflammation in epilepsy and epileptogenesis is accumulating, IVIG might have a role to play in adult epilepsy. Our literature review focuses on the purported mechanisms of IVIG, the link between inflammation and the various causes of adult epilepsy and the different steps of epileptogenesis at which inflammation might play a role. We also review the current clinical evidence supporting IVIG as a treatment for epilepsy in the adult population. Though there is interesting theoretical potential for treatment of refractory epilepsy in adults with IVIG, insufficient evidence exists to support its standard use. The question remains if IVIG should still be considered as an end-of-the-line option for patients with epilepsy poorly responsive to all other treatments. PMID- 22931699 TI - Multiple pathologies are common in Alzheimer patients in clinical trials. AB - OBJECTIVE: To determine the frequency of multiple pathology [Alzheimer Disease (AD) plus Vascular Dementia and/or Dementia with Lewy Bodies] in patients enrolled in clinical trials of AD therapy, and to compare the cognitive and functional assessments between patients with pure AD and AD with multiple pathology. METHODS: We conducted a retrospective analysis of patients with a clinical diagnosis of AD who were enrolled in AD therapy clinical trials and subsequently received an autopsy for confirmation of their diagnosis from 2000 to 2009. Performance on cognitive screening tests, namely Modified Mini Mental state (3MS) exam, Mini Mental state Exam (MMSE) and Functional Rating Scale (FRS) were compared between patients with pure AD and multiple pathology. RESULTS: Autopsy reports were available for 16/47 (34%) of deceased patients. Of these 16 patients, 5 (31%) had pure AD pathology, 10 (63%) had AD with other pathology, and 1 (6%) had non-AD pathology. Compared to patients with pure AD, patients with AD mixed with other pathology had poorer baseline FRS in problem-solving (p<0.01) and community affairs (p<0.02). CONCLUSION: While the strict enrollment criteria for clinical trials identified the presence of AD pathology in the majority of cases (15/16), multiple pathology was more common than pure AD in our series of autopsied patients. Premortem biomarkers that can distinguish between pure AD and AD with multiple pathology will be beneficial in future clinical trials and dementia patient management. PMID- 22931700 TI - Quantitative volumetric analysis post transsphenoidal pituitary adenoma surgery. AB - BACKGROUND: Computed tomogram (CT) imaging is often used for immediate postoperative assessment of transsphenoidal pituitary adenoma resection while magnetic resonance imaging (MRI) is used for follow-up. The residual mass is known to decrease in size over time but the difference between the two imaging modalities has not been quantified. Our objective was to quantify the size difference of the residual mass on immediate postoperative CT compared with delayed MRI. METHODS: Retrospective analysis of 69 patients who had undergone pituitary adenoma resection at our institution between 2004-2010. Sellar and suprasellar diameter, along with the overall volume of the residual mass were measured on both the immediate postoperative CT and delayed MRI. RESULTS: Average preoperative sellar and suprasellar diameter was 22.2 +/- 4.6mm and 20.9 +/- 5.9mm, respectively. Average sellar residual diameter on immediate postoperative CT (16.5 +/- 5.4 mm, 25% reduction) was significantly larger than delayed MRI (10.6 +/- 6.2mm, 52% reduction). The average suprasellar component on CT (15.5+/ 6.5mm, 26% reduction) was also significantly larger than that on MRI (3.3 +/- 5.4 mm, 84% reduction). The postoperative CT showed a 46% reduction in volume while a 71% reduction was noted on the delayed MRI. CONCLUSION: A significant reduction in residual mass is noted on delayed MR imaging compared with immediate postoperative CT. Therefore, from a resource management and prognostication point of view, CT should be used for immediate postoperative assessment while delayed MRI should be used to assess operative success and for communication with patients. PMID- 22931701 TI - Immune cell infiltrates in atypical teratoid/rhabdoid tumors. AB - OBJECTIVE: Atypical teratoid/rhabdoid tumor (AT/RT) is a highly malignant tumor of the central nervous system. Its pathogenesis remains unknown. Like glioblastomas, AT/RTs contain brain cancer stem cells (CSCs) that suppress the immunity of patients and are resistant to conventional chemotherapy and radiation therapy. Considerable infiltration of immune cells, including macrophages/microglia, dendritic cells and T-cells, has been noted in glioblastomas, which correlates with poor prognosis. The present study examines the significance of infiltrating immune cells in four cases of AT/RT; including one associated with an autoimmune disease, Henoch-Schonlein purpura. METHODS: Tumor tissues from four patients with AT/RT were analyzed and compared with those from four patients with glioblastomas. The frequency of immune cells, including CD68+, CD4+, and CD8+ cells, was assessed by scoring for statistical analysis. RESULTS: The infiltration of immune cells was identified in the case of AT/RT associated with HSP and three other cases of infratentorial AT/RTs. Moderate infiltration of CD68+ macrophages/microglia and CD4+ cells was noted in AT/RTs with no significant difference from that in glioblastomas (p > 0.05). However, the infiltration of CD8+ T-cells was significantly higher in AT/RTs than that in glioblastomas (p < 0.05); CD4+/CD8+ ratio was significantly lower in AT/RTs than that in glioblastomas (p < 0.05). In addition, eosinophils were found in all AT/RTs, but not in glioblastomas. CONCLUSIONS: These findings suggest an immune microenvironment of AT/RTs with more immune effectors than glioblastomas. Our observation contributes to understanding the growth environment of AT/RTs for which adjuvant immunotherapy may be potentially beneficial. PMID- 22931703 TI - Fatigue impact scale demonstrates greater fatigue in younger stroke survivors. AB - BACKGROUND: Fatigue affects 33-77% of stroke survivors. There is no consensus concerning risk factors for fatigue post-stroke, perhaps reflecting the multifaceted nature of fatigue. We characterized post-stroke fatigue using the Fatigue Impact Scale (FIS), a validated questionnaire capturing physical, cognitive, and psychosocial aspects of fatigue. METHODS: The Stroke Outcomes Study (SOS) prospectively enrolled ischemic stroke patients from 2001-2002. Measures collected included basic demographics, pre-morbid function (Oxford Handicap Scale, OHS), stroke severity (Stroke Severity Scale, SSS), stroke subtype (Oxfordshire Community Stroke Project Classification, OCSP), and discharge function (OHS; Barthel Index, BI). An interview was performed at 12 months evaluating function (BI; Modified Rankin Score, mRS), quality of life (Reintegration into Normal living Scale, RNL), depression (Geriatric Depression Scale, GDS), and fatigue (FIS). RESULTS: We enrolled 522 ischemic stroke patients and 228 (57.6%) survivors completed one-year follow-up. In total, 36.8% endorsed fatigue (59.5% rated one of worst post-stroke symptoms). Linear regression demonstrated younger age was associated with increased fatigue frequency (beta= 0.20;p=0.01), duration (beta=-0.22;p<0.01), and disability (beta=-0.24;p<0.01). Younger patients were more likely to describe fatigue as one of the worst symptoms post-stroke (beta=-0.24;p=0.001). Younger patients experienced greater impact on cognitive (beta=-0.27;p<0.05) and psychosocial (beta=-0.27;p<0.05) function due to fatigue. Fatigue was correlated with depressive symptoms and diminished quality of life. Fatigue occurred without depression as 49.0% of respondents with fatigue as one of their worst symptoms did not have an elevated GDS. CONCLUSIONS: Age was the only consistent predictor of fatigue severity at one year. Younger participants experienced increased cognitive and psychosocial fatigue. PMID- 22931702 TI - The effects of exercise intensity on p-NR2B expression in cerebral ischemic rats. AB - BACKGROUND: The current study explored the effects of treadmill exercise intensity on functional recovery and hippocampal phospho-NR2B (p-NR2B) expression in cerebral ischemic rats, induced by permanent middle cerebral artery occlusion (MCAO) surgery. METHOD: Adult male Sprague-Dawley rats were randomly divided into four groups, including sham, no exercise (NE), low intensity training (LIT, v = 15 m/min), and moderate intensity training groups (MIT, v = 20 m/min). At different time points, the hippocampal expressions of p-NR2B and total NR2B were examined. In addition, neurological deficit score (NDS), body weight, and 2,3,5 triphenyltetrazolium chloride (TTC) staining were used to evaluate brain infarct volume as assessments of post-stroke functional recovery. In order to investigate the effect of exercise on survival, the mortality rate was also recorded. RESULTS: The results showed that treadmill exercise significantly decreased hippocampal expression of p-NR2B but didn't change the total NR2B, compared to the NE group on the 3rd, 7th, and 14th days following MCAO surgery. The effect on changes in p-NR2B levels, body weight, and brain infarct volume were more significant in the LIT compared to the MIT group. DISCUSSION AND CONCLUSION: The current findings demonstrate that physical exercise can produce neuroprotective effects, in part by down-regulating p-NR2B expression. Furthermore, the appropriate intensity of physical exercise is critical for post-stroke rehabilitation. PMID- 22931704 TI - The haplotype of the TGFbeta1 gene associated with cerebral infarction in Chinese. AB - BACKGROUND: Transforming growth factor beta1 (TGFbeta1) is a multifunctional cytokine involved in inflammation and pathogenesis of atherosclerosis. The aim of the present study was to investigate the relationship between human TGFbeta1 gene +869T>C (rs1800470), -509C>T (rs1800469) single nucleotide polymorphisms (SNPs) and haplotypes and cerebral infarction (CI) in a Chinese population. METHODS: The genetic association study was performed in 450 Chinese patients (306 male and 144 female) with CI and 450 control subjects (326 male and 124 female). TGFbeta1 gene +869T>C and -509C>T polymorphisms were identified with amplification refractory mutation system polymerase chain reaction and DNA sequencing method. RESULTS: The individual SNPs analysis showed the +869T and -509C in an additive model (+869T vs +869C; -509 C vs T), +869TT genotype in a recessive model (TT vs TC+CC) and 509CC genotype in a dominant model (CC+ CT vs TT) were identified to be related to CI (P<0.05). +869T>C and -509C>T SNPs were in strong linkage disequilibrium (d'=0.87, R2=0.75). Haplotype analysis showed that +869C/-509T haplotype was associated with a significant decreased risk of CI (OR= 0.86, 95%CI, 0.70-0.92; P=0.007). Furthermore,+869T/-509C haplotype was associated with a significant increased risk of CI (OR=1.31, 95%CI, 1.10-2.03; P=0.019). CONCLUSIONS: The results of this study indicate that polymorphisms and the haplotypes in the TGFbeta1 gene might be genetic markers for CI in the Chinese population. PMID- 22931705 TI - Does extent of resection impact survival in patients bearing glioblastoma? AB - BACKGROUND: The impact of malignant glioma resection on survival is still a matter of controversy. The lack of well-designed prospective studies as well as control of all factors in retrospective studies plays an important role in this debate. Amongst some of these uncontrolled factors, are the inclusion of different histological grades, the lack of objective methods to estimate the extent of resection and unspecified delays in post-operative imaging. METHODS: We retrospectively reviewed 126 consecutive patients with glioblastoma, operated on by the senior authors at the Centre Hospitalier Universitaire de Sherbrooke, who met the following criteria: >18 years of age, newly diagnosed glioblastoma, pre operative magnetic resonance imaging (MRI) within 2 weeks prior to surgery, and a post-operative MRI within 72 hours after surgery. Extent of tumour resection was calculated using pre and post-operative tumour delimitation on gadolinium enhanced T1 MRI in a volumetric analysis. RESULTS: Applying stringent specific inclusion criteria, 126 patients were retained in the analysis. The median overall survival was 271 days and the median extent of resection was 65%. Patients with more than 90% of tumour resection had a significantly better outcome, improving median survival from 225 to 519 days (P=0.006). Other factors that significantly improved survival were the use of radiotherapy, the number of regimens and type of chemotherapy used. CONCLUSION: A more aggressive approach combining maximal safe resection and use of salvage chemotherapy seems to confer a survival advantage for glioblastoma patients. PMID- 22931706 TI - Is this subarachnoid hemorrhage significant? A National Survey of Neurosurgeons. AB - BACKGROUND: Previously all subarachnoid hemorrhage (SAH) patients were admitted, whereas now patients with angiography may be discharged. OBJECTIVE: To survey neurosurgeons to determine current practice and what constitutes a clinically significant subarachnoid hemorrhage. METHODS: We surveyed all neurosurgeons listed in the Canadian Medical Directory. We used a modified Dillman technique with up to five mailed surveys plus a pre-notification letter. Neurosurgeons rated the significance of 13 scenarios of subarachnoid hemorrhage. Scenarios varied from aneurysmal subarachnoid hemorrhage to patients with isolated xanthochromia in cerebrospinal fluid. Each scenario was rated for clinical significance using a 5-point scale [1(always) to 5(never)]. RESULTS: Of the 224 surveyed, 115 neurosurgeons responded. Scenarios with aneurysms requiring intervention, arteriovenous malformations, death or any surgical intervention all had median responses of 1 (IQR 1, 1). Scenarios having xanthochromia and few red blood cells in cerebrospinal fluid with negative computerized tomogram (CT) and angiography had median responses of 3 (IQR 1, 4). Scenarios with perimesencephalic pattern on CT with negative angiography had median of 3 (IQR 2, 4). Scenarios where patient is discharged from the emergency department had median of 4 (IQR 3, 5). CONCLUSION: Subarachnoid hemorrhages due to aneurysms or arteriovenous malformations causing death or requiring surgical intervention are always clinically significant. Other types of nonaneurysmal subarachnoid hemorrhages had inconsistent ratings for clinical significance. These survey results highlight the need for further discussions to standardize the diagnosis of what constitutes a clinically significant subarachnoid hemorrhage and what care should be afforded to these patients. PMID- 22931707 TI - Delays in initiation of acyclovir therapy in herpes simplex encephalitis. AB - BACKGROUND: Diagnosis of herpes simplex encephalitis (HSE) is based on clinical findings, MRI, and detection of herpes simplex virus (HSV) DNA in cerebrospinal fluid (CSF) using polymerase chain reaction amplification. Delays in starting treatment are associated with poorer clinical outcomes. We assessed the timing of initiation of acyclovir therapy in HSE. METHODS: Inpatient databases from seven hospitals in Winnipeg, Manitoba were used to identify individuals diagnosed with encephalitis and HSE from 2004 to 2009. The time taken to initiate therapy with acyclovir and the reasons for delays were determined. RESULTS: Seventy-seven patients were identified; 69 (90%) received acyclovir; in the others a non-HSV infection was strongly suspected. Thirteen patients were subsequently confirmed to have HSE. Acyclovir was initiated a median of 21 hours (3-407) after presentation in encephalitis cases, and a median of 11 hours (3-118) in HSE. The most common reason for delay was a failure to consider HSE in the differential diagnosis, despite suggestive clinical features. Where therapy was delayed in HSE patients, the decision to begin acyclovir was prompted by transfer of the patient to a different service (55%), recommendations by consultants (18%), imaging results (18%), and CSF pleocytosis (9%). CONCLUSIONS: Delays in initiating acyclovir for HSE are common, and are most often due to a failure to consider HSE in a timely fashion on presentation. In order to improve patient outcomes, physicians should be more vigilant for HSE, and begin acyclovir therapy expeditiously on the basis of clinical suspicion rather than waiting for confirmatory tests. PMID- 22931708 TI - Intraventricular localization of an anaplastic oligodedendroglioma: a rare event. PMID- 22931709 TI - Decompressive craniectomy in traumatic brain injury: the edge effect. PMID- 22931710 TI - COL4A1 mutation in a pediatric patient presenting with post-ictal hemiparesis. PMID- 22931711 TI - Aphemia after infarction of the left precentral gyrus and premotor area. PMID- 22931712 TI - Refractory status epilepticus associated with anti-SSA (anti-Ro) antibodies. PMID- 22931713 TI - T2-dark restricted diffusion. PMID- 22931714 TI - Increasing the appeal of neurosurgery to qualified medical students in Canada. PMID- 22931715 TI - Natalizumab risk stratification: role of a two- step anti-JCV antibody assay. PMID- 22931716 TI - Rapidly progressive dementia in a Chinese patient due to C90RF72 mutation. PMID- 22931718 TI - [Keep solidarity, collaborative and challenging]. PMID- 22931719 TI - [Diagnosis and management of bronchial fistula]. PMID- 22931720 TI - [Quantitative analysis of the ultrasonogram and histological findings in normal airway wall]. AB - OBJECTIVE: To find out the correlation between endobronchial ultrasonography (EBUS) images and histologic findings in normal bronchial wall via quantitative analysis of the airway wall thickness and the layer thickness. METHODS: From July 1st to December 31th in 2010, patients underwent lobectomy performed endobronchial ultrasonography (EBUS) before surgery and frost pathological examination after surgery. The layer thickness of EBUS and pathological images were measured. Bland-Altman plots were used to analyze the agreement between EBUS measurements and pathological measurements. RESULTS: Twenty-one patients were enrolled in the study. Five layers of the wall were distinguished at the ultrasonogram. Starting on the luminal side, the first, third and fifth layer (L1, L3, L5) were hyperechoic while the second, fourth layer (L2, L4) were hypoechoic. The wall thickness with good agreement was almost equal between the 2 kinds of images (1.877:1.745). L1 thickness was lager than the mucosa thickness (0.275:0.164). L2 thickness was smaller than the submucosa thickness (0.100:0.202). L1 + L2 thickness was almost equal to the thickness of mucosa and submucosa layer (0.375:0.366). The Bland-Altman plots showed poor agreement between the L1, L2 thickness and the mucosa thickness, the submucosa thickness while good agreement between the L1 + L2 thickness and the thickness of mucosa and submucosa layer. L3 thickness was lager than the inner perichondrium thickness (0.241:0.075), and L4 thickness was smaller than the cartilage layer thickness (0.655:0.811). L3 + L4 thickness was almost equal to thickness of the inner perichondrium and the cartilage layer (0.895:0.887). L5 thickness was almost equal to thickness of the outer perichondrium and the connective tissue outside the cartilage layer (0.533:0.491). The Bland-Altman plots showed poor agreement between the L3, L4 thickness and the inner perichondrium thickness, cartilage layer thickness, while good agreement between L5, L3 + L4, L3 + L4 + L5 thickness and the corresponding indexes. CONCLUSIONS: There is a five-layer structure on the bronchial EBUS image including the first layer at the luminal side corresponding to the mucosa and inner part of the submucosa; the second layer corresponding to the outer part of submucosal tissue; the third layer corresponding to the inner perichondrium and the inner part of the cartilage; the fourth layer corresponding to the outer part of cartilage; the fifth layer corresponding to the outer perichondrium and the connective tissue outside the cartilage layer. PMID- 22931721 TI - [Intralesional triamcinolone acetonide injection combined with conventional interventional modalities for the management of recalcitrant benign central airway stenosis: preliminary experience]. AB - OBJECTIVE: To evaluate the efficacy and security of local injection of triamcinolone acetonide (TA) combined multiple convention interventional procedures for benign central airway stenosis (BAS). METHODS: Forty patients with intractable benign central airway restenosis after treated by repeatedly traditional interventional treatment in our hospital between January 2008 to December 2010 were retrospectively analyzed. Forty intractable BAS patients were selected and averagely divided into treatment group and control group. Local injection of TA was used to cover entire stenosis lesions. Two or more procedures were combined to manage complicated airway stenosis. After a 6 months follow-up, compared to before and after the treatment of airway diameter, airway stricture rate, dyspnea score, interphase of interventional treatment and clinical stabilization, fasting blood glucose, plasma cortisol, injection local mucosal and clinical symptoms, evaluated its curative effect and side effect. RESULT: Twenty cases of treatment group patients with intractable benign central airway stenosis were treated. After 6 to 18 months follow-up, 16 patients remain stable after treatment, besides 4 patients appear restenosis. 16 patients, did not appear restenosis; 4 patients appear restenosis. Restenosis interphase time or Clinical stationary time was increased from (10.95 +/- 5.49) days before the therapy to (98.75 +/- 55.58) days after therapy of local injection of TA (P < 0.01). The long-term outcome, the control group 20 cases restenosis in a 6 months follow-up time. After 6 months the the airway diameter of treatment group is (8.70 +/- 2.52) mm compared with control group (4.50 +/- 1.64) mm, (P < 0.01); the airway narrow rate of treatment group is (29.17 +/- 14.55)%, compared with control group (64.80 +/- 13.35)%, (P < 0.01); breathlessness score of treatment group is (0.55 +/- 0.76), compared with control group (2.70 +/- 0.92, P < 0.01), with statistically significant difference. None of the twenty patients appear local injections related complications, observation period, cortisol levels remain normal without glucocorticoids related serious complications. CONCLUSION: Local injections of TA therapy combined with traditional interventional techniques for BAS has good curative effect and safety. PMID- 22931722 TI - [The clinical value of autofluorescence bronchoscopy for the diagnosis of lung cancer]. AB - OBJECTIVES: To evaluate the benefit of using autofluorescence bronchoscopy (AFB) for the detection and localization of early invasive lung cancer. METHODS: AFB and white light bronchoscopy (WLB) were performed on 198 cases of suspected lung cancer, and the relative sensitivity of WLB plus AFB compared with WLB alone. RESULTS: Included 198 biopsy specimens, and 160 were classified as positive by pathology, including 156 invasive cancer and 4 severe dysplasia. The relative sensitivity to detect intraepithelial neoplasia of WLB + FLB versus WLB was 97.5% and 80.0% respectively, significantly (P < 0.05). CONCLUSION: AFB was more sensitive than WLB in detecting preneoplastic bronchial changes and early lung cancer in high-risk subjects. PMID- 22931723 TI - [Effects of chronic Aspergillus fumigatus exposure on the expression of mucin 5AC in the airways of asthmatic rats]. AB - OBJECTIVE: To explore the effects of chronic Aspergillus fumigatus (Af) exposure on the expression of mucin 5AC (MUC5AC) in the airways of asthmatic rats. METHODS: Fifty-six male Wistar rats were randomly divided into 8 groups: chronic asthma (group A), chronic asthma plus Af spores inhalation for 1 week (group B), 3 weeks (group C) and 5 weeks (group D), chronic asthma plus saline inhalation for 5 weeks (group E), OVA-sensitized and-saline-challenged group (group F) and OVA-sensitized and-saline-challenged plus Af spores inhalation for 5 weeks (group G) (each n = 8). The airway resistance (Raw) and the change rate of Raw after acetylcholine provocation were detected using a computerized system. The level of MUC5AC mRNA in the lung tissue was measured by RT-PCR, and the expression of MUC5AC in airway epithelial cells were demonstrated by immunohistochemistry. The concentration of IL-13 in BALF was measured by ELISA. The extent of goblet cell hyperplasia was evaluated on periodic acid-Schiff stain (PAS) lung sections. RESULTS: In group B, C, and D, the level of MUC5AC mRNA (MUC5AC mRNA/beta-actin mRNA) (1.9 +/- 0.4, 2.3 +/- 0.6, 2.9 +/- 0.8, respectively), the integrated optical density (value A) of MUC5AC positive stain in airway epithelial cells (278 +/- 58, 566 +/- 64, 891 +/- 80, respectively), the concentration of IL-13 in BALF (ug/L) (96 +/- 16, 136 +/- 22, 197 +/- 34, respectively), and the ratio of goblet cell area to epithelial cell area(%) (16 +/- 5, 23 +/- 7, 36 +/- 9, respectively), were higher than those in group A, E, F and G (all P < 0.05). The change rate of Raw(%) in group C and D (61.91 +/- 5.26 and 84.69 +/- 6.38) were higher than that in group A, E, F and G (all P < 0.05). The level of MUC5AC mRNA and the value A of MUC5AC were positively correlated with the ratio of goblet cell area to epithelial cell area (r = 0.578, P < 0.05;r = 0.614, P < 0.05, respectively) and the change rate of Raw (r = 0.638, P < 0.05;r = 0.564, P < 0.05, respectively) in group B, C and D. CONCLUSION: Chronic Aspergillus fumigatus exposure upregulated the expression of MUC5AC in the airway epithelial cells and induced goblet cell hyperplasia, resulting in increased airway hypersensitivity in rats with chronic asthma. PMID- 22931724 TI - [Clinical features of respiratory failure and heart failure in patients with sleep disordered breathing]. AB - OBJECTIVE: To assess the clinical characteristics of heart failure and respiratory failure in patients with sleep disordered breathing (SDB). METHODS: Symptoms, signs, laboratory tests, clinical courses, blood gases responses to voluntary hyperventilation test and non-invasive ventilation treatment were analyzed in 29 patients with SDB. All patients were diagnosed as right and left heart failure and respiratory failure from 1994 to 2009 in Peking University People's Hospital. RESULTS: Among the 29 patients recruited, 13 were male and 16 female. The mean age was 62 +/- 13 yrs, and BMI was (34 +/- 4) kg/m(2). Fourteen (48.3%) were diagnosed as obstructive sleep apnea syndrome at first visit. Chief complains includes dyspnea, edema, cough, snoring, hypersomnolence, oliguria, and altered mental status. Common signs include obesity, narrow upper airway, cyanosis, moist rales at the base of lungs, enlarged border of cardiac dullness, edema. Polycythemia was seen in 13 patients (44.80%), among the 26 patients who had underwent pulmonary function tests, 14 had FEV(1)/FVC >= 70%, the others were FEV(1)/FVC < 70%, with 6 patients had 50% predict value <= FEV(1) < 80% predict value and 6 patients had 30% predict value <= FEV(1) < 50% predict value. After positive airway pressure (BiPAP and CPAP) treatment, symptoms and arterial blood gases test results improved. Chest X-ray, CT scan and UCG show pulmonary vascular congestion and edema with cardiomegaly and possible pleural effusion, pulmonary hypertension, left ventricular diastolic dysfunction. Five patients underwent 24 h blood pressure monitoring showed non-dipping pattern or morning risen pattern of BP. In 11 patients who undertaken the test, voluntary hyperventilation induced significant improvement of SpO(2), PaCO(2) and PaO(2), and most of the parameters returned from type II respiratory failure to normal level. CONCLUSION: The morbidity of SDB remained to be recognized. This cases report indicated that obese patients complaining of severe dyspnea and edema may have respiratory failure and bilateral heart failure secondary to SDB. The respiratory failure can be completely reversed by voluntary hyperventilation, and noninvasive treatments only could achieve good outcomes in most of the patients. PMID- 22931725 TI - [TNFR-Fc prevents lipopolysaccharide-induced acute lung injury in mice via oxidative stress inhibition]. AB - OBJECTIVE: Acute lung injury (ALI) was associated with excessive inflammation caused by high TNF-alpha concentration. We hypothesized that anti-TNF-alpha therapy would have beneficial effects in experimental ALI in mice via oxidative stress inhibition. METHODS: BALB/c mice (8 - 10 week old) were randomly assigned to an LPS group, a TNFR-Fc + LPS group and a control group. LPS (5 mg/kg) was intratracheally administered to the mice. For the TNFR-Fc + LPS group, TNFR-Fc was given intraperitoneally once at a dose of 0.4 mg/kg before LPS treatment, at 0 and 2 h after LPS treatment, the mice were sacrificed. Wet to dry ratio of the lung and the protein concentration in BALF were measured. Lung histology was evaluated for lung injury. TNF-alpha concentration in serum, MDA and total anti oxidative stability were assayed. Finally, the transcription level of iNOS, Nox1, Nox2, Nox4, XO and SOD were evaluated by qRT-PCR. RESULTS: TNFR-Fc treatment significantly decreased the serum TNF-alpha concentration (P < 0.001), reduced the score of lung histology and decreased the protein concentration in BALF (P < 0.001), but did not change the wet to dry ratio of the lung. The ALI mice treated with TNFR-Fc had a lower transcription level of Nox1, Nox2, Nox4 and XO (all P < 0.001). The total anti-oxidative stability of mice treated with TNFR-Fc was preserved better than those treated with LPS alone (P < 0.05). CONCLUSION: Treatment with TNFR-Fc significantly reduced LPS-induced ALI. The transcription level of Nox and XO was down-regulated by anti-TNF-alpha therapy, followed by oxidative stress attenuation. PMID- 22931727 TI - [Progress in idiopathic pulmonary fibrosis and microRNAs]. PMID- 22931726 TI - [The pathogenic molecular diagnosis of lower respiratory tract infection]. PMID- 22931730 TI - Hyperammonemia in children: on the crossroad of different disorders. AB - BACKGROUND: Symptoms of hyperammonemia occur in patients irrespective of the kind of metabolic diseases. Age, metabolic and nutritional status, and decompensation factors such as infections influence clinical manifestations. Prolonged, untreated hyperammonemia leads to brain injury and intellectual disability. Treatment is directed at lowering plasma ammonia. Brain ammonium concentrations are 1.5 to 3.0 times higher than that in blood. REVIEW SUMMARY: The authors discuss the pathophysiology of the symptoms and consequences of hyperammonemia in children, focusing on the metabolic disorders leading to an increased level of ammonia. CONCLUSIONS: Ammonia toxicity has been investigated for a long time. According to the main hypotheses, the neurological alterations are connected to alterations in glutamatergic neurotransmission. PMID- 22931728 TI - Clinical characteristics of symptomatic vertebral artery dissection: a systematic review. AB - BACKGROUND: Vertebral artery dissection (VAD) is an important cause of stroke in the young. It can present nonspecifically and may be misdiagnosed with adverse consequences. We assessed the frequency of head/neck pain, other neurological symptoms, and cerebrovascular events in symptomatic VAD. METHODS: We conducted a systematic review of observational studies, searching electronic databases (MEDLINE, EMBASE) for English-language manuscripts with >5 subjects with clinical or radiologic features of VAD. Two independent reviewers selected studies for inclusion; a third adjudicated differences. Studies were assessed for methodological quality, and clinical data were abstracted. Pooled proportions were calculated. RESULTS: Of 3996 citations, we screened 511 manuscripts and selected 75 studies describing 1972 VAD patients. The most common symptoms were dizziness/vertigo (58%), headache (51%), and neck pain (46%). Stroke was common (63%), especially with extracranial dissections (66% vs. 32%, P<0.0001), whereas transient ischemic attack (14%) and subarachnoid hemorrhage (10%) were uncommon. Subarachnoid hemorrhage was seen only with intracranial dissections (57% vs. 0%, P=0.003). Fewer than half of the patients had obvious trauma, and only 7.9% had a known connective tissue disease. Outcome was good (modified Rankin scale 0 to 1) in 67% and poor (modified Rankin scale 5 to 6) in 10% of patients. CONCLUSIONS: VAD is associated with nonspecific symptoms such as dizziness, vertigo, headache, or neck pain. Ischemic stroke is the most common reported cerebrovascular complication. VAD should be considered in the diagnostic assessment of patients presenting with dizziness or craniocervical pain, even in the absence of other risk factors. Future studies should compare clinical findings as predictors in well-defined, undifferentiated populations of clinical VAD suspects. PMID- 22931729 TI - Imaging characteristics of symptomatic vertebral artery dissection: a systematic review. AB - BACKGROUND: Vertebral artery dissection (VAD) is an important cause of stroke in the young. VAD can present with a range of imaging findings. We sought to summarize the diagnostic value of various imaging findings in patients with symptomatic VAD. METHODS: We conducted a systematic review of observational studies, searching electronic databases (MEDLINE, EMBASE) for English-language manuscripts with >5 subjects with clinical or radiologic features of VAD. Two independent reviewers selected studies for inclusion; a third adjudicated differences. Studies were assessed for methodological quality and imaging data were abstracted. Pooled proportions were calculated. RESULTS: Of 3996 citations, we screened 511 manuscripts and selected 75 studies describing 1972 VAD patients. Most studies utilized conventional angiography or magnetic resonance angiography (MRA) to diagnose VAD; computed tomographic angiography (CTA) and Doppler ultrasonography were described less frequently. Imaging findings reported were vertebral artery stenosis (51%), string and pearls (48%), arterial dilation (37%), arterial occlusion (36%), and pseudoaneurysm, double lumen, and intimal flap (22% each). In cases where conventional angiography was the reference standard, CTA was more sensitive (100%) than either MRA (77%) or Doppler ultrasonography (71%) (P=0.001). CONCLUSIONS: Imaging findings vary widely in patients with VAD, with no single radiographic sign present in the majority of VAD patients. Nonspecific radiographic signs predominate. CTA probably has greater sensitivity for dissection than MRA or ultrasound relative to conventional angiography. Higher quality studies on imaging techniques and radiographic criteria in subjects with VAD are needed. Future studies should compare imaging techniques in well-defined, undifferentiated populations of clinical VAD suspects. PMID- 22931731 TI - Atypical motor and behavioral presentations of Alzheimer disease: a case-based approach. AB - BACKGROUND: The correlation of clinical presentation to pathology in dementia syndromes is important to correctly classify and ultimately treat these conditions. However, despite careful clinical characterization, it remains difficult to accurately predict an underlying causative pathology in some cases. Alzheimer disease is a well-defined clinical entity having established diagnostic criteria and characteristic neuropathologic findings. Alzheimer pathology, however, can cause varying clinical syndromes, including both atypical motor and behavioral presentations. REVIEW SUMMARY: Atypical clinical presentations of Alzheimer disease are reviewed in a case-based format. Corticobasal syndrome, with asymmetric Parkinsonism, dystonia, and apraxia, is increasingly recognized as a presentation of Alzheimer pathology. Frontal variant Alzheimer, clinically indistinguishable from behavioral variant frontotemporal dementia (bv-FTD), can present with difficulties in executive function, poor attention, and behavioral issues. Posterior cortical atrophy (the "visual variant" of Alzheimer) has predominant visuospatial dysfunction and can be an Alzheimer presentation. Finally, Alzheimer can present as logopenic progressive aphasia with word-finding difficulty. CONCLUSIONS: Clinicopathologic correlation may be more complex than previously realized, and the location of the microscopic changes may have as much to do with the clinical presentation as the nature of the changes themselves. Recognizing these clinical syndromes can lead to greater accuracy in diagnosis and treatment. PMID- 22931732 TI - Intravenous thrombolysis in the treatment of ischemic stroke due to spontaneous artery dissection. AB - OBJECTIVES: Data based on randomized clinical trials regarding intravenous thrombolysis (IVT) versus placebo or any other antithrombotic treatment in ischemic stroke (IS) due to artery dissection (AD) are not available. METHODS: We used data from our observational study to examine the efficacy and safety of IVT in patients with IS due to spontaneous AD, as compared with stroke patients of the same cause who were not treated with IVT. Outcome measures were modified Rankin score (mRS) for functional outcome, death from all causes, occurrence of any intracranial hemorrhage, local signs of an intramural hematoma extension, recurrent IS, and recurrent AD. RESULTS: In a 4-year period, 19 of 46 patients with IS due to spontaneous AD were treated with IVT. Favorable outcome (mRS 0-2) after the follow-up period reached 81.5% of non-IVT patients compared with 94.7% of IVT-treated patients (odds ratio, 4.09; 95% confidence interval, 0.44-38.26; P=0.377). However, the patients who received IVT had a significantly higher chance of being without any neurological deficit (mRS 0) after adjusting for age, sex, baseline National Institutes of Health Stroke Scale score, and site of dissection compared with non-IVT patients after the follow-up period (P=0.012). No symptomatic intracerebral hemorrhage, worsening of local signs, cases of subarachnoid hemorrhage, or death occurred in both groups of patients. CONCLUSIONS: The efficacy of IVT in patients with IS due to the spontaneous AD seemed to be similar or even better to those of patients of the same cause who were not treated with IVT. The complication rate of IVT in spontaneous AD is low. PMID- 22931733 TI - Factors associated with increased carotid intima-media thickness in obstructive sleep apnea/hypopnea syndrome. AB - BACKGROUND: Obstructive sleep apnea/hypopnea syndrome (OSAHS) is strongly associated with the increase of cardiovascular and cerebrovascular disorders. Carotid intima-media thickness (IMT) is used as a surrogate marker for subclinical or early atherosclerosis. Knowledge regarding early atherosclerosis in patients with OSAHS is scarce, and factors predicting carotid IMT have not been well studied. OBJECTIVE: To compare IMT in patients with OSAHS versus controls and explore the factors associated with increased IMT in OSAHS. METHODS: One hundred fifty-six OSAHS patients and 35 controls without history of vascular events, hypertension, and diabetes mellitus who underwent polysomnography were consecutively enrolled. Carotid IMT was measured using B-mode ultrasonography. Body mass index, waist circumference, hip circumference, waist-to-hip circumference ratio, Epworth Sleepiness Scale, and polysomnographic variables including arousal index, apnea/hypopnea index, mean oxygen saturation, and lowest oxygen saturation were assessed. Fasting plasma glucose, blood lipid profile, and high-sensitivity C-reactive protein were measured. RESULTS: Average carotid IMT of OSAHS patients was significantly thicker than controls (0.66 vs. 0.58 mm, P=0.002) and multivariable logistic regression analysis revealed that arousal index [odds ratio (OR), 0.77; confidence interval (CI), 0.63-0.95; P=0.01] and lowest oxygen saturation (OR, 1.91; CI, 1.24-2.95; P=0.003) were significantly associated with OSAHS patients. Among the OSAHS patients, age (OR, 1.16; CI, 1.10 1.22; P<0.0001), fasting plasma glucose (OR, 1.05; CI, 1.01-1.10; P=0.04), low density lipoprotein cholesterol (OR, 1.03; CI, 1.02-1.05; P<0.0001), and high sensitivity C-reactive protein (OR, 1.48; CI, 1.13-1.95; P=0.005) were significantly associated with patients with IMT>=0.65 mm. CONCLUSIONS: IMT was thicker in OSAHS patients without history of vascular events, hypertension, and diabetes mellitus. This study demonstrates that early atherosclerosis exists in this group of patients. PMID- 22931734 TI - Polymorphisms of genes encoding coagulation factors II, V, VII, and XIII in relation to pediatric ischemic stroke: family-based and case-control study. AB - BACKGROUND: The investigation of a possible association between the FII, FV, FVII, and FXIII genes polymorphisms and pediatric ischemic stroke (IS). METHODS: The study group consisted of 392 individuals, including 81 children with IS, their biological parents (n=162), and 149 control children. The polymorphisms were genotyped using polymerase chain reaction-restriction fragments length polymorphism method. The relation between analyzed polymorphisms and the disease was tested by 2 independent methods: family-based association test transmission/disequilibrium test (TDT) and classic case-control model. RESULTS: We did not observe any preferential distribution of any analyzed allele from parents to the affected children. For the FVII gene polymorphism, there was a trend toward a higher frequency of the R allele. In a case-control model, the differences between the patients and controls in the frequency of the Q allele, Q allele carriers, and RR homozygotes lay close to the border of statistical significance (P=0.08). There were no significant differences in genotype and allele distribution between patients and controls in case of other polymorphisms. CONCLUSIONS: Analyzed polymorphisms of coagulation factors are not significant determinants of pediatric IS in the studied population; however, these findings require a confirmation in a larger group of participants. PMID- 22931735 TI - Early-onset ataxia with progressive external ophthalmoplegia associated with POLG mutation: autosomal recessive mitochondrial ataxic syndrome or SANDO? AB - Autosomal recessive ataxias caused by mutations of the polymerase gamma (POLG) gene make an important group of progressive ataxias accompanied by a diverse spectrum of neurological disorders. Because the clinical picture can be quite miscellaneous, it is challenging to assort patients to any of the currently described syndromes; therefore, to provide such a patient with a conclusive diagnosis can be challenging for the neurologist. A typical magnetic resonance imaging finding is probably the most useful landmark in the diagnostic process, which will steer the clinician toward POLG gene testing. To illustrate this, we present a case of progressive ataxia caused by A467T and W748S mutations of POLG gene, who presented with overlapping symptoms of autosomal recessive mitochondrial ataxic syndrome and SANDO, as well as choreoathetotic movements and dysphonia. After lengthy investigations, magnetic resonance imaging showed T2 and FLAIR hyperintensities in the thalamus, inferior olives, and cerebellum, which led us to the analysis of POLG mutations. PMID- 22931737 TI - Thrombolysis of ischemic stroke from noncompaction in metabolic myopathy. AB - BACKGROUND: Ischemic stroke has not been reported together with left ventricular hypertrabeculation/noncompaction (LVHT) and metabolic myopathy. METHODS AND RESULTS: In a 32-year-old woman with suspected metabolic myopathy, congenital AV block, pacemaker implantation at the age of 20, and reduced systolic function, LVHT was detected on echocardiography. Shortly afterward, the patient had a left sided ischemic stroke and underwent systemic thrombolysis with rTPA 3.5 hours after the onset. After the exclusion of potential causes of stroke, cerebral thromboembolism was attributed to LVHT. Oral anticoagulation was initiated and a cardiac resynchronization system was implanted. CONCLUSIONS: LVHT patients with systolic dysfunction or atrial fibrillation experiencing an ischemic stroke may benefit from oral anticoagulation. PMID- 22931736 TI - Acute intracranial in-stent thrombosis after angioplasty of middle cerebral artery symptomatic stenosis: a case report. AB - INTRODUCTION: Intracranial atherosclerotic disease is one of the major risk factors of ischemic stroke. Percutaneous transluminal angioplasty with stent deployment may be effective for the treatment of symptomatic intracranial stenosis, however its value is yet to be determined. High possibility of serious periprocedural complications, such as acute in-stent thrombosis or stroke, narrows the current recommendations for this treatment to patients with high grade stenosis (>70%), and to experienced neurointerventional centers. CASE REPORT: We present a 44-year-old male with symptomatic high-grade stenosis of the M1 segment of left middle cerebral artery, treated with percutaneous transluminal angioplasty with stenting. The procedure was complicated with acute in-stent thrombosis treated with intra-arterial thrombolysis, which resulted in a nondisabling stroke. CONCLUSIONS: The procedure-related stroke in this patient was probably caused by middle cerebral artery perforator ostium occlusion with balloon predilatation and transient in-stent thrombosis related to insufficient antiplatelet pretreatment. Exhausted cerebrovascular reserve due to long-lasting high-grade intracranial stenosis should also be considered as a factor contributing to ischemic complications. PMID- 22931738 TI - Lifting the "FOG" with laser generated visual-cueing. AB - BACKGROUND AND PURPOSE: To ascertain whether freezing of gait (FOG) and stride reduction (SR) may be relieved by the use of an attachable, adjustable laser (the Mobilaser). METHODS: Seven parkinsonian patients with FOG and SR were randomized in an open-label, randomized, cross-over clinical study at a tertiary referral center. The Mobilaser was attached to a 4-wheeled walker by Velcro and switched on, producing an adjustable red line, which the subjects stepped on or over while ambulating a standardized course. The length of time each subject took, and the number of freezes they experienced traversing the course, using a 4-wheeled walker with the device turned on and off, were compared. RESULTS: A total of 7 patients were investigated; however, one was excluded from the study due to severe deconditioning, prohibiting completion of the testing. Of the 6 enrolled, all subjects took less time to ambulate the course using the attachable, adjustable laser than without it (Wilcoxon signed-rank test, P=0.03). In addition, the total number of freezes was less in all 6 subjects when using the device than without it. No adverse events occurred during the trial. DISCUSSION AND CONCLUSIONS: The Mobilaser is potentially an effective and safe device for alleviating parkinsonian FOG and SR. PMID- 22931739 TI - Monosymptomatic clinically isolated syndrome with sudden sensorineural hearing loss: case report and critical review of the literature. AB - INTRODUCTION: Isolated cranial nerve involvement is rare in patients with multiple sclerosis (10.4%) and extremely rare is an eighth nerve palsy, especially in the context of a clinically isolated syndrome (<1%). CASE REPORT: A 34-year-old male presented with a history of left-sided tinnitus and sudden sensorineural hearing loss (SSNHL). Magnetic resonance imaging of the brain revealed >9, nonenhancing periventricular and corpus callosum lesions. Brainstem auditory evoked potentials were abnormal, ipsilateral to the affected ear, consistent with the presumed underlying demyelinating pathology. Visual evoked potentials showed bilateral prolonged P100 latencies. Oligoclonal bands were not detected in the cerebrospinal fluid, but IgG index was marginally elevated. After administration of corticosteroids, the patient recovered auditory function over a several month period. CONCLUSIONS: This report describes a case of SSNHL in the context of magnetic resonance imaging of the brain and electrophysiological findings consistent with a demyelinating etiology. SSNHL is a rare and possibly underrecognized manifestation of clinically isolated syndrome. PMID- 22931740 TI - Selective pseudohypertrophy of vastus medialis muscles associated with calpain 3 deficiency. AB - INTRODUCTION: Calpain 3 deficiency causes limb girdle muscular dystrophy type 2A, which is one of the most common forms of limb girdle muscular dystrophy. Nevertheless, calpainopathy is not always associated with mutations in the specific gene and secondary reduction in protein expression has been described. CASE REPORT: We report a case of a 43-year-old man who complained of thigh muscle stiffness and had muscle hypertrophy of both vastus medialis with prolonged myotonic contraction by percussion. A muscle biopsy showed dystrophic features and calpain 3 deficiency was shown by immunoblot analysis although mutations in the specific gene were not found. Known cases of secondary calpain 3 protein deficiency were ruled out and mutations in MD1 and MD2 genes were excluded. CONCLUSIONS: This patient represents the first case of calpain 3 deficiency with selective pseudohypertrophy of vastus medialis muscles. PMID- 22931741 TI - Septic cavernous sinus thrombosis complicated by occlusion of the internal carotid artery and multiple embolic strokes after surgery of an anorectal abscess: a clinical chameleon. AB - BACKGROUND: Septic thrombosis of the cavernous sinus (CST) is a rare and potentially life-threatening condition mostly caused by facial or ear, nose, and throat infections. Anatomic structures in vicinity of the cavernous sinus are thereby susceptible to inflammatory damage. In particular nervous system structures are almost regularly affected; however, only few authors reported severe involvement of the internal carotid artery (ICA). CASE PRESENTATION: We present an atypical clinical course of CST in a 61-year-old male diabetic patient caused by a distant focus of inflammation. Septic CST after surgical treatment of an anorectal abscess was complicated by occlusion of the ICA and multiple embolic strokes. The diagnosis was established by magnetic resonance imaging scan, symptoms resolved after antibiotic therapy and heparin anticoagulation. CONCLUSIONS: The presented case and review of literature emphasizes the variability of signs and clinical course of CST, a frequent cause of delayed diagnosis. Especially in immunocompromised patients, the primary source of CST may be a distant inflammatory focus with nonspecific and subacute symptoms. Septic CST can be a rare cause of ischemic stroke when complicated by ICA occlusion because of septic arteritis. Expedited diagnostic workup is necessary and rests upon radiologic investigations. PMID- 22931742 TI - MRI findings of bilateral posterior ischemic optic neuropathy in postcardiac transplant patient. AB - INTRODUCTION: Posterior ischemic optic neuropathy (PION) is a rare complication of prolonged surgical hypotension. It can occur in patients who have undergone nonocular surgery, particularly associated with significant blood loss, prolonged anesthesia time, and hypotension. CASE REPORT: We report a 48-year-old female patient who developed postoperative visual loss after cardiac transplantation. Her operative course was marked by prolonged hypotension. The patient's symptoms did not manifest until she was off sedatives. The initial ophthalmoscopic examination performed was normal. Magnetic resonance imaging confirmed the presence of restricted diffusion in both optic nerves consistent with bilateral PION. CONCLUSIONS: PION remains a difficult clinical diagnosis to prove. We report a magnetic resonance imaging-confirmed case of bilateral PION. Radiologic findings, especially diffusion-weighted images, can assist in the early identification of diffusion changes in ischemic optic nerves. PMID- 22931743 TI - Reversible paresis of the left hand related to a migraine without aura attack. AB - INTRODUCTION: The comorbidity between migraine and stroke continues to be a debated topic. Prior cases of reversible neuroradiologic lesions have been described in migrainous patients and in particular for those suffering from migraine with aura or complicated migraine attacks. CASE REPORT: We describe a patient that presented with a migraine without aura (MO) attack followed by paresis of the left hand that resolved completely within 4 days. An early brain magnetic resonance image (MRI) showed congruent cytotoxic-like alteration, whereas the lesion was no longer detectable on a standard 8-day MRI follow-up. A focused high-resolution MRI disclosed a very small cortical lesion, whereas a functional MRI demonstrated normal activation of the previously affected cortex at 8-month follow-up. CONCLUSIONS: This MO patient presented with an ischemic like lesion associated with migraine that reversed completely on MRI examination suggesting that migrainous infarction can occur in MO. Focused high-resolution sequences at follow-up might disclose subtle cortical lesions that could be more frequent than thought, coexisting with the well-known white matter hyperintensities not associated with neurological signs. PMID- 22931744 TI - Cervical rib, a rare cause of recurrent stroke in the young: case report. AB - BACKGROUND: Cervical rib usually causes neurological symptoms in the upper limb but stroke as an initial presentation is very uncommon. Recurrent supratentorial and infratentorial stroke in a single patient is very rare. Cervical rib can lead to anterograde or retrograde thromboembolic phenomenon leading to ischemic stroke. CASE REPORT: A 14-year-old girl presented with a history of sudden onset of loss of consciousness and left hemiparesis of 2 days duration. She had a similar episode 2 years ago, from which she had recovered to a large extent with minimal residual left hemiparesis. On examination, she was unconscious and localizing to pain on the right side. Radial pulse was absent on the right side. Magnetic resonance imaging of the brain revealed a right fronto-temporo-parietal old infarct with a new subacute infarct involving right cerebellar hemisphere and brainstem. X-ray of the chest showed a right-sided cervical rib. Computed tomographic angiography of the neck vessels revealed stenosis of subclavian artery at the site of the cervical rib with poststenosis dilatation. Patient was managed with anticoagulant and antiplatelet therapy initially and excision of the cervical rib was performed as a definitive procedure. She responded well to the treatment and at 6 months of follow-up, the strength on the left side had improved substantially. She was capable of doing her daily activities independently with little imbalance. CONCLUSIONS: The reported patient is the first in the literature who suffered recurrent supratentorial and infratentorial stroke as a complication of cervical rib. We stress the need for early diagnosis of this easily treatable cause of stroke in the young. PMID- 22931745 TI - Subarachnoid hemorrhage in neurocysticercosis: a direct or serendipitous association? AB - INTRODUCTION: The cerebrovascular complications in neurocysticercosis (NC) are uncommon. However, their pathophysiology remains unknown, but may be likely related to chronic inflammatory processes in the subarachnoid space (basal meningitis). Alterations of inflammatory cytokines in cerebrospinal fluid and sera correlate with vasospasm in SAH; these inflammatory mediators in NC may induce aneurysm formation. CASE REPORTS: A 7-year retrospective study in a neurological referral center (Instituto Nacional de Neurologia y Neurocirugia), showed 3 cases of subarachnoid hemorrhage (SAH) among the 267 NC patients admitted during the study period. The clinical status, cerebrospinal fluid parameters, and clinical outcome were retrieved to compare them with previous NC related SAH reported patients. Six of 15 patients showed aneurysm. These aneurysms were found within foci of inflammation and fibrosis surrounding the parasites. CONCLUSIONS: We found that, in contrast with the ominous prognosis of SAH for ruptured congenital aneurysm, cases associated with NC may have a more benign course. However with limited clinical information provided by previous reports, we only propose a possible direct relationship between chronic inflammation and NC as an inference because of the limited evidence available. PMID- 22931746 TI - Determination of hemispheric language dominance in the surgical epilepsy patient: diagnostic properties of functional magnetic resonance imaging. AB - BACKGROUND: Presurgical evaluation for refractory epilepsy typically includes assessment of cognitive and language functions. The reference standard for determination of hemispheric language dominance has been the intracarotid amobarbital test (IAT) but functional magnetic resonance imaging (fMRI) is increasingly used. OBJECTIVE: To critically assess current evidence regarding the diagnostic properties of fMRI in comparison with the IAT for determination of hemispheric language dominance. METHODS: The objective was addressed through the development of a structured critically appraised topic. This included a clinical scenario, structured question, literature search strategy, critical appraisal, results, evidence summary, commentary, and bottom-line conclusions. Participants included consultant and resident neurologists, a medical librarian, clinical epidemiologists, and content experts in the fields of epilepsy and neurosurgery. RESULTS: A systematic review and meta-analysis that compared the sensitivity and specificity of fMRI to IAT-determined language lateralization was selected for critical appraisal. The review included data from 23 articles (n=442); study methodology varied widely. fMRI was 83.5% sensitive and 88.1% specific for detection of hemispheric language dominance. CONCLUSIONS: There are insufficient data to support routine use of fMRI for the purpose of determining hemispheric language dominance in patients with intractable epilepsy. Larger, well-designed studies of fMRI for language and other cognitive outcomes as part of the presurgical and postsurgical evaluation of epilepsy patients are necessary. PMID- 22931747 TI - Dengue fever in South Korea, 2006-2010. PMID- 22931748 TI - The receptive function of hypothalamic and brainstem centres to hormonal and nutrient signals affecting energy balance. AB - The hypothalamic arcuate nucleus (ARC) and the area postrema (AP) represent targets for hormonal and metabolic signals involved in energy homoeostasis, e.g. glucose, amylin, insulin, leptin, peptide YY (PYY), glucagon-like peptide 1 (GLP 1) and ghrelin. Orexigenic neuropeptide Y expressing ARC neurons are activated by food deprivation and inhibited by feeding in a nutrient-dependent manner. PYY and leptin also reverse or prevent fasting-induced activation of the ARC. Interestingly, hypothalamic responses to fasting are blunted in different models of obesity (e.g. diet-induced obesity (DIO) or late-onset obesity). The AP also responds to feeding-related signals. The pancreatic hormone amylin acts via the AP to control energy intake. Amylin-sensitive AP neurons are also glucose responsive. Furthermore, diet-derived protein attenuates amylin responsiveness suggesting a modulation of AP sensitivity by macronutrient supply. This review gives an overview of the receptive function of the ARC and the AP to hormonal and nutritional stimuli involved in the control of energy balance and the possible implications in the context of obesity. Collectively, there is consistency between the neurophysiological actions of these stimuli and their effects on energy homoeostasis under experimental conditions. However, surprisingly little progress has been made in the development of effective pharmacological approaches against obesity. A promising way to improve effectiveness involves combination treatments (e.g. amylin/leptin agonists). Hormonal alterations (e.g. GLP-1 and PYY) are also considered to mediate body weight loss observed in obese patients receiving bariatric surgery. The effects of hormonal and nutritional signals and their interactions might hold the potential to develop poly-mechanistic therapeutic strategies against obesity. PMID- 22931749 TI - Prospects for the study of biological systems with high power sources of terahertz radiation. AB - The emergence of intense sources of terahertz radiation based on lasers and electron accelerators has considerable potential for research on biological systems. This perspective gives a brief survey of theoretical work and the results of experiments on biological molecules and more complex biological systems. Evidence is accumulating that terahertz radiation influences biological systems and this needs to be clarified in order to establish safe levels of human exposure to this radiation. The use of strong sources of terahertz radiation may contribute to the resolution of controversies over the mechanism of biological organization. However the potential of these sources will only be realized if they are accompanied by the development of sophisticated pump-probe and multidimensional experimental techniques and by the study of biological systems in the controlled environments necessary for their maintenance and viability. PMID- 22931750 TI - Physical constraints on the establishment of intracellular spatial gradients in bacteria. AB - BACKGROUND: Bacteria dynamically regulate their intricate intracellular organization involving proteins that facilitate cell division, motility, and numerous other processes. Consistent with this sophisticated organization, bacteria are able to create asymmetries and spatial gradients of proteins by localizing signaling pathway components. We use mathematical modeling to investigate the biochemical and physical constraints on the generation of intracellular gradients by the asymmetric localization of a source and a sink. RESULTS: We present a systematic computational analysis of the effects of other regulatory mechanisms, such as synthesis, degradation, saturation, and cell growth. We also demonstrate that gradients can be established in a variety of bacterial morphologies such as rods, crescents, spheres, branched and constricted cells. CONCLUSIONS: Taken together, these results suggest that gradients are a robust and potentially common mechanism for providing intracellular spatial cues. PMID- 22931752 TI - Analysis of prescription database extracted from standard textbooks of traditional Dai medicine. AB - BACKGROUND: Traditional Dai Medicine (TDM) is one of the four major ethnomedicine of China. In 2007 a group of experts produced a set of seven Dai medical textbooks on this subject. The first two were selected as the main data source to analyse well recognized prescriptions. OBJECTIVE: To quantify patterns of prescriptions, common ingredients, indications and usages of TDM. METHODS: A relational database linking the prescriptions, ingredients, herb names, indications, and usages was set up. Frequency of pattern of combination and common ingredients were tabulated. RESULTS: A total of 200 prescriptions and 402 herbs were compiled. Prescriptions based on "wind" disorders, a detoxification theory that most commonly deals with symptoms of digestive system diseases, accounted for over one third of all prescriptions. The major methods of preparations mostly used roots and whole herbs. CONCLUSION: The information extracted from the relational database may be useful for understanding symptomatic treatments. Antidote and detoxification theory deserves further research. PMID- 22931751 TI - Challenges and successes of recruitment in the "angiotensin-converting enzyme inhibition in infants with single ventricle trial" of the Pediatric Heart Network. AB - OBJECTIVES: Identify trends of enrolment and key challenges when recruiting infants with complex cardiac diseases into a multi-centre, randomised, placebo controlled drug trial and assess the impact of efforts to share successful strategies on enrolment of subjects. METHODS: Rates of screening, eligibility, consent, and randomisation were determined for three consecutive periods of time. Sites collectively addressed barriers to recruitment and shared successful strategies resulting in the Inventory of Best Recruiting Practices. Study teams detailed institutional practices of recruitment in post-trial surveys that were compared with strategies of enrolment initially proposed in the Inventory. RESULTS: The number of screened patients increased by 30% between the Initial Period and the Intermediate Period (p = 0.007), whereas eligibility decreased slightly by 7%. Of those eligible for entry into the study, the rate of consent increased by 42% (p = 0.025) and randomisation increased by 71% (p = 0.10). During the Final Period, after launch of a competing trial, fewer patients were screened (-14%, p = 0.06), consented (-19%, p = 0.12), and randomised (-34%, p = 0.012). Practices of recruitment in the post-trial survey closely mirrored those in the Inventory. CONCLUSIONS: Early identification and sharing of best strategies of recruitment among all recruiting sites can be effective in increasing recruitment of critically ill infants with congenital cardiac disease and possibly other populations. Strategies of recruitment should focus on those that build relationships with families and create partnerships with the medical providers who care for them. Competing studies pose challenges for enrolment in trials, but fostering trusting relationships with families can result in successful enrolment into multiple studies. PMID- 22931753 TI - Hepatitis E, a vaccine-preventable cause of maternal deaths. AB - Hepatitis E virus (HEV) is a major cause of illness and of death in the developing world and disproportionate cause of deaths among pregnant women. Although HEV vaccine trials, including trials conducted in populations in southern Asia, have shown candidate vaccines to be effective and well-tolerated, these vaccines have not yet been produced or made available to susceptible populations. Surveillance data collected during 2001-2007 from >110,000 pregnancies in a population of ~650,000 women in rural Bangladesh suggest that acute hepatitis, most of it likely hepatitis E, is responsible for ~9.8% of pregnancy-associated deaths. If these numbers are representative of southern Asia, as many as 10,500 maternal deaths each year in this region alone may be attributable to hepatitis E and could be prevented by using existing vaccines. PMID- 22931754 TI - Genetic animal models for evaluating the role of autophagy in etiopathogenesis of Parkinson disease. AB - Parkinson disease (PD) is the most common neurodegenerative movement disorder and is characterized pathologically by the formation of ubiquitin and SNCA/alpha synuclein-containing inclusions (Lewy bodies), dystrophic midbrain dopaminergic (DAergic) terminals, and degeneration of midbrain DAergic neurons. The vast majority of PD occurs sporadically, while approximately 5% of all PD cases are inherited. Genetic mutations of a few genes have been identified as causes of familiar PD, i.e., mutations in SNCA, PARK2/parkin, UCHL1, PARK7/DJ1, PINK1 and LRRK2, leading to DAergic cell death, but variable pathological changes. The evidence supports the hypothesis that several pathogenic mechanisms are likely involved at initial stages of the disease, and eventually they merge to cause parkinsonism. The current challenge facing PD research is to unravel the components in these pathways that contribute to the pathogenesis of PD. Accumulating evidence has implicated dysfunctional autophagy, a regulated lysosomal pathway with a capacity for clearing protein aggregates and cellular organelles, as one of the pathogenic systems contributing to the development of idiopathic PD. PMID- 22931759 TI - A clearance system for prostaglandin D2, a sleep-promoting factor, in cerebrospinal fluid: role of the blood-cerebrospinal barrier transporters. AB - Although the level of prostaglandin (PG) D(2) in cerebrospinal fluid (CSF) affects the action of D-type prostanoid receptors that promote physiological sleep, the regulatory system of PGD(2) clearance from the CSF is not fully understood. The purpose of this study was to investigate PGD(2) elimination from the CSF via the blood-CSF barrier (BCSFB). The in vivo PGD(2) elimination clearance from the CSF was 16-fold greater than that of inulin, which is considered to reflect CSF bulk flow. This process was inhibited by the simultaneous injection of unlabeled PGD(2). The characteristics of PGD(2) uptake by isolated choroid plexus were, at least partially, consistent with those of PG transporter (PGT) and organic anion transporter 3 (OAT3). Studies using an oocyte expression system showed that PGT and OAT3 were able to mediate PGD(2) transport with a Michaelis-Menten constant of 1.07 and 7.32 MUM, respectively. Reverse transcription-polymerase chain reaction and immunohistochemical analyses revealed that PGT was localized on the brush-border membrane of the choroid plexus epithelial cells. These findings indicate that the system regulating the PGD(2) level in the CSF involves PGT- and OAT3-mediated PGD(2) uptake by the choroid plexus epithelial cells, acting as a pathway for PGD(2) clearance from the CSF via the BCSFB. PMID- 22931760 TI - Losartan improves erectile dysfunction in diabetic patients: a clinical trial. AB - The activation of cavernous local renin-angiotensin system has an important role in pathogenesis of diabetic erectile dysfunction (ED). In our primary study, we found that angiotensin Type 1 receptor blocker improved the erectile function of diabetic rats. Therefore we explored the losartan in clinical treatment for diabetic patients suffering with ED. A total of 124 diabetic patients with ED were included in this study and treated with losartan or tadalafil or losartan plus tadalafil or watch for waiting as control for 12 weeks. Erectile function was assessed by International Index of Erectile Function (IIEF-5) questionnaire, the percentage of positive responses to sexual encounter profile questions 2 (SEP2), 3 (SEP3) and the global assessment question (GAQ). Losartan or tadalafil or losartan plus tadalafil significantly improved the mean IIEF-5 scores, the percentage of successful penetrations (SEP2), the successful intercourse completions (SEP3) and GAQ (P<0.05). The combination of losartan and tadalafil is more effective than the single-use of losartan or tadalafil (P<0.05). The patients with moderate and mild ED had better response rates to losartan than patients with severe ED. This is the first clinical trial in losartan therapy on diabetic patients suffering from ED. Losartan seems to be effective and well tolerated in diabetic ED patients, especially for mild to moderate ones. The combination therapy of losartan and tadalafil appeared to be more effective than monotherapy. PMID- 22931761 TI - The prevalence of premature ejaculation and its clinical characteristics in Korean men according to different definitions. AB - This study compared the prevalence of premature ejaculation (PE) diagnosed by the PE diagnostic tool (PEDT) score, self-reporting and stopwatch-recorded intravaginal ejaculation latency time (IELT). It examined the characteristics of males diagnosed with PE by each criterion. A questionnaire survey enrolled 2081 subjects from March to October, 2010. Stopwatch-recorded IELT was measured in 1035 of the 2081 subjects. We aimed to determine whether PE has an influence on the frequency and satisfaction of sexual intercourse, the degree of libido/erectile function and the satisfaction. These factors were evaluated according to different definitions of PE to assess whether the definition used yielded differences in the data. The prevalence of PE, based on a PEDT score of >=11, self-reporting and stopwatch-recorded IELT of <=1 min was 11.3%, 19.5% and 3%, respectively. The prevalence of PE diagnoses based on PEDT score and self reporting increased with age, but stopwatch-recorded IELT-based diagnoses did not. Males experiencing PE showed lower levels of libido, erectile function and frequency and satisfaction of sexual intercourse compared with non-PE males. PE males felt that they did not satisfy their partners in terms of the partners' sexual satisfaction and frequency of orgasm, in comparison with non-PE males. PE is a highly prevalent sexual dysfunction in males. Regardless of whether the PE diagnosis was made on the basis of self-reporting, PEDT score or stopwatch recorded IELT, subjective symptoms were similar among PE males. PMID- 22931762 TI - Intravesical penile implant reservoir: case report, literature review, and strategies for prevention. AB - To present a case of intravesical erosion of an infected multiple-component inflatable penile prosthesis (IPP) reservoir. We retrospectively reviewed a case of complete intravesical erosion of an infected IPP reservoir. We also reviewed the prior urologic literature concerning bladder-related reservoir complications, and formulated potential strategies to prevent these complications in the future. This patient was successfully managed with complete explantation of the cylinders and pump, along with cystotomy, intravesical reservoir removal and cystorraphy. Several months later, he was successfully reimplanted with a multiple-component IPP, and, with 7 months follow-up, has had no further complications. Management of intravesical placement or erosion of an IPP reservoir should be tailored to the clinical scenario. In cases with peri-prosthetic infection and subsequent intravesical reservoir erosion, complete explantation and delayed subsequent reimplantation has been successful. Inadvertent intravesical reservoir placement has been successfully managed via immediate cystotomy, reservoir repositioning and cystorraphy. Reservoir insertion via a counter-incision, an infrapubic approach and under direct vision can avoid this complication. Bladder laceration during reservoir reinflation has been successfully managed with cystorraphy and reservoir repositioning. PMID- 22931763 TI - [To promote the research and control of carbon disulfide exposure based on evidence and verification at workplace]. PMID- 22931764 TI - [Effects of carbon disulfide on cardiovascular system of workers occupationally exposed to carbon disulfide]. AB - OBJECTIVE: To study the effects of long-term exposure to carbon disulfide (SC(2)) on cardiovascular system of workers. METHODS: The concentrations of CS(2) were detected in the representative workshops with different exposure levels. The indicators related to cardiovascular system were tested in 633 workers occupationally exposed to CS(2), which included blood pressure, electrocardiogram, blood routine (blood RT), cholesterol (TCHO), triglyceride (TG) and so on. The data were analyzed by chi-square test and multiple logistic regression analysis. RESULTS: The exposure concentration of CS(2) for 389 workers was less than or equal to 5 mg/m(3), which for other 244 workers was higher than 5 mg/m(3). The maximum exposure concentration of CS(2) was 15.73 mg/m(3). There were no significant effects of CS(2) on the electrocardiogram, red blood cells, white blood cells, blood platelet, TCHO and TG of workers. However, the positive effects of CS(2) on blood pressure and negative effects of CS(2) on hemoglobin were found. The rates of high TCHO, TG and hypertension in male workers were significantly higher than those in female workers (P < 0.05). The rates of high TCHO, hypertension and sinus arrhythmia in older workers (<= 30 years old) were significantly higher than those in young workers (> 30 years old) (P < 0.05). The rate of sinus arrhythmia in workers with 1 - 10 working years was significantly higher than that in workers with more than 10 working years (P < 0.05). The rate of hypertension in workers with 1 - 10 working years was significantly lower than that in workers with more than 10 working years (P < 0.05). CONCLUSION: There were no significant effects of CS(2) exposure on the indexes of cardiovascular system of workers. PMID- 22931765 TI - [Screening of differentially expressed serum proteins in patients with asbestosis]. AB - OBJECTIVE: To screen differently expressed proteins for serum biomarkers by studying serum proteome of population with asbestosis, population exposed to asbestos without asbestosis and population never exposed to asbestos, to further understand the mechanisms of asbestosis. METHODS: The subjects of present study included 37 patients with asbestosis, 254 workers exposed to asbestos and 439 healthy controls. The 2-dimensional gel electrophoresis (2-DE) and matrix assisted laser desorption/ionization time of flight tandem mass spectrometry (MALDI-TOF-MS/MS) were used to screen and identify the differentially expressed serum proteins among all subjects. ImageMaster6.0 software was utilized to analyze the differentially expressed proteins. RESULTS: Well-qualified gel images of serum proteome were obtained, 21, 34 and 32 differentially expressed spots were found between asbestosis and normal controls, between asbestosis and negative controls or between negative controls and normal controls, respectively. Differentially displayed proteins were identified as cytokines, alpha1-AT, L ficolin, etc. CONCLUSION: Exposure to asbestos for a long period could interfere with the immune system of workers exposed to asbestos, and some proteins may serve as the biomarkers for early diagnosis and intervention of asbestosis. PMID- 22931766 TI - [Pulmonary toxicity in high-fat diet SD rats induced by intravenous injection of multi-walled carbon nanotubes]. AB - OBJECTIVE: To observe the pulmonary toxicity of multi-walled carbon nanotubes (MWCNTs) in high-fat diet SD rats. METHODS: One hundred forty male SD rats were randomly divided into 6 groups. The normal control group, high-fat diet model group, vehicle group, and group treated with low dose of MWCNTs consisted of 30 rats, respectively, which were divided in 3 subgroups (10 rats each subgroup), respectively. The groups treated with medium and high loses of MWCNTs consisted of 10 rats, respectively. All the animals were exposed to high-fat-diet except for the control group which was given with normal diet. Before intravenous exposure, the high-fat diet model group, vehicle group, and three MWCNTs treated groups were gavaged with 700 thousand U/kg Vit D3 for three days, then given with high-fat-diet. The vehicle group was exposed to normal saline containing 1% Tween 80 and the low exposure group was exposed to MWCNTs at the dose of 50 ug/kg by tail vein injection twice a week for 8, 12 or 16 weeks. Other tow exposure groups were exposed to MWCNTs at the doses of 100, and 200 ug/kg by tail vein injection twice a week, respectively for 16 weeks. The lungs were from the executed rats, the lung indexes were calculated, the pathological changes of lungs were examined under light microscope after HE staining. qRT-PCR assay was utilized to detect the expression levels of pro-inflammation cytokines IL-1beta (IL-1beta) and TNF alpha mRNA in the lungs. RESULTS: As compared with the vehicle group, the lung indexes in groups exposed to 100 and 200 ug/kg MWCNTs increased significantly (P < 0.05). It was found under light microscope that the MWCNTs were accumulated in lungs of three exposure groups in 16 weeks after exposure, including pneumorrhagia, alveolar walls thicken, fibrosis, and granulomas. As compared with the vehicle group, the levels of IL-1beta mRNA in group exposed to 50 ug/kg MWCNTs for 12 weeks and the groups exposed to 50, 100 and 200 ug/kg MWCNTs for 16 weeks decreased significantly (P < 0.05). As compared with the vehicle group, the levels of TNF-alpha mRNA in the groups exposed to 50 ug/kg MWCNTs for 8 and 16 weeks increased significantly (P < 0.05), the level of TNF-alpha mRNA in the groups exposed to 50 ug/kg MWCNTs for 12 weeks decreased significantly (P < 0.05). As compared with the vehicle group, the level of TNF-alpha mRNA in the groups exposed to 200 ug/kg MWCNTs for 16 weeks reduced significantly (P < 0.05). CONCLUSION: The MWCNTs accumulation and chronic inflammatory changes were found in the lungs of rats exposed to MWCNTs by tail vein injection. PMID- 22931767 TI - [Effect of 2,5-hexanedione on light-molecular-weight neurofilaments (NF-L) degradation of rat nerve tissues]. AB - OBJECTIVE: To investigate the effect of 2,5-hexanedione (HD) on degradation of low-molecular-weight neurofilaments (NF-L) in nervous tissue of rats, and to explore the molecular mechanism of n-hexane neuropathy. METHODS: Fifty male Wistar rats were randomly divided into one-week poisoning group (n = 10), two week poisoning group (n = 10), three-week poisoning group (n = 10), four-week poisoning group (n = 10), and control group (n = 10). In the four poisoning groups, a rat model of n-hexane neuropathy was established by intraperitoneal injection of HD (400 mg/kg/d). The change in the sciatic nerve ultrastructure of each rat was observed under an electron microscope. The progression of HD-induced peripheral neuropathy was evaluated using a gait scoring system. The degradation rates of NF-L in the sciatic nerve and spinal cord of each rat were measured by Western Blotting. RESULTS: The rats showed decrease in muscle strength and abnormal gait after two weeks of HD poisoning and mild or moderate paralysis after four weeks of HD poisoning. The sciatic nerve showed degenerative change, according to electron microscope observation. Compared with the control group, the two-week poisoning group, three-week poisoning group, and four-week poisoning group had the NF-L degradation rates decreased by 25.8%, 70.4%, and 69.7%, respectively, in the supernatant fraction of sciatic nerve, and by 14.7%, 64.6%, and 67.3%, respectively, in the sediment fraction of sciatic nerve, all showing a significant difference (P < 0.01). Compared with the control group, the one-week poisoning group had the NF-L degradation rate decreased by 33.87% in the supernatant fraction of spinal cord, the four-week poisoning group had the NF-L degradation rate increased by 16.2% in the supernatant fraction of spinal cord, and the one-week poisoning group and two-week poisoning group had the NF-L degradation rates decreased by 46.3% and 13.0% in the sediment fraction of spinal cord, all showing a significant difference (P < 0.01). CONCLUSION: HD poisoning significantly inhibits NF-L degradation in the sciatic nerve, which may be associated with NF degeneration and accumulation in the axons of patients with n hexane neuropathy. PMID- 22931768 TI - [Polymorphism of XRCC1 and chromosome damage in workers occupationally exposed to benzene]. AB - OBJECTIVE: To explore the relationship between the polymorphisms of DNA repair gene (XRCC1 194, 280 and 399) and the chromosomal damage induced by benzene. METHODS: The chromosomal damage of the peripheral lymphocytes in 459 workers occupationally exposed to benzene and 88 non-exposed controls were detected with cytokinesis-block micronucleus (CBMN) assay. PCR-RFLP technique was used to measure polymorphisms in XRCC1 194, 280 and 399. RESULTS: It was found that the MN frequency (2.120/00 +/- 1.880/00) of the exposed group was significantly higher than that (1.190/00 +/- 1.680/00) of the control group (P < 0.05), in the exposed group, the MN frequency (3.000/00 +/- 2.760/00) of older workers (> 35 years) was significantly higher than that (2.020/00 +/- 1.710/00) of younger workers (<= 35 years) (P < 0.05). The effect of genetic polymorphisms of XRCC1 on CBMN was not found. The haplotypes AAA/BAA, AAB/AAB, ABA/ABA, ABB/ABB could associated with the increased frequencies of total micronucleus (P < 0.05). CONCLUSION: Benzene exposure could result in chromosome damage. Age of workers and diplotypes of XRCC1 could associated with chromosomal damage induced by benzene. PMID- 22931769 TI - [Expression of heat shock protein 70 in lung and plasma of rats with pulmonary fibrosis induced by SiO2]. AB - OBJECTIVE: To investigate the dynamic expression of Heat shock protein 70 (Hsp70) in the lungs and plasma of rats with pulmonary fibrosis induced by silicon dioxide (SiO2). METHODS: Forty-eight Wistar rats were randomly divided into the control group exposed to normal solution and group exposed to SiO2 (50 mg/ml) with intratracheal injection. Each group was divided into four subgroups. The animals of SiO2 group and control group were sacrificed and lungs were collected on the 7th, 14th and 28th days after exposure, respectively. The left lung tissues were examined with the histopathologic HE staining. The expression and localization of Hsp70 protein in the lung tissues were examined with western blot assay and immunohistochemistry, respectively. The expression levels of Hsp70 protein in the plasma were measured by ELISA. RESULTS: The expression of Hsp70 in lung tissues of SiO2 group increased on the 7th day and reached the peak value on the 14th day then decreased, but still was significantly higher than that of the control group, the expression of Hsp70 in plasma of SiO2 group still was significantly higher than that of the control group (P < 0.05). The maximum expression level of Hsp70 in plasma of SiO2 group on the 21st day after exposure was 0.216 +/- 0.027 ug/ml. CONCLUSION: The expression levels of Hsp70 protein in the lung tissues and plasma of the group exposed to SiO2 significantly increased, which were associated with the process of pulmonary fibrosis. It was suggested that Hsp70 protein may play an important biological role in the pulmonary fibrosis induced by SiO2. PMID- 22931770 TI - [Effects of Gymnadenia conopse alcohol extract on early protein profiles in lung tissue of rats exposed to silica]. AB - OBJECTIVE: To analyze the early expression differences of lung tissue proteins in rats exposed to silica using comparative proteomics method, to explore the effects of Chinese traditional medicine (Gymnadenia conopse alcohol extract, GcAE) on silicosis (50 mg/ml). METHODS: Adult male Wistar rats were randomly divided into silica-treated group and GcAE-treated group, four rats a group. The rats were exposed to silica by intratracheal (IT) instillation of 1 ml silica suspension for 24 h. After exposure, the rats in GcAE-treated group were intragastric administration with 0.8 ml GcAE (0.8 ml/100 g a day) and the rats in silica-treated group were intragastric administration with 2 ml sterilized saline a day for 14 days. Then all rats were sacrificed and lung tissues were collected. The total proteins were separated by means of two-dimensional gel electrophoresis (2-DE) and the differentially expressed proteins were identified using matrix assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS). Western blotting was used to validate the expression of certain candidate proteins in lung tissues. RESULTS: Obvious pathological changes of lung could be observed in silica-treated group, such as the thicken of interalveolar septum, which was infiltrated with lymphocytes, macrophages and a few neutrophils with the proliferation of fibroblasts and smooth muscle cells. The accumulation of collagen, the destruction of alveolus structure and the more dotted fibrosis or granuloma could also be found. However, the pathological changes of lung in GcAE treated group were lighter than those of silica-treated group. Thirty three differentially expressed proteins were identified, including cathepsin D precursor, peroxiredoxin-1 (Prx-1) and SEC14-like protein 3. Compared with silica treated group, cathepsin D precursor and Prx-1 were significantly downregulated in GcAE-treated group, and SEC14-like protein 3 was significantly upregulated (P < 0.01). The results of western blot indicated that the expression level of Prx-1 in GcAE-treated group was 0.26 +/- 0.02, which was significantly lower than that (0.35 +/- 0.04) in silica-treated group (P < 0.01). CONCLUSION: GcAE may inhibit the progress of silicosis in the early period and cathepsin D precursor, SEC14 like protein 3 and Prx-1 may participate in this process. PMID- 22931771 TI - [Relationships between psychosocial factors and work-related musculoskeletal disorders in coal miners]. AB - OBJECTIVE: To estimate the associations of psychosocial factors with work-related musculoskeletal disorders (WMSDs), providing scientific evidence for targeted strategies for the prevention of WMSDs in Chinese coal miners. METHODS: A total of 500 coal miners were consecutively enrolled to this cross-sectional study. The prevalence of WMSDs was assessed using the Standardized Nordic Questionnaire. Logistic regression analyses were conducted to estimate the associations between psychosocial factors and WMSDs. RESULTS: Among coal miners, of 277 coal miners, 61% self-reported WMSDs in a 12-month period. Especially, back pain was the most frequent musculoskeletal symptom. WMSDs were statistically correlated with high job demands (OR = 1.3, 95%CI: 1.3 ~ 3.5), low job control (OR = 1.6, 95%CI: 1.0 ~ 2.4), low level of interpersonal relations (OR = 1.9, 95%CI: 1.2 ~ 3.0) and low job satisfaction (OR = 1.6, 95%CI: 1.0 ~ 2.4). CONCLUSION: The results of this study demonstrate psychosocial factors were associated with WMSDs among coal miners, and psychosocial factors be considered for the prevention of WMSDs. PMID- 22931772 TI - [Clinical characteristics of the patients with occupational chronic carbon disulfide poisoning in a chemical fiber factory of Nanjing]. AB - OBJECTIVE: To analyze the clinical characteristics of 267 cases with occupational chronic carbon disulfide (CS(2)) poisoning and to provide the basis for revising the items of periodical medical examination of workers occupationally exposed to CS(2). METHODS: The subjects of present study were 267 patients with mild CS(2) poisoning diagnosed according to "Diagnostic Criteria of Occupational Chronic Carbon Disulfide Poisoning (GBZ4-2002)" from April in 2006 to May in 2010. All patients were from the same chemical fiber factory. When a subject was diagnosed as patient with CS(2) poisoning, who should interview with questionnaire which included the illness and occupational history, symptoms, individual habits. The physical examination, nervous test, cardiovascular test, biochemical test and electromyogram were performed. RESULTS: The rate of decreased motor conduction velocity was 87.3% (233/267 roots). The highest detection rate of slowing conduction velocity was the common peroneal motor nerve which was 48.6% (138/248 roots) and the second was median motor nerve with delay rate of 37% (155/419 roots). The main symptoms of the patients were neurasthenia, numbness and paresthesia. The rates of abnormal achilles tendon reflex and knee jerk reflex in patients were were 79.4% and 49.8%, respectively. The detected rates of patients with ST-segment changes and hypertension were 19.1% and 27.5%, respectively. The rates of hypertension, systolic pressure and diastolic pressure were 27.3%, 22.5% and 21.1%, respectively. The rates of lactate dehydrogenase (LDH), triglycerides (TG) and low density lipoprotein (LDL) were high. The detected rates of urine acid, indirect bilirubin and total bilirubin in male patients were higher than those in female patients. In addition, the abnormal detected rate of urea nitrogen and indirect bilirubin increased with exposure years. CONCLUSION: Occupational chronic CS(2) poisoning mainly affects the nervous system, as well as liver and kidney function. Detecting the median and common peroneal motor nerve conduction velocities could be the screening indicators for the peripheral nerve injury induced by CS(2) in the occupational exposure population during the periodical occupational medical examinations. PMID- 22931773 TI - [Studing the health status of workers occupationally exposed to carbon disulfide]. AB - OBJECTIVE: To study the effects of carbon disulfide (CS(2)) on the health of workers, and to provide the basis for the further preventive measures. METHODS: The occupational health examination of 881 workers exposed to CS(2) in a chemical fiber factory was carried out according to the national technical standard of occupational health surveillance. The time weighted average concentrations (TWA) of CS(2) in the workshops of short silk and long silk exceeded the national standard, The workers in these two workshops served as the high exposure group. The workers of the other workshops were classified as low exposure group, in which TWA met the national standard. All exposed workers were also divided into long-term exposure group and short-term exposure group on the basis of average exposure years (16 years). The statistical analysis was used by t test, chi(2), and fisher exact test. RESULTS: The symptom rates of numbness, fatigue, dizziness, insomnia and headache were 12.5%, 8.5%, 8.2%, 7.5%, and 7.2% respectively. The abnormal rates of superficial sensation, three fibrillation, achilles tendon reflex, patellar reflex, EMG, hypertension, triglycerides, low density lipoprotein, and apolipoprotein B were 33.0%, 26.1%, 20.8%, 18.6%, 10.8%, 33.4%, 24.5%, 17.0% and 9.3% respectively. Among the high exposure group, the abnormal detectable rates of dizziness, headache, fatigue, insomnia, numbness, achilles tendon reflex, superficial and deep sensation, EMG, hypertension, ECG, total cholesterol, triglyceride and low density lipoprotein in long-term exposure group were significantly higher than those in short-term exposure group (P < 0.05 or P < 0.01). However, among the low exposure group, the abnormal rates of the insomnia achilles tendon reflex and superficial sensation in long term exposure group were significantly higher than those of short term exposure group (P < 0.05 or P < 0.01). The detected rates of hypertension, triglycerides, low-density lipoprotein, creatinine and uric acid were in males significantly greater than those in females (P < 0.05 or P < 0.01). CONCLUSION: Long-term exposure to high concentrations of CS(2) could lead to the damage of nervous system, elevate blood pressure and promote the development and progression of hyperlipemia and atherosclerosis. Furthermore, CS(2) had greater effects on blood pressure and lipid in males than in females. PMID- 22931774 TI - [Carbon disulfide exposure level of workers in a chemical fiber industry]. AB - OBJECTIVE: To investigate the exposure levels of carbon disulfide (CS(2)) for a chemical fiber industry. METHODS: The concentration of CS(2) was monitored in representative workshops and types of work, and the datas of that over the years were collected. RESULTS: The short-term exposure concentration of CS(2) about 80% of the type of work was less than or equal to 10 mg/m(3), which of more than 90% was less than or equal to 20 mg/m(3). The time weighted average concentration of CS(2) about 70% of the type of work was less than or equal to 5 mg/m(3), which of more than 90% was less than or equal to 10 mg/m(3). The short-term exposure concentration of CS(2) which was more than 15 mg/m(3) or the time weighted average concentration of CS(2) which was more than 30 mg/m(3) was only for little type of work. CONCLUSION: The concentration of CS(2) for the most type of work was lower, but there were still a number of types of work exposuring the higher concentration, which exceed the national occupational exposure limits. PMID- 22931775 TI - [Comprehensive analysis on variation of cardiac enzyme and troponin induced by acute organophosphorous poisoning]. AB - OBJECTIVE: To discuss the diagnostic value of cardiac enzyme and troponin in acute organophosphorus pesticide poisoning (AOPP). METHODS: A retrospective study was performed in the document published in domestic journals and PubMed from 1979 to 2010. The data of the cardiac enzyme and troponin were collected. Statistical analysis was conducted with one-way ANOVA and rank sum test. 2129 cases with AOPP were enrolled. RESULTS: The levels of creatine kinase (CK), creatine kinase-MB (CK-MB) and cardiac troponin I (cTnI) in milder, moderate and severe poisoning groups were significantly elevated compared by the healthy control group (P < 0.05). The differences were also dramatic among three patients groups (P < 0.05). The ratios of CK-MB to CK in both moderate and severe groups were significantly lower than in healthy controls (P < 0.05). The levels of CK, CK-MB and cTnI were higher especially in patients with intermediate myasthenic syndrome (IMS) than patients without IMS. Meanwhile, the levels of CK and CK-MB were elevated in patients with respiratory failure compared by non-failure ones, but decreased in the ratios of CK-MB to CK (P < 0.05). CONCLUSIONS: The elevation of CK and CK-MB in serum could not be judged as the criteria of myocardial damage in AOPP, the ratio of CK-MB to CK were more valuable; the value of cTnI in myocardial damage was still in suspect. CK, CK-MB and cTnI could be used as auxiliary criteria of AOPP classification. PMID- 22931776 TI - [Investigation of practical nurses exercise occupationally injury]. PMID- 22931777 TI - [Expression of the 4-hydroxynonenal in lung tissue in rats with paraquat poisoned and the effect of ulinastatin]. AB - OBJECTIVE: To investigate the 4-hydroxynonenal (4-HNE) expression changes and the impact of ulinastatin (UTI) METHODS: Seventy-two healthy Sprague-Dawley rats were randomly divided into three groups: the control group, poisoning group and treatment group, with 24 rats in each group. The model of lung injury was established by intragastric PQ (80 mg/kg) administration in poisoning group and treatment group, and 1 mL saline was administered intragastrically in the control group. The rats in treatment group were injected intraperitoneally with UTI (100 000 U/kg) 30 minutes after PQ administration, and the rats in the control group and poisoning group were intraperitoneally injected with the same volume of saline. After different treatments, the pathological changes and the expression of 4-HNE in lung tissue was detected in 12, 24, and 72 h in three groups. RESULTS: In the poisoning group and treatment group, the expression of 4-HNE in lung tissue of rats were increased in 12 h after poisoning and reached the peak in 48 h; in 72 h after poisoning, the expression of 4-HNE in lung tissue were decreased, but they were still high. Compared with the control group, the expression of 4-HNE in lung tissue of rats were significantly increased in the poisoning group and treatment group (P < 0.05). And compared with the poisoning group, the expression of 4-HNE in lung tissue of rats were significantly decreased in the treatment group (P < 0.01). The pathological changes were observed, including alveolar capillary expansion, diffuse alveolar hemorrhage and alveolar inflammation cell infiltration, were found in lungs of rats in poisoning group and treatment group. There is no significant change in the control group. Compared with the control group, the expression of 4-HNE in lung tissue significantly increased in poisoning group and treatment group (P < 0.01), but the expression in treatment group was lower than in poisoning group (P < 0.01). CONCLUSION: The expression of 4-HNE increased in PQ intoxicated rats. UTI may reduce the expression of 4-HNE and reduce lung injury in PQ intoxicated rats. PMID- 22931778 TI - [Occupation of chronic carbon disulfide poisoning case and the object of observation of nerve conduction measurement index analysis]. PMID- 22931779 TI - [Analysis of complications in pneumoconiosis patients treated with lung lobe bronchoalveolar lavage]. PMID- 22931780 TI - [Analysis of electrophysiological examination result of workers exposed to carbon disulfide]. PMID- 22931781 TI - [The pulmonary CT manifestations of acute moderate or severe hydrogen sulphide poisoning fishermen]. AB - OBJECTIVE: To discuss the clinical manifestations and CT features of acute moderate or severe hydrogen sulphide poisoning fishermen. METHODS: The clinic and CT datas of 8 acute moderate or severe hydrogen sulphide poisoning cases were retrospectively analysed. RESULTS: The lesions located at two pulmonary each leaf in 3 cases, located at both lower lungs in 3 cases and asymmetry leaves in 2 cases. Lesions form: little patchy shadow in 8 cases (8/8), fibrous band shadow in 4 cases (4/8), ground glass shadow in 3 cases (3/8), peripheral fuzzy interlobular nodule in 4 cases (4/8); 5 cases complicated with pleural effusion; After treatment 6 ~ 10 days, the pulmonary shadows were absorbed obviously; Fibrous band shadow was residual in a case after a follow-up of 2 months. CONCLUSION: With definite history of hydrogen sulphide inhalation and the corresponding clinical manifestations, and if fishermen contacted for a long time, who would be made chemical pulmonary damage; Combined with the imaging manifestations, the diagnosis as well as the severity of pulmonary damage could be made. PMID- 22931782 TI - [Analysis of the effect of rehabilitation on fluorspar miners with pneumoconiosis treated by non-invasive ventilator]. PMID- 22931783 TI - [The improvement of determination method of carbon disulfide in workplace air with gas chromatography]. AB - OBJECTIVE: Establishment of determination method of carbon disulfide in charcoal tube with low toxicity solvents desorption-gas chromatography. METHODS: Four types of solvent with low toxicity are applied respectively as substitution of benzene to desorb the carbon disulfide in samples of charcoal tube. The signal strength and desorption efficiency of the detector are compared by using different solvents. RESULTS: Chloroform has been considered as the best alternative solvent of benzene. Carbon disulfide has a good linearity (R = 0.9997) over the concentration of 0 ~ 54.7 ug/ml, detection limit can reach 0.2 ug/ml. When the sampling volume is 3.0 L, the minimum detectable concentration is 0.07 mg/m(3). CONCLUSION: With the use of chloroform, the health hazard to laboratory personnel and environment pollution as well as the costs of experiments are reduced. PMID- 22931784 TI - [The optimization of 2-thiothiazolidine-4-carboxylic acid back extraction in urine and determination by HPLC]. AB - OBJECTIVE: Establishment of determination method of 2-thiothiazolidine-4 carboxylic acid (TTCA) in urine with HPLC. METHODS: A volume of 0.5 ml hydrochloric acid (2 mol/L) and 0.5 ml pure water was added into 1 ml urine, and then extracted by 4 ml of diethyl ether by shaking for 2 min. Remove the water phase in a tube with plug and extract again, mix the two extraction diethyl ether together, take 4 ml by adding 2 ml borax-monopotassium phosphate buffer and shaking for 2 min to extract, then take the water phase to detect. A C(18) column and UV detector were used for separating and detecting. The wavelength was 273 nm, the flow rate was 1.0 ml/min, and the injection volume was 20 ul. RESULTS: TTCA has a good linearity (r = 0.9995) over the concentration of1 1 ~ 10 ug and the minimum detectable concentration of TTCA in urine was 0.1 ug/ml. The within day precision (RSD) were 8.4%, 3.0% and 1.7%, the between-day precision (RSD) were 11%, 3.8%, 1.9%, respectively. The extraction recovery were between 80% ~ 102%. CONCLUSION: The method was accurate and sensitive to detect TTCA in urine. PMID- 22931785 TI - [Determination of calcium cyanamide in air of workplace by spectrophotometry]. PMID- 22931786 TI - [Evaluation of uncertainty in 1,1-dichloro-1-nitroethane measurement in the air of workplace]. PMID- 22931787 TI - [The rervising of biological exposure index for carbon disulfide exposuring]. AB - OBJECTIVE: To study the biological exposure index of carbon disulfide in China. METHODS: High-performance liquid chromatography (HPLC) was used to detect the levels of 2-thiothiazolidine-4-carboxylic acid (TTCA) in the urine of the workers after working shift end, Gas chromatography was used to detect the concentrations of the carbon disulfide in the workplace air. The relationship between the urine TTCA levels and the concentrations of the carbon disulfide was analyzed, the biological exposure index and judgement result from PC-TWA were compared. RESULTS: The levels of TTCA in urine of workers occupationally exposed to carbon disulfide were closely and positively related with the concentrations of the carbon disulfide in the workplace air. The regression equation was Y = 0.265X - 0.165, The biological exposure index of carbon disulfide were calculated by regression equation according to occupational exposure limits of carbon disulfide in China. CONCLUSION: The biological exposure index of CS(2) in China might be revised for 1.2 mg/g Cr. PMID- 22931788 TI - FOXO3 induces FOXO1-dependent autophagy by activating the AKT1 signaling pathway. AB - Forkhead box O (FOXO) transcriptional protein family members, including FOXO1 and FOXO3, are involved in the modulation of autophagy. However, whether there is redundancy between FOXO1 and FOXO3 in the ability to induce autophagy remains unclear. In this study, we showed that FOXO3 induced a transcription-dependent autophagy, and FOXO1 was required for this process. Overexpression of wild-type FOXO3 (WT) or FOXO3 (3A), which harbors alanine mutations at residues Thr32, Ser253 and Ser315, but not transcription-inactive FOXO3 (?DB3A), significantly induced autophagy in the human embryonic kidney cell line HEK293T and mouse embryonic fibroblast (MEF) cell lines. Interestingly, depletion of FOXO1 by siRNA attenuated FOXO3-induced autophagy. Our data also showed that FOXO3 overexpression did not increase the expression of FOXO1 at the protein level, although FOXO3 was capable of binding the promoter region of FOXO1 and inducing an increase in the transcription of FOXO1 mRNA. Furthermore, our results showed that FOXO3 promoted the translocation of FOXO1 from the nucleus to the cytoplasm, resulting in an increase in FOXO1-induced autophagy. Moreover, our results supported a mechanism whereby FOXO3 dramatically increased the expression of the class I PtdIns3K catalytic subunit PIK3CA, leading to an increase in AKT1 activity, which resulted in the phosphorylation and nuclear export of FOXO1. To the best of our knowledge, our data are the first to suggest that FOXO1 plays a central role in FOXO3-induced autophagy. PMID- 22931789 TI - The safety of oats in the dietary treatment of coeliac disease. AB - Coeliac disease is a permanent inflammatory disorder of the small bowel affecting approximately 1% of the population. The only effective treatment that exists is exclusion of gluten from the diet. The present paper aims to review the literature as to whether oats are safe to eat for people with coeliac disease. Much data exist on the restrictive nature that adhering to a gluten-free diet imposes on an individual. If oats could be eaten, this would help reduce the restrictive nature of the diet. This in turn could lead to an increase in the quality of life. Oats are of high-nutritional value, providing a rich source of fibre, vitamins and minerals. The fibre source contains soluble fibre which is believed to help reduce LDL-cholesterol. A systematic review of the literature was conducted. Earlier studies conducted are difficult to compare as they used different methodologies and it is not known whether samples of oats in the studies were contaminated with gluten from other cereals. Many studies reviewed do not state the strain of oat used. Recent research has suggested that it may only be in certain strains of oats which could produce a toxic response to people with coeliac disease. In conclusion, research suggests that the risk from consuming oats may be less harmful than first thought; however, may vary according to the strain of oat. Handling that risk in clinical practice remains controversial. PMID- 22931790 TI - Brucellosis in takins, China. PMID- 22931791 TI - Accumulation of autophagosomes contributes to enhanced amyloidogenic APP processing under insulin-resistant conditions. AB - Alzheimer disease (AD) is sometimes referred to as type III diabetes because of the shared risk factors for the two disorders. Insulin resistance, one of the major components of type II diabetes mellitus (T2DM), is a known risk factor for AD. Insulin resistance increases amyloid-beta peptide (Abeta) generation, but the exact mechanism underlying the linkage of insulin resistance to increased Abeta generation in the brain is unknown. In this study, we investigated the effect of insulin resistance on amyloid beta (A4) precursor protein (APP) processing in mice fed a high-fat diet (HFD), and diabetic db/db mice. We found that insulin resistance promotes Abeta generation in the brain via altered insulin signal transduction, increased BACE1/beta-secretase and gamma-secretase activities, and accumulation of autophagosomes. Using an in vitro model of insulin resistance, we found that defects in insulin signal transduction affect autophagic flux by inhibiting the mechanistic target of rapamycin (MTOR) pathway. The insulin resistance-induced autophagosome accumulation resulted in alteration of APP processing through enrichment of secretase proteins in autophagosomes. We speculate that the insulin resistance that underlies the pathogenesis of T2DM might alter APP processing through autophagy activation, which might be involved in the pathogenesis of AD. Therefore, we propose that insulin resistance-induced autophagosome accumulation becomes a potential linker between AD and T2DM. PMID- 22931792 TI - Socioeconomic inequality and obesity prevalence trends in Luxembourg, 1995-2007. AB - BACKGROUND: Overweight and obesity are becoming increasingly critical problems in most developed countries. Approximately 20% of adults in most European countries are obese. This study examines the prevalence of overweight and obesity in Luxembourg and their association with different demographic, socioeconomic (SES), and behavioural factors. METHODS: The data used in this study were taken from 2 surveys on household income and living conditions conducted in 1995 and 2007. The target population was household residents aged 16 years and older, and body mass index (BMI) data were self-reported. Average BMI, overweight, and obesity prevalence rates were calculated according to each demographic (gender, nationality, marital status), SES (educational level, profession, and place of residence), and behavioural (physical activity and diet) factors. A multivariate logistic regression analysis was conducted to measure the relationship between obesity and demographic, SES, and behavioural factors. All analyses were conducted according to gender, and data used were weighted. RESULTS: Between 1995 and 2007, the average BMI remained nearly constant among men and women in the entire study population. Obesity prevalence increased by 24.5% through the study period (14.3% in 1995 to 17.8% in 2007). Obesity prevalence increased by 18.5% for men (15.1% in 1995 to 17.9% in 2007) and by 30% for women (13.6% in 1995 to 17.7% in 2007). Between 1995 and 2007, obesity increased sharply by 48.2% (from 11% to 16.3%) in Portuguese men, 76.7% (from 13.3% to 23.5%) in Portuguese women, 79.7% (from 17.2% to 30.9%) in widowed men, and 84.3% (from 12.1% to 22.3%) in divorced women. Multivariate logistic regression analysis showed that the relationship between the educational level and obesity was not statistically significant for men, but was significant for women. CONCLUSIONS: The prevalence of overweight and obesity is high in Luxembourg and has changed slightly in recent years. SES inequalities in obesity exist and are most compelling among women. The fight against obesity should focus on education, with emphasis on the socially disadvantaged segment of the population. PMID- 22931794 TI - Meaningful use and meaningful curricula: a survey of health informatics programmes in the USA. AB - The introduction of the US government's Meaningful Use criteria carries with it many implications including the training curriculum of healthcare personnel. This study examines 108 health informatics degree programmes across the USA. First, the courses offered are identified and classified into generic classes. Next, these generic groupings are mapped to two important frameworks: the Learning to Manage Health Information (LMHI) academic framework; and the Meaningful Use criteria policy framework. Results suggest that while current curricula seemed acceptable in addressing Meaningful Use Stage 1 objective, there was insufficient evidence that these curricula could support Meaningful Use Stage 2 and Stage 3. These findings are useful to both curriculum developers and the healthcare industry. Curriculum developers in health informatics must match curriculum to the emerging healthcare policy goals and the healthcare industry must now recruit highly trained and qualified personnel to help achieve these new goals of data capture, data-sharing and intelligence. PMID- 22931793 TI - Marine Microorganisms: perspectives for getting involved in cellulosic ethanol. AB - The production of ethanol has been considered as an alternative to replace part of the petroleum derivate. Brazil and the US are the leading producers, but more environmentally friendly alternatives are needed. Lignocellulose has an enormous potential but technology has to be still improve in order to economically produce ethanol. The present paper reviews the potential and problems of this technology and proposes the study of a group of microorganisms with the largest genetic pool, marine microorganism. PMID- 22931795 TI - Foundations and future application of internet-based interventions for PTSD in PR China. AB - This study examines internet-based interventions as a solution to improve mental health services for traumatised individuals in People's Republic of China (PR China). By reviewing the literature, the authors first summarise primary barriers to Chinese people's mental health help-seeking. Next, based on a research model, the authors discuss how the internet has been used to overcome these barriers and then introduce the current state of internet-based interventions. Finally, the authors conclude the necessity and feasibility of internet-based intervention applications in PR China, give implications for mental health services and discuss some limitations. PMID- 22931796 TI - Implementation of foetal e-health monitoring system through biotelemetry. AB - Continuous foetal monitoring of physiological signals is of particular importance for early detection of complexities related to the foetus or the mother's health. The available conventional methods of monitoring mostly perform off-line analysis and restrict the mobility of subjects within a hospital or a room. Hence, the aim of this paper is to develop a foetal e-health monitoring system using mobile phones and wireless sensors for providing advanced healthcare services in the home environment. The system is tested by recording the real-time Foetal Phonocardiography (fPCG) signals from 15 subjects with different gestational periods. The performance of the developed system is compared with the existing ultrasound based Doppler shift technique, ensuring an overall accuracy of 98% of the developed system. The developed framework is non-invasive, cost-effective and simple enough to be used in home care application. It offers advanced healthcare facilities even to the pregnant women living in rural areas and avoids their unnecessary visits at the healthcare centres. PMID- 22931797 TI - An object-oriented mobile health system with usability features. AB - Mobile health (m-health) comprises the concept of utilising mobile devices to carry out the task of viewing electronic medical records, reserving medical appointments with a patient's medical provider and electronically refilling prescriptions. This paper aims at developing a m-health system to improve usability from a user's perspective. Specifically, it first developed a m-health model by logically linking characteristics of the m-health system together based on information flows. Then, the system requirements were collected by using a developed questionnaire. These requirements were structured and further in-depth analysis was conducted by using an object-oriented approach based on unified modelling language, such as use-case, sequence and analysis class diagrams. This research will be beneficial to decision makers and developers in the mobile healthcare industry. PMID- 22931798 TI - [Evidence and controversial aspects of the hygiene hypothesis]. PMID- 22931799 TI - [Serum interleukin 18 and 33 levels and its clinical significance in asthma patients]. AB - OBJECTIVE: To study the levels of serum interleukin (IL)-18 and IL-33 in asthmatic patients pre-and post-treatment with glucocorticoids during the acute exacerbation period and therefore to investigate the role of IL-18 and IL-33 in the pathogenesis of bronchial asthma. METHODS: Thirty cases of moderate to severe asthma admitted in the Second Affiliated Hospital of Dalian Medical University from June, 2009 to October, 2010 were chosen as the asthma group, and 23 healthy people who underwent routine physical examination were chosen as the control group. The subjects in the 2 groups were all nonsmokers. All the patients were treated with a glucocorticoid (methylprednisolone 40 - 80 mg/d) for 3 to 5 days and combined with aerosol inhalation of budesonide for 1 to 2 weeks as adjuvant therapy. The serum levels of IL-18 and IL-33 were detected for the asthma group before and after the treatment and for the control group. Other data including immunoglobulin E (IgE), the number of eosinophil cells (EOS) and the pulmonary function (FEV(1)%pre) were measured as well. The differences of IL-18 and IL-33 levels between the asthma group before and after treatment and the control group were analyzed, and the correlation between IL-18, IL-33 and IgE, EOS and FEV(1)%pre were analyzed as well by SPSS software. RESULTS: Compared with the healthy control group [(158 +/- 45) ng/L and (143 +/- 32) ng/L], the levels of IL 18 and IL-33 in the asthma pre-treatment group were significantly increased [(300 +/- 181) ng/L and (208 +/- 95) ng/L, t = 3.67 and 3.51, all P < 0.05)]; and the IgE level and EOS count showed a similar change (t = 5.76 and 5.24, all P < 0.05). After systemic glucocorticoid treatment and local aerosol inhalation, the levels of IL-18 and IL-33 [(183 +/- 83) ng/L and (148 +/- 77) ng/L] were decreased significantly in the asthma patients [t = 5.42 and 12.09, all P < 0.05], and the IgE level and EOS count also showed a same trend as well (t = 11.87 and 4.56, all P < 0.05), whereas FEV(1)%pred [(54 +/- 14)%] increased significantly [(81 +/- 16)%, t = -7.81, P < 0.05]. The Pearson correlative analysis showed that there were positive correlations between the levels of IL 18, IL-33 and IgE and EOS, respectively (all P < 0.05), and there were negative correlations between IL-18, IL-33 levels and FEV(1)%pre, respectively (all P < 0.05). CONCLUSIONS: Our results suggest that IL-18 and IL-33 participate in the pathogenesis of asthma, and may play stimulation role in the process of the disease. PMID- 22931800 TI - [The effect of budesonide on thymic stromal lymphopoietin receptor and cytokine profile of dendritic cells in OVA-induced asthma in mice]. AB - OBJECTIVE: To investigate the effect of budesonide (BUD) on thymic stromal lymphopoietin receptor (TSLPR) of dendritic cells (DCs) in OVA-induced mouse asthma models and to explore the mechanisms by studying the effect of BUD on function of DCs from the model. METHODS: Eighteen BALB/c female mice were randomly divided into a control group, an asthma group and a BUD intervention group, with 6 mice in each group. Mice were sensitized and challenged with ovalbumin (OVA) to establish the asthmatic model. The bronchoalveolar lavage fluid (BALF) and DCs of spleen from the 3 groups were harvested and the supernatants of BALF and DCs were analyzed for levels of TSLP and TSLPR, respectively, by commercially available ELISA kit. The percentage of eosinophils (EOS) in BALF was counted. The expression of CD40, CD80 and CD86 in DCs was detected by FACS. The DCs were then washed, and co-cultured in vitro with autologous T cells purified by a nylon cotton column. The supernatants of DC-T co culture were collected after 72 h incubation, and analyzed for levels of interleukin-5 (IL-5) and interferon-gamma (IFN-gamma) by ELISA. RESULTS: The levels of TSLP in BALF and TSLPR in DCs from the asthma group were significantly increased compared with the control group [(44.0 +/- 5.1) ng/L vs (14.2 +/- 3.6) ng/L, P < 0.01 and (19.7 +/- 2.2) ng/L vs (10.4 +/- 1.2) ng/L, P < 0.05, respectively]. The expression of CD40, CD80 and CD86 of DCs and IL-5 in the culture supernatants of DC-T co-culture was significant up-regulated in the asthma group compared with the control group (P < 0.05). Furthermore, the addition of BUD reduced the expression of CD40, CD80, CD86, TSLPR in DCs, IL-5 in the culture supernatants of DC-T co-culture, TSLP and EOS in BALF. The level of INF-gamma in the DC-T co-culture supernatants of the 3 groups did not achieve statistical significance (F = 0.82, P > 0.05). CONCLUSION: These results demonstrate that the therapeutic activity of BUD in asthmatic mice may be related to modulation of Th1 and Th2 cell functions and this effect is probably mediated through the TSLP-DC pathway. PMID- 22931801 TI - [Clinical significance and intervention study of serum interleukin 18 in preeclampsia patients with coexisting obstructive sleep apnea]. AB - OBJECTIVE: To investigate the role of IL-18 in the obstructive sleep apnea syndrome (OSAS)-induced preeclampsia (PE), by comparison of the changes of serum IL-18 levels among different groups as well as before and after continuous positive airway pressure (CPAP) treatment in pregnant women with both OSAS and PE. METHODS: In control group there were 18 normal pregnant women with apnea hypopnea index (AHI) < 5. In simple PE group 18 pregnant PE patients with an AHI < 5 were recruited. In PE plus OSAS group 16 PE patients with coexisting OSAS were collected. CPAP treatment was performed for 1 week in 6 patients with AHI > 15 from PE plus OSAS group.Serum IL-18 levels were measured with ELISA. RESULT: There was a significant difference in serum IL-18 levels among control group [(261 +/- 95) ng/L], simple PE group [(382 +/- 121) ng/L], and PE plus OSAS group [(601 +/- 89) ng/L, all P < 0.001]. Following CPAP treatment, there was a significant decrease in AHI, systolic blood pressures, and serum IL-18 levels, but a significant increase in minimal SpO2 (P < 0.01). CONCLUSION: Our study demonstrated that serum IL-18 levels in PE patients with OSAS were significantly elevated, which suggested that OSAS might increase the incidence of PE by enhancing inflammatory response, while CPAP treatment could effectively improve the pathological process. PMID- 22931802 TI - [The balance of Th1 and Th17 cells in tuberculous pleural effusion]. AB - OBJECTIVE: The aim of this study was to investigate the distributions and relevance of Th1 and Th17 cells (IL-17-producing CD(+)(4) T cell), and the differentiation of Th17 cells in tuberculous pleural effusion. METHODS: The percentages of both Th1 and Th17 cells in tuberculous pleural effusion and peripheral blood from 30 patients [male/female 12/18, age 16 - 63 years (average 41.2 year)] with tuberculous pleurisy were determined by flow cytometry, and comparison was made using Student's t test. The regulations of different combinations of IFN-gamma, IL-1beta, IL-6 and IL-12 on differentiation of Th17 cells were explored. Comparisons of the data between different groups were performed using Kruskal-Wallis one-way analysis of variance on ranks. RESULTS: Both Th1 [(39 +/- 11)% vs (8 +/- 3)%; t = 17.37, P < 0.05] and Th17 cells [(2.8 +/- 0.9)% vs (0.7 +/- 0.3)%; t = 14.78, P < 0.05] were significantly increased in tuberculous pleural effusion compared with peripheral blood. The proportions of Th17 cells were correlated positively with those of Th1 cells both in tuberculous pleural effusion and in peripheral blood (r = 0.61, 0.49, respectively; both P < 0.05). IL-1beta or IL-6 promoted the differentiation of Th17 cells, and their combination resulted in further increase of the differentiation of Th17 cells, while IFN-gamma and IL-12 reduced the percentages of Th17 cells. Moreover, these two cytokines significantly impaired the promotive effect induced by IL-1beta plus IL-6. CONCLUSION: This study showed that Th1/Th17 balance existed in tuberculous pleural effusion, and was mainly due to the generation and differentiation of Th17 cells induced by IL-1beta and IL-6, but reversed by IFN gamma and IL-12 in tuberculous pleural effusion. PMID- 22931803 TI - [Effects of paclitaxel on proliferation and transition of phenotype in platelet derived growth factor-BB-induced pulmonary vascular smooth muscle cells]. AB - OBJECTIVE: To investigate the effects of paclitaxel on the phenotypic modulation induced by platelet-derived growth factor (PDGF-BB) in rat pulmonary vascular smooth muscle cells (PVSMC). METHODS: The proliferation of PVSMC isolated from SD rats cultured in vitro was induced by PDGF-BB and then intervened by different concentration of paclitaxel. MTT and [3H]-thymidine incorporation were used to detect the changes of cell proliferation. The expression level of alpha-smooth muscle-actin (SM-alpha-actin) and smooth muscle protein 22alpha (SM22alpha) were tested by Western blot. Confocal laser scanning microscopy was applied to observe the change of fluorescence intensity. RESULTS: Treatment with PDGF-BB for 24 hours results in a significant increase in [3H]-thymidine incorporation and marked change in phenotype and cytoskeleton, Paclitaxel inhibited the proliferation of PVSMC induced by PDGF-BB, the inhibition rate was 45.4%, 35.4%, 21.6% (P < 0.01) tested by[3H]-thymidine incorporation and 40.0%, 30.0%, 18.0% (P < 0.01) tested by MTT. Meanwhile, the paclitaxel promoted the expression level of SM-alpha-actin and SM22alpha. Fluorescence intensity of F-actin decreased significantly. CONCLUSION: Paclitaxel may play an important role in vascular remodeling by changing the phenotypes and cytoskeleton of VSMC stimulated by PDGF BB. PMID- 22931804 TI - [Changes of anti-Streptococcus pneumoniae status in rats with simulated weightlessness]. AB - OBJECTIVE: To study the changes of anti-Streptococcus pneumonia (SP) status in rats with simulated weightlessness, and therefore to provide theoretical basis for the aerospace medicine. METHODS: Thirty-two healthy male Wistar rats were randomly allocated into 4 groups: group A, the tail-suspension and SP group; group B, the tail-suspension without SP group; group C, the unsuspended but SP group; group D, the unsuspended and no SP group, with 8 rats in each. The tail suspension method, i.e. about 30 degrees head-down tilt, was used for the model of simulated microgravity. On day 4, 0.4 ml of SP suspension [ATCC6303, serotype III(ATCC, bacteria concentration about 9.0*108 CFU/ml)] was instilled by tracheal intubation. Sterile saline was used for the control group. The experiment was ended after 7 days of tail-suspension. Lung pathology, blood test and C-reactive protein level were studied, and the CD(4)(+)/CD(8)(+) ratios were measured by flow cytometry. RESULTS: The lung pathological changes were much more severe in Group A as compared to those in Group B, C and D. The total number of WBC showed no significant difference among groups (F = 1.57, P = 0.22). But the neutrophil number was higher in Group A [(2.4 +/- 0.53)*109/L], B [(2.0 +/- 0.31)*109/L] and C [(1.7 +/- 0.40)*109/L] as compared to Group D [(1.2 +/- 0.15)*109/L], u = 0.0001, P = 0.001; u = 1.0, P = 0.001; u = 8.5, P = 0.013, respectively. The percentage of neutrophils showed a similar difference. The total number of lymphocytes showed no significant difference among groups (F = 0.720, P = 0.548). CRP levels in the SP infection groups were significantly higher than those in the uninfected groups. The ratio of CD(4)(+)/CD(8)(+) showed no difference among groups (F = 1.225, P = 0.319). Weight loss after the experiment was most severe in Group A (F = 122.067, P < 0.001). CONCLUSIONS: In rats with simulated weightlessness, the anti-infective ability to Streptococcus pneumoniae was reduced, and the inflammatory response was significantly increased, but the anti infective immunity was compromised. PMID- 22931805 TI - [An in vitro study on the pharmacological ascorbate treatment of influenza virus]. AB - OBJECTIVE: To investigate the effects and mechanism of pharmacological ascorbate against Influenza A/CA/7/09 (H1N12009). METHODS: NHBE cells (~ 95% confluent monolayer) in 12-well plates (Corning) were kept at 37 degrees C at all times. NHBE cells were exposed to A/CA/7/09 (H1N12009) influenza virus at MOI of 0.01 for 1 h, rinsed with NHBE medium, and incubated with NHBE medium containing 20 mmol/L ascorbate or 20 mmol/L ascorbate +600 IU/ml Catalase. The cells were then incubated for an additional 4 - 12 h and the culture medium was harvested for titration. Viral titers were determined as log(10) 50% tissue culture infective doses (TCID50) assay in MDCK cells. Ascorbate in NHBE medium was determined using HPLC separation coupled with coulometric electrochemical detection. Hydrogen peroxide was detected indirectly by Clark-type oxygen electrode. RESULTS: In vitro experiments showed that pharmacological ascorbate killed not only isolated viruses, but also viruses from normal human bronchial epithelial cells. The antiviral effect of ascorbic acid appeared to be dose-dependent. 2.5 mmol/L ascorbic acid was able to eliminate 90% of the viruses and 20 mmol/L ascorbic acid totally blocked viral replication in vitro. The antiviral effect of pharmacological ascorbate varied at different phases of infection. Pharmacological ascorbate eliminated viral infectivity with treatment times as short as 4 hours at early stage of infection. But the effect was reversed by catalase. CONCLUSION: Pharmacological ascorbate (vitamin C) as a pro-drug eliminates or kills influenza virus, probable by producing steady-state concentrations of hydrogen peroxide (H2O2) in extracellular fluid. PMID- 22931806 TI - [Asthma and hypothalamic-pituitary-adrenal axis]. PMID- 22931807 TI - [Recent advances in nontuberculous mycobacterial disease]. PMID- 22931808 TI - [Advances in research for resistance mechanisms of aminoglycoside and Cyclic peptide antibiotic to Mycobacterium tuberculosis]. PMID- 22931809 TI - Francisella tularensis subspecies holarctica, Tasmania, Australia, 2011. AB - We report a case of ulceroglandular tularemia that developed in a woman after she was bitten by a ringtail possum (Pseudocheirus peregrinus) in a forest in Tasmania, Australia. Francisella tularensis subspecies holarctica was identified. This case indicates the emergence of F. tularensis type B in the Southern Hemisphere. PMID- 22931810 TI - [Mechanism of the apoptosis of rat pancreas islet beta cell strain (INS-1 cells) induced by sodium arsenite]. AB - OBJECTIVE: To study mechanism of the apoptosis of rat pancreas islet beta cell strain (INS-1 cells) induced by sodium arsenite. METHODS: INS-1 cells were exposed to sodium arsenite at the different concentrations. MTT assay was used to detect the viability of INS-1 cells. The potentials on mitochondrial membrane and lysosome membrane of INS-1 cells were determined with the fluorescence spectrophotometer. The apoptotic levels of INS-1 cells exposed to sodium arsenite were observed by a fluorescence microscope and flow cytometry. RESULTS: After exposure to sodium arsenite, the viability of INS-1 cells significantly decreased with the doses of sodium arsenite. At 24 h after exposure, the OD values of the mitochondrial membrane potentials declined observably with the doses of sodium arsenite (P < 0.01). At 48 h after exposure, the OD values of the lysosome membrane potentials significantly increased with the doses of sodium arsenite (P < 0.01). At 72 h after exposure, the apoptotic cells were observed under a fluorescence microscope and enhanced with the doses of sodium arsenite. The apoptosis cells with light blue, karyopyknosis, karyorrhexis, apoptotic body and chromatin concentration appeared. The results detected with flow cytometry indicated that after exposure, the apoptotic INS-1E cells significantly increased with the doses of sodium arsenite. CONCLUSIONS: The sodium arsenite can induce the apoptosis of INS-1 cells through the mitochondria-lysosome pathway. PMID- 22931811 TI - [The effects of methionine and choline on the expression levels of CaMKII and CREB mRNA and proteins in rats exposed to lead]. AB - OBJECTIVE: To study the effects of methionine and choline on the expression levels of CaMKII and CREB mRNA and proteins in hippocampus of rats exposed to lead. METHODS: Male SD rats were divided into five groups. (1) control group, (2) group exposed to lead+2 by drinking water with 0.40 g/L lead acetate, (3) group exposed to methionine and choline (1:1, 400 mg/kg), (4) group exposed to 0.40 g/L lead acetate plus methionine and choline (1:1, 100 mg/kg), (5) group exposed to 0.40 g/L lead acetate plus methionine and choline (1:1, 400 mg/kg). In 8 weeks after exposure, all rats were killed. Then CREB mRNA and CaMK II mRNA expression levels in hippocampus were detected by real-time PCR, CREB and CaMK II protein expression levels in hippocampus were measured by western blot assay. RESULTS: The expression levels (0.743 +/- 0.185 and 0.729 +/- 0.199) of CaMKII mRNA and CREB mRNA in the hippocampus of lead group were significantly lower than those (0.950 +/- 0.238 and 0.901 +/- 0.232) of control group (P < 0.05), also the expression levels (0.271 +/- 0.045 and 0.212 +/- 0.058) of CREB protein and pCREB protein in the hippocampus of lead group were significantly lower than those (0.319 +/- 0.058 and 0.506 +/- 0.125) of control group (P < 0.05). The expression levels (1.014 +/- 0.210 and 1.126 +/- 0.379) of CaMKII mRNA and the expression levels (1.029 +/- 0.335 and 0.932 +/- 0.251) of CREB mRNA in the hippocampus of 2 groups exposed to lead acetate plus methionine and choline were significantly higher than those of lead group (P < 0.05). The expression levels (0.407 +/- 0.951 and 0.563 +/- 0.178) of CREB protein and pCREB protein in the hippocampus of group exposed to lead acetate plus 400 mg/kg methionine and choline were significantly higher than those of lead group (P < 0.05). CONCLUSION: Methionine and choline could decrease the inhibition effects of lead on the expression of CaMKII and CREB mRNA or CREB and pCREB proteins in the hippocampus of rats. PMID- 22931812 TI - [Associations of occupational safety atmosphere and behaviors with unintentional injuries]. AB - OBJECTIVE: To evaluate the associations of perception of safety atmosphere at workplace, occupational safety attitude and behaviors with occupational unintentional injury among manufacturing workers. METHODS: A cross-sectional study was performed and a self-administered questionnaire was used to inquire socio-demographic characteristics, perceived safety atmosphere, occupational safety attitudes, occupational safety behaviors and occupational unintentional injuries among 10585 manufacturing workers selected from 46 enterprises in Guangdong. Structural equation modeling was applied to assess the relationship of the perception of safety atmosphere at workplace, occupational safety attitude, and occupational safety behaviors with occupational unintentional injury. RESULTS: Among 24 pathways supposed in structural equation model, 20 pathways (except for the attitude toward occupational safety, the attitude toward managers' support, the work posture and individual protection) were significantly related to the occupational unintentional injuries. The further analysis indicated that the perceived safety atmosphere might impact the occupational unintentional injuries by the attitude toward occupational safety and occupational safety behaviors. CONCLUSION: Workers' perception of safety atmosphere indirectly influenced on occupational unintentional injuries through occupational safety attitudes and occupational safety behaviors. PMID- 22931813 TI - [The effects of low pre-pregnant lead exposure level on maternal bone turnover during gestation and lactation in mice]. AB - OBJECTIVE: To study the effects of low pre-pregnant lead exposure level on the mobilization of lead and calcium in maternal skeleton during gestation and lactation in mice. METHODS: Seventy Kunming female mice were randomly divided into the lead exposure or control groups, 36 mice were exposed to lead by drinking water (50 mg/L) and 36 mice were exposed to deionized water for 4 weeks. The levels of calcium and lead in blood and femurs were measured on the 1st, 7th and 14th days during gestation and on the 1st,10th and 21st days during lactation with atomic absorption spectrophotometry using a heated graphite atomizer or flame atomic absorption spectrophotometry. RESULTS: As compared with the pre pregnant, at the end of lactation in exposure group the levels of calcium in blood and bones significantly decreased 18.5% and 17.75%, respectively, the levels of lead in blood significantly increased 65.22% and the levels of lead in bones significantly decreased 28.45% (P < 0.05). There was a significant negative correlation between the blood lead level and the bone lead level during gestation and lactation in exposure group (r = -0.904, P < 0.01). There were significant differences of lead and calcium levels during the gestation and lactation between exposure group and control group (P < 0.05). CONCLUSION: The lead mobilization in maternal bone occurred during gestation and lactation in mice, which could be accelerated by the low pre-pregnant lead exposure. PMID- 22931814 TI - [Association of 5-HTTLPR, DRD4 gene polymorphisms with the accident tendentiousness of drivers]. AB - OBJECTIVE: To investigate the relationship between 5-HTTLPR and/or DRD4 gene polymorphisms and the accident tendentiousness of drivers. METHODS: A case control study, including 42 patients and 46 controls, were performed using type-A behavior questionnaire and EPQ scale. 5-HTTLPR and DRD4 gene -521 C/T were detected by the PCR-RFLP technique. RESULTS: The scores of type-A behavior questionnaires, such as TH and TH + CH in exposure group were significantly higher than those in control group (P < 0.05). P and N scores of EPQ questionnaires in exposure group were significantly higher than those in control group, and L score in exposure group was significantly lower than that in control group (P < 0.05 or P < 0.01). There were significant differences in the frequencies of the genotypes and alleles of 5-HTTLPR gene between the cases and the controls (P < 0.05), but there were no significant differences in the frequencies of the genotypes and alleles of DRD4 gene between the two groups (P > 0.05). In the drivers with the accident tendentiousness, P scores in the cases with homozygous genotypes of the S/S in 5-HTTLPR gene were significantly higher than those in the cases with the genotypes of S/L and L/L in 5-HTTLPR gene (P > 0.05). E scores in subjects with homozygous genotypes of the T/T in DRD4 gene were significantly higher than those in subjects with genotypes of the T/C+C/C in DRD4 gene (P > 0.05). CONCLUSION: The driver accident tendentiousness may be associated with 5-HTTLPR gene, but not associated with DRD4 gene. The two genes are associated with the type-A behavior and personality characteristics of drivers with accident tendentiousness. However, 5-HTTLPR and DRD4 gene may not have synergism in these behaviors and personality. PMID- 22931815 TI - [Analysis of the electromyographic characteristics on shoulder fatigue caused by lifting load]. AB - OBJECTIVE: To analyze and evaluate the fatigue of shoulder skeletal muscle caused by different lifting loads with surface electromyography (sEMG). METHODS: According to the loading standard of1 Repetition Maximum (1RM), ten male volunteers performed 3 tasks of upper limb flexion, i.e. 10%, 50% and 90%-1RM. During action process, the signals of Upper Trapezius (UT), Lower Trapezius (LT), Serratus Anterior (SA) and Anterior Deltoid (AD) were recorded by sEMG. The Mean Amplitude (MA) served as an index to evaluate the changes in skeletal muscle fatigue. RESULTS: The scores of Borg were 15.6, 15.9 and 15.2 for 3 loads of 10% 1RM, 50%-1RM and 90%-1RM, respectively (P > 0.05). The mean amplitudes (MAs) of Upper Trapezius, Lower Trapezius, Anterior Deltoid and Serratus Anterior in shoulders increased obviously. Under the load intensity of 10%-1RM, the MAs of Upper Trapezius and Anterior Deltoid increased significantly (P < 0.05), which were 0.898 and 0.736, respectively. After the exhaustion, the contribution of mean amplitude in shoulder muscle did not change significantly (P > 0.05). CONCLUSION: The low-load action for long time can induce easily the fatigue of upper trapezius and anterior deltoid. PMID- 22931817 TI - [Evaluation of stress levels during parachuting training by salivary biomarker]. AB - OBJECTIVE: To evaluate the stress level during parachuting training by salivary biomarker and to study the dynamic characteristics. METHODS: Twenty recruits of military parachuting training completed 8 trainings in a month. The saliva samples were collected at 2 h and 1h before boarding and at 0.5 h after landing on the 1st, 4th and 7th trainings. The levels of cortisol, chromogranin A and alpha-amylase in saliva samples were detected. RESULTS: The concentrations of cortisol, chromogranin A and activity of alpha-amylase increased significantly from pre-boarding to landing during 3 trainings. The concentrations of cortisol, chromogranin A and activity of alpha-amylase at 2 h before boarding and at 0.5 h after landing decreased significantly with the training times. However, the changes of 3 biomarkers at 1 h before boarding among 3 trainings were not significant. CONCLUSION: The levels of stress increased significantly for 20 recruits from pre-boarding to landing during parachuting trainings. The stress levels of 20 recruits before boarding and after landing significantly decreased with parachuting training times. PMID- 22931816 TI - [Effects of noise exposure level on the relationship between SNPs of SOD1 and the susceptibility to noise-induced hearing loss (NIHL)]. AB - OBJECTIVE: To explore the effects of noise exposure level and cumulative noise exposure (CNE) on the relationship between rs2070424 and rs10432782 SNPs in SOD1 and the susceptibility to noise-induced hearing loss (NIHL). METHODS: A case control study was performed for investigating the effects of environmental risk factors on the susceptibility to NIHL in 201 sensitive workers and 202 resistant workers.A questionnaire was utilized to investigate the occupational health and to identify the occupational risk factors. The noise exposure levels were detected according to the Chinese standard Measurement of noise in the workplace (GBZ/T 189.8-2007). The peripheral blood samples (5 ml blood for each sample) were from sensitive workers and resistant workers. Genomic DNA was extracted on the basis of the standard procedures of Takara kit. SNPs were detected using standard procedures of TaqMan probe allele identification method. RESULTS: In group exposed to 85 - 92 dB noise (A), the risk of NIHL in the subjects with the AA genotype of rs2070424 was lower than that in the subjects with the GG genotype, OR = 0.37 (95%CI: 0.17~ 0.80). In group exposed to > 82 dB CNE (A), the AA genotype of rs2070424 is a protective factor of NIHL, as compared with the GG genotype, OR = 0.25 (95%CI: 0.09 ~ 0.70). In group exposed to 85 - 92 dB noise (A), the risk of NIHL in the subjects with the GG genotype of rs10432782 was compared with the risk of NIHL in the subjects with the TT genotype, OR = 3.17 (95%CI: 1.16 ~ 6.89). The GT genotype was compared with TT genotype, OR = 2.39 (95%CI: 1.16 ~ 4.97). In group exposed to 75 ~ 82 dB CNE (A), the risk of NIHL in the subjects with the GG genotype was compared with the risk of NIHL in the subjects with the TT genotype, OR = 2.35 (95%CI: 0.96 ~ 5.72), P = 0.06. The GG genotype may bea risk factor of NIHJ. CONCLUSION: The noise exposure level and CNE may influence the relationship between rs2070424, rs10432782 SNPs in SOD1 and noise-induced hearing loss. PMID- 22931818 TI - [Investigation on lens opacification of 317 welders]. PMID- 22931819 TI - [A study on the relationship between hearing impairment and blood pressure and hypertension in workers occupationally exposed to noise]. AB - OBJECTIVE: To study the correlation between noise and blood pressure and/or hypertension, and its age characteristic. METHODS: The pure tone audiometric and blood pressure examinations were performed in 14537 workers from 157 factories. Hearing impairment was used as a surrogate indicator of cumulated noise exposure. The associations of hearing impairment and duration of noise exposure with blood pressure and hypertension were analyzed respectively after age and gender stratification. RESULTS: Most of the objects were males (81.2%), younger than 35 years old (77.8%), and the duration of exposure to noise was less than 5 years (73.6%). The prevalence of hearing impairment in males was significantly higher than that in males, and increased with age and duration of noise exposure. Only in males with age younger than 35 years old, the systolic and diastolic blood pressures of subjects with sensorineural hearing loss significantly enhanced, and the diastolic blood pressure and prevalence of hypertension increased with duration of noise exposure. The risk of hypertension in males with sensorineural hearing loss significantly increased, the odds ratios in subjects with age younger than 35 years old and with age older than 35 years old were 3.0 (95%CI: 1.5 ~ 6.1) and 2.1 (95%CI: 1.2 ~ 3.4), respectively. CONCLUSION: The severe hearing impairment induced by noise was associated with hypertension. It is suggested that people should pay attention to the effects of noise on hypertension in young workers. PMID- 22931820 TI - [Methylation status of P16 gene during malignant transformation of human bronchial epithelial cells induced by glycidyl methacrylate]. AB - OBJECTIVE: To analyze the methylation status of P16 gene at the different stages of malignant transformation of human bronchial epithelial cells (16HBE) induced by glycidyl methacrylate (GMA) and to explore the DNA methylation mechanisms. METHODS: The cells exposed to GMA were harvested at the end of exposure (early stage), the 10th generation (protophase) and the 30th generation (anaphase), respectively. The methylation status of P16 promotor was detected by Methylation specific PCR (MSP). The transformed 16HBE cells were compared with the normal 16HBE cells and the cells exposed to DMSO for methylation status. RESULTS: At the early stage and protophase stage, the non-methylation status in P16 gene promotor of the normal 16HBE cells and the cells exposed to DMSO appeared, the methylation status in P16 gene promotor of the 16HBE cells exposed to GMA was detected to some extension. At the anaphase stage, the methylation status in P16 gene promotor of the 16HBE cells exposed to GMA or DMSO was detected to some extension. CONCLUSION: Methylation status of P16 gene promoter was specific at the early stage and protophase stage of malignant transforming in 16HBE cells induced by GMA, which can serve as an early sensitive biological indicator for malignant transforming in 16HBE cells induced by GMA. PMID- 22931822 TI - [Detection of serum total IgE, phadiatop and eosinophil cationic protein in patients with silicosis]. PMID- 22931821 TI - [The Effect of trichloroisocyanuric acid (TCCA) on the reproductive system of SD male rat]. PMID- 22931823 TI - [Clinical analysis of pneumonoconiosis complicated with spontaneous pneumothorax]. AB - OBJECTIVE: To study the clinical characteristics and treatment method of pneumonoconiosis with spontaneous pneumothorax. METHODS: The clinical data of 55 cases with spontaneous pneumothorax were analyzed. RESULTS: Among these 55 cases, there were 19 cases with left side pneumothorax, 25 cases with right side pneumothorax and 11 cases with bilateral pneumothorax. The lungs of 17 cases were compressed to less than 20%, the lungs of 29 cases were compressed to 20% ~ 50% and the lungs of 9 cases were compressed to more than 50%, 17 cases were treated conservatively, 7 cases were treated by thoracentesis, and 32 cases were treated by closed thoracic drainage, including 10 cases intrapleural injected with thrombin and PAMBA. After the treatment, 41 cases were cured, 10 cases were improved, 3 cases were transferred to other hospital for plugging or pleurodesis and 1 case died of the respiratory failure. CONCLUSION: The clinical symptoms of cases with pneumonoconiosis and spontaneous pneumothorax are atypical. These cases easily recur. After treatment, the healing of these cases is better. PMID- 22931824 TI - [Determination of beta-naphthol in the air of workplace by catalytic spectrophotometric]. PMID- 22931825 TI - [Detection of mercury (II) ions (Hg(2+)) in water by a nanobiosensor]. AB - OBJECTIVE: To develop a nanobiosensor for rapid colorimetric detecting Mercury (II) Ions (Hg(2+)) in water by mercury-specific oligonucleotides (MSOs) probe and gold nanoparticles. METHODS: The nanobiosensor was assembled by adsorbing the optimized MSOs on the surface of gold nanoparticles. A direct colorimetric probe of Hg(2+) which relied on the T-T mismatches in DNA duplexes was used to selectively and strongly capture Hg(2+). Hg(2+) induces the aggregation of gold nanoparticles with appropriate amount of salts, resulting the color change (red to blue). RESULTS: The diameter and concentration of the gold nanoparticle preparation were 15 nm and 2.97 nmol/L, respectively. Truncated MSOs (9 bp) showed the similar Hg(2+)-binding activity. The optimum concentration of the NaNO3 solution was 0.5 mol/L. The nanobiosensor could detect Hg(2+)in a range of 10 ~ 1000 umol/L within few minutes and the specificity was 100%. CONCLUSION: A new nanobiosensor is developed successfully for rapid colorimetric detecting Hg(2+) in water, avoiding either MSOs labeling or gold nanoparticles modification. This technique is simple, convenient and rapid detecting method with high sensitivity and specificity. PMID- 22931826 TI - [Measurement of 16 elements in blood by inductively coupled plasma mass spectrometry]. AB - OBJECTIVE: To establish a method of determining more elements in whole blood by inductively coupled plasma mass spectrometry (ICP-MS). METHODS: The whole blood samples were treated by 5% nitric acid to remove the proteins, then were centrifuged. Sixteen elements (Be, Al, Mn, V, Cr, Co, Ni, As, Mo, Ag, Cd, Sb, Ba,Tl, Pb and U) in the supernatant were directly measured by ICP-MS. RESULTS: The detection limits of 16 elements were 0.01 ~ 6.51 ug/L. The linear correlation coefficient was >= 0.999. The relative standard deviations were below 5 %. The recovery rates were 105% ~ 115%. Seronorm Trace Elements SerumL-1 LOT 0903106 and GBW09139g or GBW09140g were used in the quality control, the detected results corresponded with the standard values. CONCLUSION: ICP-MS technique is a simple, rapid, accurate and reliable method, which can be used to measure several trace elements in whole blood samples. PMID- 22931827 TI - [Determination of decabromodiphenyl ether in the air of workplace by GC/MS]. PMID- 22931828 TI - [Benzene,methylbenzene and dimethylbenzene monitoring in a new project of methylbenzene recycle]. PMID- 22931829 TI - The DUB-ious lack of ALIS in Salmonella infection: a Salmonella deubiquitinase regulates the autophagy of protein aggregates. AB - Ubiquitinated aggregates are formed in eukaryotic cells in response to several external stimuli, including exposure to bacterial lipopolysaccharide (LPS). Although Salmonella enterica serovar Typhimurium (S. Typhimurium) LPS has been shown to induce aggresome-like induced structures (ALIS) in macrophages, these have not been described in S. Typhimurium-infected macrophages. Given that LPS is present in infection, this suggests that S. Typhimurium might suppress the formation of ALIS. We found that S. Typhimurium induces the formation of ubiquitinated aggregates in epithelial cells and macrophages, but that their presence is masked by the deubiquitinase (DUB) activity of the S. Typhimurium virulence protein, SseL. SseL deubiquitinates SQSTM1/p62-bound proteins found in S. Typhimurium-induced aggregates and ALIS, and reduces the recruitment of autophagic components. While the functions of ALIS and other ubiquitinated aggregates remain unclear, they serve to sequester cytosolic proteins under a variety of stress conditions and are suggested to be involved in host immune defense. During infection, the deubiquitinase activity of SseL reduces autophagic flux in infected cells and favors bacterial replication. This is a new example of how a bacterial pathogen counteracts the autophagy pathway through the action of a translocated virulence protein. PMID- 22931830 TI - Expression patterns reveal niche diversification in a marine microbial assemblage. AB - Resolving the ecological niches of coexisting marine microbial taxa is challenging due to the high species richness of microbial communities and the apparent functional redundancy in bacterial genomes and metagenomes. Here, we generated over 11 million Illumina reads of protein-encoding transcripts collected from well-mixed southeastern US coastal waters to characterize gene expression patterns distinguishing the ecological roles of hundreds of microbial taxa sharing the same environment. The taxa with highest in situ growth rates (based on relative abundance of ribosomal protein transcripts) were typically not the greatest contributors to community transcription, suggesting strong top-down ecological control, and their diverse transcriptomes indicated roles as metabolic generalists. The taxa with low in situ growth rates typically had low diversity transcriptomes dominated by specialized metabolisms. By identifying protein encoding genes with atypically high expression for their level of conservation, unique functional roles of community members emerged related to substrate use (such as complex carbohydrates, fatty acids, methanesulfonate, taurine, tartrate, ectoine), alternative energy-conservation strategies (proteorhodopsin, AAnP, V type pyrophosphatases, sulfur oxidation, hydrogen oxidation) and mechanisms for negotiating a heterogeneous environment (flagellar motility, gliding motility, adhesion strategies). On average, the heterotrophic bacterioplankton dedicated 7% of their transcriptomes to obtaining energy by non-heterotrophic means. This deep sequencing of a coastal bacterioplankton transcriptome provides the most highly resolved view of bacterioplankton niche dimensions yet available, uncovering a spectrum of unrecognized ecological strategies. PMID- 22931833 TI - Too much sharing? PMID- 22931832 TI - Horizontal violence: can anything be done? PMID- 22931831 TI - Sizing up metatranscriptomics. AB - A typical marine bacterial cell in coastal seawater contains only ~200 molecules of mRNA, each of which lasts only a few minutes before being degraded. Such a surprisingly small and dynamic cellular mRNA reservoir has important implications for understanding the bacterium's responses to environmental signals, as well as for our ability to measure those responses. In this perspective, we review the available data on transcript dynamics in environmental bacteria, and then consider the consequences of a small and transient mRNA inventory for functional metagenomic studies of microbial communities. PMID- 22931835 TI - Refusing artificial nutrition and hydration in advanced illness. PMID- 22931836 TI - Finding room for spirituality in healthcare. PMID- 22931838 TI - Shhh! Conducting a Quiet Zone pilot study for medication safety. PMID- 22931842 TI - Understanding endovascular aneurysm repair. PMID- 22931843 TI - Three bananas and three cartons of milk. PMID- 22931845 TI - SIADH: Fluid out of balance. PMID- 22931846 TI - Stick to safe use of denture adhesives. PMID- 22931847 TI - Assessing a patient with an insulin pump. PMID- 22931848 TI - Preparing for travel to high altitudes. PMID- 22931849 TI - Aspiration pneumonia. PMID- 22931850 TI - Effectiveness and timing of vaccination during school measles outbreak. AB - Despite high vaccination coverage in most European countries, large community outbreaks of measles do occur, normally clustered around schools and resulting from suboptimal vaccination coverage. To determine whether or when it is worth implementing outbreak-response vaccination campaigns in schools, we used stochastic outbreak models to reproduce a public school outbreak in Germany, where no vaccination campaign was implemented. We assumed 2 scenarios covering the baseline vaccination ratio range (91.3%-94.3%) estimated for that school and computed outbreaks assuming various vaccination delays. In one scenario, reacting (i.e., implementing outbreak-response vaccination campaigns) within 12-24 days avoided large outbreaks and reacting within 50 days reduced outbreak size. In the other scenario, reacting within 6-14 days avoided large outbreaks and reacting within 40 days reduced the outbreak size. These are realistic time frames for implementing school outbreak response vaccination campaigns. High baseline vaccination ratios extended the time needed for effective response. PMID- 22931851 TI - Stuttering Min oscillations within E. coli bacteria: a stochastic polymerization model. AB - We have developed a 3D off-lattice stochastic polymerization model to study the subcellular oscillation of Min proteins in the bacteria Escherichia coli, and used it to investigate the experimental phenomenon of Min oscillation stuttering. Stuttering was affected by the rate of immediate rebinding of MinE released from depolymerizing filament tips (processivity), protection of depolymerizing filament tips from MinD binding and fragmentation of MinD filaments due to MinE. Processivity, protection and fragmentation each reduce stuttering, speed oscillations and MinD filament lengths. Neither processivity nor tip protection were, on their own, sufficient to produce fast stutter-free oscillations. While filament fragmentation could, on its own, lead to fast oscillations with infrequent stuttering; high levels of fragmentation degraded oscillations. The infrequent stuttering observed in standard Min oscillations is consistent with short filaments of MinD, while we expect that mutants that exhibit higher stuttering frequencies will exhibit longer MinD filaments. Increased stuttering rate may be a useful diagnostic to find observable MinD polymerization under experimental conditions. PMID- 22931852 TI - A Bayesian approach to study the risk variables for tuberculosis occurrence in domestic and wild ungulates in South Central Spain. AB - BACKGROUND: Bovine tuberculosis (bTB) is a chronic infectious disease mainly caused by Mycobacterium bovis. Although eradication is a priority for the European authorities, bTB remains active or even increasing in many countries, causing significant economic losses. The integral consideration of epidemiological factors is crucial to more cost-effectively allocate control measures. The aim of this study was to identify the nature and extent of the association between TB distribution and a list of potential risk factors regarding cattle, wild ungulates and environmental aspects in Ciudad Real, a Spanish province with one of the highest TB herd prevalences. RESULTS: We used a Bayesian mixed effects multivariable logistic regression model to predict TB occurrence in either domestic or wild mammals per municipality in 2007 by using information from the previous year. The municipal TB distribution and endemicity was clustered in the western part of the region and clearly overlapped with the explanatory variables identified in the final model: (1) incident cattle farms, (2) number of years of veterinary inspection of big game hunting events, (3) prevalence in wild boar, (4) number of sampled cattle, (5) persistent bTB infected cattle farms, (6) prevalence in red deer, (7) proportion of beef farms, and (8) farms devoted to bullfighting cattle. CONCLUSIONS: The combination of these eight variables in the final model highlights the importance of the persistence of the infection in the hosts, surveillance efforts and some cattle management choices in the circulation of M. bovis in the region. The spatial distribution of these variables, together with particular Mediterranean features that favour the wildlife-livestock interface may explain the M. bovis persistence in this region. Sanitary authorities should allocate efforts towards specific areas and epidemiological situations where the wildlife-livestock interface seems to critically hamper the definitive bTB eradication success. PMID- 22931854 TI - Food-induced brain responses and eating behaviour. AB - The brain governs food intake behaviour by integrating many different internal and external state and trait-related signals. Understanding how the decisions to start and to stop eating are made is crucial to our understanding of (maladaptive patterns of) eating behaviour. Here, we aim to (1) review the current state of the field of 'nutritional neuroscience' with a focus on the interplay between food-induced brain responses and eating behaviour and (2) highlight research needs and techniques that could be used to address these. The brain responses associated with sensory stimulation (sight, olfaction and taste), gastric distension, gut hormone administration and food consumption are the subject of increasing investigation. Nevertheless, only few studies have examined relations between brain responses and eating behaviour. However, the neural circuits underlying eating behaviour are to a large extent generic, including reward, self control, learning and decision-making circuitry. These limbic and prefrontal circuits interact with the hypothalamus, a key homeostatic area. Target areas for further elucidating the regulation of food intake are: (eating) habit and food preference formation and modification, the neural correlates of self-control, nutrient sensing and dietary learning, and the regulation of body adiposity. Moreover, to foster significant progress, data from multiple studies need to be integrated. This requires standardisation of (neuroimaging) measures, data sharing and the application and development of existing advanced analysis and modelling techniques to nutritional neuroscience data. In the next 20 years, nutritional neuroscience will have to prove its potential for providing insights that can be used to tackle detrimental eating behaviour. PMID- 22931853 TI - A bigger picture: classical cadherins and the dynamic actin cytoskeleton. AB - Classical cadherin adhesion receptors influence tissue integrity in health and disease. Their biological function is intimately linked to the actin cytoskeleton. To date, research has largely focused on identifying the molecular mechanisms that physically couple cadherin to cortical actin filaments. However, the junctional cytoskeleton is dynamic. Recent developments in understanding how filament dynamics and organization in the junctional cytoskeleton are controlled provide new insights into how the actin cytoskeleton regulates cadherin junctions in health and disease. PMID- 22931855 TI - Thyroid hormone and obesity. AB - PURPOSE OF REVIEW: To review several of the most recent and most important clinical studies regarding the effects of thyroid treatments on weight change, associations between thyroid status and weight, and the effects of obesity and weight change on thyroid function. RECENT FINDINGS: Weight decreases following treatment for hypothyroidism. However, following levothyroxine treatment for overt hypothyroidism, weight loss appears to be modest and mediated primarily by loss of water weight rather than fat. There is conflicting evidence about the effects of thyroidectomy on weight. In large population studies, even among euthyroid individuals, serum thyroid-stimulating hormone is typically positively associated with body weight and BMI. Both serum thyroid-stimulating hormone and T3 are typically increased in obese compared with lean individuals, an effect likely mediated, at least in part, by leptin. Finally, there is no consistent evidence that thyroid hormone treatment induces weight loss in obese euthyroid individuals, but thyroid hormone analogues may eventually be useful for weight loss. SUMMARY: The interrelationships between body weight and thyroid status are complex. PMID- 22931856 TI - Current world literature. PMID- 22931858 TI - Measles and secondary hemophagocytic lymphohistiocytosis. PMID- 22931859 TI - Design of a medical record review study on the incidence and preventability of adverse events requiring a higher level of care in Belgian hospitals. AB - BACKGROUND: Adverse events are unintended patient injuries that arise from healthcare management resulting in disability, prolonged hospital stay or death. Adverse events that require intensive care admission imply a considerable financial burden to the healthcare system. The epidemiology of adverse events in Belgian hospitals has never been assessed systematically. FINDINGS: A multistage retrospective review study of patients requiring a transfer to a higher level of care will be conducted in six hospitals in the province of Limburg. Patient records are reviewed starting from January 2012 by a clinical team consisting of a research nurse, a physician and a clinical pharmacist. Besides the incidence and the level of causation and preventability, also the type of adverse events and their consequences (patient harm, mortality and length of stay) will be assessed. Moreover, the adequacy of the patient records and quality/usefulness of the method of medical record review will be evaluated. DISCUSSION: This paper describes the rationale for a retrospective review study of adverse events that necessitate a higher level of care. More specifically, we are particularly interested in increasing our understanding in the preventability and root causes of these events in order to implement improvement strategies. Attention is paid to the strengths and limitations of the study design. PMID- 22931860 TI - Health information regarding diabetes mellitus reduces misconceptions and underestimation of consequences in the general population. AB - OBJECTIVE: To evaluate self-assessed knowledge about diabetes mellitus, to assess determinants of health knowledge and to evaluate consequences of health knowledge on appraisal about consequences of the disease. DESIGN: Population-based computer assisted web interview survey, supplemented with a paper-and-pencil survey via post. SETTING: Representative sample of the general Austrian population aged 15 years and older. SUBJECTS: Men (n 1935) and women (n 2065) with and without diabetes mellitus. RESULTS: Some 20.5% of men and 17.7% of women with diabetes, and 46.2% of men and 36.7% of women without diabetes, rated their knowledge about diabetes mellitus to be 'very bad' or 'rather bad'. Individuals with diabetes and individuals with a family member with diabetes rated their information level more often as 'very good' or 'rather good', with adjusted OR (95% CI) of 1.7 (1.1, 2.8) and 2.1 (1.6, 2.7), respectively, in men and 2.7 (1.5, 4.8) and 2.7 (2.1, 3.5), respectively, in women. Additional significant influencing factors on diabetes knowledge were age and educational level in both sexes, and city size in men. Independent of personal diabetes status, diabetes knowledge was associated with a lower perception of restrictions on daily life of diabetes patients and with a lower probability of underestimating health consequences of diabetes. CONCLUSIONS: Health knowledge is associated with fewer misconceptions and less underestimation of health consequences in individuals both with and without diabetes mellitus. Thus health information about diabetes is important on the individual level towards disease management as well as on the public health level towards disease prevention. PMID- 22931862 TI - Tandem repeat sequences evolutionarily related to SVA-type retrotransposons are expanded in the centromere region of the western hoolock gibbon, a small ape. AB - Hoolock hoolock (the western hoolock gibbon) is a species of the family Hylobatidae (small apes), which constitutes the superfamily Hominoidea (hominoids) together with Hominidae (great apes and human). Here, we report that centromeres or their vicinities in this gibbon species contain tandem repeat sequences that consist of 35-50-bp repeat units, and exhibit a sequence similarity with the variable number of tandem repeat (VNTR) region of the SVA, LAVA and PVA transposons. SVA is a composite retrotransposon thought to have been formed by fusion of three solo elements in the common ancestor of hominoids. LAVA and PVA are recently identified retrotransposons that have the same basic structure as SVA. Thus, the large-scale tandem repeats in the centromere region may have been derived from one or more of SVA-type transposons, including the three mentioned above and other yet unknown elements, or the repeat sequences could have served as a source for such elements. Amplification of VNTR-related sequences in another gibbon species, Hoolock leuconedys (eastern hoolock gibbon), has recently been reported, but it is yet to be examined whether the large-scale tandem repeats observed in the two species originated from a single event that occurred in their common ancestor. The repeat sequences in the western hoolock gibbon are mostly 40 kb or more in length, are present in 28 of the 38 chromosomes of the somatic cells, and are homozygous for chromosomal presence/absence. PMID- 22931861 TI - Both thyroid autoimmunity and increased serum TSH are independent risk factors for malignancy in patients with thyroid nodules. AB - AIM: To assess the relevance of thyroid autoimmunity and TSH as risk factors for malignancy in thyroid nodules (TN). SUBJECTS AND METHODS: Retrospective analysis on 2053 patients with single/prevalent TN submitted to fine needle aspiration cytology (FNAC). Anti-thyroid autoantibodies (ATA) [anti-thyroperoxidase (TPOAb), anti-thyroglobulin (TgAb)] and TSH were measured. Cytology was classified as benign (class II), indeterminate (class III), and suspicious or malignant (class IV). Histology was available in 301 patients. Associations of malignancy with independent variables were determined by multivariate logistic regression analysis. RESULTS: Higher prevalence of class IV (14.2% vs 6.8%: p<0.001) and class III (23.5% vs 17.1%: p<0.001) were found in ATA+ vs ATA- TN. Histology confirmed increased prevalence of cancer in ATA+ (p<0.05) TN and in those with diffuse lymphocytic thyroid infiltration (p<0.05). Interestingly, the prevalence of malignancies observed in operated class III nodules was strikingly lower in ATA+ (1/20, 5%), than in ATA- patients (34/67, 50.7%; p<0.001). Increased independent odds ratio (OR) for malignancy was conferred by any ATA [OR 2.21; 95% confidence interval (CI)=1.49-3.29, p<0.0001]; TPOAb (OR 2.15; CI=1.42-3.25, p<0.0001) and TgAb (OR 1.67; CI=1.05-2.67, p<0.05), by serum TSH>1.0 MUUI/ml (OR 1.95; CI=1.01-3.76, p<0.05), and by young age (10-29 yr: OR 2.09; CI=1.02-4.26, p<0.05). A formula was calculated to assess the relative contribution of ATA, TSH, and age to the risk of TN malignancy. CONCLUSIONS: Both thyroid autoimmunity and increased TSH represent independent risk factors for TN malignancy. PMID- 22931864 TI - Petrous apex vascular malformation. PMID- 22931863 TI - Sibling cases of moyamoya disease having homozygous and heterozygous c.14576G>A variant in RNF213 showed varying clinical course and severity. AB - Moyamoya disease (MMD) is a rare cerebrovascular disease characterized by progressive occlusion of the terminal portion of the internal carotid arteries and their branches. A genetic background was under speculation, because of the high incidence of familial occurrence. Sibling cases usually exhibit a similar clinical course. Recently, RNF213 was identified as the first MMD susceptibility gene. The c.14576G>A variant of RNF213 significantly increases the MMD risk, with an odds ratio of 190.8. Furthermore, there is a strong association between clinical phenotype and the dosage of this variant. The present study described sibling MMD cases having homozygous and heterozygous c.14576G>A variant in RNF213, as well as different clinical course and disease severity. The homozygote of c.14576G>A variant showed an early onset age and rapid disease progress, which resulted in significant neurological deficits with severe and wide distribution of vasculopathy. In contrast, the heterozygote of the variant showed a relatively late-onset age and mild clinical course without irreversible brain lesions with limited distribution of vasculopathy. This is the first report of sibling MMD cases with different doses of the RNF213 variant, showing its genetic impact on clinical phenotype even in members with similar genetic background. PMID- 22931865 TI - Extended frequency range hearing thresholds and otoacoustic emissions in acute acoustic trauma. AB - OBJECTIVE: We sought to evaluate the relative value of pure tone audiometry (PTA), extended high-frequency audiometry (EFA) and transiently evoked otoacoustic emissions (OAE) and distortion products when monitoring acute acoustic trauma (AAT). STUDY DESIGN: Controlled prospective clinical study. SETTING: Tertiary referral center. PATIENTS: Seventy one active duty soldiers in the same age with normal hearing INTERVENTIONS: Forty one soldiers suffered assault-rifle-induced acute acoustic traumas with hearing loss and tinnitus. Thirty soldiers served as a control group. MAIN OUTCOME MEASURES: Pure tone threshold changes detected by PTA and EFA, amplitude and reproducibility changes in transiently evoked OAE, distortion products, and tinnitus analysis based on a visual analog scale. RESULTS: Assault rifle-induced AAT caused unilateral temporary threshold shifts (TTS) in PTA and bilateral TTS in EFA. Two frequency regions with the largest threshold shifts were identified: one between 3 and 6 kHz and another between 11 and 14 kHz. The reproducibility of transiently evoked OAEs revealed changes related to the acoustic trauma in the 3- to 5-kHz frequency window. The amplitudes of the low stimulation level distortion products at 6 kHz were correlated with the audiometric AAT-induced TTS. CONCLUSION: Acute acoustic trauma-induced audiometric TTS are predominantly confined to 2 specific frequency regions. PTA and EFA are both necessary to identify the full extent of acute acoustic trauma. PTA and EFA revealed that the TTSs were correlated to with distortion product OAE amplitude shifts at 6 kHz and changes in the reproducibility of transiently evoked OAE in the 3- to 5-kHz frequency window. PTA remains the most important measurement to monitor AAT. It may be useful to complement it with EFA, focusing on the 11 to 14 kHz frequency range. If used, OAE should be analyzed in the frequency range of 3 to 6 kHz. PMID- 22931866 TI - Temporal bone histopathology case of the month: Acute unilateral facial paralysis in child from intra-aural hard tick. PMID- 22931867 TI - Imaging case of the month: Abnormalities of the cochlear nerves and internal auditory canals in pontine tegmental cap dysplasia. PMID- 22931868 TI - Functional results and quality of life after retrosigmoid vestibular neurectomy in patients with Meniere's disease. AB - BACKGROUND: Severe Meniere's disease (MD) may be debilitating and compromising, despite intensive medical treatment. Vestibular neurectomy (VN) is considered an effective surgical treatment for disabling MD. Our aim was to analyse the medium- to long-term outcome after retrosigmoid VN with special regard to vertigo, quality of life (American Academy of Otolaryngology-Head and Neck Surgery criteria), and pure tone average (PTA). METHODS: Retrospective evaluation of patients with disabling MD treated with retrosigmoid VN at the university hospital of Bern (1992-2009), after unsuccessful attempts at medical treatment. Demographics, clinical signs and symptoms, quality of life, thresholds of hearing, and adverse events were documented at baseline, 1 week, 12 months, and 24 months after surgery. RESULTS: Medium to long-term follow-up data were available from 44 of 78 patients, who had undergone retrosigmoid VN (19 men; mean age, 50.3 +/- 11.0 yr). Vertigo disappeared in 34 (77.3%) of 44 patients and improved in 6 (13.6%) of 44 patients. Quality of life significantly improved postoperatively (mean American Academy of Otolaryngology-Head and Neck Surgery, 0.68 +/- 1.14 [1 yr] and 0.57 +/- 1.19 [2 yr] versus 5.11 +/- 0.66). Mean PTA decreased (52.3 +/- 19.2 dB versus 56.2 +/- 21.6 dB [1 wk] and 60.4 +/- 20.5 dB [1 yr]; p < 0.001). Ten (22.7%) of 44 patients showed improved PTA after VN. These patients had significantly higher baseline PTA (69.4 dB versus 47.9 dB; p = 0.001). CONCLUSION: Retrosigmoid VN is a valuable and safe surgical option to treat disabling MD that has proved resistant to medical treatments. It may also be indicated for patients with preoperative severely impaired thresholds of hearing, in whom a certain hearing gain may be observed. PMID- 22931869 TI - Diabetic mice show an aggravated course of herpes-simplex virus-induced facial nerve paralysis. AB - HYPOTHESIS: Bell's palsy is highly associated with diabetes mellitus. BACKGROUND: The cause of Bell's palsy in diabetes mellitus is not completely understood. Diabetic mononeuropathy or reactivation of herpes simplex virus type 1 (HSV-1) may be responsible for the facial paralysis seen in diabetic patients. We previously reported transient and ipsilateral facial paralysis in mice inoculated with HSV-1. In this study, we examined the neuropathogenesis of HSV-1 in diabetic mice to clarify the relationship between Bell's palsy and diabetes mellitus. METHODS: We compared the incidence and course of facial paralysis after HSV-1 inoculation in diabetic and nondiabetic mice groups. Diabetic mice were prepared by intraperitoneal streptozotocin injection. Facial nerve damage was assessed by electrophysiologic and histopathologic examinations. RESULTS: Compared with the nondiabetic group, the incidence of facial nerve paralysis was significantly increased in the diabetic mice. Electrophysiologic examinations and histopathologic changes also revealed that the facial nerve damage was more severe in the diabetic group. CONCLUSION: The aggravated course of HSV-1 infection in diabetes suggests that HSV-1 may be the main causative factor for the increased incidence of facial paralysis in diabetic patients. PMID- 22931870 TI - Traumatic tympanic membrane perforations: clinical and audiometric findings in 198 patients. AB - OBJECTIVE: To obtain clinical and audiometric findings in traumatic tympanic membrane perforations from a typical patient collective in a Western industrial nation because the appropriate data have an important relevance in medicolegal questions. STUDY DESIGN: Retrospective data collection. SETTING: Germany's largest university clinic for otorhinolaryngology, head and neck surgery. SUBJECT AND METHODS: From the medical records of 198 patients with traumatic tympanic membrane perforations, the following data were collected: demographic data, date and mechanism of the trauma, otoscopic findings and collateral injuries, kind of therapy and its results, pure tone audiometry, and statement of tinnitus or vertigo in the course. RESULTS: Most patients were young (mean age, 29.2 yr) and male (62%). Men and women are equally represented in perforations resulting from a physical blow to the ear (44.7% vs 46.7%); a collision was more often the cause in men (23.6% vs 14.7%), whereas an accidental perforation by insertion of a cotton bud was approximately 2 times more common on women (13.8% vs 25.3%). The left ear was more often affected than the right ear (58.5% vs 41.5%). Collateral damage was found in only 1% of the cases. In blows, collisions, barotraumas, and the insertion of sharp objects, the inferior parts of the tympanic membrane were most often affected; the most severe (subtotal) perforations were caused by explosions, weld beads, and insertion of cotton buds. For therapy, myringoplasty had an overall success rate of 88.9%; splinting with silicon foils, 51.6%; and "no therapy," 53.3%. Bone conduction thresholds for the affected ear were higher in low, middle, and high frequencies compared with the contralateral ear by trend, but a statistical difference was only found in the high frequencies. In follow-up examinations, the hearing thresholds in the high frequencies were no longer significantly different. A "c dip" or "fis dip" was found in 18.0% and 9.2%. Tinnitus and vertigo were reported in 30.8 and 8.1%, respectively, but only in 2.0% and 0% during follow-up. CONCLUSION: High-frequency hearing loss, tinnitus, and vertigo in traumatic tympanic membrane perforations have a good prognosis. PMID- 22931871 TI - [Pathological observation of lung injury in experimental animals induced by non ferrous metal (tin) dusts]. AB - OBJECTIVE: To explore the characters of lung injury induced by tin dusts and to provide the diagnosis evidence of tin pneumoconiosis. METHODS: Forty SD rats were randomly divided into four groups: the group exposed to tin dusts from smelting workshop, the group exposed to tin dusts from tin refining workshop, the positive control group exposed to standard quartz dusts and the negative control group exposed to saline. The pathological changes of rat lungs were observed dynamically. RESULTS: In rats exposed to tin dusts, on the 30th day after exposure to tin dusts, the scattered hoar tip size of the spots in surface and section of the lungs were observed, the scattered focal granulomatous inflammation around the small bronchi and dust particles in lung tissue were observed under microscope; on the 90th day after exposure to tin dusts, the granulomatous inflammation increase, the fibroblasts proliferation, collagen fibers formation and positive VG staining were found. There were significant differences, as compared with positive or negative controls (P < 0.05). These pathological changes were basically the characters of specific pathological changes in early tin pneumoconiosis. CONCLUSION: Non-ferrous metal tin dusts can induce the specific lung injury (granuloma formation) in lung tissue of rats exposed to tin dusts, which fulfilled the diagnostic criteria of specific pathological changes in early tin pneumoconiosis. PMID- 22931872 TI - [Therapeutic effects of epidermal growth factor (EGF) combined with plasma cryoprecipitate (CRYO) on the corneal injury induced by paraquat]. AB - OBJECTIVE: To evaluate the therapeutic effects of epidermal growth factor (EGF) combined with plasma cryoprecipitate (CRYO) on the corneal injury induced by paraquat (PQ). METHODS: According to the "Toxicological test methods of pesticides for registration" (GB 15670-1995), the conjunctival sacs of 18 health New Zealand rabbits were exposed to 100 ul 20% PQ, which were randomly divided into EGF, CRYO and EGF plus CRYO groups. The routine treatments (normal saline washing and antibiotic eyedrops) were administrated to the injured eyes of 3 groups, at the same time the left eyes of 3 groups were treated with EGF, CRYO and EGF plus CRYO, respectively. The injury of conjunctival, iris and corneal, fluorescent stranded and pathology changes of corneal were observed. The injury score was calculated and the recovery time of corneal injury was recorded. RESULTS: The recovery time of corneal injury in EGF and EGF plus CRYO groups were 19.50 +/- 3.08 and 18.67 +/- 2.73 days, respectively which were significantly lower than those (27.33 +/- 2.58 and 26.83 +/- 3.13 days) in corresponding routine treatment controls (P < 0.05). CONCLUSION: EGF and EGF plus CRYO could be used to treat the corneal injury induced by paraquat. PMID- 22931873 TI - [Clinical study of correlation between the expression of ICBP90 and hematopoietic suppression in patients with chronic benzene poisoning]. AB - OBJECTIVE: To observe the change of ICBP90 expression in patients with chronic benzene poisoning and explore the correlation between the expression of ICBP90 and benzene-induced hematotoxicity. METHODS: The bone marrow samples were from 13 chronic benzene poisoning cases with hematopoietic suppression, 11 chronic benzene poisoning cases with hematopoietic regeneration and 10 controls. Western blot was applied to detect the ICBP90 expression in bone marrow mononuclear cells (BMNCs). The correlation between ICBP90 expression and hematopoietic suppression in patients with chronic benzene poisoning was analyzed. RESULTS: The ICBP90 expression of BMNCs in 13 chronic benzene poisoning cases with hematopoietic suppression was significantly lower than that in controls (P < 0.01). The ICBP90 expression of BMNCs in 11 chronic benzene poisoning cases with hematopoietic regeneration was significantly higher than those in controls and 13 chronic benzene poisoning cases with hematopoietic suppression (P < 0.05 or P < 0.01), respectively. There were good correlations between the expression of ICBP90 and white blood cell and platelet counts in patients with chronic benzene poisoning (r(1) = 0.555,P = 0.006; r(2) = 0.854,P < 0.01). CONCLUSION: The ICBP90 expression of BMNCs in the chronic benzene poisoning cases with hematopoietic suppression decreased significantly, and the ICBP90 expression of BMNCs in the chronic benzene poisoning cases with hematopoietic regeneration increased significantly. There was good correlation between hematopoietic suppression and ICBP90 expression in patients with chronic benzene poisoning. PMID- 22931874 TI - [Investigation of occupational exposure to power frequency electromagnetic fields in workers of power grid]. AB - OBJECTIVE: To measure and assess the levels of occupational exposure to power frequency electromagnetic fields in workers of power grid. METHODS: PMM8053 electromagnetic fields measuring system with EHP-50 probe was used to measure the levels of electromagnetic fields at working place. Personal dosimeters (EMDEX LITE) were utilized to measure the individual exposure levels of power frequency magnetic field. The results were evaluated with the limitation criteria of GBZ2.2 and ICNIRP. RESULTS: In the 500 kV ultra high voltage substation, the intensity at 90% measure points of power electric field was more than 5 kV/m. The magnetic field intensity in the areas nearby reactors and capacitors was often higher than 100 uT, even several hundreds uT. The mean daily exposure levels of workers in power grid were between 0.04 and 5.0 uT, and the exposure levels of 70% workers were higher than 0.4 uT. CONCLUSION: In the areas of ultra high voltage and nearby the reactors and capacitors are the key control points for occupational health in power grid. There is acute health risk of workers exposed to high accumulative exposure levels. PMID- 22931875 TI - [Sequence analysis on drug-resistant gene of rpoB in MDR-TB among pneumoconiosis patients complicated with tuberculosis in Huainan mining district]. AB - OBJECTIVE: To study the characteristics of drug-resistant genetic mutation of rpoB in multiple drugs resistant bacillus tuberculosis (MDR-TB) among patients of pneumoconiosis complicated with pulmonary tuberculosis. METHODS: A total of 114 clinical isolated strains of Mycobacterium tuberculosis were collected, MDR-TB were identified by conventional antimicrobial susceptibility test (AST). Their genomes DNA were extracted, the target genes were amplified by PCR, and the hot regions in the rpoB gene were analyzed by automated DNA sequenator. RESULTS: The results by AST showed that there were 31 strains of MDR-TB in the 114 clinical isolated strains, the rate of drug resistance was 27.19% (31/114). No mutation of rpoB was identified in 10 rifampicin-sensitive strains that randomly chosen, while conformation changes were found in MDR-TB strains, and the mutation rate of rpoB was 93.55% (29/31) in resistant strains, mainly concentrated in codon 531 (45.16%, 14/31) and 526 (29.03%, 9/31), happened base substitutions, including 27 unit point mutation and 2 two point mutation. CONCLUSIONS: The substitution of highly conserved amino acids encoded by rpoB gene results in the molecular mechanism responsible for RFP resistance in MDR-TB among patients of pneumoconiosis complicated with pulmonary tuberculosis. It also proves that rpoB gene is diversiform. PMID- 22931876 TI - [The epidemiological features of blast injury of lungs caused by gas explosion]. AB - OBJECTIVE: To investigate the clinical epidemiological features. of blast injury of lungs caused by gas explosion. METHODS: A retrospective analysis of 132 cases of blast injury of lungs caused by gas explosion injuries in our hospital from 1990 to 2010 were made, including the information of lung injury, associated injuries, treatment and mortality. RESULTS: 56 patients were conscious on admission, during 1 ~ 5 days, 30 patients got cough, hemoptysis and other pulmonary symptoms, 7 patients had hemothorax, 11 cases combined with pneumothorax, 86 cases of patients with burns, 96 cases with pulmonary aspiration compound injury, 41 cases with abdominal organs blast injuries, 76 cases with pulmonary infection, 31 cases with shock, Seven patients died of respiratory failure, two patients died of respiratory failure. CONCLUSION: Blast injury of lung featured with serious internal injuries, combined with many injuries, The incidence of compound injury was high, and it was difficult to diagnose. Chest X ray were varied. The mortality was high, and the predominant causes of death were respiratory failure, shock, sepsis. Most patients with blast injury of lung need tracheotomy and mechanical ventilation. Timely tracheotomy, mechanical ventilation were the major prognostic measures. PMID- 22931877 TI - [Hexavalent chromium pollution and exposure level in electroplating workplace]. AB - OBJECTIVE: To investigate the pollution of hexavalent chromium in the electroplating workplace and screen the biomarkers of chromium exposure. MATERIAL: Field occupational health investigation was conducted in 25 electroplating workplaces. 157 electroplating workers and 93 healthy unexposed controls were recruited. The epidemiological information was collected with face to face interview. Chromium in erythrocytes was determined by graphite furnace atomic absorption spectrophotometer. RESULTS: The median of short-term exposure concentration of chromium in the air at electroplating workplace was 0.06 mg/m(3) (median) and ranging from 0.01 (detect limit) to 0.53 mg/m(3)). The median concentration of Cr (VI) in erythrocytes in electroplating workers was 4.41 (2.50 ~ 5.29) ug/L, which was significantly higher than that in control subjects [1.54 (0.61 ~ 2.98) ug/L, P < 0.01]. After stratified by potential confounding factors such as gender, age, smoking status and alcohol consumption, significant differences still existed between electroplating workers and control subjects, except for the subjects of age less than 30 years old (P = 0.11). CONCLUSION: There was hexavalent chromium pollution in electroplating workplace. Occupational hazards prevention measures should be taken to control the chromium pollution hazards. PMID- 22931878 TI - [Meta-analysis of association of tumor necrosis factor alpha and transforming growth factor beta gene polymorphisms with pneumoconiosis]. AB - OBJECTIVE: To evaluate the relationship between tumor necrosis factor-alpha-238, transforming growth factor beta (509 and 869) gene polymorphisms and pneumoconiosis susceptibility. METHODS: We searched published full-text from foreign language databases including Elsevier, PubMed, Wiley Online Library, EMCC, Web of Science, chinese databases containing CNKI, VIP, Wanfang, CBM and Cochrane library to collect case-control or cohort study on gene gene polymorphisms said above with pneumoconiosis susceptibility from the year January1988 to August 2011. 28 relevant articles were selected and 20 of them met the criteria. The correlated index was extracted for aggregate analysis in RevMan 4.2. RESULTS: Among the 20 studies, 10 articles on TNF-alpha238 polymorphism (including 2232 pneumoconiosis cases and 1985 control subjects), 4 articles on TGF-beta509 polymorphism (including 693 pneumoconiosis cases and 663 control subjects), and 6 articles on TGF-beta869 polymorphism (including 1450 pneumoconiosis cases and 1101 control subjects) were included in the current study. Meta-analysis results showed that there was a significant association between TNF-alpha238 polymorphism and pneumoconiosis: the population with GA and AA genotypes of TNF-alpha238 had higher risks to pneumoconiosis (OR = 1.53, 95%CI: 1.25 ~ 1.88) comparing to GG genotype, and the population with A allele had higher risks to pneumoconiosis comparing to allele G (OR = 1.64, 95%CI: 1.17 ~ 2.30). The stratified analysis showed that the people with GA and AA genotypes and A allele who were silicosis, Asian or exposed to dust had higher risks to pneumoconiosis (OR = 2.14, 95%CI: 1.20 ~ 3.82; OR = 2.16, 95%CI: 1.20 ~ 3.88; OR = 1.78, 95%CI: 1.01 ~ 3.11; OR = 1.83, 95%CI: 1.04 ~ 3.22; OR = 1.80, 95%CI: 1.21 ~ 2.66; OR = 1.50, 95%CI: 1.23 ~ 1.83). No significant association was found between TGF-beta (509 and 869) gene polymorphisms with pneumoconiosis: In contrast to the CC genotype, the population who had CT and TT genotypes had no higher risks to pneumoconiosis (OR = 1.56, 95%CI: 0.81 ~ 3.01; OR = 0.96, 95%CI: 0.79 ~ 1.18); The population who had T allele had no higher risks to pneumoconiosis in contrast to the C allele (OR = 1.35, 95%CI: 0.86 ~ 2.13; OR = 1.02, 95%CI: 0.91 ~ 1.15). CONCLUSION: Significant association was found between TNFalpha238 gene polymorphism and pneumoconiosis; and TGF-beta (509 and 869) were not. PMID- 22931879 TI - [Bone mineral density changes in coal workers' pneumoconiosis in Two and Triple stages with increasing ages]. AB - OBJECTIVE: To observe the bone mineral density changes in coal workers' pneumoconiosis in Two and Triple stages with increasing ages. METHODS: Chose 70 cases of coal workers pneumoconiosis in Two and Triple stages in Jincheng Coal Mining Group, all of workers were male, of 55-years old-80 years old, an average of 67 years old. 10 years of ages to grouping, whole body bone mineral densities were measured by body dual-energy X-ray absorptiometry. We analyzed the BMD changes bone loss, osteoporosis occurrence. RESULTS: Chest bone, pelvis, spine bone mineral densities of coal workers pneumoconiosis in Two and Triple stages were significantly decreased. We found that the rate of Pelvic BMD decline of coal workers' pneumoconiosis patients in Two stage was significantly faster after 65 years of age. In Different age groups of coal workers' pneumoconiosis patients in Two and Triple stages, incidence of bone loss and osteoporosis were significantly increased. CONCLUSION: With the age increasing, Coal workers' pneumoconiosis in Two and Triple stages significantly accelerated the speed of the rate of BMD decline. This phenomenon was most obvious in the chest bone, pelvis, and spine. PMID- 22931880 TI - [An analysis on the urinary thiocyanate of 149 health crowd in Nanjing]. PMID- 22931881 TI - [A survey of sevoflurane & isoflurane concentrations in operating room of four hospitals]. PMID- 22931882 TI - [Study on dermal absorption of Imidacloprid in vitro]. AB - OBJECTIVE: The dermal absorption of Imidacloprid was studied to understand the effects of concentrations and skin reservoir on pesticide risk assessment in in vitro absorption studies. METHODS: By using Franz diffusion cell and the transdermal barrier of viable Wistar rat abdomen skin or frozen ones, the imidacloprid content in the receptor fluid and skin was determined by LC/MS/MS method, and the absorption effects were compared between two concentrations of Imidacloprid solutions and two types of skin, respectively. RESULTS: All percentages reported are % of applied dose. In vitro studies using viable skin, the Imidacloprid content in the receptor fluid of high and low concentration was 6.8%, 6.6% respectively; and 10.7%, 1.3% in skin, thus total absorption was 17.5% and 7.9%. And in vitro studies using both viable and frozen skin under the same concentration circumstances, the Imidacloprid content in the receptor fluid of viable and frozen skin was 6.6% and 0.7% respectively, in skin was 1.3% and 10.7%, and total absorption was 7.9% and 11.4%. CONCLUSION: Comparison of these in vitro results showed that either concentrations or skin reservoir had an effect on the dermal absorption. During 6h exposure, the high concentration in viable skin had the maximum dermal absorption value, which was the worst-case exposure estimate, also the best single estimate for pesticide risk assessment. PMID- 22931883 TI - [Bone mineral density changes in coal workers' pneumoconiosis]. AB - OBJECTIVE: To observe the bone mineral density changes of coal workers' pneumoconiosis. METHODS: We chose 150 cases of One-Triple coal workers pneumoconiosis in Jincheng Coal Mining Group, all of workers were male, of 55 years old-80 years old, an average of 67 years old. 10 years of age to grouping, Whole body bone mineral density and T value were measured by body dual-energy X ray absorptiometry. We analyzed the BMD changes bone loss, osteoporosis occurrence. RESULTS: The BMD of six parts were not declined obviously in One stage of coal workers' pneumoconiosis; the BMD of Chest bone, pelvis and spine were declined obviously in two stage of coal workers' pneumoconiosis; the BMD of six parts were declined obviously in Triple stage of coal workers' pneumoconiosis; The occurrence rate of bone loss was significantly higher in Two and Triple coal workers pneumoconiosis. The occurrence rate of osteoporosis was significantly higher in Triple coal workers pneumoconiosis. CONCLUSION: With the increase in the severity of coal workers' pneumoconiosis, the BMD of six parts were declined, The occurrence rate of bone loss osteoporosis was significantly higher. PMID- 22931884 TI - [Determination of methyl isocyanate (MIC) in air of workplaces by HPLC]. AB - OBJECTIVE: To establish the method of detecting the concentrations of methyl isocyanate (MIC) in air of workplaces with high performance liquid chromatographic (HPLC). METHODS: Samples are collected by XAD-7 tubes coated with 1-(2-pyridyl) piperazine (1-2PP). Samples are desorbed with acetonitrile (ACN) and analyzed by high performance liquid chromatography (HPLC) using a fluorescence detector. RESULTS: There was a linear relationship within the range of 0.01 ~ 10 ug/ml, and the detection limit was 5.3*10(-4) ug/ml. The minimum detectable concentration was 0.01 ug/ml, and the lowest detected concentration was 3.3*10(-3) mg/m(3). The relative standard deviation was 2.2% ~ 5.3%. The average desorption efficiency was 90% and the sampling efficiencies were 100%. The samples could be stored for 10 days in cold storage condition. CONCLUSION: The present method could meet with the requirements of Guide for establishing occupational health standards-Part4 Determination methods of air chemicals in workplace and be feasible for determination of MIC in workplace air. PMID- 22931885 TI - [Determination of olanzapine in serum by gas chromatography]. PMID- 22931886 TI - [Determination of trichloroacetic acid in urine by gas chromatography-mass spectrometry with HS-SPME]. PMID- 22931887 TI - [Simultaneous determination of nine organic compounds in the air of workplace]. PMID- 22931888 TI - [Comparison of the status of occupational health and safety insurance between China and developed countries]. PMID- 22931889 TI - [Research advances in the neurotoxicology of pyrethroid pesticides]. PMID- 22931890 TI - Oscillations: Theta travels to the other side. PMID- 22931892 TI - The Kavli Prize winners. Interview by Darran Yates. PMID- 22931893 TI - A simple biosynthetic pathway for large product generation from small substrate amounts. AB - A recently emerging discipline of synthetic biology has the aim of constructing new biosynthetic pathways with useful biological functions. A major application of these pathways is generating a large amount of the desired product. However, toxicity due to the possible presence of toxic precursors is one of the main problems for such production. We consider here the problem of generating a large amount of product from a potentially toxic substrate. To address this, we propose a simple biosynthetic pathway, which can be induced in order to produce a large number of the product molecules, by keeping the substrate amount at low levels. Surprisingly, we show that the large product generation crucially depends on fast non-specific degradation of the substrate molecules. We derive an optimal induction strategy, which allows as much as three orders of magnitude increase in the product amount through biologically realistic parameter values. We point to a recently discovered bacterial immune system (CRISPR/Cas in E. coli) as a putative example of the pathway analysed here. We also argue that the scheme proposed here can be used not only as a stand-alone pathway, but also as a strategy to produce a large amount of the desired molecules with small perturbations of endogenous biosynthetic pathways. PMID- 22931891 TI - Genetically encoded optical indicators for the analysis of neuronal circuits. AB - In a departure from previous top-down or bottom-up strategies used to understand neuronal circuits, many forward-looking research programs now place the circuit itself at their centre. This has led to an emphasis on the dissection and elucidation of neuronal circuit elements and mechanisms, and on studies that ask how these circuits generate behavioural outputs. This movement towards circuit centric strategies is progressing rapidly as a result of technological advances that combine genetic manipulation with light-based methods. The core tools of these new approaches are genetically encoded optical indicators and actuators that enable non-destructive interrogation and manipulation of neuronal circuits in behaving animals with cellular-level precision. This Review examines genetically encoded reporters of neuronal function and assesses their value for circuit-oriented neuroscientific investigations. PMID- 22931895 TI - Integrative molecular phylogeography in the context of infectious diseases on the human-animal interface. AB - The rate of new emerging infectious diseases entering the human population has increased over the past century, with pathogens originating from animals or from products of animal origin accounting for the vast majority. Primary risk factors for the emergence and spread of emerging zoonoses include expansion and intensification of animal agriculture and long-distance live animal transport, live animal markets, bushmeat consumption and habitat destruction. Developing effective control strategies is contingent upon the ability to test causative hypotheses of disease transmission within a statistical framework. Broadly speaking, molecular phylogeography offers a framework in which specific hypotheses regarding pathogen gene flow and dispersal within an ecological context can be compared. A number of different methods has been developed for this application. Here, our intent is firstly to discuss the application of a wide variety of statistically based methods (including Bayesian reconstruction, network parsimony analysis and regression) to specific viruses (influenza, salmon anaemia virus, foot and mouth disease and Rift Valley Fever) that have been associated with animal farming/movements; and secondly to place them in the larger framework of the threat of potential zoonotic events as well as the economic and biosecurity implications of pathogen outbreaks among our animal food sources. PMID- 22931894 TI - MVP expression in the prediction of clinical outcome of locally advanced oral squamous cell carcinoma patients treated with radiotherapy. AB - OBJECTIVE: To explore the role of Major Vault Protein (MVP) in oral cavity squamous cell carcinoma patients. SUBJECTS AND METHODS: 131 consecutive patients suffering from oral cavity squamous cell carcinoma were included in the study. In the whole series, the mean follow-up for survivors was 123.11 +/- 40.36 months. Patients in tumour stages I and II were referred to surgery; patients in stage III-IV to postoperative radiotherapy (mean dose = 62.13 +/- 7.74 Gy in 1.8-2 Gy/fraction). MVP expression was studied by immunohistochemistry in paraffin embedded tumour tissue. RESULTS: MVP expression was positive in 112 patients (85.5%) and no relation was found with clinic pathological variables. MVP overexpression (those tumours with moderate or strong expression of the protein) was related to insulin-like growth factor receptor-1 (IGF-1R) expression (P = 0.014). Tumour stage of the disease was the most important prognostic factor related to survival. Tumours overexpressing MVP and IGF-1R were strongly related to poor disease-free survival (P = 0.008, Exp(B) = 2.730, CI95% (1.302-5.724)) and cause-specific survival (P = 0.014, Exp(B) = 2.570, CI95% (1.215-5.437)) in patients achieving tumour stages III-IV, in multivariate analysis. CONCLUSIONS: MVP and IGF-1R expression were related in oral squamous cell carcinoma and conferred reduced long-term survival in patients suffering from advanced stages of the disease. PMID- 22931896 TI - Voice symptoms in patients with autoimmune disease: a cross-sectional epidemiological study. AB - OBJECTIVE: To assess the prevalence and severity of voice symptoms in individuals with a diagnosis of autoimmune disease. STUDY DESIGN: Cross-sectional survey. SETTING: Study participants were recruited from a rheumatology tertiary referral clinic at Norfolk and Norwich University Hospital. SUBJECTS AND METHODS: A cross sectional questionnaire analyzing 109 patients with autoimmune disease (rheumatoid arthritis, seronegative spondyloarthritis, connective tissue disease) and a control group of 41 patients with non-autoimmune disease (osteoarthritis/osteoporosis). Main outcome measures were the Voice Handicap Index-10 (VHI-10), xerostomia scale, acid reflux inquiry, and anxiety/depression scale. RESULTS: Patients with autoimmune disease were more likely to experience voice symptoms as assessed by the VHI-10 questionnaire (P = .0035). Subgroup analysis showed autoimmune patients were more likely to report voice symptoms regardless of whether they were on a disease-modifying antirheumatic drug (DMARD; P = .0010) or non-DMARD (P = .017), suggesting autoimmune disease may be an independent risk factor from pharmacotherapy. Xerostomia was more common in an autoimmune population compared with the control group (P = .02). A positive correlation between xerostomia and VHI-10 scores was found for the DMARD group (Spearman rank coefficient = 0.49, P < .001). No significant difference in acid reflux inquiry (P = .44) or the anxiety/depression scale (P = .36) was found when comparing the autoimmune and control groups. CONCLUSION: Patients with autoimmune disease have increased likelihood of voice symptoms when compared with a control population with non-autoimmune disease. Further prospective studies to elucidate the cause of voice disorder would be valuable. PMID- 22931897 TI - Immediate reconstruction with autologous cartilage after removal of infected alloplast in revision rhinoplasty. AB - OBJECTIVE: To assess the feasibility of immediate reconstruction with autologous cartilage after removal of infected alloplast in revision rhinoplasty. STUDY DESIGN: Case series with chart review. SETTING: Academic university hospital. SUBJECTS AND METHODS: Patients who met the following inclusion criteria were the subjects of the present study: (1) revision rhinoplasty, (2) alloplastic implant related infection, (3) immediate reconstruction with autologous cartilage at the time of implant removal, and (4) follow-up of more than 12 months. Data analysis included number of previous operations; type of alloplastic implant used; culture results; reconstruction method; complications, including reinfection and graft resorption; and aesthetic results. RESULTS: The 21 patients who met the inclusion criteria included 8 women and 13 men with a mean age of 37 years. Associated alloplast included silicone (10 cases), expanded polytetrafluoroethylene (9 cases), and Medpor (2 cases). With a mean follow-up of 35 months, infection occurred in 1 patient that subsided with antibiotics. No major clinical absorption was encountered. Revision was performed in 1 patient with costal cartilage warping. No revision was required for infection or graft absorption. CONCLUSION: Immediate reconstruction using autologous cartilage in revision rhinoplasty needing removal of an infected alloplast has shown a favorable outcome with minimal complications. PMID- 22931898 TI - A new standardized format for reporting hearing outcome in clinical trials. AB - The lack of an adequate standardized method for reporting level of hearing function in clinical trials has hampered the ability of investigators to draw comparisons across studies. Variability in data reported and presentation format inhibits meta-analysis and makes it impossible to accumulate the large patient cohorts needed for statistically significant inference. Recognizing its importance to the field and after a widely inclusive discussion, the Hearing Committee of the American Academy of Otolaryngology-Head and Neck Surgery endorsed a new minimal standard for reporting hearing results in clinical trials, consisting of a scattergram relating average pure-tone threshold to word recognition score. Investigators remain free to publish their hearing data in any format they believe is interesting and informative, as long as they include the minimal data set to facilitate interstudy comparability. PMID- 22931899 TI - Neurologic disorders among pediatric deaths associated with the 2009 pandemic influenza. AB - OBJECTIVE: The goal of this study was to describe reported influenza A (H1N1)pdm09 virus (pH1N1)-associated deaths in children with underlying neurologic disorders. METHODS: The study compared demographic characteristics, clinical course, and location of death of pH1N1-associated deaths among children with and without underlying neurologic disorders reported to the Centers for Disease Control and Prevention. RESULTS: Of 336 pH1N1-associated pediatric deaths with information on underlying conditions, 227 (68%) children had at least 1 underlying condition that conferred an increased risk of complications of influenza. Neurologic disorders were most frequently reported (146 of 227 [64%]), and, of those disorders, neurodevelopmental disorders such as cerebral palsy and intellectual disability were most common. Children with neurologic disorders were older (P = .02), had a significantly longer duration of illness from onset to death (P < .01), and were more likely to die in the hospital versus at home or in the emergency department (P < .01) compared with children without underlying medical conditions. Many children with neurologic disorders had additional risk factors for influenza-related complications, especially pulmonary disorders (48%). Children without underlying conditions were significantly more likely to have a positive result from a sterile-site bacterial culture than were those with an underlying neurologic disorder (P < .01). CONCLUSIONS: Neurologic disorders were reported in nearly two-thirds of pH1N1-associated pediatric deaths with an underlying medical condition. Because of the potential for severe outcomes, children with underlying neurologic disorders should receive influenza vaccine and be treated early and aggressively if they develop influenza-like illness. PMID- 22931900 TI - Every year is an influenza pandemic for children: can we stop them? PMID- 22931901 TI - Comparison of children hospitalized with seasonal versus pandemic influenza A, 2004-2009. AB - BACKGROUND: The extent to which pandemic H1N1 influenza (pH1N1) differed from seasonal influenza remains uncertain. METHODS: By using active surveillance data collected by the Immunization Monitoring Program, Active at 12 Canadian pediatric hospitals, we compared characteristics of hospitalized children with pH1N1 with those with seasonal influenza A. We compared demographics, underlying health status, ICU admission, and mortality during both pandemic waves versus the 2004/2005 through the 2008/2009 seasons; influenza-related complications and hospitalization duration during pH1N1 wave 1 versus the 2004/2005 through the 2008/2009 seasons; and presenting signs and symptoms during both pH1N1 waves versus the 2006/2007 through the 2008/2009 seasons. RESULTS: We identified 1265 pH1N1 cases (351 in wave 1, 914 in wave 2) and 1319 seasonal influenza A cases (816 from 2006/2007 through 2008/2009). Median ages were 4.8 (pH1N1) and 1.7 years (seasonal influenza A); P < .0001. Preexisting asthma was overrepresented in pH1N1 relative to seasonal influenza A (13.8% vs 5.5%; adjusted P < .0001). Symptoms more often associated with pH1N1 wave 1 versus seasonal influenza A were cough, headache, and gastrointestinal symptoms (adjusted P < .01 for each symptom). pH1N1 wave 1 cases were more likely to have radiologically confirmed pneumonia (adjusted odds ratio = 2.1; 95% confidence interval = 1.1-3.8) and longer median length of hospital stay (4 vs 3 days; adjusted P = .003) than seasonal influenza A. Proportions of children requiring intensive care and deaths in both pH1N1 waves (14.6% and 0.6%, respectively) were not significantly different from the seasonal influenza A group (12.7% and 0.5%, respectively). CONCLUSIONS: pH1N1 in children differed from seasonal influenza A in risk factors, clinical presentation, and length of hospital stay, but not ICU admission or mortality. PMID- 22931902 TI - Central nervous system medications and falls risk in men aged 60-75 years: the Study on Male Osteoporosis and Aging (SOMA). AB - INTRODUCTION: drugs acting on the central nervous system (CNS) increase falls risk. Most data on CNS drugs and falls are in women/mixed-sex populations. This study assessed the relationship between CNS drugs and falls in men aged 60-75 years. METHODS: a questionnaire was sent to randomly selected Danish men aged 60 75 years. Cross-sectional data on CNS drugs and falls in the previous year were available for 4,696 men. Logistic regression investigated the relationship between falls and CNS drugs. RESULTS: the median age was 66.3 (IQR = 63.1-70.0) years; 21.7% were fallers. The following were associated with fallers (OR; 95% CI): opiates (2.4; 1.5-3.7), other analgesics (1.7; 1.4-2.1), antiepileptics (2.8; 1.5-5.1), antidepressants (2.8; 1.9-4.1) and anxiolytics/hypnotics (1.5; 0.9-2.6). Effects of opiates interacted strongly and significantly with age, with a marked association with falls in the older half of the subjects only. No significant associations were found between antipsychotics and fallers. Selective serotonin reuptake inhibitors and tricyclics were significantly associated with fallers (3.1; 2.0-5.0 and 2.2; 1.0-4.7, respectively). CONCLUSION: several CNS drug classes are associated with an approximately 2-3-fold increase risk of falls in men aged 60-75 years randomly selected from the population. Further longitudinal data are now required to confirm and further investigate the role of CNS drugs in falls causation in men. PMID- 22931903 TI - Review: cochlear implants as a treatment of tinnitus in single-sided deafness. AB - PURPOSE OF REVIEW: Tinnitus is a symptom that is highly associated with hearing loss. Its incidence is expected to increase due to the detrimental effects of occupational and leisure noise. Even though no standard treatment is currently available, the effect of cochlear implants on tinnitus in single-sided deafness (SSD) is under scientific attention. This review reveals an overview of all publicly available reports about cochlear implant as a treatment for tinnitus in SSD. RECENT FINDINGS: Cochlear implantation in SSD suppresses tinnitus in most of the cases. Some studies even demonstrate complete tinnitus suppression after implantation. No tinnitus worsening is reported in any of the cases. Furthermore, tinnitus does not restore during the electrical stimulation presented by the cochlear implant. The tinnitus level seems to stabilize after 3-6 months after the first fitting. SUMMARY: Although the underlying mechanism responsible for the observed tinnitus suppression is not yet clear, cochlear implantation should be considered as a treatment option for tinnitus arising from SSD. However, appropriate patient selection is essential as it is expected that it is a requirement that tinnitus arises from cochlear deafferentation. PMID- 22931905 TI - Development of drug treatments for neurofibromatosis type 2-associated vestibular schwannoma. AB - PURPOSE OF REVIEW: To review the discoveries in molecular pathophysiology contributing to the development of neurofibromatosis type 2 (NF2)-associated vestibular schwannomas and the recent experiences with drug therapies for these tumors. The review includes discussion of diagnostic criteria for NF2, populations to clinically consider for drug therapy and drug targets currently under consideration for NF2. RECENT FINDINGS: Increased insight into the complex pathways that underlie both the genetic syndrome of NF2 and the specific pathogenesis of vestibular schwannomas has highlighted multiple potential therapeutic targets. These discoveries have been translated into clinical trials with some early promising results. Inhibition of angiogenesis as well as regulation of mammalian target of rapamycin and the epidermal growth factor receptor family of receptors are the focus of current clinical investigations. SUMMARY: Although a great deal of work is ongoing to understand the multiple effects of the lack of the regulating protein Merlin on tumorgenesis in patients with NF2, advances are ongoing with clinical therapeutics. There is cause for enthusiasm based on recent results with antiangiogenesis therapy in select patients with NF2 and progressive vestibular schwannomas; however, awareness of the notable risks and limitations of therapies currently in development is required. PMID- 22931906 TI - Radiation therapy for vestibular schwannomas. AB - PURPOSE OF REVIEW: Recently, new information on the natural course and on the results of radiation therapy of vestibular schwannomas has been published. The aim of this study is to summarize the most recent literature on the contemporary insights on the natural course and the results of the latest strategies of radiotherapy for vestibular schwannomas. RECENT FINDINGS: After diagnosis only about one-third of all vestibular schwannomas will progress. Many patients do well with a 'wait and see' policy and, when necessary, radiation treatment has the advantage that tumor control rates are high (95%) and treatment-related side effects are very low. Different approaches to radiotherapy continue to evolve. Up till now stereotactic radiosurgery (SRS) and fractionated stereotactic radiotherapy (FSRT) yield comparable results both in terms of tumor control and cranial nerve preservation. With new data available on hearing preservation after radiotherapy, a watchful waiting policy is a renewed matter of debate. SUMMARY: When a vestibular schwannoma grows, radiotherapy (SRS or FSRT) may be a valuable treatment modality. Future clinical research (properly designed randomized trials) should focus on when and when not to treat, even if a vestibular schwannoma is not growing and on potential differences in long-term effects between SRS and fractionated radiotherapy. PMID- 22931904 TI - Tinnitus and underlying brain mechanisms. AB - PURPOSE OF REVIEW: Tinnitus is the sensation of hearing a sound when no external auditory stimulus is present. Most individuals experience tinnitus for brief, unobtrusive periods. However, chronic sensation of tinnitus affects approximately 17% (44 million people) of the general US population. Tinnitus, usually a benign symptom, can be constant, loud and annoying to the point that it causes significant emotional distress, poor sleep, less efficient activities of daily living, anxiety, depression and suicidal ideation/attempts. Tinnitus remains a major challenge to physicians because its pathophysiology is poorly understood and there are few management options to offer to patients. The purpose of this article is to describe the current understanding of central neural mechanisms in tinnitus and to summarize recent developments in clinical approaches to tinnitus patients. RECENT FINDINGS: Recently developed animal models of tinnitus provide the possibility to determine neuronal mechanisms of tinnitus generation and to test the effects of various treatments. The latest research using animal models has identified a number of abnormal changes, in both auditory and nonauditory brain regions, that underlie tinnitus. Furthermore this research sheds light on cellular mechanisms that are responsible for development of these abnormal changes. SUMMARY: Tinnitus remains a challenging disorder for patients, physicians, audiologists and scientists studying tinnitus-related brain changes. This article reviews recent findings of brain changes in animal models associated with tinnitus and a brief review of clinical approach to tinnitus patients. PMID- 22931907 TI - Kymographic imaging of laryngeal vibrations. AB - PURPOSE OF REVIEW: Kymographic imaging is a modern method for displaying and evaluating vibratory behaviour of the vocal folds which is crucial for voice production. This review summarizes the state of the art of this method, and focuses on the progress in this area within the last 5 years. RECENT FINDINGS: Videokymography, using a special videocamera, offers high-speed (video)kymographic images in real time, which is advantageous in daily clinical practice. Two other methods use software to create kymograms retrospectively: digital kymography processes high-speed videolaryngoscopic recordings and offers numerous research possibilities, whereas strobovideokymography processes videostroboscopic recordings, and its use is limited to regular vibration patterns. Current studies reveal that high-speed kymographic images allow more reliable visual evaluation of vibrations than by watching video recordings. Image analysis procedures have been advanced to quantify the vibration properties of the vocal folds. New information has been obtained on asymmetry, mucosal waves, irregularities, phonation onset, and nonlinear dynamic phenomena in voice disorders, as well as in singing. SUMMARY: High-speed kymography visualizes vibratory features which are not simply observable via traditional methods. It shows large potential in better understanding the functional origin of hoarseness and unsteady phonatory states. Further research in this area is envisioned. PMID- 22931908 TI - Current role of stroboscopy in laryngeal imaging. AB - PURPOSE OF REVIEW: To summarize recent technological advancements and insight into the role of stroboscopy in laryngeal imaging. RECENT FINDINGS: Although stroboscopic technology has not undergone major technological improvements, recent clarifications have been made to the application of stroboscopic principles to video-based laryngeal imaging. Also recent advances in coupling stroboscopy with high-definition video cameras provide higher spatial resolution of vocal fold vibratory function during phonation. Studies indicate that the interrater reliability of visual stroboscopic assessment varies depending on the laryngeal feature being rated and that only a subset of features may be needed to be representative of an entire assessment. High-speed videoendoscopy (HSV) judgments have been shown to be more sensitive than stroboscopy for evaluating vocal fold phase asymmetry, pointing to the future potential of complementing stroboscopy with alternative imaging modalities in hybrid systems. Laryngeal videostroboscopy alone continues to play a central role in clinical voice assessment. Even though HSV may provide more detailed information about phonatory function, its eventual clinical adoption will depend on how remaining practical, technical, and methodological challenges will be met. SUMMARY: Laryngeal videostroboscopy continues to be the modality of choice for imaging vocal fold vibration, but technological advancements in HSV and associated research findings are driving increased interest in the clinical adoption of HSV to complement videostroboscopic assessment. PMID- 22931910 TI - Contaminated soil and transmission of influenza virus (H5N1). PMID- 22931909 TI - Evaluation of diagnostic and therapeutic approaches for suspected influenza A(H1N1)pdm09 infection, 2009-2010. AB - To assess adherence to real-time changes in guidelines for influenza diagnosis and use of oseltamivir during the 2009 influenza A(H1N1) pandemic, we reviewed medical records of patients with confirmed or suspected influenza-like illness (ILI) and those with no viral testing in a large Los Angeles (California, USA) hospital. Of 882 tested patients, 178 had results positive for influenza; 136 of the remaining patients received oseltamivir despite negative or no results. Oseltamivir use was consistent with national recommendations in >90%. Of inpatients, children were less likely than adults to have ILI at testing and to receive oseltamivir if ILI was found. Of outpatients, children were more likely to have positive test results; 20% tested did not have ILI or other influenza signs and symptoms. Twenty-five of 96 test-positive patients and 13 of 19 with lower respiratory tract disease were, inappropriately, not treated. Variations between practice and national recommendations could inform clinical education in future influenza seasons. PMID- 22931911 TI - Beverage consumption patterns of Canadian adults aged 19 to 65 years. AB - OBJECTIVE: To investigate the beverage intake patterns of Canadian adults and explore characteristics of participants in different beverage clusters. DESIGN: Analyses of nationally representative data with cross-sectional complex stratified design. SETTING: Canadian Community Health Survey, Cycle 2.2 (2004). SUBJECTS: A total of 14 277 participants aged 19-65 years, in whom dietary intake was assessed using a single 24 h recall, were included in the study. After determining total intake and the contribution of beverages to total energy intake among age/sex groups, cluster analysis (K-means method) was used to classify males and females into distinct clusters based on the dominant pattern of beverage intakes. To test differences across clusters, chi2 tests and 95 % confidence intervals of the mean intakes were used. RESULTS: Six beverage clusters in women and seven beverage clusters in men were identified. 'Sugar sweetened' beverage clusters - regular soft drinks and fruit drinks - as well as a 'beer' cluster, appeared for both men and women. No 'milk' cluster appeared among women. The mean consumption of the dominant beverage in each cluster was higher among men than women. The 'soft drink' cluster in men had the lowest proportion of the higher levels of education, and in women the highest proportion of inactivity, compared with other beverage clusters. CONCLUSIONS: Patterns of beverage intake in Canadian women indicate high consumption of sugar-sweetened beverages particularly fruit drinks, low intake of milk and high intake of beer. These patterns in women have implications for poor bone health, risk of obesity and other morbidities. PMID- 22931912 TI - A missense mutation in the MBTPS2 gene underlies the X-linked form of Olmsted syndrome. PMID- 22931913 TI - BRAF mutation, NRAS mutation, and the absence of an immune-related expressed gene profile predict poor outcome in patients with stage III melanoma. AB - Prediction of outcome for melanoma patients with surgically resected macroscopic nodal metastases is very imprecise. We performed a comprehensive clinico pathologic assessment of fresh-frozen macroscopic nodal metastases and the preceding primary melanoma, somatic mutation profiling, and gene expression profiling to identify determinants of outcome in 79 melanoma patients. In addition to disease stage 4 years, 90% confidence interval): the presence of a nodular component in the primary melanoma (6.8, 0.6-76.0), and small cell size (11.1, 0.8 100.0) or low pigmentation (3.0, 0.8-100.0) in the nodal metastases. Absence of BRAF mutation (20.0, 1.0-1000.0) or NRAS mutation (16.7, 0.6-1000.0) were both favorable prognostic factors. A 46-gene expression signature with strong overrepresentation of immune response genes was predictive of better survival (10.9, 0.4-325.6); in the full cohort, median survival was >100 months in those with the signature, but 10 months in those without. This relationship was validated in two previously published independent stage III melanoma data sets. We conclude that the presence of BRAF mutation, NRAS mutation, and the absence of an immune-related expressed gene profile predict poor outcome in melanoma patients with macroscopic stage III disease. PMID- 22931914 TI - Roles of MED1 in quiescence of hair follicle stem cells and maintenance of normal hair cycling. AB - MED1 (mediator complex subunit 1) is expressed by human epidermal keratinocytes and functions as a coactivator of several transcription factors. To elucidate the role of MED1 in keratinocytes, we established keratinocyte-specific Med1-null (Med1(epi-/-)) mice using the K5Cre/LoxP system. Development of the epidermis and appendages of Med1(epi-/-) mice were macroscopically and microscopically normal until the second catagen of the hair cycle. However, the hair cycle of Med1(epi-/ ) mice was spontaneously repeated after the second telogen, which does not occur in wild-type (WT) mice. Hair follicles of Med1(epi-/-) mice could not enter anagen after 6 months of age, resulting in sparse pelage hair in older Med1(epi-/ ) mice. Interfollicular epidermis (IFE) of Med1(epi-/-) mice was acanthotic and more proliferative than that of WT mice, whereas these findings were less evident in older Med1(epi-/-) mice. Flow cytometric analysis revealed that the numbers of hair follicle bulge stem cells were reduced in Med1(epi-/-) mice from a few months after birth. These results suggest that MED1 has roles in maintaining quiescence of keratinocytes and preventing depletion of the follicular stem cells. PMID- 22931915 TI - Response to Garrod. PMID- 22931916 TI - Incidence of hidradenitis suppurativa and associated factors: a population-based study of Olmsted County, Minnesota. AB - There are no population-based incidence studies of hidradenitis suppurativa (HS). Using the medical record linkage system of the Rochester Epidemiology Project, we sought to determine the incidence of the disease, as well as other associations and characteristics, among HS patients diagnosed in Olmsted County, Minnesota, between 1968 and 2008. Incidence was estimated using the decennial census data for the county. Logistic regression models were fit to evaluate associations between patient characteristics and disease severity. A total of 268 incident cases were identified, with an overall annual age- and sex-adjusted incidence of 6.0 per 100,000. Age-adjusted incidence was significantly higher in women compared with men (8.2 (95% confidence interval (CI), 7.0-9.3) vs. 3.8 (95% CI, 3.0-4.7). The highest incidence was among young women aged 20-29 years (18.4 per 100,000). The incidence has risen over the past four decades, particularly among women. Women were more likely to have axillary and upper anterior torso involvement, whereas men were more likely to have perineal or perianal disease. In addition, 54.9% (140/255) patients were obese; 70.2% were current or former smokers; 42.9% carried a diagnosis of depression; 36.2% carried a diagnosis of acne; and 6% had pilonidal disease. Smoking and gender were significantly associated with more severe disease. PMID- 22931918 TI - Modeling pattern formation in skin diseases by a cellular automaton. PMID- 22931917 TI - Genetic association with ERAP1 in psoriasis is confined to disease onset after puberty and not dependent on HLA-C*06. AB - HLA-C remains the strongest susceptibility candidate gene in psoriasis. Evidence for interaction between HLA-C and endoplasmic reticulum aminopeptidase 1 (ERAP1) confined to individuals carrying the HLA-C risk allele was recently reported. Psoriasis displays wide variation, and genetic heterogeneity is likely to contribute to clinical diversity. Age at disease onset is a putative discriminator, and separating psoriasis into early- (<40 years) and late-onset disease has been useful. To sharpen the age-dependent phenotype, we compared genotypes for ERAP1 (rs26653, rs30187, and rs27524) and HLA-C*06:02 in healthy controls and cases stratified for onset of psoriasis at <10, 10-20, 20-40, and >40 years of age. This approach revealed that association with ERAP1 was confined to cases with onset between 10 and 20 years (odds ratio 1.59, 95% confidence interval: 1.28-1.98, P=0.00008) and no association was detected in cases with onset below 10 years, reflecting genetic heterogeneity within the childhood psoriasis population. In contrast to earlier findings, association with ERAP1 was neither dependent on nor interacting with HLA-C*06:02. ERAP1 single-nucleotide polymorphism rs26653, which, to our knowledge, has not previously been reported in psoriasis, is nonsynonymous, has suggestive functional consequences, and herein displays strong association with disease. PMID- 22931920 TI - Rotating night-shift work and risk of psoriasis in US women. PMID- 22931921 TI - Typology of the primary outcome construction in dermatology: a systematic review of published randomized controlled trials. AB - The primary outcome is a major component of a randomized clinical trial (RCT) and several types of outcome can be chosen in a given disease. We systematically reviewed RCTs on nonneoplastic dermatological diseases published in 2009 and referenced in Medline, and described how the main outcome was defined and constructed. We assessed whether those characteristics were associated with a clearly defined primary outcome and whether they were associated with a significant statistical test for the primary outcome. Outcome construction variables were the three "VIP" questions (V denoting Variable: binary vs. quantitative variable; I denoting Item: data collection based on multiple vs. single item(s); and P denoting time Points: outcome assessment based on a "final time point" vs. "final and initial time points"). Among 122 RCTs, 32% did not have a clearly defined primary outcome. In multivariable analyses, a clearly defined primary outcome was associated with a binary variable (odds ratio (OR)=6.7; 2.5-17.7) and the composite variable "both blinding/placebo-controlled arm" (OR=4.5; 1.8-11.2); a significant statistical test was associated with a "final time point"-based outcome construction (OR=2.6; 1.2-5.5). Our study points to areas of improvement related to the definition and construction of the primary outcome in RCTs in dermatology. PMID- 22931922 TI - Filaggrin degradation by caspase-14 is required for UVB photoprotection but does not influence allergic sensitization in a mouse model of atopic dermatitis. PMID- 22931923 TI - Rejuvenation of gene expression pattern of aged human skin by broadband light treatment: a pilot study. AB - Studies in model organisms suggest that aged cells can be functionally rejuvenated, but whether this concept applies to human skin is unclear. Here we apply 3'-end sequencing for expression quantification ("3-seq") to discover the gene expression program associated with human photoaging and intrinsic skin aging (collectively termed "skin aging"), and the impact of broadband light (BBL) treatment. We find that skin aging was associated with a significantly altered expression level of 2,265 coding and noncoding RNAs, of which 1,293 became "rejuvenated" after BBL treatment; i.e., they became more similar to their expression level in youthful skin. Rejuvenated genes (RGs) included several known key regulators of organismal longevity and their proximal long noncoding RNAs. Skin aging is not associated with systematic changes in 3'-end mRNA processing. Hence, BBL treatment can restore gene expression pattern of photoaged and intrinsically aged human skin to resemble young skin. In addition, our data reveal, to our knowledge, a previously unreported set of targets that may lead to new insights into the human skin aging process. PMID- 22931924 TI - The assay that defines desmosome hyper-adhesion. PMID- 22931926 TI - Update of immune events in the murine contact hypersensitivity model: toward the understanding of allergic contact dermatitis. AB - Allergic contact dermatitis (ACD) is one of the most common skin diseases, consisting of sensitization and elicitation phases. With the advancement of technology and the discovery of new types of immune cells, our knowledge of the immunological mechanisms of contact hypersensitivity (CHS) as a murine model of ACD has expanded significantly in the past decade. For example, by introducing regulatory T cells, CD4(+) T-helper 17 cells, and Langerin-positive dermal dendritic cells, the initiation and termination mechanism of CHS has been revealed. In addition, the role of mast cells in CHS, long a matter of debate, has become apparent by developing conditional mast cell-deficient mice. Moreover, the role of the innate immunity system, such as that of Toll-like receptor signaling, has made a breakthrough in this field. In this review, we will integrate the recent advancement of immunological mechanisms of both the sensitization and elicitation phases of CHS into the classic view, and we will discuss updated mechanisms on its development and future directions. PMID- 22931925 TI - Interferon regulatory factor 6 promotes differentiation of the periderm by activating expression of Grainyhead-like 3. AB - IFN regulatory factor 6 (IRF6) is a transcription factor that, in mammals, is required for the differentiation of skin, breast epithelium, and oral epithelium. However, the transcriptional targets that mediate these effects are currently unknown. In zebrafish and frog embryos, Irf6 is necessary for differentiation of the embryonic superficial epithelium, or periderm. Here we use microarrays to identify genes that are expressed in the zebrafish periderm and whose expression is inhibited by a dominant-negative variant of Irf6 (dnIrf6). These methods identify Grainyhead-like 3 (Grhl3), an ancient regulator of the epidermal permeability barrier, as acting downstream of Irf6. In human keratinocytes, IRF6 binds conserved elements near the GRHL3 [corrected] promoter. We show that one of these elements has enhancer activity in human keratinocytes and zebrafish periderm, suggesting that Irf6 directly stimulates Grhl3 expression in these tissues. Simultaneous inhibition of grhl1 and grhl3 disrupts periderm differentiation in zebrafish, and, intriguingly, forced grhl3 expression restores periderm markers in both zebrafish injected with dnIrf6 and frog embryos depleted of Irf6. Finally, in Irf6-deficient mouse embryos, Grhl3 expression in the periderm and oral epithelium is virtually absent. These results indicate that Grhl3 is a key effector of Irf6 in periderm differentiation. PMID- 22931927 TI - Keratinocytes from induced pluripotent stem cells in junctional epidermolysis bullosa. PMID- 22931928 TI - TLR signaling and DNA repair: are they associated? AB - Toll-like receptor (TLR) signaling is a well-characterized, innate immune cellular defense mechanism used to detect and respond to pathogen-associated molecular patterns (PAMPs). TLR signaling is highly conserved and has evolved to have both extracellular and endosomal receptors that recognize PAMPs from a wide range of microbial pathogens. Recent literature has emerged to show that activation of TLRs not only leads to the upregulation of cellular defense mechanisms, but also results in upregulation of DNA repair genes and increased functional DNA repair. Endosomal TLR agonists result in increased survival and repair after both ionizing and UV radiation, suggesting that the repair pathways for single- and double-strand breaks are affected. This review brings together these and other experimental findings to examine how DNA repair pathways may be linked to TLR signaling. Also discussed are the varied outcomes and related physiological implications that increased DNA repair after injury might have. PMID- 22931929 TI - Dual role of apoptosis-associated speck-like protein containing a CARD (ASC) in tumorigenesis of human melanoma. AB - Apoptosis-associated Speck-like protein containing a CARD (caspase recruitment domain) (ASC) was originally named because it triggered apoptosis in certain tumors. More recently, however, ASC was found to be a central adaptor protein of inflammasome, which mediates the secretion of protumorigenic inflammation. Here we examined the role of ASC in tumorigenesis of human melanoma. Compared with primary melanoma, ASC protein expression was generally downregulated in metastatic melanoma. Although overexpressing ASC in metastatic melanoma showed no effects on cell viability, silencing ASC with short hairpin RNA induced G1 cell cycle arrest, reduced cell viability, and suppressed tumorigenesis in metastatic melanoma. On the other hand, silencing ASC in primary melanoma reduced cell death, increased cell viability, and enhanced tumorigenesis. In primary and metastatic melanoma cells, ASC knockdown inhibited inflammasome-mediated caspase 1 activity and IL-1beta secretion. However, phosphorylated IkappaB kinase (IKK)alpha/beta expression and NF-kappaB activity were suppressed in metastatic melanoma and enhanced in primary melanoma after ASC knockdown. These findings suggest stage-dependent dual roles of ASC in tumorigenesis. ASC expression in primary melanoma inhibits tumorigenesis by reducing IKKalpha/beta phosphorylation and inhibiting NF-kappaB activity. In metastatic melanoma, on the other hand, this inhibitory effect is diminished, and ASC induces tumorigenic pathways through enhanced NF-kappaB activity and inflammasome-mediated IL-1beta secretion. PMID- 22931930 TI - Cellular and biochemical characterization of two closely related triosephosphate isomerases from Trichomonas vaginalis. AB - The glycolytic enzyme triosephosphate isomerase catalyses the isomerization between glyceraldehyde 3-phosphate and dihydroxyacetone phosphate. Here we report that Trichomonas vaginalis contains 2 fully functional tpi genes. Both genes are located in separated chromosomal context with different promoter regulatory elements and encode ORFs of 254 amino acids; the only differences between them are the character of 4 amino acids located in alpha-helices 1, 2 and 8. Semi quantitative RT-PCR assays showed that tpi2 transcript is approximately 3.3-fold more abundant than tpi1. Using an anti-TvTIM2 polyclonal antibody it was demonstrated that TIM proteins have a cytoplasmic localization and both enzymes are able to complement an Escherichia coli strain carrying a deletion of its endogenous tpi gene. Both TIM proteins assemble as dimers and their secondary structure assessment is essentially identical to TIM from Saccharomyces cerevisiae. The kinetic catalytic constants of the recombinant enzymes using glyceraldehyde-3-phosphate as substrate are similar to the catalytic constants of TIMs from other organisms including parasitic protozoa. As T. vaginalis depends on glycolysis for ATP production, we speculate 2 possible reasons to maintain a duplicated tpi copy on its genome: an increase in gene dosage or an early event of neofunctionalization of TIM as a moonlighting protein. PMID- 22931931 TI - Is the risk of primary hyperparathyroidism increased in patients with untreated breast cancer? AB - BACKGROUND: An increased frequency of primary hyperparathyroidism (PHP) has been reported in patients with treated breast cancer (BC). PHP has been found in about 7% of BC patients after surgery and radio-, chemio- or hormonal therapy. AIM: To evaluate the frequency of PHP in untreated BC patients. SUBJECTS AND METHODS: We evaluated 186 women with BC and 233 women with thyroid cancer (TC, no.=122) or benign thyroid diseases (BTD, no.=111). In all patients, serum calcium, albumin, PTH, and 25-hydroxyvitamin D (25-OH vitD) were measured before any treatment. RESULTS: Serum calcium concentrations were significantly higher in BC than in TC and BTD groups (median values 9.5 mg/dl, 9.3 mg/dl and 9.3 mg/dl, respectively) but, according to a logistic regression model, calcium was not significantly different between the 3 groups when age was taken into account. In all patients, serum calcium was in the normal range, indicating that no case of overt PHP was present. Five patients (1 in BC, 2 in TC, and 2 in BDT groups) had serum calcium close to the upper limit of normal range, high PTH and low 25-OH vitD, indicating a possible PHP with hypercalcemia masked by concomitant 25-OH vitD deficiency. CONCLUSIONS: In untreated BC group, no patient had overt PHP and 1/186 (0.5%) presented a possible PHP masked by 25-OH vitD deficiency, a PHP frequency much lower than that observed in treated BC patients. These data suggest that the treatments of BC may be responsible for the increased frequency of PHP reported in previous studies. PMID- 22931932 TI - [Significance of exploring the definition of metabolic syndrome in Chinese children and adolescents]. PMID- 22931933 TI - [Primary carnitine deficiency in 17 patients: diagnosis, treatment and follow up]. AB - OBJECTIVE: Many children were found to have low free carnitine level in blood by tandem mass spectrometry technology. In some of the cases the problems occurred secondary to malnutrition, organic acidemia and other fatty acid oxidation metabolic diseases, and some of cases had primary carnitine deficiency (PCD). In the present article, we discuss the diagnosis of PCD and evaluate the efficacy of carnitine in the treatment of PCD. METHOD: We measured the free carnitine (C0) and acylcarnitine levels in the blood of 270 000 neonates from newborns screening program and 12 000 children with suspected clinical inherited metabolic diseases by tandem mass spectrometry. The mutations of carnitine transporter protein were tested to the children with low C0 level and the diagnosis was made. The children with PCD were treated with 100 - 300 mg/kg of carnitine. RESULT: Seventeen children were diagnosed with PCD, 6 from newborn screening program and 11 from clinical patients. Mutations were found in all of them. The average C0 level [(2.9 +/- 2.0) umol/L] in patients was lower than the reference value (10 umol/L), along with decreased level of different acylcarnitines. The clinical manifestations were diverse. For the 6 patients from newborn screening, 4 were asymptomatic, 1 showed hypoglycaemia and 1 showed movement intolerance from 2 years of age. For the 11 clinical patients, 8 showed hepatomegaly, 7 showed myasthenia, 6 showed cardiomyopathy, 1 showed chronic abdominal pain, and 1 showed restlessness and learning difficulty. Among these patients, 14 cases were treated with carnitine. Their clinical symptoms disappeared 1 to 3 months later. The C0 level in the blood rose to normal, with the average from (4.0 +/- 2.7) umol/L to (20.6 +/- 8.3) umol/L (P < 0.01). However, the level was still lower than the average level of healthy children [(27.1 +/- 4.5) umol/L, P < 0.01]. CONCLUSION: Seventeen patients were diagnosed with PCD by the test levels of free carnitine and acylcarnitines in blood with tandem mass spectrometry, and gene mutation test. Large dose of carnitine had a good effect in treatment of the PCD patients. PMID- 22931934 TI - [Abnormal findings during newborn period of 160 patients with early-onset methylmalonic aciduria]. AB - OBJECTIVE: Methylmalonic aciduria is the most common disorder of organic acidurias in the mainland of China. It is also the one of treatable metabolic disorders. The clinical spectrum of the patients varies from severe neonatal onset forms with neonatal brain injury and high mortality to milder forms with adult-onset. The clinical manifestations of neonates with methylmalonic aciduria are non-specific. Early diagnosis and adequate treatment contribute a lot to improving the prognosis of the patients. In this study, the abnormal clinical and laboratory findings in neonatal period of 160 Chinese patients with early-onset methylmalonic aciduria were investigated. METHOD: From 1996 to 2011, a total of 398 patients with methylmalonic aciduria were diagnosed in our hospital; 286 (71.9%) patients had early-onset before 1 year of age. Among 286 patients, 160 (55.9%) presented symptoms in neonatal period. Their urine organic acids were analyzed by gas chromatography-mass spectrometry. Blood amino acids and acylcarnitine profiles were determined by liquid chromatography tandem mass spectrometry. Serum and urine total homocysteine were measured using a fluorescence polarization immunoassay. In some patients, gene analysis was performed. Based on the disease types and general condition, individual dietary and medical interventions were started soon after diagnosis. RESULT: Out of the 160 patients, 131 (81.9%) had combined methylmalonic aciduria and homocysteinemia. Isolated methylmalonic aciduria was found in 29 cases (18.1%). The common presentations in neonatal period were feeding difficulty, seizures, lethargy and dyspnea. Megaloblastic anemia, liver dysfunction, hyperammonemia and metabolic acidosis were the frequent findings in the routine laboratory test. The most common initial clinical diagnosis was suspected hypoxic-ischemic encephalopathy. Even in 36 cases with abnormal family history, only 3 patients were admitted with suspected inborn errors of metabolism. Five cases (3.1%) were diagnosed by postmortem metabolic examination; 7 cases (4.4%) were detected by newborn screening. In 148 cases (92.5%), the diagnosis was much delayed to the age of one month to 8 years and 5 months (mean 13 months). Methylmalonic aciduria combined with homocysteinemia (MMACHC) gene analyses were performed in 31 cases with combined methylmalonic aciduria. CblC defect was confirmed. The patients with isolated methylmalonic aciduria were treated with protein-restricted diet, cobalamin and L-carnitine. The patients of methylmalonic aciduria combined with homocysteinemia were treated with cobalamin, L-carnitine, calcium folinate, betaine and common diet. Seven patients died without treatment. Clinical improvement was observed in 153 patients. Only 2 patients detected by newborn screening had normal mental and physical development. Mild to severe psychomotor retardation was observed in 151 cases. CONCLUSION: High mortality and disability rates were observed in the patients with early-onset methylmalonic aciduria. Combined methylmalonic aciduria and homocysteinemia is the common type of methylmalonic aciduria. The clinical manifestation in neonatal period of the patients with early-onset methylmalonic aciduria is complex. Feeding difficulty, seizures, lethargy and dyspnea are the common symptoms in neonatal period of the patients. Megaloblastic anemia, liver dysfunction, hyperammonemia and metabolic acidosis were the frequent laboratory findings. PMID- 22931935 TI - [Clinical sequelae of 17 cases with glycogen storage disease type II/Pompe disease]. AB - OBJECTIVE: To analyze and summarize the characteristics of glycogen storage disease type II (Pompe disease) patients according to the clinical description and prognosis. METHOD: Seventeen Chinese patients diagnosed by acid alpha glucosidase (GAA) enzyme activity test were reviewed. Clinical data tables were designed. Interviews were made via phone calls. Information was collected to reach the objective. RESULT: Four of 17 patients diagnosed by acid alpha glucosidase are infantile-onset, symptoms started between 2 to 6 months after birth with increased serum creatine kinase and cardiac problems, with or without respiratory concerns. Other 13 patients were later-onset cases, and their symptoms started between 2 to 22 years of age with increased serum creatine kinase. Eleven later-onset patients started with muscle weakness, 2 patients developed respiratory insufficiency, 2 patients showed scoliosis, and 1 patient expressed increased serum creatine kinase with abnormal liver function. Just 3 of the later-onset patients were treated with mechanical ventilator and adjuvant therapy, others were not. All patients' acid alpha-glucosidase (GAA) enzyme activity analysis showed lower than 10% of normal. Fourteen patients were tested by muscle biopsy pathology, and 9 of them progressed to glycogen storage disease type II; 10 patients received genetic analysis, and 6 of them had two mutations which cause the disorder. Twelve of the 17 patients were interviewed successfully. In 3 of the infant-onset patients the disease resulted in death from respiratory failure, and 1 is still alive at the age of 1 year and 7 months. In 4 of 8 later-onset patients the disease resulted in death from respiratory failure between 3 to 5 years after onset of symptoms. Three of 4 survivors had increased muscle weakness, and 1 patient kept alive with ventilator without any changes. Seven of 12 interviewed patients died, the mortality rate was 58.3%. CONCLUSION: Glycogen storage disease type II (Pompe disease) present differently in the clinic. Infant-onset Pompe disease is mainly characterized by generalized muscle weakness and obvious cardiac involvement. It's a dangerous disease, with high mortality rate. Later-onset Pompe disease is characterized by chronic proximal muscle weakness and respiratory insufficiency. GAA enzyme activity analysis, muscle biopsy and genetic analysis used to support the diagnosis of Pompe disease. Prognosis of the disease depends on age of onset and respiratory muscle involvement. PMID- 22931936 TI - [The definition of metabolic syndrome and prophylaxis and treatment proposal in Chinese children and adolescents]. PMID- 22931937 TI - [Experts consensus on principles for diagnosis and treatment of childhood functional dyspepsia]. PMID- 22931938 TI - [Studies on mechanism of polycystic ovary syndrome and the diagnosis and treatment princial for adolescents]. PMID- 22931939 TI - [Progress of diagnosis and treatment of X-linked inhibitor of apoptosis deficiency]. PMID- 22931940 TI - [Clinical analysis of 20 cases with Streptococcus pneumoniae necrotizing pneumonia in China]. AB - OBJECTIVE: Streptococcus pneumoniae necrotizing pneumonia (SPNP) was reported elsewhere but not in China yet. Inappropriate treatment due to poor recognition of this disease could influence its prognosis. This paper presents the clinical characteristics, diagnosis and treatment of SPNP hoping to elevate pediatrician's recognition level for this disease. METHOD: Clinical manifestations, radiological findings, treatment and prognosis of 20 patients (9 boys, 11 girls) who had been hospitalized with SPNP in Beijing Children's Hospital from 2004-2011 were retrospectively analyzed. RESULT: The patients included in this study aged from 9 months to 6 years [(27.9 +/- 15.8) m] and were healthy before admission. They were febrile for 8 to 50 days [(27.7 +/- 13.5) d] and hospital day was 24 - 55 days [(36.5 +/- 8.3) d]. The general condition of all subjects was relatively poor and they all had fever and cough. One child had moderate fever and nineteen children had high fever. Dyspnea was found in sixteen children. Fine rales were found on auscultation in 18 children, among whom diffuse wheeze appeared in 4 children, and wheezy phlegm was found in two children. Signs of pleural effusion were discovered in all cases by physical examination and chest X-ray. White blood cell (WBC) count was 16.2 - 60.95*10(9)/L and neutrophil was 70.5% - 80.2% in peripheral blood routine test. Erythrocyte sedimentation rate (ESR) was 44 - 109 mm/h [(69.6 +/- 16) mm/h]and C-reactive protein (CRP) was 80 - > 160 mg/L. The pleural effusion biochemistry and routine test revealed a WBC count of 6400*10(6)/L-too much to count, polykaryocyte of 51% - 90%, glucose of 0.02 - 1.8 mmol/L, protein of 32 - 51 g/L and LDH of 5475 IU/L-or higher. Pleural effusion culture in all cases and blood culture in 2 cases was positive for Streptococcus pneumoniae. Chest X-ray or CT revealed high density and well-distributed lobar consolidation in one lung or two lungs initially. Single or multiple low density lesions in the area of lobar consolidation were found a week later, accompanied by multiple cystic shadow or cavity at the same time or afterwards. Bulla of lung appeared later. Pleural effusions were found in all patients. Seven cases complicated with hydropneumothorax, two with otitis media, one with heart failure, one with cardiac insufficiency. Seventeen patients were treated with vancomycin or teicoplanin or linezolid two with amoxicillin and clavulanate potassium. Other two patients had been treated with meropenem and cephalosporin antibiotics respectively before admission, and they had been at recovery stage when they were hospitalized. Thoracic close drainage and thoracoscopy were performed respectively in 18 cases and 3 cases, respectively. After a follow up of more than 6 months, chest CT showed that almost all lesions in lungs recovered during 4-6 months. No one received pneumonectomy. CONCLUSION: SPNP has special manifestations. The incidence in infants is higher. Patients' general condition is poor and febrile course is relatively long. All patients manifested fever and cough, with a presence of dyspnea in most of them. WBC, neutrophil and CRP elevated apparently. The characteristic of pleural effusion indicates empyema. In early stage, the chest X-ray and CT showed high-density lobar lesions, followed by low-density lesions and cyst gradually. Bulla of lung and/or hydropneumothorax may appear at the late stage. But if diagnosed and treated promptly, the prognosis of SPNP was relatively good. PMID- 22931941 TI - [Characteristics of circulatory disturbance and the treatment of severe hand-foot and-mouth disease]. AB - OBJECTIVE: To investigate the characteristics of circulatory disturbance and treatment of severe hand-foot-and-mouth disease (HFMD). METHOD: The clinical characteristics, laboratory findings, therapy and outcome of 22 severe HFMD patients were retrospectively analyzed. RESULT: All the 22 severe HFMD patients came from the countryside. All these patients had encephalitis. Fifteen cases had myocardial injury. All had symptoms of sympathetic excitation and 17 cases had hypertension [(128 +/- 16)/(81 +/- 14) mm Hg (1 mm Hg = 0.133 kPa)]. Fourteen cases had exacerbation with rapid decline of blood pressure [(61 +/- 12)/(33 +/- 12) mm Hg]. In cardiorespiratory failure stage, 13 patients had neurogenic pulmonary edema accompanied by circulatory failure and 12 cases had a lower glasgow scores (less than 7). Myocardial injury and ECG change were found in some cases. Inotropic and pressor drugs were given in patients with circulatory collapse. Five cases received fluid resuscitation due to refractoriness to inotropic drugs. Nine patients received blood purification. Seventeen survived and 5 cases died due to circulatory failure. CONCLUSION: Circulation failure of severe HFMD is the main cause of death. Early and appropriate circulation support is very important to reduce mortality. PMID- 22931942 TI - [Evaluation of serum specific IgM detection in diagnosis of respiratory viral infections in children]. AB - OBJECTIVE: The present study was designed to explore the practical application of the rapid etiological diagnosis by detecting specific IgM antibody against common respiratory viruses in children with acute lower respiratory infections (ALRI). METHOD: Clinical specimens including nasopharyngeal aspirates and serum of acute phase from hospitalized children were collected from 207 infants and children with acute lower respiratory infections from March 2009 to September 2010. Seven common respiratory virus antigens were identified from the collected nasopharyngeal aspirates by direct immunofluorescence assay (DFA). ELISA was used to detect specific IgM antibody against RSV, ADV, IFVA, IFVB and PIV, while indirect immunofluorescence assay (IFA) was used to detect specific IgM antibody against RSV, ADV, IFVA, IFVB, PIV1, PIV2 and PIV3 in collected acute phase serum. RESULT: The overall positive rates to detect viral antigen by using DFA, ELISA and IFA was 67.6%, 57.5% and 39.6%, respectively. The consistent rate of ELISA and IFA versus accepted DFA were 21.7% and 31.4%, respectively. The average days from onset of the symptoms to blood sample collection for those with the consistent results by ELISA and DFA were 12.0 d for ADV, 9.6 d for PIV2, 9.5 d for IFV, and 5.3 d for RSV, respectively, and by IFA and DFA were 15.0 d for PIV3, 9.2 d for ADV, and 7.4 d for RSV, respectively. Among all age groups, the consistent rate of serum viral IgM and antigen detections was highest in children younger than 3 years old. CONCLUSION: Although there were differences between serum IgM antibody and viral antigen detections, specific IgM antibody detection was of value in early and rapid etiological diagnosis of pediatric ALRI, especially for young children. It could provide serologic evidence of respiratory virus infection. The diagnostic rate of pathogen could be improved if it was used in combination with viral antigen diagnostic methods. PMID- 22931943 TI - [Clinical and electroencephalographic characteristics of Jeavons syndrome]. AB - OBJECTIVE: The study was designed to examine the clinical and electroencephalographic characteristics of children with Jeavons syndrome. METHOD: Video-electroencephalography (VEEG) monitoring was carried out in 9 patients with Jeavons syndrome. The clinical and electroencephalographic characteristics, treatment and prognoses were analyzed. RESULT: Of the 9 patients, 8 were female, and 1 was male. The onset age of children with eyelid myoclonia (EM) was from 3 to 9 years old. It was obtained through the chief complaint, prosecution or VEEG monitoring. Three cases were misdiagnosed and 2 cases were overlooked initially. Seven out of 9 patients had generalized tonic clonic seizures (GTCS) during the course of disease, of whom 5 experienced only one episode. GTCS was the cause for the first visits to hospital in 5 patients. Since the clinical manifestations of EM with or without absence were often slight, VEEG monitoring with eye closure and intermittent photic stimulation tests helped to induce discharges and seizures. Eye closure was more potent than intermittent photic stimulation as a triggering factor. Ictal EEG showed 3 - 6 Hz generalized spike and waves and polyspikes burst. The main treatment option was valproate monotherapy (6 cases) or combined with other antiepileptic drugs (1 case). Levetiracetam, lamotrigine and topiramate were also used in patients and effective to some degree. Two patients lost follow up. The age of 7 patients at follow-up ranged from 9 y to 15 y. Seizures were controlled in 1 case, suspiciously controlled in 1 case, decreased in frequency in 4 cases and were still frequent in 1 case. During follow-up, normal intelligence was found in the former 2 cases, difficult learning in 2 cases, and slightly intellectual impairment in 2 cases. CONCLUSION: Jeavons syndrome is one of the idiopathic generalized epilepsies characterized by EM with or without absence. The age of seizure onset might be difficult to be exactly established, as EM was often misinterpreted and overlooked initially. Clinical history combined with VEEG monitoring with eye closure and intermittent photic stimulation tests could diagnose this disease. Valproate and other new antiepileptic drugs were effective for this disease. Jeavons syndrome is a lifelong disorder. Seizures sometimes could be well controlled. When seizures were resistant to treatment, cognitive and intellectual impairment might occur. PMID- 22931944 TI - [Investigation of adenovirus infection in hospitalized children with diarrhea during 2010 in Beijing, China]. AB - OBJECTIVE: The study was designed to evaluate adenovirus infection in hospitalized children with diarrhea. METHOD: Stool specimens were collected from 519 hospitalized children with diarrhea during 2010, including those defined as community-acquired diarrhea (CAD) who developed diarrhea symptoms within 48 hours after admission, and those defined as hospital-acquired diarrhea (HAD) whose symptoms of diarrhea occurred beyond 48 hours after admission. PCR was employed to identify adenovirus in fecal samples by using universal primers for adenoviruses of all types, and specific primers for adenovirus group F. PCR products with expected size were sequenced for adenovirus typing. Clinical data for children with adenovirus positive specimens were analyzed. RESULT: A total of 519 hospitalized children, including 289 with CAD and 230 with HAD, were enrolled in the study. Out of 519 stool specimens, 76 showed PCR products with expected 301 bp and identified as adenovirus by sequencing, and the overall positive rate was 14.6%. Out of 289 CAD samples, 43 were positive (positive rate was 14.9%). Of them, 20 were identified as enteric adenovirus infection (adenovirus type 41, Ad41). Thirty-three out of 230 HAD samples were positive (positive rate was 14.3%). Of them, 13 were characterized as enteric adenovirus infection (one was Ad40 and others were Ad41). Ad41 in this study could be divided into two genotypes by phylogenetic tree analysis. Non-enteric adenoviruses were identified in 43 specimens (43/76, 56.6%) including 5 of serotype 1, 8 of serotype 2, 15 of serotype 3, 10 of serotype 7, 1 of serotype 12, and 4 of serotype 31. In this study, the positive rate of adenovirus between CAD children and HAD children did not differ (chi(2) = 0.03, P > 0.05), while the positive rate of enteric adenovirus was high in CAD children. CONCLUSION: Adenovirus infection was the main cause of diarrhea in hospitalized children. In this study, the positive rate of adenovirus was similar between children with CAD and with HAD. Enteric adenovirus (adenovirus group F) was the most common adenovirus serotype detected in 2010 in Beijing, and Ad41 was the dominant type. PMID- 22931945 TI - [Oxidative stress inhibits the protective effects of insulin-like growth factor-1 on cortical neurons of neonatal rat]. AB - OBJECTIVE: To explore the protective effects of insulin-like growth factor-1(IGF 1) on the survival and apoptosis of cortical neurons of neonatal rat under oxidative stress and its significance. METHOD: Primary cortical neurons from newborn rat were cultured and the oxidative stress model was established. Then cells were randomly divided into IGF-1 group and control group. The concentration of LDH in supernatant was detected. Cell survival was determined with MTT assay and the expression of active Caspase-3 was measured using Western Blotting. RESULT: (1) The values of LDH gradually decreased with the increasing IGF-1 added to the cells [(0.5065 +/- 0.0064) to (0.435 +/- 0.0065), (P < 0.01)], but when the concentration of IGF-1 reached a certain level (> 25 ng/ml), there were no longer obvious effects on the level of LDH [(0.42 +/- 0.012) to (0.418 +/- 0.0098), (P > 0.05)]; Western blot showed that the level of active Caspase-3 was significantly decreased after treatment with IGF-1 [(0.662 +/- 0.033) to (0.199 +/- 0.01), (P < 0.01)]. (2) Compared with control group, without or with low concentration of H2O2 (0 - 40 uM), the values of LDH and the expression of active Caspase-3 in IGF-1 group were significantly decreased[(1.518 +/- 0.137) to (1.068 +/- 0.067), (P < 0.05) and 0.850 +/- 0.042 to 0.597 +/- 0.03, P < 0.01, respectively] while the values of MTT obviously elevated [(0.773 +/- 0.062) to (1.196 +/- 0.057), (P < 0.05)]; but with higher concentration (>= 60 uM) of H2O2, the values of LDH and MTT and the expression of active Caspase-3 in IGF-1 group all had no significant difference (P > 0.05). (3) When the concentration of H2O2 reached 60 uM and higher, whatever concentration of IGF-1 could not lower the level of LDH compared with control group [(2.376 +/- 0.04) to (2.442 +/- 0.046), (P > 0.05)]. CONCLUSIONS: Oxidative stress can induce IGF-1 resistance of cortical neurons in neonatal rat, and even increasing the concentration of IGF-1 can not restore their sensitivity to IGF-1. PMID- 22931946 TI - [Paternally originated Wolf-Hirschhorn syndrome detected by multiplex ligation dependent probe amplification and microarray comparative genomic hybridization]. AB - OBJECTIVE: To confirm the diagnosis of a Wolf-Hirschhorn syndrome by family study using both cytogenetic and molecular genetic techniques. METHOD: G-band karyotyping was performed for all the 6 members in the family. Multiplex ligation dependent probe amplification (MLPA) was used to detect the chromosome abnormality for the proband, his father and brother. Microarray comparative genomic hybridization (Array-CGH) was carried out to map the exact chromosomal breakpoints for the proband. RESULT: The proband presented with a typical face, delayed growth and hypotonia in Wolf-Hirschhorn syndrome. His G-band karyotype was 46, XY, der(4)t(4;8) (p16.2; p23.1)pat. MLPA showed 4pter loss and 8pter gain. Array-CGH revealed an XY male with a 3.781 Mb deletion of 4p16.3-p16.2 and a 6.760 Mb duplication of 8p23.3-p23.1. The proband's brother has mental retardation and skeletal abnormalities. His G-band karyotype was 46, XY, der(8)t(4;8)(p16.2;p23.1)pat. MLPA showed 4pter gain and 8pter loss. The proband's father had normal phenotype with a balanced translocation of 46, XY, t(4;8)(p16.2;p23.1)pat. MLPA showed a normal result. The proband's grandfather showed a normal phenotype with a balanced translocation 46, XY, t(4;8)(p16.2;p23.1). The other members in the family showed normal phenotypes with normal karyotypes. CONCLUSION: The proband has features of Wolf-Hirschhorn syndrome with partial monosomy 4p and partial trisomy 8p. The proband's brother has a partial trisomy 4p and partial monosomy 8p. The derived chromosomes are inherited from paternal balanced translocation t(4;8)(p16.2;p23.1). PMID- 22931948 TI - [A Chinese boy with familial male-confined precocious puberty caused by a mutation Ala568Val in LHCGR gene]. PMID- 22931947 TI - [Clinical characteristics of juvenile dermatomyositis complicated with interstitial lung disease]. AB - OBJECTIVE: To explore the clinical and laboratory features and the prognosis of juvenile dermatomyositis (JDM) complicated with interstitial lung disease (ILD). METHOD: Data of 39 cases of JDM complicated with ILD hospitalized in Beijing Children's Hospital from January 2005 to December 2011 were collected. The clinical features, laboratory data and prognosis of these children were analyzed. RESULT: Of the 39 cases studied, 16 were boys, and 23 girls. The average age of onset was 5.6 years, and 61.5% of the patients' age of onset (24 cases) was under 6 years. Rashes (17 cases, 43.6%), simultaneous eruption of rashes and muscle weakness (14 cases, 35.9%), fever (4 cases, 10.1%), or muscle weakness (3 cases, 7.7%) were common initial symptoms of the disease. Only 51.3% of the patients (20 cases) had the symptoms of respiratory system, but (24 cases) 61.5% were complicated with that of the gastrointestinal system; (27 cases) 69.2% had at the same time electrocardiographic and echocardiographic abnormalities. The chest high resolution computed tomography (HRCT) showed cord or band-like shadows in their lungs of more than half of the cases (25 cases, 64.1%), and other changes included ground glass-like shadow (10 cases, 25.6%), net and lineation-like shadow (9 cases, 23.1%), nodular change (5 cases, 12.8%). The patients complicated with lung essential infiltration accounted for as high as 71.8% (28 cases). These imaging changes were largely seen on both dorsal sides of their lungs. Severe patients also had mediastinal emphysema, pneumothorax, pneumorrhagia or aerodermectasia. Twenty-four patients underwent pulmonary function examination, and 62.5% of the patients' pulmonary function (15 cases) was abnormal. The fatality rate of the cases studied was 10.1%. CONCLUSION: The imaging changes of patients suffering from JDM with ILD were often more severe as compared to the clinical symptoms, and were often complicated with damages to other systems and organs. The prognosis of those patients was poorer than others. Patients with JDM especially at a younger age of onset and with various organ damages should be examined with chest HRCT examinations as early as possible. PMID- 22931949 TI - [Suggestion and explanation of pediatric cardiomyopathy]. PMID- 22931950 TI - [The treatment of infective endocarditis in children: interpretation of the guideline on diagnosis, treatment and prevention by American Heart Association and European Society of Cardiology]. PMID- 22931951 TI - Taking the pain out of pain management. PMID- 22931952 TI - Changing recommendations for calcium supplementation. PMID- 22931953 TI - Identification and predictive value of interleukin-6+ interleukin-10+ and interleukin-6- interleukin-10+ cytokine patterns in ST-elevation acute myocardial infarction. AB - RATIONALE: At the onset of ST-elevation acute myocardial infarction (STEMI), patients can present with very high circulating interleukin-6 (IL-6(+)) levels or very low-IL-6(-) levels. OBJECTIVE: We compared these 2 groups of patients to understand whether it is possible to define specific STEMI phenotypes associated with outcome based on the cytokine response. METHODS AND RESULTS: We compared 109 patients with STEMI in the top IL-6 level (median, 15.6 pg/mL; IL-6(+) STEMI) with 96 in the bottom IL-6 level (median, 1.7 pg/mL; IL-6(-) STEMI) and 103 matched controls extracted from the multiethnic First Acute Myocardial Infarction study. We found minimal clinical differences between IL-6(+) STEMI and IL-6(-) STEMI. We assessed the inflammatory profiles of the 2 STEMI groups and the controls by measuring 18 cytokines in blood samples. We exploited clustering analysis algorithms to infer the functional modules of interacting cytokines. IL 6(+) STEMI patients were characterized by the activation of 2 modules of interacting signals comprising IL-10, IL-8, macrophage inflammatory protein 1alpha, and C-reactive protein, and monocyte chemoattractant protein-1, macrophage inflammatory protein-1beta, and monokine induced by interferon-gamma. IL-10 was increased both in IL-6(+) STEMI and IL-6(-) STEMI patients compared with controls. IL-6(+)IL-10(+) STEMI patients had an increased risk of systolic dysfunction at discharge and an increased risk of death at 6 months in comparison with IL-6(-)IL-10(+) STEMI patients. We combined IL-10 and monokine induced by interferon-gamma (derived from the 2 identified cytokine modules) with IL-6 in a formula yielding a risk index that outperformed any single cytokine in the prediction of systolic dysfunction and death. CONCLUSIONS: We have identified a characteristic circulating inflammatory cytokine pattern in STEMI patients, which is not related to the extent of myocardial damage. The simultaneous elevation of IL-6 and IL-10 levels distinguishes STEMI patients with worse clinical outcomes from other STEMI patients. These observations could have potential implications for risk-oriented patient stratification and immune-modulating therapies. PMID- 22931954 TI - Stem cell factor gene transfer promotes cardiac repair after myocardial infarction via in situ recruitment and expansion of c-kit+ cells. AB - RATIONALE: There is growing evidence that the myocardium responds to injury by recruiting c-kit(+) cardiac progenitor cells to the damage tissue. Even though the ability of exogenously introducing c-kit(+) cells to injured myocardium has been established, the capability of recruiting these cells through modulation of local signaling pathways by gene transfer has not been tested. OBJECTIVE: To determine whether stem cell factor gene transfer mediates cardiac regeneration in a rat myocardial infarction model, through survival and recruitment of c-kit(+) progenitors and cell-cycle activation in cardiomyocytes, and explore the mechanisms involved. METHODS AND RESULTS: Infarct size, cardiac function, cardiac progenitor cells recruitment, fibrosis, and cardiomyocyte cell-cycle activation were measured at different time points in controls (n=10) and upon stem cell factor gene transfer (n=13) after myocardial infarction. We found a regenerative response because of stem cell factor overexpression characterized by an enhancement in cardiac hemodynamic function: an improvement in survival; a reduction in fibrosis, infarct size and apoptosis; an increase in cardiac c kit(+) progenitor cells recruitment to the injured area; an increase in cardiomyocyte cell-cycle activation; and Wnt/beta-catenin pathway induction. CONCLUSIONS: Stem cell factor gene transfer induces c-kit(+) stem/progenitor cell expansion in situ and cardiomyocyte proliferation, which may represent a new therapeutic strategy to reverse adverse remodeling after myocardial infarction. PMID- 22931955 TI - Induction of cardiomyocyte-like cells in infarct hearts by gene transfer of Gata4, Mef2c, and Tbx5. AB - RATIONALE: After myocardial infarction (MI), massive cell death in the myocardium initiates fibrosis and scar formation, leading to heart failure. We recently found that a combination of 3 cardiac transcription factors, Gata4, Mef2c, and Tbx5 (GMT), reprograms fibroblasts directly into functional cardiomyocytes in vitro. OBJECTIVE: To investigate whether viral gene transfer of GMT into infarcted hearts induces cardiomyocyte generation. METHODS AND RESULTS: Coronary artery ligation was used to generate MI in the mouse. In vitro transduction of GMT retrovirus converted cardiac fibroblasts from the infarct region into cardiomyocyte-like cells with cardiac-specific gene expression and sarcomeric structures. Injection of the green fluorescent protein (GFP) retrovirus into mouse hearts, immediately after MI, infected only proliferating noncardiomyocytes, mainly fibroblasts, in the infarct region. The GFP expression diminished after 2 weeks in immunocompetent mice but remained stable for 3 months in immunosuppressed mice, in which cardiac induction did not occur. In contrast, injection of GMT retrovirus into alpha-myosin heavy chain (alphaMHC)-GFP transgenic mouse hearts induced the expression of alphaMHC-GFP, a marker of cardiomyocytes, in 3% of virus-infected cells after 1 week. A pooled GMT injection into the immunosuppressed mouse hearts induced cardiac marker expression in retrovirus-infected cells within 2 weeks, although few cells showed striated muscle structures. To transduce GMT efficiently in vivo, we generated a polycistronic retrovirus expressing GMT separated by 2A "self-cleaving" peptides (3F2A). The 3F2A-induced cardiomyocyte-like cells in fibrotic tissue expressed sarcomeric alpha-actinin and cardiac troponin T and had clear cross striations. Quantitative RT-PCR also demonstrated that FACS-sorted 3F2A-transduced cells expressed cardiac-specific genes. CONCLUSIONS: GMT gene transfer induced cardiomyocyte-like cells in infarcted hearts. PMID- 22931956 TI - Acute psychological stress accelerates reverse cholesterol transport via corticosterone-dependent inhibition of intestinal cholesterol absorption. AB - RATIONALE: Psychological stress is associated with an increased risk of cardiovascular diseases. However, the connecting mechanisms of the stress inducing activation of the hypothalamic-pituitary-adrenal axis with atherosclerosis are not well-understood. OBJECTIVE: To study the effect of acute psychological stress on reverse cholesterol transport (RCT), which transfers peripheral cholesterol to the liver for its ultimate fecal excretion. METHODS AND RESULTS: C57Bl/6J mice were exposed to restraint stress for 3 hours to induce acute psychological stress. RCT in vivo was quantified by measuring the transfer of [(3)H]cholesterol from intraperitoneally injected mouse macrophages to the lumen of the small intestine within the stress period. Surprisingly, stress markedly increased the contents of macrophage-derived [(3)H]cholesterol in the intestinal lumen. In the stressed mice, intestinal absorption of [(14)C]cholesterol was significantly impaired, the intestinal mRNA expression level of peroxisome proliferator-activated receptor-alpha increased, and that of the sterol influx transporter Niemann-Pick C1-like 1 decreased. The stress dependent effects on RCT rate and peroxisome proliferator-activated receptor alpha gene expression were fully mimicked by administration of the stress hormone corticosterone (CORT) to nonstressed mice, and they were blocked by the inhibition of CORT synthesis in stressed mice. Moreover, the intestinal expression of Niemann-Pick C1-like 1 protein decreased when circulating levels of CORT increased. Of note, when either peroxisome proliferator-activated receptor alpha or liver X receptor alpha knockout mice were exposed to stress, the RCT rate remained unchanged, although plasma CORT increased. This indicates that activities of both transcription factors were required for the RCT-accelerating effect of stress. CONCLUSIONS: Acute psychological stress accelerated RCT by compromising intestinal cholesterol absorption. The present results uncover a novel functional connection between the hypothalamic-pituitary-adrenal axis and RCT that can be triggered by a stress-induced increase in circulating CORT. PMID- 22931957 TI - Use of dietary diversity score as a proxy indicator of nutrient adequacy of rural elderly people in Sri Lanka. AB - BACKGROUND: Macro and micro nutrient deficiencies are public health concerns in most developing countries including Sri Lanka, partly due to monotonous, cereal based diet that lacks diversity. The objective of the study was to assess validity of food variety score (FVS), dietary diversity score (DDS) and dietary serving score (DSS) as indicators of nutrient adequacy of rural elderly people in Sri Lanka. FINDINGS: A sample of 200 apparently healthy elderly people >60y of age were studied. A single 24 h recall was performed to compute dietary diversity indicators. Pearson's correlation was used to assess the utility of FVS, DDS and DSS as indicators of nutrient adequacy. Sensitivity (Se) and specificity (Spe) analysis were done to determine the most appropriate cut-off points for using FVS and DDS to categorize elderly people with adequate nutrient intake. The average (standard deviation) of the food variety score, dietary diversity score and dietary serving score was 8.4 (2), 4.4 (0.9) and 11.4 (2.5), respectively. Mean adequacy ratio (MAR) of 12 nutrients was 0.39 (39%). Pearson's correlation coefficients between MAR and FVS was 0.45 (P < 0.01), for DDS it was 0.48 ( P < 0.01) and for DSS it was 0.58 ( P < 0.01). When maximizing sensitivity and specificity, the best cut-off point for achieving 50% of MAR was about 9 and 4.5 for FVS and DDS, respectively. CONCLUSION: In conclusion, FVS, DDS and DSS were useful proxy indicators of nutrient adequacy of rural elderly people in Sri Lanka. Indeed, the performance of the indicators is improved when considering the quantities of food consumed. PMID- 22931958 TI - Bootstrapping phylogenies inferred from rearrangement data. AB - BACKGROUND: Large-scale sequencing of genomes has enabled the inference of phylogenies based on the evolution of genomic architecture, under such events as rearrangements, duplications, and losses. Many evolutionary models and associated algorithms have been designed over the last few years and have found use in comparative genomics and phylogenetic inference. However, the assessment of phylogenies built from such data has not been properly addressed to date. The standard method used in sequence-based phylogenetic inference is the bootstrap, but it relies on a large number of homologous characters that can be resampled; yet in the case of rearrangements, the entire genome is a single character. Alternatives such as the jackknife suffer from the same problem, while likelihood tests cannot be applied in the absence of well established probabilistic models. RESULTS: We present a new approach to the assessment of distance-based phylogenetic inference from whole-genome data; our approach combines features of the jackknife and the bootstrap and remains nonparametric. For each feature of our method, we give an equivalent feature in the sequence-based framework; we also present the results of extensive experimental testing, in both sequence based and genome-based frameworks. Through the feature-by-feature comparison and the experimental results, we show that our bootstrapping approach is on par with the classic phylogenetic bootstrap used in sequence-based reconstruction, and we establish the clear superiority of the classic bootstrap for sequence data and of our corresponding new approach for rearrangement data over proposed variants. Finally, we test our approach on a small dataset of mammalian genomes, verifying that the support values match current thinking about the respective branches. CONCLUSIONS: Our method is the first to provide a standard of assessment to match that of the classic phylogenetic bootstrap for aligned sequences. Its support values follow a similar scale and its receiver-operating characteristics are nearly identical, indicating that it provides similar levels of sensitivity and specificity. Thus our assessment method makes it possible to conduct phylogenetic analyses on whole genomes with the same degree of confidence as for analyses on aligned sequences. Extensions to search-based inference methods such as maximum parsimony and maximum likelihood are possible, but remain to be thoroughly tested. PMID- 22931960 TI - Let there be light-but should there be less? PMID- 22931959 TI - Evaluation of immigrant tuberculosis screening in industrialized countries. AB - In industrialized countries, tuberculosis (TB) cases are concentrated among immigrants and driven by reactivation of imported latent TB infection (LTBI). We examined mechanisms used to screen immigrants for TB and LTBI by sending an anonymous, 18-point questionnaire to 31 member countries of the Organisation for Economic Co-operation and Development. Twenty-nine (93.5%) of 31 responded; 25 (86.2%) screened immigrants for active TB. Fewer countries (16/29, 55.2%) screened for LTBI. Marked variations were observed in targeted populations for age (range <5 years of age to all age groups) and TB incidence in countries of origin of immigrants (>20 cases/100,000 population to >500 cases/100,000). LTBI screening was conducted in 11/16 countries by using the tuberculin skin test. Six countries used interferon-gamma release assays, primarily to confirm positive tuberculin skin test results. Industrialized countries performed LTBI screening infrequently and policies varied widely. There is an urgent need to define the cost-effectiveness of LTBI screening strategies for immigrants. PMID- 22931961 TI - Antenatal thrombosis of torcular herophili presenting with anemia, consumption coagulopathy and high-output cardiac failure in a preterm infant. AB - Dural sinus malformation occasionally results in the development of giant venous lakes involving torcular herophili. Such dilatation can result in the formation of a massive venous thrombus leading to ventriculomegaly/hydrocephalus. Although, majority of patients have an unremarkable clinical course owing to spontaneous resolution of the thrombus, significant morbidity and mortality has been documented. We report the first case of torcular thrombosis in a preterm infant who survived severe anemia, consumption coagulopathy and high-output cardiac failure during the neonatal period and had a normal neurological outcome. PMID- 22931962 TI - A cluster of transfusion-associated babesiosis in extremely low birthweight premature infants. AB - Babesiosis is a parasitic infection of the red blood cells most often acquired by a tick bite. As it has also been known to be transmitted vertically and via transfusion, neonates have occasionally been reported with the infection. Here, we report a series of three premature neonates who acquired babesiosis via blood transfusion from a single donor, one of whom had difficulty clearing the infection and required multiple antimicrobials. PMID- 22931963 TI - Transcutaneous bilirubinometry during phototherapy. PMID- 22931964 TI - The BUR is important! PMID- 22931967 TI - Nutrition knowledge and other determinants of food intake and lifestyle habits in children and young adolescents living in a rural area of Sicily, South Italy. AB - OBJECTIVE: The study aimed to test the reliability of a nutrition questionnaire and to assess potential associations between nutrition knowledge, food consumption and lifestyle behaviours, controlling for sociodemographic factors. DESIGN: Cross-sectional survey. SETTING: Comprehensive school in the municipality of Butera, a rural area of Sicily, South Italy. SUBJECTS: The survey was conducted between March and May 2010 on 445 students (4-16 years). RESULTS: All constructs of the questionnaire had statistically significant Cronbach's a and Pearson's correlation coefficients, showing good internal consistency and temporal stability. After controlling for covariates, nutrition knowledge was positively associated with pasta/rice, fish, vegetable and fruit intakes, and negatively with sweets, snacks, fried foods and sugary drinks consumption. Moreover, students whose parents were in the highest educational and occupational categories reported eating significantly more fruits and vegetables and less meat, sweets, snacks, fried foods and sugary drinks. Students with higher nutrition knowledge scores were less likely to have two or more snacks daily and to spend more than 3 h in sedentary activities daily (OR=0.89, 95% CI 0.83, 0.97 and OR=0.92, 95% CI 0.86, 0.99, respectively). High parental education was associated with less frequent snacking and more frequent weekly physical activity, compared with lower categories, whereas high parental occupational category was associated with daily breakfast. CONCLUSIONS: Improving nutrition knowledge in children and young adolescents may translate into educating them in good dietary habits. Moreover, nutrition intervention programmes should also involve parents to improve dietary quality and nutritional habits of the entire family. PMID- 22931966 TI - Rickettsia raoultii-like bacteria in Dermacentor spp. ticks, Tibet, China. PMID- 22931968 TI - Ion-exchange protocol to obtain antigenic fractions with potential for serodiagnosis of strongyloidiasis. AB - The aim of this study was to fractionate and partially characterize the antigenic extract of filariform larvae of Strongyloides venezuelensis in ion-exchange resin diethylaminoethyl sepharose (DEAE), to obtain antigenic fractions potentially applicable in immunoassays. Somatic antigen (SA) and its fractions DEAE S1 and DEAE S2 - which interacted with the resin - were evaluated by 1-dimensional electrophoresis to obtain protein profiles. SA and its fractions were tested in serum samples for IgG detection by ELISA. Serum samples (n = 155) were analysed: 50 from strongyloidiasis patients (G1), 55 from patients with other parasitic infections (G2) and 50 from healthy volunteers. Sensitivity (Se), specificity (Sp), area under curve (AUC) and likelihood ratios (LR) were calculated. The DEAE S2 fraction provided a high diagnostic value for IgG detection (Se 92.0%, Sp 91.4%, AUC 0.981, LR+ 10.75, LR - 0.09). In conclusion, the DEAE S2 fraction would probably be a source of immunodominant polypeptides for IgG detection in human strongyloidiasis serodiagnosis. PMID- 22931969 TI - Does urothelial cancer of bladder behave differently in young patients? AB - BACKGROUND: Bladder urothelial cancer has been diagnosed at an increasing rate among young adults in China while the clinical outcomes remain highly controversial. To optimize the management of young patients with bladder cancer, we examined whether bladder urothelial cancer in young patients behaved differently from that in the elder patients. METHODS: From 1994 to 2008, a database of bladder urothelial cancer patients at a major tertiary medical center was retrospectively reviewed. The clinical and pathological parameters of patients who were less than 40 years of age and a series of patients older than 40 years of age as the control group during the same period were compared. A survival analysis was performed using the Kaplan-Meier method and log-rank test, and Cox regression was performed to identify clinical parameters that affected the clinic outcomes. RESULTS: Young bladder cancer patients had a lower male-to female ratio and were less likely to have advanced stages and high-grade cancers at the initial diagnosis. Tumors in young bladder cancer patients tended to be less multifocal at diagnosis. In addition, young patients had a lower recurrence rate and longer recurrence interval than older patients. The Kaplan-Meier curve and Log-rank test showed that young patients had significantly better cancer specific survival than old patients. The univariate and multivariate Cox regression analysis revealed that tumor grade is the sole predictor for tumor recurrence in young patients. CONCLUSIONS: Young patients with bladder cancer have favorable pathological features and clinical outcomes than older patients. These findings argue for more conservative management approaches for young patients with bladder cancer. PMID- 22931970 TI - Effects of decline in renal function with age on the outcome of asymptomatic carotid plaque in healthy adults: a 5-year follow-up study. AB - BACKGROUND: It has been long suggested that abnormal clinical factors in the body, such as dyslipidemia and diabetes, can affect the presence of atherosclerosis. However, few studies on the effect of factors within the normal range, such as the loss of renal function with age, on the prevalence of atherosclerosis are few know in healthy individuals. The aim of this study was to investigate risk factors affecting the presence of asymptomatic carotid plaques in a middle-aged and elderly healthy population. METHODS: In this regard, we prospectively evaluated 245 healthy individuals (98 males and 147 females) at baseline and after 5 years. Changes in the presence of carotid plaque between 2003 and 2008 were categorized into four groups, i.e. subjects without plaque at entry (n = 165): Group 1 (without plaque on two occasions, n = 129) and Group 2 (with nascent plaque at follow-up, n = 36); subjects with plaque at entry (n = 80); Group 3 (with plaque regression at follow-up, n = 29) and Group 4 (with plaque on two occasions, n = 51). RESULTS: Univariate analysis showed that the positive rate of carotid plaques in males was higher than that in females at the baseline, and that a significantly inverse correlation existed between the prevalence rate of plaque and aging. Logistic regression analysis of cross sectional research showed that independent risk factors for the prevalence of atherosclerosis were male gender, lower estimated glomerular filtration rate (eGFR) and higher low-density lipoprotein cholesterol (LDL-C) at the baseline, and older age and lower eGFR were involved in the presence of carotid plaques at follow-up point. However, logistic regression analysis of the longitudinal data showed that older age, decreased eGFR and increased systolic blood pressure (SBP) independently predicted the presence of carotid plaques after 5 years in subjects without plaque at entry. In addition, in subjects with plaque at entry, age, changes in eGFR and the baseline levels of serum albumin (ALB) and serum total bilirubin (BIL) dependently influenced the outcome of carotid plaque. CONCLUSION: Physiological decline of renal function, together with advancing age, was an independent risk factor which consistently affected the presence of carotid atherosclerosis in two categories of healthy individuals. PMID- 22931971 TI - Hemodynamic changes of fractional flow reserve after double kissing crush and provisional stenting technique for true bifurcation lesions. AB - BACKGROUND: Fractional flow reserve (FFR)-guided percutaneous coronary intervention (PCI) is associated with fewer unfavorable events. However, the hemodynamic change in FFR after different stenting approaches for bifurcation lesions is still not fully studied. The aim of this study was to analyze the hemodynamic changes in FFR after double kissing (DK) crush and provisional side branch (SB) stenting (PS) for true coronary bifurcation lesions. METHODS: Seventy five patients with true bifurcated lesions were randomly divided into DK (n = 38) and PS (n = 37) groups. Additional SB stenting in the PS group was required if there was any pinched SB ostium > 70% stenosis, or >= type B dissection, or TIMI flow < grade 3. FFR at hyperemia in the main vessel (MV) and SB was measured prior- and post-stenting, and at 8 months follow-up. RESULTS: Baseline clinical, angiographic and lesion characteristics were matched well between the two groups, with the exception of the final kissing balloon inflation (FKBI, 100.0% in the DK vs. 83.8% in the PS group, P < 0.001). Baseline FFR was comparable between the DK and the PS groups, however, the acute gain and late loss of SB FFR at 8-month follow-up in the DK group were 0.18 +/- 0.15 and -0.06 +/- 0.11, compared to 0.12 +/- 0.18 (P = 0.044) and -0.002 +/- 0.07 (P = 0.037) in the PS group, respectively. MV FFR post-stenting > 0.94 was seen in about 40% of patients. There was no significant difference in the clinical events at 1-year follow-up between the two groups. CONCLUSIONS: DK crush was associated with improved acute gain and late loss of SB FFR. The lower rate of FFR > 0.94 after stenting underscored the further improvement of stenting quality. PMID- 22931972 TI - Prognostic power of abnormal cytogenetics for multiple myeloma: a multicenter study in China. AB - BACKGROUND: Chromosomal abnormalities have been shown to play an important prognostic role in multiple myeloma (MM). Interphase fluorescence in situ hybridization (i-FISH) has been much more effective to identify cytogenetic aberrations in MM than conventional cytogenetic technique (CC). To clearly determine the cytogenetic features of Chinese MM patients and identify their prognostic implications, we designed a multicenter study based on i-FISH including 672 patients from 52 hospitals in China. METHODS: All 672 patients were systematically screened for the following genomic aberrations: del(13q), IgH rearrangement, del(p53) and 1q21 amplifications. RESULTS: The analysis showed that the chromosomal changes were detected in 22.1% patients by CC and in 82.3% patients by i-FISH. The most common abnormalities by CC were chromosome 1 aberrations (48.4%), -13/13q- (37.6%), hyperdiploidy (36.6%), hypodiploidy (30.1%) and IgH rearrangements (23.7%). The most frequent abnormalities by FISH was del(13q), which was found in 60.4% patients, whereas IgH rearrangement, 1q21 amplification and p53 deletions were detected in 57.6%, 49.0% and 34.7% cases, respectively. By statistical analysis, -13/13q- by CC was associated with low level of platelet (P = 0.015), hyperdiploidy was associated with low level of serum albumin (P = 0.028), and IgH rearrangement by FISH was associated with high level of beta2 microglobulin (P = 0.019). Moreover, 1q21 amplification and del(p53) by FISH conferred a high incidence of progressive disease (PD) after initial therapy. Metaphase detection of IgH rearrangements and chromosome 1 aberrations concurrently was associated with a short progression free survival (PFS) (P = 0.036). No significant prognostic implications of other cytogenetic abnormalities were found associated with overall survival and PFS. CONCLUSIONS: Chinese MM patients had similar cytogenetic abnormalities compared with the previous reported studies. However, the prognostic significance of FISH aberrations were not clearly determined and further study is required. PMID- 22931973 TI - A single tube modified allele-specific-PCR for rapid detection of erythromycin resistant Mycoplasma pneumoniae in Beijing. AB - BACKGROUND: Mycoplasma pneumoniae (M. pneumoniae) is one of the common pathogens causing atypical pneumonia. In recent years, resistance to macrolides has become more common, especially in China. Previous studies have confirmed that the mutation at position 2063 in domain V of the 23S rRNA is the most prevalent, followed by the mutation at position 2064. Reported molecular detection methods for the identification of these mutations include direct sequencing, restriction fragment length polymorphism analysis, real-time polymerase chain reaction (PCR) with high-resolution melt analysis, and nested PCR-linked with capillary electrophoresis, etc. The most commonly used method for monitoring resistance conferring mutations in M. pneumoniae is direct DNA sequencing of PCR or nested PCR products. However, these methods are time-consuming, labor-intensive or need expensive equipments. Therefore the development of rapid and sensitive methods is very important for monitoring the resistance globally. METHODS: In this study, we reported a fast and cost-effective method for detecting 2063 and/or 2064 macrolide resistant mutations from specimens using a modified allele-specific PCR analysis, and all results were compared with the sequencing data. We also analyzed the clinical courses of these samples to confirm the modified allele specific PCR results. RESULTS: Among 97 M. pneumoniae specimens, 88 were found to possess mutations by this method, and all modified allele-specific PCR analysis results were consistent with the sequencing data. The data of the clinical courses of these 97 cases showed that they suffered from severe pneumonia. Erythromycin showed better efficacy on cases from which no macrolide resistance mutation was found on their specimens. However, in some cases from which mutations were detected, erythromycin monotherapy had poor efficacy, and on these patients severe symptoms improved only when azithromycin was added to the treatment. CONCLUSIONS: The drug-resistant M. pneumoniae is very common in Beijing, China. Our modified allele-specific PCR analysis can identify erythromycin resistant mutations more rapidly from specimens than any other method currently available. Erythromycin is still effective for treating patients infected with the mutation negative M. pneumoniae, but this treatment fails to work on mutant organisms. This method can facilitate clinicians in selecting appropriate therapy within short timescales. PMID- 22931974 TI - Efficacy and tolerability of exenatide monotherapy in obese patients with newly diagnosed type 2 diabetes: a randomized, 26 weeks metformin-controlled, parallel group study. AB - BACKGROUND: Incretin-based therapies provide additional options for treating type 2 diabetes. We aimed to evaluate the efficacy and tolerability of exenatide monotherapy in obese patients with type 2 diabetes. METHODS: A 26-week, metformin controlled, parallel-group study was conducted among antidiabetic drug-naive obese patients aged > 18 years, and with type 2 diabetes. Participating patients were randomly assigned to receive exenatide or metformin treatments. RESULTS: Fifty-nine patients (age (50.5 +/- 8.6) years, body mass index (BMI) (30.2 +/- 1.6) kg/m(2), and hemoglobin A1C (HbA(1C) (8.2 +/- 1.2)%) were enrolled in the study. Glucose control and weight reduction improved in both groups receiving treatment. HbA(1C) and oral glucose tolerance test (OGTT) 2 hour glycemia reduction with exenatide was superior to that obtained with metformin ((-2.10 +/- 1.79)% vs. (-1.66 +/- 1.38)%, (-5.11 +/- 2.68) mmol/L vs. (-2.80 +/- 2.70) mmol/L, P < 0.05). Fast plasma glucose (FPG) reduction was not significantly different between the two groups ((-1.8 +/- 2.0) mmol/L vs. (-1.6 +/- 1.7) mmol/L, P > 0.05). Patients treated with exenatide achieved HbA(1C) of < 7% (97% of patients) and < 6.5% (79%) at end-point, vs. 93% and 73% with metformin (P > 0.05). Greater weight reduction was also achieved with exenatide ((-5.80 +/- 3.66) kg) than with metformin ((-3.81 +/- 1.38) kg, P < 0.01). Homeostasis model assessment of beta-cell function (HOMA-B) was not significantly increased, but the insulinogenic index and HOMA for insulin sensitivity (HOMA-S) were greatly improved in the exenatide group (P < 0.05). Nausea was the most common adverse effect in exenatide treatment (30% vs. 8%; P < 0.05), but most cases were of mild to moderate intensity. One case in the exenatide group was withdrawn early because of severe nausea. Hypoglycemia events were often observed during the first 4 weeks, with 12% of patients in the exenatide and 3.2% in metformin groups, respectively (P < 0.05). No incidents of severe hypoglycemia were reported. CONCLUSIONS: Exenatide demonstrated more beneficial effects on HbA(1C), weight reduction and insulin resistance during 26 weeks of treatment, but there were more hypoglycemic events and mild-to-moderate nausea compared with metformin. These results suggested that exenatide monotherapy may provide a viable treatment option in newly developed type 2 diabetes. PMID- 22931975 TI - Response surface analysis of sevoflurane-remifentanil interactions on consciousness during anesthesia. AB - BACKGROUND: Recently, the combination of sevoflurane and remifentanil has been widely used in general anesthesia. In this study, we investigated the sevoflurane remifentanil pharmacodynamic interactions at clinical concentrations using the observer's assessment of alertness/sedation (OAA/S) and the bispectral index (BIS) by response surface analysis. METHODS: Totally 65 American Society of Anesthesiologists (ASA) I patients age 20 to 50 years old were included in this study. Patients were randomly assigned to be anesthetized with different target end-tidal sevoflurane concentrations that ranged from 0.2% to 3.4% in increments of 0.2%. The end-tidal sevoflurane concentration was maintained constant throughout the study. Remifentanil was infused with a target controlled infusion (TCI) system at increasing step-wise concentrations from 1 ng/ml to 10 ng/ml. The values of OAA/S and BIS at different sevoflurane-remifentanil concentration combinations were measured. The pharmacodynamic interactions between sevoflurane and remifentanil were analyzed by a response surface method. The three dimensional response surfaces were constructed with Minitab Software. Model parameters were estimated with NONMEM program. RESULTS: Sevoflurane and remifentanil acted synergistically on OAA/S. Sevoflurane alone could produce OAA/S <= 1 at a minimal alveolar concentration (MAC) of 0.93%. When used in combination with remifentanil at 1, 3, 6, and 10 ng/ml, the corresponding sevoflurane MACs were reduced to 0.79%, 0.58%, 0.48%, and 0.38%, with reductions of 17.2%, 37.6%, 48.4%, and 62.0% from baseline, respectively. In patients administered remifentanil alone, the OAA/S score was >= 3 even when the remifentanil concentration reached 10 ng/ml. BIS was closely associated with the sevoflurane concentration and the remifentanil concentration did not noticeably influence the relationship between the sevoflurane concentration and BIS. A sevoflurane concentration of (1.04 +/- 0.19)% to (1.81 +/- 0.21)% could maintain a BIS between 60 and 40. CONCLUSIONS: The response surface method can analyze the pharmacodynamic interactions between remifentanil and sevoflurane qualitatively and quantitatively. Within the range of our study (remifentanil <= 10 ng/ml, sevoflurane <= 3.4%), the two drugs produced synergistic effects on OAA/S but had no interactive effect on BIS. A guideline of BIS between 40 and 60 may cause excessive anesthesia when opioids are used to maintain anesthesia. PMID- 22931976 TI - Outcome of in vitro fertilization in endometriosis-associated infertility: a 5 year database cohort study. AB - BACKGROUND: Endometriosis affects natural fertility through various approaches, and in vitro fertilization (IVF) is a good treatment. But the IVF result of endometriosis patients is still under debate. We investigated the effect of endometriosis on IVF by analyzing the data from a single reproductive center. METHODS: A retrospective, database-searched cohort study was performed. Relevant information was collected from the electronic records of women who underwent IVF/intracytoplasmic sperm injection between January 2006 and December 2010 in the Assisted Reproductive Unit of Sir Run Run Shaw Hospital. Patients with endometriosis were enrolled the study group. The rest of the women formed the control group. The main outcome was the clinical pregnancy rate. Secondary outcomes were oocytes retrieved number, fertilization rate, high-quality embryo rate, number of high-quality embryo for embryo transplantation, and implantation embryo/high-quality embryo ratio (IE/HQE ratio). Comparisons were performed by the c(2)-test and independent t-test. RESULTS: The endometriosis group (n = 177) had a markedly lower oocytes retrieved number, fertilization rate, implantation rate, and clinical pregnancy rate (7.6 +/- 5.1, 63.6%, 27.7%, and 45.2%, respectively) compared with the non-endometriosis group (n = 4267; 11.8 +/- 7.3, 68.4%, 36.2%, and 55.2%, respectively). Stratified analysis showed that this difference was found in the subgroup younger than 35-years old, while only fertilization rate and implantation rate were different in the elder subgroup. The ratio of high-quality embryos transferred is lower in endometriosis group (53.7% vs. 71.8%, P < 0.05), but there is no difference in IE/HQE ratio between two groups. There is no significant difference in fertilization rate, implantation rate, and clinical pregnancy rate between mild and severe endometriosis patients. CONCLUSIONS: Endometriosis patients suffer a decreasing IVF pregnancy rates mainly caused by reducing oocytes number and fertilization rate, regardless of the severity of the disease. Appropriate intracytoplasmic sperm injection manipulation might improve the outcomes of IVF. PMID- 22931977 TI - Functional organization of complex brain networks modulated by acupuncture at different acupoints belonging to the same anatomic segment. AB - BACKGROUND: Noninvasive functional magnetic resonance imaging (fMRI) techniques have opened a "window" into the brain, allowing us to investigate the anatomical and physiological function involving acupuncture needling. Imaging its sustained effect rather than acute effect on the brain networks may further help elucidate the mechanisms by which acupuncture achieves its therapeutic effects. In this study, we aimed to investigate the functional brain networks during the post resting state following acupuncture at KI3 in comparison with acupuncture at GB40. METHODS: Needling at acupoints GB40 and KI3 was performed in twelve subjects. Six minutes of scanning at rest were adopted before and after acupuncture at different acupoints. Then we divided the whole brain into 39 regions and constructed functional brain networks during the post-acupuncture resting states (PARS). RESULTS: For direct comparisons, increased correlations during post-resting state following acupuncture at KI3 compared to resting state (RS) were primarily located between the dorsolateral prefrontal cortex (DLPFC) and post temporal cortex, ventromedial prefrontal cortex (vmPFC) and post temporal cortex. These brain regions were all cognitive-related functions. In contrast, the increased connections between the anterior insula and temporal cortex mainly emerged following acupuncture at GB40 compared with the RS. CONCLUSIONS: The present study demonstrates that acupuncture at different acupoints belonging to the same anatomic segment can exert different modulatory effects on the reorganizations of post-acupuncture RS networks. The heterogeneous modulation patterns between two conditions may relate to the functional specific modulatory effects of acupuncture. PMID- 22931978 TI - Ibutilide decreases defibrillation threshold by the reduction of activation pattern complexity during ventricular fibrillation in canine hearts. AB - BACKGROUND: Ibutilide has been commonly used for pharmacologic cardioversion of atrial fibrillation and flutter in clinical settings. The objective of this study was to investigate the effects of ibutilide on the defibrillation threshold (DFT), restitution properties, dispersion of refractoriness and activation patterns during ventricular fibrillation (VF). METHODS: Ibutilide was administrated intravenously in six open-chest beagles. Before and after the drug administration, 20-second episodes of VF were electrically induced and recorded with a 10*10 unipolar electrode plaque sutured on the lateral epicardium of the left ventricle. DFT and VF activation patterns, including type of epicardial activation maps, VF cycle length (VF-CL), conduction velocity, wavelength (WL) and reentry incidence, were measured. Restitution properties and dispersion of refractoriness were estimated from activation recovery intervals (ARI) during pacing. RESULTS: Compared to baseline, ibutilide markedly decreased the DFT by 31% ((491 +/- 14) V vs. (337 +/- 59) V, P < 0.01). The drug significantly reduced the maximal slope of the restitution curve (1.34 +/- 0.08 vs. 0.76 +/- 0.06, P < 0.01) and its epicardial dispersion (0.36 +/- 0.09 vs. 0.21 +/- 0.06, coefficient of variation, P = 0.03). The dispersion of refractoriness was enhanced at the pacing cycle length of 300 ms to 160 ms by ibutilide. The drug significantly increased the VF-CL ((96 +/- 19) ms vs. (112 +/- 20) ms, P < 0.01) and the WL ((41 +/- 9) mm vs. (52 +/- 14) mm, P = 0.02) during VF, and reduced the reentry incidence by 25% (0.08 +/- 0.02 vs. 0.06 +/- 0.02, P < 0.01). In the epicardial activation maps, ibutilide significantly reduced the percentage of more complex activation maps during VF. CONCLUSIONS: Intravenous ibutilide significantly decreased the DFT. It might be due to reduction of activation pattern complexity during VF. PMID- 22931979 TI - Role of the lung in the progression of multiple organ dysfunction syndrome in ageing rat model. AB - BACKGROUND: Multiple organ dysfunction syndrome in the elderly (MODSE) is a problem with high mortality in the critical care of elderly patients. The pathogenesis of MODSE remains elusive. This study aimed to establish rat models of MODSE and to investigate the pathogenetic mechanism responsible for the development of MODSE in the rat models. METHODS: Twenty-four-month old rats (elderly) received intravenous injection of lipopolysaccharide (LPS) to induce rat model of MODSE. In the model, we observed the physical responses, biochemical indices changes, histopathological features of vital organs, including lung, liver, heart, and kidney. We also investigated the sequence of individual organ dysfunction and changes of proinflammatory factors. Three-month-old rats, serving as young rat controls, received parallel procedures. Besides, normal saline injection was also performed on elderly and young control rats. RESULTS: All rats displayed different degree of physical response after LPS injection, preceded by deterioration of respiratory status. At 6 hours, lung injury was observed, which started earlier than other organ injury that was observed in about 24 hours. Furthermore, all vital organ injury was more severe in elderly rats than in young rats at the same time points. After LPS injection, pulmonary alveolar macrophages apoptosis rate increased obviously, and was more significant in elderly rats ((43.4 +/- 8.4)%) than in young rats ((24.2 +/- 3.0)%). LPS injection also enhanced tumor necrosis factor a (TNF-a) concentration significantly in these organs. Its peak concentration appeared at 6 hours in lung tissue and at 24 hours in other organs after LPS injection. TNF-a level was higher in elderly rats than in young rats at the same time points. The increase was most significant in lung tissue. After intravenous administration of LPS, toll-like receptor 4 (TLR4) expression in lung tissue was upregulated markedly, and peaked at 6 hours. In contrast, upregulation of TLR4 expression in liver peaked at 24 hours, lagging behind that in the lung. CONCLUSION: Lung is the first and most seriously injured organ in rat model of MODSE and it may play an "initiating" role in the development of MODSE. PMID- 22931980 TI - Detection of atherosclerotic plaque progression in the abdominal aorta of rabbits with 3T magnetic resonance imaging. AB - BACKGROUND: With features of high tissue contrast, MRI can be used for the qualitative and quantitative evaluation of atherosclerosis plaques. In this study we investigated the development of atherosclerosis plaque with high resolution 3T MRI in a rabbit model and compared the findings with the histopathological results. METHOD: Twenty male New Zealand white rabbits were randomly allocated into an experimental group (n = 16) and a control group (n = 4). Atherosclerotic lesions were induced in the abdominal aorta by balloon injury and cholesterol feeding. Multiple sequences MRI examination (ToF, T1WI, T2WI, and CE T1WI) were performed at the 2nd, 3rd, and 4th months after aortic denudation. Vessel wall thickness, total vessel area, lumen area, and vessel wall area were recorded. Plaque components were analyzed using histological results as a standard reference. RESULTS: Seventeen rabbits (14 in the experimental group and 3 in the control group) received all three MR examinations. Gradually, from 2 months to 4 months, vessel wall thickness and area in the experimental group increased significantly compared with the control group (P < 0.01). In the lumen area progressive stenosis was not found, even a slight dilation had developed in the experimental group. Lipid, fibrotic and calcified plaques can be differentiated by MR image. According to histological results, MRI had good performance in detection of lipid plaque. CONCLUSION: MRI can be used to monitor progression of atherosclerosis and differentiate plaque components. PMID- 22931981 TI - Quantification of left ventricular mechanics using vector-velocity imaging, a novel feature tracking algorithm, applied to echocardiography and cardiac magnetic resonance imaging. AB - BACKGROUND: Tagged magnetic resonance imaging (MRI) is the non-invasive golden standard to measure myocardial deformity. Tissue Doppler Imaging can be used to assess myocardial deformity, however, it has the limitation of angle-dependence. Our study aimed to compare left ventricular torsion and strains measured by velocity-vector imaging (VVI) using echocardiography (echo-VVI) and MRI (MRI VVI), and to validate them against harmonic phase tagged MRI (HARP MRI). METHODS: A total number of 34 subjects (14 normal and 20 patients) were evaluated. Apical and basal image of left ventricular short axis view were acquired for measurements of apical and basal rotation, circumferential and radial strain using both echo-VVI and MRI-VVI. An apical four-chamber view was obtained for measuring the distance between the apical and basal levels. RESULTS: The correlations of segmental rotations, circumferential and radial strains were high between echo-VVI and HARP MRI, while the agreement of apical rotation was poor. Left ventricular torsion showed much better correlation and agreement between echo-VVI and HARP MRI than apical rotation: the coefficient was 0.97, P < 0.001. The correlation between MRI-VVI and HARP MRI in quantifying rotational parameters and strains was similar with echo-VVI and HARP MRI. Echo-VVI could discriminate normal and dysfunctional ventricles on either hypertensive or dilated cardiomyopathy. CONCLUSION: The data from this study show that (1) it is feasible to quantify left ventricular torsion and myocardial strain using echo-VVI and MRI VVI in normal subjects, patients with left ventricular global systolic dysfunction and segment systolic dysfunction; (2) the agreement among all mechanical parameters derived from echo-VVI, MRI-VVI, and HARP MRI remained with clinically acceptable ranges. PMID- 22931982 TI - Regulation on the expression of Clara cell secretory protein in the lungs of the rats with acute lung injury by growth hormone. AB - BACKGROUND: Clara cell secretory protein (CC16) is an important lung derived protective factor and may play an important role on the pathogenesis of acute lung injury (ALI) induced by endotoxemia. Growth hormone (GH) is an important anabolism hormone secreted by GH cells of the hypophysis. Previous research showed that GH would significantly exacerbate ALI induced by endotoxemia, but the mechanism is not very clear yet. Whether the effects are related to CC16 or not is undetermined. METHODS: One hundred and twelve male Sprague-Dawley rats were randomly divided into an ALI group and a GH group. The rats in the two groups were subdivided into seven subgroups, according to injection with lipopolysaccharides (LPS) or not, then according to different intervals of time after LPS injection; 0 hour (pre-injection of LPS, acted as control group), 0.5 hour, 1 hour, 2 hours, 4 hours, 6 hours and 24 hours for subgroups. Pulmonary alveolar septa area density (PASAD) and ploymorphonuclear cells (PMN) in the lungs were analyzed morphometrically. The levels of tumor necrosis factor (TNF) and interleukin 6 (IL-6) were determined by radioimmunoassay. To analyze the expression and activation of nuclear factor kappa B (NF-kappaB), the numbers of NF-kappaB positive cells in lungs were counted after immunofluorescence staining, and the levels of NF-kappaB inhibitory protein-alpha (IkappaB-alpha) in lung homogenates of rats were detected by Western blotting. The expression levels of CC16 mRNA in lungs of the rats with ALI were determined by semi-quantitative reverse transcription polymerase chain reaction (RT-PCR). The levels of CC16 protein in lung homogenates were detected by Western blotting. RESULTS: Half an hour after LPS injury both the PASAD and PMN numbers in lungs of the rats with ALI began to increase significantly and peaked at 6-hour post-injury. They then began to recover and reached normal levels at 24-hour post-injury. Both the PASAD and PMN numbers in the GH group increased more significantly than those in the ALI group. The levels of TNF in lungs of the rats with ALI homogenates increased significantly 0.5-hour post-injury, peaked at 1-hour and maintained a high level until 6 hours then gradually recovered. The content of TNF in the GH group lung homogenates increased more significantly than in the ALI group post-injury. The contents of IL-6 in rat lung homogenates began to increase significantly at 1 hour post-injury, peaked at 4 hours then gradually returned to normal levels by 6 hours post-injury. The levels of IL-6 in the lung homogenates of the GH group were higher than in the ALI group at different time intervals post-injury. The number of NF-kappaB positive cells increased dramatically at 0.5-hour post injury, and the fluorescence intensity was enhanced. Both peaked at 4-hour post injury. The number of NF-kappaB positive cells and the enhanced intensity of fluorescence began to decrease from 6-hour post-injury, but the number of NF kappaB cells at 24 hours post-injury was still higher than in the control group. The number of NF-kappaB cells in lungs in the GH group was significantly higher than in the LPS group at the different time intervals post-injury. The IkappaB alpha expression in lungs of the rats with ALI homogenates decreased dramatically 0.5-hour post-injury, reaching a nadir at 4-hour post-injury and then began to recover. The levels of IkappaB-alpha in GH group were significantly lower than those in ALI group. Both the levels of CC16 mRNA and protein in lungs of the rats with ALI began to decrease significantly 0.5-hour post-injury, reached a nadir at 6 hours, and then began to recover. Both the expression of CC16 mRNA and CC16 protein in the GH group were significantly lower than those in the ALI group at the different time intervals post-injury. Correlation analysis indicates that CC16 correlates significantly with all the indices mentioned above. CONCLUSIONS: Down-regulation of CC16 expression plays a critical role in the pathogenesis of acute lung injury induced by endotoxemia. The application of GH can exacerbate the lung injury induced by endotoxemia through down-regulating the expression of CC16. PMID- 22931983 TI - Inhibition of epithelial-mesenchymal transition in A549 cell by transfected Napsin A. AB - BACKGROUND: Epithelial-mesenchymal transition is a cellular process characterized by the loss of cell adhesion, inhibition of E-cadherin expression, and increased cell mobility. Cells without Napsin A are susceptible to transition. Further studies are required to investigate whether this transition can be reversed by restoration of Napsin A. METHODS: A Napsin A expression vector PLJM1-Napsin A plasmid was constructed and then transfected into the epithelial cell line A549 by lentivirus transfection to obtain A549-PLJM1-Napsin A cell line. Cell proliferation was assayed by 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyltetrazolium bromide and cell cycle was measured by flow cytometry. The E-cadherin, type I collagen, and focal adhesion kinase mRNA level was detected by reverse transcription-polymerase chain reaction. The Napsin A, E-cadherin, type I collagen, and focal adhesion kinase protein level in A549 cells was detected by Western blotting. RESULTS: Transforming growth factor-b1 induced epithelial mesenchymal transition in A549 cells, as demonstrated by significant reduction of E-cadherin mRNA and protein levels (P < 0.01) as well as up-regulation of type I collagen (P < 0.01). Transfection of Napsin A in A549 cells can partially block the transforming growth factor-b1-regulated expression of E-cadherin and type I collagen (P < 0.01). In addition, transforming growth factor-b1-induced cell proliferation was inhibited by Napsin A (P < 0.01). Further study demonstrated that Napsin A caused G(0)/G(1) arrest and inhibited the expression of focal adhesion kinase (P < 0.01), a key protein in the integrin signaling pathway, in the in vitro epithelial-mesenchymal transition model. CONCLUSIONS: Sustained Napsin A expression in A549 cells can inhibit the transforming growth factor-b1 induced epithelial-mesenchymal transition. This may be due to the Napsin A mediated inhibition of focal adhesion kinase expression and integrin signaling pathway. PMID- 22931984 TI - Reversal of multidrug resistance in renal cell carcinoma by short hairpin RNA targeting MDR1 gene. AB - BACKGROUND: Over-expression of P-glycoprotein (P-gp), encoded by the MDR1 gene, confers multidrug resistance (MDR) in renal cell carcinoma (RCC) and is a major reason for unsuccessful chemotherapy. This study aimed to determine the effct of RNA interference (RNAi) on the reversal of MDR in human RCC. METHODS: We designed and selected one short hairpin RNA (shRNA) targeting MDR1 gene, which is stably expressed from integrated plasmid and transfected by lentivirus fluid in human RCC A498 cell. RESULTS: The MDR1-targeted RNAi resulted in decreased MDR1 gene mRNA level (P < 0.001), almost abolished P-gp expression and reversed MDR to different chemotherapy drugs in the RCC A498 cell line. CONCLUSION: MDR could be reversed by RNAi in human RCC A498 cell line, which may be used for clinical application in future. PMID- 22931985 TI - Research progress on the red cell diseases in China. AB - In recent years, there have been lots of progresses in the studies on red cell diseases in China, especially bone marrow failure diseases including immuno related pancytopenia, aplastic anemia, myelodysplastic syndrome, and paroxymal nocturnal hemoglobinuria. Numerous laboratory experiments as well as clinical researches have been carried out by Chinese hematologists, which brought about much clearer pathogenesis, more rational diagnosis methods and more effective therapies for red cell diseases. PMID- 22931986 TI - Neonatal ventral hippocampal lesion as a valid model of schizophrenia: evidence from sensory gating study. AB - BACKGROUND: The neonatal ventral hippocampal lesion (NVHL) rat model has been proposed as an experimental model for schizophrenia. NVHL rats display impaired central nervous system (CNS) inhibition, which may lead to a phenomenon similar to P50 sensory gating deficits observed in schizophrenic patients. In this study, we investigated whether sensory gating deficits occurred in the NVHL rat as a model for schizophrenia. METHODS: We created the NVHL rat model using ibotenate. The P20 and N40 were measured to assess sensory response and gating in NVHL and sham rats. Epidural electrodes recorded evoked potentials (EPs), from which latencies, amplitudes, difference scores (S1-S2), and gating ratios (S2/S1) were assessed. RESULTS: Compared with sham controls, prolonged S1 N40 latency and decreased S2 N40 amplitude were detected in the NVHL group. In neither difference scores nor gating ratios, a significant difference was found between NVHL group and sham controls. CONCLUSIONS: NVHL rats may be a valid animal model for schizophrenia. This strategy will be useful in future neurobiological studies investigating the etiology of schizophrenia. PMID- 22931987 TI - Differential diagnosis of cervical radiculopathy and superior pulmonary sulcus tumor. AB - BACKGROUND: The result would be disastrous if the superior pulmonary sulcus tumor (Pancoast tumor) was misdiagnosed as degenerative cervical spine diseases. The aim of this study was to investigate the differential diagnosis methods of cervical radiculopathy and superior pulmonary sulcus tumor. METHODS: Clinical manifestations, physical, and radiological findings of 10 patients, whose main complaints were radiating shoulder and arm pain and later were diagnosed with superior pulmonary sulcus tumor, were reviewed and compared with those of cervical radiculopathy. RESULTS: Superior pulmonary sulcus tumor patients have shorter mean history and fewer complaints of neck pain or limitation of neck movement. Physical examination showed almost normal cervical spine range of motion. Spurling's neck compression test was negative in all patients. Anteroposterior cervical radiographs showed the lack of pulmonary air at the top of the affected lung in all cases and first rib encroachment in one case. The diagnosis of superior pulmonary sulcus tumor can be further confirmed by CT and MRI. CONCLUSIONS: By the method of combination of history, physical examination, and radiological findings, superior pulmonary sulcus tumor can be efficiently differentiated from cervical radiculopathy. Normal motion range of the cervical spine, negative Spurling's neck compression test, and the lack of pulmonary air at the top of the affected lung in anteroposterior cervical radiographs should be considered as indications for further chest radiograph examinations. PMID- 22931988 TI - Efficacy of the long-acting octreotide formulation in patients with thyroid stimulating hormone-secreting pituitary adenomas after incomplete surgery and octreotide treatment failure. AB - BACKGROUND: Little information about the current management of patients with thyroid-stimulating hormone (TSH)-secreting pituitary adenomas or about the usefulness of the somatostatin analogue octreotide was contained in the literature. This study aimed to report the efficacy and safety of the long-acting octreotide formulation in patients with TSH-secreting pituitary adenomas after incomplete surgery and octreotide treatment failure. METHODS: Fifteen patients with TSH-secreting pituitary adenomas (8 men and 7 women), who previously underwent incomplete surgical resection and/or adjuvant radiotherapy (n = 12) and failure of octreotide treatment (n = 15), followed between 2007 and 2010 in Beijing Tiantan Hospital were included in this study. All patients received 1- to 2-months of the long-acting octreotide formulation treatment after the above combination of treatment. Paired samples t-test was used to analysis the variables. RESULTS: After two-month duration of the long-acting octreotide formulation treatment, the mean serum free or unbound thyroxine (FT4) ((16.02 +/- 1.72) pmol/L) and free triiodothyronine (FT3) ((2.87 +/- 0.43) pmol/L) levels of 15 patients significantly decreased compared with those after octreotide treatment (FT4, (35.36 +/- 7.42) pmol/L, P < 0.001; FT3, (17.85 +/- 7.22) pmol/L, P < 0.001). Mean TSH levels stayed in the normal range after the long-acting octreotide formulation treatment ((0.72 +/- 0.21) mU/L) and were significantly lower than the pretreatment value ((5.27 +/- 1.04) mU/L, P < 0.001), post-surgery value ((3.37 +/- 0.31) mU/L, P < 0.001) and post-octreotide-treatment value ((4.52 +/- 0.41) mU/L, P < 0.001). In these patients with TSH-secreting pituitary adenomas there was no evidence of tachyphylaxis. CONCLUSION: The long-acting octreotide formulation may be a useful and safe therapeutic tool to facilitate the medical treatment of TSH-secreting pituitary adenomas in patients who underwent incomplete surgery or need long-term somatostatin analog therapy. PMID- 22931989 TI - Foreign body granulomas in the left main bronchus resulting from the sutures for esophageal cancer surgery: the report of two cases. AB - In this report, we present two cases of bronchial foreign body granulomas caused by the suture ties used in bronchial surgery for esophageal cancer. Both of them was hospitalized as "tumor transfer or an invasion", but pathological examination of the neoplasms indicated an inflammatory granuloma showing reaction to the foreign body. These two cases give us an attention that the neoplasms in tracheal or bronchial was not only the invasion or transfer of the primary tumor, but also the possibility of granuloma development due to the surgical sutures. PMID- 22931990 TI - Liver transplantation for hepatic metastatic pancreatic insulinoma with a survival over five years. AB - Pancreatic neuroendocrine tumors (NETs) are one subgroup of gastroenteropancreatic NETs. Its main characteristics are slow growth, frequent metastasis to the liver, and limited to the liver for long periods. In patients with irresectable liver metastatic NET, liver transplantation is the only radical treatment. About 160 cases of liver transplantation for liver metastatic NET have been reported worldwide. However, there is no such report of liver transplantation for hepatic metastatic NET in China by now. We herein report a case of liver transplantation for hepatic metastatic pancreatic insulinoma with a survival of over 5 years. PMID- 22931991 TI - Primary Aspergillus spondylodiscitis in a liver transplant recipient. AB - Solid organ transplant recipients are at increased risk for Aspergillus infections. However, the cases of Aspergillus spondylodiscitis are rare and mostly resulted from the hematogenous spread of invasive pulmonary Aspergillosis. Here, we report a case of primary spondylodiscitis in a liver transplant recipient. Six months after transplantation, a chronic and progressive lumbar back pain was presented. The patient had no fever and the white blood cell count was normal. High plasma (1->3)-beta-d-glucan (BDG) level was detected at the time of back pain. The pathogen was Aspergillus flavus. Clinical and radiological healing was achieved through posterior only debridement and voriconazole therapy. PMID- 22931992 TI - Myocardial infarction following recombinant tissue plasminogen activator treatment for acute ischemic stroke: a dangerous complication. AB - Thrombolysis with intravenous tissue plasminogen activator (t-PA) is currently an approved therapy for patients with acute ischemic stroke. Acute myocardial infarction (AMI) immediately following t-PA treatment for stroke is a rare but serious complication. A case of acute myocardial infarction (MI) following IV t PA infusion for acute stroke was observed. This is a 52-year-old male with a known history of hypertension and chest pain, who subsequently developed MI four hours after IV t-PA was administered for acute ischemic stroke. The disruption of intra-cardiac thrombus and subsequent embolization to the coronary arteries may be an important mechanism. In addition, spontaneous recanalization of infarct related arteries may be associated with greater myocardial salvage and better prognosis. PMID- 22931993 TI - Five-level noncontiguous spinal injuries of cervical region: report of a case and literature review. AB - The incidence of multiple noncontiguous spinal injuries (MNSI) in the cervical spine is rare but has catastrophic consequences. The patient in this report was a 34-year-old woman with five-level cervical MNSI. CT and MRI showed that injuries included atlantoaxial instability, burst fracture of C6, dislocation of C6/7, rupture of the intervertebal disc or ligamentous complex, and irreversible cord damage. The mechanism for this case was a combined pattern of hyperflexion, compression, and hyperextension injuries. A review of the literature revealed that this case is the first report in the literature of a vehicle related accident causing five-level noncontiguous injuries of the cervical spine. PMID- 22931994 TI - Management of multiple type II endoleaks detected by duplex ultrasound after endovascular abdominal aneurysm repair. AB - We reported a case of multiple type II endoleaks detected by duplex ultrasound after endovascular abdominal aneurysm repair. The patient was undergoing warfarin therapy. Duplex ultrasound was applied as the sole surveillance method during follow-up and provided the concerned information for reintervention. The endoleaks were successfully repaired by coil embolization of the collaterals from the internal iliac artery feeding the fourth lumbar artery. PMID- 22931995 TI - Microsurgical denervation of the spermatic cord for treatment of idiopathic chronic orchialgia. AB - A patient referred to our hospital, diagnosed with left idiopathic chronic orchialgia, was evaluated with a thorough medical and psychiatric history, physical examination, scrotal ultrasound and magnetic resonance imaging. Conservative management failed. The patient had temporary pain relief after undergoing outpatient cord block three times. Microsurgical denervation of the left spermatic cord was operated in March, 2011. A pain questionnaire was used to determine efficacy before and after operation, and complete pain relief was noted at one week after operation. The follow up period was 12 months, at the end of which the pain score was still zero. No complications, including testicular atrophy and hydrocele, occurred. Microsurgical denervation of the spermatic cord can be a minimally invasive, safe and effective management option for treatment of idiopathic chronic orchialgia. PMID- 22931996 TI - One hemodialysis patient with headache, blurred vision, and hypotension induced by pituitary prolactinoma. AB - We reported a rare case of a dialysis patient coincident pituitary prolactinoma with calcification. A 55-year-old woman who had undergone hemodialysis for 8 years was admitted to the nephrology unit because of headache, blurred vision, and hypotension. Physical examination was normal; endocrinological examination demonstrated elevated serum levels of prolactin (> 4240 mIU/L), but other hormonal profiles, such as growth hormon, adrenocorticotropic hormone, thyroid stimulating hormone, free triiodothyronine, free thyroxine, follicle-stimulating hormone and luteinizing hormone, were absolutely or relatively lower. A cranial computed tomography (CT) suggested saddle area a high-density screenage with an anteroposterior diameter of 1.0 cm. A cerebral magnetic resonance scan confirmed the pituitary adenoma accompanied with calcification. Contrast-enhanced T1 weighted images revealed a less enhancing tumor, 14 mm wide round lesion with a high intensity signal. It enlarges the sella turcica, but the optic chiasma is not displaced. We suggest that in the differential diagnosis of any hemodialysis patient with severe headache, hypotension, and visual disturbances, this syndrome should be considered as prompt pituitary adenoma. PMID- 22931997 TI - Ocular manifestations of intracranial germinomas: three cases report and literature review. AB - Intracranial germinomas are malignant neoplasms of gonadal origin, which have some features in terms of age, sex, and clinical manifestations. They mainly occur in children and adolescents. Patients with intracranial germinomas mainly manifest with hypothalamic pituitary axis dysfunction and/or compression syndromes. Visual disturbance is one of the most significant clinical presentations, which is mainly caused by tumor cell infiltration into the optic pathway. In this article, we present three cases of patient with intracranial germinoma to analyze the ocular manifestations. All the three patients presented with endocrine symptoms in the early stage and with visual disturbances (including decreased visual acuity and visual field defects) later. In general, germinoma is diagnosed by its characteristic radiological appearance, supported by tumor markers and/or stereotactic biopsy. However, decisive diagnoses were established when ocular manifestations were presented. A suspicion for germinoma should be considered, when young patients manifest visual disturbances accompanied by endocrine symptoms. PMID- 22931998 TI - ST-elevation myocardial infarction caused by very late stent thrombosis due to drug-eluting stent fracture. PMID- 22931999 TI - A male with chronic thromboembolic pulmonary hypertension caused by isolated noncompaction of ventricular myocardium. PMID- 22932000 TI - Amelioration of symptoms and pain associated with cyclophosphamide induced cystitis and overactive bladder-emerging new therapeutic alternatives. PMID- 22932001 TI - Uveitis- a rare disease often associated with systemic diseases and infections- a systematic review of 2619 patients. AB - BACKGROUND: Uveitis is an autoimmune disease of the eye that refers to any of a number of intraocular inflammatory conditions. Because it is a rare disease, uveitis is often overlooked, and the possible associations between uveitis and extra-ocular disease manifestations are not well known. The aim of this study was to characterize uveitis in a large sample of patients and to evaluate the relationship between uveitis and systemic diseases. METHODS: The present study is a cross-sectional study of a cohort of patients with uveitis. Records from consecutive uveitis patients who were seen by the Uveitis Service in the Department of Ophthalmology at the Medical University of Vienna between 1995 and 2009 were selected from the clinical databases. The cases were classified according to the Standardization of Uveitis Nomenclature Study Group criteria for Uveitis. RESULTS: Data were available for 2619 patients, of whom 59.9% suffered from anterior, 14.8% from intermediate, 18.3% from posterior and 7.0% from panuveitis. 37.2% of all cases showed an association between uveitis and extra organ diseases; diseases with primarily arthritic manifestations were seen in 10.1% of all cases, non-infectious systemic diseases (i.e., Behcet's disease, sarcoidosis or multiple sclerosis) in 8.4% and infectious uveitis in 18.7%. 49.4% of subjects suffering from anterior uveitis tested positively for the HLA-B27 antigen. In posterior uveitis cases 29% were caused by ocular toxoplasmosis and 17.7% by multifocal choroiditis. CONCLUSION: Ophthalmologists, rheumatologists, infectiologists, neurologists and general practitioners should be familiar with the differential diagnosis of uveitis. A better interdisciplinary approach could help in tailoring of the work-up, earlier diagnosis of co-existing diseases and management of uveitis patients. PMID- 22932002 TI - Analysis of the factors motivating HCV-infected patients to accept interferon therapy. AB - BACKGROUND: The aims of this study were to analyze factors motivating the acceptance of interferon (IFN) therapy and to clarify the prevalence of oral mucosal diseases in hepatitis C virus (HCV)-infected Japanese patients treated with IFN. FINDINGS: A total of 94 HCV-infected patients who were admitted to our hospital for IFN therapy were asked questions regarding their motivation to accept IFN therapy and were investigated for the presence of oral lichen planus (OLP) before and during IFN treatment. Recommendation and encouragement from other people were the most common factors motivating the acceptance of IFN therapy (49/94, 52.13%). The other motivators were independent decision (30.85%), economic reasons (5.32%), and others. According to multivariate analysis, three factors - sex (male), retreatment after previous IFN therapy, and independent decision to accept IFN therapy - were associated with patients after curative treatment of hepatocellular carcinoma (HCC). The adjusted odds ratios for these three factors were 26.06, 14.17, and 8.72, respectively. The most common oral mucosal lesions included OLP in 11 cases (11.70%). One patient with OLP had postoperative squamous cell carcinoma of the tongue. The rate of sustained virological response (SVR) was 45.45% in cases with OLP and 54.55% in cases without OLP. There were no patients who discontinued IFN therapy because of side effects such as oral mucosal diseases. CONCLUSIONS: We should give full explanation and recommend a course of treatment for a patient to accept IFN therapy. The system to support liver disease as well as oral diseases is also necessary for patient treated for IFN therapy. PMID- 22932003 TI - Interplay between desolvation and secondary structure in mediating cosolvent and temperature induced alpha-synuclein aggregation. AB - Both increased temperature and moderate concentrations of fluorinated alcohols enhance aggregation of the Parkinson's disease-associated protein alpha-synuclein (alphaS). Here, we investigate the secondary structural rearrangements induced by heating and trifluoroethanol [TFE]. At low TFE concentrations, CD spectra feature a negative peak characteristic of disordered polypeptides near 200 nm and a slight shoulder around 220 nm suggesting some polyproline-II content. Upon heating, these peaks weaken, while a weak negative signal develops at 222 nm. At high TFE concentrations, the spectra show distinct minima at 208 and 222 nm, indicative of considerable alpha-helical structure, which diminish upon heating. We observe a crossover between the low-TFE and high-TFE behavior near 15% TFE, where we previously showed that a partially helical intermediate is populated. We postulate that the protein is well solvated by water at low TFE concentrations and by TFE at high TFE concentrations, but may become desolvated at the crossover point. We discuss the potential roles and interplay of desolvation and helical secondary structure in driving alphaS aggregation. PMID- 22932004 TI - Reference ranges for thyroid hormones in normal Italian children and adolescents and overweight adolescents. AB - BACKGROUND: As thyroid hormones are essential for normal pubertal growth and sexual development, TSH, free T3 (FT3) and free T4 (FT4) levels undergo progressive modification during childhood and puberty. AIM: To establish thyroid hormone reference ranges in pre-pubertal children, pubertal adolescents, and adults and to evaluate any differences in thyroid function between overweight and normalweight pubertal subjects. SUBJECTS AND METHODS: Chemiluminescent microparticle immunoassay was used to analyze TSH, FT3 and FT4 concentrations in serum samples from 508 children and adolescents aged 6 to 18 yr and 100 healthy adults aged 30 to 60 yr, and from 68 overweight pubertal adolescents. As data were not normally distributed, we compared them through non-parametric tests for independent samples and the reference ranges were assumed to lie between the 2.5th and 97.5th percentile. RESULTS: We found a progressive and significant reduction in TSH, FT3, and FT4 levels in the three groups with increasing age. TSH levels were significantly higher in overweight patients than in the normal weight group, but there were no significant differences for FT3 or FT4. CONCLUSIONS: This study revealed significant differences in levels of thyroid hormone between different age groups and allowed us to establish normal reference ranges for pre-pubertal children between 0.87-5.19 mIU/l for TSH, 4.75-8.59 pmol/l for FT3, and 13.09-20.61 pmol/l for FT4, and for pubertal adolescents between 0.76- 4.51 mIU/l for TSH, 4.26-8.46 pmol/l for FT3 and 10.94-19.09 pmol/l for FT4. PMID- 22932005 TI - Trends in meningococcal disease in the United States military, 1971-2010. AB - Meningococci have historically caused extensive illness among members of the United States military. Three successive meningococcal vaccine types were used from 1971 through 2010; overall disease incidence dropped by >90% during this period. During 2006-2010, disease incidence of 0.38 (cases per 100,000 person years) among members of the US military was not significantly different from the incidence of 0.26 among the age-matched US general population. Of the 26 cases in the US military, 5 were fatal, 15 were vaccine failures (e.g., illness in a person who had been vaccinated), and 9 were caused by Neisseria meningitidis serogroup Y. Incidences among 17- to 19-year-old basic trainees and among US Marines were significantly higher than among comparison military populations (p<0.05). No apparent change in epidemiology of meningococcal disease was observed after replacement of quadrivalent polysaccharide vaccine with conjugate vaccine in 2007. The data demonstrate that vaccination with meningococcal vaccine is effective. PMID- 22932006 TI - [The history and prospective of developmental-behavioral pediatrics in China]. PMID- 22932007 TI - [A longitudinal study of urban-rural growth differences among infants fed with breast milk in six economically better areas in China]. AB - OBJECTIVE: To understand the differences between urban and rural breast-fed infants' growth patterns. METHOD: In economically better regions of six provinces in China, 1147 urban and 1058 rural subjects were recruited by the project respectively, and their longitudinal weight, length, and head circumference were measured from birth to 12 months old. The monitoring frequency was 16 times in total. Analysis was conducted to compare the growth patterns between 497 of urban and 764 of rural subjects meeting the breast-fed babies definition by WHO. RESULT: During the first year after birth, urban breast-feeding boys' weight, length, head circumference increased by 7.13 kg, 26.9 cm, and 12.4 cm respectively, and 6.60 kg, 26.1 cm, and 11.9 cm for girls. The corresponding values of rural population were 6.70 kg, 25.7 cm and 12.4 cm for boys, and 6.20 kg, 25.0 cm, and 11.8 cm for girls respectively. The gaps existed in the three physical indexes between urban and rural breastfeeding babies were 110 - 480 g, 1.2 - 2.0 cm and 0.1 - 0.6 cm for boys, and 200 - 510 g, 1.3 - 1.7 cm, and 0.4 - 0.6 cm for girls. In about 50% of monitoring age points, monthly increments of urban boy's weight presented higher than rural samples, but only 17% for girl's weight, and boy/girl's length and head circumference. CONCLUSION: The urban-rural regional gaps in breast-fed infants' physical development were not optimistic and seemed to be wider in boys than in girls. There are still large room for improvement for growth of infants in rural areas. PMID- 22932008 TI - [Changes of anterior fontanel size in children aged 0 - 2 years]. AB - OBJECTIVE: To study the development of anterior fontanel(AF) in children less than 2 years of age. METHOD: The size of AF of the children under 2 years of age was measured. The criteria were: (1) All the children were singletons and term (37 weeks <= gestational age <= 40 weeks) at birth, birth weight > 2500 g. (3) Those with intracranial diseases (included trauma and asphyxia) and scalp hematoma were ruled out. (3) Healthy children (without intracranial disease, growth retardation, congenital syndrome or bone metabolic diseases such as rickets). RESULT: (1) The mean value of AF in neonates was 1.5 (0.3 - 2.5) cm, and the average of the AF at 1 month after birth was 2.2 cm, which was the largest one. The size of AF was 1.0 (0.3 - 2.0) cm at age 12 months, and 0.5 (0.3 - 0.7) cm at 24 months. (2) The percentage for the closure of the AF was 3% at 6 months, 26.5% at 12 months, and 93.0% at 24 months. (3) There were no gender differences in the size of the AF (P > 0.05). And the size of AF was not correlated with the development levels of weight, length, and head circumference (P > 0.05). CONCLUSION: (1) The size of AF at 1 month was maximum (2.2 cm), and then decreased by years. The AF was almost closed (93%) at 24 months. (2) There were no gender differences in anterior fontanel (P > 0.05). The size of AF was not correlated with the growth of weight, length, and head circumferences (P > 0.05). (3) The fontanel dimensions should be represented by oblique diameters of the fontanel in clinical pediatrics. (4) The AF closure time needs to be further evaluated in normal children. PMID- 22932009 TI - [Maternal-neonatal vitamin D status and related factors]. AB - OBJECTIVE: To determine the relationship between maternal and neonatal vitamin D status and related factors. METHOD: Serum 25-(OH)D levels were measured by ELISA in 499 pregnant women at 30 - 37 weeks gestation and in cord blood of their infants born at term (37 - 42 wk gestation) in Southeastern China at 28.9 degrees N latitude. One-way analysis of variance (ANOVA) was used to explore maternal and neonatal vitamin D levels by season. Pearson linear and linear regression of partial correlation was used to analyze the relationship between maternal and neonatal 25-(OH) D levels. The multiple factors related to maternal vitamin D status was assessed by binary logistic regression. RESULT: The levels of serum 25 (OH)D were (33.0 +/- 13.4) nmol/L in mothers and (31.0 +/- 12.5) nmol/L in their newborns. Serum 25-(OH)D < 50 nmol/L was shown in 88.8% of mothers and 91.2% of their neonates. Both maternal and neonatal 25-(OH)D levels varied with season (Ps = 0.000). Vitamin D level was the lowest in spring, with the 25-(OH)D concentration < 50 nmol/L in 98.6% of mothers and 99.3% of their neonates. The highest vitamin D level was presented in fall, but there were still 64.0% of mothers and 75.0% of neonates with 25-(OH)D < 50 nmol/L. Except for season, calcium-vitamin D supplement and intake of egg >= 600 g per week during pregnancy benefited to improve maternal vitamin D level [25-(OH)D >= 50 nmol/L] [OR = 2.3 (95%CI:1.0, 5.3), 3.4 (95%CI:1.2, 9.9) respectively]. There was a positive correlation between maternal and neonatal 25-(OH)D measures in the sample as a whole (r = 0.45, P = 0.000, N = 499), the correlation was of no statistical significance when maternal serum 25-(OH)D was <= 25 nmol/L. CONCLUSION: Hypovitaminosis D was common in late pregnant mothers and their newborns in southeastern China, especially in spring. Vitamin D supplement and intake of vitamin D-rich food were beneficial to improvement of maternal vitamin D level. There was a moderate and positive correlation between maternal and neonatal 25 (OH)D concentrations in this population. The correlation was lost when maternal serum 25-(OH)D <= 25 nmol/L. PMID- 22932010 TI - [Meta-analysis of probiotics preventing allergic diseases in infants]. AB - OBJECTIVE: To assess the preventive effect of probiotics against pediatric allergic diseases. METHOD: The authors searched all randomized controlled trials on the preventive effect of probiotics on pediatric allergic diseases from 8 databases (Pubmed, Medline, Springer link, highwire, Cochrane, Vip, Wanfang Data and CNKI) up to September 2011. Two reviewers assessed the studies to see if they meet inclusion criteria, and extracted data. Meta-analysis for the result of homogenous studies was made with RevMan 4.2 and the co-effect was pooled by using fixed-effects model of relative risk (RR) ratios. RESULT: Fifteen studies published between April 2001 and September 2011 including 3604 cases were included. All included studies were graded on randomization, allocation concealment, blinding, baseline and loss to follow-up. Meta-analysis based on included studies showed that prenatal and postnatal probiotic supplementation had preventive effect on pediatric atopic eczema by reducing the RR to 0.78 (95%CI: 0.70 - 0.88, P < 0.0001), and 3 studies in which probiotic was given only after birth, the RR was further reduced to 0.75 (95%CI: 0.66 - 0.86, P < 0.0001). Meta analysis for the effect of lactobacilus alone and combined with other bacteria showed that both decreased the RR ratios of 0.57 (95%CI: 0.44 - 0.73, P < 0.0001) and 0.79 (95%CI: 0.64 - 0.97, P = 0.02), respectively. CONCLUSION: Present evidences show that prenatal and postnatal probiotic supplementation will prevent pediatric atopic eczema, but not other allergic diseases such as sensitization, food allergy and asthma. PMID- 22932012 TI - [Intensive reading of World Allergy Organization (WAO) Diagnosis and Rationale for Action against Cow's Milk Allergy (DRACMA) guideline]. PMID- 22932011 TI - [The outline of World Allergy Organization (WAO) Diagnosis and Rationale for Action against Cow's Milk Allergy (DRACMA) guideline]. PMID- 22932013 TI - [Standardization of terminology in the field of developmental-behavioral pediatrics]. PMID- 22932014 TI - [Clinical analysis of 8 children with plastic bronchitis associated with influenza A virus (H1N1) infection]. AB - OBJECTIVE: To analyze the clinical characteristics of plastic bronchitis associated with 2009 influenza A virus (H1N1) infection. METHOD: A retrospective investigation of the clinical manifestation, bronchoscopy, and the histology of the cast, clinical course and outcome of 8 children with plastic bronchitis associated with influenza A virus (H1N1) infection during winter of 2009 and 2010 was performed. RESULT: All 8 cases were boys, the range of age was 3 to 6 years. Five cases occurred in 2009 winter, accounting for 3.3% (5/150) of hospitalized children with influenza A (H1N1) infection; 3 cases occurred in 2010 winter, accounting for 15.8% (3/19) of hospitalized children with influenza A (H1N1) infection. Two patients had an underlying chronic disease, 1 had asthma, and the other had allergic rhinitis and atopic dermatitis. All the 8 cases had fever, cough and sputum; 2 had wheezing; 5 had respiratory distress. All 8 cases were diagnosed as influenza A virus (H1N1) infection complicated with pneumonia, of whom 5 patients had atelectasis, 2 had pneumothorax, 1 had pneumomediastinum, 1 had parapneumonic effusion, 2 patients were suspected of foreign body aspiration. Seven cases were admitted to an ICU, 5 patients developed respiratory failure, and 3 patients required mechanical ventilation. Flexible bronchoscopy and bronchial lavage was performed in all cases and showed bronchial cast. Histological examination of the bronchial cast revealed a fibrinous material containing large quantity of eosinophils, neutrophils, and lymphocytes in 7 patients, fibrinous material and necrotic material without inflammatory cells in 1 patient. After the bronchial cast was removed, all patients were improved greatly, no patients died. CONCLUSION: Plastic bronchitis is a life-threatening complication associated with 2009 influenza A (H1N1) virus infection in children. In children with rapid and progressive respiratory distress with lung atelectasis or consolidation on chest radiograph, plastic bronchitis should be considered. Bronchoscopic extraction of casts should be carried out early. PMID- 22932015 TI - [Preliminary establishment of cytological examination and the normal reference values for hypertonic saline solution-induced sputum of healthy children in Guangzhou]. AB - OBJECTIVE: To establish the method of cytological examination and the normal reference values for hypertonic saline solution-induced sputum of healthy children (age range from 5 to 15 years) with physical examination in Guangzhou. METHOD: A total of 352 children, 5 to 15 years old, were enrolled from primary school and middle school in Guangzhou from January to December, 2010. All subjects completed a standardized questionnaire on the presence of respiratory, allergic symptoms and family history, the medical history and the physical examination was performed by doctors, lung function (forced expiratory volume at 1 s in predicted normal, FEV(1)%) was determined. There were 266 healthy children (137 males, 129 females) who were selected and undergone hypertonic saline solution induction of sputum, and cytological examination was performed. Hypertonic saline (5%) was nebulized and inhaled for 15 - 30 min. No expectoration within 30 min was defined as failure, and the procedure was terminated. The part of opaque and higher density sputum samples was detected by cytology. The proportion of neutrophils, lymphocytes, eosinophils, macrophages and monocytes was calculated. This study was approved by the institutional Ethics Review Committee of First Affiliated Hospital of Guangzhou Medical College. Informed consent was obtained from the legal guardians of all participants following a detailed description of the purpose and potential benefits of the study. RESULT: There were 175 subjects' induced sputum specimens (175/266, 65.8%), non-qualified sputum samples were obtained from 16 of the subjects. The proportions of median (IQR) of lymphocytes were 0.012 (0.020), 95%CI were ranged from 0.015 to 0.022; neutrophils 0.207 (0.330), 95%CI 0.266 - 0.356 macrophages 0.761 (0.327), 95%CI 0.607 - 0.699; eosinophils 0.004 (0.019), 95%CI 0.013 - 0.022. There were no significant differences in proportions of cytological findings of female or male, different age groups and second-hand smoking or not (all P > 0.05). The incidence of adverse event was 4.40% (7/159). CONCLUSION: The method and the preliminary data may be used for research, diagnosis and treatment of patients with chronic cough and airway inflammation. PMID- 22932016 TI - [Immune state in lung of BALB/c mice with ovalbumin allergy and the effects of fulvotomentoside on lungs of mice]. AB - OBJECTIVE: To investigate immune state in lung of BALB/c mice with ovalbumin (OVA) allergy and the effects of fulvotomentoside (Ful) on lungs of the mice and provide some clues for the mechanism that patients with food allergies were prone to asthma and observe the effects of the treatment with traditional Chinese medicine. METHOD: Ninety-six female BALB/c mice were randomly divided into 6 groups. Mice in group 1 and group 2 were sensitized intraperitoneally and challenged intragastrically with OVA and were exposed to phosphate buffer solution and OVA respectively by nebulized inhalation. Mice in group 3 and group 4 were treated with Ful, other processes were the same as the mice in group 1 and group 2, respectively. Mice in group 5 were not challenged intragastrically with OVA and other processes were the same as the mice in group 2. Group 6 was the control group. The number of total leukocytes and cell classification in bronchoalveolar lavage (BALF) were counted, and inflammatory characteristic of lung was scored by staining with hematoxylin and eosin. The protein expressions of transforming growth factor (TGF-beta1), interleukin-6 (IL-6), interleukin-17 (IL-17A) in lung of the mice were detected by immunohistochemical method. The activation of neutrophils in lung was assayed by the level of myeloroxidase (MPO). RESULT: There was no inflammatory cells infiltration in lung of the mice in group 1. Compared with group 6, numbers of total leukocytes and erythrocytes as well as the percentage of neutrophils and lymphocytes were increased in group 2. Inflammatory score and protein expressions of TGF-beta1 [(75 437 +/- 3 638) vs. (6 118 +/- 1 978)], IL-6 [(121 650 +/- 25 389) vs. (15 726 +/- 9 360)], IL 17A [(252 105 +/- 31 651)vs. (72 644 +/- 12 285)] in lung were increased, too. Inflammatory score and TGF-beta1 (11 054 +/- 1 468), IL-6 (50 877 +/- 11 744), IL 17A (137 864 +/- 28 986) expressions in group 5 were lower than those in group 2. Eosinophils infiltration was significant in group 5. After the treatment with Ful, TGF-beta1 expression did not change and IL-6, IL-17A expressions were decreased in lung of the mice that inhaled OVA. It was not enough for Ful to relieve the neutrophil aggregation and improve inflammatory reaction in lung. CONCLUSION: The expressions of TGF-beta1, IL-6, IL-17A in lung of the mice with OVA allergy were increased markedly after they inhaled specific antigen, which caused serious inflammation that was induced by neutrophil infiltration in lung. Ful could decrease the expressions of IL-6, IL-17A to some extent, but it was not enough to improve pathologic state in lung. PMID- 22932017 TI - [Effects of glycomacropeptide on damage to intestinal tissue and apoptosis of intestinal epithelial cells in neonatal rats with necrotizing enterocolitis]. AB - OBJECTIVE: To establish an appropriate neonatal rat model of necrotizing enterocolitis (NEC) and to investigate the protective effects of glycomacropeptide (GMP) on the gut from injury in neonatal rats with NEC. METHOD: A total of 36 neonatal SD rats were randomly divided into 3 groups: NEC model group (Group M), NEC + GMP group (Group G) and normal control group (Group N), each group had 12 rats. All the neonatal rats were fed with breast milk in the first 3 days after birth. During the second 3 days after birth, the rats of Group N were still maternal breast-fed, but the rats of Group M and Group G were separated from their mothers and lived in incubator and began to be formula fed, and were subjected to cold exposure shortly after hypoxic-reoxygenation treatment. After being fed in such means for 6 days, all the neonatal rats were placed into the incubator and fasted for 24 hours. Then all the rats were sacrificed by cervical dislocation. Intestinal tissue located at the boundary of ileum and cecum was obtained for: (1) histological examination after HE staining, (2) TUNEL detection, (3) electron microscopic observation; and the tissue homogenate was obtained for checking TNF-alpha and IL-1beta levels by ELISA and platelet activating factor (PAF) mRNA expression by quantitative fluorescence (QF)-PCR. RESULT: (1) The pathological scores of the 3 groups were 2.17 +/- 0.83 (Group M), 0.92 +/- 0.79 (Group G) and 0.17 +/- 0.39 (Group N) separately. There was significant difference between Group M and Group G (H = 8.819, P = 0.003). (2) TNF-alpha levels of 3 groups were (41.94 +/- 13.51) pg/ml (Group M), (31.69 +/- 11.68) pg/ml (Group G) and (17.42 +/- 7.18) pg/ml (Group N) separately, and TNF-alpha level in Group G was significantly lower than that of Group M (F = 3.959, P = 0.030). (3) IL-1beta levels of 3 groups were (150.33 +/- 36.41) pg/ml (Group M), (118.36 +/- 33.00) pg/ml (Group G) and (28.44 +/- 15.04) pg/ml (Group N) separately, and IL-1beta level in Group G was lower than that of Group M (F = 5.080, P = 0.013). (4) Expression levels of intestinal PAF mRNA (2(-DeltaDeltaCt) value): 3.01 +/- 0.96 (Group M), 1.56 +/- 0.29 (Group G), 1.01 +/- 0.13 (Group N), the level of Group G was significantly lower than that of Group M (F = 25.251, P = 0.000). (5)Electron microscopy: Group N showed that its cell volume was mostly occupied by the nucleus, the structure was clear, nuclear membrane existed, suggesting the normal phase of cell; Group M showed that apoptotic body existed, suggesting that the advanced stage phase of apoptosis; Group G showed that condensed chromatin marginated around the nuclear envelope, nuclear pores expanded, suggesting the early phase of apoptosis. (6) The apoptosis rate of intestinal epithelial cells by TUNEL detection: 38.79 +/- 9.79 (Group M), 29.54 +/- 7.30 (Group G), 6.37 +/- 1.96 (Group N); the apoptosis rate of intestinal epithelial cells of Group G was significantly lower than that of Group M (F = 6.888, P = 0.003). CONCLUSION: GMP has protective effects on guts of neonatal rats with NEC, which may probably work by reducing TNF-alpha, IL-1beta and PAF expression, inhibiting the apoptosis of intestinal epithelial cells and reducing intestinal tissue injury. PMID- 22932018 TI - [Clinical research of the enteral feeding of very low birth weight infants guided with a scoring system]. AB - OBJECTIVE: Along with the elevation of survival rate of very low birth weight infants (VLBWI), the enteral feeding of VLBWI has become one of the most important factors, which influence the length of stay, short and long-term prognosis. This study aimed to explore safe and effective clinical protocols of VLBWI enteral feeding. METHOD: According to different correlative degree of related factors to VLBWI enteral feeding, different scoring system was formulated for the enteral feeding and monitoring proposal of VLBWI. The safety and efficacy of the score system was evaluated. RESULT: Forty-eight VLBWIs in group A was not treated with any score system, gestational age (30.0 +/- 2.1) weeks, birth weight (1173 +/- 170) g; while 48 VLBWIs in group B were guided with the scoring system, gestational age (30.3 +/- 1.7) weeks, birth weight (1133 +/- 238) g, there was no significant difference between two groups. The incidence of newborn respiratory distress syndrome of group B was significantly higher than that of group A (P = 0.016). The time of umbilical catheterization of group B was longer than that of group A. There was no significant difference in the incidence of other complications between two groups. The beginning milk volume, milk volume on the third, seventh, fourteenth, twenty-first, twenty-eight day of group B were significantly higher than that of group A [5.6 vs. 3.5 ml/(kg.d), P = 0.008, 12.3 vs. 5.7 ml/(kg.d), P = 0.000, 29.1 vs 8.9 ml/(kg.d), P = 0.000, 62.5 vs. 44.6 ml/(kg.d), P = 0.020, 98.1 vs. 71.5 ml/(kg.d), P = 0.005, 128.0 vs. 102.4 ml/(kg.d), P = 0.011]. The time achieving full enteral feeding of group B was shorter than that of group A (26.7 vs 32.9d, P = 0.007). The incidence of necrotizing enterocolitis in group B was lower than that of group A(0/48 vs. 4/48, P = 0.041). There was no significant difference of the total amino acid dosage between two groups. The total dosage of fatty emulsion was less, and the duration of parenteral nutrition was shorter in group B than in group A (50.3 vs. 73.9 g/kg, P = 0.000, 31.5 vs. 37.8 d, P = 0.016). There was no significant difference in length of stay between two groups. VLBWI of group B began to gain weight earlier [5.0 (4.3, 6.0) vs. 5.0 (5.0, 7.0) d, P = 0.028], regained birth weight earlier (9.2 vs. 11.6 d, P = 0.001), and got more weight in the second week (178 vs. 138 g, P = 0.020). CONCLUSION: VLBWI guided with the scoring system achieved full enteral feeding faster, and shortened the duration of parenteral nutrition without increasing the incidence of necrotizing enterocolitis. PMID- 22932019 TI - [GLB1 gene mutation and clinical characteristics of a patient with mucopolysaccharidosis type IVB]. AB - OBJECTIVE: To report the results of clinical characteristics, enzyme activity determination and mutation analysis of GLB1 gene in a Chinese patient with mucopolysaccharidosis (MPS) type IVB (Morquio B disease). METHOD: A 14-year-old Chinese boy with MPS type IVB was firstly diagnosed by blood leucocytes galactosamine-6-sulfate sulfatase (GALNS) and beta-galactosidase (GLB1) determination, who was characterized by short stature, multiplex skeletal abnormalities, difficulty in walking. PCR-sequencing analysis was applied to detect the mutations in GLB1 of the patient. RESULT: The patient was characterized by dwarfism, pectus carinatum, kyphosis, normal intelligence, and no neurologic damage of spasms, linguistic capacity and so on. The patient had normal GALNS enzyme activity and very low GLB1 enzyme activity [5.03 nmol/(h.mg) vs. normal value 118 - 413 nmol/(h.mg) ] in leukocytes. A compound heterozygous missense mutations c.442C > T(p.R148C)/c.1454A > G(p.Y485C) in GLB1 gene were detected in this patient. The mutation p.Y485C is a novel variant. With the method of gene analysis of new variant, the mutation p.Y485C was considered to be a pathogenic mutation. CONCLUSION: The MPS IVB patient showed severe multiple skeletal deformities, normal intelligence, no neurologic damage and very low GLB1 enzyme activity, who carries compound heterozygous mutations p.R148C/p.Y485C. The mutation p.Y485C in GLB1 gene may be a novel pathologic mutation of MPS type IVB. PMID- 22932020 TI - [Blood glucose fluctuation and activation of oxidative stress in diabetes]. PMID- 22932021 TI - Civil society organizations: capacity to address the needs of the urban poor in Nairobi. AB - We conducted a needs assessment that describes the landscape of civil society organizations (CSOs) in three informal settlements around Nairobi, Kenya. The numbers of CSOs have rapidly increased in areas underserved by governments including poor urban neighbourhoods but little is known about CSOs capacity to meet the priority health needs of the urban poor. It is also unclear why, despite a proliferation of CSOs, residents still experience unimproved health outcomes. We collected data on core activities, financial management, and governance structures. Of the 952 CSOs assessed, 47 per cent reported HIV/AIDS counselling, prevention, and treatment as their core activity. Most CSOs reported good financial management systems and governance structures but responses were not validated. Representation in district health stakeholder fora was low; most CSOs did not have the capacity to effectively deliver services that would have impact. For CSOs to realize the desired goal to improve the well-being of low-income populations, programmes to build their management capacity are essential. PMID- 22932022 TI - The CIA's vaccination ruse. PMID- 22932023 TI - The impact of targeted subsidies for facility-based delivery on access to care and equity - evidence from a population-based study in rural Burkina Faso. AB - We conducted the first population-based impact assessment of a financing policy introduced in Burkina Faso in 2007 on women's access to delivery services. The policy offers an 80 per cent subsidy for facility-based delivery. We collected information on delivery in five repeated cross-sectional surveys carried out from 2006 to 2010 on a representative sample of 1050 households in rural Nouna Health District. Over the 5 years, the proportion of facility-based deliveries increased from 49 to 84 per cent (P<0.001). The utilization gap across socio-economic quintiles, however, remained unchanged. The amount received for all services associated with births decreased by 67 per cent (P<0.001), but women continued to pay on average 1423 CFA (?[euro]1=655 CFA), about 500 CFA more than the set tariff of 900 CFA. Our findings indicate the operational effectiveness of the policy in increasing the use of facility-based delivery services for women. The potential to reduce maternal mortality substantially has not yet been assessed by health outcome measures of neonatal and maternal mortality. PMID- 22932024 TI - Operational research and HIV policy and guidelines: lessons from a study of patients lost to follow-up from a public antiretroviral treatment program in Cameroon. AB - Can operations and implementation research guide today's unprecedented efforts to scale-up HIV/AIDS prevention, treatment, care, and support in resource-limited settings? Our study of patients with HIV/AIDS who were first seen at the Central Hospital (Yaounde, Cameroon) to begin antiretroviral therapy demonstrates the value of using operations research to explore programs, policies, and guidelines used in health care. We studied one group of patients, those lost to follow-up. Our findings confirmed the value of early treatment, systems to follow individuals, free treatment, and resources that enable operations research. We encourage health-care workers and program managers to perform operational research in their own context, and we emphasize the importance of allocating adequate human, financial, and logistic resources for this activity. Finally, we stress that the health-care workers, program managers, and researchers must work together to better inform policy and guidelines. PMID- 22932025 TI - Translating knowledge into policy: provision and use of evidence in the Tobacco Harm Prevention Law in Vietnam. AB - Vietnam is currently considering a Tobacco Harm Prevention Law and the Ministry of Health has been asked to provide supporting evidence. This analysis explores factors influencing uptake of evidence in that legislation process. The political environment reflects the government's ambivalence over how to balance health and socioeconomic issues of tobacco control in a state-owned industry. Although the growing presence of transnational tobacco companies is alarming, the role of Framework Convention on Tobacco Control in prompting government compliance with set milestones is encouraging. Evidence of effectiveness of interventions for health needs now to be complemented with socioeconomic evaluation, and strengthening of the ties between advocates and decision makers. PMID- 22932026 TI - Re: Axelsen M, Thomassen LD, Bunger C, et al. Estimating risk of pulmonary neoplastic embolism during vertebroplasty. Spine (Phila Pa 1976) 2012;37:551-6. PMID- 22932027 TI - Re: Zuo J, Joseph GB, Li X, et al. In vivo intervertebral disc characterization using magnetic resonance spectroscopy and T1[rho] imaging: association with discography and Oswestry Disability Index and Short Form-36 Health Survey. Spine (Phila Pa 1976) 2012;37:214-21. PMID- 22932028 TI - Re: Wang Z, Kim JH, Higashino K, et al. Cartilage intermediate layer protein (CILP) regulation in intervertebral discs. The effect of age, degeneration, and bone morphogenetic protein-2. Spine (Phila Pa 1976) 2012;37:E203-8. PMID- 22932030 TI - Lack of evidence for chloroquine-resistant Plasmodium falciparum malaria, Leogane, Haiti. AB - Plasmodium falciparum malaria in Haiti is considered chloroquine susceptible, although resistance transporter alleles associated with chloroquine resistance were recently detected. Among 49 patients with falciparum malaria, we found neither parasites carrying haplotypes associated with chloroquine resistance nor instances of chloroquine treatment failure. Continued vigilance to detect emergence of chloroquine resistance is needed. PMID- 22932031 TI - Leishmania (Viannia) guyanensis infection, Austria. PMID- 22932032 TI - Parasite burden and the insect immune response: interpopulation comparison. AB - The immune response affects host's survival and reproductive success. Insurmountable immune function has not evolved because it is costly and there is a trade-off between other life-history traits. In previous studies several factors such as diet and temperature have been proposed to cause interpopulation differences in immune response. Moreover, the insect immune system may be functionally more protective upon secondary exposure, thus infection history may associate with the immune response. Here we measured how geographical location and parasite burden is related to variation in immune response between populations. We included 13 populations of the Northern Damselfly Coenagrion hastulatum (Odonata: Coenagrionidae) in Finland over a latitudinal range of 880 km to this study. We found that water mites associated strongly with the immune response at interpopulation level: the more the mites, the higher the immune response. Also, in an alternative model based on AIC, latitude and individual size associated with the immune response. In turn, endoparasitic gregarines did not affect the immune response. To conclude, a positive interpopulation association between the immune response and the rate of water mite infection may indicate (i) local adaptation to chronic parasite stress, (ii) effective 'induced' immune response against parasites, or (iii) a combined effect of both of these. PMID- 22932033 TI - The ethics of authorship. PMID- 22932035 TI - The politics of women's health. PMID- 22932036 TI - The politics of women's health. PMID- 22932037 TI - Active warming study. PMID- 22932039 TI - Survivors of adolescent and young adult cancers need better care. AB - Early intervention may reduce long-term risky behaviors. PMID- 22932040 TI - Dignity-driven decision making improves advanced-illness care. AB - Collaboration revolving around patient goals and preferences drives the care plan. PMID- 22932041 TI - Canadian commission calls on nurses to be a force for change. AB - Nurses are deemed crucial to transforming Canada's health care system. PMID- 22932043 TI - A 'hospital at home' program shows good outcomes. AB - Acute care in the home setting lowered costs and improved patient satisfaction. PMID- 22932046 TI - Controlling chronic noncancer pain in an era of opioid misuse. AB - Will the new federal Risk Evaluation and Mitigation Strategy prevent abuse? Might it inhibit pain relief? PMID- 22932054 TI - Biomarkers: an important clinical assessment tool. AB - Helping clinicians to predict, diagnose, and monitor disease. PMID- 22932055 TI - Tablet technology for nurses. AB - A guided tour of uses, potential uses, and pitfalls, plus a closer look at two leading contenders. PMID- 22932056 TI - Violence prevention training for ED staff. AB - The Pennsylvania Patient Safety Reporting System is a confidential, statewide Internet reporting system to which all Pennsylvania hospitals, outpatient-surgery facilities, and birthing centers, as well as some abortion facilities, must file information on medical errors. Safety Monitor is a column from Pennsylvania's Patient Safety Authority, the authority that informs nurses on issues that can affect patient safety and presents strategies they can easily integrate into practice. For more information on the authority, visit www.patientsafetyauthority.org. For the original article discussed in this column or for other articles on patient safety, click on "Patient Safety Advisories" and then "Advisory Library" in the left-hand navigation menu. PMID- 22932057 TI - At the eye of the storm. AB - A nurse struggles with medical decision making for her ailing father. PMID- 22932058 TI - Comparative in-vivo toxicity of venoms from South Asian hump-nosed pit vipers (Viperidae: Crotalinae: Hypnale). AB - BACKGROUND: Envenoming by south Asian hump-nosed pit vipers (Genus: Hypnale) is a significant health issue in Sri Lanka and in peninsular India. Bites by these snakes frequently lead to local envenoming, coagulopathy and acute renal failure even resulting in death. Recently the genus was revised and the existence of three species viz H. hypnale, H. nepa and H. zara were recognized. There is, however, a paucity of information on the toxicity of the venoms of these species. Hence, we compared the toxic effects of the three Hypnale venoms using BALB/c mice. FINDINGS: Intraperitoneal median lethal doses (LD50) for H. hypnale, H. zara and H. nepa venoms were 1.6, 6.0 and 9.5 MUg protein/g respectively. Minimum haemorrhagic doses for venoms of H. hypnale, H. zara and H. nepa were 3.4, 11.0 and 16.6 MUg protein/mouse respectively. The minimum necrotic doses for the same venoms were 15.0, 55.1 and 68.2 MUg protein/mouse respectively. Severe congestion and petecheal haemorrhages were observed in lungs, kidneys, liver and the alimentary tract. Histopathogical examination of kidneys revealed proximal tubular cell injury and acute tubular necrosis with intact basement membrane indicating possible direct nephrotoxicity. Hypnale venoms caused pulmonary oedema, hepatocellular degeneration and necrosis, focal neuronal degeneration in brain and extramedullary haemopoiesis in spleen. H. hypnale venom caused all above histopathological alterations at lower doses compared to the other two. CONCLUSION: Hypnale venoms cause similar pathological changes with marked differences in the severity of the toxic effects in vivo. Therefore, differences in the severity of the clinical manifestations could possibly be seen among bite victims of the three Hypnale species. PMID- 22932059 TI - Benzimidazole resistance of sheep nematodes in Norway confirmed through controlled efficacy test. AB - BACKGROUND: Resistance against benzimidazoles (BZ) has recently been detected in Norwegian sheep flocks through a large scale prevalence survey based on the faecal egg count reduction test (FECRT). The use of this test in combination with bulk larval culture only gives an indication of which gastrointestinal nematodes genera that are involved and these results have to be confirmed by a controlled efficacy test (CET) to get accurate information about resistant nematodes populations at species level. A CET was therefore performed with larvae from two flocks where BZ resistance was previously detected through FECRT. RESULTS: The latter test confirmed the previous results in both flocks. In flock A, the BZ resistant nematode population consisted solely of Haemonchus contortus, whereas H. contortus and Teladorsagia circumcincta comprised the resistant worm population in flock B. CONCLUSIONS: Some discrepancies that have been recorded between FECRT and CET results regarding time for post-treatment coproscopical examination and a temporary suppression of faecal egg excretion are discussed. PMID- 22932060 TI - Experimental study of single-pin puncture asymmetrical hydroablation using a conformational radiofrequency ablation electrode in ex vivo ox liver. AB - OBJECTIVE: The aim of this study was to evaluate the feasibility of single-pin puncture asymmetrical hydroablation in liver using the multipole cluster conformable radiofrequency ablation electrode. METHODS: The conformable electrode used in this study consists of both a main electrode in a central cannula and a circle of subelectrodes comprising two groups of six subelectrodes located on opposite sides (A and B) of the circle. The two subelectrode groups can be extended to different lengths independently of one another, resulting in asymmetrical shapes. Ablation experiments were performed using ex vivo ox liver. The experiments included six groups based on six potential electrode deployments in which the subelectrodes on sides A and B were fully extended, half extended or fully retracted. After ablation, the transverse diameters of the resulting necrotic tissue from sides A and B were measured. The experiment was conducted in 12 separate sites for each group. RESULTS: When the subelectrodes were arranged symmetrically (either fully extended or half extended on both sides), the mean transverse diameter of necrotic tissue was similar for both sides A and B. When the subelectrodes were arranged asymmetrically, the fully extended side showed a significantly greater mean transverse diameter of necrotic tissue than the half extended or fully retracted side. CONCLUSION: In this study, the WHK 3-8-4 multipole cluster conformable radiofrequency ablation electrode was able to produce both symmetrical and asymmetrical necrotic tissue patterns in the liver. ADVANCES IN KNOWLEDGE: The size and shape of the ablation can be altered by both withdrawing and extending the subelectrodes to different lengths. PMID- 22932062 TI - Three-dimensional airway lumen volumetry: comparison with bronchial wall area and parenchymal densitometry in assessment of airway obstruction in pulmonary emphysema. AB - OBJECTIVES: The purpose of this study was to compare three-dimensional airway lumen volumetry with bronchial wall area and parenchymal densitometry in the assessment of airway obstruction in pulmonary emphysema. METHODS: 56 patients, who were smokers, underwent CT examination and pulmonary function tests (PFTs). For quantitative assessments, the following parameters were computationally calculated: (1) percentage of voxels -950, -960 and -970 HU in the lung (%LAA( 950), %LAA(-960) and %LAA(-970), respectively); (2) percentage of partial bronchi luminal volumes per total luminal volumes (LV(main), main and distal bronchial volume/total luminal volume; LV(lobe), lobar and distal bronchial volume/total luminal volume); and (3) mean wall area percentages of segmental bronchi of the right apical and left apicoposterior segment (WA%(seg)) and of subsegmental bronchi (WA%(sub)) in the upper lobes. These parameters were correlated with PFTs and statistically compared between a chronic obstructive pulmonary disease (COPD) group [forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC)<70] and a non-COPD group. RESULTS: FEV1, maximum mid-expiratory flow rate and forced expiratory flow at 25% vital capacity had significant correlation with LV(main) (r>0.53, p<0.0001), LV(lobe) (r>0.52, p<0.0001), WA%(seg) (|r|>0.29, p<0.05) and WA%(sub) (|r|>0.31, p<0.05). FEV1/FVC had significant correlation with all parameters (0.27<|r|<0.52, p<0.05). LV(main) and LV(lobe) and WA%(seg) and WA%(sub) were significantly different between the two groups (LV(main) and LV(lobe); p<0.0001, WA%(seg) and WA%(sub); p<0.05). CONCLUSIONS: Bronchial luminal volumetric assessment better reflected the airflow limitation parameters. ADVANCES IN KNOWLEDGE: Bronchial luminal volumetric assessment can potentially be used to gauge airflow limitation in pulmonary emphysema. PMID- 22932063 TI - Ocular health among radiologists in the age of PACS: is it time for our profession to open its eyes to this issue in light of existing European legislation? AB - The regular use of visual display units (VDUs) at work has been shown to cause the development of a constellation of symptoms ranging from dry eyes to temporary myopia. European workers who use VDUs are now protected under detailed legislation enacted by the European Union (Directive 90/270/EEC). The use of picture archiving and communications systems, which are almost ubiquitous in European countries, means that, as a profession, radiologists fall under the remit of this legislation. This paper aims to assess the impact that full implementation of this law would have on a radiologist's practice and to more broadly examine the issue of eye care as an occupational health issue in radiology. The authors conclude that eye care in the setting of regular VDU use among radiologists is an important quality control and occupational health issue. There is a clear legal basis requiring employers to provide regular eye examinations and reporting breaks. In the absence of leadership from employers on this issue individual radiologists have a responsibility to ensure that their work practices reflect the legal situation and minimise the effect of eye strain on their performance. PMID- 22932061 TI - Pulmonary arterial hypertension: an imaging review comparing MR pulmonary angiography and perfusion with multidetector CT angiography. AB - Pulmonary hypertension (PH) is a progressive disease that leads to substantial morbidity and eventual death. Pulmonary multidetector CT angiography (MDCTA), pulmonary MR angiography (MRA) and MR-derived pulmonary perfusion (MRPP) imaging are non-invasive imaging techniques for the differential diagnosis of PH. MDCTA is considered the gold standard for the diagnosis of pulmonary embolism, one of the most common causes of PH. MRA and MRPP are promising techniques that do not require the use of ionising radiation or iodinated contrast material, and can be useful for patients for whom such material cannot be used. This review compares the imaging aspects of pulmonary MRA and 64-row MDCTA in patients with chronic thromboembolic or idiopathic PH. PMID- 22932064 TI - Application of prospective ECG-triggered dual-source CT coronary angiography for infants and children with coronary artery aneurysms due to Kawasaki disease. AB - OBJECTIVES: The aim of this study was to prospectively evaluate the initial application and value of prospective electrocardiogram (ECG)-triggered dual source CT coronary angiography (DSCTCA) in the diagnosis of infants and children with coronary artery aneurysms due to Kawasaki disease. METHODS: 19 children [12 males; mean age 13.47 months, range 3 months to 5 years; mean heart rate 112 beats per minute (bpm), range 83-141 bpm] underwent prospective ECG-triggered DSCTCA with free breathing. Subjective image quality was assessed on a five-point scale (1, excellent; 5, non-diagnostic) by two blinded observers. The location, number and size of each aneurysm were observed and compared with those of transthoracic echocardiography (TTE) performed within 1 week. Interobserver agreement concerning the subjective image quality was evaluated with Cohen's kappa-test. Bland-Altman analysis was used to evaluate the agreement on measurements (diameter and length of aneurysms) between DSCTCA and TTE. The average effective dose required for DSCTCA was calculated for all children. RESULTS: All interobserver agreement for subjective image quality assessment was excellent (kappa=0.87). The mean +/- standard deviation (SD) aneurysm diameter with DSCTCA was 0.76 +/- 0.36 cm and with TTE was 0.76 +/- 0.39 cm. The mean +/- SD aneurysm length with DSCTCA was 2.06 +/- 1.35 cm and with TTE was 2.00 +/- 1.22 cm. The Bland-Altman plot for agreement between DSCTCA and TTE measurements showed good agreement. The mean effective dose was 0.36 +/- 0.06 mSv. CONCLUSION: As an alternative diagnostic modality, prospective ECG-triggered DSCTCA with excellent image quality and low radiation exposure has been proved useful for diagnosing infants and children with coronary artery aneurysms due to Kawasaki disease. ADVANCES IN KNOWLEDGE: Prospective ECG-triggered DSCTCA for infants and children allows rapid, accurate assessment of coronary aneurysms due to Kawasaki diseases, compared with TTE. PMID- 22932065 TI - Who's the doctor? Patients' perceptions of the role of the breast radiologist: a lesson for all radiologists. AB - OBJECTIVE: The aim of this study was to explore patients' perceptions of the role of the radiologist in their care. METHODS: The questionnaire used was designed in conjunction with a psychologist who had an interest in oncology, and piloted. The final questionnaires were distributed to patients attending the breast clinic at St James's Hospital, Dublin, Ireland, from 1 March to 1 July 2011. Patients requiring imaging (mammography and/or ultrasound) were asked to complete the same questionnaire again after imaging procedures were performed. Paired t-tests were used to assess for changes in parameters, including ranking of members of the breast care team in order of perceived importance and levels of anxiety pre and post consultation with the radiologist. RESULTS: 306 patients were recruited. 76% of patients thought that radiologists were radiographers and only 14% knew that radiologists were medical doctors. Nearly 40% of patients did not consider that radiologists had a role to play in their care. There was no statistically significant difference in the ranking of team members pre and post consultation. There was a significant improvement in patient anxiety levels after consultation with the breast radiologist, which is likely to be due to the patient learning the outcome of tests performed. CONCLUSION: There is a lack of awareness amongst patients and amongst our colleagues in paramedical disciplines regarding the roles and responsibilities of the modern radiologist. ADVANCES IN KNOWLEDGE: Radiology must act to increase public awareness so that future changes in the health service will reflect the scope and importance of the speciality. PMID- 22932066 TI - Different signal transduction pathways elicited by basic fibroblast growth factor and interleukin 1beta regulate CREB phosphorylation in Sertoli cells. AB - BACKGROUND AND AIM: Basic fibroblast growth factor (bFGF) and interleukin 1beta (IL1beta) belong to the set of intratesticular regulators that provide for the fine-tuning of processes implicated in the maintenance of spermatogenesis. The aim of this study was to investigate if bFGF and IL1beta activate CREB, what signaling pathways may be participating and the possible relationship between CREB activation and the regulation of Sertoli cell function. METHODS: Twenty-day old rat Sertoli cell cultures were used. RESULTS: Cultures stimulated with bFGF and IL1beta produced a time-dependent increment in phosphorylated CREB levels that reached maximal values in 5- and 15-minute incubations respectively. MEK inhibitors--PD98059 and U0126--blocked the effect of bFGF on phosphorylated CREB while a p38-MAPK inhibitor--SB203580--blocked the effect of IL1beta on phosphorylated CREB. A possible correlation between CREB regulation and two Sertoli cell-differentiated functions, Ldh A and transferrin expression, was explored. PD98059 blocked the ability of bFGF to stimulate Ldh A expression and SB203580 blocked the ability of IL1beta to stimulate Ldh A expression and LDH activity. Concerning transferrin, PD98059 and U0126 were able to inhibit the ability of bFGF to stimulate its secre tion. On the contrary, SB203580 was unable to block IL1beta induced increase in transferrin secretion suggesting that the p38-MAPK pathway does not participate in the mechanism of action of the cytokine to regulate transferrin. CONCLUSIONS: The results presented herein suggest that CREB is stimulated in response to bFGF and IL1beta through p42/p44-MAPK and p38 MAPK pathways and that this transcription factor may be partially responsible for the regulation of Sertoli cell function. PMID- 22932067 TI - Telestroke: rapid treatment of acute ischemic stroke patients using telemedicine in a Singapore emergency department. AB - STUDY OBJECTIVE: In recent years, telemedicine technology has allowed hospitals without an in-house neurology service access to 24-h neurology consultation from specialized centers, thus paving the way for these hospitals to offer thrombolysis treatment for stroke patients. This article will describe the experience of the study hospital's emergency department (ED) in its use of telemedicine technology to facilitate the rapid treatment of acute ischemic stroke patients. METHODS: The ED records, in-patient records, and paramedic records of all patients who presented to the study hospital's ED and received thrombolytic treatment for ischemic strokes were retrospectively reviewed. RESULTS: From 25 October 2010 to 25 May 2011, using the telemedicine system, a total of 18 patients received thrombolytic treatment for acute ischemic strokes. The overall mean door to needle time was 92.7 min (95% CI 80.0 to 105.5), median 86.0 min. The mean onset of symptoms to needle (OTN) time was 154.9 min (95% CI 136.7 to 173.2), median 148 min. Factors such as presentation during office hours, brought in by ambulances as standby cases, and direct management by senior doctors were associated with shorter door to needle times. CONCLUSION: Telemedicine is an invaluable tool that enables hospitals without 24-h onsite neurology service to offer emergency thrombolysis to eligible stroke patients, who otherwise will not be able to benefit from this therapy. PMID- 22932068 TI - Selective deletion of leptin receptors in adult hippocampus induces depression related behaviours. AB - Previous studies have demonstrated that leptin and its receptors (LepRb) in the central nervous system play an important role in regulating depression- and anxiety-related behaviours. However, the physiological functions of LepRb in specific brain regions for mediating different emotional behaviours remain to be defined. In this study, we examined the behavioural effects of LepRb ablation in the adult hippocampus using a series of behavioural paradigms for assessing depression- and anxiety-related behaviours. Targeted deletion of LepRb was achieved using the Cre/loxP site-specific recombination system through bilateral stereotaxic delivery of an adeno-associated virus expressing Cre-recombinase (AAV Cre) into the dentate gyrus of adult mice homozygous for a floxed leptin receptor allele. AAV-Cre-mediated deletion of the floxed region of LepRb was detected 2 wk after injection. In accordance with this, leptin-stimulated phosphorylation of Akt was attenuated in the hippocampus of AAV-Cre injected mice. Mice injected with AAV-Cre displayed normal locomotor activity and anxiety-like behaviour, as determined in the elevated plus-maze, light-dark box and open field tests, but showed increased depression-like behaviours in the tail suspension, saccharin preference and learned helplessness tests. Taken together, these data suggest that deletion of LepRb in the adult hippocampus is sufficient to induce depression-like behaviours. Our results support the view that leptin signalling in the hippocampus may be essential for positive mood states and active coping to stress. PMID- 22932069 TI - Prevention and control of fish-borne zoonotic trematodes in fish nurseries, Vietnam. AB - Worldwide, >18 million persons were infected with fish-borne zoonotic trematodes in 2002. To evaluate the effectiveness of interventions for reducing prevalence and intensity of fish-borne zoonotic trematode infections in juvenile fish, we compared transmission rates at nurseries in the Red River Delta, northern Vietnam. Rates were significantly lower for nurseries that reduced snail populations and trematode egg contamination in ponds than for nurseries that did not. These interventions can be used in the development of programs for sustained control of zoonotic trematodes in farmed fish. PMID- 22932070 TI - Long-term effects of drug-eluting stents versus bare metal stents on patients with acute ST-elevation myocardial infarction undergoing primary percutaneous coronary intervention: outcomes of 3-year clinical follow-up. AB - BACKGROUND: The long-term safety and efficacy of drug-eluting stents (DES) versus bare metal stents (BMS) are unclear and controversial issues in patients with acute ST-elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PCI). The purpose of this study was to compare the long term outcome of STEMI patients undergoing primary PCI with DES versus BMS implantation. METHODS: A total of 191 patients with acute STEMI undergoing PCI from Jan. 2005 to Dec. 2007 were enrolled. Patients received DES (n = 83) or BMS (n = 108) implantation in the infarction related artery according to physician's discretion. The primary outcome was the occurrence of major adverse cardiac events (MACE), which was defined as a composite of death, myocardial infarction (MI), target vessel revascularization (TVR) and stent thrombosis. The difference of MACE was observed between DES and BMS groups. RESULTS: The clinical follow-up duration was 3 years ((41.7 +/- 16.1) months). MACE occurred in 20 patients during three years follow-up. Logistic regression analysis showed that the left ventricular ejection fraction (LVEF) was an independent predictor for MACE in the follow-up period (P = 0.0301). There was no significant difference in all-cause mortality (3.61% vs. 7.41%, P = 0.2647), the incidence of myocardial infarction (0 vs. 0.93%, P = 0.379) and stent thrombosis (1.20% vs. 1.85%, P = 0.727) between the DES group and BMS group. The incidence of MACE was significantly lower in the DES group compared to the BMS group (4.82% vs. 14.81%, P = 0.0253). The rate of TVR was also lower in the DES group (0 vs. 5.56%, P = 0.029). In the DES group, there was no significant difference in the incidence of MACE between sirolimus eluting stents (SES, n = 73) and paclitaxel-eluting stents (PES, n = 10) subgroups (2.74% vs. 20.00%, P > 0.05). CONCLUSIONS: This finding suggested that drug-eluting stents significantly reduced the need for revascularization in patients with acute STEMI, without increasing the incidence of death or myocardial infarction. Use of DES significantly decreased the incidence of MACE compared with BMS during the 3-year follow-up. PMID- 22932071 TI - Procedural results and 30-day clinical events analysis following Edwards transcatheter aortic valve implantation in 48 consecutive patients: initial experience. AB - BACKGROUND: Transcatheter aortic valve implantation (TAVI) is a rapidly evolving strategy for therapy of aortic stenosis. We presented the procedural results and analyzed the death causes of 30-day mortality and clinical events in patients who underwent TAVI with Edwards prosthetic valves in University Hospital of Caen, France. METHODS: The patients with severe aortic stenosis but at high surgical risk or inoperable were considered as candidates for TAVI. Forty-eight patients undergoing TAVI from July 2010 to September 2011 were enrolled in this registry. The Edwards prosthetic valves were solely used in this clinical trial. RESULTS: Overall 48 patients underwent TAVI, 28 of which accepted TAVI by trans-femoral (TF) approaches, 20 by trans-apical approaches (TA). The aortic valve area (AVA) was (0.70 +/- 0.23) cm(2), left ventricular ejection fraction (LVEF) was (57.4 +/ 17.6)%, Log EuroSCORE was (19.2 +/- 15.8)%, mean gradient was (47.0 +/- 16.6) mmHg. There were no significant differences between TF and TA groups in all these baseline parameters. Device success rate was 95.8%, and procedural success rate was 93.7% in total. Procedural mortality was 6.7% (3/48): two deaths in TA group (10%), and one death in TF group (3.6%). Forty-six Edwards valves were implanted: 10 Edwards Sapien and 36 Edwards XT. Procedure-related complications included cardiac tamponade in 2 cases (4.2%), acute myocardial infarction (AMI) in 1 case (2.1%), permanent pacemaker implantation in 1 case (2.1%), life-threatening and major bleeding in 3 cases; access site related major complication in 1 case, AKI stage 3 in 3 cases (6.3%), minor stroke in 1 case (2.1%). Thirty-day survival rate was 89.6%. There were 5 deaths in total (10.4%): 4 in TA group (20%) and 1 in TF group (3.6%). CONCLUSION: The procedural success rate and 30-day mortality were acceptable in these high risk patients with Edwards prosthetic valves in the first 48 TAVI. PMID- 22932072 TI - Proteome analysis and tissue array for profiling protein markers associated with type B thymoma subclassification. AB - BACKGROUND: The prognostic relevance of World Health Organization (WHO) subtypes within type B thymomas is still controversial. Understanding of the molecular characteristics of the different histologic types of thymomas will provide meaningful information for diagnosis and therapeutic management in type B thymoma. METHODS: Proteins extracted from twelve type B thymoma tissue specimens (six type B1 and six type B2) were analyzed by two-dimensional electrophoresis (2 DE) coupled with MALDI-TOF-MS. Differentially expressed proteins were then assayed in sixty-nine type B thymoma tissues (including B1, B2 and B3) by tissue array analysis with immunohistochemistry staining. The relationship of their expression with clinicopathological parameters, such as tumor stage or WHO classification, was estimated by Spearman's Rank Correlation Test. RESULTS: Sixteen differentially expressed proteins between type B1 and B2 thymoma tissues were identified. The differential levels of ezrin and glutathione S-transferase pi (GSTP1) were validated using immunohistochemistry staining. A statistically significant difference was observed in the positive rate of ezrin expression between type B1 thymoma and type B3 thymoma (Z = -2.963, P < 0.01). Ezrin showed a tendency to be expressed in higher classification tumors from type B1 to B3. A statistical analysis demonstrated that type B2 and B3 tumors had significantly higher positive expression of GSTP1 than the B1 group (type B2 vs. B1: Z = 2.582, P = 0.01; type B3 vs. B1: Z = -4.012, P <= 0.001). The results also showed a strong correlation between GSTP1 and WHO type staging of B1 to B3 tumors (Spearman's correlation coefficient: 0.633, P <= 0.001). Statistical analysis showed that there was close correlation between GSTP1 and ezrin expression with the clinical stage (Spearman's correlation coefficients, ezrin: 0.481, P < 0.05; GSTP1: 0.484, P < 0.01). CONCLUSIONS: Differentially expressed proteins between type B1 and B2 thymoma tissues were analyzed by comparative proteomic analysis. The techniques of proteomic analysis and tissue array provide a potential tool for screening of key molecules in type B thymoma histological sub classifications. The statistical analysis of ezrin and GSTP1 expression by immunohistochemistry, especially GSTP1, may be a useful approach for type B thymoma classification. PMID- 22932073 TI - Health-related attitudes and risk factors for sexually transmitted infections of Chinese women who have sex with women. AB - BACKGROUND: Previous studies have shown evidence of health-related risk behaviors among women who have sex with women (WSW), such as sex with men, multiple bisexual partners, and drug use. Women who have sex with women have also been known to avoid routine physical examinations and conceal their same-sex history from physicians, which can affect their ability to receive an accurate diagnosis and treatment. No previous research has targeted women who have sex with women in China. We sought to describe women who have sex with women in China and explore risk factors for their reproductive tract infections (RTI)/sexually transmitted infections (STI). METHODS: Participants were recruited through outreach in venues and online for a cross-sectional study. Data were collected using interviews and laboratory tests. RESULTS: We recruited 224 women who have sex with women. In the year preceding their participation in the study, 92% (206/224) of women reported sexual relations with women. The RTI rates were: gonorrhea (15.8%), chlamydia (3.5%), syphilis (0.5%), bacterial vaginosis (14.4%), hepatitis B virus (HBV) (0.9%), hepatitis C virus (HCV) (0.5%), and candidiasis (6.9%). No HIV or herpes simplex virus (HSV) positive cases were detected. Factors associated with gonorrhea infection were non-Beijing local residency (odds ratio (OR) = 2.1, 95% confidence interval (CI): 1.2 - 3.8) and genital-genital contact (OR = 3.1, 95%CI: 1.3 - 7.2); factors associated with curable STI (excluding bacterial vaginosis, candidiasis, HBV and HCV) were non-Beijing local residency (OR = 1.9; 95%CI: 1.2 - 3.0) and bleeding during or after sex (OR = 18.1; 95%CI: 5.2 - 62.6); and the factor associated with RTI (including all the infections tested) was bleeding during or after sex (OR = 37.8, 95%CI: 11.2 - 127.4). CONCLUSIONS: Behaviors that may cause RTI/STI exist among Chinese women who have sex with women. Researchers should consider these behaviors when planning corresponding prevention and interventions. PMID- 22932074 TI - Acute responses to inhalation of Iloprost in patients with pulmonary hypertension. AB - BACKGROUND: Iloprost has been used to test acute pulmonary vasoreactivity in idiopathic pulmonary arterial hypertension (PAH). We aimed to investigate the acute hemodynamic and oxygenation responses and tolerability to 20 ug aerosolized Iloprost in Chinese patients with pulmonary hypertension. METHODS: Between March 2005 and May 2010, 212 pulmonary hypertension patients inhaled a single dose of 20 ug Iloprost over 10 - 15 minutes for vasoreactivity testing. The acute hemodynamic and oxygenation responses and adverse events were recorded. RESULTS: Iloprost decreased total pulmonary resistance ((1747 +/- 918) dyn*s*cm(-5) vs. (1581 +/- 937) dyn*s*cm(-5), P < 0.001), increased stroke volume ((45.0 +/- 22.1) ml vs. (47.0 +/- 24.2) ml, P = 0.002), and cardiac output ((3.7 +/- 1.7) L/ml vs. (3.9 +/- 1.9) L/min, P = 0.009). Heart rate and systemic vascular resistance remained stable during inhalation. However, systemic arterial blood oxygen saturation fell slightly ((91.0 +/- 6.8)% vs. (90.3 +/- 6.7)%, P = 0.002). Pulmonary and systemic arterial blood pressures declined within 1 - 3 minutes after inhalation initiation and reached their lowest levels within 10 - 15 minutes. Idiopathic PAH responded more favorably than pulmonary hypertension due to other causes (P L0.001) and patients with less severe pulmonary hypertension have better responses to Iloprost. No adverse events requiring medical care or leading to termination of inhalation occurred. CONCLUSIONS: Inhalation of 20 ug Iloprost showed potent and selective pulmonary hemodynamic effects and was well tolerated in the Chinese pulmonary hypertension patients. Patients with idiopathic PAH and less severe pulmonary hypertension responded more favorably to inhalation of Iloprost. PMID- 22932075 TI - Long-term results and radiographic findings of percutanous vertebroplasties with polymethylmethacrylate for vertebral osteoporotic fractures. AB - BACKGROUND: Percutaneous vertebroplasty (PVP) has become a popular procedure for painful vertebral osteoporotic fracture (VOF), with immediate pain relief and improved mobility; however, polymethylmethacrylate (PMMA) injected into the vertebral body is not absorbable and little information is available concerning the long-term results. In this retrospective study, we evaluated the long-term clinical results and radiological changes after PVPs for VOFs. METHODS: Fifty-one patients with VOFs were treated by PVPs with PMMA between 2000 and 2004. After > 7 years of follow-up, eight patients had died from causes unrelated to the intervention and 12 patients were lost to follow-up, thus leaving 31 patients available for evaluation with an average length of follow-up of 9.2 years (follow up rate, 72.1%). Among these 31 patients, the PMMA was injected at 43 levels with a mean volume of 4.3 ml per level (range, 2 - 6 ml). The pain was assessed with a visual analog scale (VAS), and the mobility was graded as walking without difficulty (grade 1), walking with assistance (grade 2), and bedridden (grade 3). Plain radiographs and computed tomography (CT) were obtained and assessed pre operatively, immediately post-operatively, and after 7 years of follow-up. The PMMA, vertebral height, and Cobb angle were assessed and compared. RESULTS: All of the patients experienced pain relief and improved mobility after intervention and during the follow-up period. Cement leakage was detected in post-operative CT scans in 9 of 51 patients, but without neurological compromise. For the 31 patients followed up over 7 years, the VAS decreased from 8.3 +/- 2.6 pre operatively, to 2.1 +/- 1.6 immediately post-operatively, and 1.0 +/- 0.9 at the final follow-up evaluation, with significantly improved mobility. Additional compression fractures occurred at adjacent levels in three patients, and there were no new fractures at the augmented vertebrae. Based on a review of the radiographs, neither loose nor displaced cement was detected. The changes in vertebral height and Cobb angle were not significant. On CT scans, the cement closely contacted or infiltrated the trabecular bone. The boundary between the cement and trabecular bone was indistinct and there was no evident radiolucent gap between the cement and trabecular bone. CONCLUSIONS: At an average follow-up of 9.2 years, PVPs provided sustained pain relief and improved mobility in patients with VOFs. The PMMA injected into the vertebral body combined closely with the host trabecular bone without adverse reactions. PMID- 22932076 TI - Modified super-long down-regulation protocol improves fertilization and pregnancy in patients with poor ovarian responses. AB - BACKGROUND: The successful end-point of in vitro fertilization (IVF) treatment is for a woman to give live birth. This outcome is based on various factors including adequate number of retrieved eggs. Failure to recruit adequate follicles, from which the eggs are retrieved, is called a "poor response". How to improve the clinical pregnancy rates of poor responders was one of the tough problems for IVF. METHODS: The study involved 51 patients who responded poorly to high dose gonadotropin treatment in their previous cycles at our reproductive center, between April 2010 and February 2012. The previous cycle (group A) received routine long protocol; the subsequent cycle (group B) received modified super-long down-regulation protocol. The primary outcome of the study was the number of oocytes fertilized. The increase in the pregnancy rate was the secondary outcome. Differences between the groups were assessed by using Student's t test and c(2) test where appropriate. RESULTS: The patients' average age was (36.64 +/- 3.85) years. The mean duration of ovarian stimulation cycles of the group A patients was longer than those of the group B patients. The total dose of follicle-stimulating hormone (FSH) was significantly lower in the subsequent cycle. The peak value of serum estradiol on human chorionic gonadotrophin (hCG) day was lower in group A as compared with group B. The number of metaphase II oocytes recovered was significantly higher in group B. The cleavage rate in group A was significantly lower than in group B, 49 patients in group B reached embryo transfer stage, while 46 patients in group A reached this stage. Patients in group B received significantly more embryos per transfer as compared with group A. More pregnancies and more clinical pregnancies with fetal heart activity were achieved in group B. CONCLUSIONS: This comparative trial shows that poor responder women undergoing repeated assisted reproduction treatment using modified super-long down-regulation protocol achieve more oocytes, leading to higher fertilization rate, compared to women receiving routine long protocol. Our study also showed that clinical pregnancy rate was significantly improved. PMID- 22932077 TI - Loss of membranous carcinoembryonic antigen-related cell adhesion molecule 1 expression is related to decreased relapse-free survival of hepatocellular carcinoma following liver transplantation. AB - BACKGROUND: Loss of carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) expression is an adverse prognostic factor in hepatocellular carcinoma (HCC). The purpose of this study was to investigate the expression of CEACAM1 and its effect on relapse-free survival (RFS) following liver transplantation (LT) for HCC. METHODS: Expression of CEACAM1 was immunohistochemically detected in HCC specimens from 48 patients. The relationship between CEACAM1 expression and clinicopathologic variables, as well as tumor recurrence, was further analyzed. RESULTS: Of the 48 HCC specimens, membranous CEACAM1 expression was detected in 25 specimens and cytoplasmic CEACAM1 expression was detected in 19 specimens. Four specimens had loss of CEACAM1 expression. Loss of membranous CEACAM1 expression was significantly associated with tumor size, tumor number, and serum alpha-fetoprotein levels (all P < 0.05). Patients with loss of membranous CEACAM1 had significantly poorer RFS than patients with membranous expression, determined via Kaplan-Meier analysis (P = 0.027). Multivariate analysis revealed that loss of membranous CEACAM1 expression might be an independent prognostic factor of RFS for HCC patients after liver transplantation (P = 0.037). CONCLUSION: Loss of membranous CEACAM1 expression in HCC was closely associated with aggressive tumor biology and might be a relapsing biomarker of HCC treated with LT. PMID- 22932078 TI - Beneficial effects of continual jejunal interposition after subtotal gastrectomy. AB - BACKGROUND: The ideal post-gastrectomy reconstruction procedure should maintain the normal digestive function and restore intestinal transit to improve the patient quality of life. The aim of this study was to evaluate the effects of integral continual jejunal interposition after subtotal gastrectomy on the nutritional status, glucose levels, and gastric-intestinal motility. METHODS: The study investigated the effects of the integral continual jejunal interposition, the Billroth I and Billroth II operations, and the isolated jejunal interposition following subtotal distal gastrectomy on the blood glucose, insulin, routine blood parameters, liver function, and myoelectrical activity in Beagle dogs. RESULTS: The weights of the dogs decreased during the first post-operative weeks. Dogs in the integral continual jejunal interposition, Billroth I, and Billroth II groups gained significantly more weight by 8 weeks. The prognosis nutrition index of the dogs decreased in the first 2 post-operative weeks and increased significantly by 4 weeks in the integral continual jejunal interposition and Billroth I groups. The group with duodenal exclusion (Billroth II) had significantly higher glucose levels compared to the normal control group. The insulin curve was much higher in dogs that underwent the Billroth I, continual jejunal interposition, and isolated jejunal interposition than the Billroth II and normal groups. The frequencies of fasting and postprandial jejunal pacesetter potentials (PPs) were greater in the continual jejunal interposition and Billroth I groups than that in the isolated jejunal interposition and Billroth II groups. The percentage of aboral propagation of PPs was greater in the continual jejunal interposition group than the Billroth I, isolated jejunal interposition, and Billroth II groups. CONCLUSION: Continual jejunal interposition after subtotal gastrectomy avoids jejunal transection, maintains the duodenal passage and food storage bags, and reduces the influence of blood glucose and insulin. PMID- 22932079 TI - Clinical characteristics and prognosis of heart failure with normal left ventricular ejection fraction in elderly patients. AB - BACKGROUND: The term heart failure with normal ejection fraction (HFNEF) is often used to describe the syndrome of heart failure with normal ejection fraction. Based on the previous studies, HFNEF has a significant morbidity and mortality and is associated with a similar prognosis to heart failure with reduced ejection fraction (HFREF). The present study aimed to investigate the clinical characteristics and prognosis of HFNEF in elderly patients. METHODS: Consecutive elderly patients (>= 60 years old) hospitalized for the first episode of heart failure (HF) in Beijing Hospital from January 2003 to December 2009 were retrospectively recruited. Three hundred and ten patients with HF were eligible for our study. As recently recommended, a cut-off value of 50% was used to distinguish HFNEF (LVEF >= 50%) from HFREF (LVEF < 50%). Data were retrospectively obtained from hospital records and databases. Follow-up data were obtained by telephone and from hospital records. For every eligible patient, the clinical characteristics and prognosis were collected and compared between the HFNEF and HFREF groups. RESULTS: Patients with HFNEF accounted for 54.5% of all cases of elderly patients with HF. Compared with HFREF, the elderly patients with HFNEF had a higher proportion of females (62.1% vs. 32.6%, P < 0.001), higher body mass index (BMI) ((24.9 +/- 4.7) vs. (23.5 +/- 4.0) kg/m(2), P = 0.011), higher systolic blood pressure at admission ((141.5 +/- 22.6) vs. (134.3 +/- 18.6) mmHg, P = 0.002), but lower hemoglobin levels ((118.3 +/- 22.7) vs. (125.8 +/- 23.8) g/L, P = 0.005). The incidence of coronary heart disease (43.2% vs. 65.2%, P < 0.001) and myocardial infarction (16.6% vs. 46.1%, P < 0.001) were significantly lower in elderly patients with HFNEF than in those with HFREF (P < 0.001). With a mean follow-up of 33.5 (0.5 - 93) months, 120 patients (38.7%) died, including 94 (30.3%) cardiac deaths. The HFNEF group had fewer deaths than the HFREF group at the end of the first follow-up (46/169 (27.2%) vs. 58/141 (41.1%)) and at the end of the second follow-up (56/169 (33.1%) vs. 64/141 (45.4%)). Kaplan-Meier survival analysis showed a significantly higher survival rate in elderly patients with HFNEF than those with HFREF (P = 0.021 for total mortality and P < 0.001 for cardiac mortality). Multiple Logistic regression analysis showed that LVEF < 50% was an independent risk factor for death in elderly patients with HF. CONCLUSIONS: More than half of elderly patients with HF have a normal LVEF. The prognosis of the elderly patients with HFNEF is poor, though slightly better than the elderly patients with HFREF. PMID- 22932080 TI - Comparative study of optic disc measurement by Copernicus optical coherence tomography and Heidelberg retinal tomography. AB - BACKGROUND: Copernicus optical coherence tomography (SOCT) is a new, ultra high speed and high-resolution instrument available for clinical evaluation of optic nerve. The purpose of the study was to compare the agreements between SOCT and Heidelberg retinal tomography (HRT). METHODS: A total of 44 healthy normal volunteers were recruited in this study. One eye in each subject was selected randomly. Agreement between SOCT and HRT-3 in measuring optic disc area was assessed using Bland-Altman plots. Relationships between measurements of optic nerve head parameter obtained by SOCT and HRT-3 were assessed by Pearson correlation. RESULTS: There was no significant difference in the average cup area (0.306 vs. 0.355 mm, P = 0.766), cup volume (0.158 vs. 0.130 mm, P = 0.106) and cup/disc ration (0.394 vs. 0.349 mm, P = 0.576) measured by the two instruments. However, other optic disc parameters from SOCT were significantly lower compared with HRT-3. The Bland-Altman plot revealed good agreement of cup area and cup volume measured by SOCT and HRT-3. Bad agreement of disc area, rim area, rim volume and cup/disc ratio were found between SOCT and HRT-3. The highest correlations between the two instruments were observed for cup area (r(2) = 0.783, P = 0.000) and cup/disc ratio (r(2) = 0.669, P = 0.000), whereas the lowest correlation was observed for disc area (r(2) = 0.100, P = 0.037), rim area (r(2) = 0.275, P = 0.000), cup volume (r(2) = 0.005, P = 0.391) and rim volume (r(2) = 0.021, P = 0.346). CONCLUSIONS: There were poor agreements between SOCT and HRT-3 for measurement of optic nerve parameters except cup area and cup volume. Measurement results of the two instruments are not interchangeable. PMID- 22932081 TI - Comparison of initial efficacy between single and dual growing rods in treatment of early onset scoliosis. AB - BACKGROUND: Initial results for the use of single and dual growing rod techniques in the treatment of early onset scoliosis (EOS) has been seldom documented. The aim of this research was to investigate the initial efficacy of single and dual growing rods in treatment of EOS. METHODS: A retrospective study of 25 early onset scoliosis cases treated with growing rod technique between November 2002 and May 2010 was performed, including six cases in the single growing rod group and 19 cases in the dual growing rod group. Operation time, intra-operative bleeding, correction rate, changes in C7-S1 distance, and incidence of complications of the first operation were compared for the two techniques. RESULTS: The average post-operative follow-up duration was 31.9 months. There was no statistical difference observed between operation time, intra-operative bleeding, and complication incidence between the single and dual growing rod groups. In addition, no statistical difference was observed in the pre-operative coronal Cobb's angle (P > 0.05), or in the pre-operative sagittal Cobb's angle between both groups (P > 0.05). The correction rate of the dual growing rod group was significantly superior to that of the single growing rod group in the coronal plane (P < 0.01), but not in the sagittal plane (P > 0.05). The C7-S1 distance in the dual growing rod group was significantly larger than that in the single growing rod group (P < 0.05). CONCLUSIONS: The growing rod technique is an effective option for surgical treatment of EOS. The dual growing rod technique shows relative superiority in the correction outcome as compared to the single growing rod technique. PMID- 22932082 TI - Pulmonary embolism excluded acute coronary syndrome by coronarography: a retrospective analysis. AB - BACKGROUND: Pulmonary embolism (PE) is often mistaken as acute coronary syndromes (ACS) because of the considerable overlap in their clinical features. We evaluated the factors causing misdiagnosis of PE as ACS and factors that differentiate PE from ACS to improve the diagnosis efficacy of PE. METHODS: The medical records of 22 consecutive PE patients, between 2001 and 2010, who were initially suspected of ACS were retrieved. ACS was ruled out by coronary artery angiography before a definite diagnosis of PE was given. Twenty-two contemporary cases of ACS matched by age and sex were recruited as controls. Clinical manifestations, electrocardiograms (ECG), and biomarkers of these patients were reviewed retrospectively. The factors causing misdiagnosis of PE as ACS and factors differentiating PE from ACS were evaluated. RESULTS: We found two leading causes of misdiagnosis of PE as ACS. One is that PE can resemble ACS in several clinical aspects (symptoms and signs, ECG findings, plasma cardiac troponin I, and D-dimer). The other is the insufficient recognition of PE by clinicians. Risk factors for venous thromboembolism (VTE), especially deep venous thrombosis (DVT), together with signs of PE, such as unexplained dyspnea or hypoxemia, and right ventricular pressure overload on ECGs are valuable in differentiating the two diseases. CONCLUSIONS: Differentiation between PE and ACS is sometimes challenging. Adequate awareness of the risk factors for VTE and the signs of PE are crucial in the diagnosis of PE. PMID- 22932083 TI - Toll-like receptor 9 is correlated to disease activity in Chinese systemic lupus erythematosus population. AB - BACKGROUND: Toll like receptor (TLR) 9 has been shown to play a crucial role in the pathogenesis of systemic lupus erythematosus (SLE) in animal models. Its pathogenic role in human SLE, however, was poorly elucidated. This study was performed to investigate the role of TLR9 involved in the aberrant signaling pathway and its correlation with disease activity in SLE. METHODS: mRNA level of TLR9 and interferon (IFN) regulatory factor 5 (IRF5) in peripheral blood mononuclear cells (PBMCs) were determined by real-time polymerase chain reaction (PCR). IFN-a expression was measured in the serum of the SLE patients by enzyme linked immunosorbent assay (ELISA). RESULTS: TLR9 expression was significantly higher in SLE patients than that in health controls (P = 0.011). SLE patients with positive anti-dsDNA antibody had significantly higher expression of TLR9 than that with negative anti-dsDNA antibody (P = 0.001). TLR9 expression was positively correlated with fever (P = 0.017), alopecia (P = 0.046), safety of estrogens in lupus erythematosus national assessment SLE disease activity index (SELENA-SLEDAI) score (r(s) = 0.385, P = 0.003), and the level of IRF5 (r(s) = 0.35, P = 0.027) and IFN-a (r(s) = 0.627, P = 0.001) in SLE patients. CONCLUSION: TLR9 is associated with SLE disease activity and might be involved in the IFN-a pathway of SLE. PMID- 22932084 TI - Gastro-protecting effect of gefarnate on chronic erosive gastritis with dyspeptic symptoms. AB - BACKGROUND: The role of gastro-protecting agents on symptomatic chronic gastritis is unclear. This multicenter, open, randomized trial was designed to compare the comprehensive effects of gefarnate with sucralfate on erosive gastritis with dyspeptic symptoms. METHODS: Totally 253 dyspepsia patients confirmed with erosive gastritis were enrolled from six centers in China. They randomly received either daily 300 mg gefarnate or 3 g sucralfate for six weeks. The primary endpoint was the effective rate of both treatments on endoscopic erosion at week six. RESULTS: Gefarnate showed an effective rate of 72% and 67% on endoscopic score and dyspeptic symptom release, which is statistically higher than sucralfate (40.1% and 39.3%, P < 0.001, intension-to-treat). For histological improvement, gefarnate showed both effective in decreasing mucosal chronic inflammation (57.7% vs. 24.8%, P < 0.001, intension-to-treat) and active inflammation (36.4% vs. 23.1%, P < 0.05, intension-to-treat) than the control. A significant increase of prostaglandins and decrease of myeloperoxidase in mucosa were observed in gefarnate group. Severity of erosion is non-relevant to symptoms but Helicobacter pylori (H. pylori) status does affect the outcome of therapy. CONCLUSIONS: Gefarnate demonstrates an effective outcome on the mucosal inflammation in patients with chronic erosive gastritis. Endoscopic and inflammation score should be the major indexes used in gastritis-related trials. PMID- 22932085 TI - Combination of serum inhibin B and follicle-stimulating hormone levels can not improve the diagnostic accuracy on testicular sperm extraction outcomes in Chinese non-obstructive azoospermic men. AB - BACKGROUND: It is still controversial whether the serum inhibin B level is a superior predictor of the presence of sperm in testicular sperm extraction (TESE) in azoospermic men compared with serum follicle-stimulating hormone (FSH). In this study, we evaluated the diagnostic accuracy of serum inhibin B levels as a predictor of the outcome of TESE in Chinese non-obstructive azoospermic men and compared it with the traditional marker serum FSH and testicular volumes. METHODS: Basal values of serum hormone levels, testicular volumes and histological evaluation of 305 Chinese non-obstructive azoospermic men were analyzed. The level of inhibin B was measured using a three-step enzyme-linked immunoassay before sperm extraction, and the diagnostic accuracy of prediction of the outcome of TESE was compared for different markers by the receiver operating characteristics (ROC) curve analysis. RESULTS: Testicular sperm was successfully retrieved in 137 of 305 patients (44.9%). The serum level of inhibin B, the FSH and the testicular volume were significantly different between the successful TESE group and the unsuccessful group. According to the ROC curve analysis, for inhibin B, the cut-off value for discriminating between successful and failed TESE was 28.39 pg/ml (sensitivity 83.5%, specificity 79.1%). For FSH, the best cut-off value for discriminating was 11.05 pg/ml (sensitivity 83.5%, specificity 74.5%). The area under the ROC curve of serum inhibin B was similar to that of FSH. Combining the serum inhibin B with FSH levels did not improve the predictive value for successful TESE. CONCLUSIONS: Serum inhibin B and FSH levels are correlated with spermatogenesis. However, inhibin B is not superior to FSH in predicting the presence of sperm in TESE. And the combination of them does not improve the diagnostic accuracy on TESE outcome. PMID- 22932086 TI - Changes in pathological pattern and treatment regimens based on repeat renal biopsy in lupus nephritis. AB - BACKGROUND: Relapses occur frequently in patients with lupus nephritis. Renal biopsy is the gold standard for assessing renal activity and hence guiding the treatment. Whether repeat renal biopsy is helpful during flares of lupus nephritis remains inconclusive. In the present study, we retrospectively reviewed the patients with lupus nephritis who had more than one renal biopsy with the hope to find the clinical value of repeat biopsy. METHODS: Patients who had a diagnosis of lupus nephritis and two or more renal biopsies were selected from the database of the patient pathology registration at this renal division. Renal biopsy was evaluated according to the International Society of Nephrology/Renal Pathology Society (ISN/RPS) classification of lupus nephritis. The pathological patterns and treatment regimens were analyzed after a repeat biopsy. RESULTS: We identified 44 systemic lupus erythematosus patients with serial renal biopsies. In total, there were 94 renal biopsies. Overall, the pathological transition occurred in 64% instances according to the ISN/RPS class. When the transition was analyzed according to proliferative, membranous or mix lesions, it showed different profile: 35% in patients with proliferative lesion, 23.5% patients with mix lesions, 100% in patients with pure membranous lesion. The pathological transition could not be predicted by any clinical characteristics. After the repeat renal biopsy, 34% of patients had a change in their treatment regimens. CONCLUSIONS: The pathological conversion was very prevalent in patients with lupus nephritis. However, the transitions became less prevalent when they were analyzed according to pure membranous, proliferative, and mix lesion. Repeat biopsy might be helpful to avoid unnecessary increased immunosuppression therapy. PMID- 22932087 TI - Expression of Ki-67, galectin-3, fragile histidine triad, and parafibromin in malignant and benign parathyroid tumors. AB - BACKGROUND: It is widely recognized that the diagnosis of parathyroid carcinoma (PC) is often difficult because of the overlap of characteristics between malignant and benign parathyroid tumors, especially at an early stage. Our study aimed to investigate the differential expression of Ki-67, galectin-3, fragile histidine triad (FHIT) gene, and parafibromin in PC, parathyroid adenoma (PA), parathyroid hyperplasia (PH), and normal parathyroid (NP) tissues; then to assess these expression values for use in differential diagnosis of malignant and benign parathyroid tumors. METHODS: Data of 15 cases with PC, 19 PAs, and 8 PHs were retrospectively analyzed for their clinical characteristics. The expression of Ki 67, galectin-3, FHIT, and parafibromin were detected via immunohistochemistry in the above-mentioned specimens and 6 NPs as control. RESULTS: Complete loss of parafibromin expression was seen in 9 of 15 (60%) carcinomas, and all normal parathyroid tissues and parathyroid benign tumors stained positive for parafibromin except for one (4%) adenoma. Galectin-3 staining was positive in 11 of 15 (73%) carcinomas, 5 of 19 (26%) adenomas, 1 of 8 (12%) hyperplasias, and 0 of 6 normal tissues. The Ki-67 proliferative index was high in 4 of 15 (27%) carcinomas, 1 of 19 (5%) adenomas, and none of the hyperplasia or normal tissues. FHIT expression did not differ appreciably among the tumor types. The combination of overexpression of galectin-3 or loss of parafibromin increased sensitivity for PC to 87%, while the specificity of both positive galectin-3 and positive Ki-67 could reach 100%. CONCLUSIONS: These data suggested that loss of parafibromin and overexpression of galectin-3 and Ki-67 might help to distinguish parathyroid carcinoma from other parathyroid tumors. And the combination of two or three of these markers might produce better sensitivity and/or specificity for the diagnosis of parathyroid carcinoma. PMID- 22932088 TI - A meta-analytic review of ERCC1/MDR1 polymorphism and chemosensitivity to platinum in patients with advanced non-small cell lung cancer. AB - BACKGROUND: Platinum-based regimens are used as standard first-line chemotherapy in non-small cell lung cancer (NSCLC) patients. To study if pharmacogenetic approach may allow a tailored selection of platinum chemotherapy for advanced NSCLC, we performed a meta-analysis to compare chemosensitivity to platinum with different ERCC1 C118T/ MDR1 C3435T single-nucleotide polymorphism (SNP). METHODS: Relevant studies were identified by searching the PubMed, Embase, Cochrane, OVID, Springer, EBSCO and CNKI databases. Inclusion criteria were patients with advanced NSCLC who received platinum-based chemotherapy, an evaluated polymorphism of ERCC/MDR1 and overall response rate. We excluded duplicate publications, letters and review articles. The RevMan 4.2 and STATA 11 package were used to do comprehensive quantitative assessment. RESULTS: A total of 11 studies were included in this meta-analysis. For studies evaluating ERCC1 C118T, test for heterogeneity was done (chi(2) = 13.41, P = 0.1), and the odds ratio (OR) for the wild-type C/C genotype versus the heterozygous C/T and T/T genotypes was 1.50 (95% CI 1.09 - 2.06, P = 0.01). In four studies evaluating MDR1 polymorphism, test for heterogeneity was also done (chi(2) = 3.22, P = 0.36), and the OR for the wild-type C/C genotype versus the heterozygous C/T and T/T genotypes was 2.30 (95% CI 1.44 - 3.68, P = 0.0005). CONCLUSIONS: The results indicated that platinum-based chemotherapy sensitivity was significantly associated with polymorphism of ERCC1 C118T and MDR1 C3435T SNP. In further perspective studies, the ERCC1/MDR1 SNPs might serve as simple and less invasive biomarkers for personalized chemotherapy with platinum-based anticancer drugs. PMID- 22932089 TI - Roles of eEF-2 kinase in cancer. AB - OBJECTIVE: To provide a summary of the relationship between the eEF-2/eEF-2 kinase pathway and each phase of malignant neoplasms. The speci?c importance of this relationship in understanding and treating cancer was also explored. DATA SOURCES: The data used in this review were mainly obtained from the articles listed in HighWire and PubMed in English. The search terms were "eEF-2 kinase", "oncogenesis", and "tumor progression". STUDY SELECTION: This review relates the observation that the overexpression of eEF-2 kinase is seen in cancer, and highlights that it has emerged as promoting the development of many malignant phenotypes when unregulated. This includes increasing the replicative potential of cells, angiogenesis, invasion and metastasis, and evasion of apoptosis. RESULTS: eEF-2 kinase is a structurally and functionally unique protein kinase. The increased activity of this protein in cancer cells is a protective mechanism to allow tumor growth and evolution, and resist cell death through the eEF-2/eEF 2 kinase pathway, but it also makes a potential target for therapy. CONCLUSION: eEF-2 kinase fills critical niches in the life of a cancer cell and the eEF-2/eEF 2 kinase pathway is a key biochemical sensor. PMID- 22932090 TI - Risk factors for postoperative recurrence of cardiac myxoma and the clinical managements: a report of 5 cases in one center and review of literature. AB - BACKGROUND: Recurrence or metastasis of myxomas is not rare and can lead to malignancy. We aimed to analyze the risk factors for postoperative cardiac myxoma recurrence and to summarize its clinical characteristics, treatments and classification. METHODS: The clinical data of 5 patients with recurrent cardiac myxoma were retrospectively analyzed and our clinical experience was summarized. Moreover, the relevant literatures were reviewed. RESULTS: All the five cases of primary myxomas were derived from atypical positions. One patient had early distant metastasis, one had family history, and two suffered malignant recurrence. The recurrence interval was (2.30 +/- 2.16) years and the recurrent tumors were all found in different chambers from those of the corresponding primary tumors. Re-operation was performed after recurrence. One patient died of heart failure after malignant recurrence, and the other 4 cases had satisfactory therapeutic outcomes after re-operations. Our experience advocated a clinical classification of "typical" and "atypical" cardiac myxoma, the typical myxomas referred to the tumors locating at the left atria, with single pedicle, rooted at or around the fossa ovalis, involving no genetic causes, and the atypical myxomas included the familial tumors, tumors stemming from multiple chambers, rooted in abnormal positions of the left atrium, with evident genetic mutation, or with malignant tendency. CONCLUSIONS: Postoperative follow-up is of vital importance for patients with myxomas characterized by multi-chamber distribution, early distant metastasis, atypical origin, and family history. Once recurs, re operation is necessary and should be performed immediately. PMID- 22932091 TI - Surgical treatment of symptomatic Rathke's cleft cysts: clinical features, therapy considerations and outcomes. AB - BACKGROUND: Rathke's cleft cyst (RCC) is one of the most common incidentally discovered sellar lesions, while symptomatic cases are relatively rare. Surgical treatment is recommended for symptomatic patients to drain the cyst content and to remove the capsule safely. The aim of this study was to clarify the clinical features, surgery considerations and therapy outcomes of symptomatic RCCs. METHODS: Totally 42 patients (19 males and 23 females) were retrospectively reviewed with the diagnosis of RCCs under surgery resection at the Affiliated Hospital of Medical College, Qingdao University between January 2005 and December 2010. RESULTS: Patients' age ranged from 6 to 67 years (mean of 41.6 years). The duration of symptoms ranged from 4 days to 10 years. Headache (69%), visual impairment (36%), and pituitary dysfunction (10%) were the most common presenting symptoms. The maximum diameter of cysts ranged from 6.0 to 46.7 mm (mean of 20.07 mm). Of the 42 patients, 36 underwent endonasal transsphenoidal approach and the others underwent transcranial approach. Thirty patients had a subtotal resection and decompression, while 12 patients had a total cyst resection. Cysts of 28 patients were lined by simple cubical or columnar epithelium, and cysts of 34 patients were filled by amorphous colloid material, that was the characteristic of RCCs. The majority of patients presented with a simple headache, and 93% of this group experienced a complete improvement after surgery. Twelve of 15 patients (80%) with preoperative visual deficits experienced an improvement in their vision after surgery. All of those patients with pituitary dysfunction experienced an improved endocrine status. The endocrinological complication usually was diabetes insipidus, and postoperative transient diabetes insipidus occurred in 13 (31%) patients without any permanent diabetes insipidus. The overall recurrence rate was 7% at a mean follow-up of 22 months (range 12 - 60 months). CONCLUSIONS: Surgical treatment is to drain the contents of the cyst and to remove the capsule as much as possible under the precondition that does not increase the complications. Biopsy and decompression procedures are recommended for most cases. PMID- 22932092 TI - Photodynamic therapy of condyloma acuminata in pregnant women. AB - BACKGROUND: Photodynamic therapy (PDT) with 5-aminolevulinic acid (ALA) is an emerging technique for the treatment of genital human papillomavirus (HPV) induced benign and premalignant lesions. We report here in a case series of condyloma acuminata (CA) in pregnancy successfully treated with ALA-PDT. METHODS: Five pregnant patients with CA received three to four times treatment respectively. Patients were followed up for 6 - 23 months after treatment. RESULTS: The clearance rate of genital warts was 100%. No recurrence was found during the follow-up period. Major adverse events reported were mild erosion, pain, and local edema. All pregnancies resulted in healthy live births without delivery complications. CONCLUSIONS: PDT with topical ALA seems to be safe and effective in the treatment of CA in pregnancy. It demonstrated high clearance rate of warts, was well-tolerated by patients, and showed no adverse effects on mothers or fetuses. ALA-PDT may be an ideal strategy of treatment for pregnant women with CA. PMID- 22932093 TI - Vertical deviation and A pattern of type III Duane retraction syndrome. AB - BACKGROUND: Researches in ocular electromyography (EMG) and Magnetic resonance imaging (MRI) of patients with Duane retraction syndrome (DRS) suggest that there may be additional abnormalities such as paradoxical innervation between horizontal rectus muscles and vertical rectus muscles, hypoplasia of vertical rectus muscle and that oblique muscles may also contribute to the heterogeneity of the clinical manifestation of DRS. This paper reports the results of superior rectus recession for vertical deviation and A pattern in DRS Type III and discusses the pathogenesis of the disease. METHODS: Superior and lateral rectus recession were performed in 5 cases of Huber type III DRS to treat vertical deviation and A pattern strabismus. Before operation, MRI of the brain, brainstem, cavernous sinus, and orbits were performed. RESULTS: All subjects had unilateral limitation of both abduction and adduction, with palpebral fissure narrowing and globe retraction in adduction. Three cases had A pattern of strabismus, three cases had hypertropia. The abducens nerves (CN6) were either absent or hypoplasitic in the brainstem in all patients. Two eyes had larger oculomotor foramen. Two eyes had hypoplasia of the superior rectus and the inferior rectus. There was presumably a branch of the third cranial nerve (CN3) innervating the lateral rectus (LR) in one eye. While in another eye, two branches of CN3 sent into medial rectus were revealed. After surgery, vertical deviation in the primary position was reduced in all patients and A pattern was eliminated in 3 patients. One patient developed 10Delta consecutive esotropia postoperatively. CONCLUSION: The results suggest that structural abnormalities of vertical muscle and abnormal orbital innervation may be related to vertical deviation and the presence of A pattern in DRS type III. Recession of the superior rectus muscle seems to be a safe and effective treatment for vertical deviation and A pattern strabismus in DRS Type III. PMID- 22932094 TI - Transformation of the Chinese medical and health development: from the perspective of the public hospital reform. PMID- 22932095 TI - Tracheobronchopathia osteochondroplastica: four cases. AB - Tracheobronchopathia osteochondroplastica (TO) is a rare and benign disorder of unknown cause affecting the large airways. It is characterized by the presence of multiple osseous and cartilaginous nodules in the submucosa of the trachea and main bronchi that is characterized by the progression of submucosal bone and/or cartilage including nodules through the lumen of trachea and bronchus. We present four cases that were diagnosed TO while investigating for the causes of hemoptysis and chronic cough. We plan to emphasize TO in differential diagnosis in proper patients. PMID- 22932096 TI - Delayed diagnosis of 22q11.2 deletion syndrome in an adult Chinese lady. AB - We report a 32 year-old Chinese lady with history of tetralogy of Fallot, presented to us with chest pain due to hypocalcemia secondary to hypoparathyroidism. With her dysmorphic facial features and intellectual disability 22q11.2 deletion was suspected and confirmed by genetic study. Clinicians should consider the diagnosis of DiGeorge syndrome in adult patient with past medical history of congenital heart disease, facial dysmorphism, intellectual disability and primary hypoparathyroidism. PMID- 22932097 TI - Multiple myeloma with rupture of ovarian plasmacytoma. AB - Multiple myeloma is a clonal proliferation of plasma cells with multiple osteolytic lesions. Extramedullary dissemination of multiple myeloma in ovary is relatively uncommon. A 54-year-old female patient, diagnosed as multiple myeloma three years ago, was admitted to the hospital for the complaints of intermittent abdominal pain for three days. The vaginal gynecological ultrasound showed celiac solid mass. The emergent laparotomy showed a significantly enlarged right cystic ovary and the pathological reviews showed ovarian plasmacytoma. The final diagnosis of this patient was ovarian extramedullary plasmacytoma rupture and bleeding. PMID- 22932098 TI - Reversible ischemia on treadmill exercise in left main coronary vasospasm: lead aVR and V1. PMID- 22932099 TI - Which is the best peri-operative anti-coagulative therapy of transverse sinus stenting for refractory idiopathic intracranial hypertension? AB - Treatment of refractory idiopathic intracranial hypertension (IIH) is a challenging problem. We reported a refractory IIH patient who manifested with typical intracranial hypertensive symptoms successfully treated with endovascular stent implantation. Pre-operative cerebrospinal fluid (CSF) opening pressure is 36 cmH2O. Cerebral angiography demonstrated a stenotic lesion located at the right transverse sinus (TS). The stenotic TS returned to its normal caliber and the pressure gradient deceased from 36 mmHg to 4 mmHg after the stent placement. The intracranial hypertensive symptoms resolved and one month later, the CSF opening pressure decreased to 14 cmH2O. PMID- 22932100 TI - Glycogen storage disease with ventricular hypertrophy mimicking obstructive hypertrophic myocardiopathy. PMID- 22932101 TI - Schneiderian papilloma occasionally found in the lacrimal sac. PMID- 22932103 TI - [Standardizing diagnosis, therapy and management of hypertensive disorders in pregnancy]. PMID- 22932102 TI - One case of guide wire fracture and retention in child's internal jugular vein puncture. PMID- 22932104 TI - [Study on clinical risk of maternal underlying medical conditions and onset of preeclampsia]. AB - OBJECTIVE: To investigate the effect of clinical risk factors including maternal underlying medical conditions on the development of preeclampsia (PE) in order to improve and strengthen the early assessment of high clinical risk population of PE. METHODS: Clinical observational data of patients with PE in Peking University Third Hospital from November 2008 to January 2011 were analyzed. Comparative analysis was made among medical conditions with PE (M-PE) sub-group and isolated PE (I-PE) sub-group and non-PE pregnancy with or without medical conditions (control group). RESULTS: Totally 159 cases, 43.09% (159/369) of total cases of PE had high clinical risk factors (multiple pregnancy and medical conditions) and 32.3% (97/300) of singleton PE accompanied with medical conditions. The incidence of PE in singleton pregnancies with medical conditions was significantly higher than those without medical conditions [15.0% (97/646) versus 4.45% (210/4719), P < 0.05]. In M-PE sub-group, the average age [(31.7 +/- 4.5) versus (29.3 +/- 5.2) year-old] and body mass index (BMI) in first trimester [(26.0 +/- 5.6) versus (23.3 +/- 3.7) kg/m(2)], the proportion with previous preeclampsia [11% (11/97) versus 4.9% (10/203)] and pregnancy loss in third trimester [11% (11/97) versus 3.0% (6/203)], were higher than those of I-PE sub-group (all P < 0.05). The onset of preeclampsia in M-PE sub-group was earlier than I-PE (32.9 versus 34.4 gestation weeks, P < 0.05). The proportion serious cases of PE occurring before 32 gestational weeks were higher in M-PE than that of I-PE sub-group [45% (44/97) versus 34.0% (69/203), P < 0.05]. Multivariate regression analysis showed that previous history of late pregnancy loss and irregular prenatal care were clinical risk factors for early-onset PE whether early-onset was defined as < 34 or < 32 gestational weeks respectively (all P < 0.05); medical conditions were risk factors for PE if early-onset was defined as < 32 gestational weeks (OR = 1.718, 95%CI: 1.005 - 2.937, P = 0.048). CONCLUSIONS: Multiple pregnancies and pregnancies with medical conditions exceed one-third of total subjects of PE. The onset of PE in subjects with maternal underlying medical conditions was earlier which is the subgroup should not be ignored. The difference of early pregnancy BMI may show the maternal heterogeneity in early onset and late onset of preeclampsia. Assessment of clinical risk factors including the underlying medical disorders for preeclampsia in early trimester should be strengthened. PMID- 22932105 TI - [Relationships between concentrations of free fatty acid in serum and oxidative damage levels in placental mitochondria and preeclampsia]. AB - OBJECTIVE: To investigate the relationships between concentrations of free fatty acid (FFA) in maternal serum and oxidative damage levels in placental mitochondria and preeclampsia (PE). METHODS: A total of 60 women with PE and 60 normal pregnant women as control participated in this study. All were admitted to Fujian Maternity and Child Health Hospital for delivery from August 2010 to May 2011. Patients with PE were divided into early-onset group (n = 30, presented at < 34 weeks of gestation) and late-onset group (n = 30, presented at >= 34 weeks of gestation), with 30 normal pregnant women as early control group (< 34 weeks of gestation) and 30 as late control group (>= 34 weeks of gestation). Improved copper agent colorimetry was used to detect FFA in maternal serum. Ultraviolet colorimetry was used to detect glutathione peroxidase (GPX) and catalase (CAT) activity in maternal placenta and malondialdehyde (MDA) and permeability transition (PT) pore in placental mitochondria. Total superoxide dismutase (SOD) assay kit-WST was used to detect SOD activity in placenta. Real-time fluorescent quantitative PCR was used to detect mitochondrial DNA (mtDNA) expression in placenta. RESULTS: (1) Maternal serum FFA was (1.6 +/- 0.5) mmol/L in early-onset PE group and (1.5 +/- 0.4) mmol/L in late-onset PE group, significantly elevated as compared to (1.0 +/- 0.5) mmol/L in early control group and (0.9 +/- 0.5) mmol/L in late control group (P < 0.05). However, no significant difference was found between early-onset and late-onset PE groups (P > 0.05). (2) The mean placental GPX, CAT and SOD activity were significantly decreased in the early onset PE group [(47 +/- 6), (19 +/- 5), (62 +/- 13) U/mg] and late-onset PE group [(67 +/- 6), (20 +/- 4), (96 +/- 17) U/mg] as compared to late control group [(80 +/- 3), (55 +/- 3), (123 +/- 19) U/mg], respectively (P < 0.05). (3) The mean placental mitochondria MDA was significantly elevated in the early-onset PE group [(115 +/- 22) nmol/mg] and late-onset PE group [(90 +/- 17) nmol/mg] as compared to late control group [(52 +/- 11) nmol/mg, P < 0.05]. The mean absorption value that present the permeability of placental mitochondria PT pore was significantly elevated in the early-onset PE group (0.086 +/- 0.013) and late-onset PE group (0.069 +/- 0.014) as compared to late control group (0.052 +/- 0.012, P < 0.05). The mean placental mtDNA expression was significantly elevated in the early-onset PE group (3.0 +/- 0.7) and late-onset PE group (2.8 +/- 0.7) as compared to late control group (2.6 +/- 0.6, P < 0.05). (4) The mean placental mitochondria MDA concentration correlated positively with the concentrations of FFA in maternal serum in the early-onset PE group (r = 0.703, P < 0.05) and late-onset PE group (r = 0.457, P < 0.05), and negatively with placental antioxidant enzyme in the early-onset PE group (r = -0.652, -0.787, -0.952; P < 0.05) and late-onset PE group (r = -0.378, -0.689, -0.854; P < 0.05). CONCLUSIONS: Increased FFA in maternal serum and high levels of oxidative damage in placental mitochondria may be involved in the pathogenesis of preeclampsia. Increased FFA in serum and decreased activity of antioxidant enzyme in placenta may contribute to oxidative damage levels in placental mitochondria in women with PE. PMID- 22932106 TI - [Correlation of lipocalin-2 and its receptor expressions with preeclampsia]. AB - OBJECTIVE: To research the correlation of the expressions of lipocalin-2 (LCN-2) and its receptor (NGALR) in serum and placenta with preeclampsia. METHODS: From Dec.2010 to Apr.2011, 64 women with preeclampsia who delivered in Affiliated Hospital of Qingdao University Medical College were recruited in the study, including 26 women with moderate preeclampsia (MPE group) and 38 women with severe preeclampsia (SPE group). Twenty-five healthy pregnant women were taken as control group. LCN-2 and NGALR mRNA and protein expression in placenta were measured by reverse transcription-PCR (RT-PCR) and western blot, respectively. RESULTS: (1) The serum levels of LCN-2 in MPE group and SPE group [(58 +/- 20), (90 +/- 18) ug/L] were significantly higher than that in control group [(19 +/- 6) ug/L, P < 0.01]; the serum LCN-2 level in SPE group was significantly higher than that in MPE group (P < 0.01). (2) LCN-2 mRNA expression in placenta in MPE group and SPE group (0.55 +/- 0.14, 0.61 +/- 0.14) were both significantly higher than that in control group (0.28 +/- 0.16, P < 0.01); LCN-2 protein expression in placenta of MPE group and SPE group (2.2 +/- 0.4, 2.4 +/- 0.5) were also significantly higher than that in control group (1.4 +/- 0.4, P < 0.01), no significant difference was found between MPE group and SPE group (P > 0.05). (3) No significant difference was found in the expressions of NGALR mRNA in placenta among MPE group, SPE group and control group (0.46 +/- 0.11, 0.46 +/- 0.14, 0.45 +/- 0.15, P > 0.05). (4) NGALR protein expressions in MPE group, SPE group and control group were 2.7 +/- 0.8, 3.0 +/- 0.9, and 2.7 +/- 0.9, and there were no significant difference among these three groups (P > 0.05). (5) In preeclampsia, serum LCN-2 level significant associated with 24 hours total urinary protein and uric acid (r = 0.565, 0.476, P < 0.01). LCN-2 serum level were not associated with systolic pressure and diastolic pressure (P > 0.05); there were no association with the expressions LCN-2 mRNA and protein in placenta (P > 0.05). CONCLUSIONS: Serum LCN-2 level is closely related to the progress of preeclampsia. Increasing expression of LCN-2 in placenta may be a compensatory response to preeclampsia. PMID- 22932107 TI - [Analysis of risk factors for preeclampsia in pregnancies complicated with chronic aplastic anemia]. AB - OBJECTIVE: To investigate the risk factors for preeclampsia(PE) in pregnancies complicated with chronic aplastic anemia (CAA) by analyzing the obstetric management and pregnancy outcome. METHODS: Retrospectively review the clinical data including the obstetric management, the laboratory findings and the pregnancy outcome of 41 pregnant women complicated with CAA, all of whom were hospitalized in Peking University People's Hospital from May 2002 to February 2011. Multiple logistic regression was used to explore the risk factors associated with PE. RESULTS: (1) Twenty-eight patients were diagnosed before conception while 13 were diagnosed during gestation. Eleven patients including all the 7 who were categorized as severe CAA presented with mild bleeding in the third trimester. (2) The medians of white blood cell counts, hemoglobin concentrations and platelet counts were 5.0*109/L, 66.0 g/L and 12.0*109/L respectively. (3) The obstetric management consisted of strict assessment, intensive surveillance and follow-up, appropriate supportive measures, timely recognition of complications, and delivery when necessary. Twenty-one patients received supportive transfusions. Ten patients developed PE, all of whom were diagnosed as severe PE (SPE). Twelve patients suffered postpartum hemorrhage, and 3 of them had blood loss more than 1000 ml. All were conservatively treated in success. (4) The median gestational age of delivery was 37 weeks. Sixteen cases delivered before 37 weeks and 5 delivered before 34 weeks. Two patients developed SPE at 29 weeks and 30 weeks respectively, and both of the neonates died for severe asphyxia. The birth weight of the live neonates ranged from 1500 to 3660 g. (5) The postpartum follow-up period ranged from 6 months to 7 years. Thirty three patients got improvement without dependence on transfusions. Four achieved no remission and still needed intermittent transfusions. Four were lost in follow up. (6) Significant differences were found in the bleeding tendency, the platelet counts and the delivery weeks when comparing the patients developing PE and those without PE. No differences were found with regard to the age, the gestational age of first visit, the percentage of patients diagnosed before conception, the percentage of severe CAA, the choice of treatment, the white blood cell counts and the hemoglobin level. The Multiple logistic regression showed that the platelet count less than 10*109/L was an independent risk factor for CAA patients developing PE (P = 0.006). CONCLUSIONS: Most pregnancies complicated with CAA could achieve good maternal and fetal outcome, when intensive prenatal care and supportive management are provided. SPE is the most common complication. The platelet count less than 10*109/L is perhaps an independent risk factor for CAA patients developing PE. PMID- 22932108 TI - [Relationship of adverse pregnancy outcomes and a high risk serum screen for Down syndrome in the second trimester]. AB - OBJECTIVE: To investigate the the relationship of a high risk serum screen for Down syndrome in second trimester and adverse pregnancy outcomes, and to evaluate the predictive value for adverse pregnancy outcomes. METHODS: The tri-marker second trimester maternal serum screening for Down syndrome (alpha-fetoprotein, free beta-hCG and unconjugated estriol) was performed on the pregnant women at Peking Union Medical Hospital from January 2009 to January 2011. The cutoff valvue was 1/270. Pregnancy outcomes were followed up. The general condition and pregnancy complications of the pregnant women with high risk (high-risk group) were compared to that of the pregnant women with low risk (low-risk group); and with 35 years old as a demarcation, the incidences of adverse pregnancy outcomes were calculated in the two groups. RESULTS: (1) A total of 1935 cases were collected. And 1784 cases were with low risk, and 151 cases were with high risk. The difference of weight and gestational age between the two groups was not statistically significant (P > 0.05); the difference of age between the two groups was statistically significant (P < 0.01). (2) Pregnancy complications were found in 791 cases. In high-risk group, the incidences of gestational diaetes mellitus (GDM, 13.9%), neonatal asphyxia (4.0%) and small for gestational age infant (SGA, 4.6%) were higher than that in low-risk group (8.4%, 1.0%, 1.6%), the difference was statistically significant (P < 0.05). The incidences of gestational hypertension disease, premature labor, oligohydramnios, placenta previa, placenta abruption, fetal macrosomia in the two groups was not statistically different (P > 0.05). (3) In 1705 cases aged less than 35 years, 129 cases (7.6%) were GDM, 43 cases (2.5%) were gestational hypertension disease, 61 cases (3.9%) were premature labor; in 230 cases aged 35 years or more, 41 cases (17.8%) were GDM, 12 cases (5.2%) were gestational hypertension disease, 15 cases (6.5%) were premature labor, and the difference between the two groups was statistically significant (P < 0.05). In < 35 years old group, the incidences of GDM, neonatal asphyxia and SGA (12.3%, 4.4%, 5.3%) were higher in the high-risk group than that (7.2%, 0.9%, 1.6%) in the low-risk group, and the difference was statistically significant (P < 0.05). In >= 35 years old group, the incidences of GDM, neonatal asphyxia and SGA (18.9%, 2.7%, 2.7%) were slightly higher in the high-risk group than that (17.6%, 1.6%, 1.6%) in the low-risk group, the difference between the two groups was not statistically significant (P > 0.05). CONCLUSIONS: The present study revealed apparent increase in the adverse pregnancy outcomes in women with a high risk of Down syndrome screening test. Advanced age is the most important risk factor for a high risk of Down syndrome screening test and adverse pregnancy outcomes. More attention should be attached to the patients whose age were < 35 years old and with a high risk of Down syndrome screening test. PMID- 22932109 TI - [Change of labor duration:a systematic analysis]. AB - OBJECTIVE: To evaluate the labor duration of healthy primiparas in the past 20 years compared with Friedman labor curve. METHODS: Published observational studies about labor duration in primiparas with singleton vertex presentation were searched in PubMed, EMBase, Cochrane library, CNKI, VIP and Wanfang database. The Cochrane Collaboration's RevMan 5.1 software was used for meta analysis. RESULTS: Eleven literatures involving 4534 primiparas were included, which were eligible for the criteria to investigate the labor duration. Meta analysis showed that the length of active phase was significantly different between what was showed in primiparas in the past 20 years and Friedman labor curve [P = 0.01, weighted mean difference (WMD) = 1.61, 95%CI: 0.38 to 2.83], and significant differences were also found in the second stage duration (P = 0.0006, WMD = -0.20, 95%CI: -0.31 to -0.09). CONCLUSIONS: Compared with Friedman labor curve, active phase length of healthy primiparas in the past 20 years was significantly longer and second stage length was shorter. Reassessing labor curve of healthy primiparas is required for more scientific guidance and less unnecessary interventions. PMID- 22932110 TI - [Correlation between the inflammatory factors and adipocytokines with gestational diabetes mellitus and their change in puerperium]. AB - OBJECTIVE: To investigate the relationship between inflammatory factors, including C-reactive protein(CRP), tumor necrosis factor alpha (TNF-alpha), adiponectin, leptin and gestational diabetes mellitus (GDM) and their changes in puerperium. METHODS: From June 2008 to May 2010, 40 cases with gestational diabetes mellitus, 40 cases of normal pregnancy were enrolled in this study. Fasting venous blood were obtained at early pregnancy (10 - 12 weeks), late pregnancy (36 - 38 weeks) and day 3 and 42 of postpartum. Serumal adiponectin, leptin and TNF-alpha were measured by ELISA, and serumal CRP were measured by particle enhanced immunoturbidimetric method. The levels of those 4 cytokines and homeostasis model assessment insulin resistance (HOMA-IR) index were compared between two groups. And the changes of 4 cytokines were calculated in puerperium. The receiver operating characteristic (ROC) for TNF-alpha predicting GDM was designed. RESULTS: (1) The relationship between cytokines and HOMA-IR: the levels of adiponectin of (5.7 +/- 1.8) mg/L in the GDM group were significantly lower than (8.1 +/- 2.7) mg/L in control group in early pregnancy, and the level of adiponectin was negatively correlated with HOMA-IR (r = -0.333, P < 0.05). The levels of (28 +/- 10) ug/L of leptin, (10.0 +/- 3.4) ng/L of TNF-alpha and (4.7 +/- 1.1) mg/L of CRP in GDM group were significantly higher than (20 +/- 8) ug/L of leptin, (4.6 +/- 2.7) ng/L of TNF-alpha, (2.4 +/- 1.2) mg/L of CRP in control group, which were positively correlated with HOMA-IR (r = 0.411, 0.529, 0.308, all P < 0.05). In late pregnancy, the level of adiponectin (3.9 +/- 2.2) mg/L in the GDM group was significantly lower than (6.6 +/- 2.7) mg/L in control group, and the level of adiponectin was negatively correlated with HOMA-IR (r = -0.344, P < 0.05). The levels of (37 +/- 13) ug/L of leptin, (12.7 +/- 2.6) ng/L of TNF alpha and (6.7 +/- 3.6) mg/L of CRP in the GDM group were significantly higher than (30 +/- 13) ug/L of leptin, (5.8 +/- 2.1) ng/L of TNF-alpha, (4.4 +/- 3.1) mg/L of CRP in control group, which were positively correlated with HOMA-IR (r = 0.414, 0.487, 0.285, all P < 0.05). Multiple linear regression analysis showed that the level of TNF-alpha at early and late pregnancy was most correlated with HOMA-IR (r = 0.390, 0.284, all P < 0.05). (2) The level of the cytokines and HOMA IR in puerperium: at day 3 of postpartum, the level of adiponectin of (3.3 +/- 1.1) mg/L in the GDM group was significantly lower than (6.2 +/- 1.5) mg/L in control group, which was negatively correlated with HOMA-IR (r = -0.283, P < 0.05). The levels of (31 +/- 13) ug/L of leptin, (10.1 +/- 5.7) ng/L of TNF-alpha and (35.1 +/- 6.5) mg/L of CRP in the GDM group were significantly higher than (21 +/- 15) ug/L of leptin, (5.6 +/- 3.0) ng/L of TNF-alpha, (30.5 +/- 8.5) mg/L of CRP in control group. And leptin and TNF-alpha levels were positively correlated with HOMA-IR (r = 0.372, 0.494, all P < 0.05). At day 42 of postpartum, the level of adiponectin in GDM group was negatively correlated with HOMA-IR (r = -0.299, P < 0.05), and the levels of leptin and TNF-alpha were positively correlated with HOMA-IR (r = 0.401, 0.442, all P < 0.05). Multiple linear regression analysis showed that the level of TNF-alpha at day 3 and day 42 was most correlated with HOMA-IR (r = 0.363, 0.274, all P < 0.05). (3) ROC analysis of data from early pregnancy showed that the threshold for TNF-alpha to predict GDM was 5.45 ng/L. CONCLUSION: TNF-alpha might be the index to predict GDM and evaluate prognosis. PMID- 22932111 TI - [Influence of gonadotropin releasing hormone agonist on the expression of mRNA of nerve growth factor and its receptors in eutopic endometrial stromal cells]. AB - OBJECTIVE: To investigate the influence of gonadotropin releasing hormone agonist (GnRH-a) on the expression mRNA of nerve growth factor (NGF) and its receptors (TrkA and P75NTR) in normal and eutopic endometrial stromal cells (ESC). METHODS: From January to April 2009, 3 patients with endometriosis undergoing surgery in Peking Union Medical College Hospital were obtained eutopic endometrium as study group matched with eutopic endometrium from 3 patients with teratoma as control group. ESC were incubated with different concentration of GnRH-a (0, 5*10-11, 5*10-10, 5*10-9, 5*10-8, 5*10-7 g/ml). The expression of mRNA of NGF, TrkA and P75NTR were measured by real-time-PCR. RESULTS: At concentration of 0 g/ml, the levels of NGF, TrkA and P75NTR mRNA in ESC were 6.32, 8.55, 8.08 in study group, which were significantly higher than 0.94, 0.67, 1.08 in control group (P < 0.05). Treated by the following concentration of GnRH-a (5*10-11, 5*10-10, 5*10 9, 5*10-8, 5*10-7 g/ml), the median expression of NGF, TrkA and P75NTR mRNA was 1.00, 0.96, 1.05; 1.09, 0.82, 1.27; 1.04, 0.52, 0.81;1.00, 0.55, 0.64; 0.78, 0.49, 1.02 in study group. Compared with the expressions of those untreated by GnRH-a in study group, they showed significantly lower trends (P < 0.05). In control group, the median expression of NGF, TrkA and P75NTR mRNA was 0.98, 0.37, 0.92; 0.70, 0.45, 1.15; 1.55, 0.80, 1.35; 1.09, 0.41, 1.35; 0.90, 0.82, 1.18. Compared with the expressions of those untreated by GnRH-a in control group, there were no statistically differences (P > 0.05). And treated by the same concentration of GnRH-a, the expressions of NGF, TrkA and P75NTR mRNA did not show statistically difference between the two groups (P > 0.05). CONCLUSION: The expression of NGF, TrkA and P75NTR mRNA were suppressed by GnRH-a. PMID- 22932112 TI - [Epidemiology of uterine corpus cancer in some cancer registering areas of China from 2003 - 2007]. AB - OBJECTIVE: To analyze corpus uteri epidemiology in selected cancer registering areas of China during 2003 - 2007, and to provide scientific information for its prevention and control in China. METHODS: The incident and mortality data of corpus uteri cancer in 32 cancer registering areas of China with better quality during 2003 - 2007, which were selected according to the criteria of and provided by National Center for Cancer Registration, were analyzed. RESULTS: There were 8850 new cases and 1559 death cases of corpus uteri cancer, which accounted for 2.96% (8 850/299 306) of all female new cancer cases and 0.94% (1 559/166 305) of all female cancer death cases, respectively. Corpus uteri cancer was the 9th most common cancer for all new female cancer cases which world age adjusted incidence rates was 5.04/105, and 19th most common cancer for all female cancer death cases which world age adjusted mortality rate was 0.83/105 in 32 selected cancer registering areas of China during 2003 - 2007. Zhongshan city, Guangzhou city in Guangdong province and Beijing were the areas with the highest incidence rates in which were 14.51/105, 8.51/105 and 6.69/105, respectively. Zhongshan city in Guangdong province, Dafeng city in Jiangsu province and Feicheng city in Shandong province were the areas with the highest mortality rates, in which were 4.03/105, 3.19/105 and 1.65/105 respectively during 2003 - 2007. There were increasing trends for its incidence rates in above 32 areas during 2003 - 2007, its world age adjusted incidence rates increased from 3.94/105 in 2003 to 5.56/105 in 2007 (P = 0.026), while its urban world age adjusted incidence rates increased from 4.57/105 in 2003 to 6.18/105 in 2007 (P = 0.038), and rural rates increased from 1.74/105 in 2003 to 3.01/105 in 2007 (P = 0.013), and the results showed that urban areas obviously higher than rural areas (P < 0.01). Although there was a slow increasing trend for its world age adjusted mortality rates in above 32 areas during 2003 - 2007 which increased from 0.64/105 in 2003 to 0.87/105 in 2007 (P = 0.214), and from 0.66/105 in 2003 to 0.88/105 in 2007 in urban areas (P = 0.340), and from 0.57/105 in 2003 to 0.83/105 in 2007 in rural areas (P = 0.070), while increasing trends without statistical significance.But mortality rates in urban areas were obviously higher than those of rural areas (P < 0.01). CONCLUSIONS: Although the world standardized incidence and mortality rates of corpus uteri cancer were at low level worldwide, there were increasing trends for its incidence rates during 2003 - 2007 in the 32 selected cancer registering areas of China. Moreover, its incidence and mortality rates were at high level worldwide in some areas such as Zhongshan city of Guangdong province and Dafeng city of Jiangsu province during the period, in which suggested that its prevention and control should be enhanced. PMID- 22932113 TI - [Comparative analysis of neoadjuvant therapies in stage Ib2 and IIa2 cervical carcinoma]. AB - OBJECTIVE: To compare the clinical efficacy of neoadjuvant chemotherapy plus vaginal intracavitary irradiation, neoadjuvant chemotherapy alone and vaginal intracavitary irradiation alone followed by radical hysterectomy in patients with stage Ib2 and IIa2 bulkly cervical carcinoma. METHODS: Between January 2000 and December 2009, 224 patients with stage Ib2 and IIa2 bulkly cervical carcinoma (tumor diameter > 4 cm) received neoadjuvant therapy combined surgery in Cancer Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences were respectively analyzed, and they were divided into 3 groups according to the preoperative neoadjuvant therapy, the neoadjuvant chemotherapy combined vaginal intracavitary irradiation group (chemotherapy combined irradiation group, n = 86), the neoadjuvant chemotherapy alone group (chemotherapy group, n = 48), the vaginal intracavitary irradiation alone group (irradiation group, n = 90). The efficacy, postoperative risk factors, postoperative adjuvant therapy and survival were compared among the 3 groups. RESULTS: Among the chemotherapy combined irradiation group, chemotherapy group and irradiation group, the response rate (RR) were respectively 62% (53/86), 42% (20/48) and 37% (33/90), and there was significant difference (P = 0.003). The comparison of deep stromal invasion, lymph node metastases, lympho-vascular space involvement (LVSI) and other risk factors among the 3 groups, which showed that there were no statistically significant differences (P > 0.05). In chemotherapy combined irradiation group, the percentage of stromal invasion >= 1/2 was lower than that in chemotherapy group [53% (46/86) vs. 73% (35/48), P = 0.027], and the percentage of lymph node metastases was significantly lower than irradiation group [17% (15/86) vs. 29% (26/90), P = 0.046], and the risk factors-free rate was significantly higher than chemotherapy group [44% (38/86)vs. 25% (12/48), P = 0.028]. Among the chemotherapy combined irradiation group, chemotherapy group and irradiation group, the percentage of postoperative radiation therapy were respectively 47% (40/86), 67% (32/48) and 62% (56/90), and the differences were statistically significant (P = 0.035). The five-year disease free survival (DFS) was 79%, 75% and 78%, respectively. The five-year overall survival (OS) was respectively 81%, 78% and 81% among 3 groups, and there were no statistically significant differences (P > 0.05). Among 224 patients, the five-year DFS of the patients with 0, 1 and >= 2 risk factors after surgery were 90%, 75% and 57%, and OS were 95%, 82% and 65%, and there were no statistically significant differences (P < 0.01, respectively). Of patients without postoperative risk factors, the five year OS in those without receiving postoperative radiation therapy was 96%, while 89% in received postoperative radiation therapy patients, there were no statistically significant differences (P = 0.263). CONCLUSION: There are no differences of DFS and OS among the neoadjuvant chemotherapy combined vaginal intracavitary irradiation group, the neoadjuvant chemotherapy alone group and the vaginal intracavitary irradiation alone group patients with stage Ib2 and IIa2. Patients without risk factors after neoadjuvant therapies have better prognosis. PMID- 22932114 TI - [Effect of cyclooxygenase-2 on bone loss in ovariectomized rats]. AB - OBJECTIVE: To investigate mechanism of cyclooxygenase-2 (COX-2) in bone loss in a postmenopausal osteoporosis (PMOP) rat mode with ovarietomy (OVX). METHODS: Forty female Sprague Dawley adult rats at age of 3 months were randomly divided into 4 groups, 10 in each group, including sham-operated (sham) group, OVX group, OVX treated with nilesteriol (OVX + E) group and OVX treated with aspirin (OVX + P) group. All rats in OVX, OVX + E and OVX + P groups underwent ovarietomy under abdominal anesthesia with 10% chloral hydrate. Rats in sham group were only taken with fat tissue with same weight under bilateral ovary. After surgery, penicillin was administered to prevent infection. At day 7 after surgery, agents were given by intragastric administration for 12 weeks. Nilestriol at 1.0 mg/kg was used in OVX + E group once a week, aspirin at 45 mg*kg-1(*d-1 was used in OVX + P group once a day. Saline with same volume was used in rats in sham and OVX groups. All agents were administered one time per day. Dose of agents were adjusted by weight per week. At end of study, bone mineral density (BMD) of right femurs and lumbar vertebrae 3-5 (L(3-5)) were measured. Morphology of bone was detected by hematoxylineosin, and expression of COX-2 was determined by immunohistochemistry staining. RESULTS: (1) BMD:BMD of right femur and L(3-5) was (0.209 +/- 0.010) g/cm2 and (0.230 +/- 0.012) g/cm2 in sham group and (0.181 +/- 0.008) g/cm2 and (0.201 +/- 0.016) g/cm2 in OVX group, which reached statistical difference (P < 0.01). BMD of right femur and L(3-5) was (0.203 +/- 0.009) g/cm2 and (0.224 +/- 0.028) g/cm2 in OVX + E group and (0.200 +/- 0.011) g/cm2 and (0.204 +/- 0.003) g/cm2 in OVX + P group, which were all higher than those in OVX group (P < 0.01, P < 0.05). However, there was no statistical difference in BMD between OVX + E and OVX + P group (P > 0.05). (2) Morphology of bone:bone trabeculae became fewer and degenerated in OVX group. However, bone trabeculae were regular and dense in OVX + P group and OVX + E group, which were similar to those in sham group. (3) Expression of COX-2:cells with COX-2 positive and expression of COX-2 around bone trabeculae in OVX group were more than those in sham, OVX + E and OVX + P group. CONCLUSION: COX-2 plays an important role in PMOP. Aspirin could prevent bone loss by decreasing COX-2 expression in OVX rats. PMID- 22932115 TI - Concurrent acute cellular rejection is an independent risk factor for renal allograft failure in patients with C4d-positive antibody-mediated rejection. AB - BACKGROUND: Identification of risk factors for renal allograft failure after an episode of acute antibody-mediated rejection (AMR) may help the outcome of this difficult-to-treat complication. METHODS: During December 2003 to February 2011, 833 kidney graft recipients underwent 1120 clinically indicated biopsies at our center. We reviewed the biopsy results and identified 87 biopsy specimens from 87 patients positive for the degradation product of complement component 4 (C4d) and acute AMR. We generated Kaplan-Meier survival curves and performed a multivariable analysis using the Cox proportional hazards regression model to identify risk factors for allograft failure after C4d+ acute AMR. RESULTS: Among the 87 patients, 26 had a diagnosis of acute AMR according to the Banff '09 classification schema, 29 had acute AMR and chronic active AMR, 18 had acute AMR and acute T-cell mediated rejection (TCMR), and 14 had acute AMR, chronic active AMR, and acute TCMR. Kaplan-Meier survival estimates showed that concurrent acute TCMR (P=0.001, Mantel-Cox log-rank test), concurrent chronic active AMR (P=0.03), and time to biopsy (P=0.04) are associated with graft survival. The Cox proportional hazards regression analysis identified that concurrent acute TCMR (hazard ratio, 2.59 [95% confidence interval, 1.21-5.55]; P=0.01) and estimated glomerular filtration rate (hazard ratio, 0.65 [95% confidence interval, 0.48 0.88]; P=0.01) are independent risk factors for allograft loss. Concurrent chronic active AMR or time to biopsy was not associated with graft failure by the multivariable Cox analysis. CONCLUSIONS: Our single-center study has elucidated that concurrent acute TCMR in kidney transplant recipients with C4d+ acute AMR is an independent risk factor for graft failure. Level of allograft function at the time of diagnosis was also an independent predictor of graft loss. PMID- 22932116 TI - Recipient age and time spent hospitalized in the year before and after kidney transplantation. AB - BACKGROUND: Kidney transplantation (KT) is a life-prolonging therapy in certain older end-stage renal disease patients, but concerns regarding peritransplantation morbidity remain. We estimate the relative increase in time spent hospitalized in the year post-KT for older versus younger end-stage renal disease patients. METHODS: This was a retrospective analysis of 27,247 Medicare primary KT recipients from 2000 to 2005 using United States Renal Data System and Organ Procurement and Transplantation Network data. Time spent hospitalized was enumerated in the year pre-KT and post-KT from Medicare Part A claims. Excess inpatient days were the difference in an individual's post-KT and pre-KT hospital and skilled nursing facility days, standardized by time spent alive in the year post-KT. RESULTS: The median excess inpatient days were similar by age group (9 in recipients 65 years or older vs. 7 in recipients younger than 65 years); however, the distribution was skewed, such that many more older adults had large increases in inpatient time (8.6% totaled >120 excess inpatient days vs. 4.2% in younger recipients). Among older recipients, risk factors for poor outcomes included recipient age, donor age, longer dialysis vintage, diabetic nephropathy, and congestive heart failure. Reasons for posttransplantation hospitalization were similar by age with the exception of rehabilitation, which was common only in the 65+ age group. Mean inpatient costs were equivalent pretransplantation by age but significantly higher posttransplantation among older KT recipients. CONCLUSIONS: Posttransplantation morbidity may not be so different in most of the older individuals selected for KT; however, a minority fares much worse. PMID- 22932117 TI - Protein kinase C inhibition ameliorates posttransplantation preservation injury in rat renal transplants. AB - BACKGROUND: Prolonged cold preservation frequently causes delayed renal graft function resulting from tubular epithelial injury. Inhibition of signal transduction downstream from protein kinase C (PKC) may reduce renal ischemia reperfusion injury and confer renal graft protection. We therefore evaluated the effect of sotrastaurin, a small-molecule inhibitor of Ca2+-dependent and Ca2+ independent PKC isoforms, in comparison with mycophenolic acid (MPA) on rat renal transplants with prolonged cold preservation. METHODS: Donor kidneys from male Lewis rats were cold stored in University of Wisconsin solution for 24 hr before syngeneic grafting. Recipients received sotrastaurin (30 mg/kg twice daily), MPA (20 mg/kg/day), or vehicle through gavage starting 1 hr after surgery. Renal function was evaluated by serum creatinine and histology on day 2 (acute injury) and day 7 (repair phase) after transplantation. Postreperfusion inflammation was determined by real-time polymerase chain reaction of proinflammatory genes and histology. Signaling mechanisms were studied by Western blotting and immunohistochemistry. RESULTS: Sotrastaurin enhanced immediate transplant function, attenuated epithelial injury, and accelerated renal function recovery compared with MPA. Despite the stronger anti-inflammatory capacity of MPA, only sotrastaurin treatment achieved significant cellular protection with persisting reduced apoptosis of tubular epithelial cells. Decreased phosphorylation of extracellular signal-regulated protein kinase and p66Shc adaptor protein, both involved in cellular stress and apoptosis, were likely the responsible mechanism of action. CONCLUSIONS: The PKC inhibitor sotrastaurin effectively ameliorated ischemia-reperfusion organ damage and promoted cytoprotection in a clinically relevant model of extended renal cold preservation followed by transplantation. Pharmacologic targeting of PKC may be beneficial for recipients receiving renal transplants at risk for delayed graft function. PMID- 22932118 TI - Vitamin D receptor agonists increase klotho and osteopontin while decreasing aortic calcification in mice with chronic kidney disease fed a high phosphate diet. AB - Vascular calcification is common in chronic kidney disease, where cardiovascular mortality remains the leading cause of death. Patients with kidney disease are often prescribed vitamin D receptor agonists (VDRAs) that confer a survival benefit, but the underlying mechanisms remain unclear. Here we tested two VDRAs in a mouse chronic kidney disease model where dietary phosphate loading induced aortic medial calcification. Mice were given intraperitoneal calcitriol or paricalcitol three times per week for 3 weeks. These treatments were associated with half of the aortic calcification compared to no therapy, and there was no difference between the two agents. In the setting of a high-phosphate diet, serum parathyroid hormone and calcium levels were not significantly altered by treatment. VDRA therapy was associated with increased serum and urine klotho levels, increased phosphaturia, correction of hyperphosphatemia, and lowering of serum fibroblast growth factor-23. There was no effect on elastin remodeling or inflammation; however, the expression of the anticalcification factor, osteopontin, in aortic medial cells was increased. Paricalcitol upregulated osteopontin secretion from mouse vascular smooth muscle cells in culture. Thus, klotho and osteopontin were upregulated by VDRA therapy in chronic kidney disease, independent of changes in serum parathyroid hormone and calcium. PMID- 22932119 TI - Lixivaptan safely and effectively corrects serum sodium concentrations in hospitalized patients with euvolemic hyponatremia. AB - Hyponatremia is a common electrolyte disorder associated with increased morbidity and mortality, particularly in the elderly. Lixivaptan, a new selective vasopressin V2-receptor antagonist, safely corrected serum sodium concentrations in phase II studies of patients with euvolemic hyponatremia. Here our multinational, double-blind, placebo-controlled, phase III study assessed the effect of lixivaptan on serum sodium concentrations in 106 initially hospitalized patients with euvolemic hyponatremia (serum sodium less than 130 mmol/l). Of them, 52 were randomized to receive placebo and 54 received 50 mg lixivaptan once daily and were then titrated to receive 25-100 mg once daily depending on serum sodium concentration. Fluid restriction was at the investigator's discretion. Initial titration occurred in a monitored inpatient setting; patients were then treated as outpatients for a total of 30 days. The primary end point was the change in serum sodium concentration from baseline to day 7. Lixivaptan significantly increased the serum sodium concentration from baseline to day 7 (the primary end point) by 6.7 mmol/l compared with placebo (4.5 mmol/l; P=0.034). Importantly, the serum sodium concentration was normalized safely and more rapidly in patients receiving lixivaptan than placebo (P=0.004) and was well tolerated. After drug discontinuation, serum sodium concentrations decreased to near-baseline levels within 7 days. Thus, lixivaptan safely and effectively corrects serum sodium concentrations in patients with euvolemic hyponatremia. PMID- 22932120 TI - Renal biopsy findings among Indigenous Australians: a nationwide review. AB - Australia's Indigenous people have high rates of chronic kidney disease and kidney failure. To define renal disease among these people, we reviewed 643 renal biopsies on Indigenous people across Australia, and compared them with 249 biopsies of non-Indigenous patients. The intent was to reach a consensus on pathological findings and terminology, quantify glomerular size, and establish and compare regional biopsy profiles. The relative population-adjusted biopsy frequencies were 16.9, 6.6, and 1, respectively, for Aboriginal people living remotely/very remotely, for Torres Strait Islander people, and for non-remote living Aboriginal people. Indigenous people more often had heavy proteinuria and renal failure at biopsy. No single condition defined the Indigenous biopsies and, where biopsy rates were high, all common conditions were in absolute excess. Indigenous people were more often diabetic than non-Indigenous people, but diabetic changes were still present in fewer than half their biopsies. Their biopsies also had higher rates of segmental sclerosis, post-infectious glomerulonephritis, and mixed morphologies. Among the great excess of biopsies in remote/very remote Aborigines, females predominated, with younger age at biopsy and larger mean glomerular volumes. Glomerulomegaly characterized biopsies with mesangiopathic changes only, with IgA deposition, or with diabetic change, and with focal segmental glomerulosclerosis (FSGS). This review reveals great variations in biopsy rates and findings among Indigenous Australians, and findings refute the prevailing dogma that most indigenous renal disease is due to diabetes. Glomerulomegaly in remote/very remote Aboriginal people is probably due to nephron deficiency, in part related to low birth weight, and probably contributes to the increased susceptibility to kidney disease and the predisposition to FSGS. PMID- 22932121 TI - Vascular endothelial growth factor-C and -D are involved in lymphangiogenesis in mouse unilateral ureteral obstruction. AB - Lymphatic remodeling in inflammation has been found in tracheal mycoplasma infection, human kidney transplant, skin inflammation, peritonitis, and corneal inflammation. Here we investigated lymphangiogenesis in fibrotic area in unilateral ureteral obstruction, a model of progressive renal fibrosis, and evaluated the roles of vascular endothelial growth factor (VEGF)-C and -D in the obstructed kidney. Compared to sham-operated mice, the number of LYVE-1-positive lymphatic vessels, the proliferation of LYVE-1-positive lymphatic endothelial cells, along with VEGF-C and -D mRNA expression were all significantly increased following ureteral obstruction. Depletion of macrophages with clodronate decreased lymphangiogenesis in the obstructed kidney. VEGF-C expression was higher in M2- than in M1-polarized macrophages from bone marrow-derived macrophages, and also increased in Raw 264.7 or renal proximal tubule cells by stimulation with TGF-beta1 or TNF-alpha. VEGF-D reversed the inhibitory effect of TGF-beta1 on VEGF-C-induced migration, capillary-like tube formation, and proliferation of human lymphatic endothelial cells. Additionally, the blockade of VEGF-C and VEGF-D signaling decreased obstruction-induced lymphangiogenesis. Thus, VEGF-C and VEGF-D are associated with lymphangiogenesis in the fibrotic kidney in a mouse model of ureteral obstruction. PMID- 22932123 TI - How does the DNA sequence affect the Hill curve of transcriptional response? AB - The Hill coefficient is often used as a direct measure of the cooperativity of binding processes. It is an essential tool for probing properties of reactions in many biochemical systems. Here, we analyze existing experimental data and demonstrate that the Hill coefficient characterizing the binding of transcription factors to their cognate sites can in fact be larger than one-the standard indication of cooperativity-even in the absence of any standard cooperative binding mechanism. We demonstrate that this effect occurs due to the disordered binding energy of transcription factors to the DNA molecule and the steric repulsion between the different copies of the transcription factor. We show that the enhanced Hill coefficient implies a significant reduction in the number of copies of the transcription factors which is needed to occupy a cognate site and, in many cases, can explain existing estimates for number of copies of the transcription factors in cells. PMID- 22932122 TI - Oral lixivaptan effectively increases serum sodium concentrations in outpatients with euvolemic hyponatremia. AB - Hyponatremia is the most common electrolyte disorder in clinical practice. Its incidence increases with age and it is associated with increased morbidity and mortality. Recently, the vaptans, antagonists of the arginine vasopressin pathway, have shown promise for safe treatment of hyponatremia. Here we evaluated the efficacy, safety, and tolerability of oral lixivaptan, a selective vasopressin V2-receptor antagonist, for treatment of nonhospitalized individuals with euvolemic hyponatremia (sodium less than 135 mmol/l) in a multicenter, randomized, double-blind, placebo-controlled, phase III study. About half of the 206 patients were elderly in a chronic care setting. Of these patients, 52 were given a placebo and 154 were given 25-100 mg per day lixivaptan, titrated based on the daily serum sodium measurements. Compared with placebo (0.8 mmol/l), the serum sodium concentration significantly increased by 3.2 mmol/l from baseline to day 7 (primary efficacy endpoint) with lixivaptan treatment. A significantly greater proportion of patients that received lixivaptan achieved normal serum sodium (39.4%) by day 7 relative to placebo (12.2%). Overall, lixivaptan was considered safe and well-tolerated. Thus, oral lixivaptan can be safely initiated in the outpatient setting and effectively increases serum sodium concentrations in outpatients with euvolemic hyponatremia. PMID- 22932124 TI - Infectious diseases in children and body mass index in young adults. AB - In a cohort of 1,863 Filipinos, diarrhea, fever, and unsanitary conditions in infancy were associated with a decreased body mass index in adulthood; upper respiratory tract infection was associated with an increased body mass index. These finding support the hypothesis that infections early in life play a role in body habitus in adulthood. PMID- 22932125 TI - Severe measles, vitamin A deficiency, and the Roma community in Europe. PMID- 22932126 TI - Folic acid facilitates in vitro maturation of mouse and Xenopus laevis oocytes. AB - The water-soluble B vitamins, folate and folic acid, play an important role in reproductive health, but little is known about the effects of folic acid on infertility. The present study tested the hypothesis that folic acid affects oocyte maturation, a possible cause of female infertility. We have studied the in vitro maturation of mouse and Xenopus oocytes. Hypoxanthine (Hx) was used as an inhibitor of mouse oocyte maturation to mimic in vivo conditions by maintaining high levels of cyclic-AMP. The frequency of first polar body (PB1) formation and germinal vesicle breakdown (GVBD) in mouse oocytes was decreased by Hx. This effect was counteracted by folic acid added to the medium. PB1 extrusion and GVBD percentages rose to 27.7 and 40.0% from 12.8 and 19.9%, respectively, by exposure to 500 MUM-folic acid. Folic acid also restored the spindle configuration, which had been elongated by Hx, as well as normalising the distribution of cortical granules (CG). In folic acid-treated Xenopus eggs, extracellular signal-regulated kinase 1 was phosphorylated, cyclin B2 and Mos were up-regulated and the frequency of GVBD was accelerated. Taken together, the findings suggest that folic acid facilitates oocyte maturation by altering the expression and phosphorylation of proteins involved in M-phase-promoting factor and mitogen activated protein kinase pathways, as well as causing changes in spindle configuration and CG migration. PMID- 22932127 TI - Deacetylation of H4-K16Ac and heterochromatin assembly in senescence. AB - BACKGROUND: Cellular senescence is a stress response of mammalian cells leading to a durable arrest of cell proliferation that has been implicated in tumor suppression, wound healing, and aging. The proliferative arrest is mediated by transcriptional repression of genes essential for cell division by the retinoblastoma protein family. This repression is accompanied by varying degrees of heterochromatin assembly, but little is known regarding the molecular mechanisms involved. RESULTS: We found that both deacetylation of H4-K16Ac and expression of HMGA1/2 can contribute to DNA compaction during senescence. SIRT2, an NAD-dependent class III histone deacetylase, contributes to H4-K16Ac deacetylation and DNA compaction in human fibroblast cell lines that assemble striking senescence-associated heterochromatin foci (SAHFs). Decreased H4-K16Ac was observed in both replicative and oncogene-induced senescence of these cells. In contrast, this mechanism was inoperative in a fibroblast cell line that did not assemble extensive heterochromatin during senescence. Treatment of senescent cells with trichostatin A, a class I/II histone deacetylase inhibitor, also induced rapid and reversible decondensation of SAHFs. Inhibition of DNA compaction did not significantly affect the stability of the senescent state. CONCLUSIONS: Variable DNA compaction observed during senescence is explained in part by cell-type specific regulation of H4 deacetylation and HMGA1/2 expression. Deacetylation of H4-K16Ac during senescence may explain reported decreases in this mark during mammalian aging and in cancer cells. PMID- 22932128 TI - Thought disorder in mid-childhood as a predictor of adulthood diagnostic outcome: findings from the New York High-Risk Project. AB - BACKGROUND: Thought disorder has been proposed as an indicator of schizotypy, which is considered to be necessary but not sufficient for the development of schizophrenia. It is unclear whether thought disorder is an indicator of susceptibility (i.e. an endophenotype) for schizophrenia. The goal of the present study was to elucidate the role of thought disorder in relation to schizotypy by examining its presence in high-risk individuals during mid-childhood. Method The sample consisted of 265 subjects drawn from the New York High-Risk Project. Individuals at high risk for schizophrenia (i.e. offspring of parents with schizophrenia) were compared with individuals at low risk for schizophrenia (i.e. offspring of parents with affective disorder or offspring of psychiatrically normal parents). Videotaped interviews were rated for thought disorder using the Scale for the Assessment of Thought, Language, and Communication (TLC). The same subjects were administered diagnostic interviews in late adolescence/early adulthood. RESULTS: Although positive thought disorder was equally present in subjects with affective and non-affective psychoses, negative thought disorder (namely, poverty of speech and poverty of content of speech) was elevated only in subjects with schizophrenia-related psychosis. Logistic regression analyses revealed that negative thought disorder added to the prediction of schizophrenia related psychosis outcomes over and above positive thought disorder. CONCLUSIONS: These findings suggest that negative thought disorder may have a specific association with schizotypy, rather than a more general association with psychosis. The findings also support consideration of negative thought disorder as an endophenotypic indicator of a schizophrenia diathesis. PMID- 22932129 TI - Surveillance for influenza viruses in poultry and swine, west Africa, 2006-2008. AB - To determine the extent of animal influenza virus circulation in Cote d'Ivoire, Benin, and Togo, we initiated systematic year-round active influenza surveillance in backyard birds (predominantly chickens, guinea fowl, and ducks) and pigs. A total of 26,746 swab specimens were screened by using reverse transcription PCR. Animal influenza prevalence was estimated at 0 (95% CIs for each of the 2 study years 0-0.04% to 0-1.48% [birds] and 0-0.28% to 0-5% [pigs]). In addition, 2,276 serum samples from the same populations were negative for influenza-specific antibodies. These data indicate that the environments and host populations previously identified as harboring high levels of influenza virus in Southeast Asia do not do so in these 3 countries. The combination of climate and animal density factors might be responsible for what appears to be the absence of influenza virus in the backyard sector of the 3 countries. PMID- 22932130 TI - Targeted therapy for lung cancer. AB - Lung cancer is considered the number one killer among all cancers. Recent observations have altered the treatment paradigm for non-small-cell lung cancer (NSCLC). The discovery of activating mutations in the epidermal growth factor receptor and anaplastic lymphoma kinase positivity has made personalized treatment for NSCLC more feasible. Both erlotinib and crizotinib have been shown to be effective and safe for subgroup populations, and now personalized treatment for nonsquamous NSCLC has progressed even further. New tyrosine kinase inhibitors are being tested, resistant mutations are being studied, and new detection systems are being incorporated; all these developments will make the detection and treatment of the deadliest cancer more affordable, practical, and effective. The National Comprehensive Cancer Network has already incorporated these new developments into their guidelines for advanced nonsquamous NSCLC. PMID- 22932132 TI - [Improving adherence with therapy in allergic rhinitis patients]. PMID- 22932131 TI - alpha-Cyano-4-hydroxycinnamate induces apoptosis in Dalton's lymphoma cells: role of altered cell survival-regulatory mechanisms. AB - In the present investigation, we explored the molecular mechanisms of the tumoricidal action of alpha-cyano-4-hydroxycinnamate (alphaCHC) on the cells of Dalton's lymphoma (DL), which is a murine T cell lymphoma. In-vitro treatment of the DL cells with alphaCHC resulted in the modulation of the biophysical parameters of the tumor cell culture medium with respect to pH, nitric oxide, glucose, and lactate, accompanied by an alteration in the expression of cytokines (IL-10, IL-6, and IFN-gamma) and cell survival-regulatory proteins such as Bcl2, p53, caspase-3, caspase-activated DNase, HSP70, and IL2R. The expression of the pH-regulatory proteins vacuolar ATPase and MCT1 was also found to be altered. The study discusses the possible role of the aforementioned alterations triggered by alphaCHC in the induction of tumor cell apoptosis and decreased cell survival. These findings will provide a new insight into the novel molecular mechanisms of the antitumor action of alphaCHC. PMID- 22932133 TI - [Efficacy and safety analysis with standardized mite allergen subcutaneous immunotherapy in 90 patients with allergic rhinitis]. AB - OBJECTIVE: To evaluate the three-year efficacy and safety with standardized dust mite subcutaneous immunotherapy in patients with allergic rhinitis. METHODS: Ninety patients who were diagnosed as allergic to mite by skin prick test and serum IgE were include in the standardized allergen-specific dose-escalation regimen. Nasal symptom score (0-3) were collected before treatment and three years after treatment; VAS (visual analogue scale, 0-10) of all nasal symptoms and drug use score were collected every four months; frequency of local and systemic reactions were recorded in the duration of dose escalation and maintenance. RESULTS: Nasal blocking, sneeze, rhinorrhea and nasal itch were significantly improved after 3 years treatment (before treatment: 2[2;3], 2[2;3], 2[2;3], 2[1;2] ; after treatment: all were 0[0;0]; Z value were -8.310, -8.408, 8.377, -8.287, all P were 0.000). VAS of all nasal symptoms and drug use score decreased dramatically after escalation period (before treatment: 8.00[7.00;8.85], 2.00[1.50;2.00]; after treatment: 1.00[1.00;1.50], 0 [0;0]; Z value were -8.287, -8.248, P value 0.086, 0.744), and maintained afterwards (F value were 2.483, 0.296; P value were 0.086, 0.744). Ninety-eight case times (64.47%) local reactions mainly happened in maintenance period; the frequency of systemic reactions was 2.54%. CONCLUSION: The standardized specific allergen immunotherapy for allergic rhinitis is safe and effective. PMID- 22932134 TI - [Complications of hyoid suspension with Repose system on obstructive sleep apnea hypopnea syndrome]. AB - OBJECTIVE: To investigate the complications of hyoid suspension with Repose system on obstructive sleep apnea hypopnea syndrome (OSAHS) and to find out the effective prevention strategies. METHODS: Forty four patients diagnosed by polysomnography as OSAHS were received hyoid suspension with Repose system from June 2005 to July 2009. The intraoperative and postoperative complications were analyzed retrospectively. The patients who reported abnormal swallowing were evaluated with water drinking test and video fluorography swallow study to assess biomechanical changes in swallowing. RESULTS: Incidence rate of perioperative titanium nial amotio was 15.9% (7/44). It was avoided by implanting titanium nial again. No perioperative complications occurred such as injury of superior laryngeal nerve, blood vessel and thyrohyoid membrane, fracture of hyoid bone, suture break. All patients developed dysfunctions of pronunciation and swallowing, edema of mouth floor, dysfunctions of movement of tongue that could relieved gradually after three days on most patients. No postoperative complications occurred such as titanium nial amotio, fat liquoring, edema of mouth floor, hematoma, infection, foreign body reaction, injury of root apex of anterior tooth, dysfunctions of movement and sensation of tongue, suture break and death. All patients had over 2 year postoperative follow up. Incidence rate of dysfunctions of pronunciation and swallowing was 4.5% (2/44) and 15.9% (7/44) respectively. Main situation for dysfunctions of pronunciation was speaking ambiguity. Major manifestations of swallowing abnormalities were occasional aspiration, food going down the wrong tube, food becoming stuck in the throat, deglutition with bowing head. Seven patients who had abnormal swallowing possessed normal water drinking test and occurred asynersis of hyoid movement and laryngeal elevation, but aspiration were not observed. Three patients presented obvious stagnation in epiglottic vallecula and sinus piriformis. CONCLUSIONS: Most complications of hyoid suspension with Repose system may be avoided or recovered on short term. Postoperative dysfunctions of pronunciation and swallowing may exist for a long time. PMID- 22932135 TI - [Peri-operative management on juvenile recurrent respiratory papillomatosis]. AB - OBJECTIVE: To investigate the safety of peri-operative management on children with juvenile recurrent respiratory papilloma (JORRP). METHODS: A retrospective analysis was conducted on preoperative assessment, anesthesia methods and options, operative procedure, and postoperative airway maintenance in 28 JORRP children aged from ten months to seven years old. A total of 148 times of surgery was performed on these 28 children. RESULTS: One hundred and nine JORRP children graded one and two-degree dyspnea underwent surgery within 24 hours and were intubated successfully in the first attempt after intravenous induction. Thirty nine emergency operations were performed in the children graded three and four degree dyspnea, 35 of them were intubated successfully in the first attempt after inhalation induction and 4 succeeded in the second attempt. No complications occurred in 129 JORRP children postoperatively, 17 children suffered from mild dyspnea and relieved after oxygen inhalation, 2 children were intubated and sent to intensive care unit because of postoperative hypoxemia. All JORRP children got through the peri-operative period safely. The quality of pronunciation in 101 children improved markedly and 35 suffered from slight hoarseness on the 1st postoperative day. Three children had the tracheal tube of tracheostomy removed after receiving five, four and three operations respectively. Nineteen children were followed up for 2 - 5 years. Among them, one child did not relapse 3 years after surgical management.One child suffered from laryngostenosis postoperatively. No death occurred. CONCLUSION: Complete preoperative preparation, rational anesthesia methods, careful operative procedure and airway maintenance after surgery could increase the safety for children with recurrent respiratory papilloma. PMID- 22932136 TI - [Retrospective study of 93 patients with jaw osteoradionecrosis]. AB - OBJECTIVE: To investigate the clinical feature, treatment, and prognosis of hospitalized patients with jaw osteoradionecrosis. METHODS: A total of 93 cases with jaw osteoradionecrosis treated between 2000 and 2010 was reviewed. Of the 93 cases, 79 cases were with mandible lesions, 13 cases with maxillary lesions, and 1 case with both mandible and maxillary lesions. Sixty-six cases received one course of radiotherapy, with the radiation doses of 34 - 90 Gy (mean 64.6 Gy). Twenty-two cases experienced tooth extraction or other operative procedures before exhibition of the clinical symptoms for osteoradionecrosis. The interval time between radiotherapy and the onset of osteoradionecrosis varied from 2 weeks to 32 years (mean 54 months). RESULTS: Of 93 cases, 56 patients underwent radical resection of the pathologic bone and reconstruction with free tissue flaps, in whom 7 cases received the second surgery due to microvascular thrombosis in flap vessels, and flaps were survival by new vascular anastomosis in 3 cases, the failed flaps were removed and replaced successfully by non vascularized bone grafts in 2 cases, and the failed flaps removed and the defects were repaired with adjacent skin in other 2 cases. In the 56 cases, only one case was with disease recurrence and 53 cases with significant improvement in chewing and swallowing functions. Only 2 of 93 cases underwent resection of the pathologic bone and reconstruction with titanium plates, and thereafter they encountered titanium exposure. Scaling of osteoradionecrosis lesions was applied to 20 of 93 patients and 9 cases of them were with disease recurrence. Fifteen cases had resection of the effected mandible without reconstruction. Disease relapse was encountered in 2 of them, others had poor chewing and swallowing. CONCLUSIONS: The mandible is more susceptible to osteoradionecrosis than maxilla. Radical resection with reconstruction by free tissue flap is recommended for the treatment of jaw osteoradionecrosis, and scaling and reconstruction only with titanium plate should be avoided because of high risks of titanium exposure and disease relapse. PMID- 22932137 TI - [Clinical outcomes of salvage surgery for nasopharyngeal carcinoma after irradiation failure]. AB - OBJECTIVE: To study salvage surgery for persistent or recurrent nasopharyngeal carcinoma after irradiation failure. METHODS: A total of 84 cases underwent salvage surgery for persistent or recurrent nasopharyngeal carcinoma after irradiation failure between 1993 and 2009 was reviewed. rTNM stage: rT1 34 cases, rT2 27 cases, rT3 12 cases and rT4 11 cases; rN0 70 cases, rN1 9 cases and rN2 5 cases; No with distance metastatic. The salvage surgeries were performed using maxillary swing approach (47 cases), transcervical-mandibulo-palatal approach (21 cases), palate nasopharyngectomy (6 cases), lateral rhinotomy (7 cases), and maxillectomy (3 cases). RESULTS: Persistent or recurrent nasopharyngeal carcinoma after irradiation failure was resected completely in 57 patients (67.9%) and there were microscopic residual diseases in 27 patients (32.1%). The median follow-up was 27 months. Postoperative recurrence occurred in 35 cases. Thirty six patients died of recurrence, metastasis and other diseases. The overall 5 year survival rate was 43.6%. Cox regression analysis indicated the complete resection for persistent or recurrent disease and no cervical metastasis were two independent factors affecting survival. CONCLUSIONS: Salvage surgery for persistent or recurrent nasopharyngeal carcinoma after irradiation failure is an effective treatment. PMID- 22932138 TI - [Tissue engineered tympanic membrane repairment materials with adipose-derived stem cells]. AB - OBJECTIVE: To explore the morphology, proliferative activity and adhesion of adipose-derived stem cells (ASC) seeded in the polylactic-co-glycolic acid (PLGA) scaffold, and to provide experimental data for fabricating tissue engineered tympanic membrane repairment materials. METHODS: Wistar rats were selected, and the ASC were isolated and co-cultured with the PLGA scaffold. The morphology and proliferative activity of ASC in the scaffold were examined by immunofluorescence of Vimentin and Ki67 respectively. All the immunofluorescence signals were analyzed by a confocal laser scan microscopy system FLUOVIEW FV1000. The adhesion of ASC to the PLGA scalfold was determined by scanning electron microscopy. RESULTS: Immunofluorescence of vimentin showed rats ASC displayed normal morphology and grew orderly in the PLGA scalfold. Immunofluorescence of Ki67 showed the normal active proliferation of ASC in the scaffolds. The Ki67 mean positive index (x(-) +/- s) of the ASC in the scalfold was (8.21 +/- 1.76)%, while in control group (cultured without PLGA scalfold) was (9.06 +/- 1.95)%. There was no statistic significance between the two groups (t = 1.03, P = 0.30). Scanning electron microscopy demonstrated ASC adhered well to the PLGA scalfold, the pseudopodia of ASC could also be observed and the proliferative cell conjunction was tight. CONCLUSION: ASC has good biocompatible to the PLGA scaffold and could normally adhere and proliferate in PLGA scaffold. PMID- 22932139 TI - [Mechanism of ATP release from cultured marginal cells of stria vascularis in neonatal rat]. AB - OBJECTIVE: To further confirm release of adenosine triphosphate (ATP) from cultured marginal cells in vitro of stria vascularis in neonatal rat, and to explore the mechanism of ATP release from marginal cells. METHODS: Isolation and in vitro culture of marginal cells of neonatal rats' cochlea. ATP released by marginal cells in extracellular fluid were detected using bioluminescence assay when add regain separately as follow: bafilomycin A(1), didecyl adipate (DDA), extracellular K(+), thapsigargin, extracellular Ca(2+), U73122, and aristolochic acid. RESULTS: The concentrations of ATP in the extracellular fluid significantly and gradually decreased along with increasing concentrations of bafilomycin A(1). The concentrations of ATP in the extracellular fluid were in linear increased with DDA was added to marginal cell suspensions. ATP concentrations increased as the concentration of extracellular K(+) was increased, and reached the peak with a K(+) concentration of 9.15 mmol/L. At higher K(+) concentrations, ATP concentrations decreased. With the addition of increasing concentrations of thapsigargin to test marginal cells, ATP concentrations were significantly decreased. When extracellular Ca(2+) was completely chelated, marginal cells continued to release ATP. Moreover, as extracellular Ca(2+)increased, the release of ATP decreased. However, the amount of ATP releas remained to a baseline when extracellular concentration of Ca(2+) reached 1.25 mmol/L or above. When concentrations of U73122 remained within the range of 0.25 to 1.25 umol/L, as U73122 increased, the release of ATP decreased. When concentrations of aristolochic acid ranging from 12.5 to 100.0 umol/L were added to the marginal cells suspension, the release of ATP was significantly decreased. However, with concentrations of aristolochic acid less than 100.0 umol/L, the release of ATP tended to be not significantly different from the amount of ATP released by control group. CONCLUSIONS: ATP could be release from marginal cells cultured in vitro of vascular stria in neonatal rats. ATP release from marginal cells has relevant with calcium pump, K(+) channel state and signaling pathway related enzymes. PMID- 22932140 TI - [Association between single-nucleotide polymorphisms in the IRAK-4 gene and allergic rhinitis]. AB - OBJECTIVE: To investigate the genetic association pattern between single nucleotide polymorphisms (SNP) in the interleukin-1 receptor-associated kinase 4 (IRAK-4) gene and allergic rhinitis (AR). METHODS: A population of 379 patients with the diagnosis of AR and 333 healthy controls who lived in Beijing region was recruited. A total of 8 reprehensive marker SNP which were in IRAK-4 gene region were selected according to the Beijing people database from Hapmap website. The individual genotyping was performed by MassARRAY platform. SPSS 13.0 software was used for statistic analysis. RESULTS: Subgroup analysis for the presence of different allergen sensitivities displayed associations only in the house dust mite-allergic cohorts (rs3794262: P = 0.0034, OR = 1.7388; rs4251481: P = 0.0023, OR = 2.6593), but not in subjects who were allergic to pollens as well as mix allergens. CONCLUSION: The potential genetic contribution of the IRAK-4 gene to AR demonstrated an allergen-dependant association pattern in Chinese population. PMID- 22932141 TI - [Effect of HDAC6 down-regulation on the growth of xenografted human laryngeal carcinoma cell line Hep-2 in nude mice and underlying mechanism]. AB - OBJECTIVE: To study the effect of histone deacetylation 6 (HDAC6) siRNA on the growth of xenografted human laryngeal squamous cell carcinoma cell line Hep-2 in nude mice and underlying mechanism. METHODS: Laryngeal squamous cell carcinoma cell line Hep-2 cells were subcutaneously injected to the back of nude mice and transplanted tumor model was established after one week. Nude mice was divided into three groups including blank control group, empty vector group and HDAC6 siRNA group, and the tumor growth was observed. Ki-67 proliferation index was detected by immunohistochemistry. Western blot, in situ hybridization and immunohistochemistry were used to detect the mRNA and protein expressions of HDAC6 in xenograft. The expressions of Bcl-2 and Bax proteins were examined by Western blotting. Cell apoptosis was detected by TUNEL. RESULTS: The mean volume of xenograft transfected with HDAC6 siRNA was less than that of xenograft transfected with empty vector or that of xenograft with blank control treatment (P < 0.05). HDAC6 siRNA effectively down-regulated the expressions of HDAC6 mRNA and the expressions of HDAC6 and Bcl-2 proteins, but up-regulated the expression of Bcl-2 protein in xenografts, with significant differences (all P < 0.05). The proliferation index of Ki-67 in HDAC6 siRNA transfection group was significantly lower than that in blank control group or empty vector group (P < 0.05). TUNEL assay demonstrated that HDAC6 evidently evoked cell apoptosis (P < 0.05). CONCLUSION: HDAC6 siRNA could effectively inhibited the growth of xenografted human laryngeal carcinoma cell line Hep-2 in nude mice, down-regulate the expressions of HDAC6 and bcl-2, and up-regulate the expression of bax. PMID- 22932142 TI - [Expressions and clinical significance of high mobility group box-1 mRNA and protein in laryngeal squamous cell carcinoma tissues and serum]. AB - OBJECTIVE: To investigate the mRNA and protein expressions of high mobility group box-1 (HMGB1) in the tumor tissues and sera of patients with laryngeal squamous cell carcinoma (LSCC) and their clinical significance. METHODS: Semi-quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) and Western blot were used to detected the expressions of HMGB1 mRNA and protein in the tumors and adjacent normal epithelial tissues in 30 patients with LSCC. Serum HMGB1 protein levels in the patients with LSCC and in 10 healthy volunteers were detected with enzyme-linked immunosorbent adsorption experiment (ELISA). RESULTS: RT-PCR demonstrated that the mean relative mRNA expression levels of HMGB1 (HMGB1/GAPDH) in LSCC tissues and in adjacent normal epithelial tissues were 1.25 +/- 0.12 and 0.32 +/- 0.04, respectively (t = 40.27, P < 0.05). Western blot revealed that the mean relative protein expression levels of HMGB1 (HMGB1/beta-actin) were 1.29 +/- 0.10 and 0.34 +/- 0.03 (t = 49.84, P < 0.05), respectively. Both mRNA and protein expression levels of HMGB1 were associated with T stage, clinical stage, lymph node metastasis status and smoking (all P < 0.05), but no significant correlation with age, alcohol consumption and primary tumor grade and location (all P > 0.05). Mean serum HMGB1 protein levels in patients with LSCC and healthy volunteers were (24.80 +/- 14.08) ng/ml and (23.58 +/- 14.69) ng/ml (t = 0.37, P > 0.05). CONCLUSIONS: Both mRNA and protein expressions of HMGB1 were obviously elevated in LSCC, which were associated closely with T stage, clinical stage and lymph node metastasis. PMID- 22932143 TI - [Reconstruction of segmental ear helix defect with post-auricular skin flap]. AB - OBJECTIVE: To explore the method of repairing segmental ear helix defect. METHODS: Twenty-one patients with segmental ear helix defect were repaired with post-auricular skin flap. In the first stage operation, ear helix defect was assessed, including the anterior and posterior area defect. According to the defect, post-auricular skin flap was designed and transplanted to repair the defect. Six weeks later, the pedicle of the post-auricular skin flap was cut off, elevated, and folded to form the helix. The secondary defect was directly sutured or repaired with skin graft. RESULTS: Twenty-one patients were treated with this method. In two to 12 months follow-up, all flaps survived and reconstructed ear helices were in good shape. The reconstructed ears were in symmetry to the healthy ones. CONCLUSION: The method is safe and effective for the correction of segmental ear helix defect. PMID- 22932144 TI - [Evaluation of rhythmic and timbral perception by normal-hearing and postlingually deafened adult cochlear implant users]. AB - OBJECTIVE: To assess the rhythmic and timbral perception ability in musical activities for postlingually deafened adult cochlear implant users. METHODS: Twelve normal-hearing and 12 adult cochlear implant users were recruited in this study. Rhythm discrimination, instrument identification, and instrument number detection measurements in Musical Sounds in Cochlear Implants (MuSIC) test battery were used to assess the rhythmic and timbral perception ability for both normal-hearing and cochlear implant users. RESULTS: Cochlear implant subjects achieved 84.4% correct in rhythm discrimination test on average, which was not significantly different from the performance of normal-hearing subjects (85.1%) (t = 0.116, P > 0.05). The average score of instrument identification and instrument number detection test for cochlear implant subjects were 72.3% and 39.2%, respectively. The performance of cochlear implant subjects in both of two tests were significantly poorer than those of normal-hearing subjects with 88.3% and 73.5% correct, respectively (t = 2.498 and 4.673, P < 0.05). CONCLUSION: Postlingually deafened cochlear implant subjects, on average, performed significantly poorer in timbral perception tasks relative to normal hearing subjects, while close to the ability of normal hearing subjects in rhythmic perception. PMID- 22932145 TI - [Application of minimally invasive technique of coblation in 30 infants with epiglottic cyst]. AB - OBJECTIVE: To present the efficacy of minimally invasive technology of coblation in the treatment of infant epiglottic cyst. METHODS: The clinical data of 30 infants with epiglottic cyst treated between January 2008 and January 2011 were reviewed retrospectively. All infants with epiglottic cyst were treated with the ArthroCare ENT Coblator II Surgery System after being checked completely. RESULTS: All 30 patients were successfully operated. The blood loss was less than 2 ml during the surgery. The infants recovered without any complications and were discharged from hospital in 10 days after surgery. The clinical symptoms improved significantly or disappeared. No patients showed recurrence during followed-up over 6 months. CONCLUSION: The advantage of the minimally invasive technology of coblation in infant epiglottic cyst was less bleeding, little injury and postoperative organization reaction. PMID- 22932146 TI - [Effect of dexmedetomidine on stress responses during extubation in patients undergoing uvulopalatopharyngoplasty]. AB - OBJECTIVE: To observe the effect of dexmedetomidine hydrochloride on stress responses during extubation in patients undergoing uvulopalatopharyngoplasty (UPPP). METHODS: Eighty-six scheduled for UPPP under general anesthesia were randomly divided into dexmedetomidine group (group D, n = 50) and control group (group C, n = 36). All patients were transported into post anesthesia care unit (PACU) after surgery and maintained sedation and analgesia by infusing propofol and sufentanil. Patients in group D were administrated dexmedetomidine 0.5 ug/kg, group C were administrated equivalent volume of normal saline. Both groups were treated with mechanical ventilation 6 - 24 h before extubation. Recovery time, the dosage of sedative and analgesic drugs and side effects were recorded. RESULTS: There were no significant differences between two groups in recovery time (P > 0.05). The dosage of propofol and sufentanil in group D were respectively (785 +/- 65) mg, (176 +/- 10) ug, significantly less than that in group C (950 +/- 101) mg, (209 +/- 14) ug (P < 0.05). side effects in group D were significantly less than that in group C (P < 0.01). CONCLUSIONS: Dexmedetomidine hydrochloride could efficiently restrain the stress response around tracheal extubation, reduce postoperative complications in patients undergoing UPPP. PMID- 22932147 TI - [Application of epiglottis with sternohyoid muscle in the surgery for laryngeal cancer]. AB - OBJECTIVE: To explore and evaluate the application of epiglottis with sternohyoid muscle in the surgery for laryngeal cancer. METHODS: Two fifty patients with laryngeal cancer were treated by partial laryngectomy and the laryngeal defects were reconstructed by epiglottic flap and sternohyoid muscle fascia flap. The staging of tumors: T2N0M0 23 cases, T3N1M0 14 cases, T3N2M0 13 cases. All of them received post radical radiotherapy with average 60 Gy. The patients were followed up for 3 to 5 years. Thirty patients underwent neck dissection. RESULTS: The three and five years survival rates were 90% and 80% respectively. The total cases eat breath pronounced well. The decannulation rate was 96%. CONCLUSION: After partial laryngectomy in laryngeal cancer epiglottic flap and sternohyoid muscle fascia flap were performed reconstruction of laryngeal function. PMID- 22932148 TI - [Intravenous contrast-enhanced ultrasound of metastatic lymph nodes in rabbit VX2 tongue carcinoma model]. AB - OBJECTIVE: To investigate the sonographic features of the cervical lymph nodes in rabbit VX2 tongue carcinoma model and hyperplasia cervical lymph nodes model using gray scale contrast-enhanced ultrasonography (CEUS) after intravenous administration of SonoVue (a sonographic contrast agent) and to evaluate the potential utility of CEUS in detecting early metastatic cervical lymph nodes in the rabbit VX2 tongue carcinoma model. METHODS: Twenty New Zealand rabbits were placed into 2 groups, 12 for node metastasis and 18 for node hyperplasia. Cervical CEUS was performed in the rabbits of both groups before and after intravenous administration of SonoVue(0.6 ml). The phase, pattern, beginning area and echogenicity of enhancement of the lymph nodes on the right neck were observed and recorded. Dissection of the lymph nodes were guided by the marks made during CEUS and examined histopathologically. RESULTS: On the right side of each rabbit only one lymph node were detected in both groups. All 8 cases in the hyperplasia group showed homogeneous enhancement starting from central, while in the metastasis group one case showed homogeneous enhancement starting from the central, 3 cases showed inhomogeneous enhancement starting from periphery, and 8 cases showed inhomogeneous enhancement starting both from central and periphery. One lymph node was dissected on the right side of the neck in each rabbit in both groups. Pathological examination showed all 12 lymph nodes in the metastatic group were metastatic lymph nodes, and all 8 lymph nodes in the hyperplasia group were hyperplastic lymph nodes. CONCLUSIONS: After intravenous CEUS, metastatic lymph nodes show inhomogeneous enhancement starting from periphery/central or periphery area, while hyperplastic lymph nodes show homogeneous enhancement starting from central area. Metastatic lymph nodes can be characterized as being neoplastic or benign on the basis of the enhancement patterns evaluated by CEUS. PMID- 22932149 TI - [Clinical observation of washing nasal cavity and keeping liquid method treatment pregnancy rhinitis nasal congestion]. PMID- 22932150 TI - [Case report: sepsis from a uvulopalatopharyngoplasty]. PMID- 22932151 TI - [Treatment to coma as the first symptom of primary hyperparathyroidism]. PMID- 22932152 TI - [One case of external canal neurofibromatosis]. PMID- 22932153 TI - [Small cell neuroendocrine carcinoma of middle ear: one case report]. PMID- 22932154 TI - [One case of nasal septum chordoma]. PMID- 22932155 TI - [A case with pilomatrix carcinoma]. PMID- 22932156 TI - [Analysis of genes and genetic susceptibility of olfactory disorders]. PMID- 22932157 TI - [Neck dissection for the differentiated thyroid cancer]. PMID- 22932158 TI - [Advances in the treatment of allergic rhinitis]. PMID- 22932160 TI - Long-term effects of aerobic plus resistance training on the adipokines and neuropeptides in nonalcoholic fatty liver disease obese adolescents. AB - OBJECTIVE: To compare the effects of aerobic training (AT) with aerobic plus resistance training (AT+RT) in nonalcoholic fatty liver disease (NAFLD) obese adolescents. DESIGN: Long-term interdisciplinary weight-loss therapy (1 year of clinical, nutritional, psychological, and exercise-related intervention). PARTICIPANTS: Fifty-eight postpubertal obese adolescents were randomized to AT or AT+RT according to NAFLD diagnosis. Adipokine and neuropeptide concentrations were measured by enzyme-linked immunosorbent assay, visceral fat by ultrasound, and body composition by plethysmography. RESULTS: The NAFLD group that followed the AT+RT protocol presented lower insulin, homeostasis model assessment-insulin resistance (HOMA-IR), and alanine transaminase (ALT) values after intervention compared with AT. It was verified that there was a higher magnitude of change in the subcutaneous fat, glycemia, total cholesterol (TC), low-density lipoprotein cholesterol, ALT, and adiponectin in response to AT+RT than in the control group (AT). All patients who underwent the AT+RT exhibited significantly higher adiponectin, leptin, and Deltaadiponectin and lower melanin-concentrating hormone (MCH) concentrations after therapy compared with the AT group. In the simple linear regression analysis, changes in glycemia, insulin, and HOMA-IR were independent predictors of significant improvement in adiponectin concentration. Indeed, DeltaAST (aspartate transaminase) and DeltaGGT (gamma-glutamyl transpeptidase) were independent predictors of DeltaALT, while Deltafat mass and DeltaAgRP (agouti-related protein) were independent predictors of DeltaMCH. Although the number of patients was limited, we showed for the first time the positive effects of AT+RT protocol in a long-term interdisciplinary therapy to improve inflammatory biomarkers and to reduce orexigenic neuropeptide concentrations in NAFLD obese adolescents. CONCLUSION: The long-term interdisciplinary therapy with AT+RT protocol was more effective in significantly improving noninvasive biomarkers of NAFLD that are associated with the highest risk of disease progression in the pediatric population. PMID- 22932161 TI - Taste and appetite disorders of chronic hepatitis C patients. AB - OBJECTIVE: Decreased appetite is one of the main factors that influences quality of life of patients with chronic liver diseases. The reason for appetite disorders remains unclear but taste perturbations are one of the postulated causes. The potential role of taste alterations and, connected to these, appetite disorders in chronic hepatitis C (CHC) patients are poorly investigated. The aim of this study was to evaluate potential taste alterations (dysgeusia) including all five tastes (sweet, salty, bitter, sour and umami) in CHC patients. METHODS: Forty CHC patients (16 men and 24 women) infected with genotype 1 hepatitis C virus participated in this study. All the patients had a compensated liver disease and were being treated with any agents. One hundred and ten healthy volunteers were matched to the patients by age and sex. The study included gustatory tests (taste recognition threshold, taste intensity with hedonic perception) and analysis of the pleasure derived from eating. RESULTS: In CHC patients, the recognition threshold of umami taste was increased (P<0.01) and the intensity of sweet taste perception was higher (P<0.05). The hedonic response did not differ between the groups. A significant increase in declared pleasure derived from eating (P<0.001 to P<0.05) was also observed. Some differences in case of the patients with more advanced disease were also found. CONCLUSION: Alterations in taste, especially umami and sweet taste disorders, may alter real food perception and lead to a reduction in food intake in some CHC patients. PMID- 22932162 TI - Distribution and viability of spermatozoa in the canine female genital tract during post-ovulatory oocyte maturation. AB - BACKGROUND: Unlike other domestic mammals, in which metaphase-II oocytes are ovulated, canine ovulation is characterized by the release of primary oocytes, which may take 12 to up to 36 hours. Further 60 hours are needed for maturation to secondary oocytes which then remain fertile for about 48 hours. Oestrus takes 7 to 10 days on average and may start as early as a week before ovulation. This together with the prolonged process of post-ovulatory oocyte maturation requires an according longevity of spermatozoa in the female genital tract in order to provide a population of fertile sperm when oocytes have matured to fertilizability. Therefore the distribution and viability of spermatozoa in the bitch genital tract was examined during post-ovulatory oocyte maturation. METHODS: Thirteen beagle bitches were inseminated on the day of sonographically verified ovulation with pooled semen of two beagle dogs containing one billion progressively motile spermatozoa. Ovariohysterectomy was performed two days later (group 1, n = 6) and four days later (group 2, n = 7). The oviduct and uterine horn of one side were flushed separately and the flushing's were checked for the presence of gametes. The oviducts including the utero-tubal junction and the uterine horns, both the flushed and unflushed, were histologically examined for sperm distribution. RESULTS: The total number of spermatozoa recovered by flushing was low and evaluation of viability was limited. Prophase-I oocytes were collected from oviduct flushing in group 1, whereas unfertilized metaphase-II oocytes were detected in group 2. From day 2 to day 4 after ovulation a significant decrease in the percentage of glands containing sperm (P<0.05) and a marked reduction of the mean sperm number in uterine horn glands were observed. A concomitant diminution of spermatozoa was indicated in the utero-tubal junction accompanied by a slight increase in sperm numbers in the mid oviduct. CONCLUSIONS: Oocyte maturation to metaphase-II stage is accompanied by a continuous sperm detachment and elimination in the uterine horns. Entrance of spermatozoa into the caudal oviduct seems to be steadily controlled by the utero tubal junction thus providing a selected sperm population to be shifted towards the site of fertilization when oocyte maturation is completed. PMID- 22932164 TI - Identification of pathogen in community-acquired pneumonia and its beyond. PMID- 22932163 TI - Italian Society of Endocrinology Career Award Lecture: from somatostatin to...somatomedin. AB - Somatostatin plays different parts in hormonal regulation through 5 specific receptors in human body. It has two interesting actions such as an antisecretory activity, mostly on the gastrointestinal system and pituitary level, and an antiproliferative action on tumor cells. Many synthetic somatostatin analogues, more stable than the natural one, have been developed and two are already used in different clinical settings, including endocrine oncology. The inhibitory action on tumor growth may result from both indirect actions, namely the suppression of growth factors and growth-promoting hormones (e.g., GH/IGF-I axis) and inhibition of angiogenesis, as well as modulation of the immune system, and direct actions, such as activation of anti-growth activities (e.g., apoptosis). Recently, the development of specific polyclonal antibodies allowed the precise identification of the 5 specific somatostatin receptors and their localization in different cell species. Somatostatin receptor subtypes belong to the G protein-coupled receptor family, share a common molecular topology, and can traffic not only in vitro within different cell types but also in vivo. A picture of the pathways and proteins involved in these processes is beginning to emerge. Moreover, the process of homo- and/or heterodimerization of G-protein coupled receptors and receptor tyrosine kinase families are crucial for implicating the fundamental properties of receptor proteins including receptor expression, trafficking, and desensitization, as well as signal transduction. Furthermore, functional consequences of such an interaction in modulation of signaling pathways linked to pathological conditions specifically in cancer are discussed. PMID- 22932165 TI - Etiology and antimicrobial resistance of community-acquired pneumonia in adult patients in China. AB - BACKGROUND: Appropriate antimicrobial therapy of community-acquired pneumonia (CAP) is mainly based on the distribution of etiology and antimicrobial resistance of major pathogens. We performed a prospective observational study of adult with CAP in 36 hospitals in China. METHODS: Etiological pathogens were isolated in each of the centers, and all of the isolated pathogens were sent to Zhongshan Hospital for antimicrobial susceptibility tests using agar dilution. RESULTS: A total of 593 patients were enrolled in this study, and 242 strains of bacteria were isolated from 225 patients. Streptococcus pneumoniae (79/242, 32.6%) was the most frequently isolated pathogen, followed by Haemophilus influenzae (55/242, 22.7%) and Klebsiella pneumoniae (25/242, 10.3%). Totally 527 patients underwent serological tests for atypical pathogens; Mycoplasma pneumoniae and Chlamydia pneumoniae infections were identified in 205 (38.9%) and 60 (11.4%) patients respectively. Legionella pneumophila infections were identified in 4.0% (13/324) of patients. The non-susceptibility rate of isolated Streptococcus pneumoniae to erythromycin and penicillin was 63.2% and 19.1% respectively. Six patients died from the disease, the 30-day mortality rate was 1.1% (6/533). CONCLUSIONS: The top three bacteria responsible for CAP in Chinese adults were Streptococcus pneumonia, Haemophilus influenza and Klebsiella pneumonia. There was also a high prevalence of atypical pathogens and mixed pathogens. The resistance rates of the major isolated pathogens were relatively low except for the high prevalence of macrolide resistance in Streptococcus pneumoniae. PMID- 22932166 TI - Significance of Aspergillus spp. isolation from lower respiratory tract samples for the diagnosis and prognosis of invasive pulmonary aspergillosis in chronic obstructive pulmonary disease. AB - BACKGROUND: Chronic obstructive pulmonary diseases (COPD) is an emerging population at risk for invasive infection of Aspergillus. Isolation of Aspergillus from lower respiratory tract (LRT) samples is important for the diagnosis of invasive pulmonary aspergillosis (IPA). The purpose of this study was to investigate the value of Aspergillus isolation from LRT samples for the diagnosis and prognosis of IPA in COPD population. METHODS: Clinical record with Aspergillus spp. isolation in COPD and immunocompromised patients was reviewed in a retrospective study. Patients were categorized and compared according to their severity of illness (admitted to general ward or ICU) and immunological function (COPD or immunocompromised). RESULTS: Multivariate statistical analysis showed that, combined with Aspergillus spp. isolation, APACHE II scores > 18, high cumulative doses of corticosteroids (> 350 mg prednisone or equivalent dose) and more than four kinds of broad-spectrum antibiotics received in hospital may be predictors of IPA in COPD (OR = 9.076, P = 0.001; OR = 4.073, P = 0.026; OR = 4.448, P = 0.021, respectively). The incidence of IPA, overall mortality, mortality of patients with IPA and mortality of patients with Aspergillus spp. colonization were higher in COPD patients in ICU than in general ward, but were similar between COPD and immunocompromised patients. CONCLUSIONS: Aspergillus spp. isolation from LRT in COPD may be of similar importance as in immunocompromised patients, and may indicate an increased diagnosis possibility of IPA and worse prognosis when these patients received corticosteroids, antibiotics, and need to admit to ICU. Aspergillus spp. isolation from LRT samples combined with certain risk factors may be useful in differentiating colonization from IPA and evaluating the prognosis of IPA in COPD patients. PMID- 22932167 TI - Initial computed tomography findings of invasive pulmonary aspergillosis in non hematological patients. AB - BACKGROUND: The computed tomography (CT) findings of invasive pulmonary aspergillosis (IPA) are unclear in non-hematological patients. The present study was a retrospective evaluation of CT images in non-hematological patients with IPA. METHODS: All adult patients who met the 2008 European Organization for Research and Treatment of Cancer/Mycoses Study Group (EORTC/MSG) criteria for proven or probable IPA were included during a 5-year study at our institutions. Initial CT findings in our cohort were retrospectively reviewed by two independent thoracic radiologists blinded to patient demographics and clinical outcomes. The presence, pattern, and distribution of abnormalities were recorded. RESULTS: Twenty-three non-hematological patients with pathologically confirmed IPA were included in our study. Areas of ground-glass opacities were present in 14 patients (61%), which were bilateral in 10 patients and unilateral in four. This pattern mainly involved the middle and upper lung zones. Air-space consolidation was identified in 12 patients (52%), and the areas were distributed along the bronchus or subpleura in most cases. Other findings, including five small nodules (22%), three macronodules (13%), and one halo sign (4%), were less common. CONCLUSIONS: CT findings of IPA in non-hematological patients frequently manifested as acute bronchopneumonia, and ground-glass opacities and air-space consolidations were the most common CT findings of IPA in these patients. PMID- 22932168 TI - Current asthma control predicts future risk of asthma exacerbation: a 12-month prospective cohort study. AB - BACKGROUND: The performance of asthma control test (ACT) at baseline for predicting future risk of asthma exacerbation has not been previously demonstrated. This study was designed to explore the ability of the baseline ACT score to predict future risk of asthma exacerbation during a 12-month follow-up. METHODS: This post hoc analysis included data from a 12-month prospective cohort study in patients with asthma (n = 290). The time to the first asthma exacerbation was analyzed and the association between baseline ACT scores and future risk of asthma exacerbation was calculated as adjusted odds ratio (OR) using Logistic regression models. Further, sensitivity and specificity were estimated at each cut-point of ACT scores for predicting asthma exacerbations. RESULTS: The subjects were divided into three groups, which were uncontrolled (U, n = 128), partly-controlled (PC, n = 111), and well controlled (C, n = 51) asthma. After adjustment, the decreased ACT scores at baseline in the U and PC groups were associated with an increased probability of asthma exacerbations (OR 3.65 and OR 5.75, respectively), unplanned visits (OR 8.03 and OR 8.21, respectively) and emergency visits (OR 20.00 and OR 22.60, respectively) over a 12-month follow-up period. The time to the first asthma exacerbation was shorter in the groups with U and PC asthma (all P < 0.05). The baseline ACT of 20 identified as the cut-point for screening the patients at high risk of asthma exacerbations had an increased sensitivity of over 90.0% but a lower specificity of about 30.0%. CONCLUSION: Our findings indicate that the baseline ACT score with a high sensitivity could rule out patients at low risk of asthma exacerbations and predict future risk of asthma exacerbations in clinical practice. PMID- 22932169 TI - Budesonide/formoterol maintenance and reliever therapy in Chinese patients with asthma. AB - BACKGROUND: Many studies have shown the superior efficacy of budesonide (BUD)/formoterol (FORM) maintenance and reliever therapy, but still lack evidence of its efficacy in Chinese asthma patients in a relative large patient-group. We finished this research to compare BUD/FORM maintenance and reliever therapy and high-dose salmeterol (SALM)/fluticasone (FP) maintenance plus an as-needed short acting beta(2)-agonist in Chinese patients with persistent uncontrolled asthma. This was a post hoc analysis based on a 6-month, multicenter, randomized, double blind study (NCT00242775). METHODS: A total of 222 eligible asthma patients from nine centers in China were randomized to either BUD/FORM+as-needed BUD/FORM (160/4.5 ug/inhalation) (640/18 ug/d; n = 111), or SALM/FP+as-needed terbutaline (0.4 mg/inhalation) (100/1000 ug/d; n = 111). The primary endpoint was time to first severe exacerbation while secondary endpoints included various measures of pulmonary function, symptom control and quality-of-life. RESULTS: Time to first severe exacerbation over six months was lower with the BUD/FORM than with the SALM/FP treatment (risk ratio = 0.52, 95%CI 0.22 - 1.22), but the difference did not achieve statistical significance (P = 0.13). The cumulative number of severe exacerbations in the BUD/FORM group was lower than in the SALM/FP group (7.2% vs. 13.5%; risk ratio = 0.45, P = 0.028). BUD/FORM produced significantly better improvements in reliever use, cumulative mild exacerbations, symptom-free days (%), and morning/evening peak expiratory flow (PEF) than SALM/FP (P < 0.05 in all cases). The two groups achieved similar improvements in their time to first mild exacerbation, forced expiratory volume in one second (FEV(1)), asthma control questionnaire and asthma symptom scores, and percentage of nights with awakening(s). Both treatments were well tolerated. CONCLUSIONS: In Chinese patients with persistent asthma, BUD/FORM decreased severe and mild exacerbations, decreased reliever use, increased symptom-free days, and improved morning/evening PEF compared with SALM/FP. There were no significant differences in time to first severe exacerbation or other assessments regarding daily asthma control between BUD/FORM and SALM/FP. BUD/FORM was more effective in this Chinese sub-group than in the total cohort involved in the original study. PMID- 22932170 TI - An uncontrolled open-label, multicenter study to monitor the antiviral activity and safety of inhaled zanamivir (as Rotadisk via Diskhaler device) among Chinese adolescents and adults with influenza-like illness. AB - BACKGROUND: It is the first multicenter clinical study in China to investigate zanamivir use among Chinese adolescents and adults with influenza-like illness (ILI) since 2009, when inhaled zanamivir (RELENZA((r))) was marketed in China. METHODS: An uncontrolled open-label, multicentre study to evaluate the antiviral activity, and safety of inhaled zanamivir (as Rotadisk via Diskhaler device); 10 mg administered twice daily for 5 days in subjects >= 12 years old with ILI. Patients were enrolled within 48 hours of onset and followed for eight days. Patients were defined as being influenza-positive if the real-time reverse transcriptase-polymerase chain reaction (rRT-PCR) test had positive results. RESULTS: A total of 400 patients >= 12 years old were screened from 11 centers in seven provinces from March 2010 to January 2011. Three hundred and ninety-two patients who took at least one dose of zanamivir were entered into the safety analysis. The mean age was 33.8 years and 50% were male. Cardiovascular diseases and diabetes were the most common comorbidities. All the reported adverse events, such as rash, nasal ache, muscle ache, nausea, diarrhea, headache, occurred in less than 1% of subjects. Mild sinus bradycadia or arrhythmia occurred in four subjects (1%). Most of the adverse events were mild and did not require any change of treatment. No severe adverse events (SAE) or fatal cases were reported. Bronchospasm was found in a 38 years old woman whose symptoms disappeared after stopping zanamivir and without additional treatment. All the 61 influenza virus isolates (43 before enrollment, 18 during treatment) proved to be sensitive to zanamivir. CONCLUSIONS: Zanamivir is well tolerated by Chinese adolescents and adults with ILIs. There is no evidence for the emergence of drug-resistant isolates during treatment with zanamivir. PMID- 22932171 TI - Radial probe endobronchial ultrasound scanning assessing invasive depth of central lesions in tracheobronchial wall. AB - BACKGROUND: Patients with central tracheobronchial benign or malignant lesions who have not recieved surgical treatment can be treated by interventional techniques, such as laser, afterloading radiotherapy, cryotherapy, photodynamics treatment, radiofrequency ablation and stenting, etc. The accuracy of the invasive depth of central lesion in tracheobronchial wall plays an important role in making interventional treatment plan. This study used radial probe endobronchial ultrasound (RP-EBUS) scanning to evaluate the accuracy of the invasive depth of central lesions in tracheobronchial wall, and the influence of RP-EBUS scanning in treatment plan making and guidance. METHODS: This was a prospective study of consecutive patients with central tracheobronchial lesions found by CT or bronchoscopy. We performed EBUS scanning after common bronchoscopy under local anesthesia. A radial ultrasonic probe (2.0 mm in diameter with 20-MHz frequency) with a balloon sheath was introduced through the 2.8-mm-diameter channel of a flexible bronchoscope. The balloon at the tip of the probe was inflated with distilled water until coupling with the airway wall under endoscopic control. The circular image of EBUS, which revealed the layered structure of the tracheobronchial wall, could be achieved. RESULTS: Total of 125 patients were enrolled in the study. Thirty patients underwent surgical operation and pathologically proved the RP-EBUS diagnosis accuracy of tumor invasive depth in tracheobroncial wall was 90% (27/30), sensitivity and specificity were 88.89% (24/27) and 100% (3/3), respectively. In response to EBUS images, 40 approaches were altered or guided: lymph-node metastasis and compressive lesions was diagnosed by EBUS-guided transbronchial needle aspiration (TBNA) (n = 8); Lesions ablation with laser or electricity were stopped when EBUS demonstrated close range with vessels or perforation possibility (n = 13), stents size were changed (n = 14), operation was canceled (n = 3) and foreign body was removed (n = 2). No complication associated with the use of EBUS was observed. CONCLUSION: RP-EBUS can be a useful tool in assessing the central lesion invasive depth to the tracheobronchial wall. PMID- 22932172 TI - Characteristics of pulmonary inflammation in combined pulmonary fibrosis and emphysema. AB - BACKGROUND: The condition of concomitant upper lobe emphysema and lower lobe fibrosis as identified by computer tomography is known as combined pulmonary fibrosis and emphysema (CPFE). CPFE has distinct clinical characteristics compared with emphysema alone (EA) and idiopathic pulmonary fibrosis (IPF) without emphysema. However, the pulmonary inflammation characteristics of CPFE are not well known, and the differences between CPFE and the other two diseases with regards to pulmonary inflammation need to be explored. The pulmonary inflammatory characteristics were investigated in CPFE patients and compared with EA and IPF. METHODS: Fraction exhaled nitric oxide (Fe,NO) and differential cell counts, the concentrations of monokine induced by interferon gamma (MIG/CXCL9), interferon-inducible protein 10 (IP-10/CXCL10), and interferon-inducible T cell alpha chemoattractant (I-TAC/CXCL11) were measured in induced sputum obtained from subjects with CPFE (n = 22), EA (n = 22), IPF (n = 14), and healthy volunteers (HV, n = 12). In addition, immunohistochemistry was used to quantify the expression of nitric oxide synthases in alveolar macrophages in 23 lung tissues from patients and control subjects. RESULTS: The CPFE group had higher alveolar NO than subjects in the EA and HV groups (P = 0.009, P = 0.001, respectively) but not than the IPF group (P > 0.05). Numbers of sputum eosinophils were significantly elevated in CPFE and IPF groups compared with the HV group (P = 0.001, P = 0.008). In contrast, eosinophil counts in EA group did not differ from those in the HV group. Compared with the EA and HV groups, the CPFE group had a lower concentration of I-TAC/CXCL11 in sputum supernatants (P = 0.003, P = 0.004). Immunoreactivity for inducible nitric oxide synthase (iNOS) was higher in the CPFE group than in the EA group (P = 0.018, P = 0.006, respectively). CONCLUSIONS: The pulmonary inflammation of CPFE group is more similar to IPF group, while the distal airway inflammation is more significant in CPFE and IPF groups than in EA group. Lung eosinophil cell infiltration and high NOS expression in alveolar macrophage might participate in this pathogenesis. PMID- 22932173 TI - Long-term outcomes of surgical treatment for pulmonary carcinoid tumors: 20 years' experience with 131 patients. AB - BACKGROUND: Bronchial carcinoids are rare malignant neuroendocrine neoplasms. Some issues regarding surgical treatment of bronchial carcinoids remain controversial, including the role of bronchoplastic surgery and necessity of systematic lymphadenectomy. METHODS: This retrospective study involved 131 consecutive patients surgically treated for carcinoid tumors at Shanghai Chest Hospital between March 1990 and August 2010. RESULTS: Eighty-nine (67.9%) of the patients were male, and the mean age was 46 years, ranging from 17 to 81 years. Preoperative fiberoptic bronchoscopy was performed in all patients. Endoscopic biopsy was performed in 100 patients with central tumors, and 70 (70%) patients were diagnosed as bronchial carcinoid. The resections performed consisted of 31 pneumonectomie, 32 lobectomies, 26 bilobectomies, 34 sleeve lobectomies, six bronchoplastic procedures without lung resection, and two segmentectomies. During a median of 87 months follow-up, there were nine recurrences including three local recurrences and 6 distant recurrences. No bronchial recurrences were observed. The 3-, 5- and 10-year overall survival rates of pneumonectom and bronchoplastic surgery (including sleeve lobectomy and bronchoplastic procedure without lung resection) were 93.2%, 81.0% and 69.4%, 97.5%, 91.9% and 70.0%, respectively. Multivariate Cox regression indicated that histology and nodal status were significant independent prognostic factors. CONCLUSIONS: Bronchoplastic surgery should be considered whenever possible for central carcinoids. Systematic lymphadenectomy is recommended for bronchial carcinoid patients. Histology and nodal status were significant independent prognostic factors of overall survival of patients with bronchial carcinoid. PMID- 22932174 TI - Proteomic analysis for detecting serum biomarkers related to smoking in humans. AB - BACKGROUND: Smoking is the leading cause of death in the world. This study focused on the difference of the serum proteomic profiling between healthy smokers and nonsmokers in order to find smoking-specific serum biomarkers. METHODS: Pattern-based proteomic profiling of 100 serum samples (from 50 Chinese male smokers and 50 matched nonsmokers) was performed through magnetic bead fractionation coupled with matrix-assisted laser desorption/ionization time-of flight mass spectrometry analysis (MALDI-TOF-MS) and resulting data were statistically analyzed by Ciphergen ProteinChip software 3.0.2. RESULTS: We found 72 serum peaks were significantly different between smokers and nonsmokers (P < 0.05). Marker peaks of mass-to-charge ratio (m/z) 3159.13, 7561.03 and 9407.32 were smoking-specific. CONCLUSION: The preliminary data suggested that smoking specific serum biomarkers could be detected in humans. PMID- 22932175 TI - Prevalence and risk factors of chronic post-thoracotomy pain in Chinese patients from Peking Union Medical College Hospital. AB - BACKGROUND: In clinical practice, the mechanisms underlying chronic post-surgical pain (CPSP) remain insufficiently understood. The primary goals of this study were to determine the incidence of chronic pain after thoracic surgery and to identify possible risk factors associated with the development of chronic post thoracotomy pain in Chinese patients. The secondary goal was to determine whether the difference between pre- and post-operative white blood cell (WBC) counts could predict the prevalence of CPSP after thoracotomy. The impact of chronic pain on daily life was also investigated. METHODS: We contacted by phone 607 patients who had undergone thoracotomy at our hospital during the period February 2009 to May 2010. Statistical comparisons were made between patients with or without CPSP. RESULTS: RESULTS: were ultimately analyzed from 466 qualified patients. The overall incidence of CPSP was 64.5%. Difference between pre- and post-operative WBC counts differed significantly between patients with or without CPSP (P < 0.001) and was considered as an independent risk factor for the development of CPSP following thoracotomy (P < 0.001). Other predictive factors for chronic pain included younger age (< 60 years, P < 0.001), diabetes mellitus (P = 0.023), acute post-operative pain (P = 0.005) and the duration of chest tube drainage (P < 0.001). At the time of interviews, the pain resulted in at least moderate restriction of daily activities in 15% of the patients, of which only 16 patients had paid a visit to the doctor and only three of them were satisfied with the therapeutic effects. CONCLUSIONS: Chronic pain is common after thoracotomy. WBC count may be a new independent risk factoring surgical patients during peri-operative period. Besides, age, diabetes mellitus, acute post operative pain, and duration of chest tube drainage may also play a role in chronic post-surgical pain occurrence. PMID- 22932176 TI - Pharyngeal aerodynamic characteristics of obstructive sleep apnea/hypopnea syndrome patients. AB - BACKGROUND: The role of nasal obstruction in the pathogenesis of obstructive sleep apnea/hypopnea syndrome (OSAHS) has been debated for decades. In this prospective study, we compared the pharyngeal aerodynamic characteristics of OSAHS patients and normal people, and investigated the contribution of total nasal airway resistance to the pathophysiology of OSAHS. METHODS: Computational fluid dynamics (CFD) was used to extract the average pressure and average airflow velocity in three transverse cross-sectional planes of the pharynx for statistical analysis, and the correlation between nasal resistance and the average pressure in the pharyngeal cavity was investigated. RESULTS: The negative pressure within the pharyngeal cavity was significantly higher in OSAHS patients than in normal subjects, and total nasal airway resistance correlated well with the average pressure in three consecutive transverse cross-sections of the pharyngeal cavity. CONCLUSIONS: Greater negative pressure within the pharyngeal cavity contributed to the increased collapsibility of the pharynx in OSAHS patients, and the strong correlation between nasal resistance and pharyngeal pressure suggests that the nose plays a role in the pathogenesis of OSAHS. PMID- 22932177 TI - Control method exploration of nosocomial bloodstream infection and its effect evaluation. AB - BACKGROUND: Currently, slightly more than 50% of bloodstream infections (BSIs) are hospital acquired. When these infections occur in patients in intensive care units, they are associated with a high mortality rate, additional hospital days and excess hospital costs. Because of multifactor of nosocomial BSIs, measurements of control nosocomial BSIs are wide variety and lead to some confusion in practice. The aim of this study was to explore special way in accordance with self-hospital base on common principle. METHODS: In one ward of the Intensive Care Unit, Peking Union Medical College Hospital, at first, we divided the all operation about bloodstream way into three sections used as keypoints. By surveying keypoints respectively, some operation faults of blood way were discovered. For decreasing the mobidity of nosocomial BSIs, some intervention measurements were executed. The rate of nosocomial BSIs was analyzed by chi-square test. RESULTS: According to the statistics from January to June, we received and cured 618 patients in total; among them, there were 13 cases of nosocomial BSI and the average occurrence was 2.3 cases/month. After intervention measurements from July to December 2011, we received and cured 639 patients in total with seven cases of nosocomial BSI, and the average occurrence was 1.2 cases/month (P < 0.05). From January to April 2012, no nosocomial BSI occurred in the investigated ward. CONCLUSION: Removing the operation faults of bloodstream way might decrease the nosocomial BSI rapidly and efficiently by utilizing a key point survey. PMID- 22932178 TI - Evaluation of clustering algorithms for gene expression data using gene ontology annotations. AB - BACKGROUND: Clustering is a useful exploratory technique for interpreting gene expression data to reveal groups of genes sharing common functional attributes. Biologists frequently face the problem of choosing an appropriate algorithm. We aimed to provide a standalone, easily accessible and biologically oriented criterion for expression data clustering evaluation. METHODS: An external criterion utilizing annotation based similarities between genes is proposed in this work. Gene ontology information is employed as the annotation source. Comparisons among six widely used clustering algorithms over various types of gene expression data sets were carried out based on the criterion proposed. RESULTS: The rank of these algorithms given by the criterion coincides with our common knowledge. Single-linkage has significantly poorer performance, even worse than the random algorithm. Ward's method archives the best performance in most cases. CONCLUSIONS: The criterion proposed has a strong ability to distinguish among different clustering algorithms with different distance measurements. It is also demonstrated that analyzing main contributors of the criterion may offer some guidelines in finding local compact clusters. As an addition, we suggest using Ward's algorithm for gene expression data analysis. PMID- 22932179 TI - Relationship between 6-minute walk test and pulmonary function test in stable chronic obstructive pulmonary disease with different severities. AB - BACKGROUND: The relationship between the 6-minute walk test (6MWT) and pulmonary function test in stable chronic obstructive pulmonary disease (COPD) remains unclear. We evaluate the correlation of 6MWT and spirometric parameters in stable COPD with different severities. 6MWT data assessed included three variables: the 6-minute walk distance (6MWD), 6-minute walk work (6MWORK), and pulse oxygen desaturation rate (SPO(2)%). METHODS: 6MWT and pulmonary function test were assessed for 150 stable COPD patients with different severities. Means and standard deviations were calculated for the variables of interest. Analysis of variance was performed to compare means. Correlation coefficients were calculated for 6MWT data with the spirometric parameters and dyspnea Borg scale. Multiple stepwise regression analysis was used to screen pulmonary function-related predictors of 6MWT data. RESULTS: The three variables of 6MWT all varied as the severities of the disease. The 6MWD and 6MWORK both correlated with some spirometric parameters (positive or negative correlation; the absolute value of r ranging from 0.34 to 0.67; P < 0.05) in severe and very severe patients, and the SPO2% correlated with the dyspnea Borg scale in four severities (r = -0.33, 0.34, -0.39, -0.53 respectively; P < 0.05). The 6MWD was correlated with the 6MWORK in four severities (r = 0.56, 0.57, 0.72, 0.81 respectively, P < 0.05), and neither of them correlated with the SPO(2)%. The percent of predicted forced expiratory volume in 1 second (FEV(1)% predicted) and residual volume to total lung capacity ratio (RV/TLC) were predictors of the 6MWD, and the maximum voluntary ventilation (MVV) was the predictor of the 6MWORK. CONCLUSIONS: 6MWT correlated with the spirometric parameters in severe and very severe COPD patients. 6MWT may be used to monitor changes of pulmonary function in these patients. PMID- 22932180 TI - Plasma cholinesterase in critical illness. PMID- 22932181 TI - Indoor mite allergen levels, specific IgE prevalence and IgE cross-inhibition pattern among asthmatic children in Haikou, southern China. AB - BACKGROUND: Haikou locates in tropical island with unique mite propagation. The aim of this stuy is to determine mite allergens levels in Haikou, and to investigate the prevalence of mite specific IgE-sensitization and IgE cross reactivity between house dust mites. METHODS: Allergen and antigen concentrations against six mite species were tested by enzyme-linked immunosorbent assay (ELISA). Specific IgE concentrations and cross-inhibitions were measured with ADVIA Centaur((r)). RESULTS: Allergen or antigen Dermatophagoides pteronyssinus (Der p 1), Blomia tropicalis (Blo t) and Tyrophagus putrescentia (Tyr p) were detected in dust samples. Dermatophagoides farinae (Der f 1), Lepidoglyphus destructor (Lep d 2), and Acarus siro (Aca s) were found in very few samples. Specific IgE tests showed high prevalence of sensitizations against all tested mites with high IgE levels to Der p, Der f, and Blo t. Storage mites, Blo t, Tyr p, Lep d, and Aca s, could inhibit Der p from 0 to 50%. Storage mites could inhibit Der f between 30% and 100%. Der p IgE could be inhibited by Der f with up to 90%, and vice versa. Der p could inhibit Blo t from 40% to 80%. Blo t was able to fully inhibit IgE binding to Lep d, Tyr p, and Aca s compared to partial inhibition by Der p. CONCLUSIONS: Der p is the dominating mite and has the highest specific IgE prevalence among asthmatic children. Blo t represents an important source of storage mite sensitization and some patients may be independently sensitized to both Der p and Blo t. High prevalence of sensitization to Der f may be due to IgE-mediated cross-reactivity with Der p and Blo t. PMID- 22932182 TI - Age-associated changes in pulmonary function: a comparison of pulmonary function parameters in healthy young adults and the elderly living in Shanghai. AB - BACKGROUND: The respiratory system changes with age and a better understanding of the changes contribute to detect and prevent respiratory dysfunctions in old population. The purpose of this study was to observe age-associated changes of pulmonary function parameters in healthy young adults and the elderly. METHODS: A cross-sectional study was conducted among 600 male and female subjects aged 19 to 92 years. The subjects were divided into three groups by age: young adult (19 - 39 years), middle-aged adult (40 - 59 years), and the elderly (>= 60 years). The pulmonary function was measured with routine examination methods and 13 parameters including vital capacity (VC), residual volume (RV), functional residual capacity (FRC), total lung capacity (TLC), RV/TLC, forced vital capacity (FVC), forced expiratory volume in one second (FEV(1)), FEV(1)/FVC, peak expiratory flow (PEF), forced expiratory flow at 25% of FVC exhaled (FEF(25)), forced expiratory flow at 50% of FVC exhaled (FEF(50)), diffusion capacity of the lung for carbon monoxide (D(L)CO), and specific diffusion capacity of CO (KCO) were collected and analyzed. Changes in pulmonary function parameters among the pre-elderly and elderly subjects, especially the aging influence on FEV(1)/FVC and RV were studied further. RESULTS: Ten pulmonary function parameters including VC, FVC, FEV(1), FEV(1)/FVC, PEF, FEF(25), FEF(50), TLC, D(L)CO and KCO decreased significantly with age in both male and female subjects (P < 0.01). RV and RV/TLC were increased with age (P < 0.01). FRC remained stable during aging. Except FRC, the linear relationship was significant between age and other pulmonary function parameters. In the pre-elderly and elderly subjects, RV had a non-significantly increasing tendency with age (P > 0.05), and FEV(1)/FVC did not change significantly with age (P > 0.05). CONCLUSION: Total pulmonary function was declined with advancing age, but FRC was stable, and the increasing tendency of RV and decreasing tendency of FEV(1)/FVC obviously slowed down in the pre-elderly and elderly subjects. PMID- 22932183 TI - Clinical features and imaging findings in pulmonary capillary hemangiomatosis: report of two cases and a pooled analysis. AB - BACKGROUND: Pulmonary capillary hemangiomatosis (PCH) is a rare disease and no Chinese case has been reported yet. The disease is often misdiagnosed and its clinical characteristics are incompletely described. The aim of this study was to describe two Chinese cases and to clarify the clinical and radiographic parameters of patients with PCH. METHODS: Two PCH cases were presented and other cases were searched from the English literature. All available clinical and radiographic data were collected from 62 literature reported PCH cases. A pooled analysis of total 64 cases was made. RESULTS: Dyspnea and hemoptysis were the most common clinical symptoms of PCH. Pulmonary hypertension (PH) was found in 78% of the reported cases. PCH typically showed characteristic diffuse or patchy ground-glass opacities (GGOs) and/or multiple ill-defined centrilobular nodules in the computed tomography. CONCLUSIONS: The diagnosis of PCH requires a high clinical suspicion. However, both clinical presentations and radiographic studies often provide clues to the diagnosis, which may prompt early lung biopsy for a definite diagnosis. PMID- 22932184 TI - Thioredoxin and impaired spatial learning and memory in the rats exposed to intermittent hypoxia. AB - BACKGROUND: Obstructive sleep apnea (OSA) can cause cognitive dysfunction and may be a reversible cause of cognitive loss in patients with Alzheimer's disease (AD). Chronic exposure to intermittent hypoxia (IH), such as encountered in OSA, is marked by neurodegenerative changes in rat brain. We investigated the change of thioredoxin (Trx), spatial learning and memory in rats exposed to chronic intermittent hypoxia (CIH). METHODS: Forty healthy male Sprague-Dawley (SD) rats were randomly divided into four groups of ten each: a CIH+normal saline (CIH+NS group), a N-acetylcystein-treated CIH (CIH+NAC) group, a sham CIH group (sham CIH+NS), and a sham NAC-treated sham CIH (CIH+NAC) group. Spatial learning and memory in each group was assessed with the Morris water maze. Real-time PCR and Western blotting were used to examine mRNA and protein expression of Trx in the hippocampus tissue. The terminal deoxynucleotidyl transferase-mediated dUTP-nick end-labeling (TUNEL) method was used to detect the apoptotic cells of the hippocampus CA1 region. RESULTS: CIH-rats showed impaired spatial learning and memory in the Morris water maze, including longer mean latencies for the target platform, reduced numbers of passes over the previous target platform and a smaller percentage of time spent in the target quadrant. Trx mRNA and protein levels were significantly decreased in the CIH-hippocampus, meanwhile, an elevated apoptotic index revealed apoptosis of hippocampal neurons of rats exposed to CIH. The rats, which acted better in the Morris water maze, showed higher levels of the Trx mRNA and protein in the hippocampus; apoptotic index of the neurons in the hippocampus of each group was negatively correlated with the Trx mRNA and protein levels. CONCLUSION: The Trx deficit likely plays an important role in the impaired spatial learning and memory in the rats exposed to CIH and may work through the apoptosis of neurons in the hippocampus. PMID- 22932185 TI - Effect of anterior nucleus of thalamus stimulation on glucose metabolism in hippocampus of epileptic rats. AB - BACKGROUND: Electrical stimulation of the anterior nucleus of the thalamus (ANT) appears to be effective against seizures. In this study, we investigated changes in glucose metabolism during high-frequency stimulation of ANT in epileptic rats. METHODS: Three groups of rats were used: (1) a stimulation group (n = 12), (2) a sham stimulation group (n = 12) with seizures induced by stereotactic administration of kainic acid (KA), and (3) a control group (n = 12) with sham surgery. Concentric bipolar electrodes were stereotaxically implanted unilaterally in the ANT. High-frequency stimulation was performed in each group except the sham stimulation group. Microdialysis probes were lowered into the CA3 region of the hippocampus unilaterally but bilaterally in the stimulation group. The concentrations of glucose, lactate, and pyruvate in dialysate samples were determined by an ISCUS microdialysis analyzer. RESULTS: The extracellular concentrations of lactate and lactate/pyruvate ratio (LPR) of epileptic rats were significantly higher than in control rats (P = 0.020, P = 0.001; respectively). However, no significant difference in the concentration of glucose and pyruvate was found between these groups (P > 0.05). Electrical stimulation of ANT induced decreases in lactate and LPR in the ipsilateral hippocampus (KA injected) of the stimulation group (P < 0.05), but it did not influence the glucose metabolism in the contralateral hippocampus (P > 0.05). CONCLUSIONS: This study demonstrated that the glycolysis was inhibited in the ipsilateral hippocampus of epileptic rats during electrical ANT stimulation. These findings may provide useful information for better understanding the mechanism of ANT-deep brain stimulation. PMID- 22932186 TI - Chronic intermittent hypoxia aggravates cardiomyocyte apoptosis in rat ovariectomized model. AB - BACKGROUND: The prevalence of obstructive sleep apnea (OSA) increases after menopause in women, but remains under diagnosed because of social or lifestyle factors. It is important to evaluate the hazards of OSA on cardiovascular disease in menopausal women. We tested the hypothesis that chronic intermittent hypoxia (CIH) may aggravate cardiomyocyte apoptosis in ovariectomized (OVX) Sprague Dawley (SD) rats; the changes of anti-oxidation ability in cardiac muscles may be one of the reasons for cardiomyocyte apoptosis. METHODS: Forty-eight 60-day old female SD rats were randomly divided into a CIH group, OVX group, OVX+CIH (OC) group, and handled control (HC) group, and the rats were exposed either to CIH (nadir O2 6%) or handled normoxic controls. The changes of body weight and whole heart weight were measured. Super oxide dismutase (SOD) and malonaldehyde (MDA) were used to evaluate the level of oxidative stress. TdT-mediated dUTP nick end labeling (TUNEL) was used to measure apoptosis in each rat. Western blotting was used to measure apoptosis associated proteins in cardiac muscle samples from each rat. RESULTS: When compared with the HC and CIH groups, the levels of oxidative stress in the OC and OVX groups were significantly higher. The levels of SOD in the HC, CIH, OC, and OVX groups were (47.99 +/- 4.89), (53.60 +/- 4.47), (20.99 +/- 2.72), and (30.64 +/- 3.79) mmol/mg protein; significantly increased in the CIH group (P < 0.05) and significantly decreased in the OC (P < 0.01) and OVX (P < 0.05) groups. The levels of MDA in the HC, CIH, OVX, and OC groups were (1.63 +/- 0.20), (1.93 +/- 0.77), (3.30 +/- 0.39), and (1.95 +/- 0.20) mmol/mg protein; it significantly increased in the CIH (P < 0.05), OC (P < 0.01), and OVX (P < 0.05) groups compared with the HC group. Bax protein expression was significantly increased and bcl-2 protein expression was significantly reduced after CIH compared with HC rats (P < 0.05). The protein expression of bax and bcl-2 in the OC group was not significantly different from the CIH group, but the ratio of bax/bcl-2 was significantly increased in the OC group (P < 0.05); this was associated with severe cardiomycyte apoptosis in the OC group. TUNEL confirmed this observation. CONCLUSIONS: This study found that CIH may induce oxidative stress in OVX rats but not in CIH rats, and cause more severe cardiomyocyte apoptosis in OVX rats compared with CIH rats. This means that OVX rats exposed to CIH suffered more severe cardiac injury compared with CIH rats due to reduced antioxidation. These findings may partly explain the reason why OSA has a worse cardiovascular impact on menopausal women, and emphasize the importance of detection and early treatment of OSA in menopausal patients. PMID- 22932187 TI - Protective effect of low potassium dextran solution on acute kidney injury following acute lung injury induced by oleic acid in piglets. AB - BACKGROUND: Low potassium dextran (LPD) solution can attenuate acute lung injury (ALI). However, LPD solution for treating acute kidney injury secondary to ALI has not been reported. The present study was performed to examine the renoprotective effect of LPD solution in ALI induced by oleic acid (OA) in piglets. METHODS: Twelve animals that suffered an ALI induced by administration of OA into the right atrium were divided into two groups: the placebo group (n = 6) pretreated with normal saline and the LPD group (n = 6), pretreated with LPD solution. LPD solution was injected intravenously at a dose of 12.5 ml/kg via the auricular vein 1 hour before OA injection. RESULTS: All animals survived the experiments with mild histopathological injury to the kidney. There were no significant differences in mean arterial pressure (MAP), creatinin and renal damage scores between the two groups. Compared with the placebo group, the LPD group had better gas exchange parameters at most of the observation points ((347.0 +/- 12.6) mmHg vs. (284.3 +/- 11.3) mmHg at 6 hours after ALI, P < 0.01). After 6 hours of treatment with OA, the plasma concentrations of NGAL and interleukin (IL)-6 in both groups increased dramatically compared to baseline ((6.0 +/- 0.6) and (2.50 +/- 0.08) folds in placebo group; and (2.5 +/- 0.5) and (1.40 +/- 0.05) folds in LPD group), but the change of both parameters in the LPD group was significantly lower (P < 0.01) than in the placebo group. And 6 hours after ALI the kidney tissue concentration of IL-6 in the LPD group ((165.7 +/- 22.5) pg*ml(-1)*g(-1) protein) was significantly lower (P < 0.01) than that in placebo group ((67.2 +/- 25.3) pg*ml(-1)*g(-1) protein). CONCLUSION: These findings suggest that pretreatment with LPD solution via systemic administration might attenuate acute kidney injury and the cytokine response of IL-6 in the ALI piglet model induced by OA injection. PMID- 22932188 TI - Erythropoietin decreases carbon tetrachloride-induced hepatic fibrosis by inhibiting transforming growth factor-beta. AB - BACKGROUND: In addition to hematopoietic effect, the erythropoietin is known as a multifunctional cytokine with anti-fibrosis and organ-protective activities. The purpose of this study was to evaluate the effect of recombinant human erythropoietin (rhEPO) on hepatic fibrosis and hepatic stellate cells (HSCs). METHODS: Carbon tetrachloride (CCl(4)) induced hepatic fibrosis mice models were used for in vivo study and HSCs line for in vitro study. CCl(4) and rhEPO (0, 200 or 1000 U/kg) was injected intraperitoneally in BALB/c mice three times a week for 4 weeks. Immunohistochemistry and immunoblotting were performed to evaluate expressions of transforming growth factor-beta1 (TGF-beta1), alpha-smooth muscle actin (alpha-SMA), and fibronectin in explanted liver. Immunoblotting of alpha SMA, phophorylated Smad-2 and Smad-2/3 was performed in HSCs treated with TGF beta1 and/or rhEPO. RESULTS: Expressions of TGF-beta1, alpha-SMA, and fibronectin were increased in CCl(4) injected mice livers, but significantly attenuated by co treatment with CCl(4) and rhEPO. Co-treatment of rhEPO markedly suppressed fibrosis in Masson's trichrome compared with treatment of only CCl(4). TGF-beta1 increased phosphorylated alpha-SMA, Smad-2 expressions in HSCs, which were decreased by rhEPO co-treatment. CONCLUSIONS: Treatment of rhEPO effectively suppressed fibrosis in CCl(4)-induced liver fibrosis mice models. Anti-fibrosis effect of rhEPO could be related to inhibition of TGF-beta1 induced activation of HSCs. PMID- 22932189 TI - Contrast-enhanced ultrasound of hepatocarcinogenesis in liver cirrhosis. AB - BACKGROUND: Hepatocellular carcinoma (HCC) often occurs in association with liver cirrhosis. A stepwise carcinogenesis for HCC has been proposed. The purpose of this study was to observe the enhancement pattern of hepatocellular nodules in cirrhotic patients using contrast-enhanced ultrasound (CEUS) and to correlate patterns of enhancement at CEUS with the diagnosis of hepatocellular nodules using pathologic correlation as the gold standard. METHODS: Ninety-three cirrhotic patients with indeterminate hepatocellular nodules at ultrasound, underwent biopsy of each indeterminate nodule. Patients with nodules found to have pathologic diagnoses of regenerative nodules (RNs), dysplastic nodules (DNs), or DNs with focus of HCC (DN-HCC), were enrolled in this study. Enhancement patterns of all nodules were examined throughout the various vascular phases of CEUS and classified into five enhancement patterns: type I, isoenhancement to hepatic parenchyma at all phases; type II, hypoenhancement in the arterial phase, and isoenhancement in the portal venous phase and late phase; type III, iso-to-hypoenhancement in arterial and portal venous phase, and hypoenhancement in the late phase (washout); type IV, slight hyperenhancement in the arterial and portal venous phase and hypoenhancement in the late phase (washout); and type V, partial hyperenhancement in the arterial phase and hypoenhancement in the late phase; and another partial iso-to-hypoenhancement in the arterial and portal venous phase and hypoenhancement in the late phase (washout). The correlation between the contrast enhancement patterns and the pathological diagnoses was analyzed by the chi-squared test. RESULTS: Totally 132 lesions were examined with CEUS in 93 patients. Pathologic diagnoses included 45 DN, 68 RN, and 19 DN-HCC. The enhancement patterns observed were as follows: type I, 49 (37.1%); type II, 27 (20.5%); type III, 28 (21.2%); type IV, 9 (6.8%); type V, 19 (14.4%). Nodules with type I enhancement showed dysplasia in 5 (10.2%) cases; nodules with type II were dysplastic in 11 (40.7%) of cases; nodules with type III enhancement pattern were dysplastic in 22 (78.6%), and those with type IV enhancement contained dysplasia in 7 (77.8%) of cases. Type V enhancement corresponded to DN-HCC in 19 (100%) of cases. CEUS enhancement pattern was correlated with likelihood of dysplasia at pathologic analysis (Trend chi-square test, P < 0.001). Pathological diagnosis was HCC in the enhanced area and hepatocyte dysplasia in the un-enhanced area in the 19 DN-HCC. CONCLUSION: Pattern of enhancement at CEUS correlates with the pathologic diagnosis of hepatocellular nodules in liver cirrhosis, and may be helpful in predicting the progress from RN to HCC nodules. PMID- 22932190 TI - Detection of siderotic nodules in the liver with susceptibility weighted imaging: correlations to serum ferritin, Child-Pugh grade and hyaluronic acid levels. AB - BACKGROUND: Chronic liver disease causes aberrant formation of fibrous tissue that impedes normal liver function, ultimately resulting in liver cirrhosis. Iron uptake can occur within the hepatic parenchyma or within the various nodules that form in a cirrhotic liver, termed siderotic nodules (SN). We aimed to investigate the diagnostic performance of susceptibility weighted imaging (SWI) for detection of SN in patients with liver cirrhosis, and to evaluate the potential of SN numbers for assessing the degree of hepatic iron deposition, liver function, and liver fibrosis stage. METHODS: Ninety-one patients with chronic liver cirrhosis, who underwent megnetic resonance imagine (MRI) scanning in our department between November 2010 and April 2011, were included in the study. A 3.0T MRI scanner was used to acquire T1WI, T2WI, T2WI, and SWI images. The number of nodules, signal intensity ratio (SIR), and contrast noise ratio (CNR) were recorded and analyzed by chi-square and ANOVA statistical tests. Correlation analysis was performed to evaluate the correlations between the number of SN and Child-Pugh classification, ferritin and hyaluronic acid levels. RESULTS: The sensitivity of SWI, T1WI, T2WI, and T2 WI for detecting SN was 62.5%, 12.1%, 24.2% and 41.8%, respectively. SWI detected significantly more nodules than routine T1WI, T2WI, and T2 WI procedures (P < 0.05). The SIR was the lowest in SWI (0.361 +/- 0.209), as compared to T1WI (0.852 +/- 0.163), T2WI (0.584 +/- 0.172), and T2 WI (0.497 +/- 0.196). The CNR was the highest in SWI (13.932 +/- 5.637), as compared to T1WI (9.147 +/- 5.785), T2WI (9.771 +/- 5.490), and T2 WI (11.491 +/- 4.573). The correlation coefficients of the number of SN with ferritin, Child-Pugh classification, and hyaluronic acid levels were 0.672, -0.055, and 0.163, respectively. CONCLUSIONS: The sensitivity and contrast of SWI for detecting SN in patients with liver cirrhosis are higher than conventional MRI. The number of SN can help to assess the degree of iron deposition in patients with liver cirrhosis. PMID- 22932191 TI - Macrophage-inducible C-type lectin is associated with anti-cyclic citrullinated peptide antibodies-positive rheumatoid arthritis in men. AB - BACKGROUND: Macrophage-inducible C-type lectin (MINCLE) is an important member of C-type lectin superfamily, which has been shown evidence for susceptibility to arthritis in animal models. We aimed to investigate the possible association of MINCLE with rheumatoid arthritis (RA) susceptibility in Chinese Han population. METHODS: Haplotypes from HapMap database (Chinese Han Beijing, CHB) were used to select tag-single nucleotide polymorphism (SNP) (r(2) = 0.8) residing in MINCLE gene. A total of 563 patients with RA and 404 healthy controls were TagMan genotyped for SNP rs10841845. Association analyses were performed on the whole data set and on RA subsets based on gender difference and the status of anti cyclic citrullinated peptide (anti-CCP) antibody in RA patients. Association statistics were calculated by age and sex adjusted logistic regression. RESULTS: Overall, MINCLE SNP rs10841845 was not associated with susceptibility to RA. However, following anti-CCP stratification, rs10841845 GG genotypes conferred a significantly protective effects against anti-CCP-positive RA (OR 0.65, 95%CI 0.430 - 0.995, P = 0.048). Following gender stratification, SNP rs10841845 G allele appeared to insert its RA protective effect only in male patients, both at allele level (G vs. A OR 0.66, 95%CI 0.46 - 0.93, P = 0.018) and at genotype level (GG vs. AA+AG, OR 0.429, 95%CI 0.20 - 0.95, P = 0.036). Notably, the male RA protective effect of rs10841845 G allele was only seen in anti-CCP-positive RA (G vs. A: OR 0.64, 95%CI 0.43 - 0.96, P = 0.029; GG vs. AA+AG: OR 0.375, 95%CI 0.14 - 0.94, P = 0.038). Furthermore, we observed a significant reduction of Disease Activity Score (DAS) 28 score (3.91 +/- 0.70 vs. 5.66 +/- 0.31, P = 0.022) and serum C-reactive protein levels (31.64 +/- 24.13 vs. 91.80 +/- 12.02, P = 0.012) in male anti-CCP-positive RA patients carrying rs10841845 GG genotype, compared with patients carrying AA+AG genotypes. CONCLUSIONS: Our study provides the evidence for a gender specific association between MINCLE rs10841845 and RA susceptibility. The SNP rs10841845 G allele appears to have protective effect against anti-CCP-positive RA and confer reduced RA activity in men. PMID- 22932192 TI - Nifedipine induced autophagy through Beclin1 and mTOR pathway in endometrial carcinoma cells. AB - BACKGROUND: Endometrial carcinoma is one of the most common female tract genital malignant tumors. Nifedipine, an L-type calcium channel antagonist can inhibit cell proliferation of carcinomas. Recent studies indicated that a rise in the free cytosolic calcium ([Ca(2+)](c)) was a potent inducer of autophagy. Here, we investigated the relationship between nifedipine and autophagy in Hec-1A cells. METHODS: Cells were cultured with nifedipine (10 umol/L) and harvested at different times for counting cell number. MTT assay was applied to evaluate the cell viability and transwell assay to reveal cell migration. Apoptotic cells were detected with annexin V/PI assay. Then cells were treated with 3-methyladenine (3 MA) (2.5 mmol/L) for 0, 5, 15, 30, 60, and 120 minutes and the expression of the L-type calcium channel alpha1D (Cav1.3) protein was detected. At last, cells were cultured and assigned to four groups with different treatment: untreated (control group), 10 umol/L nifedipine (N group), 2.5 mmol/L 3-MA (3-MA group), and 10 umol/L nifedipine plus 2.5 mmol/L 3-MA (N+3MA group). Autophagy was detected with GFP-LC3 modulation by fluorescent microscopy, and expression of the autophagy associated proteins (LC3, Beclin1 and P70s6K) by Western blotting and monodansylcadaverine (MDC) labeled visualization. RESULTS: Proliferation of Hec 1A cells was obviously suppressed by nifedipine compared with that of the untreated cells for 24, 48, and 96 hours (P = 0.000 for each day). The suppression of migration ability of the nifedipine-treated cells (94.0 +/- 8.2) was significantly different from that of the untreated cells (160.00 +/- 9.50, P = 0.021). The level of early period cell apoptosis induced by nifedipine was (2.21 +/- 0.19)%, which was (2.90 +/- 0.13)% in control group (P = 0.052), whereas the late period apoptosis level reached (10.38 +/- 0.96)% and (4.40 +/- 0.60)% (P = 0.020), respectively. The 3-MA group induced a slight increase in the Cav1.3 levels within 15 minutes, but significantly attenuated the Cav1.3 levels after 30 minutes. There were more autophagic vacuoles labeled by MDC in the N group (20.63 +/- 3.36) than the control group (6.29 +/- 0.16, P = 0.015). GFP-LC3 localization revealed that the LC3 levels of cells in 3-MA group, N+3MA group, 3 MA group were 2.80 +/- 0.29, 2.30 +/- 0.17, and 1.80 +/- 0.21, respectively. Cells in the N group showed significant augmentation of autophagy (P < 0.05). Western blotting analysis confirmed the down-regulation of LC3 levels in 3-MA group (0.85 +/- 0.21) and N+3MA group (1.21 +/- 0.12) compared with nifedipine treatment (2.64 +/- 0.15, P < 0.05). The annexin-V-FITC/PI assay showed that the level of early period cell apoptosis induced in the N+3-MA group ((11.22 +/- 0.91)%) differed significantly from that of the control group ((2.51 +/- 0.70)%) and N group ((3.47 +/- 0.39)%). Similarly, the late period level of the N+3-MA group ((55.19 +/- 2.51)%) differed significantly from that of the control group ((15.81 +/- 1.36)%) and the N group ((22.09 +/- 2.48)%, P < 0.05). The down regulated expression of P70s6k and up-regulated expression of the Beclin1 revealed significant differences between the N+3-MA group and control group (P = 0.025; Beclin1: P = 0.015). CONCLUSIONS: Proliferation and migration in vitro of endometrial carcinoma Hec-1A cells are significantly suppressed by nifedipine. The nifedipine leads autophagy to oppose Hec-1A cells apoptosis. Autophagy inhibition by 3-MA leads down-regulation of Cav1.3 and enhances nifedipine induced cell death. The nifedipine-induced autophagy is linked to Beclin1 and mTOR pathways. PMID- 22932193 TI - Clinical features of neoplastic pathological fracture in long bones. AB - BACKGROUND: Pathological fractures signify a potentially more aggressive subset of the original disease with higher misdiagnosis rates and inferior oncologic results. The purpose of the present study was to explore the clinical features of neoplastic pathological fracture in extremities. METHODS: From August 2002 to December 2010, a consecutive series of 139 patients suffering neoplastic pathological fracture were recruited, including 79 males and 60 females with a mean age of 31.3 years. Fractures were classified into five groups: tumor-like lesions (55), benign bone tumors (13), giant cell tumors (7), primary malignant bone tumors (28), and metastatic bone tumors (36). Based on their inducing forces, pathologic fractures were classified into four grades: spontaneous fracture, functional fracture, minor injury, and traumatic injury. Patients' age, fracture site, histological diagnoses, fracture forces, prodromes, and misdiagnosis were well reviewed. Kruskal-Wallis and chi(2) tests were used to compare forces and prodromes within different types of bone tumors. RESULTS: The highest pathologic fracture morbidity was 32.3% (45/139), which lay in the 11 - 20 year group, and 86.1% of metastatic tumors occurred in the 50 - 80 year group. The common sites of fractures were femur, humerus, and tibia. The fracture forces in benign bone tumors and tumor-like lesions are the strongest, followed by metastatic tumors and primary malignant bone tumors (H(C) = 80.980, P = 0.000). Sixty-seven patients (48.2%) had local prodromes before pathologic fracture. The incidence rates of prodromes between primary malignant tumors and metastatic bone tumors had no significant difference (P = 0.146), but they were all obviously higher than that of benign bone tumors and tumor-like lesions. Twenty patients experienced misdiagnosis. CONCLUSION: Minor injury forces and local prodromes are clinical features of neoplastic pathologic fractures and they are also the critical factor avoiding misdiagnoses. PMID- 22932194 TI - Correlation analysis between plasma D-dimer levels and orthopedic trauma severity. AB - BACKGROUND: The correlation between the plasma D-dimer level and deep vein thrombosis has not been conclusive in various studies. The aim of this research was to study the relationship between plasma D-dimer levels and the severity of orthopedic trauma by retrospective examination of orthopedic trauma cases. METHODS: Clinically acute trauma and non-acute trauma patients were selected and their plasma D-dimer levels were measured. Plasma D-dimer levels in patients of these two groups were compared. The relationship between the plasma D-dimer level and the severity of the trauma was also studied. RESULTS: There were 548 cases in the acute trauma group and 501 cases in the non-acute trauma group. The levels of plasma D-dimer were significantly higher in the acute trauma group than in the non-acute trauma group (P < 0.01). In the acute trauma group, the correlation between the D-dimer level and the number of fractures was a positive linear correlation (r = 0.9532). CONCLUSIONS: Elevated plasma D-dimer is common in trauma patients. The D-dimer level and the number of fractures in the trauma patients are closely correlated. D-dimer is not only an indicator for the diagnosis of deep vein thrombosis and pulmonary embolus, but also an indicator of the severity of trauma in acute trauma patients. PMID- 22932195 TI - Endoplasmic reticulum stress is involved in podocyte apoptosis induced by saturated fatty acid palmitate. AB - BACKGROUND: Podocyte apoptosis is recently indicated as an early phenomenon of diabetic nephropathy. Pancreatic beta-cells exposed to saturated free fatty acid palmitate undergo irreversible endoplasmic reticulum (ER) stress and consequent apoptosis, contributing to the onset of diabetes. We hypothesized that palmitate could induce podocyte apoptosis via ER stress, which initiates or aggravates proteinuria in diabetic nephropathy. METHODS: Podocyte apoptosis was detected by 4',6-diamidio-2-phenylindole (DAPI) stained apoptotic cell count and Annexin V-PI stain. The expressions of ER molecule chaperone glucose-regulated protein 78 (GRP78), indicators of ER-associated apoptosis C/EBP homologous protein (CHOP), and Bcl-2 were assayed by Western blotting and real-time PCR. GRP78 and synaptopodin were co-localized by immunofluorescence stain. RESULTS: Palmitate significantly increased the percentage of cultured apoptotic murine podocytes time-dependently when loading 0.75 mmol/L (10 hours, 13 hours, and 15 hours compared with 0 hour, P < 0.001) and dose-dependently when loading palmitate ranging from 0.25 to 1.00 mmol/L for 15 hours (compared to control, P < 0.001). Palmitate time-dependently and dose-dependently increased the protein expression of GRP78 and CHOP, and decreased that of Bcl-2. Palmitate loading ranging from 0.5 to 1.0 mmol/L for 12 hours significantly increased mRNA of GRP78 and CHOP, and decreased that of Bcl-2 compared to control (P < 0.001), with the maximum concentration being 0.75 mmol/L. Palmitate 0.5 mmol/L loading for 3 hours, 8 hours, and 12 hours significantly increased mRNA of GRP78 and CHOP, and decreased that of Bcl-2 compared to 0 hour (P < 0.001), with the maximum effect at 3 hours. Confocal microscopy demonstrated that GRP78 expression was significantly increased when exposed to 0.5 mmol/L of palmitate for 8 hours compared to control. CONCLUSION: Palmitate could induce podocyte apoptosis via ER stress, suggesting podocyte apoptosis and consequent proteinuria caused by lipotoxic free fatty acid could be ameliorated by relief of ER stress. PMID- 22932196 TI - Single-agent maintenance therapy in non-small cell lung cancer: a systematic review and meta-analysis. AB - BACKGROUND: Can single-agent maintenance therapy be considered as an ideal strategy for non-small cell lung cancer (NSCLC) treatment to achieve prolonged survival and tolerated toxicity? A systematic review and meta-analysis was performed to elucidate this issue. METHODS: The electronic databases were searched for RCTs comparing single-agent maintenance therapy with placebo, best support care or observation. The required data for estimation of response, survival and toxicity were extracted from the publications and the combined data were calculated. RESULTS: Eleven RCTs involving 3686 patients were identified. We found a statistically significant higher probability of tumor response for patients with maintenance therapy versus control patients (OR: 2.80, 95%CI: 2.15 3.64). Patients receiving maintenance therapy had significantly longer progression-free survival (PFS) (HR: 0.67, 95%CI: 0.62 - 0.71) and overall survival (OS) (HR: 0.84, 95%CI: 0.78 - 0.90). However, maintenance therapy was associated with more severe toxicities (OR: 6.45, 95%CI: 4.61 - 9.01). CONCLUSION: In patients with advanced NSCLC, the use of single-agent maintenance therapy is associated with higher response rate and significantly prolongs PFS and OS despite of the risk of additional toxicity. PMID- 22932197 TI - Interaction between smoking and obstructive sleep apnea: not just participants. AB - OBJECTIVE: To review the current evidence that links smoking to obstructive sleep apnea (OSA) and to discuss some potential mechanisms proposed for these links. DATA SOURCES: We searched PubMed and Medline to identify studies investigating the interaction between smoking and OSA. STUDY SELECTION: Articles regarding the relationship between smoking and OSA were selected. Studies considered smoking as a confounding factor were excluded. RESULTS: The association of smoking and OSA has been confirmed in several studies. The effects of smoking on the pathophysiology of OSA may include smoking-induced upper airway inflammation, stimulant effects of nicotine on upper airway muscles, and a "rebound effect" due to nightly short-term nicotine withdrawal, or all of the above. In addition, the coexistence of OSA and smoking may have more widespread implications for cardiovascular dysfunction in patients with OSA. Finally, OSA might be responsible for the addiction to nicotine. CONCLUSIONS: Smoking may act as a risk factor for OSA and join with OSA in a common pathway to increase the risk of systematic injury. OSA, in turn, may be a predisposing factor for smoking. Thus, smoking cessation is recommended when considering treatment for OSA, and treating OSA may be a necessary precondition for successful smoking cessation. PMID- 22932198 TI - Correlation of eosinophil counts in induced sputum and fractional concentration of exhaled nitric oxide and lung functions in patients with mild to moderate asthma. AB - BACKGROUND: The airway inflammation could be assessed by some noninvasive approaches. To investigate the value of eosinophil counts in induced sputum and fractional concentration of exhaled nitric oxide (FENO) for the regimen adjustment in patients with asthma, the correlation was analyzed between the two parameters and lung function parameter (forced expiratory volume in one second (FEV(1))). METHODS: Sixty-five outpatients with mild to moderate non-exacerbation asthma from Beijing Chao-Yang Hospital were enrolled as treatment group. Combined medications of inhaled corticosteroids plus long-acting beta-2 agonist were administered for one year. Lung function parameters, eosinophil counts in induced sputum, concentration of exhaled nitric oxide and the Asthma Control Test scores were recorded, at regular intervals in the follow-up period. Twenty-one healthy volunteers were enrolled as control group and underwent examination of eosinophil counts in induced sputum, lung function and concentration of exhaled nitric oxide. RESULTS: Sixty-three subjects from treatment group completed follow-up period for one year or longer. Mean FEV(1) value of the 63 subjects was (2.75 +/- 0.54) L at baseline, (2.97 +/- 0.56) L and (3.07 +/- 0.52) L at month 3 and month 6, respectively, and maintained as (3.14 +/- 0.51) L in the following six months. Mean FENO decreased from (61 +/- 25) parts per billion (ppb) at baseline to (32 +/- 19) ppb at month 3 (P < 0.05), and continued to decrease to (22 +/- 12) ppb at month 6, the difference being significant when compared to both baseline and control group ((13 +/- 8) ppb). Mean eosinophil counts decreased to (0.032 +/- 0.011) * 10(6)/ml at month 3, which was significantly different from baseline ((0.093 +/- 0.023)*10(6)/ml) and the control group ((0.005 +/- 0.003)*10(6)/ml (both P < 0.05). The eosinophil counts in induced sputum correlated positively with concentration of FENO in the first six months (all P < 0.05). The concentration of FENO had a significant negative correlation with FEV(1) value (all P < 0.05) in any time point in the follow-up period. The Asthma Control Test scores were 18 +/- 5, 19 +/- 7, 23 +/- 2, 24 +/- 1 and 24 +/- 1 at months 1, 3, 6, 9 and 12, respectively, which were significantly different from the score at baseline (14 +/- 3) (P < 0.05). The most rapid clinical effect was observed at the second month after treatment. CONCLUSION: Eosinophil counts in induced sputum and FENO are sensitive parameters to detect airway inflammation and may be useful in evaluating the efficacy of treatment and adjusting medication regimens. PMID- 22932199 TI - Expression of CD44v6 and Livin in gastric cancer tissue. AB - BACKGROUND: CD44v6 plays an important role in invasion and metastasis of tumor, Livin has anti-apoptotic effects. The present study aimed to explore the expression and clinical significance of CD44v6 and Livin in gastric cancer tissue. METHODS: Streptavidin-peroxidase linked immunohistochemical method was used to determine the expression of CD44v6 and Livin in gastric cancer tissue and adjacent normal gastric tissues from 59 patients with histopathologically confirmed gastric cancer, and in gastric tissue specimens of 15 patients with gastric polyps, and 15 patients with chronic non-atrophic gastritis. The chi square test was used for comparison of the relevant factors, Spearman's rank correlation test was applied for relationship among positive expression of the proteins. RESULTS: The expresion of CD44v6 was positive in 64.4% of the gastric cancer patients; 5.1%, 0 and 13.3% in specimens of normal tissues adjacent to the cancer tissues, in gastric tissue specimens of patients with gastric polyps, and patients with chronic non-atrophic gastritis, respectively. The expression of Livin was positive in 52.5% of the gastric cancer tissues, 6.8%, 0 and 6.7% in the adjacent normal gastric tissue, specimens of patients with gastric polyps and chronic non-atrophic gastritis, respectively. The expression of CD44v6 was significantly correlated with the depth of invasion, the degree of differentiation, and lymphnode metastasis of gastric cancer (P < 0.05). The positive expression rate of Livin protein was also significantly correlated with degree of differentiation of gastric cancer cells and metastasis to lymphnodes (P < 0.05), but not correlated with the depth of invasion and pathological types (P > 0.05). The expression of CD44v6 and Livin in the gastric cancer tissue was positively correlated (r(s) = 0.286, P = 0.028). CONCLUSIONS: The increased expression of CD44v6 and Livin in gastric cancer tissue may be closely related with development and progression of gastric cancer. CD44v6 and Livin may be new biological markers of gastric cancer. PMID- 22932200 TI - Volatile anesthetics inhibit the activity of calmodulin by interacting with its hydrophobic site. AB - BACKGROUND: Volatile anesthetics (VAs) may affect varied and complex physiology processes by manipulating Ca(2+)-calmodulin (CaM). However, the detailed mechanism about the action of VAs on CaM has not been elucidated. This study was undertaken to examine the effects of VAs on the conformational change, hydrophobic site, and downstream signaling pathway of CaM, to explore the possible mechanism of anesthetic action of VAs. METHODS: Real-time second harmonic generation (SHG) was performed to monitor the conformational change of CaM in the presence of VAs, each plus 100 umol/L Ca(2+). A hydrophobic fluorescence indicator, 8-anilinonaphthalene-1-sulfonate (ANS), was utilized to define whether the VAs would interact with CaM at the hydrophobic site or not. High-performance liquid chromatography (HPLC) was carried out to analyze the activity of CaM-dependent phosphodiesterase (PDE1) in the presence of VAs. The VAs studied were ether, enflurane, isoflurane, and sevoflurane, with their aqueous concentrations 7.6, 9.5, 11.4 mmol/L; 0.42, 0.52, 0.62 mmol/L; 0.25, 0.31, 0.37 mmol/L and 0.47, 0.59, 0.71 mmol/L respectively, each were equivalent to their 0.8, 1.0 and 1.2 concentration for 50% of maximal effect (EC50) for general anesthesia. RESULTS: The second-harmonic radiation of CaM in the presence of Ca(2+) was largely inhibited by the VAs. The fluorescence intensity of ANS, generated by binding of Ca(2+) to CaM, was reversed by the VAs. HPLC results also showed that AMP, the product of the hydrolysis of cAMP by CaM-dependent PDE1, was reduced by the VAs. CONCLUSIONS: Our findings demonstrate that the above VAs interact with the hydrophobic core of Ca(2+)-CaM and the interaction results in the inhibition of the conformational change and activity of CaM. This in vitro study may provide us insight into the possible mechanism of anesthetic action of VAs in vivo. PMID- 22932201 TI - Using optical coherence tomography to detect peripheral pulmonary thrombi. AB - BACKGROUND: Optical coherence tomography (OCT) is a new imaging technique capable of obtaining high-resolution intravascular images of small vessels and has been widely used in interventional cardiology. However, application of OCT in peripheral pulmonary arteries in patients has been seldom documented. METHODS: Three patients who were highly suspected peripheral pulmonary arteries thrombi and had undergone CT pulmonary angiography but tested negative for thrombi in peripheral pulmonary arteries were enrolled. Subsequently, OCT imaging was performed in peripheral pulmonary arteries. The patients received more than three month anticoagulative treatment if thrombi were detected by OCT. Thereafter, OCT re-evaluation of the thrombolized blood vessels detected earlier was performed. The changes of thrombi before and after anticoagulative treatment were compared. RESULTS: Three patients underwent OCT imaging of peripheral pulmonary arteries. Thrombi were found in most of imaged vessels in these patients. Red and white thrombi can be differentiated, according to features of the thrombus on OCT images. After anticoagulation treatment, these patients' symptoms and hypoxemia improved. Repeated OCT imaging showed that most thrombi disappeared or became smaller. CONCLUSION: OCT may be used as a potential tool for detecting peripheral pulmonary artery thrombi and differentiating red thrombi from white ones. PMID- 22932202 TI - Clinical efficacies of treating refractory insomnia patients with estazolam plus alternating current magnetic field. PMID- 22932203 TI - Prenatal diagnosis of anhidrotic ectodermal dysplasia with unconventional loci abnormalities: a case report. AB - Anhidrotic ectodermal dysplasia (EDA) is a relatively rare congenital hereditary disease. Because of a reduced number of sweat glands, patients are unable to perspire and consequently suffer from hyperthermia and infection. This is a potential cause of death in childhood. Domestic prenatal diagnosis methods focus on genetic diagnosis. But for some conditions, because of the uncertain molecular pathology, we need other methods to assist to in prenatal diagnosis. Here, we report one case of a new mutation locus which may be associated with EDA and the prenatal diagnosis of EDA by fetal skin biopsy under fetoscopy in mid pregnancy, combined with a review of the literature. PMID- 22932204 TI - Misdiagnosis induced intraocular lens dislocation in anterior megalophthalmos. AB - Anterior megalophthalmos (AM) is an uncommon developmental anomaly of the anterior segment of the eye with a constellation of findings that includes enlarged cornea, deep anterior chamber, posterior positioning of the iris and lens, iris stroma atrophy, hypoplasia of iris dilator, pupil displacement, large capsular bag, lens subluxation, prematurely cataract and the tendency to retinal detachment. AM, especially when symptoms are mild, is not an easy disease to diagnose. We present 3 AM cases that were misdiagnosed as congenital cataract with weak zonule and megalocornea. Intraocular lenses (IOLs) dislocated after standard cataract surgeries and subsequent surgery (replacing the dislocated IOLs with iris-claw intraocular lenses) achieved satisfactory outcome. Although rare, AM should be included in the differential diagnosis of enlarged cornea and we recommend implanting Artisan lens in AM patients. PMID- 22932205 TI - Bronchial Sparganosis mansoni accompanied by abnormal hyperplasia diagnosed by bronchoscopy. AB - Pulmonary sparganosis mansoni is rare in humans and bronchial sparganosis mansoni has not been reported. We reported a patient with a soft-tissue mass in the right hilum area on a chest computed tomography (CT) scan that was suspected of being lung cancer. Bronchoscopy identified sparganum larvae. Bronchial sparganosis mansoni accompanied by abnormal hyperplasia was diagnosed by histopathology. We introduced our experience and reviewed the clinical characteristics of three pulmonary sparganosis mansoni cases and three pleural cavity sparganosis mansoni cases that have been reported. PMID- 22932206 TI - Pulmonary-bronchus myelolipoma and review on extra-adrenal myelolipomas in Chinese literature. AB - Extra-adrenal myelolipomas are extremely rare, especially in bronchus and lung. Up to now, only nine cases of intra pulmonary lesions have been reported all over the world. Here we describe a new discovered pulmonary-bronchus myelolipoma in a 53-year-old man, which is different from the previously reported ones. And we mainly comment on the pathology and diagnosis, comparing with the findings of the extra-adrenal cases reported in Chinese literature. PMID- 22932208 TI - Renal cell carcinoma presents as pleural metastasis without pulmonary involvement. PMID- 22932207 TI - Pulmonary alveolar proteinosis associated with tuberculosis and aspergilloma formation. PMID- 22932209 TI - Organizing pneumonia associated with common variable immunodeficiency. PMID- 22932210 TI - Surgical treatment of renal cell carcinoma metastasized to the duodenum. PMID- 22932211 TI - Cassia spectabilis (DC) Irwin et Barn: a promising traditional herb in health improvement. AB - The genus Cassia, comprising about 600 species widely distributed worldwide is well known for its diverse biological and pharmacological properties. Cassia spectabilis (sin Senna spectabilis) (DC) Irwin et Barn (Fabaceae) is widely grown as an ornamental plant in tropical and subtropical areas. C. spectabilis has been commonly used in traditional medicine for many years. Information in the biomedical literature has indicated the presence of a variety of medicinally important chemical constituents in C. spectabilis. Pharmacological studies by various groups of investigators have shown that C. spectabilis possesses significant biological activity, such as antibacterial, antibiofilm, antifungal and antioxidant properties. Beside this, toxicity studies of this plant have revealed no toxic effect on mice. In view of the immense medicinal importance of C. spectabilis, this review aimed at compiling all currently available information on C. spectabilis's botany, phytochemistry, pharmacology, and mechanism of actions, toxicology and its ethnomedicinal uses. PMID- 22932212 TI - Compositional study and antioxidant potential of Ipomoea hederacea Jacq. and Lepidium sativum L. seeds. AB - The present investigation has been carried out to determine the proximate composition, amino acids, metal contents, oil composition as well as the antioxidant capacity of the seeds of Ipomoea hederacea Jacq. and Lepidium sativum L. Proximate composition indicated a great difference in oil (14.09 +/- 0.66, 28.03 +/- 1.05) and fibre (16.55 +/- 0.31, 6.75 +/- 1.20) contents for I. hederacea and L. sativum, respectively. Fatty acid profile indicated that oleic acid (19.50 +/- 0.37, 30.50 +/- 0.16) and linoleic acid (52.09 +/- 0.48, 8.60 +/- 0.38) are the major fatty acids. gamma-Tocopherol and delta-tocopherol (28.70 +/- 0.14, 111.56 +/- 0.37) were the most abundant in the seed oil of I. hederacea and L. sativum, respectively. Results of TEAC, FRAP and TRAP antioxidant assays indicated that L. sativum has much greater antioxidant potential than I. hederacea. PMID- 22932213 TI - Antibacterial and synergy of berberines with antibacterial agents against clinical multi-drug resistant isolates of methicillin-resistant Staphylococcus aureus (MRSA). AB - Antibacterial activity of berberine (Ber) and 8-acetonyl-dihydroberberine (A-Ber) alone and combined uses with antibacterial agents ampicillin (AMP), azithromycin (AZM), cefazolin (CFZ) and levofloxacin (LEV) was studied on 10 clinical isolates of SCCmec III type methicillin-resistant Staphylococcus aureus (MRSA). Susceptibility to each agent alone was tested using a broth microdilution method and the chequerboard and time-kill tests for the combined evaluations, respectively. The alone MICs/MBCs (MUg/mL) ranges were 32-128/64-256 (Ber) and 32 128/128-512 (A-Ber). Significant synergies were observed for the Ber (A-Ber)/AZM and Ber (A-Ber)/LEV combinations against 90% of the tested MRSA strains, with fractional inhibitory concentration indices (FICIs) values ranged from 0.188 to 0.500. An additivity result was also observed for the Ber/AZM combination by time kill curves. These results demonstrated for the first time that Ber and A-Ber enhanced the in vitro inhibitory efficacy of AZM and LEV to a same extent, which had potential for further investigation in combinatory therapeutic applications of patients infected with MRSA. PMID- 22932214 TI - Design and synthesis of new chacones substituted with azide/triazole groups and analysis of their cytotoxicity towards HeLa cells. AB - A series of new chalcones substituted with azide/triazole groups were designed and synthesized, and their cytotoxic activity was evaluated in vitro against the HeLa cell line. O-Alkylation, Claisen-Schmidt condensation and Cu(I)-catalyzed cycloaddition of azides with terminal alkynes were applied in key steps. Fifteen compounds were tested against HeLa cells. Compound 8c was the most active molecule, with an IC50 value of 13.03 MUM, similar to the value of cisplatin (7.37 MUM). PMID- 22932215 TI - Preparation of dry extract of Mikania glomerata Sprengel (Guaco) and determination of its coumarin levels by spectrophotometry and HPLC-UV. AB - Guaco (Mikania glomerata Sprengel) syrup is one of the most popular herbal medicines used to treat the symptoms of asthmatic bronchitis, cough and hoarseness. The coumarin 2H-1-benzopyran-2-one, is one of the major constituents of Guaco and contributes to its pharmacological effects. The pharmaceutical capsule form of dry extract of Guaco is recommended by the Brazilian Program of Medicinal Plants and Herbal Medicines and used in primary health care. In order to identify a new protocol to obtain the raw material for Guaco capsule production we evaluated two methods, including a freezedrying process (lyophilization) and the spray-dryer technique, as well as the use of two adjuvants, Maltodextrins and Aerosil(r), in different concentrations. The coumarin levels of the dried extracts were analyzed by UV-spectrophotometry and HPLC-UV/DAD. The adjuvant Aerosil(r) 8% showed better dry powder physical appearance. Lyophilization was observed to be the best process to obtain the dry extract of Guaco based on the measured coumarin levels. PMID- 22932216 TI - The dual action of epigallocatechin gallate (EGCG), the main constituent of green tea, against the deleterious effects of visible light and singlet oxygen generating conditions as seen in yeast cells. AB - Green tea extracts (GTEs) as well as their main component, the polyphenol epigallocatechin gallate (EGCG), are known for their versatile antioxidant, antimicrobial, antitumoral or anti-inflammatory effects. In spite of the huge beneficial action, there is increasing evidence that under certain conditions green tea and its components can be detrimental to living organisms. Using Saccharomyces cerevisiae strains with various defects in the response to oxidative stress, we found that GTEs or EGCG act in synergy with visible light, exhibiting either deleterious or protective effects depending on the solvent employed. Similar synergistic effects could be observed under singlet oxygen generating conditions, such as light exposure in the presence of photosensitizers or UV-A irradiation, therefore solvent variance may represent a powerful tool to modulate the preparation of green tea extracts, depending on the intended target. PMID- 22932217 TI - Antiviral effect of matrine against human enterovirus 71. AB - Human enterovirus 71, a member of the Picornaviridae family, is one of the major causative agent of hand, foot and mouth disease in children less than six years old. This illness has caused mortalities in large-scale outbreaks in the Asia Pacific region in recent years. No vaccine or antiviral therapy is available. In this study, antiviral effect of matrine against enterovirus 71 were evaluated in vitro and in vivo. Matrine could suppress the viral RNA copy number on rhabdomyosarcoma cells. Moreover, matrine treatment of mice challenged with a lethal dose of enterovirus 71 reduced the mortality and relieved clinical symptoms. The results showed that matrine may represent a potential therapeutic agent for enterovirus 71 infection. PMID- 22932219 TI - FDA oversight of cell therapy clinical trials. AB - The U.S. Food and Drug Administration applies regulatory flexibility to balance benefits and risks to subjects in cell-therapy clinical trials. PMID- 22932220 TI - Designing a public square for research computing. AB - A set of principles is proposed for sponsors and developers of research computing applications that can increase the likelihood of successful adoption by researchers. PMID- 22932221 TI - Comment on "characterization of circulating endothelial cells in acute myocardial infarction". AB - The circulating endothelial cell population characterized by Damani et al. might be contaminated by endothelium damage after femoral catheterization. PMID- 22932222 TI - Author response to comment on "characterization of circulating endothelial cells in acute myocardial infarction". AB - A substantial number of patients with the appropriate clinical phenotypes must be studied to disprove previous findings that circulating endothelial cell counts and morphology can predict atherosclerotic plaque rupture. PMID- 22932223 TI - Clonal evolution of preleukemic hematopoietic stem cells precedes human acute myeloid leukemia. AB - Given that most bone marrow cells are short-lived, the accumulation of multiple leukemogenic mutations in a single clonal lineage has been difficult to explain. We propose that serial acquisition of mutations occurs in self-renewing hematopoietic stem cells (HSCs). We investigated this model through genomic analysis of HSCs from six patients with de novo acute myeloid leukemia (AML). Using exome sequencing, we identified mutations present in individual AML patients harboring the FLT3-ITD (internal tandem duplication) mutation. We then screened the residual HSCs and detected some of these mutations including mutations in the NPM1, TET2, and SMC1A genes. Finally, through single-cell analysis, we determined that a clonal progression of multiple mutations occurred in the HSCs of some AML patients. These preleukemic HSCs suggest the clonal evolution of AML genomes from founder mutations, revealing a potential mechanism contributing to relapse. Such preleukemic HSCs may constitute a cellular reservoir that should be targeted therapeutically for more durable remissions. PMID- 22932224 TI - A dense poly(ethylene glycol) coating improves penetration of large polymeric nanoparticles within brain tissue. AB - Prevailing opinion suggests that only substances up to 64 nm in diameter can move at appreciable rates through the brain extracellular space (ECS). This size range is large enough to allow diffusion of signaling molecules, nutrients, and metabolic waste products, but too small to allow efficient penetration of most particulate drug delivery systems and viruses carrying therapeutic genes, thereby limiting effectiveness of many potential therapies. We analyzed the movements of nanoparticles of various diameters and surface coatings within fresh human and rat brain tissue ex vivo and mouse brain in vivo. Nanoparticles as large as 114 nm in diameter diffused within the human and rat brain, but only if they were densely coated with poly(ethylene glycol) (PEG). Using these minimally adhesive PEG-coated particles, we estimated that human brain tissue ECS has some pores larger than 200 nm and that more than one-quarter of all pores are >= 100 nm. These findings were confirmed in vivo in mice, where 40- and 100-nm, but not 200 nm, nanoparticles spread rapidly within brain tissue, only if densely coated with PEG. Similar results were observed in rat brain tissue with paclitaxel-loaded biodegradable nanoparticles of similar size (85 nm) and surface properties. The ability to achieve brain penetration with larger nanoparticles is expected to allow more uniform, longer-lasting, and effective delivery of drugs within the brain, and may find use in the treatment of brain tumors, stroke, neuroinflammation, and other brain diseases where the blood-brain barrier is compromised or where local delivery strategies are feasible. PMID- 22932225 TI - The stoichiometric production of IL-2 and IFN-gamma mRNA defines memory T cells that can self-renew after adoptive transfer in humans. AB - Adoptive immunotherapy using ex vivo-expanded tumor-reactive lymphocytes can mediate durable cancer regression in selected melanoma patients. Analyses of these trials have associated the in vivo engraftment ability of the transferred cells with their antitumor efficacy. Thus, there is intensive clinical interest in the prospective isolation of tumor-specific T cells that can reliably persist after transfer. Animal studies have suggested that central memory CD8(+) T cells (T(CM)) have divergent capabilities including effector differentiation to target antigen and stem cell-like self-renewal that enable long-term survival after adoptive transfer. We sought to isolate human melanoma-specific T(CM) to define their in vivo fate and function after autologous therapeutic transfer to metastatic patients. To facilitate the high-throughput identification of these rare cells from patients, we report that T(CM) have a defined stoichiometric production of interleukin-2 (IL-2) and interferon-gamma (IFN-gamma) mRNA after antigen stimulation. Melanoma-specific T cells screened for high relative IL-2 production had a T(CM) phenotype and superior in vitro proliferative capacity compared to cells with low IL-2 production. To investigate in vivo effector function and self-renewal capability, we allowed melanoma-specific T(CM) to undergo in vitro expansion and differentiation into lytic effector clones and then adoptively transferred them back into their hosts. These clones targeted skin melanocytes in all five patients and persisted long term and reacquired parental T(CM) attributes in four patients after transfer. These findings demonstrate the favorable engraftment fitness for human T(CM)-derived clones, but further efforts to improve their antitumor efficacy are still necessary. PMID- 22932226 TI - Inadequate antibody response to rabies vaccine in immunocompromised patient. AB - We describe an inadequate antibody response to rabies vaccine in an immunocompromised patient. A literature search revealed 15 additional immunocompromised patients, of whom 7 did not exhibit the minimum acceptable level of antibodies after a complete postexposure prophylaxis regimen. An international rabies registry is needed to provide a basis for determining appropriate vaccination protocols. PMID- 22932227 TI - Picobirnaviruses in the human respiratory tract. PMID- 22932228 TI - Decreasing sugar-sweetened beverage consumption in the rural adolescent population. AB - Adolescent consumption of sugar-sweetened beverages (SSBs) has increased drastically with detrimental effects such as weight gain, weakened bones, dental caries, and associated higher levels of type II diabetes in this population. While in the clinical setting, rural family nurse practitioner (FNP) students, using Kellogg-funded Smart Phones, screened adolescents aged 13 to 17 years for SSB consumption in the previous 24 hours. Adolescents initially were provided with a pamphlet and related oral teaching concerning SSBs by the FNP students, as well as a water bottle to encourage healthy fluid intake. Screening SSB information was loaded onto Smart Phones, which resulted in immediate access by the primary investigator sometimes even hundreds of miles distant. After 30 days, FNP students completed follow-up phone interviews to reassess SSB consumption in the previous 24 hours. Results concerning decreased SSB consumption were statistically significant. Additionally, Smart Phones were instrumental in high speed data transfer. Both advantages and disadvantages were encountered when using this evolving technology. PMID- 22932229 TI - Antipsychotic augmentation of serotonin reuptake inhibitors in treatment resistant obsessive-compulsive disorder: a meta-analysis of double-blind, randomized, placebo-controlled trials. AB - Because of the high number of patients with obsessive-compulsive disorder (OCD) not responding satisfactorily to initial monotherapy with serotonin reuptake inhibitors (SRIs), the evaluation of additional treatment options is highly relevant. To examine efficacy of add-on pharmacotherapy with antipsychotics, a systematic literature search was applied to identify all double-blind, randomized, placebo-controlled trials (DB-PC-RCTs) determining the efficacy of antipsychotic augmentation of SRIs in treatment-resistant OCD. The primary outcome of the pooled meta-analytic data analysis was response to the adjunctive antipsychotic treatment measured by both the rates of participants achieving response [defined as >= 35% reduction in Yale-Brown Obsessive-Compulsive Scale (YBOCS)] and mean changes in YBOCS total score. Twelve DB-PC-RCTs investigating quetiapine (N = 5), risperidone (N = 3), olanzapine (N = 2), aripiprazole (N = 1) and haloperidol (N = 1) with a total of 394 subjects were included. Significantly more patients responded to augmentation with antipsychotics than with placebo [relative risk = 2.10, 95% confidence intervals (CI) 1.16-3.80]. Additionally, the mean reduction of the YBOCS total score revealed an efficacy in favour of the antipsychotic medication [standardized mean difference (SMD) = 0.54, 95% CI 0.15 0.93]. Significant efficacy was identifiable only for risperidone, but not for quetiapine and olanzapine. The results regarding aripiprazole and haloperidol were inconsistent. Overall, about one-third of SRI-resistant OCD patients benefited from an augmentation strategy with antipsychotics. Based on the favourable risk:benefit ratio, risperidone can be considered as the agent of first choice and should be preferred to quetiapine and olanzapine. Further trials, mainly with higher antipsychotic doses, are required to optimize pharmacological treatment recommendations for SRI-refractory OCD. PMID- 22932230 TI - The effect of three different toe props on plantar pressure and patient comfort. AB - BACKGROUND: Arthritic toe pathologies frequently lead to the development of painful apical pressure skin lesions that can compromise gait and affect quality of life. Historically conservative treatments involve the use of a toe prop with the intended aim of reducing plantar pressure from the apex of the digit. However, the effect of toe prop treatment on plantar digital pressure has not been investigated. METHOD: Twenty two subjects were recruited with lesser digital deformities and associated apical skin lesions. Individual pressure sensors were placed on the apices of the lesser toes and pressure was recorded under three toe prop conditions (leather, gel and silicone mould). A modified comfort index was utilised to assess the comfort of each condition. RESULTS: Significant difference (p < 0.05) in mean peak pressure was observed at the apex of the 2nd toe when using the gel (p < 0.001) and silicone (p < 0.001) toe prop compared to no toe prop. There was also a significant difference in the mean pressure time integral at the apex of the 2nd toe when using gel (p < 0.001) and silicone (p < 0.004) toe props. There was no significant correlation between comfort and the recorded peak pressures. However, there was an indication that the silicone toe prop was more comfortable. CONCLUSION: As compared to the leather and silicone mould toe props, gel toe props were found to be the most effective for reducing peak pressure and pressure time integral on the apex of the second digit in patients with claw or hammer toe deformity. PMID- 22932231 TI - Shifted risk preferences in pathological gambling. AB - BACKGROUND: Pathological gambling (PG) is an impulse control disorder characterized by excessive monetary risk seeking in the face of negative consequences. We used tools from the field of behavioral economics to refine our description of risk-taking behavior in pathological gamblers. This theoretical framework allowed us to confront two hypotheses: (1) pathological gamblers distort winning probabilities more than controls; and (2) pathological gamblers merely overweight the whole probability range. Method Eighteen pathological gamblers and 20 matched healthy participants performed a decision-making task involving choices between safe amounts of money and risky gambles. The online adjustment of safe amounts, depending on participants' decisions, allowed us to compute 'certainty equivalents' reflecting the subjective probability weight associated with each gamble. The behavioral data were then fitted with a mathematical function known as the 'probability weighting function', allowing us to disentangle our two hypotheses. RESULTS: The results favored the second hypothesis, suggesting that pathological gamblers' behavior reflects economic preferences globally shifted towards risk, rather than excessively distorted probability weighting. A mathematical parameter (elevation parameter) estimated by our fitting procedure was found to correlate with gambling severity among pathological gamblers, and with gambling affinity among controls. CONCLUSIONS: PG is associated with a specific pattern of economic preferences, characterized by a global (i.e. probability independent) shift towards risky options. The observed correlation with gambling severity suggests that the present 'certainty equivalent' task may be relevant for clinical use. PMID- 22932233 TI - [Solidifying the concept and strategies of laryngeal preservation in the management of laryngeal cancer]. PMID- 22932232 TI - Relationships of the Mediterranean dietary pattern with insulin resistance and diabetes incidence in the Multi-Ethnic Study of Atherosclerosis (MESA). AB - Type 2 diabetes (T2D) is a highly prevalent but preventable disorder. We assessed the association between an a priori Mediterranean diet (MeDiet) score and fasting glucose and insulin at baseline and incident T2D after a 6-year follow-up in the Multi-Ethnic Study of Atherosclerosis. Dietary intake was measured at baseline using a 127-item FFQ in 5390 men and women aged 45-84 years free of prevalent diabetes and clinical CVD. A MeDiet score was created based on the intake of ten food components: vegetables; whole grains; nuts; legumes; fruits; ratio of monounsaturated:saturated fat; red and processed meat; dairy products; fish; alcohol. Multivariable linear and proportional hazards models were used to estimate the association of the MeDiet, categorised in quintiles, with baseline insulin and glucose, and incident diabetes, respectively. The models were adjusted for demographic, physiological and behavioural characteristics. After multivariable adjustment, individuals with a higher MeDiet score had lower baseline mean insulin levels (Q1: 5.8 (95% CI 5.6, 6.0) MUmol/l; Q5: 4.8 (95% CI 4.6, 5.0) MUmol/l; P for trend < 0.0001). A higher MeDiet score was also associated with significantly lower glucose levels after basic adjustment, but was attenuated after adjustment for waist circumference. During the follow-up, 412 incident diabetes events accrued. The MeDiet was not significantly related to the risk of incident diabetes (P for trend = 0.64). In summary, greater consistency with a Mediterranean-style diet, reflected by a higher a priori MeDiet score, was cross-sectionally associated with lower insulin levels among non-diabetics, and with lower blood glucose before adjustment for obesity, but not with a lower incidence of diabetes. PMID- 22932234 TI - [Preliminary report of laryngeal preservation in the surgical salvage of recurrent laryngeal cancer]. AB - OBJECTIVE: To explore the plausibility of laryngeal preservation in salvage surgery of recurrent laryngeal carcinoma. METHODS: Comprehensive clinical and radiological assessments on a specific group of patients with recurrent laryngeal cancer and their relapsed tumors were carried out to determine the methods and indications of salvage surgery for preservation of laryngeal functions. Salvage surgery with preservation of larynx was performed in a selective of 36 laryngeal cancer patients with relapsed tumors in their larynges after radiotherapy or partial laryngectomies. All patients were regularly followed up after discharge from the hospital. Postoperative survival was calculated by Kaplan-Meier's method. RESULTS: Among various laryngeal preservation regimens given, a second transoral laser surgery was carried out in 4 cases, horizontal hemilaryngectomy in 4 cases, vertical hemilaryngectomy in 13 cases and Majer-Piquet's operation in 15 cases, respectively. Simultaneous neck dissection was conducted in 18 cases. Postoperative complications were encountered in 6 cases, most common of which were local infection and laryngeal fistula with no hospital mortality and other major morbidities. Five cases with immediate postoperative complications were cured with proper management. The remained one case undergone vertical partial laryngectomy for recurrence after tumor resection via laryngeal fissure received postoperative radiation due to positive surgical margin, and complicated laryngeal atresia and obstruction with loss of his laryngeal functions. Local recurrence was observed in 5 cases and simultaneous locoregional recurrence was seen in 1 case, with the resulting local control rate of 83.3% (30/36). The 3 year postoperative survival rate was 80.6%. The cause of death was tumor recurrence in 3 cases, distant metastasis in 3 cases and non-tumor-associated disease (heart attack) in 1 case, respectively. CONCLUSIONS: Salvage surgery with laryngeal preservation can be carried out in the selected cases with early or locally-confined recurrent lesions within the larynx, on the condition that the recurrent tumors be assessed thoroughly and indications for associated surgical techniques be evaluated properly. PMID- 22932235 TI - [Clinical analysis of nimotuzumab plus cisplatin and fluorouracil regimen as induction treatment in resectable head and neck squamous cell carcinoma]. AB - OBJECTIVE: A phase II study was conducted to test the efficacy and toxicity of the combination of cisplatin, 5-Fu and nimotuzumab, as induction treatment of resectable head and neck squamous cell carcinoma (HNSCC). METHODS: Forty cases of resectable HNSCC were treated with nimotuzumab (400 mg on day 1) combined with PF regimens (cisplatin 75 mg/m2 on days 1 and 5-Fu 750 mg/m2 on days 1-5 q3wks). After 2 cycles, an organ-preservation local therapy (surgery or radiotherapy) was recommended. The primary endpoints of this study were overall response rate, pathologic complete response and safety of the induction treatment. Mean age of 40 patients was 54 years old, of them 9 patients with oropharyngeal cancer (22.5%), 16 hypopharyngeal cancer (40.0%), 10 laryngeal cancer (25.0%), and 5 oral cancer (12.5%). RESULTS: With a 2-cycle induction treatment, 34 (85.0%) patients achieved complete or partial response. Twenty-four patients (60.0%) got downstage, with T downstage in 21 (52.5%) patients and N downstage in 8 (20.0%) patients. Totally 27 patients got surgery after the induction treatment, of them 20 patients (74.1%) preserved organ functions. Four patients' primary tumors (10.0% in all 40 patients and 14.8% in operated 27 patients) showed pathologically complete responses. The toxicity was mild and manageable. The most common grade 3/4 toxicities were neutropenia (5.0%), nausea/vomiting (2.5%), stomatitis (2.5%) and thrombocytopenia (2.5%). One patient got grade 2 renal insufficiency and one patient got grade 1 skin rash. CONCLUSION: For resectable HNSCC, nimotuzumab plus PF regimen as induction treatment is highly effective for preserving the organ function and the toxicities are well tolerable. PMID- 22932236 TI - [Clinicopathological and prognostic analysis of 178 patients with hypopharyngeal cancer]. AB - OBJECTIVE: To study the clinicopathological characteristics and the prognostic factors in patients with hypopharyngeal cancer. METHODS: Clinical and pathological data of 178 cases with hypopharyngeal cancer from January 2000 to December 2006 were studied. RESULTS: Of the 178 hypopharyngeal cancer, the median survival time was 42.8 months (1 - 127 months). Total 3- and 5-year survival rates were 47% and 35%, respectively. The 5-year survival rates of stage I + II, stage III and stage IV were 76.2%, 46.7% and 29.6%, respectively. The second primary carcinoma occurred in 14.0% patients (25/178), of them 18 patients with synchronous carcinoma and 7 patients with metachronous carcinoma. The independent risk factors associated with the prognosis of these patients were T staging, N staging, clinical staging, performance status (PS), smoking index and treatment model (all P < 0.01). Multivariate Cox analysis showed that smoking index, staging of tumor and treatment were independent risk factors of prognosis. The rate of larynx function preservation was increasing with years from 2000 to 2006. CONCLUSIONS: Surgery plus radiotherapy is the most important treatment for the patients with hypopharyngeal cancer. Tumor stage and treatment model are important predictors of survival in patients with hypopharyngeal cancer. PMID- 22932237 TI - [Display of esophageal entrance by injecting gas through the laryngoscopic biopsy channel in hypopharyngeal cancer]. AB - OBJECTIVE: To investigate the method displaying the hypopharynx and esophageal entrance under laryngoscopy to determine the invasion range of hypopharyngeal cancer. METHODS: A total of 113 patients with hypopharyngeal cancer was enrolled in this study and they previously underwent conventional laryngoscopic and radiologic examinations. The esophageal entrance was exposed by injecting gas through the biopsy channel of laryngoscope. The invasion of esophageal entrance in hypopharyngeal cancers was evaluated by this method and compared with that evaluated with radiology. RESULTS: Conventional laryngoscopy was unable to evaluate appreciably esophageal entrance involvement in the 113 patients with hypopharyngeal cancer. After injecting gas through the laryngoscopic biopsy channel, the esophageal entrance was clearly displayed in 96.5% (109/113) patients, showing the presence (33 cases) and absence (76 cases) of esophageal entrance invasion. Imaging examinations only showed the invasion of the esophageal entrance in 25 patients of these patients,but did not in other 8 patients. Laryngoscopy with injecting gas through the biopsy channel was superior to radiological imaging examinations in determining the invasion of the esophageal entrance (chi2 = 9.103, P = 0.003). CONCLUSION: Laryngoscopy with injecting gas through the biopsy channel is a useful method for determining the presence or absence of esophageal entrance invasion in hypopharyngeal cancer prior to surgery. PMID- 22932238 TI - [Diagnosis and treatment of facial nerve schwannoma in patients with normal facial nerve function or slight facial palsy]. AB - OBJECTIVE: To investigate the diagnosis and treatment of facial nerve schwannomas with facial nerve function House-Brackmann grade (HB) <= grade II. METHODS: A retrospective study was conducted in Peking Union Medical College Hospital. We reviewed eight cases of facial nerve schwannomas with facial nerve function HB <= grade II, which were diagnosed and managed between Jan 1996 and March 2011. RESULTS: The initial presenting symptoms of the eight patients were not facial paralysis. Eight patients were misdiagnosed and six had mistreatment histry. CT and(or) MRI results in all patients showed that the tumors originated from different part of the facial nerves. All patients received operation. Facial nerves were completely preserved in four patients because of easy separation of the tumors from the facial nerves in surgery, facial function was gradeII-III over 17 - 180 months' follow-up. The tumors were attached with the facial nerves in two patients with wide extension involving cochlea and labyrinth, therefore the tumors were removed together with the attached facial nerves, and the nerves were repaired by using the greater auricular nerves. Facial function was grade VI over 56 - 79 months' follow-up. One patient refused to sacrifice the facial nerve, wide decompression of facial nerve and tumor was undertaken, facial function was grade III over 8 months' follow-up. One chorda tympani neuroma was removed with the branch of the facial nerve, facial function was grade II over 8 months' follow-up. CONCLUSIONS: The facial nerve schwannomas with facial nerve function HB <= grade II is difficult to diagnosis. The therapy strategy should depend on the patients' choice, position of the tumor and adherences of the tumor to facial nerve. Facial nerve could be preserved if the tumor is easy to be separated from the facial nerve during operation, if not, total remove the tumor and nerve repairment are indicted when invasion into the inner ear canal, cerebro pontine angle, cochlea or labyrinth. If patients refuse to sacrifice the facial nerve, facial nerve decompression and periodic follow-up are recommended. PMID- 22932239 TI - [Salvage management and subsequent treatment after internal carotid artery injury during transnasal endoscopic surgery]. AB - OBJECTIVE: To explore the cause, urgent management, further treatment, outcome and prevention of internal carotid artery (ICA) injury during transnasal endoscopic surgery. METHODS: Five ICA injury happened during transnasal endoscopic surgery of sphenoidal sinus and (or) sellar region, involving 1 case of traumatic optic neuropathy, 1 case of sphenoidal cyst, 1 case of fungal sphenoid sinusitis, 1 case of sellar adenoid cystic carcinoma and 1 case of pituitary tumor. These five cases were from three different hospitals in 1990 - 2009, and the clinical data were collected and retrospectively reviewed. RESULTS: Injury of ICA was related with improper anatomic localization and operative procedures. The locations of injury were in cavernous segment in 3 cases, lacerum segment in 1 case, and clinic segment in 1 case, respectively. The types of injury included 3 cases of bleeding of laceration, 1 case of carotid cavernous fistula and 1 case of pseudoaneurysm. Salvage sphenoid sinus packing with vaseline strip and subsequent intravascular stent graft implantation (2 cases) and endovascular embolization (2 cases) effectively controlled bleeding. Four cases were successfully treated without craniocerebral or ocular complications, only 1 case died of massive blood loss. Among 4 survival cases, 1 patient abandoned further therapy, the other 3 patients were cured of primary disease by reoperation or subsequent treatment. CONCLUSION: Preoperatively, reading carefully the imaging data, intraoperatively, identifying anatomical positions accurately, performing proper operation, and stopping bleeding decidedly, postoperatively, seeking interdisciplinary cooperation to repair vascular damages, all these procedures can effectively reduce the surgical risk of ICA injury. PMID- 22932240 TI - [Comparison of clinical characteristics between patients with non-allergic and allergic rhinitis]. AB - OBJECTIVE: To analyze and compare the differences of clinical characteristics and comorbidities between patients with non-allergic rhinitis (NAR) and allergic rhinitis (AR). METHODS: A total of 556 out-patients were enrolled from January 2010 to June 2011. The chief complaints of the patients included at least two of the following nasal symptoms: nasal congestion, rhinorrhea, sneezing, and nasal itching. Based on the results of the disease history, physical examination and allergen skin prick test, the patients were classified into NAR group (n = 206) and AR group (n = 350). Detailed information including general data, nasal symptoms and signs, accompanied symptoms and comorbidities were obtained by questionnaires. A scoring was adopted to estimate the severity of disease. SPSS 13.0 software was applied for statistical analysis. RESULTS: The mean age of NAR patients (31.8 +/- 16.7) was older than that of AR patients (26.3 +/- 14.8), and the difference was significant (t = 4.01, P = 0.0001). While there was no significant difference on gender distribution between two groups (chi2 = 0.12, P = 0.73). The percentage of nasal congestion was not significantly different between NAR and AR patients (89.8% and 92.0%, respectively; chi2 = 0.26, P = 0.611). However, the symptoms of rhinorrhea, sneezing, nasal itching, eyes itching, lachrymation, wheeze and cough were more popular in AR patients than those in NAR patients (all P < 0.05). Moreover, above symptoms (except cough) were more serious in AR patients, and the symptom scores were significantly higher than those in NAR patients (all P < 0.05). Most of patients with NAR (67.0%) and AR (62.9%) were moderate-severe persistent (chi2 = 1.25, P = 0.264). Accompanied asthma were more common in patients with AR (12.6%) compared with NAR (2.4%), while hypertension were more common in patients with NAR (7.3%) compared with AR (1.7%), and the differences were significant (both P < 0.05). CONCLUSION: NAR and AR are two different disease entities, which have different clinical characteristics, as well as different comorbidities. Further clinical study should be done on the rhinitis phenotypes. PMID- 22932241 TI - [Related factors of central lymph node metastasis in papillary thyroid carcinoma]. AB - OBJECTIVE: To study the related factors of central lymph node (CLN) metastasis in papillary thyroid carcinoma (PTC),the indications and the extent of central neck dissection (CND). METHODS: A total of 153 cases treated between Jan. 2009 and Dec. 2010 was analysed retrospectively. Of the cases 28 males and 125 cases females, with a mean age of (44 +/- 14) years. T1, T2, and T3 diseases accounted for 51, 10 and 81 cases, respectively; I, II, III and IV diseases for 88, 3, 26 and 36 cases, respectively. Multifocal tumors were found in 63 cases. The related clinicopathologic factors were analyzed, including sex, age, tumor size, extrathyroidal extension, and multifocal tumor. RESULTS: All the cases had total/near total thyroidectomy and CND, of them 64 cases had unilateral neck dissection and 18 cases had bilateral neck dissection. CLN metastases existed in 68.6% (105/153) cases, 37.2% (57/153) for unilateral and 31.4% (48/153) for bilateral respectively. The rates of CLN metastasis were 86.6% (71/82) in cN1 cases and 47.9% (34/71) cN0 cases, respectively,and the rates of bilateral CLN metastases were 45.1% (37/82) in cN1 cases and 15.5% (11/71) in cN0 cases. Multivariate analysis showed that extrathyroidal extension (P = 0.002, OR = 3.502) was an independent risk factor for CLN metastasis and that lateral neck lymph node metastasis (P = 0.028, OR = 3.080), surrounding tissue invasion (P = 0.014, OR = 3.113), and maximum tumor diameter greater than 1 cm (P = 0.012, OR = 3.732) were independent risk factors for bilateral CLN metastases. CONCLUSIONS: It is indicated that ipsilateral CND should be obligatory for PTC. Intraoperative frozen section examination should be routine. Bilateral CND should be conducted when ipsilateral CLN metastases accompanied by one of following issues such as more invasive tumor (surrounding tissue invasion, T3 or T4 disease), maximum tumor diameter greater than 1 cm, and lateral neck lymph node metastasis. PMID- 22932242 TI - [Minimally invasive endoscopic thyroidectomy via an anterior chest approach for early papillary thyroid cancer]. AB - OBJECTIVE: To evaluate the feasibility and safety of endoscopic thyroidectomy via anterior chest approach for early papillary thyroid cancer (T1N0M0). METHODS: From July 2004 to December 2010, 91 patients with early papillary thyroid cancer underwent minimally invasive endoscopic thyroidectomy via anterior chest approach. The clinical and pathologic characteristics of patients, operation types, operative time, postoperative hospital stay time, and postoperative complications were analyzed retrospectively. RESULTS: All 91 operations were successfully performed endoscopically. There was no case conversed to open surgery. The mean tumor size was (0.96 +/- 0.71) cm. The operation types included unilateral lobectomy (41 cases), unilateral subtotal lobectomy (3 cases), ipsilateral lobectomy and contralateral subtotal lobectomy (42 cases), and bilateral total thyroidectomy (5 cases). Central compartment node dissection was carried out in 39 cases with the tumor diameter less than 1.0 cm and in 29 cases with the tumor diameter of 1.0 - 2.0 cm. The mean operating time was (99 +/- 17) min, the mean bleeding volume was (18 +/- 12) ml, and the mean post-operative hospital stay time was (3 +/- 1) days. Temporary recurrent laryngeal nerve (RLN), paresis occurred in 2 cases and recovered within 1 to 2 months after the surgery. One patient showed permanent RLN paralysis. Two patients showed temporary hypoparathyroidism. No patient showed post-operative seroma and tracheal injury. There was no case with injury to the superior laryngeal nerve. No further complications, such as irritating cough, tetany, and emphysema developed after the operation. With the anterior chest wall approach, all patients had no surgical scar on the neck and thus they were satisfied with the cosmetic outcomes. All patients were disease free by follow-up of 7 to 85 (58.4 +/- 17.2) months. CONCLUSIONS: Minimally invasive endoscopic thyroid surgery through anterior chest approach is a feasible and safe method for the treatment of early papillary thyroid cancer. This technique had better cosmetic results and the long term effect of this technique needs further evaluation. PMID- 22932243 TI - [Histological changes of peripheral vestibular organs in the inner ears of Smad4 conditional knockout mice]. AB - OBJECTIVE: To investigate the histological changes in the vestibular endorgans of Smad4 gene conditional knockout mice and to explore the influence of the Smad4 gene on vestibular development. METHODS: Histological changes of periphery vestibular organs in inner ear of Smad4 conditional knockout mice were investigated by frozen sections, immunofluorescence, confocal microscopy, scanning electron microscopy and transmission electron microscopy. RESULTS: There was no Smad4 expression in the inner ear cartilage capsule of Smad4-/- mice. In Smad4+/- mice, Smad4 expression in the same cartilage capsule was positive, and it was strong positive in Smad4+/+ mice. Smad4 expression in vestibular sense epithelium, crista ampullaris and macula, was positive. And no difference was found among these three genotypes. Studying at scanning electron microscopy and transmission electron microscopy levels and anti-filament immunofluorescence showed that no pathological changes were observed in all the three genotype mice. CONCLUSION: Although the Smad4 gene was knockout effectively in the auricular cartilage capsule of Smad4 conditional knockout mice,the histological changes of Smad4 conditional knockout mice in vestibulum auris internal were slightly. PMID- 22932244 TI - [Therapeutic effects of photocatalytic nano-TiO2on human nasopharyngeal carcinoma xenografts in nude mice]. AB - OBJECTIVE: To study the therapeutic effect of photocatalytic nano-TiO2 on nasopharyngeal carcinoma xenograft in nude mice and underlying mechanism. METHODS: Nude mice bearing human nasopharyngeal carcinoma xenograft were randomly divided into six groups: nano-TiO2 + UV irradiation (with gradient concentration of nano-TiO2); nano-TiO2 alone and UV irradiation alone and blank control. The nano-TiO2 suspension was injected into xenografts, and 24 h after UV light with the wave length of 330 - 400 nm, all the xenografts were removed and sectioned for HE staining. Ultrastructure and apoptosis of tumor cells in the xenografts were observed by transmission electron microscope (TEM). The expression of Caspase-3 was examined immunohistochemical staining and the apoptosis was detected with TUNEL. RESULTS: Pathological analysis showed significant inflammatory responses (grade II and III) with local necrosis occurred in tumor tissues after nano-TiO2 photodynamic therapy, but not in the negative control and blank control. TEM showed the nano-TiO2 particles entered into the cytoplasm and the nucleus of tumor cells and many tumor cells had morphological changes for apoptosis. Significant positive expression of Caspase-3 and TUNEL-positive cells were found in the the xenografts with the treatments of nano-TiO2 + UV irradiation compared to control (P < 0.01), which were enhanced with the increases in nano-TiO2 concentration (P < 0.01). CONCLUSION: Photocatalytic nano TiO2 can inhibit the growth of nasopharyngeal carcinoma xenograft in nude mice by inducing Caspase-3 expression and apoptosis in the tumor cells. PMID- 22932245 TI - [Use of a linear stapler device in total laryngectomy]. AB - OBJECTIVE: To evaluate the value of using a linear stapler device for the closure of the pharynx during total laryngectomy. METHODS: Sixteen total laryngectomies were performed between August 2010 and December 2011, during the operation, the TA 60 linear stapler was used for pharyngeal closure. Among these patients, two patients had the history of pre-operative radiotherapy, four patients recurred after radiotherapy, ten patients were treated for the first time. 100 ml methylene blue was injected into the newly closed laryngopharyngeal cavity through the nasopharyngeal breather pipe for checking up whether it was watertight or not. RESULTS: Among the sixteen patients, methylene blue leakage from the mucosal joint of the gular cavity closed by the stapler were not found in fifteen patients, it was only found in one patient. The transudatory places were sutured with absorbable Vicryl sutures. This patient healed well without pharyngocutaneous fistula. Negative surgical margins were achieved in all patients. No patient needed to be transferred to open surgery. Using a linear stapler device in total laryngectomy, 45 minutes could be saved as compaired to manual suture. One patient developed a light pharyngocutaneous fistula. The incidence of pharyngocutaneous fistula was 6.25% (1/16). CONCLUSIONS: This stapled closed technique for pharyngoplasty is efficient, eliminates the risk of wound contamination, saves operation time and decreases the incidence of pharyngocutaneous fistula. This technique can be recommended as alternative for repairing the pharynx in patients undergoing total laryngectomy. PMID- 22932246 TI - [Clinical analysis of abnormal acoustic admittance in preschool children with nasal and nasopharyngeal disorders]. AB - OBJECTIVE: To investigate the risk factors of related disorders, which could lead to potential otitis media by observing the abnormal configuration of drum and abnormal acoustic immittance without symptoms in preschool children. METHODS: Eighty-one cases (162 ears) received flexible pharyngorhinoscopy, skin prick test, CT examination of sinus, and were diagnosed as allergic rhinitis, chronic sinusitis, adenoid hypertrophy. They had no complaints of ear related symptoms, but were observed to have abnormality in ear drum by physical examined. Acoustic immittance measurement were performed, so as to estimate whether they were accompany with potential otitis media. The changes of examination and tests were analyzed before and after the treatment. RESULTS: There were 15 cases (29 ears) with abnormal acoustic admittance among 81 cases (162 ears) who had no ear related symptoms but had different degree abnormality in ear drum. The morbidity rate of these 15 patients was 13.6% (6/44 ears) in allergic rhinitis patients, 18.2% (12/66 ears) in chronic sinusitis patients, and 21.2% (11/52 ears) in adenoid hypertrophy patients, respectively. The differences among the three diseases had statistical significance (chi2 = 63.02,P < 0.05). Among 29 ears, 28 ears whose type of tympanic pressure curve were transferred from type C to type A two weeks after treatment. One ear whose type of tympanic pressure curve transferred from type B to type C four weeks after treatment. All cases had been followed up with no recurrent cases. CONCLUSIONS: Some preschool children with nasal and nasopharyngeal disorders had abnormal configuration of drum and abnormal acoustic immittance, and had potential risk for otitis media. Among the disorders, adenoid hypertrophy impact more on middle ear function. The early intervention of related diseases could prevent the developing trend of otitis media. PMID- 22932247 TI - [Reshaping the nasal tip with autologous nasal septum cartilage combined with ePTFE grafts and autologous auricular cartilage grafts]. AB - OBJECTIVE: To evaluate the clinical effects of reshaping the nasal tip with autologous nasal septum cartilage combined with expanded polytetrafluoroethylene (ePTFE) and autologous auricular cartilage grafts. METHODS: The nasal septal cartilage combined with ePTFE (group A, 70 cases) and autologous auricular cartilage grafts (group B, 48 cases) were used separately. The therapeutic effect and operation time were compared using the t-test or the chi2-test by the SPSS 12.0 software. RESULTS: The mean operation time (x(-) +/- s) in group A was less than those in group B and the difference was significant (t = 13.258, P = 0.000). The width of nasal tip equal to (6 - 8) mm was found in 67 cases (95.7%) in group A, and 46 cases (95.8%) in group B. There was no statistically significant difference between group A and group B (chi2 = 0.001, P = 0.996). The correction result of the nasal tip projection, angle of ration, the included angle of nasal dorsum and nasal columella and the height of the nasal tip did not show statistically significant difference between group A and group B (chi2 value were 0.001, 0.069, 0.149, 0.073, respectively, all P > 0.05). CONCLUSION: The autologous nasal septal cartilage combined with ePTFE and autologous auricular cartilage grafts showed similar clinical effect. PMID- 22932248 TI - [One case of invasive adenoma of the middle ear]. PMID- 22932249 TI - [Thirty-two cases of adenoidal hypertrophy in adult]. PMID- 22932250 TI - [Botulinum toxin A injection under flexible fiberoptic laryngoscope guidance for treatment of adductor spasmodic dysphonia]. PMID- 22932251 TI - [One case of foreign body in the lateral skull base]. PMID- 22932252 TI - [Primary epithelioid hemangioendothelioma in the maxillary sinus:one case report]. PMID- 22932253 TI - [Clear cell carcinoma not otherwise specified involving the pterygomandibular region and infratemporal fossa - one case report]. PMID- 22932254 TI - [Overview of the materials for Chinese speech test]. PMID- 22932255 TI - [Introduction of practical guide to skin prick tests in allergy to aeroallergens]. PMID- 22932256 TI - Relationships of coronary heart disease with 27-hydroxycholesterol, low-density lipoprotein cholesterol, and menopausal hormone therapy. AB - BACKGROUND: Menopausal hormone therapy (MHT) increases the risk of coronary heart disease (CHD) in older women with elevated low-density lipoprotein (LDLC) levels. The endogenous estrogen receptor antagonist 27-hydroxycholesterol (27OHC) is correlated with LDLC levels and may block the beneficial effects of estrogen on the cardiovascular system. METHODS AND RESULTS: We conducted a nested case control study in the Women's Health Initiative trials of 350 CHD cases and 813 matched controls to explore potential mediation by 27OHC of the dependence of the CHD risk elevation with MHT on LDLC. Baseline levels of 27OHC were not associated with CHD risk when LDLC was included in the multivariable models. The odds ratio for CHD associated with increased LDLC was 1.15 (95% confidence interval, 1.08 1.23) and was unchanged at 1.14 (95% confidence interval, 1.07-1.22) when 27OHC was added to the model. Baseline 27OHC did not interact with MHT on CHD risk (P=0.81). In contrast, LDLC levels modified the effect of MHT on CHD risk (P for interaction=0.02), and adding 27OHC did not affect this result. With the use of log scales, the effect of MHT on CHD increased linearly with increasing level of baseline LDLC, with a transition from no risk to increased risk at ~3.36 mmol/L (130 mg/dL). CONCLUSIONS: This study found that 27OHC does not independently increase the risk of CHD, does not modify the increased risk of CHD resulting from MHT, and does not mediate the interaction of LDLC with MHT. Measuring blood lipids may aid in counseling individual women about initiating MHT and cardiovascular risk mitigation. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00000611. PMID- 22932257 TI - Carnitine palmitoyltransferase-1b deficiency aggravates pressure overload-induced cardiac hypertrophy caused by lipotoxicity. AB - BACKGROUND: Carnitine palmitoyltransferase-1 (CPT1) is a rate-limiting step of mitochondrial beta-oxidation by controlling the mitochondrial uptake of long chain acyl-CoAs. The muscle isoform, CPT1b, is the predominant isoform expressed in the heart. It has been suggested that inhibiting CPT1 activity by specific CPT1 inhibitors exerts protective effects against cardiac hypertrophy and heart failure. However, clinical and animal studies have shown mixed results, thereby creating concerns about the safety of this class of drugs. Preclinical studies using genetically modified animal models should provide a better understanding of targeting CPT1 to evaluate it as a safe and effective therapeutic approach. METHODS AND RESULTS: Heterozygous CPT1b knockout (CPT1b(+/-)) mice were subjected to transverse aorta constriction-induced pressure overload. These mice showed overtly normal cardiac structure/function under the basal condition. Under a severe pressure-overload condition induced by 2 weeks of transverse aorta constriction, CPT1b(+/-) mice were susceptible to premature death with congestive heart failure. Under a milder pressure-overload condition, CPT1b(+/-) mice exhibited exacerbated cardiac hypertrophy and remodeling compared with wild-type littermates. There were more pronounced impairments of cardiac contraction with greater eccentric cardiac hypertrophy in CPT1b(+/-) mice than in control mice. Moreover, the CPT1b(+/-) heart exhibited exacerbated mitochondrial abnormalities and myocardial lipid accumulation with elevated triglycerides and ceramide content, leading to greater cardiomyocyte apoptosis. CONCLUSIONS: CPT1b deficiency can cause lipotoxicity in the heart under pathological stress, leading to exacerbation of cardiac pathology. Therefore, caution should be exercised in the clinical use of CPT1 inhibitors. PMID- 22932259 TI - Hearing the right heart's sotto voce. PMID- 22932258 TI - Right ventricular structure is associated with the risk of heart failure and cardiovascular death: the Multi-Ethnic Study of Atherosclerosis (MESA)--right ventricle study. AB - BACKGROUND: Changes in right ventricular (RV) morphology are associated with morbidity and mortality in heart and lung disease. We examined the association of abnormal RV structure and function with the risk of heart failure or cardiovascular death in a population-based multiethnic sample free of clinical cardiovascular disease at baseline. METHODS AND RESULTS: The Multi-Ethnic Study of Atherosclerosis (MESA) performed cardiac magnetic resonance imaging on 5098 participants between 2000 and 2002 with follow-up for incident heart failure and cardiovascular death ("death") until January 2008. RV volumes and mass were available for 4204 participants. The study sample (n=4144) was 61.4+/-10.1 years old and 47.6% male. The presence of RV hypertrophy (increased RV mass) was associated with more than twice the risk of heart failure or death after adjustment for demographics, body mass index, education, C-reactive protein level, hypertension, and smoking status (hazard ratio, 2.52; 95% confidence interval, 1.55-4.10; P<0.001) and a doubling (or more) of risk with left ventricular mass at the mean value or lower (P for interaction=0.05). CONCLUSIONS: RV hypertrophy was associated with the risk of heart failure or death in a multiethnic population free of clinical cardiovascular disease at baseline. PMID- 22932260 TI - Langerhans cell density in cervical intraepithelial neoplasia associated with human papillomavirus infection in HIV-infected and HIV-noninfected Brazilian women. AB - OBJECTIVE: Local immunity plays an important role in the cervical defense mechanisms that prevent the development of cervical intraepithelial neoplasia. The objective of this study was to determine the involvement of local immunity by evaluating Langerhans cell (LC) density in cervical biopsies of human immunodeficiency virus (HIV)-positive and HIV-negative women. MATERIALS AND METHODS: A cross-sectional study was developed by including HIV-positive and HIV negative women. All patients presented human papillomavirus DNA from the uterine cervix, which was detected by polymerase chain reaction or hybrid capture II. Cervical biopsies were assessed for LC density and cervical intraepithelial neoplasia. Langerhans cells were identified by immunohistochemistry using anti CD1a and anti-S100 antibodies. Associations among cervical LC density, the type of cervical lesion, CD4 lymphocyte count, and HIV viral load were analyzed using logistic regression (SPSS, version 12.0). RESULTS: Seventy-seven women (40 seropositive and 37 seronegative) were enrolled. The mean +/- SD LC density identified with the anti-CD1a antibody was 0.80 +/- 0.7 cells versus 2.6 +/- 1.6 cells (P < 0.0001), whereas the mean +/- SD LC density identified by the anti S100 antibody was 1.3 +/- 1.0 cells versus 3.6 +/- 1.7 cells (P < 0.0001) among the HIV-positive and HIV-negative women, respectively. There were no associations between LC density and HIV viral load, CD4 lymphocyte count, or human papillomavirus genotype (P > 0.05). In a logistic regression model, HIV infection was the only factor independently associated with a decrease in LC density. CONCLUSIONS: Human immunodeficiency virus infection was found to be an independent factor that explains the decrease in local immunity in the uterine cervix, which could allow the development of cervical lesions. This effect was not associated with CD4 lymphocyte count or HIV viral load. PMID- 22932261 TI - Effect of health education about cervical cancer and papanicolaou testing on the behavior, knowledge, and beliefs of Turkish women. AB - BACKGROUND: Cervical cancer is the second most common form of cancer observed among women in Turkey. The participation of women in cervical cancer screening programs is strongly affected by Turkish attitudes, beliefs, and sociocultural structure. AIM: This study was conducted to assess the effectiveness of health education that aimed to raise awareness about Papanicolaou testing and to emphasize the importance of the early diagnosis of cervical cancer. MATERIALS AND METHODS: The study was conducted as a prospective, randomized, controlled trial and was carried out in 148 women. Seventy-five women in the control group were asked to fill out questionnaire forms. A 45-minute conference-style training was given to 73 women in the study group, and all of the subjects were asked to fill out the forms after the training. The sociodemographic characteristics of the 2 groups and the mean "Health Belief Model Scale for Cervical Cancer and Pap Smear Test" scores of the 2 groups were statistically analyzed by Statistical Package of Social Sciences (SPSS), version 15. RESULTS: There was no statistically significant difference noticed between the sociodemographic characteristics of the 2 groups (P > 0.05). The difference in test scores, which represented knowledge about cervical cancer and Papanicolaou testing, was statistically significant between the control group and the study group (t = 10.122, P < 0.05). In the Health Belief Model Scale for Cervical Cancer and Pap Smear Test, there were statistically significant differences in the following measures: lower levels of susceptibility to cervical cancer score (t = -2.035, P < 0.05), lower levels of perceived benefit from a Papanicolaou test score (t = 3.278, P < 0.05) and lower levels of perceived barriers to Papanicolaou test score (t = -3.182, P < 0.05). CONCLUSION: Nurses should be involved in educating women about cervical cancer and Papanicolaou testing. By doing so, they can change the attitudes, knowledge, and beliefs of the women. PMID- 22932262 TI - Feasibility and acute toxicity of Concurrent Chemoradiotherapy (CCRT) with high dose rate intracavitary brachytherapy (HDR-ICBT) and 40-mg/m2 weekly cisplatin for Japanese patients with cervical cancer: results of a Multi-Institutional Phase 2 Study (JGOG1066). AB - OBJECTIVE: To assess the feasibility and acute toxicity of concurrent chemoradiotherapy (CCRT) with high-dose rate intracavitary brachytherapy (HDR ICBT) and standard dose delivery of cisplatin for Japanese patients with cervical cancer. MATERIALS AND METHODS: The phase 2 study included Japanese patients with International Federation of Gynecology and Obstetrics stage III to IVA uterine cervical cancer who had no para-aortic lymphadenopathy (>10 mm) assessed by computed tomography. Patients were 20 to 70 years of age and had Eastern Cooperative Oncology Group performance status of 0 to 1. The radiotherapy protocol consisted of whole-pelvis external beam radiotherapy and HDR-ICBT. The cumulative linear quadratic equivalent dose (EQD2) was 62 to 65 Gy prescribed at point A. Cisplatin was administered weekly at a dose of 40 mg/m(2) for 5 courses. RESULTS: Between March 2008 and January 2009, 72 patients from 25 institutions were enrolled, and 71 patients were eligible and evaluable for compliance and severe toxicity. The median age of the patients was 57 years (range, 32-70 years). Sixty-five patients (92%) received the planned 5 courses of chemotherapy. Four patients had cisplatin dose reduction according to the protocol. Radiotherapy was completed per protocol in 68 patients (96%). Median overall treatment time was 50 days (range, 37-66 days). The following grade 3 or 4 acute adverse events were observed: neutropenia in 31 patients (44%), anemia in 10 patients (14%), diarrhea in 4 patients (6%), and anorexia in 3 patients (4%). CONCLUSIONS: Concurrent chemoradiotherapy with HDR-ICBT and standard weekly delivery of cisplatin was feasible with acceptable toxicity in Japanese patients with cervical cancer. PMID- 22932263 TI - Clear cell adenocarcinoma of the female genital tract: long-term outcome and fertility aspects after brachytherapy aimed at a conservative treatment. AB - OBJECTIVES: To assess the outcome and the fertility aspects in the particular population of cervical and/or vaginal clear cell adenocarcinoma (CCA) associated or not to previous in utero diethylstilbestrol exposure. METHODS: From January 1970 to December 2003, data from 61 consecutive patients with cervical and/or vaginal histologically proven CCA treated with brachytherapy (BT) aimed at a conservative treatment at the Institut Gustave Roussy as a part of treatment were retrospectively analyzed. RESULTS: The median follow-up was 9.4 years, ranging from 0.3 to 27.4 years. The 5-year specific overall survival rate was 79%. The median time of disease-free survival was 5.8 years. In the subgroup of 42 patients with a cervical CCA, 12 patients tried to be pregnant, 2 patients became pregnant and had miscarriages (P2M2 and P1M1). No pregnancy has been observed in 10 patients exclusively owing to anomalies of the reproductive tract: 6 patients had partial or total diaphragm, 2 patients had an anatomical alteration of the uterus, 1 patient had atrophic endometrium, and 1 patient had primary infertility. In the subgroup of 19 patients with a vaginal CCA, 7 patients tried to be pregnant. All of them had no morphological and/or functional anomalies of the genital tract. Three of 7 patients had delivered healthy babies (P1D1, P2D2, and P3M2D1), and another one had a miscarriage (P1M1). Moreover, all babies were delivered by cesarean section. The pregnancy rate was 10% (6 of 61 patients) with 3 healthy babies. CONCLUSION: Conservative approach in patients with female genital tract CCA including BT gives good results with good survival rates and an interesting global pregnancy rate. PMID- 22932264 TI - Comparison of 2 contouring methods of bone marrow on CT and correlation with hematological toxicities in non-bone marrow-sparing pelvic intensity-modulated radiotherapy with concurrent cisplatin for cervical cancer. AB - OBJECTIVES: To compare volumes and dose volume histogram (DVH) parameters for bone marrow contours using 2 methods on computed tomography (CT) and correlation with grade 2 or higher hematological toxicity (HT) in patients with cervical cancer treated with non-bone marrow-sparing intensity-modulated radiotherapy (IMRT) with concurrent cisplatin. MATERIALS AND METHODS: The planning CT scans of 47 patients prospectively enrolled and treated with IMRT arm of a phase 2 trial (NCT00193804) contoured for pelvic bone marrow in 2 sets; whole bone (WB), and freehand (FH) inner cavity of bone. Various subvolumes were made in each set- sacrum, ilium, ischium, lower pelvis, lumbosacral spine, sacrum, and whole pelvis -and compared for volume and DVH parameters (V(10), V(20), V(30), and V(40)) using paired t test. The hematological parameters during RT compiled from electronic database analyzed for higher than grade 2 (Radiation Therapy Oncology Group) HT and correlated with DVH parameters using log regression analysis (P < 0.05 significant). RESULTS: The FH subvolumes were 25% to 30% of WB. The mean DVH parameters V(10), V(20), V(30), and V(40) for whole-pelvis FH and WB were 86.5%, 77.5%, 62.5%, and 40.5%; and 88%, 79.6%, 62.9%, and 40%, respectively. There was significant difference between the DVH parameters of 2 sets (P < 0.05) for all subvolumes except ischium V(20), sacrum V(10), and lumbosacral spine V(10). The leukopenia, neutropenia, anemia, and thrombocytopenia higher than grade 2 was seen in 53%, 29.8%, 65.9%, and 10.6%, respectively. The mean V(10) for whole pelvis was less than 90% for both sets. On both univariate and multivariate analyses, only FH whole pelvis V(40) more than or equal to 40% correlated with higher than grade 2 leukopenia (Mann-Whitney U test, P = 0.026) and neutropenia (P = 0.05) with odds ratio, 4 (95% confidence interval, 1.166-13.728; P = 0.028). CONCLUSIONS: The FH bone marrow cavity volume is a better surrogate of active bone marrow on CT images and correlated with higher than grade 2 HT (V(40) >40%). Further prospective studies validating significance of high-dose effects and identifying correlation of bioimaging with CT contouring are warranted. PMID- 22932265 TI - Detection of human papillomavirus among women in Laos: feasibility of using filter paper card and prevalence of high-risk types. AB - BACKGROUND: Persistent infection with high-risk (HR) human papillomavirus (HPV) is a well-recognized cause of cervical cancer, but little is known about the situation in Laos. The aims of the study were to determine the prevalence of HR HPV among Lao women and to evaluate the use of a filter paper card (FTA Elute Micro Card) for collection of cervical cells in the humid tropical climate. METHODS: This is a cross-sectional study including 1922 women from 3 provinces in Laos. During a gynecological examination, cervical cells were collected and applied to the FTA card followed by HPV typing using a real-time polymerase chain reaction (PCR)-based assay. RESULTS: Overall, 213 of the 1922 women were positive for HR-HPV (11%). The most common type was the group HPV33/52/58 (3%), followed by the single type 16 (2%) and the group 18/45 (1%), respectively. Only 11 cards (0.6%) did not contain a sufficient amount of genomic DNA for polymerase chain reaction-based analysis. CONCLUSIONS: The prevalence of HR-HPV infections in Laos is similar to other Asian countries, and 40% of the women with an HR-HPV infection will be target of the present HPV vaccines. The FTA card is suitable for collection of cervical cells for HR-HPV typing in tropical conditions. This information is important for planning and establishing primary and secondary prevention of cervical cancer in Laos. PMID- 22932266 TI - Clinicopathological risk factors for pelvic lymph node metastasis in clinical early-stage endometrioid endometrial adenocarcinoma. AB - OBJECTIVE: To identify the clinicopathological risk factors for pelvic lymph node (PLN) metastasis and to evaluate the predictive significance of these factors for lymphadenectomy in clinical early-stage endometrioid endometrial adenocarcinoma (EEA). METHODS: Six hundred and twenty-one patients with clinical early-stage EEA (tumor confined to uterus, diagnosed preoperatively or intraoperatively) who underwent hysterectomy plus bilateral salpingo-oophorectomy plus pelvic and/or para-aortic lymphadenectomy between 1989 and 2006 in the Obstetrics and Gynecology Hospital of Fudan University were retrieved. The predictive value of the risk factors for PLN metastasis was analyzed. RESULTS: The positive PLN metastasis rate was 3.9%. The 5-year disease-related mortality rate in the positive PLN metastasis group was 25%, whereas the rate in the negative group was 0.8%. The positive PLN metastasis rates were higher in patients with higher-grade tumors, deep myometrial invasion, cervical stromal involvement, and lymphovascular space involvement (LVSI). The sensitivity and specificity of old age (>= 60 years), grade 3, cancer deep myometrial invasion, cervical stromal involvement, and LVSI in predicting the PLN metastasis were 25.0%, 41.7%, 70.8%, 20.8%, and 41.7%; and 79.1%, 88.4%, 85.6%, 95.6%, and 94.5%, respectively. The multivariate analysis revealed that the deep myometrial invasion and LVSI were independent risk factors for lymph node metastasis. Combined with these 2 factors as the diagnostic criteria, the negative predictive value and specificity were 97.3% and 89.1%, respectively. CONCLUSION: The patients with clinical early-stage EEA with PLN metastasis showed worse prognoses, although the metastasis rate was low. The deep myometrial invasion and LVSI combination were superior predictive criteria for the PLN metastasis. An accurate evaluation of these factors, both preoperatively or intraoperatively, will be beneficial to predict PLN metastasis and guide the operation. PMID- 22932267 TI - Structural and genetic basis for development of broadly neutralizing influenza antibodies. AB - Influenza viruses take a yearly toll on human life despite efforts to contain them with seasonal vaccines. These viruses evade human immunity through the evolution of variants that resist neutralization. The identification of antibodies that recognize invariant structures on the influenza haemagglutinin (HA) protein have invigorated efforts to develop universal influenza vaccines. Specifically, antibodies to the highly conserved stem region of HA neutralize diverse viral subtypes. These antibodies largely derive from a specific antibody gene, heavy-chain variable region IGHV1-69, after limited affinity maturation from their germline ancestors, but how HA stimulates naive B cells to mature and induce protective immunity is unknown. To address this question, we analysed the structural and genetic basis for their engagement and maturation into broadly neutralizing antibodies. Here we show that the germline-encoded precursors of these antibodies act as functional B-cell antigen receptors (BCRs) that initiate subsequent affinity maturation. Neither the germline precursor of a prototypic antibody, CR6261 (ref. 3), nor those of two other natural human IGHV1-69 antibodies, bound HA as soluble immunoglobulin-G (IgG). However, all three IGHV1 69 precursors engaged HA when the antibody was expressed as cell surface IgM. HA triggered BCR-associated tyrosine kinase signalling by germline transmembrane IgM. Recognition and virus neutralization was dependent solely on the heavy chain, and affinity maturation of CR6261 required only seven amino acids in the complementarity-determining region (CDR) H1 and framework region 3 (FR3) to restore full activity. These findings provide insight into the initial events that lead to the generation of broadly neutralizing antibodies to influenza, informing the rational design of vaccines to elicit such antibodies and providing a model relevant to other infectious diseases, including human immunodeficiency virus/AIDS. The data further suggest that selected immunoglobulin genes recognize specific protein structural 'patterns' that provide a substrate for further affinity maturation. PMID- 22932268 TI - Impact of caloric restriction on health and survival in rhesus monkeys from the NIA study. AB - Calorie restriction (CR), a reduction of 10-40% in intake of a nutritious diet, is often reported as the most robust non-genetic mechanism to extend lifespan and healthspan. CR is frequently used as a tool to understand mechanisms behind ageing and age-associated diseases. In addition to and independently of increasing lifespan, CR has been reported to delay or prevent the occurrence of many chronic diseases in a variety of animals. Beneficial effects of CR on outcomes such as immune function, motor coordination and resistance to sarcopenia in rhesus monkeys have recently been reported. We report here that a CR regimen implemented in young and older age rhesus monkeys at the National Institute on Aging (NIA) has not improved survival outcomes. Our findings contrast with an ongoing study at the Wisconsin National Primate Research Center (WNPRC), which reported improved survival associated with 30% CR initiated in adult rhesus monkeys (7-14 years) and a preliminary report with a small number of CR monkeys. Over the years, both NIA and WNPRC have extensively documented beneficial health effects of CR in these two apparently parallel studies. The implications of the WNPRC findings were important as they extended CR findings beyond the laboratory rodent and to a long-lived primate. Our study suggests a separation between health effects, morbidity and mortality, and similar to what has been shown in rodents, study design, husbandry and diet composition may strongly affect the life-prolonging effect of CR in a long-lived nonhuman primate. PMID- 22932269 TI - Ageing: Mixed results for dieting monkeys. PMID- 22932270 TI - Closing yield gaps through nutrient and water management. AB - In the coming decades, a crucial challenge for humanity will be meeting future food demands without undermining further the integrity of the Earth's environmental systems. Agricultural systems are already major forces of global environmental degradation, but population growth and increasing consumption of calorie- and meat-intensive diets are expected to roughly double human food demand by 2050 (ref. 3). Responding to these pressures, there is increasing focus on 'sustainable intensification' as a means to increase yields on underperforming landscapes while simultaneously decreasing the environmental impacts of agricultural systems. However, it is unclear what such efforts might entail for the future of global agricultural landscapes. Here we present a global-scale assessment of intensification prospects from closing 'yield gaps' (differences between observed yields and those attainable in a given region), the spatial patterns of agricultural management practices and yield limitation, and the management changes that may be necessary to achieve increased yields. We find that global yield variability is heavily controlled by fertilizer use, irrigation and climate. Large production increases (45% to 70% for most crops) are possible from closing yield gaps to 100% of attainable yields, and the changes to management practices that are needed to close yield gaps vary considerably by region and current intensity. Furthermore, we find that there are large opportunities to reduce the environmental impact of agriculture by eliminating nutrient overuse, while still allowing an approximately 30% increase in production of major cereals (maize, wheat and rice). Meeting the food security and sustainability challenges of the coming decades is possible, but will require considerable changes in nutrient and water management. PMID- 22932271 TI - Activation of old carbon by erosion of coastal and subsea permafrost in Arctic Siberia. AB - The future trajectory of greenhouse gas concentrations depends on interactions between climate and the biogeosphere. Thawing of Arctic permafrost could release significant amounts of carbon into the atmosphere in this century. Ancient Ice Complex deposits outcropping along the ~7,000-kilometre-long coastline of the East Siberian Arctic Shelf (ESAS), and associated shallow subsea permafrost, are two large pools of permafrost carbon, yet their vulnerabilities towards thawing and decomposition are largely unknown. Recent Arctic warming is stronger than has been predicted by several degrees, and is particularly pronounced over the coastal ESAS region. There is thus a pressing need to improve our understanding of the links between permafrost carbon and climate in this relatively inaccessible region. Here we show that extensive release of carbon from these Ice Complex deposits dominates (57 +/- 2 per cent) the sedimentary carbon budget of the ESAS, the world's largest continental shelf, overwhelming the marine and topsoil terrestrial components. Inverse modelling of the dual-carbon isotope composition of organic carbon accumulating in ESAS surface sediments, using Monte Carlo simulations to account for uncertainties, suggests that 44 +/- 10 teragrams of old carbon is activated annually from Ice Complex permafrost, an order of magnitude more than has been suggested by previous studies. We estimate that about two-thirds (66 +/- 16 per cent) of this old carbon escapes to the atmosphere as carbon dioxide, with the remainder being re-buried in shelf sediments. Thermal collapse and erosion of these carbon-rich Pleistocene coastline and seafloor deposits may accelerate with Arctic amplification of climate warming. PMID- 22932272 TI - Control of fluoroquinolone resistance through successful regulation, Australia. AB - Fluoroquinolone antimicrobial drugs are highly bioavailable, broad-spectrum agents with activity against gram-negative pathogens, especially those resistant to other classes of antimicrobial drugs. Australia has restricted the use of quinolones in humans through its national pharmaceutical subsidy scheme; and, through regulation, has not permitted the use of quinolones in food-producing animals. As a consequence, resistance to fluoroquinolones in the community has been slow to emerge and has remained at low levels in key pathogens, such as Escherichia coli. In contrast to policies in most other countries, this policy has successfully preserved the utility of this class of antimicrobial drugs for treatment of most infections. PMID- 22932273 TI - Genetic variation in thrombin-activatable fibrinolysis inhibitor is associated with the risk of diabetic nephropathy. AB - Diabetic nephropathy is a kidney disease or damage that results as a complication of diabetes, especially Type 2 diabetes, while albuminuria is an early marker for diabetic nephropathy as it can predict cardiovascular events and mortality in diabetic patients. A potent inhibitor of fibrinolysis, the thrombin-activatable fibrinolysis inhibitor (TAFI) has been isolated and characterized from human plasma. We investigated the associations of the activity-related variants in the TAFI coding gene (505A/G,1040C/T) with the risk of diabetic nephropathy by examining 297samples including 140 health controls and 157 confirmed diabetic nephropathy patients. Diabetic nephropathy grades were further categorized by the urine albumin excretion (UAE)-to-creatinine ratios (ACR). We found little difference that was statistically significant in terms of 505A/G among patients and controls. While at 1040C/T, the detected frequency for the T allele in the group of diabetic nephropathy patients was significantly smaller than that of the control group (15.6% vs 25.7%, respectively; p<0.05). This was due to the relative decrease of T/T homozygotes in the patients (p<0.05, 95% odds ratio 0.28, confidence interval 0.11-0.70). Surprisingly, the difference was only observed with initial diabetic nephropathy stages. This study clearly indicates that, at 1040C/T, the frequency for the T allele is strongly associated with increased risk for diabetic nephropathy in a subset of the general population, implying that the T allele confers protection against the onset of diabetic nephropathy only in homozygosity and may function as a recessive trait. PMID- 22932274 TI - A potentially misleading finding at somatostatin receptor scintigraphy: focal pulmonary areas of intense accumulation without computed tomography-detectable lung lesions. PMID- 22932275 TI - Endocrinology and art. Polyphemus. PMID- 22932276 TI - Making do with what we have: use your bootstraps. PMID- 22932277 TI - The spleen is a player in portal hypertension. PMID- 22932278 TI - Ethnic influences on the relations between abdominal subcutaneous and visceral adiposity, liver fat, and cardiometabolic risk profile: the International Study of Prediction of Intra-Abdominal Adiposity and Its Relationship With Cardiometabolic Risk/Intra-Abdominal Adiposity. AB - BACKGROUND: Ethnic differences in cardiometabolic risk (CMR) may be related to patterns of ethnic-specific body fat distribution. OBJECTIVE: We aimed to identify differences across ethnic groups in interrelations between BMI, abdominal adiposity, liver fat, and CMR profile. DESIGN: In the International Study of Prediction of Intra-Abdominal Adiposity and Its Relationship With Cardiometabolic Risk/Intra-Abdominal Adiposity, 297 physicians recruited 4504 patients (from 29 countries). In the current cross-sectional analyses, 2011 whites, 166 African Caribbean blacks, 381 Hispanics, 1192 East Asians, and 347 Southeast Asians were included. Computed tomography was used to assess abdominal fat distribution and to estimate liver fat content. Anthropometric variables and CMR profile were measured. RESULTS: Higher ranges of BMI were associated with higher levels of visceral [visceral adipose tissue (VAT)] and deep subcutaneous [deep subcutaneous adipose tissue (DSAT)] adiposity, with significant ethnic differences regarding the slope of these relations. Despite lower absolute BMI values, East Asians presented the largest accumulation of VAT but the lowest accumulation of DSAT with increasing adiposity. The association of BMI with liver fat did not differ between ethnic groups. Liver fat and DSAT were positively correlated with VAT with no ethnic variation. All ethnic groups had a similar association between a 1-SD increase in VAT, DSAT, or liver fat with hypertension, type 2 diabetes, hypertriglyceridemia, low HDL-cholesterol concentration, or high C-reactive protein concentration. CONCLUSIONS: Ethnicity significantly affects abdominal adiposity and liver fat partitioning, and East Asians have the most deleterious abdominal fat distribution. Irrespective of ethnicity, abdominal and hepatic fat depots are strongly interrelated and increased with obesity. Higher amounts of VAT or liver fat are associated with a more deteriorated CMR profile in all ethnic groups. PMID- 22932279 TI - Folate-status response to a controlled folate intake in nonpregnant, pregnant, and lactating women. AB - BACKGROUND: Folate dose-response studies in women of childbearing age who consumed a folic acid (FA)-containing multivitamin in the era of FA fortification are lacking. OBJECTIVE: We sought to investigate folate-status response to a known folate dose comprising an FA-containing prenatal supplement (750 MUg/d) plus natural food folate (400 MUg/d) in third-trimester pregnant women, lactating women 5-15 wk postpartum, and nonpregnant women. DESIGN: Pregnant (n = 26), lactating (n = 28), and nonpregnant (n = 21) women consumed the study folate dose under controlled intake conditions for 10-12 wk. Blood, urine, and breast milk were collected at baseline, study midpoint, and study end. RESULTS: Study-end serum total folate concentrations averaged ~30 ng/mL and did not differ by physiologic group (P = 0.876). Study-end urinary folate excretion represented ~9 43% of total folate intake and ranged from 100 to 500 MUg/d. Third-trimester pregnant women excreted less urinary folate than did lactating (P = 0.075) and nonpregnant (P < 0.001) women. Lactating women excreted less (P < 0.001) urinary FA than did nonpregnant women. Breast-milk total folate concentrations remained constant (P = 0.244; 61.8 ng/mL at study end), whereas breast-milk FA concentrations increased (P = 0.003) to 24.1 ng/mL at study end. CONCLUSIONS: The consumption of the study folate dose yielded a supranutritional folate status regardless of the physiologic state. Based on urinary folate excretion, folate use was greatest to least: pregnant > lactating > nonpregnant women. Breast-milk folate species were responsive to maternal folate intake, and FA made up ~40% of breast-milk total folate at study end. These findings warrant revisiting prenatal supplement FA formulation in populations exposed to FA-fortification programs. PMID- 22932280 TI - Effect of iron intake on iron status: a systematic review and meta-analysis of randomized controlled trials. AB - BACKGROUND: The response of status biomarkers to an increase in iron supply depends on several physiologic and environmental factors, which make it difficult to predict the outcome of an intervention. OBJECTIVE: We assessed effects of baseline iron status, sex, menopausal status, duration of intervention, iron form, and daily dose on the change in iron status in response to iron supplementation. DESIGN: A systematic review of randomized controlled trials (RCTs) of iron-supplementation and -fortification trials that assessed effects on hemoglobin, serum ferritin (SF), soluble transferrin receptor, or body iron was conducted. Subgrouping and straight-line and curved metaregression were used to describe the magnitude and dose-responsiveness of effect modifiers with respect to changes in status. RESULTS: Forty-one RCTs were included; none of the RCTs were judged at low risk of bias. Random-effects meta-analyses showed that iron supplementation significantly improved iron status but with high levels of heterogeneity. Metaregression explained approximately one-quarter of between study variance in effect size. There were clear effects on SF with study duration (increase in SF concentration/wk: 0.51 MUg/L; 95% CI: 0.02, 1.00 MUg/L; P = 0.04) and dose (increase in SF concentration/g Fe: 0.10 MUg/L; 95% CI: 0.01, 0.20 MUg/L; P = 0.036) and on hemoglobin concentrations with baseline iron status [ 0.08 g/dL (95% CI: 0.15, 0.00 g/dL) per 10-MUg/L increase in baseline SF concentration; P = 0.02]. Insufficient data were available to assess effects on body iron, sex, or menopausal status. CONCLUSION: Quantitative relations between baseline iron status, study duration, and iron dose on changes in iron-status biomarkers, which were generated from the meta-analyses, can be used to predict effects of trials of iron supplementation and fortification and to design iron intervention programs. PMID- 22932281 TI - Incorporation of eicosapentaenoic and docosahexaenoic acids into lipid pools when given as supplements providing doses equivalent to typical intakes of oily fish. AB - BACKGROUND: Estimation of the intake of oily fish at a population level is difficult. The measurement of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in biological samples may provide a useful biomarker of intake. OBJECTIVE: We identified the most appropriate biomarkers for the assessment of habitual oily fish intake and changes in intake by elucidating the dose- and time dependent response of EPA and DHA incorporation into various biological samples that represent roles in fatty acid transport, function, and storage. DESIGN: This was a double-blind, randomized, controlled intervention trial in 204 men and women that lasted 12 mo. EPA and DHA capsules were provided in a manner to reflect sporadic consumption of oily fish (ie, 1, 2, or 4 times/wk). EPA and DHA were assessed at 9 time points over 12 mo in 9 sample types (red blood cells, mononuclear cells, platelets, buccal cells, adipose tissue, plasma phosphatidylcholine, triglycerides, cholesteryl esters, and nonesterified fatty acids). RESULTS: A dose response (P < 0.05) was observed for EPA and DHA in all pools except for red blood cell EPA (P = 0.057). EPA and DHA measures in plasma phosphatidylcholine and platelets were best for the discrimination between different intakes (P < 0.0001). The rate of incorporation varied between sample types, with the time to maximal incorporation ranging from days (plasma phosphatidylcholine) to months (mononuclear cells) to >12 mo (adipose tissue). CONCLUSIONS: Plasma phosphatidylcholine EPA plus DHA was identified as the most suitable biomarker of acute changes in EPA and DHA intake, and platelet and mononuclear cell EPA plus DHA were the most suitable biomarkers of habitual intake. PMID- 22932282 TI - Effects of dairy intake on body weight and fat: a meta-analysis of randomized controlled trials. AB - BACKGROUND: Some intervention studies have suggested that dairy products may influence body weight, but the results remain controversial. OBJECTIVE: We identified and quantified the effects of dairy consumption on body weight and fat mass from randomized controlled trials (RCTs). DESIGN: We conducted a comprehensive search of PubMed and EMBASE databases (to April 2012) of English reports of RCTs regarding dairy consumption on body weight, body fat, or body weight and body fat in adults. The results across studies were pooled by using a random-effects meta-analysis. RESULTS: Twenty-nine RCTs were included with a total of 2101 participants. Overall, consumption of dairy products did not result in a significant reduction in weight (-0.14 kg; 95% CI: -0.66, 0.38 kg; I2 = 86.3%). In subgroup analysis, consumption of dairy products reduced body weight in the context of energy restriction or short-term intervention (<1 y) trials but had the opposite effect in ad libitum dietary interventions or long-term trials (>=1 y). Twenty-two RCTs that reported results on body fat showed a modest reduction in the dairy group (-0.45 kg; 95% CI: -0.79, -0.11 kg; I2 = 70.9%), and further stratified analysis indicated significant beneficial effects of dairy intervention on body fat in energy-restricted or short-term trials but not in long-term or ad libitum studies. CONCLUSIONS: This meta-analysis does not support the beneficial effect of increasing dairy consumption on body weight and fat loss in long-term studies or studies without energy restriction. However, dairy products may have modest benefits in facilitating weight loss in short-term or energy-restricted RCTs. PMID- 22932284 TI - [Diabetes mellitus and osteoporosis. Diabetes mellitus and bone and calcium metabolism]. AB - Recent studies have revealed that diabetes mellitus is associated with an increased risk of fractures. In type 1 diabetes, bone mineral density (BMD) is decreased. However, fracture risk is increased more than expected from the degree of BMD decrease. In type 2 diabetes, fracture risk is increased despite high BMD. Taken together, in diabetes, factors other than BMD, or derangements in bone quality, are major causes for bone fragility. In this review, various aspects of deranged bone and mineral metabolism in diabetes are reviewed. Treatment for osteoporosis is highly warranted in diabetic patients who have multiple risks for fractures. PMID- 22932285 TI - [Diabetes mellitus and osteoporosis. Cross talk between bone and other internal organs on lifestyle-related disease]. AB - Mounting evidence revealed that various organs form a regulatory network with each other to maintain whole body homeostasis. Bone is not the exception : neurons and neurotransmitters, including sympathetic nervous system and serotonin, are intimately involved in bone remodeling. Osteoclacin regulates glucose metabolism and male fertility. Moreover, a recent report demonstrated that bone is a target organ of insulin. Thus, bone is now considered as a major player for the whole body homeostasis. PMID- 22932283 TI - Predicting and characterizing selective multiple drug treatments for metabolic diseases and cancer. AB - BACKGROUND: In the field of drug discovery, assessing the potential of multidrug therapies is a difficult task because of the combinatorial complexity (both theoretical and experimental) and because of the requirements on the selectivity of the therapy. To cope with this problem, we have developed a novel method for the systematic in silico investigation of synergistic effects of currently available drugs on genome-scale metabolic networks. RESULTS: The algorithm finds the optimal combination of drugs which guarantees the inhibition of an objective function, while minimizing the side effect on the other cellular processes. Two different applications are considered: finding drug synergisms for human metabolic diseases (like diabetes, obesity and hypertension) and finding antitumoral drug combinations with minimal side effect on the normal human cell. The results we obtain are consistent with some of the available therapeutic indications and predict new multiple drug treatments. A cluster analysis on all possible interactions among the currently available drugs indicates a limited variety on the metabolic targets for the approved drugs. CONCLUSION: The in silico prediction of drug synergisms can represent an important tool for the repurposing of drugs in a realistic perspective which considers also the selectivity of the therapy. Moreover, for a more profitable exploitation of drug drug interactions, we have shown that also experimental drugs which have a different mechanism of action can be reconsider as potential ingredients of new multicompound therapeutic indications. Needless to say the clues provided by a computational study like ours need in any case to be thoroughly evaluated experimentally. PMID- 22932286 TI - [Diabetes mellitus and osteoporosis. Bone quality in diabetes]. AB - Diabetes deteriorate bone material properties. Not only hyperglycemia, but also oxidative stress induce the reduction in enzymatic beneficial cross-links and the accumulation of disadvantageous non-enzymatic cross-linking advanced glycation end products (AGEs) such as pentosidine in bone. In this review, I describe the mechanism of low bone quality in diabetes. PMID- 22932287 TI - [Diabetes mellitus and osteoporosis. Bone metabolic disorder in diabetic nephropathy]. AB - Life prognosis of hemodialysis patients with diabetes is remarkably bad compared with hemodialysis patients without diabetes. The major factor is existence of the specific bone metabolic disorder in patients with diabetes. Bone metabolic disorder is closely connected with vascular calcification, and it is thought that each disorder is induced by poor glycemic control. We will give an outline the influence which glycemic control has on bone metabolism and vascular calcification in hemodialysis patients with diabetes. PMID- 22932288 TI - [Diabetes mellitus and osteoporosis. Mutual interaction between bone and blood vessel in diabetes mellitus]. AB - The patients with "Diabetes Mellitus", "Hypertension" and "Hyperlipidemia" are accompanied with an osteoporosis. It is well known that increased fracture risk is observed in diabetes mellitus. Some reports indicate increased fracture risk in hypertension, arterial calcification and ischemic heart disease. Vascular calcification is an active process similar to physiological mineralization of skeletal tissues. A number of factors were reported to regulate differentiation of multiple cell types among bone and blood vessels. Thus, bone metabolism related factors activities participate in vascular calcification. However, the effective treatment for suppressing the progression of vascular calcification has not been established. Here we will review recent advances in the researches of mutual connection between bone and blood vessel and present our findings that the SERM or bisphosphonate are useful in prevention of vascular calcification in diabetes. PMID- 22932289 TI - [Diabetes mellitus and osteoporosis. Incretin as a coordinator of glucose and bone metabolism]. AB - GLP-1 and GIP play an important role as incretin to stimulate insulin secretion from pancreatic beta-cells and to maintain the homeostasis of glucose metabolism. As GLP-1 receptors are expressed in thyroid C cells and GIP receptors are expressed in osteoblasts, incretin contributes to bone metabolism. GIP maintains the homeostasis of bone metabolism through transiently activating osteoblasts. PMID- 22932290 TI - [Diabetes mellitus and osteoporosis. Predictive candidate markers for fracture risk in diabetic patients]. AB - Patients with type 2 diabetes mellitus (T2DM) have increased bone fragility due to deteriorating bone quality. Several cross-sectional and longitudinal clinical studies showed that the elevated serum and urinary pentosidine levels are associated with fracture risk independent of bone mineral density, suggesting that pentosidine is one of the possible candidate markers to predict fracture risk in diabetic patients. Other candidates are endogenous secretory receptor for advanced glycation end-products (esRAGE), insulin like growth factor-1 (IGF-1), osteocalcin (OC)/bone specific alkaline phosphatase (BAP) ratio and the condition of relatively low parathyroid hormone levels and low OC levels. However, further examinations are needed to establish whether these markers would be applicable to assess fracture risks. PMID- 22932291 TI - [Diabetes mellitus and osteoporosis. Insulin signaling and bone/glucose/energy metabolism]. AB - Recently, we reported that insulin signaling in osteoblasts was a positive regulator of bone acquisition, but also of bone resorption. Interestingly, insulin signaling in osteoblasts activated osteocalcin embedded in bone ECM by stimulating resorption activity in osteoclast. It has been demonstrated that activated osteocalcin acts as hormone and regulates glucose metabolism through increasing insulin secretion from pancreas. The interaction of bone and glucose metabolism established by these studies will be important to a study of the two scientific fields in the future, particularly a clinical field. PMID- 22932292 TI - [Diabetes mellitus and osteoporosis. The regulation of glucose metabolism by bone]. AB - Osteocalcin, which is secreted from bone tissue into the circulation, has a hormonal function in glucose metabolism. Previous in vitro and in vivo studies showed that undercarboxylated osteocalcin, but not carboxylated, regulated glucose metabolism by increasing the expression of insulin in pancreatic beta cells and adiponectin in adipocytes. Moreover, accumulating clinical studies also indicate that serum osteocalcin level is associated with blood glucose level, parameters of insulin secretion and sensitivity, as well as fat mass. However, it is still unclear whether undercarboxylated osteocalcin is the only one to have the hormonal function in human, or whether interventions for osteoporosis affect glucose metabolism. Therefore, further studies are necessary to clarify these issues. PMID- 22932293 TI - [Diabetes mellitus and osteoporosis. Effect of antidiabetic medicine on osteoporotic fracture]. AB - Type 2 diabetes is closely associated with fragility fracture risk. Metabolic control of diabetes may improve bone status, but several anti-diabetic medicines could directly affect bone metabolism. Thiazolidinediones (TZD) may have a negative effect by switching mesenchymal progenitor cells to adipose rather than bone tissue. Clinical trials and meta-analyses showed that elderly women taking TZD could be at increased risk of fractures. On the contrary, in vitro studies suggest that incretin mimetics and incretin enhancers could positively regulate bone metabolism. Dipeptidyl peptidase-4 (DPP-4) inhibitors, which enhance serum incretin concentration, have been reported to reduce clinical fractures. However, further studies would be required for their long term-efficacy and safety on bone metabolism. PMID- 22932294 TI - [Diabetes mellitus and osteoporosis. Role for vitamin D in glucose and energy metabolism]. AB - Vitamin D insufficiency has been linked to obesity, type 2 diabetes, metabolic syndrome and dyslipidemia. The data, however, is mostly derived from observational studies and only indicates correlation. Evidence from randomized controlled trials, which are necessary to prove causal relationship between vitamin D insufficiency and those metabolic abnormalities, is scarce. Thus, at this point, although substantial circumstantial evidence supports potential roles of vitamin D in glucose and energy metabolism, clinical decisions on vitamin D treatment should not be based on such non-skeletal effects including protection from cardiovascular events, according to the recent clinical guidelines. PMID- 22932295 TI - [Diabetes mellitus and osteoporosis. Dietary therapy of diabetes related osteoporosis]. AB - Diabetic patients are prone to fracture, even when their bone mineral density (BMD) is high, suggesting that BMD is not exclusive factor for bone health. Bone strength is determined by BMD and bone quality, the latter of which could influence fracture risk in diabetic patients. Calcium, vitamin D and vitamin K are essential for increasing and/or maintaining BMD. Vitamin B group and C, which contribute to maintain bone quality, are also important. Intake of these mineral and vitamins under controlling energy consumption plays a key role for bone health. PMID- 22932296 TI - [Diabetes mellitus and osteoporosis. How to start drug therapy for osteoporosis in patients with diabetes mellitus]. AB - Drug treatment for osteoporosis is intended to prevent osteoporotic fractures. Physicians should assess fracture risk in patients with diabetes not only by measuring bone mineral density (BMD) but also by taking a fracture history and evaluating prior vertebral fractures using spinal X-rays when starting drug therapy. Accumulating evidence shows that patients with diabetes (DM) have a high risk for fragility fractures independent of BMD. Thus, when DM patients have osteopenia, fracture risk could become higher than non-DM counterparts, and drug therapy should be considered to prevent fragility fractures. The criteria for starting drug treatment to prevent fragility fractures in DM patients, albeit tentative, are shown in this article. PMID- 22932297 TI - [Diabetes mellitus and osteoporosis. Therapeutic strategy for osteoporosis in patients with diabetes mellitus]. AB - Patients with either type 1 or type 2 diabetes mellitus (DM) are predisposed to fragile fracture. In particular, although bone mineral density in patients with type 2 DM is somewhat higher than control subjects, diabetic patients are more likely to break a bone. Because the number of elderly patients with DM is getting larger, it is necessary to prevent fracture in those. Unfortunately, substantial randomized control trials are yet to be done in patients with DM to clarify if anti-osteoporotic drugs are effective to prevent fractures. According to post-hoc analyses of pivotal clinical studies of alendronate and raloxifene, best available clinical data at the present time, those anti-osteoporotic drugs seem to be equally effective in diabetic patients to controls. We are now waiting for evidence of effects of teriparatide and other drugs on patients with DM. PMID- 22932298 TI - New Delhi metallo-beta-lactamase 4-producing Escherichia coli in Cameroon. PMID- 22932299 TI - Injuries from batteries among children aged <13 years--United States, 1995-2010. AB - Injuries to children caused by batteries have been documented in the medical literature and by poison control centers for decades. Of particular concern is the ingestion of button batteries, especially those >=20 mm in diameter (coin size), which can lodge in the esophagus, leading to serious complications or death. To estimate the number of nonfatal battery injuries among children aged <13 years, U.S. Consumer Product Safety Commission (CPSC) staff analyzed 1997 2010 data from the National Electronic Injury Surveillance System (NEISS). To identify fatal battery exposures, other CPSC databases covering 1995-2010 were examined, including the 1) Injury and Potential Injury Incident File; 2) Death Certificate Database (DTHS); and 3) In-Depth Investigation File (INDP). From 1997 to 2010, an estimated 40,400 children aged <13 years were treated in hospital emergency departments (EDs) for battery-related injuries, including confirmed or possible battery ingestions. Nearly three quarters of the injuries involved children aged <=4 years; 10% required hospitalization. Battery type was reported for 69% of cases, and of those, button batteries were implicated in 58%. Fourteen fatal injuries were identified in children ranging in age from 7 months to 3 years during 1995-2010. Battery type was reported in 12 of these cases; all involved button batteries. CPSC is urging the electronics industry and battery manufacturers to develop warnings and industry standards to prevent serious injuries and deaths from button batteries. Additionally, public health and health care providers can encourage parents to keep button batteries and products containing accessible button batteries (e.g., remote controls) away from young children. PMID- 22932300 TI - Increases in quitline calls and smoking cessation website visitors during a national tobacco education campaign--March 19-June 10, 2012. AB - Mass media campaigns and telephone quitlines are effective in increasing cessation rates among cigarette smokers. During March 19-June 10, 2012, CDC aired Tips from Former Smokers (TIPS), the first federally funded, nationwide, paid media tobacco education campaign in the United States. The TIPS campaign featured former smokers talking about their experiences living with diseases caused by smoking. The campaign was primarily intended to encourage adult smokers aged 18 54 years to quit by making them aware of the health damage caused by smoking and letting them know that they could call the telephone quitline portal 1-800-QUIT NOW or visit the National Cancer Institute (NCI) smoking cessation website (http://www.smokefree.gov) if they needed free help to quit. The campaign included advertising on national and local cable television, local radio, online media, and billboards, and in movie theaters, transit venues, and print media. To determine the effects of the TIPS campaign on weekly quitline call volume and weekly unique visitors to the cessation website, CDC analyzed call and visitor data immediately before, during, and immediately after the campaign period and compared them with data from the corresponding weeks in 2011. This report summarizes the results of that analysis, which found that the number of weekly calls to the quitline from the 50 states, the District of Columbia, Guam, and Puerto Rico increased 132% (207,519 additional calls) during the TIPS campaign, and the number of unique visitors to the cessation website increased 428% (510,571 additional unique visitors). These results indicate that many smokers are interested in quitting and learning more about cessation assistance, and will respond to motivational messages that include an offer of help. PMID- 22932301 TI - National and state vaccination coverage among adolescents aged 13-17 years- United States, 2011. AB - Since 2005, the Advisory Committee on Immunization Practices (ACIP) has expanded the routine adolescent vaccination schedule with administration of the following vaccines at ages 11 or 12 years: meningococcal conjugate (MenACWY), 2 doses; tetanus, diphtheria, acellular pertussis (Tdap), 1 dose; human papillomavirus (HPV), 3 doses; and influenza, 1 dose annually. To assess vaccination coverage among adolescents aged 13-17 years, CDC analyzed data from the National Immunization Survey-Teen (NIS-Teen). This report summarizes the results of that assessment, which indicated that, from 2010 to 2011, vaccination coverage increased for >=1 dose Tdap on or after age 10 years (from 68.7% to 78.2%), >=1 dose MenACWY (from 62.7% to 70.5%), and, among females, for >=1 dose of HPV (from 48.7% to 53.0%) and >=3 doses of HPV (from 32.0 to 34.8%). Vaccination coverage varied widely among states. Interventions that increase adolescent vaccination coverage include strong recommendations from health-care providers, urging consideration of every health visit as an opportunity for vaccination, reducing out-of-pocket costs, and using reminder/recall systems. Despite increasing adolescent vaccination coverage, the percentage point increase in >=1 dose HPV coverage among adolescent females was less than half that of the increase in >=1 dose of Tdap or MenACWY. The causes of lower coverage with HPV vaccine are multifactorial; addressing missed opportunities for vaccination, as well as continued evaluation of vaccination-promoting initiatives, is needed to protect adolescents against HPV-related cancers. PMID- 22932302 TI - Measles--Horn of Africa, 2010-2011. AB - Member states of the World Health Organization (WHO) African (AFR) and Eastern Mediterranean (EMR) regions have set goals for measles elimination by 2020 and 2015, respectively. The two WHO regions include AFR member states Ethiopia and Kenya, and EMR member state Somalia. All three countries are in the Horn of Africa, where measles remains endemic, with periodic outbreaks despite efforts to achieve elimination goals. This report describes outbreaks that occurred in the Horn of Africa during 2010-2011. The outbreaks were exacerbated by a complex humanitarian emergency in Somalia, with an influx of an estimated 600,000 refugees into camps in Kenya and Ethiopia near the borders with Somalia. During 2010-2011, a total of 9,756 measles cases were reported in Ethiopia and 2,566 in Kenya, with wide age distributions, and 16,135 were reported in Somalia, with 78% occurring among children aged <5 years. Cases occurred predominantly in unvaccinated persons. Outbreak response immunization (ORI) strategies were implemented; however, outbreaks continued. To reach AFR and EMR measles elimination targets, uniform high coverage with 2 doses of measles-containing vaccine (MCV) must be achieved and maintained in Horn of Africa countries, including in refugee camps. PMID- 22932303 TI - A systematic comparison of cockcroft-gault and modification of diet in renal disease equations for classification of kidney dysfunction and dosage adjustment. AB - BACKGROUND: The dosing of drugs in patients with kidney dysfunction is often based on the estimates of kidney function. OBJECTIVE: To systematically compare the performance of the Modification of Diet in Renal Disease (MDRD) and Cockcroft Gault (CG) equations for dosage adjustment. METHODS: We assessed agreement (concordance, kappa statistics [kappa,kappa(omega)]) between CG and MDRD using a Food and Drug Administration database to evaluate the effect of renal function on the pharmacokinetics of 36 approved drugs. Across the approved drugs, we compared the correlation between these 2 equations for renal drug clearance (Cl(ren)) and area under the concentration-time curve. For 26 approved drugs that require renal dose adjustment, we also compared dosing regimens and expected exposure using these equations. Sensitivity analyses were performed by adjusting the MDRD estimates for individualized body surface area and/or range of serum creatinine assay calibration errors. RESULTS: In the pharmacokinetic database with 973 subjects (age 18-95 years, weight 35-153 kg, female 33%), we found that the CG and the MDRD classification of renal function generally agreed (64.2%, kappa = 0.54, kappa(omega) = 0.73). Among the subjects studied for drugs requiring renal dose adjustment, dosages in 12% were changed to a higher or lower dosing category by the MDRD compared to the CG equation. In particular, using MDRD in place of CG for dosage modification yielded higher dosing recommendations for subjects with a combination of age >80 years, weight <55 kg, and serum creatinine >0.7 and <=1.5 mg/dL; the coefficient of determination was also higher by CG than MDRD in trials that enrolled these or similar patients. CONCLUSIONS: For patients with advanced age, low weight, and modestly elevated serum creatinine, further work is needed before the MDRD equations can replace the CG equation for dose adjustment in the labeling. PMID- 22932304 TI - Impact of continuous flow left ventricular assist device on the pharmacodynamic response to warfarin early after implantation. PMID- 22932305 TI - Drug interactions with rivaroxaban following total joint replacement surgery. AB - OBJECTIVE: To evaluate potential drug-drug interactions with rivaroxaban in patients undergoing total hip replacement (THR) and total knee replacement (TKR) surgeries. DATA SOURCES: PubMed; January 2009-April 2012 abstract databases of major congresses for hematology and cardiovascular medicine. STUDY SELECTION AND DATA EXTRACTION: Searches were performed using the key words rivaroxaban and drug interaction. Studies were included if they evaluated interactions with drugs that are commonly used in patients undergoing THR or TKR, based on our clinical experience. DATA SYNTHESIS: A Phase 1 study found that coadministration of rivaroxaban and the nonsteroidal antiinflammatory drug (NSAID) naproxen significantly increased bleeding time. However, in a retrospective analysis of 4 large trials evaluating rivaroxaban in patients undergoing THR or TKR, the difference between major and clinically relevant nonmajor bleeding was not significantly different between NSAID users and nonusers. In addition, proton pump inhibitors, which are frequently coadministered with NSAIDs to prevent gastrointestinal toxicity, have not been demonstrated to cause any appreciable changes in rivaroxaban pharmacokinetics or pharmacodynamics. A Phase 2 study that evaluated several doses and administration intervals of rivaroxaban in combination with aspirin or both aspirin and clopidogrel in patients with acute coronary syndrome found that clinically significant bleeding events occurred in patients receiving rivaroxaban 10 mg daily (the dose approved for the orthopedic indication). However, this risk was not great enough to end the trial early. CONCLUSIONS: Phase 1 drug-drug interaction studies in healthy humans provided little insight into the pharmacodynamic drug interactions between rivaroxaban and NSAIDs or antiplatelet agents. A pooled analysis of the RECORD (Regulation of Coagulation in Orthopedic Surgery to Prevent Deep Vein Thrombosis and Pulmonary Embolism) trials and data from other large trials provides clinical evidence that these agents can be coadministered with rivaroxaban, as long as proper monitoring is instituted. PMID- 22932306 TI - Improving pharmacist knowledge of oral chemotherapy in the community. AB - BACKGROUND: Approximately 10% of chemotherapy agents are administered orally, with anticipated annual growth of this practice. In the future, community pharmacy practitioners will potentially serve a larger role in the management of patients with cancer. OBJECTIVE: To improve pharmacist confidence, knowledge of oral chemotherapy agents, and dispensing behaviors through live continuing pharmacy education (CPE) programs. METHODS: A prospective cohort study of pharmacists attending live CPE programs in Rhode Island and Maine was conducted between March and May 2010. A survey was administered before and after the educational program; primary outcome measures included change in level of pharmacist confidence in oral chemotherapy knowledge, overall knowledge, and willingness to adjust behavior when dispensing oral chemotherapy agents in community pharmacy. RESULTS: Two hundred fifty-seven of the 410 pharmacists in attendance participated in the survey. Pharmacists significantly improved in confidence level, from no confidence to some confidence (p < 0.001). Counseling the family on the safe handling of oral chemotherapy increased from 37.1% pre-CPE program to 100% post-CPE program. Following the CPE program, behaviors such as (1) using a separate counting tray, (2) wearing gloves, and (3) requiring a double-check improved from 22.5%, 31.5%, and 29.4% baseline to 92.0%, 81.3%, and 81.8%, respectively. All responses to knowledge-based questions improved significantly. CONCLUSIONS: A live CPE program on oral chemotherapy designed to improve pharmacist confidence and knowledge, as well as inform about behaviors, is an effective method. Additional education to improve the knowledge of community-based practitioners to safely dispense and properly counsel patients receiving oral chemotherapy is required. PMID- 22932307 TI - The impact of antiplatelet and anticoagulant therapies on gastrointestinal symptoms in patients with atrial fibrillation: a systematic review. AB - BACKGROUND: Patients with atrial fibrillation (AF) may be susceptible to gastrointestinal (GI) effects of medications used for thromboprophylaxis. OBJECTIVE: To determine the incidence of thromboprophylaxis discontinuation due to GI symptoms and GI events. METHODS: A systematic search of MEDLINE (1950 November 2011) and Cochrane Central (through third quarter of 2011) databases was conducted for randomized trials of adults with AF published in English full-text and reporting on discontinuation due to GI symptoms or the incidence of various GI symptoms. RESULTS: Of studies comparing oral direct thrombin inhibitors (DTIs) to vitamin K antagonists (VKAs), 67%, 100%, and 100% found significantly higher incidences of discontinuation due to GI symptoms, upper GI symptoms, and nondistinct GI symptoms with DTIs, respectively. When comparing aspirin to control therapy, 50% and 33% of trials found significantly higher incidences of discontinuation due to GI symptoms and nondistinct GI symptoms with aspirin, respectively. Aspirin significantly increased the incidence of upper GI symptoms compared to VKAs in 1 trial, but VKAs did not increase the incidence of discontinuation due to GI symptoms and nondistinct GI symptoms versus control. In the only trial comparing a factor Xa inhibitor to VKAs, no significant difference in diarrhea was seen, and when a factor Xa inhibitor was compared to aspirin, there was no significant difference in nondistinct GI symptoms. The incidence of discontinuation due to GI symptoms (4 trials) ranged from 0.0% to 0.4% for control, 0.0% to 2.4% for aspirin, 0.0% to 0.63% for VKA, and 1.2% to 4.7% for oral DTI recipients. The incidence of upper GI symptoms (2 trials) was 1.2% for aspirin, 0.0-5.8% for VKA, 4.2% for VKA plus aspirin, and 11.3-11.8% for DTI recipients. The incidence of nondistinct GI symptoms (7 trials) was 0.0-12.4% for control, 0.2-17.9% for aspirin, 0.0-14.1% for VKA, 23% for DTI, and 2.42% for factor Xa inhibitor recipients. Five trials evaluated diarrhea incidence, which ranged from 0.0% to 12.4% for VKA and 3.2% to 12.2% for oral DTI, and was 5.31% for factor Xa inhibitor recipients. One trial evaluated nausea, with incidences of 1.5% and 2.7% for VKA and DTI recipients, respectively. CONCLUSIONS: GI adverse events are common in AF trial populations. DTIs were associated with more discontinuations due to GI symptoms and aspirin appeared to increase the incidence of GI symptoms compared to control. PMID- 22932309 TI - Canadian survey of critical care pharmacists' views and involvement in clinical research. AB - BACKGROUND: The involvement of Canadian critical care pharmacists in clinical research is not well documented. OBJECTIVE: To describe the clinical research experience of Canadian critical care pharmacists, describe their views about clinical research, and identify factors that facilitate their involvement in clinical research. METHODS: A cross-sectional electronic survey of Canadian critical care pharmacists was developed through an iterative process and conducted from July to October 2010. We invited 325 pharmacists from 129 hospitals across Canada to participate. Surveys with more than 30% of questions unanswered were discarded. RESULTS: Analyzable response rate was 66.2%. Overall, 33 pharmacists (15.7%) were highly involved in research, 54 (25.7%) were moderately involved, and 123 (58.6%) were minimally involved. Most respondents (97.2%) believed that critical care pharmacist involvement in research was desirable, and many (80.4%) expressed interest to be more involved in research. Nearly all respondents (99.5%) agreed that more support should be provided to pharmacists interested in conducting research. Pharmacists currently involved in research have obtained higher academic degrees (adjusted OR 11.23; p < 0.001), express a strong interest in research (adjusted OR 7.44; p < 0.001), report a higher level of training for involvement in research (adjusted OR 2.23; p = 0.047), and practice more often in a university hospital (adjusted OR 3.68; p = 0.004) within an intensive care unit where involvement in research is valued (adjusted OR 5.61; p < 0.001). Support from pharmacy departments is not related to involvement in research (adjusted OR 1.22; p = 0.633). CONCLUSIONS: Canadian critical care pharmacists are involved to varying degrees in clinical research and are very interested in initiating and supporting research activities. Opportunities are present but significant barriers exist. The value of pharmacist initiated research needs recognition as a priority within hospital pharmacy administration. PMID- 22932310 TI - Evaluation of the clinical results of posterior cruciate ligament reconstruction a comparison between the use of the bone tendon bone and semitendinosus and gracilis tendons-. PMID- 22932311 TI - Anti-adipogenic chromone glycosides from Cnidium monnieri fruits in 3T3-L1 cells. AB - Seven new chromone glycosides, monnierisides A (3), B (10), C (11), D (12), E (13), F (15) and G (16) were isolated from Cnidium. monnieri, together with ten known chromone derivatives, undulatoside A (1), cnidimol C (2), saikochromoside A (4), cnidimoside A (5), cnidimoside B (6), 2-methyl-5-hydroxy-6-(2-butenyl-3 hydroxymethyl)-7-(beta-d-glucopyranosyloxy)-4H-1-benzopyran-4-one (7), cnidimol D (8), hydroxycnidimoside A (9), umtatin (14) and 6'-hydroxylangelicain (17). The structures of isolated compounds were determined on the basis of spectroscopic analysis including 1D, 2D NMR and HR-MS. Among the compounds isolated, compounds 5, 6, 9 and 10 significantly inhibited adipocyte differentiation as measured by fat accumulation in 3T3-L1 cells using Oil Red O staining. PMID- 22932312 TI - 2-Alkynoic fatty acids inhibit topoisomerase IB from Leishmania donovani. AB - 2-Alkynoic fatty acids display antimycobacterial, antifungal, and pesticidal activities but their antiprotozoal activity has received little attention. In this work we synthesized the 2-octadecynoic acid (2-ODA), 2-hexadecynoic acid (2 HDA), and 2-tetradecynoic acid (2-TDA) and show that 2-ODA is the best inhibitor of the Leishmania donovani DNA topoisomerase IB enzyme (LdTopIB) with an EC(50)=5.3+/-0.7MUM. The potency of LdTopIB inhibition follows the trend 2-ODA>2 HDA>2-TDA, indicating that the effectiveness of inhibition depends on the fatty acid carbon chain length. All of the studied 2-alkynoic fatty acids were less potent inhibitors of the human topoisomerase IB enzyme (hTopIB) as compared to LdTopIB. 2-ODA also displayed in vitro activity against Leishmania donovani (IC(50)=11.0MUM), but it was less effective against other protozoa, Trypanosoma cruzi (IC(50)=48.1MUM) and Trypanosoma brucei rhodesiense (IC(50)=64.5MUM). The antiprotozoal activity of the 2-alkynoic fatty acids, in general, followed the trend 2-ODA>2-HDA>2-TDA. The experimental information gathered so far indicates that 2-ODA is a promising antileishmanial compound. PMID- 22932313 TI - Design and synthesis of diarylamines and diarylethers as cytotoxic antitumor agents. AB - Based on a shared structural core of diarylamine in several known anticancer drugs as well as a new cytotoxic hit 6-chloro-2-(4-cyanophenyl)amino-3 nitropyridine (7), 30 diarylamines and diarylethers were designed, synthesized, and evaluated for cytotoxic activity against A549, KB, KB-vin, and DU145 human tumor cell lines (HTCL). Four new leads 11e, 12, 13a, and 13b were discovered with GI(50) values ranging from 0.33 to 3.45MUM. Preliminary SAR results revealed that a diarylamine or diarylether could serve as an active structural core, meta chloro and ortho-nitro groups on the A-ring (either pyridine or phenyl ring) were necessary and crucial for cytotoxic activity, and the para-substituents on the other phenyl ring (B-ring) were related to inhibitory selectivity for different tumor cells. In an investigation of potential biological targets of the new leads, high thoughput kinase screening discovered that new leads 11e, 12 and 13b especially inhibit Mer tyrosine kinase, a proto-oncogene associated with munerous tumor types, with IC(50) values of 2.2-3.0MUM. Therefore, these findings provide a good starting point to optimize a new class of compounds as potential anticancer agents, particularly targeting Mer tyrosine kinase. PMID- 22932314 TI - Novel pleuromutilin derivatives as antibacterial agents: synthesis, biological evaluation and molecular docking studies. AB - Owing to the increasingly serious problems caused by multidrug resistance in community-acquired infection pathogens, it has become an urgent need to develop new classes of antibiotics for overcoming the resistance. In this paper, we describe the design and synthesis of novel pleuromutilin derivatives containing the (2-aminothiazol-4-yl)-4-methyl group, as well as their in vitro antibacterial activities against Gram-positive clinical bacteria. Most of the tested compounds displayed strong antibacterial activities against these methicillin-susceptible and methicillin-resistant bacteria. Particularly noteworthy compound 15 and its derivative 16e, both showed potent antibacterial properties (0.0625-0.5MUg/mL) that are superior to amoxicillin and tiamulin. Molecular docking studies suggested that the amino thiazole ring on the side chains of the pleuromutilin derivatives can in general be accommodated near the mutilin core in the binding pocket, and thus play an important role in the activity of the whole molecule. The findings reported herein may provide a new insight into the design of novel pleuromutilin derivatives for human clinical use. PMID- 22932315 TI - An investigation into the structure-activity relationships associated with the systematic modification of the beta(2)-adrenoceptor agonist indacaterol. AB - The synthesis of a series of indacaterol analogues in which each of the three structural regions of indacaterol are modified in a systematic manner is described. Evaluation of the affinity of these analogues for the beta(2) adrenoceptor identified the 3,4-dihydroquinolinone and 5-n-butylindanyl analogues to demonstrate the most similar profiles to indacaterol. An alpha-methyl aminoindane analogue was discovered to be 25-fold more potent than indacaterol, and functional studies revealed an atypical beta(2)-adrenoceptor activation profile for this compound consistent with that of a slowly dissociating 'super agonist'. PMID- 22932316 TI - Amide-based derivatives of beta-alanine hydroxamic acid as histone deacetylase inhibitors: attenuation of potency through resonance effects. AB - A library of amide-linked derivatives of beta-alanine hydroxamic acid were prepared (2-7) and the activity as inhibitors of Zn(II)-containing histone deacetylases (HDACs) determined in vitro against HDAC1 and the anti-proliferative activity determined in BE(2)-C neuroblastoma cells. The IC(50) values of the best performing compounds (3-7) against HDAC1 ranged between 38 and 84MUM. The least potent compound (2) inhibited a maximum of only 40% HDAC1 activity at 250MUM. The anti-proliferative activity of 2-7 at 50MUM against BE(2)-C neuroblastoma cells ranged between 57.0% and 88.6%. The structural similarity between the potent HDAC inhibitor trichostatin A (TSA, 1; HDAC1, IC(50) 12nM) and the present compounds (2-7) was high at the Zn(II) coordinating hydroxamic acid head group; and in selected compounds (2, 5), at the 4-(dimethylamino)phenyl tail. The significantly reduced potency of 2-7 relative to 1 underscores the rank importance of the linker region as part of the HDAC inhibitor pharmacophore. Molecular modeling of 1-7 using HDAC8 as the template suggested that the conformationally constrained 4'-methyl group of 1 may contribute to HDAC inhibitor potency through a sandwich like interaction with a hydrophobic region containing F152 and F208; and that the absence of this group in 2-7 may reduce potency. The close proximity of the 5' carbonyl oxygen atom in 2-7 to the sulfur atom of Met274 in HDAC8 or the corresponding isobutyl group of Leu274 in HDAC1 may attenuate potency through repulsive steric and dipole-dipole forces. In a unique resonance stabilized form of 2, this interaction could manifest as stronger ion-dipole repulsive forces, resulting in a further decrease in potency. This work suggests that resonance structures of HDAC inhibitors could modulate intermolecular interactions with HDAC targets, and potency. PMID- 22932317 TI - Design of a hypoxia-activated prodrug inhibitor of O6-alkylguanine-DNA alkyltransferase. AB - The efficacy of agents that alkylate the O-6 position of guanine is inhibited by O(6)-alkylguanine-DNA alkyltransferase (AGT) which removes these lesions from the tumor DNA. To increase differential toxicity, inhibitors must selectively deplete AGT in tumors, while sparing normal tissues where this protein serves a protective function. A newly synthesized prodrug of the AGT inhibitor O(6) benzylguanine (O(6)-BG) with an alpha,alpha-dimethyl-4-nitrobenzyloxycarbonyl moiety masking the essential 2-amino group has demonstrated the feasibility of targeting hypoxic regions that are unique to solid tumors, for drug delivery. However, these modifications resulted in greatly decreased solubility. Recently, new potent global AGT inhibitors with improved formulatability such as O(6)-[(3 aminomethyl)benzylguanine (1) have been developed. However, acetylamino (N-(3 (((2-amino-9H-purin-6-yl)oxy)methyl)benzyl)acetamide) (2) exhibits a pronounced decrease in activity. Thus, 1 would be inactivated by N-acetylation and probably N-glucuronidation. To combat potential conjugational inactivation while retaining favorable solubility, we synthesized 6-((3-((dimethylamino)methyl)benzyl)oxy)-9H purin-2-amine (3) in which the 3-aminomethyl moiety is protected by methylation; and to impart tumor selectivity we synthesized 2-(4-nitrophenyl)propan-2-yl(6-((3 ((dimethylamino)methyl)benzyl)oxy)-9H-purin-2-yl)carbamate (7), a hypoxia targeted prodrug of 3 utilizing an alpha,alpha-dimethyl-4-nitrobenzyloxycarbonyl moiety. Consistent with this design, 7 demonstrates both hypoxia selective conversion by EMT6 cells of 7 to 3 and hypoxic sensitization of AGT containing DU145 cells to the cytotoxic actions of laromustine, while exhibiting improved solubility. PMID- 22932318 TI - Yersinia enterocolitica outbreak associated with ready-to-eat salad mix, Norway, 2011. AB - In 2011, an outbreak of illness caused by Yersinia enterocolitica O:9 in Norway was linked to ready-to-eat salad mix, an unusual vehicle for this pathogen. The outbreak illustrates the need to characterize isolates of this organism, and reinforces the need for international traceback mechanisms for fresh produce. PMID- 22932319 TI - Bacterial DNA translocation and liver disease severity among HIV-infected patients with chronic hepatitis C. AB - We carried out a cross-sectional study to explore whether bacterial 16S ribosomal DNA (bactDNA) shows association with severity of liver disease among human immunodeficiency virus/hepatitis C virus coinfected patients. Patients with advanced fibrosis (F3/F4), moderate activity grade (A2/A3), and high fibrosis progression rate (FPR > 0.15) had higher values of plasma bactDNA levels than did patients without these markers of liver disease (P < 0.05). The chance of having a fibrosis stage or activity grade increased was 1.20 [95% confidence interval (CI) = 1.0 to 1.44, P = 0.045] and 1.22 (95% CI = 1.1 to 1.45, P = 0.029) times greater for every 100 copies per microliter of plasma bactDNA. Likewise, the odds of having values of FPR > 0.15 was 1.18 (95% CI = 0.98 to 1.42, P = 0.089). In addition, patients with high bactDNA levels (>=175 copies per microliter) had the highest odds of having high values of Metavir score and FPR (P < 0.05). Our data show that bacterial translocation is associated with severe liver disease among human immunodeficiency virus-infected patients with chronic hepatitis C. PMID- 22932320 TI - Programmatic impact of the evolution of WHO pediatric antiretroviral treatment guidelines for resource-limited countries (Tukula Fenna Project, Uganda). AB - BACKGROUND: World Health Organization (WHO) recommendations for the initiation of antiretroviral therapy (ART) in children were revised in 2010, but the programmatic impact has had limited study. METHODS: We used a cohort of 985 Ugandan children followed since 2003 by the Tukula Fenna project to model the differential impact of the 2006, 2008, and 2010 WHO pediatric ART inititation criteria on the proportion of children eligible for ART at enrollment and over time. RESULTS: Using the WHO 2006, 2008, and 2010 ART criteria, 40%, 57%, and 66% of children, respectively, would have been eligible for ART at enrollment and 76%, 84%, and 88% 2 years later. Evaluating the entire cohort followed for 6 years using the 2006, 2008, and 2010 guidelines, the proportion in need of ART was found to be 70%, 82%, and 87%, respectively. Between 2006 and 2008, the proportions of eligible children starting ART within 6 and 12 months were 39% and 50%, respectively; after this, the proportions starting within 6 and 12 months were 50% and 52%. Before 2008, the most common criterion met in children who did not start ART was WHO clinical stage (odds ratio = 2.0, CI 95% = 1.2 to 3.2); after the 2008 recommendations, the most common eligibility criterion in children who did not start ART was age <12 months (odds ratio = 10.5, CI 95% = 3.8 to 31.1). CONCLUSIONS: An overall increase of 17% (from 70% to 87%) in children in need of ART was observed in our cohort comparing the 2006 and 2010 guidelines; this increase was primarily driven by the introduction of universal treatment for infants <12 months in 2008. PMID- 22932321 TI - No association of abacavir use with myocardial infarction: findings of an FDA meta-analysis. AB - BACKGROUND: Several studies have reported an association between abacavir (ABC) exposure and increased risk of myocardial infarction (MI) among HIV-infected individuals. Randomized controlled trials (RCTs) and a pooled analysis by GlaxoSmithKline, however, do not support this association. To better estimate the effect of ABC use on risk of MI, the US Food and Drug Administration (FDA) conducted a trial-level meta-analysis of RCTs in which ABC use was randomized as part of a combined antiretroviral regimen. METHODS: From a literature search conducted among 4 databases, 26 RCTs were selected that met the following criteria: conducted in adults, sample size more than 50 subjects, status completed, not a pharmacokinetic trial, and not conducted in Africa. The Mantel Haenszel method, with risk difference and 95% confidence interval, was used for the primary analysis, along with additional alternative analyses, based on FDA requested adverse event reports of MI provided by each investigator. RESULTS: The 26 RCTs were conducted from 1996 to 2010, and included 9868 subjects (5028 ABC and 4840 non-ABC). Mean follow-up was 1.43 person-years in the ABC group and 1.49 person-years in the non-ABC group. Forty-six (0.47%) MI events were reported [24 (0.48%) ABC and 22 (0.46%) non-ABC], with no significant difference noted between the 2 groups (risk difference of 0.008% with 95% confidence interval: -0.26% to 0.27%). CONCLUSIONS: To the best of our knowledge, our study represents the largest trial-level meta-analysis to date of clinical trials in which ABC use was randomized. Our analysis found no association between ABC use and MI risk. PMID- 22932323 TI - [Scientific and rational performance of corneal refractive surgery]. AB - Domestic corneal refractive surgery is embarking on a steady development stage, and following the introduction of femto-second laser, which will open up a new era of corneal surgery. Facing new historical opportunity and challenge, it is vital for scientifically and healthy performance of the surgery both concerning on the improvement of visual quality and preventing the occurrence of complications. Only under a harmony and healthy environment, we will achieve the win-win situation between doctors and patients and sustainable development of corneal refractive surgery in the future. PMID- 22932322 TI - State of the science of adherence in pre-exposure prophylaxis and microbicide trials. AB - For pre-exposure prophylaxis (PrEP) and microbicides to effectively prevent HIV, optimal treatment adherence is required. Adherence to these strategies, however, has not been sufficiently studied. This investigation systematically reviews oral PrEP and microbicide trials across 4 domains of adherence: (1) definition and measures used, (2) risks for nonadherence, (3) promotion strategies, and (4) effects on outcomes. Nineteen (n = 19) trials, with 47,157 participants, published between 1987 and 2012 were identified. Reported mean adherence to microbicides was 79% and to oral PrEP 87%. Common risks for microbicide nonadherence were decreased motivation over time, sex with primary (noncommercial/casual) partners, and insufficient supply. Oral PrEP nonadherence risks were older age and medication side effects. Psychoeducation and outreach to participants and communities were frequently used promotion strategies. Most trials failed to systematically identify barriers and monitor and promote adherence, although adherence moderated outcomes. Recommendations for attending to adherence in future trials are provided. PMID- 22932324 TI - [Caution to perform excimer laser corneal ablation on the ametropia with corneal guttata]. AB - It is very important to avoid inadequate patients to perform excimer laser keratectomy in order to prevent from surgical complications. The ametropic eyes with corneal guttata is considered very carefully whether to perform excimer laser corneal ablation or not, especially for the patient with corneal guttata companied by Fuchs endothelial dystrophy family history is contraindicated to perform laser corneal refractive surgery. PMID- 22932325 TI - [Predictability of the corneal flap creation with the femtosecond laser in LASIK]. AB - OBJECTIVE: To observe the predictability of corneal flap creation with the FEMTO LDV femtosecond laser and analyze preliminarily the factors correlating to the thickness and diameter of the flap . METHODS: It was a study of serial cases. 260 eyes of 130 consecutive patients were treated with the FEMTO LDV. The eyes were assigned to two groups according to intended flap thickness, 110 um (208 eyes) and 90 um (52 eyes). Intended flap diameter varied from 8.5 to 9.5 mm. Difference analysis of flap diameter and intended diameter as well as flap thickness and intended thickness were made. The data was analyzed with SPSS to sum up a multiple stepwise regression formula that could express their quantitative relationship. RESULTS: The 90 um flap group had a average flap thickness of (95.12 +/- 7.65) um, while for the 110 um group the average flap thickness was (104.81 +/- 3.09) um. The difference between right and left eyes was not statistically significant (t(110 um) = -1.223, t(90 um) = -1.343, P > 0.05). Corneal flap thickness was inversely correlated with flap diameter (r(110 um) = 0.143, r(90 um) = -0.315, P < 0.05), but was not related to preoperative patient age, corneal thickness, keratometric value K or intraocular pressure (r(110 um) = -0.160, 0.054, -0.011, -0.363; r(90 um) = 0.024, 0.074, -0.212, -0.434, all P > 0.05). Corneal flap diameter was positively correlated with preoperative corneal keratometric value K and thickness (P < 0.001, P < 0.05). Multiple stepwise regression analysis showed flap diameter was an influencing factor for flap thickness. Preoperative corneal keratometric value K and thickness were influencing factors for flap diameter. CONCLUSIONS: The LASIK flap creation with the FEMTO LDV laser has relatively good predictability. Flap diameter is an influencing factor for flap thickness. PMID- 22932326 TI - [The investigation of microbial culturing of microkeratome blades and sponges used in laser in situ keratomileusis]. AB - OBJECTIVE: The microbial culturing results were analysed from samples of the microkeratome blade and sponges in laser in situ keratomileusis (LASIK) procedures as for crossing the rational antibiotic eye drops for preventing infectious keratitis. METHOD: In this prospective study, 106 microkeratome blades and 212 sponges were cultured in routine LASIK procedure, at Excimer laser center in Henan Eye Institute During March to April 2009. Positive cultures were then sent for routine sensitivities and the results were analysed. RESULTS: 8 of the 106 blades were culturing positive, the positive rate was 7.55%. Each four positive cultures were in male and female patients. There was no statistical difference with gender (P = 1.000). 23 of the 212 sponges cultures were positive. The positive rate was 10.38%. All positive cultures grew Staphylococcus epidermidis. Twelve sponge positive cultures were in right eye and 11 were in left eye. There was no statistical difference between the right eye and left eye (P = 0.825). All of the 31 positive cultures were sensitive to gatifloxacin. The sensitivity of gatifloxacin, tobramycin, levofloxacin, ofloxacin, and ciprofloxacin were 100.00%, 96.77% (30/31), 93.55% (29/31), 90.32% (28/31) and 74.20% (23/31) respectively. All the patients have no infectious keratitis followed-up more then 6 monthes. CONCLUSION: There could be positive cultures from samples of the microkeratome blade and sponges in routine LASIK procedures but no patients with positive cultures developed postoperative infectious keratitis. The main positive bacteria was Staphylococcus epidermidis. They are sensitive to third and the fourth-generation fluoroquinolones and tobramycin antibiotics. Pre and post-operative supply of sensitive antibiotics can prevent post-operative infection. PMID- 22932327 TI - [Comparison study on subjective and objective measurements of the accommodative convergence to accommodation ratio]. AB - OBJECTIVE: To detect the accommodative convergence to accommodation (AC/A) ratios measured respectively by objective and subjective methods. The differences and its relative factors were explored. METHODS: Forty young volunteers were measured by eye tracker to get the amount of convergence when fixating at the target at 100 cm, 50 cm, 33 cm and 25 cm and were measured by infrared auto-refractor to get corresponding accommodative responses. AC/A ratio based on these two measurements were compared with the calculated and the gradient AC/A ratio from Von Graefe tests. RESULTS: Mean value of stimulated AC/A ratio measured by eye tracker was higher than the calculated and gradient AC/A ratio by Von Graefe method (P = 0.003, 0.001). There are statistic correlation (r = 0.871, P = 0.000) and difference (P = 0.000) between stimulated AC/A ratio and response AC/A ratios both measured by eye tracker, and the difference trends to be greater with the higher AC/A ratio. CONCLUSION: The objective AC/A ratio is usually higher than the clinical subjective measurement because of more proximal effect. The response AC/A ratio measured objectively may reveal realistically the mutual effect and relationship between accommodation and convergence and it seems to be more credible to be the monitor parameter on progression of myopia in clinics. PMID- 22932328 TI - [Contrast visual acuity in adults with normal visual acuity]. AB - OBJECTIVES: To evaluate the contrast visual acuity (CVA) in Chinese normal adults and to study the effects of different contrast levels between the optotypes and background, age and sex on the CVA. METHODS: It was a cross-sectional study. Three hundreds and fifty-three normal adults with age from 20 to 70 years were selected as the normal adults (naked visual acuity equal or more than 0.8, and equivalent sphere diopter -1.00 - +1.00 DS, astigmatic diopter -0.75 - +0.75 DC). After conducting eye and refractive examination, all examinee were received the CVA measurements in the different contrast levels between the optotypes and background (100%, 25%, 10% and 5%) in the dark room by the multifunction visual acuity chart. SPSS 18.0 software package was used for one-way ANOVA (analysis of variance), Spearman correlation and paired t test. RESULTS: In the normal adults, CVA significantly decreased by the decrease of the contrast level between optotypes and background (F(OD) = 1317.21, P < 0.01; F(OS) = 991.09, P < 0.01; F(OU) = 1223.87, P < 0.01). In the same contrast level between optotypes and background, CVA significantly decreased by aging (F(100%CVAOD) = 10.86, P = 0.000; F(25%CVAOD) = 11.54, P = 0.000; F(10%CVAOD) = 7.63, P = 0.000; F(5%CVAOD) = 4.88, P = 0.001; F(100%CVAOS) = 15.26, P = 0.000; F(25%CVAOS) = 16.93, P = 0.000; F(10%CVAOS) = 8.33, P = 0.000; F(5%CVAOS) = 4.08, P = 0.003; F(100%CVAOU) = 11.87, P = 0.000; F(25%CVAOU) = 15.08, P = 0.000; F(10%CVAOU) = 11.71, P = 0.000; F(5%CVAOU) = 9.51, P = 0.000). CVA in the high contrast was similar between male and female, however, there was a significantly difference in CVA in the low contrast between male and female (F(100%CVAOD) = 0.341, P = 0.560; F(25%CVAOD) = 0.434, P = 0.510; F(10%CVAOD) = 5.615, P = 0.018; F(5%CVAOD) = 9.492, P = 0.002; F(100%CVAOS) = 0.212, P = 0.645; F(25%CVAOS) = 0.132, P = 0.716; F(10%CVAOS) = 4.588, P = 0.033; F(5%CVAOS) = 4.812, P = 0.029; F(100%CVAOU) = 0.775, P = 0.379; F(25%CVAOU) = 1.043, P = 0.308; F(10%CVAOU) = 8.555, P = 0.004; F(5%CVAOU) = 5.630, P = 0.018). A significantly correlation could be seen between the visual acuity of ETDRS and 100% CVA (r(OD) = 0.632, r(OS) = 0.536, r(OU) = 0.456, all P < 0.01). The 100% CVA was higher than the visual acuity of ETDRS (t(OD) = 20.70, t(OS) = 17.25, t(OU) = 23.47, all P < 0.01). CONCLUSIONS: Age and the different contrast levels between optotypes and background significantly affect CVA. In the low contrast between optotypes and background, CVA in the female is better than in male. PMID- 22932329 TI - [The clinical observation of conjunctivochalasis crescent conjunctival resection with bipolar coagulation]. AB - OBJECTIVE: To seek safe, effective, economical, simple treatment conjunctivochalasis surgical methods, optimize treatment, evaluation conjunctivochalasis surgical treatment. METHODS: A prospective randomized control study, 60 patients (60 eyes) conjunctivochalasis surgery patients were randomly divided into two groups, one line of bipolar coagulation therapy, another group of crescent conjunctival resection. After comparing the two surgical methods ocular surface disease index (OSDI) points, the degree of relaxation conjunctiva, tear meniscus height, BUT, surgical complications, the operation time to evaluate the two kinds of surgical methods of clinical efficacy. RESULTS: Bipolar coagulation therapy with crescent conjunctival resection in 8 weeks after the OSDI points, loose conjunctiva residual points, tear meniscus, BUT the difference was not statistically significant. 8 weeks after bipolar coagulation complications points lower than the crescent conjunctival resection is low, the difference was statistically significant (t = 4.67, P = 0.029); bipolar coagulation operating time (9.53 +/- 3.15) min crescent than conjunctival resection time (18.59 +/- 7.68) min short, the difference was statistically significant (t = 13.26, P > 0.01). CONCLUSIONS: Conjunctivochalasis line bipolar coagulation and removal of loose conjunctiva crescent with considerable effect, bipolar coagulation was significantly shorter operative time, a significant reduction in postoperative complications, surgical procedures easier. PMID- 22932330 TI - [Clinicopathological significance of expression of IGF-1R in uveal melanoma and its association with expression of p-AKT Thr308]. AB - OBJECTIVE: To investigate the clinicopathological significance of expression of insulin-like growth factor-1 receptor (IGF-1R) and its association with the expression of p-AKT Thr308 in uveal melanoma. METHODS: Experimental study. Twenty four patients with uveal melanoma were included from January 2000 to December 2008. The levels of IGF-1R and p-AKT Thr308 were detected by immunohistochemical methods, and their association with clinicopathological parameters including localization of tumor, tumor size, largest tumor diameters, cell type, necrosis, degree of pigmentation, lymphocyte infiltration, mitosis rate, scleral invasion and liver metastasis were statistically analyzed. The relationship of expression of IGF-1R with clinicopathological parameters or with the expression of p-AKT Thr308 was analyzed by chi-square test. RESULTS: The positive rate of expression of IGF-1R in 24 cases of uveal melanoma was 75%. The expression of IGF-1R were associated with the largest tumor diameters, degree of pigmentation, liver metastasis and lymphocyte infiltration (chi(2) = 15.569, P = 0.016; chi(2) = 11.348, P = 0.010; chi(2) = 8.738, P = 0.033; chi(2) = 8.362, P = 0.039). The positive rate of expression of p-AKT Thr308 was 58%. The expression of IGF-1R and p-AKT Thr308 was positively correlated (chi(2) = 17.108, P = 0.009). CONCLUSION: IGF-1R plays a role in the development of uveal melanoma which may be induced by activation in PI3K/AKT pathway. PMID- 22932331 TI - [Effects of oxidative stress on barrier function of human retina pigment epithelium and its molecular mechanisms]. AB - OBJECTIVE: To investigate the effects of hydrogen peroxide (H2O2) on the barrier function and expression of tight junction protein in human retinal pigment epithelium (RPE) cells. METHODS: Experimental study. The human RPE cell line (D407) were cultured and treated with (H2O2 treated group) or without H2O2 (normal control group). The effect of H2O2 on cell viability of RPE cells was determined by MTT test. After treated with low concentration of H2O2 for 24 h to 72 h, transepithelial electrical resistance (TER) of confluent RPE cells was measured by epithelial voltmeter. The permeability of RPE cells to sodium fluorescein was measured. The expressions of the occludin and claudin-1 to -4 were determined by real-time polymerase chain reaction and Western blot analysis.t-text and one-way ANOVA were used to assess statistical significance between H2O2 treated and normal control groups. RESULTS: H2O2 at 0.2 mmol/L showed no decrease of cell viability of D407 cells, and this concentration was selected for the present study. The TER of D407 cells gradually increased, peaking at day 8 and then remained stable for 1 week. As compared to the control group, a reduction in the TER was first evident after 3 hours of treatment. Continuous culturing of cells for longer periods further reduced the TER, with a maximum effect after 24 hours of treatment and was maintained to 72 hours (24 h: 11.86 +/- 1.19 vs. 24.13 +/- 1.26, t = 12.260, P = 0.000; 72 h: 11.56 +/- 1.47 vs. 24.33 +/- 1.52, t = 10.460, P = 0.000). At any time point after adding sodium fluorescein, the permeability values of cells after treated with H2O2 for 24 hours were significantly higher than those of cells without H2O2 treatment (20 min: 25% +/- 3% vs. 12% +/- 4%, t = -4.50, P = 0.011; 40 min: 36% +/- 4% vs. 16% +/- 5%, t = -5.41, P = 0.006; 60 min: 51% +/- 5% vs. 29% +/- 6%, t = -4.88, P = 0.008). The expression of mRNA and protein in claudin-1, -3, and -4 were all downregulated in D407 cells treated with H2O2, whereas the expression of claudin 2 was upregulated (claudin-1 mRNA: 0.98 +/- 0.18 vs. 0.28 +/- 0.12, t = 5.60, P = 0.005, claudin-1 protein, 48 +/- 10 vs. 100 +/- 12, t = 5.77, P = 0.004; claudin 3 mRNA: 0.37 +/- 0.12 vs.1.03 +/- 0.15, t = 5.95, P = 0.004; claudin-3 protein: 63 +/- 13 vs. 100 +/- 15, t = 3.23, P = 0.032; claudin-4 mRNA: 0.38 +/- 0.11 vs.0.99 +/- 0.17, t = 5.22, P = 0.002, claudin-4 protein, 57 +/- 12 vs. 100 +/- 13, t = 4.21, P = 0.014). However, the expression of these occluding did not differ between cells treated with and without H2O2 (mRNA:1.30 +/- 0.21 vs. 1.02 +/- 0.16, t = -1.84, P = 0.140; protein: 109 +/- 15 vs. 100 +/- 14, t = -0.76, P = 0.490). CONCLUSION: Oxidative stress causes increase in the paracellular permeability of RPE cells in vitro, which may depends on the changes in expression of certain transmembrane proteins associated with the tight junction. PMID- 22932332 TI - [Factors affected therapeutic results in treatment of children congenital nasolacrimal duct obstruction by Ritleng lacrimal intubation]. AB - OBJECTIVE: To evaluate the efficacy of the Ritleng lacrimal intubation system in the treatment of congenital nasolacrimal duct obstruction (CNLDO) after failed probing and to analyze the effect of various factors that affected the recovery rate. METHODS: Retrospective noncomparative case series. The outcome of 616 cases (eyes) of silicone intubation with the Ritleng lacrimal intubation system, performed between Feb. 2008 and Oct. 2009 on 546 children with CNLDO (aged from 3 to 156 months with an average at 11 months) from Beijing Children's Hospital, was retrospectively reviewed. The follow-up period varied from 4 to 17 months (average 11 months). The effects of age, treatment history, and the type of obstruction on the recovery rate were evaluated and the complications such as epistaxis, lacrimal duct edema or silicone tube prolapse were recorded. The statistics analysis included Pearson correlation coefficient and independent samples t-test. RESULTS: The overall recovery rate was 88% (544/616 cases). In the five sub-groups based on the age, 6 - 12 month, 12 - 24 month, 24 - 36 month, 36 - 48 month and older than 48 month age, the recovery rate was 96% (94/98); 94% (244/260); 87% (104/119); 77% (58/75) and 69% (44/64), respectively (R = -0.98, P = 0.003). According to the times of previous probing, there were three groups, once, twice, and more than twice, the recovery rate was 95% (291/304); 89% (163/184) and 70% (90/128), respectively (R = -0.99, P = 0.050). In the simple membranous obstruction group and the complex obstruction group, the recovery rate was 92% (343/374) and 83% (201/242), respectively (P = 0.000). Complications included laceration of lachrymal point (8 eyes, 1%) and false passage formation (14 eyes, 2%). The silicone tube prolapsed in 18 eyes (3%). CONCLUSIONS: The Ritleng lacrimal intubation system is an easy, effective and non-traumatic procedure for the treatment of CNLDO children after failed probing. Age of the patients, times of previous probing and type of obstruction influence the recovery rate. PMID- 22932333 TI - [Clinical study of optic neuritis combined with viral hepatitis]. AB - OBJECTIVE: To investigate the clinical manifestation, management and prognosis of optic neuritis combined with viral hepatitis. METHODS: Retrospective study case series. Clinical data from twenty patients with optic neuritis combined with hepatitis who were hospitalized in Beijing Tongren Hospital neural eye ward from September 2003 to June 2010 were collected, the clinical characteristics and visual field changes in the group of patients were summarized, and comparison between the vision before and after treatment was made by the Wingerchuk vision classification. RESULTS: Among the twenty patients, eighteen patients had chronic hepatitis B and two patients had chronic hepatitis C. Thirteen (65%) patient were monocular, sixteen (80%) patients were single-phase course. Twenty-seven eyes were affected. Disc edema was very common which was found in 14 eyes (52%), severe vision impairment (Best corrected visual acuity worse than 20/200) were recorded in 19 eyes (70%). Lower altitudinal visual field impairment was more common which was found in 10 eyes (50%). All patients were followed for 3 months after steroid therapy, complete visual recovery or significant improvement was seen in only 3 eyes (11%) or 4 eyes (15%). Minor improvement was seen in 12 eyes (44%), while 8 eyes (30%) had no improvement. CONCLUSIONS: In this study, optic neuritis combined with hepatitis usually showed severe visual impairment. Although the vision of some patients could completely recover after steroid therapy, most of the patients had poor recovery. Combination of steroid and anti viral therapy should be considered in the management of optic neuritis combined with hepatitis. PMID- 22932334 TI - [Clinical characteristics of mechanical ocular injury and application of ocular trauma score]. AB - OBJECTIVE: To summarize clinical characteristics of mechanical ocular injury and to analyze the role of ocular trauma score (OTS) in the estimation of final visual acuity. METHODS: All cases of ocular trauma admitted to the Department of Ophthalmology from January 2009 to December 2010 were retrospectively reviewed. Data extracted included laterality of the injured eye, gender, age, presenting time, cause, ocular trauma classification, initial and final visual acuity. These injuries were classified by ocular trauma classification system (OTCS). We also used the OTS in evaluating the final visual outcome. Comparisons between groups for discontinuous variables were analyzed using rank-sum test. Rank correlation was used in analysis between initial visual acuity and final visual acuity or between final visual acuity and OTS. Chi-square test was used to analyze variables, such as age, cause, type and visual acuity. Comparison of ages between male and female was analyzed by using t-test. RESULTS: Of the 168 eyes, there were 106 open globe injury (OGI) and 62 closed globe injury (CGI). There were 140 males (85.71%) and 22 females (14.29%). Presenting time median of OGI and CGI was 5 h and 10 h respectively, and there was significant difference between these two different injuries (Z = -2.547, P = 0.011). The high-risk age group was the young age group (100 eyes, 59.52%), vs. the middle age group (46 eyes, 27.38%) and the elder age group (22 eyes, 13.10%). Occupation-related injury (70 eyes) was the most common cause and mainly resulted in OGI (54/70). Initial and final visual acuities in CGI were better than those of OGI (chi(2) = 37.847, P = 0.000; chi(2) = 44.428, P = 0.000). Initial visual acuity was correlated with final visual acuity (r = 0.858, P = 0.000). Final visual acuity was significantly correlated with total score (r = 0.870, P = 0.000) and OTS (r = 0.869, P = 0.000). CONCLUSIONS: In this group of mechanical ocular trauma patients, male is more common than the female. Main type of injury is OGI and presenting time of OGI is earlier than that of CGI. The high-risk age group is the young. Main cause of injury is occupation-related injury. Initial and final visual acuities in CGI are better than those in OGI. OTS calculated at initial examination may be a useful parameter for the estimation of prognosis. PMID- 22932335 TI - [Explore the genotype characteristics of DNA repair enzyme XRCC1 and XPD in the lens epithelium associated with free radical level in the age-related cataract patients]. AB - OBJECTIVE: To explore the genotype characteristics of DNA repair enzyme XPD-751 and XRCC1-399 in the lens epithelium of cataract patients, and difference in free radical level. METHODS: The genome DNA was extracted from respective lens epithelium of 30 cataract patients, their peripheral blood and 12 normal control's peripheral blood by using a Genomic DNA kit, and the polymorphisms of DNA repair enzymes XPD-751 and XRCC1-399 were examined by PCR-RFLP technique. Meanwhile, that of the cultured normal human lens epithelial SRA01/04 cells was carried out same way as reference control. Besides, the free radical level was detected by related kit. RESULTS: The XRCC1-Gln399Gln or XPD-Lys751Lys genotype was found in the normal control group and cultured human SRA01/04 cells, while the polymorphism of XPD-Lys751Gln could be found in both lens epithelium and blood cells of the cataract patient group. However, there was no difference in XRCC1-399 phenotype between the patient and the normal control groups. There is difference in free radical level between the cataract (0.204 +/- 0.07; 0.188 +/- 0.07) and healthy subjects (t = 211.20, P < 0.05). CONCLUSION: The polymorphism of XPD-Lys751Gln can be found in the lens epithelium of cataract patient group, suggesting that there may be association among the XPD-751 polymorphism with higher free radical level in the age-related cataract disease. PMID- 22932336 TI - [Study on the structure and function of superior oblique connective tissue in different mammals]. AB - OBJECTIVE: The purpose of this research lied in studying the structure and function of connective tissue of superior oblique (SO) in rhesus and rabbit. METHODS: It was an experimental study. Two adult monkeys (rhesus) and five adult rabbits were involved in this study. The gross anatomy of an orbit in each animal was observed. Meanwhile, the fellow orbit was processed with paraffin imbedding and coronal serial section. Masson trichrome stain was used to distinguish muscle and collagen, and Weigert stain was performed for identification of elastin. RESULTS: Connective tissue around SO in both mammals thickened anteriorly, reflected in the trochlea along with the SO tendon, and became contiguous with the nasal aspect of the SR connective tissue ring, while the tendon passed inferior to the SR pulley to insert on the sclera. CONCLUSION: The contraction of SO OL can cause SR shift nasally. This may explain the mechanism of vestibulo ocular reflex (VOR) partly. PMID- 22932337 TI - [Effects of simvastatin on expression of connective tissue growth factor in vitreous and retina of diabetic rats]. AB - OBJECTIVE: To study the effects of simvastatin on the expression of connective tissue growth factor (CTGF) that cause fibrosis in the vitreous and retina after intravitreal injection in diabetic rats, and to explore the safety of this procedure. METHODS: It was an experimental study. Forty adult male Wistar rats were randomly divided into normal control group (10 rats) and diabetes mellitus group (30 rats). Four months later, according to whether treated with simvastatin or not, the diabetes mellitus group randomly divided into simvastatin intervention group (20 rats) and diabetic positive control group (10 rats). Simvastatin was injected into the vitreous in the simvastatin intervention group, but not in the diabetic positive control group. Seven days later, after the examination of electroretinogram (ERG), all rats were sacrificed, and their eyeballs were enucleated. Enzyme-linked immunosorbent assay (ELISA) and immunohistochemistry method were performed to determine the expression of CTGF in the vitreous and retina. Terminal DNA transferase-mediated dUTP nick end labeling (TUNEL) method was used to detect apoptosis of retina cells. Concentration of CTGF in the vitreous, retinal expression of CTGF, retinal cellular apoptosis index, ERG-b wave and oscillatory potentials (OPs) of rats in each group were compared using analysis of variance LSD test methods. RESULTS: No systemic toxic reactions, no lens opacity and no endophthalmitis occurred after injection of simvastatin into the vitreous of rats. Concentrations of CTGF in vitreous of simvastatin intervention group, diabetes positive control group and normal control group rats were 359.21 ug/L, 478.47 ug/L and 210.78 ug/L, respectively (F = 252.366, P < 0.05). The levels of CTGF in the vitreous of simvastatin intervention group and diabetic positive control group was significantly higher than that of the normal control group and showed significant difference (t = 12.123, 23.816;P < 0.05). CTGF levels in simvastatin intervention group were significantly lower than those in diabetic positive control group, and the difference was statistically significant. (t = 11.693, P < 0.05). The results of immunohistochemical staining and TUNEL staining were negative in the normal control group. Retinal expression of CTGF in simvastatin intervention group and diabetic positive control group were (26.60 +/- 2.95)% and (42.31 +/- 2.59)%, respectively. Retinal expression of CTGF in simvastatin intervention group was reduced as compared to the diabetic positive control group, the difference was statistically significant (t = 12.112, P < 0.05). Retinal cellular apoptosis index of simvastatin intervention group and diabetic positive control group was 0.19 +/- 0.02 and 0.25 +/- 0.03, respectively. Retinal cellular apoptosis index of simvastatin intervention group was significantly lower than that in diabetic positive control group (t = 4.745, P < 0.05). ERG revealed no significant changes. In simvastatin intervention group as compared with diabetic positive control group. CONCLUSIONS: Simvastatin could inhibit the expression of CTGF in the vitreous body and retina in diabetic rats. Intravitreal injection of simvastatin is a relatively safe procedure. PMID- 22932338 TI - Posterior pharyngeal wall squamous cell carcinoma arising in a patient with dyskeratosis congenita. AB - OBJECTIVES: Dyskeratosis congenita is a rare, inherited bone marrow failure syndrome characterised by telomerase dysfunction. This study aimed to demonstrate the importance of recognising that this condition predisposes individuals to head and neck malignancy, and also to discuss the challenges of treatment in such individuals. CASE REPORT: We present the case of a 30-year-old man with dyskeratosis congenita, who presented with a squamous cell carcinoma of the posterior pharyngeal wall. The patient was treated successfully with surgical resection. CONCLUSION: Dyskeratosis congenita is a rare condition; however, it is vital to recognise the increased risk of upper aerodigestive tract cancers in these patients. Management of such cancers can be particularly difficult in view of the need to avoid DNA-damaging therapies such as radiotherapy. PMID- 22932340 TI - Small steps. PMID- 22932339 TI - The potent M1 receptor allosteric agonist GSK1034702 improves episodic memory in humans in the nicotine abstinence model of cognitive dysfunction. AB - Episodic memory deficits are a core feature of neurodegenerative disorders. Muscarinic M(1) receptors play a critical role in modulating learning and memory and are highly expressed in the hippocampus. We examined the effect of GSK1034702, a potent M(1) receptor allosteric agonist, on cognitive function, and in particular episodic memory, in healthy smokers using the nicotine abstinence model of cognitive dysfunction. The study utilized a randomized, double-blind, placebo-controlled, cross-over design in which 20 male nicotine abstained smokers were tested following single doses of placebo, 4 and 8 mg GSK1034702. Compared to the baseline (nicotine on-state), nicotine abstinence showed statistical significance in reducing immediate (p=0.019) and delayed (p=0.02) recall. GSK1034702 (8 mg) significantly attenuated (i.e. improved) immediate recall (p=0.014) but not delayed recall. None of the other cognitive domains was modulated by either nicotine abstinence or GSK1034702. These findings suggest that stimulating M(1) receptor mediated neurotransmission in humans with GSK1034702 improves memory encoding potentially by modulating hippocampal function. Hence, selective M(1) receptor allosteric agonists may have therapeutic benefits in disorders of impaired learning including Alzheimer's disease. PMID- 22932342 TI - What matters for science is who runs the country. PMID- 22932341 TI - Open for business. PMID- 22932354 TI - US colliders jostle for funds. PMID- 22932353 TI - Pig fever sweeps across Russia. PMID- 22932355 TI - Doctors back circumcision. PMID- 22932356 TI - Calorie restriction falters in the long run. PMID- 22932357 TI - Brazil unveils tool to track emissions. PMID- 22932359 TI - Recycled dishes form telescope network. PMID- 22932360 TI - After the Higgs: The new particle landscape. PMID- 22932361 TI - Nanotechnology: Armed resistance. PMID- 22932362 TI - Particle physics: Beyond the Higgs. PMID- 22932363 TI - Climate science: Time to raft up. PMID- 22932368 TI - Competing interests: Judged in perpetuity. PMID- 22932369 TI - Australia: Biomass energy holds big promise. PMID- 22932370 TI - Gender matters: A call to commission more women writers. PMID- 22932371 TI - Competing interests: Expanding rapidly. PMID- 22932372 TI - Atmospheric science: Institute to continue climate monitoring. PMID- 22932373 TI - Communication: Embrace complexity but not jargon. PMID- 22932374 TI - Careers: PhDs fit for industry and commerce, too. PMID- 22932375 TI - Publishing: Curb temptation to skip quality control. PMID- 22932376 TI - Research fraud: Speed up reviews of misconduct. PMID- 22932377 TI - Bernard Lovell (1913-2012). PMID- 22932378 TI - Environmental science: Scorecard for the seas. PMID- 22932379 TI - Immunology: Licensed in the lungs. PMID- 22932380 TI - Ocean science: Ancient burial at sea. PMID- 22932381 TI - Optics: Mixing waves in a diamond. PMID- 22932382 TI - Epigenetics: Actors in the cell reprogramming drama. PMID- 22932383 TI - Microbiology: Antibiotics and adiposity. PMID- 22932384 TI - X-ray and optical wave mixing. AB - Light-matter interactions are ubiquitous, and underpin a wide range of basic research fields and applied technologies. Although optical interactions have been intensively studied, their microscopic details are often poorly understood and have so far not been directly measurable. X-ray and optical wave mixing was proposed nearly half a century ago as an atomic-scale probe of optical interactions but has not yet been observed owing to a lack of sufficiently intense X-ray sources. Here we use an X-ray laser to demonstrate X-ray and optical sum-frequency generation. The underlying nonlinearity is a reciprocal space probe of the optically induced charges and associated microscopic fields that arise in an illuminated material. To within the experimental errors, the measured efficiency is consistent with first-principles calculations of microscopic optical polarization in diamond. The ability to probe optical interactions on the atomic scale offers new opportunities in both basic and applied areas of science. PMID- 22932385 TI - A Cenozoic record of the equatorial Pacific carbonate compensation depth. AB - Atmospheric carbon dioxide concentrations and climate are regulated on geological timescales by the balance between carbon input from volcanic and metamorphic outgassing and its removal by weathering feedbacks; these feedbacks involve the erosion of silicate rocks and organic-carbon-bearing rocks. The integrated effect of these processes is reflected in the calcium carbonate compensation depth, which is the oceanic depth at which calcium carbonate is dissolved. Here we present a carbonate accumulation record that covers the past 53 million years from a depth transect in the equatorial Pacific Ocean. The carbonate compensation depth tracks long-term ocean cooling, deepening from 3.0-3.5 kilometres during the early Cenozoic (approximately 55 million years ago) to 4.6 kilometres at present, consistent with an overall Cenozoic increase in weathering. We find large superimposed fluctuations in carbonate compensation depth during the middle and late Eocene. Using Earth system models, we identify changes in weathering and the mode of organic-carbon delivery as two key processes to explain these large scale Eocene fluctuations of the carbonate compensation depth. PMID- 22932386 TI - Graphene and boron nitride lateral heterostructures for atomically thin circuitry. AB - Precise spatial control over the electrical properties of thin films is the key capability enabling the production of modern integrated circuitry. Although recent advances in chemical vapour deposition methods have enabled the large scale production of both intrinsic and doped graphene, as well as hexagonal boron nitride (h-BN), controlled fabrication of lateral heterostructures in these truly atomically thin systems has not been achieved. Graphene/h-BN interfaces are of particular interest, because it is known that areas of different atomic compositions may coexist within continuous atomically thin films and that, with proper control, the bandgap and magnetic properties can be precisely engineered. However, previously reported approaches for controlling these interfaces have fundamental limitations and cannot be easily integrated with conventional lithography. Here we report a versatile and scalable process, which we call 'patterned regrowth', that allows for the spatially controlled synthesis of lateral junctions between electrically conductive graphene and insulating h-BN, as well as between intrinsic and substitutionally doped graphene. We demonstrate that the resulting films form mechanically continuous sheets across these heterojunctions. Conductance measurements confirm laterally insulating behaviour for h-BN regions, while the electrical behaviour of both doped and undoped graphene sheets maintain excellent properties, with low sheet resistances and high carrier mobilities. Our results represent an important step towards developing atomically thin integrated circuitry and enable the fabrication of electrically isolated active and passive elements embedded in continuous, one atom-thick sheets, which could be manipulated and stacked to form complex devices at the ultimate thickness limit. PMID- 22932387 TI - Potential methane reservoirs beneath Antarctica. AB - Once thought to be devoid of life, the ice-covered parts of Antarctica are now known to be a reservoir of metabolically active microbial cells and organic carbon. The potential for methanogenic archaea to support the degradation of organic carbon to methane beneath the ice, however, has not yet been evaluated. Large sedimentary basins containing marine sequences up to 14 kilometres thick and an estimated 21,000 petagrams (1 Pg equals 10(15) g) of organic carbon are buried beneath the Antarctic Ice Sheet. No data exist for rates of methanogenesis in sub-Antarctic marine sediments. Here we present experimental data from other subglacial environments that demonstrate the potential for overridden organic matter beneath glacial systems to produce methane. We also numerically simulate the accumulation of methane in Antarctic sedimentary basins using an established one-dimensional hydrate model and show that pressure/temperature conditions favour methane hydrate formation down to sediment depths of about 300 metres in West Antarctica and 700 metres in East Antarctica. Our results demonstrate the potential for methane hydrate accumulation in Antarctic sedimentary basins, where the total inventory depends on rates of organic carbon degradation and conditions at the ice-sheet bed. We calculate that the sub-Antarctic hydrate inventory could be of the same order of magnitude as that of recent estimates made for Arctic permafrost. Our findings suggest that the Antarctic Ice Sheet may be a neglected but important component of the global methane budget, with the potential to act as a positive feedback on climate warming during ice-sheet wastage. PMID- 22932388 TI - 'Melt welt' mechanism of extreme weakening of gabbro at seismic slip rates. AB - Laboratory studies of frictional properties of rocks at slip velocities approaching the seismic range (~0.1-1 m s(-1)), and at moderate normal stresses (1-10 MPa), have revealed a complex evolution of the dynamic shear strength, with at least two phases of weakening separated by strengthening at the onset of wholesale melting. The second post-melting weakening phase is governed by viscous properties of the melt layer and is reasonably well understood. The initial phase of extreme weakening, however, remains a subject of much debate. Here we show that the initial weakening of gabbro is associated with the formation of hotspots and macroscopic streaks of melt ('melt welts'), which partially unload the rest of the slip interface. Melt welts begin to form when the average rate of frictional heating exceeds 0.1-0.4 MW m(-2), while the average temperature of the shear zone is well below the solidus (250-450 degrees C). Similar heterogeneities in stress and temperature are likely to occur on natural fault surfaces during rapid slip, and to be important for earthquake rupture dynamics. PMID- 22932392 TI - Is irisin a human exercise gene? PMID- 22932389 TI - Mutations in DMRT3 affect locomotion in horses and spinal circuit function in mice. AB - Locomotion in mammals relies on a central pattern-generating circuitry of spinal interneurons established during development that coordinates limb movement. These networks produce left-right alternation of limbs as well as coordinated activation of flexor and extensor muscles. Here we show that a premature stop codon in the DMRT3 gene has a major effect on the pattern of locomotion in horses. The mutation is permissive for the ability to perform alternate gaits and has a favourable effect on harness racing performance. Examination of wild-type and Dmrt3-null mice demonstrates that Dmrt3 is expressed in the dI6 subdivision of spinal cord neurons, takes part in neuronal specification within this subdivision, and is critical for the normal development of a coordinated locomotor network controlling limb movements. Our discovery positions Dmrt3 in a pivotal role for configuring the spinal circuits controlling stride in vertebrates. The DMRT3 mutation has had a major effect on the diversification of the domestic horse, as the altered gait characteristics of a number of breeds apparently require this mutation. PMID- 22932394 TI - Multiple synchronous outbreaks of Puumala virus, Germany, 2010. AB - To investigate 2,017 cases of hantavirus disease in Germany, we compared 38 new patient-derived Puumala virus RNA sequences identified in 2010 with bank vole derived small segment RNA sequences. The epidemic process was driven by outbreaks of 6 Puumala virus clades comprising strains of human and vole origin. Each clade corresponded to a different outbreak region. PMID- 22932393 TI - Prospective predictors of adolescent suicidality: 6-month post-hospitalization follow-up. AB - BACKGROUND: The aim of this study was to examine prospective predictors of suicide events, defined as suicide attempts or emergency interventions to reduce suicide risk, in 119 adolescents admitted to an in-patient psychiatric unit for suicidal behaviors and followed naturalistically for 6 months. Method Structured diagnostic interviews and self-report instruments were administered to adolescent participants and their parent(s) to assess demographic variables, history of suicidal behavior, psychiatric disorders, family environment and personality/temperament. RESULTS: Baseline variables that significantly predicted time to a suicide event during follow-up were Black race, high suicidal ideation in the past month, post-traumatic stress disorder (PTSD), childhood sexual abuse (CSA), borderline personality disorder (BPD), low scores on positive affectivity, and high scores on aggression. In a multivariate Cox regression analysis, only Black race, CSA, positive affect intensity and high aggression scores remained significant. CONCLUSIONS: Our findings suggest the following for adolescent populations: (1) in a very high-risk population, risk factors for future attempts may be more difficult to ascertain and some established risk factors (e.g. past suicide attempt) may not distinguish as well; and (2) cross-cutting constructs (e.g. affective and behavioral dysregulation) that underlie multiple psychiatric disorders may be stronger predictors of recurrent suicide events than psychiatric diagnoses. Our finding with respect to positive affect intensity is novel and may have practical implications for the assessment and treatment of adolescent suicide attempters. PMID- 22932395 TI - Ubiquitin C-terminal hydrolase-L1 interacts with adhesion complexes and promotes cell migration, survival, and anchorage independent growth. AB - Ubiquitin C-terminal hydrolase-L1 (UCH-L1) is a deubiquitinating enzyme of unknown function that is highly expressed in neurons and overexpressed in several human cancers. UCH-L1 has been implicated in the regulation of phenotypic properties associated with malignant cell growth but the underlying mechanisms have not been elucidated. By comparing cells expressing catalytically active or inactive versions of UCH-L1, we found that the active enzyme enhances cell adhesion, spreading, and migration; inhibits anoikis; and promotes anchorage independent growth. UCH-L1 accumulates at the motile edge of the cell membrane during the initial phases of adhesion, colocalizes with focal adhesion kinase (FAK), p120-catenin, and vinculin, and enhances the formation of focal adhesions, which correlates with enhanced FAK activation. The involvement of UCH-L1 in the regulation of focal adhesions and adherens junctions is supported by coimmunoprecipitation with key components of these complexes, including FAK, paxillin, p120-catenin, beta-catenin, and vinculin. UCH-L1 stabilizes focal adhesion signaling in the absence of adhesion, as assessed by reduced caspase dependent cleavage of FAK following cell detachment and sustained activity of the AKT signaling pathway. These findings offer new insights on the molecular interactions through which the deubiquitinating enzyme regulates the survival, proliferation, and metastatic potential of malignant cells. PMID- 22932396 TI - Host immune system strikes back: autophagy-mediated antigen presentation bypasses viral blockade of the classic MHC class I processing pathway. AB - Autophagy-mediated major histocompatibility complex (MHC) class I presentation can follow either the conventional MHC class I pathway or a recently described vacuolar pathway. In the vacuolar pathway, protein degradation is effected by lysosomal proteases, peptide exchange takes place with recirculating MHC complexes and the newly formed peptide-MHC complexes reach the cell surface by the endocytic pathway. This pathway is independent of the proteasome and the transporter associated with antigen processing (TAP) complex, but generates the same, or a similar, epitope as that from the conventional MHC class I pathway. Here, we discuss different mechanisms by which autophagy mediates MHC class I restricted antigen presentation, which is crucial to its role in the control of intracellular pathogens. PMID- 22932398 TI - Prevalence and outcomes of pediatric in-hospital cardiopulmonary resuscitation in the United States: an analysis of the Kids' Inpatient Database*. AB - OBJECTIVE: Population-based data on pediatric in-hospital cardiopulmonary resuscitation in the United States are scarce. Single-center studies and voluntary registries may skew the estimated prevalence and outcomes. This study aimed to determine the prevalence and outcomes of pediatric cardiopulmonary resuscitation on a national scale. DESIGN: A retrospective analysis of the Healthcare Cost and Utilization Project 2006 Kids' Inpatient Database was performed. Sample weighting was employed to produce national estimates. SETTING: Three thousand seven hundred thirty-nine hospitals in 38 states participating with the Kids' Inpatient Database. PATIENTS: All patients <20 yrs of age hospitalized in participating institutions in 2006. MEASUREMENTS AND MAIN RESULTS: Cardiopulmonary resuscitation was performed in 5,807 (95% confidence interval 5259-6355) children with prevalence of 0.77 per 1,000 admissions. Most patients (68%) were <1 yr old, and 44% were female. On multivariable analysis, cardiopulmonary resuscitation was associated with respiratory failure (odds ratio 41.5, 95% confidence interval 35.4-48.8), myocarditis (odds ratio 36.6, 95% confidence interval 21.9-61.0), acute renal failure (odds ratio 21.6, 95% confidence interval 17.5-26.7), heart failure (odds ratio 3.8, 95% confidence interval 3.0-4.8), and cardiomyopathy (odds ratio 3.8, 95% confidence interval 3.2-4.7). Overall mortality was 51.8% and greater among patients >=1 yr (68%) vs. <1 yr (44%) (odds ratio 2.7, 95% confidence interval 2.3-3.2). Factors associated with mortality among patients receiving cardiopulmonary resuscitation on multivariable analysis included acute renal failure (odds ratio 1.5, 95% confidence interval 1.1-1.9), hepatic insufficiency (odds ratio 1.5, 95% confidence interval 1.01-2.4), sepsis (odds ratio 1.2, 95% confidence interval 1.01-1.4), and congenital heart disease (odds ratio 1.2, 95% confidence interval 1.01-1.5). CONCLUSIONS: Cardiopulmonary resuscitation is performed in approximately one in 1,300 pediatric hospitalizations. Approximately half of patients receiving cardiopulmonary resuscitation do not survive to discharge. Independent risk factors for mortality after receiving cardiopulmonary resuscitation included congenital heart disease, age >=1 yr, acute renal failure, hepatic insufficiency, and sepsis. PMID- 22932399 TI - Circulating nucleosomes and severity of illness in children suffering from meningococcal sepsis treated with protein C. AB - OBJECTIVE: Cell death leading to circulating nucleosomes and histones is a critical step in the pathogenesis of sepsis and contributes to lethality. Activated protein C was demonstrated to attenuate the harmful effects of histones. The objective of this retrospective study was to evaluate whether nucleosomes correlate with the severity of the inflammatory response and mortality in children suffering from severe meningococcal sepsis. Furthermore, we wanted to study the effects of infusion of protein C on nucleosome levels in children with septic purpura. DESIGN: Retrospective analysis of nucleosome levels in children suffering from meningococcal sepsis treated with either placebo or protein C. SETTING: Pediatric intensive care unit of a tertiary care university center. PATIENTS: In a randomized, placebo-controlled study, either protein C or placebo was administered to 38 children suffering from meningococcal sepsis. Nucleosome levels have been measured retrospectively in these 38 children suffering from meningococcal sepsis. MEASUREMENTS AND MAIN RESULTS: Twenty-eight children were treated with protein C and 10 received placebo. Nucleosome levels were significantly higher in nonsurvivors (n = 9) at any time point measured as compared to survivors (n = 29). Nucleosome levels significantly correlated with organ dysfunction scores, cytokines, and parameters for coagulation. Patients treated with protein C had significantly higher activated protein C levels than children receiving placebo. We could not find a clear effect of activated protein C on nucleosome levels in these patients. CONCLUSION: Circulating nucleosomes correlated with the severity of the inflammatory response and were associated with mortality in children suffering from meningococcal sepsis. We show that protein C administration does not decrease nucleosome levels in these patients. PMID- 22932400 TI - MRSA harboring mecA variant gene mecC, France. AB - We describe human cases and clustered animal cases of mecA(LGA251)-positive methicillin-resistant Staphylococcus aureus in France. Our report confirms that this new variant has a large distribution in Europe. It may represent a public health threat because phenotypic and genotypic tests seem unable to detect this new resistance mechanism. PMID- 22932397 TI - Activated protein C and septic shock: a propensity-matched cohort study*. AB - BACKGROUND: Septic shock is a highly inflammatory and procoagulant state associated with significant mortality. In a single randomized controlled trial, recombinant human activated protein C (drotrecogin alfa) reduced mortality in patients with severe sepsis at high risk of death. Further clinical trials, including a recently completed trial in patients with septic shock, failed to reproduce these results. OBJECTIVE: To evaluate the effectiveness of recombinant human activated protein C on mortality in a cohort of patients with septic shock and to explore possible reasons for inconsistent results in previous studies. DESIGN: Retrospective, 2:1 propensity-matched, multicenter cohort study. SETTING: Twenty-nine academic and community intensive care units in three countries. PATIENTS: Seven thousand three hundred ninety-two adult patients diagnosed with septic shock, of which 349 received recombinant human activated protein C within 48 hrs of intensive care unit admission between 1997 and 2007. MEASUREMENTS AND MAIN RESULTS: Our primary outcomes were mortality over 30 days and mortality stratified by Acute Physiology and Chronic Health Evaluation II quartile. Using a propensity-matched Cox proportional hazard model, we observed a 6.1% absolute reduction in 30-day mortality associated with the use of recombinant human activated protein C (108/311 [34.7%] vs. 254/622 [40.8%], hazard ratio 0.72, 95% confidence interval 0.52-1.00, p = .05) and noted consistent reductions in mortality among Acute Physiology and Chronic Health Evaluation II quartiles. A time to event analysis showed that the time to appropriate antimicrobials after documented hypotension decreased for each year of study (p = .003), a finding that was congruent with a decrease in annual mortality over the study period (odds ratio 0.96 per year [95% confidence interval 0.93-0.99], p = .003). CONCLUSIONS: In this retrospective, propensity-matched, multicenter cohort study of patients with septic shock, early use of recombinant human activated protein C was associated with reduced mortality. Improvements in general quality of care such as speed of antimicrobial delivery leading to decreasing mortality of patients with septic shock may have contributed to the null results of the recently completed trial of recombinant human activated protein C in patients with septic shock. PMID- 22932401 TI - [Comparative study between primary mediastinal B-cell lymphoma and non mediastinal diffuse large B-cell lymphoma by immunoglobulin gene rearrangement and Epstein-Barr virus infection detection]. AB - OBJECTIVE: To investigate the differences between primary mediastinal B-cell lymphoma (PMBCL) and non-mediastinal conventional diffuse large B-cell common lymphoma (DLBCL) in immunoglobulin gene rearrangement and EB virus infections. METHODS: Twenty cases of PMBCL and 30 cases of non-mediastinal DLBCL were collected from September, 2000 to May, 2011. Pathological data were retrospectively analysed. Immunoglobulin heavy chain and light chain gene rearrangements and EBER in-situ hybridization were performed. RESULTS: Six of 20 cases of PMBCL showed monoclonal gene rearrangement, all of which were weakly detected. Twenty-seven of 30 cases of ordinary diffuse large B-cell lymphoma showed monoclonal gene rearrangement, which were strongly detected (90.0%). Only 1 of 20 cases PMBCL and 2 of 30 cases of DLBCL were positive for EBER in-situ hybridization. CONCLUSIONS: The detection rate of immunoglobulin gene rearrangement is significantly lower in PMBCL than that of non-mediastinal DLBCL. However, EB virus infection rates are very low in both types of lymphomas. PMID- 22932402 TI - [Expression of microRNA-223 and its clinicopathologic correlation in diffuse large B-cell lymphoma]. AB - OBJECTIVE: To study the expression of miR-223 in diffuse large B cell lymphoma (DLBCL) with correlation of histoloigcal subtypes and clinical prognosis. METHODS: A total of 45 cases of DLBCL were investigated by immunohistochemistry (EnVision method) for CD20, CD3, CD10, bcl-6 and MUM-1. The cases were classified into germinal center B cell-like (GCB) and non-germinal center B cell-like (non GCB) subtypes according to Hans' algorithm. Agilent Human miRNA Microarray 16.0 was used to detect the expression of micro-RNAs in paraffin-embedded tissue of 24 cases of DLBCL that had available clinical follow-up. The expression levels of miR-223 were examined by TaqMan real-time reverse transcription polymerase chain reaction (real-time RT-PCR). Fourteen cases of reactive lymph node were selected as control. RESULTS: Among 45 cases of DLBCL, 16 cases (35.6%) were GCB and 29 cases (64.4%) were non-GCB subtypes. The expression levels of miR-223 measured by real-time RT-PCR were 19.8 and 15.8 in GCB and non-GCB subgroups, respectively (P = 0.236). The expression of miR-223 was up-regulated in DLBCL with 17.2 folds of increase over that of the reactive lymph nodes (P = 0.014). The overexpression of miR-223 was significantly correlated with a longer overall survival (P = 0.011). Multivariate Cox proportional hazard regression analysis identified the following independent poor prognostic factors: low expression of miR-223 (RR = 5.445, 95%CI, 1.555 - 19.068, P = 0.008), abnormal level of LDH (RR = 3.974, 95%CI, 1.191 - 13.266, P = 0.025) and IPI >= 3 (RR = 4.044, 95%CI, 1.233 - 13.264, P = 0.021). CONCLUSIONS: The expression of miR-223 has no relationship with the immunophenotypes of DLBCL. As a potential prognostic biomarker, overexpression of miR-223 correlates with a longer OS of patients with DLBCL. PMID- 22932403 TI - [Detection of chromosomal translocations involving ALK gene in anaplastic large cell lymphoma by fluorescence in-situ hybridization and its clinical significance]. AB - OBJECTIVE: To investigate clinicopathologic features and clinical value of the chromosomal translocation involving anaplastic lymphoma kinase (ALK) in anaplastic large cell lymphoma (ALCL) by fluorescence in situ hybridization (FISH). METHODS: A total of 55 cases, including 45 cases of ALCL and 10 reactive lymphoid hyperplasia, were collected during 1999 to 2006 in the Department of Pathology, Fudan University Shanghai Cancer Center, and Xinhua Hospital Affiliated to Shanghai Jiaotong University. All cases were studied by FISH using dual color break apart probes of ALK for detection of chromosomal translocation, compared with the previous results of immunohistochemistry (IHC) and reverse transcriptase polymerase chain reaction (RT-PCR) for the detection of ALK aberrations. RESULTS: The result of FISH showed that the clear red and green fluorescence signals were detected in 38 cases of ALCL, in which conspicuous split signals were observed in tumor cells in 24 cases (63.2%), suggesting the rearrangement of the ALK locus, with multiple copies of ALK gene in one case. In addition, the rearrangement of the ALK locus was not identified in 14 of 38 cases (36.8%); and the FISH results were unable to be evaluated in 7 cases, because no fluorescent signals involving ALK gene were found or signals were too weak to be analyzed. The concordance for the detection ALK aberrations in ALCL between FISH and RT-PCR, FISH and IHC were both statistically significant (P < 0.01). Chromosomal translocation involving ALK gene was not found in all 10 cases of reactive lymphoid hyperplasia. CONCLUSIONS: ALCL is an entity of lymphoma characterized by special clinical presentation, morphology, and ALK aberrations. FISH is helpful for detection of the chromosomal translocations involving ALK in ALCL, however, the detection efficiency by FISH may be affected by storage time of the paraffin-embedded tissue; and therefore combined detection with IHC and RT PCR could complement each other and help for differential diagnosis of ALK(+)ALCL from ALK(-)ALCL. PMID- 22932404 TI - [Clinicopathologic study of 40 cases of mediastinal tumours of haematopoietic and lymphoid tissues]. AB - OBJECTIVE: To study clinical and histopathological features, and diagnosis of mediastinal tumours of haematopoietic and lymphoid tissues (MTHL). METHODS: Forty cases of MTHL were analyzed for clinicopathology by microscopy and immunohistochemical staining and in situ hybridization, according to the updated 2008 WHO classification of tumours of haematopoietic and lymphoid tissues. RESULTS: In 40 cases of MTHL, there were 20 males and 20 females. The ratio of male/female was 1:1. The mean age was 31.8 years and median age was 29 years (range, 12 - 70 years).Superior vena cava syndrome was observed in 28 cases. The specimens of 4 cases were obtained by lumpectomy, whereas 36 cases by biopsy (25 cases by thoracoscopy, 1 by core needle aspiration). Twenty cases lay in anterior mediastinum, and 2 in posterior, 1 in superior, 8 in anterior and superior, 2 in posterior and superior, 2 in anterior and middle, 1 in middle and anterior mediastinum.Frozen section were performed in 28 cases, and 17 cases were diagnosed as tumours of haematopoietic and lymphoid tissues (consistency ratio was 60.7%). Twelve cases were classical Hodgkin lymphomas (cHL) (8 were nodular sclerosis subtype, and 3 were mixed cellarity, 1 was lymphocyte-rich subtype), and 10 were primary mediastinal (thymic) large B cell lymphoma (PMBCL), 10 were precursor lymphocyte neoplasm [8 were T lymphoblastic leukemia/lymphomas (T-LBL), 2 were B-LBL], 1 was MALT lymphoma, 1 was composite lymphoma (PMBCL and cHL), 2 were myeloid sarcomas, 4 were gray zone lymphomas (GZL) (3 had morphology reminiscent of cHL, and 1 of DLBCL, all cases were positive for CD20, PAX5, CD30 and CD15).EBER were detected in 11 cases by in situ hybridization, 2 of which were positive (18.2%), and the 2 positive cases were cHL. CONCLUSIONS: MTHLs occur predominantly in adolescents and young adults, mainly present as superior vena cava syndrome and anterior mediasinal masses. cHL, PMBCL, T-LBL were the most common MTHLs.GZLs mainly occur in young adults, those whose morphology reminiscent of cHL, immunohistochemistry reminiscent of PMBCL, and vice versa. Thoracoscopy, frozen section and a suitable panel of antibodies were practical approaches to MTHL. PMID- 22932405 TI - [Vulvar intraepithelial neoplasia: a clinicopathologic study of twenty cases]. AB - OBJECTIVE: To investigate the clinical, pathological and immunohistochemical features of vulvar intraepithelial neoplasia (VIN). METHODS: According to the 2004 modified terminology of International Society for the Study of Vulvovaginal Diseases (ISSVD), the cases were diagnosed as VIN from patients who had performed vulvar biopsy in Beijing Wuzhou Women's Hospital from February 2009 to December 2011, which were reclassified as usual VIN and differentiated VIN. The clinical and pathological studies were conducted respectively. MaxVision immunohistochemical staining was used to detect the expression of Ki-67, p16 and p53 proteins. RESULTS: There were 20 cases of VIN in 237 patients, and the incidence of VIN was 8.4% in all of contemporary vulvar biopsy. In 17 cases of usual VIN, mean age was 29.6 years, the lesion typically presented with atypical cells involving almost all layers of the epithelium, which was equivalent to the high-grade squamous intraepithelial neoplasia of cervix. Immunohistochemistry for Ki-67 and p16 was strongly positive in usual VIN. High risk human papillomavirus (HPV) detection was also positive. The incidence of differentiated VIN was less than usual VIN, and there were only 3 cases in this study. In differentiated VIN, patients aged over 50 years, with mean of 53.7 years, and the lesion most commonly presented with lichen sclerosis background. There were epithelial thickening and extending, and parakeratosis, and atypia was strictly confined to the basal and parabasal layers of the epithelium where the cells enlarged with abundant eosinophilic cytoplasm, presented with prominent nucleoli, increased cellularity and abnormal keratinization. In differentiated VIN, p53 was strongly positive, Ki-67 and p16 immunohistochemical expression was confined to the basal layer only. CONCLUSIONS: VIN is a precursor of invasive squamous cell carcinoma of the vulva. The modified terminology of ISSVD classifies VIN as high-grade lesions. Definitive pathological diagnosis of VIN plays an important role in its timely treatment and the prevention of vulvar carcinoma. PMID- 22932406 TI - [Secondary mutation of c-kit/PDGFRalpha genotypes after imatinib mesylate therapy and its relationship with efficacy of sunitinib]. AB - OBJECTIVE: To investigate the relationship between secondary mutations of c kit/PDGFRalpha resistance to imatinib mesylate and the efficacy of sunitinib in patients with gastrointestinal stromal tumor (GIST). METHODS: Five pairs specimens were collected before and after imatinib mesylate resistance. DNA for molecular genetic investigation was extracted from formalin-fixed, paraffin embedded tissues. Mutational analysis was performed by using PCR and direct sequencing. RESULTS: Five pairs of specimens were collected before and after imatinib mesylate resistance from 5 GIST patients. C-kit exon 11 mutations were detected in 3 patients, which were all acquired mutations, including c-kit exon 13 V654A, c-kit exon 13 V654E and c-kit exon 17 N822K, after imatinib mesylate resistance. Furthermore, after sunitinib treatment, 3 patients had stable disease and progression free survival (PFS) were 3.5 months, 4.4 months and 3.8 months, respectively. C-kit exon 9 mutations were detected in 2 patients with no acquired mutations after imatinib mesylate resistance. And the both had partial response from sunitinib, following with 13.1 months and 12.0 months PFS respectively. CONCLUSION: The c-kit/PDGFRalpha genotypes after imatinib mesylate resistance may both relate to primary mutations and efficacy of sunitinib treatment. PMID- 22932407 TI - [Expression of PI3K pathway proteins in refractory epilepsy associated with cortical malformation development]. AB - OBJECTIVE: To investigate the expression of TSC1, TSC2, p-mTOR, p-4E-BP1, p p70S6K and p-S6 in refractory epilepsy associated malformation of cortical development (MCD) tissues. METHODS: A total of 43 cases of refractory epilepsy were involved in the study, and all the patients were treated in Xuanwu Hospital during 2005 - 2008, including focal cortical dysplasia type IIa (11 cases) and type IIb (11 cases), tuberous sclerosis complex (10 cases) and ganalioglioma (11 cases), and other 12 cases were used as control. These cases were divided into 7 study groups and immunohistochemical EnVision method was used. To detect the location and intensity of TSC1, TSC2, p-mTOR, p-4E-BP1, p-p70S6K and p-S6 expression in every group. Then the Image-Pro Plus 6.0 image processing and analysis software were used to measure the number, area, integrating absorbance (IA) of positive cells in every samples. The statistical software SPSS 16.0 was used to analyze the data. RESULTS: The immunolocalization of TSC1 and TSC2 was similar. It could be observed the expression of various levels in the cytoplasm of dysmorphic neurons, balloon cells, giant cells, ganglioglioma cells and normal neurons. TSC1 staining in normal neurons was more notably than others but TSC2 staining in giant cells was weaker than other samples. p-mTOR mainly presented in giant cells, which could also be observed in astrocyte. P-4E-BP1 presented in the cytoplasm and nuclear membrane of balloon cells, giant cells and ganglioglioma cells, the staining of giant cells was stronger than balloon cells, but their staining were weaker than ganglioglioma cells. P-p70S6K mainly expressed in giant cells and less commonly presented in balloon cells. P-S6 typically presented in all abnormal glioneuronal cells and it nearly did not present in the normal neurons of N-CTX group. CONCLUSIONS: PI3K pathway, at least in part, involves in the occurrence of MCD, and may play an important role in the pathogenesis. PMID- 22932408 TI - [Down-regulation of histone deacetylase 2 induces cell apoptosis and inhibits cell proliferation and migration of laryngeal squamous cell carcinoma cells]. AB - OBJECTIVE: To investigate the effects of histone deacetylase 2 (HDAC2) expression on cell proliferation, apoptosis and migration of laryngeal squamous cell carcinoma (LSCC) Hep-2 cells. METHODS: HDAC2 siRNA and control siRNA were transfected into LSCC Hep-2 cells by lipofectamine 2000, and cells were divided into three experimental groups: untreated group, control siRNA group and HDAC2 siRNA transfection group. Western blotting was utilized to detect the expression of HDAC2 protein in Hep-2 cells. Cell proliferation and apoptosis were investigated by CCK-8 kit and flow cytometry, respectively. Boyden chamber was used to study cell migration. Expressions of cell apoptosis and cell migration related proteins were detected by Western blotting. RESULTS: HDAC2 siRNA significantly down-regulated the expression of HDAC2 protein in LSCC Hep-2 cells. Down-regulation of HDAC2 expression coincided with an inhibition of cell proliferation and migration along with an induced cell apoptosis of Hep-2 cells. Moreover, down-regulation of HDAC2 expression significantly increased the expressions of caspase-3 and caspase-9 proteins but decreased the expressions of matrix metalloproteinases (MMP)-2 and MMP-9 proteins. CONCLUSIONS: HDAC2 may play a pivotal role in the initiation and development of LSCC. Down-regulation of HDAC2 expression mediates cell apoptosis. Cell migration inhibition may be tightly associated with overexpression of caspase-3 and caspase-9 along with down regulation of MMP-2 and MMP-9 expressions. PMID- 22932409 TI - [Comparative analysis of cytopathologic and histopathologic diagnosis in the transbronchial needle aspiration specimens]. AB - OBJECTIVE: To study the cytopathologic features of transbronchial needle aspiration (TBNA) samples and to evaluate the role of cytopathology in the diagnosis and staging of lung carcinomas, as compared to histopathology. METHODS: Three hundred seventy-four cytology specimens were collected by TBNA using 21 gauge needle, including 65 lung masses and 309 lymph nodes. Direct smears and liquid-based thin-layer preparations were performed for each case. The correlation between cytology and histopathologic diagnoses were analyzed. RESULTS: The sensitivity, specificity, false positive rate, false negative rate and accuracy of cytopathology in diagnosing lung carcinomas by TBNA was 95.7% (88/92) (266/278), 100% (96/96), 0 (0/96), 4.3% (12/278) and 96.8% (362/374), respectively. Overall 62.8% (167/266) of the cases were precisely typed, including 95.7% (88/92) of small cell carcinoma, 73.5% (25/34) of squamous cell carcinoma and 67.9% (53/78) of adenocarcinoma. There was no statistical difference in the diagnostic accuracy of cytopathology between lung mass aspiration and mediastinal lymph node aspiration, as well as between subcarinal lymph node aspiration and other lymph node aspiration (all P > 0.05). There was also no statistical difference in the diagnostic accuracy between direct smears and liquid-based preparations (chi(2) = 0.11, P > 0.05). CONCLUSIONS: Cytopathology of TBNA specimens is accurate and sensitive for diagnosing pulmonary carcinomas. In most cases, the lung carcinoma can be precisely typed. TBNA is useful for diagnosing and staging lung carcinomas. PMID- 22932410 TI - [Expression of ProEXC, p16 and Ki-67 in cervical intraepithelial lesion by immunohistochemistry: diagnostic and clinical significance]. PMID- 22932411 TI - [Human immunodeficiency virus/acquired immunodeficiency syndrome-related Burkitt's lymphoma: report of two cases]. PMID- 22932412 TI - [Extranodal follicular dendritic cell sarcoma of neck region: report of a case]. PMID- 22932413 TI - [Inflammatory myofibroblastic tumor of uterus: report of a case]. PMID- 22932414 TI - [Nasal chondromesenchymal hamartoma with aneuryanal bone cyst in infancy: report of a case]. PMID- 22932415 TI - [Highly cellular leiomyoma of uterus with diffuse plexiform pattern resembling sex-cord tumor: report of a case]. PMID- 22932416 TI - [Opinions on morphologic standard of lymphoma diagnosis]. PMID- 22932418 TI - [Mitochondrial cytochrome C oxidase and tumorigenesis]. PMID- 22932417 TI - [Human immunodeficiency virus/acquired immunodeficiency syndrome-related lymphoma]. PMID- 22932419 TI - Continuous time Boolean modeling for biological signaling: application of Gillespie algorithm. AB - Mathematical modeling is used as a Systems Biology tool to answer biological questions, and more precisely, to validate a network that describes biological observations and predict the effect of perturbations. This article presents an algorithm for modeling biological networks in a discrete framework with continuous time. BACKGROUND: There exist two major types of mathematical modeling approaches: (1) quantitative modeling, representing various chemical species concentrations by real numbers, mainly based on differential equations and chemical kinetics formalism; (2) and qualitative modeling, representing chemical species concentrations or activities by a finite set of discrete values. Both approaches answer particular (and often different) biological questions. Qualitative modeling approach permits a simple and less detailed description of the biological systems, efficiently describes stable state identification but remains inconvenient in describing the transient kinetics leading to these states. In this context, time is represented by discrete steps. Quantitative modeling, on the other hand, can describe more accurately the dynamical behavior of biological processes as it follows the evolution of concentration or activities of chemical species as a function of time, but requires an important amount of information on the parameters difficult to find in the literature. RESULTS: Here, we propose a modeling framework based on a qualitative approach that is intrinsically continuous in time. The algorithm presented in this article fills the gap between qualitative and quantitative modeling. It is based on continuous time Markov process applied on a Boolean state space. In order to describe the temporal evolution of the biological process we wish to model, we explicitly specify the transition rates for each node. For that purpose, we built a language that can be seen as a generalization of Boolean equations. Mathematically, this approach can be translated in a set of ordinary differential equations on probability distributions. We developed a C++ software, MaBoSS, that is able to simulate such a system by applying Kinetic Monte-Carlo (or Gillespie algorithm) on the Boolean state space. This software, parallelized and optimized, computes the temporal evolution of probability distributions and estimates stationary distributions. CONCLUSIONS: Applications of the Boolean Kinetic Monte Carlo are demonstrated for three qualitative models: a toy model, a published model of p53/Mdm2 interaction and a published model of the mammalian cell cycle. Our approach allows to describe kinetic phenomena which were difficult to handle in the original models. In particular, transient effects are represented by time dependent probability distributions, interpretable in terms of cell populations. PMID- 22932420 TI - Applied and implied semantics in crystallographic publishing. AB - BACKGROUND: Crystallography is a data-rich, software-intensive scientific discipline with a community that has undertaken direct responsibility for publishing its own scientific journals. That community has worked actively to develop information exchange standards allowing readers of structure reports to access directly, and interact with, the scientific content of the articles. RESULTS: Structure reports submitted to some journals of the International Union of Crystallography (IUCr) can be automatically validated and published through an efficient and cost-effective workflow. Readers can view and interact with the structures in three-dimensional visualization applications, and can access the experimental data should they wish to perform their own independent structure solution and refinement. The journals also layer on top of this facility a number of automated annotations and interpretations to add further scientific value. CONCLUSIONS: The benefits of semantically rich information exchange standards have revolutionised the scholarly publishing process for crystallography, and establish a model relevant to many other physical science disciplines. PMID- 22932421 TI - Thirty novel microsatellite markers for the coastal pelagic fish, Scomber japonicus (Scombridae). PMID- 22932422 TI - New St-chromosome-specific molecular markers for identifying wheat--Thinopyrum intermedium derivative lines. PMID- 22932423 TI - Isolation and characterization of fifteen polymorphic microsatellite loci for the citrus mealybug, Planococcus citri (Hemiptera: Pseudococcidae), and cross amplification in two other mealybug species. PMID- 22932424 TI - Isolation and characterization of polymorphic microsatellites for silver pomfret. PMID- 22932425 TI - Isolation and characterization of novel microsatellite loci for Asian sea bass, Lates calcarifer from genome sequence survey database. PMID- 22932426 TI - Extremely high major histocompatibility complex class IIb gene intron 2 variation and population structure in Chinese alligator. PMID- 22932427 TI - Cochlear implantation in a patient with severe cochlear hypoplasia. AB - OBJECTIVE: We report the case of a successful cochlear implantation in a patient with severe cochlear hypoplasia. CASE REPORT: The outcome of cochlear implantation is generally less favourable for patients with cochlear hypoplasia than for those with a normal cochlear structure. In the reported patient, part of the electrode array was inserted into the internal auditory canal. Nevertheless, the benefits following cochlear implantation seemed to outweigh the risks for this patient. CONCLUSION: Cochlear hypoplasia is not necessarily a contraindication for cochlear implantation. PMID- 22932428 TI - Effects of amphetamine on the human brain opioid system--a positron emission tomography study. AB - Studies in rodents have shown that psychostimulant drugs such as cocaine and amphetamine cause endorphin release in the brain reward system. There is also evidence for the involvement of the opioid system in human psychostimulant dependence. The acute effects of an i.v. psychostimulant drug on the brain opioid system, however, have not yet been investigated in humans. We hypothesized that an i.v. dose of amphetamine as compared to placebo would cause an opioid release in the human brain reward system, measurable as a reduction of the binding potential of the MU-opioid receptor radioligand [(11)C]carfentanil. Ten healthy young men were examined using positron emission tomography (PET) and [(11)C]carfentanil in three sessions: at baseline; after placebo; after an i.v. amphetamine dose of 0.3 mg/kg bodyweight. The order of amphetamine and placebo was double-blinded and randomized. PET examinations were performed with a Siemens high resolution research tomograph. Data were analysed with the simplified reference tissue model, applying manually drawn regions of interest for every subject. Using repeated measures analysis of variance, we found no significant differences in [(11)C]carfentanil binding potential between amphetamine and placebo conditions in any of the investigated brain regions. In contrast to data from rodent studies and a recent study of oral amphetamine administration in humans, an i.v. dose of amphetamine does not cause any acute opioid release in healthy human subjects. The postulated role of the opioid system in mediating the effects of amphetamine needs to be further investigated in animal models of the disease as well as in patient populations. PMID- 22932430 TI - Self-critical perfectionism and its relationship to fatigue and pain in the daily flow of life in patients with chronic fatigue syndrome. AB - BACKGROUND: Research suggests that the personality factor of self-critical or maladaptive perfectionism may be implicated in chronic fatigue syndrome (CFS). However, it is not clear whether self-critical perfectionism (SCP) also predicts daily symptoms in CFS. Method In the present study we investigated whether SCP predicted fatigue and pain over a 14-day period in a sample of 90 CFS patients using a diary method approach. After completing the Depressive Experiences Questionnaire (DEQ) as a measure of SCP, patients were asked each day for 14 days to complete Visual Analogue Scales (VAS) of fatigue, pain and severity of depression. Data were analysed using multilevel analysis. RESULTS: The results from unconditional models revealed considerable fluctuations in fatigue over the 14 days, suggesting strong temporal variability in fatigue. By contrast, pain was relatively stable over time but showed significant inter-individual differences. Congruent with expectations, fixed-effect models showed that SCP was prospectively associated with higher daily fatigue and pain levels over the 14 day period, even after controlling for levels of depression. CONCLUSIONS: This is the first study to show that SCP predicts both fatigue and pain symptoms in CFS in the daily course of life. Hence, therapeutic interventions aimed at targeting SCP should be considered in the treatment of CFS patients with such features. PMID- 22932431 TI - Acanthamoeba polyphaga mimivirus virophage seroconversion in travelers returning from Laos. AB - During January 2010, a husband and wife returned from Laos to France with probable parasitic disease. Increased antibodies against an Acanthamoeba polyphaga mimivirus virophage indicated seroconversion. While in Laos, they had eaten raw fish, a potential source of the virophage. This virophage, associated with giant viruses suspected to cause pneumonia, could be an emerging pathogen. PMID- 22932429 TI - Dependence of exhaled breath composition on exogenous factors, smoking habits and exposure to air pollutants. AB - Non-invasive disease monitoring on the basis of volatile breath markers is a very attractive but challenging task. Several hundreds of compounds have been detected in exhaled air using modern analytical techniques (e.g. proton-transfer reaction mass spectrometry, gas chromatography-mass spectrometry) and have even been linked to various diseases. However,the biochemical background for most of compounds detected in breath samples has not been elucidated; therefore, the obtained results should be interpreted with care to avoid false correlations. The major aim of this study was to assess the effects of smoking on the composition of exhaled breath. Additionally, the potential origin of breath volatile organic compounds (VOCs) is discussed focusing on diet, environmental exposure and biological pathways based on other's studies. Profiles of VOCs detected in exhaled breath and inspired air samples of 115 subjects with addition of urine headspace derived from 50 volunteers are presented. Samples were analyzed with GC MS after preconcentration on multibed sorption tubes in case of breath samples and solid phase micro-extraction (SPME) in the case of urine samples. Altogether 266 compounds were found in exhaled breath of at least 10% of the volunteers. From these, 162 compounds were identified by spectral library match and retention time (based on reference standards). It is shown that the composition of exhaled breath is considerably influenced by exposure to pollution and indoor-air contaminants and particularly by smoking. More than 80 organic compounds were found to be significantly related to smoking, the largest group comprising unsaturated hydrocarbons (29 dienes, 27 alkenes and 3 alkynes). On the basis of the presented results, we suggest that for the future understanding of breath data it will be necessary to carefully investigate the potential biological origin of volatiles, e.g., by means of analysis of tissues, isolated cell lines or other body fluids. In particular, VOCs linked to smoking habit or being the results of human exposure should be considered with care for clinical diagnosis since small changes in their concentration profiles(typically in the ppt(v) ppb(v) range) revealing that the outbreak of certain disease might be hampered by already high background. PMID- 22932432 TI - Human papillomavirus. PMID- 22932433 TI - Perspective: Vaccinate boys too. PMID- 22932434 TI - Public health: Prevention comes of age. PMID- 22932435 TI - Pathology: Three questions. PMID- 22932436 TI - Q&A: On the case. Interview by Michelle Grayson. PMID- 22932437 TI - HPV: The global burden. PMID- 22932438 TI - Clinical approval: Trials of an anticancer jab. PMID- 22932439 TI - Vaccination: A durable design. PMID- 22932440 TI - Screening: Testing times. PMID- 22932442 TI - Down syndrome with partial trisomy of chromosome 21 because of a de-novo unbalanced translocation t(13;21)(q10;q22). PMID- 22932441 TI - Characterization of antibody variants during process development: the tale of incomplete processing of N-terminal secretion peptide. AB - Monoclonal antibodies (mAbs) have emerged as one of the most important classes of biotherapeutics, although development of these molecules is long and arduous. A production cell line must be established, and growth conditions for the cells and purification processes for the product must be optimized. Integration of the appropriate analytical strategies in these activities is the cornerstone of Quality by Design and in-process control approaches are encouraged by the Food and Drug Administration. We report here the development of a reversed phase-high performance liquid chromatography (RP-HPLC) method to follow the presence of a mAb product-related variant observed during the purification process development. The variant eluted as a later peak on RP-HPLC, compared with the mAb control (3.25 min and 2.85 min, respectively). We isolated this hydrophobic variant and further analyzed it by mass spectrometry. We identified the variant as a mAb with an incompletely processed leader sequence attached to the N-terminus of one of the two heavy chains. PMID- 22932443 TI - Omphalocele in a patient with Noonan syndrome. PMID- 22932444 TI - A case of multiple congenital anomalies including unusual ear nodules and finger contractures: a new genetic syndrome? PMID- 22932445 TI - Prevalence of oral human papillomavirus infection among youth, Sweden. AB - Human papillomavirus (HPV) causes cervical, head, and neck cancers. We studied 483 patients at a youth clinic in Stockholm, Sweden, and found oral HPV prevalence was 9.3% and significantly higher for female youth with than without cervical HPV infection (p = 0.043). Most oral HPV types matched the co-occurring cervical types. PMID- 22932446 TI - Kurarinone promotes TRAIL-induced apoptosis by inhibiting NF-kappaB-dependent cFLIP expression in HeLa cells. AB - This study was designed to investigate the effects of the prenylated flavonoid kurarinone on TNF-related apoptosis inducing ligand (TRAIL)-induced apoptosis and its underlying mechanism. A low dose of kurarinone had no significant effect on apoptosis, but this compound markedly promoted tumor cell death through elevation of Bid cleavage, cytochrome c release release and caspase activation in HeLa cells treated with TRAIL. Caspase inhibitors inhibited kurarinone-mediated cell death, which indicates that the cytotoxic effect of this compound is mediated by caspase-dependent apoptosis. The cytotoxic effect of kurarinone was not associated with expression levels of Bcl-2 and IAP family proteins, such as Bcl 2, Bcl-xL, Bid, Bad, Bax, XIAP, cIAP-1 and cIAP-2. In addition, this compound did not regulate the death-inducing receptors DR4 and DR5. On the other hand, kurarinone significantly inhibited TRAIL-induced IKK activation, IkappaB degradation and nuclear translocation of NF-kappaB, as well as effectively suppressed cellular FLICE-inhibitory protein long form (cFLIPL) expression. The synergistic effects of kurarinone on TRAIL-induced apoptosis were mimicked when kurarinone was replaced by the NF-kappaB inhibitor withaferin A or following siRNA-mediated knockdown of cFLIPL. Moreover, cFLIP overexpression effectively antagonized kurarinone-mediated TRAIL sensitization. These data suggest that kurarinone sensitizes TRAIL-induced tumor cell apoptosis via suppression of NF kappaB-dependent cFLIP expression, indicating that this compound can be used as an anti-tumor agent in combination with TRAIL. PMID- 22932447 TI - The evaluation of AZ66, an optimized sigma receptor antagonist, against methamphetamine-induced dopaminergic neurotoxicity and memory impairment in mice. AB - Sigma (sigma) receptors have recently been identified as potential targets for the development of novel therapeutics aimed at mitigating the effects of methamphetamine. Particularly, sigma receptors are believed to mitigate some of the neurotoxic effects of methamphetamine through modulation of dopamine, dopamine transporters and body temperature. Furthermore, recent evidence suggests that targeting sigma receptors may prevent cognitive impairments produced by methamphetamine. In the present study, an optimized sigma receptor antagonist, AZ66, was evaluated against methamphetamine-induced neurotoxicity and cognitive dysfunction. AZ66 was found to be highly selective for sigma receptors compared to 64 other sites tested. Pretreatment of male, Swiss Webster mice with i.p. dosing of AZ66 significantly attenuated methamphetamine-induced striatal dopamine depletions, striatal dopamine transporter reductions and hyperthermia. Additionally, neurotoxic dosing with methamphetamine caused significant memory impairment in the object recognition test, which was attenuated when animals were pretreated with AZ66; similar trends were observed in the step-through passive avoidance test. Taken together, these results suggest that targeting sigma receptors may provide neuroprotection against the neurotoxicity and cognitive impairments produced by methamphetamine. PMID- 22932448 TI - Novel germline CDK4 mutations in patients with head and neck cancer. AB - BACKGROUND: Cyclin-dependent kinase 4 (CDK4) together with its regulatory subunit cyclin D1, governs cell cycle progression through G1 phase. Cyclin-dependent kinase inhibitors, including p16INK4A in turn regulate CDK4. In particular, deregulation of the p16/CDK4/cyclin D1 complex has been established in a variety of human tumors including gliomas, sarcomas, melanoma, breast and colorectal cancer. However, changes in CDK4 have rarely been observed. METHOD: In this study we used a combination of PCR-SSCP and direct sequencing for mutational screening of CDK4. DNA was isolated from peripheral blood leukocyte of patients with squamous cell carcinoma of head and neck, for screening germline mutations in coding regions of CDK4. RESULTS: Variations observed in exon 2 and 5 were three missense mutations, g5051G > C (Ser52Thr), g5095G > C (Glu67Gln), g5906C > A, g5907C > G (Pro194Ser) and novel frame shift mutations g7321_23delTGA, g7121_7122insG, g7143delG in exon 7 and 3'UTR respectively. CONCLUSION: In conclusion, two novel mutations were found in N terminal domain which indicates that CDK4 mutation may play a major role in the development and progression of squamous cell carcinoma of head and neck. PMID- 22932449 TI - A Congolese community-based health program for survivors of sexual violence. AB - Many survivors of gender based violence (GBV) in the Democratic Republic of Congo (DRC) report barriers to access health services including, distance, cost, lack of trained providers and fear of stigma. In 2004, Foundation RamaLevina (FORAL), a Congolese health and social non-governmental organization, started a mobile health program for vulnerable women and men to address the barriers to access identified by GBV survivors and their families in rural South Kivu province, Eastern DRC. FORAL conducted a case study of the implementation of this program between July 2010-June 2011 in 6 rural villages. The case study engaged FORAL staff, partner health care providers, community leaders and survivors in developing and implementing a revised strategy with the goal of improving and sustaining health services. The case study focused on: (1) Expansion of mobile clinic services and visit schedule; (2) Clinical monitoring and evaluation system; and (3) Recognition, documentation and brief psychosocial support for symptoms suggestive of anxiety, depression and PTSD. During this period, FORAL treated 772 women of which 85% reported being survivors of sexual violence. Almost half of the women (45%) reported never receiving health services after the last sexual assault. The majority of survivors reported symptoms consistent with STI. Male partner adherence to STI treatment was low (41%). The case study demonstrated areas of strengths in FORAL's program, including improved access to health care by survivors and their male partner, enhanced quality of health education and facilitated regular monitoring, follow-up care and referrals. In addition, three critical areas were identified by FORAL that needed further development: provision of health services to young, unmarried women in a way that reduces possibility of future stigma, engaging male partners in health education and clinical care and strengthening linkages for referral of survivors and their partners to psychosocial support and mental health services. FORAL's model of offering health education to all community members, partnering with local providers to leverage resources and their principal of avoiding labeling the clinic as one for survivors will help women and their families in the DRC and other conflict settings to comfortably and safely access needed health care services. PMID- 22932450 TI - Looking ahead: attending to anticipatory locations increases perception of control. AB - When people manipulate a moving object, such as writing with a pen or driving a car, they experience their actions as intimately related to the object's motion, that is they perceive control. Here, we tested the hypothesis that observers would feel more control over a moving object if an unrelated task drew attention to a location to which the object subsequently moved. Participants steered an object within a narrow path and discriminated the color of a flash that appeared briefly close to the object. Across two experiments, participants provided higher ratings of perceived control when an object moved over a flash's location than when an object moved away from a flash's location. This result suggests that we use the location of spatial attention to determine the perception of control. If an object goes where we are attending, we feel like we made it go there. PMID- 22932451 TI - [Morphologic changes of fallopian tubal epithelium in ovarian serous tumors]. AB - OBJECTIVES: To study the morphologic changes of fallopian tubal epithelium in patients with ovarian serous epithelial tumors and to explore the relationship between the tubal epithelial changes and tumorigenesis of serous ovarian carcinoma. METHODS: The fallopian tubes in 79 cases of high-grade serous ovarian carcinoma, 12 cases of low-grade serous ovarian carcinoma, 16 cases of serous borderline ovarian tumor and 11 cases of non-ovarian benign tumors were serially examined under light microscope. Immunohistochemical study with EnVision method was used to detect the expression of p53 and bcl-2 protein in the fallopian tubal epithelium in all cases. The occurrences of secretory cell outgrowth (SCOUT), p53 signature, serous tubal intraepithelial carcinoma (STIC) and serous invasive carcinoma were analyzed. RESULTS: SCOUT in tubal epithelium was observed in 60.8% (48/79) of the high-grade serous carcinoma group, 4/12 of the low-grade serous carcinoma group, 3/16 of the serous borderline tumor group and 2/11 of the non ovarian benign tumor group (P = 0.001). P53 signature, STIC and serous invasive carcinoma occurred only in the fallopian tubal epithelium of patients with high grade serous ovarian carcinoma, with the positive rates being 29.1% (23/79), 15.2% (12/79) and 44.3% (35/79), respectively. Of the 23 cases with p53 signature, 17 cases had solitary lesion and 6 cases involved more than two sites. A total of 33 p53 signature positive foci were found, with 22 foci located at fimbria and 11 at ampulla. Bcl-2 expression was demonstrated in 90.9% of those foci (30/33). Of the 12 patients with STIC, 7 cases were solitary and 5 cases involved more than two sites. A total of 18 STIC foci were found, with 16 foci located at fimbria and 2 at ampulla. All of them were positive for bcl-2. CONCLUSIONS: SCOUT is found in fallopian tubal epithelium in patients with serous ovarian epithelial tumors, especially high-grade serious carcinoma. On the other hand, p53 signature, STIC and invasive serous carcinoma of tubal epithelium are observed only in patients with high-grade serous ovarian carcinoma, with a predilection of fimbrial involvement. Correlation exists between SCOUT, p53 signature, STIC and high-grade serous ovarian carcinomas. Bcl-2 and p53 immunostaining is helpful for demonstrating such lesions. PMID- 22932452 TI - [Relationship between TAP gene promoter methylation and cervical lesions with HPV infection in Uyghur women]. AB - OBJECTIVE: To study the relationship between TAP (transporter associated with antigen processing) gene promoter regional methylation level and cervical lesions with HPV infection in Uyghur women. METHODS: A specialized software was used to design specific primers of CpG island fragments of TAP1 and TAP2 gene promoter for PCR amplification, bisulfitemodified SiHa cancer cell DNA for PCR amplification, cloning and sequencing analysis to obtain the relevant information on the gene base sequence methylation of CpG sites. Seventy-eight fresh cervical tissue samples from Uyghur women with cervicitis (number = 15), cervical intraepithelial neoplasia (CIN, number = 30) and cervical squamous cell carcinoma (number = 33) were collected. The methylation level of TAP1 and TAP2 gene promoter regions was detected using MassArray DNA technology. HPV infection status was determined by HPV gene chips. The relationship between CpG-island methylation of gene promoter regions and HPV infection was then analyzed. RESULTS: Each TAP1 and TAP2 gene corresponding target fragment contained 23 and 8 CpG sites. There were 5 and 8 CpG sites methylation occurred in SiHa cervical cancer cells genomic DNA respectively. The TAP1 methylation level increased steadily with the severity of cervical lesions. The methylation levels in cervical squamous cell carcinoma and CIN (0.048 +/- 0.039 and 0.037 +/- 0.026, respectively) were higher than that of normal cervical tissue (0.035 +/- 0.029, P < 0.05). Although TAP2 gene methylation level also demonstrated similar changes, the difference however was not statistically significant (P > 0.05). HPV gene chip detected 13 HPV genotypes, with HPV16 infection rate being 66.7% (52/78). The methylated proportion of TAP1 positively correlated with HPV16 infection (chi(2) = 6.08, P = 0.039). CONCLUSION: TAP1 methylation is a remarkable phenomenon occurring in a range of cervical lesions and significantly associated with cervical HPV infection. PMID- 22932453 TI - [Perivascular epithelioid cell tumor of urinary system: a clinicopathologic analysis of 21 cases]. AB - OBJECTIVE: To study the clinicopathologic features and differential diagnosis of perivascular epithelioid cell tumors (PEComas) occurring in the urinary system. METHODS: The clinicopathologic features of 21 cases of PEComa from September 2002 to September 2010 occurring in the urinary system were retrospectively reviewed. Immunohistochemical study for HMB 45, S-100 protein, smooth muscle actin, desmin, Melan A and Ki-67 was carried out. RESULTS: Amongst the 21 cases studied, there were 5 males and 16 females. The age of patients ranged from 16 to 76 years (median = 51.3 years). Twenty cases occurred in the kidney and 1 in the bladder. The predominant histopathologic subtype of renal PEComas was classic type (10/20), followed by epithelioid type (5/20), smooth muscle type (3/20), inflammatory type (1/20) and sclerosing type (1/20). Immunohistochemical study showed that HMB 45 and smooth muscle actin were positive in 95.2% (20/21) and 80.9% (17/21) cases, respectively. Melan A, desmin and S-100 protein were expressed in 71.4% (15/21), 61.9% (13/21) and 33.3% (7/21) cases, respectively. The mean proliferative index was 1.29% (range = 0 to 5%). HMB 45 and Melan A were expressed in all of the 5 cases of epithelioid PEComas, whereas smooth muscle actin and desmin were only expressed in one of them. There was no significant difference between epithelioid PEComas and non-epithelioid PEComas in the expression of HMB 45, Melan A, smooth muscle actin and desmin. Positive staining for HMB 45 and smooth muscle actin was demonstrated in the case of bladder PEComa. CONCLUSIONS: PEComas of the urinary system predominantly affect the kidney. Epithelioid renal PEComas and bladder PEComa are relatively rare and have unique pathologic features. It is necessary to distinguish PEComas from other malignant tumors. Immunohistochemical study for HMB 45, Melan A and smooth muscle actin is helpful for confirmation of diagnosis. PMID- 22932454 TI - [Neuroendocrine neoplasm of digestive system with different grades: a clinicopathologic and prognostic study]. AB - OBJECTIVE: To study the clinicopathologic and prognostic features of neuroendocrine neoplasm of digestive system with different grades. METHODS: The clinicopathologic features of 139 cases of neuroendocrine neoplasm occurring in digestive system were retrospectively reviewed and graded according to the 2010 World Health Organization classification of tumours of the digestive system. Immunohistochemical study for synaptophysin, chromogranin A and Ki-67 was carried out. The follow-up and survival data were analysed using Kaplan-Meier method. Prognostic factors were tested by Log-rank testing and independent risk factors were analysed using Cox regression model. RESULTS: Amongst the 139 cases studied, there were 88 cases (63.3%) of grade 1 tumors, 9 cases (6.5%) of grade 2 tumors and 42 cases (30.2%) of grade 3 tumors. There was diffusely positive staining for synaptophysin and chromogranin A in most of the grade 1 and grade 2 tumors. The staining in grade 3 tumors however was focal (P < 0.05). The differences in tumor size, depth of invasion, presence of tumor emboli, perineural permeation, nodal involvement, distant metastasis and survival rate amongst the three groups was statistically significant (P < 0.05). CONCLUSIONS: There is significant difference in the clinicopathologic and prognostic features of neuroendocrine neoplasm of digestive system with different grades. It is considered as an independent prognostic factor and represents a useful tool for prognostic evaluation of such tumors, both in clinical practice and research. PMID- 22932455 TI - [Neonatal intrahepatic cholestasis caused by citrin deficiency: a histopathologic study of 10 cases]. AB - OBJECTIVE: To investigate the diagnostic value of histopathological changes in the liver of patients with neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD). METHODS: Liver specimens from 10 cases of NICCD were evaluated by hematoxylin-eosin stain, histochemistry and immunohistochemistry (EnVision method). SLC25A13 mutation analysis was performed to correlate with histopathology. RESULTS: Most specimens showed varying degrees of fat deposition in hepatocytes, necrotic inflammation, cholestasis and fibrosis (so-called tetralogy). The combination of the above four histological changes was highly characteristic for NICCD. With the progression of the disease, hepatic fibrosis deteriorated and ultimately led to cirrhosis. CONCLUSIONS: NICCD should be suspected in the presence of cholestasis during infancy. A liver biopsy must be performed to rule out other liver diseases. The tetralogy of the hepatic histopathological changes has a highly diagnostic value for NICCD, which is also practical for accurately assessing the degree of inflammation and fibrosis, and similarly the progression of hepatic cirrhosis. PMID- 22932456 TI - [Myxoid dermatofibrosarcoma protuberans: a clinicopathologic analysis of 16 cases]. AB - OBJECTIVE: To study the clinicopathologic features and differential diagnosis of myxoid dermafibrosarcoma protuberans (DFSP). METHODS: The clinical and pathologic features of 16 cases of myxoid DFSP were reviewed. RESULTS: There were altogether 15 males and 1 female. The age of the patients ranged from 11 to 73 years (mean = 47 years and median = 48 years). The commonest site of involvement was trunk (number = 11), followed by shoulder (number = 2), head and neck (number = 2), and extremity (number = 1). Similar to conventional DFSP, most patients presented with a slowly enlarging subcutaneous nodule which showed a rapid recent growth in some cases. Amongst the 16 cases studied, 12 occurred de novo and 4 represented local recurrence. The tumors ranged from 2 to 10 cm in greatest dimension (mean = 5 cm and median = 4 cm). Histologically, they were poorly circumscribed and located in the dermis, with focal infiltration into the underlying subcutaneous tissue. Seven cases were purely myxoid and composed of spindly and stellate cells with delicate arborizing vascular meshwork. The remaining 9 cases were predominantly myxoid (> 50%), with 5 cases containing cellular areas resembling conventional DFSP and 4 cases showing fibrosarcomatous transformation. In addition, foci of giant cell fibroblastoma-like areas were noted in 1 case. Immunohistochemical study showed that the tumors cells were positive for CD34. The staining was weak in the myxoid areas, as compared with conventional DFSP. Of the 4 recurrent cases, one patient developed lung metastases. CONCLUSIONS: Myxoid DFSP represents a rare variant of DFSP and may pose important diagnostic pitfalls. It is especially so if the tumor purely consists of myxoid element. Familiarity with the histologic features helps to avoid misdiagnosis. PMID- 22932457 TI - [Diagnostic value of cytokeratin 19 fragment in nasopharyngeal carcinoma]. AB - OBJECTIVE: To explore the clinical significance of cytokeratin 19 fragments test in the diagnosis of nasopharyngeal carcinoma. METHODS: The study included 102 cases of nasopharyngeal carcinoma, 90 cases of nasal polyp/nasopharyngitis, and 150 healthy individuals. RT-PCR was used to detect CK19 mRNA expression and Western blot to detect CK19 fragment protein expression in tissues of nasopharyngeal carcinoma. Expression of CK19-2G2 was examined by immunohistochemistry. Chemiluminescence analysis was used to detect the serum levels of CK19-2G2, and ELISA to detect that of EB-VCA IgA. RESULTS: Among 102 cases of nasophryngeal carcinoma, 64 showed CK19 mRNA expression by RT-PCR, 60 showed CK19 protein fragments in tumor tissues by Western blot, and 66 showed expression of CK19-2G2 by immunohistochemistry in nasopharyngeal carcinoma, including strong positivity in 20 cases, moderate in 34 cases and weak in 12 cases. The sensitivity and specificity of CK19-2G2 in the diagnosis of nasopharyngeal carcinoma were 49.0% and 89.2%, and those of EB-VCA IgA were 52.9% and 85.4%, respectively. The combined detection of CK19-2G2 and EB-VCA IgA increased the sensitivity to 73.5% while the specificity remained at 80.0%. CONCLUSIONS: High levels of CK19-2G2 fragment expressed in tissue and serum are present in patients with nasopharyngeal carcinoma. The serum level of CK19-2G2 is helpful in the diagnosis of nasopharyngeal carcinoma. Furthermore, the combination of serum CK19-2G2 and EB-VCA IgA improves the detection sensitivity. PMID- 22932458 TI - [Effect of down-regulation of histone deacetylase 2 protein expression on cell proliferation and cell cycle in cervical carcinoma]. AB - OBJECTIVE: To study the effect of down-regulation of histone deacetylase 2 (HDAC2) expression on cell proliferation and cell cycle in cervical carcinoma cell lines HeLa. METHODS: HDAC2 siRNA and control siRNA were transfected to HeLa cells. CCK-8 and flow cytometry were used to analyze the changes of cell proliferation and cell cycle, respectively. Western blot was employed to detect the changes of cell proliferation and cell cycle-related proteins. RESULTS: HDAC2 siRNA significantly down-regulated the expression of HDAC2 protein in HeLa cells, resulting in marked inhibition of cell proliferation. In addition, the percentage of cells in G(0)/G(1) phase in HDAC2 siRNA group (63.3% +/- 2.0%) was significantly higher than that in untreated group (29.3% +/- 1.7%) or control siRNA group (29.4% +/- 1.7%), F = 354.181, P = 0.000. Furthermore, Western blot demonstrated that down-regulation of HDAC2 expression decreased the expression of cyclin D1, cyclin E and CDK2 proteins but increased the expression of p21 protein. CONCLUSIONS: Down-regulation of HDAC2 expression mediates proliferation inhibition and cell cycle arrest. It is associated with decrease in cyclin D1, cyclin E and CDK2 protein expression and increase in p21 protein expression. PMID- 22932459 TI - [Construction of a miR-23a-27a cluster expression plasmid: a preliminary study of its function]. AB - OBJECTIVE: To construct a miR-23a-27a cluster expression plasmid and to explore the target genes and function of the cluster. METHODS: The pre-miR-23a-27a pcDNA3.1, pre-miR-23a and pre-miR-27a plasmids were cloned by molecular biology method, and their expression efficiency was tested by dual luciferase reporter gene assay and real-time PCR. Several possible target genes of miR-23a and miR 27a were chosen using softwares and further tested by dual luciferase reporter gene assay. Finally, the function of miR-27a was analyzed in MCF-7 cell by Western blot and real-time PCR. RESULTS: miR-23a and miR-27a were transcribed from pre-miR-23a-27a-pcDNA3.1, pre-miR-23a and pre-miR-27a plasmids in HEK293T cells, and both influenced the MRE of Sprouty2 gene in pRL-TK vector, and only miR-27a influenced the 3'-untranslated regions (UTR) full length of Sprouty2 gene while miR-27a did not influence the 3'-UTR of Sprouty2 gene with the sited mutation in the MRE. The protein expression level of Sprouty2 gene was altered after transfection of pre-miR-27a-pcDNA3.1 plasmid while the RNA level remained unchanged. CONCLUSION: Sprouty2 may be the functional target gene of miR-27a, and the construction of plasmids in the study may provide a fundamental basis for the further functional investigation of miR-23a and miR-27a. PMID- 22932460 TI - [LiCl suppresses tumor growth and inhibits DNA replication in prostate cancer]. AB - OBJECTIVE: To assess the effects of LiCl on prostate cancer growth and to explore the underlying mechanisms. METHODS: Effects of LiCl on cell growth in vitro and in vivo were determined by cell counting and xenografts of prostate cancer cells. Alterations in cell proliferation and the expression of DNA replication-related protein were determined by MTT assay, BrdU incorporation and Western blot. RESULTS: Compared to PBS control group, the number of prostate cancer cells (PC 3) were lower treated with 10 mmol/L LiCl, the number was 1.9*10(5), 4.8*10(5) and the difference was significant (P < 0.05). The inhibition rate of cellular proliferation were 50%, 95% and 98%, respectively, in LiCl group, NaCl and KCl control group, the difference was significant (P < 0.05). The A-Value of BrdU incorporation was 1.5, 1.3 treated with 10 mmol/L, 30 mmol/L LiCl, while the A value of BrdU incorporation was 4 in PBS control group, the difference was significant (P < 0.05). On the protein level, LiCl downregulates expression of cdc 6, cyclins A and cyclins E, and cdc 25C, and upregulates expression of the CDK inhibitor p21(CIP1). The mean volume and weight of xenograft tumor were 50 mm(3) and 296 mg after LiCl intraperitoneal injection, But PBS control group were 180 mm(3) and 957 mg, the difference was significant (P < 0.05). CONCLUSION: LiCl disrupts DNA replication and suppresses tumor growth of prostate cancer cells in vitro and in vivo. PMID- 22932461 TI - [Expression of cell cycle regulator ATM, Chk2 and p53 and their clinicopathological correlation in breast infiltrative ductal carcinoma]. PMID- 22932462 TI - [Perivascular epithelioid cell tumor (PEComa) of uterus : report of a case]. PMID- 22932463 TI - [Epithelial-myoepithelial carcinoma of parotid: report of a case]. PMID- 22932464 TI - [Juxtaglomerular cell tumor with malignant features: report of a case]. PMID- 22932465 TI - [Chronic arsenic poisoning and idiopathic portal hypertension: report of a case]. PMID- 22932466 TI - [Churg-Strauss syndrome: report of a case]. PMID- 22932467 TI - [New concept in serous adenocarcinoma of fallopian tube]. PMID- 22932468 TI - [Lynch syndrome-related endometrial carcinoma]. PMID- 22932469 TI - [Research advances of research on stromal caveolin-1 and tumor energy metabolism]. PMID- 22932470 TI - Longitudinal course of depressive symptoms in adulthood: linear stochastic differential equation modeling. AB - BACKGROUND: Although many studies have addressed the topic of stability versus change in depressive symptoms, few have further decomposed the change to continuous accumulation versus non-systematic state fluctuations or measurement errors. This further step requires a longitudinal follow-up and an appropriate stochastic model; it would, for example, evaluate the hypothesis that women accumulate more susceptibility events than men. Method A linear stochastic differential equation model was estimated for a 16-year longitudinal course of depressive symptoms in the Young Finns community sample of 3596 participants (1832 women, 1764 men). This model enabled us to decompose the variance in depression symptoms into a stable trait, cumulative effects and state/error fluctuations. RESULTS: Women showed higher mean levels and higher variance of depressive symptoms than men. In men, the stable trait accounted for the majority [61%, 90% confidence interval (CI) 48.9-69.2] of the total variance, followed by cumulative effects (23%, 90% CI 9.9-41.7) and state/error fluctuations (16%, 90% CI 5.6-23.2). In women, the cumulative sources were more important than among men and accounted for 44% (90% CI 23.6-58.9) of the variance, followed by stable individual differences (32%, 90% CI 18.5-54.2) and state fluctuations (24%, 90% CI 19.1-27.3). CONCLUSIONS: The results are consistent with previous observations that women suffer more depression than men, and have more variance in depressive symptoms. We also found that continuously accumulating effects are a significant contributor to between-individual differences in depression, especially for women. Although the accumulating effects are often confounded with non-systematic state fluctuations, the latter are unlikely to exceed 27% of the total variance of depressive symptoms. PMID- 22932471 TI - Hairy polyp of the oropharynx in association with a first branchial arch sinus. AB - OBJECTIVES: Hairy polyps are rare, congenital malformations of the oropharynx and nasopharynx. To date, approximately 145 cases have been reported. However, the histogenesis of these lesions remains unclear. CASE REPORT: We report the case of a 2-day-old neonate presenting with a hairy polyp attached to the left palate, who re-presented aged 16 months with a discharging first branchial arch sinus. CONCLUSION: We propose this case as supporting evidence for the theory that hairy polyps are a malformation of the first branchial arch system. PMID- 22932472 TI - Rapid detection of carbapenemase-producing Enterobacteriaceae. AB - To rapidly identify carbapenemase producers in Enterobacteriaceae, we developed the Carba NP test. The test uses isolated bacterial colonies and is based on in vitro hydrolysis of a carbapenem, imipenem. It was 100% sensitive and specific compared with molecular-based techniques. This rapid (<2 hours), inexpensive technique may be implemented in any laboratory. PMID- 22932473 TI - Memory load affects object individuation in 18-month-old infants. AB - Accurate representation of a changing environment requires individuation-the ability to determine how many numerically distinct objects are present in a scene. Much research has characterized early individuation abilities by identifying which object features infants can use to individuate throughout development. However, despite the fact that without memory featural individuation would be impossible, little is known about how memory constrains object individuation. Here, we investigated infants' ability to individuate multiple objects at once and asked whether individuation performance changes as a function of memory load. In three experiments, 18-month-old infants saw one, two, or three objects hidden and always saw the correct number of objects retrieved. On some trials, one or more of these objects surreptitiously switched identity prior to retrieval. We asked whether infants would use this identity mismatch to individuate and, hence, continue searching for the missing object(s). We found that infants were less likely to individuate objects as memory load grew, but that infants individuated more successfully when the featural contrast between the hidden and retrieved objects increased. These results suggest that remembering more objects may result in a loss of representational precision, thereby decreasing the likelihood of successful individuation. We close by discussing possible links between our results and findings from adult working memory. PMID- 22932474 TI - Immunogenicity and long-term efficacy of botulinum toxin type B in the treatment of cervical dystonia: report of 4 prospective, multicenter trials. AB - OBJECTIVE: Therapeutic botulinum toxins are antigenic proteins with the potential to produce antibodies (Abs). It is, however, unclear whether Abs to Myobloc(r) (rimabotulinumtoxinB, botulinum toxin type B, BoNT-B) impact the efficacy and safety of BoNT-B treatment of cervical dystonia (CD). The objective was to determine if Abs to BoNT-B impact the efficacy or safety of long-term BoNT-B treatment of CD. METHODS: Four separate prospective clinical trials, with a combined total of 1134 subjects evaluable for immunogenicity over total treatment durations of up to 6+ years, were conducted studying the efficacy, safety, and immunogenicity of BoNT-B treatment of CD. Botulinum toxin type B injections were administered approximately every 3 months. Efficacy was assessed using the Toronto Western Spasmodic Torticollis Rating Scale-Total Score, the Subject Global Assessment, or the Treatment Assessment Scale. The presence of Abs to BoNT B was assessed using the mouse neutralizing antibody (MNA) assay. Cross-sectional and longitudinal statistical analyses were performed to compare efficacy by MNA status at each time point and over time in Ab-positive individuals before and after seroconversion. Safety was assessed by summarizing adverse events by Ab status. RESULTS: Long-term efficacy was observed with multiple treatments of BoNT B. Across all 4 studies, there was no correlation between MNA status and rates of clinical response, study withdrawal, or safety profile. CONCLUSIONS: Botulinum toxin type B is effective and safe in the repeat, long-term treatment of CD. The presence of Abs to BoNT-B as detected by the MNA assay does not have any meaningful clinical impact or correlation. PMID- 22932475 TI - Deprive to kill: glutamine closes the gate to anticancer monocarboxylic drugs. AB - Killing properties of antitumor drugs can be enhanced by strategies targeting biochemical adaptations of cancer cells. Recently, we reported that depriving cancer cells of glutamine is a feasible approach to enhance antitumor effects of the alkylating analog of pyruvic acid, 3-bromopyruvate, which rely on the induction of autophagic cell death by metabolic-oxidative stress. 3-bromopyruvate chemopotentiation is the result of its increased intracellular uptake mediated by the monocarboxylate transporter 1, whose expression is post-transcriptionally increased upon glutamine withdrawal. Overall, our results identified the metabolic condition able to increase the selectivity of 3-bromopyruvate targets in neoplastic tissues, thereby providing a stage for its use in clinical settings for targeting malignancies and represent a proof of principle that modulation of glutamine availability can influence the delivery of monocarboxylic drugs into tumors. PMID- 22932476 TI - The nuclear localization of SWI/SNF proteins is subjected to oxygen regulation. AB - BACKGROUND: Hypoxia is associated with many disease conditions in humans, such as cancer, stroke and traumatic injuries. Hypoxia elicits broad molecular and cellular changes in diverse eukaryotes. Our recent studies suggest that one likely mechanism mediating such broad changes is through changes in the cellular localization of important regulatory proteins. Particularly, we have found that over 120 nuclear proteins with important functions ranging from transcriptional regulation to RNA processing exhibit altered cellular locations under hypoxia. In this report, we describe further experiments to identify and evaluate the role of nuclear protein relocalization in mediating hypoxia responses in yeast. RESULTS: To identify regulatory proteins that play a causal role in mediating hypoxia responses, we characterized the time courses of relocalization of hypoxia-altered nuclear proteins in response to hypoxia and reoxygenation. We found that 17 nuclear proteins relocalized in a significantly shorter time period in response to both hypoxia and reoxygenation. Particularly, several components of the SWI/SNF complex were fast responders, and analysis of gene expression data show that many targets of the SWI/SNF proteins are oxygen regulated. Furthermore, confocal fluorescent live cell imaging showed that over 95% of hypoxia-altered SWI/SNF proteins accumulated in the cytosol in hypoxic cells, while over 95% of the proteins were nuclear in normoxic cells, as expected. CONCLUSIONS: SWI/SNF proteins relocalize in response to hypoxia and reoxygenation in a quick manner, and their relocalization likely accounts for, in part or in whole, oxygen regulation of many SWI/SNF target genes. PMID- 22932477 TI - Demographic shift of influenza A(H1N1)pdm09 during and after pandemic, rural India. AB - Population-based active surveillance in India showed higher incidence rates for influenza A(H1N1)pdm09 among children during pandemic versus postpandemic periods (345 vs. 199/1,000 person-years), whereas adults had higher rates during postpandemic versus pandemic periods (131 vs. 69/1,000 person-years). Demographic shifts as pandemics evolve should be considered in public health response planning. PMID- 22932478 TI - Multiple-insecticide resistance in Anopheles gambiae mosquitoes, Southern Cote d'Ivoire. AB - Malaria control depends on mosquito susceptibility to insecticides. We tested Anopheles gambiae mosquitoes from Cote d'Ivoire for resistance and screened a subset for target site mutations. Mosquitoes were resistant to insecticides of all approved classes. Such complete resistance, which includes exceptionally strong phenotypes, presents a major threat to malaria control. PMID- 22932479 TI - [A guideline of non-invasive tooth whitening therapy]. PMID- 22932480 TI - [Effect of bleomycin A5 on the hemangioma-derived endothelial cell line XTPS-1]. AB - OBJECTIVE: To investigate the effect of bleomycin A5 on the hemangioma-derived endothelial cell line XTPS-1. METHODS: Hemangioma-derived endothelial cell line XTPS-1 was cultured with different concentration of bleomycin A5 (1000, 100, 10, 1, 0 mg/L), and then the survival rate was measured by methyl thiazolyl terazolium (MTT), the variation of cell morphology was observed using inverted phase contrast microscope and electron microscope, the variation of cell cycle and apoptosis rate were measured using flow cytometry. RESULTS: After 24 hours culture the cell survival rate was (92.96 +/- 3.66)% and (99.86 +/- 0.12)% in lower saturation group (10 and 1 mg/L), but (34.08 +/- 3.11)% and (43.28 +/- 2.88)% in higher saturation group (1000 and 100 mg/L). The difference between them was more significant (P < 0.01). Lower saturation of bleomycin A5 (10 and 1 mg/L)could induce apoptosis but had almost no cytotoxic effect. Higher saturation of bleomycin A5 (1000 and 100 mg/L) not only induced apoptosis, but also had strong cytotoxic effect, which was concentration dependent. CONCLUSIONS: bleomycin A5 could induce apoptosis, inhibit cell proliferation and has direct cytotoxic effect. PMID- 22932481 TI - [17-beta estradiol promotes the expression of interleukin-6 in human periodontal ligament cells infected with Porphyromonas gingivalis]. AB - OBJECTIVE: To investigate the effects of 17-beta estradiol (E(2)) and Porphyromonas gingivalis (Pg) W83 on the expression of interleukin (IL)-6 and IL 8 in human periodontal ligament cells (hPDLC). METHODS: Primary cultures of hPDLC were established and the cells of passage four were treated with 10(-10) mol/L E(2), 10(-7) mol/L E(2) or PgW83 individually or E(2) combined with PgW83. The expression levels of IL-6 and IL-8 protein at 12 h and 24 h were measured with enzyme-linked immunosorbent assay and the levels of mRNA at 24 h were detected with real-time reverse transcriptase polymerase chain reaction. RESULTS: The expression level of IL-6 reached (2482.88 +/- 26.53) ng/L in hPDLC treated with Pg at multiplicity of infection (MOI) of 100 for 24 h, which was significantly higher than that in hPDLC treated with Pg at MOI of 10:1 [(734.09 +/- 87.90) ng/L, P = 0.000], the controls [(425.8 +/- 77.25) ng/L, P = 0.000] and that in hPDLC treated with Pg at MOI of 100 for 12 h [(1157.50 +/- 234.65) ng/L, P = 0.000]. The expression level of IL-8 reached (4965.81 +/- 1072.55) ng/L in hPDLC treated with Pg at MOI of 100 for 24 h, which was significantly higher than that in hPDLC treated with Pg at MOI of 10 [(803.51 +/- 162.08) ng/L, P = 0.007], the controls [(400.75 +/- 2.27) ng/L, P = 0.005] and that in hPDLC treated with Pg at MOI of 100 for 12 h [(1431.12 +/- 82.78) ng/L, P = 0.001]. E(2) did not show remarkable effect on the expressions of IL-6 and IL-8. E(2) combined with Pg (MOI = 100:1) significantly promoted the expression levels of IL-6 at 24 h while did not influence those of IL-8. The relative mRNA level of IL-6 in hPDLC treated with 10(-10) mol/L E(2) or 10(-7) mol/L E(2) combined with Pg were 0.49 +/- 0.15 (P = 0.021)and 0.53 +/- 0.16 (P = 0.036) individually, which were significantly higher than that treated with Pg alone, 0.19 +/- 0.06. The protein level of IL-6 in hPDLC treated with 10(-10) mol/L E(2) or 10(-7) mol/L E(2) combined with Pg were (5512.66 +/- 1022.07) ng/L (P = 0.012) and (6988.78 +/- 2279.13) ng/L (P = 0.000) individually, which were significantly higher than that treated with Pg alone, (3138.46 +/- 183.72) ng/L. CONCLUSIONS: PgW83 significantly increased the expression levels of IL-6 and IL-8 in hPDLC in a dose-and time-dependent manner. Without the infection of periodontal pathogens, estrogen may exert no effect on the expression of IL-6 and IL-8 while it may promote the expression of IL-6 in hPDLC when combined with Pg, which may in turn promote the process of periodontal inflammation. PMID- 22932482 TI - [Comparative study on oral candidal infection in individuals with diabetes mellitus and impaired glucose regulation]. AB - OBJECTIVE: To investigate the positive rate, infection rate and bearing rate of salivary candida in patients with type 2 diabetes mellitus (DM), individuals with impaired glucose regulation (IGR) and individuals with normal glucose tolerance (NGT) and their predisposing factors. METHODS: Questionnaire was given to 145 patients with DM, 142 individuals with IGR and 149 NGT individuals. Oral examination was carried out, and fasting plasma glucose (FPG) level and plasma glucose level of 2 hours post glucose-load (PG2h), resting salivary flow, salivary pH value were tested. Salivary candida was cultured. RESULTS: In DM, IGR and NGT groups, the positive rates of salivary candida were 21.4% (31/145), 7.0% (10/142), 4.7% (7/149) respectively, the infection rates were 7.6% (11/145), 1.4% (2/142), 1.3% (2/149) respectively, and the bearing rates of salivary candida were 13.8% (20/145), 5.6% (8/142), 3.4% (5/149) respectively. The candida positive rate, candida infection rate in DM group were higher than those of IGR and NGT groups respectively (P < 0.05). There were no significant differences in the candida positive rate, infection rate and bearing rate between IGR and NGT groups (P > 0.05). Resting salivary flow in DM [(1.30 +/- 1.20) ml/10 min] and IGR [(1.40 +/- 1.17) ml/10 min]groups were lower than that in NGT group [(1.93 +/ 1.66) ml/10 min], salivary pH values in DM (7.11 +/- 0.56) and IGR (7.05 +/- 0.48) groups were lower than that in NGT group (7.38 +/- 0.48) (P < 0.05), while FPG value in DM [(7.68 +/- 2.75) mmol/L] and IGR [(5.67 +/- 0.73) mmol/L] groups were respectively higher tham that in NGT group [(4.99 +/- 0.44) mmol/L], P < 0.05. The infection rate of salivary candida was influenced to some degree by age, FPG level and bearing denture (OR value = 1.106, 1.258, 3.166). CONCLUSIONS: The patients with DM were more subjected to bearing or infection of candida than individuals with IGR and NGT. To control the plasma glucose level will help to decrease the positive rate and infection rate of oral candida. PMID- 22932483 TI - [Application of atomic force microscopy in evaluation of three-dimensional morphology of eroded human enamel]. AB - OBJECTIVE: To compare the three dimensional morphology and surface roughness changes of enamel eroded for different etching time. METHODS: Fifteen freshly extracted sound human pre-molars for orthodontic purpose were collected. The buccal surface of teeth were prepared into smooth enamel slices, and then were randomly divided into 5 groups based on their etching time 0 s (control group), 5 s, 10 s, 20 s, 30 s, respectively by 37% phosphoric acid. The three dimensional morphology was observed under atomic force microscope (AFM). The profile was analyzed, and the value of Ra, Rq, Rz and the surface area and volume were measured. RESULTS: The AFM photograph showed that with the etching time from 0 s to 20 s the enamel surface demineralised gradually, the top structure of enamel rod and the fish scaled structure became obvious. But the morphology only changed a bit after 20 s. The surrounding inter-rod enamel eroded first, the depth increased to 2.8 um at 20 s but decreased to 1.8 um at 30 s. The value of Ra increased from (19.69 +/- 3.42) nm to (359.51 +/- 75.79) nm, and Rq from (22.02 +/- 5.57) nm to (431.02 +/- 83.09) nm, Rz from (0.24 +/- 0.08) um to (2.38 +/- 0.26) um. Except for groups 20 s and 30 s, the difference among other groups was statistically significant (P < 0.05). The surface area expanded from (406.77 +/- 3.88) um(2) to (546.69 +/- 84.02) um(2), and surface volume from (65.73 +/- 14.46) um(3) to (474.63 +/- 52.50) um(3). CONCLUSIONS: The depth, surface roughness, surface area and volume caused by erosion increased with etching time. The three dimensional morphology greatly changed by acid-etching process. PMID- 22932484 TI - [Expression of interleukin-17F in human apical periodontitis lesions]. AB - OBJECTIVE: To examine the expression of interleukin-17F (IL-17F) in apical periodontitis lesions. METHODS: Human apical periodontitis lesions were collected after periapical surgery from November 1, 2009 to August 1, 2011. After histological processing, serial sectioning, HE staining, and microscopic analysis, 33 periapical cysts and 18 periapical granulomas were selected for immunohistochemical analysis for IL-17F. Five alveolar bone samples were obtained from a group of impacted third molars recommended for extraction. These bone samples did not show any inflammation and were used as normal samples. Differences in IL-17F expression between the tissues with periapical cyst and periapica granuloma were subsequently analyzed by rank-sum test. RESULTS: IL-17F was expressed in epithelial cells, lymphocytes, fibroblast and endothelial cells of both types of lesions. Both types of lesions presented increased IL-17F expression when compared to healthy periapical alveolar bone. The expression of IL-17F in apical cyst (0.2365 +/- 0.0708) and apical granuloma (0.8852 +/- 0.0576) was significantly different (Z = 3.735, P < 0.01). CONCLUSIONS: IL-17F could be observed and might be involved in the inflammatory response and bone resorption of periapical tissues. The expression of IL-17F in periapical cyst and periapical granuloma was significantly different. PMID- 22932485 TI - [A diagnostic meta-analysis: sentinel lymph node biopsy for neck metastasis in patients with early oral squamous cell carcinoma]. AB - OBJECTIVE: To evaluate the value of sentinel lymph node biopsy in diagnosis of cervical metastasis in patients with early oral squamous cell carcinoma. METHODS: Cochrane library, evidence-based medicine (EBM), PubMed, China national knowledge internet (CNKI) were searched for 2001 - 2011 literatures on sentinel lymph node biopsy in patients with oral squamous cell carcinoma as early diagnosis of cervical metastasis. The results were analysed by using Meta-analysis software Metadisc1.4. RESULTS: There were 12 studies in which, a total of 793 patients with oral squamous cell carcinoma were involved in Meta-analysis. The combined sensitivity and specificity were 0.86 (95%CI: 0.81 - 0.90) and 0.99 (95%CI: 0.98 1.00) respectively. CONCLUSIONS: For early oral cancer patients, the sensitivity and specificity of sentinel lymph node biopsy are relatively high. The sentinel lymph node biopsy could be used to select which patients need neck dissection. PMID- 22932486 TI - [A study on the effect of biomineralization and phosphorylation performed on the titanium implant surfaces]. AB - OBJECTIVE: To suggest a chemical surface treatment for titanium and to initiate the formation of hydroxycarbonated apatite (HCA) on titanium surface during in vitro bioactivity tests in simulated body fluid (SBF). METHODS: To improve the bone-bonding ability of Ti implants, commercially pure titanium (cpTi) by a simple chemical pre-treatment in orthophosphoric acid (H(3)PO(4)) with different density was activated, and then the phosphorylation specimens were soaked in SBF to investigate the function of biomineralization. RESULTS: The scanning electron microscope (SEM) photographs showed that the surfaces of the pre-treated samples were characterized by a complex construction, which consisted of a mesh-like morphology matrix (a micro-roughened surface) and an uniform surface with different morphous of titanium dihydrogen orthophosphate [Ti(H(2)PO(4))(3)] crystal. After 14 days in SBF a homogeneous biomimetic apatite layer precipitated. CONCLUSIONS: These data suggest that the treatment of titanium by acid etching in orthophosphoric acid is a suitable method to provide the titanium implant with bone-bonding ability. PMID- 22932487 TI - [Effect of different wave-length ultraviolet light-treated micro-arc oxidation titanium surfaces on the physicochemical properties and bioactivity in vitro]. AB - OBJECTIVE: To study the effects of ultraviolet (UV) light-treatment on the physicochemical properties and bioactivity of micro-arc oxidation (MAO) titanium surfaces in vitro. METHODS: The pure titanium were prepared using MAO. MAO titanium samples were treated with 15 W bactericidal lamp UVC [lambda = (250 +/- 20) nm] or 15 W mercury lamp [lambda = (360 +/- 20) nm] for 24 h under ambient conditions. Three sample groups were prepared: MAO, UVA treated after MAO (MAO + UVA), UVC treated after MAO (MAO + UVC). The surface physicochemical properties were evaluated using scanning electron microscopy (SEM), contact angle measuring device, energy dispersive X-ray spectrometer (EDX), and X-ray diffraction (XRD). Bicinchoninic acid (BCA) based colorimetric detection was used to quantify the percentage of albumin adsorption after 2 h, 6 h, and 24 h incubation on the titanium surfaces. The rates of MG-63 cells attached to each group titanium surfaces were calculated by nucleus immunofluorescence using Hoechst 33342 after 1 h, 2 h, and 4 h incubation. SEM was used to observe cell morphology on titanium surfaces in each group. RESULTS: No obvious differences in surface topography, TiO(2) crystal and elemental composition were detected on titanium surfaces with or without UV treatment. Statistically significant difference in contact angles among MAO + UVC group (65.34 +/- 1.16) degrees , MAO + UVA group (44.64 +/- 1.28) degrees , and MAO group (3.41 +/- 0.48) degrees were found (P < 0.001). The percentage of albumin adsorption reached the plateau after 2 h incubation on MAO + UVC titanium surfaces (48.16 +/- 1.24)%, which was higher than those in MAO [(8.22 +/- 2.99)%] and MAO + UVA groups [(5.29 +/- 2.27)%, P < 0.001]. The rates of cells attached to the surfaces of MAO + UVC titanium was greater than that on MAO surfaces and MAO + UVA surfaces after 1 h [(40.71 +/- 4.08)%], 2 h [(53.72 +/ 2.38)%], 4 h [(70.32 +/- 2.85)%] incubation (P < 0.05). The MAO + UVC surfaces remarkably enhanced the spread of MG-63 cells, however, there was no significant difference between the group of MAO and MAO + UVA. CONCLUSIONS: Pretreatment of micro-arc oxidation titanium with UVC light considerably improved the surface bioactivity to MG-63 cells, which showed an increase in cellular attachment and spread. PMID- 22932489 TI - [Has the policy of "SCI Core Journals" driven or curbed development of science in China]. PMID- 22932488 TI - [Research of osteoblasts and mineralization culture method induced dental pulp stem cells into osteoblasts]. AB - OBJECTIVE: To find an ideal method inducing dental pulp stem cells (DPSC) osteogenic differentiation. To compare the effect of co-culture method and that of mineralizing culture medium. METHODS: DPSC were co-cultured with osteoblasts using cell culture inserts system as experiment group, and DPSC were cultured in mineralizing culture medium as control group. The cell morphology and ultrastructure and mineralized nodes were analyzed under phase contrast microscope, transmission electron microscope, and alizarin red S staning. Bone sialoprotein (BSP), Runx-2, osteocalcin, and collagen-1 (Col-1) osteoblastic genes expressions of DPSC cultivated in special niche of osteoblasts were assayed by reverse transcription polymerase chain reaction (RT-PCR). RESULTS: The mineralization nudoles of experiment group were more than control group. Fifteen days later, BSP and Col-1 genes in the DPSC of co-cultures were 9.807 +/- 1.135 and 2.913 +/- 0.310, respectively. And those in the DPSC of mineralizing culture medium were 6.478 +/- 0.781 and 1.703 +/- 0.184, respectively. Co-cultures and mineralizing were significantly different (P < 0.05). CONCLUSIONS: As osteoblasts can secret lots of osteogenic cell cytokines, they have more significant effect than mineralizing culture medium on osteogenesis of DPSC. PMID- 22932490 TI - [Right maintenance and self-discipline of practicing dentist on the liability in medical damage of the tortuous liability (VII): is it a lawsuit for contract or for violation of right]. PMID- 22932491 TI - Neurological soft signs in obsessive-compulsive disorder: two empirical studies and meta-analysis. AB - BACKGROUND: Neurological soft signs (NSS) have been inconsistently reported in obsessive-compulsive disorder (OCD) but may make an impact on treatment response. Method The current study examined the presence of NSS in two independent European samples of OCD patients (combined 85 patients and 88 matched healthy controls) using a standardized instrument and conducted a meta-analysis of all published studies identified in the literature with the aim to provide a more definitive answer to the question of whether OCD patients are characterized by increased NSS. RESULTS: Both empirical studies found elevated NSS scores in patients compared with matched controls. The results of the meta-analysis, which included 15 studies (combined 498 patients and 520 controls) showed large effect sizes (Hedges' g=1.27, 95% confidence interval 0.80-1.75), indicating that OCD patients have significantly higher rates of NSS than matched controls on both sides of the body and in multiple domains (motor coordination, sensory integration and primitive reflexes). The results were robust and remained largely unchanged in our reliability analyses, which controlled for possible outliers. Meta-regression was employed to examine the role of potential variables of interest including sociodemographic variables, symptom severity, medication effects and the use of different instruments, but none of these variables was clearly associated with NSS. CONCLUSIONS: As a group, OCD patients are characterized by increased rates of NSS, compared with healthy controls. However, their origins and potential clinical importance remain to be clarified. Future directions for research are discussed. PMID- 22932493 TI - Structure simulation into a lamellar supramolecular network and calculation of the metal ions/ligands ratio. AB - BACKGROUND: Research interest in phosphonates metal organic frameworks (MOF) has increased extremely in the last two decades, because of theirs fascinating and complex topology and structural flexibility. In this paper we present a mathematical model for ligand/metal ion ratio of an octahedral (Oh) network of cobalt vinylphosphonate (Co(vP).H2O). RESULTS: A recurrent relationship of the ratio between the number of ligands and the number of metal ions in a lamellar octahedral (Oh) network Co(vP).H2O, has been deducted by building the 3D network step by step using HyperChem 7.52 package. The mathematical relationship has been validated using X ray analysis, experimental thermogravimetric and elemental analysis data. CONCLUSIONS: Based on deducted recurrence relationship, we can conclude prior to perform X ray analysis, that in the case of a thermogravimetric analysis pointing a ratio between the number of metal ions and ligands number around 1, the 3D network will have a central metal ion that corresponds to a single ligand. This relation is valid for every type of supramolecular network with divalent metal central ion Oh coordinated and bring valuable information with low effort and cost. PMID- 22932494 TI - Acquired nasopharyngeal stenosis in a patient with sarcoidosis. AB - INTRODUCTION: Acquired nasopharyngeal stenosis typically occurs as a result of surgery or irradiation of the nasopharynx. Sarcoidosis has numerous manifestations in the head and neck region, although an association with nasopharyngeal stenosis has not previously been reported. CASE REPORT: A 40-year old man with sarcoidosis developed severe acquired nasopharyngeal stenosis. This was successfully managed with balloon dilatation, followed by pharyngoplasty with local pharyngeal flap reconstruction. CONCLUSION: This report is intended to prompt consideration of nasopharyngeal stenosis as a potential cause of nasal obstruction in patients with sarcoidosis, and to draw attention to the need to consider sarcoidosis in the differential diagnosis of patients with acquired nasopharyngeal stenosis. We also demonstrate the viability of pharyngoplasty in the management of nasopharyngeal stenosis in the setting of sarcoidosis. PMID- 22932495 TI - CH4 storage and CO2 capture in highly porous zirconium oxide based metal-organic frameworks. AB - A series of porous Zr oxoclusters-based MOFs was computationally explored for their gas storage/capture performances. The highly porous UiO-67(Zr) and UiO 68(Zr) solids show exceptionally high CH(4) and CO(2) adsorption capacities under operating conditions that make these thermal, water and mechanical resistant materials very promising for physisorption-based processes. PMID- 22932496 TI - Genomes against parasites. AB - Whereas once it was only possible to generate reference genome sequences one at a time, it is now feasible to design genomic experiments to maximize functional comparisons and contrasts among many genomes. Investigating the diversity of a number of related parasite genomes and their transcriptomes in multiple contexts increasingly shows us ways to intervene in the ecological and evolutionary strategies of pathogens. PMID- 22932492 TI - AMPK-dependent phosphorylation of ULK1 regulates ATG9 localization. AB - Autophagy is activated in response to a variety of cellular stresses including metabolic stress. While elegant genetic studies in yeast have identified the core autophagy machinery, the signaling pathways that regulate this process are less understood. AMPK is an energy sensing kinase and several studies have suggested that AMPK is required for autophagy. The biochemical connections between AMPK and autophagy, however, have not been elucidated. In this report, we identify a biochemical connection between a critical regulator of autophagy, ULK1, and the energy sensing kinase, AMPK. ULK1 forms a complex with AMPK, and AMPK activation results in ULK1 phosphorylation. Moreover, we demonstrate that the immediate effect of AMPK-dependent phosphorylation of ULK1 results in enhanced binding of the adaptor protein YWHAZ/14-3-3zeta; and this binding alters ULK1 phosphorylation in vitro. Finally, we provide evidence that both AMPK and ULK1 regulate localization of a critical component of the phagophore, ATG9, and that some of the AMPK phosphorylation sites on ULK1 are important for regulating ATG9 localization. Taken together these data identify an ULK1-AMPK signaling cassette involved in regulation of the autophagy machinery. PMID- 22932497 TI - Genomic insights into the other malaria. AB - Plasmodium vivax has received less attention and study than Plasmodium falciparum, due in part to difficulties in culturing this pathogen. Whole-genome sequencing of both P. vivax and Plasmodium cynomolgi and characterization of genetic variation in these species provide a genetic toolbox for tertian malaria and new insights into the monkey malaria clade. PMID- 22932498 TI - The emergence and spread of dysentery. AB - Shigella sonnei is an important cause of bacterial dysentery in the developed world and has also recently emerged in transitional countries. Phylogenetic analysis based on whole-genome sequencing of a global sample has detailed the recent evolutionary history of this pathogen and shed light on the genetic changes associated with this epidemiological shift. PMID- 22932499 TI - Incomplete methylation reprogramming in SCNT embryos. AB - The cloning of Dolly the sheep was a remarkable demonstration of the oocyte's ability to reprogram a specialized nucleus. However, embryos derived from such somatic cell nuclear transfer (SCNT) very rarely result in live births-a fate that may be linked to observed epigenetic defects. A new genome-wide study shows that epigenetic reprogramming in SCNT embryos does not fully recapitulate the natural DNA demethylation events occurring at fertilization, resulting in aberrant methylation at some promoters and repetitive elements that may contribute to developmental failure. PMID- 22932508 TI - Sleeve gastrectomy. PMID- 22932509 TI - National Breast Cancer Audit: overview of invasive breast cancer in New Zealand. AB - INTRODUCTION: The National Breast Cancer Audit collects data on the care of early breast cancer patients in Australia and New Zealand. An overview of invasive breast cancer in New Zealand is presented with emphasis on comparing the screened population with symptomatic referrals. METHODS: All New Zealand data in the National Breast Cancer Audit with a diagnosis date of 2008 have been included in the report. Data was analysed with an aim to compare the presenting features and management of screen detected invasive cancer with symptomatic referrals in New Zealand. RESULTS: There were 2371 cases of breast cancer, 52% of which were symptomatic referrals, 37% of which were BreastScreen Aotearoa referrals. Higher breast conservation rates were reported in the screening population. 3% of patients had involved margins after surgery. Almost two-thirds (62%) of BreastScreen patients underwent a sentinel node biopsy without further axillary surgery. 72% of screening patients and 86% of symptomatic patients who were high risk did not receive post mastectomy radiotherapy. A larger proportion of symptomatic patients received chemotherapy. Endocrine therapy was prescribed to 81% of hormone receptor positive patients. CONCLUSION: Patients with early invasive breast cancer in New Zealand were managed appropriately according to audit performance indicators and clinical guidelines. The numbers of high risk patients not receiving post mastectomy radiotherapy and the lack of endocrine treatment in some patients with hormone receptor positive tumours may warrant further investigation. PMID- 22932510 TI - The reasons for cancellation of urological surgery: a retrospective analysis. AB - AIM: To identify preventable reasons for surgery being cancelled and to identify steps which may minimise their occurrence. METHOD: All cancellations of surgery in the Department of Urology, Christchurch Hospital between the dates 31 March 2008 and 11 March 2011 were retrospectively identified from minutes of the Department's weekly audit meetings. These were then assigned reasons for cancellation according to those devised by the Veterans Health Administration system1. RESULTS: From 4303 total operations performed, 180 cancellations occurred over the almost-3-year study period. This equated to a cancellation rate of 4.2%.34 cases (18.9%) were due to patient factors, 66 cases (36.7%) due to work-up factors, 70 (38.9%) due to facility factors, 9 cases (5%) due to surgeon factors. CONCLUSION: A significant proportion of the 4.2% patients cancelled were preventable. Optimisation of the preadmission process as well as elucidation of the reasons for theatre over-runs were identified as key to reducing the rate of cancellation. Measurement of cancellations in the audit meeting contributes to a low cancellation rate. PMID- 22932511 TI - Screening for sexually transmitted infections in pregnancy at Middlemore Hospital, 2009. AB - AIMS: To determine the screening rate for, and the prevalence rate of, sexually transmitted infections (STIs) in pregnancy at Middlemore Hospital. METHOD: A list of all 6795 women who had a baby at Middlemore Hospital in 2009 was provided by the hospital's information systems. Details of the women including their swab results were then obtained from the Healthware and Web-Eclair databases. Comparison of screening and STI rates by categorical variables (Lead Maternity Carer (LMC), age group and ethnicity) was carried out using Chi-square statistics. Univariable and multivariable odds ratios were estimated using unconditional logistic regression. RESULTS: Only 4635 (64.3%) of women were screened in pregnancy for an STI. There was a significant difference in rates of testing by LMCs, with independent maternity providers less likely to carry out a swab than the District Health Board (DHB) providers (71.3% vs 54.0%, p<0.0001). A higher proportion of Maori and Pacific women were screened compared to other groups and younger women were screened more compared to older women. Of those women screened, 8.2% had chlamydia, 2.2% had trichomonas and 0.2% had gonorrhoea. There were higher rates of chlamydia and trichomonas seen in both Maori and Pacific women in comparison to European and Asian women. There was a pattern of decreasing STI rate with an increase in maternal age. CONCLUSION: Screening for STIs in pregnancy in Middlemore Hospital is low and does not meet the requirements of the Ministry of Health which requires all women to be screened. The STI prevalence rate is high especially in young Pacific and Maori women. Education of both women and maternity providers is important in prevention and detection of STIs in pregnancy. PMID- 22932512 TI - Unintended pregnancy and therapeutic abortion in the postpartum period. Is an opportunity to intervene being missed? AB - AIMS: To explore the reasons why women have an abortion soon after delivering an infant and what could reduce unintended pregnancy and abortion in this group of women. METHODS: Data were collected from anonymous self-complete questionnaires from women who presented to a first trimester Termination of Pregnancy service and who had delivered a live-born infant within the preceding 6 months; and also from the healthcare professionals who are responsible for maternity care to identify the reasons behind the unintended pregnancies, and around Lead Maternity Caregivers' (LMCs') usual practice of postnatal contraceptive provisions, and any barriers to its provision. RESULTS: 22 women were recruited into the study and completed the questionnaire. The majority of women (19) reported that they had discussed contraception with the LMC. However only 4 women were given a prescription for the pill and 2 women were given a prescription for condoms (which was not filled). Almost all women had previously accessed contraception from another provider. 59 LMCs responded. All LMCs reported that they discuss contraception with women, However the majority reported that they discuss contraception with all women at discharge (50) and/or postnatally (49). Only 23 LMCs reported discussing contraception antenatally or at booking. CONCLUSIONS: Opportunities to intervene are being missed. These include: discussing contraception with all women at booking and/or antenatally; for LMCs to offer prescriptions for contraception to all women and to encourage them to access the supplies, for LMCs to be trained so they feel confident to advise and supply all contraceptive options. Improvements for women could also be made by providing postnatal women with free consultations to her choice of provider, during pregnancy to organise postnatal contraception. PMID- 22932513 TI - Laparoscopic sleeve gastrectomy: its place in bariatric surgery for the severely obese patient. AB - AIM: Laparoscopic sleeve gastrectomy (LSG) was initially used as a staging procedure for high-risk patients undergoing bariatric surgery. However, it is now being increasingly favoured as a single-stage procedure. This article discusses the use of LSG as a single-stage procedure for the treatment of obesity and related comorbidities. METHODS: A literature review was conducted using specific search terms in multiple medical databases. RESULTS: Early and mid-term weight loss results show that LSG is comparable to more established bariatric procedures. It also produces satisfactory resolution of obesity related comorbidities such as type two diabetes mellitus (T2DM). There are minimal published outcome data to assess its long-term effectiveness and safety. This is particularly true in super-obese patients with current data suggesting less satisfactory acheivement of a normal BMI in this group of patients. CONCLUSION: LSG is safe and produces satisfactory weight loss and comorbidity resolution in the early and mid-term period. However, further data are required to assess its long-term effectiveness as well as its effectiveness in super-obese patients. PMID- 22932514 TI - SIDS prevention: 3000 lives saved but we can do better. AB - Mortality from sudden infant death syndrome (SIDS) has decreased substantially from the late 1980s. This has been attributed to the change in infant sleep position initially from prone (front) to side and then to predominantly supine (back). We calculate that this has saved over 3000 lives. However, we argue that we could save more infant lives, if more focus was given to the risks observed from parents sleeping in the same bed as their babies. PMID- 22932515 TI - The effect of ethnic prioritisation on ethnic health analysis: a research note. AB - Ethnicity is an important variable in studies of health inequalities in New Zealand. Yet there are ongoing concerns about the nature, quality and use of ethnic data. In 2004, Statistics New Zealand recommended that researchers and policy makers no longer use the system of ethnic prioritisation, a system originally designed to assign people with multiple ethnic responses to one ethnic category. While across a range of disciplines researchers have shifted to using either total ethnic counts or single and combination counts, many health researchers continue to use ethnic prioritisation. Census data show that when using prioritisation there are significant losses to Pacific, Asian and European groups, especially for young people. Losses are especially high for New Zealand born people in all age groups. Health researchers need to consider very carefully the costs and benefits of using prioritised data. Based on the census data we suggest the costs, in terms of loss of information and possible biases in findings, outweigh any benefits. PMID- 22932516 TI - Biological glue for persistent airleak: a case report. AB - We report the case of a pneumonthorax in 95-year-old man with three management issues: a wrongly placed drain despite fluoroscopic guidance; the need for a larger drain because of the size of the pneumonthorax; and the use of fresh frozen plasma (FFP) as a biological glue for an ongoing airleak. PMID- 22932517 TI - Medical image. Leukaemia cutis in myelomonocytic leukaemia. PMID- 22932518 TI - Response to Dr Sinead Donnelly's 'debates on euthanasia' editorial. PMID- 22932519 TI - Outpouring of public support for wider smokefree area policies in New Zealand. PMID- 22932520 TI - The heating of the dark: an agony in Christchurch. PMID- 22932521 TI - Diagnostic challenge of a proliferative nodule in a desmoplastic hairless hypopigmented nevus. PMID- 22932522 TI - A general access to 1,1-cyclopropane aminoketones and their conversion into 2 benzoyl quinolines. AB - 1,1-Cyclopropane aminoketones were efficiently synthesized in high yields by the tandem reaction of alpha-amino aryl ketones with vinyl sulfonium salts using DBU as the base in CH(2)Cl(2). This methodology was utilized to synthesize 2-benzoyl quinolines. PMID- 22932523 TI - Schmallenberg virus in domestic cattle, Belgium, 2012. AB - To determine prevalence of antibodies against Schmallenberg virus in adult cows and proportion of infection transmitted to fetuses, we tested serum samples from 519 cow/calf pairs in Belgium in spring 2012. Of cattle within 250 km of location where the virus emerged, ~91% tested positive for IgG targeting nucleoprotein. Risk for fetal infection was ~28%. PMID- 22932524 TI - ECOG 2010 and beyond: taking childhood obesity off the menu. 20th European Childhood Obesity Group Congress. PMID- 22932644 TI - Degradation of paracetamol by advance oxidation processes using modified reticulated vitreous carbon electrodes with TiO(2) and CuO/TiO(2)/Al(2)O(3). AB - The degradation of paracetamol in aqueous solutions in the presence of hydrogen peroxide was carried out by photochemistry, electrolysis and photoelectrolysis using modified 100 pores per inch reticulated vitreous carbon electrodes. The electrodes were coated with catalysts such as TiO(2) and CuO/TiO(2)/Al(2)O(3) by electrophoresis followed by heat treatment. The results of the electrolysis with bare reticulated vitreous carbon electrodes show that 90% paracetamol degradation occurs in 4 h at 1.3 V vs. SCE, forming intermediates such as benzoquinone and carboxylic acids followed by their complete mineralisation. When the electrolysis was carried out with the modified electrodes such as TiO(2)/RVC, 90% degradation was achieved in 2 h while with CuO/TiO(2)/Al(2)O(3)/RVC, 98% degradation took only 1 h. The degradation was also carried out in the presence of UV reaching 95% degradation with TiO(2)/RVC/UV and 99% with CuO/TiO(2)/Al(2)O(3)/RVC/UV in 1 h. The reactions were followed by spectroscopy UV-Vis, HPLC and total organic carbon analysis. These studies show that the degradation of paracetamol follows a pseudo first order reaction kinetics. PMID- 22932645 TI - Bacterial autophagy: the trigger, the target and the timing. AB - Autophagy is a vital process through which cellular material and dysfunctional organelles are degraded and recycled, and it is inhibited by the metabolic checkpoint kinase MTOR. Autophagy also targets intracellular bacteria (a process termed xenophagy) for lysosomal degradation, thereby playing a key role in innate immunity. In the past few years, the identification of molecules, such as CALCOCO2/NDP52, SQSTM1/p62 and ubiquitin, implicated in the specific targeting of intracellular bacteria, received considerable attention. However, it remains unclear how xenophagy is initiated, since this process commonly occurs in metabolically replete cells. In a recent study, we demonstrated that infection with Shigella and Salmonella triggered an early state of intracellular amino acid (AA) starvation causing MTOR dissociation from endomembranes, downregulation of MTOR activity and activation of the EIF2AK4/GCN2-EIF2S1/eIF2alpha/ATF3 signaling axis. We also observed that AA starvation was caused by host membrane damage, which appeared to be transient in the case of Salmonella and sustained in Shigella-infected cells, thus highlighting the existence of key timing disparities in xenophagy triggering, depending on the bacterial pathogen. Together, our findings demonstrate that xenophagy is only one arm of a more general metabolic switch geared toward AA starvation in bacteria-infected cells. PMID- 22932646 TI - Tumour suppressors: A microdependency of importance? PMID- 22932647 TI - Immunotherapy: Unlicensed to kill. PMID- 22932649 TI - Alcohol harms. PMID- 22932648 TI - Reversal of Young's procedure in hereditary haemorrhagic telangiectasia. AB - BACKGROUND: Hereditary haemorrhagic telangiectasia is an autosomal dominant condition characterised by multiple venous malformations of the skin and mucous membranes which can bleed on contact. A Young's procedure is used to control severe epistaxis in patients with this condition. However, there has been no previous report of a reversal of Young's procedure in such a patient. OBJECTIVE: A patient with hereditary haemorrhagic telangiectasia had his Young's procedure reversed under general anaesthetic by dividing the mucocutaneous flaps. Nasal vestibule patency was maintained using a custom-made silicone nasal mould. Intra operative photographs show the patient's nasal mucosa shortly following reversal of his Young's procedure, and also illustrate the creation of the custom-made nasal mould. CONCLUSION: Stopping airflow through the nasal cavity via a Young's procedure prevents the telangiectasia from bleeding but does not make them disappear completely. Young's procedure does not seem to have any long-lasting effect on the nasal mucosa of patients with hereditary haemorrhagic telangiectasia. PMID- 22932650 TI - A shining light in the New Zealand cancer gloom. PMID- 22932651 TI - Alcohol-related harm to others in New Zealand: evidence of the burden and gaps in knowledge. AB - AIM: To identify and summarise existing New Zealand data quantifying any aspects of harm experienced from the drinking of others. METHODS: Surveys, research data, and administrative databases were identified through literature searching, examination of websites of relevant agencies, and direct enquiry among those working in research, government agencies and relevant NGOs. Accessible data were analysed, and published or collated data were summarised. RESULTS: The prevalence of self-reported harm from others' drinking was higher than harm from own drinking (18% vs 12% in the past year) and was higher in women and young people. Most available data described aggression and crime, and unintentional injury due to traffic crashes and fires. No useable data were obtained on harm to children. Police records suggested that a third to a half of offences involved someone who had been drinking, and alcohol involvement increased with seriousness. Self reported violence involved a drinking perpetrator in about half of cases; more likely in stranger violence than family violence, but common in both. About 40% of those injured in alcohol-related traffic crashes were not the drinker responsible, and this represented about one in eight of all traffic injuries. Approximately one in eight unintentional residential fire deaths were innocent victims of alcohol-related fires. CONCLUSION: The range and magnitude of harms from others' drinking are substantial, but not well described. Shortcomings in the data systems of agencies dealing with people harmed by the drinking of others hamper surveillance, monitoring of effectiveness of interventions and advocacy for policy to reduce alcohol-related harm. PMID- 22932652 TI - One in three New Zealand drinkers reports being harmed by their own drinking in the past year. AB - AIM: To quantify the prevalence and distribution of negative effects of drinking among New Zealand adults. METHODS: A postal survey was completed by 1924 people aged 18-70 randomly selected from the New Zealand electoral roll (49.5% response). Information on drinking patterns, demographics and specific alcohol related harms and troubles in the previous 12 months was collected. RESULTS: 33.8% of current drinkers reported that they had been adversely affected by their own drinking in one or more specified domains in the past 12 months ("harm") and 12.7% reported one or more specified alcohol-related "troubles". Men were more likely to report alcohol-related harm (OR=1.3; 95% confidence interval [CI] 1.0 1.7) and alcohol-related trouble (OR=1.5; 95%CI 1.1-2.1) compared to women. People of Maori ethnicity and those with an NZDep06 score of 9-10 were at increased risk of both harms and troubles. The odds of reporting a harm or trouble in the past year decreased substantially with age. Heavy episodic drinking and level of average daily consumption were both associated with increased risk of both alcohol-related harm and trouble, but this did not explain all of the variation. CONCLUSIONS: Prevalence of harm and trouble resulting from drinking is high in the general population as judged by the drinkers themselves. These findings support the association of heavy alcohol consumption with increased risk of alcohol-related harm. They also suggest that being male, young, Maori or living in a very deprived area in NZ are associated with a higher risk of alcohol-related harm. PMID- 22932653 TI - The Christchurch Breast Cancer Patient Register: the first year. AB - AIMS: The aim of this article is to present the first year's findings of the Christchurch Breast Cancer Patient Register (CBCR) to establish the incidence and management of breast cancer in the Canterbury region. METHODS: CBCR commenced recruitment of breast cancer patients in Canterbury from June 2009. Ethical approval was granted by regional ethics committees to collect data. Patient data is recorded onto the database once informed consent is obtained. RESULTS: A total of 337 patients (including one male) consented. At diagnosis, 231 (68.5%) were aged 50 years or over. 48 (14.2%) patients had carcinoma in situ with no invasive component. 289 (85.8%) patients had invasive carcinoma with 47.4% undergoing mastectomy and 44.6% breast conserving surgery whereas 8% had no primary surgery. Nodes were positive in 102 (38.8%), and the predominant tumour type was Ductal NST (no special type) in 68.9% (199) of patients with invasive carcinoma. Additional data incorporating ethnicity, oncology, additional surgical management and pathological variables are also presented in detail. CONCLUSION: Findings on 337 patients recruited and recorded on CBCR database in the first year are discussed. Due to the short follow up, outcome data is not analysed. PMID- 22932654 TI - Foot problems in Maori with diabetes. AB - AIM: The prevalence of diabetes and its associated manifestations is higher in New Zealand Maori than New Zealand Europeans. There is no current evidence regarding podiatric clinical characteristics of Maori with diabetes. The aim of this study was to determine the clinical and foot characteristics of Maori with diabetes using a podiatry-specific assessment tool. METHOD: This study used a cross-sectional design. Participants with diabetes were recruited from two Maori Primary Health Organisations. Podiatric-specific characteristics (vascular, neurological and musculoskeletal) were recorded. Patient demographics and general medical conditions were also recorded. RESULTS: Fifty-three participants were recruited and displayed risk factors for diabetes-related complications (mean disease duration 12 years, mean HbA1c 8.3%) including 49% of participants with hypertension. Podiatric-specific characteristics revealed unremarkable neurovascular results. However, many participants presented with pre-ulcerative lesions and current pedal ulceration (53% and 8% respectively). Although many participants had good foot-care knowledge (>85%), a modified classification tool of foot risk status determined that a high percentage of participants required regular podiatric management and screening (60%). CONCLUSION: Despite this population living with a chronic condition for more than 10 years and displaying poor long-term glycaemic control, there was no evidence of microvascular or macrovascular complications in the lower limb. However, there was a high prevalence of pre-ulcerative lesions which unmonitored and undetected may predispose the foot to ulceration. The detection of current ulceration in this study alongside other risk factors for diabetes-related complications necessitates the need for appropriate podiatric screening and podiatry management. PMID- 22932655 TI - Providing care for women with gynaecological malignancy: the need for a coordinated national approach. AB - Gynaecological cancer services in New Zealand have followed an evolutionary process rather than being centrally organised according to evidence on best practice. A report was recently commissioned by the Ministry of Health to review gynaecological cancer services and to provide guidance on the most efficient and effective way to delivery high quality, equitable care for women diagnosed with gynaecological cancers. It is apparent the sustainability of current services is compromised by disparities in access to evidence-based multidisciplinary care, significant workforce shortages and a lack of standardised formal referral protocols. Key recommendations of the report include the establishment of an overarching national gynaecological cancer steering group and ultimately a four centre hub and spoke model of care provision. PMID- 22932656 TI - What's in a cost? Comparing economic and public health measures of alcohol's social costs. AB - Studies based on a cost of illness method frequently assert large social costs from a variety of risky activities, the harms from which most typically fall upon the risk-taker himself. Many of these costs are inadmissible in a standard economic framework; consequently, figures derived by the cost of illness method are not comparable with other economic notions of cost and are of very limited policy use. PMID- 22932657 TI - Pulmonary infiltrates with eosinophilia syndrome in ibuprofen overdose. AB - We describe the case of a 45-year-old female who developed pulmonary infiltrates and mild eosinophilia following an overdose of ibuprofen. We believe this was a case of pulmonary infiltrates with eosinophilia (PIE) syndrome and discuss the relevant literature. Although rare, PIE syndrome should be considered in those taking nonsteroidal anti-inflammatories who develop unexplained pulmonary infiltrates. PMID- 22932658 TI - Corticosteroids and monocytosis. AB - Although the association between steroid administration and neutrophilia is well known, the association with monocytosis is not as common and the mechanism less clear. This report illustrates the association and provides an update of postulated mechanisms and clinical significance. PMID- 22932660 TI - Medical image. Fingernail lines. Beau's lines. PMID- 22932659 TI - Medical image. Creeping eruption. Cutaneous larva migrans. PMID- 22932661 TI - Perioperative management of dabigatran: the Nelson experience to date. PMID- 22932662 TI - Health and nuisance impacts from outdoor smoking on public transport users: data from Auckland and Wellington. PMID- 22932663 TI - Computerised tomography indices of raised intracranial pressure and traumatic brain injury severity in a New Zealand sample. PMID- 22932664 TI - Ice nucleation by particles immersed in supercooled cloud droplets. AB - The formation of ice particles in the Earth's atmosphere strongly affects the properties of clouds and their impact on climate. Despite the importance of ice formation in determining the properties of clouds, the Intergovernmental Panel on Climate Change (IPCC, 2007) was unable to assess the impact of atmospheric ice formation in their most recent report because our basic knowledge is insufficient. Part of the problem is the paucity of quantitative information on the ability of various atmospheric aerosol species to initiate ice formation. Here we review and assess the existing quantitative knowledge of ice nucleation by particles immersed within supercooled water droplets. We introduce aerosol species which have been identified in the past as potentially important ice nuclei and address their ice-nucleating ability when immersed in a supercooled droplet. We focus on mineral dusts, biological species (pollen, bacteria, fungal spores and plankton), carbonaceous combustion products and volcanic ash. In order to make a quantitative comparison we first introduce several ways of describing ice nucleation and then summarise the existing information according to the time independent (singular) approximation. Using this approximation in combination with typical atmospheric loadings, we estimate the importance of ice nucleation by different aerosol types. According to these estimates we find that ice nucleation below about -15 degrees C is dominated by soot and mineral dusts. Above this temperature the only materials known to nucleate ice are biological, with quantitative data for other materials absent from the literature. We conclude with a summary of the challenges our community faces. PMID- 22932666 TI - The CXCL12-CXCR4 chemokine pathway: a novel axis regulates lymphangiogenesis. AB - PURPOSE: Lymphangiogenesis, the growth of lymphatic vessels, contributes to lymphatic metastasis. However, the precise mechanism underlying lymphangiogenesis remains poorly understood. This study aimed to examine chemokine/chemokine receptors that directly contribute to chemoattraction of activated lymphatic endothelial cells (LEC) and tumor lymphangiogenesis. EXPERIMENTAL DESIGN: We used quantitative RT-PCR to analyze specifically expressed chemokine receptors in activated LECs upon stimulation of vascular endothelial growth factor-C (VEGF-C). Subsequently, we established in vitro and in vivo models to show lymphangiogenic functions of the chemokine axis. Effects of targeting the chemokine axis on tumor lymphangiogenesis and lymphatic metastasis were determined in an orthotopic breast cancer model. RESULTS: VEGF-C specifically upregulates CXCR4 expression on lymphangiogenic endothelial cells. Moreover, hypoxia-inducible factor-1alpha (HIF 1alpha) mediates the CXCR4 expression induced by VEGF-C. Subsequent analyses identify the ligand CXCL12 as a chemoattractant for LECs. CXCL12 induces migration, tubule formation of LECs in vitro, and lymphangiogenesis in vivo. CXCL12 also stimulates the phosphorylation of intracellular signaling Akt and Erk, and their specific antagonists impede CXCL12-induced chemotaxis. In addition, its level is correlated with lymphatic vessel density in multiple cancer tissues microarray. Furthermore, the CXCL12-CXCR4 axis is independent of the VEGFR-3 pathway in promoting lymphangiogenesis. Intriguingly, combined treatment with anti-CXCL12 and anti-VEGF-C antibodies results in additive inhibiting effects on tumor lymphangiogenesis and lymphatic metastasis. CONCLUSIONS: These results show the role of the CXCL12-CXCR4 axis as a novel chemoattractant for LECs in promoting lymphangiogenesis, and support the potential application of combined targeting of both chemokines and lymphangiogenic factors in inhibiting lymphatic metastasis. PMID- 22932665 TI - Superior efficacy of a combined epigenetic therapy against human mantle cell lymphoma cells. AB - PURPOSE: A deregulated epigenome contributes to the transformed phenotype of mantle cell lymphoma (MCL). This involves activity of the polycomb repressive complex (PRC) 2, containing three core proteins, EZH2, SUZ12, and EED, in which the SET domain of EZH2 mediates the histone methyltransferase activity. We determined the effects of 3-deazaneplanocin A (DZNep), an S-adenosylhomocysteine hydrolase inhibitor, and/or pan-histone deacetylase inhibitor panobinostat (PS) on cultured and primary MCL cells. EXPERIMENTAL DESIGN: Following treatment with DZNep and/or PS, apoptosis and the levels and activity of EZH2 and PRC2 proteins in cultured and primary MCL cells were determined. RESULTS: Treatment with DZNep depleted EZH2, SUZ12, and 3MeK27H3 in the cultured human MCL cells. DZNep also increased expression of p21, p27, and FBXO32, whereas it depleted Cyclin D1 and Cyclin E1 levels in MCL cells. In addition, DZNep treatment induced cell-cycle arrest and apoptosis in cultured and primary MCL cells. Furthermore, as compared with treatment with each agent alone, cotreatment with DZNep and PS caused greater depletion of EZH2, SUZ12, 3MeK27H3, and Cyclin D1 levels, whereas it induced greater expression of FBXO32, p16, p21, and p27. Combined treatment with DZNep and PS synergistically induced apoptosis of cultured and primary MCL cells while relatively sparing normal CD34 + cells. Cotreatment with DZNep and PS also caused significantly greater inhibition of tumor growth of JeKo-1 xenografts in NOD/SCID mice. CONCLUSIONS: These preclinical in vitro and in vivo findings show that cotreatment with DZNep and PS is an active combined epigenetic therapy worthy of further in vivo testing against MCL. PMID- 22932667 TI - Novel tumor subgroups of urothelial carcinoma of the bladder defined by integrated genomic analysis. AB - PURPOSE: There is a need for improved subclassification of urothelial carcinoma (UC) at diagnosis. A major aim of this study was to search for novel genomic subgroups. EXPERIMENTAL DESIGN: We assessed 160 tumors for genome-wide copy number alterations and mutation in genes implicated in UC. These comprised all tumor grades and stages and included 49 high-grade stage T1 (T1G3) tumors. RESULTS: Our findings point to the existence of genomic subclasses of the "gold standard" grade/stage groups. The T1G3 tumors separated into 3 major subgroups that differed with respect to the type and number of copy number events and to FGFR3 and TP53 mutation status. We also identified novel regions of copy number alteration, uncovered relationships between molecular events, and elucidated relationships between molecular events and clinico-pathologic features. FGFR3 mutant tumors were more chromosomally stable than their wild-type counterparts and a mutually exclusive relationship between FGFR3 mutation and overrepresentation of 8q was observed in non-muscle-invasive tumors. In muscle invasive (MI) tumors, metastasis was positively associated with losses of regions on 10q (including PTEN), 16q and 22q, and gains on 10p, 11q, 12p, 19p, and 19q. Concomitant copy number alterations positively associated with TP53 mutation in MI tumors were losses on 16p, 2q, 4q, 11p, 10q, 13q, 14q, 16q, and 19p, and gains on 1p, 8q, 10q, and 12q. Significant complexity was revealed in events affecting chromosome 9. CONCLUSIONS: These findings may lead to improved biologic understanding and the development of prognostic biomarkers. Novel regions of copy number alteration may reveal potential therapeutic targets. PMID- 22932668 TI - Intraoperative near-infrared imaging of surgical wounds after tumor resections can detect residual disease. AB - PURPOSE: Surgical resection remains the most effective therapy for solid tumors worldwide. The most important prognostic indicator for cure following cancer surgery is a complete resection with no residual disease. However, intraoperative detection of retained cancer cells after surgery is challenging, and residual disease continues to be the most common cause of local failure. We hypothesized that visual enhancement of tumors using near-infrared imaging could potentially identify tumor deposits in the wound after resection. EXPERIMENTAL DESIGN: A small animal model of surgery and retained disease was developed. Residual tumor deposits in the wound were targeted using an U.S. Food and Drug Administration approved imaging agent, indocyanine green, by the enhanced permeability and retention effect. A novel handheld spectrometer was used to optically visualize retained disease after surgery. RESULTS: We found residual disease using near infrared imaging during surgery that was not visible to the naked eye or micro CT. Furthermore, examination of tumor nodules was remarkably precise in delineating margins from normal surrounding tissues. This approach was most successful for tumors with increased neovasculature. CONCLUSIONS: The results suggest that near-infrared examination of the surgical wound after curative resection can potentially enable the surgeon to locate residual disease. The data in this study is the basis of an ongoing Phase I/II clinical trial in patients who undergo resection for lung and breast cancer. PMID- 22932669 TI - Biomarkers of response to Akt inhibitor MK-2206 in breast cancer. AB - PURPOSE: We tested the hypothesis that allosteric Akt inhibitor MK-2206 inhibits tumor growth, and that PTEN/PIK3CA mutations confer MK-2206 sensitivity. EXPERIMENTAL DESIGN: MK-2206 effects on cell signaling were assessed in vitro and in vivo. Its antitumor efficacy was assessed in vitro in a panel of cancer cell lines with differing PIK3CA and PTEN status. Its in vivo efficacy was tested as a single agent and in combination with paclitaxel. RESULTS: MK-2206 inhibited Akt signaling and cell-cycle progression, and increased apoptosis in a dose-dependent manner in breast cancer cell lines. Cell lines with PTEN or PIK3CA mutations were significantly more sensitive to MK-2206; however, several lines with PTEN/PIK3CA mutations were MK-2206 resistant. siRNA knockdown of PTEN in breast cancer cells increased Akt phosphorylation concordant with increased MK-2206 sensitivity. Stable transfection of PIK3CA E545K or H1047R mutant plasmids into normal-like MCF10A breast cells enhanced MK-2206 sensitivity. Cell lines that were less sensitive to MK-2206 had lower ratios of Akt1/Akt2 and had less growth inhibition with Akt siRNA knockdown. In PTEN-mutant ZR75-1 breast cancer xenografts, MK-2206 treatment inhibited Akt signaling, cell proliferation, and tumor growth. In vitro, MK-2206 showed a synergistic interaction with paclitaxel in MK-2206 sensitive cell lines, and this combination had significantly greater antitumor efficacy than either agent alone in vivo. CONCLUSIONS: MK-2206 has antitumor activity alone and in combination with chemotherapy. This activity may be greater in tumors with PTEN loss or PIK3CA mutation, providing a strategy for patient enrichment in clinical trials. PMID- 22932671 TI - Antimicrobial drug use and macrolide-resistant Streptococcus pyogenes, Belgium. AB - In Belgium, decreasing macrolide, lincosamide, streptogramins B, and tetracycline use during 1997-2007 correlated significantly with decreasing macrolide-resistant Streptococcus pyogenes during 1999-2009. Maintaining drug use below a critical threshold corresponded with low-level macrolide-resistant S. pyogenes and an increased number of erm(A)-harboring emm77 S. pyogenes with low fitness costs. PMID- 22932670 TI - IDO expression in brain tumors increases the recruitment of regulatory T cells and negatively impacts survival. AB - PURPOSE: Glioblastoma multiforme (GBM) is an aggressive adult brain tumor with a poor prognosis. One hallmark of GBM is the accumulation of immunosuppressive and tumor-promoting CD4(+)FoxP3(+)GITR(+) regulatory T cells (Tregs). Here, we investigated the role of indoleamine 2,3 dioxygenase (IDO) in brain tumors and the impact on Treg recruitment. EXPERIMENTAL DESIGN: To determine the clinical relevance of IDO expression in brain tumors, we first correlated patient survival to the level of IDO expression from resected glioma specimens. We also used novel orthotopic and transgenic models of glioma to study how IDO affects Tregs. The impact of tumor-derived and peripheral IDO expression on Treg recruitment, GITR expression, and long-term survival was determined. RESULTS: Downregulated IDO expression in glioma predicted a significantly better prognosis in patients. Coincidently, both IDO-competent and deficient mice showed a survival advantage bearing IDO-deficient brain tumors, when compared with IDO-competent brain tumors. Moreover, IDO deficiency was associated with a significant decrease in brain-resident Tregs, both in orthotopic and transgenic mouse glioma models. IDO deficiency was also associated with lower GITR expression levels on Tregs. Interestingly, the long-term survival advantage conferred by IDO deficiency was lost in T-cell-deficient mice. CONCLUSIONS: These clinical and preclinical data confirm that IDO expression increases the recruitment of immunosuppressive Tregs that lead to tumor outgrowth. In contrast, IDO deficiency decreases Treg recruitment and enhances T-cell-mediated tumor rejection. Thus, the data suggest a critical role for IDO-mediated immunosuppression in glioma and support the continued investigation of IDO-Treg interactions in the context of brain tumors. PMID- 22932672 TI - Synthesis of hierarchical Ag2ZnGeO4 hollow spheres for enhanced photocatalytic property. AB - An Ag(2)ZnGeO(4) photocatalyst was fabricated by ion-exchange reaction between amorphous Zn(2)GeO(4) suspension and Ag(+) solutions. The Ostwald ripening effect induced the formation of hierarchical hollow spheres. Compared with the reference bulk Ag(2)ZnGeO(4), the hierarchical Ag(2)ZnGeO(4) hollow spheres showed enhanced photocatalytic activity. PMID- 22932673 TI - Transcriptome study outlines ontogeny of the maize shoot apical meristem. PMID- 22932674 TI - A missense mutation in the glucosamine-6-phosphate N-acetyltransferase-encoding gene causes temperature-dependent growth defects and ectopic lignin deposition in Arabidopsis. AB - To study the regulatory mechanisms underlying lignin biosynthesis, we isolated and characterized lignescens (lig), a previously undescribed temperature sensitive mutant of Arabidopsis thaliana that exhibits ectopic lignin deposition and growth defects under high-temperature conditions. The lig mutation was identified as a single base transition in GNA1 encoding glucosamine-6-phosphate N acetyltransferase (GNA), a critical enzyme of UDP-N-acetylglucosamine (UDP GlcNAc) biosynthesis. lig harbors a glycine-to-serine substitution at residue 68 (G68S) of GNA1. Enzyme activity assays of the mutant protein (GNA1(G68S)) showed its thermolability relative to the wild-type protein. The lig mutant exposed to the restrictive temperature contained a significantly smaller amount of UDP GlcNAc than did the wild type. The growth defects and ectopic lignification of lig were suppressed by the addition of UDP-GlcNAc. Since UDP-GlcNAc is an initial sugar donor of N-glycan synthesis and impaired N-glycan synthesis is known to induce the unfolded protein response (UPR), we examined possible relationships between N-glycan synthesis, UPR, and the lig phenotype. N-glycans were reduced and LUMINAL BINDING PROTEIN3, a typical UPR gene, was expressed in lig at the restrictive temperature. Furthermore, treatment with UPR-inducing reagents phenocopied the lig mutant. Our data collectively suggest that impairment of N glycan synthesis due to a shortage of UDP-GlcNAc leads to ectopic lignin accumulation, mostly through the UPR. PMID- 22932681 TI - BMPs go for apelin to regulate angiogenesis. Focus on "inhibition of apelin expression by BMP signaling in endothelial cells". PMID- 22932682 TI - Enrichment of neonatal rat cardiomyocytes in primary culture facilitates long term maintenance of contractility in vitro. AB - Long-term culture of primary neonatal rat cardiomyocytes is limited by the loss of spontaneous contractile phenotype within weeks in culture. This may be due to loss of contractile cardiomyocytes from the culture or overgrowth of the non cardiomyocyte population. Using the mitochondria specific fluorescent dye, tetramethylrhodamine methyl ester perchlorate (TMRM), we showed that neonatal rat cardiomyocytes enriched by fluorescence-activated cell sorting can be maintained as contractile cultures for long periods (24-wk culture vs. 2 wk for unsorted cardiomyocytes). Long-term culture of this purified cardiomyocyte (TMRM high) population retained the expression of cardiomyocyte markers, continued calcium cycling, and displayed cyclic electrical activity that could be regulated pharmacologically. These findings suggest that non-cardiomyocyte populations can negatively influence contractility of cardiomyocytes in culture and that by purifying cardiomyocytes, the cultures retain potential as an experimental model for longitudinal studies of cardiomyocyte biology in vitro. PMID- 22932676 TI - Small signaling peptides in Arabidopsis development: how cells communicate over a short distance. AB - To sustain plants' postembryonic growth and development in a structure of cells fixed in cell walls, a tightly controlled short distance cell-cell communication is required. The focus on phytohormones, such as auxin, has historically overshadowed the importance of small peptide signals, but it is becoming clear that secreted peptide signals are important in cell-cell communication to coordinate and integrate cellular functions. However, of the more than 1000 potential secreted peptides, so far only very few have been functionally characterized or matched to a receptor. Here, we will describe our current knowledge on how small peptide signals can be identified, how they are modified and processed, which roles they play in Arabidopsis thaliana development, and through which receptors they act. PMID- 22932683 TI - Kinetics of nuclear-cytoplasmic translocation of Foxo1 and Foxo3A in adult skeletal muscle fibers. AB - In skeletal muscle, the transcription factors Foxo1 and Foxo3A control expression of proteins that mediate muscle atrophy, making the nuclear concentration and nuclear-cytoplasmic movements of Foxo1 and Foxo3A of therapeutic interest in conditions of muscle wasting. Here, we use Foxo-GFP fusion proteins adenovirally expressed in cultured adult mouse skeletal muscle fibers to characterize the time course of nuclear efflux of Foxo1-GFP in response to activation of the insulin like growth factor-1 (IGF-1)/phosphatidylinositol-3-kinase (PI3K)/Akt pathway to determine the time course of nuclear influx of Foxo1-GFP during inhibition of this pathway and to show that Akt mediates the efflux of nuclear Foxo1-GFP induced by IGF-1. Localization of endogenous Foxo1 in muscle fibers, as determined via immunocytochemistry, is consistent with that of Foxo1-GFP. Inhibition of the nuclear export carrier chromosome region maintenance 1 by leptomycin B (LMB) traps Foxo1 in the nucleus and results in a relatively rapid rate of Foxo1 nuclear accumulation, consistent with a high rate of nuclear cytoplasmic shuttling of Foxo1 under control conditions before LMB application, with near balance of unidirectional influx and efflux. Expressed Foxo3A-GFP shuttles ~20-fold more slowly than Foxo1-GFP. Our approach allows quantitative kinetic characterization of Foxo1 and Foxo3A nuclear-cytoplasmic movements in living muscle fibers under various experimental conditions. PMID- 22932684 TI - Vitamin D improves the angiogenic properties of endothelial progenitor cells. AB - The main pathogenic feature of preeclampsia is maternal endothelial dysfunction that results from impaired angiogenesis and reduced endothelial repair capacity. In addition, preeclampsia risk is associated with vitamin D deficiency. We hypothesized that vitamin D(3) stimulates proangiogenic properties of endothelial colony-forming cells (ECFCs). ECFCs were obtained and cultured from cord blood and characterized by immunocytochemistry and flow cytometry. Proliferation, total length of tubule formation on Matrigel, expression of VEGF mRNA, and pro-matrix metalloproteinases (MMP)-2 activity were assessed after treatment of ECFCs with vitamin D(3). Specificity of the observed effects was tested by blocking the vitamin D receptor (VDR) or the VEGF signaling pathway. ECFCs treated with 10 nM vitamin D(3) showed a 1.27 times higher tubule formation compared with vehicle treated controls (1.27 +/- 0.19) as well as a 1.36 times higher proliferation rate (1.36 +/- 0.06). Vitamin D(3) induced pro-MMP-2 activity (1.29 +/- 0.17) and VEGF mRNA levels (1.74 +/- 0.73) in ECFCs. VDR blocking by pyridoxal-5-phosphate (0.73 +/- 0.19) or small interfering RNA (0.75 +/- 0.17) and VEGF inhibition by Su5416 (0.56 +/- 0.16) or soluble fms-like tyrosine kinase-1 (0.7 +/- 0.14) reduced tubule formation and pro-MMP-2 activity (pyridoxal-5-phosphate: 0.84 +/- 0.09; Su5416: 0.79 +/- 0.11; or sFlt: 0.88 +/- 0.13). This effect was neutralized by vitamin D(3). Consequently, vitamin D(3) significantly promoted angiogenesis in ECFCs in vitro possibly due to an increase in VEGF expression and pro-MMP-2 activity. Since angiogenesis is a crucial feature in the pathophysiology of preeclampsia these findings could explain the positive influence of vitamin D(3) in reducing preeclampsia risk. PMID- 22932686 TI - Function without form: an ongoing search for maxi-anion channel proteins. Focus on "Maxi-anion channel and pannexin 1 hemichannel constitute separate pathways for swelling-induced ATP release in murine L929 fibrosarcoma cells". PMID- 22932687 TI - Late-onset epileptic spasms may be cured by focal cortical resective surgery. AB - We report the case of a child with isolated late-onset epileptic spasms who significantly improved after focal frontal cortectomy. Clusters of axial and limb tonic contractions with head nodding began at 2 years of age. They occurred only during sleep, lasting 15 to 20 minutes and were pharmacoresistant. The child suffered slight mental delay. Interictal EEG showed left frontal spikes in slow sleep. Ictal video-EEG showed patterns of asymmetric spasms. MRI revealed a distinct white matter abnormality in the left frontal superior gyrus, corresponding clearly to localised cortical hypometabolism on FDG-PET and PET-MRI co-recording. SEEG investigation showed that the first spasm of the clusters corresponded to a localised discharge of rapid rhythms from the electrodes placed within the area identified as a lesion by MRI. Discharges then became more diffuse across the left frontal and temporal electrodes throughout the duration of the cluster. A tailored focal frontal resection was performed at 16 years of age. Spasms were very rare during the following three years (Engel class II). This observation illustrates the fact that isolated epileptic spasms can be cured by focal cortical resection despite a lack of clearly localised EEG surface anomalies. PMID- 22932685 TI - Systems biology in physiology: the vasopressin signaling network in kidney. AB - Over the past 80 years, physiological research has moved progressively in a reductionist direction, providing mechanistic information on a smaller and smaller scale. This trend has culminated in the present focus on "molecular physiology," which deals with the function of single molecules responsible for cellular function. There is a need to assemble the information from the molecular level into models that explain physiological function at cellular, tissue, organ, and whole organism levels. Such integration is the major focus of an approach called "systems biology." The genome sequencing projects provide a basis for a new kind of systems biology called "data-rich" systems biology that is based on large-scale data acquisition methods including protein mass spectrometry, DNA microarrays, and deep sequencing of nucleic acids. These techniques allow investigators to measure thousands of variables simultaneously in response to an external stimulus. My laboratory is applying such an approach to the question: "How does the peptide hormone vasopressin regulate water permeability in the renal collecting duct?" We are using protein mass spectrometry to identify and quantify the phosphoproteome of collecting duct cells. The response to vasopressin, presented in the form of a network model, includes a general downregulation of proline-directed kinases (MAP kinases and cyclin-dependent kinases) and upregulation of basophilic kinases (ACG kinases and calmodulin dependent kinases). Further progress depends on characterization and localization of candidate protein kinases in these families. The ultimate goal is to use multivariate statistical techniques and differential equations to obtain predictive models describing vasopressin signaling in the renal collecting duct. PMID- 22932688 TI - Efficient white polymer light-emitting diodes employing a silver nanowire-polymer composite electrode. AB - White polymer phosphorescent light-emitting diodes have been fabricated employing silver nanowire (AgNW)-polymer composite substrates. Solution processing is used to form all the layers in the devices, except for the cathode, for potentially low fabrication cost. The current efficiency in the front viewing direction is 20.3 cd A(-1) for devices comprising two complementary dopants (bis[(4,6 difluorophenyl)-pyridinato-N,C(2)] (picolinato)Ir(iii) (FIrpic) with sky blue emission and bis(1-phenylisoquinoline)(acetylacetonate) (Ir(piq)) for red emission). The efficiency is 42.3 cd A(-1) at 4000 cd cm(-2) for devices comprising the three primary colors (FIrpic, Ir(piq), and tris(2-(4 tolyl)pyridinato-N,C(2)) (Ir(mppy)(3)), with green emission). These values are, respectively, 35% and 41% higher than those of control devices fabricated on indium tin oxide (ITO) coated on glass substrates. The enhanced current efficiency is attributed to enhanced light out-coupling thanks to light scattering by the silver nanowires embedded in the transparent composite electrode. PMID- 22932689 TI - Chiral recognition in metal-organic frameworks studied by solid-state NMR spectroscopy using chiral solvating agents. AB - Recently, we have described the synthesis of chiral metal-organic frameworks iPr ChirUMCM-1 and Bn-ChirUMCM-1 and their use in enantioselective separation. Here, we demonstrate for the first time the use of a chiral solvating agent (1-phenyl 2,2,2-trifluoroethanol, TFPE) for chiral recognition in iPr-ChirUMCM-1 and Bn ChirUMCM-1 by means of solid-state(13)C NMR spectroscopy. PMID- 22932690 TI - A high voltage organic-inorganic hybrid photovoltaic cell sensitized with metal ligand interfacial complexes. AB - A thin solid-state photovoltaic cell of organic-inorganic hetero junctions was fabricated by forming a dye-metal charge-transfer complex as the sensitizer monolayer at the interface of crystalline state organic and inorganic semiconductors. The organic-inorganic hybrid thin-film photocell generates a high photovoltage of 1.2 V, yielding an energy conversion efficiency of up to 1.5%. PMID- 22932691 TI - Use of a custom alignment guide to improve glenoid component position in total shoulder arthroplasty. AB - PURPOSE: Total and reverse total shoulder arthroplasty (TSA) are used to treat patients with glenohumeral joint osteoarthritis. The revision rate remains high compared with hip and knee arthroplasty. Glenoid component loosening is an important complication and may be caused by poor positioning of the component. We aimed to evaluate the safety and accuracy of a custom glenoid jig created using preoperative computed tomography (CT) imaging with 3D modelling for glenoid component implantation. METHODS: Preoperative CT scans of each shoulder (N = 7) were obtained. Implants were virtually aligned and custom templates were created for intraoperative use. A two-part custom jig was manufactured for alignment of the central peg and the peripheral screws. Three-dimensional orientation of the component and screws was evaluated in postoperative CT scans. The difference between the preoperative plan and the result was then calculated. RESULTS: No technical difficulties or complications occurred. The mean absolute difference between the planned alignment and the postoperative placement of the glenoid component in the three-dimensional space was 3.4 mm (SD = 1 mm). The total average difference for all screws (N = 10) was 6.3 degrees (SD = 3.2 degrees ). CONCLUSION: A CT-based custom glenoid component alignment can reliably guide the placement of the glenoid component during conventional and reverse TSA. This custom jig may be useful for optimizing glenoid component position in the setting of reverse and TSA. PMID- 22932693 TI - Semiological study of ictal affective behaviour in epilepsy and mental retardation limited to females (EFMR). AB - Epilepsy and mental retardation limited to females (EFMR) is a genetic disorder that affects females but spares transmitting males. The condition is caused by protocadherin 19 mutations and is characterised by seizures beginning at around 1 year of age, frequently associated with cognitive regression at seizure onset or later. Seizures can be generalised or focal, exacerbated by febrile illnesses, and grouped in clusters. This report shows the first video-EEG recording of EFMR, in a 7-year-old female presenting peculiar ictal features. [Published with video sequences]. PMID- 22932692 TI - Translation, cultural adaptation, validity and reliability of the Turkish ASES questionnaire. AB - PURPOSE: The American Shoulder and Elbow Surgeons Standardized Shoulder Assessment Form (ASES) is a standard shoulder assessment form, which is comprised of objective and subjective sections and prepared by shoulder and elbow surgeons. The purpose of this study was to translate the subjective part of the ASES into Turkish and establish its cultural adaptiveness and validity. METHODS: The original version of the ASES was translated into Turkish in accordance with the stages recommended by Guillemin. Sixty-three patients (average age: 48.2 +/- 13.4; range: 18-74 years) suffering from different shoulder complaints were included in the study. The ASES was completed twice at 3- to 7-day intervals for test-retest reliability. The intraclass correlation coefficient was used to calculate the test-retest reliability, and Cronbach's alpha was used for internal consistency. Patients were asked to complete the short form 36 (SF-36) and the Shoulder Pain and Disability Index (SPADI) for correlation. Validity was evaluated by external correlation of the ASES with the SPADI and SF-S6 questionnaire, which may also be defined as 'construct validity'. The results were analysed using Pearson's correlation test. RESULTS: The test-retest reliability of the ASES pain and function subscales and total ASES score were 0.95, 0.86 and 0.94, respectively. Cronbach's alpha coefficient for the total ASES was 0.88. The correlation between the total ASES and total SPADI score was 0.82; the correlation coefficient between the ASES pain subscale and SPADI pain subscale was -0.79 (p < 0.000); and the correlation between the ASES and SPADI function subscales were -0.53 (p < 0.000). The highest correlation was between ASES and SF-36 bodily pain, as well as ASES and SF-36 mental health (r = 0.64, r = 0.56, p < 0.000), and the lowest correlations were between ASES and the SF-36 physical component score and between ASES and SF-36 social function (r = 0.28, r = 0.33 p < 0.000). CONCLUSION: The Turkish version of the ASES is a valid and reliable shoulder assessment form that can be used for numerous shoulder disorders. LEVEL OF EVIDENCE: III. PMID- 22932694 TI - A phase II study of concurrent chemoradiotherapy with weekly docetaxel and cisplatin in advanced oesophageal cancer. AB - BACKGROUND: Concurrent chemoradiotherapy (CRT) is a main treatment option for patients with advanced oesophageal cancer. However, improvement of survival outcomes and toxicities according to the selected treatment is still needed. This phase II trial was conducted to assess the efficacy and safety of concurrent CRT with weekly docetaxel and cisplatin in advanced oesophageal cancer. METHODS: Patients with unresectable oesophageal cancer due to advanced stage or patients medically unfit for surgery were enrolled. Patients received 20 mg/m(2) docetaxel and 25 mg/m(2) cisplatin in weeks 1, 2, 3, 5, 6, and 7 with concurrent 54-Gy radiotherapy at 200 cGy/day. RESULTS: Thirty-six patients with oesophageal squamous cell carcinoma were enrolled from December 2007 to December 2009. Among them, the toxicity and response rate of 35 were evaluated. Thirty-five patients completed radiotherapy as planned, and 33 completed chemotherapy as planned. Grade 3 or 4 toxicity during CRT included leucopenia (5.7 %), febrile neutropenia (2.9 %), oesophagitis (22.9 %), and tracheo-oesophageal fistula (5.7 %). After CRT, 8 patients (22.9 %) had a complete response, 22 (62.9 %) had a partial response, 4 (11.4 %) had stable disease, and 1 (2.9 %) had progressive disease. Improvement of dysphagia was observed in 85.3 %. At a median follow-up of 26.7 months, the median time to progression was 13.5 months, and median overall survival was 26.9 months. The 3-year progression-free survival rate was 16.7 %, and survival rate was 27.8 %. CONCLUSION: Concurrent CRT with weekly docetaxel and cisplatin was well tolerated and is a convenient combination with promising efficacy. This result indicated favourable activity in terms of both tumour and symptom control. PMID- 22932695 TI - Phonons, phasons and atomic dynamics in quasicrystals. AB - We review some of the results obtained for the study of phason, phonon and atomic dynamics in quasicrystals. In the framework of the hydrodynamic theory long wavelength phason modes are characteristic of quasicrystal and are diffusive modes. Quenched-in phason mode gives rise to a characteristic diffuse scattering, observed in all the 'stable' icosahedral quasicrystals studied so far. In the AlPdMn icosahedral phase, above T = 500 degrees C, equilibrium phason modes are shown to be diffusive modes in agreement with the hydrodynamic theory. The lattice dynamics has been studied by inelastic neutron or X-ray scattering. Well defined acoustic modes are only observed for wavevectors smaller than 0.3 A(-1). Above this value, the mode rapidly broadens as a result of mixing with higher energy modes. We show that the results can be interpreted using the concept of pseudo-Brillouin zone boundary and can qualitatively explain the differences observed in the response function of the ZnSc 1/1 approximant and its quasicrystalline counterpart. The observations are qualitatively and quantitatively reproduced using oscillating pair potentials, which open the route for a detailed analysis of the lattice dynamics at the atomic scale. An exceptional dynamical flexibility is also evidenced in the 1/1 approximant. A brief discussion on the implication of those results on the stabilizing mechanisms of quasicrystals is given at the end of the paper. PMID- 22932696 TI - Erg is a crucial regulator of endocardial-mesenchymal transformation during cardiac valve morphogenesis. AB - During murine embryogenesis, the Ets factor Erg is highly expressed in endothelial cells of the developing vasculature and in articular chondrocytes of developing bone. We identified seven isoforms for the mouse Erg gene. Four share a common translational start site encoded by exon 3 (Ex3) and are enriched in chondrocytes. The other three have a separate translational start site encoded by Ex4 and are enriched in endothelial cells. Homozygous Erg(DeltaEx3/DeltaEx3) knockout mice are viable, fertile and do not display any overt phenotype. By contrast, homozygous Erg(DeltaEx4/DeltaEx4) knockout mice are embryonic lethal, which is associated with a marked reduction in endocardial-mesenchymal transformation (EnMT) during cardiac valve morphogenesis. We show that Erg is required for the maintenance of the core EnMT regulatory factors that include Snail1 and Snail2 by binding to their promoter and intronic regions. PMID- 22932697 TI - Influenza A(H1N1)pdm09 virus among healthy show pigs, United States. AB - Within 5 months after the earliest detection of human influenza A(H1N1)pdm09 virus, we found molecular and culture evidence of the virus in healthy US show pigs. The mixing of humans and pigs at swine shows possibly could further the geographic and cross-species spread of influenza A viruses. PMID- 22932698 TI - PPARGC1A/PGC-1alpha, TFEB and enhanced proteostasis in Huntington disease: defining regulatory linkages between energy production and protein-organelle quality control. AB - Huntington disease (HD) results from CAG repeats that encode expanded polyglutamine tracts in the HTT/huntingtin protein. HD belongs to a large category of inherited and sporadic neurodegenerative disorders in which production of a misfolded protein initiates the pathogenic cascade. Previous studies have shown that misfolded proteins become resistant to cellular protein turnover pathways by eluding and disabling the ubiquitin-proteasome system (UPS) and autophagy-lysosome pathway. Based upon earlier work implicating impaired PPARGC1A function in HD, we derived inducible PPARGC1A mice and crossed them with HD mice. We found that PPARGC1A overexpression can rescue HD neurological phenotypes and neurodegeneration. An unexpected outcome of the rescue was the virtual elimination of huntingtin aggregates, and we found that PPARGC1A-mediated aggregate elimination required the autophagy pathway. Moreover, we observed decreased expression of transcription factor EB (TFEB), a master regulator of the autophagy-lysosome pathway, in HD cells and mice, and documented PPARGC1A co activation of TFEB in these model systems, noting that PPARGC1A is upstream of TFEB in promoting proteostasis. These findings underscore the importance of bioenergetics and autophagy in neurodegeneration, and indicate that PPARGC1A promotes mitochondrial quality control to support high-energy production states in cells, such as neurons. As impaired energy production and altered protein organelle quality control appear inextricably linked in disorders such as HD, Parkinson disease, and Alzheimer disease, efforts directed at enhancing PPARGC1A and TFEB action may represent viable strategies for therapy development in neurodegeneration. PMID- 22932699 TI - Salmonella enterica serovar Agbeni, British Columbia, Canada, 2011. PMID- 22932700 TI - Do pancreatic beta cells "taste" nutrients to secrete insulin? AB - Insulin secretion from pancreatic beta cells is controlled by nutrients, hormones, and neurotransmitters. Unlike the latter, which work through classic receptors, glucose and most other nutrients do not interact with membrane receptors but must be metabolized by beta cells to induce insulin secretion. Studies have revealed the presence of umami and sweet taste receptors and their downstream effectors in beta cells. That the receptors are functional was established by the effects of fructose and artificial sweeteners, which induced signals similar to those produced in taste buds of the tongue. These signals mediated an increase in insulin secretion in the presence of glucose. However, the physiological implications of these pathways in insulin secretion are unclear because of the large differences between plasma concentrations of fructose or sweeteners and their effective concentrations in vitro. PMID- 22932701 TI - A VASP-Rac-soluble guanylyl cyclase pathway controls cGMP production in adipocytes. AB - The ubiquitous second messenger cyclic guanosine monophosphate (cGMP) plays an important role in metabolism and promotes brown adipocyte differentiation. We showed that ablation of the gene encoding vasodilator-stimulated phosphoprotein (VASP), a major downstream component of the cGMP signaling cascade, increased cellular cGMP content in brown and white adipocytes and mouse embryonic fibroblasts. VASP-deficient cells showed increased activation of Rac1, which in turn increased the abundance of the cGMP-producing enzyme soluble guanylyl cyclase (sGC), the main receptor for nitric oxide. Consequently, loss of VASP caused increased cGMP concentrations and enhanced brown adipocyte differentiation. Consistent with the in vitro data, we found increased energy expenditure in VASP-deficient mice and exposure to cold triggered enhanced lipolysis and cellular respiration in VASP-deficient brown fat cells. In addition, VASP-deficient mice exhibited increased development of brown-like adipocytes in white fat. Our data revealed that a VASP to Rac to sGC negative feedback loop limited cGMP production, thereby regulating adipogenesis and energy homeostasis. PMID- 22932703 TI - Left ventricular mass index as a predictor of new-onset microalbuminuria in hypertensive subjects: a prospective study. AB - BACKGROUND: We aimed to investigate the predictive role of left ventricular mass and its reduction on the development of new-onset microalbuminuria (MA) in newly diagnosed hypertensive patients. METHODS: A total of 207 nondiabetic, normoalbuminuric patients without clinical organ damage (aged 50.8 +/- 10.1 years, 132 male, 84 smokers) with baseline office blood pressure (BP) 148/96 mm Hg were followed for a mean period of 3.3 +/- 1.3 years. At baseline and last follow-up visit, all patients underwent office and 24-h ambulatory BP monitoring, albumin to creatinine ratio (ACR) determination, and echocardiographic assessment of left ventricular mass index (LVMI). All patients were treated with antihypertensive therapy during the follow-up period. We defined MA as ACR between 20 and 300 mg/g for men and 30-300 mg/g for women, effective BP control as office BP <140/90 mm Hg in >=75% of total number of visits, and LVMI reduction as the decline of LVMI at end-follow-up of >=15% with respect to the baseline value. RESULTS: Between baseline and last follow-up visit, LVMI decreased by 6.84 +/- 21.5 g/m(2) (P < 0.01); 64.3% (n = 133) of participants achieved BP control during the follow-up period. Of the total population, 5.8% (n = 12) developed MA during follow-up. Cox-regression analysis, after adjustment for clinical variables, revealed that increase of LVMI by 1 s.d. (23.3 g/m(2)) conferred a 15% increased risk of new-onset MA, while LVMI reduction and BP control were both associated with almost 100% reduced risk of MA development. CONCLUSIONS: LVMI and its reduction were qualified as predictors of new-onset MA in newly diagnosed hypertensive patients, beyond BP control. PMID- 22932702 TI - The complex of G protein regulator RGS9-2 and Gbeta(5) controls sensitization and signaling kinetics of type 5 adenylyl cyclase in the striatum. AB - Multiple neurotransmitter systems in the striatum converge to regulate the excitability of striatal neurons by activating several heterotrimeric guanine nucleotide-binding protein (G protein)-coupled receptors (GPCRs) that signal to the type 5 adenylyl cyclase (AC5), the key effector enzyme that produces the intracellular second messenger cyclic adenosine monophosphate (cAMP). Plasticity of cAMP signaling in the striatum is thought to play an essential role in the development of drug addiction. We showed that the complex of the ninth regulator of G protein signaling (RGS9-2) with the G protein beta subunit (Gbeta(5)) critically controlled signaling from dopamine and opioid GPCRs to AC5 in the striatum. RGS9-2/Gbeta(5) directly interacted with and suppressed the basal activity of AC5. In addition, the RGS9-2/Gbeta(5) complex attenuated the stimulatory action of Gbetagamma on AC5 by facilitating the GTPase (guanosine triphosphatase) activity of Galpha(o), thus promoting the formation of the inactive heterotrimer and inhibiting Gbetagamma. Furthermore, by increasing the deactivation rate of Galpha(i), RGS9-2/Gbeta(5) facilitated the recovery of AC5 from inhibition. Mice lacking RGS9 showed increased cAMP production and, upon withdrawal from opioid administration, enhanced sensitization of AC5. Our findings establish RGS9-2/Gbeta(5) complexes as regulators of three key aspects of cAMP signaling: basal activity, sensitization, and temporal kinetics of AC5, thus highlighting the role of this complex in regulating both inhibitory and stimulatory GPCRs that shape cAMP signaling in the striatum. PMID- 22932704 TI - Influence of renin angiotensin system gene polymorphisms on visit-to-visit blood pressure variability in hypertensive patients. AB - BACKGROUND: Visit-to-visit blood pressure (BP) variability has been reported to be a major risk for cardiovascular events. Renin angiotensin system (RAS) gene polymorphisms are reportedly genetic risk factors for cardiovascular diseases and arterial stiffness. In this study, we aimed to reveal the relationship between visit-to-visit BP variability and RAS gene polymorphisms. METHODS: Study subjects included 427 essential hypertension patients from the Non-Invasive Atherosclerotic Evaluation in Hypertension study cohort, whose BP was measured during at least six outpatient visits. We analyzed the correlation between visit to-visit variability in systolic BP (SBP) and RAS gene polymorphisms. RESULTS: We identified angiotensinogen M235T, angiotensin II type 1 receptor A1166C, and angiotensin-converting enzyme (ACE) insertion/deletion (I/D) polymorphisms. Only ACE I/D polymorphisms were correlated with variability in diastolic BP; no gene polymorphisms were correlated with variability in SBP. CONCLUSIONS: RAS gene polymorphisms, especially ACE I/D polymorphisms, might genetically influence the visit-to-visit BP variability in hypertensive patients. PMID- 22932705 TI - Intermittent levosimendan infusions in advanced heart failure: favourable effects on left ventricular function, neurohormonal balance, and one-year survival. AB - The role of repeated infusions of Levosimendan (LEVO) in patients with chronic advanced heart failure is still unclear. Thirty-three patients with chronic heart failure presenting clinical deterioration were randomized 2:1 to receive monthly infusions of LEVO (n = 22) or Furosemide (Controls, n = 11). At the first drug's administration, noninvasive hemodynamic evaluation was performed; before and after each infusion, we assessed NYHA class, systolic and diastolic function, functional mitral regurgitation, and brain natriuretic peptide (BNP) levels. Noninvasive hemodynamic in the LEVO group showed vasodilation and decrease in thoracic conductance (index of pulmonary congestion), whereas in Controls, only a reduced thoracic conductance was observed. In the LEVO group, systolic and diastolic function, ventricular volumes, severity of mitral regurgitation, and BNP levels improved over time from baseline and persisted 4 weeks after the last infusion (P < 0.01). In Controls, no change developed over time in cardiac function and BNP levels. In LEVO-treated patients, 1-year mortality tended to be lower than in those treated with Furosemide. In conclusion, serial LEVO infusions in advanced heart failure improved ventricular performance and favorably modulated neurohormonal activation. Multicenter randomized studies are warranted to test the effect of LEVO on long-term outcome. PMID- 22932706 TI - Flecainide-induced proarrhythmia is attributed to abnormal changes in repolarization and refractoriness in perfused guinea-pig heart. AB - Flecainide is nonselective Na(+) channel blocker which may also inhibit I(Kr), the rapid component of the delayed rectifier. This study was designed to explore if proarrhythmic responses to flecainide noted in cardiac patients may be partly attributed to abnormal changes in repolarization and refractoriness. Monophasic action potential duration (APD) and effective refractory periods (ERP) were assessed at distinct epicardial and endocardial sites along with volume-conducted ECG recordings in isolated perfused guinea-pig heart preparations. Flecainide was found to prolong ventricular repolarization, with effect being greater at the left ventricular compared with the right ventricular epicardium. This change translated to reversal of the normal right ventricular-to-left ventricular transepicardial APD difference determined before drug infusion. An inverse correlation between local epicardial APD and corresponding activation time values seen at baseline was eliminated in flecainide-treated hearts, indicating the activation-to-repolarization uncoupling. Over transmural plane, flecainide produced a greater ERP lengthening at endocardium than epicardium, thus markedly increasing ERP dispersion across ventricular wall. Spontaneous short-lasting episodes of monomorphic ventricular tachycardia were observed in 45% of heart preparations upon flecainide infusion. In conclusion, in nonischemic guinea-pig heart, flecainide-induced proarrhythmia may be partly attributed to abnormal spatial gradients in repolarization and refractoriness and impaired transepicardial activation-to-repolarization coupling. PMID- 22932707 TI - Dipeptidyl peptidase-4 inhibition with saxagliptin enhanced nitric oxide release and reduced blood pressure and sICAM-1 levels in hypertensive rats. AB - Most patients with diabetes also have hypertension, a risk factor associated with atherothrombotic disease and characterized by endothelial cell (EC) dysfunction and loss of nitric oxide (NO) bioavailability. Recent studies suggest a possible antihypertensive effect with dipeptidyl peptidase-4 (DPP4) inhibition; however, the underlying mechanism is not understood. In this study, we tested the effects of the DPP4 inhibitor, saxagliptin, on EC function, blood pressure, and soluble intercellular adhesion molecule 1 (sICAM-1) levels in hypertensive rats. Spontaneously hypertensive rats were treated with vehicle or saxagliptin (10 mg.kg(-1).day(-1)) for 8 weeks. NO and peroxynitrite (ONOO(-)) release from aortic and glomerular ECs was stimulated with calcium ionophore and measured using electrochemical nanosensor technology. Changes in EC function were correlated with fasting glucose levels. Saxagliptin treatment was observed to increase aortic and glomerular NO release by 22% (P < 0.001) and 23% (P < 0.001), respectively, with comparable reductions in ONOO(-) levels; the NO/ONOO(-) ratio increased by >50% in both EC types (P < 0.001) as compared with vehicle. Saxagliptin also reduced mean arterial pressure from 170 +/- 10 to 158 +/- 10 mm Hg (P < 0.001) and decreased sICAM-1 levels by 37% (P < 0.01). The results of this study suggest that DPP4 inhibition reduces blood pressure and inflammation in hypertensive rats while increasing NO bioavailability. PMID- 22932708 TI - M3-mAChR stimulation exerts anti-apoptotic effect via activating the HIF 1alpha/HO-1/VEGF signaling pathway in H9c2 rat ventricular cells. AB - BACKGROUND: The protective role of M(3)-mAChR against apoptosis has been identified previously. However, the underlying mechanisms remain unclear. This study was performed to clarify the signaling pathways of the anti-apoptotic effect mediated by activation of M(3)-mAChR in cultured cardiac H9c2 cells. METHODS: Both H9c2 rat ventricular cells and H9c2 cells with stable expression of M(3)-mAChR were used. RESULTS: Activation of M(3)-mAChR by cabarchol produced protective effect on etoposide-induced apoptosis in H9c2 cells. Forced overexpression of M(3)-mAChR in H9c2 cells further enhanced this effect. Application of 4-diphenyl-acetoxy-N-methyl-piperidine methiodide (inhibitor of M(3)-mAChR), YC-1 [inhibitor of hypoxia-inducible factor 1, (HIF-1], or ZnPP (inhibitor of heme oxygenase-1)abrogated carbacol-induced cardioprotection, respectively. Moreover, the expression of HIF-1alpha, HO-1, and vascular endothelial growth factor (VEGF) were enhanced after the activation of M3-mAChR, and the induction of HO-1 and VEGF was reversed by HIF-1alpha inhibitor YC-1. CONCLUSIONS: These findings indicated that M(3)-mAChR upregulates HO-1 and VEGF expression likely through induction of HIF-1alpha, which at least partly underlies the cytoprotection of M(3)-mAChR activation in H9c2 cells. PMID- 22932709 TI - Selective syntheses of no-carrier-added 2- and 3-[18F]fluorohalopyridines through the radiofluorination of halopyridinyl(4'-methoxyphenyl)iodonium tosylates. AB - No-carrier-added 2- and 3-[(18)F]fluorohalopyridines were readily synthesized as potentially useful labeling synthons for prospective PET radiotracers through the selective radiofluorination of halopyridinyl(4'-methoxyphenyl)iodonium tosylates, themselves conveniently prepared in a single pot from iodohalopyridines. PMID- 22932710 TI - Entamoeba bangladeshi nov. sp., Bangladesh. PMID- 22932711 TI - Heart failure--does it matter whether LVEF is reduced? PMID- 22932712 TI - Assessment of stent retrievers in acute ischaemic stroke. PMID- 22932713 TI - Improving long-term outcome after myocardial infarction. PMID- 22932715 TI - Solitaire flow restoration device versus the Merci Retriever in patients with acute ischaemic stroke (SWIFT): a randomised, parallel-group, non-inferiority trial. AB - BACKGROUND: The Solitaire Flow Restoration Device is a novel, self-expanding stent retriever designed to yield rapid flow restoration in acute cerebral ischaemia. We compared the efficacy and safety of Solitaire with the standard, predicate mechanical thrombectomy device, the Merci Retrieval System. METHODS: In this randomised, parallel-group, non-inferiority trial, we enrolled patients from 18 sites (17 in the USA and one in France). Patients were eligible for inclusion if they had acute ischaemic stroke with moderate to severe neurological deficits and were treatable by thrombectomy within 8 h of stroke symptom onset. We used a computer-generated randomisation sequence to randomly allocate patients to receive thrombectomy treatment with either Solitaire or Merci (1:1; block sizes of four and stratified by centre and stroke severity). The primary endpoint was Thrombolysis In Myocardial Ischemia (TIMI) scale 2 or 3 flow in all treatable vessels without symptomatic intracranial haemorrhage, after up to three passes of the assigned device, as assessed by an independent core laboratory, which was masked to study assignment. Primary analysis was done by intention to treat. A prespecified efficacy stopping rule triggered an early halt to the trial. The study is registered with ClinicalTrials.gov, number NCT 01054560. RESULTS: Between February, 2010, and February, 2011, we randomly allocated 58 patients to the Solitaire group and 55 patients to the Merci group. The primary efficacy outcome was achieved more often in the Solitaire group than it was in the Merci group (61%vs 24%; difference 37% [95% CI 19-53], odds ratio [OR] 4.87 [95% CI 2.14-11.10]; p(non-inferiority)<0.0001, p(superiority)=0.0001). More patients had good 3-month neurological outcome with Solitaire than with Merci (58%vs 33%; difference 25% [6-43], OR 2.78 [1.25-6.22]; p(non-inferiority)=0.0001, p(superiority)=0.02). 90-day mortality was lower in the Solitaire group than it was in the Merci group (17 vs 38; difference -21% [-39 to -3], OR 0.34 [0.14 0.81]; p(non-inferiority)=0.0001, p(superiority)=0.02). INTERPRETATION: The Solitaire Flow Restoration Device achieved substantially better angiographic, safety, and clinical outcomes than did the Merci Retrieval System. The Solitaire device might be a future treatment of choice for endovascular recanalisation in acute ischaemic stroke. FUNDING: Covidien/ev3. PMID- 22932714 TI - Trevo versus Merci retrievers for thrombectomy revascularisation of large vessel occlusions in acute ischaemic stroke (TREVO 2): a randomised trial. AB - BACKGROUND: Present mechanical devices are unable to achieve recanalisation in up to 20-40% of large vessel occlusion strokes. We compared efficacy and safety of the Trevo Retriever, a new stent-like device, with its US Food and Drug Administration-cleared predecessor, the Merci Retriever. METHODS: In this open label randomised controlled trial, we recruited patients at 26 sites in the USA and one in Spain. We included adults aged 18-85 years with angiographically confirmed large vessel occlusion strokes and US National Institutes of Health Stroke Scale (NIHSS) scores of 8-29 within 8 h of symptom onset. We randomly assigned patients (1:1) with sequentially numbered sealed envelopes to thrombectomy with Trevo or Merci devices. Randomisation was stratified by age (<=68 years vs 69-85 years) and NIHSS scores (<=18 vs 19-29) with alternating blocks of various sizes. The primary efficacy endpoint, assessed by an unmasked core laboratory, was thrombolysis in cerebral infarction (TICI) scores of 2 or greater reperfusion with the assigned device alone. The primary safety endpoint was a composite of procedure-related adverse events. Analyses were done by intention to treat. This study is registered with ClinicalTrials.gov, number NCT01270867. FINDINGS: Between Feb 3, 2011, and Dec 1, 2011, we randomly assigned 88 patients to the Trevo Retriever group and 90 patients to Merci Retriever group. 76 (86%) patients in the Trevo group and 54 (60%) in the Merci group met the primary endpoint after the assigned device was used (odds ratio 4.22, 95% CI 1.92-9.69; p(superiority)<0.0001). Incidence of the primary safety endpoint did not differ between groups (13 [15%] patients in the Trevo group vs 21 [23%] in the Merci group; p=0.1826). INTERPRETATION: Patients who have had large vessel occlusion strokes but are ineligible for (or refractory to) intravenous tissue plasminogen activator should be treated with the Trevo Retriever in preference to the Merci Retriever. FUNDING: Stryker Neurovascular. PMID- 22932716 TI - Vorapaxar for secondary prevention of thrombotic events for patients with previous myocardial infarction: a prespecified subgroup analysis of the TRA 2 degrees P-TIMI 50 trial. AB - BACKGROUND: Vorapaxar inhibits platelet activation by antagonising thrombin mediated activation of the protease-activated receptor 1 on human platelets. The effect of adding other antiplatelet drugs to aspirin for long-term secondary prevention of thrombotic events in stable patients with previous myocardial infarction is uncertain. We tested this effect in a subgroup of patients from the Thrombin Receptor Antagonist in Secondary Prevention of Atherothrombotic Ischemic Events (TRA 2 degrees P)-TIMI 50 trial. METHODS: In TRA 2 degrees P-TIMI 50--a randomised, placebo-controlled, parallel trial--we randomly assigned patients with a history of atherothrombosis to receive vorapaxar (2.5 mg daily) or matching placebo in a 1:1 ratio. Patients, and those giving treatment, assessing outcomes, and analysing results were masked to treatment allocation. Patients with a qualifying myocardial infarction within the previous 2 weeks to 12 months were analysed as a pre-defined subgroup. The primary efficacy endpoint was cardiovascular death, myocardial infarction, or stroke, analysed by intention to treat. We analysed events by Kaplan-Meier analysis and compared groups with a Cox proportional hazard model. TRA 2 degrees P-TIMI 50 is registered at ClinicalTrials.gov (NCT00526474). FINDINGS: 17,779 of 26,449 patients had a qualifying myocardial infarction and were assigned treatment (8898 to vorapaxar and 8881 to placebo). Median follow-up was 2.5 years (IQR 2.0-2.9). Cardiovascular death, myocardial infarction, or stroke occurred in 610 of 8898 patients in the vorapaxar group and 750 of 8881 in the placebo group (3-year Kaplan-Meier estimates 8.1%vs 9.7%, HR 0.80, 95% CI 0.72-0.89; p<0.0001). Moderate or severe bleeding was more common in the vorapaxar group versus the placebo group (241/8880 [3.4%, 3-year Kaplan-Meier estimate] vs 151/8849 [2.1%, 3 year Kaplan-Meier estimate], HR 1.61, 95% CI 1.31-1.97; p<0.0001). Intracranial haemorrhage occurred in 43 of 8880 patients (0.6%, 3-year Kaplan-Meier estimate) with vorapaxar versus 28 of 8849 (0.4%, 3-year Kaplan-Meier estimate) with placebo (p=0.076). Other serious adverse events were equally distributed between groups. INTERPRETATION: For patients with a history of myocardial infarction, inhibition of protease-activated receptor 1 with vorapaxar reduces the risk of cardiovascular death or ischaemic events when added to standard antiplatelet treatment, including aspirin, and increases the risk of moderate or severe bleeding. FUNDING: Merck. PMID- 22932718 TI - Chemo- and enantioselective Rh-catalysed hydrogenation of 3-methylene-1,2 diazetidines: application to vicinal diamine synthesis. AB - Rhodium catalysed hydrogenation of 3-methylene-1,2-diazetidines with a range of chiral ligands is reported. Using Mandyphos, excellent levels of chemo- and enantioselectivity (up to 89% ee) can be achieved. Reductive cleavage of the derived 3-substituted 1,2-diazetidine with LiDBB provides the enantioenriched biscarbamate protected 1,2-diamine. PMID- 22932719 TI - Self-assembly of isomeric clamshell dimers of platinum(II). AB - The controlled synthesis of isomeric organoplatinum clamshell dimers [Pt(2)Me(2)(MU(2)-kappa(3)-6-dppd)(2)](2+), 6-dppd = 1,4-di-2-pyridyl 5,6,7,8,9,10-hexahydrocycloocta[d]pyridazine, is reported. The new complexes are formed selectively by self-assembly from mononuclear precursors, taking advantage of the slow cis-trans isomerization at platinum(II). Thus reaction of endo [PtClMe(kappa(2)-6-dppd)] with AgOTf gave endo,endo-[Pt(2)Me(2)(MU(2)-kappa(3)-6 dppd)(2)](2+), while the reaction of [PtMe(2)(kappa(2)-6-dppd)] with HOTf in solvent S = Me(2)C=O or MeCN gave first a mixture of exo- and endo [PtMe(S)(kappa(2)-6-dppd)](+) and then, by loss of solvent, a mixture of exo,exo- and endo,endo-[Pt(2)Me(2)(MU(2)-kappa(3)-6-dppd)(2)](2+). The endo,endo isomer slowly isomerized to the more stable exo,exo isomer in solution. Reaction of PPh(3) with endo-[PtClMe(kappa(2)-6-dppd)] gave a mixture of endo- and exo [PtMe(PPh(3))(kappa(2)-6-dppd)](+) but reaction with exo,exo-[Pt(2)Me(2)(MU(2) kappa(3)-6-dppd)(2)](2+) gave exo-[PtMe(PPh(3))(kappa(2)-6-dppd)](+) selectively, with retention of stereochemistry. The structures of the clamshell dimers and of key precursors are reported and equilibria are studied both experimentally and by DFT calculations. PMID- 22932717 TI - The angiotensin receptor neprilysin inhibitor LCZ696 in heart failure with preserved ejection fraction: a phase 2 double-blind randomised controlled trial. AB - BACKGROUND: Heart failure with preserved ejection fraction is associated with substantial morbidity and mortality, but effective treatments are lacking. We assessed the efficacy and safety of LCZ696, a first-in-class angiotensin receptor neprilysin inhibitor (ARNI), in patients with this disorder. METHODS: PARAMOUNT was a phase 2, randomised, parallel-group, double-blind multicentre trial in patients with New York Heart Association (NYHA) class II-III heart failure, left ventricular ejection fraction 45% or higher, and NT-proBNP greater than 400 pg/mL. Participants were randomly assigned (1:1) by central interactive voice response system to LCZ696 titrated to 200 mg twice daily or valsartan titrated to 160 mg twice daily, and treated for 36 weeks. Investigators and participants were masked to treatment assignment. The primary endpoint was change in NT-proBNP, a marker of left ventricular wall stress, from baseline to 12 weeks; analysis included all patients randomly assigned to treatment groups who had a baseline and at least one postbaseline assessment. This trial is registered at Clinicaltrials.gov, number NCT00887588. FINDINGS: 149 patients were randomly assigned to LCZ696 and 152 to valsartan; 134 in the LCZ696 group and 132 in the valsartan group were included in analysis of the primary endpoint. NT-proBNP was significantly reduced at 12 weeks in the LCZ696 group compared with the valsartan group (LCZ696: baseline, 783 pg/mL [95% CI 670-914], 12 weeks, 605 pg/mL [512 714]; valsartan: baseline, 862 pg/mL [733-1012], 12 weeks, 835 [710-981]; ratio LCZ696/valsartan, 0.77, 95% CI 0.64-0.92, p=0.005). LCZ696 was well tolerated with adverse effects similar to those of valsartan; 22 patients (15%) on LCZ696 and 30 (20%) on valsartan had one or more serious adverse event. INTERPRETATION: In patients with heart failure with preserved ejection fraction, LCZ696 reduced NT-proBNP to a greater extent than did valsartan at 12 weeks and was well tolerated. Whether these effects would translate into improved outcomes needs to be tested prospectively. FUNDING: Novartis. PMID- 22932720 TI - The National Institute on Aging-Alzheimer's Association research criteria for mild cognitive impairment due to Alzheimer's disease: predicting the outcome. AB - The National Institute on Aging-Alzheimer's Association (NIA-AA) clinical research criteria for mild cognitive impairment (MCI) due to Alzheimer's disease (AD) incorporate the use of biomarkers to classify patients according to the likelihood of the presence of AD pathology. The aim of the study was to compare the risk of progression to AD dementia between the four NIA-AA MCI subgroups using data from the AD Neuroimaging Initiative. Patients with MCI were categorised according to the NIA-AA criteria into subgroups with high, intermediate, and low likelihood of the presence of AD pathology (MCI-high, MCI intermediate, and MCI-unlikely, respectively) or into a group of patients that only met the MCI-core clinical criteria (MCI-core). Data of follow-up visits conducted 6-60 months after baseline were used to compare the relative risk of future AD dementia between the four subgroups employing a Cox regression model. The MCI-high subgroup (N = 22) had a 2.3 times higher risk of developing AD dementia compared with the MCI-core subgroup (N = 327; P = 0.002), while there was a trend for a higher risk in the MCI-high subgroup in contrast to the MCI intermediate subgroup (N = 31, P = 0.08). No patients in the MCI-unlikely subgroup (N = 17) progressed to AD dementia. Patients with MCI-high have a higher risk for developing AD dementia. The new NIA-AA MCI criteria represent a valuable research instrument that could be incorporated into the diagnostic process of the MCI syndrome after optimisation and refinement. PMID- 22932721 TI - Neuroenhancement strategies for psychiatric disorders: rationale, status quo and perspectives. AB - With the growing mechanistic understanding of higher brain functions like learning and memory, vigilance and social cognition, new pharmacological approaches for the treatment of psychiatric disorders arise. Substances used as neuroenhancers for the improvement of cognitive or emotional functions in healthy subjects might provide novel pharmacological opportunities in psychiatry. Intriguingly, drugs like modafinil, D-cycloserine or oxytocin have shown significant improvements in key symptoms in several psychiatric disorders. When used as augmentation strategies, they could either directly interfere with psychopathological impairments or improve response to other treatment modalities like psychotherapy or psychopharmacological drugs. While initial studies yielded promising results, further research on beneficial or adverse effects is required. PMID- 22932722 TI - Chances and risks of predicting psychosis. AB - Prevention is currently regarded a promising strategy for fighting the unfavorable consequences of psychosis. Yet, for the error probability inherent in any predictive approach, benefits and costs must be carefully weighed against each other. False attribution of risk may unnecessarily provoke stress and anxiety, and lead to unwarranted intervention exposure. However, clinical risk samples already exhibit psychopathological symptoms, cognitive and functional impairments, and help-seeking for mental problems. Thus, the risk of futile interventions is low as long as preventive measures also provide treatment for current complaints. Differentiation between still normal and clinically relevant mental states is another challenge as psychotic-like phenomena occur frequently in the general population, especially in younger adolescents. Reported prevalence rates vary with age, and if severe in terms of frequency and persistence, these phenomena considerably increase risk of psychosis in clinical as well as general population samples. Stigmatization is another concern, though insufficiently studied. Yet, at least more severe states of risk, which are accompanied by changes in thinking, feeling, and behavior, might lead to unfavorable, (self-) stigmatizing effects already by themselves, independent of any diagnostic "label," and to stress and confusion for the lack of understanding of what is going on. To further improve validity of risk criteria, advanced risk algorithms combining multi-step detection and risk stratification procedures should be developed. However, all prediction models possess a certain error probability. Thus, whether a risk model justifies preventive measures can only be decided by weighing the costs of unnecessary intervention and the benefits of avoiding a potentially devastating outcome. PMID- 22932723 TI - Exosome-mediated shuttling of microRNA-29 regulates HIV Tat and morphine-mediated neuronal dysfunction. AB - Neuronal damage is a hallmark feature of HIV-associated neurological disorders (HANDs). Opiate drug abuse accelerates the incidence and progression of HAND; however, the mechanisms underlying the potentiation of neuropathogenesis by these drugs remain elusive. Opiates such as morphine have been shown to enhance HIV transactivation protein Tat-mediated toxicity in both human neurons and neuroblastoma cells. In the present study, we demonstrate reduced expression of the tropic factor platelet-derived growth factor (PDGF)-B with a concomitant increase in miR-29b in the basal ganglia region of the brains of morphine dependent simian immunodeficiency virus (SIV)-infected macaques compared with the SIV-infected controls. In vitro relevance of these findings was corroborated in cultures of astrocytes exposed to morphine and HIV Tat that led to increased release of miR-29b in exosomes. Subsequent treatment of neuronal SH-SY5Y cell line with exosomes from treated astrocytes resulted in decreased expression of PDGF-B, with a concomitant decrease in viability of neurons. Furthermore, it was shown that PDGF-B was a target for miR-29b as evidenced by the fact that binding of miR-29 to the 3'-untranslated region of PDGF-B mRNA resulted in its translational repression in SH-SY5Y cells. Understanding the regulation of PDGF-B expression may provide insights into the development of potential therapeutic targets for neuronal loss in HIV-1-infected opiate abusers. PMID- 22932725 TI - High-mobility group A1 protein inhibits p53-mediated intrinsic apoptosis by interacting with Bcl-2 at mitochondria. AB - The high-mobility group A (HMGA) proteins are a family of non-histone chromatin factors, encoded by the HMGA1 and HMGA2 genes. Several studies demonstrate that HMGA proteins have a critical role in neoplastic transformation, and their overexpression is mainly associated with a highly malignant phenotype, also representing a poor prognostic index. Even though a cytoplasmic localization of these proteins has been previously reported in some highly malignant neoplasias, a clear role for this localization has not been defined. Here, we first confirm the localization of the HMGA1 proteins in the cytoplasm of cancer cells, and then we report a novel mechanism through which HMGA1 inhibits p53-mitochondrial apoptosis by counteracting the binding of p53 to the anti-apoptotic factor Bcl-2. Indeed, we demonstrate a physical and functional interaction between HMGA1 and Bcl-2 proteins. This interaction occurs at mitochondria interfering with the ability of p53 protein to bind Bcl-2, thus counteracting p53-mediated mitochondrial apoptosis. This effect is associated with the inhibition of cytochrome c release and activation of caspases. Consistent with this mechanism, a strong correlation between HMGA1 cytoplasmic localization and a more aggressive histotype of thyroid, breast and colon carcinomas has been observed. Therefore, cytoplasmic localization of HMGA1 proteins in malignant tissues is a novel mechanism of inactivation of p53 apoptotic function. PMID- 22932724 TI - An in vitro perspective on the molecular mechanisms underlying mutant huntingtin protein toxicity. AB - Huntington's disease (HD) is a devastating neurodegenerative disorder whose main hallmark is brain atrophy. However, several peripheral organs are considerably affected and their symptoms may, in fact, manifest before those resulting from brain pathology. HD is of genetic origin and caused by a mutation in the huntingtin gene. The mutated protein has detrimental effects on cell survival, but whether the mutation leads to a gain of toxic function or a loss of function of the altered protein is still highly controversial. Most currently used in vitro models have been designed, to a large extent, to investigate the effects of the aggregation process in neuronal-like cells. However, as the pathology involves several other organs, new in vitro models are critically needed to take into account the deleterious effects of mutant huntingtin in peripheral tissues, and thus to identify new targets that could lead to more effective clinical interventions in the early course of the disease. This review aims to present current in vitro models of HD pathology and to discuss the knowledge that has been gained from these studies as well as the new in vitro tools that have been developed, which should reflect the more global view that we now have of the disease. PMID- 22932726 TI - Aeromonas spp. bacteremia in pregnant women, Thailand-Myanmar border, 2011. PMID- 22932727 TI - The ryanodine receptor leak: how a tattered receptor plunges the failing heart into crisis. AB - It has been persuasively shown in the last two decades that the development of heart failure is closely linked to distinct alterations in Ca(2+) cycling. A crucial point in this respect is an increased spontaneous release of Ca(2+) out of the sarcoplasmic reticulum during diastole via ryanodine receptors type 2 (RyR2). The consequence is a compromised sarcoplasmic reticulum Ca(2+) storage capacity, which impairs systolic contractility and possibly diastolic cardiac function due to Ca(2+) overload. Additionally, leaky RyR2 are more and more regarded to potently induce proarrhythmic triggers. Elimination of spontaneously released Ca(2+) via RyR2 in diastole can cause a transient sarcolemmal inward current and hence delayed after depolarisations as substrate for cardiac arrhythmias. In this article, the pathological role and consequences of the SR Ca(2+)-leak and its regulation are reviewed with a main focus on protein kinase A and Ca(2+)-calmodulin-dependent kinase II. We summarise clinical consequences of "leaky RyR2" as well as possible therapeutic strategies in order to correct RyR2 dysfunction and discuss the significance of the available data. PMID- 22932728 TI - Changes in plasma norepinephrine to combat-related stimuli among Vietnam veterans with posttraumatic stress disorder. J Nerv Ment Dis. 179: 371-373, 1991. PMID- 22932730 TI - Managing the classification of psychiatric diagnoses: a systematics perspective. AB - For almost a century, the American Psychiatric Association has improved psychiatric practice via its diagnostic manual series. However, the increasing number of diagnoses has created predicaments for clinicians and society. This report suggests explanations for this "inflation" and, using systematics, proposes the following five linked strategies for improving our diagnostic schema. First, criteria based on purposes underlying diagnosis should form the basis for including and excluding psychiatric diagnoses. Second, the major categories (or classes) should be reduced from 17 to one half to one third that number. Third, many psychiatric diagnoses should be removed from their current status as independent diagnoses (or subclasses) and relegated to a more specific taxonomic stratum (e.g., infraclass). Fourth, promising information for new or modified taxons would compose a fourth stratum (or parvclass). Fifth, comorbidity would become a more useful concept if defined as major, intermediate, and minor comorbidity, occurring at class, subclass, and infraclass levels. PMID- 22932729 TI - Understanding the neurobiology of fear conditioning and emergence of posttraumatic stress disorder psychobiology: commentary on Blanchard et al. AB - In this article, we discuss the historical evolution of posttraumatic stress disorder (PTSD) after the Vietnam War, with a focus on an article by Blanchard, Kolb, Prins, Gates, and McCoy (J Nerv Ment Dis 179:371-373, 1991) published in this Journal in 1991 entitled Changes in Plasma Norepinephrine to Combat-Related Stimuli Among Vietnam Veterans With Posttraumatic Stress Disorder. In this commentary, we discuss the significance of this brief article and the developments in the PTSD field before, during, and after the Blanchard publication. Within this context, we discuss the eventual recognition in both the clinical and scientific fields that PTSD had a major neurobiological foundation. Finally, we examine the key implication of these discoveries from an epidemiological, a clinical, and a public health perspective. PMID- 22932731 TI - Nocturnal time monitoring behavior ("clock-watching") in patients presenting to a sleep medical center with insomnia and posttraumatic stress symptoms. AB - Time monitoring behavior (TMB) commonly occurs among insomnia patients, often leads to frustration about sleeplessness, and perpetuates insomnia symptoms. Few studies have explored relationships between time monitoring and insomnia, and none have studied the potential relationships between insomnia, TMB, and posttraumatic stress symptoms (PSSs). In this retrospective chart review of 1078 patients seeking care at a sleep medical center, the patients presented with one of three chief sleep complaints (poor sleep quality, 51%; sleep-disordered breathing, 26%; and insomnia, 24%), and 32% reported moderate to severe PSSs. Both insomnia and time monitoring severity were greater in the 350 patients with PSSs compared with the 728 patients with minimal or no such symptoms. Insomnia and time monitoring severity correlated significantly with total posttraumatic stress scores and most strongly with the arousal subscale. Research on interventions to treat TMB may inform relationships between insomnia and posttraumatic stress. PMID- 22932732 TI - Autochthonous Leishmania siamensis in horse, Florida, USA. PMID- 22932733 TI - Sensitization of nickel oxide: improved carrier lifetime and charge collection by tuning nanoscale crystallinity. AB - A new record conversion efficiency of 0.61% that stands for a 50% increase in current dye-sensitized NiO photocathode in iodide-triiodide electrolyte was achieved by simply tuning the nanoscale crystallinity of NiO. PMID- 22932735 TI - Syntheses of a pillar[4]arene[1]quinone and a difunctionalized pillar[5]arene by partial oxidation. AB - A pillar[4]arene[1]quinone and a difunctionalized pillar[5]arene have been synthesized by partial oxidation. PMID- 22932734 TI - Positive skeletal effects of cladrin, a naturally occurring dimethoxydaidzein, in osteopenic rats that were maintained after treatment discontinuation. AB - Effects of cladrin treatment and withdrawal in osteopenic rats were studied. Cladrin improved trabecular microarchitecture, increased lumbar vertebral compressive strength, augmented coupled remodeling, and increased bone osteogenic genes. A significant skeletal gain was maintained 4 weeks after cladrin withdrawal. Findings suggest that cladrin has significant positive skeletal effects. INTRODUCTION: We showed that a standardized extract of Butea monosperma preserved trabecular bone mass in ovariectomized (OVx) rats. Cladrin, the most abundant bioactive compound of the extract, promoted peak bone mass achievement in growing rats by stimulating osteoblast function. Here, we studied the effects of cladrin treatment and withdrawal on the osteopenic bones. METHODS: Adult female Sprague-Dawley rats were OVx and left untreated for 12 weeks to allow for significant estrogen deficiency-induced bone loss, at which point cladrin (1 and 10 mg/kg/day) was administered orally for another 12 weeks. Half of the rats were killed at the end of the treatments and the other half at 4 weeks after treatment withdrawal. Sham-operated rats and OVx rats treated with PTH or 17beta-estradiol (E2) served as various controls. Efficacy was evaluated by bone microarchitecture using microcomputed tomographic analysis and fluorescent labeling of bone. qPCR and western blotting measured mRNA and protein levels in bone and uterus. Specific ELISA was used for measuring levels of serum PINP and urinary CTx. RESULTS: In osteopenic rats, cladrin treatment dose dependently improved trabecular microarchitecture, increased lumbar vertebral compression strength, bone formation rate (BFR), cortical thickness (Cs.Th), serum PINP levels, and expression of osteogenic genes in bones; and reduced expression of bone osteoclastogenic genes and urinary CTx levels. Cladrin had no uterine estrogenicity. Cladrin at 10 mg/kg maintained acquired skeletal gains 4 weeks after withdrawal. CONCLUSION: Cladrin had positive skeletal effects in osteopenic rats that were maintained after treatment withdrawal. PMID- 22932737 TI - Vitamin C for attenuating postherpetic neuralgia pain: an emerging treatment alternative. PMID- 22932739 TI - Letter to the editor re: "diagnostic performance of stress myocardial perfusion imaging for coronary artery disease: a systematic review and meta-analysis" unfair study selection in meta-analysis. PMID- 22932738 TI - Assessment of grating-based X-ray phase-contrast CT for differentiation of invasive ductal carcinoma and ductal carcinoma in situ in an experimental ex vivo set-up. AB - OBJECTIVE: Limited contrast between healthy and tumour tissue is a limiting factor in mammography and CT of the breast. Phase-contrast computed tomography (PC-CT) provides improved soft-tissue contrast compared with absorption-based techniques. In this study, we assessed the technical feasibility of grating-based PC-CT imaging of the breast for characterisation of ductal carcinoma in situ (DCIS). METHODS: Grating-based PC-CT was performed on one breast specimen containing an invasive ductal carcinoma and DCIS using monochromatic radiation of 23 keV. Phase-contrast and absorption-based images were compared qualitatively and quantitatively with histopathology in a blinded fashion. RESULTS: Grating based PC-CT showed improved differentiation of soft-tissue components. Circular structures of high phase-shift contrast corresponding to the walls of the dilated ductuli of the DCIS were visualised with a contrast-to-noise ratio (CNR) of 9.6 using PC-CT but were not detectable on absorption-based images (CNR = 0.27). The high phase-shift structures of the dilated ductuli were identifiable in the PC-CT volume data set allowing for 3D characterisation of DCIS. CONCLUSIONS: Our results indicate that unlike conventional CT, grating-based PC-CT may allow the differentiation between invasive carcinoma and intraductal carcinoma and healthy breast tissue and provide 3D visualisation of DCIS. PMID- 22932740 TI - Carcinoid tumours: predicting the location of the primary neoplasm based on the sites of metastases. AB - OBJECTIVES: To predict the primary neuroendocrine tumour of the gastrointestinal tract site based on observed metastatic sites. METHODS: We studied data from the radiology database of a single, large cancer centre on 250 patients with pathologically confirmed neuroendocrine tumours. Primary tumour sites and the locations of metastases were collected from pathologic and radiologic reports of all available imaging modalities, such as computed tomography (CT), positron emission tomography (PET/CT), magnetic resonance imaging (MRI) and octreotide scans in the database. A nominal regression model was used to predict primary tumour site using the observed metastatic sites. Regression coefficients that were not statistically significant at the 5 % level were eliminated from the model in a stepwise procedure. RESULTS: Lung and liver metastases were not statistically significant predictors of the location of primary tumours (p = 0.86 and 0.074, respectively); whereas, lymph node, bone, and peritoneal metastases were significant predictors (p < 0.0001, 0.0004, and 0.014, respectively). CONCLUSIONS: Metastatic neuroendocrine tumours to the lymph nodes, bone, and peritoneum can be used to predict the primary neuroendocrine site; however, metastases in the lung and liver alone cannot predict the site of the primary tumour site. PMID- 22932741 TI - "Reply to letter to the editor re: diagnostic performance of stress myocardial perfusion imaging for coronary artery disease: a systematic review and meta analysis". PMID- 22932742 TI - Bone mineral density measurements of the proximal femur from routine contrast enhanced MDCT data sets correlate with dual-energy X-ray absorptiometry. AB - OBJECTIVES: To evaluate the utility of femoral bone mineral density (BMD) measurements in routine contrast-enhanced multi-detector computed tomography (ceMDCT) using dual-energy X-ray absorptiometry (DXA) as the reference standard. METHODS: Forty-one patients (33 women, 8 men) underwent DXA measurement of the proximal femur. Subsequently, transverse sections of routine ceMDCT of these patients were used to measure BMD of the femoral head and femoral neck. The MDCT to-DXA conversion equations for BMD and T-score were calculated using linear regression analysis. The conversion equations were applied to the MDCT data sets of 382 patients (120 women, 262 men) of whom 74 had osteoporotic fractures. RESULTS: A correlation coefficient of r = 0.84 (P < 0.05) was calculated for BMD(MDCT) values of the femoral head and DXA T-scores of the total proximal femur using the conversion equation T-score = 0.021 * BMD(MDCT) - 5.90. The correlation coefficient for the femoral neck was r = 0.79 (P < 0.05) with the conversion equation T-score = 0.016 * BMD(MDCT) - 4.28. Accordingly, converted T-scores for the femoral neck in patients with versus those without osteoporotic fractures were significantly different (female, -1.83 versus -1.47; male, -1.86 versus 1.47; P < 0.05). CONCLUSION: BMD measurements of the proximal femur were computed in routine contrast-enhanced MDCT and converted to DXA T-scores, which adequately differentiated patients with and without osteoporotic fractures. PMID- 22932743 TI - The Family Spirit trial for American Indian teen mothers and their children: CBPR rationale, design, methods and baseline characteristics. AB - The purpose of this paper is to describe the rationale, design, methods and baseline results of the Family Spirit trial. The goal of the trial is to evaluate the impact of the paraprofessional-delivered "Family Spirit" home-visiting intervention to reduce health and behavioral risks for American Indian teen mothers and their children. A community based participatory research (CBPR) process shaped the design of the current randomized controlled trial of the Family Spirit intervention. Between 2006 and 2008, 322 pregnant teens were randomized to receive the Family Spirit intervention plus Optimized Standard Care, or Optimized Standard Care alone. The Family Spirit intervention is a 43 session home-visiting curriculum administered by American Indian paraprofessionals to teen mothers from 28 weeks gestation until the baby's third birthday. A mixed methods assessment administered at nine intervals measures intervention impact on parental competence, mother's and children's social, emotional and behavioral risks for drug use, and maladaptive functioning. Participants are young (mean age = 18.1 years), predominantly primiparous, unmarried, and challenged by poverty, residential instability and low educational attainment. Lifetime and pregnancy drug use were ~2-4 times higher and ~5-6 times higher, respectively, than US All Races. Baseline characteristics were evenly distributed between groups, except for higher lifetime cigarette use and depressive symptoms among intervention mothers. If study aims are achieved, the public health field will have new evidence supporting multi-generational prevention of behavioral health disparities affecting young American Indian families and the utility of indigenous paraprofessional interventionists in under resourced communities. PMID- 22932744 TI - The community epidemiology of underage drinking: variation across communities in relations of risk to alcohol use. AB - To test the assumption embedded in state-of-the-art, community assessment and decision-making regarding prevention of underage drinking: that there is minimal variation in the way that risk and protective factors (RPF) are associated with underage drinking across communities. Three large datasets provided the same measures of adolescent alcohol use and RPFs. Multilevel ordered-logistic regression models were carried out separately for each dataset and separately for males and females in 8th and 10th grades, testing random slopes for each RPF index. Predicted school-level coefficients were derived from these models, representing the association between RPFs and alcohol use. The variation in associations between RPFs and alcohol use across schools was greatest for antisocial peer risk and community protection; the lowest variation across schools was found for family cohesion and individual antisocial behavior. Ranges in predicted coefficients indicate large differences across schools for many RPFs. Bivariate correlations indicated that school-level associations vary across RPFs in expected directions. Policy makers should recognize that the magnitude of associations between RPFs and adolescent alcohol use vary considerably across communities, and that such variability is greater for certain RPFs than others. These findings have implications for policies regarding how prevention resources are targeted within and across communities. PMID- 22932745 TI - Effects of three depression prevention interventions on risk for depressive disorder onset in the context of depression risk factors. AB - Study aims were to identify subgroups of adolescents with elevated depressive symptoms who had the highest likelihood of developing future major/minor depressive disorder on the basis of depression risk factors and participation in three depression prevention programs, with the goal of evaluating the preventive effect of indicated prevention interventions in the context of known risk factors. Adolescents (N = 341) with elevated depressive symptoms were randomized to one of four prevention intervention conditions (cognitive-behavioral group, supportive-expressive group, cognitive-behavioral bibliotherapy, educational brochure control). By 2-year follow-up, 14% showed onset of major/minor depressive disorders. Classification tree analysis (CTA) revealed that negative attributional style was the most important risk factor: Youth with high scores showed a 4-fold increase in depression onset compared to youth who did not endorse this attributional style. For adolescents with negative attributional style, prevention condition emerged as the most important predictor: Those receiving bibliotherapy showed a 5-fold reduction in depression disorder onset relative to adolescents in the three other intervention conditions. For adolescents who reported low negative attributional style scores, elevated levels of depressive symptoms at baseline emerged as the most potent predictor. Results implicate two key pathways to depression involving negative attributional style and elevated depressive symptoms in this population, and suggest that bibliotherapy may offset the risk conveyed by the most important depression risk factor in this sample. PMID- 22932746 TI - Optical coherence tomography aspect of crystalline macular dystrophy in Sjogren Larsson syndrome. AB - Sjogren-Larsson syndrome is an autosomal-recessive disease caused by a deficiency of the microsomal fatty aldehyde dehydrogenase enzyme. The syndrome is defined by congenital ichthyosis, spasticity, mental retardation and ocular features. We report the case of a 10-year-old boy presenting with bilateral visual impairment and photophobia. Fundus examination showed a mark of yellow-white refractile, perifoveal crystals in each eye. Optical coherence tomography (OCT) detected focal reflective structures corresponding to clinically visible intraretinal crystals and macular macrocystoids space. This case is presented to highlight the ocular findings and to evaluate the contribution of OCT in the study of the fovea anatomic changes. PMID- 22932747 TI - Stable, trinuclear Zn(II)- and Cd(II)-metallocycles: TWIM-MS, photophysical properties, and nanofiber formation. AB - A series of trimeric, Zn(II)- and Cd(II)-metallocycles is reported. Structural characterization of the highly stable triangles was supported by traveling-wave ion mobility-mass spectrometry (TWIM-MS) and gradient tandem mass spectrometry (gMS(2)). Their unique photophysical properties and self-assembly to form nanofibers are also described. PMID- 22932748 TI - A randomized clinical trial of lithium in multiple system atrophy. AB - The aim of our study was to test the safety and tolerability of lithium in multiple system atrophy (MSA). The study was randomized, placebo-controlled, and double-blind. The primary endpoint of the study was safety and tolerability. An interim analysis, performed 1 year after the first patient was randomized, showed a higher proportion of trial abandon (P < 0.01) and a higher number of adverse events (P < 0.02) in the lithium group. The trial was stopped by the Data Monitoring Committee. Overall, lithium was not well tolerated, and we do not encourage future studies with lithium in MSA patients. PMID- 22932749 TI - Expression of VEGF gene isoforms in a rat segmental bone defect model treated with EPCs. AB - OBJECTIVES: Angiogenesis and osteogenesis are essential for bone growth, fracture repair, and bone remodeling. Vascular endothelial growth factor (VEGF) has an important role in bone repair by promoting angiogenesis and osteogenesis. In our previous study, endothelial progenitor cells (EPCs) promoted bone healing in a rat segmental bone defect as confirmed by radiological, histological, biomechanical, and micro-CT evaluations. Although EPCs have demonstrated effectiveness in animal models of fracture healing, the mechanism by which EPCs enhance fracture healing remains unclear. We hypothesized a possible paracrine mechanism of action, where the secretion of growth factors critical to the processes of fracture healing (such as VEGF), is responsible for the positive effects of EPC therapy. The purpose of this study was to evaluate VEGF gene expression after local EPC therapy for a rat segmental bone defect. METHODS: Rat bone marrow-derived EPCs were isolated by the Ficoll-paque gradient centrifuge technique. The EPCs were cultured for 7-10 days in endothelial cell growth medium with supplements and collected for treatment of the rat segmental bone defect. EPCs were identified by immunocytochemistry staining with primary antibodies for CD34, CD133, fetal liver kinase-1, and Von Willebrand factor. A total of 56 rats were studied. A 5-mL segmental bone defect was created in the middle one-third of each femur followed by miniplate fixation. The treatment group received 1 * 10 EPCs locally at the bone defect on a gelfoam scaffold and control animals received the gelfoam scaffold only. Seven control and 7 EPC-treated rats were included in each group at 1, 2, 3, and 10 weeks. The animals were sacrificed at the end of the treatment period, and specimens from the fracture gap area were collected and immediately frozen. Rat VEGF mRNA was measured by reverse transcriptase-polymerase chain reaction and quantified by VisionWorksLS. All measurements were performed in triplicate. RESULTS: Cultured EPCs at 1 week showed positive staining for CD34, CD133, fetal liver kinase-1, and Von Willebrand factor markers. The EPC group had a greater VEGF expression than the control group at weeks 1, 2, and 3, but not at week 10. Three VEGF isoforms were detected in this rat model: VEGF120, VEGF164, and VEGF188. VEGF120 and VEGF164 levels peaked at 2 weeks, whereas VEGF188 levels peaked at 3 weeks. All 3 VEGF isoform levels were low at 10 weeks. DISCUSSION AND CONCLUSIONS: EPC-based therapy for a segmental bone defect results in increased VEGF expression during the early period of fracture repair. In addition, the specific VEGF isoform may be a key regulator of the bone healing process. These findings demonstrate that EPCs may promote fracture healing by increasing VEGF levels and thus stimulating angiogenesis, a process that is essential for early callus formation and bone regeneration. PMID- 22932750 TI - Comparison of cannulated screw with tension band wiring versus compressive cannulated locking bolt and nut device (CompresSURE) in patella fractures-a cadaveric biomechanical study. AB - OBJECTIVE: The purpose of this study was to determine if proximity of cannulated lag screws to the articular surface of the patella combined with the tension band technique affects resistance to fracture gap opening, and if an alternative locking nut and bolt device without a tension band behaves in a biomechanically similar fashion. METHODS: Thirty-three cadaveric knees were allocated to 3 transverse patella fracture fixation groups: cannulated lag screw placement close to the articular (TBA) or non-articular (TBNA) surface with tension, and placement of a compressive locking nut and bolt device without tension band (CompresSURE) close to the articular surface. Knees were cycled through flexion extension motion for 1000 cycles during which the fracture gap opening was quantified after the first flexion-extension cycle and after the 1,000 th cycle using an optoelectronic motion analysis system. RESULTS: After the first range of motion cycle, there was no significant difference in fracture gap opening between the 3 groups on the articular surface (P > 0.600). Total fracture gap displacement after the 1,000 th cycle was not significantly different between groups (P > 0.408). In general and irrespective of fixation technique, fractures opened in a wedge-like fashion with larger measured gap on the ventral surface relative to the articulating surface. CONCLUSIONS: When combined with the tension band, the proximity of cannulated lag screws to the articular surface did not affect resistance to fracture gap opening. Additionally, the stand-alone CompreSURE cannulated locking nut and bolt device without tension band was able to resist fracture gap opening in transverse fractures as effectively as the cannulated screw with tension band technique. PMID- 22932751 TI - Prevention of atrophic nonunion by the systemic administration of parathyroid hormone (PTH 1-34) in an experimental animal model. AB - OBJECTIVES: Recombinant human parathyroid hormone (PTH 1-34) has been previously shown to enhance fracture healing in animal models. Here, we sought to determine whether the systemic administration of PTH 1-34 is effective in preventing atrophic fracture nonunion in a murine, surgical nonunion model. METHODS: We used an established reproducible long-bone murine fracture nonunion model by generating a midshaft femur fracture, followed by fracture distraction using an intramedullary pin and custom metallic clip to maintain a fracture gap of 1.7 mm. Mice were randomized to receive either daily intraperitoneal injections of 30 MUg/kg PTH 1-34 for 14 days or saline injections. At 6 weeks after the procedure, radiographic and histologic assessment of fracture healing was performed. RESULTS: At 6 weeks after surgery, the group treated with PTH showed higher rates of bony union (50% vs 8%; P < 0.05) as assessed by radiographic analysis. Mean gap size was also significantly lower in the PTH group (1.42 vs 0.36 mm in the control group; P < 0.05). Histologic analysis of atrophic nonunions in the control group revealed a persistent fracture gap with intervening fibrous tissue. In contrast, healed subjects in the PTH-treated group had cortical bridging with mature bone and relatively little callus, which is consistent with primary intramembranous ossification. CONCLUSIONS: Daily systemic administration of recombinant PTH 1-34 increased the rate of union in a mouse atrophic nonunion model. This may have important implications for the potential clinical role of PTH 1-34 in the treatment of atrophic fracture nonunions. PMID- 22932752 TI - Excellent results after bone grafting and K-wire fixation for scaphoid nonunion surgery in skeletally immature patients: a midterm follow-up study of 11 adolescents after 6.9 years. AB - OBJECTIVES: Scaphoid nonunion is relatively rare in children and adolescents, and no long-term follow-up has been reported. DESIGN: Retrospective follow-up study. PATIENTS: Eleven patients (10 boys and 1 girl), mean 15.2 (13.9-15.9) years of age, with scaphoid nonunion and open growth plates were operated with bone grafting, Kirschner-wire fixation and 12 weeks of cast immobilization. MAIN OUTCOME MEASUREMENTS: Bony union, degenerative wrist changes, and restoration of the carpal architecture were assessed with CT and radiographs. Clinical parameters included active range of motion, grip strength, key pinch strength, and subjective outcome scores (quick disabilities of arm, shoulder and hand (DASH), visual analog scale). RESULTS: The patients were followed up after mean 6.9 (3.1-15.1) years; all patients attended. Radiographs and CT confirmed healing of all nonunions, the carpal anatomy was restored, and the wrists were rated as 0 according to the scaphoid nonunion advanced collapse, without degenerative changes. The clinical result was excellent with visual analog scale at rest = 1, at activity = 6, and quick DASH score = 3.3. Active range of motion and grip strength were insignificantly reduced (14 degrees and 2 kg); the key pinch strength remained similar. CONCLUSIONS: Healing of a scaphoid nonunion can be expected in adolescents after open reduction, Kirschner-wire fixation, bone grafting, and plaster immobilization, resulting in pain relief and excellent wrist function without degenerative changes after longer term follow-up. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence. PMID- 22932753 TI - Subtrochanteric fractures: treatment with cerclage wire and long intramedullary nail. AB - Fracture malalignment and nonunion are not infrequent after treating subtrochanteric fractures with intramedullary nails. The use of a cerclage wire with a minimally invasive approach to aid and maintain reduction in certain subtrochanteric fracture patterns can be an effective surgical strategy to improve outcome. It allows the surgeon to obtain and maintain an anatomic reduction with more bone contact, which will aid in fracture consolidation. This has the added advantage of optimizing the greater trochanteric starting point. It minimizes malreductions of the proximal femoral fragment, and, we believe, that its rational use with a minimally invasive technique is a key factor in achieving good results. PMID- 22932754 TI - Biomechanical testing of pin configurations in supracondylar humeral fractures: the effect of medial column comminution. AB - OBJECTIVES: We measured biomechanical stability in simulated supracondylar humeral fractures fixed with each of 6 pin configurations, 2 with associated medial comminution, and developed a technique for reproducible pin placement and divergence. METHODS: A transverse supracondylar osteotomy was performed on 36 biomechanical humerus models. Of these, 24 (4 groups of 6 specimens each) were fixed with pins in 1 of 4 lateral entry configurations. The remaining 12 (2 groups of 6 specimens each) had a 30-degree medial wedge removed from the distal humerus and were fixed with 1 of 2 configurations. Half of each group was tested under axial rotation and the other half under varus bending. The distal humerus was divided into 4 equal regions from lateral to medial (1-4). Lateral entry pins were inserted through regions 1-3, whereas the medial pin was inserted through region 4. RESULTS: Without comminution, 3 widely spaced, divergent lateral entry pins resulted in higher torsional stiffness (0.36 Nm/degree) than 2 pins in adjacent regions (P < 0.055), but similar to 2 pins in nonadjacent regions (P = 0.57). Three lateral entry pins had higher bending stiffness (79.6 N/mm) than 2 pins, which ranged from 46.7 N/mm (P < 0.01) to 62.5 N/mm (P = 0.21). With comminution, adding a third medial entry pin increased torsional stiffness (0.13 0.24 Nm/degree, P < 0.01) and increased bending stiffness (38.7-44.7 N/mm, P = 0.10). CONCLUSIONS: For fractures without medial column comminution, fixation using 3 lateral entry pins may provide the greatest combination of torsional and bending stiffness. With medial comminution, adding a third medial pin increased torsional stiffness (P < 0.01) and bending stiffness (P = 0.10). PMID- 22932755 TI - Primary progressive aphasia and Alzheimer's disease: brief history, recent evidence. AB - Primary progressive aphasia (PPA) has been recognized as a syndrome distinct from the usual pattern of language deterioration in Alzheimer's disease and typically more related to the pathology of frontotemporal dementia (FTD). In recent years, however, the syndromes of primary progressive aphasia have become more complex, divided into the three subtypes of progressive nonfluent aphasia (PNFA), semantic dementia (SD), and logopenic/phonological progressive aphasia (LPA). These syndromes have not only made the linguistic analysis more complex, but the associated pathologies have also become more variable. In particular, PNFA is usually, but not always, associated with FTD pathology and often evidence of a tau mutation, but rarely AD; SD is usually associated with FTD of the ubiquitin staining or progranulin (TAR-DNA) mutation type, but, again, occasionally AD; LPA is typically associated with AD pathology. Patterns of atrophy on magnetic resonance imaging (MRI) generally conform to these subtypes, with PNFA associated with left frontal and insular atophy, SD associated with bilateral temporal atrophy, and LPA associated with L superior-posterior temporal and parietal atrophy. These patterns can also be seen on positron emission (PET) scanning with fluorodeoxyglucose. The newer amyloid binding ligand PET technologies are less useful for detecting regional atrophy patterns but more useful for indication of the underlying pathology. We can thus speak of syndromes of PPA or underlying pathological bases of PPA. PMID- 22932756 TI - Acyl editing and headgroup exchange are the major mechanisms that direct polyunsaturated fatty acid flux into triacylglycerols. AB - Triacylglycerols (TAG) in seeds of Arabidopsis (Arabidopsis thaliana) and many plant species contain large amounts of polyunsaturated fatty acids (PUFA). These PUFA are synthesized on the membrane lipid phosphatidylcholine (PC). However, the exact mechanisms of how fatty acids enter PC and how they are removed from PC after being modified to participate in the TAG assembly are unclear, nor are the identities of the key enzymes/genes that control these fluxes known. By reverse genetics and metabolic labeling experiments, we demonstrate that two genes encoding the lysophosphatidylcholine acyltransferases LPCAT1 and LPCAT2 in Arabidopsis control the previously identified "acyl-editing" process, the main entry of fatty acids into PC. The lpcat1/lpcat2 mutant showed increased contents of very-long-chain fatty acids and decreased PUFA in TAG and the accumulation of small amounts of lysophosphatidylcholine in developing seeds revealed by [14C]acetate-labeling experiments. We also showed that mutations in LPCATs and the PC diacylglycerol cholinephosphotransferase in the reduced oleate desaturation1 (rod1)/lpcat1/lpcat2 mutant resulted in a drastic reduction of PUFA content in seed TAG, accumulating only one-third of the wild-type level. These results indicate that PC acyl editing and phosphocholine headgroup exchange between PC and diacylglycerols control the majority of acyl fluxes through PC to provide PUFA for TAG synthesis. PMID- 22932757 TI - Tie-dyed2 encodes a callose synthase that functions in vein development and affects symplastic trafficking within the phloem of maize leaves. AB - The tie-dyed2 (tdy2) mutant of maize (Zea mays) displays variegated green and yellow leaves. Intriguingly, the yellow leaf tissues hyperaccumulate starch and sucrose, the soluble sugar transported long distance through the phloem of veins. To determine the molecular basis for Tdy2 function, we cloned the gene and found that Tdy2 encodes a callose synthase. RNA in situ hybridizations revealed that in developing leaves, Tdy2 was most highly expressed in the vascular tissue. Comparative expression analysis with the vascular marker maize PINFORMED1a-yellow fluorescent protein confirmed that Tdy2 was expressed in developing vein tissues. To ascertain whether the defect in tdy2 leaves affected the movement of sucrose into the phloem or its long-distance transport, we performed radiolabeled and fluorescent dye tracer assays. The results showed that tdy2 yellow leaf regions were defective in phloem export but competent in long-distance transport. Furthermore, transmission electron microscopy of tdy2 yellow leaf regions showed incomplete vascular differentiation and implicated a defect in cell-to-cell solute movement between phloem companion cells and sieve elements. The disruption of sucrose movement in the phloem in tdy2 mutants provides evidence that the Tdy2 callose synthase functions in vascular maturation and that the vascular defects result in impaired symplastic trafficking into the phloem translocation stream. PMID- 22932759 TI - Impact of preservation of the intercostobrachial nerve during axillary dissection on sensory change and health-related quality of life 2 years after breast cancer surgery. AB - BACKGROUND: Sensory loss or paresthesia due to division of the intercostobrachial nerve (ICBN) is a complication of axillary lymph node dissection (ALND). Preservation of the ICBN may be of value, but few prospective studies have shown an impact of preservation on sensory changes or health-related quality of life (HRQOL) after breast cancer surgery. METHODS: This prospective study was performed to evaluate the association between ICBN preservation and sensory change and HRQOL at 1 (baseline), 6, 12, and 24 months after breast cancer surgery in 140 patients. The sensory examination included dysesthesia, paresthesia, and abnormal touch and pain sensation in the upper arm. RESULTS: Division of the ICBN did not influence the frequency or severity of subjective dysesthesia and paresthesia. There was no marked difference in touch or pain sensation at baseline between patients with a preserved (group P) and divided (group D) ICBN. In group P, the percentage of patients aware of a sensory deficit or loss decreased with time, and that of patients aware of a hypersensitive sensation increased. These changes did not occur in group D, leading to a significant difference between the groups at 24 months. The main difference between the groups was the area with reduced touch or pain sensation. This area decreased with time in group P, but not in group D. ICBN preservation or division did not influence HRQOL. CONCLUSION: ICBN preservation in ALND has a benefit of a reduced area with long-term axillary hypoesthesia, but has no influence on improvement of pain and HRQOL. PMID- 22932758 TI - Vacuolar CAX1 and CAX3 influence auxin transport in guard cells via regulation of apoplastic pH. AB - CATION EXCHANGERs CAX1 and CAX3 are vacuolar ion transporters involved in ion homeostasis in plants. Widely expressed in the plant, they mediate calcium transport from the cytosol to the vacuole lumen using the proton gradient across the tonoplast. Here, we report an unexpected role of CAX1 and CAX3 in regulating apoplastic pH and describe how they contribute to auxin transport using the guard cell's response as readout of hormone signaling and cross talk. We show that indole-3-acetic acid (IAA) inhibition of abscisic acid (ABA)-induced stomatal closure is impaired in cax1, cax3, and cax1/cax3. These mutants exhibited constitutive hypopolarization of the plasma membrane, and time-course analyses of membrane potential revealed that IAA-induced hyperpolarization of the plasma membrane is also altered in these mutants. Both ethylene and 1-naphthalene acetic acid inhibited ABA-triggered stomatal closure in cax1, cax3, and cax1/cax3, suggesting that auxin signaling cascades were functional and that a defect in IAA transport caused the phenotype of the cax mutants. Consistent with this finding, chemical inhibition of AUX1 in wild-type plants phenocopied the cax mutants. We also found that cax1/cax3 mutants have a higher apoplastic pH than the wild type, further supporting the hypothesis that there is a defect in IAA import in the cax mutants. Accordingly, we were able to fully restore IAA inhibition of ABA-induced stomatal closure in cax1, cax3, and cax1/cax3 when stomatal movement assays were carried out at a lower extracellular pH. Our results suggest a network linking the vacuolar cation exchangers to apoplastic pH maintenance that plays a crucial role in cellular processes. PMID- 22932760 TI - Urinary BTA: indicator of bladder cancer or of hematuria. AB - BACKGROUND: In this study, we investigated the influence of hematuria on the performance of the bladder tumor antigen (BTA) tests in a clinical cohort and in an experimental model. MATERIALS AND METHODS: Urine samples from a cohort of 126 subjects (64 with BCa and 62 controls) were analyzed by ELISA for hemoglobin and BTA. The experimental model involved the spiking of urine with blood from the same subject, and hemoglobin, red blood cell count, and BTA levels (BTA stat(c) and BTA-TRAK(c)). BTA-TRAK(c) analyses were also performed on serum samples obtained from 40 subjects (20 with confirmed with BCa). RESULTS: In the 126 subject cohort, correlation between hemoglobin and BTA was 0.732. Of the 64 BCa samples, 72 % had a positive BTA assay, but 47 % of controls were also positive. The sensitivity and specificity of BTA to detect BCa was 72 and 53 %, respectively. Hematuria, measured by urinary hemoglobin, was a better indicator of BCa with 75 % sensitivity and 90 % specificity. Spiking of BTA-negative urine samples with as little as 1 MUl/10 ml was enough to produce a positive BTA test. High levels of BTA were found equally in the serum of subjects with or without BCa (mean BTA levels 355,159 vs. 332,329 U/ml, respectively). CONCLUSIONS: Rather than detecting a bladder tumor antigen, urinary BTA assays may be measuring serum cFH introduced by bleeding, a common presenting factor in BCa subjects. The presence of hematuria in subjects without malignant disease can result in false positive BTA assays. PMID- 22932761 TI - Nutritional supplementation with L-arginine prevents pelvic radiation-induced changes in morphology, density, and regulating factors of blood vessels in the wall of rat bladder. AB - PURPOSE: To determine whether L-arginine has protective effects against radiation induced alterations in the morphology and regulatory factors of vesical blood vessels in rats. METHODS: Male rats aged 3-4 months were divided into groups of 10 animals each: (a) controls, consisting of non-treated animals; (b) radiated only rats; and (c) radiated rats receiving L-arginine supplementation. Radiation was in one session of 10 Gy and was aimed at the pelvic-abdominal region. L arginine was administered once a day (0.65 g/kg body weight), starting 7 days before radiation and continuing until killing on the 16th day after radiation. The density, relative area, and wall thickness of blood vessels were measured in the vesical lamina propria using histological methods, and the expression of vascular endothelial growth factor (VEGF) and fibroblast growth factors (FGF) in the bladder wall was assessed by RT-PCR. RESULTS: Compared with controls, radiation alone decreased the density and relative area of blood vessels by 32 % (p < 0.01) and 25 % (p < 0.05), respectively, and reduced the arterial wall thickness by 42 % (p < 0.004). VEGF and FGF mRNA levels after radiation were diminished by 67 % (p < 0.002) and 56 % (p < 0.04), respectively. The radiated animals supplemented with L-arginine were not significantly different from controls. CONCLUSIONS: Pelvic radiation leads to significant vesical modifications, as in the morphology of blood vessels and in VEGF and FGF expression. All these changes, however, were prevented by L-arginine treatment. These results emphasize, therefore, the potential use of this amino acid as a radioprotective drug. PMID- 22932762 TI - Novel vectors of malaria parasites in the western highlands of Kenya. PMID- 22932763 TI - Metabolite target analysis of human urine combined with pattern recognition techniques for the study of symptomatic gout. AB - Recurrent attacks and irregularity are two important characteristics of gout disease. Uric acid as a single evaluation indicator for clinical diagnosis is insufficient considering the versatile properties of gout. The aim of this work is to identify several endogenous metabolites from urine samples for the elucidation and prediction of gout disease. Metabolite target analysis was established for human urine by high performance liquid chromatography-diode array detection (HPLC-DAD). The targeted metabolites selected included hippuric acid, uracil, phenylalanine, tryptophan, uric acid and creatinine as well as nine purine compounds. Useful information was extracted from multivariate data through Fisher Linear Discriminant Analysis (FDA) and Orthogonal Signal Correction Partial Least Squares Discriminant Analysis (OSC-PLS-DA). Uric acid, hypoxanthine, xanthosine, guanosine, inosine and tryptophan were identified as important metabolites among the acute and chronic gout and controls. Based on OSC PLS-DA models, the regression equations obtained could discriminate gout from the controls as well as the acute from chronic. The recognition and prediction ability is respectively 100% and 85.0% for the gout, 100% and 83.3% for the acute, and 90.91% and 89.9% for the chronic. Metabolic dysfunction of tryptophan and excessive metabolism of xanthosine and hypoxanthine to xanthine were confirmed for gout disease. Metabolic dysfunction of tryptophan was also proven to be induced by allopurinol in case of Kunming mice with hyperuricemia. Potential biomarkers can be used not only to distinguish gout patients from healthy people, but also to evaluate the disease state. PMID- 22932768 TI - Inhibition of return in response to eye gaze and peripheral cues in young people with Asperger's syndrome. AB - Inhibition of return (IOR) reflects slower reaction times to stimuli presented in previously attended locations. In this study, we examined this inhibitory after effect using two different cue types, eye-gaze and standard peripheral cues, in individuals with Asperger's syndrome and typically developing individuals. Typically developing participants showed evidence of IOR for both eye-gaze and peripheral cues. In contrast, the Asperger group showed evidence of IOR to previously peripherally cued locations but failed to show IOR for eye-gaze cues. This absence of IOR for eye-gaze cues observed in the participants with Asperger may reflect an attentional impairment in responding to socially relevant information. PMID- 22932769 TI - Relationship between children's sleep and mental health in mothers of children with and without autism. AB - The study employed 90 children with autism spectrum disorders (ASDs) who were matched to 90 typically developing children on age, gender, and ethnicity. Using structural equation modeling, maternal sleep and maternal stress mediated the relationship between children's sleep and mothers' mental health for mothers of children with and without ASDs. Mothers of children with ASDs reported more problems related to children's sleep, their own sleep, greater stress, and poorer mental health; however, children's sleep and maternal sleep were more closely related to maternal stress for mothers of typically developing children. Implications of these findings and future directions for research are discussed. PMID- 22932770 TI - From supramolecular triangle to heteroleptic rhombus: a simple bridge can make a difference. AB - Multicomponent, self-assembled rhomboidal constructs are reported, in which bis terpyridines possessing 120 degrees or 60 degrees directionality and Zn(II) or Cd(II) in a stoichiometric ratio (1 : 1 : 2) initially form rhomboid and triangle mixtures; whereas, a tris-terpyridine reacts with the 60 degrees -based bis ligand and metal to quantitatively form a heteroleptic, centrally fused, rhomboidal structure. PMID- 22932771 TI - Screening mutant libraries of T7 RNA polymerase for candidates with increased acceptance of 2'-modified nucleotides. AB - We present a screening assay based on fluorescence readout for the directed evolution of T7 RNA polymerase variants with acceptance of 2'-modified nucleotides. By using this screening we were able to identify a T7 RNA polymerase mutant with increased acceptance of 2'-methylseleno-2'-deoxyuridine 5' triphosphate. PMID- 22932772 TI - "Balancing risk in ophthalmic prescribing: assessing the safety of anti-VEGF therapies and the risks associated with unlicensed medicines". PMID- 22932773 TI - Severe ulcerative keratitis in ocular cowpox infection. PMID- 22932774 TI - Recurrent acute coronary events in a young adult. AB - Acute myocardial infarction (MI) in young adults is rare. Clinicopathological conditions such as nephrotic syndrome, antiphospholipid syndrome, spontaneous coronary artery spasms or embolism can be attributed to such events. In this case report, we present a 30-year-old male who had his first MI at the age of 20 years. He received percutaneous intervention as initial treatment. Despite aggressive risk factor management, he continued to have acute coronary events and was later diagnosed with antiphospholipid syndrome (APS). At the same time, he was diagnosed with severe chronic thromboembolic pulmonary hypertension and severe tricuspid regurgitation. He underwent pulmonary endartererectomy, tricuspid annuloplasty and radial artery bypass graft to the first obtuse marginal artery. Warfarin therapy was initiated upon the diagnosis of APS. Despite being therapeutic on warfarin and aggressive risk factor management, he had yet another MI. Coronary angiogram at this time showed fresh occlusion of the right coronary artery at the mid-segment, and the patient received two overlapping stents that achieved a good effect. This case emphasizes the importance of awareness, early recognition and aggressive management of patients with APS presenting chest pain or acute coronary events. Despite appropriate treatment, such as risk factor management and percutaneous interventions, recurrence of an acute coronary event is high. The presentation of younger patients with recurrent coronary events but no significant risk factors of atherosclerosis should evoke the suspicion of APS-related coronary artery disease, and all risk factors should be aggressively managed. PMID- 22932775 TI - Contribution of coagulation factor VII R353Q, -323P0/10 and HVR4 polymorphisms to coronary artery disease in Tunisians. AB - We examined the contribution of two factor VII (FVII) bi-allelic (R353Q, 323P0/10) and one tandem repeat (HVR4) polymorphisms to the risk of coronary artery disease (CAD) in Tunisians. Study subjects comprised 308 CAD patients and 312 age-, gender- and ethnically-matched controls. Regression analysis was used in assessing the FVII association to CAD risk. While the distribution of 323P0/10 alleles and genotypes were comparable between cases and controls, marginal association of the R353Q variant was noted, with the Q allele (19.1 vs. 23.8%; P = 0.05) and Q allele-containing genotypes (R/Q + Q/Q; 33.8 vs. 48.0%) being slightly under-represented in cases than in controls. On the other hand, four alleles of FVII microsatellite HVR4 were detected at variable frequencies in Tunisians, and comprised H6 (63.2%), H7 (33.8%), and to lesser extents H5 (1.9%) and H8 (0.8%). Of these, the H7 variant was under-represented in patients [P = 0.038; OR (95%CI) = 0.75 (0.58-0.97)]. Of the major genotypes detected (H6/H6, H6/H7, H7/H7) only H6/H6 was positively associated with CAD [P = 0.047; OR (95%CI) = 1.39 (1.00-1.94)]. In conclusion, our study underscores the role of polymorphisms in the FVII gene in modulating the susceptibility to CAD in (North African) Tunisian Arabs. PMID- 22932776 TI - Galantamine increases hippocampal insulin-like growth factor 2 expression via alpha7 nicotinic acetylcholine receptors in mice. AB - RATIONALE AND OBJECTIVE: Galantamine, a drug for the treatment of Alzheimer's disease, has neuroprotection in several experimental models and stimulates adult neurogenesis in the rodent brain, but the exact mechanism remains unclear. This study examined whether galantamine affects the expression of neurotrophic/growth factors in the mouse hippocampus and prefrontal cortex. METHODS: Nine-week-old male ddY mice were used. The mRNA levels of neurotrophic/growth factors were analyzed by a real-time quantitative PCR. The protein levels of insulin-like growth factor 2 (IGF2) were analyzed by Western blotting. RESULTS: Acute administration of galantamine (0.3-3 mg/kg, i.p.) increased IGF2 mRNA levels in the hippocampus, but not in the prefrontal cortex, in time- and dose-dependent manner. Galantamine (3 mg/kg, i.p.) caused a transient increase in fibroblast growth factor 2 mRNA levels and a decrease in brain-derived neurotrophic factor mRNA levels in the hippocampus, while it did not affect the mRNA levels of other neurotrophic/growth factors. The galantamine-induced increase in the hippocampal IGF2 mRNA levels was blocked by mecamylamine, a nonselective nicotinic acetylcholine (ACh) receptor (nAChR) antagonist, and methyllycaconitine, a selective alpha7 nAChR antagonist, but not by telenzepine, a preferential M(1) muscarinic ACh receptor antagonist. Moreover, the selective alpha7 nAChR agonist PHA-543613 increased the IGF2 mRNA levels, while donepezil, an acetylcholinesterase inhibitor, did not. Galantamine also increased hippocampal IGF2 protein, which was blocked by methyllycaconitine. CONCLUSIONS: These findings suggest that galantamine increases hippocampal IGF2 levels via alpha7 nAChR activation in mice and imply that the effect may contribute to its neuroprotection or neurogenesis. PMID- 22932777 TI - Docosahexaenoic acid-concentrated fish oil supplementation in subjects with mild cognitive impairment (MCI): a 12-month randomised, double-blind, placebo controlled trial. AB - RATIONALE: Epidemiological studies have suggested a beneficial effect of fish oil supplementation in halting the initial progression of Alzheimer's disease. However, it remains unclear whether fish oil affects cognitive function in older people with mild cognitive impairment (MCI). OBJECTIVES: This study investigated the effects of fish oil supplementation on cognitive function in elderly person with MCI. METHODS: This was a 12-month, randomised, double-blind, placebo controlled study using fish oil supplementation with concentrated docosahexaenoic acid (DHA). Thirty six low-socioeconomic-status elderly subjects with MCI were randomly assigned to receive either concentrated DHA fish oil (n = 18) or placebo (n = 18) capsules. The changes of memory, psychomotor speed, executive function and attention, and visual-constructive skills were assessed using cognitive tests. Secondary outcomes were safety and tolerability of the DHA concentrate. RESULTS: The fish oil group showed significant improvement in short-term and working memory (F = 9.890; etap (2) = 0.254; p < 0.0001), immediate verbal memory (F = 3.715; etap (2) = 0.114; p < 0.05) and delayed recall capability (F = 3.986; etap (2) = 0.121; p < 0.05). The 12-month change in memory (p < 0.01) was significantly better in the fish oil group. Fish oil consumption was well tolerated, and the side effects were minimal and self-limiting. CONCLUSIONS: This study suggested the potential role of fish oil to improve memory function in MCI subjects. Studies with larger sample sizes, longer intervention periods, different fish oil dosages and genetic determinations should be investigated before definite recommendations can be made. PMID- 22932779 TI - In reply: response to Marioni. PMID- 22932780 TI - Robotic surgery for gynaecologic cancer: an overview. AB - After decades of reluctance to change surgical approaches, new technologies have created new perspectives for surgery. Initially, the laparoscopic approach was considered to be only one useful for relatively simple procedures as the design of the instruments and the limited access hampered free movements to perform complicated surgery. Robotic systems overcame this problem and boosted the use of minimally invasive techniques also for radical gynaecological surgery. Robot assisted laparoscopy can now routinely be used for the surgical treatment of early or downstaged cervical carcinoma, endometrial carcinoma and staging of early ovarian carcinoma. Robot-assisted laparoscopy has proven to be feasible, although the benefits for the patient are less clear than those for the surgeon. The main advantage of robot-assisted laparoscopy over conventional laparoscopy is probably not that it is safer or better, but that it allows more types of radical surgery to be performed and that it prevents the surgeon from developing complaints and muscular conditions that interfere with the ability to perform surgery. New applications have emerged with the introduction of new devices to be used in conjunction with the robotic system as well as with totally new robotic systems. Training in these new tools should be more systematic and structured to allow their safe introduction and use. PMID- 22932781 TI - Perinatal exercise improves glucose homeostasis in adult offspring. AB - Emerging research has shown that subtle factors during pregnancy and gestation can influence long-term health in offspring. In an attempt to be proactive, we set out to explore whether a nonpharmacological intervention, perinatal exercise, might improve offspring health. Female mice were separated into sedentary or exercise cohorts, with the exercise cohort having voluntary access to a running wheel prior to mating and during pregnancy and nursing. Offspring were weaned, and analyses were performed on the mature offspring that did not have access to running wheels during any portion of their lives. Perinatal exercise caused improved glucose disposal following an oral glucose challenge in both female and male adult offspring (P < 0.05 for both). Blood glucose concentrations were reduced to lower values in response to an intraperitoneal insulin tolerance test for both female and male adult offspring of parents with access to running wheels (P < 0.05 and P < 0.01, respectively). Male offspring from exercised dams showed increased percent lean mass and decreased fat mass percent compared with male offspring from sedentary dams (P < 0.01 for both), but these parameters were unchanged in female offspring. These data suggest that short-term maternal voluntary exercise prior to and during healthy pregnancy and nursing can enhance long-term glucose homeostasis in offspring. PMID- 22932782 TI - Effect of vertical sleeve gastrectomy on food selection and satiation in rats. AB - Vertical sleeve gastrectomy (VSG) is a restrictive procedure that reduces food intake to produce weight loss. Here we assess volume and nutrient effects on the ingestive behavior of VSG and sham surgery animals. Rats given access to Ensure or pelleted chow were used to determine if liquid foods would adversely affect weight loss after surgery. Volume effects were studied by altering the caloric density of Ensure, and dietary preferences for fat and carbohydrate (sucrose) were assessed using a two-bottle test. c-Fos was used to measure neuronal activation in the nucleus of the solitary tract and area postrema in response to intragastric infusions of water, sucrose, or Intralipid. The degree of colocalization with catecholaminergic neurons was also assessed. VSG rats did not show the expected preference for a liquid diet over chow and lacked dietary preferences for fat seen in shams. Preferences for carbohydrate/sucrose solutions were unaffected by surgery. Meal size was reduced by VSG; however, VSG rats were able to alter their volume of intake to compensate for changes in caloric density, and intragastric infusions of water produced similar levels of neuronal activation among VSG, sham, and pair-fed rats. In comparison, nutrient-induced c Fos activation was substantially increased by VSG. Colocalization between c-Fos and catecholaminergic-expressing neurons was similar among rats treated with water, sucrose, or Intralipid. VSG alters nutrient sensing in a manner that lowers the threshold for satiety and reduces fat preference to induce and maintain weight loss. PMID- 22932783 TI - Relaxin exerts two opposite effects on mechanical activity and nitric oxide synthase expression in the mouse colon. AB - The hormone relaxin exerts a variety of functions on the smooth muscle of reproductive and nonreproductive organs, most of which occur through a nitric oxide (NO)-mediated mechanism. In the stomach and ileum, relaxin causes muscle relaxation by modulating the activity and expression of different nitric oxide synthase (NOS) isoforms region-dependently. Nothing is known on the effects of relaxin in the colon, the gut region expressing the highest number of neuronal (n) NOSbeta-immunoreactive neurons and mainly involved in motor symptoms of pregnancy and menstrual cycle. Therefore, we studied the effects of relaxin exposure in the mouse proximal colon in vitro evaluating muscle mechanical activity and NOS isoform expression. The functional experiments showed that relaxin decreases muscle tone and increases amplitude of spontaneous contractions; the immunohistochemical results showed that relaxin increases nNOSbeta and endothelial (e) NOS expression in the neurons and decreases nNOSalpha and eNOS expression in the smooth muscle cells (SMC). We hypothesized that, in the colon, relaxin primarily increases the activity and expression of nNOSbeta and eNOS in the neurons, causing a reduction of the muscle tone. The downregulation of nNOSalpha and eNOS expression in the SMC associated with increased muscle contractility could be the consequence of continuous exposue of these cells to the NO of neuronal origin. These findings may help to better understand the physiology of NO in the gastrointestinal tract and the role that the "relaxin-NO" system plays in motor disorders such as functional bowel disease. PMID- 22932784 TI - Peripubertal-onset but not adult-onset obesity increases IGF-I and drives development of lean mass, which may lessen the metabolic impairment in adult obesity. AB - It has been suggested that adult metabolic dysfunction may be more severe in individuals who become obese as children compared with those who become obese later in life. To determine whether adult metabolic function differs if diet induced weight gain occurs during the peripubertal age vs. if excess weight gain occurs after puberty, male C57Bl/6J mice were fed a low-fat (LF; 10% kcal from fat) or high-fat (HF; 60% kcal from fat) diet starting during the peripubertal period (pHF; 4 wk of age) or as adults (aHF; 12 wk of age). Both pHF and aHF mice were hyperinsulinemic and hyperglycemic, and both showed impaired glucose tolerance and insulin resistance compared with their LF-fed controls. However, despite a longer time on diet, pHF mice were relatively more insulin sensitive than aHF mice, which was associated with higher lean mass and circulating IGF-I levels. In addition, HF feeding had an overall stimulatory effect on circulating corticosterone levels; however, this rise was associated only with elevated plasma ACTH in the aHF mice. Despite the belief that adult metabolic dysfunction may be more severe in individuals who become obese as children, data generated using a diet-induced obese mouse model suggest that adult metabolic dysfunction associated with peripubertal onset of obesity is not worse than that associated with adult-onset obesity. PMID- 22932785 TI - SSTR2 is the functionally dominant somatostatin receptor in human pancreatic beta and alpha-cells. AB - Somatostatin-14 (SST) inhibits insulin and glucagon secretion by activating G protein-coupled somatostatin receptors (SSTRs), of which five isoforms exist (SSTR1-5). In mice, the effects on pancreatic beta-cells are mediated by SSTR5, whereas alpha-cells express SSTR2. In both cell types, SSTR activation results in membrane hyperpolarization and suppression of exocytosis. Here, we examined the mechanisms by which SST inhibits secretion from human beta- and alpha-cells and the SSTR isoforms mediating these effects. Quantitative PCR revealed high expression of SSTR2, with lower levels of SSTR1, SSTR3, and SSTR5, in human islets. Immunohistochemistry showed expression of SSTR2 in both beta- and alpha cells. SST application hyperpolarized human beta-cells and inhibited action potential firing. The membrane hyperpolarization was unaffected by tolbutamide but antagonized by tertiapin-Q, a blocker of G protein-gated inwardly rectifying K+ channels (GIRK). The effect of SST was mimicked by an SSTR2-selective agonist, whereas a SSTR5 agonist was marginally effective. SST strongly (>70%) reduced depolarization-evoked exocytosis in both beta- and alpha-cells. A slightly weaker inhibition was observed in both cell types after SSTR2 activation. SSTR3- and SSTR1-selective agonists moderately reduced the exocytotic responses in beta- and alpha-cells, respectively, whereas SSTR4- and SSTR5-specific agonists were ineffective. SST also reduced voltage-gated P/Q-type Ca2+ currents in beta-cells, but normalization of Ca2+ influx to control levels by prolonged depolarizations only partially restored exocytosis. We conclude that SST inhibits secretion from both human beta- and alpha-cells by activating GIRK and suppressing electrical activity, reducing P/Q-type Ca2+ currents, and directly inhibiting exocytosis. These effects are mediated predominantly by SSTR2 in both cell types. PMID- 22932786 TI - BRAF mutation in papillary thyroid cancer and its value in tailoring initial treatment: a systematic review and meta-analysis. AB - Clinicians have long sought to characterize biological markers of neoplasia as objective indicators of tumor presence, pathogenicity, and prognosis. Armed with data that correlate biomarker activity with disease presence and progression, clinicians can develop treatment strategies that address risks of disease recurrence or persistence and progression. The B-type Raf kinase (BRAF V600E) mutation in exon 15 of the BRAF gene has been noted to be a putative prognostic marker of the most prevalent form of thyroid cancer, papillary thyroid cancer (PTC)--a tumor type with high proclivity for recurrence or persistence. There has been a remarkable interest in determining the association of BRAF mutation with PTC recurrence or persistence. Using many new studies that have been published recently, we performed a meta-analysis to investigate correlations of BRAF mutation status with PTC prognosis, focusing on the recurrence or persistence of the disease after initial treatment. The study was based on published studies included in the PubMed and Embase databases addressing the BRAF mutation and the frequency of recurrence of PTC. We selected studies with data that enabled measurement of the risk ratio for recurrent disease. We also analyzed the factors that are classically known to be associated with recurrence. These factors included lymph node metastasis, extrathyroidal extension, distant metastasis, and American Joint Committee on Cancer (AJCC) stages III/IV. We used 14 articles that included an analysis of these factors as well as PTC recurrence data, with a total of 2470 patients from 9 different countries. The overall prevalence of the BRAF mutation was 45%. The risk ratios in BRAF mutation-positive patients were 1.93 (95% confidence interval [CI], 1.61-2.32; Z = 7.01; p < 0.00001) for PTC recurrence, 1.32 (95% CI, 1.20-1.45; Z = 5.73; p < 0.00001) for lymph node metastasis, 1.71 (95% CI, 1.50-1.94; Z = 8.09; p < 0.00001) for extrathyroidal extension, 0.95 (95% CI, 0.63-1.44; Z = 0.23; p = 0.82) for distant metastasis, and 1.70 (95% CI, 1.45-1.99; Z = 6.46; p < 0.00001) for advanced stage AJCC III/IV. Thus, in this meta-analysis, the BRAF mutation in PTC was significantly associated with PTC recurrence, lymph node metastasis, extrathyroidal extension, and advanced stage AJCC III/IV. Patients with PTC harboring mutated BRAF are likely to demonstrate factors that are associated with an increased risk for recurrence of the disease, offering new prospects for optimizing and tailoring initial treatment strategies to prevent recurrence. PMID- 22932788 TI - Malignant retroperitoneal fibrosis: MRI characteristics in 50 patients. AB - We analyzed magnetic resonance imaging (MRI) morphologic patterns of retroperitoneal fibrosis (RF) to identify those able to distinguish malignant RF (mRF) from idiopathic RF (iRF). This retrospective study concerned 50 consecutive patients with MRI-based RF diagnoses, 35 of whom also had histologically proven RF. Previous radiotherapy, abdominal or pelvic surgery or infection during the preceding 6 months, vascular aneurysm (aorta or iliac artery), presence of retroperitoneal multiple nodular masses, or enlarged lymph nodes with a diameter >15 mm constituted exclusion criteria. Patients with mRF differed from those with iRF by age, smoking habits, and follow-up duration but not by clinical manifestations, inflammatory syndrome, or renal insufficiency. MRI-documented mRF extension along the aorta, from above the renal arteries to below the aortic bifurcation, was more frequent than iRF (47% vs. 0%; p = 0.001) but less frequent between the renal arteries and the aortic bifurcation (18% vs. 50%; p = 0.04); mRF extension behind the aorta was wider than iRF (5.0 vs. 2.5 mm; p = 0.03). Neither urinary tract nor vessel involvement differed. Medial ureteral attraction was significantly less frequent in mRF than iRF (24% vs. 83%; p < 0.001), according to univariate and multivariate analyses. An algorithm based on the most discriminant criteria (RF extending from above the renal arteries to below the aortic bifurcation and the absence of medial ureteral attraction) for mRF diagnosis had 82% sensitivity and 83% specificity. When applied to the 15 iRF patients without histologic data, specificity was 73%. This mRF decision tree, consisting of the 2 most discriminant MRI criteria, could be used as a supplementary argument to support RF biopsy. PMID- 22932789 TI - Lupus anticoagulant-hypoprothrombinemia syndrome: report of 8 cases and review of the literature. AB - The lupus anticoagulant-hypoprothrombinemia syndrome (LAHS)--the association of acquired factor II deficiency and lupus anticoagulant--is a rare disease drastically different from antiphospholipid syndrome in that it may cause predisposition not only to thrombosis but also to severe bleeding. We performed a retrospective study of 8 patients with LAHS referred to 6 French tertiary care centers between January 2003 and February 2011, and a literature review retrieving all related articles published between 1960 and April 2011. Including our 8 new cases, LAHS has been reported in 74 cases. The disease mostly occurs in young adults, with a female to male sex ratio of 1.4. Associated conditions mostly include autoimmune diseases such as systemic lupus erythematosus and infectious diseases. Bleeding is a frequent feature (89% of cases), while arterial and/or venous thrombosis is less common (13%). Factor II level is severely decreased at diagnosis (median value, 11%; range, 1%-40%). LAHS associated with autoimmune diseases is more persistent than LAHS associated with infection, and hemorrhagic complications are more common. Corticosteroids should be considered the first-line treatment, but the thrombotic risk strongly increases during treatment because of the improvement of factor II level. Despite the fact that 50% of patients develop severe bleeding, the mortality rate is <5%, after a median follow-up of 13 months (range, 0.5-252 mo). LAHS associated with autoimmune diseases should be diagnosed and managed carefully because the disease is persistent and severe hemorrhagic complications are common. PMID- 22932787 TI - Cochlear implantation in older adults. AB - Cochlear implants allow individuals with severe to profound hearing loss access to sound and spoken language. The number of older adults in the United States who are potential candidates for cochlear implantation (CI) is approximately 150,000 and will continue to increase with the aging of the population. Should CI be routinely recommended for these older adults, and do these individuals benefit from CI? We reviewed our 12-year experience with CI in adults aged >=60 years (n = 445) at Johns Hopkins Medical Institutions to investigate the impact of CI on speech understanding and to identify factors associated with speech performance. Complete data on speech outcomes at baseline and 1 year post-CI were available for 83 individuals. Our results demonstrate that CI in adults aged >=60 years consistently improved speech understanding scores, with a mean increase of 60.0% (SD 24.1) on HINT (Hearing in Noise Test) sentences in quiet. The magnitude of the gain in speech scores was negatively associated with age at implantation, such that for every increasing year of age at CI the gain in speech scores was 1.3 percentage points less (95% confidence interval [95% CI], 0.6-1.9) after adjusting for age at hearing loss onset. Conversely, individuals with higher pre CI speech scores (HINT scores between 40% and 60%) had significantly greater post CI speech scores by a mean of 10.0 percentage points (95% CI, 0.4-19.6) than those with lower pre-CI speech scores (HINT <40%) after adjusting for age at CI and age at hearing loss onset. These results suggest that older adult CI candidates who are younger at implantation and with higher preoperative speech scores obtain the highest speech understanding scores after CI, with possible implications for current United States Medicare policy. Finally, we provide an extended discussion of the epidemiology and impact of hearing loss in older adults. Future research of CI in older adults should expand beyond simple speech outcomes to take into account the broad cognitive, social, and physical functioning outcomes that are likely detrimentally affected by hearing loss and may be mitigated by CI. PMID- 22932790 TI - Aspergillus tracheobronchitis: report of 8 cases and review of the literature. AB - Aspergillus tracheobronchitis (AT) is an infrequent but severe form of invasive pulmonary aspergillosis in which the fungal infection is entirely or predominantly confined to the tracheobronchial tree. We reviewed 8 cases of AT diagnosed in our tertiary care center during an 18-year period, as well as 148 cases previously reported in the English literature from 1985 to July 2011. The demographic, clinical, imaging, bronchoscopic, and outcome characteristics of every eligible patient were excerpted, and predictors of inhospital mortality were identified by logistic regression. Solid organ transplantation (SOT) (44.2%), hematologic malignancy (21.2%), neutropenia (18.7%), and chronic obstructive pulmonary disease (15.4%) were the most common underlying conditions reported. Most cases occurred in patients receiving long-term corticosteroid treatment (71.8%) or chemotherapy (25.0%). Fever and respiratory complaints (cough, dyspnea, stridor, or wheezing) were the most frequent symptoms; one-third of patients developed acute respiratory distress at presentation, and 15.1% were asymptomatic at the time of diagnosis. Initial imaging studies were not informative in 47.4% of the cases. Aspergillus fumigatus was the predominant species (74.4%). The pseudomembranous form was the most commonly observed (31.9% of cases) and was more frequent in neutropenic patients (p = 0.007), whereas ulcerative AT (31.2%) was associated with SOT (p = 0.001). The most frequent antifungal monotherapy regimens were amphotericin B deoxycholate (23.1%) and itraconazole (18.6%), whereas combined therapy was administered in 35.9% of the cases. Overall inhospital mortality was 39.1%, with neutropenia (odds ratio [OR], 20.47; p < 0.001) and acute respiratory distress at presentation (OR, 9.54; p = 0.002) as independent prognostic factors. Our pooled analysis of the literature shows that AT remains a rare opportunistic infection with a nonspecific presentation and a variable course depending on the nature of the predisposing factor. PMID- 22932791 TI - Effects of thiazolidinediones on polycystic ovary syndrome: a meta-analysis of randomized placebo-controlled trials. AB - INTRODUCTION: Thiazolidinedione (TZD) is one of the therapy options for polycystic ovary syndrome (PCOS) patients; however, the effectiveness of TZD in the treatment of PCOS remains controversial. The aim of this metaanalysis was to clarify the role that TZDs play in the treatment of PCOS. METHODS: The authors searched the following databases for any date up to June 2012 for randomized controlled trials on PCOS treatment in which interventions for the experimental and control groups were TZDs and placebo, respectively: Medline, Embase, and the Cochrane library. RESULTS: The search strategy identified 173 potential publications, eight of which were included. In the treatment of PCOS, the insulin lowering effects of TZDs were superior to placebo (95% CI -1.50 to -0.12; P=0.021), and the lowering of fasting blood glucose was superior to placebo (95% CI -1.06 to -0.05; P=0.031). There was no difference in reduction of the Ferriman Gallwey scores or the androgen levels between TZDs and placebo (95% CI -0.57 to 0.10; P=0.169 and 95% CI -0.64 to 0.09; P=0.141, respectively). The effects of TZDs on body weight reduction were inferior to placebo (95% CI 0.13 to 0.66; P=0.003). Significant between-study heterogeneity was detected for several variables assessed. CONCLUSION: This is the first meta-analysis to evaluate the role that TZDs plays in the treatment of PCOS compared with placebo. The currently available data showed that TZDs can effectively reduce insulin and fasting blood glucose levels in patients with PCOS, but TZDs may not effectively reduce the Ferriman-Gallwey score or androgen levels and may increase body weight. PMID- 22932792 TI - Dysfunctional Vgamma9Vdelta2 T cells are negative prognosticators and markers of dysregulated mevalonate pathway activity in chronic lymphocytic leukemia cells. AB - The role of Vgamma9Vdelta2 T cells in chronic lymphocytic leukemia (CLL) is unexplored, although these cells have a natural inclination to react against B cell malignancies. Proliferation induced by zoledronic acid was used as a surrogate of gammadelta TCR-dependent stimulation to functionally interrogate Vgamma9Vdelta2 T cells in 106 untreated CLL patients. This assay permitted the identification of responder and low-responder (LR) patients. The LR status was associated with greater baseline counts of Vgamma9Vdelta2 T cells and to the expansion of the effector memory and terminally differentiated effector memory subsets. The tumor immunoglobulin heavy chain variable region was more frequently unmutated in CLL cells of LR patients, and the mevalonate pathway, which generates Vgamma9Vdelta2 TCR ligands, was more active in unmutated CLL cells. In addition, greater numbers of circulating regulatory T cells were detected in LR patients. In multivariate analysis, the LR condition was an independent predictor of shorter time-to-first treatment. Accordingly, the time-to-first treatment was significantly shorter in patients with greater baseline numbers of total Vgamma9Vdelta2 T cells and effector memory and terminally differentiated effector memory subpopulations. These results unveil a clinically relevant in vivo relationship between the mevalonate pathway activity of CLL cells and dys functional Vgamma9Vdelta2 T cells. PMID- 22932793 TI - Autoantibodies specific to a peptide of beta2-glycoprotein I cross-react with TLR4, inducing a proinflammatory phenotype in endothelial cells and monocytes. AB - beta(2)-glycoprotein I (beta(2)GPI) is the major antigenic target for antiphospholipid Abs. Anti-beta(2)GPI Abs are a heterogeneous population of Igs targeting all domains of the molecule. Abs specific to beta(2)GPI domain I are strongly associated with thrombosis and obstetric complications. In the present study, we sought to understand the possible pathogenic mechanism for this subset of anti-beta(2)GPI Abs, investigating their potential cross-reactivity with other self-proteins involved in inflammatory or coagulant events. We compared the amino acid sequence of the beta(2)GPI domain I with human proteins in a protein databank and identified a peptide sharing 88% identity with an epitope of human TLR4. A high percentage of patients with antiphospholipid syndrome (41%) and systemic lupus erythematosus (50%) presented serum IgG specific to this peptide. Anti-beta(2)GPI peptide Abs binding the TLR4 were able to induce NF-kappaB activation in HEK293 cells that were stably transfected with the TLR4 gene. Anti beta(2)GPI peptide Abs induced activation of TLR4 and triggered interleukin-1 receptor-associated kinase phosphorylation and NF-kappaB translocation, promoting VCAM expression on endothelial cells and TNF-alpha release by monocytes. In conclusion, our observations suggest a novel pathogenic mechanism in the TLR4 stimulation by anti-beta(2)GPI peptide Abs that links adaptive immune responses with innate immunity in antiphospholipid syndrome and systemic lupus erythematosus. PMID- 22932794 TI - Interphase Chromosome Flow-FISH. AB - A 2-day method using flow cytometry and FISH for interphase cells was developed to detect monosomy 7 cells in myelodysplastic syndrome patients. The method, Interphase Chromosome Flow-FISH (IC Flow-FISH), involves fixation of leukocytes from blood, membrane permeabilization, hybridization of cellular DNA with peptide nucleic acid probes with cells intact, and analysis by flow cytometry. Hundreds to thousands of monosomy 7 cells were consistently detected from 10-20 mL of blood in patients with monosomy 7. Proportions of monosomy 7 cells detected in IC Flow-FISH were compared with results from conventional cytogenetics; identification of monosomy 7 populations was verified with FACS; and patient and donor cells were mixed to test for sensitivity. IC Flow-FISH allows for detecting monosomy 7 without requiring bone marrow procurement or the necessity of metaphase spreads, and wider applications to other chromosomal abnormalities are in development. PMID- 22932795 TI - The clinical implication of SRSF2 mutation in patients with myelodysplastic syndrome and its stability during disease evolution. AB - Recurrent somatic mutation of SRSF2, one of the RNA splicing machinery genes, has been identified in a substantial proportion of patients with myelodysplastic syndrome (MDS). However, the clinical and biologic characteristics of MDS with this mutation remain to be addressed. In this study, 34 (14.6%) of the 233 MDS patients were found to have SRSF2 mutation. SRSF2 mutation was closely associated with male sex (P = .001) and older age (P < .001). It occurred concurrently with at least 1 additional mutation in 29 patients (85.3%) and was closely associated with RUNX1, IDH2, and ASXL1 mutations (P = .004, P < .001, and P < .001, respectively). Patients with SRSF2 mutation had an inferior overall survival (P = .010), especially in the lower risk patients. Further exploration showed that the prognostic impact of SRSF2 mutation might be attributed to its close association with old age. Sequential analyses in 173 samples from 66 patients showed that all SRSF2-mutated patients retained their original mutations, whereas none of the SRSF2-wild patients acquired a novel mutation during disease evolution. In conclusion, SRSF2 mutation is associated with distinct clinical and biologic features in MDS patients. It is stable during the clinical course and may play little role in disease progression. PMID- 22932797 TI - Neutrophil extracellular traps mediate transfer of cytoplasmic neutrophil antigens to myeloid dendritic cells toward ANCA induction and associated autoimmunity. AB - Antineutrophil cytoplasmic antibodies (ANCAs) target proteins normally retained within neutrophils, indicating that cell death is involved in the autoimmunity process. Still, ANCA pathogenesis remains obscure. ANCAs activate neutrophils inducing their respiratory burst and a peculiar form of cell death, named NETosis, characterized by formation of neutrophil extracellular traps (NETs), decondensed chromatin threads decorated with cytoplasmic proteins endorsed with antimicrobial activity. NETs have been consistently detected in ANCA-associated small-vessel vasculitis, and this association prompted us to test whether the peculiar structure of NET favors neutrophil proteins uploading into myeloid dendritic cells and the induction of ANCAs and associated autoimmunity. Here we show that myeloid DCs uploaded with and activated by NET components induce ANCA and autoimmunity when injected into naive mice. DC uploading and autoimmunity induction are prevented by NET treatment with DNAse, indicating that NET structural integrity is needed to maintain the antigenicity of cytoplasmic proteins. We found NET intermingling with myeloid dendritic cells also positive for neutrophil myeloperoxidase in myeloperoxidase-ANCA-associated microscopic poliangiitis providing a potential correlative picture in human pathology. These data provide the first demonstration that NET structures are highly immunogenic such to trigger adaptive immune response relevant for autoimmunity. PMID- 22932796 TI - Targeting the insulin-like growth factor-1 receptor to overcome bortezomib resistance in preclinical models of multiple myeloma. AB - Proteasome inhibition with bortezomib is a validated approach to the treatment of multiple myeloma, but drug resistance often emerges and limits its utility in the retreatment setting. To begin to identify some of the mechanisms involved, we developed bortezomib-resistant myeloma cell lines that, unlike previously reported models, showed no beta5 subunit mutations. Instead, up-regulation of the insulin-like growth factor (IGF)-1 axis was identified, with increased autocrine and paracrine secretion of IGF-1, leading to increased activation of the IGF-1 receptor (IGF-1R). Exogenous IGF-1 reduced cellular sensitivity to bortezomib, whereas pharmacologic or small hairpin RNA-mediated IGF-1R suppression enhanced bortezomib sensitivity in cell lines and patient samples. In vitro studies with OSI-906, a clinically relevant dual IGF-1R and insulin receptor inhibitor, showed it acted synergistically with bortezomib, and potently resensitized bortezomib resistant cell lines and patient samples to bortezomib. Importantly, OSI-906 in combination with bortezomib also overcame bortezomib resistance in an in vivo model of myeloma. Taken together, these data support the hypothesis that signaling through the IGF-1/IGF-1R axis contributes to acquired bortezomib resistance, and provide a rationale for combining bortezomib with IGF-1R inhibitors like OSI-906 to overcome or possibly prevent the emergence of bortezomib-refractory disease in the clinic. PMID- 22932799 TI - Interim FDG-PET in Hodgkin lymphoma: a compass for a safe navigation in clinical trials? AB - Despite the rewarding results achieved in the treatment of Hodgkin lymphoma (HL), concerns have been raised regarding the long-term complications induced by therapy. Hence, the current challenge is to develop a new therapeutic strategy maintaining excellent patient outcome while reducing potentially life-threatening late adverse effects. Therefore, it would be beneficial to identify chemoresistant or refractory patients early during therapy for appropriate and timely escalation of treatment. Recently, compelling data have emerged on the prognostic role of interim [18F]-fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) performed early during the course of treatment to predict ultimate outcome, even proving superior to conventional prognostic factors. Several ongoing prospective trials are exploring the feasibility of treatment de escalation strategies in patients with a negative interim PET, as well as therapy escalation in advanced-stage HL patients who have a positive interim PET result. In this article, the published reports on the contribution of interim PET to the design of ongoing response-adapted clinical trials are reviewed. Moreover, some of the unresolved issues revolving around the suboptimal positive predictive value of interim PET are addressed with an emphasis on the interpretation criteria. A final remark on the appropriate use of interim PET is also provided. PMID- 22932798 TI - Cdc42 regulates neutrophil migration via crosstalk between WASp, CD11b, and microtubules. AB - Chemotaxis promotes neutrophil participation in cellular defense by enabling neutrophil migration to infected tissue and is controlled by persistent cell polarization. One long-standing question of neutrophil polarity has been how the pseudopod and the uropod are coordinated. In our previous report, we suggested that Rho GTPase Cdc42 controls neutrophil polarity through CD11b signaling at the uropod, albeit through an unknown mechanism. Here, we show that Cdc42 controls polarity, unexpectedly, via its effector WASp. Cdc42 controls WASp activation and its distant localization to the uropod. At the uropod, WASp regulates the reorganization of CD11b integrin into detergent resistant membrane domains; in turn, CD11b recruits the microtubule end binding protein EB1 to capture and stabilize microtubules at the uropod. This organization is necessary to maintain neutrophil polarity during migration and is critical for neutrophil emigration into inflamed lungs. These results suggest unrecognized mechanism of neutrophil polarity in which WASp mediates long-distance control of the uropod by Cdc42 to maintain a proper balance between the pseudopod and the uropod. Our study reveals a new function for WASp in the control of neutrophil polarity via crosstalk between CD11b and microtubules. PMID- 22932800 TI - How I treat anticoagulated patients undergoing an elective procedure or surgery. AB - The periprocedural management of patients receiving long-term oral anticoagulant therapy remains a common but difficult clinical problem, with a lack of high quality evidence to inform best practices. It is a patient's thromboembolic risk that drives the need for an aggressive periprocedural strategy, including the use of heparin bridging therapy, to minimize time off anticoagulant therapy, while the procedural bleed risk determines how and when postprocedural anticoagulant therapy should be resumed. Warfarin should be continued in patients undergoing selected minor procedures, whereas in major procedures that necessitate warfarin interruption, heparin bridging therapy should be considered in patients at high thromboembolic risk and in a minority of patients at moderate risk. Periprocedural data with the novel oral anticoagulants, such as dabigatran, rivaroxaban, and apixaban, are emerging, but their relatively short half-life, rapid onset of action, and predictable pharmacokinetics should simplify periprocedural use. This review aims to provide a practical, clinician-focused approach to periprocedural anticoagulant management. PMID- 22932802 TI - Heparin-induced thrombocytopenia: further evidence for a unique immune response. AB - Cardiopulmonary bypass surgery (CPB) is associated with a high incidence of IgG Abs against platelet factor 4/heparin (PF4/H) complexes by day 6 after surgery. These Abs are associated with an immune-mediated adverse drug reaction, heparin induced thrombocytopenia. Although the early onset of the anti-PF4/H IgG response is compatible with a secondary immune response, the rapid decline of Ab titers thereafter is not. To shed light on the origin of these Abs, in the present study, we prospectively compared the kinetics of these Abs with that of Abs against 2 recall Ags and to that of autoantibodies in 166 CPB patients over 4 months. Surgery induced strong inflammation, as shown by an increase in mean C reactive protein levels. Consistent with previous studies, anti-PF4/H IgG optical density transiently increased between baseline and day 10 (P < .001; not associated with C-reactive protein levels), followed by a decrease over the next months. In contrast, concentrations of antidiphtheria toxin IgG and antitetanus toxin IgG increased constantly over the 4 months after surgery by 25%-30%. IgG autoantibodies did not change. Therefore, the transient kinetics of the anti PF4/H IgG response resembled neither that of recall Abs nor that of IgG autoantibodies, but rather showed a unique profile. PMID- 22932801 TI - Massive evolution of the immunoglobulin heavy chain locus in children with B precursor acute lymphoblastic leukemia. AB - The ability to distinguish clonal B-cell populations based on the sequence of their rearranged immunoglobulin heavy chain (IgH) locus is an important tool for diagnosing B-cell neoplasms and monitoring treatment response. Leukemic precursor B cells may continue to undergo recombination of the IgH gene after malignant transformation; however, the magnitude of evolution at the IgH locus is currently unknown. We used next-generation sequencing to characterize the repertoire of IgH sequences in diagnostic samples of 51 children with B precursor acute lymphoblastic leukemia (B-ALL). We identified clonal IgH rearrangements in 43 of 51 (84%) cases and found that the number of evolved IgH sequences per patient ranged dramatically from 0 to 4024. We demonstrate that the evolved IgH sequences are not the result of amplification artifacts and are unique to leukemic precursor B cells. In addition, the evolution often follows an allelic exclusion pattern, where only 1 of 2 rearranged IgH loci exhibit ongoing recombination. Thus, precursor B-cell leukemias maintain evolution at the IgH locus at levels that were previously underappreciated. This finding sheds light on the mechanisms associated with leukemic clonal evolution and may fundamentally change approaches for monitoring minimal residual disease burden. PMID- 22932803 TI - NKT cell adjuvant-based tumor vaccine for treatment of myc oncogene-driven mouse B-cell lymphoma. AB - Immunomodulators are effective in controlling hematologic malignancy by initiating or reactivating host antitumor immunity to otherwise poorly immunogenic and immune suppressive cancers. We aimed to boost antitumor immunity in B-cell lymphoma by developing a tumor cell vaccine incorporating alpha galactosylceramide (alpha-GalCer) that targets the immune adjuvant properties of NKT cells. In the EMU-myc transgenic mouse model, single therapeutic vaccination of irradiated, alpha-GalCer-loaded autologous tumor cells was sufficient to significantly inhibit growth of established tumors and prolong survival. Vaccine induced antilymphoma immunity required NKT cells, NK cells, and CD8 T cells, and early IL-12-dependent production of IFN-gamma. CD4 T cells, gamma/delta T cells, and IL-18 were not critical. Vaccine treatment induced a large systemic spike of IFN-gamma and transient peripheral expansion of both NKT cells and NK cells, the major sources of IFN-gamma. Furthermore, this vaccine approach was assessed in several other hematopoietic tumor models and was also therapeutically effective against AML-ETO9a acute myeloid leukemia. Replacing alpha-GalCer with beta mannosylceramide resulted in prolonged protection against EMU-myc lymphoma. Overall, our results demonstrate a potent immune adjuvant effect of NKT cell ligands in therapeutic anticancer vaccination against oncogene-driven lymphomas, and this work supports clinical investigation of NKT cell-based immunotherapy in patients with hematologic malignancies. PMID- 22932804 TI - Elevated serum soluble CD40 ligand in cancer patients may play an immunosuppressive role. AB - Tumor cells can induce certain cytokines and soluble receptors that have a suppressive effect on the immune system. In this study, we showed that an extracellular portion of a membrane-bound ligand of CD40 (soluble CD40 ligand; sCD40L) was significantly elevated in the serum of cancer patients compared with healthy donors. In addition, PBMCs from cancer patients had a relatively larger population of myeloid-derived suppressor cells (MDSCs), defined as CD33(+)HLA-DR( ) cells, and these cells expressed higher levels of CD40. T-cell proliferation and IFN-gamma production decreased when stimulated T cells were cocultured with an increased amount of autologous MDSCs. The addition of recombinant monomeric sCD40L enriched MDSCs and had an additive inhibitory effect on T-cell proliferation. PBMCs cultured in vitro with sCD40L also showed an expansion of regulatory T cells (CD4(+)CD25(high)Foxp3(+)), as well as induction of cytokines, such as IL-10 and IL-6. Moreover, sCD40L-induced enrichment of programmed death-1 expressing T cells was greater in cancer patients than in healthy donors. Preexisting sCD40L also inhibited IL-12 production from monocytes on activation. These data suggest that the higher levels of sCD40L seen in cancer patients may have an immunosuppressive effect. PMID- 22932805 TI - The human GFI136N variant induces epigenetic changes at the Hoxa9 locus and accelerates K-RAS driven myeloproliferative disorder in mice. AB - The coding single nucleotide polymorphism GFI136N in the human gene growth factor independence 1 (GFI1) is present in 3%-7% of whites and increases the risk for acute myeloid leukemia (AML) by 60%. We show here that GFI136N, in contrast to GFI136S, lacks the ability to bind to the Gfi1 target gene that encodes the leukemia-associated transcription factor Hoxa9 and fails to initiate histone modifications that regulate HoxA9 expression. Consistent with this, AML patients heterozygous for the GFI136N variant show increased HOXA9 expression compared with normal controls. Using ChipSeq, we demonstrate that GFI136N specific epigenetic changes are also present in other genes involved in the development of AML. Moreover, granulomonocytic progenitors, a bone marrow subset from which AML can arise in humans and mice, show a proliferative expansion in the presence of the GFI136N variant. In addition, granulomonocytic progenitors carrying the GFI136N variant allele have altered gene expression patterns and differ in their ability to grow after transplantation. Finally, GFI136N can accelerate a K-RAS driven fatal myeloproliferative disease in mice. Our data suggest that the presence of a GFI136N variant allele induces a preleukemic state in myeloid precursors by deregulating the expression of Hoxa9 and other AML-related genes. PMID- 22932807 TI - Erratum to: Surgical aspects and complications of continuous intraperitoneal insulin infusion with an implantable pump. PMID- 22932806 TI - Conditional TRF1 knockout in the hematopoietic compartment leads to bone marrow failure and recapitulates clinical features of dyskeratosis congenita. AB - TRF1 is part of the shelterin complex, which binds telomeres and it is essential for their protection. Ablation of TRF1 induces sister telomere fusions and aberrant numbers of telomeric signals associated with telomere fragility. Dyskeratosis congenita is characterized by a mucocutaneous triad, bone marrow failure (BMF), and presence of short telomeres because of mutations in telomerase. A subset of patients, however, show mutations in the shelterin component TIN2, a TRF1-interacting protein, presenting a more severe phenotype and presence of very short telomeres despite normal telomerase activity. Allelic variations in TRF1 have been found associated with BMF. To address a possible role for TRF1 dysfunction in BMF, here we generated a mouse model with conditional TRF1 deletion in the hematopoietic system. Chronic TRF1 deletion results in increased DNA damage and cellular senescence, but not increased apoptosis, in BM progenitor cells, leading to severe aplasia. Importantly, increased compensatory proliferation of BM stem cells is associated with rapid telomere shortening and further increase in senescent cells in vivo, providing a mechanism for the very short telomeres of human patients with mutations in the shelterin TIN2. Together, these results represent proof of principle that mutations in TRF1 lead to the main clinical features of BMF. PMID- 22932808 TI - An efficient biosurfactant-producing bacterium Selenomonas ruminantium CT2, isolated from mangrove sediment in south of Thailand. AB - Biosurfactant-producing bacteria, isolate CT2, was isolated from mangrove sediment in the south of Thailand. The sequence of the 16S rRNA gene from isolate CT2 showed 100 % similarity with Selenomonas ruminantium. The highest biosurfactant production (5.02 g/l) was obtained when the cells were grown on minimal salt medium containing 15 g/l molasses and 1 g/l commercial monosodium glutamate supplemented with 1 g/l NaCl, 0.1 g/l leucine, 5 % (v/v) inoculum size at 30 degrees C and 150 rpm after 54 h of cultivation. The biosurfactant obtained by extraction with ethyl acetate showed high surface tension reduction (25.5 mN/m), a small CMC value (8 mg/l), thermal and pH stability with respect to surface tension reduction and emulsification activity and a high level of salt tolerance. The biosurfactant obtained was confirmed as a lipopeptide by using a biochemical test, FT-IR, MNR and mass spectrometry. The crude biosurfactant showed a broad spectrum of antimicrobial activity and also had the ability to emulsify oil and enhance PAHs solubility. PMID- 22932809 TI - Esophageal submucosal dissection under steady pressure automatically controlled endoscopy (SPACE): a randomized preclinical trial. AB - BACKGROUND AND STUDY AIMS: A new overtube system has been developed for steady pressure automatically controlled endoscopy (SPACE) in the gastrointestinal tract. The objectives of this study were to validate the feasibility and safety of SPACE in the esophagus, and to evaluate its potential advantages over conventional (manually insufflating) endoscopy in endoscopic submucosal dissection (ESD). METHODS: This was a multicenter preclinical trial using acute porcine models (n = 20). In Experiment 1 (feasibility/safety study), SPACE was attempted in the esophagus with continuous monitoring of cardiopulmonary parameters and intraluminal pressures in the downstream bowel. Different insufflation pressures were tested to optimize the insufflation condition. Each session was video-recorded and scored by blinded reviewers. In Experiment 2 (randomized trial), esophageal ESD was attempted using either SPACE or conventional endoscopy, and results were compared. RESULTS: In Experiment 1, SPACE was performed safely without intraluminal pressure elevation in the downstream bowel. According to video review, SPACE provided more stable, reproducible, and rapid visualization than conventional endoscopy. The insufflation pressure was optimized at 14 mmHg for esophageal SPACE. In Experiment 2, ESD was completed in all animals. The ESD time was significantly shorter with SPACE compared with conventional endoscopy (1326 vs. 1616 seconds; P = 0.009). Responses to questionnaires showed that 94 % - 100 % of participants considered SPACE to provide improved exposure and more uniform tissue tension than conventional endoscopy. Other data were comparable. CONCLUSIONS: SPACE is feasible, safe, and potentially effective for complicated endoscopic procedures, such as ESD. SPACE improves and standardizes endoscopic exposure and tissue tension. A clinical study is required to further confirm its safety and clinical effectiveness. PMID- 22932810 TI - On-line immobilized acetylcholinesterase microreactor for screening of inhibitors from natural extracts by capillary electrophoresis. AB - In this study we developed a simple capillary electrophoresis (CE) method with an on-line acetylcholinesterase (AChE) microreactor at the inlet of capillary for inhibitor screening. The fused-silica capillary surface was modified with a polycationic polyethylenimine coating. Solutions of the enzyme and chitosan were then injected to immobilize the enzyme in approximately 2.9 cm of the capillary inlet (total length of capillary 60.2 cm) by electrostatic interaction and the film overlay technique. Separation of enzyme reaction product (thiocholine, ThCh) and unreacted substrate (acetylthiocholine, AThCh) was achieved within 3.0 min. The conditions affecting the efficiency of reaction of the enzyme were optimized by measuring the peak area of ThCh. Under the optimum conditions, using Huperzine A as model inhibitor, K (i) and IC (50) were 0.551 MUmol L(-1) and 1.52 MUmol L( 1), respectively, for immobilized AChE. Finally, screening of a small compound library containing two known AChE inhibitors and 30 natural extracts was conducted, and species with inhibition activity were directly identified. Compared with previous publications on screening for AChE inhibitors in natural products based on CE methods, the method developed in this work has the advantages of lower cost per analysis, less leakage, and better bioaffinity for the immobilized enzyme because of the unique properties of sodium alginate and chitosan. PMID- 22932811 TI - SPE-NMR metabolite sub-profiling of urine. AB - NMR-based metabolite profiling of urine is a fast and reproducible method for detection of numerous metabolites with diverse chemical properties. However, signal overlap in the (1)H NMR profiles of human urine may hamper quantification and identification of metabolites. Therefore, a new method has been developed using automated solid-phase extraction (SPE) combined with NMR metabolite profiling. SPE-NMR of urine resulted in three fractions with complementary and reproducible sub-profiles. The sub-profile from the wash fraction (100 % water) contained polar metabolites; that from the first eluted fraction (10 % methanol 90 % water) semi-polar metabolites; and that from the second eluted fraction (100 % methanol) aromatic metabolites. The method was validated by analysis of urine samples collected from a crossover human nutritional intervention trial in which healthy volunteers consumed capsules containing a polyphenol-rich mixture of red wine and grape juice extract (WGM), the same polyphenol mixture dissolved in a soy drink (WGM_Soy), or a placebo (PLA), over a period of five days. Consumption of WGM clearly increased urinary excretion of 4-hydroxyhippuric acid, hippuric acid, 3-hydroxyphenylacetic acid, homovanillic acid, and 3-(3-hydroxyphenyl)-3 hydroxypropionic acid. However, there was no difference between the excreted amounts of these metabolites after consumption of WGM or WGM_Soy, indicating that the soy drink is a suitable carrier for WGM polyphenols. Interestingly, WGM_Soy induced a significant increase in excretion of cis-aconitate compared with WGM and PLA, suggesting a higher demand on the tricarboxylic acid cycle. In conclusion, SPE-NMR metabolite sub-profiling is a reliable and improved method for quantification and identification of metabolites in urine to discover dietary effects and markers of phytochemical exposure. PMID- 22932812 TI - Use of crude extract of lentil plant (Lens culinaris Medikus) in peroxidase-based analyses: fast kinetic determination of hydrogen peroxide and sarcosine in urine. AB - Peroxidase-catalysed reactions are used in a wide variety of analytical applications, most of them based on the final quantification of hydrogen peroxide. Clinical tests for glucose, cholesterol, creatine, creatinine or uric acid in blood or urine and enzyme-linked immunosorbent assays for pesticides, hepatitis or acquired immune deficiency syndrome are good examples of such applications. The most widely used and commercially available peroxidase for biotechnological processes and analytical applications is horseradish peroxidase followed, although in much lower proportion, by soybean peroxidase. The high commercial interest in peroxidases has led to the search for new sources of these enzymes. This work describes the analytical use of lentil plant peroxidase (LPP), which is a new peroxidase extracted from lentil plants (Lens culinaris Medikus); an abundant post-harvest agricultural waste in the area of Castilla y Leon (Spain). A procedure for the quantification of hydrogen peroxide in urine is first proposed using crude extract of lentil plant instead of the purified enzyme. This procedure is then applied to the determination of sarcosine; a natural amino acid that has attracted considerable interest in clinical diagnostics since urinary sarcosine was proposed and later questioned as a biomarker for prostate cancer. Under the action of sarcosine oxidase, sarcosine is oxidized by molecular oxygen to give glycine, formaldehyde and hydrogen peroxide that is quantified according to the previously proposed procedure. The limit of detection for both hydrogen peroxide and sarcosine is around 5 * 10(-7) M. In the determination of sarcosine, the high selectivity of the overall enzymatic reaction, the simple sample treatment and instrumentation, the high sample throughput and the use of LPP in the plant extract instead of the purified enzyme provide a rapid and inexpensive procedure with characteristics very suitable for routine analysis in a clinical laboratory. PMID- 22932813 TI - Simultaneous diastereo- and enantioseparation of farnesoid X receptor (FXR) agonists with a quinine carbamate-based chiral stationary phase. AB - In the frame of a project aimed at finding non-steroidal farnesoid X receptor (FXR) agonists, we identified 4-(2,4-dimethoxyphenyl)-3,6-dimethyl-1-(2-tolyl) 4,8-dihydro-1H-pyrazole[3,4-e][1,4]thiazepin-7-one (1) as a hit endowed with FXR activity. Most of the compounds synthesised during the hit-to-lead optimisation work were characterised by the presence of two chiral centres and were therefore obtained as mixtures of anti(+/-)- and syn(+/-)-diastereoisomers. A restricted sub-set of species harboured with a carboxylic acid group on the distal phenyl ring of the biphenyl (a(+/-)5 (A1) and s(+/-)5 (S1)) or the phenoxyphenyl (a(+/ )6 (A2) and s(+/-)6 (S2)) moiety at C-4 position of the pyrazole[3,4 e][1,4]thiazepin-7-one core, resulted in suitable diastereo- and enantioresolution with a quinine (QN) carbamate-derived chiral stationary phase (CSP). Differently from the compounds usually analysed with QN-based CSPs, the couples A1/S1 and A2/S2 were atypical selectands, in which the two chiral carbon atoms reside at a remote position with respect to the carboxylic function, the main "point of attack" to the CSP. We produced evidence that the scarcely employed normal-phase (NP) eluent systems represent the elective choice for achieving the simultaneous diastereo- and enantioseparation of this class of compounds over the usually preferred reversed-phase (RP) and polar-organic (PO) modes of elution. Indeed, after the optimisation of the eluent composition, NP conditions allowed to obtain profitable enantioselectivity profiles, along with excellent diastereoselectivity levels (alpha(A1) = 1.07, R (S)(A1) = 1.15; alpha(S1) = 1.09, R (S)(S1) = 1.47; alpha(A2) = 1.08, R (S)(A2) = 1.31; and alpha(S2) = 1.06, R (S)(S2) = 1.18). The optimised NP methods are suitable for simultaneously providing information on the diastereo- and enantiopurity of the investigated compounds. PMID- 22932814 TI - Dual modulation of the T-cell receptor-activated signal transduction pathway by morphine in human T lymphocytes. AB - PURPOSE: In this study, we aimed to investigate the effect of morphine on the activation of extracellular signal-regulated kinase (ERK) and nuclear factor kappaB (NF-kappaB), both of which play crucial roles in T-cell activation. METHODS: Human CD3+ T cells and Jurkat T cells were stimulated by anti-CD3 antibody or phorbol 12-myristate 13-acetate plus ionomycin with or without 24-h pretreatment with morphine. Activation of ERK was assessed by immunoblot analysis of phosphorylated ERK. Activation of the NF-kappaB signaling pathway was examined by analyzing nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha (IkappaBalpha) phosphorylation using immunoblotting, and interleukin-2 (IL-2) gene expression using quantitative real-time reverse transcriptase polymerase chain reaction. RESULTS: Morphine pretreatment enhanced ERK phosphorylation, but inhibited IkappaBalpha phosphorylation and IL-2 gene expression in activated T cells. The effects of morphine on ERK phosphorylation and IL-2 gene expression were not antagonized by naloxone. We detected kappa opioid receptor transcript in T cells, but U50,488, a kappa-receptor-selective agonist, did not enhance ERK phosphorylation. CONCLUSION: Morphine enhances ERK signaling, whereas it inhibits NF-kappaB signaling in activated human T cells. These effects of morphine are unlikely to be mediated by known opioid receptors. PMID- 22932816 TI - A strategy for combining minor genetic susceptibility genes to improve prediction of disease in type 1 diabetes. AB - Genome-wide association studies have identified gene regions associated with type 1 diabetes. The aim of this study was to determine how the combined allele frequency of multiple susceptibility genes can stratify islet autoimmunity and/or type 1 diabetes risk. Children of parents with type 1 diabetes and prospectively followed from birth for the development of islet autoantibodies and diabetes were genotyped for single-nucleotide polymorphisms at 12 type 1 diabetes susceptibility genes (ERBB3, PTPN2, IFIH1, PTPN22, KIAA0350, CD25, CTLA4, SH2B3, IL2, IL18RAP, IL10 and COBL). Non-human leukocyte antigen (HLA) risk score was defined by the total number of risk alleles at these genes. Receiver operator curve analysis showed that the non-HLA gene combinations were highly effective in discriminating diabetes and most effective in children with a high-risk HLA genotype. The greatest diabetes discrimination was obtained by the sum of risk alleles for eight genes (IFIH1, CTLA4, PTPN22, IL18RAP, SH2B3, KIAA0350, COBL and ERBB3) in the HLA-risk children. Non-HLA-risk allele scores stratified risk for developing islet autoantibodies and diabetes, and progression from islet autoimmunity to diabetes. Genotyping at multiple susceptibility loci in children from affected families can identify neonates with sufficient genetic risk of type 1 diabetes to be considered for early intervention. PMID- 22932815 TI - Transdermal hormonal therapy in perimenstrual migraine: why, when and how? AB - Experimental and clinical evidence is strongly in favor of a role for estrogens in migraine. It is clear that estrogen fluctuations represent trigger factors for the attacks, while the resolution of these fluctuations (menopause) may be associated to the remission or, conversely, to the worsening of the disease. However, the exact mechanisms and mediators underlying the effects of estrogens in migraine are largely unknown. The exact mechanisms and mediators underlying the effects of estrogens in migraine are largely unknown. In this review, we summarize clinical and preclinical data that are relevant for the role of estrogens in migraine and we discuss how estrogen modulation can be exploited positively to improve hormonal-related migraine. PMID- 22932817 TI - Post-transcriptional control of candidate risk genes for type 1 diabetes by rare genetic variants. AB - The genetic variation causal for predisposition to type 1 diabetes (T1D) remains unidentified for the majority of known T1D risk loci. MicroRNAs function as post transcriptional gene regulators by targeting microRNA-binding sites in the 3' untranslated regions (UTR) of mRNA. Genetic variation within the 3'-UTR of T1D associated genes may contribute to T1D development by altering microRNA-mediated gene regulation. In silico analysis of variable sites predicted altered microRNA binding in established T1D loci. Functional implications were assessed for variable sites in the 3'-UTR of T1D candidate risk genes CTLA4 and IL10, both involved in immune regulation. We confirmed that in these genes 3'-UTR variation either disrupted or introduced a microRNA-binding site, affecting the repressive capacity of miR-302a* and miR-523, respectively. Our study points to the potential of 3'-UTR variation to affect T1D pathogenesis by altering post transcriptional gene regulation by microRNAs. PMID- 22932818 TI - Right ventricular ejection fraction measured by multigated planar equilibrium radionuclide ventriculography is an independent prognostic factor in patients with ischemic heart disease. AB - BACKGROUND: The number of studies on the prognostic value of the right ventricular ejection fraction (RVEF) in patients with ischemic heart disease (IHD) is limited, whereas it is widely accepted that the left ventricular ejection fraction (LVEF) is a strong prognostic factor. We assessed whether RVEF measured by multigated planar equilibrium radionuclide ventriculography (RNV) is an independent prognostic factor in patients with IHD. METHODS AND RESULTS: We retrospectively identified 347 consecutive patients with IHD (mean age 71 +/- 11 years; 18% women) who underwent multigated planar equilibrium RNV between 2004 and 2008 to determine the LVEF, which also provided the RVEF (mean 44.7% +/- 11.0%). We categorized patients according to RVEF in >=40% (n = 240) and <40% (n = 107). Patients were followed for a median of 826 days (range 3-2,400) for the occurrence of events [all-cause mortality (n = 60), cardiac mortality (n = 33), and cardiac hospitalization (n = 78)]. Cox regression analysis with significant univariate predictors [coronary artery revascularization (P = .003), diuretics (P = .03), and statins (P < .001)] showed that an RVEF <40% was associated with a 2.90 (1.68-5.00)-fold higher risk of all-cause death. Accordingly, a decreased RVEF was associated with a 2.15 (1.34-3.43)-fold increase in the risk of cardiac hospitalization and a 5.11(2.32-11.23)-fold risk of cardiac death. CONCLUSION: RVEF measured by multigated planar equilibrium RNV is an independent prognostic factor in patients with chronic IHD. PMID- 22932819 TI - Quantification of myocardial blood flow with PET: ready for clinical application. PMID- 22932821 TI - Copper-catalyzed cyanation of arenes using benzyl nitrile as a cyanide anion surrogate. AB - The copper-catalyzed cyanation of arenes using benzyl nitrile as a cyanide anion surrogate furnishes aromatic nitriles in moderate to good yields. The cascade process involves a copper-catalyzed aerobic C-H oxidation, a retro cyanohydrination, and a copper-catalyzed aerobic oxidative C-H functionalization. PMID- 22932823 TI - Light-controlled synthesis of gold nanoparticles using a rigid, photoresponsive surfactant. AB - We report a new strategy for shape control over the synthesis of gold nanoparticles (AuNPs) by using a photoresponsive surfactant based on a modified seed growth method. Owing to photoresponsive properties of the azo group, the designed surfactant, N(1),N(3),N(5)-tris[(4'-azobenzene-4-sulphonic acid)phenyl]benzene-1,3,5-tricarboxamide, exhibits a distinctive molecular configuration under light leading to different growth processes of AuNPs. As a result, the blackberry-like, spherical AuNPs and multilayered Au plates were successfully prepared in high yield under visible and UV light. The size and morphological control of Au nanocrystals are described and the synthesized Au nanocrystals are evaluated for SERS applications. PMID- 22932824 TI - Cyanation of alpha,beta-unsaturated enones by malononitrile in open air under metal-catalyst-free conditions. AB - Cyanation of alpha,beta-unsaturated enones by employing malononitrile as the organic cyanation source has been disclosed, which proceeds efficiently at room temperature in open air under metal-catalyst-free conditions. PMID- 22932820 TI - Regulation of the grapevine polygalacturonase-inhibiting protein encoding gene: expression pattern, induction profile and promoter analysis. AB - Regulation of defense in plants is a complex process mediated by various signaling pathways. Promoter analysis of defense-related genes is useful to understand these signaling pathways involved in regulation. To this end, the regulation of the polygalacturonase-inhibiting protein encoding gene from Vitis vinifera L. (Vvpgip1) was analyzed with regard to expression pattern and induction profile as well as the promoter in terms of putative regulatory elements present, core promoter size and the start of transcription. Expression of Vvpgip1 is tissue-specific and developmentally regulated. Vvpgip1 expression was induced in response to auxin, salicylic acid and sugar treatment, wounding and pathogen infection. The start of transcription was mapped to 17 bp upstream of the ATG and the core promoter was mapped to the 137 bp upstream of the ATG. Fructose- and Botrytis responsiveness were identified in the region between positions -3.1 and -1.5 kb. The analyses showed induction in water when the leaves were submersed and this response and the response to wounding mapped to the region between positions -1.1 and -0.1 kb. In silico analyses revealed putative cis-acting elements in these areas that correspond well to the induction stimuli tested. PMID- 22932825 TI - [New job profiles for medical assistants (MFA) in care provision for elderly people - project in the framework of the funding initiative of the German Medical Association (Bundesarztekammer) for research on care provision]. AB - AIM OF THE STUDY: Against the background of the discussion on the delegation of medical tasks to medical/physician assistants (Medizinische Fachangestellte/MFA) in order to avoid imminent shortages in the care provision by general practitioners (GPs), the aim of the study was to evaluate such a delegation. The delegation of tasks was based on the additional professional qualification/speciality training of medical/physician assistants (MFA) following the curriculum "ambulatory care of elderly people" of the German Medical Association (Bundesarztekammer/BAK). 2 such projects of additional professional qualification of MFA and tasks delegation were evaluated. The projects were supported by the German Medical Association (BAK) and implemented by the Scientific Institute of the German Medical Doctors (Wissenschaftliches Institut der Arzte Deutschlands/WIAD) and the Chamber of Physicians of Schleswig-Holstein (Arztekammer Schleswig-Holstein/AK S-H) from October 2008 until December 2010. METHODOLOGY: The common evaluation of both projects applied a multi-perspective approach and was mainly based on the data collected by questioning MFA, GPs and patients. These data were complemented with the results collected during experts' interviews and internal evaluations of the additional professional qualification. In total, 61 medical practices, 65 MFA and 669 patients were included. RESULTS: The curriculum mentioned has proven its worth; the additional qualification broadened the field of competence of the trained MFA. The implementation of the delegation concept in the medical practices is unproblematic, enhances the team spirit, relieves the GPs of some of their workload and strengthens the binding to patients. In the ambulatory care of elderly people, the following diagnoses/diagnosis groups are the most relevant for the delegation of tasks: dementia, nutrition-related diseases, apoplexy, coronary heart diseases, hypertension and peripheral vascular diseases. Tasks were delegated in the following fields: diagnostics, therapy, control/monitoring, medicines control, prevention measures, assessment of living environment, health status, mobility, etc. BENEFITS FOR THE PATIENTS: Improvement of compliance, stabilisation of the care status, improved monitoring through home visits for immobile patients (quick parameter checks, awareness of living conditions), etc. CONCLUSION: The implementation of the model in the care provision by general practitioners to elderly people is recommended without reservations. Legal and economic barriers (above all: insufficient compensation of home visits) should be resolved rapidly. PMID- 22932826 TI - [Identification and sampling of people with migration background for epidemiological studies in Germany]. AB - In 2009, 19.6% of the population of Germany either had migrated themselves or were the offspring of people with migration experience. Migrants differ from the autochthonous German population in terms of health status, health awareness and health behaviour. To further investigate the health situation of migrants in Germany, epidemiological studies are needed. Such studies can employ existing databases which provide detailed information on migration status. Otherwise, onomastic or toponomastic procedures can be applied to identify people with migration background. If migrants have to be recruited into an epidemiological study, this can be done register-based (e. g., data from registration offices or telephone lists), based on residential location (random-route or random-walk procedure), via snowball sampling (e. g., through key persons) or via settings (e. g., school entry examination). An oversampling of people with migration background is not sufficient to avoid systematic bias in the sample due to non participation. Additional measures have to be taken to increase access and raise participation rates. Personal contacting, multilingual instruments, multilingual interviewers and extensive public relations increase access and willingness to participate. Empirical evidence on 'successful' recruitment strategies for studies with migrants is still lacking in epidemiology and health sciences in Germany. The choice of the recruitment strategy as well as the measures to raise accessibility and willingness to participate depend on the available resources, the research question and the specific migrant target group. PMID- 22932827 TI - [Inpatient treatment of adolescents with acute alcohol intoxication: the tip of the iceberg?]. AB - AIMS: This study assessed whether (i) adolescents treated in hospital for acute alcohol intoxication show different habitual drinking patterns from adolescents of the general population and whether (ii) predictors for repeated treatment can be identified. METHODS: A sample of adolescents who had undergone inpatient treatment for intoxication (clinical sample) comprised n=482 under 18-year-old subjects, who had additionally been surveyed within the context of the project "Hart am Limit" (HaLT) between 2008 and 2010 (mean age: 15.1 years, 44.4% girls). The population sample consisted of n=1 994 Bavarian students who had taken part in the European School Survey Project on Alcohol and other Drugs (ESPAD) in 2007 (mean age: 15.7 years; 54.4% girls). RESULTS: Within the clinical sample, gender differences in age, level of education and motivation to get drunk were found. Adolescents of the clinical sample were on average younger and had a higher level of education than adolescents in the general population sample. Although students in the clinical sample drank alcohol less often (2.8 vs. 5.0 times within the past 30 days), they drank more alcohol per occasion (36.4 g vs. 22.3 g pure alcohol per drinking day). Assessments by a third-party show that the risk of repeated inpatient treatment due to alcohol intoxication is positively associated with perceived psychosocial stress and negatively associated with perceived family support. CONCLUSIONS: A hospitalisation due to alcohol intoxication does not sufficiently indicate alarming habitual drinking behaviour. The risk of hospitalisation seems to depend on the drinking context and other factors of the drinking situation. Nevertheless, a sub-group of adolescents, who seem to display an elevated risk for intoxications, could be identified. It is for this sub group, that supportive measures must be made available. PMID- 22932828 TI - [Satisfied general practitioners and critical nursing staff - problems of interprofessional cooperation in the home care of dementia patients]. AB - AIM OF THE STUDY: Analysis of views of general practioners and nurses of interprofessional cooperation between general practititoners and nurses in the ambulatory care of dementia patients is presented. METHODS: A survey was carried out among general practitioners and nurses caring for community dwelling dementia patients in Hamburg. RESULTS: The majority of GPs and nurses consider interprofessional cooperation to be good and beneficial for their own work. GPs are generally more positive about the quality of cooperation than nurses. Joint sessions for planning and evaluation of care are seldom. Even so, more GPs than nurses evaluate the frequency of these meetings to be sufficient. Although nurses are more critical about the quality of the cooperation with the GPs, they seldom address the GP to express their criticism. CONSEQUENCES: To make cooperation work, the matter should be part of the training of both physicians and nurses and the hierarchy between the 2 groups should be reduced. PMID- 22932829 TI - [Discretionary decisions in claims data analyses and their effects - an explorative comparison using the example of a cost of illness study on dementia]. AB - Claims data-based studies provide insight into the delivery of health care services within the statutory health insurance (SHI) system. So far discretionary decisions concerning the definition of service utilization are seldom discussed. Using claims data of 9 147 dementia patients insured with AOK Bavaria SHI fund as an example, this paper compares different definitions of service utilisation and the corresponding costs of care. In total, the different approaches do not always result in different figures. Indeed the observed variation depends on the relative frequency of equivocally interpretable services within the study sample. Based on these results it is possible to provide recommendations for future standards for claims data analyses. PMID- 22932830 TI - [Cigarette prices, tobacco taxes and the proportion of contraband cigarettes in Germany]. AB - Taxes on tobacco products are among the most efficient instruments against tobacco consumption and the arising cost of illness associated with them. The main argument of the tobacco industry against increases of excise taxes on cigarettes is a presumed substitution effect of smokers turning from consumption of legal cigarettes to smuggled ones. Besides deriving this proposition from the tobacco industry's own funded research, it has never been tested empirically. This article analyses the interdependence between contraband cigarettes and cigarette prices in Germany. Using VAR-modelling on the time-series of the variables of interest, we find no empirically valid correlation or causation between prices and untaxed contraband cigarettes. Furthermore, we find a positive relationship between contraband and legal taxed cigarettes, i. e., when the demand for legal cigarettes decreased in amount, so did the quantity of untaxed cigarettes. We conclude that the proposed relationship between prices and smuggled cigarettes as well as an overall substitution effect among smokers is non-existent. This has important implications for public health policy. The proposition that higher taxes on tobacco products incur social costs from increased smuggling activity cannot be corroborated empirically. Furthermore, this finding should encourage public health policy to keep using tobacco taxes as an instrument for prevention. PMID- 22932831 TI - ["Are you ok?" Self-rated health of boys and girls with externalising behavior problems]. AB - BACKGROUND: Externalising behavior problems involve a huge developmental risk potential as they can substantially interface with the parallel process of establishing and forming identity in peer groups during adolescence while simultaneously coping with expectations regarding academic achievement and behaviour. Therefore adolescents with externalising behavior constitute a potential target audience for health promotion. AIM OF THE STUDY: The purpose of this paper is to clarify in what kind of social contexts externalising behavior problems are associated with decreased subjective health in adolescence. METHOD: An analysis of secondary data from the KiGGS study (Robert Koch-Institute, 2009) was undertaken. Calculations of logistic regression models for boys and girls were performed on the basis of preceding stratifications using the indicator subjective health and including relevant social demographic factors. OUTCOME: Externalising adolescents face a higher risk of decreased subjective health than inconspicuous adolescents of the same age group, while there is a gender-specific difference (boys OR 2.76; girls OR 1.48). The gender-specific differences in subjective health appraisal found in inconspicuous adolescents cannot be verified in adolescents with externalising behaviour. Related to social demographic predictors a classic social gradient for girls is verified whereas externalising behaviour in boys is predominantly associated from high social class and decreased subjective health. In multivariate procedures a higher odds ratio for decreased subjective health becomes apparent for adolescents who ascend or descend in relation to their education level as well as for adolescents from higher social classes who had to repeat a school year. CONCLUSION: Adolescents with externalising behavior frequently rate their health situation as being bad. The fact that it is primarily boys with behavior problems and boys who are intergenerational mobile educationwise who exhibit decreased psychosocial well being, indicates that an increased context related exclusion risk (ostracism) is an essential health risk factor. Micro-groups of adolescents facing risk of being ostracised appear to be an essential target group for prevention and health promotion which so far is not being taken into consideration on the basis of school type related recommendations. PMID- 22932832 TI - [Surface reconstruction for limbal stem cell deficiency: current research and perspectives]. PMID- 22932833 TI - [The biological basis of limbal stem cell deficiency]. AB - Limbal stem cell deficiency results from the loss of tissue regenerating stem and progenitor cells. Corneal epithelial regeneration is maintained by stem and progenitor cells which reside in the schlerocorneal limbus. They possess stem cell characteristics and can be stimulated to proliferate by external signals. The limbus is the stem cell niche for corneal epithelial stem cells and forms a unique microenvironment in which stem cell characteristics are conserved. Regulation of limbal epithelial stem cells is produced by a network of signals within the niche which governs cell fate decisions with regards to proliferation, differentiation or maintenance of a quiescent status. PMID- 22932834 TI - [The clinical aspects of limbal stem cell deficiency]. AB - Stem cells are the ultimate source of the rapidly self-renewing corneal epithelium and are located in the basal layer of the limbal epithelium. Ocular surface defense mechanisms are important for the integrity of the ocular surface under normal and compromised conditions. A variety of diseases can compromise the stem cell pool causing an entity called limbal stem cell deficiency. Clinical symptoms can range from foreign body sensation and glare up to blindness. The exact diagnosis is crucial for adequate therapeutic measures. PMID- 22932835 TI - [Ocular surface reconstruction in limbal stem cell insufficiency: transplantation of limbal tissue]. AB - Reconstruction of the ocular surface in patients with limbal stem cell insufficiency (LSI) remains one of the most challenging tasks in ophthalmology. The transplantation of lamellar limbal tissue in total LSI represents an established therapeutic concept, while an abrasion of the conjunctival pannus allowing normal limbal epithelium to recolonize the cornea is the treatment of choice in partial LSI. Surgery must be postponed until an inflammation-free period is reached and lid abnormalities have been corrected. In unilateral total LSI autologous limbal tissue from the healthy eye is transplanted in order to circumvent immunological adverse events. In bilateral total LSI cadaveric or living related allogenic limbal tissue is used for transplantation, in which case systemic immunosuppression and HLA matching are mandatory. The combination with amniotic membrane transplantation and mitomycin C treatment can further improve long-term outcome of limbal stem cell transplantation. PMID- 22932836 TI - [Ocular surface reconstruction in limbal stem cell deficiency : Transplantation of cultivated limbal epithelium]. AB - Various ocular surface diseases are caused by loss of corneal epithelial stem cells or dysfunction of the limbal stem cell niche. Besides conventional transplantation of autologous or allogenic limbal tissue, recent advances in tissue engineering have led to the development of new culture and expansion techniques of human limbal stem and progenitor cells (LSPC) as a new strategy to successfully treat limbal stem cell deficiency (LSCD). From a small autologous limbal biopsy with a limited amount of LSPC an epithelium ready for transplantation is achieved. Autologous grafting of cultured limbal epithelium led in most of the treated cases to a successful reconstruction of the corneal surface. Alternative methods which have recently been introduced to treat LSCD use other stem cell sources including the transplantation of oral mucosal epithelium. In this article the challenges and controversies associated with these stem cell culture techniques for ocular surface reconstruction are reviewed. PMID- 22932837 TI - [Development of the human eye]. AB - The development of the human eye requires a coordinated interplay between cells from different origins. The optic cup which is neuroectodermal in origin and derives from the neural tube, gives rise to the neuronal retina, the retinal pigmented epithelium, the epithelial layers of ciliary body and iris, and the iris musculature. The lens which is displaced into the optic cup during development originates from the surface ectoderm. Cells of the neural crest provide the ocular mesenchyme while ocular blood vessels are of mesodermal origin. The basic morphogenetic processes of eye development are completed at the end of the second month of embryonic life. However, for correct functioning further maturation processes are required which are not completed before birth or several months after. Examples are aqueous humor circulation, maturation of cones in the foveola, myelination of optic nerve axons and completion of the retinal vasculature. PMID- 22932838 TI - Prompt or delayed appendectomy? Influence of timing of surgery for acute appendicitis. AB - PURPOSE: The aim of the study was to compare the clinical outcomes and histological findings in prompt and delayed appendectomy for acute appendicitis. METHODS: All patients who underwent appendectomy for histologically confirmed acute appendicitis from 2003 to 2009 were included in this study. Patients were divided into three groups according to the time of surgery after hospital admission: The early appendectomy (EA) group underwent surgery within 12 h, the early-delayed appendectomy (EDA) group between 12 and 24 h and the delayed appendectomy (DA) group more than 24 h. The perioperative data and pathological state of the appendix were evaluated and compared. RESULTS: A total of 723 patients, with histologically confirmed acute appendicitis, were included in the study: There were 518 patients in the EA group, 140 patients in the EDA group and 65 patients in the DA group. The operative times were similar in each group. Postoperative complications occurred in 49 patients (6.8 %) and were significantly higher in the DA group in comparison to the EA group (p = 0.0012) and EDA group (p = 0.003). Two patients (3 %) in the DA group died. There were no differences in the length of the hospital stay. The gangrenous appendicitis rate was significantly higher in the DA group (p < 0.05) in comparison to the EA and EDA groups. CONCLUSIONS: Performing appendectomy within 24 h from presentation does not increase the length of hospital stay or rate of complications. However, delayed appendectomy after 24 h from onset increases the rate of complications. PMID- 22932839 TI - Radiofrequency ablation of the great saphenous vein with the ClosureFASTTM procedure: mid-term experience on 400 patients from a single centre. AB - INTRODUCTION: Endovascular obliteration of the great saphenous vein (GSV) has been proposed as an alternative to conventional extirpative treatment of varicose veins. MATERIALS AND METHODS: This report reviewed the initial experience with the ClosureFASTTM procedure in 407 legs over a one-year period. Occlusion of the GSV was seen on 98 % of completion scans and in all patients within 1 week of the procedure. Persistent occlusion was documented in all cases. One had paresthesias and one had skin pigmentation. Three patients had transient superficial thrombophlebitis in a treated segment of a superficial collateral of the GSV. One patient was found to have extension of an asymptomatic, nonocclusive thrombus into the common femoral vein 1 week after the procedure. CONCLUSION: Radiofrequency ablation of the GSV appears to be a safe alternative to conventional stripping and ligation. Randomised clinical trials and longer follow up periods are required to establish the overall superiority of the procedure in comparison to conventional stripping. PMID- 22932840 TI - Successful treatment of a common hepatic artery pseudoaneurysm using a coronary covered stent following pancreatoduodenectomy: report of a case. AB - This report presents the case of a common hepatic artery (CHA) pseudoaneurysm secondary to postoperative pancreatic fistula (POPF) after pancreatoduodenectomy (PD), which was successfully treated using a coronary covered stent. A 70-year old female underwent subtotal stomach-preserving PD for middle cholangiocarcinoma. POPF was identified on postoperative day (POD) 7, and the patient suddenly lost 500 ml of blood via the abdominal drain on POD 19. Urgent celiac arteriography revealed a CHA pseudoaneurysm. A coronary covered stent was placed to prevent rupture of the pseudoaneurysm and to maintain hepatic arterial flow, instead of performing transarterial embolization. No vascular adverse events were encountered during or after the procedure. Computed tomography and angiography showed a patent stent graft and good hepatic arterial flow 9 months after placement of the stent. Endovascular stent-graft placement not only treated the pseudoaneurysm, but also preserved the arterial blood flow. This report describes the placement of a covered stent graft for delayed hemorrhage after PD. PMID- 22932844 TI - Cardiopulmonary interactions and volume status assessment. AB - Assessment of the hemodynamics and volume status is an important daily task for physicians caring for critically ill patients. There is growing consensus in the critical care community that the "traditional" methods-e.g., central venous pressure or pulmonary artery occlusion pressure-used to assess volume status and fluid responsiveness are not well supported by evidence and can be misleading. Our purpose is to provide here an overview of the knowledge needed by ICU physicians to take advantage of mechanical cardiopulmonary interactions to assess volume responsiveness. Although not perfect, such dynamic assessment of fluid responsiveness can be helpful particularly in the passively ventilated patients. We discuss the impact of phasic changes in lung volume and intrathoracic pressure on the pulmonary and systemic circulation and on the heart function. We review how respirophasic changes on the venous side (great veins geometry) and arterial side (e.g., stroke volume/systolic blood pressure and surrogate signals) can be used to detect fluid responsiveness or hemodynamic alterations commonly encountered in the ICU. We review the physiological limitations of this approach. PMID- 22932845 TI - CHUP1 mediates actin-based light-induced chloroplast avoidance movement in the moss Physcomitrella patens. AB - Chloroplasts change their intracellular distribution in response to light intensity. CHUP1 (CHLOROPLAST UNUSUAL POSITIONING1) is indispensable for this response in Arabidopsis thaliana. However, involvement of CHUP1 in light-induced chloroplast movement is unknown in other plants. In this study, CHUP1 orthologues were isolated from a moss, Physcomitrella patens, and a fern, Adiantum capillus veneris, by cDNA library screening and PCR cloning based on the P. patens genome sequence. Functional motifs found in CHUP1 of A. thaliana were conserved among the CHUP1 orthologues. In addition to the putative functional regions, the C terminal regions (approximately 250 amino acids), which are unique in CHUP1s, were highly conserved. Green fluorescent protein (GFP) fusions of P. patens CHUP1s (PpCHUP1A, PpCHUP1B and PpCHUP1C) were transiently expressed in protoplast cells. All GFP fusions were localized on the chloroplasts. Light-induced chloroplast avoidance movement of chup1 disruptants of P. patens was examined in the presence of cytoskeletal inhibitors because of the utilization of both microtubules and actin filaments for the movement in P. patens. When actin filaments were disrupted by cytochalasin B, the wild type (WT) and all chup1 disruptants showed chloroplast avoidance movement. However, when microtubules were disrupted by Oryzalin, chloroplasts in ?chup1A and ?chup1A/B rarely moved and stayed in the strong light-irradiated area. On the other hand, WT, ?chup1B and ?chup1C showed chloroplast avoidance movement. These results suggest that PpCHUP1A predominantly mediates the actin-based light-induced chloroplast avoidance movement. This study reveals that CHUP1 functions on the chloroplasts and is involved in the actin-based light-induced chloroplast avoidance movement in P. patens. PMID- 22932846 TI - Phospholipase Ddelta is involved in nitric oxide-induced stomatal closure. AB - Nitric oxide (NO) has recently emerged as a second messenger involved in the complex network of signaling events that regulate stomatal closure. Little is known about the signaling events occurring downstream of NO. Previously, we demonstrated the involvement of phospholipase D (PLD) in NO signaling during stomatal closure. PLDdelta, one of the 12 Arabidopsis PLDs, is involved in dehydration stress responses. To investigate the role of PLDdelta in NO signaling in guard cells, we analyzed guard cells responses using Arabidopsis wild type and two independent plddelta single mutants. In this work, we show that plddelta mutants failed to close the stomata in response to NO. Treatments with phosphatidic acid, the product of PLD activity, induced stomatal closure in plddelta mutants. Abscisic acid (ABA) signaling in guard cells involved H(2)O(2) and NO production, both required for ABA-induced stomatal closure. plddelta guard cells produced similar NO and H(2)O(2) levels as the wild type in response to ABA. However, ABA- or H(2)O(2)-induced stomatal closure was impaired in plddelta plants. These data indicate that PLDdelta is downstream of NO and H(2)O(2) in ABA induced stomatal closure. PMID- 22932848 TI - Characterization of glycosyltransferase activity of wild-type Leuconostoc mesenteroides strains from Bulgarian fermented vegetables. AB - Glycosyltransferase activity of 13 Leuconostoc mesenteroides strains isolated from Bulgarian fermented vegetables was investigated. All the strains displayed a mucoid phenotype on sucrose-containing agar media. Strains were characterized according to carbohydrate fermentation, species-specific multiple PCR using several primers, repetitive element-PCR fingerprinting using (GTG)(5) primers and glycosyltransferase activity. Level of activity and cellular localization (soluble or cell-associated) were variable among strains. Precipitation of exopolysaccharides produced from sucrose by the soluble fractions from these strains allowed recovery of only glucans and further characterization by (1)H and (13)C NMR analysis and enzymatic digestion with dextranase revealed dextran production. However, levans could be detected in presence of raffinose as fructosyl donor. Both fructosyltransferase and glucosyltransferase encoding genes were detected by PCR and both active enzymes were detected after functional characterization by SDS-PAGE electrophoresis and in situ polymer production after incubation with sucrose. This work therefore showed that concomitant production of glucosyltransferase and fructosyltransferase is widespread in L. mesenteroides strains. PMID- 22932847 TI - Pilot monitoring study of ibuprofen in surface waters of north of Portugal. AB - Ibuprofen is amongst the most worldwide consumed pharmaceuticals. The present work presents the first data in the occurrence of ibuprofen in Portuguese surface waters, focusing in the north area of the country, which is one of the most densely populated areas of Portugal. Analysis of ibuprofen is based on pre concentration of the analyte with solid phase extraction and subsequent determination with liquid chromatography coupled to fluorescence detection. A total of 42 water samples, including surface waters, landfill leachates, Wastewater Treatment Plant (WWTP), and hospital effluents, were analyzed in order to evaluate the occurrence of ibuprofen in the north of Portugal. In general, the highest concentrations were found in the river mouths and in the estuarine zone. The maximum concentrations found were 48,720 ng L(-1) in the landfill leachate, 3,868 ng L(-1) in hospital effluent, 616 ng L(-1) in WWTP effluent, and 723 ng L( 1) in surface waters (Lima river). Environmental risk assessment was evaluated and at the measured concentrations only landfill leachates reveal potential ecotoxicological risk for aquatic organisms. Owing to a high consumption rate of ibuprofen among Portuguese population, as prescribed and non-prescribed medicine, the importance of hospitals, WWTPs, and landfills as sources of entrance of pharmaceuticals in the environment was pointed out. Landfill leachates showed the highest contribution for ibuprofen mass loading into surface waters. On the basis of our findings, more studies are needed as an attempt to assess more vulnerable areas. PMID- 22932849 TI - Effect of additives on freeze-drying and storage of Yarrowia lipolytica lipase. AB - The extracellular lipase of Yarrowia lipolytica presents numerous potentialities for biotechnological applications. This work describes the development and storage of powders obtained from supernatants containing Y. lipolytica lipase by freeze-drying as downstream process that is important in obtaining a stable lipase powder with high enzymatic activity. Lipase was produced by Y. lipolytica U6 mutant strain in 20-L bioreactor. Non-concentrated cell-free culture supernatant samples were supplemented with different concentrations (0.5-1 %) of maltodextrin and glycerol as additives to freeze-drying. Effects of additives, temperature, pH, and storage time on lipase powders were determined. After addition of additives, freeze-drying yield increased 3.5-fold compared to supernatant without additive. Maltodextrin with 0.5 % concentration gave the best protection of lipase during dehydration treatment and its freeze-drying yield (77 %) is better than other formulations. Lipase powders were stored at 4 and 25 degrees C for 46 weeks without loss of lipase activity. A common impediment to the production of commercial enzyme is their low-stability aqueous solutions. The present study shows that freeze-dried lipase powders of Y. lipolytica have good stability for storage and various applications. PMID- 22932850 TI - Creating high yield water soluble luminescent graphene quantum dots via exfoliating and disintegrating carbon nanotubes and graphite flakes. AB - We have developed an effective method to exfoliate and disintegrate multi-walled carbon nanotubes and graphite flakes. With this technique, high yield production of luminescent graphene quantum dots with high quantum yield and low oxidization can be achieved. PMID- 22932852 TI - [Bioreactors in regenerative medicine--from a technical device to a reconstructive alternative?]. AB - With the advent of the era of tissue engineering (TE), experimental settings have been developed that allow for a defined environment with optimised cell growth conditions and/or the production of specific substitutes. These isolated systems have been termed "bioreactors". By translating the principles of bioreactors into an in vivo context, advances in biomaterial sciences and cell biology have been merged into an integrative research concept. Even today, in the age of regenerative Medicine (RegMed) the transfer of experimental in vitro findings into a clinical in vivo approach still remains a vast challenge. In order to fulfil these specific requirements bioreactors had to be defined anew. Latest advances in areas like reconstructive medicine (the arteriovenous loop as a means of organogenesis) or modern wound management (topical negative pressure therapy as a perfusion bioreactor) give new impulses towards the translation of Reg-Med concepts into the clinical routine. PMID- 22932851 TI - [Comparison of the iCare tonometer with the Goldmann tonometer in Malawi]. AB - BACKGROUND: The risk for glaucoma is 4-5 times higher in patients from sub Saharan Africa. Thus, especially in developing countries an easy and effective method for assessing the intraocular pressure (IOP) is needed. METHODOLOGY: In this hospital-based survey 150 eyes were divided into 3 groups concerning the IOP (group I < 16 mmHg, group II 16-23 mmHg and group III > 23 mmHg) and underwent examination with ultrasound pachymetry followed by iCare tonometry (ICT) and Goldmann applanation tonometry (GAT). Agreement of the measurements by two tonometers was assessed with the Bland-Altman method and the influence of the central corneal thickness (CCT) on the ICT measurements was determined. RESULTS: The mean difference between the IOD measured with GAT and ICT was 0.84 +/- 2.63 mmHg. The differences were similar in all three groups (0.77-0.97 mmHg), however, the standard deviation in group III (4.04 mmHg) was greater than in groups I (1.98 mmHg) and II (1.79 mmHg). The mean CCT was 513.51 +/- 36.22 um. CONCLUSIONS: The agreement of measurements by GAT and ICT was good for lower IOP values but less accurate in patients with higher IOP values (group III). A dependency of the CCT on the ICT measurements was observed. In comparison to other countries the lowest CCTs were found in Malawian patients. PMID- 22932853 TI - [Microvascular effects of burn plasma transfer and therapeutic options in a rat model]. AB - INTRODUCTION: Thermal injuries with more than 20% of burned body surface area (BSA) lead to systemic shock with generalised oedema in addition to local tissue destruction. This condition, known as burn injury, is caused by immunmodulative mediators whose individual significance is not known in detail. We present an experimental model where plasma of burned animals (burn plasma) is transmitted to healthy animals, to trigger burn iniury without performing direct burn trauma. MATERIAL AND METHODS: The systemic oedema is measured by extravasation of fluorescent albumin in mesenterial venules of Wistar rats. In addition, leukocyte endothelial interactions ("leukocyte rolling and sticking") is examined. RESULTS: The systemic capillary leak is induced by both direct thermal trauma as well as by infusion of burn plasma. This is evident even after plasma dilution (1% in Ringer's lactate) of the burn plasma. In addition, topical therapy for burned animals (donors) with cerium nitrate led to a significant reduction of plasma extravasation in receiver animals. In addition, systemic antioxidant therapy with high-dose vitamin C of receiver animals, led to a significant reduction of the capillary leak. Leukocyte-endothelial interactions are not significantly affected in either case. CONCLUSION: In summary, for the first time a reliable model of burn injury has been established, which eliminates mediator-independent effects. In addition, our studies show that antioxidant therapy with high doses of vitamin C and topical treatment with cerium nitrate both reduce the systemic capillary leak in receiver animals. Their positive influence could therefore soon be integrated in clinical treatment algorithms. PMID- 22932854 TI - [Patients satisfaction after primary transaxillary submuscular breast augmentation]. AB - The axillary approach to augmentation mammaplasty produces no visible scar in the aesthetic unit of the breast. An endoscopic technique is recommended by some authors. 105 bilateral primary transaxillary submuscular breast augmentations were performed between 2004 and 2007. The dissection of the implant pocket after skin incision was performed strictly bluntly using the surgeon's finger cranially and a breast dissector caudally. Endoscopic instruments were in stand by for the first cases of the series but were finally never needed. All patients received textured silicon gel filled implants. Round implants with a moderate profile were used for the majority of the patients. Only 4 patients received high profile implants. The implant size varied between 225 and 500 mL. The patients were clinically followed up until 3 months postoperatively. 2 patients experienced a unilateral implant dislocation, one with a seroma requiring puncture and one further with a low grade infection which was managed by oral antibiotics. Only one patient required re-operation due to the complication, 2 others because they wished for a further enlargement of their breasts. 67 patients (64%) were recruited to assess the client satisfaction questionnaire - CSQ 8. The average score was 28.97+/-3.07 points (15 to 32 points, median 32 points). The transaxillary submuscular breast augmentation without endoscopic assistance avoids visible scars in the aesthetic unit of the breast, leads to a high patient satisfaction and low complication rate, not higher than for any other technique. PMID- 22932855 TI - [3-dimensional imaging systems: first experience in planning and documentation of plastic surgery procedures]. AB - A reproducible 3-dimensional photographic system enables plastic surgeons to perform preoperative planning and helps them to understand the patient's expectations. There are a few systems available that allow a reproducible 3 dimensional scans of the patient with direct simulation of the planned procedure. The Vectra Volumetric 3D Surface Imaging(r) by Canfield(r) provides such an option and helps the surgeons to document and compare postoperative changes at different time points. Since January 2011 we are digitally documenting all patients receiving form-modulating procedures in our plastic surgery unit. We present the spectrum of clinical implications and discuss advantages and disadvantages of the system. Furthermore, we have studied the accuracy of the system in comparison to direct measurement in 15 volunteers. The system is especially suited for planning and evaluation of breast augmentation, facial aesthetic and reconstructive surgery as well as volumetric measurements before and after liposuction and lipofilling. Computer-assisted measurements correlate with a median deviation of 2.3% with manually measured distances in the face. We found the user-friendly Vectra(r) system to be a reliable and reproducible device for planning plastic surgery therapies and for documenting postoperative results. PMID- 22932856 TI - [Quo vadis? Breast implants--current trends and new concepts]. AB - BACKGROUND: Breast augmentation is one of the most frequent surgical procedures performed by plastic surgeons. Furthermore, in the majority of breast reconstructions implants are still in use. With the focus on surface modifications and biomaterials, the article provides an overview of the latest trends and concepts in increase of implant biocompatibility and reduction of capsular contracture. Because of the recent events regarding PIP(r) implants, a short report on this topic is presented as well. MATERIALS AND METHODS: The literature was searched for experimental and clinical studies, as well as meta analysis and reviews, using the databases PubMed, Embase and Cochrane Collaboration. Based on the title, year of publication and abstracts, thematically relevant and recent publications in English or German were selected and full text articles were studied. RESULTS: According to the classification, 4 5 generations of breast implants have been developed since the 1960s. Modifications affected diverse areas including various surface textures as well as coatings with polyurethane or titanium. Some of these changes were able to reduce capsular contracture, however, without resolving the issue sufficiently. Recent experimental studies mostly evaluated different surface coatings with antifibrotic and antibacterial substances. For the local drug release various carrier substances were used. Furthermore, drugs were covalently bonded to the implant surface or applied by surface impregnation. In different approaches biocompatibility could be increased by biomimicry or nanotechnologically modified biomaterials, which could additionally contribute to the reduction of capsular contracture. CONCLUSION: The development of coating technologies for the locally controlled sustained drug release using the implant surface as drug delivery system could potentially enable the local administration of drugs, which were orally delivered in clinical trials, and effectively reduced capsular contracture. This kind of application could potentially minimize the risk of adverse side effects. However, there are still some questions concerning controlled drug release systems for implant surfaces, as well as long-term results and possible side effects of drugs in a continuous local administration to be answered in further studies. PMID- 22932857 TI - The impact of vascular resection on early postoperative outcomes after pancreaticoduodenectomy: an analysis of the American College of Surgeons National Surgical Quality Improvement Program database. AB - BACKGROUND: Several single-center reports suggest that vascular resection (VR) during pancreaticoduodenectomy (PD) for patients with pancreatic adenocarcinoma is feasible without affecting early postoperative mortality or morbidity. Our objective is to review the outcomes associated with VR during PD using a large multicenter data source. METHODS: A retrospective cohort analysis was performed using the National Surgical Quality Improvement Program Participant User Files for 2005-2009. All patients undergoing PD for a postoperative diagnosis of malignant neoplasm of the pancreas were included. Forward stepwise multivariate regression analysis was used to determine the association between VR during PD and 30-day postoperative mortality and morbidity after adjustment for patient demographics and comorbidities. RESULTS: 3,582 patients were included for analysis, 281 (7.8 %) of whom underwent VR during PD. VR during PD was associated with significantly greater risk-adjusted 30-day postoperative mortality [5.7 % with VR versus 2.9 % without VR, adjusted odds ratio (AOR) 2.1, 95 % confidence interval (CI) 1.22-3.73, P = 0.008] and overall morbidity (39.9 % with VR versus 33.3 % without VR, AOR 1.36, 95 % CI 1.05-1.75, P = 0.02). There was no significant difference in risk-adjusted postoperative mortality or morbidity between those patients undergoing VR by the primary surgical team versus those patients undergoing VR by a vascular surgical team. CONCLUSIONS: Contrary to the findings of several previously published single-center analyses, the current study demonstrates increased 30-day postoperative morbidity and mortality in PD with VR when compared with PD alone. PMID- 22932858 TI - Morbidity of staged proctectomy after hepatectomy for colorectal cancer: a matched case-control analysis. AB - BACKGROUND: Proctectomy after hepatectomy, or the reverse approach, is an alternative to traditional sequencing for advanced liver metastases with asymptomatic colorectal primary tumors. We sought to evaluate the surgical morbidity of proctectomy for colorectal cancer after previous liver surgery. METHODS: A single-institution colorectal database was queried for patients treated with proctectomy after previous hepatectomy from 2003 to 2011. Reverse approach patients (n = 31) were matched 1:2 with a cohort of standard proctectomy patients (n = 62) using operation, age, gender, and surgeon. Perioperative factors were analyzed by univariate/multivariate models for associations with complications graded by Dindo-Clavien criteria. RESULTS: Thirty-one patients with adenocarcinoma <= 20 cm from the anal verge underwent proctectomy after hepatectomy. Median time from hepatectomy to proctectomy was 5.1 months. Median tumor distance was 8.5 cm. Before proctectomy, patients underwent 28 (90 %) major hepatectomies and 7 (22 %) portal vein embolizations. There were no perioperative deaths. Reverse-approach patients did not differ from control patients in operation, demographics, body mass index (BMI), comorbidities, tumor distance, operative time, estimated blood loss, length of stay, or complication rates (p > 0.05). Grade 2 or higher complications developed in 42 % of reverse-approach and 27 % of standard proctectomies (p = 0.17). Grade 3 or higher complications developed in 10 % and 8 %, respectively (p = 1.00). Independent predictors of complications of grade 2 or higher were BMI >=30 kg/m(2) (p = 0.007), operative time >=300 min (p = 0.012), intraoperative transfusion (p = 0.044), concurrent procedures (p = 0.024), and age >=50 years (p = 0.030). CONCLUSIONS: Risk factors for morbidity of staged proctectomy are similar to those for standard proctectomy. In selected patients, the reverse-approach proctectomy is safe with acceptable morbidity. PMID- 22932860 TI - Exploiting adamantane as a versatile organic tecton: multicomponent catalytic cascade reactions. AB - 3- And 9-component Pd(0) catalysed assembly of allenes, aryl iodides and N nucleophiles with concomitant installation of trisubstituted Z-alkenes is readily achieved. PMID- 22932859 TI - Laparoscopic radical hysterectomy after preoperative brachytherapy for stage IB1 cervical cancer: feasibility, results, and surgical implications in a large bicentric study of 162 consecutive cases. AB - PURPOSE: To examine the feasibility and to report the results of laparoscopic radical hysterectomy (LRH) after initial uterovaginal brachytherapy (BT) for stage IB1 cervical cancer. METHODS: We retrospectively reviewed patients at 2 comprehensive cancer centers who underwent initial BT followed 6-8 weeks later by LRH and lymph node dissection. RESULTS: Between 2003 and 2010, a total of 162 patients underwent LRH. The procedure was feasible via this approach in 160 cases (98.8%) (2 conversions to laparotomy). Eight perioperative complications occurred. Nineteen patients had nodal involvement. Peri- or postoperative ureteral morbidity occurred in 10 patients (6%). Twenty-four patients (15%) experienced postoperative dysuria. Histologically, only 9 patients had residual cervical disease >=5 mm, and only 1 patient had parametrial lymphovascular space involvement (associated with nodal spread). No patient had vaginal disease or involved surgical margins. After a median follow-up of 39 (range 3-118) months, 9 patients experienced relapse. Five-year overall survival was 95% (range 88.2 97.9%). CONCLUSIONS: Radical hysterectomy using a laparoscopic approach is feasible and reproducible after initial BT for stage IB1 cervical cancer and is associated with excellent survival. Morbidity is close to that reported in patients treated with up-front surgery. In this large series, the morbidity associated with parametrial dissection and the fact that parametrial spread was observed in only 0.6% of the patients suggest that a simple extrafascial hysterectomy is perhaps sufficient in this context; the rate of urinary tract morbidity would then be reduced. PMID- 22932861 TI - Measurement of cell-bound complement activation products enhances diagnostic performance in systemic lupus erythematosus. AB - OBJECTIVE: To determine the value of cell-bound complement activation products in combination with antinuclear antibody (ANA), anti-double-stranded DNA antibody (anti-dsDNA), and anti-mutated citrullinated vimentin antibody (anti-MCV) for the diagnosis of systemic lupus erythematosus (SLE). METHODS: This was a multicenter cross-sectional study in which 593 subjects were enrolled (210 SLE patients, 178 patients with other rheumatic diseases, and 205 healthy subjects). Complement receptor 1 levels on erythrocytes (ECR1) together with complement C4d levels on erythrocytes (EC4d), platelets (PC4d), and B cells (BC4d) were determined using fluorescence-activated cell sorting. Serologic markers were measured by enzyme linked immunosorbent assay. Statistical analyses were performed using area under the curve (AUC), logistic regression, and calculations of diagnostic sensitivity and specificity. RESULTS: Anti-dsDNA was an insensitive (30%) but specific (>95%) marker for SLE. Levels of EC4d, BC4d, and PC4d were several times higher, and levels of ECR1 lower, in SLE patients compared to patients with other rheumatic diseases and healthy subjects. Among 523 anti-dsDNA-negative subjects, multivariate logistic regression analysis revealed that SLE was associated with ANA positivity (>=20 units), anti-MCV negativity (<=70 units), and elevated levels of both EC4d and BC4d (AUC 0.918, P < 0.001). A positive index score corresponding to the weighted sum of these 4 markers correctly categorized 72% of SLE patients. Specificity in relation to patients with other rheumatic diseases and healthy controls was >90%. The combination of anti-dsDNA and index score positivity yielded 80% sensitivity for SLE and 87% specificity against other rheumatic diseases. CONCLUSION: An assay panel combining anti-dsDNA, ANA, anti MCV, EC4d, and BC4d is sensitive and specific for the diagnosis of SLE. PMID- 22932863 TI - The impact of brain shift in deep brain stimulation surgery: observation and obviation. AB - BACKGROUND: The impact of brain shift on deep brain stimulation surgery is considerable. In DBS surgery, brain shift is mainly caused by CSF loss. CSF loss can be estimated by post-surgical intracranial air. Different approaches and techniques exist to minimize CSF loss and hence brain shift. The aim of this survey was to investigate the extent and dynamics of CSF loss during DBS surgery, analyze its impact on final electrode position, and describe a simple and inexpensive method of burr hole closure. METHODS: Sixty-six patients being treated with deep brain stimulation were retrospectively analyzed for this treatise. During surgery, CSF loss was minimized using bone wax as a burr hole closure. Intracranial air volume was calculated based on early post-surgery stereotactic 3D CT and correlated with duration of surgery and electrode deviations derived from post-surgery image fusion. RESULTS: Median early post surgery intracranial air was 2.1 cm(3) (range 0-35.7 cm(3), SD 8.53 cm(3)). No correlation was found between duration of surgery and CSF-loss (R = 0.078, p = 0.534), indicating that CSF loss mainly occurs early during surgery. Linear regression analysis revealed no significant correlations regarding volume of intracranial air and electrode displacement in any of the three principal axes. No significant difference regarding electrode deviations between first and second side of surgery were observed. CONCLUSIONS: CSF loss mainly occurs during the early phase of DBS surgery. CSF loss during a later phase of surgery can be effectively averted by burr hole closure. Postoperative intracranial air volumes up to 35 cm(3) did not result in significant electrode displacement in our series. Comparing our results to studies previously published on this subject, burr hole closure using bone wax is highly effective. PMID- 22932864 TI - A prospective randomised study to compare the utility and outcomes of subdural and subperiosteal drains for the treatment of chronic subdural haematoma. AB - BACKGROUND: The usage of a drain following evacuation of a chronic subdural haematoma (CSDH) is known to reduce recurrence. In this study we aim to compare the clinical outcomes and recurrence rate of utilising two different types of drains (subperiosteal and subdural drain) following drainage of a CSDH. METHODS: Prospective randomised single-centre study analysing 50 patients who underwent CSDH treatment. Two types of drains, subperiosteal (SPD) and subdural (SDD), were utilised on consecutive alternate patients following burr-hole craniostomy, with a total of 25 patients in each group. The drains were left in for 48-h duration and then removed. The modified Rankin Scale (mRS) was used for outcome measurement at 3 and 6 months. RESULTS: Data analysis was performed by unpaired t test with Welch's correction. It was observed that none of the patients in either group had haematoma recurrence during a 6-month follow-up, and a significant difference in outcome was noted at 6 months (p = 0.0118) more than at 3 months (p = 0.0493) according to the statistical analysis. Postoperative seizure and inadvertent placement of the subdural drain into the brain parenchyma were the two complications noted in this study. Anticoagulant use prior to the surgery did not affect the outcome in either group. CONCLUSIONS: We conclude there was no recurrence of CSDH utilising the SDD and SPD following burr-hole craniostomy. The mRS measurement at the 6-month follow-up was found to be statistically significant, with better outcomes with utilisation of the SPD. The SPD may thus prove to be more beneficial than the SDD in the treatment of CSDH. A multi-centre study with a larger group of patients is recommended to reinforce the results from our study. PMID- 22932865 TI - Abiotic induction affects the costs and benefits of inducible herbivore defenses in Datura wrightii. AB - We evaluated the costs and benefits of continuous high-level expression of defenses relative to naturally-induced defenses in field-grown Datura wrightii in the presence and absence of herbivores. We induced D. wrightii plants with monthly applications of the plant hormone methyl jasmonate (MeJA) and assessed levels of inducible proteinase inhibitors (Pins). MeJA application increased Pin production by 124 %, whereas the increase in Pins due to herbivory was more modest (36 %). Pin induction was costly and significantly reduced plant fitness compared to unmanipulated plants both in the presence and absence of herbivores. Although MeJA-treated plants exposed to herbivory suffered significantly less herbivore damage than unmanipulated plants exposed to herbivory, this was not accompanied by a corresponding fitness benefit. In contrast to glasshouse studies in which protected plants never expressed Pins, Pin induction occurred in field grown plants not treated with MeJA and completely protected from herbivory. Subsequent experiments confirmed that putative herbivore defenses can be induced abiotically in D. wrightii as: 1) Pin levels did not differ significantly between field-grown plants protected from herbivory and plants exposed to chronic herbivory over the full season; and 2) plants exposed to ambient UV-B light in the absence of herbivory expressed low levels of Pins after two wk of exposure, whereas plants protected from UV-B remained uninduced. The costs of induced responses may be relatively easily determined under field conditions, but there may be many inducing agents in the field, and the benefits of induction may be difficult to associate with any single inducing agent. PMID- 22932866 TI - Induction of chlamydospore formation in fusarium by cyclic lipopeptide antibiotics from Bacillus subtilis C2. AB - The culture filtrate of Bacillus subtilis strain C2 showed strong activity against the pathogenic fungus Fusarium solani f. sp. radicicola. A partially purified fraction (PPF) from the extract induced chlamydospore formation in Fusarium. Reverse-phase high performance liquid chromatography yielded 8 different fractions, six of which had chlamydospore-inducing activity. Mass spectrometry and nuclear magnetic resonance analyses identified the main active constituent as C(17) fengycin A (FA17), a cyclic lipopeptide. The effect of FA17 on morphology and physiology of two Fusarium species was dependent on the lipopeptide concentration. When challenged with FA17 at concentrations (0.5, 8, 64 MUg ml(-1)) below the minimum inhibitory concentration (MIC) (128 MUg ml(-1)), two species of Fusarium formed chlamydospores from hyphae, germ tubes, or inside the conidia within 2 days. At concentrations close to the MIC, FA17 caused Fusarium to form sparse and swollen hyphae or lysed conidia. The other five fractions were identified as fengycin A homologues. The homologues could also induce chlamydospore-like structures in 17 species of filamentous fungi including some specimens that do not normally produce chlamydospores, according to their taxonomic descriptions. Like other chlamydospores, these structures contained nuclei and lipid bodies as revealed by DAPI and Nile Red staining, and could germinate. This is the first study to demonstrate that under laboratory conditions fengycin, an antifungal lipopeptide produced by B. subtilis, can induce chlamydospore formation in Fusarium and chlamydospore-like structures in many filamentous fungi. PMID- 22932867 TI - Possible ecological role of pseudopterosins G and P-U and seco-pseudopterosins J and K from the gorgonian Pseudopterogorgia elisabethae from Providencia Island (SW Caribbean) in regulating microbial surface communities. AB - The gorgonian Pseudopterogorgia elisabethae collected at Providencia Island (Colombia) has an unfouled surface, free of obvious algal and invertebrate growth. This gorgonian produces significant amounts of the glycosilated diterpenes pseudopterosins and seco-pseudopterosins (Ps and seco-Ps). Our previous experiments have shown activity of these compounds against eukaryotic (human cancer cell lines and Candida albicans) and prokaryotic cells (Staphylococcus aureus and Enterococcus faecalis). However, the potential role of pseudopterosins on the regulation of the fouling process is still under study. We evaluated the activity of these compounds against bacteria isolated from heavily fouled marine surfaces as an indicator of antifouling activity. Additionally, we assessed their activity against bacteria isolated from P. elisabethae to determine whether potentially they play a role in preventing surface bacterial colonization, thus impairing presumptively the establishment of further successional stages of fouling communities. Results showed that Ps and seco-Ps seem to modulate bacterial growth (controlling Gram-positive bacterial growth and inducing Gram-negative bacterial associations). We thus hypothesized that Ps and seco-Ps may play a role in controlling microbial fouling communities on the surface of this gorgonian. By using bTEFAP and FISH we showed that the most abundant bacteria present in the microbial communities associated with P. elisabethae are Gram-negative bacteria, with Proteobacteria and Gammaproteobacteria the most representative. To evaluate whether Ps and seco-Ps have a direct effect on the structure of the bacterial community associated with P. elisabethae, we tested these compounds against culturable bacteria associated with the surface of P. elisabethae, finding remarkable selectivity against Gram positive bacteria. The evidence presented here suggests that Ps and seco-Ps might have a role in the selection of organisms associated with the gorgonian surface and in the regulation of the associated bacterial community composition. PMID- 22932869 TI - Axonal branching patterns of ventral pallidal neurons in the rat. AB - The ventral pallidum (VP) is a key component of the cortico-basal ganglia circuits that process motivational and emotional information, and also a crucial site for reward. Although the main targets of the two VP compartments, medial (VPm) and lateral (VPl) have already been established, the collateralization patterns of individual axons have not previously been investigated. Here we have fully traced eighty-four axons from VPm, VPl and the rostral extension of VP into the olfactory tubercle (VPr), using the anterograde tracer biotinylated dextran amine in the rat. Thirty to fifty percent of axons originating from VPm and VPr collateralized in the mediodorsal thalamic nucleus and lateral habenula, indicating a close association between the ventral basal ganglia-thalamo-cortical loop and the reward network at the single axon level. Additional collateralization of these axons in diverse components of the extended amygdala and corticopetal system supports a multisystem integration that may take place at the basal forebrain. Remarkably, we did not find evidence for a sharp segregation in the targets of axons arising from the two VP compartments, as VPl axons frequently collateralized in the caudal lateral hypothalamus and ventral tegmental area, the well-known targets of VPm, while VPm axons, in turn, also collateralized in typical VPl targets such as the subthalamic nucleus, substantia nigra pars compacta and reticulata, and retrorubral field. Nevertheless, VPl and VPm displayed collateralization patterns that paralleled those of dorsal pallidal components, confirming at the single axon level the parallel organization of functionally different basal ganglia loops. PMID- 22932868 TI - Kv4.2 potassium channels segregate to extrasynaptic domains and influence intrasynaptic NMDA receptor NR2B subunit expression. AB - Neurons of the intercalated cell clusters (ITCs) represent an important relay site for information flow within amygdala nuclei. These neurons receive mainly glutamatergic inputs from the basolateral amygdala at their dendritic domains and provide feed-forward inhibition to the central nucleus. Voltage-gated potassium channels type-4.2 (Kv4.2) are main players in dendritic signal processing and integration providing a key component of the A currents. In this study, the subcellular localization and distribution of the Kv4.2 was studied in ITC neurons by means of light- and electron microscopy, and compared to other types of central principal neurons. Several ultrastructural immunolocalization techniques were applied including pre-embedding techniques and, most importantly, SDS digested freeze-fracture replica labeling. We found Kv4.2 densely expressed in somato-dendritic domains of ITC neurons where they show a differential distribution pattern as revealed by nearest neighbor analysis. Comparing ITC neurons with hippocampal pyramidal and cerebellar granule cells, a cell type- and domain-dependent organization in Kv4.2 distribution was observed. Kv4.2 subunits were localized to extrasynaptic sites where they were found to influence intrasynaptic NMDA receptor subunit expression. In samples of Kv4.2 knockout mice, the frequency of NR1-positive synapses containing the NR2B subunit was significantly increased. This indicates a strong, yet indirect effect of Kv4.2 on the synaptic content of NMDA receptor subtypes, and a likely role in synaptic plasticity at ITC neurons. PMID- 22932870 TI - Metabolic hypothesis for human altriciality. AB - The classic anthropological hypothesis known as the "obstetrical dilemma" is a well-known explanation for human altriciality, a condition that has significant implications for human social and behavioral evolution. The hypothesis holds that antagonistic selection for a large neonatal brain and a narrow, bipedal-adapted birth canal poses a problem for childbirth; the hominin "solution" is to truncate gestation, resulting in an altricial neonate. This explanation for human altriciality based on pelvic constraints persists despite data linking human life history to that of other species. Here, we present evidence that challenges the importance of pelvic morphology and mechanics in the evolution of human gestation and altriciality. Instead, our analyses suggest that limits to maternal metabolism are the primary constraints on human gestation length and fetal growth. Although pelvic remodeling and encephalization during hominin evolution contributed to the present parturitional difficulty, there is little evidence that pelvic constraints have altered the timing of birth. PMID- 22932871 TI - Causes, consequences, and remedies for growth-induced solid stress in murine and human tumors. AB - The presence of growth-induced solid stresses in tumors has been suspected for some time, but these stresses were largely estimated using mathematical models. Solid stresses can deform the surrounding tissues and compress intratumoral lymphatic and blood vessels. Compression of lymphatic vessels elevates interstitial fluid pressure, whereas compression of blood vessels reduces blood flow. Reduced blood flow, in turn, leads to hypoxia, which promotes tumor progression, immunosuppression, inflammation, invasion, and metastasis and lowers the efficacy of chemo-, radio-, and immunotherapies. Thus, strategies designed to alleviate solid stress have the potential to improve cancer treatment. However, a lack of methods for measuring solid stress has hindered the development of solid stress-alleviating drugs. Here, we present a simple technique to estimate the growth-induced solid stress accumulated within animal and human tumors, and we show that this stress can be reduced by depleting cancer cells, fibroblasts, collagen, and/or hyaluronan, resulting in improved tumor perfusion. Furthermore, we show that therapeutic depletion of carcinoma-associated fibroblasts with an inhibitor of the sonic hedgehog pathway reduces solid stress, decompresses blood and lymphatic vessels, and increases perfusion. In addition to providing insights into the mechanopathology of tumors, our approach can serve as a rapid screen for stress-reducing and perfusion-enhancing drugs. PMID- 22932872 TI - Autophagy activators rescue and alleviate pathogenesis of a mouse model with proteinopathies of the TAR DNA-binding protein 43. AB - TDP-43 is a multifunctional DNA/RNA-binding protein that has been identified as the major component of the cytoplasmic ubiquitin (+) inclusions (UBIs) in diseased cells of frontotemporal lobar dementia (FTLD-U) and amyotrophic lateral sclerosis (ALS). Unfortunately, effective drugs for these neurodegenerative diseases are yet to be developed. We have tested the therapeutic potential of rapamycin, an inhibitor of the mammalian target of rapamycin (mTOR) and three other autophagy activators (spermidine, carbamazepine, and tamoxifen) in a FTLD-U mouse model with TDP-43 proteinopathies. Rapamycin treatment has been reported to be beneficial in some animal models of neurodegenerative diseases but not others. Furthermore, the effects of rapamycin treatment in FTLD-U have not been investigated. We show that rapamycin treatment effectively rescues the learning/memory impairment of these mice at 3 mo of age, and it significantly slows down the age-dependent loss of their motor function. These behavioral improvements upon rapamycin treatment are accompanied by a decreased level of caspase-3 and a reduction of neuron loss in the forebrain of FTLD-U mice. Furthermore, the number of cells with cytosolic TDP-43 (+) inclusions and the amounts of full-length TDP-43 as well as its cleavage products (35 kDa and 25 kDa) in the urea-soluble fraction of the cellular extract are significantly decreased upon rapamycin treatment. These changes in TDP-43 metabolism are accompanied by rapamycin-induced decreases in mTOR-regulated phospho-p70 S6 kinase (P-p70) and the p62 protein, as well as increases in the autophagic marker LC3. Finally, rapamycin as well as spermidine, carbamazepine, and tamoxifen could also rescue the motor dysfunction of 7-mo-old FTLD-U mice. These data suggest that autophagy activation is a potentially useful route for the therapy of neurodegenerative diseases with TDP-43 proteinopathies. PMID- 22932873 TI - Effect of left-sided brain stem decompression on blood pressure and short-term cardiovascular regulation in resistant hypertension. PMID- 22932874 TI - Maternal protein deprivation: sexually dimorphic programming of hypertension in the mouse. AB - Epidemiological data in humans and experiments in laboratory animals have demonstrated that the developmental programming of hypertension may occur as a consequence of dietary manipulations during pregnancy. Surprisingly, there is a scarcity of data regarding the development of hypertension as a consequence of a maternal low-protein diet (MLPD), particularly in the mouse. Furthermore, the role of sex in developmental programming is not well understood. We used FVB/NJ mice, because of their value in genetic/mechanistic analysis, to test the hypothesis that a MLPD during gestation leads to the sexually dimorphic developmental programming of hypertension and related disorders, such as intra uterine growth restriction (IUGR), type 2 diabetes mellitus and obesity. We administered iso-caloric, normal (control), moderate protein (moderate MLPD) and severe protein (severe MLPD) diets to the mice, beginning 1 week before mating and continuing until the delivery of the pups. From 4 weeks onward, using a non invasive tail-cuff method, we measured blood pressure and other parameters in the offspring. Our results demonstrate the following: (1) MLPD caused IUGR (low birthweight) in a dose-dependent manner; (2) Female offspring developed severe hypertension, whereas males were affected only moderately; (3) The blood glucose level was elevated only in females from the moderate MLPD group, although their insulin levels remained normal; (4) Rapid catch-up growth was observed in both sexes, with moderate MLPD females and severe MLPD males becoming overweight. Notably, blood leptin levels in the control group were significantly higher in females than in male offspring and were reduced in females from the severe MLPD group. We conclude that an antenatal MLPD during gestation leads to sexually dimorphic programming in mice. PMID- 22932875 TI - Association of adrenomedullin gene polymorphisms and blood pressure in a Chinese population. AB - Genetic factors may determine an individual's blood pressure (BP) level and risk for hypertension. This study aimed to examine the associations between genetic variants of the adrenomedullin (ADM) gene and essential hypertension, as well as BP levels, in a Chinese Han population. In this study, 2410 hypertensive patients and 2346 normal controls were recruited. Three tagging single-nucleotide polymorphisms (SNPs) based on the HapMap CHB data were selected and genotyped. No significant associations between the three SNPs of the ADM gene and hypertension status were observed. However, SNP rs4399321 was found to be associated with BP levels among the controls. GG homozygotes for this SNP had higher systolic BP (SBP) levels than carriers of the A allele (P=0.002). Particularly in non drinkers, GG homozygotes had significantly higher SBP (116.9+/-0.9 vs. 113.7+/ 0.3 mm Hg, P=0.001) and diastolic (74.0+/-0.7 vs. 72.6+/-0.2 mm Hg, P=0.046) BP levels than carriers of the A allele. Neither rs4910118 nor rs7944706 was associated with BP levels in the controls either before or after being stratified by drinking status. The results of this study showed that genetic variations in the ADM gene were not associated with the risk of hypertension in a Chinese population. However, the genotype at common variation rs4399321 may influence the BP level in normotensive subjects, especially among non-drinkers. In addition, replications in other populations and further functional studies are required to confirm and interpret the association of ADM with BP. PMID- 22932876 TI - Carotid cross-sectional wall area is significantly associated with serum leptin levels, independent of body mass index: the SABPA study. AB - Hypertension and obesity are serious health burdens in sub-Saharan Africa. Urbanized Africans seem to be more susceptible to the development of these diseases than Caucasians. Current research suggests that leptin may be an important contributor to the development of hypertension and atherosclerosis. The aim of this study was to investigate leptin levels and their associations with cardiovascular function in urbanized Africans and Caucasians. Serum leptin, ambulatory blood pressure and carotid intima-media thickness were measured, and the cross-sectional wall area (CSWA) was calculated. The results showed that Africans had higher leptin levels (P<0.001), ambulatory blood pressure (P<0.001), carotid intima-media thickness (P<0.01) and CSWA (P<0.01) than Caucasians. As we found no interaction between ethnicity and gender for the association between leptin and the cardiovascular variables, we focused mainly on the total group of Africans and Caucasians. In single, partial and multiple regression analyses, positive associations of ambulatory systolic blood pressure (beta=0.256; P<0.001), diastolic blood pressure (beta=0.143; P=0.012), pulse pressure (beta=0.327; P<0.001) and CSWA (beta=0.107; P=0.038) with leptin were observed. Even after adjusting for body mass index (BMI), the association between CSWA (beta=0.107; P=0.038) and leptin remained. Our findings therefore suggest that leptin may contribute to the development of atherosclerosis, independent of BMI. PMID- 22932877 TI - Alcohol consumption and cardiovascular disease incidence in men with and without hypertension: the Suita study. AB - The relationship between alcohol consumption and the risk for cardiovascular disease (CVD) is U-shaped, whereas alcohol drinking is linearly associated with blood pressure, and the CVD risk also increases linearly according to blood pressure level. Accordingly, we investigated the net effect of alcohol consumption and hypertension on CVD and its subtypes in this study. A 13-year prospective study of 2336 Japanese men who were free from CVD was performed; ex drinkers were excluded. The participants were divided into eight groups classified by the combination of the presence of hypertension (systolic/diastolic blood pressure >=140/90 mm Hg) and alcohol consumption (never-, current- (light, moderate and heavy) drinkers). Multivariate-adjusted hazard ratios (HRs) for the incidence of CVD, coronary artery disease (CAD) and stroke due to the combination of hypertension and alcohol consumption were calculated and compared with non hypertensive never-drinkers. The HRs for CVD and its subtypes were higher in hypertensives than those in non-hypertensives; in hypertensives without medication for hypertension, the relationship between alcohol consumption and the risks for CVD and CAD was U-shaped, with the highest and most significant increase in never-drinkers. The risk for total stroke was the highest in heavy drinkers, which was significant. In non-hypertensives, there was no evident increase or decrease in the HRs for CVD and its subtypes in drinkers. Accordingly, controlling blood pressure is important to prevent CVD. In hypertensives, heavy drinking should be avoided to prevent CVD, although light-to moderate drinking could be protective for CAD. Furthermore, in non-hypertensives, drinkers may need to continuously monitor their blood pressure. PMID- 22932878 TI - Molecular AND logic gate based on bacterial anaerobic respiration. AB - Enzyme coding genes that integrate information for anaerobic respiration in Shewanella oneidensis MR-1 were used as input for constructing an AND logic gate. The absence of one or both genes inhibited electrochemically-controlled anaerobic respiration, while wild type bacteria were capable of accepting electrons from an electrode for DMSO reduction. PMID- 22932879 TI - Frontiers in reproductive aging-challenge and perspective. PMID- 22932880 TI - Mechanisms of reproductive aging in the females. AB - Aging is a developmental process occurring in all living organisms after reaching a critical developmental stage, characterized by progressive loss of functions until death. Different cells/tissues age differently depending on epigenetics and cell-cell interactions. While males maintain fertility for the most part of their life females only maintain reproductive ability for a short time compared with their lifespan. The interesting question is why and how the females lose fertility so quickly. There have been many hypotheses proposed from different perspectives and recent research has revealed unusual interactions between germ cells and somatic cells which may determine the lifespan of reproduction in the females. This review briefly discusses recent progress in reproductive aging in the well studied model, C. elegans, and focuses on the molecular mechanisms which may be conserved across all animals including humans. PMID- 22932881 TI - Current understanding of ovarian aging. AB - The reproductive system of human female exhibits a much faster rate of aging than other body systems. Ovarian aging is thought to be dominated by a gradual decreasing numbers of follicles, coinciding with diminished quality of oocytes. Menopause is the final step in the process of ovarian aging. This review focuses on the mechanisms underlying the ovarian aging involving a poor complement of follicles at birth and a high rate of attrition each month, as well as the alternated endocrine factors. We also discuss the possible causative factors that contribute to ovarian aging, e.g., genetic factors, accumulation of irreparable damage of microenvironment, pathological effect and other factors. The appropriate and reliable methods to assess ovarian aging, such as quantification of follicles, endocrine measurement and genetic testing have also been discussed. Increased knowledge of the ovarian aging mechanisms may improve the prevention of premature ovarian failure. PMID- 22932882 TI - Epigenetic changes associated with oocyte aging. AB - It is well established that the decline in female reproductive outcomes is related to postovulatory aging of oocytes and advanced maternal age. Poor oocyte quality is correlated with compromised genetic integrity and epigenetic changes during the oocyte aging process. Here, we review the epigenetic alterations, mainly focused on DNA methylation, histone acetylation and methylation associated with postovulatory oocyte aging as well as advanced maternal age. Furthermore, we address the underlying epigenetic mechanisms that contribute to the decline in oocyte quality during oocyte aging. PMID- 22932883 TI - An update on primary ovarian insufficiency. AB - Primary ovarian insufficiency (POI) occurs in about 1% of female population under the age of 40, leading to reproductive problems, an earlier encounter with menopausal symptoms, and complicated diseases. There are three presumable mechanisms involved in the development of POI, namely apoptosis acceleration, follicular maturation blocking and premature follicle activation, through the following studied causes: (i) chromosomal abnormalities or gene mutations: mostly involve X chromosome, such as FMR1 premutation; more and more potentially causal genes have been screened recently; (ii) metabolic disorders such as classic galactosaemia and 17-OH deficiency; (iii) autoimmune mediated ovarian damage: observed alone or with some certain autoimmune disorders and syndromes; but the specificity and sensitivity of antibodies towards ovary are still questionable; (iv) iatrogenic: radiotherapy or chemotherapy used in cancer treatment, as well as pelvic surgery with potential threat to ovaries' blood supply can directly damage ovarian function; (v) virus infection such as HIV and mumps; (vi) toxins and other environmental/lifestyle factors: cigarette smoking, toxins (e.g., 4 vinylcyclohexene diepoxide), and other environmental factors are associated with the development of POI. The etiology of a majority of POI cases is not identified, and is believed to be multifactorial. Strategies to POI include hormone replacement and infertility treatment. Assisted conception with donated oocytes has been proven to achieve pregnancy in POI women. Embryo cryopreservation, ovarian tissue cryopreservation and oocyte cryopreservation have been used to preserve ovarian reserve in women undergoing cancer treatments. PMID- 22932884 TI - Determinants of uterine aging: lessons from rodent models. AB - The uterus is an indispensable organ for the development of a new life in eutherian mammals. The female mammalian reproductive capacity diminishes with age. In this respect, the senescence of uterine endometrium is convinced to contribute to this failure. This review focuses on the physiological function of the uterus and the related influence of aging mainly in rodent models. A better understanding of the underlying mechanisms governing the process of uterine aging is hoped to generate new strategies to prolong the reproductive lifespan in humans. PMID- 22932885 TI - Effect of maternal age on the outcomes of in vitro fertilization and embryo transfer (IVF-ET). AB - This is a retrospective, observational study to evaluate the effect of maternal age on the outcomes of in vitro fertilization and embryo transfer (IVF-ET). 11830 IVF-ET cycles from 10268 women were included. Four groups of different maternal age periods were compared. The groups were 21-30 years old group (4549 cycles), 31-35 years old group (4424 cycles), 36-40 years old group (2429 cycles), and over 40 years old group (428 cycles). The mean starting dose of Gn and mean total dose of Gn in each cycle were significantly higher (P<0.01), while the mean retrieved oocyte number was significantly lower (P<0.01) in groups of higher maternal age period than those in each of the lower groups. The biochemical pregnancy rate and the clinical pregnancy rate were significantly lower (P<0.01), while the miscarriage rate was significantly higher (P<0.01) in groups of higher maternal age period than those in the lower groups. No difference was found in two-pronuclear zygotes (2PN) rate and good quality embryo rate among different groups. Birth defect rate was also comparable in the born babies in different groups. In the group with patients' age over 40 years old, the pregnancy rate was 26.87%, the clinical pregnancy rate was 19.39%, while the miscarriage rate after clinical pregnancy was 36.14%. To draw the conclusion, patients with higher maternal age had worse IVF outcomes. In women of fertile age, patients between 20 and 30 years old have the best IVF outcomes. Patients over 40 years old have poor IVF outcome and high miscarriage rate, which suggested the necessity of preimplantation genetic screening (PGS). PMID- 22932886 TI - Single nucleotide polymorphisms in the human corticosteroid-binding globulin promoter alter transcriptional activity. AB - Corticosteroid-binding globulin (CBG) is a high-affinity plasma protein that transports glucocorticoids and progesterone. Others and we have reported non synonymous single nucleotide polymorphisms (SNPs) that influence CBG production or steroid-binding activity. However, no promoter polymorphisms affecting the transcription of human CBG gene (Cbg) have been reported. In the present study we investigated function implications of six promoter SNPs, including -26 C/G, -54 C/T, -144 G/C, -161 A/G, -205 C/A, and -443/-444 AG/-, five of which are located within the first 205 base pairs of 5'-flanking region and close to the highly conserved footprinted elements, TATA-box, or CCAAT-box. Luciferase reporter assays demonstrated that basal activity of the promoter carrying -54 T or -161 G was significantly enhanced. The first three polymorphisms, -26 C/G, -54 C/T, and 144 G/C located close to the putative hepatic nuclear factor (HNF) 1 binding elements, altered the transactivation effect of HNF1beta. We also found a negative promoter response to dexamethasone-activated glucocorticoid receptor (GR) alpha, although none of the SNPs affected its transrepression function. Our results suggest that human Cbg -26 C/G, -54 C/T, -144 G/C, and -161 A/G promoter polymorphisms alter transcriptional activity, and further studies are awaited to explore their association with physiological and pathological conditions. PMID- 22932887 TI - Primate phylogeny: molecular evidence for a pongid clade excluding humans and a prosimian clade containing tarsiers. AB - Unbiased readings of fossils are well known to contradict some of the popular molecular groupings among primates, particularly with regard to great apes and tarsiers. The molecular methodologies today are however flawed as they are based on a mistaken theoretical interpretation of the genetic equidistance phenomenon that originally started the field. An improved molecular method the 'slow clock' was here developed based on the Maximum Genetic Diversity hypothesis, a more complete account of the unified changes in genotypes and phenotypes. The method makes use of only slow evolving sequences and requires no uncertain assumptions or mathematical corrections and hence is able to give definitive results. The findings indicate that humans are genetically more distant to orangutans than African apes are and separated from the pongid clade ~17.6 million years ago. Also, tarsiers are genetically closer to lorises than simian primates are. Finally, the fossil times for the radiation of mammals at the K/T boundary and for the Eutheria-Metatheria split in the Early Cretaceous were independently confirmed from molecular dating calibrated using the fossil split times of gorilla-orangutan, mouse-rat, and opossum-kangaroo. Therefore, the re-established primate phylogeny indicates a remarkable unity between molecules and fossils. PMID- 22932888 TI - Conformational changes in photosynthetic pigment proteins on thylakoid membranes can lead to fast non-photochemical quenching in cyanobacteria. AB - A high non-photochemical quenching (NPQ) appeared below the phase transition temperature when Microcystis aeruginosa PCC7806 cells were exposed to saturated light for a short time. This suggested that a component of NPQ, independent from state transition or photo-inhibition, had been generated in the PSII complex; this was a fast component responding to high intensity light. Glutaraldehyde (GA), commonly used to stabilize membrane protein conformations, resulted in more energy transfer to PSII reaction centers, affecting the energy absorption and dissipation process rather than the transfer process of phycobilisome (PBS). In comparison experiments with and without GA, the rapid light curves (RLCs) and fluorescence induction dynamics of the fast phase showed that excess excitation energy was dissipated by conformational change in the photosynthetic pigment proteins on the thylakoid membrane (PPPTM). Based on deconvolution of NPQ relaxation kinetics, we concluded that the fast quenching component (NPQf) was closely related to PPPTM conformational change, as it accounted for as much as 39.42% of the total NPQ. We hypothesize therefore, that NPQf induced by PPPTM conformation is an important adaptation mechanism for Microcystis blooms under high-intensity light during summer and autumn. PMID- 22932889 TI - Effects of Epstein-Barr virus infection on the development of multiple myeloma after liver transplantation. AB - Reduced cellular immune function in patients after liver transplantation easily results in many types of viral infections, such as Epstein-Barr virus. Epstein Barr virus is a Gamma-herpesvirus and is related to many malignant diseases, especially epithelial and lymph tumors. The abnormal interaction of cluster of differentiation 40 with cluster of differentiation 40 ligand and expression of cluster of differentiation 40 ligand are considered closely related to the development of myeloma cells. This study explored the influence and mechanism of Epstein-Barr virus infection on the phenotype and biological behavior of myeloma cells after liver transplantation. Flow cytometry was used to detect coexpression of cluster of differentiation 40 and cluster of differentiation 40 ligand in 10 samples of freshly isolated multiple myeloma cells. Cluster of differentiation 40 and cluster of differentiation 40 ligand were coexpressed in sample Nos. 5, 8, 9, and 10, particularly in sample No. 5. Western blot analysis was used to detect the expression of the Epstein-Barr virus antigens latent membrane protein 1 and Epstein-Barr virus nuclear antigen 2 in the multiple myeloma cell line RPMI 8226 infected with Epstein-Barr virus. The antigen expression indicated that Epstein Barr virus can infect multiple myeloma virus cells in vitro. Reverse transcription-polymerase chain reaction revealed upregulated expression of cluster of differentiation 40 ligand on the infected RPMI 8226 cells, which may be involved in the anti-apoptosis activity of the infected cells. Confocal microscopy showed that pairs of molecules of cluster of differentiation 40, cluster of differentiation 40 ligand, and latent membrane protein 1 were colocalized on the surface of the infected cells. CXC chemokine receptor 4 was upregulated on the RPMI 8226 cells after Epstein-Barr virus infection. The migratory ability of the infected cells improved in the presence of the chemokine stromal cell-derived factor-1alpha. Anti-apoptosis and migration are known important biological characteristics of malignant cells. Our results indicate the involvement of Epstein-Barr virus in the origin and development of multiple myeloma. The risk of multiple myeloma increases when Epstein-Barr virus infects B cells in the germinal center, which may result in an anti-apoptosis effect of B cells and an improved ability to migrate from the germinal center to peripheral blood. PMID- 22932890 TI - On Ca(2+) signalling research. PMID- 22932891 TI - Zinc suppressed the airway inflammation in asthmatic rats: effects of zinc on generation of eotaxin, MCP-1, IL-8, IL-4, and IFN-gamma. AB - Airway epithelium is rich in labile zinc (Zn), which may have an important protective role in the airway epithelium. The aim of this study is to investigate the effects of Zn on the airway inflammation and the generation of eotaxin, monocyte chemoattractant protein-1 (MCP-1), interleukin-8 (IL-8), interleukin-4 (IL-4), and interferon-gamma (IFN-gamma) in rat models of ovalbumin (OVA)-induced allergic airway inflammation. For this purpose, animal model of asthma was established by OVA challenge and zinc-deficient and zinc-supplemented diets were given. Thirty-two Sprague-Dawley rats were divided into four groups: zinc deficient diet with OVA treatment group, zinc-supplemented diet with OVA treatment group, zinc-normal diet with OVA treatment group, and zinc-normal diet with saline treatment group. Twenty-four hours after asthma was induced, lung histomorphological changes, cells in bronchoalveolar lavage fluid (BALF), contents of eotaxin, MCP-1, and IL-8 in BALF, and the expression of IFN-gamma and IL-4 mRNAs were observed. Compared with the group of zinc-normal diet with OVA challenge rats, the group of zinc-deficient rats had higher numbers of eosinophils, neutrophils, and monocytes in BALF, as well as higher contents of eotaxin and MCP-1 in BALF and lower expression of lung IFN-gamma mRNA. Conversely, Zn supplementation would decrease the numbers of eosinophils, neutrophils, and monocytes in BALF; suppress eotaxin and MCP-1 protein secretion; and increase lung IFN-gamma mRNA expression. No significant difference was observed in IL-8 and IL-4 among OVA-challenged rats with different zinc diets. These studies suggested that Zn may be an important anti-inflammatory mediator of airway inflammation. PMID- 22932892 TI - Sustained submicromolar H2O2 levels induce hepcidin via signal transducer and activator of transcription 3 (STAT3). AB - The peptide hormone hepcidin regulates mammalian iron homeostasis by blocking ferroportin-mediated iron export from macrophages and the duodenum. During inflammation, hepcidin is strongly induced by interleukin 6, eventually leading to the anemia of chronic disease. Here we show that hepatoma cells and primary hepatocytes strongly up-regulate hepcidin when exposed to low concentrations of H(2)O(2) (0.3-6 MUM), concentrations that are comparable with levels of H(2)O(2) released by inflammatory cells. In contrast, bolus treatment of H(2)O(2) has no effect at low concentrations and even suppresses hepcidin at concentrations of >50 MUM. H(2)O(2) treatment synergistically stimulates hepcidin promoter activity in combination with recombinant interleukin-6 or bone morphogenetic protein-6 and in a manner that requires a functional STAT3-responsive element. The H(2)O(2) mediated hepcidin induction requires STAT3 phosphorylation and is effectively blocked by siRNA-mediated STAT3 silencing, overexpression of SOCS3 (suppressor of cytokine signaling 3), and antioxidants such as N-acetylcysteine. Glycoprotein 130 (gp130) is required for H(2)O(2) responsiveness, and Janus kinase 1 (JAK1) is required for adequate basal signaling, whereas Janus kinase 2 (JAK2) is dispensable upstream of STAT3. Importantly, hepcidin levels are also increased by intracellular H(2)O(2) released from the respiratory chain in the presence of rotenone or antimycin A. Our results suggest a novel mechanism of hepcidin regulation by nanomolar levels of sustained H(2)O(2). Thus, similar to cytokines, H(2)O(2) provides an important regulatory link between inflammation and iron metabolism. PMID- 22932893 TI - Dual effect of phosphatidylinositol (4,5)-bisphosphate PIP(2) on Shaker K(+) [corrected] channels. AB - Phosphatidylinositol (4,5)-bisphosphate (PIP(2)) is a phospholipid of the plasma membrane that has been shown to be a key regulator of several ion channels. Functional studies and more recently structural studies of Kir channels have revealed the major impact of PIP(2) on the open state stabilization. A similar effect of PIP(2) on the delayed rectifiers Kv7.1 and Kv11.1, two voltage-gated K(+) channels, has been suggested, but the molecular mechanism remains elusive and nothing is known on PIP(2) effect on other Kv such as those of the Shaker family. By combining giant-patch ionic and gating current recordings in COS-7 cells, and voltage-clamp fluorimetry in Xenopus oocytes, both heterologously expressing the voltage-dependent Shaker channel, we show that PIP(2) exerts 1) a gain-of-function effect on the maximal current amplitude, consistent with a stabilization of the open state and 2) a loss-of-function effect by positive shifting the activation voltage dependence, most likely through a direct effect on the voltage sensor movement, as illustrated by molecular dynamics simulations. PMID- 22932894 TI - Fibroblast growth factor receptor 3 (FGFR3) associated with the CD20 antigen regulates the rituximab-induced proliferation inhibition in B-cell lymphoma cells. AB - Rituximab is reported to inhibit the proliferation of lymphoma cells through an unknown CD20-mediated signal transduction pathway. Herein, we investigated cell surface molecules involved in the CD20-mediated signal transduction pathway by using a recently developed technique named enzyme-mediated activation of radical sources. Using this method, we found that under stimulation with rituximab and another anti-CD20 antibody B-Ly1, CD20 was physically associated with fibroblast growth factor receptor 3 (FGFR3) as well as some other receptor tyrosine kinases in Raji cells. However, under stimulation with a noncytotoxic anti-CD20 antibody 2H7, CD20 was not associated with FGFR3 but with the PDGF receptor beta. When the tyrosine kinase activity of FGFR3 was inhibited by the chemical inhibitor PD173074 or an siRNA knockdown strategy, the proliferation inhibition by rituximab was attenuated, indicating that FGFR3 participates in the rituximab dependent signal transduction pathway leading to proliferation inhibition. These observations raise the possibility that concomitant targeted therapy toward FGFR3 might improve the efficacy and safety of the rituximab therapy. PMID- 22932895 TI - Identical RNA-protein interactions in vivo and in vitro and a scheme of folding the newly synthesized proteins by ribosomes. AB - A distinct three-dimensional shape of rRNA inside the ribosome is required for the peptidyl transfer activity of its peptidyltransferase center (PTC). In contrast, even the in vitro transcribed PTC RNA interacts with unfolded protein(s) at about five sites to let them attain their native states. We found that the same set of conserved nucleotides in the PTC interact identically with nascent and chemically unfolded proteins in vivo and in vitro, respectively. The time course of this interaction, difficult to follow in vivo, was observed in vitro. It suggested nucleation of folding of cytosolic globular proteins vectorially from hydrophilic N to hydrophobic C termini, consistent with our discovery of a regular arrangement of cumulative hydrophobic indices of the peptide segments of cytosolic proteins from N to C termini. Based on this observation, we propose a model here for the nucleation of folding of the nascent protein chain by the PTC. PMID- 22932896 TI - Canonical transient receptor potential (TRPC) 1 acts as a negative regulator for vanilloid TRPV6-mediated Ca2+ influx. AB - TRP proteins mostly assemble to homomeric channels but can also heteromerize, preferentially within their subfamilies. The TRPC1 protein is the most versatile member and forms various TRPC channel combinations but also unique channels with the distantly related TRPP2 and TRPV4. We show here a novel cross-family interaction between TRPC1 and TRPV6, a Ca(2+) selective member of the vanilloid TRP subfamily. TRPV6 exhibited substantial co-localization and in vivo interaction with TRPC1 in HEK293 cells, however, no interaction was observed with TRPC3, TRPC4, or TRPC5. Ca(2+) and Na(+) currents of TRPV6-overexpressing HEK293 cells are significantly reduced by co-expression of TRPC1, correlating with a dramatically suppressed plasma membrane targeting of TRPV6. In line with their intracellular retention, remaining currents of TRPC1 and TRPV6 co-expression resemble in current-voltage relationship that of TRPV6. Studying the N-terminal ankyrin like repeat domain, structurally similar in the two proteins, we have found that these cytosolic segments were sufficient to mediate a direct heteromeric interaction. Moreover, the inhibitory role of TRPC1 on TRPV6 influx was also maintained by expression of only its N-terminal ankyrin-like repeat domain. Our experiments provide evidence for a functional interaction of TRPC1 with TRPV6 that negatively regulates Ca(2+) influx in HEK293 cells. PMID- 22932897 TI - The R1275Q neuroblastoma mutant and certain ATP-competitive inhibitors stabilize alternative activation loop conformations of anaplastic lymphoma kinase. AB - Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase that, when genetically altered by mutation, amplification, chromosomal translocation or inversion, has been shown to play an oncogenic role in certain cancers. Small molecule inhibitors targeting the kinase activity of ALK have proven to be effective therapies in certain ALK-driven malignancies and one such inhibitor, crizotinib, is now approved for the treatment of EML4-ALK-driven, non-small cell lung cancer. In neuroblastoma, activating point mutations in the ALK kinase domain can drive disease progression, with the two most common mutations being F1174L and R1275Q. We report here crystal structures of the ALK kinase domain containing the F1174L and R1275Q mutations. Also included are crystal structures of ALK in complex with novel small molecule ALK inhibitors, including a classic type II inhibitor, that stabilize previously unobserved conformations of the ALK activation loop. Collectively, these structures illustrate a different series of activation loop conformations than has been observed in previous ALK crystal structures and provide insight into the activating nature of the R1275Q mutation. The novel active site topologies presented here may also aid the structure-based drug design of a new generation of ALK inhibitors. PMID- 22932898 TI - A proteasome inhibitor-stimulated Nrf1 protein-dependent compensatory increase in proteasome subunit gene expression reduces polycomb group protein level. AB - The polycomb group (PcG) proteins, Bmi-1 and Ezh2, are important epigenetic regulators that enhance skin cancer cell survival. We recently showed that Bmi-1 and Ezh2 protein level is reduced by treatment with the dietary chemopreventive agents, sulforaphane and green tea polyphenol, and that this reduction involves ubiquitination of Bmi-1 and Ezh2, suggesting a key role of the proteasome. In the present study, we observe a surprising outcome that Bmi-1 and Ezh2 levels are reduced by treatment with the proteasome inhibitor, MG132. We show that this is associated with a compensatory increase in the level of mRNA encoding proteasome protein subunits in response to MG132 treatment and an increase in proteasome activity. The increase in proteasome subunit level is associated with increased Nrf1 and Nrf2 level. Moreover, knockdown of Nrf1 attenuates the MG132-dependent increase in proteasome subunit expression and restores Bmi-1 and Ezh2 expression. The MG132-dependent loss of Bmi-1 and Ezh2 is associated with reduced cell proliferation, accumulation of cells in G(2), and increased apoptosis. These effects are attenuated by forced expression of Bmi-1, suggesting that PcG proteins, consistent with a prosurvival action, may antagonize the action of MG132. These studies describe a compensatory Nrf1-dependent, and to a lesser extent Nrf2-dependent, increase in proteasome subunit level in proteasome inhibitor-treated cells and confirm that PcG protein levels are regulated by proteasome activity. PMID- 22932899 TI - The X-ray crystal structure of human aminopeptidase N reveals a novel dimer and the basis for peptide processing. AB - Human aminopeptidase N (hAPN/hCD13) is a dimeric membrane protein and a member of the M1 family of zinc metallopeptidases. Within the rennin-angiotensin system, its enzymatic activity is responsible for processing peptide hormones angiotensin III and IV. In addition, hAPN is also involved in cell adhesion, endocytosis, and signal transduction and it is an important target for cancer therapy. Reported here are the high resolution x-ray crystal structures of the dimeric ectodomain of hAPN and its complexes with angiotensin IV and the peptidomimetic inhibitors, amastatin and bestatin. Each monomer of the dimer is found in what has been termed the closed form in other M1 enzymes and each monomer is characterized by an internal cavity surrounding the catalytic site as well as a unique substrate/inhibitor-dependent loop ordering, which in the case of the bestatin complex suggests a new route to inhibitor design. The hAPN structure provides the first example of a dimeric M1 family member and the observed structural features, in conjunction with a model for the open form, provide novel insights into the mechanism of peptide processing and signal transduction. PMID- 22932900 TI - Activation of peroxisome proliferator-activated receptor alpha (PPARalpha) suppresses hypoxia-inducible factor-1alpha (HIF-1alpha) signaling in cancer cells. AB - Activation of peroxisome proliferator-activated receptor alpha (PPARalpha) has been demonstrated to inhibit tumor growth and angiogenesis, yet the mechanisms behind these actions remain to be characterized. In this study, we examined the effects of PPARalpha activation on the hypoxia-inducible factor-1alpha (HIF 1alpha) signaling pathway in human breast (MCF-7) and ovarian (A2780) cancer cells under hypoxia. Incubation of cancer cells under 1% oxygen for 16 h significantly induced HIF-1alpha expression and activity as assayed by Western blotting and reporter gene analysis. Treatment of the cells with PPARalpha agonists, but not a PPARgamma agonist, prior to hypoxia diminished hypoxia induced HIF-1alpha expression and activity, and addition of a PPARalpha antagonist attenuated the suppression of HIF-1alpha signaling. Activation of PPARalpha attenuated hypoxia-induced HA-tagged HIF-1alpha protein expression without affecting the HA-tagged HIF-1alpha mutant protein level, indicating that PPARalpha activation promotes HIF-1alpha degradation in these cells. This was further confirmed using proteasome inhibitors, which reversed PPARalpha-mediated suppression of HIF-1alpha expression under hypoxia. Using the co immunoprecipitation technique, we found that activation of PPARalpha enhances the binding of HIF-1alpha to von Hippel-Lindau tumor suppressor (pVHL), a protein known to mediate HIF-1alpha degradation through the ubiquitin-proteasome pathway. Following PPARalpha-mediated suppression of HIF-1alpha signaling, VEGF secretion from the cancer cells was significantly reduced, and tube formation by endothelial cells was dramatically impaired. Taken together, these findings demonstrate for the first time that activation of PPARalpha suppresses hypoxia induced HIF-1alpha signaling in cancer cells, providing novel insight into the anticancer properties of PPARalpha agonists. PMID- 22932901 TI - Biochemical analysis of the interactions between the proteins involved in the [FeFe]-hydrogenase maturation process. AB - [FeFe]-hydrogenases are iron-sulfur proteins characterized by a complex active site, the H-cluster, whose assembly requires three conserved maturases. HydE and HydG are radical S-adenosylmethionine enzymes that chemically modify a H-cluster precursor on HydF, a GTPase with a dual role of scaffold on which this precursor is synthesized, and carrier to transfer it to the hydrogenase. Coordinate structural and functional relationships between HydF and the two other maturases are crucial for the H-cluster assembly. However, to date only qualitative analysis of this protein network have been provided. In this work we showed that the interactions of HydE and HydG with HydF are distinct events, likely occurring in a precise functional order driven by different kinetic properties, independently of the HydF GTPase activity, which is instead involved in the dissociation of the maturases from the scaffold. We also found that HydF is able to interact with the hydrogenase only when co-expressed with the two other maturases, indicating that under these conditions it harbors per se all the structural elements needed to transfer the H-cluster precursor, thus completing the maturation process. These results open new working perspectives aimed at improving the knowledge of how these complex metalloenzymes are biosynthesized. PMID- 22932902 TI - High selectivity of the gamma-aminobutyric acid transporter 2 (GAT-2, SLC6A13) revealed by structure-based approach. AB - The solute carrier 6 (SLC6) is a family of ion-dependent transporters that mediate uptake into the cell of osmolytes such as neurotransmitters and amino acids. Four SLC6 members transport GABA, a key neurotransmitter that triggers inhibitory signaling pathways via various receptors (e.g., GABA(A)). The GABA transporters (GATs) regulate the concentration of GABA available for signaling and are thus targeted by a variety of anticonvulsant and relaxant drugs. Here, we characterize GAT-2, a transporter that plays a role in peripheral GABAergic mechanisms, by constructing comparative structural models based on crystallographic structures of the leucine transporter LeuT. Models of GAT-2 in two different conformations were constructed and experimentally validated, using site-directed mutagenesis. Computational screening of 594,166 compounds including drugs, metabolites, and fragment-like molecules from the ZINC database revealed distinct ligands for the two GAT-2 models. 31 small molecules, including high scoring compounds and molecules chemically related to known and predicted GAT-2 ligands, were experimentally tested in inhibition assays. Twelve ligands were found, six of which were chemically novel (e.g., homotaurine). Our results suggest that GAT-2 is a high selectivity/low affinity transporter that is resistant to inhibition by typical GABAergic inhibitors. Finally, we compared the binding site of GAT-2 with those of other SLC6 members, including the norepinephrine transporter and other GATs, to identify ligand specificity determinants for this family. Our combined approach may be useful for characterizing interactions between small molecules and other membrane proteins, as well as for describing substrate specificities in other protein families. PMID- 22932903 TI - dTIS11 Protein-dependent polysomal deadenylation is the key step in AU-rich element-mediated mRNA decay in Drosophila cells. AB - The destabilization of AU-rich element (ARE)-containing mRNAs mediated by proteins of the TIS11 family is conserved among eukaryotes including Drosophila. Previous studies have demonstrated that Tristetraprolin, a human protein of the TIS11 family, induces the degradation of ARE-containing mRNAs through a large variety of mechanisms including deadenylation, decapping, and P-body targeting. We have previously shown that the degradation of the mRNA encoding the antimicrobial peptide Cecropin A1 (CecA1) is controlled by the TIS11 protein (dTIS11) in Drosophila cells. In this study, we used CecA1 mRNA as a model to investigate the molecular mechanism of dTIS11-mediated mRNA decay. We observed that during the biphasic deadenylation and decay process of this mRNA, dTIS11 enhances deadenylation performed by the CCR4-CAF-NOT complex while the mRNA is still associated with ribosomes. Sequencing of mRNA degradation intermediates revealed that the complete deadenylation of the mRNA triggers its decapping and decay in both the 5'-3' and the 3'-5' directions. Contrary to the observations made for its mammalian homologs, overexpression of dTIS11 does not promote the localization of ARE-containing mRNAs in P-bodies but rather decreases the accumulation of CecA1 mRNA in these structures by enhancing the degradation process. Therefore, our results suggest that proteins of the TIS11 family may have acquired additional functions in the course of evolution from invertebrates to mammals. PMID- 22932904 TI - Regulation of the Plasmodium motor complex: phosphorylation of myosin A tail interacting protein (MTIP) loosens its grip on MyoA. AB - The interaction between the C-terminal tail of myosin A (MyoA) and its light chain, myosin A tail domain interacting protein (MTIP), is an essential feature of the conserved molecular machinery required for gliding motility and cell invasion by apicomplexan parasites. Recent data indicate that MTIP Ser-107 and/or Ser-108 are targeted for intracellular phosphorylation. Using an optimized MyoA tail peptide to reconstitute the complex, we show that this region of MTIP is an interaction hotspot using x-ray crystallography and NMR, and S107E and S108E mutants were generated to mimic the effect of phosphorylation. NMR relaxation experiments and other biophysical measurements indicate that the S108E mutation serves to break the tight clamp around the MyoA tail, whereas S107E has a smaller but measurable impact. These data are consistent with physical interactions observed between recombinant MTIP and native MyoA from Plasmodium falciparum lysates. Taken together these data support the notion that the conserved interactions between MTIP and MyoA may be specifically modulated by this post translational modification. PMID- 22932906 TI - Transfer status is a risk factor for increased in-hospital mortality in patients with diverticular hemorrhage. AB - PURPOSE: Gastrointestinal tract hemorrhage is a common problem accounting for approximately 1 % of hospital admissions. It is estimated that one third of the episodes of lower gastrointestinal hemorrhage are secondary to diverticular disease. Inter-institutional transfer has been associated with delay in care and increased in-hospital mortality. We hypothesized that patients with diverticular hemorrhage that were transferred from an acute care hospital to tertiary care institutions have increased in-hospital morbidity and mortality when compared to primarily admitted patients. MATERIALS AND METHODS: We performed a retrospective analysis of the Nationwide Inpatient Sample for the year 2008. Patients with a primary discharge diagnosis of diverticular hemorrhage were selected. Multivariate logistic regression was used to identify the relationship between transfer status and in-hospital mortality. RESULTS: A total of 99,415 hospitalizations for diverticular hemorrhage were identified. Transferred patients had higher in-hospital mortality rates compared to primarily admitted patients (3.5 vs. 1.8 %, p < 0.001), as well as increased length of stay (8.4 vs. 5.4 days, p < 0.001) and a higher rate of total abdominal colectomy (1.2 vs. 0.6 %, p < 0.001). Multivariate analysis indicated that transfer status was associated with increased in-hospital mortality [OR 1.8, 95 % CI 1.5-2.8, p < 0.001]. CONCLUSIONS: Inter-institutional transfer for diverticular bleeding is associated with increased in-hospital mortality, increased total abdominal colectomy rate, as well as increased economic burden including mean length of stay and total hospital charges. Further prospective studies are needed to analyze the clinical information of patients requiring transfer to another hospital in order to identify those patients who would truly benefit from inter institutional transfer. PMID- 22932905 TI - S-adenosylmethionine-dependent protein methylation is required for expression of selenoprotein P and gluconeogenic enzymes in HepG2 human hepatocytes. AB - Cellular methylation processes enable expression of gluconeogenic enzymes and metabolism of the nutrient selenium. Selenium status has been proposed to relate to type II diabetes risk, and plasma levels of selenoprotein P (SEPP1) have been positively correlated with insulin resistance. Increased expression of gluconeogenic enzymes glucose-6-phosphatase (G6PC) and phosphoenolpyruvate carboxykinase 1 (PCK1) has negative consequences for blood glucose management in type II diabetics. Transcriptional regulation of SEPP1 is directed by the same transcription factors that control the expression of G6PC and PCK1, and these factors are activated by methylation of arginine residues. We sought to determine whether expression of SEPP1 and the aforementioned glucoconeogenic enzymes are regulated by protein methylation, the levels of which are reliant upon adequate S adenosylmethionine (SAM) and inhibited by S-adenosylhomocysteine (SAH). We treated a human hepatocyte cell line, HepG2, with inhibitors of adenosylhomocysteine hydrolase (AHCY) known to increase concentration of SAH before analysis of G6PC, PCK1, and SEPP1 expression. Increasing SAH decreased 1) the SAM/SAH ratio, 2) protein-arginine methylation, and 3) expression of SEPP1, G6PC, and PCK1 transcripts. Furthermore, hormone-dependent induction of gluconeogenic enzymes was reduced by inhibition of protein methylation. When protein-arginine methyltransferase 1 expression was reduced by siRNA treatment, G6PC expression was inhibited. These findings demonstrate that hepatocellular SAM dependent protein methylation is required for both SEPP1 and gluconeogenic enzyme expression and that inhibition of protein arginine methylation might provide a route to therapeutic interventions in type II diabetes. PMID- 22932907 TI - Chronic radiation-induced proctitis: the 4 % formalin application as non-surgical treatment. AB - PURPOSE: Radiation proctitis is a known complication following radiation therapy for pelvic malignancy. The majority of cases are treated nonsurgically. Rectal instillation of formalin solution has been described as a successful treatment for chronic radiation-induced hemorrhagic proctitis resistant to medical treatment. We present our results in patients undergoing treatment with application of 4 % formalin for radiation-induced injury to the rectum. METHODS: All patients were treated under anesthesia by direct application of 4 % formalin solution to the affected rectal areas. Patient gender, initial malignancy, grade of proctitis, need for blood transfusion, previous therapy, number of applications and response to treatment with formalin, complications, and length of follow-up were reviewed. RESULTS: A total of 15 patients with a mean age of 68.9 (range, 48-77) years were followed for 31.3 (range, 18-51) months. The mean interval from the conclusion of radiotherapy and the onset of symptoms was 6.9 months. The mean duration of hemorrhagic proctitis before formalin application was 7.9 months. Ten patients had only one formalin application and five patients required a second application because of the persistent bleeding. Thirteen patients (87 %) had complete cessation of bleeding. No complications related to the formalin treatment were observed. CONCLUSIONS: According to a revision of the literature and our experience, despite the small number of patients in our trial, we can state that the application of 4 % formalin solution is an effective, safe, and well-tolerated treatment for chronic radiation-induced hemorrhagic proctitis with minimal discomfort and no severe complications. PMID- 22932909 TI - Appendectomy in Germany-an analysis of a nationwide survey 2011/2012. AB - INTRODUCTION: Although appendectomies are frequently performed and new procedural techniques have emerged, no nationwide analysis exists after the cessation of the German quality control in 2004. METHODS: One thousand eight hundred seventy surgical hospitals in Germany were asked to answer questions anonymously concerning the size of the department, applied procedural techniques, various technical details, as well as the approach to the intraoperative finding of an inconspicuous appendix. RESULTS: We received 643 questionnaires (34.4 %) for evaluation. Almost all hospitals (95.5 %) offer laparoscopic appendectomy (LA), 15.4 % offer single-port (SPA), and 2.2 % (hybrid-) NOTES technique (NA). LA is the standard procedure in 85.2 % of male and in 89.1 % for female patients. In an open procedure (OA), the appendix and mesoappendix are mostly ligated (93.8 and 91.5 %). A Veress needle and open access are employed equally for LA. In 66.6 % of LA, the appendix is divided using an Endo-GIA, the mesoappendix in 45.5 % with bipolar coagulation. Almost half of the hospitals routinely flush the site in OA and LA. In open surgery with an inconspicuous appendix but a pathological finding elsewhere in the abdomen, it is resected "en principe" in 64.7 % and in the absence of any pathological finding in 91.2 %. For laparoscopic procedures, the numbers are 54.8 and 88.4 %. CONCLUSIONS: Most German hospitals perform appendectomies laparoscopically regardless of patients' gender. Usage of an Endo GIA is widely established. SPA has not gained much acceptance, nor is NA widely used yet. In the absence of any pathological findings in particular, the macroscopically inconspicuous appendix results in an appendectomy "en principe" in most German hospitals. PMID- 22932910 TI - CSF leak from epidural catheter site: a nightmare turned into reality. PMID- 22932911 TI - Self-assembly of a poly(glutamate) dendrimer: solvent-dependent expression of molecular chirality and a [2 + 2] photocrosslinking reaction. AB - Upon photoirradiation of a stilbene-cored poly(glutamate) dendrimer, the photocrosslinking reaction preferentially occurred to produce the [2 + 2] cycloadduct in benzene. In addition, blue-shifted absorption spectra and a bisignate circular dichroism (CD) signal were observed, indicating that the aggregates of the stilbene core were chiral. PMID- 22932912 TI - Target-triggered deprotonation of 6-hydroxyindole-based BODIPY: specially switch on NIR fluorescence upon selectively binding to Zn2+. AB - Based on 6-hydroxyindole BODIPY with a Schiff-base structure, NIR fluorescence with impressively high selectivity is triggered by deprotonation of the phenol group upon binding with Zn(2+) due to the chelation-enhanced fluorescence effect, thus realizing a promising application in bioimaging of Zn(2+). PMID- 22932913 TI - Reversion of steatosis by SREBP-1c antisense oligonucleotide did not improve hepatic insulin action in diet-induced obesity mice. AB - The literature has associated hepatic insulin action with NAFLD. In this sense, treatments to revert steatosis and improve hepatic insulin action become important. Our group has demonstrated that inhibition of Sterol Regulatory Element Binding Proteins-1c (SREBP-1c) reverses hepatic steatosis. However, insulin signals after NAFLD reversion require better investigation. Thus, in this study, we investigated if the reversal of NAFLD by SREBP-1c inhibitor results in improvement in the hepatic insulin signal in obesity mice. After installation/achievement of diet-induced obesity and insulin resistance, Swiss mice were divided into 3 groups: i) Lean, ii) D-IHS, diet-induced hepatic steatosis [no treatment with antisense oligonucleotide (ASO)], and iii) RD-IHS, reversion of diet-induced hepatic steatosis (treated with ASO). The mice were treated with ASO SREBP-1c as previously described by our group. After ASO treatment, one set of animals was anesthetized and used for in vivo test, and another mice set was anesthetized and used for histology and Western blot analysis. Reversion of diet-induced hepatic steatosis did not change blood glucose, glucose decay constant (k(ITT)), body weight, or serum insulin levels. In addition, results showed that the protocol did not improve insulin pathway signaling, as confirmed by the absence of changes in IR, IRS1, Akt and Foxo1 phosphorylation in hepatic tissue. In parallel, no alterations were observed in proinflammatory molecules. Thus, our results suggest that the inhibition of SREBP 1c reverts steatosis, but without improving insulin hepatic resistance. PMID- 22932914 TI - 11Beta-hydroxylase deficiency and other syndromes of mineralocorticoid excess as a rare cause of endocrine hypertension. AB - Hypertension represents a major public and global health problem, most of which likely can be improved by lifestyle changes including changing dietary habits with less consumption of processed and preserved foods, which generally contain higher amounts of salt than freshly prepared food items. Among causes for endocrine hypertension are syndromes of mineralocorticoid excess. This group of mostly monogenic and acquired disorders typically causes hypertension through activation of the mineralocorticoid receptor either directly or indirectly via hormonal mediators and from overactive amiloride-sensitive epithelial sodium channels located in the distal tubule and collecting ducts of the kidneys. Apart from primary aldosteronism, mineralocorticoid excess can be caused by congenital adrenal hyperplasia (CAH) due to mutations of the 11beta-hydroxylase and 17alpha hydroxylase genes, by inactivating mutations of the glucocorticoid receptor gene (Chrousos syndrome), endogenous hypercortisolism (Cushing's syndrome), by mutations of the 11beta-hydroxysteroid dehydrogenase type 2 gene (apparent mineralocorticoid excess/AME) or licorice/carbenoxolone intake, mutations of the epithelial sodium channel genes (Liddle syndrome), mutations of the mineralocorticoid receptor gene (Geller syndrome), and by mutations in the WNK1, WNK4, KLHL3, CUL3 genes (pseudohypoaldosteronism type 2 or Gordon syndrome). Most of these conditions are treated by restricting dietary salt intake. However, some require special therapies including dexamethasone/hydrocortisone (CAH), spironolactone/eplerenone (AME), epithelial sodium channel inhibitors amiloride/triamterene (Liddle and Gordon syndrome), while in others spironolactone and MR antagonists may be contraindicated due to an abnormally structured MR (Geller syndrome). We here review the pathophysiology, diagnosis, and therapy of these rare conditions including the presentation of a patient with 11beta-hydroxylase deficiency. PMID- 22932915 TI - Developing a Performance Brain TrainingTM approach for baseball: a process analysis with descriptive data. AB - Neurofeedback may be useful for improving sports performance but few studies have examined this potential. Here we present data of five development players from a major league baseball team. The aims were to evaluate the feasibility of conducting sessions within a professional organization, assess changes in quantitative electroencephalograph (QEEG), NeuroPerformance ProfileTM, and report qualitative self-report data before and after brain training. The EEG was recorded with 19 electrodes for 20 min of baseline conditions and approximately 21 min of a continuous performance test. The fast Fourier transform analysis provided average cross-spectral matrices for bands delta (1-3.5 Hz), theta (4-7.5 Hz), alpha (8-12 Hz), low beta (13-16 Hz), beta 1 (13-21 Hz), beta 2 (22-32 Hz), and gamma (32-45 Hz) from the pre and post intervention evaluations in the baseline condition of eyes open. The continuous performance test metrics included the errors of omission, errors of commission, response time and response time variability. The 9 scales of the NeuroPerformance ProfileTM were examined. The QEEG data, CPT data and NeuroPerformance ProfileTM data were all compared between the pre and post 15 sessions of brain training using a within subject paired t test design corrected for multiple comparisons using false discovery rate method. Following brain training, comparative QEEG, CPT and NeuroPerformance ProfileTM analyses illustrated significant differences. The QEEG findings of all participants illustrated significant changes within the training parameters but also across other frequency bands and electrode sites. Overall, the positive findings in both objective and subjective measures suggest further inquiry into the utility of brain training for performance enhancement with the specific application of sport is warranted. Particularly QEEG and CPT gains were noted in the areas that correspond to client self-report data demonstrating improvement in attention, decreased intrusive thought patterns and improvements in sleep patterns. PMID- 22932916 TI - Value of diffusion-weighted imaging in central pontine and extrapontine myelinolysis. AB - INTRODUCTION: Central pontine myelinolysis (CPM) and extrapontine myelinolysis (EPM) are rare neurological disorders characterized by demyelination in and/or outside the pons. Whether diffusion-weighted imaging (DWI) might facilitate an earlier diagnosis has not yet been studied systematically. METHODS: We describe demographics, clinical presentation, and early magnetic resonance imaging (MRI) findings with special emphasis on the relevance for diagnosis of CPM and/or EPM in eight patients. RESULTS: Of the analysed eight patients (aged 37-70 years; two men, six women), CPM was diagnosed in three, EPM in one, and a combination of CPM and EPM in four patients. Aetiology was rapid correction of sodium in two patients; a combination of hyponatremia, alcoholism and alcohol withdrawal in five patients and unclear in one patient. Seven patients suffered from chronic alcoholism and four from malnutrition. Demyelinating lesions were found in the pons, thalamus, caudate nucleus, putamen and midbrain. While the lesions could be clearly delineated on T2- and T1-weighted images, DWI demonstrated a strong signal in only six patients. Furthermore, DWI demonstrated lesions only to some extent in two patients and was completely negative in two patients on initial MRI. In none of the patients did the demonstration of hyperintense lesions on DWI precede detection on conventional MRI sequences. Apparent diffusion coefficient (ADC) values were heterogenous with a decrease in two cases and an increase in the remainder. CONCLUSIONS: We conclude that early DWI changes are a common finding in CPM/EPM but do not regularly precede tissue changes detectable on conventional MRI sequences. Heterogenous ADC values possibly represent different stages of disease. PMID- 22932917 TI - Intracellular-signaling tumor-regression modeling of the pro-apoptotic receptor agonists dulanermin and conatumumab. AB - Dulanermin (rhApo2L/TRAIL) and conatumumab bind to transmembrane death receptors and trigger the extrinsic cellular apoptotic pathway through a caspase-signaling cascade resulting in cell death. Tumor size time series data from rodent tumor xenograft (COLO205) studies following administration of either of these two pro apoptotic receptor agonists (PARAs) were combined to develop a intracellular signaling tumor-regression model that includes two levels of signaling: upstream signals unique to each compound (representing initiator caspases), and a common downstream apoptosis signal (representing executioner caspases) shared by the two agents. Pharmacokinetic (PK) models for each drug were developed based on plasma concentration data following intravenous and/or intraperitoneal administration of the compounds and were used in the subsequent intracellular-signaling tumor regression modeling. A model relating the PK of the two PARAs to their respective and common downstream signals, and to the resulting tumor burden was developed using mouse xenograft tumor size measurements from 448 experiments that included a wide range of dose sizes and dosing schedules. Incorporation of a pro-survival signal--consistent with the hypothesis that PARAs may also result in the upregulation of pro-survival factors that can lead to a reduction in effectiveness of PARAs with treatment--resulted in improved predictions of tumor volume data, especially for data from the long-term dosing experiments. PMID- 22932919 TI - Management of renal colic. PMID- 22932918 TI - Prevalence of abnormalities in knees detected by MRI in adults without knee osteoarthritis: population based observational study (Framingham Osteoarthritis Study). AB - OBJECTIVE: To examine use of magnetic resonance imaging (MRI) of knees with no radiographic evidence of osteoarthritis to determine the prevalence of structural lesions associated with osteoarthritis and their relation to age, sex, and obesity. DESIGN: Population based observational study. SETTING: Community cohort in Framingham, MA, United States (Framingham osteoarthritis study). PARTICIPANTS: 710 people aged >50 who had no radiographic evidence of knee osteoarthritis (Kellgren-Lawrence grade 0) and who underwent MRI of the knee. MAIN OUTCOME MEASURES: Prevalence of MRI findings that are suggestive of knee osteoarthritis (osteophytes, cartilage damage, bone marrow lesions, subchondral cysts, meniscal lesions, synovitis, attrition, and ligamentous lesions) in all participants and after stratification by age, sex, body mass index (BMI), and the presence or absence of knee pain. Pain was assessed by three different questions and also by WOMAC questionnaire. RESULTS: Of the 710 participants, 393 (55%) were women, 660 (93%) were white, and 206 (29%) had knee pain in the past month. The mean age was 62.3 years and mean BMI was 27.9. Prevalence of "any abnormality" was 89% (631/710) overall. Osteophytes were the most common abnormality among all participants (74%, 524/710), followed by cartilage damage (69%, 492/710) and bone marrow lesions (52%, 371/710). The higher the age, the higher the prevalence of all types of abnormalities detectable by MRI. There were no significant differences in the prevalence of any of the features between BMI groups. The prevalence of at least one type of pathology ("any abnormality") was high in both painful (90-97%, depending on pain definition) and painless (86-88%) knees. CONCLUSIONS: MRI shows lesions in the tibiofemoral joint in most middle aged and elderly people in whom knee radiographs do not show any features of osteoarthritis, regardless of pain. PMID- 22932921 TI - Clinicopathologic characteristics and molecular subtypes of invasive papillary carcinoma of the breast: a large case study. AB - PURPOSE: Although patients with invasive papillary carcinoma (IPC) often have favorable prognoses, it remains unclear whether this special type of breast cancer represents a distinct morphological entity with its own biological features and clinical behavior distinct from those of invasive ductal carcinoma (IDC) and whether its four molecular subtypes are associated with different prognoses. METHODS: The study is a retrospective analysis of a large patient cohort from a single institution. 284 IPC samples were collected from January 2000 to May 2011. 300 IDC cases were selected randomly from 13,428 cases of IDC during the same periods. We assessed the clinicopathologic characteristics, molecular features, and prognostic value of IPC (n = 284) and compared them to those of IDC (n = 300). Clinicopathologic features and survival status of the four subtypes of IPC were also evaluated. RESULTS: IPC differed from IDC with respect to age upon diagnosis, tumor grade, lymph node status, and menopausal status (P < 0.05). IPC was associated with a better 5-year overall survival rate (OS) (92.77 vs. 87.95 %) and disease-free survival rate (DFS) (87.95 vs. 80.72 %) than IDC. Tumors of the luminal A subtype had a better 5-year OS (97.78 %) and DFS (95.56 %) than other subtypes. CONCLUSIONS: The biologic behavior of IPC is more favorable to patient outcome than that of IDC. The chance of pure IPC causing death without an intervening event of a different histologic type is exceptionally low. Luminal A subtypes have better outcomes when compared to the other subtypes. PMID- 22932922 TI - Awareness of human papillomavirus infection, genitoanal warts and cancer in a dermatological outpatient clinic setting. AB - There has been little research into awareness of human papillomavirus (HPV) among dermatological out-patients, despite the fact that management of HPV infection causing genitoanal warts/cancer is part of the routine practice of dermato venereologists. The aim of this study was to explore awareness of HPV among dermatological outpatients. A self-administered questionnaire was distributed to 360 consecutive attendees of a Munich dermatological outpatient clinic in November 2009. Of the total number of questionnaires, 77.2% were returned, and 69.7% (n=251, 51.8% females) were included in the analysis. 39.4% of the respondents had heard of HPV infection, and 23.9% of vaccination. Of those who had heard of HPV, 81.8% knew that HPV risk is associated with non-use condoms, number of sexual partners (77.8%), smoking (8.1%), and that HPV causes genital warts (65.7%), anal warts (39.4%) and cervical cancer (57.6%). HPV ignorance (never having heard of HPV) was predicted by being male (adjusted odds ratio=2.23, 95% confidence interval=1.32-3.80) and being a parent (adjusted odds ratio=2.11, 95% confidence interval=1.24-3.59). We conclude that dermatological outpatients have insufficient knowledge of HPV, its sequelae and prevention. PMID- 22932923 TI - Genotype composition of populations of grapefruit-cross-protecting citrus tristeza virus strain GFMS12 in different host plants and aphid-transmitted sub isolates. AB - Citrus tristeza virus (CTV) causes severe losses in grapefruit production in South Africa and requires mild-strain cross-protection to maintain production. Unfortunately, cross-protection breakdown of the pre-immunizing CTV grapefruit mild source GFMS12 is prevalent in grapefruit in South Africa. The CTV genotype composition of the GFMS12 population inoculated onto different hosts was determined by sequencing part of ORF1a and the p23 gene of multiple clones from each plant. Analysis of the GFMS12 population in Mexican lime and Marsh and Star Ruby grapefruit varieties revealed that at least four genotypes occur in the GFMS12 population and that genotype compositions differed amongst the populations in different host plants. Single-aphid-transmitted sub-isolates derived from the GFMS12 mother population on Mexican lime appeared to contain three populations of a mixture of VT-like and recombinant B165/VT-like genotypes; a mixture of recombinant RB/VT- and B165/VT-like genotypes; and a single recombinant B165/VT like genotype. This study underlines the importance of determining the genotype composition of a potential CTV pre-immunizing source on a range of inoculated host species before utilization. PMID- 22932924 TI - The International Code of Virus Classification and Nomenclature (ICVCN): proposal to delete Rule 3.41. PMID- 22932925 TI - FRET-based ratiometric detection of Hg2+ and biothiols using naphthalimide rhodamine dyads. AB - A new naphthalimide-rhodamine-based dyad in CH(3)CN-HEPES (1 : 1) buffer solution exhibits fluorescence resonance energy transfer (FRET) from naphthalimide to the rhodamine moiety on addition of only Hg(2+) ions and allows ratiometric absorption and fluorimetric estimation of Hg(2+) ions between 50 nM (10 ppb) to 2 MUM (0.4 ppm). FRET-induced fluorescence changes were recovered again by the subsequent addition of thiol amino acids via reverse FRET. The interconversion of probe and via the complexation/decomplexation by the modulation of Hg(2+)/Cys exhibited a selective probe for biothiols in real samples. PMID- 22932926 TI - The structure, function, and regulation of Mycobacterium FtsZ. AB - FtsZ is a widely distributed major cytoskeletal protein involved in the archaea and bacteria cell division. It is the most critical component in the division machinery and similar to tubulin in structure and function. Four major roles of FtsZ have been characterized: cell elongation, GTPase, cell division, and bacterial cytoskeleton. FtsZ subunits can be assembled into protofilaments. Mycobacteria consist of a large family of medical and environmental important bacteria, such as M. leprae, M. tuberculosis, the pathogen of leprosy, and tuberculosis. Structure, function, and regulation of mycobacteria FtsZ are summarized here, together with the implication of FtsZ as potential novel drug target for anti-tuberculosis therapeutics. PMID- 22932927 TI - CEA fluorescence biosensor based on the FRET between polymer dots and Au nanoparticles. AB - Polymer dots were employed as luminophors to design a fluorescence biosensor for carcinoembryonic antigen (CEA) with high sensitivity and selectivity; the increased fluorescence intensity is proportional to CEA concentration in the range of 0.1-10 ng mL(-1). PMID- 22932929 TI - A strategically designed porous iron-iron oxide matrix on graphene for heavy metal adsorption. AB - The iron oxide nanoparticles were transformed to a matrix of iron-iron oxide on the graphene surface at an elevated temperature in a H(2)/Ar atmosphere. The resultant iron-iron oxide dispersed graphene was highly porous, robust and attractive for a variety of potential applications. PMID- 22932930 TI - Enhanced photosynthetic output via dichroic beam-sharing. AB - Microbial solar biofuels offer great promise for future sustainable food, fuels and chemicals but are limited by low productivities and a requirement for large land areas to harvest sunlight. A 71 % increase in combined photosynthetic activity was achieved by illuminating both Rhodobacter sphaeroides and Arthrospira (Spirulina) platensis from a single beam of simulated sunlight, divided using a dichroic mirror. Therefore, this technique is termed 'dichroic beam-sharing', in which the complementary action spectra of two different useful micro-organisms, belonging to green and purple groups, is exploited and allows a single beam of sunlight to be shared efficiently between separate photobioreactors. Because the action spectra of these two organisms are typical of large groups, this novel method could increase the productivity of photosynthetic micro-organisms in the production of diverse commodities. PMID- 22932931 TI - D-lactic acid production from dry biomass of Hydrodictyon reticulatum by simultaneous saccharification and co-fermentation using Lactobacillus coryniformis subsp. torquens. AB - D-lactic acid production from dry biomass of the microalga, Hydrodictyon reticulatum, was carried out in a 5-l jar fermentor (initial pH 6, 34 degrees C using CaCO(3) as a neutralizing agent) through simultaneous saccharification and co-fermentation using the Lactobacillus coryniformis subsp. torquens. After 36 h, 36.6 g lactic acid/l was produced from 80 g H. reticulatum/l in the medium containing 3 g yeast extract/l and 3 g peptone/l in the absence of mineral salts. The maximum productivity, average productivity and yield were 2.38 g/l h, 1.02 g/l h and 45.8 %, respectively. The optical purity of D-Lactic acid ranged from 95.8-99.6 %. H. reticulatum is thus a promising biomass material for the production of D-Lactic acid. PMID- 22932928 TI - Multiple somatic symptoms predict impaired health status in functional somatic syndromes. AB - BACKGROUND: The relationship between functional somatic syndromes and multiple somatic symptoms is unclear. PURPOSE: We assessed whether the number of somatic symptoms is a predictor of health status in three functional somatic syndromes (FSS). METHODS: In a population-based study of 990 UK adults we assessed chronic widespread pain (CWP), chronic fatigue (CF) and irritable bowel syndrome (IBS) by questionnaire and medical record data. We assessed health status (Short Form 12 and EQ-5D), number of somatic symptoms (Somatic Symptom Inventory) and anxiety/depression (Hospital Anxiety and Depression Scale) both at baseline and at follow-up 1 year later. RESULTS: The proportion of people with an FSS who also have multiple somatic symptoms (52-55 %) was similar in the three functional syndromes. The presence of multiple somatic symptoms was associated with more impaired health status both at baseline and at follow-up. This finding was not explained by severity of FSS. In the absence of multiple somatic symptoms, the health status of the FSS was fair or good. In multiple regression analysis, the number of somatic symptoms, the presence of a functional syndrome (CWP or CF) and anxiety/depression were predictors of EQ-5D thermometer at follow-up after adjustment for confounders. CONCLUSIONS: Multiple somatic symptoms in people with an FSS are associated with impaired health status and this cannot be explained by more severe functional syndrome or the presence of anxiety and depression. PMID- 22932932 TI - Effect of immunization with a recombinant cholera toxin B subunit/somatostatin fusion protein on immune response and growth hormone levels in mice. AB - Somatostatin (SS) is a hormone that inhibits growth hormone secretion. Cholera toxin B subunit (CTB) is a widely used adjuvant to improve the immunogenicity of co-administrated antigen. To block the growth hormone-inhibiting effect of SS, a fusion gene of CTB and SS was constructed and expressed in Escherichia coli. The purified CTB/SS fusion protein polymerized into a biologically active pentamer required for CTB binding to the GM1 ganglioside receptor. Immunization with the CTB/SS protein induced specific immunity against CTB and SS in mice. The serum growth hormone of the CTB/SS-treated mice increased by 29 % (P < 0.05) compared with the control. The results indicated that the CTB/SS fusion protein was effective in inducing immune response against SS as well as elevating the growth hormone level. PMID- 22932933 TI - Pretreatment of Populus tomentosa with Trametes velutina supplemented with inorganic salts enhances enzymatic hydrolysis for ethanol production. AB - Different nutrients were added into the solid fermentation of woody biomass, Populus tomentosa, to improve pretreatment by a white rot fungus, Trametes velutina. Fungal pretreatment supplemented with trace elements resulted in large amount of lignin loss but low degradation of carbohydrate. Only 12.6 % of Klason lignin was left in the residues pretreated by T. velutina for 8 weeks supplemented with 1 % trace elements (TE group). When fungal-pretreated residues were subjected to enzymatic hydrolysis for 96 h, a maximum reducing sugar yield of 44 % was obtained from the TE group at the 8th week, 2.3 times higher than that of untreated samples. In addition, the highest ethanol yield of 22 % was observed by the fermentation of 8-week pretreated residues from the basic medium plus trace element group, which was five times more than that of untreated samples. PMID- 22932934 TI - Antifungal effect and mechanism of chitosan against the rice sheath blight pathogen, Rhizoctonia solani. AB - The antifungal properties and mechanism of three types of chitosan against the rice sheath blight pathogen, Rhizoctonia solani, were evaluated. Each chitosan had strong antifungal activity against R. solani and protected rice seedlings from sheath blight, in particular, two types of acid-soluble chitosan caused a 60 91 % inhibition in mycelial growth, 31-84 % inhibition of disease incidence, and 66-91 % inhibition in lesion length. The mechanism of chitosan in protection of rice from R. solani pathogen was attributed to direct destruction of the mycelium, evidenced by scanning and transmission electron microscopic observations and pathogenicity testing; indirect induced resistance was evidenced by the changes in the activities of the defense-related phenylalanine ammonia lyase, peroxidase and polyphenol oxidase in rice seedling. To our knowledge, this is the first report on the antifungal activity of chitosan against rice R. solani. PMID- 22932935 TI - Practical solutions for lymphaticovenous anastomosis. AB - Lymphedema is a chronic debilitating disease affecting a considerable part of the population that results from impairment of the lymphatic system. Lymphovenous anastomosis (LVA), a technique that attempts to achieve a physiologic lymphatic load of the edematous limb, is an accepted treatment. Techniques make anastomosis of 0.3 to 0.8 mm lymphatics to subdermal veins possible, but it is a challenge for microsurgeons because it requires a high degree of concentration and skill. An associated problem that we sometimes face when doing LVA is the absence of suitable veins in the proximity of an ideal lymphatic vessel. In situations like this, the presence of large veins with a higher diameter than the lymphatics is an alternative to consider. In these cases, end-to-side anastomosis is recommended. We describe a helpful technique to perform end-to-side LVA, using a thin catheter to create a round hole in the lateral wall of subdermal veins having the same diameter as the neighboring lymphatic that is going to be anastomosed. We also describe our personal modification of the intravascular stenting technique. PMID- 22932936 TI - Pyrethroid insecticide transport into Monterey Bay through riverine suspended solids. AB - Pyrethroid pesticides are used widely in both agricultural and urban landscapes. Toxicity has been recorded in creeks and rivers throughout California, confirming that pyrethroids move at least short distances from the areas of terrestrial application into downstream waterways. However, their further downstream transport into the marine ecosystem has received little study. The Monterey Bay was chosen as the study system in the current project due to the close proximity of both urban centers and intense agriculture. Suspended sediments were sampled from three major rivers during storm events and showed that pyrethroids were routinely discharged from these coastal rivers, with concentrations of bifenthrin and permethrin in suspended solids of 22 and 83 ng/g, respectively. These suspended solids were deposited in estuaries and downstream reaches of rivers as they approached the coast where concentrations of pyrethroids in the sediment were greater than those expected to be toxic. However, despite their transport onto the continental shelf, pyrethroid residues were not detected in bed sediments of the shelf or in the nearby deep sea canyon, presumably due to dilution and degradation. PMID- 22932937 TI - Comparison of in vivo with in vitro pharmacokinetics of mercury between methylmercury chloride and methylmercury cysteine using rats and Caco2 cells. AB - The in vivo and in vitro pharmacokinetics of mercury (Hg) were compared between methylmercury chloride (MeHg.Cl) and methylmercury cysteine (MeHg-Cys) using rats and Caco2 cells because humans can be exposed to MeHg compounds through dietary fish. The in vivo pharmacokinetics of Hg immediately after the digestion of MeHg compounds are still obscure. In Caco2 cells, membrane uptake and subcellular distribution of MeHg compounds were examined. When rats received it intravenously, MeHg.Cl showed 20-fold greater plasma and 2-fold greater blood concentrations of Hg than MeHg-Cys, indicating that their pharmacokinetic properties are different. One hour later, however, Hg concentrations in plasma and blood became virtually identical between MeHg.Cl and MeHg-Cys, although blood Hg concentrations were >100-fold greater than those in plasma. When administered into the closed rat's jejunum loop, MeHg.Cl and MeHg-Cys were rapidly and efficiently taken up by intestinal membranes, and Hg was retained in intestinal membranes for a relatively long time. When administered orally, no difference was observed in plasma and blood Hg concentrations between MeHg.Cl and MeHg-Cys: plasma and blood Hg concentrations increased gradually and reached steady levels at 8 h after administration. In Caco2 cells, uptake of MeHg-Cys was significantly suppressed by L-leucine, although this was not seen with MeHg.Cl. In Caco2 cells, 81 % of Hg was recovered from cytosol fractions and 13 % of Hg from nuclear fractions (including debris) after a 2-h incubation with MeHg-Cys. In conclusion, the mechanism of membrane uptake and volume of distribution in the initial distribution phase were clearly different between MeHg.Cl and MeHg-Cys. However, such pharmacokinetic differences between them disappeared 1 h after intravenous and after oral routes of administration, possibly due to the metabolism in the body. PMID- 22932938 TI - Glucose and fructose to platform chemicals: understanding the thermodynamic landscapes of acid-catalysed reactions using high-level ab initio methods. AB - Molecular level understanding of acid-catalysed conversion of sugar molecules to platform chemicals such as hydroxy-methyl furfural (HMF), furfuryl alcohol (FAL), and levulinic acid (LA) is essential for efficient biomass conversion. In this paper, the high-level G4MP2 method along with the SMD solvation model is employed to understand detailed reaction energetics of the acid-catalysed decomposition of glucose and fructose to HMF. Based on protonation free energies of various hydroxyl groups of the sugar molecule, the relative reactivity of gluco-pyranose, fructo-pyranose and fructo-furanose are predicted. Calculations suggest that, in addition to the protonated intermediates, a solvent assisted dehydration of one of the fructo-furanosyl intermediates is a competing mechanism, indicating the possibility of multiple reaction pathways for fructose to HMF conversion in aqueous acidic medium. Two reaction pathways were explored to understand the thermodynamics of glucose to HMF; the first one is initiated by the protonation of a C2-OH group and the second one through an enolate intermediate involving acyclic intermediates. Additionally, a pathway is proposed for the formation of furfuryl alcohol from glucose initiated by the protonation of a C2-OH position, which includes a C-C bond cleavage, and the formation of formic acid. The detailed free energy landscapes predicted in this study can be used as benchmarks for further exploring the sugar decomposition reactions, prediction of possible intermediates, and finally designing improved catalysts for biomass conversion chemistry in the future. PMID- 22932939 TI - Spermatozoon cytoarchitecture of Amphilina foliacea (Platyhelminthes, Amphilinidea). AB - The mature spermatozoon of Amphilina foliacea Rudolphi, 1819 has been examined using transmission electron microscopy. The male gamete is filiform and tapered at both extremities. Its moderately electron-dense cytoplasm possesses two parallel axonemes of unequal lengths with the 9 + "1" trepaxonematan pattern, a mitochondrion, a nucleus, parallel cortical microtubules, four electron-dense attachment zones, and electron-dense glycogen granules. A crested body is absent. The anterior extremity of the cell exhibits a single axoneme. The anteriormost cortical microtubules have been observed with the appearance of the second axoneme. The number of cortical microtubules reaches a maximum (up to 25) in the nucleated region III of the spermatozoon. A single mitochondrion extends from the middle of region II to the end of region III of the cell. Both axonemes have become disorganized in a similar way: the axonemal doublets disappear first, followed by the central core. The nucleus is surrounded by a few cortical microtubules in the proximal part of region V. In the distal extremity of the mature spermatozoon, there is only the nucleus. Differences of spermatozoon ultrastructure within Amphilinidea and other Neodermata are discussed. PMID- 22932940 TI - Molecular characterization of a cytokine-induced apoptosis inhibitor from Schistosoma japonicum. AB - Cytokine-induced apoptosis inhibitor (CIAP) is a novel antiapoptotic molecule, which is different to inhibitor of apoptosis protein or B-cell lymphoma 2. CIAP was originally identified as a molecule that conferred resistance to apoptosis induced by growth factor starvation. However, it remains to be undercharacterized in schistosomes. Here, we molecularly characterize a novel cytokine-induced apoptosis inhibitor from Schistosoma japonicum (SjCIAP). The transcription of the SjCIAP occurred at all of developmental stages investigated including eggs, cercariae, schistosomula, and adult schistosomes. Functional assay indicated that the SjCIAP could inhibit caspase activity in either human cell lines or schistosome lysates. Our preliminary results suggest that the SjCIAP may play important roles in parasitic living and development by regulating apoptosis, and drug target of SjCIAP might be a potential for schistosomiasis control. PMID- 22932941 TI - Overexpression of tissue factor pathway inhibitor in CHO-K1 cells results in increased activation of NF-kappaB and apoptosis mediated by a caspase-3 independent pathway. AB - There is now circumstantial evidence that tissue factor pathway inhibitor (TFPI) is not only a major anticoagulant, but also has proapoptotic properties. The current study was designed to address the role of TFPI on signalling pathways and apoptosis. The non-TFPI expressing cell line CHO-K1 was stably transfected with pcDNA3.1/V5-His-TOPO-TFPI and control cells were established by transfecting the CHO-K1 cells with pcDNA3.1/V5-His-TOPO. Sodium butyrate (NaBut) has been shown to induce the expression of recombinant proteins. Here we have used NaBut to increase the expression of TFPI as assessed by qRT-PCR and ELISA. Compared to the control cells, TFPI induced apoptosis in a concentration dependent manner as measured by a cell death detection assay. Independent of caspase-3 activation an increased cleavage of PARP was detected in the TFPI expressing cells. This was accompanied by downregulation of Bcl-XL, elevated levels of Bax, and increased translocation of the apoptosis initiating factor. Increased DNA binding activity of NF-kappaB was revealed by electrophoretic mobility shift assay when the TFPI level was elevated by NaBut together with an increased translocation of the NF kappaB subunit p65. The results indicate that TFPI affected the apoptotic activity through a process independent of caspase-3, and was also able to increase the activation of the NF- kappaB pathway. PMID- 22932943 TI - Second-tier test for quantification of underivatized amino acids in dry blood spot for metabolic diseases in newborn screening. AB - The quantitative analysis of amino acids (AAs) in single dry blood spot (DBS) samples is an important issue for metabolic diseases as a second-tier test in newborn screening. An analytical method for quantifying underivatized AAs in DBS was developed by using liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS). The sample preparation in this method is simple and ion pairing agent is not used in the mobile phase that could avoid ion suppression, which happens in mass spectrometry and avoids damage to the column. Through chromatographic separation, some isomeric compounds could be identified and quantified, which cannot be solved through only appropriate multiple reactions monitoring transitions by MS/MS. The concentrations of the different AAs were determined using non-deuterated internal standard. All calibration curves showed excellent linearity within test ranges. For most of the amino acids the accuracy of extraction recovery was between 85.3 and 115 %, and the precision of relative standard deviation was <7.0 %. The 35 AAs could be identified in DBS specimens by the developed LC-MS/MS method in 17-19 min, and eventually 24 AAs in DBS were quantified. The results of the present study prove that this method as a second tier test in newborn screening for metabolic diseases could be performed by the quantification of free AAs in DBS using the LC-MS/MS method. The assay has advantages of high sensitive, specific, and inexpensive merits because non deuterated internal standard and acetic acid instead of ion-pairing agent in mobile phase are used in this protocol. PMID- 22932942 TI - Association of the C242T polymorphism in the NADPH oxidase p22 phox gene with carotid atherosclerosis in Slovenian patients with type 2 diabetes. AB - Oxidative stress plays an important role in the pathogenesis of diabetes and its complications. Genetic variations of enzymes producing reactive oxygen species could change their activity, thus contributing to the susceptibility to oxidative stress. The aim of this study was to examine the role of the NADPH oxidase C242T polymorphism in the development of carotid atherosclerosis in patients with type 2 diabetes. 286 diabetic patients and 150 healthy controls were enrolled in the study. Carotid atherosclerosis was quantified ultrasonographically as carotid intima-media thickness, plaque score (0-6) and plaque type (1-5). Diabetic patients were divided into low and high risk groups based on ultrasound phenotypes of carotid atherosclerosis. Genotypes were determined by real-time PCR. Levels of 8-hydroxy-2-deoxyguanosine (8-OHdG) were measured by enzyme-linked immunosorbent assay (ELISA). Diabetic patients demonstrated a statistically significant difference compared to healthy controls in the following parameters: age, BMI, waist circumference, smoking prevalence, glucose, triglyceride and 8 OHdG serum levels. Control subjects had significantly higher levels of HDL, LDL and total cholesterol than diabetics (p < 0.001). The NADPH C242T polymorphism was not related with clinical characteristics, lipid parameters and 8-OHdG serum levels. We found no significant difference in the NADPH genotype distribution between diabetics and controls (p = 0.19) nor between low and high risk subgroups of diabetics (mean CIMT: p = 0.67; plaque score: p = 0.49, plaque type: p = 0.56). In the present study the NADPH C242T polymorphism was not associated with the degree of oxidative stress and carotid atherosclerosis. Further studies will show if it can be used as a genetic marker for carotid atherosclerosis in diabetic patients. PMID- 22932944 TI - Video-laryngoscopy versus direct laryngoscopy in critically ill patients: a pilot randomized trial. AB - PURPOSE: Endotracheal intubation in critically ill patients is associated with a high risk of complications that tend to increase with multiple attempts at laryngoscopy. In this pilot study, we compared direct laryngoscopy (DL) with video-laryngoscopy (VL) with regard to the number of attempts and other clinical parameters during endotracheal intubation of critically ill patients performed by novice providers. METHODS: Patients were randomized to either VL or DL for endotracheal intubation. Exclusion criteria for the study included: requirement for immediate endotracheal intubation, cervical spine precautions, anticipated difficult intubation, oxygen saturation < 90%, or systolic blood pressure < 80 mmHg despite resuscitation. The providers, predominantly non-anesthesiology residents in their first three years of postgraduate training, received a one hour teaching and mannequin session prior to performing the procedures. RESULTS: Forty patients, mean age 65 (standard deviation, 16) yr were randomized to VL (n = 20) or DL (n = 20). Sixty percent of the patients received endotracheal intubation for respiratory failure, and all patients received a neuromuscular blocker. Multiple attempts were required in 25/40 (63%) patients, and this did not differ with technique (P = 1.0) Video-laryngoscopy resulted in improved glottic visualization with 85% of patients having a Cormack-Lehane grade 1 view compared with 30% of patients in the DL group (P < 0.001). Total time-to intubation for VL was 221 sec (interquartile range [IQR 103-291]) vs 156 sec [IQR 67-220] for DL (P = 0.15). Video-laryngoscopy resulted in a lower median SaO(2) (86%) during endotracheal intubation [IQR 75-93] compared with a median SaO(2) of 95% in the DL group [IQR 85-99] (P = 0.04). CONCLUSIONS: Video-laryngoscopy resulted in improved glottic visualization compared with DL; however, this did not translate into improved clinical outcomes. The trial was registered on ClinicalTrials.gov number, NCT00911755. PMID- 22932945 TI - Child mortality is falling but some developing regions will miss millennium targets. PMID- 22932946 TI - Towards an engineering-oriented strategy for building microbial anodes for microbial fuel cells. AB - The objective of the work was to give some first insight into an engineering oriented approach to MFC design by focusing on anode optimisation. The effect of various parameters was firstly investigated in half cell set-ups under well controlled conditions. Microbial anodes were formed from soil leachate under polarisation at -0.2 V vs. SCE with different concentrations of substrate, salt and buffer. It was shown that non-turnover CV could be used to assess the electroactive maturity of the anodes during polarisation. This first phase resulted in the definition of a set of optimal parameter values. In the second phase, an optimal anode was formed in a half-cell under the defined optimal conditions. A numerical approach was then developed to calculate the theoretical maximum power that the anode could provide in an ideal MFC. The concept of "ideal MFC" introduced here allowed the theoretical maximum power to be calculated on the sole basis of the kinetic characteristics of the anode. Finally, a MFC designed in the aim of approaching such ideal conditions generated stable power densities of 6.0 W m(-2), which were among the highest values reported so far. The discrepancy between the theoretical maximum (8.9 W m(-2)) and the experimental results pointed out some limit due to the source of inoculum and suggested possible paths to improvement. PMID- 22932947 TI - A novel formulation of L-thyroxine (L-T4) reduces the problem of L-T4 malabsorption by coffee observed with traditional tablet formulations. AB - The purpose of this work is to evaluate if the coffee-associated malabsorption of tablet levothyroxine (L-T4) is reduced by soft gel capsule. We recruited 8 patients with coffee-associated L-T4 malabsorption including one hypothyroid patient. For 6 months, the patients were switched to the capsule maintaining the L-T4 daily dose. Patients took the capsule with water, having coffee 1 h later (proper habit, PH) on days 1-90, or with coffee <= 5 min later (improper habit, IH) on days 91-180. After 6 months, 2 patients volunteered for an acute loading test of 600 MUg L-T4 (capsule) ingested with water (PH) or with coffee (IH). In the single hypothyroid patient, the post-switch TSH ranged 0.06-0.16 mU/L (PH) versus 5.8-22.4 mU/L pre-switch (PH) and 0.025-0.29 mU/L (IH) versus 26-34 mU/L pre-switch (IH). In the other 7 patients, post-switch TSH was 0.41 +/- 0.46 (PH) versus 0.28 +/- 0.20 pre-switch (PH) (P = 0.61) and 0.34 +/- 0.30 (IH) versus 1.23 +/- 1.47 pre-switch (IH) (P < 0.001). Importantly, TSH levels in PH versus IH habit did not differ post-switch (P = 0.90), but they did pre-switch (P < 0.0001). The proportions of post-switch TSH levels <0.10 mU/L with PH (33.3 %) or with IH (33.3 %) were borderline significantly greater than the corresponding pre switch levels with PH (10.3 %) (P = 0.088) or with IH (0 %) (P = 0.0096). In the two volunteers, the L-T4 loading test showed that coffee influenced L-T4 pharmacokinetics minimally. Soft gel capsules can be used in patients who are unable/unwilling to change their IH of taking L-T4. PMID- 22932948 TI - COL4A1-related disease: raised creatine kinase and cerebral calcification as useful pointers. AB - BACKGROUND: Mutations in COL4A1 are responsible for a spectrum of clinical phenotypes characterized by neurological, ocular, and renal involvement. Neurological features are the most prominent but as such are rather nonspecific. CASE PRESENTATION: Here, we report three new cases that, like five patients we previously described, show the novel common finding of raised creatine kinase (CK) concentration. CONCLUSION: Raised CK concentration, in addition to intracranial calcification, is to be considered another useful pointer to a final diagnosis of COL4A1-related disease. PMID- 22932949 TI - Head circumference growth function as a marker of neurological impairment in a cohort of microcephalic infants and children. AB - Our aim was to investigate the correlations between head circumference (HC) growth and neurological impairment in microcephalic patients.HC charts of 3,269 patients from a tertiary pediatric neurology section were reviewed and 136 microcephalic participants were selected. Standardized HC Minimum, HC Drop, and HC Catch-up variables were defined. Children with evidence of significant learning disability and/or significant cerebral palsy were classified within the neurologically impaired group and the rest of participants within the normal group.Using discriminant analysis, we found that HC Minimum and HC Drop were relevant markers of neurological impairment. A positive HC Catch-up was significantly linked to a better outcome although this variable did not add significant information to HC Minimum and HC Drop. A Fisher linear discrimination cutoff function (C-function) was obtained as C = HC Minimum + HC Drop with a cutoff level of C = -4.28 standard deviations (SD).In our cohort, the addition of the lowest HC z-score to the preceding HC z-score drop was below -4.28 SD in 6 out of 10 neurologically impaired patients , whereas in the normal group, the result was over -4.28 SD in 9 out of 10 participants. PMID- 22932950 TI - Antenatal supplementation of taurine for protection of fetal rat brain with intrauterine growth restriction from injury by reducing neuronal apoptosis. AB - This study aimed to investigate whether antenatal taurine can reduce neuronal apoptosis in fetal rat brains with intrauterine growth restriction (IUGR) and its possible mechanisms. A total of 15 pregnant rats were randomly divided into the following three groups: control, IUGR, and IUGR+ antenatal taurine supplements. Neuronal apoptosis was detected using transferase-mediated dUTP biotin nick end labeling (TUNEL); the expression of Bcl-2, Bax, and caspase-3 mRNA and proteins was detected by reverse transcription-polymerase chain reaction and immunohistochemistry. In IUGR groups, the results were as follows: (1) the expression of Bcl-2 decreased whereas the expression of Bax increased, accordingly, the ratio of Bcl-2/Bax decreased, (2) the expression of caspase-3 increased significantly, and (3) apoptotic neuron counts in IUGR groups was significantly increased compared with controls. In taurine supplement groups, the results were as follows: (1) the expression of Bcl-2 increased whereas the expression of Bax decreased, accordingly, the ratio of Bcl-2/Bax increased, (2) the expression of caspase-3 in fetal rat cerebral cortex tissues decreased significantly, and (3) the number of apoptotic neurons was significantly decreased compared with IUGR groups. In addition, the changes in the expression of Bcl-2, Bax, and caspase-3 mRNA and protein were correlated. So we concluded that antenatal supplementation of taurine may reduce neuronal apoptosis in IUGR fetal rats via up-regulating the ratio of Bcl-2/Bax and down-regulating the expression of caspase-3. PMID- 22932951 TI - Tuning the leaving group in 2-deoxy-2-fluoroglucoside results in improved activity-based retaining beta-glucosidase probes. AB - The potency of 2-deoxy-2-fluoroglycosides in activity-based profiling of human acid beta-glucosidase is drastically improved by introducing an N-phenyl trifluoroacetimidate leaving group at the anomeric center. Protonation by the general acid-base catalyst in the active site turned out to be a prerequisite, making the imidate probe a genuine mechanism-based glycosidase inactivator. PMID- 22932953 TI - Encapsulation of atmospheric CO2 by a self-assembled decanuclear cadmium complex via unfamiliar perchlorato and carbonato bridges. AB - A decanuclear Cd complex has been found as a carbonate-containing capsule. The structure strongly resembles a ten-blade waterwheel with a central carbonate ligand surrounded by two superimposed Cd(5)O(5) crowns with a pentagonal antiprism-like disposition. The capsule is doubly capped by two pentadentate perchlorate anions. PMID- 22932952 TI - Burden of cervical, anal, and oral HPV in an inner-city pre-vaccine adolescent population. PMID- 22932955 TI - Thermally biased AC electrokinetic pumping effect for lab-on-a-chip based delivery of biofluids. AB - One major motivation for microfluidic research is to develop point of care diagnostic tools, which often demands a solution for chip-scale pumping that is of low cost, small size and light weight. Electrokinetics has been extensively studied for disposable pumping since only electrodes are needed to induce microflows. However, it encounters difficulties with conductive biofluids because of the associated high salt content. In electrokinetic pumps, electrodes are in direct contact with fluid, so high salt content will compress the electric double layer that is essential to electroosmostic flows. Alternating current electrothermal (ACET) effect is the only electrokinetic method found viable for biofluid actuation. While high frequency (>10 kHz) operation can suppress electrochemical reactions, electrical potential that could be applied over biofluids is still limited within several volts due to risk of electrolysis or impedance mismatch. Since ACET flow velocity has a quartic dependence on the voltage, ACET flows would be rather slow if electric field alone is used for actuation. This work studies the effect of a thermal bias on enhancing AC electrokinetic pumping. With proper imposition of external thermal gradients, significant improvement in flow velocity has been demonstrated by numerical simulation and preliminary experiments. Both showed that with 4 V(rms) at 100 kHz, flow velocity increased from ~10 MUm/s when there was no thermal biasing to ~112 MUm/s when a heat flux was applied. PMID- 22932954 TI - Percutaneous implantation of the Edwards SAPIEN(TM) pulmonic valve: initial results in the first 22 patients. AB - BACKGROUND: Percutaneous pulmonary valve implantation (PPVI) was introduced in 2000 as an interventional procedure for the treatment of right ventricular outflow tract (RVOT) dysfunction. The new Edwards SAPIEN(TM) pulmonic valve has reached CE certification at the end of 2010 thus offering an attractive alternative with extended sizes (23 and 26 mm) to the conventional Melody((r)) valve (sizes 18, 20 and 22 mm). PATIENTS: Over a 1-year period, PPVI using the Edwards SAPIEN(TM) pulmonic valve was performed in 22 patients using a standardized procedure. Primary diagnosis was tetralogy of Fallot (n = 11), pulmonary atresia (n = 2), Truncus arteriosus (n = 3), TGA/PS-Rastelli (n = 1), Ross surgery (n = 2), double outlet right ventricle (n = 2) and absent pulmonary valve syndrome (n = 1). The character of the RVOT for PPVI was transannular patch (n = 4), bioprosthesis (n = 2), homograft (n = 5) and Contegra((r)) conduit (n = 11). The leading hemodynamic problem consisted of a pulmonary stenosis (PS) (n = 2), pulmonary regurgitation (PR) (n = 11) and a combined PS/PR lesion (n = 9). RESULTS: In 21/22 patients, PPVI was performed successfully (10 * 23 and 11 * 26 mm). There were 9 female and 13 male patients; the mean age was 21.7 years (range 6-83 years), the mean length was 162 cm (range 111-181 cm) and the weight 56.5 kg (range 20-91 kg). Invasive data showed a decrease of RV-systolic pressure from 61.2 mmHg (+/- 23.1) to 41.2 mmHg (+/- 8.6) and reduction of RV-PA gradient from 37.3 mmHg (+/- 23.2) to 6.9 mmHg (+/- 5.3). The PA-systolic pressure increased from 25.8 mmHg (+/- 8.6) to 33.9 mmHg (+/- 9.3) as did the PA diastolic pressure (from 6.0 mmHg (+/- 5.6) to 14.6 mmHg (+/- 4.3). There was a substantial reduction of pulmonary regurgitation from before (none/trivial n = 0, mild n = 2, mode rate n = 9, severe n = 11) to after PPVI (none/trivial n = 20, mild n = 1). During the short-term follow-up of 5.7 months there was no change in the immediate results. CONCLUSION: PPVI using the Edwards SAPIEN(TM) pulmonic valve can be performed safely in a wide range of patients with various diagnoses and underlying pathology of the RVOT and enables the restoration of an adult-size RVOT diameter. Although the immediate and short-term results seem promising, the long-term effects and safety have to be assessed in further clinical follow-up studies. PMID- 22932956 TI - Impedimetric monitoring of IGF-1 protection of in vitro cortical neurons under ischemic conditions. AB - Microelectrode arrays (MEAs) incorporated with the electric cell substrate impedance sensing (ECIS) technique provide a method for acquiring cellular electrophysiological information, which is useful for the time-course monitoring of cellular outgrowth and damage. This research utilizes the ECIS technique for monitoring the time-course impedimetric changes in normal and insulin-like growth factor 1 (IGF-1)-protected cortical neurons under the ischemic insult of oxygen glucose deprivation (OGD) created in a microperfusion environment. The neuronal apoptosis is reflected by the relatively low cell viability (28 +/- 11.5 %) after 30-min OGD followed by 24 h of re-oxygenation. Also the hyperpolarization phase of mitochondrial membrane potential (MMP) occurs during 2 h of the re-oxygenation period. In contrast, cortical neurons treated with 50 and 100 ng/mL IGF-1 show higher survival rates of 45 +/- 5.2 % and 49 +/- 9.2 %, respectively, and no occurrence of the hyperpolarization of MMP during the re-oxygenation period. The ECIS results demonstrate that the measured impedance of cortical neurons decreased from 826 +/- 86 kOmega to 224 +/- 32 kOmega due to cell detachment under the insult of OGD. The measured impedance of IGF-1-protected cortical neurons slowly decreased to about 50 % of the original value (560 +/- 45 kOmega for 50 ng/mL and 593 +/- 44 kOmega for 100 ng/mL) compared to saline control of 232 +/- 37 kOmega, which indicates improved cell adhesion under OGD conditions. The time-course impedimetric results show that the proposed ECIS-based MEAs platform incorporated with a microperfusion environment can be used for the real time monitoring of cortical neurons under in vitro OGD and the IGF-1 protective effect against OGD-induced ischemic neuronal death. PMID- 22932958 TI - Effects of Pimenta pseudocaryophyllus (Gomes) L. R. Landrum, on melanized and non melanized Cryptococcus neoformans. AB - In the present study, the in vitro susceptibility and capsular width from both melanized and non-melanized Cryptococcus neoformans cells in the presence of Pimenta pseudocaryophyllus crude extract were determined. The results were compared with those obtained for voriconazole and amphotericin B. Melanization was obtained in minimal medium broth with the addition of L-dopa, and the antifungal susceptibility tests were performed using the broth microdilution method. Capsular width of 30 cells of each one of the isolates in medium with crude extracts of P. pseudocaryophyllus or voriconazole or amphotericin B at a concentration corresponding to 0.5 times the minimal inhibitory concentration (MIC) was measured, and the mean was calculated. The MICs and minimal fungicidal concentrations (MFCs) for plant extract and voriconazole were identical for both melanized and non-melanized C. neoformans isolates, but for amphotericin, the MFCs for melanized cells were up to 8 times higher than for non-melanized cells. The capsular width of C. neoformans cells was smaller (p < 0.001) in the presence crude extract of P. pseudocaryophyllus and of voriconazole regardless melanization. The findings of capsule alterations of C. neoformans verified in this study provide fertile ways for future research into the effects of antifungal agents on the pathogenesis of cryptococcosis. PMID- 22932957 TI - Resetting epigenetic signatures to induce somatic cell reprogramming. AB - Somatic cell reprogramming consists of the induction of a complex sequence of events that results in the modification of the developmental state of the cell. It is now routinely possible to reprogram fully differentiated cells back to pluripotent cells, and to transdifferentiate cells of a given type in cells of a totally different lineage origin. However, whether there are key initiating factors that are distinct from those that control stem-cell renewal and that can initiate the reprogramming process remains unknown. In contrast, what is clear is that, by modifying the epigenetic status of a cell, its reprogramming can be initiated. Here, we review the current literature that shows how the plasticity of a cell can be modulated by modifying its epigenetic status, and we discuss how epigenetic barriers can be removed, to induce an efficient reprogramming process. PMID- 22932960 TI - Highly thermo-halo-alkali-stable beta-1,4-endoxylanase from a novel polyextremophilic strain of Bacillus halodurans. AB - A novel bacterial isolate, capable of producing extracellular highly thermostable, halo-alkali-stable and cellulase-free xylanase, was isolated from soil and identified as Bacillus halodurans TSPV1 by polyphasic approach. The Plackett-Burman design identified wheat bran, lactose, tryptone and NaCl as the factors that significantly affect xylanase production, and thus, these were optimized by response surface methodology. The data analysis suggested that optimum levels of wheat bran (15-20 g L(-1)), lactose (1.0-1.5 g L(-1)), tryptone (2-2.5 g L(-1)) and NaCl (7.0-8.0 g L(-1)) support 6.75-fold higher xylanase production than that in the un-optimized medium. The xylanase is optimally active at 90 degrees C and pH 10, and stable for 4 h at 90 degrees C (T 1/2 60 h) over a broad range of NaCl concentrations (0-29 %). This is the first report on the isolation of polyextremophilic B. halodurans strain that produces thermo-halo alkali-stable xylanase in submerged fermentation. This enzyme efficiently saccharifies agro residues like wheat bran and corncobs. Fifty-six percent of hemicellulose of wheat bran could be hydrolyzed by xylanase (100 U g(-1) substrate) along with cellulase (22 U FPase and 50 U CMCase g(-1)). The xylanase, being thermo-alkali stable and cellulase free, can find applications in pre bleaching of paper pulps and hydrolysis of xylan in agricultural residues. PMID- 22932961 TI - What factors determine whether a woman becomes depressed during the perimenopause? AB - Perimenopause has long been associated with psychological distress, both anecdotally and clinically. Research has identified this time as a period of increased risk for both first-episode depression and for depression reoccurrence. However, we know that the majority of women do not experience these difficulties during perimenopause. This review examines the current research literature looking at the factors associated with depression during perimenopause, with a view to identifying those factors which are protective and those factors which predict increased risk. From the literature, it is evident that some women have a hormonal vulnerability to mood disorders. However, this does not account for the phenomenon of perimenopausal depression in and of itself. Rather, there appears to be a complex interplay between hormonal vulnerability, the psychosocial resources one has (coping skills and social support), their overall well-being (exercise and other lifestyle factors) and the demands on their coping resources (stressful life events). The complexity of the relationship between perimenopause and depression means that there is a need to look beyond either as a sole explanation of mood during midlife. Education is required for both general practitioners and for women regarding the individual risks of psychological distress during perimenopause, as well as the knowledge of the life factors which we know to be protective. PMID- 22932962 TI - Presyrinx in a child with acquired Chiari I malformation. AB - Spinal cord signal abnormality resulting from alterations in cerebrospinal fluid flow at the craniocervical junction has been termed a presyrinx state. This condition has been described in the adult literature in association with a variety of conditions that cause obstruction to normal cerebrospinal fluid flow. We present a case of presyrinx in a child in the setting of acquired Chiari I malformation caused by lumboperitoneal overshunting. Awareness of the potentially reversible nature of this condition might allow for intervention before irreversible neurological damage has occurred. PMID- 22932964 TI - Survival comparison between surgical resection and percutaneous radiofrequency ablation for patients in Barcelona Clinic Liver Cancer early stage hepatocellular carcinoma. AB - AIM: To compare the survival outcome between surgical resection (SR) and radiofrequency ablation (RFA) for Barcelona Clinic Liver Cancer (BCLC) early stage hepatocellular carcinoma (HCC). METHODS: The retrospective study enrolled eighty-two patients with newly diagnosed BCLC early HCC (single nodule, size ?3 cm, and Child-Pugh class A) treated either surgically (n = 46) or with RFA (n = 36) from year 2004 to 2009. The patients' survival outcomes were compared. RESULTS: There were no significant differences in overall survival (OS) rates between SR and RFA (p = 0.204). The 3- and 5-year disease-free survival (DFS) rates were 65.8 % and 53.7 % respectively, in the SR group, which were significantly higher than those in the RFA group (34.8 % and 14.9 % respectively) (p = 0.009 and p = 0.001). In subgroup analysis, the DFS was similar between RFA and SR in patients with presentation of lower platelet count (?100,000/mL) and smaller tumor size (tumor size ?1 cm). Multivariate analysis showed SR as a procedure type was a significant predictive factor for DFS [HR = 2.26 (CI 1.462 5.227), p = 0.002]. CONCLUSION: SR yielded similar OS but better DFS when compared to RFA for patients with BCLC early HCC (single nodule, ?3 cm and Child Pugh class A). In subgroup patients with lower platelet count (?100,000/mL) and smaller tumor size (tumor size ?1 cm), DFS was similar between both treatments. PMID- 22932963 TI - Audit of patients with severe acute pancreatitis admitted to an intensive care unit. AB - BACKGROUND: Severe acute pancreatitis (SAP) is a disease with high morbidity and mortality. We undertook a study of patients with SAP admitted to the intensive care unit (ICU) of a tertiary referral hospital. METHODS: Between 2002 and 2007, 50 patients with SAP were admitted in our intensive care unit (ICU). Data were collected from their medical records and their clinical profile, course and outcome were retrospectively analyzed. Patients were categorized into survivor and nonsurvivor groups, and were further classified based on interventions such as percutaneous drainage and surgical necrosectomy. RESULTS: SAP contributed 5 % of total ICU admissions during the study period. Median age of survivors (n = 20) was 34 against 44 years in nonsurvivors (n = 30). Median Acute Physiology and Chronic Health Evaluation (APACHE) II score in nonsurvivors was 16.5 (8-32) vs. 12.5 (5-20) in survivors (p = 0.002). Patients with APACHE II score >=12 had mortality >80 % compared to 23 % with score <12 (p < 0.001). Median Sequential Organ Failure Assessment (SOFA) scores on admission and on days 3, 7, 14, and 21 were significantly higher in nonsurvivors compared to survivors (p < 0.05). Mean (SD) intraabdominal pressure was 23 (3.37) mmHg in nonsurvivors vs. 19.05 (2.51) in survivors (p < 0.05). Patients with renal failure had significant mortality (p < 0.001). Length of ICU stay, requirement for vasopressor, total parenteral nutrition, and the amount of blood and blood product transfusions differed significantly between patients with and without intervention. CONCLUSIONS: APACHE II and SOFA scores and other clinical data correlated with outcome in SAP admitted to ICU. PMID- 22932965 TI - Spirodiazaselenuranes: synthesis, structure and antioxidant activity. AB - In this paper, the synthesis, characterization and glutathione peroxidase and peroxynitrite scavenging activities of a series of stable spirodiazaselenuranes are described. The spiro compounds were synthesized in good yields by oxidative cyclization of diaryl selenides bearing amide moieties. All the selenides and spiro derivatives were characterized by (1)H, (13)C and (77)Se NMR spectroscopy, mass spectral techniques and the structures of some of the spirodiazaselenuranes were confirmed by single crystal X-ray crystallography. The structures reveal that the selenium atom occupies the center of a distorted trigonal bipyramid core with two nitrogen atoms occupying the apical positions and two carbon atoms and the selenium lone pair occupying the equatorial positions. Mechanistic investigations indicate that the spirocyclization occurs via the formation of selenoxide intermediates. The new compounds were evaluated for their glutathione peroxidase (GPx) mimetic activity by using H(2)O(2) as a substrate and glutathione (GSH) as a co-substrate. It was found that the substituents attached to the nitrogen atom of the selenazole ring have a significant effect on the GPx activity. While the introduction of electron withdrawing groups such as -Cl, -Br etc. to the phenyl ring decreases the activity, the introduction of electron donating groups such as -OH, -OMe significantly enhances the GPx activity of both diaryl selenides and spirodiazaselenuranes. In addition to GPx activity, the selenides and spiro derivatives were studied for their ability to inhibit peroxynitrite (PN)-mediated nitration of bovine serum albumin (BSA) and oxidation of dihydrorhodamine 123. These studies indicate that the diarylselenides effectively inhibit the PN-mediated nitration and oxidation reactions by reacting with PN to produce the corresponding spirodiazaselenuranes. PMID- 22932966 TI - Hepatitis D(delta). PMID- 22932967 TI - Virology of hepatitis D virus. AB - Although much of the current understanding of the replication of hepatitis D virus (HDV) has been gained from ex vivo rather than in vivo studies, many seemingly unique aspects have been discovered. These include the ultra-small size and circular conformation of the RNA genome, the presence on the viral RNAs of two ribozymes, the role of RNA-directed RNA transcription by redirection of host enzymes, the requirement of site-specific, posttranscriptional RNA-editing, and more. This review addresses recent insights, remaining controversies, and just plain deficits in our understanding of HDV replication. PMID- 22932968 TI - Viroids and hepatitis delta virus. AB - There is a subviral world, whose most prominent representatives are viroids. Despite being solely composed by a circular, highly structured RNA of ~250 to 400 nucleotides without protein-coding ability (all viruses code for one or more proteins), viroids can infect and incite specific diseases in higher plants. The RNA of human hepatitis delta virus (HDV), the smallest genome of an animal virus, displays striking similarities with viroids: It is circular, folds into a rodlike secondary structure, and replicates through a rolling-circle mechanism catalyzed by host enzymes and cis-acting ribozymes. However, HDV RNA is larger (~1700 nucleotides), encodes a protein in its antigenomic polarity (the ? antigen), and depends for transmission on hepatitis B virus. The presence of ribozymes in some viroids and in HDV RNA, along with their structural simplicity, makes them candidates for being molecular fossils of the RNA world that presumably preceded our extant world based on DNA and proteins. PMID- 22932969 TI - Epidemiology of hepatitis D. AB - Hepatitis D occurs worldwide. The major victims of the hepatitis D virus (HDV) are individuals carrying the hepatitis B surface antigen (HBsAg); around 5% of the HBsAg carriers in the world are infected also by HDV. With the implementation of a hepatitis B virus (HBV) vaccination since the 1990s, the incidence of hepatitis D has consistently declined in the developed world, particularly in Southern Europe; however, immigrants from areas where HDV remains endemic are reintroducing the infection.Hepatitis D continues to ravage populations of developing and poor countries where HBV remains unchecked; action is needed to enforce HBV vaccination as effective prophylaxis not only against HBV, but against HDV as well. PMID- 22932970 TI - Hepatitis delta virus diagnosis. AB - The first step in the diagnosis of hepatitis delta virus (HDV) infection is testing HBsAg-positive individuals for the antibody to the HD antigen (anti HD).In anti-HD-positive patients, the next step is testing for HDV RNA in serum to determine whether the antibody reflects an ongoing active HDV infection (HDV RNA-positive) or represents a serologic scar to past HDV infection (HDV-RNA negative). In the HDV-positive individual with liver disease, it is critical to distinguish acute HDV/hepatitis B virus (HBV) coinfection from chronic HDV superinfection in HBsAg carriers; the course, prognosis, and management of the two conditions are different. The differential diagnosis can be achieved through the scrutiny of the battery of HDV and HBV markers, which combine in patterns characteristic for each condition.Standardized competitive and MU-capture commercial assays are available to determine the IgG and IgM antibody to HDV. Several in-house assays were developed to determine HDV RNA in serum; the sensitivity threshold of current polymerase chain reaction-based assays is 10 copies of HDV RNA/mL. Unfortunately, HDV-RNA assays are not yet standardized and the results from different laboratories often are not comparable due to different sensitivities. The development of an international reference HDV-RNA standard remains an unmet diagnostic need. PMID- 22932971 TI - Clinical features of hepatitis D. AB - Hepatitis D is caused by infection with hepatitis D virus (HDV), a defective RNA virus that requires the obligatory helper function of hepatitis B virus (HBV) for its in vivo transmission. Thus, HDV is acquired only by coinfection with HBV or by superinfection of an HBV carrier. The clinical outcome of hepatitis D differs according to the modality of infection. Whereas coinfection evolves to chronicity in only 2% of the cases, superinfection results in chronic infection in over 90% of the cases. HDV is a highly pathogenic virus that causes acute, often fulminant hepatitis, as well as a rapidly progressive form of chronic viral hepatitis, leading to cirrhosis in 70 to 80% of the cases. The clinical picture of HDV disease is evolving as a consequence of a significant change in the epidemiology of HDV infection, which has led to a significant decline in incidence in Western countries, mainly as a result of universal HBV vaccination programs. However, in the face of a declining prevalence in areas of old endemicity like Europe, immigration poses a threat of HDV resurgence. The interaction of HDV with other hepatitis viruses or human immunodeficiency virus is complex and may lead to different patterns in terms of virologic expression and immunologic responses. Multiple viral infections are associated with rapid progression of liver fibrosis and eventually with the development of hepatocellular carcinoma. Hepatitis D is not a vanishing disease, and continuous efforts should be made to improve its prevention and treatment. PMID- 22932972 TI - Treatment of chronic delta hepatitis. AB - Chronic delta hepatitis (CDH) remains the most progressive form of chronic viral hepatitis and as such its successful treatment is important. However, in striking contrast to the situation in chronic hepatitis B and C, no new drugs for its treatment have been introduced in the recent past and interferons remain the only evidence-based effective treatment of CDH. However, results are far from optimal. Overall, around 25 to 30% of patients may have a sustained response after one year of conventional or pegylated interferon (Peg-INF) treatment and such treatment may favorably affect the natural history of the disease. The superiority of Peg-INF over its conventional form is possible, but has not been demonstrated in a clinical trial. Several unanswered questions remain in the context of INF treatment such as (1) the need for standardization of HDV-RNA quantitation, the most widely used surrogate marker of treatment efficacy; (2) validation of this treatment end point as an index of long-term containment of HDV; (3) optimal duration of treatment; (4) baseline and on-treatment parameters of treatment efficacy; and (5) development of new markers of treatment efficacy. Nucleos(t)ide analogs (NAs) have been widely tested in CDH, but they appear to be ineffective when used for a duration of up to 2 years. Combination treatment of NAs with INFs also proved to be disappointing. New approaches to treatment are hepatocyte entry inhibitors and prenylation inhibitors to be hopefully tested in human CDH in the not-too-distant future. PMID- 22932973 TI - Liver transplantation in delta virus infection. AB - Liver transplantation is the only therapy for patients with end-stage liver disease, hepatocellular carcinoma, or fulminant hepatitis due to hepatitis D virus (HDV) and hepatitis B virus (HBV) coinfection or superinfection. Patients chronically coinfected with HDV are less at risk of HBV recurrence and have a better survival rate than patients infected with HBV alone. Patients coinfected with HDV generally do not require pretransplant antiviral therapy. Rates of recurrent HBV-HDV infection are lower than 5% using low-dose intramuscular (IM) HBIg and antiviral prophylaxis in combination. Few studies have evaluated the possibility of using shorter-term HBIg (12-24 months) then switching to antiviral therapy. Although HBV replication can be controlled by potent HBV-polymerase inhibitors, reappearance of HBsAg and/or the persistence of HBV DNA in serum, liver, or peripheral blood mononuclear cells might have deleterious consequences in the setting of HBV-HDV coinfection as they may provide the biologic substrate to the reactivation of HDV. No effective antiviral drug is available for the treatment of graft infection with HDV. PMID- 22932974 TI - Perspectives for a vaccine against hepatitis delta virus. AB - Hepatitis delta virus (HDV) causes severe hepatitis in carriers of hepatitis B virus (HBV). In ~90% of patients, HDV persists together with HBV and causes early development of cirrhosis and liver carcinoma. Worldwide ~15 million people are coinfected with HBV-HDV. Specific defects in the immune response causing persistence of the virus have not been identified. Several approaches to develop a vaccine to prevent superinfection in the preclinical model of the woodchuck have failed. Recent findings show that a DNA prime and viral vectors boost immunization regimen can induce a HDV specific CD8 T cell response and can prevent HDV infection in simultaneous infection of woodchuck hepatitis virus-HDV. The vaccine-induced specific CD8 T cell response is effective in preventing HDV replication and spread in the liver. However, the perspectives for a HDV vaccine against genotype-1 to prevent superinfection are much less promising. The T-cell response induced by the current DNA prime and viral vector boost immunization in the preclinical woodchuck model seems insufficient to prevent the spread of HDV in chronic HBV carriers. A more potent vaccine and repeated vaccinations are necessary to induce a HDV-specific T-cell response, which may prevent superinfection in HBsAg carriers. PMID- 22932975 TI - A case of quadruple viral infections and elevated aminotransferase activities. AB - A 40-year-old man with human immunodeficiency virus (HIV), hepatitis C virus (HCV), and hepatitis B virus (HBV) infection was referred for evaluation of abnormal liver enzyme activities. The patient was maintained on antiretroviral therapy for HIV as well as medication to suppress HBV and had previously undergone treatment for HCV with durable sustained virologic response. The patient was clinically well without any symptoms or evidence of liver decompensation. Laboratory findings were notable for aminotransferase activities in the 200 to 225 U/L range that had been persistent for several months. An extensive workup for the etiology of the aminotransferase elevation ensued. Imaging studies showed no evidence of biliary obstruction. Serology revealed negative autoantibodies, negative serum HCV-RNA, and low level HBV-DNA by polymerase chain reaction. Further testing revealed positive hepatitis delta virus (HDV) antibody and positive HDV RNA in the serum. A percutaneous liver biopsy was performed to further elucidate the cause of the elevated aminotransferase activities. Based on histology, serology, and clinical presentation, a diagnosis of chronic HDV infection was made. HDV infection should be considered in patients with known chronic viral hepatitis B with low viral load, who present with worsening liver function or elevation in aminotransferase activities. PMID- 22932977 TI - Production of singlet oxygen by the reaction of non-basic hydrogen peroxide with chlorine gas. AB - Non-basic hydrogen peroxide was found to be very easy to react with Cl(2) to produce singlet oxygen O(2)(a(1)Delta(g)) (i.e. the molecular oxygen in its first electronic excited state) when an H(+) absorbent such as C(5)H(5)N, CH(3)COONH(4), HCOONH(4) or NH(4)F was added into H(2)O(2) aqueous solution, and the long concealed fact that molecular H(2)O(2) can react with Cl(2) to produce O(2)(a(1)Delta(g)) was then uncovered. It is only when an H(+) absorbent has provided a stronger base than H(2)O to absorb the H(+) produced during the reaction that O(2)(a(1)Delta(g)) can be produced. PMID- 22932976 TI - System for integrated neuroimaging analysis and processing of structure. AB - Mapping brain structure in relation to neurological development, function, plasticity, and disease is widely considered to be one of the most essential challenges for opening new lines of neuro-scientific inquiry. Recent developments with MRI analysis of structural connectivity, anatomical brain segmentation, cortical surface parcellation, and functional imaging have yielded fantastic advances in our ability to probe the neurological structure-function relationship in vivo. To date, the image analysis efforts in each of these areas have typically focused on a single modality. Here, we extend the cortical reconstruction using implicit surface evolution (CRUISE) methodology to perform efficient, consistent, and topologically correct analyses in a natively multi parametric manner. This effort combines and extends state-of-the-art techniques to simultaneously consider and analyze structural and diffusion information alongside quantitative and functional imaging data. Robust and consistent estimates of the cortical surface extraction, cortical labeling, diffusion inferred contrasts, diffusion tractography, and subcortical parcellation are demonstrated in a scan-rescan paradigm. Accompanying this demonstration, we present a fully automated software system complete with validation data. PMID- 22932978 TI - Macromolecular binding and kinetic analysis with optically sectioned planar format assays. AB - Real-time analysis of macromolecular interactions and competitive binding of ligands to receptors on surfaces are not typically performed using fluorescence intensity methods due to background interference from solution fluorescence. Separation-free optically sectioned planar format assays (OSPFAs) with confocal detection remove this problem. We report OSPFAs for indicator displacement and kinetic assessment of binding. A commercial androgen receptor binding domain indicator displacement assay adapted as an OSPFA yielded an IC(50) of 6.5 nM for testosterone with Z' = 0.77. These measured IC(50) and Z' values are in ranges suitable for drug screening applications with Z' > 0.5 indicating good to excellent screenability. An OSPFA was applied to study the rate of antibody binding to a sandwich immunoassay on a planar surface. Langmuir fits provided forward rate constants in the range 2 * 10(3) M(-1) s(-1) to 6 * 10(4) M(-1) s( 1) and reverse constants 1 * 10(-4) s(-1) to 4 * 10(-3) s(-1) which cover a useful range for characterising probe-target interactions. This work demonstrates the suitability of OSPFAs for investigating kinetics and binding interactions using fluorescence under wash-free conditions. OSPFAs are an alternative to other separation-free methods such as acoustic, surface plasmon resonance, ellipsometry, fluorescence polarisation and other related methods. OSPFAs should make practical dynamic binding studies for small and large molecules including cases where the reaction under investigation results in no appreciable mass change on a surface. PMID- 22932979 TI - Graphene oxide-photosensitizer conjugate as a redox-responsive theranostic agent. AB - A nano-sized graphene oxide-photosensitizer conjugate with a redox-responsive cleavable disulfide linker is non-fluorescent and non-phototoxic, even upon light irradiation. It becomes highly fluorescent and phototoxic inside cancer cells, where glutathione is used as an initiator for activating the photosensitizer. PMID- 22932980 TI - [Extra-articular manifestations of rheumatoid arthritis]. AB - Rheumatoid arthritis (RA) represents an autoimmune disease affecting mostly joints, in particular small finger and toe joints. In addition RA can show extra articular manifestations in many organs. Information on the frequency of extra articular manifestations (EAMs) in RA varies greatly in different publications from 17.8% to 40.9% and EAMs tend to become higher with increasing duration and severity of the disease. The exact etiology and pathogenesis are still unclear but vasculitic alterations together with deposition of immune complexes can often be found histopathologically in affected organs. It must also be taken into consideration that EAMs can also be a result of the pharmaceutical therapy. The organ findings can vary greatly which is also reflected in the multitude of clinical symptoms. Possible target organs are the blood vessels, kidneys, central nervous system, cardiovascular system, the lungs, eyes, skin, nails as well as blood and the hemopoetic system. The prognosis for RA becomes progressively worse in the presence of EAMs. Regular and continuous control investigations are necessary in order to be able to diagnose EAMs early and to begin therapy. Therapy includes the administration of non-steroidal anti-inflammatory drugs (NSAIDs) and disease-modifying antirheumatic drugs (DMARDs) and especially in advanced stages cyclophosphamide or biologicals. Therapy is still very empirical due to the lack of appropriate studies. PMID- 22932981 TI - [Role of increased tissue pressure in the pathophysiology of osteoarthritis]. AB - Osteoarthritis is characterized by increased internal pressure in the subchondral bone tissue as well as in the joint capsule. In analogy to the pathophysiological mechanism of venous compartment syndrome it is demonstrated that the increased pressure is maintained by high protein edema and initiates a vicious circle. Drug induced resorption of the osmotically active proteins leads to elimination of the high protein edema and is able to interrupt the pathophysiological process. PMID- 22932982 TI - Questions raised over use of misoprostol to prevent postpartum haemorrhage in poor countries. PMID- 22932983 TI - Molecular recognition driven catalysis using polymeric nanoreactors. AB - The concept of using polymeric micelles to catalyze organic reactions in water is presented and compared to surfactant based micelles in the context of molecular recognition. We report for the first time enzyme-like specific catalysis by tethering the catalyst in the well-defined hydrophobic core of a polymeric micelle. PMID- 22932984 TI - Phase I trial of verubulin (MPC-6827) plus carboplatin in patients with relapsed glioblastoma multiforme. AB - Verubulin (MPC-6827) is a microtubule-destabilizing agent that achieves high concentrations in the brain. Verubulin disrupts newly formed blood vessels in xenografts. We determined the safety and tolerability of verubulin administered in combination with carboplatin in patients with relapsed glioblastoma multiforme (GBM). Three pre-selected doses of verubulin were tested: 2.1, 2.7, and 3.3 mg/m(2) in a standard "3+3" design. Verubulin was given every second week of a 6 week cycle in the 2.1 mg/m(2) cohort or weekly for 3 weeks of a 4-week cycle in subsequent cohorts. Carboplatin was administered intravenously at an area under the curve (AUC) dosage 4 every 2 weeks for the 2.1 mg/m(2) cohort or on day 1 of each 4-week cycle in subsequent cohorts. Nineteen patients with GBM in first or second relapse were enrolled. Four patients (21 %) experienced a grade 3 or greater verubulin- or carboplatin-related adverse event, including hypesthesia, cerebral ischemia, anemia, and thrombocytopenia. The mean plasma half life of verubulin was 3.2 h (SD = 0.82). Two patients achieved at least a partial response by Macdonald criteria. One of these patients remains progression free and off treatment more than 24 months beyond his initiation of verubulin. Five patients had stable disease. Median progression-free survival (PFS) across all patients was 8 weeks, and the 6-month PFS rate was 21 %. The combination of verubulin at the previously determined single-agent maximum tolerated dose of 3.3 mg/m(2) with carboplatin in patients with recurrent/refractory GBM is safe and well tolerated. In this patient population with a highly vascularized tumor, no cerebral hemorrhage was observed. PMID- 22932985 TI - Predictors of organ damage in systemic lupus erythematosus: the Hopkins Lupus Cohort. AB - OBJECTIVE: The Systemic Lupus International Collaborating Clinics/American College of Rheumatology (ACR) Damage Index (SDI) is the accepted measure of permanent organ damage in systemic lupus erythematosus (SLE). We analyzed data from a large SLE cohort to identify variables associated with rates of damage accrual as measured by the SDI. METHODS: The study included 2,054 SLE patients (92% female, 56% white, and 37% African American) with a mean age at diagnosis of 33 years. The SDI score was calculated retrospectively at the time of cohort entry and prospectively during followup. The relationships between time-invariant patient characteristics and rates of damage accrual were assessed based on the damage score at the last available followup visit. The relationships between time varying patient characteristics and damage accrual were assessed based on the timing of damage accrual during cohort participation. RESULTS: Overall, the SDI score increased at a rate of 0.13 per year. Higher rates of damage were observed for those who were older, male, or African American, had a lower income or education level, were hypertensive, were positive for lupus anticoagulant, or had proteinuria. During followup, the risk of damage was higher for those who were older, had more disease activity, had low complement levels, were positive for anti-double-stranded DNA, satisfied more ACR criteria for SLE, or were receiving corticosteroids. Lower risk was observed among patients receiving hydroxychloroquine. After adjustment for other variables, age, hypertension, and corticosteroid use emerged as the most important predictors of damage accrual. CONCLUSION: Our findings indicate that rates of damage vary in demographic subgroups, but much variation appears to be explained by hypertension and corticosteroid use. These data clearly point to the need for tight control of disease activity without reliance on corticosteroids. PMID- 22932986 TI - Growth and metabolism characteristics of anaerobic ammonium-oxidizing bacteria aggregates. AB - The present study reported the growth and metabolism characteristics of anaerobic ammonium-oxidizing (anammox) bacteria aggregates in an expanded granular sludge bed (EGSB). The results showed that the anammox bacteria aggregates presented starvation, growth, and inhibition phase along with the increase of substrate supply. The substrate conversion rates for survival were 0.05 kgNH4(+) N/(kgVSS.day), 0.07 kgNO2(-)-N/(kgVSS.day), and 0.12 kgN/(kgVSS.day); the substrate conversion rates for maximum growth were 0.21 kgNH4(+)-N/(kgVSS.day), 0.24 kgNH4(+)-N/(kgVSS.day), and 0.45 kgNH4(+)-N/(kgVSS.day), respectively. In the growth phase, the yield of anammox bacteria aggregates was 0.14 gVSS/(gNH4(+) N), 0.12 gVSS/(gNO2(-)-N), and 0.70 gVSS/(gNO3(-)-N); the yield of extracellular polymeric substances (EPS) was 0.11 gEPS/(gNH4(+)-N), 0.09 gEPS/(gNO2(-)-N), and 0.55 gEPS/(gNO3(-)-N), respectively. The EPS contents in anammox bacteria aggregates were high compared to that in anaerobic granular sludge. Speculated from the cell yield, the energy for anammox bacteria growth was not only from nitrite oxidation, but also from anammox reaction. PMID- 22932987 TI - Hyperperfusion syndrome after stent/coiling of a ruptured carotid bifurcation aneurysm. AB - The authors report a syndrome of regional, symptomatic cerebral hyperperfusion, and edema mimicking infarction in a 54-year-old woman following coiling of a ruptured right carotid bifurcation aneurysm and stenting of the right middle cerebral artery. The patient presented with a Hunt and Hess grade III subarachnoid hemorrhage 7 days after developing thunderclap headache. She underwent successful coiling under general anesthesia of the 1.6 * 1.5 * 1.6 cm aneurysm, but immediately after the coil was placed occlusion of the proximal M1 segment was developed. This occlusion was stented after ~5-min delay, and flow restored without angiographic evidence of distal emboli. Following the procedure, she was extubated and noted to have left hemiparesis, neglect, and mutism without a CT correlate. Cerebral infarction was suspected, but urgent repeat angiography demonstrated patent cerebral vasculature. On the following day, symptoms persisted, and non-contrast head CT now showed cerebral edema localized to the right middle cerebral artery territory mimicking subacute infarction. CT perfusion imaging and angiography showed a widely patent MCA circulation, and suggested a regional hyperperfusion syndrome. The blood pressure was incrementally lowered, with rapid and sustained neurological improvement. Hyperperfusion events following aneurysm repair and related circumstances are reviewed. PMID- 22932989 TI - Emergency neurological life support: approach to the patient with coma. AB - Coma is an acute failure of neuronal systems governing arousal and awareness and represents a neurological emergency. When encountering a comatose patient, the clinician must have an organized approach to detect easily remedial causes, prevent ongoing neurologic injury, and determine a hierarchy of diagnostic tests, treatments, and neuromonitoring. Coma was chosen as an Emergency Neurological Life Support (ENLS) protocol because timely medical and surgical interventions can be life-saving, and the initial work-up of such patients is critical to establishing a correct diagnosis. PMID- 22932988 TI - Emergency neurological life support: resuscitation following cardiac arrest. AB - Cardiac arrest is the most common cause of death in North America. Neurocritical care interventions, including therapeutic hypothermia (TH), have significantly improved neurological outcomes in patients successfully resuscitated from cardiac arrest. Therefore, resuscitation following cardiac arrest was chosen as an Emergency Neurological Life Support protocol. Patients remaining comatose following resuscitation from cardiac arrest and who are not bleeding are potential candidates for TH. This protocol will review induction, maintenance, and re-warming phases of TH, along with management of TH side effects. Aggressive shivering suppression is necessary with this treatment to ensure the maintenance of a target temperature. Ancillary testing, including electrocardiography, computed tomography imaging of the brain, continuous electroencephalography, monitoring, and correction of electrolyte, blood gas, and hematocrit changes are also necessary to optimize outcomes. PMID- 22932990 TI - Emergency neurological life support: subarachnoid hemorrhage. AB - Subarachnoid hemorrhage (SAH) is a neurological emergency because it may lead to sudden neurological decline and death and, depending on the cause, has treatment options that can return a patient to normal. Because there are interventions that can be life-saving in the first hour of onset, SAH was chosen as an Emergency Neurological Life Support protocol. PMID- 22932991 TI - Frequency of non-convulsive seizures and non-convulsive status epilepticus in subarachnoid hemorrhage patients in need of controlled ventilation and sedation. AB - BACKGROUND: Non-convulsive seizures (NCSZ) can be more prevalent than previously recognized among comatose neuro-intensive care patients. The aim of this study was to evaluate the frequency of NCSZ and non-convulsive status epilepticus (NCSE) in sedated and ventilated subarachnoid hemorrhage (SAH) patients. METHODS: Retrospective study at a university hospital neuro-intensive care unit, from January 2008 until June 2010. Patients were treated according to a local protocol, and were initially sedated with midazolam or propofol or combinations of these sedative agents. Thiopental was added for treatment of intracranial hypertension. No wake-up tests were performed. Using NicoletOne((r)) equipment (VIASYS Healthcare Inc., USA), continuous EEG recordings based on four electrodes and a reference electrode was inspected at full length both in a two electrode bipolar and a four-channel referential montage. RESULTS: Approximately 5,500 h of continuous EEG were registered in 28 SAH patients (33 % of the patients eligible for inclusion). The median Glasgow Coma scale was 8 (range 3-14) and the median Hunt and Hess score was 4 (range 1-4). During EEG registration, no clinical seizures were observed. In none of the patients inter ictal epileptiform activity was seen. EEG seizures were recorded only in 2/28 (7 %) patients. One of the patients experienced 4 min of an NCSZ and one had a 5 h episode of an NCSE. CONCLUSION: Continuous EEG monitoring is important in detecting NCSZ in sedated patients. Continuous sedation, without wake-up tests, was associated with a low frequency of subclinical seizures in SAH patients in need of controlled ventilation. PMID- 22932992 TI - Trajectory of functional recovery after hospital discharge for subarachnoid hemorrhage. AB - BACKGROUND: Although there are extensive data on long-term disability after subarachnoid hemorrhage (SAH), there are few data on the trajectory of functional recovery after hospital discharge. METHODS: From October 2009 to April 2010, we prospectively followed consecutive patients with non-traumatic SAH discharged from a university hospital. Modified Rankin Scale (mRS) scores were calculated at discharge from chart review and at 6 months by standardized telephone interview. Good functional status was defined as a mRS score of 0-2, and poor status as an mRS score of 3-6. Descriptive statistics were used to assess the trajectory of functional recovery and determine the proportion of patients whose functional status improved from poor to good. RESULTS: Among 52 patients with non-traumatic SAH (79 % aneurysmal) who were discharged alive, most (71 %) were discharged home. Median (IQR) mRS score was 3 (2-4) at discharge and 2 (1-2) at 6 months. Some functional recovery (any improvement in mRS score) was seen in most patients (83 %; 95 % CI, 72-93 %). Of the 28 patients with poor functional status at discharge, 16 (57 %) improved to good functional status at 6 months. All patients with Hunt-Hess grade 4 or 5 hemorrhages (n = 14) had poor functional status at discharge, but half (95 % CI, 20-80 %) recovered to a good functional status at 6 months. CONCLUSIONS: Although our sample size is small, our findings suggest that a substantial proportion of patients with SAH who are disabled at discharge go on to regain functional independence within 6 months. PMID- 22932993 TI - Prognostic performance of diffusion-weighted MRI combined with NSE in comatose cardiac arrest survivors treated with mild hypothermia. AB - BACKGROUND: MRI-based prognostication of comatose cardiac arrest survivors has shown promising results. However, the technique has not been validated in patients treated with therapeutic hypothermia and it is unknown how it might add to NSE-based prognostication. We sought to evaluate the prognostic performance of regional apparent diffusion coefficient (ADC) in comatose out-of-hospital cardiac arrest (OHCA) patients treated with mild hypothermia and its added value to NSE based prognostication. METHODS: An OHCA registry was analyzed to identify OHCA patients older than 15 who were treated with therapeutic hypothermia and underwent brain MRI between 2008 and 2011. Quantitative measurement of regional ADCs was performed by a radiologist blinded to the clinical outcome. RESULTS: Of the 43 eligible patients, 11 (18.6 %) achieved a good outcome (6-month CPC of 1 or 2). The regional ADC of the occipital cortex showed the highest discriminatory power with an area under the curve of receiver operating characteristic (AUROC) of 0.943 (95 % CI, 0.872-1.000) and predicted poor outcomes with a sensitivity of 90.6 % and a specificity of 100 %. The AUROC for NSE levels (48-h) was 0.911 (95 % CI, 0.801-1.000) which was significantly correlated with the regional ADC (Pearson's r = -0.674, p < .001). The ADC-based predictions identified an additional 5 (35.7 %) poor outcome patients out of 14 with 48-h NSE levels less than 78.9 ng/mL, which is the cutoff point suggested in a previous study. However, additional prognostic information was not provided when the 48-h NSE levels were >78.9 ng/mL. CONCLUSIONS: Regional ADC-based prognostication was accurate in OHCA patients who were treated with mild hypothermia. However, it only provided additional prognostic information when the 48-h NSE levels indicated a good prognosis (48-h NSE <78.9 ng/mL). PMID- 22932994 TI - Transient amnesia after coiling of a posterior circulation aneurysm. AB - BACKGROUND: Acute amnesia can be caused by medication effect, transient global amnesia, ischemia, metabolic abnormalities, and seizures. METHODS: Case report. RESULTS: A 56-year-old woman developed acute amnesia resembling transient global amnesia (TGA) after aneurysm coiling. She was started on abciximab for possible thromboembolic complications related to coiling. Abciximab was discontinued after she developed chest pain. Her chest pain resolved after discontinuing abciximab. She was subsequently found to have small medial temporal lobe strokes on diffusion weighted MRI. CONCLUSIONS: Ischemia in the posterior circulation should be considered in the differential diagnosis of TGA, especially in situations predisposing to thromboembolism such as coiling. PMID- 22932995 TI - The association of adult kidney size with childhood vesicoureteral reflux. AB - BACKGROUND: We used ultrasound to measure kidney volumes in adults with a history of childhood vesicoureteral reflux (VUR) and assessed whether total renal volume, small kidney size or the thickness of the upper pole correlated with renal function or hypertension. METHODS: The kidneys of 123 adults were studied by ultrasound, calculating their volumes using an ellipsoid formula normalised to body surface area (Vol(N)). The thickness of the upper pole parenchyma and the number of small kidneys (<80% of normal volume) were recorded. Blood pressure measurements and laboratory tests were also performed. RESULTS: Kidneys with a history of VUR were 12% smaller than those without known VUR (p < 0.05), and those with prior dilating VUR were 16% smaller than those with non-dilating VUR (p < 0.05). There was a moderate correlation (r = 0.42, p < 0.05) between total Vol(N) and GFR values in the total patient series. Thirteen percent of the patients had a moderate decrease in kidney function. The occurrence of hypertension and proteinuria was not affected by either kidney size or a thin upper pole. CONCLUSIONS: Total Vol(N) in ultrasound in early adulthood could probably predict possible renal deterioration in later life. The occurrence of one small kidney was a common finding and seemed not to affect the prevalence of proteinuria or hypertension. PMID- 22932997 TI - Rapid screening of five phthalate esters from beverages by ultrasound-assisted surfactant-enhanced emulsification microextraction coupled with gas chromatography. AB - A rapid ultrasound-assisted surfactant-enhanced emulsification microextraction (UASEME) method coupled with gas chromatography-flame ionization detection (GC FID) is proposed for the rapid screening of five phthalate esters in bottled beverages. In the UASEME procedure, a nonionic surfactant (Triton X-100) was used as the emulsifier, without application of any organic dispersive solvents typically required in dispersive liquid-liquid microextraction. Triton X-100 as the emulsifier accelerated the formation of fine droplets from the extraction solvent in the sample solution under ultrasound radiation, thus combining the advantages of dispersive liquid-liquid microextraction (DLLME) and ultrasound assisted emulsification microextraction (UAEME). Under the optimum conditions, the enrichment factors of the five analytes ranged from 230 to 288 fold and the recoveries ranged from 89.3% to 100.1%. The limits of detection (LODs) based on signal to noise of 3 were 0.41-0.79 MUg L(-1). Intra-assay and inter-assay precision, expressed as the relative standard deviation (RSD), were <=5.46% and 5.81%, respectively. The proposed UASEME-GC/FID method was demonstrated to be simple, practical and environmentally friendly for the determination of trace phthalate esters in beverage samples. PMID- 22933001 TI - [Videoclips in Zentralblatt fur Chirurgie - a new rubric]. PMID- 22932999 TI - [Place of malaria among febrile illnesses in two ethnic tribes living in sympatry in Mali from 1998 to 2008]. AB - In Africa, malaria is responsible for 25-40% of all outpatient visits and 20-50% of all hospitalizations. In malaria-endemic areas, individuals do not behave the same toward the outcome of clinical malaria. The aim of this study is to determine the prevalence of malaria in the locality among the different ethnic groups, evaluate the place of malaria among febrile illnesses, and assess the relationship between fever and parasite density of Plasmodium falciparum. Studies on susceptibility to malaria between the Fulani and Dogon groups in Mali were conducted in Manteourou and the surrounding villages from 1998 to 2008. We carried out six cross-sectional studies during the malaria transmission and longitudinal surveys (July to December depending on the year) during the 10-year duration. In longitudinal studies, clinical data on malaria and other diseases frequently observed in the population were recorded. It appears from this work that malaria is the leading cause of febrile syndromes. We observed a significant reduction in malaria morbidity in the study population from 1998 to 2008. The pyrogenic threshold of parasitaemia was 1,000 parasites/mm(3) of blood in the Dogon and 5,000 parasites/mm(3) of blood in the Fulani.We have also found that high parasitical densities were not always associated with fever. Malaria morbidity was higher among the Dogon than in Fulani. The immunogenetic factors might account for this difference in susceptibility to malaria between Fulani and Dogon in the area under study. With regard to this study, it is important to take into account the ethnic origin of subjects when interpreting data of clinical and malarial vaccine trials. PMID- 22932996 TI - Membrane trafficking in podocyte health and disease. AB - Podocytes are highly specialized epithelial cells localized in the kidney glomerulus. The distinct cell signaling events and unique cytoskeletal architecture tailor podocytes to withstand changes in hydrostatic pressure during glomerular filtration. Alteration of glomerular filtration leads to kidney disease and frequently manifests with proteinuria. It has been increasingly recognized that cell signaling and cytoskeletal dynamics are coupled more tightly to membrane trafficking than previously thought. Membrane trafficking coordinates the cross-talk between protein networks and signaling cascades in a spatially and temporally organized fashion and may be viewed as a communication highway between the cell exterior and interior. Membrane trafficking involves transport of cargo from the plasma membrane to the cell interior (i.e., endocytosis) followed by cargo trafficking to lysosomes for degradation or to the plasma membrane for recycling. Yet, recent studies indicate that the conventional classification does not fully reflect the complex and versatile nature of membrane trafficking. While the increasing complexity of elaborate protein scaffolds and signaling cascades is being recognized in podocytes, the role of membrane trafficking is less well understood. This review will focus on the role of membrane trafficking in podocyte health and disease. PMID- 22933002 TI - [Transduodenal resection of ampullary tumors]. AB - OBJECTIVE: Whether the treatment of benign ampullary tumors should be performed as transduodenal surgical excision or endoscopic ampullectomy depends on the size and spread of the tumor. In this videopaper we report technical hints on the surgical resection. INDICATIONS: Surgical resection is indicated for benign ampullary lesions if endoscopic resection is not possible. In addition, local resection can be performed in cases with high risk of malignancy or in a palliative intention. PROCEDURE: The duodenum is mobilized by the Kocher maneuver. It is recommendable to perform a cholecystectomy to introduce a flexible catheter antegrade into the common bile duct through the cystic duct for identification of the papilla of Vater by digital palpation. An anterolateral oblique duodenotomy is made and thereby the tumor of the papilla is exposed, followed by a submucosal injection of epinephrine to elevate the tumor. Afterwards a 5-10 mm margin is scored circumferentially in the mucosa around the adenoma. The extent of the excision is based on the preoperative and intraoperative assessment; a submucosal or full thickness (for transmural lesions) excision can be performed. After submucosal excision the mucosa of the ampulla is approximated to the mucosa of the duodenum. In cases with full thickness ampullectomy the borders of the pancreatic and bile duct are approximated and then the entire complex is sutured to the full wall of the duodenum. Furthermore in some cases with extensive resection a separate reconstruction of the pancreatic and bile duct may be required. A terminal assessment of the ductal patency is imperative. The duodenectomy is closed and a paraduodenal drain is placed. CONCLUSION: Transduodenal resection of periampullary tumors can be technically demanding, but provides a stage-adapted treatment modality for benign and premalignant lesions of the papilla of Vater. PMID- 22933003 TI - [Functional disorders of the pelvic diaphragm]. PMID- 22933004 TI - [Significance of conservative treatment for faecal incontinence]. AB - Based on a variety of aetiological factors and combined disorders in faecal incontinence, a conservative treatment option as the primary treatment can be recommended. Conservative treatment includes medical therapy influencing stool consistency and stool passage, pelvic floor exercises and biofeedback as well as local treatment options. However, defining the role of conservative treatment concepts related to success or failure remains a challenging task. The lack of evidence derived from studies is related to a variety of reasons including inclusion criteria, patient selection, treatment standardisation, and the principal difficulty to objectively define functional success. PMID- 22933005 TI - [Anal sphincter repair in the treatment of anal incontinence - when and how to do it?]. AB - Anal incontinence is a disease of high prevalence. For many patients the disease causes severe stress and often results in social isolation. Whenever a sphincter lesion has been diagnosed by digital rectal examination and endosonographic access, anal sphincter reconstruction can be performed with the same results either in overlapping or in end-to-end suture technique. sing these procedures, in more than 60 % of patients the continence can be initially improved. However, benefit decreases after 5 years down to 40-50 %. The prognosis gets worse with increasing age and supplementary descending pelvic floor. Anal repair with reconstruction of internal and external sphincters is performed in neurogenic incontinence. This can be achieved by posterior or anterior anal repair (total pelvic floor repair). Nowadays these procedures are not common, due to unsuccessfulness. Instead, sacral nerve stimulation as a more expensive but less invasive method has displaced the anal repair on this indication. Interpretation of the published results remains delicate because of heterogenous evaluation criteria of postoperative outcome: subjective amelioration, postoperative satisfaction and quality of life, improvement of incontinence score or achievement of complete anal continence. However, it is proven that after immediate reconstruction of traumatic sphincter lesions the postoperative outcome is better than a two-step operation with primary ostomy. PMID- 22933006 TI - [Sacral nerve stimulation (SNS) in the treatment of faecal incontinence]. AB - Sacral nerve stimulation (SNS, sacral neuromodulation) has become an important tool in the treatment of incontinence. Idiopathic, muscular as well as neurogenous disorders can be treated successfully with this method. Possible complications like infections, cable breaks and electrode displacements may be treated very well conservatively. However, in some patients a surgical revision or removal of the stimulation system may be necessary. PMID- 22933007 TI - [The artificial sphincter: therapy for faecal incontinence]. AB - INTRODUCTION: Faecal incontinence (FI) challenges a patient's professional, social and sexual life. Often the patient becomes depressive and socially isolated. If able to break open for therapy the patient should receive as first line a conservative treatment (like dietary measures, pelvic re-education, biofeedback, bulking agents, irrigation). DISCUSSION: When is the time to implant an artificial anal sphincter? If conservative therapy fails as well as surgical options (like a sphincteroplasty - if indicated a reconstruction of the pelvic floor if insufficient, or a sacral nerve stimulation) an ultimo surgical procedure should be offered to appropriate and compliant patients: an artificial anal sphincter. Worldwide, there are two established devices on the market: the artificial bowel sphincter(r) (ABS) from A. M. S. (Minnetonka, MN, USA) and the soft anal band(r) from A. M. I. (Feldkirch, Austria). How to implant the artificial anal sphincter? Both devices consist of a silicon cuff which can be filled with fluid. Under absolute aseptic conditions this cuff is placed in the lithotomy position by perianal incisions around the anal canal below the pelvic floor. A silicon tube connects the anal cuff with a reservoir (containing fluid) which is placed either behind the pubis bone in front of the bladder (ABS) or below the costal arch (anal band). With a pump placed in the scrotum/labia (ABS) or by pressing the balloon (anal band) in both types operated by the patient the fluid is shifted forth and back between the anal cuff and the reservoir closing or opening the anal canal. Both systems are placed completely subcutaneously. CONCLUSIONS: Both devices improve significantly the anal continence. Both systems have a high rate of reoperations. However, the causes for the redos are different. The ABS is associated with high infection and anal penetration rates of the cuff leading to an explantation rate to up to 60 % of the implants. This kind of complication seems to be much lower with the anal band. The major problem in the anal band is a defunctioning valve which occasionally has to be replaced. Despite these problems both types of artificial anal sphincters improve faecal incontinence significantly and, thus, quality of life of incontinent patients. PMID- 22933008 TI - [MR defaecography for the diagnosis of obstructive defaecation disorders]. AB - As a consequence of demographic changes, outlet obstruction represents an increasingly common disease. The presence and ample interactions of morphological and functional pathologies contribute to the complexity of pelvic floor dysfunction. Additionally, multiple compartments of the pelvic floor are frequently affected. MR defaecography allows for the simultaneous and detailed assessment of morphological as well as functional changes of the pelvic floor. Hence, this approach constitutes an integral part of the diagnostic work-up and preoperative evaluation of the anorectum. The supine patient position can be regarded as a drawback compared to conventional defaecography, as sufficient emptying of the rectum can be impaired or even rendered impossible in individual cases. This inherent disadvantage is, however, compensated by the high anatomic resolution, the possibility of multiplanar imaging, easy execution and especially the lack of ionising radiation. Consequently, MR defaecography is considered the method of choice for the routine evaluation of functional anorectal disorders. PMID- 22933009 TI - [Laparoscopic resection rectopexy as treatment for obstructive defecation syndrome]. AB - Anorectal outlet obstruction constitutes one form of chronic constipation. Combinations of morphological alterations of the pelvis, the pelvic floor and the colorectum are nearly always evident. The goal of the diagnostic work-up is to identify those patients who will profit from a surgical intervention. Resection rectopexy aims at restoring the physiological anatomy thereby ameliorating the functional interaction of structures effected with the laparoscopic approach entailing all advantages of minimally invasive surgery. Besides a detailed description of the surgical technique used and an algorithm for indications to operate we present our results after 19 years of experience. Throughout this period, 264 laparoscopic resection rectopexies for outlet obstruction were performed. With a mean follow-up of 58.2 months the rate of improvement of obstructive symptoms was 79.5 % (n = 128 of 161 available for follow-up). Present studies suggest that (laparoscopic) resection rectopexy entails better results in comparison to non-resecting procedures and procedures with the implantation of allogenic material. Certainly, in order to achieve these results a correct patient selection and an expertise in laparoscopic surgery are essential. Both the perioperative and the functional results of our own collective fortify the advantages of laparoscopic resection rectopexy in patients with an outlet obstruction. PMID- 22933010 TI - [Stapled transanal resection for the treatment of obstructed defaecation syndrome]. AB - Stapled transanal rectal resection (STARR) has become a well-evaluated surgical procedure for the treatment of outlet obstruction in the context of conservative refractory obstructed defaecation syndrome (ODS). The diagnosis of ODS needs to be objectified which can be best ensured by clinical scoring systems. Besides a general coloproctological examination, dynamic defecography represents the most important diagnostic procedure. Pelvic floor dyssynergia and slow transit constipation should always be taken into account for the differential diagnosis and for which the STARR procedure is generally contraindicated. Surgery is performed via a transanal approach using a full thickness rectal resection of either the ventral or dorsal proportion of the rectal wall in the PPH01 conventional procedure or circumferentially by monoblock resection in the contour transtar(r) procedure. Morbidity is best characterised by data of the European STARR registry which contains a total number of n = 2,838 consecutive patients. The overall morbidity rate was 36 % whereby urgency (20 %) and bleeding (5 %) were the most frequent complications. More favourable data have been published in single centre studies. Functional results are available with a follow-up of 1 year up to 68 months postoperatively. Response rates of up to 90 % were reported whereas recurrence rates were given with a maximum of 18 % at 68 months follow up. In summary, the STARR procedure provides good functional results in conservative refractory outlet obstruction with minor morbidity and the outcome seems to remain stable in the long-term follow-up. PMID- 22933011 TI - [Dedication to Professor Stelzner]. PMID- 22933012 TI - [The crural diaphragm belongs to the pharyngeo-cardial continence organ (PET-CT and impedance measurements on the stretch sphincter and its fixation in the hiatus oesophageus of the diaphragm)]. AB - This paper provides evidence that pharyngeo-cardial propulsion in the oesophagus follows similar principles as translocation of luminal contents in other locations in the body. In brief, the following statements are discussed in the paper: 1. Only animals with a lung-based respiratory system have an oesophagus. 2. Its bulky muscular wall is made up of the elastic fibres which ensure that the oesophagus stays elastic during an entire lifetime. 3. While short-segment ring sphincter systems exist in several locations in the body, the lower oesophageal sphincter is maximally elongated. This configuration helps with the propulsion of luminal contents in addition to this sphincter's opening and occlusive functions. 4. The musculature of the diaphragm is genetically related to the cervical muscles. The crural portion of the diaphragm works in coordination with the lower oesophageal stretch sphincter. 5. Gastro-oesophageal reflux disease is fairly common. In patients with this disorder, the oesophagus is too short and the stretch sphincter remains patent for abnormal periods of time. 6. When the stretch sphincter is surgically retightened by transposition of the oesophageal cardia into the abdomen, a proper function of the regulatory lower oesophageal stretch sphincter can be restored. 7.-9. All fundoplication procedures place the lower oesophageal sphincter under stretch, squeeze and create an oesophageal wrap out of gastric fundus tissue. X-ray images confirm in many patients undergoing fundoplication that the anatomic stretch sphincter already starts above and proximally to the plicated cuff. PMID- 22933013 TI - Supramolecular squares of dirhodium(II) tetracarboxylate: combining carboxylate exchange and metal-ligand coordination for self-assembly. AB - Square self-assemblies are obtained from dirhodium(II) tetracarboxylate complexes using an isonicotinate-type ligand to act as an equatorial ligand to one dirhodium unit and an axial ligand to another. It is shown that the supramolecular squares are formed selectively out of a number of possible compounds in the dynamic carboxylate exchange library. PMID- 22933014 TI - Astrocyte TNFR2 is required for CXCL12-mediated regulation of oligodendrocyte progenitor proliferation and differentiation within the adult CNS. AB - Multiple sclerosis (MS) is characterized by episodes of inflammatory demyelination with progressive failure of remyelination. Prior studies using murine models of MS indicate that remyelination within the adult central nervous system (CNS) requires the expression and activity of TNFR2 and CXCR4 by oligodendrocyte progenitor cells (OPCs), promoting their proliferation and differentiation into mature oligodendrocytes. Here, we extend these studies by examining the role of TNFR2 in the expression of the CXCR4 ligand, CXCL12, within the corpus callosum (CC) during cuprizone (CPZ) intoxication and by demonstrating that lentiviral-mediated gene delivery of CXCL12 to the demyelinated CC improves OPC proliferation and myelin expression during remyelination. Activated astrocytes and microglia express both TNFR1 and TNFR2 within the demyelinated CC. However, CPZ intoxicated TNFR2-/- mice exhibit loss of up-regulation of CXCL12 in astrocytes with concomitant decreases in numbers of CXCR4+ NG2+ OPCs within the CC. While CXCR4 antagonism does not affect OPC migration from subventricular zones into the CC, it decreases their proliferation and differentiation within the CC. Stereotactic delivery of lentivirus expressing CXCL12 protein into the CC of acutely demyelinated TNFR2-/- mice increases OPC proliferation and expression of myelin. In contrast, chronically demyelinated wild-type mice, which exhibit significant loss of astrocytes and OPCs, are unable to be rescued via CXCL12 lentivirus alone but instead required engraftment of CXCL12-expressing astrocytes for increased myelin expression. Our results show that TNFR2 activation induces CXCL12 expression in the demyelinated CC via autocrine signaling specifically within astrocytes, which promotes OPC proliferation and differentiation. In addition, gene delivery of critical pro-myelinating proteins might be a feasible approach for the treatment of remyelination failure in MS. PMID- 22933015 TI - Triggered in situ drug supersaturation and hydrophilic matrix self-assembly. AB - PURPOSE: To understand in situ drug thermodynamic activity when embedded in a supramolecular structured hydrophilic matrix that simultaneously self-assembled during drug supersaturation. METHODS: A propylene glycol (PG)/water, hydroxypropyl methyl cellulose matrix containing ethanol was used to support diclofenac supersaturation. Phase behaviour, thermodynamics and drug transport were assessed through the determination of evaporation kinetics, supersaturation kinetics and transmembrane penetration. RESULTS: Initial ethanol evaporation from the drug loaded matrix (2.9 +/- 0.4 mg.min(-1).cm(-2)) was comparable to that of the pure solvent (ca. 3 mg.min(-1).cm(-2)). When 25% w/w of the total ethanol from the applied phase was lost (ethanol/water/PG molar ratio of 7:5:1.2), an inflection point in the evaporation profile and a sudden decrease in drug solubility demonstrated that a defined supramolecular structure was formed. The 55-fold decrease in drug solubility observed over the subsequent 8 h drove in situ supersaturation, the rate of which was a function of the drug load in the matrix (y = 0.0078x, R(2) < 0.99). CONCLUSION: The self-assembling supramolecular matrix prevented drug re-crystallisation for >24 h, but did not hinder mobility and this allowed the thermodynamic activity of the drug to be directly translated into highly efficient transmembrane penetration. PMID- 22933016 TI - Novel assessment of the sternoclavicular joint with computed tomography for planning interventional approach. AB - OBJECTIVES: To describe the plane of the sternoclavicular joint (SCJ) to aid planning of instrument orientation during invasive procedures. METHODS: Computed tomography (CT) images of 80 consecutive patients aged 25 to 40 years with appropriate chest imaging series were retrospectively reviewed. Patients with a previous median sternotomy, fused manubriosternal joint or fracture were excluded. The medial clavicle was found to vary greatly in its anatomy such that a representative morphology could not be described. The manubrium was found to be a more consistent structure and was examined in more detail. The angulation of the SCJ was measured in three orthogonal planes using CT multiplanar reformats. Each SCJ (160 in total) was assessed for transverse, coronal, and sagittal angulation of the central manubrial articular surface in respect to the long axis of the manubrial body using a newly devised measurement technique. RESULTS: The mean angles (+/- standard deviation) of the SCJs were 62.4 +/- 9.7 degrees to the transverse plane, 149.3 +/- 7.3 degrees to the coronal plane and 69.8 +/- 7.5 to the sagittal plane. There was no significant difference in transverse (p = 0.41) or sagittal (p = 0.60) angulation between sides, however there was a significant difference for the coronal plane (p = 0.04). No significant differences were noted between the sexes in any plane. CONCLUSIONS: Increasing use of invasive diagnostic and treatment techniques dictate that a safe approach to the joint should be used to reduce the risk of iatrogenic injury. This study adds to existing knowledge of SCJ anatomy and its variation within the population. Understanding this can minimize the risk to adjacent structures when approaching the SCJ with injection needles or arthroscopic instruments. PMID- 22933017 TI - Publication rate of scientific abstracts presented at ESSR 2008 and 2009. AB - OBJECTIVE: During the ESSR 2011 Research Committee Meeting, the duration of intellectual property of a research proposal was discussed. A duration of 2 years from idea to publication was suggested. The purpose of this study was to evaluate how many ESSR 2008 and 2009 scientific abstracts were PubMed cited in print within 2 years of the congress. MATERIALS AND METHODS: In September of 2011, two researchers independently performed a literature search using author names and title words of all ESSR 2008 and 2009 scientific abstracts published in Skeletal Radiology. In case of similarity or doubt, a senior reviewer made the final decision. Publication details were recorded and analyses were performed in Microsoft Excel (Microsoft, Redmond, WA, USA). RESULTS: Until September of 2011, 62 out of 137 ESSR 2008 and 2009 scientific abstracts (45%) were PubMed cited in print [2008: 34/73 (47%); 2009: 28/64 (44%)]. 54 out of 137 abstracts (39%) were PubMed cited in print within 2 years of the congress [2008: 30/73(41%); 2009: 23/64 (36%)] including eight out of 137 abstracts (6%), which were already published before the congress [2008: 4/73 (5%); 2009: 4/64 (6%)]. The top-ranking journal in absolute numbers of publications was Skeletal Radiology. The top publishing country was the United Kingdom. Study sample size and first author position between abstract and publication did not change in the majority. CONCLUSIONS: Thirty-nine percent of ESSR 2008 and 2009 scientific abstracts were published within 2 years of the congress including 6% that were already PubMed cited in print before the congress. PMID- 22933018 TI - Direct measurement of nitrous oxide kinetics. AB - BACKGROUND: Using conscious subjects, measurement of the effects of low concentrations of anaesthetic agents can allow the dynamics of onset and offset of the agent to be measured and kinetic values estimated. However, the tests have to be rapid and preferably assess cerebral function. METHODS: We used a short version of the digit symbol substitution test (DSST) that allowed frequent measurement of the impairment caused by nitrous oxide. We compared 10 min of onset and offset of breathing 5% and 30% nitrous oxide in 30% oxygen, compared with 30% oxygen only. End-tidal nitrous oxide concentrations were used to predict the concentration in a central compartment, according to a range of T(1/2) values chosen to be consistent with possible cerebral blood flow values. RESULTS: We studied 19 volunteers and estimated a mean response. Only 30% nitrous oxide decreased the DSST. When DSST scores were related to the values in the predicted central compartment, the best dose-effect relationship was found when the T(1/2) was 37 s, consistent with a regional blood flow of about 120 ml 100 g(-1) min( 1). CONCLUSIONS: The onset of nitrous oxide effect on DSST is rapid, consistent with the perfusion of metabolically active cerebral cortical tissues. The rate of onset is greater than previous measures based on a motor test which involved the function of subcortical structures in the central nervous system. PMID- 22933019 TI - Antibody levels correlate with creatine kinase levels and strength in anti-3 hydroxy-3-methylglutaryl-coenzyme A reductase-associated autoimmune myopathy. AB - OBJECTIVE: Autoantibodies recognizing 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) are found in patients with statin-associated immune-mediated necrotizing myopathy and, less commonly, in statin-unexposed patients with autoimmune myopathy. The main objective of this study was to define the association of anti-HMGCR antibody levels with disease activity. METHODS: Anti HMGCR levels, creatine kinase (CK) levels, and strength were assessed in anti HMGCR-positive patients. Associations of antibody level with CK level and strength at visit 1 were analyzed in 55 patients, 40 of whom were exposed to statins. In 12 statin-exposed and 5 statin-unexposed patients with serum from 5 serial visits, the evolution of antibody levels, CK levels, and strength was investigated. RESULTS: Antibody levels were associated with CK levels (P < 0.001), arm strength (P < 0.05), and leg strength (P < 0.05) at visit 1, but these associations were only significant among statin-exposed patients in stratified analyses. With immunosuppressive treatment over 26.2 +/- 12.6 months (mean +/- SD), antibody levels declined (P < 0.05) and arm abduction strength improved (P < 0.05) in the 17 patients followed up longitudinally. The separate analysis showed that statin-exposed patients developed decreased antibody levels (P < 0.01), decreased CK levels (P < 0.001), improved arm strength (P < 0.05), and improved hip flexion strength (P < 0.05) with treatment. Anti-HMGCR antibody levels did not normalize in any patient. CONCLUSION: In the entire cohort, initial anti-HMGCR levels correlated with indicators of disease activity; with immunosuppressive treatment, antibody levels declined and arm strength improved. Statin-exposed patients had significant improvements in CK levels and strength whereas statin-unexposed patients did not, suggesting a phenotypic difference between statin-exposed and statin-unexposed anti-HMGCR-positive patients. PMID- 22933020 TI - Stanniocalcin-1 in the subfornical organ inhibits the dipsogenic response to angiotensin II. AB - Recently, receptors for the calcium-regulating glycoprotein hormone stanniocalcin 1 (STC-1) have been found within subfornical organ (SFO), a central structure involved in the regulation of electrolyte and body fluid homeostasis. However, whether SFO neurons produce STC-1 and how STC-1 may function in fluid homeostasis are not known. Two series of experiments were done in Sprague-Dawley rats to investigate whether STC-1 is expressed within SFO and whether it exerts an effect on water intake. In the first series, experiments were done to determine whether STC-1 was expressed within cells in SFO using immunohistochemistry, and whether protein and gene expression for STC-1 existed in SFO using Western blot and quantitative RT-PCR, respectively. Cells containing STC-1 immunoreactivity were found throughout the rostrocaudal extent of SFO. STC-1 protein expression within SFO was confirmed with Western blot, and SFO was also found to express STC-1 mRNA. In the second series, microinjections (200 nl) of STC-1, ANG II, a combination of the two or the vehicle were made into SFO in conscious, unrestrained rats. Water intake was measured at 0700 for a 1-h period after each injection in animals. Microinjections of STC-1 (17.6 or 176 nM) alone had no effect on water intake compared with controls. However, STC-1 not only attenuated the drinking responses to ANG II for about 30 min, but also decreased the total water intake over the 1-h period. These data suggest that STC-1 within the SFO may act in a paracrine/autocrine manner to modulate the neuronal responses to blood-borne ANG II. These findings also provide the first direct evidence of a physiological role for STC-1 in central regulation of body fluid homeostasis. PMID- 22933021 TI - Apolipoprotein E does not cross the blood-cerebrospinal fluid barrier, as revealed by an improved technique for sampling CSF from mice. AB - Apolipoprotein E (apoE) is a 34-kDa glycoprotein that is important in lipoprotein metabolism both peripherally and centrally. Because it is primarily produced in the liver, apoE observed in the brain or cerebrospinal fluid (CSF) could have originated in the periphery; i.e., circulating apoE may cross the blood-brain barrier (BBB) and/or enter CSF and be taken up by brain cells. To determine whether this occurs, a second-generation adenovirus encoding human apoE3 was administered intravenously (iv) to C57BL/6J mice, and the detection of human apoE3 in the CSF was used as a surrogate measure of central availability of this protein utilizing an improved method for sampling CSF from mice. This improved technique collects mouse CSF samples with a 92% success rate and consistently yields relatively large volumes of CSF with a very low rate of blood contamination, as determined by molecular assessment of apolipoprotein B, a plasma-derived protein that is absent in the central nervous system. Through this improved method, we demonstrated that in mice receiving the administered apoE3 adenovirus, human apoE3 was expressed at high levels in the liver, leading to high levels of human apoE3 in mouse plasma. In contrast, human apoE3 levels in the CSF, as assessed by a sensitive ELISA, were essentially undetectable in human apoE3 adenovirus-treated mice, and comparable to levels in LacZ adenovirus treated control mice. These data indicate that apoE in the CSF cannot be derived from the plasma pool and, therefore, must be synthesized locally in the brain. PMID- 22933022 TI - A physiological increase in insulin suppresses gluconeogenic gene activation in fetal sheep with sustained hypoglycemia. AB - Reduced maternal glucose supply to the fetus and resulting fetal hypoglycemia and hypoinsulinemia activate fetal glucose production as a means to maintain cellular glucose uptake. However, this early activation of fetal glucose production may be accompanied by hepatic insulin resistance. We tested the capacity of a physiological increase in insulin to suppress fetal hepatic gluconeogenic gene activation following sustained hypoglycemia to determine whether hepatic insulin sensitivity is maintained. Control fetuses (CON), hypoglycemic fetuses induced by maternal insulin infusion for 8 wk (HG), and 8 wk HG fetuses that received an isoglycemic insulin infusion for the final 7 days (HG+INS) were studied. Glucose and insulin concentrations were 60% lower in HG compared with CON fetuses. Insulin was 50% higher in HG+INS compared with CON and four-fold higher compared with HG fetuses. Expression of the hepatic gluconeogenic genes, PCK1, G6PC, FBP1, GLUT2, and PGC1A was increased in the HG and reduced in the HG+INS liver. Expression of the insulin-regulated glycolytic and lipogenic genes, PFKL and FAS, was increased in the HG+INS liver. Total FOXO1 protein expression, a gluconeogenic activator, was 60% higher in the HG liver. Despite low glucose, insulin, and IGF1 concentrations, phosphorylation of AKT and ERK was higher in the HG liver. Thus, a physiological increase in fetal insulin is sufficient for suppression of gluconeogenic genes and activation of glycolytic and lipogenic genes in the HG fetal liver. These results demonstrate that fetuses exposed to sustained hypoglycemia have maintained hepatic insulin action in contrast to fetuses exposed to placental insufficiency. PMID- 22933023 TI - Thigh oxygen uptake at the onset of intense exercise is not affected by a reduction in oxygen delivery caused by hypoxia. AB - In response to hypoxic breathing most studies report slower pulmonary oxygen uptake (Vo2) kinetics at the onset of exercise, but it is not known if this relates to an actual slowing of the Vo2 in the active muscles(.) The aim of the present study was to evaluate whether thigh Vo2 is slowed at the onset of intense exercise during acute exposure to hypoxia. Six healthy male subjects (25.8 +/- 1.4 yr, 79.8 +/- 4.0 kg, means +/- SE) performed intense (100 +/- 6 watts) two legged knee-extensor exercise for 2 min in normoxia (NOR) and hypoxia [fractional inspired oxygen concentration (Fi(O2)) = 0.13; HYP]. Thigh Vo2 was measured by frequent arterial and venous blood sampling and blood flow measurements. In arterial blood, oxygen content was reduced (P < 0.05) from 191 +/- 5 ml O2/l in NOR to 180 +/- 5 ml O2/l in HYP, and oxygen pressure was reduced (P < 0.001) from 111 +/- 4 mmHg in NOR to 63 +/- 4 mmHg in HYP. Thigh blood flow was the same in NOR and HYP, and thigh oxygen delivery was consequently reduced (P < 0.05) in HYP, but femoral arterial-venous oxygen difference and thigh Vo(2) were similar in NOR and HYP. In addition, muscle lactate release was the same in NOR and HYP, and muscle lactate accumulation during the first 25 s of exercise determined from muscle biopsy sampling was also similar (0.35 +/- 0.07 and 0.36 +/- 0.07 mmol.kg dry wt(-1).s(-1) in NOR and HYP). Thus the increase in thigh Vo2 was not attenuated at the onset of intense knee-extensor exercise despite a reduction in oxygen delivery and pressure. PMID- 22933024 TI - Evidence for an interaction of neuronostatin with the orphan G protein-coupled receptor, GPR107. AB - Neuronostatin, derived from the somatostatin preprohormone, is a recently described peptide that is produced by several tissues involved in cardiovascular regulation and metabolism, including the hypothalamus. Injection of neuronostatin into the lateral cerebroventricle led to a dose-related increase in mean arterial pressure (MAP) in rats. Any attempt to inhibit the production of neuronostatin would alter somatostatin production as well, making determination of the physiological relevance of the peptide's pharmacologic effects by compromise of production approaches impossible. Therefore, we employed an alternative approach to identify and compromise the production of the neuronostatin receptor. Because neuronostatin was shown to signal via a PKA dependent mechanism, we hypothesized that the neuronostatin receptor was a G protein-coupled receptor (GPCR), in particular, one of the orphan GPCRs for which the ligand is unknown. Therefore, we screened neuronostatin-responsive tissues, including hypothalamus, heart, pancreatic alpha-cells, and the gastric tumor cell line KATOIII, for expression of orphan GPCRs. Four orphan GPCRs were expressed by all cell types, including GPR56 and GPR107. Knockdown of GPR107, but not GPR56 or GPR146, led to a loss of responsiveness to neuronostatin by KATOIII cells. Rats injected with siRNA directed against GPR107 (2 MUg/day for 2 days) into the lateral cerebroventricle did not exhibit an increase in MAP in response to neuronostatin treatment. Rats with compromised GPR107 expression also displayed blunted reactivity in a baroreflex sensitivity test, indicating that GPR107 and neuronostatin may be important regulators of cardiovascular function. Thus, GPR107 is a promising candidate receptor for neuronostatin, and neuronostatin, interacting with GPR107, may play an important role in the central control of cardiovascular function. PMID- 22933025 TI - IGF-I measurement across blood, interstitial fluid, and muscle biocompartments following explosive, high-power exercise. AB - Insulin-like growth factor-I (IGF-I) resides across different biocompartments [blood, interstitial fluid (ISF), and muscle]. Whether circulating IGF-I responses to exercise reflect local events remains uncertain. We measured the IGF I response to plyometric exercise across blood, ISF, and muscle biopsy from the vastus lateralis. Twenty volunteers (8 men, 12 women, 22 +/- 1 yr) performed 10 sets of 10 plyometric jump repetitions at a 40% 1-repetition maximum. Blood, ISF, and muscle samples were taken pre- and postexercise. Circulating IGF-I increased postexercise: total IGF-I (preexercise = 546 +/- 42, midexercise = 585 +/- 43, postexercise = 597 +/- 45, +30 = 557 +/- 42, +60 = 536 +/- 40, +120 = 567 +/- 42 ng/ml; midexercise, postexercise, and +120 greater than preexercise, P < 0.05); Free IGF-I (preexercise = 0.83 +/- 0.09, midexercise = 0.78 +/- 0.10, postexercise = 0.79 +/- 0.11, +30 = 0.93 +/- 0.10, +60 = 0.88 +/- 0.10, + 120 = 0.91 +/- 0.11 ng/ml; +30 greater than all other preceding time points, P < 0.05). No exercise-induced changes were observed for ISF IGF-I (preexercise = 2.35 +/- 0.29, postexercise = 2.46 +/- 0.35 ng/ml). No changes were observed for skeletal muscle IGF-I protein, although IGF-I mRNA content increased ~40% postexercise. The increase in circulating total and free IGF-I was not correlated with increases in ISF IGF-I or muscle IGF-I protein content. Our data indicate that exercise-induced increases in circulating IGF-I are not reflective of local IGF-I signaling. PMID- 22933026 TI - Remodeling of intrinsic cardiac neurons: effects of beta-adrenergic receptor blockade in guinea pig models of chronic heart disease. AB - Chronic heart disease induces remodeling of cardiac tissue and associated neuronal components. Treatment of chronic heart disease often involves pharmacological blockade of adrenergic receptors. This study examined the specific changes in neuronal sensitivity of guinea pig intrinsic cardiac neurons to autonomic modulators in animals with chronic cardiac disease, in the presence or absence of adrenergic blockage. Myocardial infarction (MI) was produced by ligature of the coronary artery and associated vein on the dorsal surface of the heart. Pressure overload (PO) was induced by a banding of the descending dorsal aorta (~20% constriction). Animals were allowed to recover for 2 wk and then implanted with an osmotic pump (Alzet) containing either timolol (2 mg.kg( 1).day(-1)) or vehicle, for a total of 6-7 wk of drug treatment. At termination, intracellular recordings from individual neurons in whole mounts of the cardiac plexus were used to assess changes in physiological responses. Timolol treatment did not inhibit the increased sensitivity to norepinephrine seen in both MI and PO animals, but it did inhibit the stimulatory effects of angiotensin II on the norepinephrine-induced increases in neuronal excitability. Timolol treatment also inhibited the increase in synaptically evoked action potentials observed in PO animals with stimulation of fiber tract bundles. These results demonstrate that beta-adrenergic blockade can inhibit specific aspects of remodeling within the intrinsic cardiac plexus. In addition, this effect was preferentially observed with active cardiac disease states, indicating that the beta-receptors were more influential on remodeling during dynamic disease progression. PMID- 22933027 TI - The Piper Fatigue Scale-12 (PFS-12): psychometric findings and item reduction in a cohort of breast cancer survivors. AB - Brief, valid measures of fatigue, a prevalent and distressing cancer symptom, are needed for use in research. This study's primary aim was to create a shortened version of the revised Piper Fatigue Scale (PFS-R) based on data from a diverse cohort of breast cancer survivors. A secondary aim was to determine whether the PFS captured multiple distinct aspects of fatigue (a multidimensional model) or a single overall fatigue factor (a unidimensional model). Breast cancer survivors (n = 799; stages in situ through IIIa; ages 29-86 years) were recruited through three SEER registries (New Mexico, Western Washington, and Los Angeles, CA) as part of the Health, Eating, Activity, and Lifestyle (HEAL) study. Fatigue was measured approximately 3 years post-diagnosis using the 22-item PFS-R that has four subscales (Behavior, Affect, Sensory, and Cognition). Confirmatory factor analysis was used to compare unidimensional and multidimensional models. Six criteria were used to make item selections to shorten the PFS-R: scale's content validity, items' relationship with fatigue, content redundancy, differential item functioning by race and/or education, scale reliability, and literacy demand. Factor analyses supported the original 4-factor structure. There was also evidence from the bi-factor model for a dominant underlying fatigue factor. Six items tested positive for differential item functioning between African-American and Caucasian survivors. Four additional items either showed poor association, local dependence, or content validity concerns. After removing these 10 items, the reliability of the PFS-12 subscales ranged from 0.87 to 0.89, compared to 0.90-0.94 prior to item removal. The newly developed PFS-12 can be used to assess fatigue in African-American and Caucasian breast cancer survivors and reduces response burden without compromising reliability or validity. This is the first study to determine PFS literacy demand and to compare PFS-R responses in African Americans and Caucasian breast cancer survivors. Further testing in diverse populations is warranted. PMID- 22933028 TI - Improving size, lymph node metastatic rate, breast conservation, and mortality of invasive breast cancer in Rhode Island women, a well-screened population. AB - The beneficial impact of screening mammography on breast cancer outcome continues to be debated as demonstrated by guidelines published by the United States Preventive Services Task Force. A previous report from Rhode Island, which has a very high rate of mammographic screening, demonstrated significant improvements in invasive breast cancer presentation and mortality through 2001. This report updates data through 2008 to determine whether previous favorable trends continued. Rhode Island Cancer Registry data regarding invasive breast cancer presentation and mortality in 17,522 female residents diagnosed between 1987 and 2008, inclusive, were analyzed for demographic and pathological factors. Data were analyzed by four time periods: 1987-1992, 1993-1998, 1999-2003, and 2004 2008 and overall. Statistically significant improvements occurred over the four successive time periods, in mean cancer size (23.7, 20.9, 19.6, and 19.3 mm, p < 0.0001), pathologic grade (Grade I: 12, 15, 19, and 17 %; Grade III 57, 41, 36, and 35 %, p < 0.0001), breast conserving surgery (38, 56, 67, and 71 %, p < 0.0001) and mortality (37.3, 31.4, 25.1, and 22.6 per 100,000/year, p < 0.0001). The results showed that high screening rates favorably impacted presentation of and mortality from invasive breast cancer in Rhode Island. From 1987 to 2008, there has been a 39 % decline in breast cancer mortality considering 5 year periods (37.3 vs. 22.6 deaths per 100,000) and 41 % comparing the period from 1990 to 2008, which may exceed the goal of 50 % mortality reduction by 2015 established by the American Cancer Society. PMID- 22933029 TI - Shared decision-making in breast cancer: discrepancy between the treatment efficacy required by patients and by physicians. AB - Several factors can influence individual perceptions of the expected benefit of recommended adjuvant treatment for breast cancer. This study investigated differences between patients and physicians with regard to the required efficacy of treatment and the factors influencing patients' and physicians' willingness to accept different therapeutic options. A total of 9,000 questionnaires were distributed to patients with breast cancer, and 6,938 questionnaires were distributed to physicians treating breast cancer patients. The patients were asked for personal information and about their medical history and experiences during treatment. The physicians were asked about personal information and their specialty and work environment. The treatment efficacy required by the two groups was assessed using six virtual cases of breast cancer and the treatment regimens proposed, with specific benefits and side effects. A total of 2,155 patients and 527 physicians responded to the questionnaire (return rates of 23.9 and 7.6 %). Significantly different ratings between patients and physicians with regard to the expected benefit of certain treatment options were observed. The differences were noted not only for chemotherapy but also for antihormonal and antibody treatments. Whereas physicians had a quite realistic view of the expected treatment benefits, the patients' expectations were varied. Approximately one fifth of the patients were willing to accept treatment regimens even with marginal anticipated benefits, whereas one-third required unrealistic treatment benefits. Several influencing factors that were significantly associated with the quality rating of treatment regimens in the groups of breast cancer patients and physicians were also identified. In contrast to physicians, many breast cancer patients required treatment benefits beyond what was realistically possible, although a large group of patients were also satisfied with minimal benefits. Individual factors were also identified in both groups that significantly influence thresholds for accepting adjuvant treatment, independently of risk estimates and therapy guidelines. PMID- 22933030 TI - Metformin in early breast cancer: a prospective window of opportunity neoadjuvant study. AB - Metformin may exert anti-cancer effects through indirect (insulin-mediated) or direct (insulin-independent) mechanisms. We report results of a neoadjuvant "window of opportunity" study of metformin in women with operable breast cancer. Newly diagnosed, untreated, non-diabetic breast cancer patients received metformin 500 mg tid after diagnostic core biopsy until definitive surgery. Clinical (weight, symptoms, and quality of life) and blood [fasting serum insulin, glucose, homeostasis model assessment (HOMA), C-reactive protein (CRP), and leptin] attributes were compared pre- and post-metformin as were terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) and Ki67 scores (our primary endpoint) in tumor tissue. Thirty-nine patients completed the study. Mean age was 51 years, and metformin was administered for a median of 18 days (range 13-40) up to the evening prior to surgery. 51 % had T1 cancers, 38 % had positive nodes, 85 % had ER and/or PgR positive tumors, and 13 % had HER2 overexpressing or amplified tumors. Mild, self-limiting nausea, diarrhea, anorexia, and abdominal bloating were present in 50, 50, 41, and 32 % of patients, respectively, but no significant decreases were seen on the EORTC30-QLQ function scales. Body mass index (BMI) (-0.5 kg/m(2), p < 0.0001), weight (-1.2 kg, p < 0.0001), and HOMA (-0.21, p = 0.047) decreased significantly while non significant decreases were seen in insulin (-4.7 pmol/L, p = 0.07), leptin (-1.3 ng/mL, p = 0.15) and CRP (-0.2 mg/L, p = 0.35). Ki67 staining in invasive tumor tissue decreased (from 36.5 to 33.5 %, p = 0.016) and TUNEL staining increased (from 0.56 to 1.05, p = 0.004). Short-term preoperative metformin was well tolerated and resulted in clinical and cellular changes consistent with beneficial anti-cancer effects; evaluation of the clinical relevance of these findings in adequately powered clinical trials using clinical endpoints such as survival is needed. PMID- 22933032 TI - [Are non-cancer-related deaths from suicide, cardiovascular disease, and pneumonia in patients with oral cavity and oropharyngeal squamous carcinoma avoidable?]. PMID- 22933031 TI - Combining advanced radiotherapy technologies to maximize safety and tumor control probability in stage III non-small cell lung cancer. AB - BACKGROUND: The goal of the current study was to investigate the tumor control probability (TCP) of advanced radiotherapy technologies for stage III non-small cell lung cancer (NSCLC) and to evaluate potential interplay effects between their applications. MATERIALS AND METHODS: Three-dimensional conformal radiotherapy (3D-CRT) with conventionally fractionated doses of 66 Gy served as reference for 13 patients with stage III NSCLC. Isotoxic dose escalation relative to the corresponding 3D-CRT plans was performed for three technologies and their combinations: intensity-modulated radiotherapy (IMRT), IMRT with a simultaneous integrated boost (IMRT-SIB) of 10% to the gross tumor volume (GTV), and adaptive re-planning twice during the treatment course (ART). All analyses were based on accumulated dose distributions using deformable image registration of CT images, which were acquired weekly during the treatment course. RESULTS: IMRT reduced the mean lung dose (MLD) by 5.6% +/- 3.8% compared to 3D-CRT. ART resulted in lung sparing of 7.9% +/- 4.8% and 9.2% +/- 3.9% in 3D-CRT and IMRT planning, respectively. IMRT and ART escalated the irradiation dose by 6.6% +/- 3.2% and 8.8% +/- 6.3%, respectively, which was not statistically different. For the 7 patients with the largest GTVs, IMRT-SIB was superior to IMRT and ART with dose escalation of 11.9% +/- 3.7%. The combination of ART, IMRT, and SIB achieved maximum dose escalation in all 13 patients by 17.1% +/- 5.4% on average, which increased TCP from 19.9% +/- 7.0 to 37.1% +/- 10.1%. Adaptive re-planning was required to continuously conform the escalated and hypofractionated SIB doses to the shrinking tumor. CONCLUSION: Combining advanced radiotherapy technologies is considered as a safe and effective strategy to maximize local tumor control probability in stage III NSCLC. PMID- 22933033 TI - Quality of life after intensity-modulated radiotherapy for prostate cancer with a hydrogel spacer. Matched-pair analysis. AB - BACKGROUND: Hydrogel spacer is an innovative method to protect the rectal wall during prostate cancer radiotherapy. Clinical effects are not well known. METHODS: Patients have been surveyed before, at the last day, and 2-3 months after radiotherapy using a validated questionnaire (Expanded Prostate Cancer Index Composite). Median dose to the prostate in the spacer subgroup (SP) was 78 Gy in 2 Gy fractions. The results were independently compared with two matched pair subgroups (treated conventionally without spacer): 3D conformal 70.2 Gy in 1.8 Gy fractions (3DCRT) and intensity-modulated radiotherapy (IMRT) 76 Gy in 2 Gy fractions. There were 28 patients in each of the three groups. RESULTS: Baseline mean bowel bother scores were 96 points in all subgroups. Similar mean changes (SP 16, 3DCRT 14, IMRT 17 points) were observed at the end of radiotherapy. The smallest difference resulted in the spacer subgroup 2-3 months after radiotherapy (SP 2, 3DCRT 8, IMRT 6 points). Bowel bother scores were only significantly different in comparison to baseline levels in the spacer subgroup. The percentage of patients reporting moderate/big bother with specific symptoms did not increase for any item (urgency, frequency, diarrhoea, incontinence, bloody stools, pain). CONCLUSION: Moderate bowel quality-of-life changes can be expected during radiotherapy irrespective of spacer application or total dose. Advantages with a spacer can be expected a few weeks after treatment. PMID- 22933035 TI - Papillary cystadenoma of the lower lip exhibiting ciliated pseudostratified columnar epithelium: report of a bizarre case and review of the literature. AB - BACKGROUND: Salivary gland tumors are uncommon and constitute 2-6.5 % of all head and neck neoplasms. Tumors of minor salivary gland origin account for less than 25 % of all salivary gland neoplasms. Papillary cystadenoma of salivary glands is a rare benign epithelial neoplasm characterized by multicystic growth in which the epithelium exhibits adenomatous proliferation. Papillary cystadenoma of minor salivary glands most frequently involves the lip, buccal mucosa, and palate. This tumor typically presents as a slow-growing, painless mass, usually with diameter of less than 1 cm and clinical resemblance to a mucocele. Although most papillary cystadenomas are predominantly of one cell type, a regional variability may be present. CASE REPORT: We present a case of papillary cystadenoma of the minor salivary glands in a 58-year-old patient exhibiting an upper respiratory tract epithelium, a profoundly atypical benign tumor. DISCUSSION: This type of minor salivary gland tumor epithelium in the lower lip may be the result of a metaplastic process or simply another neoplastic manifestation of papillary cystadenoma. As far as the differential diagnosis of this entity is concerned, it is important to distinguish it from papillary cystadenoma lymphomatosum (Warthin's tumor), low-grade mucoepidermoid carcinoma, the papillary-cystic variant of acinic cell carcinoma, and cystadenocarcinoma Recognition of this lesion is important for the clinician since the differential diagnosis includes lesions with similar clinical appearance and infiltrative behavior. PMID- 22933036 TI - The use of Le Fort I Approach in the resection of an extensive ossifying fibroma. AB - INTRODUCTION: Ossifying fibroma (OF) is a well-defined benign neoplasm characterized by slow growth and predilection for the posterior mandible site, usually treated by conservative surgical approaches. In this context, Le Fort I Approach (LFIA) has been increasingly used providing good visualization and an easy access to the lesion. It also allows removal of the lesion quickly. Although there are case reports using LFIA for the management of benign neoplasms, odontogenic cysts and tumors of the middle third of face, to our knowledge, only one article describes the use of surgical LFIA for OF of the maxilla. Thus, the objective of this study was to report the second paper on the use of horizontal osteotomy of the maxilla in the resection of an extensive OF and conduct a brief literature review on this surgical approach. CASE REPORT: The following case report describes a 33-year-old man who was diagnosed with OF. Oral examination showed a painless swelling of hard consistency, covered by normal mucosa in edentulous alveolar ridge of the maxillary posterior region of the right side. Tomographic slices revealed that the image with mixed density had a centrifugal growth, with expansion of the buccal and lingual cortical with an upper displacement of the maxillary sinus. The patient was admitted to the hospital for surgical resection of the lesion via LFIA. Satisfactory functional results were obtained after 18-month follow-up period. In addition, no recurrence or clinical complaints were noted. DISCUSSION: LFIA shall be considered as a feasible option when planning surgery for removal of extensive benign lesions located in midfacial region because it is a predictable technique and routinely performed by the oral and maxillo-facial surgeons. PMID- 22933037 TI - The role of 'soaking' in spiteful toxin production in Pseudomonas aeruginosa. AB - The ubiquitous production of antibacterial toxins, such as bacteriocins, is an ecologically significant class of interbacterial interactions that have primarily evolved through their indirect fitness benefits to the producer. Bacteria release bacteriocins into the environment at a cost to individual cell, but individual bacteriocin-producing cells are unlikely to gain any direct benefit from their own toxin; indeed, cell lysis is required in many species. There is a growing body of research describing the ecological conditions that can favour the evolution of bacteriocin production. However, an important aspect of many bacteriocins has yet to be investigated: the ability of bacteriocin-producing cells to neutralize toxin ('soaking') produced by other clonemates. By competing Pseudomonas aeruginosa bacteriocin-producing wild-type and 'non-soaking' strains against a bacteriocin-susceptible strain, we find that soaking markedly reduces the fitness of a bacteriocin-producing strain at both high and low frequencies. PMID- 22933038 TI - Spatial memory: are lizards really deficient? AB - In many animals, behaviours such as territoriality, mate guarding, navigation and food acquisition rely heavily on spatial memory abilities; this has been demonstrated in diverse taxa, from invertebrates to mammals. However, spatial memory ability in squamate reptiles has been seen as possible, at best, or non existent, at worst. Of the few previous studies testing for spatial memory in squamates, some have found no evidence of spatial memory while two studies have found evidence of spatial memory in snakes, but have been criticized based on methodological issues. We used the Barnes maze, a common paradigm to test spatial memory abilities in mammals, to test for spatial memory abilities in the side blotched lizard (Uta stansburiana). We found the existence of spatial memory in this species using this spatial task. Thus, our study supports the existence of spatial memory in this squamate reptile species and seeks to parsimoniously align this species with the diverse taxa that demonstrate spatial memory ability. PMID- 22933039 TI - The consequences of climate change at an avian influenza 'hotspot'. AB - Avian influenza viruses (AIVs) pose significant danger to human health. A key step in managing this threat is understanding the maintenance of AIVs in wild birds, their natural reservoir. Ruddy turnstones (Arenaria interpres) are an atypical bird species in this regard, annually experiencing high AIV prevalence in only one location-Delaware Bay, USA, during their spring migration. While there, they congregate on beaches, attracted by the super-abundance of horseshoe crab eggs. A relationship between ruddy turnstone and horseshoe crab (Limulus polyphemus) population sizes has been established, with a declining horseshoe crab population linked to a corresponding drop in ruddy turnstone population sizes. The effect of this interaction on AIV prevalence in ruddy turnstones has also been addressed. Here, we employ a transmission model to investigate how the interaction between these two species is likely to be altered by climate change. We explore the consequences of this modified interaction on both ruddy turnstone population size and AIV prevalence and show that, if climate change leads to a large enough mismatch in species phenology, AIV prevalence in ruddy turnstones will increase even as their population size decreases. PMID- 22933041 TI - A new water...Na+ coordination motif in an unexpected diatrizoic acid disodium salt crystal form. AB - The disodium salt of diatrizoic acid crystallises as a tetragonal channel hydrate structure. One of the incorporated water molecules is coordinated to three individual sodium cations in a unique geometry. PMID- 22933042 TI - Face age and sex modulate the other-race effect in face recognition. AB - Faces convey a variety of socially relevant cues that have been shown to affect recognition, such as age, sex, and race, but few studies have examined the interactive effect of these cues. White participants of two distinct age groups were presented with faces that differed in race, age, and sex in a face recognition paradigm. Replicating the other-race effect, young participants recognized young own-race faces better than young other-race faces. However, recognition performance did not differ across old faces of different races (Experiments 1, 2A). In addition, participants showed an other-age effect, recognizing White young faces better than White old faces. Sex affected recognition performance only when age was not varied (Experiment 2B). Overall, older participants showed a similar recognition pattern (Experiment 3) as young participants, displaying an other-race effect for young, but not old, faces. However, they recognized young and old White faces on a similar level. These findings indicate that face cues interact to affect recognition performance such that age and sex information reliably modulate the effect of race cues. These results extend accounts of face recognition that explain recognition biases (such as the other-race effect) as a function of dichotomous ingroup/outgroup categorization, in that outgroup characteristics are not simply additive but interactively determine recognition performance. PMID- 22933040 TI - Agrochemicals, alpha-synuclein, and Parkinson's disease. AB - Epidemiological, population-based case-control, and experimental studies at the molecular, cellular, and organism levels revealed that exposure to various environmental agents, including a number of structurally different agrochemicals, may contribute to the pathogenesis of Parkinson's disease (PD) and several other neurodegenerative disorders. The role of genetic predisposition in PD has also been increasingly acknowledged, driven by the identification of a number of disease-related genes [e.g., alpha-synuclein, parkin, DJ-1, ubiquitin C-terminal hydrolase isozyme L1 (UCH-L1), and nuclear receptor-related factor 1]. Therefore, the etiology of this multifactorial disease is likely to involve both genetic and environmental factors. Various neurotoxicants, including agrochemicals, have been shown to elevate the levels of alpha-synuclein expression in neurons and to promote aggregation of this protein in vivo. Many agrochemicals physically interact with alpha-synuclein and accelerate the fibrillation and aggregation rates of this protein in vitro. This review analyzes some of the aspects linking alpha-synuclein to PD, provides brief structural and functional descriptions of this important protein, and represents some data connecting exposure to agrochemicals with alpha-synuclein aggregation and PD pathogenesis. PMID- 22933043 TI - The influence of 8-prenylnaringenin on the activity of voltage-gated Kv1.3 potassium channels in human Jurkat T cells. AB - Using the whole-cell patch-clamp technique, we investigated the influence of 8 prenylnaringenin on the activity of the voltage-gated Kv1.3 potassium channels in the human leukemic T lymphocyte cell line Jurkat. 8-prenylnaringenin is a potent plant-derived phytoestrogen that has been found to inhibit cancer cell proliferation. The results show that it inhibited the Kv1.3 channels in a concentration-dependent manner. Complete inhibition occurred at concentrations higher than 10 MUM. The inhibitory effect of 8-prenylnaringenin was reversible. It was accompanied by a significant acceleration of channel inactivation without any pronounced change in the activation rate. Of the naringenin derivatives tested to date, 8-prenylnaringenin is the most potent inhibitor of the Kv1.3 channels. The potency of the inhibition may be due to the presence of a prenyl group in the molecule of this flavonoid. The inhibition of the Kv1.3 channels might be involved in the antiproliferative and pro-apoptotic effects of 8 prenylnaringenin that have been observed in cancer cell lines expressing these channels. PMID- 22933044 TI - Sulphamoylated estradiol analogue induces antiproliferative activity and apoptosis in breast cell lines. AB - Research into potential anticancer agents has shown that 2-methoxyestradiol exerts antiproliferative activity in vitro and in vivo in an estrogen receptor independent manner. Due to its limited biological accessibility and rapid metabolic degradation, several new analogues have been developed in recent years. This study investigated the in vitro effects of a novel in silicodesigned compound (C16) in an estrogen receptor-positive breast adenocarcinoma epithelial cell line (MCF-7), an estrogen receptor-negative breast adenocarcinoma epithelial cell line (MDA-MB-231) and a nontumorigenic breast cell line (MCF-12A). Light microscopy revealed decreased cell density, cells blocked in metaphase and the presence of apoptotic characteristics in all three cell lines after exposure to C16 for 24 h. Polarizationoptical transmitted light differential interference contrast revealed the presence of several rounded cells and decreased cell density. The xCELLigence real-time label-independent approach revealed that C16 exerted antiproliferative activity. Significant inhibition of cell growth was demonstrated after 24 h of exposure to 0.2 MUM C16 in all three cell lines. However, the non-tumorigenic MCF-12A cell line recovered extremely well after 48 h when compared to the tumorigenic cell lines. This indicates that C16 acts as an antiproliferative agent, possesses antimitotic activity and induces apoptosis in vitro. These features warrant further investigation. PMID- 22933046 TI - An N-heterocyclic carbene adduct of diatomic tin, :Sn=Sn:. AB - Reduction of an N-heterocyclic carbene (NHC) adduct of SnCl(2), viz. [(IPr)SnCl(2)] (IPr = :C{N(Dip)C(H)}(2); Dip = 2,6-diisopropylphenyl), with a magnesium(I) dimer, has afforded the first NHC complex of a row 5 element in its diatomic form, [(IPr)Sn=Sn(IPr)]; a computational analysis of the complex indicates that it comprises a singlet state, doubly bonded tin(0) fragment, :Sn=Sn:, datively bonded by two NHC ligands. PMID- 22933045 TI - Estrogen treatment for acromegaly. AB - Estrogens have been used in patients with acromegaly since the 1930-1940s, suppressing plasma IGF-1 levels and improving clinical signs and symptoms of acromegaly. Estrogens antagonize GH function at the post-receptor level, inhibiting GH signaling, thus decreasing GH-induced hepatic IGF-1 synthesis. We report our experience with four female patients with active acromegaly, naive to medical treatment or inadequately controlled by somatostatin receptor ligands (SRLs) or the GH-receptor antagonist. Adding estrogen treatment (contraceptive pills or transdermal estrogen patches) to their ongoing medical treatment, suppressed IGF-1 significantly in all patients, achieving hormonal remission in three of them. We review the available data on the use of estrogens and selective estrogen receptor modulators in acromegaly, and their mechanisms of action. Estrogens could be an alternative, inexpensive adjuvant treatment for females with active acromegaly, who are only partially responding to SRLs or to the GH receptor antagonist. PMID- 22933047 TI - Synthesis and pharmacological investigation of 5-substituted-3-methylsulfanyl-1H pyrazole-4-carboxylic acid ethyl esters as new analgesic and anti-inflammatory agents. AB - PURPOSE: To synthesize a new series of 5-substituted-3-methylsulfanyl-1H-pyrazole 4-carboxylic acid ethyl esters for their analgesic and anti-inflammatory activity. METHODS: The title compound synthesized by reacting the amino group of 5-amino-3-methylsulfanyl-1H-pyrazole-4-carboxylic acid ethyl ester with acid anhydrides, acid chlorides and phenyl dithiocarbamates. The synthesized compounds were characterized by IR, 1H-NMR and mass spectral data; the purity of the compounds was determined by elemental analysis. The title compounds were investigated for analgesic, anti-inflammatory and ulcerogenic behaviour. RESULTS: The compound 5-benzoylamino-3-methylsulfanyl-1-phenyl-1H-pyrazole-4-carboxylic acid ethyl ester (4c) emerged as the most active compound and exhibiting imperative analgesic and anti-inflammatory activities. Interestingly the test compounds showed only mild ulcerogenic potential when compared to indomethacin. CONCLUSION: The compound (4c) could serve as a lead molecule for further modification to obtain a clinically useful novel class of analgesic and anti inflammatory agents. PMID- 22933048 TI - Pharmacokinetics and bioequivalence of 2 tablet formulations of olanzapine in healthy Chinese volunteers: a randomized, open-label, single-dose study. AB - Olanzapine is a widely used agent for the treatment of schizophrenia.The aim of this study was to evaluate bioequivalence of two 10-mg tablet formulations of olanzapine following single oral dose in adult male volunteers.This was a randomized, single-dose, open-label, crossover bioequivalence study. Plasma samples were collected before dosing and at 0.5, 1.0, 1.5, 2.0, 3.0, 4.0, 5.0, 6.0, 8.0, 12.0, 24.0, 36.0, 48.0, 72.0, 96.0, 120.0 and 144.0 h after dosing. Plasma concentrations of olanzapine were determined by using a liquid chromatography-tandem mass spectrometric (LC-MS/MS) method. Statistical analysis of the pharmacokinetic parameters Cmax, AUC0-144, and AUC0-infinity was conducted to determine bioequivalence. Adverse events were monitored, recorded and evaluated by investigators throughout the study.24 healthy male Chinese volunteers between the ages of 18-40 years with a body mass index (BMI) between 19 and 24 kg/m2 were enrolled in the study. The mean (SD) Cmax, AUC0-144, and AUC0-infinity values after administration of the test and reference formulations, respectively, were as follows: 18.91 (5.320) vs. 18.44 (4.758) ng/mL, 582.9 (118.23) vs. 587.3 (127.12) ng/mL . h, and 615.4 (131.39) vs. 615.8 (137.45) ng/mL . h. The 90% CIs for the ratios of AUC0-144 and Cmax were 96.9% to 102.4% and 93.7% to 110.2%, respectively. The relative bioavailability of the test formulation to reference formulation was 100.1%. Both formulations were generally well tolerated and no serious AEs were reported in the study.The 90% CIs for the ratios of mean Cmax, AUC0-144, and AUC0-infinity met the regulatory criteria for bioequivalence. PMID- 22933049 TI - Bioequivalence of lamotrigine 50-mg tablets in healthy male volunteers: a randomized, single-dose, 2-period, 2-sequence crossover study. AB - OBEJCTIVE: To compare the bioavailability of two 50-mg lamotrigine dispersible tablet formulations (Epilepax(r), Ivax-TEVA Argentina Laboratories, Argentina, as a test formulation, and Lamictal(r), GlaxoSmithKline, UK, as a reference formulation) in 24 healthy male volunteers. MATERIAL AND METHODS: This study was a randomized, 2-period, 2-sequence crossover design that was open for subjects and investigators, but blind for the bioanalytical lab. Serum samples were obtained over a 120-h interval. A 9-day wash-out period was allowed between treatments. The concentrations of lamotrigine were analyzed by high-performance liquid chromatography followed by ultraviolet-visible detection. Lamotrigine time concentrations curves were obtained and the following pharmacokinetic parameters were calculated: AUC0-t, AUC0-inf and Cmax. Bioequivalence was declared if the 90% confidence interval (CI) of the mean test/reference ratios for AUC0-t, AUC0 inf and Cmax were within 80.00-125.00%. RESULTS: The geometric mean and respective 90% CI of test/reference percent ratios were 100.83% (92.53-107.88%) for AUC0-t, 99.91% (93.79-108.40%) for AUC0-inf, and 95.62% (90.91-100.57%) for Cmax. No serious adverse events were observed. 1 patient reported a mild rash following the administration of each formulation. CONCLUSION: This single dose study found that the test and reference products met the regulatory criteria for bioequivalence in this sample of fasting healthy volunteers. These results suggest that bioequivalence studies evaluating 50-mg doses of Lamotrigine are feasible and recommended, since such doses may minimize the risk of severe rash or Stevens-Johnson Syndrome. This study was registered at the Argentinean Clinical Trials National Registry (www.anmat.gov.ar), No 1666/2008. PMID- 22933050 TI - The faltering solid organ donor pool in the United States (2001-2010). AB - BACKGROUND: Organ shortage is the greatest challenge facing the field of organ transplantation today. Use of more organs of marginal quality has been advocated to address the shortage. METHOD: We examined the pattern of donation and organ use in the United States as shown in the Organ Procurement and Transplantation Network/United Network for Organ Sharing database of individuals who were consented for and progressed to organ donation between January 2001 and December 2010. RESULTS: There were 66,421 living donors and 73,359 deceased donors, including 67,583 (92.1%) identified as donation after brain death and 5,776 (7.9%) as donation after circulatory death (DCD). Comparing two periods, era 1 (01/2001-12/2005) and era 2 (01/2006-12/2010), the number of deceased donors increased by 20.3% from 33,300 to 40,059 while there was a trend for decreasing living donation. The DCD subgroup increased from 4.9 to 11.7% comparing the two eras. A significant increase in cardiovascular/cerebrovascular disease as a cause of death was also noted, from 38.1% in era 1 to 56.1% in era 2 (p<0.001), as was a corresponding decrease in the number of deaths due to head trauma (48.8 vs. 34.9%). The overall discard rate also increased from 13,411 (11.5%) in era 1 to 19,516 (13.7%) in era 2. This increase in discards was especially prominent in the DCD group [440 (20.9%) in era 1 vs. 2,089 (24.9%) in era 2]. CONCLUSIONS: We detect a significant change in pattern of organ donation and use in the last decade in the United States. The transplant community should consider every precaution to prevent the decay of organ quality and to improve the use of marginal organs. PMID- 22933051 TI - Surgical management by one-stage posterior transforaminal lumbar debridement, interbody fusion, and posterior instrumentation for lumbo-sacral tuberculosis in the aged. AB - PURPOSE: To evaluate the clinical study efficacy and feasibility of 17 aged patients with lumbo-sacral tuberculosis treated by one-stage posterior transforaminal lumbar debridement, interbody fusion, and posterior instrumentation. METHODS: 17 aged patients who suffered from lumbo-sacral tuberculosis were admitted into our hospital between March 2003 and October 2010. All of them were treated by one-stage posterior transforaminal lumbar debridement, interbody fusion, and posterior instrumentation. Then the clinical efficacy with statistical analysis was evaluated based on the materials on the lumbo-sacral angle, neurological status that was recorded by Frankel grade system, and erythrocyte sedimentation rate (ESR), which were collected at certain time. RESULTS: The average follow-up period was 47.5 +/- 17.1 months (17-71 months), In the 17 cases, no postoperative complications related to instrumentation occurred and neurologic function was improved in various degrees. The mean preoperative lumbo-sacral angle was 20.5 degrees +/- 1.7 degrees (range 18.0 degrees -23.0 degrees ). The lumbo-sacral angle became 29.1 degrees +/- 1.5 degrees (range 26.4 degrees -31.0 degrees ) postoperatively. The average pretreatment ESR was 57.4 +/- 16.8 mm/h (33-95 mm/h), which got normal (9.2 +/- 3.1 mm/h) within 3 months in all patients. All patients got bony fusion within 6 8 months after surgery. CONCLUSIONS: One-stage posterior transforaminal lumbar debridement, interbody fusion, and posterior instrumentation can be an effective treatment method for the treatment of lumbo-sacral tuberculosis in the aged patients. PMID- 22933052 TI - Cementless second-generation hydroxyapatite CaP-coated tibial component: an 8.7 year follow-up. AB - BACKGROUND: This is the first study that reports on the mid-term results of 81 patients suffering from arthritis of the knee, treated with a cementless second generation hydroxyapatite calcium phosphate (CaP)-coated tibial component. MATERIALS AND METHODS: Seventy-six knees with osteoarthritis were evaluated according to the Knee Society clinical, functional and radiological score, the Hospital for Special Surgery Rating System and the Patella Score. The clinical and radiological parameters were assessed preoperatively and after a mean follow up of 8.7 years. RESULTS: All the three score systems revealed excellent clinical outcomes after the follow-up period. The mean preoperative Knee Society clinical Score was 124.41 +/- 12.99 and the mean postoperative score was 187.07 +/- 14.59 at the time of the final consultation (p = 0.0008). The survival rate was 97.5 %. Radiolucency of <1 mm around the uncemented hydroxyapatite CaP-coated tibial component without accompanying pain symptoms was seen in fewer than 6 % of cases. In two cases, a medial cyst, also without other clinical symptoms, was observed beside the tip of the tibial fixation screw. CONCLUSION: These findings indicate that the uncemented second-generation hydroxyapatite CaP-coated tibial component performed well at mid-term follow-up, and provides sufficiently stable bone ingrowth fixation. PMID- 22933053 TI - Effect of metal surface characteristics on the adhesion performance of the integrated low-level energies method of adhesion. AB - We have previously proposed a new method of adhesion using the integrated low level energy sources heat, vibration, and pressure. This adhesion method can be used to attach biological tissue to a metal object. Effects of surface roughness and energy of the metal subject on adhesion performance were studied by using commercially pure titanium (cpTi) and stainless steel (SUS304). Surface roughness and energy were changed by sandblast treatment and heat treatment, respectively. A porcine aorta was adhered to sandblast-treated SUS304 by use of an adhesion temperature of 80 degrees C, a vibration amplitude of 15 MUm, a pressure of 2.5 MPa, an adhesion time of 120 s, and a surface roughness of an Ra 0.25 MUm. The shear tensile strength of the adhesion was 0.45 MPa. The adhesion performance was improved by roughening the surface of the metal specimen. Surface energy has an insignificant effect on adhesive strength. The adhesion performance varied depending on metal material for the same surface roughness, Ra, and energy. Results from analysis of the surface roughness profile suggested that the size of surface asperity has an effect on adhesion performance. PMID- 22933054 TI - Intake of omega-3 and omega-6 fatty acids and risk of ovarian cancer. AB - OBJECTIVES: Limited experimental evidence suggests that omega-3 polyunsaturated (n-3) fatty acids inhibit the proliferation of ovarian cancer cells in vitro, whereas omega-6 polyunsaturated (n-6) fatty acids have been shown to promote carcinogenesis, but epidemiological studies to date have been inconclusive. Our aim was to evaluate the role of polyunsaturated fatty acids in ovarian carcinogenesis. METHODS: Participants in the Australian Ovarian Cancer Study (1,366 cases and 1,414 population controls) self-completed risk factor and food frequency questionnaires. Logistic regression models were used to calculate adjusted odds ratio (OR) and 95 % confidence intervals (CI). RESULTS: We found no association between intake of total n-3 fatty acids from foods, or the individual n-3 fatty acids-alpha-linolenic, eicosapentaenoic, docosapentaenoic, docosahexaenoic acids-and ovarian cancer risk. High intake of total n-6 fatty acids was inversely associated with risk (OR for highest vs. lowest category 0.78, 95 % CI 0.60-1.00, p-trend 0.04); however, the association was restricted to n-6 fatty acids from avocado, vegetables, and nuts. Neither higher intake of the individual n-6 fatty acids nor the ratio of n-3 to n-6 fatty acids was associated with ovarian cancer risk. We found no evidence that risk varied by supplement use. CONCLUSIONS: Our data provide no evidence of a protective role for n-3 fatty acids in ovarian carcinogenesis. The benefit, if any, of higher intake of n-6 fatty acids is due to general properties of the food sources, rather than due to the n-6 fatty acids per se. PMID- 22933055 TI - Virtual selves, real relationships: an exploration of the context and role for social interactions in the emergence of self in virtual environments. AB - With the evolution of computer-mediated communication and the arrival of new virtual environments, there are potential implications for how the Self may be conceptualised. This paper considers these implications by examining the continuities and discontinuities between the Self in virtual and non-virtual environments, and contemporary and historical settings. Symbolic Interaction and Activity Theory approaches emphasise the Self as emerging in context, through Self-Other and Self-environment interactions in the minutiae of everyday life, but to some extent foreground physical rather than virtual interactions. Interactions in virtual environments are characterised by specific forms of embodiment and the experience of "presence", with avatars providing embodiment for interaction separate from the physical world and interaction with others being one of the determinants of presence. The complexion of Self-Other interactions in virtual environments is circumscribed by the characteristics of communications and relationships that occur in them, which are constrained by reduced social cues but overcome through the invention of techniques driven by the desire to socially interact. This paper highlights the role of symbolic mediation in the emergence of Self in virtual environments and posits that, while emergence of Self is interactive in nature, virtual environments are particular sites for a Self where the specific role of social interaction must be foregrounded. PMID- 22933056 TI - [Minimally invasive balloon-assisted reduction and internal fixation of tibial plateau fractures]. AB - The management of tibial plateau fractures can be challenging because of the scarcity of soft tissue associated with a high rate of wound healing disorders. Classic open reduction and internal plate fixation require extensive soft tissue dissection and periosteal stripping, and elevation of depressed fragments and maintenance of the reduction is difficult. In the current report the authors describe a novel operative approach to percutaneously reduce depressed tibial plateau fractures using an inflatable balloon in combination with minimally invasive plate fixation. The results of the first 5 cases treated with this technique are reported. PMID- 22933057 TI - Does human evolution in different latitudes influence susceptibility to obesity via the circadian pacemaker?: migration and survival of the fittest in the modern age of lifestyle-induced circadian desynchrony. AB - The variable photoperiods of Northern latitudes challenge the entrainment capacity of the circadian pacemaker, which evolved under constant photoperiods in Equatorial regions. Entrainment to the erratic photoperiods facilitated by artificial light presents an additional challenge. Metabolic dysfunction and obesity are potential consequences of such desynchronization of circadian and environmental rhythms. PMID- 22933058 TI - Mammography screening before introduction of the national breast screening programme in Norway. PMID- 22933059 TI - The selenite-capped polyoxo-4-aurate(III), [Au(III)4O4(Se(IV)O3)4]4-. AB - The discrete heteropolyaurate [Au(III)(4)O(4)(Se(IV)O(3))(4)](4-) (Au(4)Se(4)) represents only the second member of this class ever reported, and was synthesized via one-pot room temperature condensation in aqueous medium. was structurally characterized in the solid state and in solution by single-crystal XRD, TGA, FT-IR, (77)Se NMR, mass spectrometry and electrochemistry. PMID- 22933060 TI - Ploidy and large-scale genomic instability consistently identify basal-like breast carcinomas with BRCA1/2 inactivation. AB - BRCA1 inactivation is a frequent event in basal-like breast carcinomas (BLC). However, BRCA1 can be inactivated by multiple mechanisms and determining its status is not a trivial issue. As an alternate approach, we profiled 65 BLC cases using single-nucleotide polymorphism arrays to define a signature of BRCA1 associated genomic instability. Large-scale state transitions (LST), defined as chromosomal break between adjacent regions of at least 10 Mb, were found to be a robust indicator of BRCA1 status in this setting. Two major ploidy-specific cutoffs in LST distributions were sufficient to distinguish highly rearranged BLCs with 85% of proven BRCA1-inactivated cases from less rearranged BLCs devoid of proven BRCA1-inactivated cases. The genomic signature we defined was validated in a second independent series of 55 primary BLC cases and 17 BLC-derived tumor cell lines. High numbers of LSTs resembling BRCA1-inactivated BLC were observed in 4 primary BLC cases and 2 BLC cell lines that harbored BRCA2 mutations. Overall, the genomic signature we defined predicted BRCA1/2 inactivation in BLCs with 100% sensitivity and 90% specificity (97% accuracy). This assay may ease the challenge of selecting patients for genetic testing or recruitment to clinical trials of novel emerging therapies that target DNA repair deficiencies in cancer. PMID- 22933061 TI - Diminished cartilage-lubricating ability of human osteoarthritic synovial fluid deficient in proteoglycan 4: Restoration through proteoglycan 4 supplementation. AB - OBJECTIVE: The purposes of this study were 1) to quantify the proteoglycan 4 (PRG4) and hyaluronan (HA) content in synovial fluid (SF) from normal donors and from patients with chronic osteoarthritis (OA) and 2) to assess the cartilage boundary-lubricating ability of PRG4-deficient OA SF as compared to that of normal SF, with and without supplementation with PRG4 and/or HA. METHODS: OA SF was aspirated from the knee joints of patients with symptomatic chronic knee OA prior to therapeutic injection. PRG4 concentrations were measured using a custom sandwich enzyme-linked immunosorbent assay (ELISA), and HA concentrations were measured using a commercially available ELISA. The molecular weight distribution of HA was measured by agarose gel electrophoresis. The cartilage boundary lubricating ability of PRG4-deficient OA SF, PRG4-deficient OA SF supplemented with PRG4 and/or HA, and normal SF was assessed using a cartilage-on-cartilage friction test. Two friction coefficients (MU) were calculated: static (MU(static, Neq) ) and kinetic () (where N(eq) represents equilibrium axial load and angle brackets indicate that the value is an average). RESULTS: The mean +/- SEM PRG4 concentration in normal SF was 287.1 +/- 31.8 MUg/ml. OA SF samples deficient in PRG4 (146.5 +/- 28.2 MUg/ml) as compared to normal were identified and selected for lubrication testing. The HA concentration in PRG4 deficient OA SF (mean +/- SEM 0.73 +/- 0.08 mg/ml) was not significantly different from that in normal SF (0.54 +/- 0.09 mg/ml). In PRG4-deficient OA SF, the molecular weight distribution of HA was shifted toward the lower range. The cartilage boundary-lubricating ability of PRG4-deficient OA SF was significantly diminished as compared to normal (mean +/- SEM = 0.043 +/- 0.008 versus 0.025 +/- 0.002; P < 0.05) and was restored when supplemented with PRG4 ( = 0.023 +/- 0.003; P < 0.05). CONCLUSION: These results indicate that some OA SF may have decreased PRG4 levels and diminished cartilage boundary-lubricating ability as compared to normal SF and that PRG4 supplementation can restore normal cartilage boundary lubrication function to these OA SF. PMID- 22933062 TI - Pathogenesis and spectrum of autoimmunity. AB - The immune system specifically recognizes and eliminates foreign antigens and, thus, protects integrity of the host. During maturation of the immune system, tolerance mechanisms develop that prevent or inhibit potentially harmful reactivities to self-antigens. Autoreactive B and T cells that are generated during immune responses are eliminated by apoptosis in the thymus, lymph nodes, or peripheral circulation or actively suppressed by regulatory T cells. However, autoreactive cells may survive due to failure of apoptosis or molecular mimicry, i.e., presentation and recognition of cryptic epitopes of self-antigens, or aberrant lymphokine production. Preservation of the host requires the development of immune responses to foreign antigen and tolerance to self-antigens. Autoimmunity results from a breakdown of tolerance to self-antigens through an interplay of genetic and environmental factors.One of the basic functions of the immune system is to specifically recognize and eliminate foreign antigens and, thus, protect integrity of the host. Through rearrangements and somatic mutations of various gene segments encoding T and B cell receptors and antibody molecules, the immune system acquires tremendous diversity. During maturation of the immune system, recognition of self-antigens plays an important role in shaping the repertoires of immune receptors. Tolerance mechanisms develop that prevent or inhibit potentially harmful reactivities to self-antigens. These self-defense mechanisms are mediated on the levels of central and peripheral tolerance, i.e., autoreactive T cells are either eliminated by apoptosis in the thymus, lymph nodes, or peripheral circulation or actively suppressed by regulatory T cells. Likewise, autoreactive B cells are eliminated in the bone marrow or peripheral lymphoid organs. However, immune responses triggered by foreign antigens may be sustained by molecular mimicry, i.e., presentation and recognition of cryptic epitopes of self-antigens. Further downstream, execution of immune responses depends on the functioning of intracellular signaling networks and the cooperation of many cell types communicating via surface receptors, cytokines, chemokines, and antibody molecules. Therefore, autoimmunity represents the end result of the breakdown of one or multiple basic mechanisms of immune tolerance (Table 1). PMID- 22933063 TI - Mapping susceptibility gene in systemic lupus erythematosus. AB - Genome-wide association studies have identified many dozen genetic intervals that harbor single-nucleotide polymorphisms (SNPs) showing statistical association with systemic lupus erythematosus. Despite the wealth of data produced, there are limitations of these studies. The causal alleles at a given locus are not identified; only SNP is strong linkage disequilibrium with the putative causative alleles. In order to address identification of the causative SNPs for lupus susceptibility genes, we have initiated a candidate gene study for which more than 40 investigators have contributed patient and control samples. In addition, these investigators have designated SNPs to be placed on a custom array. In this way fine mapping of genetic association findings can occur in order to identify causal alleles. These efforts have thus far benefitted greatly from comparisons of different ethnicities. Work on about ten previously identified associations has been published using this resource. Genome-wide association studies cannot identify rare SNPs or mutations, which may impart greater relative risks than common variants. Much of the genetics of lupus may be from rare variants or mutations. In order to approach this aspect of lupus genetics, next-generation sequencing has begun in which all exons will be sequenced in controls and patients. This effort can also be used to identify causal alleles from association intervals not yet otherwise identified. PMID- 22933064 TI - Methods and protocols to study T cell signaling abnormalities in human systemic lupus erythematosus. AB - Abnormal expression of key signaling molecules and defective functions of T lymphocytes play a significant role in the pathogenesis of systemic lupus erythematosus (SLE). T cell receptor (TCR/CD3)-mediated stimulation of SLE T cells show increased protein tyrosine phosphorylation of cellular proteins with faster kinetics, heightened calcium flux response, and decreased IL-2 production. The molecular mechanisms of T cell signaling abnormalities in SLE T cells are complex. Current research has been directed towards investigating various factors that contribute to abnormal tyrosine phosphorylation, intracellular calcium response, and cytokine production. Central to this dysfunction is the aberrant expression and function of the TCR/CD3zeta chain. Latest developments suggest multiple explanations are involved, including altered receptor structure, supramolecular assembly, modulation of membrane clustering, aberrant cellular distribution, and pre-compartmentalization with lipid-rafts. The methods and protocols described here pertaining to T cell signaling abnormalities in SLE T cells are optimized in many ways and are derived by the combined task and continuous efforts of many researchers in the lab over a long period of time. These simplified protocols can be readily applied to study T cell signaling abnormalities in SLE to identify the genetic, molecular, and biochemical factors contributing to aberrant immune cell function and unravel the pathophysiology of SLE. PMID- 22933065 TI - Assessment of mitochondrial dysfunction in lymphocytes of patients with systemic lupus erythematosus. AB - Systemic lupus erythematosus (SLE) is characterized by abnormal activation and cell death signaling within the immune system. Activation, proliferation, or death of cells of the immune system is dependent on controlled reactive oxygen intermediates (ROI) production and ATP synthesis in mitochondria. The mitochondrial transmembrane potential (?psi (m)) reflects the energy stored in the electrochemical gradient across the inner mitochondrial membrane which, in turn, is used by F(0)F(1)-ATPase to convert ADP to ATP during oxidative phosphorylation. Mitochondrial hyperpolarization (MHP) and transient ATP depletion represent early and reversible steps in T cell activation and apoptosis. By contrast, T lymphocytes of patients with SLE exhibit elevated ?psi (m), i.e., persistent mitochondrial hyperpolarization (MHP), cytoplasmic alkalinization, increased ROI production, as well as diminished levels of intracellular glutathione and ATP. Increased production of nitric oxide has been identified as a cause of MHP and increased mitochondrial biogenesis. Oxidative stress affects signaling through the T cell receptor as well as activity of redox -sensitive caspases. ATP depletion causes diminished activation-induced apoptosis and sensitizes lupus T cells to necrosis. Activation of the mammalian target of rapamycin (mTOR) has recently emerged as a key sensor of MHP and mediator of enhanced Ca(2+) flux in lupus T cells. PMID- 22933066 TI - The role of endocytic recycling in autoimmunity. AB - Abnormalities in T cell signal transduction underlie pathology in systemic lupus erythematosus. Lupus T cells are more sensitive to stimulation, yet have reduced expression of T cell antigen receptor (TCR) at the surface. The amount of TCR expressed at the surface of a T cell directly determines the ability of a T cell to become activated. The endocytic recycling machinery regulates transport of T cell receptors to the plasma membrane, internalization of surface receptors, and recycling to the cell surface, which determines the ability of a T cell to become activated. Increased recycling of CD3 and CD4 receptors occurs in lupus T cells, and could represent a mechanism by which T cells are sensitized to stimulation. This chapter explains methods used to investigate endocytic recycling of the TCR, CD4, and CD8 co-receptors in peripheral blood lymphocytes, T cells, and in splenocytes from lupus-prone murine models. The assays described will allow the study of surface receptor turnover in live untouched lymphocytes by flow cytometry. PMID- 22933068 TI - Experimental use of mouse models of systemic lupus erythematosus. AB - Mouse models of lupus have for many years provided accessible and reliable research systems for the pathogenesis and therapy of systemic autoimmune disease, spanning a spectrum of inbred strains that develop spontaneous disease to experimentally induced, sometimes genetically manipulated animals. Nearly all the models share in common the development of glomerulonephritis and autoantibodies, including antinuclear and DNA specificities, the most common endpoints examined in experimental studies, but exhibit specific differences in the incidence of other end-organ manifestations such as hemolytic anemia, arthritis, dermatitis, and vasculitis. This chapter contrasts the clinical characteristics of these various models, providing an outline for their use and analysis. PMID- 22933069 TI - Murine models of lupus induced by hypomethylated T cells (DNA hypomethylation and lupus...). AB - CD4+ T cell DNA hypomethylation may contribute to the development of drug induced and idiopathic human lupus. Inhibiting DNA methylation in mature CD4+ T cells causes MHC-specific autoreactivity in vitro. The lupus-inducing drugs hydralazine and procainamide also inhibit T cell DNA methylation and induce autoreactivity, and T cells from patients with active lupus have hypomethylated DNA and a similarly autoreactive T cell subset. Further, T cells treated with DNA methylation inhibitors demethylate the same sequences that demethylate in T cells from patients with active lupus. The pathologic significance of the autoreactivity induced by inhibiting T cell DNA methylation has been tested by treating murine T cells in vitro with drugs which modify DNA methylation, then injecting the cells into syngeneic female mice. Mice receiving CD4+ T cells demethylated by a variety of agents including procainamide and hydralazine develop a lupus-like disease. Further, transgenic mice with an inducible T cell DNA methylation defect also develop lupus-like autoimmunity. This chapter describes the protocols for inducing autoreactivity in murine T cells in vitro and for inducing autoimmunity in vivo using an adoptive transfer approach or transgenic animal models. PMID- 22933067 TI - Multiparameter flow cytometry and bioanalytics for B cell profiling in systemic lupus erythematosus. AB - B lymphocyte involvement in systemic lupus erythematosus has been recognized for several decades, mainly in the context of autoantibody production. Both mouse and human studies reveal that different types of antibody responses, as well as antibody-independent effector functions can be ascribed to distinct subpopulations (subsets) of circulating B cells. Characterizing human B cell subsets can advance the field of autoimmunity even further by establishing B cell signatures associated with disease severity, progression, and response-to treatment. For this purpose, we have developed specialized B cell reagent panels for multiparameter flow cytometry, and combine their use with advanced bioinformatics strategies that together will likely be advantageous for improving the characterization, prognosis, and for possibly improving treatment regimens of chronic inflammatory diseases such as lupus. PMID- 22933070 TI - Aspects of CNS lupus: mouse models of anti-NMDA receptor antibody mediated reactivity. AB - This chapter describes methods utilized in establishing a mouse model of neuropsychiatric lupus encompassing both cognitive and emotional dysfunction, and a model of the influence of maternal antibody on the developing brain. The antibody of interest binds the N-methyl-D: -aspartate receptor (NMDAR), a receptor for glutamate that is a major excitatory neurotransmitter in the brain involved in synaptic plasticity, in memory and learning, and in emotional responses.We introduce basic concepts of these models and provide protocols for the following: (1) the induction of anti-dsDNA, anti-NMDAR antibodies, (2) testing serum antibody titer by ELISA, (3) breaching blood brain barrier (BBB) integrity with LPS and epinephrine, (4) passive transfer of pathology by injecting human and mouse brain-reactive antibodies into adult mouse as well as injecting the antibody into gestating mice and transfer of antibody from dam to fetus, (5) blocking NMDAR-mediated pathogenicity in vivo, (6) evacuation of blood from the brain by cardiac perfusion to preserve the brain for histology, (7) evaluating injured/apoptotic neurons in brain histology, (8) preparing membrane enriched brain -fractions for NMDAR analysis. PMID- 22933071 TI - Analysis of renal mononuclear phagocytes in murine models of SLE. AB - In this chapter we present methods for the isolation and characterization of mononuclear phagocytes from the kidneys of mice with SLE. Activation of these cells is associated with the onset of clinical disease in mice and infiltration with these cells is associated with poor prognosis in humans. Using magnetic beads followed by flow cytometric sorting, pure populations of cells are obtained that are functional in a variety of assays. Sufficient numbers of cells are obtained for genomic characterization. An analysis of the function of these cells should lead to a better understanding of the inflammatory processes that cause renal impairment in SLE and other renal inflammatory diseases. PMID- 22933072 TI - A murine autoimmune model of rheumatoid arthritis and systemic lupus erythematosus associated with deregulated production of IL-17 and IL-21. AB - T-helper cell 17 (Th17) cells play an important role in the pathogenesis of many autoimmune disorders including Rheumatoid Arthritis (RA) and Systemic Lupus Erythematosus (SLE). In this chapter we describe a murine model where deregulated production of IL-17 and IL-21 can lead to either lupus-like disease or RA-like symptoms depending on the genetic background. We delineate the key techniques that can be used to dissect the mechanisms responsible for the pathogenesis of these diseases at both a cellular and molecular level including in vitro Th17 cell differentiation, chromatin immunoprecipitation assays, and retroviral transduction experiments. We also describe the methodologies that can be utilized to monitor the classic clinical findings of RA and SLE in murine models. Given the broad involvement of deregulated production of IL-17 and IL-21 in autoimmunity, many of these techniques could also be valuable for the investigation of these pathways in murine models of other autoimmune diseases. PMID- 22933073 TI - The parent-into-F1 murine model in the study of lupus-like autoimmunity and CD8 cytotoxic T lymphocyte function. AB - The transfer of homozygous C57Bl/6 (B6) or DBA/2 (DBA) parental strain T cells into normal B6D2F1 mice in the parent-into-F1 (p -> F1) model results in a graft vs.-host disease (GVHD) that takes one of the following two forms: (a) acute GVHD seen with B6 -> F1 mice and mediated by donor CD8 cytotoxic T cells that eliminate host lymphocytes and (b) a chronic lupus-like GVHD seen with DBA -> F1 mice and mediated by donor CD4 T cell cognate help to autoreactive B cells resulting in autoantibody production and renal disease similar to human lupus. Importantly, these two phenotypes can be distinguished by flow cytometry as early as 2 weeks after donor cell transfer. The p -> F1 model can be used to screen for agents that alter lupus development. Additionally, the model is useful for preclinical screening of biologic agents with immunomodulatory potential. Agents that selectively inhibit CD8 T cell function will convert acute GVHD to chronic GVHD in B6 -> F1 mice. Conversely, agents that promote CD8 CTL function will convert chronic GVHD to acute GVHD in DBA -> F1 mice. Agents that completely suppress T cell function will block both phenotypes. The model is also useful for examining the effects of T cell mutations by transferring mutant T cells into wild-type hosts and assessing the effects on disease phenotype. Differences observed from wild-type T cells -> F1 can be directly ascribed to alterations in mutant T cell function. Because of the early 2-week phenotype development, the p > F1 model is well suited to screening of potential immunomodulatory therapeutic compounds and the assessment of T cell mutations on in vivo function. PMID- 22933074 TI - Genetic approach to study lupus glomerulonephritis. AB - Genetic and environmental factors contribute in the pathogenesis of systemic lupus erythematosus (SLE). Lupus nephritis, the most common and severe manifestation of SLE, involves inflammation in the kidney leading to loss of renal function. However, it is not clear what controls the progression of lupus nephritis; this is an important research question, considering its implications in clinical treatment of lupus nephritis. Finding genes that underlie the development and progression of lupus nephritis will shed light on this question. NZM2328 is a spontaneous mouse model for SLE. Most NZM2328 female mice develop autoantibodies (e.g., antinuclear antibody and anti-dsDNA antibody), glomerulonephritis (GN), and severe proteinuria between 5 and 12 months of age. In contrast, C57L/J mice fail to exhibit similar signs of autoimmune disease. We used classical genetics to map and identify SLE genes in offspring generated by backcrossing C57L/J to NZM2328. Quantitative trait loci (QTL) controlling acute (Agnz1 and Agnz2) and chronic (Cgnz1) GN features were uncovered by the analysis. To verify the Cgnz1 and Agnz1 on distal mouse chromosome 1, we produced the NZM23238.C57Lc1 (Lc1) congenic strain, which replaced NZM2328 Cgnz1 and Agnz1 alleles with those derived from C57L/J. The development of acute GN and chronic GN was markedly reduced in Lc1 mice, confirming the linkage findings. Further mapping by the generation of intrachromosomal recombinants of NZM2328.Lc1 support the thesis that acute GN and chronic GN are under separate genetic control. PMID- 22933075 TI - Animal models of primary biliary cirrhosis: materials and methods. AB - Primary biliary cirrhosis (PBC) is a female-predominant autoimmune disease of the liver characterized by immune-mediated destruction of the intrahepatic bile ducts and the presence of antimitochondrial antibodies (AMAs). There have been limited advances in understanding the molecular pathogenesis of the disease because of the difficulty in accessing human tissues and the absence of appropriate animal models. Recently, several unique murine models that manifest the serological, biochemical, and histological features similar to human PBC have been described. In this article, we discuss the current data on three spontaneous and two induced murine models of PBC. The spontaneous models are: (a) NOD.c3c4, (b) dominant negative TGF-beta receptor II (dnTGFbetaRII), and (c) IL-2Ralpha(-/-) mouse line models. The two induced models are: (a) xenobiotic and (b) Novosphingobium aromaticivorans immunized mice. These animal models provide various important platforms to further investigate the etiology and mechanisms of pathogenesis in PBC. Laboratory methodologies and the protocols that are used in evaluating these animal models are described. Finally, we stress the importance of realizing the strengths and limitations of the animal models are essential in data analysis and their application in therapeutic studies. PMID- 22933076 TI - Modeling innate immunity in murine skin: utilization of subcutaneous osmotic pumps for inflammatory and fibrotic skin disease. AB - Current models for systemic sclerosis have many limitations for mimicking human disease. We have recently described a novel model based on chronic stimulation of skin by poly(I:C), a form of double-stranded RNA known to stimulate innate immune responses. This model shows inflammation and extracellular matrix deposition, and upregulated expression of genes associated with fibrosis and vascular injury. We detail here the methodology for this model, utilizing osmotic pumps to deliver innate immune stimuli to subcutaneous tissue. Subcutaneous osmotic pumps provide a flexible system for studying innate immunity in the skin as well as the affects of other ligands on skin inflammation and fibrosis. PMID- 22933077 TI - Flow cytometric identification of fibrocytes in scleroderma lung disease. AB - Scleroderma is an autoimmune disease characterized by the progressive and dysregulated accumulation of collagen in the skin and internal organs. Pulmonary complications including interstitial lung disease have emerged as the greatest cause of mortality in this disease. Because treatments are limited, new areas of investigation are sorely needed. An emerging area of interest in this field is a potential role for fibrocytes as biomarkers or mediators of disease. Fibrocytes are monocyte-derived mesenchymal progenitor cells that exhibit features of extracellular matrix production and wound contraction in addition to immunologic functions such as cytokine and chemokine production, antigen presentation, leukocyte trafficking, and modulation of angiogenesis. Fibrocytes could participate in the pathogenesis of scleroderma lung disease through any or all of these functions and may be useful biomarkers of disease activity. This chapter presents protocols that have been developed for the study of fibrocytes obtained from human circulation and tissues. Protocols for the quantification of fibrocytes in murine models also are described, along with discussion of common technical challenges. It is hoped that this information will allow further investigation of the role that fibrocytes might play in Scleroderma-related lung disease and perhaps lead to new areas of study in this difficult-to-treat and deadly disease. PMID- 22933078 TI - Oxidative stress and beta cell dysfunction. AB - Autoimmune Type 1 A Diabetes (T1D) is characterized by dependence on exogenous insulin consequential to the autoimmune attack and destruction of insulin producing islet beta cells. Pancreatic islet cell inflammation, or insulitis, precedes beta cell death and T1D onset. In the insulitic lesion, innate immune cells produce chemokines and cytokines that recruit and activate adaptive immune cells (Eizirik D et al., Nat Rev Endocrinol 5:219-226, 2009). Locally produced cytokines not only increase immune surveillance of beta cells (Hanafusa T and Imagawa A, Ann NY Acad Sci 1150:297-299, 2008), but also cause beta cell dysfunction and decreased insulin secretion due to the generation of reactive oxygen species (ROS) and reactive nitrogen species (RNS) by the beta cells. This, coupled to the high levels of ROS and RNS secreted by activated macrophages and the low antioxidant capacities of beta cells (Huurman VA, PLoS One 3:e2435, 2008; Schatz D, Pediatr Diabetes 5:72-79, 2004; Verge CF, Diabetes 44:1176-1179, 1995), implicates free radicals as important effectors in T1D pathogenesis (Eizirik D et al., Nat Rev Endocrinol 5:219-226, 2009; Hanafusa T and Imagawa A, Ann NY Acad Sci 1150:297-299, 2008; Eisenbarth GS and Jeffrey J, Arq Bras Endocrinol Metabol 52:146-155, 2008; Pietropaolo M et al., Pediatr Diabetes 6:184-192, 2005). PMID- 22933079 TI - Experimental autoimmune encephalomyelitis. AB - Experimental autoimmune encephalomyelitis (EAE) is an inflammatory demyelinating disease of the central nervous system that is induced in laboratory animals by the generation of an immune response against myelin epitopes. It has been used as a prototype of Th1- and/or Th17-driven, organ-specific autoimmunity and as a model for the human disease, multiple sclerosis. In this chapter we describe two classic protocols for EAE induction (active immunization and adoptive transfer of Th1- or Th17-polarized cells) in Subheadings 3.1 and 3.2, respectively. Subheading 3.3 describes methods for rating clinical disease in symptomatic animals. Subheading 3.4 includes instructions for the isolation of mononuclear cells from the inflamed spinal cords of mice with EAE. Subheading 3.5 describes a method for performing the enzyme-linked immunospot assay. PMID- 22933081 TI - Pathogenesis of multiple sclerosis: what can we learn from the cuprizone model. AB - Multiple sclerosis is an inflammatory demyelinating and neurodegenerative disorder of the central nervous system (CNS). The primary cause of the disease remains unknown, but an altered immune regulation with features of autoimmunity has generally been considered to play a critical role in the pathogenesis. Historically, lesion development has been attributed to activation of CD4 and CD8 T lymphocytes, B lymphocytes, and monocytes in the peripheral circulation and the migration of these cells through the blood-brain barrier to exert direct or indirect cytotoxic effects on myelin, oligodendrocytes and neuronal processes in the CNS. This broadly accepted concept was significantly influenced by the experimental autoimmune encephalitis (EAE) model, in which either immunization with myelin antigens or injection of a myelin antigen-specific T cell line into a recipient results in inflammatory demyelination in the CNS. More recent studies reveal that the loss of oligodendrocytes and neurons begins in the earliest stages of the disease and may not always be associated with blood-derived inflammatory cells. The pathology affects both the white and the gray matters and the clinical disability best correlates with the overall neurodegenerative process. These newer observations prompted several revisions of the classical concept of MS and facilitated a shift from using EAE to using other model systems. This chapter summarizes the classical and more contemporary concepts of MS, and provides methodologies for employing the cuprizone model for further explorations of the pathogenesis and treatment of the disease. PMID- 22933082 TI - Assessing inflammatory disease at mucosal surfaces in murine genetic models. AB - Inflammatory diseases of the mucosal surfaces are rising worldwide and particularly in the Western world that is witnessing unprecedented increases in the number and incidence of both asthma and inflammatory bowel disease. The laboratory mouse allows the application of the full panoply of modern genetic, immunological and biochemical tools to increase our understanding of how inflammation arises and how it might be controlled at mucosal surfaces. Here we provide a detailed description of how to systematically assess inflammatory disease in the lung and intestines of the laboratory mouse. We provide histopathology examples from SHIP mutant mice that are the only known genetic mutant to suffer from pulmonary consolidation, asthma, and Crohn's disease. The intent of this chapter is to facilitate increased surveillance of mucosal inflammation in studies where the laboratory mouse is utilized so that we can better understand the cell types, genes, and microorganisms that contribute to mucosal inflammatory disease and thereby develop more effective therapies and preventive strategies. PMID- 22933080 TI - Mouse models of multiple sclerosis: experimental autoimmune encephalomyelitis and Theiler's virus-induced demyelinating disease. AB - Experimental autoimmune encephalomyelitis (EAE) and Theiler's Murine Encephalitis Virus-Induced Demyelinating Disease (TMEV-IDD) are two clinically relevant murine models of multiple sclerosis (MS). Like MS, both are characterized by mononuclear cell infiltration into the CNS and demyelination. EAE is induced by either the administration of myelin protein or peptide in adjuvant or by the adoptive transfer of encephalitogenic T cell blasts into naive recipients. The relative merits of each of these protocols are compared. Depending on the type of question being asked, different mouse strains and peptides are used. Different disease courses are observed with different strains and different peptides in active EAE. These variations are also addressed. Additionally, issues relevant to clinical grading of EAE in mice are discussed. In addition to EAE induction, useful references for other disease indicators such as DTH, in vitro proliferation, and immunohistochemistry are provided. TMEV-IDD is a useful model for understanding the possible viral etiology of MS. This section provides detailed information on the preparation of viral stocks and subsequent intracerebral infection of mice. Additionally, virus plaque assay and clinical disease assessment are discussed. Recently, recombinant TMEV strains have been created for the study of molecular mimicry which incorporate various 30 amino acid myelin epitopes within the leader region of TMEV. PMID- 22933084 TI - Tolerance induction via B-cell delivered gene therapy. AB - A master control of both the innate and adaptive immune system is the body's ability to distinguish between self and foreign entities. This is accomplished by the elimination of autoreactive leukocytes through a series of checkpoints both in the thymus (central deletion) and in the circulating periphery (peripheral tolerance), thus establishing tolerance to self-antigens. When one or more of these controls is disrupted, there is the potential for the development of autoimmune disease. Current available therapies for these diseases often rely on global immune suppression or expensive treatments that are not affordable to all. Herein, we describe a novel therapeutic technique in which tolerance to self can be re-established via B-cell delivered antigen-specific tolerogenic gene constructs. Furthermore, this technique shows promise in the gene therapeutic treatment of monogenic disorders and the acceptance of tissue transplants. PMID- 22933083 TI - Rodent models of experimental autoimmune uveitis. AB - The model of experimental autoimmune uveitis (EAU) in mice and in rats is described. EAU targets immunologically privileged retinal antigens and serves as a model of autoimmune uveitis in humans as well as a model for autoimmunity in a more general sense. EAU is a well-characterized, robust, and reproducible model that is easily followed and quantitated. It is inducible with synthetic peptides derived from retinal autoantigens in commonly available strains of rats and mice. The ability to induce EAU in various gene-manipulated, including HLA-transgenic, mouse strains makes the EAU model suitable for the study of basic mechanisms as well as in clinically relevant interventions. PMID- 22933085 TI - Properties- and applications of quasicrystals and complex metallic alloys. AB - This article aims at an account of what is known about the potential for applications of quasicrystals and related compounds, the so-called family of Complex Metallic Alloys (CMAs?). Attention is focused at aluminium-based CMAs, which comprise a large number of crystalline compounds and quasicrystals made of aluminium alloyed with transition metals (like Fe or Cu) or normal metals like Mg. Depending on composition, the structural complexity varies from a few atoms per unit cell up to thousands of atoms. Quasicrystals appear then as CMAs of ultimate complexity and exhibit a lattice that shows no periodicity anymore in the usual 3-dimensional space. Properties change dramatically with lattice complexity and turn the metal-type behaviour of simple Al-based crystals into a far more complex behaviour, with a fingerprint of semi-conductors that may be exploited in various applications, potential or realised. An account of the ones known to the author is given in the light of the relevant properties, namely light absorption, reduced adhesion and friction, heat insulation, reinforcement of composites for mechanical devices, and few more exotic ones. The role played by the search for applications of quasicrystals in the development of the field is briefly addressed in the concluding section. PMID- 22933087 TI - The fate of lead at abandoned and active shooting ranges in a boreal pine forest. AB - Changes in leaching, availability, bioaccumulation, and vertical distribution of lead (Pb) in soil 20 years after the cessation of shooting activity were studied by comparing three pine forest sites in southern Finland: an active shooting range, an abandoned shooting range, and a noncontaminated control site. At both shooting ranges, shooting activity had lasted for 20 years, but it had taken place 20 years earlier at the abandoned range. Up to 4 kg m(-2) of Pb pellets had accumulated in the soil at both shooting ranges, and extremely high Pb concentrations, reaching 50,000 mg kg(-1) , were detected in the organic soil layer. Elevated Pb concentrations were also found in leachate waters and in the biota. Concentrations of Pb in the top organic soil layer and in some of the biota were lower at the abandoned shooting range, which can be taken as a sign of starting recovery of the forest ecosystem. However, the concentration of water extractable Pb had not decreased in the topsoil, possibly indicating the release of Pb from decaying litter. Deeper in the organic soil layer, weathering of Pb pellets enhanced Pb availability and leaching, indicating an increased risk of groundwater contamination over time at shooting sites located above aquifers. PMID- 22933086 TI - Cardiovascular surgery for realization of regenerative medicine. AB - Regenerative medicine is emerging as a new approach to the treatment of severe cardiovascular diseases that are resistant to conventional therapies. Although the type of cell transplanted (e.g., pluripotent stem cells, bone marrow-derived stem cells, skeletal myoblasts, or cardiac stem cells) influences the outcome of stem cell transplantation, the method of transplantation is also important, as the efficiency of engraftment after simple needle injection is poor. Scaffold free cell sheet transplantation technology is one of the most promising methods in this regard. Although the results of clinical trials of stem cell therapy have been marginal to date, further elucidation of the actual mechanisms of cardiac repair following cell therapy would enhance the potential for full-scale implementation of stem cell therapy. In addition to stem cell therapy, the field of cardiovascular regenerative medicine includes interspecific chimera technology, drug delivery systems using biodegradable materials, and gene therapy. Integration of these new modalities with conventional therapies will be important to realize the goal of cardiovascular regenerative medicine tailored to the condition of each individual patient. Cardiovascular surgery would be an excellent means of carrying out this strategy and could potentially resolve the health problems of the increasing number of advanced cardiovascular patients. Herein, we review the recent basic and clinical research associated with the realization of regenerative medicine in the field of cardiovascular surgery. PMID- 22933088 TI - Outcomes at 7 years for babies who developed neonatal necrotising enterocolitis: the ORACLE Children Study. AB - BACKGROUND: Within the ORACLE Children Study Cohort, the authors have evaluated long-term consequences of the diagnosis of confirmed or suspected neonatal necrotising enterocolitis (NEC) at age of 7 years. METHODS: Outcomes were assessed using a parental questionnaire, including the Health Utilities Index (HUI-3) to assess functional impairment, and specific medical and behavioural outcomes. Educational outcomes for children in England were explored using national standardised tests. Multiple logistic regression was used to explore independent associates of NEC within the cohort. RESULTS: The authors obtained data for 119 (77%) of 157 children following proven or suspected NEC and compared their outcomes with those of the remaining 6496 children. NEC was associated with an increase in risk of neonatal death (OR 14.6 (95% CI 10.4 to 20.6)). At 7 years, NEC conferred an increased risk of all grades of impairment. Adjusting for confounders, risks persisted for any HUI-3 defined functional impairment (adjusted OR 1.55 (1.05, 2.29)), particularly mild impairment (adjusted OR 1.61 (1.03, 2.53)) both in all NEC children and in those with proven NEC, which appeared to be independent. No behavioural or educational associations were confirmed. Following NEC, children were more likely to suffer bowel problems than non-NEC children (adjusted OR 3.96 (2.06, 7.61)). CONCLUSIONS: The ORACLE Children Study provided opportunity for the largest evaluation of school age outcome following neonatal NEC and demonstrates significant long-term consequences of both gut function (presence of stoma, admission for bowel problems and continuing medical care for gut-related problems) and motor, sensory and cognitive outcomes as measured using HUI-3. PMID- 22933089 TI - Trends and centre-to-centre variability in survival rates of very preterm infants (<32 weeks) over a 10-year-period in Switzerland. AB - BACKGROUND: The publication of Swiss guidelines for the care of infants at the limit of viability (22-25 completed weeks) was followed by increased survival rates in the more mature infants (25 completed weeks). At the same time, considerable centre-to-centre (CTC) differences were noted. OBJECTIVES: To examine the trend of survival rates of borderline viable infants over a 10-year period and to further explore CTC differences. DESIGN: Population-based, retrospective cohort study. SETTING: All nine level III neonatal intensive care units (NICUs) and affiliated paediatric hospitals in Switzerland. PATIENTS: 6532 preterm infants with a gestational age (GA) <32 weeks born alive between 1 January 2000 and 31 December 2009. MAIN OUTCOME MEASURES: Trends of GA-specific delivery room and NICU mortality rates and survival rates to hospital discharge were assessed. For CTC comparisons, centre-specific risk-adjusted ORs for survival were calculated in three GA groups: A: 23 0/7 to 25 6/7 weeks (n=976), B: 26 0/7 to 28 6/7 weeks (n=1943) and C: 29 0/7 to 31 6/7 weeks (n=3399). RESULTS: Survival rates of infants with a GA of 25 completed weeks which had improved from 42% in 2000/2001 to 60% in 2003/2004 remained unchanged at 63% over the next 5 years (2005-2009). Statistically significant CTC differences have persisted and are not restricted to borderline viable infants. CONCLUSIONS: In Switzerland, survival rates of infants born at the limit of viability have remained unchanged over the second half of the current decade. Risk-adjusted CTC outcome variability cannot be explained by differences in baseline demographics or centre case loads. PMID- 22933090 TI - Study of the costs and morbidities of late-preterm birth. AB - OBJECTIVE: To compare late-preterm infants (33-36 weeks) with term infants (>=37 weeks) on incidence of morbidities in the first 3 years of life and healthcare costs during the first 2 years of life and third year of life. METHODS: Administrative health records of live infants born between January 1, 1997, and December 31, 2000 with 3 years follow-up data (N=35733) were linked. First, diagnoses of morbidities were compared between late-preterm and term infants using Cox's proportional hazards models. Healthcare costs expressed as mean total costs and cost ratios, accrued following initial hospital discharge after birth, were also examined. RESULTS: The three most common reasons for hospitalisation in late-preterm and term infants were acute bronchitis, otitis media and pneumonia. The most frequent reasons for physician visits included acute upper respiratory infections, otitis media and bronchiolitis. The highest HR were detected for chronic bronchitis 1.64 (1.13-2.39), hearing loss 1.56 (1.14-2.15) and bacterial diseases 1.28 (1.09-1.49). The mean total cost for late-preterm infants during the first 2 years of life was $2568 CAD compared with $1285 CAD for term infants, cost ratio =1.99 (95% CI 1.90 to 2.09). In the third year of life, the cost ratio reduced to 1.46 (95% CI 1.39 to 1.54). CONCLUSIONS: Late-preterm infants are at higher risk of specific morbidities compared with term infants. Their mean total costs fall from almost double that of term infants during the first 2 years of life, to just 46% greater in the third year of life. PMID- 22933091 TI - Distribution and severity of hypoxic-ischaemic lesions on brain MRI following therapeutic cooling: selective head versus whole body cooling. AB - BACKGROUND: Whole body cooling (WBC) cools different parts of the brain uniformly, and selective head cooling (SHC) cools the superficial brain more than the deeper brain structures. In this study, the authors hypothesised that the hypoxic-ischaemic lesions on brain MRI following cooling would differ between modalities of cooling. AIM: To compare the frequency, distribution and severity of hypoxic-ischaemic lesions on brain MRI between SHC or WBC. METHODS: In a single centre retrospective study, 83 infants consecutively cooled using either SHC (n=34) or WBC (n=49) underwent brain MRI. MRI images were evaluated by a neuroradiologist, who was masked to clinical parameters and outcomes, using a basal ganglia/watershed (BG/W) scoring system. Higher scores (on a scale of 0 to 4) were given for more extensive injury. The score has been reported to be predictive of neuromotor and cognitive outcome at 12 months. RESULTS: The two groups were similar for severity of depression as assessed by a history of an intrapartum sentinel event, Apgar scores, initial blood pH and base deficit and early neurological examination. However, abnormal MRI was more frequent in the SHC group (SHC 25 of 34, 74% vs WBC 22 of 49, 45%; p=0.0132, OR 3.4, 95% CI 1.3 to 8.8). Infants from the SHC group also had more severe hypoxic-ischaemic lesions (median BG/W score: SHC 2 vs WBC 0, p=0.0014). CONCLUSIONS: Hypoxic ischaemic lesions on brain MRI following therapeutic cooling were more frequent and more severe with SHC compared with WBC. PMID- 22933092 TI - Continuous non-invasive cardiac output measurements in the neonate by electrical velocimetry: a comparison with echocardiography. AB - OBJECTIVE: Electrical velocimetry (EV) is a non-invasive method of continuous left cardiac output monitoring based on measurement of thoracic electrical bioimpedance. The objective was to validate EV by investigating the agreement in cardiac output measurements performed by EV and echocardiography. DESIGN: In this prospective observational study, left ventricular output (LVO) was simultaneously measured by EV (LVO(ev)) using Aesculon and by echocardiography (LVO(echo)) in healthy term neonates during the first 2 postnatal days. To determine the agreement between the two methods, we calculated the bias (mean difference) and precision (1.96*SD of the difference). As LVO(echo) has its own limitations, the authors also calculated the 'true precision' of EV adjusted for echocardiography as the reference method. RESULTS: The authors performed 115 paired measurements in 20 neonates. LVO(ev) and LVO(echo) were similar (534+/-105 vs 538+/-105 ml/min, p=0.7). The bias and precision of EV were -4 and 234 ml/min, respectively. The authors found the true precision of EV to be similar to the precision of echocardiography (31.6% vs 30%, respectively). There was no difference in bias and precision between the measurements obtained in patients with or without a haemodynamically significant patent ductus arteriosus. CONCLUSIONS: EV is as accurate in measuring LVO as echocardiography and the variation in the agreement between EV and echocardiography among the individual subjects reflects the limitations of both techniques. PMID- 22933094 TI - Thrombocytopaenia and intraventricular haemorrhage in very premature infants: a tale of two cities. AB - OBJECTIVE: To study whether the incidence of intraventricular haemorrhage (IVH) in very premature infants (<32 weeks gestation) with thrombocytopaenia is lower when using a liberal platelet-transfusion guideline compared with a restrictive guideline. STUDY DESIGN: A retrospective cohort study comparing the incidence of IVH in very premature infants with thrombocytopaenia (platelet count <150*10(9)/l) admitted between 2007 and 2008 to two neonatal intensive care unit in The Netherlands. The restrictive platelet-transfusion unit (N=353 infants <32 weeks gestation) transfused only in case of active haemorrhage and a platelet count <50*10(9)/l. The liberal-transfusion unit (N=326 infants <32 weeks gestation) transfused according to predefined platelet count thresholds. Primary outcome was the incidence and severity of IVH in infants with thrombocytopaenia in both units. RESULTS: The number of infants with thrombocytopaenia that received a platelet transfusion was significantly lower in the restrictive transfusion unit compared with the liberal-transfusion unit, 15% (21/145) versus 31% (41/141), (p<0.001). The incidence of IVH in infants with thrombocytopaenia in the restrictive-transfusion and liberal-transfusion units was 30% (44/145) and 29% (41/141), respectively (p=0.81). The incidence of severe IVH (grade 3 or 4) in the restrictive-transfusion and liberal-transfusion units was 8% (12/145) and 11% (16/141), respectively (p=0.38). CONCLUSION: In the restrictive-transfusion unit, the rate of platelet transfusions was significantly lower, but the incidence and severity of IVH was similar to the liberal-transfusion unit. PMID- 22933093 TI - Superior vena cava flow and management of neonates with vein of Galen malformation. AB - OBJECTIVE: Vein of Galen malformation (VGAM) in neonates presents a complex management challenge. Measurement of superior vena cava (SVC) blood flow may provide insights into the haemodynamics of VGAM and the effects of therapeutic intervention. METHODS: SVC flow was assessed in 15 neonates with VGAM. SVC flow results, Bicetre scores (clinical assessment), echocardiographic assessment and clinical outcomes are presented. RESULTS: SVC flows (166-581 ml/kg/min) were significantly elevated at presentation (p<0.001; normal range 55-111 ml/kg/min). Endovascular intervention was undertaken in 12 cases, with nine survivors. SVC flows decreased sequentially with each embolisation, with a median SVC flow at discharge of 124 ml/kg/min (IQR 79-155 ml/kg/min). All cases with SVC flow >400 ml/kg/min (n=5) had an adverse outcome (death or profound neurological damage). Cases with SVC flow <400 ml/kg (n=10) required embolisation before discharge at a median age of 6 days. There were no survivors with Bicetre scores <8 (n=2) but the predictive value of early Bicetre score was poor. CONCLUSIONS: SVC flow measurements provide insight into the haemodynamic challenges of VGAM and provide additional useful prognostic information. PMID- 22933095 TI - Epidemiology of small intestinal atresia in Europe: a register-based study. AB - BACKGROUND: The epidemiology of congenital small intestinal atresia (SIA) has not been well studied. This study describes the presence of additional anomalies, pregnancy outcomes, total prevalence and association with maternal age in SIA cases in Europe. METHODS: Cases of SIA delivered during January 1990 to December 2006 notified to 20 EUROCAT registers formed the population-based case series. Prevalence over time was estimated using multilevel Poisson regression, and heterogeneity between registers was evaluated from the random component of the intercept. RESULTS: In total 1133 SIA cases were reported among 5126, 164 registered births. Of 1044 singleton cases, 215 (20.6%) cases were associated with a chromosomal anomaly. Of 829 singleton SIA cases with normal karyotype, 221 (26.7%) were associated with other structural anomalies. Considering cases with normal karyotype, the total prevalence per 10 000 births was 1.6 (95% CI 1.5 to 1.7) for SIA, 0.9 (95% CI 0.8 to 1.0) for duodenal atresia and 0.7 (95% CI 0.7 to 0.8) for jejunoileal atresia (JIA). There was no significant trend in SIA, duodenal atresia or JIA prevalence over time (RR=1.0, 95% credible interval (CrI): 1.0 to 1.0 for each), but SIA and duodenal atresia prevalence varied by geographical location (p=0.03 and p=0.04, respectively). There was weak evidence of an increased risk of SIA in mothers aged less than 20 years compared with mothers aged 20 to 29 years (RR=1.3, 95% CrI: 1.0 to 1.8). CONCLUSION: This study found no evidence of a temporal trend in the prevalence of SIA, duodenal atresia or JIA, although SIA and duodenal atresia prevalence varied significantly between registers. PMID- 22933096 TI - Provision of servo-controlled cooling during neonatal transport. AB - INTRODUCTION: Therapeutic hypothermia is a time critical intervention for infants who have experienced a hypoxic-ischaemic event. Previously reported methods of cooling during transport do not demonstrate the same stability achieved in the neonatal unit. The authors developed a system which allowed provision of servo controlled cooling throughout transport, and present their first year's experience. METHODS: Retrospective review of routinely collected patient data. RESULTS: 14 out-born infants were referred for cooling during a 12-month period. Nine infants were managed with the servo-controlled system during transport. Cooling was commenced in all infants before 6 h of life. Median time from team arrival to the infant having a temperature in the target range (33-34 degrees C) was 45 min. Median temperature during transfer was 33.5 degrees C (range 33-34 degrees C). Temperature on arrival at the cooling centre ranged from 33.4 degrees C to 33.8 degrees C. CONCLUSION: Servo-controlled cooling during transport is feasible and provides an optimal level of thermal control. PMID- 22933098 TI - An interlabial mass. PMID- 22933097 TI - Procalcitonin in detecting neonatal nosocomial sepsis. AB - OBJECTIVE: To investigate the accuracy of procalcitonin (PCT) as a diagnostic marker of nosocomial sepsis (NS) and define the most accurate cut-off to distinguish infected from uninfected neonates. SETTING: Six neonatal intensive care units (NICUs). PATIENTS: 762 neonates admitted to six NICUs during a 28 month observational study for whom at least one serum sample was taken on admission. MAIN OUTCOME MEASURES: Positive and negative predictive values at different PCT cut-off levels. RESULTS: The overall probability of an NS was doubled or more if PCT was >0.5 ng/ml. In very-low-birth-weight (VLBW) infants, a cut-off of >2.4 ng/ml gave a positive predictive value of NS near to 50% with a probability of a false-positive diagnosis of NS in about 10% of the patients. CONCLUSIONS: In VLBW neonates, a serum PCT value >2.4 ng/ml prompts early empirical antibiotic therapy, while in normal-birth-weight infants, a PCT value <=2.4 ng/ml carries a low risk of missing an NS. PMID- 22933099 TI - Neonatal stroke. AB - Neonatal stroke encompasses a range of focal and multifocal ischaemic and haemorrhagic tissue injuries. This review will concentrate on focal brain injury that occurs as a consequence of arterial infarction, most frequently the left middle cerebral artery, or more rarely as a consequence of cerebral sinus venous thrombosis (CSVT). Both conditions are multifactorial in origin. The incidence of both acquired and genetic thrombophilic disorders in both mothers and infants is high although rarely causal in isolation. Neurodevelopmental morbidity occurs in over 50% of children. Specific therapy in the form of anticoagulation is currently only recommended in CSVT and needs to be carefully monitored in the presence of haemorrhage. PMID- 22933100 TI - How reliably can paediatric professionals identify pale stool from cholestatic newborns? AB - BACKGROUND: The success of surgery in infants with hepatobiliary disease is inversely proportional to the age when surgery was performed. Pale stool colour is a major indicator of biliary obstruction. However, simple recognition has been inadequate, resulting in late diagnosis and referral. Objective To assess the skills of healthcare professionals in recognising pale stools. METHOD: Photographs of normal, acholic and indeterminate infant stools were shown to paediatric professionals who have regular contact with jaundiced babies at three London teaching hospitals. Each stool was classified as 'healthy' or 'suspect'. RESULTS: One-third of the stools were not correctly identified by physicians and nurses. CONCLUSION: Experienced professionals often do not recognise stool colour associated with biliary obstruction. The authors propose that stool colour cards similar to those used in Japan and Taiwan may improve early detection of hepatobiliary disease at a minimal cost. PMID- 22933101 TI - Congenital right-sided para-umbilical abdominal wall hernia. PMID- 22933102 TI - Determination of the nonlethal margin inside the visible "ice-ball" during percutaneous cryoablation of renal tissue. AB - OBJECTIVE: The study was designed to determine the distance between the visible "ice-ball" and the lethal temperature isotherm for normal renal tissue during cryoablation. METHODS: The Animal Care Committee approved the study. Nine adult swine were used: three to determine the optimum tissue stain and six to test the hypotheses. They were anesthetized and the left renal artery was catheterized under fluoroscopy. Under MR guidance, the kidney was ablated and (at end of a complete ablation) the nonfrozen renal tissue (surrounding the "ice-ball") was stained via renal artery catheter. Kidneys were explanted and sent for slide preparation and examination. From each slide, we measured the maximum, minimum, and an in-between distance from the stained to the lethal tissue boundaries (margin). We examined each slide for evidence of "heat pump" effect. RESULTS: A total of 126 measurements of the margin (visible "ice-ball"-lethal margin) were made. These measurements were obtained from 29 slides prepared from the 6 test animals. Mean width was 0.75 +/- 0.44 mm (maximum 1.15 +/- 0.51 mm). It was found to increase adjacent to large blood vessels. No "heat pump" effect was noted within the lethal zone. Data are limited to normal swine renal tissue. CONCLUSIONS: Considering the effects of the "heat pump" phenomenon for normal renal tissue, the margin was measured to be 1.15 +/- 0.51 mm. To approximate the efficacy of the "gold standard" (partial nephrectomy, ~98 %), a minimum margin of 3 mm is recommended (3 * SD). Given these assumptions and extrapolating for renal cancer, which reportedly is more cryoresistant with a lethal temperature of -40 degrees C, the recommended margin is 6 mm. PMID- 22933103 TI - An assessment of heavy metal contamination in soils of fresh water aquifer system and evaluation of eco-toxicity by lithogenic implications. AB - The chemistry of heavy metals in sediments with respect to bio-availability and chemical reactivity is regulated by pH, texture, and organic matter contents of the sediments and specific binding form and coupled reactivity of the metals within. To focus on the metal distribution (Fe, Mn, Pb, Cd, Zn, Co, Cu, and Cr) and behavior in a fresh water aquifer system along with the ecological toxicity parameters, a four-step sequential extraction method was applied on 18 Eastern Ghats' type sediments from fluorosis-hit Nayagarh district, India. Geo accumulation index of metals in the sediments indicates that they are practically uncontaminated and/or less contaminated with and Fe, Mn, and Cu; contaminated to moderately contaminated with Pb, Zn, and Cr; and strongly contaminated with Cd. Rather, more than 80 % recovered Cd metal concentration in sediments constitute the labile fractions. Temporal clustering of metal fractions indicates transition metal fraction distribution claiming the sediment pH regulation. Similarly, base metal distribution accounts for organic carbon and soil conductivity due to their greater availability in exchangeable and sulfide fractions. Correlation analysis and factor analysis scores demonstrate lack of inter-relationship between transition group and base metal fractions. High fluoride concentration in ground water is associated with high sodium-bicarbonate-iron affinity with elevated pH values (i.e., >7.0) and high positive factor score with the total iron concentration in ground water. PMID- 22933104 TI - A physicochemical model of sorption processes in NO2 passive sampling with air humidity effects. AB - Aqueous triethanolamine (TEA) solutions are widely used as sorption medium for passive sampling of ambient NO(2), with NO(2) trapped and accumulated as nitrite ion. The results of test measurements of ambient NO(2) concentrations using passive sampling method showed that the simple approach commonly used to describe passive sampling process might lead to substantial systematic errors. Presented in the article is a new physicochemical model of the process of passive sampling of gaseous NO(2), with aqueous TEA solution used as a trapping medium. The model is based on the available results of experimental studies of interaction of gaseous NO(2) with TEA/water solutions. The key principles underlying the model are: (1) when absorbed by a trapping solution, NO(2) forms nitrite ion only on the condition that TEA is hydrated; (2) coefficient of conversion of NO(2) to NO(2)(-) is equal to one when reacting with hydrated TEA; and (3) the fraction of hydrated TEA molecules depends on air humidity at the moment of measurement. Validation of the model was made using the data of the field measurements carried out in the Middle Urals in 2007-2009. The new model was used to calculate average NO(2) concentrations. Concentrations calculated agreed well with the results obtained by reference methods. The difference between the datasets was statistically insignificant. PMID- 22933105 TI - Evaluation of possible health risks of heavy metals by consumption of foodstuffs available in the central market of Rajshahi City, Bangladesh. AB - Considering the human health risk due to the consumption of foodstuffs, the concentrations of heavy metals (lead, manganese, chromium, cadmium, and arsenic) are investigated in vegetables, fruits, and fish species collected from the central market (called Shaheb Bazar) of Rajshahi City, Bangladesh. The foodstuffs examined for metal constituents are the basis of human nutrition in the study area. The highest concentrations of Mn and As in vegetables (onion and pointed gourd, respectively), Cr and Cd in fruits (black berry and mango, respectively), and Pb in fish (catla) are recorded. Health risks associated with these heavy metals are evaluated due to dietary intake. Target hazard quotient (THQ) and hazard index (HI) are calculated to evaluate the non-carcinogenic health risk from individual and combined heavy metals. The THQ values for individual heavy metals are below 1, suggesting that people would not experience significant health risks if they ingest a single heavy metal from one kind of foodstuff (e.g., vegetables). However, consumption of several of the foodstuffs could lead a potential health risk to human population since HI value is higher than 1. The relative contributions of vegetables, fishes, and fruits to HI are 49.44, 39.07, and 11.53 %, respectively. Also, the relative contributions of Pb, Cd, As, Mn, and Cr to HI are 51.81, 35.55, 11.73, 0.85, and 0.02 %, respectively. The estimation shows that the carcinogenic risk of arsenic exceeds the accepted risk level of 1 * 10(-6). Thus, the carcinogenic risk of arsenic for consumers is a matter of concern. PMID- 22933106 TI - Activation of enteroendocrine membrane progesterone receptors promotes incretin secretion and improves glucose tolerance in mice. AB - Glucagon-like peptide-1 (GLP-1) secretion is classically regulated by ingested nutrients. To identify novel molecular targets controlling incretin secretion, we analyzed enteroendocrine cell pathways important for hormone biosynthesis and secretion. We demonstrate that progesterone increases GLP-1 secretion and extracellular signal-related kinase 1/2 (ERK1/2) phosphorylation in enteroendocrine GLUTag cells via mechanisms sensitive to the mitogen-activated protein kinase inhibitor U0126. The stimulatory effects of progesterone (P4) or the synthetic progestin R5020 on ERK1/2 phosphorylation were independent of the classical progesterone receptor antagonist RU486. Furthermore, a cell-impermeable BSA-progesterone conjugate rapidly increased ERK1/2 phosphorylation and GLP-1 secretion. Knockdown of the membrane progesterone receptors Paqr5 or Paqr7 in GLUTag cells eliminated the stimulatory effect of R5020 and progesterone on GLP-1 secretion. Enteral progesterone administration increased plasma levels of GLP-1, glucose-dependent insulinotropic polypeptide (GIP), and insulin, and improved oral glucose tolerance in an RU486-insensitve manner in mice: however, systemic progesterone exposure did not improve glucose homeostasis. Unexpectedly, the glucoregulatory actions of enteral progesterone did not require classical incretin receptor signaling and were preserved in Glp1r(-/-) and Glp1r(-/-):Gipr( /-) mice. Intestine-restricted activation of membrane progesterone receptors may represent a novel approach for stimulation of incretin hormone secretion and control of glucose homeostasis. PMID- 22933107 TI - Manganese-enhanced magnetic resonance imaging detects declining pancreatic beta cell mass in a cyclophosphamide-accelerated mouse model of type 1 diabetes. AB - Currently, there is no ideal noninvasive method to quantify the progressive loss of pancreatic beta-cell mass (BCM) that occurs in type 1 diabetes. Magnetic resonance imaging has detected gross differences in BCM between healthy and diabetic mice using the contrast agent manganese, which labels functional beta cells and increases the water proton relaxation rate (R1), but its ability to measure gradations in BCM during disease progression is unknown. Our objective was to test the hypothesis that measurements of the manganese-enhanced pancreatic R1 could detect decreasing BCM in a mouse model of type 1 diabetes. We used cyclophosphamide-accelerated BDC2.5 T-cell receptor transgenic nonobese diabetic mice, which experience development of type 1 diabetes during a 7-day time period after cyclophosphamide injection, whereas transgene-negative mice do not. We measured the manganese-enhanced pancreatic R1 before cyclophosphamide injection (day 0) and on days 3, 4, 5, and 7 afterward. Pancreatic R1 remained constant in transgene-negative mice and decreased stepwise day-to-day in transgene-positive mice, mirroring their loss of BCM, confirmed by pancreatic insulin measurements and histology. Changes in R1 in transgene-positive mice occurred before elevations in blood glucose, a clinical indicator of diabetes, suggesting potential for early noninvasive detection of changes in functional BCM. PMID- 22933108 TI - Loss of ACE2 exaggerates high-calorie diet-induced insulin resistance by reduction of GLUT4 in mice. AB - ACE type 2 (ACE2) functions as a negative regulator of the renin-angiotensin system by cleaving angiotensin II (AII) into angiotensin 1-7 (A1-7). This study assessed the role of endogenous ACE2 in maintaining insulin sensitivity. Twelve week-old male ACE2 knockout (ACE2KO) mice had normal insulin sensitivities when fed a standard diet. AII infusion or a high-fat, high-sucrose (HFHS) diet impaired glucose tolerance and insulin sensitivity more severely in ACE2KO mice than in their wild-type (WT) littermates. The strain difference in glucose tolerance was not eliminated by an AII receptor type 1 (AT1) blocker but was eradicated by A1-7 or an AT1 blocker combined with the A1-7 inhibitor (A779). The expression of GLUT4 and a transcriptional factor, myocyte enhancer factor (MEF) 2A, was dramatically reduced in the skeletal muscles of the standard diet-fed ACE2KO mice. The expression of GLUT4 and MEF2A was increased by A1-7 in ACE2KO mice and decreased by A779 in WT mice. A1-7 enhanced upregulation of MEF2A and GLUT4 during differentiation of myoblast cells. In conclusion, ACE2 protects against high-calorie diet-induced insulin resistance in mice. This mechanism may involve the transcriptional regulation of GLUT4 via an A1-7-dependent pathway. PMID- 22933109 TI - The apoptosis inhibitor ARC alleviates the ER stress response to promote beta cell survival. AB - Type 2 diabetes involves insulin resistance and beta-cell failure leading to inadequate insulin secretion. An important component of beta-cell failure is cell loss by apoptosis. Apoptosis repressor with caspase recruitment domain (ARC) is an inhibitor of apoptosis that is expressed in cardiac and skeletal myocytes and neurons. ARC possesses the unusual property of antagonizing both the extrinsic (death receptor) and intrinsic (mitochondria/endoplasmic reticulum [ER]) cell death pathways. Here we report that ARC protein is abundant in cells of the endocrine pancreas, including >99.5% of mouse and 73% of human beta-cells. Using genetic gain- and loss-of-function approaches, our data demonstrate that ARC inhibits beta-cell apoptosis elicited by multiple inducers of cell death, including ER stressors tunicamycin, thapsigargin, and physiological concentrations of palmitate. Unexpectedly, ARC diminishes the ER stress response, acting distal to protein kinase RNA-like ER kinase (PERK) and inositol-requiring protein 1alpha, to suppress C/EBP homologous protein (CHOP) induction. Depletion of ARC in isolated islets augments palmitate-induced apoptosis, which is dramatically rescued by deletion of CHOP. These data demonstrate that ARC is a previously unrecognized inhibitor of apoptosis in beta-cells and that its protective effects are mediated through suppression of the ER stress response pathway. PMID- 22933110 TI - PPARdelta activation protects endothelial function in diabetic mice. AB - Recent evidence highlights the therapeutic potential of peroxisome proliferator activated receptor-delta (PPARdelta) agonists to increase insulin sensitivity in diabetes. However, the role of PPARdelta in regulating vascular function is incompletely characterized. We investigate whether PPARdelta activation improves endothelial function in diabetic and obese mice. PPARdelta knockout (KO) and wild type (WT) mice fed with high-fat diet and db/db mice were used as diabetic mouse models, compared with PPARdelta KO and WT mice on normal diet and db/m(+) mice. Endothelium-dependent relaxation (EDR) was measured by wire myograph. Flow mediated vasodilatation (FMD) was measured by pressure myograph. Nitric oxide (NO) production was examined in primary endothelial cells from mouse aortae. PPARdelta agonist GW1516 restored EDRs in mouse aortae under high-glucose conditions or in db/db mouse aortae ex vivo. After oral treatment with GW1516, EDRs in aortae and FMDs in mesenteric resistance arteries were improved in obese mice in a PPARdelta-specific manner. The effects of GW1516 on endothelial function were mediated through phosphatidylinositol 3-kinase (PI3K) and Akt with a subsequent increase of endothelial nitric oxide synthase (eNOS) activity and NO production. The current study demonstrates an endothelial-protective effect of PPARdelta agonists in diabetic mice through PI3K/Akt/eNOS signaling, suggesting the therapeutic potential of PPARdelta agonists for diabetic vasculopathy. PMID- 22933111 TI - Increased hepatic glucose production in fetal sheep with intrauterine growth restriction is not suppressed by insulin. AB - Intrauterine growth restriction (IUGR) increases the risk for metabolic disease and diabetes, although the developmental origins of this remain unclear. We measured glucose metabolism during basal and insulin clamp periods in a fetal sheep model of placental insufficiency and IUGR. Compared with control fetuses (CON), fetuses with IUGR had increased basal glucose production rates and hepatic PEPCK and glucose-6-phosphatase expression, which were not suppressed by insulin. In contrast, insulin significantly increased peripheral glucose utilization rates in CON and IUGR fetuses. Insulin robustly activated AKT, GSK3beta, and forkhead box class O (FOXO)1 in CON and IUGR fetal livers. IUGR livers, however, had increased basal FOXO1 phosphorylation, nuclear FOXO1 expression, and Jun NH(2) terminal kinase activation during hyperinsulinemia. Expression of peroxisome proliferator-activated receptor gamma coactivator 1alpha and hepatocyte nuclear factor-4alpha were increased in IUGR livers during basal and insulin periods. Cortisol and norepinephrine concentrations were positively correlated with glucose production rates. Isolated IUGR hepatocytes maintained increased glucose production in culture. In summary, fetal sheep with IUGR have increased hepatic glucose production, which is not suppressed by insulin despite insulin sensitivity for peripheral glucose utilization. These data are consistent with a novel mechanism involving persistent transcriptional activation in the liver that seems to be unique in the fetus with IUGR. PMID- 22933112 TI - Altered MAPK signaling in progressive deterioration of endothelial function in diabetic mice. AB - We aimed to investigate specific roles of mitogen-activated protein kinases (MAPK) in the deterioration of endothelial function during the progression of diabetes and the potential therapeutic effects of MAPK inhibitors and agonists in the amelioration of endothelial function. Protein expression and phosphorylation of p38, c-Jun NH(2)-terminal kinase (JNK), and extracellular signal-regulated kinase (Erk) were assessed in mesenteric arteries of 3- (3M) and 9-month-old (9M) male diabetic and control mice. The expression of p38, JNK, and Erk was comparable in all groups of mice, but the phosphorylation of p38 and JNK was increased in 3M and further increased in 9M diabetic mice, whereas the phosphorylation of Erk was substantially reduced in 9M diabetic mice. NADPH oxidase-dependent superoxide production was significantly increased in vessels of two ages of diabetic mice. Inhibition of either p38 with SB203580 or JNK with SP600125 reduced superoxide production and improved shear stress-induced dilation (SSID) in 3M, but not in 9M, diabetic mice. Treating the vessels of 9M diabetic mice with resveratrol increased Erk phosphorylation and shear stress-induced endothelial nitric oxide synthase (eNOS) phosphorylation and activity, but resveratrol alone did not improve SSID. Administration of resveratrol and SB203580 or resveratrol and SP600125 together significantly improved SSID in vessels of 9M diabetic mice. The improved response was prevented by U0126, an Erk inhibitor. Thus, p38/JNK-dependent increase in oxidative stress diminished nitric oxide-mediated dilation in vessels of 3M diabetic mice. Oxidative stress and impaired Erk-dependent activation of eNOS exacerbates endothelial dysfunction in the advanced stage of diabetes. PMID- 22933113 TI - Autocrine function of aldehyde dehydrogenase 1 as a determinant of diet- and sex specific differences in visceral adiposity. AB - Mechanisms for sex- and depot-specific fat formation are unclear. We investigated the role of retinoic acid (RA) production by aldehyde dehydrogenase 1 (Aldh1a1, a2, and -a3), the major RA-producing enzymes, on sex-specific fat depot formation. Female Aldh1a1(-/-) mice, but not males, were resistant to high-fat (HF) diet-induced visceral adipose formation, whereas subcutaneous fat was reduced similarly in both groups. Sexual dimorphism in visceral fat (VF) was attributable to elevated adipose triglyceride lipase (Atgl) protein expression localized in clusters of multilocular uncoupling protein 1 (Ucp1)-positive cells in female Aldh1a1(-/-) mice compared with males. Estrogen decreased Aldh1a3 expression, limiting conversion of retinaldehyde (Rald) to RA. Rald effectively induced Atgl levels via nongenomic mechanisms, demonstrating indirect regulation by estrogen. Experiments in transgenic mice expressing an RA receptor response element (RARE-lacZ) revealed HF diet-induced RARE activation in VF of females but not males. In humans, stromal cells isolated from VF of obese subjects also expressed higher levels of Aldh1 enzymes compared with lean subjects. Our data suggest that an HF diet mediates VF formation through a sex-specific autocrine Aldh1 switch, in which Rald-mediated lipolysis in Ucp1-positive visceral adipocytes is replaced by RA-mediated lipid accumulation. Our data suggest that Aldh1 is a potential target for sex-specific antiobesity therapy. PMID- 22933114 TI - Bcl-2 and Bcl-xL suppress glucose signaling in pancreatic beta-cells. AB - B-cell lymphoma 2 (Bcl-2) family proteins are established regulators of cell survival, but their involvement in the normal function of primary cells has only recently begun to receive attention. In this study, we demonstrate that chemical and genetic loss-of-function of antiapoptotic Bcl-2 and Bcl-x(L) significantly augments glucose-dependent metabolic and Ca(2+) signals in primary pancreatic beta-cells. Antagonism of Bcl-2/Bcl-x(L) by two distinct small-molecule compounds rapidly hyperpolarized beta-cell mitochondria, increased cytosolic Ca(2+), and stimulated insulin release via the ATP-dependent pathway in beta-cell under substimulatory glucose conditions. Experiments with single and double Bax-Bak knockout beta-cells established that this occurred independently of these proapoptotic binding partners. Pancreatic beta-cells from Bcl-2(-/-) mice responded to glucose with significantly increased NAD(P)H levels and cytosolic Ca(2+) signals, as well as significantly augmented insulin secretion. Inducible deletion of Bcl-x(L) in adult mouse beta-cells also increased glucose-stimulated NAD(P)H and Ca(2+) responses and resulted in an improvement of in vivo glucose tolerance in the conditional Bcl-x(L) knockout animals. Our work suggests that prosurvival Bcl proteins normally dampen the beta-cell response to glucose and thus reveals these core apoptosis proteins as integrators of cell death and physiology in pancreatic beta-cells. PMID- 22933115 TI - NADPH oxidase NOX2 defines a new antagonistic role for reactive oxygen species and cAMP/PKA in the regulation of insulin secretion. AB - In insulin-secreting cells, expression of NADPH oxidase (NOX), a potent source of ROS, has been reported, along with controversial findings regarding its function. Here, the role of NOXs was investigated: first by expression and cellular localization in mouse and human pancreatic islets, and then by functional studies in islets isolated from Nox isoform-specific knockout mice. Both human and mouse beta-cells express NOX, in particular NOX2. With use of Nox isoform-specific knockout mice, functional analysis revealed Nox2 as the predominant isoform. In human islets, NOX2 colocalized with both insulin granules and endosome/lysosome membranes. Nox2-deficient islets stimulated with 22.8 mmol/L glucose exhibited potentiation of insulin release compared with controls, an effect confirmed with in vitro knockdown of Nox2. The enhanced secretory function in Nox2-deficient islets was associated with both lower superoxide levels and elevated cAMP concentrations. In control islets, GLP-1 and other cAMP inducers suppressed glucose-induced ROS production similarly to Nox2 deficiency. Inhibiting cAMP dependent protein kinase reduced the secretory response in Nox2-null islets, although not in control islets. This study ascribes a new role for NOX2 in pancreatic beta-cells as negative modulator of the secretory response, reducing cAMP/PKA signaling secondary to ROS generation. Results also show reciprocal inhibition between the cAMP/PKA pathway and ROS. PMID- 22933116 TI - Direct control of brown adipose tissue thermogenesis by central nervous system glucagon-like peptide-1 receptor signaling. AB - We studied interscapular brown adipose tissue (iBAT) activity in wild-type (WT) and glucagon-like peptide 1 receptor (GLP-1R)-deficient mice after the administration of the proglucagon-derived peptides (PGDPs) glucagon-like peptide (GLP-1), glucagon (GCG), and oxyntomodulin (OXM) directly into the brain. Intracerebroventricular injection of PGDPs reduces body weight and increases iBAT thermogenesis. This was independent of changes in feeding and insulin responsiveness but correlated with increased activity of sympathetic fibers innervating brown adipose tissue (BAT). Despite being a GCG receptor agonist, OXM requires GLP-1R activation to induce iBAT thermogenesis. The increase in thermogenesis in WT mice correlates with increased expression of genes upregulated by adrenergic signaling and required for iBAT thermogenesis, including PGC1a and UCP-1. In spite of the increase in iBAT thermogenesis induced by GLP-1R activation in WT mice, Glp1r(-/-) mice exhibit a normal response to cold exposure, demonstrating that endogenous GLP-1R signaling is not essential for appropriate thermogenic response after cold exposure. Our data suggest that the increase in BAT thermogenesis may be an additional mechanism whereby pharmacological GLP-1R activation controls energy balance. PMID- 22933117 TI - Activin receptor-like kinase 7 suppresses lipolysis to accumulate fat in obesity through downregulation of peroxisome proliferator-activated receptor gamma and C/EBPalpha. AB - We previously identified a quantitative trait locus for adiposity, non-insulin dependent diabetes 5 (Nidd5), on mouse chromosome 2. In the current study, we identified the actual genetic alteration at Nidd5 as a nonsense mutation of the Acvr1c gene encoding activin receptor-like kinase 7 (ALK7), one of the type I transforming growth factor-beta receptors, which results in a COOH-terminal deletion of the kinase domain. We further showed that the ALK7 dysfunction causes increased lipolysis in adipocytes and leads to decreased fat accumulation. Conversely, ALK7 activation inhibits lipolysis by suppressing the expression of adipose lipases. ALK7 and activated Smads repress those lipases by downregulating peroxisome proliferator-activated receptor gamma (PPARgamma) and CCAAT/enhancer binding protein (C/EBP) alpha. Although PPARgamma and C/EBPalpha act as adipogenic transcription factors during adipocyte differentiation, they are lipolytic in sum in differentiated adipocytes and are downregulated by ALK7 in obesity to accumulate fat. Under the obese state, ALK7 deficiency improves glucose tolerance and insulin sensitivity by preferentially increasing fat combustion in mice. These findings have uncovered a net lipolytic function of PPARgamma and C/EBPalpha in differentiated adipocytes and point to the ALK7 signaling pathway that is activated in obesity as a potential target of medical intervention. PMID- 22933118 TI - Mobilization of Stowaway-like MITEs in newly formed allohexaploid wheat species. AB - Transposable elements (TEs) dominate the genetic capacity of most eukaryotes, especially plants, where they can account for up to 90 % of the genome, such as in wheat. The relationship between TEs and their hosts and the role of TEs in organismal biology are poorly understood. In this study, we have applied next generation sequencing, together with a transposon display technique in order to test whether a Stowaway-like MITE, termed Minos, transposes following allopolyploidization events in wheat. We have generated a 454-pyrosequencing database of Minos-specific amplicons (transposon display products) from a newly formed wheat allohexaploid and its parental lines and retrieved hundreds of novel MITE insertions in the allohexaploid. Clear mobilization of Minos was also seen by site-specific PCR analysis and sequence validation. In addition, using real time qPCR analysis we observed an insignificant change in the relative quantity of Minos from the expected value of merging the two parental genomes, indicating that, despite its activation, no significant burst in Minos copy number can be seen in the newly formed allohexaploid. Interestingly, we found that CCGG sites surrounding Minos underwent massive hypermethylation following the allohexaploidization process. Our data suggest that MITEs have maintained their capacity for activity throughout the evolution of wheat and might be epigenetically deregulated in the first generations following allopolyploidization. PMID- 22933120 TI - Intra-operative hydrotubation improves fertility of women with distal tubal occlusion after reproductive surgery. AB - PURPOSE: Hydrotubation has been considered to be a complimentary procedure to reproductive surgery, usually being conducted after surgery. The objective of this work was to assess the potential value of intra-operative hydrotubation in improving fertility of tubal infertile women. METHODS: 180 tubal infertile women were randomly assigned to one of the three groups: intra-operative hydrotubation (IH), post-operative hydrotubation (PH) or control group. In IH group, the hydrotubation was performed immediately after adhesiolysis during the surgery process, while in PH group it was performed within 3-7 days after the first post operative menstruation. The incidence of post-operative pelvic infection and average hospitalization length were recorded. The post-operative pregnancy outcomes, including intrauterine pregnancy (IUP) rate and incidence of ectopic pregnancy, were recorded at 2 years follow-up. RESULTS: No significant difference was found among the three groups, either in the incidence of pelvic infection (P = 0.877) or in the average hospitalization length (P = 0.596). At 2 years of follow-up, the rate of IUP in IH group was significantly higher than that in either PH or control group (P = 0.017 and 0.039, respectively), but no difference was observed between PH and control group (P = 0.752). No significant difference in the incidence of ectopic pregnancy was showed among three groups (P = 0.947). CONCLUSIONS: The appropriate use of intra-operative hydrotubation can improve the post-operative IUP rate, serving as a complementary procedure for the surgical treatment of fertility reversal. PMID- 22933119 TI - Characterization of Osmads6-5, a null allele, reveals that OsMADS6 is a critical regulator for early flower development in rice (Oryza sativa L.). AB - AGL6-clade genes are a subfamily of MADS-box genes and preferentially expressed in floral organs. OsMADS6 and OsMADS17 are two AGL6-like genes in rice. OsMADS17 has been shown to play a minor role in floral development and appears to result from a duplication of OsMADS6. OsMADS6 was initially named as MFO1 for mosaic floral organs based on its moderate mutant phenotypes. So far, four moderate or weak mutant alleles of OsMADS6 have been described, providing valuable insights into its role in flower development. Here, we report a null allele of OsMADS6 (Osmads6-5), which exhibited a strong mutant phenotype in spikelet without affecting vegetative traits, causing all floral organs except lemma homeotically transformed into lemma-like organs (LLOs) as well as an indeterminate floral meristem, thus resulting in a mutant floret consisting of reiterating whorls of lemma and LLOs. In consistently, over-expression of OsMADS6 led to additional lodicule-, stamen- and carpel-like organs. Expression analysis showed that OsMADS6 controls the formation of the incipient primordia of lodicule, stamen and carpel via regulating the expression of class B, C and SEP-like MADS-box genes. Taken together, our results revealed that OsMADS6 acts as a critical regulator for early flower development in rice and provide novel insights into the molecular mechanism of OsMADS6. PMID- 22933121 TI - Comparison of robotic-assisted laparoscopic myomectomy outcomes with laparoscopic myomectomy. AB - PURPOSE: This study aimed at comparing short-term outcomes of patients who underwent robotic-assisted laparoscopic myomectomy and laparoscopic myomectomy. METHODS: From January 2008 to August 2010, prospective data including 15 consecutive patients who underwent robotic-assisted myomectomy (RALM) with the da Vinci surgical system were recorded. These cases were compared with a retrospective cohort of 23 patients who underwent laparoscopic myomectomy (LM). Patient demographics, fibroid characteristics and peri-operative data (operative time, anesthesia time, set-up time, console time for robotic cohort, Estimated blood loss (EBL), length of hospital stay, conversion to laparotomy and operative complications were collected in both groups. RESULTS: Mean operative time for the robotic group was 138.73 +/- 39.51 min compared with 140.57 +/- 38.17 min for the laparoscopy group (p = 0.887). No significant differences were noted between RALM versus LM for hospital stay (1.67 +/- 0.58 vs. 1.87 +/- 0.67 days, p = 0.369) and EBL (101.33 +/- 39.84 vs. 119.78 +/- 43.70 ml, p = 0.549). The numbers, size and location of myomas removed for two groups were similar. None of the cases in both groups required conversion to laparotomy. There were no significant intra operative and post-operative complications in either group. CONCLUSION: RALM appears to provide the same surgical outcomes when compared with traditional laparoscopic myomectomy. PMID- 22933122 TI - Rise in cesarean section rate over a 20-year period in a public sector hospital in northern Thailand. AB - OBJECTIVE: To determine a trend of cesarean section rate (CSR) and main contributing factors in a public sector hospital, representing northern part of Thailand. METHODS: A retrospective descriptive analysis was conducted by assessing the database of maternal-fetal medicine unit, which had prospectively been collected for 20 years. Trends were evaluated using data for the years 1992 2011. Private sector patients were excluded. RESULTS: A total of 50,872 public sector patients were available for analysis. The number of deliveries was gradually decreased from 3,802 in 1992 to 1,748 in 2011. Of them, 7,480 underwent cesarean section, CSR of 14.7 %. However, the CSR was significantly increased from 11.3 % in 1992 to 23.6 % in 2011 (p value <0.001). The CSRs indicated by cephalopelvic disproportion (CPD) and previous CSs were mainly responsible for a marked increase over the study period. CSR due to CPD was increased from 3.2 % in 1992 to 7.9 % in 2011 (p value <0.0001). While CSR due to other indications either breech presentation, fetal distress and twin pregnancies were only slightly, but significantly increased in the last decades but they are relatively constant in the recent years. CONCLUSIONS: In our public sector, CSR has gradually increased. The main reasons of such an increase were likely to be associated with over-diagnosis of CPD and subsequent repeated CS, while other indications played only a minimal role. To achieve the appropriate CSR, audit system for diagnosis of CPD must be instituted. PMID- 22933124 TI - Ferromagnetic heteronuclear {Fe4(Er,Lu)2} cyclic coordination clusters based on ferric wheels. AB - A new family of hexanuclear ferric-lanthanide [Fe(III)(4)Ln(III)(2)(Htea)(4)(Piv)(6)(N(3))(4)] clusters, where Ln(III) = Er(1) and Lu(2) is reported. Variable temperature solid-state magnetic susceptibility studies of 1 and 2 reveal the presence of ferromagnetic (1) or competing anti- and ferromagnetic exchange interactions (2) between the constituent Fe(III) ions. PMID- 22933123 TI - Variation between countries in the frequency of diabetic ketoacidosis at first presentation of type 1 diabetes in children: a systematic review. AB - AIMS/HYPOTHESIS: Type 1 diabetes is the most frequent endocrine disease in children, with 65,000 children diagnosed worldwide every year. Up to 80% of these children present with diabetic ketoacidosis (DKA), which is associated with both short-term risks and long-term consequences. This study aimed to characterise the worldwide variation in presentation of type 1 diabetes to inform future interventions to reduce this excess morbidity and mortality. METHODS: This was a systematic review of studies indexed on PubMed, EMBASE, Web of Science, Scopus or CINAHL before March 2011 that included unselected groups of children presenting with new-onset type 1 diabetes, reported the proportion presenting with DKA and used a definition of DKA based on measurement of pH or bicarbonate. RESULTS: Sixty-five studies of cohorts comprising over 29,000 children in 31 countries were included. The frequency of DKA at diagnosis ranged from 12.8% to 80%, with highest frequencies in the United Arab Emirates, Saudi Arabia and Romania, and the lowest in Sweden, the Slovak Republic and Canada. Multivariable modelling showed the frequency of DKA was inversely associated with gross domestic product, latitude and background incidence of type 1 diabetes. CONCLUSIONS/INTERPRETATION: This is the first description of the variation in frequency of DKA at presentation of type 1 diabetes in children across countries. It demonstrates large variations that may, at least in part, be explained by different levels of disease awareness and healthcare provision and suggests ways to decrease the excess morbidity and mortality associated with DKA at diagnosis. PMID- 22933125 TI - Transient osteoporosis of the hip, complete resolution after treatment with alendronate as observed by MRI description of eight cases and review of the literature. AB - Transient osteoporosis of the hip (TOH), also referred to as transient bone marrow edema syndrome, is most common in middle-aged men and often after trivial trauma or sport-related injuries. Diagnosis is usually made by eliminating other possible causes of hip pain. Magnetic resonance imaging (MRI) plays an important role in diagnosis and demonstrates a typical pattern of bone marrow edema (BME) in the form of diffuse low signal on T1-weighted images and high signal on T2 fat suppressed or short T1 inversion recovery images. No consensus exists about the management of TOH, as it may progress to avascular necrosis. We describe eight cases of TOH treated with alendronate resulting in improvement of pain and function and complete resolution of BME on MRI. The literature is reviewed regarding TOH and the relationship with bone marrow edema syndrome, avascular necrosis of the hip, and regional migratory osteoporosis. To our knowledge, this is the first report describing the improvement of this condition after of alendronate with documented radiological improvement on follow-up MRI. PMID- 22933126 TI - Clinical significance of peripheral blood lymphocyte subsets in patients with polymyositis and dermatomyositis. AB - Peripheral blood lymphocyte subsets were determined by flow cytometry in 89 Chinese patients with polymyositis (PM) and dermatomyositis (DM). We aimed to investigate the clinical significance of peripheral blood lymphocyte subsets in PM/DM. Patients with active DM showed significant decreases in numbers of CD3(+) cells, CD3(+)CD4(+) cells, and CD3(+)CD8(+) cells, as compared to patients with inactive DM and healthy controls (P < 0.05). CD3(+) and CD3(+)CD4(+) cell counts were significantly lower in DM before treatment, compared with after treatment (t = -5.714 and -3.665, P < 0.05). Counts of CD3(+) cells, CD3(+)CD4(+) cells, CD3(+)CD8(+) cells, and CD19(+)CD5(-) cells were all correlated with the total disease activity score as determined by the Myositis Disease Activity Assessment Visual Analogue Scale (P < 0.05). The decreased number of CD3(+) cells and the decreased percentage of CD3(+)CD4(+) cells were additionally correlated with the presence of interstitial lung disease in PM/DM (P < 0.05). The presence of levels of CD3(+)CD8(+) cells was risk factor for death (b = -0.011, OR = 0.989, P < 0.05). The identification of peripheral blood T lymphocyte subsets in PM/DM appears to be useful as a reference marker in the evaluation of clinical disease activity, and be useful in the comprehensive assessment of clinical lung involvement. A decrease in CD8(+) T cells may predict a poor outcome in patients with PM/DM. PMID- 22933127 TI - Impact of variability on the choice of biosimilarity limits in assessing follow on biologics. AB - With larger variation in biological products compared with small molecular drugs, it is suggested that the assessment of biosimilarity of follow-on biologics (FOBs) should take variability into consideration in addition to average as standard in bioequivalence tests in small molecule drugs. Recent research on assessing variability in biosimilarity of FOBs has focused on direct assessment of variances, individual biosimilar index aggregating average and variability, and comparison of the entire distributions. However, the choice of biosimilarity limits for evaluating FOBs has not been investigated in the literature. In this article, we first explore the impact of variability on biosimilarity limits for the average biosimilarity assessment. On the basis of the derived relationship between variability and biosimilarity limit that result in the same power given all other parameters fixed, we propose several scaled biosimilarity limits to incorporate highly variable biological products. PMID- 22933129 TI - Fast-track rehabilitation program and conventional care after esophagectomy: a retrospective controlled cohort study. AB - PURPOSE: The purpose of this article is to evaluate fast-track rehabilitation program and conventional care after esophagectomy using a retrospective controlled cohort study in esophageal cancer patients. METHODS: Fifty-five patients underwent fast-track rehabilitation program and 57 patients underwent conventional care after esophagectomy. Fast-track rehabilitation program was performed to patients who have early movement, epidural analgesia control, fluid infusion volume control and enteral nutrition for early discharge. The other 57 patients underwent conventional care after esophagectomy. The average of hospital stay and complications were calculated in the patients between the two groups. RESULTS: The median length of hospital stay in the patients was significantly shorter after fast-track rehabilitation program than after conventional care (7.7 vs 14.8 day, P < 0.01). The percentage of patients who developed complications was significantly lower 30 day after fast-track rehabilitation program than after conventional care (29.1 vs 47.4%, P < 0.05). 87.3% in patients of the fast-track rehabilitation program group and 54.4% in those of the conventional care group reported excellent to very good satisfaction with their pain control (P = 0.000). CONCLUSIONS: The fast-track rehabilitation program results in fewer complications, less postoperative pain, a reduction in the hospital length of stay, and quicker return to work and normal activities after esophagectomy. PMID- 22933130 TI - Coping with newly diagnosed upper gastrointestinal cancer: a longitudinal qualitative study of family caregivers' role perception and supportive care needs. AB - BACKGROUND: Family caregivers of patients with poor prognosis upper gastrointestinal (GI) cancers are at high risk of experiencing psychological distress and carer burden. The early postoperative period is a time of high patient care needs and transition of care, with carers new to the caring role. This study aimed to explore the experiences of family caregivers of people diagnosed with upper GI cancer after surgical intervention to (1) identify their unmet supportive care needs and (2) investigate how family caregivers perceive their role during this time. METHODS: Family caregivers of newly diagnosed postsurgical upper GI cancer patients were recruited. Semi-structured telephone interviews were conducted at 3 weeks and 3 months post-surgery. Analysis involved a constant comparative approach. Sampling was discontinued when information redundancy was achieved. Fifteen family caregivers participated in the first interview and eight agreed to a second interview. RESULTS: Family caregivers reported significant information and support needs. Family caregiver distress was exacerbated by a lack of patient care knowledge. Access to support was limited by caregivers' lack of understanding of the health system. Family caregivers view their role as part of their family responsibility. CONCLUSIONS: This study provides new insight into the supportive care needs of family caregivers of upper GI cancer patients and the impact of unmet need on the emotional well-being of family caregivers. These results will inform future supportive care service development and intervention research aimed at reducing unmet supportive care needs and psychological distress of family caregivers of patients with poor prognosis upper GI cancer. PMID- 22933132 TI - Health-related quality of life, depression, and sexual function in testicular cancer survivors in a developing country: a Serbian experience. AB - PURPOSE: The aims of this study were to assess health-related quality of life (HRQoL), depression, adverse physical symptoms, and sexual function within Serbian long-term testicular cancer survivors (TCS) and to address cultural specificity. METHODS: This is a cross-sectional study involving 202 TCS, followed up after platinum-based chemotherapy. The HRQoL was measured using the Short Form 36 and the European Organization for Research and Treatment of Cancer Quality of Life questionnaire. The Beck Depression Inventory (BDI) was used to explore general depressive status while sexual function was assessed using a nine-item questionnaire. RESULTS: The mean follow-up time since treatment was 47.3 +/- 26.8 months. The highest values of the SF-36 scales were obtained for physical functioning, and the lowest SF-36 values were obtained for vitality. Age of patients and BDI scores statistically significantly influenced total quality of life. The mean score of the whole sample on the BDI-II was 4.0. Age is the only statistically significant risk factor for the development of depression. A total of 27.3% TCS reported decreased sexual function compared to the period before treatment. Any level of impairment of erectile function was reported by 20.8% patients and problems with ejaculation by 25.7% patients. Loss of desire was reported by 17.3% TCS. The presence of sexual problems statistically significantly lowered scores of SF-36 domains. CONCLUSION: Sexual problems seriously impaired HRQoL in TCS. Additionally, HRQoL was also affected by age, depression, and fatigue. Serbian TCS achieved high levels of SF-36 scores, and these results are comparable to studies conducted in developed countries. PMID- 22933131 TI - Hepatitis B virus management to prevent reactivation after chemotherapy: a review. AB - PURPOSE: Reactivation of hepatitis B virus (HBV) infection after chemotherapy can lead to liver failure and death. Conflicting recommendations regarding HBV screening in cancer patients awaiting chemotherapy mean that some patients at risk for HBV reactivation are not being identified and treated with prophylactic antiviral therapy. METHODS: We performed a narrative review of the existing evidence regarding screening for and management of HBV infection among patients with cancer using Ovid Medline, PubMed, and the Cochrane Library. RESULTS: Our review showed inconsistencies in the definition and management strategies for HBV reactivation. The timeframe of reactivation is variable, and its molecular mechanisms are not clear. There are five effective antiviral agents that can be used as prophylaxis to prevent reactivation of HBV infection in cancer patients; however, the optimal drug and duration of therapy are unknown. Reactivation is more commonly reported in patients with hematologic malignancies receiving rituximab treatment, but reactivation can occur after other chemotherapies and in patients with solid tumors. Screening with all three screening tests-HBsAg, anti HBc, and anti-HBs-allows the most thorough interpretation of a patient's serologic profile and assessment of reactivation risk; however, decision-making and cost-effectiveness studies are needed to determine optimal screening strategies. CONCLUSIONS: Prevention of reactivation of HBV infection depends on identification of patients at risk and initiation of antiviral prophylaxis, but data to guide screening and treatment strategies are lacking. Additional research is necessary to accurately define and predict reactivation, identify best antiviral treatment strategies, and identify cost-effective HBV screening strategies. PMID- 22933133 TI - In-advance end-of-life discussions and the quality of inpatient end-of-life care: a pilot study in bereaved primary caregivers of advanced cancer patients. AB - PURPOSE: Advanced cancer care planning is encouraged to achieve individualized care. We hypothesized that in-advance end-of-life (EOL) discussions and establishment of do-not-resuscitate (DNR) status prior to the terminal admission would be associated with better quality of inpatient EOL care. METHODS: We conducted a post-mortality survey, utilizing the validated Toolkit of Instruments to Measure End-of-Life Care. Primary caregivers (PCGs) of the advanced cancer patients who died at our institution between January 2009 and December 2010 were contacted more than 3 months after the patients' death. The endpoints included overall score for EOL care (0-10; 10 = best care), problem scores of six domains (0-1; 1 = worst problem), and score for supporting family's self-efficacy (knowing what to expect/do during the dying process) (1-3; 3 = greatest support). RESULTS: Of 115 PCGs contacted, 50 agreed to participate (43.5 %). Patients with EOL discussions (n = 20), as compared to those without (n = 29), had higher rating of overall EOL care (9.7 vs. 8.7; p = 0.001): lower problem scores in "informing and promoting shared decision-making" (0.121 vs. 0.239; p = 0.007), "encouraging advanced care planning" (0.033 vs. 0.167; p = 0.010), "focusing on individual" (0.051 vs. 0.186; p = 0.014), "attending to emotional/spiritual needs of family" (0.117 vs. 0.333; p = 0.010), and "providing care coordination" (0.100 vs. 0.198; p = 0.032), and greater support for family's self-efficacy (2.734 vs. 2.310; p < 0.001). No significant differences were found in these outcomes between patients with DNR (n = 19) and those with full code (n = 31) on admission. CONCLUSION: Advanced cancer patients may receive higher quality of inpatient EOL care if they had in-advance EOL discussions. PMID- 22933134 TI - Limited use of nonprogram screening in Norway. PMID- 22933135 TI - Molecular nesting in co-crystals of tetrabenzoquadrannulene and C60: application of the sphere in a cone model. AB - We report the X-ray crystal structure of TMS(4)-TBQ with C(60) and analyse their interaction using a sphere in a cone model. PMID- 22933137 TI - A new model for environmental assessment and exposure reduction. AB - Environmental assessment and exposure reduction are a set of diagnostic and treatment techniques that work in tandem with the traditional medical approach by reducing a patient's exposure to adverse environmental conditions as part of medical care. Assessment involves identifying the specific exposures to which a patient is sensitive and locating the corresponding contaminants in the patient's environment. This provides a more complete diagnostic evaluation of a patient's problem than could be obtained merely by examining the patient alone. Exposure reduction involves reducing the identified triggers to levels that are below thresholds that are associated with increased risk of sensitization and disease morbidity. Assessment of an environment for contaminants focuses on a chain of factors that include contaminant sources such as cockroaches, rodents, dust mites and fungi that excrete contaminants into an environment, facilitative factors such as moisture, food, water and shelter that help sources to thrive, and reservoirs where contaminants can accumulate prior to subsequent transport to occupants. By using this model to guide environmental assessments and their corresponding interventions, the root cause of health problems can be addressed, leading to improved quality of life for patients and reduced need for chronic medications. PMID- 22933138 TI - The role of psychoneuroimmunology in personalized and systems medicine. AB - Psychoneuroimmunology (PNI) may provide the scientific basis for personalized and systems medicine. The exploration of the extensive interactions among psychological and behavioral factors, the nervous system, the immune system, and the endocrine system may help understand the mechanisms underlying health, wellness, and diseases. PNI theories based on systems biology methodologies may contribute to the identification of patient patterns for establishing psychological and physiological profiles for personalized medicine. A biopsychosocial model will help elucidate the systemic interrelationships between psychosocial and bio-physiological factors for the development of systems medicine. Many evidences have supported the close relationships between stress, depression, inflammation, and disorders including obesity, cardiovascular disease, diabetes, arthritis, skin diseases, infectious diseases, and sleep disorders. As inflammation is a critical connection among different diseases, the elucidation of the associations may contribute to the findings of systemic therapeutic targets. With the understanding of the translational implications of PNI, integrative interventions in multiple dimensions can be applied to modulate stress responses and promote healthier behaviors. These interventions include combination drug therapies, diets, nutritional supplements, meditation, and other behavioral and mind-body strategies. PMID- 22933136 TI - Pathogenesis of food allergy in the pediatric patient. AB - In the US and other developed countries, food allergy is a growing epidemic in pediatric populations with a substantial impact on health-related quality of life. As such, there are great efforts underway to unravel the mechanisms of oral mucosal tolerance and to better define the factors related to host and allergen exposure that contribute to the aberrant immune response leading to sensitization and clinical food allergy. Although more research is needed to eventually develop targeted treatment and prevention strategies, this review highlights our current understanding of the pathogenesis of IgE-mediated food allergy. PMID- 22933139 TI - Psychoneuroimmunology: the experiential dimension. AB - Accumulating evidence has made clear that experience--the knowledge an individual acquires during a lifetime of sensing and acting--is of fundamental biological relevance. Experience makes an impact on all adaptive systems, including the endocrine, immune, and nerve systems, and is of the essence, not only for the unfolding of an organisms' healthy status, but also for the development of malfunctional traits. Nevertheless, experience is often excluded from empirical approaches. A variety of complex interactions that influence life histories are thereby neglected. Such ignorance is especially detrimental for psychoneuroimmunology, the science that seeks to understand how the exquisite and dynamic interplay between mind, body, and environment relates to behavioral characteristics. The article reviews claims for incorporating experience as a member of good explanatory standing in biology and medicine, and more specifically, claims that experiential knowledge is required to enable meaningful and relevant explanations and predictions in the psychoneuroimmunological realm. PMID- 22933140 TI - Psychosocial job stress and immunity: a systematic review. AB - The purpose of this review was to provide current knowledge about the possible association between psychosocial job stress and immune parameters in blood, saliva, and urine. Using bibliographic databases (PubMed, PsychINFO, Web of Science, Medline) and the snowball method, 56 studies were found. In general, exposure to psychosocial job stress (high job demands, low job control, high job strain, job dissatisfaction, high effort-reward imbalance, overcommitment, burnout, unemployment, organizational downsizing, economic recession) had a measurable impact on immune parameters (reduced NK cell activity, NK and T cell subsets, CD4+/CD8+ ratio, and increased inflammatory markers). The evidence supports that psychosocial job stresses are related to disrupted immune responses but further research is needed to demonstrate cause-effect relationships. PMID- 22933141 TI - Immune cells listen to what stress is saying: neuroendocrine receptors orchestrate immune function. AB - Over the past three decades, the field of psychoneuroimmunology research has blossomed into a major field of study, gaining interests of researchers across all traditionally accepted disciplines of scientific research. This chapter provides an overview of our current understanding in defining neuroimmune interactions with a primary focus of discussing the neuroendocrine receptor activity by immune cells. This chapter highlights the necessity of neuroimmune responses as it relates to a better understanding of the pathophysiological mechanisms of health and disease. PMID- 22933142 TI - Physical activity, stress reduction, and mood: insight into immunological mechanisms. AB - Psychosocial factors, such as chronic mental stress and mood, are recognized as an important predictor of longevity and wellbeing. In particular, depression is independently associated with cardiovascular disease and all-cause mortality, and is often comorbid with chronic diseases that can worsen their associated health outcomes. Regular exercise is thought to be associated with stress reduction and better mood, which may partly mediate associations between depression, stress, and health outcomes. The underlying mechanisms for the positive effects of exercise on wellbeing remain poorly understood. In this overview we examine epidemiological evidence for an association between physical activity and mental health. We then describe the exercise withdrawal paradigm as an experimental protocol to study mechanisms linking exercise, mood, and stress. In particular we will discuss the potential role of the inflammatory response as a central mechanism. PMID- 22933143 TI - Translational implications of inflammatory biomarkers and cytokine networks in psychoneuroimmunology. AB - Developments in psychoneuroimmunology (PNI) need to be translated into personalized medicine to achieve better clinical outcomes. One of the most critical steps in this translational process is to identify systemic biomarkers for better diagnosis and treatment. Applications of systems biology approaches in PNI would enable the insights into the correlations among various systems and different levels for the identification of the basic elements of the psychophysiological framework. Among the potential PNI biomarkers, inflammatory markers deserve special attention as they play a pivotal role linking various health conditions and disorders. The elucidation of inflammatory markers, cytokine networks, and immune-brain-behavior interactions may help establish PNI profiles for the identification of potential targets for personalized interventions in at risk populations. The understanding of the general systemic pathways among different disorders may contribute to the transition from the disease-centered medicine to patient-centered medicine. Integrative strategies targeting these factors and pathways would be useful for the prevention and treatment of a spectrum of diseases that share the common links. Examples of the translational implications of potential PNI biomarkers and networks in diseases including depression, Alzheimer's disease, obesity, cardiovascular disease, stroke, and HIV are discussed in details. PMID- 22933144 TI - Cytokines as potential biomarkers for Parkinson's disease: a multiplex approach. AB - Cytokines, which are immunological messengers facilitating both intra- and inter system communication, are considered central players in the neuroinflammatory cascades associated with the neurodegenerative process in Parkinson's disease (PD) and other neurological disorders. They have also been implicated in depression and other cognitive (e.g., memory impairment, dementia) and affective disturbances (e.g., anxiety) that show high co-morbidity with neurodegenerative diseases. As such, cytokines may hold great promise as serological biomarkers in PD, with potential applications ranging from early diagnosis and disease staging, to prognosis, drug discovery, and tracking the response to treatment. Subclassification or risk stratification in PD could be based (among other things) on reliably determined cytokine panel profiles or "signatures" of particular co-morbid disease states or at-risk groups (e.g., PD alone, PD with depression and/or dementia). Researchers and clinicians seeking to describe cytokine variations in health vs. disease will benefit greatly from technologies that allow a high degree of multiplexing and thus permit the simultaneous determination of a large roster of cytokines in single small-volume samples. The need for such highly paralleled assays is underscored by the fact that cytokines do not act in isolation but rather against a backdrop of complementary and antagonistic cytokine effects; ascribing valence to the actions of any one cytokine thus requires specific knowledge about the larger cytokine milieu. This chapter provides a technological overview of the major cytokine multiplex assay platforms before discussing the implications of such tools for biomarker discovery and related applications in PD and its depressive and cognitive co morbidities. PMID- 22933145 TI - Exploring the diagnostic potential of immune biomarker coexpression in Gulf War Illness. AB - Complex disorders like Gulf War Illness (GWI) often defy diagnosis on the basis of a single biomarker and may only be distinguishable by considering the coexpression of multiple markers measured in response to a challenge. We demonstrate the practical application of such an approach using an example where blood was collected from 26 GWI, 13 healthy control subjects, and 9 unhealthy controls with Chronic Fatigue at three points during a graded exercise challenge. A 3-way multivariate projection model based on 12 markers of endocrine and immune function was constructed using a training set of n = 10 GWI and n = 11 healthy controls. These groups were separated almost completely on the basis of two coexpression patterns. In a separate test set these same features allowed for discrimination of new GWI subjects (n = 16) from unhealthy (n = 9) and healthy control subjects with a sensitivity of 70% and a specificity of 90%. PMID- 22933146 TI - Neuroimmune mechanisms of depression in heart failure. AB - Heart failure (HF) is a major and costly public health concern, and its prognosis is grim-with high hospitalization and mortality rates. It is well documented that HF patients experience disproportionately high rates of depression and that depressed HF patients have worse clinical outcomes than their non-depressed counterparts. The purpose of this chapter is to introduce the reader to the study of depression in HF, and how psychoneuroimmunologic principals have been applied to further elucidate the mechanisms (i.e., neurohormonal and cytokine activation) linking these co-morbid disorders. PMID- 22933147 TI - A reinterpretation of the pathogenesis and cure of cancer according to the psychoneuroimmunological discoveries. AB - The recent discoveries in the oncological researches have demonstrated that the prognosis of the neoplastic diseases depends on not only the biological characteristics of tumors, including oncogene expression and growth factor receptor activity, but also on the immune status of cancer patients. This is because the well-documented importance of the anticancer immunity in the initiation of the tumor that is mainly modulated by lymphocytes. In addition, the knowledge on the interactions between the immune and neuroendocrine systems has demonstrated that the immune responses are physiologically under a psychoneuroendocrine control. In particular, it has been confirmed that the activation of the brain opioid tone may suppress the generation of an effective anticancer immunity, whereas it is stimulated by other neuroendocrine structure, namely the pineal gland, through the release of at least two indole hormones with anticancer activity, melatonin and 5-methoxytryptamine, exerting both antiproliferative and immunostimulatory effects. By investigating the immune and neuroendocrine functions in cancer patients, it has been observed that cancer progression is associated with a progressive decline in the pineal function, which would constitute the main cancer-related endocrine deficiency, and the occurrence of the irreversible immune alterations. The most prognostically important factors would consist of a diminished endogenous production of anticancer cytokines, such as IL-2 and IL-12, as well as an abnormally enhanced secretion of cytokines provided by suppressive effect on the anticancer immunity, namely IL-14, TGF-beta, and IL-6. The psychoneuroimmunotherapeutic approach in the treatment of cancer would simply consist of the corrections of the various endocrine and immune cancer-related alterations in an attempt to re-establish the neuroimmune condition of the health status. PMID- 22933148 TI - Aging microglia: relevance to cognition and neural plasticity. AB - Over the years it has become evident that the immune system can affect the function of the central nervous system (CNS), including altering cognitive processes. The impact of immune activation on the CNS is particularly important for aged individuals, as the brain's resident immune cells, microglia, acquire a pro-inflammatory profile. The low-grade chronic neuroinflammation that develops with normal aging likely contributes to the susceptibility to cognitive deficits and a host of age-related pathologies. Understanding why microglia show increased inflammatory activity (i.e., neuroinflammation) and identifying effective treatments to reduce microglia activation is expected to have beneficial effects on cognitive performance and measures of neural plasticity. However, microglia also promote regeneration after injury. Therefore, effective treatments must dampen inflammatory activity while preserving microglia's neuroprotective function. Discovering factors that induce neuroinflammation and investigating potential preventative therapies is expected to uncover the ways of maintaining normal microglia activity in the aged brain. PMID- 22933149 TI - Autism spectrum disorders: from immunity to behavior. AB - Autism spectrum disorders (ASD) are complex and heterogeneous with a spectrum of diverse symptoms. Mounting evidence from a number of disciplines suggests a link between immune function and ASD. Although the causes of ASD have yet to be identified, genetic studies have uncovered a host of candidate genes relating to immune regulation that are altered in ASD, while epidemiological studies have shown a relationship with maternal immune disturbances during pregnancy and ASD. Moreover, decades of research have identified numerous systemic and cellular immune abnormalities in individuals with ASD and their families. These include changes in immune cell number, differences in cytokine and chemokine production, and alterations of cellular function at rest and in response to immunological challenge. Many of these changes in immune responses are associated with increasing impairment in behaviors that are core features of ASD. Despite this evidence, much remains to be understood about the precise mechanism by which the immune system alters neurodevelopment and to what extent it is involved in the pathogenesis of ASD. With estimates of ASD as high as 1% of children, ASD is a major public health issue. Improvements in our understanding of the interactions between the nervous and immune system during early neurodevelopment and how this interaction is different in ASD will have important therapeutic implications with wide ranging benefits. PMID- 22933150 TI - Mouse testing methods in psychoneuroimmunology: an overview of how to measure sickness, depressive/anxietal, cognitive, and physical activity behaviors. AB - The field of psychoneuroimmunology (PNI) aims to uncover the processes and consequences of nervous, immune, and endocrine system relationships. Behavior is a consequence of such interactions and manifests from a complex interweave of factors including immune-to-neural and neural-to-immune communication. Often the signaling molecules involved during a particular episode of neuroimmune activation are not known but behavioral response provides evidence that bioactives such as neurotransmitters and cytokines are perturbed. Immunobehavioral phenotyping is a first-line approach when examining the neuroimmune system and its reaction to immune stimulation or suppression. Behavioral response is significantly more sensitive than direct measurement of a single specific bioactive and can quickly and efficiently rule in or out relevance of a particular immune challenge or therapeutic to neuroimmunity. Classically, immunobehavioral research was focused on sickness symptoms related to bacterial infection but neuroimmune activation is now a recognized complication of diseases and disorders ranging from cancer to diabesity. Immunobehaviors include lethargy, loss of appetite, and disinterest in social activity and the surrounding environment. In addition, neuroimmune activation can precipitate feelings of depression and anxiety while negatively impacting cognitive function and physical activity. Provided is a detailed overview of behavioral tests frequently used to examine neuroimmune activation in mice with a special emphasis on preexperimental conditions that can confound or prevent successful immunobehavioral experimentation. PMID- 22933151 TI - The MRL model: an invaluable tool in studies of autoimmunity-brain interactions. AB - The link between systemic autoimmunity, brain pathology, and aberrant behavior is still largely unexplored field of biomedical science. Accumulating evidence points to causal relationships between immune factors, neurodegeneration, and neuropsychiatric manifestations. By documenting autoimmunity-associated neuronal degeneration and cytotoxicity of the cerebrospinal fluid from disease-affected subjects, the murine MRL model had shown high validity in revealing principal pathogenic circuits. In addition, unlike any other autoimmune strain, MRL mice produce antibodies commonly found in patients suffering from lupus and other autoimmune disorders. This review highlights importance of the MRL model as an indispensible preparation in understanding the links between immune system and brain function. PMID- 22933152 TI - Interleukin-2 and the brain: dissecting central versus peripheral contributions using unique mouse models. AB - Although many studies have documented peripheral immune alterations in patients with psychiatric and neurological disorders, almost all these data in humans are correlative. The actions of IL-2 on neurodevelopment, function, and disease are the result of both IL-2's actions in the peripheral immune system and intrinsic actions in the CNS. Determining if, and under what conditions (e.g., development, acute injury) these different actions of IL-2 are operative in the brain is essential to make advances in understanding the multifaceted affects of IL-2 on CNS function and disease. Mouse models have provided ways to obtain new insights into how the complex biology of a cytokine such as IL-2 can have simultaneous, dynamic effects on multiple systems (e.g., regulating homeostasis in the brain and immune system, autoimmunity that can affect both systems). Here we describe some of the relevant literature and our research using different mouse models. This includes models such as congenic IL-2 knockout mice bred on immunodeficient backgrounds coupled with immune reconstitution strategies used to dissect neuroimmunological processes involved in the development of septohippocampal pathology, and test the hypothesis that dysregulation of the brain's endogenous neuroimmunological milieu may occur with the loss of brain IL-2 gene expression and be involved in initiating CNS autoimmunity. Use of animal models like these in the field of psychoneuroimmunology may lead to critical advances into our understanding of the role of brain cytokines and autoimmunity in neurodegenerative diseases (e.g., Alzheimer's disease), neurodevelopmental disorder (e.g., autism, schizophrenia), and autoimmune diseases including multiple sclerosis. PMID- 22933153 TI - Psychoneuroimmunology and natural killer cells: the chromium release whole blood assay. AB - Natural killer (NK) cells are an essential component of innate immunity. These lymphocytes are also sensitive barometers of the effects of endogenous and exogenous stressors on the immune system. This chapter will describe a chromium ((51)Cr) release bioassay designed to measure the target cell killing capacity of NK cells (NKCC). Key features of the cytotoxicity assay are that it is done with whole blood and that numbers of effector cells are determined for each sample by flow cytometry and lymphocyte count. Effector cells are defined as CD3-CD56+ lymphocytes. Target cells are the K562 eyrthroleukemia cell line. Killing capacity is defined as number of target cells killed per effector cell, at an effector cell/target cell ratio of 1:1 during a 4 h in vitro assay. PMID- 22933154 TI - The application of PET imaging in psychoneuroimmunology research. AB - Positron emission tomography (PET) imaging is a research tool that allows in vivo measurements of brain metabolism and specific target molecules. PET imaging can be used to measure these brain variables in a variety of species, including human and non-human primates, and rodents. PET imaging can therefore be combined with various experimental and clinical model systems that are commonly used in psychoneuroimmunology research. PMID- 22933155 TI - The vaccination model in psychoneuroimmunology research: a review. AB - This chapter explores the reasoning behind using the vaccination model to examine the influence of psychosocial factors on immunity. It then briefly discusses the mechanics of the vaccination response and the protocols used in Psychoneuroimmunology vaccine research, before giving examples from the research literature of the studies examining relationships such as the association between stress and the vaccination response. It also explores the ways the vaccination model can be used to answer key questions in Psychoneuroimmunology, such as: "does it matter when stressful life events occur relative to when the vaccine is received?" "what are the effects of prior exposure to the antigen?" and "do other psychosocial factors influence vaccine response besides stress?" Finally, it briefly considers the mechanisms underlying psychosocial factors and vaccination response associations and the future research needed to understand these better, and indeed to use current and future knowledge to improve and enhance vaccine responses in key at risk populations. PMID- 22933156 TI - Using vaccinations to assess in vivo immune function in psychoneuroimmunology. AB - Finding clinically relevant measures of immune function is an important challenge in psychoneuroimmunological research. Here, we discuss the advantages of the vaccination model, and provide guidance on the methodological decisions that are important to consider in the use of this technique. These include the choice of vaccination, timing of assessments, and the available outcome measures. PMID- 22933157 TI - Translational bioinformatics in psychoneuroimmunology: methods and applications. AB - Translational bioinformatics plays an indispensable role in transforming psychoneuroimmunology (PNI) into personalized medicine. It provides a powerful method to bridge the gaps between various knowledge domains in PNI and systems biology. Translational bioinformatics methods at various systems levels can facilitate pattern recognition, and expedite and validate the discovery of systemic biomarkers to allow their incorporation into clinical trials and outcome assessments. Analysis of the correlations between genotypes and phenotypes including the behavioral-based profiles will contribute to the transition from the disease-based medicine to human-centered medicine. Translational bioinformatics would also enable the establishment of predictive models for patient responses to diseases, vaccines, and drugs. In PNI research, the development of systems biology models such as those of the neurons would play a critical role. Methods based on data integration, data mining, and knowledge representation are essential elements in building health information systems such as electronic health records and computerized decision support systems. Data integration of genes, pathophysiology, and behaviors are needed for a broad range of PNI studies. Knowledge discovery approaches such as network-based systems biology methods are valuable in studying the cross-talks among pathways in various brain regions involved in disorders such as Alzheimer's disease. PMID- 22933158 TI - Commentary on "First hand accounts of events in the laboratory of Prof. Eduard Pernkopf" by S.H. Aharinejad and S.W. Carmichael. PMID- 22933159 TI - The role of interleukin-1beta in arthritic pain: main involvement in thermal, but not mechanical, hyperalgesia in rat antigen-induced arthritis. AB - OBJECTIVE: Interleukin-1beta (IL-1beta) is considered a pronociceptive cytokine, but its role in the generation of arthritic pain is unknown. The aim of this study was to investigate the role of IL-1beta in arthritic pain and to explore the antinociceptive potential of the IL-1 receptor type I (IL-1RI) antagonist anakinra. METHODS: Antigen-induced arthritis (AIA) was induced in rats. Expression of IL-1RI in the dorsal root ganglia (DRGs) was determined, and the effects of anakinra on inflammation, pain-related behavior, and receptor expression were assessed. In cultured DRG neurons, the effect of IL-1beta on the expression of the transient receptor potential vanilloid 1 (TRPV-1) ion channel was examined. Recordings of action potentials from joint nociceptors were made after intraarticular injection of IL-1beta into the rat knee joints. RESULTS: AIA generated pronounced and persistent mechanical and thermal hyperalgesia, and IL 1RI expression in the lumbar DRGs was significantly up-regulated. Treatment with anakinra did not significantly reduce the severity of arthritis or mechanical hyperalgesia, but did result in a pronounced reduction in thermal hyperalgesia. In cultured DRG neurons, IL-1beta up-regulated the expression of TRPV-1, a major transduction molecule involved in thermal hyperalgesia. During AIA, anakinra treatment down-regulated the expression of TRPV-1, consistent with the pronounced reduction in thermal hyperalgesia. IL-1beta increased the mechanosensitivity of C fibers of the joint, but reduced the mechanosensitivity of Adelta-fibers, thus having opposite effects on these mechanonociceptive nerve fibers. CONCLUSION: In the context of arthritic knee pain, IL-1beta and IL-1 receptors appear to be involved in thermal, rather than mechanical, hyperalgesia. Therefore, neutralization of IL-1beta may be mainly antinociceptive in disease states characterized by thermal hyperalgesia, but not in disease states mainly characterized by mechanical hyperalgesia. PMID- 22933160 TI - Effect of iron overload on endocrinopathies in patients with beta-thalassaemia major and intermedia. AB - INTRODUCTION: Iron overload is a major problem in patients with b-thalassemia major, and it has many structural and metabolic consequences. In this study, we aimed to consider the prevalence of endocrine abnormalities in patients with beta thalassemia major and thalassemia intermedia. MATERIALS AND METHODS: We ordered following tests for consideration endocrine abnormalities: fasting plasma glucose, oral glucose tolerance, iron, total iron binding capacity, ferritin, thyroid-stimulating hormone (TSH), free thyroxin (fT4), free triiodothyronine (fT3), parathyroid hormone levels. RESULTS: According to our study including 70 patients with thalassemia major, 7 (10%) had diabetes, 5 (7.1%) had impaired glucose tolerance, 9 (12.8%) had hypothyroidism, 2 (2.8%) had hypoparathyroidism, 2 (2.8%) had hyperparathyroidism. Of 22 patients with thalassemia intermedia, 1 (4.5%) had diabetes. CONCLUSIONS: These findings reinforce the importance of regular follow-up of patients with b-thalassemia major and thalassemia intermedia for early detection and management of associated complications. In this way, the prevalence of endocrine abnormalities can be decreased in future. PMID- 22933161 TI - Bone mineral density in adult patients with major thalassaemia: our experience and a brief review of the literature. AB - INTRODUCTION: Metabolic bone disease represents a major cause of morbidity in patients with thalassaemia major. The aim of our study was to assess the prevalence and underlying contributory factors of osteopenia/osteoporosis in a randomly selected population of adult patients with thalassaemia major. PATIENTS AND METHODS: The study population was selected using the random sampling method from the patients' database of our thalassaemia clinic. Only transfusion dependent beta-thalassaemia patients aged over 17 and with no history of treatment with bisphosphonates were included. BMD of lumbar spine and right femoral neck were measured by means of the calibrated dual energy X-ray absorption method. Independent factors likely to be associated with low bone mass were determined and included in the analysis to ascertain possible associations. RESULTS: Our study included 40 patients (19 female and 21 male; mean age: 23.0 +/ 4.1). The mean Z score of the right femoral neck was -1.2 (95% CI: -0.9 to -1.5) and for lumbar spine was -2.1 (95% CI: -1.7 to -2.5). The prevalences of osteopenia and osteoporosis involving the right femoral neck were 37.5%, and 12.5%, respectively. The respective prevalence rates for lumbar spine were 47.5% and 37.5%. Our study showed patient's weight, age, duration of the disease and history of hypogonadism or concurrent hypothyroidism are significant contributory factors or predictors of bone mineral loss. CONCLUSIONS: Regarding the high prevalence of osteopenia/osteoporosis in patients with thalassaemia major, all patients should be screened periodically for bone disease. The uncertainty and disagreements as to the possible role of different factors indicate the necessity for further studies in order to recognise the pathophysiologic fundamentals of this serious complication of thalassaemia major. PMID- 22933162 TI - Low bone mineral density in adult patients with coeliac disease. AB - INTRODUCTION: Calcium and vitamin D malabsorption in coeliac disease (CD) predispose to skeletal demineralisation. The aim of this study was to evaluate the prevalence of bone mineral density (BMD) and calcium deficiencies in adult patients with CD and assess whether a gluten-free diet is sufficiently effective for BMD restoration. MATERIAL AND METHODS: BMD and biochemical parameters of bone and mineral metabolism were measured in 35 adult CD patients receiving (19) or not receiving (16) a gluten-free diet (GFD) and in 36 controls. Then the CD patients were treated with a GFD and calcium (1.0 g/day) plus alfacalcidol (0.25 1 MUg/day) for one year. RESULTS: Reduced BMD was diagnosed in 57-77% of the patients. Mean calcaemia, calciuria, and 25(OH) vitamin D were lower, but serum PTH and bone-turnover markers (ALP, osteocalcin, ICTP) were significantly higher in the CD patients than in the controls. In the patients on the diet (GFD(+)), BMD was higher than in the GFD(-) patients, but lower than in the controls. The biochemical parameters were normal in the GFD(+) patients except for diminished calciuria. Mean BMD after one year of treatment significantly increased (p < 0.05), mostly in the lumbar spine (mean: 7.3%), but decreased in five patients who did not strictly adhere to the GFD. CONCLUSIONS: Deficiencies in calcium, vitamin D, and BMD are very common in adult CD patients. Gluten avoidance increased BMD, although the values remained markedly lower in several patients. Because of chronic calcium deficiency despite GFD, calcium and vitamin D supplementation in most adult CD patients is proposed. PMID- 22933163 TI - Complications of Cushing's disease - prospective evaluation and clinical characteristics. Do they affect the efficacy of surgical treatment? AB - INTRODUCTION: Hypercortisolaemia is the cornerstone of Cushing's disease (CD). It leads to the occurrence of typical somatic symptoms as well as cardiovascular and metabolic complications, which significantly increase morbidity and mortality and decrease quality of life in CD. MATERIAL AND METHODS: A prospective study included 36 patients with CD who were assessed in terms of duration of their disease symptoms as well as the incidence of: arterial hypertension, glucose intolerance and diabetes, overweight, obesity and decreased bone mineral density (BMD). The relation was assessed between these particular complications and their impact on the efficacy of surgical treatment for CD. RESULTS: The prevalence in the study group of arterial hypertension was 79%, and diabetes was 16.7%, whereas the proportion of pre-diabetic states was 33%. 36.1% of patients fulfilled the criteria of obesity and an additional 44% were overweight. Decreased BMD was reported in 72.2% of patients. There was a confirmed relationship between the duration of CD symptoms and the occurrence of overt diabetes (p < 0.01) and any type of glucose homeostasis alterations (p = 0.04). In this studied group with CD, there was also an association demonstrated between the occurrence of arterial hypertension and overweight or obesity (p = 0.03). Simultaneously, there was no relationship between the duration of symptoms or the presence of particular organ complications and the efficacy of surgical treatment for CD. CONCLUSIONS: Longer duration of CD is associated with a higher risk of glucose intolerance and/or diabetes. The overweight/obesity presented in the majority of patients increases the risk of secondary hypertension in CD. However, the efficacy of transsphenoidal surgery does not depend directly on either disease duration or type of occurring complications. PMID- 22933164 TI - Evaulation of atrial conduction abnormalities and left atrial mechanical functions in patients with subclinical thyroid disorders. AB - INTRODUCTION: Changes of thyroid hormones levels may lead to effects, not only in ventricular function, but also atrial function. The aim of this study was to investigate left atrial (LA) mechanical functions, atrial electromechanical coupling and P wave dispersion in patients with subclinical thyroid disorders. MATERIAL AND METHODS: Eighty patients with subclinical thyroid disorders and forty controls were included. A diagnosis of subclinical thyroid disorders were reached with increased or decreased serum TSH and normal free T4 (fT4) levels. LA volumes were measured using the biplane area length method and LA active and passive emptying volumes and fraction were calculated. Intra- and interatrial electromechanical delay were measured by tissue Doppler imaging (TDI). RESULTS: All groups had similar demographic findings. LA mechanical functions significantly impaired in subclinical thyroid disorders than control group. Intra and Interatrial delay, were measured significantly higher in patients with subclinical thyroid disorders than control group. PA lateral and interatrial delay were positively correlated with TSH (r = 0.507, p = 0.006 and r = 0.455, p = 0.015, respectively) in subclinical hypothyroid patients. There was negative correlation between TSH and interatrial delay (r = -0.492, p = 0.006) in subclinical hyperthyroid patients. Linear multivariate regression analysis demonstrated that, TSH was the only an independent factor of interatrial delay in patients with subclinical thyroid disorders. CONCLUSIONS: This study showed that impaired LA mechanical and electromechanical function in subclinical thyroid disorders. TSH was an independent determinant of interatrial delay. Prolonged atrial electromechanical coupling time and impaired mechanical atrial functions may be related to the increased incidence of arrhythmias. PMID- 22933165 TI - Comparison and assessment of thyroid morphology and function in inhabitants of Lower Silesia before and after administration of a single dose of iodine containing contrast agent during cardiac intervention procedure. AB - INTRODUCTION: Inhabitants living in areas with endemic dietary iodine intake deficiency develop nodular goitre. The aim of our study was to evaluate thyroid morphology and function among adults residing in Lower Silesia and to assess the effect on the thyroid gland of an iodine-based contrasting agent administered during a cardiac intervention procedure. MATERIALS AND METHODS: The first part of the study (evaluation of thyroid gland) was carried out on 120 subjects (78 men and 42 women). From among this group, invasive cardiac procedures were performed on 60 subjects (38 men and 22 women) during the second part of the study. Endocrine tests were repeated one, three, and six months after the invasive procedure. RESULTS: 1) Within the studied group, pathological changes in thyroid morphology were found in 49.1%, and thyroid function disturbances in 9.3%, of all subjects. 2) A decrease in TSH concentration with a corresponding increase in fT3 concentration was seen at the second visit (four weeks after iodine administration) leading to the diagnosis of hyperthyroidism in 15% of subjects. CONCLUSIONS: 1) Considering the multitude of silent thyroid pathologies, particular care is required before administering an iodine-based medium. 2) It is reasonable and advisable to monitor TSH and fT3 levels before and at four weeks after administration of an iodine-containing contrast agent. 3) Thyroid morphology and function disturbances after iodine administration do not necessitate treatment, as they are of transient character and only require monitoring. PMID- 22933166 TI - Hypothyroidism during treatment with tyrosine kinase inhibitors. AB - Tyrosine kinase inhibitors are relatively new targeted therapy drugs used for the treatment of metastatic clear cell kidney carcinoma, gastrointestinal stromal tumours, thyroid carcinoma and pancreatic neuroendocrine tumours during the progression of the disease. Hypothyroidism or thyroid dysfunction is often a side effect of this treatment. Therefore, monitoring of thyroid hormone levels before the beginning and during the treatment of tyrosine kinase inhibitors is a necessity. Hypothyroidism correlates with objective response to the treatment. Sunitinib. This is the most described tyrosine kinase inhibitor which causes hypothyroidism. The mechanism of hypothyroidism is still unclear. Sorafenib. Symptoms of hypothyroidism occur in 18% of patients treated with sorafenib due to metastatic renal cell carcinoma. Imatinib. Hypothyroidism is one of the most frequent side effects of the treatment. Emergent tracheotomy was necessary due to larynx swelling during marked hypothyroidism. Motesanib. Hypothyroidism or increased TSH level is diagnosed in 22% to 69% of patients with metastatic differentiated or medullary thyroid carcinomas. The management of patients with thyroid dysfunction and related symptoms such as fatigue is undoubtedly a challenge to an oncologist. PMID- 22933167 TI - Adrenocortical oncocytoma - a case report. AB - Adrenocortical oncocytoma is found very rarely. Most such tumours are benign and nonfunctioning. We report the case of a nonfunctioning adrenocortical oncocytoma located in the right adrenal gland in a 35-year-old man. The patient was tested because of arrhythmia. An adrenal mass of 68 * 64 mm was found during ultrasonography, followed by CT examination. Physical examination indicated obesity with BMI of 32.8 kg/m(2). Abnormal laboratory findings based on an oral glucose tolerance test revealed impaired glucose tolerance and elevated cholesterol level. The patient underwent a laparotomy for a pathological mass located in the right adrenal gland. The pathology report confirmed adrenocortical oncocytoma of uncertain malignant potential. The patient is still alive with no metastases, 37 months after the surgery. Adrenocortical oncocytoma, although extremely rare, should be considered in the differential diagnosis of adrenal tumours. PMID- 22933168 TI - Normal bone turnover markers in a patient with active Paget's disease of bone: response to treatment with zoledronic acid. AB - The treatment of Paget's disease of bone (PDB) aims at the suppression of abnormal bone turnover; bisphosphonates are currently the treatment of choice. Indications for antiresorptive treatment in symptomatic patients with PDB include bone or joint pain, neurological complications, surgery planned at an active pagetic site and hypercalcaemia from immobilisation. The goals of antiresorptive treatment are clinical improvement and biochemical remission, as assessed by the normalisation of bone turnover markers. Clinical deterioration, especially bone pain, should be considered before deciding to treat patients with late sclerotic (burned-out) PDB. Bone scintigraphy may be of importance in these patients, because it depicts increased osteoblastic activity, when bone markers may not. We present a case of late sclerotic PDB with clinical deterioration but normal bone turnover markers, who experienced significant clinical improvement after treatment with zoledronic acid. PMID- 22933169 TI - The influence of lactose intolerance and other gastro-intestinal tract disorders on L-thyroxine absorption. AB - The preferred treatment for hypothyroidism is oral levothyroxine (LT4) ingestion, in doses that ensure a sustained state of hormonal balance. Many different factors may significantly influence the absorption of LT4, including: interval between the ingestion of the drug and the last meal, eating habits, and different functional and organic pathologies of the gastro-intestinal tract. The main purpose of this paper is to review and systematise the available literature on the subject of the influence of different malabsorption syndromes on the effectiveness of LT4 preparations. The need to use high LT4 doses in the substitutional treatment of hypothyroidism is often the very first sign of one of the pathologies that are connected with malabsorption syndrome, which might have been asymptomatic and undiagnosed previously. Patients who require more than 2 MUg/kg body weight of LT4 per day, with constantly increased thyrotropin level, should be diagnosed with the suspicion of pseudomalabsorption or real absorption disorder. An LT4 absorption test, using high doses of LT4, may be useful in the diagnosis of pseudomalabsorption. After excluding non-compliance, the differential diagnosis should include such disorders as lactose intolerance, coeliac disease, atrophic gastritis, Helicobacter pylori infection, bowel resection, inflammatory bowel disease, and parasite infection. Where there is a diagnosis of lactose intolerance, both a low lactose diet and a lactose-free LT4 preparation should be administered to restore euthyroidism or make it possible to decrease the dose of the LT4 preparation. In coeliac disease, a gluten-free diet usually allows a normalisation of the need for LT4, as do eradication of the H. pylori infection or parasite colonisation. In cases of atrophic gastritis or inflammatory bowel disease, treating the underlying diseases and regaining the state of remission may improve the absorption of LT4. In patients after gastro intestinal tract surgery, a dose of LT4 higher than that typically used is needed to restore euthyroidism. PMID- 22933170 TI - Primary aldosteronism: a common and important problem. A practical guide to the diagnosis and treatment. AB - In view of the fact that primary aldosteronism (PA) is a problem that is more prevalent than previously thought and its diagnosis is of greater clinical significance than previously believed, the Endocrine Society has recently published recommendations on the diagnosis and management of PA. Due to the fact that the currently available tests cannot be considered the gold standard in the diagnosis of PA and the discrepancies in the results of determination of aldosterone levels and plasma renin activity (PRA) are considerable the authors of this document do not provide strict cutoff values, leaving the interpretation of results to clinicians. This paper, which focuses on screening and confirmatory tests and on the aetiological diagnosis and treatment of PA, is based on the experience of the Department of Endocrinology, Diabetes and Internal Diseases, Medical University in Bialystok, Poland, but it also takes into account other points of view presented in papers published in the past few years. PMID- 22933171 TI - Copper losses in surface runoff from flatwoods citrus production areas. AB - Crop production in areas with a high water table and poorly drained soils requires special drainage infrastructure to allow adequate rooting depth. In addition to facilitating drainage, this infrastructure also facilitates discharge of agrichemicals dissolved in drainage and runoff water. Copper export from bedded citrus production areas was evaluated using simulated rainfall events following application of copper. Copper concentrations in runoff water from individual water furrows ranged from 13 to 223 MUg/L during the staged events, while copper loadings ranged from 32 to 302 g/water furrow. PMID- 22933172 TI - Determination of cyantraniliprole and its major metabolite residues in pakchoi and soil using ultra-performance liquid chromatography-tandem mass spectrometry. AB - A rapid, simple and reliable analytical method was developed for the determination of cyantraniliprole and its major metabolite J9Z38 in pakchoi and soil by using ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). The sample preparation approach is known as QuEChERS, which stands for quick, easy, cheap, effective, rugged and safe. Samples were extracted with acetonitrile, and cleaned up with dispersive primary and secondary amine sorbent before analysis by UPLC-MS/MS. The limit of quantitation for cyantraniliprole and J9Z38 was 0.01 mg/kg in both pakchoi and soil. Average recoveries of cyantraniliprole and J9Z38 at three fortified levels (0.01, 0.05, 0.1 mg/kg) ranged from 77.8% to 102.5% with relative standard deviation of 1.6%-8.9%. This method has been applied to the analysis of cyantraniliprole and J9Z38 residues in real pakchoi and soil samples selected from field. The results of the residue dynamic experiment showed that the half-life of cyantraniliprole ranged from 2.9 to 6.4 days in pakchoi and 8.7 to 18.2 days in soil, respectively. The final residual levels of cyantraniliprole in pakchoi and soil from Guangdong and Shanghai were below 0.20 and 0.10 mg/kg, respectively; similarly, the final residual levels of J9Z38 in pakchoi and soil from Guangdong and Shanghai were <0.07 and 0.01 mg/kg. These results will be helpful in setting maximum residue limit guidance for cyantraniliprole in pakchoi in China. PMID- 22933173 TI - Effects of environmental factors on the uptake rates of dissolved nitrogen by a salt-water green alga (Oocystis borgei Snow). AB - Uptake rates for dissolved nitrogen (DN) by a marine alga (Oocystis borgei) were examined in a (15)N tracer experiment. Maximal uptake rates for all forms of DN were observed at temperatures between 25 and 30 degrees C and at algal concentrations between 3.22 * 10(8) and 4.78 * 10(8 )cell L(-1). Light intensity required to achieve the maximal uptake rate was 45 MUmol m(-2) s(-1) for dissolved inorganic nitrogen (DIN = NO(3) (-), NO(2) (-), NH(4) (+)) and methionine, and 126 MUmol m(-2) s(-1) for urea. Salinity required to achieve the maximal uptake rate was 12.85 ppt for DIN, 19.89 ppt for urea and 26.2 ppt for methionine. PMID- 22933174 TI - Comparison of the metal concentrations in the feathers of three bird species from southern Iran. AB - This study was conducted to determine the concentration of metals, namely cadmium, lead, cobalt and copper, in the feathers of chukar (Alectoris chukar), see-see partridge (Ammoperdix griseogularis) and rock dove (Columba livia) in order to: examine the species, gender and age related variations in trace metal accumulation, and identify any relationships between species. Bird samples were collected in February 2012 from the Hormod protected area, southern Iran and the concentration of metals were measured using a Shimadzu AA 660 flame atomic absorption spectrophotometer. The concentrations in all three species were copper > lead > cadmium > cobalt. The average cadmium concentrations were 2.0, 1.9, and 1.9 MUg/g for A. chukar, A. griseogularis, and C. livia, respectively. The average lead concentrations were 8.0, 5.4, and 7.7 MUg/g for A. chukar, A. griseogularis, and C. livia, respectively. The results showed that in all three species, the highest metal concentrations were observed in female/adult birds and the lowest concentrations were found in female/juvenile birds (except lead in A. chukar and copper in C. livia). PMID- 22933175 TI - Gold(II) phthalocyanine revisited: synthesis and spectroscopic properties of gold(III) phthalocyanine and an unprecedented ring-contracted phthalocyanine analogue. AB - In 1965, gold(II) phthalocyanine (AuPc, 1) was described to be synthesized from unsubstituted 1,3-diiminoisoindoline and gold powder or AuBr. Compound 1 has been regarded as a rare example of a paramagnetic gold(II) complex. However, its chemistry, especially the oxidation state of the central gold ion, has not been previously explored due to the inherent insolubility of 1 caused by its unsubstituted structure. In our attempt to synthesize soluble AuPcs by using 5,6 di-substituted 1,3-diiminoisoindolines, gold(III) phthalocyanine chloride (3) and a gold(III) complex of an unprecedented ring-contracted phthalocyanine analogue ([18]tribenzo-pentaaza-triphyrin(4,1,1), 4) were isolated. With this discrepant result from the original literature in hand, a reinvestigation of the original AuPc synthesis by using unsubstituted 1,3-diiminoisoindoline and various gold salts (including gold powder and AuBr) was performed, finding that only unsubstituted analogues of 3 and 4 or free-base phthalocyanine were obtained. No gold(II)-containing species could be isolated. PMID- 22933176 TI - Perforator arteries of the medial upper arm: anatomical basis of a new flap donor site. AB - The development of perforator flaps' concept based on knowledge on vascular anatomy of the skin represents a major improvement in reconstructive surgery. Succeeding description about vascular territories and anatomical basics of the main donor sites, the study of hidden donor sites, such as medial upper arm, constitutes a new step and an additional refinement. 20 upper limbs of 10 fresh adult cadavers were studied with colored latex injections. The origin and distribution of the perforator arteries of the superior ulnar collateral artery and the brachial artery were investigated. We have noted constant perforator arteries and described the limits of vascular territories of the medial upper arm. PMID- 22933177 TI - Adjuvant mitomycin C in functional endoscopic sinus surgery. PMID- 22933178 TI - Genetic linkage between melanism and winglessness in the ladybird beetle Adalia bipunctata. AB - We report a case of genetic linkage between the two major loci underlying different wing traits in the two-spot ladybird beetle, Adalia bipunctata (L.) (Coleoptera: Coccinellidae): melanism and winglessness. The loci are estimated to be 38.8 cM apart on one of the nine autosomes. This linkage is likely to facilitate the unravelling of the genetics of these traits. These traits are of interest in the context of the evolution of intraspecific morphological diversity, and for the application of ladybird beetles in biological control programs. PMID- 22933179 TI - Social learning in juvenile lemon sharks, Negaprion brevirostris. AB - Social learning is taxonomically widespread and can provide distinct behavioural advantages, such as in finding food or avoiding predators more efficiently. Although extensively studied in bony fishes, no such empirical evidence exists for cartilaginous fishes. Our aim in this study was to experimentally investigate the social learning capabilities of juvenile lemon sharks, Negaprion brevirostris. We designed a novel food task, where sharks were required to enter a start zone and subsequently make physical contact with a target in order to receive a food reward. Naive sharks were then able to interact with and observe (a) pre-trained sharks, that is, 'demonstrators', or (b) sharks with no previous experience, that is, 'sham demonstrators'. On completion, observer sharks were then isolated and tested individually in a similar task. During the exposure phase observers paired with 'demonstrator' sharks performed a greater number of task-related behaviours and made significantly more transitions from the start zone to the target, than observers paired with 'sham demonstrators'. When tested in isolation, observers previously paired with 'demonstrator' sharks completed a greater number of trials and made contact with the target significantly more often than observers previously paired with 'sham demonstrators'. Such experience also tended to result in faster overall task performance. These results indicate that juvenile lemon sharks, like numerous other animals, are capable of using socially derived information to learn about novel features in their environment. The results likely have important implications for behavioural processes, ecotourism and fisheries. PMID- 22933180 TI - An adapted F-test for homogeneity of variability in follow-on biological products. AB - In recent years, follow-on biological products (biosimilars) have received much attention from both the biotechnology industry and the regulatory agencies, especially after the passage of the 2010 healthcare reform bill. Unlike the traditional small-molecule drug products, the development of biological products is not only more complicated but also sensitive to small changes (both mean and variation) in procedure/environment during the manufacturing process because of some fundamental differences between drug products and biological products. A small change will have an impact on the quality of the product and consequently the treatment effect. Thus, in addition to the assessment of biosimilarity in average, it was suggested that biosimilarity in variability between biological products should be assessed. In this article, we propose an adapted F-test for homogeneity of variances to assess biosimilarity in variability. We study the performance and concordance of the proposed adapted F-test and compare it with probability-based method by extensive Monte Carlo simulations. PMID- 22933181 TI - Ddi1-like protein from Leishmania major is an active aspartyl proteinase. AB - Eukaryotic cells respond to DNA damage by activating damage checkpoint pathways, which arrest cell cycle progression and induce gene expression. We isolated a full-length cDNA encoding a 49-kDa protein from Leishmania major, which exhibited significant deduced amino acid sequence homology with the annotated Leishmania sp. DNA damage-inducible (Ddi1-like) protein, as well as with the Ddi1 protein from Saccharomyces cerevisiae. In contrast to the previously described Ddi1 protein, the protein from L. major displays three domains: (1) an NH2-terminal ubiquitin like; (2) a COOH terminal ubiquitin-associated; (3) a retroviral aspartyl proteinase, containing the typical D[S/T]G signature. The function of the L. major Ddi1-like recombinant protein was investigated after expression in baculovirus/insect cells and biochemical analysis, revealing preferential substrate selectivity for aspartyl proteinase A2 family substrates, with optimal activity in acidic conditions. The proteolytic activity was inhibited by aspartyl proteinase inhibitors. Molecular modeling of the retroviral domain of the Ddi1 like Leishmania protein revealed a dimer structure that contained a double Asp Ser-Gly-Ala amino acid sequence motif, in an almost identical geometry to the exhibited by the homologous retroviral aspartyl protease domain of yeast Ddi1 protein. Our results indicate that the isolated Ddi1-like protein is a functional aspartyl proteinase in L. major, opening possibility to be considered as a potential target for novel antiparasitic drugs. PMID- 22933182 TI - Radiosensitization of wildtype p53 cancer cells by the MDM2-inhibitor PXN727 is associated with altered heat shock protein 70 (Hsp70) levels. AB - The oncoprotein MDM2 (murine double minute 2) is often overexpressed in human tumors and thereby attenuates the function of the tumor suppressor p53. In this study, we investigated the effects of the novel MDM2-inhibitor PXN727 on p53 activation, cell proliferation, cell cycle distribution and radiosensitivity. Since the localization of heat shock protein 70 (Hsp70) exerts different effects on radioresistance of tumor cells, we investigated the impact of PXN727 on intracellular, membrane, and secreted Hsp70 levels. We could show that PXN727 exerts its effects on wildtype p53 (HCT116 p53+/+, A549) but not p53 depleted (HCT116 p53-/-) or mutated (FaDu) tumor cells. PXN727 activates p53, induces the expression of p21, reduces the proportion of cells in the radioresistant S-phase and induces senescence. Radiosensitivity was significantly increased by PXN727 in HCT116 p53+/+ tumor cells. Furthermore, PXN727 causes a downregulation of Hsp70 membrane expression and an upregulated secretion of Hsp70 in wildtype p53 tumor cells. Our data suggest that re-activation of p53 by MDM2-inhibition modulates Hsp70 membrane expression and secretion which might contribute to the radiosensitizing effect of the MDM2-inhibitor PXN727. PMID- 22933183 TI - Body mass index is the most useful predictive factor for the onset of nonalcoholic fatty liver disease: a community-based retrospective longitudinal cohort study. AB - BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) can progress to advanced liver disease and non-liver-related diseases. To prevent NAFLD onset, clinicians must be able to easily identify high-risk NAFLD patients so that intervention can begin at an earlier stage. We sought to identify the predictive factors for NAFLD onset. METHODS: In a community-based, longitudinal design, the records of 6,403 Japanese subjects were reviewed to identify those meeting the criteria for NAFLD onset. Univariate and multivariate logistic regression analyses were used to identify predictive factors for NAFLD onset. The accuracy of different models was evaluated according to their areas under the receiver operating characteristic curves. Comparative risk analysis was performed using the Kaplan-Meier method. RESULTS: Multivariate analysis of 400 subjects who met the criteria for the onset of NAFLD during the observation period confirmed that body mass index (BMI) at baseline was the most useful predictive factor for NAFLD onset in both sexes. Cutoff levels of BMI for NAFLD onset were estimated at 23 kg/m2 for men and 22.2 kg/m2 for women. The cumulative onset rate of NAFLD was significantly higher in the high BMI group than in the low BMI group in both sexes (P < 0.001). CONCLUSION: BMI was confirmed as the most useful predictive factor for NAFLD onset in both sexes; its cutoff levels were similar to those recommended by the World Health Organization for helping to prevent metabolic disease. An accurate BMI cutoff level will enable clinicians to identify subjects at risk for NAFLD onset. PMID- 22933185 TI - Embodied linearity of speed control in Drosophila melanogaster. AB - Fruitflies regulate flight speed by adjusting their body angle. To understand how low-level posture control serves an overall linear visual speed control strategy, we visually induced free-flight acceleration responses in a wind tunnel and measured the body kinematics using high-speed videography. Subsequently, we reverse engineered the transfer function mapping body pitch angle onto flight speed. A linear model is able to reproduce the behavioural data with good accuracy. Our results show that linearity in speed control is realized already at the level of body posture-mediated speed control and is therefore embodied at the level of the complex aerodynamic mechanisms of body and wings. Together with previous results, this study reveals the existence of a linear hierarchical control strategy, which can provide relevant control principles for biomimetic implementations, such as autonomous flying micro air vehicles. PMID- 22933184 TI - Psychopathic traits and their association with adjustment problems in girls. AB - Psychopathic traits, and specifically callous-unemotional (CU) traits, are associated with a variety of adverse outcomes in adolescence and adulthood. The majority of research in this area has focused on men and boys, though there is some evidence that psychopathy is expressed differently in girls and women. Accordingly, the purpose of this study was to test if the relationships of callous-unemotional (CU) traits with adjustment differed between girls and boys at risk for antisocial behavior. The sample was composed of children whose biological father had past or current alcohol or drug problems. A total of 234 children (116 boys, 118 girls; ages 10-12) were rated by their parent or guardian on CU traits and overall adjustment. Boys were generally rated higher on measures of CU traits; however, these traits were more prominently related to adjustment problems among girls. These results suggest that expression of psychopathic traits may have more negative effects on adjustment for girls than boys. One possible mechanism by which CU traits could be impacting adjustment in girls is by impairing interpersonal relationships. PMID- 22933186 TI - Hierarchical virtual screening for the discovery of new molecular scaffolds in antibacterial hit identification. AB - One of the initial steps of modern drug discovery is the identification of small organic molecules able to inhibit a target macromolecule of therapeutic interest. A small proportion of these hits are further developed into lead compounds, which in turn may ultimately lead to a marketed drug. A commonly used screening protocol used for this task is high-throughput screening (HTS). However, the performance of HTS against antibacterial targets has generally been unsatisfactory, with high costs and low rates of hit identification. Here, we present a novel computational methodology that is able to identify a high proportion of structurally diverse inhibitors by searching unusually large molecular databases in a time-, cost- and resource-efficient manner. This virtual screening methodology was tested prospectively on two versions of an antibacterial target (type II dehydroquinase from Mycobacterium tuberculosis and Streptomyces coelicolor), for which HTS has not provided satisfactory results and consequently practically all known inhibitors are derivatives of the same core scaffold. Overall, our protocols identified 100 new inhibitors, with calculated K(i) ranging from 4 to 250 MUM (confirmed hit rates are 60% and 62% against each version of the target). Most importantly, over 50 new active molecular scaffolds were discovered that underscore the benefits that a wide application of prospectively validated in silico screening tools is likely to bring to antibacterial hit identification. PMID- 22933187 TI - Quasi-potential landscape in complex multi-stable systems. AB - The developmental dynamics of multicellular organisms is a process that takes place in a multi-stable system in which each attractor state represents a cell type, and attractor transitions correspond to cell differentiation paths. This new understanding has revived the idea of a quasi-potential landscape, first proposed by Waddington as a metaphor. To describe development, one is interested in the 'relative stabilities' of N attractors (N > 2). Existing theories of state transition between local minima on some potential landscape deal with the exit part in the transition between two attractors in pair-attractor systems but do not offer the notion of a global potential function that relates more than two attractors to each other. Several ad hoc methods have been used in systems biology to compute a landscape in non-gradient systems, such as gene regulatory networks. Here we present an overview of currently available methods, discuss their limitations and propose a new decomposition of vector fields that permits the computation of a quasi-potential function that is equivalent to the Freidlin Wentzell potential but is not limited to two attractors. Several examples of decomposition are given, and the significance of such a quasi-potential function is discussed. PMID- 22933188 TI - Thirteen years of breast screening had no measurable effect on breast cancer mortality in Norway. PMID- 22933189 TI - Neuroendovascular optical coherence tomography imaging for cerebrovascular disease: current concepts and clinical potential. PMID- 22933190 TI - Efficient synthesis of anthranilic esters via Pd-catalyzed dehydrogenative/decarbonylative coupling of anilides and glyoxylates. AB - A novel way of synthesizing anthranilic esters was developed via Pd-catalyzed dehydrogenative/decarbonylative coupling between anilides and glyoxylates. PMID- 22933191 TI - Responsive polyelectrolyte multilayers assembled at high ionic strength with an unusual collapse at low ionic strength. AB - Responsive polyelectrolyte multilayers (PEMs) of poly(diallyl dimethyl ammonium chloride) (PDADMAC) and poly(styrene sodium sulfonate) (PSS) with thicknesses between 350 and 400 nm for 11 deposited polyelectrolyte layers were fabricated assembling the polyelectrolytes at 3 M NaCl. When the 3 M NaCl bulk solution is replaced by water, the PEMs release water, approximately a 46% of the total mass, and experience a thickness reduction of more than 200 nm. Changes in thickness and water content are fully reversible. The film recovers its original thickness and water content when it is exposed again to a 3 M NaCl solution. A responsive polymer film is achieved with the capability of swelling at high ionic strength and collapsing in water with variations in thickness of hundred of nanometers. PMID- 22933192 TI - [Does an increasing intima media thickness predict the cardiovascular risk? - A non evidence-based procedure does not reveal clinical significant results]. PMID- 22933193 TI - [Rheumatology: present and future]. PMID- 22933194 TI - [Camptocormia in the differential diagnosis of hyperkyphosis and ankylosing spondylitis]. AB - HISTORY AND ADMISSION FINDINGS: An 83-year-old patient with Parkinson's disease was referred because of pain in the thoracolumbar spine, increasing kyphosis and gait disturbance. Clinically, the main anomaly was a marked hyperkyphosis of the spine during standing and sitting which regressed while recumbent. INVESTIGATIONS: Radiologically, spondylosis, osteochondrosis, and facet joint arthrosis demonstrated marked degeneration of the spine (diffuse skeletal hyperostosis, DISH). But the postural disorder could not adequately be explained by these pathological changes. The sacroiliac joints were age-appropriate, syndesmophytes or ankylosis typically of AS were not detectable. DIAGNOSIS, TREATMENT AND COURSE: A diagnosis of camptocormia in connection with the known Parkinson's disease was made together with the neurologist. Intensive physio- and balneotherapy, the administration of non-steroidal anti-inflammatory drugs (NSAIDs) and an intensification of the Parkinson medication led to a slight improvement of gait disturbance and pain, but not of the tendency to hyperkyphosis. CONCLUSION: In the differential diagnosis of postural disorders in spinal diseases, especially in case of hyperkyphosis, camptocormia is of importance as a rare manifestation of different diseases, such as Parkinson's disease. The treatment of camptocormia is difficult and usually not satisfactory. PMID- 22933195 TI - [Differential diagnosis of back pain in patients with ankylosing spondylitis: instable cervical spine fracture]. AB - HISTORY AND ADMISSION FINDINGS: A 65-year-old patient with longstanding ankylosing spondylitis (AS) complained of persistent pain in the right shoulder and the neck; elevation of the shoulder was impaired. The symptoms had started a week before admission after a fall. Physical examination revealed generally decreased mobility of an already hyperkyphotic cervical spine (CS) and decreased thoracic excursion. The paravertebral muscles were stiff . CLINICAL INVESTIGATIONS: Because of the trauma extensive imaging procedures with conventional radiographs, magnetic resonance imaging (MRI) and computed tomography (CT) of the CS were performed. These showed a compression fracture of C5, detachment of the dorsal and ventral ligaments and a ventral dislocation of C4 with dislocation (Type C fracture). TREATMENT AND COURSE: After immediate consultation of the cooperating center for spinal surgery corpectomy of C5 and ventral fusion of C3-7 were performed on the same day, together with a dorsal transpedicular fusion. During the imaging procedures symptoms of a beginning paraplegia occurred. After successful surgery and early postoperative rehabilitation, the patient was discharged to an in-patient rehabiltation unit. At discharge, there was but a slight paresis of the right arm. CONCLUSION: Patients with AS and advanced spinal ankylosis are at increased risk of vertebral fracture after minor accidents. Regardless of the initial report of clinical symptoms it is mandatory to perform appropriate imaging procedures usually including MRI. PMID- 22933196 TI - [34-year-old patient with non-radiographic axial spondyloarthritis and acute back pain]. PMID- 22933197 TI - [Spondyloarthritis - the novel concept. An introduction to the diagnosis and treatment of axial spondyloarthritis]. AB - The characteristic features of spondyloarthritis are inflammation in the axial skeleton (sacroiliitis, spondylitis) and inflammation in peripheral joints (arthritis) and entheses (enthesitis). According to the leading clinical symptom SpA is today differentiated in the either predominant axial or the peripheral form. The axial SpA are further subdivided in ankylosing spondylitis and non radiographic axial SpA. This subset is characterized by the absence of structural changes on conventional x-rays. In this review we describe the clinical symptoms, the diagnosis and therapy of patients with axial SpA. PMID- 22933198 TI - [Antiphospholipid-syndrome - when to treat?]. PMID- 22933199 TI - [Glucocorticoids in rheumatic diseases - what is the optimal dose?]. AB - Glucocorticoids (GCs) have been an invaluable tool in the treatment of patients with rheumatic diseases. The aims of GC therapy vary for different indications from symptom management to disease-modification and immunmodulation. Even after 60 years of GC use, there is still a lack of knowledge concerning optimal therapeutic strategies with GCs. Taking this into account, optimal dosage schedules for inflammatory rheumatic diseases are discussed. PMID- 22933200 TI - [B-cell-directed therapy in patients with connective tissue diseases]. AB - B cells are able to present antigen, secrete cytokines and differentiate into (auto)antibody secreting cells and are therefore considered as an important therapeutic target in patients with autoantibody-mediated autoimmune disease. Benefits and limitations of B-cell-directed therapies and unmet medical needs are discussed in this minireview. B cell targeting broadens our armamentarium available to treat SLE and other connective tissue diseases. But further research addressing unmet medical needs is required and refractory patients receiving B cell-directed off-label therapeutics should be enrolled in registries to collect information on the value and safety of these drugs in rare autoimmune diseases. PMID- 22933201 TI - [Autoantibodies in systemic sclerosis]. PMID- 22933202 TI - [Treat-to-target and remission: current strategies in rheumatoid arthritis]. PMID- 22933203 TI - [Recent progress in arthrosis research]. PMID- 22933204 TI - [Editor's words]. PMID- 22933205 TI - Does the method of heart transplantation affect left ventricular filling? AB - BACKGROUND: For over 40 years now orthotopic heart transplantation (OHT) has been the treatment of choice in patients with advanced heart failure. For many years patients undergoing OHT have been treated with the classical approach involving anastomosis of the donor atria with the recipient atria resulting in a heart in which the atria are enlarged. An alternative method for OHT is the bicaval anastomosis technique, which involves connecting both of the donor's venae cavae with the recipient's venae cavae. AIM: To assess left ventricular (LV) filling in patients undergoing OHT using the classical (biatrial) versus bicaval approach. METHODS: We analysed 60 patients who had undergone OHT between 1 and 36 months before. Myocardial biopsy at echocardiography revealed grade 0 or 1A rejection in all the patients. All the patients were also in NYHA functional class I. The patients were divided in two groups: patients who had undergone biatrial anastomosis (Group 1, n = 40) and patients who had undergone bicaval OHT (Group 2, n = 20). In order to render the results independent of pre-OHT blood pressure values in the pulmonary circulation we assessed the values of right ventricular systolic pressure (RVSP), mean pulmonary artery pressure (PAP) and transpulmonary gradient (TPG) in all the patients before OHT. We assessed the following echocardiographic parameters: peak early filling velocity (E-wave), peak atrial filling velocity (A-wave), E-wave deceleration time, early diastolic mitral valve ring motion velocity (E'), E/E', isovolumetric relaxation time of the LV, duration of the A-wave, right atrial area and left atrial area, LV mass, LV mass index, LV end-diastolic and end-systolic dimension, and the severity of tricuspid regurgitation (TR). RESULTS: The values of RVSP, PAP and TPG in the study groups before OHT did not differ significantly. The values of E (86.5 +/- 12.5 vs. 67.3 +/- 8.5; p < 0.001), E' (11.9 +/- 1.1 vs. 10.9 +/- 0.9; p = 0.003) and E/E' (7.4 +/- 1.5 vs. 6.1 +/- 0.85; p = 0.006) differed between the groups and were significantly higher in the group undergoing surgery using the biatrial approach. The duration of the A-wave was significantly longer in the group undergoing surgery using the bicaval approach (129.0 +/- 5.1 vs. 136.7 +/- 10.0; p = 0.001). There were no significant differences in the other parameters of LV filling. Right atrial area was significantly lower in the group undergoing surgery using the bicaval approach (19.2 +/- 3.0 vs. 14.0 +/- 2.0; p < 0.001). LV size, LV mass and LV mass index did not differ significantly between the groups. The lack of TR was more commonly observed in the group undergoing surgery using the bicaval approach at the limit of p = 0.05. Pacemaker implantation was required in 12 (30%) patients from the group undergoing surgery using the classical method and 2 (10%) patients from the group undergoing OHT using the bicaval approach (p = 0.04). CONCLUSIONS: Certain echocardiographic parameters suggest a better LV filling in patients undergoing OHT using the bicaval approach. Preservation of the right atrial geometry in patients undergoing OHT using the bicaval approach plays an important role in LV filling. PMID- 22933206 TI - [One heart, two methods]. PMID- 22933207 TI - Participation in thrombolytic trials delays reperfusion therapy in acute myocardial infarction. AB - BACKGROUND: Shortening the time delay at the beginning of treatment in ST-segment elevation myocardial infarction (STEMI) has proven to be clinically essential. Invasive vs. thrombolytic treatment strategy is currently under investigation, particularly in terms of the time from the onset of symptoms to treatment initiation. It is likely that enrolment to trials in STEMI may paradoxically prolong the time delay to treatment if randomisation procedures are too complex. AIM: To evaluate time to the onset of reperfusion therapy (door-to-thrombolysis time - DtT) in patients randomised to trials (TT) or treated routinely with thrombolytics (Thrx). METHODS: We evaluated DtT in a group of 189 consecutive STEMI patients (TT: n = 96; Thrx: n = 93). The inclusion criteria for the analysis were identical in both groups: 1. STEMI diagnosis was given on admission. 2. Patients had no signs of heart failure. 3. Patients did not require any additional therapy prior to thrombolysis (no need for electrical cardioversion or blood pressure lowering). 4. There were no contraindications for immediate reperfusion therapy. The comparison of DtT between evaluated groups was performed. To find out the independent predictors of DtT prolongation, the impact of patients' age, gender, admission time, pre-hospital delay and trial participation has been evaluated in multivariate analysis. RESULTS: Highly statistically longer mean value of DtT was measured in the entire TT group than in Thrx (41 +/- 18 vs. 22 +/- 8 min; p < 0.001). The difference was also significant for patients who constituted the subgroup of TT who were proposed and refused to participate in trials (37 +/- 13 vs. 22 +/- 8 min; p < 0.01). No differences in DtT were found between groups of patients enrolled to various trials. The participation in TT was found to be the strongest predictor of DtT prolongation over 30 min (OR 13.2; 95% CI 6.1-28.5; p < 0.001). The risk of over 30 min DtT prolongation was five times higher if patients were admitted in an early phase of the trial. CONCLUSIONS: 1. Participating in trials delays the beginning of reperfusion therapy. 2. This delay may be clinically important, particularly in patients hospitalised in a very early phase of STEMI. 3. The call for reappraisal of informed consent issues and randomisation procedures in the context of simplicity seems to be justified. PMID- 22933208 TI - [Ensuring informed consent]. PMID- 22933209 TI - An assessment of regression of left ventricular hypertrophy following alcohol ablation of the interventricular septum in patients with hypertrophic cardiomyopathy with left ventricular outflow tract obstruction. AB - BACKGROUND: Hypertrophic obstructive cardiomyopathy (HOCM) is characterised by asymmetric myocardial hypertrophy, which is most pronounced in the interventricular septum (IVS) and is responsible for the dynamic obstruction of the left ventricular outflow tract (LVOT). Successful alcohol septal ablation (ASA) of the IVS allows to reduce the thickness of the parabasal part of the IVS myocardium and, in most cases, to permanently reduce the gradient in the LVOT. AIM: To assess, using cardiac magnetic resonance imaging (MRI) and transthoracic echocardiography (TTE), the impact of gradient reduction in the LVOT on the type and severity of left ventricular (LV) remodelling. METHODS: The study included 30 patients (aged 56.9 +/- 11.9 years) with HOCM and the mean peak gradient (PG) in the LVOT of 123 +/- 33 mm Hg who underwent ASA. MRI measurements were performed before and at 6 months after ASA and TTE measurements were performed before, at 3 months and at 6 months after ASA. RESULTS: PG in the LVOT decreased to an average of 52 +/- 37 mm Hg (p < 0.0001) at 3 months after ASA and to 37 +/- 28 mm Hg (p < 0.0001) at 6 months after ASA. TTE revealed a decrease in IVS thickness outside the scar following ASA from 23.6 +/- 3.5 mm to 19.3 +/- 4.0 mm (p < 0.0001) and 19.4 +/- 0.4 mm (p < 0.0001) at 3 and 6 months, respectively. There was also a decrease in lateral wall (PW) thickness from 15.9 +/- 3.2 mm to 14.9 +/- 2.9 mm (p = 0.046) and 14.16 +/- 2.00 (p = 0.0065) at 3 and 6 months, respectively. MRI revealed a decrease in IVS thickness from 23.7 +/- 2.8 mm to 18.04 +/- 4.00 mm (p = 0.0001) at 6 months following ASA. We observed a regression of the PW hypertrophy from 13.2 +/- 3.35 mm to 12.18 +/- 2.4 mm (p = 0.0225). There was a decrease in IVS mass from 108.9 +/- 20 g to 91.5 +/- 29 g (p = 0.0006). There was a trend towards a decreased LV mass and LV mass excluding IVS mass at 6 months. CONCLUSIONS: A significant decrease in PG in the LVOT is associated with a decrease in LV mass and with regression of LV hypertrophy outside the scar after ASA. PMID- 22933210 TI - Frequency spectra analysis suggests outcomes in patients with paroxysmal atrial fibrillation. AB - BACKGROUND AND AIM: The purpose of this study was to determine the role of dominant frequency (DF) and organised index (OI) in outcomes of pulmonary vein (PV) isolation for paroxysmal atrial fibrillation (AF). METHODS: OI and DF of electrograms in coronary vein (CS) during AF were obtained by frequency spectra analysis in 60 patients with paroxysmal AF who underwent PV isolation. Based on the results of 12 months follow up, 14 patients with recurrent AF were included in group 1 and 46 patients with sinus rhythm were included in group 2. RESULTS: In group 1, no spectral component was reduced by PV isolation. Spectral components were reduced by PV isolation in 23 patients in group 2. The changes of DF after PV isolation was significantly different between groups 1 and 2 (1.2 +/- 1.2 vs. 2.4 +/- 1.3, p = 0.01); the increment of OI after PV isolation in group 1 was significantly lower than in group 2 (9 +/- 13% vs. 22 +/- 17%, p = 0.02. CONCLUSIONS: A decrease in DF and an increase in OI after PV isolation may suggest a better clinical outcome. PMID- 22933211 TI - The problem of indeterminate microvolt T-wave alternans results in patients with left ventricular dysfunction referred for implantable cardioverter-defibrillator implantation in the primary prevention of sudden cardiac death. AB - BACKGROUND: Microvolt T-wave alternans (MTWA) is a recommended noninvasive diagnostic test for predicting the risk of sudden cardiac death (SCD). However, about 6% to 41% of MTWA results are indeterminate. The causes, interpretation and clinical significance of these results have not been not clearly established. AIM: To assess frequency, causes, and prognostic significance of indeterminate MTWA results in a group of patients with left ventricular dysfunction referred for implantable cardioverter-defibrillator (ICD) placement in the primary prevention of SCD. METHODS: Patients with left ventricular ejection fraction (LVEF) <= 35% underwent MTWA evaluation during a treadmill exercise test (CH2000 system, Cambridge Heart Inc. Bedford MA, USA). MTWA results (spectral analysis) were categorised as positive, negative, or indeterminate (MTWApos, MTWAneg, and MTWAnd, respectively). Patients were followed up for the occurrence of SCD, ventricular tachycardia (VT), and ventricular fibrillation (VF). RESULTS: Mean age of participants (n = 93) was 63 +/- 13 years, an ischaemic cause of left ventricular dysfunction was present in 70 (75%) patients, and average LVEF was 30 +/- 7%. MTWApos was found in 27 (29%) patients, MTWAneg in 41 (44%) patients, and MTWAnd in 25 (27%) patients. Causes of MTWAnd included inability to achieve a diagnostic HR in 12 (48%) patients, ventricular ectopy in 5 (20%) patients, nonsustained alternans in 3 (12%) patients, and technical factors (artifacts due to a high noise level) in 5 patients (20% of indeterminate results, 5.4% of the whole study group). During follow-up, 8 SCD/VT/VF events were noted (4 patients with MTWApos and 4 patients with MTWAnd due to patient-related factors). The rate of SCD/VT/VF was 35% in patients with MTWApos and 34.6% in MTWAnd due to patients related factors, significantly higher compared to those with MTWAneg or MTWAnd due to technical factors (p < 0.05). CONCLUSIONS: Although the proportion of indeterminate MTWA results in patients with left ventricular dysfunction referred for ICD implantation in the primary prevention of SCD was high, the proportion of indeterminate MTWA results due to technical factors, probably of no prognostic significance, was small. PMID- 22933212 TI - Is level of social support associated with health behaviours modifying cardiovascular risk? Results of the WOBASZ study. AB - BACKGROUND: Psychosocial risk factors affected the human health both by autonomic, neuroendocrine and immunological mechanisms and by the influence on human lifestyle. Lack of social support can reflect the person's lifestyle to more unhealthy. AIM: To assess if low, compared to high social support level (SSL), contributes to the unhealthy lifestyle in Polish general population. METHODS: The random sample of Polish population of 6164 men and 6915 women, aged 20-74, filled-in the Berkman and Syme questionnaire in 2003-2005 in the frame of National Multicenter Health Survey (WOBASZ). RESULTS: 31% of men and 39% of women had low SSL and they more often had high cardiovascular risk, depressive symptoms and cardiovascular disease risk factors, especially women. Men and women with low SSL more often smoked cigarettes than those with high SSL, rarely try to quit smoking, made regular physical activity, and rarely self-measured their blood pressure. Additionally men more often drank alcohol >= 30.0 g/day. They also more often did not take the prescribed medication, although they bought them. Out of unhealthy elements, lack of regular physical activity and blood pressure self measuring were significantly and independently associated with SSL in both genders and additionally smoking habit and lack of quit smoking in the past in women. CONCLUSIONS: Persons with low SSL had more unhealthy lifestyle than those without. In Polish population the low SSL played a greater role in creating the cardiovascular risk in women than in men. PMID- 22933213 TI - [Social support - myth or need in the twenty-first century?]. PMID- 22933214 TI - Risk factors of neurological complications in cardiac surgery. AB - BACKGROUND: Postoperative complications are integral to cardiac surgery. The most serious ones are stroke, which develops in about 7.5% of the patients, and postoperative encephalopathy, which affects 10-30% of the patients. According to bibliographical data, the number of complications is increasing. AIM: To analyse the risk factors and the types of neurological complications in patients undergoing heart surgery. METHODS: We assessed retrospectively 323 consecutive patients undergoing surgery at the Department of Cardiac Surgery, University Teaching Hospital, Medical University of Bialystok, Poland, between July 2007 and June 2008. Group 1 comprised patients without neurological complications (n = 287; 89%) and Group 2 consisted of patients with neurological complications (n = 36; 11%). Our analysis included the following: preoperative status (age, sex, co morbidities), intraoperative course (surgery type, duration of cardiopulmonary bypass [CPB], duration of aortic cross-clamping, types of medications administered, necessity of reinfusion from the cardiotomy reservoir and the necessity of tranexamic acid infusion) and the postoperative course (time to regaining consciousness, duration of mechanical ventilation, development of complications, types of complications). The results were then analysed statistically: arithmetic means and standard deviations were calculated for quantitative variables and the quantitative and percentage distributions were calculated for qualitative variables. The between- group comparisons of the quantitative variables were carried out using the t-Student test, while the qualitative variables were compared using the chi(2) test. The variables that proved significant in the univariate comparisons were included in the multivariate model. Regression analysis was the final step of the analysis of the risk factors for neurological complications. Based on the analysis of the ROC curve we calculated the cutoff values for the continuous variables. We calculated odds ratios with their 95% confidence intervals. P values of less than 0.05 were considered statistically significant. RESULTS: Among the 36 patients in Group 2, postoperative encephalopathy developed in 22 patients, transient ischaemic attacks in 7 patients, ischaemic stroke in 6 patients (associated with right hemisphere damage in 3 patients and with left hemisphere damage in 3 patients) and haemorrhagic stroke in 1 patient (right hemisphere). Early mortality was 5% with 2 (0.69%) patients dying in Group 1 and 14 (38.9%) in Group 2. Univariate analysis revealed that the preoperative risk factors of neurological complications were: age >68 years (with a cutoff value of 58.5 years), a history of stroke with paresis, atrial fibrillation (AF) and a euroSCORE of >6 (with a cutoff value of 4.5). The peri- and postoperative risk factors included: surgery type (complex coronary and valvular surgeries aortic valve surgeries), duration of CPB of >142 min, duration of aortic crossclamping of >88 min, mean perfusion pressure during CPB of <70 mm Hg, haemodilution manifested by a haematocrit (HCT) of <28%, perfusate supply, time to regaining consciousness of >14.5 h and duration of artificial ventilation of >30.5 h. Multivariate analysis revealed the following factors to increase the risk of neurological complications: long duration of ventilation, a history of stroke with paresis, AF, low HCT values and long duration of aortic cross-clamping. The Nagelkerke R2 coefficient of determination was 0.636, the sensitivity was 74.36%, the specificity was 97.545% and the accuracy was 94.74%. CONCLUSIONS: In patients undergoing heart surgery, the independent risk factors of neurological complications in the first 30 days include: long duration of ventilation, a history of stroke with paresis, AF, haemodilution manifested by an HCT of <28% and long duration of aortic cross clamping. Neurological complications are associated with high postoperative mortality. PMID- 22933215 TI - Minimally invasive hybrid ablation procedure for the treatment of persistent atrial fibrillation: one year results. AB - BACKGROUND: The concept of a hybrid approach, combining the most effective techniques of surgical and endocardial catheter ablation has resulted in the creation of the convergent ablation procedure. This novel, pericardioscopic, hybrid approach can be an effective option for highly symptomatic patients with persistent atrial fibrillation (PSAF) and longstanding persistent atrial fibrillation (LSPAF) for whom standalone surgical or endocardial ablation procedures offer sometimes unsatisfactory outcomes. AIM: To assess the safety, efficacy and effectiveness of a hybrid epicardial and endocardial radiofrequency ablation for the treatment of PSAF and LSPAF. METHODS: Single-centre, prospective, non-randomised clinical study. Between August 2009 and December 2011, 27 patients with PSAF (n = 5) and LSPAF (n = 22) underwent hybrid ablation (HABL). Mean age was 52.52 +/- 11.27 years, and the mean EHRA class was 2.5; 14 (51.8%) patients had a history of electrical cardioversion (n = 6) or catheter ablation (n = 8). Five patients had left ventricular ejection fraction (LVEF) of less than 35%. Mean AF duration for all patients was 3.46 +/- 2.5 years. All patients were on antiarrhythmic drugs (AAD) and oral anticoagulation. Patients were scheduled for three, six and 12 month follow-up with seven day Holters, REVEAL(r) XT and ECHO measurements. RESULTS: The HABL procedure was feasible in all patients. At six months post procedure, 72.2% (13/18) of patients were in SR, and 66.5% (12/18) were off class I/III AADs. Four patients were in AF and one patient developed right atrial flutter. At one year post procedure, 80% (8/10) of patients were in SR and off class I/III AADs. At two year post procedure, 100% (6/6) of patients were in SR and off class I/III AADs. Rapid change in left ventricular function was noted in patients with low LVEF (<= 35%) prior to the procedure. Patients with LVEF +40% had less apparent improvement. CONCLUSIONS: Hybrid, epicardial and endocardial, radiofrequency ablation is feasible and safe, effectively restoring sinus rhythm in the vast majority of patients with PSAF and LSPAF. PMID- 22933216 TI - [Hybrid treatment of persistent AF. Is it already time for a electrophysiologic "heart team"?]. PMID- 22933217 TI - [Papillary fibroelastoma of the aortic valve in a 67-year-old patient after myocardial infarction]. AB - We present a case of a 67-year-old female patient with diagnosed papillary fibroelastoma (PFE) of the aortic valve. Eight months before the tumour discovery a non-ST segment elevation myocardial infarction without essential coronary artery restriction was diagnosed. The tumour was excised (during the aortotomy under cardiopulmonary bypass at systemic hypothermia) without any aortic valve injury. The main symptoms of PFE along with diagnostic techniques and treatment were described. PMID- 22933218 TI - [SAM not only in hypertrophic cardiomyopathy]. AB - Hypertrophic obstructive cardiomyopathy with significant hypertrophy of the basal septum is the most frequently reported cause of left ventricular outflow tract obstruction (LVOTO) in the mechanism of systolic anterior movement (SAM). Additionally, other conditions such as dehydration, vasodilatation, mitral valve repair, dobutamine stress echocardiography and pheochromocytoma have been associated with LVOTO. In this report, we present a case of a patient without hypertrophic cardiomyopathy who developed severe LVOTO in the SAM mechanism. The presented case serves as a reminder that hypovolaemia together with hyperdynamic state resulting from increased catecholemines may result in the development of dynamic LVOTO. PMID- 22933219 TI - [Liddle's syndrome--a case report and genetic diagnostics]. AB - We present a case of a 52-year-old male with Liddle syndrome. The results of genetic studies and treatment in this condition is described. PMID- 22933220 TI - [Tumour in left atrium diagnosed 6 years after ablation of pulmonary vein ostia and inferior right atrial isthmus: thrombus or myxoma?]. AB - We present a case of the left atrial myxoma 6 years after atrial fibrillation ablation. The initial diagnosis of the mass revealed on echocardiography was a thrombus. Failure of anticoagulant treatment and transesophageal echocardiography led to diagnosis of myxoma, confirmed intraoperatively and histologically. PMID- 22933221 TI - [Current concepts in treatment of left main coronary artery disease: a review of epidemiological data]. PMID- 22933222 TI - [Green tea as a protective factor in prophylaxis and treatment of selected cardiovascular diseases]. PMID- 22933224 TI - [ECG in a competitive athlete]. PMID- 22933223 TI - [Dynamic changes of repolarization pattern associated with deep breathing and exercise in a young athlete: the sign "athletes heart" or concealed heart disease?]. AB - We described ECG of a 22-year-old healthy man, professional basketball player, who has been training since he was 14. Physical examination was normal. In ECG the following abnormalities of repolarisation were observed: biphasic, positive/negative T waves in leads V3-V6. This changes normalised during deep breathing test. The echocardiogram revealed normal size of the heart's chambers, left ventricular walls hypertrophy - septum and posterior wall: 14 mm, normal mitral inflow - E/A = 1.1, normal ejection fraction (68%). The exercise test (ExT, 20 METS) was without symptoms. During ExT normalisation of repolarisation abnormalities was observed. From 6(th) minute of the recovery phase the repolarisation abnormalities were observed again. In unselected population of young athletes abnormal ECG is observed in 4.8-11.8% of athletes. Negative T waves in precordial leads are observed 2.3% of the young athletes and in 2.7% young, professional athletes. The repolarisation abnormalities described in our patient belong to electrocardiographic spectrum of the early repolarisation pattern mainly seen in black, young athletes. PMID- 22933225 TI - [Myocardial viability imaging in ischaemic heart disease, part 2: current role of radionuclide imaging. Expert consensus statement of the Polish Clinical Forum for Cardiovascular Imaging]. PMID- 22933226 TI - [Resistant coronary lesion in post coronary artery bypass grafting patient]. AB - A presented case of a 64-year-old male who underwent unsuccessful rotational atherectomy. PMID- 22933228 TI - [Arrythmogenic right ventricular cardiomyopathy in patient with abnormal origin of right coronary artery and ventricular tachycardia during exercises]. AB - A 18-year-old patient with abnormal origin of right coronary artery and ventricular tachycardia during exercises is presented. Myocardial biopsy revealed arrhythmogenic right ventricular cardiomyopathy. PMID- 22933229 TI - [Summary of the article: Furlan A J, Reisman M, Massaro J et al. Closure or medical therapy for cryptogenic stroke with patent foramen ovale. N Engl J Med, 2012; 366: 991-999 ]. PMID- 22933230 TI - [CLOSURE I study argues that it is not worth closing PFO in patients after ischemic stroke]. PMID- 22933231 TI - [Shear-activated nanotherapeutics. Are we witnessing a breakthrough in the treatment of thrombosis and atherosclerosis?]. PMID- 22933232 TI - Stress-induced cartilage degradation does not depend on the NLRP3 inflammasome in human osteoarthritis and mouse models. AB - OBJECTIVE: The main feature of osteoarthritis (OA) is degradation and loss of articular cartilage. Interleukin-1beta (IL-1beta) is thought to have a prominent role in shifting the metabolic balance toward degradation. IL-1beta is first synthesized as an inactive precursor that is cleaved to the secreted active form mainly in the "inflammasome," a complex of initiators (including NLRP3), adaptor molecule ASC, and caspase 1. The aim of this study was to clarify the roles of IL 1beta and the inflammasome in cartilage breakdown. METHODS: We assessed IL-1beta release by cartilage explants from 18 patients with OA. We also evaluated the lipopolysaccharide (LPS)-, IL-1alpha-, and tumor necrosis factor alpha (TNFalpha) induced activity of matrix metalloproteinase 3 (MMP-3), MMP-9, and MMP-13 in NLRP3-knockout mice and wild-type mice and the inhibition of caspase 1 with Z YVAD-FMK and the blockade of IL-1beta with IL-1 receptor antagonist (IL-1Ra). Cartilage explants from NLRP3-knockout mice and IL-1R type I (IL-1RI)-knockout mice were subjected to excessive dynamic compression (0.5 Hz, 1 MPa) to trigger degradation, followed by assessment of load-induced glycosaminoglycan (GAG) release and MMP enzymatic activity. RESULTS: Despite the expression of NLRP3, ASC, and caspase 1, OA cartilage was not able to produce active IL-1beta. LPS, IL 1alpha, and TNFalpha dose-dependently increased MMP-3, MMP-9, and MMP-13 activity in cultured chondrocytes and in NLRP3(-/-) chondrocytes, and this effect was not changed by inhibiting caspase 1 or IL-1beta. The load-induced increase in GAG release and MMP activity was not affected by knockout of NLRP3 or IL-1RI in cartilage explants. CONCLUSION: OA cartilage may be degraded independently of any inflammasome activity, which may explain, at least in part, the lack of effect of IL-1beta inhibitors observed in previous trials. PMID- 22933233 TI - Brachypodium distachyon as a model for defining the allergen potential of non prolamin proteins. AB - Epitope databases and the protein sequences of published plant genomes are suitable to identify some of the proteins causing food allergies and sensitivities. Brachypodium distachyon, a diploid wild grass with a sequenced genome and low prolamin content, is the closest relative of the allergen cereals, such as wheat or barley. Using the Brachypodium genome sequence, a workflow has been developed to identify potentially harmful proteins which may cause either celiac disease or wheat allergy-related symptoms. Seed tissue-specific expression of the potential allergens has been determined, and intact epitopes following an in silico digestion with several endopeptidases have been identified. Molecular function of allergen proteins has been evaluated using Gene Ontology terms. Biologically overrepresented proteins and potentially allergen protein families have been identified. PMID- 22933234 TI - Lung involvement at initial presentation in blastic plasmacytoid dendritic cell neoplasm lacking cutaneous lesion. PMID- 22933235 TI - Nephrolithiasis in beta thalassemia major patients treated with deferasirox: an advent or an adverse event? A single Greek center experience. PMID- 22933236 TI - Lanosterol biosynthesis: the critical role of the methyl-29 group of 2,3 oxidosqualene for the correct folding of this substrate and for the construction of the five-membered D ring. AB - Lanosterol synthase catalyzes the polycyclization reaction of (3S)-2,3 oxidosqualene (1) into tetracyclic lanosterol 2 by folding 1 in a chair-boat chair-chair conformation. 27-Nor- and 29-noroxidosqaulenes (7 and 8, respectively) were incubated with this enzyme to investigate the role of the methyl groups on 1 for the polycyclization cascade. Compound 7 afforded two enzymatic products, namely, 30-norlanosterol (12) and 26-normalabaricatriene (13; 12/13 9:1), which were produced through the normal chair-boat-chair-chair conformation and an atypical chair-chair-boat conformation, respectively. Compound 8 gave two products 14 and 15 (14/15 4:5), which were generated by the normal and the unusual polycyclization pathways through a chair-chair-boat-chair conformation, respectively. It is remarkable that the twist-boat structure for the B-ring formation was changed to an energetically favored chair structure for the generation of 15. Surprisingly, 14 and 15 consisted of a novel 6,6,6,6-fused tetracyclic ring system, thus differing from the 6,6,6,5-fused lanosterol skeleton. Together with previous results, we conclude that the methyl-29 group is critical to the correct folding of 1, with lesser contributions from the other branched methyl groups, such as methyl-26, -27, and -28. Furthermore, we demonstrate that the methyl-29 group has a crucial role in the formation of the five-membered D ring of the lanosterol scaffold. PMID- 22933237 TI - Effects of aripiprazole augmentation in treatment-resistant obsessive-compulsive disorder (a double blind clinical trial). AB - BACKGROUND: Obsessive-compulsive disorder (OCD) is a chronic disorder with unknown etiology. Failure in OCD treatmentcompulsive is common and finding effective augmentations in treatment of OCD will benefit patients. Antipsychotic augmentation is a common strategy for treatment resistant OCD. This trial evaluated the efficacy of adding aripiprazole in patients whose OCD was insufficiently responsive to an adequate SSRI treatment. METHODS: Thirty-nine adult outpatients, who met the DSM-IV-TR criteria for OCD and had treatment resistant OCD were evaluated in a double-blind randomized clinical trial. The patients received either aripiprazole 10 mg/day or placebo, for 12 weeks. Data were analyzed using intention-to-treat analysis with last observation carried forward. All statistical tests were two-sided, and were considered statistically significant at P < 0.05. RESULTS: A significant reduction in total scores of Y BOCS (P < 0.0001) was found in the aripiprazole group. Aripiprazole was generally well tolerated. There was no significant difference between the two groups in terms of observed side effects. CONCLUSION: Results of the present study indicate that aripiprazole could be an effective augmentation medicine in treatment resistant OCD. PMID- 22933238 TI - Foodomics: a new comprehensive approach to food and nutrition. AB - In the past 20 years, the scientific community has faced a great development in different fields due to the development of high-throughput, omics technologies. Starting from the four major types of omics measurements (genomics, transcriptomics, proteomics, and metabolomics), a variety of omics subdisciplines (epigenomics, lipidomics, interactomics, metallomics, diseasomics, etc.) has emerged. Thanks to the omics approach, researchers are now facing the possibility of connecting food components, foods, the diet, the individual, the health, and the diseases, but this broad vision needs not only the application of advanced technologies, but mainly the ability of looking at the problem with a different approach, a "foodomics approach". Foodomics is the comprehensive, high-throughput approach for the exploitation of food science in the light of an improvement of human nutrition. Foodomics is a new approach to food and nutrition that studies the food domain as a whole with the nutrition domain to reach the main objective, the optimization of human health and well-being. PMID- 22933240 TI - Scientific considerations for assessing biosimilar products. AB - The problem for assessing biosimilarity and drug interchangeability of follow-on biologics (biosimilar products) is studied. Unlike the generic products, the development of biosimilar products is much more complicated because of fundamental differences in functional structures and manufacturing processes. As a result, the criteria and standard methods for the design and analysis of bioequivalence assessment of generic drug products may not be directly applicable to assessing biosimilarity of biosimilar products. In this article, we provide some scientific considerations for criteria, design, and analysis regarding the assessment of biosimilarity and drug interchangeability of biosimilar products. In addition, we discuss scientific and practical issues raised at the 2010 FDA public hearing and the 2011 FDA public meeting on biosimilar products. PMID- 22933239 TI - Purification and characterization of beta-xylosidase that is active for plant complex type N-glycans from tomato (Solanum lycopersicum): removal of core alpha1 3 mannosyl residue is prerequisite for hydrolysis of beta1-2 xylosyl residue. AB - In this study, we purified and characterized the beta-xylosidase involved in the turnover of plant complex type N-glycans to homogeneity from mature red tomatoes. Purified beta-xylosidase (beta-Xyl'ase Le-1) gave a single band with molecular masses of 67 kDa on SDS-PAGE under a reducing condition and 60 kDa on gelfiltration, indicating that beta-Xyl'ase Le-1 has a monomeric structure in plant cells. The N-terminal amino acid could not be identified owing to a chemical modification. When pyridylaminated (PA-) N-glycans were used as substrates, beta-Xyl'ase Le-1 showed optimum activity at about pH 5 at 40 degrees C, suggesting that the enzyme functions in a rather acidic circumstance such as in the vacuole or cell wall. beta-Xyl'ase Le-1 hydrolyzed the beta1-2 xylosyl residue from Man1Xyl1GlcNAc2-PA, Man1Xyl1Fuc1GlcNAc2-PA, and Man2Xyl1Fuc1GlcNAc2-PA, but not that from Man3Xyl1GlcNAc2-PA or Man3Xyl1Fuc1GlcNAc2-PA, indicating that the alpha1-3 arm mannosyl residue exerts significant steric hindrance for the access of beta-Xyl'ase Le-1 to the xylosyl residue, whereas the alpha1-3 fucosyl residue exerts little effect. These results suggest that the release of the beta1-2 xylosyl residue by beta-Xyl'ase Le-1 occurs at least after the removal the alpha-1,3-mannosyl residue in the core trimannosyl unit. PMID- 22933241 TI - Orthopedic wear debris mediated inflammatory osteolysis is mediated in part by NALP3 inflammasome activation. AB - Activation of myeloid cells by orthopedic particulate debris is a key event in the pathogenesis of periprosthetic osteolysis and implant loosening after total joint replacement (TJR). Several lines of evidence implicate NACHT, LRR, and PYD domains-containing protein 3 (NALP3) inflammasome-mediated production of interleukin 1 beta (IL-1beta) in the pathogenesis of clinical disorders ascribable to foreign particulate materials, including asbestos, silica, and urate crystals. Recent reports indicate that orthopedic polymer products and metallic particulates and ions may activate the same pathway. Here, we investigated the contribution of the NALP3 inflammasome to the pathogenesis of peri-implant osteolysis. Pharmaceutical and genetic perturbations of caspase-1 and inflammasome components were used to assess the role of the NALP3 inflammasome in IL-1beta production and osteoclast formation by human monocytes and mouse macrophages in response to polymethylmethacrylate (PMMA) particle phagocytosis. The role of caspase-1 in a mouse calvarial model of particle mediated osteolysis was assessed using uCT. Phagocytosis of PMMA particles induces caspase-1 dependent release of IL-1beta from human monocytes and mouse macrophages. Importantly, using macrophages from mice deficient in components of the NALP3 inflammasome, we show PMMA-induced IL-1beta production is strictly dependent on these components. Mice lacking caspase-1, the sole effector of the NALP3 inflammasome, show reduced orthopedic wear particle-induced calvarial osteolysis compared to wild-type controls. Absence of NALP3 inflammasome components fails to alter osteoclast formation in vitro. Our findings identify the NALP3 inflammasome as a critical mediator of orthopedic wear-induced osteolysis and as a viable therapeutic target for the treatment of periprosthetic osteolysis. PMID- 22933242 TI - A histological comparison of the original and regenerated tail in the green anole, Anolis carolinensis. AB - This study provides a histological comparison of the mature regenerated and original tail of the lizard Anolis carolinensis. These data will provide a framework for future studies of this emerging model organism whose genome was recently published. This study demonstrated that the cartilage skeleton of the regenerated tail enclosed a spinal cord with an ependymal core, but there was no evidence that dorsal root ganglia or peripheral nerves are regenerated. The cartilage tube contained foramina that allowed the vasculature to cross, but was otherwise a rigid structure. The original tail has muscle groups arranged in quadrants in a regular pattern that attach to the vertebral column. The regenerated tail has irregular muscle bundles of variable number that form unusual attachments to each other and to the cartilage tube. Furthermore, the data show that there was increased connective tissue within the muscle bundles. Implications for functionality of the regenerated tail and for future biomechanical studies are discussed. PMID- 22933243 TI - Should cyclophosphamide be a first-line medication for class V lupus nephritis? Comment on the article by Hahn et al. PMID- 22933244 TI - Author's reply: Breast cancer mortality in Norway after the introduction of mammography screening. PMID- 22933245 TI - Synthetic lethality of PARP and NAMPT inhibition in triple-negative breast cancer cells. AB - PARP inhibitors have been proposed as a potential targeted therapy for patients with triple-negative (ER-, PR-, HER2-negative) breast cancers. However, it is as yet unclear as to whether single agent or combination therapy using PARP inhibitors would be most beneficial. To better understand the mechanisms that determine the response to PARP inhibitors, we investigated whether enzymes involved in metabolism of the PARP substrate, beta-NAD(+) , might alter the response to a clinical PARP inhibitor. Using an olaparib sensitization screen in a triple-negative (TN) breast cancer model, we identified nicotinamide phosphoribosyltransferase (NAMPT) as a non-redundant modifier of olaparib response. NAMPT is a rate-limiting enzyme involved in the generation of the PARP substrate beta-NAD(+) and the suppression of beta-NAD(+) levels by NAMPT inhibition most likely explains these observations. Importantly, the combination of a NAMPT small molecule inhibitor, FK866, with olaparib inhibited TN breast tumour growth in vivo to a greater extent than either single agent alone suggesting that assessing NAMPT/PARP inhibitor combinations for the treatment of TN breast cancer may be warranted. PMID- 22933246 TI - Reproductive and developmental genomics retreat at Cornell University, 2012. PMID- 22933248 TI - Three-dimensional microsurgical anatomy of cerebellar peduncles. AB - The microsurgical anatomy of cerebellar peduncles and their relationships with neighbouring fasciculi were investigated by using a fibre dissection technique. As the dissection progressed, photographs of each progressive layer were obtained and stereoscopic images were created using the 3D anaglyphic method. These findings provided the anatomical basis for a conceptual division of cerebellar peduncles into segments. The middle cerebellar peduncle (MCP) was divided into two segments: cisternal and intracerebellar segments. The inferior cerebellar peduncle (ICP) was divided into three segments: cisternal, ventricular and intracerebellar segments. The superior cerebellar peduncle (SCP) was divided into three segments: intracerebellar, intermediate and intrategmental segments. The fibre dissection technique disclosed a constant course of peduncular fibres inside the white core of the cerebellum. The pontocerebellar fibres of the MCP pass over and laterally to the bundles of the ICP and SCP. The centripetal fibres of the ICP wrap around the radiation of the SCP and the dentate nucleus, directed towards the cortex of the vermis. The centrifugal bundle of the SCP ascends towards the mesencephalon where it sinks passing below the fibres the lateral lemniscus. The knowledge gained by studying the intrinsic anatomy of the cerebellum is useful to accomplish appropriate surgical planning and, ultimately, to understand the repercussions of surgical procedures on the white matter tracts in this region. PMID- 22933249 TI - Photophysics of the geminate polaron-pair state in copper phthalocyanine organic photovoltaic blends: evidence for enhanced intersystem crossing. AB - Geminate polaron-pair recombination directly to the triplet state of the small dye molecule copper(II) 1,4,8,11,15,18,22,25-octabutoxy-29H,31H- phthalocyanine (CuPC) and exciton trapping in CuPC domains, combine to reduce the internal quantum efficiency of free polaron formation in the bulk-heterojunction blends of CuPC doped with [6,6]-phenyl-C61-butyric acid methyl ester (PCBM) as the electron acceptor. PMID- 22933247 TI - Interventions to address chronic disease and HIV: strategies to promote exercise and nutrition among HIV-infected individuals. AB - Food insecurity, micronutrient deficits, dyslipidemia, insulin resistance, obesity, cardiovascular disease, and bone disorders complicate the treatment of HIV infection. Nutrition and exercise interventions can be effective in ameliorating these symptoms that are associated with HIV and antiretroviral therapy (ART). In this literature review, we examine the most recent nutrition and exercise interventions for HIV-infected patients. Macronutrient supplementation can be useful in treating malnutrition and wasting. Multivitamin (vitamin B complex, vitamin C, and vitamin E) supplements and vitamin D may improve quality of life and decrease morbidity and mortality. Nutritional counseling and exercise interventions are effective for treating obesity, fat redistribution, and metabolic abnormalities. Physical activity interventions improve body composition, strength, and fitness in HIV-infected individuals. Taken collectively, the evidence suggests that a proactive approach to nutrition and physical activity guidance and interventions can improve outcomes and help abrogate the adverse metabolic, cardiovascular, and psychological consequences of HIV and its treatments. PMID- 22933251 TI - Brief report: adrenal autoimmunity in primary Sjogren's syndrome. AB - OBJECTIVE: To evaluate the prevalence of antibodies to 21-hydroxylase (anti 21[OH]), a marker of autoimmune adrenal disease, in a cohort of patients with primary Sjogren's syndrome (SS) and to investigate whether the presence of anti 21(OH) correlates with clinical, serologic, and salivary gland features of the disease. METHODS: Sera from 63 consecutive patients with primary SS, 32 patients with autoimmune thyroid disease (AITD), and 20 healthy controls were obtained and anti-21(OH) levels were determined by radioimmunoassay. Clinical, serologic, and histopathologic features were recorded, and a short Synacthen test was used to assess adrenal function reserve. Seven available minor salivary gland (MSG) tissue specimens from patients in the primary SS cohort were also assessed for interferon-alpha (IFNalpha), BAFF, and interleukin-21 (IL-21) cytokine transcripts, which are all implicated in B cell activation. RESULTS: Anti-21(OH) positivity was detected in 17.5% and 28.1% of primary SS and AITD patients, respectively, and in none of the healthy controls. While no evidence of adrenal insufficiency was detected in any of the patients studied, a blunted rate of increase in cortisol levels was observed in patients with detectable serum autoantibodies against 21(OH), compared to their anti-21(OH)-negative counterparts. A strong correlation between the serum titer of anti-21(OH) antibodies and expression of IFNalpha, BAFF, and IL-21 messenger RNA in MSG tissues was also detected. CONCLUSION: Adrenal autoimmunity occurs in almost 20% of patients with primary SS in association with markers of B cell activation. Although the presence of adrenal autoantibodies was not associated with adrenal insufficiency in the present study, there was a blunted adrenal response, suggesting the need for further followup and monitoring of adrenal function in patients with primary SS who are positive for the autoantibodies. PMID- 22933252 TI - Unsupervised clustering of multivariate circular data. AB - In this paper, we study an unsupervised clustering problem. The originality of this problem lies in the data, which consist of the positions of five separate X ray beams on a circle. Radiation therapists positioned the five X-ray beam 'projectors' around each patient on a predefined circle. However, similarities exist in positioning for certain groups of patients, and we aim to describe these similarities with the goal of creating pre-adjustment settings that could help save time during X-ray positioning. We therefore performed unsupervised clustering of observed X-ray positions. Because the data for each patient consist of five angle measurements, Euclidean distances are not appropriated. Furthermore, we cannot perform k-means algorithm, usually used for minimizing corresponding distortion because we cannot calculate centers of clusters. We present here solutions to these problems. First, we define a suitable distance on the circle. Then, we adapt an algorithm based on simulated annealing to minimize distortion. This algorithm is shown to be theoretically convergent. Finally, we present simulations on simulated and real data. PMID- 22933253 TI - Successful endoscopic management of large upper gastrointestinal perforations following EMR using over-the-scope clipping combined with stenting. PMID- 22933254 TI - Endoscopic retrieval of a scalpel from the terminal ileum. PMID- 22933250 TI - Endocrine and metabolic regulation of renal drug transporters. AB - Renal xenobiotic transporters are important determinants of urinary secretion and reabsorption of chemicals. In addition to glomerular filtration, these processes are key to the overall renal clearance of a diverse array of drugs and toxins. Alterations in kidney transporter levels and function can influence the efficacy and toxicity of chemicals. Studies in experimental animals have revealed distinct patterns of renal transporter expression in response to sex hormones, pregnancy, and growth hormone. Likewise, a number of disease states including diabetes, obesity, and cholestasis alter the expression of kidney transporters. The goal of this review is to provide an overview of the major xenobiotic transporters expressed in the kidneys and an understanding of metabolic conditions and hormonal factors that regulate their expression and function. PMID- 22933255 TI - Cholelithiasis in a patient with an anatomical variation of the cystic duct. PMID- 22933256 TI - Fatal air embolism after upper endoscopy in a 48-year-old man. PMID- 22933257 TI - Dynamic water gravity rotation for endoscopic submucosal dissection: changing the location of the lesion. PMID- 22933258 TI - Peroral endoscopic myotomy (POEM) in a 3-year-old girl with severe growth retardation, achalasia, and Down syndrome. PMID- 22933259 TI - Combination of the "bear claw" (over-the-scope-clip system) and fully covered stent for the treatment of post-operative anastomotic leak. PMID- 22933260 TI - Bile duct adenoma causing recurrent cholangitis: diagnosis and management with targeted Spyglass access and radiofrequency ablation. PMID- 22933261 TI - Conservative treatment of perforation following balloon dilation of the papilla after sphincterotomy. PMID- 22933262 TI - Acute cholangitis secondary to a recently migrated cystic duct clip, 15 years after cholecystectomy. PMID- 22933263 TI - Perforation posterior to endoscopic band ligation of a gastric submucosal tumor. PMID- 22933264 TI - Endobronchial ultrasonic videoscope for transgastric/transesophageal fine-needle aspiration in special situations: another tool for the gastrointestinal endosonographer. PMID- 22933265 TI - Simulating target lesion for endoscopic submucosal dissection training in a live pig model. PMID- 22933266 TI - Visceral dissemination of herpes zoster with multiple ulcers in the upper gastrointestinal tract of an apparently immunocompetent patient. PMID- 22933267 TI - Successful endoscopic ultrasound-assisted resection of a giant ulcerated rectal lipoma causing hematochezia. PMID- 22933268 TI - Efficient NIR-light emission from solid-state complexes of boron difluoride with 2'-hydroxychalcone derivatives. AB - This article describes a series of nine complexes of boron difluoride with 2' hydroxychacone derivatives. These dyes were synthesized very simply and exhibited intense NIR emission in the solid state. Complexation with boron was shown to impart very strong donor-acceptor character into the excited state of these dyes, which further shifted their emission towards the NIR region (up to 855 nm for dye 5 b, which contained the strongly donating triphenylamine group). Strikingly, these optical features were obtained for crystalline solids, which are characterized by high molecular order and tight packing, two features that are conventionally believed to be detrimental to luminescence in organic crystals. Remarkably, the emission of light from the pi-stacked molecules did not occur at the expense of the emission quantum yield. Indeed, in the case of pyrene containing dye 4, for example, a fluorescence quantum yield of about 15 % with a fluorescence emission maximum at 755 nm were obtained in the solid state. Moreover, dye 3 a and acetonaphthone-based compounds 1 b, 2 b, and 3 b showed no evidence of degradation as solutions in CH(2) Cl(2) that contained EtOH. In particular, solutions of brightly fluorescent compound 3 a (brightness: epsilon*Phi(f) =45,000 M(-1) cm(-1)) could be stored for long periods without any detectable changes in its optical properties. All together, these new dyes possess a set of very interesting properties that make them promising solid-state NIR fluorophores for applications in materials science. PMID- 22933269 TI - Dose-response effect of an intra-tendon application of recombinant human platelet derived growth factor-BB (rhPDGF-BB) in a rat Achilles tendinopathy model. AB - The purpose of this study was to assess whether intra-tendon delivery of recombinant human platelet-derived growth factor-BB (rhPDGF-BB) would improve Achilles tendon repair in a rat collagenase-induced tendinopathy model. Seven days following collagenase induction of tendinopathy, one of four intra-tendinous treatments was administered: (i) Vehicle control (sodium acetate buffer), (ii) 1.02 ug rhPDGF-BB, (iii) 10.2 ug rhPDGF-BB, or (iv) 102 ug rhPDGF-BB. Treated tendons were assessed for histopathological (e.g., proliferation, tendon thickness, collagen fiber density/orientation) and biomechanical (e.g., maximum load-to-failure and stiffness) outcomes. By 7 days post-treatment, there was a significant increase in cell proliferation with the 10.2 and 102 ug rhPDGF-BB treated groups (p=0.049 and 0.015, respectively) and in thickness at the tendon midsubstance in the 10.2 ug of rhPDGF-BB group (p=0.005), compared to controls. All groups had equivalent outcomes by Day 21. There was a dose-dependent effect on the maximum load-to-failure, with no significant difference in the 1.02 and 102 ug rhPDGF-BB doses but the 10.2 ug rhPDGF-BB group had a significant increase in load-to-failure at 7 (p=0.003) and 21 days (p=0.019) compared to controls. The rhPDGF-BB treatment resulted in a dose-dependent, transient increase in cell proliferation and sustained improvement in biomechanical properties in a rat Achilles tendinopathy model, demonstrating the potential of rhPDGF-BB treatment in a tendinopathy application. Consequently, in this model, data suggest that rhPDGF-BB treatment is an effective therapy and thus, may be an option for clinical applications to treat tendinopathy. PMID- 22933270 TI - Identification of RNA-protein interaction networks involved in the norovirus life cycle. AB - Human noroviruses are one of the major causes of acute gastroenteritis in the developed world, yet our understanding of their molecular mechanisms of genome translation and replication lags behind that for many RNA viruses. Due to the nonculturable nature of human noroviruses, many related members of the Caliciviridae family of small RNA viruses are often used as model systems to dissect the finer details of the norovirus life cycle. Murine norovirus (MNV) has provided one such system with which to study the basic mechanisms of norovirus translation and replication in cell culture. In this report we describe the use of riboproteomics to identify host factors that interact with the extremities of the MNV genome. This network of RNA-protein interactions contains many well characterized host factors, including PTB, La, and DDX3, which have been shown to play a role in the life cycle of other RNA viruses. By using RNA coimmunoprecipitation, we confirmed that a number of the factors identified using riboproteomics are associated with the viral RNA during virus replication in cell culture. We further demonstrated that RNA inhibition-mediated knockdown of the intracellular levels of a number of these factors inhibits or slows norovirus replication in cell culture, allowing identification of new intracellular targets for this important group of pathogens. PMID- 22933271 TI - The human metapneumovirus fusion protein mediates entry via an interaction with RGD-binding integrins. AB - Paramyxoviruses use a specialized fusion protein to merge the viral envelope with cell membranes and initiate infection. Most paramyxoviruses require the interaction of two viral proteins to enter cells; an attachment protein binds cell surface receptors, leading to the activation of a fusion (F) protein that fuses the viral envelope and host cell plasma membrane. In contrast, human metapneumovirus (HMPV) expressing only the F protein is replication competent, suggesting a primary role for HMPV F in attachment and fusion. We previously identified an invariant arginine-glycine-aspartate (RGD) motif in the HMPV F protein and showed that the RGD-binding integrin alphaVbeta1-promoted HMPV infection. Here we show that both HMPV F-mediated binding and virus entry depend upon multiple RGD-binding integrins and that HMPV F can mediate binding and fusion in the absence of the viral attachment (G) protein. The invariant F-RGD motif is critical for infection, as an F-RAE virus was profoundly impaired. Further, F-integrin binding is required for productive viral RNA transcription, indicating that RGD-binding integrins serve as receptors for the HMPV fusion protein. Thus, HMPV F is triggered to induce virus-cell fusion by interactions with cellular receptors in a manner that is independent of the viral G protein. These results suggest a stepwise mechanism of HMPV entry mediated by the F protein through its interactions with cellular receptors, including RGD-binding integrins. PMID- 22933272 TI - Differential roles of Hsp70 and Hsp90 in the assembly of the replicase complex of a positive-strand RNA plant virus. AB - Assembly of viral replicase complexes of eukaryotic positive-strand RNA viruses is a regulated process: multiple viral and host components must be assembled on intracellular membranes and ordered into quaternary complexes capable of synthesizing viral RNAs. However, the molecular mechanisms underlying this process are poorly understood. In this study, we used a model virus, Red clover necrotic mosaic virus (RCNMV), whose replicase complex can be detected readily as the 480-kDa functional protein complex. We found that host heat shock proteins Hsp70 and Hsp90 are required for RCNMV RNA replication and that they interact with p27, a virus-encoded component of the 480-kDa replicase complex, on the endoplasmic reticulum membrane. Using a cell-free viral translation/replication system in combination with specific inhibitors of Hsp70 and Hsp90, we found that inhibition of p27-Hsp70 interaction inhibits the formation of the 480-kDa complex but instead induces the accumulation of large complexes that are nonfunctional in viral RNA synthesis. In contrast, inhibition of p27-Hsp90 interaction did not induce such large complexes but rendered p27 incapable of binding to a specific viral RNA element, which is a critical step for the assembly of the 480-kDa replicase complex and viral RNA replication. Together, our results suggest that Hsp70 and Hsp90 regulate different steps in the assembly of the RCNMV replicase complex. PMID- 22933273 TI - Discovery of severe fever with thrombocytopenia syndrome bunyavirus strains originating from intragenic recombination. AB - This study analyzes available severe fever with thrombocytopenia syndrome virus (SFTSV) genomes and reports that a sublineage of lineage I bears a unique M segment recombined from two of three prevailing SFTSV lineages. Through recombination, the sublineage has acquired nearly complete G1 associated with protective epitopes from lineage III, suggesting that this recombination has the capacity to induce antigenic shift of the virus. Therefore, this study provides some valuable implications for the vaccine design of SFTSV. PMID- 22933274 TI - Epitope mapping of broadly neutralizing HIV-2 human monoclonal antibodies. AB - Recent studies have shown that natural infection by HIV-2 leads to the elicitation of high titers of broadly neutralizing antibodies (NAbs) against primary HIV-2 strains (T. I. de Silva, et al., J. Virol. 86:930-946, 2012; R. Kong, et al., J. Virol. 86:947-960, 2012; G. Ozkaya Sahin, et al., J. Virol. 86:961-971, 2012). Here, we describe the envelope (Env) binding and neutralization properties of 15 anti-HIV-2 human monoclonal antibodies (MAbs), 14 of which were newly generated from 9 chronically infected subjects. All 15 MAbs bound specifically to HIV-2 gp120 monomers and neutralized heterologous primary virus strains HIV-2(7312A) and HIV-2(ST). Ten of 15 MAbs neutralized a third heterologous primary virus strain, HIV-2(UC1). The median 50% inhibitory concentrations (IC(50)s) for these MAbs were surprisingly low, ranging from 0.007 to 0.028 MUg/ml. Competitive Env binding studies revealed three MAb competition groups: CG-I, CG-II, and CG-III. Using peptide scanning, site-directed mutagenesis, chimeric Env constructions, and single-cycle virus neutralization assays, we mapped the epitope of CG-I antibodies to a linear region in variable loop 3 (V3), the epitope of CG-II antibodies to a conformational region centered on the carboxy terminus of V4, and the epitope(s) of CG-III antibodies to conformational regions associated with CD4- and coreceptor-binding sites. HIV-2 Env is thus highly immunogenic in vivo and elicits antibodies having diverse epitope specificities, high potency, and wide breadth. In contrast to the HIV-1 Env trimer, which is generally well shielded from antibody binding and neutralization, HIV-2 is surprisingly vulnerable to broadly reactive NAbs. The availability of 15 human MAbs targeting diverse HIV-2 Env epitopes can facilitate comparative studies of HIV/SIV Env structure, function, antigenicity, and immunogenicity. PMID- 22933276 TI - Maintenance of the flip sequence orientation of the ears in the parvoviral left end hairpin is a nonessential consequence of the critical asymmetry in the hairpin stem. AB - Parvoviral terminal hairpins are essential for viral DNA amplification but are also implicated in multiple additional steps in the viral life cycle. The palindromes at the two ends of the minute virus of mice (MVM) genome are dissimilar and are processed by different resolution mechanisms that selectively direct encapsidation of predominantly negative-sense progeny genomes and conserve a single Flip sequence orientation at the 3' (left) end of such progeny. The sequence and predicted structure of these 3' hairpins are highly conserved within the genus Parvovirus, exemplified by the 121-nucleotide left-end sequence of MVM, which folds into a Y-shaped hairpin containing small internal palindromes that form the "ears" of the Y. To explore the potential role(s) of this hairpin in the viral life cycle, we constructed infectious clones with the ear sequences either inverted, to give the antiparallel Flop orientation, or with multiple transversions, conserving their base composition but changing their sequence. These were compared with a "bubble" mutant, designed to activate the normally silent origin in the inboard arm of the hairpin, thus potentially rendering symmetric the otherwise asymmetric junction resolution mechanism that drives maintenance of Flip. This mutant exhibited a major defect in viral duplex and single-strand DNA replication, characterized by the accumulation of covalently closed turnaround forms of the left end, and was rapidly supplanted by revertants that restored asymmetry. In contrast, both sequence and orientation changes in the hairpin ears were tolerated, suggesting that maintaining the Flip orientation of these structures is a consequence of, but not the reason for, asymmetric left end processing. PMID- 22933275 TI - High variety of known and new RNA and DNA viruses of diverse origins in untreated sewage. AB - Deep sequencing of untreated sewage provides an opportunity to monitor enteric infections in large populations and for high-throughput viral discovery. A metagenomics analysis of purified viral particles in untreated sewage from the United States (San Francisco, CA), Nigeria (Maiduguri), Thailand (Bangkok), and Nepal (Kathmandu) revealed sequences related to 29 eukaryotic viral families infecting vertebrates, invertebrates, and plants (BLASTx E score, <10(-4)), including known pathogens (>90% protein identities) in numerous viral families infecting humans (Adenoviridae, Astroviridae, Caliciviridae, Hepeviridae, Parvoviridae, Picornaviridae, Picobirnaviridae, and Reoviridae), plants (Alphaflexiviridae, Betaflexiviridae, Partitiviridae, Sobemovirus, Secoviridae, Tombusviridae, Tymoviridae, Virgaviridae), and insects (Dicistroviridae, Nodaviridae, and Parvoviridae). The full and partial genomes of a novel kobuvirus, salivirus, and sapovirus are described. A novel astrovirus (casa astrovirus) basal to those infecting mammals and birds, potentially representing a third astrovirus genus, was partially characterized. Potential new genera and families of viruses distantly related to members of the single-stranded RNA picorna-like virus superfamily were genetically characterized and named Picalivirus, Secalivirus, Hepelivirus, Nedicistrovirus, Cadicistrovirus, and Niflavirus. Phylogenetic analysis placed these highly divergent genomes near the root of the picorna-like virus superfamily, with possible vertebrate, plant, or arthropod hosts inferred from nucleotide composition analysis. Circular DNA genomes distantly related to the plant-infecting Geminiviridae family were named Baminivirus, Nimivirus, and Niminivirus. These results highlight the utility of analyzing sewage to monitor shedding of viral pathogens and the high viral diversity found in this common pollutant and provide genetic information to facilitate future studies of these newly characterized viruses. PMID- 22933277 TI - Recent transmission of a novel alphacoronavirus, bat coronavirus HKU10, from Leschenault's rousettes to pomona leaf-nosed bats: first evidence of interspecies transmission of coronavirus between bats of different suborders. AB - Although coronaviruses are known to infect various animals by adapting to new hosts, interspecies transmission events are still poorly understood. During a surveillance study from 2005 to 2010, a novel alphacoronavirus, BatCoV HKU10, was detected in two very different bat species, Ro-BatCoV HKU10 in Leschenault's rousettes (Rousettus leschenaulti) (fruit bats in the suborder Megachiroptera) in Guangdong and Hi-BatCoV HKU10 in Pomona leaf-nosed bats (Hipposideros pomona) (insectivorous bats in the suborder Microchiroptera) in Hong Kong. Although infected bats appeared to be healthy, Pomona leaf-nosed bats carrying Hi-BatCoV HKU10 had lower body weights than uninfected bats. To investigate possible interspecies transmission between the two bat species, the complete genomes of two Ro-BatCoV HKU10 and six Hi-BatCoV HKU10 strains were sequenced. Genome and phylogenetic analyses showed that Ro-BatCoV HKU10 and Hi-BatCoV HKU10 represented a novel alphacoronavirus species, sharing highly similar genomes except in the genes encoding spike proteins, which had only 60.5% amino acid identities. Evolution of the spike protein was also rapid in Hi-BatCoV HKU10 strains from 2005 to 2006 but stabilized thereafter. Molecular-clock analysis dated the most recent common ancestor of all BatCoV HKU10 strains to 1959 (highest posterior density regions at 95% [HPDs], 1886 to 2002) and that of Hi-BatCoV HKU10 to 1986 (HPDs, 1956 to 2004). The data suggested recent interspecies transmission from Leschenault's rousettes to Pomona leaf-nosed bats in southern China. Notably, the rapid adaptive genetic change in BatCoV HKU10 spike protein by ~40% amino acid divergence after recent interspecies transmission was even greater than the ~20% amino acid divergence between spike proteins of severe acute respiratory syndrome related Rhinolophus bat coronavirus (SARSr-CoV) in bats and civets. This study provided the first evidence for interspecies transmission of coronavirus between bats of different suborders. PMID- 22933279 TI - Enhanced recognition and neutralization of HIV-1 by antibody-derived CCR5-mimetic peptide variants. AB - A tyrosine-sulfated CCR5-mimetic peptide, CCR5mim1, inhibits HIV-1 infection more efficiently than sulfopeptides based on the CCR5 amino terminus. Here we characterized sulfopeptide chimeras of CCR5mim1 and the heavy-chain CDR3 of the antibody PG16. Two chimeras bound a range of envelope glycoproteins and neutralized HIV-1 more efficiently than CCR5mim1. An immunoadhesin form of one of these, CCR5mim2-Ig, synergized with CD4-Ig to neutralize HIV-1. These sulfopeptides are among the broadest and most potent CCR5-mimetic peptides described to date. PMID- 22933278 TI - p33-Independent activation of a truncated p92 RNA-dependent RNA polymerase of Tomato bushy stunt virus in yeast cell-free extract. AB - Plus-stranded RNA viruses replicate in membrane-bound structures containing the viral replicase complex (VRC). A key component of the VRC is the virally encoded RNA-dependent RNA polymerase (RdRp), which should be activated and incorporated into the VRC after its translation. To study the activation of the RdRp of Tomato bushy stunt virus (TBSV), a small tombusvirus of plants, we used N-terminal truncated recombinant RdRp, which supported RNA synthesis in a cell-free yeast extract-based assay. The truncated RdRp required a cis-acting RNA replication element and soluble host factors, while unlike the full-length TBSV RdRp, the truncated RdRp did not need the viral p33 replication cofactor or cellular membranes for RNA synthesis. Interestingly, the truncated RdRp used 3'-terminal extension for initiation and terminated prematurely at an internal cis-acting element. However, the truncated RdRp could perform de novo initiation on a TBSV plus-strand RNA template in the presence of the p33 replication cofactor, cellular membranes, and soluble host proteins. Altogether, the data obtained with the truncated RdRp indicate that this RdRp still requires activation, but with the participation of fewer components than with the full-length RdRp, making it suitable for future studies on dissection of the RdRp activation mechanism. PMID- 22933280 TI - Human CRM1 augments production of infectious human and feline immunodeficiency viruses from murine cells. AB - Productive replication of human immunodeficiency virus type 1 (HIV-1) occurs efficiently only in humans. The posttranscriptional stages of the HIV-1 life cycle proceed poorly in mouse cells, with a resulting defect in viral assembly and release. Previous work has shown that the presence of human chromosome 2 increases HIV-1 production in mouse cells. Recent studies have shown that human chromosome region maintenance 1 (hCRM1) stimulates Gag release from rodent cells. Here we report that expressions of hCRM1 in murine cells resulted in marked increases in the production of infectious HIV-1 and feline immunodeficiency virus (FIV). HIV-1 production was also increased by hSRp40, and a combination of hCRM1 and hSRp40 resulted in a more-than-additive effect on HIV-1 release. In contrast, the overexpression of mouse CRM1 (mCRM1) minimally affected HIV-1 and FIV production and did not antagonize hCRM1. In the presence of hCRM1 there were large increases in the amounts of released capsid, which paralleled the increases in the infectious titers. Consistent with this finding, the ratios of unspliced to spliced HIV-1 mRNAs in mouse cells expressing hCRM1 and SRp40 became similar to those of human cells. Furthermore, imaging of intron-containing FIV RNA showed that hCRM1 increased RNA export to the cytoplasm.By testing chimeras between mCRM1 and hCRM1 and comparing those sequences to feline CRM1, we mapped the functional domain to HEAT (Huntingtin, elongation factor 3, protein phosphatase 2A, and the yeast kinase TOR1) repeats 4A to 9A and a triple point mutant in repeat 9A, which showed a loss of function. Structural analysis suggested that this region of hCRM1 may serve as a binding site for viral or cellular factors to facilitate lentiviral RNA nuclear export. PMID- 22933281 TI - Foot-and-mouth disease virus nonstructural protein 2C interacts with Beclin1, modulating virus replication. AB - Foot-and-mouth disease virus (FMDV), the causative agent of foot-and-mouth disease, is an Apthovirus within the Picornaviridae family. Replication of the virus occurs in association with replication complexes that are formed by host cell membrane rearrangements. The largest viral protein in the replication complex, 2C, is thought to have multiple roles during virus replication. However, studies examining the function of FMDV 2C have been rather limited. To better understand the role of 2C in the process of virus replication, we used a yeast two-hybrid approach to identify host proteins that interact with 2C. We report here that cellular Beclin1 is a specific host binding partner for 2C. Beclin1 is a regulator of the autophagy pathway, a metabolic pathway required for efficient FMDV replication. The 2C-Beclin1 interaction was further confirmed by coimmunoprecipitation and confocal microscopy to actually occur in FMDV-infected cells. Overexpression of either Beclin1 or Bcl-2, another important autophagy factor, strongly affects virus yield in cell culture. The fusion of lysosomes to autophagosomes containing viral proteins is not seen during FMDV infection, a process that is stimulated by Beclin1; however, in FMDV-infected cells overexpressing Beclin1 this fusion occurs, suggesting that 2C would bind to Beclin1 to prevent the fusion of lysosomes to autophagosomes, allowing for virus survival. Using reverse genetics, we demonstrate here that modifications to the amino acids in 2C that are critical for interaction with Beclin1 are also critical for virus growth. These results suggest that interaction between FMDV 2C and host protein Beclin1 could be essential for virus replication. PMID- 22933282 TI - A novel assay for antibody-dependent cell-mediated cytotoxicity against HIV-1- or SIV-infected cells reveals incomplete overlap with antibodies measured by neutralization and binding assays. AB - The resistance of human immunodeficiency virus type 1 (HIV-1) to antibody mediated immunity often prevents the detection of antibodies that neutralize primary isolates of HIV-1. However, conventional assays for antibody functions other than neutralization are suboptimal. Current methods for measuring the killing of virus-infected cells by antibody-dependent cell-mediated cytotoxicity (ADCC) are limited by the number of natural killer (NK) cells obtainable from individual donors, donor-to-donor variation, and the use of nonphysiological targets. We therefore developed an ADCC assay based on NK cell lines that express human or macaque CD16 and a CD4(+) T-cell line that expresses luciferase from a Tat-inducible promoter upon HIV-1 or simian immunodeficiency virus (SIV) infection. NK cells and virus-infected targets are mixed in the presence of serial plasma dilutions, and ADCC is measured as the dose-dependent loss of luciferase activity. Using this approach, ADCC titers were measured in plasma samples from HIV-infected human donors and SIV-infected macaques. For the same plasma samples paired with the same test viruses, this assay was approximately 2 orders of magnitude more sensitive than optimized assays for neutralizing antibodies-frequently allowing the measurement of ADCC in the absence of detectable neutralization. Although ADCC correlated with other measures of Env specific antibodies, neutralizing and gp120 binding titers did not consistently predict ADCC activity. Hence, this assay affords a sensitive method for measuring antibodies capable of directing ADCC against HIV- or SIV-infected cells expressing native conformations of the viral envelope glycoprotein and reveals incomplete overlap of the antibodies that direct ADCC and those measured in neutralization and binding assays. PMID- 22933283 TI - An Sp1/Sp3 site in the downstream region of varicella-zoster virus (VZV) oriS influences origin-dependent DNA replication and flanking gene transcription and is important for VZV replication in vitro and in human skin. AB - The distribution and orientation of origin-binding protein (OBP) sites are the main architectural contrasts between varicella-zoster virus (VZV) and herpes simplex virus (HSV) origins of DNA replication (oriS). One important difference is the absence of a downstream OBP site in VZV, raising the possibility that an alternative cis element may replace its function. Our previous work established that Sp1, Sp3, and YY1 bind to specific sites within the downstream region of VZV oriS; we hypothesize that one or both of these sites may be the alternative cis element(s). Here, we show that the mutation of the Sp1/Sp3 site decreases DNA replication and transcription from the adjacent ORF62 and ORF63 promoters following superinfection with VZV. In contrast, in the absence of DNA replication or in transfection experiments with ORF62, only ORF63 transcription is affected. YY1 site mutations had no significant effect on either process. Recombinant viruses containing these mutations were then constructed. The Sp1/Sp3 site mutant exhibited a significant decrease in virus growth in MeWo cells and in human skin xenografts, while the YY1 site mutant virus grew as well as the wild type in MeWo cells, even showing a late increase in VZV replication in skin xenografts following infection. These results suggest that the Sp1/Sp3 site plays an important role in both VZV origin-dependent DNA replication and ORF62 and ORF63 transcription and that, in contrast to HSV, these events are linked during virus replication. PMID- 22933284 TI - Sequences in glycoprotein gp41, the CD4 binding site, and the V2 domain regulate sensitivity and resistance of HIV-1 to broadly neutralizing antibodies. AB - The swarm of quasispecies that evolves in each HIV-1-infected individual represents a source of closely related Env protein variants that can be used to explore various aspects of HIV-1 biology. In this study, we made use of these variants to identify mutations that confer sensitivity and resistance to the broadly neutralizing antibodies found in the sera of selected HIV-1-infected individuals. For these studies, libraries of Env proteins were cloned from infected subjects and screened for infectivity and neutralization sensitivity. The nucleotide sequences of the Env proteins were then compared for pairs of neutralization-sensitive and -resistant viruses. In vitro mutagenesis was used to identify the specific amino acids responsible for the neutralization phenotype. All of the mutations altering neutralization sensitivity/resistance appeared to induce conformational changes that simultaneously enhanced the exposure of two or more epitopes located in different regions of gp160. These mutations appeared to occur at unique positions required to maintain the quaternary structure of the gp160 trimer, as well as conformational masking of epitopes targeted by neutralizing antibodies. Our results show that sequences in gp41, the CD4 binding site, and the V2 domain all have the ability to act as global regulators of neutralization sensitivity. Our results also suggest that neutralization assays designed to support the development of vaccines and therapeutics targeting the HIV-1 Env protein should consider virus variation within individuals as well as virus variation between individuals. PMID- 22933285 TI - Visualization of the two-step fusion process of the retrovirus avian sarcoma/leukosis virus by cryo-electron tomography. AB - Retrovirus infection starts with the binding of envelope glycoproteins to host cell receptors. Subsequently, conformational changes in the glycoproteins trigger fusion of the viral and cellular membranes. Some retroviruses, such as avian sarcoma/leukosis virus (ASLV), employ a two-step mechanism in which receptor binding precedes low-pH activation and fusion. We used cryo-electron tomography to study virion/receptor/liposome complexes that simulate the interactions of ASLV virions with cells. Binding the soluble receptor at neutral pH resulted in virions capable of binding liposomes tightly enough to alter their curvature. At virion-liposome interfaces, the glycoproteins are ~3-fold more concentrated than elsewhere in the viral envelope, indicating specific recruitment to these sites. Subtomogram averaging showed that the oblate globular domain in the prehairpin intermediate (presumably the receptor-binding domain) is connected to both the target and the viral membrane by 2.5-nm-long stalks and is partially disordered, compared with its native conformation. Upon lowering the pH, fusion took place. Fusion is a stochastic process that, once initiated, must be rapid, as only final (postfusion) products were observed. These fusion products showed glycoprotein spikes on their surface, with their interiors occupied by patches of dense material but without capsids, implying their disassembly. In addition, some of the products presented a density layer underlying and resolved from the viral membrane, which may represent detachment of the matrix protein to facilitate the fusion process. PMID- 22933286 TI - Antibody-independent thrombocytopenia in lactate dehydrogenase-elevating virus infected mice. AB - Previously we demonstrated that antibody-mediated thrombocytopenia is strongly enhanced by lactate dehydrogenase-elevating virus (LDV) infection. Here we report that mice infected with LDV develop a moderate thrombocytopenia, even in the absence of immunoglobulins or Fc receptors. A similar decrease of platelet counts was observed after mouse hepatitis virus infection. LDV-induced type I interferon independent thrombocytopenia was partly suppressed by treatment with clodronate containing liposomes. Therefore, we conclude that the thrombocytopenia results from increased phagocytosis of nonopsonized platelets by macrophages. PMID- 22933287 TI - Modification of one epitope-flanking amino acid allows for the induction of friend retrovirus-specific CD8+ T cells by Adenovirus-based immunization. AB - While Friend retrovirus-infected mice readily mount a vigorous CD8(+) T cell response to the leader-gag-derived peptide GagL(85-93), no GagL(85-93)-specific T cells were detectable in mice immunized against Friend virus (FV) with viral vectors or DNA vaccines. By exchanging one epitope-flanking amino acid or using a scaffold protein we were able to demonstrate for the first time the induction of GagL(85-93)-specific CD8(+) T cells by genetic vaccination and show their high protective effect against FV challenge infection. PMID- 22933288 TI - The ac53, ac78, ac101, and ac103 genes are newly discovered core genes in the family Baculoviridae. AB - The family Baculoviridae is a large group of insect viruses containing circular double-stranded DNA genomes of 80 to 180 kbp, which have broad biotechnological applications. A key feature to understand and manipulate them is the recognition of orthology. However, the differences in gene contents and evolutionary distances among the known members of this family make it difficult to assign sequence orthology. In this study, the genome sequences of 58 baculoviruses were analyzed, with the aim to detect previously undescribed core genes because of their remote homology. A routine based on Multi PSI-Blast/tBlastN and Multi HaMStR allowed us to detect 31 of 33 accepted core genes and 4 orthologous sequences in the Baculoviridae which were not described previously. Our results show that the ac53, ac78, ac101 (p40), and ac103 (p48) genes have orthologs in all genomes and should be considered core genes. Accordingly, there are 37 orthologous genes in the family Baculoviridae. PMID- 22933289 TI - Epstein-Barr virus BGLF4 kinase downregulates NF-kappaB transactivation through phosphorylation of coactivator UXT. AB - Epstein-Barr virus (EBV) BGLF4 is a member of the conserved herpesvirus kinases that regulate multiple cellular and viral substrates and play an important role in the viral lytic cycles. BGLF4 has been found to phosphorylate several cellular and viral transcription factors, modulate their activities, and regulate downstream events. In this study, we identify an NF-kappaB coactivator, UXT, as a substrate of BGLF4. BGLF4 downregulates not only NF-kappaB transactivation in reporter assays in response to tumor necrosis factor alpha (TNF-alpha) and poly(I.C) stimulation, but also NF-kappaB-regulated cellular gene expression. Furthermore, BGLF4 attenuates NF-kappaB-mediated repression of the EBV lytic transactivators, Zta and Rta. In EBV-positive NA cells, knockdown of BGLF4 during lytic progression elevates NF-kappaB activity and downregulates the activity of the EBV oriLyt BHLF1 promoter, which is the first promoter activated upon lytic switch. We show that BGLF4 phosphorylates UXT at the Thr3 residue. This modification interferes with the interaction between UXT and NF-kappaB. The data also indicate that BGLF4 reduces the interaction between UXT and NF-kappaB and attenuates NF-kappaB enhanceosome activity. Upon infection with short hairpin RNA (shRNA) lentivirus to knock down UXT, a spontaneous lytic cycle was observed in NA cells, suggesting UXT is required for maintenance of EBV latency. Overexpression of wild-type, but not phosphorylation-deficient, UXT enhances the expression of lytic proteins both in control and UXT knockdown cells. Taking the data together, transcription involving UXT may also be important for EBV lytic protein expression, whereas BGLF4-mediated phosphorylation of UXT at Thr3 plays a critical role in promoting the lytic cycle. PMID- 22933290 TI - Reconstituting the epidemic history of HIV strain CRF01_AE among men who have sex with men (MSM) in Liaoning, northeastern China: implications for the expanding epidemic among MSM in China. AB - HIV CRF01_AE accounted for 84% of the recent infections among men who have sex with men (MSM) in Liaoning Province of northeastern China. CRF01_AE strains were grouped into two distinct clusters (designated clusters 1 and 2) that were also detected in other regions in China. Phylodynamics study revealed that these two CRF01_AE strains were independently introduced into the population of MSM in China in the early and mid-1990s. Our study elucidated unique features of dynamics and interrelationships of MSM epidemics in China. PMID- 22933292 TI - Probing, by self-assembly, the number of potential binding sites for minor protein subunits in the procapsid of double-stranded RNA bacteriophage Phi6. AB - The double-stranded RNA bacteriophage Phi6 is an extensively studied prokaryotic model system for virus assembly. There are established in vitro assembly protocols available for the Phi6 system for obtaining infectious particles from purified protein and RNA constituents. The polymerase complex is a multifunctional nanomachine that replicates, transcribes, and translocates viral RNA molecules in a highly specific manner. The complex is composed of (i) the major structural protein (P1), forming a T=1 icosahedral lattice with two protein subunits in the icosahedral asymmetric unit; (ii) the RNA-dependent RNA polymerase (P2); (iii) the hexameric packaging nucleoside triphosphatase (NTPase) (P4); and (iv) the assembly cofactor (P7). In this study, we analyzed several Phi6 virions and recombinant polymerase complexes to investigate the relative copy numbers of P2, P4, and P7, and we applied saturated concentrations of these proteins in the self-assembly system to probe their maximal numbers of binding sites in the P1 shell. Biochemical quantitation confirmed that the composition of the recombinant particles was similar to that of the virion cores. By including a high concentration of P2 or P7 in the self-assembly reaction mix, we observed that the numbers of these proteins in the resulting particles could be increased beyond those observed in the virion. Our results also suggest a previously unidentified P2-P7 dependency in the assembly reaction. Furthermore, it appeared that P4 must initially be incorporated at each, or a majority, of the 5-fold symmetry positions of the P1 shell for particle assembly. Although required for nucleation, excess P4 resulted in slower assembly kinetics. PMID- 22933291 TI - Temporal association of HLA-B*81:01- and HLA-B*39:10-mediated HIV-1 p24 sequence evolution with disease progression. AB - HLA-B*81:01 and HLA-B*39:10 alleles have been associated with viremic control in HIV-1 subtype C infection. Both alleles restrict the TL9 epitope in p24 Gag, and cytotoxic-T-lymphocyte (CTL)-mediated escape mutations in this epitope have been associated with an in vitro fitness cost to the virus. We investigated the timing and impact of mutations in the TL9 epitope on disease progression in five B*81:01 and two B*39:10-positive subtype C-infected individuals. Whereas both B*39:10 participants sampled at 2 months postinfection had viruses with mutations in the TL9 epitope, in three of the five (3/5) B*81:01 participants, TL9 escape mutations were only detected 10 months after infection, taking an additional 10 to 15 months to reach fixation. In the two remaining B*81:01 individuals, one carried a TL9 escape variant at 2 weeks postinfection, whereas no escape mutations were detected in the virus from the other participant for up to 33 months postinfection, despite CTL targeting of the epitope. In all participants, escape mutations in TL9 were linked to coevolving residues in the region of Gag known to be associated with host tropism. Late escape in TL9, together with coevolution of putative compensatory mutations, coincided with a spontaneous increase in viral loads in two individuals who were otherwise controlling the infection. These results provide in vivo evidence of the detrimental impact of B*81:01-mediated viral evolution, in a single Gag p24 epitope, on the control of viremia. PMID- 22933293 TI - Evidence that in vitro susceptibility of CD3+ T lymphocytes to equine arteritis virus infection reflects genetic predisposition of naturally infected stallions to become carriers of the virus. AB - We investigated the correlation between in vitro susceptibility of CD3(+) T lymphocytes to equine arteritis virus (EAV) infection and establishment of persistent infection among 14 stallions following natural infections. The data showed that carrier stallions with a CD3(+) T lymphocyte susceptibility phenotype to in vitro EAV infection may be at higher risk of becoming carriers than those that lack this phenotype (P = 0.0002). PMID- 22933294 TI - Identification of a varicella-zoster virus replication inhibitor that blocks capsid assembly by interacting with the floor domain of the major capsid protein. AB - A novel anti-varicella-zoster virus compound, a derivative of pyrazolo[1,5 c]1,3,5-triazin-4-one (coded as 35B2), was identified from a library of 9,600 random compounds. This compound inhibited both acyclovir (ACV)-resistant and sensitive strains. In a plaque reduction assay under conditions in which the 50% effective concentration of ACV against the vaccine Oka strain (V-Oka) in human fibroblasts was 4.25 MUM, the 50% effective concentration of 35B2 was 0.75 MUM. The selective index of the compound was more than 200. Treatment with 35B2 inhibited neither immediate-early gene expression nor viral DNA synthesis. Twenty four virus clones resistant to 35B2 were isolated, all of which had a mutation(s) in the amino acid sequence of open reading frame 40 (ORF40), which encodes the major capsid protein (MCP). Most of the mutations were located in the regions corresponding to the "floor" domain of the MCP of herpes simplex virus 1. Treatment with 35B2 changed the localization of MCP in the fibroblasts infected with V-Oka but not in the fibroblasts infected with the resistant clones, although it did not affect steady-state levels of MCP. Overexpression of the scaffold proteins restored the normal MCP localization in the 35B2-treated infected cells. The compound did not inhibit the scaffold protein-mediated translocation of MCP from the cytoplasm to the nucleus. Electron microscopic analysis demonstrated the lack of capsid formation in the 35B2-treated infected cells. These data indicate the feasibility of developing a new class of antivirals that target the herpesvirus MCPs and inhibit normal capsid formation by a mechanism that differs from those of the known protease and encapsidation inhibitors. Further biochemical studies are required to clarify the precise antiviral mechanism. PMID- 22933295 TI - Trafficking and replication patterns reveal splenic macrophages as major targets of dengue virus in mice. AB - Human postmortem studies of natural dengue virus (DENV) infection have reported systemically distributed viral antigen. Although it is widely accepted that DENV infects mononuclear phagocytes, the sequence in which specific tissues and cell types are targeted remains uncharacterized. We previously reported that mice lacking alpha/beta and gamma interferon receptors permit high levels of DENV replication and show signs of systemic disease (T. R. Prestwood et al., J. Virol. 82:8411-8421, 2008). Here we demonstrate that within 6 h, DENV traffics to and replicates in both CD169(+) and SIGN-R1(+) macrophages of the splenic marginal zone or draining lymph node, respectively, following intravenous or intrafootpad inoculation. Subsequently, high levels of replication are detected in F4/80(+) splenic red pulp macrophages and in the bone marrow, lymph nodes, and Peyer's patches. Intravenously inoculated mice begin to succumb to dengue disease 72 h after infection, at which time viral replication occurs systemically, except in lymphoid tissues. In particular, high levels of replication occur in CD68(+) macrophages of the kidneys, heart, thymus, and gastrointestinal tract. Over the course of infection, proportionately large quantities of DENV traffic to the liver and spleen. However, late during infection, viral trafficking to the spleen decreases, while trafficking to the liver, thymus, and kidneys increases. The present study demonstrates that macrophage populations, initially in the spleen and other lymphoid tissues and later in nonlymphoid tissues, are major targets of DENV infection in vivo. PMID- 22933296 TI - Ultrasensitive allele-specific PCR reveals rare preexisting drug-resistant variants and a large replicating virus population in macaques infected with a simian immunodeficiency virus containing human immunodeficiency virus reverse transcriptase. AB - It has been proposed that most drug-resistant mutants, resulting from a single nucleotide change, exist at low frequency in human immunodeficiency virus type 1 (HIV-1) and simian immunodeficiency virus (SIV) populations in vivo prior to the initiation of antiretroviral therapy (ART). To test this hypothesis and to investigate the emergence of resistant mutants with drug selection, we developed a new ultrasensitive allele-specific PCR (UsASP) assay, which can detect drug resistance mutations at a frequency of >=0.001% of the virus population. We applied this assay to plasma samples obtained from macaques infected with an SIV variant containing HIV-1 reverse transcriptase (RT) (RT-simian-human immunodeficiency [SHIV](mne)), before and after they were exposed to a short course of efavirenz (EFV) monotherapy. We detected RT inhibitor (RTI) resistance mutations K65R and M184I but not K103N in 2 of 2 RT-SHIV-infected macaques prior to EFV exposure. After three doses over 4 days of EFV monotherapy, 103N mutations (AAC and AAT) rapidly emerged and increased in the population to levels of ~20%, indicating that they were present prior to EFV exposure. The rapid increase of 103N mutations from <0.001% to 20% of the viral population indicates that the replicating virus population size in RT-SHIV-infected macaques must be 10(6) or more infected cells per replication cycle. PMID- 22933298 TI - Aldosterone-dependent and -independent regulation of the epithelial sodium channel (ENaC) in mouse distal nephron. AB - Aldosterone is thought to be the main hormone to stimulate the epithelial sodium channel (ENaC) in the aldosterone-sensitive distal nephron (ASDN) comprising the late distal convoluted tubule (DCT2), the connecting tubule (CNT) and the entire collecting duct (CD). There is immunohistochemical evidence for an axial gradient of ENaC expression along the ASDN with highest expression in the DCT2 and CNT. However, most of our knowledge about renal ENaC function stems from studies in the cortical collecting duct (CCD). Here we investigated ENaC function in the transition zone of DCT2/CNT or CNT/CCD microdissected from mice maintained on different sodium diets to vary plasma aldosterone levels. Single-channel recordings demonstrated amiloride-sensitive Na(+) channels in DCT2/CNT with biophysical properties typical for ENaC previously described in CNT/CCD. In animals maintained on a standard salt diet, the average ENaC-mediated whole cell current (DeltaI(ami)) was higher in DCT2/CNT than in CNT/CCD. A low salt diet increased DeltaI(ami) in CNT/CCD but had little effect on DeltaI(ami) in DCT2/CNT. To investigate whether aldosterone is necessary for ENaC activity in the DCT2/CNT, we used aldosterone synthase knockout (AS(-/-)) mice that lack aldosterone. In CNT/CCD of AS(-/-) mice, DeltaI(ami) was lower than that in wild type (WT) animals and was not stimulated by a low salt diet. In contrast, in DCT2/CNT of AS(-/-) mice, DeltaI(ami) was similar to that in DCT2/CNT of WT animals both on a standard and on a low salt diet. We conclude that ENaC function in the DCT2/CNT is largely independent of aldosterone which is in contrast to its known aldosterone sensitivity in CNT/CCD. PMID- 22933297 TI - Prostaglandin E(2) mediates proliferation and chloride secretion in ADPKD cystic renal epithelia. AB - Prostaglandin E(2) (PGE(2)) contributes to cystogenesis in genetically nonorthologous models of autosomal dominant polycystic kidney disease (ADPKD). However, it remains unknown whether PGE(2) induces the classic features of cystic epithelia in genetically orthologous models of ADPKD. We hypothesized that, in ADPKD epithelia, PGE(2) induces proliferation and chloride (Cl(-)) secretion, two archetypal phenotypic features of ADPKD. To test this hypothesis, proliferation and Cl(-) secretion were measured in renal epithelial cells deficient in polycystin-1 (PC-1). PC-1-deficient cells increased in cell number (proliferated) faster than PC-1-replete cells, and this proliferative advantage was abrogated by cyclooxygenase inhibition, indicating a role for PGE(2) in cell proliferation. Exogenous administration of PGE(2) increased proliferation of PC-1-deficient cells by 38.8 +/- 5.2% (P < 0.05) but inhibited the growth of PC-1-replete control cells by 49.4 +/- 1.9% (P < 0.05). Next, we tested whether PGE(2) specific E prostanoid (EP) receptor agonists induce intracellular cAMP and downstream beta-catenin activation. PGE(2) and EP4 receptor agonism (TCS 2510) increased intracellular cAMP concentration and the abundance of active beta catenin in PC-1-deficient cells, suggesting a mechanism for PGE(2)-mediated proliferation. Consistent with this hypothesis, antagonizing EP4 receptors reverted the growth advantage of PC-1-deficient cells, implicating a central role for the EP4 receptor in proliferation. To test whether PGE(2)-dependent Cl(-) secretion is also enhanced in PC-1-deficient cells, we used an Ussing chamber to measure short-circuit current (I(sc)). Addition of PGE(2) induced a fivefold higher increase in I(sc) in PC-1-deficient cells compared with PC-1-replete cells. This PGE(2)-induced increase in I(sc) in PC-1-deficient cells was blocked by CFTR-172 and flufenamic acid, indicating that PGE(2) activates CFTR and calcium-activated Cl(-) channels. In conclusion, PGE(2) activates aberrant signaling pathways in PC-1-deficient epithelia that contribute to the proliferative and secretory phenotype characteristic of ADPKD and suggests a therapeutic role for PGE(2) inhibition and EP4 receptor antagonism. PMID- 22933299 TI - alpha2-Adrenoceptor agonist dexmedetomidine protects septic acute kidney injury through increasing BMP-7 and inhibiting HDAC2 and HDAC5. AB - Bone morphogenetic protein (BMP)-7 protects sepsis-induced acute kidney injury (AKI). Dexmedetomidine (DEX), an alpha(2)-adrenoceptor (alpha(2)-AR) agonist, has anti-inflammatory effects. We investigated the protective effects of DEX on sepsis-induced AKI and the expression of BMP-7 and histone deacetylases (HDACs). In vitro, the effects of DEX or trichostatin A (TSA, an HDAC inhibitor) on TNF alpha, monocyte chemotactic protein (MCP-1), BMP-7, and HDAC mRNA expression in LPS-stimulated rat renal tubular epithelial NRK52E cells, was determined using real-time PCR. In vivo, mice were intraperitoneally injected with DEX (25 MUg/kg) or saline immediately and 12 h after cecal ligation and puncture (CLP) surgery. Twenty-four hours after CLP, we examined kidney injury and renal TNF-alpha, MCP 1, BMP-7, and HDAC expression. Survival was monitored for 120 h. LPS increased HDAC2, HDAC5, TNF-alpha, and MCP-1 expression, but decreased BMP-7 expression in NRK52E cells. DEX treatment decreased the HDAC2, HDAC5, TNF-alpha, and MCP-1 expression, but increased BMP-7 and acetyl histone H3 expression, whose effects were blocked by yohimbine, an alpha(2)-AR antagonist. With DEX treatment, the LPS induced TNF-alpha expression and cell death were attenuated in scRNAi-NRK52E but not BMP-7 RNAi-NRK52E cells. In CLP mice, DEX treatment increased survival and attenuated AKI. The expression of HDAC2, HDAC5, TNF-alpha, and MCP-1 mRNA in the kidneys of CLP mice was increased, but BMP-7 was decreased. However, DEX treatment reduced those changes. DEX reduces sepsis-induced AKI by decreasing TNF alpha and MCP-1 and increasing BMP-7, which is associated with decreasing HDAC2 and HDAC5, as well as increasing acetyl histone H3. PMID- 22933300 TI - beta-Adrenergic receptor stimulation increases surface NKCC2 expression in rat thick ascending limbs in a process inhibited by phosphodiesterase 4. AB - The thick ascending limb of the loop of Henle (THAL) reabsorbs ~30% of the filtered NaCl in a process mediated by the apical Na-K-2Cl cotransporter NKCC2. Stimulation of beta-adrenergic receptors in the THAL enhances NaCl reabsorption and increases intracellular cAMP. We found that intracellular cAMP stimulates NKCC2 trafficking to the apical membrane via protein kinase A (PKA). Several cAMP specific phosphodiesterases (PDE) have been identified in rat THALs, and PDE4 decreases cAMP generated by beta-adrenergic stimulation in other cells. However, it is not known whether beta-adrenergic receptors activation stimulates NKCC2 trafficking. Thus we hypothesized that beta-adrenergic receptor stimulation enhances THAL apical membrane NKCC2 expression via the PKA pathway and PDE4 blunts this effect. THAL suspensions were obtained from Sprague-Dawley rats, and surface NKCC2 expression was measured by surface biotinylation and Western blot. Incubation of THALs with the beta-adrenergic receptor agonist isoproterenol at 0.5 and 1.0 MUM increased surface NKCC2 by 17 +/- 1 and 29 +/- 5% respectively (P < 0.05). Preventing cAMP degradation with 3-isobutyl-methylxanthine (IBMX; a nonselective phosphodiesterase inhibitor) enhanced isoproterenol-stimulated surface NKCC2 expression to 51 +/- 7% (P < 0.05 vs. isoproterenol). The beta adrenergic receptor antagonist propranolol or the PKA inhibitor H-89 completely blocked isoproterenol + IBMX-induced increase on surface NKCC2, while propranolol or H-89 alone had no effect. Selective inhibition of PDE4 with rolipram (20 MUM) potentiated the effect of isoproterenol on surface NKCC2 and increased cAMP levels. We concluded that beta-adrenergic receptor stimulation enhances surface NKCC2 expression in the THALs via PKA and PDE4 blunts this effect. PMID- 22933301 TI - Use of ultrasound to assess renal reperfusion and P-selectin expression following unilateral renal ischemia. AB - Renal ischemia-reperfusion injury is a major cause of acute kidney injury that carries a high mortality rate and increases the risk of later development of hypertension and chronic kidney disease. Although mouse models have contributed much to our understanding of the mechanisms involved, studying aspects of the injury process in vivo remains technically challenging. This study validates the use of noninvasive ultrasound imaging to assess both renal perfusion and vascular adhesion molecule expression following 1-h unilateral renal ischemia in male and female mice. Pulsed-wave Doppler measurements of renal arterial blood velocity revealed renal perfusion recoveries of 56 +/- 9% in male and 69 +/- 10% in female mice 1 h after the commencing of reperfusion, which is similar to what we have previously published using conventional invasive methodology. At 24 h postischemia, renal perfusion was 40 +/- 8% in male and 46 +/- 7% in female mice, representing a further significant reduction of perfusion (P(Time) < 0.001). Using ultrasound imaging of a P-selectin-targeted contrast agent, a significant increase in vascular P-selectin protein expression was observed after 1-h reperfusion in the cortex of the postischemic compared with contralateral kidney in both male and female mice (18 +/- 5 vs. 3 +/- 3 intensity units in male and 30 +/- 6 vs. 0 +/- 4 in female mice, P(Ischemia) < 0.01). An approximately sixfold increase in P-selectin mRNA was observed ex vivo in the renal vasculature of male and female mice at this time point (P < 0.01). In conclusion, ultrasound represents an effective and noninvasive method for the measurement of both renal perfusion and vascular adhesion molecule expression in mice. PMID- 22933302 TI - Epicatechin limits renal injury by mitochondrial protection in cisplatin nephropathy. AB - Cisplatin nephropathy can be regarded as a mitochondrial disease. Intervention to halt such deleterious injury is under investigation. Recently, the flavanol (-) epicatechin emerges as a novel compound to protect the cardiovascular system, owing in part to mitochondrial protection. Here, we have hypothesized that epicatechin prevents the progression of cisplatin-induced kidney injury by protecting mitochondria. Epicatechin was administered 8 h after cisplatin injury was induced in the mouse kidney. Cisplatin significantly induced renal dysfunction and tubular injury along with an increase in oxidative stress. Mitochondrial damages were also evident as a decrease in loss of mitochondrial mass with a reduction in the oxidative phosphorylation complexes and low levels of MnSOD. The renal damages and mitochondrial injuries were significantly prevented by epicatechin treatment. Consistent with these observations, an in vitro study using cultured mouse proximal tubular cells demonstrated that cisplatin-induced mitochondrial injury, as revealed by a decrease in mitochondrial succinate dehydrogenase activity, an induction of cytochrome c release, mitochondrial fragmentation, and a reduction in complex IV protein, was prevented by epicatechin. Such a protective effect of epicatechin might be attributed to decreased oxidative stress and reduced ERK activity. Finally, we confirmed that epicatechin did not perturb the anticancer effect of cisplatin in HeLa cells. In conclusion, epicatechin exhibits protective effects due in part to its ability to prevent the progression of mitochondrial injury in mouse cisplatin nephropathy. Epicatechin may be a novel option to treat renal disorders associated with mitochondrial dysfunction. PMID- 22933303 TI - Relationship between cyclic AMP-dependent protein tyrosine phosphorylation and extracellular calcium during hyperactivation of boar spermatozoa. AB - In mammalian spermatozoa, the state of protein tyrosine phosphorylation is modulated by protein tyrosine kinases and protein tyrosine phosphatases that are controlled via cyclic AMP (cAMP)-protein kinase A (PKA) signaling cascades. The aims of this study were to examine the involvement of cAMP-induced protein tyrosine phosphorylation in response to extracellular calcium and to characterize effects of pharmacological modulation of the cAMP-induced protein phosphorylation state and calmodulin activity during hyperactivation in boar spermatozoa. Ejaculated spermatozoa were incubated with cBiMPS (a cell-permeable cAMP analog) and CaCl(2) at 38.5 degrees C to induce hyperactivation, and then used for Western blotting and indirect immunofluorescence of phosphorylated proteins and for the assessment of motility. Both cBiMPS and CaCl(2) were necessary for hyperactivation. The increase in hyperactivated spermatozoa exhibited a dependence on the state of cBiMPS-induced protein tyrosine phosphorylation in the connecting and principal pieces. The addition of calyculin A (an inhibitor for protein phosphatases 1/2A (PP1/PP2A), 50-100 nM) coincidently promoted hyperactivation and cAMP-induced protein tyrosine phosphorylation in the presence of cBiMPS and CaCl(2). Moreover, the addition of W-7 (a calmodulin antagonist, 2 4 uM) enhanced the percentages of hyperactivated spermatozoa after incubation with cBiMPS and CaCl(2), independently of protein tyrosine phosphorylation. These findings indicate that cAMP-induced protein tyrosine phosphorylation in the connecting and principal pieces is involved in hyperactivation in response to extracellular calcium, and that calmodulin may suppress hyperactivation via the signaling cascades that are independent of cAMP-induced protein tyrosine phosphorylation. PMID- 22933304 TI - Studying mechanisms of regeneration in amphibian and reptilian vertebrate models. PMID- 22933305 TI - The other side of the risk equation: exploring the dangers of unplanned pregnancy in women with lupus nephritis. Comment on the article by Hahn et al. PMID- 22933307 TI - Laparoscopic transabdominal lateral adrenalectomy. AB - Laparoscopic adrenalectomy is a mainstay of operative options for adrenal tumors and allows surgeons to perform adrenalectomies with less morbidity, less post operative pain, and shorter hospital stays. The literature has demonstrated its efficacy to be equal to open adrenalectomy in most cases. With regard to malignant primary and metastatic lesions, controversy still remains, however, consideration of a laparoscopic approach for smaller, well circumscribed and non invasive lesions is reasonable. During any laparoscopic resection, when there is doubt about the ability to safely remove the lesion with an intact capsule, conversion to an open approach should be considered. The primary goal of a safe and complete oncologic resection cannot be compromised. For most benign lesions, laparoscopic approaches are safe and feasible and conversion to an open approach is necessary only for lesions where size limits the ability of a minimally invasive resection. PMID- 22933308 TI - The influence of body mass index on lumbar disc degeneration: comment on the article by Samartzis et al. PMID- 22933306 TI - Thioredoxin-80 is a product of alpha-secretase cleavage that inhibits amyloid beta aggregation and is decreased in Alzheimer's disease brain. AB - Thioredoxin-1 (Trx1) is an endogenous dithiol reductant and antioxidant that was shown to be decreased in Alzheimer's disease (AD) neurons. A truncated form of Trx1, thioredoxin 80 (Trx80), was reported to be secreted from monocytes having cytokine activity. Here, we show that Trx80 is present in human brain in an aggregated form. Trx80 localizes mainly to neurons and is dramatically decreased in AD brains. Trx80 levels in cerebrospinal fluid (CSF) correlate with those of the classical AD biomarkers amyloid-beta (Abeta) 1-42 and total tau. Moreover, Trx80 measurements in CSF discriminate between patients with stable mild cognitive impairment, prodomal AD and mild AD. We report that ADAM10 and 17, two alpha-secretases processing the Abeta precursor protein, are responsible for Trx80 generation. In contrast to the periphery, Trx80 has no pro-inflammatory effects in glia, either by itself or in combination with Abeta or apolipoprotein E. Instead, Trx80 inhibits Abeta(1-42) aggregation and protects against its toxicity. Thus, a reduction in Trx80 production would result in increased Abeta polymerization and enhanced neuronal vulnerability. Our data suggest that a deficit in Trx80 could participate in AD pathogenesis. PMID- 22933309 TI - A case of Behcet's disease developing after poststreptococcal acute glomerulonephritis. AB - We report a case of a 73-year-old Japanese male patient who developed Behcet's disease (BD) after poststreptococcal acute glomerulonephritis. Three months after the initial presentation, acneiform eruption and oral and genital ulcers appeared. Treatment with oral prednisolone (20 mg/day) resulted in the remarkable disappearance of these symptoms. These findings support the hypothesis that Streptococcus pyogenes may be an etiologic factor of BD. PMID- 22933310 TI - A case of an SLE patient with febrile neutropenia who experienced exacerbation of cutaneous manifestations after the administration of G-CSF. AB - Systemic lupus erythematosus (SLE) is a chronic inflammatory autoimmune disease. Although hematological anomalies are commonly found in SLE, severe polymorphonuclear leukocyte depletion is rare. Most episodes of severe granulocytopenia in SLE patients tend to occur as part of drug toxicity-induced medullar hypoplasia, and recombinant human (rh) granulocyte colony-stimulating factor (G-CSF) has been shown to be effective for treating neutropenia associated with SLE. However, flares of some autoimmune diseases, including flares in six SLE patients, have been reported after G-CSF therapy. This report presents the case of a patient with SLE who experienced exacerbation of skin symptoms after G CSF therapy. There is sufficient evidence to suggest that G-CSF can exacerbate inflammatory disease. Furthermore, the possibility that several factors other than rhG-CSF may affect the disease activity of SLE should be considered when SLE patients with neutropenia require the administration of rhG-CSF. Therefore rhG CSF should be used with considerable caution in neutropenic patients with SLE. PMID- 22933311 TI - Highlight--lowly sea squirt [corrected] leads the evolutionary race. PMID- 22933312 TI - Highlight: "keeping the boys in the conversation: male fitness shapes the location of genes that interact with mitochondria". PMID- 22933313 TI - Barrierless photoisomerisation of the "simplest cyanine": joining computational and femtosecond optical spectroscopies to trace the full reaction path. AB - The photoisomerisation of 1,1'-diethyl-2,2'-pyridocyanine, regarded by Brooker as the simplest cyanine, is examined in methanol by time-resolved experiments and PCM/TD-CAM-B3LYP calculations. Femtosecond transient absorption, fluorescence upconversion, and stimulated Raman scattering, all with broadband coverage, provide a panoramic view of the photoreaction. On the computational side, evolving distributions on an S(1) minimum-energy path are obtained by solving the Smoluchowski equation for drift and diffusion of torsional motion. Absorption and fluorescence bandshapes are calculated and compared to the observations; near quantitative agreement implies that the entire S(1) path has been observed. Most importantly the global S(1) minimum, i.e. the perpendicular "phantom state" P*, can be identified and characterized in this way. Internal conversion of P* (3.7 ps), assisted by solvent equilibration, leads to the hot ground state. Within 5 ps, vibrational bands of cis and trans isomers are recognized with the help of calculated Raman spectra. The differences between observed and simulated spectra are discussed. PMID- 22933314 TI - A soft copper(II) porous coordination polymer with unprecedented aqua bridge and selective adsorption properties. AB - Herein, the synthesis, crystal structure, and full characterization of a new soft porous coordination polymer (PCP) of ([Cu(2)(dmcapz)(2)(OH(2))]DMF(1.5))(n) (1) formulation, which is easily obtained in the reaction of CuX(2) (X = Cl, NO(3)) salts with 3,5-dimethyl-4-carboxypyrazole (H(2)dmcapz) is present. Compound 1 shows a copper(II) dinuclear secondary building unit (SBU), which is supported by two pyrazolate bridges and an unprecedented H(2)O bridge. The dinuclear SBUs are further bridged by the carboxylate ligands to build a diamondoid porous network. The structural transformations taking place in 1 framework upon guest removal/uptake has been studied in detail. Indeed, the removal of the bridging water molecules gives rise to a metastable evacuated phase (1 b) that transforms into an extremely stable porous material (1 c) after freezing at liquid-nitrogen temperature. The soaking of 1 c into water allows the complete and instantaneous recover of the water-exchanged material (1 a'). Remarkably, 1 b and 1 c materials possess structural bistability, which results in the switchable adsorptive functions. Therefore, the gas-adsorption properties of both materials have been studied by means of single-component gas adsorption isotherms as well as by variable-temperature pulse-gas chromatography. Both materials present permanent porosity and selective gas-adsorption properties towards a variety of gases and vapors of environmental and industrial interest. Moreover, the flexible nature of the coordination network and the presence of highly active convergent open metal sites confer on these materials intriguing gas-adsorption properties with guest triggered framework-breathing phenomena being observed. The plasticity of Cu(II) metal center and its ability to form stable complexes with different coordination numbers is at the origin of the structural transformations and the selective adsorption properties of the studied materials. PMID- 22933315 TI - Comparison of long-term clinical outcome with etanercept treatment and adalimumab treatment of rheumatoid arthritis with respect to immunogenicity. AB - OBJECTIVE: To compare rates of sustained low and minimal disease activity and remission according to the American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) criteria during 3-year followup in rheumatoid arthritis (RA) patients treated with etanercept and adalimumab in routine care. METHODS: Four hundred seven RA patients previously unexposed to tumor necrosis factor antagonists were treated with etanercept (n = 203) or adalimumab (n = 204) and assessed at 3- and later 6-month intervals. Treatment allocation was at the discretion of the treating rheumatologist. Clinical parameters were measured at each time point, as were anti-adalimumab antibodies in adalimumab-treated patients. Achievement of clinical outcome was defined as the occurrence of sustained (at least 12 consecutive months) low disease activity (28-joint Disease Activity Score [DAS28] <3.2), minimal disease activity (DAS28 <2.6), or ACR/EULAR remission based on the Simplified Disease Activity Index (SDAI). Non-overlapping response rates were calculated. RESULTS: Among the adalimumab group, 13% reached sustained low disease activity but not sustained minimal disease activity, 15% reached sustained minimal disease activity but not sustained remission according to the SDAI, and 16% reached sustained ACR/EULAR remission. In the etanercept group the corresponding rates were 16%, 11%, and 12%, respectively (P = 0.42, overall test for linear trend). Adalimumab-treated patients without anti adalimumab antibodies (n = 150 [74%]) had the best outcomes, and adalimumab treated patients with anti-adalimumab antibodies the worst, with outcomes in etanercept-treated patients in between (P < 0.0001). Differences were most apparent in the sustained SDAI remission and sustained minimal disease activity categories. For example, 40% of anti-adalimumab antibody-negative patients, 23% of etanercept-treated patients, and 4% of anti-adalimumab antibody-positive patients achieved at least sustained minimal disease activity. CONCLUSION: Overall, etanercept and adalimumab treatment appear similar in inducing a good long-term clinical outcome. However, in the case of adalimumab this is strongly dependent on the presence or absence of anti-adalimumab antibodies. PMID- 22933316 TI - Photoresponsive molecules in well-defined nanoscale environments. AB - Stimuli-responsive molecules are key building blocks of functional molecular materials and devices. These molecules can operate in a range of environments. A molecule's local environment will dictate its conformation, reactivity, and function; by controlling the local environment we can ultimately develop interfaces of individual molecules with the macroscopic environment. By isolating molecules in well-defined environments, we are able to obtain both accurate measurements and precise control. We exploit defect sites in self-assembled monolayers (SAMs) to direct the functional molecules into precise locations, providing a basis for the measurements and engineering of functional molecular systems. The structure and functional moieties of the SAM can be tuned to control not only the intermolecular interactions but also molecule-substrate interactions, resulting in extraction or control of desired molecular functions. Herein, we report our progress toward the assembly and measurements of photoresponsive molecules and their precise assemblies in SAM matrices. PMID- 22933317 TI - Adaptive linear rank tests for eQTL studies. AB - Expression quantitative trait loci (eQTL) studies are performed to identify single-nucleotide polymorphisms that modify average expression values of genes, proteins, or metabolites, depending on the genotype. As expression values are often not normally distributed, statistical methods for eQTL studies should be valid and powerful in these situations. Adaptive tests are promising alternatives to standard approaches, such as the analysis of variance or the Kruskal-Wallis test. In a two-stage procedure, skewness and tail length of the distributions are estimated and used to select one of several linear rank tests. In this study, we compare two adaptive tests that were proposed in the literature using extensive Monte Carlo simulations of a wide range of different symmetric and skewed distributions. We derive a new adaptive test that combines the advantages of both literature-based approaches. The new test does not require the user to specify a distribution. It is slightly less powerful than the locally most powerful rank test for the correct distribution and at least as powerful as the maximin efficiency robust rank test. We illustrate the application of all tests using two examples from different eQTL studies. PMID- 22933319 TI - Small-angle X-ray scattering reveals architecture and A2B2 stoichiometry of the UvrA-UvrB DNA damage sensor. AB - The UvrA-UvrB (AB) protein complex operates in the bacterial nucleotide excision repair pathway as the main sensor of DNA damage. Crystallographic analysis of the AB complex revealed a linear UvrB-UvrA-UvrA-UvrB arrangement of subunits with an internal two-fold axis that became incorporated into the crystal. Here, we have used small-angle X-ray scattering (SAXS) to show close correspondence between the crystal structure and the entity in solution. This result confirms the number and disposition of subunits in the crystallographic model and rules out other possible arrangements suggested by packing in the crystal. The current SAXS analysis failed to detect significant changes to the structure as a function of nucleotide. PMID- 22933320 TI - Sometimes double negative is positive. PMID- 22933318 TI - Chemical biology for understanding matrix metalloproteinase function. AB - The matrix metalloproteinase (MMP) family has long been associated with normal physiological processes such as embryonic implantation, tissue remodeling, organ development, and wound healing, as well as multiple aspects of cancer initiation and progression, osteoarthritis, inflammatory and vascular diseases, and neurodegenerative diseases. The development of chemically designed MMP probes has advanced our understanding of the roles of MMPs in disease in addition to shedding considerable light on the mechanisms of MMP action. The first generation of protease-activated agents has demonstrated proof of principle as well as providing impetus for in vivo applications. One common problem has been a lack of agent stability at nontargeted tissues and organs due to activation by multiple proteases. The present review considers how chemical biology has impacted the progress made in understanding the roles of MMPs in disease and the basic mechanisms of MMP action. PMID- 22933321 TI - Calcium channel blockers prevent endothelial cell activation in response to necrotic trophoblast debris: possible relevance to pre-eclampsia. AB - AIMS: Pre-eclampsia is characterized by endothelial activation, which is triggered by placental factor(s). One such factor may be trophoblastic debris that is shed into the maternal blood to become trapped against the maternal pulmonary endothelium. Phagocytosis of necrotic trophoblastic debris (NTD) induces endothelial cell activation with increased secretion of interleukin-6 (IL 6) and transforming growth factor beta1 (TGFbeta1), which may induce systemic endothelial cell activation. In addition to its effects on vascular smooth muscle, evidence suggests that nifedipine may also affect the endothelium, contributing to the therapeutic benefits of the drug. We investigated whether nifedipine could reverse the endothelial cell activation induced by NTD. METHODS AND RESULTS: Trophoblastic debris was collected from placental explants and exposed to endothelial cells with or without nifedipine, verapamil, or a nitric oxide (NO) donor for 24 h. Endothelial cell activation was measured by cell surface intracellular adhesion molecule-1 and E-selectin, as well as monocyte adhesion. The activation of endothelial cells exposed to NTD or sera from pre eclamptic women was significantly reduced by nifedipine or verapamil. In addition, the increases in the levels of IL-6 or TGFbeta1 in conditioned media from endothelial cells following phagocytosis of NTD were significantly reduced by nifedipine. These actions of nifedipine were reversed by the NO synthetase inhibitor l-NAME and mimicked by a NO donor. CONCLUSION: Our results suggest that calcium channel blockers may have a direct effect upon endothelial cells, reducing the endothelial cell activation that is a key pathogenic feature of pre eclampsia. This action may be mediated, in part, by NO. PMID- 22933322 TI - Induction of intracellular heat-shock protein 72 prevents the development of vascular smooth muscle cell calcification. AB - AIMS: Vascular calcification (VC) is a significant contributor to cardiovascular mortality in patients with chronic kidney disease (CKD) and coronary artery disease (CAD). Osteo/chondrocytic transformation and simultaneous dedifferentiation of smooth muscle cells (SMCs) are important in the pathogenesis of VC. Heat-shock protein 72 (HSP72) is a cardioprotective inducible heat-shock protein that functions as a molecular chaperone. However, its role in the development of accelerated vascular dysfunction and calcification is largely unexplored. METHODS AND RESULTS: We describe for the first time marked reduction in HSP72 expression in arteries from patients with CKD and CAD, compared with healthy controls, in vivo. Induction of HSP72 by heat-shock treatment (HST) significantly prevented the development of calcification of human aortic smooth muscle cells (HA-SMCs), in vitro. These anti-calcific effects were abolished following treatment with both quercetin, an HST inhibitor, and HSP72 siRNA knockdown. Induction of HSP72 suppressed Cbfa-1-dependent osteo/chondrocytic transformation and stabilized SMC contractile phenotype through the myocardin serum response factor (SRF) pathway. Co-immunoprecipitation studies demonstrated physical association between SRF and HSP72. Furthermore, organ culture of arteries from CKD and CAD patients showed that these arteries retained their ability to induce HSP72 following HST, despite initially reduced expression. CONCLUSION: Our study shows for the first time that intracellular HSP72 may function as a central regulator of molecular pathways involved in the development of VC. We suggest treatment strategies that up-regulate HSP72 as a new approach to inhibit VC. PMID- 22933325 TI - Visual detection of glucose using conformational switch of i-Motif DNA and non crosslinking gold nanoparticles. AB - i-Motif tuned: glucose is a ubiquitous fuel for metabolic pathways; its oxidation can trigger i-motif DNA formation. Using this unique conformational switch and non-crosslinking gold nanoparticles, a label-free colorimetric glucose sensor has been developed. PMID- 22933323 TI - A mouse model for distal renal tubular acidosis reveals a previously unrecognized role of the V-ATPase a4 subunit in the proximal tubule. AB - The V-ATPase is a multisubunit complex that transports protons across membranes. Mutations of its B1 or a4 subunit are associated with distal renal tubular acidosis and deafness. In the kidney, the a4 subunit is expressed in intercalated cells of the distal nephron, where the V-ATPase controls acid/base secretion, and in proximal tubule cells, where its role is less clear. Here, we report that a4 KO mice suffer not only from severe acidosis but also from proximal tubule dysfunction with defective endocytic trafficking, proteinuria, phosphaturia and accumulation of lysosomal material and we provide evidence that these findings may be also relevant in patients. In the inner ear, the a4 subunit co-localized with pendrin at the apical side of epithelial cells lining the endolymphatic sac. As a4 KO mice were profoundly deaf and displayed enlarged endolymphatic fluid compartments mirroring the alterations in pendrin KO mice, we propose that pendrin and the proton pump co-operate in endolymph homeostasis. Thus, our mouse model gives new insights into the divergent functions of the V-ATPase and the pathophysiology of a4-related symptoms. PMID- 22933326 TI - Patients' perception of dignity in Iranian healthcare settings: a qualitative content analysis. AB - PURPOSE: The importance of recognising patient dignity has been realised in recent years. Despite being a central phenomenon in medicine, dignity is a controversial concept, the definition of which in healthcare centres is influenced by a multitude of factors. The aim of this study was to explore the perspective of Iranian patients on respect for their dignity in healthcare centres. METHODS: With the use of purposeful sampling, 20 patients were interviewed over an 11-month period in three educational hospitals affiliated with the government. They were questioned about experiences related to respect for their dignity during their hospital encounter. Data were processed by qualitative content analysis. RESULTS: Data analysis identified nine categories and four themes. Respondents expressed their expectations and attitudes about dignity by the following themes: seeking a haven; disrespecting privacy; communicating in a vacuum; and disregard for secondary caregivers. They described how respect for their privacy, effective communication, access to facilities, and a regard for the requirements of their companions made them feel that their dignity had been conserved. CONCLUSIONS: The findings indicate that almost no patient is satisfied with the quality of services with respect to maintenance of their dignity. Regardless of their hospital location and state of health, most participants had common complaints. These findings agree with the literature and confirm that grounds should be provided for conserving dignity in the healthcare system. To reach this goal, healthcare professionals should be aware of the factors that violate or preserve dignity from the patient's perspective. PMID- 22933327 TI - Dual-responsive nanoparticles and their self-assembly. AB - Dual-responsive nanoparticles are designed by functionalizing magnetic cores with light-responsive ligands. These materials respond to both light and magnetic fields and can be assembled into various higher-order structures, depending on the relative contributions of these two stimuli. PMID- 22933329 TI - Current issues in clinical trials: standing on the shoulders of Jerome Cornfield. AB - Jerome Cornfield was one of the leading biostatisticians of the mid-20th century and made major contributions to the methods and practice of statistics in many areas. One of Cornfield's major areas of interest was clinical trials. He considered and wrote about many of the issues that continue to concern clinical trialists today. His work ranged from philosophical treatises about the approaches to inference from clinical trials, all the way to assessing the details of the conduct of a particular trial to determine how to best interpret the results. It is interesting to see how many of today's 'hot topics' in clinical trials methodology were addressed in Cornfield's works in the 1960s and 1970s. PMID- 22933328 TI - The biophysical mechanisms of altered hyaluronan concentration in synovial fluid after anterior cruciate ligament transection. AB - OBJECTIVE: The residence time of hyaluronan (HA) in knee joint synovial fluid (SF) was investigated using a rabbit anterior cruciate ligament transection (ACLT) model. The aims of this study were to assess, at 7 and 28 days after surgery, the 1) HA concentration and molecular mass (M(r) ) distribution in the SF, 2) endogenous replenishment of HA after saline washout, 3) HA residence times in the SF, and 4) synovium and subsynovium cellularity of the knee joints of rabbits subjected to ACLT, compared to sham-operated and nonoperated control joints. METHODS: Adult NZW rabbits underwent ACLT or sham surgery on one hind limb, while each contralateral limb was the nonoperated control. On day 7 or 28 after surgery, the joints were aspirated for SF, lavaged with saline, and injected with saline or polydisperse HA, and samples were obtained for analysis at set time points up to 8 hours after injection. Joint fluid samples were analyzed for the concentration and M(r) distribution of HA to calculate the HA residence time constant. RESULTS: Analysis of HA concentrations and M(r) distributions showed 1) loss of high-M(r) HA in the SF on day 7 and a shift toward a lower-M(r) distribution on day 28, 2) endogenous replenishment of high M(r) HA after washout, and 3) M(r) -dependent loss of HA from the knee joints after ACLT, particularly on day 7 postsurgery. The HA residence time decreased with decreasing HA M(r) (residence time ~27 hours with an M(r) load of 7,000 2,500 kd, to ~7 hours with an M(r) load of 250-50 kd). HA residence time also decreased (by ~70%) in the knee joints on day 7 after ACLT. The subsynovium of the joints subjected to ACLT displayed increased cellularity and neovascularization on days 7 and 28 postsurgery. CONCLUSION: The residence time of HA in the SF is transiently decreased after ACLT, suggesting that a biophysical transport mechanism is responsible for the altered composition of the SF after joint injury or during inflammation. PMID- 22933330 TI - A young woman with systemic lupus erythematosus and extensive mesenteric vasculitis involving small and medium vessels. PMID- 22933331 TI - Conformational control of the electronic properties of an alpha-beta terthiophene: lessons from a precursor towards dendritic hyperbranched oligo- and poly-thiophenes. AB - Herein we investigate the conformational and electronic properties of the 2,2';3',2"-terthiophene (B3T) unit as the building block of thiophene dendrimeric materials. By means of DFT ground electronic state dihedral energy profiles, we get insight in the flexibility of B3 T as the prominent feature promoting the 3D arrangement. The presence of diverse conformers is explored by Raman and (1)H NMR spectroscopies. A theoretical estimation of the Raman and (1)H NMR spectra over the most energetically accessible conformers is found to be crucial for the appropriate assignment of the major conformer population derived from the experimental spectra. We show that energy barriers for the interconversion of conformers also play a role. Finally, the impact on the optical spectra (absorption and emission) of the alpha-alpha and alpha-beta connections is studied and addressed by scanning the properties of the relevant low-lying excited states. These studies highlight the relevance of the architecture of the basic molecular unit to understand charge and exciton behavior in organic semiconductors, particularly for those useful in photovoltaics. PMID- 22933332 TI - Swfoldrate: predicting protein folding rates from amino acid sequence with sliding window method. AB - Protein folding is the process by which a protein processes from its denatured state to its specific biologically active conformation. Understanding the relationship between sequences and the folding rates of proteins remains an important challenge. Most previous methods of predicting protein folding rate require the tertiary structure of a protein as an input. In this study, the long range and short-range contact in protein were used to derive extended version of the pseudo amino acid composition based on sliding window method. This method is capable of predicting the protein folding rates just from the amino acid sequence without the aid of any structural class information. We systematically studied the contributions of individual features to folding rate prediction. The optimal feature selection procedures are adopted by means of combining the forward feature selection and sequential backward selection method. Using the jackknife cross validation test, the method was demonstrated on the large dataset. The predictor was achieved on the basis of multitudinous physicochemical features and statistical features from protein using nonlinear support vector machine (SVM) regression model, the method obtained an excellent agreement between predicted and experimentally observed folding rates of proteins. The correlation coefficient is 0.9313 and the standard error is 2.2692. The prediction server is freely available at http://www.jci-bioinfo.cn/swfrate/input.jsp. PMID- 22933333 TI - Incidence of 17p deletions and TP53 mutation in myelodysplastic syndrome and acute myeloid leukemia with 5q deletion. AB - TP53 mutations are frequent in myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) with complex karyotype that include del(5q) and are often associated with deletion of 17p. They have also recently been observed in MDS with isolated del(5q). We assessed the incidence of 17p deletion detected by fluorescence in situ hybridization (FISH) and of TP53 mutations detected by direct sequencing and their correlation and prognostic value in 26 MDS and 17 AML with del(5q). In the 20 cases with isolated del(5q) or one additional abnormality, no 17p deletion was found and 3 of the 18 cases analyzed (17%) had TP53 mutation. In the 23 patients with complex karyotype, 17p deletion was suspected by conventional cytogenetics in 15 cases and confirmed by FISH in 10 of them, while TP53 mutation was found in 8 of the 15 patients tested (53%), only five of whom had 17p deletion. In the whole patient series, TP53 mutations were associated with shorter survival (P = 0.07). We confirm the existence of TP53 mutations in 17% of MDS with isolated del(5q). In patients with del(5q) and complex karyotype, FISH and direct sequencing are complementary techniques to analyze TP53 abnormalities. Our findings also suggest that sequencing of the TP53 gene should be included in the study of patients with del(5q) as a single abnormality or in complex karyotype before lenalidomide treatment. PMID- 22933334 TI - A Golgi study of the camel cuneate nucleus. AB - Neurons in the cuneate nucleus of the camel brain stem were studied by Golgi method. Six types of neurons were identified based on soma size and shape, density of dendritic trees, morphology and distribution of spines, and appendages. Type I neurons had large spherical somata with somatic appendages. Dendritic appendages were predominant on proximal dendrites with terminal flower like appendages. Type II neurons had medium to large soma. Appendages and spines were found for the soma as well as along dendrites of different orders. Axons with local branches were seen for these neurons. Type III neurons were small to medium spheroidal or triangulated with large number of spines and appendages on all parts of neurons including soma, dendrites, and initial axonal segments. Axons of these neurons branch profusely and formed rich local axonal arborizations. Type IV medium-size neurons have bipolar, round, or fusiform soma with somatic spines. Their dendrites were sparsely branching with spines and terminal side branches. Type V neurons were spheroid or triangular with small soma with somatic appendages. Their dendrites were sparsely branching and terminate as thin spiny side branches. Type VI neurons were small-size unipolar, round, or fusiform with some dendritic spines and protrusions. These findings shed some light on the structure of the cuneate nucleus of one of the largest animals (the camel). PMID- 22933335 TI - Photosynthetic efficiency and rate of CO2 assimilation by Arthrospira (Spirulina) platensis continuously cultivated in a tubular photobioreactor. AB - Similar to other photosynthetic microorganisms, the cyanobacterium Arthrospira platensis can be used to produce pigments, single cell proteins, fatty acids (which can be used for bioenergy), food and feed supplements, and biofixation of CO(2) . Cultivation in a specifically designed tubular photobioreactor is suitable for photosynthetic biomass production, because the cultivation area can be reduced by distributing the microbial cells vertically, thus avoiding loss of ammonia and CO(2) . The aim of this study was to investigate the influence of light intensity and dilution rate on the photosynthetic efficiency and CO(2) assimilation efficiency of A. platensis cultured in a tubular photobioreactor in a continuous process. Urea was used as a nitrogen source and CO(2) as carbon source and for pH control. Steady-state conditions were achieved in most of the runs, indicating that continuous cultivation of this cyanobacterium in a tubular photobioreactor could be an interesting alternative for the large-scale fixation of CO(2) to mitigate the greenhouse effect while producing high protein content biomass. PMID- 22933336 TI - The selective synthesis of metallanucleosides and metallanucleotides: a new tool for the functionalization of nucleic acids. AB - Nucleobases team up: the efficient and selective preparation of purine-derived metallanucleosides, metallanucleotides, and metalladinucleotides having M-C bonds (M=Ir(III), Rh(III)) is reported for the first time. The results presented may be applied to the synthesis of functionalized nucleic acids, or DNA/RNA-modified segments. PMID- 22933337 TI - Integration of photoswitchable proteins, photosynthetic reaction centers and semiconductor/biomolecule hybrids with electrode supports for optobioelectronic applications. AB - Light-triggered biological processes provide the principles for the development of man-made optobioelectronic systems. This Review addresses three recently developed topics in the area of optobioelectronics, while addressing the potential applications of these systems. The topics discussed include: (i) the reversible photoswitching of the bioelectrocatalytic functions of redox proteins by the modification of proteins with photoisomerizable units or by the integration of proteins with photoisomerizable environments; (ii) the integration of natural photosynthetic reaction centers with electrodes and the construction of photobioelectrochemical cells and photobiofuel cells; and (iii) the synthesis of biomolecule/semiconductor quantum dots hybrid systems and their immobilization on electrodes to yield photobioelectrochemical and photobiofuel cell elements. The fundamental challenge in the tailoring of optobioelectronic systems is the development of means to electrically contact photoactive biomolecular assemblies with the electrode supports. Different methods to establish electrical communication between the photoactive biomolecular assemblies and electrodes are discussed. These include the nanoscale engineering of the biomolecular nanostructures on surfaces, the development of photoactive molecular wires and the coupling of photoinduced electron transfer reactions with the redox functions of proteins. The different possible applications of optobioelectronic systems are discussed, including their use as photosensors, the design of biosensors, and the construction of solar energy conversion and storage systems. PMID- 22933339 TI - A sequential testing approach to detecting multiple change points in the proportional hazards model. AB - The semi-parametric proportional hazards model has been widely adopted in clinical trials with time-to-event outcomes. A key assumption in the model is that the hazard ratio function is a constant over time, which is frequently violated as there is often a lag period before an experimental treatment reaches its full effect. One existing approach uses maximal score tests and Monte Carlo sampling to identify multiple change points in the hazard ratio function, which requires the number of change points that exist in the model to be known. We propose a sequential testing approach to detecting multiple change points in the hazard ratio function using likelihood ratio tests, and the distributions of the likelihood ratio statistics under the null hypothesis are evaluated via resampling. An important feature of the proposed approach is that the number of change points in the model is inferred from the data and does not need to be specified. Numerical results based on simulated clinical trials and a real time to-event study show that the proposed approach can accurately detect the change points in the hazard ratio function. PMID- 22933340 TI - CAD-score: a new contact area difference-based function for evaluation of protein structural models. AB - Evaluation of protein models against the native structure is essential for the development and benchmarking of protein structure prediction methods. Although a number of evaluation scores have been proposed to date, many aspects of model assessment still lack desired robustness. In this study we present CAD-score, a new evaluation function quantifying differences between physical contacts in a model and the reference structure. The new score uses the concept of residue residue contact area difference (CAD) introduced by Abagyan and Totrov (J Mol Biol 1997; 268:678-685). Contact areas, the underlying basis of the score, are derived using the Voronoi tessellation of protein structure. The newly introduced CAD-score is a continuous function, confined within fixed limits, free of any arbitrary thresholds or parameters. The built-in logic for treatment of missing residues allows consistent ranking of models of any degree of completeness. We tested CAD-score on a large set of diverse models and compared it to GDT-TS, a widely accepted measure of model accuracy. Similarly to GDT-TS, CAD-score showed a robust performance on single-domain proteins, but displayed a stronger preference for physically more realistic models. Unlike GDT-TS, the new score revealed a balanced assessment of domain rearrangement, removing the necessity for different treatment of single-domain, multi-domain, and multi-subunit structures. Moreover, CAD-score makes it possible to assess the accuracy of inter domain or inter-subunit interfaces directly. In addition, the approach offers an alternative to the superposition-based model clustering. The CAD-score implementation is available both as a web server and a standalone software package at http://www.ibt.lt/bioinformatics/cad-score/. PMID- 22933338 TI - Endothelial nitric oxide synthase inhibits the development of autoimmune-mediated vasculitis in mice. AB - OBJECTIVE: Many different genes or mediators have been implicated in promoting the development of vasculitis, although little is known regarding the mechanisms that normally act to suppress lesion formation. Endothelial nitric oxide synthase (eNOS) has been shown to inhibit vascular inflammation in many different model systems, but its roles in the pathogenesis of vasculitis have not been elucidated. This study was undertaken to determine the functions of eNOS in the initiation and progression of vasculitic lesion formation. METHODS: MRL/MpJ Fas(lpr) mice lacking the gene for eNOS (Nos3(-/-) ) were generated and comprehensively evaluated and compared to controls with regard to the development of autoimmune disease, including vasculitic lesion formation and glomerulonephritis. RESULTS: Nos3(-/-) MRL/MpJ-Fas(lpr) mice exhibited accelerated onset and increased incidence of renal vasculitis compared to Nos3(+/+) controls. In contrast, no significant differences in severity of glomerulonephritis were observed between groups. Vasculitis was also observed in other organs of eNOS-deficient mice, including in the lungs of several of these animals. Ultrastructural analyses of renal lesions revealed the presence of electron-dense deposits in affected arteries, and IgG, IgA, and C3 deposition was observed in some vessels in the kidneys of Nos3(-/-) mice. In addition, Nos3(-/ ) MRL/MpJ-Fas(lp) mice showed increased levels of circulating IgG-IgA immune complexes at 20 weeks of age, compared to Nos3(+/+) MRL/MpJ-Fas(lpr) and Nos3( /-) C57BL/6 mice. CONCLUSION: These findings strongly indicate that eNOS serves as a negative regulator of vasculitis in MRL/MpJ-Fas(lpr) mice and further suggest that NO produced by this enzyme may be critical for inhibiting lesion formation and vascular damage in human vasculitic diseases. PMID- 22933341 TI - Patient race and surgical outcomes after total knee arthroplasty: an analysis of a large regional database. AB - OBJECTIVE: To examine racial differences in surgical complications, mortality, and revision rates after total knee arthroplasty. METHODS: We studied patients undergoing primary total knee arthroplasty using 2001-2007 Pennsylvania Health Care Cost Containment Council data. We conducted bivariate analyses to assess the risk of complications such as myocardial infarction, venous thromboembolism, wound infections, and failure of prosthesis, as well as 30-day and 1-year overall mortality after elective total knee arthroplasty, between racial groups. We estimated Kaplan-Meier 1- and 5-year surgical revision rates, and fit multivariable Cox proportional hazards models to compare surgical revision by race, incorporating 5 years of followup. We adjusted for patient age, sex, length of hospital stay, surgical risk of death, type of health insurance, hospital surgical volume, and hospital teaching status. RESULTS: In unadjusted analyses, there were no significant differences by racial group for either overall 30-day or in-hospital complication rates, or 30-day and 1-year mortality rates. Adjusted Cox models incorporating 5 years of followup showed an increased risk of revisions for African American patients (hazard ratio [HR] 1.39, 95% confidence interval [95% CI] 1.08-1.80), younger patients (HR 2.30, 95% CI 1.96-2.69), and lower risk for female patients (HR 0.81, 95% CI 0.71-0.92). CONCLUSION: In this sample of patients who underwent knee arthroplasty, we found no significant racial differences in major complication rates or mortality. However, African American patients, younger patients, and male patients all had significantly higher rates of revision based on 5 years of followup. PMID- 22933342 TI - Representativeness of diabetes patients participating in a web-based adverse drug reaction monitoring system. AB - PURPOSE: Lareb Intensive Monitoring, LIM, is a non-interventional observational cohort method which follows first-time users of certain drugs during a certain period of time and collects information about adverse drug reactions, ADRs. In order for LIM to be a useful pharmacovigilance tool, it is important to know whether the LIM population is comparable to the whole population using the drug. The aim of this study is to compare the LIM diabetes population with an external diabetes reference population on characteristics that may influence the patient's susceptibility for ADRs. METHODS: In this study, a LIM diabetes population was compared to a reference diabetes population derived from The Groningen Initiative to ANalyse Type 2 diabetes Treatment project. Comparisons were made regarding age, gender, body mass index and polypharmacy, as well as diabetes medication used and disease/treatment duration. RESULTS: LIM patients were more often men (58.5% vs 50.8%) and in general younger (59.1 vs 64.7 years) and healthier, by that meaning they had a higher percentage of de novo treated patients (55.5% vs 53.2%), a shorter diabetes treatment duration (3.7 vs 5.5 years) and used less co medication than patients in the reference population. CONCLUSIONS: This study shows that diabetes patients participating in a web-based intensive monitoring system differ from a reference population. The observed differences might lead to an underestimation of ADRs, but it is not clear whether this would also influence the type or time-course of the reported ADRs. When interpreting results from LIM studies, one should take these differences into account. PMID- 22933343 TI - Efficient reversal of phiC31 integrase recombination in mammalian cells. AB - Over the past decade, the integrase enzyme from phage phiC31 has proven to be a useful genome engineering tool in a wide variety of species, including mammalian cells. The enzyme efficiently mediates recombination between two distinct sequences, attP and attB, producing recombinant product sites, attL and attR. The reaction proceeds exclusively in a unidirectional manner, because integrase is unable to synapse attL and attR. To date, use of phiC31 integrase has been limited to attP * attB recombination. The factor needed for the reverse reaction- the excisionase or recombination directionality factor (RDF)--was identified recently and shown to function in vitro and in bacterial cells. To determine whether the phiC31 RDF could also function in mammalian cells, we cloned and tested several vectors that permit assessment of phiC31 RDF activity in mammalian environments. In the human and mouse cell lines tested (HeLa, HEK293, and NIH3T3), we observed robust RDF activity, using plasmid and/or genomic assays. This work is the first to demonstrate attL-attR serine integrase activity in mammalian cells and validates phiC31 RDF as a new tool that will enable future studies to take advantage of phiC31 integrase recombination in the forward or reverse direction. PMID- 22933344 TI - Identification of CYP isozymes involved in benzbromarone metabolism in human liver microsomes. AB - Benzbromarone (BBR) is metabolized to 1'-hydroxy BBR and 6-hydroxy BBR in the liver. 6-Hydroxy BBR is further metabolized to 5,6-dihydroxy BBR. The aim of this study was to identify the CYP isozymes involved in the metabolism of BBR to 1' hydroxy BBR and 6-hydroxy BBR and in the metabolism of 6-hydroxy BBR to 5,6 dihydroxy BBR in human liver microsomes. Among 11 recombinant P450 isozymes examined, CYP3A4 showed the highest formation rate of 1'-hydroxy BBR. The formation rate of 1'-hydroxy BBR significantly correlated with testosterone 6beta hydroxylation activity in a panel of 12 human liver microsomes. The formation of 1'-hydroxy BBR was completely inhibited by ketoconazole in pooled human liver microsomes. On the other hand, the highest formation rate of 6-hydroxy BBR was found in recombinant CYP2C9. The highest correlation was observed between the formation rate of 6-hydroxy BBR and diclofenac 4'-hydroxylation activity in 12 human liver microsomes. The formation of 6-hydroxy BBR was inhibited by tienilic acid in pooled human liver microsomes. The formation of 5,6-dihydroxy BBR from 6 hydroxy BBR was catalysed by recombinant CYP2C9 and CYP1A2. The formation rate of 5,6-dihydroxy BBR was significantly correlated with diclofenac 4'-hydroxylation activity and phenacetin O-deethylation activity in 12 human liver microsomes. The formation of 5,6-dihydroxy BBR was inhibited with either tienilic acid or alpha naphthoflavone in human liver microsomes. These results suggest that (i) the formation of 1'-hydroxy BBR and 6-hydroxy BBR is mainly catalysed by CYP3A4 and CYP2C9, respectively, and (ii) the formation of 5,6-dihydroxy BBR is catalysed by CYP2C9 and CYP1A2 in human liver microsomes. PMID- 22933345 TI - Benefit of renal artery stenting: is on-target therapy the observational bias? PMID- 22933346 TI - Bad kidneys are bad for the heart: but what can we do about it? PMID- 22933347 TI - Coronary stent thrombosis in patients with chronic kidney disease: balancing anti ischemic efficacy and hemorrhagic risk. PMID- 22933348 TI - Early and late outcome associated with bleeding events in the setting of dual antiplatelet therapy following stent placement. PMID- 22933349 TI - Less may be more: insights on dual antiplatelet therapy duration after drug eluting stent implantation from the MATRIX registry. PMID- 22933350 TI - The Guideliner: Keeping your procedure on track or derailing it? PMID- 22933351 TI - Foreign body in the heart: be careful how you remove it. PMID- 22933352 TI - Challenges in understanding rare but serious problems associated with septal occluders. PMID- 22933353 TI - Potential role of Demodex mites and bacteria in the induction of rosacea. AB - Rosacea is a common dermatological condition that predominantly affects the central regions of the face. Rosacea affects up to 3 % of the world's population and a number of subtypes are recognized. Rosacea can be treated with a variety of antibiotics (e.g. tetracycline or metronidazole) yet no role for bacteria or microbes in its aetiology has been conclusively established. The density of Demodex mites in the skin of rosacea patients is higher than in controls, suggesting a possible role for these mites in the induction of this condition. In addition, Bacillus oleronius, known to be sensitive to the antibiotics used to treat rosacea, has been isolated from a Demodex mite from a patient with papulopustular rosacea and a potential role for this bacterium in the induction of rosacea has been proposed. Staphylococcus epidermidis has been isolated predominantly from the pustules of rosacea patients but not from unaffected skin and may be transported around the face by Demodex mites. These findings raise the possibility that rosacea is fundamentally a bacterial disease resulting from the over-proliferation of Demodex mites living in skin damaged as a result of adverse weathering, age or the production of sebum with an altered fatty acid content. This review surveys the literature relating to the role of Demodex mites and their associated bacteria in the induction and persistence of rosacea and highlights possible therapeutic options. PMID- 22933355 TI - Regio- and chemoselective reduction of nitroarenes and carbonyl compounds over recyclable magnetic ferrite-nickel nanoparticles (Fe(3)O(4)-Ni) by using glycerol as a hydrogen source. AB - Reduction by magnetic nano-Fe(3)O(4)-Ni: a facile, simple and environmentally friendly hydrogen-transfer reaction that takes place over recyclable ferrite nickel magnetic nanoparticles (Fe(3)O(4)-Ni) by using glycerol as hydrogen source allows aromatic amines and alcohols to be synthesized from the precursor nitroarenes and carbonyl compounds. PMID- 22933354 TI - Children with autism show reduced somatosensory response: an MEG study. AB - The neural underpinnings of sensory processing differences in autism remain poorly understood. This prospective magnetoencephalography (MEG) study investigates whether children with autism show atypical cortical activity in the primary somatosensory cortex (S1) in comparison with matched controls. Tactile stimuli were clearly detectable, and painless taps were applied to the distal phalanx of the second (D2) and third (D3) fingers of the right and left hands. Three tactile paradigms were administered: an oddball paradigm (standard taps to D3 at an interstimulus interval (ISI) of 0.33 and deviant taps to D2 with ISI ranging from 1.32 s to 1.64 s); a slow-rate paradigm (D2) with an ISI matching the deviant taps in the oddball paradigm; and a fast-rate paradigm (D2) with an ISI matching the standard taps in the oddball. Study subjects were boys (age 7-11 years) with and without autism disorder. Sensory behavior was quantified using the Sensory Profile questionnaire. Boys with autism exhibited smaller amplitude left hemisphere S1 response to slow and deviant stimuli during the right-hand paradigms. In post-hoc analysis, tactile behavior directly correlated with the amplitude of cortical response. Consequently, the children were re-categorized by degree of parent-report tactile sensitivity. This regrouping created a more robust distinction between the groups with amplitude diminution in the left and right hemispheres and latency prolongation in the right hemisphere in the deviant and slow-rate paradigms for the affected children. This study suggests that children with autism have early differences in somatosensory processing, which likely influence later stages of cortical activity from integration to motor response. PMID- 22933356 TI - Organic switches for surfaces and devices. AB - The pursuit to achieve miniaturization has tantalized researchers across the fields of chemistry, physics, biology, materials science and engineering for over half a century because of its many alluring potential applications. As alternatives to traditional "top-down" manufacturing, "bottom-up" approaches, originating from the (supra)molecular level, have enabled researchers to develop switches which can be manipulated on surfaces at nanoscale dimensions with deft precision using simple external triggers. Once on surfaces, these organic switches have been shown to modulate both the physical and chemical surface properties. In this Progress Report, we shed light on recent advances made in our laboratories towards integrated systems using all-organic switches on a variety of substrates. Design concepts are revealed, as well as the overall impact of all organic switches on the properties of their substrates, while emphasizing the considerable promise and formidable challenges these advanced composite materials pose when it comes to conferring function on them. PMID- 22933357 TI - Cortisol-mediated adhesion of synovial fibroblasts is dependent on the degradation of anandamide and activation of the endocannabinoid system. AB - OBJECTIVE: In rheumatoid arthritis (RA) synovial fluid, levels of the endocannabinoids anandamide (AEA) and 2-arachidonylglycerol are elevated. Since synovial fibroblasts (SFs) possess all of the enzymes necessary for endocannabinoid synthesis, it is likely that these cells contribute significantly to elevated endocannabinoid levels. While glucocorticoids initiate endocannabinoid synthesis in neurons, this study was undertaken to test whether cortisol also regulates endocannabinoid levels in mesenchymal cells such as SFs, and whether this interferes with integrin-mediated adhesion. METHODS: Adhesion was determined in 1-minute intervals over 60 minutes using an xCELLigence system. Slopes from individual treatment groups were averaged and compared to the control. Fatty acid amide hydrolase (FAAH) and cyclooxygenase 2 (COX-2) were detected by immunocytochemistry, and AEA was detected by mass spectrometry. RESULTS: Cortisol increased the adhesion of RASFs and osteoarthritis SFs with a maximum of 200% at both 10(-7) M and 10(-8) M. When cortisol was administered together with either cannabinoid receptor 1 (CB(1) ) antagonist (rimonabant; 100 nM), CB(2) antagonist (JTE907; 100 nM), transient receptor potential vanilloid channel 1 (TRPV-1) antagonist (capsazepine; 1 MUM), FAAH inhibitor, or COX-2 inhibitor, adhesion was reduced below the level in controls. Concomitant inhibition of FAAH and COX-2 reversed these effects. Mass spectrometry revealed the presence of AEA in SFs. CONCLUSION: Our findings indicate that glucocorticoid induced adhesion is dependent on CB(1) /CB(2) /TRPV-1 activation. Since AEA is produced in SFs, this endocannabinoid is the most likely candidate to mediate these effects. Since AEA levels are regulated by COX-2 and FAAH, inhibition of both enzymes along with low-dose glucocorticoids may provide a therapeutic option to maximally boost the endocannabinoid system in RA, with possible beneficial effects. PMID- 22933358 TI - Sixteen novel microsatellite markers developed for Dendrocalamus sinicus (Poaceae), the strongest woody bamboo in the world. AB - PREMISE OF THE STUDY: Microsatellite primers were developed in the strongest and most economically important bamboo species, Dendrocalamus sinicus, to investigate its genetic variability. METHODS AND RESULTS: Using the Fast Isolation by AFLP of Sequences COntaining Repeats (FIASCO) protocol, 16 polymorphic primer sets were identified within 24 individuals from two geographic locations. The number of alleles per locus ranged from two to four, with a mean of 2.6. The observed and expected heterozygosities varied from 0 to 1.000 and from 0.311 to 0.754, respectively. The cross-amplification of the 16 primer pairs was tested in four other Dendrocalamus species, and nine to 13 (56.3-81.3%) primer pairs were successfully amplified. CONCLUSIONS: These markers will be useful for studies on the genetic diversity of D. sinicus, which may facilitate conservation of this species. PMID- 22933359 TI - Development of 35 microsatellite markers from heat stress transcription factors in Populus simonii (Salicaceae). AB - PREMISE OF THE STUDY: Microsatellite markers within regulators of heat stress transcription factors were identified in the Populus trichocarpa genome, and then developed for P. simonii to investigate the genetic diversity of germplasm resources and to further identify favorable alleles significantly associated with stress-resistant traits. METHODS AND RESULTS: Thirty-five novel microsatellite markers were identified from genes controlling heat stress transcription factors in P. simonii using a Sanger sequencing protocol. Polymorphisms in 48 individuals from 16 populations of P. simonii revealed that the number of alleles per locus ranged from two to nine with an average of 4.6; the observed heterozygosity and expected heterozygosity per locus varied from 0.143 to 0.857 and from 0.257 to 0.948, respectively. CONCLUSIONS: The new polymorphic markers developed during this study will facilitate the construction of genetic linkage maps and will aid in marker-assisted breeding of a new germplasm with desirable abiotic stress resistance in Populus species. PMID- 22933360 TI - Characterization of novel microsatellite markers for Eschscholzia californica (Papaveraceae), an invasive species in central Chile. AB - PREMISE OF THE STUDY: We isolated and characterized microsatellite markers for the California poppy, Eschscholzia californica, which is an invasive species in central Chile. METHODS AND RESULTS: A total of eight polymorphic and six monomorphic loci were developed for the species. Between one and 12 alleles were observed per locus. Polymorphic loci showed heterozygosity ranging from 0 to 0.875 in a sample of 96 individuals obtained from four populations. Only one locus showed significant departures from Hardy-Weinberg equilibrium at all sites. CONCLUSIONS: The successful microsatellite amplification makes this set of primers an important tool for understanding the recent and future patterns of invasion and adaptation of E. californica into the new Chilean geographic area. The variation detected is currently being used in a more inclusive study that assesses population expansion in central Chile. PMID- 22933361 TI - Microsatellite markers for population studies of Phytophthora megakarya (Pythiaceae), a cacao pathogen in Africa. AB - PREMISE OF THE STUDY: Phytophthora megakarya is the agent of black pod disease of cacao and is the main pathogen of this crop in Africa. Population genetic studies are required to investigate how this pathogen emerged. To this end, we developed 12 novel polymorphic microsatellite markers for P. megakarya. METHODS AND RESULTS: Microsatellite sequences were obtained by pyrosequencing of multiplex enriched libraries. Candidate loci with di- or trinucleotide motifs were selected, and primer pairs were tested with nine P. megakarya isolates. The 12 most polymorphic and unambiguous loci were selected to develop three multiplex PCR pools. The total number of alleles varied from two to nine, depending on loci, and higher than expected heterozygosity was observed. CONCLUSIONS: These markers were used for population genetic studies of P. megakarya in Cameroon and for comparison with reference strains from West Africa. This is the first time that microsatellite markers have been developed for P. megakarya. PMID- 22933362 TI - A hierarchical order within protein structures underlies large separations between strands in beta-sheets. AB - Protein beta-sheets often involve nonlocal interactions between parts of the polypeptide chain that are separated by hundreds of residues, raising the question of how these nonlocal contacts form. A recent study of the smallest beta sheets found that their formation was not driven by signals hidden in the primary sequence. Instead, the strands in these sheets were either local in sequence, or, when separated by large sequential distances, the intervening residues were found to fold into compact modules that anchored distant parts of the chain in close spatial proximity. Here, we examine larger beta-sheets to investigate the extensibility of this principle. From an analysis of the beta-sheets in a nonredundant protein dataset, we find that a highly ordered hierarchical relationship exists in the intervening structure between nonlocal beta-strands. This observation is almost universal: virtually all beta-sheets, no matter their complexity, appear to adopt an antiparallel model to manage the nonlocal aspects of their assembly, one where the chain, having left the vicinity of an unfinished beta-sheet, retraces its steps via the same route to complete the initial sheet. Exceptions typically involve unstructured regions at chain termini. Moreover, an analysis of the residues involved in nonlocal crossstrand interactions did not produce any evidence of a signal hidden in the sequence that might direct long range interactions. These results build on those reported for the smallest sheets, suggesting that sheet formation is either local in sequence or local in space following prior folding events that anchor disparate parts of the chain in close proximity. PMID- 22933363 TI - Two-level resampling as a novel method for the calculation of the expected value of sample information in economic trials. AB - It has already been pointed out that the bootstrap can be used to calculate the expected value of perfect information (EVPI) when individual-level data from a randomized controlled trial (RCT) is at hand. However, as mentioned by others, it is not clear if and how such a method can be extended to calculate the expected value of sample information (EVSI). In this article, we provide a nonparametric definition for EVPI and EVSI, which is based on considering the entire population distribution as the uncertain entity for which the current RCT provides partial information. This enables a theoretical justification for using the bootstrap for EVPI calculation and allows us to propose a two-level resampling method for EVSI calculation. What is considered as the sampling unit in this algorithm can range from the individual level net benefits to the full panel of the RCT data for an individual, enabling the analyst to decide on a trade-off between computational efficiency and comprehensiveness in value of information analysis. As such, we argue that this method, in addition to being consistent with the popular bootstrap method of RCT-based economic evaluations, is a flexible approach for EVPI and EVSI calculations. PMID- 22933365 TI - Reactions of propargyl compounds containing a cyclobutyl group induced by a ruthenium complex. AB - Reactions of [Ru]Cl ([Ru] = {Cp(PPh(3))(2)Ru}; Cp = cyclopentadienyl) with three alkynyl compounds, 1, 5, and 8, each containing a cyclobutyl group, are explored. For 1, the reaction gives the vinylidene complex 2, with a cyclobutylidene group, through dehydration at C(delta)H and C(gamma)OH. With an additional methylene group, compound 5 reacts with [Ru]Cl to afford the cyclic oxacarbene complex 6. The reaction proceeds via a vinylidene intermediate followed by an intramolecular cyclization reaction through nucleophilic addition of the hydroxy group onto C(alpha) of the vinylidene ligand. Deprotonation of 2 with NaOMe produces the acetylide complex 3 and alkylations of 3 by allyl iodide, methyl iodide, and ethyl iodoacetate generate 4 a-c, respectively, each with a stable cyclobutyl group. Dehydration of 1 is catalyzed by the cationic ruthenium acetonitrile complex at 70 degrees C to form the 1,3-enyne 7. The epoxidation reaction of the double bond of 7 yields oxirane 8. Ring expansion of the cyclobutyl group of 8 is readily induced by the acidic salt NH(4)PF(6) to afford the 2-ethynyl-substituted cyclopentanone 9. The same ring expansion is also seen in the reaction of [Ru]Cl with 8 in CH(2)Cl(2), affording the vinylidene complex 10, which can also be obtained from 9 and [Ru]Cl. However, in MeOH, the same reaction of [Ru]Cl with 8 affords the bicyclic oxacarbene complex 12 a through an additional cyclization reaction. Transformation of 10 into 12 a is readily achieved in MeOH/HBF(4), but, in MeOH alone, acetylide complex 11 is produced from 10. In the absence of MeOH, cyclization of 10, induced by HBF(4), is followed by fluorination to afford complex 13. Crystal structures of 6 and 12 a' were determined by single-crystal diffraction analysis. PMID- 22933364 TI - Validation of the Pediatric Automated Neuropsychological Assessment Metrics in childhood-onset systemic lupus erythematosus. AB - OBJECTIVE: To evaluate the reproducibility and validity of the Pediatric Automated Neuropsychological Assessment Metrics (Ped-ANAM) when used in childhood onset systemic lupus erythematosus (cSLE). METHODS: Forty children with cSLE and 40 matched controls were followed for up to 18 months. Formal neuropsychological testing at baseline was repeated after 18 months of followup; overall cognitive performance and domain-specific cognition (attention, working memory, processing speed, and visuoconstructional ability) were measured and categorized as normal cognition, mild/moderate, or moderate/severe impairment. The 10 Ped-ANAM subtests were completed every 6 months and twice at baseline. Ped-ANAM performance was based on accuracy (AC), mean time to correct response (MNc), throughput, and coefficient of variation of the time required for a correct response (CVc) as a measure of response consistency. RESULTS: Particularly, MNc scores demonstrated moderate to substantial reproducibility (intraclass correlation coefficients 0.47 0.80). Means of select Ped-ANAM scores (MNc, AC, CVc) differed significantly between children with different levels of cognitive performance and allowed for the detection of moderate or severe cognitive impairment with 100% sensitivity and 86% specificity. Six Ped-ANAM subtests significantly correlated with the change in overall cognitive function in cSLE (baseline versus 18 months; Spearman's correlation coefficient >0.4, P < 0.05; n = 24). CONCLUSION: The Ped ANAM has moderate to substantial reproducibility, criterion and construct validity, and may be responsive to change in cSLE. Additional research is required to confirm the outstanding accuracy of the Ped-ANAM in identifying cognitive impairment, as well as its usefulness in detecting clinically relevant changes in cognition over time. PMID- 22933366 TI - In situ labeling and imaging of endogenous neural stem cell proliferation and migration. AB - Endogenous neural stem cells (eNSCs) reside in defined regions of the adult brain and have the potential to generate new brain cells, including neurons. Stimulation of adult neurogenesis presents an enormous potential for regenerative therapies in the central nervous system. However, the methods used to monitor the proliferation, migration, differentiation, and functional integration of eNSCs and their progeny are often invasive and limited in studying dynamic processes. To overcome this limitation, novel techniques and contrast mechanisms for in vivo imaging of neurogenesis have recently been developed and successfully applied. In vivo labeling of endogenous neuronal progenitor cells in situ with contrast agents or tracers enables longitudinal visualization of their proliferation and/or migration. Labeling of these cells with magnetic nanoparticles has proven to be very useful for tracking neuroblast migration with MRI. Alternatively, genetic labeling using reporter gene technology has been demonstrated for optical and MR imaging, leading to the development of powerful tools for in vivo optical imaging of neurogenesis. More recently, the iron storage protein ferritin has been used as an endogenously produced MRI contrast agent to monitor neuroblast migration. The use of specific promoters for neuronal progenitor cell imaging increases the specificity for visualizing neurogenesis. Further improvements of detection sensitivity and neurogenesis-specific contrast are nevertheless required for each of these imaging techniques to further improve the already high utility of this toolbox for preclinical neurogenesis research. PMID- 22933367 TI - Pharmacokinetic interactions among major bioactive components in Radix Scutellariae via metabolic competition. AB - Baicalein (B), wogonin (W) and oroxylin A (OA) are major components in Radix Scutellariae with similar pharmacokinetic properties. Due to the co-presence of these three flavones in herbal formulations for Radix Scutellariae, they are likely consumed together. The aim of this study is to investigate whether the pharmacokinetics of individual flavones is influenced by each other and the underlying mechanism of the interaction. Various systems were utilized in the current study including a rat in vivo study, a Caco-2 cell monolayer model and a rat in situ single-pass intestinal perfusion as well as in vitro enzymatic kinetics studies. The B, W and OA given singly as well as in a mixture were administered and the corresponding pharmacokinetic parameters were calculated and compared. After co-administration of the three flavones to rats, OA absorption increased significantly in comparison with when OA was administered alone. Mechanistic studies on the Caco-2 cell monolayer and rat in situ single-pass intestinal perfusion models revealed that co-administration of B, W and OA could significantly enhance their absorption and decrease the extent of phase II metabolism. Further in vitro enzymatic study and a transport study in transfected MDCK cells revealed that metabolic competition rather than membrane transporters might contribute to the pharmacokinetic interactions. The co-presence of multiple active components would result in metabolic interactions, which may induce further changes in pharmacodynamics. PMID- 22933368 TI - Inhaled Cissampelos sympodialis down-regulates airway allergic reaction by reducing lung CD3+ T cells. AB - Cissampelos sympodialis Eichl. (Menispermaceae) root infusion is used in Northeast Brazil to treat allergic asthma. We have previously shown that oral use of the plant extract reduces eosinophil infiltration into the lung of ovalbumin (OVA)- sensitized mice. However, drugs taken by inhalation route to treat asthma achieve better outcomes. Thereby, in this study, we evaluated the inhaled C. sympodialis alcoholic extract as a therapeutic treatment in OVA-sensitized BALB/c mice. The parameters which were analyzed consisted of leukocyte recruitment to the airway cavity, tissue remodeling and cell profile. The inhaled extract inhibited mainly eosinophil recruitment to the pleural cavity, bronchoalveolar lavage and peripheral blood. This treatment reduced the OVA-specific IgE serum titer and leukocyte infiltration in the peribronchiolar and pulmonary perivascular areas as well as mucus production. In addition, we also tested isolated alkaloids from the plant extract. The flow cytometric analysis showed that methylwarifteine (MW) and, mainly, the inhaled extract reduced the number of CD3+T cells and eosinophil-like cells. Therefore, inhaled C. sympodialis extract and MW lead to down-regulation of inflammatory cell infiltration with remarkable decrease in the number of T cells in an experimental model of respiratory allergy, suggesting that the plant can be delivered via inhalation route to treat allergic asthma. PMID- 22933369 TI - Impact of tricyclazole and azoxystrobin on growth, sporulation and secondary infection of the rice blast fungus, Magnaporthe oryzae. AB - BACKGROUND: Rice blast, caused by Magnaporthe oryzae B. Couch sp. nov., is one of the most destructive rice diseases worldwide, causing substantial yield losses every year. In Italy, its management is based mainly on the use of two fungicides, azoxystrobin and tricyclazole, that restrain the disease progress. The aim of this study was to investigate and compare the inhibitory effects of the two fungicides on the growth, sporulation and secondary infection of M. oryzae. RESULTS: Magnaporthe oryzae mycelium growth was inhibited at low concentrations of azoxystrobin and relatively high concentrations of tricyclazole, while sporulation was more sensitive to both fungicides and was affected at similarly low doses. Furthermore, infection efficiency of conidia obtained from mycelia exposed to tricyclazole was affected to a higher extent than for conidia produced on azoxystrobin-amended media, even though germination of such conidia was reduced after azoxystrobin treatment. CONCLUSIONS: This study presents for the first time detailed azoxystrobin and tricyclazole growth response curves for M. oryzae mycelium growth and sporulation. Furthermore, high efficacy of tricyclazole towards inhibition of sporulation and secondary infection indicates an additional possible mode of action of this fungicide that is different from inhibition of melanin biosynthesis. PMID- 22933371 TI - Low fertility increases descendant socioeconomic position but reduces long-term fitness in a modern post-industrial society. AB - Adaptive accounts of modern low human fertility argue that small family size maximizes the inheritance of socioeconomic resources across generations and may consequently increase long-term fitness. This study explores the long-term impacts of fertility and socioeconomic position (SEP) on multiple dimensions of descendant success in a unique Swedish cohort of 14 000 individuals born during 1915-1929. We show that low fertility and high SEP predict increased descendant socioeconomic success across four generations. Furthermore, these effects are multiplicative, with the greatest benefits of low fertility observed when SEP is high. Low fertility and high SEP do not, however, predict increased descendant reproductive success. Our results are therefore consistent with the idea that modern fertility limitation represents a strategic response to the local costs of rearing socioeconomically competitive offspring, but contradict adaptive models suggesting that it maximizes long-term fitness. This indicates a conflict in modern societies between behaviours promoting socioeconomic versus biological success. This study also makes a methodological contribution, demonstrating that the number of offspring strongly predicts long-term fitness and thereby validating use of fertility data to estimate current selective pressures in modern populations. Finally, our findings highlight that differences in fertility and SEP can have important long-term effects on the persistence of social inequalities across generations. PMID- 22933372 TI - Neighbouring chimpanzee communities show different preferences in social grooming behaviour. AB - Grooming handclasp (GHC) behaviour was originally advocated as the first evidence of social culture in chimpanzees owing to the finding that some populations engaged in the behaviour and others do not. To date, however, the validity of this claim and the extent to which this social behaviour varies between groups is unclear. Here, we measured (i) variation, (ii) durability and (iii) expansion of the GHC behaviour in four chimpanzee communities that do not systematically differ in their genetic backgrounds and live in similar ecological environments. Ninety chimpanzees were studied for a total of 1029 h; 1394 GHC bouts were observed between 2010 and 2012. Critically, GHC style (defined by points of bodily contact) could be systematically linked to the chimpanzee's group identity, showed temporal consistency both within and between groups, and could not be accounted for by the arm-length differential between partners. GHC has been part of the behavioural repertoire of the chimpanzees under study for more than 9 years (surpassing durability criterion) and spread across generations (surpassing expansion criterion). These results strongly indicate that chimpanzees' social behaviour is not only motivated by innate predispositions and individual inclinations, but may also be partly cultural in nature. PMID- 22933370 TI - Evolutionary medicine: its scope, interest and potential. AB - This review is aimed at readers seeking an introductory overview, teaching courses and interested in visionary ideas. It first describes the range of topics covered by evolutionary medicine, which include human genetic variation, mismatches to modernity, reproductive medicine, degenerative disease, host pathogen interactions and insights from comparisons with other species. It then discusses priorities for translational research, basic research and health management. Its conclusions are that evolutionary thinking should not displace other approaches to medical science, such as molecular medicine and cell and developmental biology, but that evolutionary insights can combine with and complement established approaches to reduce suffering and save lives. Because we are on the cusp of so much new research and innovative insights, it is hard to estimate how much impact evolutionary thinking will have on medicine, but it is already clear that its potential is enormous. PMID- 22933373 TI - Endosymbiotic flexibility associates with environmental sensitivity in scleractinian corals. AB - Flexibility in biological systems is seen as an important driver of macro ecosystem function and stability. Spatially constrained endosymbiotic settings, however, are less studied, although environmental thresholds of symbiotic corals are linked to the function of their endosymbiotic dinoflagellate communities. Symbiotic flexibility is a hypothesized mechanism that corals may exploit to adapt to climate change. This study explores the flexibility of the coral Symbiodinium symbiosis through quantification of Symbiodinium ITS2 sequence assemblages in a range of coral species and genera. Sequence assemblages are expressed as an index of flexibility incorporating phylogenetic divergence and relative abundance of Symbiodinium sequences recovered from the host. This comparative analysis reveals profound differences in the flexibility of corals for Symbiodinium, thereby classifying corals as generalists or specifists. Generalists such as Acropora and Pocillopora exhibit high intra- and inter species flexibility in their Symbiodinium assemblages and are some of the most environmentally sensitive corals. Conversely, specifists such as massive Porites colonies exhibit low flexibility, harbour taxonomically narrow Symbiodinium assemblages, and are environmentally resistant corals. Collectively, these findings challenge the paradigm that symbiotic flexibility enhances holobiont resilience. This underscores the need for a deeper examination of the extent and duration of the functional benefits associated with endosymbiotic diversity and flexibility under environmental stress. PMID- 22933374 TI - Altitude acts as an environmental filter on phylogenetic composition, traits and diversity in bee communities. AB - Knowledge about the phylogeny and ecology of communities along environmental gradients helps to disentangle the role of competition-driven processes and environmental filtering for community assembly. In this study, we evaluated patterns in species richness, phylogenetic structure and life-history traits of bee communities along altitudinal gradients in the Alps, Germany. We found a linear decline in species richness and abundance but increasing phylogenetic clustering in communities with increasing altitude. The proportion of social- and ground-nesting species, as well as mean body size and altitudinal range of bee communities, increased with increasing altitude, whereas the mean geographical distribution decreased. Our results suggest that community assembly at high altitudes is dominated by environmental filtering effects, whereas the relative importance of competition increases at low altitudes. We conclude that inherent phylogenetic and ecological species attributes at high altitudes pose a threat for less competitive alpine specialists with ongoing climate change. PMID- 22933375 TI - Development of lateralization of the magnetic compass in a migratory bird. AB - The magnetic compass of a migratory bird, the European robin (Erithacus rubecula), was shown to be lateralized in favour of the right eye/left brain hemisphere. However, this seems to be a property of the avian magnetic compass that is not present from the beginning, but develops only as the birds grow older. During first migration in autumn, juvenile robins can orient by their magnetic compass with their right as well as with their left eye. In the following spring, however, the magnetic compass is already lateralized, but this lateralization is still flexible: it could be removed by covering the right eye for 6 h. During the following autumn migration, the lateralization becomes more strongly fixed, with a 6 h occlusion of the right eye no longer having an effect. This change from a bilateral to a lateralized magnetic compass appears to be a maturation process, the first such case known so far in birds. Because both eyes mediate identical information about the geomagnetic field, brain asymmetry for the magnetic compass could increase efficiency by setting the other hemisphere free for other processes. PMID- 22933376 TI - Stable isotopes provide independent support for the use of mesowear variables for inferring diets in African antelopes. AB - We examine the relationship between mesowear variables and carbon and nitrogen isotopes in 16 species of African antelope (Mammalia: Bovidae). We show significant differences in carbon and nitrogen isotope values between individuals exhibiting sharp versus round cusps, and high versus low occlusal relief. We show significant correlations between mesowear variables and both carbon and nitrogen isotopes. We find significant correlations between mesowear score and nitrogen, but not carbon isotopes. Finally, we find no significant correlations between hypsodonty index and either isotope examined. Our results provide strong support for the use of mesowear variables in palaeodietary reconstructions of antelopes. Our results further suggest that for the antelopes examined here, mesowear signals are a direct result of diet, while hyposodonty may be the result of phylogenetic legacy. PMID- 22933377 TI - Giant electrostriction in Gd-doped ceria. AB - Gd-doped CeO(2) exhibits an anomalously large electrostriction effect generating stress that can reach 500 MPa. In situ XANES measurements indicate that the stress develops in response to the rearrangement of cerium-oxygen vacancy pairs. This mechanism is fundamentally different from that of materials currently in use and suggests that Gd-doped ceria is a representative of a new family of high performance electromechanical materials. PMID- 22933378 TI - Alterations in resting-state regional cerebral blood flow demonstrate ongoing pain in osteoarthritis: An arterial spin-labeled magnetic resonance imaging study. AB - OBJECTIVE: Increasing evidence suggests a central nervous system (CNS) component underpinning persistent pain disease states. This study was undertaken to determine regional cerebral blood flow (rCBF) changes representing ongoing pain experienced by patients with painful osteoarthritis (OA) of the carpometacarpal (CMC) joint and to examine rCBF variability across sessions. We used pulsed continuous arterial spin labeling (pCASL), a perfusion magnetic resonance imaging (MRI) technique. METHODS: The study included 16 patients with CMC OA and 17 matched controls. Two pCASL scans and numerical rating scale (NRS) estimates of ongoing pain were acquired in each of two identical sessions. Voxelwise general linear model analyses were performed to determine rCBF differences between OA and control groups, rCBF differences between sessions within each group, and whether sessionwise rCBF differences were related to variability in perceived ongoing pain. RESULTS: In the OA group, rCBF increases representing ongoing pain were identified in the primary and secondary somatosensory, insula, and cingulate cortices; thalamus; amygdala; hippocampus; and dorsal midbrain/pontine tegmentum, including the periaqueductal gray/nucleus cuneiformis. Sessionwise rCBF differences in the OA group in the postcentral, rostral/subgenual cingulate, mid/anterior insula, prefrontal, and premotor cortices were related to changes in perceived ongoing pain. No significant sessionwise rCBF differences were observed in controls. CONCLUSION: This is the first quantitative endogenous perfusion MRI study of the cerebral representation of ongoing, persistent pain due to OA. Observed rCBF changes potentially indicate dysregulated CNS appraisal and modulation of pain, most likely the maladaptive neuroplastic sequelae of living with painful OA. Understanding the neural basis of ongoing pain is likely to be important in developing novel treatment strategies. PMID- 22933379 TI - How maltose influences structural changes to bind to maltose-binding protein: results from umbrella sampling simulation. AB - A well-studied periplasmic-binding protein involved in the abstraction of maltose is maltose-binding protein (MBP), which undergoes a ligand-induced conformational transition from an open (ligand-free) to a closed (ligand-bound) state. Umbrella sampling simulations have been us to estimate the free energy of binding of maltose to MBP and to trace the potential of mean force of the unbinding event using the center-of-mass distance between the protein and ligand as the reaction coordinate. The free energy thus obtained compares nicely with the experimentally measured value justifying our theoretical basis. Measurement of the domain angle (N-terminal-domain - hinge - C-terminal-domain) along the unbinding pathway established the existence of three different states. Starting from a closed state, the protein shifts to an open conformation during the initial unbinding event of the ligand then resides in a semi-open conformation and later resides predominantly in an open-state. These transitions along the ligand unbinding pathway have been captured in greater depth using principal component analysis. It is proposed that in mixed-model, both conformational selection and an induced fit mechanism combine to the ligand recognition process in MBP. PMID- 22933380 TI - Psycho-educational interventions for melanoma survivors: a systematic review. AB - OBJECTIVE: To systematically review psycho-educational interventions developed for melanoma survivors. METHODS: Electronic databases Medline, PsycINFO, Embase, and CINAHL were systematically searched using key words and subject headings for articles describing educational or psychological interventions designed specifically for people affected by melanoma. RESULTS: Twenty-seven articles, generated by 16 unique interventions, were included for detailed review. Overall, educational interventions showed increased patient satisfaction with clinical care and information provision, as well as increased frequency of skin self examination, although accuracy and thoroughness of skin examination were seldom reported. Participation in psychological interventions was associated with decreases in anxiety, health-related distress, and melanoma recurrence rates, as well as positive changes in coping with illness. Programs, when implemented as part of routine clinical care, were found to be cost-effective. CONCLUSIONS: Interventions in this field vary widely, limiting the identification of 'active ingredients' for psychological or behavioral change. Future intervention studies should ensure sufficient information is provided to support program replication and comprehensive assessment of program outcomes. PMID- 22933381 TI - Fabrication of porous scaffolds by three-dimensional plotting of a pasty calcium phosphate bone cement under mild conditions. AB - The major advantage of hydroxyapatite (HA)-forming calcium phosphate cements (CPCs) used as bone replacement materials is their setting under physiological conditions without the necessity for thermal treatment that allows the incorporation of biological factors. In the present study, we have combined the biocompatible consolidation of CPCs with the potential of rapid prototyping (RP) techniques to generate calcium phosphate-based scaffolds with defined inner and outer morphology. We demonstrate the application of the RP technique three dimensional (3D) plotting for the fabrication of HA cement scaffolds. This was realized by utilizing a paste-like CPC (P-CPC) which is stable as a malleable paste and whose setting reaction is initiated only after contact with aqueous solutions. The P-CPC showed good processability in the 3D plotting process and allowed the fabrication of stable 3D structures of different geometries with adequate mechanical stability and compressive strength. The cytocompatibility of the plotted P-CPC scaffolds was demonstrated in a cell culture experiment with human mesenchymal stem cells. The mild conditions during 3D plotting and post processing and the realization of the whole procedure under sterile conditions make this approach highly attractive for fabrication of individualized implants with respect to patient-specific requirements by simultaneous plotting of biological components. PMID- 22933383 TI - Thermoresponsive polymer induced sweating surfaces as an efficient way to passively cool buildings. AB - Buildings can be effectively cooled by a bioinspired sweating-like action based on thermoresponsive hydrogels (PNIPAM), which press out their stored water when exceeding the lower critical solution temperature. The surface temperature is reduced by 15 degrees C compared to that of a conventional hydrogel (pHEMA) and by 25 degrees C compared to the bare ground. PMID- 22933382 TI - Nanoparticle-mediated photothermal therapy: a comparative study of heating for different particle types. AB - INTRODUCTION: Near-infrared (NIR) absorbing plasmonic nanoparticles enhance photothermal therapy of tumors. In this procedure, systemically delivered gold nanoparticles preferentially accumulate at the tumor site and when irradiated using laser light, produce localized heat sufficient to damage tumor cells. Gold nanoshells and nanorods have been widely studied for this purpose, and while both exhibit strong NIR absorption, their overall absorption and scattering properties differ widely due to their geometry. In this paper, we compared the photothermal response of both nanoparticle types including the heat generation and photothermal efficiency. METHODS: Tissue simulating phantoms, with varying concentrations of gold nanoparticles, were irradiated with a near-infrared diode laser while concurrently monitoring the surface temperature with an infrared camera. We calculated nanoshell and nanorod optical properties using the Mie solution and the discrete dipole approximation, respectively. In addition, we measured the heat generation of nanoshells and nanorods at the same optical density to determine the photothermal transduction efficiency for both nanoparticle types. RESULTS: We found that the gold nanoshells produced more heat than gold nanorods at equivalent number densities (# of nanoparticles/ml), whereas the nanorods generated more heat than nanoshells at equivalent extinction values at the irradiance wavelength. To reach an equivalent heat generation, we found that it was necessary to have ~36* more nanorods than nanoshells. However, the gold nanorods were found to have two times the photothermal transduction efficiency than the gold nanoshells. CONCLUSION: For the nanoparticles tested, the nanoshells generated more heat, per nanoparticle, than nanorods, primarily due to their overall larger geometric cross-section. Conversely, we found that the gold nanorods had a higher photothermal efficiency than the gold nanoshells. In conclusion, the ideal choice of plasmonic nanoparticle requires not only per particle efficiency, but also the in vivo particle targeting ability under study. PMID- 22933384 TI - Effect of distribution and concentration of topically applied neonicotinoid insecticides in buffalograss, Buchloe dactyloides, leaf tissues on the differential mortality of Blissus occiduus under field conditions. AB - BACKGROUND: Neonicotinoid insecticides are generally efficacious against many turfgrass pests, including several important phloem-feeding insects. However, inconsistencies in control of western chinch bugs, Blissus occiduus, have been documented in field efficacy studies. This research investigated the efficacy of three neonicotinoid insecticides (clothianidin, imidacloprid and thiamethoxam) against B. occiduus in buffalograss under field conditions and detected statistically significant differences in B. occiduus numbers among treatments. A subsequent study documented the relative quantity and degradation rate of these insecticides in buffalograss systemic leaf tissues, using HPLC. RESULTS: Neonicotinoid insecticides initially provided significant reductions in B. occiduus numbers, but mortality diminished over the course of the field studies. Furthermore, while all three neonicotinoids were present in the assayed buffalograss leaf tissues, imidacloprid concentrations were significantly higher than those of clothianidin and thiamethoxam. Over the course of the 28 day study, thiamethoxam concentrations declined 700-fold, whereas imidacloprid and clothianidin declined only 70-fold and 60-fold respectively. CONCLUSIONS: Field studies continued to verify inconsistencies in B. occiduus control with neonicotinoid insecticides. This is the first study to document the relative concentrations of topically applied neonicotinoid insecticides in buffalograss systemic leaf tissues. PMID- 22933385 TI - Sanguisorbae radix protects against 6-hydroxydopamine-induced neurotoxicity by regulating NADPH oxidase and NF-E2-related factor-2/heme oxygenase-1 expressions. AB - 6-Hydroxydopamine (6-OHDA) produces neuronal cell damage by generating reactive oxygen species (ROS). The major mechanisms of protection against ROS-induced stress are inhibiting expression of ROS generating genes such as NADPH oxidase (NOX) and increasing expression of endogenous antioxidant genes such as heme oxygenase-1 (HO-1). This study investigated whether a standardized Sanguisorbae Radix extract (SRE), a medical herb commonly used in Asian traditional medicine, has a protective effect on 6-OHDA-induced cell toxicity by regulating ROS in SH SY5Y cells. SRE at 10 and 50 ug/mL significantly reduced 6-OHDA-induced cell damage dose dependently in the 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide assay and by Hoechst 33342 staining. SRE increased the B-cell lymphoma 2 (Bcl-2)/Bcl-2-associated X ratio and decreased cytochrome C release and caspase-3 activity. SRE also abolished 6-OHDA-induced ROS by inhibiting NOX expression and by inducing HO-1 expression via NF-E2-related factor-2 activation. Taken together, these results demonstrate that SRE has protective effects against 6-OHDA-induced cell death by regulating ROS in SH-SY5Y cells. PMID- 22933386 TI - Collagen antibody-induced arthritis evokes persistent pain with spinal glial involvement and transient prostaglandin dependency. AB - OBJECTIVE: Pain is one of the most debilitating symptoms reported by rheumatoid arthritis (RA) patients. While the collagen antibody-induced arthritis (CAIA) model is used for studying the effector phase of RA pathologic progression, it has not been evaluated as a model for studies of pain. Thus, this study was undertaken to examine pain-like behavior induced by anticollagen antibodies and to assess the effect of currently prescribed analgesics for RA. In addition, the involvement of spinal glia in antibody-induced pain was explored. METHODS: CAIA was induced in mice by intravenous injection of a collagen antibody cocktail, followed by intraperitoneal injection of lipopolysaccharide. Disease severity was assessed by visual and histologic examination. Pain-like behavior and the antinociceptive effect of diclofenac, buprenorphine, gabapentin, pentoxifylline, and JNK-interacting protein 1 were examined in mechanical stimulation experiments. Spinal astrocyte and microglia reactivity were investigated by real time polymerase chain reaction and immunohistochemistry. RESULTS: Following the induction of CAIA, mice developed transient joint inflammation. In contrast, pain like behavior was observed prior to, and outlasted, the visual signs of arthritis. Whereas gabapentin and buprenorphine attenuated mechanical hypersensitivity during both the inflammatory and postinflammatory phases of arthritis, diclofenac was antinociceptive only during the inflammatory phase. Spinal astrocytes and microglia displayed time-dependent signs of activation, and inhibition of glial activity reversed CAIA-induced mechanical hypersensitivity. CONCLUSION: CAIA represents a multifaceted model for studies exploring the mechanisms of pain induced by inflammation in the articular joint. Our findings of a time-dependent prostaglandin and spinal glial contribution to antibody induced pain highlight the importance of using appropriate disease models to assess joint-related pain. PMID- 22933389 TI - Response to "Compliance and efficacy of titratable thermoplastic versus custom mandibular advancement devices" from Friedman M et al. PMID- 22933388 TI - Medical harm and risk. PMID- 22933387 TI - Analgesic use and the risk of hearing loss in women. AB - Use of analgesics is common and is associated with increased risk of hearing loss in men; however, the relation has not been examined prospectively in women. The authors prospectively examined the relation between frequency of aspirin, ibuprofen, and acetaminophen use and risk of hearing loss among 62,261 women aged 31-48 years at baseline (1995) in Nurses' Health Study II. The outcome was self reported hearing loss (n = 10,012), and the follow-up period was 1995-2009. Cox proportional hazards regression was used to adjust for potential confounders. During 764,247 person-years of follow-up, ibuprofen use and acetaminophen use were independently associated with increased risk of hearing loss, but aspirin use was not. For ibuprofen, the multivariate-adjusted relative risk of hearing loss was 1.13 (95% confidence interval (CI): 1.06, 1.19) for use 2-3 days/week, 1.21 (95% CI: 1.11, 1.32) for use 4-5 days/week, and 1.24 (95% CI: 1.14, 1.35) for use >=6 days/week (P-trend < 0.0001), compared with use less than once per week. For acetaminophen, the corresponding relative risks were 1.11 (95% CI: 1.02, 1.19), 1.21 (95% CI: 1.07, 1.37), and 1.08 (95% CI: 0.95, 1.22), respectively (P-trend = 0.0007). In this study, use of ibuprofen or acetaminophen (but not aspirin) 2 or more days per week was associated with an increased risk of hearing loss in women. PMID- 22933391 TI - Changes in symptom severity, schemas and modes in heterogeneous psychiatric patient groups following short-term schema cognitive-behavioural group therapy: a naturalistic pre-treatment and post-treatment design in an outpatient clinic. AB - Schema therapy has proven to be an effective treatment for patients with borderline personality disorder. However, little is known of its merits in other psychiatric (personality) disorders. OBJECTIVE: This study investigated whether schema therapy in a group setting (group schema cognitive-behavioural therapy [SCBT-g]) was associated with changes in symptom and schema and mode severity. Furthermore, the aim was to search for baseline predictors and possible mediators of treatment outcome. DESIGN AND METHOD: Sixty-three heterogeneous psychiatric outpatients who attended the SCBT-g were included as participants. In this naturalistic pre-treatment and post-treatment design, data were available on the Symptom Checklist 90, the Schema Questionnaire and the Young-Atkinson Mode Inventory. RESULTS: All outcome measurements showed changes with moderate to high effect sizes, with 53.2% of the patients showing a significant reduction in severity of psychiatric symptoms and schemas and modes. Higher pre-treatment levels of the schema domain Other Directedness predicted greater symptom reduction. Pre-treatment to mid-treatment changes in schema severity predicted subsequent symptom improvement, but change in symptoms and schemas proved to be strongly correlated. CONCLUSIONS: In this naturalistic study, SCBT-g was associated with reduced symptom and schema and mode severity in more than half of the psychiatric outpatients. Furthermore, the results suggest that changes in schemas and symptomatology mutually reinforce each other. KEY PRACTITIONER MESSAGE: Over 50% of ambulatory patients show clinical improvement after treatment in a short-term schema therapy group. Other Directedness seems to be a predictor of schema group therapy success. More randomized controlled trial studies and prediction and mediation studies on (short-term) schema group therapy are sorely needed. PMID- 22933392 TI - Wnt signalling in an in vitro niche model for conjunctival progenitor cells. AB - Mimicking an environment in vitro that is more similar to the stem cell niche in vivo, by co-culture of mitotically active conjunctival fibroblasts (HCF) with human conjunctival epithelial cells (HCECs), improves the maintenance of epithelial cells with progenitor cell characteristics during in vitro expansion. However, little is known about the pathways controlling the fate of the epithelial progenitor cells during in vitro culture. In this study, differences in gene expression between this in vitro 'niche' model and standard culture conditions, in which growth-arrested 3 T3 feeder cells and fetal calf serum are used, were explored using a genome level microarray platform, quantitative (q)RT PCR and western blot. The microarray analysis revealed significant alterations of biological processes involved in cell proliferation, differentiation and cell death. The analysis of stem cell-related pathways indicated changes in expression of genes involved in the Wnt signalling pathway, and further investigation by qPCR revealed significant downregulation of the Wnt ligands Wnt3, Wnt4, Wnt7B and Wnt10A, Wnt receptor proteins FZD1, LRP5, LRP6, beta-catenin and TCF7L1 and important Wnt target genes, such as CCND1, also confirmed by western blot and immunocytochemistry. The results indicate that epithelial cell expansion in the HCEC-HCF co-culture system is accompanied by significant changes in expression of genes involved in the Wnt signalling pathway. This altered pathway activation might be involved in the enhanced maintenance of epithelial progenitor cells in this in vitro 'niche' model. PMID- 22933393 TI - Surface anatomy of the pulmonary fissures determined by high-resolution computed tomography. AB - The aim of our study was to describe the surface anatomy of the interlobar fissures using volumetric thin-section high-resolution computed tomography (HRCT). Retrospective assessment of HRCT examinations of 250 patients was performed. The localization of the oblique fissures was marked at three sites: posteriorly at its most superior medial limit, laterally in the midaxillary line, and inferiorly at the junction of the middle and lateral thirds of the hemithorax; posteriorly and laterally, this was to the nearest rib whilst inferiorly the position was described in relation to the diaphragm or chest wall. The localization of the horizontal fissure was marked anteriorly in relation to the nearest rib (or costal cartilage) and posteriorly where it intersected with the oblique fissure (superior, middle, or inferior third). Shapes of the fissures and differences between inspiration and expiration were also documented. Descriptive statistics were used to report the most frequent positions. The most frequent localization of the oblique fissure on the left side was posteriorly at the fourth rib (45%), laterally at the sixth rib (52%), and inferiorly in the anterior third of the hemidiaphragm (60%). The right oblique fissure was located posteriorly at the fifth rib (50%), laterally at the sixth rib (50%), and inferiorly in the anterior third of the hemidiaphragm (71%). The horizontal fissure most commonly originated in the middle third of the oblique fissure (61%) and met the anterior thoracic wall at the level of the fourth rib (51%). The most frequent shape of the left oblique fissure was linear (78%), whereas S-shaped and linear configurations (28% each) were most frequent on the right. No difference was found in the surface markings of the fissures between inspiration and expiration in 90% of cases. The considerable individual variation in the position and shape of the interlobar fissures helps to explain the variable descriptions of their surface anatomy in the literature. PMID- 22933394 TI - Anti-inflammatory, antinociceptive and cytotoxic effects of the methanol extract of Cecropia pachystachya Trecul. AB - Cecropia pachystachya is widely used in the traditional medicine as anti inflammatory, antitusive, expectorant, antiasthmatic and hypoglycemic. It is also commercially available to treat skin cancer. To validate some of the popular uses of this species, its methanol leaves extract (CPM) was tested for anti inflammatory, antinociceptive and cytotoxic effects. The anti-inflammatory activity was evaluated by croton oil-induced ear edema test. When used orally, the anti-inflammatory effect of CPM at 300 mg/kg was similar to that of indomethacin with 53% inhibition of the ear edema. Also, results on topical treatment were similar to that of dexamethasone with 83% inhibition of the edema. To evaluate the antinociceptive activity, acetic acid-induced writhing and formalin-induced pain tests were employed. CPM (100 and 300 mg/kg) reduced the number of writhing by 61% and 67%, respectively. In both doses, the activity was comparable to the reference drug, indomethacin. The oral administration of CPM was ineffective in the first phase of formalin test but exhibited great effects on the second phase decreasing the licking time by 85% at 300 mg/kg. The cytotoxic potential of CPM was also investigated against HL60, HL60.bcl2 and Jurkat tumor cell lines and showed an inhibition of more than 50% of cell proliferation. The flavones orientin and isoorientin were detected in CPM. PMID- 22933395 TI - Carbon dot-based inorganic-organic nanosystem for two-photon imaging and biosensing of pH variation in living cells and tissues. AB - A carbon dot (C-Dot)-based two-photon fluorescent probe has been developed for the monitoring of pH changes across a broad range with high sensitivity and selectivity. The inorganic-organic probe also shows good biocompatibility and cell permeability, and thus can be successfully applied in bioimaging and biosensing of physiological pH in living cells, as well as living tissues at a depth of 65-185 MUm. PMID- 22933396 TI - Laboratory evaluation of the effects of Manilkara subsericea (Mart.) Dubard extracts and triterpenes on the development of Dysdercus peruvianus and Oncopeltus fasciatus. AB - BACKGROUND: Studies were carried out to evaluate the effects of Manilkara subsericea extracts and triterpenes on the development of two species of agricultural pest insects, Oncopelus fasciatus and Dysdercus peruvianus. RESULTS: All treatments of insects with M. subsericea extracts induced mortality, delayed development and inhibited moulting. Some extracts assayed (FH, FB and FD in D. peruvianus, and FH, FB and FEA in O. fasciatus) also produced body deformities in the few adults that emerged. Other extracts (FH, FEA, FB, FD and LET in both insects), however, induced either permanent (overaged) or extranumerary nymphs, both of which were unable to achieve the adult stage and reproductive status. The insects were also treated with triterpenes (alpha- and beta-amyrin acetates) which showed high lethality at 30 days after treatment and delayed the intermoult period so that overaged nymphs were detected. CONCLUSION: The results indicate that extracts and triterpenes from Manilkara subsericea act as potent growth inhibitors of phytophagous hemipteran nymphs. It is also concluded that the mixture of several different molecules in the extracts used produces synergic effects that do not occur after using the triterpenes (PFT) alone. These secondary metabolites in the M. subsericea extracts can potentially be used in integrated control programmes against crop pests. PMID- 22933397 TI - Intranasal vaccination with replication-defective adenovirus type 5 encoding influenza virus hemagglutinin elicits protective immunity to homologous challenge and partial protection to heterologous challenge in pigs. AB - Influenza A virus (IAV) is widely circulating in the swine population and causes significant economic losses. To combat IAV infection, the swine industry utilizes adjuvanted whole inactivated virus (WIV) vaccines, using a prime-boost strategy. These vaccines can provide sterilizing immunity toward homologous virus but often have limited efficacy against a heterologous infection. There is a need for vaccine platforms that induce mucosal and cell-mediated immunity that is cross reactive to heterologous viruses and can be produced in a short time frame. Nonreplicating adenovirus 5 vector (Ad5) vaccines are one option, as they can be produced rapidly and given intranasally to induce local immunity. Thus, we compared the immunogenicity and efficacy of a single intranasal dose of an Ad5 vectored hemagglutinin (Ad5-HA) vaccine to those of a traditional intramuscular administration of WIV vaccine. Ad5-HA vaccination induced a mucosal IgA response toward homologous IAV and primed an antigen-specific gamma interferon (IFN-gamma) response against both challenge viruses. The Ad5-HA vaccine provided protective immunity to homologous challenge and partial protection against heterologous challenge, unlike the WIV vaccine. Nasal shedding was significantly reduced and virus was cleared from the lung by day 5 postinfection following heterologous challenge of Ad5-HA-vaccinated pigs. However, the WIV-vaccinated pigs displayed vaccine-associated enhanced respiratory disease (VAERD) following heterologous challenge, characterized by enhanced macroscopic lung lesions. This study demonstrates that a single intranasal vaccination with an Ad5-HA construct can provide complete protection from homologous challenge and partial protection from heterologous challenge, as opposed to VAERD, which can occur with adjuvanted WIV vaccines. PMID- 22933398 TI - Acquisition of maternal antibodies both from the placenta and by lactation protects mouse offspring from Yersinia pestis challenge. AB - Artificially passive immunization has been demonstrated to be effective against Yersinia pestis infection in animals. However, maternal antibodies' protective efficacy against plague has not yet been demonstrated. Here, we evaluated the kinetics, protective efficacy, and transmission modes of maternal antibodies, using mice immunized with plague subunit vaccine SV1 (20 MUg of F1 and 10 MUg of rV270). The results showed that the rV270- and F1-specific antibodies could be detected in the sera of newborn mice (NM) until 10 and 14 weeks of age, respectively. There was no antibody titer difference between the parturient mice immunized with SV1 (PM-S) and the caesarean-section newborns (CSN) from the PM-S or between the lactating mice immunized by SV1 (LM-S) and the cross-fostered mice (CFM) during 3 weeks of lactation. The NM had a 72% protection against 4,800 CFU Y. pestis strain 141 challenge at 6 weeks of age, whereas at 14 weeks of age, NM all succumbed to 5,700 CFU of Y. pestis challenge. After 7 weeks of age, CFM had an 84% protection against 5,000 CFU of Y. pestis challenge. These results indicated that maternal antibodies induced by the plague subunit vaccine in mother mice can be transferred to NM by both placenta and lactation. Passive antibodies from the immunized mothers could persist for 3 months and provide early protection for NM. The degree of early protection is dependent on levels of the passively acquired antibody. The results indicate that passive immunization should be an effective countermeasure against plague during its epidemics. PMID- 22933399 TI - A three-dose intramuscular injection schedule of anthrax vaccine adsorbed generates sustained humoral and cellular immune responses to protective antigen and provides long-term protection against inhalation anthrax in rhesus macaques. AB - A 3-dose (0, 1, and 6 months) intramuscular (3-IM) priming series of a human dose (HuAVA) and dilutions of up to 1:10 of anthrax vaccine adsorbed (AVA) provided statistically significant levels of protection (60 to 100%) against inhalation anthrax for up to 4 years in rhesus macaques. Serum anti-protective antigen (anti PA) IgG and lethal toxin neutralization activity (TNA) were detectable following a single injection of HuAVA or 1:5 AVA or following two injections of diluted vaccine (1:10, 1:20, or 1:40 AVA). Anti-PA and TNA were highly correlated (overall r(2) = 0.89 for log(10)-transformed data). Peak responses were seen at 6.5 months. In general, with the exception of animals receiving 1:40 AVA, serum anti-PA and TNA responses remained significantly above control levels at 28.5 months (the last time point measured for 1:20 AVA), and through 50.5 months for the HuAVA and 1:5 and 1:10 AVA groups (P < 0.05). PA-specific gamma interferon (IFN-gamma) and interleukin-4 (IL-4) CD4(+) cell frequencies and T cell stimulation indices were sustained through 50.5 months (the last time point measured). PA-specific memory B cell frequencies were highly variable but, in general, were detectable in peripheral blood mononuclear cells (PBMC) by 2 months, were significantly above control levels by 7 months, and remained detectable in the HuAVA and 1:5 and 1:20 AVA groups through 42 months (the last time point measured). HuAVA and diluted AVA elicited a combined Th1/Th2 response and robust immunological priming, with sustained production of high-avidity PA specific functional antibody, long-term immune cell competence, and immunological memory (30 months for 1:20 AVA and 52 months for 1:10 AVA). Vaccinated animals surviving inhalation anthrax developed high-magnitude anamnestic anti-PA IgG and TNA responses. PMID- 22933402 TI - Attitudes towards emotional expression mediate the relationship between childhood invalidation and adult eating concern. AB - Previous research has suggested that invalidating childhood environments are positively related to the symptoms of eating disorders. However, it is unclear how childhood environments might impact upon the development of eating disorder symptoms. This study examined the relationship between parental invalidation and eating disorder-related attitudes in a nonclinical sample and tested the mediating effect of attitudes towards emotional expression. Two hundred women, with a mean age of 21 years, completed measures of invalidating childhood environments, attitudes towards emotional expression, and eating pathology. Eating concerns were positively associated with recollections of an invalidating parental environment. The belief that the expression of emotions is a sign of weakness fully mediated the relationship between childhood maternal invalidation and adult eating concern. Following replication and extension to a clinical sample, these results suggest that targeting the individual's attitude towards emotional expression might reduce eating attitudes among women who have experienced an invalidating childhood environment. PMID- 22933401 TI - Oral gene application using chitosan-DNA nanoparticles induces transferable tolerance. AB - Oral tolerance is a promising approach to induce unresponsiveness to various antigens. The development of tolerogenic vaccines could be exploited in modulating the immune response in autoimmune disease and allograft rejection. In this study, we investigated a nonviral gene transfer strategy for inducing oral tolerance via antigen-encoding chitosan-DNA nanoparticles (NP). Oral application of ovalbumin (OVA)-encoding chitosan-DNA NP (OVA-NP) suppressed the OVA-specific delayed-type hypersensitivity (DTH) response and anti-OVA antibody formation, as well as spleen cell proliferation following OVA stimulation. Cytokine expression patterns following OVA stimulation in vitro showed a shift from a Th1 toward a Th2/Th3 response. The OVA-NP-induced tolerance was transferable from donor to naive recipient mice via adoptive spleen cell transfer and was mediated by CD4(+)CD25(+) T cells. These findings indicate that nonviral oral gene transfer can induce regulatory T cells for antigen-specific immune modulation. PMID- 22933400 TI - Determinants of hepatitis A vaccine immunity in a cohort of human immunodeficiency virus-infected children living in Switzerland. AB - Vaccination in HIV-infected children is often less effective than in healthy children. The goal of this study was to assess vaccine responses to hepatitis A virus (HAV) in HIV-infected children. Children of the Swiss Mother and Child HIV Cohort Study (MoCHiV) were enrolled prospectively. Recommendations for initial, catch-up, and additional HAV immunizations were based upon baseline antibody concentrations and vaccine history. HAV IgG was assessed by enzyme-linked immunosorbent assay (ELISA) with a protective cutoff value defined as >=10 mIU/ml. Eighty-seven patients were included (median age, 11 years; range, 3.4 to 21.2 years). Forty-two patients were seropositive (48.3%) for HAV. Among 45 (51.7%) seronegative patients, 36 had not received any HAV vaccine dose and were considered naive. Vaccine responses were assessed after the first dose in 29/35 naive patients and after the second dose in 33/39 children (25 initially naive patients, 4 seronegative patients, and 4 seropositive patients that had already received 1 dose of vaccine). Seroconversion was 86% after 1 dose and 97% after 2 doses, with a geometric mean concentration of 962 mIU/ml after the second dose. A baseline CD4(+) T cell count below 750 cells/MUl significantly reduced the post 2nd-dose response (P = 0.005). Despite a high rate of seroconversion, patients with CD4(+) T cell counts of <750/MUl had lower anti-HAV antibody concentrations. This may translate into a shorter protection time. Hence, monitoring humoral immunity may be necessary to provide supplementary doses as needed. PMID- 22933403 TI - Evidence to support that adventitial cysts, analogous to intraneural ganglion cysts, are also joint-connected. AB - Cystic adventitial disease (CAD) is a rare condition in which cyst is found within a vessel, typically producing symptoms of vascular compromise. Most commonly located in the popliteal artery near the knee, it has been reported in arteries and veins throughout the body. Its pathogenesis has been poorly understood and various surgical approaches have been recommended. We extrapolated some recent information about a similar condition, intraneural ganglion cyst affecting the deep fibular (peroneal) nerve, to the prototype, CAD of the popliteal artery. In intraneural ganglion cysts affecting the deep fibular nerve we have shown that an articular (neural) branch is the conduit between the superior tibiofibular joint and the main parent nerve for which epineurial dissection of joint fluid can occur. We hypothesized that the same principles would apply to CAD and that an articular (vascular) branch would be the conduit from the knee joint leading to dissection to the main parent vessel. We reviewed five patients with CAD of the popliteal artery in whom MRIs were available: two treated by the primary author well familiar with the proposed articular theory, and three treated by others at our institution, less familiar with it. We then reviewed the literature critically to assess for additional evidence to support our articular (synovial) theory and an anatomic explanation. In the two cases treated by the primary author a joint connection was identified on high resolution MRI prospectively and intraoperatively through the middle genicular artery (MGA); postoperatively in these cases there was no recurrence. In the other three cases, a joint connection was not identified on imaging or at operation. Reinterpretation of these cases revealed a joint connection through the MGA in the one patient who had preoperative imaging and subclinical persistence/recurrence in the two patients who underwent postoperative MRIs done for other reasons. Our review of the literature and imaging studies revealed unrecognized joint connections in CAD to the knee and other joints as well as evidence that the MGA is the conduit in cases of CAD of the popliteal artery. We believe that adventitial cysts originate in neighboring joints and dissect within articular (vascular) branches. In our opinion, the unifying articular theory and the principles introduced for intraneural ganglion cysts apply equally to common and rare sites of adventitial cysts. PMID- 22933405 TI - Chronic resveratrol treatment ameliorates cell adhesion and mitigates the inflammatory phenotype in senescent human fibroblasts. AB - We evaluated the effect of resveratrol on the senescence-associated secretory phenotype (SASP) and on adhesion-related processes in cultured human MRC5 fibroblasts. Presenescent cultures were chronically treated with or without 5 uM resveratrol. The development of SASP in MRC5 fibroblasts approaching senescence was significantly attenuated by resveratrol treatment, which reduced both gene expression and release of proinflammatory cytokines. Although to a lesser extent, 1 uM resveratrol proved to be effective on cytokine gene expression. Cell spreading capacity and plating efficiency were strikingly increased and accompanied by recovery of type I collagen expression to presenescent levels. As p16(INK4a) protein expression was not significantly modified, and based on our previous data, we propose that resveratrol does not affect fibroblast replicative senescence, but improves tissue maintenance and repair during normal cellular aging. Considering these low concentrations proved effective in vitro, translation of these data to human research on inflammation-related pathologies can be envisaged. PMID- 22933406 TI - A 55-year-old woman with orbital inflammation. PMID- 22933404 TI - Transgenic analysis of signaling pathways required for Xenopus tadpole spinal cord and muscle regeneration. AB - The Xenopus tadpole has the capacity fully to regenerate its tail after amputation. Previously, we have established that this regeneration process requires the operation of several signaling pathways including the bone morphogenic protein, Wnt, and Fgf pathways. Here, we have addressed the signaling requirements for spinal cord and muscle regeneration in a tissue-specific manner. Two methods were used namely grafts of transgenic spinal cord to a wild type host, and the use of the Tet-on conditional transgenic system to express inhibitors in the individual tissues. For the grafting experiments, the tail was amputated through the graft, which contained a temperature inducible inhibitor of the Wnt-beta-catenin pathway. For the Tet-on experiments, treatment with doxycycline was used to induce cell autonomous inhibitors of the Wnt-beta-catenin or the Fgf pathway in either spinal cord or muscle. The results show that both spinal cord and muscle regeneration depend on both the Wnt-beta-catenin and the Fgf pathways. This experimental design also enables us to observe the effect of inhibition of regeneration of one tissue on the regeneration of the others. Regardless of the method of inhibition, we find that reduction of spinal cord regeneration reduces regeneration of other parts of the tail, including the myotomal muscles. In contrast, reduction of muscle regeneration has no effect on the regeneration of the spinal cord. In common with other regeneration systems, this indicates that soluble factors from the spinal cord are needed to promote the regeneration of the other tissues in the tail. PMID- 22933408 TI - Radiation shielding concrete made of Basalt aggregates. AB - In spite of the fact that Basalt is a widespread type of rock, there is very little available information on using it as aggregates for concrete radiation shielding. This paper investigates the possibility of using Basalt for the aforementioned purpose. The results have shown that Basalt could be used successfully for preparing radiation shielding concrete, but some attention should be paid to the choice of the suitable types of Basalt and for the neutron activation problem that could arise in the concrete shield. PMID- 22933407 TI - Effect of plant polyphenols on ischemia-reperfusion injury of the isolated rat heart and vessels. AB - In the present study, we investigated the potential protective effect of selected natural substances in a rat model of heart and mesenteric ischemia-reperfusion (I/R). Experiments were performed on isolated Langendorff-perfused rat hearts, subjected to 30-min global ischemia, followed by 30-min reperfusion. Arbutin, curcumin, rosmarinic acid and extract of Mentha x villosa were applied in the concentration of 1 * 10-5 mol/l 10 min before the onset of ischemia and during reperfusion, through the perfusion medium. Mesenteric ischemia was induced by clamping the superior mesenteric artery (SMA) for 60 min, subsequent reperfusion lasted 30 min. Production of reactive oxygen species (ROS) by SMA ex vivo was determined by luminol-enhanced chemiluminiscence (CL). The effect of the substances was tested after their incubation with tissue. Curcumin and extract of Mentha x villosa were found to be the most effective in reducing reperfusion induced dysrhythmias--ventricular tachycardia and fibrillation. This effect was accompanied by bradycardic effect. The mesenteric I/R induced an increase in CL in vascular tissue which was dampened by substances tested. All substances tested were found to have antioxidant properties, as demonstrated by a reduction in ROS production in mesenteric vessels. This effect was confirmed in curcumin and extract of Mentha x villosa which reduced reperfusion dyshythmias. PMID- 22933409 TI - Characteristics of radon and thoron exhalation rates in Okinawa, subtropical region of Japan. AB - Radon and thoron exhalation rates from the ground surface were estimated in three islands of Okinawa Prefecture, a subtropical region of Japan. In situ measurements of the exhalation rates were conducted at a total of 88 points using an accumulation technique with a ZnS(Ag) scintillation detector. The radon and thoron exhalation rates were calculated to be 1-137 (arithmetic mean: 21) mBq m( 2) s(-1) and 32-6244 (1801) mBq m(-2) s(-1), respectively. In the surface soil samples collected at 53 measurement points, (238)U and (232)Th series concentrations were estimated to be 17.9-254.0 (64.0) Bq kg(-1) dry and 17.8 136.1 (58.8) Bq kg(-1) dry, respectively. The maximum rates and concentrations were observed in the dark red soil area. Recent studies strongly suggest that the base material of the soils may be the eolian dust derived from the southeastern part of China, a high background radiation area. The eolian dust is, therefore, considered to be an enhancer for the radon and thoron exhalations in Okinawa. PMID- 22933410 TI - Radioactive pollution from Fukushima Daiichi nuclear power plant in the terrestrial environment. AB - Major contaminants from venting and hydrogen explosions at the Fukushima Daiichi nuclear reactors between 12 and 15 March 2011 were transported northwestward and deposited on soil and plants via precipitation. Surface soils and plant leaves were sampled at 64 sites in the Fukushima Prefecture. The highest concentrations of (134)Cs (84.4 kBq kg(-1)) and (137)Cs (82.0 kBq kg(-1)) in surface soils were observed at Nagadoro in Iidate village located 32 km northwest from the Fukushima Daiichi nuclear power plant. Furthermore, (131)I, (129)Te, (129 m)Te, (110 m)Ag and (140)La were detected in the same samples. Outer surface of plant leaves, such as bamboo, cabbage and grasses were highly contaminated at the high-dose rate areas of Tsushima and Minami-Tsushima in Namie town. Mugwort leaves that grew after the pollution event had extremely low concentration of radionuclides; however, the plant/soil radiocaesium ratio was 0.023 +/- 0.006. It is anticipated that decomposition of fallen leaves will promote recycling of radionuclides in the environment. PMID- 22933411 TI - Stacking-order-dependent optoelectronic properties of bilayer nanofilm photodetectors made from hollow ZnS and ZnO microspheres. AB - Innovative bilayer nanofilms composed of semiconducting ZnS and ZnO hollow microspheres are successfully fabricated by an oil-water interfacial self assembly strategy. The photocurrent of the bilayer film-based photodetectors is dependent on the stacking orders of the building blocks. The optimal optoelectronic properties of the ZnS(up)/ZnO(down) device are much better than those of the monolayer-film based device. PMID- 22933412 TI - Improved anticancer potency by head-to-tail cyclization of short cationic anticancer peptides containing a lipophilic beta(2,2) -amino acid. AB - We have recently reported a series of synthetic anticancer heptapeptides (H KKWbeta(2,2) WKK-NH(2) ) containing a central achiral and lipophilic beta(2,2) amino acid that display low toxicity against non-malignant cells and high proteolytic stability. In the present study, we have further investigated the effects of increasing the rigidity and amphipathicity of two of our lead heptapeptides by preparing a series of seven to five residue cyclic peptides containing the two most promising beta(2,2) -amino acid derivatives as part of the central lipophilic core. The peptides were tested for anticancer activity against human Burkitt's lymphoma (Ramos cells), haemolytic activity against human red blood cells (RBC) and cytotoxicity against healthy human lung fibroblast cells (MRC-5). The results demonstrated a considerable increase in anticancer potency following head-to-tail peptide cyclization, especially for the shortest derivatives lacking a tryptophan residue. High-resolution NMR studies and molecular dynamics simulations together with an annexin-V-FITC and propidium iodide fluorescent assay showed that the peptides had a membrane disruptive mode of action and that the more potent peptides penetrated deeper into the lipid bilayer. The need for new anticancer drugs with novel modes of action is demanding, and development of short cyclic anticancer peptides with an overall rigidified and amphipathic structure is a promising approach to new anticancer agents. PMID- 22933413 TI - Genetic engineering of plant volatile terpenoids: effects on a herbivore, a predator and a parasitoid. AB - BACKGROUND: Most insect-resistant transgenic crops employ toxins to control pests. A novel approach is to enhance the effectiveness of natural enemies by genetic engineering of the biosynthesis of volatile organic compounds (VOCs). Before the commercialisation of such transgenic plants can be pursued, detailed fundamental studies of their effects on herbivores and their natural enemies are necessary. The linalool/nerolidol synthase gene FaNES1 was constitutively expressed from strawberry in three Arabidopsis thaliana accessions, and the behaviour of the aphid Brevicoryne brassicae L., the parasitoid Diaeretiella rapae McIntosh and the predator Episyrphus balteatus de Geer was studied. RESULTS: Transgenic FaNES1-expressing plants emitted (E)-nerolidol and larger amounts of (E)-DMNT and linalool. Brevicoryne brassicae was repelled by the transgenic lines of two of the accessions, whereas its performance was not affected. Diaeretiella rapae preferred aphid-infested transgenic plants over aphid-infested wild-type plants for two of the accessions. In contrast, female E. balteatus predators did not differentiate between aphid-infested transgenic or wild-type plants. CONCLUSION: The results indicate that the genetic engineering of plants to modify their emission of VOCs holds considerable promise for facilitating biological control of herbivores. Validation for crop plants is a necessary next step to assess the usefulness of modified volatile emission in integrated pest management. PMID- 22933414 TI - Influence of a fabella in the gastrocnemius muscle on the common fibular nerve in Japanese subjects. AB - The fabella is a sesamoid bone located in the proximal tendon of the gastrocnemius muscle. In rare cases, its presence may lead to a variety of clinical problems, including fabella syndrome and common fibular (CF) nerve palsy. The purpose of this study was to analyze the morphology of the fabella and CF nerve and discuss the influence of any existing fabellae on the size of the CF nerve. The morphology of the fabella and CF nerve in the popliteal region of the lateral head of the gastrocnemius muscle was investigated in 102 knees of 51 Japanese cadavers. The maximum circumference of the thigh, knee, and calf and the frequency, position, and size of the fabella were measured. In addition, the CF nerve width and thickness were measured proximal to the fabellar region and again as the CF nerve passed posterior, lateral, or medial to the region. A fabella was observed in 70 knees (68.6%). The CF nerve adjacent to the fabella was significantly wider and thinner than in the region proximal to the fabella (P < 0.001). In cases in which a bony fabella was present, there was a significant relationship between the thickness of the CF nerve and the circumference of the thigh and knee. The following factors were observed to contribute to the presence of a fabella causing alterations in the size of the CF nerve: a bony fabella, a CF nerve path posterior or lateral to the fabella, and subjects with a thin physique and bony fabella. PMID- 22933415 TI - Night temperature and source-sink effects on overall growth, cell number and cell size in bell pepper ovaries. AB - BACKGROUND AND AIMS: Ovary swelling, and resultant fruit malformation, in bell pepper flowers is favoured by low night temperature or a high source-sink ratio. However, the interaction between night temperature and source-sink ratio on ovary swelling and the contribution of cell size and cell number to ovary swelling are unknown. The present research examined the interactive effects of night temperature and source-sink ratio on ovary size, cell number and cell size at anthesis in bell pepper flowers. METHODS: Bell pepper plants were grown in growth chambers at night temperatures of either 20 degrees C (HNT) or 12 degrees C (LNT). Within each temperature treatment, plants bore either 0 (non-fruiting) or two developing fruits per plant. Ovary fresh weight, cell size and cell number were measured. KEY RESULTS: Ovary fresh weights in non-fruiting plants grown at LNT were the largest, while fresh weights were smallest in plants grown at HNT with fruits. In general, mesocarp cell size in ovaries was largest in non fruiting plants grown at either LNT or HNT and smallest in fruiting plants at HNT. Mesocarp cell number was greater in non-fruiting plants under LNT than in the rest of the night temperature/fruiting treatments. These responses were more marked in ovaries sampled after 18 d of treatment compared with those sampled after 40 d of treatment. CONCLUSIONS: Ovary fresh weight of flowers at anthesis increased 65 % in non-fruiting plants grown under LNT compared with fruiting plants grown under HNT. This increase was due primarily to increases in mesocarp cell number and size. These results indicate that the combined effects of LNT and high source-sink ratio on ovary swelling are additive. Furthermore, the combined effects of LNT and low source-sink ratio or HNT and high source-sink ratio can partially overcome the detrimental effects of LNT and high source-sink ratio. PMID- 22933416 TI - Collenchyma: a versatile mechanical tissue with dynamic cell walls. AB - BACKGROUND: Collenchyma has remained in the shadow of commercially exploited mechanical tissues such as wood and fibres, and therefore has received little attention since it was first described. However, collenchyma is highly dynamic, especially compared with sclerenchyma. It is the main supporting tissue of growing organs with walls thickening during and after elongation. In older organs, collenchyma may become more rigid due to changes in cell wall composition or may undergo sclerification through lignification of newly deposited cell wall material. While much is known about the systematic and organographic distribution of collenchyma, there is rather less information regarding the molecular architecture and properties of its cell walls. SCOPE AND CONCLUSIONS: This review summarizes several aspects that have not previously been extensively discussed including the origin of the term 'collenchyma' and the history of its typology. As the cell walls of collenchyma largely determine the dynamic characteristics of this tissue, I summarize the current state of knowledge regarding their structure and molecular composition. Unfortunately, to date, detailed studies specifically focusing on collenchyma cell walls have not been undertaken. However, generating a more detailed understanding of the structural and compositional modifications associated with the transition from plastic to elastic collenchyma cell wall properties is likely to provide significant insights into how specific configurations of cell wall polymers result in specific functional properties. This approach, focusing on architecture and functional properties, is likely to provide improved clarity on the controversial definition of collenchyma. PMID- 22933417 TI - Elderly- versus younger-onset rheumatoid arthritis: higher levels of ultrasound detected inflammation despite comparable clinical disease activity. AB - OBJECTIVE: To compare ultrasound-verified joint inflammation between elderly onset rheumatoid arthritis (EORA) and younger-onset rheumatoid arthritis (YORA) patients. METHODS: We conducted a retrospective analysis of 145 consecutive rheumatoid arthritis patients routinely assessed by sonography of wrists, metacarpophalangeal joints, and proximal interphalangeal joints, including semiquantitative scoring of synovial hypertrophy/effusion (SH/E) and power Doppler (PD) signals. Global ultrasound (GU) scores were calculated adding SH/E and PD results. EORA was defined by disease onset at age >=60 years. Number of tender joints and swollen joints, global assessment of disease activity by physician or patient, Disease Activity Score in 28 joints (DAS28), Clinical Disease Activity Index (CDAI), and Simplified Disease Activity Index (SDAI) scores were recorded. Respective values for disease activity were accounted for in group comparisons using SPSS statistical software (version 18.0). RESULTS: Seventy patients were diagnosed with EORA (mean +/- SD age 71.0 +/- 7.3 years, 81.4% women) and 75 patients with YORA (mean +/- SD age 46.8 +/- 10.2 years, 86.7% women). EORA patients had higher GU scores (median 18.5 [interquartile range (IQR) 17.0] versus 12.0 [IQR 15.0], P = 0.009) and SH/E scores (median 12.0 [IQR 10.0] versus median 9.0 [IQR 9.0], P = 0.004) than patients with YORA. Patients with EORA were more likely to show PD signals in at least 1 joint than YORA patients (85% versus 72%; odds ratio 3.9 [95% confidence interval 1.3-11.5], P = 0.015). DAS28, CDAI, and SDAI scores did not differ between the groups. The sonographic pattern of joint involvement was similar in both groups, with active inflammation most commonly presenting at the wrists. CONCLUSION: Ultrasound examination indicated higher inflammatory burden in EORA patients than in YORA patients despite similar clinical disease activity. PMID- 22933418 TI - The developing Xenopus limb as a model for studies on the balance between inflammation and regeneration. AB - The roles of inflammation and immune cell reactivity triggered by amputation have only recently begun to be addressed in investigations of epimorphic regeneration, although studies of tissue repair in mammals clearly show the importance of the immune system in determining the quality of the repair process. Here, we first review inflammation-related work in non-mammalian systems of epimorphic regeneration which suggests that regeneration of an amputated appendage requires continuous modulation of the local immune response, from the first hours after amputation through the period of blastema patterning. We then present data on the effects of anti-inflammatory and proinflammatory agents on regeneration of larval Xenopus hindlimbs. Treatment with the glucocorticoid beclomethasone immediately after amputation inhibits regeneration in regeneration-complete stage 53 limbs. Other anti-inflammatory agents, including the inhibitors of cyclooxygenase-2 (COX 2) activity celecoxib and diclofenac, applied similarly to larvae amputated at stage 55, when the capacity for limb regeneration is normally being lost, restore regenerative capacity. This suggests that although injury-related events sensitive to glucocorticoids are necessary for regeneration, resolution of the inflammatory response may also be required to allow the complete regenerative response and normal blastema patterning. Conversely, if resolution of inflammation is prevented by local treatment of amputated limbs with beryllium, a strong immunoadjuvant, regeneration is inhibited, and gene expression data suggest that this inhibition results from a failure of normal blastema patterning. Both positive and negative effects of immune- or inflammation-related activities occur during anuran limb regeneration and this underscores the importance of considering immune cells in studies of epimorphic regeneration. PMID- 22933419 TI - In amenable mortality--deaths avoidable through health care--progress in the US lags that of three European countries. AB - We examined trends and patterns of amenable mortality-deaths that should not occur in the presence of timely and effective health care-in the United States compared to those in France, Germany, and the United Kingdom between 1999 and 2007. Americans under age sixty-five during this period had elevated rates of amenable mortality compared to their peers in Europe. For Americans over age sixty-five, declines in amenable mortality slowed relative to their peers in Europe. Overall, amenable mortality rates among men from 1999 to 2007 fell by only 18.5 percent in the United States compared to 36.9 percent in the United Kingdom. Among women, the rates fell by 17.5 percent and 31.9 percent, respectively. Although US men and women had the lowest mortality from treatable cancers among the four countries, deaths from circulatory conditions-chiefly cerebrovascular disease and hypertension-were the main reason amenable death rates remained relatively high in the United States. These findings strengthen the case for reforms that will enable all Americans to receive timely and effective health care. PMID- 22933420 TI - Silymarin decreases connective tissue growth factor to improve liver fibrosis in rats treated with carbon tetrachloride. AB - Silymarin is an herbal product showing potential as protection against hepatic disorders. In an attempt to develop the agent for the treatment of hepatic fibrosis, we screened the effects of silymarin on a rat model of hepatic fibrosis induced by carbon tetrachloride (CCl4). Intraperitoneal administration of CCl4 to rats for 8 weeks not only increased the plasma levels of glutamic oxaloacetic transaminase (GOT) and glutamic pyruvic transaminase (GPT) but also induced a marked increase in the formation of hepatic fibrosis. Moreover, the activities of superoxide dismutase (SOD) and glutathione peroxidase (GPx) were also reduced in the liver of rats treated with CCl4. Oral administration of silymarin (200 mg/kg, three times daily), in parallel, decreased the plasma levels of GOT and GPT. Furthermore, in addition to the improvement of hepatic fibrosis, the hepatic levels of hydroxyproline and connective tissue growth factor (CTGF) were both markedly decreased by silymarin. Silymarin also elevated the activities of SOD and GPx in liver isolated from CCl4-treated rats. The results suggest that oral administration of silymarin protects against CCl4-induced hepatic fibrosis in rats, likely due to the decrease in fibrotic parameters such as CTGF. PMID- 22933421 TI - Formation mechanism of cross-linking Maillard compounds in peptide-xylose systems. AB - The formation mechanism of Maillard peptides was explored in Maillard reaction through diglycine/glutathione(GSH)/(Cys-Glu-Lys-His-Ile-Met)-xlyose systems by heating at 120 degrees C for 30-120 min. Maximum fluorescence intensity of Maillard reaction products (MRPs) with an emission wavelength of 420~430 nm in all systems was observed, and the intensity values were proportional to the heating time. Taken diglycine/GSH-[(13) C(5) ]xylose systems as a control, it was proposed that the compounds with high m/z values of 379 and 616 have the high molecular weight (HMW) products formed by cross-linking of peptides and sugar. In (Cys-Glu-Lys-His-Ile-Met)-xylose system, the m/z value of HMW MRPs was not observed, which might be due to the weak signals of these products. According to the results of gel permeation chromatography, HMW MRPs were formed by Maillard reaction, especially in (Cys-Glu-Lys-His-Ile-Met)-xylose system, the percentage of Maillard peptides reached 52.90%. It was concluded that Maillard peptides can be prepared through the cross-linking of sugar and small peptides with a certain MW range. PMID- 22933423 TI - Direct detection of key intermediates in rhodium(I)-catalyzed [2+2+2] cycloadditions of alkynes by ESI-MS. AB - The mechanism of the Rh-catalysed [2+2+2] cycloaddition reaction of diynes with monoynes has been examined using ESI-MS and ESI-CID-MS analysis. The catalytic system used consisted of the combination of a cationic rhodium(I) complex with bisphosphine ligands, which generates highly active complexes that can be detected by ESI(+) experiments. ESI-MS on-line monitoring has allowed the detection for the first time of all of the intermediates in the catalytic cycle, supporting the mechanistic proposal based mainly on theoretical calculations. For all ESI-MS experiments, the structural assignments of ions are supported by tandem mass spectrometry analyses. Computer model studies based on density functional theory (DFT) support the structural proposal made for the monoyne insertion intermediate. The collective studies provide new insight into the reactivity of cationic rhodacyclopentadienes, which should facilitate the design of related rhodium-catalysed C-C couplings. PMID- 22933422 TI - Age of onset and effect size in genome-wide association studies. AB - BACKGROUND: Genome-wide association studies (GWAS) have identified many susceptibility loci for complex traits, but have not identified the majority of the genetic contribution to common diseases. We explored whether the magnitude of associations detected in GWAS and, therefore, the likelihood of detecting a significant association for a given sample size, is generally greater for childhood-onset traits (e.g., birth defects) than for traits with onset in adulthood. METHODS: Data were obtained from the National Human Genome Research Institute Catalog of Published GWAS. Traits were categorized as having an average age of onset in childhood (<18 years, n = 15 traits), early adulthood (18-54 years, n = 32 traits), or late adulthood (>=55 years, n = 31 traits). The relationship between age of onset category and the magnitude of significant associations detected by GWAS was assessed using logistic regression. RESULTS: Associations characterized by an odds ratio (OR) >= 1.5 were significantly more common for GWAS of childhood traits than for late adulthood-onset traits after adjustment for several covariates (adjusted OR, 2.55; 95% confidence interval, 1.37-4.73). Results in subgroup analyses using more stringent inclusion criteria (based on sample size, effect size, p value threshold for inclusion, and novel variant-trait associations) were similar. CONCLUSIONS: These findings suggest that, on average, marker-trait associations detected in GWAS for traits with young onset may have a larger magnitude of effect than those for traits with adult onset. Therefore, GWAS for young-onset traits, such as birth defects, may be more likely than those for adult-onset traits to identify major genetic risk factors. Birth Defects Research (Part A) 2012. (c) 2012 Wiley Periodicals, Inc. PMID- 22933424 TI - Impact of obesity and hypertriglyceridemia on gout development with or without hyperuricemia: a prospective study. AB - OBJECTIVE: Hyperuricemia is the most important risk factor for the development of gout; however, not all patients with hyperuricemia develop gout, and patients experiencing a gout attack are not necessarily found to have hyperuricemia. We hypothesized that the interactions between serum uric acid (sUA) and other potential metabolic comorbidities increase the risk of gout development. METHODS: A prospective study was conducted to link baseline metabolic profiles from the MJ Health Screening Center to gout outcomes extracted from the Taiwan National Health Insurance database. A Cox proportional hazards model was used to assess the metabolic risks for incident gout stratified by hyperuricemia status (sUA level >7 mg/dl or not). RESULTS: During a mean followup period of 6.45 years (261,500 person-years), 1,189 patients with clinical gout (899 men, 202 women ages >50 years, and 88 women ages <=50 years) were identified among the 40,513 examinees. The multivariate adjusted hazard ratios (HRs) of hyperuricemia for gouty arthritis were 5.80 (95% confidence interval [95% CI] 4.93-6.81) in men and 4.37 (95% CI 3.38-5.66) in women. Hypertriglyceridemia (triglyceride level >150 mg/dl) was found as an independent risk factor, with HRs of 1.38 (95% CI 1.18 1.60) in men with hyperuricemia and 1.40 (95% CI 1.02-1.92) in men without hyperuricemia. General obesity (body mass index >27 kg/m(2) ) was independently associated with gout in older women, with HRs of 1.72 (95% CI 1.15-2.56) in women with hyperuricemia and 2.19 (95% CI 1.47-3.26) in women without hyperuricemia. CONCLUSION: General obesity in women and hypertriglyceridemia in men may potentiate an sUA effect for gout development. Further investigation is needed. PMID- 22933425 TI - Scar-free wound healing and regeneration following tail loss in the leopard gecko, Eublepharis macularius. AB - Many lizards are able to undergo scar-free wound healing and regeneration following loss of the tail. In most instances, lizard tail loss is facilitated by autotomy, an evolved mechanism that permits the tail to be self-detached at pre existing fracture planes. However, it has also been reported that the tail can regenerate following surgical amputation outside the fracture plane. In this study, we used the leopard gecko, Eublepharis macularius, to investigate and compare wound healing and regeneration following autotomy at a fracture plane and amputation outside the fracture plane. Both forms of tail loss undergo a nearly identical sequence of events leading to scar-free wound healing and regeneration. Early wound healing is characterized by transient myofibroblasts and the formation of a highly proliferative wound epithelium immunoreactive for the wound keratin marker WE6. The new tail forms from what is commonly referred to as a blastema, a mass of proliferating mesenchymal-like cells. Blastema cells express the protease matrix metalloproteinase-9. Apoptosis (demonstrated by activated caspase 3 immunostaining) is largely restricted to isolated cells of the original and regenerating tail tissues, although cell death also occurs within dermal structures at the original-regenerated tissue interface and among clusters of newly formed myocytes. Furthermore, the autotomized tail is unique in demonstrating apoptosis among cells adjacent to the fracture planes. Unlike mammals, transforming growth factor-beta3 is not involved in wound healing. We demonstrate that scar-free wound healing and regeneration are intrinsic properties of the tail, unrelated to the location or mode of tail detachment. PMID- 22933426 TI - The association between NSAID use and colorectal cancer mortality: results from the women's health initiative. AB - BACKGROUND: Randomized trial evidence shows that nonsteroidal anti-inflammatory drug (NSAID) use, particularly long-term use, reduces the incidence of colorectal neoplasia. Recent data also suggests an inverse association between NSAID use and death due to colorectal cancer (CRC). METHODS: We examined the association between NSAID use and CRC mortality among 160,143 postmenopausal women enrolled in the Women's Health Initiative. Women provided details on medication use at baseline and three years after enrollment. Reported CRC cases were locally confirmed and centrally adjudicated; cause of death was determined according to centralized medical record and death certificate review. Cox regression was used to investigate the association between NSAID use and CRC mortality. RESULTS: Overall, NSAID use at baseline was not associated with CRC mortality [HR: 0.93; 95% confidence interval (CI) 0.76, 1.14]. However, women who reported NSAID use at both baseline and year 3 experienced reductions in CRC mortality (HR: 0.72; 95% CI 0.54, 0.95) compared with nonusers. CONCLUSION: Results suggest that NSAID use is associated with lower CRC mortality among postmenopausal women who use these medications more consistently over time. impact: Our results support prolonged NSAID use in postmenopausal women for the prevention of poor CRC outcomes. PMID- 22933429 TI - Fibroblast growth factor 21 predicts the metabolic syndrome and type 2 diabetes in Caucasians. AB - OBJECTIVE: The incidence of the metabolic syndrome and type 2 diabetes mellitus (T2DM) is rising worldwide. Liver-derived fibroblast growth factor (FGF)-21 affects glucose and lipid metabolism. The aim of this study was to analyze the predictive value of FGF-21 on the incidence of T2DM and the metabolic syndrome. RESEARCH DESIGN AND METHODS: The Metabolic Syndrome Berlin Potsdam (MeSyBePo) recall study includes 440 individuals. Glucose metabolism was analyzed using an oral glucose tolerance test, including insulin measurements. FGF-21 was measured using enzyme-linked immunosorbent assay. Primary study outcome was diabetes and the metabolic syndrome incidence and change of glucose subtraits. RESULTS: During a mean follow-up of 5.30 +/- 0.1 years, 54 individuals developed the metabolic syndrome, 35 developed T2DM, and 69 with normal glucose tolerance at baseline progressed to impaired glucose metabolism, defined as impaired fasting glucose, impaired glucose tolerance, or T2DM. FGF-21 predicted incident metabolic syndrome (lnFGF-21 odds ratio [OR] 2.6 [95% CI 1.5 - 4.5]; P = 0.001), T2DM (2.4 [1.2 4.7]; P = 0.01), and progression to impaired glucose metabolism (2.2 [1.3 - 3.6]; P = 0.002) after adjustment for age, sex, BMI, and follow-up time. Additional adjustment for waist-to-hip ratio, systolic blood pressure, HDL cholesterol, triglycerides, and fasting glucose did not substantially modify the predictive value of FGF-21. CONCLUSIONS: FGF-21 is an independent predictor of the metabolic syndrome and T2DM in apparently healthy Caucasians. These results may indicate FGF-21 resistance precedes the onset of the metabolic syndrome and T2DM. PMID- 22933427 TI - Hormone therapy, estrogen metabolism, and risk of breast cancer in the Women's Health Initiative Hormone Therapy Trial. AB - BACKGROUND: In the Women's Health Initiative Hormone Trials (WHI-HT), breast cancer risk was increased with estrogen plus progestin (E+P) but not with unopposed estrogen (E-alone). We hypothesized that E+P would preferentially metabolize to 16alpha-hydroxyestrone (16alpha-OHE1) rather than 2-hydroxyestrone (2-OHE1), and that breast cancer risk would be associated with baseline and 1 year changes in estrogen metabolites: positively for 16alpha-OHE1 levels and negatively for levels of 2-OHE-1 and the 2:16 ratio. METHODS: In a prospective case-control study nested in the WHI-HT, 845 confirmed breast cancer cases were matched to 1,690 controls by age and ethnicity. Using stored serum, 2-OHE1 and 16alpha-OHE1 levels were measured by enzyme immunoassay at baseline, and for those randomized to active treatment (n = 1,259), at 1 year. RESULTS: The 1-year increase in 16alpha-OHE1 was greater with E+P than E-alone (median 55.5 pg/mL vs. 43.5 pg/mL, P < 0.001), but both increased 2-OHE1 by ~300 pg/mL. Breast cancer risk was modestly associated with higher baseline levels of 2-OHE1 and the 2:16 ratio, and for estrogen receptor+/progesterone+ cases only, higher baseline 16alpha-OHE1 levels. For those randomized to active treatment, breast cancer risk was associated with greater increase in 2-OHE-1 and the 2:16 ratio, but associations were not significant. CONCLUSIONS: Although E+P modestly increased 16alpha-OHE1 more than E-alone, increase in 16alpha-OHE1 was not associated with breast cancer. IMPACT: Study results do not explain differences between the WHI E+P and WHI E-alone breast cancer results but metabolism of oral HT, which may explain smaller than expected increase in breast cancer compared with endogenous estrogens. PMID- 22933430 TI - Adiponectin trajectories before type 2 diabetes diagnosis: Whitehall II study. AB - OBJECTIVE: The role of adiponectin in the natural history of diabetes is not well characterized. We set out to characterize prediagnosis trajectories of adiponectin in individuals who develop type 2 diabetes. RESEARCH DESIGN AND METHODS: In a case-cohort study (335 incident diabetes case and 2,474 noncase subjects) nested in the Whitehall II study, serum adiponectin was measured up to three times per participant (1991-1993, 1997-1999, and 2003-2004). Multilevel models adjusted for age and ethnicity were fitted to assess 13-year trajectories of log-transformed adiponectin preceding diabetes diagnosis or a randomly selected time point during follow-up (year(0)) based on 755/5,095 (case/noncase) person-examinations. RESULTS: Adiponectin levels were lower in diabetes case than in noncase subjects (median 7,141 [interquartile range 5,187-10,304] vs. 8,818 [6,535-12,369] ng/mL at baseline, P < 0.0001). Control subjects showed a modest decline in adiponectin throughout follow-up (0.3% per year, P < 0.0001) at higher levels in women than in men (difference at year(0): 5,358 ng/mL, P < 0.0001). Female case and early-onset case (age at diagnosis <52 years) subjects had a steeper decline than control subjects (slope difference -1.1% per year, P = 0.001 in females, -1.6% per year in early-onset case subjects, P = 0.034). In men, adiponectin slopes for case and noncase subjects were parallel. The slope differences by diabetes onset were largely attenuated after adjustment for changes in obesity, whereas the sex-specific slope differences were independent of obesity. CONCLUSIONS: Lower adiponectin levels were observed already a decade before the diagnosis of diabetes. The marked sex difference in trajectories suggests that sex-specific mechanisms affect the association between adiponectin levels and diabetes development. PMID- 22933431 TI - Association of serum ferritin and the development of metabolic syndrome in middle aged Korean men: a 5-year follow-up study. AB - OBJECTIVE: Elevated serum ferritin has been known to be associated with the prevalence of metabolic syndrome (MetS). However, there was no research to examine whether serum ferritin levels have been actually associated with the prospective development of MetS. Accordingly, we carried out a prospective study to evaluate the longitudinal effects of baseline serum ferritin levels on the development of MetS. RESEARCH DESIGN AND METHODS: A MetS-free cohort of 18,022 healthy Korean men, who had participated in a medical health checkup program in 2005, was followed until 2010. MetS was defined according to the joint interim statement of the International Diabetes Federation Task Force on Epidemiology and Prevention. Cox proportional hazards models were performed. RESULTS: During 45,919.3 person-years of follow-up, 2,127 incident cases of MetS developed between 2006 and 2010. After adjusting for multiple covariates, the hazard ratios (95% CI) for incident MetS comparing the second quintile to the fifth quintile of serum ferritin levels versus the first quintile were 1.19 (0.98-1.45), 1.17 (0.96 1.43), 1.36 (1.12-1.65), and 1.66 (1.38-2.01), respectively (P for trend <0.001). These associations were apparent in the clinically relevant subgroup analyses. CONCLUSIONS: Elevated serum ferritin levels were independently associated with future development of MetS during the 5-year follow-up period. PMID- 22933432 TI - Personalized genetic risk counseling to motivate diabetes prevention: a randomized trial. AB - OBJECTIVE: To examine whether diabetes genetic risk testing and counseling can improve diabetes prevention behaviors. RESEARCH DESIGN AND METHODS: We conducted a randomized trial of diabetes genetic risk counseling among overweight patients at increased phenotypic risk for type 2 diabetes. Participants were randomly allocated to genetic testing versus no testing. Genetic risk was calculated by summing 36 single nucleotide polymorphisms associated with type 2 diabetes. Participants in the top and bottom score quartiles received individual genetic counseling before being enrolled with untested control participants in a 12-week, validated, diabetes prevention program. Middle-risk quartile participants were not studied further. We examined the effect of this genetic counseling intervention on patient self-reported attitudes, program attendance, and weight loss, separately comparing higher-risk and lower-risk result recipients with control participants. RESULTS: The 108 participants enrolled in the diabetes prevention program included 42 participants at higher diabetes genetic risk, 32 at lower diabetes genetic risk, and 34 untested control subjects. Mean age was 57.9 +/- 10.6 years, 61% were men, and average BMI was 34.8 kg/m(2), with no differences among randomization groups. Participants attended 6.8 +/- 4.3 group sessions and lost 8.5 +/- 10.1 pounds, with 33 of 108 (30.6%) losing >=5% body weight. There were few statistically significant differences in self-reported motivation, program attendance, or mean weight loss when higher-risk recipients and lower-risk recipients were compared with control subjects (P > 0.05 for all but one comparison). CONCLUSIONS: Diabetes genetic risk counseling with currently available variants does not significantly alter self-reported motivation or prevention program adherence for overweight individuals at risk for diabetes. PMID- 22933433 TI - Moderate amounts of fructose consumption impair insulin sensitivity in healthy young men: a randomized controlled trial. AB - OBJECTIVE: Adverse effects of hypercaloric, high-fructose diets on insulin sensitivity and lipids in human subjects have been shown repeatedly. The implications of fructose in amounts close to usual daily consumption, however, have not been well studied. This study assessed the effect of moderate amounts of fructose and sucrose compared with glucose on glucose and lipid metabolism. RESEARCH DESIGN AND METHODS: Nine healthy, normal-weight male volunteers (aged 21 25 years) were studied in this double-blind, randomized, cross-over trial. All subjects consumed four different sweetened beverages (600 mL/day) for 3 weeks each: medium fructose (MF) at 40 g/day, and high fructose (HF), high glucose (HG), and high sucrose (HS) each at 80 g/day. Euglycemic-hyperinsulinemic clamps with [6,6]-(2)H(2) glucose labeling were used to measure endogenous glucose production. Lipid profile, glucose, and insulin were measured in fasting samples. RESULTS: Hepatic suppression of glucose production during the clamp was significantly lower after HF (59.4 +/- 11.0%) than HG (70.3 +/- 10.5%, P < 0.05), whereas fasting glucose, insulin, and C-peptide did not differ between the interventions. Compared with HG, LDL cholesterol and total cholesterol were significantly higher after MF, HF, and HS, and free fatty acids were significantly increased after MF, but not after the two other interventions (P < 0.05). Subjects' energy intake during the interventions did not differ significantly from baseline intake. CONCLUSIONS: This study clearly shows that moderate amounts of fructose and sucrose significantly alter hepatic insulin sensitivity and lipid metabolism compared with similar amounts of glucose. PMID- 22933434 TI - Socioeconomic status and mortality: contribution of health care access and psychological distress among U.S. adults with diagnosed diabetes. AB - OBJECTIVE: Although several studies have examined the association between socioeconomic status (SES) and mortality in the general population, few have investigated this relationship among people with diabetes. This study sought to determine how risk of mortality associated with measures of SES among adults with diagnosed diabetes is mitigated by association with demographics, comorbidities, diabetes treatment, psychological distress, or health care access and utilization. RESEARCH DESIGN AND METHODS: The study included 6,177 adults aged 25 years or older with diagnosed diabetes who participated in the National Health Interview Surveys (1997-2003) linked to mortality data (follow-up through 2006). SES was measured by education attained, financial wealth (either stocks/dividends or home ownership), and income-to-poverty ratio. RESULTS: In unadjusted analysis, risk of death was significantly greater for people with lower levels of education and income-to-poverty ratio than for those at the highest levels. After adjusting for demographics, comorbidities, diabetes treatment and duration, health care access, and psychological distress variables, the association with greater risk of death remained significant only for people with the lowest level of education (relative hazard 1.52 [95% CI 1.04-2.23]). After multivariate adjustment, the risk of death was significantly greater for people without certain measures of financial wealth (e.g., stocks, home ownership) (1.56 [1.07-2.27]) than for those with them. CONCLUSIONS: The findings suggest that after adjustments for demographics, health care access, and psychological distress, the level of education attained and financial wealth remain strong predictors of mortality risk among adults with diabetes. PMID- 22933435 TI - Cost-effectiveness of hepatitis B vaccination in adults with diagnosed diabetes. AB - OBJECTIVE To examine the cost-effectiveness of a hepatitis B vaccination program for unvaccinated adults with diagnosed diabetes in the U.S. RESEARCH DESIGN AND METHODS We used a cost-effectiveness simulation model to estimate the cost effectiveness of vaccinating adults 20-59 years of age with diagnosed diabetes not previously vaccinated for or infected by hepatitis B virus (HBV). The model estimated acute and chronic HBV infections, complications, quality-adjusted life years (QALYs), and incremental cost-effectiveness ratios. Data sources included surveillance data, epidemiological studies, and vaccine prices. RESULTS With a 10% uptake rate, the intervention will vaccinate 528,047 people and prevent 4,271 acute and 256 chronic hepatitis B infections. Net health care costs will increase by $91.4 million, and 1,218 QALYs will be gained, producing a cost-effectiveness ratio of $75,094 per QALY gained. Results are most sensitive to age, the discount rate, the hepatitis B incidence ratio for people with diabetes, and hepatitis B infection rates. Cost-effectiveness ratios rise with age at vaccination; an alternative intervention that vaccinates adults with diabetes 60 years of age or older had a cost-effectiveness ratio of $2.7 million per QALY. CONCLUSIONS Hepatitis B vaccination for adults with diabetes 20-59 years of age is modestly cost-effective. Vaccinating older adults with diabetes is not cost-effective. The study did not consider hepatitis outbreak investigation costs, and limited information exists on hepatitis progression among older adults with diabetes. Partly based on these results, the Advisory Committee on Immunization Practices recently recommended hepatitis B vaccination for people 20-59 years of age with diagnosed diabetes. PMID- 22933436 TI - beta- and alpha-cell dysfunctions in africans with ketosis-prone atypical diabetes during near-normoglycemic remission. AB - OBJECTIVE: Ketosis-prone atypical diabetes (KPD) is a subtype of diabetes in which the pathophysiology is yet to be unraveled. The aim of this study was to characterize beta- and alpha-cell functions in Africans with KPD during remission. RESEARCH DESIGN AND METHODS: We characterized beta- and alpha-cell functions in Africans with KPD during remission. The cohort comprised 15 sub Saharan Africans who had been insulin-free for a median of 6 months. Patients in remission were in good glycemic control (near-normoglycemic) and compared with 15 nondiabetic control subjects matched for age, sex, ethnicity, and BMI. Plasma insulin, C-peptide, and glucagon concentrations were measured in response to oral and intravenous glucose and to combined intravenous arginine and glucose. Early insulin secretion was measured during a 75-g oral glucose tolerance test. Insulin secretion rate and glucagon were assessed in response to intravenous glucose ramping. RESULTS: Early insulin secretion and maximal insulin secretion rate were lower in patients compared with control participants. In response to combined arginine and glucose stimulation, maximal insulin response was reduced. Glucagon suppression was also decreased in response to oral and intravenous glucose but not in response to arginine and insulin. CONCLUSIONS: Patients with KPD in protracted near-normoglycemic remission have impaired insulin response to oral and intravenous glucose and to arginine, as well as impaired glucagon suppression. Our results suggest that beta- and alpha-cell dysfunctions both contribute to the pathophysiology of KPD. PMID- 22933437 TI - Novel risk factors and the prediction of type 2 diabetes in the Atherosclerosis Risk in Communities (ARIC) study. AB - OBJECTIVE: The objective of this study was to determine potential added value of novel risk factors in predicting the development of type 2 diabetes beyond that provided by standard clinical risk factors. RESEARCH DESIGN AND METHODS: The Atherosclerosis Risk in Communities (ARIC) Study is a population-based prospective cohort study in four U.S. communities. Novel risk factors were either measured in the full cohort or in a case-control sample nested within the cohort. We started with a basic prediction model, previously validated in ARIC, and evaluated 35 novel risk factors by adding them independently to the basic model. The area under the curve (AUC), net reclassification index (NRI), and integrated discrimination index (IDI) were calculated to determine if each of the novel risk factors improved risk prediction. RESULTS: There were 1,457 incident cases of diabetes with a mean of >7.6 years of follow-up among 12,277 participants at risk. None of the novel risk factors significantly improved the AUC. Forced expiratory volume in 1 s was the only novel risk factor that resulted in a significant NRI (0.54%; 95% CI: 0.33-0.86%). Adiponectin, leptin, gamma-glutamyl transferase, ferritin, intercellular adhesion molecule 1, complement C3, white blood cell count, albumin, activated partial thromboplastin time, factor VIII, magnesium, hip circumference, heart rate, and a genetic risk score each significantly improved the IDI, but net changes were small. CONCLUSIONS: Evaluation of a large panel of novel risk factors for type 2 diabetes indicated only small improvements in risk prediction, which are unlikely to meaningfully alter clinical risk reclassification or discrimination strategies. PMID- 22933438 TI - Insulin degludec/insulin aspart administered once daily at any meal, with insulin aspart at other meals versus a standard basal-bolus regimen in patients with type 1 diabetes: a 26-week, phase 3, randomized, open-label, treat-to-target trial. AB - OBJECTIVE: To evaluate efficacy and tolerability of a co-formulation of insulin degludec and insulin aspart (IDegAsp) with insulin aspart (IAsp) at other meals compared with basal-bolus therapy using insulin detemir (IDet) and IAsp. RESEARCH DESIGN AND METHODS: Adults (n = 548) with type 1 diabetes (A1C 7.0-10.0%; BMI <=35.0 kg/m(2)) were randomized 2:1 in a 26-week, multinational, parallel-group, treat-to-target trial to IDegAsp or IDet. IDegAsp was given with a meal, and IDet was given in the evening, with a second (breakfast) dose added if needed. RESULTS: Non-inferiority for IDegAsp versus IDet was confirmed; A1C improved by 0.75% with IDegAsp and 0.70% with IDet to 7.6% in both groups (estimated treatment difference IDegAsp - IDet: -0.05% [95% CI -0.18 to 0.08]). There was no statistically significant difference between IDegAsp and IDet in the rates of severe hypoglycemia (0.33 and 0.42 episodes/patient-year, respectively) or overall confirmed (plasma glucose <3.1 mmol/L) hypoglycemia (39.17 and 44.34 episodes/patient-year, respectively). Nocturnal confirmed hypoglycemia rate was 37% lower with IDegAsp than IDet (3.71 vs. 5.72 episodes/patient-year, P < 0.05). Weight gain was 2.3 and 1.3 kg with IDegAsp and IDet, respectively (P < 0.05). Total insulin dose was 13% lower in the IDegAsp group (P < 0.0001). No treatment differences were detected in Health-Related Quality of Life, laboratory measurements, physical examination, vital signs, electrocardiograms, fundoscopy, or adverse events. CONCLUSIONS: IDegAsp in basal-bolus therapy with IAsp at additional mealtimes improves overall glycemic control and was non-inferior to IDet, with a reduced risk of nocturnal hypoglycemia and fewer injections in comparison with IDet + IAsp basal-bolus therapy. PMID- 22933439 TI - Longitudinal effects of MRI-measured hepatic steatosis on biomarkers of glucose homeostasis and hepatic apoptosis in obese youth. AB - OBJECTIVE: We used fast-gradient magnetic resonance imaging (MRI) to determine the longitudinal associations between the hepatic fat content (HFF), glucose homeostasis, and a biomarker of hepatocellular apoptosis in obese youth. RESEARCH DESIGN AND METHODS: Baseline and longitudinal liver and abdominal MRI were performed with an oral glucose tolerance test in 76 obese youth followed for an average of 1.9 years. Cytokeratin-18 (CK-18) was measured at baseline and follow up as a biomarker of hepatic apoptosis. The relationship between baseline HFF and metabolic parameters and circulating levels of CK-18 at follow-up were assessed using a bivariate correlation. RESULTS: At baseline, 38% had hepatic steatosis based on %HFF >=5.5% with alterations in indices of insulin sensitivity and secretion. At follow-up, BMI increased in both groups and baseline %HFF correlated strongly with the follow-up %HFF (r = 0.81, P < 0.001). Over time, markers of insulin sensitivity and 2-h glucose improved significantly in the group without fatty liver, in contrast with the persistence of the insulin resistance and associated correlates in the fatty liver group. Baseline HFF correlated with 2-h glucose (r = 0.38, P = 0.001), whole-body insulin sensitivity (r = -0.405, P = 0.001), adiponectin (r = -0.44, P < 0.001), CK-18 levels, (r = 0.63, P < 0.001), and disposition index (r = -0.272, P = 0.021) at follow-up. In a multivariate analysis, we showed that baseline HFF is an independent predictor of 2-h glucose and whole-body insulin sensitivity. CONCLUSIONS: In obese youth, the phenotype of MRI-measured hepatic steatosis is persistent. Baseline HFF strongly modulates longitudinally 2-h blood glucose, biomarkers of insulin resistance, and hepatocellular apoptosis. PMID- 22933440 TI - Influence of type 2 diabetes on brain volumes and changes in brain volumes: results from the Women's Health Initiative Magnetic Resonance Imaging studies. AB - OBJECTIVE: To study how type 2 diabetes adversely affects brain volumes, changes in volume, and cognitive function. RESEARCH DESIGN AND METHODS: Regional brain volumes and ischemic lesion volumes in 1,366 women, aged 72-89 years, were measured with structural brain magnetic resonance imaging (MRI). Repeat scans were collected an average of 4.7 years later in 698 women. Cross-sectional differences and changes with time between women with and without diabetes were compared. Relationships that cognitive function test scores had with these measures and diabetes were examined. RESULTS: The 145 women with diabetes (10.6%) at the first MRI had smaller total brain volumes (0.6% less; P = 0.05) and smaller gray matter volumes (1.5% less; P = 0.01) but not white matter volumes, both overall and within major lobes. They also had larger ischemic lesion volumes (21.8% greater; P = 0.02), both overall and in gray matter (27.5% greater; P = 0.06), in white matter (18.8% greater; P = 0.02), and across major lobes. Overall, women with diabetes had slightly (nonsignificant) greater loss of total brain volumes (3.02 cc; P = 0.11) and significant increases in total ischemic lesion volumes (9.7% more; P = 0.05) with time relative to those without diabetes. Diabetes was associated with lower scores in global cognitive function and its subdomains. These relative deficits were only partially accounted for by brain volumes and risk factors for cognitive deficits. CONCLUSIONS: Diabetes is associated with smaller brain volumes in gray but not white matter and increasing ischemic lesion volumes throughout the brain. These markers are associated with but do not fully account for diabetes-related deficits in cognitive function. PMID- 22933442 TI - Metabolic syndrome model definitions predicting type 2 diabetes and cardiovascular disease. AB - OBJECTIVE: Metabolic syndrome (MetS) is a cluster of abdominal obesity, hyperglycemia, hypertension, and dyslipidemia, which increases the risk for type 2 diabetes and cardiovascular diseases (CVDs). Some argue that MetS is not a single disorder because the traditional MetS features do not represent one entity, and they would like to exclude features from MetS. Others would like to add additional features in order to increase predictive ability of MetS. The aim of this study was to identify a MetS model that optimally predicts type 2 diabetes and CVD while still representing a single entity. RESEARCH DESIGN AND METHODS: In a random sample (n = 1,928) of the EPIC-NL cohort and a subset of the EPIC-NL MORGEN study (n = 1,333), we tested the model fit of several one-factor MetS models using confirmatory factor analysis. We compared predictive ability for type 2 diabetes and CVD of these models within the EPIC-NL case-cohort study of 545 incident type 2 diabetic subjects, 1,312 incident CVD case subjects, and the random sample, using survival analyses and reclassification. RESULTS: The standard model, representing the current MetS definition (EPIC-NL comparative fit index [CFI] = 0.95; MORGEN CFI = 0.98); the standard model excluding blood pressure (EPIC-NL CFI = 0.95; MORGEN CFI = 1.00); and the standard model extended with hsCRP (EPIC-NL CFI = 0.95) had an acceptable model fit. The model extended with hsCRP predicted type 2 diabetes (integral discrimination index [IDI]: 0.34) and CVD (IDI: 0.07) slightly better than did the standard model. CONCLUSIONS: It seems valid to represent the traditional MetS features by a single entity. Extension of this entity with hsCRP slightly improves predictive ability for type 2 diabetes and CVD. PMID- 22933441 TI - Relationship of insulin sensitivity, insulin secretion, and adiposity with insulin clearance in a multiethnic population: the insulin Resistance Atherosclerosis study. AB - OBJECTIVE: We aimed to examine insulin clearance, a compensatory mechanism to changes in insulin sensitivity, across sex, race/ethnicity populations, and varying states of glucose tolerance. RESEARCH DESIGN AND METHODS: We measured insulin sensitivity index (S(I)), acute insulin response (AIR), and metabolic clearance rate of insulin (MCRI) by the frequently sampled intravenous glucose tolerance test in 1,295 participants in the Insulin Resistance Atherosclerosis Study. RESULTS: MCRI was positively related to S(I) and negatively to AIR and adiposity across sex, race/ethnicity populations, and varying states of glucose tolerance, adiposity, and family history of diabetes. Differences in MCRI by race/ethnicity (lower in African Americans and Hispanics compared with non Hispanic whites) and glucose tolerance were largely explained by differences in adiposity, S(I), and AIR. CONCLUSIONS: Insulin sensitivity, insulin secretion, and adiposity are correlates of insulin clearance and appear to explain differences in insulin clearance by race/ethnicity and glucose tolerance status. PMID- 22933443 TI - Assessment of long-term storage on antimicrobial and cyclooxygenase-inhibitory properties of South African medicinal plants. AB - In traditional medicine, plant materials are often stored by traditional healers, plant gatherers and traders before they are eventually consumed or sold. The critical point is whether stored medicinal plants are as active as freshly harvested dried material. We evaluated the effects of long-term storage (12 or 16 years) on the antimicrobial (microplate dilution method) and anti-inflammatory (COX-1 and COX-2 inhibition) potencies of 21 extensively used traditional medicinal plants in treating pain and infection-related ailments. The minimum inhibitory concentration (MIC) values obtained against Staphylococcus aureus and Pseudomonas aeruginosa in the stored plant materials were generally either lower or roughly the same as in the fresh material. Most of the stored plant material had comparable minimum microbicidal concentration (MMC) values as the fresh material against S. aureus and P. aeruignosa. Similarly, the majority (71%) of the stored plant material had similar MIC and/or MMC values as fresh material against the fungus Candida albicans. The percentage inhibition of COX-1 by the majority (88%) of the stored material was not significantly different when compared to those freshly collected. Stored material of Clausena anisata, Ekebergia capensis and Trichilia dregeana showed a significantly higher COX-1 inhibition than the fresh material. The therapeutic and conservation implications of the results are discussed. PMID- 22933444 TI - Higher lipoprotein-associated phospholipase A2 levels are associated with coronary atherosclerosis documented by coronary angiography. AB - BACKGROUND: Lipoprotein-associated phospholipase A2 (Lp-PLA2) has been proposed as an inflammatory marker of cardiovascular disease. The present study investigates associations between Lp-PLA2 and other important biomarkers in Japanese patients with coronary artery disease. METHODS: We measured Lp-PLA2 levels in 141 consecutive patients (age 62.6 +/- 3.8 years; men 69.2%) with angiographic evidence of coronary artery disease (acute coronary syndrome [ACS]; n = 38), stable angina pectoris (SAP; n = 72) or with angiographically normal coronary arteries (NCA; n = 31). RESULTS: Levels of Lp-PLA2 significantly correlated with low-density lipoprotein-cholesterol (r = 0.302), homocysteine (r = 0.528) and paraoxonase (r = 0.401) in all patients (all P < 0.01). Levels of Lp PLA2 were significantly higher in patients with coronary atherosclerosis (ACS and SAP) than with NCA (P < 0.05). Levels of highly sensitive C-reactive protein were significantly higher in patients with ACS than with SAP and NCA (both P < 0.05). Multivariate logistic regression analyses revealed that higher Lp-PLA2 levels were independently associated with coronary atherosclerosis (odds ratio: 1.058; 95% confidence interval: 1.012-1.121; P = 0.001). CONCLUSIONS: Higher Lp-PLA2 levels are associated with coronary atherosclerosis independently of traditional coronary risk factors. Thus, Lp-PLA2 is a novel biomarker of coronary atherosclerosis in Japanese patients. PMID- 22933445 TI - Activated platelet-derived microparticle numbers are elevated in patients with severe fungal (Candida albicans) sepsis. AB - BACKGROUND: The treatment of severe sepsis highly depends on the identification of bacteria or fungi from blood and/or other body materials. Although widely available blood culturing and risk assessment scores are not completely reliable, current guidelines do not recommend the wide empirical use of antifungal medications based on questionable benefit or possible side-effects. We aimed to test whether platelet-derived microparticle (MP) measurements can improve the early detection of the infective agent behind sepsis. METHODS: Thirty-three consecutive severe septic patients from our university intensive care unit were included in our prospective study. MP number and surface antigen characteristics were followed by flow cytometry on days 1 (admission), 3 and 5. For microbiological identification, various specimens were collected on admission and in case of overall status deterioration. RESULTS: On admission, septic patients showed elevated annexin V and constitutive platelet marker (CD41)-positive MP numbers compared with volunteers. Mixed fungal septic patients showed significantly elevated annexin V and CD41-positive particle numbers on day 1 (P < 0.05) compared with the non-fungal septic group. Adhesive platelet marker (CD42a) harbouring vesicles were negligible in the non-fungal group, while fungal septic patients showed significantly elevated numbers in all measurements (P < 0.01). Particles from activated platelets (PAC1) had elevated numbers in the first and fifth study days compared with non-fungal septic patients (P < 0.05). CONCLUSIONS: The measurement of CD42a- and PAC1-positive microparticles may provide important additional information which can help to improve the early instalment of antifungal therapy of severe septic patients. PMID- 22933446 TI - Obesity in sub-Saharan Africa: development of an ecological theoretical framework. AB - The prevalence of overweight and obesity is increasing in sub-Saharan Africa (SSA). There is a need for theoretical frameworks to catalyze further research and to inform the development of multi-level, context-appropriate interventions. In this commentary, we propose a preliminary ecological theoretical framework to conceptualize factors that contribute to increases in overweight and obesity in SSA. The framework is based on a Causality Continuum model [Coreil et al. Social and Behavioral Foundations of Public Health. Sage Publications, Thousand Oaks] that considers distant, intermediate and proximate influences. The influences incorporated in the model include globalization and urbanization as distant factors; occupation, social relationships, built environment and cultural perceptions of weight as intermediate factors and caloric intake, physical inactivity and genetics as proximate factors. The model illustrates the interaction of factors along a continuum, from the individual to the global marketplace, in shaping trends in overweight and obesity in SSA. The framework will be presented, each influence elucidated and implications for research and intervention development discussed. There is a tremendous need for further research on obesity in SSA. An improved evidence base will serve to validate and develop the proposed framework further. PMID- 22933448 TI - Chronic hydrocarbon exposure of harlequin ducks in areas affected by the Selendang Ayu oil spill at Unalaska Island, Alaska. AB - We evaluated chronic exposure of harlequin ducks (Histrionicus histrionicus) to hydrocarbons associated with the 2004 M/V Selendang Ayu oil spill at Unalaska Island, Alaska. We measured levels of hepatic 7-ethoxyresorufin-O-deethylase activity (EROD) in liver biopsy samples as an indicator of hydrocarbon exposure in three oiled bays and one reference bay in 2005, 2006, and 2008. Median EROD activity in ducks from oiled bays was significantly higher than in the reference bay in seven of nine pairwise comparisons. These results indicated that harlequin ducks were exposed to lingering hydrocarbons more than three years after the spill. PMID- 22933449 TI - Disclosing the structure/activity correlation in trivalent boron-containing compounds: a tendency map. AB - Most trivalent boron reagents are electrophiles owing to the vacancy for two electrons to fill the outer orbital of boron; however, interestingly, trivalent boron compounds can change their electrophilic character to a nucleophilic character by only changing the nature of the substituents on the boron atoms. With the help of computational tools, we have analyzed the structural- and electronic properties of boryl fragments that were either bonded to main-group metals or coordinated to transition-metals/rare-earth-metals and we have designed a map that might help to identify certain trends. This trend map will be useful for selecting an appropriate trivalent boron compound, depending on the sought reactivity. PMID- 22933447 TI - Neural tube defects and maternal intake of micronutrients related to one-carbon metabolism or antioxidant activity. AB - BACKGROUND: Maternal nutritional status has been evaluated to clarify its role in development of neural tube defects (NTDs). Maternal folate intake during pregnancy has been closely evaluated for its association with NTDs. The study objective was to examine associations between NTDs and other dietary periconceptional micronutrient intake, particularly nutrients involved in one carbon metabolism or antioxidant activity. METHODS: Using data from the National Birth Defects Prevention Study, 1997-2005, logistic regression models were used to estimate the relative risk of NTDs based on maternal micronutrient intake. RESULTS: Results were stratified according to folic acid supplement use, race/ethnicity, and maternal body mass index. Analyses included 954 cases (300 with anencephaly, 654 with spina bifida) and 6268 controls. Higher intakes of folate, thiamin, betaine, iron, and vitamin A were associated with decreased risk of anencephaly among some ethnic and clinical groups. In some groups, higher intakes of thiamin, riboflavin, vitamin B(6) , vitamin C, vitamin E, niacin, and retinol were associated with decreased risk of spina bifida. CONCLUSION: In addition to folic acid, other micronutrients, including thiamin, betaine, riboflavin, vitamin B(6) , vitamin C, vitamin E, niacin, iron, retinol, and vitamin A, may decrease the risk of NTD occurrence. Birth Defects Research (Part A) 2012. (c) 2012 Wiley Periodicals, Inc. PMID- 22933450 TI - Perception and presentation of function in patients with unilateral versus bilateral knee osteoarthritis. AB - OBJECTIVE: Lower extremity functional performance and perception of functional abilities influence clinical management in people diagnosed with unilateral or bilateral knee osteoarthritis (OA). The purpose of this study was to determine if there were differences in perception of function and performance during functional tasks between individuals with unilateral and bilateral knee OA. METHODS: The functional abilities of patients with symptomatic and radiographic diagnosed unilateral (n = 84) or bilateral (n = 68) knee OA were evaluated with self-report measures and performance-based tests. Self-report measures included the Knee Outcome Survey, the Global Rating Scale, and the physical component of the Short Form 36 health survey; functional tests included the Timed Up-and-Go Test, the Stair Climbing Test, and the 6-Minute Walk Test. Multivariate analyses of variance were performed separately for men and women to determine if perception (self-report measures) and performance (functional tests) were dependent on the number of involved knees. RESULTS: No significant main effects were observed in functional performance between groups for either sex. Similarly, the perception measures did not differ between groups. In general, individuals diagnosed with unilateral and bilateral knee OA both performed functional tasks and perceived their functional ability similarly. CONCLUSION: Regardless of the number of involved knees, individuals with knee OA perform and perceive their functional ability similarly, which suggests that clinicians need to consider other factors, such as how long the disease has been progressing or how functional abilities have changed, when treating patients with knee OA. PMID- 22933451 TI - Self-report and clinician-rated measures of depression severity: can one replace the other? AB - BACKGROUND: It has been suggested that clinician-rated scales and self-report questionnaires may be interchangeable in the measurement of depression severity, but it has not been tested whether clinically significant information is lost when assessment is restricted to either clinician-rated or self-report instruments. The aim of this study is to test whether self-report provides information relevant to short-term treatment outcomes that is not captured by clinician-rating and vice versa. METHODS: In genome-based drugs for depression (GENDEP), 811 patients with major depressive disorder treated with escitalopram or nortriptyline were assessed with the clinician-rated Montgomery-Asberg Depression Rating Scale (MADRS), Hamilton Rating Scale for Depression (HRSD), and the self-report Beck Depression Inventory (BDI). In sequenced treatment alternatives to relieve depression (STAR*D), 4,041 patients treated with citalopram were assessed with the clinician-rated and self-report versions of the Quick Inventory of Depressive Symptomatology (QIDS-C and QIDS-SR) in addition to HRSD. RESULTS: In GENDEP, baseline BDI significantly predicted outcome on MADRS/HRSD after adjusting for baseline MADRS/HRSD, explaining additional 3 to 4% of variation in the clinician-rated outcomes (both P < .001). Likewise, each clinician-rated scale significantly predicted outcome on BDI after adjusting for baseline BDI and explained additional 1% of variance in the self-reported outcome (both P < .001). The results were confirmed in STAR*D, where self-report and clinician-rated versions of the same instrument each uniquely contributed to the prediction of treatment outcome. CONCLUSIONS: Complete assessment of depression should include both clinician-rated scales and self-reported measures. PMID- 22933454 TI - Cardiac proton spectroscopy using large coil arrays. AB - Large coil arrays are widely used in clinical routine for cardiovascular imaging providing extended spatial coverage and enabling accelerated acquisition using parallel imaging approaches. This work investigates the use of large coil arrays in single-voxel cardiac spectroscopy for the detection of myocardial creatine and triglyceride content. For this purpose, a navigator-gated and cardiac-triggered point-resolved spectroscopy sequence was implemented, and data obtained in 11 healthy volunteers using 32- and 5-element coil arrays were compared. For combination of the individual coil element signals, four strategies were evaluated differing in the manner of estimation of the complex coil weights and the amount of additional information required for coil combination. In all volunteers, and with both the 32- and 5-channel coil arrays, triglyceride-to water (0.44 +/- 0.19% and 0.45 +/- 0.17%) and total creatine-to-water (0.05 +/- 0.02% and 0.05 +/- 0.01%) contents were computed. The values were found to agree well, showing an intraclass correlation coefficient of 0.76 (p < 0.003). The results revealed a gain in signal-to-noise ratio of approximately 24% with the 32 channel coil relative to the 5-channel array. The findings may foster the integration of cardiac spectroscopy into clinical practice using large coil arrays, provided that appropriate reconstruction algorithms are implemented. PMID- 22933455 TI - Stepping out of the caveman's shadow: nations' gender gap predicts degree of sex differentiation in mate preferences. AB - An influential explanation for gender differences in mating strategies is that the sex-specific reproductive constraints faced by human ancestors shaped these differences. Other theorists have emphasized the role of societal factors, hypothesizing, for example, that gender differences in mate preferences should wane in gender-equal societies. However, findings have been ambiguous. Using recent data and a novel measure of gender equality, we revisited the role of gender parity in gender differentiation for mate preferences. In the first study, 3,177 participants from 10 nations with a gradually decreasing Global Gender Gap Index (GGI) provided online ratings of the desirability of mate attributes with reportedly evolutionary origins. In the second study, GGI scores were related to gender differences in mate preferences previously reported for 8,953 participants from 31 nations (Buss, 1989). Both studies show that gender differences in mate preferences with presumed evolutionary roots decline proportionally to increases in nations' gender parity. PMID- 22933452 TI - Transducing bioelectric signals into epigenetic pathways during tadpole tail regeneration. AB - One important component of the cell-cell communication that occurs during regenerative patterning is bioelectrical signaling. In particular, the regeneration of the tail in Xenopus laevis tadpoles both requires, and can be initiated at non-regenerative stages by, specific regulation of bioelectrical signaling (alteration in resting membrane potential and a subsequent change in sodium content of blastemal cells). Although standing gradients of transmembrane voltage and ion concentration can provide positional guidance and other morphogenetic cues, these biophysical parameters must be transduced into transcriptional responses within cells. A number of mechanisms have been described for linking slow voltage changes to gene expression, but recent data on the importance of epigenetic regulation for regeneration suggest a novel hypothesis: that sodium/butyrate transporters link ion flows to influx of small molecules needed to modify chromatin state. Here, we briefly review the data on bioelectricity in tadpole tail regeneration, present a technique for convenient alteration of transmembrane potential in vivo that does not require transgenes, show augmentation of regeneration in vivo by manipulation of voltage, and present new data in the Xenopus tail consistent with the hypothesis that the monocarboxlyate transporter SLC5A8 may link regeneration-relevant epigenetic modification with upstream changes in ion content. PMID- 22933456 TI - Is choice-induced preference change long lasting? AB - The idea that decisions alter preferences has had a considerable influence on the field of psychology and underpins cognitive dissonance theory. Yet it is unknown whether choice-induced changes in preferences are long lasting or are transient manifestations seen in the immediate aftermath of decisions. In the research reported here, we investigated whether these changes in preferences are fleeting or stable. Participants rated vacation destinations before making hypothetical choices between destinations, immediately afterward, and 2.5 to 3 years later. We found that choices altered preferences both immediately after being made and after the delay. These changes could not be accounted for by participants' preexisting preferences, and they occurred only when participants made the choices themselves. Our findings provide evidence that making a decision can lead to enduring change in preferences. PMID- 22933457 TI - Identifying the bad guy in a lineup using confidence judgments under deadline pressure. AB - Eyewitness-identification tests often culminate in witnesses not picking the culprit or identifying innocent suspects. We tested a radical alternative to the traditional lineup procedure used in such tests. Rather than making a positive identification, witnesses made confidence judgments under a short deadline about whether each lineup member was the culprit. We compared this deadline procedure with the traditional sequential-lineup procedure in three experiments with retention intervals ranging from 5 min to 1 week. A classification algorithm that identified confidence criteria that optimally discriminated accurate from inaccurate decisions revealed that decision accuracy was 24% to 66% higher under the deadline procedure than under the traditional procedure. Confidence profiles across lineup stimuli were more informative than were identification decisions about the likelihood that an individual witness recognized the culprit or correctly recognized that the culprit was not present. Large differences between the maximum and the next-highest confidence value signaled very high accuracy. Future support for this procedure across varied conditions would highlight a viable alternative to the problematic lineup procedures that have traditionally been used by law enforcement. PMID- 22933458 TI - Inattention abolishes binocular rivalry: perceptual evidence. AB - Binocular rivalry refers to the unstable perceptual experience that arises when an observer views a different image with each eye: Each image reaches awareness in turn as the other becomes temporarily invisible. Using a novel experimental paradigm, we provide the first direct, perceptual evidence that binocular rivalry occurs only in the presence of attention. Observers in our experiment withdrew attention from a binocular rivalry stimulus shortly after one of the eyes' images was forced to visibility. Seconds later, they shifted attention back to the stimulus to report their perception. For all observers, reported perception strongly and significantly deviated from the results that would be expected if binocular rivalry continued during inattention. Strikingly, reports instead exactly matched those obtained when the stimulus was physically removed for seconds rather than left unattended. These results show that disregarding a binocular rivalry stimulus is equivalent to having it removed from view. Thus, inattention abolishes binocular rivalry. PMID- 22933459 TI - Aging and wisdom: culture matters. AB - People from different cultures vary in the ways they approach social conflicts, with Japanese being more motivated to maintain interpersonal harmony and avoid conflicts than Americans are. Such cultural differences have developmental consequences for reasoning about social conflict. In the study reported here, we interviewed random samples of Americans from the Midwest United States and Japanese from the larger Tokyo area about their reactions to stories of intergroup and interpersonal conflicts. Responses showed that wisdom (e.g., recognition of multiple perspectives, the limits of personal knowledge, and the importance of compromise) increased with increasing age among Americans, but older age was not associated with wiser responses among Japanese. Younger and middle-aged Japanese showed greater use of wise-reasoning strategies than younger and middle-aged Americans did. This cultural difference was weaker for older participants' reactions to interpersonal conflicts and was actually reversed for intergroup conflicts. This research has important implications for the study of aging, cultural psychology, and wisdom. PMID- 22933460 TI - Psychometric properties of the dimensional anxiety scales for DSM-V in an unselected sample of German treatment seeking patients. AB - BACKGROUND: Dimensional assessments are planned to be included as supplements to categorical diagnoses in DSM-V. The aim of this study was to examine the unidimensionality, reliability, validity, and clinical sensitivity of brief self rated scales for specific anxiety disorders in an unselected German sample of consecutive attendees to a psychological clinic. These scales use a common template to assess core constructs of fear and anxiety. METHODS: Dimensional scales for social anxiety disorder, specific phobia, agoraphobia, panic disorder, and generalized anxiety disorder were administered along with established scales to 102 adults seeking treatment for mental health problems at a German university outpatient clinic for psychotherapy. The computer-assisted clinical version of the Munich-Composite International Diagnostic Interview was used to assess mental disorders according to DSM-IV criteria. Dimensionality and scale reliability were examined using confirmatory factor analyses. Convergent and discriminant validity were examined by testing differences in the size of correlations between each dimensional anxiety scale and each of the previously validated scales. Each dimensional scale's ability to correctly differentiate between individuals with versus without an anxiety diagnosis was examined via the area under the curve. RESULTS: Analyses revealed unidimensionality for each scale, high reliability, and convergent and discriminant validity. Classification performance was good to excellent for all scales except for specific phobia. CONCLUSIONS: The application of the dimensional anxiety scales may be an effective way to screen for specific anxiety disorders and to supplement categorical diagnoses in DSM-V, although further evaluation and refinement of the scales (particularly the specific phobia scale) is needed. PMID- 22933461 TI - Micro-computed tomography for visualizing limb skeletal regeneration in young Xenopus frogs. AB - For studies of vertebrate limb regeneration it is often desirable to visualize the regenerated skeleton, which is mostly cartilage, and also section the specimen for histological or immunohistochemical visualization of other tissues. However, the normal skeletal staining techniques are incompatible with immunohistochemistry. Here, we describe a contrast-based micro-computed tomography (microCT) method for direct and nondestructive observation of regenerated cartilage spikes in Xenopus frog limbs. In addition, we show that contrast based microCT imaging is compatible with immunohistochemistry protocols. This approach provides versatile and high contrast images of the cartilage allowing us to measure the regenerated skeletal structure in detail as well as carrying out the other types of analysis. It opens a wide range of potential microCT applications in research on vertebrate limb regeneration. PMID- 22933462 TI - A molecular shuttle driven by fullerene radical-anion recognition. AB - We describe a electrochemically driven molecular shuttle, in which shuttling takes place by means of fullerene radical-anion recognition that results in a very low operation potential (E(1/2) =-0.580 V vs. decamethylferrocene). This has been achieved by introducing positive charges on the macrocycle, which strengthen the existing pi-pi interactions between the macrocycle and the electrogenerated fullerene radical anion by means of an electrostatic component. In addition, the synthesis of such a molecular shuttle has been accomplished by developing a new synthetic approach that exploits the controlled translocation of the macrocycle as a selective protecting group. PMID- 22933467 TI - Improving abstinence in comorbid substance disorder in a mental health unit. PMID- 22933468 TI - A murder-suicide in sculpture. PMID- 22933464 TI - Coupling diffusion imaging with histological and gene expression analysis to examine the dynamics of cortical areas across the fetal period of human brain development. AB - As a prominent component of the human fetal brain, the structure of the cerebral wall is characterized by its laminar organization which includes the radial glial scaffold during fetal development. Diffusion tensor imaging (DTI) is useful to quantitatively delineate the microstructure of the developing brain and to clearly identify transient fetal layers in the cerebral wall. In our study, the spatio-temporal microstructural changes in the developing human fetal cerebral wall were quantitatively characterized with high-resolution DTI data of postmortem fetal brains from 13 to 21 gestational weeks. Eleven regions of interest for each layer in the entire cerebral wall were included. Distinctive time courses of microstructural changes were revealed for 11 regions of the neocortical plate. A histological analysis was also integrated to elucidate the relationship between DTI fractional anisotropy (FA) and histology. High FA values correlated with organized radial architecture in histological image. Expression levels of 17565 genes were quantified for each of 11 regions of human fetal neocortex from 13 to 21 gestational weeks to identify transcripts showing significant correlation with FA change. These correlations suggest that the heterogeneous and regionally specific microstructural changes of the human neocortex are related to different gene expression patterns. PMID- 22933478 TI - Three-dimensional graphene network composites for detection of hydrogen peroxide. AB - A three-dimensional graphene network (3DGN) prepared by CVD is used as a template to synthesize various composites. These composites are further used as electrodes for electrochemical sensors, which exhibit a low detection limit, quick response time, and wide linear range toward the detection of H2O2 . PMID- 22933479 TI - Telemonitoring for infants at risk of apnoea, bradycardia and hypoxaemia: transmission of data improves the family compliance during home monitoring. AB - We evaluated the compliance of families using telemonitoring and families using conventional home monitoring in infants at risk of apnoea, bradycardia and hypoxaemia. Families who used the telemedicine system could perform the remote data transmission from their home. Families who used the conventional system had to come to the regional centre to download the cardiorespiratory traces captured by the monitor. A total of 175 patients examined at the Regional Centre for Sudden Infant Death Syndrome (SIDS) in Florence were included in the 5-year study. Good compliance was defined as an average daily use of 10 hours or more; insufficient compliance was defined as an average daily use of less than 10 hours. The Centre analysed 612 data downloads, 339 from the telemedicine system and 273 from the conventional system. This represented a total of 105,061 hours of data during 12,862 days of home monitoring. The compliance of families who used the telemedicine system was significantly higher than that of families who used the conventional system. Of the 105 families who used the conventional system, 50 (48%) were good compliers. Of the 70 families who used the telemedicine system, 49 (70%) were good compliers. Telemedicine was associated with a significant improvement in the compliance of families using cardiorespiratory monitors. PMID- 22933480 TI - Validity of the Patient Health Questionnaire, PHQ-9, administered through interactive-voice-response technology. AB - We compared the administration of the 9-item Patient Health Questionnaire (PHQ-9) to assess depressive symptoms using interactive voice response (IVR) technology with the method of administration using paper-and-pencil. Data were collected from 51 veterans participating in an 8-week randomized controlled trial of an illness management programme for heart failure. To counter possible bias in answering questions via IVR technology, the anchoring responses of the PHQ-9 questionnaire were reversed so that lower numbers corresponded to more severe depression. The mean for the pencil-and-paper administered PHQ-9 was 4.1 (SD = 4.5) and the mean for IVR administration was 2.8 (SD = 3.1). The internal consistency (Cronbach's alpha) of the PHQ-9 was 0.76 for IVR administration and 0.82 for paper administration. The intraclass correlation coefficient for the two modes of administration was 0.65, indicating moderate agreement. IVR administration of the PHQ-9 produces similar results to pencil-and-paper administration, but the former is not as sensitive to higher levels of depressive symptom severity. This suggests that a lower threshold for probable depression is warranted when assessing depressive symptoms with IVR. PMID- 22933481 TI - What can the management of kidney transplantation teach us about the management of lupus nephritis? Comment on the article by Hahn et al. PMID- 22933482 TI - Early regulation of axolotl limb regeneration. AB - Amphibian limb regeneration has been studied for a long time. In amphibian limb regeneration, an undifferentiated blastema is formed around the region damaged by amputation. The induction process of blastema formation has remained largely unknown because it is difficult to study the induction of limb regeneration. The recently developed accessory limb model (ALM) allows the investigation of limb induction and reveals early events of amphibian limb regeneration. The interaction between nerves and wound epidermis/epithelium is an important aspect of limb regeneration. During early limb regeneration, neurotrophic factors act on wound epithelium, leading to development of a functional epidermis/epithelium called the apical epithelial cap (AEC). AEC and nerves create a specific environment that inhibits wound healing and induces regeneration through blastema formation. It is suggested that FGF-signaling and MMP activities participate in creating a regenerative environment. To understand why urodele amphibians can create such a regenerative environment and humans cannot, it is necessary to identify the similarities and differences between regenerative and nonregenerative animals. Here we focus on ALM to consider limb regeneration from a new perspective and we also reported that focal adhesion kinase (FAK)-Src signaling controlled fibroblasts migration in axolotl limb regeneration. PMID- 22933484 TI - The local infiltration of analgesia following total knee replacement: a review of current literature. AB - Controversy remains regarding the optimal post-operative analgesic regimen following total knee replacement. A delicate balance is required between the provision of adequate pain relief and early mobilisation. By reviewing 29 randomised trials we sought to establish whether local infiltration of analgesia directly into the knee during surgery provides better pain relief and a more rapid rehabilitation. Although we were able to conclude that local infiltration can provide improved post-operative pain relief, and to suggest the most promising technique of administration, there is no evidence that it reduces hospital stay. PMID- 22933485 TI - The operative management of osteoporotic fractures of the knee: to fix or replace? AB - This review considers the surgical treatment of displaced fractures involving the knee in elderly, osteoporotic patients. The goals of treatment include pain control, early mobilisation, avoidance of complications and minimising the need for further surgery. Open reduction and internal fixation (ORIF) frequently results in loss of reduction, which can result in post-traumatic arthritis and the occasional conversion to total knee replacement (TKR). TKR after failed internal fixation is challenging, with modest functional outcomes and high complication rates. TKR undertaken as treatment of the initial fracture has better results to late TKR, but does not match the outcome of primary TKR without complications. Given the relatively infrequent need for late TKR following failed fixation, ORIF is the preferred management for most cases. Early TKR can be considered for those patients with pre-existing arthritis, bicondylar femoral fractures, those who would be unable to comply with weight bearing restrictions, or where a single definitive procedure is required. PMID- 22933486 TI - The use of a virtual learning environment in promoting virtual journal clubs and case-based discussions in trauma and orthopaedic postgraduate medical education: the Leicester experience. AB - The use of journal clubs and, more recently, case-based discussions in order to stimulate debate among orthopaedic surgeons lies at the heart of orthopaedic training and education. A virtual learning environment can be used as a platform to host virtual journal clubs and case-based discussions. This has many advantages in the current climate of constrained time and diminishing trainee and consultant participation in such activities. The virtual environment model opens up participation and improves access to journal clubs and case-based discussions, provides reusable educational content, establishes an electronic record of participation for individuals, makes use of multimedia material (including clinical imaging and photographs) for discussion, and finally, allows participants to link case-based discussions with relevant papers in the journal club. The Leicester experience highlights the many advantages and some of the potential difficulties in setting up such a virtual system and provides useful guidance for those considering such a system in their own training programme. As a result of the virtual learning environment, trainee participation has increased and there is a trend for increased consultant input in the virtual journal club and case-based discussions. It is likely that the use of virtual environments will expand to encompass newer technological approaches to personal learning and professional development. PMID- 22933487 TI - Imaging the vascularisation of the femoral head by CT angiography. AB - The femoral head receives its blood supply primarily from the medial femoral circumflex artery, with its deep branch being the most important. In a previous study, we performed classical anatomical dissections of 16 hips. We have extended our investigation with a radiological study, in which we aimed to visualise the arteries supplying the femoral head in healthy individuals. We analysed 55 CT angiographic images of the hip. Using 64-row CT angiography, we identified three main arteries supplying the femoral head: the deep branch of the medial femoral circumflex artery and the posterior inferior nutrient artery originating from the medial femoral circumflex artery, and the piriformis branch of the inferior gluteal artery. CT angiography is a good method for visualisation of the arteries supplying the femoral head. The current radiological studies will provide information for further investigation of vascularity after traumatic dislocation of the hip, using CT angiography. PMID- 22933488 TI - The ten-year survival of the Birmingham hip resurfacing: an independent series. AB - Recent events have highlighted the importance of implant design for survival and wear-related complications following metal-on-metal hip resurfacing arthroplasty. The mid-term survival of the most widely used implant, the Birmingham Hip Resurfacing (BHR), has been described by its designers. The aim of this study was to report the ten-year survival and patient-reported functional outcome of the BHR from an independent centre. In this cohort of 554 patients (646 BHRs) with a mean age of 51.9 years (16.5 to 81.5) followed for a mean of eight years (1 to 12), the survival and patient-reported functional outcome depended on gender and the size of the implant. In female hips (n = 267) the ten-year survival was 74% (95% confidence interval (CI) 83 to 91), the ten-year revision rate for pseudotumour was 7%, the mean Oxford hip score (OHS) was 43 (SD 8) and the mean UCLA activity score was 6.4 (SD 2). In male hips (n = 379) the ten-year survival was 95% (95% CI 92.0 to 97.4), the ten-year revision rate for pseudotumour was 1.7%, the mean OHS was 45 (SD 6) and the mean UCLA score was 7.6 (SD 2). In the most demanding subgroup, comprising male patients aged < 50 years treated for primary osteoarthritis, the survival was 99% (95% CI 97 to 100). This study supports the ongoing use of resurfacing in young active men, who are a subgroup of patients who tend to have problems with conventional THR. In contrast, the results in women have been poor and we do not recommend metal-on-metal resurfacing in women. Continuous follow-up is recommended because of the increasing incidence of pseudotumour with the passage of time. PMID- 22933489 TI - Can T1-rho MRI detect acetabular cartilage degeneration in femoroacetabular impingement?: a pilot study. AB - Advanced MRI cartilage imaging such as T(1)-rho (T1rho) for the diagnosis of early cartilage degradation prior to morpholgic radiological changes may provide prognostic information in the management of joint disease. This study aimed first to determine the normal T1rho profile of cartilage within the hip, and secondly to identify any differences in T1rho profile between the normal and symptomatic femoroacetabular impingement (FAI) hip. Ten patients with cam-type FAI (seven male and three female, mean age 35.9 years (28 to 48)) and ten control patients (four male and six female, mean age 30.6 years (22 to 35)) underwent 1.5T T1rho MRI of a single hip. Mean T1rho relaxation times for full thickness and each of the three equal cartilage thickness layers were calculated and compared between the groups. The mean T1rho relaxation times for full cartilage thickness of control and FAI hips were similar (37.17 ms (SD 9.95) and 36.71 ms (SD 6.72), respectively). The control group demonstrated a T1rho value trend, increasing from deep to superficial cartilage layers, with the middle third having significantly greater T1rho relaxation values than the deepest third (p = 0.008). The FAI group demonstrated loss of this trend. The deepest third in the FAI group demonstrated greater T1rho relaxation values than controls (p = 0.028). These results suggest that 1.5T T1rho MRI can detect acetabular hyaline cartilage changes in patients with FAI. PMID- 22933490 TI - The classification of degenerative hip disease. AB - It is probable that both genetic and environmental factors play some part in the aetiology of most cases of degenerative hip disease. Geneticists have identified some single gene disorders of the hip, but have had difficulty in identifying the genetics of many of the common causes of degenerative hip disease. The heterogeneity of the phenotypes studied is part of the problem. A detailed classification of phenotypes is proposed. This study is based on careful documentation of 2003 consecutive total hip replacements performed by a single surgeon between 1972 and 2000. The concept that developmental problems may initiate degenerative hip disease is supported. The influences of gender, age and body mass index are outlined. Biomechanical explanations for some of the radiological appearances encountered are suggested. The body weight lever, which is larger than the abductor lever, causes the abductor power to be more important than body weight. The possibility that a deficiency in joint lubrication is a cause of degenerative hip disease is discussed. Identifying the phenotypes may help geneticists to identify genes responsible for degenerative hip disease, and eventually lead to a definitive classification. PMID- 22933491 TI - Medial patellofemoral ligament reconstruction: a prospective outcome assessment of a large single centre series. AB - We report a prospective analysis of clinical outcome in patients treated with medial patellofemoral ligament (MPFL) reconstruction using an autologous semitendinosus graft. The technique includes superolateral portal arthroscopic assessment before and after graft placement to ensure correct graft tension and patellar tracking before fixation. Between October 2005 and October 2010, a total of 201 consecutive patients underwent 219 procedures. Follow-up is presented for 211 procedures in 193 patients with a mean age of 26 years (16 to 49), and mean follow-up of 16 months (6 to 42). Indications were atraumatic recurrent patellar dislocation in 141 patients, traumatic recurrent dislocation in 50, pain with subluxation in 14 and a single dislocation with persistent instability in six. There have been no recurrent dislocations/subluxations. There was a statistically significant improvement between available pre- and post-operative outcome scores for 193 patients (all p < 0.001). Female patients with a history of atraumatic recurrent dislocation and all patients with history of previous surgery had a significantly worse outcome (all p < 0.05). The indication for surgery, degree of dysplasia, associated patella alta, time from primary dislocation to surgery and evidence of associated cartilage damage at operation did not result in any significant difference in outcome. This series adds considerably to existing evidence that MPFL reconstruction is an effective surgical procedure for selected patients with patellofemoral instability. PMID- 22933492 TI - MRI evaluation of rotational alignment and synovitis in patients with pain after total knee replacement. AB - Component malalignment can be associated with pain following total knee replacement (TKR). Using MRI, we reviewed 50 patients with painful TKRs and compared them with a group of 16 asymptomatic controls to determine the feasibility of using MRI in evaluating the rotational alignment of the components. Using the additional soft-tissue detail provided by this modality, we also evaluated the extent of synovitis within these two groups. Angular measurements were based on the femoral transepicondylar axis and tibial tubercle. Between two observers, there was very high interobserver agreement in the measurements of all values. Patients with painful TKRs demonstrated statistically significant relative internal rotation of the femoral component (p = 0.030). There was relative internal rotation of the tibial to femoral component and combined excessive internal rotation of the components in symptomatic knees, although these results were significant only with one of the observers (p = 0.031). There was a statistically significant association between the presence and severity of synovitis and painful TKR (p < 0.001). MRI is an effective modality in evaluating component rotational alignment. PMID- 22933493 TI - Outcome of combined unicompartmental knee replacement and combined or sequential anterior cruciate ligament reconstruction: a study of 52 cases with mean follow up of five years. AB - The Oxford unicompartmental knee replacement (UKR) is an established treatment option in the management of symptomatic end-stage medial compartmental osteoarthritis (MCOA), which works well in the young and active patient. However, previous studies have shown that it is reliable only in the presence of a functionally intact anterior cruciate ligament (ACL). This review reports the outcomes, at a mean of five years and a maximum of ten years, of 52 consecutive patients with a mean age of 51 years (36 to 57) who underwent staged or simultaneous ACL reconstruction and Oxford UKR. At the last follow-up (with one patient lost to follow-up), the mean Oxford knee score was 41 (sd 6.3; 17 to 48). Two patients required conversion to TKR: one for progression of lateral compartment osteoarthritis and one for infection. Implant survival at five years was 93% (95% CI 83 to 100). All but one patient reported being satisfied with the procedure. The outcome was not significantly influenced by age, gender, femoral or tibial tunnel placement, or whether the procedure was undertaken at one- or two-stages. In summary, ACL reconstruction and Oxford UKR gives good results in patients with end-stage MCOA secondary to ACL deficiency. PMID- 22933494 TI - Comparison of the Genesis II total knee replacement with oxidised zirconium and cobalt-chromium femoral components in the same patients: a prospective, double blind, randomised controlled study. AB - Despite many claims of good wear properties following total knee replacement (TKR) with an oxidised zirconium (OxZr) femoral component, there are conflicting clinical results. We hypothesised that there would be no difference in either the mid-term clinical and radiological outcomes or the characteristics of the polyethylene wear particles (weight, size and shape) in patients using an OxZr or cobalt-chrome (CoCr) femoral component. In all 331 patients underwent bilateral TKR, receiving an OxZr femoral component in one knee and a CoCr femoral component in the other. The mean follow-up was 7.5 years (6 to 8). Following aspiration, polyethylene wear particles were analysed using thermogravimetric methods and scanning electron microscopy. At the most recent follow-up, the mean Knee Society score, Western Ontario and McMaster Universities Osteoarthritis Index score, range of movement and satisfaction score were not significantly different in the two groups. The mean weight, size, aspect ratio and roundness of the aspirated wear particles were similar for each femoral component. Survivorship of the femoral, tibial and patellar components was 100% in both groups. In the absence of evidence of an advantage in the medium term we cannot justify the additional expense of an OxZr femoral component. PMID- 22933495 TI - Does circumpatellar electrocautery improve the outcome after total knee replacement?: a prospective, randomised, blinded controlled trial. AB - The incidence of anterior knee pain following total knee replacement (TKR) is reported to be as high as 49%. The source of the pain is poorly understood but the soft tissues around the patella have been implicated. In theory circumferential electrocautery denervates the patella thereby reducing efferent pain signals. However, there is mixed evidence that this practice translates into improved outcomes. We aimed to investigate the clinical effect of intra operative circumpatellar electrocautery in patients undergoing TKR using the LCS mobile bearing or Kinemax fixed bearing TKR. A total of 200 patients were randomised to receive either circumpatellar electrocautery (diathermy) or not (control). Patients were assessed by visual analogue scale (VAS) for anterior knee pain and Oxford knee score (OKS) pre-operatively and three months, six months and one year post-operatively. Patients and assessors were blinded. There were 91 patients in the diathermy group and 94 in the control. The mean VAS improvement at one year was 3.9 in both groups (control; -10 to 6, diathermy; -9 to 8, p < 0.001 in both cases, paired, two-tailed t-test). There was no significant difference in VAS between the groups at any other time. The mean OKS improvement was 17.7 points (0 to 34) in the intervention group and 16.6 (0 to 42) points in the control (p = 0.36). There was no significant difference between the two groups in OKS at any other time. We found no relevant effect of patellar electrocautery on either VAS anterior knee pain or OKS for patients undergoing LCS and Kinemax TKR. PMID- 22933496 TI - A comparison of radiological and computer navigation measurements of lower limb coronal alignment before and after total knee replacement. AB - We compared lower limb coronal alignment measurements obtained pre- and post operatively with long-leg radiographs and computer navigation in patients undergoing primary total knee replacement (TKR). A series of 185 patients had their pre- and post-implant radiological and computer-navigation system measurements of coronal alignment compared using the Bland-Altman method. The study included 81 men and 104 women with a mean age of 68.5 years (32 to 87) and a mean body mass index of 31.7 kg/m(2) (19 to 49). Pre-implant Bland Altman limits of agreement were -9.4 degrees to 8.6 degrees with a repeatability coefficient of 9.0 degrees . The Bland-Altman plot showed a tendency for the radiological measurement to indicate a higher level of pre operative deformity than the corresponding navigation measurement. Post-implant limits of agreement were -5.0 degrees to 5.4 degrees with a repeatability coefficient of 5.2 degrees . The tendency for valgus knees to have greater deformity on the radiograph was still seen, but was weaker for varus knees. The alignment seen or measured intra-operatively during TKR is not necessarily the same as the deformity seen on a standing long-leg radiograph either pre- or post-operatively. Further investigation into the effect of weight-bearing and surgical exposure of the joint on the mechanical femorotibial angle is required to enable the most appropriate intra-operative alignment to be selected. PMID- 22933497 TI - The effect on mechanical axis deviation of femoral lengthening with an intramedullary telescopic nail. AB - Internal lengthening devices in the femur lengthen along the anatomical axis, potentially creating lateral shift of the mechanical axis. We aimed to determine whether femoral lengthening along the anatomical axis has an inadvertent effect on lower limb alignment. Isolated femoral lengthening using the Intramedullary Skeletal Kinetic Distractor was performed in 27 femora in 24 patients (mean age 32 years (16 to 57)). Patients who underwent simultaneous realignment procedures or concurrent tibial lengthening, or who developed mal- or nonunion, were excluded. Pre-operative and six-month post-operative radiographs were used to measure lower limb alignment. The mean lengthening achieved was 4.4 cm (1.5 to 8.0). In 26 of 27 limbs, the mechanical axis shifted laterally by a mean of 1.0 mm/cm of lengthening (0 to 3.5). In one femur that was initially in varus, a 3 mm medial shift occurred during a lengthening of 2.2 cm. In a normally aligned limb, intramedullary lengthening along the anatomical axis of the femur results in a lateral shift of the mechanical axis by approximately 1 mm for each 1 cm of lengthening. PMID- 22933498 TI - The effectiveness of injections of hyaluronic acid or corticosteroid in patients with subacromial impingement: a three-arm randomised controlled trial. AB - A total of 159 patients (84 women and 75 men, mean age of 53 (20 to 87)) with subacromial impingement were randomised to treatment with subacromial injections using lidocaine with one of hyaluronic acid (51 patients), corticosteroid (53 patients) or placebo (55 patients). Patients were followed up for 26 weeks. The primary outcome was pain on a visual analogue score (VAS), and secondary outcomes included the Constant Murley score, shoulder pain score, functional mobility score, shoulder disability questionnaire and pain-specific disability score. The different outcome measures showed similar results. After three, six and 12 weeks corticosteroid injections were superior to hyaluronic acid injections and only at six weeks significantly better than placebo injections. The mean short-term reduction in pain on the VAS score at 12 weeks was 7% (SD 2.7; 97.5% confidence interval (CI) 0.207 to 1.55; p = 0.084) in the hyaluronic acid group, 28% (SD 2.8; 97.5% CI 1.86 to 3.65; p < 0.001) in the corticosteroid group and 23% (SD 3.23; 97.5% CI 1.25 to 3.26; p < 0.001) in the placebo group. At 26 weeks there was a reduction in pain in 63% (32 of 51) of patients in the hyaluronic acid group, 72% (38 of 53) of those in the corticosteroid group and 69% (38 of 55) of those in the placebo group. We were not able to show a convincing benefit from hyaluronic acid injections compared with corticosteroid or placebo injections. Corticosteroid injections produced a significant reduction in pain in the short term (three to 12 weeks), but in the long term the placebo injection produced the best results. PMID- 22933499 TI - The outcome of scapulothoracic fusion for painful winging of the scapula in dystrophic and non-dystrophic conditions. AB - Scapulothoracic fusion (STF) for painful winging of the scapula in neuromuscular disorders can provide effective pain relief and functional improvement, but there is little information comparing outcomes between patients with dystrophic and non-dystrophic conditions. We performed a retrospective review of 42 STFs in 34 patients with dystrophic and non dystrophic conditions using a multifilament trans-scapular, subcostal cable technique supported by a dorsal one-third semi-tubular plate. There were 16 males and 18 females with a mean age of 30 years (15 to 75) and a mean follow up of 5.0 years (2.0 to 10.6). The mean Oxford shoulder score improved from 20 (4 to 39) to 31 (4 to 48). Patients with non-dystrophic conditions had lower overall functional scores but achieved greater improvements following STF. The mean active forward elevation increased from 59 degrees (20 degrees to 90 degrees ) to 97 degrees (30 degrees to 150 degrees ), and abduction from 51 degrees (10 degrees to 90 degrees ) to 83 degrees (30 degrees to 130 degrees ) with a greater range of movement achieved in the dystrophic group. Revision fusion for nonunion was undertaken in five patients at a mean time of 17 months (7 to 31) and two required revision for fracture. There were three pneumothoraces, two rib fractures, three pleural effusions and six nonunions. The main risk factors for nonunion were smoking, age and previous shoulder girdle surgery. STF is a salvage procedure that can provide good patient satisfaction in 82% of patients with both dystrophic and non-dystrophic pathologies, but there was a relatively high failure rate (26%) when poor outcomes were analysed. Overall function was better in patients with dystrophic conditions which correlated with better range of movement; however, patients with non-dystrophic conditions achieved greater functional improvement. PMID- 22933500 TI - Results of the Latarjet procedure for recurrent anterior dislocation of the shoulder in patients with epilepsy. AB - A total of 12 epileptic patients (14 shoulders) with recurrent seizures and anterior dislocations of the shoulder underwent a Latarjet procedure and were reviewed at a mean of 8.3 years (1 to 20) post-operatively. Mean forward flexion decreased from 165 degrees (100 degrees to 180 degrees ) to 160 degrees (90 degrees to 180 degrees ) (p = 0.5) and mean external rotation from 54 degrees (10 degrees to 90 degrees ) to 43 degrees (5 degrees to 75 degrees ) (p = 0.058). The mean Rowe score was 76 (35 to 100) at the final follow-up. Radiologically, all shoulders showed a glenoid-rim defect and Hill Sachs lesions pre-operatively. Osteo-arthritic changes of the glenohumeral joint were observed in five shoulders (36%) pre-operatively and in eight shoulders (57%) post-operatively. Re-dislocation during a seizure occurred in six shoulders (43%). Five of these patients underwent revision surgery using a bone buttress from the iliac crest and two of these patients re-dislocated due to a new seizure. Due to the unacceptably high rate of re-dislocation after surgery in these patients, the most important means of reducing the incidence of further dislocation is the medical management of the seizures. The Latarjet procedure should be reserved for the well-controlled patient with epilepsy who has recurrent anterior dislocation of the shoulder during activities of daily living. PMID- 22933501 TI - The incidence and consequences of early wound infection after internal fixation for trauma in HIV-positive patients. AB - We report a prospective single-blind controlled study of the incidence of early wound infection after internal fixation for trauma in 609 patients, of whom 132 were HIV-positive. Wounds were assessed for healing using the ASEPSIS score. There was no significant difference in the rate of infection between HIV positive and HIV-negative patients undergoing clean surgery (4.2% vs 6%, respectively; p = 0.65). HIV-positive patients did not receive additional antibiotic prophylaxis or antiretroviral therapy as part of their management. The difference in the rate of infection between HIV-positive and HIV-negative patients with an open fracture or other contamination was not significant (33% vs 15%, respectively; p = 0.064). There was no relationship between CD4 count and infection rate. HIV status did not significantly influence the number of secondary surgical procedures (p = 0.183) or the likelihood of developing chronic osteomyelitis (p = 0.131). Although previous contamination from the time of injury was a risk factor for infection in mal- and nonunions, it was not significantly increased in HIV-positive patients (p = 0.144). We conclude that clean implant surgery in HIV-positive patients is safe, with no need for additional prophylaxis. PMID- 22933502 TI - Is adapted measured resection superior to gap-balancing in determining femoral component rotation in total knee replacement? AB - Obtaining a balanced flexion gap with correct femoral component rotation is one of the prerequisites for a successful outcome after total knee replacement (TKR). Different techniques for achieving this have been described. In this study we prospectively compared gap-balancing versus measured resection in terms of reliability and accuracy for femoral component rotation in 96 primary TKRs performed in 96 patients using the Journey system. In 48 patients (18 men and 30 women) with a mean age of 65 years (45 to 85) a tensor device was used to determine rotation. In the second group of 48 patients (14 men and 34 women) with a mean age of 64 years (41 to 86), an 'adapted' measured resection technique was used, taking into account the native rotational geometry of the femur as measured on a pre-operative CT scan. Both groups systematically reproduced a similar external rotation of the femoral component relative to the surgical transepicondylar axis: 2.4 degrees (SD 2.5) in the gap-balancing group and 1.7 degrees (SD 2.1) in the measured resection group (p = 0.134). Both gap-balancing and adapted measured resection techniques proved equally reliable and accurate in determining femoral component rotation after TKR. There was a tendency towards more external rotation in the gap-balancing group, but this difference was not statistically significant (p = 0.134). The number of outliers for our 'adapted' measured resection technique was much lower than reported in the literature. PMID- 22933503 TI - The results of total humeral replacement following excision for primary bone tumour. AB - Rarely, the extent of a malignant bone tumour may necessitate resection of the complete humerus to achieve adequate oncological clearance. We present our experience with reconstruction in such cases using a total humeral endoprosthesis (THER) in 20 patients (12 male and eight female) with a mean age of 22 years (6 to 59). We assessed the complications, the oncological and functional outcomes and implant survival. Surgery was performed between June 2001 and October 2009. The diagnosis included osteosarcoma in nine, Ewing's sarcoma in eight and chondrosarcoma in three. One patient was lost to follow up. The mean follow-up was 41 months (10 to 120) for all patients and 56 months (25 to 120) in survivors. There were five local recurrences (26.3%) and 11 patients were alive at time of last follow-up, with overall survival for all patients being 52% (95% confidence interval (CI) 23.8 to 74) at five years. The mean Musculoskeletal Tumor Society score for the survivors was 22 (73%; 16 to 23). The implant survival was 95% (95% CI 69.5 to 99.3) at five years. The use of a THER in the treatment of malignant tumours of bone is oncologically safe; it gives consistent and predictable results with low rates of complication. PMID- 22933504 TI - Biological reconstruction after excision, irradiation and reimplantation of diaphyseal tibial tumours using an ipsilateral vascularised fibular graft. AB - The purpose of this study was to assess the outcome of 15 patients (mean age 13.6 years (7 to 25)) with a primary sarcoma of the tibial diaphysis who had undergone excision of the affected segment that was then irradiated (90 Gy) and reimplanted with an ipsilateral vascularised fibular graft within it. The mean follow-up was 57 months (22 to 99). The mean time to full weight-bearing was 23 weeks (9 to 57) and to complete radiological union 42.1 weeks (33 to 55). Of the 15 patients, seven required a further operation, four to obtain skin cover. The mean Musculoskeletal Society Tumor Society functional score at final follow up was 27 out of 30 once union was complete. The functional results were comparable with those of allograft reconstruction and had a similar rate of complication. We believe this to be a satisfactory method of biological reconstruction of the tibial diaphysis in selected patients. PMID- 22933505 TI - Slipped upper tibial epiphysis in infantile tibia vara: three cases. AB - We describe three cases of infantile tibia vara resulting from an atraumatic slip of the proximal tibial epiphysis upon the metaphysis. There appears to be an association between this condition and severe obesity. Radiologically, the condition is characterised by a dome-shaped metaphysis, an open growth plate and disruption of the continuity between the lateral borders of the epiphysis and metaphysis, with inferomedial translation of the proximal tibial epiphysis. All patients were treated by realignment of the proximal tibia by distraction osteogenesis with an external circulator fixator, and it is suggested that this is the optimal method for correction of this complex deformity. There are differences in the radiological features and management between conventional infantile Blount's disease and this 'slipped upper tibial epiphysis' variant. PMID- 22933506 TI - Neurogenic claudication without spinal stenosis arising as a result of lumbar epidural varices. AB - Neurogenic claudication is most frequently observed in patients with degenerative lumbar spinal stenosis. We describe a patient with lumbar epidural varices secondary to obstruction of the inferior vena cava by pathological lymph nodes presenting with this syndrome. Following a diagnosis of follicular lymphoma, successful chemotherapy led to the resolution of the varices and the symptoms of neurogenic claudication. The lumbar epidural venous plexus may have an important role in the pathogenesis of spinal stenosis. Although rare, epidural venous engorgement can induce neurogenic claudication without spinal stenosis. Further investigations should be directed at identifying an underlying cause. PMID- 22933508 TI - Familial hemiplegic migraine with prolonged global aura: follow-up findings of subtraction ictal SPECT co-registered to MRI (SISCOM). AB - All authors contributed equally to this work. Susana Arias-Rivas wrote the main paper. Manuel Rodriguez-Yanez investigated the supplementary data. Julia Cortes and Pablo Aguiar performed the nuclear image studies and analysed and described the neuroimaging results. Maria Pardo, Rogelio Leira and Jose Castillo jointly conceived the study, followed the patient and prepared the manuscript. Miguel Blanco discussed the results. All authors discussed the results and implications and commented on the manuscript at all stages. PMID- 22933509 TI - Microfluidics for manipulating cells. AB - Microfluidics, a toolbox comprising methods for precise manipulation of fluids at small length scales (micrometers to millimeters), has become useful for manipulating cells. Its uses range from dynamic management of cellular interactions to high-throughput screening of cells, and to precise analysis of chemical contents in single cells. Microfluidics demonstrates a completely new perspective and an excellent practical way to manipulate cells for solving various needs in biology and medicine. This review introduces and comments on recent achievements and challenges of using microfluidics to manipulate and analyze cells. It is believed that microfluidics will assume an even greater role in the mechanistic understanding of cell biology and, eventually, in clinical applications. PMID- 22933510 TI - Validated LC-MS-MS method for the determination of prodrug of ginkgolide B in rat plasma and brain: application to pharmacokinetic study. AB - A sensitive, simple and rapid liquid chromatography-tandem mass spectrometry method was developed and validated for the simultaneous determination of ginkgolide B (GB) and the prodrug of ginkgolide B (PGB) in rat plasma and brain tissue. Detection was performed on a triple quadrupole tandem mass spectrometry in multiple reaction monitoring mode using the electrospray ionization technique in negative ionization mode. The total run time was only 2.0 min. Good linearity was found between 1-200 ng/mL (r > 0.9993) for plasma samples and 0.5-50 ng/mL (r = 0.9995) for the brain tissue samples. The lower limits of quantification of PGB and GB were 1 ng/mL for plasma and 0.5 ng/mL for brain tissue. Intra-day and inter-day precision was less than 11.67%. Intra-day accuracy was in the range of 2.61-10.67%, inter-day accuracy was in the range of -2.36-8.98%. The mean recovery for PGB and GB was between 82.5 and 97.0%. The validated method was successfully applied to a pharmacokinetic study of PGB and GB in rats after intravenous administration. PMID- 22933511 TI - High-performance liquid chromatographic analysis of felotaxel, a novel anti cancer drug, in rat plasma and in human plasma and urine. AB - A high-performance liquid chromatographic method was developed for the determination of a new derivative of docetaxel, felotaxel, in rat plasma and human plasma and urine. The separation of felotaxel was performed on a Dikma C18 column with 0.2% formic acid and acetonitrile (50:50) as the mobile phase. The flow rate was 0.8 mL/min and the column effluent was monitored by an ultraviolet detector set at 275 nm. The method was validated and found to be linear in the range of 5-1,000 ng/mL. The lower limit of quantification was 5 ng/mL based on 100 uL of plasma. The variations for intra-day and inter-day precision were less than 6.9%, and the accuracy values were between 87.3 and 107.4%. The extraction recoveries were more than 80.5%. These data confirm that the developed method has satisfactory sensitivity, accuracy and precision for the quantification of felotaxel in rat plasma and in human plasma and urine. The method was successfully applied to a pharmacokinetics study of felotaxel after intravenous doses of 5 mg/kg in rats. PMID- 22933512 TI - Prevalence of alpha1-antitrypsin deficiency alleles PI*S and PI*Z worldwide and effective screening for each of the five phenotypic classes PI*MS, PI*MZ, PI*SS, PI*SZ, and PI*ZZ: a comprehensive review. AB - Genetic epidemiological studies on the prevalence and numbers of individuals with alpha1-antitrypsin deficiency in each of 97 countries worldwide were used to estimate the numbers in each of the five following phenotypic classes: PI*MS, PI*MZ, PI*SS, PI*SZ, and PI*ZZ. These 97 countries were then grouped into 10 major geographic regions to make it possible to compare the numbers in each of these five phenotypic classes in immediately adjacent countries. Such groupings also make it possible to review the spread of the PI*S and PI*Z alleles from one major geographic grouping to another in the world as well as the spread of these two deficiency alleles within a major geographic region. The data in the 10 tables on the numbers in each of the five phenotypic classes in the countries in the same geographic region as well as the prevalence of the PI*S and PI*Z alleles in countries in the same geographic region provide a novel database for the identification of large numbers of individuals in a given phenotypic class. The database also provides useful information for the identification of countries with high numbers of PI*ZZ individuals for augmentation therapy within a given geographic region. PMID- 22933513 TI - An update on the use of ambrisentan in pulmonary arterial hypertension. AB - The development of effective oral treatments that are capable of modulating the activity of endothelin receptor 1 (ET-1) represents a significant milestone in the field of pulmonary arterial hypertension (PAH). Randomized clinical trials confirm that endothelin receptor antagonist (ERA) treatments confer significant improvements on important clinical endpoints, such as exercise capacity, functional class, quality of life and pulmonary hemodynamics. Moreover, ERAs may prevent or delay clinical worsening and retard disease progression. Ambrisentan is a propanoic acid-based ERA, showing preferential affinity for the type A ET-1 over the type B receptor. It provides another valuable, effective treatment option in PAH. Two large, randomized-placebo controlled trials demonstrated the efficacy of ambrisentan in PAH at improving exercise tolerance as measured by the 6 min walk distance. Additional secondary measures of improvement including time to clinical worsening, survival, functional class, quality of life and hemodynamic variables have been reported in clinical trials. A favorably low incidence of aminotransferase elevation indicating lower hepatic toxicity than other ERAs has been observed. Ambrisentan can be safely administered with warfarin or sildenafil without the need for dose adjustment of either therapy. A once daily oral medication with relatively few side effects is an attractive option, especially as the use of therapies in combination continues to increase. Long-term data and hemodynamic data confirm the benefits can be compared with other ERAs with fewer drug-drug interactions and a better liver safety profile. PMID- 22933514 TI - Bronchopleural fistula after robotic-assisted pulmonary lobectomy. PMID- 22933515 TI - Sperm motility is lost in vitro as a consequence of mitochondrial free radical production and the generation of electrophilic aldehydes but can be significantly rescued by the presence of nucleophilic thiols. AB - The prolonged incubation of human spermatozoa in vitro was found to induce a loss of motility associated with the activation of mitochondrial reactive oxygen species generation in the absence of any change in mitochondrial membrane potential. The increase in mitochondrial free radical production was paralleled by a loss of protein thiols and a concomitant rise in the formation of 4 hydroxynonenal, an electrophilic product of lipid peroxidation that was found to directly suppress sperm movement. These results prompted a search for nucleophiles that could counteract the action of such cytotoxic aldehydes, as a means of ensuring the long-term survival of spermatozoa in vitro. Four nucleophilic compounds were consequently assessed (penicillamine, homocysteine, N acetylcysteine, and mercaptosuccinate) in three species (human, rat, and horse). The results of this analysis revealed drug and species specificity in the manner in which these compounds affected sperm function, with penicillamine conferring the most consistent, effective support. This prosurvival effect was achieved downstream of mitochondrial reactive oxygen species generation and was associated with the stabilization of 4-hydroxynonenal generation, the preservation of sperm thiols, and a reduction in 8-hydroxy-2'-deoxyguanosine formation. Theoretical calculations of Fe-S and Cu-S bond distances and corresponding binding energies suggested that the particular effectiveness of penicillamine may, in part, reflect the ability of this nucleophile to form stable complexes with transition metals that catalyze lipid peroxidation. The practical implications of these findings were indicated by the effective preservation of equine spermatozoa for 8 days at ambient temperature when the culture medium was supplemented with penicillamine. PMID- 22933516 TI - Development of quantitative microscopy-based assays for evaluating dynamics of living cultures of mouse spermatogonial stem/progenitor cells. AB - Spermatogonial stem cell (SSC) self-renewal and differentiation are required for continuous production of spermatozoa and long-term fertility. Studying SSCs in vivo remains challenging because SSCs are rare cells and definitive molecular markers for their identification are lacking. The development of a method for propagating SSCs in vitro greatly facilitated analysis of SSCs. The cultured cells grow as clusters of a dynamic mixture of "true" stem cells and differentiating progenitor cells. Cells in the stem/progenitor culture system share many properties with spermatogonia in vivo; however, to fully exploit it as a model for spermatogonial development, new assays are needed that account for the dynamic heterogeneity inherent in the culture system. Here, assays were developed for quantifying dynamics of cultures of stem/progenitor cells that expressed histone-green fluorescent protein (GFP). First, we built on published results showing that cluster formation in vitro reliably predicts the relative number of SSCs. The GFP-based in vitro cluster assay allows quantification of SSCs with significantly fewer resources than a transplantation assay. Second, we compared the dynamics of differentiation in two experimental paradigms by imaging over a 17-day time frame. Finally, we performed short-term live imaging and observed cell migration, coordinated cell proliferation, and cell death resembling that of spermatogonia in the testes. The methods that we present provide a foundation for the use of fluorescent reporters in future microscopy based high-throughput screens by using living spermatogonial stem/progenitor cultures applicable to toxicology, contraceptive discovery, and identification of regulators of self-renewal and differentiation. PMID- 22933517 TI - Impaired fertilizing ability of superoxide dismutase 1-deficient mouse sperm during in vitro fertilization. AB - The oxidative modification of gametes by a reactive oxygen species is a major deleterious factor that decreases the successful rate of in vitro fertilization. Superoxide dismutase 1 (SOD1) plays a pivotal role in antioxidation by scavenging the superoxide anion, and its deficiency causes infertility in female mice, but the significance of the enzyme in male mice remains unclear. In the present study, we characterized Sod1(-/-) (Sod1-KO) male reproductive organs and compiled the first report of the impaired fertilizing ability of Sod1-KO sperm in in vitro fertilization. Insemination of wild-type oocytes with Sod1-KO sperm exhibited lower rates of fertility compared with insemination by wild-type sperm. The low fertilizing ability found for Sod1-KO sperm was partially rescued by reductant 2 mercaptoethanol, which suggested the oxidative modification of sperm components. The numbers of motile and progressive sperm decreased during the in vitro fertilization process, and a decline in ATP content and elevation in lipid peroxidation occurred in the Sod1-KO sperm in an incubation time-dependent manner. Tyrosine phosphorylation, which is a hallmark for sperm capacitation, was also impaired in the Sod1-KO sperm. These results collectively suggest that machinery involved in sperm capacitation and motility are vulnerable to oxidative damage during the in vitro fertilization process, which could increase the rate of inefficient fertilization. PMID- 22933518 TI - Small RNA profile of the cumulus-oocyte complex and early embryos in the pig. AB - Small RNA represent several unique noncoding RNA classes that have important function in the development of germ cells and early embryonic development. Deep sequencing was performed on small RNA from cumulus cells (recovered from germinal vesicle [GV] and metaphase II-arrested [MII] oocytes), GV and MII oocytes, in vitro fertilization-derived embryos at 60 h postfertilization (4- to 8-cell stage), and Day 6 blastocysts. Additionally, a heterologous miRNA microarray method was also used to identify miRNA expressed in the oocyte during in vitro maturation. Similar to the results of expression analysis of other species, these data demonstrate dynamic expression regulation of multiple classes of noncoding RNA during oocyte maturation and development to the blastocyst stage. Mapping small RNA to the pig genome indicates dynamic distribution of small RNA organization across the genome. Additionally, a cluster of miRNA and Piwi interacting RNA (piRNA) was discovered on chromosome 6. Many of the small RNA mapped to annotated repetitive elements in the pig genome, of which the SINE/tRNA Glu and LINE/L1 elements represented a large proportion. Two piRNA (piR84651 and piR16993) and seven miRNA (MIR574, MIR24, LET7E, MIR23B, MIR30D, MIR320, and MIR30C) were further characterized using quantitative RT-PCR. Secretory carrier membrane protein 4 (SCAMP4) was predicted to be subject to posttranscriptional gene regulation mediated by small RNA, by annotating small RNA reads mapped to exonic regions in the pig genome. Consistent with the prediction results, SCAMP4 was further confirmed to be differentially expressed at both transcriptional and translational levels. These data establish a small RNA expression profile of the pig cumulus-oocyte complex and early embryos and demonstrate their potential capacity to be utilized for predictions of functional posttranscriptional regulatory events. PMID- 22933519 TI - Tissue-restricted transcription from a conserved intragenic CpG island in the Klf1 gene in mice. AB - Beyond Mendelian inheritance, an understanding of the complexities and consequences of the transfer of nonhereditary information to successive generations is at an early stage. Such epigenetic functionality is exemplified by DNA methylation and, as genome-wide high-throughput methodologies emerge, is increasingly being considered in the context of conserved intragenic and intergenic CpG islands that function as alternate sites of transcription initiation. Here we characterize an intragenic CpG island in exon 2 of the protein-coding mouse Klf1 gene, from which clustered transcription initiation sites yield positive-strand, severely truncated, capped and spliced RNAs. Expression from this CpG island in the testis begins between Postnatal Days 14 20, increases during development, and is temporally correlated with the maturation of secondary spermatocytes as they become the dominant cell population in the seminiferous epithelium. Only full-length KLF1-encoding mRNAs are detected in the hematopoietic tissue, spleen; thus, expression from the exon 2 CpG island is both developmentally regulated and tissue restricted. DNA methylation analysis indicates that spatiotemporal expression from the Klf1 CpG island is not associated with hypermethylation. Finally, our computational analysis from multiple species confirms intragenic transcription initiation and indicates that the KLF1 CpG island is evolutionarily conserved. Currently we have no evidence that these truncated RNAs can be translated via nonconventional mechanisms such as in-frame, conserved non-AUG-dependent Kozak consensus sequences; however, high quality carboxyl-terminal antibodies will more effectively address this issue. PMID- 22933520 TI - On the embodiment of emotion regulation: interoceptive awareness facilitates reappraisal. AB - The ability to cognitively regulate emotional responses to aversive events is essential for mental and physical health. One prerequisite of successful emotion regulation is the awareness of emotional states, which in turn is associated with the awareness of bodily signals [interoceptive awareness (IA)]. This study investigated the neural dynamics of reappraisal of emotional responses in 28 participants who differed with respect to IA. Electroencephalography was used to characterize the time course of emotion regulation. We found that reappraisal was accompanied by reduced arousal and significant modulation of late neural responses. What is more, higher IA facilitated downregulation of affect and was associated with more pronounced modulation of underlying neural activity. Therefore, we conclude that IA not only advances the consolidation of somatic markers required for guiding individual behaviour but also creates processing advantages in tasks referring to these bodily markers. PMID- 22933521 TI - Cost-effectiveness of computed tomographic angiography before reoperative coronary artery bypass grafting: a decision-analytic model. AB - BACKGROUND: The risks of repeat thoracotomy can be reduced if thoracic multidetector computed tomographic angiography (CTA) is used to guide preventive surgical strategies (PSS: peripheral cardiopulmonary bypass, circulatory arrest, and non-median sternotomy). We sought to define the cost-effectiveness of CTA using a Markov model. METHODS AND RESULTS: We studied outcomes and costs of CTA and non-CTA strategies in a modeled cohort of 10 000 patients undergoing redo coronary artery bypass grafting. Rates of PSS implementation were anticipated to follow identification of risk by CTA. Transitions, costs, and utilities were informed by our experience and the literature. Sensitivity analyses included testing a range of costs of CTA and PSS on model outcome. In the reference case, cost and quality-adjusted life years accrued with the use of CTA ($74 869, 4.63 quality-adjusted life-years) were slightly higher than nonuse ($73 471, 4.59 quality-adjusted life-years), yielding an incremental cost-effectiveness ratio of $34 950/quality-adjusted life-years. Cost of PSS (equipment and operating time) was the most significant determinant of incremental cost-effectiveness ratio. In the reference case (cost of CTA ~$300), identification and avoidance of potential procedural difficulties with CTA rendered it cost-effective if the cost of PSS was <$12 000. Across a range of CTA costs, incremental cost-effectiveness ratio was not materially influenced by outcomes across a broad range of imputed values. CONCLUSIONS: The cost of CTA appears justified in the setting of isolated reoperative coronary artery bypass grafting, because it aids in appropriate selection of PSS. The cost-effectiveness of this imaging seems more influenced by the costs of subsequent PSS than by the cost of CTA. PMID- 22933522 TI - Kepler-47: a transiting circumbinary multiplanet system. AB - We report the detection of Kepler-47, a system consisting of two planets orbiting around an eclipsing pair of stars. The inner and outer planets have radii 3.0 and 4.6 times that of Earth, respectively. The binary star consists of a Sun-like star and a companion roughly one-third its size, orbiting each other every 7.45 days. With an orbital period of 49.5 days, 18 transits of the inner planet have been observed, allowing a detailed characterization of its orbit and those of the stars. The outer planet's orbital period is 303.2 days, and although the planet is not Earth-like, it resides within the classical "habitable zone," where liquid water could exist on an Earth-like planet. With its two known planets, Kepler-47 establishes that close binary stars can host complete planetary systems. PMID- 22933523 TI - Editorial: molecular endocrinology articles in the spotlight for September 2012. PMID- 22933525 TI - National survey of hospital strategies to reduce heart failure readmissions: findings from the Get With the Guidelines-Heart Failure registry. AB - BACKGROUND: Reducing 30-day heart failure readmission rates is a national priority. Yet, little is known about how hospitals address the problem and whether hospital-based processes of care are associated with reductions in readmission rates. METHODS AND RESULTS: We surveyed 100 randomly selected hospitals participating in the Get With the Guidelines-Heart Failure quality improvement program regarding common processes of care aimed at reducing readmissions. We grouped processes into 3 domains (ie, inpatient care, discharge and transitional care, and general quality improvement) and scored hospitals on the basis of survey responses using processes selected a priori. We used linear regression to examine associations between these domain scores and 30-day risk standardized readmission rates. Of the 100 participating sites, 28% were academic centers and 64% were community hospitals. The median readmission rate among participating sites (24.0%; 95% CI, 22.6%-25.7%) was comparable with the national average (24.6%; 23.5-25.9). Sites varied substantially in care processes used for inpatient care, education, discharge process, care transitions, and quality improvement. Overall, neither inpatient care nor general quality improvement domains were associated with 30-day readmission rates. Hospitals in the lowest readmission rate quartile had modestly higher discharge and transitional care domain scores (P=0.03). CONCLUSIONS: A variety of strategies are used by hospitals in an attempt to improve 30-day readmission rates for patients hospitalized with heart failure. Although more complete discharge and transitional care processes may be modestly associated with lower 30-day readmission rates, most current strategies are not associated with lower readmission rates. PMID- 22933526 TI - Clinical and functional correlates of early microvascular dysfunction after heart transplantation. AB - BACKGROUND: Microvascular dysfunction is emerging as a strong predictor of outcome in heart transplant recipients. At this time, the determinants and consequences of early microvascular dysfunction are not well established. The objective of the study was to determine the risk factors and functional correlates associated with early microvascular dysfunction in heart transplant recipients. METHODS AND RESULTS: Sixty-three heart transplant recipients who had coronary physiology assessment, right heart catheterization, and echocardiography performed at the time of their first annual evaluation were included in the study. Microvascular dysfunction was assessed using the recently described index of microcirculatory resistance. The presence of microvascular dysfunction, predefined by an index of microcirculatory resistance >20, was observed in 46% of patients at 1 year. A history of acute rejection and undersized donor hearts were associated with microvascular dysfunction at 1 year, with odds ratio of 4.0 (1.3 12.8) and 3.6 (1.2-11.1), respectively. Patients with microvascular dysfunction had lower cardiac index (3.1+/-0.7 versus 3.5+/-0.7 L/min per m(2); P=0.02) and mild graft dysfunction measured by echocardiography-derived left and right myocardial performance indices ([0.54+/-0.09 versus 0.43+/-0.09; P<0.01] and [0.47+/-0.14 versus 0.32+/-0.05; P<0.01], respectively). Microvascular dysfunction was also associated with a higher likelihood of death, graft failure, or allograft vasculopathy at 5 years after transplant (hazard ratio, 2.52 [95% CI, 1.04-5.91]). CONCLUSIONS: A history of acute rejection during the first year and smaller donor hearts were identified as risk factors for early microvascular dysfunction. Microvascular dysfunction assessed using index of microcirculatory resistances at 1 year was also associated with worse graft function and possibly worse clinical outcomes. PMID- 22933527 TI - Birth outcomes after induced abortion: a nationwide register-based study of first births in Finland. AB - STUDY QUESTION: Is the perinatal health of first-born children affected by the mother's previous induced abortion(s) (IAs)? SUMMARY ANSWER: Prior IAs, particularly repeat IAs, are correlated with an increased risk of some health problems at first birth; even in a country with good health care quality. WHAT IS KNOWN ALREADY: A positive association between IA and risk of preterm birth or a dose-response effect has been found in some previous studies. Limited information and conflicting results on other infant outcomes are available. STUDY DESIGN, SIZE AND DURATION: Nationwide register-based study including 300 858 first-time mothers during 1996-2008 in Finland. PARTICIPANTS/MATERIALS, SETTING AND METHODS: All the first-time mothers with a singleton birth (obtained from the Medical Birth Register) in the period 1996-2008 (n = 300 858) were linked to the Abortion Register for the period 1983-2008. MAIN RESULTS AND THE ROLE OF CHANCE: Of the first-time mothers, 10.3% (n = 31 083) had one, 1.5% had two and 0.3% had three or more IAs. Most IAs were surgical (88%) performed before 12 weeks (91%) and carried out for social reasons (97%). After adjustment, perinatal deaths and very preterm birth (<28 gestational week) suggested worse outcomes after IA. Increased odds for very preterm birth were seen in all the subgroups and exhibited a dose response relationship: 1.19 [95% confidence interval (CI) 0.98-1.44] after one IA, 1.69 (1.14-2.51) after two and 2.78 (1.48-5.24) after three IAs. Increased odds for preterm birth (<37 weeks) and low birthweight (<2500 g and <1500 g) were seen only among mothers with three or more IAs: 1.35 (1.07-1.71), 1.43 (1.12 1.84) and 2.25 (1.43-3.52), respectively. LIMITATIONS, REASONS FOR CAUTION: Observational studies like ours, however large and well-controlled, will not prove causality. WIDER IMPLICATIONS OF THE FINDINGS: In terms of public health and practical implications, health education should contain information of the potential health hazards of repeat IAs, including very preterm birth and low birthweight in subsequent pregnancies. Health care professionals should be informed about the potential risks of repeat IAs on infant outcomes in subsequent pregnancy. STUDY FUNDING/COMPETING INTEREST(S): National Institute for Health and Welfare and the Academy of Finland. No competing interests. PMID- 22933528 TI - Menstrual disorders in adolescence: a marker for hyperandrogenaemia and increased metabolic risks in later life? Finnish general population-based birth cohort study. AB - STUDY QUESTION: Are self-reported menstrual disorders associated with hyperandrogenaemia and metabolic disturbances as early as in adolescence? SUMMARY ANSWER: Menstrual disorders at the age 16 are a good marker of hyperandrogenaemia, and an adverse lipid profile was associated with higher androgen levels. WHAT IS KNOWN AND WHAT THIS PAPER ADDS: Hyperandrogenism per se has been suggested to be a significant metabolic risk factor in women and a cause of physical and psychological morbidity in adolescent girls. A weak positive correlation has been described between hyperandrogenaemia and obesity in adolescent girls, but the clinical consequences are still poorly understood. Hyperandrogenism and insulin resistance are also key features of polycystic ovary syndrome (PCOS), and women with PCOS are consequently at an increased risk of developing type 2 diabetes mellitus and/or metabolic syndrome, and may have increased cardiovascular morbidity. Our findings confirm that the association between menstrual disorders, hyperandrogenism, obesity and metabolic risks is already evident in adolescence. STUDY DESIGN: This population-based, cross sectional study used postal questionnaires to targeting 15-16-year-old girls in the Northern Finland Birth Cohort 1986 (n= 4567). PARTICIPANTS AND SETTING: There were 3669 girls who answered the postal questionnaire and out of 3373 girls who also underwent clinical examinations and blood tests, 2448 were included in the analyses. The questionnaire included one question about the regularity and length of the menstrual cycle: 'Is your menstrual cycle (the interval from the beginning of one menstrual period to the beginning of the next period) often (more than twice a year) longer than 35 days?' The girls who answered 'yes' to this question were considered to be suffering from menstrual disorders and were classified as 'symptomatic'. The girls who answered 'no' were defined as 'non-symptomatic'. MAIN RESULTS AND THE ROLE OF CHANCE: There were 709 (29%) girls who reported menstrual disorders (symptomatic girls) and 1739 who had regular periods (non symptomatic girls). In the whole population and in both study groups, there were significant correlations between body mass index (BMI) (and waist-to-hip ratio), hyperandrogenaemia and metabolic parameters. Symptomatic girls exhibited significantly higher serum concentrations of testosterone (P= 0.010), lower levels of sex hormone-binding globulin (P =0.042) and higher free androgen indices [FAIs; geometric mean 3.38 (interquartile range (IQR): 2.27, 5.18) versus 3.08 (IQR: 2.15, 4.74), P= 0.002]. The two groups had comparable BMI and insulin sensitivity, and serum levels of glucose, insulin and lipids. There was a significant linear trend towards higher FAI values in the higher BMI quartiles in both symptomatic and non-symptomatic girls. In the whole population, there was a statistically significant linear decrease in high-density lipoprotein concentrations (P < 0.001) and higher triglyceride concentrations (P =0.004) in the upper FAI quartile. IMPLICATIONS: Information regarding menstrual disorders in adolescence is a good marker of hyperandrogenaemia and may be an early risk factor for the development of PCOS in adulthood. The association between obesity, hyperandrogenism and metabolic risks is already evident in adolescence, which strengthens the importance of noting menstrual disorders at an early stage. BIAS, LIMITATIONS, GENERALIZABILITY: The cross-sectional nature of the study does not allow us to draw conclusions concerning the metabolic risks of this population in later life. The diagnosis of menstrual disorders was based on a questionnaire, suggesting a risk of information bias in reporting the symptoms. This study was not designed to diagnose PCOS, as ultrasonography was not available and there was no clinical evaluation of hyperandrogenism (i.e. hirsutism). However, we were able to take into account potential confounding factors in the analyses. STUDY FUNDING/COMPETING INTERESTS: This work was supported by grants from the Finnish Medical Society Duodecim, the North Ostrobothnia Regional Fund, the Academy of Finland (project grants 104781, 120315, 129269, 1114194, SALVE), University Hospital Oulu, Biocenter, University of Oulu, Finland (75617), the European Commission (EURO-BLCS, Framework 5 award QLG1-CT-2000-01643) and the Medical Research Council, UK (PrevMetSyn/SALVE). None of the authors have any conflict of interest to declare. PMID- 22933529 TI - Object position and image magnification in dental panoramic radiography: a theoretical analysis. AB - OBJECTIVES: The purpose of our study was to investigate how image magnification and distortion in dental panoramic radiography are influenced by object size and position for a small round object such as a ball bearing used for calibration. METHODS: Two ball bearings (2.5 mm and 6 mm in diameter) were placed at approximately the same position between the teeth of a plastic skull and radiographed 21 times. The skull was replaced each time. Their images were measured by software using edge detection and ellipse-fitting algorithms. Using a standard definition of magnification, equations were derived to enable an object's magnification to be determined from its position and vice versa knowing the diameter and machine parameters. RESULTS: The average magnification of the 2.5 mm ball bearing was 1.292 (0.0445) horizontally and 1.257 (0.0067) vertically with a mean ratio of 1.028 (0.0322); standard deviations are in parentheses. The figures for the 6 mm ball bearing were 1.286 (0.0068), 1.255 (0.0018) and 1.025 (0.0061), respectively. Derived positions of each ball bearing from magnification were more consistent horizontally than vertically. There was less variation in either direction for the 6 mm ball bearing than the 2.5 mm one. CONCLUSIONS: Automatic measurement of image size resulted in less variation in vertical magnification values than horizontal. There are only certain positions in the focal trough that achieve zero distortion. Object location can be determined from its diameter, measured magnification and machine parameters. The 6 mm diameter ball bearing is preferable to the 2.5 mm one for more reliable magnification measurement and position determination. PMID- 22933530 TI - Cone beam CT detection of foramen tympanicum or foramen of Huschke. PMID- 22933531 TI - Dental cone beam CT image quality possibly reduced by patient movement. AB - Patient artefacts in dental cone beam CT scans can happen for various reasons. These range from artefacts from metal restorations to movement. An audit was carried out in the Glasgow Dental Hospital analysing how many scans showed signs of "motion artefact", and then to assess if there was any correlation between patient age and movement artefacts. Specific age demographics were then analysed to see if these cohorts were at a higher risk of "movement artefacts". PMID- 22933532 TI - Dosimetry of a cone beam CT device for oral and maxillofacial radiology using Monte Carlo techniques and ICRP adult reference computational phantoms. AB - OBJECTIVES: The aim of this study was to calculate organ and effective doses for a range of available protocols in a particular cone beam CT (CBCT) scanner dedicated to dentistry and to derive effective dose conversion factors. METHODS: Monte Carlo simulations were used to calculate organ and effective doses using the International Commission on Radiological Protection voxel adult male and female reference phantoms (AM and AF) in an i-CAT CBCT. Nine different fields of view (FOVs) were simulated considering full- and half-rotation modes, and also a high-resolution acquisition for a particular protocol. Dose-area product (DAP) was measured. RESULTS: Dose to organs varied for the different FOVs, usually being higher in the AF phantom. For 360 degrees , effective doses were in the range of 25-66 MUSv, and 46 MUSv for full head. Higher contributions to the effective dose corresponded to the remainder (31%; 27-36 range), salivary glands (23%; 20-29%), thyroid (13%; 8-17%), red bone marrow (10%; 9-11%) and oesophagus (7%; 4-10%). The high-resolution protocol doubled the standard resolution doses. DAP values were between 181 mGy cm(2) and 556 mGy cm(2) for 360 degrees . For 180 degrees protocols, dose to organs, effective dose and DAP were approximately 40% lower. A conversion factor (DAP to effective dose) of 0.130 +/- 0.006 MUSv mGy( 1) cm(-2) was derived for all the protocols, excluding full head. A wide variation in dose to eye lens and thyroid was found when shifting the FOV in the AF phantom. CONCLUSIONS: Organ and effective doses varied according to field size, acquisition angle and positioning of the beam relative to radiosensitive organs. Good positive correlation between calculated effective dose and measured DAP was found. PMID- 22933533 TI - Influence of cone beam CT on treatment plan before surgical intervention of mandibular third molars and impact of radiographic factors on deciding on coronectomy vs surgical removal. AB - OBJECTIVES: To assess the influence of cone beam CT (CBCT) on treatment plan before surgical intervention of mandibular third molars and to identify radiographic factors with an impact on deciding on coronectomy. METHODS: 186 mandibular third molars with an indication for surgical intervention underwent a radiographic examination with two methods: (1) panoramic imaging in combination with stereo-scanography and (2) CBCT. After the radiographic examination a treatment plan (TP) was established: either surgical removal (Sr) or coronectomy (Co). The first TP was based on the panoramic image and stereo-scanogram, while the second TP was established after CBCT was available. Logistic regression analyses were used to identify factors predisposing for Co after CBCT. RESULTS: Treatment was performed according to the second TP. Agreement between the first and second TP was seen in 164 cases (88%), while the TP changed for 22 teeth (12%) after CBCT. Direct contact between the third molar and the mandibular canal had the highest impact on deciding on Co [odds ratio (OR) = 101.8, p < 0.001]. Direct contact was not a sufficient factor, however; thus, lumen narrowing of the canal (OR = 38.9-147.2, p < 0.001) and canal positioned in a bending or a groove in the root complex (OR = 32.8, p = 0.016) were additional canal-related factors for deciding on Co. CONCLUSION: CBCT influenced the treatment plan for 12%. Direct contact in combination with narrowing of the canal lumen and canal positioned in a bending or a groove in the root complex observed in CBCT images were significant factors for deciding on coronectomy. PMID- 22933534 TI - Ultrasound-guided combined intermediate and deep cervical plexus nerve block for regional anaesthesia in oral and maxillofacial surgery. AB - OBJECTIVES: We examined the application of an ultrasound-guided combined intermediate and deep cervical plexus nerve block for regional anaesthesia in patients undergoing oral and maxillofacial surgery. METHODS: A total of 19 patients receiving ultrasound-guided combined intermediate and deep cervical plexus anaesthesia followed by neck surgery were examined prospectively. The sternocleidomastoid and the levator of the scapula muscles as well as the cervical transverse processes were used as easily depicted ultrasound landmarks for the injection of local anaesthetics. Under ultrasound guidance, a needle was advanced in the fascial band between the sternocleidomastoid and the levator of the scapula muscles and 15 ml of ropivacaine 0.75% was injected. Afterwards, the needle was advanced between the levator of the scapula and the hyperechoic contour of the cervical transverse processes and a further 15 ml of ropivacaine 0.75% was injected. The sensory block of the cervical nerve plexus, the analgesic efficacy of the block within 24 h after injection and potential block-related complications were assessed. RESULTS: All patients showed a complete cervical plexus nerve block. No patient required analgesics within the first 24 h after anaesthesia. Two cases of blood aspiration were recorded. No further cervical plexus block-related complications were observed. CONCLUSIONS: Ultrasound-guided combined intermediate and deep cervical plexus block is a feasible, effective and safe method for oral and maxillofacial surgical procedures. PMID- 22933535 TI - Influence of cone beam CT scanning parameters on grey value measurements at an implant site. AB - OBJECTIVES: The aim of this study was to determine the grey value variation at the implant site with different scan settings, including field of view (FOV), spatial resolution, number of projections, exposure time and dose selections in two cone beam CT (CBCT) systems and to compare the results with those obtained from a multislice CT system. METHODS: A partially edentulous human mandibular cadaver was scanned by three CT modalities: multislice CT (MSCT) (Philips, Best, the Netherlands), and two CBCT systems: (Accuitomo 170((r)), Morita, Japan) and (NewTom 5G((r)), QR, Verona, Italy). Using different scan settings 36 and 24 scans were obtained from the Accuitomo and the NewTom, respectively. The scans were converted to digital imaging and communications in medicine 3 format. The analysis of the data was performed using 3Diagnosys((r)) software (v. 3.1, 3diemme, Cantu, Italy) and Geomagic studio((r)) 2012 (Morrisville, NC). On the MSCT scan, one probe designating the site for pre-operative implant placement was inserted. The inserted probe on MSCT was transformed to the same region on each CBCT scan using a volume-based three-dimensional registration algorithm. The mean voxel grey value of the region around the probe was derived separately for each CBCT. The influence of scanning parameters on the measured mean voxel grey values was assessed. RESULTS: Grey values in both CBCT systems significantly deviated from Hounsfield unit values measured with MSCT (p = 0.0001). In both CBCT systems, scan FOV and spatial resolution selections had a statistically significant influence on grey value measurements (p = 0.0001). The number of projections selection had a statistically significant influence in the Accuitomo system (p = 0.0001) while exposure time and dose selections had no statistically significant influence on grey value measurements in the NewTom (p = 0.43 and p = 0.37, respectively). CONCLUSIONS: Grey-level values from CBCT images are influenced by device and scanning settings. PMID- 22933536 TI - Validity of wax and acrylic as soft-tissue simulation materials used in in vitro radiographic studies. AB - OBJECTIVE: To determine the thickness of wax and acrylic that provides a radiographic density similar to that of the human cheek. METHODS: An intraoral film radiograph of the human cheek including a 40*30*3 mm reference aluminium block was recorded under standardized conditions in 61 subjects. Radiographic density was measured by a densitometer in ten randomly selected sites of the film to serve as the gold standard for density values of the cheek soft tissues. Thereafter, the density of series of radiographs of two tissue-simulating materials-wax and acrylic-in systematically increasing thicknesses (wax, 1.5-30 mm; acrylic, 2-40 mm) plus the reference block were measured and compared with the gold-standard values. RESULTS: The radiographic density of wax with a thickness of 13-17 mm or acrylic with a thickness of 14.5 mm corresponded to the average density of the human cheek. CONCLUSION: The soft tissues of the average human cheek can be simulated with 13-17 mm wax or 14.5 mm acrylic in in vitro radiographic studies. PMID- 22933537 TI - Disc displacement and changes in condylar position. AB - OBJECTIVES: To determine whether disc displacement (DD) can be a factor causing changes in condylar position in the glenoid fossa, using limited cone beam CT (LCBCT) images taken in the same time period as MRI that verified DD. METHODS: The study included 60 joints in 57 male and female subjects aged 12-20 years (mean age 14.8 years). Subjects fulfilling the inclusion criteria were enrolled from a pool of post-orthodontic patients, and divided into four groups according to their disc status confirmed by MRI: partial DD (PDD), total DD with reduction (TDDWR), lateral DD (LDD) and medial DD (MDD). Changes in joint space from previously reported norms were measured on LCBCT images. RESULTS: In PDD, the condyles were displaced posteriorly in the fossae with a mean anterior space of 2.7 +/- 0.5 mm (normal 1.3 +/- 0.2 mm) and a posterior space of 1.8 +/- 0.4 mm (normal 2.1 +/- 0.3 mm). In TDDWR, the condyles were displaced not only posteriorly as observed in PDD, but also vertically with a reduced superior space of 1.9 +/- 0.4 mm (normal 2.5 +/- 0.5 mm). In LDD, the lateral space was significantly increased to 2.5 +/- 0.3 mm (normal 1.8 +/- 0.4 mm), while central and medial spaces were significantly decreased to 2.2 +/- 0.5 mm (normal 2.7 +/- 0.5 mm) and 1.7 +/- 0.4 mm (normal 2.4 +/- 0.5 mm), respectively. In MDD, the medial space was increased and the lateral and central spaces were significantly decreased. CONCLUSIONS: These results indicate that DD in adolescents and young adults can cause the condyle to change its position in the fossa with alterations in joint space which depend on the direction and extent of DD. PMID- 22933538 TI - Taking the long view: a systematic review reporting long-term perspectives on child unintentional injury. AB - OBJECTIVE: The relative significance of child injury as a cause of preventable death has increased as mortality from infectious diseases has declined. Unintentional child injuries are now a major cause of death and disability across the world with the greatest burden falling on those who are most disadvantaged. A review of long-term data on child injury mortality was conducted to explore trends and inequalities and consider how data were used to inform policy, practice and research. METHODS: The authors systematically collated and quality appraised data from publications and documents reporting unintentional child injury mortality over periods of 20 years or more. A critical narrative synthesis explored trends by country income group, injury type, age, gender, ethnicity and socioeconomic group. FINDINGS: 31 studies meeting the inclusion criteria were identified of which 30 were included in the synthesis. Only six were from middle income countries and none were from low income countries. An overall trend in falling child injury mortality masked rising road traffic injury deaths, evidence of increasing vulnerability of adolescents and widening disparities within countries when analysed by ethnic group and socioeconomic status. CONCLUSIONS: Child injury mortality trend data from high and middle income countries has illustrated inequalities within generally falling trends. There is scope for greater use of existing trend data to inform policy and practice. Similar evidence from low income countries where the burden of injury is greatest is needed. PMID- 22933539 TI - Insulin-mediated FFA suppression is associated with triglyceridemia and insulin sensitivity independent of adiposity. AB - CONTEXT: A central/visceral fat distribution and excess free fatty acid (FFA) availability are associated with dyslipidemia and insulin resistance. However, these two characteristics often coexist, making it difficult to detect the independent contributions of each. Whether FFA suppression is more closely linked to metabolic abnormalities is not clear. OBJECTIVE: The aim of the study was to examine the relationship between FFA suppression, body fat distribution, and fitness as contributors toward insulin resistance and hypertriglyceridemia. DESIGN: We measured systemic palmitate turnover using an iv infusion of [9,10 (3)H]palmitate; upper body sc adipose tissue (UBSQ) and visceral adipose tissue (VAT) with dual-energy x-ray absorptiometry and a single-slice abdominal computed tomography scan; fitness with a graded exercise treadmill test; and insulin sensitivity with both the iv glucose tolerance test (IVGTT) (SI(IVGTT)) and mixed meal tolerance test (SI(Meal)). SETTING: The study was conducted at a General Clinical Research Center. PARTICIPANTS: Baseline data were obtained from 140 elderly adults (age, 60-88 yr; 83 males) and 60 young adults (age, 18-31 yr; 31 males) who participated in a previously published trial assessing the effects of 2-yr supplementation of dehydroepiandrosterone or testosterone on body composition, glucose metabolism, and bone density. INTERVENTIONS: There were no interventions. MAIN OUTCOME MEASURES: We measured fasting plasma triglyceride (TG) concentrations, SI(IVGTT), and SI(Meal). RESULTS: Using multivariate regression analysis, the strongest combined predictors of TG concentrations were VAT, postmeal nadir FFA concentrations, sex, and age. The best predictors of SI(IVGTT) were IVGTT nadir palmitate concentration, VAT, UBSQ fat, fitness, and age, whereas the best predictors of SI(Meal) were meal nadir palmitate concentration, UBSQ fat, fitness, and sex. CONCLUSIONS: FFA suppression is associated with both fasting TG concentrations and insulin sensitivity, independent of measures of adiposity. PMID- 22933541 TI - High-dose vitamin d intervention in infants--effects on vitamin d status, calcium homeostasis, and bone strength. AB - CONTEXT: Guidelines in Finland recommend 10 MUg of vitamin D3 daily for all infants. Recent observations suggest that this may be insufficient to maintain optimal serum 25-hydroxyvitamin D (S-25-OHD). OBJECTIVE: The aim of the study was to evaluate effects of various vitamin D doses and determine a dose ensuring S-25 OHD of at least 80 nmol/liter in infants without signs of vitamin D excess. DESIGN: We conducted a randomized double-blind intervention study. Cord blood was obtained at birth for S-25-OHD; 113 infants were randomized to receive vitamin D3 10, 30, or 40 MUg/d from age 2 wk to 3 months. SETTING: An investigator-initiated study was performed in a single maternity hospital in Helsinki, Finland. MAIN OUTCOME MEASURES: S-25-OHD, calcium homeostasis, and skeletal characteristics were evaluated with peripheral quantitative computed tomography at age 3 months. RESULTS: Baseline S-25-OHD was similar in all three groups (median, 53 nmol/liter). At 3 months, the mean S-25-OHD values were 88, 124, and 153 nmol/liter, and the minimum values were 46, 57, and 86 nmol/liter in the groups receiving 10, 30, and 40 MUg (ANOVA; P < 0.001). No hypercalcemia occurred; plasma calcium, serum PTH, and urine calcium excretion was similar between the groups. Peripheral quantitative computed tomography showed a trend toward larger tibial total bone and cortical bone area with higher vitamin D doses. CONCLUSION: Vitamin D3 supplementation with up to 40 MUg/d from age 2 wk to 3 months was safe and caused no hypercalcemia or hypercalciuria. The 40-MUg dose maintained S-25 OHD above 80 nmol/liter in all infants. More extensive and longer intervention studies are necessary to assess long-term effects. PMID- 22933540 TI - Determinants of bone microarchitecture and mechanical properties in obese men. AB - CONTEXT: Recent studies have suggested that obesity in men is associated with increased fracture risk. Obesity in men is also associated with dysregulation of the GH/IGF-I and gonadal steroid axes, important regulators of bone homeostasis. OBJECTIVE: The aim of the study was to investigate body composition and endocrine determinants of bone microarchitecture and mechanical properties in obese men. DESIGN AND SETTING: We conducted a cross-sectional study at a clinical research center. PARTICIPANTS: Thirty-five obese men (mean age, 33.8 +/- 6.4 yr; mean body mass index, 36.5 +/- 5.8 kg/m(2)) participated in the study. OUTCOME MEASURES: Distal radius microarchitecture and mechanical properties were measured by three dimensional high-resolution peripheral quantitative computed tomography and microfinite element analysis; body composition by computed tomography; bone marrow fat by proton magnetic resonance spectroscopy; total and free estradiol and testosterone; IGF-I; peak glucagon-stimulated GH; 25-hydroxyvitamin D. RESULTS: Men with high visceral adipose tissue (VAT) had impaired mechanical properties compared to men with low VAT (P < 0.05), despite comparable body mass index. VAT was inversely associated and thigh muscle was positively associated with mechanical properties (P < 0.05). Bone marrow fat was inversely associated with cortical parameters (P <= 0.02). Free estradiol was positively associated with total density (P = 0.05). Free testosterone was positively associated with trabecular thickness and inversely with trabecular number (P <= 0.05). Peak stimulated GH was positively associated with trabecular thickness, as was IGF-I with cortical area (P <= 0.04). CONCLUSION: VAT and bone marrow fat are negative predictors and muscle mass is a positive predictor of microarchitecture and mechanical properties in obese men. Testosterone, estradiol, and GH are positive determinants of trabecular microarchitecture, and IGF-I is a positive determinant of cortical microarchitecture. This supports the notion that VAT is detrimental to bone and that decreased GH and testosterone, characteristic of male obesity, may exert deleterious effects on microarchitecture, whereas higher estradiol may be protective. PMID- 22933542 TI - Serum 25-hydroxyvitamin D response to vitamin D3 supplementation 50,000 IU monthly in youth with HIV-1 infection. AB - CONTEXT: Vitamin D deficiency and insufficiency occur frequently in youth with HIV infection, particularly among those receiving the antiretroviral drug efavirenz. Optimal vitamin D dosing for treatment is unclear. OBJECTIVE: Our objective was to evaluate safety and measure change in 25-hydroxyvitamin D (25 OHD) concentration from baseline to study wk 4 and 12 during treatment with vitamin D(3), 50,000 IU monthly. DESIGN, SETTING, AND PARTICIPANTS: We conducted a randomized double-blind, placebo-controlled multicenter trial of HIV-infected youth ages 18-24 yr, with viral load below 5000 copies/ml, on stable antiretroviral therapy. INTERVENTION: INTERVENTION included vitamin D(3), 50,000 IU (n = 102), or matching placebo (n = 101) administered in three directly observed oral doses at monthly intervals. RESULTS: At baseline, mean (sd) age was 20.9 (2.0) yr; 37% were female and 52% African-American, and 54% were vitamin D deficient/insufficient (25-OHD < 20 ng/ml), with no randomized group differences. Of evaluable participants vitamin D deficient/insufficient at baseline who were administered vitamin D, 43 of 46 (93%) had sufficient 25-OHD by wk 12. Vitamin D supplementation increased 25-OHD serum concentration from a baseline of 21.9 (13.3) to 35.9 (19.1) ng/ml at wk 12 (P < 0.001) with no change for placebo. Although use of the antiretroviral efavirenz was associated with lower baseline 25-OHD concentration, efavirenz did not diminish the response to vitamin D supplementation. There was no treatment-related toxicity. CONCLUSIONS: Supplementation with vitamin D(3) 50,000 IU monthly for three doses was safe. Increases in 25-OHD occurred in treated participants regardless of antiretroviral regimen. PMID- 22933544 TI - Effects of age and serum 25-OH-vitamin D on serum parathyroid hormone levels. AB - CONTEXT: Several studies define optimal serum 25-hydroxyvitamin D (25-OHD) levels based on serum PTH level reaching an asymptote. However, results differ widely, ranging from 25-OHD levels of 12-44 ng/ml: many studies are constrained by small sample size. OBJECTIVE: The objective of the study was to determine the relationship between serum PTH and 25-OHD levels and age in a very large reference laboratory database. DESIGN: This was a detailed cross-sectional analysis of 312,962 paired serum PTH and 25-OHD levels measured from July 2010 to June 2011. RESULTS: Median PTH levels and the proportion of patients (PTH > 65 pg/ml), from 63 successive 25-OHD frequency classes of 5000 patients, provide smooth, exceptionally well-fitted curves (R(2) = 0.994 and R(2) = 0.995, respectively) without discernible inflection points or asymptotes but with striking age dependencies. Serum 25-OHD was below the recent Institute of Medicine sufficiency guidance of 20 ng/ml in 27% (85,000) of the subjects. More importantly, 40 and 51% of subjects (serum 25-OHD <20 and 10 ng/ml, respectively) had biochemical hyperparathyroidism (PTH > 65 pg/ml). CONCLUSIONS: This analysis, despite inevitable inherent limitations, introduces several clinical implications. First, median 25-OHD-dependent PTH levels revealed no threshold above which increasing 25-OHD fails to further suppress PTH. Second, the large number of subjects with 25-OHD deficiency and hyperparathyroidism reinforces the Third International Workshop on Asymptomatic Primary Hyper parathyroidism's recommendations to test for, and replete, vitamin D depletion before considering parathyroidectomy. Third, strong age dependency of the PTH-25-OHD relationship likely reflects the composite effects of age-related decline in calcium absorption and renal function. Finally, this unselected large population database study could guide clinical management of patients based on an age-dependent, PTH 25-OHD continuum. PMID- 22933545 TI - Maternal lipid profile during early pregnancy and pregnancy complications and outcomes: the ABCD study. AB - CONTEXT: Elevated lipid levels during late pregnancy are associated with complications and adverse outcome for both mother and newborn. However, it is inconclusive whether a disturbed lipid profile during early pregnancy has similar negative associations. OBJECTIVE: Our objective was to investigate whether nonfasting maternal total cholesterol and triglyceride levels during early pregnancy are associated with six major adverse pregnancy outcomes. METHODS: Data were derived from the Amsterdam Born Children and Their Development (ABCD) cohort study. Random blood samples of nonfasting total cholesterol and triglyceride levels were determined during early gestation (median = 13, interquartile range = 12-14 wk). Outcome measures were pregnancy-induced hypertension (PIH), preeclampsia, preterm birth, small/large for gestational age (SGA/LGA), and child loss. Only nondiabetic women with singleton deliveries were included; the baseline sample consisted of 4008 women. Analysis for PIH and preeclampsia were performed in nulliparous women only (n = 2037). RESULTS: Mean (sd) triglyceride and total cholesterol levels were 1.33 (0.55) and 4.98 (0.87) mmol/liter, respectively. The incidence of pregnancy complications and perinatal outcomes were as follows: PIH, 4.9%; preeclampsia, 3.7%; preterm birth, 5.3%; SGA, 9.3%; LGA, 9.3%; and child loss, 1.4%. After adjustments, every unit increase in triglycerides was linearly associated with an increased risk of PIH [odds ratio (OR) = 1.60, P = 0.021], preeclampsia (OR = 1.69, P = 0.018), LGA (OR = 1.48, P < 0.001), and induced preterm delivery (OR = 1.69, P = 0.006). No associations were found for SGA or child loss. Total cholesterol was not associated with any of the outcome measures. CONCLUSIONS: Elevated maternal triglyceride levels measured during early pregnancy are associated with pregnancy complications and adverse pregnancy outcomes. These results suggest that future lifestyle programs in women of reproductive age with a focus on lowering triglyceride levels (i.e. diet, weight reduction, and physical activity) may help to prevent hypertensive complications during pregnancy and adverse birth outcomes. PMID- 22933543 TI - Novel microcephalic primordial dwarfism disorder associated with variants in the centrosomal protein ninein. AB - CONTEXT: Microcephalic primordial dwarfism (MPD) is a rare, severe form of human growth failure in which growth restriction is evident in utero and continues into postnatal life. Single causative gene defects have been identified in a number of patients with MPD, and all involve genes fundamental to cellular processes including centrosome functions. OBJECTIVE: The objective of the study was to find the genetic etiology of a novel presentation of MPD. DESIGN: The design of the study was whole-exome sequencing performed on two affected sisters in a single family. Molecular and functional studies of a candidate gene were performed using patient-derived primary fibroblasts and a zebrafish morpholino oligonucleotides knockdown model. PATIENTS: Two sisters presented with a novel subtype of MPD, including severe intellectual disabilities. MAIN OUTCOME MEASURES: NIN, encoding Ninein, a centrosomal protein critically involved in asymmetric cell division, was identified as a candidate gene, and functional impacts in fibroblasts and zebrafish were studied. RESULTS: From 34,606 genomic variants, two very rare missense variants in NIN were identified. Both probands were compound heterozygotes. In the zebrafish, ninein knockdown led to specific and novel defects in the specification and morphogenesis of the anterior neuroectoderm, resulting in a deformity of the developing cranium with a small, squared skull highly reminiscent of the human phenotype. CONCLUSION: We identified a novel clinical subtype of MPD in two sisters who have rare variants in NIN. We show, for the first time, that reduction of ninein function in the developing zebrafish leads to specific deficiencies of brain and skull development, offering a developmental basis for the myriad phenotypes in our patients. PMID- 22933546 TI - Frequent expression of fibroblast growth factor-23 (FGF23) mRNA in aneurysmal bone cysts and chondromyxoid fibromas. AB - Osteomalacia has multiple aetiologies including the least common, tumour-induced osteomalacia (TIO). Recently, most cases of TIO have been confirmed to be due to phosphaturic mesenchymal tumour of mixed connective tissue type (PMTMCT). Most cases of TIO are the result of production of the fibroblast growth factor-23 (FGF 23) by the tumour. The authors recently showed reverse transcriptase PCR (RT-PCR) for FGF-23 to be valuable in the diagnosis of PMTMCT. However, the authors also noted FGF-23 expression in some cases of aneurysmal bone cyst (ABC) and chondromyxoid fibroma (CMF). For the present study, the authors studied FGF-23 expression by RT-PCR in 19 cases of ABC and eight cases of CMF, all with typical clinical and radiographic features and without evidence of TIO. Seven of 16 (44%) ABC and two of seven (29%) CMF were positive for FGF-23. These results confirm that ABC and CMF not uncommonly express FGF-23. These results strongly suggest caution and careful integration with all other clinical and radiographic data in the use of FGF-23 RT-PCR for the diagnosis of PMTMCT. PMID- 22933547 TI - Cervical pessary reduces spontaneous delivery before 34 weeks and adverse outcomes in pregnant women with a short cervix. PMID- 22933548 TI - Intensive glucose control in patients with type 2 diabetes is associated with a reduction in albuminuria and may be associated with reduced end-stage renal disease. PMID- 22933549 TI - Opposite impacts of dietary versus supplemental calcium on cardiovascular health. PMID- 22933550 TI - Genotoxicity and oxidative stress in chromium-exposed tannery workers in North India. AB - Trivalent chromium (Cr) is an environmental contaminant, which is extensively used in tanning industries throughout the world and causes various forms of health hazards in tannery workers. Therefore, a cross-sectional study design was used to evaluate the DNA damage and oxidative stress condition in tannery workers exposed to Cr in North India. The study population comprised 100 male tanners in the exposed group and 100 healthy males (no history of Cr exposure) in the comparable control group. Baseline characteristics including age, smoking, alcohol consumption habits and duration of exposure were recorded via interviewing the subjects. Blood Cr level (measured by atomic absorption spectrophotometry), DNA damage (measured by comet assay) and oxidative stress parameters (malondialdehyde (MDA), glutathione (GSH) and superoxide dismutase (SOD)) were estimated in both the groups. As a result of statistical analysis, exposed group showed significantly higher level of Cr (p < 0.0001), DNA damage (p < 0.0001), MDA (p < 0.0001), SOD (p < 0.05) and lower level of GSH (p < 0.001) when compared with controls. Smoking, alcohol consumption habits and age had no significant effect (p > 0.05) on DNA damage and oxidative stress parameters in both the groups. In simple and multiple correlation analysis, DNA damage and oxidative stress parameters showed significant correlation with Cr level and duration of exposure in exposed group. The findings of the present study revealed that chronic occupational exposure to trivalent Cr may cause DNA damage and oxidative stress in tannery workers. PMID- 22933551 TI - Evaluation of acute toxicity potential of water hyacinth leaves. AB - Although higher protein yield per hectare of water hyacinth than that of soy, high protein content of its leaves and good essential amino acid pattern have been proven, its dietary toxicity for human or animal consumption has not yet been evaluated. Therefore, the acute toxicity of water hyacinth leaves has been evaluated by an animal feeding test. The concentrations of common toxic metals including cadmium, lead, platinum, palladium, tin, mercury, barium, silver, stibium and aluminum in the water hyacinth leaf powder (WHLP) used for the animal feeding test were within their maximum limits in food additives as reported by the World Health Organization. The median lethal dose (LD50) of WHLP was more than 16 g kg(-1) body weight. In the study, after feeding for 7 and 28 days, the body weight of all the mice increased. The results of hematological analysis, clinical biochemical analysis, histopathological evaluation, general dissection or investigations of internal organs, appearance and behavior observations did not indicate any adverse effects from the diet containing WHLP. It is therefore concluded that water hyacinth leaves are not acutely toxic. PMID- 22933552 TI - Physiological-based pharmacokinetic modeling of endotoxin in the rat. AB - We have previously measured the distribution and pharmacokinetics of biosynthetically radiolabeled endotoxin of Salmonella typhimurium following intraperitoneal (IP) dosing (200 MUg/kg) in Sprague-Dawley rats. In our experiments, the fatty acid residues were labeled with (3)H and the glucosamine residues were labeled with (14)C. To predict the dynamics of endotoxin exposure, we developed a physiological-based pharmacokinetic model using our measured distribution results. The model was validated with published low-dose (30 MUg/kg) IP exposure results in rats. Endotoxin pharmacokinetics depended on dose and route. At high IP doses, absorption was followed by biphasic decay over 48 h in plasma. There were tissue accumulations of the fatty acid and glucosamine residues in various target organs, including the brain. We also found that the glucosamine and fatty acid components separated in vivo about 3 h after IP injection. At the lower IP dose, a smaller fraction of the dose was distributed to the tissues, with most of the dose remaining in the blood. Each component had its own dynamic behavior and target tissue distribution in the rat. The fatty acid components tended to remain in the brain stem, caudate nucleus, cerebellum, frontal cortex, hippocampus, and hypothalamus. Other organs (spleen, kidney, meninges, and choroid plexus) had similar biphasic distribution. The liver had the unique accumulation of both glucosamine and fatty acid residues. PMID- 22933553 TI - Distribution and pharmacokinetics of double-radiolabeled endotoxin in the rat brain and peripheral organs. AB - The endotoxin, lipopolysaccharide (LPS), of Salmonella typhimurium was biosynthetically labeled with (3)H and (14)C incorporated into the fatty acyl chains and glucosamine residues, respectively. The radio-labeled LPS was isolated from the bacteria and then injected into Sprague-Dawley rats. The distribution of (14)C and (3)H-LPS in plasma and other organs was determined following intraperitoneal (IP) doses of (14)C and (3)H-LPS (200 MUg/kg). Plasma concentrations of both fatty acyl chains and glucosamine residues were biphasic, with a relatively rapid decay followed by a slow decline for 48 h. Similar biphasic results were found in the peripheral organs (kidney and heart) and brain barrier tissues (meninges and choroid plexus). In other brain tissues (brain stem, caudate nucleus, hypothalamus, frontal cortex, cerebellum and hippocampus), the glucosamine residue was biphasic, whereas the fatty acyl chains showed accumulation. Highest concentrations of LPS were found in the plasma, spleen and the liver. In addition, in the liver, sustained elevations of (14)C-glucosamine and (3)H-fatty acyl chains were observed. This indicates LPS accumulation in the liver. By contrast, the spleen showed biphasic decay of glucosamine residues and accumulation of fatty acyl chains. In the brain barrier tissues, peak LPS concentrations were significantly reduced (about 70%) and were further reduced (about 95%) in other brain tissues. The high elevation of LPS in the spleen is considered indicative of an immune response. Our findings highlight the potential significant role of lipid A as shown with the sustained elevation of (3)H-fatty acyl chains in the brain. PMID- 22933554 TI - Effects of shock waves on oxidative stress in parotid gland of rat. AB - This study was designed to investigate whether extracorporeal shock wave lithotripsy (ESWL) exposure to parotid gland produces an oxidative stress in parotid glands of rats. Twelve male Wistar-albino rats, 6 months of age with an average body weight of 250-300 g, were divided randomly into two groups, each consisting of six rats. The animals in the first group did not receive any treatment and served as control. The left parotid glands of animals in group 2 (ESWL treated) received a thousand 18 kV shock waves after anesthetizing the rats with 50 mg/kg of ketamine. The animals in both groups were killed 72 hours after the ESWL treatment, and the parotid glands were harvested for the determination of lipid peroxidation product malondialdehyde (MDA), antioxidant glutathione (GSH) levels and the activities of antioxidant enzymes such as superoxide dismutase (SOD), GSH-Px and catalase (CAT). It was found that MDA level increased in parotid glands of rats after the ESWL treatment. The SOD, GSH-Px and CAT enzyme activities, and the level of antioxidant GSH decreased in parotid gland of rats after the ESWL treatment. It was concluded that short-term ESWL treatment caused an increase in the free radical production and a decrease in the antioxidant enzyme activity in parotid glands of ESWL-treated rats. PMID- 22933555 TI - Hematological effect of benzene exposure with emphasis of muconic acid as a biomarker. AB - Human exposure to benzene in work environment is a global occupational health problem. It is established that benzene requires to be metabolized to induce its effects. Benzene has been associated with various hematotoxins and carcinogens. The aim of this study was to investigate the effect of benzene on complete blood picture, with emphasis of trans, trans-muconic acid (t,t-MA) as a biomarker of benzene in urine, considering the influence of cigarette smoke. A total of 81 workers (61 males and 20 females) have been occupationally exposed to benzene. In addition, 83 workers (55males and 28 females) were also recruited as a control group. Complete blood picture was analyzed and urinary t,t-MA was determined by liquid chromatography. In addition, creatinine in the urine samples was determined. Levels of blood elements (white blood cells, red blood cells and platelets) were decreased among exposed workers compared with the controls. The urinary level of t,t-MA/creatinine of the exposed workers was elevated especially in the smoking group compared to the controls. This study recommends that complete blood picture and t,t-MA are helpful biomarker tests that should be done to detect the early effects of benzene exposure. PMID- 22933556 TI - Results of a 90-day inhalation study of dicyclopentadiene in B6C3F1 mice. AB - The objective of this inhalation study was to determine and evaluate the potential toxic effects of dicyclopentadiene vapor in mice exposed for 13-weeks of repeated inhalation. Four groups, each consisting of 45 male and 45 female B6C3F1 mice, were exposed to dicyclopentadiene vapor by inhalation 6 h/day, 5 days/week, for 13 weeks (64 exposures) at targeted concentrations of 0, 1.0, 5.0, or 50 ppm. An assessment of toxicity is carried out after 2, 6, and 13 weeks of inhalation exposures. Additionally, animals were evaluated during the recovery period of 4 or 13 weeks after the last exposure. Observations and measurements to assess toxicity include clinical observations, body weight, organ weights, serum chemistry, and hematologic, ophthalmologic, gross pathologic, and histologic evaluations. The only systemic effects observed were a few statistically significant changes in organ weights; but these were considered spurious in nature. Ten male and nine female mice in the highest exposure group died during the study, while no more than two mice died in any other group. However, the excess mortality was without an apparent etiology or association to exposure and was attributed to pulmonary congestion as a consequence of pulmonary irritation. Under the conditions of this study, these data demonstrated that in the absence of overt systemic toxicity, respiratory congestion has the predominant effect at the exposure levels of 50 ppm. This observation contributes to the Globally Harmonized System harmonized hazard classification of Single Target Organ Toxicity - Single Exposure (H335, may cause respiratory irritation) for this substance. PMID- 22933557 TI - Sodium 3,5,6-trichloropyridin-2-ol poisoning: report of four cases. AB - Sodium 3,5,6-trichloropyridin-2-ol (STCP) is an important intermediate for synthesizing organophosphate insecticide chlorpyrifos. At present, chlorpyrifos is one of the world's largest species of pesticide products. Many studies have focused on the toxicity of chlorpyrifos, but few reports have looked at the toxicity mechanism of STCP. Even fewer studies have looked at STCP poisoning. With increasing production and usage of STCP, the chances of such poisoning will increase. In this study, we present a report on four workers who helped in the industrial manufacture of STCP and who were affected by exposure to it. We hope that these case studies will provide a foundation for further research into STCP. PMID- 22933558 TI - The role of bacterial enhancer binding proteins as specialized activators of sigma54-dependent transcription. AB - Bacterial enhancer binding proteins (bEBPs) are transcriptional activators that assemble as hexameric rings in their active forms and utilize ATP hydrolysis to remodel the conformation of RNA polymerase containing the alternative sigma factor sigma(54). We present a comprehensive and detailed summary of recent advances in our understanding of how these specialized molecular machines function. The review is structured by introducing each of the three domains in turn: the central catalytic domain, the N-terminal regulatory domain, and the C terminal DNA binding domain. The role of the central catalytic domain is presented with particular reference to (i) oligomerization, (ii) ATP hydrolysis, and (iii) the key GAFTGA motif that contacts sigma(54) for remodeling. Each of these functions forms a potential target of the signal-sensing N-terminal regulatory domain, which can act either positively or negatively to control the activation of sigma(54)-dependent transcription. Finally, we focus on the DNA binding function of the C-terminal domain and the enhancer sites to which it binds. Particular attention is paid to the importance of sigma(54) to the bacterial cell and its unique role in regulating transcription. PMID- 22933560 TI - Regulation of the histidine utilization (hut) system in bacteria. AB - The ability to degrade the amino acid histidine to ammonia, glutamate, and a one carbon compound (formate or formamide) is a property that is widely distributed among bacteria. The four or five enzymatic steps of the pathway are highly conserved, and the chemistry of the reactions displays several unusual features, including the rearrangement of a portion of the histidase polypeptide chain to yield an unusual imidazole structure at the active site and the use of a tightly bound NAD molecule as an electrophile rather than a redox-active element in urocanase. Given the importance of this amino acid, it is not surprising that the degradation of histidine is tightly regulated. The study of that regulation led to three central paradigms in bacterial regulation: catabolite repression by glucose and other carbon sources, nitrogen regulation and two-component regulators in general, and autoregulation of bacterial regulators. This review focuses on three groups of organisms for which studies are most complete: the enteric bacteria, for which the regulation is best understood; the pseudomonads, for which the chemistry is best characterized; and Bacillus subtilis, for which the regulatory mechanisms are very different from those of the Gram-negative bacteria. The Hut pathway is fundamentally a catabolic pathway that allows cells to use histidine as a source of carbon, energy, and nitrogen, but other roles for the pathway are also considered briefly here. PMID- 22933561 TI - Anaerobic ammonium-oxidizing bacteria: unique microorganisms with exceptional properties. AB - Anaerobic ammonium-oxidizing (anammox) bacteria defy many microbiological concepts and share numerous properties with both eukaryotes and archaea. Among their most intriguing characteristics are their compartmentalized cell plan and archaeon-like cell wall. Here we review our current knowledge about anammox cell biology. The anammox cell is divided into three separate compartments by bilayer membranes. The anammox cell consists of (from outside to inside) the cell wall, paryphoplasm, riboplasm, and anammoxosome. Not much is known about the composition or function of both the anammox cell wall and the paryphoplasm compartment. The cell wall is proposed to be proteinaceous and to lack both peptidoglycan and an outer membrane typical of Gram-negative bacteria. The function of the paryphoplasm is unknown, but it contains the cell division ring. The riboplasm resembles the standard cytoplasmic compartment of other bacteria; it contains ribosomes and the nucleoid. The anammoxosome occupies most of the cell volume and is a so-called "prokaryotic organelle" analogous to the eukaryotic mitochondrion. This is the site where the anammox reaction takes place, coupled over the curved anammoxosome membrane, possibly giving rise to a proton motive force and subsequent ATP synthesis. With these unique properties, anammox bacteria are food for thought concerning the early evolution of the domains Bacteria, Archaea, and Eukarya. PMID- 22933559 TI - DNA repair and genome maintenance in Bacillus subtilis. AB - From microbes to multicellular eukaryotic organisms, all cells contain pathways responsible for genome maintenance. DNA replication allows for the faithful duplication of the genome, whereas DNA repair pathways preserve DNA integrity in response to damage originating from endogenous and exogenous sources. The basic pathways important for DNA replication and repair are often conserved throughout biology. In bacteria, high-fidelity repair is balanced with low-fidelity repair and mutagenesis. Such a balance is important for maintaining viability while providing an opportunity for the advantageous selection of mutations when faced with a changing environment. Over the last decade, studies of DNA repair pathways in bacteria have demonstrated considerable differences between Gram-positive and Gram-negative organisms. Here we review and discuss the DNA repair, genome maintenance, and DNA damage checkpoint pathways of the Gram-positive bacterium Bacillus subtilis. We present their molecular mechanisms and compare the functions and regulation of several pathways with known information on other organisms. We also discuss DNA repair during different growth phases and the developmental program of sporulation. In summary, we present a review of the function, regulation, and molecular mechanisms of DNA repair and mutagenesis in Gram-positive bacteria, with a strong emphasis on B. subtilis. PMID- 22933562 TI - Culture history and population heterogeneity as determinants of bacterial adaptation: the adaptomics of a single environmental transition. AB - Diversity in adaptive responses is common within species and populations, especially when the heterogeneity of the frequently large populations found in environments is considered. By focusing on events in a single clonal population undergoing a single transition, we discuss how environmental cues and changes in growth rate initiate a multiplicity of adaptive pathways. Adaptation is a comprehensive process, and stochastic, regulatory, epigenetic, and mutational changes can contribute to fitness and overlap in timing and frequency. We identify culture history as a major determinant of both regulatory adaptations and microevolutionary change. Population history before a transition determines heterogeneities due to errors in translation, stochastic differences in regulation, the presence of aged, damaged, cheating, or dormant cells, and variations in intracellular metabolite or regulator concentrations. It matters whether bacteria come from dense, slow-growing, stressed, or structured states. Genotypic adaptations are history dependent due to variations in mutation supply, contingency gene changes, phase variation, lateral gene transfer, and genome amplifications. Phenotypic adaptations underpin genotypic changes in situations such as stress-induced mutagenesis or prophage induction or in biofilms to give a continuum of adaptive possibilities. Evolutionary selection additionally provides diverse adaptive outcomes in a single transition and generally does not result in single fitter types. The totality of heterogeneities in an adapting population increases the chance that at least some individuals meet immediate or future challenges. However, heterogeneity complicates the adaptomics of single transitions, and we propose that subpopulations will need to be integrated into future population biology and systems biology predictions of bacterial behavior. PMID- 22933566 TI - Apixaban in renal insufficiency: successful navigation between the Scylla and Charybdis. PMID- 22933563 TI - Biogenesis of the Saccharomyces cerevisiae pheromone a-factor, from yeast mating to human disease. AB - The mating pheromone a-factor secreted by Saccharomyces cerevisiae is a farnesylated and carboxylmethylated peptide and is unusually hydrophobic compared to other extracellular signaling molecules. Mature a-factor is derived from a precursor with a C-terminal CAAX motif that directs a series of posttranslational reactions, including prenylation, endoproteolysis, and carboxylmethylation. Historically, a-factor has served as a valuable model for the discovery and functional analysis of CAAX-processing enzymes. In this review, we discuss the three modules comprising the a-factor biogenesis pathway: (i) the C-terminal CAAX processing steps carried out by Ram1/Ram2, Ste24 or Rce1, and Ste14; (ii) two sequential N-terminal cleavage steps, mediated by Ste24 and Axl1; and (iii) export by a nonclassical mechanism, mediated by the ATP binding cassette (ABC) transporter Ste6. The small size and hydrophobicity of a-factor present both challenges and advantages for biochemical analysis, as discussed here. The enzymes involved in a-factor biogenesis are conserved from yeasts to mammals. Notably, studies of the zinc metalloprotease Ste24 in S. cerevisiae led to the discovery of its mammalian homolog ZMPSTE24, which cleaves the prenylated C terminal tail of the nuclear scaffold protein lamin A. Mutations that alter ZMPSTE24 processing of lamin A in humans cause the premature-aging disease progeria and related progeroid disorders. Intriguingly, recent evidence suggests that the entire a-factor pathway, including all three biogenesis modules, may be used to produce a prenylated, secreted signaling molecule involved in germ cell migration in Drosophila. Thus, additional prenylated signaling molecules resembling a-factor, with as-yet-unknown roles in metazoan biology, may await discovery. PMID- 22933567 TI - Efficacy of apixaban when compared with warfarin in relation to renal function in patients with atrial fibrillation: insights from the ARISTOTLE trial. AB - AIMS: Atrial fibrillation (AF) is common among patients with impaired renal function. Apixaban, a novel oral anticoagulant with partial renal excretion, was compared with warfarin and reduced the rate stroke, death and bleeding in the ARISTOTLE trial. We evaluated these outcomes in relation to renal function. METHODS AND RESULTS: Baseline glomerular filtration rate (GFR) was estimated using the Cockcroft-Gault and Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equations as well as cystatin C measurements. According to baseline Cockcroft-Gault, there were 7518 patients (42%) with an estimated GFR (eGFR) of >80 mL/min, 7587 (42%) between >50 and 80 mL/min, and 3017 (15%) with an eGFR of <=50 mL/min. The rate of cardiovascular events and bleeding was higher at impaired renal function (<=80 mL/min). Apixaban was more effective than warfarin in preventing stroke or systemic embolism and reducing mortality irrespective of renal function. These results were consistent, regardless of methods for GFR estimation. Apixaban was associated with less major bleeding events across all ranges of eGFRs. The relative risk reduction in major bleeding was greater in patients with an eGFR of <=50 mL/min using Cockcroft-Gault {hazard ratio (HR) 0.50 [95% confidence interval (CI) 0.38-0.66], interaction P = 0.005} or CKD-EPI equations [HR 0.48 (95% CI 0.37-0.64), interaction P = 0.003]. CONCLUSION: In patients with AF, renal impairment was associated with increased risk of cardiovascular events and bleeding. When compared with warfarin, apixaban treatment reduced the rate of stroke, death, and major bleeding, regardless of renal function. Patients with impaired renal function seemed to have the greatest reduction in major bleeding with apixaban. PMID- 22933568 TI - Mitral valve surgery: wait and see vs. early operation. AB - Mitral valve repair represents the optimal surgical treatment for severe degenerative mitral regurgitation. According to the current guidelines, mitral repair is indicated in the presence of symptoms and/or signs of left ventricular (LV) dysfunction. In asymptomatic patients with preserved LV function, surgery should be considered in the presence of atrial fibrillation (AF) and/or pulmonary hypertension. In asymptomatic patients with preserved LV function, normal pulmonary artery pressure, and no episodes of AF, surgical timing is still an object of debate. The controversial issue is whether, in those circumstances, a 'wait and see (watchful waiting)' approach should be followed or an 'early repair' policy should be preferred. Indeed, a randomized trial comparing the two strategies has never been performed. In the absence of evidence-based arguments definitely supporting any particular course of action, advantages, drawbacks, and requirements for both strategies will be discussed in this review on the basis of the most significant observational studies which have focused on this issue. PMID- 22933564 TI - The multiple functions of TRBP, at the hub of cell responses to viruses, stress, and cancer. AB - The TAR RNA binding protein (TRBP) has emerged as a key player in many cellular processes. First identified as a cellular protein that facilitates the replication of human immunodeficiency virus, TRBP has since been shown to inhibit the activation of protein kinase R (PKR), a protein involved in innate immune responses and the cellular response to stress. It also binds to the PKR activator PACT and regulates its function. TRBP also contributes to RNA interference as an integral part of the minimal RNA-induced silencing complex with Dicer and Argonaute proteins. Due to its multiple functions in the cell, TRBP is involved in oncogenesis when its sequence is mutated or its expression is deregulated. The depletion or overexpression of TRBP results in malignancy, suggesting that the balance of TRBP expression is key to normal cellular function. These studies show that TRBP is multifunctional and mediates cross talk between different pathways. Its activities at the molecular level impact the cellular function from normal development to cancer and the response to infections. PMID- 22933565 TI - Interactions between diatoms and bacteria. AB - Diatoms and bacteria have cooccurred in common habitats for hundreds of millions of years, thus fostering specific associations and interactions with global biogeochemical consequences. Diatoms are responsible for one-fifth of the photosynthesis on Earth, while bacteria remineralize a large portion of this fixed carbon in the oceans. Through their coexistence, diatoms and bacteria cycle nutrients between oxidized and reduced states, impacting bioavailability and ultimately feeding higher trophic levels. Here we present an overview of how diatoms and bacteria interact and the implications of these interactions. We emphasize that heterotrophic bacteria in the oceans that are consistently associated with diatoms are confined to two phyla. These consistent bacterial associations result from encounter mechanisms that occur within a microscale environment surrounding a diatom cell. We review signaling mechanisms that occur in this microenvironment to pave the way for specific interactions. Finally, we discuss known interactions between diatoms and bacteria and exciting new directions and research opportunities in this field. Throughout the review, we emphasize new technological advances that will help in the discovery of new interactions. Deciphering the languages of diatoms and bacteria and how they interact will inform our understanding of the role these organisms have in shaping the ocean and how these interactions may change in future oceans. PMID- 22933569 TI - Failing stentless aortic valves: redo aortic root replacement or valve in a valve? AB - OBJECTIVES: Reoperation for failing stentless aortic valve replacement is a technically demanding procedure that has traditionally been tackled in one of two ways: either root replacement or the more conservative option of implanting a stented valve within the valve. We sought to determine the relative operative risks, follow-up status and medium to long-term survival of these two methods. METHODS: We conducted a retrospective review of a single surgeon's experience of the two techniques over a 10-year period from 2000 to 2010. Excluding cases of active endocarditis, 110 patients were identified, of which 65 underwent 'valve in-valve' procedures ('Group A') and 45 had redo root replacement ('Group B'). The most common bioprostheses reoperated were homografts (roots or subcoronary implants) and Toronto Stentless Porcine Valves. Aortic valve replacement alone was performed in 68% in Group A and 64% in Group B, with males comprising 75% of Group A and 82% of Group B. Average ages were 61.5 +/- 14.2 years and 61.9 +/- 12.1 years, respectively. RESULTS: Operative and cardiopulmonary bypass durations were significantly greater for redo root procedures and correspondingly, postoperative complications were more common. Thirty-day mortality after valve-in valve replacement was 3%, and after redo root replacement it was 11%. Despite significantly higher transvalvular gradients in Group B, the symptomatic status was equally good at 2 months, 1 year and last follow-up. At an average interval of 5.1 +/- 2.7 years for Group A, survival was 83% vs 76% at 7.3 +/- 2.9 years for Group B. There have been two reinterventions in Group A and 3 in Group B. Only one valve-in-valve patient has developed a paraprosthetic leak. CONCLUSIONS: This retrospective review has confirmed our hypothesis that where both root diameter permits and satisfactory debridement can be performed, valve-in-valve replacement is the more conservative surgical strategy for stentless aortic valve replacement revision. Although transvalvular gradients on echocardiography are significantly higher with the introduction of a stented prosthesis, medium-term outcomes in terms of symptomatic status, late complications and reintervention rate were non-inferior. We await the medium-term results of transcatheter aortic valve implantation for the same indication with interest. PMID- 22933571 TI - The Tom40 assembly process probed using the attachment of different intramitochondrial sorting signals. AB - The TOM40 complex is a protein translocator in the mitochondrial outer membrane and consists of several different subunits. Among them, Tom40 is a central subunit that constitutes a protein-conducting channel by forming a beta-barrel structure. To probe the nature of the assembly process of Tom40 in the outer membrane, we attached various mitochondrial presequences to Tom40 that possess sorting information for the intermembrane space (IMS), inner membrane, and matrix and would compete with the inherent Tom40 assembly process. We analyzed the mitochondrial import of those fusion proteins in vitro. Tom40 crossed the outer membrane and/or inner membrane even in the presence of various sorting signals. N terminal anchorage of the attached presequence to the inner membrane did not prevent Tom40 from associating with the TOB/SAM complex, although it impaired its efficient release from the TOB complex in vitro but not in vivo. The IMS or matrix-targeting presequence attached to Tom40 was effective in substituting for the requirement for small Tim proteins in the IMS for the translocation of Tom40 across the outer membrane. These results provide insight into the mechanism responsible for the precise delivery of beta-barrel proteins to the outer mitochondrial membrane. PMID- 22933572 TI - Nucleolar AATF regulates c-Jun-mediated apoptosis. AB - The AP-1 transcription factor c-Jun has been shown to be essential for stress induced apoptosis in several models. However, the molecular mechanisms underlying the proapoptotic activity of c-Jun are poorly understood. We identify the apoptosis-antagonizing transcription factor (AATF) as a novel nucleolar stress sensor, which is required as a cofactor for c-Jun-mediated apoptosis. Overexpression or down-regulation of AATF expression levels led to a respective increase or decrease in the amount of activated and phosphorylated c-Jun with a proportional alteration in the induction levels of the proapoptotic c-Jun target genes FasL and TNF-alpha. Accordingly, AATF promoted commitment of ultraviolet (UV)-irradiated cells to c-Jun-dependent apoptosis. Whereas AATF overexpression potentiated UV-induced apoptosis in wild-type cells, c-Jun-deficient mouse embryonic fibroblasts were resistant to AATF-mediated apoptosis induction. Furthermore, AATF mutants defective in c-Jun binding were also defective in inducing AP-1 activity and c-Jun-mediated apoptosis. UV irradiation induced a translocation of AATF from the nucleolus to the nucleus, thereby enabling its physical association to c-Jun. Analysis of AATF deletion mutants revealed that the AATF domains required for compartmentalization, c-Jun binding, and enhancement of c-Jun transcriptional activity were all also required to induce c Jun-dependent apoptosis. These results identify AATF as a nucleolar-confined c Jun cofactor whose expression levels and spatial distribution determine the stress-induced activity of c-Jun and the levels of c-Jun-mediated apoptosis. PMID- 22933573 TI - Hect E3 ubiquitin ligase Tom1 controls Dia2 degradation during the cell cycle. AB - The ubiquitin proteasome system plays a pivotal role in controlling the cell cycle. The budding yeast F-box protein Dia2 is required for genomic stability and is targeted for ubiquitin-dependent degradation in a cell cycle-dependent manner, but the identity of the ubiquitination pathway is unknown. We demonstrate that the Hect domain E3 ubiquitin ligase Tom1 is required for Dia2 protein degradation. Deletion of DIA2 partially suppresses the temperature-sensitive phenotype of tom1 mutants. Tom1 is required for Dia2 ubiquitination and degradation during G1 and G2/M phases of the cell cycle, whereas the Dia2 protein is stabilized during S phase. We find that Tom1 binding to Dia2 is enhanced in G1 and reduced in S phase, suggesting a mechanism for this proteolytic switch. Tom1 recognizes specific, positively charged residues in a Dia2 degradation/NLS domain. Loss of these residues blocks Tom1-mediated turnover of Dia2 and causes a delay in G1-to-S phase progression. Deletion of DIA2 rescues a delay in the G1-to S phase transition in the tom1Delta mutant. Together our results suggest that Tom1 targets Dia2 for degradation during the cell cycle by recognizing positively charged residues in the Dia2 degradation/NLS domain and that Dia2 protein degradation contributes to G1-to-S phase progression. PMID- 22933574 TI - Ain't no mountain high enough? Setting high weight loss goals predict effort and short-term weight loss. AB - Although psychological theories outline that it might be beneficial to set more challenging goals, people attempting to lose weight are generally recommended to set modest weight loss goals. The present study explores whether the amount of weight loss individuals strive for is associated with more positive psychological and behavioral outcomes. Hereto, 447 overweight and obese participants trying to lose weight completed two questionnaires with a 2-month interval. Many participants set goals that could be considered unrealistically high. However, higher weight loss goals did not predict dissatisfaction but predicted more effort in the weight loss attempt, as well as more self-reported short-term weight loss when baseline commitment and motivation were controlled for. PMID- 22933575 TI - General self-efficacy in relation to unprotected sexual encounters among persons living with HIV. AB - This study examined general self-efficacy in relation to sexual risk behavior among persons living with HIV and evaluated psychometric properties of the Positive Self Questionnaire, a novel measure of general self-efficacy. The Positive Self Questionnaire showed high internal consistency, a factor analysis supported by a single factor structure, and convergent validity supported by significant correlations in predicted directions with indicators of mental health. The Positive Self Questionnaire was related to unprotected sexual encounters, even after controlling for other factors. Results suggest that general self-efficacy is important to examine when assessing sexual risk behavior; an internally consistent measure is available for such endeavors. PMID- 22933576 TI - Symptom experiences in patients after heart transplantation. AB - Patients' perceptions of immunosuppression-related symptom experience impact on quality of life and medication adherence. Using The Modified Transplant Symptom Occurrence and Symptom Distress Scale capturing items on symptom occurrence and symptom distress, 261 heart transplant recipients reported on their symptom experiences. Symptoms occurring with the highest prevalence were tiredness, lack of energy, and nervousness. Men showed erectile dysfunction causing the most distress. Women and younger patients reported significantly higher levels of symptom distress. Distress levels increased with time after transplant. Investigating responses to immunosuppression-related symptom experiences should help develop interventional methods to support long-term outcome. PMID- 22933577 TI - The evaluation of primary idiopathic focal hyperhidrosis patients in terms of alexithymia. AB - The aim of this study was to evaluate the primary focal hyperhidrosis patients in terms of alexithymia. Participants (n = 50) diagnosed with primary focal hyperhidrosis by a dermatologist were referred to a psychiatrist and evaluated via Structured Clinical Interview for DSM-IV Axis I Disorders and Toronto Alexithymia Scale-20. The rate of alexithymia was 45.6 percent and 18.2 percent, respectively, for primary focal hyperhidrosis and control participants (n = 44). Multivariate analysis of variance results showed that the primary focal hyperhidrosis group scored significantly higher than the control group in Difficulty Identifying Feelings and Difficulty Describing Feelings subscales, and total score. Psychotherapeutic interventions can increase the chances of dermatological treatment success and can have a positive impact on the quality of life in chronic cases. PMID- 22933578 TI - Social and cognitive predictors of fruit and vegetable intake among adolescents: the context of changes in body weight. AB - Two studies investigated differences in the relationships between adolescents' fruit and vegetable intake (FVI) and the predictors specified in the Health Action Process Approach and Social-Cognitive Theory. Retrospective (Study 1; N = 502) and prospective (Study 2; N = 668) designs were applied. Among adolescents with overweight/obesity, intention was cross-sectionally associated with FVI (Study 1); no social or cognitive predictors explained FVI at 14-month follow-up (Study 2). The planning - FVI and self-efficacy - FVI relationships were stronger among adolescents who reduced their body weight to normal, compared to effects observed among those who maintained their body weight (Studies 1 and 2). PMID- 22933579 TI - To end life or not to prolong life: the effect of message framing on attitudes toward euthanasia. AB - People ascribe "euthanasia" different values and view it differently. This study hypothesized that a different framing of objectively the same euthanasia situations would affect people's attitudes toward it. Indeed, "positive" framing of euthanasia as not prolonging life resulted in more support for both passive and active euthanasia relative to "negative" framing of the objectively same situations as ending life. Two experiments replicated this pattern using either continuous measures of attitude or dichotomous measures of choice. The article offers two theoretical explanations for the effect of message framing on attitudes toward euthanasia, discusses implications of this effect, and suggests future research. PMID- 22933580 TI - Attachment and barriers to cervical screening. AB - The present study explored the role of attachment insecurity in cervical screening behaviors and barriers in a sample of 257 female undergraduates. Information on attachment dimensions as well as attachment style was collected. Attachment anxiety and attachment avoidance were associated with decreased likelihood of having participated in cervical screening and positively associated with screening barriers. Screening barriers were elevated among individuals with insecure attachment styles (preoccupied, fearful, and dismissing), and dismissing participants were less likely to have engaged in screening compared to secure participants. Our findings demonstrate that attachment insecurity may be a risk factor for inadequate cervical screening and screening barriers. PMID- 22933581 TI - Stroke assessment with diffusional kurtosis imaging. AB - BACKGROUND AND PURPOSE: Despite being the gold standard technique for stroke assessment, conventional diffusion MRI provides only partial information about tissue microstructure. Diffusional kurtosis imaging is an advanced diffusion MRI method that yields, in addition to conventional diffusion information, the diffusional kurtosis, which may help improve characterization of tissue microstructure. In particular, this additional information permits the description of white matter (WM) in terms of WM-specific diffusion metrics. The goal of this study is to elucidate possible biophysical mechanisms underlying ischemia using these new WM metrics. METHODS: We performed a retrospective review of clinical and diffusional kurtosis imaging data of 44 patients with acute/subacute ischemic stroke. Patients with a history of brain neoplasm or intracranial hemorrhages were excluded from this study. Region of interest analysis was performed to measure percent change of diffusion metrics in ischemic WM lesions compared with the contralateral hemisphere. RESULTS: Kurtosis maps exhibit distinct ischemic lesion heterogeneity that is not apparent on apparent diffusion coefficient maps. Kurtosis metrics also have significantly higher absolute percent change than complementary conventional diffusion metrics. Our WM metrics reveal an increase in axonal density and a larger decrease in the intra axonal (Da) compared with extra-axonal diffusion microenvironment of the ischemic WM lesion. CONCLUSIONS: The well-known decrease in the apparent diffusion coefficient of WM after ischemia is found to be mainly driven by a significant drop in the intra-axonal diffusion microenvironment. Our results suggest that ischemia preferentially alters intra-axonal environment, consistent with a proposed mechanism of focal enlargement of axons known as axonal swelling or beading. PMID- 22933582 TI - Hyperintense vessels on acute stroke fluid-attenuated inversion recovery imaging: associations with clinical and other MRI findings. AB - BACKGROUND AND PURPOSE: Hyperintense vessels (HVs) have been observed in fluid attenuated inversion recovery imaging of patients with acute ischemic stroke and been linked to slow flow in collateral arterial circulation. Given the potential importance of HV, we used a large, multicenter data set of patients with stroke to clarify which clinical and imaging factors play a role in HV. METHODS: We analyzed data of 516 patients from the previously published PRE-FLAIR study (PREdictive value of FLAIR and DWI for the identification of acute ischemic stroke patients<=3 and <=4.5 hours of symptom onset-a multicenter study) study. Patients were studied by MRI within 12 hours of symptom onset. HV were defined as hyperintensities in fluid-attenuated inversion recovery corresponding to the typical course of a blood vessel that was not considered the proximal, occluded main artery ipsilateral to the diffusion restriction. Presence of HV was rated by 2 observers and related to clinical and imaging findings. RESULTS: Presence of HV was identified in 240 of all 516 patients (47%). Patients with HV showed larger initial ischemic lesion volumes (median, 12.3 versus 4.9 mL; P<0.001) and a more severe clinical impairment (median National Institutes of Health Stroke Scale 10.5 versus 6; P<0.001). In 198 patients with MR angiography, HVs were found in 80% of patients with vessel occlusion and in 17% without vessel occlusion. In a multivariable logistic regression model, vessel occlusion was associated with HV (OR, 21.7%; 95% CI, 9.6-49.9; P<0.001). HV detected vessel occlusion with a specificity of 0.86 (95% CI, 0.80-0.90) and sensitivity of 0.76 (95% CI, 0.69 0.83). CONCLUSIONS: HVs are a common finding associated with proximal arterial occlusions and more severe strokes. HVs predict arterial occlusion with high diagnostic accuracy. PMID- 22933583 TI - Long-term mortality in patients with stroke of undetermined etiology. AB - BACKGROUND AND PURPOSE: The determination of stroke etiology is essential for planning treatment for stroke prevention. However, the etiology of stroke is undetermined in many patients. METHODS: During a 10-year period, consecutive patients with acute ischemic stroke were enrolled. The stroke etiology was determined based on the Trial of ORG 10172 in Acute Stroke Treatment classification. Long-term mortality and causes of death were identified using death certificates. The standardized mortality ratio was calculated to compare the mortality in patients with stroke and that in the general Korean population. RESULTS: In total, 3278 patients were enrolled and followed-up for a median of 3.4 years (interquartile range, 1.5-5.7). The stroke subtype was undetermined in 37% because of negative evaluation (21.2%), multiple causes (10.6%), and incomplete evaluation (4.8%). Poor functional outcome at 3 months (modified Rankin scale score >2) was more frequent in patients with an incomplete evaluation than in those with the other stroke subtypes (49.6% vs 24.5%; P<0.001). During follow-up, 781 patients (23.8%) died. The overall cumulative death rate was highest in patients with an incomplete evaluation (12.7% within 30 days, 25.5% within 1 year, and 35.7% within 3 years), followed by those with cardioembolism. Multivariate analysis after adjusting for covariates including initial stroke severity, the mortality of patients with an incomplete evaluation was second lowest after cardioembolism, whereas that in patients with a negative evaluation was low. CONCLUSIONS: Long-term mortality in patients with an incomplete evaluation was quite high. Etiologic work-up helps to better define the stroke subtype and determine the prognosis. PMID- 22933584 TI - Quantification of cerebral volumes on MRI 6 months after aneurysmal subarachnoid hemorrhage. AB - BACKGROUND AND PURPOSE: MRI can be used to assess structural damage to the brain after aneurysmal subarachnoid hemorrhage. We tuned, validated, and applied k Nearest Neighbor-based segmentation to quantify cerebral volumes on MRI 6 months after aneurysmal subarachnoid hemorrhage. METHODS: After tuning, the accuracy of k-Nearest Neighbor-based segmentation was assessed with manual segmentations. Next, supratentorial cerebral parenchymal, peripheral cerebrospinal fluid, and lateral ventricular volumes of 55 patients were compared with those of 25 age- and sex-matched control subjects and related to clinical outcome (modified Rankin Scale). RESULTS: k-Nearest Neighbor-based segmentation showed good agreement with manual segmentations. Compared with control subjects, patients had a larger lateral ventricular volume (difference: log-transformed values 0.54; 95% CI,0.33 0.75), smaller peripheral cerebrospinal fluid volume (-26 mL; 95% CI, -40 to 11), and similar cerebral parenchymal volume (2 mL; 95% CI, -10 to 15). In patients, parenchymal (median split; OR, 38.8; 95% CI, 4.6-329.0) and ventricular volumes (7.4; 95% CI, 1.6-33.5) correlated with functional outcome. CONCLUSIONS: k-Nearest Neighbor-based segmentation provides accurate cerebral volume measurements after aneurysmal subarachnoid hemorrhage. In this proof-of-principle study of this volumetric technique, we demonstrated volume changes relative to controls, which correlated with functional outcome. PMID- 22933585 TI - Neuron-specific prolyl-4-hydroxylase domain 2 knockout reduces brain injury after transient cerebral ischemia. AB - BACKGROUND AND PURPOSE: Numerous factors involved in the adaptive response to hypoxia, including erythropoietin and vascular endothelial growth factor are transcriptionally regulated by hypoxia-inducible factors (HIFs). During normoxia, prolyl-4-hydroxylase domain (PHD) proteins hydroxylate HIF-alpha subunits, resulting in their degradation. We investigated the effect of neuronal deletion of PHD2, the most abundant isoform in brain, for stroke outcome. METHODS: We generated neuron-specific Phd2 knockout mice and subjected animals to systemic hypoxia or transient middle cerebral artery occlusion. Infarct volume and cell death were determined by histology. HIF-1alpha, HIF-2alpha, and HIF target genes were analyzed by immunoblotting and real-time polymerase chain reaction, respectively. RESULTS: Neuron-specific ablation of Phd2 significantly increased protein stability of HIF-1alpha and HIF-2alpha in the forebrain and enhanced expression of the neuroprotective HIF target genes erythropoietin and vascular endothelial growth factor as well as glucose transporter and glycolysis-related enzymes under hypoxic and ischemic conditions. Mice with Phd2-deficient neurons subjected to transient cerebral ischemia exhibited a strong reduction in infarct size, and cell death of hippocampal CA1 neurons located in the peri-infarct region was dramatically reduced in these mice. Vessel density in forebrain subregions, except for caudate-putamen, was not altered in Phd2-deficient animals. CONCLUSIONS: Our findings denote that the endogenous adaptive response on hypoxic-ischemic insults in the brain is at least partly dependent on the activity of HIFs and identify PHD2 as the key regulator for the protective hypoxia response. The results suggest that specific inhibition of PHD2 may provide a useful therapeutic strategy to protect brain tissue from ischemic injury. PMID- 22933586 TI - Letter by Lin et al regarding article, "does body mass index impact on the relationship between systolic blood pressure and cardiovascular disease? Meta analysis of 419 488 individuals from the Asia pacific cohort studies collaboration". PMID- 22933587 TI - Burden of risk alleles for hypertension increases risk of intracerebral hemorrhage. AB - BACKGROUND AND PURPOSE: Genetic variation influences risk of intracerebral hemorrhage (ICH). Hypertension (HTN) is a potent risk factor for ICH and several common genetic variants (single nucleotide polymorphisms [SNPs]) associated with blood pressure levels have been identified. We sought to determine whether the cumulative burden of blood pressure-related SNPs is associated with risk of ICH and pre-ICH diagnosis of HTN. METHODS: We conducted a prospective multicenter case-control study in 2272 subjects of European ancestry (1025 cases and 1247 control subjects). Thirty-nine SNPs reported to be associated with blood pressure levels were identified from the National Human Genome Research Institute genomewide association study catalog. Single-SNP association analyses were performed for the outcomes ICH and pre-ICH HTN. Subsequently, weighted and unweighted genetic risk scores were constructed using these SNPs and entered as the independent variable in logistic regression models with ICH and pre-ICH HTN as the dependent variables. RESULTS: No single SNP was associated with either ICH or pre-ICH HTN. The blood pressure-based unweighted genetic risk score was associated with risk of ICH (OR, 1.11; 95% CI, 1.02-1.21; P=0.01) and the subset of ICH in deep regions (OR, 1.18; 95% CI, 1.07-1.30; P=0.001), but not with the subset of lobar ICH. The score was associated with a history of HTN among control subjects (OR, 1.17; 95% CI, 1.04-1.31; P=0.009) and ICH cases (OR, 1.15; 95% CI, 1.01-1.31; P=0.04). Similar results were obtained when using a weighted score. CONCLUSIONS: Increasing numbers of high blood pressure-related alleles are associated with increased risk of deep ICH as well as with clinically identified HTN. PMID- 22933588 TI - Microglia/macrophage polarization dynamics reveal novel mechanism of injury expansion after focal cerebral ischemia. AB - BACKGROUND AND PURPOSE: Mononuclear phagocytes are highly plastic cells that assume diverse phenotypes in response to microenvironmental signals. The phenotype-specific roles of microglia/macrophages in ischemic brain injury are poorly understood. A comprehensive characterization of microglia/macrophage polarization after ischemia may advance our knowledge of poststroke damage/recovery. METHODS: Focal transient cerebral ischemia was induced in mice for 60 minutes; animals were euthanized at 1 to 14 days of reperfusion. Reverse transcriptase polymerase chain reaction and immunohistochemical staining for M1 and M2 markers were performed to characterize phenotypic changes in brain cells, including microglia and infiltrating macrophages. In vitro experiments using a transwell system, a conditioned medium transfer system, or a coculture system allowing cell-to-cell contacts were used to further elucidate the effect of neuronal ischemia on microglia/macrophage polarization and, conversely, the effect of microglia/macrophage phenotype on the fate of ischemic neurons. RESULTS: Local microglia and newly recruited macrophages assume the M2 phenotype at early stages of ischemic stroke but gradually transformed into the M1 phenotype in peri-infarct regions. In vitro experiments revealed that ischemic neurons prime microglial polarization toward M1 phenotype. M1-polarized microglia or M1-conditioned media exacerbated oxygen glucose deprivation-induced neuronal death. In contrast, maintaining the M2 phenotype of microglia protected neurons against oxygen glucose deprivation. CONCLUSIONS: Our results suggest that microglia/macrophages respond dynamically to ischemic injury, experiencing an early "healthy" M2 phenotype, followed by a transition to a "sick" M1 phenotype. These dual and opposing roles of microglia/macrophages suggest that stroke therapies should be shifted from simply suppressing microglia/macrophage toward adjusting the balance between beneficial and detrimental microglia/macrophage responses. PMID- 22933589 TI - Variability in carotid endarterectomy practice patterns within a metropolitan area. AB - BACKGROUND AND PURPOSE: Previous clinical studies have suggested that patients with carotid stenosis with high surgical risk features may fare better with carotid artery stenting or aggressive medical therapy. The extent to which carotid endarterectomy is still being performed in this group of patients is unclear. METHODS: A retrospective audit was performed among 4 hospitals over a 2 year period. The proportion of high surgical risk patients was compared and the in-hospital stroke, myocardial infarction, and death rates were compared among conventional and high surgical risk patients. RESULTS: Three hundred thirty-five carotid endarterectomy operations were performed (63% asymptomatic) with 37.9% being high surgical risk subjects. The stroke, myocardial infarction, and death rate was 4.6% in conventional risk subjects and 10.2% in high surgical risk patients (P<0.05). The only hospital with multidisciplinary carotid conferences had the lowest proportion of carotid endarterectomy operations in asymptomatic patients. CONCLUSIONS: A substantial proportion of carotid endarterectomy operations are performed in patients with high surgical risk features. These patients experienced a 2-fold increase in major in-hospital complications, raising doubts about whether they benefit from carotid surgery. The use of preintervention multidisciplinary conferences may improve patient safety. PMID- 22933590 TI - Gendered uncertainty and variation in physicians' decisions for coronary heart disease: the double-edged sword of "atypical symptoms". AB - Nonmedical factors and diagnostic certainty contribute to variation in clinical decision making, but the process by which this occurs remains unclear. We examine how physicians' interpretations of patient sex-gender affect diagnostic certainty and, in turn, decision making for coronary heart disease. Data are from a factorial experiment of 256 physicians who viewed 1 of 16 video vignettes with different patient-actors presenting the same symptoms of coronary heart disease. Physician participants completed a structured interview and provided a narrative about their decision-making processes. Quantitative analysis showed that diagnostic uncertainty reduces the likelihood that physicians will order tests and medications appropriate for an urgent cardiac condition in particular. Qualitative analysis revealed that a subset of physicians applied knowledge that women have "atypical symptoms" as a generalization, which engendered uncertainty for some. Findings are discussed in relation to social-psychological processes that underlie clinical decision making and the social framing of medical knowledge. PMID- 22933591 TI - Cancer patient disclosure and patient-doctor communication of complementary and alternative medicine use: a systematic review. AB - OBJECTIVE: To explore the nondisclosure of complementary and alternative medicine (CAM) use among cancer patients, including reasons for and outcomes from nondisclosure of CAM use, within the context of patient-doctor communication. METHOD: A systematic review was conducted exploring investigations surrounding the communication of CAM use for patients with cancer published until August 2011. RESULTS: A total of 21 studies were located, which reported a prevalence of CAM use among patients with cancer ranging between 11% and 95%; of these patients, 20% to 77% did not disclose their CAM use. The main reasons for nondisclosure were the doctor's lack of inquiry; patient's anticipation of the doctor's disapproval, disinterest, or inability to help; and patient's perception that disclosure of CAM use is irrelevant to their conventional care. There is some evidence to suggest that patient-doctor communication about the use of CAM was associated with an enhanced patient-doctor relationship and higher patient satisfaction. CONCLUSIONS: Although the use of CAM by patients with cancer is high, patients frequently fail to disclose its use to their health professionals for reasons emanating from both sides of the dyadic patient-doctor relationship. Because a substantial proportion of patients with cancer may use CAM and there is potential for herb- or vitamin-drug interactions, further research in patient doctor communication about CAM is necessary to maintain patient safety and wellbeing. The development of effective interventions to improve the disclosure of CAM use should be an integral part of this future research. PMID- 22933592 TI - Otitis media and otomastoiditis caused by Mycobacterium massiliense (Mycobacterium abscessus subsp. bolletii). AB - We describe two patients with otologic infections caused by Mycobacterium massiliense (M. abscessus subsp. bolletti) which were identified using erm(41) PCR, 23S rRNA, and rpoB gene sequence analysis. They were middle-aged adults with underlying otologic diseases and were treated successfully with clarithromycin based combination regimens for 3 and 9 months, respectively. PMID- 22933593 TI - Comparative evaluation of tigecycline susceptibility testing methods for expanded spectrum cephalosporin- and carbapenem-resistant gram-negative pathogens. AB - We evaluated the Vitek2, Etest, and MIC Test Strip (MTS) methods of tigecycline susceptibility testing with 241 expanded-spectrum cephalosporin-resistant and/or carbapenem-resistant Enterobacteriaceae and Acinetobacter baumannii clinical isolates by using dry-form broth microdilution (BMD) as the reference method. The MIC(50/90)s were as follows: BMD, 1/4 MUg/ml; Vitek2, 4/>=8 MUg/ml; Etest, 2/4 MUg/ml; MTS, 0.5/2 MUg/ml. Vitek2 produced 9.1/21.2% major errors, Etest produced 0.4/0.8% major errors, and MTS produced no major errors but 0.4/3.3% very major errors (FDA/EUCAST breakpoints). Vitek2 tigecycline results require confirmation by BMD or Etest for multidrug-resistant pathogens. PMID- 22933594 TI - Rapid determination of lymphogranuloma venereum serovars of Chlamydia trachomatis by quantitative high-resolution melt analysis (HRMA). AB - A quantitative high-resolution melt analysis assay was developed to differentiate lymphogranuloma venereum-causing serovars of Chlamydia trachomatis (L1 to L3) from other C. trachomatis serovars (D to K). The detection limit of this assay is approximately 10 copies per reaction, comparable to the limits of other quantitative-PCR-based methods. PMID- 22933595 TI - Russian "successful" clone B0/W148 of Mycobacterium tuberculosis Beijing genotype: a multiplex PCR assay for rapid detection and global screening. AB - We describe a multiplex PCR assay to detect the Mycobacterium tuberculosis Beijing genotype variant B0/W148, which is considered a "successful" clone of M. tuberculosis, widespread in Russia. Specificity and sensitivity of the assay were 100% based on the analysis of a collection of 516 M. tuberculosis isolates of different genotypes and origins. This assay may be used for accurate and simple detection and surveillance of this clinically and epidemiologically important variant of M. tuberculosis. PMID- 22933597 TI - Acute infective endocarditis caused by Delftia acidovorans, a rare pathogen complicating intravenous drug use. AB - Gram-negative bacilli causing infective endocarditis (IE) is rare, even in intravenous drug users. This case report underscores several clinically important aspects of Delftia acidovorans IE: the organism's ability to cause rapid destruction of normal native valves and to cause embolic occlusion of large arteries and its resistance to all aminoglycosides. PMID- 22933596 TI - Cryopreservation of Mycobacterium tuberculosis complex cells. AB - Successful long-term preservation of Mycobacterium tuberculosis cells is important for sample transport, research, biobanking, and the development of new drugs, vaccines, biomarkers, and diagnostics. In this report, Mycobacterium bovis bacillus Calmette-Guerin and M. tuberculosis H37Ra were used as models of M. tuberculosis complex strains to study cryopreservation of M. tuberculosis complex cells in diverse sample matrices at different cooling rates. Cells were cryopreserved in diverse sample matrices, namely, phosphate-buffered saline (PBS), Middlebrook 7H9 medium with or without added glycerol, and human sputum. The efficacy of cryopreservation was quantified by microbiological culture and microscopy with BacLight LIVE/DEAD staining. In all sample matrices examined, the microbiological culture results showed that the cooling rate was the most critical factor influencing cell viability. Slow cooling (a few degrees Celsius per minute) resulted in much higher M. tuberculosis complex recovery rates than rapid cooling (direct immersion in liquid nitrogen) (P < 0.05). Among the three defined cryopreservation media (PBS, 7H9, and 7H9 plus glycerol), there was no significant differential effect on viability (P = 0.06 to 0.87). Preincubation of thawed M. tuberculosis complex cells in 7H9 broth for 20 h before culture on solid Middlebrook 7H10 plates did not help the recovery of the cells from cryoinjury (P = 0.14 to 0.71). The BacLight LIVE/DEAD staining kit, based on Syto 9 and propidium iodide (PI), was also applied to assess cell envelope integrity after cryopreservation. Using the kit, similar percentages of "live" cells with intact envelopes were observed for samples cryopreserved under different conditions, which was inconsistent with the microbiological culture results. This implies that suboptimal cryopreservation might not cause severe damage to the cell wall and/or membrane but instead cause intracellular injury, which leads to the loss of cell viability. PMID- 22933598 TI - Genetic characterization of a vancomycin-resistant Staphylococcus aureus isolate from the respiratory tract of a patient in a university hospital in northeastern Iran. AB - Emergence of vancomycin-intermediate Staphylococcus aureus (VISA) and vancomycin resistant S. aureus (VRSA) strains has led to global concerns about treatments for staphylococcal infections. These strains are currently rare even though there is an upward trend in their reported incidence. Therefore, appropriate screening and epidemiological evaluation of VRSA strains can affect future global health care policies. Isolates of Staphylococcus aureus were obtained from various clinical samples and were then evaluated with agar screening, disk diffusion, and MIC methods to determine resistance to vancomycin and methicillin. After confirmation of the isolated VRSA strain, genetic analysis was performed by evaluating mecA and vanA gene presence, SCCmec, agr, and spa types, and toxin profiles. Multilocus sequence typing (MLST) and plasmid analysis were also performed. The VRSA strain was resistant to oxacillin (MIC of 128 MUg/ml) and vancomycin (MIC of 512 MUg/ml). Disk diffusion antimicrobial susceptibility tests showed resistance to oxacillin, vancomycin, levofloxacin, ciprofloxacin, trimethoprim-sulfamethoxazole, clindamycin, rifampin, and tetracycline. The isolate was susceptible to minocycline and gentamicin. PCRs were positive for the mecA and vanA genes. Other genetic characteristics include SCCmec type III, agr I, spa type t037, and sequence type (ST) 1283. The plasmid profile shows five plasmids with a size of ~1.7 kb to >10 kb. The isolated VRSA strain was obtained from a critically ill hospitalized patient. Genetic analysis of this strain suggested that the strain was a methicillin-resistant S. aureus (MRSA) clone endemic in Asia that underwent some genetic changes, such as mutation in the gmk gene and acquisition of the vanA gene. PMID- 22933600 TI - Peritonitis and technique failure caused by Roseomonas mucosa in an adolescent infected with HIV on continuous cycling peritoneal dialysis. AB - We report the first case of peritonitis caused by Roseomonas mucosa which led to technique failure in an adolescent patient with HIV receiving peritoneal dialysis. Identification of the causative organism by 16S rRNA gene sequencing and phylogenetic analysis is described. PMID- 22933599 TI - Evaluation of methods for identification and determination of the taxonomic status of strains belonging to the Streptococcus porcinus-Streptococcus pseudoporcinus complex isolated from animal, human, and dairy sources. AB - Ninety-seven animal, human, and dairy Streptococcus porcinus or Streptococcus pseudoporcinus isolates in the CDC Streptococcus strain collection were evaluated on the basis of DNA-DNA reassociation, 16S rRNA and rpoB gene sequencing, conventional biochemical and Rapid ID 32 Strep identification methods, and antimicrobial susceptibility testing to determine their taxonomic status, characteristics for species differentiation, antimicrobial susceptibility, and relevance of clinical source. Nineteen of the 97 isolates (1 human, 18 swine) were identified as S. porcinus. The remaining 72 human isolates and 6 dairy isolates were identified as S. pseudoporcinus. The use of 16S rRNA or rpoB gene sequencing was required to differentiate S. porcinus from S. pseudoporcinus. The human and dairy S. pseudoporcinus isolates were biochemically distinct from each other as well as distinct by 16S rRNA and rpoB gene sequencing. Therefore, we propose the subspecies denominations S. pseudoporcinus subsp. hominis subsp. nov. for the human isolates and S. pseudoporcinus subsp. lactis subsp. nov. for the dairy isolates. Most strains were susceptible to the antimicrobials tested, with the exception of tetracycline. Two strains of each species were also resistant to clindamycin and erythromycin and carried the erm(A) (S. pseudoporcinus) or the erm(B) (S. porcinus) gene. S. porcinus was identified from a single human isolate recovered from a wound in an abattoir worker. S. pseudoporcinus was primarily isolated from the genitourinary tract of women but was also associated with blood, placental, and wound infections. Isolates reacting with group B antiserum and demonstrating wide beta-hemolysis should be suspected of being S. pseudoporcinus and not S. agalactiae. PMID- 22933601 TI - Usability and performance of CHROMagar STEC medium in detection of Shiga toxin producing Escherichia coli strains. AB - The performance and usability of CHROMagar STEC medium (CHROMagar Microbiology, Paris, France) for routine detection of Shiga toxin-producing Escherichia coli (STEC) strains were examined. The ability of the medium to selectively propagate STEC strains differing by their serotypes and virulence genes was studied with a collection of diarrheagenic E. coli isolates (n = 365) consisting of 49 different serotypes and with non-STEC and other bacterial isolates (n = 264). A total of 272 diarrheagenic E. coli (75.0%) isolates covering 24 different serotypes grew on CHROMagar STEC. The highest detection sensitivities were observed within the STEC serogroups O26 (90.0%), O111 (100.0%), O121 (100.0%), O145 (100.0%), and O157 (84.9%), and growth on CHROMagar STEC was highly associated with the presence of the tellurite resistance gene (terD). The specificity of the medium was 98.9%. In addition, CHROMagar STEC was used in parallel with a Shiga toxin detecting immunoassay (Ridaquick Verotoxin/O157 Combi; R-biopharm, Darmstadt, Germany) to screen fecal specimens (n = 47) collected from patients suffering from hemorrhagic diarrhea. Positive growth on CHROMagar STEC was confirmed by the Premier EHEC enzyme immunoassay (Meridian Bioscience, Inc., Cincinnati, OH), and discrepant results between the two screening methods were confirmed by stx gene detecting PCR. All 16 of the 47 stool samples that showed positive growth on CHROMagar STEC were also positive in the confirmatory tests. CHROMagar STEC proved to be an interesting option for STEC screening, allowing good detection sensitivity and specificity and permitting strain isolation for further outbreak investigations when required. PMID- 22933602 TI - Rapid detection of the Mycobacterium tuberculosis complex by use of quenching probe PCR (geneCube). AB - Early detection of tuberculosis (TB) is essential for infection control. The geneCube (Toyobo) is a novel fully automated gene analyzer that can amplify target DNAs within 60 min. In this study, we evaluated the ability of the geneCube to directly detect Mycobacterium tuberculosis complex (MTBC) and Mycobacterium avium complex (MAC) in clinical specimens. The results were then compared with those obtained using conventional culture, microscopy, and the Cobas Amplicor assay (Roche). We examined a total of 516 frozen samples from 69 patients who showed culture-positive infection (73 samples; 39 MTBC, 32 MAC, and 2 mixed infections) and from 354 patients who were culture negative (443 samples). Assays using the geneCube had a sensitivity of 85.4% and a specificity of 99.8% for detection of MTBC and a sensitivity of 85.3% and a specificity of 99.8% for detection of MAC. These results are similar to those obtained using the Amplicor system but were obtained much more rapidly (1 h with the geneCube versus 5.5 h with the Amplicor system). The geneCube thus enables a significant shortening of the assay time with no loss of sensitivity or specificity. PMID- 22933603 TI - Genetic heterogeneity and recombination in human type 2 astroviruses. AB - Novel lineages of human astrovirus (HAstV) types 2, 2c, and 2d have been identified. Upon sequencing of the 3' end of the genome, the type 2c and 2d HAstVs were found to be open reading frame 1b (ORF1b)-ORF2 recombinant, with ORF1b being derived from type 3 and type 1 HAstVs, respectively. An ORF2 interlineage recombinant strain, 2c/2b, was also identified. PMID- 22933604 TI - Fast assessment of resistance to carbapenems and ciprofloxacin of clinical strains of Acinetobacter baumannii. AB - Infections caused by multidrug-resistant Acinetobacter baumannii constitute a major life-threatening problem worldwide, and early adequate antibiotic therapy is decisive for success. For these reasons, rapid detection of antibiotic susceptibility in this pathogen is a clinical challenge. Two variants of the Micromax kit were evaluated for a rapid detection in situ of susceptibility or resistance to meropenem or ciprofloxacin, separately, in 322 clinical isolates. Release of the nucleoid is the criterion of susceptibility to the beta-lactams (carbapenems), whereas diffusion of DNA fragments emerging from the nucleoid characterizes the quinolone activity. All the susceptible and resistant strains were correctly categorized in 100 min according to the MIC results and CLSI criteria. Thus, our technology is a promising tool for rapid identification of carbapenem and quinolone resistance of A. baumannii strains in hospital settings. PMID- 22933605 TI - Microbiological analysis of nontyphoidal Salmonella strains causing distinct syndromes of bacteremia or enteritis in HIV/AIDS patients in San Diego, California. AB - Recurrent invasive nontyphoidal Salmonella (NTS) infection is an AIDS-defining illness that has become less common in the developed world in the era of highly active antiretroviral therapy (HAART), while it has emerged as a major public health problem in developing countries, particularly sub-Saharan Africa. We retrospectively analyzed Salmonella (NTS) infection in HIV/AIDS patients from June 2003 until December 2009 at the University of California, San Diego (UCSD), Medical Center. Bacterial isolates from all patients were tested for selected microbiological properties, including major Salmonella (NTS) virulence loci rpoS, sodCI, spvB, and sseI. Fourteen percent of all Salmonella (NTS) cases recorded at the UCSD Medical Center during this period occurred in known HIV/AIDS patients. The clinical presentations in HIV patients fell into two distinct groups, bacteremia and enteritis. There was little clinical overlap between these two syndromes. All strains were positive for the presence of the rpoS and sodCI virulence loci, and 75% of strains were positive for the presence of the spvB and sseI loci. Antibiotic susceptibility assay showed that all strains were susceptible to trimethoprim-sulfamethoxazole and ciprofloxacin. The clinical presentation did not have a clear relationship to the CD4(+) cell count. Of the bacteremic isolates, all but one isolate, drawn from a patient with substantial enteric comorbidities, had all of the virulence genes tested, but 66% of nonbacteremic, enteritis strains also contained all the tested virulence loci. In conclusion, neither patients' CD4(+) cell count nor bacterial strain properties necessarily predicted the clinical presentation of HIV/AIDS patients with Salmonella (NTS) infection, and AIDS patients can have episodes of Salmonella enteritis without dissemination. PMID- 22933606 TI - Periostin is down-regulated during periodontal inflammation. AB - Periostin, a matricellular adapter protein highly expressed by periodontal ligament fibroblasts, is implicated in the maintenance of periodontal integrity, which is compromised during periodontal diseases. The aim of this study was to explore the influence of chronic periodontal inflammation on tissue periostin levels. Periodontal breakdown was induced in a pre-clinical ligature periodontal inflammatory disease model. Periodontal tissue specimens were harvested at baseline, 2 weeks, and 4 weeks and prepared for histologic, immunofluorescence, and micro-CT examination. Statistical analyses were conducted by Kruskal-Wallis, Mann-Whitney, and Spearman's tests. Periostin detection levels were reduced over time in response to the inflammatory process (1 +/- 0.05; 0.67 +/- 0.03; 0.31 +/- 0.02; p < 0.001; baseline, 2, and 4 weeks, respectively). Simultaneously, alveolar bone loss increased from baseline to the 2- and 4-week time-points (0.40 +/- 0.02 mm; 1.39 +/- 0.08 mm; 1.33 +/- 0.15 mm; p < 0.001), which was inversely correlated with the levels of periostin (rho = -0.545; p < 0.001). In conclusion, periostin PDL tissue levels significantly decrease under chronic inflammatory response and correlate with the detrimental changes to the periodontium over time. PMID- 22933607 TI - Remineralization of demineralized enamel via calcium phosphate nanocomposite. AB - Secondary caries remains the main problem limiting the longevity of composite restorations. The objective of this study was to investigate the remineralization of demineralized human enamel in vitro via a nanocomposite containing nanoparticles of amorphous calcium phosphate (NACP). NACP were synthesized by a spray-drying technique and incorporated into a dental resin. First, caries-like subsurface enamel lesions were created via an acidic solution. Then, NACP nanocomposite or a commercial fluoride-releasing control composite was placed on the demineralized enamel, along with control enamel without a composite. These specimens were then treated with a cyclic demineralization/remineralization regimen for 30 days. Quantitative microradiography showed typical enamel subsurface demineralization before cyclic demineralization/remineralization treatment, and significant remineralization in enamel under the NACP nanocomposite after the demineralization/remineralization treatment. The NACP nanocomposite had the highest enamel remineralization (mean +/- SD; n = 6) of 21.8 +/- 3.7%, significantly higher than the 5.7 +/- 6.9% for fluoride-releasing composite (p < 0.05). The enamel group without composite had further demineralization of -26.1 +/- 16.2%. In conclusion, a novel NACP nanocomposite was effective in remineralizing enamel lesions in vitro. Its enamel remineralization was 4-fold that of a fluoride-releasing composite control. Combined with the good mechanical and acid-neutralization properties reported earlier, the new NACP nanocomposite is promising for remineralization of demineralized tooth structures. PMID- 22933608 TI - Structural changes in amelogenin upon self-assembly and mineral interactions. AB - Amelogenin, the major protein of forming dental enamel, plays a crucial role in the biomineralization of this tissue. Amelogenin is soluble at low pH and self assembles to form higher order structures at physiological pH. To understand the mechanisms of its assembly and interactions with calcium phosphate mineral, we conducted FTIR spectroscopy (FTIRS) studies of pH-triggered assembly of recombinant porcine amelogenin rP172 and its interactions with mature hydroxyapatite and apatitic mineral formed in situ. Analysis of our data indicated that rP172 at pH 3.0 exists in an unfolded disordered state, while increases in pH led to structural ordering, manifested by increases in intra- and intermolecular beta-sheet structures and a decrease in random coil and beta turns. Amelogenin assembled at pH 7.2 was also found to contain large portions of extended intramolecular beta-sheet and PPII. These FTIRS findings are consistent with those previously obtained with other techniques, thus verifying the validity of our experimental approach. Interestingly, interactions with mineral led to a reduction in protein structural organization. The findings obtained show that amelogenin has intrinsic structural flexibility to accommodate interactions with both forming and mature calcium phosphate mineral phases, providing new insights into the potential importance of amelogenin-mineral interactions in enamel biomineralization. PMID- 22933609 TI - How US mothers store and handle their expressed breast milk. AB - BACKGROUND: Many mothers express and store their milk to later feed to their infant. Health organizations provide recommendations on expressed milk storage and handling because these practices can affect milk quality and safety. However, little information exists on US mothers' practices. OBJECTIVE: To describe how US mothers of healthy infants store and handle their expressed milk and to compare their practices with recommendations. METHODS: Mothers participating in the Infant Feeding Practices Study II from 2005-2006 who were expressing milk formed the cohort for this analysis (n = 436-1060, depending on infant age). Participants in this longitudinal mail survey were drawn from a consumer opinion panel and answered questions about milk expression around 2, 5, and 7 months postpartum. Data were analyzed cross sectionally using frequency procedures, and the analysis compared mothers who fed expressed milk with and without also feeding formula. RESULTS: Few mothers stored their milk longer than recommended. Among mothers of the youngest infants in this analysis, 12% heated their milk in a microwave and 17% rinsed bottle nipples with only water before reuse; percentages were similar as infants aged. These practices may pose risks to infant health. Compared with those who fed no formula, mothers who fed both expressed milk and formula were more likely to heat milk in a microwave and, among those with the youngest infants, to rinse bottle nipples with only water between uses. CONCLUSION: Consumer education should emphasize safe warming and cleaning practices for feeding expressed milk. PMID- 22933610 TI - Wingbeat kinematics and motor control of yaw turns in Anna's hummingbirds (Calypte anna). AB - The biomechanical and neuromuscular mechanisms used by different animals to generate turns in flight are highly variable. Body size and body plan exert some influence, e.g. birds typically roll their body to orient forces generated by the wings whereas insects are capable of turning via left-right wingbeat asymmetries. Turns are also relatively brief and have low repeatability, with almost every wingbeat serving a different function throughout the change in heading. Here we present an analysis of Anna's hummingbirds (Calypte anna) as they fed continuously from an artificial feeder revolving around the outside of the animal. This setup allowed for examination of sustained changes in yaw without requiring any corresponding changes in pitch, roll or body position. Hummingbirds sustained yaw turns by expanding the wing stroke amplitude of the outer wing during the downstroke and by altering the deviation of the wingtip path during both downstroke and upstroke. The latter led to a shift in the inner-outer stroke plane angle during the upstroke and shifts in the elevation of the stroke plane and in the deviation of the wingtip path during both strokes. These features are generally more similar to how insects, as opposed to birds, turn. However, time series analysis also revealed considerable stroke-to-stroke variation. Changes in the stroke amplitude and the wingtip velocity were highly cross-correlated, as were changes in the stroke deviation and the elevation of the stroke plane. As was the case for wingbeat kinematics, electromyogram recordings from pectoral and wing muscles were highly variable, but no correlations were found between these two features of motor control. The high variability of both kinematic and muscle activation features indicates a high level of wingbeat-to-wingbeat adjustments during sustained yaw. The activation timing of the muscles was more repeatable than the activation intensity, which suggests that the former may be constrained by harmonic motion and that the latter may play a large role in kinematic adjustments. Comparing the revolution frequency of the feeder with measurements of free flight yaws reveals that feeder tracking, even at one revolution every 2 s, is well below the maximum yaw capacity of the hummingbirds. PMID- 22933611 TI - Biomechanical determinants of transverse and rotary gallop in cursorial mammals. AB - Transverse and rotary gallop differ in the placement of the leading hindfeet and forefeet: ipsilateral in the former gait, contralateral in the latter. We analysed 351 filmed sequences to assess the gallop type of 89 investigated mammalian species belonging to Carnivora, Artiodactyla and Perissodactyla orders. Twenty-three biometrical, ecological and physiological parameters were collected for each species both from literature data and from animal specimens. Most of the species showed only one kind of gallop: transverse (42%) or rotary (39%), while some species performed rotary gallop only at high speed (19%). In a factorial analysis, the first principal component (PC), which accounted for 40% of the total variance, was positively correlated to the relative speed and negatively correlated to size and body mass. The second PC was correlated to the ratio between distal and proximal limb segments. Large size and longer proximal limb segments were associated with transverse gallop, while rotary and speed-dependent species showed higher metacarpus/humerus and metatarsus/femur length ratio and faster relative speeds. The resulting limb excursion angles were proportional to the square-root of the Froude number, and significantly higher in rotary gallopers. The gait pattern analysis indicated significant differences between transverse and rotary gallop in forelimb and hindlimb duty factor (t-test; P<0.001), and in duration of the forelimb contact (t-test; P=0.045). Our results show that an exclusive gallop gait is adopted by a large number of mammalian species, and indicate that the gallop pattern depends on diverse environmental, morphometrical and biomechanical characters. PMID- 22933612 TI - Does immune suppression during stress occur to promote physical performance? AB - Two adaptationist hypotheses have been proposed to explain why stress, particularly elevation of stress hormones (i.e. glucocorticoids), tends to suppress immune functions. One is that immune suppression represents efforts to minimize autoimmune responses to self-antigens released as organisms cope with stressors (i.e. the autoimmune-avoidance hypothesis). The other is that immune suppression occurs to promote a shunting of resources to life processes more conducive to survival of the stressor (i.e. the re-allocation hypothesis). Here in wild-caught house sparrows (Passer domesticus), we tested the second hypothesis, asking whether sustained elevation of baseline glucocorticoids, due to captivity, caused a greater rate of decline in immune functions than flight performance. A greater decline in immune functions than flight performance would support the re-allocation hypothesis. As in previous studies, we found that captivity tended to alter baseline corticosterone, suggesting that house sparrows experience captivity as a stressor. Captivity also affected several constitutive and induced innate immune metrics: bacterial (Escherichia coli) killing activity of blood and oxidative burst of leukocytes both changed in a manner consistent with immune disregulation. In contrast, breast muscle size and vertical flight (hovering) duration improved over captivity. Collectively, these changes provide indirect support for the re-allocation hypothesis, although within individuals, changes in immune and physical performance were unrelated. PMID- 22933613 TI - Light interference as a possible stressor altering HSP70 and its gene expression levels in brain and hepatic tissues of golden spiny mice. AB - Light at night and light interference (LI) disrupt the natural light:dark cycle, causing alterations at physiological and molecular levels, partly by suppressing melatonin (MLT) secretion at night. Heat shock proteins (HSPs) can be activated in response to environmental changes. We assessed changes in gene expression and protein level of HSP70 in brain and hepatic tissues of golden spiny mice (Acomys russatus) acclimated to LI for two (SLI), seven (MLI) and 21 nights (LLI). The effect of MLT treatment on LI-mice was also assessed. HSP70 levels increased in brain and hepatic tissues after SLI, whereas after MLI and LLI, HSP70 decreased to control levels. Changes in HSP70 levels as a response to MLT occurred after SLI only in hepatic tissue. However, hsp70 expression following SLI increased in brain tissue, but not in hepatic tissue. MLT treatment and SLI caused a decrease in hsp70 levels in brain tissue and an increase in hsp70 in hepatic tissue. SLI acclimation elicited a stress response in A. russatus, as expressed by increased HSP70 levels and gene expression. Longer acclimation decreases protein and gene expression to their control levels. We conclude that for brain and hepatic tissues of A. russatus, LI is a short-term stressor. Our results also revealed that A. russatus can acclimate to LI, possibly because of its circadian system plasticity, which allows it to behave both as a nocturnal and as a diurnal rodent. To the best of our knowledge, this is the first study showing the effect of LI as a stressor at the cellular level, by activating HSP70. PMID- 22933614 TI - The effects of a variable temperature regime on the physiology of the reef building coral Seriatopora hystrix: results from a laboratory-based reciprocal transplant. AB - To understand the effects of global climate change on reef-building corals, a thorough investigation of their physiological mechanisms of acclimatization is warranted. However, static temperature manipulations may underestimate the thermal complexity of the reefs in which many corals live. For instance, corals of Houbihu, Taiwan, experience changes in temperature of up to 10 degrees C over the course of a day during spring-tide upwelling events. To better understand the phenotypic plasticity of these corals, a laboratory-based experiment was conducted whereby specimens of Seriatopora hystrix from an upwelling reef (Houbihu) and conspecifics from a non-upwelling reef (Houwan) were exposed to both a stable seawater temperature (26 degrees C) regime and a regime characterized by a 6 degrees C fluctuation (23-29 degrees C) over a 12 h period for 7 days. A suite of physiological and molecular parameters was measured in samples of both treatments, as well as in experimental controls, to determine site of origin (SO) and temperature treatment (TT) responses. Only chlorophyll a (chl a) concentration and growth demonstrated the hypothesized trend of higher levels when exposed to a TT that mimicked SO conditions. In contrast, chl a, maximum dark-adapted quantum yield of photosystem II (F(v)/F(m)), and Symbiodinium ribulose-1,5-bisphosphate carboxylase/oxygenase (rbcL), photosystem I (psI, subunit III) and phosphoglycolate phosphatase (pgpase) mRNA expression demonstrated significant TT effects. Specifically, levels of these response variables were higher in samples exposed to a variable temperature regime, suggesting that S. hystrix may acclimate to fluctuating temperatures by increasing its capacity for photosynthesis. PMID- 22933615 TI - Nanodiamonds as platforms for biology and medicine. AB - Nanoparticles possess a wide range of exceptional properties applicable to biology and medicine. In particular, nanodiamonds (NDs) are being studied extensively because they possess unique characteristics that make them suitable as platforms for diagnostics and therapeutics. This carbon-based material (2-8 nm) is medically relevant because it unites several key properties necessary for clinical applications, such as stability and compatibility in biological environments, and scalability in production. Research by the Ho group and others has yielded ND particles with a variety of capabilities ranging from delivery of chemotherapeutic drugs to targeted labeling and uptake studies. In addition, encouraging new findings have demonstrated the ability for NDs to effectively treat chemoresistant tumors in vivo. In this review, we highlight the progress made toward bringing nanodiamonds from the bench to the bedside. PMID- 22933616 TI - Simultaneous quantification of cells and nanomaterials by inductive-coupled plasma techniques. AB - We demonstrate that endogenous cellular magnesium levels can be used as an accurate determinant of total cell number by inductively coupled plasma techniques, increasing the throughput and reproducibility of nanoparticle-uptake studies. Uptake of either gold nanoparticles or quantum dots did not affect intracellular concentration of Mg. To demonstrate this technique, we show the decreased uptake of nano-urchins in A549 cells compared with gold nanospheres. PMID- 22933617 TI - Fused deposition modeling provides solution for magnetic resonance imaging of solid dosage form by advancing design quickly from prototype to final product. AB - The release profile of active pharmaceutical ingredient (API) from its solid dosage form is an important aspect of drug development as it is often used to predict potential drug release characteristics of a product in vivo. In recent years, magnetic resonance imaging has emerged as a nondestructive technique that captures the physical changes of solid dosage forms during dissolution. An example that highlights this application is in the dissolution of modified release tablet studies. As the tablet dissolves, API disperses in a hydrogel matrix within the tablet, and swelling of the hydrogel layer eventually leads to release of API over time. To achieve optimum signal-to-noise ratios, the tablet should be placed in the most homogeneous region of the magnet and remain there throughout the dissolution experiment. Moreover, the tablet holder must maintain the tablet position without interfering with the natural dissolution process, such as by crushing the softened tablet. This can be difficult because the size, shape, and rigidity of the tablet change during dissolution. This article describes the process, material, and manufacture of a novel device that meets these challenges, with emphasis on how additive manufacturing on a 3D printer enabled an efficient and inexpensive process of design improvements. PMID- 22933618 TI - Robotic liquid handling and automation in epigenetics. AB - Automated liquid-handling robots and high-throughput screening (HTS) are widely used in the pharmaceutical industry for the screening of large compound libraries, small molecules for activity against disease-relevant target pathways, or proteins. HTS robots capable of low-volume dispensing reduce assay setup times and provide highly accurate and reproducible dispensing, minimizing variation between sample replicates and eliminating the potential for manual error. Low volume automated nanoliter dispensers ensure accuracy of pipetting within volume ranges that are difficult to achieve manually. In addition, they have the ability to potentially expand the range of screening conditions from often limited amounts of valuable sample, as well as reduce the usage of expensive reagents. The ability to accurately dispense lower volumes provides the potential to achieve a greater amount of information than could be otherwise achieved using manual dispensing technology. With the emergence of the field of epigenetics, an increasing number of drug discovery companies are beginning to screen compound libraries against a range of epigenetic targets. This review discusses the potential for the use of low-volume liquid handling robots, for molecular biological applications such as quantitative PCR and epigenetics. PMID- 22933619 TI - Examining the acceptability, attractiveness, and effects of a school-based validating interview for adolescents who self-injure. AB - Nonsuicidal self-injury (NSSI) in adolescents is a significant problem that needs to be addressed, and in some cases managed, in school settings. The current feasibility study uses screening questionnaires and follow up-interviews on NSSI in a community sample of adolescents (N = 1,052) in Sweden. Both adolescents reporting self-injury (n = 66) and a comparison group (n = 31) were interviewed, and information disclosed about self-injury, as well as the results from the interviewers assessments of the seriousness of these behaviors, were examined. Generally, adolescents reported positive feelings about being interviewed, and 52% of those who had reported self-injury in the questionnaire disclosed NSSI in the interviews. Further, a majority of these cases, 76%, were not assessed as very serious. When NSSI was reported in a questionnaire 1 year after the interview, there were no indications of iatrogenic effects from participating in the interview. The results support the feasibility of using NSSI screening questionnaires in combination with follow-up interviews in schools. PMID- 22933621 TI - Prolactin in multiple sclerosis. AB - Multiple sclerosis (MS) is more common among women than men. MS often goes into remission during pregnancy, when prolactin (PRL) levels are known to be high. In an animal model of demyelination, PRL promoted myelin repair, suggesting it has potential as a remyelinating therapy in MS. In this systematic review, we examined the known associations between PRL and MS, in order to elucidate its potential role in the pathophysiology and treatment of MS. A systematic search was performed in the electronic databases PubMed and EMBASE, using the keywords "prolactin" AND "multiple sclerosis." The inclusion criteria were met by 23 studies. These studies suggested to us that elevated PRL may be more common in MS patients than in controls. Hyperprolactinemia may also be associated with clinical relapse in MS, especially among patients with hypothalamic lesions or optic neuritis; however, it is unknown if this is a cause or consequence of a relapse. Overall, most people with MS have normal PRL levels. The impact of PRL on MS outcomes remains unclear. PMID- 22933622 TI - SIGLEC1 and SIGLEC7 expression in circulating monocytes of patients with multiple sclerosis. AB - BACKGROUND: Sialic acid binding immunoglobulin-like lectins (Siglecs) are cell surface receptors that recognize sialic acids and may attenuate immune responses and reduce inflammation. OBJECTIVE: The purpose of this study was to investigate the role of two members of the Siglec family, SIGLEC1 and SIGLEC7, in the clinical course and disease activity of patients with multiple sclerosis (MS). METHODS: SIGLEC1 and SIGLEC7 expression was determined by flow cytometry in the blood monocytes of 16 healthy controls and 55 untreated MS patients (13 primary progressive MS (PPMS) patients, 13 secondary progressive MS (SPMS) patients and 29 relapsing-remitting MS (RRMS) patients (18 during clinical remission and 11 during relapse)). RESULTS: SIGLEC1 expression by CD14+ monocytes was significantly increased in MS patients compared with controls (p=0.025 for percentage of positive cells; p=0.007 for mean fluorescence intensity (MFI)). Stratification of patients into different clinical forms revealed increased SIGLEC1 expression in patients with progressive forms of the disease, particularly in those with PPMS (p=0.003 for percentage of positive cells and p=0.001 for MFI when compared with controls; p=0.031 for percentage of positive cells when compared with RRMS patients). Both inflammatory and resident monocytes contributed to the increase in SIGLEC1 expression observed in PPMS patients. SIGLEC7 expression was significantly up-regulated in blood monocytes from RRMS during relapse compared with patients during clinical remission (p=0.001 for MFI). CONCLUSIONS: These findings suggest roles for SIGLEC1 in the chronic progressive phases of MS and for SIGLEC7 in acute disease activity. PMID- 22933620 TI - C6 knock-out mice are protected from thrombophilia mediated by antiphospholipid antibodies. AB - BACKGROUND: Complement activation plays a role in pathogenesis of the antiphospholipid syndrome (APS), but the involvement of the C5b-9 membrane attack complex (MAC) is unknown. Here we studied the effects of human polyclonal antiphospholipid (aPL) antibodies on thrombosis and tissue factor (TF) up regulation in C6 deficient (C6(-/-)) mice. METHODS: C6(-/-) mice or the wild-type C3H/HeJ (C6(+/+)) mice were injected twice with IgG-APS (n = 2) or IgM-APS (n = 1) isolated from APS patients or with the corresponding control immunoglobulins (Igs) of normal human serum, (NHS) (IgG-NHS or IgM-NHS). Then, the sizes of induced thrombi in the femoral vein were determined 72 hours after the first injection. Tissue factor was determined in homogenates of carotid arteries and in peritoneal macrophages. RESULTS: Thrombus sizes were significantly larger in C6(+/+) treated with IgG-APS1 or with IgG-APS2 or with IgM-APS when compared with C6(+/+) mice treated with IgG-NHS or with IgM-NHS, respectively. The sizes of thrombi were significantly smaller in the C6(-/-) mice injected with IgG-APS1, IgG-APS2 or IgM-APS (p < 0.001), compared to their C6(+/+) counterparts showing an important abrogation of thrombus formation in mice lacking C6. The TF expression and activity in the C6(-/-) mice treated with IgG-APS or IgM-APS were diminished when compared to C3H/HeJ (C6(+/+)) mice treated with the same Igs. All mice injected with IgG-APS and IgM-APS had medium-high titers of anticardiolipin (aCL) and anti-beta(2)glycoprotein I (abeta(2)GPI) antibodies. CONCLUSIONS: These data indicate that the C6 component of the complement system mediates aPL thrombogenic effects, underscoring an important pathogenic mechanism and indicating the possibility of inhibiting complement to ameliorate APS-related manifestations. PMID- 22933623 TI - Self-reported sleep problems, but not fatigue, lead to decline in sustained attention in MS patients. AB - OBJECTIVE: According to the compensation theory, fatigue in MS results from efforts to compensate for a reduction in capacity due to demyelination or neurodegeneration. Recently, it has been argued that fatigue may result from poor sleep. Both explanations predict a worsening of fatigue and a cognitive decline during sustained attention tasks (higher fatigability). METHOD: We compared MS patients with and without self-reported cognitive fatigue, in three sessions with a two-back working memory task, registering hits and response latencies as well as changes in fatigue. In the two breaks between the sessions, either a video instruction to relax or a stimulating video was presented. Subsequently, patients were divided into those with and those without self-reported sleep problems and the analyses were repeated. RESULTS: Patients with fatigue performed worse than healthy controls, irrespective of task duration and type of video during the break. The task-related increase of fatigue also did not differ between the groups and no differential effect of the videos was observed in the MS patients with fatigue. In contrast, patients with sleep problems did show a performance decline as predicted by the compensation theory. CONCLUSION: MS patients with fatigue were impaired in working memory, but did not show greater fatigability, whereas MS participants with self-reported sleep problems showed fatigability, which could be improved with a restorative rest period. Our data therefore do not support the compensation theory of fatigue, and we argue that sleep problems and fatigue in MS patients differ with respect to their functional consequences. PMID- 22933624 TI - Human lupus serum induces neutrophil-mediated organ damage in mice that is enabled by Mac-1 deficiency. AB - Systemic lupus erythematosus (SLE) is a chronic, multiorgan inflammatory autoimmune disorder associated with high levels of circulating autoantibodies and immune complexes. We report that passive transfer of human SLE sera into mice expressing the uniquely human FcgammaRIIA and FcgammaRIIIB on neutrophils induces lupus nephritis and in some cases arthritis only when the mice additionally lack the CD18 integrin, Mac-1. The prevailing view is that Mac-1 on macrophages is responsible for immune complex clearance. However, disease permitted by the absence of Mac-1 is not related to enhanced renal immune complex deposition or in situ C1q/C3 complement activation and proceeds even in the absence of macrophages. Instead, disease is associated with increased FcgammaRIIA-induced neutrophil accumulation that is enabled by Mac-1 deficiency. Intravital microscopy in the cremasteric vasculature reveals that Mac-1 mitigates FcgammaRIIA-dependent neutrophil recruitment in response to deposited immune complexes. Our results provide direct evidence that human SLE immune complexes are pathogenic, demonstrate that neutrophils are primary mediators of end organ damage in a novel humanized lupus mouse model, and identify Mac-1 regulation of FcgammaRIIA-mediated neutrophil recruitment as a key step in development of target organ damage. PMID- 22933626 TI - Evidence of IgY subclass diversification in snakes: evolutionary implications. AB - Mammalian IgG and IgE are thought to have evolved from IgY of nonmammalian tetrapods; however, no diversification of IgY subclasses has been reported in reptiles or birds, which are phylogenetically close to mammals. To our knowledge, we report the first evidence of the presence of multiple IgY-encoding (upsilon) genes in snakes. Two upsilon genes were identified in the snake Elaphe taeniura, and three upsilon genes were identified in the Burmese python (Python molurus bivittatus). Although four of the upsilon genes displayed a conventional four-H chain C region exon structure, one of the upsilon genes in the Burmese python lacked the H chain C region 2 exon, thus exhibiting a structure similar to that of the mammalian gamma genes. We developed mouse mAbs specific for the IgY1 and IgY2 of E. taeniura and showed that both were expressed in serum; each had two isoforms: one full-length and one truncated at the C terminus. The truncation was not caused by alternative splicing or transcriptional termination. We also identified the MU and delta genes, but no alpha gene, in both snakes. This study provides valuable clues for our understanding of Ig gene evolution in tetrapods. PMID- 22933625 TI - IL-10 triggers changes in macrophage phenotype that promote muscle growth and regeneration. AB - We examined the function of IL-10 in regulating changes in macrophage phenotype during muscle growth and regeneration following injury. Our findings showed that the Th1 cytokine response in inflamed muscle is characterized by high levels of expression of CD68, CCL-2, TNF-alpha, and IL-6 at 1 d postinjury. During transition to the Th2 cytokine response, expression of those transcripts declined, whereas CD163, IL-10, IL-10R1, and arginase-1 increased. Ablation of IL 10 amplified the Th1 response at 1 d postinjury, causing increases in IL-6 and CCL2, while preventing a subsequent increase in CD163 and arginase-1. Reductions in muscle fiber damage that normally occurred between 1 and 4 d postinjury did not occur in IL-10 mutants. In addition, muscle regeneration and growth were greatly slowed by loss of IL-10. Furthermore, myogenin expression increased in IL 10 mutant muscle at 1 d postinjury, suggesting that the mutation amplified the transition from the proliferative to the early differentiation stages of myogenesis. In vitro assays showed that stimulation of muscle cells with IL-10 had no effect on cell proliferation or expression of MyoD or myogenin. However, coculturing muscle cells with macrophages activated with IL-10 to the M2 phenotype increased myoblast proliferation without affecting MyoD or myogenin expression, showing that M2 macrophages promote the early, proliferative stage of myogenesis. Collectively, these data show that IL-10 plays a central role in regulating the switch of muscle macrophages from a M1 to M2 phenotype in injured muscle in vivo, and this transition is necessary for normal growth and regeneration of muscle. PMID- 22933627 TI - IRF4 promotes cutaneous dendritic cell migration to lymph nodes during homeostasis and inflammation. AB - Migration of resident dendritic cells (DC) from the skin to local lymph nodes (LN) triggers T cell-mediated immune responses during cutaneous infection, autoimmune disease, and vaccination. In this study, we investigated whether the development and migration of skin-resident DC were regulated by IFN regulatory factor 4 (IRF4), a transcription factor that is required for the development of CD11b(+) splenic DC. We found that the skin of naive IRF4(-/-) mice contained normal numbers of epidermal Langerhans cells (eLC) and increased numbers of CD11b(+) and CD103(+) dermal DC (dDC) populations, indicating that tissue DC development and skin residency is not disrupted by IRF4 deficiency. In contrast, numbers of migratory eLC and CD11b(+) dDC were significantly reduced in the cutaneous LN of IRF4(-/-) mice, suggesting a defect in constitutive migration from the dermis during homeostasis. Upon induction of skin inflammation, CD11b(+) dDC in IRF4(-/-) mice did not express the chemokine receptor CCR7 and failed to migrate to cutaneous LN, whereas the migration of eLC was only mildly impaired. Thus, although dispensable for their development, IRF4 is crucial for the CCR7 mediated migration of CD11b(+) dDC, a predominant population in murine and human skin that plays a vital role in normal and pathogenic cutaneous immunity. PMID- 22933629 TI - Marginal zone B cell is a major source of Il-10 in Listeria monocytogenes susceptibility. AB - Rag-1-knockout (KO) mice are highly resistant to Listeria monocytogenes infection. The role played by the many Rag-1-dependent lymphocyte lineages was studied using a genetic approach in which each Rag-1-dependent lymphocyte lineage was eliminated one at a time. Only B cell-deficient Igh-KO mice displayed reduced bacterial load and improved survival upon Listeria infection. Listeria infection of Rag-1-KO and Il-10-KO hosts that had been adoptively transferred with wild type marginal zone B (MZB) cells, but not follicular B cells, resulted in heightened bacterial load and increased Il-10 production in the spleen, but not the liver. This MZB cell-dependent increase in bacterial load was eliminated by anti-Il-10 mAb. In addition, Listeria infection of MZB cell-deficient Rbpj-cKO mice showed decreased bacterial load and increased survival. Whereas multiple cell types have been shown to be capable of Il-10 production, our results indicate that the MZB cell is the most dominant and relevant Il-10 source in the context of Listeria susceptibility. In marked contrast to the generally protective nature of MZB cells in defending against pathogenic infection, our results demonstrate that MZB cells play a detrimental role in Listeria infection and possibly other infections as well. PMID- 22933630 TI - A sphingosine-1-phosphate receptor 1-directed agonist reduces central nervous system inflammation in a plasmacytoid dendritic cell-dependent manner. AB - Gradients of the sphingolipid sphingosine-1-phosphate (S1P) are responsible for the egress of lymphocytes from lymph nodes by activating the S1P1 receptor expressed on the surface of lymphocytes. Small molecule drugs that downregulate S1P receptors induce the sequestration of lymphocytes within lymph nodes, thus preventing lymphocytes from accessing sites of inflammation. In particular, FTY720, a pan-S1P receptor agonist, has been efficacious in the treatment of multiple sclerosis as well as its animal model, experimental autoimmune encephalomyelitis (EAE), by virtue of its ability to restrain lymphocytes within the lymph nodes, thus precluding their migration into the CNS. However, multiple leukocyte subsets express S1P receptors of varying types, and although it is beneficial to prevent transmigration of proinflammatory lymphocytes into the CNS, allowing access of regulatory leukocyte subsets to the CNS is desirable. In this study, we show that an S1P1-specific agonist (AUY954) is clinically efficacious in ameliorating pre-established EAE in SJL/J mice. Efficacy of AUY954 correlated with a reduction of lymphocytes in the CNS, but access of plasmacytoid dendritic cells (pDCs) to the CNS was unimpaired, and the presence of pDCs was found to be an important cofactor in mediating the clinical efficacy of AUY954. These results indicate that pDCs are important in quieting autoimmune responses during EAE, and that trafficking inhibitors that are permissive for pDC accumulation in the CNS may be of therapeutic value for the treatment of multiple sclerosis. PMID- 22933628 TI - Monocytes from Irf5-/- mice have an intrinsic defect in their response to pristane-induced lupus. AB - The transcription factor IFN regulatory factor (IRF)5 has been identified as a human systemic lupus erythematosus (SLE) susceptibility gene by numerous joint linkage and genome-wide association studies. Although IRF5 expression is significantly elevated in primary blood cells of SLE patients, it is not yet known how IRF5 contributes to SLE pathogenesis. Recent data from mouse models of lupus indicate a critical role for IRF5 in the production of pathogenic autoantibodies and the expression of Th2 cytokines and type I IFN. In the present study, we examined the mechanisms by which loss of Irf5 protects mice from pristane-induced lupus at early time points of disease development. We demonstrate that Irf5 is required for Ly6C(hi) monocyte trafficking to the peritoneal cavity, which is thought to be one of the initial key events leading to lupus pathogenesis in this model. Chemotaxis assays using peritoneal lavage from pristane-injected Irf5(+/+) and Irf5(-/-) littermates support an intrinsic defect in Irf5(-/-) monocytes. We found the expression of chemokine receptors CXCR4 and CCR2 to be dysregulated on Irf5(-/-) monocytes and less responsive to their respective ligands, CXCL12 and CCL2. Bone marrow reconstitution experiments further supported an intrinsic defect in Irf5(-/-) monocytes because Irf5(+/+) monocytes were preferentially recruited to the peritoneal cavity in response to pristane. Taken together, these findings demonstrate an intrinsic role for IRF5 in the response of monocytes to pristane and their recruitment to the primary site of inflammation that is thought to trigger lupus onset in this experimental model of SLE. PMID- 22933631 TI - IL-2 and IL-7 determine the homeostatic balance between the regulatory and conventional CD4+ T cell compartments during peripheral T cell reconstitution. AB - Work over the last decades has led to the identification of the factors that influence the survival and homeostasis of conventional T cells. IL-7 and TCR signaling promote the survival of naive CD4(+) and CD8(+) T cells in lymphoreplete mice and their proliferation in a lymphopenic environment, whereas survival and homeostatic proliferation of memory CD4(+) and CD8(+) T cells crucially depend on a combination of IL-7 and IL-15. In contrast, there is little information regarding the factors driving the proliferation of regulatory CD4(+) T cells in response to lymphopenia. In this study, we investigated whether regulatory CD4(+) T cell proliferation in response to lymphopenia was guided by classical homeostatic resources, such as IL-2, IL-7, or TCR-MHC interactions. Altogether, our data suggest that, although homeostatic proliferation of conventional naive CD4(+) T cells is closely related to IL-7 levels, the proliferation of regulatory CD4(+) T cells in response to lymphopenia appears to be primarily controlled by IL-2. The capacity of IL-7 to augment conventional T cell proliferation with minimal concomitant regulatory T cell expansion may be clinically exploitable in the treatment of patients with lymphopenia, especially in the case of chronic viral diseases or cancer immunotherapy. PMID- 22933633 TI - The TRPM4 channel controls monocyte and macrophage, but not neutrophil, function for survival in sepsis. AB - A favorable outcome following acute bacterial infection depends on the ability of phagocytic cells to be recruited and properly activated within injured tissues. Calcium (Ca(2+)) is a ubiquitous second messenger implicated in the functions of many cells, but the mechanisms involved in the regulation of Ca(2+) mobilization in hematopoietic cells are largely unknown. The monovalent cation channel transient receptor potential melastatin (TRPM) 4 is involved in the control of Ca(2+) signaling in some hematopoietic cell types, but the role of this channel in phagocytes and its relevance in the control of inflammation remain unexplored. In this study, we report that the ablation of the Trpm4 gene dramatically increased mouse mortality in a model of sepsis induced by cecal ligation and puncture. The lack of the TRPM4 channel affected macrophage population within bacteria-infected peritoneal cavities and increased the systemic level of Ly6C(+) monocytes and proinflammatory cytokine production. Impaired Ca(2+) mobilization in Trpm4(-/-) macrophages downregulated the AKT signaling pathway and the subsequent phagocytic activity, resulting in bacterial overgrowth and translocation to the bloodstream. In contrast, no alteration in the distribution, function, or Ca(2+) mobilization of Trpm4(-/-) neutrophils was observed, indicating that the mechanism controlling Ca(2+) signaling differs among phagocytes. Our results thus show that the tight control of Ca(2+) influx by the TRPM4 channel is critical for the proper functioning of monocytes/macrophages and the efficiency of the subsequent response to infection. PMID- 22933632 TI - Microbial heat shock protein 65 attenuates airway hyperresponsiveness and inflammation by modulating the function of dendritic cells. AB - Heat shock proteins (HSPs), produced in response to stress, are suppressive in disease models. We previously showed that Mycobacterium leprae HSP65 prevented development of airway hyperresponsiveness and inflammation in mice. Our goal in this study was to define the mechanism responsible for the suppressive effects of HSP. In one in vivo approach, BALB/c mice were sensitized to OVA, followed by primary OVA challenges. Several weeks later, HSP65 was administered prior to a single, provocative secondary challenge. In a second in vivo approach, the secondary challenge was replaced by intratracheal instillation of allergen-pulsed bone marrow-derived dendritic cells (BMDCs). The in vitro effects of HSP65 on BMDCs were examined in coculture experiments with CD4(+) T cells. In vivo, HSP65 prevented the development of airway hyperresponsiveness and inflammation. Additionally, Th1 cytokine levels in bronchoalveolar lavage fluid were increased. In vitro, HSP65 induced Notch receptor ligand Delta1 expression on BMDCs, and HSP65-treated BMDCs skewed CD4(+) T cells to Th1 cytokine production. Thus, HSP65 induced effects on allergen-induced airway hyperresponsiveness and inflammation were associated with increased Delta1 expression on dendritic cells, modulation of dendritic cell function, and CD4(+) Th1 cytokine production. PMID- 22933634 TI - The beta-glucan receptor dectin-1 promotes lung immunopathology during fungal allergy via IL-22. AB - Sensitization to fungi, such as the mold Aspergillus fumigatus, is increasingly becoming linked with asthma severity. We have previously shown that lung responses generated via the beta-glucan receptor Dectin-1 are required for lung defense during acute, invasive A. fumigatus infection. Unexpectedly, in an allergic model of chronic lung exposure to live A. fumigatus conidia, beta-glucan recognition via Dectin-1 led to the induction of multiple proallergic (Muc5ac, Clca3, CCL17, CCL22, and IL-33) and proinflammatory (IL-1beta and CXCL1) mediators that compromised lung function. Attenuated proallergic and proinflammatory responses in the absence of Dectin-1 were not associated with changes in Ido (IDO), Il12p35/Ebi3 (IL-35), IL-10, or TGF-beta levels. Assessment of Th responses demonstrated that purified lung CD4(+) T cells produced IL-4, IL 13, IFN-gamma, and IL-17A, but not IL-22, in a Dectin-1-dependent manner. In contrast, we observed robust, Dectin-1-dependent IL-22 production by unfractionated lung digest cells. Intriguingly, the absence of IL-22 alone mimicked the attenuated proallergic and proinflammatory responses observed in the absence of Dectin-1, suggesting that Dectin-1-mediated IL-22 production potentiated responses that led to decrements in lung function. To this end, neutralization of IL-22 improved lung function in normal mice. Collectively, these results indicate that the beta-glucan receptor Dectin-1 contributes to lung inflammation and immunopathology associated with persistent fungal exposure via the production of IL-22. PMID- 22933639 TI - The history of twins, as a criterion of the relative powers of nature and nurture (1,2). PMID- 22933635 TI - The TCR repertoires of regulatory and conventional T cells specific for the same foreign antigen are distinct. AB - The relationship between the TCR repertoires of natural regulatory T cells (nTregs) and conventional CD4(+) T cells (Tconv) capable of responding to the same antigenic epitope is unknown. In this study, we used TCRbeta-chain transgenic mice to generate polyclonal nTreg and Tconv populations specific for a foreign Ag. CD4(+) T cells from immunized 3.L2beta(+/-) TCRalpha(+/-) Foxp3(EGFP) mice were restimulated in culture to yield nTregs (EGFP(+)) and Tconv (EGFP(-)) defined by their antigenic reactivity. Relative to Tconv, nTreg expansion was delayed, although a higher proportion of viable nTregs had divided after 72 h. Spectratype analysis revealed that both the nTreg and Tconv responses were different and characterized by skewed distributions of CDR3 lengths. CDR3 sequences from nTregs displayed a divergent pattern of Jalpha usage, minimal CDR3 overlap (3.4%), and less diversity than did CDR3 sequences derived from Tconv. These data indicate that foreign Ag-specific nTregs and Tconv are clonally distinct and that foreign Ag-specific nTreg populations are constrained by a limited TCR repertoire. PMID- 22933640 TI - Commentary: Francis Galton and the twin method. PMID- 22933641 TI - Commentary: The birth of the twin study--a commentary on Francis Galton's 'The history of twins'. PMID- 22933642 TI - Commentary: Discussion of 'The history of twins, as a criterion of the relative powers of nature and nurture' by Francis Galton (1875). PMID- 22933643 TI - Commentary: Francis Galton, twins and intelligence. PMID- 22933644 TI - Cohort profile: the QSkin Sun and Health Study. AB - The QSkin Sun and Health Study comprises a cohort of 43 794 men and women aged 40 69 years randomly sampled from the population of Queensland, Australia in 2011. The cohort was established to study the development of skin cancer and melanoma in the population with the highest reported incidence of these diseases in the world. At baseline, besides demographic items and general medical history, information about standard pigmentary characteristics (including hair and eye colour, freckling tendency, tanning ability and propensity to sunburn), past and recent history of sun exposure and sunburns, sun protection behaviours, use of tanning beds and history of skin cancer was collected by self-completed questionnaire. Participants have given their consent for data linkage to the universal national health insurance scheme and for linkage to cancer registries and pathology databases, thus ensuring complete ascertainment of all future skin cancer and melanoma occurrences and medical treatments and other cancer events. Linkage to these registers will occur at predetermined intervals. Approval to access QSkin data can be obtained on application to the study investigators and submission of a formal research plan that has previous approval from the human research ethics committee of the applicant's institution. PMID- 22933645 TI - Profile of the Navrongo Health and Demographic Surveillance System. AB - Located in the Kassena-Nankana districts of northern Ghana, the Navrongo health and demographic surveillance system (NHDSS) was established in 1992 by the Navrongo health research centre (NHRC). The NHRC is one of three research centres of the Ghana health service. The activities and potential of the NHDSS for collaborative research are described. The NHDSS monitors health and demographic dynamics of the two Kassena-Nankana districts of northern Ghana and facilitates evaluation of the morbidity and mortality impact of health and social interventions. The total population currently under surveillance is 152 000 residing in 32 000 households. Events monitored routinely include pregnancies, births, morbidity, deaths, migration, marriages and vaccination coverage. Data updates are done every 4 months by trained fieldworkers. The NHRC also undertakes biomedical and socio-economic studies. Additional features of the NHDSS include the community key informant system where trained volunteers routinely report key events, such as births and deaths as they occur in their locality and the verbal autopsy (VA) system for determining the probable causes of deaths that occur at the community level. Data from the NHDSS are shared with funders and collaborators and partners in the INDEPTH Network. The Director of the NHDSS is the contact person for potential collaboration with the NHDSS and the use of its data. PMID- 22933646 TI - Profile: the KEMRI/CDC Health and Demographic Surveillance System--Western Kenya. AB - The KEMRI/Centers for Disease Control and Prevention (CDC) Health and Demographic Surveillance System (HDSS) is located in Rarieda, Siaya and Gem Districts (Siaya County), lying northeast of Lake Victoria in Nyanza Province, western Kenya. The KEMRI/CDC HDSS, with approximately 220 000 inhabitants, has been the foundation for a variety of studies, including evaluations of insecticide-treated bed nets, burden of diarrhoeal disease and tuberculosis, malaria parasitaemia and anaemia, treatment strategies and immunological correlates of malaria infection, and numerous HIV, tuberculosis, malaria and diarrhoeal disease treatment and vaccine efficacy and effectiveness trials for more than a decade. Current studies include operations research to measure the uptake and effectiveness of the programmatic implementation of integrated malaria control strategies, HIV services, newly introduced vaccines and clinical trials. The HDSS provides general demographic and health information (such as population age structure and density, fertility rates, birth and death rates, in- and out-migrations, patterns of health care access and utilization and the local economics of health care) as well as disease or intervention-specific information. The HDSS also collects verbal autopsy information on all deaths. Studies take advantage of the sampling frame inherent in the HDSS, whether at individual, household/compound or neighbourhood level. PMID- 22933648 TI - Commentary: Twins, worms and life course epidemiology. PMID- 22933647 TI - Profile: Agincourt health and socio-demographic surveillance system. AB - The Agincourt health and socio-demographic surveillance system (HDSS), located in rural northeast South Africa close to the Mozambique border, was established in 1992 to support district health systems development led by the post-apartheid ministry of health. The HDSS (90 000 people), based on an annual update of resident status and vital events, now supports multiple investigations into the causes and consequences of complex health, population and social transitions. Observational work includes cohorts focusing on different stages along the life course, evaluation of national policy at population, household and individual levels and examination of household responses to shocks and stresses and the resulting pathways influencing health and well-being. Trials target children and adolescents, including promoting psycho-social well-being, preventing HIV transmission and reducing metabolic disease risk. Efforts to enhance the research platform include using automated measurement techniques to estimate cause of death by verbal autopsy, full 'reconciliation' of in- and out-migrations, follow up of migrants departing the study area, recording of extra-household social connections and linkage of individual HDSS records with those from sub-district clinics. Fostering effective collaborations (including INDEPTH multi-centre work in adult health and ageing and migration and urbanization), ensuring cross-site compatibility of common variables and optimizing public access to HDSS data are priorities. PMID- 22933649 TI - Commentary: A single biomarker in a complex metabolic pathway. PMID- 22933651 TI - Commentary: Alcohol, child development and harm to others: a 'hard' problem. PMID- 22933652 TI - Review and evaluation of innovative technologies for measuring diet in nutritional epidemiology. AB - INTRODUCTION: The use of innovative technologies is deemed to improve dietary assessment in various research settings. However, their relative merits in nutritional epidemiological studies, which require accurate quantitative estimates of the usual intake at individual level, still need to be evaluated. OBJECTIVE: To report on the inventory of available innovative technologies for dietary assessment and to critically evaluate their strengths and weaknesses as compared with the conventional methodologies (i.e. Food Frequency Questionnaires, food records, 24-hour dietary recalls) used in epidemiological studies. METHODS: A list of currently available technologies was identified from English-language journals, using PubMed and Web of Science. The search criteria were principally based on the date of publication (between 1995 and 2011) and pre-defined search keywords. RESULTS: Six main groups of innovative technologies were identified ('Personal Digital Assistant-', 'Mobile-phone-', 'Interactive computer-', 'Web-', 'Camera- and tape-recorder-' and 'Scan- and sensor-based' technologies). Compared with the conventional food records, Personal Digital Assistant and mobile phone devices seem to improve the recording through the possibility for 'real-time' recording at eating events, but their validity to estimate individual dietary intakes was low to moderate. In 24-hour dietary recalls, there is still limited knowledge regarding the accuracy of fully automated approaches; and methodological problems, such as the inaccuracy in self-reported portion sizes might be more critical than in interview-based applications. In contrast, measurement errors in innovative web-based and in conventional paper-based Food Frequency Questionnaires are most likely similar, suggesting that the underlying methodology is unchanged by the technology. CONCLUSIONS: Most of the new technologies in dietary assessment were seen to have overlapping methodological features with the conventional methods predominantly used for nutritional epidemiology. Their main potential to enhance dietary assessment is through more cost- and time-effective, less laborious ways of data collection and higher subject acceptance, though their integration in epidemiological studies would need additional considerations, such as the study objectives, the target population and the financial resources available. However, even in innovative technologies, the inherent individual bias related to self-reported dietary intake will not be resolved. More research is therefore crucial to investigate the validity of innovative dietary assessment technologies. PMID- 22933650 TI - Association between adult height, genetic susceptibility and risk of glioma. AB - BACKGROUND: Some, but not all, observational studies have suggested that taller stature is associated with a significant increased risk of glioma. In a pooled analysis of observational studies, we investigated the strength and consistency of this association, overall and for major sub-types, and investigated effect modification by genetic susceptibility to the disease. METHODS: We standardized and combined individual-level data on 1354 cases and 4734 control subjects from 13 prospective and 2 case-control studies. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) for glioma and glioma sub-types were estimated using logistic regression models stratified by sex and adjusted for birth cohort and study. Pooled ORs were additionally estimated after stratifying the models according to seven recently identified glioma-related genetic variants. RESULTS: Among men, we found a positive association between height and glioma risk (>= 190 vs 170-174 cm, pooled OR = 1.70, 95% CI: 1.11-2.61; P-trend = 0.01), which was slightly stronger after restricting to cases with glioblastoma (pooled OR = 1.99, 95% CI: 1.17-3.38; P-trend = 0.02). Among women, these associations were less clear (>= 175 vs 160-164 cm, pooled OR for glioma = 1.06, 95% CI: 0.70-1.62; P trend = 0.22; pooled OR for glioblastoma = 1.36, 95% CI: 0.77-2.39; P-trend = 0.04). In general, we did not observe evidence of effect modification by glioma related genotypes on the association between height and glioma risk. CONCLUSION: An association of taller adult stature with glioma, particularly for men and stronger for glioblastoma, should be investigated further to clarify the role of environmental and genetic determinants of height in the etiology of this disease. PMID- 22933653 TI - Alternatives to principal components analysis to derive asset-based indices to measure socio-economic position in low- and middle-income countries: the case for multiple correspondence analysis. PMID- 22933655 TI - Lignification in poplar tension wood lignified cell wall layers. AB - The lignification process in poplar tension wood lignified cell wall layers, specifically the S(1) and S(2) layers and the compound middle lamella (CML), was analysed using ultraviolet (UV) and transmission electron microscopy (TEM). Variations in the thickness of the gelatinous layer (G-layer) were also measured to clarify whether the lignified cell wall layers had completed their lignification before the deposition of G-layers, or, on the contrary, if lignification of these layers was still active during G-layer formation. Observations using UV microscopy and TEM indicated that both UV absorbance and the degree of potassium permanganate staining increased in the CML and S(1) and S(2) layers during G-layer formation, suggesting that the lignification of these lignified layers is still in progress during G-layer formation. In the context of the cell-autonomous monolignol synthesis hypothesis, our observations suggest that monolignols must go through the developing G-layer during the lignification of CML and the S(1) and S(2) layers. The alternative hypothesis of external synthesis (in the rays) does not require that monolignols go through the G-layer before being deposited in the CML, or the S(1) and S(2) layers. Interestingly, the previous observation of lignin in the poplar G-layer was not confirmed with the microscopy techniques used in the present study. PMID- 22933657 TI - Draft genome sequence of Aspergillus oryzae strain 3.042. AB - Aspergillus oryzae is the most important fungus for the traditional fermentation in China and is particularly important in soy sauce fermentation. We report the 36,547,279-bp draft genome sequence of A. oryzae 3.042 and compared it to the published genome sequence of A. oryzae RIB40. PMID- 22933658 TI - Replacing immunoassays for mephedrone, ketamines and six amphetamine-type stimulants with flow injection analysis tandem mass spectrometry. AB - A screening procedure was developed for the simultaneous detection of mephedrone, six amphetamine-type stimulants (ATS), ketamine and its two metabolites with electrospray ionization flow injection analysis tandem mass spectrometry (FIA-MS MS). Urine samples were fortified with deuterated analogues as internal standards, extracted with ethyl acetate and analyzed with FIA-MS-MS. The mass analyzer was operated in multiple reaction monitoring mode. Two product ions were monitored for each drug and internal standards. For each analyte, the limit of detection was less than 4 ug/L, within-day and between-day precisions (percent coefficient of variation) at three different concentrations were less than 7.3% and bias was between -17.3 and 11.8%. Total analysis time with FIA-MS-MS is 1.8 min per sample. A group of 215 urine samples were screened with immunoassay for ATS and analyzed with FIA-MS-MS and gas chromatography-mass spectrometry (GC-MS) for ketamines and ATS. The analysis of ATS by immunoassay and GC-MS was 96.7% concordant. The analysis of three ketamines and seven ATS by FIA-MS-MS and GC-MS was 97.2% concordant. The FIA-MS-MS procedure is efficient, accurate, flexible and capable of detecting analytes of different chemical groups. It can replace immunoassays for the screening of new designer drugs when commercial immunoassays are unavailable. PMID- 22933659 TI - Development and validation of a new GC-MS method for the detection of tramadol, O desmethyltramadol, 6-acetylmorphine and morphine in blood, brain, liver and kidney of Wistar rats treated with the combination of heroin and tramadol. AB - Heroin is one of the most dangerous abused drugs in the world. Tramadol is an additive recently found at high concentration levels in street heroin seizures in Egypt. This substance could affect the usual analytical method for the detection of heroin and metabolites, as well as the pharmacokinetic and disposition of single analytes. One shortfall regarding this issue is present in the literature. This study describes a validated, simple, sensitive and selective method to determine tramadol, O-desmethyltramadol, 6-acetylmorphine and free morphine in the blood, brain, liver and kidney of Wistar rats, intraperitoneally treated with a combination of heroin and tramadol (10 and 70 mg/kg, respectively) using liquid liquid extraction and gas chromatography-mass spectrometry detection. The calibration curves of tramadol, O-desmethyltramadol and 6-acetylmorphine in blood were linear in the concentration range from 25-5,000 ng/mL and morphine was found in the concentration range 50-5,000 ng/mL. The analytes were detected in all tested matrices, except 6-acetylmorphine, which was not detected in liver. The highest concentrations of tramadol and O-desmethyltramadol were observed in kidney (22,9381 and 28,498 ng/g), while 6-acetylmorphine and morphine were found at the highest levels in brain (3,280 and 3,899 ng/g, respectively). The present method is simple, rapid and sensitive and can be used to study the pharmacokinetics, disposition and interaction of these drugs in several animal models. PMID- 22933660 TI - Impact of lowering confirmatory test cutoff value in pre-enlistment urine cannabinoids screening: about five years' experience in the French Gendarmerie. AB - The guidelines for screening of urinary cannabinoids require that all specimens testing positive should be confirmed by gas chromatography-mass spectrometry at a confirmatory test cutoff value of 15 ng/mL of 11-nor-9-carboxy-Delta9 tetrahydrocannabinol (THCCOOH). To assess the impact of lowering the confirmatory test cutoff value on the diagnostic sensitivity and efficiency of a cannabinoid testing program, the results of 986 confirmation analyses of positive screening tests, conducted in the framework of medical fitness examinations prior to enlistment in the French Gendarmerie between January 1, 2005, and December 31, 2009, were retrospectively studied. If the confirmatory test cutoff value of THCCOOH is set at 5 ng/mL instead of 15 ng/mL as recommended by guidelines, the number of confirmed results increases by 25.2%. The positive predictive value of the initial screening test rises from 63.9 to 80.0%. Only one true-positive applicant has appealed. His THCCOOH urinary concentration, which was incompatible with passive cannabis smoke exposure, was confirmed by another laboratory. The use of a confirmatory test cutoff value lower than that recommended significantly increases the diagnostic sensitivity of the screening program for urinary cannabinoids without altering its specificity. PMID- 22933661 TI - J-waves in patients with an acute ST-elevation myocardial infarction who underwent successful percutaneous coronary intervention: prevalence, pathogenesis, and clinical implication. AB - AIMS: The prevalence, clinical significance, and pathogenesis of J-waves were studied in the patients with an ST-elevation myocardial infarction (MI) after percutaneous coronary intervention (PCI). METHODS AND RESULTS: One hundred and fifty-two consecutive patients with an acute ST-elevation MI were included. The mean age was 68.6 +/- 13.5 years, and 78.3% of the patients were male. Following successful PCI, 12-lead electrocardiograms (ECGs) were monitored, and J-waves were measured 1 week after the MI and analysed in relation to the location of the MI and arrhythmias. Clinical and ECG parameters were compared between the groups with and without J-waves. The rate dependency of the J-wave amplitude was analysed in the conducted atrial premature beats (APBs). J-waves were present in 60.5% (>=0.1 mV) or 48.9% (>=0.2 mV) of the 152 patients. The J-waves were more often located in the inferior leads and more frequently in an inferior MI. The presence of J-waves was associated with ventricular arrhythmias, including ventricular fibrillation. The J-wave amplitude increased in the conducted APB, mechanistically suggesting a phase 3 block. CONCLUSION: Many patients in the early recovery phase after an acute MI had J-waves. This ECG phenomenon was associated with an increased incidence of ventricular arrhythmias. The tachycardia-dependent augmentation of the J-wave amplitude suggested a mechanistic role of conduction delay. PMID- 22933662 TI - Ventricular resynchronization therapy by direct His-bundle pacing using an internal cardioverter defibrillator. AB - AIMS: Cardiac resynchronization therapy (CRT) has been demonstrated to improve the functional class of patients with refractory heart failure if QRS width is >120 ms. Addition of an internal cardioverter defibrillator diminishes the prevalence of mortality of such patients. The technique for CRT requires selective stimulation of the left ventricle (LV), commonly undertaken through the coronary sinus. This procedure is not always feasible. Direct His-bundle pacing (DHBP) might be an alternative for CRT. METHODS AND RESULTS: Patients were selected from a population with refractory heart failure derived for CRT and internal cardioverter defibrillator insertion. Of those, patients in whom LV stimulation via the coronary sinus was not achievable and DHBP obtained left bundle branch block disappearance were included. Direct His-bundle pacing corrected basal conduction disturbances in 13 of the 16 patients (81%) selected. In four patients in whom DHBP was attempted, the electrode was not successfully fixed. In the nine remaining patients, a definitive resynchronization by DHBP was achieved, with consequent improvement in functional class and parameters of LV function as assessed by echocardiography. CONCLUSION: Direct His-bundle pacing might be an alternative treatment for CRT in selected cases. PMID- 22933663 TI - Inactivation of influenza virus haemagglutinin by chlorine dioxide: oxidation of the conserved tryptophan 153 residue in the receptor-binding site. AB - Airborne influenza virus infection of mice can be prevented by gaseous chlorine dioxide (ClO(2)). This study demonstrated that ClO(2) abolished the function of the haemagglutinin (HA) of influenza A virus (H1N1) in a concentration-, time- and temperature-dependent manner. The IC(50) during a 2 min reaction with ClO(2) at 25 degrees C was 13.7 uM, and the half-life time of HA with 100 uM ClO(2) at 25 degrees C was 19.5 s. Peptides generated from a tryptic digest of ClO(2) treated virus were analysed by mass spectrometry. An HA fragment, (150)NLLWLTGK(157) was identified in which the tryptophan residue (W153) was 32 mass units greater than expected. The W153 residue of this peptide, which is derived from the central region of the receptor-binding site of HA, is highly conserved. It was shown that W153 was oxidized to N-formylkynurenine in ClO(2) treated virus. It was concluded that the inactivation of influenza virus by ClO(2) is caused by oxidation of W153 in HA, thereby abolishing its receptor binding ability. PMID- 22933664 TI - Identification of a novel B-cell epitope of Hantaan virus glycoprotein recognized by neutralizing 3D8 monoclonal antibody. AB - Hantaan virus (HTNV), a member of the family Bunyaviridae, is a major agent causing haemorrhagic fever with renal syndrome, a high-mortality-rate disease threatening approximately 150 000 people around the world yearly. The 3D8 mAb displays a neutralizing activity to HTNV infection. In this study, the B-cell epitopes of HTNV glycoproteins (GPs) were finely mapped by peptide scanning. A new B-cell epitope (882)GFLCPEFPGSFRKKC(896) of HTNV, which locates on Gc, has been screened out from a set of 15-mer synthesized peptides covering the full length of HTNV-GPs. It has been shown by the alanine-scanning technique that (885)C, (893)R, (894)K, (895)K and (896)C are the key amino acids of the binding sites of the GPs. The implications of identifying a novel B-cell epitope for hantavirus immunology and vaccinology are discussed. PMID- 22933666 TI - Serological cross-reactions between four polyomaviruses of birds using virus-like particles expressed in yeast. AB - Polyomaviruses are aetiological agents of fatal acute diseases in various bird species. Genomic analysis revealed that avian polyomavirus (APyV), crow polyomavirus (CPyV), finch polyomavirus (FPyV) and goose hemorrhagic polyomavirus (GHPyV) are closely related to each other, but nevertheless form separate viral species; however, their serological relationship was previously unknown. As only APyV can be grown efficiently in tissue culture, virus-like particles (VLPs) were generated by expression of the genomic regions encoding the major structural protein VP1 of these viruses in yeast; these were used to elicit type-specific antibodies in rabbits and as antigens in serological reactions. For increased VLP assembly, a nuclear-localization signal was introduced into APyV-VP1. VLPs derived from the VP1 of the monkey polyomavirus simian virus 40 served as control. APyV-, GHPyV- and CPyV-VLPs showed haemagglutinating activity with chicken and human erythrocytes. CPyV- and GHPyV-specific sera showed slight cross reactions in immunoblotting, haemagglutination-inhibition assay and indirect ELISA. The FPyV-specific serum inhibited the haemagglutination activity of APyV VLPs slightly and showed a weak cross-neutralizing activity against APyV in cell culture tests. Generally, these data indicate that the four polyomaviruses of birds are serologically distinct. However, in accordance with genetic data, a relationship between CPyV and GHPyV as well as between APyV and FPyV is evident, and grouping into two different serogroups may be suggested. The haemagglutinating activity of APyV, CPyV and GHPyV may indicate similar receptor binding mechanisms for these viruses. Our data could be useful for the development of vaccines against the polyomavirus-induced diseases in birds and for interpretation of diagnostic test results. PMID- 22933665 TI - Evolution of the human immunodeficiency virus type 1 protease: effects on viral replication capacity and protease robustness. AB - The rapid spread of human immunodeficiency virus type 1 (HIV-1) in humans has been accompanied by continuous extensive genetic diversification of the virus. The aim of this study was to investigate the impact of HIV-1 diversification on HIV-1 replication capacity (RC) and mutational robustness. Thirty-three HIV-1 protease sequences were amplified from three groups of viruses: two naive sample groups isolated 15 years apart plus a third group of protease inhibitor-(PI) resistant samples. The amplified proteases were recombined with an HXB2 infectious clone and RC was determined in MT-4 cells. RC was also measured in these three groups after random mutagenesis in vitro using error-prone PCR. No significant RC differences were observed between recombinant viruses from either early or recent naive isolates (P = 0.5729), even though the proteases from the recent isolates had significantly lower sequence conservation scores compared with a subtype B ancestral sequence (P<0.0001). Randomly mutated recombinant viruses from the three groups exhibited significantly lower RC values than the corresponding wild-type viruses (P<0.0001). There was no significant difference regarding viral infectivity reduction between viruses carrying randomly mutated naive proteases from early or recent sample isolates (P = 0.8035). Interestingly, a significantly greater loss of RC was observed in the PI-resistant protease group (P = 0.0400). These results demonstrate that protease sequence diversification has not affected HIV-1 RC or protease robustness and indicate that proteases carrying PI resistance substitutions are less robust than naive proteases. PMID- 22933667 TI - Comparison of tibial bone coverage of 6 knee prostheses: a magnetic resonance imaging study with controlled rotation. AB - PURPOSE: To compare the extent of tibial bone covered by the tibial tray in 6 most commonly used total knee arthroplasty designs in order to strike a balance between mediolateral cortical fit and optimal tibial component rotation. METHODS: In 74 men and 27 women aged 17 to 60 (mean, 32) years with suspected soft-tissue injuries, their magnetic resonance images of the knee in full extension were superimposed with scans of the tibial trays of the 6 designs (one asymmetric and 5 symmetric). The tibial coverage by the tray and any posterolateral/posteromedial overhang/underhang were measured. RESULTS: All 6 tray designs achieved tibial bone coverage of over 80%. Only 28% of all trays achieved optimal posterolateral fit, whereas 49% had posterolateral overhang enough to cause popliteal tendon impingement. Although the asymmetric tray provided highest tibial coverage (88%), its rates of relative and absolute posterolateral and posteromedial overhang were also highest (64%). CONCLUSION: The asymmetric tray provided improved tibial coverage at the expense of posterolateral and posteromedial overhang of the tibial tray. PMID- 22933668 TI - Total knee arthroplasty for rheumatoid arthritis patients with large tibial condyle defects. AB - PURPOSE: To review clinical results of total knee arthroplasty (TKA) in rheumatoid arthritis (RA) patients with large bone defects of the tibial condyle. METHODS: Records of 33 knees in 27 women and 3 men aged 44 to 80 (mean, 63.6) years who underwent primary TKA for RA with large tibial bone defects were reviewed. 16 knees had peripheral defects extending to the bone cortex, whereas 17 knees had central defects that did not extend to the bone cortex. The femorotibial angle (FTA) was <170o in 15 knees, 170o to 180o in 3 knees, and >180o in 15 knees. The mean duration of RA was 13.5 (range, 3-35) years. In 14 knees with severe bone defects, bone grafts (harvested from articular surfaces of knee bones and fixed without screws or Kirschner wires) and/ or metal wedges (for peripheral defects) were used to fill the defects. Clinical outcome was assessed pre- and post-operatively using Knee Society scores. RESULTS: The mean follow-up duration was 6.3 (range, 2.3-13.2) years. The mean depth of tibial bone defects was 11.2 (range, 1-25) mm, whereas the mean width ratio of the bone defects was 36.5% (range, 16.4-76.9%). Mean extension and flexion (range of motion) improved from -12.5o and 113.4o to -5.1o and 115.6o, respectively. The mean Knee Society knee score improved from 35 (range, 21-59) to 85 (range, 49-95), whereas the mean Knee Society function score improved from 30 (range, 25-53) to 80 (range, 44-97) [p<0.001, Wilcoxon signed rank test]. The cruciate retention prosthesis was used in 6 knees; the posterior stabilised prosthesis was used in 27 knees; and the constrained condylar knee prosthesis was used in 3 knees. No patient had any infection or implant loosening. CONCLUSION: TKA achieved favourable outcome for RA patients with large tibial bone defects. The type of prosthesis used and the use of bone grafts and/ or metal wedges were based on the depth and width ratio of the bone defects. PMID- 22933669 TI - Gender-specific high-flexion knee prosthesis in Indian women: a prospective randomised study. AB - PURPOSE: To compare outcomes in Indian women who underwent total knee arthroplasty (TKA) using the standard Legacy Posterior Stabilised (LPS) versus the gender-specific LPS high-flexion knee prosthesis. METHODS: 100 women (200 knees) aged 60 to 80 years with an arc of flexion of >=90o underwent simultaneous sequential TKA for primary osteoarthritis of both knees. They were randomised to receive the standard NexGen LPS prosthesis (n=50) or the gender-specific NexGen LPS High-Flex prosthesis (n=50). Both knees in each patient received the same prosthesis. The resected bone from the posterior femoral condyle was 2 mm greater when the gender-specific prosthesis was used. Patients were followed up at 3, 6, 12, and 24 months. Range of motion, Knee Society score, and Hospital for Special Surgery score were evaluated pre- and post-operatively by a single assessor. RESULTS: The mean follow-up duration was 2.1 (range, 1.6-2.5) years. Respectively for the standard and gender-specific groups, the mean range of motion was 111o and 112o preoperatively and 120o and 123o at the latest follow-up. The gender specific group gained approximately 3o more in range of motion (p=0.007). The Knee Society score and the Hospital for Special Surgery score between groups were not significantly different pre- and post-operatively. CONCLUSION: The perceived advantage of a gender-specific prosthesis over a standard prosthesis did not translate into better clinical and functional outcome scores. PMID- 22933670 TI - Medium-term results of Oxford phase-3 medial unicompartmental knee arthroplasty. AB - PURPOSE: To review medium-term results of 49 consecutive patients who underwent Oxford phase-3 medial unicompartmental knee arthroplasty by a single surgeon. METHODS: Records of 28 women (mean age, 71 years) and 21 men (mean age, 68 years) who underwent minimally invasive Oxford phase-3 medial unicompartmental knee arthroplasty by a single surgeon were retrospectively reviewed. The Oxford knee score and visual analogue scale (VAS) scores for pain and satisfaction were assessed at the latest follow-up by an independent observer, as were postoperative radiographs for implant position, osteoarthritic changes in the non replaced compartments, and radiolucent lines of >2 mm or implant subsidence. The survival rate was calculated using Kaplan-Meier survival analysis. Patient demographics, postoperative alignment (varus/ valgus), Oxford knee scores, and the progression of osteoarthritis in the other compartments were included in a multiple logistic regression (MLR) analysis to identify significant factors affecting the probability of being satisfied (VAS scores for satisfaction of <=2). RESULTS: The mean follow-up duration was 7.2 years. No patient was lost to follow-up. Two patients with no knee symptoms died (unrelated to surgery) before the 5-year follow-up. The cumulative survival rate at the 9-year follow-up was 91.2% (95% confidence interval, 87.6-94.5%). There were 4 early failures (before 4 years). One patient early in the series developed avascular necrosis of the lateral femoral condyle with an over-corrected tibiofemoral valgus of 12o at 8 months; the other 3 complained of anterior knee pain, without signs of osteoarthritis. All 4 patients underwent revision with total knee arthroplasty. There were 43 patients with more than 5 years of follow-up and without revision of the prosthesis. Patients who were not satisfied (n=6) were more likely to be <65 years old (n=4, adjusted odds ratio [OR], 3.1; MLR p=0.002) and male (n=4; adjusted OR, 2.3; MLR p=0.02). Six of the 43 patients had lucent lines on radiographs, all of which were partial and under the tibial component. Progression of the arthritis in the patellofemoral and/or lateral compartments was worse in 5 patients. CONCLUSION: Careful patient selection and good surgical technique contributed to good outcome. Younger male patients should be counselled regarding the higher chance of limited satisfaction. PMID- 22933671 TI - Hyaluronic acid instillation following arthroscopic anterior cruciate ligament reconstruction: a double-blinded, randomised controlled study. AB - PURPOSE: To assess the effect of hyaluronic acid instillation after arthroscopic anterior cruciate ligament (ACL) reconstruction for improving pain, range of movement, and function of the knee. METHODS: 28 men and 4 women underwent arthroscopic ACL reconstruction for isolated ACL rupture (partial or complete) and instability after recreational sports injury 2 to 120 months earlier. They were randomised to undergo arthroscopic ACL reconstruction followed by intra articular viscoseal instillation (13 men and 3 women) or arthroscopic ACL reconstruction alone (15 men and 1 woman). The knee injury osteoarthritis outcome score (for pain, symptoms, activities of daily living, sport and recreation function, and quality of life), range of movement, knee circumference, and analgesic use were assessed on days -1, 1, and 2, and weeks 2, 6 and 12. RESULTS: Patient demographics were similar at baseline. At postoperative days 1 and 2, all subscales of the knee injury osteoarthritis outcome score (except for quality of life) were significantly higher in the viscoseal group. At weeks 2, 6, and 12, improvement in both groups equalised. Knee swelling (change in knee circumference) was significantly less in the viscoseal group at days 1 and 2 (p=0.009 and p=0.038, respectively, Mann-Whitney U test). Only one patient in the viscoseal group had a limited range of movement. No patient developed any adverse reaction. CONCLUSION: Intra-articular viscoseal instillation improved pain control and swelling 2 days after arthroscopic ACL reconstruction. PMID- 22933672 TI - Percutaneous tension band wiring for patellar fractures. AB - PURPOSE: To evaluate outcome of percutaneous tension band wiring for transverse fractures of the patella. METHODS: 16 men and 7 women aged 27 to 65 (mean, 40) years underwent percutaneous tension band wiring for transverse fractures of the patella with a displacement of >3 mm. Pain, operating time, mobility, functional score, and complications were evaluated. RESULTS: 20 patients underwent successful percutaneous tension band wiring. The remaining 3 patients in whom closed reduction failed underwent open reduction and tension band wiring. The mean operating time was 46 (range, 28-62) minutes. The mean follow-up period was 20 (range, 15-30) months. At the latest follow-up, all patients had regained full extension. The objective score was excellent in 20 patients and good in 3, whereas the subjective score was excellent in 17, good in 5, and fair in one. All patients had radiological union at week 8. One patient had patellofemoral arthritis (secondary to a postoperative articular step). Two patients developed superficial infections, which resolved after antibiotic therapy. Mean thigh muscle wasting was 0.7 (range, 0.4-1) cm. Three patients encountered hardware problems (impingement/irritation of the skin over the knee) necessitating implant removal. CONCLUSION: Percutaneous tension band wiring is a viable option for transverse fractures of the patella. PMID- 22933673 TI - Screw and wire fixation for Lisfranc fracture dislocations. AB - PURPOSE: To assess mid-term outcome of screw and wire fixation for Lisfranc fracture dislocations to determine the risk factors of post-traumatic arthritis. METHODS: 15 men and 4 women aged 21 to 58 (mean, 41) years with Lisfranc fractures underwent open/ closed reduction and internal fixation (using screw and wire). Fractures were classified as homolateral (n=7), isolated (n=7), and divergent (n=5). Six patients had open fractures; 8 patients injured 5 tarsometatarsal joints; and 6 patients had pure ligamentous injury. Outcome (pain, function, and cosmesis) was assessed using the Maryland foot score and the American Orthopedic Foot and Ankle Society (AOFAS) score. Weight-bearing radiographs were evaluated for non-union, subluxation, malalignment, and post traumatic arthritis. RESULTS: Patients were followed up for 24 to 40 (mean, 30) months. Patients with anatomic reduction (n=14) achieved higher mean AOFAS foot score (79.3 vs. 67.5, p=0.0007) and Maryland foot score (80.4 vs. 69.4, p=0.0009) than did patients with non-anatomic reduction (n=5). Post-traumatic arthritis occurred significantly more often in patients with non-anatomic than anatomic reduction (3/5 vs. 1/14, p=0.037). Four patients developed post-traumatic arthritis, one of whom also developed lateral subluxation after implant removal. Two patients developed flat foot. Two patients had severe symptoms that limited function, one of whom underwent an arthrodesis. Two patients with compound fractures developed superficial infections. Three patients had broken screws. CONCLUSION: Anatomic reduction is the main predictor of outcome in patients with Lisfranc fracture dislocations. PMID- 22933674 TI - Conservative treatment for juvenile osteochondritis dissecans of the talus. AB - PURPOSE: To assess outcome of 6 juvenile patients with osteochondritis dissecans (OCD) of the ankle treated conservatively. METHODS: Records of 4 males and one female aged 10.8 to 14.1 (mean, 12.3) years who underwent cast immobilisation and/or restriction of physical activities for OCD of the talus (4 on the left and 2 on the right) were reviewed. OCD lesions were graded using the Berndt and Harty classification. Functional outcome was assessed using the ankle-hindfoot score of the American Orthopaedic Foot and Ankle Society. Clinical and radiographic outcomes were assessed according to the Higuera classification. RESULTS: The mean follow-up period was 30.5 (range, 11-63) months. The mean ankle-hindfoot score was 90 (range, 86-100). Radiological resolution of OCD was noted in 2 ankles, although all ankles showed some degree of healing. All patients had resolution of pain after a mean of 7 (range, 3-12) months. According to the Higuera classification, clinical outcome was excellent in one and good in 5 ankles, whereas radiological outcome was excellent in 2, good in 2, and fair in 2 ankles. In one patient, the OCD of the right posteromedial talar dome resolved spontaneously. CONCLUSION: Almost all patients achieved good functional outcome after conservative management, regardless of the presence of radiological evidence of healing. Surgery should only be performed if the OCD is unstable. PMID- 22933675 TI - Rates of pin site infection during distraction osteogenesis based on monthly observations: a pilot study. AB - PURPOSE: To assess the monthly rates of infection of individual pin sites in 7 patients during distraction osteogenesis. METHODS: Five men and 2 women aged 15 to 35 (mean, 23) years underwent distraction osteogenesis for 8 tibias using the Ilizarov ring external fixator or Taylor Spatial Frame. Patients were taught to perform standard daily pin site care at home, and were evaluated monthly for pin site infection by a single observer using a standardised grading system. RESULTS: Of 1334 observations made on 110 pin/wire sites, there were 83 (6%) pin site infections; 44 (3%) were grade 1 and 39 (3%) were grade 2. The risk of infection was higher at half pin than wire sites. The highest rates occurred in the distal segment. CONCLUSION: Monthly evaluation of individual pin sites enables comparison between studies. PMID- 22933676 TI - Distraction osteogenesis using a monolateral external fixator for infected non union of the femur with bone loss. AB - PURPOSE: To review records of 15 patients who underwent distraction osteogenesis/bone transport using a monolateral external fixator for infected non union of the femoral shaft. METHODS: 13 men and 2 women aged 18 to 47 years underwent adequate debridement and resection of nonviable bone, followed by bone transport using a monolateral external fixator for infected non-union of the femoral shaft with bone loss. All patients had a bone defect of >5 cm. The lengthening index, radiographic consolidation index, functional status, bone healing, and various problems, obstacles and complications encountered during the treatment were assessed. RESULTS: The patients had undergone a mean of 2.9 (range, 1-7) surgical procedures before presentation. The mean duration from trauma to presentation was 7.7 (range, 6-18) months. The mean bone defect after adequate resection/debridement was 7.9 (range, 5.5-17) cm. The mean treatment duration was 7.3 (range, 5-15) months. The mean lengthening index was 12.3 (range, 11.5-15) days/cm. The mean treatment index was 27.9 (range, 24-40) days/cm. The mean follow-up duration was 19.3 (range, 15-41) months. Functional outcome was excellent in 5, good in 8, and fair in 2 patients. All patients achieved bone union and eradication of infection. Bone healing was excellent in 12 and good in 3 patients. All the patients were satisfied with the procedure. None had neurovascular complications, joint subluxations, or refracture of the regenerated bone. True complications encountered included knee stiffness (n=6) and knee flexion contracture (n=1). Three patients with an initial bone defect of >10 cm had delayed union and underwent bone grafting. CONCLUSION: Bone transport using a monolateral external fixator is safe and effective for treating infected non-union of the femoral shaft. PMID- 22933677 TI - Fixation using cannulated screws and fibular strut grafts for fresh femoral neck fractures with posterior comminution. AB - PURPOSE: To evaluate the use of fibular grafting for fresh femoral neck fractures with posterior comminution. METHODS: 18 women and 15 men aged 20 to 60 years underwent osteosynthesis and fibular strut grafting supplemented with 7.0-mm cannulated hip screws for Garden grades III (n=21) and IV (n=12) femoral neck fractures associated with posterior comminution. All fractures were reduced by closed methods, and no hip was aspirated. Clinical and radiological outcomes were evaluated. RESULTS: The mean delay in presentation after injury was 3.2 (range, 1 12) days. The mean delay in operation was 8.8 (range, 5-21) days. The mean follow up period was 2 (range, 1-4) years. According to the Harris hip score, outcome was good to excellent in 20 patients, fair in 7, and poor in 6. 27 of the 33 patients achieved bone union after a mean of 4.7 (range, 4.2-7) months. In 5 patients, the bone was united with a mean of 10o of varus collapse and a mean of 1 cm of shortening. Six patients had non-union. Other complications included screw migration in the joint space (n=1), graft migration into the joint space (n=3), and screw pullout (n=5). No patient had avascular necrosis of the femoral head. CONCLUSION: Osteosynthesis and fibular grafting for freshly displaced femoral neck fractures with posterior comminution is an inexpensive and technically less demanding procedure for retaining a stable, painless, mobile, and functional hip. PMID- 22933678 TI - Venous thromboembolism in Japanese patients with fractures of the pelvis and/or lower extremities using physical prophylaxis alone. AB - PURPOSE: To investigate the rate of venous thromboembolism (VTE) in Japanese patients with fractures of the pelvis and/or lower extremities using physical prophylaxis alone. METHODS: Records of 66 men and 60 women aged 15 to 95 (mean, 57) years with fractures of the pelvis and/ or lower extremities were retrospectively reviewed. They were screened for VTE based on D-dimer values. Contrast-enhanced computed tomography and/or ultrasonography were performed when the D-dimer value did not decline predictably or exceeded 20 MUg/ml even 5 days after injury or surgery. Physical prophylaxis for VTE in terms of graduated compression stockings and intermittent pneumatic compression were applied for all patients. RESULTS: Of the 126 patients, 24 were detected to have VTE (10 of 29 with multiple fractures and 14 of 97 with single fractures). Six patients were detected to have asymptomatic pulmonary thromboembolism (PTE), whereas 20 patients were detected to have deep vein thrombosis (bilaterally in 7). The rates of VTE were high in patients with multiple fractures (35%), pelvic fractures (18%), and femoral shaft fractures (50%). The rate of PTE was high in patients with pelvic fractures (12%). CONCLUSION: The rate of VTE in the Japanese patients was similar to that in western populations. Our screening method was useful for preventing fatal PTEs. Surgeons should be vigilant for VTE during the first 2 weeks after injury, especially in patients with multiple and pelvic fractures. PMID- 22933679 TI - Aneurysmal bone cysts of the vertebrae. AB - PURPOSE: To review records of 14 patients with aneurysmal bone cysts (ABCs) of the spine. METHODS: Using the Scottish Bone Tumour Registry for the period of October 1952 to November 2005, records of 9 females and 5 males aged 8 to 63 (mean, 25.3) years who had ABCs of the spine and were followed up for a mean of 7.1 years were reviewed. RESULTS: The most commonly involved site was the lumbar vertebrae (n=6), followed by the thoracic (n=4), cervical (n=3), and sacral (n=1) vertebrae. The mean duration of symptoms at presentation was 8.8 (range, 0.3-24) months. The symptoms included gradually increasing pain in the back (n=14), a palpable spinal mass (n=4), spinal deformity (n=2), and neurological deficits (n=5). All the patients underwent surgery: intra-lesional excision (curettage) without bone grafting (n=3), excision (n=7, 2 of whom had adjuvant radiotherapy), and open excisional biopsy (n=4, 2 of whom had iliac crest bone grafting). One patient with a cervical ABC underwent preoperative angiographic embolisation. Another patient with a sacral ABC underwent percutaneous sclerotherapy. Two patients had recurrence. One had recurrence within 4 months and underwent adjuvant radiotherapy; another had recurrence 16.8 years later and underwent repeat curettage. No major complications were encountered. CONCLUSION: Most ABCs of the spine occurred in young females. Intra-lesional excision was an effective treatment. PMID- 22933680 TI - The male osteoporosis risk estimation score and the osteoporosis self-assessment screening tool for Indonesian men. AB - PURPOSE: To evaluate the male osteoporosis risk estimation score (MORES) and the osteoporosis self-assessment screening tool (OST) score as a means of screening for osteoporosis in men. METHODS: Records of 113 Indonesian men aged 50 to 91 (mean, 71) years who underwent evaluation of bone mineral density (T-score) using Dual-energy X-ray absorptiometry were retrospectively reviewed. The MORES was determined by 3 osteoporosis risk factors: age (in years), body weight (in kg), and chronic obstructive pulmonary disorder. A MORES of >=6 indicated osteoporosis and corresponded to a T-score of <=-2.5. The OST score was calculated as body weight (in kg) minus age (in years) multiplied by 0.2. An OST score of <=2 indicated osteoporosis and corresponded to a T-score of <=-2.5. Sensitivity, specificity, and positive and negative predictive values of the MORES and the OST score were determined. RESULTS: Respectively for the MORES and the OST score, sensitivity values were 100% and 74%, specificity values were 7% and 41%, positive predictive values were 25% and 28%, and negative predictive values were 100% and 83%. Using receiver operating characteristic curves, the area under curve was 0.535 for the MORES and 0.574 for the OST score. CONCLUSION: The MORES and the OST score should be used together to screen for osteoporosis in men. PMID- 22933681 TI - Correlation between a bone resorption marker and structural geometry of the proximal femur in osteoporotic women treated with raloxifene. AB - PURPOSE: To assess correlations between a bone resorption marker and the structural geometry of the proximal femur in raloxifene-treated postmenopausal women with osteoporosis. METHODS: 45 postmenopausal, osteoporotic women aged 57 to 79 (mean, 67) years underwent raloxifene treatment (60 mg/day) for 12 months. Serum type-I collagen crosslinked N-telopeptide (sNTX) as the bone resorption marker was measured at baseline and 6 months, whereas hip structure analysis (HSA) parameters of the femur (neck, intertrochanter, and shaft) were measured at baseline and 12 months using dual energy X-ray absorptiometry. The HSA parameters included areal bone mineral density (BMD), inner diameter, mean cortical thickness, cross-sectional area, section modulus, and buckling ratio. Correlations between sNTX and HSA parameters were analysed using Pearson's R. RESULTS: At baseline, sNTX correlated inversely with BMD, cross-sectional area, mean cortical thickness, and section modulus, and positively with buckling ratio in the intertrochanter and shaft (but not the neck). These correlations were significant both crude and adjusted for age. After 12 months of raloxifene treatment, HSA parameters improved significantly for the intertrochanter and shaft only. Of the 3 femoral sites, only the change in sNTX at month 6 correlated positively with changes in the inner diameter at the intertrochanter at month 12 (r=0.303, p=0.045 adjusted for age). Changes in sNTX did not correlate with changes in any other parameters. CONCLUSION: The surrogate markers for hip fracture including sNTX, BMD, and HSA parameters correlated significantly with each other. Improvement (decrease) of sNTX indicated reduction in bone resorption. PMID- 22933682 TI - Mycobacterium marinum infection of the hand and wrist. AB - PURPOSE: To review records of 166 patients who underwent treatment for Mycobacterium marinum tenosynovitis of the hand and wrist to identify factors associated with functional outcome. METHODS: Records of 97 men and 69 women aged 13 to 85 (mean, 50) years who underwent treatment for suspected M marinum tenosynovitis of the hand and wrist were retrospectively reviewed. All underwent open biopsy; synovectomy was performed when florid synovitis was present. Rifampicin and ethambutol were usually prescribed. Clarithromycin, minocycline and/or levofloxacin were used as adjuvants if there was drug intolerance, allergy, or relapse. The duration of antibiotic treatment depended on the clinical recovery. Patients were followed up for one year after completion of drug treatment. Functional outcome was considered excellent for those with >195o total active motion (TAM) and >75% return of motion, good for those with 130o to 195o TAM and 50 to 75% return of motion, fair for those with 65o to 129o TAM and 25 to 49% return of motion, and poor for those with<65o TAM and <25% return of motion. RESULTS: The mean delay in presentation was 4.9 (0.3-120) months. 93 of the patients presented with disabilities (flexion deformity or reduced range of motion), 64 of whom presented one month after injury. 37 (22%) of the patients had received intralesional steroids prior to admission, 30 of whom presented one month after injury. 32 (19%) patients were treated with antibiotics alone, whereas 134 (81%) patients underwent debridement in addition to antibiotic treatment. The mean duration of antibiotic treatment was 7.2 (range, 0-29) months. Of the 156 patients who completed the follow-up, functional outcome was satisfactory in 128 (82%) and unsatisfactory in 28 (17%). Steroid injections and late presentation led to worse functional outcome. Patients with unsatisfactory outcome were more likely to have received intralesional steroid injections (43% [16/37] vs. 10% [12/118], p<0.001, Pearson Chi squared test), have presented >2 months after injury (27% [21/79] vs. 9% [7/77], p=0.004, Pearson Chi squared test), and have undergone synovectomy (23% [28/124]) vs. 0% [0/32], p=0.001, Fisher's exact test). Worse functional outcome correlated with late presentation (r=0.218) and the greater number of debridement procedures (r=0.453). CONCLUSION: Delayed antibiotic treatment of M marinum infections and steroid injections were associated with unsatisfactory outcome. Clinicians must have a high index of suspicion for this condition and avoid inappropriate management such as intralesional steroid injections. Public awareness to this condition should be raised. PMID- 22933683 TI - Arthroscopic synovectomy for rheumatoid wrists and elbows. AB - PURPOSE: To evaluate the treatment outcome of wrist and elbow arthroscopic synovectomy for patients with rheumatoid arthritis. METHODS: 3 men and 18 women aged 27 to 71 (mean, 54) years underwent arthroscopic synovectomy for rheumatoid arthritis of the wrist (n=12) and elbow (n=13). All patients had received multiple medications including non-steroidal anti-inflammatory drugs, disease modifying anti-rheumatic drugs, and steroids, as well as physiotherapy and splintage for 6 months, but the joint pain and disability persisted. The median duration of rheumatoid arthritis was 89 (range, 24-156) and 108 (range, 36-360) months for the wrist and elbow joints, respectively. According to the Larsen grading, the radiographic stages of the wrists and elbows were classified as grade 1 (n=4+4), grade 2 (n=4+5), and grade 3 (n=4+4). Visual analogue scale for pain, the wrist and elbow flexion-extension arcs, grip strength, key pinch strength, inflammatory markers, disability and symptoms were compared pre- and post-operatively. RESULTS: The median follow-up period was 30 (range, 18-78) and 34 (range, 18-78) months for wrists and elbows, respectively. There was significant improvement in pain, joint motion, inflammatory markers, and disability score. All patients were satisfied with the surgery. There was no neurovascular or wound complication. No patient was taking longterm pain-control drugs. One patient underwent a second arthroscopic synovectomy after 15 months owing to exacerbation of arthritis. CONCLUSION: Arthroscopic synovectomy is recommended for patients with rheumatoid arthritis who fail conservative treatment. PMID- 22933684 TI - Kirschner wire fixations for scapholunate dissociation: a cadaveric, biomechanical study. AB - PURPOSE: To compare 5 different Kirschner wire fixation techniques in terms of the failure loads seen as scapholunate (SL) dissociation in a cadaveric, biomechanical study. METHODS: 10 fresh-frozen, finger-amputated wrists with sectioned SL ligaments from 3 male and 2 female cadavers were tested. The change of SL angle, SL dissociation, and the load to failure of the 5 different Kirschner wire fixation techniques (using 1.4-mm Kirschner wires) were compared using an axial loading testing machine. The techniques were: (1) SL fixation (using one wire), (2) SL fixation (using 2 wires), (3) SL and scaphocapitate (SC) fixation, (4) SL, SC, and capitolunate (CL) fixation, and (5) CL fixation alone. RESULTS: There was no significant difference between SL fixations using one or 2 wires. The force for SL dissociation was significantly greater in the SL-SC fixation than the SL fixation using one wire (p=0.003). The SL-SC-CL fixation was not significantly stronger than the SL-SC fixation. CONCLUSION: The SL-SC fixation achieved adequate stabilisation of both carpal rows with minimal biological impairment. PMID- 22933685 TI - Magnetic resonance arthrography for assessing severity of glenohumeral labroligamentous lesions. AB - PURPOSE: To compare magnetic resonance (MR) arthrography and arthroscopy as a means of assessing the severity of labral tear in anterior glenohumeral instability. METHODS: 52 patients presenting with traumatic recurrent anterior shoulder instability were evaluated using MR arthrography; 30 shoulders with a labroligamentous lesion were treated with arthroscopic Bankart repair. Their MR arthrographic images were interpreted by 3 senior musculoskeletal radiologists, and a radiological diagnosis was reached by consensus. The sensitivity and positive predictive values of MR arthrography for detecting a labral tear were determined. Agreement between MR arthrography and arthroscopy in terms of the width and depth of the labral tear was analysed. RESULTS: On arthroscopy, a labroligamentous lesion (Bankart lesion and its variants) was present in all the 30 shoulders. Agreement between the MR arthrography and arthroscopy in terms of the width and depth of the labral tears was good. CONCLUSION: MR arthrography is an accurate means of assessing the severity of anterior labroligamentous lesions and yields a good correlation with arthroscopy. PMID- 22933686 TI - Review article: Risk factors of infection following total knee arthroplasty. AB - 22 PubMed articles in English were identified using the key words: 'risk factors', 'infection', and 'primary total knee arthroplasty (TKA)'. The 10 most relevant articles were reviewed. In one study, obesity and diabetes were considered risk factors for infection following TKA. In another study, postoperative infection correlated with a history of open reduction and internal fixation, male gender, remnants of previous internal fixation material, and body mass index. In yet another study, the risk factors were (in decreasing order of significance): congestive heart failure, chronic pulmonary disease, preoperative anaemia, diabetes, depression, renal disease, pulmonary circulation disorders, obesity, rheumatologic disease, psychoses, metastatic tumour, peripheral vascular disease, and valvular disease. PMID- 22933687 TI - Unicameral bone cyst of the scaphoid: a report of two cases. AB - Unicameral bone cysts are benign, fluid-filled lesions that occur mostly in long bones (proximal humerus, 50-60%; femur, 30%) of male children aged 5 to 15 years. Occurrence in the scaphoid of an adult is rare. We report 2 such patients who presented with wrist pain, with and without a history of trauma. Both underwent curettage and bone grafting (harvested from the distal radius) and achieved good functional recovery. PMID- 22933688 TI - Impaction-fracture of the capitate and lunate: a case report. AB - We report a 15-year-old girl who underwent a mid-carpal fusion for undiagnosed impaction-fractures of the capitate, lunate, and triquetrum after a fall on her outstretched left hand in a dorsiflexed and radially deviated position. The joint was dis-impacted, and the height of the lunate was restored using a cortical bone graft. The damaged proximal capitate articular surface was decorticated to facilitate fusion, as was the lunotriquetral articulation. Kirschner wires were inserted along the coronal plane. At the one-year follow-up, the patient had achieved a satisfactory range of motion and fusion of the capitate-lunate triquetral articulations. PMID- 22933689 TI - Double clavicular fractures associated with scapular neck and coracoid process fractures. AB - We report a 38-year-old man with a combination of fractures in his left shoulder involving the middle and distal clavicle, the scapular neck, and the coracoid process, associated with scapulothoracic dissociation and an upper brachial plexus injury. The middle clavicular fracture was fixed with a plate, whereas the distal clavicular fracture was fixed with tension band wiring. Internal fixation for fractures of the scapular neck and coracoid process was not performed, as they were in an acceptable position after fixation of the clavicular fractures. At the 14-month follow-up, the range of motion of the left elbow, the wrist, and all fingers had recovered fully, whereas that of the left shoulder was limited to 35o abduction, 20o flexion, and 20o external rotation. The strength of the left shoulder abduction, flexion, and external rotation was M2. Elbow flexion, wrist extension, and finger extension strength had recovered to normal (M5). Sensation corresponding to the C5-6 dermatome had also improved to almost normal. PMID- 22933690 TI - Cauda equina syndrome following sacral fractures: a report of three cases. AB - We report 3 patients with cauda equina syndrome (CES) secondary to a sacral fracture. The difficulty in early diagnosis of CES and the lack of evidence and guidance on treatment are highlighted. When there is a sacral fracture, CES should be suspected. Thorough clinical examination including digital rectal examinations and bladder function quantification is advised. The threshold for performing computed tomography and/or magnetic resonance imaging of the pelvis should be low. Patients should be treated by a multi-disciplinary team with both orthopaedic and neurosurgical input. Further studies are needed to identify the timing and to which patients surgical decompression should be performed. PMID- 22933691 TI - Calcium pyrophosphate dihydrate crystal deposition of multiple lumbar facet joints: a case report. AB - Pseudogout of the lumbar facet joints is rare. We report on a 69-year-old woman with 2-level symptomatic synovial cysts of the facet joints caused by calcium pyrophosphate dihydrate crystal deposition. She underwent surgical decompression for sciatica and low back pain. At one-year follow-up, she had recovered completely. PMID- 22933692 TI - A glass foreign body migrating into the lumbar spinal canal: a case report. AB - We report on a 12-year-old boy in whom a glass fragment migrated into the lumbar spinal canal causing low back pain and radiculopathy 6 years after injury. Computed tomography showed a foreign body in the anterior spinal canal of L5/S1. The patient underwent recapping T-saw laminoplasty to remove the foreign body. Scar formation was noted at the anterior dura. The glass fragment seemed to have penetrated into the intradural space from an anterior site. Postoperatively, the pain resolved immediately. At the 9-year follow-up, the alignment of the lumbar spine and healing of L5 was good, with no features of aseptic necrosis. PMID- 22933693 TI - Bilateral subcapital femoral neck fractures secondary to transient osteoporosis during pregnancy: a case report. AB - Transient osteoporosis during pregnancy is a rare, self-limiting disease. We report on a 36-year-old woman who had bilateral subcapital femoral neck fractures during the 6th month of pregnancy. The diagnosis was made 4 days after delivery, because radiography was declined by the patient for fear of radiation. Fixation was not feasible owing to bone resorption, and 2-stage bipolar hemiarthroplasty was therefore performed. Magnetic resonance imaging is the best non-invasive investigative tool for pregnant women with hip pain. Early detection can prevent complications and resorting to major surgeries. PMID- 22933694 TI - Mating of a PROSTALAC spacer with an intramedullary nail for reconstruction of an infected interprosthetic femoral shaft fracture: a case report. AB - Reconstruction for concurrent infection of an ipsilateral total hip arthroplasty (THA) and total knee arthroplasty (TKA) is a challenge. We report a 2-stage reconstruction of a THA for chronic infection of both the THA and TKA with severe femoral bone loss secondary to interprosthetic fractures. The reconstruction involved using a custom-made, temporary, antibiotic-impregnated PROSTALAC spacer mated with an intramedullary nail. The acetabulum was then exposed and the necrotic cartilage was removed and curetted. The acetabulum was reamed to accept a PROSTALAC acetabular shell. The shell was cemented into the acetabulum with antibiotic cement. The custom-made spacer was then inserted distally first into the tibia. The distal end of the intramedullary nail was interlocked with a bicortical bolt to minimise nail rotation. Antibiotic-impregnated cement was moulded around the nail and spacer. The proximal end of the spacer was then reduced into the acetabular socket, and the joint was irrigated and the wound closed. A customised abduction brace was fitted, and partial weight bearing was allowed. Sufficient leg length, soft-tissue tension, and range of hip motion were restored, and a total femur and constrained liner was re-implanted 4 months later. Mating of an intramedullary nail with a PROSTALAC spacer is a viable reconstructive option. PMID- 22933695 TI - Shelf syndrome of the knee in elderly people: a report of three cases. AB - Shelf syndrome occurs mainly in younger people (particularly athletes) and rarely in elderly people. We report on 3 elderly patients with a medial synovial plica causing severe pain and locked knees. They had had no symptoms in their early or middle life. After removal of the shelf, the symptoms improved considerably. Although shelf syndrome is rare in the elderly, it should be suspected whenever severe pain and a locked knee are present. PMID- 22933696 TI - Septic arthritis of the knee associated with calf abscess. AB - Septic arthritis associated with extra-articular abscess is rare. We report on 2 non-rheumatic patients with septic arthritis of the knee associated with calf abscess. Magnetic resonance imaging showed a distinct leakage pathway from the knee joint in each patient. One was a ruptured popliteal cyst (posteromedial). Another was a pathologic popliteus hiatus (posterolateral). These patients underwent open drainage of the calf abscess via a small incision, followed by arthroscopic debridement of the knee. Careful palpation of the lower leg, followed by magnetic resonance imaging and needle aspiration, is important to exclude a possible extra-articular abscess regardless of the presence of a popliteal cyst. PMID- 22933697 TI - Portal vein thrombosis after total knee replacement: a case report. AB - We present a 74-year-old woman who developed a portal vein thrombosis following an elective total knee replacement. She had atrial fibrillation for which she was taking warfarin for anticoagulation. Seven days prior to surgery, she was instructed to discontinue warfarin and replace it with prophylactic low-molecular weight heparin. On postoperative day 1, routine blood tests revealed deranged hepatic synthetic function, despite standard anticoagulation management. Doppler ultrasonography confirmed a portal vein thrombosis. She was treated with therapeutic doses of low-molecular-weight heparin until her international normalised ratio reached therapeutic levels. Her liver function results had normalised 2 weeks later. Portal vein thrombosis is a potentially fatal complication that is reversible if identified and treated early. PMID- 22933698 TI - Using science to advance wound care practice: lessons from the literature. AB - Wound care professionals can improve clinical, patient-oriented wound outcomes and do so cost-effectively by using scientific evidence to meet patient and wound care goals and needs. A review of the literature was conducted to define evidence based wound management, describe the potential of science to improve outcomes in wound care, and summarize strategies, tactics, and tools for wound care providers and recipients to utilize science to their mutual benefit. In addition, changes in the availability of randomized and nonrandomized and clinical and preclinical evidence during the past 50 years were examined using MEDLINE database searches of English-language publications, combining the search terms wound, ulcer, or burn limited by the terms randomized or clinical for each decade since 1960. The number of published, nonrandomized wound studies has increased exponentially during the last five decades but, more recently, evidence from randomized controlled trials also has become available. Moreover, while many questions remain unanswered, a substantial number of publications have shown the use of available evidence-based guidelines and wound care strategies improves outcomes of care while saving time and money. The application of science-based wound care in clinical practice is increasing slowly; expensive techniques supported by limited or inconsistent evidence are still in use and add to wound care costs without certainty they improve outcomes. The literature provides compelling evidence that patients with a wide variety of diagnoses benefit when opinion based care is replaced by clinical wisdom applied on a substrate of best available evidence. Patients with wounds deserve no less. PMID- 22933699 TI - Content validation of algorithms to guide negative pressure wound therapy in adults with acute or chronic wounds:a cross-sectional study . AB - Despite extensive use of negative pressure wound therapy (NPWT) and reported patient safety concerns, evidence-based algorithms to guide its safe and appropriate use in various wounds have only recently been developed. Preliminary content validity was established using literature review and expert-based face validity with a small sample of experts (N = 12). To examine the content validity of this set of three NPWT algorithms and to enhance understanding about previously identified wound terminology issues, a cross-sectional, mixed-methods, quantitative study was conducted among wound experts. The paper/pencil survey instrument consisted of the algorithms, a demographic questionnaire, and request to provide definitions of five commonly used terms: acute wound, chronic wound, and primary, secondary, and tertiary intention healing. A Likert scale (range 1 to 4) was included to rate the relevance of each of the 34 unique steps/statements/decision points contained in the algorithms, and space was provided to comment on each component. Convenience-sampling methods were used in three different settings: an international professional wound care meeting; a regional wound, ostomy, continence (WOC) nurses meeting; and an urban university with a suburban satellite campus. Of the 190 wound care experts invited to participate, 114 accepted. Participants' average age was 48 (range 23 to 68) years, and most were registered nurses (72%) practicing in the United States (94%). The content validity of the NPWT components was strong, with an overall mean rating of 3.76 (SD = 0.56, range 3.49 to 3.92; very relevant/appropriate, relevant/appropriate). The overall content validity index for the 5,696 responses received was 0.96 (range 0.88 to 1.0). Qualitative themes included comments about wound terminology and definitions, the presentation of the central algorithm, reading level, helpfulness/ease of use, the use of color, and information placement in the algorithm document. Some consensus on wound definitions was observed, but results also confirmed that important disparities in mutual understanding of what constitutes acute versus chronic wounding remain. Commonly used surgical closure definitions of primary, secondary, tertiary intention also were not clearly or correctly understood by a substantial number of participants. These NPWT algorithms are the first evidence-based, content validated algorithms developed for a variety of acute and chronic wounds in adult patients. Future research is needed to test whether they facilitate safe patient care in clinical practice. PMID- 22933700 TI - A mechanically powered negative pressure device used in conjunction with a bioengineered cell-based product for the treatment of pyoderma gangrenosum: a case report . AB - Pyoderma gangrenosum (PG), an uncommon inflammatory and ulcerative skin disease, typically is treated medically with a combination of immunosuppression and local wound care, but evidence to guide care is limited. PG wounds can be difficult to heal. A 76-year-old male patient presented with a history of rheumatoid arthritis and recalcitrant PG. After 9 months of treatment with local wound care, steroids, and topical tacrolimus, the wound had increased in size from 1.8 cm x 1.5 cm to 7.2 cm x 5.6 cm. At that time, he was started on a regimen of five applications of a bioengineered cell- based product (one application every 2 weeks for a total of five applications) with twice-weekly mechanically powered negative pressure device changes. The latter was started at 75 mm Hg and changed to 125 mm Hg after 4 weeks. Oral corticosteroid therapy was initially started at 40 mg of prednisone, then slowly tapered to 20 mg, but could not be completely discontinued due to a flare in the patient's rheumatoid symptoms. The wound was completely healed after 16 weeks. Research to ascertain the effectiveness of protocols of PG care, including the combination treatment described, is needed to help clinicians provide evidence-based care for these challenging wounds. PMID- 22933701 TI - Efficacy of a bio-electric dressing in healing deep, partial-thickness wounds using a porcine model . AB - Numerous physical modalities have been used in attempts to augment the healing process, including ultrasound, low- energy light therapy, and electrical stimulation (ES). ES has been shown to benefit tissue repair in a variety of wound types, but variations in study designs, administration, and parameters render its application in clinical practice somewhat unconventional. A dressing was designed to generate an electric potential of 0.6 V to 0.7 V in the presence of moisture, thereby delivering a sustained micro-current without the need for an external power source. The purpose of this study was to examine the effects of this bio-electric dressing (BED) on deep, partial-thickness wounds using six female specific pathogen-free animals and a well established porcine model for wound healing. Wounds (10 mm x 7 mm x 0.5 mm) were created in paravertebral and thoracic areas of these animals using a specialized electrokeratome and covered with the active polyester BED and a polyurethane film dressing (n = 30) (treatment) or an inactive polyester and film dressing (n = 30). Using an epidermal migration assay, wounds were assessed daily from day 4 through day 8 post-wounding. Differences in the proportion of wounds healed were statistically significant (P <0.001) on days 5 and 6 post-wounding. These results show BED is more effective than a control dressing treatment with moisture-retentive dressings in this animal model. Controlled clinical studies are warranted to elucidate the potential clinical implications of this treatment modality. PMID- 22933702 TI - Loss of the malignant phenotype of human neuroblastoma cells by a catalytically inactive dominant-negative hTERT mutant. AB - Telomerase, a ribonucleoprotein complex mainly composed of the reverse transcriptase catalytic subunit (human telomerase reverse transcriptase, hTERT) and the RNA component (hTR), is a key enzyme of cancer progression. That aggressive stage 4-neuroblastoma expressed high levels of telomerase activity, whereas favorable tumors had no or little telomerase expression and activity, prompted us to investigate the role of this enzyme in this tumor model of altered proliferation, neuronal differentiation, and apoptosis. A human MYCN-amplified neuroblastoma cell line (IGR-N-91) was engineered to stably express either the normal hTERT protein (WT-hTERT) or a catalytically inactive dominant-negative mutant of this protein (DN-hTERT). We showed that DN-hTERT expression inhibited the endogenous hTERT in the malignant neuroblasts without telomere shortening nor loss of in vitro proliferative capacity. Importantly, DN-hTERT expression induced major changes in cell morphology of neuroblasts that switched them from a neuronal to a substrate adherent phenotype, which was more prone to apoptosis and lost their tumorigenic properties in nude mice. These biologic effects arose from modifications in the expression of genes involved in both apoptosis and neuroblastoma biology. Taken together these results highlighted the functional relevance of noncanonical functions of hTERT in the determination of neuroblast cell fate. Therefore, our results envision new therapeutic strategies for metastatic neuroblastoma therapeutic management. PMID- 22933703 TI - Perillyl alcohol for the treatment of temozolomide-resistant gliomas. AB - Perillyl alcohol (POH) is a monoterpene that has been used orally for the treatment of systemic cancer. However, when used orally significant gastrointestinal side effects and lack of overall efficacy were documented. Recently, in a phase II trial in Brazil for the treatment of temozolomide (TMZ) resistant malignant gliomas, POH was well tolerated when administered intranasally. The present study explores the effects and mechanisms of POH on TMZ sensitive and TMZ-resistant glioma cells. In vitro studies showed that POH was cytotoxic to TMZ-resistant as well as TMZ-sensitive glioma cells, and this effect was independent of O(6)-methylguanine-DNA methyltransferase expression. POH induced cytotoxicity, in part, through the endoplasmic reticulum (ER) stress pathway as shown by the increased expression of glucose-regulated protein-78 (GRP78), activating transcription factor 3, and C/EBP-homologous protein. In addition, POH impeded survival pathways, such as mTOR and Ras. As well, POH reduced the invasive capacity of sensitive and resistant glioma cells. POH alone and/or in combination with other ER stress-inducing cytotoxic drugs (i.e., 2, 5 dimethyl-celecoxib, nelfinavir) further induced apoptosis in TMZ-sensitive and TMZ-resistant glioma cells. To show whether intranasal delivery of POH was effective for the treatment of TMZ-resistant gliomas, animals bearing intracranial tumors were given POH intranasally. Animals treated through intranasal administration of POH exhibited a decrease in tumor growth and an increase in survival. Our data show that POH is an effective anti-glioma cytotoxic agent for TMZ-resistant gliomas when administered intranasally. PMID- 22933704 TI - Evaluating the therapeutic potential of a non-natural nucleotide that inhibits human ribonucleotide reductase. AB - Human ribonucleotide reductase (hRR) is the key enzyme involved in de novo dNTP synthesis and thus represents an important therapeutic target against hyperproliferative diseases, most notably cancer. The purpose of this study was to evaluate the ability of non-natural indolyl-2'-deoxynucleoside triphosphates to inhibit the activity of hRR. The structural similarities of these analogues with dATP predicted that they would inhibit hRR activity by binding to its allosteric sites. In silico analysis and in vitro characterization identified one particular analogue designated as 5-nitro-indolyl-2'-deoxyribose triphosphate (5 NITP) that inhibits hRR. 5-NITP binding to hRR was determined by isothermal titration calorimetry. X-ray crystal structure of 5-NITP bound to RR1 was determined. Cell-based studies showed the anti-cancer effects of the corresponding non-natural nucleoside against leukemia cells. 5-NITP binds to hRR with micromolar affinity. Binding does not induce hexamerization of hRR1 like dATP, the native allosteric inhibitor of hRR that binds with high affinity to the A-site. The X-ray crystal structure of Saccharomyces cerevisiae RR1-5-NITP (ScRR1 5-NITP) complex determined to 2.3 A resolution shows that 5-NITP does not bind to the A-site but rather at the S-site. Regardless, 5-nitro-indolyl-2' deoxynucleoside (5-NIdR) produces cytostatic and cytotoxic effects against human leukemia cells by altering cell-cycle progression. Our studies provide useful insights toward developing new inhibitors with improved potency and efficacy against hRR. PMID- 22933705 TI - Stromal platelet-derived growth factor receptor alpha (PDGFRalpha) provides a therapeutic target independent of tumor cell PDGFRalpha expression in lung cancer xenografts. AB - In lung cancer, platelet-derived growth factor receptor alpha (PDGFRalpha) is expressed frequently by tumor-associated stromal cells and by cancer cells in a subset of tumors. We sought to determine the effect of targeting stromal PDGFRalpha in preclinical lung tumor xenograft models (human tumor, mouse stroma). Effects of anti-human (IMC-3G3) and anti-mouse (1E10) PDGFRalpha monoclonal antibodies (mAb) on proliferation and PDGFRalpha signaling were evaluated in lung cancer cell lines and mouse fibroblasts. Therapy studies were conducted using established PDGFRalpha-positive H1703 cells and PDGFRalpha negative Calu-6, H1993, and A549 subcutaneous tumors in immunocompromised mice treated with vehicle, anti-PDGFRalpha mAbs, chemotherapy, or combination therapy. Tumors were analyzed for growth and levels of growth factors. IMC-3G3 inhibited PDGFRalpha activation and the growth of H1703 cells in vitro and tumor growth in vivo, but had no effect on PDGFRalpha-negative cell lines or mouse fibroblasts. 1E10 inhibited growth and PDGFRalpha activation of mouse fibroblasts, but had no effect on human cancer cell lines in vitro. In vivo, 1E10-targeted inhibition of murine PDGFRalpha reduced tumor growth as single-agent therapy in Calu-6 cells and enhanced the effect of chemotherapy in xenografts derived from A549 cells. We also identified that low expression cancer cell expression of VEGF-A and elevated expression of PDGF-AA were associated with response to stromal PDGFRalpha targeting. We conclude that stromal PDGFRalpha inhibition represents a means for enhancing control of lung cancer growth in some cases, independent of tumor cell PDGFRalpha expression. PMID- 22933706 TI - Drug resistance to inhibitors of the human double minute-2 E3 ligase is mediated by point mutations of p53, but can be overcome with the p53 targeting agent RITA. AB - The human double minute (HDM)-2 E3 ubiquitin ligase plays a key role in p53 turnover and has been validated preclinically as a target in multiple myeloma (MM) and mantle cell lymphoma (MCL). HDM-2 inhibitors are entering clinical trials, and we therefore sought to understand potential mechanisms of resistance in lymphoid models. Wild-type p53 H929 MM and Granta-519 MCL cells resistant to MI-63 or Nutlin were generated by exposing them to increasing drug concentrations. MI-63-resistant H929 and Granta-519 cells were resistant to Nutlin, whereas Nutlin-resistant cells displayed cross-resistance to MI-63. These cells also showed cross-resistance to bortezomib, doxorubicin, cisplatin, and melphalan, but remained sensitive to the small molecule inhibitor RITA (reactivation of p53 and induction of tumor cell apoptosis). HDM-2 inhibitor resistant cells harbored increased p53 levels, but neither genotoxic nor nongenotoxic approaches to activate p53 induced HDM-2 or p21. Resequencing revealed wild-type HDM-2, but mutations were found in the p53 DNA binding and dimerization domains. In resistant cells, RITA induced a G(2)-M arrest, upregulation of p53 targets HDM-2, PUMA, and NOXA, and PARP cleavage. Combination regimens with RITA and MI-63 resulted in enhanced cell death compared with RITA alone. These findings support the possibility that p53 mutation could be a primary mechanism of acquired resistance to HDM-2 inhibitors in MCL and MM. Furthermore, they suggest that simultaneous restoration of p53 function and HDM-2 inhibition is a rational strategy for clinical translation. PMID- 22933707 TI - Smoking induces epithelial-to-mesenchymal transition in non-small cell lung cancer through HDAC-mediated downregulation of E-cadherin. AB - Epidemiological studies have shown that most cases of lung cancers (85%-90%) are directly attributable to tobacco smoking. Although association between cigarette smoking and lung cancer is well documented, surprisingly little is known about the molecular mechanisms of how smoking is involved in epithelial-to-mesenchymal transition (EMT) through epigenetic changes. Here, we show that lung cancer patients with a smoking history have low E-cadherin levels and loss of E-cadherin is a poor prognostic factor in smokers. Moreover, the downregulation of E cadherin correlates with the number of pack years. In an attempt to determine the role of long-term cigarette smoking on EMT, we observed that treatment of lung cell lines with cigarette smoke condensate (CSC) induces EMT through downregulation of epithelial markers, including E-cadherin and upregulation of mesenchymal markers. CSC decreases E-cadherin expression at the transcriptional level through upregulation of LEF1 and Slug, and knockdown of these two proteins increases E-cadherin expression. Importantly, chromatin immunoprecipitation assays suggest that LEF-1 and Slug binding to E-cadherin promoter is important for CSC-mediated downregulation of E-cadherin. The histone deacetylase (HDAC) inhibitor MS-275 reverses CSC-induced EMT, migration, and invasion through the restoration of E-cadherin expression. These results suggest that recruitment of HDACs by transcriptional repressors LEF-1 and Slug is responsible for E-cadherin suppression and EMT in cigarette smokers and provide a potential drug target toward the treatment of lung cancer. PMID- 22933708 TI - Selective targeting of interferon gamma to stromal fibroblasts and pericytes as a novel therapeutic approach to inhibit angiogenesis and tumor growth. AB - New approaches to block the function of tumor stromal cells such as cancer associated fibroblasts and pericytes is an emerging field in cancer therapeutics as these cells play a crucial role in promoting angiogenesis and tumor growth via paracrine signals. Because of immunomodulatory and other antitumor activities, IFNgamma, a pleiotropic cytokine, has been used as an anticancer agent in clinical trials. Unfortunately only modest beneficial effects, but severe side effects, were seen. In this study, we delivered IFNgamma to stromal fibroblasts and pericytes, considering its direct antifibrotic activity, using our platelet derived growth factor-beta receptor (PDGFbetaR)-binding carrier (pPB-HSA), as these cells abundantly express PDGFbetaR. We chemically conjugated IFNgamma to pPB-HSA using a heterobifunctional PEG linker. In vitro in NIH3T3 fibroblasts, pPB-HSA-IFNgamma conjugate activated IFNgamma-signaling (pSTAT1alpha) and inhibited their activation and migration. Furthermore, pPB-HSA-IFNgamma inhibited fibroblasts-induced tube formation of H5V endothelial cells. In vivo in B16 tumor bearing mice, pPB-HSA-IFNgamma rapidly accumulated in tumor stroma and pericytes and significantly inhibited the tumor growth while untargeted IFNgamma and pPB HSA carrier were ineffective. These antitumor effects of pPB-HSA-IFNgamma were attributed to the inhibition of tumor vascularization, as shown with alpha-SMA and CD-31 staining. Moreover, pPB-HSA-IFNgamma induced MHC-II expression specifically in tumors compared with untargeted IFNgamma, indicating the specificity of this approach. This study thus shows the impact of drug targeting to tumor stromal cells in cancer therapy as well as provides new opportunities to use cytokines for therapeutic application. PMID- 22933709 TI - False-positive antibody signals for the pluripotency factor OCT4A (POU5F1) in testis-derived cells may lead to erroneous data and misinterpretations. AB - Octamer-binding protein 4 (OCT4) is a key player in pluripotent embryonic stem (ES) cells and is essential for the generation of induced pluripotent stem cells. Recently, several reports indicated the spontaneous recovery of pluripotency in cultured adult human testis-derived cells. This was evidenced also by the detection of OCT4 using antibodies. However, the soundness of some data was recently put into question. During our attempts to derive pluripotent cells from the common marmoset monkey (Callithrix jacchus) testis, we obtained inconsistent data which prompted us to analyze deeper the characteristics of three independent OCT4 antibodies that were used in numerous published studies that received greatest attention. All antibodies detected OCT4 by immunofluorescence (IF) in a marmoset monkey ES cell line. Two of the three OCT4 antibodies also gave robust nuclear signals in testis-derived cells. However, the latter cells expressed no OCT4 mRNA as revealed by quantitative RT-PCR and turned out to be mesenchymal cells. When tested in western blot analyses, all antibodies detected heterologously expressed marmoset monkey OCT4 protein. But, importantly, those antibodies that resulted in non-specific signals in IF also showed additional non specific bands in western blots. In summary, some commercially available OCT4 antibodies result in false-positive signals which may provoke erroneous conclusions when used in studies aiming at the generation of pluripotent cells in vitro. We conclude that (i) antibodies must be carefully characterized before use to prevent misleading observations and (ii) OCT4 expression must be monitored by a second antibody-independent method. PMID- 22933710 TI - Recent advances in plant cell nuclear signaling. PMID- 22933711 TI - Multiple calcium-dependent kinases modulate ABA-activated guard cell anion channels. PMID- 22933712 TI - The long-sought-after salicylic acid receptors. PMID- 22933713 TI - Arabidopsis transcription factor genes NF-YA1, 5, 6, and 9 play redundant roles in male gametogenesis, embryogenesis, and seed development. AB - Nuclear factor Y (NF-Y) is a highly conserved transcription factor presented in all eukaryotic organisms, and is a heterotrimer consisting of three subunits: NF YA, NF-YB, and NF-YC. In Arabidopsis, these three subunits are encoded by multigene families. The best-studied member of the NF-Y transcription factors is LEAFY COTYLEDON1 (LEC1), a NF-YB family member, which plays a critical role in embryogenesis and seed maturation. However, the function of most NF-Y genes remains elusive. Here, we report the characterization of four genes in the NF-YA family. We found that a gain-of-function mutant of NF-YA1 showed defects in male gametogenesis and embryogenesis. Consistently, overexpression of NF-YA1, 5, 6, and 9 affects male gametogenesis, embryogenesis, seed morphology, and seed germination, with a stronger phenotype when overexpressing NF-YA1 and NF-YA9. Moreover, overexpression of these NF-YA genes also causes hypersensitivity to abscisic acid (ABA) during seed germination, retarded seedling growth, and late flowering at different degrees. Intriguingly, overexpression of NF-YA1, 5, 6, and 9 is sufficient to induce the formation of somatic embryos from the vegetative tissues. However, single or double mutants of these NF-YA genes do not have detectable phenotype. Collectively, these results provide evidence that NF-YA1, 5, 6, and 9 play redundant roles in male gametophyte development, embryogenesis, seed development, and post-germinative growth. PMID- 22933714 TI - Arabidopsis thaliana AtUTr7 encodes a golgi-localized UDP-glucose/UDP-galactose transporter that affects lateral root emergence. AB - Nucleotide sugar transporters (NSTs) are antiporters comprising a gene family that plays a fundamental role in the biosynthesis of complex cell wall polysaccharides and glycoproteins in plants. However, due to the limited number of related mutants that have observable phenotypes, the biological function(s) of most NSTs in cell wall biosynthesis and assembly have remained elusive. Here, we report the characterization of AtUTr7 from Arabidopsis (Arabidopsis thaliana (L.) Heynh.), which is homologous to multi-specific UDP-sugar transporters from Drosophila melanogaster, humans, and Caenorhabditis elegans. We show that AtUTr7 possesses the common structural characteristics conserved among NSTs. Using a green fluorescent protein (GFP) tagged version, we demonstrate that AtUTr7 is localized in the Golgi apparatus. We also show that AtUTr7 is widely expressed, especially in the roots and in specific floral organs. Additionally, the results of an in vitro nucleotide sugar transport assay carried out with a tobacco and a yeast expression system suggest that AtUTr7 is capable of transferring UDP-Gal and UDP-Glc, but not a range of other UDP- and GDP-sugars, into the Golgi lumen. Mutants lacking expression of AtUTr7 exhibited an early proliferation of lateral roots as well as distorted root hairs when cultivated at high sucrose concentrations. Furthermore, the distribution of homogalacturonan with a low degree of methyl esterification differed in lateral root tips of the mutant compared to wild-type plants, although additional analytical procedures revealed no further differences in the composition of the root cell walls. This evidence suggests that the transport of UDP-Gal and UDP-Glc into the Golgi under conditions of high root biomass production plays a role in lateral root and root hair development. PMID- 22933715 TI - Evaluation of general 16S ribosomal RNA gene PCR primers for classical and next generation sequencing-based diversity studies. AB - 16S ribosomal RNA gene (rDNA) amplicon analysis remains the standard approach for the cultivation-independent investigation of microbial diversity. The accuracy of these analyses depends strongly on the choice of primers. The overall coverage and phylum spectrum of 175 primers and 512 primer pairs were evaluated in silico with respect to the SILVA 16S/18S rDNA non-redundant reference dataset (SSURef 108 NR). Based on this evaluation a selection of 'best available' primer pairs for Bacteria and Archaea for three amplicon size classes (100-400, 400-1000, >= 1000 bp) is provided. The most promising bacterial primer pair (S-D-Bact-0341-b-S 17/S-D-Bact-0785-a-A-21), with an amplicon size of 464 bp, was experimentally evaluated by comparing the taxonomic distribution of the 16S rDNA amplicons with 16S rDNA fragments from directly sequenced metagenomes. The results of this study may be used as a guideline for selecting primer pairs with the best overall coverage and phylum spectrum for specific applications, therefore reducing the bias in PCR-based microbial diversity studies. PMID- 22933716 TI - Promoter propagation in prokaryotes. AB - Transcriptional activation or 'rewiring' of silent genes is an important, yet poorly understood, phenomenon in prokaryotic genomes. Anecdotal evidence coming from experimental evolution studies in bacterial systems has shown the promptness of adaptation upon appropriate selective pressure. In many cases, a partial or complete promoter is mobilized to silent genes from elsewhere in the genome. We term hereafter such recruited regulatory sequences as Putative Mobile Promoters (PMPs) and we hypothesize they have a large impact on rapid adaptation of novel or cryptic functions. Querying all publicly available prokaryotic genomes (1362) uncovered >4000 families of highly conserved PMPs (50 to 100 long with >=80% nt identity) in 1043 genomes from 424 different genera. The genomes with the largest number of PMP families are Anabaena variabilis (28 families), Geobacter uraniireducens (27 families) and Cyanothece PCC7424 (25 families). Family size varied from 2 to 93 homologous promoters (in Desulfurivibrio alkaliphilus). Some PMPs are present in particular species, but some are conserved across distant genera. The identified PMPs represent a conservative dataset of very recent or conserved events of mobilization of non-coding DNA and thus they constitute evidence of an extensive reservoir of recyclable regulatory sequences for rapid transcriptional rewiring. PMID- 22933719 TI - Eye position effects in saccadic adaptation in macaque monkeys. AB - The saccadic amplitude of humans and monkeys can be adapted using intrasaccadic target steps in the McLaughlin paradigm. It is generally believed that, as a result of a purely retinal reference frame, after adaptation of a saccade of a certain amplitude and direction, saccades of the same amplitude and direction are all adapted to the same extent, independently from the initial eye position. However, recent studies in humans have put the pure retinal coding in doubt by revealing that the initial eye position has an effect on the transfer of adaptation to saccades of different starting points. Since humans and monkeys show some species differences in adaptation, we tested the eye position dependence in monkeys. Two trained Macaca fascicularis performed reactive rightward saccades from five equally horizontally distributed starting positions. All saccades were made to targets with the same retinotopic motor vector. In each session, the saccades that started at one particular initial eye position, the adaptation position, were adapted to shorter amplitude, and the adaptation of the saccades starting at the other four positions was measured. The results show that saccades that started at the other positions were less adapted than saccades that started at the adaptation position. With increasing distance between the starting position of the test saccade and the adaptation position, the amplitude change of the test saccades decreased with a Gaussian profile. We conclude that gain decreasing saccadic adaptation in macaques is specific to the initial eye position at which the adaptation has been induced. PMID- 22933718 TI - Cortical stimulation causes long-term changes in H-reflexes and spinal motoneuron GABA receptors. AB - The cortex gradually modifies the spinal cord during development, throughout later life, and in response to trauma or disease. The mechanisms of this essential function are not well understood. In this study, weak electrical stimulation of rat sensorimotor cortex increased the soleus H-reflex, increased the numbers and sizes of GABAergic spinal interneurons and GABAergic terminals on soleus motoneurons, and decreased GABA(A) and GABA(B) receptor labeling in these motoneurons. Several months after the stimulation ended the interneuron and terminal increases had disappeared, but the H-reflex increase and the receptor decreases remained. The changes in GABAergic terminals and GABA(B) receptors accurately predicted the changes in H-reflex size. The results reveal a new long term dimension to cortical-spinal interactions and raise new therapeutic possibilities. PMID- 22933720 TI - Neural mechanisms for predictive head movement strategies during sequential gaze shifts. AB - Humans adopt very different head movement strategies for different gaze behaviors, for example, when playing sports versus watching sports on television. Such strategy switching appears to depend on both context and expectation of future gaze positions. Here, we explored the neural mechanisms for such behaviors by training three monkeys to make head-unrestrained gaze shifts toward eccentric radial targets. A randomized color cue provided predictive information about whether that target would be followed by either a return gaze shift to center or another, more eccentric gaze shift, but otherwise animals were allowed to develop their own eye-head coordination strategy. In the first two animals we then stimulated the frontal eye fields (FEF) in conjunction with the color cue, and in the third animal we recorded from neurons in the superior colliculus (SC). Our results show that 1) monkeys can optimize eye-head coordination strategies from trial to trial, based on learned associations between color cues and future gaze sequences, 2) these cue-dependent coordination strategies were preserved in gaze saccades evoked during electrical stimulation of the FEF, and 3) two types of SC responses (the saccade burst and a more prolonged response related to head movement) modulated with these cue-dependent strategies, although only one (the saccade burst) varied in a predictive fashion. These data show that from one moment to the next, the brain can use contextual sensory cues to set up internal "coordination states" that convert fixed cortical gaze commands into the brain stem signals required for predictive head motion. PMID- 22933717 TI - Stimulus selectivity and response latency in putative inhibitory and excitatory neurons of the primate inferior temporal cortex. AB - The cerebral cortex is composed of many distinct classes of neurons. Numerous studies have demonstrated corresponding differences in neuronal properties across cell types, but these comparisons have largely been limited to conditions outside of awake, behaving animals. Thus the functional role of the various cell types is not well understood. Here, we investigate differences in the functional properties of two widespread and broad classes of cells in inferior temporal cortex of macaque monkeys: inhibitory interneurons and excitatory projection cells. Cells were classified as putative inhibitory or putative excitatory neurons on the basis of their extracellular waveform characteristics (e.g., spike duration). Consistent with previous intracellular recordings in cortical slices, putative inhibitory neurons had higher spontaneous firing rates and higher stimulus-evoked firing rates than putative excitatory neurons. Additionally, putative excitatory neurons were more susceptible to spike waveform adaptation following very short interspike intervals. Finally, we compared two functional properties of each neuron's stimulus-evoked response: stimulus selectivity and response latency. First, putative excitatory neurons showed stronger stimulus selectivity compared with putative inhibitory neurons. Second, putative inhibitory neurons had shorter response latencies compared with putative excitatory neurons. Selectivity differences were maintained and latency differences were enhanced during a visual search task emulating more natural viewing conditions. Our results suggest that short-latency inhibitory responses are likely to sculpt visual processing in excitatory neurons, yielding a sparser visual representation. PMID- 22933721 TI - Signal coding in cockroach photoreceptors is tuned to dim environments. AB - In dim light, scarcity of photons typically leads to poor vision. Nonetheless, many animals show visually guided behavior with dim environments. We investigated the signaling properties of photoreceptors of the dark active cockroach (Periplaneta americana) using intracellular and whole-cell patch-clamp recordings to determine whether they show selective functional adaptations to dark. Expectedly, dark-adapted photoreceptors generated large and slow responses to single photons. However, when light adapted, responses of both phototransduction and the nontransductive membrane to white noise (WN)-modulated stimuli remained slow with corner frequencies ~20 Hz. This promotes temporal integration of light inputs and maintains high sensitivity of vision. Adaptive changes in dynamics were limited to dim conditions. Characteristically, both step and frequency responses stayed effectively unchanged for intensities >1,000 photons/s/photoreceptor. A signal-to-noise ratio (SNR) of the light responses was transiently higher at frequencies <5 Hz for ~5 s after light onset but deteriorated to a lower value upon longer stimulation. Naturalistic light stimuli, as opposed to WN, evoked markedly larger responses with higher SNRs at low frequencies. This allowed realistic estimates of information transfer rates, which saturated at ~100 bits/s at low-light intensities. We found, therefore, selective adaptations beneficial for vision in dim environments in cockroach photoreceptors: large amplitude of single-photon responses, constant high level of temporal integration of light inputs, saturation of response properties at low intensities, and only transiently efficient encoding of light contrasts. The results also suggest that the sources of the large functional variability among different photoreceptors reside mostly in phototransduction processes and not in the properties of the nontransductive membrane. PMID- 22933722 TI - Spatiotemporal structure of visual receptive fields in macaque superior colliculus. AB - Saccades are useful for directing the high-acuity fovea to visual targets that are of behavioral relevance. The selection of visual targets for eye movements involves the superior colliculus (SC), where many neurons respond to visual stimuli. Many of these neurons are also activated before and during saccades of specific directions and amplitudes. Although the role of the SC in controlling eye movements has been thoroughly examined, far less is known about the nature of the visual responses in this area. We have, therefore, recorded from neurons in the intermediate layers of the macaque SC, while using a sparse-noise mapping procedure to obtain a detailed characterization of the spatiotemporal structure of visual receptive fields. We find that SC responses to flashed visual stimuli start roughly 50 ms after the onset of the stimulus and last for on average ~70 ms. About 50% of these neurons are strongly suppressed by visual stimuli flashed at certain locations flanking the excitatory center, and the spatiotemporal pattern of suppression exerts a predictable influence on the timing of saccades. This suppression may, therefore, contribute to the filtering of distractor stimuli during target selection. We also find that saccades affect the processing of visual stimuli by SC neurons in a manner that is quite similar to the saccadic suppression and postsaccadic enhancement that has been observed in the cortex and in perception. However, in contrast to what has been observed in the cortex, decreased visual sensitivity was generally associated with increased firing rates, while increased sensitivity was associated with decreased firing rates. Overall, these results suggest that the processing of visual stimuli by SC receptive fields can influence oculomotor behavior and that oculomotor signals originating in the SC can shape perisaccadic visual perception. PMID- 22933723 TI - Cross inhibition from ON to OFF pathway improves the efficiency of contrast encoding in the mammalian retina. AB - The retina is divided into parallel and mostly independent ON and OFF pathways, but the ON pathway "cross" inhibits the OFF pathway. Cross inhibition was thought to improve signal processing by the OFF pathway, but its effect on contrast encoding had not been tested experimentally. To quantify the effect of cross inhibition on the encoding of contrast, we presented a dark flash to an in vitro preparation of the mammalian retina. We then recorded excitatory currents, inhibitory currents, membrane voltages, and spikes from OFF alpha-ganglion cells. The recordings were subjected to an ideal observer analysis that used Bayesian methods to determine how accurately the recordings detected the dark flash. We found that cross inhibition increases the detection accuracy of currents and membrane voltages. Yet these improvements in encoding do not fully reach the spike train, because cross inhibition also hyperpolarizes the OFF alpha-cell below spike threshold, preventing small signals in the membrane voltages at low contrast from reaching the spike train. The ultimate effect of cross inhibition is to increase the accuracy with which the spike train detects moderate contrast, but reduce the accuracy with which it detects low contrast. In apparent compensation for the loss of accuracy at low contrast, cross inhibition, by hyperpolarizing the OFF alpha-cell, reduces the number of spikes required to detect the dark flash and thereby increases encoding efficiency. PMID- 22933724 TI - Activity-dependent changes in intrinsic excitability of human spinal motoneurones produced by natural activity. AB - The current study was designed to evaluate activity-dependent changes intrinsic to the spinal motoneurones (MNs) associated with sustained contractions. The excitability of spinal MNs (reflected by the antidromically evoked F-wave) innervating the abductor digiti minimi muscle (ADM) was measured in 12 healthy subjects following maximum voluntary contractions (MVCs) of ADM lasting 5 s, 15 s, 30 s, and 60 s. Upon cessation of the contractions, F-waves showed a depression, which increased in depth and duration with increasing duration of contraction. Following a 5-s contraction, there was a 20% decrease, which waned in 2 min, whereas a 60-s contraction produced a 40% decrease and waned in over 15 min. The changes in excitability of peripheral motor axons produced by the MVCs were measured by recording an ADM compound muscle action potential (CMAP) of ~50% of maximum to a constant ulnar nerve electrical stimulation. On cessation of the contractions, there was a prominent decrease in size of the CMAP: following a 5-s MVC, it produced a 10% decrease in the size of the test CMAP, which recovered in 2 min, whereas following a 60-s MVC, it produced a 30% decrease, which recovered in over 15 min. Statistical analysis (correntropy) showed a high-order mutual dependence between F-wave and CMAP, and both were significantly dependent on MVC duration. Because of the parallel excitability changes in peripheral axons and spinal MNs, our interpretation is that intrinsic excitability of the axon initial segment (i.e., where the action potential is generated) and peripheral axon segments changed in a similar, activity-dependent manner. PMID- 22933725 TI - Neuromodulator-evoked synaptic metaplasticity within a central pattern generator network. AB - Synapses show short-term activity-dependent dynamics that alter the strength of neuronal interactions. This synaptic plasticity can be tuned by neuromodulation as a form of metaplasticity. We examined neuromodulator-induced metaplasticity at a graded chemical synapse in a model central pattern generator (CPG), the pyloric network of the spiny lobster stomatogastric ganglion. Dopamine, serotonin, and octopamine each produce a unique motor pattern from the pyloric network, partially through their modulation of synaptic strength in the network. We characterized synaptic depression and its amine modulation at the graded synapse from the pyloric dilator neuron to the lateral pyloric neuron (PD->LP synapse), driving the PD neuron with both long square pulses and trains of realistic waveforms over a range of presynaptic voltages. We found that the three amines can differentially affect the amplitude of graded synaptic transmission independently of the synaptic dynamics. Low concentrations of dopamine had weak and variable effects on the strength of the graded inhibitory postsynaptic potentials (gIPSPs) but reliably accelerated the onset of synaptic depression and recovery from depression independently of gIPSP amplitude. Octopamine enhanced gIPSP amplitude but decreased the amount of synaptic depression; it slowed the onset of depression and accelerated its recovery during square pulse stimulation. Serotonin reduced gIPSP amplitude but increased the amount of synaptic depression and accelerated the onset of depression. These results suggest that amine-induced metaplasticity at graded chemical synapses can alter the parameters of synaptic dynamics in multiple and independent ways. PMID- 22933727 TI - Control of ankle extensor muscle activity in walking cats. AB - Our objective was to gain insight into the relative importance of feedforward control and different proprioceptive feedback pathways to ongoing ankle extensor activity during walking in the conscious cat. We asked whether the modulation of stance phase muscle activity is due primarily to proprioceptive feedback and whether the same proprioceptive gains and feedforward commands can automatically generate the muscle activity required for changes in walking slope. To test these hypotheses, we analyzed previously collected muscle activity and mechanics data from cats with an isolated medial gastrocnemius muscle walking along a sloped pegway. Models of proprioceptor dynamics predicted afferent activity from the measured muscle mechanics. We modeled muscle activity as the weighted sum of the activity predicted from the different proprioceptive pathways and a simple model of central drive. We determined the unknown model parameters using optimization procedures that minimized the error between the predicted and measured muscle activity. We found that the modulation of muscle activity within the stance phase and across walking slopes is indeed well described by neural control that employs constant central drive and constant proprioceptive feedback gains. Furthermore, it is force feedback from Ib afferents that is primarily responsible for modulating muscle activity; group II afferent feedback makes a small contribution to tonic activity, and Ia afferent feedback makes no contribution. Force feedback combined with tonic central drive appears to provide a simple control mechanism for automatically compensating for changes in terrain without requiring different commands from the brain or even modification of central nervous system gains. PMID- 22933726 TI - Signal-to-noise ratio in the membrane potential of the owl's auditory coincidence detectors. AB - Owls use interaural time differences (ITDs) to locate a sound source. They compute ITD in a specialized neural circuit that consists of axonal delay lines from the cochlear nucleus magnocellularis (NM) and coincidence detectors in the nucleus laminaris (NL). Recent physiological recordings have shown that tonal stimuli induce oscillatory membrane potentials in NL neurons (Funabiki K, Ashida G, Konishi M. J Neurosci 31: 15245-15256, 2011). The amplitude of these oscillations varies with ITD and is strongly correlated to the firing rate. The oscillation, termed the sound analog potential, has the same frequency as the stimulus tone and is presumed to originate from phase-locked synaptic inputs from NM fibers. To investigate how these oscillatory membrane potentials are generated, we applied recently developed signal-to-noise ratio (SNR) analysis techniques (Kuokkanen PT, Wagner H, Ashida G, Carr CE, Kempter R. J Neurophysiol 104: 2274-2290, 2010) to the intracellular waveforms obtained in vivo. Our theoretical prediction of the band-limited SNRs agreed with experimental data for mid- to high-frequency (>2 kHz) NL neurons. For low-frequency (<=2 kHz) NL neurons, however, measured SNRs were lower than theoretical predictions. These results suggest that the number of independent NM fibers converging onto each NL neuron and/or the population-averaged degree of phase-locking of the NM fibers could be significantly smaller in the low-frequency NL region than estimated for higher best-frequency NL. PMID- 22933728 TI - Motor learning reveals the existence of multiple codes for movement planning. AB - Coordinate systems for movement planning are comprised of an anchor point (e.g., retinocentric coordinates) and a representation (encoding) of the desired movement. One of two representations is often assumed: a final-position code describing desired limb endpoint position and a vector code describing movement direction and extent. The existence of movement-planning systems using both representations is controversial. In our experiments, participants completed reaches grouped by target location (providing practice for a final-position code) and the same reaches grouped by movement vector (providing vector-code practice). Target-grouped reaches resulted in the isotropic (circular) distribution of errors predicted for position-coded reaches. The identical reaches grouped by vector resulted in error ellipses aligned with the reach direction, as predicted for vector-coded reaches. Manipulating only recent movement history to provide better learning for one or the other movement code, we provide definitive evidence that both movement representations are used in the identical task. PMID- 22933730 TI - Re: body mass index and risk of lung cancer among never, former, and current smokers. PMID- 22933729 TI - Functional maps within a single neuron. AB - The presence and plasticity of dendritic ion channels are well established. However, the literature is divided on what specific roles these dendritic ion channels play in neuronal information processing, and there is no consensus on why neuronal dendrites should express diverse ion channels with different expression profiles. In this review, we present a case for viewing dendritic information processing through the lens of the sensory map literature, where functional gradients within neurons are considered as maps on the neuronal topograph. Under such a framework, drawing analogies from the sensory map literature, we postulate that the formation of intraneuronal functional maps is driven by the twin objectives of efficiently encoding inputs that impinge along different dendritic locations and of retaining homeostasis in the face of changes that are required in the coding process. In arriving at this postulate, we relate intraneuronal map physiology to the vast literature on sensory maps and argue that such a metaphorical association provides a fresh conceptual framework for analyzing and understanding single-neuron information encoding. We also describe instances where the metaphor presents specific directions for research on intraneuronal maps, derived from analogous pursuits in the sensory map literature. We suggest that this perspective offers a thesis for why neurons should express and alter ion channels in their dendrites and provides a framework under which active dendrites could be related to neural coding, learning theory, and homeostasis. PMID- 22933732 TI - Should neurointerventional fellowship training be suspended indefinitely? PMID- 22933733 TI - Stenting in acute stroke. Introduction to point/counterpoint. PMID- 22933731 TI - Risks of primary extracolonic cancers following colorectal cancer in lynch syndrome. AB - BACKGROUND: Lynch syndrome is a highly penetrant cancer predisposition syndrome caused by germline mutations in DNA mismatch repair (MMR) genes. We estimated the risks of primary cancers other than colorectal cancer following a diagnosis of colorectal cancer in mutation carriers. METHODS: We obtained data from the Colon Cancer Family Registry for 764 carriers of an MMR gene mutation (316 MLH1, 357 MSH2, 49 MSH6, and 42 PMS2), who had a previous diagnosis of colorectal cancer. The Kaplan-Meier method was used to estimate their cumulative risk of cancers 10 and 20 years after colorectal cancer. We estimated the age-, sex-, country- and calendar period-specific standardized incidence ratios (SIRs) of cancers following colorectal cancer, compared with the general population. RESULTS: Following colorectal cancer, carriers of MMR gene mutations had the following 10 year risk of cancers in other organs: kidney, renal pelvis, ureter, and bladder (2%, 95% confidence interval [CI] = 1% to 3%); small intestine, stomach, and hepatobiliary tract (1%, 95% CI = 0.2% to 2%); prostate (3%, 95% CI = 1% to 5%); endometrium (12%, 95% CI = 8% to 17%); breast (2%, 95% CI = 1% to 4%); and ovary (1%, 95% CI = 0% to 2%). They were at elevated risk compared with the general population: cancers of the kidney, renal pelvis, and ureter (SIR = 12.54, 95% CI = 7.97 to 17.94), urinary bladder (SIR = 7.22, 95% CI = 4.08 to 10.99), small intestine (SIR = 72.68, 95% CI = 39.95 to 111.29), stomach (SIR = 5.65, 95% CI = 2.32 to 9.69), and hepatobiliary tract (SIR = 5.94, 95% CI = 1.81 to 10.94) for both sexes; cancer of the prostate (SIR = 2.05, 95% CI = 1.23 to 3.01), endometrium (SIR = 40.23, 95% CI = 27.91 to 56.06), breast (SIR = 1.76, 95% CI = 1.07 to 2.59), and ovary (SIR = 4.19, 95% CI = 1.28 to 7.97). CONCLUSION: Carriers of MMR gene mutations who have already had a colorectal cancer are at increased risk of a greater range of cancers than the recognized spectrum of Lynch syndrome cancers, including breast and prostate cancers. PMID- 22933734 TI - Stenting in acute stroke: point. PMID- 22933735 TI - Stenting in acute stroke: counterpoint. PMID- 22933736 TI - Chocolate consumption and risk of stroke: a prospective cohort of men and meta analysis. AB - OBJECTIVE: To investigate the association between chocolate consumption and risk of stroke in men and conduct a meta-analysis to summarize available evidence from prospective studies of chocolate consumption and stroke. METHODS: We prospectively followed 37,103 men in the Cohort of Swedish Men. Chocolate consumption was assessed at baseline using a food-frequency questionnaire. Cases of first stroke were ascertained from the Swedish Hospital Discharge Registry. For the meta-analysis, pertinent studies were identified by searching the PubMed and EMBASE databases through January 13, 2012. Study-specific results were combined using a random-effects model. RESULTS: During 10.2 years of follow-up, we ascertained 1,995 incident stroke cases, including 1,511 cerebral infarctions, 321 hemorrhagic strokes, and 163 unspecified strokes. High chocolate consumption was associated with a lower risk of stroke. The multivariable relative risk of stroke comparing the highest quartile of chocolate consumption (median 62.9 g/week) with the lowest quartile (median 0 g/week) was 0.83 (95 % CI 0.70-0.99). The association did not differ by stroke subtypes. In a meta-analysis of 5 studies, with a total of 4,260 stroke cases, the overall relative risk of stroke for the highest vs lowest category of chocolate consumption was 0.81 (95% CI 0.73 0.90), without heterogeneity among studies (p = 0.47). CONCLUSION: These findings suggest that moderate chocolate consumption may lower the risk of stroke. PMID- 22933737 TI - Extreme delta brush: a unique EEG pattern in adults with anti-NMDA receptor encephalitis. AB - OBJECTIVES: To determine continuous EEG (cEEG) patterns that may be unique to anti-NMDA receptor (NMDAR) encephalitis in a series of adult patients with this disorder. METHODS: We evaluated the clinical and EEG data of 23 hospitalized adult patients with anti-NMDAR encephalitis who underwent cEEG monitoring between January 2005 and February 2011 at 2 large academic medical centers. RESULTS: Twenty-three patients with anti-NMDAR encephalitis underwent a median of 7 (range 1-123) days of cEEG monitoring. The median length of hospitalization was 44 (range 2-200) days. Personality or behavioral changes (100%), movement disorders (82.6%), and seizures (78.3%) were the most common symptoms. Seven of 23 patients (30.4%) had a unique electrographic pattern, which we named "extreme delta brush" because of its resemblance to waveforms seen in premature infants. The presence of extreme delta brush was associated with a more prolonged hospitalization (mean 128.3 +/- 47.5 vs 43.2 +/- 39.0 days, p = 0.008) and increased days of cEEG monitoring (mean 27.6 +/- 42.3 vs 6.2 +/- 5.6 days, p = 0.012). The modified Rankin Scale score showed a trend toward worse scores in patients with the extreme delta brush pattern (mean 4.0 +/- 0.8 vs 3.1 +/- 1.1, p = 0.089). CONCLUSIONS: Extreme delta brush is a novel EEG finding seen in many patients with anti-NMDAR encephalitis. The presence of this pattern is associated with a more prolonged illness. Although the specificity of this pattern is unclear, its presence should raise consideration of this syndrome. PMID- 22933738 TI - Disease-modifying drugs for multiple sclerosis in pregnancy: a systematic review. AB - OBJECTIVE: To systematically review the literature regarding safety of disease modifying drug (DMD) use during pregnancy on perinatal and developmental outcomes in offspring of patients with multiple sclerosis (MS). METHODS: A PubMed and EMBASE search up to February 2012 was conducted with a manual search of references from relevant articles. Selected studies were evaluated using internationally accepted criteria. RESULTS: Fifteen studies identified 761 interferon beta-, 97 glatiramer acetate-, and 35 natalizumab-exposed pregnancies. Study quality ranged from poor to good; no study was rated excellent. Small sample sizes limited most studies. Compared with data for unexposed pregnancies, fair- to good-quality prospective cohort studies reported that interferon beta exposure was associated with lower mean birth weight, shorter mean birth length, and preterm birth (<37 weeks), but not low birth weight (<2,500 g), cesarean delivery, congenital anomaly (including malformation), or spontaneous abortion. Fewer studies of fair quality were available for glatiramer acetate and natalizumab. Glatiramer acetate exposure was not associated with lower mean birth weight, congenital anomaly, preterm birth, or spontaneous abortion. Natalizumab exposure did not appear to be associated with shorter mean birth length, lower mean birth weight, or lower mean gestational age. No studies examined mitoxantrone or fingolimod exposure. One study of paternal DMD use during conception found no effect on gestational age or birth weight. Few studies examined longer-term developmental outcomes. CONCLUSION: Further studies are needed to determine the potential risks associated with preconceptional and in utero DMD exposure in patients with MS. Discontinuation of DMDs before conception is still recommended. PMID- 22933739 TI - Recurrent hyperCKemia with normal muscle biopsy in a pediatric patient with neuromyelitis optica. PMID- 22933740 TI - Genetic dysfunction of MT-ATP6 causes axonal Charcot-Marie-Tooth disease. AB - OBJECTIVE: Charcot-Marie-Tooth (CMT) disease is the most common inherited neuromuscular disorder, affecting 1 in 2,500 individuals. Mitochondrial DNA (mtDNA) mutations are not generally considered within the differential diagnosis of patients with uncomplicated inherited neuropathy, despite the essential requirement of ATP for axonal function. We identified the mtDNA mutation m.9185T>C in MT-ATP6, encoding the ATP6 subunit of the mitochondrial ATP synthase (OXPHOS complex V), at homoplasmic levels in a family with mitochondrial disease in whom a severe motor axonal neuropathy was a striking feature. This led us to hypothesize that mutations in the 2 mtDNA complex V subunit encoding genes, MT ATP6 and MT-ATP8, might be an unrecognized cause of isolated axonal CMT and distal hereditary motor neuropathy (dHMN). METHODS: A total of 442 probands with CMT type 2 (CMT2) (270) and dHMN (172) were screened for MT-ATP6/8 mutations after exclusion of mutations in known CMT2/dHMN genes. Mutation load was quantified using restriction endonuclease analysis. Blue-native gel electrophoresis (BN-PAGE) was performed to analyze the effects of m.9185T>C on complex V structure and function. RESULTS: Three further probands with CMT2 harbored the m.9185T>C mutation. Some relatives had been classified as having dHMN. Patients could be separated into 4 groups according to their mutant m.9185T>C levels. BN-PAGE demonstrated both impaired assembly and reduced activity of the complex V holoenzyme. CONCLUSIONS: We have shown that m.9185T>C in MT-ATP6 causes CMT2 in 1.1% of genetically undefined cases. This has important implications for diagnosis and genetic counseling. Recognition that mutations in MT-ATP6 cause CMT2 enhances current understanding of the pathogenic basis of axonal neuropathy. PMID- 22933742 TI - Epstein-Barr virus infection: a smoking gun for multiple sclerosis? PMID- 22933741 TI - Abeta-amyloid deposition in patients with Parkinson disease at risk for development of dementia. AB - OBJECTIVE: The aim of our study was to examine the relationship between corticostriatal Abeta-amyloid deposition and cognitive dysfunction in a cohort of patients with Parkinson disease (PD) at risk for dementia. METHODS: This was a cross-sectional study of 40 patients with PD with mild cognitive impairment (MCI) or other known dementia risk factors. Subjects underwent dynamic Abeta-amyloid and vesicular monoamine transporter 2 PET imaging using [(11)C] Pittsburgh compound B (PiB) and [(11)C]dihydrotetrabenazine (DTBZ), respectively, and neuropsychological assessment. PiB and DTBZ PET data were analyzed using the Logan graphical method to determine cerebral PiB deposition relative to the cerebellar hemispheres and striatal DTBZ binding relative to occipital neocortex. Component z scores were calculated for individual cognitive domains (memory, visuospatial processing, working memory/attention, and executive function) and combined linearly for global estimation of cognition. Correlation of cognitive function and cortical PiB binding was investigated. RESULTS: Elevated cerebral PiB binding at levels seen in patients with AD was infrequent (6 of 40 subjects). Mean cortical PiB binding in the entire cohort was 1.16 +/- 0.16 (distribution volume ratio; range 0.96-1.78). A significant correlation was noted between cortical PiB binding and global composite cognitive function (r = -0.55, p < 0.005) as well as the Wechsler Adult Intelligence Scale score (r = -0.54, p = 0.0004). CONCLUSION: Elevated cerebral Abeta-amyloid deposition at levels seen in Alzheimer disease is uncommon in subjects with PD at risk for dementia. In our sample, the prevalence of markedly elevated PiB binding was significantly lower than that found in prior studies of cognitively normal elderly individuals. Neocortical PiB binding correlated robustly with measures of cognitive impairment in our cohort. PMID- 22933744 TI - Lack of replication of interaction between EBNA1 IgG and smoking in risk for multiple sclerosis. AB - BACKGROUND: Epstein-Barr virus infection, smoking, HLA-A*02, and DRB1*15 have all been proposed as risk factors for multiple sclerosis (MS). In 2010, Simon et al. described an interaction on the multiplicative scale between EBNA1 immunoglobulin G (IgG) and smoking regarding risk of MS, a finding that we attempted to replicate. METHODS: This Swedish case-control study consisted of patients with newly diagnosed MS and matched controls. Using logistic regression, we analyzed association to MS risk and interactions between EBNA1 IgG and smoking, HLA DRB1*15, and A*02, respectively, on the multiplicative scale. In addition, we analyzed interactions on the additive scale using attributable proportion due to interaction (AP). RESULTS: We did not observe any interaction on the multiplicative scale between EBNA1 IgG and any of the 3 risk factors, smoking, DRB1*15, or absence of A*02, although in a conditional analysis the interaction with absence of A*02 becomes significant. However, we observed interactions on the additive scale between EBNA1 IgG and DRB1*15 (AP = 0.34, 95% confidence interval 0.11-0.57, p = 5 * 10-3) and between EBNA1 IgG and absence of A*02 (AP = 0.36, 0.13-0.59, p = 2 * 10-3) but not between smoking and DRB1*15 and EBNA1 IgG. The interaction between EBNA1 IgG and DRB1*15 was not significant in the conditional analysis. CONCLUSION: We did not observe any interaction between EBNA1 IgG and smoking, regardless of scale used, and thus did not replicate the observations from Simon et al. PMID- 22933743 TI - Psychiatric disorders in rapid-onset dystonia-parkinsonism. AB - OBJECTIVE: Rapid-onset dystonia-parkinsonism (RDP) is caused by a variety of missense mutations in the ATP1A3 gene. Psychiatric comorbidity has been reported, although systematic examination of psychiatric disease in individuals with RDP is lacking. This study examines psychiatric morbidity for 23 patients with RDP in 10 families with family member control subjects and in 3 unrelated patients with RDP, totaling 56 individuals. METHODS: Twenty-nine ATP1A3 mutation-positive individuals were examined; 26 exhibited motor symptoms (motor manifesting carrier [MMC]) and 3 did not (nonmotor manifesting carriers [NMC]). Twenty-seven ATP1A3 mutation-negative participants (noncarriers [NC]) were included. Rates of psychiatric illness for patients with RDP and related asymptomatic gene mutation carriers were compared with those for related nonmutation carriers. Outcome measures included the Unified Parkinson's Disease Rating Scale, Burke-Fahn Marsden Dystonia Rating Scale, Instrumental Activities of Daily Living, Composite International Diagnostic Interview, Structured Clinical Interview for DSM-IV, Hamilton Depression Scale, Hamilton Anxiety Scale, and Yale-Brown Obsessive Compulsive Scale. RESULTS: NMC participants did not report any history of psychiatric disorder. Findings in MMC and NC groups included anxiety (MMC 48, NC 41%), mood (MMC 50%, NC 22%), psychotic (MMC 19%, NC 0%), and substance abuse/dependence (MMC 38%, NC 27%). CONCLUSIONS: ATP1A3 mutations cause a wide spectrum of motor and nonmotor features. Psychotic symptoms tended to emerge before or concurrent with motor symptom onset, suggesting that this could be another expression of the ATP1A3 gene mutation. PMID- 22933745 TI - Oculomotor and visual axis systems sparing in spinocerebellar ataxia type 13(R420H). PMID- 22933746 TI - Looking anew at cognitive dysfunction in multiple sclerosis: the gorilla in the room. AB - OBJECTIVE: Inattentional blindness refers to a phenomenon in which individuals fail to notice an object in plain sight. Present in healthy, cognitively intact individuals, it has not been studied in patients with MS in whom it could theoretically act as a marker for real-world cognitive difficulties in those deemed cognitively intact on conventional neuropsychological batteries. Our hypothesis was that difficulty sustaining attention in patients with MS would paradoxically be associated with less inattentional blindness. METHODS: A cross sectional study was undertaken in which a consecutive sample of 68 patients with MS completed neuropsychological testing with the Minimal Assessment of Cognitive Function in Multiple Sclerosis (MACFIMS) battery. Two additional tests were administered, the Stroop Test and a measure of inattentional blindness, i.e., the gorilla in the room paradigm. The gorilla test elicited 2 variables: the ability to detect the gorilla and the number of times a ball was passed between members of one team. RESULTS: Cognitive dysfunction by MACFIMS criteria was present in 36.8 of subjects. There were no differences between patients with MS and healthy control subjects on the gorilla indices. Similarly, no inattentional differences were present between cognitively intact and impaired patients with MS. However, patients with MS who were impaired on the Stroop and 2-second Paced Auditory Serial Addition Test were more likely than their intact counterparts to detect the gorilla (p = 0.038 and 0.014, respectively), with Stroop-impaired patients detecting fewer ball passes (p = 0.002). CONCLUSIONS: The results support our hypothesis that less inattentional blindness is associated with heightened distractibility. This may explain why some patients with MS deemed cognitively intact on a battery of tests such as the MACFIMS still struggle with real-world challenges such as multitasking and filtering distracting stimuli. PMID- 22933747 TI - Eating competence of Hispanic parents is associated with attitudes and behaviors that may mediate fruit and vegetable-related behaviors of 4th grade youth. AB - Parent self-efficacy, outcome expectancies, and behaviors toward cooking and fruits and vegetables mediate children's eating. Eating competence, an intra individual approach to food-related attitudes and behaviors, is associated with healthful outcomes but has not been studied as a moderator of parent food-related behaviors that mediate healthful eating in 4th grade children. Parents (n = 339; 78% Hispanic, 89% female) of 4th graders who participated in an impact study of the Cooking with Kids curriculum in Santa Fe, NM schools eligible for Supplemental Nutrition Assistance Program Education completed the following surveys: Satter eating competence inventory for low-income (ecSI/LI) (16 items, Likert scale, possible score 0-48); modeling behaviors related to food preparation and fruits/vegetables (11 items, Likert scale, possible score 0-33); self-efficacy/outcome expectancies (SE/OE) (12 items, Likert scale, possible score 12-60); and availability of fruits/vegetables (20 items, possible score 0 20). Higher scores indicate more desired behaviors. The mean ecSI/LI score was 33.6 +/- 8.5; 59% were eating competent, i.e., ecSI/LI >= 32. Eating-competent parents demonstrated more modeling (16.3 +/- 5.0 vs. 14.0 +/- 4.3; P < 0.001), greater SE/OE (53.7 +/- 10.1 vs. 51.2 +/- 8.5; P = 0.03), and greater in-home fruit/vegetable availability (12.7 +/- 3.0 vs. 11.9 +/- 3.2; P = 0.02). Two clusters of modeling behavior were defined: achievers and strivers. Modeling achievers (34.9 +/- 6.9) were more eating competent (P < 0.001) than strivers (30.3 +/- 8.9). Eating competence moderated parent food-related behaviors. Measuring eating competence may contribute to understanding parent behavior as a mediator in school-based nutrition interventions. PMID- 22933748 TI - Food insecurity is negatively associated with home health and out-of-pocket expenditures in older adults. AB - Food insecurity is a persistent, growing, and clinically relevant problem in older adults; however, its effect on healthcare expenditures is not known. This study examined the relationship of food insecurity with Medicare and out-of pocket expenditures in older Georgians enrolled in Medicare and meal services using 2 complementary datasets: Georgia Advanced Performance Outcomes Measures Project 6 (GA Advanced POMP6) and Medicare claims data in 2008 (n = 903, mean age 76.9 +/- 7.8 y, 31.0% male, 64.2% white). Due to the mixed distribution of healthcare expenditure data (e.g., high nonusers, right-skewed distribution for users), 2-part models were used. Approximately one-half of the sample was food insecure (50.4%) and was more likely to report poorer health status and to have chronic diseases than food-insecure individuals. Food-insecure older adults were less likely to have any Medicare expenditure than food-secure older adults. Among those who had positive Medicare expenditure, however, food-insecure and food secure individuals had similar Medicare expenditures. Food-insecure and food secure older individuals were equally likely to incur out-of-pocket expenditure. However, among those who had positive out-of-pocket expenditure, food-insecure older individuals had lower out-of-pocket expenditures than their counterparts. Adjusted mean Medicare and out-of-pocket expenditures of food-insecure individuals were $1875 and $310 less than food-secure individuals in 2008, respectively. These findings based on the innovative methodological approaches and datasets suggest complex relationships between food insecurity and healthcare expenditures in older adults, reflecting unique healthcare access and usage patterns. PMID- 22933750 TI - Daily consumption of orange-fleshed sweet potato for 60 days increased plasma beta-carotene concentration but did not increase total body vitamin A pool size in Bangladeshi women. AB - We assessed the effect of daily consumption of orange-fleshed sweet potatoes (OFSP), with or without added fat, on the vitamin A (VA) status of Bangladeshi women with low initial VA status. Women (n = 30/group) received one of the following for 6 d/wk over 10 wk: 1) 0 MUg retinol activity equivalents (RAE)/d as boiled white-fleshed sweet potatoes (WFSP) and a corn oil capsule, 2) 600 MUg RAE/d as boiled OFSP and a corn oil capsule, 3) fried OFSP and a corn oil capsule, or 4) boiled WFSP and a retinyl palmitate capsule in addition to their home diets. Plasma concentrations of retinol and beta-carotene and total body VA pool size were assessed before and after the 60-d intervention. Initial and final plasma retinol concentrations (mean +/- SD) were 0.75 +/- 0.18 MUmol/L and 0.84 +/- 0.19 MUmol/L, respectively (P = 0.31); final means did not differ by group. Initial and final plasma beta-carotene concentrations were 0.10 +/- 00 MUmol/L and 0.18 +/- 0.09 MUmol/L, respectively (P < 0.0001); final mean plasma beta carotene concentrations were higher in groups that received OFSP (P < 0.0001), and final mean plasma beta-carotene was marginally higher in the group that received fried OFSP compared with boiled OFSP (P = 0.07). Initial and final total body VA pool sizes were 0.060 +/- 0.047 mmol and 0.091 +/- 0.070 mmol, respectively (P = 0.05, n = 110) and did not differ by group. Despite an increase in plasma beta-carotene concentration, the impact of OFSP on VA status appears to be limited in Bangladeshi women residing in a resource-poor community. PMID- 22933749 TI - Endogenous and exogenous equol are antiestrogenic in reproductive tissues of apolipoprotein e-null mice. AB - Equol is an isoflavone (IF) metabolite produced by intestinal microbiota in a subset of people consuming dietary soy. Equol producers may show different responses to soy foods and phenotypes related to cancer risk. Here, we assessed the effects of soy IF, endogenous microbial equol production, and dietary racemic equol in a 3 * 2 * 2 factorial experiment using gnotobiotic apoE-null mice (n = 9 11/group/sex). At age 3-6 wk, equol-producing microbiota were introduced to one half of the colony (n = 122). At age 6 wk, mice were randomized to receive a diet that contained 1 of 3 protein sources: casein and lactalbumin, alcohol-washed soy protein (low IF), and intact soy protein (high IF), with total IF amounts of 0, 42, and 566 mg/kg diet, respectively. One-half of each diet group also received racemic equol (291 mg/kg diet). After 16 wk of dietary treatment, serum isoflavonoid profiles varied with sex, soy IF amount, and intestinal microbiota status. There were no treatment effects on tissues of male mice. In females, reproductive tissue phenotypes differed by equol-producing ability (i.e., microbiota status) but not dietary equol or IF content. Equol producers had lower uterine weight, vaginal epithelial thickness, total uterine area, endometrial area, and endometrial luminal epithelial height compared with nonproducers (P < 0.05 for all), with an association between microbiota status and estrous cycle (P > chi-square = 0.03). Exogenous equol reduced expression of progesterone receptor (PGR) and the proliferation marker Ki67 (P < 0.0001) in vaginal epithelium and endometrium; for endogenous equol, only PGR was reduced (P < 0.0005). Our findings indicate that equol diminishes estrogen-dependent tissue responses in apoE-null mice. PMID- 22933751 TI - Responsibilities to plan for ancillary care pose ethical challenges for nutrition research in the community setting. AB - Investigators who conduct nutrition research in the community setting, particularly among underserved populations, face the ethical question of whether and how to respond to participants' unmet health needs. The research ethics literature conceptualizes this question as one of ancillary care (AC): what is the nature and extent of researchers' ethical responsibilities, if any, to provide or facilitate health care that research participants need but that is not necessary to ensure the safety or scientific validity of the research? In this paper, we highlight 3 ethical challenges involved in the planning of AC responses for nutrition research conducted in the community setting: influence of provision of AC on primary study outcomes as an issue of trial design; whether to extend the provision of AC beyond research participants to nonparticipants with the same health needs; and how best to train field workers who may be the most likely members of the study team to encounter the health needs anticipated among participants. Although the global ethical discussion of AC is gaining in depth, breadth, and practical influence, it remains relatively uninformed by perspectives specific to nutrition research. Our objective is to encourage nutrition researchers to engage proactively in the emerging ethical discussion of AC, so that their relevant experiences and concerns can be taken into account in the eventual formation of ethical guidelines and policies. PMID- 22933752 TI - Genome sequence of Lactococcus garvieae IPLA 31405, a bacteriocin-producing, tetracycline-resistant strain isolated from a raw-milk cheese. AB - This work describes the draft genome sequence of Lactococcus garvieae IPLA 31405, isolated from a traditional Spanish cheese. The genome contains a lactose galactose operon, a bacteriocin locus, two integrated phages, a transposon harboring an active tet(M) gene, and two theta-type plasmid replicons. Genes encoding virulence factors were not recorded. PMID- 22933753 TI - Genome sequence of n-alkane-degrading Hydrocarboniphaga effusa strain AP103T (ATCC BAA-332T). AB - Hydrocarboniphaga effusa strain AP103(T) (ATCC BAA-332(T)) is a member of the Gammaproteobacteria utilizing n-alkanes as the sole source of carbon and energy. Here we report the draft genome sequence of AP103(T), which consists of 5,193,926 bp with a G + C content of 65.18%. PMID- 22933754 TI - Draft genome sequence of Actinomyces massiliensis strain 4401292T. AB - A draft genome sequence of Actinomyces massiliensis, an anaerobic bacterium isolated from a patient's blood culture, is described here. CRISPR-associated proteins, insertion sequences, and toxin-antitoxin loci were found on the genome. PMID- 22933755 TI - Whole-genome sequences and comparative genomics of Salmonella enterica serovar Typhi isolates from patients with fatal and nonfatal typhoid fever in Papua New Guinea. AB - Many of the developing countries of the Southeast Asian region are significantly affected by endemic typhoid fever, possibly as a result of marginal living standards. It is an important public health problem in countries such as Papua New Guinea, which is geographically close to some of the foci of endemicity in Asia. The severity of the disease varies in different regions, and this may be attributable to genetic diversity among the native strains. Genome sequence data on strains from different countries are needed to clearly understand their genetic makeup and virulence potential. We describe the genomes of two Salmonella Typhi isolates from patients with fatal and nonfatal cases of typhoid fever in Papua New Guinea. We discuss in brief the underlying sequencing methodology, assembly, genome statistics, and important features of the two draft genomes, which form an essential step in our functional molecular infection epidemiology program centering on typhoid fever. The comparative genomics of these and other isolates would enable us to identify genetic rearrangements and mechanisms responsible for endemicity and the differential severity of pathogenic salmonellae in Papua New Guinea and elsewhere. PMID- 22933756 TI - Insights from the genome sequence of a Salmonella enterica serovar Typhi strain associated with a sporadic case of typhoid fever in Malaysia. AB - Salmonella enterica serovar Typhi is the causative agent of typhoid fever, which causes nearly 21.7 million illnesses and 217,000 deaths globally. Herein, we describe the whole-genome sequence of the Salmonella Typhi strain ST0208, isolated from a sporadic case of typhoid fever in Kuala Lumpur, Malaysia. The whole-genome sequence and comparative genomics allow an in-depth understanding of the genetic diversity, and its link to pathogenicity and evolutionary dynamics, of this highly clonal pathogen that is endemic to Malaysia. PMID- 22933757 TI - Genome sequence of Enterococcus hirae (Streptococcus faecalis) ATCC 9790, a model organism for the study of ion transport, bioenergetics, and copper homeostasis. AB - Enterococcus hirae ATCC 9790 is a Gram-positive lactic acid bacterium that has been used in basic research for over 4 decades. Here we report the sequence and annotation of the 2.8-Mb genome of E. hirae and its endemic 29-kb plasmid pTG9790. PMID- 22933758 TI - Genome analysis of Mycobacterium massiliense strain M172, which contains a putative mycobacteriophage. AB - The genome of Mycobacterium massiliense M172, isolated from a human sputum sample, was sequenced using Illumina GA IIX technology and found to contain 5,204,460 bp, including putative genes for virulence and antibiotic resistance as well as a 92-kb genomic region most likely to correspond to a mycobacteriophage. PMID- 22933759 TI - Genome sequence of Rickettsia australis, the agent of Queensland tick typhus. AB - Rickettsia australis strain Phillips(T) was isolated in Queensland, Australia, in 1950. It is the tick-borne agent of Queensland tick typhus, a disease endemic in Australia. The 1.29-Mb genome sequence of this bacterium is highly similar to that of Rickettsia akari but contains two plasmids. PMID- 22933760 TI - Genome sequence of Rickettsia conorii subsp. israelensis, the agent of Israeli spotted fever. AB - Rickettsia conorii subsp. israelensis is the agent of Israeli spotted fever. The present study reports the draft genome of Rickettsia conorii subsp. israelensis strain ISTT CDC1, isolated from a Rhipicephalus sanguineus tick collected in Israel. PMID- 22933761 TI - Complete genome sequence of Streptococcus agalactiae ZQ0910, a pathogen causing meningoencephalitis in the GIFT strain of Nile tilapia (Oreochromis niloticus). AB - Streptococcus agalactiae (group B streptococcus [GBS]) is a pathogen that causes meningoencephalitis in Nile tilapia (Oreochromis niloticus). Here, we reported the complete genome sequence of S. agalactiae strain ZQ0910, which was isolated from the GIFT strain of Nile tilapia in Guangdong, China. PMID- 22933762 TI - Complete genome sequence of Brucella canis strain HSK A52141, isolated from the blood of an infected dog. AB - Brucella canis infection can be clinically inapparent in dogs, and when infection goes unnoticed, there is a chance for dog-to-human transmission. A new strain of B. canis was isolated from the blood of an infected dog in order to analyze the pathogenic mechanism, compare genetic properties, and develop new genetic tools for early diagnosis of canine brucellosis. Herein, we report the complete genome sequence of the strain B. canis HSK A52141. This is the second complete genome sequence and biological annotation available for a member of B. canis. PMID- 22933763 TI - Genome sequence of pectin-degrading Alishewanella agri, isolated from landfill soil. AB - Alishewanella agri BL06(T) (= KCTC 22400(T) = JCM 15597(T)) was isolated from landfill soil in Pohang, South Korea. A. agri showed the ability to degrade pectin, a structural heteropolysaccharide present in the cell wall of plants. Here we report the genome sequence of Alishewanella agri BL06(T), the second sequenced strain in the genus Alishewanella. PMID- 22933764 TI - Genome sequence of Novosphingobium sp. strain Rr 2-17, a nopaline crown gall associated bacterium isolated from Vitis vinifera L. grapevine. AB - Novosphingobium sp. strain Rr 2-17 is an N-acyl homoserine lactone (AHL) producing bacterium isolated from the crown gall tumor of a grapevine. To our knowledge, this is the first draft genome announcement of a plant-associated strain from the genus Novosphingobium. PMID- 22933765 TI - Genome sequence of Ralstonia sp. strain PBA, a bacterium involved in the biodegradation of 4-aminobenzenesulfonate. AB - Ralstonia sp. strain PBA was isolated from textile wastewater in a coculture with Hydrogenophaga sp. strain PBC. Here we present the assembly and annotation of its genome, which may provide further insights into the mechanism of its interaction with strain PBC during 4-aminobenzenesulfonate degradation. PMID- 22933766 TI - Genome sequence of Staphylococcus equorum subsp. equorum Mu2, isolated from a French smear-ripened cheese. AB - Staphylococcus equorum subsp. equorum is a member of the coagulase-negative staphylococcus group and is frequently isolated from fermented food products and from food-processing environments. It contributes to the formation of aroma compounds during the ripening of fermented foods, especially cheeses and sausages. Here, we report the draft genome sequence of Staphylococcus equorum subsp. equorum Mu2 to provide insights into its physiology and compare it with other Staphylococcus species. PMID- 22933767 TI - Draft genome sequence of the human pathogen Halomonas stevensii S18214T. AB - Halomonas stevensii is a Gram-negative, moderately halophilic bacterium causing environmental contamination and infections in a dialysis center. Here we present the 3.7-Mb draft genome sequence of the type strain (S18214(T)) of H. stevensii, which will give insight into the pathogenic potential of H. stevensii. PMID- 22933768 TI - Genome sequence of a Neisseria meningitidis capsule null locus strain from the clonal complex of sequence type 198. AB - Neisseria meningitidis is a commensal and accidental pathogen exclusively of humans. Although the production of polysaccharide capsules is considered to be essential for meningococcal virulence, there have been reports of constitutively unencapsulated strains causing invasive meningococcal disease (IMD). Here we report the genome sequence of a capsule null locus (cnl) strain of sequence type 198 (ST-198), which is found in half of the reported cases of IMD caused by cnl meningococcal strains. PMID- 22933769 TI - Draft genome sequences of eight Salmonella enterica serotype newport strains from diverse hosts and locations. AB - Salmonellosis is a major contributor to the global public health burden. Salmonella enterica serotype Newport has ranked among three Salmonella serotypes most commonly associated with food-borne outbreaks in the United States. It was thought to be polyphyletic and composed of independent lineages. Here we report draft genomes of eight strains of S. Newport from diverse hosts and locations. PMID- 22933771 TI - Draft genome sequence of Escherichia coli W26, an enteric strain isolated from cow feces. AB - An enteric bacterium, Escherichia coli W26 (KACC 16630), was isolated from feces from a healthy cow in South Korea. Here, we report the draft genome sequence of the isolate, which is closely affiliated with commensal strains belonging to E. coli phylogroup B1. PMID- 22933770 TI - Draft genome sequences for two metal-reducing Pelosinus fermentans strains isolated from a Cr(VI)-contaminated site and for type strain R7. AB - Pelosinus fermentans 16S rRNA gene sequences have been reported from diverse geographical sites since the recent isolation of the type strain. We present the genome sequence of the P. fermentans type strain R7 (DSM 17108) and genome sequences for two new strains with different abilities to reduce iron, chromate, and uranium. PMID- 22933772 TI - Draft genome sequence of Brevibacterium massiliense strain 541308T. AB - A draft genome sequence of Brevibacterium massiliense, an aerobic bacterium isolated from a human ankle discharge, is described here. CRISPR-associated proteins were found to be encoded in the genome, and analysis of transport proteins was performed. PMID- 22933773 TI - Draft genome sequence of Alcaligenes faecalis subsp. faecalis NCIB 8687 (CCUG 2071). AB - Alcaligenes faecalis subsp. faecalis NCIB 8687, the betaproteobacterium from which arsenite oxidase had its structure solved and the first "arsenate gene island" identified, provided a draft genome of 3.9 Mb in 186 contigs (with the largest 15 comprising 90% of the total) for this opportunistic pathogen species. PMID- 22933774 TI - Complete genome sequence of the naphthalene-degrading Pseudomonas putida strain ND6. AB - Pseudomonas putida strain ND6 is an efficient naphthalene-degrading bacterium. The complete genome of strain ND6 was sequenced and annotated. The genes encoding the enzymes involved in catechol degradation by the ortho-cleavage pathway were found in the chromosomal sequence, which indicated that strain ND6 is able to metabolize naphthalene by the catechol meta- and ortho-cleavage pathways. PMID- 22933775 TI - Genome sequence of Acinetobacter sp. strain HA, isolated from the gut of the polyphagous insect pest Helicoverpa armigera. AB - In this study, Acinetobacter sp. strain HA was isolated from the midgut of a fifth-instar larva of Helicoverpa armigera. Here, we report the draft genome sequence (3,125,085 bp) of this strain that consists of 102 contigs, 2,911 predicted coding sequences, and a G+C content of 41%. PMID- 22933776 TI - Genome sequence of Methylobacterium sp. strain GXF4, a xylem-associated bacterium isolated from Vitis vinifera L. grapevine. AB - Methylobacterium sp. strain GXF4 is an isolate from grapevine. Here we present the sequence, assembly, and annotation of its genome, which may shed light on its role as a grapevine xylem inhabitant. To our knowledge, this is the first genome announcement of a plant xylem-associated strain of the genus Methylobacterium. PMID- 22933777 TI - GSK3beta/axin-1/beta-catenin complex is involved in semaphorin3A signaling. AB - Semaphorin3A (Sema3A) exerts a wide variety of biological functions by regulating reorganization of actin and tubulin cytoskeletal proteins through signaling pathways including sequential phosphorylation of collapsin response mediator protein 1 (CRMP1) and CRMP2 by cyclin-dependent kinase-5 and glycogen synthase kinase-3beta (GSK3beta). To delineate how GSK3beta mediates Sema3A signaling, we here determined the substrates of GSK3beta involved. Introduction of either GSK3beta mutants, GSK3beta-R96A, L128A, or K85M into chick dorsal root ganglion (DRG) neurons suppressed Sema3A-induced growth cone collapse, thereby suggesting that unprimed as well as primed substrates are involved in Sema3A signaling. Axin 1, a key player in Wnt signaling, is an unprimed substrate of GSK3beta. The phosphorylation of Axin-1 by GSK3beta accelerates the association of Axin-1 with beta-catenin. Immunocytochemical studies revealed that Sema3A induced an increase in the intensity levels of beta-catenin in the DRG growth cones. Axin-1 siRNA knockdown suppressed Sema3A-induced growth cone collapse. The reintroduction of RNAi-resistant Axin-1 (rAxin-1)-wt rescued the responsiveness to Sema3A, while that of nonphosphorylated mutants, rAxin S322A/S326A/S330A and T485A/S490A/S497A, did not. Sema3A also enhanced the colocalization of GSK3beta, Axin-1, and beta catenin in the growth cones. The increase of beta-catenin in the growth cones was suppressed by the siRNA knockdown of Axin-1. Furthermore, either Axin-1 or beta catenin RNAi knockdown suppressed the internalization of Sema3A. These results suggest that Sema3A induces the formation of GSK3beta/Axin-1/beta-catenin complex, which regulates signaling cascade of Sema3A via an endocytotic mechanism. This finding should provide clue for understanding of mechanisms of a wide variety of biological functions of Sema3A. PMID- 22933778 TI - Adaptor protein APPL1 couples synaptic NMDA receptor with neuronal prosurvival phosphatidylinositol 3-kinase/Akt pathway. AB - It is well known that NMDA receptors (NMDARs) can both induce neurotoxicity and promote neuronal survival under different circumstances. Recent studies show that such paradoxical responses are related to the receptor location: the former to the extrasynaptic and the latter to the synaptic. The phosphoinositide 3-kinase (PI3K)/Akt kinase cascade is a key pathway responsible for the synaptic NMDAR dependent neuroprotection. However, it is still unknown how synaptic NMDARs are coupled with the PI3K/Akt pathway. Here, we explored the role of an adaptor protein-adaptor protein containing pH domain, PTB domain, and leucine zipper motif (APPL1)-in this signal coupling using rat cortical neurons. We found that APPL1 existed in postsynaptic densities and associated with the NMDAR complex through binding to PSD95 at its C-terminal PDZ-binding motif. NMDARs, APPL1, and the PI3K/Akt cascade formed a complex in rat cortical neurons. Synaptic NMDAR activity increased the association of this complex, induced activation of the PI3K/Akt pathway, and consequently protected neurons against starvation-induced apoptosis. Perturbing APPL1 interaction with PSD95 by a peptide comprising the APPL1 C-terminal PDZ-binding motif dissociated the PI3K/Akt pathway from NMDARs. Either the peptide or lentiviral knockdown of APPL1 blocked synaptic NMDAR dependent recruitment and activation of PI3K/Akt pathway, and consequently blocked synaptic NMDAR-dependent neuroprotection. These results suggest that APPL1 contributes to connecting synaptic NMDARs with the intracellular PI3K/Akt cascade and the downstream prosurvival signaling pathway in rat cortical neurons. PMID- 22933779 TI - p300/CBP-associated factor selectively regulates the extinction of conditioned fear. AB - It is well established that the activity of chromatin-modifying enzymes is crucial for regulating gene expression associated with hippocampal-dependent memories. However, very little is known about how these epigenetic mechanisms influence the formation of cortically dependent memory, particularly when there is competition between opposing memory traces, such as that which occurs during the acquisition and extinction of conditioned fear. Here we demonstrate, in C57BL/6 mice, that the activity of p300/CBP-associated factor (PCAF) within the infralimbic prefrontal cortex is required for long-term potentiation and is necessary for the formation of memory associated with fear extinction, but not for fear acquisition. Further, systemic administration of the PCAF activator SPV106 enhances memory for fear extinction and prevents fear renewal. The selective influence of PCAF on fear extinction is mediated, in part, by a transient recruitment of the repressive transcription factor ATF4 to the promoter of the immediate early gene zif268, which competitively inhibits its expression. Thus, within the context of fear extinction, PCAF functions as a transcriptional coactivator, which may facilitate the formation of memory for fear extinction by interfering with reconsolidation of the original memory trace. PMID- 22933780 TI - The C-type natriuretic peptide induces thermal hyperalgesia through a noncanonical Gbetagamma-dependent modulation of TRPV1 channel. AB - Natriuretic peptides (NPs) control natriuresis and normalize changes in blood pressure. Recent studies suggest that NPs are also involved in the regulation of pain sensitivity, although the underlying mechanisms remain essentially unknown. Many biological effects of NPs are mediated by guanylate cyclase (GC)-coupled NP receptors, NPR-A and NPR-B, whereas the third NP receptor, NPR-C, lacks the GC kinase domain and acts as the NP clearance receptor. In addition, NPR-C can couple to specific Galpha(i)-Gbetagamma-mediated intracellular signaling cascades in numerous cell types. We found that NPR-C is coexpressed in transient receptor potential vanilloid-1 (TRPV1)-expressing mouse dorsal root ganglia (DRG) neurons. NPR-C can be coimmunoprecipitated with Galpha(i), and C-type natriuretic peptide (CNP) treatment induced translocation of protein kinase Cepsilon (PKCepsilon) to the plasma membrane of these neurons, which was inhibited by pertussis toxin pretreatment. Application of CNP potentiated capsaicin- and proton-activated TRPV1 currents in cultured mouse DRG neurons and increased their firing frequency, an effect that was absent in DRG neurons from TRPV1(-/-) mice. CNP induced sensitization of TRPV1 activity was attenuated by pretreatment of DRG neurons with the specific inhibitors of Gbetagamma, phospholipase C-beta (PLCbeta), or PKC, but not of protein kinase A, and was abolished by mutations at two PKC phosphorylation sites in TRPV1. Furthermore, CNP injection into mouse hindpaw led to the development of thermal hyperalgesia that was attenuated by administration of specific inhibitors of Gbetagamma or TRPV1 and was also absent in TRPV1(-/-) mice. Thus, our work identifies the Gbetagamma-PLCbeta-PKC dependent potentiation of TRPV1 as a novel signaling cascade recruited by CNP in mouse DRG neurons that can lead to enhanced nociceptor excitability and thermal hypersensitivity. PMID- 22933781 TI - Dynamics of cortical neuronal ensembles transit from decision making to storage for later report. AB - Decisions based on sensory evaluation during single trials may depend on the collective activity of neurons distributed across brain circuits. Previous studies have deepened our understanding of how the activity of individual neurons relates to the formation of a decision and its storage for later report. However, little is known about how decision-making and decision maintenance processes evolve in single trials. We addressed this problem by studying the activity of simultaneously recorded neurons from different somatosensory and frontal lobe cortices of monkeys performing a vibrotactile discrimination task. We used the hidden Markov model to describe the spatiotemporal pattern of activity in single trials as a sequence of firing rate states. We show that the animal's decision was reliably maintained in frontal lobe activity through a selective state sequence, initiated by an abrupt state transition, during which many neurons changed their activity in a concomitant way, and for which both latency and variability depended on task difficulty. Indeed, transitions were more delayed and more variable for difficult trials compared with easy trials. In contrast, state sequences in somatosensory cortices were weakly decision related, had less variable transitions, and were not affected by the difficulty of the task. In summary, our results suggest that the decision process and its subsequent maintenance are dynamically linked by a cascade of transient events in frontal lobe cortices. PMID- 22933782 TI - Food intake adaptation to dietary fat involves PSA-dependent rewiring of the arcuate melanocortin system in mice. AB - Hormones such as leptin and ghrelin can rapidly rewire hypothalamic feeding circuits when injected into rodent brains. These experimental manipulations suggest that the hypothalamus might reorganize continually in adulthood to integrate the metabolic status of the whole body. In this study, we examined whether hypothalamic plasticity occurs in naive animals according to their nutritional conditions. For this purpose, we fed mice with a short-term high-fat diet (HFD) and assessed brain remodeling through its molecular and functional signature. We found that HFD for 3 d rewired the hypothalamic arcuate nucleus, increasing the anorexigenic tone due to activated pro-opiomelanocortin (POMC) neurons. We identified the polysialic acid molecule (PSA) as a mediator of the diet-induced rewiring of arcuate POMC. Moreover, local pharmacological inhibition and genetic disruption of the PSA signaling limits the behavioral and metabolic adaptation to HFD, as treated mice failed to normalize energy intake and showed increased body weight gain after the HFD challenge. Altogether, these findings reveal the existence of physiological hypothalamic rewiring involved in the homeostatic response to dietary fat. Furthermore, defects in the hypothalamic plasticity-driven adaptive response to HFD are obesogenic and could be involved in the development of metabolic diseases. PMID- 22933783 TI - Mechanisms of hippocampal long-term depression are required for memory enhancement by novelty exploration. AB - It is well known that novel environments can enhance learning and memory. However, the underlying mechanisms remain poorly understood. Here, we report that, in freely moving rats, novelty exploration facilitates the production of hippocampal CA1 long-term depression (LTD), a well characterized form of synaptic plasticity believed to be a cellular substrate of spatial learning, and thereby converts short-term memory (STM) into long-term memory (LTM) in an inhibitory avoidance learning procedure. Blocking the induction or the expression of CA1 LTD with two mechanistically and structurally distinct inhibitors prevents not only novelty acquisition but also the novelty exploration-promoted conversion of STM into LTM. Moreover, production of LTD with a strong electrical stimulation induction protocol or facilitation of hippocampal LTD by pharmacological inhibition of glutamate transporter activity mimics the behavioral effects of novelty exploration, sufficiently promoting the conversion of STM into LTM. Together, our findings suggest that induction of LTD may play an essential role not only in novelty acquisition but also in novelty-mediated memory enhancement. PMID- 22933785 TI - Actin polymerization-dependent increase in synaptic Arc/Arg3.1 expression in the amygdala is crucial for the expression of aversive memory associated with drug withdrawal. AB - Aversive memories associated with drug withdrawal may contribute to persistent drug seeking. Molecular mechanisms that are critical for aversive memory formation have yet to be elucidated. Recently, we showed in a rat conditioned place aversion (CPA) model that synaptic actin polymerization in the amygdala were required for aversive memory information. Here, we demonstrated that actin polymerization within the amygdala triggered transportation of activity-regulated cytoskeletal-associated protein (Arc/Arg3.1) into amygdalar synapses. Increased synaptic Arc/Arg3.1 expression contributed to aversive memory formation by regulating synaptic AMPA receptor (AMPAR) endocytosis, as in vivo knockdown of amygdalar Arc/Arg3.1 with Arc/Arg3.1-shRNA prevented both AMPAR endocytosis and CPA formation. We also demonstrated that conditioned morphine withdrawal led to induction of LTD in the amygdala through AMPAR endocytosis. We further demonstrated that Arc/Arg3.1-regulated AMPAR endocytosis was GluR2 dependent, as intra-amygdala injection of Tat-GluR2(3Y), a GluR2-derived peptide that has been shown to specifically block regulated, but not constitutive, AMPAR endocytosis, prevented AMPAR endocytosis, LTD induction, and aversive memory formation. Therefore, this study extends previous studies on the role of actin polymerization in synaptic plasticity and memory formation by revealing the critical molecular events involved in aversive memory formation as well as LTD induction, and by showing that Arc/Arg3.1 is a crucial mediator for actin polymerization functions, and, thus, underscores the unknown details of how actin polymerization mediates synaptic plasticity and memory. PMID- 22933786 TI - NMDA antagonist ketamine reduces task selectivity in macaque dorsolateral prefrontal neurons and impairs performance of randomly interleaved prosaccades and antisaccades. AB - Ketamine, an NMDA receptor antagonist, has been shown to induce behavioral abnormalities in humans that mimic the positive, negative, and most importantly cognitive deficits observed in schizophrenia. Similar cognitive deficits have been observed in nonhuman primates after a subanesthetic dose of ketamine, including an impairment in their ability to perform the antisaccade task, which requires the suppression of a prosaccade toward a flashed stimulus and the generation of a saccade in the opposite direction. The neural basis underlying these cognitive impairments remains unknown. Here, we recorded single-neuron activity in the lateral prefrontal cortex of macaque monkeys before and after the administration of subanesthetic doses of ketamine during the performance of randomly interleaved prosaccade and antisaccade trials. Ketamine impeded the monkeys' ability to maintain and apply the correct task rule and increased reaction times of prosaccades and antisaccades. These behavioral changes were associated with an overall increase in activity of PFC neurons and a reduction in their task selectivity. Our results suggest that the mechanism underlying ketamine-induced cognitive abnormalities may be the nonspecific increase in PFC activity and the associated reduction of task selectivity. PMID- 22933784 TI - Cholinergic dysfunction alters synaptic integration between thalamostriatal and corticostriatal inputs in DYT1 dystonia. AB - Projections from thalamic intralaminar nuclei convey sensory signals to striatal cholinergic interneurons. These neurons respond with a pause in their pacemaking activity, enabling synaptic integration with cortical inputs to medium spiny neurons (MSNs), thus playing a crucial role in motor function. In mice with the DYT1 dystonia mutation, stimulation of thalamostriatal axons, mimicking a response to salient events, evoked a shortened pause and triggered an abnormal spiking activity in interneurons. This altered pattern caused a significant rearrangement of the temporal sequence of synaptic activity mediated by M(1) and M(2) muscarinic receptors in MSNs, consisting of an increase in postsynaptic currents and a decrease of presynaptic inhibition, respectively. Consistent with a major role of acetylcholine, either lowering cholinergic tone or antagonizing postsynaptic M(1) muscarinic receptors normalized synaptic activity. Our data demonstrate an abnormal time window for synaptic integration between thalamostriatal and corticostriatal inputs, which might alter the action selection process, thereby predisposing DYT1 gene mutation carriers to develop dystonic movements. PMID- 22933787 TI - Focal increases of axoplasmic Ca2+, aggregation of sodium-calcium exchanger, N type Ca2+ channel, and actin define the sites of spheroids in axons undergoing oxidative stress. AB - Axonal spheroids occur as part of the pathology of a variety of neurologic diseases. Reactive oxygen species (ROS) trigger formation of spheroids, axonal severing, and Ca(2+) overload. The mechanisms by which ROS lead to the spheroid formation at specific axonal sites remain elusive. Here, using adult mouse primary neurons, we investigate the role of Ca(2+), its regulating systems, and cytoskeletal changes in formation of axonal spheroids triggered by ROS. The results reveal that dramatically higher axoplasmic Ca(2+) levels occur at the sites of axonal spheroids than in the rest of the axon. High focal axoplasmic Ca(2+) levels correlate with focal aggregation of the reverse Na(+)/Ca(2+) exchanger 1, voltage-gated N-type Ca(2+) channel alpha1B subunit, and actin at the sites of spheroids in individual axons. This study provides new insights into the mechanism of a spheroid formation at specific sites along axons undergoing oxidative stress and a basis for new neuroprotective strategies. PMID- 22933788 TI - Selectivity for three-dimensional shape and grasping-related activity in the macaque ventral premotor cortex. AB - Anatomical studies indicate that area F5 in the macaque ventral premotor cortex consists of three different sectors. One of these is F5a in the posterior bank of the inferior arcuate sulcus, but no functional characterization of F5a at the single-cell level exists. We investigated the neuronal selectivity for three dimensional (3D) shape and grasping activity in F5a. In contrast to neighboring regions F5p and 45B, the great majority of F5a neurons showed selectivity for disparity-defined curved surfaces, and most neurons preserved this selectivity across positions in depth, indicating higher-order disparity selectivity. Thus, as predicted by monkey fMRI data, F5a neurons showed robust 3D-shape selectivity in the absence of a motor response. To investigate the relationship between disparity selectivity and grasping activity, we recorded from 3D-shape-selective F5a neurons during a visually guided grasping task and during grasping in the dark. F5a neurons encoding the depth profile of curved surfaces frequently responded during grasping of real-world objects in the light, but not in the dark, whereas nearby neurons were also active in the dark. The presence of 3D shape-selective and "visual-dominant" neurons demonstrates that the F5a sector is distinct from neighboring regions of ventral premotor cortex, in line with recent anatomical connectivity studies. PMID- 22933790 TI - Corticostriatal connectivity underlies individual differences in the balance between habitual and goal-directed action control. AB - Why are some individuals more susceptible to the formation of inflexible habits than others? In the present study, we used diffusion tensor imaging to demonstrate that brain connectivity predicts individual differences in relative goal-directed and habitual behavioral control in humans. Specifically, vulnerability to habitual "slips of action" toward no-longer-rewarding outcomes was predicted by estimated white matter tract strength in the premotor cortex seeded from the posterior putamen (as well as by gray matter density in the posterior putamen as determined with voxel-based morphometry). In contrast, flexible goal-directed action was predicted by estimated tract strength in the ventromedial prefrontal cortex seeded from the caudate. These findings suggest that integrity of dissociable corticostriatal pathways underlies individual differences in action control in the healthy population, which may ultimately mediate vulnerability to impulse control disorders. PMID- 22933789 TI - Cell-autonomous inactivation of the reelin pathway impairs adult neurogenesis in the hippocampus. AB - Adult hippocampal neurogenesis is thought to be essential for learning and memory, and has been implicated in the pathogenesis of several disorders. Although recent studies have identified key factors regulating neuroprogenitor proliferation in the adult hippocampus, the mechanisms that control the migration and integration of adult-born neurons into circuits are largely unknown. Reelin is an extracellular matrix protein that is vital for neuronal development. Activation of the Reelin cascade leads to phosphorylation of Disabled-1, an adaptor protein required for Reelin signaling. Here we used transgenic mouse and retroviral reporters along with Reelin signaling gain-of-function and loss-of function studies to show that the Reelin pathway regulates migration and dendritic development of adult-generated hippocampal neurons. Whereas overexpression of Reelin accelerated dendritic maturation, inactivation of the Reelin signaling pathway specifically in adult neuroprogenitor cells resulted in aberrant migration, decreased dendrite development, formation of ectopic dendrites in the hilus, and the establishment of aberrant circuits. Our findings support a cell-autonomous and critical role for the Reelin pathway in regulating dendritic development and the integration of adult-generated granule cells and point to this pathway as a key regulator of adult neurogenesis. Moreover, our data reveal a novel role of the Reelin cascade in adult brain function with potential implications for the pathogenesis of several neurological and psychiatric disorders. PMID- 22933792 TI - The processing of unexpected positive response outcomes in the mediofrontal cortex. AB - The human mediofrontal cortex, especially the anterior cingulate cortex, is commonly assumed to contribute to higher cognitive functions like performance monitoring. How exactly this is achieved is currently the subject of lively debate but there is evidence that an event's valence and its expectancy play important roles. One prominent theory, the reinforcement learning theory by Holroyd and colleagues (2002, 2008), assigns a special role to feedback valence, while the prediction of response-outcome (PRO) model by Alexander and Brown (2010, 2011) claims that the mediofrontal cortex is sensitive to unexpected events regardless of their valence. However, paradigms examining this issue have included confounds that fail to separate valence and expectancy. In the present study, we tested the two competing theories of performance monitoring by using an experimental task that separates valence and unexpectedness of performance feedback. The feedback-related negativity of the event-related potential, which is commonly assumed to be a reflection of mediofrontal cortex activity, was elicited not only by unexpected negative feedback, but also by unexpected positive feedback. This implies that the mediofrontal cortex is sensitive to the unexpectedness of events in general rather than their valence and by this supports the PRO model. PMID- 22933791 TI - Identification of functional circuitry between retrosplenial and postrhinal cortices during fear conditioning. AB - The retrosplenial cortex (RSP) and postrhinal cortex (POR) are heavily interconnected with medial temporal lobe structures involved in learning and memory. Previous studies indicate that RSP and POR are necessary for contextual fear conditioning, but it remains unclear whether these regions contribute individually or instead work together as a functional circuit to modulate learning and/or memory. In Experiment 1, learning-related neuronal activity was assessed in RSP from home cage, shock-only, context-only, or fear-conditioned rats using real-time PCR and immunohistochemical methods to quantify immediate early gene expression. A significant increase in activity-regulated cytoskeleton associated protein (Arc) mRNA and Arc and c-Fos protein expression was detected in RSP from fear-conditioned rats compared with all other groups. In Experiment 2, retrograde tracing combined with immunohistochemistry revealed that, compared with controls, a significant proportion of cells projecting from RSP to POR were immunopositive for c-Fos in fear-conditioned rats. These results demonstrate that neurons projecting from RSP to POR are indeed active during fear conditioning. In Experiment 3, a functional disconnection paradigm was used to further examine the interaction between RSP and POR during fear conditioning. Compared with controls, rats with unilateral lesions of RSP and POR on opposite sides of the brain exhibited impaired contextual fear memory, whereas rats with unilateral lesions in the same hemisphere displayed intermediate levels of freezing compared with controls and rats with contralateral lesions. Collectively, these results are the first to show that RSP and POR function as a cortical network necessary for contextual fear learning and memory. PMID- 22933793 TI - Kainic acid-induced neuronal degeneration in hippocampal pyramidal neurons is driven by both intrinsic and extrinsic factors: analysis of FVB/N<->C57BL/6 chimeras. AB - The excitotoxic effects of kainic acid (KA) in the mouse hippocampus is strain dependent. Following KA administration, the large majority of hippocampal pyramidal cells die in the FVB/N (FVB) mouse, while the pyramidal cells of the C57BL/6 (B6) strain are largely spared. We generated aggregation chimeras between the sensitive FVB and the resistant B6 strains to investigate whether intrinsic or extrinsic features of a neuron confer cell vulnerability or resistance to KA. The constitutive expression of transgenic green fluorescence protein (GFP) or beta-galactosidase expressed from the ROSA26 locus was used to mark cells in FVB or B6 mice, respectively. These makers enable the identification of cells from each parental genotype while TUNEL (terminal deoxynucleotidyl transferase mediated biotinylated dUTP nick end labeling)-staining labeled dying cells. The analysis of the percentage of dying cells in FVB-GFP <-> B6-ROSA chimeras yielded an intriguing mix of both intrinsic and extrinsic factors in the readout of cell phenotype. Thus, normally resistant B6-ROSA pyramidal neurons demonstrated an increasing sensitivity to KA, in a linear fashion, when the percentage of FVB-GFP cells was increased, either across chimeras or in different regions of the same chimera. However, the death of B6-ROSA pyramidal cells never exceeded ~70% of the total amount of B6 neurons regardless of the amount of FVB cells in the chimeric hippocampus. In a similar manner, FVB-GFP cells show lower amounts of cell death in chimeras that are colonized by B6-ROSA cells, but again, are never fully rescued. These data indicate that both intrinsic and extrinsic factors modulate the sensitivity of hippocampal pyramidal cells to kainic acid. PMID- 22933794 TI - Coding rate and duration of vocalizations of the frog, Xenopus laevis. AB - Vocalizations involve complex rhythmic motor patterns, but the underlying temporal coding mechanisms in the nervous system are poorly understood. Using a recently developed whole-brain preparation from which "fictive" vocalizations are readily elicited in vitro, we investigated the cellular basis of temporal complexity of African clawed frogs (Xenopus laevis). Male advertisement calls contain two alternating components--fast trills (~300 ms) and slow trills (~700 ms) that contain clicks repeated at ~60 and ~30 Hz, respectively. We found that males can alter the duration of fast trills without changing click rates. This finding led us to hypothesize that call rate and duration are regulated by independent mechanisms. We tested this by obtaining whole-cell patch-clamp recordings in the "fictively" calling isolated brain. We discovered a single type of premotor neuron with activity patterns correlated with both the rate and duration of fast trills. These "fast-trill neurons" (FTNs) exhibited long-lasting depolarizations (LLDs) correlated with each fast trill and action potentials that were phase-locked with motor output-neural correlates of call duration and rate, respectively. When depolarized without central pattern generator activation, FTNs produced subthreshold oscillations and action potentials at fast-trill rates, indicating FTN resonance properties are tuned to, and may dictate, the fast-trill rhythm. NMDA receptor (NMDAR) blockade eliminated LLDs in FTNs, and NMDAR activation in synaptically isolated FTNs induced repetitive LLDs. These results suggest FTNs contain an NMDAR-dependent mechanism that may regulate fast-trill duration. We conclude that a single premotor neuron population employs distinct mechanisms to regulate call rate and duration. PMID- 22933796 TI - Red nucleus neurons actively contribute to the acquisition of classically conditioned eyelid responses in rabbits. AB - The red nucleus (RN) is a midbrain premotor center that has been suggested as being involved in the acquisition and/or performance of classically conditioned nictitating membrane/eyelid responses. We recorded in rabbits the activity of RN and pararubral neurons during classical eyeblink conditioning using a delay paradigm. Neurons were identified by their antidromic activation from contralateral facial and accessory abducens nuclei and by their synaptic activation from the ipsilateral motor cortex (MC) and the contralateral cerebellar interpositus (IP) nucleus. For conditioning, we used a tone as a conditioned stimulus (CS) followed 250 ms later by a 100 ms air puff as an unconditioned stimulus (US) coterminating with it. Conditioned responses (CRs) were determined from the evoked changes in the electromyographic activity of the orbicularis oculi (OO) muscle. Recorded neurons were classified by their antidromic activation and by their changes in firing rate during the CS-US interval. Identified neurons increased their firing rates in relation to the successive conditioning sessions, but their discharge rates were related more to the EMG activity of the OO muscle than to the learning curves. Reversible inactivation of the IP nucleus with lidocaine during conditioning evoked a complete disappearance of both conditioned and unconditioned eyelid responses, and a progressive decrease in CR-related activity of RN neurons. In contrast, MC inactivation evoked a decrease in the acquisition process and an initial disfacilitation of neuronal firing (which was later recovered), together with the late appearance of CRs. Thus, RN neurons presented learning-dependent changes in activity following MC inactivation. PMID- 22933795 TI - Time to pay attention: attentional performance time-stamped prefrontal cholinergic activation, diurnality, and performance. AB - Although the impairments in cognitive performance that result from shifting or disrupting daily rhythms have been demonstrated, the neuronal mechanisms that optimize fixed-time daily performance are poorly understood. We previously demonstrated that daily practice of a sustained attention task (SAT) evokes a diurnal activity pattern in rats. Here, we report that SAT practice at a fixed time produced practice time-stamped increases in prefrontal cholinergic neurotransmission that persisted after SAT practice was terminated and in a different environment. SAT time-stamped cholinergic activation occurred regardless of whether the SAT was practiced during the light or dark phase or in constant-light conditions. In contrast, prior daily practice of an operant schedule of reinforcement, albeit generating more rewards and lever presses per session than the SAT, neither activated the cholinergic system nor affected the animals' nocturnal activity pattern. Likewise, food-restricted animals exhibited strong food anticipatory activity (FAA) and attenuated activity during the dark phase but FAA was not associated with increases in prefrontal cholinergic activity. Removal of cholinergic neurons impaired SAT performance and facilitated the reemergence of nocturnality. Shifting SAT practice away from a fixed time resulted in significantly lower performance. In conclusion, these experiments demonstrated that fixed-time, daily practice of a task assessing attention generates a precisely practice time-stamped activation of the cortical cholinergic input system. Time-stamped cholinergic activation benefits fixed-time performance and, if practiced during the light phase, contributes to a diurnal activity pattern. PMID- 22933797 TI - Neural correlates of reactivation and retrieval-induced distortion. AB - Reactivation of recently acquired information can strengthen memory storage and likely contributes to memory consolidation. Retrieval (generating information about prior events) may improve memory storage because it entails reactivation. Alternatively, retrieval may promote storage of retrieved information, and, if retrieval is inaccurate, subsequent recall could be distorted by the retrieved information. If retrieval modifies memory storage, as hypothesized, neural signals associated with accurate retrieval at that time may be distinct from neural signals associated with the degree of repeated retrieval error evident at some later time. We tested this prediction using a 3-session protocol. During session 1, people learned object-location associations to criterion and completed a cued-recall test in which locations were recalled upon viewing objects. During session 2, an electroencephalogram (EEG) was recorded during cued recall for a subset of the associations. During session 3, cued recall was tested for all associations. Retrieval improved storage, in that recall at session 3 was superior for objects tested in session 2 compared with those not tested. Retrieval-induced distortion was revealed in session 3 for those objects tested in session 2, in that those objects were generally placed closer to locations retrieved at session 2 relative to original study locations. EEG analyses revealed positive potentials (400-700 ms) associated with relatively accurate recall at session 2. Memory updating was reflected in positive potentials after 700 ms that differentially predicted the degree to which recall promoted storage of the session-2-retrieved location. These findings demonstrate unique neurocognitive processing whereby memories are updated with information produced during retrieval. PMID- 22933800 TI - The selectivity of task-dependent attention varies with surrounding context. AB - Attention is thought to operate by enhancing the target of interest and suppressing the surroundings. We hypothesized that the spatial profile of attention depends on the surround's relationship to the target. Using high density electroencephalographic measurements, we examined the spatial profile of attention to a grating target surrounded by an annular grating that was either coextensive with the target (unsegmented) or appeared segmented from it due to a gap or phase offset. We directly probed the spread of attention from the central target into the surround by flickering the surround and monitoring frequency tagged steady-state visual-evoked potentials. Observers were required to detect a contrast increment that occurred only on the target. Successful detection of the increment required selecting the target and suppressing the surround, particularly when the target did not readily segment from the surround. The profile of attention was investigated in five visual regions of interest (ROIs) (V1, V4, V3A, lateral occipital complex, and human middle temporal area), mapped in a separate anatomical magnetic resonance imaging scan. We found that in most ROIs, attention to the target generated smaller responses from the surrounding annulus when it was contiguous compared with when it was clearly segmented. This result shows that the profile of attention depends on task demands and on surrounding context; attention is tightly focused when the target region needs to be isolated but loosely focused when the target region is clearly segmented. PMID- 22933799 TI - Selective functional interactions between excitatory and inhibitory cortical neurons and differential contribution to persistent activity of the slow oscillation. AB - The neocortex depends upon a relative balance of recurrent excitation and inhibition for its operation. During spontaneous Up states, cortical pyramidal cells receive proportional barrages of excitatory and inhibitory synaptic potentials. Many of these synaptic potentials arise from the activity of nearby neurons, although the identity of these cells is relatively unknown, especially for those underlying the generation of inhibitory synaptic events. To address these fundamental questions, we developed an in vitro submerged slice preparation of the mouse entorhinal cortex that generates robust and regular spontaneous recurrent network activity in the form of the slow oscillation. By performing whole-cell recordings from multiple cell types identified with green fluorescent protein expression and electrophysiological and/or morphological properties, we show that distinct functional subpopulations of neurons exist in the entorhinal cortex, with large variations in contribution to the generation of balanced excitation and inhibition during the slow oscillation. The most active neurons during the slow oscillation are excitatory pyramidal and inhibitory fast spiking interneurons, receiving robust barrages of both excitatory and inhibitory synaptic potentials. Weak action potential activity was observed in stellate excitatory neurons and somatostatin-containing interneurons. In contrast, interneurons containing neuropeptide Y, vasoactive intestinal peptide, or the 5 hydroxytryptamine (serotonin) 3a receptor, were silent. Our data demonstrate remarkable functional specificity in the interactions between different excitatory and inhibitory cortical neuronal subtypes, and suggest that it is the large recurrent interaction between pyramidal neurons and fast spiking interneurons that is responsible for the generation of persistent activity that characterizes the depolarized states of the cortex. PMID- 22933798 TI - PEDF is a novel oligodendrogenic morphogen acting on the adult SVZ and corpus callosum. AB - Pigment epithelium-derived factor (PEDF) is a serine protease inhibitor (serpin) protein with well established neuroprotective and anti-angiogenic properties. Recent studies have also shown that PEDF enhances renewal of adult subventricular zone (SVZ) neural precursors. In neurosphere cultures prepared from the SVZ of adult mice, we found that addition of recombinant PEDF to the medium enhanced expressions of oligodendroglial lineage markers (NG2 and PDGFralpha) and transcription factors (Olig1, Olig2, and Sox10). Similarly, continuous PEDF administration into the lateral ventricles of adult glial fibrillary acidic protein:green fluorescent protein (GFAP:GFP) transgenic mice increased the proportions of GFAP:GFP+ and GFAP:GFP- SVZ neural precursors coexpressing oligodendroglial lineage markers and transcription factors. Notably, PEDF infusion also resulted in an induction of doublecortin- and Sox10 double-positive cells in the adult SVZ. Immunoreactive PEDF receptor was detectable in multiple cell types in both adult SVZ and corpus callosum. Furthermore, PEDF intracerebral infusion enhanced survival and maturation of newly born oligodendroglial progenitor cells in the normal corpus callosum, and accelerated oligodendroglial regeneration in lysolecithin-induced corpus callosum demyelinative lesions. Western blot analysis showed a robust upregulation of endogenous PEDF in the corpus callosum upon lysolecithin-induced demyelination. Our results document previously unrecognized oligodendrotrophic effects of recombinant PEDF on the adult SVZ and corpus callosum, demonstrate induction of endogenous CNS PEDF production following demyelination, and make PEDF a strong candidate for pharmacological intervention in demyelinative diseases. PMID- 22933801 TI - Deletion of the presynaptic scaffold CAST reduces active zone size in rod photoreceptors and impairs visual processing. AB - How size and shape of presynaptic active zones are regulated at the molecular level has remained elusive. Here we provide insight from studying rod photoreceptor ribbon-type active zones after disruption of CAST/ERC2, one of the cytomatrix of the active zone (CAZ) proteins. Rod photoreceptors were present in normal numbers, and the a-wave of the electroretinogram (ERG)--reflecting their physiological population response--was unchanged in CAST knock-out (CAST(-/-)) mice. Using immunofluorescence and electron microscopy, we found that the size of the rod presynaptic active zones, their Ca(2+) channel complement, and the extension of the outer plexiform layer were diminished. Moreover, we observed sprouting of horizontal and bipolar cells toward the outer nuclear layer indicating impaired rod transmitter release. However, rod synapses of CAST(-/-) mice, unlike in mouse mutants for the CAZ protein Bassoon, displayed anchored ribbons, normal vesicle densities, clustered Ca(2+) channels, and essentially normal molecular organization. The reduction of the rod active zone size went along with diminished amplitudes of the b-wave in scotopic ERGs. Assuming, based on the otherwise intact synaptic structure, an unaltered function of the remaining release apparatus, we take our finding to suggest a scaling of release rate with the size of the active zone. Multielectrode-array recordings of retinal ganglion cells showed decreased contrast sensitivity. This was also observed by optometry, which, moreover, revealed reduced visual acuity. We conclude that CAST supports large active zone size and high rates of transmission at rod ribbon synapses, which are required for normal vision. PMID- 22933803 TI - Synapsins contribute to the dynamic spatial organization of synaptic vesicles in an activity-dependent manner. AB - The precise subcellular organization of synaptic vesicles (SVs) at presynaptic sites allows for rapid and spatially restricted exocytotic release of neurotransmitter. The synapsins (Syns) are a family of presynaptic proteins that control the availability of SVs for exocytosis by reversibly tethering them to each other and to the actin cytoskeleton in a phosphorylation-dependent manner. Syn ablation leads to reduction in the density of SV proteins in nerve terminals and increased synaptic fatigue under high-frequency stimulation, accompanied by the development of an epileptic phenotype. We analyzed cultured neurons from wild type and Syn I,II,III(-/-) triple knock-out (TKO) mice and found that SVs were severely dispersed in the absence of Syns. Vesicle dispersion did not affect the readily releasable pool of SVs, whereas the total number of SVs was considerably reduced at synapses of TKO mice. Interestingly, dispersion apparently involved exocytosis-competent SVs as well; it was not affected by stimulation but was reversed by chronic neuronal activity blockade. Altogether, these findings indicate that Syns are essential to maintain the dynamic structural organization of synapses and the size of the reserve pool of SVs during intense SV recycling, whereas an additional Syn-independent mechanism, whose molecular substrate remains to be clarified, targets SVs to synaptic boutons at rest and might be outpaced by activity. PMID- 22933802 TI - Age-related changes in the neurophysiology of language in adults: relationship to regional cortical thinning and white matter microstructure. AB - Although reading skill remains relatively stable with advancing age in humans, neurophysiological measures suggest potential reductions in efficiency of lexical information processing. It is unclear whether these age-related changes are secondary to decreases in regional cortical thickness and/or microstructure of fiber tracts essential to language. Magnetoencephalography, volumetric MRI, and diffusion tensor imaging were performed in 10 young (18-33 years) and 10 middle aged (42-64 years) human individuals to evaluate the spatiotemporal dynamics and structural correlates of age-related changes in lexical-semantic processing. Increasing age was associated with reduced activity in left temporal lobe regions from 250 to 350 ms and in left inferior prefrontal cortex from 350 to 450 ms (i.e., N400). Hierarchical regression indicated that age no longer predicted left inferior prefrontal activity after cortical thickness and fractional anisotropy (FA) of the uncinate fasciculus (UF) were considered. Interestingly, FA of the UF was a stronger predictor of the N400 response than cortical thickness. Age related reductions in left-lateralization of language responses were observed between 250 and 350 ms, and were associated with left temporal thinning and frontotemporal FA reductions. N400 reductions were not associated with poorer task performance. Rather, increasing age was associated with reduction in the left prefrontal N400, which in turn was also associated with slower response time. These results reveal that changes in the neurophysiology of language occur by middle age and appear to be partially mediated by structural brain loss. These neurophysiological changes may reflect an adaptive process that ensues as communication between left perisylvian regions declines. PMID- 22933804 TI - T-type calcium channels consolidate tonic action potential output of thalamic neurons to neocortex. AB - The thalamic output during different behavioral states is strictly controlled by the firing modes of thalamocortical neurons. During sleep, their hyperpolarized membrane potential allows activation of the T-type calcium channels, promoting rhythmic high-frequency burst firing that reduces sensory information transfer. In contrast, in the waking state thalamic neurons mostly exhibit action potentials at low frequency (i.e., tonic firing), enabling the reliable transfer of incoming sensory inputs to cortex. Because of their nearly complete inactivation at the depolarized potentials that are experienced during the wake state, T-channels are not believed to modulate tonic action potential discharges. Here, we demonstrate using mice brain slices that activation of T-channels in thalamocortical neurons maintained in the depolarized/wake-like state is critical for the reliable expression of tonic firing, securing their excitability over changes in membrane potential that occur in the depolarized state. Our results establish a novel mechanism for the integration of sensory information by thalamocortical neurons and point to an unexpected role for T-channels in the early stage of information processing. PMID- 22933805 TI - Voluntary and reactive recruitment of locomotor muscle synergies during perturbed walking. AB - The modular control of muscles in groups, often referred to as muscle synergies, has been proposed to provide a motor repertoire of actions for the robust control of movement. However, it is not clear whether muscle synergies identified in one task are also recruited by different neural pathways subserving other motor behaviors. We tested the hypothesis that voluntary and reactive modifications to walking in humans result from the recruitment of locomotor muscle synergies. We recorded the activity of 16 muscles in the right leg as subjects walked a 7.5 m path at two different speeds. To elicit a second motor behavior, midway through the path we imposed ramp and hold translation perturbations of the support surface in each of four cardinal directions. Variations in the temporal recruitment of locomotor muscle synergies could account for cycle-by-cycle variations in muscle activity across strides. Locomotor muscle synergies were also recruited in atypical phases of gait, accounting for both anticipatory gait modifications before perturbations and reactive feedback responses to perturbations. Our findings are consistent with the idea that a common pool of spatially fixed locomotor muscle synergies can be recruited by different neural pathways, including the central pattern generator for walking, brainstem pathways for balance control, and cortical pathways mediating voluntary gait modifications. Together with electrophysiological studies, our work suggests that muscle synergies may provide a library of motor subtasks that can be flexibly recruited by parallel descending pathways to generate a variety of complex natural movements in the upper and lower limbs. PMID- 22933806 TI - Navigating the auditory scene: an expert role for the hippocampus. AB - Over a typical career piano tuners spend tens of thousands of hours exploring a specialized acoustic environment. Tuning requires accurate perception and adjustment of beats in two-note chords that serve as a navigational device to move between points in previously learned acoustic scenes. It is a two-stage process that depends on the following: first, selective listening to beats within frequency windows, and, second, the subsequent use of those beats to navigate through a complex soundscape. The neuroanatomical substrates underlying brain specialization for such fundamental organization of sound scenes are unknown. Here, we demonstrate that professional piano tuners are significantly better than controls matched for age and musical ability on a psychophysical task simulating active listening to beats within frequency windows that is based on amplitude modulation rate discrimination. Tuners show a categorical increase in gray matter volume in the right frontal operculum and right superior temporal lobe. Tuners also show a striking enhancement of gray matter volume in the anterior hippocampus, parahippocampal gyrus, and superior temporal gyrus, and an increase in white matter volume in the posterior hippocampus as a function of years of tuning experience. The relationship with gray matter volume is sensitive to years of tuning experience and starting age but not actual age or level of musicality. Our findings support a role for a core set of regions in the hippocampus and superior temporal cortex in skilled exploration of complex sound scenes in which precise sound "templates" are encoded and consolidated into memory over time in an experience-dependent manner. PMID- 22933808 TI - A precluding but not ensuring role of entrained low-frequency oscillations for auditory perception. AB - Oscillatory activity in sensory cortices reflects changes in local excitation inhibition balance, and recent work suggests that phase signatures of ongoing oscillations predict the perceptual detection of subsequent stimuli. Low frequency oscillations are also entrained by dynamic natural scenes, suggesting that the chance of detecting a brief target depends on the relative timing of this to the entrained rhythm. We tested this hypothesis in humans by implementing a cocktail-party-like scenario requiring subjects to detect a target embedded in a cacophony of background sounds. Using EEG to measure auditory cortical oscillations, we find that the chance of target detection systematically depends on both power and phase of theta-band (2-6 Hz) but not alpha-band (8-12 Hz) oscillations before target. Detection rates were higher and responses faster when oscillatory power was low and both detection rate and response speed were modulated by phase. Intriguingly, the phase dependency was stronger for miss than for hit trials, suggesting that phase has a inhibiting but not ensuring role for detection. Entrainment of theta range oscillations prominently occurs during the processing of attended complex stimuli, such as vocalizations and speech. Our results demonstrate that this entrainment to attended sensory environments may have negative effects on the detection of individual tokens within the environment, and they support the notion that specific phase ranges of cortical oscillations act as gatekeepers for perception. PMID- 22933807 TI - Parietal influence on temporal encoding indexed by simultaneous transcranial magnetic stimulation and electroencephalography. AB - Previous studies have suggested that contingent negative variation (CNV), as recorded by electroencaphalography (EEG), may serve as an index of temporal encoding. The interpretation of these studies is complicated by the fact that, in a majority of studies, the CNV signal was obtained at a time when subjects were not only registering stimulus duration but also making decisions and preparing to act. Previously, we demonstrated that repetitive transcranial magnetic stimulation (rTMS) of the right supramarginal gyrus (rSMG) in humans lengthened the perceived duration of a visual stimulus (Wiener et al., 2010a), suggesting the rSMG is involved in basic encoding processes. Here, we report a replication of this effect with simultaneous EEG recordings during the encoding of stimulus duration. Stimulation of the rSMG led to an increase in perceived duration and the amplitude of N1 and CNV components recorded from frontocentral sites. Furthermore, the size of the CNV amplitude, but not N1, positively correlated with the size of the rTMS effect but negatively correlated with bias (the baseline tendency to report a comparison stimulus as shorter), suggesting that the CNV indexes stimulus duration. These results suggest that a feedforward mechanism from parietal to prefrontal regions mediates temporal encoding and demonstrate a dissociation between early and late phases of encoding processes. PMID- 22933809 TI - Top-down processing of symbolic meanings modulates the visual word form area. AB - Functional magnetic resonance imaging (fMRI) studies on humans have identified a region in the left middle fusiform gyrus consistently activated by written words. This region is called the visual word form area (VWFA). Recently, a hypothesis, called the interactive account, is proposed that to effectively analyze the bottom-up visual properties of words, the VWFA receives predictive feedback from higher-order regions engaged in processing sounds, meanings, or actions associated with words. Further, this top-down influence on the VWFA is independent of stimulus formats. To test this hypothesis, we used fMRI to examine whether a symbolic nonword object (e.g., the Eiffel Tower) intended to represent something other than itself (i.e., Paris) could activate the VWFA. We found that scenes associated with symbolic meanings elicited a higher VWFA response than those not associated with symbolic meanings, and such top-down modulation on the VWFA can be established through short-term associative learning, even across modalities. In addition, the magnitude of the symbolic effect observed in the VWFA was positively correlated with the subjective experience on the strength of symbol-referent association across individuals. Therefore, the VWFA is likely a neural substrate for the interaction of the top-down processing of symbolic meanings with the analysis of bottom-up visual properties of sensory inputs, making the VWFA the location where the symbolic meaning of both words and nonword objects is represented. PMID- 22933810 TI - Suppressive surrounds of receptive fields in monkey frontal eye field. AB - A critical step in determining how a neuron contributes to visual processing is determining its visual receptive field (RF). While recording from neurons in frontal eye field (FEF) of awake monkeys (Macaca mulatta), we probed the visual field with small spots of light and found excitatory RFs that decreased in strength from RF center to periphery. However, presenting stimuli with different diameters centered on the RF revealed suppressive surrounds that overlapped the previously determined excitatory RF and reduced responses by 84%, on average. Consequently, in that overlap area, stimulation produced excitation or suppression, depending on the stimulus. Strong stimulation of the RF periphery with annular stimuli allowed us to quantify this effect. A modified difference of gaussians model that independently varied center and surround activation accounted for the nonlinear activity in the overlap area. Our results suggest that (1) the suppressive surrounds found in FEF are fundamentally the same as those in V1 except for the size and strength of excitatory and suppressive mechanisms, (2) methodically assaying suppressive surrounds in FEF is essential for correctly interpreting responses to large and/or peripheral stimuli and therefore understanding the effects of stimulus context, and (3) regulating the relative strength of the surround clearly changes neuronal responses and may therefore play a significant part in the neuronal changes resulting from visual attention and stimulus salience. PMID- 22933811 TI - Attention distributed across sensory modalities enhances perceptual performance. AB - This study investigated the interaction between top-down attentional control and multisensory processing in humans. Using semantically congruent and incongruent audiovisual stimulus streams, we found target detection to be consistently improved in the setting of distributed audiovisual attention versus focused visual attention. This performance benefit was manifested as faster reaction times for congruent audiovisual stimuli and as accuracy improvements for incongruent stimuli, resulting in a resolution of stimulus interference. Electrophysiological recordings revealed that these behavioral enhancements were associated with reduced neural processing of both auditory and visual components of the audiovisual stimuli under distributed versus focused visual attention. These neural changes were observed at early processing latencies, within 100-300 ms poststimulus onset, and localized to auditory, visual, and polysensory temporal cortices. These results highlight a novel neural mechanism for top-down driven performance benefits via enhanced efficacy of sensory neural processing during distributed audiovisual attention relative to focused visual attention. PMID- 22933812 TI - Neuroanatomical substrates of visual hallucinations in patients with non-demented Parkinson's disease. AB - BACKGROUND: Visual hallucinations (VH), which are common in patients with Parkinson's disease (PD), lead to increased disability and are a significant predictor of the development of dementia. However, the neuroanatomical basis for VH in non-demented PD patients remains controversial. METHODS: A total of 110 patients with PD were classified into PD with VH (n=46) and PD without VH (n=64) groups, depending on the presence of VH assessed by the caregiver-based structured interview of the Neuropsychiatric Inventory. We performed voxel-based morphometry (VBM) for grey matter (GM) volume and a region-of-interest-based volumetric analysis of the substantia innominata (SI) between two groups. RESULTS: The comprehensive neuropsychological assessment showed that PD patients with VH showed more severe cognitive deficits in delayed visual memory and frontal executive functions compared with those without VH. A VBM analysis revealed that PD patients with VH had significantly lower GM volume in the right orbitofrontal, left temporal and left thalamic areas compared with those without VH. The normalised SI volume was significantly reduced in PD patients with VH compared with those without VH (1.28 +/- 0.22 vs 1.41 +/- 0.25, p=0.005). CONCLUSIONS: The present study demonstrates that non-demented PD patients with VH exhibited a smaller volume in the frontal, temporal and thalamic areas as well as the SI, suggesting that PD hallucinators may have distinctive neuroanatomical bases relative to PD non-hallucinators. PMID- 22933813 TI - A longitudinal MRI study of traumatic axonal injury in patients with moderate and severe traumatic brain injury. AB - OBJECTIVE: To study the evolution of traumatic axonal injury (TAI) detected by structural MRI in patients with moderate and severe traumatic brain injury (TBI) during the first year and relate findings to outcome. METHODS: 58 patients with TBI (Glasgow Coma Scale score 3-13) were examined with MRI at a median of 7 days, 3 months and 12 months post injury. TAI lesions were evaluated blinded and categorised into three stages based on location: hemispheres, corpus callosum and brainstem. Lesions in T2* weighted gradient echo (GRE), fluid attenuated inversion recovery (FLAIR) and diffusion weighted imaging (DWI) were counted and FLAIR lesion volumes were estimated. Inter-rater reliability score was calculated. Outcome was assessed 12 months post injury using the Glasgow Outcome Scale Extended. RESULTS: In the initial MRI, 31% had brainstem lesions compared with 17% at 3 months (p=0.008). In the FLAIR sequences, number and volumes of lesions were reduced from early to 3 months (p<0.001). In T2*GRE sequences, the number of lesions persisted at 3 months but was reduced at 12 months (p=0.007). The number of lesions in DWI and volume of FLAIR lesions on early MRI predicted worse clinical outcome in adjusted analyses (p<0.05). CONCLUSION: This is the first study to demonstrate and quantify attenuation of non-haemorrhagic TAI lesions on structural MRI during the first 3 months after TBI; most importantly, the disappearance of brainstem lesions. Haemorrhagic TAI lesions attenuate first after 3 months. Only early MRI findings predicted clinical outcome after adjustment for other prognostic factors. Hence valuable clinical information may be missed if MRI is performed too late after TBI. PMID- 22933814 TI - KOMET: an unblinded, randomised, two parallel-group, stratified trial comparing the effectiveness of levetiracetam with controlled-release carbamazepine and extended-release sodium valproate as monotherapy in patients with newly diagnosed epilepsy. AB - OBJECTIVE: To compare the effectiveness of levetiracetam (LEV) with extended release sodium valproate (VPA-ER) and controlled-release carbamazepine (CBZ-CR) as monotherapy in patients with newly diagnosed epilepsy. METHODS: This unblinded, randomised, 52-week superiority trial (NCT00175903) recruited patients (>=16 years of age) with >=2 unprovoked seizures in the previous 2 years and >=1 in the previous 6 months. The physician chose VPA or CBZ as preferred standard treatment; each patient was randomised to standard treatment or LEV. The primary outcome was time to treatment withdrawal (LEV vs standard antiepileptic drugs (AEDs)). Analyses also compared LEV with VPA-ER, and LEV with CBZ-CR. FINDINGS: 1688 patients (mean age 41 years; 44% female) were randomised to LEV (n=841) or standard AEDs (n=847). Time to treatment withdrawal was not significantly different between LEV and standard AEDs: HR (95% CI) 0.90 (0.74 to 1.08). Time to treatment withdrawal (HR (95% CI)) was 1.02 (0.74 to 1.41) for LEV/VPA-ER and 0.84 (0.66 to 1.07) for LEV/CBZ-CR. Time to first seizure (HR, 95% CI) was significantly longer for standard AEDs, 1.20 (1.03 to 1.39), being 1.19 (0.93 to 1.54) for LEV/VPA-ER and 1.20 (0.99 to 1.46) for LEV/CBZ-CR. Estimated 12-month seizure freedom rates from randomisation: 58.7% LEV versus 64.5% VPA-ER; 50.5% LEV versus 56.7% CBZ-CR. Similar proportions of patients within each stratum reported at least one adverse event: 66.1% LEV versus 62.0% VPA-ER; 73.4% LEV versus 72.5% CBZ-CR. CONCLUSIONS: LEV monotherapy was not superior to standard AEDs for the global outcome, namely time to treatment withdrawal, in patients with newly diagnosed focal or generalised seizures. PMID- 22933815 TI - Distal myopathy with cachexia: an unrecognised phenotype caused by dominantly inherited mitochondrial polymerase gamma mutations. AB - BACKGROUND: The myopathy associated with mutations in the nuclear-encoded mitochondrial DNA maintenance gene POLG, coding for the catalytic subunit of DNA polymerase, is typically proximal with early ophthalmoplegia. RESULTS: We report two unrelated patients in whom a distal, mainly upper limb, myopathy was the predominant and early clinical feature. One patient also suffered with marked cachexia. DNA genomic sequence analysis identified novel dominant heterozygous missense POLG mutations (Leu896Arg and Tyr951His) located within the conserved catalytic polymerase domain of the protein in both cases. CONCLUSIONS: Distal upper limb myopathy/cachexia is not previously described with dominant POLG mutations and our observations further highlight the diverse clinical spectrum of POLG-related mitochondrial disorders. These data indicate that dominant POLG mutations should be considered in the differential diagnosis of distal upper limb predominant myopathy. PMID- 22933816 TI - Episodic memory and the medial temporal lobe: not all it seems. Evidence from the temporal variants of frontotemporal dementia. AB - BACKGROUND: Disproportionate medial temporal lobe atrophy (MTA) is an early finding in Alzheimer's disease (AD). Episodic memory impairment in AD is associated with the degree of MTA. Episodic memory impairment and MTA are also found in semantic dementia (SD) and in right temporal lobe atrophy (RTLA), the temporal variants of frontotemporal dementia, but their relationship is unclear. OBJECTIVE: To compare episodic memory impairment among patients with these temporal variants of frontotemporal dementia with that of patients with AD with the same degree of MTA. METHODS: Episodic memory was tested with the visual association test, and semantic memory (SM) with animal fluency and the visual association naming test. MTA was measured using a visual rating scale. Each patient with SD or RTLA was matched for MTA with two patients with AD. Comparisons of episodic memory and SM were made for patients with SD versus matched patients with AD; patients with RTLA versus matched patients with AD and for SD, RTLA and all patients with AD. RESULTS: 27 patients with SD and 11 with RTLA were matched with 54 and 22 patients with AD, respectively. Episodic memory was less impaired in patients with SD than in those with AD (8 versus 2; p<0.001) and in patients with RTLA than in those with AD (10 versus 4.5; p=0.009). Semantic memory was more affected in patients with SD than in those with AD, and the Mini Mental State Examination score was higher in patients with RTLA than in those with AD. Comparison of the three diagnostic groups showed that episodic memory was most impaired in AD, whereas SM was most impaired in SD. CONCLUSION: Since episodic memory impairment is more severe in AD than in SD and RTLA, despite a comparable degree of MTA, atrophy of the medial temporal lobe alone cannot account for episodic memory dysfunction. PMID- 22933817 TI - Clinical features of dopamine agonist withdrawal syndrome in a movement disorders clinic. AB - BACKGROUND: Recently, symptoms similar to addictive drug withdrawal have been reported in a structured longitudinal study of patients with idiopathic Parkinson's Disease (PD) withdrawing from dopamine agonists (DA): the dopamine agonist withdrawal syndrome (DAWS). OBJECTIVES: The objective of this study was to establish the frequency, predictors, and outcomes of DAWS in a movement disorders clinic. METHODS: We conducted a retrospective chart review of a sample of patients with a clinical diagnosis of PD treated with DA in whom withdrawal or attempted withdrawal of DA was carried out because of adverse effects, or for any other reason. Out of 487 PD patient charts reviewed, 84 were withdrawn from the agonists and were evaluable. RESULTS: Thirteen patients (15.5%) met criteria for DAWS (DAWS+) and 71 did not (DAWS-). DAWS developed upon withdrawal from pergolide, pramipexole and ropinirole, and did not respond to levodopa. DAWS outcomes included recovery in less than 6 months in 61%, in more than a year in 23%, and an inability to discontinue DA in 15% of patients. Development of impulse control disorders was the reason for DA withdrawal in all DAWS+, but only in 41% of DAWS- patients (p<0.0001). DAWS+ and DAWS- patients did not differ in other variables. CONCLUSION: DAWS is a disabling complication of DA use. Critical features of the syndrome are the strong link with impulse control disorders, possibly the independence of DA dosage and type, and the resistance to treatment, including levodopa. Further studies are required to characterise those at risk as well as to define an effective treatment. PMID- 22933818 TI - Frightening music triggers rapid changes in brain monoamine receptors: a pilot PET study. AB - Frightening music can rapidly arouse emotions in listeners that mimic those from actual life-threatening experiences. However, studies of the underlying mechanism for perceiving danger created by music are limited. METHODS: We investigated monoamine receptor changes induced by frightening music using (11)C-N-methyl spiperone ((11)C-NMSP) PET. Ten healthy male volunteers were included, and their psychophysiologic changes were evaluated. RESULTS: Compared with the baseline condition, listening to frightening music caused a significant decrease in (11)C NMSP in the right and left caudate nuclei, right limbic region, and right paralimbic region; a particularly significant decrease in the right anterior cingulate cortex; but an increase in the right frontal occipital and left temporal lobes of the cerebral cortex. CONCLUSION: Transient fright triggers rapid changes in monoamine receptors, which decrease in the limbic and paralimbic regions but increase in the cerebral cortex. PMID- 22933819 TI - Clinical performance of 2 dedicated PET scanners for breast imaging: initial evaluation. AB - The purpose of this study was to investigate the diagnostic performance of 2 newly developed dedicated breast PET scanners in patients with known or suspected breast cancer. METHODS: Two types of scanner were evaluated, an O-shaped scanner and a C-shaped scanner. The O scanner was designed for imaging patients who were prone, and the C scanner was designed for those patients positioned leaning forward. Sixty-nine women with known or suspected breast carcinoma (80 lesions: 72 invasive carcinomas, 4 noninvasive carcinomas [ductal carcinoma in situ, or DCIS], 1 case of adenomatous ductal hyperplasia, and 3 benign lesions) were enrolled in this study. All patients underwent a conventional whole-body PET/CT scan, followed by breast scanning using both dedicated devices. The diagnostic performance of each scanner was assessed. RESULTS: The maximal diameter of invasive tumors ranged from 4 to 112 mm, with an average of 26 mm. With the O scanner, 62 of 76 malignant lesions (including 3 DCIS) were detected, 5 lesions were not detected, and the remaining 9 lesions were outside the field of view. With the C scanner, 63 of 76 malignant lesions (including 2 DCIS) were detected, 7 lesions were not detected, and the remaining 6 lesions were outside the field of view. The lesion-based sensitivities of the O and C scanners were 82% (62/76) and 83% (63/76), respectively; sensitivities excluding lesions outside the field of view were 93% (62/67) and 90% (63/70), respectively. The sensitivity of conventional PET/CT was 92% (70/76). All lesions outside the field of view were close to the chest wall. The breast-based specificities of the O, C, and conventional scanners were 98% (48/49), 98% (56/57), and 100% (70/70), respectively. CONCLUSION: Our preliminary study indicates that both dedicated breast PET scanners are clinically feasible and yield reasonably high sensitivity. More detailed information was obtained with these scanners than with the conventional scanner. PMID- 22933820 TI - Optimized in vivo detection of dopamine release using 18F-fallypride PET. AB - The high-affinity D(2/3) PET radioligand (18)F-fallypride offers the possibility of measuring both striatal and extrastriatal dopamine release during activation paradigms. When a single (18)F-fallypride scanning protocol is used, task timing is critical to the ability to explore both striatal and extrastriatal dopamine release simultaneously. We evaluated the sensitivity and optimal timing of task administration for a single (18)F-fallypride PET protocol and the linearized simplified reference region kinetic model in detecting both striatal and extrastriatal reward-induced dopamine release, using human and simulation studies. METHODS: Ten healthy volunteers underwent a single-bolus (18)F fallypride PET protocol. A reward responsiveness learning task was initiated at 100 min after injection. PET data were analyzed using the linearized simplified reference region model, which accounts for time-dependent changes in (18)F fallypride displacement. Voxel-based statistical maps, reflecting task-induced D(2/3) ligand displacement, and volume-of-interest-based analysis were performed to localize areas with increased ligand displacement after task initiation, thought to be proportional to changes in endogenous dopamine release (gamma parameter). Simulated time-activity curves for baseline and hypothetical dopamine release functions (different peak heights of dopamine and task timings) were generated using the enhanced receptor-binding kinetic model to investigate gamma as a function of these parameters. RESULTS: The reward task induced increased ligand displacement in extrastriatal regions of the reward circuit, including the medial orbitofrontal cortex, ventromedial prefrontal cortex, and dorsal anterior cingulate cortex. For task timing of 100 min, ligand displacement was found for the striatum only when peak height of dopamine was greater than 240 nM, whereas for frontal regions, gamma was always positive for all task timings and peak heights of dopamine. Simulation results for a peak height of dopamine of 200 nM showed that an effect of striatal ligand displacement could be detected only when task timing was greater than 120 min. CONCLUSION: The prefrontal and anterior cingulate cortices are involved in reward responsiveness that can be measured using (18)F-fallypride PET in a single scanning session. To measure both striatal and extrastriatal dopamine release, the height of dopamine released and task timing need to be considered in designing activation studies depending on regional D(2/3) density. PMID- 22933824 TI - Observation of room-temperature negative differential resistance in Gd-doped Si nanowires on Si(110) surface. AB - The massively parallel arrays of highly periodic Gd-doped Si nanowires (SiNWs) self-organized on Si(110)-16 * 2 surface were investigated by scanning tunneling microscopy and spectroscopy. These periodic Gd-doped SiNWs are atomically precise and show equal size, periodic positions, and high-integration densities. Surprisingly, the scanning tunneling spectroscopy results show that each metallic like, Gd-doped SiNW exhibits room-temperature negative differential resistance (RT-NDR) behavior, which can be reproducible with various Gd dopings and is independent of the tips. Such massively parallel arrays of highly ordered and atomically identical Gd-doped SiNWs with one-dimensional laterally confined RT NDR can be exploited in Si-based RT-NDR nanodevices. PMID- 22933821 TI - Image-guided PO2 probe measurements correlated with parametric images derived from 18F-fluoromisonidazole small-animal PET data in rats. AB - (18)F-fluoromisonidazole PET, a noninvasive means of identifying hypoxia in tumors, has been widely applied but with mixed results, raising concerns about its accuracy. The objective of this study was to determine whether kinetic analysis of dynamic (18)F-fluoromisonidazole data provides better discrimination of tumor hypoxia than methods based on a simple tissue-to-plasma ratio. METHODS: Eleven Dunning R3327-AT prostate tumor-bearing nude rats were immobilized in custom-fabricated whole-body molds, injected intravenously with (18)F fluoromisonidazole, and imaged dynamically for 105 min. They were then transferred to a robotic system for image-guided measurement of intratumoral partial pressure of oxygen (Po(2)). The dynamic (18)F-fluoromisonidazole uptake data were fitted with 2 variants of a 2-compartment, 3-rate-constant model, one constrained to have K(1) equal to k(2) and the other unconstrained. Parametric images of the rate constants were generated. The Po(2) measurements were compared with spatially registered maps of kinetic rate constants and tumor-to-plasma ratios. RESULTS: The constrained pharmacokinetic model variant was shown to provide fits similar to that of the unconstrained model and did not introduce significant bias in the results. The trapping rate constant, k(3), of the constrained model provided a better discrimination of low Po(2) than the tissue to-plasma ratio or the k(3) of the unconstrained model. CONCLUSION: The use of kinetic modeling on a voxelwise basis can identify tumor hypoxia with improved accuracy over simple tumor-to-plasma ratios. An effective means of controlling noise in the trapping rate constant, k(3), without introducing significant bias, is to constrain K(1) equal to k(2) during the fitting process. PMID- 22933825 TI - Application of well-defined indium tin oxide nanorods as Raman active platforms. AB - We determine the surface enhanced Raman (SER) capability of indium tin oxide nanorods (ITO NRs) whose physical, chemical, and optical properties are precisely and uniformly controlled during synthesis. We demonstrate that the Raman intensities observed from varying concentrations of the pure and mixed molecules of rhodamine 6G and 4',6-diamidino-2-phenylindole are much larger on ITO NRs relative to those measured on commercially available ITO-coated glass or Si. Our efforts signify the first attempt to assess the SER capability of precisely controlled metal oxide NRs and will be highly beneficial to many basic and applied Raman applications requiring exceptional detection sensitivity. PMID- 22933826 TI - Dielectric relaxation and alternating current conductivity of lanthanum, gadolinium, and erbium-polyvinyl alcohol doped films. AB - Fourier transform infrared (FTIR) spectrum dielectric constant, epsilon', loss tangent, tan(delta), electric modulus, M*, and ac conductivity, sigma(ac), of pure polyvinyl alcohol (PVA) as well as La-, Gd-, and Er-PVA doped samples have been carried out. The dielectric properties have been studied in the temperature and frequency ranges; 300-450 K and 1 kHz-4 MHz, respectively. FTIR measurements reveal that La(3+), Gd(3+), and Er(3+) ions form complex configuration within PVA structure. Two relaxation processes, namely, rho and alpha were observed in pure PVA sample. The first process is due to the interfacial or Maxwell-Wagner-Sillers polarization. The second one is related to the micro-Brownian motion of the main chains. For doped PVA samples, alpha-relaxation process splits into alpha(a) and alpha(c). This splitting is due to the segmental motion in the amorphous (alpha(a)) and crystalline (alpha(c)) phases of PVA matrix. Electric modulus analysis was discussed to understand the mechanism of the electrical transport process. The behavior of ac conductivity for all PVA samples indicates that the conduction mechanism is correlated barrier hopping. PMID- 22933827 TI - Socioeconomic Differences in the Health of Black Union Army Soldiers. AB - This paper investigates patterns of socioeconomic difference in the wartime morbidity and mortality of black Union Army soldiers. Among the factors that contributed to a lower probability of contracting and dying from diseases were (1) lighter skin color, (2) a non-field occupation, (3) residence on a large plantation, and (4) residence in a rural area prior to enlistment. Patterns of disease-specific mortality and timing of death suggest that the differences in the development of immunity against diseases and in nutritional status prior to enlistment were responsible for the observed socioeconomic differences in wartime health. For example, the advantages of light-skinned soldiers over dark-skinned and of enlisted men formerly engaged in non-field occupations over field hands resulted from differences in nutritional status. The lower wartime mortality of ex-slaves from large plantations can be explained by their better-developed immunity as well as superior nutritional status. The results of this paper suggest that there were substantial disparities in the health of the slave population on the eve of the Civil War. PMID- 22933828 TI - Are CORNER and BROTHER Morphologically Complex? Not in the Long Term. AB - Previous studies haves shown that under masked priming conditions, CORNER primes CORN as strongly as TEACHER primes TEACH and more strongly than BROTHEL primes BROTH. This result has been taken as evidence of a purely structural level of representation at which words are decomposed into morphological constituents in a manner that is independent of semantics. The research reported here investigated the influence of semantic transparency on long-term morphological priming. Two experiments demonstrated that while lexical decisions were facilitated by semantically transparent primes like TEACHER, semantically opaque words like CORNER had no effect. Although differences in the nonword foils used in each experiment gave rise to somewhat different patterns of results, this difference in the effects of transparent and opaque primes was found in both experiments. The implications of this finding for accounts of morphological effects on visual word identification are discussed. PMID- 22933829 TI - On the Interaction of Letter Transpositions and Morphemic Boundaries. AB - Investigations of the impact of morphemic boundaries on transposed-letter priming effects have yielded conflicting results. Five masked priming lexical decision experiments were conducted to examine the interaction of letter transpositions and morphemic boundaries with English suffixed derivations. Experiments 1-3 found that responses to monomorphemic target words (e.g., SPEAK) were facilitated to the same extent by morphologically related primes containing letter transpositions that did (SPEAEKR) or did not (SPEKAER) cross a morphemic boundary. This pattern was also observed in Experiments 4 and 5, in which the targets (e.g. SPEAKER) were the base forms of the transposed-letter primes. Thus, in these experiments the influence of the morphological structure of a transposed letter prime did not depend on whether the letter transposition crossed a morphological boundary. PMID- 22933831 TI - Cytokines in placental physiology and disease. PMID- 22933830 TI - A role of fluoride on free radical generation and oxidative stress in BV-2 microglia cells. AB - The generation of ROS and lipid peroxidation has been considered to play an important role in the pathogenesis of chronic fluoride toxicity. In the present study, we observed that fluoride activated BV-2 microglia cell line by observing OX-42 expression in immunocytochemistry. Intracellular superoxide dismutase (SOD), glutathione (GSH), malondialdehyde (MDA), reactive oxygen species (ROS), superoxide anions (O(2)(?-)), nitric oxide synthase (NOS), nitrotyrosine (NT) and nitric oxide (NO), NOS in cell medium were determined for oxidative stress assessment. Our study found that NaF of concentration from 5 to 20 mg/L can stimuli BV-2 cells to change into activated microglia displaying upregulated OX 42 expression. SOD activities significantly decreased in fluoride-treated BV-2 cells as compared with control, and MDA concentrations and contents of ROS and O(2)(?-) increased in NaF-treated cells. Activities of NOS in cells and medium significantly increased with fluoride concentrations in a dose-dependent manner. NT concentrations also increased significantly in 10 and 50 mg/L NaF-treated cells compared with the control cells. Our present study demonstrated that toxic effects of fluoride on the central nervous system possibly partly ascribed to activiting of microglia, which enhanced oxidative stress induced by ROS and reactive nitrogen species. PMID- 22933832 TI - Atherosclerosis in juvenile idiopathic arthritis. AB - Atherosclerosis is a chronic inflammatory disease of the arteries. Clinical consequences of the atherosclerotic process occur in the adult population, however atherosclerotic process begins in childhood. The classic risk factors for atherosclerosis include obesity, dyslipidaemia, age, gender or family history. In recent years, attention has been drawn to the similarity between atherosclerotic inflammatory processes and inflammatory changes in the course of systemic connective tissue disease, in particular systemic lupus etythematosus (SLE) or rheumatoid arthritis (RA). There is also observed the similarity of the pathogenetic background of development of atherosclerosis and juvenile idiopathic arthritis (JIA). Elevated levels of pro-inflammatory cytokines are observed in the course of juvenile idiopathic arthritis. Also homocysteine concentrations, which may play a significant role in the development of atherosclerotic lesions, are observed higher in patients with JIA. Some studies revealed higher carotid intima-media thickness (IMT) index values in children with JIA. In view of the fact that atherosclerotic process begins as early as in childhood, the introduction of appropriate preventive measures in children is a matter of utmost importance. PMID- 22933834 TI - Cytopathic effect of Acanthamoeba on human corneal fibroblasts. AB - PURPOSE: Acanthamoeba keratitis is associated with keratocyte depletion in humans. We investigated how Acanthamoebae isolated from corneas affected by Acanthamoeba keratitis interacted with human corneal stromal cells in vitro. METHODS: Acanthamoebae were isolated from 6 patients with Acanthamoeba keratitis and genotyping was done. Whether the isolated Acanthamoebae could invade the corneal stroma was assessed with denuded corneal stroma ex vivo. The cytopathic effect of Acanthamoeba on cultured corneal fibroblasts from donor corneas was quantitatively evaluated by the MTT assay after culture under various conditions. Terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) and Annexin V staining were employed to detect apoptotic cells among the corneal fibroblasts co-cultured with Acanthamoebae. RESULTS: All 6 Acanthamoebae isolated from the patients with Acanthamoeba keratitis were shown to have the T4 genotype by 18S rDNA sequence analysis. Acanthamoebae invaded the denuded corneal stroma in the ex vivo experiments and had a cytopathic effect on human corneal fibroblasts after direct adhesion, but not via chemical mediators. A cytopathic effect was detected with all 6 Acanthamoebae and corneal fibroblasts mainly died by apoptosis, as evidenced by Annexin V staining. CONCLUSIONS: Acanthamoebae isolated from patients with Acanthamoeba keratitis had a cytopathic effect on human corneal fibroblasts, mainly via induction of apoptosis after direct adhesion. Our findings may provide some clues to the pathophysiology of corneal keratocyte depletion in patients with Acanthamoeba keratitis. PMID- 22933835 TI - PLXNC1 and RDH13 associated with bilateral convergent strabismus with exophthalmus in German Brown cattle. AB - PURPOSE: We performed an association study for bilateral convergent strabismus with exophthalmus (BCSE) in German Brown cattle using single nucleotide polymorphisms (SNPs) located within six positional candidate genes and additional SNPs from bovine SNP databases surrounding these candidate genes. Mutation analyses included synaptotagmin 3 and 5 (SYT3, SYT5), carnitine palmitoyl transferase 1C (CPT1C) on bovine chromosome 18 (BTA18), and plexin C1 (PLXNC1), intracellular suppressor of cytokine signaling-2 (SOCS2), and kinesin family member 21A (KIF21A) on BTA5. METHODS: For all six candidate genes, we performed cDNA analyses using eye tissues of three BCSE-affected and three unaffected controls and searched the sequences for polymorphisms. Furthermore, we screened a total of 213 SNPs on BTA5 and 136 SNPs on BTA18 from the bovine SNP databases in 29 BCSE-affected German Brown cattle and 23 breed and sex matched controls for association with BCSE. All SNPs detected within the open reading frame (ORF) of the candidate genes and all SNPs from bovine databases putatively associated with BCSE in the detection sample were genotyped in a random sample of 179 BCSE affected German Brown cows and 161 breed and sex matched controls and tested for association with BCSE. RESULTS: In total, we detected five novel SNPs within the coding sequence of the candidate genes PLXNC1 and KIF21A. The association analyses for single SNPs and haplotypes in 340 German Brown cattle revealed significant associations for five SNPs with BCSE. Four of these five SNPs were located within PLXNC1 and RDH13 and one SNP in the neighborhood of PLXNC1. Each one SNP within PLXNC1 (DN825458:c.168G>T) and RDH13 (AM930553:c.703C>A) were significantly associated with BCSE after correcting for multiple testing whereas all other SNPs failed this significance threshold. The marker-trait associations for haplotypes confirmed the significant associations with BCSE for both genes, PLXNC1 and RDH13. CONCLUSIONS: The association analyses for single SNPs and haplotypes corroborated the results of the linkage study that the centromeric region of BTA5 and the telomeric end of BTA8 harbor genes responsible for BCSE. Intragenic SNPs of the genes PLXNC1 and RDH13 were experiment-wide significantly associated with BCSE and seem to play an important role in the pathogenesis of BCSE. PMID- 22933833 TI - Innate immune cells in liver inflammation. AB - Innate immune system is the first line of defence against invading pathogens that is critical for the overall survival of the host. Human liver is characterised by a dual blood supply, with 80% of blood entering through the portal vein carrying nutrients and bacterial endotoxin from the gastrointestinal tract. The liver is thus constantly exposed to antigenic loads. Therefore, pathogenic microorganism must be efficiently eliminated whilst harmless antigens derived from the gastrointestinal tract need to be tolerized in the liver. In order to achieve this, the liver innate immune system is equipped with multiple cellular components; monocytes, macrophages, granulocytes, natural killer cells, and dendritic cells which coordinate to exert tolerogenic environment at the same time detect, respond, and eliminate invading pathogens, infected or transformed self to mount immunity. This paper will discuss the innate immune cells that take part in human liver inflammation, and their roles in both resolution of inflammation and tissue repair. PMID- 22933836 TI - Low prevalence of myocilin mutations in an African American population with primary open-angle glaucoma. AB - PURPOSE: Mutations in the myocilin gene (MYOC) are associated with primary open angle glaucoma (POAG) in many different populations. This study represents the first large survey of MYOC mutations in an African American population. METHODS: We recruited 529 African American subjects with POAG and 270 African American control subjects in this study. A complete eye examination and blood collection was performed in all study subjects. Genomic DNA was extracted. The entire coding sequence of MYOC was amplified and sequenced using the Sanger method. Identified MYOC variants were compared with previously reported MYOC mutations. RESULTS: We identified a total of 29 MYOC variants including six potential MYOC mutations. Two mutations (Thr209Asn and Leu215Gln) are novel and are found only in cases and no controls. We also identified four previously reported MYOC mutations in cases and no controls (Tyr453MetfsX11, Gln368X, Thr377Met, and Ser393Arg). The overall frequency of glaucoma-causing MYOC mutations in our African American population with POAG was 1.4%. CONCLUSIONS: We identified two novel probable glaucoma causing MYOC mutations (Thr209Asn and Leu215Gln). This study indicates that, despite the high prevalence of POAG, MYOC mutations are rare in the African American population. PMID- 22933837 TI - A cross-ethnicity investigation of genes previously implicated in primary angle closure glaucoma. AB - PURPOSE: To investigate the underlying genetic variation between candidate genes and primary angle closure glaucoma (PACG) in both Nepalese and Australian populations. METHODS: A total of 213 patients with PACG (106 Nepalese and 107 Australian) and 492 age and sex matched controls (204 Nepalese and 288 Australian) were included in the current study. Three candidate genes were selected; methyl-tetrahydrofolate reductase (MTHFR), calcitonin receptor-like receptor gene (CALCRL), and membrane frizzled-related protein (MFRP). Tag single nucleotide polymorphisms (SNPs) were selected and genotyped to capture the majority of common variation across each locus. Allele and haplotype analyses were conducted using PLINK. RESULTS: SNPs in the nanophthalmos gene MFRP were found to be nominally associated with PACG under the allelic model. Two SNPs were associated in the Australian cohort (rs948414; p=0.02 and rs36015759; p=0.02), and a single SNP in the Nepalese cohort (rs10790289; p=0.03), however these SNPs failed to remain significant after adjustment for sex and age. A haplotype at the CALCRL gene (AATACAGAT) was associated in the Australian cohort (corrected p value=0.024). No association was observed in either cohort for MTHFR. CONCLUSIONS: This study implicates genetic variation at the CALCRL gene in the pathogenesis of PACG in an Australian Caucasian cohort. Additionally, the MFRP gene shows tendency to be associated with PACG in both the Australian and Nepalese cohorts. Further investigation in a larger cohort is warranted to confirm these findings. No statistically significant associations were identified between MTHFR and PACG in either population. PMID- 22933838 TI - Murine corneal stroma cells inhibit LPS-induced dendritic cell maturation partially through TGF-beta2 secretion in vitro. AB - PURPOSE: The peripheral cornea contains mature and immature resident dendritic cells (DCs) while the central cornea is exclusively equipped with immature DCs. There must be some factors that cause immature DCs. This study investigated whether corneal stroma cells (CSCs) inhibit DC maturation by secreting cytokines. METHODS: The messenger ribonucleic acid (mRNA) and protein level of transforming growth factor beta 2 (TGF-beta(2)) was analyzed using reverse transcription polymerase chain reaction (RT-PCR) and enzyme-linked immunosorbent assay (ELISA). Immature DCs were induced to mature in the presence of lipopolysaccharide (LPS) and with concentrations of CSC culture supernatant (containing and not containing neutralizing TGF-beta(2) antibodies). Then, the DC phenotypic and functional maturation were analyzed. RESULTS: CSCs exhibited positive expressions of TGF beta(2) mRNA and secreted high concentrations of TGF-beta(2) protein. In the presence of LPS, DCs, which were treated with a CSC culture supernatant, displayed reduced expressions of cluster of differentiation 80 (CD80), CD86, and major histocompatibility complex II (MHC II) in a dose-dependent manner. Moreover, treated DCs showed lower T-cell stimulation capacity and a higher endocytosis function. However, these phenotypic and functional modifications were partially reversed after the application of neutralizing TGF-beta(2) antibodies. CONCLUSIONS: This study demonstrates that CSCs can partially inhibit LPS-induced DC maturation through TGF-beta(2) secretion in vitro. PMID- 22933839 TI - Aqueous humor concentrations of vascular endothelial growth factor and pigment epithelium-derived factor in high myopic patients. AB - PURPOSE: To compare the aqueous humor levels of vascular endothelial growth factor (VEGF) and pigment epithelium-derived factor (PEDF) in high myopic eyes and control eyes. METHODS: Aqueous humor samples were collected from 21 highly myopic eyes of 20 patients (high myopia group) and from 30 cataract eyes of 30 patients with no choroidal neovascularization (CNV) or other ocular or systemic diseases (control group). Of the 21 high myopic eyes, 13 had no complications secondary to high myopia (high myopia with no complications group), 3 had posterior staphyloma (high myopia with staphyloma group), and 5 had chorioretinal atrophy (high myopia with chorioretinal atrophy group). The aqueous humor levels of VEGF and PEDF were determined by using commercially available enzyme-linked immunosorbent assay kits. RESULTS: Aqueous humor levels of VEGF were significantly lower in the high myopia group compared to that in the control group (p<0.001). VEGF levels decreased with an increase in the axial length (p<0.001). PEDF levels tended to be higher in the high myopia group compared to that in the control group; however, the difference was not significant. Three high myopia groups had significantly lower VEGF/PEDF ratios than the control group (p=0.000, 0.002, and 0.005). CONCLUSIONS: Aqueous humor levels of VEGF in the high myopia group were significantly lower than those in the control group. The differing levels of VEGF and PEDF in the high myopia and control groups suggest that high myopia disrupts the VEGF/PEDF balance in retinal pigment epithelium (RPE) cells. PMID- 22933841 TI - Advanced pulse oximetry system for remote monitoring and management. AB - Pulse oximetry data such as saturation of peripheral oxygen (SpO(2)) and pulse rate are vital signals for early diagnosis of heart disease. Therefore, various pulse oximeters have been developed continuously. However, some of the existing pulse oximeters are not equipped with communication capabilities, and consequently, the continuous monitoring of patient health is restricted. Moreover, even though certain oximeters have been built as network models, they focus on exchanging only pulse oximetry data, and they do not provide sufficient device management functions. In this paper, we propose an advanced pulse oximetry system for remote monitoring and management. The system consists of a networked pulse oximeter and a personal monitoring server. The proposed pulse oximeter measures a patient's pulse oximetry data and transmits the data to the personal monitoring server. The personal monitoring server then analyzes the received data and displays the results to the patient. Furthermore, for device management purposes, operational errors that occur in the pulse oximeter are reported to the personal monitoring server, and the system configurations of the pulse oximeter, such as thresholds and measurement targets, are modified by the server. We verify that the proposed pulse oximetry system operates efficiently and that it is appropriate for monitoring and managing a pulse oximeter in real time. PMID- 22933840 TI - Association analysis of genetic and environmental risk factors in the cuticular drusen subtype of age-related macular degeneration. AB - PURPOSE: To assess the association of gender, cigarette smoking, body-mass index, and nine genetic risk variants with cuticular drusen (CD), a well recognized subtype of age-related macular degeneration (AMD). METHODS: A total of 757 patients with AMD, including 217 patients with CD, and 553 control individuals were interviewed with a questionnaire and underwent an ophthalmic examination. Venous blood samples were obtained for genomic DNA extraction, and genotyping was performed of single nucleotide polymorphisms previously associated with AMD. Odds ratios were calculated for patients with CD, using unaffected control individuals as a reference. Furthermore, odds ratios in patients with CD were compared to those in patients with "non-CD" AMD. RESULTS: The CD subtype of AMD was significantly associated with current smoking as well as variants in the complement factor H (CFH), age-related maculopathy susceptibility 2 (ARMS2), complement factor B/complement component 2 (CFB/C2), complement component 3 (C3), and apolipoprotein E (APOE) genes. In patients with CD, the association with the CFH Y402H risk allele was significantly higher (p=0.022), whereas the association with current smoking was significantly lower (p<0.001) than in the heterogeneous group of patients with "non-CD" AMD. CONCLUSIONS: The AMD subtype of CD was associated with previously identified genetic AMD risk factors. However, the association with the CFH Y402H risk allele appeared to be stronger, whereas the association with smoking was less pronounced when compared to AMD as a whole. This study suggests a more important role for genetic factors than environmental factors in the development of this well defined subtype of AMD. These findings stress the importance of detailed phenotyping in AMD to identify homogeneous AMD subtypes, which may be associated with different risk factors and disease mechanisms. Such studies will improve the accuracy of predictive models and the effectiveness of preventive and therapeutic options in AMD. PMID- 22933842 TI - Development and Initial Validation of a Client-Rated MET-CBT Adherence Measure. AB - Traditional mechanisms for rating adherence or fidelity are labor-intensive. We developed and validated a tool to rate adherence to Motivational Enhancement Therapy-Cognitive Behavioral Treatment (MET-CBT) through anonymous client surveys. The instrument was used to survey clients in 3 methadone programs over 2 waves. Explanatory and Confirmatory Factor Analyses were used to establish construct validity for both MET and CBT. Internal consistency based on Cronbach's alpha was within adequate range (alpha > 0.70) for all but 2 of the subscales in one of the samples. Consensus between clients' ratings (r(wg(j)) scores) were in the range of 0.6 and higher, indicating a moderate to strong degree of agreement among clients' ratings of the same counselor. These results suggest that client surveys could be used to measure adherence to MET-CBT for quality monitoring that is more objective than counselor self-report and less resource-intensive than supervisor review of taped sessions. However, additional work is needed to develop this scale. PMID- 22933843 TI - When research meets reality-lessons learned from a pragmatic multisite group randomized clinical trial on psychosocial interventions in the psychiatric and addiction field. AB - Research on treatments for patients with co-occurring psychiatric and substance use disorders is of core importance and at the same time highly challenging as it includes patients that are normally excluded from clinical studies. Such research may require methodological adaptations which in turn create new challenges. However, the challenges that arise in such studies are insufficiently discussed in the literature. The aim of this methodology paper is, firstly, to discuss the methodological adaptations that may be required in such research; secondly, to describe how such adaptations created new challenges in a group-randomized clinical trial on Integrated Treatment amongst patients with co-occurring psychiatric and substance use disorders. We also discuss how these challenges might be understood and highlight lessons for future research in this field. TRIAL REGISTRATION: NCT00447733. PMID- 22933846 TI - Studies of the genus Enchodelus Thorne, 1939 (Nematoda, Nordiidae) from Arctic polar deserts. 1. Species with long odontostyle: E. makarovae sp. n. and E. groenlandicus (Ditlevsen, 1927) Thorne, 1939, with an identification key to the species of the E. macrodorus group. AB - Two nematode species of the genus Enchodelus Thorne, 1939, one new and one known from Arctic polar deserts were studied. Enchodelus makarovaesp. n. is an amphimictic species, characterised by females with body length of 1.57-2.00 mm, lip region 15-17.5 um wide, amphid duplex, odontostyle 38-43 um long or 2.3-2.8 times lip region diam. Odontophore with flanges, 1.2-1.4 times as long as odontostyle; pharynx length 320-377 um, pharyngeal expansion 113-130 um long or 32-37% of total pharynx length; female genital system amphidelphic, uterus tripartite, pars refringens vaginae with two trapezoid sclerotisations, vulva a transverse slit (V=45-51%); tail bluntly conoid (25-35 um, c=45.8-70.3, c'=0.6 0.9 in females, and 29-33 um, c=46.4-58.9, c'=0.7-0.8 in males). Males with 65-74 um long spicules and 10-12 spaced ventromedian supplements. Additional information for Enchodelus groenlandicus is provided, this being a new geographic record for the Putorana Plateau, Russian Arctic. PMID- 22933847 TI - Four new species of the leafhopper genus Kapsa Dworakowska from China (Hemiptera, Cicadellidae, Typhlocybinae), with a key to Chinese species. AB - In the present paper, four new species, Kapsa acuminata, Kapsa quadrispina, Kapsa puerensis and Kapsa yanheensisspp. n. from southwest China are described and illustrated, and a key to the species recorded from China is provided. PMID- 22933844 TI - Treatment-induced bone loss and fractures in cancer patients undergoing hormone ablation therapy: efficacy and safety of denosumab. AB - Hormone ablation therapy (HALT) for breast or prostate cancer accelerates the development of osteoporosis in both men and women by causing estrogen deficiency, which increases the risk for fracture by promoting bone resorption mediated by osteoclasts. Denosumab, a fully human monoclonal antibody that inhibits osteoclast formation and function, increases bone mass in patients undergoing hormone ablation therapy. In the HALT study of 1,468 men with prostate cancer on androgen-deprivation therapy, denosumab significantly reduced the risk of new vertebral fractures, increased bone mineral density (BMD), and reduced markers of bone turnover. In a study of 252 women with breast cancer undergoing adjuvant aromatase inhibitor (AI) therapy, denosumab increased BMD at 12 and 24 months, overall and in all patient subgroups. The overall rates of adverse events were similar to placebo. Clinicians should consider fracture risk assessment and therapies such as denosumab to increase bone mass in patients on hormone ablation therapy who are at high risk for fracture. PMID- 22933845 TI - Polymorphisms of the serotonin transporter and receptor genes: susceptibility to substance abuse. AB - Serotonin (5-hydroxytryptamine [5-HT]) is an important neurotransmitter implicated in regulating substance-use disorder (SUD) acquisition, maintenance, and recovery. During the past several years, an abundance of research has begun discovering and describing specific 5-HT genetic polymorphisms associated with SUDs. Genetic variations in the 5-HT system, such as SLC6A4, HTR1B, HTR2A, HTR2C, HTR3 (HTR3A, HTR3B, HTR3C, HTR3D, and HTR3E), likely play a role contributing to SUD patient heterogeneity. The 5-HT transporter-linked polymorphic region S allele, located in SLC6A4, has now been modestly associated with alcohol dependence in two large meta-analyses. Additional 5-HT genes may also play a role but have not been extensively investigated. A limited number of SUD treatment studies have included 5-HT gene variation as moderating treatment outcomes, but the results have been equivocal. Future research on 5-HT addiction genetics should adopt whole-genome sequencing technology, utilize large study samples, and collect data from multiple ethnic groups. Together, these methods will build on the work already conducted with the aim of utilizing 5-HT genetics in SUD treatment settings. PMID- 22933848 TI - A new ant species of the genus Tapinoma (Hymenoptera, Formicidae) from Saudi Arabia with a key to the Arabian species. AB - Tapinoma wilsonisp. n. is described and illustrated from Saudi Arabia based on the worker caste collected from Al Baha, Saudi Arabia. It closely resembles Tapinoma lugubre Santschi 1917, from Zimbabwe in body measurements but can be distinguished from the latter species by the yellowish brown color; the yellowish pubescence, the two pairs of hairs present on the anterior part of the head; and the distinctly concave anterior clypeal margin. Biological and ecological notes of the new species are presented. An identification key to the workers of the Arabian species of the genus Tapinoma is given. PMID- 22933849 TI - On immature and adult forms of Trichognathus marginipennis Latreille, 1829 (Coleoptera, Carabidae, Galeritini). AB - The pupa of Trichognathus marginipennis Latreille, 1829 is described for the first time and the adult is redescribed. Habitus and important structures of larva, pupa and adult are illustrated. This work improves the knowledge on immatures and adults of Trichognathus marginipennis. PMID- 22933850 TI - Cucujus tulliae sp. n. - an endemic Mediterranean saproxylic beetle from genus Cucujus Fabricius, 1775 (Coleoptera, Cucujidae), and keys for identification of adults and larvae native to Europe. AB - Cucujus tulliaesp. n. is described as a new member of genus Cucujus Fabricius, 1775 (Coleoptera, Cucujidae), which enumerates at present eleven species distributed in Eurasia and northern America. This saproxylic beetle is the first Cucujus species known only from Mediterranean and it is probably endemic to Calabria (Italy). The species was found especially in old-growth mountain forests of high conservation value (i.e. national parks) dominated by Calabrian pine (Pinus laricio calabrica). We hypothesize that Cucujus tulliae sp. n. probably evolved from isolated populations of Cucujus haematodes Erichson, 1845. The species is thus relictual and of high conservation value, corresponding at least to endangered (EN) category with respect to recent IUCN criterion. Cucujus tulliae sp. n. is here compared with two species native to Europe - Cucujus haematodes and Cucujus cinnaberinus (Scopoli, 1763) and with the Caucasian Cucujus haematodes caucasicus Motschulsky, 1845, which is confirmed as a valid subspecies. The male genitalia of this Caucasian form have been examined and illustrated for the first time. A comprehensive key to adults and larvae of European species is provided. PMID- 22933851 TI - A new species of the genus Microtendipes Kieffer, 1915 (Diptera, Chironomidae) from Oriental China. AB - A new species of the genus Microtendipes Kieffer, 1915, Microtendipes zhejiangensissp.n., is described, and its morphological description and illustrations are given. A catalogue of the genus in Oriental Region is provided and a key to the males of Microtendipes in the Oriental Region is given. PMID- 22933852 TI - Review of the odd chrysidid genus Loboscelidia Westwood, 1874 (Hymenoptera, Chrysididae, Loboscelidiinae). AB - The chrysidid genus Loboscelidia is reviewed and 11 new species are described, including Loboscelidia cinnamonea (Borneo), Loboscelidia fulgens (Viet Nam), Loboscelidia fulva (Thailand), Loboscelidia incompleta (India), Loboscelidia kafae (Borneo), Loboscelidia laminata (Viet Nam), Loboscelidia meifungae (Borneo), Loboscelidia nasiformis (Thailand), Loboscelidia nitidula (Thailand), Loboscelidia pecki (Viet Nam), and Loboscelidia sisik (Borneo). A key to males of the species of Loboscelidia is given. PMID- 22933853 TI - A new species of Apechoneura Kriechbaumer (Hymenoptera, Ichneumonidae, Labeninae) from Colombia. AB - A new species of the ichneumonid subfamily Labeninae, Apechoneura seminigrasp. n., is described. Specimens were collected from the Amazon Rainforest of Colombia. PMID- 22933854 TI - Revised concept of the genus Euryporus Erichson (Coleoptera, Staphylinidae, Staphylininae) and phylogenetic significance of Staphylinini from New Guinea. AB - The Staphylinini rove beetle genus Euryporus Erichson from the subtribe Quediina is restricted to include only three species from the Western Palearctic region: Euryporus picipes (Paykull, 1800), Euryporus aeneiventris (Lucas, 1846), and Euryporus princeps Wollaston, 1864. Euryporus argentatus Fauvel, 1881, Euryporus warisensis Last, 1987 and Euryporus multicavus Last, 1980, which do not even belong to the subtribe Quediina, are excluded fromthe genus. Of these, two were transferred to different genera: Tympanophorus argentatus (Fauvel, 1881), comb. nov., from Sumatra;and Hesperus warisensis (Last, 1987), comb. nov.,from New Guinea. "Euryporus" multicavus could not be placed to any of the described genera of Staphylinini and is left as incertae sedis pending a broader study of the relevant fauna of this tribe in New Guinea and adjacent regions. The taxonomic history of Euryporus is reviewed, and an updated diagnosis of this genus is provided. PMID- 22933855 TI - A revision of the genus Mecistostethus Marseul (Histeridae, Histerinae, Exosternini). AB - We revise the genus Mecistostethus Marseul, sinking the monotypic genus Tarsilister Bruch as a junior synonym. Mecistostethus contains six valid species: Mecistostethus pilifer Marseul, Mecistostethus loretoensis (Bruch), comb. n., Mecistostethus seagorumsp. n., Mecistostethus carltonisp. n., Mecistostethus marseulisp. n., and Mecistostethus flechtmannisp. n. The few existing records show the genus to be widespread in tropical and subtropical South America, from northern Argentina to western Amazonian Ecuador and French Guiana. Only a single host record associates one species with the ant Pachycondyla striata Smith (Formicidae: Ponerinae), but it is possible that related ants host all the species. PMID- 22933856 TI - Description of two new Stenohya species from China (Pseudoscorpiones, Neobisiidae). AB - Two new species of the genus Stenohya Beier, 1967 are described from China: Stenohya pengaesp. n. (male and female; type locality Daming Mountain, Nanning City, Guangxi Zhuang Autonomous Region) and Stenohya huangisp. n. (female; type locality Gushan Mountain, Fuzhou City, Fujian Prov.).The presence of Stenohya pengaesp. n. in the tree crown of Castanopsis fabri represents a new habitat for Neobisiidae. A key and a distribution map of the Chinese Stenohya species are also provided. PMID- 22933857 TI - Membrane Protein Crystallization in Lipidic Mesophases. Hosting lipid affects on the crystallization and structure of a transmembrane peptide. AB - Gramicidin is an apolar pentadecapeptide antibiotic consisting of alternating D and L-amino acids. It functions, in part, by creating pores in membranes of susceptible cells rendering them leaky to monovalent cations. The peptide should be able to traverse the host membrane either as a double stranded, intertwined double helix (DSDH) or as a head-to-head single stranded helix (HHSH). Current structure models are based on macromolecular X-ray crystallography (MX) and nuclear magnetic resonance (NMR). However, the HHSH form has only been observed by NMR. The shape and size of the different gramicidin conformations differ. We speculated therefore that reconstituting it into a lipidic mesophase with bilayers of different microstructures would preferentially stabilize one form over the other. By using such mesophases for in meso crystallogenesis the expectation was that at least one would generate crystals of gramicidin in the HHSH form for structure determination by MX. This was tested using commercial and in-house synthesised lipids that support in meso crystallogenesis. Lipid acyl chain lengths were varied from 14 to 18 carbons to provide mesophases with a range of bilayer thicknesses. Unexpectedly, all lipids produced high quality, structure-grade crystals with gramicidin only in the DSDH conformation. PMID- 22933858 TI - Analysis of Hydrogen Tunneling in an Enzyme Active Site using von Neumann Measurements. AB - We build on our earlier quantum wavepacket study of hydrogen transfer in the biological enzyme, soybean lipoxygenase-1, by using von Neumann quantum measurement theory to gain qualitative insights into the transfer event. We treat the enzyme active site as a measurement device which acts on the tunneling hydrogen nucleus via the potential it exerts at each configuration. A series of changing active site geometries during the tunneling process effects a sequential projection of the initial, reactant state onto the final, product state. We study this process using several different kinds of von Neumann measurements and show how a discrete sequence of such measurements not only progressively increases the projection of the hydrogen nuclear wavepacket onto the product side but also favors proton over deuteron transfer. Several qualitative features of the hydrogen tunneling problem found in wavepacket dynamics studies are also recovered here. These include the shift in the "transition state" towards the reactant as a result of nuclear quantization, greater participation of excited states in the case of deuterium, and presence of critical points along the reaction coordinate that facilitate hydrogen and deuterium transfer and coincide with surface crossings. To further "tailor" the dynamics, we construct a perturbation to the sequence of measurements, that is a perturbation to the dynamical sequence of active site geometry evolution, which leads us to insight on the existence of sensitive regions of the reaction profile where subtle changes to the dynamics of the active site can have an effect on the hydrogen and deuterium transfer process. PMID- 22933859 TI - Letter from the editor. PMID- 22933862 TI - Do statins reduce patients' risk of hepatocellular carcinoma? PMID- 22933861 TI - Determination of serum antibodies to Clostridium difficile toxin B in patients with inflammatory bowel disease. AB - Clostridium difficile infection has increased in prevalence among patients with inflammatory bowel disease (IBD). Serum antibodies against C. difficile toxins have been detected in susceptible populations and may be protective; however, such antibodies have not been previously characterized in IBD patients. This study measured immunoglobulin G antibody levels to C. difficile toxin B in serum from IBD patients in remission and IBD patients in relapse. IBD patients demonstrated significantly higher antibody levels than non-IBD patients. In addition, a higher proportion of IBD patients in remission had positive antibody levels compared to IBD patients in relapse. Further characterization of antibody responses may elucidate understanding of susceptibility to C. difficile infection among IBD patients. PMID- 22933860 TI - Hepatitis C virus infection and nonalcoholic steatohepatitis. AB - Nonalcoholic fatty-liver disease (NAFLD) is one of the most prevalent liver diseases in the Western hemisphere. The rising rates of obesity and diabetes mellitus correlate with the increasing incidence of NAFLD, which is the hepatic manifestation of metabolic syndrome. Hepatitis C virus infection is another common cause of liver disease worldwide. Up to 70% of patients with chronic hepatitis C (CHC) will have concomitant steatosis. The presence of NAFLD has been implicated as a cause of lower viral response rates in CHC patients who are treated with pegylated interferon and ribavirin. This review will focus on the factors that lead to NAFLD in the setting of hepatitis C virus infection, including viral and host factors-in particular, inflammatory mediators, cytokines, and lipid peroxidation. This paper will also discuss the implications of NAFLD and nonalcoholic steatohepatitis regarding fibrosis progression, risk of hepatocellular carcinoma, and limitations with antiviral therapy. PMID- 22933863 TI - Improved understanding of risk factors could help to reduce the incidence of hepatocellular carcinoma. PMID- 22933864 TI - Adverse metabolic sequelae following restorative proctocolectomy with an ileal pouch. AB - Ileal pouch-anal anastomosis (IPAA) following total proctocolectomy has become the surgical treatment of choice for ulcerative colitis patients who have medically refractory disease or neoplasia. Unfortunately, various metabolic complications have been reported with this surgical procedure, including anemia, vitamin B(12) deficiency, bile salt and fat malabsorption, vitamin D deficiency, bone loss, and nephrolithiasis. Recognition and early diagnosis of these complications are important when managing IPAA patients. PMID- 22933866 TI - Recent research on pneumatic dilatation versus laparoscopic heller myotomy for achalasia treatment. PMID- 22933865 TI - Management of arthritis in patients with inflammatory bowel disease. PMID- 22933867 TI - The adaptive response (drug tolerance) helps to prevent drug-induced liver injury. PMID- 22933868 TI - Inappropriate uses of colonoscopy. PMID- 22933869 TI - "Cat scratch" colon in a female patient after a difficult screening colonoscopy. PMID- 22933870 TI - Gastro-hep news. PMID- 22933871 TI - Community Perspectives: Combining Serology, Genetics, and Inflammation Markers for the Diagnosis of IBD and Differentiation Between CD and UC. AB - Diagnosis of inflammatory bowel disease (IBD) is complicated and is based on a combination of patient history and physical examination in association with laboratory, endoscopic, histologic, and radiographic investigations. Determination of the correct diagnosis is important for its implications in selecting treatment and in the timing and type of surgery that may be required. Information from testing incorporating serologic, genetic, and inflammatory markers can help to clarify the clinical picture. Measurement of biomarkers not only helps to differentiate a diagnosis of IBD versus non-IBD, it can also help to distinguish between ulcerative colitis and Crohn's disease in difficult cases. In this monograph, 5 cases illustrate how specialized testing can provide important information that can aid in diagnosis. PMID- 22933872 TI - Letter from the editor. PMID- 22933873 TI - Drug interactions: a primer for the gastroenterologist. AB - One of the most clinically significant complications related to the use of pharmacotherapy is the potential for drug-drug or drug-disease interactions. The gastrointestinal system plays a large role in the pharmacokinetic profile of most medications, and many medications utilized in gastroenterology have clinically significant drug interactions. This review will discuss the impact of alterations of intestinal pH, interactions mediated by phase I hepatic metabolism enzymes and P-glycoprotein, the impact of liver disease on drug metabolism, and interactions seen with commonly utilized gastrointestinal medications. PMID- 22933875 TI - Techniques for Performing ERCP in Roux-en-Y Gastric Bypass Patients. PMID- 22933874 TI - Update on natural orifice translumenal endoscopic surgery. AB - Natural orifice translumenal endoscopic surgery (NOTES) has moved from the realm of laboratory experiments to the realm of human clinical trials. This paper reviews the spectrum of NOTES procedures currently available in the United States and worldwide. It also discusses the limitations and avenues for further development of these procedures, particularly those involving the transgastric approach. PMID- 22933876 TI - Use of parenteral nutrition in patients with inflammatory bowel disease. PMID- 22933877 TI - Screening for hepatitis C virus infection. PMID- 22933878 TI - Is There a Relationship Between GERD and Asthma? PMID- 22933879 TI - Life-threatening variceal hemorrhage in a woman with severe pulmonary arterial hypertension. PMID- 22933880 TI - Pulmonary arterial hypertension: an unusual cause of portal hypertension. PMID- 22933881 TI - Esophageal injury following radiofrequency ablation for atrial fibrillation: injury classification. PMID- 22933882 TI - Esophageal injury following left atrial ablation. PMID- 22933883 TI - Water Confined in Cylindrical Pores: A Molecular Dynamics Study. AB - Molecular dynamics simulations of water confined in two hydrophilic cylindrical pores-PH and PL-that differ in their silanol surface concentration (7.6 and 3.0 nm(-2), respectively) have been performed at 300 K. A strong interaction of interfacial water molecules with the pore was systematically found and gives rise to a layering effect, a significant distortion of both the hydrogen bond network (HBN) and the tetrahedral structure of these water molecules, and a corresponding subdiffusive mean square displacement along the main axis of the pores. By contrast, water molecules in the inner part of both pores were found to behave similarly to bulk water. The HBN and the tetrahedral configuration of water were more gradually distorted in the PL pore given the larger heterogeneity and rugosity of the surface, and the number of water-pore hydrogen bonds did not scale linearly with the silanol surface concentration of the pores, in part because of the close proximity between silanols in the PH pore. With the PL pore, the dynamic slowing down of water was found consistent with the experiment, suggesting that it provides a better model for the cylindrical MCM-41 mesopores. The structural and dynamical properties of water vary little with the silica force field. PMID- 22933884 TI - Role of radiotherapy in melanoma management. AB - BACKGROUND: In melanoma, radiotherapy has generally been considered as a palliative treatment option indicated only for advanced cases or disseminated disease. In the 70s of the previous century, the technological advances in radiotherapy, linked to rapid development of computer sciences, resulted in restored interest for radiotherapy in melanoma management. Although a fundamental lack of well designed prospective and/or randomized clinical trials critically influenced the integration of radiotherapy into treatment strategies in melanoma, radiotherapy was recently recognized as an indispensable part in the multidisciplinary management of patients with melanoma. Altogether, approximately 23% of melanoma patients should receive at least one course of radiotherapy during the course of the disease. In this review, radiobiological properties of melanoma that govern the decisions for the fractionation patterns used in the treatment of this disease are described. Moreover, the indications for irradiation and the results of pertinent clinical studies from the literature, creating a rationale for the use of radiotherapy in the management of this disease, are reviewed and a brief description of radiotherapy techniques is given. CONCLUSIONS: Basic treatment modality in melanoma is surgery. However, whenever surgery is not radical or there are adverse prognostic factors identified on histopathological examination of resected tissue specimen, it needs to be supplemented. Also, in patients with unresectable disease or in those not being suitable for major surgery or who refuse proposed surgical intervention, other effective mode(s) of therapy need to be implemented. From this perspective, supported by clinical experiences and literature results, radiotherapy is a valuable option: it is effective and safe, in curative and palliative setting. PMID- 22933885 TI - Genetic markers in oligodendroglial tumours. AB - BACKGROUND: Oliogodendrogliomas are brain tumours composed of the cells resembling oligodendrocytes. They represent the third most common glial tumour, comprising 2.5% of all primary brain tumours and 5-20% of all gliomas. CONCLUSIONS: Oligodendroglial tumours with 1p and 19q loss demonstrate a better overall prognosis due to more indolent clinical behaviour and higher sensitivity to treatment. Additionally, 1p and 19q loss is a marker of clinical utility, helping to assess tumour sensitivity to chemotherapy and harbouring the potential for improving the diagnosis and survival of oligodendroglioma patients as well as future clinical practice. PMID- 22933886 TI - CT colonography in detection of colorectal carcinoma. AB - BACKGROUND: Diagnostic methods used in screening and detecting colorectal carcinoma are digitorectal examination, faecal occult blood testing, sigmoidoscopy, DNA stool analysis, barium enema, colonoscopy, and as of recently CT colonography. The aim of this study was to establish diagnostic accuracy and comfort of CT colonography compared to colonoscopy and barium enema. PATIENTS AND METHODS: We included 231 patients in the prospective study. For all patients CT colonography and barium enema followed by colonoscopy were performed. After the procedures a comfort assessment was done in all patients. Diagnostic positive results were verified by the pato-histological examination. Sensitivity, specificity, positive predicative value (PPV) and negative predicative value (NPV) were calculated for each procedure. RESULTS: With CT colonography, barium enema and colonoscopy 95 lesions were found, 56 (59%) of them were tumours and 39 (41%) were polyps. Among polyps pato-histology revealed 34 adenomas, 3 tubulovillous adenomas and 2 lipomas, among tumours there were 55 adenocarcinomas and 1 lymphoma. Results showed CT colonography sensitivity to polyps to be 89.7%, barium enema 48.7%, and colonoscopy 94.9%. Sensitivity to tumours of CT colonography and colonoscopy was 100% and of barium enema 94.6%. Specificities and PPV were 100% in all procedures. The comfort assessment showed CT colonography as the far most comfortable out of three procedures. PMID- 22933887 TI - Diffusion weighted MR imaging in the differential diagnosis of haemangiomas and metastases of the liver. AB - BACKGROUND: The purpose of the study was to evaluate the value of diffusion weighted imaging in the differential diagnosis of haemangiomas from metastases of the liver. PATIENTS AND METHODS.: We analyzed 69 lesions in 38 patients (33 haemangiomas; 36 metastases) in the retrospective study. Diffusion-weighted imaging was performed using a breath-hold single-shot echo-planar spin echo sequence with three b factors (0, 500 and 1000 sec/mm(2)), and apparent diffusion coefficients (ADCs) were calculated. For the quantitative evaluation, signal intensity of the lesions, lesion-to-liver signal intensity ratios, ADC of the lesions, and lesion-to-liver ADC ratios were compared between the groups. The statistical significance was determined by student's-t test. RESULTS: With the b factor 500 sec/mm(2), no statistical significance was achieved (p>0.05). With the b factor of 1000 sec/mm(2), both the signal intensity and lesion-to-liver signal intensity ratio of the metastases were significantly higher than those for haemangiomas (p<0.001). The cut-off value at 2.6 yielded a sensitivity of 86% and a specificity of 82% for the lesion-to-liver signal intensity ratio. The ADC, and lesion-to-liver ADC ratio of the metastases were significantly lower than those of haemangiomas (p<0.001). With cut-off value of 1.7, ADC ratio had a sensitivity of 88% and a specificity of 72% for ADC lesion/liver. CONCLUSIONS: Diffusion weighted imaging with high b value may help in the differential diagnosis of metastases from haemangiomas of the liver. PMID- 22933888 TI - Percutaneous transcatheter arterial embolization in haemodynamically stable patients with blunt splenic injury. AB - BACKGROUND: The nonoperative management of the blunt splenic injury in haemodynamically stable patients has become an accepted treatment in recent years. We present a case of the blunt splenic injury successfully treated by supraselective embolization with microspheres. CASE REPORT: A young hockey player was brought to the Emergency Department with the history of blunt abdominal trauma 2 h earlier. A Grade III splenic injury with haemoperitoneum was diagnosed on sonographic evaluation and the patient was treated with the selective distal splenic artery embolization with microspheres. Postprocedural ultrasound and computed tomography follow-up a year later revealed only a small area of parenchymal irregularity. CONCLUSIONS: The percutaneous splenic arterial embolization has a major role in the management of traumatic splenic injuries. Embolization is particularly beneficial in injuries of grade III or higher. PMID- 22933889 TI - Numerical study of the electroporation pulse shape effect on molecular uptake of biological cells. AB - BACKGROUND: In order to reduce the side-effects of chemotherapy, combined chemotherapy-electroporation (electrochemotherapy) has been suggested. Electroporation, application of appropriate electric pulses to biological cells, can significantly enhance molecular uptake of cells due to formation of transient pores in the cell membrane. It was experimentally demonstrated that the efficiency of electroporation is under the control of electric pulse parameters. However, the theoretical basis for these experimental results is not fully explained. In order to predict the outcome of experiments and optimize the efficiency of electroporation before each treatment, we developed a model to investigate the effect of pulse shape on efficiency of electroporation. RESULTS: Our model is based on a developed chemical-kinetics scheme and trapezium barrier model, while self-consistency was taken into account. This model is further supplemented with a molecular transport model to acquire the molecular uptake of cells. The investigated pulse shapes in this study were unipolar rectangular pulses with different rise and fall times, triangular, sinusoidal and bipolar rectangular pulses and also sinusoidal modulated unipolar pulses with different percentages of modulation. The obtained results from our modelling and simulations are in good agreement with previously published experimental results. CONCLUSIONS: We therefore conclude that this model can be used to predict the effects of arbitrarily shaped electroporation pulses on cell membrane conductivity and molecular transport across the cell membrane. PMID- 22933890 TI - Development of human cell biosensor system for genotoxicity detection based on DNA damage-induced gene expression. AB - BACKGROUND: Human exposure to genotoxic agents in the environment and everyday life represents a serious health threat. Fast and reliable assessment of genotoxicity of chemicals is of main importance in the fields of new chemicals and drug development as well as in environmental monitoring. The tumor suppressor gene p21, the major downstream target gene of activated p53 which is responsible for cell cycle arrest following DNA damage, has been shown to be specifically up regulated by genotoxic carcinogens. The aim of our study was to develop a human cell-based biosensor system for simple and fast detection of genotoxic agents. METHODS: Metabolically active HepG2 human hepatoma cells were transfected with plasmid encoding Enhanced Green Fluorescent Protein (EGFP) under the control of the p21 promoter (p21HepG2GFP). DNA damage was induced by genotoxic agents with known mechanisms of action. The increase in fluorescence intensity, due to p21 mediated EGFP expression, was measured with a fluorescence microplate reader. The viability of treated cells was determined by the colorimetric MTS assay. RESULTS: The directly acting alkylating agent methylmethane sulphonate (MMS) showed significant increase in EGFP production after 48 h at 20 MUg/mL. The indirectly acting carcinogen benzo(a)pyren (BaP) and the cross-linking agent cisplatin (CisPt) induced a dose- dependent increase in EGFP fluorescence, which was already significant at concentrations 0.13 MUg/mL and 0.41 MUg/mL, respectively. Vinblastine (VLB), a spindle poison that does not induce direct DNA damage, induced only a small increase in EGFP fluorescence intensity after 24 h at the lowest concentration (0.1 MUg/mL), while exposure to higher concentrations was associated with significantly reduced cell viability. CONCLUSIONS: The results of our study demonstrated that this novel assay based on the stably transformed cell line p21HepG2GFP can be used as a fast and simple biosensor system for detection of genetic damage caused by chemical agents. PMID- 22933891 TI - Attitudes of midwifery students towards teaching breast-self examination. AB - BACKGROUND: The purpose of this study was to asses the attitude of undergraduate midwifery students towards teaching other women in methods of breast self examination (BSE). PARTICIPANTS AND METHODS.: The study was performed at the beginning and at the end of students' study at the Faculty of Health Sciences in Ljubljana, Slovenia. It was carried out during the academic year 2002/2003 and involved 28 first and 25 third year undergraduate midwifery students. The data were gathered from questionnaires and processed with the use of descriptive and inferential statistics. RESULTS: All study participants were of the opinion that teaching other women in methods of BSE is of great importance for an early detection of breast cancer (BC) and that this task ought to be one of their duties. There were no significant differences between the two groups when the readiness to upgrade their own knowledge of BSE or when the optimism regarding the progress in breast cancer detection and therapy in the future were concerned. CONCLUSIONS: The readiness of midwifery students to pass the knowledge of BSE to other women could help to increase their breast health awareness and thus improve their willingness and ability to detect early changes, associated with BC. PMID- 22933892 TI - Genetic testing for young-onset colorectal cancer: case report and evidence-based clinical guidelines. AB - BACKGROUND: Young-onset colorectal cancer is clinicopathologically different from older-onset colorectal cancer and tends to occur in patients with hereditary germline conditions such as Lynch syndrome and familial adenomatous polyposis. CASE REPORT: We describe the case of a 44-year-old man with a paternal history of colon polyps, a personal 2-year history of hematochezia, and a diagnosis of rectal cancer. Further clinical evaluation of the patient at our institution determined the cancer to be stage IIIA. The patient underwent genetic counseling and testing, which indicated he was negative for the most common familial cancer syndromes. After treatment with neoadjuvant chemoradiotherapy, surgery, and adjuvant chemotherapy, the patient has done well. We review the hereditary cancer syndromes and genetic tests to consider for patients with early-onset colorectal cancer. CONCLUSIONS: This case underscores the importance of following cancer screening guidelines. PMID- 22933893 TI - A neutron track etch detector for electron linear accelerators in radiotherapy. AB - BACKGROUND: Electron linear accelerators in medical radiotherapy have replaced cobalt and caesium sources of radiation. However, medical accelerators with photon energies over 10 MeV generate undesired fast neutron contamination in a therapeutic X-ray photon beam. Photons with energies above 10 MeV can interact with the atomic nucleus of a high-Z material, of which the target and the head of an accelerator consist, and lead to the neutron ejection. RESULTS AND CONCLUSIONS: Our neutron dosimeter, composed of the LR-115 track etch detector and boron foil BN-1 converter, was calibrated on thermal neutrons generated in the nuclear reactor of the Josef Stefan Institute (Slovenia), and applied to dosimetry of undesirable neutrons in photon radiotherapy by the linear accelerator 15 MV Siemens Mevatron. Having considered a high dependence of a cross-section between neutron and boron on neutron energy, and broad neutron spectrum in a photon beam, as well as outside the entrance door to maze of the Mevatron, we developed a method for determining the effective neutron detector response. A neutron dose rate in the photon beam was measured to be 1.96 Sv/h. Outside the Mevatron room the neutron dose rate was 0.62 MUSv/h. PACS: 87.52. Ga; 87.53.St; 29.40.Wk. PMID- 22933894 TI - Radiotherapy in combination with vascular-targeted therapies. AB - BACKGROUND: Given the critical role of tumor vasculature in tumor development, considerable efforts have been spent on developing therapeutic strategies targeting the tumor vascular network. A variety of agents have been developed, with two general approaches being pursued. Antiangiogenic agents (AAs) aim to interfere with the process of angiogenesis, preventing new tumor blood vessel formation. Vascular-disrupting agents (VDAs) target existing tumor vessels causing tumor ischemia and necrosis. Despite their great therapeutic potential, it has become clear that their greatest clinical utility may lie in combination with conventional anticancer therapies. Radiotherapy is a widely used treatment modality for cancer with its distinct therapeutic challenges. Thus, combining the two approaches seems reasonable. CONCLUSIONS: Strong biological rationale exist for combining vascular-targeted therapies with radiation. AAs and VDAs were shown to alter the tumor microenvironment in such a way as to enhance responses to radiation. The results of preclinical and early clinical studies have confirmed the therapeutic potential of this new treatment strategy in the clinical setting. However, concerns about increased normal tissue toxicity, have been raised. PMID- 22933895 TI - Hyperhomocysteinemia and the role of B vitamins in cancer. AB - BACKGROUND: Patients suffering from malignancies have increased complications due to corresponding cardiovascular diseases and risk factor for the development of venous thromboembolism. Epidemiological studies have shown that increased homocysteine plasma concentration (hyperhomocysteinemia) is related to a higher risk of coronary heart disease, stroke, peripheral vascular disease and malignancies. Homocysteine (tHcy) is an intermediate sulfur-containing amino acid produced from methionine during processing of dietary proteins. The plasma homocysteine levels are strongly influenced by diet, as well as by genetic factors. Folic acid, vitamins B6 and B12 are dietary components which influence the plasma homocysteine levels the most. Several studies have found that high blood levels of B vitamins are related to the integrity and function of DNA, and, are at least related to lower concentration of homocysteine. Folate depletion has been found to change DNA methylation and DNA synthesis in both animal and human studies. Because of this critical role of folate, most studies including homocysteine have focused on these two actions. CONCLUSIONS: Hyperhomocysteinemia proves to be the most common condition highly associated with both venous and arterial thrombosis in many cancer patients, while the associated pathophysiology has not been precisely established yet. Therefore, of current interest is the possible role of folate metabolism developing into a cancer initiating hyperhomocysteinemia. This review will discuss this possibility. PMID- 22933896 TI - Hemostatic efficacy of chitosan-based bandage for closure of percutaneous arterial access sites: An experimental study in heparinized sheep model. AB - BACKGROUND: Most of the presently used percutaneous arterial closure devices (PACD) for hemostasis after interventional vascular procedures are effective, but carry risk of complications by deposition of a foreign body. A new promising externally applied PACD - chitosan-based HemCon Bandage (HCB) was explored in sheep. The HCB hemostatic efficacy and complications occurring with its use were compared to those with the standard manual compression (SMC). MATERIAL AND METHODS: Both superficial femoral arteries (SFA) of 9 heparinized sheep were catheterized with an 8F sheath for 5 minutes. After the sheath withdrawal, hemostasis with the HCB was compared with hemostasis achieved with SMC in the contralateral SFA. Iliac angiograms performed by carotid artery approach determined the hemostasis time. RESULTS: The HCB use shortened time to hemostasis with a mean time of 6.9 +/- 3.9 minutes versus 10.8 +/- 2.8 minutes for the SMC (P-value 0.019). Seven SFAs in the HCB group and only 1 SFA in the SMC group exhibited hemostasis in 5 minutes. All nine SFAs using the HCB showed femoral artery patency and demonstrated less hematoma (2/9) than in the SMC group (8/9). No complications developed in the HCB group, one SFA occlusion was seen in the SMC group. CONCLUSIONS: The externally applied HCB in heparinized sheep was safe and effective. It significantly shortened time to hemostasis at the SFA access sites following 8F sheath removal. Proper application of the HCB was necessary to shorten hemostasis and prevent hematoma formation. The HCB should be tested in a clinically controlled study to evaluate its efficacy in humans. PMID- 22933897 TI - 3T MRI in evaluation of asbestos-related thoracic diseases - preliminary results. AB - BACKGROUND: 3T high-field magnetic resonance imaging (MRI) scanners have recently become available for the clinical use and are being increasingly applied in the field of whole-body imaging and chest imaging as well. The aim of this study was to evaluate the diagnostic potential of 3 T MRI as a complementary imaging modality to CT in detecting the pathological changes of asbestos-related thoracic diseases. PATIENTS AND METHODS: Fifteen patients with the asbestos-related thoracic disease were scheduled for 3T MRI. Five had a benign form of the disease and 10 had malignant pleural mesothelioma (MPM). From the patients with a benign form of the disease their last CT examination in digital form was acquired and patients with MPM were scheduled for CT examination with contrast media. The protocol of MR imaging consists of T2-weighted cardiac-gated breath-hold turbo spin echo (TSE) sequences in coronal, sagittal and axial plane and T1-weighted cardiac-gated breath-hold TSE black blood in axial plane. In T2-weighted sequences in axial plane, fat saturation was also used. CT examinations were obtained with the administration of the contrast medium from lung apices to the lower end of the liver. Images of 5 mm (mediastinum window) and 3 mm (lung window) in axial plan were reconstructed. MRI signal intensity of lesions and adjacent muscles on Syngo MultiModality Work Place were measured. RESULTS: Compared to muscles pleural plaques appeared hypo-intense to iso-intense on T1 weighted images (in 100%) and also hypo-intense on T2 fs-weighted images (in 100%). MPM appeared inhomogeneous hypo-intense to iso-intense on T1-weighted and hyperintense on T2 fs-weighted images in all patients (100%). CONCLUSIONS: These preliminary results pointed out that MRI was equal or even better compared with CT examination for detecting possible malignant potential of pleural changes in the asbestos-related pleural disease, using signal intensity measurements of T2 fs-weighted images. The 3T MRI enabled the accurate determination of chest pathology and it could be used for imaging of patients with the asbestos-related thoracic disease. MRI is particularly valuable because a patient is not exposed to the harmful radiation which is important if imaging methods are used repeatedly, like in screening programs or in monitoring of treatment results. This finding turned us to propose 3T MRI imaging technique as a non-ionizing imaging method for the follow-up of patients with the isolated pleural form of the asbestos-related disease. PMID- 22933898 TI - Reliability of diffusion weighted MR imaging in differentiating degenerative and infectious end plate changes. AB - BACKGROUND: The aim of the study was to investigate the value of diffusion weighted MR imaging in the diagnosis of Modic type 1 change, which may be confused with the acute infectious spondylodiscitis on conventional MR imaging. PATIENTS AND METHODS: Twenty-seven patients with erosive intervertebral osteochondrosis, Modic type 1 and 18 patients with spondylodiscitis were included in this retrospective study. All images were acquired using on 1.5 Tesla MR units. Lumbar spinal MR imaging of 45 patients were retrieved from a digital database of a radiology record system and evaluated by one experienced radiologist. Patients with Modic type 1 change had CT slices obtained from the diseased disc space and the affected vertebrae. RESULTS: Bone marrow adjacent to the vertebral end plate in both Modic type 1 change and acute spondylodiscitis were hypointense on T1-weighted images. On T2-weighted images corresponding levels of vertebral end-plates showed hyperintense signal intensity in both group. All the patients with spondylodiscitis and Modic type 1 change were hyperintense and hypointense on diffusion-weighted MR images, respectively. CONCLUSIONS: Our findings suggest that diffusion weighted MR imaging is an useful method in differentiating Modic type 1 changes from acute spondylodiscitis, both of which may mimic each other, either on clinical or conventional MRI findings. PMID- 22933899 TI - Post-traumatic high-flow priapism treated by endovascular embolization using N butyl-cyanoacrylate. AB - BACKGROUND: Priapism, persistent erection without arousal, can be classified into low-flow (venous or ischemic) and high-flow (arterial or non-ischemic). The diagnosis of high-flow priapism can be confirmed by colour Doppler and arteriography and it is usually treated by the endovascular embolization. CASE REPORT: We present a case of a 20-year-old man with a post-traumatic high-flow priapism as a result of the previous perineal trauma. After a period of watchful waiting and an unsuccessful attempt at endovascular embolization using the resorptive gelatinous foam he was successfully treated by the endovascular embolization using N-butyl-cyanoacrylate. CONCLUSIONS: High-flow priapism can be successfully treated by the endovascular embolization, but the optimal choice of the embolization agent and a careful technique is essential. PMID- 22933900 TI - Antigen expression on recurrent meningioma cells. AB - INTRODUCTION: Meningiomas are intracranial brain tumours that frequently recur. Recurrence rates up to 20% in 20 years for benign meningiomas, up to 80% for atypical meningiomas and up to 100% for malignant meningiomas, have been reported. The most important prognostic factors for meningioma recurrence are meningioma grade, meningioma invasiveness and radicality of neurosurgical resection. The aim of our study was to evaluate the differences in antigenic expression on the surface of meningioma cells between recurrent and non-recurrent meningiomas. METHODS: 19 recurrent meningiomas and 35 non-recurrent meningiomas were compared regarding the expression of MIB-1 antigen, progesterone receptors, cathepsin B and cathepsin L, using immunohistochemistry. RESULTS: MIB-1 antigen expression was higher in the recurrent meningioma group (p=0.001). No difference in progesterone receptor status between recurrent and non-recurrent meningiomas was confirmed. Immunohistochemical intensity scores for cathepsin B (p= 0.007) and cathepsin L (p<0.001) were both higher in the recurrent than in the non recurrent meningioma group. CONCLUSIONS: [corrected] MIB-1 antigen expression is higher in recurrent compared to non-recurrent meningiomas. There is no difference in expression of progesterone receptors between recurrent and non-recurrent meningiomas. Cathepsins B and L are expressed more in recurrent meningiomas. PMID- 22933901 TI - Frequent MGMT (0(6)-methylguanine-DNA methyltransferase) hypermethylation in long term survivors of glioblastoma: a single institution experience. AB - BACKGROUND: The aim of this retrospective study was to analyse the MGMT (0(6) methylguanine-DNA methyltransferase) promoter methylation status in long-term surviving (>= 3 years) patients with glioblastoma multiforme (GBM). METHODS: The methylation status of the MGMT promoter was determined by bisulfite modification of the DNA and subsequent methylation-specific polymerase-chain-reaction (MSP). DNA was extracted from routinely formalin-fixed and paraffin-embedded tumour tissue samples. RESULTS: MSP yielded interpretable results in only 14 of 33 (42%) long-term surviving patients with GBM. A methylated band was seen in 3 of 14, methylated as well as unmethylated bands in 8 of 14 and an only unmethylated band in 3 of 14 patients, thus, yielding MGMT promoter methylation in 11 of 14 patients. The two groups of patients with methylated and unmethylated MGMT promoter status were too small to draw any firm statistical conclusions. CONCLUSIONS: Long-term surviving patients with GBM have very frequently intratumoural MGMT promoter methylation. This phenomenon discriminates long-term survivors from a non-selected group of patients with GBM. The standardization of the MSP for the determination of the MGMT promoter methylation status seems to be necessary in order to make this methodology a more reliable one. PMID- 22933902 TI - A clinical case of the penile metastasis from the rectal carcinoma. AB - BACKGROUND: Penile metastases are rare and usually secondary to genitourinary and colorectal cancer. CASE REPORT: We present a case of a 77-year-old man with penile metastasis who was operated for rectal carcinoma. He was referred to our clinic for penile ulcerous lesion, semierectile penis and voiding dysfunction. Imaging studies showed nodular lesion at glans penis and multiple bone metastases. He did not respond to chemoradiotherapy and he had bad prognosis. CONCLUSIONS: Imaging methods and biopsy may help to clarify the diagnosis but the treatment modalities are insufficient in these patients. PMID- 22933904 TI - Effect of 905 MHz microwave radiation on colony growth of the yeast Saccharomyces cerevisiae strains FF18733, FF1481 and D7. AB - BACKGROUND: The aim of this study was to evaluate the effect of weak radiofrequency microwave (RF/MW) radiation emitted by mobile phones on colony growth of the yeast Saccharomyces cerevisiae. MATERIALS AND METHODS: S. cerevisiae strains FF18733 (wild-type), FF1481 (rad1 mutant) and D7 (commonly used to detect reciprocal and nonreciprocal mitotic recombinations) were exposed to a 905 MHz electromagnetic field that closely matched the Global System for Mobile Communication (GSM) pulse modulation signals for mobile phones at a specific absorption rate (SAR) of 0.12 W/kg. RESULTS: Following 15-, 30- and 60 minutes exposure to RF/MW radiation, strain FF18733 did not show statistically significant changes in colony growth compared to the control sample. The irradiated strains FF1481 and D7 demonstrated statistically significant reduction of colony growth compared to non-irradiated strains after all exposure times. Furthermore, strain FF1481 was more sensitive to RF/MW radiation than strain D7. CONCLUSIONS: The findings indicate that pulsed RF/MW radiation at a low SAR level can affect the rate of colony growth of different S. cerevisiae strains. PMID- 22933903 TI - A fully electronic intensity-modulated radiation therapy quality assurance (IMRT QA) process implemented in a network comprised of independent treatment planning, record and verify, and delivery systems. AB - BACKGROUND: The purpose of this study is to implement an electronic method to perform and analyze intensity-modulated radiation therapy quality assurance (IMRT QA) using an aSi megavoltage electronic portal imaging device in a network comprised of independent treatment planning, record and verify (R&V), and delivery systems. METHODS: A verification plan was generated in the treatment planning system using the actual treatment plan of a patient. After exporting the treatment fields to the R&V system, the fields were delivered in QA mode with the aSi imager deployed. The resulting dosimetric images are automatically stored in a DICOM-RT format in the delivery system treatment console computer. The relative dose density images are subsequently pushed to the R&V system. The absolute dose images are then transferred electronically from the treatment console computer to the treatment planning system and imported into the verification plan in the dosimetry work space for further analysis. Screen shots of the gamma evaluation and isodose comparison are imported into the R&V system as an electronic file (e.g. PDF) to be reviewed prior to initiation of patient treatment. A relative dose image predicted by the treatment planning system can also be sent to the R&V system to be compared with the relative dose density image measured with the aSi imager. RESULTS: Our department does not have integrated planning, R&V, and delivery systems. In spite of this, we are able to fully implement a paperless and filmless IMRT QA process, allowing subsequent analysis and approval to be more efficient, while the QA document is directly attached to its specific patient chart in the R&V system in electronic form. The calculated and measured relative dose images can be compared electronically within the R&V system to analyze the density differences and ensure proper dose delivery to patients. CONCLUSIONS: In the absence of an integrated planning, verifying, and delivery system, we have shown that it is nevertheless possible to develop a completely electronic IMRT QA process. PMID- 22933905 TI - Post-treatment surveillance in colorectal cancer. AB - BACKGROUND: Though the post treatment surveillance of patients with colorectal cancer (CRC) treated with curative intent is common practice, its value is controversial. In the absence of conclusive clinical data, various modalities for the routine follow-up of patients with CRC have been proposed. In practice, the guidelines across countries and regions differ and are influenced by different health care policies, resource availability and doubts about effectiveness of follow-up. CONCLUSIONS: The results of metaanalyses of available clinical trials demonstrated a survival benefit of intensified monitoring, but the questions regarding the optimal frequency of visits and the examinations to be performed remain unanswered. Furthermore, intensive monitoring of CRC survivors may be difficult to be administrated, causes discomfort and morbidity to the patient and can have serious cost-implications to the healthcare system. However, as it seems from available data, a comprehensive surveillance program does not affect the quality of patients' life. Ongoing large prospective multi-institutional randomised trials might elucidate some of the crucial questions and existing dilemmas to establish adequate surveillance strategy for CRC patients. PMID- 22933906 TI - Fluorescence imaging agents in cancerology. AB - BACKGROUND: One of the major challenges in cancer therapy is to improve early detection and prevention using novel targeted cancer diagnostics. Detection requests specific recognition. Tumor markers have to be ideally present on the surface of cancer cells. Their targeting with ligands coupled to imaging agents make them visible/detectable. CONCLUSIONS: Fluorescence imaging is a newly emerging technology which is becoming a complementary medical method for cancer diagnosis. It allows detection with a high spatio-temporal resolution of tumor markers in small animals and in clinical studies. In this review, we focus on the recent outcome of basic studies in the design of new approaches (probes and devices) used to detect tumor cells by fluorescence imaging. PMID- 22933907 TI - Infrahepatic caudal/inferior vena cava interruption with azygos/hemiazygos continuation. Vascular anomaly in swine. AB - BACKGROUND: Swine are commonly used as a model to study congenital cardiovascular defects that occur in humans and these models have been both spontaneous and experimentally induced. Ventricular septal defect, patent ductus arteriosus, and atrial septal defect (ASD) are examples of experimentally induced models. Absence of caudal/inferior vena cava (CVC/IVC) with azygos/hemiazygos continuation is an uncommon vascular anomaly. CASE REPORT: The vascular anomaly presented in this case report was an incidental finding on a pig that was evaluated for experimental percutaneous atrial septal defect creation and its closure using a percutaneous femoral vein approach. Absence of CVC/IVC was confirmed by venography and necropsy. CONCLUSIONS: To the best of the investigators knowledge, this is the first report of absence of CVC/IVC with azygos/hemiazygos continuation in the swine. PMID- 22933908 TI - Direct coronary stenting in reducing radiation and radiocontrast consumption. AB - INTRODUCTION: Coronary stenting is the primary means of coronary revascularization. There are two basic techniques of stent implantation: stenting with balloon predilatation of stenosis and stenting without predilatation (direct stenting). Limiting the time that a fluoroscope is activated and by appropriately managing the intensity of the applied radiation, the operator limits radiation in the environment, and this saves the exposure to the patient and all personnel in the room. Nephrotoxicity is one of the most important properties of radiocontrast. The smaller amount of radiocontrast used also provides multiple positive effects, primarily regarding the periprocedural risk for the patients with the reduced renal function. The goal of the study was to compare fluoroscopy time, the amount of radiocontrast, and expenses of material used in direct stenting and in stenting with predilatation. PATIENTS AND METHODS: In a prospective study, 70 patients with coronary disease were randomized to direct stenting, or stenting with predilatation. RESULTS: Fluoroscopy time and radiocontrast use were significantly reduced in the directly stented patients in comparison to the patients stented with balloon-predilatation. The study showed a significant reduction of expenses when using a direct stenting method in comparison to stenting with predilatation. CONCLUSIONS: If the operator predicts that the procedure can be performed using direct stenting, he is encouraged to do so. Direct stenting is recommended for all percutaneous coronary interventions when appropriate conditions have been met. If direct stenting has been unsuccessful, the procedure can be converted to predilatation. PMID- 22933909 TI - Diagnostic imaging of traumatic pseudoaneurysm of the thoracic aorta. AB - BACKGROUND: The purpose of the study was the presentation of findings and diagnostic imaging in patients with traumatic pseudoaneurysms of the thoracic aorta, as a rare consequence of road traffic accidents. PATIENTS AND METHODS: In 22 years we have found 8 traumatic pseudoaneurysms of the thoracic aorta, out of which 7 (87.5%) in male and 1 (12.5%) in female patients. At the time of accidents the youngest patient was 21 and the oldest was 55 (mean age 33.8 years), and at the moment of diagnosing a pseudoaneurysm they were 26 and 55 years old, respectively (mean age 38.7 years). In all patients chest radiography was performed as well as CT scan, in 6 (75%) patients intra-venous digital subtraction angiography was performed (i.v. DSA) and in 1 (12.5%) MRI. CT was performed with the application of 120 ml, and i.v. DSA with 60 ml of contrast medium, respectively. RESULTS: In 8 (100%) patients, who suffered a road traffic accident, and whose chest radiograph showed the enlargement of the aortic knob and widening of the mediastinum, CT, i.v. DSA and MRI revealed a traumatic pseudoaneurysm of the thoracic aorta. Periods of time between the accidents and the initial diagnosis of the pseudoaneurysm varied from 7 days to 18 years (median 2.0 years). The diameter of the pseudoaneurysm was from 4.5 to 9.2 cm (median 5.5 cm). In 7 (87.5%) isthmus was involved, and in 1 (12.5%) descending thoracic aorta, respectively. The chest radiograph revealed marginal calcifications in 4 (50%), and on the CT in 5 (62.5%) patients. Intraluminal thrombosis was found by CT in 2(25%) traumatized patients. CONCLUSIONS: Traumatic pseudoaneurysm should be taken into consideration in blunt chest trauma, where a chest radiograph shows suspicious regions. A multislice CT is a diagnostic method of choice. PMID- 22933910 TI - Radiological considerations in von Hippel-Lindeau disease: imaging findings and the review of the literature. AB - BACKGROUND: Von Hippel Lindau disease is an autosomal dominant multisystem/multitumoral cancer disease diagnosed by clinical, radiologic and genetic findings. Its prevalence has been estimated to be of 1/36000 inhabitants. The tumours can be benign or malignant. CASE REPORT: We represent MR findings of a family with ten children. Mother and five siblings had von Hippel-Lindau disease. CONCLUSIONS: Radiologic imaging is very important for the early diagnosis and treatment of asymptomatic patients. Diagnosing it early is important because the tumours in von Hippel Lindau disease are treatable. Also, an early detection allows the patient's survival and quality of life. A multidisciplinary team approach is important in screening. PMID- 22933911 TI - Loss of heterozygosity of CDKN2A (p16INK4a) and RB1 tumor suppressor genes in testicular germ cell tumors. AB - BACKGROUND: Testicular germ cell tumors (TGCTs) are the most frequent malignances in young adult men. The two main histological forms, seminomas and nonseminomas, differ biologically and clinically. pRB protein and its immediate upstream regulator p16INK4a are involved in the RB pathway which is deregulated in most TGCTs. The objective of this study was to evaluate the occurrence of loss of heterozygosity (LOH) of the CDKN2A (p16INK4a) and RB1 tumor suppressor genes in TGCTs. MATERIALS AND METHODS.: Forty TGCTs (18 seminomas and 22 nonseminomas) were analyzed by polymerase chain reaction using the restriction fragment length polymorphism or the nucleotide repeat polymorphism method. RESULTS: LOH of the CDKN2A was found in two (6%) out of 34 (85%) informative cases of our total TGCT sample. The observed changes were assigned to two (11%) nonseminomas out of 18 (82%) informative samples. Furthermore, LOH of the RB1 was detected in two (6%) out of 34 (85%) informative cases of our total TGCT sample. Once again, the observed changes were assigned to two (10.5%) nonseminomas out of 19 (86%) informative samples. Both LOHs of the CDKN2A were found in nonseminomas with a yolk sac tumor component, and both LOHs of the RB1 were found in nonseminomas with an embryonal carcinoma component. CONCLUSIONS: The higher incidence of observed LOH in nonseminomas may provide a clue to their invasive behavior. PMID- 22933912 TI - Study of radiation induced changes of phosphorus metabolism in mice by (31)P NMR spectroscopy. AB - BACKGROUND: The aim of this study was to examine whether (31)P NMR can efficiently detect X-ray radiation induced changes of energy metabolism in mice. Exposure to ionizing radiation causes changes in energy supply that are associated with the tissue damage because of oxidative stress and uncoupled oxidative phosphorylation. This has as a consequence decreased phosphocreatine to adenosine triphosphate ratio (Pcr/ATP) as well as increased creatine kinase (CK) and liver enzymes (transaminases AST and ALT) levels in serum. MATERIALS AND METHODS: In this study, experimental mice that received 7 Gy of X-ray radiation and a control group were studied by (31)P NMR spectroscopy and biochemically by measuring CK and liver enzyme levels in plasma. Mice (irradiated and control) were measured at regular time intervals for the next three weeks after the exposure to radiation. RESULTS: A significant change in the Pcr/ATP ratio, determined from corresponding peaks of (31)P NMR spectra, was observed in the 7 Gy group 2 days or more after the irradiation, while no significant change in the Pcr/ATP ratio, was observed in the control group. This result was supported by parallel measurements of CK levels that were highly increased immediately after the irradiation which correlates with the observed decrease of the Pcr/ATP ratio and with it associated drop of muscle energy supply. CONCLUSIONS: The (31)P NMR measurements of the Pcr/ATP ratio can in principle serve as an instantaneous and noninvasive index for assessment of the received dose of irradiation. PMID- 22933913 TI - Prophylactic cranial irradiation in patients with small-cell lung cancer: the experience at the Institute of Oncology Ljubljana. AB - BACKGROUND: Prophylactic cranial irradiation (PCI) has been used in patients with small-cell lung cancer (SCLC) to reduce the incidence of brain metastases (BM) and thus increase overall survival. The aim of this retrospective study was to analyze the characteristics of patients with SCLC referred to the Institute of Oncology Ljubljana, their eligibility for PCI, patterns of dissemination, and survival. PATIENTS AND METHODS: Medical charts of 357 patients with SCLC, referred to the Institute of Oncology Ljubljana between January 2004 and December 2006, were reviewed to determine characteristics of patients chosen for PCI. The following data were collected: age, gender, performance status (PS), extent of the disease, smoking status, type of primary treatment with outcome, haematological and biochemical parameters, PCI use, and finally brain metastases (BM) status at diagnoses and after treatment. RESULTS: PCI was performed in 24 (6.7%) of all patients. Six (25%) patients developed brain metastases after they were treated with PCI. Brain was the only site of metastases in 4 patients, two progressed to multiple organs. Median overall survival of patients with PCI was 21.9 months, without PCI 12.13 months (p = 0.004). From the collected data there were good prognostic factors: age under 65 years, limited disease (LD), performance status, normal levels of lactate dehydrogenase (LDH) and normal levels of C-reactive protein levels (CRP). Other prognostic factors did not show statistical significant values. CONCLUSIONS: Survival of patients with LD, who have had PCI, was significantly better than those who had not. We decided to perform PCI in patients with LD, in those with complete or near complete response, and those with good performance status (>= 80). We did not use PCI in extended disease (ED). The reason for that shall be addressed in the future. Doses for PCI were not uniform, therefore more standard approach should be considered. PMID- 22933914 TI - Gonadal function in patients treated for Hodgkin's disease in childhood. AB - BACKGROUND: The long-term survival of patients treated for Hodgkin's disease (HD) in childhood is high and the chief concern is now being directed toward the late effects of the treatment, including the endocrine dysfunction. PATIENTS AND METHODS.: Testicular and ovarian functions were assessed in 64 long term survivors (24 females, 40 males) treated for HD in childhood in Slovenia between 1972 and 1994. At diagnosis they were 3-16 years old and had gonadal evaluation 4 27 years later at the age of 13-34. Fifty-four (84%) patients received chemotherapy (ChT), 49 in combination with radiation therapy (RT), 10 received RT alone. Gonadal function was assessed by the clinical examination and measurement of serum concentrations of estradiol and testosterone. Serum levels of LH and FSH were determined in the basal state and after the stimulation. RESULTS: Primary hypogonadism (PH) was found in 30 (47%) patients. Twenty-four of 40 (60%) males had PH with evidence of damage of germinal epithelium, 4 of them had evidence of damage of Leydig cells (LC) and 10 had evidence of dysfunction of LC as well. PH was found in 6 of 24 (25%) females. CONCLUSIONS: After therapy for HD PH was more frequent in males than in females. Not only RT but also alkylating agents and procarbazine alone caused damage of LC. Age of patient at the time of treatment was not an important risk factor for gonadal toxicity. Pelvic RT in combination with ChT is the most important risk factor of the development PH both, in males and females. PMID- 22933915 TI - Intensity modulated radiotherapy (IMRT) in bilateral retinoblastoma. AB - BACKGROUND: External beam radiotherapy (EBRT) for retinoblastoma has traditionally been done with conventional radiotherapy techniques which resulted high doses to the surrounding normal tissues. CASE REPORT: A 20 month-old girl with group D bilateral retinoblastoma underwent intensity modulated radiotherapy (IMRT) to both eyes after failing chemoreduction and focal therapies including cryotherapy and transpupillary thermotherapy. In this report, we discuss the use of IMRT as a method for reducing doses to adjacent normal tissues while delivering therapeutic doses to the tumour tissues compared with 3-dimensional conformal radiotherapy (3DCRT). At one year follow-up, the patient remained free of any obvious radiation complications. CONCLUSIONS: Image guided IMRT provides better dose distribution than 3DCRT in retinoblastoma eyes, delivering the therapeutic dose to the tumours and minimizing adjacent tissue damage. PMID- 22933916 TI - Linear array measurements of enhanced dynamic wedge and treatment planning system (TPS) calculation for 15 MV photon beam and comparison with electronic portal imaging device (EPID) measurements. AB - INTRODUCTION: Enhanced dynamic wedges (EDW) are known to increase drastically the radiation therapy treatment efficiency. This paper has the aim to compare linear array measurements of EDW with the calculations of treatment planning system (TPS) and the electronic portal imaging device (EPID) for 15 MV photon energy. MATERIALS AND METHODS: The range of different field sizes and wedge angles (for 15 MV photon beam) were measured by the linear chamber array CA 24 in Blue water phantom. The measurement conditions were applied to the calculations of the commercial treatment planning system XIO CMS v.4.2.0 using convolution algorithm. EPID measurements were done on EPID-focus distance of 100 cm, and beam parameters being the same as for CA24 measurements. RESULTS: Both depth doses and profiles were measured. EDW linear array measurements of profiles to XIO CMS TPS calculation differ around 0.5%. Profiles in non-wedged direction and open field profiles practically do not differ. Percentage depth doses (PDDs) for all EDW measurements show the difference of not more than 0.2%, while the open field PDD is almost the same as EDW PDD. Wedge factors for 60 deg wedge angle were also examined, and the difference is up to 4%. EPID to linear array differs up to 5%. CONCLUSIONS: The implementation of EDW in radiation therapy treatments provides clinicians with an effective tool for the conformal radiotherapy treatment planning. If modelling of EDW beam in TPS is done correctly, a very good agreement between measurements and calculation is obtained, but EPID cannot be used for reference measurements. PMID- 22933917 TI - Urine and bladder washing cytology for detection of urothelial carcinoma: standard test with new possibilities. AB - BACKGROUND: Light microscopic evaluation of cell morphology in preparations from urine or bladder washing containing exfoliated cells is a standard and primary method for the detection of bladder cancer and also malignancy from other parts of the urinary tract. The cytopathologic examination is a valuable method to detect an early recurrence of malignancy or new primary carcinoma during the follow-up of patients after the treatment of bladder cancer. CONCLUSIONS: Characteristic cellular and nuclear signs of malignancy indicate invasive or in situ urothelial carcinoma or high-grade papillary urothelial carcinoma. However, low sensitivity of the method reflects the unreliable cytopathologic diagnosis of low-grade urothelial neoplasms as cellular and nuclear signs of malignancy in these neoplasms are poorly manifested. Many different markers were developed to improve the diagnosis of bladder carcinoma on urinary samples. UroVysionTM test is among the newest and most promising tests. By the method of in situ hybridization one can detect specific cytogenetic changes of urothelial carcinoma. PMID- 22933918 TI - Imaging findings in bisphosphonate-induced osteonecrosis of the jaws. AB - BACKGROUND: Bisphosphonates are drugs used in the treatment of lytic bone metastases, multiple myeloma, hypercalcemia of malignant origin, osteoporosis, and diseases such as Paget's disease. Recently osteonecrosis of the jaw has been associated with the use of bisphosphonates. This study describes the imaging findings of bisphosphonate-associated osteonecrosis of the jaws. PATIENTS AND METHODS: Eleven patients, receiving bisphosphonate medication for approximately 28 months, with pain on affected side, nonhealing extraction sockets, purulent discharge and swelling in soft tissue were examined. Imaging consisted of non contrast enhanced CT and contrast enhanced MRI. All patients underwent surgery of affected bone and histology confirmed osteonecrosis. RESULTS: CT scan showed osteolytic and sclerotic lesions with cortical bone destruction in all patients. The osteonecrosis was identified as delimited focal lesions with reduction of the signal on T1- weighted imaging and T2- weighted imaging. All the patients had soft-tissue involvement with enhancement in orbicular, buccinator muscle of the mouth or masticator space and adenopathy in submandibular and jugular digastric chain. CONCLUSIONS: Bisphosphonate related osteonecrosis of the jaw presents a variety of imaging findings that help to determine the extent of the disease and track the progression, however they are not specific for this disease. PMID- 22933919 TI - MRI in evaluation of perianal fistulae. AB - BACKGROUND: Fistula is considered to be any abnormal passage which connects two epithelial surfaces. Parks' fistulae classification demonstrates the biggest practical significance and divides fistulae into: intersphincteric, transsphincteric, suprasphincteric and extrasphincteric. Etiology of perianal fistulae is most commonly linked with the inflammation of anal glands in Crohn's disease, tuberculosis, pelvic infections, pelvic malignant tumours, and with the radiotherapy. Diagnostic method options are: RTG fistulography, CT fistulography and magnetic resonance imaging (MRI) of pelvic organs. PATIENTS AND METHODS: We have included 24 patients with perirectal fistulae in the prospective study. X rays fistulography, CT fistulography, and then MRI of the pelvic cavity have been performed on all patients. Accuracy of each procedure in regards to the patients and the etiologic cause have been statistically determined. RESULTS: 29.16% of transphincteric fistulae have been found, followed by 25% of intersphincteric, 25% of recto-vaginal, 12.5% of extrasphincteric, and 8.33% of suprasphincteric. Abscess collections have been found in 16.6% patients. The most frequent etiologic cause of perianal fistulae was Crohn's disease in 37.5%, where the accuracy of classification of MRI was 100%, CT was 11% and X-rays 0%. Ulcerous colitis was the second cause, with 20.9% where the accuracy of MRI was 100%, while CT was 80% and X-rays was 0%. All other etiologic causes of fistulae were found in 41.6% patients. CONCLUSIONS: MRI is a reliable diagnostic modality in the classification of perirectal fistulae and can be an excellent diagnostic guide for successful surgical interventions with the aim to reduce the number of recurrences. Its advantage is that fistulae and abscess are visible without the need to apply any contrast medium. PMID- 22933920 TI - Mammographycally occult high grade ductal carcinoma in situ (DCIS) as second primary breast cancer, detected with MRI: a case report. AB - BACKGROUND: Contralateral breast cancer (CLB) is the most common second primary breast cancer in patients diagnosed with breast cancer. The majority of patients harbouring CLB tumours develop the invasive disease. Almost all invasive carcinomas are believed to begin as ductal carcinoma in situ (DCIS) lesions. The sensitivity of MRI for DCIS is much higher than that of mammography. CASE REPORT: We report the case of a woman who was treated with breast conserving therapy 10 years ago. At that time the invasive medullary carcinoma was diagnosed in the left breast. Ten years later mammographically occult DCIS was diagnosed with MRI guided core biopsy in contralateral breast. CONCLUSIONS: There might be a potential role of MRI screening as part of an annual follow-up for patients diagnosed with breast cancer. PMID- 22933921 TI - Effect of response quality and line of treatment with rituximab on overall and disease-free survival of patients with B-cell lymphoma. AB - BACKGROUND: The introduction of rituximab into the treatment of patients with non Hodgkin's lymphomas has improved the overall response rate, as well as the response duration and the overall survival of patients with B-cell lymphomas. But only a few studies have addressed the question whether the better response (complete response) and the early introduction of rituximab into the treatment translate into the better survival. The aim of this retrospective study was to assess the potential relationship between either the quality of the response or the line of the rituximab treatment and the overall survival (OS) as well as the disease-free survival (DFS) of patients with B-cell lymphomas. PATIENTS AND METHODS.: In the study, we analysed treatment outcomes in patients with different histological types of B-cell lymphomas who were treated at the Institute of Oncology between 2003 and 2007 with rituximab and chemotherapy. We included only patients who had the level of CD20 expression assessed prior to the introduction of the treatment with quantitative flow-cytometric measurements. The OS and DFS were evaluated by Kaplan-Meier survival curves. RESULTS: One hundred and fourteen patients were enrolled in the study. Patients who achieved a complete response after the rituximab containing treatment had a significantly longer OS than those reaching a partial response (hazard ratio [HR], 0.34; 95% CI, 0.05 to 0.91, P = 0.0375) and than patients with stable (hazard ratio [HR], 0.11; 95% CI, 0.0002 to 0.033, P < 0.0001) or progressive disease (hazard ratio [HR], 0.09; 95% CI, 0.003 to 0.03, P < 0.0001). Patients who achieved a complete response (CR; n = 70; 61.4%) had also a significantly longer DFS (hazard ratio [HR], 0.26; 95% CI, 0.021 to 0.538, P = 0.0068) than those reaching only a partial response (PR; n = 17; 14.9%). Patients treated with rituximab as the first-line treatment (n = 50; 43.9%) had a significantly longer OS than those treated with rituximab for the first (hazard ratio [HR], 0.27; 95% CI, 0.106 to 0.645, P = 0.0036) or second relapse (hazard ratio [HR], 0.22; 95% CI, 0.078 to 0.5, P = 0.0006). Also the DFS of patients treated with rituximab as the first-line treatment (n = 46; 52.9%) was significantly longer (hazard ratio [HR], 0.32; 95% CI, 0.088 to 0.9, P = 0.0325) than in patients treated with rituximab for their first relapse (n = 25; 28.7%). CONCLUSIONS: These data indicate that a better response to rituximab therapy presumably translates into an improved OS and DFS for patients with B cell lymphomas. The early introduction of rituximab into the treatment (i.e. first-line treatment) might improve OS. Therefore, the response adapted first line therapy with rituximab should be considered when the treatment decision is taken in B-cell lymphoma patients. PMID- 22933922 TI - Second primary cancers in patients with gastric cancer. AB - BACKGROUND: The risk of developing a second primary tumour in patients with gastric carcinoma is higher than among the general population. The aim was to investigate the clinicopathological characteristics of the second primary cancers in patients with gastric cancer in this study. PATIENTS AND METHODS: In the retrospective study, patients with gastric cancers were evaluated between 1995 and 2005 for primary tumours according to Warren and Gates' criteria related with the second primary cancers. RESULTS: Nine of the 112 patients with gastric cancer had second primary cancers. Seven of the patients were males and two females. Six patients with gastric cancers had synchronous, and three had metachronous tumours. The age of the patients ranged from 53 to 78 years, and the mean age was 61 +/- 8.3 years. The most frequent site of occurrence of the second tumours was the colo-rectum (33%) followed by the upper respiratory system (22%), and the urogenital system (22%) in descending order of frequency. CONCLUSIONS: The incidence of the second primary cancer in gastric cancer patients was 8% in the current report. It is recommended that careful preoperative and postoperative examinations for other primary cancers, as well as for the extent of the primary gastric carcinoma, are carried out. Because colorectal cancer was the most common carcinoma combined with gastric carcinoma, the surveillance for this carcinoma (e.g., colonoscopy, abdominopelvic CT) would be appropriate after the diagnosis of gastric carcinoma. PMID- 22933923 TI - Lymphedema following cancer therapy in Slovenia: a frequently overlooked condition? AB - INTRODUCTION: Secondary lymphedema following cancer therapy is a frequent, often painful, quality of life disturbing condition, reducing the patients' mobility and predisposing them to complications, e.g. infections and malignancies. The critical aspect of lymphedema therapy is to start as soon as possible to prevent the irreversible tissue damage. PATIENTS AND METHODS: We performed a retrospective study of patients with lymphedema, treated at the Department of Dermatovenereology, University Medical Center Ljubljana, from January 2002 to June 2010. The patients' demographic and medical data were collected, including type of cancer, type and stage of lymphedema, and time to first therapy of lymphedema. The number of referred patients with lymphedema following the therapy of melanoma, breast cancer, and uterine/cervical cancer, was compared to the number of patients expected to experience lymphedema following cancer therapy, calculated from the incidence reported in the literature. RESULTS: In the period of 8.5 years, 543 patients (432 females, 112 males) with lymphedema were treated. The results show that probably many Slovenian patients with secondary lymphedema following cancer therapy remain unrecognized and untreated or undertreated. In the majority of our patients, the management of lymphedema was delayed; on average, the patients first received therapy for lymphedema 3.6 years after the first signs of lymphedema. CONCLUSIONS: To avoid a delay in diagnosis and therapy, and the complications of lymphedema following cancer therapy, the physician should actively look for signs or symptoms of lymphedema during the follow-up period, and promptly manage or refer the patients developing problems. PMID- 22933924 TI - Evaluation of clinical interventions made by pharmacists in chemotherapy preparation. AB - BACKGROUND: Cancer drugs are high risk drugs and medication errors in their prescribing, preparation and administration have serious consequences, including death. The importance of a multidisciplinary approach and the benefits of pharmacists' contribution to cancer treatment to minimise risk have been established. However, the impact of services provided by pharmacists to cancer patient care is poorly studied. This study explored the clinical interventions made by pharmacists in dispensing of chemotherapy doses, and evaluated pharmacists' contribution to patient care. METHODS: Pharmacists at the Chemotherapy Preparation Unit at a tertiary cancer centre in London were shadowed by two research pharmacists during the clinical screening of chemotherapy prescriptions and release of prepared drugs. An expert panel of pharmacy staff rated the clinical significance of the recorded interventions. RESULTS: Twenty one pharmacists' interventions were recorded during the screening or releasing of 130 prescriptions or drugs. "Drug and therapy" (38%), "clerical" (22%) and "dose, frequency and duration" (19%) related problems most often required an intervention, identifying areas in chemotherapy prescribing that need improvement. The proposed recommendations were implemented in 86% of the cases. Many recorded interventions (48%) were ranked to have had a "very significant" influence on patient care. CONCLUSION: Clinical interventions made by pharmacists had a significant impact on patient care. The integration of pharmacists' technical and clinical roles into dispensing of chemotherapy doses is required for providing high-quality cancer services. PMID- 22933925 TI - Digital ischemic events related to gemcitabine: Report of two cases and a systematic review. AB - BACKGROUND: Gemcitabine is a potent cytotoxic agent used in the treatment of many solid tumours, sarcomas and lymphomas. Vascular toxicity and thrombotic events related to gemcitabine seem to be underreported. CASE REPORT: We report two cases of gemcitabine related digital ischemic events. Case 1. A 65-year-old man was given the first-line treatment with gemcitabine for the advanced adenocarcinoma of pancreas. After four weekly doses of gemcitabine (total dose 4000 mg/m(2)) he presented with Raynaud's like phenomenon and ischemic fingertips necrosis in five digits of both hands. Symptoms resolved in all but one digit after stopping chemotherapy and treatment with iloprost trometamol infusion. Case 2. A 77-year old man, ex-smoker, was administered a combination of gemcitabine and cisplatin as the first-line treatment for the locally advanced bladder cancer. After 4 cycles of the treatment (total dose of gemcitabine 4000 mg/m(2)) the patient suffered digital ischemia and necrosis on two digits of a right leg. Arteriography revealed preexisting peripheral arterial occlusive disease (PAOD) of both legs with very good peripheral collateral circulation and absent microcirculation of affected two digits. The gemcitabine treatment was stopped and the patient was treated with iloprost trometamol infusion and percutaneous transluminal angioplasty with dilatation of the right superficial femoral artery. Digital changes resolved without consequences. Severe thrombocytosis (platelet count 1211 * 10(9)/L) might have also contributed to the ischemic digital event in the second case. CONCLUSIONS: Digital ischemic events associated with gemcitabine chemotherapy seem to be more common in patients with tobacco associated cancers, especially when used in combination with platinum salt. The treatment with gemcitabine in patients with evolving Raynaud's phenomenon and/or preexisting PAOD should be done with caution. PMID- 22933926 TI - Ureteral metastasis as the first and sole manifestation of gastric cancer dissemination. AB - BACKGROUND: Isolated ureteral metastasis from gastric cancer is extremely rare. CASE REPORT: We describe a 50 year old man with a history of subtotal gastrectomy who presented 4 years later with an ureteral metastasis. He was asymptomatic and diagnostic tests were performed due to the elevated creatinine level disclosed incidentally. The partial resection of distal right ureter as well as the resection of the right ureterovesical junction was performed with the implantation of double J stent. Histopathology revealed a metastasis of the adenocarcinoma that matched perfectly a tumour specimen from the gastric cancer surgery. It was first and isolated manifestation of gastric cancer dissemination. CONCLUSIONS: Although rare, the ureteral metastasis from gastric cancer can be the first, sole and asymptomatic manifestation of gastric cancer dissemination after a period of time. PMID- 22933927 TI - Management of cetuximab-induced skin toxicity with the prophylactic use of topical vitamin K1 cream. PMID- 22933929 TI - Role of (18)F-choline PET/CT in evaluation of patients with prostate carcinoma. AB - BACKGROUND: Choline presents a high affinity for malignant prostate tissue. It can be labelled with positron emitting (18)F, and used for the evaluation of patients with prostate carcinoma by PET/CT imaging. The aim of this paper is to summarise our experience with fluoromethylcholine ((18)F-choline) PET/CT in patients with prostate cancer. METHODS: In 4 months we investigated the patients with histopathological (or cytological) confirmed prostate cancer. Two observers evaluated the early and late (18)F-choline PET images in correlation with corresponding localising CT images and using the semiquantitative standard uptake value (SUV) calculation. RESULTS: The (18)F-choline PET/CT was made in 50 patients with prostate cancer. There were 18 patients after radical prostatectomy and 32 without surgery. In all patients without surgery the pathological uptake was seen in the prostate. In 14 (44 %) patients of this group there was evidence of metastatic spread in local or distant lymph nodes and/or bones. In out of 18 patients after radical prostatectomy the local recurrence was detected in 6 patients (33%) and distant metastases were present in 2 patients (10%). CONCLUSIONS: (18)F-choline PET/CT seems to be useful imaging modality in patients with prostate carcinoma; it can demonstrate spread of the disease preoperatively and detect the local recurrence after radical prostatectomy. PMID- 22933930 TI - Pelvic hemangiopericytoma: the role of diffusion weighted imaging in targeting the biopsy site and in monitoring the tumour response to radiotherapy. AB - BACKGROUND: Despite advances in imaging, the accurate characterization of soft tissue tumours remains a challenging task. Furthermore, the interpretation of post treatment changes and evaluation of tumour response to therapy is another complicating issue regarding soft tissue tumour imaging. CASE REPORT: Herein, a patient with a pelvic hemangiopericytoma, by whom different diagnostic imaging methods were used, is presented. CONCLUSIONS: Diffusion weighted imaging (DWI) might provid useful information in guiding biopsy and enabled monitoring of the radiation therapy results. PMID- 22933931 TI - (Mis)placed central venous catheter in the left superior intercostal vein. AB - BACKGROUND: Chest X-ray is routinely performed to check the position of the central venous catheter (CVC) inserted through the internal jugular or subclavian vein, while the further evaluation of CVC malfunction is usually performed by contrast venography. In patients with superior vena cava obstruction, the tip of the catheter is often seen in collateral mediastinal venous pathways, rather than in the superior vena cava. In such cases detailed knowledge of thoracic vessel anatomy is necessary to identify the exact location of the catheter. CASE REPORT: We report a case of 32-year-old female patient with relapsing mediastinal lymphoma and previous superior vena cava obstruction with collateral azygos hemiazygos venous pathways. The patient had CVC inserted through the left subclavian vein and its position was detected by CT to be in the dilated left superior intercostal vein and accessory hemiazygos vein. Considering that dilated accessory hemiazygos vein can tolerate infusion, the CVC was left in place and the patient had no complaints related to CVC (mal)position. Furthermore, we present anatomical and radiological observations on the azygos-hemiazygos venous system with the special emphasis on the left superior intercostal vein. CONCLUSIONS: Non-contrast CT scans can be a valuable imaging tool in the detection of the CVC position, especially in patients with renal insufficiency and contrast media hypersensitivity. PMID- 22933928 TI - Magnetic nanoparticles as targeted delivery systems in oncology. AB - BACKGROUND: Many different types of nanoparticles, magnetic nanoparticles being just a category among them, offer exciting opportunities for technologies at the interfaces between chemistry, physics and biology. Some magnetic nanoparticles have already been utilized in clinical practice as contrast enhancing agents for magnetic resonance imaging (MRI). However, their physicochemical properties are constantly being improved upon also for other biological applications, such as magnetically-guided delivery systems for different therapeutics. By exposure of magnetic nanoparticles with attached therapeutics to an external magnetic field with appropriate characteristics, they are concentrated and retained at the preferred site which enables the targeted delivery of therapeutics to the desired spot. CONCLUSIONS: The idea of binding chemotherapeutics to magnetic nanoparticles has been around for 30 years, however, no magnetic nanoparticles as delivery systems have yet been approved for clinical practice. Recently, binding of nucleic acids to magnetic nanoparticles has been demonstrated as a successful non-viral transfection method of different cell lines in vitro. With the optimization of this method called magnetofection, it will hopefully become another form of gene delivery for the treatment of cancer. PMID- 22933932 TI - Electrogene therapy with interleukin-12 in canine mast cell tumors. AB - BACKGROUND: Mast cell tumors (MCT) are the most common malignant cutaneous tumors in dogs with extremely variable biological behaviour. Different treatment approaches can be used in canine cutaneous MCT, with surgical excision being the treatment of choice. In this study, electrogene therapy (EGT) as a new therapeutic approach to canine MCTs, was established. MATERIALS AND METHODS.: Eight dogs with a total of eleven cutaneous MCTs were treated with intratumoral EGT using DNA plasmid encoding human interleukin-12 (IL-12). The local response to the therapy was evaluated by repeated measurements of tumor size and histological examination of treated tumors. A possible systemic response was assessed by determination of IL-12 and interferon- gamma (IFN-gamma) in patients' sera. The occurence of side effects was monitored with weekly clinical examinations of treated animals and by performing basic bloodwork, consisting of the complete bloodcount and determination of selected biochemistry parameters. RESULTS: Intratumoral EGT with IL-12 elicits significant reduction of treated tumors' size, ranging from 13% to 83% (median 50%) of the initial tumor volume. Additionally, a change in the histological structure of treated nodules was seen. There was a reduction in number of malignant mast cells and inflammatory cell infiltration of treated tumors. Systemic release of IL-12 in four patients was detected, without any noticeable local or systemic side effects. CONCLUSIONS: These data suggest that intratumoral EGT with plasmid encoding IL-12 may be useful in the treatment of canine MCTs, exerting a local antitumor effect. PMID- 22933933 TI - Image cytometric nuclear texture features in inoperable head and neck cancer: a pilot study. AB - BACKGROUND: Image cytometry can measure numerous nuclear features which could be considered a surrogate end-point marker of molecular genetic changes in a nucleus. The aim of the study was to analyze image cytometric nuclear features in paired samples of primary tumor and neck metastasis in patients with inoperable carcinoma of the head and neck. MATERIALS AND METHODS.: Image cytometric analysis of cell suspensions prepared from primary tumor tissue and fine needle aspiration biopsy cell samples of neck metastases from 21 patients treated with concomitant radiochemotherapy was performed. Nuclear features were correlated with clinical characteristics and response to therapy. RESULTS: Manifestation of distant metastases and new primaries was associated (p<0.05) with several chromatin characteristics from primary tumor cells, whereas the origin of index cancer and disease response in the neck was related to those in the cells from metastases. Many nuclear features of primary tumors and metastases correlated with the TNM stage. CONCLUSIONS: A specific pattern of correlation between well established prognostic indicators and nuclear features of samples from primary tumors and those from neck metastases was observed. Image cytometric nuclear features represent a promising candidate marker for recognition of biologically different tumor subgroups. PMID- 22933934 TI - Triple negative breast cancer - prognostic factors and survival. AB - BACKGROUND: Triple negative breast cancer (TNBC) is defined by a lack of expression of both estrogen (ER) and progesteron (PgR) receptors as well as human epidermal growth factor receptor 2 (HER2). Our retrospective analysis addressed prognostic factors for short- and long-term outcomes of patients (pts) with TNBC pts treated in routine clinical practice. PATIENT AND METHODS.: Our retrospective study included 269 TNBC treated at Institute of Oncology Ljubljana between March 2000 and December 2006. The collected data included patients', tumours' and treatments' characteristics. The survival analyses were performed using the Kaplan-Meier method. The Cox proportional hazard model was used in the multivariate analysis. RESULTS: The median age of our patients was 55.3 yrs (23 88.5) and the median follow-up was 5.9 yrs (0.3-9.6). Six (2%) pts experienced local only, 79 (92%) pts distal recurrence and 66 (24%) died. The predominant localisation of the first relapse was in visceral organs (70.4%). The 5-year disease-free survival (DFS) for the entire group was 68.2% and the 5-year overall survival (OS) was 74.5%. We found a pattern of high recurrence rate in the first 3 years following the diagnosis and a clear decline in recurrence rate over the next 3 years. In the univariate analysis age, nodal status, size and lymphovascular invasion (LVI) were found to have a significant impact on DFS as well as on OS. In the multivariate analysis only age (HR=1.79; 95%CI=1.14-2.82; p=0.012) and nodal status (HR=2.71; 95%CI=1.64-4.46; p<0.001) retained their independent prognostic value for DFS and for OS only the nodal status (HR=2.96; 95%CI=1.51-5.82; p=0.002). CONCLUSIONS: In our series of TNBC pts nodal status and age (older than 65 yrs) were found to be independent prognostic factors for DFS, whereas for OS only the nodal status. We found a pattern of a high recurrence rate in the first 3 years following the diagnosis and a decline in the recurrence rate over the next 3 yrs with higher rate of distal versus local recurrence and a predominant localization of distal metastases in visceral organs. PMID- 22933935 TI - Metastatic tumours to the thyroid gland: report of 3 cases and brief review of the literature. AB - BACKGROUND: Metastases to the thyroid are encountered rarely in clinical practice, but the number of cases seems to have increased in recent years. The reason of this increase may be a more frequent use of fine-needle aspiration biopsy (FNAB) and the use of more sophisticated, complicated imaging techniques in patients with thyroid masses. Also, in addition to these reasons, the use of more organo-specific immunohistochemical antibodies in the examination of surgical specimens may affect the differential diagnosis of malignant tumours. CASE REPORTS: Three metastatic tumours to thyroid were found in the retrospective review of malignant thyroid tumours diagnosed between January 1993 and December 2007. The primary tumours were clear cell carcinoma of the kidney, squamous cell carcinoma of the lung and breast carcinoma-ductal type. CONCLUSIONS: A detailed clinical history, careful histological examination and essential immunohistochemistry helped in attaining the correct diagnosis. PMID- 22933936 TI - Mesenteric fibromatosis with intestinal involvement mimicking a gastrointestinal stromal tumour. AB - INTRODUCTION: Mesenteric fibromatosis or intra-abdominal desmoid tumour is a rare proliferative disease affecting the mesentery. It is a locally aggressive tumour that lacks metastatic potential, but the local recurrence is common. Mesenteric fibromatosis with the intestinal involvement can be easily confused with other primary gastrointestinal tumours, especially with that of the mesenchymal origin. CASE REPORT: We report a case of a 44-year-old female who presented with an abdominal mass that radiologically and pathologically mimicked a gastrointestinal stromal tumour. CONCLUSIONS: The diagnosis of mesenteric fibromatosis should always be considered in the case of mesenchymal tumours apparently originating from the bowel wall that diffusely infiltrate the mesentery. PMID- 22933937 TI - Dosimetric evaluation of a 320 detector row CT scanner unit. AB - BACKGROUND: The technologic improvements in Multislice scanners include the increment in the X-ray beam width. Some new CT scanners are equipped with a 320 detector row which allows a longitudinal coverage of 160 mm and a total of 640 slices for a single rotation. When such parameters are used the length of the traditional pencil chamber (10 cm) is no more appropriate to measure the standard weighted computed tomography dose index (CTDI(w)) value. MATERIALS AND METHODS.: Dosimetric measurements were performed on a 640 slices Toshiba Aquilion One CT scanner using common instrumentation available in Medical Physics Departments. RESULTS: For the measurements in air, two different ionization chambers were completely exposed to the beam. Dosimeters showed an acceptable agreement in the measurements. To evaluate the actual shape of the dose profile strips of Gafchromic XRQA film were used. Films were previously calibrated on site. From the graphic response of the scanned film it is possible to evaluate the full width at half maximum (FWHM) of the dose profile which represent the actual beam width. CONCLUSIONS: Computed Tomography Dose Index (CTDI) and Dose Length Product (DLP) need to be changed when the beam width of the CT scanner is over 100 mm. To perform dose evaluation with the conventional instrumentation, two parameters should be considered: the average absorbed dose and the actual beam width. To measure the average absorbed dose, the conventional ionization chamber can be used. For the measurement of the width of the dose profile, Gafchromic XRQA film seemed to be suitable. PMID- 22933938 TI - Verification of quality parameters for portal images in radiotherapy. AB - BACKGROUND: The purpose of the study was to verify different values of quality parameters of portal images in radiotherapy. MATERIALS AND METHODS: We investigated image qualities of different field verification systems. Four EPIDs (Siemens OptiVue500aSi((r)), Siemens BeamView Plus((r)), Elekta iView((r)) and Varian PortalVisionTM) were investigated with the PTW EPID QC PHANTOM((r)) and compared with two portal film systems (Kodak X-OMAT((r)) cassette with Kodak X OMAT V((r)) film and Kodak EC-L Lightweight((r)) cassette with Kodak Portal Localisation ReadyPack((r)) film). RESULTS: A comparison of the f50 and f25 values of the modulation transfer functions (MTFs) belonging to each of the systems revealed that the amorphous silicon EPIDs provided a slightly better high contrast resolution than the Kodak Portal Localisation ReadyPack((r)) film with the EC-L Lightweight((r)) cassette. The Kodak X-OMAT V((r)) film gave a poor low contrast resolution: from the existing 27 holes only 9 were detectable. CONCLUSIONS: On the base of physical characteristics, measured in this work, the authors suggest the use of amorphous-silicon EPIDs producing the best image quality. Parameters of the EPIDs with scanning liquid ionisation chamber (SLIC) were very stable. The disadvantage of older versions of EPIDs like SLIC and VEPID is a poor DICOM implementation, and the modulation transfer function (MTF) values (f50 and f25) are less than that of aSi detectors. PMID- 22933939 TI - Microsatellite instability in colorectal cancer. AB - BACKGROUND: Colorectal cancer (CRC) is the third most common cancer in the world. In 75% CRC develops sporadically, in 25% hereditary or as a consequence of inflammatory bowel disease. CRC carcinogenesis develops over many years. The cause of CRC in 85% is chromosomal instability (CIN) and in 15% microsatellite instability (MSI-H), where hereditary nonpolyposis colorectal cancer (HNPCC) represents 10-20%. Microsatellite sequences (MS) are repeated sequences of short stretches of DNA all over the genome. Microsatellite stability (MSS) means MS are the same in each cell of an individual, whereas microsatellite instability (MSI H) means MS differ in normal and cancer cells of an individual. The cause of MSI H is a damaged mismatch repair mechanism (MMR), with the most important MMR proteins being MSH2, MLH1 and MSH6. CONCLUSIONS: MSI-H seems to be an important prognostic factor in CRC and an important predictive factor of CRC chemotherapeutic treatment efficacy. Clinical trials conducted until now have shown contradictory findings in different chemotherapeutic settings, adjuvant and palliative; therefore MSI-H is going to be the object of the future research. The future of cancer treatment is in the individualized therapy based on molecular characteristics of the tumour, such as MSI-H in CRC. PMID- 22933940 TI - Analysis of peripheral artery velocity tracing in a porcine model. AB - BACKGROUND: The aim of the study was to trace the peripheral artery velocity with ultrasound in pigs and provide inference on diagnosis of the type, location and severity of vascular diseases. MATERIALS AND METHODS: Limb tightening, adrenaline administration and arterial wall pinching were performed independently in six pigs, and then the evolution of the external iliac artery or femoral artery velocity tracing were monitored. RESULTS: With the increase of the extents of hindlimb tightening, peak systolic velocity (PSV) of ipsilateral external iliac artery turned from 36.33+/-1.77 cm/s to 59.72+/-2.67 cm/s, minimum post-principal wave velocity (MPV from 13.68+/-1.11 cm/s to -7.48+/-0.82 cm/s, peak diastolic velocity (PDV) from 19.31+/-0.86 cm/s to 8.98+/-0.45 cm/s, and, end diastolic velocity (EDV) from 13.2+/-0.45 cm/s to 0. With the increase of the dose of the epinephrine injection, PSV increased from 36.33+/-1.77 cm/s to 43.97+/-2.15 cm/s but then decreased to 35.43+/-3.01 cm/s, and MPV negatively increased to -23.53+/ 0.82 cm/s after decreasing from 13.68+/-1.11 cm/s to 0. PDV and EDV gradually decreased to zero. With the increase of the stenosis severity in the abdominal aortic wall pinching, PSV was reduced and had a linearly negative correlation with the stenosis severity (R=0.983, R2=0.967). MPV gradually increased, and its direction reversed when the stenosis severity increased, then diminished when the blood flow was occluded by more than 2/3. CONCLUSIONS: The formation of peripheral artery velocity is the result of concurrent effects of cardiac ejection, vascular resistance, effective circulating blood volume and elastic recoil. Vascular resistance exerts pronounced effects on the diastolic waveform, and the occurrence of backward wave indicates that the downstream circulation resistance significantly increases. PMID- 22933941 TI - Comparison of CT and MRI in diagnosis of cerebrospinal leak induced by multiple fractures of skull base. AB - BACKGROUND: Multiple basilar skull fracture and cerebrospinal leak are common complications of traumatic brain injury, which required a surgical repair. But due to the complexity of basilar skull fracture after severe trauma, preoperatively an exact radiological location is always difficult. Multi-row spiral CT and MRI are currently widely applied in the clinical diagnosis. The present study was performed to compare the accuracy of cisternography by multi row spiral CT and MRI in the diagnosis of cerebrospinal leak. METHODS: A total of 23 patients with multiple basilar skull fracture after traumatic brain injury were included. The radiological and surgical data were retrospectively analyzed. 64-row CT (mm/row) scan and three-dimensional reconstruction were performed in 12 patients, while MR plain scan and cisternography were performed in another 11 patients. The location of cerebrospinal leak was diagnosed by 2 experienced physicians majoring neurological radiology. Surgery was performed in all patients. The cerebrospinal leak location was confirmed and repaired during surgery. The result was considered as accurate when cerebrospinal leak was absent after surgery. RESULTS: According to the surgical exploration, the preoperative diagnosis of the active cerebrospinal leak location was accurate in 9 out of 12 patients with CT scan. The location could not be confirmed by CT because of multiple fractures in 2 patients and the missed diagnosis occurred in 1 patient. The preoperative diagnosis was accurate in 10 out of 11 patients with MRI examination. CONCLUSIONS: MRI cisternography is more advanced than multi-row CT scan in multiple basilar skull fracture. The combination of the two examinations may increase the diagnostic ratio of active cerebrospinal leak. PMID- 22933942 TI - Diffusion differences between pilocytic astrocytomas and grade II ependymomas. AB - BACKGROUND: The aim of our study was to differentiate between cerebellar pilocytic astrocytomas and grade II ependymomas on the basis of their diffusion properties. PATIENTS AND METHODS: The study prospectively included 12 patients with pilocytic astrocytomas and 5 with ependymomas. Apparent diffusion coefficients (ADC) were compared between tumour types. RESULTS: ADC values were significantly higher in pilocytic astrocytomas than ependymomas, with almost no overlapping of the range of measured ADCs between the two tumour types. CONCLUSIONS: Significant diffusion differences between pilocytic astrocytomas and grade II ependymomas enable their preoperative distinction, in combination with conventional magnetic resonance images. PMID- 22933943 TI - CD133/prominin1 is prognostic for GBM patient's survival, but inversely correlated with cysteine cathepsins' expression in glioblastoma derived spheroids. AB - INTRODUCTION: CD133 is a marker for a population of glioblastoma (GBM) and normal neural stem cells (NNSC). We aimed to reveal whether the migratory potential and differentiation of these stem cells is associated with CD133 expression and with cathepsin proteases (Cats). MATERIALS AND METHODS.: The invasiveness of normal NNSC, GBM/CD133+ cell lines and GBM spheroids was evaluated in 3D collagen, as well as of U87-MG and normal astrocytes (NHA) grown in monolayers in 2D Matrigel. Expression of Cats B, L and S was measured at mRNA and activity levels and their relation to invasiveness, to CD133 mRNA in 26 gliomas, and to the survival of these patients. RESULTS: The average yield of CD133+ cells from GBM samples was 9.6 %. Survival of patients with higher CD133 mRNA expression was significantly shorter (p< 0.005). Invasion, associated with proteolytic degradation of matrix, was higher in normal stem cells and GBM spheroids and cells than in isolated GBM CD133+ cells. In glioma samples, there was no correlation between CD133 mRNA expression and Cat mRNAs, but there was an inverse correlation with Cat activities. CONCLUSIONS: The study confirms CD133 as a prognostic marker for the survival of GBM patients. We demonstrated that NNSC have higher invasion potential and invade the collagen matrix in a mode different from that of GBM, initiating stem cell spheres. This result could have implications for the design of new therapeutics, including protease inhibitors that specifically target invasive tumour stem cells. Increased activity of cathepsins in CD133- cells suggests their role in the invasive behaviour of GBM. PMID- 22933944 TI - Chemotherapy increases caspase-cleaved cytokeratin 18 in the serum of breast cancer patients. AB - BACKGROUND: Apoptosis is thought to be induced by chemotherapy in cancer patients. Therefore, the measurement of its amplitude may be a useful tool to predict the effectiveness of cancer treatment sooner than conventional methods do. PATIENTS AND METHODS: In the study presented, apoptosis was assessed with an ELISA-based assay in which caspase-cleaved cytokeratin 18 (M30-antigen), a novel specific biomarker of apoptosis, is measured. Thirty seven patients with malignant (nonmetastatic and metastatic) breast cancer, 35 patients with benign breast disease, and 34 healthy subjects were studied. Cancer patients received neoadjuvant chemotherapy consisting of either fluorouracil, epirubicin, and cyclophosphamide (FEC) or epirubicin plus docetaxel (ED). Apoptosis was detected before chemotherapy, 24 and 48 h after chemotherapy in the malignant group. RESULTS: It was found that the baseline apoptosis level in either malignant but nonmetastatic group or benign group was not statistically different from that in the control group (p>0.05). However, it was statistically significantly higher in the metastatic group than that in the control group (p<0.05). Following the drug application, M30-antigen levels significantly increased at 24 h (p<0.05). The baseline M30-antigen levels increased about 3-times in patients showing tumor regression. CONCLUSIONS: M30-antigen level is increased after chemotherapy and its measurement may help clinicians to predict the effectiveness of chemotherapy sooner in breast cancer cases although confirmative larger trials are needed. PMID- 22933945 TI - Clinical efficacy of local targeted chemotherapy for triple-negative breast cancer. AB - BACKGROUND: The aim of the study was to evaluate the clinical efficacy of superselective intra-arterial targeted neo-adjuvant chemotherapy in the treatment of estrogen receptor (ER)-negative, progesterone receptor (PR)-negative, and human epidermal growth factor receptor 2 (HER2)-negative (triple-negative) breast cancer. PATIENTS AND METHODS.: A total of 47 triple-negative breast cancer patients (29 at stage II, 13 at stage III and 5 at stage IV) were randomly assigned to two groups: targeted chemotherapy group (n=24) and control group (n=23). Patients in the targeted chemotherapy group received preoperative superselective intra-arterial chemotherapy with CEF regimen (C: cyclophosphamide [600 mg/m(2)]; E: epirubicin [90 mg/m(2)]; F: 5-fluorouracil [600 mg/m(2)]), and those in the control group received routine neoadjuvant chemotherapy with CEF. The duration of the treatment, changes in lesions and the prognosis were determined. RESULTS: The average course of the treatment was 15 days in the targeted chemotherapy group which was significantly shorter than that in the control group (31 days) (P<0.01). The remission rate of lesions was 91.6% in the targeted chemotherapy group and 60.9% in the control group, respectively. Among these patients, 9 died within two years, including 2 (both at IV stage) in the targeted chemotherapy group and 7 (2 at stage II, 4 at stage III and 1 at stage IV) in the control group. CONCLUSIONS: As an neoadjuvant therapy, the superselective intra-arterial chemotherapy is effective for triple-negative breast cancer, with advantages of the short treatment course and favourable remission rates as well as prognoses. PMID- 22933946 TI - Giant Brunner's gland adenoma as an unusual cause of anaemia: report of a case. AB - BACKGROUND: Brunner's gland adenoma (BGA) is a rare benign duodenal tumour proliferating from Brunner's glands. Here, we present a giant BGA leading to anaemia, with its clinical, endoscopic, radiological, surgical and pathological findings. CASE REPORT: A 48-year-old Turkish man complained of a six months history of vague epigastric discomfort, loss of appetite and nausea after meals without vomiting. The physical examination had no unremarkable finding. Laboratory findings, including liver function tests, were within normal limits except a hypochromic, microcytic anaemia. The upper gastrointestinal endoscopic examination revealed a lobulated, red, polypoid tumour with a smooth surface covered with normal mucosa. The tumour was located on the anterior surface of duodenal bulb and had a wide base measuring 3.5 * 4 cm in size. Endoscopic ultrasonography revealed a submucosal polypoid mass located at the anterior surface of duodenal bulb. The endoscopic excision was tried but was not successful. The patient was operated and transduodenal polypectomy was done. The postoperative period was uneventful and the pathologic diagnosis was assessed as Brunner's gland adenoma. During the follow-up period, the endoscopic examination was normal at 12th month postoperatively. CONCLUSIONS: BGA is a rare benign cause of anaemia that can be treated with excellent results. PMID- 22933947 TI - Target and peripheral dose from radiation sector motions accompanying couch repositioning of patient coordinates with the Gamma Knife((r)) Perfexion(TM). AB - BACKGROUND: The GammaPlan(TM) treatment planning system (TPS) does not fully account for shutter dose when multiple shots are required to deliver a patient's treatment. The unaccounted exposures to the target site and its periphery are measured in this study. The collected data are compared to a similar effect from the Gamma Knife((r)) model 4C. MATERIALS AND METHODS.: A stereotactic head frame was attached to a Leksell((r)) 16 cm diameter spherical phantom; using a fiducial box, CT images of the phantom were acquired and registered in the TPS. Measurements give the relationship of measured dose to the number of repositions with the patient positioning system (PPS) and to the collimator size. An absorbed dose of 10 Gy to the 50% isodose line was prescribed to the target site and all measurements were acquired with an ionization chamber. RESULTS: Measured dose increases with frequency of repositioning and with collimator size. As the radiation sectors transition between the beam on and beam off states, the target receives more shutter dose than the periphery. Shutter doses of 3.53+/-0.04 and 1.59+/-0.04 cGy/reposition to the target site are observed for the 16 and 8 mm collimators, respectively. The target periphery receives additional dose that varies depending on its position relative to the target. CONCLUSIONS: The radiation sector motions for the Gamma Knife((r)) Perfexion(TM) result in an additional dose due to the shutter effect. The magnitude of this exposure is comparable to that measured for the model 4C. PMID- 22933948 TI - Thyroid volume's influence on energy deposition from (131)I calculated by Monte Carlo (MC) simulation. AB - BACKGROUND: It is well known that the success of the radiomethabolic (131)I treatment of hyperthyroidism could depend on the absorbed dose to the thyroid. It is, thus, very important to calculate the individual radiation dose as accurately as possible for different masses of thyroid lobes. The aim of this work is to evaluate the influence of thyroid volume on the energy deposition from beta and gamma rays of (131)I by Monte Carlo (MC) simulation. MATERIALS AND METHODS: We have considered thyroid lobes having an ellipsoidal shape, with a density of 1.05 g/ cm(3) and the material composition suggested by International Commission on Radiological Protection (ICRP). We have calculated the energy deposition of (131)I rays for different volumes of thyroid lobes by using the MCNPX code, with a full transport of beta and gamma rays. RESULTS AND CONCLUSIONS: The results show that the total energy deposition has a significant difference, till 11%, when the lobe's volume varies from 1 ml to 25 ml, respect to the value presented in MIRDOSE for a 10 g sphere. The absorbed energy fraction increases by volume, because the increasing volume to surface ratio of ellipsoidal lobe causes the decrease of beta ray fraction escaping from the lobe. PMID- 22933949 TI - Croatian Society of Radiology (1928-2008), the Croatian Medical Association - 80 years of existence and activity. AB - OFTEN AND IN VARIOUS CONNOTATIONS ONE CAN HEAR OR READ THE FOLLOWING SYNTAGMA: "Let's leave the past in the past - and turn to the future". Even more frequent and numerous are opposite opinions, e.g. "There is no future without past", "Future is built on past" or "Remembering our past - reaching for our future", and many more. PMID- 22933950 TI - New developments in surgery of malignant gliomas. AB - BACKGROUND: Malignant gliomas account for a high proportion of brain tumours. With new advances in neurooncology, the recurrence-free survival of patients with malignant gliomas has been substantially prolonged. It, however, remains dependent on the thoroughness of the surgical resection. The maximal tumour resection without additional postoperative deficit is the goal of surgery on patients with malignant gliomas. In order to minimize postoperative deficit, several pre- and intraoperative techniques have been developed. CONCLUSIONS: Several techniques used in malignant glioma surgery have been developed, including microsurgery, neuroendoscopy, stereotactic biopsy and brachytherapy. Imaging and functional techniques allowing for safer tumour resection have a special value. Imaging techniques allow for better preoperative visualization and choice of the approach, while functional techniques help us locate eloquent regions of the brain. PMID- 22933951 TI - Polydimethylsiloxane: a new contrast material for localization of occult breast lesions. AB - BACKGROUND: The radioguided localization of occult breast lesions (ROLL) technique often utilizes iodinated radiographic contrast to assure that the local injection of (99m)Tc-MAA corresponds to the location of the lesion under investigation. However, for this application, this contrast has several shortcomings. The objective of this study was to evaluate the safety, effectiveness and technical feasibility of the use of polydimethylsiloxane (PDMS) as radiological contrast and tissue marker in ROLL. MATERIALS AND METHODS.: The safety assessment was performed by the acute toxicity study in Wistar rats (n = 50). The radiological analysis of breast tissue (n = 32) from patients undergoing reductive mammoplasty was used to verify the effectiveness of PDMS as contrast media. The technical feasibility was evaluated through the scintigraphic and histologic analysis. RESULTS: We found no toxic effects of PDMS for this use during the observational period. It has been demonstrated in human breast tissue that the average diameter of the tissue marked by PDMS was lower than when marked by the contrast medium (p <0.001). PDMS did not interfere with the scintigraphic uptake (p = 0.528) and there was no injury in histological processing of samples. CONCLUSIONS: This study demonstrated not only the superiority of PDMS as radiological contrast in relation to the iodinated contrast, but also the technical feasibility for the same applicability in the ROLL. PMID- 22933952 TI - Magnetic resonance urography in children - when and why? AB - BACKGROUND: The aim of the study was to determine the potential of magnetic resonance urography (MRU) in evaluation of paediatric urinary tract pathologies. PATIENTS AND METHODS.: Twenty-one paediatric urological patients were evaluated with T1, T2 prior and after and 3D gradient echo sequences after the contrast administration. Results were compared with findings obtained with ultrasound which was performed to all of patients, intravenous urography performed to 14 patients with the diagnosis of hydronephrosis and voiding cystouretrography performed to 6 patients where hydronephrosis was suspected to be caused by vesicoureteral reflux (VUR). RESULTS: MRU not only established the cause of hydronephrosis in all 14 cases (5 ureteropelvic junction (UPJ) stenosis, 1 functional stenosis, 3 residual hydronephrosis, 1 combination of UPJ and vesico ureteric junction (VUJ) stenosis with hydromegaureter, 2 fetal ureters and 3 insufficient broad ureteral orifices), but gave additional information about existing pathological conditions in all of patients compared to other previously performed examination (1 caliceal lithiasis, 4 UPJ stenosis, 1 VUJ stenosis, 1 neurogenic bladder, 1 hypotonic ureter, 1 urinary infection, 1 duplication of pelvis and ureter, 1 urinary retention and 1 fetal ureter). Other MRU findings were: 3 polycystic kidney disease, 1 caliceal cyst, 2 simple renal cysts, 1 long hypotonic twisted ureters and 1 hypertrophied column of Bertini. CONCLUSIONS: Because of the ability to acquire high contrast and spatial resolution images of the whole urinary tract in any orthogonal plane, MRU enables a precise detection and differentiation of pathological urological conditions. We believe that in the future, because of its advantages, MRU will replace traditional methods in the evaluation of urinary tract pathologies. PMID- 22933953 TI - With computed tomography confirmed anterolateral left ventricular pseudoaneurysm in patient with dilatative alcoholic cardiomyopathy. AB - BACKGROUND: Pseudoaneurysms are rare complications of myocardial infarction with propensity for rupture. There is still a challenge with which diagnostic imaging we performed a final diagnosis of pseudoaneurysm and differentiate it from true aneurysm what is clinically important due to the different treatment. CASE REPORT: We presented the unusual case of a 56-year-old man with signs of decompensated heart failure which had worsened a few months before hospitalization. We believed that during worsening of symptoms the patient suffered a silent myocardial infarction complicated by subacute free wall rupture which resulted into left ventricular pseudoaneurysm formation without tamponade. Echocardiography showed dilatative cardiomyopathy which was already present years before and a very rare location of the left ventricular pseudoaneurysm on the anterolateral part of the left ventricle. Pseudoaneurysm was confirmed with CT scan. Due to the severity of contractile dysfunction and no response in treatment for congestive heart failure the directive for the resection was tempered and the patient died due to the progressive heart failure and embolic phenomena. CONCLUSIONS: This report shows the importance of non-invasive imaging diagnostic evaluation of acute decompensated heart failure where echocardiography and chest X-ray are the first diagnostic steps. Based on those findings further imaging diagnostic steps must be performed such as CT scan in our case which finally confirms left ventricular pseudoaneurysm with dilatative cardiomyopathy. PMID- 22933954 TI - Scatterogram: a method for outlining the body during lymphoscintigraphy without using external flood source. AB - BACKGROUND: We evaluated the feasibility of outlining the body with scattered photons using a low dose intradermal injection of the radiotracer. PATIENTS AND METHODS.: Sixty breast cancer patients were included into the study. 30 minutes post radiotracer injection static lymphoscintigraphy images were acquired using low energy high resolution collimator in anterior and lateral views. For patients with 2-day protocol another set of images was taken 20 hours post-injection. Two photopeaks were used during imaging: 1-Tc-99m (130-150 keV) and 2- Scatter photons (60-120). The fusion image of these two images was constructed by NM-NM fusion workflow of the workstation. The usual body outline of the patients was also acquired in 20 cases using the external flood source without moving the patients from their positions. RESULTS: The early (30 minute image) scatterograms of the patients clearly showed the contour of the body. The 20 hour scatterograms were not as high quality as the corresponding early images. The constructed overlaid images showed the location of the axillary sentinel nodes and the body contours clearly for early scatterograms but not the delayed (20 hour) ones. The processing of the images for the reconstruction of overlaid scatterograms took the mean time of 10+/-5 seconds. CONCLUSIONS: Imaging the scattered photons is feasible for the intradermal low dose injection of the radiotracers in order to outline the body contour. This imaging method does not increase the radiation exposure of the patients or operators and does not extend the time of imaging either. PMID- 22933955 TI - Usefulness of low iodine diet in managing patients with differentiated thyroid cancer - initial results. AB - BACKGROUND: Low iodine diet (LID) is recommended in patients with differentiated thyroid cancer before radioiodine administration. Patients with increased thyroglobulin (Tg) level, but negative (131)I whole body scan present diagnostic and therapeutic dilemma. This study was designed to evaluate the benefit of a two week LID in patients with elevated serum Tg levels and negative (131)I whole body scans. PATIENTS AND METHODS.: For the impact assessment of two-week LID on radioiodine tissue avidity, radioiodine scans before and after LID were compared. Sixteen patients with serum Tg > 2 MUg/L, negative Tg-antibodies, and negative radioiodine scans underwent two-week LID before the (131)I administration. Fourteen patients underwent diagnostic scanning and two patients received radioiodine therapy. Iodine concentration in the morning urine specimens were measured in each patient, a day before and 15(th) day after starting LID. RESULTS: Following self-managed LID, patients were able to significantly reduce their iodine body content by 50% (range 28-65%, p<0,001). 13 patients (82%) accomplished mild iodine deficiency (50-99 MUg/L) and one patient (6%) achieved targeted moderate iodine deficient state (<50 MUg/L). All diagnostic post-LID scans were negative. Both post-therapy (131)I scans showed radioiodine accumulation outside of normal (131)I distribution (neck region and diffuse hepatic uptake). This study demonstrated that two-week LID is effective way to decrease total body iodine content, although without a visible effect on post-LID diagnostic (131)I scans. CONCLUSIONS: A more stringent dietary protocol and longer iodine restriction period are probably needed to achieve targeted moderate iodine deficiency in patients preparing for (131)I administration. This might result in higher radioiodine avidity of thyroid remnant/metastases. PMID- 22933956 TI - Knockdown of stat3 expression by RNAi inhibits in vitro growth of human ovarian cancer. AB - BACKGROUND: The aim of the study was to investigate the suppressive effects of pSilencer2.1-U6-siRNA-stat3 recombinant plasmids on the growth of ovarian cancer in vitro. MATERIAL AND METHODS.: Three pairs of DNA template (stat3-1, stat3-2, stat3-3) specific for different target sites on stat3 mRNA were synthesized to reconstruct pSilencer2.1-U6-siRNA-stat3s, which were transfected into SKOV3 cells. The expressions of STAT3, BcL-2, cyclin D1 and C-myc in these cells were detected by Western blot and Northern blot. The cell cycle and the growth were determined by flow cytometry (FCM) and MTT assay, respectively. Cell apoptosis was determined by TUNEL staining. RESULTS: Of the three siRNAs, only siRNA targeting stat3-3 markedly suppressed the protein expression of stat3 in SKOV3 cells; MTT assay and FCM showed that transfection of stat3-3 siRNA could significantly suppress the growth of SKOV3 cells and arrest the cell cycle in vitro. TUNEL staining also showed massive apoptosis in SKOV3 cells transfected with stat3-3 siRNA. CONCLUSIONS: pSilencer2.1-U6-siRNA-stat3-3 can significantly inhibit the STAT3 expression in human ovarian cancer cells resulting in the inhibition of the cancer growth and the increase of apoptosis of cancer cells. PMID- 22933957 TI - Pipette tip with integrated electrodes for gene electrotransfer of cells in suspension: a feasibility study in CHO cells. AB - BACKGROUND: Gene electrotransfer is a non-viral gene delivery method that requires successful electroporation for DNA delivery into the cells. Changing the direction of the electric field during the pulse application improves the efficacy of gene delivery. In our study, we tested a pipette tip with integrated electrodes that enables changing the direction of the electric field for electroporation of cell suspension for gene electrotransfer. MATERIALS AND METHODS: A new pipette tip consists of four cylindrical rod electrodes that allow the application of electric pulses in different electric field directions. The experiments were performed on cell suspension of CHO cells in phosphate buffer. Plasmid DNA encoding for green fluorescent protein (GFP) was used and the efficiency of gene electrotransfer was determined by counting cells expressing GFP 24 h after the experiment. RESULTS: Experimental results showed that the percentage of cells expressing GFP increased when the electric field orientation was changed during the application. The GFP expression was almost two times higher when the pulses were applied in orthogonal directions in comparison with single direction, while cell viability was not significantly affected. CONCLUSIONS: We can conclude that results obtained with the described pipette tip are comparable to previously published results on gene electrotransfer using similar electrode geometry and electric pulse parameters. The tested pipette tip, however, allows work with small volumes/samples and requires less cell manipulation. PMID- 22933958 TI - Differences in plasma TIMP-1 levels between healthy people and patients with rectal cancer stage II or III. AB - BACKGROUND: The purpose of the study was to analyse whether the levels of the tissue inhibitor of matrix metalloproteinases-1 (TIMP-1) are higher in patients with rectal cancer as compared with healthy blood donors. PATIENTS AND METHODS.: Two hundred and seventeen patients (147 male, 70 female) with histologically confirmed non-metastatic rectal cancer (clinical stage II-III) and 45 healthy blood donors (15 male, 30 female) were included in analysis. Patient's mean age was 66 years (range: 34-87 years) and healthy blood donor's mean age was 35 years (range: 18-64 years). Plasma TIMP-1 concentrations were measured with an enzyme linked immunosorbent assay (ELISA) using commercially available TIMP-1 ELISA kit. Mann-Whitney-test for independent groups was used to assess the differences of plasma TIMP-1 levels and clinicopathological parameters. Two-sided tests were used and the differences at P<0.05 were considered as statistically significant. RESULTS: Median patients TIMP-1 level was 180 ng/mL (range: 22-538 ng/mL); the mean (+/-SD) level was 193.7 (79.5) ng/mL. The median healthy blood donors TIMP-1 level was 112 ng/mL (range: 48-211 ng/mL); the mean (+/-SD) level was 115 (35.7) ng/mL. TIMP-1 levels in patients with rectal cancer were statistically significantly higher than TIMP-1 levels in healthy blood donors (P<0.0001). Significant differences in TIMP-1 levels were not found comparing gender (P=0.43), but in both groups TIMP-1 levels were increased with higher age (P=0.007). CONCLUSIONS: Patients with rectal cancer had statistically significantly higher mean and median TIMP-1 level than healthy blood donors which is in accordance with the results published in other publications. These findings suggest possibility that plasma TIMP-1 levels could be used as new biological markers for early cancer detection. PMID- 22933959 TI - 3-D conformal radiotherapy with concomitant and adjuvant temozolomide for patients with glioblastoma multiforme and evaluation of prognostic factors. AB - BACKGROUND: The aim of the retrospective study was to evaluate the outcome and prognostic factors of newly diagnosed glioblastoma patients who received 3-D conformal radiotherapy (RT) combined with concomitant and/or adjuvant temozalamide (TMZ) postoperatively. PATIENTS AND METHODS: Fifty patients with glioblastoma multiforme were treated with 3-D conformal RT combined with concomitant and/or adjuvant TMZ postoperatively. Median age was 57 years (range, 12-79) and median Karnofsky performance status (KPS) was 70 (range, 40-100). A multivariate Cox regression model was used to test the effect of age, sex, KPS, extent of surgery, tumour dimension (<5cm vs. >=5cm), full dose RT (>=60 Gy vs. <60 Gy), concurrent TMZ and adjuvant TMZ treatment (adjuvant therapy plus 6 cycles of TMZ group versus <6 cycles of TMZ group) on the overall survival. RESULTS: The median follow up time was 10 months (range 3-42). One- and 2-year overall survival rates were 46% and 20%, respectively. The prognostic factors important for the overall survival were a full dose RT (>=60 Gy) (p=0.005) and the application of adjuvant TMZ for 6 cycles (p=0.009). CONCLUSIONS: The results of our study confirm the efficiency of RT plus concomitant and adjuvant TMZ, with an acceptable toxicity in patients. We suggest that at least 6 cycles of adjuvant TMZ should be administered to obtain a benefit from the adjuvant treatment. PMID- 22933960 TI - Feasibility study on effect and stability of adaptive radiotherapy on kilovoltage cone beam CT. AB - BACKGROUND: We have analyzed the stability of CT to density curve of kilovoltage cone-beam computerized tomography (kV CBCT) imaging modality over the period of six months. We also, investigated the viability of using image value to density table (IVDT) generated at different time, for adaptive radiotherapy treatment planning. The consequences of target volume change and the efficacy of kV CBCT for adaptive planning issues is investigated. MATERIALS AND METHODS.: Standard electron density phantom was used to establish CT to electron density calibrations curve. The CT to density curve for the CBCT images were observed for the period of six months. The kV CBCT scans used for adaptive planning was acquired with an on-board imager system mounted on a "Trilogy" linear accelerator. kV CBCT images were acquired for daily setup registration. The effect of variations in CT to density curve was studied on two clinical cases: prostate and lung. RESULTS: The soft tissue contouring is superior in kV CBCT scans in comparison to mega voltage CT (MVCT) scans. The CT to density curve for the CBCT images was found steady over six months. Due to difficulty in attaining the reproducibility in daily setup for the prostate treatment, there is a day-to day difference in dose to the rectum and bladder. CONCLUSIONS: There is no need for generating a new CT to density curve for the adaptive planning on the kV CBCT images. Also, it is viable to perform the adaptive planning to check the dose to target and organ at risk (OAR) without performing a new kV CT scan, which will reduce the dose to the patient. PMID- 22933961 TI - Titanium dioxide in our everyday life; is it safe? AB - BACKGROUND: Titanium dioxide (TiO(2)) is considered as an inert and safe material and has been used in many applications for decades. However, with the development of nanotechnologies TiO(2) nanoparticles, with numerous novel and useful properties, are increasingly manufactured and used. Therefore increased human and environmental exposure can be expected, which has put TiO(2) nanoparticles under toxicological scrutiny. Mechanistic toxicological studies show that TiO(2) nanoparticles predominantly cause adverse effects via induction of oxidative stress resulting in cell damage, genotoxicity, inflammation, immune response etc. The extent and type of damage strongly depends on physical and chemical characteristics of TiO(2) nanoparticles, which govern their bioavailability and reactivity. Based on the experimental evidence from animal inhalation studies TiO(2) nanoparticles are classified as "possible carcinogenic to humans" by the International Agency for Research on Cancer and as occupational carcinogen by the National Institute for Occupational Safety and Health. The studies on dermal exposure to TiO(2) nanoparticles, which is in humans substantial through the use of sunscreens, generally indicate negligible transdermal penetration; however data are needed on long-term exposure and potential adverse effects of photo oxidation products. Although TiO(2) is permitted as an additive (E171) in food and pharmaceutical products we do not have reliable data on its absorption, distribution, excretion and toxicity on oral exposure. TiO(2) may also enter environment, and while it exerts low acute toxicity to aquatic organisms, upon long-term exposure it induces a range of sub-lethal effects. CONCLUSIONS: Until relevant toxicological and human exposure data that would enable reliable risk assessment are obtained, TiO(2) nanoparticles should be used with great care. PMID- 22933962 TI - Assessing renal function in children with hydronephrosis - additional feature of MR urography. AB - BACKGROUND: Magnetic resonance urography (MRU) is one of the most attractive imaging modalities in paediatric urology, providing largest diagnostic information in a single protocol. Therefore, the aim of our study was to assess the diagnostic value of MRU in children with urogenital anomalies (especially anomalies of the renal pelvis and ureter) and the renal function using different post-processing functional software. PATIENTS AND METHODS: Ninety six children (7 days - 18 years old) were examined. In 54 patients of them, a static T(2) MRU was completed by excretory T(1) MRU after gadolinium administration and functional analysis has been performed using two functional analysis softwares "CHOP-fMRU" and "ImageJ" software. RESULTS: MRU showed suspicious renal and the whole urinary tract anomalies with excellent image quality in all children. In ureteropelvic obstruction, MRU was confirmatory to the other imaging techniques, but it was superior modality concerning the evaluation of end-ureteral anomalies. There was an excellent correlation between the MRU data and diagnosis, determined by surgery. The renal transit times, renal volumes and volumetric differential renal function were assessed separately by "CHOP-fMRU" and "ImageJ" with excellent agreement with 99(m)Tc-DTPA and among them. CONCLUSIONS: MRU overcomes a lot of limitations of conventional imaging modalities and has a potential to become a leading modality in paediatric uroradiology. Synthesis of both anatomical and functional criteria in MR urography enables to select the best candidates for surgical treatment. Even small kidney dysfunction can be detected by functional analysis software. PMID- 22933963 TI - Cathepsin H indirectly regulates morphogenetic protein-4 (BMP-4) in various human cell lines. AB - BACKGROUND: Cathepsin H is a cysteine protease considered to play a major role in tumor progression, however, its precise function in tumorigenesis is unclear. Cathepsin H was recently proposed to be involved in processing of bone morphogenetic protein 4 (BMP-4) in mice. In order to clarify whether cathepsin H also regulates BMP-4 in humans, its impact on BMP-4 expression, processing and degradation was investigated in prostate cancer (PC-3), osteosarcoma (HOS) and pro-monocytic (U937) human cell lines. MATERIALS AND METHODS: BMP-4 expression was founded to be regulated by cathepsin H using PCR array technology and confirmed by real time PCR. Immunoassays including Western blot and confocal microscopy were used to evaluate the influence of cathepsin H on BMP-4 processing. RESULTS: In contrast to HOS, the expression of BMP-4 mRNA in U937 and PC3 cells was significantly decreased by cathepsin H. The different regulation of BMP-4 synthesis could be associated with the absence of the mature 28 kDa cathepsin H form in HOS cells, where only the intermediate 30 kDa form was observed. No co-localization of BMP-4 and cathepsin H was observed in human cell lines and the multistep processing of BMP-4 was not altered in the presence of specific cathepsin H inhibitor. Isolated cathepsin H does not cleave mature recombinant BMP-4, neither with its amino- nor its endopeptidase activity. CONCLUSIONS: Our results exclude direct proteolytic processing of BMP-4 by cathepsin H, however, they provide support for its involvement in the regulation of BMP-4 expression. PMID- 22933964 TI - Sinonasal inverted papilloma associated with squamous cell carcinoma. AB - BACKGROUND: The aims of the study were to review single-institution experiences with sinonasal inverted papilloma associated with squamous cell carcinoma (IP/SCC), to analyze the presence of human papillomavirus (HPV) and to evaluate the role of radiotherapy. PATIENTS AND METHODS: Five patients with IP/SCC were identified in the prospective institutional databases (1995-2005) and HPV status was determined in all five tumors. RESULTS: Four out of five patients had T3-4 tumors; no nodal involvement was seen in any of them. Four patients had curative surgery, supplemented in three of them with radiotherapy. Debulking surgery was performed in the patient with a non-resectable tumor followed by radical radiotherapy. Tumor was controlled locally in three patients at 8, 46 and 58 months post-surgery. Local failure occurred in two patients: after endoscopic resection of a T1 tumor (the recurrent tumor was successfully salvaged with additional surgery) and in a patient with an inoperable tumor. No regional or distant metastases occurred. HPV status was determined in all five tumors and three of them were found positive for HPV type 11. CONCLUSIONS: In operable sinonasal IP/SCC, upfront surgery and postoperative radiotherapy to the tumor bed with dose levels comparable to those used for invasive SCC are recommended. For non-resectable disease, radical radiotherapy to a dose of 66-70 Gy could be of benefit. PMID- 22933965 TI - Comparison of survival of patients receiving laparoscopic and open radical resection for stage II colon cancer. AB - BACKGROUND: The aim of the study was to compare the survival of patients receiving laparoscopic vs. open radical resection for stage II colon cancer. PATIENTS AND METHODS: Two hundred and twenty patients with stage II colon cancer were enrolled from Beijing Chaoyang Hospital of Capital Medical University from January 2000 to December 2009, including 61 patients in the laparoscopic radical resection group and 159 patients in the open radical resection group. The survival data in both groups were compared using the log rank test based on Kaplan-Meier survival curves. RESULTS: There was no statistically significant difference in the 3-year survival (88.5% vs. 80.5%; X(2)=1.98, P=0.159) and the 5 year survival (81.9% vs. 69.2%; X(2)=1.98, P=0.159) between both groups. However, statistically significant difference was found in median overall survival (mOS), which was 102.6 (95% CI: 76.8-122.7) months in the laparoscopic group and 90.0 (95% CI: 70.4-109.6) months in the open radical resection group (X(2)=4.183, P=0.041). mOS was 96 (95% CI: 68.6-111.4) months and 92.6 (95% CI: 56.8-107.2) months in those with and without postoperative chemotherapy, respectively (X(2)=6.389, P=0.011). For patients older than 75 years the mOS was 90.0 (95% CI: 25.3-105.0) months and 83.4 (95% CI: 13.1-96.9) months in the laparoscopic and open group, respectively. The difference between the both groups was statistically significant (X(2)=6.191, P=0.013). CONCLUSIONS: The mOS of patients receiving laparoscopic radical resection was better than open radical resection for stage II colon cancer, especially for patients over 75 years old. PMID- 22933966 TI - Expression of NF-kappaB p65 phosphorylated at serine-536 in rectal cancer with or without preoperative radiotherapy. AB - BACKGROUND: In the present study, we investigated NF-kappaB p65 phosphorylated at Serine-536 (phosphor-Ser536-p65) in rectal cancer and its relationship to preoperative radiotherapy (RT), clinicopathological variables and biological factors. PATIENTS AND METHODS: Expression of phosphor-Ser536-p65 was examined by using immunohistochemistry in 141 primary rectal cancers, 149 normal mucosa specimens and 48 metastases in the lymph nodes, from rectal cancer patients who participated in a Swedish clinical trial of preoperative RT. RESULTS: The expression of phosphor-Ser536-p65 in the cytoplasm increased from normal mucosa to primary tumour (p<0.0001, for both the group that did and the group that did not received RT). The expression did not further increase from primary tumour to metastasis in either group (p>0.05). Expression of phosphor-Ser536-p65 was positively related to, or tended to be related to, the expression of tumour endothelium marker 1 (TEM1, p=0.02), FXYD-3 (p=0.001), phosphatase of regenerating liver (PRL, p=0.02), p73 (p=0.048) and meningioma associated protein (MAC30, p=0.05) in the group that received RT but there were no such relationships in the group that did not received RT (p>0.05). The expression of phosphor-Ser536-p65 was not related to clinicopathological factors including survival (p>0.05). CONCLUSIONS: The increased expression of phosphor-Ser536-p65 may be involved in rectal cancer development. After RT, phosphor-Ser536-p65 seems to be positively related to the biological factors, which associated with more malignant features of tumours. However, phosphor-Ser536-p65 was not directly related to the response of RT based on recurrence and survival. PMID- 22933967 TI - Efficacy of first-line systemic treatment in correlation with BRAF V600E and different KRAS mutations in metastatic colorectal cancer - a single institution retrospective analysis. AB - BACKGROUND: KRAS mutation status in codons 12 and 13 is recognized as a predictive factor for resistance to anti-EGFR monoclonal antibodies. Despite having a wild type KRAS (wt-KRAS), not all patients with wt-KRAS respond to anti EGFR antibody treatment. Additional mechanisms of resistance may activate mutations of the other main EGFR effectors pathway. Consequently, other molecular markers in colorectal cancer are needed to be evaluated to predict the response to therapy. PATIENTS AND METHODS: In this retrospective study, objective responses (OR), time to progression (TTP), overall survival (OS) were analyzed in 176 metastatic colorectal cancer (mCRC) patients treated with first-line chemotherapy in combination with monoclonal antibodies in respect of KRAS status in codons 12 and 13 and BRAF mutational status. RESULTS: The KRAS mutations were found in 63 patients (35.8 %), the KRAS mutation in codon 12 in 53 patients (30.1%) and the KRAS mutation in codon 13 in 10 patients (5.7%). The BRAF V600E mutation was detected in 13 of 176 patients (7.4%). In the subgroup of mCRC patients having wt-KRAS and wild type BRAF (wt-BRAF), the objective response rates were higher (OR 54.0% ,CR 14.7%, PR 39.3%) than in the patients with wt KRAS and mt-BRAF (OR 38.5%,CR 15.4%, PR 23.1%), the difference was not statistically significant (p= 0.378). Median OS in patients with wt-KRAS wt-BRAF, and in patients with wt-KRAS mt-BRAF, was 107.4 months and 45 months, respectively. The difference was statistically significant (p= 0.042). TTP in patients with wt-KRAS wt-BRAF, and in patients with wt-KRAS mt-BRAF, was 16 months and 12 months, respectively. The difference was not statistically significant (p= 0.558). CONCLUSIONS: Patients with BRAF V600E mutation have statistically significantly worse prognosis than the patients with wt-BRAF and progress earlier during treatment. The definitive role of the BRAF V600E mutation as a prognostic and predictive factor for the response to anti-EGFR monoclonal antibodies needs to be analyzed in large prospective clinical studies. PMID- 22933968 TI - Hepatocellular carcinoma with subcutaneous metastasis of the scalp. AB - BACKGROUND: The majority of subcutaneous metastases from hepatocellular carcinoma (HCC) originate from needle tracks or surgical wound contamination. Non iatrogenic subcutaneous metastasis from hepatocellular carcinoma was rarely reported. CASE REPORT: A 70-year-old man presented with a mass in his left occipital region of the scalp. The surgical complete resection was performed. The histopathology report of the scalp mass showed a characteristic metastatic HCC. Computed tomography (CT) of the abdomen showed no primary or metastatic lesion in the abdomen; that's why the adjuvant treatment was not given after the surgery. Five months later, magnetic resonance imaging (MRI) of the brain revealed a 6 * 5.5 cm mass at the left posterior parietal region of the scalp. Second surgery was performed and histopathology of the specimen excised was again metastatic HCC. The external beam radiation therapy (XRT) was administered after the surgery. A follow-up MRI of the brain showed no recurrent disease after 9 months from XRT. CONCLUSIONS: HCCs should be considered in the differential diagnosis of carcinomas metastatic to the skin, even in the absence of liver symptoms. PMID- 22933969 TI - Genotyping of BRCA1, BRCA2, p53, CDKN2A, MLH1 and MSH2 genes in a male patient with secondary breast cancer. AB - BACKGROUND: Some tumour suppressor genes (BRCA2) and mismatch repair genes (MSH2, MLH1) are correlated with an increased risk for male breast cancer. CASE REPORT: Our patient developed secondary breast cancer after the treatment for Hodgkin's disease in childhood. DNA was isolated from the patients' blood and screened for mutations, polymorphisms and variants in BRCA1, BRCA2, p53, CDKN2A, MLH1 and MSH2 genes. We found no mutations but common polymorphisms, and three variants in mismatch repair genes. CONCLUSIONS: Nucleotide variants c.2006-6T>C and p.G322D in MSH2 might be correlated with male breast cancer. PMID- 22933970 TI - Periampullary localized pancreatic intraepithelial neoplasia-3 (PanIN-3): evaluation with contrast-enhanced MR cholangiography (MRCP). AB - BACKGROUND: The early determination of premalignant lesions of pancreas can prevent unnecessary excessive surgical procedures and can reduce morbidity and mortality. Pancreatic intraepithelial neoplasia-3 (PanIN-3) is a preinvasive form of adenocarcinoma (carcinoma in situ). PanINs have not taken place in the literature of radiology yet, it should be considered in differential diagnosis of pancreatic cystic lesions. CASE REPORT: A patient with preliminary diagnosis of chronic cholecystitis who had choledocolithiasis and periampullary pancreatic cyst detected by noncontrast-enhanced (NCE) and contrast-enhanced (CE) magnetic resonance cholangiography (MRCP) is presented. Pathological examination results of gallbladder and pancreatic cyst were reported as gallbladder adenocarcinoma and PanIN-3, respectively. CONCLUSIONS: Pancreatic cystic lesions with thin septa which enhances slightly with the administration of contrast material may represent PanIN-3. In patients with cystic pancreatic lesion localized at periampullary region, using CE-MRCP together with NCE-MRCP could be useful in the evaluation of pancreatic cystic masses as well as other abdominal pathologies. PMID- 22933971 TI - Brain meningioma invading and destructing the skull bone: replacement of the missing bone in vivo. AB - BACKGROUND: Meningiomas are frequently encountered tumours. In those invading locally into the adjacent tissue, reconstructions may pose a problem. CASE REPORT: We report a case of a benign convexity brain meningioma with invasion into the skull bone and subcutaneous tissue. The tumour was removed completely, together with the infiltrated tissue and the defects were successfully closed with in vivo bone reconstruction. CONCLUSIONS: The reconstruction of the skull bone is sometimes needed after the benign meningioma excision. Artificial bone may be a suitable material, allowing fast intraoperative reconstruction with excellent brain protection and cosmetic effect during the one-stage procedure. PMID- 22933972 TI - Dosimetric verification of compensated beams using radiographic film. AB - INTRODUCTION: External photon beam modulation using compensators in order to achieve a desired dose distribution when brachytherapy treatment is followed by external beam radiation is a well-established technique. A compensator modulates the central part of the beam, and the dose beneath the thickest part of the compensator is delivered mostly by scattered, low energy photons. A two dimensional detector with a good spatial resolution is needed for the verification of those beams. In this work, the influence of different types of detectors on the measured modulated dose distributions was examined. MATERIALS AND METHODS: Dosimetric verification was performed using X-Omat V, Eastman Kodak radiographic films at different depths in a solid water phantom. The film measurements were compared with those made by ionization chambers. Photon beams were also modelled using EGSnrc Monte Carlo algorithm to explain the measured results. RESULTS: Monte Carlo calculated over-response of the film under the thickest part of the compensator was over 15%, which was confirmed by measurements. The magnitude of over-response could be associated with changes in the spectra of photon energy in the beam. CONCLUSIONS: The radiographic film can be used for the dosimetry of compensated high energy photon beams, with limitations in volumes where photon spectra are hardly degraded. PMID- 22933973 TI - Human tooth pulp anatomy visualization by 3D magnetic resonance microscopy. AB - BACKGROUND: Precise assessment of dental pulp anatomy is of an extreme importance for a successful endodontic treatment. As standard radiographs of teeth provide very limited information on dental pulp anatomy, more capable methods are highly appreciated. One of these is 3D magnetic resonance (MR) microscopy of which diagnostic capabilities in terms of a better dental pulp anatomy assessment were evaluated in the study. MATERIALS AND METHODS: Twenty extracted human teeth were scanned on a 2.35 T MRI system for MR microscopy using the 3D spin-echo method that enabled image acquisition with isotropic resolution of 100 MUm. The 3D images were then post processed by ImageJ program (NIH) to obtain advanced volume rendered views of dental pulps. RESULTS: MR microscopy at 2.35 T provided accurate data on dental pulp anatomy in vitro. The data were presented as a sequence of thin 2D slices through the pulp in various orientations or as volume rendered 3D images reconstructed form arbitrary view-points. Sequential 2D images enabled only an approximate assessment of the pulp, while volume rendered 3D images were more precise in visualization of pulp anatomy and clearly showed pulp diverticles, number of pulp canals and root canal anastomosis. CONCLUSIONS: This in vitro study demonstrated that MR microscopy could provide very accurate 3D visualization of dental pulp anatomy. A possible future application of the method in vivo may be of a great importance for the endodontic treatment. PMID- 22933974 TI - Intra- and inter-observer variability in measurement of target lesions: implication on response evaluation according to RECIST 1.1. AB - BACKGROUND: The assessment of cancer treatment in oncological clinical trials is usually based on serial measurements of tumours' size according to the Response Evaluation Criteria in Solid Tumours (RECIST) guidelines. The aim of our study was to evaluate the variability of measurements of target lesions by readers as well as the impact on response evaluation, workflow and reporting. PATIENTS AND METHODS: Twenty oncologic patients were included to the study with CT examinations from thorax to pelvis performed at a 64 slices CT scanner. Four readers defined and measured the size of target lesions independently at baseline and follow-up with PACS (Picture Archiving and Communication System) and LMS (Lesion Management Solutions, Median technologies, Valbonne Sophia Antipolis, France), according to the RECIST 1.1 criteria. Variability in measurements using PACS or LMS software was established with the Bland and Altman approach. The inter- and intra-observer variabilities were calculated for identical lesions and the overall response per case was determined. In addition, time required for evaluation and reporting in each case was recorded. RESULTS: For single lesions, the median intra-observer variability ranged from 4.9-9.6% (mean 5.9%) and the median inter-observer variability from 4.3-11.4% (mean 7.1%), respecting different evaluation time points, image systems and observers. Nevertheless, the variability in change of Delta sum longest diameter (LD), mandatory for classification of the overall response, was 24%. The overall response evaluation assessed by a single respectively different observer was discrepant in 6.3% respectively 12% of the cases compared with the mean results of multiple observers. The mean case evaluation time was 286s vs. 228s at baseline and 267s vs. 196s at follow-up for PACS and LMS, respectively. CONCLUSIONS: Uni dimensional measurements of target lesions show low intra- and inter-observer variabilities, but the high variability in change of Delta sum LD shows the potential for misclassification of the overall response according to the RECIST 1.1 guidelines. Nevertheless, the reproducibility of RECIST reporting can be improved for the case assessment by a single observer and by mean results of multiple observers. Case-based evaluation time was shortened up to 27% using custom software. PMID- 22933975 TI - Percutaneous transthoracic CT guided biopsies of lung lesions; fine needle aspiration biopsy versus core biopsy. AB - BACKGROUND: The purpose of this retrospective study was to compare the results and complication rate in CT guided percutaneous trans-thoracic fine needle aspiration biopsies (FNAB) and core biopsies of lung lesions, and to determine the applicability of these needles. PATIENTS AND METHODS: In 242 patients (166 males; 76 females) with mean age of 58.9 years (13-84 years) CT guided biopsies of lung lesions were performed on dual slice CT equipment. The average diameter of lung lesion was 2.9 cm (1.2-6.3 cm). For FNAB's 20 - 22 G Chiba needles and for core biopsies 14 G biopsy needles were used. The samples were sent for the histological analysis. The cytological or histological results and the eventual complications were compared. RESULTS: FNAB's cytological samples were adequate for definitive diagnosis in 117 patients (79.60 %) and inadequate in 30 patients (20.40 %). Core biopsies samples were adequate in 92 (96.85 %) patients and non- representative (necrotic tissue) in 3 (3.15 %). Pneumothorax as the most frequent complication was detected in 14 (9.7 %) of the patients in the group of FNAB's and in 30 (31.5 %) of the patients with the core biopsy group. CONCLUSIONS: The results showed that percutaneous transthoracic CT guided biopsies of lung lesions were an effective and safe procedure in the diagnosis of lung lesions. Core biopsy gives a higher percentage of representative samples than FNAB, and is a preferred method regardless of the higher rate of complications. PMID- 22933976 TI - Recurrent invasive lobular carcinoma presenting as a ruptured breast implant. AB - BACKGROUND: For years, the treatment for invasive lobular carcinoma (ILC) has been mastectomy secondary to the lack of studies investigating the efficacy of breast conservation therapy on patients afflicted with ILC and due to the lack of long-term follow up investigating locoregional recurrence in this patient population. In this article we report the clinical course of a patient diagnosed with ILC. CASE REPORT: We describe the case of a 50-year-old woman with stage IIB (T2N1M0) ER/PR positive right breast ILC who underwent a right modified radical mastectomy, postoperative chemotherapy, a prophylactic left simple mastectomy with bilateral breast reconstruction and tamoxifen. Approximately 12 years later, she presented with a deflated breast implant and recurrent breast cancer with metastatic spread. She received palliative radiotherapy then palliative chemotherapy. Unfortunately, she succumbed to the cancer less than a year after being diagnosed with metastatic disease. CONCLUSIONS: This may be the first case report of a ruptured breast implant presenting at the same time as the diagnosis of recurrent breast cancer. PMID- 22933977 TI - The false-positive radioiodine I-131 uptake in the foreign body granuloma located in gluteal adipose tissue. AB - BACKGROUND: The purpose of using a whole-body scanning after the radioactive I 131 treatment is to screen functional residual or metastatic thyroid tissues. In whole-body scanning of some patients, false positive radioiodine I-131 uptakes may be seen in physiological uptake regions or atypical localizations. CASE REPORT: A 54 year-old woman underwent total thyroidectomy for papillary thyroid carcinoma. A positive appearance seen in the upper postero-lateral part of the right gluteal region was determined by a post-therapy I-131 whole body scan. The colour Doppler ultrasonography, magnetic resonance imaging features and histopathological characteristics of the excised lesion were presented. The lesion was demonstrated to be a foreign body granuloma. CONCLUSIONS: Unexpected positive findings in the post-therapy I-131 whole body scan should be confirmed with other imaging modalities in order to avoid unnecessary treatments. In uncertain situations, the diagnosis should be established histopathologically. PMID- 22933978 TI - Assessment of the tumourigenic and metastatic properties of SK-MEL28 melanoma cells surviving electrochemotherapy with bleomycin. AB - BACKGROUND: Electrochemotherapy is a local treatment combining chemotherapy and electroporation and is highly effective treatment approach for subcutaneous tumours of various histologies. Contrary to surgery and radiation, the effect of electrochemotherapy on metastatic potential of tumour cells has not been extensively studied. The aim of the study was to evaluate the effect of electrochemotherapy with bleomycin on the metastatic potential of human melanoma cells in vitro. MATERIALS AND METHODS: Viable cells 48 hours after electrochemotherapy were tested for their ability to migrate and invade through Matrigel coated porous membrane. In addition, microarray analysis and quantitative Real-Time PCR were used to detect changes in gene expression after electrochemotherapy. RESULTS: Cell migration and invasion were not changed in melanoma cells surviving electrochemotherapy. Interestingly, only a low number of tumourigenesis related genes was differentially expressed after electrochemotherapy. CONCLUSIONS: Our data suggest that metastatic potential of human melanoma cells is not affected by electrochemotherapy with bleomycin, confirming safe role of electrochemotherapy in the clinics. PMID- 22933979 TI - Genetic polymorphisms in homologous recombination repair genes in healthy Slovenian population and their influence on DNA damage. AB - BACKGROUND: Homologous recombination (HR) repair is an important mechanism involved in repairing double-strand breaks in DNA and for maintaining genomic stability. Polymorphisms in genes coding for enzymes involved in this pathway may influence the capacity for DNA repair. The aim of this study was to select tag single nucleotide polymorphisms (SNPs) in specific genes involved in HR repair, to determine their allele frequencies in a healthy Slovenian population and their influence on DNA damage detected with comet assay. MATERIALS AND METHODS: In total 373 individuals were genotyped for nine tag SNPs in three genes: XRCC3 722C>T, XRCC3 -316A>G, RAD51 -98G>C, RAD51 -61G>T, RAD51 1522T>G, NBS1 553G>C, NBS1 1197A>G, NBS1 37117C>T and NBS1 3474A>C using competitive allele-specific amplification (KASPar assay). Comet assay was performed in a subgroup of 26 individuals to determine the influence of selected SNPs on DNA damage. RESULTS: We observed that age significantly affected genotype frequencies distribution of XRCC3 -316A>G (P = 0.039) in healthy male blood donors. XRCC3 722C>T (P = 0.005), RAD51 -61G>T (P = 0.023) and NBS1 553G>C (P = 0.008) had a statistically significant influence on DNA damage. CONCLUSIONS: XRCC3 722C>T, RAD51 -61G>T and NBS1 553G>C polymorphisms significantly affect the repair of damaged DNA and may be of clinical importance as they are common in Slovenian population. PMID- 22933980 TI - Outcome of small cell lung cancer (SCLC) patients with brain metastases in a routine clinical setting. AB - BACKGROUND: Small cell lung cancer (SCLC) represents approximately 13 to 18% of all lung cancers. It is the most aggressive among lung cancers, mostly presented at an advanced stage, with median survival rates of 10 to12 months in patients treated with standard chemotherapy and radiotherapy. In approximately 15-20% of patients brain metastases are present already at the time of primary diagnosis; however, it is unclear how much it influences the outcome of disease according the other metastatic localisation. The objective of this analysis was to evaluate the median survival of SCLC patients treated by specific therapy (chemotherapy and/or radiotherapy) with regard to the presence or absence of brain metastases at the time of diagnosis. PATIENTS AND METHODS: All SCLC patients have been treated in a routine clinical practice and followed up at the University Clinic Golnik in Slovenia. In the retrospective study the medical files from 2002 to 2007 were review. All patients with cytological or histological confirmed disease and eligible for specific oncological treatment were included in the study. They have been treated according to the guidelines valid at the time. Chemotherapy and regular followed-up were carried out at the University Clinic Golnik and radiotherapy at the Institute of Oncology Ljubljana. RESULTS: We found 251 patients eligible for the study. The median age of them was 65 years, majority were male (67%), smokers or ex-smokers (98%), with performance status 0 to 1 (83%). At the time of diagnosis no metastases were found in 64 patients (25.5%) and metastases outside the brain were presented in 153 (61.0%). Brain metastases, confirmed by a CT scan, were present in 34 patients (13.5%), most of them had also metastases at other localisations. All patients received chemotherapy and all patients with confirmed brain metastases received whole brain irradiation (WBRT). The radiotherapy with radical dose at primary tumour was delivered to 27 patients with limited disease and they got 4-6 cycles of chemotherapy. Median overall survival (OS) of 34 patients with brain metastases was 9 months (95% CI 6 12) while OS of 153 patients with metastases in other locations was 11 months (95% CI 10-12); the difference did not reach the level of significance (p = 0.62). As expected, the OS of patients without metastases at the time of primary diagnosis turned out to be significantly better compared to the survival of patients with either brain or other location metastases at the primary diagnosis (15 months vs 9 and 11 months, respectively, p < 0.001). CONCLUSIONS: In our investigated population, the prognosis of patients with extensive SCLS with brain metastases at the primary diagnosis treated with chemotherapy and WBRT was not significantly worse compared to the prognosis of patients with extensive SCLC and metastases outside the brain. In extensive SCLC brain metastases were not a negative prognostic factor per se if the patients were able to be treated appropriately. However, the survival rates of extensive SCLC with or without brain metastases remained poor and novel treatment approaches are needed. The major strength of this study is that it has been done on a population of patients treated in a routine clinical setting. PMID- 22933981 TI - Lower tumour burden and better overall survival in melanoma patients with regional lymph node metastases and negative preoperative ultrasound. AB - BACKGROUND: The purpose of the study was to evaluate the ability of ultrasound (US) and fine needle aspiration biopsy (FNAB) in reducing the number of melanoma patients requiring a sentinel node biopsy (SNB); to compare the amount of metastatic disease in regional lymph nodes in SNB candidates with clinically uninvolved lymph nodes and of those with US uninvolved lymph nodes; and to compare the overall survival (OS) of both groups. METHODS: Between 2000 and 2007, a SNB was successfully performed in 707 patients with melanoma. The preoperative US of the regional lymph node basins was performed in 405 SNB candidates. In 14 of these patients, the US-guided FNAB was positive and they proceeded directly to lymph node dissection. In 391 patients, the preoperative US was either negative (343 patients) or suspicious (48 patients) (US group). In the remaining 316 patients the preoperative US was not performed (non-US group). RESULTS: The proportion of macrometastatic sentinel lymph nodes (SN), number of metastatic lymph nodes per patient and proportion of nonsentinel lymph node metastases were found to be lower in the US group compared to the non-US group. The smaller tumour burden of the US group was reflected in a significantly better OS of patients with SN metastases. CONCLUSIONS: The preoperative US of regional lymph nodes spares some patients with melanoma from undergoing a SNB. Patients with regional metastases and a negative preoperative US have a significantly lower tumour burden in comparison to those with clinically negative lymph nodes, which is also reflected in a better OS. PMID- 22933982 TI - A comparison of virtual touch tissue quantification and digital rectal examination for discrimination between prostate cancer and benign prostatic hyperplasia. AB - BACKGROUND: Virtual touch tissue quantification (VTTQ) is a new, promising technique for detecting the stiffness of tissues. The aim of this study is to compare the performance of VTTQ and digital rectal examination (DRE) in discrimination between prostate cancer and benign prostatic hyperplasia (BPH). PATIENTS AND METHODS: VTTQ was performed in 209 prostate nodular lesions of 107 patients with BPH and suspected prostate cancer before the prostate histopathologic examination. The shear wave velocity (SWV) at each nodular lesion was quantified by implementing an acoustic radiation force impulse (ARFI). The performance of VTTQ and DRE in discrimination between prostate cancer and BPH was compared. The diagnostic value of VTTQ and DRE for prostate cancer was evaluated in terms of the sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and accuracy. RESULTS: Prostate cancer was detected in 57 prostate nodular lesions by histopathologic examination. The SWV values (m/s) were significantly greater in prostate cancer and BPH than in normal prostate (2.37 +/- 0.94, 1.98 +/- 0.82 vs. 1.34 +/- 0.47). The area under the receiver operating characteristic curve (AUC) for VTTQ (SWV>2.5m/s) to differentiate prostate nodules as benign hyperplasia or malignancy was 0.86, while it was 0.67 for DRE. The diagnostic sensitivity, specificity, PPV, NPV and accuracy were 71.93 %, 87.5 %, 68.33 %, 89.26 %, 83.25 %, respectively for VTTQ (SWV>2.5m/s), whereas they were 33.33 %, 81.57 %, 40.43 %, 76.54 %, 68.42 % respectively for DRE. CONCLUSIONS: VTTQ can effectively detect the stiffness of prostate nodular lesions, which has a significantly higher performance than DRE in discrimination between prostate cancer and BPH. PMID- 22933983 TI - Efficacy of high-energy collimator for sentinel node lymphoscintigraphy of early breast cancer patients. AB - INTRODUCTION: Lymphoscintigraphy is an important part of sentinel node mapping in breast cancer patients. Sometimes star shaped artefacts due to septal penetration can be problematic during imaging. In the current study, we evaluated the possibility of high energy (HE) collimators use for lymphoscintigraphy. PATIENTS AND METHODS: Twenty patients with early breast carcinoma were included. Thirty minutes after radiotracer injection (99mTc-antimony sulphide colloid), anterior and lateral images were acquired using a dual head gamma camera equipped with a parallel hole low energy high resolution (LEHR) collimator on one head and HE collimator on another head. All images were reviewed by two nuclear medicine specialists regarding detectability and number of axillary sentinel nodes and presence of star artefact. RESULTS: All images taken by LEHR collimators showed star artefact of the injection site. No image taken by HE collimator showed this effect. In two patients the sentinel node was visible only by HE collimator. Tumour location in both of these patients was in the upper lateral quadrant and both had history of excisional biopsy. In two patients additional sentinel node was visible adjacent to the first one only on the LEHR images. CONCLUSIONS: HE collimators can be used for sentinel lymph node mapping and lymphoscintigraphy of the breast cancer patients. This collimator can almost eliminate star-shaped artefacts due to septal penetration which can be advantageous in some cases. However, to separate two adjacent sentinel nodes from each other LEHR collimators perform better. PMID- 22933984 TI - The development of nuclear medicine in Slovenia and Ljubljana; half a century of nuclear medicine in Slovenia. AB - BACKGROUND: Nuclear medicine began to be developed in the USA after 1938 when radionuclides were introduced into medicine and in Europe after radionuclides began to be produced at the Harwell reactor (England, 1947). Slovenia began its first investigations in the 1950s. This article describes the development of nuclear medicine in Slovenia and Ljubljana. The first nuclear medicine interventions were performed in Slovenia at the Internal Clinic in Ljubljana in the period 1954-1959. In 1954, Dr Joze Satler started using radioactive iodine for thyroid investigations. In the same year, Dr Bojan Varl, who is considered the pioneer of nuclear medicine in Slovenia, began systematically introducing nuclear medicine. The first radioisotope laboratories were established in January 1960 at the Institute of Oncology and at the Internal Clinic. Under the direction of Dr. Varl, the laboratory at the Internal Clinic developed gradually and in 1973 became the Clinic for Nuclear Medicine with departments for in vivo and in vitro diagnostics and for the treatment of inpatients and outpatients at the thyroid department. The Clinic for Nuclear Medicine became a teaching unit of the Medical Faculty and developed its own post-graduate programme - the first student enrolled in 1972. In the 1960s, radioisotope laboratories opened in the general hospitals of Slovenj Gradec and Celje, and in the 1970s also in Maribor, Izola and Sempeter pri Novi Gorici. CONCLUSIONS: Nowadays, nuclear medicine units are modernly equipped and the staff is trained in morphological, functional and laboratory diagnostics in clinical medicine. They also work on the treatment of cancer, increased thyroid function and other diseases. PMID- 22933985 TI - Acute liver failure in an antimitochondrial antibody-positive 63-year-old man. AB - Antimitochondrial antibody (AMA) is one of the representative features of primary biliary cirrhosis (PBC). PBC is a female-dominant disease usually presenting intrahepatic bile duct destruction, cholestasis and fibrosis with or without chronic nonsuppurative destructive cholangitis. We presented the case of a 63 year-old man with acute liver failure who had AMA, pronounced alanine aminotransferase elevation and high bilirubinemia. We administered corticosteroids and rescued this patient without liver transplantation. It is well known that some patients within the spectrum of autoimmune liver disease present with characteristics of both PBC and autoimmune hepatitis. Although corticosteroids may be associated with a significant worsening of adverse events in patients with PBC, if acute liver failure in AMA-positive cases is progressive, the administration of corticosteroids has to be considered, as well as the preparation of urgent liver transplantation. PMID- 22933986 TI - Comparative Study on the Difference in Functional Outcomes at Discharge between Proximal and Total Gastrectomy. AB - Several studies have regarded proximal gastrectomy (PG) as optimal compared to total gastrectomy (TG) for upper stomach cancer. In addition to the traditional outcomes of complication and mortality, change in functional status should be considered as another relevant outcome in aging generations. However, there has been no community-based appraisal of functional outcomes between PG and TG. Using an administrative database, we compared functional outcomes between PG and TG. Among 12,508 patients who survived for >=15 years and underwent open gastrectomy between 2008 and 2010, we examined patient characteristics, comorbidities, functional status estimated by the Barthel index (BI) at admission and discharge, complications, ICU care, ventilation administration, blood transfusion, operating room time, resumption of oral intake, length of stay and total charges. With reference to distal gastrectomy (DG), we performed multivariate analyses to assess the impacts of PG and TG on complications and BI deterioration. A total of 434 PGs and 4,941 TGs were observed in 148 and 295 hospitals, respectively. Patient characteristics, care process, resumption of oral intake, operating room time, length of stay and total charges were also significantly different among the three gastrectomy types. PG, TG and DG were not associated with complications or functional deterioration. Patient characteristics, preoperative blood transfusion and longer operating room time were significantly associated with more complications and BI deterioration. Since patient case mix and longer operating room time were associated with poor outcomes, physicians should recognize the role of PG and might optimally challenge and complete gastrectomies within the appropriate indications. PMID- 22933987 TI - FDG-PET Findings of Intraductal Oncocytic Papillary Neoplasms of the Pancreas: Two Case Reports. AB - Intraductal oncocytic papillary neoplasm (IOPN) of the pancreas is a rare pancreatic tumor. To date, there have been three case reports of IOPN which showed strong positivity on 18F-fluorodeoxyglucose positron emission tomography (FDG-PET), raising the possibility of distinguishing IOPNs from other intraductal papillary mucinous neoplasms (IPMNs) using FDG-PET. However, all three cases had large tumors, approximately 10 cm in diameter, and there are no case reports of FDG-PET findings of small IOPNs, i.e. tumors the average size of malignant IPMNs (3-5 cm). We report two cases with IOPN of average size with FDG-PET findings. Computed tomography (CT) showed a multilocular cystic lesion 4 cm in diameter with a mural nodule 1 cm in diameter (case 1) and a cystic lesion 5 cm in diameter with a papillary mural nodule 4 cm in diameter (case 2). FDG-PET showed abnormal uptake at the same location as the pancreatic tumor revealed by CT in both cases. The maximum standardized uptake values of the lesions were 3.4 and 4.2, respectively. Surgical resection was performed and the tumor was diagnosed as IOPN with carcinoma in situ (case 1) and IOPN with minimal invasion (case 2). FDG-PET may be useful for diagnosing malignancy in IOPN, as it is in IPMN. However, in our two cases, strong accumulation was not observed in the IOPNs, which were within the average size range of malignant IPMNs. PMID- 22933988 TI - Argon plasma coagulation for the treatment of hemorrhagic radiation colitis. AB - Radiation colitis is a common consequence of pelvic radiation. Its complications may include anemia due to chronic bleeding requiring transfusions. Many of these patients are managed with rectal medications which are often inadequate for control. Argon plasma coagulation (APC) has been well described for its efficacy in treating radiation proctitis. Here we present two cases in whom APC therapy was used to treat severe radiation colitis. We reviewed two cases originally seen at the regional cancer center (Cross Cancer Institute) in Edmonton, Alberta, Canada. Both patients received pelvic radiation for recurrent endometrial cancers and were referred for active bleeding secondary to radiation colitis that had required numerous transfusions. Radiation-induced telangiectasias were found from 10-50 cm in the sigmoid colon. Both patients had significant improvement of symptoms after one session of APC treatment set at 40-60 W and gas flow of 2.0 l/min. There were no complications from the procedures. Neither patient required blood transfusions after the treatment with improvement in their hemoglobin levels and were doing well at 3- and 6-month follow-up. APC can be used effectively to provide immediate and sustained resolution of symptoms in patients with radiation colitis. PMID- 22933989 TI - Naming ability changes in physiological and pathological aging. AB - Over the last two decades, age-related anatomical and functional brain changes have been characterized by evidence acquired primarily by means of non-invasive functional neuroimaging. These functional changes are believed to favor positive reorganization driven by adaptations to system changes as compensation for cognitive decline. These functional modifications have been linked to residual brain plasticity mechanisms, suggesting that all areas of the brain remain plastic during physiological and pathological aging. A technique that can be used to investigate changes in physiological and pathological aging is non-invasive brain stimulation (NIBS). The present paper reviews studies that have applied NIBS in younger and older adults and in patients with dementia to track changes in the cerebral areas involved in a language task (naming). The results of this research suggest that the left frontal and temporal areas are crucial during naming. Moreover, it is suggested that in older adults and patients with dementia, the right prefrontal cortex is also engaged during naming tasks, and naming performance correlates with age and/or the degree of the pathological process. Potential theories underlying the bilateral involvement of the prefrontal cortex are discussed, and the relationship between the bilateral engagement of the prefrontal cortex and the age or degree of pathology is explored. PMID- 22933990 TI - Key factors for the emergence of collective decision in invertebrates. AB - In many species of group living invertebrates, in particular arthropods, collective decisions can emerge from the combined actions of individuals and the direct or indirect interactions between individuals. These decisions allow groups of individuals to respond quickly and accurately to changes that occur in their environment. Examples of such decisions are found in a variety of invertebrate taxa and in many different contexts, e.g., exploring a new territory, foraging for food, finding a suitable location where to aggregate or to establish a nest, defending oneself against predators, etc. In this paper we review the collective decisions that have been documented in different invertebrate taxa where individuals are known to live temporarily or permanently in social or gregarious groups. We first present some simple examples of collective decisions involving the choice between two alternatives. We then define the fundamental rules required for these collective decisions to emerge throughout the invertebrate taxon, from simple organisms such as caterpillars, to animals endowed with highly developed perceptive and cognitive capacities such as ants and bees. The presentation of these rules gives us the opportunity to illustrate one of the pitfalls of the study of collective choice in animals by showing through computer simulations how a choice between two alternatives can be misinterpreted as the result of the action of self-organized mechanisms. In the second part, we discuss the peculiarities of collective decisions in invertebrates, their properties, and characteristics. We conclude by discussing the issue of individual complexity in collective decision-making process. PMID- 22933991 TI - Morphological and physiological characteristics of laminar cells in the central nucleus of the inferior colliculus. AB - The central nucleus of the inferior colliculus (IC) is organized into a series of fibro-dendritic laminae, orthogonal to the tonotopic progression. Many neurons have their dendrites confined to one lamina while others have dendrites that cross over a number of laminae. Here, we have used juxtacellular labeling in urethane anesthetized guinea pigs to visualize the cells with biocytin and have analyzed their response properties, in order to try and link their structure and function. Out of a sample of 38 filled cells, 15 had dendrites confined within the fibro-dendritic laminae and in 13 we were also able to reconstruct their local axonal tree. Based on dendritic morphology they were subdivided into flat or less flat; small, medium, or large; elongated or disk-shaped cells. Two of the elongated cells had many dendritic spines while the other cells had few or none. Twelve of the cells had their local axonal tree restricted to the same lamina as their dendrites while one cell had its dendrites in a separate lamina from the axon. The axonal plexus was more extensive (width 0.7-1.4 mm) within the lamina than the dendrites (width generally 0.07-0.53 mm). The intrinsic axons were largely confined to a single lamina within the central nucleus, but at least half the cells also had output axons with two heading for the commissure and five heading into the brachium. We were able to identify similarities in the physiological response profiles of small groups of our filled cells but none appeared to represent a homogeneous morphological cell type. The only common feature of our sample was one of exclusion in that the onset response, a response commonly recorded from IC cells, was never seen in laminar cells, but was in cells with a stellate morphology. Thus cells with laminar dendrites have a wide variety of physiological responses and morphological subtypes, but over 90% have an extensive local axonal tree within their local lamina. PMID- 22933992 TI - Recovery cycle times of inferior colliculus neurons in the awake bat measured with spike counts and latencies. AB - Neural responses in the mammalian auditory midbrain (inferior colliculus; IC) arise from complex interactions of synaptic excitation, inhibition, and intrinsic properties of the cell. Temporally selective duration-tuned neurons (DTNs) in the IC are hypothesized to arise through the convergence of excitatory and inhibitory synaptic inputs offset in time. Synaptic inhibition can be inferred from extracellular recordings by presenting pairs of pulses (paired tone stimulation) and comparing the evoked responses of the cell to each pulse. We obtained single unit recordings from the IC of the awake big brown bat (Eptesicus fuscus) and used paired tone stimulation to measure the recovery cycle times of DTNs and non temporally selective auditory neurons. By systematically varying the interpulse interval (IPI) of the paired tone stimulus, we determined the minimum IPI required for a neuron's spike count or its spike latency (first- or last-spike latency) in response to the second tone to recover to within >=50% of the cell's baseline count or to within 1 SD of it's baseline latency in response to the first tone. Recovery times of shortpass DTNs were significantly shorter than those of bandpass DTNs, and recovery times of bandpass DTNs were longer than allpass neurons not selective for stimulus duration. Recovery times measured with spike counts were positively correlated with those measured with spike latencies. Recovery times were also correlated with first-spike latency (FSL). These findings, combined with previous studies on duration tuning in the IC, suggest that persistent inhibition is a defining characteristic of DTNs. Herein, we discuss measuring recovery times of neurons with spike counts and latencies. We also highlight how persistent inhibition could determine neural recovery times and serve as a potential mechanism underlying the precedence effect in humans. Finally, we explore implications of recovery times for DTNs in the context of bat hearing and echolocation. PMID- 22933993 TI - Differential efferent projections of the anterior, posteroventral, and posterodorsal subdivisions of the medial amygdala in mice. AB - The medial amygdaloid nucleus (Me) is a key structure in the control of sociosexual behavior in mice. It receives direct projections from the main and accessory olfactory bulbs (AOB), as well as an important hormonal input. To better understand its behavioral role, in this work we investigate the structures receiving information from the Me, by analysing the efferent projections from its anterior (MeA), posterodorsal (MePD) and posteroventral (MePV) subdivisions, using anterograde neuronal tracing with biotinylated and tetrametylrhodamine conjugated dextranamines. The Me is strongly interconnected with the rest of the chemosensory amygdala, but shows only moderate projections to the central nucleus and light projections to the associative nuclei of the basolateral amygdaloid complex. In addition, the MeA originates a strong feedback projection to the deep mitral cell layer of the AOB, whereas the MePV projects to its granule cell layer. The Me (especially the MeA) has also moderate projections to different olfactory structures, including the piriform cortex (Pir). The densest outputs of the Me target the bed nucleus of the stria terminalis (BST) and the hypothalamus. The MeA and MePV project to key structures of the circuit involved in the defensive response against predators (medial posterointermediate BST, anterior hypothalamic area, dorsomedial aspect of the ventromedial hypothalamic nucleus), although less dense projections also innervate reproductive-related nuclei. In contrast, the MePD projects mainly to structures that control reproductive behaviors [medial posteromedial BST, medial preoptic nucleus, and ventrolateral aspect of the ventromedial hypothalamic nucleus], although less dense projections to defensive-related nuclei also exist. These results confirm and extend previous results in other rodents and suggest that the medial amygdala is anatomically and functionally compartmentalized. PMID- 22933994 TI - Hypocretin/orexin regulation of dopamine signaling: implications for reward and reinforcement mechanisms. AB - The hypocretins/orexins are comprised of two neuroexcitatory peptides that are synthesized exclusively within a circumscribed region of the lateral hypothalamus. These peptides project widely throughout the brain and interact with a variety of regions involved in the regulation of arousal-related processes including those associated with motivated behavior. The current review focuses on emerging evidence indicating that the hypocretins influence reward and reinforcement processing via actions on the mesolimbic dopamine system. We discuss contemporary perspectives of hypocretin regulation of mesolimbic dopamine signaling in both drug free and drug states, as well as hypocretin regulation of behavioral responses to drugs of abuse, particularly as it relates to cocaine. PMID- 22933995 TI - Understanding how the brain ensures its energy supply. PMID- 22933996 TI - Sequencing of cabazitaxel in metastatic castrate-resistant prostate cancer: a case report. AB - Prostate cancer is a common cancer in men; for metastatic disease, it has a 5 year survival rate of 30%. No FDA-approved therapy for castrate-resistant prostate cancer (CRPC) known to improve survival was available until 2004, when based on a significant survival benefit over mitoxantrone, docetaxel in combination with prednisone was approved. In combination with prednisone, cabazitaxel, which was approved in the United States in 2010, is indicated for patients with metastatic CRPC previously treated with a docetaxel-containing regimen. This case report describes the treatment of a man 58 years of age who was diagnosed with advanced prostate cancer in 2006. He was initially managed with radical prostatectomy followed by androgen deprivation therapy, but a rising prostate-specific antigen (PSA) level led to enrollment in a clinical trial of HE3235 for 6 months. Subsequently, with progression of disease, he was treated with docetaxel for 4 months and then palliative radiation therapy. Cabazitaxel was initiated in October 2010; his condition stabilized within weeks, and he experienced a progressive decline in his PSA level from a peak of 5,424 ng/ml. Continued treatment with cabazitaxel resulted in his being weaned off pain medications and resuming his normal activities. After 16 cycles of cabazitaxel, his PSA declined to 994 ng/ml as of January 2012. He tolerated the cabazitaxel well and occasionally received myeloid growth factors for treatment of neutropenia; otherwise, he experienced only mild diarrhea. This response to cabazitaxel is notable, particularly in light of prior failure of multiple therapies. PMID- 22933997 TI - Disseminated Intracranial Ewing's Sarcoma in an Adult: A Rare and Difficult Diagnosis. AB - The Ewing sarcoma family of tumors comprises a rare class of cancers of mesenchymal origin. Cases of Ewing's sarcoma in the central nervous system - specifically, intracranial Ewing's - are extremely rare. Almost all reported cases have occurred in children. However, this rare presentation can also occur in the adult population. It is important to distinguish these tumors from primitive neuroectodermal tumors at the time of diagnosis. Testing for EWSR1(22q12) gene rearrangement using fluorescence in situ hybridization is a useful tool for making the distinction between these 2 similar but distinct entities. We present here the case of a middle-aged male patient with intracranial Ewing's sarcoma, and discuss diagnostic challenges and potential new treatment approaches for this rare disease. PMID- 22933998 TI - Appendiceal goblet cell carcinoid tumour: a case of unexpected lung metastasis. AB - Goblet cell carcinoid tumours are often considered a subset of appendiceal neuroendocrine tumours which behave more aggressively. They usually metastasize through transcoelomic/peritoneal invasion and common sites include the ovaries, peritoneum, and liver. Metastases may have goblet cell carcinoid, signet ring cell carcinoma or classic carcinoid histology. We report the first case in the literature of a patient with a goblet cell carcinoid with lung metastasis, which was associated with unfavourable outcome. PMID- 22933999 TI - Systemic steroid-pulse therapy in a patient with idiopathic choroidal detachment: a case report. AB - AIM: To report on the effectiveness of systemic steroid-pulse therapy in treating idiopathic choroidal detachment. CASE PRESENTATION: Our patient developed idiopathic choroidal detachment after cataract surgery for pseudoexfoliation glaucoma and glaucoma filtration surgery. Systemic steroid-pulse therapy was performed, and the choroidal detachment resolved completely. CONCLUSION: We suggest systemic steroid-pulse therapy as a treatment option for idiopathic choroidal detachment with low intraocular pressure. PMID- 22934000 TI - Current State and Future Prospects of Direct-to-Consumer Pharmacogenetics. AB - Direct-to-consumer (DTC) DNA testing has grown from contentious beginnings into a global industry, by providing a wide range of personal genomic information directly to its clients. These companies, typified by the well-established 23andMe, generally carry out a gene-chip analysis of single-nucleotide polymorphisms (SNPs) using DNA extracted from a saliva sample. These genetic data are then assimilated and provided direct to the client, with varying degrees of interpretation. Although much debate has focused on the limitations and ethical aspects of providing genotypes for disease risk alleles, the provision of pharmacogenetic results by DTC companies is less studied. We set out to evaluate current DTC pharmacogenetics offerings, and then to consider how these services might best evolve and adapt in order to play a potentially useful future role in delivery of personalized medicine. PMID- 22934001 TI - From bottom-up approaches to levels of organization and extended critical transitions. AB - Biological thinking is structured by the notion of level of organization. We will show that this notion acquires a precise meaning in critical phenomena: they disrupt, by the appearance of infinite quantities, the mathematical (possibly equational) determination at a given level, when moving at an "higher" one. As a result, their analysis cannot be called genuinely bottom-up, even though it remains upward in a restricted sense. At the same time, criticality and related phenomena are very common in biology. Because of this, we claim that bottom-up approaches are not sufficient, in principle, to capture biological phenomena. In the second part of this paper, following (Bailly, 1991b), we discuss a strong criterium of level transition. The core idea of the criterium is to start from the breaking of the symmetries and determination at a "first" level in order to "move" at the others. If biological phenomena have multiple, sustained levels of organization in this sense, then they should be interpreted as extended critical transitions. PMID- 22934003 TI - Effects of n-3 Polyunsaturated Fatty Acids on Cardiac Ion Channels. AB - Dietary n-3 polyunsaturated fatty acids (PUFAs) have been reported to exhibit antiarrhythmic properties, and these effects have been attributed to their capability to modulate ion channels. In the present review, we will focus on the effects of PUFAs on a cardiac sodium channel (Na(v)1.5) and two potassium channels involved in cardiac atrial and ventricular repolarization (K(v)) (K(v)1.5 and K(v)11.1). n-3 PUFAs of marine (docosahexaenoic, DHA and eicosapentaenoic acid, EPA) and plant origin (alpha-linolenic acid, ALA) block K(v)1.5 and K(v)11.1 channels at physiological concentrations. Moreover, DHA and EPA decrease the expression levels of K(v)1.5, whereas ALA does not. DHA and EPA also decrease the magnitude of the currents elicited by the activation of Na(v)1.5 and calcium channels. These effects on sodium and calcium channels should theoretically shorten the cardiac action potential duration (APD), whereas the blocking actions of n-3 PUFAs on K(v) channels would be expected to produce a lengthening of cardiac action potential. Indeed, the effects of n-3 PUFAs on the cardiac APD and, therefore, on cardiac arrhythmias vary depending on the method of application, the animal model, and the underlying cardiac pathology. PMID- 22934002 TI - In Search for Factors that Drive Hantavirus Epidemics. AB - In Europe, hantaviruses (Bunyaviridae) are small mammal-associated zoonotic and emerging pathogens that can cause hemorrhagic fever with renal syndrome (HFRS). Puumala virus, the main etiological agent carried by the bank vole Myodes glareolus is responsible for a mild form of HFRS while Dobrava virus induces less frequent but more severe cases of HFRS. Since 2000 in Europe, more than 3000 cases of HFRS have been recorded, in average, each year, which is nearly double compared to the previous decade. In addition to this upside long-term trend, significant oscillations occur. Epidemic years appear, usually every 2-4 years, with an increased incidence, generally in localized hot spots. Moreover, the virus has been identified in new areas in the recent years. A great number of surveys have been carried out in order to assess the prevalence of the infection in the reservoir host and to identify links with different biotic and abiotic factors. The factors that drive the infections are related to the density and diversity of bank vole populations, prevalence of infection in the reservoir host, viral excretion in the environment, survival of the virus outside its host, and human behavior, which affect the main transmission virus route through inhalation of infected rodent excreta. At the scale of a rodent population, the prevalence of the infection increases with the age of the individuals but also other parameters, such as sex and genetic variability, interfere. The contamination of the environment may be correlated to the number of newly infected rodents, which heavily excrete the virus. The interactions between these different parameters add to the complexity of the situation and explain the absence of reliable tools to predict epidemics. In this review, the factors that drive the epidemics of hantaviruses in Middle Europe are discussed through a panorama of the epidemiological situation in Belgium, France, and Germany. PMID- 22934004 TI - Toward a multiscale description of microvascular flow regulation: o(2)-dependent release of ATP from human erythrocytes and the distribution of ATP in capillary networks. AB - Integration of the numerous mechanisms that have been suggested to contribute to optimization of O(2) supply to meet O(2) need in skeletal muscle requires a systems biology approach which permits quantification of these physiological processes over a wide range of length scales. Here we describe two individual computational models based on in vivo and in vitro studies which, when incorporated into a single robust multiscale model, will provide information on the role of erythrocyte-released ATP in perfusion distribution in skeletal muscle under both physiological and pathophysiological conditions. Healthy human erythrocytes exposed to low O(2) tension release ATP via a well characterized signaling pathway requiring activation of the G-protein, Gi, and adenylyl cyclase leading to increases in cAMP. This cAMP then activates PKA and subsequently CFTR culminating in ATP release via pannexin 1. A critical control point in this pathway is the level of cAMP which is regulated by pathway-specific phosphodiesterases. Using time constants (~100 ms) that are consistent with measured erythrocyte ATP release, we have constructed a dynamic model of this pathway. The model predicts levels of ATP release consistent with measurements obtained over a wide range of hemoglobin O(2) saturations (sO(2)). The model further predicts how insulin, at concentrations found in pre-diabetes, enhances the activity of PDE3 and reduces intracellular cAMP levels leading to decreased low O(2)-induced ATP release from erythrocytes. The second model, which couples O(2) and ATP transport in capillary networks, shows how intravascular ATP and the resulting conducted vasodilation are affected by local sO(2), convection and ATP degradation. This model also predicts network-level effects of decreased ATP release resulting from elevated insulin levels. Taken together, these models lay the groundwork for investigating the systems biology of the regulation of microvascular perfusion distribution by erythrocyte-derived ATP. PMID- 22934005 TI - Muscle afferent receptors engaged in augmented sympathetic responsiveness in peripheral artery disease. AB - The exercise pressor reflex (EPR) is a neural control mechanism responsible for the cardiovascular responses to exercise. As exercise is initiated, thin fiber muscle afferent nerves are activated by mechanical and metabolic stimuli arising in the contracting muscles. This leads to reflex increases in arterial blood pressure (BP) and heart rate primarily through activation of sympathetic nerve activity (SNA). Studies of humans and animals have indicated that the EPR is exaggerated in a number of cardiovascular diseases. For the last several years, studies have specifically employed a rodent model to examine the mechanisms at receptor and cellular levels by which responses of SNA and BP to static exercise are heightened in peripheral artery disease (PAD), one of the most common cardiovascular disorders. A rat model of this disease has well been established. Specifically, femoral artery occlusion is used to study intermittent claudication that is observed in human PAD. The receptors on thin fiber muscle afferents that are engaged in this disease include transient receptor potential vanilloid type 1 (TRPV1), purinergic P2X, and acid sensing ion channel (ASIC). The role played by nerve growth factor in regulating those sensory receptors in the processing of amplified EPR was also investigated. The purpose of this review is to focus on a theme namely that PAD accentuates autonomic reflex responses to exercise and further address regulatory mechanisms leading to abnormal sympathetic responsiveness. This review will present some of recent results in regard with several receptors in muscle sensory neurons in contribution to augmented autonomic reflex responses in PAD. Review of the findings from recent studies would lead to a better understanding in integrated processing of sympathetic nervous system in PAD. PMID- 22934006 TI - Liver fibrogenesis in non-alcoholic steatohepatitis. AB - Non-alcoholic fatty liver disease (NAFLD) is emerging as one of the most common chronic liver diseases in developed western countries. Non-alcoholic steatohepatitis (NASH) is the most severe form of NAFLD, and can progress to more severe forms of liver disease, including fibrosis, cirrhosis, and even hepatocellular carcinoma. The activation of hepatic stellate cells plays a critical role in NASH-related fibrogenesis. Multiple factors, such as insulin resistance, oxidative stress, pro-inflammatory cytokines and adipokines, and innate immune responses, are known to contribute to the development of NASH related fibrogenesis. Furthermore, these factors may share synergistic interactions, which could contribute to the process of liver fibrosis. Given the complex etiology of NASH, combined treatment regimes that target these different factors provide potential treatment strategies for NASH-related liver fibrosis. PMID- 22934007 TI - The emergence and maintenance of vector-borne diseases in the khyber pakhtunkhwa province, and the federally administered tribal areas of pakistan. AB - Human populations throughout much of the world are experiencing unprecedented changes in their relationship to the environment and their interactions with the animals with which so many humans are intimately dependent upon. These changes result not only from human induced changes in the climate, but also from population demographic changes due to wars, social unrest, behavioral changes resulting from cultural mixing, and large changes in land-use practices. Each of these social shifts can affect the maintenance and emergence of arthropod vectors disease or the pathogenic organisms themselves. A good example is the country of Pakistan, with a large rural population and developing urban economy, it also maintains a wide diversity of entomological disease vectors, including biting flies, mosquitoes, and ticks. Pathogens endemic to the region include the agents of piroplasmosis, rickettsiosis, spirochetosis, and viral hemorrhagic fevers and encephalitis. The northwestern region of the country, including the Khyber Pakhtunkhwa Province (KPK), formerly the North-West Frontier Provence (NWFP), and the Federally Administered Tribal Areas (FATA) are mountainous regions with a high degree of habitat diversity that has recently undergone a massive increase in human population density due to an immigrating refugee population from neighboring war-torn Afghanistan. Vector-borne diseases in people and livestock are common in KPK and FATA regions due to the limited use of vector control measures and access to livestock vaccines. The vast majority of people in this region live in abject poverty with >70% of the population living directly from production gained in animal husbandry. In many instances whole families live directly alongside their animal counterparts. In addition, there is little to no awareness of the threat posed by ticks and transmission of either zoonotic or veterinary pathogens. Recent emergence of Crimean-Congo hemorrhagic fever virus in rural populations, outbreaks of Dengue hemorrhagic fever have been reported in the region, and high prevalence of cattle infected and co-infected with multiple species of hemoparasites (Theileria, Babesia, Anaplasma). The emergence of which has followed the increased density of the rural population due to an influx of refugees from violent conflicts in Afghanistan and is exacerbated by an already impoverished society and wide diversity of potential arthropod vectors. These human outbreaks may be exacerbated by episodes of social upheaval but are also tied to the historically close association of people in the region with their livestock and subsequent zoonosis that result from spillover from co-habitation with infected domestic animals. PMID- 22934008 TI - Prevalence of chronic cough in relation to upper and lower airway symptoms; the Skovde population-based study. AB - The aim of this study was to determine the prevalence of chronic cough in relation to upper airway symptoms, in a cross-sectional, population-based epidemiological study. Another aim was to relate coughing to other explanatory variables and risk factors. A random sample of 1900 inhabitants from the age of 20, stratified for age and gender, was recruited. Subjects were invited for clinical examinations that included questions about general odor intolerance, respiratory symptoms, and smoking habits, and a smell identification test. In total, 1387 volunteers (73% of the sample) were investigated. The overall prevalence of self-reported chronic cough was 6.3% [95% confidence interval (CI): 5.0-7.6%]. Female gender, age, height, BMI, and smoking were significantly related to cough. Furthermore, nasal blockage, nasal secretion, sneezing, asthma, odor and cold air sensitivity, and aspirin intolerance also related to cough with statistical significance, indicating a close connection between chronic cough and upper airway symptoms. In keeping with other studies, this study demonstrates that chronic cough is a widespread problem in society, and is about twice as common in women than in men. PMID- 22934009 TI - Docosahexaenoic Acid reduces the incidence of early afterdepolarizations caused by oxidative stress in rabbit ventricular myocytes. AB - Accumulating evidence has suggested that omega3-polyunsaturated fatty acids (omega3-PUFAs) may have beneficial effects in the prevention/treatment of cardiovascular diseases, while controversies still remain regarding their anti arrhythmic potential. It is not clear yet whether omega-3-PUFAs can suppress early afterdepolarizations (EADs) induced by oxidative stress. In the present study, we recorded action potentials using the patch-clamp technique in ventricular myocytes isolated from rabbit hearts. The treatment of myocytes with H(2)O(2) (200 MUM) prolonged AP durations and induced EADs, which were significantly suppressed by docosahexaenoic acid (DHA, 10 or 25 MUM; n = 8). To reveal the ionic mechanisms, we examined the effects of DHA on L-type calcium currents (I(Ca.L)), late sodium (I(Na)), and transient outward potassium currents (I(to)) in ventricular myocytes pretreated with H(2)O(2). H(2)O(2) (200 MUM) increased I(Ca.L) by 46.4% from control (-8.4 +/- 1.4 pA/pF) to a peak level ( 12.3 +/- 1.8 pA/pF, n = 6, p < 0.01) after 6 min of H(2)O(2) perfusion. H(2)O(2) enhanced I(Ca.L) was significantly reduced by DHA (25 MUM; -7.1 +/- 0.9 pA/pF, n = 6, p < 0.01). Similarly, H(2)O(2)-increased the late I(Na) (-3.2 +/- 0.3 pC) from control level (-0.7 +/- 0.1 pC). DHA (25 MUM) completely reversed the H(2)O(2)-induced increase in late I(Na) (to -0.8 +/- 0.2 pC, n = 5). H(2)O(2) also increased the peak amplitude of and the steady state I(to) from 8.9 +/- 1.0 and 2.16 +/- 0.25 pA/pF to 12.8 +/- 1.21 and 3.13 +/- 0.47 pA/pF respectively (n = 6, p < 0.01, however, treatment with DHA (25 MUM) did not produce significant effects on current amplitudes and dynamics of I(to) altered by H(2)O(2). In addition, DHA (25 MUM) did not affect the increase of intracellular reactive oxygen species (ROS) levels induced by H(2)O(2) in rabbit ventricular myocytes. These findings demonstrate that DHA suppresses exogenous H(2)O(2)-induced EADs mainly by modulating membrane ion channel functions, while its direct effect on ROS may play a less prominent role. PMID- 22934010 TI - Tonic neuromodulation of the inspiratory rhythm generator. AB - The generation of neural network dynamics relies on the interactions between the intrinsic and synaptic properties of their neural components. Moreover, neuromodulators allow networks to change these properties and adjust their activity to specific challenges. Endogenous continuous ("tonic") neuromodulation can regulate and sometimes be indispensible for networks to produce basal activity. This seems to be the case for the inspiratory rhythm generator located in the pre-Botzinger complex (preBotC). This neural network is necessary and sufficient for generating inspiratory rhythms. The preBotC produces normal respiratory activity (eupnea) as well as sighs under normoxic conditions, and it generates gasping under hypoxic conditions after a reconfiguration process. The reconfiguration leading to gasping generation involves changes of synaptic and intrinsic properties that can be mediated by several neuromodulators. Over the past years, it has been shown that endogenous continuous neuromodulation of the preBotC may involve the continuous action of amines and peptides on extrasynaptic receptors. I will summarize the findings supporting the role of endogenous continuous neuromodulation in the generation and regulation of different inspiratory rhythms, exploring the possibility that these neuromodulatory actions involve extrasynaptic receptors along with evidence of glial modulation of preBotC activity. PMID- 22934011 TI - Regulators of epithelial mesenchymal transition in pancreatic cancer. AB - Pancreatic cancer is a leading cause of cancer-related death due to its invasive nature. Despite the improvement of diagnostic strategy, early diagnosis of pancreatic cancer is still challenging. Surgical resection is the only curative therapy, while vast majority of patients are not eligible for this therapeutic option. Complex biological processes are involved in the establishment of invasion and metastasis of pancreatic cancer and epithelial-mesenchymal transition (EMT) has been reported to play crucial role. EMT is part of the normal developmental processes which mobilizes epithelial cells and yields mesenchymal phenotype. Deregulation of EMT inducing molecules in pancreatic cancer is reported, such as multiple cytokines, growth factors and downstream transcriptional factors. In addition to these molecules, non-coding RNA including miRNA also contributes to EMT. EMT of cancer cell also correlates with cancer stem cell (CSC) properties such as chemoresistance or tumorigenicity, therefore these upstream regulators of EMT could be attractive therapeutic targets and several candidates are examined for clinical application. This review summarizes recent advances in this field, focusing the regulatory molecules of EMT and their downstream targets. Further understanding and research advances will clarify the cryptic mechanism of cancer metastasis and delineate novel therapeutic targets. PMID- 22934012 TI - Zebrafish: a novel research tool for cardiac (patho)electrophysiology and ion channel disorders. AB - The zebrafish is a cold-blooded tropical freshwater teleost with two-chamber heart morphology. A major advantage of the zebrafish for heart studies is that the embryo is transparent, allowing for easy assessment of heart development, heart rate analysis and phenotypic characterization. Moreover, rapid and effective gene-specific knockdown can be achieved using morpholino oligonucleotides. Lastly, zebrafish are small in size, are easy to maintain and house, grow fast, and have large offspring size, making them a cost-efficient research model. Zebrafish embryonic and adult heart rates as well as action potential (AP) shape and duration and electrocardiogram morphology closely resemble those of humans. However, whether the zebrafish is truly an attractive alternative model for human cardiac electrophysiology depends on the presence and gating properties of the various ion channels in the zebrafish heart, but studies into the latter are as yet limited. The rapid component of the delayed rectifier K(+) current (I(Kr)) remains the best characterized and validated ion current in zebrafish myocytes, and zebrafish may represent a valuable model to investigate human I(Kr) channel-related disease, including long QT syndrome. Arguments against the use of zebrafish as model for human cardiac (patho)electrophysiology include its cold-bloodedness and two-chamber heart morphology, absence of t tubuli, sarcoplamatic reticulum function, and a different profile of various depolarizing and repolarizing ion channels, including a limited Na(+) current density. Based on the currently available literature, we propose that zebrafish may constitute a relevant research model for investigating ion channel disorders associated with abnormal repolarization, but may be less suitable for studying depolarization disorders or Ca(2+)-modulated arrhythmias. PMID- 22934013 TI - Plasticity of TRPV1-Expressing Sensory Neurons Mediating Autonomic Dysreflexia Following Spinal Cord Injury. AB - Spinal cord injury (SCI) triggers profound changes in visceral and somatic targets of sensory neurons below the level of injury. Despite this, little is known about the influence of injury to the spinal cord on sensory ganglia. One of the defining characteristics of sensory neurons is the size of their cell body: for example, nociceptors are smaller in size than mechanoreceptors or proprioceptors. In these experiments, we first used a comprehensive immunohistochemical approach to characterize the size distribution of sensory neurons after high- and low-thoracic SCI. Male Wistar rats (300 g) received a spinal cord transection (T3 or T10) or sham-injury. At 30 days post-injury, dorsal root ganglia (DRGs) and spinal cords were harvested and analyzed immunohistochemically. In a wide survey of primary afferents, only those expressing the capsaicin receptor (TRPV1) exhibited somal hypertrophy after T3 SCI. Hypertrophy only occurred caudal to SCI and was pronounced in ganglia far distal to SCI (i.e., in L4-S1 DRGs). Injury-induced hypertrophy was accompanied by a small expansion of central territory in the lumbar spinal dorsal horn and by evidence of TRPV1 upregulation. Importantly, hypertrophy of TRPV1-positive neurons was modest after T10 SCI. Given the specific effects of T3 SCI on TRPV1 positive afferents, we hypothesized that these afferents contribute to autonomic dysreflexia (AD). Rats with T3 SCI received vehicle or capsaicin via intrathecal injection at 2 or 28 days post-SCI; at 30 days, AD was assessed by recording intra-arterial blood pressure during colo-rectal distension (CRD). In both groups of capsaicin-treated animals, the severity of AD was dramatically reduced. While AD is multi-factorial in origin, TRPV1-positive afferents are clearly involved in AD elicited by CRD. These findings implicate TRPV1-positive afferents in the initiation of AD and suggest that TRPV1 may be a therapeutic target for amelioration or prevention of AD after high SCI. PMID- 22934014 TI - Altered patterns of reflex excitability, balance, and locomotion following spinal cord injury and locomotor training. AB - Spasticity is an important problem that complicates daily living in many individuals with spinal cord injury (SCI). While previous studies in human and animals revealed significant improvements in locomotor ability with treadmill locomotor training, it is not known to what extent locomotor training influences spasticity. In addition, it would be of considerable practical interest to know how the more ergonomically feasible cycle training compares with treadmill training as therapy to manage SCI-induced spasticity and to improve locomotor function. Thus the main objective of our present studies was to evaluate the influence of different types of locomotor training on measures of limb spasticity, gait, and reflex components that contribute to locomotion. For these studies, 30 animals received midthoracic SCI using the standard Multicenter Animal Spinal cord Injury Studies (MASCIS) protocol (10 g 2.5 cm weight drop). They were divided randomly into three equal groups: control (contused untrained), contused treadmill trained, and contused cycle trained. Treadmill and cycle training were started on post-injury day 8. Velocity-dependent ankle torque was tested across a wide range of velocities (612-49 degrees /s) to permit quantitation of tonic (low velocity) and dynamic (high velocity) contributions to lower limb spasticity. By post-injury weeks 4 and 6, the untrained group revealed significant velocity-dependent ankle extensor spasticity, compared to pre surgical control values. At these post-injury time points, spasticity was not observed in either of the two training groups. Instead, a significantly milder form of velocity-dependent spasticity was detected at postcontusion weeks 8-12 in both treadmill and bicycle training groups at the four fastest ankle rotation velocities (350-612 degrees /s). Locomotor training using treadmill or bicycle also produced significant increase in the rate of recovery of limb placement measures (limb axis, base of support, and open field locomotor ability) and reflex rate-depression, a quantitative assessment of neurophysiological processes that regulate segmental reflex excitability, compared with those of untrained injured controls. Light microscopic qualitative studies of spared tissue revealed better preservation of myelin, axons, and collagen morphology in both locomotor trained animals. Both locomotor trained groups revealed decreased lesion volume (rostro-caudal extension) and more spared tissue at the lesion site. These improvements were accompanied by marked upregulation of BDNF, GABA/GABA(b), and monoamines (e.g., norepinephrine and serotonin) which might account for these improved functions. These data are the first to indicate that the therapeutic efficacy of ergonomically practical cycle training is equal to that of the more labor-intensive treadmill training in reducing spasticity and improving locomotion following SCI in an animal model. PMID- 22934015 TI - Dendritic Signaling in Inhibitory Interneurons: Local Tuning via Group I Metabotropic Glutamate Receptors. AB - Communication between neurons is achieved by rapid signal transduction via highly specialized structural elements known as synaptic contacts. In addition, numerous extrasynaptic mechanisms provide a flexible platform for the local regulation of synaptic signals. For example, peri- and extra-synaptic signaling through the group I metabotropic glutamate receptors (mGluRs) can be involved in the highly compartmentalized regulation of dendritic ion conductances, the induction of input-specific synaptic plasticity, and the local release of retrograde messengers. Therefore, extrasynaptic mechanisms appear to play a key role in the local tuning of dendritic computations. Here, we review recent findings on the role of group I mGluRs in the dendritic signaling of inhibitory interneurons. We propose that group I mGluRs provide a dual-mode signaling device that integrates different patterns of neural activity. By implementing distinct forms of intrinsic and synaptic regulation, group I mGluRs may be responsible for the local fine-tuning of dendritic function. PMID- 22934016 TI - Sarcopenia, dynapenia, and the impact of advancing age on human skeletal muscle size and strength; a quantitative review. AB - Changing demographics make it ever more important to understand the modifiable risk factors for disability and loss of independence with advancing age. For more than two decades there has been increasing interest in the role of sarcopenia, the age-related loss of muscle or lean mass, in curtailing active and healthy aging. There is now evidence to suggest that lack of strength, or dynapenia, is a more constant factor in compromised wellbeing in old age and it is apparent that the decline in muscle mass and the decline in strength can take quite different trajectories. This demands recognition of the concept of muscle quality; that is the force generating per capacity per unit cross-sectional area (CSA). An understanding of the impact of aging on skeletal muscle will require attention to both the changes in muscle size and the changes in muscle quality. The aim of this review is to present current knowledge of the decline in human muscle mass and strength with advancing age and the associated risk to health and survival and to review the underlying changes in muscle characteristics and the etiology of sarcopenia. Cross-sectional studies comparing young (18-45 years) and old (>65 years) samples show dramatic variation based on the technique used and population studied. The median of values of rate of loss reported across studies is 0.47% per year in men and 0.37% per year in women. Longitudinal studies show that in people aged 75 years, muscle mass is lost at a rate of 0.64-0.70% per year in women and 0.80-00.98% per year in men. Strength is lost more rapidly. Longitudinal studies show that at age 75 years, strength is lost at a rate of 3 4% per year in men and 2.5-3% per year in women. Studies that assessed changes in mass and strength in the same sample report a loss of strength 2-5 times faster than loss of mass. Loss of strength is a more consistent risk for disability and death than is loss of muscle mass. PMID- 22934017 TI - The involvement of actin, calcium channels and exocytosis proteins in somato dendritic oxytocin and vasopressin release. AB - Hypothalamic magnocellular neurons release vasopressin and oxytocin not only from their axon terminals into the blood, but also from their somata and dendrites into the extracellular space of the brain, and this can be regulated independently. Differential release of neurotransmitters from different compartments of a single neuron requires subtle regulatory mechanisms. Somato dendritic, but not axon terminal release can be modulated by changes in intracellular calcium concentration [(Ca(2+))] by release of calcium from intracellular stores, resulting in priming of dendritic pools for activity dependent release. This review focuses on our current understanding of the mechanisms of priming and the roles of actin remodeling, voltage-operated calcium channels (VOCCs) and SNARE proteins in the regulation somato-dendritic and axon terminal peptide release. PMID- 22934018 TI - Impact of behavioral control on the processing of nociceptive stimulation. AB - How nociceptive signals are processed within the spinal cord, and whether these signals lead to behavioral signs of neuropathic pain, depends upon their relation to other events and behavior. Our work shows that these relations can have a lasting effect on spinal plasticity, inducing a form of learning that alters the effect of subsequent nociceptive stimuli. The capacity of lower spinal systems to adapt, in the absence of brain input, is examined in spinally transected rats that receive a nociceptive shock to the tibialis anterior muscle of one hind leg. If shock is delivered whenever the leg is extended (controllable stimulation), it induces an increase in flexion duration that minimizes net shock exposure. This learning is not observed in subjects that receive the same amount of shock independent of leg position (uncontrollable stimulation). These two forms of stimulation have a lasting, and divergent, effect on subsequent learning: controllable stimulation enables learning whereas uncontrollable stimulation disables it (learning deficit). Uncontrollable stimulation also enhances mechanical reactivity. We review evidence that training with controllable stimulation engages a brain-derived neurotrophic factor (BDNF)-dependent process that can both prevent and reverse the consequences of uncontrollable shock. We relate these effects to changes in BDNF protein and TrkB signaling. Controllable stimulation is also shown to counter the effects of peripheral inflammation (from intradermal capsaicin). A model is proposed that assumes nociceptive input is gated at an early sensory stage. This gate is sensitive to current environmental relations (between proprioceptive and nociceptive input), allowing stimulation to be classified as controllable or uncontrollable. We further propose that the status of this gate is affected by past experience and that a history of uncontrollable stimulation will promote the development of neuropathic pain. PMID- 22934020 TI - A joint computational respiratory neural network-biomechanical model for breathing and airway defensive behaviors. AB - Data-driven computational neural network models have been used to study mechanisms for generating the motor patterns for breathing and breathing related behaviors such as coughing. These models have commonly been evaluated in open loop conditions or with feedback of lung volume simply represented as a filtered version of phrenic motor output. Limitations of these approaches preclude assessment of the influence of mechanical properties of the musculoskeletal system and motivated development of a biomechanical model of the respiratory muscles, airway, and lungs using published measures from human subjects. Here we describe the model and some aspects of its behavior when linked to a computational brainstem respiratory network model for breathing and airway defensive behavior composed of discrete "integrate and fire" populations. The network incorporated multiple circuit paths and operations for tuning inspiratory drive suggested by prior work. Results from neuromechanical system simulations included generation of a eupneic-like breathing pattern and the observation that increased respiratory drive and operating volume result in higher peak flow rates during cough, even when the expiratory drive is unchanged, or when the expiratory abdominal pressure is unchanged. Sequential elimination of the model's sources of inspiratory drive during cough also suggested a role for disinhibitory regulation via tonic expiratory neurons, a result that was subsequently supported by an analysis of in vivo data. Comparisons with antecedent models, discrepancies with experimental results, and some model limitations are noted. PMID- 22934019 TI - The endoplasmic reticulum stress response in aging and age-related diseases. AB - The endoplasmic reticulum(ER) is a multifunctional organelle within which protein folding, lipid biosynthesis, and calcium storage occurs. Perturbations such as energy or nutrient depletion, disturbances in calcium or redox status that disrupt ER homeostasis lead to the misfolding of proteins, ER stress and up regulation of several signaling pathways coordinately called the unfolded protein response (UPR). The UPR is characterized by the induction of chaperones, degradation of misfolded proteins and attenuation of protein translation. The UPR plays a fundamental role in the maintenance of cellular homeostasis and thus is central to normal physiology. However, sustained unresolved ER stress leads to apoptosis. Aging linked declines in expression and activity of key ER molecular chaperones and folding enzymes compromise proper protein folding and the adaptive response of the UPR. One mechanism to explain age associated declines in cellular functions and age-related diseases is a progressive failure of chaperoning systems. In many of these diseases, proteins or fragments of proteins convert from their normally soluble forms to insoluble fibrils or plaques that accumulate in a variety of organs including the liver, brain or spleen. This group of diseases, which typically occur late in life includes Alzheimer's, Parkinson's, type II diabetes and a host of less well known but often equally serious conditions such as fatal familial insomnia. The UPR is implicated in many of these neurodegenerative and familial protein folding diseases as well as several cancers and a host of inflammatory diseases including diabetes, atherosclerosis, inflammatory bowel disease and arthritis. This review will discuss age-related changes in the ER stress response and the role of the UPR in age-related diseases. PMID- 22934021 TI - Alveolar gas exchange and tissue oxygenation during incremental treadmill exercise, and their associations with blood O(2) carrying capacity. AB - The magnitude and timing of oxygenation responses in highly active leg muscle, less active arm muscle, and cerebral tissue, have not been studied with simultaneous alveolar gas exchange measurement during incremental treadmill exercise. Nor is it known, if blood O(2) carrying capacity affects the tissue specific oxygenation responses. Thus, we investigated alveolar gas exchange and tissue (m. vastus lateralis, m. biceps brachii, cerebral cortex) oxygenation during incremental treadmill exercise until volitional fatigue, and their associations with blood O(2) carrying capacity in 22 healthy men. Alveolar gas exchange was measured, and near-infrared spectroscopy (NIRS) was used to monitor relative concentration changes in oxy- (Delta[O(2)Hb]), deoxy- (Delta[HHb]) and total hemoglobin (Delta[tHb]), and tissue saturation index (TSI). NIRS inflection points (NIP), reflecting changes in tissue-specific oxygenation, were determined and their coincidence with ventilatory thresholds [anaerobic threshold (AT), respiratory compensation point (RC); V-slope method] was examined. Blood O(2) carrying capacity [total hemoglobin mass (tHb-mass)] was determined with the CO rebreathing method. In all tissues, NIPs coincided with AT, whereas RC was followed by NIPs. High tHb-mass associated with leg muscle deoxygenation at peak exercise (e.g., Delta[HHb] from baseline walking to peak exercise vs. tHb-mass: r = 0.64, p < 0.01), but not with arm muscle- or cerebral deoxygenation. In conclusion, regional tissue oxygenation was characterized by inflection points, and tissue oxygenation in relation to alveolar gas exchange during incremental treadmill exercise resembled previous findings made during incremental cycling. It was also found out, that O(2) delivery to less active m. biceps brachii may be limited by an accelerated increase in ventilation at high running intensities. In addition, high capacity for blood O(2) carrying was associated with a high level of m. vastus lateralis deoxygenation at peak exercise. PMID- 22934022 TI - An integrated fluid-chemical model toward modeling the formation of intra-luminal thrombus in abdominal aortic aneurysms. AB - Abdominal Aortic Aneurysms (AAAs) are frequently characterized by the presence of an Intra-Luminal Thrombus (ILT) known to influence their evolution biochemically and biomechanically. The ILT progression mechanism is still unclear and little is known regarding the impact of the chemical species transported by blood flow on this mechanism. Chemical agonists and antagonists of platelets activation, aggregation, and adhesion and the proteins involved in the coagulation cascade (CC) may play an important role in ILT development. Starting from this assumption, the evolution of chemical species involved in the CC, their relation to coherent vortical structures (VSs) and their possible effect on ILT evolution have been studied. To this end a fluid-chemical model that simulates the CC through a series of convection-diffusion-reaction (CDR) equations has been developed. The model involves plasma-phase and surface-bound enzymes and zymogens, and includes both plasma-phase and membrane-phase reactions. Blood is modeled as a non-Newtonian incompressible fluid. VSs convect thrombin in the domain and lead to the high concentration observed in the distal portion of the AAA. This finding is in line with the clinical observations showing that the thickest ILT is usually seen in the distal AAA region. The proposed model, due to its ability to couple the fluid and chemical domains, provides an integrated mechanochemical picture that potentially could help unveil mechanisms of ILT formation and development. PMID- 22934025 TI - alpha-Adrenergic Blockade Unmasks a Greater Compensatory Vasodilation in Hypoperfused Contracting Muscle. AB - We previously demonstrated that acute hypoperfusion in exercising human muscle causes an immediate increase in vascular resistance that is followed by a partial restoration (less than 100% recovery) of flow. In the current study we examined the contribution of alpha-adrenergic vasoconstriction in the initial changes in vascular resistance at the onset of hypoperfusion as well as in the recovery of flow over time. Nine healthy male subjects (29 +/- 2) performed rhythmic forearm exercise (20% of maximum) during hypoperfusion evoked by intra-arterial balloon inflation. Each trial included; baseline, exercise prior to inflation, exercise with inflation, and exercise after deflation (3 min each). Forearm blood flow (FBF; ultrasound), local (brachial artery), and systemic arterial pressure (MAP; Finometer) were measured. The trial was repeated during phentolamine infusion (alpha-adrenergic receptor blockade). Forearm vascular conductance (FVC; ml min( 1) 100 mmHg(-1)) and resistance (mmHg ml min(-1)) was calculated from BF (ml min( 1)) and local MAP (mmHg). Recovery of FBF and FVC (steady state inflation plus exercise value - nadir)/[steady state exercise (control) value - nadir] with phentolamine was enhanced compared with the respective control (no drug) trial (FBF = 97 +/- 5% vs. 81 +/- 6%, P < 0.05; FVC = 126 +/- 9% vs. 91 +/- 5%, P < 0.01). However, the absolute (0.05 +/- 0.01 vs. 0.06 +/- 0.01 mmHg ml min(-1); P = 0.17) and relative (35 +/- 5% vs. 31 +/- 2%; P = 0.41) increase in vascular resistance at the onset of balloon inflation was not different between the alpha adrenergic receptor inhibition and control (no drug) trials. Therefore, our data indicate that alpha-adrenergic mediated vasoconstriction restricts compensatory vasodilation during forearm exercise with hypoperfusion, but is not responsible for the initial increase in vascular resistance at the onset of hypoperfusion. PMID- 22934026 TI - Omega 3 fatty acid inhibition of inflammatory cytokine-mediated Connexin43 regulation in the heart. AB - BACKGROUND: The proinflammatory cytokine Interleukin-1beta (IL-1beta), which increases in the heart post myocardial infarction (MI), has been shown to cause loss of Connexin43 (Cx43) function, an event known to underlie formation of the arrhythmogenic substrate. Omega 3 Fatty acids exhibit antiarrhythmic properties and impact IL-1beta signaling. We hypothesize that Omega-3 fatty acids prevent arrhythmias in part, by inhibiting IL-1beta signaling thus maintaining functional Cx43 channels. METHODS: Rat neonatal myocytes or Madin-Darby Canine Kidney Epithelial (MDCK) cells grown in media in the absence (Ctr) or presence of 30 MUM docosahexaenoic acid (DHA, an Omega-3 Fatty acid) were treated with 0.1 MUM activated IL-1beta. We determined Cx43 channel function using a dye spread assay. Western blot and immunostaining were used to examine Cx43 levels/localization and downstream effectors of IL-1beta. In addition we used a murine model of MI for 24 h to determine the impact of an Omega-3 fatty acid enriched diet on Cx43 levels/localization post MI. RESULTS: IL-1beta significantly inhibited Cx43 function in Ctr cells (200.9 +/- 17.7 MUm [Ctr] vs. 112.8 +/- 14.9 MUm [0.1 uM IL 1beta], p<0.05). However, DHA-treated cells remained highly coupled in the presence of IL-1beta [167.9 +/- 21.9 MUm [DHA] vs. 164.4 +/- 22.3 MUm [DHA + 0.1 uM IL-1beta], p<0.05, n = 4]. Additionally, western blot showed that IL-1beta treatment caused a 38.5% downregulation of Cx43 [1.00 au [Ctr] vs. 0.615 au (0.1 MUM IL-1beta) which was completely abolished in DHA-treated cells (0.935 au [DHA] vs. 1.02 au [DHA + 0.1 MUM IL-1beta), p < 0.05, n = 3]. Examination of the downstream modulator of IL-1beta, NFkappabeta showed that while hypoxia caused translocation of NFkappabeta to the nucleus, this was inhibited by DHA. Additionally we found that a diet enriched in Omega-3 Fatty acids inhibited lateralization of Cx43 in the post-MI murine heart as well as limited activation of fibroblasts which would lead to decreased fibrosis overall. CONCLUSIONS: Omega 3 Fatty acid treatment inhibited IL-1beta-stimulated loss of Cx43 protein, and more importantly, inhibited loss of Cx43 function by inhibiting translocation of NFkappabeta. In the intact heart a diet enriched in Omega 3 Fatty Acids limited loss of Cx43 at the intercalated disk in the heart following MI. These data suggest that one of cardio-protective mechanisms by which Omega 3 Fatty acids work includes prevention of the pro-arrhythmic loss of Cx43 post MI and the attenuation of cardiac fibrosis after injury. PMID- 22934023 TI - Human pluripotent stem cells: applications and challenges in neurological diseases. AB - The ability to generate human pluripotent stem cells (hPSCs) holds great promise for the understanding and the treatment of human neurological diseases in modern medicine. The hPSCs are considered for their in vitro use as research tools to provide relevant cellular model for human diseases, drug discovery, and toxicity assays and for their in vivo use in regenerative medicine applications. In this review, we highlight recent progress, promises, and challenges of hPSC applications in human neurological disease modeling and therapies. PMID- 22934024 TI - LRP-1 and LRP-2 receptors function in the membrane neuron. Trafficking mechanisms and proteolytic processing in Alzheimer's disease. AB - Low density lipoprotein receptor-related protein (LRP) belongs to the low-density lipoprotein receptor family, generally recognized as cell surface endocytic receptors, which bind and internalize extracellular ligands for degradation in lysosomes. Neurons require cholesterol to function and keep the membrane rafts stable. Cholesterol uptake into the neuron is carried out by ApoE via LRPs receptors on the cell surface. In neurons the most important are LRP-1 and LRP-2, even it is thought that a causal factor in Alzheimer's disease (AD) is the malfunction of this process which cause impairment intracellular signaling as well as storage and/or release of nutrients and toxic compounds. Both receptors are multifunctional cell surface receptors that are widely expressed in several tissues including neurons and astrocytes. LRPs are constituted by an intracellular (ICD) and extracellular domain (ECD). Through its ECD, LRPs bind at least 40 different ligands ranging from lipoprotein and protease inhibitor complex to growth factors and extracellular matrix proteins. These receptors has also been shown to interact with scaffolding and signaling proteins via its ICD in a phosphorylation-dependent manner and to function as a co-receptor partnering with other cell surface or integral membrane proteins. Thus, LRPs are implicated in two major physiological processes: endocytosis and regulation of signaling pathways, which are both involved in diverse biological roles including lipid metabolism, cell growth processes, degradation of proteases, and tissue invasion. Interestingly, LRPs were also localized in neurons in different stages, suggesting that both receptors could be implicated in signal transduction during embryonic development, neuronal outgrowth or in the pathogenesis of AD. PMID- 22934027 TI - The role of the Wnt signaling pathway in incretin hormone production and function. AB - Glucose metabolism is tightly controlled by multiple hormones and neurotransmitters in response to nutritional, environmental, and emotional changes. In addition to insulin and glucagon produced by pancreatic islets, two incretin hormones, namely glucagon-like peptide-1 (GLP-1) and gastric inhibitory polypeptide (GIP, also known as glucose-dependent insulinotropic peptide), also play important roles in blood glucose homeostasis. The incretin hormones mainly exert their regulatory effects via their corresponding receptors, which are expressed in pancreatic islets as well as many other extra-pancreatic organs. Recent studies have shown that the genes which encode these two incretin hormones can be regulated by the effectors of the Wnt signaling pathway, including TCF7L2, a transcription factor identified recently by extensive genome wide association studies as an important type 2 diabetes risk gene. Interestingly, TCF7L2 and beta catenin (beta-cat), another effector of Wnt signaling pathway, may also mediate the function of the incretin hormones as well as the expression of their receptors in pancreatic beta-cells. In this review, we have introduced the incretin hormones and the Wnt signaling pathway, summarized recent findings in the field, and provided our perspectives. PMID- 22934028 TI - Noise destroys feedback enhanced figure-ground segmentation but not feedforward figure-ground segmentation. AB - Figure-ground (FG) segmentation is the separation of visual information into background and foreground objects. In the visual cortex, FG responses are observed in the late stimulus response period, when neurons fire in tonic mode, and are accompanied by a switch in cortical state. When such a switch does not occur, FG segmentation fails. Currently, it is not known what happens in the brain on such occasions. A biologically plausible feedforward spiking neuron model was previously devised that performed FG segmentation successfully. After incorporating feedback the FG signal was enhanced, which was accompanied by a change in spiking regime. In a feedforward model neurons respond in a bursting mode whereas in the feedback model neurons fired in tonic mode. It is known that bursts can overcome noise, while tonic firing appears to be much more sensitive to noise. In the present study, we try to elucidate how the presence of noise can impair FG segmentation, and to what extent the feedforward and feedback pathways can overcome noise. We show that noise specifically destroys the feedback enhanced FG segmentation and leaves the feedforward FG segmentation largely intact. Our results predict that noise produces failure in FG perception. PMID- 22934029 TI - Arsenomics: omics of arsenic metabolism in plants. AB - Arsenic (As) contamination of drinking water and groundwater used for irrigation can lead to contamination of the food chain and poses serious health risk to people worldwide. To reduce As intake through the consumption of contaminated food, identification of the mechanisms for As accumulation and detoxification in plant is a prerequisite to develop efficient phytoremediation methods and safer crops with reduced As levels. Transcriptome, proteome, and metabolome analysis of any organism reflects the total biological activities at any given time which are responsible for the adaptation of the organism to the surrounding environmental conditions. As these approaches are very important in analyzing plant As transport and accumulation, we termed "Arsenomics" as approach which deals transcriptome, proteome, and metabolome alterations during As exposure. Although, various studies have been performed to understand modulation in transcriptome in response to As, many important questions need to be addressed regarding the translated proteins of plants at proteomic and metabolomic level, resulting in various ecophysiological responses. In this review, the comprehensive knowledge generated in this area has been compiled and analyzed. There is a need to strengthen Arsenomics which will lead to build up tools to develop As-free plants for safe consumption. PMID- 22934030 TI - The power of boolean implication networks. AB - Human diseases have been investigated in the context of single genes as well as complex networks of genes. Though single gene approaches have been extremely successful in the past, most human diseases are complex and better characterized by multiple interacting genes commonly known as networks or pathways. With the advent of high-throughput technologies, a recent trend has been to apply network based analysis to the huge amount of biological data. Analysis on Boolean implication network is one such technique that distinguishes itself based on its simplicity and robustness. Unlike traditional analyses, Boolean implication networks have the power to break into the mechanistic insights of human diseases. A Boolean implication network is a collection of simple Boolean relationships such as "if A is high then B is low." So far, Boolean implication networks have been employed not only to discover novel markers of differentiation in both normal and cancer tissues, but also to develop robust treatment decisions for cancer patients. Therefore, analyses based on Boolean implication networks have potential to accelerate discoveries in human diseases, suggest therapeutics, and provide robust risk-adapted clinical strategies. PMID- 22934031 TI - Upper gastrointestinal dysmotility after spinal cord injury: is diminished vagal sensory processing one culprit? AB - Despite the widely recognized prevalence of gastric, colonic, and anorectal dysfunction after spinal cord injury (SCI), significant knowledge gaps persist regarding the mechanisms leading to post-SCI gastrointestinal (GI) impairments. Briefly, the regulation of GI function is governed by a mix of parasympathetic, sympathetic, and enteric neurocircuitry. Unlike the intestines, the stomach is dominated by parasympathetic (vagal) control whereby gastric sensory information is transmitted via the afferent vagus nerve to neurons of the nucleus tractus solitarius (NTS). The NTS integrates this sensory information with signals from throughout the central nervous system. Glutamatergic and GABAergic NTS neurons project to other nuclei, including the preganglionic parasympathetic neurons of the dorsal motor nucleus of the vagus (DMV). Finally, axons from the DMV project to gastric myenteric neurons, again, through the efferent vagus nerve. SCI interrupts descending input to the lumbosacral spinal cord neurons that modulate colonic motility and evacuation reflexes. In contrast, vagal neurocircuitry remains anatomically intact after injury. This review presents evidence that unlike the post-SCI loss of supraspinal control which leads to colonic and anorectal dysfunction, gastric dysmotility occurs as an indirect or secondary pathology following SCI. Specifically, emerging data points toward diminished sensitivity of vagal afferents to GI neuroactive peptides, neurotransmitters and, possibly, macronutrients. The neurophysiological properties of rat vagal afferent neurons are highly plastic and can be altered by injury or energy balance. A reduction of vagal afferent signaling to NTS neurons may ultimately bias NTS output toward unregulated GABAergic transmission onto gastric-projecting DMV neurons. The resulting gastroinhibitory signal may be one mechanism leading to upper GI dysmotility following SCI. PMID- 22934032 TI - Microneurographic research in women. AB - This article reviews microneurographic research on sympathetic neural control in women under both physiological and pathophysiological conditions across the lifespan. Specifically, the effects of sex, age, race, the menstrual cycle, oral contraceptives, estrogen replacement therapy, and normal pregnancy on neural control of blood pressure in healthy women are reviewed. In addition, sympathetic neural activity during neurally mediated (pre)syncope, the Postural Orthostatic Tachycardia Syndrome (POTS), obesity, the Polycystic Ovary Syndrome (PCOS), gestational hypertension, and preeclampsia, chronic essential hypertension, heart failure, and myocardial infarction in women are also reviewed briefly. It is suggested that microneurographic studies provide valuable information regarding autonomic circulatory control in women of different ages and in most cases, excessive sympathetic activation is associated with specific medical conditions regardless of age and sex. In some situations, sympathetic inhibition or withdrawal may be the underlying mechanism. Information gained from previous and recent microneurographic studies has significant clinical implications in women's health, and in some cases could be used to guide therapy if more widely available. PMID- 22934033 TI - Persistence of pro-arrhythmic spatio-temporal calcium patterns in atrial myocytes: a computational study of ping waves. AB - Clusters of ryanodine receptors within atrial myocytes are confined to spatially separated layers. In many species, these layers are not juxtaposed by invaginations of the plasma membrane (transverse tubules; 'T-tubules'), so that calcium-induced-calcium signals rely on centripetal propagation rather than voltage-synchronized channel openings to invade the interior of the cell and trigger contraction. The combination of this specific cellular geometry and dynamics of calcium release can lead to novel autonomous spatio-temporal calcium waves, and in particular ping waves. These are waves of calcium release activity that spread as counter-rotating sectors of elevated calcium within a single layer of ryanodine receptors, and can seed further longitudinal calcium waves. Here we show, using a computational model, that these calcium waves can dominate the response of a cell to electrical pacing and hence are pro-arrhythmic. This highlights the importance of modeling internal cellular structures when investigating mechanisms of cardiac dysfunction such as atrial arrhythmia. PMID- 22934034 TI - Caveolin as a potential drug target for cardiovascular protection. AB - Caveolae and caveolin are key players in a number of disease processes. Current research indicates that caveolins play a significant role in cardiovascular disease and dysfunction. The far-reaching roles of caveolins in disease and dysfunction make them particularly notable therapeutic targets. In particular, caveolin-1 (Cav-1) and caveolin-3 (Cav-3) have been identified as potential regulators of vascular dysfunction and heart disease and might even confer cardiac protection in certain settings. Such a central role in vascular health therefore makes manipulation of Cav-1/3 function or expression levels clear therapeutic targets in a variety of cardiovascular related disease states. Here, we highlight the role of Cav-1 and Cav-3 in cardiovascular health and explore the potential of Cav-1 and Cav-3 derived experimental therapeutics. PMID- 22934035 TI - The importance of modeling epileptic seizure dynamics as spatio-temporal patterns. AB - The occurrence of seizures is the common feature across the spectrum of epileptic disorders. We describe how the use of mechanistic neural population models leads to novel insight into the dynamic mechanisms underlying two important types of epileptic seizures. We specifically stress the need for a spatio-temporal description of the rhythms to deal with the complexity of the pathophenotype. Adapted to functional and structural patient data, the macroscopic models may allow a patient-specific description of seizures and prediction of treatment outcome. PMID- 22934036 TI - Field phenotyping strategies and breeding for adaptation of rice to drought. AB - This paper is a section of the book "Drought phenotyping in crops: from theory to practice" (Monneveux Philippe and Ribaut Jean-Marcel eds, published by CGIAR Generation Challenge Programme. Texcoco, Mexico). The section describes recent experience in drought phenotyping in rice which is one of the most drought susceptible crops. The section contains genetic and genomic resources for drought adaptation and methods for selection of drought-resistant varieties in rice. In appendix, there is experience from Thailand on integration of direct selection for grain yield and physiological traits to confer drought resistance. PMID- 22934037 TI - Sympathetic regulation of vascular function in health and disease. AB - The sympathetic nervous system (SNS) is known to play a pivotal role in short- and long-term regulation of different functions of the cardiovascular system. In the past decades increasing evidence demonstrated that sympathetic neural control is involved not only in the vasomotor control of small resistance arteries but also in modulation of large artery function. Sympathetic activity and vascular function, both of which are key factors in the development and prognosis of cardiovascular events and disease, are linked at several levels. Evidence from experimental studies indicates that the SNS is critically influenced, at the central and also at the peripheral level, by the most relevant factors regulating vascular function, such as nitric oxide (NO), reactive oxygen species (ROS), endothelin (ET), the renin-angiotensin system. Additionally, there is indirect evidence of a reciprocal relationship between endothelial function and activity of the SNS. A number of cardiovascular risk factors and diseases are characterized both by increased sympathetic outflow and decreased endothelial function. In healthy subjects, muscle sympathetic nerve activity (MSNA) appears to be related to surrogate markers of endothelial function, and an acute increase in sympathetic activity has been associated with a decrease in endothelial function in healthy subjects. However, direct evidence of a cause-effect relationship from human studies is scanty. In humans large artery stiffness has been associated with increased sympathetic discharge, both in healthy subjects and in renal transplant recipients. Peripheral sympathetic discharge is also able to modulate wave reflection. On the other hand, large artery stiffness can interfere with autonomic regulation by impairing carotid baroreflex sensitivity. PMID- 22934039 TI - Cell-to-Cell Communication Circuits: Quantitative Analysis of Synthetic Logic Gates. AB - One of the goals in the field of synthetic biology is the construction of cellular computation devices that could function in a manner similar to electronic circuits. To this end, attempts are made to create biological systems that function as logic gates. In this work we present a theoretical quantitative analysis of a synthetic cellular logic-gates system, which has been implemented in cells of the yeast Saccharomyces cerevisiae (Regot et al., 2011). It exploits endogenous MAP kinase signaling pathways. The novelty of the system lies in the compartmentalization of the circuit where all basic logic gates are implemented in independent single cells that can then be cultured together to perform complex logic functions. We have constructed kinetic models of the multicellular IDENTITY, NOT, OR, and IMPLIES logic gates, using both deterministic and stochastic frameworks. All necessary model parameters are taken from literature or estimated based on published kinetic data, in such a way that the resulting models correctly capture important dynamic features of the included mitogen activated protein kinase pathways. We analyze the models in terms of parameter sensitivity and we discuss possible ways of optimizing the system, e.g., by tuning the culture density. We apply a stochastic modeling approach, which simulates the behavior of whole populations of cells and allows us to investigate the noise generated in the system; we find that the gene expression units are the major sources of noise. Finally, the model is used for the design of system modifications: we show how the current system could be transformed to operate on three discrete values. PMID- 22934038 TI - Macrophages, dendritic cells, and regression of atherosclerosis. AB - Atherosclerosis is the number one cause of death in the Western world. It results from the interaction between modified lipoproteins and cells such as macrophages, dendritic cells (DCs), T cells, and other cellular elements present in the arterial wall. This inflammatory process can ultimately lead to the development of complex lesions, or plaques, that protrude into the arterial lumen. Ultimately, plaque rupture and thrombosis can occur leading to the clinical complications of myocardial infarction or stroke. Although each of the cell types plays roles in the pathogenesis of atherosclerosis, the focus of this review will be primarily on the macrophages and DCs. The role of these two cell types in atherosclerosis is discussed, with a particular emphasis on their involvement in atherosclerosis regression. PMID- 22934040 TI - The effect of octopamine on the locust stomatogastric nervous system. AB - Octopamine (OA) is a prominent neuromodulator of invertebrate nervous systems, influencing multiple physiological processes. Among its many roles in insects are the initiation and maintenance of various rhythmic behaviors. Here, the neuromodulatory effects of OA on the components of the locust stomatogastric nervous system were studied, and one putative source of OA modulation of the system was identified. Bath application of OA was found to abolish the endogenous rhythmic output of the fully isolated frontal ganglion (FG), while stimulating motor activity of the fully isolated hypocerebral ganglion (HG). OA also induced rhythmic movements in a foregut preparation with intact HG innervation. Complex dose-dependent effects of OA on interconnected FG-HG preparations were seen: 10( 5) M OA accelerated the rhythmic activity of both the HG and FG in a synchronized manner, while 10(-4) M OA decreased both rhythms. Intracellular stimulation of an identified octopaminergic dorsal unpaired median neuron in the subesophageal ganglion was found to exert a similar effect on the FG motor output as that of OA application. Our findings suggest a mechanism of regulation of insect gut patterns and feeding-related behavior during stress and times of high energy demand. PMID- 22934041 TI - Effect of acute hypoxia on post-exercise parasympathetic reactivation in healthy men. AB - In this study we assessed the effect of acute hypoxia on post-exercise parasympathetic reactivation inferred from heart rate (HR) recovery (HRR) and HR variability (HRV) indices. Ten healthy males participated in this study. Following 10 min of seated rest, participants performed 5 min of submaximal running at the speed associated with the first ventilatory threshold (Sub) followed by a 20-s all-out supramaximal sprint (Supra). Both Sub and Supra runs were immediately followed by 15 min of seated passive recovery. The resting and exercise sequence were performed in both normoxia (N) and normobaric hypoxia (H; FiO(2) = 15.4%). HRR indices (e.g., heart beats recovered in the first minute after exercise cessation, HRR(60s)) and vagal-related HRV indices [i.e., natural logarithm of the square root of the mean of the sum of the squared differences between adjacent normal R-R intervals (Ln rMSSD)] were calculated for both conditions. Difference in the changes between N and H for all HR-derived indices were also calculated for both Sub and Supra. HRR(60s) was greater in N compared with H following Sub only (60 +/- 14 vs. 52 +/- 19 beats min(-1), P = 0.016). Ln rMSSD was greater in N compared with H (post Sub: 3.60 +/- 0.45 vs. 3.28 +/- 0.44 ms in N and H, respectively, and post Supra: 2.66 +/- 0.54 vs. 2.65 +/- 0.63 ms, main condition effect P = 0.02). When comparing the difference in the changes, hypoxia decreased HRR(60s) (-14.3% +/- 17.2 vs. 5.2% +/- 19.3; following Sub and Supra, respectively; P = 0.03) and Ln rMSSD (-8.6% +/- 7.0 vs. 2.0% +/- 13.3, following Sub and Supra, respectively; P = 0.08, Cohen's effect size = 0.62) more following Sub than Supra. While hypoxia may delay parasympathetic reactivation following submaximal exercise, its effect is not apparent following supramaximal exercise. This may suggest that the effect of blood O(2) partial pressure on parasympathetic reactivation is limited under heightened sympathetic activation. PMID- 22934042 TI - A novel member of the trehalose transporter family functions as an h(+)-dependent trehalose transporter in the reabsorption of trehalose in malpighian tubules. AB - In insects, Malpighian tubules are functionally analogous to mammalian kidneys in that they not only are essential to excrete waste molecules into the lumen but also are responsible for the reabsorption of indispensable molecules, such as sugars, from the lumen to the principal cells. Among sugars, the disaccharide trehalose is highly important to insects because it is the main hemolymph sugar to serve as a source of energy and carbon. The trehalose transporter TRET1 participates in the transfer of newly synthesized trehalose from the fat body across the cellular membrane into the hemolymph. Although transport proteins must play a pivotal role in the reabsorption of trehalose in Malpighian tubules, the molecular context underlying this process remains obscure. Previously, we identified a Tret1 homolog (Nlst8) that is expressed principally in the Malpighian tubules of the brown planthopper (BPH). Here, we used the Xenopus oocyte expression system to show that NlST8 exerts trehalose transport activity that is elevated under low pH conditions. These functional assays indicate that Nlst8 encodes a proton-dependent trehalose transporter (H-TRET1). To examine the involvement of Nlst8 in trehalose reabsorption, we analyzed the sugar composition of honeydew by using BPH with RNAi gene silencing. Trehalose was detected in the honeydew as waste excreted from Nlst8-dsRNA-injected BPH under hyperglycemic conditions. However, trehalose was not expelled from GFP-dsRNA-injected BPH even under hyperglycemic conditions. We conclude that NlST8 could participate in trehalose reabsorption driven by a H(+) gradient from the lumen to the principal cells of the Malpighian tubules. PMID- 22934043 TI - Understanding complexity in neurodegenerative diseases: in silico reconstruction of emergence. AB - Healthy functioning is an emergent property of the network of interacting biomolecules that comprise an organism. It follows that disease (a network shift that causes malfunction) is also an emergent property, emerging from a perturbation of the network. On the one hand, the biomolecular network of every individual is unique and this is evident when similar disease-producing agents cause different individual pathologies. Consequently, a personalized model and approach for every patient may be required for therapies to become effective across mankind. On the other hand, diverse combinations of internal and external perturbation factors may cause a similar shift in network functioning. We offer this as an explanation for the multi-factorial nature of most diseases: they are "systems biology diseases," or "network diseases." Here we use neurodegenerative diseases, like Parkinson's disease (PD), as an example to show that due to the inherent complexity of these networks, it is difficult to understand multi factorial diseases with simply our "naked brain." When describing interactions between biomolecules through mathematical equations and integrating those equations into a mathematical model, we try to reconstruct the emergent properties of the system in silico. The reconstruction of emergence from interactions between huge numbers of macromolecules is one of the aims of systems biology. Systems biology approaches enable us to break through the limitation of the human brain to perceive the extraordinarily large number of interactions, but this also means that we delegate the understanding of reality to the computer. We no longer recognize all those essences in the system's design crucial for important physiological behavior (the so-called "design principles" of the system). In this paper we review evidence that by using more abstract approaches and by experimenting in silico, one may still be able to discover and understand the design principles that govern behavioral emergence. PMID- 22934044 TI - Advanced glycation end product cross-link breaker attenuates diabetes-induced cardiac dysfunction by improving sarcoplasmic reticulum calcium handling. AB - Diabetic heart disease is a distinct clinical entity that can progress to heart failure and sudden death. However, the mechanisms responsible for the alterations in excitation-contraction coupling leading to cardiac dysfunction during diabetes are not well known. Hyperglycemia, the landmark of diabetes, leads to the formation of advanced glycation end products (AGEs) on long-lived proteins, including sarcoplasmic reticulum (SR) Ca(2+) regulatory proteins. However, their pathogenic role on SR Ca(2+) handling in cardiac myocytes is unknown. Therefore, we investigated whether an AGE cross-link breaker could prevent the alterations in SR Ca(2+) cycling that lead to in vivo cardiac dysfunction during diabetes. Streptozotocin-induced diabetic rats were treated with alagebrium chloride (ALT 711) for 8 weeks and compared to age-matched placebo-treated diabetic rats and healthy rats. Cardiac function was assessed by echocardiographic examination. Ventricular myocytes were isolated to assess SR Ca(2+) cycling by confocal imaging and quantitative Western blots. Diabetes resulted in in vivo cardiac dysfunction and ALT-711 therapy partially alleviated diastolic dysfunction by decreasing isovolumetric relaxation time and myocardial performance index (MPI) (by 27 and 41% vs. untreated diabetic rats, respectively, P < 0.05). In cardiac myocytes, diabetes-induced prolongation of cytosolic Ca(2+) transient clearance by 43% and decreased SR Ca(2+) load by 25% (P < 0.05); these parameters were partially improved after ALT-711 therapy. SERCA2a and RyR2 protein expression was significantly decreased in the myocardium of untreated diabetic rats (by 64 and 36% vs. controls, respectively, P < 0.05), but preserved in the treated diabetic group compared to controls. Collectively, our results suggest that, in a model of type 1 diabetes, AGE accumulation primarily impairs SR Ca(2+) reuptake in cardiac myocytes and that long-term treatment with an AGE cross-link breaker partially normalized SR Ca(2+) handling and improved diabetic cardiomyopathy. PMID- 22934045 TI - Oncogenic extracellular vesicles in brain tumor progression. AB - The brain is a frequent site of neoplastic growth, including both primary and metastatic tumors. The clinical intractability of many brain tumors and their distinct biology are implicitly linked to the unique microenvironment of the central nervous system (CNS) and cellular interactions within. Among the most intriguing forms of cellular interactions is that mediated by membrane-derived extracellular vesicles (EVs). Their biogenesis (vesiculation) and uptake by recipient cells serves as a unique mechanism of intercellular trafficking of complex biological messages including the exchange of molecules that cannot be released through classical secretory pathways, or that are prone to extracellular degradation. Tumor cells produce EVs containing molecular effectors of several cancer-related processes such as growth, invasion, drug resistance, angiogenesis, and coagulopathy. Notably, tumor-derived EVs (oncosomes) also contain oncogenic proteins, transcripts, DNA, and microRNA (miR). Uptake of this material may change properties of the recipient cells and impact the tumor microenvironment. Examples of transformation-related molecules found in the cargo of tumor-derived EVs include the oncogenic epidermal growth factor receptor (EGFRvIII), tumor suppressors (PTEN), and oncomirs (miR-520g). It is postulated that EVs circulating in blood or cerebrospinal fluid (CSF) of brain tumor patients may be used to decipher molecular features (mutations) of the underlying malignancy, reflect responses to therapy, or molecular subtypes of primary brain tumors [e.g., glioma or medulloblastoma (MB)]. It is possible that metastases to the brain may also emit EVs with clinically relevant oncogenic signatures. Thus, EVs emerge as a novel and functionally important vehicle of intercellular communication that can mediate multiple biological effects. In addition, they provide a unique platform to develop molecular biomarkers in brain malignancies. PMID- 22934046 TI - Hydrogen sulfide: role in ion channel and transporter modulation in the eye. AB - Hydrogen sulfide (H(2)S), a colorless gas with a characteristic smell of rotten eggs, has been portrayed for decades as a toxic environmental pollutant. Since evidence of its basal production in mammalian tissues a decade ago, H(2)S has attracted substantial interest as a potential inorganic gaseous mediator with biological importance in cellular functions. Current research suggests that, next to its counterparts nitric oxide and carbon monoxide, H(2)S is an important multifunctional signaling molecule with pivotal regulatory roles in various physiological and pathophysiological processes as diverse as learning and memory, modulation of synaptic activities, cell survival, inflammation, and maintenance of vascular tone in the central nervous and cardiovascular systems. In contrast, there are few reports of a regulatory role of H(2)S in the eye. Accumulating reports on the pharmacological role of H(2)S in ocular tissues indicate the existence of a functional trans-sulfuration pathway and a potential physiological role for H(2)S as a gaseous neuromodulator in the eye. Thus, understanding the role of H(2)S in vision-related processes is imperative to our expanding knowledge of this molecule as a gaseous mediator in ocular tissues. This review aims to provide a comprehensive and current understanding of the potential role of H(2)S as a signaling molecule in the eye. This objective is achieved by discussing the involvement of H(2)S in the regulation of (1) ion channels such as calcium (L-type, T-type, and intracellular stores), potassium (K(ATP) and small conductance channels) and chloride channels, (2) glutamate transporters such as EAAT1/GLAST and the L-cystine/glutamate antiporter. The role of H(2)S as an important mediator in cellular functions and physiological processes that are triggered by its interaction with ion channels/transporters in the eye will also be discussed. PMID- 22934049 TI - Estimation of cardiac output and peripheral resistance using square-wave approximated aortic flow signal. AB - This paper presents a model-based approach to estimation of cardiac output (CO) and total peripheral resistance (TPR). In the proposed approach, the response of cardiovascular system (CVS), described by the windkessel model, is tuned to the measurements of systolic, diastolic and mean arterial blood pressures (BP) so as to yield optimal individual- and time-specific system time constant that is used to estimate CO and TPR. Unique aspects of the proposed approach are that it approximates the aortic flow as a train of square waves and that it also assumes pressure-dependent arterial compliance, as opposed to the traditional windkessel model in which aortic flow is approximated as a train of impulses and constant arterial compliance is assumed. It was shown that the proposed model encompasses the standard windkessel model as a limiting case, and that it also yields more realistic BP waveform response than the standard windkessel model. The proposed approach has potential to outperform its standard counterpart by treating systolic, diastolic, and mean BP as independent features in estimating CO and TPR, rather than solely resorting to pulse pressure as in the case of the standard windkessel model. Experimental results from in-vivo data collected from a number of animal subjects supports the viability of the proposed approach in that it could achieve approximately 29% and 24% reduction in CO and TPR errors when compared with its standard counterpart. PMID- 22934048 TI - An extracellular mechanism that can explain the neurotoxic effects of alpha synuclein aggregates in the brain. AB - Neurodegenerative diseases, such as Parkinson's disease (PD), Alzheimer's disease (AD), and Dementia with Lewy bodies (DLB), display an accumulation of proteins including alpha-synuclein aggregates in cortical and subcortical regions of the brain. PD is a complex, progressive disease which involves damage of motor and cognitive brain regions, as well as autonomic and sensory areas. Since alpha synuclein is a neuronal cytosolic protein, it is assumed that pathogenic changes induced by alpha-synuclein aggregates occur only at the cytoplasmic level. However, recent studies have identified the presence of extracellular alpha synuclein, suggesting that the pathogenic action of this protein may also occur in the extracellular milieu through an unknown mechanism. One of the hypotheses is that extracellular alpha-synuclein aggregates or oligomers may directly disrupt the neuronal membrane by the formation of a pore reminiscent to the ones formed by beta-amyloid aggregates. Here, we will review some evidence that support this mechanism, analyzing the interactions of alpha-synuclein with components of the plasma membrane, the formation of pore/perforated structures, and the implications on ionic dyshomeostasis. Furthermore, we will also discuss how this mechanism can be integrated into a general phenomenon that may explain the synaptotoxicity and neurotoxicity observed in different neurodegenerative diseases. PMID- 22934050 TI - Integration of expression data in genome-scale metabolic network reconstructions. AB - With the advent of high-throughput technologies, the field of systems biology has amassed an abundance of "omics" data, quantifying thousands of cellular components across a variety of scales, ranging from mRNA transcript levels to metabolite quantities. Methods are needed to not only integrate this omics data but to also use this data to heighten the predictive capabilities of computational models. Several recent studies have successfully demonstrated how flux balance analysis (FBA), a constraint-based modeling approach, can be used to integrate transcriptomic data into genome-scale metabolic network reconstructions to generate predictive computational models. In this review, we summarize such FBA-based methods for integrating expression data into genome-scale metabolic network reconstructions, highlighting their advantages as well as their limitations. PMID- 22934047 TI - An introduction to murine models of atrial fibrillation. AB - Understanding the mechanism of re-entrant arrhythmias in the past 30 years has allowed the development of almost curative therapies for many rhythm disturbances. The complex, polymorphic arrhythmias of atrial fibrillation (AF) and sudden death are, unfortunately, not yet well understood, and hence still in need of adequate therapy. AF contributes markedly to morbidity and mortality in aging Western populations. In the past decade, many genetically altered murine models have been described and characterized. Here, we review genetically altered murine models of AF; powerful tools that will enable a better understanding of the mechanisms of AF and the assessment of novel therapeutic interventions. PMID- 22934051 TI - Sub-chronic exposure to second hand smoke induces airspace leukocyte infiltration and decreased lung elastance. AB - Exposure to second hand tobacco smoke is associated with the development and/or exacerbation of several different pulmonary diseases in humans. To better understand the possible effects of second hand smoke exposure in humans, we sub chronically (4 weeks) exposed mice to a mixture of mainstream and sidestream tobacco smoke at concentrations similar to second hand smoke exposure in humans. The inflammatory response to smoke exposures was assessed at the end of this time by enumeration of pulmonary leukocyte infiltration together with measurements of lung elastance and pathology. This response was measured in both healthy wild type (C57BL/6) mice as well as mouse mutants deficient in the expression of Arhgef1 (Arhgef1(-/-)) that display constitutive pulmonary inflammation and decreased lung elastance reminiscent of emphysema. The results from this study show that sub-chronic second hand smoke exposure leads to significantly increased numbers of airspace leukocytes in both healthy and mutant animals. While sub chronic cigarette smoke exposure is not sufficient to induce changes in lung architecture as measured by mean linear intercept, both groups exhibit a significant decrease in lung elastance. Together these data demonstrate that even sub-chronic exposure to second hand smoke is sufficient to induce pulmonary inflammation and decrease lung elastance in both healthy and diseased animals and in the absence of tissue destruction. PMID- 22934052 TI - RAGE and tobacco smoke: insights into modeling chronic obstructive pulmonary disease. AB - Chronic obstructive pulmonary disease (COPD) is a progressive condition characterized by chronic airway inflammation and airspace remodeling, leading to airflow limitation that is not completely reversible. Smoking is the leading risk factor for compromised lung function stemming from COPD pathogenesis. First- and second-hand cigarette smoke contain thousands of constituents, including several carcinogens and cytotoxic chemicals that orchestrate chronic lung inflammation and destructive alveolar remodeling. Receptors for advanced glycation end products (RAGE) are multi-ligand cell surface receptors primarily expressed by diverse lung cells. RAGE expression increases following cigarette smoke exposure and expression is elevated in the lungs of patients with COPD. RAGE is responsible in part for inducing pro-inflammatory signaling pathways that culminate in expression and secretion of several cytokines, chemokines, enzymes, and other mediators. In the current review, new transgenic mouse models that conditionally over-express RAGE in pulmonary epithelium are discussed. When RAGE is over-expressed throughout embryogenesis, apoptosis in the peripheral lung causes severe lung hypoplasia. Interestingly, apoptosis in RAGE transgenic mice occurs via conserved apoptotic pathways also known to function in advanced stages of COPD. RAGE over-expression in the adult lung models features of COPD including pronounced inflammation and loss of parenchymal tissue. Understanding the biological contributions of RAGE during cigarette smoke-induced inflammation may provide critically important insight into the pathology of COPD. PMID- 22934053 TI - Avalanche Analysis from Multielectrode Ensemble Recordings in Cat, Monkey, and Human Cerebral Cortex during Wakefulness and Sleep. AB - Self-organized critical states are found in many natural systems, from earthquakes to forest fires, they have also been observed in neural systems, particularly, in neuronal cultures. However, the presence of critical states in the awake brain remains controversial. Here, we compared avalanche analyses performed on different in vivo preparations during wakefulness, slow-wave sleep, and REM sleep, using high density electrode arrays in cat motor cortex (96 electrodes), monkey motor cortex and premotor cortex and human temporal cortex (96 electrodes) in epileptic patients. In neuronal avalanches defined from units (up to 160 single units), the size of avalanches never clearly scaled as power law, but rather scaled exponentially or displayed intermediate scaling. We also analyzed the dynamics of local field potentials (LFPs) and in particular LFP negative peaks (nLFPs) among the different electrodes (up to 96 sites in temporal cortex or up to 128 sites in adjacent motor and premotor cortices). In this case, the avalanches defined from nLFPs displayed power-law scaling in double logarithmic representations, as reported previously in monkey. However, avalanche defined as positive LFP (pLFP) peaks, which are less directly related to neuronal firing, also displayed apparent power-law scaling. Closer examination of this scaling using the more reliable cumulative distribution function (CDF) and other rigorous statistical measures, did not confirm power-law scaling. The same pattern was seen for cats, monkey, and human, as well as for different brain states of wakefulness and sleep. We also tested other alternative distributions. Multiple exponential fitting yielded optimal fits of the avalanche dynamics with bi-exponential distributions. Collectively, these results show no clear evidence for power-law scaling or self-organized critical states in the awake and sleeping brain of mammals, from cat to man. PMID- 22934055 TI - The role of the epithelial Na(+) channel (ENaC) in high AVP but low aldosterone states. AB - Due to the abundance of seminal discoveries establishing a strong causal relation between changes in aldosterone signaling, the activity of the epithelial Na(+) channel (ENaC) and blood pressure, the role of ENaC in health and disease is understood almost exclusively through the concept that this channel functions (in the distal nephron) as a key end-effector controlling renal sodium excretion during feedback regulation of blood pressure by the renin-angiotensin-aldosterone system (RAAS). Recent findings of aldosterone-independent stimulation of ENaC by vasopressin challenge the completeness of dogmatic understanding where ENaC serves solely as an end-effector of the RAAS important for control of sodium balance. Rather the consequences of activating ENaC in the distal nephron appear to depend on whether the channel is activated in the absence (by aldosterone) or presence [by vasopressin (AVP)] of simultaneous activation of aquaporin 2 water channels. Thus, a unifying paradigm has ENaC at the junction of two signaling systems that sometimes must compete: one controlling and responding to changes in sodium balance, perceived as mean arterial pressure, and the other water balance, perceived as plasma osmolality. PMID- 22934056 TI - Phenotyping maize for adaptation to drought. AB - The need of a better adaptation of crops to drought is an issue of increasing urgency. However, enhancing the tolerance of maize has, therefore, proved to be somewhat elusive in terms of plant breeding. In that context, proper phenotyping remains as one of the main factors limiting breeding advance. Topics covered by this review include the conceptual framework for identifying secondary traits associated with yield response to drought and how to measure these secondary traits in practice. PMID- 22934057 TI - Hemodialysis fatigue: just "simple" fatigue or a syndrome on its own right? PMID- 22934054 TI - The genetic pleiotropy of musculoskeletal aging. AB - Musculoskeletal aging is detrimental to multiple bodily functions and starts early, probably in the fourth decade of an individual's life. Sarcopenia is a health problem that is expected to only increase as a greater portion of the population lives longer; prevalence of the related musculoskeletal diseases is similarly expected to increase. Unraveling the biological and biomechanical associations and molecular mechanisms underlying these diseases represents a formidable challenge. There are two major problems making disentangling the biological complexity of musculoskeletal aging difficult: (a) it is a systemic, rather than "compartmental," problem, which should be approached accordingly, and (b) the aging per se is neither well defined nor reliably measurable. A unique challenge of studying any age-related condition is a need of distinguishing between the "norm" and "pathology," which are interwoven throughout the aging organism. We argue that detecting genes with pleiotropic functions in musculoskeletal aging is needed to provide insights into the potential biological mechanisms underlying inter-individual differences insusceptibility to the musculoskeletal diseases. However, exploring pleiotropic relationships among the system's components is challenging both methodologically and conceptually. We aimed to focus on genetic aspects of the cross-talk between muscle and its "neighboring" tissues and organs (tendon, bone, and cartilage), and to explore the role of genetics to find the new molecular links between skeletal muscle and other parts of the "musculoskeleton." Identification of significant genetic variants underlying the musculoskeletal system's aging is now possible more than ever due to the currently available advanced genomic technologies. In summary, a "holistic" genetic approach is needed to study the systems's normal functioning and the disease predisposition in order to improve musculoskeletal health. PMID- 22934058 TI - What kind of noise is brain noise: anomalous scaling behavior of the resting brain activity fluctuations. AB - The study of spontaneous fluctuations of brain activity, often referred as brain noise, is getting increasing attention in functional magnetic resonance imaging (fMRI) studies. Despite important efforts, much of the statistical properties of such fluctuations remain largely unknown. This work scrutinizes these fluctuations looking at specific statistical properties which are relevant to clarify its dynamical origins. Here, three statistical features which clearly differentiate brain data from naive expectations for random processes are uncovered: First, the variance of the fMRI mean signal as a function of the number of averaged voxels remains constant across a wide range of observed clusters sizes. Second, the anomalous behavior of the variance is originated by bursts of synchronized activity across regions, regardless of their widely different sizes. Finally, the correlation length (i.e., the length at which the correlation strength between two regions vanishes) as well as mutual information diverges with the cluster's size considered, such that arbitrarily large clusters exhibit the same collective dynamics than smaller ones. These three properties are known to be exclusive of complex systems exhibiting critical dynamics, where the spatio-temporal dynamics show these peculiar type of fluctuations. Thus, these findings are fully consistent with previous reports of brain critical dynamics, and are relevant for the interpretation of the role of fluctuations and variability in brain function in health and disease. PMID- 22934059 TI - Face cooling with mist water increases cerebral blood flow during exercise: effect of changes in facial skin blood flow. AB - Facial cooling (FC) increases cerebral blood flow (CBF) at rest and during exercise; however, the mechanism of this response remains unclear. The purpose of the present study was to test our hypothesis that FC causes facial vasoconstriction that diverts skin blood flow (SkBF(face)) toward the middle cerebral artery (MCA V(mean)) at rest and to a greater extent during exercise. Nine healthy young subjects (20 +/- 2 years) underwent 3 min of FC by fanning and spraying the face with a mist of cold water (~4 degrees C) at rest and during steady-state exercise [heart rate (HR) of 120 bpm]. We focused on the difference between the averaged data acquired from 1 min immediately before FC and last 1 min of FC. SkBF(face), MCA V(mean), and mean arterial blood pressure (MAP) were higher during exercise than at rest. As hypothesized, FC decreased SkBF(face) at rest (-32 +/- 4%) and to a greater extent during exercise (-64 +/- 10%, P = 0.012). Although MCA V(mean) was increased by FC (Rest, +1.4 +/- 0.5 cm/s; Exercise, +1.4 +/- 0.6 cm/s), the amount of the FC-evoked changes in MCA V(mean) at rest and during exercise differed among subjects. In addition, changes in MCA V(mean) with FC did not correlate with concomitant changes in SkBF(face) (r = 0.095, P = 0.709). MAP was also increased by FC (Rest, +6.2 +/- 1.4 mmHg; Exercise, +4.2 +/- 1.2 mmHg). These findings suggest that the FC-induced increase in CBF during exercise could not be explained only by change in SkBF(face). PMID- 22934061 TI - The influence of ontogenetic dietary fluctuations on zebrafish size and swimming performance. AB - Phenotypic flexibility is critical in determining fitness. As conditions change during ontogeny, continued responsiveness is necessary to meet the demands of the environment. Studies have shown that subsequent ontogenetic periods of development can interact with one another and shape developmental outcomes. The role genetic variation within populations plays in shaping these outcomes remains unclear. Four full-sib families of zebrafish Danio rerio were raised under for dietary regimes: high food rations for 60 days (HH), low food rations for 60 days (LL), high food rations for 30 days followed by low food rations for 30 (HL), and low food rations for 30 days followed by high food rations for 30 (LH). While the low ration diet significantly reduced body length at 30 days, diet was no longer a significant factor at day 60. Only family level variation influenced body length. Furthermore, there was significant family level variation in the manner in which swimming performance responded to fluctuating dietary conditions. Some families increased swimming performance in response to dietary change, while others did not. These results suggest that plastic responsiveness to subsequent environmental changes can be trait specific and vary significantly within populations. PMID- 22934060 TI - Nociceptors as chronic drivers of pain and hyperreflexia after spinal cord injury: an adaptive-maladaptive hyperfunctional state hypothesis. AB - Spinal cord injury (SCI) causes chronic peripheral sensitization of nociceptors and persistent generation of spontaneous action potentials (SA) in peripheral branches and the somata of hyperexcitable nociceptors within dorsal root ganglia (DRG). Here it is proposed that SCI triggers in numerous nociceptors a persistent hyperfunctional state (peripheral, synaptic, and somal) that originally evolved as an adaptive response to compensate for loss of sensory terminals after severe but survivable peripheral injury. In this hypothesis, nociceptor somata monitor the status of their own receptive field and the rest of the body by integrating signals received by their peripheral and central branches and the soma itself. A nociceptor switches into a potentially permanent hyperfunctional state when central neural, glial, and inflammatory signal combinations are detected that indicate extensive peripheral injury. Similar signal combinations are produced by SCI and disseminated widely to uninjured as well as injured nociceptors. This paper focuses on the uninjured nociceptors that are altered by SCI. Enhanced activity generated in below-level nociceptors promotes below-level central sensitization, somatic and autonomic hyperreflexia, and visceral dysfunction. If sufficient ascending fibers survive, enhanced activity in below-level nociceptors contributes to below-level pain. Nociceptor activity generated above the injury level contributes to at- and above-level sensitization and pain (evoked and spontaneous). Thus, SCI triggers a potent nociceptor state that may have been adaptive (from an evolutionary perspective) after severe peripheral injury but is maladaptive after SCI. Evidence that hyperfunctional nociceptors make large contributions to behavioral hypersensitivity after SCI suggests that nociceptor specific ion channels required for nociceptor SA and hypersensitivity offer promising targets for treating chronic pain and hyperreflexia after SCI. PMID- 22934063 TI - NFAT5 expression in bone marrow-derived cells enhances atherosclerosis and drives macrophage migration. AB - OBJECTIVE: We have previously shown that the transcription factor, nuclear factor of activated T-cells 5 (NFAT5), regulates vascular smooth muscle cell phenotypic modulation, but the role of NFAT5 in atherosclerosis is unknown. Our main objective was to determine if NFAT5 expression in bone marrow (BM)-derived cells altered atherosclerotic development and macrophage function. METHODS AND RESULTS: NFAT5(+/-)ApoE(-/-) mice were generated for in vivo atherosclerosis studies. Following high fat diet feeding, en face analysis of the thoracic aorta established that genome-wide NFAT5 haploinsufficiency reduced atherosclerotic lesion formation by 73%. BM transplant studies revealed that transplantation of NFAT5(+/-)ApoE(-/-) marrow into NFAT5(+/+)ApoE(-/-) mice resulted in a similar 86% reduction in lesion formation. In vitro functional analysis of BM-derived macrophages demonstrated that NFAT5 is required for macrophage migration, which is a key event in the propagation of atherosclerosis. CONCLUSION: We have identified NFAT5 in BM-derived cells as a positive regulator of atherosclerotic lesion formation and macrophage function in the vasculature. PMID- 22934062 TI - Reactive oxygen species-targeted therapeutic interventions for atrial fibrillation. AB - Atrial fibrillation (AF) is the most common arrhythmia that requires medical attention, and its incidence is increasing. Current ion channel blockade therapies and catheter ablation have significant limitations in treatment of AF, mainly because they do not address the underlying pathophysiology of the disease. Oxidative stress has been implicated as a major underlying pathology that promotes AF; however, conventional antioxidants have not shown impressive therapeutic effects. A more careful design of antioxidant therapies and better selection of patients likely are required to treat effectively AF with antioxidant agents. Current evidence suggest inhibition of prominent cardiac sources of reactive oxygen species (ROS) such as nicotinamide adenine dinucleotide phosphate (NADPH) oxidase and targeting subcellular compartments with the highest levels of ROS may prove to be effective therapies for AF. Increased serum markers of oxidative stress may be an important guide in selecting the AF patients who will most likely respond to antioxidant therapy. PMID- 22934064 TI - Arterial baroreflex control of muscle sympathetic nerve activity under orthostatic stress in humans. AB - The mechanisms by which blood pressure is maintained against the orthostatic stress caused by gravity's effect on the fluid distribution within the body are important issues in physiology, especially in humans who usually adopt an upright posture. Peripheral vasoconstriction and increased heart rate (HR) are major cardiovascular adjustments to orthostatic stress and comprise part of the reflex response elicited via the carotid sinus and aortic baroreceptors (arterial baroreflex: ABR) and cardiopulmonary stretch receptors (cardiopulmonary baroreflex). In a series of studies, we have been characterizing the ABR-mediated regulation of cardiovascular hemodynamics and muscle sympathetic nerve activity (MSNA) while applying orthostatic stress in humans. We have found that under orthostatic stress, dynamic carotid baroreflex responses are modulated as exemplified by the increases in the MSNA, blood pressure, and HR responses elicited by carotid baroreflex unloading and the shorter period of MSNA suppression, comparable reduction and faster recovery of mean arterial blood pressure (MAP) and greater HR response to carotid baroreflex stimulation. Our results also show that ABR-mediated beat-to-beat control over burst incidence, burst strength and total MSNA is progressively modulated as orthostatic stress is increased until induction of syncope, and that the sensitivity of ABR control over the aforementioned MSNA variables is substantially reduced during the development of syncope. We suggest that in humans, the modulation of ABR function under orthostatic stress may be one of the mechanisms by which blood pressure is maintained and orthostatic hypotension limited, and impairment of ABR control over sympathetic vasomotor activity leads to the severe hypotension associated with orthostatic syncope. PMID- 22934065 TI - Malaria in East African highlands during the past 30 years: impact of environmental changes. AB - East African highlands are one of the most populated regions in Africa. The population densities in the highlands ranged between 158 persons/km(2) in Ethiopia and 410 persons/km(2) in Rwanda. According to the United Nations Population Fund, the region has the world's highest population growth rate. These factors are likely behind the high rates of poverty among the populations. As there were no employment opportunities other than agricultural, this demographic pressure of poor populations have included in an extensive unprecedented land use and land cover changes such as modification of bushland, woodland, and grassland on hillsides to farmland and transformation of papyrus swamps in valley bottoms to dairy pastures and cropland and changing of fallows on hillsides from short or seasonal to longer or perennial. Areas harvested for food crops were therefore increased by more than 100% in most of the highlands. The lost of forest areas, mainly due to subsistence agriculture, between 1990 and 2010 ranged between 8000 ha in Rwanda and 2,838,000 ha in Ethiopia. These unmitigated environmental changes in the highlands led to rise temperature and optimizing the spread and survival of malaria vectors and development of malaria parasites. Malaria in highlands was initially governed by low ambient temperature, trend of malaria transmission was therefore increased and several epidemics were observed in late 1980s and early 2000s. Although, malaria is decreasing through intensified interventions since mid 2000s onwards, these environmental changes might expose population in the highlands of east Africa to an increase risk of malaria and its epidemic particularly if the current interventions are not sustained. PMID- 22934066 TI - Understanding Dupuytren's Disease Using Systems Biology: A Move Away from Reductionism. PMID- 22934068 TI - Insights into the beneficial effect of caloric/ dietary restriction for a healthy and prolonged life. AB - Over the last several years, new evidence has kept pouring in about the remarkable effect of caloric restriction (CR) on the conspicuous bedfellows- aging and cancer. Through the use of various animal models, it is now well established that by reducing calorie intake one can not only increase life span but, also, lower the risk of various age related diseases such as cancer. Cancer cells are believed to be more dependent on glycolysis for their energy requirements than normal cells and, therefore, can be easily targeted by alteration in the energy-metabolic pathways, a hallmark of CR. Apart from inhibiting the growth of transplantable tumors, CR has been also shown to inhibit the development of spontaneous, radiation, and chemically induced tumors. The question regarding the potentiality of the anti-tumor effect of CR in humans has been in part answered by the resistance of a cohort of women, who had suffered from anorexia in their early life, to breast cancer. However, human research on the beneficial effect of CR is still at an early stage and needs further validation. Though the complete mechanism of the anti-tumor effect of CR is far from clear, the plausible involvement of nutrient sensing pathways or IGF-1 pathways proposed for its anti-aging action cannot be overruled. In fact, cancer cell lines, mutant for proteins involved in IGF-1 pathways, failed to respond to CR. In addition, CR decreases the levels of many growth factors, anabolic hormones, inflammatory cytokines, and oxidative markers that are deregulated in several cancers. In this review, we discuss the anti-tumor effect of CR, describing experiments done in vitro in tumor models and in vivo in mouse models in which the tumor was induced by means of radiation or chemical exposure, expressing oncogenes or deleting tumor suppression genes. We also discuss the proposed mechanisms of CR anti-tumor action. Lastly, we argue the necessity of gene expression studies in cancerous versus normal cells upon CR. PMID- 22934067 TI - Application of in vitro bioaccessibility and bioavailability methods for calcium, carotenoids, folate, iron, magnesium, polyphenols, zinc, and vitamins B(6), B(12), D, and E. AB - A review of in vitro bioaccessibility and bioavailability methods for polyphenols and selected nutrients is presented. The review focuses on in vitro solubility, dialyzability, the dynamic gastrointestinal model (TIM)TM, and Caco-2 cell models, the latter primarily for uptake and transport, and a discussion of how these methods have been applied to generate data for a range of nutrients, carotenoids, and polyphenols. Recommendations are given regarding which methods are most justified for answering bioaccessibility or bioavailability related questions for specific nutrients. The need for more validation studies in which in vivo results are compared to in vitro results is also discussed. PMID- 22934070 TI - Functional enhancement of chitosan and nanoparticles in cell culture, tissue engineering, and pharmaceutical applications. AB - As a biomaterial, chitosan has been widely used in tissue engineering, wound healing, drug delivery, and other biomedical applications. It can be formulated in a variety of forms, such as powder, film, sphere, gel, and fiber. These features make chitosan an almost ideal biomaterial in cell culture applications, and cell cultures arguably constitute the most practical way to evaluate biocompatibility and biotoxicity. The advantages of cell cultures are that they can be performed under totally controlled environments, allow high throughput functional screening, and are less costly, as compared to other assessment methods. Chitosan can also be modified into multilayer composite by combining with other polymers and moieties to alter the properties of chitosan for particular biomedical applications. This review briefly depicts and discusses applications of chitosan and nanoparticles in cell culture, in particular, the effects of chitosan and nanoparticles on cell adhesion, cell survival, and the underlying molecular mechanisms: both stimulatory and inhibitory influences are discussed. Our aim is to update the current status of how nanoparticles can be utilized to modify the properties of chitosan to advance the art of tissue engineering by using cell cultures. PMID- 22934071 TI - Construction of calcium release sites in cardiac myocytes. AB - Local character of calcium release in cardiac myocytes, as defined by confocal recordings of calcium sparks, implies independent activation of individual calcium release sites based on ryanodine receptor (RyR) channel recruitment. We constructed virtual calcium release sites (vCRSs) composed of a variable number of RyR channels distributed in clusters in accordance with the experimentally observed cluster size distribution. The vCRSs consisted either of a single virtual calcium release unit (vCRU), in which all clusters shared a common dyadic space, or of multiple virtual calcium release units (CRUs) containing one cluster each and having separate dyadic spaces. We explored the stochastic behavior of vCRSs to understand the activation and recruitment of RyRs during calcium sparks. RyRs were represented by the published allosteric gating model that included regulation by cytosolic Ca(2+) and Mg(2+). The interaction of Mg(2+) with the RyR Ca(2+)-binding sites and the refractory period of vCRSs were optimized to accord with the experimentally observed calcium dependence of calcium spark frequency. The Mg(2+)-binding parameters of RyRs that provided the best description of spark frequency depended on the number of RyRs assembled in the vCRSs. Adequate inhibitory effect of Mg(2+) on the calcium dependence of RyR open probability was achieved if the vCRSs contained at least three clusters. For the distribution of the number of open RyRs in evoked calcium sparks to correspond to the experimentally observed distribution of spark calcium release fluxes, at least three clusters had to share a common virtual CRU, in which ~3 RyRs open to form an average spark. These results reconcile the small cluster size and stochastic placement of RyRs in the release sites with the estimates of the amount of RyR protein, volume density of calcium release sites, and the size of calcium release sites in rat cardiac myocytes. PMID- 22934069 TI - Alzheimer's disease models and functional genomics-How many needles are there in the haystack? AB - Alzheimer's disease (AD) and frontotemporal lobar degeneration (FTLD) are complex human brain disorders that affect an increasing number of people worldwide. With the identification first of the proteins that aggregate in AD and FTLD brains and subsequently of pathogenic gene mutations that cause their formation in the familial cases, the foundation was laid for the generation of animal models. These recapitulate essential aspects of the human conditions; expression of mutant forms of the amyloid-beta protein-encoding APP gene in mice reproduces amyloid-beta (Abeta) plaque formation in AD, while that of mutant forms of the tau-encoding microtubule-associated protein tau (MAPT) gene reproduces tau containing neurofibrillary tangle formation, a lesion that is also prevalent in FTLD-Tau. The mouse models have been complemented by those in lower species such as C. elegans or Drosophila, highlighting the crucial role for Abeta and tau in human neurodegenerative disease. In this review, we will introduce selected AD/FTLD models and discuss how they were instrumental, by identifying deregulated mRNAs, miRNAs and proteins, in dissecting pathogenic mechanisms in neurodegenerative disease. We will discuss some recent examples, which includes miRNA species that are specifically deregulated by Abeta, mitochondrial proteins that are targets of both Abeta and tau, and the nuclear splicing factor SFPQ that accumulates in the cytoplasm in a tau-dependent manner. These examples illustrate how a functional genomics approach followed by a careful validation in experimental models and human tissue leads to a deeper understanding of the pathogenesis of AD and FTLD and ultimately, may help in finding a cure. PMID- 22934073 TI - Vascular aging: facts and factors. PMID- 22934074 TI - Bridging the phenotypic and genetic data useful for integrated breeding through a data annotation using the Crop Ontology developed by the crop communities of practice. AB - The Crop Ontology (CO) of the Generation Challenge Program (GCP) (http://cropontology.org/) is developed for the Integrated Breeding Platform (IBP) (http://www.integratedbreeding.net/) by several centers of The Consultative Group on International Agricultural Research (CGIAR): bioversity, CIMMYT, CIP, ICRISAT, IITA, and IRRI. Integrated breeding necessitates that breeders access genotypic and phenotypic data related to a given trait. The CO provides validated trait names used by the crop communities of practice (CoP) for harmonizing the annotation of phenotypic and genotypic data and thus supporting data accessibility and discovery through web queries. The trait information is completed by the description of the measurement methods and scales, and images. The trait dictionaries used to produce the Integrated Breeding (IB) fieldbooks are synchronized with the CO terms for an automatic annotation of the phenotypic data measured in the field. The IB fieldbook provides breeders with direct access to the CO to get additional descriptive information on the traits. Ontologies and trait dictionaries are online for cassava, chickpea, common bean, groundnut, maize, Musa, potato, rice, sorghum, and wheat. Online curation and annotation tools facilitate (http://cropontology.org) direct maintenance of the trait information and production of trait dictionaries by the crop communities. An important feature is the cross referencing of CO terms with the Crop database trait ID and with their synonyms in Plant Ontology (PO) and Trait Ontology (TO). Web links between cross referenced terms in CO provide online access to data annotated with similar ontological terms, particularly the genetic data in Gramene (University of Cornell) or the evaluation and climatic data in the Global Repository of evaluation trials of the Climate Change, Agriculture and Food Security programme (CCAFS). Cross-referencing and annotation will be further applied in the IBP. PMID- 22934075 TI - Para-Cycling Performance was Rather Limited by Physiological than Functional Factors. PMID- 22934072 TI - TRP channels: sensors and transducers of gasotransmitter signals. AB - The transient receptor potential (trp) gene superfamily encodes cation channels that act as multimodal sensors for a wide variety of stimuli from outside and inside the cell. Upon sensing, they transduce electrical and Ca(2+) signals via their cation channel activities. These functional features of TRP channels allow the body to react and adapt to different forms of environmental changes. Indeed, members of one class of TRP channels have emerged as sensors of gaseous messenger molecules that control various cellular processes. Nitric oxide (NO), a vasoactive gaseous molecule, regulates TRP channels directly via cysteine (Cys) S nitrosylation or indirectly via cyclic GMP (cGMP)/protein kinase G (PKG) dependent phosphorylation. Recent studies have revealed that changes in the availability of molecular oxygen (O(2)) also control the activation of TRP channels. Anoxia induced by O(2)-glucose deprivation and severe hypoxia (1% O(2)) activates TRPM7 and TRPC6, respectively, whereas TRPA1 has recently been identified as a novel sensor of hyperoxia and mild hypoxia (15% O(2)) in vagal and sensory neurons. TRPA1 also detects other gaseous molecules such as hydrogen sulfide (H(2)S) and carbon dioxide (CO(2)). In this review, we focus on how signaling by gaseous molecules is sensed and integrated by TRP channels. PMID- 22934076 TI - Quantitative and qualitative analyses of human salivary NEFA with gas chromatography and mass spectrometry. AB - Salivary non-esterified fatty acids (NEFA) are proposed to play a role in oral health, oral fat detection, and they may hold diagnostic and prognostic potential. Yet, little is known about the array and concentrations of NEFA in saliva. The aim of the study was to conduct qualitative and quantitative analyses of salivary NEFA in healthy humans and to present a new, efficient protocol to perform such analyses. Resting saliva samples from fifteen participants were collected. The salivary lipids were extracted using a modified Folch extraction. The NEFA in the extracted lipids were selectively subjected to pentafluorobenzyl bromide (PFB) derivatization and qualitatively and quantitatively analyzed using gas chromatography-mass spectrometry (GC-MS). A total of 16 NEFA were identified in resting saliva. The four major NEFA were palmitic, linoleic, oleic, and stearic acids. Their concentrations ranged from 2 to 9 MUM. This is the first study to characterize individual human salivary NEFA and their respective concentrations. The method used in the study is sensitive, precise, and accurate. It is specific to fatty acids in non-esterified form and hence enables analysis of NEFA without their separation from other lipid classes. Thus, it saves time, reagents and prevents loss of sample. These properties make it suitable for large scale analysis of salivary NEFA. PMID- 22934077 TI - Effects of gabapentin on muscle spasticity and both induced as well as spontaneous autonomic dysreflexia after complete spinal cord injury. AB - We recently reported that the neuropathic pain medication, gabapentin (GBP; Neurontin), significantly attenuated both noxious colorectal distension (CRD) induced autonomic dysreflexia (AD) and tail pinch-induced spasticity compared to saline-treated cohorts 2-3 weeks after complete high thoracic (T4) spinal cord injury (SCI). Here we employed long-term blood pressure telemetry to test, firstly, the efficacy of daily versus acute GBP treatment in modulating AD and tail spasticity in response to noxious stimuli at 2 and 3 weeks post-injury. Secondly, we determined whether daily GBP alters baseline cardiovascular parameters, as well as spontaneous AD events detected using a novel algorithm based on blood pressure telemetry data. At both 14 and 21 days after SCI, irrespective of daily treatment, acute GBP given 1 h prior to stimulus significantly attenuated CRD-induced AD and pinch-evoked tail spasticity; conversely, acute saline had no such effects. Moreover, daily GBP did not alter 24 h mean arterial pressure (MAP) or heart rate (HR) values compared to saline treatment, nor did it reduce the incidence of spontaneous AD events compared to saline over the three week assessment period. Power spectral density (PSD) analysis of the MAP signals demonstrated relative power losses in mid frequency ranges (0.2-0.8 Hz) for all injured animals relative to low frequency MAP power (0.02-0.08 Hz). However, there was no significant difference between groups over time post-injury; hence, GBP had no effect on the persistent loss of MAP fluctuations in the mid frequency range after injury. In summary, the mechanism(s) by which acute GBP treatment mitigate aberrant somatosensory and cardiophysiological responses to noxious stimuli after SCI remain unclear. Nevertheless, with further refinements in defining the dynamics associated with AD events, such as eliminating requisite concomitant bradycardia, the objective repeatability of automatic detection of hypertensive crises provides a potentially useful tool for assessing autonomic function pre- and post-SCI, in conjunction with experimental pharmacotherapeutics for neuropathic pain, such as GBP. PMID- 22934078 TI - Plasticity in ascending long propriospinal and descending supraspinal pathways in chronic cervical spinal cord injured rats. AB - The high clinical relevance of models of incomplete cervical spinal cord injury (SCI) creates a need to address the spontaneous neuroplasticity that underlies changes in functional activity that occur over time after SCI. There is accumulating evidence supporting long projecting propriospinal neurons as suitable targets for therapeutic intervention after SCI, but focus has remained primarily oriented toward study of descending pathways. Long ascending axons from propriospinal neurons at lower thoracic and lumbar levels that form inter enlargement pathways are involved in forelimb-hindlimb coordination during locomotion and are capable of modulating cervical motor output. We used non invasive magnetic stimulation to assess how a unilateral cervical (C5) spinal contusion might affect transmission in intact, long ascending propriospinal pathways, and influence spinal cord plasticity. Our results show that transmission is facilitated in this pathway on the ipsilesional side as early as 1 week post-SCI. We also probed for descending magnetic motor evoked potentials (MMEPs) and found them absent or greatly reduced on the ipsilesional side as expected. The frequency-dependent depression (FDD) of the H-reflex recorded from the forelimb triceps brachii was bilaterally decreased although H(max)/M(max) was increased only on the ipsilesional side. Behaviorally, stepping recovered, but there were deficits in forelimb-hindlimb coordination as detected by BBB and CatWalk measures. Importantly, epicenter sparing correlated to the amplitude of the MMEPs and locomotor recovery but it was not significantly associated with the inter-enlargement or segmental H-reflex. In summary, our results indicate that complex plasticity occurs after a C5 hemicontusion injury, leading to differential changes in ascending vs. descending pathways, ipsi- vs. contralesional sides even though the lesion was unilateral as well as cervical vs. lumbar local spinal networks. PMID- 22934079 TI - Pressure overload-induced mild cardiac hypertrophy reduces left ventricular transmural differences in mitochondrial respiratory chain activity and increases oxidative stress. AB - OBJECTIVE: Increased mechanical stress and contractility characterizes normal left ventricular (LV) subendocardium (Endo) but whether Endo mitochondrial respiratory chain complex activities is reduced as compared to subepicardium (Epi) and whether pressure overload-induced LV hypertrophy (LVH) might modulate transmural gradients through increased reactive oxygen species (ROS) production is unknown. METHODS: LVH was induced by 6 weeks abdominal aortic banding and cardiac structure and function were determined with echocardiography and catheterization in sham-operated and LVH rats (n = 10 for each group). Mitochondrial respiration rates, coupling, content and ROS production were measured in LV Endo and Epi, using saponin-permeabilized fibers, Amplex Red fluorescence and citrate synthase activity. RESULTS: In sham, a transmural respiratory gradient was observed with decreases in endo maximal oxidative capacity (-36.7%, P < 0.01) and complex IV activity (-57.4%, P < 0.05). Mitochondrial hydrogen peroxide (H(2)O(2)) production was similar in both LV layers. Aortic banding induced mild LVH (+31.7% LV mass), associated with normal LV fractional shortening and end diastolic pressure. LVH reduced maximal oxidative capacity (-23.6 and -33.3%), increased mitochondrial H(2)O(2) production (+86.9 and +73.1%), free radical leak (+27.2% and +36.3%) and citrate synthase activity (+27.2% and +36.3%) in Endo and Epi, respectively. Transmural mitochondrial respiratory chain complex IV activity was reduced in LVH (-57.4 vs. -12.2%; P = 0.02). CONCLUSIONS: Endo mitochondrial respiratory chain complexes activities are reduced compared to LV Epi. Mild LVH impairs mitochondrial oxidative capacity, increases oxidative stress and reduces transmural complex IV activity. Further studies will be helpful to determine whether reduced LV transmural gradient in mitochondrial respiration might be a new marker of a transition from uncomplicated toward complicated LVH. PMID- 22934080 TI - Re-visiting the embryogenesis of the human lower lip: an overlooked paradigm. AB - The rare opportunity to study a human fetus showing bilateral clefting of the lower lip along with other associated anomalies resembling those of the equally rare Pena-Shokeir phenotype prompts this report. The scarcity of reports on bilateral clefts of the lower lip has strengthened the conventional understanding or, perhaps even dogma that the lower lip and jaw develop from the progressive midline merging of just two mandibular prominences in the embryo. On the basis of observations stemming from this case report, it is proposed that yet another developmental event or process (in addition to the midline merging of the mandibular prominences) may be operable in the normal morphogenesis of the lower lip and anterior mandibular region. The bilateral paramedian clefting observed provides evidence that another distinct developmental region, a small medial process complements mandibular morphogenesis. PMID- 22934081 TI - Extrasynaptic glutamate receptor activation as cellular bases for dynamic range compression in pyramidal neurons. AB - Repetitive synaptic stimulation overcomes the ability of astrocytic processes to clear glutamate from the extracellular space, allowing some dendritic segments to become submerged in a pool of glutamate, for a brief period of time. This dynamic arrangement activates extrasynaptic NMDA receptors located on dendritic shafts. We used voltage-sensitive and calcium-sensitive dyes to probe dendritic function in this glutamate-rich location. An excess of glutamate in the extrasynaptic space was achieved either by repetitive synaptic stimulation or by glutamate iontophoresis onto the dendrites of pyramidal neurons. Two successive activations of synaptic inputs produced a typical NMDA spike, whereas five successive synaptic inputs produced characteristic plateau potentials, reminiscent of cortical UP states. While NMDA spikes were coupled with brief calcium transients highly restricted to the glutamate input site, the dendritic plateau potentials were accompanied by calcium influx along the entire dendritic branch. Once initiated, the glutamate-mediated dendritic plateau potentials could not be interrupted by negative voltage pulses. Activation of extrasynaptic NMDA receptors in cellular compartments void of spines is sufficient to initiate and support plateau potentials. The only requirement for sustained depolarizing events is a surplus of free glutamate near a group of extrasynaptic receptors. Highly non-linear dendritic spikes (plateau potentials) are summed in a highly sublinear fashion at the soma, revealing the cellular bases of signal compression in cortical circuits. Extrasynaptic NMDA receptors provide pyramidal neurons with a function analogous to a dynamic range compression in audio engineering. They limit or reduce the volume of "loud sounds" (i.e., strong glutamatergic inputs) and amplify "quiet sounds" (i.e., glutamatergic inputs that barely cross the dendritic threshold for local spike initiation). Our data also explain why consecutive cortical UP states have uniform amplitudes in a given neuron. PMID- 22934083 TI - Period2 gene mutant mice show compromised insulin-mediated endothelial nitric oxide release and altered glucose homeostasis. AB - Period2 (Per2) is an important component of the circadian clock. Mutation of this gene is associated with vascular endothelial dysfunction and altered glucose metabolism. The aim of this study is to further characterize whole body glucose homeostasis and endothelial nitric oxide (NO) production in response to insulin in the mPer2(Brdm1) mice. We show that mPer2(Brdm1) mice exhibit compromised insulin receptor activation and Akt signaling in various tissues including liver, fat, heart, and aortas with a tissue-specific heterogeneous diurnal pattern, and decreased insulin-stimulated NO release in the aortas in both active and inactive phases of the animals. As compared to wild type (WT) mice, the mPer2(Brdm1) mice reveal hyperinsulinemia, hypoglycemia with lower fasting hepatic glycogen content and glycogen synthase level, no difference in glucose tolerance and insulin tolerance. The mPer2(Brdm1) mice do not show increased predisposition to obesity either on normal chow or high fat diet compared to WT controls. Thus, mice with Per2 gene mutation show altered glucose homeostasis and compromised insulin stimulated NO release, independently of obesity. PMID- 22934082 TI - Oxidative stress in the brain causes hypertension via sympathoexcitation. AB - Activation of the sympathetic nervous system (SNS) has an important role in the pathogenesis of hypertension, and is determined by the brain. Previous many studies have demonstrated that oxidative stress, mainly produced by angiotensin II type 1 (AT(1)) receptor and nicotinamide adenine dinucleotide phosphate (NAD (P) H) oxidase, in the autonomic brain regions was involved in the activation of the SNS of hypertension. In this concept, we have investigated the role of oxidative stress in the rostral ventrolateral medulla (RVLM), which is known as the cardiovascular center in the brainstem, in the activation of the SNS, and demonstrated that AT(1) receptor and NAD (P) H oxidase-induced oxidative stress in the RVLM causes sympathoexcitation in hypertensive rats. The mechanisms in which brain oxidative stress causes sympathoexcitation have been investigated, such as the interactions with nitric oxide (NO), effects on the signal transduction, or inflammations. Interestingly, the environmental factors of high salt intake and high calorie diet may also increase the oxidative stress in the brain, particularly in the RVLM, thereby activating the central sympathetic outflow and increasing the risk of hypertension. Furthermore, several orally administered AT(1) receptor blockers have been found to cause sympathoinhibition via reduction of oxidative stress through the inhibition of central AT(1) receptor. In conclusion, we must consider that AT(1) receptor and the related oxidative stress production in the brain cause the activation of SNS in hypertension, and that AT(1) receptor in the brain could be novel therapeutic target of the treatments for hypertension. PMID- 22934084 TI - Pravastatin-induced improvement in coronary reactivity and circulating ATP and ADP levels in young adults with type 1 diabetes. AB - AIMS: Extracellular ATP and ADP regulate diverse inflammatory, prothrombotic and vasoactive responses in the vasculature. Statins have been shown to modulate their signaling pathways in vitro. We hypothesized that altered intravascular nucleotide turnover modulates vasodilation in patients with type 1 diabetes (T1DM), and this can be partly restored with pravastatin therapy. METHODS: In this randomized double blind study, plasma ATP and ADP levels and echocardiography-derived coronary flow velocity response to cold pressor test (CPT) were concurrently assessed in 42 normocholesterolemic patients with T1DM (age 30 +/- 6 years, LDL cholesterol 2.5 +/- 0.6 mmol/L) before and after four month treatment with pravastatin 40 mg/day or placebo (n = 22 and n = 20, respectively), and in 41 healthy control subjects. RESULTS: Compared to controls, T1DM patients had significantly higher concentrations of ATP (p < 0.01) and ADP (p < 0.01) and these levels were partly restored after treatment with pravastatin (p = 0.002 and p = 0.007, respectively), but not after placebo (p = 0.06 and p = 0.14, respectively). Coronary flow velocity acceleration was significantly lower in T1DM patients compared to control subjects, and it increased from pre- to post intervention in the pravastatin (p = 0.02), but not in placebo group (p = 0.15). CONCLUSIONS: Pravastatin treatment significantly reduces circulating ATP and ADP levels of T1DM patients, and concurrently improves coronary flow response to CPT. This study provides a novel insight in purinergic mechanisms involved in pleiotropic effects of pravastatin. PMID- 22934086 TI - The role of association in early word-learning. AB - Word-learning likely involves a multiplicity of components, some domain-general, others domain-specific. Against the background of recent studies that suggest that word-learning is domain-specific, we investigated the associative component of word-learning. Seven- and 14-month-old infants viewed a pair of events in which a monkey or a truck moved back and forth, accompanied by a sung syllable or a tone, matched for pitch. Following habituation, infants were presented with displays in which the visual-auditory pairings were preserved or switched, and looked longer at the "switch" events when exposure time was sufficient to learn the intermodal association. At 7 months, performance on speech and tones conditions was statistically identical; at 14 months, infants had begun to favor speech. Thus, the associative component of word-learning does not appear (in contrast to rule-learning, Marcus et al., 2007) to initially privilege speech. PMID- 22934085 TI - Social communication and theory of mind in boys with autism and fragile x syndrome. AB - Impairments in the social use of language, or pragmatics, constitute a core characteristic of autism. Problems with pragmatic language have also been documented in fragile X syndrome (FXS), a monogenic condition that is the most common known genetic cause of autism. Evidence suggests that social cognitive ability, or theory of mind, may also be impaired in both conditions, and in autism, may importantly relate to pragmatic language ability. Given the substantial overlap observed in autism and FXS, this study aimed to better define those social-communicative phenotypes that overlap in these two conditions by comparing pragmatic language ability and theory of mind in children with idiopathic autism and children with FXS, with and without autism, as well as children with Down syndrome and typically developing controls. We further examined correlations between these cognitive-behavioral phenotypes and molecular genetic variation related to the Fragile X Mental Retardation-1 gene (FMR1) in the FXS group. Results indicated that children with idiopathic autism and those with FXS and autism performed comparably on direct-assessment measures of pragmatic language and theory of mind, whereas those with FXS only did not differ from controls. Theory of mind was related to pragmatic language ability in all groups. Pragmatic language and theory of mind also correlated with genetic variation at the FMR1 locus (Cytosine-Guanine-Guanine repeats and percent methylation). These results point toward substantial overlap in the social and language phenotypes in autism and FXS and suggest a molecular genetic basis to these phenotypic profiles. PMID- 22934087 TI - The time course of contextual effects on visual word recognition. AB - Sentence comprehension depends on continuous prediction of upcoming words. However, when and how contextual information affects the bottom-up streams of visual word recognition is unknown. This study examined the effects of word frequency and contextual predictability (cloze probability of a target word embedded in the sentence) on N1, P200, and N400 components, which are related to various cognitive operations in early visual processing, perceptual decoding, and semantic processing. The data exhibited a significant interaction between predictability and frequency at the anterior N1 component. The predictability effect, in which the low predictability words elicited a more negative N1 than high predictability words, was only observed when reading a high frequency word. A significant predictability effect occurred during the P200 time window, in which the low predictability words elicited a less positive P200 than high predictability words. There is also a significant predictability effect on the N400 component; low predictability words elicited a greater N400 than high predictability words, although this effect did not interact with frequency. The temporal dynamics of the manner in which contextual information affects the visual word recognition is discussed. These findings support the interactive account, suggesting that contextual information facilitates visual-feature and orthographic processing in the early stage of visual word processing and semantic integration in the later stage. PMID- 22934088 TI - Improving research of children using a rights-based approach: a case study of some psychological research about socioeconomic status. PMID- 22934089 TI - Neural mechanisms of attentional control differentiate trait and state negative affect. AB - The present research examined the hypothesis that cognitive processes are modulated differentially by trait and state negative affect (NA). Brain activation associated with trait and state NA was measured by fMRI during an attentional control task, the emotion-word Stroop. Performance on the task was disrupted only by state NA. Trait NA was associated with reduced activity in several regions, including a prefrontal area that has been shown to be involved in top-down, goal-directed attentional control. In contrast, state NA was associated with increased activity in several regions, including a prefrontal region that has been shown to be involved in stimulus-driven aspects of attentional control. Results suggest that NA has a significant impact on cognition, and that state and trait NA disrupt attentional control in distinct ways. PMID- 22934090 TI - The Involvement of TRP Channels in Bone Homeostasis. AB - Calcium and bone homeostasis are intimately related. On the one hand, bone relies on a sufficient supply of calcium to maintain its structural and mechanical properties and thus largely depends on calcium absorption in the intestine and calcium reabsorption in the kidney. On the other hand, bone serves as a calcium reserve from which calcium is mobilized to maintain normal calcium levels in blood. A negative external calcium balance will therefore at all times impair skeletal integrity. In addition to the external calcium balance, skeletal homeostasis also depends on the proper differentiation and functioning of bone cells, which relies for a large part on intracellular Ca(2+) signaling. Members of the transient receptor potential (TRP) family of ion channels affect skeletal homeostasis by mediating processes involved in the extracellular as well as intracellular Ca(2+) balance, including intestinal calcium absorption (TRPV6), renal calcium reabsorption (TRPV5), and differentiation of osteoclasts (TRPV1, TRPV2, TRPV4, TRPV5), chondrocytes (TRPV4), and possibly osteoblasts (TRPV1). In this review, we will give a brief overview of the systemic calcium homeostasis and the intracellular Ca(2+) signaling in bone cells with special focus on the TRP channels involved in these processes. PMID- 22934091 TI - Dynamics of bacterial communities in two unpolluted soils after spiking with phenanthrene: soil type specific and common responders. AB - Considering their key role for ecosystem processes, it is important to understand the response of microbial communities in unpolluted soils to pollution with polycyclic aromatic hydrocarbons (PAH). Phenanthrene, a model compound for PAH, was spiked to a Cambisol and a Luvisol soil. Total community DNA from phenanthrene-spiked and control soils collected on days 0, 21, and 63 were analyzed based on PCR-amplified 16S rRNA gene fragments. Denaturing gradient gel electrophoresis (DGGE) fingerprints of bacterial communities increasingly deviated with time between spiked and control soils. In taxon specific DGGE, significant responses of Alphaproteobacteria and Actinobacteria became only detectable after 63 days, while significant effects on Betaproteobacteria were detectable in both soils after 21 days. Comparison of the taxonomic distribution of bacteria in spiked and control soils on day 63 as revealed by pyrosequencing indicated soil type specific negative effects of phenanthrene on several taxa, many of them belonging to the Gamma-, Beta-, or Deltaproteobacteria. Bacterial richness and evenness decreased in spiked soils. Despite the significant differences in the bacterial community structure between both soils on day 0, similar genera increased in relative abundance after PAH spiking, especially Sphingomonas and Polaromonas. However, this did not result in an increased overall similarity of the bacterial communities in both soils. PMID- 22934092 TI - Genomic analysis indicates the presence of an asymmetric bilayer outer membrane in planctomycetes and verrucomicrobia. AB - Bacteria of the phylum Planctomycetes are of special interest for the study of compartmental cellular organization. Members of this phylum share a very unusual prokaryotic cell plan, featuring several membrane-bound compartments. Recently, it was shown that this cellular organization might extend to certain members of the phylum Verrucomicrobia. The Planctomycete cell plan has been defined as featuring a proteinaceous cell wall, a cytoplasmic membrane surrounding the paryphoplasm, and an intracytoplasmic membrane defining the riboplasm. So far it was presumed that Planctomycetes did not have an asymmetric bilayer outer membrane as observed in Gram-negative bacteria. However, recent work on outer membrane biogenesis has provided several marker genes in the outer membrane protein (OMP) assembly and the lipopolysaccharide (LPS) insertion complexes. Additionally, advances in computational prediction of OMPs provided new tools to perform more accurate genomic screening for such proteins. Here we searched all 22 Planctomycetes and Verrucomicrobia genomes available in GenBank, plus the recently published genome of "Candidatus Scalindua profunda," for markers of outer membrane biogenesis and OMPs. We were able to identify the key components of LPS insertion, OMP assembly and at least eight OMPs in all genomes tested. Additionally, we have analyzed the transcriptome and proteome data of the Planctomycetes "Candidatus Kuenenia stuttgartiensis" and "Ca. S. profunda" and could confirm high expression of several predicted OMPs, including the biomarkers of outer membrane biogenesis. These analyses provide a strong indication that an asymmetrical outer membrane may be present in bacteria of both phyla. However, previous experiments have made obvious that the cell envelope of Planctomycetes is clearly divergent from both the Gram-negative and Gram-positive cell types. Thus, the functional implications of the presence of an outer membrane for the Planctomycete cell plan and compartmentalization are discussed and a revised model including an outer membrane is proposed. Although this model agrees with most experimental data, we do note that the presence, location, and role of an outer membrane within the Planctomycetes and Verrucomicrobia awaits further experimental validation. PMID- 22934093 TI - Comparative genomics of two independently enriched "candidatus kuenenia stuttgartiensis" anammox bacteria. AB - Bacteria capable of anaerobic oxidation of ammonium (anammox) form a deep branching clade within the Planctomycetes. Although the core metabolic pathway of anammox bacteria is largely resolved, many questions still remain. Data mining of the (meta) genomes of anammox bacteria is a powerful method to address these questions or identify targets for further study. The availability of high quality reference data greatly aids such analysis. Currently, only a single "near complete" (~98%) reference genome of an anammox bacterium is available; that of model organism "Candidatus Kuenenia stuttgartiensis." Here we present a comparative genomic analysis of two "Ca. K. stuttgartiensis" anammox bacteria that were independently enriched. The two anammox bacteria used are "Ca. K. stuttgartiensis" RU1, which was originally sequenced for the reference genome in 2002 and "Ca. K. stuttgartiensis" CH1, independently enriched from a Chinese wastewater treatment plant. The two different "Ca. Kuenenia" bacteria have a very high sequence identity (>99% at nucleotide level) over the entire genome, but 31 genomic regions (average size 11 kb) were absent from strain CH1 and 220 kb of sequence was unique to the CH1 assembly. The high sequence homology between these two bacteria indicates that mobile genetic elements are the main source of variation between these geographically widely separated strains. Comparative analysis of the RU1 and CH1 assemblies led to the identification of 49 genes absent from the reference genome. These include a leucyl-tRNA-synthase, the absence of which led to the estimation of the 98% completeness of the reference genome. Finally, a set of 244 genes was present in the reference genome, but absent in the RU1 and CH1 assemblies. These could represent either identical gene duplicates or assembly errors in the published genome. We are confident that this analysis has further improved the most complete available high quality reference genome of an anammox bacterium and will aid further studies on this globally important group of organisms. PMID- 22934095 TI - Cytokine-neuroantigen fusion proteins as a new class of tolerogenic, therapeutic vaccines for treatment of inflammatory demyelinating disease in rodent models of multiple sclerosis. AB - Myelin-specific induction of tolerance represents a promising means to modify the course of autoimmune inflammatory demyelinating diseases such as multiple sclerosis (MS). Our laboratory has focused on a novel preclinical strategy for the induction of tolerance to the major encephalitogenic epitopes of myelin that cause experimental autoimmune encephalomyelitis (EAE) in rats and mice. This novel approach is based on the use of cytokine-NAg (neuroantigen) fusion proteins comprised of the native cytokine fused either with or without a linker to a NAg domain. Several single-chain cytokine-NAg fusion proteins were tested including GMCSF-NAg, IFNbeta-NAg, NAgIL16, and IL2-NAg. These cytokine-NAg vaccines were tolerogenic, therapeutic vaccines that had tolerogenic activity when given as pre treatments before encephalitogenic immunization and also were effective as therapeutic interventions during the effector phase of EAE. The rank order of inhibitory activity was as follows: GMCSF-NAg, IFNbeta-NAg > NAgIL16 > IL2-NAg > MCSF-NAg, IL4-NAg, IL-13-NAg, IL1RA-NAg, and NAg. Several cytokine-NAg fusion proteins exhibited antigen-targeting activity. High affinity binding of the cytokine domain to specific cytokine receptors on particular subsets of APC resulted in the concentrated uptake of the NAg domain by those APC which in turn facilitated the enhanced processing and presentation of the NAg domain on cell surface MHC class II glycoproteins. For most cytokine-NAg vaccines, the covalent linkage of the cytokine domain and NAg domain was required for inhibition of EAE, thereby indicating that antigenic targeting of the NAg domain to APC was also required in vivo for tolerogenic activity. Overall, these studies introduced a new concept of cytokine-NAg fusion proteins as a means to induce tolerance and to inhibit the effector phase of autoimmune disease. The approach has broad application for suppressive vaccination as a therapy for autoimmune diseases such as MS. PMID- 22934094 TI - Translating tolerogenic therapies to the clinic - where do we stand? AB - Manipulation of the immune system to prevent the development of a specific immune response is an ideal strategy to improve outcomes after transplantation. A number of experimental techniques exploiting central and peripheral tolerance mechanisms have demonstrated success, leading to the first early phase clinical trials for tolerance induction. The first major strategy centers on the facilitation of donor-cell mixed chimerism in the transplant recipient with the use of bone marrow or hematopoietic stem cell transplantation. The second strategy, utilizing peripheral regulatory mechanisms, focuses on cellular therapy with regulatory T cells. This review examines the key studies and novel research directions in the field of immunological tolerance. PMID- 22934096 TI - Resolution of inflammation in obesity-induced liver disease. AB - Low-grade inflammation in adipose tissue is recognized as a critical event in the development of obesity-related co-morbidities. This chronic inflammation is powerfully augmented through the infiltration of macrophages, which together with adipocytes, perpetuate a vicious cycle of inflammatory cell recruitment and secretion of free fatty acids and deleterious adipokines that predispose to greater incidence of metabolic complications. In the last decade, many factors have been identified to contribute to mounting unresolved inflammation in obese adipose tissue. Among them, pro-inflammatory lipid mediators (i.e., leukotrienes) derived from the omega-6 polyunsaturated arachidonic acid have been shown to play a prominent role. Of note, the same lipid mediators that initially trigger the inflammatory response also signal its termination by stimulating the formation of anti-inflammatory signals. Resolvins and protectins derived from the omega-3 polyunsaturated docosahexaenoic and eicosapentaenoic acids have emerged as a representative family of this novel class of autacoids with dual anti inflammatory and pro-resolving properties that act as "stop-signals" of the inflammatory response. This review discusses the participation of these endogenous autacoids in the resolution of adipose tissue inflammation, with a special emphasis in the amelioration of obesity-related metabolic dysfunctions, namely insulin resistance and non-alcoholic fatty liver disease. PMID- 22934097 TI - KIR2DL4 (CD158d): An activation receptor for HLA-G. AB - KIR2DL4 is an unusual killer cell immunoglobulin-like receptor (KIR) family member in terms of its structure, expression, cellular localization, and signaling properties. The most conserved KIR in evolution, it is referred to as a framework KIR gene and is expressed by all natural killer (NK) cells and a subset of T cells. Although it has a long cytoplasmic tail that is typical of inhibitory KIR, engagement of this receptor results in the activation of NK cells, not for cytotoxicity, but for cytokine and chemokine secretion. Unlike all other KIRs, which are expressed on the surface of NK cells, KIR2DL4 resides in endosomes. It signals from this intracellular site for a proinflammatory and proangiogenic response, using a novel endosomal signaling pathway that involves the serine/threonine kinases DNA-PKcs and Akt. The only known ligand of KIR2DL4 is HLA-G. Soluble HLA-G accumulates in KIR2DL4(+) endosomes. Unlike classical HLA molecules that serve as ligands for other KIR family members, in healthy individuals, HLA-G expression is restricted to the fetal trophoblast cells that invade the maternal decidua during early pregnancy. Since NK cells constitute the predominant lymphocyte subset at this site, the proinflammatory/proangiogenic outcome of the interaction between KIR2DL4 and soluble HLA-G supports a role for KIR2DL4 in the extensive remodeling of the maternal vasculature during the early weeks of pregnancy. PMID- 22934098 TI - Stromal cell induction of regulatory dendritic cells. AB - Dendritic cells (DCs) are specialized antigen presenting cells of bone marrow origin that can exist in tissues in either an immature or mature state. DCs have a myriad of roles in immunity and tolerance induction, but are perhaps best known for their role in the activation and differentiation of naive T cells at the onset of an acquired immune response. Over the past decade, a body of literature has developed that suggests that DCs, as well as many other myeloid cell populations, are also capable of exerting "regulatory" effects on T cell responses. However, relatively little is known regarding the mechanisms by which such regulatory myeloid cells arise in vivo. In this mini-review, we first define the characteristics of "regulatory" DCs (rDCs) and then focus on the contribution of non-hematopoietic stromal cells to their generation within specific tissue microenvironments. We also highlight areas of research that warrant future attention, arguing for a focusing of efforts toward a better understanding of the features of stromal cell populations that enable the induction of rDCs. Finally, we discuss how an understanding of stromal cell-myeloid cell interactions may lead to new therapeutic strategies for cancer, autoimmunity, and infectious disease. PMID- 22934099 TI - Predicting and analyzing protein phosphorylation sites in plants using musite. AB - Although protein phosphorylation sites can be reliably identified with high resolution mass spectrometry, the experimental approach is time-consuming and resource-dependent. Furthermore, it is unlikely that an experimental approach could catalog an entire phosphoproteome. Computational prediction of phosphorylation sites provides an efficient and flexible way to reveal potential phosphorylation sites and provide hypotheses in experimental design. Musite is a tool that we previously developed to predict phosphorylation sites based solely on protein sequence. However, it was not comprehensively applied to plants. In this study, the phosphorylation data from Arabidopsis thaliana, B. napus, G. max, M. truncatula, O. sativa, and Z. mays were collected for cross-species testing and the overall plant-specific prediction as well. The results show that the model for A. thaliana can be extended to other organisms, and the overall plant model from Musite outperforms the current plant-specific prediction tools, Plantphos, and PhosphAt, in prediction accuracy. Furthermore, a comparative study of predicted phosphorylation sites across orthologs among different plants was conducted to reveal potential evolutionary features. A bipolar distribution of isolated, non-conserved phosphorylation sites, and highly conserved ones in terms of the amino acid type was observed. It also shows that predicted phosphorylation sites conserved within orthologs do not necessarily share more sequence similarity in the flanking regions than the background, but they often inherit protein disorder, a property that does not necessitate high sequence conservation. Our analysis also suggests that the phosphorylation frequencies among serine, threonine, and tyrosine correlate with their relative proportion in disordered regions. Musite can be used as a web server (http://musite.net) or downloaded as an open-source standalone tool (http://musite.sourceforge.net/). PMID- 22934101 TI - Large homogeneous genome regions (isochores) in soybean [glycine max (L.) merr]. AB - The landscape of plant genomes, while slowly being characterized and defined, is still composed primarily of regions of undefined function. Many eukaryotic genomes contain isochore regions, mosaics of homogeneous GC content that can abruptly change from one neighboring isochore to the next. Isochores are broken into families that are characterized by their GC levels. We identified 4,339 compositionally distinct domains and 331 of these were identified as long homogeneous genome regions (LHGRs). We assigned these to four families based on finite mixture models of GC content. We then characterized each family with respect to exon length, gene content, and transposable elements. The LHGR pattern of soybeans is unique in that while the majority of the genes within LHGRs are found within a single LHGR family with a narrow GC range (Family B), that family is not the highest in GC content as seen in vertebrates and invertebrates. Instead Family B has a mean GC content of 35%. The range of GC content for all LHGRs is 16-59% GC which is a larger range than what is typical of vertebrates. This is the first study in which LHGRs have been identified in soybeans and the functions of the genes within the LHGRs have been analyzed. PMID- 22934100 TI - 14-3-3 phosphoprotein interaction networks - does isoform diversity present functional interaction specification? AB - The 14-3-3 proteins have emerged as major phosphoprotein interaction proteins and thereby constitute a key node in the Arabidopsis Interactome Map, a node through which a large number of important signals pass. Throughout their history of discovery and description, the 14-3-3s have been described as protein families and there has been some evidence that the different 14-3-3 family members within any organism might carry isoform-specific functions. However, there has also been evidence for redundancy of 14-3-3 function, suggesting that the perceived 14-3-3 diversity may be the accumulation of neutral mutations over evolutionary time and as some 14-3-3 genes develop tissue or organ-specific expression. This situation has led to a currently unresolved question - does 14-3-3 isoform sequence diversity indicate functional diversity at the biochemical or cellular level? We discuss here some of the key observations on both sides of the resulting debate, and present a set of contrastable observations to address the theory functional diversity does exist among 14-3-3 isoforms. The resulting model suggests strongly that there are indeed functional specificities in the 14-3-3s of Arabidopsis. The model further suggests that 14-3-3 diversity and specificity should enter into the discussion of 14-3-3 roles in signal transduction and be directly approached in 14-3-3 experimentation. It is hoped that future studies involving 14-3-3s will continue to address specificity in experimental design and analysis. PMID- 22934102 TI - Single-neuron RNA-Seq: technical feasibility and reproducibility. AB - Understanding brain function involves improved knowledge about how the genome specifies such a large diversity of neuronal types. Transcriptome analysis of single neurons has been previously described using gene expression microarrays. Using high-throughput transcriptome sequencing (RNA-Seq), we have developed a method to perform single-neuron RNA-Seq. Following electrophysiology recording from an individual neuron, total RNA was extracted by aspirating the cellular contents into a fine glass electrode tip. The mRNAs were reverse transcribed and amplified to construct a single-neuron cDNA library, and subsequently subjected to high-throughput sequencing. This approach was applied to both individual neurons cultured from embryonic mouse hippocampus, as well as neocortical neurons from live brain slices. We found that the average pairwise Spearman's rank correlation coefficient of gene expression level expressed as RPKM (reads per kilobase of transcript per million mapped reads) was 0.51 between five cultured neuronal cells, whereas the same measure between three cortical layer 5 neurons in situ was 0.25. The data suggest that there may be greater heterogeneity of the cortical neurons, as compared to neurons in vitro. The results demonstrate the technical feasibility and reproducibility of RNA-Seq in capturing a part of the transcriptome landscape of single neurons, and confirmed that morphologically identical neurons, even from the same region, have distinct gene expression patterns. PMID- 22934104 TI - Acute coronary syndromes: an old age problem. AB - The increasing population in older age will lead to greater numbers of them presenting with acute coronary syndromes (ACS). This has implications on global healthcare resources and necessitates better management and selection for evidenced-based therapies. The elderly are a high risk group with more significant treatment benefits than younger ACS. Nevertheless, age related inequalities in ACS care are recognised and persist. This discrepancy in care, to some extent, is explained by the higher frequency of atypical and delayed presentations in the elderly, and less diagnostic electrocardiograms at presentation, potentiating a delay in ACS diagnosis. Under estimation of mortality risk in the elderly due to limited consideration for physiological frailty, co-morbidity, cognitive/psychological impairment and physical disability, less input by cardiology specialists and lack of randomised, controlled trials data to guide management in the elderly may further confound the inequality of care. While these inequalities exist, there remains a substantial opportunity to improve age related ACS outcomes. The selection of elderly patients for specific therapies and medication regimens are unanswered. There is a growing need for randomised, controlled trial data to be more representative of the population and enroll those of advanced age with co morbidity. A lack of reporting of adverse events, such as renal impairment post coronary angiography, in the elderly further limit risk benefit decisions. Substantial improvements in care of elderly ACS patients are required and should be advocated. Ultimately, these improvements are likely to lead to better outcomes post ACS. However, the improvement in outcome is not infinite and will be limited by non-modifiable factors of age-related risk. PMID- 22934106 TI - Is Post-ERCP Pancreatitis a Genetically Predisposed Complication? AB - Background/Objectives. Pancreatitis remains the most common complication of ERCP. History of post-ERCP pancreatitis is an independent risk factor for a new episode, suggesting a genetic background. The N34S mutation in serine protease inhibitor Kazal type 1 (SPINK 1) gene may downregulate the threshold for the development of pancreatitis. The aim of the present study is to evaluate the presence of this mutation among patients with post-ERCP pancreatitis. Methods. During a period of four years, thirty patients with post-ERCP pancreatitis entered the study. Patients and procedural data were collected, focusing on risk factors for pancreatitis. Blood samples were taken for genetic testing for the presence of N34S mutation in SPINK 1 gene. After DNA extraction, we used an allele-specific polymerase chain reaction as an initial screening method for the N34S mutation, and in order to confirm the results and to determine the hetero- and homozygosity genotype status, we used a restriction fragment length polymorphism (RFLP) method. Results. None of the thirty patients was found to carry the N34S mutation, with both of the applied methods. Patients had an average of two of the known risk factors. Conclusion. SPINK1 N34S mutation does not seem to play a role in post-ERCP pancreatitis, but larger studies needed to confirm our results. PMID- 22934107 TI - Web-Based Specialist Support for Spinal Cord Injury Person's Care: Lessons Learned. AB - Persons with disability from spinal cord injury (SCI) are subject to high risk of pathological events and need a regular followup even after discharge from the rehabilitation hospital. To help in followup, we developed a web portal for providing online specialist as well as GP support to SCI persons. After a feasibility study with 13 subjects, the portal has been introduced in the regional healthcare network in order to make it compliant with current legal regulations on data protection, including smartcard authentication. Although a number of training courses have been made to introduce SCI persons to portal use (up to 50 users), the number of accesses remained very low. Reasons for that have been investigated by means of a questionnaire submitted to the initial feasibility study subjects and included the still easier use of telephone versus our web-based smartcard-authenticated portal, in particular, because online communications are still perceived as an unusual way of interacting with the doctor. To summarize, the overall project has been appreciated by the users, but when it is time to ask for help to, the specialist, it is still much easier to make a phone call. PMID- 22934105 TI - Anti- and Protumorigenic Effects of PPARgamma in Lung Cancer Progression: A Double-Edged Sword. AB - Peroxisome proliferator-activated receptor-gamma (PPARgamma) is a member of the nuclear receptor superfamily of ligand-activated transcription factors that plays an important role in the control of gene expression linked to a variety of physiological processes, including cancer. Ligands for PPARgamma include naturally occurring fatty acids and the thiazolidinedione class of antidiabetic drugs. Activation of PPARgamma in a variety of cancer cells leads to inhibition of growth, decreased invasiveness, reduced production of proinflammatory cytokines, and promotion of a more differentiated phenotype. However, systemic activation of PPARgamma has been reported to be protumorigenic in some in vitro systems and in vivo models. Here, we review the available data that implicate PPARgamma in lung carcinogenesis and highlight the challenges of targeting PPARgamma in lung cancer treatments. PMID- 22934103 TI - Development of Therapeutic-Grade Small Interfering RNAs by Chemical Engineering. AB - Recent successes in clinical trials have provided important proof of concept that small interfering RNAs (siRNAs) indeed constitute a new promising class of therapeutics. Although great efforts are still needed to ensure efficient means of delivery in vivo, the siRNA molecule itself has been successfully engineered by chemical modification to meet initial challenges regarding specificity, stability, and immunogenicity. To date, a great wealth of siRNA architectures and types of chemical modification are available for promoting safe siRNA-mediated gene silencing in vivo and, consequently, the choice of design and modification types can be challenging to individual experimenters. Here we review the literature and devise how to improve siRNA performance by structural design and specific chemical modification to ensure potent and specific gene silencing without unwarranted side-effects and hereby complement the ongoing efforts to improve cell targeting and delivery by other carrier molecules. PMID- 22934108 TI - Adaptation of Ritchie's Method for Parasites Diagnosing with Minimization of Chemical Products. AB - Latin America, Africa, and Asia present wide dissemination and high prevalence rates of waterborne parasitic diseases, which is a strong indicative of the fragility of public sanitation systems. In this context, parasitological analyses represent extremely relevant instruments. Several parasite diagnosis methods exist, among which Ritchie's method (1948) stands out. This method uses formaldehyde and ether, two reagents of toxicological importance that can cause damages to environmental and occupational health. The present study aimed to compare Ritchie's method modified by Regis Anecimo, without use of solvents, with the traditional Ritchie's method, routinely used for helminth and protozoa diagnosing in Brazil. Some changes were introduced in the modified method, such as controlled increase of water temperature used after stool dilution and substitution of formaldehyde and ether by a neutral detergent before material centrifugation for observation of parasites. In examined samples by both methods, multiple infections were commonly observed; the modified method presented a similar sensitivity to identify the parasites. The development of analytic diagnosis methods that minimize the use of chemical products like ether and formaldehyde represents an important tool to prevent occupational diseases among exposed professionals, as well as to preserve environmental quality through the use of clean techniques. PMID- 22934109 TI - Producing high-accuracy lattice models from protein atomic coordinates including side chains. AB - Lattice models are a common abstraction used in the study of protein structure, folding, and refinement. They are advantageous because the discretisation of space can make extensive protein evaluations computationally feasible. Various approaches to the protein chain lattice fitting problem have been suggested but only a single backbone-only tool is available currently. We introduce LatFit, a new tool to produce high-accuracy lattice protein models. It generates both backbone-only and backbone-side-chain models in any user defined lattice. LatFit implements a new distance RMSD-optimisation fitting procedure in addition to the known coordinate RMSD method. We tested LatFit's accuracy and speed using a large nonredundant set of high resolution proteins (SCOP database) on three commonly used lattices: 3D cubic, face-centred cubic, and knight's walk. Fitting speed compared favourably to other methods and both backbone-only and backbone-side chain models show low deviation from the original data (~1.5 A RMSD in the FCC lattice). To our knowledge this represents the first comprehensive study of lattice quality for on-lattice protein models including side chains while LatFit is the only available tool for such models. PMID- 22934110 TI - Metabolic context regulates distinct hypothalamic transcriptional responses to antiaging interventions. AB - The hypothalamus is an essential relay in the neural circuitry underlying energy metabolism that needs to continually adapt to changes in the energetic environment. The neuroendocrine control of food intake and energy expenditure is associated with, and likely dependent upon, hypothalamic plasticity. Severe disturbances in energy metabolism, such as those that occur in obesity, are therefore likely to be associated with disruption of hypothalamic transcriptomic plasticity. In this paper, we investigated the effects of two well-characterized antiaging interventions, caloric restriction and voluntary wheel running, in two distinct physiological paradigms, that is, diabetic (db/db) and nondiabetic wild type (C57/Bl/6) animals to investigate the contextual sensitivity of hypothalamic transcriptomic responses. We found that, both quantitatively and qualitatively, caloric restriction and physical exercise were associated with distinct transcriptional signatures that differed significantly between diabetic and non diabetic mice. This suggests that challenges to metabolic homeostasis regulate distinct hypothalamic gene sets in diabetic and non-diabetic animals. A greater understanding of how genetic background contributes to hypothalamic response mechanisms could pave the way for the development of more nuanced therapeutics for the treatment of metabolic disorders that occur in diverse physiological backgrounds. PMID- 22934111 TI - Radiolabeled somatostatin analogues therapy in advanced neuroendocrine tumors: a single centre experience. AB - The aim of this study was to assess the efficacy of PRRT in patients with advanced neuroendocrine tumors (NETs). Patients and Methods. From January 2007 to August 2011, we enrolled 65 patients (m/f 38/27; mean age 65 years, range 33-83) with advanced NETs having enhanced SSTR expression, treated with PRRT. The enhanced expression of SSTR was assessed using (68)Ga-DOTATOC/DOTATATE PET/CT. Among all the enrolled patients, 6 of them were excluded from the present analysis since they voluntarily interrupted treatment. Mean activity/cycle of 2.6 GBq ((90)Y-DOTATOC/DOTATATE) or 6.0 GBq ((177)Lu-DOTATOC/DOTATATE) was administrated intravenously (max 9 cycles). Results. Complete response (CR) was found in 1/59 (2%) patients, partial remission (PR) in 24/59 (40.5%) patients, stable disease (SD) in 24/59 (40.5%), and progression (PD) in 10/59 (17%) patients. The overall tumor response rate (CR + PR) was 42.5%. In 40.5% of patients, the disease could be stabilized. Overall, 49 out of 59 patients had no tumor progression (83%). Twelve patients out of 59 (20%) had grade 2-3 hematological side effects including anemia, thrombocytopenia, and leukopenia. Long-term nephrotoxicity was observed in 3 patients (2 moderate, 1 severe). Conclusions. PRRT is a promising perspective for patients with advanced NETs. PMID- 22934113 TI - Management Strategies for Aggressive Cushing's Syndrome: From Macroadenomas to Ectopics. AB - Cushing's syndrome (CS) is a rare but severe clinical condition represented by an excessive endogenous cortisol secretion and hence excess circulating free cortisol, characterized by loss of the normal feedback regulation and circadian rhythm of the hypothalamic-pituitary axis due to inappropriate secretion of ACTH from a pituitary tumor (Cushing's disease, CD) or an ectopic source (ectopic ACTH secretion, EAS). The remaining causes (20%) are ACTH independent. As soon as the diagnosis is established, the therapeutic goal is the removal of the tumor. Whenever surgery is not curative, management of patients with CS requires a major effort to control hypercortisolemia and associated symptoms. A multidisciplinary approach that includes endocrinologists, neurosurgeons, oncologists, and radiotherapists should be adopted. This paper will focus on traditional and novel medical therapy for aggressive ACTH-dependent CS. Several drugs are able to reduce cortisol levels. Their mechanism of action involves blocking adrenal steroidogenesis (ketoconazole, metyrapone, aminoglutethimide, mitotane, etomidate) or inhibiting the peripheral action of cortisol through blocking its receptors (mifepristone "RU-486"). Other drugs include centrally acting agents (dopamine agonists, somatostatin receptor agonists, retinoic acid, peroxisome proliferator-activated receptor gamma "PPAR-gamma" ligands) and novel chemotherapeutic agents (temozolomide and tyrosine kinase inhibitors) which have a significant activity against aggressive pituitary or ectopic tumors. PMID- 22934112 TI - Current and emerging therapeutic options in adrenocortical cancer treatment. AB - Adrenocortical carcinoma (ACC) is a very rare endocrine tumour, with variable prognosis, depending on tumour stage and time of diagnosis. The overall survival is five years from detection. Radical surgery is considered the therapy of choice in the first stages of ACC. However postoperative disease-free survival at 5 years is only around 30% and recurrence rates are frequent. o,p'DDD (ortho-, para'-, dichloro-, diphenyl-, dichloroethane, or mitotane), an adrenolytic drug with significant toxicity and unpredictable therapeutic response, is used in the treatment of ACC. Unfortunately, treatment for this aggressive cancer is still ineffective. Over the past years, the growing interest in ACC has contributed to the development of therapeutic strategies in order to contrast the neoplastic spread. In this paper we discuss the most promising therapies which can be used in this endocrine neoplasia. PMID- 22934114 TI - Severity of occlusal disharmonies in down syndrome. AB - Objective. To quantify the severity of malocclusion and dental esthetic problems in untreated Down syndrome (DS) and untreated non-Down syndrome children age 8-14 years old using the PAR and ICON Indices. Materials and Methods. This retrospective study evaluated pretreatment study models, intraoral photographs, and panoramic radiographs of 30 Down syndrome and two groups of 30 non-Down syndrome patients (private practice and university clinic) age 8-14 years. The models were scored via PAR and ICON Indices, and descriptive characteristics such as Angle classification, missing or impacted teeth, crossbites, open bites, and other dental anomalies were recorded. Results. The DS group had significantly greater PAR and ICON scores, as well as 10 times more missing teeth than the non DS group. The DS group possessed predominantly Class III malocclusions, with the presence of both anterior and posterior crossbites in a majority of the patients. The non-DS group had mostly Class I or II malocclusion with markedly fewer missing teeth and crossbites. The DS group also had more severe malocclusions based upon occlusal traits such as open bite and type of malocclusion. Conclusion. The DS group had very severe malocclusions, while the control group from the university clinic had more severe malocclusions than a control group from a private practice. PMID- 22934115 TI - Gut microbial translocation in critically ill children and effects of supplementation with pre- and pro biotics. AB - Bacterial translocation as a direct cause of sepsis is an attractive hypothesis that presupposes that in specific situations bacteria cross the intestinal barrier, enter the systemic circulation, and cause a systemic inflammatory response syndrome. Critically ill children are at increased risk for bacterial translocation, particularly in the early postnatal age. Predisposing factors include intestinal obstruction, obstructive jaundice, intra-abdominal hypertension, intestinal ischemia/reperfusion injury and secondary ileus, and immaturity of the intestinal barrier per se. Despite good evidence from experimental studies to support the theory of bacterial translocation as a cause of sepsis, there is little evidence in human studies to confirm that translocation is directly correlated to bloodstream infections in critically ill children. This paper provides an overview of the gut microflora and its significance, a focus on the mechanisms employed by bacteria to gain access to the systemic circulation, and how critical illness creates a hostile environment in the gut and alters the microflora favoring the growth of pathogens that promote bacterial translocation. It also covers treatment with pre- and pro biotics during critical illness to restore the balance of microbial communities in a beneficial way with positive effects on intestinal permeability and bacterial translocation. PMID- 22934116 TI - Advances in bacteriophage-mediated control of plant pathogens. AB - There is continuing pressure to maximise food production given a growing global human population. Bacterial pathogens that infect important agricultural plants (phytopathogens) can reduce plant growth and the subsequent crop yield. Currently, phytopathogens are controlled through management programmes, which can include the application of antibiotics and copper sprays. However, the emergence of resistant bacteria and the desire to reduce usage of toxic products that accumulate in the environment mean there is a need to develop alternative control agents. An attractive option is the use of specific bacteriophages (phages), viruses that specifically kill bacteria, providing a more targeted approach. Typically, phages that target the phytopathogen are isolated and characterised to determine that they have features required for biocontrol. In addition, suitable formulation and delivery to affected plants are necessary to ensure the phages survive in the environment and do not have a deleterious effect on the plant or target beneficial bacteria. Phages have been isolated for different phytopathogens and have been used successfully in a number of trials and commercially. In this paper, we address recent progress in phage-mediated control of plant pathogens and overcoming the challenges, including those posed by CRISPR/Cas and abortive infection resistance systems. PMID- 22934117 TI - Antimicrobial Activity of Xoconostle Pears (Opuntia matudae) against Escherichia coli O157:H7 in Laboratory Medium. AB - The objective of this study was to investigate the antimicrobial activity of xoconostle pears (Opuntia matudae) against Escherichia coli O157:H7. Xoconostle pears were sliced, blended, and centrifuged. The supernatant was then filtered using a 0.45 MUm filter to obtain direct extract. Direct extract of xoconostle pears was tested against four strains of E. coli O157:H7 in brain heart infusion (BHI) laboratory medium using growth over time and agar well diffusion assays. Our results showed that direct extract of xoconostle pears had a significant (P < 0.05) inhibitory effect at 4, 6, and 8% (v/v) concentrations and complete inhibitory effect at 10% (v/v) during 8 h of incubation at 37 degrees C. Minimum inhibitory volume (MIV) was 400 MUL mL(-1) (v/v) and minimum lethal volume (MLV) was 650 MUL mL(-1) (v/v). The inhibitory effect of xoconostle pears found to be concentration dependent and not strain dependent. Thus, xoconostle pears extract has the potential to inhibit the growth of E. coli O157:H7 and could provide a natural means of controlling pathogenic contamination, thereby mitigating food safety risks. PMID- 22934118 TI - Evaluation of anti-mutated citrullinated vimentin antibodies, anti-cyclic citrullinated Peptide antibodies and rheumatoid factor in omani patients with rheumatoid arthritis. AB - Rheumatoid factor (RF) is currently used in the diagnosis of rheumatoid arthritis (RA). The discovery of anticitrullinated protein autoantibodies has led to the development of various new tests, such as anti-cyclic citrullinated peptide (anti CCP) antibodies, and anti-mutated citrullinated vimentin (anti-MCV) antibodies, to diagnose RA. The aims of this study were to determine the sensitivity and specificity of anti-MCV antibodies in comparison with anti-CCP antibodies and RF in Omani Arab patients with RA and compare our findings with published values from different ethnic groups. The sensitivity of anti-MCV antibodies was 72% with 87% specificity. For anti-CCP antibodies the sensitivity was 52% and the specificity was 97%. The sensitivity of RF was 57% with 94% specificity. Anti-CCP antibodies have higher diagnostic specificity and positive predictive value than RF and anti-MCV antibodies. Anti-MCV antibodies have the highest sensitivity when compared to anti-CCP antibodies and RF. Anti-MCV antibodies do not appear to be very useful in the diagnosis of RA. However, long-term study is required to find out whether anti-MCV antibodies can be used as predictive test for incidence of RA. PMID- 22934119 TI - Developmental origins of pediatric obesity. PMID- 22934120 TI - External validity of studies on aggressive behavior in patients with schizophrenia: systematic review. AB - STUDIES ON VIOLENCE IN SCHIZOPHRENIA USE TWO DIFFERENT APPROACHES: use of epidemiological data, and clinical studies recording direct patient data after gaining informed consent. With regard to informed consent requiring agreement and cooperation, the question arises as to what extent participants represent patients with schizophrenia and violent behaviour (external validity). We conducted a systematic literature research. In most of the studies, aggression or violence, respectively, were poorly defined. Only 5 (15.2%) studies used a cut off score on an aggression scale. Only 6 studies (18.2%) reported the number of patients who refused to participate, and 16 (48.5%) reported the number of drop outs. Only 3 studies (9.1%) reported a systematic comparison of participants and non-participants. We found that data which allow for the assessment of representativeness of the investigated samples are poorly reported. For most studies, doubts regarding external validity seem justified and generalisability is questionable due to possible selection bias. PMID- 22934121 TI - Anti-purkinje cell and natural autoantibodies in a group of psychiatric patients. Evidences for a correlation with the psychopathological status. AB - Phenomena of autoimmunity are frequent among psychiatric patients, but we don't know yet if they should be considered primary and linked to the pathophisiology of the disorder, or aspecific and associated to a general immune system activation. Paraneoplastic Cerebellar Degeneration (PCD) represents a well known model of specific autoimmunity. In order to better understand the abovementioned issues, we used this condition to compare a set of immune dysfunctions found in a group of psychiatric patients. For this reason we tested sera from 48 psychiatric patients (24 schizophrenics, 17 bipolars and 7 obsessive-compulsive), 22 PCD patients and 52 healthy controls for the presence of anti-Purkinje autoantibodies and of some natural autoantibodies (ANAs, AMAs, APCAs, ASMAs). Psychopatological status of the psychiatric patients was assessed with BPRS, SANS, SAPS, HAM-D, CGI S. In the psychiatric group anti-Purkinje autoantibodies were identified in 11/48 (22,9%) patients, while they were present in 22/22 (100%) PCD patients and in 0/52 (0%) healthy controls. Among all anti-Purkinje autoantibody positive patients (in the PCD and psychiatric samples), only those belonging to the psychiatric sample, but not those with PCD, were frequently found positive also for natural autoantibodies, that are considered good markers of aspecific immune activation. In these patients, both anti-Purkinje and natural autoantibodies were found associated with acute/positive psychopathological symptoms. These results seem to point out that some phenomena of auto-immunity described in psychiatric patients could be aspecific, unrelated to the pathophysiology of the concomitant mental disorders and could be more frequent during phases of acute/positive symptoms. PMID- 22934122 TI - A signal-processing-based approach to time-varying graph analysis for dynamic brain network identification. AB - In recent years, there has been a growing need to analyze the functional connectivity of the human brain. Previous studies have focused on extracting static or time-independent functional networks to describe the long-term behavior of brain activity. However, a static network is generally not sufficient to represent the long term communication patterns of the brain and is considered as an unreliable snapshot of functional connectivity. In this paper, we propose a dynamic network summarization approach to describe the time-varying evolution of connectivity patterns in functional brain activity. The proposed approach is based on first identifying key event intervals by quantifying the change in the connectivity patterns across time and then summarizing the activity in each event interval by extracting the most informative network using principal component decomposition. The proposed method is evaluated for characterizing time-varying network dynamics from event-related potential (ERP) data indexing the error related negativity (ERN) component related to cognitive control. The statistically significant connectivity patterns for each interval are presented to illustrate the dynamic nature of functional connectivity. PMID- 22934123 TI - Connectionism and the Role of Morphology in Visual Word Recognition. AB - This paper provides a review of the connectionist perspective on the role of morphology in visual word recognition. Several computational models of morphological effects in reading are described and relationships between these models, models of past tense production, and models of other aspects of word recognition are traced. Limitations of extant models are noted, as are some of the technical challenges that must be solved to develop the next generation of models. Finally, some directions for future research are identified. PMID- 22934124 TI - Reappraisal of spontaneous closure rate of idiopathic full-thickness macular holes. AB - We retrospectively reviewed the records of 142 eyes of 138 patients with idiopathic full-thickness macular hole. Spontaneous closure of idiopathic full thickness macular hole was observed in five eyes (3.5%) of four patients before the planned vitrectomy. In the era when surgical treatment was not available for macular hole, the rate of spontaneous closure of idiopathic full-thickness macular hole was reported as 6.2%. Among several case reports on spontaneous closure of idiopathic full-thickness macular hole based on the optical coherence tomography images only one study reported the rate of spontaneous closure as 2.7%. According to the previous reports and our results, small idiopathic full thickness macular holes may close spontaneously in a few percent of all macular hole cases. The rate of spontaneous closure may be affected by the waiting time before vitrectomy. PMID- 22934125 TI - Topical prostaglandin analogues and conjunctival inflammation in uveitic glaucoma. AB - PURPOSE: A pilot study to determine whether topical prostaglandin analogues alter the expression of conjunctival inflammatory markers in patients with uveitic glaucoma. METHODS: Prospective, single-masked case series of 20 patients with uveitis and secondary raised intraocular pressure. Participants were divided into four groups of five patients dependent on their use of topical medication: (1) prostaglandin analogues only, (2) corticosteroids only, (3) both prostaglandin analogues and corticosteroids, (4) no topical medication. Conjunctival cells were harvested by impression cytology and were examined for inflammatory markers (CD3, CD54, HLA-DR, CCR4, CCR5) by flow cytometry. A tear fluid sample was also examined for inflammatory cytokines (IL-12p70, IL-2, IL-10, IL-8, IL-6, IL-4, IL 5, IFN-gamma, IL-1beta, IFN-alpha, IFN-beta) by multiplex bead arrays. RESULTS: All groups demonstrated increased markers of conjunctival inflammation. There was no significant difference in levels of any inflammatory markers between the four groups, suggesting that the use of topical prostaglandin analogues does not increase conjunctival levels of inflammation beyond those already seen in uveitis. CONCLUSIONS: The use of topical prostaglandins does not appear to induce conjunctival inflammation over that which is already present in patients with uveitic glaucoma. This supports the use of topical prostaglandin analogues in patients with uveitic glaucoma, indicating that their use is unlikely to adversely affect subsequent glaucoma filtration surgery through the induction of chronic conjunctival inflammation. PMID- 22934126 TI - CKD Express (c) - A New IT-Software Proposed for a Paradigm Change in CKD Care. PMID- 22934127 TI - Retrieval of radiology reports citing critical findings with disease-specific customization. AB - BACKGROUND: Communication of critical results from diagnostic procedures between caregivers is a Joint Commission national patient safety goal. Evaluating critical result communication often requires manual analysis of voluminous data, especially when reviewing unstructured textual results of radiologic findings. Information retrieval (IR) tools can facilitate this process by enabling automated retrieval of radiology reports that cite critical imaging findings. However, IR tools that have been developed for one disease or imaging modality often need substantial reconfiguration before they can be utilized for another disease entity. PURPOSE: THIS PAPER: 1) describes the process of customizing two Natural Language Processing (NLP) and Information Retrieval/Extraction applications - an open-source toolkit, A Nearly New Information Extraction system (ANNIE); and an application developed in-house, Information for Searching Content with an Ontology-Utilizing Toolkit (iSCOUT) - to illustrate the varying levels of customization required for different disease entities and; 2) evaluates each application's performance in identifying and retrieving radiology reports citing critical imaging findings for three distinct diseases, pulmonary nodule, pneumothorax, and pulmonary embolus. RESULTS: Both applications can be utilized for retrieval. iSCOUT and ANNIE had precision values between 0.90-0.98 and recall values between 0.79 and 0.94. ANNIE had consistently higher precision but required more customization. CONCLUSION: Understanding the customizations involved in utilizing NLP applications for various diseases will enable users to select the most suitable tool for specific tasks. PMID- 22934128 TI - Fullerene nanowires as a versatile platform for organic electronics. AB - The development of organic semiconducting nanowires that act as charge carrier transport pathways in flexible and lightweight nanoelectronics is a major scientific challenge. We report on the fabrication of fullerene nanowires that is universally applicable to its derivatives (pristine C(60), methanofullerenes of C(61) and C(71), and indene C(60) bis-adduct), realized by the single particle nanofabrication technique (SPNT). Nanowires with radii of 8-11 nm were formed via a chain polymerization reaction induced by a high-energy ion beam. Fabrication of a poly(3-hexylthiophene) (P3HT): [6,6]-phenyl C(61) butyric acid methyl ester (PC(61)BM) bulk heterojunction organic photovoltaic cell including PC(61)BM nanowires with precisely-controlled length and density demonstrates how application of this methodology can improve the power conversion efficiency of these inverted cells. The proposed technique provides a versatile platform for the fabrication of continuous and uniform n-type fullerene nanowires towards a wide range of organic electronics applications. PMID- 22934129 TI - Widespread binding of FUS along nascent RNA regulates alternative splicing in the brain. AB - Fused in sarcoma (FUS) and TAR DNA-binding protein 43 (TDP-43) are RNA-binding proteins pathogenetically linked to amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD), but it is not known if they regulate the same transcripts. We addressed this question using crosslinking and immunoprecipitation (iCLIP) in mouse brain, which showed that FUS binds along the whole length of the nascent RNA with limited sequence specificity to GGU and related motifs. A saw-tooth binding pattern in long genes demonstrated that FUS remains bound to pre-mRNAs until splicing is completed. Analysis of FUS(-/-) brain demonstrated a role for FUS in alternative splicing, with increased crosslinking of FUS in introns around the repressed exons. We did not observe a significant overlap in the RNA binding sites or the exons regulated by FUS and TDP-43. Nevertheless, we found that both proteins regulate genes that function in neuronal development. PMID- 22934130 TI - Optical properties of in-vitro biomineralised silica. AB - Silicon is the second most common element on the Earth's crust and its oxide (SiO(2)) the most abundant mineral. Silica and silicates are widely used in medicine and industry as well as in micro- and nano-optics and electronics. However, the fabrication of glass fibres and components requires high temperature and non-physiological conditions, in contrast to biosilica structures in animals and plants. Here, we show for the first time the use of recombinant silicatein alpha, the most abundant subunit of sponge proteins catalyzing biosilicification reactions, to direct the formation of optical waveguides in-vitro through soft microlithography. The artificial biosilica fibres mimic the natural sponge spicules, exhibiting refractive index values suitable for confinement of light within waveguides, with optical losses in the range of 5-10 cm(-1), suitable for application in lab-on-chips systems. This method extends biosilicification to the controlled fabrication of optical components by physiological processing conditions, hardly addressed by conventional technologies. PMID- 22934131 TI - Tryptophan-based chromophore in fluorescent proteins can be anionic. AB - Cyan fluorescent proteins (CFP) with tryptophan66-based chromophore are widely used for live cell imaging. In contrast to green and red fluorescent proteins, no charged states of the CFP chromophore have been described. Here, we studied synthetic CFP chromophore and found that its indole group can be deprotonated rather easily (pKa 12.4).We then reproduced this effect in the CFP mCerulean by placing basic amino acids in the chromophore microenvironment. As a result, green emitting variant with an anionic chromophore and key substitution Val61Lys was obtained. This is the first evidence strongly suggesting that tryptophan-based chromophores in fluorescent proteins can exist in an anionic charged state. Switching between protonated and deprotonated Trp66 in fluorescent proteins represents a new unexplored way to control their spectral properties. PMID- 22934132 TI - Proxy-to-proxy calibration: increasing the temporal resolution of quantitative climate reconstructions. AB - High-resolution paleoclimate reconstructions are often restricted by the difficulties of sampling geologic archives in great detail and the analytical costs of processing large numbers of samples. Using sediments from Lake Braya So, Greenland, we introduce a new method that provides a quantitative high-resolution paleoclimate record by combining measurements of the alkenone unsaturation index (U37(K)) with non-destructive scanning reflectance spectroscopic measurements in the visible range (VIS-RS). The proxy-to-proxy (PTP) method exploits two distinct calibrations: the in situ calibration of U37(K) to lake water temperature and the calibration of scanning VIS-RS data to down core U37(K) data. Using this approach, we produced a quantitative temperature record that is longer and has 5 times higher sampling resolution than the original U37(K) time series, thereby allowing detection of temperature variability in frequency bands characteristic of the AMO over the past 7,000 years. PMID- 22934133 TI - X-ray imaging of tumor growth in live mice by detecting gold-nanoparticle-loaded cells. AB - We show that sufficient concentrations of gold nanoparticles produced by an original synthesis method in EMT-6 and CT-26 cancer cells make it possible to detect the presence, necrosis and proliferation of such cells after inoculation in live mice. We first demonstrated that the nanoparticles do not interfere with the proliferation process. Then, we observed significant differences in the tumor evolution and the angiogenesis process after shallow and deep inoculation. A direct comparison with pathology optical images illustrates the effectiveness of this approach. PMID- 22934134 TI - Predicting effects of structural stress in a genome-reduced model bacterial metabolism. AB - Mycoplasma pneumoniae is a human pathogen recently proposed as a genome-reduced model for bacterial systems biology. Here, we study the response of its metabolic network to different forms of structural stress, including removal of individual and pairs of reactions and knockout of genes and clusters of co-expressed genes. Our results reveal a network architecture as robust as that of other model bacteria regarding multiple failures, although less robust against individual reaction inactivation. Interestingly, metabolite motifs associated to reactions can predict the propagation of inactivation cascades and damage amplification effects arising in double knockouts. We also detect a significant correlation between gene essentiality and damages produced by single gene knockouts, and find that genes controlling high-damage reactions tend to be expressed independently of each other, a functional switch mechanism that, simultaneously, acts as a genetic firewall to protect metabolism. Prediction of failure propagation is crucial for metabolic engineering or disease treatment. PMID- 22934135 TI - Are video-assisted thoracoscopic surgery (VATS) and robotic video-assisted thoracic surgery (RVATS) for pulmonary resection ready for prime time? PMID- 22934136 TI - Nonintubated thoracoscopic lung resection: a 3-year experience with 285 cases in a single institution. AB - OBJECTIVE: Tracheal intubation with one-lung ventilation is considered mandatory for thoracoscopic surgery. This study reported the experience of thoracoscopic lung resection without endotracheal intubation in a single institution. METHODS: From August 2009 through July 2012, 285 consecutive patients were treated by nonintubated thoracoscopic surgery using epidural anesthesia, intrathoracic vagal blockade, and sedation for lobectomy, segmentectomy, or wedge resection in a tertiary medical center. The feasibility and safety of this technique were evaluated. RESULTS: The final diagnosis for surgery were primary lung cancer in 159 patients (55.8%), metastatic lung cancer in 17 (6.0%), benign lung tumor in 104 (36.5%), and pneumothorax in 5 (1.8%). The operative methods consisted of conventional (83.2%) and needlescopic (16.8%) thoracoscopic surgery. The operative procedures included lobectomy in 137 patients (48.1%), wedge resection in 132 (46.3%), and segmentectomy in 16 (5.6%). Collapse of the operative lung and inhibition of coughing were satisfactory in most of the patients. Fourteen (4.9%) patients required conversion to tracheal intubation because of significant mediastinal movement [5], persistent hypoxemia [2], dense pleural adhesions [2], ineffective epidural anesthesia [2], bleeding [2], and tachypnea [1]. One patient (0.4%) was converted to thoracotomy because of bleeding. No mortality was noted in our patients. CONCLUSIONS: Nonintubated thoracoscopic lung resection is technically feasible and safe in selected patients. It can be a valid alternative in managing patients with pulmonary lesions. PMID- 22934137 TI - The association of topoisomerase 2alpha expression with prognosis in surgically resected non-small cell lung cancer (NSCLC) patients. AB - BACKGROUND: Topoisomerase 2alpha (Topo 2alpha) is a nuclear enzyme that alters the topology of DNA. It's essential for normal chromosome segregation during cellular division. We aimed to investigate the association of Topo 2alpha expression with clinical, pathological parameters and prognosis in surgically resected non-small cell lung cancer (NSCLC) patients. METHODS: The study is comprised of 100 surgically resected NSCLC (squamous cell carcinoma in 50 patients, adenocarcinoma in 50 patients). The paraffin embedded tumor sections were retrieved for expression of Topo 2alpha. Nuclear and cytoplasmic expression of Topo 2alpha was determined by immunohistochemistry. Clinical, pathological data and survival of patients were determined from the hospital files. Median follow-up time was 35 (range, 4-120) months. RESULTS: Nuclear and cytoplasmic expression of Topo 2alpha was positive in 41 (41%) and 66 (66%) patients, respectively. There was no significant association between nuclear or cytoplasmic expression of Topo 2alpha and age, gender, smoking history. While nuclear expression was significantly increased in squamous cell carcinoma (P=0.008), OR (95% CI): 3.01 (1.31-6.92), cytoplasmic expression wasn't different. Both nuclear and cytoplasmic expression didn't show any association with tumor diameter, pathological stage, tumor differentiation and relapse. There was no significant association between nuclear or cytoplasmic expression of Topo 2alpha and survival. Tumor diameter (P=0.031) and metastasis to N2 lymph nodes (P=0.005) were independent prognostic factors. CONCLUSIONS: There was no association between Topo 2alpha expression and prognosis in surgically resected NSCLC patients. Nuclear expression of Topo 2alpha was significantly higher in patients with squamous cell carcinoma. PMID- 22934138 TI - A method for limiting pitfalls in the production of enhancement kinetic curves in 3T dynamic magnetic resonance mammography. AB - PURPOSE: The aim of the present study is to investigate means for the reduction or even elimination of enhancement kinetic curve errors due to breast motion in order to avoid pitfalls and to increase the sensitivity and specificity of the method. METHODS: 115 women underwent breast Magnetic Resonance Imaging (MRI). All patients were properly immobilized in a dedicated bilateral phased array coil. A magnetic resonance unit 3-Tesla (Signa, GE Healthcare) was used. The following sequences were applied: (I) axial Tau2-TSE, (II) axial STIR and (III) Vibrant axial T1-weighted fat saturation (six phases). Kinetic curves were derived semi automatically using the software of the system and manually by positioning the regions of interest (ROI) from stable reference points in all the phases. RESULTS: 376 abnormalities in 115 patients were investigated. In 81 (21.5%) cases, a change of the enhancement kinetic curve type was found when the two different methods were used. In cases of large fatty breasts, a change of the enhancement kinetic curve type in 13 lesions was found. In cases of small and dense breasts, only in 4 lesions the kinetic curve type changed, whereas in cases of small and fatty breasts, the kinetic curve type changed in 64 lesions (50 were observed in left breasts and 14 in right breasts). CONCLUSIONS: The derivation of enhancement kinetic curves should be performed by controlling and verifying that the ROIs lay at the same location of the lesion in all the phases of the dynamic study. PMID- 22934139 TI - Theoretical models of carcinogenic particle deposition and clearance in children's lungs. AB - INTRODUCTION: Deposition and clearance of carcinogenic particles in the lungs of subjects belonging to four different age groups (infants, children, adolescents, and adults) were theoretically investigated. The study is thought to contribute to the improvement of our knowledge concerning the behaviour of inhaled particles in lungs that may be attributed to different stages of development. METHODS: Particle deposition and clearance were simulated by using a well established stochastic lung model, allowing the generation of nearly realistic scenarios. For the computation of particle deposition all main deposition forces were considered. Additionally, any influences on particle behaviour due to particle geometry were covered by using the aerodynamic diameter concept. Particle clearance was simulated by defining both a fast mucociliary clearance phase and a slow bronchial/alveolar clearance phase, the latter of which is based on previously published models and suggestions. RESULTS: As clearly provided by the modelling computations, lung deposition of particles with aerodynamic diameters ranging from 1 nm to 10 um may significantly differ between the studied age groups. Whilst in infants and children most particles are accumulated in the extrathoracic region and in the upper bronchi, in adolescents and adults high percentages of inhaled particular substances may also reach the lower bronchi and alveoli. Although mucus velocities are significantly lower in young subjects compared to the older ones, fast clearance is more efficient in small lungs due to the shorter clearance paths that have to be passed. Slow clearance is commonly characterized by insignificant discrepancies between the age groups. CONCLUSIONS: From the study presented here it may be concluded that particle behaviour in infants' and children's lungs has to be regarded in a different light with respect to that in adolescents and adults. Although young subjects possess natural mechanisms of protecting their lungs from hazardous aerosols (e.g., expressed by breathing behaviour and lung size), they are much more sensitive to any particle exposure, since particle concentrations per lung tissue area may reach alarming values within a short period of inhalation. PMID- 22934140 TI - Relationship between respiratory viral load and lung lesion severity: a study in 24 cases of pandemic H1N1 2009 influenza A pneumonia. AB - OBJECTIVE: To investigate the relationship between respiratory viral load and lung lesion severity of patients with pandemic H1N1 2009 influenza A pneumonia. STUDY DESIGN: Cross-sectional observation study. METHODS: 24 consecutive H1N1 influenza patients with viral pneumonia (13 males, 11 females, mean age: 17.5 years) during their presentation to hospital were retrospectively analysed. Viral load were first measured on average 5.2 days after the onset of symptoms. The initial CT and viral load measurement was carried on the same day in 13 patients. The rest were carried out with a mean interval time of 1.5 days. All patients had viral load follow-up till turned negative. Thirteen patients had radiological follow-up. RESULTS: There was no significant correlation between the initial lung lesion severity and viral load (P=0.4). Both viral load and lung lesion severity decreased over time, being highest value at initial presentation. The patients had higher initial viral load or higher initial lung lesion severity tended to be slower in resolving. The lung lesion decreased at a slower rate than viral load. CONCLUSIONS: While there was no correlation between the initial viral load and lung lesion severity, these two indices provide valuable information for epidemiological control. PMID- 22934141 TI - Contralateral breast metastasis from pulmonary adenocarcinoma: two cases report and literature review. AB - Carcinoma metastatic to breast from extra-mammary malignancy is rare and only accounts for 0.4-1.3% of all breast cancer. Two rare cases of single breast metastasis from pulmonary adenocarcinoma were reported here with a brief review of the pertinent literature. The only complaint of the these two female patients was painless breast mass found recently. Most breast metastasis previously reported are present in the upper outer quadrant, however, in our study, one case was found to be located in the lower inner quadrant and the other in the upper inner quadrant. Tumor cells from breast biopsy were immune-positive for thyroid transcription factor-1. The two patients survived 5 and 8 months, respectively, following the diagnosis of both the primary lung tumor and the breast metastasis. Breast metastasis from lung adenocarcinoma is rare but does exist. The awareness of this possibility may help to differentiate the tumor from primary breast carcinoma. Clinical history and immunohistochemical studies are essential to reach the final diagnosis. PMID- 22934142 TI - DNA topoisomerase I drugs and radiotherapy for lung cancer. AB - Lung cancer represents the most common cause of cancer-related mortality in the United States and around the world. DNA topoisomerase I (TOP1) drugs such as irinotecan and topotecan represent a unique class of chemotherapeutic agents that exhibit not only potent cytotoxic effect, but also tumor-selective radiation sensitizing effect. The mechanism of cytotoxicity and radiation sensitization by TOP1 drugs has been intensely investigated. Modern radiotherapy, aided by improved imaging and treatment delivery technology, is capable of targeting tumors more precisely, while sparing surrounding critical structures. Clinical trials with camptothecin derivatives and radiotherapy have been conducted in lung cancers. Combined modality therapy with TOP1 drugs and radiotherapy offers a new frontier for lung cancer therapy. We review the present state of TOP1-targeted chemotherapy and modern radiotherapy for lung cancer. PMID- 22934143 TI - Revisiting signs, strengths and weaknesses of Standard Chest Radiography in patients of Acute Dyspnea in the Emergency Department. AB - Dyspnoea, defined as an uncomfortable awareness of breathing, together with thoracic pain are two of the most frequent symptoms of presentation of thoracic diseases in the Emergency Department (ED). Causes of dyspnoea are various and involve not only cardiovascular and respiratory systems. In the emergency setting, thoracic imaging by standard chest X-ray (CXR) plays a crucial role in the diagnostic process, because it is of fast execution and relatively not expensive. Although radiologists are responsible for the final reading of chest radiographs, very often the clinicians, and in particular the emergency physicians, are alone in the emergency room facing this task. In literature many studies have demonstrated how important and essential is an accurate direct interpretation by the clinician without the need of an immediate reading by the radiologist. Moreover, the sensitivity of CXR is much impaired when the study is performed at bedside by portable machines, particularly in the diagnosis of some important causes of acute dyspnoea, such as pulmonary embolism, pneumothorax, and pulmonary edema. In these cases, a high inter-observer variability of bedside CXR reading limits the diagnostic usefulness of the methodology and complicates the differential diagnosis. The aim of this review is to analyze the radiologic signs and the correct use of CXR in the most important conditions that cause cardiac and pulmonary dyspnoea, as acute exacerbation of chronic obstructive pulmonary disease, acute pulmonary oedema, acute pulmonary trombo-embolism, pneumothorax and pleural effusion, and to focus indications and limitations of this diagnostic tool. PMID- 22934144 TI - Cryosurgery for lung cancer. AB - Cryosurgery is suited for patients with lung cancer who are not considered for lung resection because of the advanced stage of the disease or the patient's poor general condition or poor respiratory function and with tumor recurrence following radiotherapy, chemotherapy or lung resection, and those patients who have localized lung cancer but refuse to receive operative therapy. Procedures of cryosurgery for lung cancer can be performed through endobronchial, direct intrathoracic (at exploratory thoracotomy) or percutaneous routes depending upon location and size of tumor. Six hundred and twenty-five patients with Non-small cell lung cancer (NSCLC) received percutaneous cryoablation in Fuda Cancer Hospital Guangzhou, China. One hundred and fifty patients were followed-up for 12 to 38 months. Results showed that 1-, 2-, and 3-year survival rates were 64%, 45% and 32%, respectively. The adverse effects after cryosurgery of lung cancer include haemoptysis, pneumothorax, bloody thorax, pleural effusion and pulmonary infection which are generally mild, transient, and recovery with symptomatic management. In vitro studies have shown cryotherapy of lung cancer cells can improve the immune system to trigger the specific anti-tumor response. In the future, comparative studies between this modality and other therapies should be conducted for the treatment of lung cancer. In addition, more attention needs to be put on the immunomodulators that enhance the cryoimmunology. PMID- 22934145 TI - The evolution of the role of surgery in the management of breast cancer lung metastasis. AB - Breast cancer is the second leading cause of cancer death among women in the United States. Patients with metastatic disease have a median survival of 12 to 24 months and most present with disseminated disease; however, some present with isolated pulmonary metastases which may benefit from surgical resection. Although the initial experience with resection of pulmonary metastases in the late 19th and early 20th centuries produced some encouraging results, patient selection criteria for resection were strict until the mid-1960's when a significant improvement in survival resulted from aggressive management of pulmonary metastasis in osteosarcoma patients. The application of this approach to breast cancer patients similarly produced encouraging results, with five year survival rates in select patients ranging from 36-54%, but this was not without controversy. In this review, we discuss the evaluation of the breast cancer patient with a pulmonary nodule, the historical evolution of the role of surgery in the management of pulmonary metastasis, as well as the latest evidence to guide patient selection and management. PMID- 22934146 TI - Cardiac obstruction secondary to metastatic invasion - A rare complication of Human Herpes Virus 8-positive plasmablastic lymphoma in acquired immunodeficiency syndrome. AB - Human herpes virus 8 (HHV8)-positive plasmablastic lymphoma (PBL) is a particularly rare and aggressive subtype of non-Hodgkin lymphoma, strongly associated with human immunodeficiency virus infection, with poor response to therapy and short survival. Characteristically, it shows proliferation of large plasmablastic cells with often eccentrically placed nuclei, with immunohistochemical assay positive for HHV8 latent nuclear antigen 1 and IgM. Primary mediastinal occurrence of a HHV8-positive PBL is rare and metastatic disease even more uncommon; tumor invasion to the heart leading to intracardiac obstruction with a rapidly fatal disease course has not been previously described. PMID- 22934147 TI - Fibrosingmediastinitis and consequent superior vena cava syndrome - A case report. AB - Fibrosing mediastinitis is a rare, chronic inflammatory disease that has several implicated etiologies. We describe a case of a 41-year old woman who presented with the classic signs and symptoms of superior vena cava syndrome. Imaging revealed a diffuse infiltrative mediastinal process, which on biopsy was consistent with fibrosing mediastintis. PMID- 22934148 TI - Recurrent spontaneous pneumomediastinum: a rare but possible event! AB - A number of risk indices have been formulated in an attempt to predict risk of a major hemorrhage in an individual on warfarin therapy. No single index to date is able to reliably predict this risk in an individual patient. Although most warfarin related hemorrhages are gastrointestinal or intracranial in origin this case represents a particularly rare entity of a major hemorrhage presenting as an encysted empyema. To the best of our knowledge this has never before been described. PMID- 22934149 TI - Double whammy - mediastinal and ovarian teratoma: a rare clinical co-existence. AB - Teratomas are germ cell tumours arising as the result of abnormal development of totipotential cells. They are commonly encountered in the gonads and occasionally found in mediastinum. We report a case of asymptomatic 28 years old lady with concomitant mature cystic teratoma in her mediastinum and left ovary which was diagnosed incidentally during health check up. This case is reported because of its rare and unusual coexistence. PMID- 22934150 TI - HIV-1 Resistant CDK2-Knockdown Macrophage-Like Cells Generated from 293T Cell Derived Human Induced Pluripotent Stem Cells. AB - A major challenge in studies of human diseases involving macrophages is low yield and heterogeneity of the primary cells and limited ability of these cells for transfections and genetic manipulations. To address this issue, we developed a simple and efficient three steps method for somatic 293T cells reprogramming into monocytes and macrophage-like cells. First, 293T cells were reprogrammed into induced pluripotent stem cells (iPSCs) through a transfection-mediated expression of two factors, Oct-4 and Sox2, resulting in a high yield of iPSC. Second, the obtained iPSC were differentiated into monocytes using IL-3 and M-CSF treatment. And third, monocytes were differentiated into macrophage-like cells in the presence of M-CSF. As an example, we developed HIV-1-resistant macrophage-like cells from 293T cells with knockdown of CDK2, a factor critical for HIV-1 transcription. Our study provides a proof-of-principle approach that can be used to study the role of host cell factors in HIV-1 infection of human macrophages. PMID- 22934151 TI - A prospective, multinational pharmacoepidemiological study of clinical conversion to sirolimus immunosuppression after renal transplantation. AB - This prospective pharmacoepidemiological study examined treatment and outcomes in patients converted to sirolimus (SRL) after renal transplantation. 484 subjects in 36 centres in 7 countries were followed for up to 5 years. Principal reasons for conversion were declining graft function (146/484, 30%) and side effects of prior therapy (144/484, 30%) and the major treatment combinations after conversion were SRL +/- MMF (62%), SRL + TAC (21.5%), SRL + CSA (16.5%). The cumulative probability of biopsy-confirmed acute rejection (BCAR) was 5% (n = 22), death-censored graft loss 12% (n = 56) and death 6% (n = 22), and there was no significant relationship to the treatment combination employed. Median calculated creatinine clearance was 48.4 (29.3, 64.5) mL/min at conversion, rising to 54.1 (41.2, 69.0) mL/min at month 1, 55.7 (39.0, 73.0) mL/min at month 12, 58.6 (39.7, 75.2) mL/min at two years and 60.9 (36.0, 77.0) mL/min at three years post-conversion. The most common adverse events were hypertension (47%), hyperlipidemia (26%), urinary tract infections (25%), anaemia (24%) and diarrhea (14%), and cardiac events, hyperlipemia and CMV infection were more common in patients converted during the first year. SRL was most frequently combined with MMF after conversion, but principal clinical outcomes were not significantly influenced by the treatment combination employed in normal practice. PMID- 22934152 TI - Does Cattle Milieu Provide a Potential Point to Target Wild Exophilic Anopheles arabiensis (Diptera: Culicidae) with Entomopathogenic Fungus? A Bioinsecticide Zooprophylaxis Strategy for Vector Control. AB - Background. Anopheles arabiensis is increasingly dominating malaria transmission in Africa. The exophagy in mosquitoes threatens the effectiveness of indoor vector control strategies. This study aimed to evaluate the effectiveness of fungus against An. arabiensis when applied on cattle and their environments. Methods. Experiments were conducted under semi-field and small-scale field conditions within Kilombero valley. The semi-field reared females of 5-7 days old An. arabiensis were exposed to fungus-treated and untreated calf. Further, wild An. arabiensis were exposed to fungus-treated calves, mud-huts, and their controls. Mosquitoes were recaptured the next morning and proportion fed, infected, and survived were evaluated. Experiments were replicated three times using different individuals of calves. Results. A high proportion of An. arabiensis was fed on calves (>0.90) and become infected (0.94) while resting on fungus-treated mud walls than on other surfaces. However, fungus treatments reduced fecundity and survival of mosquitoes. Conclusion. This study demonstrates for the first time the potential of cattle and their milieu for controlling An. arabiensis. Most of An. arabiensis were fed and infected while resting on fungus treated mud walls than on other surfaces. Fungus treatments reduced fecundity and survival of mosquitoes. These results suggest deployment of bioinsecticide zooprophylaxis against exophilic An. arabiensis. PMID- 22934153 TI - The effect of antihelminthic treatment on subjects with asthma from an endemic area of schistosomiasis: a randomized, double-blinded, and placebo-controlled trial. AB - This is a prospective, double-blinded, and placebo-controlled trial evaluating the influence of antihelminthic treatments on asthma severity in individuals living in an endemic area of schistosomiasis. Patients from group 1 received placebo of Albendazole or of Praziquantel and from group 2 received Albendazole and Praziquantel. Asthma severity was assessed by clinical scores and by pulmonary function test. There was no significant difference in the asthma scores from D0 to D1-D7 after Albendazole or Praziquantel and from D0 to D30-90 after Albendazole or Praziquantel in both, group 1 and 2. It was observed, however, a clinical worsening of the overall studied population after 6 months and 12 months of antihelminthic treatments. Additionally, we observed increased frequency of forced expiratory volume in 1 second (FEV1) <80% on 12 and 18 months after treatment. The worsening of asthma severity after repeated antihelminthic treatments is consistent with the hypothesis of the protective role conferred by helminths in atopic diseases. PMID- 22934154 TI - The influence of poverty and culture on the transmission of parasitic infections in rural nicaraguan villages. AB - Intestinal parasitic infections cause one of the largest global burdens of disease. To identify possible areas for interventions, a structured questionnaire addressing knowledge, attitude, and practice regarding parasitic infections as well as the less studied role of culture and resource availability was presented to mothers of school-age children in rural communities around San Juan del Sur, Nicaragua. We determined that access to resources influenced knowledge, attitude, and behaviors that may be relevant to transmission of parasitic infections. For example, having access to a clinic and prior knowledge about parasites was positively correlated with the practice of having fencing for animals, having fewer barefoot children, and treating children for parasites. We also found that cultural beliefs may contribute to parasitic transmission. Manifestations of machismo culture and faith in traditional medicines conflicted with healthy practices. We identified significant cultural myths that prevented healthy behaviors, including the beliefs that cutting a child's nails can cause tetanus and that showering after a hot day caused sickness. The use of traditional medicine was positively correlated with the belief in these cultural myths. Our study demonstrates that the traditional knowledge, attitude, and practice model could benefit from including components that examine resource availability and culture. PMID- 22934155 TI - Survey of the synanthropic flies associated with human habitations in ubon ratchathani province of northeast Thailand. AB - Synanthropic fly surveys were performed to determine the species composition and abundance in Ubon Ratchathani province in Northeast Thailand. Adult fly collections were conducted in various human habitations from two districts-Muang Ubon Ratchathani and Warinchamrap, at fresh-food markets, garbage piles, restaurants, school cafeterias, and rice paddy fields. Customized reconstructable funnel fly traps baited with 250 g of 1-day tainted beef were used for fly collections from September 2010-February 2011. A total of 3,262 flies were captured, primarily consisting of three families including: Calliphoridae (6 species), Muscidae (3 species), and Sarcophagidae (11 species). The blow fly, Chrysomya megacephala, and the house fly, Musca domestica, were the dominant species collected from both districts at all collection sites. C. megacephala was predominant in paddy fields, restaurants and garbage piles, while M. domestica was numerically dominant in fresh-food markets and school cafeterias. The current survey identified various species of synanthropic flies with close associations to humans and with the ability to transmit human pathogens in Ubon Ratchathani province; providing crucial information that may be used for developing control and sanitation management plans in this particular area. PMID- 22934156 TI - Application of anterior segment optical coherence tomography in pediatric ophthalmology. AB - Purpose. Application of anterior segment optical coherence (AS-OCT) in pediatric ophthalmology. Methods. Retrospective clinical study case series of 26 eyes of 19 pediatric patients throughout a 21-month period, presenting anterior segment pathologies, were submitted to AS-OCT examination (OCT Visante, 1310 nm, Zeiss), noncontact technique, no sedation requirement. Results. AS-OCT images were obtained from 19 patients (range: 2 months to 12 years). Clinical diagnosis of anterior segment abnormalities included cornea disease (n = 7), congenital anterior segment conditions (n = 10), ocular trauma (n = 1), anterior segment surgeries (n = 2), iridocorneal angle abnormalities (n = 4), intermediate uveitis (n = 2). The most common OCT findings were corneal hyperreflectivity and thickening (n = 15), shallow anterior chamber with iris-lens diaphragm anterior displacement (n = 4), atypical corneal curvature (n = 4), corneal thinning (n = 4), peripheral synechiae with angle closure (n = 3), increased anterior chamber depth (n = 2), and proximal portion of glaucoma drainage tube (n = 2). Conclusion. In the present study, noncontact AS-OCT demonstrated to be a feasible technique to evaluate the anterior segment providing anatomic details and useful to clarify diagnosis in the pediatric population. PMID- 22934157 TI - Increased mesohippocampal dopaminergic activity and improved depression-like behaviors in maternally separated rats following repeated fasting/refeeding cycles. AB - We have previously reported that rats that experienced 3 h of daily maternal separation during the first 2 weeks of birth (MS) showed binge-like eating behaviors with increased activity of the hypothalamic-pituitary-adrenal axis when they were subjected to fasting/refeeding cycles repeatedly. In this study, we have examined the psychoemotional behaviors of MS rats on the fasting/refeeding cycles, together with their brain dopamine levels. Fasting/refeeding cycles normalized the ambulatory activity of MS rats, which was decreased by MS experience. Depression-like behaviors, but not anxiety, by MS experience were improved after fasting/refeeding cycles. Fasting/refeeding cycles did not significantly affect the behavioral scores of nonhandled (NH) control rats. Fasting/refeeding cycles increased dopamine levels not only in the hippocampus but also in the midbrain dopaminergic neurons in MS rats, but not in NH controls. Results demonstrate that fasting/refeeding cycles increase the mesohippocampal dopaminergic activity and improve depression-like behaviors in rats that experienced MS. Together with our previous paper, it is suggested that increased dopamine neurotransmission in the hippocampus may be implicated in the underlying mechanisms by which the fasting/refeeding cycles induce binge-like eating and improve depression-like behaviors in MS rats. PMID- 22934159 TI - Assessment of psychological distress in epilepsy: perspective from pakistan. AB - The unpredictable nature & elongated course of epilepsy affect all dimensions (physical, psychological, and social) of an individual's life. People with the diagnosis of epilepsy are a high-risk group for different psychiatric problems that is anxiety, depression as well as social problems (marriage, education, and daily activities). The findings of present research revealed high rate (70%) of psychological distress among fifty adult individuals with epilepsy. It was also found that people with uncontrolled epilepsy experience high level of psychological distress (100%) as compared to those with controlled (42%). Demographic and clinical factors associated with distress include lack of occupation, the presence of an underlying disabling condition (with treatment), and the severity of epilepsy. The finding generated here showed that 13 out of 19 females with epilepsy reported psychological distress. It was also found that none of these women was employed (a cultural specific phenomenon) with a slightly high number of unmarried females (74%). So by understanding the relationship between clinical and psychosocial variables, a good management plan can be devised with a focus on social and gender differences. The present research can also help to increase the awareness and to lower the stigmatization related to epilepsy. PMID- 22934158 TI - Epilepsy, mental health disorder, or both? AB - Temporal lobe epilepsy (TLE), a subset of the seizure disorder family, represents a complex neuropsychiatric illness, where the neurological presentation may be complemented by varying severity of affective, behavioral, psychotic, or personality abnormalities, which, in turn, may not only lead to misdiagnosis, but also affect the management. This paper outlines a spectrum of mental health presentations, including psychosis, mood, anxiety, panic, and dissociative states, associated with epilepsy that make the correct diagnosis a challenge. PMID- 22934160 TI - Anatomy of the temporal lobe. AB - Only primates have temporal lobes, which are largest in man, accommodating 17% of the cerebral cortex and including areas with auditory, olfactory, vestibular, visual and linguistic functions. The hippocampal formation, on the medial side of the lobe, includes the parahippocampal gyrus, subiculum, hippocampus, dentate gyrus, and associated white matter, notably the fimbria, whose fibres continue into the fornix. The hippocampus is an inrolled gyrus that bulges into the temporal horn of the lateral ventricle. Association fibres connect all parts of the cerebral cortex with the parahippocampal gyrus and subiculum, which in turn project to the dentate gyrus. The largest efferent projection of the subiculum and hippocampus is through the fornix to the hypothalamus. The choroid fissure, alongside the fimbria, separates the temporal lobe from the optic tract, hypothalamus and midbrain. The amygdala comprises several nuclei on the medial aspect of the temporal lobe, mostly anterior the hippocampus and indenting the tip of the temporal horn. The amygdala receives input from the olfactory bulb and from association cortex for other modalities of sensation. Its major projections are to the septal area and prefrontal cortex, mediating emotional responses to sensory stimuli. The temporal lobe contains much subcortical white matter, with such named bundles as the anterior commissure, arcuate fasciculus, inferior longitudinal fasciculus and uncinate fasciculus, and Meyer's loop of the geniculocalcarine tract. This article also reviews arterial supply, venous drainage, and anatomical relations of the temporal lobe to adjacent intracranial and tympanic structures. PMID- 22934161 TI - Functional magnetic resonance imaging for language mapping in temporal lobe epilepsy. AB - Functional magnetic resonance imaging (fMRI) is a noninvasive technique that is increasingly used to understand the cerebral cortical networks and organizations. In this paper, we describe the role of fMRI for mapping language networks in the presurgical workup of patients with medically intractable temporal lobe epilepsy (TLE). Studies comparing fMRI with the intracarotid sodium amobarbital (Wada) test and fMRI with intraoperative cortical stimulation mapping for language lateralization and/or localization in medically intractable TLE are discussed. PMID- 22934162 TI - Temporal lobe epilepsy surgery failures: a review. AB - Patients with temporal lobe epilepsy (TLE) are refractory to antiepileptic drugs in about 30% of cases. Surgical treatment has been shown to be beneficial for the selected patients but fails to provide a seizure-free outcome in 20-30% of TLE patients. Several reasons have been identified to explain these surgical failures. This paper will address the five most common causes of TLE surgery failure (a) insufficient resection of epileptogenic mesial temporal structures, (b) relapse on the contralateral mesial temporal lobe, (c) lateral temporal neocortical epilepsy, (d) coexistence of mesial temporal sclerosis and a neocortical lesion (dual pathology); and (e) extratemporal lobe epilepsy mimicking TLE or temporal plus epilepsy. Persistence of epileptogenic mesial structures in the posterior temporal region and failure to distinguish mesial and lateral temporal epilepsy are possible causes of seizure persistence after TLE surgery. In cases of dual pathology, failure to identify a subtle mesial temporal sclerosis or regions of cortical microdysgenesis is a likely explanation for some surgical failures. Extratemporal epilepsy syndromes masquerading as or coexistent with TLE result in incomplete resection of the epileptogenic zone and seizure relapse after surgery. In particular, the insula may be an important cause of surgical failure in patients with TLE. PMID- 22934163 TI - Epileptic Encephalopathies with Status Epilepticus during Sleep: New Techniques for Understanding Pathophysiology and Therapeutic Options. AB - Encephalopathy with status epilepticus during sleep (ESES) is an epileptic encephalopathy, as defined by the International League Against Epilepsy (ILAE) Task Force on Classification and Terminology, that is, a condition in which the epileptic processes themselves are believed to contribute to the disturbance in cerebral function. Clinical manifestations of ESES are heterogeneous: apart from different seizure types, they consist in combinations of cognitive, motor, and behavioural disturbances associated with a peculiar electroencephalographic pattern of paroxysmal activity significantly activated during slow sleep, which culminates in a picture of continuous spikes and waves during sleep (CSWS). The pathophysiological mechanisms underlying this condition are still incompletely understood. Establishing a clear-cut correlation between EEG abnormalities and clinical data, though interesting, is very complex. Computer-assisted EEG analyses especially if combined with functional magnetic resonance imaging (EEG fMRI) and metabolic neuroimaging have recently emerged as useful approaches to better understand the pathophysiological processes underlying ESES. Treatment of ESES is not just limited to seizures control but it should be focused on controlling neuropsychological outcome through an improvement of the continuous epileptiform activity. General agreement on treatment guidelines is still lacking. Implementation of new techniques might allow a better understanding of the pathophysiology of ESES and could enhance therapeutics options. PMID- 22934164 TI - Intensity-modulated radiation therapy for rectal carcinoma can reduce treatment breaks and emergency department visits. AB - Purpose. To compare the acute toxicities of IMRT to 3D-conformal radiation therapy (3DCRT) in the treatment of rectal cancer. Methods and Materials. Eighty six patients with rectal cancer preoperatively treated with IMRT (n = 30) and 3DCRT (n = 56) were retrospectively reviewed. Rates of acute toxicity between IMRT and 3DCRT were compared for anorexia, dehydration, diarrhea, nausea, vomiting, weight loss, radiation dermatitis, fatigue, pain, urinary frequency, and blood counts. Fisher's exact test and chi-square analysis were applied to detect statistical differences in incidences of toxicity between these two groups of patients. Results. There were fewer hospitalizations and emergency department visits in the group treated with IMRT compared with 3DCRT (P = 0.005) and no treatment breaks with IMRT compared to 20% with 3DCRT (P = 0.0002). Patients treated with IMRT had a significant reduction in grade >=3 toxicities versus grade <=2 toxicities (P = 0.016) when compared to 3DCRT. The incidence of grade >=3 diarrhea was 9% among 3DCRT patients compared to 3% among IMRT patients (P = 0.31). Conclusions. IMRT for rectal cancer can reduce treatment breaks, emergency department visits, hospitalizations, and all grade >=3 toxicities compared to 3DCRT. Further evaluation and followup is warranted to determine late toxicities and long-term results of IMRT. PMID- 22934165 TI - The Role of HCN Channels on Membrane Excitability in the Nervous System. AB - Hyperpolarization-activated and cyclic nucleotide-gated (HCN) channels were first reported in heart cells and are recently known to be involved in a variety of neural functions in healthy and diseased brains. HCN channels generate inward currents when the membrane potential is hyperpolarized. Voltage dependence of HCN channels is regulated by intracellular signaling cascades, which contain cyclic AMP, PIP(2), and TRIP8b. In addition, voltage-gated potassium channels have a strong influence on HCN channel activity. Because of these funny features, HCN channel currents, previously called funny currents, can have a wide range of functions that are determined by a delicate balance of modulatory factors. These multifaceted features also make it difficult to predict and elucidate the functional role of HCN channels in actual neurons. In this paper, we focus on the impacts of HCN channels on neural activity. The functions of HCN channels reported previously will be summarized, and their mechanisms will be explained by using numerical simulation of simplified model neurons. PMID- 22934166 TI - A Novel Mathematical Approach to Define the Genes/SNPs Conferring Risk or Protection in Sporadic Amyotrophic Lateral Sclerosis Based on Auto Contractive Map Neural Networks and Graph Theory. AB - Background. Complex diseases like amyotrophic lateral sclerosis (ALS) implicate phenotypic and genetic heterogeneity. Therefore, multiple genetic traits may show differential association with the disease. The Auto Contractive Map (AutoCM), belonging to the Artificial Neural Network (ANN) architecture, "spatializes" the correlation among variables by constructing a suitable embedding space where a visually transparent and cognitively natural notion such as "closeness" among variables reflects accurately their associations. Results. In this pilot case control study single nucleotide polymorphism (SNP) in several genes has been evaluated with a novel data mining approach based on an AutoCM. We have divided the ALS dataset into two dataset: Cases and Control dataset; we have applied to each one, independently, the AutoCM algorithm. Six genetic variants were identified which differently contributed to the complexity of the system: three of the above genes/SNPs represent protective factors, APOA4, NOS3, and LPL, since their contribution to the whole complexity resulted to be as high as 0.17. On the other hand ADRB3, LIPC, and MMP3, whose hub relevancies contribution resulted to be as high as 0.13, seem to represent susceptibility factors. Conclusion. The biological information available on these six polymorphisms is consistent with possible pathogenetic pathways related to ALS. PMID- 22934167 TI - Sertraline may improve language developmental trajectory in young children with fragile x syndrome: a retrospective chart review. AB - Young children with fragile X syndrome (FXS) often experience anxiety, irritability, and hyperactivity related to sensory hyperarousal. However, there are no medication recommendations with documented efficacy for children under 5 years old of age with FXS. We examined data through a chart review for 45 children with FXS, 12-50 months old, using the Mullen Scales of Early Learning (MSEL) for baseline and longitudinal assessments. All children had clinical level of anxiety, language delays based on MSEL scores, and similar early learning composite (ELC) scores at their first visit to our clinic. Incidence of autism spectrum disorder (ASD) was similar in both groups. There were 11 children who were treated with sertraline, and these patients were retrospectively compared to 34 children who were not treated with sertraline by chart review. The baseline assessments were done at ages ranging from 18 to 44 months (mean 26.9, SD 7.99) and from 12 to 50 months (mean 29.94, SD 8.64) for treated and not treated groups, respectively. Mean rate of improvement in both expressive and receptive language development was significantly higher in the group who was treated with sertraline (P < 0.0001 and P = 0.0071, resp.). This data supports the need for a controlled trial of sertraline treatment in young children with FXS. PMID- 22934168 TI - The development of executive function in autism. AB - Autism is a common and often highly debilitating neurodevelopmental condition, whose core behavioral features are believed to be rooted in disrupted neurocognitive processes, including especially "executive function." Researchers have predominantly focused upon understanding the putative causal relationship between difficulties in EF and autistic symptomatology. This paper suggests, however, that the effects of individual differences in EF should be more far reaching, playing a significant part in the real-life outcomes of individuals with autism, including their social competence, everyday adaptive behavior, and academic achievement. It further considers the nature of the EF-outcome relationship, including the possible determinants of individual differences in EF, and makes several recommendations for future research. PMID- 22934169 TI - Prenatal and Postnatal Epigenetic Programming: Implications for GI, Immune, and Neuronal Function in Autism. AB - Although autism is first and foremost a disorder of the central nervous system, comorbid dysfunction of the gastrointestinal (GI) and immune systems is common, suggesting that all three systems may be affected by common molecular mechanisms. Substantial systemic deficits in the antioxidant glutathione and its precursor, cysteine, have been documented in autism in association with oxidative stress and impaired methylation. DNA and histone methylation provide epigenetic regulation of gene expression during prenatal and postnatal development. Prenatal epigenetic programming (PrEP) can be affected by the maternal metabolic and nutritional environment, whereas postnatal epigenetic programming (PEP) importantly depends upon nutritional support provided through the GI tract. Cysteine absorption from the GI tract is a crucial determinant of antioxidant capacity, and systemic deficits of glutathione and cysteine in autism are likely to reflect impaired cysteine absorption. Excitatory amino acid transporter 3 (EAAT3) provides cysteine uptake for GI epithelial, neuronal, and immune cells, and its activity is decreased during oxidative stress. Based upon these observations, we propose that neurodevelopmental, GI, and immune aspects of autism each reflect manifestations of inadequate antioxidant capacity, secondary to impaired cysteine uptake by the GI tract. Genetic and environmental factors that adversely affect antioxidant capacity can disrupt PrEP and/or PEP, increasing vulnerability to autism. PMID- 22934171 TI - Support, Inclusion, and Special Education Teachers' Attitudes toward the Education of Students with Autism Spectrum Disorders. AB - This study is aimed at assessing special education teachers' attitudes toward teaching pupils with autism spectrum disorders (ASDs) and at determining the role of variables associated with a positive attitude towards the children and their education. Sixty-nine special education teachers were interviewed. The interview included two multiple-choice Likert-type questionnaires, one about teachers' attitude, and another about teachers' perceived needs in relation to the specific education of the pupil with ASD. The study shows a positive view of teachers' expectations regarding the education of pupils with ASD. A direct logistic regression analysis was performed testing for experience with the child, school relationship with an ASD network and type of school (mainstream or special) as potential predictors. Although all three variables are useful in predicting special education teachers' attitudes, the most relevant was the relationship with an ASD network. Need for information and social support are the relatively highest needs expressed by teachers. PMID- 22934170 TI - Assessment and treatment in autism spectrum disorders: a focus on genetics and psychiatry. AB - Autism spectrum disorders (ASDs) are neurobehavioral disorders characterized by abnormalities in three behavioral domains including social interaction, impaired communication, and repetitive stereotypic behaviors. ASD affects approximately 1% of children and is on the rise with significant genetic mechanisms underlying these disorders. We review the current understanding of the role of genetic and metabolic factors contributing to ASD with the use of new genetic technology. Fifty percent is diagnosed with chromosomal abnormalities, small DNA deletions/duplications, single-gene conditions, or metabolic disturbances. Genetic evaluation is discussed along with psychiatric treatment and approaches for selection of medication to treat associated challenging behaviors or comorbidities seen in ASD. We emphasize the importance of prioritizing treatment based on target symptom clusters and in what order for individuals with ASD, as the treatment may vary from patient to patient. PMID- 22934172 TI - Mood disorders in mothers of children on the autism spectrum are associated with higher functioning autism. AB - Mood disorders occur more frequently in family members of individuals with autism spectrum disorders (ASD) than in the general population. There may be associations between maternal mood disorder history patterns and specific ASD phenotypes. We therefore examined the relationship between maternal mood disorders and child autism spectrum disorders in 998 mother-child dyads enrolled in a national online autism registry and database. Mothers of children with ASD completed online questionnaires addressing their child's ASD as well as their own mood disorder history. In multivariate logistic regression models of ASD diagnoses, the odds of an Asperger disorder versus autistic disorder diagnosis were higher among those children whose mothers had a lifetime history of bipolar disorder (OR 2.11, CI 1.20, 3.69) or depression (OR 1.62, CI 1.19, 2.19). Further, maternal mood disorder onset before first pregnancy was associated with higher odds (OR 2.35, CI 1.48, 3.73) of an Asperger versus autism diagnosis among this sample of children with ASD. These data suggest that differences in maternal mood disorder history may be associated with ASD phenotype in offspring. PMID- 22934173 TI - Meta-analysis of studies incorporating the interests of young children with autism spectrum disorders into early intervention practices. AB - Incorporating the interests and preferences of young children with autism spectrum disorders into interventions to promote prosocial behavior and decrease behavior excesses has emerged as a promising practice for addressing the core features of autism. The efficacy of interest-based early intervention practices was examined in a meta-analysis of 24 studies including 78 children 2 to 6 years of age diagnosed with autism spectrum disorders. Effect size analyses of intervention versus nonintervention conditions and high-interest versus low interest contrasts indicated that interest-based intervention practices were effective in terms of increasing prosocial and decreasing aberrant child behavior. Additionally, interest-based interventions that focused on two of the three core features of autism spectrum disorders (poor communication, poor interpersonal relationships) were found most effective in influencing child outcomes. Implications for very early intervention are discussed in terms addressing the behavior markers of autism spectrum disorders before they become firmly established. PMID- 22934174 TI - Unique theory of mind differentiation in children with autism and asperger syndrome. AB - This study was designed to determine if ToM abilities of children with autism and Asperger syndrome differentiate into Intrapersonal ToM and Social ToM. A battery of Social and Intrapersonal ToM tasks was administered to 39 children with autism and 34 children with Asperger syndrome. For both groups of children, ToM differentiated and Intrapersonal ToM was stronger than Social ToM. This asymmetry was greater for children with autism, whose Social ToM was especially weak. These results support a differentiated, as opposed to integrated, ToM. Moreover, the findings provide a more thorough understanding of the cognitive abilities associated with autism and Asperger syndrome. PMID- 22934175 TI - Gait symmetry in children with autism. AB - Most studies examining gait asymmetry have focused on infants and toddlers and have tended to use subjective methods of evaluating movement. No previous studies have examined gait symmetry in older children with autism using objective motion capture systems. The purpose of this paper was to quantify gait symmetry in children with autism versus age-matched controls. Fourteen children with autism (N = 14) and twenty-two (N = 22) age, height, and weight-matched controls participated in the study. An eight camera Vicon motion capture system and four Kistler force plates were used to compute temporal-spatial parameters and symmetry indices during walking. Group differences in these measures were tested using MANOVAs. No significant differences between the autism and control group were found for any of the temporal-spatial measures or symmetry indices. Therefore, results suggest that children with autism demonstrate typical symmetry or interlimb movement during gait. Further research is needed to examine the use of different gait inputs to the symmetry indices (e.g., joint angles and moments). A greater awareness of the movement patterns associated with autism may increase our understanding of this disorder and have important implications for treatment planning. PMID- 22934176 TI - Looking through the Same Eyes? Do Teachers' Participation Ratings Match with Ratings of Students with Autism Spectrum Conditions in Mainstream Schools? AB - To create an inclusive classroom and act accordingly, teachers' understanding of the experiences of participation of students with autism spectrum conditions (ASCs) is crucial. This understanding may depend on the teachers' professional experiences, support and personal interests. The aim of the present questionnaire study was to investigate how well the teachers' ratings of their students with ASCs' perception of participation matched with the students' own ratings. Furthermore, possible correlations between the accuracy of teachers' ratings and the teachers' self-reported professional experience, support (including support staff), and personal interest were investigated. Teachers' ratings were also used to examine how their understandings correlated with classroom actions. The agreements between teachers' and students' ratings were moderate to high, and the ability to attune to the students' perception of participation was not affected by the presence of a support-staff. The teachers' personal interest in teaching students with ASC correlated with their accuracy, suggesting that this is a factor to consider when planning for successful placements in mainstream schools. Teachers' understandings of the students with ASCs' perception of being bullied or unpopular correlated with implementation of activities to improve the attitudes of classmates, but not with actions to enhance social relations for the students with ASC. PMID- 22934177 TI - IGF1 as a Potential Treatment for Rett Syndrome: Safety Assessment in Six Rett Patients. AB - Rett syndrome (RTT) is a devastating neurodevelopmental disorder that affects one in ten thousand girls and has no cure. The majority of RTT patients display mutations in the gene that codes for the methyl-CpG-binding protein 2 (MeCP2). Clinical observations and neurobiological analysis of mouse models suggest that defects in the expression of MeCP2 protein compromise the development of the central nervous system, especially synaptic and circuit maturation. Thus, agents that promote brain development and synaptic function, such as insulin-like growth factor 1 (IGF1), are good candidates for ameliorating the symptoms of RTT. IGF1 and its active peptide, (1-3) IGF1, cross the blood brain barrier, and (1-3) IGF1 ameliorates the symptoms of RTT in a mouse model of the disease; therefore they are ideal treatments for neurodevelopmental disorders, including RTT. We performed a pilot study to establish whether there are major risks associated with IGF1 administration in RTT patients. Six young girls with classic RTT received IGF1 subcutaneous injections twice a day for six months, and they were regularly monitored by their primary care physicians and by the unit for RTT in Versilia Hospital (Italy). This study shows that there are no risks associated with IGF1 administration. PMID- 22934178 TI - Social Competence Intervention for Parents (SCI-P): Comparing Outcomes for a Parent Education Program Targeting Adolescents with ASD. AB - Research has shown that parent education programs can address some of the distinct challenges that parents of youth with autism spectrum disorders (ASDs) encounter. This study examined the effectiveness of the Social Competence Intervention for Parents (SCI-P), a parent education program, administered in conjunction with a social competence intervention that targeted youth with ASD ages 11-14 (SCI-A). Using a quasi-experimental pre-post design, parents were assigned to either the SCI-P group (n = 16) or to the waitlist comparison group (n = 10). Analyses of covariance (ANCOVAs) revealed a significant effect for parent education participation such that SCI-P participants experienced significantly greater reductions in levels of stress and a trend for increases in parenting sense of competence from pre- to post-intervention. Moreover, parents in the SCI-P group reported high satisfaction with the program. These findings suggest that parent education can result in positive outcomes for parents' well being. PMID- 22934179 TI - Improving psychiatric hospital care for pediatric patients with autism spectrum disorders and intellectual disabilities. AB - Pediatric patients with autism spectrum disorders (ASD) and/or intellectual disabilities (ID) are at greater risk for psychiatric hospitalization compared to children with other disorders. However, general psychiatric hospital environments are not adapted for the unique learning styles, needs, and abilities of this population, and there are few specialized hospital-based psychiatric care programs in the United States. This paper compares patient outcomes from a specialized psychiatric hospital program developed for pediatric patients with an ASD and/or ID to prior outcomes of this patient population in a general psychiatric program at a children's hospital. Record review data indicate improved outcomes for patients in the specialized program of reduced recidivism rates (12% versus 33%) and decreased average lengths of inpatient stay (as short as 26 days versus 45 days). Available data from a subset of patients (n = 43) in the specialized program showed a decrease in irritability and hyperactivity behaviors from admission to discharge and that 35 previously undetected ASD diagnoses were made. Results from this preliminary study support specialized psychiatric care practices with this population to positively impact their health care outcomes. PMID- 22934180 TI - Identification of Four Novel Synonymous Substitutions in the X-Linked Genes Neuroligin 3 and Neuroligin 4X in Japanese Patients with Autistic Spectrum Disorder. AB - Mutations in the X-linked genes neuroligin 3 (NLGN3) and neuroligin 4X (NLGN4X) were first implicated in the pathogenesis of X-linked autism in Swedish families. However, reports of mutations in these genes in autism spectrum disorder (ASD) patients from various ethnic backgrounds present conflicting results regarding the etiology of ASD, possibly because of genetic heterogeneity and/or differences in their ethnic background. Additional mutation screening study on another ethnic background could help to clarify the relevance of the genes to ASD. We scanned the entire coding regions of NLGN3 and NLGN4X in 62 Japanese patients with ASD by polymerase chain reaction-high-resolution melting curve and direct sequencing analyses. Four synonymous substitutions, one in NLGN3 and three in NLGN4X, were identified in four of the 62 patients. These substitutions were not present in 278 control X-chromosomes from unrelated Japanese individuals and were not registered in the database of Single Nucleotide Polymorphisms build 132 or in the Japanese Single Nucleotide Polymorphisms database, indicating that they were novel and specific to ASD. Though further analysis is necessary to determine the physiological and clinical importance of such substitutions, the possibility of the relevance of both synonymous and nonsynonymous substitutions with the etiology of ASD should be considered. PMID- 22934181 TI - Prevalence and quality of life of slovenian children with primary nocturnal enuresis. AB - Aim. To get epidemiologic data about primary nocturnal enuresis (PNE) and its influence on the quality of life of Slovenian children and adolescents and to find out the knowledge about the disorder among school population. Methods. Prospective epidemiologic study was performed in Slovenia in 2011 and supported with two questionnaires. The first questionnaire was distributed among primary school population that included 1248 children. The second questionnaire included 44 children, who have been treated for PNE in Nephrology Unit of our Department of Paediatrics. Results. PNE was diagnosed in 12.4% of children, in 11.8% of girls and in 13.0% of boys. There was evident linkage between the appearance of PNE in children and their relatives. The study showed that PNE influences the quality of life in less than half of the investigated children. Disorder restricts them mostly in relations with coevals. Knowledge about PNE among children in elementary schools was found to be insufficient. Conclusion. We found out that the prevalence of PNE in Slovenia is comparable to prevalence in other countries. More than half of children questioned in a survey think that PNE does not affect their lives significantly. General lack of knowledge about PNE is still a problem. PMID- 22934183 TI - Rapid Screening of the Epidermal Growth Factor Receptor Phosphosignaling Pathway via Microplate-Based Dot Blot Assays. AB - Expression profiling on a large scale, as is the case in drug discovery, is often accomplished through use of sophisticated solid-phase protein microarrays or multiplex bead technologies. While offering both high-throughput and high-content analysis, these platforms are often too cost prohibitive or technically challenging for many research settings. Capitalizing on the favorable attributes of the standard ELISA and slot blotting techniques, we developed a modified dot blot assay that provides a simple cost-effective alternative for semiquantitative expression analysis of multiple proteins across multiple samples. Similar in protocol to an ELISA, but based in a membrane bound 96-well microplate, the assay takes advantage of vacuum filtration to expedite the tedious process of washing in between binding steps. We report on the optimization of the assay and demonstrate its use in profiling temporal changes in phosphorylation events in the well-characterized EGF-induced signaling cascade of A431 cells. PMID- 22934182 TI - The glomerular filtration barrier: components and crosstalk. AB - The glomerular filtration barrier is a highly specialized blood filtration interface that displays a high conductance to small and midsized solutes in plasma but retains relative impermeability to macromolecules. Its integrity is maintained by physicochemical and signalling interplay among its three core constituents-the glomerular endothelial cell, the basement membrane and visceral epithelial cell (podocyte). Understanding the pathomechanisms of inherited and acquired human diseases as well as experimental injury models of this barrier have helped to unravel this interdependence. Key among the consequences of interference with the integrity of the glomerular filtration barrier is the appearance of significant amounts of proteins in the urine. Proteinuria correlates with kidney disease progression and cardiovascular mortality. With specific reference to proteinuria in human and animal disease phenotypes, the following review explores the roles of the endothelial cell, glomerular basement membrane, and the podocyte and attempts to highlight examples of essential crosstalk within this barrier. PMID- 22934184 TI - Clinical proteomics. PMID- 22934185 TI - Migraine-asthma comorbidity and risk of hypertensive disorders of pregnancy. AB - BACKGROUND: To evaluate the association of migraine and asthma and to estimate the risk of hypertensive disorders of pregnancy in relation to maternal comorbid migraine and asthma. METHODS: Reproductive age women (N = 3.731) were interviewed during early pregnancy. At the time of interview, we ascertained participants' migraine and asthma status. From medical records, we collected information to allow the diagnosis of pregnancy-induced hypertension (PIH) and preeclampsia. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using logistic regression procedures. RESULTS: After adjusting for confounders, migraineurs had 1.38-fold increased odds of asthma as compared with nonmigraineurs (95% CI 1.09-1.38). The odds of hypertensive disorders of pregnancy were highest among women with comorbid migraine-asthma. The ORs for PIH preeclampsia and the two disorders combined were 2.53 (95% CI 1.39-4.61), 3.53 (95% CI 1.51-8.24), and 2.64 (95% CI 1.56-4.47), respectively, for women with comorbid migraine-asthma as compared with those who had neither disorder. CONCLUSION: These findings confirm prior reports and extend the literature by documenting particularly high odds of pregnancy-induced hypertension and preeclampsia among women with comorbid migraine-asthma. Increased knowledge about the prevalence and sequelae of comorbidities during pregnancy may lead to improved symptom management and perinatal outcomes. PMID- 22934186 TI - The role of free tissue transfer in merkel cell carcinoma of the head and neck. AB - Merkel cell carcinoma (MCC) is an uncommon neuroendocrine malignancy with a propensity for the head and neck. It typically presents asymptomatically in elderly Caucasians and is characterized by early local and regional spread. There is currently limited data on the appropriate algorithm for treatment of MCC. However, multimodal therapy with wide surgical excision with or without radiation therapy has become standard of care. The location of the primary tumor and intensive adjuvant therapy is often required, provides a challenge to the reconstructive head and neck surgeon. Occasionally, free tissue transfer reconstructive techniques are employed in the reconstruction of MCC defects. This paper will discuss the role of free tissue transfer as a reconstructive option after surgery for advanced head and neck MCC. PMID- 22934187 TI - Eleven-year distribution pattern of hepatitis C virus in southern Italy. AB - Analysis of the Hepatitis C Virus (HCV) genotype spread in a particular area has a crucial impact on public health. In this study, we update information on the distribution of HCV genotypes, by evaluating a hospital-based cohort of 2,153 chronic hepatitis C patients, collected prospectively among subjects attending University Hospital of Catanzaro, within an area of Southern Italy. We assessed the rates (%) of HCV genotypes during two consecutive periods, from 2001 to 2005 and from 2006 to 2011, according to age and gender. Considering overall observation time, subtype 1b was predominant followed by subtypes 2a/2c, genotype 3 and 4. Statistical evaluation of the age of HCV patients stratified by genotypes, revealed a slight but significant increase in the median age of 1b, 2a/2c and 3 HCV genotype-infected subjects, during the 2006-2011 period, whilst genotype 4 patients exhibited a decrease in the median age during the same period studied. Moreover genotype 4 increased between 2002 and 2003 as well as between 2010 and 2011. Due to the peculiar diagnostic/clinical/therapeutic features of HCV-4, our findings warrant a deeper investigation to better control infections caused by such genotype. PMID- 22934188 TI - Novel simplified and rapid method for screening and isolation of polyunsaturated Fatty acids producing marine bacteria. AB - Bacterial production of polyunsaturated fatty acids (PUFAs) is a potential biotechnological approach for production of valuable nutraceuticals. Reliable method for screening of number of strains within short period of time is great need. Here, we report a novel simplified method for screening and isolation of PUFA-producing bacteria by direct visualization using the H(2)O(2)-plate assay. The oxidative stability of PUFAs in growing bacteria towards added H(2)O(2) is a distinguishing characteristic between the PUFAs producers (no zone of inhibition) and non-PUFAs producers (zone of inhibition) by direct visualization. The confirmation of assay results was performed by injecting fatty acid methyl esters (FAMEs) produced by selected marine bacteria to Gas Chromatography-Mass Spectrometry (GCMS). To date, this assay is the most effective, inexpensive, and specific method for bacteria producing PUFAs and shows drastically reduction in the number of samples thus saves the time, effort, and cost of screening and isolating strains of bacterial PUFAs producers. PMID- 22934189 TI - Nonalcoholic Fatty liver disease in chronic hepatitis B and C patients from Western Amazon. AB - Nonalcoholic fatty liver disease (NAFLD) includes a wide spectrum of histological conditions, extending from simple steatosis to end-stage liver failure. The aim of this study was to examine the prevalence of NAFLD and its associations in chronic hepatitis B and C patients. Methods. We included all patients diagnosed with chronic hepatitis B and C who underwent a liver biopsy between January 2010 and October 2011 (n = 104). Parameters studied included hepatitis type, anthropometric data, histologic, hepatic, metabolic and lipid assessments, presence of hypertension and viral load. Results. Hepatitis B was presented in 28.8% (n = 30) of patients, while hepatitis C was presented in 71.2% (n = 74). In addition, hepatic steatosis was present in 25% (n = 26) of the patients. Steatosis was frequently found in hepatitis C patients (31.1%; 25% n = 23), but infrequently in hepatitis B patients (10%; n = 3) (P = 0.024). It was also found that steatosis was frequently present in hepatitis C patients with intense fibrosis (52.94%) (P = 0.025). Discussion. Our results suggest that steatosis is a common feature in patients with viral chronic hepatitis, and that it plays a different role in each type of hepatitis. PMID- 22934190 TI - Designing Paclitaxel drug delivery systems aimed at improved patient outcomes: current status and challenges. AB - Paclitaxel is one of the most widely used and effective antineoplastic agents derived from natural sources. It has a wide spectrum of antitumor activity, particularly against ovarian cancer, breast cancer, nonsmall cell lung cancer, head and neck tumors, Kaposi's sarcoma, and urologic malignancies. It is a highly lipophilic compound with a log P value of 3.96 and very poor aqueous solubility of less than 0.01 mg/mL. In addition, the compound lacks functional groups that are ionizable which could potentially lead to an increase in its solubility with the alteration in pH. Therefore, the delivery of paclitaxel is associated with substantial challenges. Until the introduction of Abraxane, only commercial formulation was solution of paclitaxel in cremophor, which caused severe side effects. However, in recent years, a number of approaches have been reported to solubilize paclitaxel using cosolvents and inclusion complexes. In addition, innovative approaches have been reported for passive targeting of tumors using nanoparticles, nanosuspensions, liposomes, emulsions, micelles, implants, pastes and gels. All approaches for delivery of improved therapeutic outcome have been discussed in this paper. PMID- 22934191 TI - Synthesis, urease inhibition, antioxidant, antibacterial, and molecular docking studies of 1,3,4-oxadiazole derivatives. AB - A series of eighteen 1,3,4-oxadiazole derivatives have been synthesized by treating aromatic acid hydrazides with carbon disulfide in ethanolic potassium hydroxide yielding potassium salts of 1,3,4-oxadiazoles. Upon neutralization with 1 N hydrochloric acid yielded crude crystals of 1,3,4-oxadiazoles, which were purified by recrystallization in boiling methanol. The synthesized 1,3,4 oxadiazoles derivatives were evaluated in vitro for their urease inhibitory activities, most of the investigated compounds were potent inhibitors of Jack bean urease. The molecular docking studies were performed by docking them into the crystal structure of Jack bean urease to observe the mode of interaction of synthesized compounds. The synthesized compounds were also tested for antibacterial and antioxidant activities and some derivatives exhibited very promising results. PMID- 22934192 TI - Influence of Alternanthera brasiliana (L.) Kuntze on Altered Antioxidant Enzyme Profile during Cutaneous Wound Healing in Immunocompromised Rats. AB - Alternanthera brasiliana (L.) Kuntze (Amaranthaceae) is a herbaceous plant used against inflammation, cough, and diarrhea in Brazilian popular medicine. In our preliminary study, promising wound healing activity of methanol extract of leaves of A. brasiliana (MEAB) was observed in normal excision and incision wound models. Therefore, the present study was designed to investigate the wound healing activity along with the antioxidant enzyme profile during cutaneous excision immunocompromised wound after topical application of 5% w/w ointment of MEAB in rats. Immunocompromised state was induced by pretreatment with hydrocortisone (HC) at 40 mg/kg body weight (i.m.) in male rats. Following one week pretreatment with HC, wounds were created. The vehicle, 5% (w/w) ointment of MEAB, or standard drug (Himax) was applied topically twice daily. Healing potential was evaluated by the rate of wound contraction, estimation of enzymatic and nonenzymatic antioxidants like catalase, SOD, GSH, protein, vitamin C, and hydroxyproline content, which was supported by histopathological study on the 8th day following wounding. There was significant increase in the enzymatic and nonenzymatic antioxidant parameters in the extract-reated group as compared to control group. Histopathological study revealed collagen deposition, fibroblast proliferation, angiogenesis, and development of basement membrane in A. brasiliana group. The results of the present investigation revealed significant wound healing activity of MEAB. PMID- 22934193 TI - Lesions of acetylcholine neurons in refractory epilepsy. AB - We have examined brainstem lesions in patients with refractory epilepsy disorders, including West syndrome (WS), Lennox-Gastaut syndrome (LGS), and dentatorubral-pallidoluysian atrophy (DRPLA). Acetylcholinergic neurons (AchNs) in the pedunculopontine tegmental nucleus (PPN) are involved in mental development, and disruption of neuronal nicotinic acetylcholine receptors can lead to epilepsy. In order to investigate the involvement of lesions of AchNs in refractory epilepsy, we performed immunohistochemical analyses of AchNs in the PPN in autopsy cases who had a past history of WS and/or LGS and in DRPLA cases who showed progressive myoclonic epilepsy. In addition, we performed a preliminary quantification of the levels of acetylcholine, neuropeptides, and monoamine metabolites in the cerebrospinal fluid (CSF) of patients with WS and benign convulsions associated with mild gastroenteritis (CwG). In the PPN analysis, the total number of neurons and the number of AchNs were reduced in WS/LGS and WS cases, while DRPLA cases showed a decrease in the number and percentage of AchNs. In the CSF analysis, WS patients demonstrated a reduction in the levels of inhibitory neuropeptides, while CwG patients showed increased levels of acetylcholine and decreased levels of serotonin metabolites. These data suggest the possible involvement of lesions of AchNs in WS and DRPLA. PMID- 22934194 TI - Review of hypofractionated radiotherapy for prostate cancer. AB - Hypofractionated radiotherapy for prostate cancer has become of increasing interest with the recognition of a potential improvement in therapeutic outcome with treatments delivered in large-sized daily fractions. In addition, hypofractionation offers a reduction in fraction number and produces attractive cost and increased convenience for patients. There is convincing evidence, by several clinical trials, that biochemical control is significantly improved with higher administered radiation doses to the prostate gland. Furthermore, the improved radiation delivery techniques such as 3D conformal radiotherapy (3DCRT) or, better, intensity modulated radiation therapy (IMRT) allow high administered doses to the prostate while sparing the normal surrounding tissues. Several studies of the radiobiology of prostate cancer suggest that it may be more susceptible to large fraction sizes compared with conventional fractionation of external beam radiation. PMID- 22934195 TI - The opposing roles of cellular inhibitor of apoptosis proteins in cancer. AB - Cellular inhibitors of apoptosis proteins 1 and 2 (cIAP1/2) are members of the inhibitor of apoptosis protein (IAP) family that has been implicated in the pathology of human cancers due to their overexpression and function as blockers of cell death in various cancers. As a result, small molecule IAP antagonists have been developed and are currently under clinical evaluation for potential therapeutic use. In contrast, recent evidence has indicated a tumour-suppressing role for the cIAPs. Mutations in or loss of cIAPs have been identified as molecular lesions that contribute to constitutive activation of NF-kappaB in hematopoietic malignancies. These studies reveal a context-dependent role for the cIAPs wherein both their overexpression and loss may contribute to tumourigenesis. PMID- 22934196 TI - Kocher-debre-semelaigne syndrome: hypothyroid muscular pseudohypertrophy-a rare report of two cases. AB - Kocher-Debre-Semelaigne syndrome (KDSS) is a rare association of muscular pseudohypertrophy and long-standing moderate-to-severe hypothyroidism in the pediatric age group. It may be confused with primary muscle disorders, lest one is cautious enough to investigate for hypothyroidism. The striking clinical features, availability of a simple treatment and a good prognosis for the condition makes it worthwhile to report the case so that all practitioners be aware of the condition and its management. PMID- 22934197 TI - Cushing's Syndrome due to Ectopic ACTH from Bronchial Carcinoid: A Case Report and Review. AB - Despite advances in analytic and imaging techniques, the syndrome of ectopic adrenocorticotrophic hormone (ACTH) secretion from a tumour resulting in Cushing's syndrome continues to pose difficult diagnostic and therapeutic challenges. Dynamic testing may be equivocal and radiology indeterminate. We report a patient presenting with Cushing's syndrome associated with ectopic ACTH secretion from a bronchial carcinoid whose management presented diagnostic and therapeutic challenges. PMID- 22934198 TI - Osteopetrosis, hypophosphatemia, and phosphaturia in a young man: a case presentation and differential diagnosis. AB - We report the case of a 30-year-old African-American male with osteopetrosis and hypophosphatemia, presenting with diffuse myalgias. Laboratory evaluation performed revealed a low serum phosphorus level with urinary phosphate wasting, low calcium, and 25-hydroxyvitamin D concentrations, as well as elevated alkaline phosphatase. Skull and pelvic radiographs revealed high bone density consistent with high bone mass found on bone mineral density reports. PHEX gene mutation analysis was negative. Patient was started on calcium and phosphorus replacement, and he clinically improved. This paper will review the different subtypes of osteopetrosis, and the evaluation of hypophosphatemia. PMID- 22934199 TI - Thyroglobulin gene mutation with cold nodule on thyroid scintigraphy. AB - Thyroglobulin gene mutation is a rare cause of congenital hypothyroidism, but thyroglobulin gene mutations are thought to be associated with thyroid cancer development. A 21-year-old Japanese man treated with levothyroxine for congenital hypothyroidism had an enlarged thyroid gland with undetectable serum thyroglobulin despite elevated serum TSH level. The patient was diagnosed with thyroglobulin gene mutation, with compound heterozygosity for Gly304Cys missense mutation and Arg432X nonsense mutation. Ultrasonography showed a hypovascular large tumor in the left lobe that appeared as a cold nodule on thyroid scintigraphy. He underwent total thyroidectomy, but pathological study did not reveal findings of thyroid carcinoma, but rather a hyperplastic nodule with hemorrhage. Strong cytoplasmic thyroglobulin immunostaining was observed, but sodium iodide symporter immunostaining was hardly detected in the hyperplastic nodule. The clinical characteristics of patients with thyroglobulin gene mutations are diverse, and some patients are diagnosed by chance on examination of goiter in adults. The presence of thyroid tumors that appear as cold nodules on thyroid scintigraphy should consider the potential for thyroid carcinoma, if the patient has relatively low serum thyroglobulin concentration in relation to the degree of TSH without thyroglobulin autoantibody. PMID- 22934200 TI - Complete heart block in thyrotoxicosis, is it a manifestation of thyroid storm? A case report and review of the literature. AB - Thyrotoxicosis complicated by advance degree atrioventricular block, a rare complication of a common disease. The term apathetic thyrotoxicosis, where palpitations and cardiac involvement are the sole manifestations of disease, is well known. Thyroxin's ability to sensitize the catecholamine receptors causing tachyarrhythmias is well addressed. However, as an aetiology for advanced heart block, thyrotoxicosis is ranked as one of the rarest. PMID- 22934201 TI - Adjuvant growth hormone for ovulation induction with gonadotropins in the treatment of a woman with hypopituitarism. AB - Objective. To report the prestimulation use of adjuvant GH for gonadotropin ovulation induction in a woman with hypopituitarism and GH deficiency who previously failed to respond. Design, Patients, and Measurements. A 31-year-old nulliparous woman presented with hypopituitarism and GH deficiency after failing ovulation induction with high dose gonadotropins. A trial of GH was undertaken for 5 months prior to ovulation induction resulting in normalization of IGF-I levels. Results. Women with hypopituitarism are known to have lower pregnancy rates after ovulation induction with need for higher doses of gonadotropins. A small subset of these patients do not ovulate. This patient had successful ovulation induction and pregnancy with prestimulation GH. Conclusions. This case suggests that the use of adjuvant GH in a GH-deficient patient several months before the use of human menopausal gonadotropin results in ovulation and pregnancy. PMID- 22934202 TI - Pituitary apoplexy associated with endocrine stimulation test: endocrine stimulation test, treatment, and outcome. AB - Pituitary apoplexy is a rare clinical syndrome attributable to hemorrhage or hemorrhagic infarction of pituitary tumors or pituitary glands. The features of pituitary apoplexy associated with the endocrine stimulation test remain to be elucidated and the importance of surgical treatment has not been discussed enough. We report two rare patients who were treated successfully by endoscopic endonasal transsphenoidal surgery within several hours after onset of pituitary apoplexy associated with the endocrine stimulation test. Their postoperative course was uneventful. We reviewed earlier reports on this clinical entity, document its features especially as related to the endocrine stimulation test, discuss the significance of immediate surgical treatment, and present our treatment outcomes. Performing only conservative treatment is not recommended. We suggest that the necessity of endocrine stimulation test should be assessed on a case-by-case basis and in patients subjected to the test, and neurosurgical support should be sought. PMID- 22934203 TI - Cerebral venous thrombosis as an extrahepatic manifestation of acute anicteric hepatitis a infection. AB - Among the many infective causes of cerebral venous thrombosis (CVT), viral hepatitis has been regarded as a rare associated condition. We report the case of a 31-year-old woman presenting with CVT associated with hepatitis A virus (HAV) infection, outlining probable pathogenic mechanisms. We suggest that hepatitis A serological markers should be routinely included in the investigation of cerebral venous thrombosis of unknown etiology, in nonvaccinated patients with risk factors of a recent HAV exposure. PMID- 22934204 TI - Multiple Pulmonary Metastases following Total Removal of a Bilateral Parasagittal Meningioma with Complete Occlusion of the Superior Sagittal Sinus: Report of a Case. AB - Pulmonary metastases of benign meningiomas are extremely rare. The case of a 34 year-old man with bilateral parasagittal meningioma who developed pulmonary metastases is described. The meningioma was an enormous hypervascular tumor with invasion of the superior sagittal sinus. The tumor was resected completely and histologically diagnosed as transitional meningioma. The Ki-67 labeling index was 5%. Four months after operation, the patient subsequently developed bilateral multiple lung lesions later identified as metastases. The lung lesions were partially removed surgically and histologically diagnosed as meningothelial meningioma WHO grade I. The Ki-67 labeling index was 2%. The histological findings demonstrated that the tumor occupied the arterial lumen and the perivascular space, suggesting that pulmonary tumors might metastasize via the vascular route. The histopathological features and mechanisms of metastasizing meningiomas are reviewed and discussed. PMID- 22934205 TI - Hemifacial Spasm due to Compression of the Posterior Inferior Cerebellar Artery Aneurysm Treated with Botulinum Toxin Type-A: A Case Report. AB - A 79-year-old female presented with five months history of progressive involuntary twitching movement on left face. Brain MR imaging revealed a heterogeneous T2 hyperintense lesion at left cerebellopontine angle. CT angiography showed a partially thrombosed saccular aneurysm of left PICA (posterior inferior cerebellar artery). The patient was treated with Botulinum toxin type A and almost total relief of symptoms was noticed during one month followup. Botulinium toxin injection is an effective symptomatic treatment option in nonsurgical secondary hemifacial spasm (HFS) cases. PMID- 22934206 TI - Ataxia, ophthalmoplegia, and areflexia: what would you think? AB - We present here a case of carcinomatous meningitis presenting as Miller Fisher syndrome (MFS). There are four further cases described in the literature with evidence of tumour invasion within the central nervous system (CNS) shown either in cerebrospinal fluid examination or on histology. There are further five cases described in which an association between cancer and a Miller Fisher phenotype has been shown. Some of these have identified antiganglioside antibodies in the serum and, in one case, also showed antibodies deposited within the primary tumour itself. This raises a question as to whether there is a paraneoplastic form. It would be informative when further cases present in this way to histologically examine for malignant CNS invasion, and the presence of antiganglioside antibodies in both the malignant primary and areas of nervous system thought to be affected by MFS. PMID- 22934208 TI - Presentation of Bilateral Peripheral Seventh Cranial Nerve Palsy in an HIV Patient. AB - Neurological manifestations in patients infected with human immunodeficiency virus can significantly increase overall morbidity and mortality. These complications are neither limited to a specific location in the nervous system nor a focal time period in the disease's progression. A literature review yielded several cases of peripheral facial palsy associated with HIV seropositivity, but few cases have been reported where the patient had bilateral peripheral facial palsy. In this paper, we present a patient with bilateral peripheral facial palsy and aseptic meningitis in the context of newly diagnosed HIV. PMID- 22934207 TI - An operation in the park bench position complicated by massive tongue swelling. AB - This paper presents a case of massive tongue swelling as a complication after an operation in the park bench position. A 43-year-old male who had undergone a resection of a mass in the petrous bone of the clivus showed massive tongue swelling after the surgery in the left park bench position. A direct compression of the bite block caused the swelling of tongue. Tongue swelling may become fatal if it progresses to an airway obstruction; therefore the intraoperative and postoperative management is important. PMID- 22934209 TI - A case of classic raymond syndrome. AB - Classic Raymond syndrome consists of ipsilateral abducens impairment, contralateral central facial paresis, and contralateral hemiparesis. However, subsequent clinical observations argued on the presentation of facial involvement. To validate this entity, we present a case of classic Raymond syndrome with contralateral facial paresis. A 50 year-old man experienced acute onset of horizontal diplopia, left mouth drooling and left-sided weakness. Neurological examination showed he had right abducens nerve palsy, left-sided paresis of the lower part of the face and limbs, and left hyperreflexia. A brain MRI showed a subacute infarct in the right mid-pons. The findings were consistent with those of classic Raymond syndrome. To date, only a few cases of Raymond syndrome, commonly without facial involvement, have been reported. Our case is a validation of classic Raymond syndrome with contralateral facial paresis. We propose the concept of two types of Raymond syndrome: (1) the classic type, which may be produced by a lesion in the mid-pons involving the ipsilateral abducens fascicle and undecussated corticofacial and corticospinal fibers; and (2) the common type, which may be produced by a lesion involving the ipsilateral abducens fascicle and undecussated corticospinal fibers but sparing the corticofacial fibers. PMID- 22934211 TI - 5q Minus Myelodysplasia Associated with Multiple Epithelioid Granulomas within Conventional Renal Cell Carcinoma. AB - A 69-year-old Caucasian female, with a previous diagnosis of 5q minus myelodysplastic syndrome, presented with conventional renal cell carcinoma (RCC) associated with multiple-epithelioid nonnecrotizing granulomas. Two previous reports of sarcoidosis, primarily involving the lung and skin, have been described in patients with 5q minus myelodysplasia. A cluster of closely linked genes encoding for cytokines such as IL-4, IL-5, and IL-3 are present on chromosome 5q. Hence, in sarcoidosis, cytokine imbalances associated with the deletion of these cytokine genes have been postulated. However, an occurrence of epithelioid granulomas within a carcinoma, in preexisting clonal myelodysplastic syndrome, has not been described. The patient, in the current study, had long standing 5q minus deletion, clinically characterized by refractory anemia associated with hypolobated megakaryocytes. However, the patient's history was negative for sarcoidosis and the extensive nonnecrotizing epithelioid granulomas were confined within RCC. Due to the absence of Th-2 cytokines, such as IL-4 and IL-5, in a subset of 5q minus myelodysplastic syndrome, proinflammatory Th-1 cytokines such as IFN-gamma and TNF-alpha may be exaggerated in an environment conducive to antigen expression. Hence, we propose a greater susceptibility for the development of granulomas, at least in a subset of patients with 5q minus myelodysplasia. PMID- 22934210 TI - Familial Bell's Palsy: A Case Report and Literature Review. AB - Objective. To describe a unique case of familial Bell's palsy and summarize the current literature regarding possible hereditary influences. Design. Case report. Main Outcome Measures. Clinical exam, CSF analysis, and family history provided per the patient. Results. We report the case of a 58-year-old female who presented with recurrent and bilateral episodes of facial palsy. The patient underwent multiple CSF investigations to rule out a possible infectious and rheumatologic etiology that were all negative. Further questioning revealed she was one of seven family members with a history of unilateral facial nerve paralysis. Conclusion. The sheer number of similar case studies to date suggests that familial clustering of Bell's palsy is a real, noncoincidental phenomenon. Our case represents a unique and perplexing example of one such family. Familial Bell's palsy may represent an autoimmune disease secondary to inherited HLA alloantigens or a structural predisposition to disease based on the dimensions of the facial canal. PMID- 22934212 TI - Development of hepatocellular carcinoma associated with anabolic androgenic steroid abuse in a young bodybuilder: a case report. AB - Introduction. Many different etiological factors are involved in the development of hepatocellular carcinoma (HCC). We report the case of HCC in a 37-year-old male professional bodybuilder with extensive anabolic androgenic (AAS) steroid abuse. Case Presentation. Because of increasing epigastric and abdominal pain, abdominal ultrasound was performed in a 37-year-old male professional bodybuilder. A hyperechoic lesion in the liver was detected in segment VI. The magnetic resonance imaging showed hepatomegaly and confirmed the lesion, which showed features of a hepatocellular adenoma (HCA). Laboratory values were inconspicuous. After laparoscopic segmentectomy the histological examination revealed HCC. Conclusion. While the development of HCA in the liver by chronic intake of AAS is well known, little is known about the association with HCC. The presented case may indicate aetiological association of chronic intake of AAS and the development of HCC. PMID- 22934213 TI - Malignant adenomyoepithelioma of the breast with lymph node metastasis: a detailed immunohistochemical study. AB - Malignant adenomyoepithelioma of the breast is a rare tumour with around 30 cases reported in the literature. Metastases associated with these tumours are usually haematogenous. Axillary lymph node metastases are thought to be unusual, and it has been recently suggested that axillary node dissection is not indicated unless clinically palpable. We here present a case of a 63-year-old woman, who developed a malignant adenomyoepithelioma with axillary lymph node metastasis, that included epithelial and myoepithelial elements, in spite of the absence of clinically enlarged nodes. We suggest that histological examination of axillary sentinel node(s) or node sampling may be worthwhile in this condition. PMID- 22934214 TI - The mural form of eosinophilic esophagitis is accompanied by superficial esophageal squamous cell carcinoma. AB - Eosinophilic esophagitis (EE) is an increasingly recognized primary clinicopathologic disorder of the esophagus which lacks a specific etiology. Most reports on EE have been limited to the esophagus mucosa. We present a 56-year-old man with the mural form of EE and superficial squamous cell carcinoma in the esophagus. The eosinophils diffusely invaded the full-thickness of the esophagus, mainly infiltrating the muscularis, including the skeletal and smooth muscles. The lesions in the mucosa, submucosa, and adventitia were slight. Although the superficial squamous cell carcinoma was excited by an endoscopic biopsy, there were some changes in the architecture and size of the squamous epithelial cells. The changed cells also expressed the p53 protein. It appears that the eosinophils stimulated cell proliferation, followed by genetic mutations and cancer development. The patient survived with resection of the esophagus and inhaled corticosteroids. PMID- 22934215 TI - Primary epithelial myoepithelial carcinoma of lung, reporting of a rare entity, its molecular histogenesis and review of the literature. AB - Primary epithelial myoepithelial carcinoma of lung is a rare entity and is thought to arise from the submucosal bronchial glands distributed throughout the lower respiratory tract. Because of the rarity of this tumor, we describe one case of epithelial myoepithelial carcinoma arising in the bronchus intermedius and presenting as an endobronchial mass. A 57-year-old male patient presented with an incidental finding of an endobronchial mass located in the lumen of the right lower lobe bronchus and caused near total luminal occlusion of the bronchus. An endobronchial carcinoid tumor was entertained clinically. Subsequently the patient underwent an uneventful videothoracoscopic lobectomy of lower and middle lobes of the right lung. Morphologically and immunohistochemically the tumor was characterized by two cell populations with epithelial and myoepithelial cells forming duct-like structure. The final diagnosis of epithelial myoepithelial carcinoma of lung was rendered. PMID- 22934216 TI - Giant cell angiofibroma in unusual localization: a case report. AB - Giant cell angiofibroma (GCA) was initially described as a potentially recurrent tumor in the orbit of adults. However, it is now recognized that it can also present in other locations. The morphological hallmark is a richly vascularized patternless spindle cell proliferation containing pseudovascular spaces and floret like multinucleate giant cells. Our case was a 32-years-old female complaining of painless solitary nodule arising on the occipital region of the scalp, which was diagnosed as giant cell angiofibroma. We report the case because of its extremely rare localization. PMID- 22934217 TI - Emotional memory in patients with Alzheimer's disease: a report of two cases. AB - Highly emotional events in daily life can be preserved in memory and such memory is generally referred to as emotional memory. Some reports have demonstrated that emotional memory is also found in patients with Alzheimer's disease (AD). However, to our knowledge, there have been no reports about how long memory retention for emotional events can continue in patients with AD. In this paper, we present two patients with AD who lost an immediate family member during followup and retained the memory over a long period despite progression of the AD. PMID- 22934218 TI - Priapism in antipsychotic drug use: a rare but important side effect. AB - Priapism is a rare but important side effect of antipsychotic drugs which may evolve into a urological emergency. Most antipsychotic drugs are alpha-1 adrenergic antagonists, which is thought to be the principal mechanism involved in antipsychotic-induced priapism. Other aetiologies exist, however. A case is presented with multiple episodes of priapism during the use of several different antipsychotic drugs. The case is representative of many patients treated with antipsychotic drugs, as there were hyperprolactinemia, and illicit drug use, which are known causes of priapism. Moreover, the patient used combinations of antipsychotic drugs. The case thus illustrates the etiological complexity which could delay a diagnosis of antipsychotic-induced priapism, and the problem of establishing a link between priapism and one particular ingredient of a drug combination. The case presents how a treatment regimen was finally established balancing antipsychotic efficacy to acceptable side effects and offers guidance to physicians regarding how antipsychotic-induced priapism may be resolved. PMID- 22934219 TI - The Value of Desmethylclozapine and Serum CRP in Clozapine Toxicity: A Case Report. AB - Clozapine, an atypical antipsychotic, has proved to be superior to other antipsychotics in treating patients with refractory schizophrenia. An increased plasma clozapine level above the therapeutic window may be associated with serious adverse events including paralytic ileus. Clozapine toxicity may occur in association with infection or after drug overdose. In a medical emergency situation, differentiating between a toxic clozapine ingestion and an infection induced toxicity might be hindered by associated CNS changes and by the clozapine modulation of the inflammatory process. This may delay prompt initiation of a tailored treatment strategy. Here, we report a case of paralytic ileus developed within the context of clozapine toxicity. Although the underlying cause of toxicity was not clinically obvious, giving antimicrobial therapy resulted in an improvement in the patient's clinical condition. This report indicates the value of serum levels of C-reactive protein and desmethylclozapine, major metabolite of clozapine, in the treatment of aetiologically unclear clozapine toxicity. PMID- 22934220 TI - The subject, its biology, and the chronic recurrent cystitis. AB - Functional disorders in urology are troubling for both patients and physicians. Moreover, advances in recent research promise to provide biological insights into psycho-neuro-endocrino-immunological pathways that are one important facet of chronic urogenital inflammations. We present a case of a middle-aged woman with long-lasting recurrent cystitis for which especially a psychosomatic approach helped to understand and cure the disorder. Altogether, as practitioners treat subjects, not illnesses, a biopsychosocial understanding of human disease should be taken into account in cases of chronic recurrent cystitis. PMID- 22934221 TI - Quetiapine-associated pancreatitis in a geriatric critical care patient with delirium. AB - We report the case of a 78-year-old male who developed acute pancreatitis related to quetiapine that was administered for the treatment of delirium. No evidence of hypertriglyceridemia, infection, ischemia, chololithiasis or hypercalcemia could be documented.Clinicians should be alerted when treating critical care patients with antipsychotics, as risks might present and potentially lead to hazardous results. PMID- 22934222 TI - Trichotillomania and dermatitis artefacta: a rare coexistence. AB - A 24-year-old pregnant female patient presented with complains of bilateral lower limb swelling and fever for 1 month. On examination, blood pressure was 144/94 mmHg along with pitting pedal edema. She had bizarre skin lesions, aligned longitudinally and distributed over the approachable site of the body with tapering ends and in various stages of healing. Lower limbs examination also revealed similar lesions with signs of cellulitis. Her scalp had short and distorted hair suggesting pulling and plucking. These skin lesions and the denial of self-infliction by the patient made us reach the diagnosis of dermatitis artefacta with trichotillomania. Psychotherapy was advocated along with conservative management of skin lesions. The patient improved and is under our follow up. PMID- 22934223 TI - Traveling thrombus in the right atrium: is it the final destination? AB - Right heart thrombus is rare in structurally normal heart. Here, we report a 74 year-old man with a right atrial thrombus who presented with shortness of breath. PMID- 22934224 TI - Cerebral arterial air embolism associated with mechanical ventilation and deep tracheal aspiration. AB - Arterial air embolism associated with pulmonary barotrauma has been considered a rare but a well-known complication of mechanical ventilation. A 65-year-old man, who had subarachnoid hemorrhage with Glasgow coma scale of 8, was admitted to intensive care unit and ventilated with the help of mechanical ventilator. Due to the excessive secretions, deep tracheal aspirations were made frequently. GCS decreased from 8-10 to 4-5, and the patient was reevaluated with cranial CT scan. In CT scan, air embolism was detected in the cerebral arteries. The patient deteriorated and spontaneous respiratory activity lost just after the CT investigation. Thirty minutes later cardiac arrest appeared. Despite the resuscitation, the patient died. We suggest that pneumonia and frequent tracheal aspirations are predisposing factors for cerebral vascular air embolism. PMID- 22934225 TI - Anesthesia for suboccipital craniotomy in a patient with lymphangioleiomyomatosis: a case report. AB - Lymphangioleiomyomatosis (LAM) is a rare pulmonary condition often presenting with spontaneous pneumothorax. Imaging or biopsy confirm the diagnosis. Published case reports describe the anesthetic management of patients with LAM undergoing brief procedures. No reports describe the anesthetic management for lengthy neurosurgical procedures. We describe anesthetic management for craniotomy in a patient with LAM. Clinical Features. A woman presented with 2 spontaneous left pneumothoraces. She received a diagnosis of LAM by imaging. She did well after pleurodesis. Hearing loss and tinnitus led to brain imaging demonstrating a large left cerebello-pontine angle mass. She presented for elective craniotomy to remove the mass while preserving cranial nerve function. Our technique for general endotracheal anesthesia aimed to reduce the likelihood of another pneumothorax while providing good surgical conditions and permitting neuromonitoring. Conclusion. We demonstrate the successful anesthetic management of a patient with LAM undergoing a lengthy suboccipital craniotomy for a posterior fossa mass. PMID- 22934226 TI - Diffuse alveolar hemorrhage: a rare life-threatening condition in systemic lupus erythematosus. AB - Diffuse alveolar hemorrhage (DAH) is a rare life-threatening complication in systemic lupus erythematosus (SLE) associated with high mortality rates. DAH is more common in women, and mean age of onset is around 30 years. It mostly occurs in patients with established diagnosis of SLE but can be the initial presentation of lupus in approximately 20%. DAH should be suspected in lupus patient presenting with new pulmonary infiltrates, decline in hemoglobin, hemoptysis, dyspnea, hypoxemia, and increase in carbon monoxide diffusion capacity. Radiographic evidence of bilateral pulmonary alveolar infiltrates that are usually perihilar or basilar with sparing of apices is seen. DAH can often mimic clinically and radiologically severe pneumonia or ARDS. Treatment includes high dose corticosteroids, cyclophosphamide, and plasmapheresis. We report a case of diffuse alveolar hemorrhage complicating SLE flare-up in a male patient. PMID- 22934227 TI - An unusual transudative pleural effusion succeeded by pulmonary and brain edema and death. AB - Here we report a 22-year old woman with massive and bilateral transudative effusion succeeded by pulmonary edema and brain edema and death. Investigations for systemic disorders were negative. Exacerbation of dyspnea after intravenous fluid infusion was a main problem. As effusion was refractory to medical treatment, the patient was referred for surgical pleurodesis and bilateral surgical pleurodesis were done separately. Postsurgically, dyspnea exacerbation occurred after each common cold infection. Vertigo and high intracranial pressure were also a problem postsurgically. CSF pressure was 225 mm/H(2)O. Therapeutic lumbar puncture was done in two sequential weeks, and the patient was on acetazolamide 250 mg/trivise a day. Despite the medical treatment, progressive dyspnea, headache, and high intracranial pressure followed by death nine months after pleurodesis. As there is a gradient of pressure between pleura and CSF, after pleurodesis brain edema must be a consequence of inversing this gradient. In conclusion, when there are any abnormalities about fluid volume or pressure in any of these cavities, we have to study other cavities. PMID- 22934228 TI - Scimitar syndrome in an asymptomatic adult: fortuitous diagnosis by imaging technique. AB - Congenital cardiopathies in adults are a rare clinical entity in the cardiology consultations. Advances in imaging techniques allow the fortuitous diagnosis of mild forms of these congenital abnormalities. We describe a case of an asymptomatic 41-year-old man, with a medical history of recurrent pneumonia during childhood and an established diagnosis of scimitar syndrome by computed tomography. PMID- 22934229 TI - Inadvertent subclavian artery cannulation: endovascular repair using a collagen closure device-report of two cases and review of the literature. AB - Inadvertent line insertion into the subclavian artery is an uncommon complication of subclavian venous catheterisation, and its timely recognition is vital to minimise risk of harm to the patient. We describe the radiographic, computed tomographic (CT), and angiographic findings in two patients and illustrate the subsequent endovascular management using collagen vascular closure devices. PMID- 22934230 TI - Congenital absence of left circumflex artery detected by computed tomography coronary angiography: a case report. AB - The congenital absence of the left circumflex artery (LCx) is a very rare congenital anomaly of coronary arteries, but it is benign. Currently, the best modality for the diagnosis of coronary anomalies is computed tomography coronary angiography (CTCA). We report a case of congenitally absent LCx with an atypical chest pain. PMID- 22934231 TI - Posttraumatic pedal artery pseudoaneurysm: a case report. AB - Pseudoaneurysm of the pedal artery is usually caused by traumatic or iatrogenic events. Diagnosis is suspected by palpation of a pulsatile mass and detection of an associated systolic bruit. Confirmation is made by Doppler US. Angiography can demonstrate the presence of collateral circulation and assure distal vascular flow. We present the case of a 49-year-old man who presents 3 months after a traumatic contusion of his left foot with a pulsatile mass. A color Doppler ultrasound confirms a pseudoaneurysm of the pedal artery. The patient underwent surgical resection of the mass and suture ligation of the artery with full recovery and no ischemic complications. PMID- 22934232 TI - Lessons learned from a case of abdominal aortic aneurysm accompanied by unstable coagulopathy. AB - Preoperative examination for abdominal aortic aneurysms (AAAs) occasionally reveals an abnormal decrease in coagulation factors and thrombocytopenia, fulfilling the criteria for disseminated intravascular coagulation (DIC). Treatment of the underlying disorder is indispensable for alleviating DIC. We report an uncommon case of a patient with AAA and DIC who showed prolonged thrombocytopenia despite successful treatment of AAA and temporary recovery of coagulation factors. A 70-year-old man presented with AAA and shaggy aorta accompanied by DIC and underwent aneurysmectomy. Combined preoperative use of nafamostat mesilate and recombinant human soluble thrombomodulin was effective in controlling DIC. Although recovery of coagulation factors was observed after surgery, the thrombocytopenia continued throughout the postoperative course and was refractory to platelet transfusion. Because HPA antibody and PA-IgG were present, a trial administration of gamma-globulin was performed; this resulted in rapid improvement of thrombocytopenia. Although DIC recurred again 2 weeks thereafter, coagulation factors subsequently recovered without any medication. PMID- 22934233 TI - Left Hemibody Swelling in an HIV-Positive Patient with Congenital Heart Disease. AB - We report the case of a 50-year-old HIV-positive woman with a congenital cyanotic heart disease who developed left axillary, subclavian, and brachiocephalic vein thrombosis and left lower aortopulmonary collateral arterial thrombosis, presenting as left hemibody swelling. We also briefly overview the literature regarding upper extremity deep vein thrombosis (UEDVT). Given the absence of other risk factors, it was our firm believe that our patient's UEDVT was due to a hypercoagulable state associated with congestive heart failure (CHF) and HIV infection. PMID- 22934234 TI - Genetic Background Strongly Influences the Bone Phenotype of P2X7 Receptor Knockout Mice. AB - The purinergic P2X7 receptor is expressed by bone cells and has been shown to be important in both bone formation and bone resorption. In this study we investigated the importance of the genetic background of the mouse strains on which the P2X7 knock-out models were based by comparing bone status of a new BALB/cJ P2X7(-/-) strain with a previous one based on the C57BL/6 strain. Female four-month-old mice from both strains were DXA scanned on a PIXImus densitometer; femurs were collected for bone strength measurements and serum for bone marker analysis. Bone-related parameters that were altered only slightly in the B6 P2X7( /-) became significantly altered in the BALB/cJ P2X7(-/-) when compared to their wild type littermates. The BALB/cJ P2X7(-/-) showed reduced levels of serum C telopeptide fragment (s-CTX), higher bone mineral density, and increased bone strength compared to the wild type littermates. In conclusion, we have shown that the genetic background of P2X7(-/-) mice strongly influences the bone phenotype of the P2X7(-/-) mice and that P2X7 has a more significant regulatory role in bone remodeling than found in previous studies. PMID- 22934236 TI - The feasibility of using natural language processing to extract clinical information from breast pathology reports. AB - OBJECTIVE: The opportunity to integrate clinical decision support systems into clinical practice is limited due to the lack of structured, machine readable data in the current format of the electronic health record. Natural language processing has been designed to convert free text into machine readable data. The aim of the current study was to ascertain the feasibility of using natural language processing to extract clinical information from >76,000 breast pathology reports. APPROACH AND PROCEDURE: Breast pathology reports from three institutions were analyzed using natural language processing software (Clearforest, Waltham, MA) to extract information on a variety of pathologic diagnoses of interest. Data tables were created from the extracted information according to date of surgery, side of surgery, and medical record number. The variety of ways in which each diagnosis could be represented was recorded, as a means of demonstrating the complexity of machine interpretation of free text. RESULTS: There was widespread variation in how pathologists reported common pathologic diagnoses. We report, for example, 124 ways of saying invasive ductal carcinoma and 95 ways of saying invasive lobular carcinoma. There were >4000 ways of saying invasive ductal carcinoma was not present. Natural language processor sensitivity and specificity were 99.1% and 96.5% when compared to expert human coders. CONCLUSION: We have demonstrated how a large body of free text medical information such as seen in breast pathology reports, can be converted to a machine readable format using natural language processing, and described the inherent complexities of the task. PMID- 22934235 TI - Potential Extensions of the US FRAX Algorithm. AB - To determine if the revised US FRAX can identify those at high risk for fractures at any skeletal site, we studied 250 women and 249 men >=40 years old from an age stratified random sample of Rochester, MN residents. At baseline, femoral neck (FN) bone density was assessed, as were the clinical risk factors included in FRAX, along with additional fracture risk factors such as bone turnover markers and fall history. Fracture ascertainment through periodic interviews and comprehensive medical record review was performed over 10 years of followup. In both women and men, a higher FRAX probability at baseline was associated with greater subsequent likelihood of a major osteoporotic fracture. However, a relative 10% increase in the FRAX 10-year fracture probability was also associated with a 1.4-fold increase (95% confidence interval (CI) 1.1-1.7) in other fractures in women and a 1.7-fold increase (95% CI 0.8-3.1) in men. Furthermore, FRAX predicted asymptomatic vertebral fractures and fractures generally in both sexes. The addition of risk factors not currently included in FRAX did not appear to improve the accuracy of fracture risk prediction. FRAX may provide a conservative estimate of risk for major osteoporotic fractures, but it also predicts fractures generally. PMID- 22934237 TI - Image microarrays derived from tissue microarrays (IMA-TMA): New resource for computer-aided diagnostic algorithm development. AB - BACKGROUND: Conventional tissue microarrays (TMAs) consist of cores of tissue inserted into a recipient paraffin block such that a tissue section on a single glass slide can contain numerous patient samples in a spatially structured pattern. Scanning TMAs into digital slides for subsequent analysis by computer aided diagnostic (CAD) algorithms all offers the possibility of evaluating candidate algorithms against a near-complete repertoire of variable disease morphologies. This parallel interrogation approach simplifies the evaluation, validation, and comparison of such candidate algorithms. A recently developed digital tool, digital core (dCORE), and image microarray maker (iMAM) enables the capture of uniformly sized and resolution-matched images, with these representing key morphologic features and fields of view, aggregated into a single monolithic digital image file in an array format, which we define as an image microarray (IMA). We further define the TMA-IMA construct as IMA-based images derived from whole slide images of TMAs themselves. METHODS: Here we describe the first combined use of the previously described dCORE and iMAM tools, toward the goal of generating a higher-order image construct, with multiple TMA cores from multiple distinct conventional TMAs assembled as a single digital image montage. This image construct served as the basis of the carrying out of a massively parallel image analysis exercise, based on the use of the previously described spatially invariant vector quantization (SIVQ) algorithm. RESULTS: Multicase, multifield TMA-IMAs of follicular lymphoma and follicular hyperplasia were separately rendered, using the aforementioned tools. Each of these two IMAs contained a distinct spectrum of morphologic heterogeneity with respect to both tingible body macrophage (TBM) appearance and apoptotic body morphology. SIVQ-based pattern matching, with ring vectors selected to screen for either tingible body macrophages or apoptotic bodies, was subsequently carried out on the differing TMA-IMAs, with attainment of excellent discriminant classification between the two diagnostic classes. CONCLUSION: The TMA-IMA construct enables and accelerates high-throughput multicase, multifield based image feature discovery and classification, thus simplifying the development, validation, and comparison of CAD algorithms in settings where the heterogeneity of diagnostic feature morphologic is a significant factor. PMID- 22934238 TI - ImageJS: Personalized, participated, pervasive, and reproducible image bioinformatics in the web browser. AB - BACKGROUND: Image bioinformatics infrastructure typically relies on a combination of server-side high-performance computing and client desktop applications tailored for graphic rendering. On the server side, matrix manipulation environments are often used as the back-end where deployment of specialized analytical workflows takes place. However, neither the server-side nor the client side desktop solution, by themselves or combined, is conducive to the emergence of open, collaborative, computational ecosystems for image analysis that are both self-sustained and user driven. MATERIALS AND METHODS: ImageJS was developed as a browser-based webApp, untethered from a server-side backend, by making use of recent advances in the modern web browser such as a very efficient compiler, high end graphical rendering capabilities, and I/O tailored for code migration. RESULTS: Multiple versioned code hosting services were used to develop distinct ImageJS modules to illustrate its amenability to collaborative deployment without compromise of reproducibility or provenance. The illustrative examples include modules for image segmentation, feature extraction, and filtering. The deployment of image analysis by code migration is in sharp contrast with the more conventional, heavier, and less safe reliance on data transfer. Accordingly, code and data are loaded into the browser by exactly the same script tag loading mechanism, which offers a number of interesting applications that would be hard to attain with more conventional platforms, such as NIH's popular ImageJ application. CONCLUSIONS: The modern web browser was found to be advantageous for image bioinformatics in both the research and clinical environments. This conclusion reflects advantages in deployment scalability and analysis reproducibility, as well as the critical ability to deliver advanced computational statistical procedures machines where access to sensitive data is controlled, that is, without local "download and installation". PMID- 22934239 TI - Ac/Ds-induced chromosomal rearrangements in rice genomes. AB - A closely-linked pair of Ac/Ds elements induces chromosomal rearrangements in Arabidopsis and maize. This report summarizes the Ac/Ds systems that generate an exceptionally high frequency of chromosomal rearrangements in rice genomes. From a line containing a single Ds element inserted at the OsRLG5 locus, plants containing a closely-linked pair of inversely-oriented Ds elements were obtained at 1% frequency among the population regenerated from tissue culture. Subsequent regeneration of the lines containing cis-paired Ds elements via tissue culture led to a high frequency (35.6%) of plants containing chromosomal rearrangements at the OsRLG5 locus. Thirty-four rearrangement events were characterized, revealing diverse chromosomal aberrations including deletions, inversions and duplications. Many rearrangements could be explained by sister chromatid transposition (SCT) and homologous recombination (HR), events previously demonstrated in Arabidopsis and maize. In addition, novel events were detected and presumably generated via a new alternative transposition mechanism. This mechanism, termed single chromatid transposition (SLCT), resulted in juxtaposed inversions and deletions on the same chromosome. This study demonstrated that the Ac/Ds system coupled with tissue culture-mediated plant regeneration could induce higher frequencies and a greater diversity of chromosomal rearrangements than previously reported. Understanding transposon-induced chromosomal rearrangements can provide new insights into the relationship between transposable elements and genome evolution, as well as a means to perform chromosomal engineering for crop improvement. Rice is a staple cereal crop worldwide. Complete genome sequencing and rich genetic resources are great advantages for the study of the genomic complexity induced by transposable elements.(1) (-) (2) The combination of tissue culture with genetic lines carrying a pair of closely located Ac/Ds elements greatly increases the frequency and diversity of rearrangements in rice genomes. The methodology and its efficiency and significance are briefly summarized. PMID- 22934240 TI - The diversity of inducible and constitutively expressed erm(C) genes and association to different replicon types in staphylococci plasmids. AB - The aim of this study was to analyze the diversity of the macrolide resistance gene, erm(C) in relation to structural alterations affecting the gene expression. In addition, the association of erm(C) to mobile genetic elements (MGEs) in staphylococci mainly from Danish pigs was investigated. In total, 78 erythromycin resistant isolates were screened for erm(C) by PCR. The erm(C) genes incl. the upstream regulatory region were sequenced and the expression types were characterized phenotypically (agar diffusion test) and genotypically (sequence analysis). Phylogenetic analysis of erm(C) was compared with structural alterations affecting the gene expression. Plasmids carrying erm(C) from seven selected isolates were fully or partially sequenced. Thirty-seven isolates were shown to be erm(C) positive and erm(C) from pigs were all constitutively expressed, mainly caused by different sized deletions (118, 111, 107, 70, 66, 16 and 3 bp) in the regulatory region. Duplication (63 bp) and substitutions were also found to cause a constitutive phenotype. Only one horse isolate had an inducible expression type. Phylogenetic analysis showed that structural alterations have happened in different erm(C) allele groups and not only in one group. Furthermore erm(C) was found mainly on plasmids (~2.4-8 kb) and gene sequence types correlated with plasmid replication (rep) gene types. One erm(C) type was linked to an IS257 element able to circularize. In conclusion, structural alterations giving rise to constitutive expression of erm(C) have happened several times in the evolution of erm(C). Interestingly, the diversity of erm(C) appears to be linked to the plasmid type or MGE carrying the gene. PMID- 22934241 TI - Eukaryote to gut bacteria transfer of a glycoside hydrolase gene essential for starch breakdown in plants. AB - Lateral gene transfer (LGT) between bacteria constitutes a strong force in prokaryote evolution, transforming the hierarchical tree of life into a network of relationships between species. In contrast, only a few cases of LGT from eukaryotes to prokaryotes have been reported so far. The distal animal intestine is predominantly a bacterial ecosystem, supplying the host with energy from dietary polysaccharides through carbohydrate-active enzymes absent from its genome. It has been suggested that LGT is particularly important for the human microbiota evolution. Here we show evidence for the first eukaryotic gene identified in multiple gut bacterial genomes. We found in the genome sequence of several gut bacteria, a typically eukaryotic glycoside-hydrolase necessary for starch breakdown in plants. The distribution of this gene is patchy in gut bacteria with presence otherwise detected only in a few environmental bacteria. We speculate that the transfer of this gene to gut bacteria occurred by a sequence of two key LGT events; first, an original eukaryotic gene was transferred probably from Archaeplastida to environmental bacteria specialized in plant polysaccharides degradation and second, the gene was transferred from the environmental bacteria to gut microbes. PMID- 22934242 TI - Virus-host swinging party in the oceans: Incorporating biological complexity into paradigms of antagonistic coexistence. AB - Bacteria and their viruses (phages) are antagonists, yet have coexisted in nature for billions of years. Models proposed to explain the paradox of antagonistic coexistence generally reach two types of solutions: Arms race-like dynamics that lead to hosts and viruses with increasing resistance and infection ranges; and population fluctuations between diverse host and viral types due to a metabolic cost of resistance. Recently, we found that populations of the marine cyanobacterium, Prochlorococcus, consist of cells with extreme hypervariability in gene sequence and gene content in a viral susceptibility region of the genome. Furthermore, we found a novel cost of resistance where resistance to one set of viruses is accompanied by changes in infection dynamics by other viruses. In this combined mini-review and commentary paper we discuss these findings in the context of existing ecological, evolutionary and genetic models of host-virus coexistence. We suggest that this coexistence is governed mainly by fluctuations between microbial subpopulations with differing viral susceptibility regions and that these fluctuations are driven by both metabolic and enhanced infection costs of resistance. Furthermore, we suggest that enhanced infection leads to passive host-switching by viruses, preventing the development of hosts with universal resistance. These findings highlight the vital importance of community complexity for host-virus coexistence. PMID- 22934243 TI - Distribution of horizontally transferred heavy metal resistance operons in recent outbreak bacteria. AB - Mankind is confronted by the outbreaks of highly virulent and multi-drug resistant pathogens. The outbreak strains often belong to well-known diseases associated species such as Salmonella, Klebsiella and Mycobacterium, but even normally commensal and environmental microorganisms may suddenly acquire properties of virulent bacteria and cause nosocomial infections. The acquired virulence is often associated with lateral exchange of pathogenicity genomic islands containing drug and heavy metal resistance determinants. Metal ions are used by the immune system of macro-organisms against bactericidal agents. The ability to control heavy metal homeostasis is a factor that allows the survival of pathogenic microorganisms in macrophages. In this paper, we investigate the origin of heavy metal resistance operons in the recent outbreak strains and the possible routes which may lead to acquisitions of these genes by potentially new pathogens. We hypothesize that new outbreak microorganisms appear intermittently on an intersection of the non-specialized, genetically naive strains of potential pathogens and virulence factor comprising vectors (plasmid and/or phages) newly generated in the environmental microflora. Global contamination of the environment and climate change may also have an effect toward the acceleration and appearance of new pathogens. PMID- 22934244 TI - Endosymbiotic and horizontal gene transfer in microbial eukaryotes: Impacts on cell evolution and the tree of life. AB - The evolution of microbial eukaryotes, in particular of photosynthetic lineages, is complicated by multiple instances of endosymbiotic and horizontal gene transfer (E/HGT) resulting from plastid origin(s). Our recent analysis of diatom membrane transporters provides evidence of red and/or green algal origins of 172 of the genes encoding these proteins (ca. 25% of the examined phylogenies), with the majority putatively derived from green algae. These data suggest that E/HGT has been an important driver of evolutionary innovation among diatoms (and likely other stramenopiles), and lend further support to the hypothesis of an ancient, cryptic green algal endosymbiosis in "chromalveolate" lineages. Here, we discuss the implications of our findings on the understanding of eukaryote evolution and inference of the tree of life. PMID- 22934245 TI - Positive selection of co-opted mobile genetic elements in a mammalian gene: If you can't beat them, join them. AB - The proopiomelanocortin (Pomc) gene encodes a prepropeptide with essential functions in the response to stress and energy balance, which is expressed in the pituitary and hypothalamus of vertebrate animals. Neuronal expression of Pomc is controlled by two distal enhancers named nPE1 and nPE2. Using transgenic mice, we observed that both enhancers drive identical expression patterns in the mammalian hypothalamus, starting at embryonic day 10.5, when endogenous Pomc expression commences. This overlapping enhancer activity is maintained throughout hypothalamic development and into adulthood. We also found that nPE1 and nPE2 were exapted as neuronal enhancers into the POMC locus after the sequential insertion of two unrelated retroposons. Thus, nPE1 and nPE2 are functional analogs and represent an authentic first example of convergent molecular evolution of cell-specific transcriptional enhancers. In this Commentary we discuss the following questions that remain unanswered: (1) how does transcriptional control of POMC operate in hypothalamic neurons of non-mammalian vertebrates? (2) What evolutionary forces are maintaining two discrete neuronal POMC enhancers under purifying selection for the last ~100 million years in all placental mammals? (3) What is the contribution of MaLRs to genome evolution? PMID- 22934247 TI - Cargo capacity of phages and plasmids and other factors influencing horizontal transfers of prokaryote transposable elements. AB - Horizontal transfer of transposable elements (TEs) plays a key role in prokaryote genome evolution. Most TEs do not encode the enzymatic machinery allowing them to transfer between host cells and it is widely assumed in the literature that horizontal transfer of prokaryote TEs is mediated by other mobile genetic elements such as phages and plasmids. In a recent study, we have shown that phages are less tolerant to insertion sequences (IS, the most frequent class of prokaryote TEs) and therefore have a lower cargo capacity than plasmids. Consequently, while our analysis confirmed the crucial role of plasmids as efficient vehicles of IS horizontal transfer, we concluded that phages are unlikely to efficiently shuttle IS elements between prokaryotes. Here, we discuss whether or not the distribution pattern observed for IS elements in phages and plasmids also holds for other TEs, such as transposons and mobile introns. We also further explore various factors that may impact the relative capacity of phages and plasmids to mediate TE horizontal transfer among prokaryotes. PMID- 22934246 TI - Can silencing of transposons contribute to variation in effector gene expression in Phytophthora infestans? AB - Transposable elements are ubiquitous residents in eukaryotic genomes. Often considered to be genomic parasites, they can lead to dramatic changes in genome organization, gene expression, and gene evolution. The oomycete plant pathogen Phytophthora infestans has evolved a genome organization where core biology genes are predominantly located in genome regions that have relatively few resident transposons. In contrast, disease effector-encoding genes are most frequently located in rapidly evolving genomic regions that are rich in transposons. P. infestans, as a eukaryote, likely uses RNA silencing to minimize the activity of transposons. We have shown that fusion of a short interspersed element (SINE) to an effector gene in P. infestans leads to the silencing of both the introduced fusion and endogenous homologous sequences. This is also likely to occur naturally in the genome of P. infestans, as transcriptional inactivation of effectors is known to occur, and over half of the translocated "RXLR class" of effectors are located within 2 kb of transposon sequences in the P. infestans genome. In this commentary, we review the diverse transposon inventory of P. infestans, its control by RNA silencing, and consequences for expression modulation of nearby effector genes in this economically important plant pathogen. PMID- 22934248 TI - Diversity of integrating conjugative elements in actinobacteria: Coexistence of two mechanistically different DNA-translocation systems. AB - Conjugation is certainly the most widespread and promiscuous mechanism of horizontal gene transfer in bacteria. During conjugation, DNA translocation across membranes of two cells forming a mating pair is mediated by two types of mobile genetic elements: conjugative plasmids and integrating conjugative elements (ICEs). The vast majority of conjugative plasmids and ICEs employ a sophisticated protein secretion apparatus called type IV secretion system to transfer to a recipient cell. Yet another type of conjugative DNA translocation machinery exists and to date appears to be unique to conjugative plasmids and ICEs of the Actinomycetales order, a sub-group of high G + C Gram-positive bacteria. This conjugative system is reminiscent of the machinery that allows segregation of chromosomal DNA during bacterial cell division and sporulation, and relies on a single FtsK-homolog protein to translocate double-stranded DNA molecules to the recipient cell. Recent thorough sequence analyses reveal that while this latter strategy appears to be used by the majority of ICEs in Actinomycetales, the former is also predicted to be important in exchange of genetic material in actinobacteria. PMID- 22934249 TI - Can the exome and the immunome converge on the design of efficient cancer vaccines? AB - Human cancers carry hundreds of non-synonymous mutations, several dozens among which may lead to the generation of tumor-specific MHC Class I-restricted epitopes. Hence every patient's tumor harbors a highly specific mutational and antigenic signature and up to 95% of these mutations are unique. This "mutanome" can be identified by deep sequencing and can be subjected to systematic analyses of the immunogenicity of mutated proteins/peptides. We anticipate that this approach will lead to individualized immunotherapies by means of tailored vaccines. PMID- 22934250 TI - Cross-priming for antitumor CTL induced by soluble Ag + polyI:C depends on the TICAM-1 pathway in mouse CD11c(+)/CD8alpha(+) dendritic cells. AB - PolyI:C is a nucleotide pattern molecule that induces cross-presentation of foreign Ag in myeloid dendritic cells (DC) and MHC Class I-dependent proliferation of cytotoxic T lymphocytes (CTL). DC (BM or spleen CD8alpha(+)) have sensors for dsRNA including polyI:C to signal facilitating cross presentation. Endosomal TLR3 and cytoplasmic RIG-I/MDA5 are reportedly responsible for polyI:C sensing and presumed to deliver signal for cross presentation via TICAM-1 (TRIF) and IPS-1 (MAVS, Cardif, VISA) adaptors, respectively. In fact, when tumor-associated Ag (TAA) was simultaneously taken up with polyI:C in DC, the DC cross-primed CTL specific to the TAA in a syngenic mouse model. Here we tested which of the TICAM-1 or IPS-1 pathway participate in cross-presentation of tumor-associated soluble Ag and retardation of tumor growth in the setting with a syngeneic tumor implant system, EG7/C57BL6, and exogenously challenged soluble Ag (EG7 lysate) and polyI:C. When EG7 lysate and polyI:C were subcutaneously injected in tumor-bearing mice, EG7 tumor growth retardation was observed in wild-type and to a lesser extent IPS-1(-/-) mice, but not TICAM-1(-/ ) mice. IRF-3/7 were essential but IPS-1 and type I IFN were minimally involved in the polyI:C-mediated CTL proliferation. Although both TICAM-1 and IPS-1 contributed to CD86/CD40 upregulation in CD8alpha(+) DC, H2K(b)-SL8 tetramer and OT-1 proliferation assays indicated that OVA-recognizing CD8 T cells predominantly proliferated in vivo through TICAM-1 and CD8alpha(+) DC is crucial in ex vivo analysis. Ultimately, tumor regresses > 8 d post polyI:C administration. The results infer that soluble tumor Ag induces tumor growth retardation, i.e., therapeutic potential, if the TICAM-1 signal coincidentally occurs in CD8alpha(+) DC around the tumor. PMID- 22934251 TI - Sequential metastases of colorectal cancer: Immunophenotypes and spatial distributions of infiltrating immune cells in relation to time and treatments. AB - The role of the immune system in the course of colorectal cancer has been elucidated in the last decade. While quantification of immune cell infiltrates within the resected specimen at diagnosis has a clear power to estimate the prognosis of the patient, the role of infiltrating immune cells within the metastatic situation and especially within the metastatic lesion itself requires further detailed analyses. Recent analyses of infiltrates in colorectal cancer liver metastases revealed a role for the infiltrate density not only for prognosis but also in the prediction of treatment response. This not only broadens the view on these infiltrates and indicates a systematic role of the local immunological microenvironment, but also raises the question how these infiltrates change during repeated courses of treatment (i.e., resection, chemotherapy, etc.). To address this question, sequential lung or sequential liver metastases of colorectal cancer patients were analyzed using whole slide image quantification after immunohistochemical staining against CD3, CD8, FOXP3, CD68 and Granzyme B. The clinical data and interventions were associated with each individual patient and the metastatic lesions. The resulting cell densities reveal a heterogeneous profile: after successful treatment of a metastatic lesion, the recurrent lesion can still have the same immunophenotype with similar cell distributions. In a situation of a favorable immune cell profile, this profile can return and apparently convey a similar favorable course throughout the disease. But also the opposite was found: the recurrent metastatic lesion could have a different profile with alterations in specific immune cell subsets over time. Further analyses are required to elucidate the different patterns and their associations to the treatment, the tumor cell phenotype and other dynamic factors. However, it is clear from this data however, that there is an immune cell plasticity that needs to be analyzed for individual patients. PMID- 22934252 TI - The protooncogene Vav1 regulates murine leukemia virus-induced T-cell leukemogenesis. AB - Vav1 is expressed exclusively in hematopoietic cells and is required for T cell development and activation. Vav1-deficient mice show thymic hypocellularity due to a partial block during thymocyte development at the DN3 stage and between the double positive (DP) and single positive (SP) transition. Vav1 has been shown to play a significant role in several non-hematopoietic tumors but its role in leukemogenesis is unknown. To address this question, we investigated the role of Vav1 in retrovirus-induced T cell leukemogenesis. Infection of Vav1-deficient mice with the Moloney strain of murine leukemia virus (M-MuLV) significantly affected tumor phenotype without modulating tumor incidence or latency. M-MuLV infected Vav1-deficient mice showed reduced splenomegaly, higher hematocrit levels and hypertrophic thymi. Notably, Vav1-deficient mice with M-MuLV leukemias presented with markedly lower TCRbeta/CD3 levels, indicating that transformation occurred at an earlier stage of T cell development than in WT mice. Thus, impaired T cell development modulates the outcome of retrovirus-induced T cell leukemias, demonstrating a link between T cell development and T cell leukemogenesis. PMID- 22934253 TI - Selective BRAF inhibition decreases tumor-resident lymphocyte frequencies in a mouse model of human melanoma. AB - The development of targeted therapies and immunotherapies has markedly advanced the treatment of metastasized melanoma. While treatment with selective BRAF(V600E) inhibitors (like vemurafenib or dabrafenib) leads to high response rates but short response duration, CTLA-4 blocking therapies induce sustained responses, but only in a limited number of patients. The combination of these diametric treatment approaches may further improve survival, but pre-clinical data concerning this approach is limited. We investigated, using Tyr::CreER(T2)PTEN(F-/-)BRAF(F-V600E/+) inducible melanoma mice, whether BRAF(V600E) inhibition can synergize with anti-CTLA-4 mAb treatment, focusing on the interaction between the BRAF(V600E) inhibitor PLX4720 and the immune system. While PLX4720 treatment strongly decreased tumor growth, it did not induce cell death in BRAF(V600E)/PTEN(-/-) melanomas. More strikingly, PLX4720 treatment led to a decreased frequency of tumor-resident T cells, NK-cells, MDSCs and macrophages, which could not be restored by the addition of anti-CTLA-4 mAb. As this effect was not observed upon treatment of BRAF wild-type B16F10 tumors, we conclude that the decreased frequency of immune cells correlates to BRAF(V600E) inhibition in tumor cells and is not due to an off-target effect of PLX4720 on immune cells. Furthermore, anti-CTLA-4 mAb treatment of inducible melanoma mice treated with PLX4720 did not result in enhanced tumor control, while anti-CTLA-4 mAb treatment did improve the effect of tumor-vaccination in B16F10-inoculated mice. Our data suggest that vemurafenib may negatively affect the immune activity within the tumor. Therefore, the potential effect of targeted therapy on the tumor-microenvironment should be taken into consideration in the design of clinical trials combining targeted and immunotherapy. PMID- 22934255 TI - Insufficient autophagy promotes bronchial epithelial cell senescence in chronic obstructive pulmonary disease. AB - Tobacco smoke-induced accelerated cell senescence has been implicated in the pathogenesis of chronic obstructive pulmonary disease (COPD). Cell senescence is accompanied by the accumulation of damaged cellular components suggesting that in COPD, inhibition of autophagy may contribute to cell senescence. Here we look at whether autophagy contributes to cigarette smoke extract (CSE) - induced cell senescence of primary human bronchial epithelial cells (HBEC), and further evaluate p62 and ubiquitinated protein levels in lung homogenates from COPD patients. We demonstrate that CSE transiently induces activation of autophagy in HBEC, followed by accelerated cell senescence and concomitant accumulation of p62 and ubiquitinated proteins. Autophagy inhibition further enhanced accumulations of p62 and ubiquitinated proteins, resulting in increased senescence and senescence-associated secretory phenotype (SASP) with interleukin (IL)-8 secretion. Conversely, autophagy activation by Torin1, a mammalian target of rapamycin (mTOR inhibitor), suppressed accumulations of p62 and ubiquitinated proteins and inhibits cell senescence. Despite increased baseline activity, autophagy induction in response to CSE was significantly decreased in HBEC from COPD patients. Increased accumulations of p62 and ubiquitinated proteins were detected in lung homogenates from COPD patients. Insufficient autophagic clearance of damaged proteins, including ubiquitinated proteins, is involved in accelerated cell senescence in COPD, suggesting a novel protective role for autophagy in the tobacco smoke-induced senescence-associated lung disease, COPD. PMID- 22934254 TI - Environment-mediated drug resistance in Bcr/Abl-positive acute lymphoblastic leukemia. AB - Although cure rates for acute lymphoblastic leukemia (ALL) have increased, development of resistance to drugs and patient relapse are common. The environment in which the leukemia cells are present during the drug treatment is known to provide significant survival benefit. Here, we have modeled this process by culturing murine Bcr/Abl-positive acute lymphoblastic leukemia cells in the presence of stroma while treating them with a moderate dose of two unrelated drugs, the farnesyltransferase inhibitor lonafarnib and the tyrosine kinase inhibitor nilotinib. This results in an initial large reduction in cell viability of the culture and inhibition of cell proliferation. However, after a number of days, cell death ceases and the culture becomes drug-tolerant, enabling cell division to resume. Using gene expression profiling, we found that the development of drug resistance was accompanied by massive transcriptional upregulation of genes that are associated with general inflammatory responses such as the metalloproteinase MMP9. MMP9 protein levels and enzymatic activity were also increased in ALL cells that had become nilotinib-tolerant. Activation of p38, Akt and Erk correlated with the development of environment-mediated drug resistance (EMDR), and inhibitors of Akt and Erk in combination with nilotinib reduced the ability of the cells to develop resistance. However, inhibition of p38 promoted increased resistance to nilotinib. We conclude that development of EMDR by ALL cells involves changes in numerous intracellular pathways. Development of tolerance to drugs such as nilotinib may therefore be circumvented by simultaneous treatment with other drugs having divergent targets. PMID- 22934256 TI - Tumor antigen specific iTreg accumulate in the tumor microenvironment and suppress therapeutic vaccination. AB - Tumor specific antigens (TSA) provide an opportunity to mobilize therapeutic immune responses against cancer. To evade such responses, tumor development in immunocompetent hosts is accompanied by acquisition of both active and passive mechanisms of immune suppression, including recruitment of CD4+FoxP3+ regulatory T cells (Treg). Thymic derived Treg (nTreg) may recognize self-antigens in the tumor microenvironment, while peripherally induced Treg (iTreg) may preferentially recognize the same TSA which provide an opportunity for therapeutic immunity from peripheral T cells. In this study we provide a systematic analysis of nTreg and iTreg accumulation in the tumor microenvironment (TME) at the cellular level. iTreg accumulation to the TME was influenced by the abundance of a known TSA, and in the absence of a known TSA intratumoral Treg displayed a unique TCR repertoire from peripheral Treg. In vivo suppression assays demonstrate that cognate-antigen matched iTreg are more potent suppressors of CD4+ than are polyclonal iTreg or nTreg, but were unable to suppress CD8+ T cell proliferation. Suppression occurred only locally at the site of immunization, and correlated with decreased expression of CD80 and CD86 on CD11c positive cells. Although established tumors facilitated the induction of TSA specific iTreg, these iTreg suppressed CD4+ T cell accumulation only locally to the TME. Tumor mediated suppression of CD8+ T cell immunity appeared independent of TSA-specific iTreg. PMID- 22934257 TI - Tumor-mediated inhibition of human dendritic cell differentiation and function is consistently counteracted by combined p38 MAPK and STAT3 inhibition. AB - Targeting dendritic cells (DC) through the release of suppressive factors is an effective means for tumors to escape immune control. We assessed the involvement of downstream signaling through the JAK2/STAT3 and p38 MAPK pathways in tumor induced suppression of human DC development. Whereas the JAK2/STAT3 pathway has been pinpointed in mouse studies as a key regulator of myeloid suppression, in human DC this is less well established. We studied the effects of STAT3 inhibition on the suppression of monocyte-derived DC differentiation mediated by a short-list of four predominant suppressive factors and found that pharmacological STAT3 inhibition could only counteract the effects of IL-6. Accordingly, in testing a panel of supernatants derived from 11 cell lines representing various types of solid tumors, STAT3 inhibition only modestly affected the suppressive effects of a minority of supernatants. Importantly, combined interference in the STAT3 and p38 pathways completely prevented inhibition of DC differentiation by all tested supernatants and effected superior DC function, evidenced by increased allogeneic T cell reactivity with elevated IL 12p70/IL-10 ratios and Th1 skewing. Combined STAT3 and p38 inhibition also afforded superior protection against the suppressive effects of primary glioma and melanoma supernatants and induced a shift from CD14(+) cells to CD1a(+) cells in metastatic melanoma single-cell suspensions, indicating a potential for improved DC differentiation in the tumor microenvironment. We conclude that combined interference in the STAT3 and p38 MAPK signaling pathways is a promising approach to overcome tumor-induced inhibitory signaling in DC precursors and will likely support clinical immunotherapeutic strategies. PMID- 22934258 TI - CD26 expression and adenosine deaminase activity in regulatory T cells (Treg) and CD4(+) T effector cells in patients with head and neck squamous cell carcinoma. AB - Adenosine deaminase (ADA) is responsible for the deamination of immunosuppressive adenosine to inosine. In human T lymphocytes, ADA is associated with dipeptidyl peptidase IV (CD26). ADA expression and activity were evaluated in regulatory T cells (Treg) and CD4(+) T effector cells (Teff) of patients with head and neck squamous cell cancer (HNSCC). CD4(+)CD39(+) and CD4(+)CD39(neg) T cells were isolated by single-cell sorting from the peripheral blood of 15 HNSCC patients and 15 healthy donors (NC). CD26/ADA expression in these cells was studied by multicolor flow cytometry, confocal microscopy, RT-PCR and immunohistochemistry in tumor tissues. ADA activity was evaluated by mass spectrometry, suppression of Teff proliferation in CFSE assays and cytokine production by Luminex. CD4(+)CD39(+) Treg had low and CD4(+)CD39(neg) Teff high CD26/ADA expression and ADA activity in NC or HNSCC. The frequency and suppressor activity of CD39(+)CD26(neg) Treg were elevated in patients relative to NC (p < 0.01). However, ADA activity in patients' CD4(+)CD39(neg) Teff was decreased (p < 0.05), resulting in extracellular adenosine accumulation. Also, patients' Teff were more sensitive to inhibitory signals delivered via adenosine receptors. IL-2, IL12 and INFgamma upregulated ADA expression and activity in CD4(+)CD39(neg) Teff, whereas IL-10, PGE(2) and CADO downregulated it. The differentially expressed CD26/ADA can serve as surface markers for functionally-active CD39(+)CD26(neg) Treg. PMID- 22934260 TI - TLR4 signaling induces the release of microparticles by tumor cells that regulate inflammatory cytokine IL-6 of macrophages via microRNA let-7b. AB - Tumor cells expressing TLRs is generally recognized to mediate tumor inflammation. However, whether and how tumor TLR signaling pathways negatively regulate tumor inflammation remains unclear. In this report, we find that TLR4 signaling of H22 hepatocarcinoma tumor cells is transduced through MyD88 pathway to actin cytoskeletons, leading to the release of microparticles (MPs), the cellular membrane-derived vesicles. As a result, tumor macrophages take up MPs and acquire MP-contained microRNA let-7b, which attenuates tumor inflammation by targeting proinflammatory cytokine IL-6. Thus, tumor TLR signaling, contrary to the original promoting effect, may play an opposite role in downregulating tumor inflammation through MP pathways. PMID- 22934259 TI - Widespread CD4+ T-cell reactivity to novel hTERT epitopes following vaccination of cancer patients with a single hTERT peptide GV1001. AB - Understanding the basis of a successful clinical response after treatment with therapeutic cancer vaccines is essential for the development of more efficacious therapy. After vaccination with the single telomerase (hTERT) 16-mer peptide, GV1001, some patients experienced clinical responses and long-term survival. This study reports in-depth immunological analysis of the T-cell response against telomerase (hTERT) in clinically responding patients compared with clinical non responders following vaccination with the single hTERT 16-mer peptide, GV1001. Extensive characterization of CD4+ T-cell clones specific for GV1001 generated from a lung cancer patient in complete remission after vaccination demonstrated a very broad immune response to this single peptide vaccine with differences in fine specificity, HLA restriction, affinity and function. Some CD4+ T-cell clones were cytotoxic against peptide-loaded target cells and also recognized processed recombinant hTERT protein. Furthermore, T-cell responses against several unrelated hTERT epitopes, some of which are novel, were detected, indicating extensive epitope spreading which was confirmed in other clinical responders. In contrast, patients responding immunologically, but not clinically, after vaccination did not display this intramolecular epitope spreading. Multifunctional CD4+ T-cell clones specific for novel hTERT epitopes were generated and shown to recognize a melanoma cell line. Pentamer analysis of T cells in peripheral blood also demonstrated the presence of an important CD8+ T cell response recognizing an HLA-B7 epitope embedded in GV1001 not previously described. These results indicate that the highly diverse hTERT-specific T-cell response, integrating both T helper and CTL responses, is essential for tumor regression and the generation of long-term T-cell memory. PMID- 22934261 TI - Detection of functional antigen-specific T cells from urine of non-muscle invasive bladder cancer patients. AB - To gain further insights into the role of T lymphocytes in immune responses against bladder tumors, we developed a method that monitors the presence of functional antigen-specific T cells in the urine of non-muscle invasive bladder cancer patients. As relatively few immune cells can usually be recovered from urine, we examined different isolation/amplification protocols and took advantage of patients treated with weekly intravesical instillations of Bacillus Calmette Guerin, resulting in large amounts of immune cells into urine. Our findings demonstrate that, upon in vitro amplification, antigen-specific T cells can be detected by an interferon gamma (IFNgamma)-specific ELISPOT assay. PMID- 22934263 TI - The split nature of tumor-infiltrating leukocytes: Implications for cancer surveillance and immunotherapy. AB - An important development in tumor immunology was the identification of highly diverse tumor-infiltrating leukocyte subsets that can play strikingly antagonistic functions. Namely, "anti-tumor" vs. "pro-tumor" roles have been suggested for Th1 and Th17 subsets of CD4(+) T cells, Type I or Type II NKT cells, M1 and M2 macrophages, or N1 and N2 neutrophils, respectively. While these findings are being validated in cancer patients, it is also clear that the balance between infiltrating CD8(+) cytotoxic and Foxp3(+) regulatory T cells has prognostic value. Here we review the pre-clinical and clinical data that have shaped our current understanding of tumor-infiltrating leukocytes. PMID- 22934265 TI - PD-1 and BTLA and CD8(+) T-cell "exhaustion" in cancer: "Exercising" an alternative viewpoint. AB - The elevated expression of PD-1, BTLA, and other co-inhibitory molecules on T cells from cancer patients has become an accepted signature for a state called T cell "exhaustion" that has emerged almost as dogma in the field. However, here we propose that in some cases this "exhausted" T-cell phenotype may instead be an indicator of T cells that are in a more heightened state of T-cell activation more susceptible to negative regulation rather than being "exhausted." This alternative interpretation fits in line with the view that CD8(+) T-cell activation in cancer results from a continuum of signals regulating their differentiation towards potent effector cells. PMID- 22934264 TI - Plasmacytoid dendritic cells and their therapeutic activity in cancer. AB - In the last decade several studies provided evidence that plasmacytoid dendritic cells (pDCs) infiltrate human neoplasms with poor prognosis. However, the role of tumor-associated pDCs remains controversial. Various studies indicate that pDCs play an immuno-suppressive role and facilitate tumor progression in both animal models and humans. In contrast, others found that the presence of activated tumor associated pDCs results in tumor regression in mice. Given these findings, understanding pDC function in tumor biology is an important necessity and may pave the way for novel therapeutic strategies to fight malignancies. PMID- 22934266 TI - Cytomegalovirus infection in brain tumors: A potential new target for therapy? AB - Emerging evidence demonstrate a high prevalence of cytomegalovirus (CMV) proteins and nucleic acids in different tumors. CMV is confined to tumor cells and non cancer cells in close proximity to tumors are consistently virus negative. CMV confers both oncogenic and oncomodulatory mechanisms, and may therefore provide a novel target in cancer treatment. PMID- 22934267 TI - Combining forces to hit cancer stem cells: TRAIL-lymphocytes and EpCAMxCD3 bispecific antibody show efficacy against pancreatic cancer. AB - TRAIL selectively kills cancer cells while bispecific antibody EpCAMxCD3 guides effector lymphocytes to cancer cells. Arming of ex vivo constructed TRAIL lymphocytes with EpCAMxCD3 enhances contact time and affinity between lymphocytes and tumor cells and enforces tumor elimination. This boosts endogenous immune responses and augments the effect of cytotoxic tumor therapy. PMID- 22934262 TI - Trial Watch: Experimental Toll-like receptor agonists for cancer therapy. AB - Toll-like receptors (TLRs) are prototypic pattern recognition receptors (PRRs) best known for their ability to activate the innate immune system in response to conserved microbial components such as lipopolysaccharide and double-stranded RNA. Accumulating evidence indicates that the function of TLRs is not restricted to the elicitation of innate immune responses against invading pathogens. TLRs have indeed been shown to participate in tissue repair and injury-induced regeneration as well as in adaptive immune responses against cancer. In particular, TLR4 signaling appears to be required for the efficient processing and cross-presentation of cell-associated tumor antigens by dendritic cells, which de facto underlie optimal therapeutic responses to some anticancer drugs. Thus, TLRs constitute prominent therapeutic targets for the activation/intensification of anticancer immune responses. In line with this notion, long-used preparations such as the Coley toxin (a mixture of killed Streptococcus pyogenes and Serratia marcescens bacteria) and the bacillus Calmette-Guerin (BCG, an attenuated strain of Mycobacterium bovis originally developed as a vaccine against tuberculosis), both of which have been associated with consistent anticancer responses, potently activate TLR2 and TLR4 signaling. Today, besides BCG, only one TLR agonist is FDA-approved for therapeutic use in cancer patients: imiquimod. In this Trial Watch, we will briefly present the role of TLRs in innate and cognate immunity and discuss the progress of clinical studies evaluating the safety and efficacy of experimental TLR agonists as immunostimulatory agents for oncological indications. PMID- 22934268 TI - Insight into the dynamics, localization and magnitude of antigen-specific immune responses by [(18)F]FLT PET imaging. AB - In order for cellular therapeutics to succeed, comprehensive monitoring of the transplanted cells in vivo is required i.e., their localization, functionality and numbers in a longitudinal manner. Recently, dendritic cell based vaccines have been monitored by their effect on lymphocyte activation using [(18)F]FLT PET in cancer patients. PMID- 22934269 TI - miRNA-mediated GALNT modulation of invasion and immune suppression: A sweet deal for metastatic cells. AB - Glycosylation is a key process impacting on many aspects of cellular interactions. We recently reported that a miRNA cluster controls glycosylation by directly targeting N-acetylgalactosamine transferases (GALNTs), resulting in increased tumor invasion and immunosuppression. Here we further discuss how defective glycosylation or GALNTs dysregulation may contribute to tumor progression. PMID- 22934270 TI - Bcl-2: Live and let die. AB - Recent findings from our laboratory provide the first indication that overexpression of Bcl-2 in Eu-myc transgenic cells enhances tumor immunosurveillance by inducing NKG2D ligands. Initial evidence suggests that this model is relevant to human patients. Thus, antitumor therapies that target Bcl-2 harbor the risk of reducing tumor immunogenicity. PMID- 22934271 TI - Tumor conditioned media from colorectal cancer patients inhibits dendritic cell maturation. AB - Tumors inhibit dendritic cell maturation and function in order to evade host immunity. We showed that conditioned media from tumor explant tissue, taken from metastatic colorectal cancer patients, significantly inhibits maturation of dendritic cells. PMID- 22934272 TI - Mast cells in pancreatic ductal adenocarcinoma. AB - Using in vivo models of pancreatic ductal adenocarcinoma (PDAC), we demonstrated that mast cells migrate to the tumor site and provide a microenvironment that allows for tumor progression. These results indicate that targeting mast cells may be a promising novel therapy for PDAC. PMID- 22934273 TI - DKK1 as a novel target for myeloma immunotherapy. AB - Novel, potent tumor-associated antigens are needed to improve the efficacy of immunotherapy for myeloma. We demonstrated that active vaccination using the DKK1 DNA vaccine in the myeloma mouse model protected mice from developing myeloma and effectively treated established myeloma. Therefore, DKK1 could be developed as a novel vaccine for myeloma immunotherapy. PMID- 22934274 TI - Innate immune recognition of breast tumor cells mediates CCL22 secretion favoring Treg recruitment within tumor environment. AB - Regulatory T cells (Treg) have been reported of poor prognosis for overall survival in primary breast tumors (BT). As CCL22 plays a major role in Treg recruitment within primary BT we deciphered the mechanisms involved in the CCL22 production by breast epithelial tumor cells and propose herein the major role of their innate immune recognition in this production. PMID- 22934275 TI - Key role of the positive feedback between PGE(2) and COX2 in the biology of myeloid-derived suppressor cells. AB - PGE(2) is the key factor needed for MDSCs development, accumulation and functional stability. PGE(2) initiates an EP2/EP4-mediated positive feedback between COX2 and PGE(2) in monocytic precursors, redirecting dendritic cell differentiation to MDSCs. COX2- or EP2/EP4- blockade abrogates MDSC functions and their CXCR4-CXCL12-mediated attraction to cancer environment, providing convenient immunotherapeutic targets. PMID- 22934276 TI - New strategies for melanoma immunotherapy: How to overcome immunosuppression in the tumor microenvironment. AB - Using ret transgenic mouse model of spontaneous melanoma, we showed an accumulation of melanoma antigen-specific memory T cells. However, their antitumor effects could be blocked by myeloid-derived suppressor cells, tolerogenic dendritic cells and regulatory T cells. We suggest that effective melanoma immunotherapy should include the neutralization of immunosuppressive tumor microenvironment. PMID- 22934277 TI - Targeting the tumor mutanome for personalized vaccination therapy. AB - Next generation sequencing enables identification of immunogenic tumor mutations targetable by individualized vaccines. In the B16F10 melanoma system as pre clinical proof-of-concept model, we found a total of 563 non-synonymous expressed somatic mutations. Of the mutations we tested, one third were immunogenic. Immunization conferred in vivo tumor control, qualifying mutated epitopes as source for effective vaccines. PMID- 22934278 TI - Antagonizing the innate pattern recognition receptor CD204 to improve dendritic cell-targeted cancer immunotherapy. AB - Extensive studies have established a role of scavenger receptor CD204 in pattern recognition and ligand uptake. Strikingly, we recently revealed a previously unrecognized feature of CD204 action in attenuating T-cell activation and antitumor immunity. Blocking its activity in dendritic cells represents a promising approach to the improvement of cancer immunotherapy. PMID- 22934279 TI - Combining targeted therapy with immunotherapy (interferon-alpha): Rational, efficacy in gastrointestinal stromal tumor model and implications in other malignancies. AB - Imatinib revolutionized gastrointestinal stromal tumor (GIST) treatment but median-progression-free-survival of unresectable/metastatic disease is < 2 y. B RAF(V600)-mutated-melanoma responds to vemurafenib dramatically but median progression-free-survival is < 9 mo. Combining imatinib with immunotherapy (peginterferon alpha-2b) in GIST showed significant induction of antitumor immunity and highly promising clinical outcomes. This strategy warrants further testing in other malignancies. PMID- 22934280 TI - Development of a novel universal immune receptor for antigen targeting: To Infinity and beyond. AB - Chimeric antigen receptors (CARs) possess fixed specificity for a single antigen and require empirical testing in T cells. To address this, we have developed a novel, adaptable immune receptor strategy that allows for the rapid generation and testing of T cells of nearly infinite antigen specificity. PMID- 22934281 TI - Effect of CpG ODN on monocytic myeloid derived suppressor cells. AB - CpG oligonucleotides stimulate via TLR9 and enhance anti-tumor immunity, an effect attributed to the activation of NK and CD8(+) T cells. Our recent work demonstrates that CpG ODN also induce monocytic myeloid-derived suppressor cells to mature into M1 macrophages, further aiding tumor elimination. This provides insight into the mechanism through which CpG promote tumor regression. PMID- 22934282 TI - IL-17A is a central regulator of lung tumor growth. AB - In a recent study we reported increased expression of IL-17A in the lung of patients with lung adenocarcinoma. Local blockade of IL-17A in the lung, in a model of lung cancer revealed enhanced anti-tumor immunity characterized by increased IFNgamma, a diminished T-regulatory cell number and reduced tumor growth. PMID- 22934283 TI - The emergence of phox-ER stress induced immunogenic apoptosis. AB - Primary induction of photo-oxidative (phox)-ER stress in cancer cells evoked immunogenic apoptosis (IA) associated with pre-apoptotic emission of calreticulin and ATP, and protective antitumor immunity. This IA subroutine involved "core" functions (e.g., PERK/PI3K-based modulation of secretory trafficking) rather than "private" ones (caspase-8 and eIF2alpha-phosphorylation) engaged by other IA inducers. PMID- 22934284 TI - Tumor high endothelial venules (HEVs) predict lymphocyte infiltration and favorable prognosis in breast cancer. AB - Lymphocyte migration into tumors remains poorly understood, despite the critical impact of these cells on cancer clinical outcome. Our recent study demonstrates the presence of blood vessels specialized in lymphocyte recruitment called high endothelial venules (HEVs) in human solid tumors and their correlation with lymphocyte infiltration and favorable prognosis in breast cancer. PMID- 22934285 TI - TG4010: A therapeutic vaccine against MUC1 expressing tumors. AB - TG4010 is a therapeutic cancer vaccine based on a viral vector, a modified vaccinia of Ankara (MVA), expressing MUC1 as well as interleukine 2. Today the clinical development is focused on advanced non-small cell lung cancer in combination with first line chemotherapy. Potential biomarkers predictive of activity have been identified. PMID- 22934286 TI - Comparative cost-effectiveness of stereotactic body radiation therapy versus intensity-modulated and proton radiation therapy for localized prostate cancer. AB - OBJECTIVE: To determine the cost-effectiveness of several external beam radiation treatment modalities for the treatment of patients with localized prostate cancer. METHODS: A lifetime Markov model incorporated the probabilities of experiencing treatment-related long-term toxicity or death. Toxicity probabilities were derived from published sources using meta-analytical techniques. Utilities and costs in the model were obtained from publicly available secondary sources. The model calculated quality-adjusted life expectancy and expected lifetime cost per patient, and derived ratios of incremental cost per quality-adjusted life year (QALY) gained between treatments. Analyses were conducted from both payer and societal perspectives. One-way and probabilistic sensitivity analyses were performed. RESULTS: Compared to intensity modulated radiation therapy (IMRT) and proton beam therapy (PT), stereotactic body radiation therapy (SBRT) was less costly and resulted in more QALYs. Sensitivity analyses showed that the conclusions in the base-case scenario were robust with respect to variations in toxicity and cost parameters consistent with available evidence. At a threshold of $50,000/QALY, SBRT was cost-effective in 75% and 94% of probabilistic simulations compared to IMRT and PT, respectively, from a payer perspective. From a societal perspective, SBRT was cost-effective in 75% and 96% of simulations compared to IMRT and PT, respectively, at a threshold of $50,000/QALY. In threshold analyses, SBRT was less expensive with better outcomes compared to IMRT at toxicity rates 23% greater than the SBRT base-case rates. CONCLUSION: Based on the assumption that each treatment modality results in equivalent long-term efficacy, SBRT is a cost-effective strategy resulting in improved quality-adjusted survival compared to IMRT and PT for the treatment of localized prostate cancer. PMID- 22934287 TI - Quantification of cellular volume and sub-cellular density fluctuations: comparison of normal peripheral blood cells and circulating tumor cells identified in a breast cancer patient. AB - Cancer metastasis, the leading cause of cancer-related deaths, is facilitated in part by the hematogenous transport of circulating tumor cells (CTCs) through the vasculature. Clinical studies have demonstrated that CTCs circulate in the blood of patients with metastatic disease across the major types of carcinomas, and that the number of CTCs in peripheral blood is correlated with overall survival in metastatic breast, colorectal, and prostate cancer. While the potential to monitor metastasis through CTC enumeration exists, the basic physical features of CTCs remain ill defined and moreover, the corresponding clinical utility of these physical parameters is unknown. To elucidate the basic physical features of CTCs we present a label-free imaging technique utilizing differential interference contrast (DIC) microscopy to measure cell volume and to quantify sub-cellular mass-density variations as well as the size of subcellular constituents from mass density spatial correlations. DIC measurements were carried out on CTCs identified in a breast cancer patient using the high-definition (HD) CTC detection assay. We compared the biophysical features of HD-CTC to normal blood cell subpopulations including leukocytes, platelets (PLT), and red blood cells (RBCs). HD-CTCs were found to possess larger volumes, decreased mass-density fluctuations, and shorter-range spatial density correlations in comparison to leukocytes. Our results suggest that HD-CTCs exhibit biophysical signatures that might be used to potentially aid in their detection and to monitor responses to treatment in a label-free fashion. The biophysical parameters reported here can be incorporated into computational models of CTC-vascular interactions and in vitro flow models to better understand metastasis. PMID- 22934289 TI - Bibliography. Pediatric anesthesia. Current world literature. PMID- 22934290 TI - Bibliography. Anesthesia and medical disease. Current world literature. PMID- 22934291 TI - Periprocedural antithrombotic and bridging therapy: recommendations for standardized reporting in patients with arterial indications for chronic oral anticoagulant therapy. PMID- 22934288 TI - Expression of E-selectin ligands on circulating tumor cells: cross-regulation with cancer stem cell regulatory pathways? AB - Although significant progress has been made in the fight against cancer, successful treatment strategies have yet to be developed to combat those tumors that have metastasized to distant organs. Poor characterization of the molecular mechanisms of cancer spread is a major impediment to designing predictive diagnostics and effective clinical interventions against late stage disease. In hematogenous metastasis, it is widely suspected that circulating tumor cells (CTCs) express specific adhesion molecules that actively initiate contact with the vascular endothelium lining the vessel walls of the target organ. This "tethering" is mediated by ligands expressed by CTCs that bind to E-selectin expressed by endothelial cells. However, it is currently unknown whether expression of functional E-selectin ligands on CTCs is related to cancer stem cell regulatory or maintenance pathways, particularly epithelial-to-mesenchymal transition and the reverse, mesenchymal-to-epithelial transition. In this hypothesis and theory article, we explore the potential roles of these mechanisms on the dynamic regulation of selectin ligands mediating CTC trafficking during metastasis. PMID- 22934292 TI - Discrepancy of the international normalized ratio observed in the external quality assessment survey: a cause for concern. PMID- 22934293 TI - Comparison of thrombin generation for paired-platelet-rich plasma collected with and without corn trypsin inhibitor from hemophiliacs treated with factor-VIII inhibitor bypassing agents. PMID- 22934294 TI - How we treat: Considerations for physiotherapy in the patient with haemophilia and inhibitors undergoing elective orthopaedic surgery. PMID- 22934295 TI - A conversation with Tadataka Yamada. Interview by Ushma S. Neill. PMID- 22934296 TI - The growing burden of cardiovascular disease. AB - Will the new EU research funding programme Horizon 2020 provide what is needed? PMID- 22934297 TI - Cardiology in Greece. AB - From its birth in 1954, Greek cardiology has been integrated with the European Society of Cardiology, while its Society predates the ACC and ESC. PMID- 22934298 TI - The Leipzig Heart Center. AB - Prof. Gerhard Schuler, Director of cardiology, discusses the institution's history, achievements, and plans for the future with Emma Wilkinson MA. PMID- 22934299 TI - Inventory of European databases related to cardiovascular diseases. AB - Under the auspices of the ESC the authors discuss databases for managing CVD. PMID- 22934300 TI - The Journal of Interventional Cardiology. AB - In a small field with an abundance of journals, the Journal of Interventional Cardiology is carving out its niche with articles about technologies on the horizon. PMID- 22934301 TI - The clinical academic pathway in New Zealand cardiology. AB - Cardiologists Martin Stiles and Nigel Lever speak of the challenges facing clinicians in academia to Iona MacDonald. PMID- 22934302 TI - Why an ERJ series on air pollution? PMID- 22934303 TI - Working together on disease surveillance and animal welfare. PMID- 22934304 TI - New group formed to advise on TB eradication. PMID- 22934305 TI - Schmallenberg virus 'likely to spread to new areas'. PMID- 22934306 TI - Making a difference to animal welfare in Malawi. PMID- 22934307 TI - Facing challenges together. PMID- 22934308 TI - Ampicillin-resistant Actinobacillus pleuropneumoniae in pigs. PMID- 22934309 TI - Retraction notice to: Cell adhesion-dependent control of microRNA decay. Molecular Cell 43, 1005-1014; September 16, 2011. PMID- 22934310 TI - At the cliff's edge. PMID- 22934311 TI - Time to talk. PMID- 22934312 TI - [Nursing care in distress]. PMID- 22934313 TI - [Tell me, where nursing is, where has it stayed?]. PMID- 22934326 TI - Pre-existing condition insurance plan program. Amendment to interim final rule with request for comments. AB - This document contains an amendment regarding program eligibility to the interim final regulation implementing the Pre-Existing Condition Plan program under provisions of the Patient Protection and Affordable Care Act. In light of a new process recently announced by the Department of Homeland Security, eligibility for the program is being amended so that the program does not inadvertently expand the scope of that process. PMID- 22934327 TI - Information Governance and Safeguarding Children Study Day, London, 18 November 2011. PMID- 22934328 TI - The Royal Photographic Society 'Good Picture--2011' symposium, London, 3 December 2011. PMID- 22934329 TI - Making and Using Clinical and Healthcare Recordings for Teaching and Learning- workshop and launch of guidance website, London, 5 December 2011. PMID- 22934330 TI - On the Way to Health. AB - Information technology (IT) has fundamentally changed the way we work, bank, and communicate. Its impact on health care and health research, however, has been limited by the lack of a comprehensive infrastructure to connect patients, providers, and researchers. As we learn more about how to address the unhealthy behaviors that underlie many chronic conditions, researchers are seeking IT solutions to connect to patients in scalable ways. This Issue Brief describes the development and use of a new web-based IT platform, Way to Health, to deliver and evaluate behavioral interventions to improve health. PMID- 22934331 TI - [Recent progress in study of idiopathic normal pressure hydrocephalus]. PMID- 22934332 TI - [Hungarian consensus regarding the role of vitamin D in the prevention and treatment of diseases]. PMID- 22934333 TI - [Expressions of EOS and COX-2 in nasal polyps in patients with aspirin triad syndrome and its significance]. AB - OBJECTIVE: To explore the regulatory role of COX-2 and aggregation of EOS in the pathogenesis of Aspirin triad syndrome. METHOD: There were 34 patients with ST (group 1), 30 patients with chronic sinusitis and nasal polyps and asthma (group 2), 30 patients with sinusitis (control group). Nasal polyps of 94 patients were obtained in endoscopic sinus surgery,HE staining and immunohistochemical SP staining were performed to detect the distribution of eosinophils(EOS) and the expression of COX-2. Statistical analysis was performed using the SPSS software and then the relationship between their expression and distribution with clinical pathology and pathogenesis was analyzed. RESULT: EOS infiltrated extensively in nasal polyps, and EOS counts in these groups were 80.02 +/- 6.11, 76.62 +/- 5.22, 65.97 +/- 4.78,respectively. The difference between ST group, ATA group and control group are significant (P < 0.05), no significant difference between ST group and ATA group. COX-2 in the nasal polyps was mainly expressed in submucosal glands, glandular epithelial cells, epithelial cells, endothelial cells and EOS in interstitium. The positive cell count were 88.13 +/- 6.26, 89.46 +/- 5.97, 91.22 +/- 4.11, respectively. There was significant difference (P < 0.05) between ST group and control group. No significant difference (P > 0.05) was found between ATA group and control group,ST group and ATA group. CONCLUSION: The difference of EOS infiltration in patients with ST may be associated with an inflammatory response underlying specific clinical manifestations after exposure to non-steroidal anti-inflammatory drugs, and the difference of COX-2 expression in patients with ST may be related to the conversion of metabolic pathway of arachidonic acid and the formation of nasal polyps. PMID- 22934334 TI - [Efficacy evaluation of specific immunotherapy with standardized house dust mite allergen preparation for allergic rhinitis]. AB - OBJECTIVE: To evaluate the efficacy of specific immunotherapy (SIT) with standardized house dust mite allergen preparation for allergic rhinitis (AR). METHOD: Fifty-five patients with allergic rhinitis caused by house dust mites were selected in this self-control study. Clinical efficacy was evaluated by symptom and sign score after two years of specific immunotherapy and compared with pre-treatment scores. RESULT: After completing the study, a clinically significant reduction in symptom and sign score in these patients was noted, compared with that of pretreatment. And the difference was statistically significant (P < 0.01). CONCLUSION: Standardized house dust mite allergen preparation is an effective treatment in patients suffering from allergic rhinitis due to house dust mites. PMID- 22934335 TI - [Culture and induced multilineage differentiation of mesenchymal stem cells derived from human nasal mucosa]. AB - OBJECTIVE: To establish an in vitro method to culture mesenchymal stem cells(MSCs) derived from human nasal mucosa, and explore their stemness and differentiation potential. METHOD: Based on the observation of distribution of MSCs in human nasal mucosa, we cultured and proliferated MSCs in vitro and identified the expression of stem cell markers on them including Nestin, CD133, Vimentin and Sa114 with immunofluorescence. The MSCs were induced to differentiate to osteoblasts with medium containing dexamethasone, ascorbic acid and beta sodium glycerophosphate, and to neurons with Neurobasal medium containing B27, ATRA and TSA. Histochemistry and immunofluorescence were applied to evaluate the differentiation. RESULT: The nestin and vimentin immunofluorescence-positive MSCs existed extensively in human nasal mucosa. While the MSCs were cultured in the osteogenic-inducing medium, activities of alkaline phosphatase were increased significantly, and bone nodules were found on the surface of the osteoblasts by alizarin red staining. After the induction by neural-inducing medium, the MSCs adopted neuron like appearance with many slim protrusions interconnected as a network. The induced cells expressed neural markers NF-200 and BM88 strongly. CONCLUSION: The MSCs derived from human nasal mucosa are multipotent stem cells and can be utilized as seed cells to repair bone or neural injury. PMID- 22934336 TI - [Relationship between eosinophils in nasal discharge and responses to treatment of inhaled glucocorticosteroid in patients with persistent allergic rhinitis]. AB - OBJECTIVE: To evaluate the treatment responses of persistent allergic rhinitis with and without eosinophils (EOS) in nasal discharge to inhaled glucocorticosteroid (CS), and therefore to verify whether low eosinophil level in nasal discharge can predict poor response to treatment with CS. METHOD: Forty-two symptomatic allergic rhinitis patients, who had not received CS therapy in three months preceding the study, were examined before and 2 month, 4 months and 6 months after treatment with CS. At each visit, all patients underwent symptom scoring and physical sign scoring. The level of eosinophil cationic protein (ECP) in the nasal discharge supernatants was measured by radioimmunoassay. The patients were divided into 2 groups according to nasal discharge EOS percentages, an EOS group (EOS > or = 3%) and a non-EOS group (EOS < 3%). The response to CS therapy (as measured by symptom and physical sign scores) and the changes of nasal discharge measurements were compared between the 2 groups. RESULT: In the EOS group, the baseline EOS [0.086 (0.065; 0.176)] and ECP level [(326 +/- 145) microg/L] were significantly higher than EOS [0.016 (0.005; 0.022)] and ECP level [(154 +/- 58) microg/L] of the non-EOS group, t = 4.40, 3.32, respectively, all P < 0.01. After 2 months and 6 months of CS therapy, the nasal discharge EOS, ECP level were 0.038 (0.006; 0.070), 0.019 (0.010; 0.060), (175 +/- 122) microg/L, (175 +/- 153) microg/L, respectively in the EOS group,which were significantly different as compared to baseline values (F = 6.73, 7.38, respectively all P < 0.05). But in the non-EOS group, the nasal discharge EOS and ECP level were 0.014 (0.004; 0.032), 0.015 (0.010; 0.026), (118 +/- 60) microg/L, (112 +/- 60) microg/L, respectively at 2 and 6 months, which showed that the nasal discharge EOS level and the symptom and physical sign scores did not improve significantly (F = 0.82, P > 0.05), but the ECP level did improve (F = 3.78, P < 0.05). The average daily dose of CS was not different between the two groups at any visits. CONCLUSION: In persistent allergic rhinitis with low EOS in nasal discharge, CS therapy for 6 months failed to improve symptoms and physical signs. PMID- 22934337 TI - [The expression of E-cadherin and occludin in epithelium of chronic rhinosinositis and its significance]. AB - OBJECTIVE: To explore the expression and distribution of barrier molecules in epithelium of various types of chronic rhinosinusitis and its significance. METHOD: There were four groups including control (13 samples), Eos-CRSwNP (10 samples), nonEos-CRSwNP (14 samples), CRSsNP (11 samples). The method of immunohistochemistry was used to detect the protein expression of E-cadherin and occludin in nasal mucosa. RESULT: There was positive staining extensively distributed among cells in nasal mucosa. There was no significant difference in these groups. However, the occludin mainly located on the top of epithelial cells. In normal nasal mucosa, the positive expression was continuous, however, it was discontinuous both in CRSwNP and CRSsNP groups. CONCLUSION: There was no E cadherin loss in the progression of pathophysiology of chronic rhinosinusitis. But the loss of occludin may correlate to the dysfunction of epithelial barrier, which was beneficial for the pathogen invasion. PMID- 22934338 TI - [Expression of PCNA and LNGFr in olfactory epithelium of patients suffering from dysosmia caused by chronic sinusitis]. AB - OBJECTIVE: To study the expression of PCNA and LNGFr in olfactory epithelium of patients suffering from dysosmia caused by chronic sinusitis, and the function of LNGFr. METHOD: Forty-six patients undergoing FESS were chosen. Before operation, their olfactory functions were examined with CCCRC. According to their CCCRC scores, they were divided into three groups. Group A: Patients with chronic sinusitis and dysosmia 25 cases; Group B: Patients with chronic sinusitis and a normal olfactory function 10 cases; Group C: Patients with deviation of nasal septum and a normal olfactory function 11 cases. The expressions of PCNA and LNGFr were measured in olfactory mucosas of the three groups by immunohistochemistry. RESULT: In basal cells, the expression of PCNA and LNGFr in group A was higher than that in group B (P < 0.01). and in group C (P < 0.01). There was negative correlation between positive cells of PCNA and CCCRC score in basal cells of group A (r = -0.7441, P < 0.01); There was negative correlation between integral optical density of LNGFr and CCCRC score in basal cells of group A (r = -0.4407, P < 0.05). There was positive correlation between positive cells of PCNA and integral optical density of LNGFr in basal cells of group A (r = 0.5317, P < 0.01). CONCLUSION: Basal cells proliferated dramatically in patients suffering from dysosmia caused by chronic sinusitis. The proliferating capacity of basal cells was related to up-regulation of LNGFr expression. PMID- 22934339 TI - [The application septonasal bidirectional mucoperiosteal flap in treatment of refractory choanal atresia in adults]. AB - OBJECTIVE: To explore the effects of septonasal bidirectional mucoperiosteal flap in the treatment of refractory choanal atresia in adults. METHOD: Analysis of 9 cases for choanal atresia was conducted. Two cases were of congenital origin and 7 cases of acquired origin, which was a complication of radiotherapy for nasopharyngeal carcinoma. The patients received transnasal endoscopic surgery using the septonasal bidirectional mucoperiosteal flap, without positioning the postoperative expansion tube. After the operation, the changes of symptoms were observed and the recurrent rate of restenosis or atresia was investigated in the follow-up time. RESULT: The symptoms of nasal obstruction and mouth breathing improved significantly in the 9 patients. At an average follow-up time of 19.3 months, the new forming posterior nare remained patent. The mucoperiosteal flap had no shift or necrosis. No restenosis or atresia happened. Nasal adhesion occurred in two patients. Granulation tissue hyperplasia was found in 1 patient, who underwent endoscopic revision without recurrence. CONCLUSION: The application of mucoperiosteal flap in transnasal endoscopic surgery for the choanal atresia can reduce the incidence of restenosis or atresia. Postoperative expansion tube is not mandatory. PMID- 22934340 TI - [The efficacy and safety of subcutaneous immuno-therapy with dermatophagoides pteronyssinus for allergic rhinitis]. AB - OBJECTIVE: To evaluate the efficacy and safety of subcutaneous immunotherapy with a standardized Dermatophagoides pteronyssinus extract for allergic rhinitis. METHOD: Sixty-eight patients with allergic rhinitis who received specific immunotherapy with a standardized dermatophagoides pteronyssinus extract were enrolled in this study. The clinical symptoms and signs were scored before and 2 years after treatment. Side effects were registered. Symptom and side effect scores were assessed to evaluate the clinical efficacy and safety. RESULT: There was a significant difference (P < 0.01) in symptom and medication scores between the two groups tow years after treatment. The patients had fewer symptoms and lower intake of medication. No severe systemic reactions were registered. CONCLUSION: Immunotherapy with a standardized dermatophagoides pteronyssinus extract is effective and safe to treat patients clinically sensitive to this allergen. PMID- 22934341 TI - [Feasibility of endoscope assisted resection of submandibular gland through a dermatoglyph incision]. AB - OBJECTIVE: To investigate the feasibility of endoscope assisted resection of submandibular gland through a dermatoglyph incision. METHOD: We choose 5 patients diagnosed as benign diseases of submandibular gland from 2005 to 2010 in Beijing Tongren Hospital. Each patient was given a careful design of dermatoglyph incision preoperatively and an endoscope assisted surgery on the submandibular gland. The details of surgery procedure were described as follow. The inferior edge of the capsule of the submandibular gland was incised, and the traveling characteristics of facial artery, submandibuar gland branch of submental artery, branches of anterior facial vein were identified with endoscopic assistance. Branches of vascular and submandibular postganglionic fibers were treated with bipolar coagulation hemostasis. The submandibular duct was identified and isolated, teased downward from the floor of the mouth, and then ligated. The gland was lifted off the digastric tendon and removed. Suction drainage was used with a plastic tube and the incision was closed with mattress suture. The incision length, intraoperative bleeding, complication and operation duration were retrospectively, reviewed in the traditional group. RESULT: Of the endoscopic group, the incision lengths varied from 2.0-2.5 cm with an average of 2.3 cm. The operation durations varied from 41-87 min, with an average of 64 min. The total intraoperative bleeding was about 5 to 10 ml. No facial paralysis nor infection occurred both intra-and post-operatively. No relapse was detected in the long-term follow-up (4 months to 5 years). Compared with the traditional group, the incision length and bleeding decreased dramatically while the operational duration increased. CONCLUSION: Endoscope assisted resection of submandibular gland through dermatoglyph incision will minimize the damage to surrounding tissue and obtain good cosmetic results. PMID- 22934342 TI - [The assessment of anxiety and depression state in Meniere's disease patients]. AB - OBJECTIVE: To investigate the incidence of anxiety and depression state in patients with Meniere's disease, to provide objective evidence for curing Meniere's disease effectively. METHOD: Hamilton anxiety scale and Hamilton depression scale were used to quantitatively analyze the anxiety and depression state of 60 patients with untreated definite Meniere's disease and 20 normal controls. RESULT: The scores of patients with Meniere's disease was significantly higher than that of normal controls (P < 0.05). There was no significant difference in scores between the males and females in Meniere's disease patients (P > 0.05). CONCLUSION: Patients with Meniere's disease experienced high level of anxiety and depression. The treatment should not only focus on the physiological disorder but also the psychiatric and emotional problems. PMID- 22934343 TI - [Observation on ultrastructure of maxillary sinus mucosa in experimental acute sinusitis]. AB - OBJECTIVE: To observe ultrastructure of maxillary sinus mucosa of experimental acute sinusitis in rabbits. METHOD: Twenty-five rabbits were randomly divided into experimental group (20 rabbits) and blank control group (5 rabbits). We established a rhinogenic model of experimental acute sinusitis in experimental group. Five rabbits chosen randomly in experimental group were sacrificed and dissected after 1, 2, 3, and 4 weeks, and the tissue (0.3 cm x 0.3 cm) of sinus mucosa were prepared for visualization by transmission electron microscope (TEM). Animals in blank control group were sacrificed after 1 week. RESULT: Under the transmission electron microscope, in the blank control group, cilia of maxillary sinus mucosa lined up in order without ciliary loss, no stretched endoplasmic reticulum or turgescent mitochondria was observed. However, in the experimental group, inordinate array and loss of cilia was observed, a few compound cilia and cytoplasmic protrusion were also found. Both endoplasmic reticulum and mitochondria were swelling, and the lymphocytes were infiltrating with fibroblast proliferation in the submucosa. There was statistically significant difference between the experimental group and the blank control group (P < 0.05). In the experimental group, the number of compound cilia increased from 1 to 4 weeks, and the amount of compound cilia of the mucosa at 3 and 4 weeks was significantly higher than that at 1 week (P < 0.05). Swelling of mitochondria and endoplasmic reticulum was severe at 2 weeks and abated gradually with time, the results at 2 weeks were different from those of experimental group at 4 weeks (P < 0.05). CONCLUSION: The obstruction of nasal sinuses and the bacterial infection might lead to ultrastructural changes of maxillary sinus mucosa, and these ultrastructural changes were believed to the important processes of pathological changes in acute sinusitis. PMID- 22934344 TI - [The effect of gelatin sponge soaked in triamcinolone acetonide and gentamicin solution on mucosal healing after endoscopic sinus surgery]. PMID- 22934345 TI - [Research update on the eosinophils and allergic disease]. AB - The incidence of allergic diseases (asthma, allergic rhinitis, atopic dermatitis and food allergy) increased gradually over recent decades, and an increasing number of patients are suffering from allergic diseases, thus the rise in allergic disease incidence warrants concern. Researchers have already had a deeper understanding of the pathogenesis of allergic diseases. Mounting evidence has shown that the eosinophils play an important role in the pathogenesis of allergic diseases. Many systematic studies have been conducted about eosinophils, therefore, this review will provide a summary on recent progress in eosinophils and allergic diseases. PMID- 22934346 TI - [Recent advance on the genus nocardioides--a review]. AB - The Nocardioides genus was established by Prauser H. in 1976 according to morphological and physiological characteristics, as well as partial chemotaxonomic analyses of 17 nocardio-form actinobacteria isolated from soil, based on which a novel species Nocardioides albus was proposed as the type species. With the development in the technologies of isolation, purification and taxonomy, more and more members of this genus with varied morphological, physiological and biochemical characteristics were increasingly discovered from different sources, while all of them shared the same diagnostic characteristics of the genus. In the past 50 years, some of the members of the genus Nocardioides were ever transferred in or out and then some species description was ever emended. Till date, there were 56 validly described species in this genus. Some members of this genus were used in agriculture and industry. The objective of this review is to summarize the research advances in the genus Nocardioides, such as the changes of the taxonomic position and emendation description of the species as well as the application prospect in industry and agriculture. PMID- 22934347 TI - [Fimbriae of animal-originated enterotoxigenic Escherichia coli--a review]. AB - Animal-originated enterotoxigenic Escherichia coli (ETEC) are major pathogens resulting in newborn and young animal diarrhea. Adhesins and enterotoxins, both are essential for the pathogenicity of ETEC, are two major virulent factors of ETEC. Adhesion of animal-originated ETEC fimbrial adhesins (mainly including K88, K99, 987P, F18, F17 and F41) to intestinal epithelial cells is the initial and most important step involved in the ETEC infection. From the 1960s, studies on ETEC fimbrial genes, structure, biosynthesis, regulation of expression, interaction between fimbriae and host receptors have helped to better understand the biology and role of these organelles in pathogenesis. These studies also provide insight into new diagnostic tools and development of vaccines and inhibitors of ETEC colonization. PMID- 22934348 TI - [Phylogenetic analysis and nitrogen removal characteristics of a heterotrophic nitrifying-aerobic denitrifying bacteria strain from marine environment]. AB - OBJECTIVE: We determined the phylogenetic position of a heterotrophic nitrifying aerobic denitrifying bacterium X3, and detected its nitrogen removal characteristics for providing evidence to explain the principle of heterotrophic nitrification-aerobic denitrification and to improve the process in purification of marine-culture wastewater. METHODS: The evolutionary position of the strain was determined based on its morphological, physiological, biochemical characteristics and 16SrRNA gene sequence. The nitrification-denitrification ability of this strain was detected by detecting its nitrogen removal efficiency and growth on different inorganic nitrogen source. RESULTS: Strain X3 was identified as Halomonas sp. It grew optimally at salinity 3%, pH 8.5, C:N 10:1 at 28 degrees C, and it could still survive at 15% salinity. The removal of NH4+ -N, NO2(-) -N and NO3(-) -N was 98.29%, 99.07%, 96.48% respectively within 24 h. When three inorganic nitrogen existed simultaneously, it always utilized ammonia firstly, and the total inorganic nitrogen removal was higher than with only one nitrogen, suggesting that strain X3 has the ability of simultaneous nitrification and denitrification and completing the whole nitrogen removing process. CONCLUSION: Strain X3 belonged to the genus of Halomonas. It had strong simultaneous nitrification and denitrification capability and could live in high salinity environment. PMID- 22934349 TI - [Screening and identification of a bacterium capable of converting daidzein to S equol]. AB - OBJECTIVE: To screen and identify a bacterium capable of converting daidzein to S equol. METHODS: We used antibiotics to limit unrelated bacterial growth and enrich the target bacteria, and isolated the aim bacterial strain from rat intestine. The metabolite of daidzein was tested by HPLC, MS and NMR. The taxonomic group of the strain was identified by 16S rDNA sequence analysis and phylogenetic tree; the strain's morphological and physiological biochemical characters were also tested. RESULTS: A gram-negative facultative bacterial strain LH-52 (JN861767) capable of transforming daidzein to S-equol was isolated. Basic Local Alignment Search Tool (BLAST) search of LH-52's 16S rDNA sequence on GenBank suggested that this strain has 99% similarity to that of Proteus mirabilis, the morphological and physiological biochemical characteristics of LH 52 also showed highly similarity to P. mirabilis. Based on these data, we identified LH-52 as P. mirabilis, and named it as P. mirabilis LH-52. The results of HPLC, MS and NMR suggested that the metabolite of daidzien was S-equol. CONCLUSIONS: Bacteria strain P. mirabilis LH-52 was the first reported facultative bacteria strain capable of converting daidzein to S-equol, and might be more suitable in industrial application than obligate anareobic bacterial strains. PMID- 22934350 TI - [Function of flgK gene in Pectobacterium carotovorum subsp, carotovorum]. AB - OBJECTIVE: To investigate functions of flgKpcc gene in Pectobacterium carotovorum subsp. carotovorum (P. c. c). METHODS: The gene knock-out mutant deltaflgKpcc and complemented strain deltaflgKpcc-KH were generated by biparental mating and their phenotypes including cell morphology, motility, pathogenic factors, and pathogenicity were investigated. RESULTS: Non-flagellum, cell precipitation in the culture and significantly attenuated motility on 0.3% semisolid medium were observed in deltaflgKpcc compared to Pectobacterium carotovorum subsp. carotovorum S1. In addition, significant decrease in cellulase and protease activity, biofilm formation, and pathogenicity on host plant were found in deltaflgKpcc. While there were no apparent difference in growth rate in vitro, deltaflgKpcc-KH, the complementation strain, restored the phenotype of deltaflgKpcc to the wild type level. CONCLUSION: The gen of flgKpcc not only influences the cell motility, but also pathogenic factors to lead to the decreased pathogenicity in Pectobacterium carotovorum subsp. Carotovorum. PMID- 22934351 TI - [MvaT and MvaV transcriptionally regulate PcoI/PcoR quorum-sensing system in Pseudomonas fluorescens 2P24]. AB - OBJECTIVE: Pseudomonas fluorescens 2P24 is an effective biocontrol agent for soil borne plant diseases caused by microbial pathogens. The PcoI/PcoR quorum-sensing system, which influences the colonization ability of 2P24 on wheat rhizosphere, is an important factor for disease suppression. In this study we performed random mutagenesis to screen novel regulators of the pcoI gene, a biosynthase gene responsible for N-acyl-homoserine lactone (AHL) production. METHODS: A gacA gene mutant carrying a pcoI-lacZ fusion was employed as the reporter strain and subjected to a random mini-Tn5 insertion mutagenesis. Expression of pcol kept at a low level under the gacA(-) negative background. The Tn5-mutants with increased pcoI transcription were selected. RESULTS: Two mutants with significantly increased pcoI expression were identified from approximately 10000 Tn5-inserted colonies. The interrupted locus in the mutants was identified as the mvaT gene, a global regulator belonging to the H-NS family. A homolog of the mvaT gene, named mvaV, was also found in the genome draft sequence of 2P24. Genetic inactivation of mvaT or mvaV gene resulted in increased transcription of pcoI and the production of AHL molecules. Further qutitification by HPLC showed that the 2,4 diacetylphloroglucinol (2, 4-DAPG) levels in culture supernatant of the mvaT and mvaV mutants were significantly lower than that of the wild type strain. Furthermore, the mvaT or mvaV mutation drastically improved biofilm formation in 2P24. CONCLUSION: MvaT and MvaV may function as an important regulatory complex controlling biocontrol capacity of P. fluorescens 2P24. PMID- 22934352 TI - [Effects of overexpression of key enzyme genes on guanosine accumulation in Bacillus amyloliquefaciens]. AB - OBJECTIVE: To study the effects of overexpression of key enzyme genes (prs, purF and guaB) on guanosine production in Bacillus amyloliquefaciens TA208. METHODS: The prs, purF, guaB and prs-purF genes were inserted into constructed expression plasmid PBE43. All these constructed plasmids were electroporated into B. amyloliquefaciens TA208. The transcriptional level of various genes in the resulting strains was tested by real-time quantitative PCR. The activity of inosine 5'-monophosphate dehydrogenase in the resulting strains was detected. Finally, cell growth, glucose consumption and guanosine production of 4 engineering strains along with control strain were examined. RESULTS: The transcriptional analysis showed that overexpression of prs, purF and guaB gene accompanied by their own transcription level up-regulated. Overexpression of prs or purF genes alone slightly down-regulated the transcriptional level of purine operon, but overexpression of guaB gene independently did not disturb the transcription of prs gene and purine operon. Enzyme activity analysis showed that overexpression of prs or purF gene did not change the activity of inosine 5' monophosphate dehydrogenase and its activity increased by 126% through overexpression of guaB gene. Finally, by fermentation flask test, we found that overexpression of prs and purF gene alone could not promote guanosine accumulation. However, overexpression of guaB gene resulted in an increase in the production of guanosine, which was 20.7% higher than the control strain. The guanosine concentration and the conversion ratio from glucose to guanosine in the host strain containing co-expression plasmid were 14.4% and 6.8% higher than the control strain. CONCLUSION: Overexpression of guaB gene could enhance the guanosine yield in the culture broth. However, for prs and purF gene, only co expression of them could lead to a significant improvement of guanosine production in B. amyloliquefaciens. It should provide a valuable insight into the construction of industrially important strains for guanosine production by metabolic engineering. PMID- 22934353 TI - Cloning and characterization of a novel NAD+ -dependent xylitol dehydrogenase from Gluconobacter oxydans CGMCC 1. 637. AB - OBJECTIVE: To clone the xylitol dehydrogenase gene from Gluconobacter oxydans CGMCC 1.637, to characterize enigmatic properties of xylitol dehydrogenase and to investigate the induction abilities of various carbon sources on the oxidative activity of xylitol dehydrogenase and the effect of various carbon sources on the bioconversion of d-xylulose to xylitol in G. oxydans CGMCC 1.637. METHODS: Touch down polymerase chain reaction (PCR) was applied to clone the xylitol dehydrogenase gene from chromosomal DNA of G. oxydans CGMCC 1.637. RESULTS: The 798-bp open reading frame of xylitol dehydrogenase encoded a protein of 265 amino acids, with the molecular mass of 27.95 kDa. Sequence analysis of the putative protein revealed it to be a member of short-chain dehydrogenase/reductase family. Xylitol dehydrogenase showed oxidative activity with xylitol and sorbitol and no activity with other polyols, such as d-arabitol. K(m) and V(max) with xylitol was 78.97 mmol/L and 40.17 U/mg, respectively. The highest oxidative activity of xylitol dehydrogenase for xylitol was only 23.27 U/mg under optimum conditions (pH 10.0, 35 degrees C). However, the activity of its reverse reaction, d xylulose reduction, reached 255.55 U/mg under optimum conditions (pH 6.0, 30 degrees C), 10-times higher than that of xylitol oxidation. Oxidative activity of xylitol dehydrogenase was induced when G. oxydans CGMCC 1.637 was cultivated on d sorbitol. D-arabitol, which supported a high cell growth, inhibited the oxidative activity of xylitol dehydrogenase and the bioconversion ability of G. oxydans CGMCC 1.637. CONCLUSIONS: The obtained gene from G. oxydans CGMCC 1.637 was a novel gene encoding xylitol dehydrogenase. Oxidative activity of xylitol dehydrogenase in G. oxydans CGMCC 1.637 and the bioconversion ability of G. oxydans CGMCC 1.637 after grown on d-arabitol were inhibited, which provided a valuable clue for further study to increase xylitol yield from d-arabitol. PMID- 22934354 TI - [Comparison of bacterial and archaeal community of mangrove soil under different vegetation in Dongzhaigang, Hainan Island]. AB - OBJECTIVE: We compared bacterial and archaeal diversity and community structure of mangrove soil under different vegetation, and to reveal better understanding of microbial resources. METHODS: Bacterial and archaeal 16S rRNA gene libraries were constructed and analyzed for soils under Kandelia candel trees, Sonneratia apetala trees, and naked tideland, in Dongzhaigang Mangrove National Nature Reserve of Hainan Island. Template DNA was directly extracted from soil samples. PCR were amplified using primers 27F/1492R (bacterial) and Arch21F/Arch958R (archaeal). RESULTS: A total of 16 phyla dominated by Proteobacteria and Chloroflexi were detected in bacterial libraries, and 6 groups of Crenarchaeota and 7 groups of Euryarchaeota, predominated by Marine Benthic Group C and Marine Benthic Group D, respectively were found in archaeal libraries. Shannon-Wiener index (H') and S(chao1) estimator indicated that soil microbial diversity under the introduced species Sonneratia apetala was much lower than indigenous species Kandelia candel, even lower than naked tidal flat sediment near mangrove. Distinct differences in microbial community structure under different vegetation were observed. Soil microbial community structure under Kandelia candel was much similar with that of naked tideland. CONCLUSION: Mangrove soil contained rich population of bacteria and archaea; there existed distinct differences in mangrove soil microbial community structure and diversity among different vegetation. PMID- 22934355 TI - [Electricity generation from lactate using microbial fuel cell and the distribution characteristics of anode microbial community]. AB - OBJECTIVE: Two-chamber microbial fuel cells (MFCs) were set up to understand the electrogenic capacity of MFCs fed with lactic acid to investigate the distribution characteristics of microflora in the anode biofilm, supernatant, and sediment. METHODS: Using lactic acid as a carbon source in the anode, we explored the MFCs start-up process and the efficiency of electricity production, and also investigated the spatial distribution of microbial communities using scanning electron microscope (SEM) and PCR-denaturing gradient gel electrophoresis (DGGE) techniques. RESULTS: The results indicate that the MFCs reached the highest voltage, 0.56 V on the seventh day after startup. When external resistance and current density was 80 omega and 415 mA/m2, respectively, the power density reached its maximum at 82 mW/m2. SEM revealed that a massive bacillus was attached tightly to the surface of the positive electrode. DGGE profiles revealed that microorganisms on the anode's surface were most similar to that of inoculated sludge, consistent with the major microorganism groups in anode suspension and sludge substrate. Communities developed on the anodes included exoelectrogenic bacteria, i. e. Comamonas testosterone, and Arcobacter butzleri. CONCLUSION: This research demonstrates that MFCs fed with lactic acid can generate a high efficiency of current density, and that the dominant microbes on the anodes are similar to that of inoculated sludge. PMID- 22934356 TI - [Characterization the immunogenicity of recombinant VP2 of infectious bursal disease virus containing N-terminal M2e of avian influenza virus]. AB - OBJECTIVE: We developed subunit vaccines against H5 or H9 subtype avian influenza viruses (AIV) and infectious bursal disease viruses (IBDV). Viral protein 2 (VP2) of IBDV was used as cargo protein to display a 12-amino-acid (aa) immunodominant epitope derived from N-terminal M2 extracelluar domain (nM2e) of H5 or H9 subtype AIV. METHODS: The aa and nucleotide sequence of nM2e was determined by comparing the available avian influenza vaccine strains and alignment the AIV sequence available in GenBank. One copy of H5 or H9 nM2e was inserted into P(BC) region of VP2 origin from IBDV B87 vaccine strain by fusion polymerase chain reaction. The VP2(BC)nM2e recombinants were cloned into Bac-to-Bac expression system and transfected to Sf9 cell. The expressed chimeric protein was characterized by indirect immunofluorescence assay and Western blotting, and subsequently was used as antigen to develop vaccine. The non-immunized chicken was given two injections with the vaccine at a 4-week interval. Serum against VP2 and nM2e was tested by indirect ELISA and virus neutralization in chick embryo fibroblast. RESULTS: Both VP2(BC)nM2e recombinants were successfully constructed and expressed in Sf9 cell. Both chimeric proteins elicited antibody against VP2 and nM2e. The antibody level elicited by VP2(BC)nM2e(H5) vaccine was higher than that of VP2(BC)nM2e(H9). CONCLUSION: Both chimeric proteins were immunigenic, and the efficacy of VP2(BC)nM2e(H5) was higher than VP2(BC)nM2e(H9) chicken. PMID- 22934357 TI - [Fingerprinting analysis of photopigments in purple bacteria]. AB - OBJECTIVE: Photopigments, including carotenoid and bacteriochlorophyll a, are the most important functional units of photosynthesis in purple bacteria. We developed rapid qualitative and quantitative methods to determine photopigments. METHODS: Using Rhodopesudomonas palustris CQV97 as a reference, we used image gray intensity analysis, absorption spectrophotometry, thin layer chromatography (TLC), HPLC and mass spectrometry (MS) for photopigment analysis. RESULTS: The total amount of photopigments increased by 13.5% by using modified acetone methanol extraction. We developed two types of photopigment fingerprintings by TLC and HPLC, estimated the apparent relative content of each photopigment of fingerprintings, and determined the corresponding relationships between R(f) value of each photopigment on TLC fingerprinting and retention time of each photopigment elution in HPLC fingerprinting. Based on the data from the absorption spectra, MS and related photopigment biosynthetic pathway analysis, we identified 11 photopigments in CQV97 strain. Using this strain as a standard, we analyzed photopigments of the tested samples by TLC or HPLC. It was shown that (1) the relative standard deviation (RSD) of the two methods was less than 5%; (2) the compositions and contents of the theory sample were consistent with that of the standard sample; (3) the photopigment compositions of the real sample was the same as the standard sample, but the photopigment content was different. CONCLUSION: Both of TLC and HPLC analyses for photopigment determination have good stability and repeatability. The fingerprintings analyses are suitable for rapid determination of photopigments of purple bacteria and have important application in control of regulation mechanism for photopigment synthesis. PMID- 22934358 TI - [Archaeal diversity in sediment of Dunbasitawu salt lake, Xinjiang, China, estimated by 16S rRNA gene sequence analyses]. AB - OBJECTIVE: We surveyed the composition and diversity of uncultured archaea in Xinjiang Dunbasitawu salt Lake sediment. METHODS: Environmental total DNA was directly extracted from the sediment. We constructed clone library of 16S rRNA gene amplified with archaea-specific primers. A total of 59 positive clones were randomly selected from the library and identified by restriction length polymorphism (RFLP) with enzyme Hae III. Clones with the unique RFLP pattern were sequenced, and then by phylogenetic analysis. RESULTS: The clone coverage C value was 89%, and Shannon-Wiener index was 2.69. In total, 21 Operational Taxonomic Units (OTUs) were obtained and affiliated with Euryarchaeota (92%) and Crenarchaeota (8%). The most of clones were affiliated to Halobacterium (24%), Haloarcula (18%), Natronorubrum (14%), and Halorubrum (8%), which belonged to family Halobacteriaceae (88%) with high similarity to that from thalassohaline environment. In addition, 11% of clones had less than 97% similarity with archaea sequences deposited in GenBank database. CONCLUSION: Compared with other similar Hypersaline environments, archaea diversity in Dunbasitawu salt lake was a little lower. The proportion of archara was different, but the composition is consistent. It was implied that some potential new species or lineages maybe exist in Dunbasitawu salt lake. PMID- 22934359 TI - [Isolation, identification and agarose degradation of a polysaccharide-degrading marine bacterium Persicobacter sp. JZB09]. AB - OBJECTIVE: To isolate and identify a versatile carbohydrate-degrading bacterium from marine environments, and characterize the extracellular agarase activity. METHODS: The I2 staining method was applied in the isolation of agarose-degrading bacteria from coastal sediments of the Jiaozhou bay nearby Qingdao city, China. The JZB09 strain was cultured in multiple media using various complex polysaccharides as the sole carbon source to test the carbohydrate utilizing abilities. The 16S rRNA gene was cloned, sequenced and analyzed to identify the taxonomic position of the strain. Crude extracellular proteins were prepared using (NH4)2SO4 precepitation method. The dialyzed enzyme extract was applied in further studies including activity testing, activity staining, and agarose degrading for oligosaccharides purifiction. Three purified oligosaccharides were individually analyzed using thin layer chromatograph (TLC) and MALDI-TOF MS method. RESULTS: The agarolytic marine bacterium, Persicobacter sp. JZB09, could use multiple complex polysaccharides as the sole carbon source and grew well on agarose, cellulose and xylan. The extracellular enzyme extract exhibits efficient and extensive degradation activity on agarose with an activity of 77.2 U/mg proteins. The extracellular agarase system (EAS) in the crude extracellular enzymes contains at least two agarose depolymerases with molecular masses of approximately 45 kDa and 70 kDa, respectively. A series of degradation products from agarose by the EAS was purified and identified as neoagaro-oligosaccharides, among which neoagarotetraose was the major product of the crude enzymatic products, which suggests that beta-agarase is the major constituent of the JZB09 EAS. CONCLUSION: The polysaccharide-degrading bacterium Persicobacter sp. JZB09 and its polysaccharide-degrading system is promising for the exploration of polysaccharide depolymerase resources including beta-agarases. PMID- 22934360 TI - [Effects of algicidal bacterium BS03 (Microbulbifer sp.) on the growth and antioxidant systems of Alexandrium tamarense]. AB - OBJECTIVE: We studied the algicidal mechanism of extracellular substances of algicidal bacteria strain BS03 (Microbulbifer sp.) on photosynthetic characteristics, antioxident enzyme system and cysteine-dependent aspartate specific protease-3 (Caspase-3) of Alexandrium tamarense. METHODS: We tested photosynthetic pigments, chlorophyll fluorescence efficiency, antioxidant systems and caspase-3 activity in the algae cells treated with 0.5%, 1.0% , 1.5% and 2.0% BS03 cell-free filtrate after 12, 24, 36 and 48 h. RESULTS: (1) The chlorophyll-a and chlorophyll fluorescence efficiency Fv/Fm decreased with the increase of BS03 cell-free filtrate and treatment time. Carotenoids contents of A. tamarense cells treated with low BS03 (0.5% and 1.0%) cell-free filtrate were higher than the control. (2) Antioxident enzyme activities varied as treatment time and concentration. Malodialdehyde (MDA) contents increased significantly with BS03 cell-free filtrate treatment. (3) Caspase-3 protease activities of algal cells increased by BS03 cell-free filtrate. CONCLUSION: BS03 inhibited the photosynthesis whereas enhanced the lipid peroxidation of the cellular membrane of Alexandrium tamarense, indicating its algicidal activity. PMID- 22934361 TI - Characterized of class I integron in Acinetobacter baumannii isolated from upper respiratory tract. AB - OBJECTIVE: To characterize the class I integron in Acinetobacter baumannii and to analyze the correlation between integron and drug resistance. METHODS: In total 187 strains were collected between 2008 and 2009. All strains were tested by Kirb Bauer disk diffusion test for drug resistance. PCR and DNA sequencing were used to detected class I integrase gene and to clarify the context of gene cassette. RESULTS: Class I integrase gene was detected in 100 (53.4%) of the isolates analyzed. Seven different gene cassettes were identified, including a new integron (GenBank: HQ322622) carrying an unknown protein probably associated with recombination. The vast majority of the cassettes encoded amonoglycoside resistance gene, including aacA4, aadA1, aacC1, aac6 II , aadA2. Susceptibility data show that strains carrying class I integron were significantly more resistant to all of the antibiotics tested than isolates lacking class I integron. The correlation between the presence of integron and the multidrug resistance of A. baumannii was statistically significant. CONCLUSION: Drug resistance genes integrated by Class I integron were widespread in A. baumannii. Class I integron plays an important role in resistance of A. baumannii. PMID- 22934362 TI - In response to: "Postdeployment mental health screening: an application of the soldier adaptation model," published in the April issue (Mil Med 2011; 177(4): 366-73). PMID- 22934363 TI - In response to: "The ANAM lacks utility as a diagnostic or screening tool for concussion more than 10 days following injury," published in the February issue (mil med 2011; 177(2): 179-83). PMID- 22934364 TI - Mentorship and job satisfaction among Navy family physicians. AB - OBJECTIVE: Among civilian academic physicians, having a mentor is associated with greater job satisfaction. Whether this is true for military physicians is unknown. We sought to examine whether having a mentor is associated with positive job satisfaction among Navy family physicians. METHODS: A web-based survey was sent to all Navy family physicians in the Specialty leader's database in May 2008. Our main outcome variable was "positive job satisfaction," and our main exposure variable was being in a mentor relationship. Chi-square was used to test for difference in frequencies in categorical variables and logistic regression was used to adjust for covariates. RESULTS: The response rate was 60.2% (186/309). Among respondents, 73.7% reported positive job satisfaction. Factors associated with positive job satisfaction included having a mentor, being >9 years postresidency, spending <50% of time in patient care, higher rank, male gender, and being active in research. After adjustment for these factors, having a mentor remained significantly associated with positive job satisfaction (odds ratio 2.86, 95% confidence interval 1.22-6.71). CONCLUSION: Having a mentor is associated with positive job satisfaction among Navy family physicians, even after adjusting for multiple other factors. An implication is that a mentorship program may be a strategy for improving job satisfaction. PMID- 22934365 TI - Deployment experiences of Army nurse practitioners. AB - Army Nurse Practitioners (NPs) provide immediate and lifesaving care during combat operations. The most recent conflicts of Operation Iraqi Freedom and Operation Enduring Freedom have seen an increasing number of NP deployments. The uniqueness of these conflicts has also seen NPs being used in nontraditional roles. This study surveyed 50 Army NPs with deployment experience to explore and elucidate their clinical practices in a combat environment. Over 70% reported seeing greater than 11 patients a day with the top three diagnoses of musculoskeletal/soft tissue (noncombat), spinal pain (mechanical, sciatica), and gastrointestinal complaints. Over 74% reported having a physician available for collaboration, but 50% reported providing independent emergency care and 58% treating life-threatening injuries. The NPs in this study report standard credentialing privileges with most care falling within this realm. However, a few report nontraditional roles such as hospital admitting privileges. This study adds to the growing body of knowledge on NP practice in a combat environment, which shows increased decision making and advanced clinical skills. NPs are battlefield multipliers who bring additional skills and abilities to the combat environment. PMID- 22934366 TI - Perceptions of deployment of Australian Army reservists by their employers. AB - The views and concerns of the employers of reservists sent on overseas deployments are largely unknown. A survey was conducted of 126 Australian employers who participated in Exercise Boss Lift sponsored by the Australian Defence Force, which involved a visit to their employees deployed on overseas service in the Solomon Islands and Malaysia during the period 2006-2010. Employers reported a substantial number of positive aspects of reservist deployment for both their enterprise and the individual reservist employee, including an increase in leadership, teamwork, skills, maturity, and confidence. There were 40% fewer reported negatives, which primarily concerned the costs associated with the absence of an important employee. The employers expressed needs for greater information regarding dates of absence of their reservist employee and assistance from the ADF to enable them to enhance the overall deployment. Importantly, employers sought confirmation of ways to effectively manage the transition of their reservist from military service back to their civilian roles. Some employers offered to act as advocates. PMID- 22934367 TI - Training modalities and self-confidence building in performance of life-saving procedures. AB - OBJECTIVE: Physicians and paramedics in the Israel Defense Forces are trained to perform advanced medical procedures using standardized training modalities, such as manikins. We studied the association of experience using these training modalities with self-reported confidence in procedure performance. METHODS: Providers were sent a questionnaire regarding their experience with and self confidence levels for performing endotracheal intubation, cricothyroidotomy, needle chest decompression, tube thoracostomy, and intraosseous infusion. RESULTS: Provider level (physician or paramedic) and gender were associated with reported self-confidence levels. Manikin and supervised and unsupervised patient experience exhibited positive associations with self-confidence, but (animal) model experience did not. For many procedure-training modality pairs, we identified a plateau level above which additional experience was minimally associated with an increase in self-confidence. CONCLUSIONS: Among military advanced life support providers, self-confidence levels in procedure performance are positively associated with experience gained from manikins and supervised and unsupervised patient application. We were not able to demonstrate a clear benefit of an animal model in increasing self-confidence. A plateau was generally identified, indicating decreased benefit from the use of a particular training modality for a particular procedure. Modifying training regimens in light of these findings may help maximize the self-confidence of advanced life support providers more efficiently. PMID- 22934368 TI - Use of animals by NATO countries in military medical training exercises: an international survey. AB - Among the 28 member nations of the North Atlantic Treaty Organization (NATO), a variety of training methodologies--including simulators, moulage scenarios, didactics and live animal laboratories-are used to prepare military medical personnel to treat injured civilians and soldiers. For ethical, educational, practical, and economic reasons, the necessity of animal use for this purpose has come into question. This article reports the results of a survey examining the prevalence of animal use in military medical training exercises among all NATO nations, finding that more than three-quarters of these countries do not use animals. PMID- 22934369 TI - Simulated aeromedical evacuation does not affect systemic inflammation or organ injury in a murine model of hemorrhagic shock. AB - Hemorrhagic shock is a primary injury amongst combat casualties. Aeromedical evacuation (AE) of casualties exposes patients to a hypobaric, hypoxic environment. The effect of this environment on the host response to hemorrhagic shock is unknown. In the present study, we sought to determine the effect of simulated AE on systemic inflammation and organ injury using a murine model of hemorrhagic shock. Mice underwent femoral artery cannulation and were hemorrhaged for 60 minutes. Mice were then resuscitated with a 1:1 ratio of plasma:packed red blood cells. At 1 or 24 hours after resuscitation, mice were exposed to a 5-hour simulated AE or remained at ground level (control). Serum was analyzed for cytokine concentrations and organs were assessed for neutrophil accumulation and vascular permeability. Mice in the simulated AE groups demonstrated reduced arterial oxygen saturation compared to ground controls. Serum cytokine concentrations, neutrophil recruitment, and vascular permeability in the lung, ileum, and colon in the simulated AE groups were not different from the ground controls. Our results demonstrate that mice exposed to simulated AE following hemorrhagic shock do not exhibit worsened systemic inflammation or organ injury compared to controls. The data suggest that AE has no adverse effect on isolated hemorrhagic shock. PMID- 22934370 TI - High altitude headache and acute mountain sickness at moderate elevations in a military population during battalion-level training exercises. AB - Few studies have evaluated high altitude headache (HAH) and acute mountain sickness (AMS) in military populations training at moderate (1,500-2,500 m) to high altitudes (>2,500 m). In the current study, researchers interviewed active duty personnel training at Marine Corps Mountain Warfare Training Center. Participants were asked about HAH and AMS symptoms, potential risk factors, and medications used. In a sample of 192 U.S. Navy and Marine Corps personnel, 14.6% reported AMS (Lake Louise Criteria > or = 3) and 28.6% reported HAH. Dehydration and recent arrival at altitude (defined as data collected on days 2-3) were significantly associated with AMS; decreased sleep allowance was significantly associated with HAH. Although ibuprofen/Motrin users were more likely to screen positive for AMS, among AMS-positive participants, ibuprofen/Motrin users had decreased likelihood of reporting robust AMS relative to non-ibuprofen/Motrin users (p < 0.01). These results suggest that maintenance of hydration and adequate sleep allowance may be critical performance requirements at altitude. Further, ibuprofen/Motrin may be a reasonable treatment for the symptoms of AMS and HAH, although further study is warranted. PMID- 22934371 TI - Varicella outbreak among Afghan National Civil Order Police recruits-Herat Regional Military Training Center, Herat, Afghanistan, 2010. AB - In December 2010, an outbreak of varicella was reported among student recruits enrolled at the Afghan National Civil Order Police Herat Regional Military Training Center. The outbreak had an overall attack rate of 9.8% (31 of 316 recruits) with primary, secondary, and tertiary attack rates of 6.3% (20 of 316), 3.4% (10 of 296), and 0.35% (1 of 286). Fortunately, the outbreak did not lead to any deaths or serious complications. However, it significantly interfered with Afghan National Civil Order Police training by causing a loss of 378 person-days of training. Medical personnel from the Afghan National Police, DynCorp International, Government of the Islamic Republic of Afghanistan Ministry of Public Health, and NATO Training Mission-Afghanistan Herat Joint Medical Operation Cell joined together to control and characterize the outbreak and prepare and disseminate recommendations for preventing future outbreaks. Control measures were quickly implemented, but less than ideal. Varicella vaccine was not available in Afghanistan to immunize exposed recruits. The outbreak was reported to medical authorities through a slow and convoluted process. And the majority of varicella cases did not self-report for care. Rather, medical personnel diagnosed most cases only after recruits were directed to report for a physical examination. PMID- 22934372 TI - Self-induced bleeding diathesis in soldiers at a FOB in south eastern Afghanistan. AB - Modern warfare necessitates that the physician recognize risk factors and clinical scenarios that contribute to the development of acute coagulopathy of trauma and the need for massive transfusion. To date, this is the only prospective study done in an active war zone that specifically looks at a self induced bleeding diathesis problem among soldiers. If correct, then large numbers of soldiers are exposed to bleeding abnormalities well before sustaining injury. PMID- 22934373 TI - An investigation of bloodborne pathogen transmission due to multipatient sharing of insulin pens. AB - On January 30, 2009, nursing staff at a military hospital in Texas reported that single-patient use insulin pens were used on multiple patients. An investigation was initiated to determine if patient-to-patient bloodbome transmission occurred from the practice. Human immunodeficiency virus (HIV), hepatitis B virus (HBV), and hepatitis C virus (HCV) testing was offered to patients hospitalized from August 2007 to January 2009 and prescribed insulin pen injections. Virus from HCV infected patients' sera was sequenced and compared for relatedness. An anonymous survey was administered to nurses. Of 2,113 patients prescribed insulin pen injections, 1,501 (71%) underwent testing; 6 (0.4%) were HIV positive, 6 (0.4%) were hepatitis B surface antigen positive, and 56 (3.7%) had HCV antibody. No viral sequences from 10 of 28 patients with newly diagnosed and 12 of 28 patients with preexisting HCV infection were closely related. Of 54 nurses surveyed, 74% reported being trained on insulin pen use, but 24% believed nurses used insulin pens on more than one patient. We found no clear evidence of bloodborne pathogen transmission. Training of hospital staff on correct use of insulin pens should be prioritized and their practices evaluated. Insulin pens should be more clearly labeled for single-patient use. PMID- 22934374 TI - Pacific partnership 2010: Anesthesia support aboard the USNS Mercy humanitarian civic assistance. AB - INTRODUCTION: The USNS Mercy has been integral in providing humanitarian and civic assistance as part of the Department of Defense's ongoing Combatant Commander Theater Security Cooperation Plans. The purpose of this study was to critically assess patient demographics and procedures performed to provide guidance for future missions. METHODS: A retrospective review was performed on a cohort of 825 surgical patients who underwent surgery during a 4-month period during Pacific Partnership 2010. Patient demographics, anesthesia exam findings, comorbidities, and surgical data were compared among the mission sites. RESULTS: Of the 825 patients, the mean age ranged from 39.7 to 24.7 with a statistical difference between Vietnam (39.7, p < 0.0087 for all tests) and the remaining sites. Poorer health by American Society of Anesthesiologist grading was noted in Vietnam (1.61) as compared to patients in Cambodia (1.21, p < 0.001) and Timor Leste (1.40, p = 0.001). No difference in complication rates was noted. DISCUSSION: The reason for apparent differences in age or health status by site weren't clearly explained, but these differences had no bearing on surgical outcome. CONCLUSION: Analysis of anesthesia data compiled during Pacific Partnership 2010 provided meaningful data for future humanitarian efforts at these sites. PMID- 22934375 TI - Early pregnancy confirmation--the role of urine pregnancy test in military primary care clinics. AB - Pregnancy detection is a common procedure in primary care and can be challenging in the setting of military primary care clinics. The objective of this study was to determine whether the introduction of urine pregnancy tests to military primary care clinics is associated with earlier pregnancy detection. We conducted a cross-sectional study using data from female soldiers, aged 18 to 20 years. Pregnancy was diagnosed using urine pregnancy tests. Ultrasonographic gestational age at presentation was compared between pregnant soldiers diagnosed in primary care clinics and pregnant soldiers diagnosed in gynecology secondary care clinics. A total of 150 female soldiers performed urine pregnancy tests in 5 different primary care clinics, from which 28 (19%) were pregnant. Mean gestational age at diagnosis was significantly lower among patients diagnosed in primary care clinics as compared with patients diagnosed in gynecology secondary care clinics (41.07 days (SD, 6.72) vs. 48.42 days (SD, 21.94), p < 0.001). In conclusion, the availability of urine pregnancy tests in the setting of military primary care clinics was strongly associated with early pregnancy detection at a time point in which presentation for both antenatal care and abortion services potentially improve maternal and neonatal health. PMID- 22934376 TI - Retrospective review of serum creatinine and creatinine-based measures of estimated glomerular filtration rate in an amputee population. AB - A variety of equations are used to estimate glomerular filtration rate (eGFR). These formulas have never been validated in the setting of traumatic amputation. In this retrospective study involving 255 military personnel with traumatic amputations at a single outpatient center, muscle mass lost was estimated using percentage of estimated body weight lost (% EBWL). Serum creatinine (Scr) and eGFR by the Modification of Diet in Renal Disease (MDRD) and Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equations were compared to % EBWL for each patient. The average Scr for the group studied was also compared with a cohort matched for age, sex, and race from the Third National Health and Nutrition Examination Survey (NHANES III). Percentage EBWL correlated significantly with Scr (R2 = 0.095, p < 0.0001), eGFR by MDRD (R2 = 0.077, p < 0.0001), and eGFR by CKD-EPI (R2 = 0.074, p < 0.0001). The average Scr was significantly lower than a similar population from NHANES III (0.83 +/- 0.137 mg/dL vs. 1.14 +/- 0.127 mg/dL, p < 0.0001). Percentage EBWL has a significant correlation with Scr and eGFR by both the MDRD and CKD-EPI equations. Furthermore, patients with traumatic amputation have significantly lower Scr values than the general population. Creatinine-based estimators of GFR may overestimate renal function in the setting of traumatic amputation. PMID- 22934377 TI - Prevalence of post-traumatic stress disorder and physical health complaints among Portuguese Army Special Operations Forces deployed in Afghanistan. AB - BACKGROUND: Investigations conducted with several U.S. and U.K. military veterans returning from Afghanistan and Iraq have reported the existence of mental and physical health complaints. METHODS: A total of 113 participants completed a self report questionnaire that assessed post-traumatic stress disorder (PTSD) symptoms, physical health complaints, and reported illnesses. RESULTS: Overall, 2.7% of the participants reported symptoms compatible with a PTSD diagnosis and 8.8% have partial PTSD. The most common physical health complaints were back pain, fatigue, and muscle pain. In addition, participants experienced gastrointestinal, nervous, and respiratory diseases. PTSD symptoms further explain the variance in physical health complaints after controlling for the contribution of reported illnesses to the same variables. CONCLUSIONS: The prevalence of PTSD in the study sample is low, but PTSD symptoms are significantly related to physical health complaints and reported illnesses and explain the variance in physical symptoms. This fact should be considered by clinical support services, and military personnel with physical complaints should be screened for PTSD. These Portuguese results obtained from participants belonging to a well-prepared Special Operations Forces group contribute to a better understanding of the physical and mental impact of the war in Afghanistan. PMID- 22934378 TI - Injuries to deployed U.S. Army soldiers involved in HMMWV crashes, 2002-2006. AB - Highly mobile multipurpose wheeled vehicle (HMMWV or Humvee) crashes present an important issue for the U.S. military. The aim of this study was to provide a descriptive analysis of occupants of military motor vehicle (MMV) crashes involving HMMWVs that occurred among deployed U.S. Army Soldiers. Crash-related data were collected from the U.S. Army Combat Readiness/Safety Center on MMV crashes among active duty Army personnel between 1999 and 2006. Records for 964 occupants with injuries from HMMWV crashes were analyzed, which represented 52% of the total occupants of MMV crashes. A significant association was observed between injury and engagement in combat, odds ratio 1.49 (1.03, 2.16). The risk of injury was greatest for gunners, odds ratio 2.37 (1.43, 3.92), and injury cost related to the crash was significantly related to prior deployment status (p < 0.001) and role of Soldier in the vehicle (Operator p = 0.005, Gunner p = 0.003). There was also a decrease over time in the number of crashes resulting in injury (p < 0.001). These data support the development of interventions that address the specific risks detailed, including the use of combat simulation training, increased protection for vulnerable positions, and enforcement of safety regulations. PMID- 22934379 TI - Clavicle fractures in the United States military: incidence and characteristics. AB - BACKGROUND: Although it is generally known that clavicle fractures represent a common injury of the shoulder girdle in the general population, the true incidence in the active duty military population is unknown. Given the implications for such injuries on the ability to perform occupation-specific tasks, determining the incidence in the U.S. military population is worthwhile. The purpose of this study was to determine the incidence of clavicle fractures in the U.S. military and to identify any demographic risk factors for injury. METHODS: We performed a query of the Defense Medical Epidemiology Database with the code from the International Classification of Diseases, Ninth Revision, for clavicle fractures for the years 1999 through 2008. An overall injury incidence was calculated, in addition to multivariate analysis, to determine independent risk factors among the following demographic considerations: sex, race, branch of military service, rank, and age. RESULTS: During the study period, a total of 12,514 clavicle fractures were documented among an at-risk population of 13,770,767 person-years for an incidence rate (IR) of 0.91 per 1,000 person-years in the U.S. Military. Males, when compared with females, were more than twice as likely to sustain a clavicle fracture (IR ratios [IRR], 2.30; 95% confidence intervals [CI], 2.12-2.49). The peak incidence of clavicle fractures occurred in the age groups of <20 and 20 to 24. Compared to black service members, the white service members were associated with significantly higher rate of clavicle fractures (IRR, 2.45; 95% CI, 2.28-2.63). The service members serving in the Marine Corps were associated with a higher IR of clavicle fractures when compared to those in the Navy (IRR, 1.44; 95% CI, 1.35-1.53). Junior enlisted service members were 34% as likely to sustain a clavicle fracture when compared to senior officers (IRR, 1.46; 95% CI, 1.34-1.60 and IRR, 1.12; 95% CI, 0.99-1.28, respectively). CONCLUSIONS: The incidence of clavicle fractures among U.S. military personnel (0.908 per 1,000 person-years) is higher than previous epidemiological reports. PMID- 22934380 TI - An analysis of shoulder outcomes scores in 275 consecutive patients: disease specific correlation across multiple shoulder conditions. AB - OBJECTIVES: To determine the outcomes scores of military patients who initially present with a variety of shoulder conditions, identify which scores demonstrate the highest correlation per diagnosis, and determine if a difference exists for patients who went onto surgery. METHODS: Two-hundred and seventy five consecutive patients with mean age of 36.5 +/- 12.9 at presentation completed baseline outcomes assessments that included Single Assessment Numeric Evaluation (SANE), American Shoulder and Elbow Surgeons (ASES) Score, Western Ontario Shoulder Instability Index (WOSI), Western Ontario Rotator Cuff Index (WORC), the Simple Shoulder Test (SST), and the Disabilities of the Arm, Shoulder, and Hand Index (DASH). The patients were grouped by clinical, radiographic, and surgical findings into 10 diagnostic categories. OUTCOMES: The initial mean outcomes scores were SANE 48.8, ASES 50.1, WOSI 1279 (40% normal), WORC 1122.4 (47% normal), SST 6.7, and DASH 33.1. Patients with superior labrum anterior-posterior tears demonstrated the lowest mean scores, followed by instability and rotator cuff tear patients. For all conditions, scores were lower for patients who went onto surgery compared with those managed nonoperatively (p = 0.008). CONCLUSIONS: Our findings may be utilized as a baseline to compare and track patient-derived disability across multiple shoulder conditions and serve to define mean diagnosis specific shoulder patient preoperative scores. PMID- 22934381 TI - Is point-of-care ultrasound accurate and useful in the hands of military medical technicians? A review of the literature. AB - Over the past decade, point-of-care ultrasound (US) use by nonphysician providers has grown substantially. The purpose of this article is to (1) summarize the literature evaluating military medics' facility at US, (2) more clearly define the potential utility of military prehospital US technology, and (3) lay a pathway for future research of military prehospital US. The authors performed a keyword search using multiple search engines. Each author independently reviewed the search results and evaluated the literature for inclusion. Of 30 studies identified, five studies met inclusion criteria. The applications included evaluation of cardiac activity, pneumothorax evaluation, and fracture evaluation. Additionally, a descriptive study demonstrated distribution of US exam types during practical use by Army Special Forces Medical Sergeants. No studies evaluated retention of skills over prolonged periods. Multiple studies demonstrate the feasibility of training military medics in US. Even under austere conditions, the majority of studies conclude that medic can perform US with a high degree of accuracy. Lessons learned from these studies tend to support continued use of US in out-of-hospital settings and exploration of the optimal curriculum to introduce this skill. PMID- 22934382 TI - Sonographic localization and management of metallic fragments: a report of five cases. AB - Ultrasound was used as adjunct to radiographic imaging in the assessment and management of metallic fragments in five cases encountered in forward-deployed military facilities. Although metallic fragments are usually seen well on radiographs, ultrasound can add details of the surrounding soft-tissue structures and clarify location. Portable handheld units are well suited for studies when probe selection and equipment adjustments are correct. In selected cases, ultrasound information can favorably influence case management. PMID- 22934384 TI - Vaginal hemorrhage from transobturator sling controlled with QuikClot combat gauze. AB - A 42-year-old woman underwent an outside-in transobturator sling procedure, with subsequent venous hemorrhage. Two rolls of Combat Gauze were placed intravaginally and taken out on postoperative day 2 with good hemostasis. Despite careful technique, hemorrhage is a known complication of midurethral slings. Advanced hemostatic dressings may provide hemorrhage control and avoid the need for surgical intervention. After an extensive literature review, we present the first case of QuikClot Combat Gauze used as a hemostatic agent due to vaginal hemorrhage. PMID- 22934383 TI - Bilateral compartment syndrome of the anterior thigh following functional fitness exercises: a case report. AB - We present a case of delayed, acute bilateral exertional compartment syndrome of the anterior thigh induced by callisthenic exercise. Symptoms consisted of pain out of proportion to examination findings, inability to ambulate, and severe pain with knee flexion. Treatment consisted of bilateral thigh fasciotomies and supportive therapy for concomitant rhabdomyolysis. Full strength, range of motion, and return to all military duties were achieved by 4 months postinjury. PMID- 22934385 TI - [Effects of encircled needling plus electroacupuncture on hyperplastic mammary glands and serum sex hormones in the rat]. AB - OBJECTIVE: To observe the effect of encircled needling plus electroacupuncture (EA) of the second pair of nipples on hyperplastic mammary glands, serum estradiol (E2), progesterone (P), prolactin (PRL) and testosterone (T) contents, estrogen receptor (ER) expression of the mammary glands in mammary hyperplasia rats. METHODS: Forty Wistar rats were equally randomized into normal control, model, acupuncture and medication groups. Mammary gland hyperplasia model was established by intramuscular injection of diethylstilbestrol (0.5 mg/kg, once daily for 25 days) and progesterone (4 mg/kg, once daily for 5 days). For rats of the acupuncture group, 4 filiform needles were inserted into the surrounding tissues of the second pair of breasts, respectively, followed by giving the animal with EA stimulation for 30 min. Another one acupuncture needle was inserted into "Danzhong" (CV 17) and retained for 30 min. For rats of the medication group, tamoxifen solution (1.8 mg/kg) was given by gavage. Both medication and EA intervention were given once daily for 30 days. The diameter and height of the second pair of nipples were measured before and on the 10th, 20th and 30th days of the treatment. Serum E2, P, PRL and T levels were assayed by radioimmunoassay, and the tissues of the second pair of nipples were stained with H. E. method. Estrogen receptor immunoactivity of the breast tissue was detected by immunohistochemistry. RESULTS: The diameter and height of the second pair of nipples, serum E2, PRL and T contents, and breast ER protein expression level were significantly higher in the model group than in the normal control group (P<0.05), while serum P content was remarkably lower in the model group than in the normal control group (P<0.05). In comparison with the model group, the diameter and height of the second pair of nipples, serum E2, PRL and T contents, and breast ER protein expression level were considerably lower in both acupuncture and medication groups (P<0.05), and serum P contents were significantly higher in the latter two groups (P<0.05). In addition, H.E. staining showed that the numbers of the lobule, alveolus and ducts of mammary glands were significantly increased, and the expansion of the acinar lumina and ducts was found in the model group. These pathological changes were relatively milder in both acupuncture and medication groups. CONCLUSION: Encircled needling plus EA stimulation of the surrounding tissues of the nipples can improve the hyperplasic nipples and pathological changes of the breast tissue in mammary gland hyperplasia rats, which is closely associated with its functions in lowering serum estradiol, prolactin, testosterone contents and estrogen receptor protein expression of the breast, and in increasing serum progesterone level. PMID- 22934386 TI - [Effects of electroacupuncture on endothelial progenitor cells in peripheral blood and bone marrow in local cerebral ischemia/reperfusion rats]. AB - OBJECTIVE: To observe the influence of electroacupuncture (EA) of "Hegu" (LI 4) on blood stromal cell-derived factor 1alpha (SDF-1alpha), CXC chemokine receptor 4+ (CXCR 4+) positive cells and endothelial progenitor cells (EPCs) and bone marrow (BM) EPCs levels in local cerebral ischemia/reperfusion injury (CI/IR) rats, so as to study its mechanisms underlying improvement of cerebral ischemia. METHODS: A total of 54 SD rats were randomly divided into normal control, model, and EA groups. The latter two groups were further divided into 1 d, 2 d, 3 d and 7 d subgroups (4 time-points), respectively. CI/RI model was established by occlusion of the middle cerebral artery. EA (40 Hz/60 Hz, 1-2 mA) was applied to bilateral "Hegu" (LI 4) for 15 min, once daily, 1, 2, 3 and 7 days, respectively. Flow cytometer was used to detect the counts of EPCs and CXCR 4+ cells in the peripheral blood, and BM EPCs. Serum SDF-1alpha was detected by enzyme linked immunosorbent assay (ELISA). RESULTS: Compared with the normal control group, the percentages of blood EPCs and CXCR 4+ cells and BM EPCs, and serum SDF-1alpha content on the 1st day, and the percentage of blood CXCR 4+ cells on the 2nd day were increased significantly in the model group (P<0.01, P<0.05). In comparison with the model group, percentages of blood EPCs and CXCR 4+ cells on the 1st day of EA group were reduced significantly (P<0.01), but the percentage of blood EPCs on the 2nd day, those of blood CXCR 4+ cells on the 2nd day and 3rd day, serum SDF-1alpha content on the 2nd day, and the percentage of BM EPCs on the 2nd day in the EA group were all up-regulated significantly (P<0.05, P<0.01). No significant differences were found among the 3 groups in blood EPCs percentages on the 3rd day and 7th day, in blood SDF-1alpha content and BM EPCs percentage on the 7th day (P>0.05). CONCLUSION: Generally, 2 days' EA of LI 4 can up-regulate the percentages of blood and BM EPCs and blood CXCR 4+ cells as well as blood SDF 1alpha protein content in CI/RI rats, which may contribute to its effect in improving cerebral ischemia. PMID- 22934387 TI - [Effects of acupuncture on behavior and striatal apoptosis in mice with Parkinson disease]. AB - OBJECTIVE: To observe the effect of acupuncture of "Baihui" (GV 20), "Fengfu" (GV 16) and "Yanglingquan" (GB 34) on behavior and striatal apoptosis in Parkinson disease (PD) mice. METHODS: Twenty-eight adult male C57/ BL mice were randomly divided into normal control, PD model, acupuncture and medication (Levodopa and Benserazide Hydrochloride) groups. Acupuncture was applied to "Baihui"(GV 20), "Fengfu" (GV 16) and electroacupuncture (2 Hz, 1 mA) was applied to "Yanglingquan"(GB 34) for 15 min, once a day for 14 days. PD model was duplicated by intragastric administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). The locomotor test, pole test and swimming test were conducted for assessing the animals' locomotion behavior before and after MPTP administration and after the treatment. The apoptotic neurons of the striatum were detected by terminal deoxyncleotidyl transferase-mediated dUTP-biotin nick end labeling assay. RESULTS: In comparison with the normal control group, the pole test score and apoptotic neuronal percentage were increased significantly (P<0.01), and the locomotor count, swimming test score were decreased remarkably in the model group (P<0.01). Compared with the model group, the locomotor counts and swimming test scores were increased obviously (P<0.05, P<0.01) and the pole test scores decreased apparently (P<0.05) in both acupuncture and medication groups after the treatment. No significant differences were found between the acupuncture and medication groups in the motor behavior (P>0.05). The effect of acupuncture was significantly superior to that of the medication in reducing neuronal apoptosis of the striatum (P<0.01). CONCLUSION: Acupuncture of "Baihui" (GV 20), "Fengfu" (GV 16) and "Yanglingquan"(GB 34) can improve PD mice's locomotor function, which is closely associated with its function in reducing neuronal apoptosis of the striatum. PMID- 22934388 TI - [Effects of electroacupuncture at "Futu"(LI 18), etc. on pain threshold and cervico-spinal mGlu receptor 5/cAmp/CREB signaling in rats with neck incision pain]. AB - OBJECTIVE: To observe the effect of electroacupuncture (EA) at "Futu" (LI 18),etc. on the pain threshold and expression of metabotropic glutamate receptor subtype 5 (mGluR 5), cyclic adenosine monophosphate (cAMP), mitogen-activated protein kinase (MAPK), cAMP responsive element binding protein (CREB) genes in the cervico-spinal dorsal region in rats with neck incision pain so as to analyze its underlying analgesic mechanism in performing thyroid surgery. METHODS: Forty male Wistar rats were randomly divided into control, model, Futu (LI 18), Hegu (LI 4)-Neiguan (PC 6), Zusanli (ST 36)-Yanglingquan (GB 34) groups, with 8 cases in each group. Neck-incision pain model was established by making a longitudinal incision along the midline of the neck under anesthesia (isoflurane) except rats in the control group. EA(2 Hz/15 Hz, 1-2 mA) was applied to bilateral LI 18, LI 4 PC 6 and ST 36-GB 34 for 30 min, 4 h, 24 h and 48 h after modeling, respectively. The thermal pain threshold was detected before modeling, and before and after each treatment. After removing the ventral part, the spinal tissue of the cervical 1 -4 segments was collected for detecting the expression of mGluR 5, cAMP, MAPK, CREB genes by using quantitative real-time-PCR technique. RESULTS: In comparison with the control group, the pain threshold of the model group was decreased obviously (P<0.05). Compared with the model group, the pain thresholds of the LI 18 and LI 4-PC 6 groups were upregulated markedly after treatment (P<0.05). No significant differences were found between the LI 18 and LI 4-PC 6 groups, and between the model and ST 36-GB 34 groups in pain thresholds (P>0.05). Compared with the control group, the expression le-vels of mGluR 5 mRNA, cAMP mRNA and CREB mRNA in the cervico-spinal cord were upregulated significantly in the model group (P<0.05). While in comparison with the model group, cervico spinal cAMP mRNA, and CREB mRNA were down-regulated markedly (P<0.05) and mGluR 5 mRNA was down-regulated moderately (P>0.05) in the LI 18 group, rather than in the LI 4-PC 6 and ST 36-GB 34 groups (P>0.05). CONCLUSION: EA-LI 18 can significantly suppress neck incision pain induced pain reaction, which may be closely associated with its functions in down-regulating expression levels of intracellular cAMP mRNA and CREB mRNA in the cervico-spinal cord. PMID- 22934389 TI - [Effects of electroacupuncture of acupoints of pericardium meridian on serum VEGF content and cerebral VEGF expression in cerebral ischemia rats]. AB - OBJECTIVE: To observe the effect of Electroacupuncture (EA) of "Quze" (PC 3) and "Neiguan" (PC 6) on cerebral angiogenesis in cerebral ischemia (CI) rats, so as to research its mechanisms underlying improvement of stroke. METHODS: Fifty SD rats were randomized into normal control, sham, model, EA-PC 3-PC 6, and EA-Hegu (LI 4)-Quchi (LI 11) groups. CI model was established by occlusion of the middle cerebral artery. EA (2-4 V, 20 Hz) was applied to PC3, PC6, LI 4 and LI 11 respectively 6 h, 24 h, 48 h and 72 h after modeling, 30 min for each time. Serum vascular endothelial growth factor (VEGF) content was assayed by enzyme linked immunosorbent assay (ELISA), and cerebral VEGF immunoactivity was detected by immunohistochemistry. RESULTS: Compared to the normal control group, serum VEGF content, cerebral VEGF expression level, and the number of VEGF-positive microvessels in the ischemic cerebral region in the model, EA-PC 3-PC 6 and EA-LI 4-LI 11 groups were increased significantly (P<0.01). In comparison with the model group, serum VEGF content, cerebral VEGF expression level, and the number of VEGF-positive microvessels in the EA-LI 4-LI 11 and EA-PC 3-PC 6 groups were up-regulated further (P<0.01), and the effects of the EA-PC 3-PC 6 group were obviously superior to those of the EA-LI4-LI 11 group in up-regulating VEGF expression and the number of VEGF-positive microvessels (P<0.01). No significant difference was found between the EA-LI 4-LI 11 and EA-PC 3-PC 6 groups in serum VEGF levels (P>0.05). CONCLUSION: EA of acupoints of both Large Intestine Meridian and Pericardium Meridian can up-regulate serum VEGF, cerebral VEGF expression and the number of VEGF-positive microvessels in CI rats, suggesting an increase of cerebral angiogenesis after the treatment. The effect of EA-PC 3-PC 6 is markedly superior to that of EA-LI 4-LI 11. PMID- 22934390 TI - [Effects of different quantity of moxibustion at "Dazhui" (GV 14) on cellular immunity in asthma rats]. AB - OBJECTIVE: To observe the effects of different quantity of moxibustion of "Dazhui" (GV 14)on the levels of serum interleukin-4 (IL-4), interferon-gamma (IFN-gamma), and immunoglobulin E (IgE) in asthma rats, so as to reveal its mechanisms underlying immune regulation. METHODS: Sixty male SD rats were randomly divided into control, model, moxibustion-15 min (M-15 min), M-30 min, M 60 min, and M-120 min groups (10 rats/group). Asthma model was established by intraperitoneal injection of sensitized-suspension (containing egg albumin, aluminium hydroxide, and deactivated Bacillus pertussis) and ovalbumin-aerosol inhalation. Moxibustion was applied to "Dazhui" (GV 14) for 15, 30, 60 and 120 min, respectively. Serum IL-4, IFN-gamma and IgE contents were assayed by ELISA (enzyme-linked immunosorbent assay). RESULTS: Compared with the control group, serum IL-4, IFN-gamma and IgE levels were increased significantly (P<0.01), and serum IFN-gamma/IL-4 level was down-regulated obviously (P<0.01)in the model group. After the moxibustion treatment, the levels of serum IL-4 and IgE in the M 15 min, M-30 min, M-60 min, and M-120 min groups were reduced significantly compared with the model group (P<0.01, P<0.05). The ratios of IFN-gamma/IL-4 in the M-15 min, M-30 min, M-60 min, and M-120 min groups were significantly higher than that in the model group (P<0.05, P<0.01). Comparison among the M-15 min, M 30 min, M-60 min, and M-120 min groups showed that the therapeutic effects of the M-30 min group were evidently superior to those of the M-15 min group, and those of the M-60 min group were significantly superior to those of the M-30 min group in lowering serum IL-4 and IgE contents and up-regulating IFN-gamma/IL-4 (P<0.05, P<0.01). No significant differences were found between the M-60 min and M-120 min groups in down-regulating IL-4 and IgE levels, and in raising IFN-gamma/IL-4 level, as well as among the M-15min, M-30 min, M-60 min and M-120 min groups in elevating serum IFN-gamma levels (P>0.05). CONCLUSION: Moxibustion can restrain the secretion of IL-4, relieve the inflammatory reaction of IgE, and enhance the ratio of IFN-gamma/IL-4 in asthma rats, which presents an increase tendency of the curative effect along with the extension of the treatment time from 15 min to 60 min. Excessively long time (>60 min)of treatment is not necessary. PMID- 22934391 TI - [Effect of electroacupuncture on lipid metabolism in male and female obesity rats]. AB - OBJECTIVE: To investigate the influence of electroacupuncture (EA) on lipid metabolism in both sexes of obesity model rats. METHODS: A total of 30 male and 30 female SD rats were randomized into normal control, model and EA groups respectively, with 10 rats in each group. EA (2 Hz, 1-2 mA) was applied to the ipsilateral "Zusanli" (ST 36)-"Sanyin-jiao"(SP 6) and bilateral "Fenglong" (ST 40) for 30 min, once daily for 28 days. In addition,"Quchi" (LI 11),"Zhongwan" (CV 12) and "Guanyuan" (CV 4) were punctured with filiform needles and stimulated by manipulating the needle for 1 min, separately. Obesity model was duplicated by subcutaneous injection of 15% glutamic sodium (0.2 mL/10 g) once daily for 5 days and by feeding the animal with high fat forage for 36 days. Lee's index was calculated, and plasma triglyeride (TG) concentration detected by glycerol phosphoric acid oxidase-peroxydase method, total cholesterol (TC) detected by cholesterol oxidase method, and plasma low-density lipoprotein-cholesterol (LDL C) and high-density lipoprotein-cholesterol (HDL-C) contents were assayed by one step method, respectively. RESULTS: In both male and female rats, compared to their own normal groups, the Lee's index, plasma TG, TC and LDL-C contents were increased significantly and plasma HDL-C contents decreased obviously in the model groups (P<0.01), while compared to their own model groups, the Lee's index, plasma TG, TC and LDL-C levels in the EA groups were down-regulated considerably and plasma HDL-C contents up-regulated remarkably after the treatment (P<0.01, P<0.05). The efficacies of the EA intervention were obviously better in reducing Lee's index for male rats, and in down-regulating plasma TG and TC contents in female rats (P<0.05). No significant differences were found between male and female rats in EA intervention for plasma LDL-C and HDL-C levels. CONCLUSION: EA intervention can effectively regulate obesity rats' Lee's index and plasma TG, TC, LDL-C and HDL-C levels. The effects are different in male and female rats. PMID- 22934392 TI - [Effect of electroacupuncture on electrical activities of pressor reflex related neurons in the nucleus of tractus solitarii (NTS) in rats]. AB - OBJECTIVE: To observe the effect of electroacupuncture (EA) of auricular point "Xin" (Heart), "Neiguan" (PC 6) and "Zusanli" (ST 36) on electrical activities of the presser reflex-related neurons in the nucleus of the solitary tract (NTS) in rats. METHODS: A total of 47 SD rats were used in the present study. Extracellular electrical activities of neurons in the NTS (AP: 1.0 mm, Left and right:0 - 1.0 mm, depth: 0.3-0.8 mm)were recorded by using glass microelectrodes (10 - 15 M(omega)). Carotid arterial pressure changes were monitored and recorded by using a pressure transducer. EA(2 mA, 10 Hz, duration: 500 ms) was randomly applied to the left auricular point "Xin", "Neiguan" (PC 6) and "Zusanli" (ST 36) for 30 s, respectively. Elevation of arterial pressure was induced by intravenous injection of Phenylephrine (PE, 6- 12 microg/kg, 2 microg/mL). RESULTS: Of the 67 NTS neurons, 15 were activated by intravenous injection of PE (which were called as presser reflex-related neurons). Following EA of the auricular point "Xin" and ST 36, the mean arterial pressure (MAP) levels in normal rats and PE-induced MAP increase rats were lowered significantly (P<0.001, P<0.05). Concomitantly, the firing rates of presser reflex-related NTS neurons were increased considerably by EA stimulation of auricular point "Xin" and ST 36, but not by EA of PC 6. EA of PC 6 had no apparent influence on MAP in normal rats and in PE-induced MAP increase rats (P>0.05). CONCLUSION: Electroacupuncture stimulation of auricular point "Xin" and "Zusanli" (ST 36) can lower MAP in normal rats and PE-induced MAP elevation rats, and enhance presser reflex induced increase of firing rates of NTS neurons, suggesting an interaction between signals from electroacupuncture stimulation of "Xin" and "Zusanli" (ST 36) and from cardiovascular activities in the NTS neurons. PMID- 22934393 TI - [Effect of electroacupuncture intervention on expression of vascular PKC in the ischemic cerebral tissue in rats with cerebral infarction]. AB - OBJECTIVE: To observe the effect of electroacupunctur (EA) of Shuigou(GV 26)on the expression of vascular protein kinase C (PKC) in the focal ischemia cerebral tissue in rats so as to study its dynamic regulation mechanism. METHODS: A total of 78 Wistar rats were randomly divided into model group (n = 24), EA group (n = 24), sham operation (sham) group (n = 24) and control group (n = 6). The first 3 groups were further divided into 0. 5 h, 1 h, 3 h and 6 h subgroups, with 6 cases in each. Cerebral ischemia (CI) model was established by occlusion of the middle cerebral artery. EA (15 Hz, 1.0 mA) was applied to "Shuigou" (GV 26) for 20 min. The anterior, middle and posterior cerebral arteries on the infarct side of the brain were collected for assaying the expression of PKC protein by using Western blot, and the formalin-fixed artery samples were embedded with paraffin, followed by sectioning and staining with immunohistochemistry. RESULTS: Compared with the control group, the expression levels of cerebral vascular smooth PKC protein shown by both immunohistochemistry and Western blot were upregulated significantly at the time-points of 0.5 h, 1 h, 3 h and 6 h after CI in the model group (P<0.05, P<0.01). In comparison with the model group, the expression levels of PKC protein in the cerebral vascular smooth muscle shown by the aforementioned two methods were down-regulated considerably in the EA group (P<0.01, P<0.05). No statistic differences were found between the control and sham groups in the expression of vascular PKC protein at different time-points (P>0.05). CONCLUSION: EA Intervention can significantly inhibit PKC expression in the cerebral vascular smooth muscle in CI rats, which may be responsible for its efficacy in improving ischemic stroke. PMID- 22934394 TI - [Effect of electroacupuncture pre-treatment on myocardial enzyme levels in recurrent myocardial ischemia rabbits]. AB - OBJECTIVE: To observe the effect of electroacupuncture (EA) preconditioning of "Neiguan" (PC 6) on myocardial enzyme levels in acute recurrent myocardial ischemia rabbits so as to study its mechanisms underlying protection of ischemic myocardium. METHODS: A total of 40 healthy rabbits were randomized into normal control, myocardial ischemia (MI) model, EA preconditioning (EA-P), recurrent MI (RMI), EA-P+ RMI groups. MI model was duplicated by auricular intravenous administration of Posterior Pituitary Injection (PPI, 0.3 mL/kg). EA (2 Hz/70 Hz, 2-4 mA) was applied to bilateral PC 6 for 30 min, once daily for 7 d before MI. The contents of serum aspartate aminotransferase (AST), isoenzymes of creatine kinase (CK-MB), lactate dehydrogenase (LDH), creatine kinase (CK), alpha hydroxybutyrate dehydrogenase (alpha-HBD) were detected by automatic biochemistry analyzer. RESULTS: Following administration of PPI, ECG-ST(II), serum AST, CK-MB, LDH, CK and alpha-HBD levels were increased significantly in the MI and RMI groups (P<0.01). Compared with the MI model group, ECG-ST(II), serum AST, CK-MB, LDH, CK and alpha-HBD levels were down-regulated considerably in the EA-P group (P<0.01), and ECG-ST(II), serum AST, CK-MB, LDH, CK and alpha-HBD levels were obviously lower in the EA-P+ RMI group than in the RMI group (P<0.01). No significant differences were found between the MI and RMI groups, and between EA P and EA-P + RMI groups in the above-mentioned 6 indexes (P>0.05). CONCLUSION: Electroacupuncture preconditioning has a remarkable effect in the prevention of ischemic myocardial injury of both acute and recurrent myocardial ischemia in the rabbit, which is closely associated with its functions in lowering serum AST, CK MB, LDH, CK and alpha-HBD contents. PMID- 22934395 TI - [Effects of acupoint injection of autologous blood on symptoms and plasma motilin and gastrin levels of diabetic gastroparesis patients]. AB - OBJECTIVE: To observe the curative effect of autologous blood point injection on diabetic gastroparesis and to study its underlying mechanism. METHODS: A total of 42 type-II diabetes outpatients and inpatients were randomly and equally divided into treatment group and control group according to a random digit table. Patients of the treatment group were treated by injection of the patient's own venous blood (2 mL/acupoint) into the unilateral Zusanli (ST 36), Zhongwan (OV 12) and Weishu (BL 21), once every week, 4 times together. Patients of the control group were ordered to take motilium (10 mg/time), 3 times daily for 4 weeks. Plasma motilin and gastrin were detected by radioimmunoassay before and 4 weeks after the treatment. RESULTS: Of the two 21 cases in the control and treatment groups, 3 and 7 experienced marked improvement in their symptoms, 4 and 8 were effective, 14 and 6 were failed in the treatment, with the effective rates being 33.3% and 71.4% respectively. The effective rate of the treatment group was significantly higher than that of the control group (P<0.05). The contents of plasma motilin and gastrin in both control and treatment groups were reduced obviously after the treatment (P<0.01), and the effect of the treatment group was significantly superior to that of the control group in lowering plasma motilin and gastrin levels (P<0.01). CONCLUSION: Acupoint injection of the diabetes patients' own blood can obviously alleviate the symptoms of diabetic gastroparesis, which is closely associated with its effects in lowering plasma motilin and gastrin levels. PMID- 22934396 TI - [Effect of acupuncture needle-retention duration at Baihui (GV 20) and sishencong (EX-HN 1) on blood pressure in hypertension patients]. AB - OBJECTIVE: To observe the effect of needle-retention duration at Baihui (GV 20) and Sishencong (EX-HN 1) on blood pressure in hypertension patients. METHODS: Twenty-four patients with essential hypertension were randomly divided into acupuncture group and medication group. For patients of the acupuncture group, single-use sterilized filiform needles were inserted into Baihui (GV 20) and Sishencong (EX-HN 1) and manipulated for about 10 s till "Deqi", and retained for 8 h. Patients of the medication group were treated by oral administration of Nifedipine tablets(20 mg)in the morning. Blood pressure (right brachial artery) was detected 0.5, 2, 4, 6 and 8 h after the treatment respectively. RESULTS: In comparison with pre-treatment, the systolic pressure levels at the time-points of 0.5, 2, 4, 6 and 8 h after taking Nifedipine in the medication group, and the systolic pressure levels at the time-points of 2, 4 and 6 h after the treatment in the acupuncture group, and the diastolic pressure levels at the time-points of 2, 4, 6 and 8 h in both acupuncture and medication groups were decreased obviously (P<0.05, P<0.01). The effect of acupuncture group was significantly weaker than that of the medication group in lowering systolic pressure at the time-points of 0.5 and 8 h after the treatment (P<0.01). No significant differences were found between the acupuncture and medication groups in lowering systolic pressure at the time-points of 2, 4 and 6 h after the treatment, and in lowering diastolic pressure at the time-points of 0.5, 2, 4, 6 and 8 h after the treatment (P>0.05). CONCLUSION: Acupuncture stimulation of Baihui (GV 20) and Sishencong (EX-HN 1) with sustained needle-retention works well in lowering blood pressure in hypertension patients, but is relatively slower and has a shorter period of time in lowering blood-pressure efficacy. PMID- 22934397 TI - [Observation on curative effect of thermal acupuncture needle muscular stimulation therapy for knee osteoarthritis patients]. AB - OBJECTIVE: To observe the therapeutic effect of thermal acupuncture needle muscular stimulation for treatment of knee osteoarthritis patients. METHODS: A total of 120 outpatients with knee osteoarthritis were randomly and equally divided into control and treatment groups. Patients of the treatment group were treated by inserting the acupuncture needles into the attached sites of the quadriceps femoris, musculus vastus medialis, vastus lateralis, etc. around the knee joint. The needles were manipulated repeately till "Deqi", followed by attaching a piece of ignited moxa-roll (about 2 cm length) to the needle handle. The treatment was conducted once a week, 4 weeks altogether. Patients of the control group were treated by oral administration of Celebrex (a specific inhibitor of COX-2, 200 mg/time, once daily, 4 weeks together). The therapeutic effect was evaluated by using visual analogue scale (VAS), Lequesne Index (Chinese Version) of osteoarthritis after 4 weeks' treatment and 3 months after the treatment. RESULTS: After 4 weeks' treatment and 3 months after the treatment, the effective rates were 78.3% (47/60) and 81.7% (49/60) in the control group, and 96.6% (58/60) and 96.6% (58/60) in the treatment group, respectively, being significantly higher in the treatment group (P<0.05). Both VAS scores and Lequesne Indexes in the treatment group, and VAS scores in the control group were decreased significantly after 4 weeks' treatment and 3 months' follow-up (P<0.05). The effects of the treatment group were considerably superior to those of the control group (P<0.05). CONCLUSION: Thermal needle muscular stimulation therapy is effective for relieving knee osteoarthritis patients' symptoms of pain, knee-joint stiffness, swelling, walking capability, etc. PMID- 22934398 TI - [Development of studies on acupuncture treatment of childhood autism]. AB - With the development of autism therapy, acupuncture, an alternative therapy, is becoming popular for autism children. There have been many papers found about the treatment of autism by acupuncture therapy so far. In the present review, the authors briefly introduce the theoretical basis of autism in traditional Chinese medicine and the application history, and sum up the acupoint prescriptions, effectiveness as well as the assessment tools of acupuncture therapy for autism. It is suggested that acupuncture therapy is a relatively effective therapy for autism children. It has positive roles in improving autistic syndromes without any side-effects, especially in improving language development, daily-life self care, and social communications. The underlying mechanism of this therapy may be explained by acupuncture intervention induced favorable changes of neurochemistry, cerebral blood flow, and cerebral functional activities. Although there are lots of questions to be answered about acupuncture treatment of autism, we hold a positive opinion that this therapy might be a green effective therapy for autistic children in the future. PMID- 22934399 TI - [Progress of researches on involvement of serotonin in the central nervous system in acupuncture analgesia and other effects]. AB - As for an important central regulatory neurotransmitter involving acupuncture effect, serotonin (5-HT) is worthy of being paid with more attention. In the present paper, the authors review development of researches on the involvement of 5-HT and its receptor subunits in pain perception, acupuncture analgesia, and other effects of acupuncture (anti-depression, weight-reduction, etc.). Many studies showed that acupuncture intervention could modulate the content and activity of central 5-HT, and these changes varied under different conditions. Hence, the relationship between 5-HT and other neurotransmitters in acupuncture analgesia and its different functions in different regions of the central nervous system should be considered comprehensively. PMID- 22934400 TI - [On feasibility of researching acupoint combination by using complex network analysis techniques]. AB - One of the fundamental factors for achieving a better clinical efficacy of acupuncture therapy is to compose an appropriate acupoint recipe or a set of acupoint recipes for an illness or a clinical condition. The present article reviews recent development of researches about acupoint combination from the methods of combination style, properties and functions (synergic or antagonistic role) of different acupoints, etc., and holds that "integrity" and "nonlinear" ideas are probably the key factors for composing reasonable acupoint prescriptions. Moreover, with reference to the achievements got in the field of complex network researches of Chinese medicine, the authors discuss the applicability of studies about acupoint combination literature, and biological data integration for acupoint compatibility. The authors point out that the current complex network analysis approach may be an effective measure for understanding the regularities and mechanisms of reasonable combination of acupoints. PMID- 22934401 TI - [Development of legislation and standardization of acupuncture therapy in the United States of America]. AB - In the present article, the authors summarized the state of acupuncture therapy in the United States of America from 1) history and current state, 2) legislation and its contents, management system and introduction of health insurance system, and 3) standardization. Acupuncture therapy, as a complementary or alternative therapy, has been widely supported and approved by majority of states in the USA. The authors hold that due to differences between the oriental and western cultures and difficulties of Chinese medicine in quantitative and qualitative studies, the legislation on acupuncture therapy for approval of the American Parliament needs paying more efforts. PMID- 22934402 TI - [Current highlights of research on porous monoliths]. PMID- 22934403 TI - [Progress in techniques for determination of microcystins in aquatic products]. AB - Microcystins (MCs) produced by blue-green algae, is one of the algal toxins with features of highest frequency and production. MCs could cause serious multi-organ toxicity, genetic toxicity and carcinogenicity. Monitoring of MCs residue in aquatic products is important for evaluating the potential risk for human beings. Therefore, the trace analytical technique of MCs is needed. In this paper, the progress of the microcystins extraction, purification and analytical techniques is reviewed. PMID- 22934404 TI - [Preparation of poly(methyl acrylate) microfluidic chips surface-modified by hyperbranched polyamide ester and their application in the separation of biomolecules]. AB - The surface of poly (methyl acrylate) (PMMA) microfluidic chips were modified using hyperbranched polyamide ester via chemical bonding. The contact angles of the modified chips were measured. The surface morphology was observed by scanning electron microscope (SEM) and stereo microscope. The results showed that the surface of the modified chips was coated by a dense, uniform, continuous, hydrophilic layer of hyperbranched polyamide ester. The hydrophilic of the chip surface was markedly improved. The contact angle of the chips modified decreased from 89.9 degrees to 29.5 degrees. The electro osmotic flow (EOF) in the modified microchannel was lower than that in the unmodified microchannel. Adenosine and L lysine were detected and separated via the modified PMMA microfluidic chips. Compared with unmodified chips, the modified chips successfully separated the two biomolecules. The detection peaks were clear and sharp. The separation efficiencies of adenosine and L-lysine were 8.44 x 10(4) plates/m and 9.82 x 10(4) plates/m respectively, and the resolutions (Rs) was 5.31. The column efficiencies and resolutions of the modified chips were much higher than those of the unmodified chips. It was also observed that the modified chips possessed good reproducibility of migration time. This research may provide a new and effective method to improve the hydrophilicity of the PMMA surface and the application of PMMA microfluidic chips in the determination of trace biomolecules. PMID- 22934405 TI - [Simultaneous determination of penicillin G and its major metabolites in blood using ultra performance liquid chromatography-tandem mass spectrometry]. AB - A fast method for the quantitative determination of penicillin G (PEN G) , penicilloic acid and penilloic acid in blood with ultra performance liquid chromatography-electrospray tandem mass spectrometry was developed. A simple deproteinization of the blood was used with a mixed solution of acetonitrile and water (4:1, v/v) as extraction solvent. The blood extract was directly injected onto an LC column. The chromatographic separation of the components was performed on a BEH C18 column (50 mm x 2.1 mm, 1.7 microm) using acetonitrile and water containing 0.1% formic acid. The mass spectrometer was operated in positive electrospray ion mode. Finally, the analysis was carried out with multiple reaction monitoring (MRM) mode. The limits of detection (LODs) for these three compounds were in the range of 0.1 to 2.0 ng/mL and the limits of quantification (LOQs) in the range of 0.5 to 5.0 ng/mL. Within the linear range, the correlation coefficients (r) of PEN G and its metabolites were all more than 0.9974. Accuracies for these targeted compounds were ranged from 92.3% to 105.5%, and the within-day precisions were less than 10%. The stabilities of the components were evaluated in the temperature range from 18 to 80 degrees C, and the mass concentration of penicillin G was decreased significantly with the extensions of storage temperature and storage time. Biological samples of the rats medicated with PEN G were analyzed using the developed method. The results show that PEN G can just be detected at 0.5 h after administration. However, the detection time limitation of penicilloic acid can be extended to 36 h. The established method has been further expanded for the applicability of forensic identification, and has a reference value for the detection of penicillin G residue in food. PMID- 22934406 TI - [Determination of ilaprazole in beagle plasma and its pharmaeokineties by high performance liquid chromatography-mass spectrometry]. AB - A sensitive, simple and specific high performance liquid chromatography-electro spray ionization mass spectrometry method was developed for the determination of ilaprazole in the plasma of beagles administered via i.v. bolus doses of ilaprazole. The procedure employed buspirone as the internal standard and a simple protein precipitation step. The separation was achieved using a C18 column (100 mm x 2.1 mm, 5 microm) with a mobile phase consisting of water-methanol acetonitrile (69:8:23, v/v/v) containing 0.1% (v/v) formic acid at a flow rate of 0.2 mL/min. The detection was accomplished by a mass spectrometer using selected ion monitoring (SIM) in positive mode. The linearity was from 5 microg/L to 10,000 microg/L with a sensitivity of 5 microg/L as the lower limit of quantification. The inter- and intra- day precisions were within 9.00%. The mean recoveries at three spiked levels were about 106% and the matrix effects were less than 142.0%. The method described above was successfully applied to analyze the beagle plasma samples of ilaprazole in a pharmacokinetic study. The area under the plasma concentration-time curve (AUC(0-infinity) of ilaprazole after i.v. doses of 0.2, 0.8 and 3.2 mg/kg were (2.4 x 10(4) +/- 3 x 10(3)), (8.8 x 10(4) +/- 1.6 x 10(4)) and (5.4 x 10(5) +/- 8 x 10(4)) microg/L x min, respectively. On the basis of AUC, the pharmacokinetic property of ilaprazole was proposed to be linear dynamics. PMID- 22934407 TI - [Simultaneous determination of 10 unapproved sedative drugs in feeds by ultra performance liquid chromatography-quadrupole-time-of-flight mass spectrometry]. AB - A new analytical method using ultra-performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF-MS) was developed for screening and confirmation of 10 unapproved sedative drugs in feeds. The samples were extracted using the solution of methanol-0.1 mol/L HCl (9:1, v/v), and the extracts were centrifuged and then directly purified through MCX cartridges. The identification and detection were achieved in positive electrospray ionization (ESI) mode using Q-TOF-MS. The potential of UPLC-Q-TOF MS for confirmatory analysis was shown by determining the accurate mass of all the compounds and fragment ions upon collision-induced-dissociation (CID) at different energies. The extra mass measurement errors for all the sedative drugs were found to be within 5 ppm. The calibration graphs were linear in the concentration range of 5-100 microg/L with the correlation coefficients more than 0.99 for the 10 drugs. The limits of quantification (LOQ, S/N = 10) were 8 microg/kg for nitrazepam, zolpidem and thioridazine; 10 microg/kg for thriazolam, estazolam, diazepam, promethazine, chlorpromazine and midazolam; 20 microg/kg for clozapine. The recoveries for all the compounds in feeds were 60.6%-108.5% with the relative standard deviations less than 10% at the spiked levels of LOQ, 2LOQ and 4LOQ. PMID- 22934408 TI - [Determination of virginiamycin M1 and S1 residues in livestock and poultry products by liquid chromatography-tandem mass spectrometry]. AB - A liquid chromatography-tandem mass spectrometry method was established for the determination of virginiamycin M1 and S1 residues in livestock and poultry products. The sample was extracted by methanol-acetonitrile solution (1:1, v/v). The supernatant was diluted with 0.01 mol/L ammonium dihydrogen phosphate solution, then purified and concentrated on an Oasis HLB cartridge. The separation of virginiamycin M1 and S1 was performed on a Luna C18 column with the mobile phases acetonitrile and 5 mmol/L ammonium acetate aqueous solution (containing 0.1% (v/v) formic acid) in a gradient elution mode. The identification and quantification of the drugs were carried out by positive electrospray ionization (ESI + ) in the multiple reaction monitoring (MRM) mode using external standard method. The calibration curves showed good linearity in the range of 0.15-10.0 microg/L with correlation coefficients (r2) above 0. 999. The limits of quantities (LOQs) were both 0.25 microg/kg. The average recoveries of the two drugs spiked at 0.25, 0.5 and 2.5 microg/kg levels in different matrices were between 71.2% and 98.4%, and the relative standard deviations (RSDs) were between 3.6% and 15.4%. The method is simple, rapid, sensitive and accurate. It is suitable for the confirmation and quantification of virginiamycin M1 and S1 residues in livestock and poultry products. PMID- 22934409 TI - [Simultaneous determination of 8 polybrominated biphenyls in human serum using gas chromatography-mass spectrometry]. AB - A comprehensive analytical method based on gas chromatography-mass spectrometry (GC-MS) has been developed for the simultaneous determination of 8 polybrominated biphenyl congeners (PBBs: BB-15, 18, 52, 101, 153, 180, 194 and 206) in human serum. After the protein was removed, the sample was cleaned-up by an Oasis HLB solid-phase extraction (SPE) cartridge, then purified further by a two-layer cartridge containing activated silica gel and a mixture of silica gel and sulfuric acid, in which elution solvent was optimized. The eluent was evaporated to about 100 microL by a gentle nitrogen stream for GC-MS analysis. The separation was performed on a DB-5ms column (15 m x 0.25 mm x 0.1 microm) and the qualitative and quantitative analyses were carried out in electron impact (EI) selected ion monitoring (SIM) mode, in which isotope was used as internal standard. The limits of detection (LODs, 3.14 times of standard deviation) and the limits of quantification (LOQs, 10 times of standard deviation) were 0.002 0.029 ng/mL and 0.008-0.092 ng/mL respectively for the 8 PBBs. The average recoveries for all PBBs at three spiked levels were 74.24%-119.49% with the relative standard deviations in the range of 1.23%-12.02%. The method was verified by accurate analysis of BB-153 in organic contaminant standard reference materials (SRM) 1957 and 1958. This method is simple, rapid, accurate, precise and fit for the determination of PBBs in human serum. PMID- 22934410 TI - [Rapid determination of benzene series in seawater by gas chromatography-mass spectrometry with static headspace extraction]. AB - A method for the simultaneous determination of 13 benzene series (BTEX) in seawater using gas chromatography-mass spectrometry with static headspace extraction (HS-GC/MS) was developed. To carefully characterize the performance of this method, several factors affecting parameters were studied in detail, such as the type of column, heating procedure, equilibrium temperature, equilibrium time and the volume ratio of gas phase to liquid phase. The optimized conditions were as follows: the polar column of DB-WAX; heating procedure, 40 degrees C kept for 4 min, then raised to 120 degrees C at 10 degrees C/min, to 180 degrees C at 25 degrees C/min; equilibrium temperature, 80 degrees C; equilibrium time, 10 min; and the volume ratio of gas phase to liquid phase, 1:1. Under the optimized conditions, the linear equations were obtained in the concentration range of 0.16 320 microg/L with correlation coefficients greater than 0.999. The limits of detection (S/N = 3) were 0.019-0.033 microg/L. The recoveries at the three spiked levels of 1.6, 16 and 160 microg/L ranged from 81. 25% to 103.73% with the relative standard deviations (RSD, n=6) from 0.3% to 4.4%. The analytical results of the practical seawater samples from Shanghai Huangpu District were satisfactory. The determination of the 13 benzene series can be finished in 12 min. The method is simple, accurate, reliable, efficient and environmental friendly. PMID- 22934411 TI - [Determination of 21 fragrance allergens in toys by gas chromatography-ion trap mass spectrometry]. AB - A method of gas chromatography-ion trap mass spectrometry (GC-IT-MS) was developed for the determination of 21 fragrance allergens in sticker toys, plush toys and plastic toys. The experimental conditions, such as sample pretreatment conditions, and the analytical conditions of GC-IT-MS, were optimized. The sticker toy samples and plush toy samples were extracted with acetone by ultrasonic wave, and the extracts were separated on an Agilent HP-1 MS column (50 m x 0.2 mm x 0.5 microm), then determined by IT-MS and quantified by external standard method. The plastic toy samples were extracted by the dissolution precipitation approach, cleaned up with an Envi-carb solid phase extraction column and concentrated by rotary evaporation and nitrogen blowing, then determined by GC-IT-MS and quantified by external standard method. The calibration curves showed good linearity in the range of 0.002-50 mg/L with the correlation coefficients greater than 0.996 8. The limits of quantification (LOQ, S/N > 10) were 0.02-40 mg/kg. The average recoveries of the target compounds spiked in the sample at three concentration levels were in the range of 82.2% 110.8% with the relative standard deviations (RSDs) of 0.6%-10.5%. These results show that this method is accurate and sensitive for the qualitative and quantitative determination of the 21 fragrance allergens in the 3 types of toys. PMID- 22934412 TI - [Preparation of new hydrophilic monolithic columns and their applications in capillary liquid chromatography and pressurized capillary electrochromatography]. AB - New hydrophilic monolithic columns were prepared with {[3-(methacryloylamino) propyl] dimethyl(3-sulfopropyl)ammonium hydroxide inner salt (SPP)} as monomer, pentaerythritol triacrylate (PETA) as crosslinking agent, azobisisobutyronitrile (AIBN) as initiator with two different porogens consisting of ethanol/ethylene glycol and methanol/1 ,4-butanediol, separately. In order to obtain monolithic columns with satisfactory efficiency, electroosmotic flow (EOF) velocity and permeability, the contents of the polymerization mixture were investigated and optimized. The performances of the two columns were compared in the permeability and separation performance. It was found that the monolithic column prepared with ethanol/ ethylene glycol had a better column efficiency and selectivity than that with methanol/1,4-butanediol, but was inferior to the latter in permeability. The effect of salt concentration (from 10 to 70 mmol/L ammonium formate) on the retention of nucleosides was investigated. It was observed that the retention factors of these nucleosides increased at first and then decreased. The columns were used in capillary liquid chromatography (cLC) and pressurized capillary electrochromatography (pCEC) for the separation of a test mixture of amines, phenols and nucleosides separately, and satisfactory separations for these samples were achieved. The column used in pCEC system showed better separation and higher speed of the mixture consisted of phenols and nucleosides compared to those used in cLC system. PMID- 22934413 TI - [Capillary electrophoresis fingerprints of Baizi Yangxin Wan]. AB - The capillary electrophoresis fingerprint (CEFP) of Baizi Yangxin Wan (BZYXW) was established by capillary zone electrophoresis (CZE). The chromatographic fingerprint resolution index (RF) was applied to optimize the CEFP conditions. The electrophoretic separation was performed on a 75 cm (the effective length of 57 cm) x 75 microm uncoated fused silica capillary with 50 mmol/L sodium borate 50 mmol/L Na2HPO(4)-200 mmol/L H3BO(3)-150 mmol/L NaHCO3 (7:7:1:1, v/v/v/v) containing 4% acetonitrile (pH 9.70) as the background electrolyte (BGE), and the BGE was chosen by using the triangular prism optimization method. The running voltage was set at 12 kV, and the detection wavelength at 228 nm. The sample solution was injected into the capillary by hydraulic pressure in 25 s. The CEFPs were produced by the electropherograms from 12 batches of BZYXW, and the 17 co possessing peaks were selected as the fingerprint peaks of BZYXW's CEFP by choosing ferulic acid peak as the referential peak. According to the results of classification, the reference CEFP (RCEFP) was synthesized from 12 batches of BZYXW. Taking the RCEFP for the qualified model, the systematically quantified fingerprint method(SQFM) was applied to evaluate the quality of 17 batches of BZYXW, in which the qualities of 3 batches was evaluated as good, 1 batch as fine, 3 batches as moderate, 1 batch as common, and 4 batches as inferior. The triangular prism optimization method was suggested to be good to optimize the BGE. The results showed that the BZYXW-CEFP was established with good precision and reproducibility, which can be served as a novel reference to identify and control the quality of BZYXW. PMID- 22934414 TI - [Determination of loureirin A and loureirin B in dragon's blood by capillary zone electrophoresis]. AB - A capillary zone electrophoresis method (CZE) for the simultaneous determination of loureirin A and loureirin B was developed based on the optimized conditions of the pH, composition and concentration of the running buffer solution. Loureirin A and loureirin B were separated and determined effectively within 15 min in a running buffer solution of 20 mmol/L Na2B4O7 (pH 9.98 adjusted with NaOH solution) containing 10.0% (v/v) acetonitrile, 5.0% (v/v) ethylene glycol and 1.0% (v/v) butanol, with the applied voltage of 20 kV, capillary temperature of 25 degrees C, detection wavelength of 211 nm, and injection of 5 s at 3447 Pa. The linear ranges for the determination of loureirin A and loureirin B were 1.00 100 mg/L and 0.50-100 mg/L, respectively. The determination of loureirin A and loureirin B in dragon's blood from natural and artificial inoculation was performed by the proposed method. The relative standard deviations for the determination of the two constituents in samples were from 0.6% to 3.8%, and the recoveries ranged between 95.1% and 105.8%. The method is simple, rapid and possesses higher reproducibility and efficiency. It can be used for the determination of loureirin A and loureirin B in dragon's blood. PMID- 22934415 TI - [Analysis of emodin and its metabolites based on hollow fiber liquid phase microextraction]. AB - Hollow fiber liquid phase microextraction (HFLPME) coupled with high performance liquid chromatography (HPLC) has been developed to analyze the emodin and its metabolites in plasma and urine samples. The abilities of the absorption and metabolism for the active components in traditional Chinese medicines between the male and female rats were compared, and the biological metabolism and transmutation of the analyte were detailed discussed. Emodin and its metabolites in plasma and urine samples were extracted into n-octanol (acceptor) in hollow fiber. The acceptor phase was dried and dissolved by 50 microL methanol and then analyzed by HPLC. Under the optimal conditions, the linearities of the analytes were all very good in biological samples (r > 0.9960), the detection limits of the analytes were within the ranges of 0.1-3.0 microg/L. The enrichment factors were 12.2 to 26.3. The relative standard deviations for intra-day and inter-day precision were lower than 11.0%. The average recoveries of the analytes in plasma and urine samples were all in the range of 97.9% to 103%. HFLPME-HPLC can eliminate interference from complex biological samples, improve the sensitivity and reduce the detection limit, thus this method is suitable for the determination of trace compounds in complex sample. PMID- 22934416 TI - [Analysis of volatile compounds from Curcuma by microwave assisted solid phase headspace-gas chromatography]. AB - A novel method of microwave assisted solid phase headspace gas chromatography (MASP-HSGC) was developed through online coupling of solvent-free microwave extraction (SFME) and headspace-gas chromatography via a six-way valve. The method can quickly and directly analyze the volatile compounds from solid samples with its ability of simultaneous extraction, separation and analysis without any pretreatment. The method was applied to analyze the volatile compounds of solid Curcuma. Some experimental parameters such as the chromatographic conditions, microwave power and irradiation time were studied. Curcumol was used as the standard to evaluate the recovery, the limit of detection and the contents of compounds in a Curcuma sample. The essential oils were prepared by hydrodistillation extraction (HD) and SFME separately, and analyzed by gas chromatography-mass spectrometry (GC-MS) to compare the results with those from the developed method. It showed that the numbers of compounds obtained by the three methods of HD-GC, SFME-GC and MASP-HSGC were 35, 33, 40 respectively. The contents of curcumol using the three methods were (0.294 +/- 0.015), (0.331 +/- 0.023), (0.297 +/- 0.009) mg/g respectively. The method was approved to be suitable for the rapid analysis of volatile components in Curcuma. PMID- 22934417 TI - Adsorption behavior of plasmid DNA onto perfusion chromatographic matrix. AB - Anion exchange chromatography is the most popular chromatographic method for plasmid separation. POROS RI 50 is a perfusion chromatographic support which is a reversed phase matrix and is an alternative to conventional ones due to its mass transfer properties. The adsorption and elution of the pIDKE2 plasmid onto reversed phase POROS R1 50 was studied. Langmuir isotherm model was adjusted in order to get the maximum adsorption capacity and the dissociation constant for POROS R1 50-plasmid DNA (pDNA) system. Breakthrough curves were obtained for volumetric flows between 0.69-3.33 mL/min, given dynamic capacity up to 2.3 times higher than those reported for ionic exchange matrix used during the purification process of plasmids with similar size to that of pIDKE2. The efficiency was less than 45% for the flow conditions and initial concentration studied, which means that the support will not be operated under saturation circumstances. PMID- 22934418 TI - [Simultaneous determination of 6 forbidden colorants in cosmetics by high performance liquid chromatography-tandem mass spectrometry]. AB - A method of high performance liquid chromatography-tandem mass spectrometry (HPLC MS/MS) has been established for the simultaneous determination of six forbidden colorants including Sudan IV, Acid Violet 49, Sudan Blue 2, Solvent Red 49, Basic Violet 1 and Pigment Orange 5 in cream and powdery matrix cosmetics. The samples were extracted with ethanol-acetonitrile (3:2, v/v) solution by ultrasonic technique for 20 min, then centrifuged for purification and enriched by nitrogen blowing sequentially. The analytes were isolated on a Luna C18 column (150 mm x 2.1 mm, 5 microm) by gradient elution with methanol and 10 mmol/L ammonium acetate as the mobile phases, and detected by MS/MS in the multiple reaction monitoring (MRM) mode. The qualitative analysis was based on the retention time and the relative abundance ratio of the characteristic ions, and the quantitative analysis on calibration curve method. The results showed that the limits of quantification (LOQ, S/N= 10) of the six colorants ranged from 0.1 to 10 microg/kg and the average recoveries were from 86.67% to 98.22% with the relative standard deviations (RSDs) from 4.01% to 7.01%. The method is simple and rapid with high sensitivity and good reproducibility, and suitable for the determination of the six forbidden colorants in cosmetics. PMID- 22934419 TI - [Analysis of global deoxyribonucleic acid 5-hydroxymethylcytosine in tissue by liquid chromatography-tandem mass spectrometry]. AB - As preventing deoxyribonucleic acid (DNA) methylation transferase 1 (DNMT1) methylation of the target cytosine, 5-hydroxymethylcytosine could cause alterations in DNA methylation. A rapid analytical method for the determination of the degree of global DNA hydroxymethylation in tissues using liquid chromatography-tandem mass spectrometry (LC-MS/MS) has been developed. After the extraction with phenol-chloroform, DNA was hydrolyzed to nucleobases by 88% formic acid at 140 degrees C, dried under nitrogen, followed by spiking with cytosine-13C15SN2 as internal standard, and reconstituted in a mixture of acetonitrile-water (9:1, v/v) for the analysis with LC-MS/MS. The LC separation was performed on a BEH HILIC column (100 mm x 2.1 mm, 1.7 microm) by gradient elution with 10 mmol/L ammonium acetate and acetonitrile as mobile phases. The analytes were detected by MS/MS with positive ion electrospray ionization (ESI+) in multiple reaction monitoring (MRM) mode to satisfy qualitative and quantitative detections. The results showed that the linear range of the calibration curve for 5-hydroxymethylcytosine was 0.1-30 ng/mL, and the correlation coefficient was higher than 0.99. The limit of detection (LOD, S/N = 3) and the limit of quantification (LOQ, S/N = 10) were 0.057 and 0.090 ng/mL, respectively. The intraday and interday precisions were 5.13% and 6.24%, respectively. The recoveries of the spiked standards varied from 90.24% to 97.53%. The method was applied to the analysis of DNA from cerebrums of rats, and the average degree of 5-hydroxymethylcytosine was 0.66%. The method is simple, reproducible, sensitive and suitable for the quantitative analysis of 5 hydroxymethylcytosine in global DNA from tissues. PMID- 22934420 TI - [Highly efficient and rapid capillary electrophoretic analysis of seven organic acid additives in beverages using polymeric ionic liquid as additive]. AB - A new capillary electrophoretic method for the rapid and direct separation of seven organic acids in beverages was developed, with poly (1-vinyl-3 butylimidazolium bromide) as the reliable background electrolyte modifier to reverse the direction of anode electroosmotic flow (EOF) severely. Several factors that affected the separation efficiency were investigated in detail. The optimal running buffer consisted of 125 mmol/L sodium dihydrogen phosphate (pH 6.5) and 0.01 g/L poly (1-vinyl-3-butylimidazolium bromide). Highly efficient separation (105,000 to 636,000 plates/m) was achieved within 4 min and standard deviations of the migration times (n=3) were lower than 0.0213 min under optimal conditions. The limits of detection (S/N = 3) ranged from 0.001 to 0.05 g/L. The present method was applied to determine a beverage sample (Mirinda) for sodium citrate, benzoic acid and sorbic acid with concentration of 2.64, 0.10 and 0.08 g/L, respectively. The recoveries of the three analytes in the sample were 100.3%, 100.7% and 131.7%, respectively. The method is simple, rapid, inexpensive, and can be applied to determine organic acids as additives in beverages. PMID- 22934421 TI - [Preparative separation of two xanthones from Halenia elliptica by high-speed counter-current chromatography]. AB - A high performance method for isolation and purification of two xanthones from a crude extract of Halenia elliptica was successfully established by utilizing high speed countercurrent chromatography (HSCCC). The separation was performed with a two-phase solvent system composed of n-hexane-ethyl acetate-methanol-water (5:5:7:5, v/v/v/v) with the lower phase as the mobile phase at a flow rate of 1.5 mL/min. The apparatus was rotated at 800 r/min. The effluent was detected at 254 nm. Under the optimized conditions, 18 mg of 1-hydroxy-2,3, 5-trimethoxyxanthone and 14 mg of 1-hydroxy-2,3,4,5-tetramethoxyxanthone were obtained from 100 mg of the crude extract of Halenia elliptica in one-step separation within 360 min. The results of high performance liquid chromatographic (HPLC) analysis showed that the purity of each of the target compounds was over 98%. The chemical structures of the two compounds were confirmed by 1H nuclear magnetic resonance (1H NMR) and 13C NMR. The established method is simple, highly efficient and suitable for large scale separation of xanthones from Halenia elliptica. PMID- 22934422 TI - [Efficiency comparison between PET/CT and conventional work-up for evaluating distant metastasis of nasopharyngeal carcinoma]. AB - OBJECTIVE: The large sample retrospective cohort study were used to compare the diagnostic efficiency of PET/CT with conventional work-up (CWU) for evaluating nasopharyngeal carcinoma (NPC) distant metastasis. METHOD: Five hundred and fourteen patients with NPC were divided into PET/CT group and CWU group according the method of detecting distant metastasis. Chest film, abdominal ultrasonography, and bone scan were used in CWU group. Then the diagnostic efficiency of the two groups was compared. RESULT: Two hundred and sixteen patints were enrolled in PET/CT group and two hundred and nineteen-eight ones in CWU group. There were 28 out of 412 suspicious patients in CWU group were confirmed, another 3 patients confirmed without positive findings, compared with PET/CT group that all 32 suspicious patients were confirmed. The sensitivity and specificity of PET/CT were 100.0% (32/32) and 100.0% (184/184), as compared to 90.3% (28/31) and 94.8% (253/267) with CWU respectively, while there was no statistical significance. Further research found out that the percentage of patients with multiple distant metastatic sites and multiple organ metastases was higher in PET/CT group (P < 0.05), and similarly of patients with distant metastasis in N2-3 stages (P < 0.01). CONCLUSION: Our results suggest that PET/CT appears to be slightly superior to conventional work-up in assessment of distant metastasis in NPC patients, but CWU is still a cheap and practical method. PMID- 22934423 TI - [The surgical treatment effect on upper airway in treating refractory hypertension accompanied with OSAHS]. AB - OBJECTIVE: To investigate the clinical treatment effect of refractory hypertension accompanied with OSAHS by surgery on upper airway. METHOD: Thirty two patients were enrolled in our research. PSG and blood pressure were examined on preoperation and 6th month, 1 year, 2 year of postoperation. RESULT: The AHI and the time of SaO2 < 90% were lower significantly, and LSaO2 was improved (P < 0.01). The blood pressures of 32 patients were decreased. CONCLUSION: The operation on upper airway could improve the hypertension of patient with OSAHS effectively. PMID- 22934424 TI - [The treatment method and effect of orbital floor defects repaired with autologous tragus cartilage through Cald-well-Luc approach under nasal endoscope]. AB - OBJECTIVE: To explore the operative method and effect of fracture of orbital floor defects repaired with tragus cartilage through Cald-well-Luc approach under nasal endoscope. METHOD: Fifteen cases suffered fracture of orbital floor defects(blow out fracture) were analyzed retrospectively. Oral vestibular incision were done directly to tip teeth kennel, maxillary sinus anterior forewall was chiseled with 2 cm x 2 cm size, orbital floor fracture defect size was probed under nasal endoscope, and the fracture of orbital floor defects was repaired with tragus cartilage. RESULT: Fifteen cases were successfully operated and no cases showed vision loss,diplopia, enophthalmos obviously after operation,while 3 case were a little eyeball limitation of activity and restored basically after one month. With two years of follow up, there were no spurious eyelid drooping, up-eyelid lacuna deepen, eyelid diameter shorten and facial deformity were found. Both eye-balls were basical symmetry and no complications were happened. CONCLUSION: It is a satisfactory, effective and aminimally invasive surgical method without facial scars and eyelid ectropion for fracture of orbital floor defects repaired with tragus cartilage through Cald-well-Luc approach under nasal endoscope. PMID- 22934425 TI - [The study on AHI, LSaO2 and ET-1 in patients with obstructive sleep apnea hypopnea syndrome after H-UPPP]. AB - OBJECTIVE: To explore the treatment effect of H-UPPP on patients with obstructive sleep apnea hypopnea syndrome (OSAHS). METHOD: Seventy-nine patients were enrolled in our study. Among which 49 patients were done with H-UPPP, and the other 30 patients were done with UPPP. AHI and LSaO2 were monitored by polysomnography and plasma endothelins-1 were tested with enzyme linked immunosorbent assay (ELISA) before and after operation. RESULT: Forty-one patients were improved with reduced snoring and daytime sleepiness one year after operation in H-UPPP group,and the overall efficiency was 83.7%. Twenty-six patients were improved with reduced snoring and daytime sleepiness one year after operation in UPPP group, and the overall efficiency was 86.7%. There were significant differences of AHI, LSaO2 and ET-1 before and after operation between the two groups. Negative correlation was showed between AHI and LSaO2, also between LSaO2 and ET-1. CONCLUSION: Both H-UPPP and UPPP were proved to be effective to patients with OSAHS. The perioperative complications with H-UPPP was less than UPPP. PMID- 22934426 TI - [Comparative study of auditory event-related potentials evoked by different Chinese speech stimuli]. AB - OBJECTIVE: To research the responsibility and mechanism of auditory event-related potentials (AERP) evoked by pure-tone and different Chinese speech (including single-syllable words, two-syllable words and munbers) stimuli respectively. Meanwhile, to explore feasibility of using different Chinese speech forms as stimulation to evoke AERP in Chinese people. METHOD: AERPs were measured in 37 young normal post-graduated students (70 ears) with pure-tone and three different Chinese speech forms as stimuli. The mean incidence rates, latencies and amplitudes of AERPs were analyzed, the waveforms of AERPs were quantitatively scored. Then all data were statistically analyzed and compared. RESULT: The typical wave P1, N1, P2, N2 and P3 of AERPs could be recorded by both pure-tone and three different Chinese speech stimuli, in which the Chinese two-syllable word was most likely to evoked AERP than pure-tone and remains of Chinese speech forms, and the differences were statistical significance (Chi2 = 0.046, P < 0.05). The quantitative scores and amplitudes of P3 evoked by pure-tone and three different Chinese speech stimuli were analyzed in 56 ears, whose results showed no significant difference (P > 0.05) among different stimuli. However, the waveforms of AERPs were smoother and much satisfied evoked by Chinese character and two-syllable word than pure-tone and Chinese number stimuli. The latencies of P3 evoked by number stimulus were significant longer than by other stimuli (P < 0.05). Nevertheless, the latencies of P3 were no significant differences among the other stimuli (P > 0.05). CONCLUSION: Besides pure-tone and Chinese single syllable words, other Chinese speech such as two-syllable words and numbers could be used to evoke AERP with satisfied waveform, which indicated that the Chinese character, two-syllable words and numbers were available to apply for AERP measurement as stimuli for Chinese people. PMID- 22934427 TI - [Behavior research of allergic rhinitis with adenoid hypertrophy in children]. AB - OBJECTIVE: To investigate the behavior difference of allergic rhinitis with adenoid hypertrophy between study group and control group. METHOD: One hundred and seventeen children diagnosed as allergic rhinitis with adenoid hypertrophy were enrolled in our study were divided into study group and control group. Forty two children treated with local steroid nasal spray for two to three months and antihistamine were control group. Seventy-five children treated with endoscopic adenoidectomy and drug treatment were study group; All children' parents were inquired for their clinical presentation. RESULT: No distinctive differences were found between the two groups (P > 0.05) in adenoid hypertrophy, accompanying nasal problems and clinical questionnaire scoring. Significant statistical distinction were found (P < 0.05) in snoring, sleep disturbance and frequent arousal, nasal obstructive moth-breathing, and recurrent respiratory tract infection between the two groups after three-month follow up. CONCLUSION: Endoscopic adenoidectomy should be taken into account for allergic rhinitis with adenoid hypertrophy in children. Adenoidectomy would be useful for the improvement of behavior symptoms. PMID- 22934428 TI - [Effects of Bmi-1 RNAi gene on laryngeal carcinoma Hep-2 cells]. AB - OBJECTIVE: To construct the Bmi-1 RNAi expression vector and investigate its influence on the proliferation and invasiveness of laryngeal carcinoma Hep-2 cells. METHOD: The recombinant vshRNA-Bmi-1 plasmid of Bmi-1 RNAi was constructed by the lentiviral expression system, pHelper1.0/pHelper2.0/pGCL2GFP. Bmi-1mRNA and protein expressions of stably transfected laryngeal carcinoma cells were identified tespectively by real-time PCR and Western blot analyses. The changes of the proliferation and invasiveness of laryngeal carcinoma were detected by clone formation test and an invasion assay. RESULT: The Bmi-1 mRNA expressions of stably transfected laryngeal carcinoma Hep-2 cells were significantly decreased. The expression of Bmi-1 protein in laryngeal carcinoma Hep-2 cells was significantly decreased. And the inhibitory rates were 79% and 88% respectively. Whereas the proliferation and invasiveness of Hep-2 cells were significantly reduced. CONCLUSION: The Bmi-1 RNAi expression vector were constructed successful. Reduced Bmi-1 expression of Hep-2 cells demonstrated the role of Bmi 1 RNAi in restraining proliferation and invasiveness of laryngeal carcinoma cells. PMID- 22934429 TI - [Animal model of obstructive sleep apnea with New Zealand rabbit]. AB - OBJECTIVE: To build up a steady and credible animal model on obstructive sleep apnea-hypopnea syndrome (OSAHS) with New Zealand rabbit. METHOD: Ten New Zealand rabbit were divided into two groups (A and B, 5 for each). Group A was treated by injecting Dimethiconum from exterior. Group B was blank. EEG, snoring and oxygen saturation were recorded by PSG after operation. Examination was repeated two weeks later and one month later. CT was done in the operation and two weeks later. Animals were sacrificed three months later and the Dimethiconum in the body was used for examination with light microscopy. RESULT: Group A showed apnea or hypopnea and decreasing SaO2 after operation. The changes in group A were more obvious at two weeks and one month. CONCLUSION: A steady and credible animal model of OSAHS has been built. The model provides a tool to study the pathogenesy and pathophysiology of OSAHS. PMID- 22934430 TI - [The function of lymphangiogenesis and the expression of Cathepsin D in laryngeal carcinoma metabasis]. AB - OBJECTIVE: To study the function of lymphangiogenesis and the expression of Cathepsin D (Cath-D) in laryngeal carcinoma metabasis and clinical pathology character. METHOD: The expression of Cath-D were detected in 76 laryngeal carcinoma with immunohistochemistry (SP method). Podoplanin was used as the marker of lympgatic vessel endotheliocytes to label lympgatic vessel in 76 laryngeal carcinoma,lymphatic microvessel density were measured,and the paraneoplastic tissues was used as control group. RESULT: The positive rate of Cath-D in paraneoplastic tissue, laryngeal carcinoma and in pathology classification, in clinical stage, in cervicale lymphonode metastasis negative and positive group were significantly different. However, there had no difference between the positive rate of Cath-D in the age specific and clinical classification. c) The lymphatic microvessel density in paraneoplastic tissue, laryngeal carcinoma and clinical stage, in glottic carcinoma and supraglottic carcinoma, in cervical lymphonode metastasis negative and positive group were significantly different; but there had no difference in age-specific and pathology classification. CONCLUSION: (1) The high expression of lymphatic microvessel density and the increasing expression of Cath-D could promote cervical lymphonode metastasis in aryngeal carcinoma. (2) There had a correlation between the high expression of lymphangiogenesis and Cath-D in laryngeal carcinoma, and had cooperation in aryngeal carcinoma lymphonode metastasis. PMID- 22934431 TI - [Efficacy surgery of closed reduction of arytenoid dislocation under direct laryngoscopy]. PMID- 22934432 TI - [Clinical applications of magnifying laryngoscopy combined with nasal endoscopy on nasopharyngeal examination]. PMID- 22934433 TI - [Clinical features and efficay of epiglottidean cyst resection under microlaryngoscope]. PMID- 22934434 TI - [Bronchial foreign body of a 8-month infant: a case report]. AB - A foreign body was found in left bronchi of a 8-month infant. A fish bone of 26 mm long was pulled out with bronchoscopy under general anesthesia. This kind of surgery done in infant is more challenging than that done in child. PMID- 22934435 TI - [An animal model of obstructive sleep apnea syndrome]. AB - Obstructive sleep apnea syndrome (OSAS) is endangering human health seriously now. We had reviewed some typical animal model which had at least one OSAS character of intermittent hypoxia and/or hypercapnia, upper airway obstruction and sleep structure disorder. However, all of these models could not simulate clinical and pathological features of OSAS completely. Establishing a suitable animal model to study OSAS and related diseases is very important. PMID- 22934436 TI - [Endonasal endoscopic salvage surgical treatment for local recurrent nasopharyngeal cancer]. AB - Nasopharyngeal cancer is a low differentiated squamous cell carcinoma, and the radiation therapy is the primary choice. It's 5 year survival rate may reach 64.4%, while 10.0% cases may suffer from the local recurrence. The salvage radiation or surgery is still the main choice for recurrent cases now. However the recurrent tumor become radiation insensitive and meanwhile, morbidity and mortality become higher. The experience of open salvage surgery on the recurrent radiation insensitive tumor had been proved safely, and the related morbidity and mortality are acceptable. Recently, the endoscopic salvage surgery has been developed, some preliminary experience has been obtained and the result looks promising. In this article, the pathobiological characteristics of the postradiation local recurrent nasopharyngeal cancer, the anatomy of nasopharyngus and related skull base area, especially the petroclival region and current situation of endonasal endoscopic salvage surgery were reviewed here. Basic principle of oncological surgery that endoscopic surgery should followed and possible endoscopic surgical approaches were proposed. PMID- 22934437 TI - Monitoring of the bed time body temperature and body weight to prevent the occurrence of heat stroke in the Royal Thai Army recruits, Lopburi Province, Thailand. AB - OBJECTIVE: Heat stroke is still an important health problem in Thai army recruits. The authors aimed to evaluate a new method for preventing heat stroke in the newly army recruits during basic training in May-June 2006, by monitoring the bed time body temperature and body weight. MATERIAL AND METHOD: One thousand one hundred and fifteen recruits from five army units in Lopburi Province, Thailand were enrolled in the present study. Standardized questionnaire was used for data collection including unit information, personal information, environmental information and daily activity information. Bed time body temperature and body weight were recorded daily. Anyone who had a body temperature > 37.8 degrees C or body weight lossing > 10% in 24 h had to stop training until these indicators were normal. RESULTS: There was no incidence of heat stroke in these army units during this training period. There were 191 recruits who had a body temperature > 37.8 degrees C. The mean duration of the fever was 3.3 +/- 3.3 days. The incidence of fever was 21.4 per 100 persons month. There were 30 recruits with the body weight lossing > 10%. The duration of body weight loss was one day. Analyzed by mixed model using STATA program, there was statistically significant difference of the body temperature (p < 0.001) but not the body weight (p = 0.644) among the period of time. CONCLUSION: This monitoring of the bed time body temperature and body weight seems to be effective for the prevention of the occurrence of heat stroke because there was no case of heat stroke in the present study. However, further large-scale study with a control group should be performed. PMID- 22934438 TI - Impact of parental alcohol consumption on emotional and behavioral problems in children age 3-4 years. AB - BACKGROUND: Children of alcoholic parents have been shown to be at risk for the development of mental health, for instance a reduction in cognitive abilities and deficit in social behavior. Moreover, poor communication, under socialization, neglect, and violence are common and associated with parental drinking related stress. OBJECTIVE: To exposit the emotional and behavioral problems generated by their parents drinking behaviors. MATERIAL AND METHOD: The authors conducted a case-control study in 148 children attending the outpatient department at Phramongkutklao Hospital by using the Strength and Difficulty Questionnaire (SDQ), the children were classified into two groups which was the abnormal behavior group and normal behavior. 38 were classified as borderline groups and discarded. Subsequently, the authors used WHO screening instrument; an alcohol use disorder identification test (AUDIT) questionnaire to identify parents with hazardous and harmful patterns of alcohol consumption. The emotional and behavioral problems were compared between children whose parents had drinking problems. The authors used descriptive statistics for demographic data and Fisher Exact test for analyzing the difference between the groups of children with and without emotional and behavioral problems. To compare emotional and behavioral problems between children whose parents had alcohol drinking problems and whose parents had no drinking problem, Fisher exact test and odd ratio with 95% confidence interval were performed. RESULTS: There was no difference in demographic data. 95% of families were married, 73.6% of fathers worked for the government and only 22% had more than 12 years of education. 36% of mothers were employed as well as being housewife mothers. Birth order had statistical difference in both groups (p = 0.006). 52% were the last child and 32% were the only child. The overall emotional and behavioral problems were not statistically different (OR = 1.07, 95% CI = 0.508-2.27) from those whose parents did not have the problem. More specifically, the hyperactivity and emotional problems were not more common in children with a parental drinking problem (OR = 1.2, 95% CI = 0.4 3.4, OR = 1.17, 95% CI = 0.07-19.3, respectively). There were no differences between conduct, peer problems and pro social behaviors in children of both groups (OR = 0.85, 95% CI = 0.34-2.1, p = 0.81; OR = 0.14, 95% CI = 0.016-1.2, OR = 0.4, 95% CI = 0.14-1.17, respectively). CONCLUSION: There was no difference of emotional and behavioral problem in children between the groups of parents with and without alcohol drinking problems. The limitation of the present study was probably due to small sample size, the design of questionnaire and confounding factors which was 21% of both groups who lived in an extended family. Moreover, mothers had the major role in taking care of the children in about half of the families but the parents who had alcohol problems were fathers which was 92 percent. PMID- 22934439 TI - Malignancy in renal transplant recipients: a single-center experience in Thailand. AB - BACKGROUND: Malignancy is the second most common cause of death in renal transplant patients with functioning graft and its incidence increases with time after organ transplantation. OBJECTIVE: To present the cumulative incidence and manifestations of malignancy among renal transplant recipients in Phramongkutklao hospital between 1987 and 2009. MATERIAL AND METHOD: To retrospectively review of the transplant charts and records of 168 kidney transplant recipients from October 1, 1987 to November 15, 2009 at Phramongkutklao Hospital. The data related to malignancy were recorded. RESULTS: The cumulative incidence of malignancy was 4/168 (2.4%) recipients with a median age of 45 years (range, 8-55 years). The median time of diagnosis of malignancy after transplantation was 7.3 years (range, 0.8-10.4 years). All four patients had posttransplantation malignancy. The diagnosis was based on pathological specimens. All of them received cyclosporine, prednisolone and azathioprine or mycophenolate mofetil as immunosuppressive regimen. Two patients had native renal cell carcinoma (RCC), one had post-transplant lymphoproliferative disorder (PTLD), the other had a malignant hemangiopericytoma. Two patients (PTLD and advanced RCC cases) are alive, one patient died of malignancy (malignant hemangiopericytoma) and the other died of infection (Pseudallescheria boydii brain abscess). CONCLUSION: The incidence of malignancies in the present study was increased among renal transplant recipients compared to the general population especially renal cell carcinoma. Because of the higher risk to develop malignancy in transplant recipients, a close surveillance for early detection of malignancy is necessary in the long term follow-up. PMID- 22934440 TI - A comparative study of two-hour daytime and overnight polysomnography in high risk snorers. AB - OBJECTIVE: To compare two-hour daytime polysomnography (DPSG) and overnight polysomnography (ONPSG) (as the gold standard) in screening for high risk snorers. STUDY DESIGN: Descriptive study (diagnostic test). SETTING: Snoring Clinic, Phramongkutklao Hospital. MATERIAL AND METHOD: The present study was carried out among patients attending the Snoring clinic at Phramongkutklao hospital from September 2005 to February 2006 who had high risk of sleep apnea (pre-test) and scheduled for overnight PSG. Additionally, subjects were willing to take a two-hour daytime polysomnography. Both tests were performed less than two months apart. Each case was assessed using the Epworth sleepiness scale (ESS) > or = 8/24 and/or BMI > or = 27.5 kg/sqm as criteria to define as high risk snorer. After performing polysomnography, the subjects were categorized as high risk obstructive sleep apnea syndrome (OSAS, AHI > or = 20/hour) and low risk OSAS (AHI < 20/hour). Regarding snoring sound, subjects were divided into three groups: mild, moderate and severe. RESULTS: Fifty subjects, 33 males and 17females, were enrolled in the present study. Two males were excluded due to a daytime PSG recording less than two hours. The mean age was 48.3 +/- 10.64 years (22-65), mean BMI was 27.69 +/- 3.95 kg/sqm (22.5-36.9) and ESS 10.56 +/- 2.25/24. The mean AI and AHI for daytime PSG vs. overnight PSG were 24.31 +/- 21.36, 28.30 +/- 21.44 vs. 22.39 +/- 20.43 and 25.30 +/- 20.91 respectively. The sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of daytime PSG compared with overnight PSG were 92%, 91.3%, 92% and 91.3% respectively. The agreement of snoring during day and night (K-value) was 0.716 +/- 0.1 (p = 0.03). CONCLUSION: Sleep parameters (AI, AHI) for daytime PSG had high sensitivity, specificity, PPV and NPV compared with standard overnight PSG. These can be used as reliable screening tests for high risk snorers and also be used to assess the outcome of OSAS patients undergoing surgical intervention. PMID- 22934441 TI - Radiation-related vocal fold palsy in patients with head and neck carcinoma. AB - OBJECTIVE: Recurrent laryngeal nerve damage is a rare complication after receiving conventional radiotherapy for treatment of head and neck cancers and will always be underestimated. The purpose of the present study was to focus on the prevalence of vocal cord paralysis after irradiation and the natural history in those patients. MATERIAL AND METHOD: All patients who received more than 60 Gy radiation dose of convention radiotherapy for treatment of head and neck carcinoma from Phramongkutklao Hospital and Nation Cancer Institute of Thailand were recruited in the present study duringfollow-up period between May 2006 December 2007. The subjects had to have good mobility of bilateral vocal cords with no recurrence or persistent tumor before the enrollment. Baseline characteristic and the associated symptoms of the recurrent laryngeal nerve paralysis were recorded. Laryngeal examinations were done byfiberoptic laryngoscope and in suspicious cases; stroboscope and/or laryngeal electromyography were also performed. The vocal fold paralysis was diagnosed by reviewing recorded VDO by 2 laryngologist who were not involved in the present study. RESULTS: 70 patients; 51 male and 19female were recruited. 5 patients (7.14%) were diagnosed to have vocal cord paralysis and 2 patients (2.86%) were found to have vocal cord paresis confirmed by electromyography. Most of them were the patients with nasopharyngeal cancers (6/7) with the only one had oropharyngeal cancer (1/7). All of the paralysis/paresis was unilateral lesion; 4 on the left and 3 on the right side. The duration from the patients completed radiotherapy to the time of the diagnosis of vocal cord palsy was 14-35 months. The measure of agreement or Kappa value with 95% CI was 0.818 +/- 0.245. Associated symptoms of vocal cord palsy are hoarseness (100%), dysphagia (28.6%) and aspiration (28.6%). CONCLUSION: A significant number of vocal fold palsy may occur in patients with head and neck carcinoma after receiving conventional radiotherapy. Subcutaneous fibrosis or compromised blood vessels at the skull base or the neck area may be important risk factors for development of the complications and further studies are need to solve the pathogenesis. PMID- 22934442 TI - Switching to sertraline or venlafaxine after failure of SSRIs treatment in major depressive disorder: an economic evaluation of the STAR*D trial. AB - BACKGROUND: Switching to another antidepressant is one of the alternative treatment strategies employed in major depressive disorder (MDD) patients who have no remission despite an adequate trial of an antidepressant. The aim of the present study was to present an economic evaluation of sertraline compared with venlafaxine after unsuccessful treatment for depression with citalopram. MATERIAL AND METHOD: An economic model was constructed in line with the design of the sequenced treatment alternatives to relieve depression (STAR*D) study. MDD patients who did not have a remission with or who had an intolerance to citalopram were randomly assigned to be switched to either sertraline or venlafaxine. Patients who had no remission at the end of the switching treatment phase still continued the antidepressants and received an adjunctive treatment with aripiprazole. The event probabilities were used to derive the transitional probabilities use in the model. The primary model outcome was remission of symptoms and the secondary outcome was quality-adjusted life-years (QALYs). Incremental cost-effectiveness ratios (ICEs) were estimated for the costs per unit of effectiveness. Sensitivity analyses were done to assess the effects of model assumptions. RESULTS: The total direct costs per remission were 27,830 Baht for sertraline and 30,147 Baht for venlafaxine. Sertraline had lower total costs per QALY than venlafaxine (34,788 Baht vs. 37,683 Baht). The more cost effectiveness of sertraline resulted in 7.68% of cost saving. The incremental cost of venlafaxine compared with sertraline was 2,316 Baht per remission gained and 2895 Baht per QALY gained. By varying the remission rate of venlafaxine from 20% to 40%, the sensitivity analysis results in a decrease in total costs of venlafaxine from 31,926 Baht to 24,808 Baht. In addition, incremental cost per remission gained changed from 4096 Baht in favour of sertraline to 3023 Baht in favour of venlafaxine. Similarly, incremental cost per QALY gained changedfrom in favour of sertraline to in favour of venlafaxine. CONCLUSION: Based on the STAR*D trial, the results of the economic study indicate that a switch to sertraline is a cost-effectiveness treatment option compared with a switch to venlafaxine in MDD patients who have no remission or cannot tolerate citalopram. PMID- 22934443 TI - Human papillomavirus infection following radiation therapy or concurrent chemoradiation for invasive cervical cancer. AB - OBJECTIVE: To determine the prevalence of Human Papillomavirus (HPV) infection in patients with invasive cervical cancer after treatment by concurrent chemoradiation therapy. MATERIAL AND METHOD: Cervicovaginal mucous samples were collected from fifty-five patients with invasive cervical cancer two months after treatment completion and tested for HPV genotypes. RESULTS: Of the 55 patients, 31 (56.36%) were found to be positive for HPV among these 25 (45.46%) were positive for high-risk HPV. The most common high-risk HPV found was type 16 which accounted for 35.48% (11/31) of cases. Other high-risk HPV found were types 18 (16.13%), 52 (16.13%) and 58 (12.90%). Follow-up time for patients were 3 to 22 months with mean follow-up of 13 months. In patients positive for high-risk HPV 24.00% (6/25) were found to have persistent or recurrent disease. While 30 patients negative for high-risk HPV 3.33% (1/30) were found to have persistent or recurrent disease. CONCLUSION: The prevalence of HPV infection in cervical cancer patients with positive high-risk HPV after treatment by radiation or concurrent chemoradiation seems to be a risk factor for persistent and recurrent disease. Testing for high-risk HPV may be a useful modality for follow-up of these patients. PMID- 22934444 TI - Prevalence and risk factors of dyspepsia in Thai schoolchildren. AB - BACKGROUND AND OBJECTIVE: Dyspepsia is a common form of chronic abdominal pain in children and adolescents. Although it is usually functional or non-organic in origin, it disturbs daily activities, school attendance and the child's wellbeing. The authors evaluated prevalence and factors associated with dyspepsia among schoolchildren by comparing life-style of dyspeptic children with their asymptomatic peers. MATERIAL AND METHOD: Total 1181 schoolchildren (mean age 14.7 +/- 1.8 years) were recruited from three schools in Bangkok. Data on dyspeptic symptoms were collected by using a questionnaire based on Rome III classification system. Potential precipitating factors for dyspepsia and life-style related to dyspepsia were also explored in the questionnaire. RESULTS: Dyspepsia was reported in 24.0% of the subjects. Prevalence was significantly higher in girls than in boys (27.0% vs. 20.0% p = 0.006). There was no difference between the comparison groups in terms of school test scores, past medical illness, parental marital status, parental income, number of siblings,frequency of stool and spicy food, carbonated beverage or dairy product consumption. The dyspepsia group had higher percentage of family history of peptic ulcer (odds ratio [OR] = 2.5 [95% CI = 1.7 to 3.7]), history of taking medicine (OR 1.7 [1 .0 to 2.9]), alcohol consumption (OR 2.4 [1.0 to 5.7]), severe stress (OR = 3.4 [1.2 to 9.9]) and extreme stress (OR = 3.9 [1.3 to 12.0]). CONCLUSION: Prevalence of self-reported dyspepsia among schoolchildren in this survey was similar to those previously reported; with family history of peptic ulcer, history of taking medicine, alcohol consumption, stresses in life as potential risk factors. PMID- 22934445 TI - Associated factors of blood pressure control and complications of hypertension in hypertensive rural Thai populations of Baan Nayao, Chachoengsao Province. AB - OBJECTIVE: To assess associated factors of uncontrolled blood pressure and complications of hypertension in hypertensive rural Thai populations. MATERIAL AND METHOD: A cross-sectional study was conducted in hypertensive rural Thai people aged > or =35 years-old in Baan Nayao, Chachoengsao Province, Thailand. Blood pressure (BP) was measured and questionnaires were answered. After 12-hr fasting, blood samples were taken for determining plasma glucose, lipid profiles and serum creatinine. Morning urine samples were collected for microalbuminuria testing and electrocardiography (ECG) was performed to detect left ventricular hypertrophy (LVH). RESULTS: Of the 289 participants (97 males and 192 females) mean duration of hypertension was 4.29 +/- 4.95 years and 61.5% did not achieve target BP control. Among participants who had ECG performed and urine sample investigation, 15.7% demonstrated LVH and 25.3% had microalbuminuria. In uncontrolled BP participants, 20% had LVH and 24.8% had microalbuminuria whereas in controlled BP participants, 7.8% had LVH and 26.1% had microalbuminuria. Uncontrolled BP was associated with males, dyslipidemia, diabetes, abdominal obesity, metabolic syndrome, always having salty food and salts added for seasoning. The independent risks of uncontrolled BP were hypertensive male (OR = 2.48, 95% CI = 1.07-5.76) and metabolic syndrome (OR = 2.59, 95% CI = 1.24-5.40). Males were also at risk for LVH (OR = 2.86, 95% CI = 1.31-6.23) and history of lipid disorders was a risk of microalbuminuria (OR = 3.13, 95% CI = 1.47-6.67). CONCLUSION: Males and metabolic syndrome were independently associated with uncontrolled BP in hypertensive participants. Males had more risk than females to develop LVH and having history of lipid disorders lead to microalbuminuria occurrence. Thus, life style modification may prove beneficial to these rural hypertensive participants. PMID- 22934446 TI - Clinical efficacy of pioglitazone: generic vs. original product. AB - BACKGROUND: Pioglitazone, an oral antidiabetic agent in the class of thiazolidinediones (TZDs), was widely used in the case of insulin tolerance as it provided more benefit to patients with type 2 diabetes. However, the original product is costly while some generic products are available at the substantial lower cost in Thailand. The objective of the present study was to assess bioequivalence in terms of efficacy between generic and original pioglitazone products. MATERIAL AND METHOD: A randomized double blind, crossover controlled trial was performed on 60 patients with type 2 diabetes at the Endocrine Unit, Department of Medicine, Phramongkutklao Hospital, Thailand. All subjects were randomly selected for group A and B (30 volunteers in each group). Duration of observation for efficacy of treatment with pioglitazone (both generic and original products) was totally 24 weeks. The dose of pioglitazone was 15 mg once daily. RESULTS: Finally, 22 males and 37 females remained in the trial. The reduction in means of HbA1c in group A and group B were 0.7% and 0.6% respectively. The least squares means of the HbA1c reduction of the generic and original group were 0.75% and 0.79%, respectively. There was no significant difference in HbA1c reduction between both groups. The average equality of HbA1c in all subjects in both groups was 100.7% (87.9-113.5%) at 90% confidence interval. CONCLUSION: These findings indicated that both formulations were bioequivalent as their efficacy or therapeutic effects in reduction ofHbA1c in the type 2 diabetic subjects were statistically the same. PMID- 22934447 TI - Prevalence of allergic rhinitis and types of sensitized allergen in adult at Wat Intaram community, Hua Raeu, Phra Nakhon Si Ayutthaya District, Phra Nakhon Si Ayutthaya Province, Thailand. AB - Allergic rhinitis is a common problem in many countries. The incidence of Allergic rhinitis is about 10-25% of the population and increasing worldwide especially in large cities where air pollution is the main problem causing respiratory illness. In Thailand, the surveys of allergic rhinitis on children were found about 13-44% while the prevalence of allergic rhinitis in Thai adults was as high as 20%. The information of the prevalence of allergic rhinitis in the suburban area has not been continuously done especially in the adult population. OBJECTIVE: To present study the prevalence of allergic rhinitis and other atopic diseases and to determine the aeroallergen sensitivity of allergic patients in suburban area. MATERIAL AND METHOD: Observational descriptive cross-sectional study as one-stage cluster sampling, Using ISAAC questionnaires interviewed adults at War Intaram community, Hua Raeu, Phra Nakhon Si Ayutthaya District, Phra Nakhon Si Ayutthaya Province, Thailand during September-October 2008. Participants who had allergic rhinitis symptoms described in the questionnaires were enrolled to perform the skin prick test voluntary to determine the aeroallergen sensitivity. RESULTS: There were 324 subjects, female 64.8% and male 35.2%. Age ranges between 20-66 years old (mean 42.2). The prevalence of allergic rhinitis, asthma and chronic pruritic rash were 37.7%, 16%, 21.3% and history of allergic rhinitis, asthma and chronic pruritic rash within 12 months were 32.1%, 10.5%, 17.3%. The sensitized allergen was mixed mite (62.2%), mixed cockroach (61.1%), house dust (48.9%), cat (37.8%), Johnson glass (30.0%), dog (20.0%), careless weed (20.0%), mixed mold (12.2%), cotton (7.8%) and feather (6.7%). CONCLUSION: The present study revealed that the prevalence of allergic rhinitis and atopic diseases has been increasing in number when compared with previous reports. The most common sensitized allergen was Mite mix, similar to other studies, but mixed cockroach was found significantly higher. PMID- 22934448 TI - Prevalence of tonsillectomy and adenoidectomy complication at Phramongkutklao Hospital. AB - Tonsillectomy and adenoidectomy, one of the major procedures among otolaryngologist, may have risk in post operative complications which can be either non severe complications (dysphagia, wound pain, dehydration) or serious complications (Bleeding, partial airway obstruction). Meticulous attention to surgical techniques and technical advance in anesthesiology have significantly reduced the number of complications. In Thailand, there are few reports about the adenotonsillectomy complications so the objectives of the present study were to determine the prevalence and related risk factors in patients visiting the department of Otolaryngology, Phramongkutklao Hospital. OBJECTIVE: To determine the prevalence ofcomplications and related risk factors in patients who underwent adenotonsillectomy in Phramongkutklao Hospital. MATERIAL AND METHOD: The patients who had undergone adenotonsillectomy from January 2003 to December 2006 in the department of Otolaryngology, Phramongkutklao Hospital was retrospectively and prospectively reviewed. Information extracted included age, tonsillar size, indication for surgery, the post operative complications (anesthetic complication, primary bleeding, secondary bleeding, airway obstruction, dysphagia, wound pain, dehydration, length of stay in hospital and re-admission. RESULTS: Four hundred and eighty-one patients were enrolled, of which 36.8% were younger than 12 years-old and 63.2% were over 12 years-old; 39.3% male and 60.7% female. Indication for surgery provided by chronic hypertrophic tonsillitis 73%, obstructive sleep apnea 23.5%, peritonsillar abscess and others 3.5%. The prevalence of complications was anesthetic complication 1.6%, primary bleeding 4.1%, secondary bleeding 3.9%, dysphagia 29.0%, dehydration 4.6%, wound pain 48.1%. The average length of hospital stay was 3.6 days and re-admission 3.7%. CONCLUSION: The prevalence of post operative complication after tonsillectomy and adenoidectomy was low but higher than other previous studies included the primary bleeding and secondary bleeding. PMID- 22934449 TI - The assessment of retinal nerve fiber layer thickness changing after glaucoma surgery by optical coherence tomography, Phramongkutklao Hospial. AB - OBJECTIVE: To assess retinal nerve fiber (RNFL) thickness change in glaucoma patients after glaucoma surgery. MATERIAL AND METHOD: A prospective and cohort study of 19 patients who underwent trabeculectomy with mitomicin C or combined procedures or glaucoma drainage device surgery in Phramongkutklao Hospital were included. All subjects had obtained informed consents. Preoperative and 3 month postoperative IOP and RNFL thickness were determined. Areas of peripapilllary RNFL thickness were evaluated by Stratus OCT scanning. The relationship between IOP reduction and RNFL thickness change after glaucoma surgery was analyzed. RESULTS: Postoperative RNFL thickness analysis found no significant increase in inferior, superior, nasal and temporal quadrants. The average of preoperative RNFL thickness was 59.58 +/- 17.59 microns, whereas the average of postoperative RNFL thickness was 57.19 +/- 14.97 microns (p = 0.426). Postoperative IOP was decreased significantly from 29.26 +/- 8.58 mmHg to 12.11 +/- 4.52 mmHq (p < 0.001). The mean of postoperative RNFL thickness was not significantly correlated with IOP reduction (r = 0.306, p = 0.250). CONCLUSION: Post glaucoma surgery, RNFL thickness was not significantly increased although the IOP had significantly reduced. No correlation between IOP reduction and RNFL thickness was found. PMID- 22934450 TI - Serosurveillance of varicella and hepatitis B infection after reported cases in medical students and the relationship between past varicella disease history and immunity status. AB - OBJECTIVE: To identify seroprevalence of varicella and the relationship with their histories of experiences of varicella diseases and to provide appropriate immunization against varicella, mumps, measles, rubella and hepatitis B to medical students. MATERIAL AND METHOD: All of the medical students were eligible for participation after informed consents. Immunization history against varicella, mumps, measles, rubella (MMR) and hepatitis B were obtained from a questionnaire. A blood sample was obtained from each student for IgG antibody against VZV by ELISA. Medical students with an uncertain history or no documentation of hepatitis B vaccination were tested for HBsAg and anti-HBcIgG by ELISA. RESULTS: There were 383 medical students enrolled. The mean age at enrollment was 21.6 years (median 21.4 years; range 18-25.8 years). Of 383 medical students, 372 (97.2%) had documents of receiving MMR immunizations. The blood samples were obtained from 374 of 383 (97.6%) medical students to identify the immunity against varicella zoster virus (VZV) and the seroprevalence rate was 92%. Using VZVIgG antibody detection as a standard test, history of experience of varicella disease provided positive predictive value of 99.3% (148/149). Of 383 medical students, 277 (72.3%) were tested for hepatitis B markers and 243 (87.7%) students showed negative results. The prevalence of HBsAg carriers was 0.01% (4/383). CONCLUSION: Suboptimal immunities against vaccine preventable diseases could be demonstrated in the medical students including varicella and hepatitis B. New recommendations of immunizations against varicella, MMR and hepatitis B viruses for a particular group of the population were provided. PMID- 22934451 TI - Identification of patients with high-risk for pulmonary metastases after curative resection of colorectal cancer. AB - BACKGROUND: The presence of distant metastases from colorectal cancer (CRC) does not preclude curative treatment. Early detection of pulmonary metastases at a potentially curable stage could improve survival. The aim of the present study was to assess the prognostic significance of commonly reported clinicopathologic features to identify high-risk patients who would likely benefit from more intensive chest surveillance for pulmonary metastases. MATERIAL AND METHOD: A total of 351 consecutive patients, with surgical stages I-III colorectal cancer, who underwent curative resection at Phramongkutklao hospital from 1999 to 2005, were followed regularly according to the established guidelines with routine physical examination, serum carcinoembryonic antigen (CEA) and colonoscopic surveillance. Imaging studies for detecting metastases were computed tomography (CT), plain film radiography, and ultrasonograpy. Clinical and pathologic features were analyzed for their association with pulmonary metastasis. RESULTS: There were 145 patients who had been operated for longer than five years after curative intent surgery. Of these, nineteen patients were lost to follow-up or died from other causes that were unrelated to colorectal cancer. Pulmonary metastases were detected in 26 patients by either CXR or CT scan. Median time to pulmonary metastasis was 19 months (95 percent CI, 12-35). According to an univariate analysis, with log-rank test, identified four factors associated with pulmonary metastasis: Tumor stage T4, Nodal stage N2, elevation of serum CEA > 3.4 ng/ml and presence of lymphovascular invasion(LVI). According to a multivariate analysis, with Cox regression, found an elevation of serum CEA > 3.4 ng/ml which was an independent factor that was significantly associated with pulmonary metastasis (Hazard ratio (HR), 8.9; 95 percent CI, 3.6-22; p < 0.01). The present study revealed that 50 percent of patients who had more than one of these risk factors would eventually develop pulmonary metastases. CONCLUSION: An elevation of serum CEA > or = 3.4 ng/ml was found as an independent factor that was significantly associated with pulmonary metastasis whereas tumor stage T4, nodal stage N2 and presence of lymphovascular invasion (LVI) were not independent clinicopathologic features associated with subsequent pulmonary metastases. Chest CT scan has greater sensitivity than chest radiography in detection of pulmonary metastasis and should be considered as an imaging study of choice for intensive chest surveillance for patients who had more than one of these risk factors. PMID- 22934452 TI - Triple immunosuppressive therapy can accelerate the recovery of antibody-mediated pure red cell aplasia and allow successful concurrent resumption of erythropoietin. AB - Antibody (Ab)-mediated pure red cell aplasia (PRCA) is a rare hematologic disorder. For the first time here, the authors report the use of combination therapy which consists of mycophenolate mofetil 500-1000 mg/day, intravenous cyclophosphamide 600 mg monthly and monthly intravenous methylprednisolone 1 gm/day for 2 days followed by oral prednisolone 10 mg/day. A 62-year-old woman developed Ab-mediated PRCA after using subcutaneous erythropoietin-beta 3000 U weekly for 14 months at the predialysis stage. Ab-mediated PRCA was diagnosed based on (1) the transfusion need of more than 1 unit/wk to keep hemoglobin level stable, (2) corrected reticulocyte count 0.36% and (3) < 5% erythroblasts with normal myeloid cells and megakaryocytes in bone marrow biopsy. Serum assay confirmed the anti-erythropoietin antibody of 230 ng/mL. The patient recovered from PRCA after the triple immunosuppressive therapy for 3 months. The rapid recovery occurred despite the fact that the patient was receiving intravenous erythropoietin-alpha while having the antibody in the serum. The present case describes the acceleration of the recovery and successful resumption of erythropoietin concurrently despite the positive serum anti-erythropoietin antibody. PMID- 22934453 TI - The average collective equivalent dose and fatal cancer risk for radiation workers in Radiology Department at Phramongkutklao Hospital, 2004-2008. AB - OBJECTIVE: To evaluate the five years average equivalent dose, the average collective equivalent dose and fatal cancer risk for the radiation workers in Radiology Department at Phramongkutklao Hospital. MATERIAL AND METHOD: In the Radiology Department at Phramongkutklao Hospital, occupationally exposed workers are measured by the Division of Radiation Protection Services, Department of Medical Sciences which measures radiation exposures and evaluated doses from external exposures. Individual's doses of external exposure were monitored using film badges. The present study design describes a retrospective survey of occupational exposure in the Radiology Department at Phramongkutklao Hospital 2004-2008. RESULTS: The distribution of radiation workers monitored according to the groups in the years 2004-2008, physicist, technologist and assistant of technologist were the most numerous occupational group (51.13%). Nurse, assistant of nurse and nurse aids constituted 22.73%. About 59.73% of radiation workers in the Radiology Department at Phramongkutklao Hospital received an annual average equivalent dose below 0.02 mSv which defined as recording level and no radiation workers received doses above the International Commission on Radiological Protection (ICRP) Publication 60 recommended dose limit (20 mSv per year). The five years average equivalent dose per radiation worker was 1.098 mSv. Of all occupational groups measurably exposed, the nuclear medicine group received the highest of the five years average equivalent dose, collective equivalent dose and fatal cancer risk. The five years average equivalent dose, collective equivalent dose and fatal cancer risk for the physicist, technologist and assistant of technologist were the highest. CONCLUSION: Total risk per the whole monitored radiation workers were 3.86 x lW due to receive the five years average collective equivalent dose 0.096 man Sv. These values were estimated from a very small of number of radiation workers. PMID- 22934454 TI - Efficacy of plant essential oils for the repellents against chiggers (Leptotrombidium imphalum) vector of scrub typhus. AB - Scrub typhus caused by the Orientia tsutsugamushi. Rodents, particularly rats, serve as principal reservoir hosts. Infection in man is transmitted by the, chigger bite. Repellents provide an effective agent of protecting individuals from chigger. In the present study 6 plant essential oils were tested for evaluation of their repellent activity against the chigger, Leptotrombidium imphalum. The results showed that Clove oil was significantly more effective than others with ED50 and EC50 of 0.420 mg and 2.3%, followed by Zingiber oil (8.458 mg and 42.3%), Vetiver oil (19.582 mg and 97.9%), Turmeric oil (24.343 mg and 121.7%), Orange oil (27.310 mg and 136.6%) and Boesenbergia oil (30.486 mg and 152.4%). These results suggested that Clove oil was the most efficient repellent against chigger which is the vector for scrub typhus. PMID- 22934455 TI - Assessment of different wetting time and paper strip size of Schirmer test in dry eye patients. AB - OBJECTIVE: To evaluate the correlation between different wetting time and paper strip size of Schirmer test with anesthesia in dry eye patient. Finally the authors determined the agreement on using the ocular surface disease index (OSDI), index for evaluate the severity of the dry eye patient, compare to the standard Schirmer test with anesthesia. MATERIAL AND METHOD: A prospective study was performed in 140 eyes of 70 subjects. All subjects had symptoms of dry eye syndrome which was confirmed by Schirmer test with anesthesia before inclusion. The correlation between Schirmer test with anesthesia at 1, 2, 3 and 4 minutes and standard 5-minute test of both 3 mm and 5 mm width of paper strip was evaluated using intraclass correlation coefficient (ICC). The correlation between clinical questions and Schirmer test was documented in Kappa value. RESULTS: The ICCs were higher than 0.8 after 2 minutes in both 3-mm and 5-mm width of paper strip. Furthermore, it indicated that cut-off value for diagnosis of severe dry eye was 2.5 mm for 5-mm width of paper strip and 4.25 mm for 3-mm width of paper strip at 2-minute measurement. The association between data from the OSDI and objective data from Schirmer test were analyzed by Kappa statistic and showed poor agreement beyond chance (p = 0.591). CONCLUSION: Our results suggested that shorter wetting time of 2-minute Schirmer test with anesthesia could be used instead of the standard 5-minute test. The authors found that the 3-mm width of paper strip could be used instead of the standard 5-mm width of paper strip as well. PMID- 22934456 TI - Tonsillectomy with uvulopalatopharyngoplasty and tongue base surgery for treatment of obstructive sleep apnea. AB - OBJECTIVE: The present study aimed to evaluate the efficacy of tonsillectomy with UPPP and tongue base surgery in the treatment of moderate to severe OSA. STUDY DESIGN: The present study employed a cross sectional design among 18 OSA patients undergoing surgery by a single surgeon from 2005 to 2009. The follow-up period was 25 to 37 months. Data included BMI, ESS and full night PSG recorded to compare pre- and post-operation. RESULTS: In all, 14 of 18 patients (77.8%) carried out the reduction of AHI 50% or lower than 20, postoperatively, defined as the success group. Mean ESS was decreased from 11.11 to 4.77 (p < 0.001). Most patients were satisfied with their postoperative results and reduction of subjective symptoms. CONCLUSION: A combined surgery in moderate and severe OSA had a surgical success rate of 77.8% in short and long term pos-toperation. PMID- 22934457 TI - Cytokine profiles in HIV-1 subtype CRF01_AE infected individuals with different rates of diseases progression: a multiplex immunoassay. AB - OBJECTIVE: Cytokines play an important role in controlling the homeostasis of the immune system and contribute to the pathogenesis of HIV infection. The measurement soluble cytokines in plasma of HIV-1 infected individuals with different rates of disease progression may provide additional information to complement prognostic markers and understand disease process. The aim of the present study was to determine the cytokine profiles in plasma of Thai HIV-1 CRFO1_AE infected individuals with different rates of disease progression by using a multiplex system for simultaneous detection of 7 cytokines. MATERIAL AND METHOD: The authors used a multiplex immunoassay method to measure 7 cytokines (IL-2, IL-4, IL-6, IL-7, IL-10, IL-15 and IFN-gamma) in plasma of 23 progressors (PRs; symptomatic or AIDS within 5 years and CD4+ < 200/mm3), 23 slower progressors (SPs; asymptomatic more than 5 years and CD4+ > 350/mm3) and 23 normal healthy individuals. RESULTS: Both PRs and SPs demonstrated significantly higher levels of IL-7, IL-10 and IFN-gamma than healthy controls (p < 0.05). No significant difference in IL-6 between SPs and healthy controls but significant difference between RPs and controls were found. Furthermore, PRs showed significantly higher levels of plasma IL-6 (p = 0.001), IL-7 (p = 0.016), IL-10 (p < 0.001) and IFN-gamma (p = 0.026) than SPs. No significant difference in IL 2, IL-4 and IL-15 was found among 3 groups (PRs, SPs and healthy control). CONCLUSION: These results suggested that a Th1 to Th2 cytokine switch did not occur. However, the measurements of plasma levels of cytokines could be used for predicting disease progression. PMID- 22934458 TI - Prevalence and hematological parameters of thalassemia in Tha Kradarn subdistrict Chachoengsao Province, Thailand. AB - OBJECTIVE: To determine the prevalence, molecular characteristics and hematological study of thalassemia in Tha Kradarn Subdistrict Chachoengsao Province. MATERIAL AND METHOD: The present study population consisted of266 participants from Moo 19 Baan Na-Ngam, Chachoengsao Province, Thailand. After blood collection, all samples were screened for thalassemia by initial screening with the OF and DCIP tests and additional testing by CBC, RBC indices, hemoglobin typing and determination of Hb A2 and Hb E. All common alpha-thalassemia mutations were determined using the PCR with allele specific primers and Gap PCR for common deletions. RESULTS: The prevalence of alpha-thal 1, alpha-thal 2 and beta-thal were found as 2.72%, 11.26% and 0.97%, respectively. Regarding the abnormal hemoglobins, the prevalence of Hb E, Hb Constant Spring and Hb Pakse was 38.45%, 3.69% and 0.78%, respectively. MCV and MCH were significantly different between P-thalassemia as well as a-thal 1 carriers and normal subjects. In all alpha-thal 1 traits, it was found that the MCV and MCH were less than 75 fL and 25 pg, therefore, these parameters can be used for alpha-thal 1 screening. CONCLUSION: In the present study, the prevalence of thalassemia was similar to previous studies. Moreover, using the combination of OF and DCIP tests compared with MCV, MCH and DCIP tests for the initial thalassemia screening, it was found that the OF and DCIP tests gave more false positive results, which increased the need for further Hb typing. Hence, the MCV and MCH combined with DCIP tests provide cost minimization and practical for a large population-based screening program. PMID- 22934459 TI - Study of curcumin on microvasculature characteristic in diabetic rat's liver as revealed by vascular corrosion cast/scanning electron microscope (SEM) technique. AB - OBJECTIVE: To investigate the effect of curcumin on the structural change ofmicrovasculature in STZ-induced diabetic rat' liver. MATERIAL AND METHOD: Diabetic rats were induced by streptozotocin (60 mg/kg BW). Male rats were divided into thre groups, control (C), diabetic (DM) and diabetic rats treated with curcumin (DMC) (200 mg/kg BW). After 8 weeks o experiments, blood vessels of rat's liver were studied under conventional light microscope (LM) and vascular corrosion cas technique with scanning electron microscope (SEM). RESULTS: LM observation demonstrated that there were pathology and destruction of liver tissues and microvasculature in diabetic animals. The sinusoids around central veins were dilated and filled with red blood cells. There was an accumulation of lipid droplets in the cytoplasm of hepatocytes and hepatocyte nuclei showed pathological sign of pyknosis. Moreover, the inflammation change of liver tissues revealed the infiltration of lymphocytes and increasing of collagen deposition in the area of portal triad. In curcumin-treated rats, the distinguished recovery of liver tissues showed regained normal pattern of central veins, sinusoids, hepatocytes and portal triad, when compared with liver tissues of control group. By using vascular corrosion casting with SEM, the liver blood vessels of DM group revealed higher and expanded sizes, compared with control group; proximal parts of portal veins (C = 577.75 +/- 126.23, DM = 892 +/- 35.79, DMC = 469.5 +/- 8553 microm), distal parts of portal veins (C = 76.72 +/- 1.48, DM = 200 +/- 31.05, DMC = 76.38 +/- 2.98 microm) and venules (C = 27.03 +/- 0.55, DM = 45.15 +/- 5.03, DMC = 28.38 +/- 3.67 microm) and corresponding to increased blood volumes compared with control group; proximal parts of portal veins (C = 20.8 +/- 1.28, DM = 62.2 +/- 3.39, DMC = 14.9 +/- 0.67 microm3), distal parts of portal veins (C = 0.46 +/- 0.03, DM = 3.81 +/- 0.18, DMC = 0.41 +/- 0.05 microm3) and venules (C = 0.05 +/- 0.05, DM = 0.24 +/- 0.013, DMC = 0.05 +/- 0.05 microm3) respectively. Fascinatingly, liver microvasculature in curcumin treated group developed into regenerate and repair into healthy and normal characteristics. CONCLUSION: Efficiency of curcumin treatment beneficially repaired and regenerated liver tissues of diabetic groups and also redeveloped the liver's microvascular complications. These results optimistically demonstrated the potential use of curcumin as a novel therapeutic agent in liver pathology of diabetic rats. PMID- 22934460 TI - Comparision of overweight and obesity in medical cadets before and after 6 months studying at Phramongkutklao College. AB - OBJECTIVE: To evaluate prevalence of overweight and obesity in second-year medical cadets and to determine risk behaviors before and after 6 months studying at Phramongkutklao College of Medicine (PCM). MATERIAL AMD METHOD: Data on self report behavioral questionnaires was collected from 92 medical cadets before and after 6 months studying at PCM in 2008. Body weight, height, waist circumference, blood pressure and body fat were measured according to standard protocols. RESULTS: Overall, prevalence of overweight and obese medical cadets before studying at PCM was 16.30% and 15.22% according to BMI and 27.17% and 15.22% by percent body fat. After 6 months of study, overall mean of body fat and systolic blood pressure were significantly reduced. For males, the mean of weight, BMI and waist circumference were reduced significantly. In contrast, the mean of body weight and BMI of females were significantly increased. The prevalence of overweight in total participants determined by body fat was significantly reduced from 27.17% to 15.22%. Determination by BMI, obesity was significantly reduced from 34.29% to 14.29% only in males. Behaviors that were found to be significantly increased (p < 0.001) were regular physical activity, night eating, sugar-sweet beverage consumption, amount and frequency of coffee or tea consumption. Significant decrease in time of watching TV or using a computer, and duration of sleep was also determined. CONCLUSION: The present study indicated that overweight, obesity, waist circumference and body fat of medical cadets were decreased after study at PCM which is possibly due to increasing exercise. Nevertheless, behavioral risks for obesity were also increasing, therefore, it might result in increased the prevalence of obesity in the future. PMID- 22934461 TI - Predicting fluid responsiveness in septic shock patients by using 3 dynamic indices: is it all equally effective? AB - OBJECTIVE: To evaluate the effectiveness and accuracy of three dynamic indices, currently available in intensive care monitoring devices, which are pulse pressure variation (PPV), stroke volume variation (SVV) and pulse oximetry plethysmographic waveform variation (POPV) in septic patients. MATERIAL AND METHOD: This prospective clinical trial was conducted in 20 deeply sedated septic patients 18 years of age and older who had invasive blood pressure monitoring with an intraarterial cannula. PPV, SVV and POPV (%) were calculated using five consecutive snapshots from every patient's monitor. Statistical analysis compared using linear regression, paired t-test or student t-test, and receiver operating characteristic (ROC) curve analysis. RESULTS: The authors found that, strong correlation existed of PPV for the detection of percent cardiac index change (r2 = 0.794, p < 0.001). A respiratory variation in POPV exceeding 14% (sensitivity of 72%, specificity of 90%), SVV exceeding 11% (sensitivity 90%, specificity 92%) allowed detection of PPV exceeding 12% (sensitivity 84%, specificity 96%). CONCLUSION: Comparing of PPV, SVV and POPV, PPV is the most correlate with percent change in cardiac index and the most effective dynamic index for predict fluid responsiveness in adult septic critically ill patients who are on controlled mechanical ventilator, followed by SVV and POPV. PMID- 22934462 TI - Comparing the effect between oral and injection form of carnitine on skin flap survival in rats. AB - BACKGROUND: Carnitine is an endogenous cofactor, having a regulatory action on the energy flow from different oxidative sources. Carnitine has been used for ischemic conditions such as coronary heart diseases, peripheral vascular diseases with satisfactory results. So ischemic skin flaps should obtain benefit from carnitine. OBJECTIVE: To determine the effect of oral and injection form of carnitine on skin flap survival in a rat model. MATERIAL AND METHOD: Twenty-one Sprague-Dawley rats were divided into 3 groups, each group had 7 rats; a control group and two carnitine-treated groups. Random skin flap was elevated on the backs of the rats. The control group was not given any pharmacologic agent. Two treated groups, group 1 received carnitine orally (150 mg/kg/day) for 3 days before flap elevation and continuing to 1 week after the procedure, Group 2 received carnitine intraperitoneally (100 mg/kg/day) for 1 week after flap elevation. The surface area of flap survival was measured in each group. RESULTS: The median areas of flap survival of the control groups and two carnitine treated groups were 65.89%, 69.03%, 77.47%, respectively. There was significant improvement of flaps survival in carnitine-treated groups, especially carnitine injected group was found to be significantly higher than the control group and carnitine-oral group (p < 0.05). The carnitine-oral group could slightly increase flap survival compared to the control group but was not statistically significant. CONCLUSION: Effect of carnitine has increased flap survival in random skin flap. Carnitine injection form is more effective than the oral one. PMID- 22934463 TI - Causes and attitude of husbands toward thalassemic carrier screening test when their partners have abnormal screening tests. AB - OBJECTIVE: To assess the attitude of husbands toward the thalassemic carrier screening test and to explore the causes of non-participation of having a blood test. STUDY DESIGN: Descriptive study. MATERIAL AND METHOD: During 2007-2008, 100 husbands of pregnant women with screening-positive test for thalassemia who refused to have blood test were enrolled by voluntariness. They would fill out a structured questionnaire designed for the present study which was divided into 3 parts; (1) participant's personal characteristics (2) their attitudes toward thalassemic carrier screening test with the score ranging from 1-5, and (3) reasons for their refusal of having a blood test. RESULTS: The husbands had a favorable attitude toward testing for thalassemia, with overall mean score and standard deviation of 3.57 and 0.38. Commonly expressed reasons against testing were the self-belief of having a non-affected child and the inconvenience of coming to the hospital. CONCLUSION: Husbands had a favorable attitude toward test for thalassemia. PMID- 22934465 TI - Pullout button suture for the treatment of type IV avulsion of the flexor digitorum profundus tendon: case report. AB - A variety of surgical treatment methods for an avulsion of the flexor digitorum profundus (FDP) from its insertion and simultaneous fracture of the volar base of the distal phalanx, the so-called type IV FDP avulsion had been reported. The need to simultaneously reattach the FDP tendon and fixate the avulsed bony fragment makes the treatment of this injury challenging. The authors described a surgical technique of repair using a pullout suture tied over an external dorsal button without the need for retained hardware. PMID- 22934464 TI - Isometric tubular vacuolization in renal transplant recipient: the first case report in Thailand. AB - Cyclosporine can cause acute and chronic nephrotoxicity. Renal biopsy is a reliable tool for the diagnosis of cyclosporine nephrotoxicity. The authors report a 56-year-old Thai female with a history of end-stage renal disease who underwent cadaveric renal transplantation. A transplanted kidney biopsy was performed on day 9 post-transplant to identify the cause of delayed graft function. Light and electron microscopic findings revealed widespread (> 50% involvement) numerous tubules filled with uniformly-sized vacuoles in cytoplasm (isometric vacuolization). Serum cyclosporine trough level was 534 ng/mL. Neither acute rejection nor acute tubular necrosis was seen. Diagnosis of acute cyclosporine nephrotoxicity was made. Isometric vacuolization in more than 50% involvement of the tubules is rare (3%) in biopsy specimens. The tubular isometric vacuolization might not have the strong impact to the long term graft outcome. This is the first case report of isometric tubular vacuolization due to cyclosporine toxicity in renal transplant recipient in Thailand. PMID- 22934466 TI - Rapunzel syndrome in a Thai girl with an asymptomatic abdominal mass: a case report. AB - Rapunzel syndrome is an uncommon form of trichobezoar (a collection of ingested hair in the stomach that fails to pass through the intestine) with an extension of hair into the small bowel. The authors report in the present article a case of Rapunzel syndrome in a 10-year-old Thai girl with an asymptomatic abdominal mass incidentally detected during a hospital visit. She did not have nausea, vomiting, abdominal pain, weight loss, or any other symptoms. A movable, firm and smooth epigastric mass 10 x 12 cm in size was found upon examination. Eventually the trichobezoar mass was surgically removed after a failed endoscopic removal. PMID- 22934467 TI - Outcome of Kasabach-Merritt phenomenon: the role of vincristine as monotherapy: report of a case. AB - Kasabach-Merrit phenomenon (KMP) is a rare disorder of pediatric hematological malignancies which is previously referred to Kasabach-Merrit syndrome (KMS). The disorder is characterized by prominent vascular mass resulting from abnormal proliferation of blood vessels, consumption coagulopathy and thrombocytopenia. The diagnosis is based upon three basic findings as above. The authors describe a 6-month-old girl with a huge ecchymotic mass at left buttock who is found to have thrombocytopenia and consumption coagulopathy. The clinical and imaging studies strongly suggested the diagnosis of KMP. Vincristine was administered after a trial of corticosteroids was failed to show clinical and laboratory improvement. After 2 weeks, the patient showed that the platelet count and fibrinogen level become to be normal without blood transfusion and gradually decreased in tumor size without any surgical procedure in 4 weeks and disappeared in 5 months without any complications. In the present report, the authors present the findings from successfully specific treatment with vincristine alone and supportive treatment for life-threatening hemorrhage with platelet concentrate and cryoprecipitate should be the best management in our situation. PMID- 22934469 TI - [The stakes of preventive medicine]. PMID- 22934468 TI - Case series: the paradox of epilepsy surgery and psychiatric disorder. AB - De novo psychiatric disorder following epilepsy surgery is an infrequent but very interesting phenomenon. The authors described 4 distinct cases with medically intractable epilepsy who had epilepsy surgery and developed postsurgical psychiatric disorder. The onset of psychiatric disorder was during dramatic improvement of their epilepsy after surgery. There was no history of psychiatric disorder in their familial members or in the patients prior to the surgery. Since three patients also had mental retardation, presurgical cognitive impairment may be one of the risk factors for developing postsurgical psychiatric disorder. Potential mechanisms include volume reduction of gray matter in frontal, temporal and parietal cortexes secondary to epilepsy surgery as well as forced normalization. Several other mechanisms may also play important role for this phenomenon and further studies will be required which may reveal the connection between these two aspects. PMID- 22934470 TI - [The Framework Convention for Tobacco Control (FCTC): a powerful public health instrument]. AB - The Framework Convention on Tobacco Control (FCTC) isa global and comprehensive legal framework for reducing demand for tobacco (e.g. price measures; ban on smoking in enclosed places; contents of tobacco products; packaging and labeling; advertising, promotion and sponsorship; liability, tobacco cessation, etc.) and supply (e.g. illicit trade; sales to/by minors, etc.). Adopted in 2003, the FCTC has been ratified by 174 countries so far. Switzerland has signed the treaty in 2004 but ratification will necessitate the implementation of stronger tobacco control measures at the national level. The FCTC is a priority of any strategy to reduce noncommunicable diseases in populations. Broad implementation of the FCTC has the potential to prevent a substantial proportion of the billion of tobacco related deaths expected in the 21st century. PMID- 22934471 TI - [Population reduction of salt consumption: opportunities, impact and strategies]. AB - A national survey showed that Swiss people eat high quantity of salt (9.1 g per day on average). The Swiss Federal Office of Public Health (FOPH) has launched a strategy to reduce salt intake in the population in order to decrease cardiovascular morbidity and mortality, mainly via blood pressure reduction. The most effective public health measures are to reduce the salt content of processed food rich in salt because they do not need to change consumers' eating behaviours. The FOPH has chosen to collaborate with the food industry on a voluntary basis. Regular population-based surveys will be needed to monitor the impact of current measures on salt consumption, hypertension prevalence as well as cardiovascular morbidity and mortality in the years to come. PMID- 22934472 TI - [Encouraging patients to exercise and maintain regular physical activity]. PMID- 22934473 TI - [Promotion of exercise in older people: issues and strategies]. AB - Regular physical activity is among the most effective interventions to prevent or delay functional decline and disability, even in older persons. Despite relatively strong scientific evidence supporting these benefits, the majority of older persons remain mostly sedentary. For these persons, concerns about injury or fear of negative consequences on their chronic diseases are among the most powerful barriers to participation in regular physical activity. Promotion of physical activity among older persons has therefore become one of the five main themes of the health promotion project "Via", a project that aims at promoting good practice in prevention and health promotion directed toward older adults in Switzerland. This paper summarizes the main recommendations issued from this national project supported by the Swiss Health Promotion Foundation. PMID- 22934474 TI - [Effects of calcium and vitamin D supplementations on cardiovascular disease: review article]. AB - Studies exploring the effect of calcium supplementation on cardiovascular risk suggest that systolic blood pressure decreases with supplementation. A lower calcium intake has been associated with an increased risk of stroke. By contrast, calcium supplementation may increase the risk of myocardial infarction. The effect of vitamin D supplementation on blood pressure is still unclear and no effect of vitamin D supplementation on coronary heart disease or stroke has been clearly demonstrated. There is a lack of randomized clinical trials primarily addressing the effect of these parameters on CVD. Currently, the use of calcium and vitamin D supplementations for the prevention of cardiovascular disease is not justified. PMID- 22934475 TI - [Organized screening for colorectal cancer: challenges and issues for a Swiss pilot study]. AB - Colorectal cancer is among the three most common and lethal neoplasms in Switzerland (about 4,000 new cases and 1,600 deaths per year, respectively). Several screening modalities are available. The effectiveness of colorectal cancer screening on mortality is established. The implementation of a successful screening intervention shall follow specified phases and conditions, and abide with global principles: pooling and coordinating efforts from all partners, setting goals and priorities, and identifying action plans. A feasibility (pilot) study is needed to verify requirements for quality, effectiveness, efficiency and innocuousness. Endeavours towards implementing a pilot programme for colorectal cancer screening in the Vaud canton (Switzerland) are presented and discussed. PMID- 22934476 TI - [Are there differences between men and women with pain?]. AB - An increasing number of articles are published on the differences about pain in men and women. These differences seem to be due to the sex, the biological dimension of the person, and to the gender, which is the role given to that person in a given social and culture environment. The pain prevalence is higher in women, its threshold and tolerance are lower. The pain interpretation, its perception and the coping is also different in men and women. Finally doctors translate and treat pain differently. This article proposes some explanations on these differences which should help us to treat this frequent and noxious symptom for the quality of life in a better way. PMID- 22934478 TI - [Before vacation]. PMID- 22934477 TI - [Night work and breast cancer]. PMID- 22934479 TI - [Doping and sudden death in sports]. PMID- 22934480 TI - [Doctor Guillotin and the machine named after him (1)]. PMID- 22934481 TI - [The worship of the present]. PMID- 22934482 TI - [Application of layered filling technology with light cured resin]. AB - Layered resin filling technology is based on resin curing shrinkage characteristics and aesthetic effects. This article, from several aspects such as curing light of cured resin, aesthetic effect needs, reducing shrinkage and shrinkage tension, wear resistance and intensity, gives a detailed description. PMID- 22934483 TI - [Effects of intracellular osmolality changes on the voltage-gated sodium channels currents of trigeminal ganglion neuron]. AB - OBJECTIVE: To evaluate the biomechanical effects of intracellular changes on the voltage-gated sodium channels (VGSCs) on trigeminal ganglion neuron (TRGN). METHODS: TRGN cells were acutely isolated from the neonatal SD rats. The voltage dependent currents of the VGSCs on these neurons were elicited and analyzed by whole-cell patch-clamp recordings and the intracellular anisotonicity stimuli was established by adjusting the content of pipette solution. The effects of hypo (260 mOsm) and hypertonic (350 mOsm) osmolarity on the activation and inactivation kinetics of VGSCs on TRGN were evaluated, compared with the normal intracellular environment. RESULTS: The results demonstrated that intracellular hypotonic stimuli could influence both the activation and inactivation characteristics of VGSCs currents, including the membrane potential at half inactivation (V0.5) of the G-V and inactivation curves had obvious statistics significance (P<0.05) between hypotonicity (260mOsm) and isotonicity (306mOsm). However, only inactivation properties changed under intracellular hypertonic effects, including inactivation rate and k value. CONCLUSION: It suggests that the kinetics of VGSCs on TRGN can be modulated both by intracellular hypo- and hypertonic with different characteristics. PMID- 22934484 TI - [Bond strength evaluation of four adhesive systems to dentin in vitro]. AB - OBJECTIVE: To compare the adhesive strength and observe the bonding interface. According to statistic analysis and scanning electron microscope (SEM) observation, the resistance capacity of four adhesive systems is evaluated. METHODS: Prime & Bond NT (PBNT), Tetric N-Bond (TNB), Clearfil SE Bond (CSEB), G Bond (GB) were bonded to the occlusal surfaces and mesial surfaces of third molars respectively. The mesial resins received shear force experiment and the fracture load were recorded. The tensile bond strength (TBS) of the remaining parts were tested. The interfacial configuration were observed under SEM. RESULTS: In the shear bond strength (SBS) experiment, PBNT and TNB showed the best result, but there was no significant difference between them (P>0.05). The SBS of PBNT was stronger than that of CSEB and GB (P<0.05). The SBS of TNB was stronger than that of GB (P<0.05). There was no significant difference between TNB and CSEB (P>0.05). In accordance with the shear force result, the TBS of PBNT and TNB was larger than CSEB and GB (P<0.05). Under SEM, resin tags of PBNT and TNB were longer and slender, the bonding layer was thick. Resin tags of CSEB were shorter, the ones of GB were the fewest and shortest. CONCLUSION: Compared to self-etching system, total-etching system could reach better bonding strength. There is some connection between the interfacial configuration of adhesives and bond strength of them. PMID- 22934485 TI - [Change of T lymphocyte subsets, interleukin-2 and tumor necrosis factor-alpha in tumor-bearing mice and patients with oral cancer receiving thermo-chemotherapy]. AB - OBJECTIVE: To investigate the change of T lymphocyte subsets, interleukin (IL)-2 and tumor necrosis factor (TNF)-alpha in the tumor- bearing mice and patients with oral cancer receiving thermo-chemotherapy, and investigate the correlation among them. METHODS: After treatments, the expression of lymphocyte transformation index (LTI), IL-2 and TNF-alpha in the tumor-bearing mice were detected with methyl thiazolyl tetrazolium (MTT), the expression of IL-2 and TNF alpha in the patients with oral cancer were detected with MTT, the expression of LTI, CD4+ and CD8+ were detected with 3H-TdR incorporation. RESULTS: LTI, IL-2 and TNF-alpha of thermo-chemotherapy group (HP group) had no significant difference comparing with those of normal mice group (N group) (P>0.05), but which were significantly higher than those of chemotherapy group (P group) and no treatment group (NT group) (P<0.01). In clinical trials, the expression of LTI, CD4+, CD4+/CD8+, IL-2 and TNF-alpha on oral cancer patients after thermo chemotherapy were significantly higher than those before thermo-chemotherapy (P<0.01). CONCLUSION: After thermo-chemotherapy, the expression of LTI, IL-2 and TNF-alpha of tumor-bearing hosts are significantly improved, there is a significant correlation between IL-2 and T cell. PMID- 22934486 TI - [Biological effect of micro ribonucleic acid-21 on human tongue squamous cell carcinoma lines]. AB - OBJECTIVE: To detect the biological influence to human tongue squamous cell carcinoma (TSCC) cells of micro ribonucleic acid-21 (miR-21). METHODS: Referring to mature miR-21 sequence, the sense and antisense oligonucleotide (sense-miR-21 and AS-miR-21) modified by 2'O-Me were designed to transfect into TSCC cells (Tca8113 and high metastasis cells) by liposome transfection technology, in order to establish an in vitro TSCC cell model. The expression changes of miR-21 in the transfected cells were detected with real-time fluorescence quantitative polymerase chain reaction (real-time PCR). The changes of cell proliferation, cell cycle, cell early apoptosis, cell migration and invasion capabilities were detected respectively by the technologies of methyl thiazolyl tetrazolium (MTT), flow cytometry, Annexin V cell early apoptosis assay, scratch assay and Transwell assay, to check AS-miR-21's effect on the biological characteristics of human TSCC cell lines. RESULTS: For the TSCC cells, the antisense oligonucleotide of targeting miR-21 could effectively inhibit cell proliferation, promoted cell apoptosis, and inhibited the capability of cell's migration and invasion. CONCLUSION: The expressions of miR-21 decrease after AS-miR-21 transfected into TSCC cells, and miR-21 can affect biological behavior of TSCC cells. PMID- 22934487 TI - [Finite element stress analysis of all-ceramic crown of the upper central incisor in differential thickness]. AB - OBJECTIVE: To investigate the stress distributions under load in an all-ceramic crown of the upper central incisor in differential thickness. METHODS: The 3 dimensional finite element model of all-ceramic crown of the upper central incisor in differential thickness was applied with differential loads (100, 150, 200 N). The stress values and distributions of all-ceramic crown were calculated and expressed. RESULTS: The tendency of stress distributions in all-ceramic crown of differential thickness and loads was similar. The maximal stress intensity value was located in the loading site and the cervical region. As the thickness of all-ceramic crown increased, the stress concentration reduced. When the load increased, the stress values increased, especially in the loading site and the cervical region. CONCLUSION: The increasing of the thickness of all-ceramic crown will decrease stress concentration. Because stress concentration is mainly in cervical region and loading site, these regions should be cared in fabrication of all-ceramic crown. PMID- 22934488 TI - [The expression and significance of receptor activator of nuclear factor kappaB ligand and osteoprotegerin in periapical cyst and periapical granuloma]. AB - OBJECTIVE: To investigate the expression of receptor activator of nuclear factor kappaB ligand (RANKL) and osteoprotegerin (OPG) in periapical cyst and periapical granuloma by comparison with the expression in the normal periodontal tissue as control, and to identify their functional mechanism in the bone destruction of periapical cyst and granuloma. METHODS: 20 periapical cyst tissues (cyst group), 20 periapical granuloma tissues (granuloma group), and 20 normal periodontal tissues (control group) were collected respectively. Immunohistochemical technology was performed to detect the expression of RANKL and OPG in above three groups. RESULTS: In cyst group, granuloma group and control group, the expression of RANKL were 75.00 +/- 7.54, 68.40 +/- 6.74 and 29.40 +/- 2.46, respectively. The expression of OPG were 38.10 +/- 7.09, 47.65 +/- 13.85 and 58.60 +/- 5.88, respectively. The differences among the three groups were statistically significant (P<0.05). RANKL and OPG in cysts group were negatively correlated (r= 0.56, P=0.01) and were not correlated with granuloma and control group (P>0.05). CONCLUSION: RANKL and OPG play roles in the bone absorption of periapical disease. In periapical disease, abnormal expression of RANKL and OPG are detected, RANKL significantly increase, OPG decrease, bone absorption accelerate and osteolytic lesion are observed. In periapical cyst, the bone absorption is more active compared with periapical granuloma. PMID- 22934489 TI - [Tyrosine kinase 2 with immunoglobulin-like and epidermal growth factor homology domains RNA interference inhibit the proliferation of human umbilical vein endothelial cells]. AB - OBJECTIVE: The purpose of this study was to investigate the regulatory role of tyrosine kinase 2 with immunoglobulin-like and epidermal growth factor homology domains (Tie2) on apoptosis and proliferation in the endothelial cells. METHODS: RNA interference (RNAi) technique was used to silence Tie2 gene expression by transfecting an expression vector containing short hairpin RNA(shRNA) for Tie2 into human umbilical vein endothelial cells (HUVECs). Real time quantitation reverse transcriptase polymerase chain reaction (QRT-PCR) and Western blot were used to monitor Tie2 mRNA, as well as protein expression. The proliferation of HUVECs was examined by methyl thiazolyl tetrazolium (MTT), and the apoptosis was detected under microscope. HUVECs transfected with pGenesil-hk was negative control, and HUVECs transfected with nothing was empty control. RESULTS: Tie2 mRNA expression was down-regulated 24 h and 48 h after transfection, and Tie2 protein expression was significantly down-regulated at 24 h and 48 h (P< 0.05), especially 48 h after transfection. The apoptosis rate was conspicuously higher in experimental group than in negative control and empty control group after 48 h (P<0.05). The growth monitoring showed that proliferation was also markedly inhibited in experimental group (P<0.05) compared with two control groups. CONCLUSION: Down-regulated expression of Tie2 by RNAi can promotes apoptosis of HUVECs and has an anti-proliferation activity effect on them. PMID- 22934490 TI - [Relationship of development between third molar and second molar, canine in aged 11]. AB - OBJECTIVE: To analyze the imaging manifestations of third molar (M3) in aged 11, and to explore the relationship of development between M3 and second molar (M2), canine (C). METHODS: A total of 399 cases, aged 11, of West China School of Stomatology in June-August 2010 were selected as the imaging database. The M3, M2, C on the panoramic images were observed and the development degree in 399 was divided. And then the correlation analysis was done. RESULTS: 45.5% of M3 in aged 11 was in stage C. 30.8% of M2 was in stage F. 36.1% of C was in stage G. The development of M3 appeared earlier in girls than in boys, and earlier in the mandible than in the maxillary. There was no significant difference between the left and right side. The correlation coefficient between M3 and M2 was 0.437, and the correlation coefficient between M3 and C was 0.132. CONCLUSION: The general trends of the developments of M3 and M2, C were the same. The development of M3 can be used to describe the development of M2 and C, according to the close relationship in radiograph. PMID- 22934491 TI - [Effects of surface treatment on the fracture resistance of teeth restored with fiber posts and core system]. AB - OBJECTIVE: To evaluate the effects of different surface treatment on the fracture resistance of teeth restored with fiber posts and core system. METHODS: 24 fiber posts were divided into three groups according to different surface treatment techniques, including sandblasting, etching with hydrogen peroxide, and no treatment performed (the control group). All fiber posts were luted with a composite resin luting agent in the canal roots. The teeth were restored with composite resin cores and metal crowns. After cementation, the teeth were subjected to simulated aging conditions consisting of mechanical loading cycles and thermal cycles. All teeth were loaded in a mechanical testing machine, and the fracture load and fracture mode of each teeth were recorded. RESULTS: The fracture resistances of sandblasting and hydrogen peroxide groups were higher than the control group (P<0.05), while the fracture resistances of two test groups had no significant differences (P>0.05). Fracture modes of all fiber post groups were nearer to the coronal third of the root. CONCLUSION: Sandblasting and etching with hydrogen peroxide can improve the fracture resistance of teeth. PMID- 22934492 TI - [Research on the mental health of the parents of cleft lip and palate patients and social impact factor from the perspective of social network]. AB - OBJECTIVE: This paper explores the relationships between mental health status of the patients' parents, whose children have cleft lip and palate, and their social impact factors. METHODS: The 12-item general health questionnaire (GHQ-12) and the social support rating scale were used to conduct a questionnaire survey of 59 patients' parents. A data statistical analysis was done by using SPSS 13.0 software and Excel 2007 software. RESULTS: 1)The mental health status of the patients' parents was in the middle level. 2) The mental health status of the patients' parents was related with the basic personal situations. It was apparently influenced by the qualifications and subjective state of mind. 3) The structure and relationship of the interpersonal networks of the patients' parents were the major constraint factors on the mental health status. 4) The social support degree and mental health status were positively correlated. CONCLUSION: The social network and social support have important influences on the mental health status of the parents whose children have cleft lip and palate. It should create a more harmonious and tolerant social environment. PMID- 22934493 TI - [Retrospective study of 18 cases with chronic sublinguitis]. AB - OBJECTIVE: To further understand the clinical features of chronic sublinguitis (CS) and to guide the clinical practice by a retrospective study. METHODS: 18 cases with CS were enrolled in the retrospective study and the age, gender, history of present illness, signs, diagnosis and treatment were analyzed. RESULTS: In 18 patients with CS, 15 patients (83.33%) had palpable masses. 8 masses (53.33%) had poor-defined borders, 11 masses (73.33%) were unmovable. There were only 3 patients (16.67%) who were diagnosed correctly in all 18 cases, while 10 patients (55.56%) were diagnosed as tumor. CONCLUSION: CS are often misdiagnosed as sublingual gland tumor and the way to confirm diagnosis is pathological examination. Auxiliary examination should be used properly with clinical manifestation to make the right diagnosis. PMID- 22934494 TI - [Evaluation of orthodontic teeth moving in bone graft area by dental CT]. AB - OBJECTIVE: To evaluate alveolar bone shape changing after orthodontic teeth moving in the alveolar bone graft area by dental CT. METHODS: Three unilateral complete alveolar cleft patients were chosen in this study. Patients were examined before and after alveolar bone grafting, after orthodontic treatment by dental CT. The alveolar bone shape changing after orthodontic teeth moving in bone graft area was evaluated. RESULTS: The orthodontic teeth could move in the bony graft area, and graft alveolar bone could reshape the morphology followed the teeth move in. CONCLUSION: Alveolar bone grafting and orthodontic treatment are good for reconstruct dental arch integrity. PMID- 22934496 TI - [Semi-attached quad-helix appliance can expand the maxillary arches in patients with cleft lip and palate before alveolar bone grafting]. AB - OBJECTIVE: To evaluate the clinical effect of semi-attached quad-helix appliance in expanding the narrow maxillary arches in patients with cleft lip and palate. METHODS: 15 cases with cleft lip and palate were selected and treated by semi attached quad-helix appliance. Before, during, and after treatment, the dental arch width between cuspid, the first premolar and first molar were measured. RESULTS: The upper dental arches of all patients were expanded effectively in about five months. After orthodontic treatment, the upper dental arches were expanded, and the teeth were alined regularly, which provided good conditions for alveolar bone grafting. CONCLUSION: The semi-attached quad-helix appliance with the fixed orthodontic treatment can expand the narrow maxillary arches in patients with cleft lip and palate effectively and conveniently. PMID- 22934495 TI - [One year evaluation of endodontic microsurgery in 54 cases with persistent apical periodontitis]. AB - OBJECTIVE: To evaluate the outcome of endodontic microsurgery in 54 cases with persistent apical periodontitis. METHODS: All surgical procedures were performed under a dental operating microscope after root canal treatment. Surgical procedures included periapical curettage, root-end resection, retropreparation with ultrasonic microtips, and root-end filling with mineral trioxide aggregate (MTA). Healing was monitored clinically and radiographically. RESULTS: One year later, 31 (57.41%) cases were cured, 19 (35.19%) cases were improved, 4 (7.41%) cases were failure. There were no statistical difference between sex, age, tooth location, size of the lesion and pathological features (P>0.05). CONCLUSION: The outcome of the present study indicates that endodontic microsurgery may result in a predictable treatment outcome in teeth with persistent periradicular lesions. PMID- 22934497 TI - [The preliminary study on nursing the extraction of mandibular mesioangular impacted third molar using reversal high-speed air turbine]. AB - OBJECTIVE: To study the nursing methods and its effect in mandibular mesioangular impacted third molar extraction with reversal high-speed air turbine. METHODS: 60 patients with mandibular mesioangular impacted third molar were selected in this study, who were treated in Department of Senior Dentists, West China School of Stomatology, Sichuan University, between June to December 2010. They were randomly and equally divided into control group and experimental group (n=30). The former was treated with tradition chisel splint method while the latter was treated with reversal high-speed air turbine extraction and provided appropriate nursing interventions. Postoperative reactions and wound healing status were evaluated through consultation. RESULTS: There were significant differences between control group and experimental group in terms of postoperative bleeding wound, swelling, dry socket and so on (P<0.05). CONCLUSION: Mandibular mesioangular impacted third molar extraction with reversal high-speed air turbine is effective, and the corresponding nursing measure is worthy further promotion. PMID- 22934498 TI - [Evaluation of cone-beam CT in diagnosis of supernumerary teeth in the anterior maxilla]. AB - OBJECTIVE: To evaluate the value of cone-beam CT (CBCT) in the diagnosis and orientation of supernumerary teeth in the anterior maxilla. METHODS: 195 supernumerary teeth in the anterior maxilla of 146 patients were included, which were examined by CBCT. The number, shape, size, 3-dimensional position, growth direction of the supernumeraries and their relationship with the neighboring teeth were analyzed. RESULTS: The 146 patients aged from 5 to 39, and males were affected more than females in a ratio of 2.95:1. 102 (69.9%) patients had single supernumerary teeth. Of the 195 supernumerary teeth, 126 (64.6%) were near the middle line, 131 (67.2%) were conical, 51 (26.2%) were curved root, 98 (50.3%) were inverted and had a length of (11.97 +/- 2.40) mm. The supernumerary teeth often caused complications. CONCLUSION: The position of the supernumerary teeth is varied in the maxilla, and often causes permanent dentition complications. CBCT imaging yields accurate 3-dimensional pictures of supernumerary teeth, local dental and bony structures, which is helpful for diagnosis and orientation of supernumerary teeth. PMID- 22934499 TI - [Manufacture method and clinical application of minimally invasive dental implant guide template based on registration technology]. AB - OBJECTIVE: To guide doctors in precisely positioning surgical operation, a new production method of minimally invasive implant guide template was presented. METHODS: The mandible of patient was scanned by CT scanner, and three-dimensional jaw bone model was constructed based on CT images data The professional dental implant software Simplant was used to simulate the plant based on the three dimensional CT model to determine the location and depth of implants. In the same time, the dental plaster models were scanned by stereo vision system to build the oral mucosa model. Next, curvature registration technology was used to fuse the oral mucosa model and the CT model, then the designed position of implant in the oral mucosa could be determined. The minimally invasive implant guide template was designed in 3-Matic software according to the design position of implant and the oral mucosa model. Finally, the template was produced by rapid prototyping. RESULTS: The three-dimensional registration technology was useful to fuse the CT data and the dental plaster data, and the template was accurate that could provide the doctors a guidance in the actual planting without cut-off mucosa. CONCLUSION: The guide template which fabricated by comprehensive utilization of three-dimensional registration, Simplant simulation and rapid prototyping positioning are accurate and can achieve the minimally invasive and accuracy implant surgery, this technique is worthy of clinical use. PMID- 22934500 TI - [Investigation of differences in subjective demand for orthodontic treatment of middle school students in zones with different economic levels]. AB - OBJECTIVE: To investigate the acquaintance to orthodontics and possible factors that obstruct orthodontic treatment in middle school students in zones with different economic levels in Jiangjin, Chongqing. METHODS: The students were randomly divided into four groups: A class from a junior high school in town (group 1), a class from a senior high school in town (group 2), a class from a junior high school in the countryside (group 3), a class from a senior high school in the countryside (group 4). The information was collected by questionnaire, and the statistical analysis of results was carried out by SPSS 17.0 software. RESULTS: Sex made difference in the acquaintance to orthodontics treatment. Girls worried more about teeth extraction and pain that may occur during treatment than the boys. Students in the city had more access to related consultations compared to those in the countryside. Different economic conditions made much contribution to the proportion to go for orthodontics treatment in cities and rural areas. The evaluation from families and friends may affect patients' subjective estimation to themselves. CONCLUSION: Orthodontists should learn more about student patiens from various aspects, and make different therapies according to their sexes, economic conditions of family, education levels, etc. Only so can orthodontists get better compliance from their patients. PMID- 22934501 TI - [Analysis of reconstruction using non-vascularized iliac bone graft for patients with mandibular defects]. AB - OBJECTIVE: To make a clinical retrospective analysis of reconstruction using autogenous non-vascularized iliac bone graft for patients with mandibular defects, and then to evaluate the treatment effectiveness and operation announcements of this method. METHODS: 34 patients who were suffered from discontinued mandibule because of tumor or trauma, were treated with autogenous non-vascularized iliac bone graft. The surgery technique, postoperative outcomes and complications were analyzed. RESULTS: In 34 patients adopted non-vascularized iliac bone graft, 31 patients adopted rigid internal fixation with titanium mini plate, 3 patients with bridging titanium plate. 27 bone grafts survived completely, the overall success rate was 79.41%. 3(8.82%) of the bone grafts healed after infection, 4(11.76%) bone grafts lost because of infection. CONCLUSION: The autogenous non-vascularized iliac bone graft is one of the most important way for the reconstruction of mandibular defects. The methods of internal fixation includes titanium mini pate and bridging titanium plate. PMID- 22934502 TI - [Effects of bleaching agents on the microleakage of class V cavities restored with glass-ionomer cements]. AB - OBJECTIVE: To evaluate the effects of a bleaching gel and a whitening strip on the microleakage of three different glass-ionomer cements. METHODS: Forty-five freshly extracted human premolars were used and class V cavity was prepared on the buccal and lingual surfaces. The teeth were randomly assigned to A, B and C groups and restored as follows: Conventional strengthen glass-ionomer cement (Ketac Molar Easymix), compomer (F2000) and compomer (Dyract AP). Teeth were kept in distilled water at 37 degrees C for 7 days. Then the specimens were thermocycled for 500 times. Each group was randomly divided into 3 subgroups which were treated for 21 days with one of the following: Whitening strip (14% hydrogen peroxide), bleaching gel (10% carbamide peroxide), or distilled water (control). After bleaching, the teeth were placed in a solution of basic fuchsin dye for 24 hours, then the teeth were sectioned longitudinally to evaluate the dye penetration. The depth of staining along the tooth restoration interface was recorded with a stereomicroscope. RESULTS: There were no signicant differences between the two bleaching agents in microleakage of restorations (P>0.05). The two bleaching agents did not significantly affect the microleakage of compomer (P>0.05), whereas the microleakage of glass-ionomer cement in the experimental groups was higher than that in the control group (P<0.05). CONCLUSION: There are no significant differences in microleakage of restorations between bleaching gel (10% carbamide peroxide) and whitening strip (14% hydrogen peroxide). The two bleaching agents do not significantly affect the microleakage of compomer but adversely affect the microleakage of strengthen glass-ionomer cement. PMID- 22934503 TI - [The effects of firing numbers on the opening total pore volume, translucency parameter and color of dental all-ceramic systems]. AB - OBJECTIVE: To evaluate the effects of firing numbers on the total opening pore volume (TPV), translucency parameter (TP) and color of dental all-ceramic systems. METHODS: Specimens of three kinds of all-ceramics systems were made, i.e. heat pressed all-ceramic (IPS Empress II), alumina all-ceramic (In-Cream alumina blanks) and zirconia all-ceramic (Cercon CAD/CAM zirconia). The specimens' TP, lightness (deltaL), chroma (deltaC) and TPV after 1, 3 and 5 firings were measured and calculated by spectrophotometer and surface area/porosity system. The data were analyzed statistically using SAS 8.0 software. RESULTS: There were significant differences in TPV, TP, deltaL and deltaC for all-ceramic specimens at same number of firings (P<0.05), i.e. IPS>alumina and zirconia for TPV (P<0.05); IPS>zirconia>alumina for TP and deltaL (P<0.05); IPS and alumina>zirconia for deltaC (P<0.05). The significant differences also presented in TPV, TP, deltaL and deltaC for a same specimen at different number of firings (P<0.05). With increasing number of firings, TPV decreased, and TP, deltaL and deltaC increased gradually. There were negative linear correlation between number of firings and TPV, TP, deltaL and deltaC (P<0.05). CONCLUSION: Repeated firings will affect TP and deltaL of all-ceramic restorations via the change of TPV. PMID- 22934504 TI - [Response of bone morphogenetic protein-2 and basic fibroblast growth factor in bone marrow stromal cells in ectopic and in situ bone formation]. AB - OBJECTIVE: We ascertained the effect of bone morphogenetic protein-2 (BMP-2) and basic fibroblast growth factor (bFGF) by a series of experiments: Proliferation and differentiation of bone marrow stromal cells (BMSCs) in vitro, ectopic and in situ bone formation and loaded porous calcium phosphate cement (CPC) on the repair of bone defects around dental implants. METHODS: BMSCs from Beagle dogs were cultured in vitro with basic culture medium containing BMP-2, bFGF, and BMP 2+bFGF. Proliferation and differentiation of BMSCs were quantified using methyl thiazolyl tetrazolium (MTT) and alkaline phosphatase (ALP) test. The CPC seeded with BMSCs and BMP-2, bFGF, combined BMP-2 with bFGF were implanted subcutaneously into nude rats in ectopic bone formation, and were implanted into critical-sized bone defects of Beagle dogs in the in situ bone formation. The bone formation was detected by histology examination and quantified using an image analysis system. Polychrome sequential fluorescent labels and fluorescence histological examinations of undecalcified sections were performed post operatively. RESULTS: It was determined that BMP-2+bFGF promoted BMSCs statistically significant proliferation and differentiation compared to either BMP-2 or bFGF in vitro. The CPC with BMP-2+bFGF group yielded more bone than those with either BMP-2 or bFGF in ectopic bone formation test. The percentages of newly ectopic formed bone were higher in the BMP-2+bFGF group (48.79% +/- 11.31%) than those in other groups (BMP-2 group, 30.71% +/- 10.85%; bFGF group, 27.33% +/- 9.67%; and the control group, 10.65% +/- 6.05%). Undecalcified showed that new bone was actively formed in the BMP-2+bFGF group after 12 weeks in the in situ bone formation test. The bone mineralization apposition rate (MAR) was better in the BMP-2+bFGF group than in other groups (P<0.01). CONCLUSION: BMP-2 combined with bFGF are more effective than one alone in promoting the formation of new bone. PMID- 22934505 TI - [The effect of bone morphogenetic protein-2 and osteoprotegerin in trans-sutural distraction osteogenesis]. AB - OBJECTIVE: To determine if locally administered bone morphogenetic protein-2 (BMP 2) and osteoprotegerin (OPG) improved osteogenesis and new bone formation by trans-sutural distraction osteogenesis. METHODS: Twenty four dogs were divided into three groups randomly and received new internal trans-sutural distraction osteogenesis treatment. Five days after operation, infusion apparatus with double tube was inserted to submucosa near the distracted zone to deliver controlled release agent of recombinant human bone morphogenetic protein-2/poly (lactic-co glycolic acid)/fibrin sealant (rhBMP-2/PLGA/FS) in group A and group C. Recombinant human osteoprotegerin/fibrin sealant (rhOPG/ FS) was injected three weeks later in group B and group C. Histology staining and bone histomorphometry were used to measure the changes of maxillary bone sutura after distraction for 1, 2, 4 and 6 weeks. RESULTS: New bone formation observed in distracted zone showed a significant increase in group A and C. Transmission electron microscope showed the osteoblast and osteocyte were active with dilated rough endoplasmic reticulum and a large number of chondriosomes and Golgi complex. After distraction for 6 weeks, indexes of osteoblast of group A, B, and C were 38.5 +/- 7.7, 35.7 +/- 6.5, and 41.7 +/- 11.0, indexes of osteoclast (Ioc) were 5.9 +/- 1.0, 1.2 +/- 0.3, and 2.8 +/- 0.4, bone trabecula thicknesses were (38.36 +/- 13.28), (66.20 +/- 9.16), and (51.85 +/- 9.92) microm respectively. Increased bone density and decreased Ioc were found in group B and C. CONCLUSION: The new elastic distractor is effective in inducing new bone formation. BMP-2 and OPG combination acts synergistically, and leads to significant enhancement of bone formation and remodeling. PMID- 22934506 TI - [The relationship between c-fos gene and filamentous actin cytoskeleton in MG-63 osteoblasts under cyclic tensile stress]. AB - OBJECTIVE: To investigate the relationship between c-fos gene and filamentous actin (F-actin) in MG-63 osteoblasts under cyclic tensile stress. METHODS: MG-63 osteoblasts were subjected to cyclic tensile stress (0.5 Hz, 2 000 microstrain) for 3, 6, and 12 h. The changes of c-fos gene were investigated by fluorescent quantitation polymerase chain reaction. Then the best loading time group was screened as the experimental group compared with 0 h group. The changes of F actin and c-fos were investigated with or without cytochalasin D treatment. RESULTS: Cyclic tensile stress induced high expression of c-fos mRNA, and peaked at 3 h. After loading, F-actin had a structure reorganization, but had no change in expression. After cytochalasin D treatment, the formation of stress fibers and the fluorescence intensity of F-actin cytoskeleton significantly reduced, meanwhile the c-fos mRNA expression was inhibited. CONCLUSION: After loading, there is only structure reorganization for F-actin, and the expression has not any change. That means the remodeling F-actin is the existing one. F-actin reorganization is an important part in c-fos gene expression induced by stress. PMID- 22934507 TI - [The effect of different fluoride concentrations on the expression of transforming growth factor-beta1 in ameloblast of rat incisor]. AB - OBJECTIVE: To investigate the effect of different concentrations of fluoride on the expression of transforming growth factor-beta1 (TGF-beta1), and explore the mechanism of dental fluorosis. METHODS: 40 Wistar rats were randomly divided into three groups, and supplied with low dose F(-)(60 mgxL(-1), 13 rats), high dose F( )(120 mgxL(-1), 13 rats) and distilled water(control group, 14 rats) respectively. After 10 weeks, hematoxylin-eosin (HE) and immunohistochemistry staining were used to observe the changes of the ameloblasts and the expression of TGF-beta1 in rat incisors. RESULTS: The fluoride groups showed typical symptoms of dental fluorosis. The surfaces of the rat teeth fed with fluoride appeared chalky color and cross striation on the enamel surface. The HE staining showed that the morphous of ameloblast were disarranged and cellular derangement, even appeared vacuolar change. TGF-beta1 were expressed both in ameloblast of the secretory and maturation stage, and also in stellate reticulum and stratum intermedium. The expression of TGF-beta1 in rat's ameloblasts in experiment group was significantly lower than that in the control group (P<0.01), yet low dose group and high dose group still had no significant difference (P>0.05). CONCLUSION: By inhibiting the expression of TGF-beta1 in ameloblast, fluoride interferes the normal signal transduction between epithelial and mesenchymal, and affect the differentiation and development of enamel, so leading to the occurrence of dental fluorosis. PMID- 22934508 TI - [Biological characteristics of cells expressing high level of aldehyde dehydrogenase subpopulation in tongue squamous cell carcinoma Tca8113 cell line]. AB - OBJECTIVE: To detect the expression of aldehyde dehydrogenase (ALDH) in tongue squamous cell carcinoma Tca8113 cell line and observe the biological characteristics of tumor cells expressing high level of ALDH (ALDH(hig)). METHODS: The expression of ALDH in tongue squamous cell carcinoma Tca8113 cell line was detected by the flow cytometry. The ALDH(hig) and ALDH(low) subpopulation cells were isolated and cultured in vitro respectively. The ability of differentiation, proliferation and tumorsphere formation were detected. Suppression subtractive hybridization (SSH) was employed to screen the genes overexpressed in ALDH(hig) subpopulation cells. RESULTS: The ALDH(hig) cells in tongue squamous cell carcinoma Tca8113 cell line was rarely 1.3%. Compared with ALDH(low) cells and unsorted cells, ALDH(hig) cells demonstrated increased proliferation capacity. After culture in vitro, the percentage of ALDH(hig) cells decreased gradually to the level of that in unsorted tumor cells. The ALDH(hig) subpopulation cells could survive in serum free medium and generate tumorspheres. SSH analysis revealed these tumor cells also expressed stem cell related genes. CONCLUSION: There is a rare subpopulation cells expressing ALDH highly, which displays characteristics similar to stem cells. ALDH may be one of markers for cancer stem cells of tongue squamous cell carcinoma Tca8113 cell line. PMID- 22934509 TI - [Both of adenolymphoma and pleomorphic adenoma occurred in unilateral parotid gland: a case report]. AB - A case diagnosed as adenolymphoma and pleomorphic adenoma in unilateral parotid gland was reported. The clinic pathological features, possible mechanism, diagnosis and treatment were discussed based on previously reports in the literature. PMID- 22934510 TI - [Effective English writing for tables and figures in andrological papers]. AB - Tables and figures play a critical role in enhancing the quality of an andrological paper. As visual elements, well-presented tables and figures can reduce the length of the manuscript and meanwhile efficiently capture a large amount of information by clear and concise display of detailed results and complex relationships, patterns and trends, offer explicit statistical or graphical support to important ideas, and add to the value of the whole paper. The effectiveness of a table or figure lies not only in its well-crafted structural design, but even more in its language presentation. This article presents some essential and practical guidelines to effective English writing of the title, body and footnotes of tables and figures in andrological papers. PMID- 22934511 TI - [Diethylstilbestrol affects LGR8 expression in mouse gubernaculum testis]. AB - OBJECTIVE: To investigate the impact of prenatal exposure to diethylstilbestrol (DES) on the specific receptor LGR8 of insulin-like factor 3 (INSL3) in the mouse gubernaculum testis, and that of exoestrogens on descensus testis in mice. METHODS: A total of 120 pregnant KM mice aged 8 to 10 weeks were assigned to a normal, a blank control and 4 DES groups of equal number, the blank controls injected subcutaneously with dimethyl sulfoxide plus normal saline, and the DES groups with DES at 0.1, 1, 10 and 100 microg/kg body weight, respectively, from embryonic day 9 (ED9) through ED17. Immunohistochemistry and RT-PCR were used to detect the expressions of LGR8 protein and mRNA in the gubernaculum testis of the ED18 fetuses and PND20 (postnatal day 20) offspring of the mice. RESULTS: Histological analysis showed that the gubernaculum testis of the ED18 fetuses were well developed in both the normal and control groups, with an inner mesenchymal core and muscular outer layer. In contrast, the gubernaculum testis were poorly developed in the experimental groups, morphologically abnormal and without visible dividing line between the mesenchymal tissue and the muscular outer layer. No obvious differences were found in the gubernaculum testis development of the neonates between the normal and experimental groups. Positive immunostaining was seen in the mesenchymal core and muscular outer layer, but mainly in the latter. The expression of LGR8 was weaker in the experimental groups than in the normal group (P < 0.05), but that of LGR8 mRNA was increased in the high-dose (10 and 100 microg/kg) DES groups (P < 0.05). No obvious mutations were observed in the PCR products in any of the experimental groups. CONCLUSION: Prenatal exposure to diethylstilbestrol affected the expression of LGR8 mRNA in the mouse gubernaculum testis, which suggests that diethylstilbestrol may induce cryptorchidism by interfering with the INSL3-LGR8 signaling system and consequently the development of the gubernaculum testis. PMID- 22934512 TI - [Inhibitory effect of siRNA targeting ADAM17 on the proliferation of prostate cancer PC-3 cells]. AB - OBJECTIVE: To study the effect of siRNA targeting ADAM17 (ADAM17-siRNA) on the proliferation of prostate cancer PC-3 cells. METHODS: After transfecting PC-3 cells with ADAM17-siRNA 1 and ADAM17-siRNA 2, we detected the expressions of ADAM17 mRNA and protein by RT- PCR and Western blotting, respectively. We measured the changes in the proliferation and DNA synthesis of PC-3 cells by MTT and bromodeoxyuridine (BrdU) incorporation assay, examined the cell cycle profile by flow cytometry, and determined the expressions of the genes associated with PC 3 cell proliferation by Western blotting. RESULTS: Both ADAM17-siRNA 1 and 2 effectively reduced the expressions of ADAM17 mRNA and protein in the PC-3 cells. Knockdown of ADAM17 with the two siRNAs significantly inhibited cell proliferation as compared with the control group (0.43 +/- 0.57 and 0.44 +/- 0.64 vs 0.80 +/- 0.51, P < 0.05) and down-regulated DNA synthesis (0.48 +/- 0.43 and 0.54 +/- 0.59 vs 0.79 +/- 0.72, P < 0.05). The cell cycle profile showed that the cell population of the G1 phase was markedly higher in both the ADAM17-siRNA groups than in the control ([61.83 +/- 2.41]% and [59.78 +/- 1.92]% vs [41.38 +/- 1.53]%, P < 0.05), but that of the S phase remarkably lower in the former two than in the latter ([23.64 +/- 2.56]% and [25.24 +/- 1.86]% vs [33.51 +/- 1.47]%, P < 0.05), with a concomitant decrease in the expression of the cell cycle protein cyclin D1 and increase in the cyclin-dependent kinase inhibitor p21. CONCLUSION: ADAM17-siRNA can effectively inhibit the proliferation of PC-3 cells by up-regulating cyclin D1 and down-regulating p21 protein, and ADAM17 has a potential value in the gene therapy of prostate cancer. PMID- 22934513 TI - [Effects of PPAR-gamma on the proliferation and glycolysis metabolism of prostate cancer cells]. AB - OBJECTIVE: To investigate the effects of the expression of the PPAR-gamma gene on the proliferation and glycolysis metabolism of prostate cancer cells. METHODS: Using RNAi, we constructed lowly--expressed shRNA-PPARgamma adenoviruses and transfected them to PC3 prostate cancer cells, with blank vectors as controls. Then we detected the proliferation and apoptosis of the cells, glycolysis metabolism related genes and lactate accumulation by CCK-8 kit, and compared the results between the two groups. RESULTS: Compared with the control group, the PPAR-gamma gene expression was obviously inhibited by RNAi in the PC3 cells, and its protein expression was reduced to (26.00 +/- 4.06)%. The proliferation inhibition rate was (39.5 +/- 4.92)% on the 2nd day, and the apoptosis rate was as high as (21.03 +/- 3.08)%. The glycolysis metabolism related gene products (Myc and Glut-1) were significantly decreased, and the lactate concentration was reduced to 69.71% of that of the controls on the 4th day. There were statistically significant differences in the above findings as compared with the control group (P < 0.01). CONCLUSION: PPAR-gamma gene knockdown is expected to be a new way to treat prostate cancer. PMID- 22934514 TI - [Transfection of iNOS suppresses the growth of androgen-independent prostate cancer DU145 cells]. AB - OBJECTIVE: To observe the effect of the inducible nitric oxide synthase (iNOS) gene on androgen-independent prostate cancer DU145 cells in vitro. METHODS: The iNOS gene was transfected into androgen-independent prostate cancer DU145 cells. The positive cells were selected as the transfected group for amplification, and an empty vector (EV) group and a control group were also set. The mRNA transcription of iNOS was analyzed by RT-PCR. The morphological changes of the cells were observed, the effect of iNOS transfection on the cell growth determined using the MTB method, and the apoptosis of DU145 cells detected by flow cytometry, followed by analysis of the effect of NOS inhibitors on the transfected cells. RESULTS: DU145 cells transfected with iNOS secreted significantly more nitric oxide ([272.50 +/- 15.82] micromol/L) than those of the EV and control groups ([122.00 +/- 18.93] micromol/L and [121.00 +/- 6.98] micromol/L) (P < 0.05). The rate of cell apoptosis was markedly enhanced in the transfected group as compared with the EV and control groups ([42.78 +/- 2.01]% vs [30.65 +/- 1.46]% and [28.96 +/- 1.50]%, P < 0.05). MTP test indicated a slower growth of the DU145 cells in the former than in the latter two (P < 0.05). NOS inhibitors enhanced their growth, but with no significance (P > 0.05). CONCLUSION: DU145 cells transfected with iNOS could secrete high-concentration nitric oxide, induce cell apoptosis, and suppress cell proliferation, which may provide a potentially effective gene therapy for advanced androgen-independent prostate cancer. PMID- 22934515 TI - [Benign prostate hyperplasia induced by urogenital sinus implantation in rats: a histomorphological study]. AB - OBJECTIVE: To study the histomorphological and immunochemical characteristics of benign prostate hyperplasia (BPH) induced by urogenital sinus (UGS) implantation in the rat model. METHODS: We randomized 32 seven-week old male SD rats into a sham operation control and three (2-, 3- and 6-week) UGS model groups. We made the UGS model by implanting two urogenital sinuses from homogeneous male rat embryos into the host rats' right anterior lobe, and killed the model rats 2, 3 and 6 weeks later for measuring the wet weight, volume and micromorphological parameters of the right anterior lobe and detecting the factors expressed in the epithelium, stroma and smooth muscle by immunochemistry. RESULTS: The model rats showed significant increases in the wet weight, volume and relevant indexes of the right anterior lobe (P < 0.05), as well as in the proportion of stromal area and relative stromal volume (P < 0.1) with the prolonging of time. The mean stromal proportion of the 3-week models was as high as 75.32%. There was also a time-dependent increase in the relative total volume of epithelia in the model groups. The luminal area and the proportions of the luminal and epithelial volumes were obviously reduced in the model rats as compared with the sham operation controls. Pan-cytokeratin positive particles were located in epithelial cells, vimentins abundantly expressed in mesenchymocytes, and alpha-smooth muscle actins expressed around the lumen of the gland. CONCLUSION: BPH induced by urogenital sinus implantation in rats is typically stromal hyperplasia, and the locations of related factors are similar to those in men with BPH. PMID- 22934516 TI - [Aggressiveness and extent of prostatic inflammation relates with serum PSA levels in type IV prostatitis]. AB - OBJECTIVE: To investigate the relationship of the histopathologic grade and extent of prostatic inflammation with the level of serum PSA in patients with type IV prostatitis. METHODS: We performed transrectal ultrasound-guided prostate biopsy for 120 patients suspected of prostate cancer and included in this study only those with benign prostate hyperplasia (BPH) and prostatitis (n = 46), excluding the cases with prostate cancer and those with BPH but no prostatitis. We evaluated the relationship between prostatic inflammation and serum PSA levels based on the three-grade pathohistologic criteria for the extent, location and aggressiveness of prostatic inflammation. The serum tPSA levels, fPSA levels, % fPSA, and PSAD were compared among different groups. RESULTS: As for the extent of inflammation, 35 of the 46 included cases were grade I (tPSA: [8.46 +/- 4.09] microg/L; fPSA: [1.75 +/- 0.93] microg/L; PSAD: 0.15 +/- 0.11), 7 were grade II (tPSA: [15.26 +/- 5.26] microg/L; fPSA: [2.54 +/- 0.72] microg/L; PSAD: 0.26 +/- 0.07) and 4 were grade III (tPSA: [21.05 +/- 7.58] microg/L; fPSA: [3. 19 +/- 1.13] microg/L; PSAD: 0.42 +/- 0.19), with statistically significant differences among the three groups in the levels of tPSA (P = 0.001), fPSA (P = 0.008) and PSAD (P < 0.001). Regarding the location of inflammation, 19 cases were grade I, 17 were grade II and 10 were grade II, with no significant differences in tPSA, fPSA and %fPSA among the three grades (P > 0.05). As for the aggressiveness of inflammation, 32 cases were grade I (tPSA: [8.37 +/- 4.07] microg/L; fPSA: [1.76 +/- 0.93] microg/L; PSAD: 0.14 +/- 0.11), 10 were grade II (tPSA: [13.30 +/- 5.69] microg/L; fPSA: [3.27 +/- 2.21] microg/L ; PSAD: 0.25 +/- 0.06) and 4 were grade III (tPSA: [21.05 +/- 7.58] microg/L; fPSA: [3.19 +/- 1.13] microg/L; PSAD: 0.42 +/- 0.19), with statistically significant differences among the three grades in the levels of tPSA (P = 0.002), fPSA (P = 0.024) and PSAD (P < 0.001). The extent of inflammation was positively correlated with the levels of tPSA (r = 0.6, P < 0.001), fPSA (r = 0.5, P = 0.001) and PSAD (r = 0.6, P < 0.001), and so was the aggressiveness of inflammation (tPSA: r = 0.5, P < 0.001; fPSA: r = 0.4, P = 0.008; PSAD: r = 0.7, P < 0.001), but a negative correlation was found between the aggressiveness of inflammation and %fPSA (r = -0.4, P = 0.013). CONCLUSION: The aggressiveness and extent of prostatic inflammation in asymptomatic prostatitis patients are significantly correlated with the level of serum PSA, which may help pathologists to avoid unnecessary repeated biopsies for patients with high-grade prostatitis. PMID- 22934517 TI - [Paraganglioma of the prostate: a case report and review of the literature]. AB - OBJECTIVE: To investigate the clinical presentation, pathologic features, treatment and prognosis of prostatic paraganglioma. METHODS: We retrospectively studied a case of prostatic paraganglioma and reviewed relevant literature. The patient was a 39-year-old man, admitted for repeated hematospermia for over 12 months. After misdiagnosed as having prostate cancer, he underwent suprapubic prostatectomy, with the tumor completely removed. RESULTS: Postoperative pathological examination confirmed the tumor to be prostatic paraganglioma, which was non-functional, with the immunohistochemical results of NSE (+), CGA (+), S100 (+), CK (-) and Desmin (-). Postoperative blood pressure was stable. Two weeks after surgery, the urethral catheter was removed and the patient discharged. No recurrence was found during 48 months of follow-up. CONCLUSION: Lacking specific clinical characteristics, paraganglioma of the prostate is easily misdiagnosed, and can be confirmed only by postoperative pathology and immunohistochemistry. For the treatment of this rare tumor, little experience has been accumulated, and further studies are needed. PMID- 22934518 TI - [Clinicopathological characterization of true hermaphroditism complicated with seminoma and review of the literature]. AB - OBJECTIVE: To study the clinicopathological characteristics and diagnosis of true hermaphroditism complicated with seminoma. METHODS: We retrospectively analyzed the clinicopathological data of a case of true hermaphroditism complicated with seminoma and reviewed the related literature. RESULTS: The patient was a 42-year old male, admitted for bilateral lower back pain and discomfort. CT showed a huge mass in the lower middle abdomen. Gross pathological examination revealed a mass of uterine tissue, 7 cm x 2 cm x 6 cm in size, with bilateral oviducts and ovarian tissue. There was a cryptorchidism (4.0 cm x 2.5 cm x 1.5 cm) on the left and a huge tumor (22 cm x9 cm x6 cm) on the right of the uterine tissue. The tumor was completely encapsulated, with some testicular tissue. Microscopically, the tumor tissue was arranged in nests or sheets divided and surrounded by fibrous tissue. The tumor cells were large, with abundant and transparent cytoplasm, deeply stained nuclei, coarse granular chromatins, visible mitosis, and infiltration of a small number of lymphocytes in the stroma. The karyotype was 46, XX. Immunohistochemistry showed that PLAP and CD117 were positive, while the AFP, Vimentin, EMA, S100, CK-LMW, Desmin, CD34 and CD30 were negative, and Ki 67 was 20% positive. A small amount of residual normal testicular tissue was seen in the tumor tissue. CONCLUSION: True hermaphroditism complicated with seminoma is rare. Histopathological analysis combined with immunohistochemical detection is of great value for its diagnosis and differential diagnosis. PMID- 22934519 TI - [Penile rehabilitation with vacuum erection device for erectile dysfunction after radical prostatectomy]. AB - OBJECTIVE: To investigate the efficacy and safety of vacuum erection device (VED) for erectile dysfunction (ED) after radical prostatectomy (RP). METHODS: Six cases of ED after open RP were reviewed. Three of the patients started a daily rehabilitation protocol using VED 10 min/d within 3 months after RP (group A, early intervention), while the other 3 initiated the same protocol after 12 months (group B, late intervention). We compared the IIEF-5 scores as well as stretched penile lengths and mid-shaft circumferences before and after 3 and 6 months of VED rehabilitation. We also assessed the safety of the device and sexual satisfaction of the patients and their partners. RESULTS: The mean IIEF-5 score of the six cases was remarkably increased at 3 and 6 months of VED rehabilitation (P < 0.05), significantly higher in group A than in B at 3 months (8.7 +/- 0.6 vs 6.7 +/- 0.6, P < 0.05) and 6 months (13.0 +/- 1.0 vs 8.3 +/- 1.5, P < 0.05). After 6 months of VED rehabilitation, there were no significant changes in stretched penile length or mid-shaft circumference in group A, both significantly decreased in group B (P < 0.05), and sexual satisfaction of the patients and their partners were 83.3% and 50%, respectively. No serious adverse events were observed except mild complaint of pe- nile skin darkening in 1 case and numb feeling during the intercourse in 2. CONCLUSION: Early use of VED after RP improves erectile function and helps to preserve the length and mid-shaft circumference of the penis. PMID- 22934520 TI - [Single-nucleotide polymorphisms of MAMLD1 and hypospadias in Chinese]. AB - OBJECTIVE: To investigate the role of the MAMLD1 gene mutation in the pathogenesis of hypospadias in the Chinese population. METHODS: We collected peripheral venous blood from 150 Chinese children with hypospadias (the case group) and another 120 normal healthy ones (the control group), aged 0.5 to 6 years. We obtained their DNA samples and performed DNA sequencing on the single nucleotide polymorphisms of MAMLD1, followed by comparative analysis. RESULTS: A known missense mutation polymorphism p. N589S was identified in 12 (8.0%) of the hypospadias patients and 4 (3.0%) of the normal controls, and a novel missense mutation polymorphism p. N567S was identified in 4 (2.7%) of the patients and 3 (2.5%) of the controls, neither with statistically significant differences between the two groups (P > 0.05). CONCLUSION: The results re-emphasized the importance of replication in genetic association approaches, and might reveal a real difference in susceptibility genes among different populations. The single nucleotide polymorphisms of MAMLD1 bear no obvious correlation with hypospadias, and MAMLD1 is not a candidate gene in its pathogenesis in the Chinese population. PMID- 22934521 TI - [Application of factor analysis in comprehensive evaluation of semen quality]. AB - OBJECTIVE: To explore the application of factor analysis in comprehensive evaluation of semen quality. METHODS: Using factor analysis, we examined the semen samples from normal fertile men and comprehensively evaluated their quality by extracting typical common factors from the sperm parameters, such as semen volume, sperm concentration, total number of sperm, total motility, progressive motility, vitality, sperm morphology, total number of progressive motile sperm, total number of valid progressive motile sperm, teratozoospermia index (TZI), sperm deformity index (SDI), curvilinear velocity (VCL), straight-line velocity (VSL), average path velocity (VAP), amplitude of lateral head displacement (ALH), linearity (LIN), wobble (WOB), straightness (STR), beat-cross frequency (BCF) and mean angular displacement (MAD). RESULTS: Based on the principle of the cumulative variance contribution rate of 85% or more, we extracted 6 common factors with the cumulative variance contribution rate of 86. 647%, which in sequence represented sperm count, velocity, direction of movement, deformity index, semen volume and normal sperm morphology. The composite factor scores were calculated by the formula of (36.243 * F1 + 23.342 * F2 + 8.910 * F3 + 8.500 * F4 + 5.538 * F5 +4.115 * F6)/ 86.647, with a median of -0.0180. With the 5th percentile as the lower reference limit, 95.1% of the fertile males met the WHO limit for composite factor scores, while only 79.2% of them met the limit for semen parameters (P = 0. 000). CONCLUSION: Compared with the routine detection of sperm parameters, factor analysis or composite factor scores could give a more accurate comprehensive evaluation of semen quality. PMID- 22934522 TI - [Mechanisms of electromagnetic radiation damaging male reproduction]. AB - More and more evidence from over 50 years of researches on the effects of electromagnetic radiation on male reproduction show that a certain dose of electromagnetic radiation obviously damages male reproduction, particularly the structure and function of spermatogenic cells. The mechanisms of the injury may be associated with energy dysmetabolism, lipid peroxidation, abnormal expressions of apoptosis-related genes and proteins, and DNA damage. PMID- 22934523 TI - [Sildenafil: 10-year application in clinical andrology in China]. AB - Sildenafil (Viagra) citrate has been well accepted by physicians and patients for its reliable efficacy and safety in the treatment of erectile dysfunction (ED) ever since its introduction into clinical andrology in China 10 years ago. It has been proved effective for various ED subgroups, regardless of causes, severity and age. Recent studies show that sildenafil also benefits patients with premature ejaculation, either used alone or in combination with other therapies. PMID- 22934524 TI - [Can antibiotic treatment exclude inflammation in the differential diagnosis of elevated PSA?]. AB - Considering that antibiotic treatment may elevated the level of prostate-specific antigen (PSA) and hence limit the specificity of PSA test for prostate cancer, urologists use empiric antibiotic treatment for men with increased PSA levels. But it is controversial whether antibiotic treatment can exclude inflammation in the differential diagnosis of PSA elevation. Some researchers have found that antibiotic treatment can decrease inflammation-induced PSA elevation and help to reduce unnecessary biopsies, while others have reported that antibiotic treatment has no significant effect on the PSA level, and the lowered level of PSA following antibiotic treatment does not mean the decreased risk of prostate cancer. Further researches are needed to confirm the value of antibiotic treatment before biopsy. PMID- 22934525 TI - [Sperm selection in assisted reproductive technology: an update]. AB - Sperm selection plays an important role in assisted reproductive technology. In recent years, sperm evaluation is not limited to the assessment of sperm motility and morphology, but involves more other sperm characteristics such as sperm ultrastructure, DNA integrity, apoptosis and membrane. Assessment based on these characteristics is becoming the aim of sperm selection. This article gives an overview on several newly developed techniques for sperm selection according to different technical principles, such as electrophoretic separation, zeta potential, HA binding, Annexin V binding, intracytoplasmic morphologically selected sperm injection (IMSI) and microfluidic sperm sorter, which have all been applied to IVF or ICSI with the exception of microfluidic sperm sorter. It also introduces the advantages, disadvantages and application effects of these techniques. PMID- 22934526 TI - [Shengjing prescription improves semen parameters of oligoasthenozoospermia patients: efficacy and mechanism]. AB - OBJECTIVE: To investigate the clinical efficacy of Shengjing prescription for oligoasthenozoospermia and its action mechanism. METHODS: We equally assigned 120 patients with oligoasthenozoospermia to receive Shengjing prescription (treatment group) and vitamin E (control group), respectively, for 12 weeks. Before and after the treatment, were obtained sperm concentration, sperm motility, the percentage of morphologically normal sperm, the levels of serum follicle stimulating hormone (FSH), testosterone (T) and luteinizing hormone (LH), sperm DNA fragmentation index (DFI), the percentage of hypotonic swelling sperm, and the levels of seminal plasma elastase, x-glucosidase, fructose, zinc and acrosin. RESULTS: Compared with vitamin E, Shengling prescription significantly improved sperm concentration, motility and morphology (P < 0.01), decreased the serum FSH level, elevated the serum T level (P <0. 01) , reduced DFI and seminal plasma elastase, and increased the percentage of hypotonic swelling sperm as well as the levels of seminal plasma cx-glucosidase, fructose, zinc and acrosin. CONCLUSION: Shengjing prescription improves semen parameters of patients with oligoasthenozoospermia at multiple levels and through multiple channels. PMID- 22934527 TI - Asymmetric hydrogenation of thiophenes and benzothiophenes. AB - An efficient and highly asymmetric ruthenium-N-heterocyclic carbene-catalyzed hydrogenation of substituted thiophenes and benzothiophenes is described, providing a new strategy for the formation of valuable enantiomerically pure tetrahydrothiophenes and 2,3-dihydrobenzothiophenes. PMID- 22934528 TI - Effect of 10% and 15% carbamide peroxide on fracture toughness of human dentin in situ. AB - PURPOSE: Although damage to the structural integrity of the tooth is not usually considered a significant problem associated with tooth bleaching, there have been some reported negative effects of bleaching on dental hard tissues in vitro. More studies are needed to determine whether the observed in vitro effects have practical clinical implications regarding tooth structural durability. OBJECTIVES: This in situ study evaluated the effect of 10% and 15% carbamide peroxide (CP) dental bleach, applied using conventional whitening trays by participants at home, on the fracture toughness of dentin. METHODS: Ninety-one adult volunteers were recruited (n ~ 30/group). Compact fracture toughness specimens (approximately 4.5 * 4.6 * 1.7 mm) were prepared from the coronal dentin of recently extracted human molars and gamma-radiated. One specimen was fitted into a prepared slot, adjacent to a maxillary premolar, within a custom made bleaching tray that was made for each adult participant. The participants were instructed to wear the tray containing the dentin specimen with placebo, 10% CP, or 15% CP treatment gel overnight for 14 nights and to store it in artificial saliva when not in use. Pre-bleach and post-bleach tooth color and tooth sensitivity were also evaluated using ranked shade tab values and visual analogue scales (VASs), respectively. Within 24-48 hours after the last bleach session, the dentin specimens were tested for fracture toughness using tensile loading at 10 mm/min. Analysis of variance, Kruskal-Wallis, chi (2) , Tukey's, and Mann Whitney U tests were used for statistical analysis. The level of significance was set at p<0.05 for all tests, except for the Mann-Whitney U tests, which used a Bonferroni correction for post hoc analyses of the nonparametric data (p<0.017). Results : The placebo, 10% CP, and 15% CP groups contained 30, 31, and 30 participants, respectively. Mean fracture toughness (+ standard deviation) for the placebo, 10% CP, and 15% CP groups were 2.3 +/- 0.9, 2.2 +/- 0.7, and 2.0 +/- 0.5 MPa*m(1/2) respectively. There were no significant differences in mean fracture toughness results among the groups (p=0.241). The tooth sensitivity VAS scores indicated a significantly greater incidence (p=0.000) and degree of tooth sensitivity (p=0.049 for VAS change and p=0.003 for max VAS) in the bleach groups than in the placebo group. The color change results showed generally greater color change in the bleach groups than in the placebo group (p=0.008 for shade guide determination and p=0.000 for colorimeter determination). CONCLUSIONS: There were no significant differences in in situ dentin fracture toughness results among the groups. The results of this study provide some reassurance that dentin is not overtly weakened by the bleaching protocol used in this study. However, the lack of a statistically significant difference cannot be used to state that there is no effect of bleach on dentin fracture toughness. PMID- 22934529 TI - Directed drop transport rectified from orthogonal vibrations via a flat wetting barrier ratchet. AB - We introduce the wetting barrier ratchet, a digital microfluidic technology for directed drop transport in an open air environment. Cyclic drop footprint oscillations initiated by orthogonal vibrations as low as 37 MUm in amplitude at 82 Hz are rectified into fast (mm/s) and controlled transport along a fabricated ratchet design. The ratchet is made from a simple wettability pattern atop a microscopically flat surface consisting of periodic semi-circular hydrophilic features on a hydrophobic background. The microfluidic ratchet capitalizes on the asymmetric contact angle hysteresis induced by the curved features to drive transport. In comparison to the previously reported texture ratchets, wetting barrier ratchets require 3-fold lower actuation amplitudes for a 10 MUL drop, have a simplified fabrication, and can be made optically flat for applications where transparency is paramount. PMID- 22934530 TI - Learning word meanings during reading: effects of phonological and semantic cues on children with language impairment. AB - Phonological and semantic deficits in spoken word learning have been documented in children with language impairment (LI), and cues that address these deficits have been shown to improve their word learning performance. However, the effects of such cues on word learning during reading remain largely unexplored. This study investigated whether (a) control, (b) phonological, (c) semantic, and (d) combined phonological-semantic conditions affected semantic word learning during reading in 9- to 11-year-old children with LI (n = 12) and with typical language (TL, n = 11) from low-income backgrounds. Children were exposed to 20 novel words across these four conditions prior to reading passages containing the novel words. After reading, a dynamic semantic assessment was given, which included oral definitions, contextual clues, and multiple choices. Results indicated that the LI group performed more poorly than the TL group in phonological and combined conditions, but not in the control or semantic conditions. Also, a similar trend for both groups was suggested, with improved performance in the semantic and combined conditions relative to the control and phonological conditions. Clinical implications include a continued need for explicit instruction in semantic properties of novel words to facilitate semantic word learning during reading in children with LI. PMID- 22934531 TI - Chemodynamics of soft nanoparticulate complexes: Cu(II) and Ni(II) complexes with fulvic acids and aquatic humic acids. AB - The dynamics of metal complexation by small humic substances (fulvic acid and aquatic humic acid, collectively denoted as "fulvic-like substance", FS) are explored within the framework of concepts recently developed for soft nanoparticulate complexants. From a comprehensive collection of published equilibrium and dissociation rate constants for CuFS and NiFS complexes, the association rate constant, ka, is determined as a function of the degree of complexing site occupation, theta. From this large data set, it is shown for the first time that ka is independent of theta. This result has important consequences for finding the nature of the rate limiting step in the association process. The influence of electric effects on the rate of the association process is described, namely (i) the accelerating effect of the negatively charged electrostatic field of FS on the diffusion of metal ions toward it, and (ii) the extent to which metal ions electrostatically accumulate in the counterionic atmosphere of FS. These processes are discussed qualitatively in relation to the derived values of ka. For slowly dehydrating metal ions such as Ni(H2O)6 2+ (dehydration rate constant, kw), ka is expected to derive straight from kw. In contrast, for rapidly dehydrating metal ions such as Cu(H2O)6 2+, transport limitations and electric effects involved in the formation of the precursor outer sphere associate appear to be important overall rate-limiting factors. This is of great significance for understanding the chemodynamics of humic complexes in the sense that inner-sphere complex formation would not always be the (sole) rate limiting step. PMID- 22934532 TI - Monodisperse Fe3O4 and gamma-Fe2O3 magnetic mesoporous microspheres as anode materials for lithium-ion batteries. AB - Monodisperse Fe(3)O(4) and gamma-Fe(2)O(3) magnetic mesoporous microspheres are prepared via a surfactant-free solvothermal combined with precursor thermal transformation method. The as-prepared Fe(3)O(4) and gamma-Fe(2)O(3) magnetic mesoporous microspheres have a relatively high specific surface area of 122.3 and 138.6 m(2)/g, respectively. The Fe(3)O(4) and gamma-Fe(2)O(3) magnetic mesoporous microspheres are explored as the anode materials for lithium-ion batteries, and they have a high initial discharge capacity of 1307 and 1453 mA h/g, respectively, and a good reversible performance (450 mA h/g for Fe(3)O(4) and 697 mA h/g for gamma-Fe(2)O(3) after 110 cycles) at the current density of 0.2C. PMID- 22934533 TI - Curcumin-mediated photodynamic inactivation of Candida albicans in a murine model of oral candidiasis. AB - In vitro investigations of curcumin-mediated photodynamic therapy (PDT) are encouraging, but there is a lack of reliable in vivo evidence of its efficacy. This study describes the photoinactivation of Candida albicans in a murine model of oral candidiasis, using curcumin as a photosensitizer. Forty immunosuppressed mice were orally inoculated with C. albicans and after five days, they received topical curcumin (20, 40 and 80 MUM) and illumination with LED light. The use of curcumin or light alone were also investigated. Positive control animals did not receive any treatment and negative control animals were not inoculated with C. albicans. The number of surviving yeast cells was determined and analyzed by ANOVA and Tukey's post-hoc test (alpha = 0.05). Histological evaluation of the presence of yeast and inflammatory reaction was also conducted. All exposures to curcumin with LED light caused a significant reduction in C. albicans viability after PDT, but the use of 80 MUM curcumin associated with light was able to induce the highest log10 reduction in colony counts (4 logs). It was concluded that curcumin-mediated PDT proved to be effective for in vivo inactivation of C. albicans without harming the host tissue of mice. PMID- 22934534 TI - Long-term impact of entecavir monotherapy in chronic hepatitis B patients with a partial virologic response to entecavir therapy. AB - OBJECTIVE: Partial virologic response (PVR) in chronic hepatitis B (CHB) patients during antiviral therapy is associated with an increased risk of occurrence of viral resistance and treatment failure. The aim of this study was to evaluate the clinical and virological responses of partial responders to long-term entecavir (ETV) monotherapy. MATERIAL AND METHOD: In this open-labeled prospective study, 128 treatment-naive CHB patients treated with 0.5 mg ETV once daily for more than 12 months were monitored at baseline and at 3-month intervals during treatment. RESULTS: At baseline, the mean age of subjects was 47.0 +/- 13.0 years, and the median duration of treatment was 27 months; 85 subjects (66.4%) were HBeAg positive, and 47 patients (36.7%) had liver cirrhosis. Eighteen of 128 patients (14.0%) showed PVR to 48 weeks of ETV treatment, and 13 patients were followed up for over 24 months. Among them, 9 of 13 patients (69.2 %) achieved a complete virologic response (VR, HBV-DNA < 60 IU/mL) during prolonged ETV treatment. Four showed persistent PVR, but only one patient with poor compliance developed genetic resistance to ETV at month 27. The occurrence of PVR was independently associated with a high viral load, more than 7 log(10) IU/mL (p = 0.014). CONCLUSIONS: CHB patients with a high viral load, more than 7 log log(10) IU/mL, are related to the occurrence of PVR during ETV monotherapy. Long-term ETV monotherapy may be effective for suppressing serum HBV DNA levels in treatment- naive CHB patients with a PVR to ETV. PMID- 22934535 TI - Novel missense mutations of WNK1 in patients with hypokalemic salt-losing tubulopathies. AB - Clinical and genetic studies have suggested that a loss of function and gain of function mutation in the same gene can cause different diseases. The aim of this study was to test the hypothesis that inactivating mutations in WNK1 (with no K (lysine) protein kinase-1) or WNK4 could be a new candidate for causing hypokalemic salt-losing tubulopathy (SLT) in those patients with unknown genetic defects because SLT is the opposite phenotype to pseudohypoaldosteronism type II (PHAII). We screened 44 SLTs patients and found that 33 (75%) cases had homozygous or compound heterozygous mutations in CLCNKB or SLC12A3. Two novel missense mutations were identified in WNK1, but not in WNK4, in 2 of the remaining 11 patients. The WNK1 mutations occurred in the protein C-terminus domain, de novo and inherited, respectively. One of these WNK1 mutations was shown to reduce NCC protein membrane expression in vitro because of impairing the suppressive effect of WNK4-mediated inhibition. Taken together, our findings suggest that inactivating mutations in WNK1 may cause SLT, a phenotype opposite to that of PHAII caused by WNK1 intronic deletion. PMID- 22934536 TI - Quality of life in elderly diabetic patients with peripheral arterial disease. AB - AIM: To study the impact of peripheral arterial disease (PAD) on quality of life and functional status in Egyptian elderly diabetic patients. METHODS: This case control study included 90 non-demented patients aged 60 years and older. Quality of life assessment was carried out using the Short Form 36 health survey (SF-36), Arterial duplex for diagnosis of peripheral arterial disease; Mini-Mental State Examination, Geriatric Depression Scale, Activity of Daily Living and Instrumental Activity of Daily Living were used. RESULTS: SF-36 domains (except emotional well-being) were significantly affected in diabetic patients with PAD compared with the diabetic patients without PAD. Most of functional assessment items were significantly affected in diabetic patients with PAD compared with diabetic patients without PAD. Increasing PAD severity and presence of PAD symptoms had a significant negative impact on SF-36 scores. Among diabetic complications in PAD patients, cardiovascular disease or stroke significantly affected quality of life. CONCLUSION: PAD significantly affects quality of life and functional status in elderly diabetic patients. PMID- 22934537 TI - Plakilactones from the marine sponge Plakinastrella mamillaris. Discovery of a new class of marine ligands of peroxisome proliferator-activated receptor gamma. AB - In this paper we report the isolation and the molecular characterization of a new class of PPARgamma ligands from the marine environment. Biochemical characterization of a library of 13 oxygenated polyketides isolated from the marine sponge Plakinastrella mamillaris allowed the discovery of gracilioether B and plakilactone C as selective PPARgamma ligands in transactivation assays. Both agents covalently bind to the PPARgamma ligand binding domain through a Michael addition reaction involving a protein cysteine residue and the alpha,beta unsaturated ketone in their side chains. Additionally, gracilioether C is a noncovalent agonist for PPARgamma, and methyl esters 1 and 2 are noncovalent antagonists. Structural requirements for the interaction of these agents within the PPARgamma ligand binding domain were obtained by docking analysis. Gracilioether B and plakilactone C regulate the expression of PPARgamma-dependent genes in the liver and inhibit the generation of inflammatory mediators by macrophages. PMID- 22934538 TI - A general and regioselective synthesis of 5-trifluoromethyl-pyrazoles. AB - Two synthetic approaches to 4-trifluoromethylsydnones, a novel class of these mesoionic reagents, are reported. These compounds undergo regioselective alkyne cycloaddition reactions, thereby providing a general approach to 5 trifluoromethylpyrazoles. This method has been employed in a short formal synthesis of the herbicide fluazolate. PMID- 22934539 TI - Theory and model use in social marketing health interventions. AB - The existing literature suggests that theories and models can serve as valuable frameworks for the design and evaluation of health interventions. However, evidence on the use of theories and models in social marketing interventions is sparse. The purpose of this systematic review is to identify to what extent papers about social marketing health interventions report using theory, which theories are most commonly used, and how theory was used. A systematic search was conducted for articles that reported social marketing interventions for the prevention or management of cancer, diabetes, heart disease, HIV, STDs, and tobacco use, and behaviors related to reproductive health, physical activity, nutrition, and smoking cessation. Articles were published in English, after 1990, reported an evaluation, and met the 6 social marketing benchmarks criteria (behavior change, consumer research, segmentation and targeting, exchange, competition and marketing mix). Twenty-four articles, describing 17 interventions, met the inclusion criteria. Of these 17 interventions, 8 reported using theory and 7 stated how it was used. The transtheoretical model/stages of change was used more often than other theories. Findings highlight an ongoing lack of use or underreporting of the use of theory in social marketing campaigns and reinforce the call to action for applying and reporting theory to guide and evaluate interventions. PMID- 22934541 TI - Predicting hypothyroidism from the Whickham Survey. PMID- 22934540 TI - Twins and the mystery of missing heritability: the contribution of gene environment interactions. AB - Since 2006, the advent of increasingly larger genome-wide association studies and their meta-analyses have led to numerous, replicated findings of genetic polymorphisms associated with many diseases and traits. Early studies suggested that the identified loci generally accounted for a small fraction of the genetic variance estimated from twin and family studies. This led to the concept of 'missing heritability'. Here, the progress in accounting for a greater proportion of the variance is reviewed. In particular, gene-environment interactions can, for some traits and in certain circumstances, explain part of this missing heritability. PMID- 22934542 TI - The effects of GM-CSF and IL-5 as molecular adjuvants on immune responses and contraception induced by mZP3 DNA vaccination. AB - PROBLEM: Various approaches have been developed to improve the antibody response of zona pellucida glycoprotein-3 (ZP3) vaccination. In this study, we investigated whether GM-CSF and IL-5 can be used as cytokine adjuvants to increase the humoral immune response generated by mouse ZP3 (mZP3) DNA vaccine. METHOD OF STUDY: Mice in experimental group were injected by GM-CSF 4 days before the co-immunization of IL-5 and mZP3 DNA vaccine. The contraception and the correlation with humoral and cellular immune responses were analyzed after immunization and mating. The effect of cytokine adjuvant on the maturation of DCs was evaluated. RESULTS: Co-immunization of GM-CSF and IL-5 with mZP3 DNA vaccine induced the highest level of serum IgG and IL-4 expression in CD4(+) T cells. Importantly, this strategy reduced mice fertility without disrupting normal ovarian morphology. GM-CSF enhanced the maturation of DCs evidenced by up regulating the expression of MHC-II and CD86. CONCLUSION: GM-CSF and IL-5 co administration enhanced humoral immune responses to mZP3, and this may be a potential strategy for development of immunocontraceptive vaccine. PMID- 22934543 TI - Projecting overwintering regions of the beet armyworm, Spodoptera exigua in China using the CLIMEX model. AB - The beet armyworm, Spodoptera exigua Hubner (Lepidoptera: Noctuidae) is a serious agricultural pest worldwide. However, population sources of S. exigua in outbreak regions are still vague due to the lack of understanding the distribution of overwintering regions, especially in China. In the present study, the potential overwintering regions of S. exigua in China are projected using the method of Compare Location in the CLIMEX model in order to understand the population sources in outbreak regions and establish an accurate forecasting system. The results showed the southern and northern overwintering boundaries near the Tropic of Cancer (about 23.5 ( degrees )N) and the Yangtze River valley (about 30 ( degrees )N), respectively. Meanwhile, the projection was supported by the data of fieldwork in 14 countries/cities during winter from 2008-2010. In conclusion, results of this study indicated that the overwintering regions of S. exigua were accurately projected by the CLIMEX model. PMID- 22934544 TI - Intrinsic properties of mesemchymal stem cells from human bone marrow, umbilical cord and umbilical cord blood comparing the different sources of MSC. AB - The past decade has witnessed numerous publications on mesenchymal stem cells (MSC), which have great potential in regenerative medicine. MSC from various types of origins exhibit different characteristics, which may relate to the maintenance role of MSC in that specific source. Reports have emerged that among the most widely investigated sources, umbilical cord (UC) or umbilical cord blood (UCB) derived MSC throw advantages over bone marrow (BM) derived MSC due to their close to fetal origin. Here the methodologies used to separate MSC from UC or UCB, and the intrinsic properties, including proliferation capacity, multipotency, cytokine profile, cell surface protein expression and gene expression, between UC, UCB and BM derived MSC, are discussed in details, though may not in a full picture, for the first time. PMID- 22934545 TI - The management of the infected diabetic foot. AB - Diabetes is a chronic disease with a worldwide increasing trend. Foot complications, closely related to neuropathy and obstructive peripheral vascular disease, are responsible for more than 1 million of leg amputations every year. Foot infection can dramatically increase the risk of amputation. Although many ulcer classification systems have been proposed to stratify the severity of the infectious process, the definition of a specific therapeutic approach still remains an unsolved problem. A Diabetic Foot Triage and an Integrated Surgical Protocol are proposed to identify a diagnostic flowchart and a step-by-step surgical protocol that can be applied in the treatment of diabetic foot infection. Considering the rapid climbing of multidrug resistant strains it is very important to rationalize the use of antibiotics utilizing them only for the treatment of true infected ulcers. PAD is widely considered the most important factor conditioning the outcome of a diabetic foot ulcer. Currently no randomized control trials are reported in the international literature directly comparing open versus endovascular revascularisation in diabetic patients with CLI. Insufficient data are available to demonstrate whether open bypass surgery or endovascular interventions are more effective in these patients. A decisional flow chart in choosing the best revascularization strategy in diabetic patients with CLI is proposed. Goals and technical aspects of emergency and elective surgical procedures in diabetic foot are analysed to evaluate critical aspects and to suggest proper surgical choices. PMID- 22934546 TI - Review of evidence that epidemics of type 1 diabetes and type 2 diabetes/metabolic syndrome are polar opposite responses to iatrogenic inflammation. AB - There is an epidemic in children of metabolic syndrome, obesity, type 2 diabetes and other individual diseases that form the components of metabolic syndrome. Poor diet and low exercise can not explain many facets of the epidemic including the onset in children 6 month of age, the protective effect of obesity on the incidence of type 1 diabetes and the epidemic of type 2 diabetes/metabolic syndrome in grass fed horses. Poor diet and exercise also do not explain the epidemic of type 1 diabetes in children that resembles the epidemic of type 2 diabetes/metabolic syndrome. Several papers have been published to indicate that the epidemics of type 1 and type 2 diabetes/metabolic syndrome in children are linked and are polar opposite responses to iatrogenic inflammation. Several lines of research support this. Data from different races indicates that there is an inverse relationship between developing type 1 diabetes and type 2 diabetes. Races with high risk of developing type 2 diabetes have a decreased risk of developing type 1 diabetes. Data from Italy confirmed an inverse association between obesity and type 1 diabetes. Further studies indicate the inverse relationship between type 1 diabetes and type 2 diabetes/obesity is due to cortisol production. Data indicates those with low cortisol responses have a predilection for type 1 diabetes and other autoimmune disorders following inflammation, while those with high cortisol/ immune suppressive responses develop type 2 diabetes/metabolic syndrome/obesity which resembles a Cushingoid state but are spared in the autoimmune disorders. Japanese children produce much more cortisol following immunization than Caucasian children. The later explains why discontinuation of BCG vaccination was associated with a decrease in type 1 diabetes in European children and a decrease in type 2 diabetes in Japanese children. Both the epidemics of type 1 diabetes and metabolic syndrome correlate with an increase in immunization. Finally, there is a strong mechanism data that macrophage produced interleukin 1, tumor necrosis factor and interleukin 6, which are released following inflammation, causing destruction of insulin secreting islet cells and increase cortisol release, and thus have the ability to cause both type 1 and type 2 diabetes/metabolic syndrome (which resembles a Cushingoid state). The propensity to develop type 1 diabetes or type 2 diabetes/metabolic syndrome depends on the propensity to release of cortisol which correlates with race. PMID- 22934548 TI - Quality of life of children with type 1 diabetes: a systematic review. AB - INTRODUCTION: Children with type 1 diabetes mellitus (T1DM) have to deal with a complex and demanding daily treatment regime which can have a negative impact on the quality of life (QoL) of these patients. The objective of the present study is to review studies that have compared generic quality of life of children and adolescents with T1DM with that of healthy peers. In addition, we will examine whether QoL differs between boys and girls, and across different developmental stages. METHODS: A systematic literature search using PubMed was conducted for the years 2000 through May 2012. 17 studies were eligible for the current review. Effect sizes were computed to estimate the effects of having T1DM on QoL in children and adolescents. RESULTS: Although individual studies reported small to moderate effect sizes on the distinct QoL-domains, the weighted effect sizes across all studies indicated no differences in QoL-domains between children and adolescents with T1DM and healthy controls. However, disease-specific problems were certainly present. Girls with T1DM reported lower generic and disease specific QoL than boys with T1DM. Relationships between age and generic or disease-specific QoL remained unclear. CONCLUSIONS: Although children and adolescents with T1DM have to live with a demanding treatment regime, overall results revealed that their generic QoL is not impaired compared to healthy peers. However, disease-specific QoL problems, including a negative impact of diabetes on daily functioning, and diabetes-related worries were certainly present. Longitudinal research is needed in order to provide tailored care for children of all ages with T1DM. PMID- 22934549 TI - Long-term reproductive and metabolic consequences of PCOS. AB - Polycystic ovary syndrome (PCOS) is associated with reproductive and metabolic consequences. The review of findings indicate that the long-term reproductive outcomes of women with PCOS are surprisingly similar compared to women with normal ovaries, and that they have an ovarian reserve possibly superior to women with normal ovaries. The typical features of PCOS, specifically the anovulatory cycles tend to normalize over time, but in spite of a decrease over time, free androgen levels remain elevated compared to age-matched control subjects. Women with PCOS diagnosed at young age continue to display reduced insulin sensitivity in the perimenopausal age, independent from phenotypic expression of PCOS, both at diagnosis and at follow-up. Insulin resistance does not seem to deteriorate further, however. Overall, the accumulated data from several European cohort studies of older women with a previous diagnosis of PCOS suggest an increased incidence of type 2 diabetes, increased prevalence of several features of the metabolic syndrome, but no increased incidence of mortality from CVD. PMID- 22934547 TI - The immunosuppressive role of adenosine A2A receptors in ischemia reperfusion injury and islet transplantation. AB - Activation of adenosine A2A receptors (A2AR) reduces inflammation by generally inhibiting the activation of pro-inflammatory cells, decreasing endothelial adhesion molecule expression and reducing the release of proinflammatory cytokine mediators. Numerous preclinical studies using selective A2AR agonists, antagonists, A2AR knockout as well as chimeric mice have suggested the therapeutic potential of A2AR agonists for the treatment of ischemia reperfusion injury (IRI) and autoimmune diseases. This review summarizes the immunosuppressive actions of A2AR agonists in murine IRI models of liver, kidney, heart, lung and CNS, and gives details on the cellular effects of A2AR activation in neutrophils, macrophages, dendritic cells, natural killer cells, NKT cells, T effector cells and CD4+CD25+FoxP3+ T regulatory cells. This is discussed in the context of cytokine mediators involved in inflammatory cascades. Whilst the role of adenosine receptor agonists in various models of autoimmune disease has been well-documented, very little information is available regarding the role of A2AR activation in type 1 diabetes mellitus (T1DM). An overview of the pathogenesis of T1DM as well as early islet graft rejection in the immediate peri-transplantation period offers insight regarding the use of A2AR agonists as a beneficial intervention in clinical islet transplantation, promoting islet graft survival, minimizing early islet loss and reducing the number of islets required for successful transplantation, thereby increasing the availability of this procedure to a greater number of recipients. In summary, the use of A2AR agonists as a clinical intervention in IRI and as an adjunct to clinical immunesuppressive regimen in islet transplantation is highlighted. PMID- 22934551 TI - Impact of diabetes in blood-testis and blood-brain barriers: resemblances and differences. AB - Blood-tissue barriers prevent an uncontrolled exchange of large molecules between adjacent but metabolically separated compartments. There are several known barriers and two of the most important and tightest blood-tissue barriers are the blood-testis barrier (BTB) and the blood-brain barrier (BBB). Under normal conditions these barriers, formed by tight junctions between adjacent cells, control the entry of substances and metabolites. However, hyperglycemia and other diabetes-related complications, such as hypertension, impair the function of these biological barriers with dramatic consequences. Although both, BBB and BTB, are responsible for the maintenance of different biological processes, they have some remarkable similarities not always explored when looking at metabolic related diseases such as diabetes. These barriers possess their own glucose sensing machinery, suffer a tied hormonal control and have specific mechanisms to counteract hyper- and hypoglycemia. In BBB and BTB the insulin signaling is also distinct from other tissues and organs thus evidencing their importance in protecting against or exacerbating the effects of diabetes on glucose metabolism. The control of glucose and lactate levels in brain and testis highlights the role of these barriers in protecting against peripheral glucose and lactate fluctuations that occur in the diabetic individual. We review the role of BBB and BTB in the control of glucose and metabolic dysfunction caused by diabetes in the brain and seminiferous epithelium. Gaining a better understanding of the molecular mechanisms through which glucose metabolism disrupts BBB and BTB function may highlight new opportunities for the treatment of diabetic complications in brain and male reproductive function. PMID- 22934550 TI - Biological activities of receptor-interacting protein 140 in adipocytes and metabolic diseases. AB - Receptor-interacting protein 140 (RIP140) is best known for its functional role as a wide-spectrum transcriptional co-regulator. It is highly expressed in metabolic tissues including mature adipocyte. In the past decade, molecular biological and biochemical studies revealed extensive and sequential post translational modifications (PTMs) of RIP140. Some of these PTMs affect RIP140's sub-cellular distribution and biological activities that contribute to the development and progression of metabolic diseases. The biological activity of RIP140 that translocates to the cytoplasm in adipocytes is to regulate glucose uptake, adiponectin secretion and lipolysis. Accumulation of RIP140 in the cytoplasm promotes adipocyte dysfunctions, and provides a biomarker of early stages of metabolic diseases. Administering compounds that reduce cytoplasmic accumulation of RIP140 in high fat diet-fed animals can ameliorate metabolic dysfunctions, manifested in improving insulin sensitivity and adiponectin secretion, and reducing incidences of hepatic steatosis. This review summarizes studies demonstrating RIP140's PTMs and biological activities in the cytoplasm of adipocyte, signaling pathways stimulating these PTMs, and a proof-of-concept that targeting cytoplasmic RIP140 can be an effective strategy in managing metabolic diseases. PMID- 22934552 TI - A primary reduced TCA flux governs substrate oxidation in T2D skeletal muscle. AB - Our current knowledge on substrate oxidation in skeletal muscle in relation to insulin resistance and type 2 diabetes (T2D) originate mainly from in vivo studies. The oxidative capacity of skeletal muscle is highly influenced by physical activity, ageing, hormonal status, and fiber type composition, rendering it difficult to determine the contribution of heritable factors to the alteration in oxidative metabolism. Cultured human myotubes offer a unique model to distinguish between primary and environmental factors in the etiology of insulin resistance. The objective of this review is to summarise our studies on substrate oxidation in human myotubes established from lean, obese and T2D subjects, especially focusing on whether the increased respiratory quotient seen in T2D subjects is based on primary traits and whether changes in substrate oxidation may have a common explanation. Obtained results add further regulatory mechanism to our understanding of substrate oxidation in human skeletal muscle during normo an pathophysiological conditions, focusing especially on the governing influence of a primary reduced TCA flux for the diabetic phenotype in skeletal muscle. PMID- 22934553 TI - Toll-like receptors and diabetes complications: recent advances. AB - Diabetes mellitus (DM) is a disease with constellation of metabolic aberrations resulting in debilitating complications. The prevalence of DM worldwide was 2.8% (171 million people) in 2000 and estimated to be at 4.4% (366 million people) in 2030. DM is a major risk factor for heart, kidney diseases, and lower limb amputations. Emerging in vitro and in vivo data suggest that systemic inflammation plays a role in the pathogenesis of DM complications via innate immune receptors. Toll-like receptors (TLRs) are key innate immune receptors that mediate the inflammatory responses in DM. There are no reviews that collectively summarize and examine the detrimental role of TLRs in the manifestation of DM complications namely heart disease, nephropathy, neuropathy, and wound healing. Thus, in this review, we will provide summaries of the TLR expression and activation and elucidate their role in propagating inflammation seen in DM complications. PMID- 22934554 TI - Cancer in adolescents and young adults (15-29 years): a population-based study in the Netherlands 1989-2009. AB - BACKGROUND: Cancer among adolescents and young adults (AYAs; 15-29 years old) is relatively rare but its incidence is increasing worldwide. To define the extent and nature of the AYA patients, this population-based study was performed to explore trends in cancer incidence, survival and risk of second primary cancers in AYAs. MATERIAL AND METHODS: Data from all AYAs diagnosed with cancer between 1989 and 2009 were obtained from the Netherlands Cancer Registry. Age standardized incidence rates with estimated annual percentage of change (EAPC) and five-year relative survival rates were calculated. Relative survival was used as a good approximation of cause-specific survival. All analyses were stratified by gender, five-year age group and calendar period. In addition, Standardized Incidence Ratios were determined to evaluate the risk of second primary cancers. RESULTS: 23 161 AYAs were diagnosed with cancer between 1989 and 2009. Since 1989 the cancer incidence has increased significantly from 28 to 43 per 100 000 person years in males (EAPC: 1.9) and from 30 to 40 per 100 000 person years in females (EAPC: 1.4). The most frequently diagnosed cancers in male AYAs included testicular cancer, melanoma and Hodgkin's disease, whereas in females melanoma, breast cancer and Hodgkin's disease were the most frequently occurring cancers. Five-year relative survival rates were 80% and 82% for males and females, respectively. Over time, the five-year relative survival increased from 74% to 86% and from 79% to 86% in males and females, respectively. The risk of developing a second primary cancer was increased three to six times in males and two to five times in females, depending on rules for counting second primary cancers. CONCLUSIONS: Although the overall survival has improved over time, the progress made in AYAs for specific cancers is still less compared to improvements made in children and adults. This and the increasing incidence and high risk of second primary cancers warrants further research. PMID- 22934555 TI - Combined analysis of vascular invasion, grade, HER2 and Ki67 expression identifies early breast cancer patients with questionable benefit of systemic adjuvant therapy. AB - INTRODUCTION: Over-treatment of low-risk early breast cancer patients with adjuvant systemic therapies is an important clinical challenge. Better techniques are required which can be used to distinguish between the large group of patients with no residual disease after surgery and consequently no benefit of adjuvant treatment, from the smaller group with high relapse risk. A better integration of available prognostic factors might contribute to improved prediction of clinical outcome. MATERIAL AND METHODS: The current study included 346 unselected pT1pN0 patients who did not receive adjuvant systemic treatment. In Norway, no patients with this stage were recommended systemic treatment at the time of the study (1995-1998). Histological type, tumour size, grade, vascular invasion (VI), hormone receptor (HR) status, HER2 and Ki67 (cut-off 10%) were analysed. Median follow-up was 86 months for relapse and 101 months for death. RESULTS: Thirty eight patients experienced relapse, 31 with distant metastasis. Twenty-one patients died of breast cancer. In univariate analysis grade, HER2, HR, VI and Ki67 had impact on clinical outcome (p < 0.005, log rank). In multivariate analysis, only grade 1-2 vs. grade 3, HER2, VI, and Ki67 status were significant for disease free survival, distant disease free survival, and/or breast cancer specific survival. These factors were used in combination, to separate patients into groups based on the number of unfavourable factors present [combined prognostic score (CPS) 0-4]. Close to 2/3 of the patients (61.4%) had no unfavourable factor (CPS0), whilst 18.4% had CPS >= 2. Only 3.6% of those with CPS0 developed metastasis (p < 0.001). The outcome was clearly worse for patients with CPS >= 2 (p < 0.001), systemic relapse was detected in approximately 40%. CONCLUSIONS: This study indicates that the combined use of grade, VI, HER2 and Ki67 identifies a subgroup of breast cancer patients with a relapse risk that may question the benefit of adjuvant systemic therapy. PMID- 22934556 TI - Regression in cancer following fever and acute infection. PMID- 22934557 TI - Long-term clinical outcome of patients with soft tissue sarcomas treated with limb-sparing surgery and postoperative radiotherapy. AB - BACKGROUND: To evaluate long-term local control, survival, radiation side effects and functional outcome after limb-sparing surgery followed by postoperative radiotherapy (RT) for soft tissue sarcoma (STS). MATERIAL AND METHODS: Between 1995 and 2010, 118 patients with STS of an extremity were treated with limb sparing surgery and postoperative RT. Follow-up was complete for all patients. Acute and late radiation related toxicities were scored using CTCAE v4.0. RESULTS: Median follow-up was 93 months. RT dose was 60 Gy in 92.4% of the patients; 5.1% received 66 Gy; 2.5% 50-56 Gy. Actuarial local recurrence rates at five and 10 years were 9% and 12%. Five- and 10-year overall survival rates were 69% and 51%. Acute radiation toxicities occurred in 91% of the patients; 19% were grade 3, 2% grade 4. Late radiation toxicities were reported in 71% of the patients: 50% grade 1, 18% grade 2, and 3% grade 3. Limb and joint function after treatment were good, 19% having mild limitation of motion, 1.5% moderate, and 2.5% severe limitations. CONCLUSION: Limb-sparing surgery with 60 Gy postoperative radiotherapy for patients with STS provides excellent local control and high survival rates with acceptable toxicity and functional outcomes. PMID- 22934558 TI - Interventions for alleviating cancer-related dyspnea: a systematic review and meta-analysis. AB - BACKGROUND: Dyspnea is commonly encountered by many cancer patients in the terminal stage of their disease and it severely hampers their quality of life. We aimed to evaluate the role of interventions to alleviate dyspnea. METHODS: Systematic review and meta-analysis of randomized controlled trials assessing all interventions for dyspnea palliation in cancer patients, and searched the Cochrane Library, MEDLINE, conference proceedings, and references. RESULTS: Our search yielded 18 trials. Eight studies evaluated opioids in any route of administration, seven studies evaluated the use of oxygen, two studies assessed the role of benzodiazepines and two studies evaluated the role of furosemide in alleviating cancer-related dyspnea. Weighted mean difference (WMD) was calculated for continuous variables that were reported on the same scale. For continuous data reported in different scales, standardized mean difference (SMD) was calculated. Meta-analysis of three trials yielded a positive effect for opioid administration, WMD -1.31[95% CI (-2.49)-(- 0.13)]. Meta-analysis of the six studies showed lack of benefit to oxygen to improve dyspnea, SMD -0.3[95% CI 1.06-0.47]. The role of benzodiazepines remains unclear, furosemide was not beneficial. CONCLUSIONS: Our systematic review and meta-analysis demonstrate a beneficial effect to opioids in alleviating cancer-related dyspnea, and no advantage for the use of oxygen. PMID- 22934559 TI - Anxiety and depression in oncology patients; a longitudinal study of a screening, assessment and psychosocial support intervention. AB - BACKGROUND: Anxiety and depression in cancer patients are associated with poor health-related quality of life (HRQOL). Clinical interventions to detect and support patients with these symptoms need to be developed and evaluated. We investigated the feasibility of screening with the Hospital Anxiety and Depression Scale (HADS) in a clinical oncology setting. In patients with anxiety or depression symptoms (HADS >7) we explored the use of clinical assessment and psychosocial support and described the development of anxiety, depression and HRQOL during a six-month period. MATERIAL AND METHODS: Four hundred and ninety five consecutive patients were screened for anxiety and depression at the time of their first visit at an oncology department (baseline). Half of the patients with HADS >7 on any of the two HADS subscales were referred to clinical assessment and psychosocial support (intervention group, IG) and half received standard care (SCG) using a historical control group design. HADS and EORTC QLQ-C30 were completed at baseline and after one, three and six months. RESULTS: One hundred and seventy-six (36%) of 495 patients had anxiety or depression symptoms at screening, HRQOL at baseline was clearly impaired for them. Thirty-six (43%) of 84 IG patients attended clinical assessment, resulting in subsequent psychosocial support for 20 (24%) of them. In the SCG, only five (5%) patients attended clinical assessment after self referral, two received subsequent psychosocial support. Anxiety and depression decreased and HRQOL increased statistically significantly over time although anxiety was frequent and HRQOL impaired during the entire six month period. There were no differences between the SCG and IG regarding anxiety, depression or HRQOL at any time point. CONCLUSION: Systematic screening with HADS is feasible for oncology patients in clinical settings; it identifies patients with persistent symptoms and increases referral to clinical assessment and utilisation of psychosocial support. PMID- 22934561 TI - My life as an astrobiologist. PMID- 22934560 TI - Did mineral surface chemistry and toxicity contribute to evolution of microbial extracellular polymeric substances? AB - Modern ecological niches are teeming with an astonishing diversity of microbial life in biofilms closely associated with mineral surfaces, which highlights the remarkable success of microorganisms in conquering the challenges and capitalizing on the benefits presented by the mineral-water interface. Biofilm formation capability likely evolved on early Earth because biofilms provide crucial cell survival functions. The potential toxicity of mineral surfaces toward cells and the complexities of the mineral-water-cell interface in determining the toxicity mechanisms, however, have not been fully appreciated. Here, we report a previously unrecognized role for extracellular polymeric substances (EPS), which form biofilms in shielding cells against the toxicity of mineral surfaces. Using colony plating and LIVE/DEAD staining methods in oxide suspensions versus oxide-free controls, we found greater viability of wild-type, EPS-producing strains of Pseudomonas aeruginosa PAO1 compared to their isogenic knockout mutant with defective biofilm-producing capacity. Oxide toxicity was specific to its surface charge and particle size. High resolution transmission electron microscopy (HRTEM) images and assays for highly reactive oxygen species (hROS) on mineral surfaces suggested that EPS shield via both physical and chemical mechanisms. Intriguingly, qualitative as well as quantitative measures of EPS production showed that toxic minerals induced EPS production in bacteria. By determining the specific toxicity mechanisms, we provide insight into the potential impact of mineral surfaces in promoting increased complexity of cell surfaces, including EPS and biofilm formation, on early Earth. PMID- 22934562 TI - Upregulation of Sirt1 in carbon-tetrachloride-induced acute liver injury. AB - Sirtuin 1 (Sirt1) has been the focus of intense scrutiny because of its longevity activity. Recent studies also revealed the important role of Sirt1 in metabolic liver diseases. The present study was designed to elucidate the pathophysiological significance of Sirt1 in CCl(4)-induced acute liver injury (ALI). The expression of Sirt1 in liver tissue of mice with CCl(4)-induced ALI was determined by real-time polymerase chain reaction and western blotting. Sirt1 inhibitor nicotinamide (NAM) was administrated to investigate the role of Sirt1 in hepatocyte damage, leukocyte infiltration, and proinflammatory cytokine production. Results indicated that the messenger RNA and protein level of Sirt1 in the liver was gradually increased after CCl(4) administration. Inhibition of Sirt1 by its inhibitor (NAM) exacerbated liver injury, as evidenced by increased serum aminotransferases (alanine aminotransferase and aspartate aminotransferase) levels and more-severe histological damage. The worst liver injury was accompanied by higher myeloperoxidase acitivity in liver tissue and increased circulating levels of both tumor necrosis factor alpha and interleukin-6. These data indicated that the induction of Sirt1 might provide protective effects during CCl(4)-induced ALI. These findings suggest that Sirt1 might be an endogenous hepatoprotective target with potential pharmacological value in inflammation-based liver diseases. PMID- 22934563 TI - LAC2 encoding a secreted laccase is involved in appressorial melanization and conidial pigmentation in Colletotrichum orbiculare. AB - Both Colletotrichum and Magnaporthe spp. develop appressoria pigmented with melanin, which is essential for fungal pathogenicity. 1,8-Dihydroxynaphthalene (1,8-DHN) is believed to be polymerized to yield melanin around the appresorial cell wall through the oxidative activity of laccases. However, no 1,8-DHN laccase has yet been identified in either Colletotrichum or Magnaporthe spp. Here, we report a laccase gene, LAC2, that is involved in the appressorial melanization of Colletotrichum orbiculare, which causes cucumber anthracnose. LAC2 encodes a protein with a signal peptide and has high homology to fungal laccases. The conidial color of lac2 mutants is distinct from that of the C. orbiculare wild type, and the mutants are nonpathogenic. Notably, the mutant appressoria are defective in melanization, and a host invasion assay showed that the appressoria are nonfunctional. LAC2 was induced during appressorial melanization. These results suggest that LAC2 oxidizes 1,8-DHN in the appressoria. The LAC2 homologues of other fungi located in the same phylogenetic clade as LAC2 fully complemented the lac2 mutants. Interestingly, a LAC2 homologue, located in a different clade, complemented the conidial pigmentation but not appressorial melanization of the mutants, suggesting that the LAC2 function in appressorial melanization might only be conserved in laccases of the LAC2 clade. PMID- 22934564 TI - Pathogen-induced accumulation of an ellagitannin elicits plant defense response. AB - In an incompatible interaction between Colletotrichum fragariae and strawberry plants, the accumulation of phenolic compounds in plant leaves was observed. A particularly abundant penta-esterified ellagitannin that accumulated in response to pathogen attack was identified as 1-0-galloyl-2,3;4,6-bis-hexahydroxydiphenoyl beta-d-glucopyranose (HeT) by mass spectroscopy and nuclear magnetic resonance. Foliar application of purified HeT prior to inoculation with a virulent pathogen was shown to increase resistance toward C. acutatum in strawberry plants and to Xanthomonas citri subsp. citri in lemon plants. The induced resistance in strawberry was associated with a rapid oxidative burst, callose deposition, a transient increase of salicylic acid in phloem, and induction of gene expression responsive to salicylic acid. Results obtained suggested that HeT could be a common plant defense response molecule capable of inducing pathogen resistance in different plant species. PMID- 22934565 TI - Comment on serum FGF21 and RBP4 levels in patients with chronic hepatitis C. PMID- 22934566 TI - Toxicological actions of plant-derived and anthropogenic methylenedioxyphenyl substituted chemicals in mammals and insects. AB - The methylenedioxyphenyl (MDP) substituent is a structural feature present in many plant chemicals that deter foraging by predatory insects and herbivores. With increasing use of herbal extracts in alternative medicine, human exposure to MDP-derived plant chemicals may also be significant. Early studies found that most MDP agents themselves possess relatively low intrinsic toxicity, but strongly influence the actions of other xenobiotics in mammals and insects by modulating cytochrome P-450 (CYP)-dependent biotransformation. Thus, after exposure to MDP chemicals an initial phase of CYP inhibition is followed by a sustained phase of CYP induction. In insects CYP inhibition by MDP agents underlies their use as pesticide synergists, but analogous inhibition of mammalian CYP impairs the clearance of drugs and foreign compounds. Conversely, induction of mammalian CYP by MDP agents increases xenobiotic oxidation capacity. Exposure of insects to MDP-containing synergists in the environment, in the absence of coadministered pesticides, may also enhance xenobiotic detoxication. Finally, although most MDP agents are well tolerated, several, typified by safrole, aristolochic acid, and MDP-kavalactones, are associated with significant toxicities, including the risk of hepatotoxicity or tumorigenesis. Thus, the presence of MDP-substituted chemicals in the environment may produce a range of direct and indirect toxicities in target and nontarget species. PMID- 22934568 TI - Stress in the wild: chronic predator pressure and acute restraint affect plasma DHEA and corticosterone levels in a songbird. AB - The effects of chronic stressors on glucocorticoid levels are well described in laboratory rodents, but far less is known about the effects of chronic stressors on wild animals or on dehydroepiandrosterone (DHEA) levels. DHEA can be produced by the adrenal cortex and has prominent antiglucocorticoid properties. Here, we examined wild songbirds to elucidate the relationship between chronic predator pressure and plasma DHEA and corticosterone levels. We measured circulating steroid levels at baseline and after acute restraint in the breeding and nonbreeding seasons. During the breeding season, males in low predator pressure (LPP) environments had higher baseline DHEA levels than males in high predator pressure (HPP) environments. Also, acute restraint decreased DHEA levels in LPP males only but increased corticosterone levels in HPP and LPP males similarly. During the nonbreeding season, DHEA and corticosterone levels were lower than during the breeding season, and acute restraint decreased DHEA levels in both HPP and LPP males. Unlike males, breeding females showed no effect of predator pressure on baseline DHEA or corticosterone levels. These data suggest that naturalistic chronic and acute stressors affect circulating DHEA and corticosterone levels in wild animals and highlight the importance of using multiple endpoints when studying the physiological effects of chronic stress. PMID- 22934569 TI - Intercropping for management of insect pests of castor, Ricinus communis, in the semi-arid tropics of India. AB - Intercropping is one of the important cultural practices in pest management and is based on the principle of reducing insect pests by increasing the diversity of an ecosystem. On-farm experiments were conducted in villages of semi-arid tropical (SAT) India to identify the appropriate combination of castor (Ricinus communis L.) (Malpighiales: Euphorbiaceae) and intercropping in relation to pest incidence. The diversity created by introducing cluster bean, cowpea, black gram, or groundnut as intercrops in castor (1:2 ratio proportions) resulted in reduction of incidence of insect pests, namely semilooper (Achaea janata L.), leaf hopper (Empoasca flavescens Fabricius), and shoot and capsule borer (Conogethes punctiferalis Guenee). A buildup of natural enemies (Microplitis, coccinellids, and spiders) of the major pests of castor was also observed in these intercropping systems and resulted in the reduction of insect pests. Further, these systems were more efficient agronomically and economically, and were thus more profitable than a castor monocrop. PMID- 22934567 TI - Kerosene: a review of household uses and their hazards in low- and middle-income countries. AB - Kerosene has been an important household fuel since the mid-19th century. In developed countries its use has greatly declined because of electrification. However, in developing countries, kerosene use for cooking and lighting remains widespread. This review focuses on household kerosene uses, mainly in developing countries, their associated emissions, and their hazards. Kerosene is often advocated as a cleaner alternative to solid fuels, biomass and coal, for cooking, and kerosene lamps are frequently used when electricity is unavailable. Globally, an estimated 500 million households still use fuels, particularly kerosene, for lighting. However, there are few studies, study designs and quality are varied, and results are inconsistent. Well-documented kerosene hazards are poisonings, fires, and explosions. Less investigated are exposures to and risks from kerosene's combustion products. Some kerosene-using devices emit substantial amounts of fine particulates, carbon monoxide (CO), nitric oxides (NO(x)), and sulfur dioxide (SO(2)). Studies of kerosene used for cooking or lighting provide some evidence that emissions may impair lung function and increase infectious illness (including tuberculosis), asthma, and cancer risks. However, there are few study designs, quality is varied, and results are inconsistent. Considering the widespread use in the developing world of kerosene, the scarcity of adequate epidemiologic investigations, the potential for harm, and the implications for national energy policies, researchers are strongly encouraged to consider collecting data on household kerosene uses in studies of health in developing countries. Given the potential risks of kerosene, policymakers may consider alternatives to kerosene subsidies, such as shifting support to cleaner technologies for lighting and cooking. PMID- 22934570 TI - Catalytic electrochemistry of xanthine dehydrogenase. AB - We report the mediated electrocatalytic voltammetry of the molybdoenzyme xanthine dehydrogenase (XDH) from Rhodobacter capsulatus at a thiol-modified Au electrode. The 2-electron acceptor N-methylphenazinium methanesulfonate (phenazine methosulfate, PMS) is an effective artificial electron transfer partner for XDH instead of its native electron acceptor NAD(+). XDH catalyzes the oxidative hydroxylation of hypoxanthine to xanthine and xanthine to uric acid. Cyclic voltammetry was used to generate the active (oxidized) form of the mediator. Simulation of the catalytic voltammetry across a broad range of substrate and PMS concentrations at different sweep rates was achieved with the program DigiSim to yield a set of consistent rate and equilibrium constants that describe the catalytic system. This provides the first example of the mediated electrochemistry of a xanthine dehydrogenase (or oxidase) that is uncomplicated by interference from product oxidation. A remarkable two-step, sequential oxidation of hypoxanthine to uric acid via xanthine by XDH is observed. PMID- 22934571 TI - Formation of self-organized nanoporous anodic oxide from metallic gallium. AB - This paper reports the formation of self-organized nanoporous gallium oxide by anodization of solid gallium metal. Because of its low melting point (ca. 30 degrees C), metallic gallium can be shaped into flexible structures, permitting the fabrication of nanoporous anodic oxide monoliths within confined spaces like the inside of a microchannel. Here, solid gallium films prepared on planar substrates were employed to investigate the effects of anodization voltage (1, 5, 10, 15 V) and H(2)SO(4) concentration (1, 2, 4, 6 M) on anodic oxide morphology. Self-organized nanopores aligned perpendicular to the film surface were obtained upon anodization of gallium films in ice-cooled 4 and 6 M aqueous H(2)SO(4) at 10 and 15 V. Nanopore formation could be recognized by an increase in anodic current after a current decrease reflecting barrier oxide formation. The average pore diameter was in the range of 18-40 nm with a narrow diameter distribution (relative standard deviation ca. 10-20%), and was larger at lower H(2)SO(4) concentration and higher applied voltage. The maximum thickness of nanoporous anodic oxide was ca. 2 MUm. In addition, anodic formation of self-organized nanopores was demonstrated for a solid gallium monolith incorporated at the end of a glass capillary. Nanoporous anodic oxide monoliths formed from a fusible metal will lead to future development of unique devices for chemical sensing and catalysis. PMID- 22934572 TI - Spatially resolved tracer diffusion in complex responsive hydrogels. AB - Thermosensitive composite hydrogels that consist of a poly(acrylamide) hydrogel matrix with embedded micrometer-sized poly(N-isopropylacrylamide) microgel beads are promising models for complex, heterogeneous gels. We investigate the coupling of the microgel beads with the gel matrix and the formation of interpenetrating networks inside the microgels by confocal two-focus fluorescence correlation spectroscopy (2fFCS). This technique serves to study the effects of the heterogeneous structure of the composite hydrogels on the diffusive mobility of nanoscopic dextran tracers within the gels. Our investigations reveal that the formation of interpenetrating networks inside the embedded microgel beads depends on their cross-link density: whereas interpenetrating networks are formed inside weakly cross-linked beads, they are not formed inside strongly cross-linked beads. If the formation of interpenetrating networks occurs, the temperature dependent swelling and deswelling of the beads is obstructed. In addition, the mobility of dextran tracers inside the embedded microgel beads is hindered compared to those in free beads and in the surrounding gel matrix. Surprisingly, the surrounding poly(acrylamide) hydrogel matrix swells inhomogeneously when the embedded poly(N-isopropylacrylamide) beads collapse upon heating. This indicates the formation of pores near the surface of the collapsed beads, offering promising means to tailor composite hydrogels for applications as membranes with tunable permeability. Our experiments also demonstrate the utility of 2fFCS to study spatially resolved diffusion in complex environments, which is of great interest in biomaterials research. PMID- 22934573 TI - Characterization of leached phosphorus from soil, manure, and manure-amended soil by physical and chemical fractionation and Diffusive Gradients in Thin films (DGT). AB - We are challenged to date to fully understand mechanisms controlling phosphorus (P) mobilization in soil. In this study we evaluated physical properties, chemical reactivity, and potential bioavailability of P mobilized in soil during a leaching event and examined how the amounts and properties of leached P were influenced by surface application of cattle manure. Leaching experiments on manure itself, and on intact soil columns (14.1 cm inner dia., 25 cm height) before and after manure application, were carried out at an irrigation rate of 1 mm h(-1) for 48 h. High concentrations of dissolved reactive P (DRP) were found in manure leachates (up to 32 mg L(-1)), whereas concentrations of P in soil leachates were low both before and after manure application (around 0.04 mg L(-1) before application and up to 0.4 mg L(-1) afterward). This result indicates that the soil retained most of the P added with manure. Manure particles themselves were also largely retained by the soil. Combined physical (centrifugation) and chemical (molybdate reactiveness) fractionation of leached P showed that leachates in the manure treated soils were dominated by dissolved unreactive P (DUP), mainly originating from manure. However, centrifugation only removed a small fraction of total particles from the leachates, indicating that the so called dissolved fraction may be associated with low density particulate matter. Deployment of Diffusive Gradients in Thin films (DGT) devices in the leachates proved to be a good approach for measuring reactive P in soil leachates. The results indicated that total reactive P (TRP) gave a better estimate of potentially bioavailable P than both total P (TP) and DRP in these experiments. PMID- 22934574 TI - Age-related changes of dopamine, noradrenaline and adrenaline in adrenal glands of mice. AB - AIM: Catecholamines, which are physiologically important neurotransmitters and hormones, apparently decrease in the brain and plasma as some species age. Because this observation has engendered controversy, we used mice to investigate whether age-related changes occur in adrenal catecholamine levels and in the expression of catecholamine synthetic enzymes. METHODS: Adrenal glands were collected from male C57BL/6NCr mice at the ages of 6, 12 and 24 months. Catecholamines, such as dopamine (DA), noradrenaline (NA) and adrenaline (AD) from those glands, were measured by using a highly sensitive liquid chromatographic method with peroxyoxalate chemiluminescence reaction detection. Tyrosine hydroxylase (TH), dopa decarboxylase, dopamine beta hydroxylase (DBH) and phenylethanolamine N-methyltransferase (PNMT) mRNA expression levels were measured by quantitative real-time polymerase chain reaction. RESULTS: Although DA levels in the adrenals of 24-month-old mice were higher than in 6- and 12 month-old mice, the AD content decreased with age. In such mice, the ratio of DA to NA at 24 months was lower than at 12 months, and the ratio of NA to AD content at 24 months was significantly lower than at 6 months. The mRNA expression ratios in TH, DBH and PNMT in 24-month-old mice were all lower than in 12-month-old mice. CONCLUSIONS: These results strongly suggest that catecholamine synthesis, in general, declines with aging in the adrenal glands of mice and that AD, in particular, undergoes a significant decrease with advancing age. PMID- 22934576 TI - Behaviour in children with neurofibromatosis type 1: cognition, executive function, attention, emotion, and social competence. AB - AIM: This systematic review aimed to pull together the findings from research into behavioural systems and attention in children with neurofibromatosis type 1 (NF1) and to identify areas that need further study. METHOD: Relevant papers were identified through searches of electronic databases (MEDLINE, PsycINFO, EMBASE) and manual searches through reference lists. In total, 5746 articles were identified and 57 met the inclusion criteria. The data were synthesized using the narrative approach, as the studies varied considerably in terms of participants and measures. RESULTS: The results of the review showed that intelligence, academic skills, visuospatial skills, social competence, and attention are impaired in children with NF1. Evidence of deficits in memory, motor functioning, language, and executive functions was less clear. INTERPRETATION: Research has made marked progress in outlining the behavioural phenotype of NF1. However, although the general areas of impairment are becoming better known, the exact nature of the impairment is still not understood in many areas of behaviour. Care needs to be taken with the way in which behavioural constructs are defined and measured, and the variability of problems in NF1 is a particular challenge. Nevertheless, research is steadily moving towards comprehensive understanding of behaviour in children with NF1. PMID- 22934575 TI - Discovery and preclinical pharmacology of a selective ATP-competitive Akt inhibitor (GDC-0068) for the treatment of human tumors. AB - The discovery and optimization of a series of 6,7-dihydro-5H cyclopenta[d]pyrimidine compounds that are ATP-competitive, selective inhibitors of protein kinase B/Akt is reported. The initial design and optimization was guided by the use of X-ray structures of inhibitors in complex with Akt1 and the closely related protein kinase A. The resulting compounds demonstrate potent inhibition of all three Akt isoforms in biochemical assays and poor inhibition of other members of the cAMP-dependent protein kinase/protein kinase G/protein kinase C extended family and block the phosphorylation of multiple downstream targets of Akt in human cancer cell lines. Biological studies with one such compound, 28 (GDC-0068), demonstrate good oral exposure resulting in dose dependent pharmacodynamic effects on downstream biomarkers and a robust antitumor response in xenograft models in which the phosphatidylinositol 3-kinase-Akt mammalian target of rapamycin pathway is activated. 28 is currently being evaluated in human clinical trials for the treatment of cancer. PMID- 22934577 TI - Enantioselective synthesis of 2,6-cis-disubstituted tetrahydropyrans via a tandem catalytic asymmetric hydrogenation/oxa-Michael cyclization: an efficient approach to (-)-centrolobine. AB - A highly efficient one-pot process via a tandem reaction of catalytic asymmetric hydrogenation and oxa-Michael cyclization for the synthesis of 2,6-cis disubstituted tetrahydropyrans has been developed (ee up to 99.9%, cis/trans selectivity up to 99:1). This method provides a concise route to (-)-centrolobine (68.8% yield, three steps). PMID- 22934578 TI - Mid-pregnancy maternal leptin levels, birthweight for gestational age and preterm delivery. AB - OBJECTIVE: Maternal blood leptin levels are positively associated with adiposity. Recent studies suggest that leptin is also abundantly produced by the placenta and may function as a regulator of foetal growth. Our goal was to examine mid pregnancy levels of leptin in maternal blood in relation to birthweight for gestational age (BW/GA) and timing of delivery after accounting for maternal prepregnancy body mass index (prepreg-BMI) and pregnancy complications. PATIENTS: Data were from 1304 subcohort mother/infant pairs who participated in the Pregnancy Outcomes and Community Health (POUCH) Study (1998-2004). MEASUREMENTS: Leptin levels, measured at 16-27 weeks' gestation, were log-transformed. Geometric mean (GMean) leptin levels were estimated by weighted linear regression with gestational age at blood draw as a covariate. GMean was re-transformed to the original scale for reporting. RESULTS: Using the GMeans leptin in mothers of term appropriate-for-gestational age (AGA) neonates as the referent (25.2 MUg/l), we observed lower levels in mothers of preterm-AGA (21.9 MUg/l), term small-for gestational age (SGA) (20.3 MUg/l) and preterm-SGA neonates (21.7 MUg/l). Results were largely unchanged after adjustment for prepreg-BMI. Leptin levels were higher in mothers who delivered large-for-gestational age (LGA) neonates, both preterm (33.6 MUg/l) and term (29.1 MUg/l), but the GMeans were markedly attenuated after adjustment for prepreg-BMI. CONCLUSION: The association between BW/GA and maternal leptin levels after adjustment for prepreg-BMI may represent: (i) a residual effect of maternal adiposity that is not fully captured by BMI; and/or (ii) variation in placental leptin levels entering the maternal circulation. In conclusion, mid-pregnancy maternal blood leptin levels may be an early indicator of foetal growth status. PMID- 22934579 TI - An improved prediction of the human in vivo intestinal permeability and BCS class of drugs using the in vitro permeability ratio obtained for rat intestine using an Ussing chamber system. AB - The Biopharmaceutics Classification System (BCS) was developed to facilitate estimation of the in vivo pharmacokinetic performance of drugs from human intestinal permeability and solubility. However, the measurement of human in vivo intestinal permeability, unlike that of solubility, is problematic and inefficient. Thus, rat in vitro intestinal permeability results obtained via the Ussing chamber technique are often used instead. However, these data could be unreliable due to difficulty in maintaining the viability of the dissected intestinal membrane in the Ussing chamber. Therefore, a more efficient method to obtain a reliable in vitro permeability is mandatory. Here, we propose a new approach by introducing a novel factor called the permeability ratio (PR). Basically, PR is a rat in vitro intestinal permeability obtained from the Ussing chamber, which is then corrected by the permeability of lucifer yellow, a paracellular permeability marker. To prove the validity of the method, 12 model drugs representing different BCS classes were tested, and the correlation with human in vivo intestinal permeability was high. More importantly, the new method perfectly classified all 12 model drugs. The results indicate that PR is a reliable factor with high correlation to human in vivo intestinal permeability, which can further be used to accurately predict the BCS classification. PMID- 22934580 TI - Clinical and radiographic features of moyamoya disease in patients with both cerebral ischaemia and haemorrhage. AB - OBJECTIVES: Patients with moyamoya disease (MMD) very rarely develop both cerebral ischaemia and haemorrhage. The aim of this study was to clarify the clinical and radiographic features of MMD in patients who presented with both ischaemia and haemorrhage, compared with MMD patients who presented with one or the other. MATERIALS AND METHODS: The records of 92 consecutive patients with MMD were reviewed. These patients were divided into three groups, according to the type of presentation: ischaemic presentation (Group I); haemorrhagic presentation (Group H); and haemorrhagic-ischaemic presentation (Group H-I). The patient characteristics, areas of infarction, and angiographic findings were evaluated. RESULTS: Seventy-six (82%) of the 92 patients were categorised as Group I, 7 (8%) as Group H, and 9 (10%) as Group H-I. Median follow-up periods for Group H-I was 55 months (IQR, 36-116 months). There were eight females in Group H-I, in which the median age was 30 years. Of the nine cases in Group H-I, six presented with cerebral haemorrhage as the precedent event and three had complications during the acute phase. In Group H-I, the prevalence of posterior cerebral artery (PCA) lesions was high (42%) and infarctions were most frequently found in PCA-related areas. CONCLUSIONS: The presence of steno-occlusive PCA lesions may be of pathogenic importance in MMD patients who develop both cerebral ischaemia and haemorrhage. The prevalence of this type of stroke in MMD patients is higher than expected, and further investigation in clinical settings is thus warranted. PMID- 22934581 TI - Transient detection of Chlamydial-specific Th1 memory cells in the peripheral circulation of women with history of Chlamydia trachomatis genital tract infection. AB - PROBLEM: Development of safe and effective Chlamydia trachomatis vaccines requires better understanding of the host immune responses elicited by natural infection. METHOD OF STUDY: Peripheral blood mononuclear cells isolated from women with or without history of genital tract chlamydial infection were stimulated with inactivated C. trachomatis elementary bodies (EB) in ELISPOT assays that enumerated frequencies of cells producing interferon (IFN)-gamma or interleukin (IL)-17. RESULTS: IFN-gamma-positive cells were highest among women sampled 30-60 days after diagnosis of C. trachomatis infection and treatment initiation, while the numbers of IFN-gamma-positive cells were equally low among uninfected women and women sampled <30 or >60 days after diagnosis of infection. Conversely, IL-17-positive cell numbers were uniformly low among all participants. CONCLUSION: Dramatically reduced numbers of Chlamydia-specific Th1 memory cells in the peripheral circulation of study participants sampled more than 2 months after diagnosis, and initiation of treatment provides new insight into the results from C. trachomatis vaccine trials, in which immunization with EB provided only short-lived protection. Our results also suggest that an effective vaccine against this weakly antigenic intracellular pathogen will need to generate immunological memory more durable than that elicited by natural infection. PMID- 22934583 TI - Declining health anxiety throughout medical studies: it is mainly about a more relaxed perception of the health-related concerns. AB - BACKGROUND: Reports on effects of advancing medical education on health anxiety are scarce and contradictory. AIM: To evaluate a hypothesis that its components could be differently affected. METHOD: A cross-sectional study assessed the Health Anxiety Questionnaire (HAQ), Anxious Thoughts Inventory, and Somatosensory Amplification Scale scores in medical (n = 214) and law (controls, n = 821) students at different study years. RESULTS: In the controls, all outcomes minimally differed across the study-year levels. Medical scores were similar to control scores at the lower and intermediate level and were significantly lower at higher study years. However, health worry, fear, and reassurance seeking only differed mildly between the medical study levels (adjusted effect sizes <= 0.23), whereas tendency toward amplification, meta-worry, social worry, and the HAQ interference with life score were significantly lower at higher than at the lower years (adjusted effect sizes 0.31-0.47). In the medical students, the HAQ interference with life score was affected mainly by the level of meta-worry, whereas in controls the major impact was that of health-related concerns. CONCLUSIONS: Studying medicine does not seem to relevantly affect the level of health-related concerns, but the degree by which they are perceived as disruptive declines as a specific function of advancing stages of education. This is closely related to progressively declining tendency toward amplification and levels of meta-worry. PMID- 22934584 TI - The use of innovations in medical education: a workshop to maximise effectiveness. PMID- 22934582 TI - Analysis of current antifungal agents and their targets within the Pneumocystis carinii genome. AB - Pneumocystis pneumonia (PCP) remains a leading opportunistic infection in patients with weakened immune systems. The fungus causing the infection belongs to the genus, Pneumocystis, and its members are found in a large variety of mammals. Adaptation to the lung environment of a host with an intact immune system has been a key to its successful survival. Unfortunately, the metabolic strategies used by these fungi to grow and survive in this context are largely unknown. There were considerable impediments to standard approaches for investigation of this unique pathogen, the most problematic being the lack of a long term in vitro culture system. The absence of an ex vivo cultivation method remains today, and many fundamental scientific questions about the basic biology, metabolism, and life cycle of Pneumocystis are unanswered. Recent progress in sequencing of the Pneumocystis carinii genome, a species infecting rats, permitted a more informative search for genes and biological pathways within this pathogen that are known to be targets for existing antifungal agents. In this work, we review the classes of antifungal drugs with respect to their potential applicability to the treatment of PCP. Classes covered in the review are the azoles, polyenes, allylamines, and echinocandins. Factors limiting the use of standard antifungal treatments and the currently available alternatives (trimethoprim-sulfamethoxazole, atovaquone, and pentamidine) are discussed. A summary of genomic sequences within Pneumocystis carinii associated with the corresponding targeted biological pathways is provided. All sequences are available via the Pneumocystis Genome Project at http://pgp.cchmc.org/. PMID- 22934585 TI - Reflective learning in a patient safety course for final-year medical students. AB - BACKGROUND: Patient safety has become an important topic over the last decade and has also been increasingly implemented in the undergraduate curriculum. However, the best timing and method of teaching still remains to be decided. AIMS: To develop and evaluate a patient safety course for final-year students. The course is based on reflective learning and personal experiences to improve the transfer of theory into practice. METHODS: We performed a mixed method evaluation study of the course. An evaluation questionnaire and the number of completed incident report cards were analyzed using descriptive statistics. Focus groups, organized two and four weeks after the course, were analyzed using template analysis; the Theory of Planned Behaviour (TPB) was used to interpret the results. RESULTS: Students found the course overall instructive and reacted positively towards many elements of the course. Focus group analysis showed that an increase in knowledge about patient safety topics resulted in a change of attitudes towards these subjects and in an increase in awareness of patient safety. This influenced students' behavioral intention and their behavior. CONCLUSIONS: A course based on students' personal experiences enables them to transfer theory on patient safety issues into their own practice and has an effect on their awareness, attitudes and behavior. This could have a large impact on their future role as resident. PMID- 22934586 TI - Learning the CanMEDS roles in a near-peer shadowing program: a mixed methods randomized control trial. AB - BACKGROUND: The development of competency frameworks, such as CanMEDS, has helped define professional behavior, but programs that translate their theoretical aspects into practical learning are lacking. AIM: To improve instruction of the CanMEDS framework, the University of Alberta implemented a program in which 83 first-year medical students shadowed a first-year resident for eight months. METHODS: A randomized trial compared participants' attitudes and knowledge regarding CanMEDS to controls. A concurrent-triangulation mixed methods design with questionnaires and interviews provided a comprehensive understanding of program experiences. RESULTS: Students reported increasing their understanding of CanMEDS and increased their acceptance of the framework's importance and knowledge of its contents when compared to controls. Residents also reported that their knowledge of CanMEDS had increased. Participants considered the program to be effective for learning CanMEDS and developing professionalism, especially when paired with clinical encounters relevant to given professional roles. CONCLUSION: This simple, low cost, near-peer shadowing program can be useful for teaching professional behavior. PMID- 22934587 TI - The sociocultural contribution to learning: why did my students fail to learn Aseptic Non-Touch Technique? Multidimensional factors involved in medical students' failure to learn this skill. AB - BACKGROUND: Infection control in the hospital environment is a topical issue in the UK. Aseptic Non-Touch Technique (ANTT) has been recommended as an example of best practice for clinical skills requiring aseptic technique. ANTT is taught to clinical staff and to medical students at a West Midlands teaching hospital. AIMS: To determine the effectiveness of ANTT training within an undergraduate population and to explore the factors involved in medical students' failure to learn this skill Method: 132 Students underwent training and assessment in ANTT. A sample of 42 students underwent re-testing in ANTT 7-10 weeks later. Student questionnaires and semi-structured interviews with students and trainers were undertaken to determine students' daily practice of ANTT, and practice observed in staff. RESULTS: Student performance deteriorated significantly 10 weeks after initial ANTT training (p < 0.001). Qualitative data demonstrates an emphasis on assessment, poor observed practice in staff, and a lack of resources in the clinical setting. Further themes include acceptance of hierarchy, and a lack of belief in ANTT amongst students. CONCLUSION: In order to bring about effective training in ANTT, we must look to the sociocultural contribution of the hospital environment alongside formal ANTT training. PMID- 22934588 TI - The impact of various transitions in the medical education continuum on perceived readiness of trainees to be entrusted with professional tasks. AB - BACKGROUND: Medical trainees go through various transitions during the medical education continuum. AIMS: The aim of this study was to understand how transitions in licensure and increased responsibility may affect trainees' competence development. METHOD: We carried out a questionnaire study in Leeds (UK). Trainees and supervisors were asked to determine the trainee's competence at different stages of training to carry out a diversity of medical activities on a five-point Likert scale. The questionnaires were completed by final-year medical students, trainees of foundation year 1 (FY1) and 2 (FY2), and their supervisors. RESULTS: For all activities listed: (1) the trainees' presumed competence increased over time and (2) the mean scores given by trainees were significantly higher than the mean scores given by supervisors across all years the questionnaire covered. As estimated by both trainees and supervisors, the impact of a responsibility transition, i.e., from medical school to FY1, is larger than that of a licensure transition, i.e., from FY1 (pre-MD) to FY2 (post MD). CONCLUSIONS: The transition to formal responsibility with a license to practice medicine seems to have less impact on confidence of trainees and their supervisors to execute critical activities than the transition to informal but significantly higher responsibility. PMID- 22934589 TI - Assessing a faculty development workshop in narrative medicine. AB - BACKGROUND: Narrative medicine is increasingly popular in undergraduate medical curricula. Moreover, although faculty are expected to use narrative approaches in teaching, few faculty development learning activities have been described. In addition, data on the impact of faculty development initiatives designed to teach narrative are limited, and there is a paucity of tools to assess their impact. AIMS: To assess the impact and outcomes of a faculty development workshop on narrative medicine. METHODS: Two groups of clinical teachers were studied; one group had already attended a half-day narrative medicine workshop (N = 10) while the other had not yet attended (N = 9). Both groups were interviewed about their uses of narrative in teaching and practice. Additionally, the understanding of a set of narrative skills was assessed by first viewing a video of a narrative based teaching session followed by completion of an 18-item assessment tool. RESULTS: Both groups reported that they used narrative in both their teaching and clinical practice. Those who had attended the workshop articulated a more nuanced understanding of narrative terms compared to those who had not yet attended. CONCLUSION: This study is one of the first to describe measureable impacts of a faculty development workshop on narrative medicine. PMID- 22934590 TI - Psychometrics of the scale of attitudes toward physician-pharmacist collaboration: a study with medical students. AB - BACKGROUND: Despite the emphasis placed on interdisciplinary education and interprofessional collaboration between physicians and pharmacologists, no psychometrically sound instrument is available to measure attitudes toward collaborative relationships. AIM: This study was designed to examine psychometrics of an instrument for measuring attitudes toward physician pharmacist collaborative relationships for administration to students in medical and pharmacy schools and to physicians and pharmacists. METHODS: The Scale of Attitudes Toward Physician-Pharmacist Collaboration was completed by 210 students at Jefferson Medical College. Factor analysis and correlational methods were used to examine psychometrics of the instrument. RESULTS: Consistent with the conceptual framework of interprofessional collaboration, three underlying constructs, namely "responsibility and accountability;" "shared authority;" and "interdisciplinary education" emerged from the factor analysis of the instrument providing support for its construct validity. The reliability coefficient alpha for the instrument was 0.90. The instrument's criterion-related validity coefficient with scores of a validated instrument (Jefferson Scale of Attitudes Toward Physician-Nurse Collaboration) was 0.70. CONCLUSIONS: Findings provide support for the validity and reliability of the instrument for medical students. The instrument has the potential to be used for the evaluation of interdisciplinary education in medical and pharmacy schools, and for the evaluation of patient outcomes resulting from collaborative physician-pharmacist relationships. PMID- 22934591 TI - The feasibility and acceptability of integrating regular centralised laboratory based skills training into a surgical training programme. AB - BACKGROUND: Traditional laboratory-based skills training provides mass training that does not match clinical experience and is not tailored to individual needs. This compromises the transfer and retention of skills into clinical practice. AIM: To demonstrate the feasibility of integrating a centralised programme of laboratory-based surgical skills training into a higher surgical training programme and to evaluate its effectiveness and acceptability to trainees. METHODS: Laboratory-based skills training was provided at a central site, delivered by consultants and tailored to the trainees' level of clinical experience. Each trainee was expected to attend one session a month for 11 months a year. Evaluation was conducted through attendance records, structured evaluations by participants, independent qualitative questionnaires and web interviews. RESULTS: Forty-two specialist surgical trainees in the North West London higher surgical training programme participated in laboratory-based skills sessions delivered by 19 consultants over a period of two years. The average attendance was 70.5% for trainees and 100% for trainers. All sessions were rated by trainees as well-organised and useful with an average score of more than 4 out of 5. Trainees felt that the Skills Programme can complement surgical training by allowing practice under expert supervision in a safe environment. CONCLUSIONS: Centralising laboratory-based skills training and integrating it into a clinical programme is feasible and acceptable and represents a paradigm shift in surgical training. Involvement of trainees in designing the content is valuable. PMID- 22934592 TI - E-learning and deliberate practice for oral case presentation skills: a randomized trial. AB - BACKGROUND: Oral case presentations are critical for patient care and student assessment. The best method to prepare early medical students for oral presentations is unknown. AIM: We aimed to develop and evaluate a curriculum of on-line learning and deliberate practice to improve pre-clinical students' case presentation skills. METHODS: We developed a web-based, interactive curriculum emphasizing conciseness and clinical reasoning. Using a waitlist control design, we randomly assigned groups of second-year students to receive the curriculum in December 2010 or in April 2011. We evaluated their presentations at three time points. We also examined the performance of an untrained class of students as a historical comparison. RESULTS: We evaluated 132 second-year medical students at three time points. After the curriculum, mean scores of the intervention students improved from 60.2% to 70.1%, while scores of the waitlist control students improved less, from 61.8% to 64.5% (p < 0.01 for between-group difference in improvement). Once all students had received the curriculum, mean scores for the intervention and waitlist control students rose to 77.8% and 78.4%, respectively, compared to 68.1% for the untrained comparison students (p < 0.0001 compared to all curriculum students). CONCLUSION: An on-line curriculum followed by deliberate practice improved students' oral presentation skills. PMID- 22934593 TI - Indomethacin-induced small intestinal injury is ameliorated by cilostazol, a specific PDE-3 inhibitor. AB - BACKGROUND: Neutrophil migration, one of the major factors predisposing to nonsteroidal anti-inflammatory drugs (NSAIDs)-induced intestinal lesions, consists of several steps, including interaction with P-selectin from platelets. Cilostazol, a specific phosphodiesterase (PDE)-3 inhibitor, suppresses the expression of P-selectin from platelets and reduces interaction between platelets and leukocytes, leading to inflammatory amelioration in several disease models. We tried to clarify the therapeutic effectiveness of cilostazol for NSAID-induced small intestinal lesions. SUBJECTS AND METHODS: 1) Anti-PSGL-1 antibody (2 mg/kg) or cilostazol (100 mg/kg) was administered to mice one hour before Indomethacin (IND, 2.5 mg/kg) administration for 4 days to evaluate small intestinal lesions. 2) IND-induced migratory behaviors of neutrophils and platelets were evaluated in intestinal vessels by an intravital microscopy. RESULTS: i) IND induced small intestinal lesions with an increase in MPO activity. Anti-PSGL-1 antibody and cilostazol ameliorated intestinal lesions along with suppression of MPO activity. ii) Intravital microscopy revealed that administration of IND increased migration of platelet-bearing neutrophils. Cilostazol treatment ameliorated neutrophil migration by blocking interaction between platelets and neutrophils. CONCLUSION: Our results suggest that enhanced platelets-bearing neutrophil migration is critically involved in the pathogenesis of IND-induced small intestinal lesions and suggest a potential application of cilostazol for prevention of NSAID-induced small intestinal lesions. PMID- 22934594 TI - Prospective comparative study of endoscopic papillary large balloon dilation and endoscopic sphincterotomy for removal of large bile duct stones in patients above 45 years of age. AB - OBJECTIVE: Although endoscopic papillary large balloon dilation (EPLBD) with limited endoscopic sphincterotomy (ES) showed excellent outcomes for treatment of large bile duct stones, hemorrhage and recurrence of stones are problematic complications. Recent studies suggest that EPLBD alone is safe and effective for removal of large bile duct stones. This study aimed to determine the therapeutic outcomes and safety of EPLBD, compared with ES, for removal of large bile duct stones. MATERIAL AND METHODS: Eighty-three patients above 45 years of age with bile duct stones >1 cm in diameter were randomized to EPLBD and ES groups for removal of common bile duct stones from September 2010 to August 2011. Prophylactic gabexate mesilate was given to all patients. RESULTS: Baseline characteristics were not significantly different, except diabetes and gallbladder stones between the EPLBD group (n = 40) and ES group (n = 43). The overall complete stone removal rate in each group was 97.5% (39/40) and 95.3% (41/43), respectively (p = 0.600). Requirement of mechanical lithotripsy was not significantly different between the EPLBD and ES group (10% vs. 21%, p = 0.171). Complete ductal clearance in one session was achieved in 82.4% and 81.4% of cases in each group, respectively (p = 0.577). There were no differences in complication rates between the EPLBD and ES group; pancreatitis, 5.0% vs. 7.0%; hemorrhage, 10.0% vs. 16.3%; acute cholangitis, 5.0% vs. 2.3%, and perforation, 2.5% vs. 0%. CONCLUSIONS: The therapeutic outcomes and complications of EPLBD for removal of large bile duct stones are comparable to those of ES. PMID- 22934595 TI - Dominant-negative effects in prion diseases: insights from molecular dynamics simulations on mouse prion protein chimeras. AB - Mutations in the prion protein (PrP) can cause spontaneous prion diseases in humans (Hu) and animals. In transgenic mice, mutations can determine the susceptibility to the infection of different prion strains. Some of these mutations also show a dominant-negative effect, thus halting the replication process by which wild type mouse (Mo) PrP is converted into Mo scrapie. Using all atom molecular dynamics (MD) simulations, here we studied the structure of HuPrP, MoPrP, 10 Hu/MoPrP chimeras, and 1 Mo/sheepPrP chimera in explicit solvent. Overall, ~2 MUs of MD were collected. Our findings suggest that the interactions between alpha1 helix and N-terminal of alpha3 helix are critical in prion propagation, whereas the beta2-alpha2 loop conformation plays a role in the dominant-negative effect. An animated Interactive 3D Complement (I3DC) is available in Proteopedia at http://proteopedia.org/w/Journal:JBSD:4 . PMID- 22934596 TI - Long-term recovery of benthic communities in sediments amended with activated carbon. AB - Using activated carbon (AC) for sediment remediation may have negative effects on benthic communities. To date, most AC effect studies were short-term and limited to single species laboratory tests. Here, we studied the effects of AC on the recolonization of benthic communities. Sediment from an unpolluted site was amended with increasing levels of AC, placed in trays and randomly embedded in the original site, which acted as a donor system for recolonization of benthic species. After 3 and 15 months, the trays were retrieved and benthic organisms identified. A positive trend with AC was detected for species abundance after 3 months, whereas after 15 months a negative trend with AC was detected for Lumbriculidae and Pisidiidae. On the community level, statistical analyses showed a considerable recovery in terms of species diversity and abundance in 3 months and full recovery of the community after 15 months. This was explained from migration of individuals from the donor system, followed by further migration and reproduction of the species in the next year. AC treatments explained 3% of the variance in the community data. This work suggests that AC community effects are mild as long as AC levels are not too high (1-4%). PMID- 22934597 TI - Nutrigenetic screening strains of the mulberry silkworm, Bombyx mori, for nutritional efficiency. AB - The activity of sericulture is declining due the reduction of mulberry production area in sericulture practicing countries lead to adverse effects on silkworm rearing and cocoon production. Screening for nutrigenetic traits in silkworm, Bombyx mori L. (Lepidoptera: Bombycidae) is an essential prerequisite for better understanding and development of nutritionally efficient breeds/hybrids, which show less food consumption with higher efficiency conversion. The aim of this study was to identify nutritionally efficient polyvoltine silkworm strains using the germplasm breeds RMW(2), RMW(3), RMW(4), RMG(3), RMG(1), RMG(4), RMG(5), RMG(6) and APM(1) as the control. The 1(st) day of 5(th) stage silkworm larvae of polyvoltine strains were subjected to standard gravimetric analysis until spinning for three consecutive generations covering 3 different seasons on 19 nutrigenetic traits. Highly significant (p <= 0.001) differences were found among all nutrigenetic traits of polyvoltine silkworm strains in the experimental groups. The nutritionally efficient polvoltine silkworm strains were resulted by utilizing nutrition consumption index and efficiency of conversion of ingesta/cocoon traits as the index. Higher nutritional efficiency conversions were found in the polyvoltine silkworm strains on efficiency of conversion of ingesta to cocoon and shell than control. Comparatively smaller consumption index, respiration, metabolic rate with superior relative growth rate, and quantum of food ingesta and digesta requisite per gram of cocoon and shell were found; the lowest amount was in new polyvoltine strains compared to the control. Furthermore, based on the overall nutrigenetic traits utilized as index or 'biomarkers', three polyvoltine silkworm strains (RMG(4), RMW(2), and RMW(3)) were identified as having the potential for nutrition efficiency conversion. The data from the present study advances our knowledge for the development of nutritionally efficient silkworm breeds/hybrids and their effective commercial utilization in the sericulture industry. PMID- 22934598 TI - One-dimensional assembly of silica nanospheres: effects of nonionic block copolymers. AB - The effects of polymers on the one-dimensional assembly of silica nanospheres (SNSs) in the liquid phase are systematically investigated using nonionic poly(ethylene oxide)-b-poly(propylene oxide)-b-poly(ethylene oxide) (abbreviated as PEO-PPO-PEO) triblock copolymers with varying hydrophilic-lipophilic balance (HLB) values. Scanning electron microscopy is employed for morphological observations of the polymer-mediated assemblies of SNSs on the basis of which the optimal pH for 1D assembly (pH(1D)) is determined. To clarify the polymers' effects on the 1D assembly of SNSs, the relationships between pH(1D) and polymers' HLB values, the numbers of hydrophilic EO and hydrophobic PO units, and the relative ratio of N(PO)/N(EO) are examined. Zeta potential measurements are conducted to investigate the electrostatic repulsion among the SNSs in the presence of block copolymers. It is found that the relative hydrophilicity of the block copolymers greatly affects the balance of interactions in the 1D assembly of SNSs. Block copolymers with large HLB values promote the 1D assembly of SNSs under near-neutral pH conditions, whereas the block copolymers with small HLB values promote 1D assembly under basic pH conditions. Therefore, the 1D assembly of SNSs is achieved over an extensive pH range (7.5-9.5) through the employment of block copolymers of different hydrophilic and hydrophobic block lengths. PMID- 22934599 TI - Analysis of human monoclonal antibodies generated by dengue virus-specific memory B cells. AB - Dengue, caused by the four serotypes of dengue virus (DENV), represents an expanding global health challenge. The potential for serotype-cross-reactive antibodies to exacerbate disease during a secondary infection with a heterologous DENV serotype has driven efforts to study human DENV-specific antibodies. Most DENV-specific antibodies generated in humans are serotype-cross-reactive, weakly neutralizing, and directed against the immature pre-membrane (prM), envelope (E), and nonstructural 1 (NS1) proteins. To broaden the characterization of human DENV specific antibodies, we assessed B-cell responses by ELISpot assays and isolated B cells from the peripheral blood of a human subject with previous DENV infection. Forty-eight human IgG monoclonal antibodies (hMAbs) were initially characterized by their potential to bind to an inactivated lysate of DENV infected cells. Subsequently, most DENV-specific hMAbs were found to bind soluble, recombinant E protein (rE). Two hMAbs were unable to bind rE, despite strongly binding to the DENV-infected cell lysate. Further analyses showed that these two hMAbs bound conformation-dependent, reduction-sensitive epitopes on E protein. These data shed light on the breadth of DENV-specific hMAbs generated within a single immune donor. PMID- 22934600 TI - Potent HGF/c-Met axis inhibitors from Eucalyptus globulus: the coupling of phloroglucinol and sesquiterpenoid is essential for the activity. AB - Eucalyptin A (1), together with two known compounds 2 and 3 exhibiting potent inhibition on HGF/c-Met axis, was discovered from the fruits of Eucalyptus globulus. 1 possessed an unprecedented carbon framework of phloroglucinol-coupled sesquiterpenoid, and its structure was elucidated by spectroscopic method and ECD calculation. A brief structure-activity relationship discussion indicated that the coupling of a phloroglucinol and a sesquiterpenoid is essential for the activity. PMID- 22934601 TI - Peptide self-assembly on cell membranes to induce cell lysis. AB - Self-assembling into aggregates with defined structures is a common phenomenon for many peptides at high concentrations. In this study, we found that when PTP 7b (FLGALFKALSHLL), a concentration-dependent self-assembling peptide, bound to tissue cells and accumulated on cell surfaces, it migrated and self-assembled into exosome-like aggregates at certain locations on the cell membranes. Studies using confocal microscopy and scanning electron microscopy revealed that peptide PTP-7b induced cell tissue damage through a new cell lysis mechanism that involved peptide self-assembly on cell surfaces, extracting lipids from cell membranes, and transporting peptides into the cytoplasm. Peptide self-assembly attributed greatly to peptide-cell interactions and thus the biological activity of a peptide. Because peptide self-assembly was a slow process, PTP-7b-induced cell lysis showed a biphasic behavior: a gradual viability decrease was followed by a rapid decline. These results suggest that peptide self-assembly could be equally as important as charge and secondary structure of a peptide in determining the anticancer and antibacterial activities of therapeutic peptides. PMID- 22934602 TI - Differential hydration of tricyanomethanide observed by time resolved vibrational spectroscopy. AB - The degenerate transition corresponding to asymmetric stretches of the D(3h) tricyanomethanide anion, C(CN)(3)(-), in aqueous solution was investigated by linear FTIR spectroscopy, femtosecond pump-probe spectroscopy, and 2D IR spectroscopy. Time resolved vibrational spectroscopy shows that water induces vibrational energy transfer between the degenerate asymmetric stretch modes of tricyanomethanide. The frequency-frequency correlation function and the vibrational energy transfer show two significantly different ultrafast time scales. The system is modeled with molecular dynamics simulations and ab initio calculations. A new model for theoretically describing the vibrational dynamics of a degenerate transition is presented. Microscopic models, where water interacts axially and radially with the ion, are suggested for the transition dipole reorientation mechanism. PMID- 22934603 TI - Nonenzymatic dynamic kinetic resolution of secondary alcohols via enantioselective acylation: synthetic and mechanistic studies. AB - Because of the ubiquity of the secondary carbinol subunit, the development of new methods for its enantioselective synthesis remains an important ongoing challenge. In this report, we describe the first nonenzymatic method for the dynamic kinetic resolution (DKR) of secondary alcohols (specifically, aryl alkyl carbinols) through enantioselective acylation, and we substantially expand the scope of this approach, vis-a-vis enzymatic reactions. Simply combining an effective process for the kinetic resolution of alcohols with an active catalyst for the racemization of alcohols did not lead to DKR, due to the incompatibility of the ruthenium-based racemization catalyst with the acylating agent (Ac(2)O) used in the kinetic resolution. A mechanistic investigation revealed that the ruthenium catalyst is deactivated through the formation of a stable ruthenium acetate complex; this deleterious pathway was circumvented through the appropriate choice of acylating agent (an acyl carbonate). Mechanistic studies of this new process point to reversible N-acylation of the nucleophilic catalyst, acyl transfer from the catalyst to the alcohol as the rate-determining step, and carbonate anion serving as the Bronsted base in that acyl-transfer step. PMID- 22934604 TI - Catalyst-free intramolecular oxidative cyclization of N-allylbenzamides: a new route to 2,5-substituted oxazoles. AB - A catalyst-free intramolecular oxidative cyclization reaction of N allylbenzamides has been developed to prepare 2,5-disubstituted oxazoles with good yields. This reaction gives an efficient synthetic strategy to form an oxazole nucleus directly from easily accessible substrates under temperate conditions. PMID- 22934605 TI - Phylogenetic distribution of traits associated with plant colonization in Escherichia coli. AB - Plants are increasingly considered as secondary reservoirs for commensal and pathogenic Escherichia coli strains, but the ecological and functional factors involved in this association are not clear. To address this question, we undertook a comparative approach combining phenotypic and phylogenetic analyses of E. coli isolates from crops and mammalian hosts. Phenotypic profiling revealed significant differences according to the source of isolation. Notably, isolates from plants displayed higher biofilm and extracellular matrix production and higher frequency of utilization of sucrose and the aromatic compound p hydroxyphenylacetic acid. However, when compared with mammalian-associated strains, they reached lower growth yields on many C-sources commonly used by E. coli. Strikingly, we observed a strong association between phenotypes and E. coli phylogenetic groups. Strains belonging to phylogroup B1 were more likely to harbour traits indicative of a higher ability to colonize plants, whereas phylogroup A and B2 isolates displayed phenotypes linked to an animal-associated lifestyle. This work provides clear indications that E. coli phylogroups are specifically affected by niche-specific selective pressures, and provides an explanation on why E. coli population structures vary in natural environments, implying that different lineages in E. coli have substantially different transmission ecology. PMID- 22934606 TI - Motor coordination and executive functions. PMID- 22934607 TI - Combination of adalimumab with traditional systemic antipsoriatic drugs - a report of 39 cases. AB - BACKGROUND: Monotherapy with TNF-alpha inhibitors does not always produce a sufficient response in psoriasis patients. Combinations of TNF-alpha antagonists such as adalimumab with systemic antipsoriatic therapies such as methotrexate are not approved for use in psoriasis, and the published data are scarce. PATIENTS AND METHODS: The charts of 39 psoriasis patients from 6 dermatology departments were reviewed retrospectively. All patients were given adalimumbab with another systemic antipsoriatic drug. RESULTS: Combination therapy with methotrexate was most common (n = 32), followed by acitretin (n = 4) and cyclosporine (n = 3). Combination therapy with methotrexate lasted 10.8 +/- 11.2 months (mean), with cyclosporine for 6.8 +/- 3.3 months, and with acitretin 12.9 +/- 12.4 months. Combinations were effective in the majority of patients: 30/39 (76.9 %) had a good (n = 9) or excellent (n = 21) response. Two patients had a moderate response and 7 patients had a poor response and were switched to another treatment. Overall, safety was very good. Eighteen patients experienced 24 adverse events; none was severe and/or required hospitalization. Of these, 10/24 adverse events were infections, most often infections of the upper respiratory tract (n = 5), bronchitis (n = 2), and influenza (n = 1). CONCLUSIONS: Combinations of adalimumab with traditional systemic antipsoriatic treatments offer a promising method for managing severe or recalcitrant psoriasis. More data are needed to determine the long-term safety and efficacy of these combinations. PMID- 22934608 TI - Host-guest chemistry of dendrimer-cyclodextrin conjugates: selective encapsulations of guests within dendrimer or cyclodextrin cavities revealed by NOE NMR techniques. AB - In this study, G5 PAMAM dendrimer and alpha-, beta-, gamma-cyclodextrin (CD) conjugates were synthesized. Host-guest behaviors of the conjugates toward five guest molecules including sodium methotrexate (MTX), amantadine hydrochloride (ADH), sulfamethoxazole (SMZ), sodium deoxycholate (SDC), and sodium dodecyl sulfate (SDS) were analyzed by NOE NMR techniques. Among the five guest molecules, ADH only binds with beta-CD in G5-beta-CD, SDC shows higher priority to localize within the cavity of gamma-CD in G5-gamma-CD, while MTX exhibits selective encapsulation within the cavities of G5 dendrimer in G5-alpha-CD. SDS has high binding affinity with alpha-CD in G5-alpha-CD but forms a precipitate in the complex solution. SMZ shows simultaneous encapsulation within CDs (alpha-, beta-, and gamma-CD) or G5 in the presence of the three conjugates. The host behavior of G5-CD conjugates depends on CD cavity size, guest size, and hydrophobicity. The results obtained in this study are helpful in the optimization of dendrimer-CD conjugate-based drug delivery systems. PMID- 22934609 TI - Endobronchial ultrasound images may predict malignant involvement of mediastinal lymph nodes: is tissue still the issue? PMID- 22934610 TI - Confabulation in healthy aging is related to poor encoding and retrieval of over learned information. AB - Normal aging is characterized by deficits that cross multiple cognitive domains including episodic memory and attention. Compared to young adults (YA), older adults (OA) not only show reduction in true memories, but also an increase in false memories. In this study we aim to elucidate how the production of confabulation is influenced by encoding and retrieval processes. We hypothesized that in OA, compared to YA, over-learned information interferes with the recall of specific, unique past episodes and this interference should be more prominent when a concurrent task perturbs the encoding of the episodes to be recalled. We tested this hypothesis using an experimental paradigm in which a group of OA and a group of YA had to recall three different types of story: a previously unknown story, a well-known fairy tale (Snow White), and a modified well-known fairy tale (Little Red Riding Hood is not eaten by the wolf), in three different experimental conditions: (1) free encoding and free retrieval; (2) Divided attention (DA) at encoding and free retrieval; and (3) free encoding and DA at retrieval. Results showed that OA produced significantly more confabulations than YA, particularly, in the recall of the modified fairy tale. Moreover, DA at encoding markedly increased the number of confabulations, whereas DA at retrieval had no effect on confabulation. Our findings reveal the implications of two phenomena in the production of confabulation in normal aging: the effect of poor encoding and the interference of strongly represented, over-learned information in episodic memory recall. PMID- 22934611 TI - Bone formation around zirconia implants combined with rhBMP-2 gel in the canine mandible. AB - OBJECTIVE: The aim of this study was to estimate the effects of zirconia implants and recombinant human bone morphogenetic protein-2 (rhBMP-2) gel on the acceleration of local bone formation and osseointegration in the canine mandible. MATERIALS AND METHODS: Four groups of 48 implants with identical geometry were installed in the mandibles of beagle dogs: alumina-blasted zirconia implants applied with rhBMP-2, alumina-blasted zirconia implants applied with demineralized bone matrix (DBM), alumina-blasted zirconia implants, and resorbable blast media-treated titanium (Ti) implants. For the first two groups, zirconia implants were inserted after the surgical sites were filled with rhBMP-2 or DBM gel. For the other two groups, zirconia or Ti implants were installed with no adjunctive treatment. Fluorescent bone markers were administered to monitor bone remodeling at weeks 2, 4, and 5 postimplantation. After healing periods of 3 weeks and 6 weeks, the animals were sacrificed, and fluorescent microscopy, histology, and histomorphometric analyses were performed. RESULTS: Fluorescent microscopy showed that bone formation around the zirconia implants installed with rhBMP-2 gel was the most prominent at 2 weeks postimplantation, while the Ti implants acquired bone apposition mainly at week 5. No significant differences were found in bone area among the groups (P > 0.05). The zirconia implants showed similar bone-to-implant contact to the Ti implants. There were no significant differences in bone-to-implant contact between the zirconia implants with rhBMP-2 gel and those with DBM (P > 0.05). CONCLUSIONS: The zirconia implants with alumina-blasted surfaces may achieve osseointegration in much the same manner as the well-established Ti implants. The area influenced by rhBMP-2 gel, including the alveolar crest, may cause active remodeling and early bone formation. PMID- 22934612 TI - A new perspective on the mechanical evaluation of granular material. AB - The mechanical strength of granules is an important parameter to be determined prior to any further downstream formulation processing. It is important to have a good gauge on the granule integrity to forecast any foreseeable powder issues associated with the material processability such as segregation, content uniformity, and material flow-ability. In this study, a systematic methodology has been developed to quantify the integrity of these granules subjected to a low frequency acoustic field to arrive at the Granule Integrity (GI) index. This methodology has been compared to existing well-established bulk characterization techniques reported in the literature such as Heckel analysis, Kawakita analysis, and Young's modulus for four different processed samples. Heckel analysis is more amenable to examine the material deformability while Kawakita analysis is better suited to understand the mechanics of granular material. Individual granule strength measurements to determine Young's modulus often show large variations across the bulk sample. The GI index in conjunction with the Kawakita analysis provides us with more mechanistic insight and understanding into the formation of these granules from a processing perspective. This paper shows the benefits of using the GI index as a practical and direct methodology to characterize the GI of bulk samples in an industrial setting. PMID- 22934613 TI - Interrelationship of oral health status, swallowing function, nutritional status, and cognitive ability with activities of daily living in Japanese elderly people receiving home care services due to physical disabilities. AB - OBJECTIVES: Malnutrition and cognitive impairment lead to declines in activities of daily living (ADL). Nutritional status and cognitive ability have been shown to correlate with oral health status and swallowing function. However, the complex relationship among the factors that affect decline in ADL is not understood. We examined direct and indirect relationships among oral health status, swallowing function, nutritional status, cognitive ability, and ADL in Japanese elderly people living at home and receiving home care services because of physical disabilities. METHODS: Participants were 286 subjects aged 60 years and older (mean age, 84.5+/-7.9 years) living at home and receiving home care services. Oral health status (the number of teeth and wearing dentures) was assessed, and swallowing function was examined using cervical auscultation. Additionally, ADL, cognitive ability, and nutritional status were assessed using the Barthel Index, the Clinical Dementia Rating Scale, and the Mini Nutritional Assessment-Short Form, respectively. Path analysis was used to test pathways from these factors to ADL. RESULTS: The mean number of teeth present in the participants was 8.6+/-9.9 (edentates, 40.6%). Dysphagia, malnutrition, and severe cognitive impairment were found in 31.1%, 14.0%, and 21.3% of the participants, respectively. Path analysis indicated that poor oral health status and cognitive impairment had a direct effect on denture wearing, and the consequent dysphagia, in addition to cognitive impairment, was positively associated with malnutrition. Malnutrition as well as dysphagia and cognitive impairment directly limited ADL. CONCLUSIONS: A lower number of teeth are positively related to swallowing dysfunction, whereas denture wearing contributes to recovery of swallowing function. Dysphagia, cognitive impairment, and malnutrition directly and indirectly decreased ADL in elderly people living at home and receiving home nursing care. The findings suggest that preventing tooth loss and encouraging denture wearing when teeth are lost may indirectly contribute to maintaining or improving ADL, mediated by recovery of swallowing function and nutritional status. PMID- 22934614 TI - Application of COI sequences in studies of phylogenetic relationships among 40 Apionidae species. AB - The systematics of the family Apionidae, as well as the superfamily Curculionoidea, is currently in a state of flux. The comparative analyses of COI sequences from our studies shed some light on the systematics of these weevils. To study the relationship among the organisms of the family Apionidae, we determined the COI sequences of representatives of 23 species and 15 genera, i.e., Apion, Betulapion, Catapion, Ceratapion, Cyanapion, Eutrichapion, Exapion, Hemitrichapion, Holotrichapion, Ischnopterapion, Protapion, Pseudoperapion, Psudoprotapion, Pseudostenapion, and Stenopterapion. Then, they were compared with the COI sequences of 19 species and eight genera from GenBank (Aspidapion, Ceratapion, Exapion, Ischnopterapion, Lepidapion, Omphalapion, Oxystoma, and Protapion). The phylogenetic relationships inferred from molecular data are similar to the classification system developed by Alonso-Zarazaga and Lyal ( 1999 ), with some exceptions within the tribe Oxystomatini, and genera Ceratapion and Exapion. PMID- 22934615 TI - Design and synthesis of a stable oxidized phospholipid mimic with specific binding recognition for macrophage scavenger receptors. AB - Macrophage scavenger receptors appear to play a major role in the clearance of oxidized phospholipid (OxPL) products. Discrete peptide-phospholipid conjugates with the phosphatidylcholine headgroup have been shown to exhibit binding affinity for these receptors. We report the preparation of a water-soluble, stable peptide-phospholipid conjugate (9) that possesses the necessary physical properties to enable more detailed study of the role(s) of OxPL in metabolic disease. PMID- 22934616 TI - Sorptive bioaccessibility extraction (SBE) of soils: combining a mobilization medium with an absorption sink. AB - In principle, soil bioaccessibility extraction methods are simple dissolution experiments, where the fraction of compounds that is transferred to the extraction medium is measured and considered to be bioaccessible. For hydrophobic organic chemicals (HOCs) such techniques can lead to underestimation of bioaccessibility when the capacity of the extraction medium is insufficient to provide infinite sink conditions for the target compounds. A sorptive bioaccessibility extraction (SBE) method was thus developed and validated, which integrates the key processes of desorption from the matrix and subsequent consumption or depletion. Cyclodextrin was used as a diffusive carrier to enhance desorption from the matrix, while a silicone rod was used as a dominating sink that continuously absorbed the HOC molecules from the cyclodextrin solution. The silicone rod was then solvent extracted and the HOCs measured by GC-MS. For wood soot, the SBE method yielded PAH bioaccessibility estimates that were 3-24 times higher compared to a cyclodextrin extraction without a sink. The study demonstrated that the inclusion of an absorption sink into an established bioaccessibility extraction method (1) is rather simple, (2) can have a major impact on the obtained results, especially for the more hydrophobic compounds and (3) can simplify the analytics. PMID- 22934617 TI - Retroviral protein transfer: falling apart to make an impact. AB - Retroviral vectors represent evolutionarily optimized gene delivery vehicles, which stably integrate their coding DNA into the host cell genome. In contrast to other gene delivery platforms, retroviral entry and integration are relatively efficient due to the utilization of cellular mechanisms for particle transport, DNA repair and gene expression, features that can be exploited for gene therapy and cell modification. Arresting the retroviral life cycle at specific steps, i.e. prior to reverse transcription or integration, allows for the utilization of intermediate structures (mRNA) or by-products (episomes) as tools for transient applications. However, it is often overlooked that retroviral particles are composed of up to 2500 Gag structural proteins, as well as further proteins involved in viral replication, all of which can be harnessed for the transfer of heterologous proteins into target cells. In this review, we describe the general biology of retroviruses and their derived vector systems, and then discuss the potential of engineering their protein components. We focus on lentiviral, gammaretroviral and alpharetroviral vector systems, and address current developments in the visualization of retrovirus-cell interactions (live cell imaging), and potential applications of engineered retroviral particles in biotechnology and biomedical research. Compared to conventional protein transduction techniques, we envisage protein-transducing retrovirus-like particles as a highly flexible platform for the efficient and cell-targeted delivery of designer proteins, even in combination with transduction of retroviral mRNA, episomal DNA or integrating DNA. PMID- 22934618 TI - Genetically-modified hematopoietic stem cells and their progeny for widespread and efficient protein delivery to diseased sites: the case of lysosomal storage disorders. AB - Efficient therapeutic protein delivery is a challenging task in several disease contexts and particularly when the CNS is concerned. Different approaches for brain-directed delivery have been thus far investigated, including direct injection of molecules or of their coding information carried by dedicated vector systems within the brain parenchyma or in the ventricular space, intravenous systemic administration of molecules/vectors modified to target and cross the blood-brain-barrier, and exploitation of allogeneic and/or autologous and genetically modified cells as vehicles for the therapeutic of interest. Among these, we here review one of the most promising approaches based on hematopoietic stem cells, taking advantage of lysosomal storage disorders as representative disease setting. PMID- 22934619 TI - Ruthenium(II)-catalyzed C-H bond activation and functionalization. PMID- 22934620 TI - Highly sensitive NH3 detection based on organic field-effect transistors with tris(pentafluorophenyl)borane as receptor. AB - We have increased organic field-effect transistor (OFET) NH(3) response using tris(pentafluorophenyl)borane (TPFB) as a receptor. OFETs with this additive could detect concentrations of 450 ppb v/v, with a limit of detection of 350 ppb, the highest sensitivity reported to date for semiconductor films; in comparison, when triphenylmethane (TPM) or triphenylborane (TFB) was used as an additive, no obvious improvement in the sensitivity was observed. These OFETs also showed considerable selectivity with respect to common organic vapors and stability toward storage. Furthermore, excellent memory of exposure was achieved by keeping the exposed devices in a sealed container stored at -30 degrees C, the first such capability demonstrated with OFETs. PMID- 22934621 TI - Kinetics of the sphere-to-rod like micelle transition in a pluronic triblock copolymer. AB - The kinetics of the sphere-to-rod transition was studied in aqueous micelle solutions of triblock copolymer poly(ethylene oxide)-poly(propylene oxide) poly(ethylene oxide) pluronic P103 (PEO(17)PPO(60)PEO(17)). This transition was triggered by a temperature jump from the sphere phase to the rod phase and monitored with dynamic light scattering. The combination of the scattering intensity and the hydrodynamic radius were used to show that the micelles grow steadily as rods throughout the growth process. The transition was found to exhibit a single exponential behavior even in the case of large deviations from equilibrium. The linear increase in the decay rate with increasing copolymer concentration shows that the transition is dominated by a mechanism involving fusion and fragmentation of proper micelles. The decays of the sphere-to-rod transition were simulated for two pathways: random fusion fragmentation and successive addition of spherical micelles to rods. We show that micelle growth most likely occurs via random fusion-fragmentation. The second order rate constant for fusion and the fragmentation rate are calculated for the case of random fusion-fragmentation. PMID- 22934624 TI - On-surface assembly of coiled-coil heterodimers. AB - The coiled coil is a widespread protein motif responsible for directing the assembly of a wide range of protein complexes. To date, research has focused largely on the solution phase assembly of coiled-coil complexes. Here, we describe an investigation into coiled-coil heterodimer assembly where one of the peptides is immobilized directly onto a gold electrode. Immobilization is achieved by the introduction of a unique cysteine residue at the C terminus, allowing for covalent and orientated attachment to a thiol-reactive surface, here the gold electrode. We show an electrochemical impedance of the resulting self assembled polypeptide monolayer around |Z| = 4 * 10(4) Omega cm(2) at 100 mHz with a minimum phase angle of -84 degrees , consistent with the formation of a densely packed, insulating layer. The thickness of the peptide monolayer, as measured using ellipsometry, is around 3 nm, close to that expected for a self assembled monolayer assembled from helical peptides. Crucially, we find that the efficiency of dimerization between a peptide in solution and its coiled-coil partner peptide immobilized on a surface is strongly dependent upon the density of the immobilized peptide layer, with dimer assembly being strongly suppressed by high-density peptide monolayers. We thus develop an approach for controlling the density of the immobilized peptide by diluting the monolayer with a thiolated, random-coil peptide to modulate dimerization efficiency and demonstrate electrochemical detection of highly specific, coiled-coil heterodimer on-surface assembly. PMID- 22934625 TI - Polycyclic aromatic hydrocarbon for the detection of nonpolar analytes under counteracting humidity conditions. AB - Real-world samples contain reducing and oxidizing chemical agents as well as large and small (bio)molecules, which are polar or nonpolar in nature. Sensing nonpolar analytes, which is of paramount importance for a wide variety of applications, is generally more difficult to achieve than sensing polar analytes. Here, we report on empirical observations of a unique polycyclic aromatic hydrocarbon derivative, referred as PAH-A, whose structure has a triangular shaped aromatic core (with a carbon number of 60) and contains hydrophobic mesogens terminated with hydrophobic alkyl chains. We show that films made of PAH A enable excellent sensitivity to nonpolar analytes, compared to polar analytes, in a setting of 5-40% counteracting relative humidity. This finding is based on monitoring the changes in the physical/optical properties of thin PAH-A films upon exposure to nonpolar and polar analytes, by means of quartz crystal microbalance and spectroscopic ellipsometry measurements. A comparison with other polycyclic aromatic hydrocarbon derivatives with different cores or organic functionalities is provided and discussed. PMID- 22934626 TI - Pd(II)-mediated cyclization of o-allylbenzaldehydes in water: a novel synthesis of isocoumarins. AB - A novel, concise and efficient synthesis of substituted isocoumarins is disclosed. o-Allylbenzaldehydes prepared from isovanillin were mediated by PdCl(2)-CuCl(2) in water to undergo a domino reaction sequence, including 6-exo trig cyclization, the addition of water, the elimination of PdHCl, the isomerization of carbon-carbon double bond, the oxidation of hemiacetals with the elimination of PdHCl, and regeneration of PdCl(2)in situ to yield a series of new substituted isocoumarins in high yields, in one pot. PMID- 22934627 TI - Neurocognitive and behavioral correlates of non-right-handedness in internationally adopted children. AB - The incidence of non-right-handedness was assessed among a sample of international adoptees. Neurocognitive and behavioral correlates to handedness were also examined among participants. A sample of 139 international adoptees (54 males; mean age at testing = 111.4 months +/- 32.9 months) underwent a comprehensive neuropsychological evaluation, assessing verbal and visual reasoning, language, memory, attention, impulse control, processing speed, academic functioning, manual dexterity, and behavioral functioning. Over 26% of participants reported non-right-handedness. Non-right- and right-handers did not differ on demographic or orphanage specific variables. The groups were found to significantly differ on behavioral indices of attention and several neurocognitive variables, including visual memory, verbal memory, and manual dexterity of the dominant hand, with non-right-handers having worse performance. Possible mechanisms for these findings are discussed. PMID- 22934628 TI - Recent patent in controlled porosity osmotic pump. AB - The porous osmotic pump based drug delivery system for excellent controlled release of drug for 24 hrs. The porous osmotic pump contains pore forming water soluble additives in the coating membrane, which after coming in contact with water, dissolve, resulting in an in situ formation of a microporous structure. The porous osmotic pump delivery from this system is not influenced by the different physiological factors. The present review is concerned with the patent study of drug release through controlled porous osmotic pump. This patent review is useful in knowledge of controlled porous osmotic pump for its application. PMID- 22934629 TI - Coated with nanomaterials intraocular lenses, ophthalmic and human body implantable devices with high catalytic antioxidant activities: a new nanotechnology strategy of peroxidase cellular enzyme mimics increasing the biocompatibility and therapeutic deployment of the medical prosthetic device. AB - While cataract surgery is generally recognized as being one of the safest operations, there is still a significant complication rate. From 30 to 50% of all patients in the United States having cataract extraction develop opacification of the posterior lens capsule within two years and require laser treatment with its own significant risk of complications. Of the patients having cataract surgery, 0.8% develop retinal detachments, from 0.6% to 1.3% were rehospitalized for corneal edema or required corneal transplantation and about 0.1% presented with endophthalmitis . Thus, aside from secondary cataract, about 2% of 1.3 million people, or 26,000 individuals in the United States annually develop serious complications as a result of cataract surgery. The aim of this investigation was to increase the safety and effectiveness of an individual intraocular lens (IOL) preventing an impairment in peroxide metabolism of the mature human cataractous lenses compared to normal lenses employing the specific nanotechnology coating which substitutes the inhibitory effect of the implantable device towards the active species of oxygen and the ability of IOL to regulate the H2O2 and lipid hydroperoxides levels in the surrounding medium. The implantation of IOLs with metabolic activity improves the capability of the surrounding ocular tissues to withstand oxidative stress induced in ocular humors by the photochemical and other metabolic reactions. The coated implantable medical device with thin film of platinum applied with magnetron sputtering, reacts as a body enzyme with deleterious peroxide compounds and free radical oxygen species in body fluids and tissue when said device is implanted into human body. The IOL having haptics coated with thin film of platinum, catalyzes the reduction of peroxide compounds to decrease their levels within the aqueous humor. Further, the coatings also scavenge toxic free radicals of oxygen, thus preventing cellular dysfunction resulting from oxidative attack. Coated IOLs according to the patented nanotechnology can address the vast majority of cataract surgery-induced complications, such as secondary cataract, intraocular inflammation (endophthalmitis) and foreign body reactions, cystoid macular oedema, corneal edema. The nanotechnology offers physicians and surgeons to develop and commercialize costeffective therapeutic medical implantable devices, products and support systems with metabolic activities for the treatment of ophthalmic diseases and of a wide range of pathological states and disorders which are treated by insertion of the implantable and prosthetic (polymeric) devices. PMID- 22934630 TI - Postural and locomotor contributions to affordance perception. AB - The authors sought to evaluate the relative importance of locomotor control and postural control in the perception of affordances. While seated in a stationary wheelchair, participants made a series of judgments about the minimum lintel height under which they could roll in the wheelchair. Prior to making judgments, participants were given brief (~2 min) experience with wheelchair locomotion. They expected that this practice would influence the accuracy of subsequent affordance judgments. During practice, participants moved under their own power (using their hands on the wheels) or with an experimenter pushing the wheelchair. Also during wheelchair locomotion the participant's head was restrained, or was not. Results revealed that head restraint during the practice session had no effect on the accuracy of subsequent judgments. By contrast, the judgments of participants who controlled locomotion during practice were significantly more accurate than the judgments of participants who had not controlled their locomotion during practice. PMID- 22934632 TI - Abnormal cerebrospinal fluid (CSF) dynamics in Alzheimer's disease and normal pressure hydrocephalus: CSF-amyloid beta precursor protein metabolites as possible biomarkers. PMID- 22934631 TI - Biocontrol of tomato wilt disease by Bacillus subtilis isolates from natural environments depends on conserved genes mediating biofilm formation. AB - Bacillus subtilis and other Bacilli have long been used as biological control agents against plant bacterial diseases but the mechanisms by which the bacteria confer protection are not well understood. Our goal in this study was to isolate strains of B. subtilis that exhibit high levels of biocontrol efficacy from natural environments and to investigate the mechanisms by which these strains confer plant protection. We screened a total of 60 isolates collected from various locations across China and obtained six strains that exhibited above 50% biocontrol efficacy on tomato plants against the plant pathogen Ralstonia solanacearum under greenhouse conditions. These wild strains were able to form robust biofilms both in defined medium and on tomato plant roots and exhibited strong antagonistic activities against various plant pathogens in plate assays. We show that plant protection by those strains depended on widely conserved genes required for biofilm formation, including regulatory genes and genes for matrix production. We provide evidence suggesting that matrix production is critical for bacterial colonization on plant root surfaces. Finally, we have established a model system for studies of B. subtilis-tomato plant interactions in protection against a plant pathogen. PMID- 22934633 TI - Reflectance confocal microscopy characteristics of eight cases of pustular eruptions and histopathological correlations. AB - BACKGROUND: Reflectance confocal microscopy (RCM)'s interest has been well established for the non-invasive diagnosis of skin cancers, especially melanocytic, and in the differential diagnosis between benign and malignant cutaneous lesions. However, its diagnostic interest in inflammatory skin diseases still needs to be demonstrated. Our purpose was to evaluate the correlation between RCM and conventional histopathology in a series of pustular eruptions of different pathogeny. METHODS: Reflectance confocal microscopy analysis was performed in eight consecutive unselected patients in whom the diagnoses of pustular psoriasis, bacterial sur-infection, herpes-type virus skin sur infection, Sneddon-Wilkinson subcorneal putulosis and Hailey-Hailey disease have been made and images were compared to conventional histopathology. RESULTS: Neutrophils within the epidermis exhibited never reported earlier specific features, with either a shiny granular sludge or polylobated particules with a bright granular content. Moreover, some specific etiologies could be identified, such as acantholysis and herpes-type virus-infected keratinocytes. CONCLUSION: Our studies show a good correlation between RCM and conventional histopathology in pustular eruptions. Reflectance confocal microscopy may play an important role in the differential diagnosis of pustular eruptions; as most of the pathologic clues are epidermal, narrow thickness of the field of imaging, its main technical limitation, is indeed of lesser importance. PMID- 22934634 TI - Effect of molecular structure on the relative reactivity of naphthenic acids in the UV/H2O2 advanced oxidation process. AB - The large volume of oil sands process-affected water (OSPW) produced by the oil sands industry in Northern Alberta, Canada, is an environmental concern. The toxicity of OSPW has been attributed to a complex mixture of naturally occurring acids, including naphthenic acids (NAs). Highly cyclic or branched NAs are highly biopersistent in tailings ponds, thus understanding structure-reactivity relationship for NAs is very important for OSPW reclamation. In this study, we hypothesized that large, branched and cyclic NAs may be better oxidized in the UV/H(2)O(2) process than small, linear and acyclic NAs. Relative rate measurements using binary mixtures of model NA compounds confirmed that reactivity favored compounds with more carbons, and also favored NAs with one saturated ring, relative to the corresponding linear NA. However, for model compound with three rings, no increased reactivity was observed relative to monocyclic NA. UV/H(2)O(2) treatment of OSPW confirmed our findings with model compounds, indicating that the compounds with more carbons are favored for degradation. However, increasing the number of rings (or double bond equivalents) in OSPW NAs did not show any clear structure-reactivity. Microbial degradation studies of the UV/H(2)O(2) treated OSPW should be conducted to examine the overall benefit of this treatment for the real applications. PMID- 22934635 TI - An affective dimension within oppositional defiant disorder symptoms among boys: personality and psychopathology outcomes into early adulthood. AB - BACKGROUND: A dimension of negatively oriented affect within oppositional defiant disorder (ODD) symptoms, which has been described as irritability, has been shown to predict depression and anxiety. Related constructs have been linked to temperament and personality constructs. However, only a few studies have examined the prediction from irritability within ODD to psychopathology or personality outcomes. Further, no studies have investigated whether irritability distinguishes among classes of youth. METHODS: Data from a clinic-referred sample of 7-12-year-old boys followed up to age 18 were used. Measures included structured clinical interviews with parents through adolescence, and youth self report of depression and personality domains at age 18. RESULTS: Variable oriented analyses found predictive links between irritability and outcomes of depression, anxiety, and Neuroticism. Latent classes of youth were distinguished by the presence or absence of irritability symptoms. Youth classified by irritability symptoms at baseline were significantly more likely to show anxiety and depression through adolescence and depression and Neuroticism at 18. No relationship was observed for the other of the Big Five personality factors. CONCLUSION: Irritability symptoms within ODD distinguish youth at risk for persisting problems with internalizing disorders and Neuroticism into adulthood. The findings are suggestive of a model in which the early emergence of irritability marks life-course risks for specific types of psychopathology and personality problems. PMID- 22934636 TI - Antibacterial spirobisnaphthalenes from the North American cup fungus Urnula craterium. AB - Urnucratins A-C (1-3), which possess an unusual bisnaphthospiroether skeleton with one oxygen bridge and one C-C bridge and represent a new subclass of bisnaphthalenes, were isolated from the North American cup fungus Urnula craterium. Their structures, including absolute configurations, were determined by means of HRMS, NMR, and quantum chemical CD calculations. Urnucratin A (1) was found to be active against methicillin-resistant Staphylococcus aureus, vancomycin-resistant Enterococcus faecium, and Streptococcus pyogenes with MIC values of 2, 1, and 0.5 MUg/mL, respectively. PMID- 22934637 TI - A study of the genus Limnophora Robineau-Desvoidy (Diptera: Muscidae), with descriptions of six new species from China. AB - This paper provides the characters of genus Limnophora (Diptera: Muscidae) and a key to the Chinese species of Limnophora, six new species collected from Hainan Island of China, namely, L. brevispatula, n. sp., L. cothurnosurstyla, n. sp., L. dyadocerca, n. sp., L. longitarsis, n. sp., L. nuditibia, n. sp. and L. ypocerca, n. sp. are diagnosed, described and illustrated, a new record species in China, namely, L. argentifrons ( Shinonaga et Kano, 1977 ), is also included. PMID- 22934638 TI - Evolutionary implications of horizontal gene transfer. AB - The flow of genes between different species represents a form of genetic variation whose implications have not been fully appreciated. Here I examine some key findings on the extent of horizontal gene transfer (HGT) revealed by comparative genome analysis and their theoretical implications. In theoretical terms, HGT affects ideas pertaining to the tree of life, the notion of a last universal common ancestor, and the biological unities, as well as the rules of taxonomic nomenclature. This review discusses the emergence of the eukaryotic cell and the occurrence of HGT among metazoan phyla involving both transposable elements and structural genes for normal housekeeping functions. I also discuss the bacterial pangenome, which provides an important case study on the permeability of species boundaries. An interesting observation about bdelloid rotifers and their reversion to asexual reproduction as it pertains to HGT is included. PMID- 22934639 TI - Fusion and fission: interlinked processes critical for mitochondrial health. AB - Mitochondria are dynamic organelles that continually undergo fusion and fission. These opposing processes work in concert to maintain the shape, size, and number of mitochondria and their physiological function. Some of the major molecules mediating mitochondrial fusion and fission in mammals have been discovered, but the underlying molecular mechanisms are only partially unraveled. In particular, the cast of characters involved in mitochondrial fission needs to be clarified. By enabling content mixing between mitochondria, fusion and fission serve to maintain a homogeneous and healthy mitochondrial population. Mitochondrial dynamics has been linked to multiple mitochondrial functions, including mitochondrial DNA stability, respiratory capacity, apoptosis, response to cellular stress, and mitophagy. Because of these important functions, mitochondrial fusion and fission are essential in mammals, and even mild defects in mitochondrial dynamics are associated with disease. A better understanding of these processes likely will ultimately lead to improvements in human health. PMID- 22934640 TI - Genetics of climate change adaptation. AB - The rapid rate of current global climate change is having strong effects on many species and, at least in some cases, is driving evolution, particularly when changes in conditions alter patterns of selection. Climate change thus provides an opportunity for the study of the genetic basis of adaptation. Such studies include a variety of observational and experimental approaches, such as sampling across clines, artificial evolution experiments, and resurrection studies. These approaches can be combined with a number of techniques in genetics and genomics, including association and mapping analyses, genome scans, and transcription profiling. Recent research has revealed a number of candidate genes potentially involved in climate change adaptation and has also illustrated that genetic regulatory networks and epigenetic effects may be particularly relevant for evolution driven by climate change. Although genetic and genomic data are rapidly accumulating, we still have much to learn about the genetic architecture of climate change adaptation. PMID- 22934641 TI - Plant virus metagenomics: biodiversity and ecology. AB - Viral metagenomics is the study of viruses in environmental samples, using next generation sequencing that produces very large data sets. For plant viruses, these studies are still relatively new, but are already indicating that our current knowledge grossly underestimates the diversity of these viruses. Some plant virus studies are using thousands of individual plants so that each sequence can be traced back to its precise host. These studies should allow for deeper ecological and evolutionary analyses. The finding of so many new plant viruses that do not cause any obvious symptoms in wild plant hosts certainly changes our perception of viruses and how they interact with their hosts. The major difficulty in these (as in all) metagenomic studies continues to be the need for better bioinformatics tools to decipher the large data sets. The implications of this new information on plant viruses for international agriculture remain to be addressed. PMID- 22934642 TI - Regeneration and transdetermination in Drosophila imaginal discs. AB - The study of regeneration in Drosophila imaginal discs provides an opportunity to use powerful genetic tools to address fundamental problems pertaining to tissue regeneration and cell plasticity. We present a historical overview of the field and describe how the application of modern methods has made the study of disc regeneration amenable to genetic analysis. Discs respond to tissue damage in several ways: (a) Removal of part of the disc elicits localized cell proliferation and regeneration of the missing tissue. (b) Damage at specific locations in the disc can cause cells to generate disc-inappropriate structures (e.g., wing instead of leg), a phenomenon known as transdetermination. (c) Diffuse damage to imaginal discs, results in compensatory proliferation of surviving cells. Candidate-gene approaches have implicated the JNK, Wingless, and Hippo pathways in regeneration. Recently developed systems will enable extensive genetic screens that could provide new insights into tissue regeneration, transdetermination and compensatory proliferation. PMID- 22934643 TI - The biosynthetic capacities of the plastids and integration between cytoplasmic and chloroplast processes. AB - Plastids are semiautonomous organelles derived from cyanobacterial ancestors. Following endosymbiosis, plastids have evolved to optimize their functions, thereby limiting metabolic redundancy with other cell compartments. Contemporary plastids have also recruited proteins produced by the nuclear genome of the host cell. In addition, many genes acquired from the cyanobacterial ancestor evolved to code for proteins that are targeted to cell compartments other than the plastid. Consequently, metabolic pathways are now a patchwork of enzymes of diverse origins, located in various cell compartments. Because of this, a wide range of metabolites and ions traffic between the plastids and other cell compartments. In this review, we provide a comprehensive analysis of the well known, and of the as yet uncharacterized, chloroplast/cytosol exchange processes, which can be deduced from what is currently known about compartmentation of plant cell metabolism. PMID- 22934644 TI - The unfolded protein response in secretory cell function. AB - The endoplasmic reticulum (ER) controls many important aspects of cellular function, including processing of secreted and membrane proteins, synthesis of membranes, and calcium storage. Maintenance of ER function is controlled through a network of signaling pathways collectively known as the unfolded protein response (UPR). The UPR balances the load of incoming proteins with the folding capacity of the ER and allows cells to adapt to situations that disrupt this balance. This disruption is referred to as ER stress. Although ER stress often arises in pathological situations, the UPR plays a central role in the normal development and function of cells specializing in secretion. Many aspects of this response are conserved broadly across eukaryotes; most organisms use some subset of a group of ER transmembrane proteins to signal to the nucleus and induce a broad transcriptional upregulation of genes involved in ER function. However, new developments in metazoans, plants, and fungi illustrate interesting variations on this theme. Here, we summarize mechanisms for detecting and counteracting ER stress, the role of the UPR in normal secretory cell function, and how these pathways vary across organisms and among different tissues and cell types. PMID- 22934645 TI - Border crossings: colicins and transporters. AB - Colicins are protein toxins produced by Escherichia coli to kill related bacteria. They must cross the target cell outer membrane (OM), and some must also cross the inner membrane (IM). To accomplish cellular import, colicins have parasitized E. coli nutrient transporters as well as IM and periplasmic proteins normally used to maintain cell wall integrity or provide energy for nutrient uptake through transporters. Colicins have evolved to use both transporters and other membrane proteins through mechanisms different from those employed in physiological substrate uptake. Extended receptor-binding domains allow some colicins to search by lateral diffusion for binding sites on their OM translocators while bound to their primary OM receptor. Transport across the OM is initiated by entry of the unstructured N-terminal translocation domain into the translocator. Periplasmic and IM networks subsequently accomplish insertion of the colicin cytotoxic domain into or across the IM. PMID- 22934647 TI - Genetics of aggression. AB - Aggression mediates competition for food, mating partners, and habitats and, among social animals, establishes stable dominance hierarchies. In humans, abnormal aggression is a hallmark of neuropsychiatric disorders and can be elicited by environmental factors acting on an underlying genetic susceptibility. Identifying the genetic architecture that predisposes to aggressive behavior in people is challenging because of difficulties in quantifying the phenotype, genetic heterogeneity, and uncontrolled environmental conditions. Studies on mice have identified single-gene mutations that result in hyperaggression, contingent on genetic background. These studies can be complemented by systems genetics approaches in Drosophila melanogaster, in which mutational analyses together with genome-wide transcript analyses, artificial selection studies, and genome-wide analysis of epistasis have revealed that a large segment of the genome contributes to the manifestation of aggressive behavior with widespread epistatic interactions. Comparative genomic analyses based on the principle of evolutionary conservation are needed to enable a complete dissection of the neurogenetic underpinnings of this universal fitness trait. PMID- 22934646 TI - Genetics of reproduction and regulation of honeybee (Apis mellifera L.) social behavior. AB - Honeybees form complex societies with a division of labor for reproduction, nutrition, nest construction and maintenance, and defense. How does it evolve? Tasks performed by worker honeybees are distributed in time and space. There is no central control over behavior and there is no central genome on which selection can act and effect adaptive change. For 22 years, we have been addressing these questions by selecting on a single social trait associated with nutrition: the amount of surplus pollen (a source of protein) that is stored in the combs of the nest. Forty-two generations of selection have revealed changes at biological levels extending from the society down to the level of the gene. We show how we constructed this vertical understanding of social evolution using behavioral and anatomical analyses, physiology, genetic mapping, and gene knockdowns. We map out the phenotypic and genetic architectures of food storage and foraging behavior and show how they are linked through broad epistasis and pleiotropy affecting a reproductive regulatory network that influences foraging behavior. This is remarkable because worker honeybees have reduced reproductive organs and are normally sterile; however, the reproductive regulatory network has been co-opted for behavioral division of labor. PMID- 22934648 TI - Chromosome replication and segregation in bacteria. AB - In dividing cells, chromosome duplication once per generation must be coordinated with faithful segregation of newly replicated chromosomes and with cell growth and division. Many of the mechanistic details of bacterial replication elongation are well established. However, an understanding of the complexities of how replication initiation is controlled and coordinated with other cellular processes is emerging only slowly. In contrast to eukaryotes, in which replication and segregation are separate in time, the segregation of most newly replicated bacterial genetic loci occurs sequentially soon after replication. We compare the strategies used by chromosomes and plasmids to ensure their accurate duplication and segregation and discuss how these processes are coordinated spatially and temporally with growth and cell division. We also describe what is known about the three conserved families of ATP-binding proteins that contribute to chromosome segregation and discuss their inter-relationships in a range of disparate bacteria. PMID- 22934650 TI - Protective properties of novel S-acyl-glutathione thioesters against ultraviolet induced oxidative stress. AB - UV-induced toxicity is characterized by marked oxidative stress, accompanied by the depletion of key cellular antioxidants, particularly glutathione (GSH). Replenishing cellular GSH may represent a means of counteracting UV-induced toxicity: however, treatment with free GSH is not therapeutically effective due to its unfavorable pharmacokinetic properties. In this study, we show that S-acyl glutathione (acyl-SG) derivatives, which consist of an acyl chain (of variable length and saturation) linked via a thioester bond to GSH, increase intracellular levels of reduced GSH in primary skin fibroblasts, adenocarcinoma HeLa and neuroblastoma SH-SY5Y cells. Consistent with this, acyl-SG derivatives protect against UV-induced reactive oxygen species (ROS) production and UV-B/C-mediated lipid peroxidation and caspase-3 activation in the analyzed cell lines, with unsaturated thioesters displaying a significantly greater protective effect. Taken together, our findings suggest that acyl-SG thioesters may be therapeutically effective in the treatment of UV-related skin disorders and oxidative stress-mediated conditions in general. PMID- 22934651 TI - Molecular sinkers: X-ray photoemission and atomistic simulations of benzoic acid and benzoate at the aqueous solution/vapor interface. AB - In this work, we provide a detailed microscopic picture of the behavior of benzoic acid at the aqueous solution/vapor interface in its neutral as well as in its dissociated form (benzoate). This is achieved through a combination of highly surface-sensitive X-ray photoelectron spectroscopy experiments and fully atomistic molecular simulations. We show that significant changes occur in the interface behavior of the neutral acid upon release of the proton. The benzoic acid molecules are found to be strongly adsorbed at the interface layer with the planes of the aromatic rings oriented almost parallel to the water surface. In contrast, in the benzoate form, the carboxylate group shows a sinker-like behavior while the aromatic ring acts as a buoy, oriented nearly perpendicular to the surface. Furthermore, a significant fraction of the molecular ions move from the interface layer into the bulk of the solution. We rationalize these findings in terms of the very different hydration properties of the carboxylic group in the two charge states. The molecule has an amphiphilic nature, and the deprotonation thus changes the hydrophobic/hydrophilic balance between the nonpolar aromatic and the polar carboxylic parts of the molecule. That, consequently, leads to a pronounced reorientation and depletion of the molecules at the interface. PMID- 22934652 TI - Methyliminopropadienone CH3-N?C?C?C?O: photoelectron spectrum and electronic structure. AB - N-Methyliminopropadienone MeN?C?C?C?O 1a was generated by flash vacuum thermolysis of three 5-(aminomethylene)-1,3-dioxane-4,6-diones (Meldrum's acid derivatives). Online monitoring of the reactions permitted the recording of the UV-photoelectron spectra and the determination of the first two ionization energies of 1a as 9.0 and 12.4 eV. The first ionization energy (and the calculated highest occupied molecular orbital energy) of 1a are more comparable with those of N-methylketenimine than with ketene. In contrast, the calculated lowest unoccupied molecular orbital energy is significantly lower than those of both ketene and N-methylketenimine, thereby making iminopropadienones powerful electrophiles. Calculated charge densities indicate that electrophiles should attack at C3 or O and nucleophiles at C2 or C4 in broad agreement with experimental observations. PMID- 22934653 TI - Life course experiences and lay diagnosis explain low-income parents' child dental decisions: a qualitative study. AB - OBJECTIVE: This study aimed to better understand low-income parents' child dental care decisions through a life course approach that captured parents' experiences within the social context of poverty. METHODS: We conducted 43 qualitative life history interviews with 10 parents, who were long-term social assistance recipients living in Montreal, Canada. Thematic analysis involved interview debriefing, transcript coding, theme identification and data interpretation. RESULTS: Our interviews identified two emergent themes: lay diagnosis and parental oral health management. Parents described a process of 'lay diagnosis' that consisted of examining their children's teeth and interpreting their children's oral signs and symptoms based on their observations. These lay diagnoses were also shaped by their own dental crises, care experiences and oral health knowledge gained across a life course of poverty and dental disadvantage. Parents' management strategies included monitoring and managing their children's oral health themselves or by seeking professional recourse. Parents' management strategies were influenced both by their lay diagnoses and their perceived ability to manage their children's oral health. Parents felt responsible for their children's dental care, empowered to manage their oral health and sometimes forgo dental visits for their children because of their own self-management life history. CONCLUSION: This original approach revealed insights that help to understand why low-income parents may underutilize free dental services. Further research should consider how dental programs can nurture parental empowerment and capitalize on parents' perceived ability to diagnose and manage their children's oral health. PMID- 22934649 TI - Disentangling the many layers of eukaryotic transcriptional regulation. AB - Regulation of gene expression in eukaryotes is an extremely complex process. In this review, we break down several critical steps, emphasizing new data and techniques that have expanded current gene regulatory models. We begin at the level of DNA sequence where cis-regulatory modules (CRMs) provide important regulatory information in the form of transcription factor (TF) binding sites. In this respect, CRMs function as instructional platforms for the assembly of gene regulatory complexes. We discuss multiple mechanisms controlling complex assembly, including cooperative DNA binding, combinatorial codes, and CRM architecture. The second section of this review places CRM assembly in the context of nucleosomes and condensed chromatin. We discuss how DNA accessibility and histone modifications contribute to TF function. Lastly, new advances in chromosomal mapping techniques have provided increased understanding of intra- and interchromosomal interactions. We discuss how these topological maps influence gene regulatory models. PMID- 22934654 TI - Surface-enhanced Raman scattering-active Au/SiO2 nanocomposites prepared using sonoelectrochemical pulse deposition methods. AB - For improving signals, reproducibility, and stabilities of surface-enhanced Raman scattering (SERS), numerous technologies have recently been reported in the literature. However, the fabrication processes are usually complicated. It is well-known that nanoparticles (NPs) of Au and SiO(2) are SERS active and inactive materials, respectively. In this work, a simple synthesis route based on sonoelectrochemical pulse deposition (SEPD) methods has been developed to synthesize effectively SERS-active Au/SiO(2) nanocomposites (NCs) with an enhancement factor of 5.4 * 10(8). Experimental results indicate that pH value of solution and addition of SiO(2) NPs before and after oxidation-reduction cycles (ORCs) can significantly influence the corresponding SERS activities. Encouragingly, the SERS of Rhodamine 6G (R6G) adsorbed on the developed Au/SiO(2) NCs exhibits a higher intensity by more than 1 order of magnitude, as compared with that of R6G adsorbed on Au NPs synthesized using the same method. Moreover, this improved SERS activity is successfully verified from the mechanisms of electromagnetic (EM) and chemical (CHEM) enhancements. PMID- 22934655 TI - Titanium dioxide nanoparticles disturb the fibronectin-mediated adhesion and spreading of pre-osteoblastic cells. AB - In the context of rapid development of nanoparticles (NPs) for industrial applications, the question of their toxicity and biological effects must be considered. In this work, we have assessed the influence of titanium dioxide NPs on the adhesion and spreading of MC-3T3 pre-osteoblasts by using a cell subclone that does not produce its own extracellular matrix. Petri dishes were coated with the important adhesion protein fibronectin (Fn). By incubating these Fn-coated surfaces with different amounts of TiO(2) NPs, we have shown that the adhesion of pre-osteoblasts is disturbed, with an important decrease in the number of adherent cells (from 40 to 75% depending upon the concentration and type of NPs). Petri-dish surfaces were analyzed with environmental scanning electron microscropy (ESEM), with images showing that TiO(2) NP aggregates are bound to the layer of adsorbed Fn molecules. The cells cultured on these Fn/NP surfaces adopted an irregular shape and an aberrant organization of actin cytoskeleton, as revealed by fluorescence microscopy. Most importantly, these results, taken together, have revealed that the actin cytoskeleton forms abnormal aggregates, even on top of the nucleus, that coincide with the presence of large aggregates of NPs on top of cells. On the basis of these observations, we propose that some Fn molecules are able to desorb from the Petri dish surface to coat TiO(2) NPs. Fn/NP complexes are not attached firmly enough on the surface to allow for normal cell adhesion/spreading and the development of tense actin fibers. These results stress the paramount need for the assessment of the toxicology of NPs, with special attention to their interactions with biomolecules. PMID- 22934656 TI - Molecular dynamics of beta-hairpin models of epigenetic recognition motifs. AB - The conformations and stabilities of the beta-hairpin model peptides of Waters (Riemen, A. J.; Waters, M. L. Biochemistry 2009, 48, 1525; Hughes, R. M.; Benshoff, M. L.; Waters, M. L. Chemistry 2007, 13, 5753) have been experimentally characterized as a function of lysine epsilon-methylation. These models were developed to explore molecular recognition of known epigenetic recognition motifs. This system offered an opportunity to computationally examine the role of cation-pi interactions, desolvation of the epsilon-methylated ammonium groups, and aromatic/aromatic interactions on the observed differences in NMR spectra. AMOEBA, a second-generation force field (Ponder, J. W.; Wu, C.; Ren, P.; Pande, V. S.; Chodera, J. D.; Schnieders, M. J.; Haque, I.; Mobley, D. L.; Lambrecht, D. S.; DiStasio, R. A., Jr.; Head-Gordon, M.; Clark, G. N.; Johnson, M. E.; Head Gordon, T. J. Phys. Chem. B 2010, 114, 2549), was chosen as it includes both multipole electrostatics and polarizability thought to be essential to accurately characterize such interactions. Independent parametrization of epsilon-methylated amines was required from which aqueous solvation free energies were estimated and shown to agree with literature values. Molecular dynamics simulations (100 ns) using the derived parameters with model peptides, such as Ac-R-W-V-W-V-N-G-Orn K(Me)(n)-I-L-Q-NH(2), where n = 0, 1, 2, or 3, were conducted in explicit solvent. Distances between the centers of the indole rings of the two-tryptophan residues, 2 and 4, and the epsilon-methylated ammonium group on Lys-9 as well as the distance between the N- and C-termini were monitored to estimate the strength and orientation of the cation-pi and aromatic/aromatic interactions. In agreement with the experimental data, the stability of the beta-hairpin increased significantly with lysine epsilon-methylation. The ability of MD simulations to reproduce the observed NOEs for the four peptides was further estimated for the monopole-based force fields, AMBER, CHARMM, and OPLSAA. AMOEBA correctly predicted over 80% of the observed NOEs for all 4 peptides, while the three monopole force fields were 40-50% predictive in only 2 cases and approximately 10% in the other 10 examples. Preliminary analysis suggests that the decreased cost of desolvation of the substituted ammonium group significantly compensated for the reduced cation-pi interaction resulting from the increased separation due to steric bulk of the epsilon-methylated amines. PMID- 22934657 TI - HPV infection and intraepithelial lesions: comparison between HIV positive and negative women. AB - INTRODUCTION: Human Papillomavirus infections have been shown to be crucial for the development of cervical intraepithelial neoplasia and subsequent cervical cancer. The aim of this study is to describe the prevalence of different genotypes of HPV, in a population of HIV-positive women, compared to the negative ones, and their oncogenic risk. PATIENTS AND METHOD: A case-control study comparing HPV genotype distribution between 93 HIV-seropositive and 186 HIV seronegative women, matched for age and severity of cervical lesions, who attending colposcopic service of our departments for periodical Pap smear and HPV DNA full genotyping by SPF-10 LiPA assay. RESULTS: No significant difference was found in genotype distribution between HIV positive and HIV negative women. Only the prevalence of HPV56 was higher in HIV positive women (p=0,046). The rates of HPV 6, 11, 16 and 18 were similar in both groups. The likelihood of the detection of three or more HPV genotypes was significantly associated with CIN (OR=2.0; 95% CI=1.1-3.8; p= 0.026) but only marginally to HIV-positive serostatus (OR=1.68; 95% CI=0.89-3.16; p= 0.1). High grade cervical lesions are associated with high risk viruses like HPV 16 and 18 and with multiple cervical HPV infections. CONCLUSIONS: The tendency to treat HIV disease with high active antiretroviral therapy may reduce the impact of immunosuppression and make the course of such HPV infections more similar to that among women who are not HIVinfected. As in immunocompetent women, high oncogenic risk viral type and multiple infections are associated with a histologically proven cervical intraepithelial lesions. PMID- 22934658 TI - In vitro infection of human umbilical cord blood CD34+ hematopoietic progenitor cells by HIV-1 CRF07_BC enveloped pseudovirus. AB - To determine whether CRF07_BC, one of the most predominant strains that accounts for one third HIV-1 prevalence in China, has the ability to infect hematopoietic progenitor cells (HPCs), human Umbilical Cord Blood (UCB) derived CD34+ HPCs isolated with high purity were infected by HIV-1 pseudotyped with CRF07_BC envelope. After HIV-1 infection, ~0.86% CD34+ HPCs were co-stained for CD34 and intracellular HIV Gag. HIV p24 antigen was detectable and reached maximal release between day 2-4 after HIV-1 infection. The data of nested Alu-LTR PCR proved the integration of HIV-1 genome into the host genome occurred in HIV-1-infected HPCs. These data demonstrated that the envelope of CRF07_BC from China has the capability of resulting in infection to CD34+ HPCs, which may serve as a mechanism for long-term latency of HIV-1 infection in vivo. PMID- 22934659 TI - Ongoing development of social cognition in adolescence. AB - Age differences in social cognition between adolescents and young adults were investigated. Two large groups of adolescents and young adults were given tasks of theory of mind and emotion recognition. In addition, to control for possibly related basic cognitive development, working memory, speed of processing, and verbal ability were assessed. A strong age effect was revealed across both measures of social cognition. Adolescents performed with a lower accuracy than adults. Further analyses indicated that those age differences remained significant even after controlling for basic cognitive abilities. Exploratory analyses indicated no influence of pubertal phase on social cognition. Results suggest ongoing development of social cognition across adolescence, independent of individual differences in more basic cognitive abilities. PMID- 22934660 TI - Utility of the hyperbranched polymer Hybrane S1200 for production of instant release particles by hot melt extrusion. AB - Particles composed of 90:10 or 80:20 mixtures of the hyperbranched poly(esteramide) Hybrane S1200 and the poorly water-soluble drug hydrochlorothiazide were produced by hot melt extrusion at maximum temperatures of 90 degrees C without any need for addition of a plasticizer. In dissolution rate assays in USP 29 apparatus II, particles of the smallest size category (<250 um) containing 10% of hydrochlorothiazide released 95% of their load within 5 min. This fast release is attributed to the combination of the high solubility of Hybrane S1200, the dispersion of the drug in non-crystalline form in the polymer matrix (attested to by the results of powder X-ray diffractometry, and scanning electron microscopy), and to the fact that the main interaction between drug and polymer is through hydrogen bonds (attested to by ATR-IR difference spectra). PMID- 22934661 TI - Smoking and socio-economic status may affect myasthenia gravis. AB - BACKGROUND AND PURPOSE: The influence of environmental factors in myasthenia gravis (MG) is unknown. The aim of this cross-sectional population-based study was to investigate if smoking and socio-economic status (SES) were associated with MG in the Norwegian population. METHODS: Subjects were 491 MG patients identified in Norway at the time of the study (point prevalence 12.7/100 000). A questionnaire covering smoking habits and markers of SES (education and occupation) was mailed to all patients. Population data were obtained from Statistics Norway. RESULTS: A total of 375 (76.6%) patients completed the questionnaire (236 women, mean age 59 +/- 18 years), of which 193 reported to be early onset MG (EOMG, onset <=40 years, 155 women). Compared with the general population, current smoking was more prevalent amongst MG patients [risk ratio (RR) 1.5; 95% confidence interval (CI) 1.1-1.9], most of whom had EOMG. Female MG patients had higher education compared with the general population (RR 4.5; 95% CI 3.2-6.2). Male MG patients were similar to the general population regarding both education and occupation, except for a subset of late onset MG who had shorter education (RR 1.9; 95% CI 1.1-3.2) and had worked in crafts and related trades. About half of working age MG patients received disability pension, a finding significantly related to low educational level and a more severe disease course (P < 0.001). CONCLUSION: This is the first report indicating that smoking and SES may affect MG. Further studies investigating their role as potential risk factors are warranted. PMID- 22934663 TI - Reduction of hexavalent chromium using naturally-derived flavonoids. AB - Quercetin is a naturally occurring flavonoid that is known to form complexes with metals; a process that reduces the environmental availability of toxic metals such as chromium. We hereby report the first evidence of the removal of Cr(VI) from environmental samples using quercetin (QCR) and two synthetic derivatives: namely quercetin pentaphosphate (QPP) and quercetin sulfonic acid (QSA). We successfully synthesized both QPP and QSA using simple procedures while characterizing them with UV-vis spectroscopy, H(1)-NMR, (13)C NMR, (31)P-NMR, and LC-MS techniques. The solubility of QPP was found to be 840 mg/mL and aqueous solutions of both QPP and QSA were stable for over a period of 1 year. Quercetin and these derivatives were subsequently utilized for the reduction of Cr(VI) and QCR was found to have a higher reduction efficiency of 99.8% (30 min), followed by QPP/palladium nanoparticles mixture (PdNPs) at 96.5% (60 min), and finally QSA/PdNPs mixtures at 91.7% (60 min). PdNPs catalyst increased the efficiency by ~36.5% while a change in operating temperature from 25 to 45 degrees C improved the efficiency by ~46.8%. Electron paramagnetic resonance spectroscopy was used to confirm the presence of Cr (III) in the reaction products. This reduction approach was validated in environmental (Binghamton University) BU and standard reference material (BRS) soil samples. Results showed that the analysis could be completed within one hour and the efficiency was higher in BU soil than in BRS soil by 16.1%. QPP registered the highest % atom economy of 94.6%. This indicates enhanced performance compared to bioremediation approach that requires several months to achieve about 90% reduction efficiency. PMID- 22934662 TI - The relationship between large cavum septum pellucidum and antisocial behavior, callous-unemotional traits and psychopathy in adolescents. AB - BACKGROUND: The presence of a large cavum septum pellucidum (CSP) has been previously associated with antisocial behavior/psychopathic traits in an adult community sample. AIMS: The current study investigated the relationship between a large CSP and symptom severity in disruptive behavior disorders (DBD; conduct disorder and oppositional defiant disorder). METHOD: Structural MRI scans of youth with DBDs (N = 32) and healthy comparison youth (N = 27) were examined for the presence of a large CSP and if this was related to symptom severity. RESULTS: Replicating previous results, a large CSP was associated with DBD diagnosis, proactive aggression, and level of psychopathic traits in youth. However, the presence of a large CSP was unrelated to aggression or psychopathic traits within the DBD sample. CONCLUSIONS: Early brain mal-development may increase the risk of a DBD diagnosis, but does not mark a particularly severe form of DBD within patients receiving these diagnoses. PMID- 22934664 TI - Attentional demands associated with postural control depend on task difficulty and visual condition. AB - The authors aimed to assess the effect of vision on variations in attentional resources allocated to postural control during tasks of various levels of difficulty. Test-retest reliability of postural and cognitive parameters was also evaluated. Twenty adults stood quietly on a force platform during 30-s trials (primary task). Twelve conditions involving combinations of three bases of support, two vision conditions, and the presence or absence of a simple reaction time task (secondary task) were tested. Baseline trials of the reaction time task were also performed with the participants seated. Reaction time and postural parameters demonstrated good to excellent test-retest reliability in most conditions. Postural control was altered by the reduction of the base of support and by the absence of vision. Maintaining an upright stance increased reaction time compared with a seated position, indicating that quiet standing tasks required some attention even in young adults. Changes in postural steadiness were correlated with changes in reaction time, showing a significant relationship between the difficulty of the postural task and the attentional resources allocated to postural control. However, reaction time increased with the reduction of the base of support only without vision. This dual task paradigm showed that vision can compensate for the increase in attentional demands during the most difficult postural tasks. PMID- 22934665 TI - Dynamic thiol exchange with beta-sulfido-alpha,beta-unsaturated carbonyl compounds and dithianes. AB - A reversible covalent bond exchange of thiols, beta-sulfido-alpha,beta unsaturated carbonyls, and dithianes has been studied in DMSO and D(2)O/DMSO mixtures. The equilibrium between thiols and beta-sulfido-alpha,beta-unsaturated carbonyls is obtained within a few hours, while the equilibration starting with the beta-dithiane carbonyls and thiols requires a few days. This time scale makes the system ideal for utilization in dynamic combinatorial chemistry. PMID- 22934666 TI - Antiulcerogenic and antibacterial activities of Apium graveolens essential oil and extract. AB - This study investigates the antiulcerogenic and antibacterial activities of Apium graveolens extracts. The antiulcerogenic activity was evaluated in rats by the HCl/EtOH method. Inhibition of gastric lesions by A. graveolens extracts was dose dependent for both aerial part (53-76%) and seeds (51-95%). The methanolic extract as well as the aqueous extracts used at 300 mg kg(-1) dose exhibited a highly significant inhibition of gastric lesions (91% and 95%, respectively) which was similar to that induced by omeprazole (94%). Essential oil and aqueous extract prepared from the aerial parts of A. graveolens were tested to determine their antibacterial activity using the paper disc-diffusion method, the minimal inhibitory concentration and the minimal bactericidal concentration. Essential oil of A. graveolens was strongly inhibitory against Escherichia coli and moderately inhibitory against Pseudomonas aeruginosa and Staphylococcus aureus. The chemical composition of the volatile oil was investigated by gas chromatography analysis. The major components identified were beta-pinene, camphene, cumene, limonene, alpha-thuyene, alpha-pinene, beta-phellendrene, p cymene, gamma-terpinene, sabinene and terpinolene. PMID- 22934668 TI - Editorial Comment to CD74 expression is increased in high-grade, invasive urothelial carcinoma of the bladder. PMID- 22934667 TI - Fabrication of blended polycaprolactone/poly(lactic-co-glycolic acid)/beta tricalcium phosphate thin membrane using solid freeform fabrication technology for guided bone regeneration. AB - This study developed a bioabsorbable-guided bone regeneration membrane made of blended polycaprolactone (PCL), poly(lactic-co-glycolic acid) (PLGA), and beta tricalcium phosphate (beta-TCP) using solid freeform fabrication (SFF) technology. The chemical and physical properties of the membrane were evaluated using field emission scanning electron microscopy, energy dispersive spectroscopy, and a tensile test. In vitro cell activity assays revealed that the adhesion, proliferation, and osteogenic differentiation of seeded adipose-derived stem cells (ADSCs) were significantly promoted by the PCL/PLGA/beta-TCP membranes compared with PCL/PLGA membranes. When the PCL/PLGA and PCL/PLGA/beta-TCP membranes were implanted on rabbit calvaria bone defects without ADSCs, microcomputed tomography and histological analyses confirmed that the SFF-based PCL/PLGA/beta-TCP membranes greatly increased bone formation without the need for bone substitute materials. Moreover, tight integration, which helps to prevent exposure of the membrane, between both membranes and the soft tissues was clearly observed histologically. The SFF-based PCL/PLGA and PCL/PLGA/beta-TCP membranes retained their mechanical stability for up to 8 weeks without significant collapse. Furthermore, PCL/PLGA/beta-TCP underwent adequate degradation without a significant immune response at 8 weeks. PMID- 22934669 TI - A molecular approach to identifying the natural prey of the African creeping water bug Naucoris, a potential reservoir of Mycobacterium ulcerans. AB - The extra-oral digestion of creeping water bugs (Naucoridae: Hemiptera) hinders the study of their diet using the standard method of identifying prey body parts in the gut. Genetic methods are available, but rely on PCR tests or similar diagnostics to confirm suspected prey. Where the potential prey is unknown and a broad search for all possible prey is desirable, methods that can potentially capture any prey item are required. Naucoris sp. is known to harbor Mycobacterium ulcerans (Actinomycetales: Mycobacteriaceae), the causative bacterium of Buruli ulcer. Outbreaks of Buruli ulcer have been associated with disturbed freshwater habitats, but the mode of transmission to humans remains unclear. Here we examine the diet of Naucoris sp., a dominant aquatic predator in water bodies in Ghana where the prevalence of Buruli ulcer is high. We cloned and sequenced 576 PCR products (mtDNA rrnL, cox1) isolated from the gut of 60 Naucoris sp. individuals to determining diet composition as broadly as possible. Using phylogenetic analysis of newly sequenced clones and 6 potential prey taxa collected from the site, sequences isolated from Naucoris sp. guts matched locally collected Coleoptera (Hydrophilidae). Blastn queries to GenBank of other clone sequences produced matches to (Anura) (n = 1), Rotifera (n = 5), and fungi (n = 4) as additional components of the diet. Our results suggest that sp. in this Buruli ulcer-endemic area feeds on a wide range of prey and body sizes, and that the approach could be successfully applied to studies of aquatic food webs where morphological identification of prey is impossible and where little or no a priori knowledge is available. PMID- 22934670 TI - Editorial comment. PMID- 22934671 TI - Biologically active dibenzofurans from Pilidiostigma glabrum, an endemic Australian Myrtaceae. AB - In an effort to identify new anti-inflammatory and antibacterial agents with potential application in wound healing, five new dibenzofurans, 1,3,7,9 tetrahydroxy-2,8-dimethyl-4,6-di(2-methylbutanoyl)dibenzofuran (1), 1,3,7,9 tetrahydroxy-2,8-dimethyl-4-(2-methylbutanoyl)-6-(2-methylpropionyl)dibenzofuran (2), 1,3,7,9-tetrahydroxy-2,8-dimethyl-4,6-di(2-methylpropionyl)dibenzofuran (3), 1,3,7,9-tetrahydroxy-4,6-dimethyl-2-(2-methylbutanoyl)-8-(2 methylpropionyl)dibenzofuran (4), and 1,3,7,9-tetrahydroxy-4,6-dimethyl-2,8-di(2 methylpropionyl)dibenzofuran (5), were isolated from the leaves of Pilidiostigma glabrum together with one previously described dibenzofuran. Structure elucidation was achieved by way of spectroscopic measurements including 2D-NMR spectroscopy. Compounds with 2,8-acyl substitutions had potent antibacterial activity against several Gram-positive strains (MIC in the low micromolar range), while compounds with 4,6-acyl substitutions were less active. All compounds except 3 inhibited the synthesis of nitric oxide in RAW264 macrophages with IC(50) values in the low micromolar range. Compounds with 2,8-acyl substitutions also inhibited the synthesis of PGE(2) in 3T3 cells, whereas 4,6-acyl-substituted compounds were inactive. None of the compounds inhibited the synthesis of TNF alpha in RAW264 cells. The compounds showed variable but modest antioxidant activity in the oxygen radical absorbance capacity assay. These findings highlight that much of the Australian flora remains unexplored and may yet yield many new compounds of interest. Initial clues are provided on structure/activity relationships for this class of bioactives, which may enable the design and synthesis of compounds with higher activity and/or selectivity. PMID- 22934672 TI - Brucella as a potential agent of bioterrorism. AB - Perception on bioterrorism has changed after the deliberate release of anthrax by the postal system in the United States of America in 2001. Potential bioterrorism agents have been reclassified based on their dissemination, expected rate of mortality, availability, stability, and ability to lead a public panic. Brucella species can be easily cultured from infected animals and human materials. Also, it can be transferred, stored and disseminated easily. An intentional contamination of food with Brucella species could pose a threat with low mortality rate. Brucella spp. is highly infectious through aerosol route, making it an attractive pathogen to be used as a potential agent for biological warfare purposes. Recently, many studies have been concentrated on appropriate sampling of Brucella spp. from environment including finding ways for its early detection and development of new decontamination procedures such as new drugs and vaccines. There are many ongoing vaccine development studies; some of which recently received patents for detection and therapy of Brucella spp. However, there is still no available vaccine for humans. In this paper, recent developments and recent patents on brucellosis are reviewed and discussed. PMID- 22934673 TI - Coastal iodine emissions. 1. Release of I2 by Laminaria digitata in chamber experiments. AB - Tidally exposed macroalgae emit large amounts of I(2) and iodocarbons that produce hotspots of iodine chemistry and intense particle nucleation events in the coastal marine boundary layer. Current emission rates are poorly characterized, however, with reported emission rates varying by 3 orders of magnitude. In this study, I(2) emissions from 25 Laminaria digitata samples were investigated in a simulation chamber using incoherent broadband cavity-enhanced absorption spectroscopy (IBBCEAS). The chamber design allowed gradual extraction of seawater to simulate tidal emersion of algae. Samples were exposed to air with or without O(3) and to varying irradiances. Emission of I(2) occurred in four distinct stages: (1) moderate emissions from partially submerged samples; (2) a strong release by fully emerged samples; (3) slowing or stopping of I(2) release; and (4) later pulses of I(2) evident in some samples. Emission rates were highly variable and ranged from 7 to 616 pmol min(-1) gFW(-1) in ozone-free air, with a median value of 55 pmol min(-1) gFW(-1) for 20 samples. PMID- 22934675 TI - The role of telomere biology in cancer. AB - Telomere biology plays a critical and complex role in the initiation and progression of cancer. Although telomere dysfunction resulting from replicative attrition constrains tumor growth by engaging DNA-damage signaling pathways, it can also promote tumorigenesis by causing oncogenic chromosomal rearrangements. Expression of the telomerase enzyme enables telomere-length homeostasis and allows tumor cells to escape the antiproliferative barrier posed by short telomeres. Telomeres and telomerase also function independently of one another. Recent work has suggested that telomerase promotes cell growth through pathways unrelated to telomere maintenance, and a subset of tumors elongate telomeres through telomerase-independent mechanisms. In an effort to exploit the integral link between telomere biology and cancer growth, investigators have developed several telomerase-based therapeutic strategies, which are currently in clinical trials. Here, we broadly review the state of the field with a particular focus on recent developments of interest. PMID- 22934676 TI - Preparation and characterization of molecularly homogeneous silica-titania film by sol-gel process with different synthetic strategies. AB - Three silica-titania thin films with various degrees of molecular homogeneity were synthesized by the sol-gel process with the same precursor formula but different reaction paths. The dried films prepared by a single spin-coating process have a thickness of 500-700 nm and displayed no cracks or pin holes. The transmittances and refractive indices of the samples are >97.8% in the range of 350-1800 nm and 1.62-1.65 at 500 nm, respectively. The in-plane and out-of-plane chemical homogeneities of the films were analyzed by X-ray photoelectron spectroscopy and Auger electron spectroscopy, respectively. For the film with the highest degree of homogeneity, the deviations of O, Si, and Ti atomic contents in both in-plane and out-of-plane directions are less than 1.5%, indicating that the film is highly molecularly homogeneous. It also possesses the highest transparency and the lowest refractive index among the three samples. PMID- 22934677 TI - Resolving photo-induced twisted intramolecular charge transfer with vibrational anisotropy and TDDFT. AB - The interplay between reaction environment and photochemical outcome has wide ranging implications for designing and directing light driven chemical conversions. We present a detailed mechanistic description of photoisomerization in julolidine malononitrile (JDMN) as the first step to characterizing this interplay between reaction pathways and reaction environment. We have used polarization resolved UV pump-mid-IR probe spectroscopy and time dependent DFT calculations to investigate the dynamics of charge transfer induced intramolecular rotation in JDMN. We have probed the mechanism and dynamics of photoisomerization with the symmetric and antisymmetric CN-stretch of the malononitrile group. These measurements show the S1 electronic excited state relaxes with a 12.3 ps time constant by isomerizing around both the C-C single and C-C double bond of the malononitrile group with a branching ratio of 1:5. Isomerization around the single bond leads to the formation of a metastable twisted excited state, while isomerization around the double bond leads to excited state quenching via a conical intersection between the S1 and S0 electronic states. We have characterized the electronic and nuclear structure of the long-lived excited state with pump-probe anisotropy measurements and time dependent DFT calculations using the CAM-B3LYP functional and the 6-31G(d,p) basis set. These calculations further confirm that isomerization around the malononitrile single bond forms a twisted intermolecular charge transfer excited state. PMID- 22934674 TI - Molecular pathophysiology of myelodysplastic syndromes. AB - The clinicopathologic heterogeneity of myelodysplastic syndromes (MDS) is driven by diverse, somatically acquired genetic abnormalities. Recent technological advances have enabled the identification of many new mutations, which have implicated novel pathways in MDS pathogenesis, including RNA splicing and epigenetic regulation of gene expression. Molecular abnormalities, either somatic point mutations or chromosomal lesions, can be identified in the vast majority of MDS cases and underlie specific disease phenotypes. As the full array of molecular abnormalities is characterized, genetic variables are likely to complement standard morphologic evaluation in future MDS classification schemes and risk models. PMID- 22934678 TI - Impact of educational intervention on implementation of tobacco counselling among oral health professionals: a cluster-randomized community trial. AB - OBJECTIVES: Tobacco use adversely affects oral health. Clinical guidelines recommend that oral health professionals promote tobacco abstinence and provide patients who use tobacco with brief tobacco use cessation counselling. Research shows that these guidelines are seldom implemented successfully. This study aimed to evaluate two interventions to enhance tobacco use prevention and cessation (TUPAC) counselling among oral health professionals in Finland. METHODS: We used a cluster-randomized community trial to test educational and fee-for-service interventions in enhancing TUPAC counselling among a sample of dentists (n=73) and dental hygienists (n=22) in Finland. Educational intervention consisted of 1 day of training, including lectures, interactive sessions, multimedia demonstrations and a role play session with standard patient cases. Fee-for service intervention consisted of monetary compensation for providing tobacco use prevention or cessation counselling. TUPAC counselling procedures provided were reported and measured using an electronic dental records system. In data analysis, intent-to-treat principles were followed at both individual and cluster levels. Descriptive analysis included chi-square and t-tests. A general linear model for repeated measures was used to compare the outcome measures by intervention group. RESULTS: Of 95 providers, 73 participated (76.8%). In preventive counselling, there was no statistically significant time effect or group-by-time interaction. In cessation counselling, statistically significant group-by-time interaction was found after a 6-month follow-up (F=2.31; P=0.007), indicating that counselling activity increased significantly in intervention groups. On average, dental hygienists showed greater activity in tobacco prevention (F=12.13; P=0.001) and cessation counselling (F=30.19; P<0.001) than did dentists. In addition, cessation counselling showed a statistically significant provider-by-group-by-time interaction (F=5.95; P<0.001), indicating that interventions to enhance cessation counselling were more effective among dental hygienists. CONCLUSIONS: Educational intervention yielded positive short term effects on cessation counselling, but not on preventive counselling. Adding a fee-for-service to education failed to significantly improve TUPAC counselling performance. Other approaches than monetary incentives may be needed to enhance the effectiveness of educational intervention. Further studies with focus on how to achieve long-term changes in TUPAC counselling activity among oral health professionals are needed. PMID- 22934679 TI - Excited-state dynamics of bis-dehydroxycurcumin carboxylic acid, a water-soluble derivative of the photosensitizer curcumin. AB - Bis-dehydroxycurcumin carboxylic acid (K2A23) is a synthetic curcuminoid designed to exhibit enhanced water solubility and photosensitizing potential with respect to natural curcumin. In this work, the tendency of the compound to form intra- and intermolecular hydrogen bonds in the ground state is studied by UV-visible absorption and by nuclear magnetic resonance (NMR). The excited-state dynamics of the drug are probed in different environments by means of time-correlated single photon counting measurements and related to its hydrogen bonding affinity in the excited state. PMID- 22934680 TI - Applications of colloidal inorganic nanoparticles: from medicine to energy. AB - The synthesis of well-defined inorganic nanoparticles in colloidal solution, which evolved gradually from the 1950s onward, has now reached the point where applications in both the research world and the wider world can be realized. This Perspective explores some of the successes and still-remaining challenges in nanoparticle synthesis and ligand analysis, highlights selected work in the areas of biomedicine and energy conversion that are enabled by colloidal nanomaterials, and discusses technical barriers that need to be overcome by chemists and other scientists in order for nanotechnology to achieve its promise. PMID- 22934681 TI - Enhanced brain delivery of the opioid peptide DAMGO in glutathione pegylated liposomes: a microdialysis study. AB - Glutathione PEGylated (GSH-PEG) liposomes were evaluated for their ability to enhance and prolong blood-to-brain drug delivery of the opioid peptide DAMGO (H Tyr-d-Ala-Gly-MePhe-Gly-ol). An intravenous loading dose of DAMGO followed by a 2 h constant rate infusion was administered to rats, and after a washout period of 1 h, GSH-PEG liposomal DAMGO was administered using a similar dosing regimen. DAMGO and GSH-PEG liposomal DAMGO were also administered as a 10 min infusion to compare the disposition of the two formulations. Microdialysis made it possible to determine free DAMGO in brain and plasma, while the GSH-PEG liposomal encapsulated DAMGO was measured with regular plasma sampling. The antinociceptive effect of DAMGO was determined with the tail-flick method. All samples were analyzed using liquid chromatography-tandem mass spectrometry. The short infusion of DAMGO resulted in a fast decline of the peptide concentration in plasma with a half-life of 9.2 +/- 2.1 min. Encapsulation in GSH-PEG liposomes prolonged the half-life to 6.9 +/- 2.3 h. Free DAMGO entered the brain to a limited extent with a steady state ratio between unbound drug concentrations in brain interstitial fluid and in blood (Kp,uu) of 0.09 +/- 0.04. GSH-PEG liposomes significantly increased the brain exposure of DAMGO to a Kp,uu of 0.21 +/- 0.17 (p < 0.05). By monitoring the released, active substance in both blood and brain interstitial fluid over time, we were able to demonstrate that GSH-PEG liposomes offer a promising platform for enhancing and prolonging the delivery of drugs to the brain. PMID- 22934684 TI - Optimizing the sensitivity of photoluminescent probes using time-resolved spectroscopy: a molecular beacon case study. AB - Improving probes so that they can perform more sensitive and accurate detections is at the heart of much fundamental and applied research. Within the past few years a considerable amount of effort has been devoted to the study of photoluminescent probes in combination with time-resolved photoluminescence spectroscopy (TRPS). Although TRPS is a powerful and important technique for improving the sensitivity of long-lived probes, there is a lack of a general methodology that would allow one to unambiguously optimize the parameter affecting this technique. In this manuscript it will be shown how parameters that are probe- and technique-specific can affect the effectiveness of TRPS in improving sensitivity. Furthermore, it will be demonstrated that, when TRPS is used, the sensitivity of the probe is strongly dependent on the time window used to generate the time-resolved emission spectra (TRES). A method will be described that will allow one to remove the uncertainty in the selection of the time window that would yield the optimum improvement in probe performance, as well as the experimental parameters that need to be considered. Molecular beacon probes (MBs) were used to demonstrate these points. These probes show signal-to-background ratios (S/B) of less than 9 when SSPS is used, which can be easily enhanced to 17 using TRPS. The detection limits were also improved when TRPS is used allowing detecting target DNA with concentrations as low as 13.6 nM. PMID- 22934683 TI - Ethnicity, familism and willingness to care: important influences on caregiver mood? AB - OBJECTIVE: Few studies have to date examined the effects of ethnicity on caregiver motivations, coping responses and mood. This theoretically informed study uses the socio-cultural model of stress and coping to explore these relationships amongst a White-British and British South-Asian caregiver sample. METHOD: A total of 235 primary family caregivers were recruited for a cross sectional questionnaire survey; of which 162 were White-British and 73 were British South-Asian. RESULTS: British South-Asian caregivers differed from White British caregivers on several variables within the stress-coping framework. British South-Asian caregivers were younger, had significantly higher levels of familism, used significantly more behavioural disengagement and religious coping and reported having significantly less support than White-British caregivers. White-British caregivers were more likely to make use of substances and humour as coping methods, and also in these caregivers, familism was significantly related to caregiver depression. Whilst levels of willingness to care did not differ between the two caregiver groups, opposing relationships were seen in the association between willingness to care and caregiver anxiety. Regression analyses found that self-blame explained a significant proportion of variance in South-Asian anxiety and depression, whereas depression amongst White-British caregivers was associated with high use of substances, low use of humour and low mean satisfaction with support. CONCLUSION: These findings offer support to the socio-cultural model of stress and coping in that coping is associated with two outcomes (anxiety and depression), but motivational factors are also highlighted which have additional implications for the development of culturally specific interventions aimed at reducing caregiver distress. PMID- 22934682 TI - Using dual tasks to test immediate transfer of training between naturalistic movements: a proof-of-principle study. AB - Theories of motor learning predict that training a movement reduces the amount of attention needed for its performance (i.e., more automatic). If training one movement transfers, then the amount of attention needed for performing a second movement should also be reduced, as measured under dual task conditions. The authors' purpose was to test whether dual task paradigms are feasible for detecting transfer of training between two naturalistic movements. Immediately following motor training, subjects improved performance of a second untrained movement under single and dual task conditions. Subjects with no training did not. Improved performance in the untrained movement was likely due to transfer, and suggests that dual tasks may be feasible for detecting transfer between naturalistic actions. PMID- 22934685 TI - Removal of Cr, Mn, and Co from textile wastewater by horizontal rotating tubular bioreactor. AB - Environmental pollution by industrial wastewaters polluted with toxic heavy metals is of great concern. Various guidelines regulate the quality of water released from industrial plants and of surface waters. In wastewater treatment, bioreactors with microbial biofilms are widely used. A horizontal rotating tubular bioreactor (HRTB) is a combination of a thin layer and a biodisc reactor with an interior divided by O-ring shaped partition walls as carriers for microbial biomass. Using a biofilm of heavy metal resistant bacteria in combination with this special design provides various advantages for wastewater treatment proven in a pilot study. In the presented study, the applicability of HRTB for removing metals commonly present in textile wastewaters (chromium, manganese, cobalt) was investigated. Artificial wastewaters with a load of 125 mg/L of each metal underwent the bioreactor treatment. Different process parameters (inflow rate, rotation speed) were applied for optimizing the removal efficiency. Samples were drawn along the bioreactor length for monitoring the metal contents on site by UV-vis spectrometry. The metal uptake of the biomass was determined by ICP-MS after acidic microwave assisted digestion. The maximum removal rates obtained for chromium, manganese, and cobalt were: 100%, 94%, and 69%, respectively. PMID- 22934686 TI - Cognitive deficits after subcortical infarction are comparable with deficits after cortical infarction. AB - BACKGROUND AND PURPOSE: Cerebral cortical infarctions are often considered to be associated with more severe cognitive deficits than subcortical infarctions, but the evidence is conflicting. We compared early and late cognitive deficits between cortical and subcortical lesions. METHODS: Consecutive patients with first-ever cortical (n = 61) or subcortical (n = 71) cerebral infarctions were assessed neuropsychologically after a mean of 8 days and again at 6 months after infarction. Examinations included evaluation of verbal memory, executive functions, psychomotor speed and visuospatial function as well as orientation, insight and mood state. At 6 months, verbal and non-verbal reasoning were also evaluated. Neurological examinations included National Institutes of Health Stroke Scale and Barthel Index at both time-points and the modified Rankin Scale at 6 months. RESULTS: In the acute phase, memory (P = 0.007), especially delayed verbal recall (P = 0.005), was more severely affected in patients with subcortical infarctions than in those with cortical infarctions, and this trend persisted at 6 months post-infarction. Psychomotor speed (P = 0.040) was lower in the subcortical group in the acute phase than in the cortical group. Neurological scores did not differ between the two groups either in the acute phase or at 6 months. CONCLUSIONS: Patients with subcortical cerebral infarctions may have even worse cognitive profiles than patients with cortical infarctions. PMID- 22934687 TI - Permeation of indomethacin from semisolid preparations through various semipermeable membranes. AB - OBJECTIVE: The aim of this study was to evaluate and compare the permeation of model drug indomethacin (IND) from various types of gels through several semipermeable membranes. METHODS: Permeation of IND from gels based on carbomer (CA), hydroxyethylcellulose (HEC), and polyacrylamid/laureth-7/isoparaffin was performed via diffusion cell method through membranes: shed snake skin, full thickness chicken skin, mucosa of pork small intestine, and cellophane. RESULTS: The least permeation of IND was observed in the case of shed snake skin and full thickness chicken skin. It did not exceed 5.4% of original amount in the preparation after 3 h of measurement regardless the type of gel. In the case of mucosa of pork small intestine and cellophane the permeated amount of IND ranged from 9.4 to 55.4% depending on the type of gelling agent used. There was also quite a significant influence of a gelling agent on the permeation of IND observed. The permeation of IND was highest from CA gel, where it ranged from 0.6 to 52.2% of original amount in the preparation depending on the type of membrane used. Gelling agent inhibiting the permeation the most was HEC, where the permeated amount of IND did not exceed 12.3% regardless the type of membrane used. CONCLUSIONS: In general the permeated amount of IND through biological membranes containing stratum corneum represented just a small part of the amount in original preparation. Gelling agent has significant effect on the extent and rate of permeation. PMID- 22934688 TI - Furostanol saponins from the fruits of Tribulus terrestris. AB - Two new steroidal saponins were isolated from the fruits of Tribulus terrestris. Their structures were assigned by spectroscopic analysis and colour reaction as 26-O-beta-D-glucopyranosyl-(25R)-5alpha-furostane-12-one-3beta,22alpha,26-triol-3 O-beta-D-glucopyranosyl(1 -> 4)-beta-D-galactopyranoside (1); 26-O-beta- D glucopyranosyl-25(R)-5alpha-furostan-12-one-3beta,22alpha,26-triol-3-O-alpha-L rhamnopyranosyl-(1 -> 2)-O-[beta-D-glucopyranosyl-(1 -> 4)]-beta-D galactopyranoside (2). PMID- 22934690 TI - Remarkable improvement achieved by imidazole derivatives in ruthenium-catalyzed hydroesterification of alkenes using formates. AB - Imidazole derivatives are revealed to be effective ligands in the Ru-catalyzed hydroesterification of alkenes using formates, affording one-carbon-elongated esters in high yields. Further, intramolecular hydroesterification was successfully performed to give lactones for the first time. Imidazole derivatives can contribute to promote the reaction as well as to suppress the undesired decarbonylation of formate. Toxic CO gas, a directing group, and large excess alkenes are not required. PMID- 22934691 TI - Renal pelvic villous adenoma presented with mucusuria: report of a case and literature review. AB - Villous adenomas of the urinary tract are an uncommon condition, and appear mostly in patients where the disease occurred in the lower urinary tract. In contrast, upper urinary tract villous adenomas are a rare condition. Currently, just three cases of villous adenoma in the renal pelvis have been published. Herein, we present the fourth case of a renal pelvic villous adenoma, along with muconephrosis and mucusuria. A 73-year-old man presented with abdominal discomfort and a palpable abdominal mass. He had a history of bilateral anatrophic nephrolithotomy, 8 years and 6 years earlier. The preoperative radiographic investigation showed severe right hydronephrosis. A right nephrectomy was carried out and the intraoperative finding showed severe perinephric adhesion and a great deal of mucus in the renal pelvis. The pathological examination showed a villous adenoma and urothelial metaplasia in the kidney. PMID- 22934692 TI - Antiangiogenic triterpenes isolated from Chinese herbal medicine Actinidia chinensis Planch. AB - Actinidia chinensis Planch. is a famous Chinese herbal medicine to treat many diseases such as cancers. Triterpenes, polyphenols and anthraquinones are normally considered as the main constituents for its effects. In this study, eleven known triterpenes were isolated from the root of Actinidia chinensis., and were examined for its antiangiogenic activities. Their structures were elucidated by comprehensive spectroscopic methods, including IR, UV, HR-ESI-MS, and 1D and 2D NMR techniques. The eleven compounds are following: 2alpha,3alpha,19 trihydroxyurs-12-en-28-oic acid (1), 2alpha,3beta-dihydroxyurs-12-en-28-oic acid (2), 2alpha,3alpha,23-trihydroxyurs-12-en-28-oic acid (3), asiatic acid (4), ursolic acid (5), 2alpha,3beta,19,24-tetrahydroxyurs-12-en-28-oic acid (6), 2alpha,3beta,19-trihydroxyolean-12-en-28-oic acid (7), 2alpha,3alpha,24 trihydroxyolean-12-en-28-oic acid (8), oleanolic acid (9), 3beta-O acetyloleanolic acid (10), 2alpha,23-dihydroxylmicromeric acid (11). All these compounds were evaluated with respect to their antiangiogenic activities utilizing the assays of human umbilical vein endothelial cells (HUVEC) proliferation and tube formation and Ursolic acid (used as control) and compounds 2, 3, 4, and 8 exhibited significant, dose-dependently, antiangiogenic activity in the tested concentration range. Our findings suggest that antitumor action of Actinidia chinensis Planch. is partly via inhibiting tumor angiogenesis by triterpenes, and compounds 2, 3, 4, and 8 as the novel potential antiangiogenic agents are worthy of further translational research. PMID- 22934689 TI - Cancer, immunodeficiency and antiretroviral treatment: results from the Australian HIV Observational Database (AHOD). AB - OBJECTIVES: The objective of the study was to conduct a within-cohort assessment of risk factors for incident AIDS-defining cancers (ADCs) and non-ADCs (NADCs) within the Australian HIV Observational Database (AHOD). METHODS: A total of 2181 AHOD registrants were linked to the National AIDS Registry/National HIV Database (NAR/NHD) and the Australian Cancer Registry to identify those with a notified cancer diagnosis. Included in the current analyses were cancers diagnosed after HIV infection. Risk factors for cancers were also assessed using logistic regression methods. RESULTS: One hundred and thirty-nine cancer cases were diagnosed after HIV infection among 129 patients. More than half the diagnoses (n = 68; 60%) were ADCs, of which 69% were Kaposi's sarcoma and 31% non-Hodgkin's lymphoma. Among the NADCs, the most common cancers were melanoma (n = 10), lung cancer (n = 6), Hodgkin's lymphoma (n = 5) and anal cancer (n = 5). Over a total of 21021 person-years (PY) of follow-up since HIV diagnosis, the overall crude cancer incidence rate for any cancer was 5.09/1000 PY. The overall rate of cancers decreased from 15.9/1000 PY [95% confidence interval (CI) 9.25-25.40/1000 PY] for CD4 counts < 100 cells/MUL to 2.4/1000 PY (95% CI 1.62-3.39/1000 PY) for CD4 counts > 350 cells/MUL. Lower CD4 cell count and prior AIDS diagnoses were significant predictors for both ADCs and NADCs. CONCLUSIONS: ADCs remain the predominant cancers in this population, although NADC rates have increased in the more recent time period. Immune deficiency is a risk factor for both ADCs and NADCs. PMID- 22934693 TI - Antidepressant desipramine leads to C6 glioma cell autophagy: implication for the adjuvant therapy of cancer. AB - Depression is the most common psychiatric syndrome in cancer patients and adversely affects anti-cancer immune system and life quality of patients. Antidepressant desipramine (DMI) is clinically prescribed in the auxiliary treatment of cancer patients. Increasing evidences suggest that DMI has a broad spectrum of target-off biological effects, such as anticancer properties. Our previous study revealed that DMI at the clinical relevant concentrations could induce CHOP-dependent apoptotic death in C6 glioma cells. In this study, we further explored the pro-autophagic effect of DMI in C6 glioma cells and its underlying mechanism. Treatment with DMI could induce autophagic cell death characterized by the formation of autophagosome and the elevated level of autophagic protein Beclin-1 and cellular redistribution of marker LC3. Meanwhile, DMI inhibited the activation of PI3K-AKT-mTOR pathway which is considered as a negative regulator of autophagy. Furthermore, DMI activated PERK-eIF2alpha and ATF6 of endoplasmic reticulum (ER) stress pathway, while knockdown of PERK with the PERK-specific short interfering RNA (siRNA) could obviously attenuate the autophagy. The results strongly suggested that DMI could induce autophagy through the PERK-ER stress pathway in C6 glioma cells. Our findings provided new insights into another beneficial potential of antidepressant DMI in the adjuvant therapy of cancer. PMID- 22934694 TI - Functional nanoplatforms for enhancement of chemotherapeutic index. AB - Recently, the advancement of nanotechnology has had a significant impact on clinical therapeutics. Advances in biocompatible drug carriers using organic/inorganic nanoparticles have enabled safer and more efficient delivery of anti-cancer agents. In particular, nanoparticles designed and fabricated by sophisticated processes can (as drug carriers) deliver precise doses of multiple anti-cancer agents to target cancer cells, improving therapeutic efficacy and minimizing side effects. In addition, a comprehensive understanding of cancer biology, chemo-resistance, cancer relapse, and metastasis is essential for successful development of combination therapy using nanoparticles. In this review, we discuss the species of functional nanoparticles for delivery of anti cancer agents and their potential to improve chemotherapeutic indices via combination therapy. We also discuss novel therapeutic strategies using functional nanoparticles developed through multidisciplinary collaboration for combination chemotherapy. PMID- 22934695 TI - UGT1A1 gene polymorphisms and the toxicities of FOLFIRI in Chinese Han patients with gastrointestinal cancer. AB - BACKGROUND: Neutropenia and diarrhea are the common dose-limiting toxicities of irinotecan, and uridine diphosphate glucuronosyltransferases (UGTs) gene polymorphisms are considered to be one of the predictive markers of irinotecan related toxicities. This study aims to investigate the association between UGT1A1 gene polymorphisms and irinotecan related toxicities in Chinese Han gastrointestinal cancer patients receiving FOLFIRI regimen chemotherapy. METHODS: A total of 94 gastrointestinal cancer patients with metastasis (72 colon and rectum, 20 stomach, 1 pancreas and 1 duodenum), were enrolled from 2007 to 2010 in Shanghai Ruijin Hospital. All patients received standard dosage of FOLFIRI regimen (irinotecan 180mg/m2 d1, CF 200mg/m2 d1-d2, 5-FU 400mg/m2 d1-d2, followed by continuous infusion of 5-FU 600mg/m2 for 22h d1-d2, every 2 weeks). UGT1A1 gene polymorphisms (*60 -3279T > G, *93 -3156G > A, *28 -53TA6 > TA7, *6 211G > A) were detected by direct sequencing of DNA extracted from peripheral blood. The incidence of neutropenia, diarrhea, and time to severe toxicity were recorded. The relationship between UGT1A1 gene polymorphisms and toxicities was analyzed. RESULTS: The frequencies of UGT1A1*60 (-3279 G/G), UGT1A1*93 (-3156 A/A), UGT1A1*28 (-53 7/7) and UGT1A1*6 (211 A/A) homozygote were 6.4% (6/94), 1.1% (1/94), 1.1% (1/94) and 2.1% (2/94), respectively. The incidences of grade 3/4 neutropenia and diarrhea were 53.2% (50/94) and 12.8% (12/94), respectively. Comparing those with wild type, patients with UGT1A1*28 or *93 allele had significantly high risk of grade 3/4 diarrhea (6/7, 7/7 vs. 6/6: 27.8% vs. 9.2%, OR=3.791, P=0.034; G/A, A/A vs. G/G: 29.4% vs. 9.1%, OR=4.167, P=0.023). No relationship was found between UGT1A1 allele polymorphism and grade 3/4 neutropenia. The baseline serum total bilirubin was elevated in UGT1A1*28, *93 allele carriers and *60 homozygote, but with no relationship with severe toxicities. CONCLUSION: In Chinese Han gastrointestinal cancer patients receiving standard FOLFIRI regimen, UGT1A1*28 or *93 allele carriers may have high risk of severe diarrhea. PMID- 22934696 TI - DNA methylation as a target of epigenetic therapeutics in cancer. AB - Epigenetic alterations have been implicated in the development and progression of human cancer. It is noteworthy that epigenetic modifications, in contrast to genetic mutations, are intrinsically reversible. This triggers an impressive interest of researchers in treatment of cancer patients via targeting epigenetic mechanisms, leading to subsequent intensive investigations of epigenetic drugs as a novel therapeutic intervention. DNA methylation, the major form of epigenetic modifications, is catalyzed by the maintenance DNA methyltransferase (DNMT) 1 and/or the de novo methyltransferases DNMT3A and DNMT3B. Aberrant expression of DNMTs and disruption of DNA methylation are closely associated with multiple forms of cancer, although the exact mechanisms underlying this link remain elusive. An array of tumor suppressor genes (TSGs) frequently sustain promoter hypermethylation, which results in epigenetic silencing of these genes and makes cancer cells acquire growth advantages. DNA demethylating agents, re-activating TSGs via inhibiting hypermethylation of their promoter regions, are currently being tested in clinical trials, and several of them are already applied in clinics. DNA demethylating agents, used either alone or in combination with other agents, such as chemotherapeutic drugs and the histone deacetylase inhibitors, have shown to be effective in treatment of cancer, although only in a small set of patients. In this review, we examine and discuss the most recent advances in epigenetic therapy of cancer, with a focus on DNA demethylating agents. PMID- 22934698 TI - Oncogenic miR-544 is an important molecular target in gastric cancer. AB - MicroRNAs (miRNAs) and promoter hypermethylation are vital epigenetic mechanisms for transcriptional inactivation of tumor suppressor. IRX1 is a newly identified tumor suppressor gene and hypermethylation involves the decreased expression in gastric cancer. However, the microRNA regulatory mechanism on IRX1 expression is still unclear. In this study, we report an IRX1-targeting miRNA-544, which directly targets 3'-UTR of IRX1 gene by luciferase reporter assay. miR-544 suppresses the protein expression of IRX1 gene by Western blot and immunocytochemistry. Ectopic expression of miR-544 promotes cell proliferation and cell cycle progression significantly in vitro on gastric cancer cells. The study suggests that miR-544 is an oncogenic microRNA in gastric cancer. Over expression of miR-544 contributes to the inactivation and low-expression of IRX1 in gastric cancer. These findings are helpful for clarifying the molecular mechanisms involved in gastric carcinogenesis and indicate that miR-544 is a key regulator in switching cell cycle on or off. miR-544 may be a potential molecular target in miRNA-based strategy on gastric cancer. PMID- 22934697 TI - BRCA2 dysfunction promotes malignant transformation of pancreatic intraepithelial neoplasia. AB - Pancreatic ductal adenocarcinoma (PDAC) is an almost lethal disease. Thus, it is important to better understand its genetic progression from normal cells through precancerous lesions pancreatic intraepithelial neoplasia (PanIN) to invasive pancreatic cancer. Carriers of a germline mutation in BRCA2 have an increased risk of developing PDAC when compared with the general population. The purpose of our study was to examine the role of BRCA2 dysfuction in the progression of PDAC. Here we generated a novel in vitro model of pancreatic carcinogenesis. Cancerous PanIN-BR1 cells were established by stable transduction with lentiviral-mediated BRCA2 RNA interference in PanIN cell isolated from mice with oncogenic KrasG12D. Our data showed that silencing of BRCA2 promoted cell proliferation, migration and invasion in vitro. The tumorigenic potential of PanIN-BR1 were assessed by xenograft tumor formation in BALB/c nude mice. The expression of PCNA , Snail and Slug in the tumor xenografts was detected by immunohistochemistry. The staining for PCNA, Snail and Slug in PanIN-BR1-formed xenograft tissue was significantly more intense than PanIN-formed xenograft tissue. Microarray assay was also performed. Based on gene expression profiling and further validation by real-time PCR and Western Blot, we found that the expression of Cyclinb2, Cyclina2, Twist1, Wisp1 and Cxcr4 revealed a significant increase in the PanIN-BR1 cells, however, the expression of p15, p16 and Wisp2 showed a significant decrease in the PanIN BR1 cells, compared to the PanIN cells. Collectively, these data reported here demonstrate that BRCA2 may be a promising therapeutic targets for PDAC progression. PMID- 22934699 TI - A cohort study and meta-analysis between histopathological classification and prognosis of gastric carcinoma. AB - BACKGROUND AND AIM: To determine the correlation of histopathological classification and patient outcomes, we performed a meta-analysis of histological subtypes on postoperative survival in gastric cancer. METHODS: A dataset composed of 11073 gastric cancers from 21 publications, combined with our cohort was included in the metaanalysis. We evaluated the association between the 5-year survival rate and the subtypes of gastric cancer based on histological grading or Lauren classification. All literatures were from Pubmed and Embase (up to December 2011). RESULTS: In our cohort from Shanghai Ruijin Hospital, the differentiated gastric cancer revealed a significantly higher accumulative 5-year survival rate, compared to that in poor-differentiated cases (62.6% vs 44.8%, P < 0.001). Intestinal-type gastric cancer shown a higher accumulative 5-year survival rate, compared to that in diffuse-type cases (61.7% vs 41.1%, P < 0.001). In overall meta-analysis, the poordifferentiated gastric cancer significantly increased the postoperative 5-year death risk, compared to the differentiated cases (OR=1.24, 95% CI 1.13-1.36, P < 0.001). The 5-year death risk was increased in the diffuse-type cases relative to the intestinal-type cases (OR=1.29, 95% CI 1.11-1.49, P < 0.001). CONCLUSIONS: Gastric cancer with a differentiated histology or intestinal-type shows a better prognosis than individual with a poordifferentiated histology or a diffuse-type. Accurate histologic classification is desirable for gastric cancer handling. PMID- 22934700 TI - Conventional chemotherapy and emerging targeted therapy for advanced adrenocortical carcinoma. AB - Adrenocortical carcinoma (ACC) is a rare but typically aggressive malignancy. Radical surgery remains the potentially curative option. However, about one third of patients initially present with distant metastases. Regarding to chemotherapy, mitotane alone or in combination with cytotoxic drugs should be the first selection. Meanwhile, a phase lll clinical trial of etoposide, doxorubicin, cisplatin plus mitotane or streptozotocin plus mitotane is currently undergoing worldwide. The study on molecular pathogenesis of ACC is progressing. A lot of targeted therapies are also enrolled in preclinical investigations and clinical trials, including small-molecule tyrosine kinase inhibitors, antiangiogenic compounds. This article introduced the conventional chemotherapy, newly developed targeted therapy for advanced ACC. PMID- 22934701 TI - Progress in evaluation of pathologic response to neoadjuvant chemotherapy of breast cancer. AB - Neoadjuvant chemotherapy is provided to patients with locally advanced breast cancer. Its main objective is to bring about a complete pathologic response which is correlated with long term patient survival, a clinical end point of preoperative chemotherapy. Besides, it may downsize the tumor, enabling breast conserving or limited mastectomy. Preoperative chemotherapy also provides the opportunity of assessing the chemosensitivity of the tumor in vivo so that postoperative chemotherapy is tailored according to the outcome of the neoadjuvant chemotherapy. Pathological complete response is considered when there is complete eradication of the local regional disease. Residual disease in the primary focus and/or axilla after preoperative chemotherapy is associated with poor prognosis. Standard preoperative and postoperative specimen collection, handling, processing, and examination are essential components of proper evaluation and reporting of pathologic response to neoadjuvant chemotherapy. PMID- 22934702 TI - Cell dormancy and tumor refractory. AB - Metastasis of tumor cells from primary tumor and growth at secondary sites are the major cause of mortality in cancer patients. This event may occur years and even decades after successful removal of the primary tumor and adjuvant therapy. Relapse and metastasis are universally existed in various malignancies. This phenomenon is attributed to a small amount of residual tumor cells remained in host for years, which is called as dormancy. Tumor dormancy is characterized by the balanced cell proliferation and cell death, immune evasion from host, non angiogenic feature, insufficiency of metastatic capacity, cell cycle arrest as well as resistant to conventional chemotherapy. The molecular expressing profile suggested that dormancy is a state of quiescent cancer stem-like cells (CSCs), which are more resistant to chemotherapy and targeted therapy. Hitherto, the progression on tumor dormancy is relatively slow because there are no proper experimental models and biomarkers for identifying the dormant cells. It is no doubt that clarifying the regulatory mechanism of enter or exit of dormancy will help scientists to develop targeted strategy for eliminating dormant tumor cells, and then hinder the distant relapse and metastasis for various malignancies. This review focuses on tumor dormancy, the association of tumor dormancy with CSCs and strengthens the angiogenic switch for enter or exit of dormancy. It enlightens researchers to explore and develop more specific targeted drugs for clearance of the relapse danger. PMID- 22934704 TI - Editorial: translational medicine is promoting cross-talk of inter discipline. PMID- 22934703 TI - A sample selection strategy to boost the statistical power of signature detection in cancer expression profile studies. AB - In case-control profiling studies, increasing the sample size does not always improve statistical power because the variance may also be increased if samples are highly heterogeneous. For instance, tumor samples used for gene expression assay are often heterogeneous in terms of tissue composition or mechanism of progression, or both; however, such variation is rarely taken into account in expression profiles analysis. We use a prostate cancer prognosis study as an example to demonstrate that solely recruiting more patient samples may not increase power for biomarker detection at all. In response to the heterogeneity due to mixed tissue, we developed a sample selection strategy termed Stepwise Enrichment by which samples are systematically culled based on tumor content and analyzed with t-test to determine an optimal threshold for tissue percentage. The selected tissue-percentage threshold identified the most significant data by balancing the sample size and the sample homogeneity; therefore, the power is substantially increased for identifying the prognostic biomarkers in prostate tumor epithelium cells as well as in prostate stroma cells. This strategy can be generally applied to profiling studies where the level of sample heterogeneity can be measured or estimated. PMID- 22934705 TI - Upregulation of focal adhesion kinase by 14-3-3epsilon via NFkappaB activation in hepatocellular carcinoma. AB - Focal adhesion kinase (FAK) is implicated in cancer cell survival, proliferation and migration. Expression of FAK expression is elevated and associated with tumor progression and metastasis in various tumors, including hepatocellular carcinoma (HCC). Increased 14-3-3epsilon expression is shown to be a potential prognostic factor to predict higher risk of distant metastasis and worse overall survival in HCC. The aim of this study is to investigate whether FAK is associated or regulated by 14-3-3epsilon to modulate tumor progression in HCC. In this study, 114 primary HCC tumors including 34 matched metastatic tumors were subjected to immunohistochemistry analysis of FAK and 14-3-3epsilon expression. Overexpression of FAK was significantly associated with increased risk of extrahepatic metastasis (p=0.027) and reduced 5-year overall survival rate (p=0.017). A significant correlation of FAK and 14-3-3epsilon expression was observed in primary tumor (p < 0.001) and also metastatic tumors. Furthermore, overexpression of 14-3-3 epsilon induced FAK expression and promoter activity which were determined by Western blotting analysis and luciferase-reporter assay. Moreover, 14-3-3epsilon enhanced NFkappaB activation and increased nuclear translocation of NFkappaB. Results from chromatin immunoprecipitation assay revealed that 14-3 3epsilon induced NFkappaB binding on FAK promoter region. These findings suggest that FAK expression is correlated with and upregulated by 14-3-3epsilon via activation of NFkappaB. Target to suppress or inactivate FAK alone, or combine with 14-3-3epsilon is thus considered as the potential therapeutic strategy for preventing HCC tumor progression. PMID- 22934707 TI - FAK and Nanog cross talk with p53 in cancer stem cells. AB - This review is focused on the role of Focal Adhesion Kinase (FAK) signaling in cancer stem cells. The recent data demonstrate the important role of FAK in cancer stem cell proliferation, differentiation, motility, and invasion. We showed recently that the transcription factor Nanog binds the FAK promoter and up regulates FAK expression, and that FAK binds Nanog and phosphorylates it. This review discusses the interaction of FAK, Nanog, Oct-3/4, and Sox-2 signaling pathways that are critical for the regulation of cancer stem cells. The cross linked signaling of FAK with p53 and Nanog signaling in cancer stem cell and function and targeted therapeutics approaches are discussed. PMID- 22934708 TI - The role of focal adhesion kinase in lung cancer. AB - Focal adhesion kinase (FAK) is a nonreceptor tyrosine kinase implicated in carcinogenesis through its pleitropic effects on cell proliferation, survival and metastasis. This article provides a summary of the existing data implicating FAK in lung cancer. PMID- 22934710 TI - Survival signaling through focal adhesion kinase in tumors. PMID- 22934709 TI - FAK and HAS inhibition synergistically decrease colon cancer cell viability and affect expression of critical genes. AB - Focal adhesion kinase (FAK), hyaluronan (HA), and hyaluronan synthase-3 (HAS3) have been implicated in cancer growth and progression. FAK inhibition with the small molecule inhibitor Y15 decreases colon cancer cell growth in vitro and in vivo. HAS3 inhibition in colon cancer cells decreases FAK expression and activation, and exogenous HA increases FAK activation. We sought to determine the genes affected by HAS and FAK inhibition and hypothesized that dual inhibition would synergistically inhibit viability. Y15 (FAK inhibitor) and the HAS inhibitor 4-methylumbelliferone (4-MU) decreased viability in a dose dependent manner; viability was further inhibited by treatment with Y15 and 4-MU in colon cancer cells. HAS inhibited cells treated with 2 MUM of Y15 showed significantly decreased viability compared to HAS scrambled cells treated with the same dose (p < 0.05) demonstrating synergistic inhibition of viability with dual FAK/HAS inhibition. Microarray analysis showed more than 2-fold up- or down-regulation of 121 genes by HAS inhibition, and 696 genes by FAK inhibition (p < 0.05) and revealed 29 common genes affected by both signaling. Among the genes affected by FAK or HAS3 inhibition were genes, playing role in apoptosis, cell cycle regulation, adhesion, transcription, heatshock and WNT pathways. Thus, FAK or HAS inhibition decreases SW620 viability and affects several similar genes, which are involved in the regulation of tumor survival. Dual inhibition of FAK and HAS3 decreases viability to a greater degree than with either agent alone, and suggests that synergistic inhibition of colon cancer cell growth can result from affecting similar genetic pathways. PMID- 22934706 TI - Cell survival signaling in neuroblastoma. AB - Neuroblastoma is the most common extracranial solid tumor of childhood and is responsible for over 15% of pediatric cancer deaths. Neuroblastoma tumorigenesis and malignant transformation is driven by overexpression and dominance of cell survival pathways and a lack of normal cellular senescence or apoptosis. Therefore, manipulation of cell survival pathways may decrease the malignant potential of these tumors and provide avenues for the development of novel therapeutics. This review focuses on several facets of cell survival pathways including protein kinases (PI3K, AKT, ALK, and FAK), transcription factors (NF kappaB, MYCN and p53), and growth factors (IGF, EGF, PDGF, and VEGF). Modulation of each of these factors decreases the growth or otherwise hinders the malignant potential of neuroblastoma, and many therapeutics targeting these pathways are already in the clinical trial phase of development. Continued research and discovery of effective modulators of these pathways will revolutionize the treatment of neuroblastoma. PMID- 22934711 TI - The persistence and stability of psychiatric problems in adolescents with autism spectrum disorders. AB - BACKGROUND: Psychiatric problems are common in autism spectrum disorders (ASDs), but the reasons are poorly understood. We use a longitudinal population representative cohort to examine for the first time the persistence of psychiatric problems and to identify risk factors for their occurrence and stability. METHODS: Eighty-one 16-year olds (75 male, six female), initially seen at 12 years, were re-assessed using the parent-report Strengths and Difficulties Questionnaire (SDQ). Child, family and contextual characteristics from age 12 were tested as risk factors for psychopathology. RESULTS: Prevalence rates varied depending on whether general population or ASD-specific SDQ cut-offs were used. While the former suggested a decrease in psychiatric problems over time, the ASD specific cut-offs showed no significant differences. With the exception of ADHD, the ASD-specific cut-offs identified a smaller proportion of individuals as 'affected' than did the general population cut-offs. There was longitudinal domain specificity, with parent correlations ranging from 0.50 to 0.58 and teacher SDQ reports at age 12 correlating 0.33-0.53 with parent reports at 16 years. In examining the role of risk factors, lower IQ and adaptive functioning predicted higher hyperactivity and total difficulties scores. Greater emotional problems at 16 were predicted by poorer maternal mental health, family-based deprivation and lower social class. Improvement from 12 to 16 years in conduct problems was predicted by greater neighbourhood deprivation and special school attendance. CONCLUSIONS: This is the first longitudinal study of other psychiatric symptoms in ASD. Additional psychiatric problems in ASD are persistent and domain-specific from childhood to adolescence. The finding that age-related reduction in SDQ symptoms does not apply when ASD-specific cut-offs are used requires further evaluation using diagnostic measures. Only a few of the expected risk factor-psychopathology predictions expected from general population studies were found, raising the possibility that the causes of psychopathology in ASD differ from those in the general population. PMID- 22934712 TI - The effect of salvaged blood on coagulation function as measured by thromboelastography. AB - BACKGROUND: There is concern that salvaged blood has the potential to activate the coagulation system, which might place patients at risk of thrombotic complications. The aim of this study was to determine whether transfusion of salvaged blood after total knee arthroplasty (TKA) would lead to procoagulopathic changes as measured by thromboelastography (TEG) and furthermore if washing would reduce this risk. STUDY DESIGN AND METHODS: Twenty-two patients undergoing TKA were enrolled. Control samples were venous blood samples taken before surgery. Test samples were created by mixing the control samples with postoperatively salvaged blood, either washed or unwashed. TEG profiles were measured, noting the time to initiate clotting (R), the time of clot formation (K), the angle of clot formation (alpha-angle), and the maximum amplitude (clot strength [MA]). RESULTS: The changes in the coagulation profile from control samples to test samples were consistent for both the washed and the unwashed groups: R time decreased, MA decreased, and K and alpha-angle remained the same. However, the changes were more pronounced in the unwashed group than the washed group, with a 61% decrease in R time compared with 14%, and a 26% decrease in MA compared with 6%. CONCLUSION: The addition of salvaged blood to the patient's preoperative blood resulted in decreased MA as well as decreased R time. This suggests that the reinfusion of postoperatively salvaged washed or unwashed blood after TKA favors a change toward a more hypocoagulable state, and washing appears to reduce this effect. PMID- 22934714 TI - Treatment monitoring of HIV-infected patients based on mechanistic models. AB - For most patients, the HIV viral load can be made undetectable by highly active antiretroviral treatments highly active antiretroviral therapy: the virus, however, cannot be eradicated. Thus, the major problem is to try to reduce the side effects of the treatment that patients have to take during their life time. We tackle the problem of monitoring the treatment dose, with the aim of giving the minimum dose that yields an undetectable viral load. The approach is based on mechanistic models of the interaction between virus and the immune system. It is shown that the "activated cells model," allows making good predictions of the effect of dose changes and, thus, could be a good basis for treatment monitoring. Then, we use the fact that in dynamical models, there is a nontrivial equilibrium point, that is with a virus load larger than zero, only if the reproductive number R(0) is larger than one. For reducing side effects, we may give a dose just above the critical dose corresponding to R(0) equal to 1. A prior distribution of the parameters of the model can be taken as the posterior arising from the analysis of previous clinical trials. Then the observations for a given patient can be used to dynamically tune the dose so that there is a high probability that the reproductive number is below one. The advantage of the approach is that it does not depend on a cost function, weighing side effects and efficiency of the drug. It is shown that it is possible to approach the critical dose if the model is correct. A sensitivity analysis assesses the robustness of the approach. PMID- 22934715 TI - Compared morphology of the immatures of males of two urban ant species of Camponotus. AB - The immatures of males of two species of Camponotus ants (Hymenoptera: Formicidae) are described and compared by light and electron microscopy. The numbers of larval instars were determined: Camponotus rufipes Fabricius (Hymenoptera: Formicidae) have four instars; and Camponotus vittatus Forel have three. Male larvae of the two species are similar to previously described Camponotus larvae, sharing the following traits: basic shape of body and mandible, presence of 'chiloscleres', 'praesaepium' (some specimens), labial pseudopalps, and ten pairs of spiracles. However, larvae of the two species can be separated by bodily dimensions and based on their hair number and types. Worker larvae of C. vittatus previously described are extensively similar to male larvae, with only a few inconspicuous differences that may result from intraspecific variation or sexual differences. PMID- 22934716 TI - Comparison of Alternaria spp. collected in Italy from apple with A. mali and other AM-toxin producing strains. AB - Since 1999, a disease of apple caused by an Alternaria sp. has been affecting orchards in northern Italy resulting in necrotic spots on leaves and on fruit. Forty-four single-spored isolates were obtained from diseased plant materials to investigate the diversity of this fungus in Italy and to compare these isolates to isolates of Alternaria associated with apple disease in previous studies, including A. mali, causal agent of apple blotch. All isolates, including the reference strains, were tested for pathogenicity utilizing in vitro bioassays on detached leaf or on fruit ('Golden Delicious'). In addition, morphological characterizations were conducted describing both the three-dimensional sporulation pattern and the colony morphology of each isolate. In order to assess the genetic diversity within the Italian Alternaria population, sequence characterization of specific loci and anonymous regions (endoPG, OPA1-3, OPA2-1, and OPA10-2) and genetic fingerprinting based on amplified fragment length polymorphism and inter simple sequence repeat markers were performed. The single spore isolates exhibited differential pathogenicity, which did not correlate with the morphological groupings or to groupings defined by molecular approaches. Moreover, 10 pathogenic isolates out of the 44 single-spored tested were positive for the host-specific AM-toxin gene based upon polymerase chain reaction amplification using specific primers for the AM-toxin gene. This suggests that the production of the AM-toxin may be involved in pathogenesis by some of the Italian isolates of A. alternata from apple. However, this research also suggests that a number of different Alternaria genotypes and morphotypes may be responsible for the apple disease in Italy and that a single taxon cannot be defined as the sole causal agent. PMID- 22934717 TI - In vitro and in vivo evaluation of microporous chitosan hydrogel/nanofibrin composite bandage for skin tissue regeneration. AB - In this work, we have developed chitosan hydrogel/nanofibrin composite bandages (CFBs) and characterized using Fourier transform-infrared spectroscopy and scanning electron microscopy. The homogeneous distribution of nanofibrin in the prepared chitosan hydrogel matrix was confirmed by phosphotungstic acid hematoxylin staining. The mechanical strength, swelling, biodegradation, porosity, whole-blood clotting, and platelet activation studies were carried out. In addition, the cell viability, cell attachment, and infiltration of the prepared CFBs were evaluated using human umbilical vein endothelial cells (HUVECs) and human dermal fibroblast (HDF) cells. It was found that the CFBs were microporous, flexible, biodegradable, and showed enhanced blood clotting and platelet activity compared to the one without nanofibrin. The prepared CFBs were capable of absorbing fluid and this was confirmed when immersed in phosphate buffered saline. Cell viability studies on HUVECs and HDF cells proved the nontoxic nature of the CFBs. Cell attachment and infiltration studies showed that the cells were found attached and proliferated on the CFBs. In vivo experiments were carried out in Sprague-Dawley rats and found that the wound healing occurred within 2 weeks when treated with CFBs than compared to the bare wound and wound treated with Kaltostat. The deposition of collagen was found to be more on CFB treated wounds compared to the control. The above results proved the use of these CFBs as an ideal candidate for skin tissue regeneration and wound healing. PMID- 22934718 TI - Coastal iodine emissions: part 2. Chamber experiments of particle formation from Laminaria digitata-derived and laboratory-generated I2. AB - Laboratory studies into particle formation from Laminaria digitata macroalgae were undertaken to elucidate aerosol formation for a range of I(2) (0.3-76 ppb(v)) and O(3) (<3-96 ppb(v)) mixing ratios and light levels (E(PAR) = 15, 100, and 235 MUmol photons m(-2) s(-1)). No clear pattern was observed for I(2) or aerosol parameters as a function of light levels. Aerosol mass fluxes and particle number concentrations, were, however, correlated with I(2) mixing ratios for low O(3) mixing ratios of <3 ppb(v) (R(2) = 0.7 and 0.83, respectively for low light levels, and R(2) = 0.95 and 0.98, respectively for medium light levels). Additional experiments into particle production as a function of laboratory-generated I(2), over a mixing ratio range of 1-8 ppb(v), were conducted under moderate O(3) mixing ratios (~24 ppb(v)) where a clear, 100-fold or greater, increase in the aerosol number concentrations and mass fluxes was observed compared to the low O(3) experiments. A linear relationship between particle concentration and I(2) was found, in reasonable agreement with previous studies. Scaling the laboratory relationship to aerosol concentrations typical of the coastal boundary layer suggests a I(2) mixing ratio range of 6-93 ppt(v) can account for the observed particle production events. Aerosol number concentration produced from I(2) is more than a factor of 10 higher than that produced from CH(2)I(2) for the same mixing ratios. PMID- 22934719 TI - Ultrastructure of the seminiferous tubules in oligoasthenoteratozoospermic men associated with varicocele. AB - Varicocele is associated with venous reflux that may cause increased heat and interstitial pressure within the testes, with variable pathological effects on spermatogenesis. This study aimed to study the ultrastructural testicular changes in the seminiferous tubules of 20 infertile severe oligoasthenoteratozoospermia (OAT) men associated with varicocele and five patients with obstructive azoospermia without varicocele as controls. They were subjected to testicular biopsy which was evaluated by transmission electron microscopy. Ultrastructurally, the seminiferous epithelium in the testicular biopsies of infertile severe OAT men associated with varicocele was variably affected in the form of thickening of the peritubular connective tissue, vacuolation of Sertoli cell and germ cell cytoplasm, presence of degenerated and apoptotic cells among the germinal epithelium, altered spermatids and abnormal spermatozoa. It is concluded that varicocele in severe OAT men is associated with ultrastructural changes in the seminiferous tubule. PMID- 22934720 TI - Visible light-induced hole injection into rectifying molecular wires anchored on Co3O4 and SiO2 nanoparticles. AB - Tight control of charge transport from a visible light sensitizer to a metal oxide nanoparticle catalyst for water oxidation is a critical requirement for developing efficient artificial photosynthetic systems. By utilizing covalently anchored molecular wires for hole transport from sensitizer to the oxide surface, the challenge of high rate and unidirectionality of the charge flow can be addressed. Functionalized hole conducting molecular wires of type p oligo(phenylenevinylene) (3 aryl units, abbreviated PV3) with various anchoring groups for the covalent attachment to Co(3)O(4) catalyst nanoparticles were synthesized and two alternative methods for attachment to the oxide nanoparticle surface introduced. Covalent anchoring of intact PV3 molecules on Co(3)O(4) nanoparticles (and on SiO(2) nanoparticles for control purposes) was established by FT-Raman, FT-IR, and optical spectroscopy including observation, in some cases, of the vibrational signature of the anchored functionality. Direct monitoring of the kinetics of hole transfer from a visible light sensitizer in aqueous solution ([Ru(bpy)(3)](2+) (and derivatives) light absorber, [Co(NH(3))(5)Cl](2+) acceptor) to wire molecules on inert SiO(2)(12 nm) particles by nanosecond laser absorption spectroscopy revealed efficient, encounter controlled rates. For wire molecules anchored on Co(3)O(4) nanoparticles, the recovery of the reduced sensitizer at 470 nm indicated similarly efficient hole transfer to the attached PV3, yet no transient hole signal was detected at 600 nm. This implies hole injection from the anchored wire molecule into the Co(3)O(4) particle within 1 MUs or shorter, indicating efficient charge transport from the visible light sensitizer to the oxide catalyst particle. PMID- 22934721 TI - How can the treatment of bacterial vaginosis be improved to reduce the risk of preterm delivery? PMID- 22934722 TI - Adhesions during and after surgical procedures, their prevention and impact on women's health. PMID- 22934724 TI - Daily menstrual blood loss and quality of life in women with heavy menstrual bleeding. AB - AIM: Excessive blood loss during menstruation is a major problem for women of reproductive age. Women who experience heavy menstrual bleeding (HMB) often present to physicians because of the subsequent negative impact HMB has on their daily lives and activities. The objective of this post-hoc analysis is to evaluate daily menstrual blood loss (MBL) in women with HMB and assess the relationship between daily MBL and women's perceptions of MBL, limitations in physical activities and limitations in social/leisure activities as measured by the Menorrhagia Impact Questionnaire. MATERIALS & METHODS: Data from two randomized, placebo-controlled studies of an oral tranexamic acid formulation in women with HMB were assessed. Daily MBLs and Menorrhagia Impact Questionnaire scores were evaluated for two pretreatment cycles and the first three tranexamic acid treatment cycles of each study. Effect-size analyses were not conducted. RESULTS & CONCLUSION: Highest daily MBLs occurred on days 2 and 3 of menstrual cycles. Women's perceptions of daily MBL were consistent with objective measures of MBL. Higher daily MBL was related to increased limitations in physical activities and limitations in social/leisure activities. Daily MBL values were consistent with women's perceptions of MBL. Reduced daily MBL was associated with improvements in health-related quality of life. PMID- 22934725 TI - Changes in maternal weight 5-10 years after a first delivery. AB - AIM: The objective of this study was to identify maternal, obstetrical and reproductive factors associated with long-term changes in maternal weight after delivery. MATERIALS & METHODS: Participants were enrolled in a longitudinal cohort study of maternal health 5-10 years after childbirth. Data were obtained from obstetrical records and a self-administered questionnaire. Weight at the time of first delivery (5-10 years prior) was obtained retrospectively and each woman's weight at the time of her first delivery was compared with her current weight. RESULTS: Among 948 women, obesity was associated with race, parity, education, history of diabetes and history of cesarean at the time of first delivery. On average, the difference between weight at the time of first delivery and weight 5-10 years later was -11 kg (11 kg weight loss). In a multivariate model, black race and diabetes were associated with significantly less weight loss. Cesarean delivery, parity and breastfeeding were not associated with changes in maternal weight. CONCLUSION: Black women and those with a history of diabetes may be appropriate targets for interventions that promote a long-term healthy weight after childbirth. PMID- 22934726 TI - Resistin gene expression in visceral adipose tissue of postmenopausal women and its association with insulin resistance. AB - AIM: The present study evaluates resistin mRNA expression in visceral adipose tissue (VAT) and its correlation with insulin resistance (homeostatic model assessment) in postmenopausal obese women. MATERIALS & METHODS: A total of 68 (nonobese = 34 and obese = 34) age-matched (49-70 years) postmenopausal women were recruited for the study. Fasting blood samples were collected at admission and abdominal VAT were obtained during surgery for gall bladder stones or hysterectomy. Physical parameters (age, height, weight and BMI) were measured. Biochemical parameters (plasma insulin, plasma glucose and serum resistin) were estimated by enzymatic methods. The VAT resistin mRNA expression was evaluated by real-time PCR. RESULTS: The relative mean (+/- standard deviation) VAT resistin mRNA expression in postmenopausal obese women lowered significantly by 20.4% compared with postmenopausal nonobese women (0.029 +/- 0.011 vs 0.023 +/- 0.013; p = 0.047). Furthermore, VAT resistin mRNA expression in postmenopausal obese women was downregulated by 0.69-fold when compared with age-matched postmenopausal nonobese women. Furthermore, the relative VAT resistin mRNA expression in postmenopausal obese women showed significant inverse association with insulin resistance (r = -0.48; p < 0.01) and serum resistin (r = -0.84; p < 0.001), while in postmenopausal nonobese women it did not show any association with both insulin resistance (r = 0.03; p > 0.05) and serum resistin (r = -0.03; p > 0.05). CONCLUSION: The VAT resistin mRNA expression in postmenopausal obese women is associated to insulin resistance. PMID- 22934727 TI - Treatment strategies for menstrually related migraine. AB - Approximately 50% of migrainous women suffer from menstrually related migraine (MRM), a type of migraine in which the attacks occur at the same time as or near the menstrual flow. Attacks of MRM tend to be longer, more intense and disabling and sometimes less responsive to treatment than non-menstrual migraines. Similar to the management of non-menstrual migraine, the use of triptans and NSAIDs is the gold standard for MRM treatment. In this paper, the most important studies in the literature that report the effectiveness of triptans, of certain associated drugs and other analgesic agents are summarized. Preventive strategies that can be used if a prophylactic treatment is needed is also analyzed, with particular attention paid to the use of perimenstrual prophylaxis with triptans and/or NSAIDs. Moreover, considering the peculiar interaction between menstrual migraine and female sex hormones, brief mention is made to possible hormonal manipulations. PMID- 22934728 TI - BRCA carriers, prophylactic salpingo-oophorectomy and menopause: clinical management considerations and recommendations. AB - Women who inherit a mutation in either the BRCA1 or BRCA2 gene have greatly elevated lifetime risks of ovarian cancer, fallopian tube cancer and breast cancer. Preventive surgical removal of the ovaries and fallopian tubes (salpingo oophorectomy) is recommended to these women, often prior to natural menopause, to prevent cancer. The ensuing hormone deprivation may impact on health and quality of life. Most of these women experience menopausal symptoms shortly after surgery; however, there may also be longer term consequences that are less well understood. In this review, we highlight recent studies that examine the implications of salpingo-oophorectomy on health and quality of life in BRCA positive women and we discuss the care of women following prophylactic surgery. PMID- 22934729 TI - Surgical options for apical prolapse repair. AB - Pelvic organ prolapse is a common medical condition that affects the quality of life of many women. Approximately 50% of parous women have pelvic organ prolapse and the lifetime risk for surgical intervention is 6.7% at the age of 80 years. In the USA, the number of women at risk for symptomatic prolapse is increasing, which is consistent with the recent increase in the overall number of prolapse and incontinence procedures being performed. Although prolapse is usually multicompartmental and isolated defects are rare, the apical compartment deserves special attention because apical support is integral to a durable prolapse repair. Since many women may initially present to their primary care physicians, all members of the medical community should have a basic understanding of the diagnosis and treatment for apical prolapse. PMID- 22934730 TI - Management of mixed urinary incontinence. AB - Mixed urinary incontinence accounts for 33% of all incontinence and is the involuntary loss of urine associated with the sensation of urgency; it is also associated with exertion, sneezing or coughing. Risk factors include vaginal delivery, obesity, age and possible genetic factors. Treatment includes lifestyle changes, behavioral therapies, medication and nerve modulation. Surgery with midurethral slings can cure both stress and urge components in 40-50% of cases. Future therapies may include new medications adapting potassium and calcium channels and more widespread use of sacral neuromodulation. This review focuses on the investigation and optimal management of mixed urinary incontinence. PMID- 22934731 TI - Women's awareness of cancer symptoms: a review of the literature. AB - Improvements in cancer detection and treatment have led to consistent declines in mortality from many cancers. However, many patients present for treatment at a point where more invasive treatment is required and/or treatment outcomes are less than optimal. One factor that has been consistently shown to be associated with late diagnosis and treatment is delay in seeking help for symptoms. This paper reviews the literature on women's awareness of cancer symptoms and aims to identify knowledge gaps that need to be addressed in order to improve help seeking behaviors. The discovery of substantial gaps in awareness suggest a need for improved community education regarding cancer symptoms. PMID- 22934732 TI - Characteristics of systemic diseases in the breast: clinical, imaging and pathologic features. AB - Despite tremendous efforts placed on advances in diagnosis and treatment of the spectrum of breast disease, the impact of systemic diseases on the breast has remained under recognized. Distinction between a variety of benign breast diseases versus those that are manifestations of a systemic disease is critically important for appropriate treatment planning and follow-up of patients. This article is designed to provide an overview of different systemic diseases that can present as a breast lesion. Attempts are made to highlight the significance of the distinction between benign breast disease versus benign conditions that present as the result of a systemic disease. Naturally, distinction between any benign condition versus breast carcinoma is a part of the evaluation process. PMID- 22934735 TI - Shock tube study on the thermal decomposition of n-butanol. AB - Dilute concentrations of normal-butanol has been decomposed in single pulse shock tube studies in the presence of large quantities of a chemical inhibitor that suppresses contributions from chain decomposition. Reaction temperatures and pressures are in the range of [1126-1231] K and [1.3-6.5] bar. Ethylene and 1 butene are the only products. The mechanism of the initial decomposition steps involves direct elimination of water and C-C bond cleavage. The fundamental high pressure unimolecular decomposition rate expressions are k(C(4)H(9)OH -> CH(3) + CH(2)CH(2)CH(2)OH) = 10(16.4+/-0.4) exp(42410 +/- 800 [K]/T) s(-1); k(C(4)H(9)OH > CH(3)CH(2) + CH(2)CH(2)OH) = 10(16.4+/-0.4) exp(-41150 +/- 800 [K]/T) s(-1); k(C(4)H(9)OH -> CH(3)CH(2)CH(2) + CH(2)OH) = 10(16.4+/-0.4) exp(-41150 +/- 800 [K]/T) s(-1); and k(C(4)H(9)OH -> CH(3)CH(2)CH?CH(2) + H(2)O) = 10(14.0+/-0.4) exp(-35089 +/- 800 [K]/T) s(-1), where the rate expressions for C-C bond cleavage are based on assumptions regarding the relative rates of the three processes derived from earlier studies on the effect of an OH group on rate expressions. All reactions are in the high pressure limit and suggest that the step size down in the presence of argon is at least 1300 cm(-1). These rate expressions are consistent with the following H-C bond dissociation energies: BDE(H CH(2)CH(2)CH(2)OH) = 417.2 +/- 7 kJ/mol, BDE(H-CH(2)CH(2)OH) = 419.2 +/- 7 kJ/mol, and BDE(H-CH(2)OH) = 401.7 +/- 9 kJ/mol, with an estimated uncertainty of 6 kJ/mol. The kinetics and thermodynamic results are compared with estimates used in the building of combustion kinetics databases. PMID- 22934734 TI - Formation, spectroscopic characterization, and solution stability of an [Fe4S4]2+ cluster derived from beta-cyclodextrin dithiolate. AB - The formation and solution properties, including stability in mixed aqueous Me(2)SO media, have been investigated for an [Fe(4)S(4)](2+) cluster derived from beta-cyclodextrin (CD) dithiolate. Clusters of the type [Fe(4)S(4)(SAr)(4)](2-) (Ar = Ph, C(6)H(4)-3-F) are generated in Me(2)SO by redox reactions of [Fe(4)S(4)(SEt)(4)](2-) with 2 equiv of ArSSAr. An analogous reaction with the intramolecular disulfide of 6(A),6(D)-(3-NHCOC(6)H(4)-1-SH)(2)-6(A),6(D)-dideoxy beta-cyclodextrin (14), whose synthesis is described, affords a completely substituted cluster formulated as [Fe(4)S(4){beta-CD-(1,3 NHCOC(6)H(4)S)(2)}(2)](2-) (15). Ligand binding is indicated by a circular dichroism spectrum and also by UV-visible and isotropically shifted (1)H NMR spectra and redox behavior convincingly similar to [Fe(4)S(4)(SPh)(4)](2-). One formulation of 15 is a single cluster to which two dithiolates are bound, each in bidentate coordination. With there being no proven precedent for this binding mode, we show that the cluster [Fe(4)S(4)(S(2)-m-xyl)(2)](2-) is a single cubane whose m-xylyldithiolate ligands are bound in a bidentate arrangement. This same structure type was proposed for a cluster formulated as [Fe(4)S(4){beta-CD-(1,3 SC(6)H(4)S)(2)}(2)](2-) (16; Kuroda et al. J. Am. Chem. Soc.1988, 110, 4049-4050) and reported to be water-stable. Clusters 15 and 16 are derived from similar ligands differing only in the spacer group between the thiolate binding site and the CD platform. In our search for clusters stable in aqueous or organic-aqueous mixed solvents that are potential candidates for the reconstitution of scaffold proteins implicated in cluster biogenesis, 15 is the most stable cluster that we have thus far encountered under anaerobic conditions in the absence of added ligand. PMID- 22934736 TI - Formulation and evaluation of matrix type mucoadhesive tablets aimed at treating oral aphtha. AB - CONTEXT: Nonsteroidal anti-inflammatory drugs (NSAIDs) are administered for pain relief from oral mucositis. However, the systemic administration of NSAIDs is limited due to the side effects of thrombocytopenia. OBJECTIVE: To avoid systemic side effects, a matrix type mucoadhesive tablet as a topical application preparation to treat oral aphtha was developed. METHODS: A mixture of hard fat with a low irritant property and mucoadhesive polymers was used as the matrix base, and indomethacin was used as a model drug. RESULTS: Among the water-soluble polymers, carbopol and xanthan gum increased the adhesive force of tablets prepared by the suspending method, but the tensile strength was not increased. Tablets containing ethylcellulose 10 or 45 (EC10, EC45) from a water-insoluble polymer increased the adhesive force and tensile strength. Tablets prepared by the dissolve-drying method containing EC45 showed a 1.8-fold increase of adhesiveness to the eggshell membrane compared with hard fat tablets, and showed a sustained release of the drug (17%) over an 8 h period. The drug release was increased to 28% by a modification to the dissolve-drying method using EC10. CONCLUSIONS: Since this matrix type tablet has long-acting properties, adhesiveness and low irritating properties, its potential as a newly designed preparation to treat oral aphtha is suggested. PMID- 22934737 TI - Commentary: Unravelling the effects of additional sex chromosomes on cognition and communication--reflections on Lee et al. (2012). PMID- 22934738 TI - Follow-up study of 25 Chinese children with PLA2G6-associated neurodegeneration. AB - BACKGROUND: To perform a follow-up of 25 Chinese children with gene-confirmed PLA2G6-associated neurodegeneration (PLAN). METHODS: We recruited patients with infantile neuroaxonal dystrophy (INAD) according to the criteria proposed by Nardocci et al. Follow-up was conducted from 7 months to 8 years after the first visit. The PLA2G6 gene was sequenced, and copy number variation (CNV) was detected in patients with only one mutant allele and in mutation-negative patients. Patients with late-onset PLAN until 2012 were reviewed. RESULTS: All patients with INAD exhibited rapid decline in motor and mental function, consistent with previous reports from other populations. Epileptic seizures occurred in 16.7%. One teenager with late-onset PLAN was diagnosed and followed up. The age of disease onset in published late-onset PLAN ranged between 18 months and 37 years. Initial presentations included gait instability (79.0%), mood/behavior changes (10.5%), dysarthria (5.26%) and cognitive deterioration (5.3%). Compared with INAD, cerebellar atrophy (42.1%) was less frequent in the late-onset cases, with cerebral atrophy more common (71.4%). Brain iron accumulation was seen in 52.6%. PLA2G6 mutations were identified by DNA sequencing in 92.3% of clinically diagnosed INAD cases and in the late-onset case. Twenty-seven different mutations were found, of which 13 were novel. No CNVs were detected. Maternal uniparental disomy was confirmed in one INAD case. CONCLUSIONS: This is the largest report on PLAN in the Chinese population. We suggest that PLA2G6 should be screened in any patient exhibiting progressive gait disturbance, bradykinesia, dysarthria, tremors, mood/behavior changes or cognitive decline, especially when associated with cerebellar atrophy and/or iron accumulation and/or cerebral atrophy. PMID- 22934739 TI - Preoperative hemostasis and its association with bleeding and blood component transfusion requirements in cardiopulmonary bypass surgery. AB - BACKGROUND: Variables of hemostasis before surgery might indicate an elevated risk of bleeding. We determined hemostasis tests and standardized bleeding history and their association with bleeding and transfusion requirements in cardiopulmonary bypass (CPB) surgery. STUDY DESIGN AND METHODS: In a prospective trial, variables from 104 patients were associated with postsurgical bleeding and with red blood cells (RBCs) and platelet concentrate (PC) transfusions. Variables included standardized bleeding history, prothrombin time (PT), fibrinogen, fibrin monomers, Factor VIII, von Willebrand factor (VWF), multiple electrode aggregation (MEA), and the day of aspirin or thienopyridine withdrawal before operation. RESULTS: Multiple linear regression revealed bleeding history score, ADP-induced MEA, CPB time, and hemoglobin (Hb) independently associated with postoperative bleeding and bleeding history, arachidonic acid (AA)-induced MEA, CPB time, and PT associated with RBC transfusions. The logistic regression model for the outcome of bleeding within 24 hours after operation indicated ADP-induced MEA, the day of aspirin withdrawal before operation, and CPB time as predictors. AA-induced MEA, CPB time, Hb, and PT were predictors of RBCs transfusion. ADP induced MEA, the day of aspirin withdrawal, PT, and VWF were associated with PC transfusion. CONCLUSIONS: A standardized bleeding history may help to identify patients undergoing CPB surgery whose risk of bleeding is elevated. ADP-induced MEA appears to predict postoperative bleeding and PC transfusion requirements, while AA-induced MEA and preoperative Hb indicate the need for RBCs. The time of aspirin withdrawal before surgery influences perioperative blood loss and PC transfusion. PMID- 22934740 TI - New megastigmane glycoside and alkaloids from Streptomyces sp. YIM 63342. AB - New sesquiterpene glycoside, cyclodipeptide and piperidine derivative were isolated from Streptomyces sp. YIM 63342. On the basis of spectral data, their structures were determined as 3R, 5R, 6S, 7E, 9R-megastigman-7-en-3,5,6,9-tetrol 9-O-beta-D-apiofuranosyl-(1-> 2)-beta-D-glucopyranoside (1), cyclo (L-Pro-L-OMet) (2) and (R)-(E, E)-2-(l,3-pentadienyl) piperidine (3), together with three known compounds as N-acetyltyramine (4), lycoperodine-1 (5), cyclo(L-Pro-L-Tyr)(6). PMID- 22934741 TI - Application of small molecules/macromolecules in ocular inflammatory diseases. AB - Macrobiomolecular treatments for ocular inflammatory diseases have been described in a previous review. This article mainly discusses the application of small molecules in uveitis therapy, which includes corticosteroids, salicylic acid (aspirin), metabolite analogs, and anti-oxidative agents. Additionally, we update recent advances in peptide and nucleic acid related therapies, and focus mainly on the calcineurin inhibitor, cyclosporine, oral tolerant retinal proteins/peptides, gene therapy and ribonucleic acid interference strategies. We classify these immunomodulatory agents by their molecular signatures and highlight the molecular structure and mechanisms of function. These developments in understanding molecular mechanisms of the diseases, with the advent of new technologies, advance current therapeutic approaches. The future direction is to tailor treatments to individual patients in order to provide the safest and most effective therapies for ocular inflammatory diseases. PMID- 22934743 TI - Clinical pharmacology of non-steroidal anti-inflammatory drugs: a review. AB - Non-steroidal anti-inflammatory drugs (NSAIDs) are a group of often chemically unrelated compounds with some common therapeutic actions and side effects. They have potent anti-inflammatory, analgesic and antipyretic activity, and are among the most widely used drugs worldwide. It is generally thought that one of their main mechanisms of action is the inhibition of cyclo-oxygenase (COX), the enzyme responsible for biosynthesing the prostaglandins and thromboxane. NSAIDs are also associated with an increased risk of adverse gastrointestinal, renal and cardiovascular effects. This review describes the clinical pharmacology of NSAIDs, their classification, molecular mechanisms of action and adverse effects, including their possible contribution to neuro-inflammation and carcinogenesis, as well as some recent developments aimed at designing effective anti inflammatory agents with improved safety and tolerability profiles. PMID- 22934744 TI - Analysis of anti-inflammatory enantiomers by HPLC in human plasma and urine: a review. AB - The analysis of drugs in various biological fluids is an important criterion for the determination of the physiological performance of a drug. NSAIDs are non selective inhibitors of prostaglandin biosynthesis and indicated for the acute or long-term treatment of the signs and symptoms of rheumatoid arthritis and osteoarthritis. This paper reviews the recent developments in bioanalysis of these drugs. In particular, sample preparation end, handling procedures, chromatographic conditions and detection methods are discussed. A summary of published HPLC assays for individual antiinflammatory drugs is included. PMID- 22934745 TI - Role of formyl peptide receptors (FPR) in abnormal inflammation responses involved in neurodegenerative diseases. AB - Neurodegenerative disorders, such as multiple sclerosis, prion diseases, Alzheimer's disease and Parkinson's disease are often associated with inflammatory process, which involves various components of the immune system in the central nervous system, in particular astrocytes and microglial cells. Inflammation mediators such as cytokines, leukotrienes, superoxide radicals, eicosanoids, the complement cascade, and FPR agonists (formyl peptides) may play a significant role in pro-inflammatory responses, in which infiltration of activated mononuclear phagocytes at the sites of lesion is a common feature. To prevent long-term inflammation damage, the central nervous system could be treated with antinflammatory agents such as non-steroidal anti-inflammatory drugs (NSAIDs), but only few drugs were found to be effective and their therapeutic benefits is limited by side effects. Accumulating evidences suggest that targeting glia-neuron system might be a therapeutic approach in the treatment of neurodegenerative disease progression, in particular of Alzheimer's disease. Aminopyridazine derivative discovered in unbiased cell-based screens for new synthetic compounds, have proved to be able to suppress selective glial activation responses via mechanisms distinct from NSAIDs. In this review, we report the potential involvement of FPR receptors in inflammatory responses and the potential use of their antagonists to modulate the inflammatory responses of the microglia. Recent results demonstrate that targeting of inflammatory glia cytokine pathways, can suppress Abeta-induced neuroinflammation in vivo, resulting in the attenuation of neuronal damage. PMID- 22934746 TI - Isolation and quantitative methods for analysis of non-steroidal anti inflammatory drugs. AB - Non-steroidal anti-inflammatory drugs are widespread employed in both human and animal health care to reduce ongoing inflammation, pain and fever due to their anti-inflammatory, analgesic and, antipyretic actions. Apart from the well-known biological samples, nowadays these compounds are frequently found in the environment, leading to longterm exposure resulting in adverse effects on humans and wildlife. Therefore, it is important to develop analytical methodologies to detect and control the presence of these pharmaceuticals in very different kinds of samples, from urine, serum or plasma, to river and waste water, sediments or sewage sludge, most of them having very complex matrices. Other problems to solve are the low concentration of the target analytes, the presence of a great number of potential interferences and, sometimes, incompatibilities with the detection systems. Consequently, sample pre-treatment is a very important step to take into account in the non-steroidal anti-inflammatory drugs determination. Herein we reviewed the main extraction and clean-up procedures reported in the literature for these substances: ultrasonic extraction, Soxhlet extraction, pressurized- liquid extraction, supercritical fluid extraction, microwave-assisted extraction, dispersive liquid-liquid microextraction, hollow fiber liquid phase microextraction, pressurized hot water extraction, solid-phase extraction, molecularly imprinted solid-phase extraction and solid-phase microextraction. Several analytical methodologies have been developed to quantify non-steroidal anti-inflammatory drugs, including gas chromatography-mass spectrometry, liquid chromatography with ultraviolet detection, diode array detection, fluorescence detection and tandem mass spectrometry. PMID- 22934747 TI - Anti-inflammatory properties of drugs from saffron crocus. AB - The medicinal uses of saffron (Crocus sativus Linnaeus) have a long history beginning in Asian countries since the Late Bronze Age. Recent studies have validated its potential to lower the risk of several diseases. Some metabolites derived from saffron stigmas exert numerous therapeutic effects due to hypolipidemic, antitussive, antioxidant, antidiabetic activities and many others. Water and ethanol extracts of Crocus sativus L. are cardioprotective and counteract neurodegenerative disorders. Many of these medicinal properties of saffron can be attributed to a number of its compounds such as crocetin, crocins and other substances having strong antioxidant and radical scavenger properties against a variety of radical oxygen species and pro-inflammatory cytokines. Botany, worldwide spreading of cultivars, biochemical pathways, active constituents and chemical detection methods are reviewed. Therapeutic uses of saffron principles with particular regard to those exhibiting antioxidant and thus anti-inflammatory features are discussed. To date, very few adverse health effects of saffron have been demonstrated. At high doses (more than 5 g/die day), it should be avoided in pregnancy owing to its uterine stimulation activity. PMID- 22934748 TI - Naturally occurring and synthetic agents as potential anti-inflammatory and immunomodulants. AB - Terpenes in general and triterpenes in particular showed anti-inflammatory activity and act as immunomodulators in nutraceutical agents. Antiinflammation, a useful and attractive approach in experimental oncology, helps to investigate the inflammation preventive potential of natural products and synthetic entities. During the course of our research work in natural product chemistry and synthesis of novel structures in the field of heterocyclic chemistry, we found interesting results. In natural product betulinic acid, alpha-amyrin acetate, lupeol acetate, oleanolic acid, ursolic acid and their derivatives showed interesting potential analgesic and anti-inflammatory activity. In this review specific reference has been made to novel classes and newly discovered compounds in the literature, which exhibited required activities. Indomethacine is a potent synthetic compound, which becomes the basis of novel anti-inflammatory agents. Shen postulated a receptor theory which indicates the physical parameters responsible for anti-inflammatory activity. Attempt has been made to cover almost all the anti-inflammatory agents which fall under the various chemical structural classes of compounds showing required activity. The objective of this review is to compile relevant data on the mechanism of action of terpenes isolated from active ethnomedicinal plants to examine the role terpenoids have in medicinal plants used against inflammatory diseases, especially those in which an immune response is implicated. In addition, a selection of several structurally related compounds has been compiled in order to analyze the possible structural characteristics and relationships between the different types of structures found in triterpenoids. The selection of active species was made on the basis of their immunomodulatory activity, and their role in the resolution of diseases in which the immune system is implicated to examine the mechanism by which they are useful as ethnopharmacological medicines. These terpenes include ursolic acid, oleanolic acid, betulinic acid. This review discusses in detail the preclinical studies conducted with triterpenes and provides an insight into its mechanism of action. PMID- 22934749 TI - Recent advances in anti-inflammatory and immune-modulator drugs development and analytical tools for their characterization. PMID- 22934750 TI - The multi-kinase inhibitor TG02 overcomes signalling activation by survival factors to deplete MCL1 and XIAP and induce cell death in primary acute myeloid leukaemia cells. AB - The novel multi-kinase inhibitor TG02 has selectivity against cell cycle and transcriptional cyclin dependent kinases (CDKs) as well as fms-like tyrosine kinase receptor-3 (FLT3). Inhibition of transcriptional CDKs preferentially depletes short-lived proteins such as MCL1. We evaluated the in vitro toxicity of TG02 to primary acute myeloid leukaemia (AML) cells in the presence of survival signalling pathway activation by cytokines and fibronectin. One hundred nanomolar TG02 induced a median decrease of 40% in bulk cell survival and 43% in the CD34(+) CD38(-) CD123(+) subset. A 90% inhibitory concentration of 500 nmol/l indicated that TG02 toxicity is not halted by protective cell cycle arrest. Samples with FLT3 internal tandem duplication were not preferentially targeted. By flow cytometry, TG02 treatment caused loss of RNA Polymerase II serine 2 phosphorylation in patient samples, which correlated strongly with BAX activation (R(2) =0.89), suggesting these as potential biomarkers for clinical studies. MCL1 and XIAP expression also decreased. Repeated brief exposure to TG02 in MOLM-13 cells did not result in compensatory up-regulation of survival protein expression. In conclusion, TG02 is potently cytotoxic towards CD34(+) CD38(-) CD123(+) and bulk AML cells, despite protective signalling pathway activation. This antitumour activity is most likely mediated by dephosphorylation of RNA Polymerase II leading to depletion of survival molecules such as MCL1 and XIAP, with subsequent BAX activation and apoptosis. PMID- 22934751 TI - Targeting to 5-HT1F receptor subtype for migraine treatment: lessons from the past, implications for the future. AB - The effective anti-migraine drugs triptans, all bind with high affinity to three serotonin (5-HT) subtypes, the 5-HT1B, 5-HT1D and 5-HT1F. 5-HT1B mRNA is densely localized within smooth muscle, and less in the endothelium of cerebral blood vessels. This vascular distribution of 5-HT1B receptor has been shown to mediate the vasoconstrictive properties of the triptans, responsible for potential cardiac adverse events. Activation of 5-HT1D subtype, although effective in animal models of migraine, was not enough efficient to attenuate migraine attacks in clinical trials. The 5-HT1F receptor is located both in vessels and within the trigeminal ganglion (TG) and the trigeminal nucleus caudalis (Sp5C), but with the difference that the 5-HT1F receptor lack vasoconstrictive properties, making it an attractive target for new anti-migraine drugs. Selective activation of 5-HT1F receptor potently inhibited markers associated with electrical stimulation of the TG. Thus 5-HT1F receptor represents an ideal target for anti-migraine drugs. So far two selective 5-HT1F agonists have been tested in human trials for migraine: LY334370 and lasmiditan. Both molecules were efficient in attenuating migraine attacks with efficacy in the same range as oral sumatriptan 100mg, the gold standard for triptans. The LY334370 project withdrew because of toxicity in animals, while lasmiditan is still testing. In this review we present all the available preclinical and clinical data on the 5-HT1F agonists as a potential new class of anti-migraine drugs lacking vascular activity and we discuss related issues on the vascular and neuronal aspects of migraine pathogenesis. PMID- 22934753 TI - Methylphenidate transdermal system in attention-deficit hyperactivity disorder in adolescents: profile report. PMID- 22934752 TI - A longitudinal study of differences in late- and early-onset geriatric depression: depressive symptoms and psychosocial, cognitive, and neurological functioning. AB - OBJECTIVES: Studies suggest early-onset depression (EOD) is associated with a more severe course of the depressive disorder, while late-onset depression (LOD) is associated with more cognitive and neuroimaging changes. This study examined if older adults with EOD, compared with those with LOD, would exhibit more severe symptoms of depression and, consistent with the glucocorticoid cascade hypothesis, have more hippocampal volume loss. A second goal was to determine if LOD, compared with EOD, would demonstrate more cognitive and neuroimaging changes. METHOD: At regular intervals over a four-year period non-demented, older, depressed adults were assessed on the Mini-Mental Status Examination and the Montgomery-Asberg Depression Rating Scale. They were also assessed on magnetic resonance imaging. RESULTS: Compared with LOD, EOD had more depressive symptoms, more suicidal thoughts, and less social support. Growth curve analyses indicated that EOD demonstrated higher levels of residual depressive symptoms over time. The LOD group exhibited a greater decrement in cognitive scores. Contrary to the glucocorticoid cascade hypothesis, participants with EOD lost right hippocampal volume at a slower rate than did participants with LOD. Right cerebrum gray matter was initially smaller among participants with LOD. CONCLUSIONS: EOD is associated with greater severity of depressive illness. LOD is associated with more severe cognitive and neurological changes. These differences are relevant to understanding cognitive impairment in geriatric depression. PMID- 22934755 TI - Zero echo time magnetic resonance imaging of contrast-agent-enhanced calcium phosphate bone defect fillers. AB - Calcium phosphate cements (CPCs) are widely used bone substitutes. However, CPCs have similar radiopacity as natural bone, rendering them difficult to be differentiated in classical X-ray and computed tomography imaging. As conventional magnetic resonance imaging (MRI) of bone is cumbersome, due to low water content and very short T(2) relaxation time, ultra-short echo time (UTE) and zero echo time (ZTE) MRI have been explored for bone visualization. This study examined the possibility to differentiate bone and CPC by MRI. T(1) and T(2)* values determined with UTE MRI showed little difference between bone and CPC; hence, these materials were difficult to separate based on T(1) or T(2) alone. Incorporation of ultra-small particles of iron oxide and gadopentetatedimeglumine (Gd-DTPA; 1 weight percentage [wt%] and 5 wt% respectively) into CPC resulted in visualization of CPC with decreased intensity on ZTE images in in vitro and ex vivo experiments. However, these additions had unfavorable effects on the solidification time and/or mechanical properties of the CPC, with the exception of 1% Gd-DTPA alone. Therefore, we tested this material in an in vivo experiment. The contrast of CPC was enhanced at an early stage postimplantation, and was significantly reduced in the 8 weeks thereafter. This indicates that ZTE imaging with Gd-DTPA as a contrast agent could be a valid radiation-free method to visualize CPC degradation and bone regeneration in preclinical experiments. PMID- 22934756 TI - Interprofessional supervision in an intercultural context: a qualitative study. AB - Our understanding of the qualities and value of clinical supervision is based on uniprofessional clinical education models. There is little research regarding the role and qualities needed in the supervisor role for supporting interprofessional placements. This paper reports the views and perceptions of medical and allied heath students and supervisors on the characteristics of clinical supervision in an interprofessional, international context. A qualitative case study was used involving semi-structured interviews of eight health professional students and four clinical supervisors before and after an interprofessional, international clinical placement. Our findings suggest that supervision from educators whose profession differs from that of the students can be a beneficial and rewarding experience leading to the use of alternative learning strategies. Although all participants valued interprofessional supervision, there was agreement that profession-specific supervision was required throughout the placement. Further research is required to understand this view as interprofessional education aims to prepare graduates for collaborative practice where they may work in teams supervised by staff whose profession may differ from their own. PMID- 22934754 TI - Topical rapamycin therapy to alleviate the cutaneous manifestations of tuberous sclerosis complex: a double-blind, randomized, controlled trial to evaluate the safety and efficacy of topically applied rapamycin. AB - BACKGROUND AND OBJECTIVES: Facial angiofibromas are disfiguring facial lesions, present in up to 80% of patients with tuberous sclerosis complex. Recent elucidation of the complex cell signaling pathways that are disrupted in tuberous sclerosis indicates that rapamycin may be successful in alleviating the appearance of these lesions. The objectives of the current study were to evaluate the safety of topically applied rapamycin in patients with tuberous sclerosis complex and to determine its potential effectiveness in treatment of facial angiofibromas. PATIENTS AND METHODS: The study was a prospective, randomized, double-blind, placebo-controlled study performed at the University of Texas Health Science Center at Houston. Study subjects were recruited from the patient populations at the University of Texas Tuberous Sclerosis Center of Excellence. All subjects were over the age of 13 years and had a diagnosis of tuberous sclerosis complex. Subjects were excluded if they were using any form of rapamycin or if they were pregnant. Study subjects applied the study product to their facial angiofibromas nightly for a duration of 6 months. The investigational product contained one of three doses of rapamycin compounded with Skincerity(r): (i) no rapamycin; (ii) 1 mg of rapamycin per 30 cc (0.003%); or (iii) 5 mg of rapamycin per 30 cc (0.015%). Plasma rapamycin concentrations were measured monthly to test for systemic absorption. Complete blood counts were performed monthly to test for anemia, neutropenia, or thrombocytopenia. Upon completion of the trial, subjects were asked if the formulation had improved the appearance of their facial angiofibromas. RESULTS: Twenty-three subjects completed the study. There was no detectable systemic absorption of rapamycin (all blood concentrations were <1.0 ng/mL). There were no significant changes in white blood cell, red blood cell, or platelet counts. Seventy-three percent of subjects in the treatment arms versus 38% of subjects in the placebo arm reported a subjective improvement in the appearance of their facial angiofibromas. CONCLUSION: The application of low-dose topical rapamycin (0.003-0.015%) to the face can safely decrease the appearance of facial angiofibromas in patients with tuberous sclerosis complex. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01031901. PMID- 22934758 TI - Enhanced CD4+CD25+ regulatory T cells with splenic proliferation and protection against oxidative stress by nicotinamide in gestational diabetes. AB - Gestational diabetes mellitus (GDM) is a common complication during pregnancy. Metabolic changes in GDM affect fetal development and fetal glucose homeostasis. Several complications of diabetes are related to increased intracellular oxidative stress where prooxidants exceed antioxidant capacity. The present study was initiated to evaluate the effects of nicotinamide on CD4+CD25+ regulatory T cells (Tregs), proliferation of splenocytes, production of reactive oxygen species (ROS) by neutrophils and serum glucose levels. Changes in mRNA levels of two antioxidant genes in liver, viz, superoxide dismutase (SOD1) and catalase (CAT) were quantified with real-time PCR (QRT-PCR). Nicotinamide (50, 100 and 200 mg/kg) was supplemented p.o. to pregnant diabetic rats from days 6 through 20 of gestation. The highest dose enhanced expression of Tregs and increased splenocytes proliferation in both resting and lipopolysaccharide (LPS) stimulated cells. Oxidative burst activity of neutrophils in response to phorbol myristate acetate (PMA), N-formyl-methionyl-leucyl-phenylalanine (FMLP) or E. coli activation was reduced. mRNA expressions of superoxide dismutase (SOD) and catalase (CAT) genes were upregulated by nicotinamide. In summary, nicotinamide boosted the immune system through stimulation of adaptive immune cells with enhancement of antioxidant defences and reduced production of ROS. Serum glucose level was normalised by nicotinamide (200 mg/kg). These findings provide evidence for usage of nicotinamide as a supplement or as adjunct to therapeutic agents in gestational diabetes and in pregnant individuals with weakened immune systems. PMID- 22934757 TI - "Acute caring" in the emergency department. AB - The aim of this essay was to discuss the ways in which the dynamics of interprofessional communication and collaboration among healthcare providers ultimately affect patient quality of care in the acute setting. Interprofessionalism describes a care model whereby health providers use complementary skills, knowledge and competencies to provide quality care to a group of patients. These interactions are characterized by trust, respect and an understanding of each other's skill and knowledge. At its best, the interprofessional care model has made great strides in the amelioration of patient outcomes, including reduction in negative outcomes, decreased health access needs and increased patient satisfaction. However, challenges with regard to communication and implementation have translated to a steep learning curve for healthcare providers. As such, a new-found emphasis has been placed on interprofessional education for today's healthcare students with the goal of promoting a more efficient and collaborative philosophy for tomorrow's healthcare teams. PMID- 22934759 TI - Tuning the electronic properties by width and length modifications of narrow- diameter carbon nanotubes for nanomedicine. AB - The distinctive characteristics of nanoparticles, resulting from properties that arise at the nano-scale, underlie their potential applications in the biomedical sector. However, the very same characteristics also result in widespread concerns about the potentially toxic effects of nanoparticles. Given the large number of nanoparticles that are being developed for possible biomedical use, there is a need to develop rapid screening methods based on in silico methods. This study illustrates the application of conceptual Density Functional Theory (DFT) to some carbon nanotubes (CNTs) optimized by means of static DFT calculations. The computational efforts are focused on the geometry of a family of packed narrow diameter carbon nanotubes (CNTs) formed by units from four to twelve carbons evaluating the strength of the C-C bonds by means of Mayer Bond Orders (MBO). Thus, width and length are geometrical features that might be used to tune the electronic properties of the CNTs. At infinite length, partial semi-conductor characteristics are expected. PMID- 22934760 TI - Photobiostimulation on wound healing treatment by ClAlPc-nanoemulsion from a multiple-wavelength portable light source on a 3D-human stem cell dermal equivalent. AB - This research evaluated the effect of multiple-wave lasertherapy on the healing process of surgical wounds based on in vitro models denominated stem-dermal equivalents. These human skin models were obtained from a co-culture of dermal cells and bone marrow mesenchymal stem cells. The experimental tests were carried out using a LED portable to multiple waves (operating at 660 nm and 810 nm) at different doses to induce photobiostimulation (10 to 70 mJ.cm-2). Moreover, a photosensitizer drug was employed as a new advanced designed nanomaterial, being a nanoemulsion with biopolymers to obtain an efficient drug delivery system to release lipophilic compounds. The studies were performed considering the light combination application monitoring the kinetic contraction of the dermal equivalent model and the quantification of important macromolecules (as metaloproteases derivatives), related directly with wound healing process. Results showed that an appropriate photomodulation using the combination of both wavelengths (in the red and infrared range) is possible, such that it can contribute to wound healing therapy and/or other pathological skin disease treatment. PMID- 22934761 TI - Proteasome modulator 9 and depression in type 2 diabetes. AB - BACKGROUND: The chromosome 12q24 locus is linked to bipolar disorder, depression, and type 2 diabetes (T2D). PSMD9 lies in the 12q24 locus and is linked to MODY3, T2D, T2D-nephropathy, T2D-neuropathy, retinopathy, macrovascular pathology, hypertension, and hypercholesterolemia in Italian families. Interestingly, PSMD9 gene common variants contribute to the therapeutic response to anti-depressant treatment. Further, PSMD9 is implicated in a model of prediction to susceptibility to depression. AIMS: Our goal was to determine whether PSMD9 is linked to depression in 200 T2D Italian families. METHODS: We characterized the Italian families' members for presence and/or absence of depression using the diagnostic criteria of DSM-IV. The phenotype was described as unknown in all cases in which the diagnosis was unclear or data were not available. We tested in the 200 Italians families for evidence of linkage of the PSMD9 single nucleotide polymorphisms (SNPs) IVS3+nt460 A > G, IVS3+nt437 T > C and E197G A > G with the depression phenotype. The non-parametric linkage analysis was performed by using the Merlin software. To rule out results due to random chance, 1000 replicates were executed. RESULTS: The PSMD9 gene SNPs studied and/or any gene variants in linkage disequilibrium with them are linked to depression in our Italian families. CONCLUSIONS: This is the first report of PSMD9 linkage to depression. This finding highlights the pleiotropic effects of PSMD9. PMID- 22934762 TI - DNA aptamers for human thrombin with high anticoagulant activity demonstrate target- and species-specificity. AB - G-quadruplex-based DNA aptamers for human thrombin represent promising pharmaceuticals having high anticoagulant activity, rapid clearance from the bloodstream, and availability of DNA antidote. High specificity of aptamers minimizes side-effects but at the same time leads to difficulties when choosing animal model for preclinical trials. Well described minimal G-quadruplex 15-TBA, elongated with hinge and duplex regions 31-TBA, and developed recently modular aptamer RA-36 were investigated thoroughly and compared in this paper. To estimate the species-specificity of aptamers the inhibition constants and types were determined for human fibrinogen hydrolysis with human, bovine, porcine, rabbit, rat, and mouse thrombins using turbidimetric assay. Coagulation tests on human fibrinogen, factor II deficient human plasma and animal plasmas were conducted to verify turbidimetric data and reveal either the concentration effects or the influence of other plasma components. And finally, a set of tests on blood clotting cascade was performed to investigate target-specificity of RA 36 aptamer. PMID- 22934763 TI - In vitro neuronal induction of adipose-derived stem cells and their fate after transplantation into injured mouse brain. AB - The effect of substances known as inducers of neuronal differentiation on cultured human and mouse adipose-derived mesenchymal stem cells (ASCs) and their fate after transplantation into the injured and ischemic mouse brains were studied. ASCs were isolated from the human and mouse adipose tissue. Inducers of neuronal differentiation included beta-mercaptoethanol, glial cell line-derived neurotrophic factor (GNDF), brain-derived neurotrophic factor (BDNF), retinoic acid (RA), 5-azacytidine, as well as their combinations. Three days after the induction, the phenotype of the induced cells was analyzed using immunocytochemistry and real-time PCR assay for differential expression of specific genes. The induction efficiency was evaluated by the increased transcription of neuronal differentiation markers: nestin, beta-III-tubulin (Tub B), microtubule-associated protein 2 (MAP2), and neuron-specific enolase (ENO2). The expression of marker genes was tested by immunocytochemical analysis. ASC cultivation in the medium with RA or BDNF in combination with 5- azacytidine for a week increased the mRNA and protein levels of nestin, Tub-B, and ENO2. The transplantation of induced mouse ASCs into the mouse brain increased the lifespan of the cells relative to control uninduced cells and promoted their migration from the transplantation site to the recipient cerebral parenchyma. The transplantation of the induced cells into the mouse brain pre-exposed to endothelin- 1 promoted a more active cell migration into the surrounding ischemic brain tissue. Thus, ASC exposure to RA or BDNF in combination with 5-azacytidine elevated the transcription of the neuronal differentiation markers and improved the viability and integration of ASCs grafted into the mouse brain. PMID- 22934764 TI - Fragment based drug design: from experimental to computational approaches. AB - Fragment based drug design has emerged as an effective alternative to high throughput screening for the identification of lead compounds in drug discovery in the past fifteen years. Fragment based screening and optimization methods have achieved credible success in many drug discovery projects with one approved drug and many more compounds in clinical trials. The fragment based drug design starts with the identification of fragments or low molecular weight compounds that generally bind with weak affinity to the target of interest. The fragments that form high quality interactions are then optimized to lead compounds with high affinity and selectivity. The weak affinity of fragments for their target requires the use of biophysical techniques such as nuclear magnetic resonance, X ray crystallography or surface plasmon resonance to identify hits. These techniques are very sensitive and some of them provide detailed protein fragment interaction information that is important for fragment to lead optimization. Despite the huge advances in technology in the past years, experimental methods of fragment screening suffer several challenges such as low throughput, high cost of instruments and experiments, high protein and fragment concentration requirements. To address challenges posed by experimental screening approaches, computational methods were developed that play an important role in fragment library design, fragment screening and optimization of initial fragment hits. The computational approaches of fragment screening and optimization are most useful when they are used in combination with experimental approaches. The use of virtual fragment based screening in combination with experimental methods has fostered the application of fragment based drug design to important biological targets including protein-protein interactions and membrane proteins such as GPCRs. This review provides an overview of experimental and computational screening approaches used in fragment based drug discovery with an emphasis on recent successes achieved in discovering potent lead molecules using these approaches. PMID- 22934765 TI - Design of Smart PEO-PPO-PEO-Magnetic Drug Delivery System for Alzheimer's Diseases Diagnosis and Therapy. AB - Amyloid-beta (Abeta) oligomers are more likely to be the pathogenic agents of Alzheimer's disease. Development of multiple approaches in detection and clearance pathway for Abeta, may eventually lead to diagnosis and treatments of AD. Following this concept, we proposed temperature-responsive magnetic drug delivery system (DDS). This system designed to enhance imaging tool and controlled drug delivery with the aid of conjugated antibodies to amyloid-derived diffusible ligands (anti-ADDLs), which can identify targeted ADDLs. The magnetic cores compose of conjugated Congo red (CR) to maghemite (Fe2O3) (CR-Fe2O3) have shown great advantage as multimodal imaging agents, while superparamagnetic Fe2O3 also possesses the hyperthermia therapy function. Pluronic F127 poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) PEO-PPO-PEO block copolymer known to be stimuli-responsive and show structure changes when subjected to external, temperature and magnetic signals. To form nanocomposites, magnetic cores coated with Pluronic and produce core/shell structure. X-ray diffraction (XRD), field-emission scanning electron microscopy (FE-SEM), and high-resolution transmission electron microscope (HR-TEM) were used to characterize as synthesized magnetic nanocomposites (MNCs). Furthermore, Vibrating magnetometer experiments showed that MNCs have higher magnetization value than bare magnetic nanoparticles (MNPs) and are easy to conduct with an external magnetic field. The dependence of hydrodynamic size of MNCs to the temperature showed an increase in temperature corresponds to a decrease in the size. These results confirm that proposed system can be engineered and employed as smart drug delivery system for AD treatment. PMID- 22934766 TI - Non-ribosomal halogenated protease inhibitors from cyanobacterial isolates as attractive drug targets. AB - Cyanobacteria possess the ability to produce compounds with remarkable biological activity, and have thus attracted the attention of the pharmaceutical industry. Cyanopeptides acting as protease inhibitors have shown potential in the field of pharmacotherapy through regulation of abnormal physiological processes in the human body. Despite the already described cyanopeptide protease inhibitors, the search for new congeners is of considerable interest which may pave the way for more efficient molecules. In this study, the presence of the protease inhibitors aeruginosin and cyanopeptolin with non-, mono- and dichlorination and also genes coding for their synthetases was investigated in 90 cyanobacterial strains. Mass spectrometry analyses highlighted production of 91, 19 and 3 non-, mono- and dichlorinated congeners, respectively. The purified extract of Microcystis botrys SPC759 inhibited 61% of pepsin protease. PCR amplifications of aeruginosin and cyanopeptolin synthetase gene regions were observed in 41 and 28% of evaluated strains, respectively. The sequences obtained for the aerA-aerB (aeruginosin) and mcnC-mcnE (cyanopeptolin) gene regions grouped together with their homologues found in other cyanobacterial strains in the phylogenetic analyses with high bootstrap support. Antimicrobial activity assays performed using all intracellular extracts inhibited 31 and 26% of Gram-negative and Gram-positive pathogenic bacterial growth, respectively. The results of this study showed the production of aeruginosin and cyanopeptolin and the presence of their genes in several cyanobacterial genera for the first time besides the discovery of novel congeners. PMID- 22934767 TI - A new target for diagnosis and treatment of CNS disorders: agmatinergic system. AB - A polyamine agmatine is produced through decarboxylation of L -arginine by the enzyme arginine decarboxylase and is a new neurotransmitter in central nervous system (CNS). It has been suggested that agmatine has analgesic, anxiolytic and antidepressant activities in animals. In experimental studies, it also generates some favorable effects on cerebral damages and withdrawal syndromes involved in addictive drugs. Furthermore, it modulates some processes of learning and memory. Thus, agmatine may be an important target for the treatment of CNS disorders. However, the abnormal release and transmission of agmatine in brain may also be related to some CNS disorders, such as schizophrenia. Interaction of agmatine with other central neurotransmitter systems, such as the glutamatergic and nitrergic systems, seems to be very important. According to the current literature, we can expect that the central agmatinergic system may be a new key target in development of novel approaches for understanding the etiopathogenesis of CNS disorders and their treatment with drugs. The main goal of this article is to evaluate the effects of agmatine in CNS and underline its pharmacological actions in CNS and drug development. PMID- 22934768 TI - Effect of nicotine on the proliferation and differentiation of mouse induced pluripotent stem cells. AB - The molecular mechanisms that regulate the proliferation and differentiation of induced pluripotent stem (iPS) cells are of great interest. However, whether stimulation with nicotine enhances the proliferation and differentiation of iPS cells has not been investigated. In the present study, western blot analysis revealed that the alpha4-nAchR and alpha7-nAchR are expressed in mouse iPS cells. Mouse iPS cells were treated with nicotine for 24 h under feeder-free conditions. Mouse iPS cells were guided to differentiate into mesodermal progenitor cells on type IV collagen (Col IV)-coated dishes in differentiation medium. Mouse iPS cells were guided to differentiate into neural progenitor cells by embryoid body (EB) formation on ultra-low-attachment dishes. After 4 days of growth, all-trans retinoic acid (ATRA; 1 MUM) or nicotine (300 nM) was added to the EB cultures and maintained for additional 4 days and plated onto fibronectincoated plates. A BrdU incorporation assay showed that treatment with 300 nM nicotine significantly increased the DNA synthesis of mouse iPS cells or mouse iPS cell-derived mesodermal progenitor cells. This effect was significantly inhibited by pretreatment with an alpha4-nAchR antagonist, an alpha7-nAchR antagonist, or a CaMKII inhibitor. The differentiation potential of mouse iPS cells into mesodermal progenitor cells or neural progenitor cells was not affected by the nicotine treatment. The present study indicates that stimulation of the alpha4 nAchR and alpha7-nAchR may lead to a significant increase in the proliferation of mouse iPS cells or mouse iPS cell-derived mesodermal progenitor cells through the CaMKII signaling pathway. PMID- 22934769 TI - Oxidized-LDL and paraoxonase-1 as biomarkers of coronary artery disease in patients with sleep-disordered breathing. AB - Coronary Artery Disease (CAD) and OBJECTIVES: Sleep Disordered Breathing (SDB) are both oxidative stress disorders. SDB intermittent hypoxia induces oxidative stress, and reduces NO(.) availability, causing endothelial dysfunction. Low density lipoprotein (LDL) peroxidation is involved in atherosclerosis, and is reported in SDB. Oxidized LDL (ox-LDL) and malondialdehyde (MDA) are lipid peroxidation markers. High-density lipoprotein (HDL) presents antiatherosclerotic properties related to paraxonase-1 (PON-1) activity. PON-1 hydrolyseyses lipid peroxides as ox-LDL. This study compares the relationship of HDL and PON-1, the lipid peroxidation markers ox-LDL and MDA, and 8-OHdG DNA damage marker in the association of SDB and CAD. DESIGN AND METHODS: 29 controls and 27 cases with CAD (defined as > 30% coronary narrowing) patients were included. The apnea-hypopnea index (AHI), and several lipid and oxidative stress parameters were measured in these patients. RESULTS: AHI is increased in CAD patients, and PON-1 activity and HDL levels are decreased. Regression analyseyses showed that lower PON-1 activity and higher ox-LDL levels are important CAD predictors, compared to HDL or MDA levels and present an age-dependent increase. Nitrites and nitrates, indirect NO(.) markers, are positive vs correlated with PON-1 and are negatively correlated to ox-LDL. SDB is not correlated to PON-1 activity decrease or ox-LDL increase. AHI is inversely correlated to HDL levels. CONCLUSIONS: These results indicate that PON-1 and ox-LDL are important predictors of CAD, however they may not be directly related to SDB. PMID- 22934770 TI - State of the art of the therapeutic perspective of sorafenib against hematological malignancies. AB - The bi-aryl urea multi-kinase inhibitor Sorafenib (BAY 43-9006, Nexavar) was initially approved for the treatment of unresectable hepatocellular carcinoma and advanced renal cell carcinoma. Eleven years after its first description in PubMed, the therapeutic potential of Sorafenib has been evaluated in an increasing number of studies, mainly focused on solid tumors. More recently, the potential usefullness of Sorafenib has started to emerge also against hematological malignancies. At the molecular level, besides the RAF kinase pathway, which represents the first therapeutic target of Sorafenib, additional kinases, in particular the vascular endothelial growth factor receptor, have been identified as important targets of Sorafenib. A great interest for the potential use of Sorafenib against acute myeloid leukemia (AML) arose when it was demonstrated that a specific mutation of a kinase gene, called FMS-like tyrosin kinase-3- internal tandem duplication (FLT-3-ITD) and occurring in more than 30% of AML, represents a molecular target of Sorafenib. However, recent phase I and II clinical studies showed that, in spite of its ability to suppress the activity of this mutated kinase, resistence to Sorafenib rapidly occurs in AML, suggesting that Sorafenib will be more effective in combined therapy than used as single drug. Another critical molecular target of Sorafenib is the anti-apoptotic protein Mcl-1. The ability of Sorafenib to rapidly shut-off Mcl-1 in virtually all the hematological malignancies investigated, including the B-chronic lymphocytic leukemia, represents a key element for its antileukemic activity as well as for therapeutic combinations based on Sorafenib. In this respect, it is of particular interest that many chemotherapeutic drugs or innovative anti neoplastic compounds, such as recombinant TRAIL or inibitors of MDM2 protein, are either unable to down-regulate Mcl-1 or in some instances promote a paradoxical induction of Mcl-1. In this review, the growing evidences for the role of Mcl-1 in mediating the anti-leukemic activity of Sorafenib will be discussed in relationship with promising therapeutic perspectives. PMID- 22934771 TI - A liver-derived rat epithelial cell line from biliary origin acquires hepatic functions upon sequential exposure to hepatogenic growth factors and cytokines. AB - Withdrawal of promising drug candidates is often due to the detection of liver toxicity. In particular the parenchymal liver cells or hepatocytes are targeted since they are the major sites of drug transport and of metabolite formation and thus also the place where not only detoxification, but also activation of new chemical (NCE) and biological (NBE) entities may occur. Therefore, primary hepatocyte- based cultures are currently the preferred in vitro model to screen for liver toxicity. However, within a few days, they undergo dedifferentiation with loss of liver-specific functionality, including xenobiotic biotransformation capacity, making them only suitable for short-term applications. A plausible alternative to primary hepatocyte cultures that can be maintained for longer periods of time could be the use of liver-derived epithelial cell lines and their optimized derivatives. Therefore, in the present study, we evaluated the stability and the hepatic differentiation potential of a neonatal liver-derived rat epithelial cell line from biliary origin (rLEC). Undifferentiated rLEC stably express the hepatic progenitor markers CEBPA, FOXA2, GJA1, ONECUT1, KRT18 and KRT19 for at least 15 consecutive passages after cryopreservation. Upon sequential exposure to hepatogenic growth factors and cytokines, rLEC generate functional hepatic progeny, expressing mature hepatic markers including Alb, Ahr, Car, C/ebpalpha, Cx32, Foxa2, Hnf1alpha, Hnf1beta and Onecut1. Furthermore, an active polarization is observed for the hepatic drug transporters Oatp4 and Ntcp. rLEC-derived hepatic cells also acquire the ability to store glycogen, express genes encoding for key hepatic enzymes as shown by Affymetrix microarray data, and display stable CYP1A1/2- and CYP2B1/2-dependent activities for several weeks at levels comparable to those observed in cultured primary rat hepatocytes. The acquisition of such a stable and active biotransformation capacity is key for the applicability of liver-based in vitro models for long-term toxicity testing. PMID- 22934772 TI - Side effects of cocaine abuse: multiorgan toxicity and pathological consequences. AB - Cocaine is a powerful stimulant of the sympathetic nervous system by inhibiting catecholamine reuptake, stimulating central sympathetic outflow, and increasing the sensitivity of adrenergic nerve endings to norepinephrine (NE). It is known, from numerous studies, that cocaine causes irreversible structural changes on the brain, heart, lung and other organs such as liver and kidney and there are many mechanisms involved in the genesis of these damages. Some effects are determined by the overstimulation of the adrenergic system. Most of the direct toxic effects are mediated by oxidative stress and by mitochondrial dysfunction produced during the metabolism of noradrenaline or during the metabolism of norcocaina, as in cocaine-induced hepathotoxicity. Cocaine is responsible for the coronary arteries vasoconstriction, atherosclerotic phenomena and thrombus formation. In this way, cocaine favors the myocardial infarction. While the arrhythmogenic effect of cocaine is mediated by the action on potassium channel (blocking), calcium channels (enhances the function) and inhibiting the flow of sodium during depolarization. Moreover chronic cocaine use is associated with myocarditis, ventricular hypertrophy, dilated cardiomyopathy and heart failure. A variety of respiratory problems temporally associated with crack inhalation have been reported. Cocaine may cause changes in the respiratory tract as a result of its pharmacologic effects exerted either locally or systemically, its method of administration (smoking, sniffing, injecting), or its alteration of central nervous system neuroregulation of pulmonary function. Renal failure resulting from cocaine abuse has been also well documented. A lot of studies demonstrated a high incidence of congenital cardiovascular and brain malformations in offspring born to mothers with a history of cocaine abuse. PMID- 22934773 TI - Interstitial lung damage due to cocaine abuse: pathogenesis, pharmacogenomics and therapy. AB - Medicinal agents, beside occupational and environmental agents, remain one of the most common causes for interstitial lung diseases (ILD). A major problem with ILD is the recognition of the causative agent. In some cases more or less characteristic features of presentation are described. Often, the connection between drug-use and the development of related inflammatory damage or idiosyncratic toxicities is hard to recognize and objectify. Cocaine, a xenobiotic and the most commonly used illicit drug, causes serious medical and social problems. An increasing incidence of lung toxicity related to cocaine or crack-use is being reported worldwide. However, the mechanism of the resulting lung injury is not fully understood. This review summarizes possible molecular mechanisms explaining intraindividual variability in cocaine response and lung toxicity. The importance of including pharmacogenomics in the work-up of patients with suspected drug-induced lung toxicity is highlighted. PMID- 22934774 TI - Immunoliposomes. AB - Since their discovery by Bangham about 50 years ago, liposomes have become promising tools in drug delivery systems. This has increased the therapeutic index of many drugs, and offers improved drug targeting and controlled release. In order to further improve the specificity of liposomes for malignant tissues, targeted liposomal formulations have been developed which represent the next step of liposomal drug delivery in medical treatment. Antibodies and antibody fragments are the most widely used targeting moieties for liposomes due to the high specificity for their target antigens. This has given rise to a new class of drug delivery vehicles, the so-called immunoliposomes. Immunoliposomes are generated by coupling of antibodies to the liposomal surface and allow for an active tissue targeting through binding to tumor cell-specific receptors. Such antibody modified liposomes are attracting great interest for their potential use in specific drug delivery to cancer cells, gene therapy, drug delivery through blood brain barrier, or molecular imaging. Thus far, immunoliposomes show promising results in vitro and in vivo and appear to be effective systems for improvements in cancer treatment. This review covers the literature of the past decade with special emphasis on in vitro and in vivo studies. PMID- 22934775 TI - Tandem mass spectrometry newborn screening for inborn errors of intermediary metabolism: abnormal profile interpretation. AB - Expanded newborn screening for inherited metabolic disorders using tandem mass spectrometry was introduced in 1990's and is widely used around the world. In contrast to conventional screening methods, tandem mass spectrometry does not measure single analytes but identifies and quantifies metabolite profiles; one single blood spot analyzed provides information of about 60 metabolites including amino acids, acylcarnitines and related ratios that enable the diagnosis of approximately 50 different diseases. However, the interpretation of these profiles can become quite complex. The aim of this work is to present in an easy and practical manner a comprehensive compilation of information needed for tandem mass neonatal screening profile interpretation, and basic actions for immediate follow up of abnormal results, including the tests that are required for confirmatory purposes. Other conditions not attributable to metabolic disorders which can lead to an abnormal profile of these markers are also described as well as a series of general recommendations which would be useful for health professionals who are beginning newborn screening for inborn errors of intermediary metabolism using tandem mass spectrometry. PMID- 22934776 TI - Transdermal drug delivery in vitro using diffusion cells. AB - The assessment of percutaneous absorption of molecules is a very important step in the evaluation of any dermal or transdermal drug delivery system. In order to perform percutaneous drug absorption studies, it is essential that the methods are standardized and that the integrity of the skin is monitored and maintained to ensure that the data obtained are valid and relevant. Reproducible data on percutaneous absorption in humans are as well required to predict the systemic risk from dermal exposure to chemicals, such as hazardous substances at the workplace, agrochemicals and cosmetic ingredients. In vitro and animal models provide important tools for screening a series of drug formulations, evaluation of skin permeation enhancing properties and mechanism of action of the carrier systems and estimation of rank of skin transport for a series of drug molecules. In this review, we have summarized in vitro testing of skin absorption using static Franz-type diffusion cells. PMID- 22934777 TI - A novel u-opioid receptor ligand with high in vitro and in vivo agonist efficacy. AB - The aims of this study were to synthesize 14-O-Methylmorphine-6-O-sulfate (14-O MeM6SU) and examine its opioid properties (potency, affinity, efficacy) in receptor ligand binding and isolated tissues (mouse vas deferens, MVD and rat vas deferens, RVD bioassays). The results were then compared to the parent compounds morphine-6-O-sulfate (M6SU) and morphine, as well as the ?- opioid receptor (MOR) selective agonist peptide [D-Ala2,N-Me-Phe4,Gly-ol5]enkephalin (DAMGO). An additional objective was to compare the effect of subcutaneously (s.c.) or intracerebroventricularly (i.c.v.) administered 14-O-MeM6SU, M6SU and morphine in thermal nociception, rat tail-flick (RTF) test. In MVD, the EC50 (nM) value was 4.38 for 14-O-MeM6SU, 102.81 for M6SU, 346.63 for morphine and 238.47 for DAMGO. The effect of 14-O-MeM6SU and DAMGO was antagonized by naloxone (NAL) with Ke value 1-2.00 nM. The Emax values (%) were 99.10, 36.87, 42.51 and 96.99 for 14-O MeM6SU, M6SU, morphine and DAMGO, respectively. In RVD 14-O-MeM6SU and DAMGO but not M6SU or morphine showed agonist activity. In binding experiments the affinity of 14-OMeM6SU, M6SU, morphine and DAMGO for MOR was 1.12, 11.48, 4.37 and 3.24 nM, respectively. The selectivity of 14-O-MeM6SU was kappa/MU= 269 and delta/MU= 9. In G-protein activation experiments, 14-O-MeM6SU and DAMGO showed higher Emax values than M6SU or morphine. S.c. or i.c.v-injected 14-O-MeM6SU, M6SU and morphine produced a dose and time-dependent increase in RTF response latency. 14 O-MeM6SU was the most potent. Our results showed that introduction of 14-O-Me in M6SU increased the binding affinity, agonist potency, and most importantly, the intrinsic efficacy (Emax). PMID- 22934778 TI - Protocatechuic acid alkyl esters: hydrophobicity as a determinant factor for inhibition of NADPH oxidase. AB - This study presents the increased efficiency of NADPH oxidase inhibition produced by esterification of protocatechuic acid (P0). Alkyl esters bearing chain lengths of 4 (P4), 7 (P7) and 10 (P10) carbons were synthesized and their oxidation potential, hydrophobicity, antiradical activity, inhibition of superoxide anion (O2 degrees (-)), and the abilities to affect hypochlorous acid (HOCl) production by leukocytes and inhibit myeloperoxidase (MPO) chlorinating activity were studied. The increased hydrophobicity (logP, 0.81-4.82) of the esters was not correlated with a significant alteration in their oxidation potential (0.222 0.298 V). However, except for P10, the esters were ~ 2-fold more effective than the acid precursor for the scavenging of DPPH and peroxyl radicals. The esters were strong inhibitors of O2 degrees (-) released by activated neutrophils (PMNs) and peripheral blood mononuclear cells (PBMCs). A correlation was found between the carbon chain length and the relative inhibitory potency. P7, the most active ester, was ~ 10-fold more efficient as NADPH oxidase inhibitor than apocynin. The esters strongly inhibited the release of HOCl by PMNs, which was a consequence of the inhibition of NADPH oxidase activity in these cells. In conclusion, as effective inhibitors of NADPH oxidase, the esters of protocatechuic acid are promising drugs for treatment of chronic inflammatory diseases. Moreover, this is the first demonstration that, besides the redox active moiety, the hydrophobicity can also be a determinant factor for the design of NADPH oxidase inhibitors. PMID- 22934779 TI - Medicinal chemistry of drugs with active metabolites (N-, O-, and S-desalkylation and some specific oxidative alterations). AB - Metabolic fate plays an important role in the elimination of drugs and other foreign compounds from the body. Metabolism through various enzyme systems, makes the parent compound more hydrophilic, thus, it can be readily excreted from the body. Some active metabolites of drugs are produced following N-, O-, and S desalkylation. These metabolites are either more or less potent, or as potent as their parent drugs. The removal of alkyl groups from tertiary aliphatic and acyclic amines is carried out by hepatic cytochrome P450 mixed-function oxidase enzymes. Several drugs undergo this process, which yields free hydroxyl-, or amino-groups, in addition to aldehyde from the splitted alkyl group. Metabolism of drugs into clinically active compounds indicates an extra target of therapeutic drug monitoring. Numerical data of logP values show how lipophilicity changes through metabolism to facilitate excretion. The example of phenacetin - paracetamol opened up a way for improving pharmacological effect by the use of a metabolite. This review gives a detailed description of these drugs, their active and major metabolites found in humans or animals, metabolizing cytochrome P450s, and the most recent analytical methods for their determination. PMID- 22934780 TI - Socializing, networking and development: a report from the second 'Young Microbiologists Symposium on Microbe Signalling, Organization and Pathogenesis'. AB - In mid-June, the second Young Microbiologists Symposium took place under the broad title of 'Microbe signalling, organization and pathogenesis' on the picturesque campus of University College Cork, Ireland. The symposium attracted 150 microbiologists from 15 different countries. The key feature of this meeting was that it was specifically aimed at providing a platform for junior scientists to present their work to a broad audience. The meeting was principally supported by Science Foundation Ireland with further backing from the Society for General Microbiology, the American Society for Microbiology and the European Molecular Biology Organization. Sessions focused on microbial gene expression, biogenesis, pathogenicity and host interaction. In this MicroMeeting report, we highlight some of the most significant advances and exciting developments reported during various talks and poster presentations given by the young and talented microbiologists. PMID- 22934781 TI - Assessing group differences in biodiversity by simultaneously testing a user defined selection of diversity indices. AB - Comparing diversities between groups is a task biologists are frequently faced with, for example in ecological field trials or when dealing with metagenomics data. However, researchers often waver about which measure of diversity to choose as there is a multitude of approaches available. As Jost (2008, Molecular Ecology, 17, 4015) has pointed out, widely used measures such as the Shannon or Simpson index have undesirable properties which make them hard to compare and interpret. Many of the problems associated with the use of these 'raw' indices can be corrected by transforming them into 'true' diversity measures. We introduce a technique that allows the comparison of two or more groups of observations and simultaneously tests a user-defined selection of a number of 'true' diversity measures. This procedure yields multiplicity-adjusted P-values according to the method of Westfall and Young (1993, Resampling-Based Multiple Testing: Examples and Methods for p-Value Adjustment, 49, 941), which ensures that the rate of false positives (type I error) does not rise when the number of groups and/or diversity indices is extended. Software is available in the R package 'simboot'. PMID- 22934783 TI - Melanocytic tumors of uncertain malignant potential in childhood: do we really need sentinel node biopsy? PMID- 22934782 TI - Sialidase, chondroitinase ABC, and combination therapy after spinal cord contusion injury. AB - Axon regeneration in the central nervous system is severely hampered, limiting functional recovery. This is in part because of endogenous axon regeneration inhibitors that accumulate at the injury site. Therapeutic targeting of these inhibitors and their receptors may facilitate axon outgrowth and enhance recovery. A rat model of spinal cord contusion injury was used to test the effects of two bacterial enzyme therapies that target independent axon regeneration inhibitors, sialidase (Vibrio cholerae) and chondroitinase ABC (ChABC, Proteus vulgaris). The two enzymes, individually and in combination, were infused for 2 weeks via implanted osmotic pumps to the site of a moderate thoracic spinal cord contusion injury. Sialidase was completely stable, whereas ChABC retained>30% of its activity in vivo over the 2 week infusion period. Immunohistochemistry revealed that infused sialidase acted robustly throughout the spinal cord gray and white matter, whereas ChABC activity was more intense superficially. Sialidase treatment alone resulted in improved behavioral and anatomical outcomes. Rats treated exclusively with sialidase showed significantly increased hindlimb motor function, evidenced by higher Basso Beattie and Bresnahan (BBB) and BBB subscores, and fewer stepping errors on a horizontal ladder. Sialidase-treated rats also had increased serotonergic axons caudal to the injury. ChABC treatment, in contrast, did not enhance functional recovery or alter axon numbers after moderate spinal cord contusion injury, and dampened the response of sialidase in the dual enzyme treatment group. We conclude that sialidase infusion enhanced recovery from spinal cord contusion injury, and that combining sialidase with ChABC failed to improve outcomes. PMID- 22934784 TI - Can hearing puter activate pupil? Phonological competition and the processing of reduced spoken words in spontaneous conversations. AB - In listeners' daily communicative exchanges, they most often hear casual speech, in which words are often produced with fewer segments, rather than the careful speech used in most psycholinguistic experiments. Three experiments examined phonological competition during the recognition of reduced forms such as [pjuter] for computer using a target-absent variant of the visual world paradigm. Listeners' eye movements were tracked upon hearing canonical and reduced forms as they looked at displays of four printed words. One of the words was phonologically similar to the canonical pronunciation of the target word, one word was similar to the reduced pronunciation, and two words served as unrelated distractors. When spoken targets were presented in isolation (Experiment 1) and in sentential contexts (Experiment 2), competition was modulated as a function of the target word form. When reduced targets were presented in sentential contexts, listeners were probabilistically more likely to first fixate reduced-form competitors before shifting their eye gaze to canonical-form competitors. Experiment 3, in which the original /p/ from [pjuter] was replaced with a "real" onset /p/, showed an effect of cross-splicing in the late time window. We conjecture that these results fit best with the notion that speech reductions initially activate competitors that are similar to the phonological surface form of the reduction, but that listeners nevertheless can exploit fine phonetic detail to reconstruct strongly reduced forms to their canonical counterparts. PMID- 22934785 TI - Cd2+ complexation with P(CH2OH)3, OP(CH2OH)3, and (HOCH2)2PO2(-): coordination in solution and coordination polymers. AB - The coordination of Cd(2+) with P(CH(2)OH)(3) (THP) in methanol was followed by (31)P and (111)Cd NMR techniques. A cadmium-to-phosphine coordination ratio of 1:3 has been established, and effective kinetic parameters have been calculated. Air oxidation of THP in the presence of CdCl(2) at room temperature produces coordination polymer (3)(infinity)[Cd(3)Cl(6)(OP(CH(2)OH)(3))(2)] (1). The same oxidation reaction at 70 degrees C gives another coordination polymer, (infinity)[CdCl(2)(OP(CH(2)OH)(3))] (2). Complexes 1 and 2 are the first structurally characterized complexes featuring OP(CH(2)OH)(3) as a ligand that acts as a linker between Cd atoms. The addition of NaBPh(4) to the reaction mixture gives coordination polymer (infinity)[Na(2)CdCl(2)(O(2)P(CH(2)OH)(2))(2)(H(2)O)(3)] (3) with (HOCH(2))(2)PO(2)(-) as the ligand. Coordination polymers 1-3 have been characterized by X-ray analysis, elemental analysis, and IR spectroscopy. PMID- 22934786 TI - Expansion of interferon-gamma-secreting HIV-specific T cells during successful antiretroviral therapy. AB - OBJECTIVES: Antiretroviral therapy (ART) suppresses HIV viraemia, thereby reducing the antigenic drive for T cells to proliferate. Accordingly, selected HIV-specific T-cell responses have been described to contract within weeks of ART initiation. Here, we sought to investigate whether these findings apply to the entire repertoire of HIV-specific T cells. METHODS: Using interferon (IFN)-gamma enzyme linked immuno spot (ELISpot), we performed retrospective 2-year proteome wide monitoring of HIV-specific T cells in 17 individuals with undetectable viral loads during ART. The sample pool for each study subject consisted of one pre-ART time-point and at least two time-points after initiation of therapy. RESULTS: Peripheral pools of HIV-specific T cells decreased nonsignificantly within the first 2 years under ART in our cohort of patients, in terms of both breadth and magnitude. However, in most cases, the seeming decrease masked ongoing expansion of individual HIV-specific T-cell responses. We detected synchronous contraction and expansion of T-cell responses - with different peptide specificities - in 12 out of 17 study participants during follow-up. Importantly, the observed expansions and contractions of individual HIV-specific T-cell responses reached similar ranges, supporting the biological relevance of our findings. CONCLUSIONS: We conclude that successful ART enables both contraction and expansion of HIV specific T-cell responses. Our results should prompt a renewed interest in HIV specific T-cell dynamics under ART, in particular to elucidate the mechanisms that uncouple, to some extent, particular HIV-specific T-cell responses from variations in circulating antigen load and functionally characterize expanding/contracting T-cell populations beyond IFN-gamma secretion. Assuming that expanding HIV-specific T-cell responses under ART are protective and functional, harnessing those mechanisms may provide novel opportunities for assisting viral control in chronically infected individuals. PMID- 22934788 TI - Molecular modeling studies of the structural, electronic, and UV absorption properties of benzophenone derivatives. AB - Benzophenone derivatives (BZP), an important class of organic UV filters, are widely used in sunscreen products due to their ability to absorb in the UVA and UVB ranges. The structural, electronic, and spectral properties of BZP derivatives have been studied by density functional theory (DFT) and time dependent DFT (TD-DFT) methods. DFT/B3LYP with the 6-31G(d) basis set is an accurate method for optimizing the geometry of BZPs. The absorption maxima obtained from the TD-DFT calculations in a vacuum were in agreement with the experimental absorption bands and showed that the main electronic transitions in the UVA/UVB range present pi -> pi* character, the major transition being HOMO -> LUMO. The oscillator strength seems to increase in the presence of disubstitution at the para position. For protic substituents, the position appears to be related to the absorption band. Absorption in the UVB range occurs in the presence of para substitution, whereas ortho substitution leads to absorption in the UVA spectral region. The obtained results provide some features for BZP derivatives that can be useful for customizing absorption properties (wavelengths and intensities) and designing new BZP derivatives as sunscreens. PMID- 22934787 TI - Mycophenolic acid glucuronide is transported by multidrug resistance-associated protein 2 and this transport is not inhibited by cyclosporine, tacrolimus or sirolimus. AB - 1. The purpose of this study was to investigate the contribution of MRP2 to the efflux of mycophenolic acid (MPA), and its phenyl glucuronide (MPAG) and acyl glucuronide (AcMPAG) metabolites, using Madin-Darby canine kidney II cells stably transfected with human MRP2 gene (MDCKII/MRP2 cells). 2. Compared to parental MDCKII cells, MPAG was significantly translocated from basolateral (BL) to apical (AP) side in MDCKII/MRP2 cells, indicating MPAG is a substrate for MRP2. AcMPAG is highly translocated from BL to AP side in both cells, suggesting that AcMPAG is actively secreted possibly through an efflux transporter other than MRP2. Appreciable translocation of MPA was not observed in MDCKII/MRP2 cells. 3. Furthermore, using MRP2-expressing Sf9 membrane vesicles, the Michaelis-Menten constant (Km) value for MRP2-mediated MPAG transport was calculated at 224.2 +/- 42.7 uM. In the vesicle system, cyclosporine, tacrolimus and sirolimus did not inhibit the uptake of MPAG via MRP2. 4. These findings indicate that only MPAG not MPA and AcMPAG is a substrate for MRP2 and that the interaction between MPAG and concomitantly administered immunosuppressive agents does not occur at MRP2 level. PMID- 22934789 TI - Unraveling the physics of vertical organic field effect transistors through nanoscale engineering of a self-assembled transparent electrode. AB - While organic transistors' performances are continually pushed to achieve lower power consumption, higher working frequencies, and higher current densities, a new type of organic transistors characterized by a vertical architecture offers a radically different design approach to outperform its traditional counterparts. Naturally, the distinct vertical architecture gives way to different governing physical ground rules and structural key features such as the need for an embedded transparent electrode. In this paper, we make use of a zero-frequency electric field-transparent patterned electrode produced through block-copolymer self-assembly based lithography to control the performances of the vertical organic field effect transistor (VOFET) and to study its governing physical mechanisms. Unlike other VOFET structures, this design, involving well-defined electrode architecture, is fully tractable, allowing for detailed modeling, analysis, and optimization. We provide for the first time a complete account of the physics underpinning the VOFET operation, considering two complementary mechanisms: the virtual contact formation (Schottky barrier lowering) and the induced potential barrier (solid-state triode-like shielding). We demonstrate how each mechanism, separately, accounts for the link between controllable nanoscale structural modifications in the patterned electrode and the VOFET performances. For example, the ON/OFF current ratio increases by up to 2 orders of magnitude when the perforations aspect ratio (height/width) decreases from ~0.2 to ~0.1. The patterned electrode is demonstrated to be not only penetrable to zero frequency electric fields but also transparent in the visible spectrum, featuring uniformity, spike-free structure, material diversity, amenability with flexible surfaces, low sheet resistance (20-2000 Omega sq(-1)) and high transparency (60 90%). The excellent layer transparency of the patterned electrode and the VOFET's exceptional electrical performances make them both promising elements for future transparent and/or efficient organic electronics. PMID- 22934790 TI - Inhibitory effects of SA4503 on the rewarding effects of abused drugs. AB - Previous findings have shown that sigma-1 receptors (Sig-1Rs) are upregulated by the self-administration of methamphetamine, whereas Sig-1R antisense can attenuate the behavioral effects of psychostimulants in rodents. Sig-1R is an endoplasmic reticulum chaperone protein. However, the effects of Sig-1R agonist on the rewarding effects of abused drugs are not fully understood. Therefore, we examined the effects of selective Sig-1R agonists, such as SA4503 and (+) pentazocine, on the rewarding effects of abused drugs such as methamphetamine, cocaine and morphine in rats, as measured by the conditioned place preference. Methamphetamine, cocaine and morphine induced a significant place preference. SA4503, but not (+)-pentazocine, significantly attenuated the abused drug-induced place preference. We recently showed that (+)-pentazocine exerts U50,488H-like discriminative stimulus effects, which are related to its psychotomimetic/aversive effects. However, SA4503 did not generalize to the discriminative stimulus effects of U50,488H. These results suggest that SA4503 inhibits the rewarding effects of abused drugs, and that psychotomimetic/aversive effects may not play a role in the attenuating effects of SA4503 on the rewarding effects of abused drugs. PMID- 22934791 TI - Disappearance of superconductivity in the solid solution between (Ca4Al2O6)(Fe2As2) and (Ca4Al2O6)(Fe2P2) superconductors. AB - The effect of alloying the two perovskite-type iron-based superconductors (Ca(4)Al(2)O(6))(Fe(2)As(2)) and (Ca(4)Al(2)O(6))(Fe(2)P(2)) was examined. While the two stoichiometric compounds possess relatively high T(c)'s of 28 and 17 K, respectively, their solid solutions of the form (Ca(4)Al(2)O(6))(Fe(2)(As(1 x)P(x))(2)) do not show superconductivity over a wide range from x = 0.50 to 0.95. The resultant phase diagram is thus completely different from those of other typical iron-based superconductors such as BaFe(2)(As,P)(2) and LaFe(As,P)O, in which superconductivity shows up when P is substituted for As in the non-superconducting "parent" compounds. Notably, the solid solutions in the non-superconducting range exhibit resistivity anomalies at temperatures of 50-100 K. The behavior is reminiscent of the resistivity kink commonly observed in various non-superconducting parent compounds that signals the onset of antiferromagnetic/orthorhombic long-range order. The similarity suggests that the suppression of the superconductivity in the present case also has a magnetic and/or structural origin. PMID- 22934792 TI - Electronic health record surveillance algorithms facilitate the detection of transfusion-related pulmonary complications. AB - BACKGROUND: Transfusion-related acute lung injury (TRALI) and transfusion associated circulatory overload (TACO) are leading causes of transfusion-related mortality. Notably, poor syndrome recognition and underreporting likely result in an underestimate of their true attributable burden. We aimed to develop accurate electronic health record-based screening algorithms for improved detection of TRALI/transfused acute lung injury (ALI) and TACO. STUDY DESIGN AND METHODS: This was a retrospective observational study. The study cohort, identified from a previous National Institutes of Health-sponsored prospective investigation, included 223 transfused patients with TRALI, transfused ALI, TACO, or complication-free controls. Optimal case detection algorithms were identified using classification and regression tree (CART) analyses. Algorithm performance was evaluated with sensitivities, specificities, likelihood ratios, and overall misclassification rates. RESULTS: For TRALI/transfused ALI detection, CART analysis achieved a sensitivity and specificity of 83.9% (95% confidence interval [CI], 74.4%-90.4%) and 89.7% (95% CI, 80.3%-95.2%), respectively. For TACO, the sensitivity and specificity were 86.5% (95% CI, 73.6%-94.0%) and 92.3% (95% CI, 83.4%-96.8%), respectively. Reduced PaO2 /FiO2 ratios and the acquisition of posttransfusion chest radiographs were the primary determinants of case versus control status for both syndromes. Of true-positive cases identified using the screening algorithms (TRALI/transfused ALI, n = 78; TACO, n = 45), only 11 (14.1%) and five (11.1%) were reported to the blood bank by physicians, respectively. CONCLUSIONS: Electronic screening algorithms have shown good sensitivity and specificity for identifying patients with TRALI/transfused ALI and TACO at our institution. This supports the notion that active electronic surveillance may improve case identification, thereby providing a more accurate understanding of TRALI/transfused ALI and TACO epidemiology. PMID- 22934793 TI - Attomolar determination of coumaphos by electrochemical displacement immunoassay coupled with oligonucleotide sensing. AB - Coumaphos, an organophosphorus pesticide (OP) used worldwide, has raised serious public concerns due to its positive association with major types of cancer. Herein, a novel method for attomolar coumaphos detection was developed on the basis of an electrochemical displacement immunoassay coupled with oligonucleotide sensing. An optimized displacement immunoassay was constructed to improve the binding efficiency of an antigen-antibody pair, and a guanine-rich single-strand DNA label, in combination with oligonucleotide sensing, was used to amplify the detection signal with "direct" relationship to the analyte. As a result, coumaphos was sensitively determined from the enhanced catalytic cycle of guanine Ru(bpy)(3)(2+) by chronoamperometry. The limit of detection (LOD) was down to 0.18 ng L(-1) (S/N = 3), which is equal to 49.6 amol in a sample solution of 100 MUL. In comparison with conventional methods, the proposed method has the lowest LOD and better accessibility to high-throughput sensing systems. Besides, it can complete the whole analysis process in under 50 min and exhibits good performance of excellent selectivity to the OPs. With regard to the advantages of rapidity, convenience, low cost, and ease of operation, the proposed method has provided a promising platform capable of fast and in-field OP detection, which may make the system promising for potential applications in the detection of other small molecules. PMID- 22934795 TI - Safety and efficacy of catheter directed thrombolysis in children with deep venous thrombosis. PMID- 22934794 TI - Association of CD14-260 polymorphisms, red-complex periodontopathogens and gingival crevicular fluid cytokine levels with cyclosporine A-induced gingival overgrowth in renal transplant patients. AB - BACKGROUD AND OBJECTIVE: Genetic factors may influence the colonization of pathogenic bacteria, therefore increasing the risk for the initiation and development of periodontal disease. The present study was carried out to investigate the association of CD14-260 polymorphisms, subgingival microbiota, and gingival crevicular fluid (GCF) cytokine levels with cyclosporine A (CsA) induced gingival overgrowth (GO) in renal transplant patients. MATERIAL AND METHODS: A total of 204 patients were dichotomized into two groups: 124 with GO and 80 without GO. The CD14-260 polymorphisms were measured using an allele specific PCR method. The levels of periodontal pathogens were determined by real time PCR of subgingival samples. GCF levels of IL-1beta and sCD14 were detected by ELISA. RESULTS: The frequency of CD14-260 genotype CT + TT was found to be similar in both groups. Patients with GO presented increased prevalence of Pg, Td, and Tf (red complex) and significantly higher levels of interleukin -1beta than those without GO. Patients with GO carrying CT + TT genotypes were found to have higher frequencies of Pg, Td, and Tf than those carrying the CC genotype. Furthermore, in the presence of red complex, CT + TT genotypes were associated with higher interleukin -1beta levels and severe GO. Multiple logistic regression analysis demonstrated that the severity of GO is not dependent on age, gender and pharmacological variables, being only associated with CD14-260 genotype and red complex periodontopathogens. CONCLUSION: No association between CD14-260 polymorphisms and the prevalence of GO was revealed in renal transplant patients administered CsA. However, CD14-260 CT + TT genotypes are associated with the prevalence of red complex periodontopathogens in patients with GO, and may thus play some role in the development of severe CsA-induced GO. PMID- 22934796 TI - Interferon-free hepatitis C therapy: how close are we? AB - Two oral direct-acting antivirals (DAA) are now available for the treatment of chronic hepatitis C infection and several generations of DAA are in development. Expectations are that, at some time in the near future, hepatitis C will be 'curable' with an all-oral DAA regimen. This article reviews the current problems associated with interferon-based hepatitis C treatments that are combined with DAAs, including adverse events and complications of therapy, contraindications, drug-drug interactions and cost. The article further discusses difficulties with new drug development and provides an opinion on the research issues still to be dealt with and the requirements for the successful implementation of such a strategy. These include lack of efficacy in certain populations, unexpected side effects, antiviral resistance, late relapse, lack of cooperation between drug developers and cost. PMID- 22934798 TI - Vibrating perception threshold and body mass index are associated with abnormal foot plantar pressure in type 2 diabetes outpatients. AB - AIMS: This study investigated the influencing factors of foot plantar pressure and attempted to find practical indicators to predict abnormal foot pressure in patients with type 2 diabetes mellitus (T2DM). SUBJECTS AND METHODS: Vibration perception threshold (VPT) and foot plantar pressure in 1,126 T2DM outpatients were examined. Patients were assigned to Group A (n=599), Group B (n=312), and Group C (n=215) according to VPT values and to Group I (n=555), Group II (n=436), and Group III (n=135) based on body mass index (BMI). The clinical characteristics and pressure-time integral (PTI) were compared among the three groups, and the associated factors of the total PTI in the entire foot (T-PTI) were analyzed. RESULTS: PTI of Group C in heel medial and heel lateral was significantly higher than that of Group A (all P<0.01). PTI of Group B in the right fifth metatarsal and heel medial was significantly higher than that of Group A (all P<0.05). T-PTI of Group C was significantly higher than those of Groups A and B, and that of Group B was higher than that of Group A (all P<0.01). PTI of Groups II and III in the second, third, and fourth metatarsal, midfoot, heel medial, and heel lateral was significantly higher than that of Group I (all P<0.05). T-PTI of Groups II and III was significantly higher than that of Group I (all P<0.01). Pearson correlation analysis showed that T-PTI was positively associated with age, VPT, waist circumference, waist-to-hip ratio, and BMI (P<0.05). In multiple stepwise regression analysis, VPT (P=0.004) and BMI (P=0.000) were independent risk factors of T-PTI, and each 1 unit increase in BMI increased the T-PTI by 5.962 kPa*s. Receiver operator characteristic curve analysis further revealed that the optimal cutpoint of VPT and BMI to predict the abnormal PTI was 21 V (odds ratio=2.33, 95% confidence interval 1.67-3.25) and 24.9 kg/m(2) (odds ratio=2.12, 95% confidence interval 1.55-2.90), respectively. CONCLUSIONS: Having a VPT higher than 21 V and a BMI above 24.9 kg/m(2) increases the risk of excessive foot plantar pressure in Chinese T2DM. PMID- 22934799 TI - Can continuous glucose monitoring systems predict glycemia? AB - BACKGROUND: We investigated whether the arrow on a continuous glucose monitoring system (CGMS) screen predicts the course of the capillary glucose level 15 min later. SUBJECTS AND METHODS: Twenty-three patients with type 1 diabetes (age, 40+/-13 years; diabetes duration, 19+/-12 years; hemoglobin A1c, 8.5+/-1.5%) admitted for education in the use of a CGMS performed 242 observations: the arrow was noted at time 0, and the interstitial and capillary glucose levels were noted at time 0 and 15 min later. RESULTS: The capillary glucose courses were -15+/-28 mg/dL after a descending arrow (n=55), +1+/-23 mg/dL after a stable arrow (n=147) (P<0.001 vs. descending), and +2+/-23 mg/dL after an ascending arrow (n=40) (P<0.01 vs. descending), with similar findings for the 67 observations after an interstitial glucose level <100 mg/dL. There were 4.5% grossly erroneous arrows: six descending with later increasing and five ascending with later decreasing capillary glucose. CONCLUSIONS: Although there is a large room for improvement, the arrow on the CGMS screen does predict the decline in capillary glucose 15 min later. PMID- 22934797 TI - Thrombolytic therapy for acute ischaemic stroke: what can we do to improve outcomes? AB - Constant efforts are being made in the stroke community to aim for maximum benefit from thrombolytic therapy since the approval of intravenous recombinant tissue plasminogen activator (rt-PA; alteplase) for the management of acute ischaemic stroke. However, fear of symptomatic haemorrhage secondary to thrombolytic therapy has been a major concern for treating physicians. Certain imaging and clinical variables may help guide the clinician towards better treatment decision making. Aggressive management of some predictive variables that have been shown to be surrogate outcome measures has been related to better clinical outcomes. Achieving faster, safer and complete recanalization with evolving endovascular techniques is routinely practiced to achieve better clinical outcomes. Selection of an 'ideal candidate' for thrombolysis can maximize functional outcomes in these patients. Although speed and safety are the key factors in acute management of stroke patients, there must also be a systematic and organized pattern to assist the stroke physician in making decisions to select the 'ideal candidate' for treatment to maximize results. PMID- 22934800 TI - Electroencephalography to assess motor control during balance tasks in people with diabetes. AB - BACKGROUND: Balance is sensed through peripheral and central receptors and mediated by central control through the brain and spinal cord. Although some evidence exists as to the areas of the brain involved and how processing of data occurs in young individuals, nothing has been published on people with diabetes. The purpose of this study was to examine the electroencephalogram (EEG) during common sensorimotor and balance training tasks and to relate these to task difficulty. SUBJECTS AND METHODS: Postural sway and EEG change of alpha, beta, and sigma wave bands were measured in 17 young subjects, 10 older subjects, and 10 subjects with diabetes during eight progressively more difficult balance tasks with eyes open and closed, feet in tandem or apart, and on foam or a firm surface. RESULTS: EEG power of beta and sigma wave bands showed significant increases on the cortical and parietal areas of the brain relative to the control tasks when eyes were open (P<0.05). The cortical involvement decreased as the task became more difficult with vision and somatosensory information reduced, whereas that of the parietal area increased with task difficulty. The greatest increase was in subjects with diabetes, and the least was in younger people. Individuals with diabetes had increased sigma and beta EEG power in all regions of the brain examined with increased complexity of the balance task. CONCLUSIONS: This study demonstrated cortical and parietal involvement in static balance tasks commonly used in sensorimotor training. The results support the proposal that there was increased subcortical control with increase in task difficulty in the young subjects, but in subjects with diabetes, there was a major increase in activity across the brain. PMID- 22934801 TI - Inner strength in relation to perceived physical and mental health among the oldest old people with chronic illness. AB - OBJECTIVES: The aim of this study was to examine inner strength, defined as connectedness, firmness, flexibility, and creativity, and its relation to mental and physical health in a sample of the oldest old chronically ill women and men living at home. METHODS: A sample of 79 older women and 41 men in the age range of 80-101 years old (mean = 87.5) participated in this study. Inner strength measured by Resilience Scale, Sense of Coherence Scale (SOC), Purpose in Life Test (PIL), and Self-Transcendence Test (STS) was viewed in relation to mental and physical health (SF-36 Health Survey). RESULTS: Experiencing connectedness, firmness, flexibility, and creativity were equal for women and men. SOC, PIL, and STS showed moderate inner strength. Medium and low resilience made the participants feel vulnerable. A significant correlation was observed between the variables for inner strength and mental health for women, men, and the total sample. STS was associated with mental and physical health for the total sample and for women. CONCLUSIONS: Although the oldest old women and men were vulnerable, they had inner strength. Encouraging participation using the inner strength of the oldest old can contribute to strengthen their experiences of independence, integrity, and enjoying life. PMID- 22934802 TI - Genomic signatures of divergent selection and speciation patterns in a 'natural experiment', the young parallel radiations of Nicaraguan crater lake cichlid fishes. AB - Divergent selection is the main driving force in sympatric ecological speciation and may also play a strong role in divergence between allopatric populations. Characterizing the genome-wide impact of divergent selection often constitutes a first step in unravelling the genetic bases underlying adaptation and ecological speciation. The Midas cichlid fish (Amphilophus citrinellus) species complex in Nicaragua is a powerful system for studying evolutionary processes. Independent colonizations of isolated young crater lakes by Midas cichlid populations from the older and great lakes of Nicaragua resulted in the repeated evolution of adaptive radiations by intralacustrine sympatric speciation. In this study we performed genome scans on two repeated radiations of crater lake species and their great lake source populations (1030 polymorphic AFLPs, n ~ 30 individuals per species). We detected regions under divergent selection (0.3% in the crater lake Xiloa flock and 1.7% in the older crater lake Apoyo radiation) that might be responsible for the sympatric diversifications. We find no evidence that the same genomic regions have been involved in the repeated evolution of parallel adaptations across crater lake flocks. However, there is some genetic parallelism apparent (seven out of 51 crater lake to great lake outlier loci are shared; 13.7%) that is associated with the allopatric divergence of both crater lake flocks. Interestingly, our results suggest that the number of outlier loci involved in sympatric and allopatric divergence increases over time. A phylogeny based on the AFLP data clearly supports the monophyly of both crater lake species flocks and indicates a parallel branching order with a primary split along the limnetic-benthic axis in both radiations. PMID- 22934803 TI - Following the cognitive work analysis train of thought: exploring the constraints of modal shift to rail transport. AB - Environmental concerns show that transport is responsible for almost a quarter of all greenhouse gas emissions, and it is also the fastest growing sector. Modal shift towards public transport could help slow down, or even reverse, this trend. There appear to be a number of constraints that are preventing this from happening. This paper explores the constraints to modal shift to rail transport from the perspective of cognitive work analysis, specifically the abstraction hierarchy, the contextual activity template and social organisational and cooperation analyses. Whilst these analyses may not present any new barriers, they do show how the constraints are interlinked in an explicit manner. These interrelations are important for two reasons. First, in consideration of constraint removal, one must anticipate the likely effects on the remainder of the system. Second, by linking functions and situations, new concepts of travel may be identified and explored. PRACTITIONER SUMMARY: The purpose of this study was to use a semi-structured approach to identifying constraints to modal shift from a variety of perspectives. It is argued that cognitive work analysis offers a new way of thinking about the modal shift problem and helps to generate new insights into potential solutions. PMID- 22934805 TI - Quantifying altered long-term potentiation in the CA1 hippocampus. AB - Long-term potentiation (LTP) of synaptic transmission is a widely accepted model of learning and memory. In vitro brain slice techniques were used to investigate the effects of cortical-spreading depression and picrotoxin, an antagonist of the gamma-aminobutyric acid A (GABA(A)) receptor, on the tetanus-induced long-term potentiation of field excitatory postsynaptic potentials. Cortical-spreading depression is involved in glutamate desensitization; on the other hand, GABA(A) antagonists could increase postsynaptic excitability. This study shows that picrotoxin effectively induced long-term potentiation with 142.25 +/- 4.18% of the baseline in the picrotoxin group (n = 8) versus 134.36 +/- 2.35% of the baseline in the control group (n = 10). In group with picrotoxin applied to CSD, we obtained the smallest magnitude of LTP (120.15 +/- 3.73% of the baseline, n = 8). These results suggest that picrotoxin could increase hippocampal activity and LTP; on the contrary, CSD reduced LTP magnitude. In addition, the results also suggest that the decay rate of post-tetanic potentiation has a direct relationship with LTP. Moreover, data were interpreted by nonlinear least squares quantifying, and LTP could also be quantified. The nonlinear attribute of LTP had an influence on the fitting, with respect to increasing the accuracy of the parameters and the compatibility of combination of stimuli that produce LTP. PMID- 22934806 TI - Sentence comprehension following moderate closed head injury in adults. AB - The current study explores sentence comprehension impairments among adults following moderate closed head injury. It was hypothesized that if the factor of syntactic complexity significantly affects sentence comprehension in these patients, it would testify to the existence of syntactic processing deficit along with working-memory problems. Thirty-six adults (18 closed head injury patients and 18 healthy controls matched in age, gender, and IQ) participated in the study. A picture-sentence matching task together with various tests for memory, language, and reading abilities were used to explore whether sentence comprehension impairments exist as a result of a deficit in syntactic processing or of working-memory dysfunction. Results indicate significant impairment in sentence comprehension among adults with closed head injury compared with their non-head-injured peers. Results also reveal that closed head injury patients demonstrate considerable decline in working memory, short-term memory, and semantic knowledge. Analysis of the results shows that memory impairment and syntactic complexity contribute significantly to sentence comprehension difficulties in closed head injury patients. At the same time, the presentation mode (spoken or written language) was found to have no effect on comprehension among adults with closed head injury, and their reading abilities appear to be relatively intact. PMID- 22934804 TI - Surfing biological surfaces: exploiting the nucleoid for partition and transport in bacteria. AB - The ParA family of ATPases is responsible for transporting bacterial chromosomes, plasmids and large protein machineries. ParAs pattern the nucleoid in vivo, but how patterning functions or is exploited in transport is of considerable debate. Here we discuss the process of self-organization into patterns on the bacterial nucleoid and explore how it relates to the molecular mechanism of ParA action. We review ParA-mediated DNA partition as a general mechanism of how ATP-driven protein gradients on biological surfaces can result in spatial organization on a mesoscale. We also discuss how the nucleoid acts as a formidable diffusion barrier for large bodies in the cell, and make the case that the ParA family evolved to overcome the barrier by exploiting the nucleoid as a matrix for movement. PMID- 22934807 TI - Development of mitotane lipid nanocarriers and enantiomers: two-in-one solution to efficiently treat adreno-cortical carcinoma. AB - Adrenocortical carcinoma (ACC) is a rare but aggressive malignancy with a poor prognosis. Treatment options for advanced ACC are limited. Indeed, radical tumor resection can lead to local or metastatic recurrence, and mitotane (Lysodren((r))), the only recognized adrenolytic drug, offers modest response rates, notably due to some of its physico-chemical and pharmacological properties (i.e. hydrophobicity, low bioavailability). Meantime, high cumulative doses of Lysodren((r)) usually cause systemic toxicities. To reduce adverse health effects, the search of safe and efficient mitotane nano-formulations as well as the full characterization and testing of its enantiomers can represent valuable therapeutic options. Interestingly, recent investigations showed that solid lipid nanoparticles (SLN) and nanostructured lipid carriers (NLC) could considerably improve the efficacy of mitotane (i.e. enhanced solubility and bioavailability, progressive release of the loaded drug into blood and targeted tissues) as well as its safety (i.e. lower toxicity, higher biocompatibility). These two nano carriers for mitotane delivery and targeting are of particular interest over other polymeric particles (i.e. low-cost, efficient and simple scaling to an industrial production level following green methods). Besides, emerging studies suggested that the S-(-)- mitotane is more potent than the R-(+)-mitotane for ACC treatment. Therefore, the production of pure and active S-(-)-mitotane might offer synergic or additive benefits for ACC patients when combined to solid lipid based nanocarriers. In this review, we first provide an updated overview of the ACC disease before emphasizing on the promising mitotane drug nano-systems, as well as on the separation, purification and production of single mitotane enantiomer using state-of-art chromatographic-based methods. PMID- 22934808 TI - Yersinia pestis and approaches to targeting its outer protein H protein-tyrosine phosphatase (YopH). AB - Plague is an infectious disease with a high mortality rate that has repeatedly impacted human society. It remains a threat in many parts of the world today. Plague is caused by the bacterium, Yersinia pestis (Y. pestis), which has as one of its required virulence factors, the protein-tyrosine phosphatase, YopH. Therefore, YopH represents a potential target for the treatment of Y. pestis infection. Recent recognition of Y. pestis as a possible bioterrorism agent and the fact that it is still the cause of endemic disease around the world make it an important object of study and heighten the need for new anti-plague agents. The current review covers aspects of plague and its historical occurrence and summarizes approaches to developing YopH inhibitors. PMID- 22934809 TI - Therapeutic potential of cholesteryl O-acyl alpha-glucoside found in Helicobacter pylori. AB - Steryl glycosides are derivatives of sterols where the 3beta-hydroxy group is glycosylated. Some of them are further converted to steryl O-acyl glycosides. Steryl glycosides and their derivatives are widely distributed in plants, algae, and fungi, but are relatively rarely distributed in bacteria and animals. Accumulating evidence suggests that glycosylation of sterols not only modifies physicochemical properties of cell membranes but also alters immunogenicity of the cells. Helicobacter pylori, that colonizes the stomach and causes gastric diseases, is auxotrophic for cholesterol, so that it extracts this lipid from plasma membranes of epithelial cells of the host stomach. Since incorporation of cholesterol promotes immune responses of the host, Helicobacter pylori converts cholesterol to cholesteryl glucoside (ChG) and then to cholesteryl 6'-O-acyl glucoside (ChAcG) to evade the immune surveillance. We have found that ChAcG thus produced is specifically recognized by invariant Valpha14-Jalpha18 TCR(+) (Valpha14) NKT cells in a CD1-dependent manner. We have also found that activation of Valpha14 NKT cells by administration of ChAcG retains homeostasis of immunity upon exposure to allergens and reduces the incidence of allergy. In this article, overview of immunological functions of steryl glycosides with an emphasis on the immunoregulatory functions of ChAcG, is demonstrated. PMID- 22934810 TI - Development of polyphenols as HIV-1 integrase inhibitors: a summary and perspective. AB - Raltegravir, the only drug targeting the integration step in HIV-1 life cycle, makes beta-ketoenol integrase (IN) strand transfer inhibitor (STI) gain a definitive place in the treatment of HIV-1 infection. However, the emergence of viral strains resistant to beta-ketoenol STI demands a continued effort toward the discovery of novel IN inhibitors interfering with HIV-1 IN in a mechanistically different manner. Polyphenols, among the most developed IN inhibitors, exhibit a different mechanism of action compared with beta-ketoenol STI. Some of them exhibit strong IN inhibitory activity and anti-viral activity at nanomolar level and 1,5-DCQA has been in phase II clinical trial in China. It is undoubted that this kind of compounds are attractive candidates for future inhibitor design, as they should be effective against STI resistant viral strains and display synergistic effect when combined with the current existing STI. However, almost all reviews about IN inhibitors have been focused on beta ketoenol STI, while the thorough evolution and general structure-activity relationship (SAR) summaries of polyphenols as IN inhibitors had never been specially discussed. In this review, we provide a comprehensive report of the nearly twenty years development of polyphenols as IN inhibitors: summarizing general SAR and suggesting the orientation for further research. Compilation of such data will prove beneficial in developing a novel generation of IN inhibitors. PMID- 22934811 TI - The HIV-1 non-nucleoside reverse transcriptase inhibitors (part V): capravirine and its analogues. AB - Capravirine (S-1153, AG1549), a 1,2,4,5-tetrasubstituted imidazole derivative, was firstly reported by the Shionogi company to inhibit HIV-1 strains which were resistant to other NNRTIs. However, safety and efficacy studies showed that capravirine had no specific advantages over currently used NNRTIs. Consequently, clinical trials were discontinued after phase IIb. Notwithstanding, with aim to obtain novel inhibitors against drug-resistant HIV-1 strains, an in-depth analysis of the particular binding mode of capravirine, together with the wide use of analogue-based chemical evolution strategies, such as bioisosteric replacement, molecular hybridization, prodrug approach, ligand efficiency, etc., gave a huge impetus to the optimization of capravirine. Especially, lersivirine (UK-453,061) was selected for further clinical evaluation due to its very impressive potency against a broad panel of key HIV-1 mutants, safety, pharmacokinetics and other pharmaceutical factors. In this review, we present a comprehensive survey of the literature on the development of capravirine-based NNRTIs. Other interesting NNRTIs with the same or similar binding mode like capravirine have been reported to highlight the structural diversity, pharmacophoric similarity of NNRTIs, which provided important hints for drug design. PMID- 22934812 TI - Transportin 1 colocalization with Fused in Sarcoma (FUS) inclusions is not characteristic for amyotrophic lateral sclerosis-FUS confirming disrupted nuclear import of mutant FUS and distinguishing it from frontotemporal lobar degeneration with FUS inclusions. AB - AIMS: Transportin 1 (TNPO 1) is an abundant component of the Fused in Sarcoma (FUS)-immunopositive inclusions seen in a subgroup of frontotemporal lobar degeneration (FTLD-FUS). TNPO 1 has been shown to bind to the C-terminal nuclear localizing signal (NLS) of FUS and mediate its nuclear import. Amyotrophic lateral sclerosis (ALS)-linked C-terminal mutants disrupt TNPO 1 binding to the NLS and impair nuclear import in cell culture. If this held true for human ALS then we predicted that FUS inclusions in patients with C-terminal FUS mutations would not colocalize with TNPO 1. METHODS: Expression of TNPO 1 and colocalization with FUS was studied in the frontal cortex of FTLD-FUS (n = 3) and brain and spinal cord of ALS-FUS (n = 3), ALS-C9orf72 (n = 3), sporadic ALS (n = 7) and controls (n = 7). Expression levels and detergent solubility of TNPO 1 was measured by Western blot. RESULTS: Aggregates of TNPO 1 were abundant and colocalized with FUS inclusions in the cortex of all FTLD-FUS cases. In contrast, no TNPO 1-positive aggregates or FUS colocalization was evident in two-thirds, ALS-FUS cases and was rare in one ALS-FUS case. Nor were they present in C9orf72 or sporadic ALS. No increase in the levels of TNPO 1 was seen in Western blots of spinal cord tissues from all ALS cases compared with controls. CONCLUSIONS: These findings confirm that C-terminal FUS mutations prevent TNPO 1 binding to the NLS, inhibiting nuclear import and promoting cytoplasmic aggregation. The presence of TNPO 1 in wild-type FUS aggregates in FTLD-FUS distinguishes the two pathologies and implicates different disease mechanisms. PMID- 22934813 TI - International collaboration in primary care: a win-win situation. PMID- 22934816 TI - Working for more and better primary care in the Baltic Sea Region. PMID- 22934817 TI - Evaluation of general practitioners' assessment of overweight among children attending the five-year preventive child health examination: a cross-sectional survey. AB - OBJECTIVE: To evaluate general practitioners' (GPs') assessment of potential overweight among children attending the five-year preventive child health examination (PCHE) by comparing their assessment of the children's weight-for stature with overweight defined by body mass index (BMI) according to paediatric standard definitions. DESIGN: A cross-sectional survey. Data were obtained from a questionnaire survey of children's health in general and their growth in particular. SETTING: The five-year preventive child health examination (PCHE) in general practice in the Central Denmark Region. SUBJECTS: Children attending the five-year PCHE in general practice, regardless of their weight status. MAIN OUTCOME MEASURES: Paediatric standard definitions for childhood overweight based on BMI were used as the gold standard for categorizing weight-for-stature. Identification of overweight was analysed with regard to sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of the GPs' assessment of weight-for-stature. RESULTS: A total of 165 GPs conducted 1138 PCHEs. GPs assessed that 171 children had a weight-for-stature above normal. Use of the Danish Standards (DS), i.e. the Danish national growth charts for BMI, as the gold standard yielded a sensitivity of 70.1% (95% CI 62.0 77.3) and a specificity of 92.4% (95% CI 90.6-93.9). The sensitivity was influenced by the GPs' use of BMI and the presence of previous notes regarding abnormal weight development. CONCLUSION: At the five-year PCHE almost one-third of overweight children were assessed to be normal weight by GPs. Use of BMI and presence of notes on abnormal weight in medical records were positively associated with a higher identification. Hence, utilization of medical record data and BMI charts may refine GPs' assessment of childhood overweight. PMID- 22934818 TI - Segmental spinal root avulsion in the adult rat: a model to study avulsion injury pain. AB - Road traffic accidents are the most common cause of avulsion injury, in which spinal roots are torn from the spinal cord. Patients suffer from a loss of sensorimotor function, intractable spontaneous pain, and border-zone hypersensitivity. The neuropathic pains are particularly difficult to treat because the lack of a well-established animal model of avulsion injury prevents identifying the underlying mechanisms and hinders the development of efficacious drugs. This article describes a hindlimb model of avulsion injury in adult rats where the L5 dorsal and ventral spinal root are unilaterally avulsed (spinal root avulsion [SRA]), leaving the adjacent L4 spinal root intact. SRA produced a significant ipsilateral hypersensitivity to mechanical and thermal stimulation by 5 days compared with sham-operated or naive rats. This hypersensitivity is maintained for up to 60 days. No autotomy was observed and locomotor deficits were minimal. The hypersensitivity to peripheral stimuli could be temporarily ameliorated by administration of amitriptyline and carbamazepine, drugs that are currently prescribed to avulsion patients. Histological assessment of the L4 ganglion cells revealed no significant alterations in calcitonin gene-related peptide (CGRP), IB4, transient receptor potential cation channel subfamily V member 1 (TrpV1), or N52 staining across groups. Immunohistochemistry of the spinal cord revealed a localized glial response, phagocyte infiltration, and neuronal loss within the ipsilateral avulsed segment. A comparable response from glia and phagocytes was also found in the intact L4 spinal cord, supporting the role for central mechanisms within the L4-5 spinal cord in contributing to the generation of the pain-related behavior. The SRA model provides a platform to investigate possible new pharmacological treatments for avulsion injuries. PMID- 22934819 TI - Efficient display of active Geotrichum sp. lipase on Pichia pastoris cell wall and its application as a whole-cell biocatalyst to enrich EPA and DHA in fish oil. AB - Geotrichum sp. lipase (GSL) was first displayed on the cell wall of Pichia pastoris on the basis of the a-agglutinin anchor system developed in Saccharomyces cerevisiae . Surface display levels were monitored using Western blotting, immunofluorescence miscroscopy, and fluorescence-activated cell sorting analysis. Lipase activity of the yeast whole cells reached a maximum at 273 +/- 2.4 U/g of dry cells toward olive oil after 96 h of culture at 30 degrees C, with optimal pH and temperature at 7.5 and 45 degrees C, respectively. Displayed GSL exhibited relatively high stability between pH 6.0 and 8.0 and retained >70% of the maximum activity. The surface-displayed lipase retained 80% of its original activity after incubation at 45 degrees C for 4 h. Moreover, the GSL displaying yeast whole cells were then used as a biocatalyst to enrich eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) from fish oil on the basis of selective hydrolysis. As a result, EPA and DHA increased from 1.53 and 24.1% in the original fish oil to 1.85 and 30.86%, which were increases of 1.21- and 1.29-fold, respectively. The total yield of EPA and DHA reached 46.62%. PMID- 22934821 TI - Efficient gene expression profiling of laser-microdissected melanoma metastases. AB - Comparing the transcriptomes of primary and metastatic tumour tissues is a useful strategy for studying tumour progression. One factor limiting the interpretation of tissue-based transcriptomic data is the lack of cell-type purity. Laser capture microdissection (LCM) has been shown to be useful for overcoming this limitation. We established an efficient protocol for gene expression profiling of LCM and matched metastatic melanomas using a transgenic mouse model. This optimized workflow combines microsurgical recovery of mouse lungs, appropriate tissue freezing, laser microdissection of homogeneous tumour cell populations from cryosections, isolation of high-quality RNA and gene expression analysis. The RNA isolated from laser-microdissected material was not contaminated by stroma cells, was of excellent quality, and the synthesis of cDNAs was homogeneous and highly reproducible. Subsequent custom-based Taqman-low-density array (TLDA)-based gene expression profiling identified stronger expression of five genes (M-MITF, TYR, STAT3, CCND1 and PAX3) in primary than metastatic melanoma. We detected only minor transcriptomic differences between primary and metastatic melanoma tissue. This optimized workflow could be very valuable for various studies requiring cell type-specific transcriptomic analysis. PMID- 22934820 TI - Has testing been normalized? An analysis of changes in barriers to HIV testing among men who have sex with men between 2000 and 2010 in Scotland, UK. AB - OBJECTIVES: This paper examines changes in barriers to HIV testing amongst gay men. We compared data collected in 2000 and 2010 to assess changes in HIV testing behaviours, in community-level perceptions of barriers to HIV testing, and in the relative contributions of barrier measures. METHODS: Cross-sectional surveys were conducted within the commercial gay scene in Glasgow with good response rates (78% and 62%) using a form of time and location sampling. RESULTS: Major changes in HIV testing behaviours were observed between 2000 and 2010 (30.6% increase in testing within previous year). At the community level, the perceived benefits of testing [t (1284) = -8.46; P < 0.001] and the norm for HIV testing [t (1236) = 11.62; P < 0.001] increased; however, other perceived barriers did not change (fear of a positive result, clinic-related barriers and attitudes to sex with HIV positive men). Multinomial logistic regression showed that fear of a positive test result remained a key barrier to HIV testing; however, a significant fear * year of survey interaction indicated that fear played a lesser role in differentiating those who had never been tested from those who had been tested in 2010 than it had in 2000. CONCLUSIONS: These findings suggest the partial normalization of HIV testing. While some barriers have reduced, other key barriers remain important. Interventions should be designed and evaluated that attend to both the biomedical and the psychosocial aspects of HIV testing (e.g. the meaning of positive test results, the sexual exclusion of positive men, and HIV-related stigma). PMID- 22934822 TI - Reductive elimination of alkylamines from low-valent, alkylpalladium(II) amido complexes. AB - A series of three-coordinate norbornylpalladium amido complexes ligated by bulky N-heterocyclic carbene (NHC) ligands were prepared that undergo reductive eliminations to form the alkyl-nitrogen bond of alkylamine products. The rates of reductive elimination reveal that complexes containing more-electron-donating amido groups react faster than those with less-electron-donating amido groups, and complexes containing more-sterically bulky amido groups undergo reductive elimination more slowly than complexes containing less-sterically bulky amido groups. Complexes ligated by more-electron-donating ancillary NHC ligands undergo reductive elimination faster than complexes ligated by less-electron-donating NHC ligands. In contrast to the reductive elimination of benzylamines from bisphosphine-ligated palladium amides, these reactions occur with retention of configuration at the alkyl group, indicating that these reductive eliminations proceed by a concerted pathway. The experimentally determined free energy barrier of 26 kcal/mol is close to the computed free energy barrier of 23.9 kcal/mol (363 K) for a concerted reductive elimination from the isolated, three-coordinate NHC ligated palladium anilido complex. PMID- 22934823 TI - Probing the electronic structures and properties of neutral and charged monomethylated arsenic species (CH3As(n)((-1,0,+1)), n = 1-7) using Gaussian-3 theory. AB - The structures and energies of neutral and charged monomethylated arsenic species CH(3)As(n)((-1,0,+1)) (n = 1-7) have been systematically investigated with the Gaussian-3 (G3) method. The ground-state structures of monomethylated arsenic species including the neutrals and the ions are vertex-methylated type. The lowest-energy structures of neutral methylated arsenic species and their ions can be viewed as being derived from corresponding to neutral and ionic arsenic clusters, respectively. The reliable electron affinities and ionization potentials of CH(3)As(n) have been evaluated. And there are odd-even alternations in both electron affinities and ionization potentials as a function of size of CH(3)As(n). The dissociation energies of CH(3) from neutral CH(3)As(n) and their ions have been calculated to examine relative stabilities. The results characterized the odd-numbered neutral CH(3)As(n) as more stable than the even numbered systems, and the even-numbered cationic CH(3)As(n)(+) as more stable than the odd-numbered species with the exception of n = 1. The dissociation energy of CH(3)As(+) is the maximum among all of these values. There are no odd even alternations for anionic CH(3)As(n)(-) with n <= 7. PMID- 22934825 TI - Identification of source-sink dynamics in mountain lions of the Great Basin. AB - Natural and anthropogenic boundaries have been shown to affect population dynamics and population structure for many species with movement patterns at the landscape level. Understanding population boundaries and movement rates in the field for species that are cryptic and occur at low densities is often extremely difficult and logistically prohibitive; however genetic techniques may offer insights that have previously been unattainable. We analysed thirteen microsatellite loci for 739 mountain lions (Puma concolor) using muscle tissue samples from individuals in the Great Basin throughout Nevada and the Sierra Nevada mountain range to test the hypothesis that heterogeneous hunting pressure results in source-sink dynamics at the landscape scale. We used a combination of non-spatial and spatial model-based Bayesian clustering methods to identify genetic populations. We then used a recently developed Bayesian multilocus genotyping method to estimate asymmetrical rates of contemporary movement between those subpopulations and to identify source and sink populations. We identified two populations at the highest level of genetic structuring with a total of five subpopulations in the Great Basin of Nevada and the Sierra Nevada range. Our results suggest that source-sink dynamics occur at landscape scales for wide ranging species, such as mountain lions, and that source populations may be those that are under relatively less hunting pressure and that occupy refugia. PMID- 22934824 TI - Host cell cytotoxicity and cytoskeleton disruption by CerADPr, an ADP ribosyltransferase of Bacillus cereus G9241. AB - Bacillus cereus G9241 was isolated from a welder suffering from an anthrax-like inhalation illness. B. cereus G9241 encodes two megaplasmids, pBCXO1 and pBC210, which are analogous to the toxin- and capsule-encoding virulence plasmids of Bacillus anthracis. Protein modeling predicted that the pBC210 LF homologue contained an ADP-ribosyltransferase (ADPr) domain. This putative bacterial ADP ribosyltransferase domain was denoted CerADPr. Iterative modeling showed that CerADPr possessed several conserved ADP-ribosyltransferase features, including an alpha-3 helix, an ADP-ribosyltransferase turn-turn loop, and a "Gln-XXX-Glu" motif. CerADPr ADP-ribosylated an ~120 kDa protein in HeLa cell lysates and intact cells. EGFP-CerADPr rounded HeLa cells, elicited cytoskeletal changes, and yielded a cytotoxic phenotype, indicating that CerADPr disrupts cytoskeletal signaling. CerADPr(E431D) did not possess ADP-ribosyltransferase or NAD glycohydrolase activities and did not elicit a phenotype in HeLa cells, implicating Glu431 as a catalytic residue. These experiments identify CerADPr as a cytotoxic ADP-ribosyltransferase that disrupts the host cytoskeleton. PMID- 22934826 TI - Drosophila mauve mutants reveal a role of LYST homologs late in the maturation of phagosomes and autophagosomes. AB - Chediak-Higashi syndrome (CHS) is a lethal disease caused by mutations that inactivate the lysosomal trafficking regulator protein (LYST). Patients suffer from diverse symptoms including oculocutaneous albinism, recurrent infections, neutropenia and progressive neurodegeneration. These defects have been traced back to over-sized lysosomes and lysosome-related organelles (LROs) in different cell types. Here, we explore mutants in the Drosophila mauve gene as a new model system for CHS. The mauve gene (CG42863) encodes a large BEACH domain protein of 3535 amino acids similar to LYST. This reflects a functional homology between these proteins as mauve mutants also display enlarged LROs, such as pigment granules. This Drosophila model also replicates the enhanced susceptibility to infections and we show a defect in the cellular immune response. Early stages of phagocytosis proceed normally in mauve mutant hemocytes but, unlike in wild type, late phagosomes fuse and generate large vacuoles containing many bacteria. Autophagy is similarly affected in mauve fat bodies as starvation-induced autophagosomes grow beyond their normal size. Together these data suggest a model in which Mauve functions to restrict homotypic fusion of different pre-lysosomal organelles and LROs. PMID- 22934827 TI - Downstream processing of lentiviral vectors: releasing bottlenecks. AB - Lentiviral vectors (LVs) hold great potential as gene delivery vehicles. However, the manufacturing and purification of these vectors still present major challenges, mainly because of the low stability of the virus, essentially due to the fragility of the membrane envelope. The main goal of this work was the establishment of a fast, scalable, and robust downstream protocol for LVs, combining microfiltration, anion-exchange, and ultrafiltration membrane technologies toward maximization of infectious LVs recovery. CIM((r)) (Convective Interaction Media) monolithic columns with diethylaminoethanol (DEAE) anion exchangers were used for the purification of clarified LV supernatants, allowing infectious vector recoveries of 80%, which is 10% higher than the values currently reported in the literature. These recoveries, combined with the results obtained after optimization of the remaining downstream purification steps, resulted in overall infectious LV yields of 36%. Moreover, the inclusion of a Benzonase step allowed a removal of approximately 99% of DNA impurities. The entire downstream processing strategy herein described was conceived based on disposable and easily scalable technologies. Overall, CIM DEAE columns have shown to be a good alternative for the purification of LVs, since they allow faster processing of the viral bulks and enhanced preservation of virus biological activity, consequently, increasing infectious vector recoveries. PMID- 22934829 TI - Biotin-streptavidin cross-bridging: a novel and feasible approach for targeting transplanted cells to damaged tissue. AB - BACKGROUND: Accumulating evidence indicates the positive impact of endothelium derived cell therapy in vascular repair. However, low cell transplantation efficiency inevitably and greatly reduces the treatment efficacy of cell transplants. PURPOSE: To modify the surfaces of cells with polypeptides or small molecule proteins that specifically recognize and bind to damaged tissue. METHODS: We used a biotin-streptavidin binding approach to attach annexin V, which recognizes apoptotic cells, onto bEnd.3 cells that express vascular endothelial growth factor receptor 2 (VEGFR2) and verified that the modified cells could efficiently bind to dead cells in vitro. RESULTS: We analyzed biotinylated VEGFR2-bEnd.3 cells, streptavidin-biotinylated VEGFR2-bEnd.3 cells, and biotinylated annexin V-streptavidin-biotinylated VEGFR2-bEnd.3 cells. Our results from flow cytometry analysis and immunofluorescent examination demonstrated that we successfully labeled the cells in a three-step process. Furthermore, we determined that the positive binding rate correlated with reagent concentration. Immunofluorescent examination illustrated that adding the biotinylated annexin V-streptavidin-biotinylated VEGFR2-bEnd.3 cells to dead cells led to the clustering and aggregation of the modified cells and the dead cells. CONCLUSIONS: Annexin V can be attached to bEnd.3 cells using a biotin streptavidin binding approach, and the modified cells can specifically recognize and bind to dead cells. PMID- 22934828 TI - Restricted transgene expression in the brain with cell-type specific neuronal promoters. AB - Tissue-targeted expression is of major interest for studying the contribution of cellular subpopulations to neurodegenerative diseases. However, in vivo methods to investigate this issue are limited. Here, we report an analysis of the cell specificity of expression of fluorescent reporter genes driven by six neuronal promoters, with the ubiquitous phosphoglycerate kinase 1 (PGK) promoter used as a reference. Quantitative analysis of AcGFPnuc expression in the striatum and hippocampus of rodents showed that all lentiviral vectors (LV) exhibited a neuronal tropism; however, there was substantial diversity of transcriptional activity and cell-type specificity of expression. The promoters with the highest activity were those of the 67 kDa glutamic acid decarboxylase (GAD67), homeobox Dlx5/6, glutamate receptor 1 (GluR1), and preprotachykinin 1 (Tac1) genes. Neuron specific enolase (NSE) and dopaminergic receptor 1 (Drd1a) promoters showed weak activity, but the integration of an amplification system into the LV overcame this limitation. In the striatum, the expression profiles of Tac1 and Drd1a were not limited to the striatonigral pathway, whereas in the hippocampus, Drd1a and Dlx5/6 showed the expected restricted pattern of expression. Regulation of the Dlx5/6 promoter was observed in a disease condition, whereas Tac1 activity was unaffected. These vectors provide safe tools that are more selective than others available, for the administration of therapeutic molecules in the central nervous system (CNS). Nevertheless, additional characterization of regulatory elements in neuronal promoters is still required. PMID- 22934830 TI - Cytochrome P450 2A isoenzymes in freshly prepared blood lymphocytes isolated from rats and validation as a biomarker for clinical studies in humans. AB - 1. The present study aimed to identify the expression of carcinogen metabolizing cytochrome P4502A (CYP2A) isoenzymes in freshly prepared rat peripheral blood lymphocytes (PBL) isolated from adult rats and investigate similarities in the regulation of lymphocyte CYP2A-isoenzymes with the tissue enzyme. 2. qRT-PCR studies demonstrated significant constitutive mRNA expression of CYP2A-isoenzymes in PBL isolated from male and female rats which further increases significantly after pretreatment with nicotine or 3-methylcholanthrene (MC) indicating responsiveness of CYP2A-isoenzymes in PBL. This increase in the CYP2A expression was associated with an increase in the protein expression and CYP2A3-dependent coumarin hydroxylase (COH) activity in PBL. 3. Clinical studies further demonstrated significant increase in the expression of CYP2A6 and associated enzyme activity in PBL isolated from lung cancer patients. Our data thus provided evidence for similarities in the regulation of carcinogen metabolizing CYP2A isoenzymes in PBL with the tissue enzymes. Further, responsiveness of blood CYP2A6 in human blood lymphocytes isolated from lung cancer patients has led us to suggest that associating expression profiles of CYP2A6 and other polycyclic aromatic hydrocarbons (PAH)-responsive CYPs in PBL with the genotyping data could lead to the development of a possible screen to monitor and predict environment induced diseases and toxicity in humans. PMID- 22934831 TI - Loss of dentin sialophosphoprotein leads to periodontal diseases in mice. AB - BACKGROUND AND OBJECTIVE: Dentin sialophosphoprotein (DSPP) and its cleaved products, dentin phosphoprotein (DPP) and dentin sialoprotein (DSP), play important roles in biomineralization. Recently, we observed that DSPP is highly expressed in the alveolar bone and cementum, indicating that this molecule may play an important role in the formation and maintenance of a healthy periodontium, and its deletion may cause increased susceptibility to periodontal diseases. The objective of this investigation was to study the effects of Dspp ablation on periodontal tissues by analyzing Dspp null mice. MATERIAL AND METHODS: Newborn to 6-mo-old Dspp null mice were examined, and the 3- and 6-mo old Dspp null mice were characterized in detail using X-ray radiography, histology and scanning electron microscopy (backscattered as well as resin infiltrating). Wild-type mice of the same age groups served as the normal controls. RESULTS: The Dspp null mice showed significant loss of alveolar bone and cementum, particularly in the furcation and interproximal regions of the molars. The alveolar bone appeared porous while the quantity of cementum was reduced in the apical region. The canalicular systems and osteocytes in the alveolar bone were abnormal, with reduced numbers of canaliculi and altered osteocyte morphology. The loss of alveolar bone and cementum along with the detachment of the periodontal ligaments (PDL) led to the apical migration of the epithelial attachment and formation of periodontal pockets. CONCLUSION: Inactivation of DSPP leads to the loss of alveolar bone and cementum and increased susceptibility to bacterial infections in PDL of Dspp null mice. The fact that the loss of DSPP results in periodontal diseases indicates that this molecule plays a vital role in maintaining the health of the periodontium. PMID- 22934832 TI - Acquired copy number neutral loss of heterozygosity of chromosome 7 associated with clonal haematopoiesis in a patient with Shwachman-Diamond syndrome. PMID- 22934833 TI - High-performance organic nanomembrane based sensors for rapid in situ acid detection. AB - Here, we demonstrate the fabrication, characterization, and tailoring of porous organic nanomembranes and their direct integration on inorganic substrates for sensing applications. The chemically prepared nanomembranes can be integrated on both conducting and insulating substrates by either transfer or direct synthesis. We also successfully demonstrate their use for the detection of commonly used acids including HCl, H(2)SO(4), or H(3)PO(4) and their respective counterions, chlorides, sulfates, and phosphates. Impressively, the in situ acid detection is achieved down to 5 nmol.L(-1), while the quantification is feasible between 5 MUmol.L(-1) and 10 mmol.L(-1). These values are among the lowest values reported so far in literature. Furthermore, the organic nanomembrane based sensor covers a wide concentration range of almost 8 orders of magnitude including the environmental limits currently adopted. PMID- 22934834 TI - Inhibitory mechanism of the Qbeta lysis protein A2. AB - The lysis protein A2 , present as a single copy on the surface of Qbeta virion particles, was previously shown to inhibit the activity of MurA, an enzyme that catalyses the first committed step of murein biosynthesis. Here we report experiments with a two-hybrid study that indicates A2 and MurA interact directly. Moreover, experiments with a soluble MBP-A2 fusion indicate that the interaction between MurA and A2 is dependent on a substrate-induced conformational change featured in the UDP-NAG-liganded state of MurA but not the tetrahedral intermediate state. Moreover, based on the location of L138Q, the original dominant A2 -resistant mutant that identified MurA as the target, a directed mutagenesis strategy has identified a continuous surface required for A2 binding. This surface spans the catalytic loop/cleft and encompasses both the catalytic and C-terminal domains. These data support a model in which A2 preferentially binds MurA liganded with UDP-NAG, thereby preventing catalysis by occluding PEP from accessing the active site. PMID- 22934835 TI - Green buildings need good ergonomics. AB - A retrospective post-occupancy evaluation survey of 44 occupants in two Leadership in Energy and Environmental Design (LEED) Platinum buildings on a US college campus is reported. The Internet survey covered a range of indoor environment and ergonomics issues. Results show that working in these buildings were a generally positive experience for their health, performance and satisfaction. However, in one building there were persistent issues of variability in air temperature, air freshness, air quality and noise that affected the perceived health and performance of the occupants. Although the buildings were energy-efficient and sustainable structures, ergonomics design issues were identified. Implications for the role of ergonomics in green buildings and in the US LEED rating system are discussed. PRACTITIONER SUMMARY: This survey identified a number of ergonomics design issues present in the LEED Platinum energy-efficient and sustainable buildings that were studied. These results highlight the importance of integrating ergonomics design into green buildings as a component in the US LEED rating system. PMID- 22934836 TI - Interaction of combat exposure and unit cohesion in predicting suicide-related ideation among post-deployment soldiers. AB - Suicide is one of the leading causes of death among U.S. Army soldiers. Suicide related ideation, which is associated with suicide attempts and suicide, can cause considerable distress. In a sample of 1,663 recently redeployed soldiers, we used factor analysis and structural equation modeling to test the associations between combat exposure, unit cohesion, and their interaction in predicting suicide-related ideation. We found that combat exposure was a significant risk factor for suicide-related ideation, while unit cohesion was a significant protective factor. The significant interaction between the two factors indicated that soldiers who experienced greater combat exposure but also had higher levels of unit cohesion had relatively lower levels of suicide-related ideation. In addition, those who had higher levels of combat exposure and lower unit cohesion were most at risk for suicide-related ideation. Our findings indicate the importance of unit cohesion in protecting soldiers from suicide-related ideation and suggest a higher risk group of soldiers who should be targeted for interventions. PMID- 22934839 TI - Long-term follow-up of turned single implants placed in periodontally healthy patients after 16 to 22 years: microbiologic outcome. AB - BACKGROUND: Survival rates in implant dentistry today are high, although late failures do occur for many reasons, including peri-implant infections. The primary objective of this study is to investigate microbiota around single turned implants after 16 to 22 years. Secondary objectives are to compare teeth and implants and to correlate microbiologic, radiographic, and clinical parameters. METHODS: A total of 46 patients with single implants were invited for a clinical examination. Clinical data were collected from implants and contralateral natural teeth. Radiographic bone level was measured around implants. Microbiologic samples were taken from implants, contralateral teeth, and the deepest pocket per quadrant. Samples were analyzed with DNA-DNA hybridization including 40 species. Statistical analysis was performed using Wilcoxon signed-rank tests, McNemar tests, and Spearman correlation coefficients with a 0.05 significance level. RESULTS: Mean follow-up was 18.5 years (range 16 to 22 years). Tannerella forsythia (1.5 * 10(5)) and Veillonella parvula (1.02 * 10(5)) showed the highest concentrations around implants and teeth, respectively. Porphyromonas gingivalis, Prevotella intermedia, and T. forsythia were significantly more present around implants than teeth. Mean counts were significantly higher around implants than teeth for Parvimonas micra, P. gingivalis, P. intermedia, T. forsythia, and Treponema denticola. Total DNA count was correlated to interproximal bleeding index (r = 0.409) and interproximal probing depth (r = 0.307). No correlations were present with plaque index or radiographic bone level. CONCLUSIONS: In the present study, bacterial counts around single implants in periodontally healthy patients are rather low. Although pathogenic bacteria are present, some in higher numbers around implants than teeth (five of 40), the majority of implants present with healthy peri-implant tissues without progressive bone loss. PMID- 22934837 TI - Alcohol effects on cognitive change in middle-aged and older adults. AB - OBJECTIVES: This study examines cognitive outcomes for alcohol drinking status over time, across cognitive ability and age groups. METHODS: Data (1998-2005) from n = 571 Seattle Longitudinal Study participants aged 45+years (middle-aged: 45-64, young-old: 65-75, old-old: 75+) were analyzed to examine the alcohol drinking status effect (e.g., abstinent, moderate (less than seven drinks/week), at-risk (more than eight drinks/week)) on cognitive ability (e.g., memory, reasoning, spatial, verbal number, speed abilities). RESULTS: Findings indicated that alcohol drinking status was associated with change in verbal ability, spatial ability, and perceptual speed. Decline in verbal ability was seen among alcohol abstainers and moderate alcohol consumers, but at-risk drinkers displayed relative stability. At-risk old-old adults and middle-aged adults (regardless of drinking status), displayed relative stability in spatial ability. Decline in spatial ability was however present among young-old adults across drinking status, and among abstaining and moderate drinking old-old adults. At-risk drinkers showed the most positive spatial ability trajectory. A gender effect in perceptual speed was detected, with women who abstained from drinking displaying the most decline in perceptual speed compared with women that regularly consumed alcohol, and men displaying decline in perceptual speed across drinking status. DISCUSSION: In this study, consuming alcohol is indicative of cognitive stability. This conclusion should be considered cautiously, due to study bias created from survivor effects, analyzing two time points, health/medication change status, and overrepresentation of higher socioeconomic status and white populations in this study. Future research needs to design studies that can make concrete recommendations about the relationship between drinking status and cognition. PMID- 22934838 TI - SALL4 is a key transcription regulator in normal human hematopoiesis. AB - BACKGROUND: Stem cell factor SALL4 is a zinc finger transcription factor. It plays vital roles in the maintenance of embryonic stem cell properties, functions as an oncogene in leukemia, and has been recently proposed to use for cord blood expansion. The mechanism(s) by which SALL4 functions in normal human hematopoiesis, including identification of its target genes, still need to be explored. STUDY DESIGN AND METHODS: Chromatin immunoprecipitation followed by microarray hybridization (ChIP-chip) was used for mapping SALL4 global gene targets in normal primary CD34+ cells. The results were then correlated with SALL4 functional studies in the CD34+ cells. RESULTS: More than 1000 potential SALL4 downstream target genes have been identified, and validation of binding by ChIP-quantitative polymerase chain reaction was performed for 5% of potential targets. These include genes that are involving in hematopoietic differentiation and self-renewal, such as HOXA9, RUNX1, CD34, and PTEN. Down regulation of SALL4 expression using small-hairpin RNA in these cells led to decreased in vitro myeloid colony-forming abilities and impaired in vivo engraftment. Furthermore, HOXA9 was identified to be a major SALL4 target in normal human hematopoiesis and the loss of either SALL4 or HOXA9 expression in CD34+ cells shared a similar phenotype. CONCLUSION: Taken together, SALL4 is a key regulator in normal human hematopoiesis and the mechanism of its function is at least in part through the HOXA9. Future study will determine whether modulating the SALL4/HOXA9 pathway can be used in cellular therapy such as cord blood expansion and/or myeloid engraftment. PMID- 22934840 TI - Matrix metalloproteinases, tissue inhibitors of matrix metalloproteinases, and inflammation in cyclosporine A-induced gingival enlargement: a pilot in vitro study using a three-dimensional model of the human oral mucosa. AB - BACKGROUND: It has been suggested that cyclosporine A (CsA) induces gingival enlargement by promoting an increase in the gingival extracellular matrix (ECM). Nonetheless, the variable occurrence of CsA-induced gingival enlargement in patients receiving this medication indicates a multifactorial pathogenesis. Clinical observations suggest that local inflammation is associated with the development and severity of CsA-induced gingival enlargement. Therefore, the purpose of this study is to investigate the effects of CsA and inflammation on the production of ECM homeostatic mediators. METHODS: The effects of CsA and inflammation (as assessed using interleukin [IL]-1beta) on the secretion of mediators involved in ECM homeostasis were determined using fibroblast monolayers and three-dimensional (3D) models of the human oral mucosa. Fibroblast monolayers and 3D cultures were treated with CsA alone or in combination with IL-1beta for up to 72 hours, and the secretion of matrix metalloproteinases (MMPs) 1, 2, 3, 8, 9, 10, and 13 and tissue inhibitors of MMPs (TIMPs) 1, 2, and 4 into the culture medium was assessed using enzyme-linked immunoassay-based antibody arrays. RESULTS: Fibroblast monolayers responded to CsA with no changes in the secretion of ECM mediators. Conversely, 3D cultures responded to CsA treatment with a reduction in MMP-10 secretion. IL-1beta alone triggered higher secretory levels of MMPs in both fibroblast monolayers (MMP-3 and MMP-10) and 3D cultures (MMP-9 and MMP-10). Importantly, fibroblast monolayers and 3D cultures treated with a combination of IL-1beta and CsA showed a decrease in the MMP-1/TIMP-1 ratio. CONCLUSIONS: These data support the hypothesis that inflammation may alter the pathogenesis of CsA-induced gingival enlargement by promoting a synergistic decrease in the MMP-1/TIMP-1 ratio. PMID- 22934841 TI - Neuroprotection by manganese superoxide dismutase (MnSOD) mimics: antioxidant effect and oxidative stress regulation in acute experimental stroke. AB - AIMS: Manganese superoxide dismutase (MnSOD), one of the most crucial antioxidant enzymes in the central nervous system, is thought to be one of the major mechanisms by which cells counteract the injuries of reactive oxygen species after cerebral ischemia. In this study, we used a novel synthesized compound (MnTm4PyP) with highly effective superoxide dismutase activity to study the therapeutic potential of MnSOD and the possible underlying mechanisms in cerebral ischemia. METHODS: Primary cultured cortical neurons were used to examine the protective effect of the compounds. Mice with middle cerebral artery occlusion were used as ischemic stroke animal model. Animals were pretreated with MnTm4PyP intravenously 30 min before surgery. At 24 h after surgery, neurological behavior and histological function were observed. Infarcted cortex tissues and cultured neurons were collected for investigation of the oxidative stress signaling pathways. RESULTS: In vitro studies revealed that MnSOD mimic MnTm4PyP pretreatment significantly increased viability of neurons after injury by H(2) O(2) . Intracellular superoxide radical levels were eliminated. In vivo experiments demonstrated MnTm4PyP pretreatment reduced infarct volume and improved neurological function. The MnSOD mimic alleviated oxidative stress and apoptosis. CONCLUSION: MnSOD is an effective therapeutic target in ischemic stroke prevention because of its antioxidant effects and oxidative stress regulation. PMID- 22934842 TI - Visible absorption and fluorescence spectroscopy of conformationally constrained, annulated BODIPY dyes. AB - Six conformationally restricted BODIPY dyes with fused carbocycles were synthesized to study the effect of conformational mobility on their visible electronic absorption and fluorescence properties. The symmetrically disubstituted compounds (2, 6) have bathochromically shifted absorption and fluorescence spectral maxima compared to those of the respective asymmetrically monosubstituted dyes (1, 5). Fusion of conjugation extending rings to the alpha,beta-positions of the BODIPY core is an especially effective method for the construction of boron dipyrromethene dyes absorbing and emitting at longer wavelengths. The fluorescence quantum yields Phi of dyes 1-6 are high (0.7 <= Phi <= 1.0). The experimental results are backed up by quantum chemical calculations of the lowest electronic excitations in 1, 2, 5, 6, and corresponding dyes of related chemical structure but without conformational restriction. The effect of the molecular structure on the visible absorption and fluorescence emission properties of 1-6 has been examined as a function of solvent by means of the recent, generalized treatment of the solvent effect, proposed by Catalan (J. Phys. Chem. B 2009, 113, 5951-5960). Solvent polarizability is the primary factor responsible for the small solvent-dependent shifts of the visible absorption and fluorescence emission bands of these dyes. PMID- 22934843 TI - Optical spectroscopy techniques can accurately distinguish benign and malignant renal tumours. AB - WHAT'S KNOWN ON THE SUBJECT? AND WHAT DOES THE STUDY ADD?: There is little known about optical spectroscopy techniques ability to evaluate renal tumours. This study shows for the first time the ability of Raman and optical reflectance spectroscopy to distinguish benign and malignant renal tumours in an ex vivo environment. We plan to develop this optical assistance in the operating room in the near future. OBJECTIVE: To evaluate the ability of Raman spectroscopy (RS) and optical reflectance spectroscopy (ORS) to distinguish benign and malignant renal tumours at surgery. MATERIALS AND METHODS: Between March and October 2011, RS and ORS spectra were prospectively acquired on surgical renal specimens removed for suspicion of renal cell carcinoma (RCC). Optical measurements were done immediately after surgery. Optical signals were normalised to ensure comparison between spectra. Initial and final portions of each spectrum were removed to avoid artefacts. A support vector machine (SVM) was built and tested using a leave-one-out cross-validation. Classification scores, including accuracy, sensitivity and specificity were calculated on the entire population and in patients with tumours of <4 cm. RESULTS: In all, 60 nephrectomies were performed for 53 malignant tumours (41 clear-cell, eight papillary and four chromophobe carcinomas) and seven benign tumours (four oncocytomas, two angiomyolipomas and a haemorrhagic cyst). In all, >700 optical spectra were obtained and submitted to SVM classification. The SVM could recognise benign and malignant renal tumours with an accuracy of 96% (RS) and 88% (ORS) in the whole population and with an accuracy of 93% (RS) and 95% (ORS) in the present subset of small renal tumours (<4 cm). Histological subtype could be determined in 80% and 88% of the cases with RS and ORS, respectively. The SVM was able to differentiate chromophobe carcinomas and benign lesions with an accuracy of 96% in RS and 98% in ORS. CONCLUSION: Benign and malignant renal tumours can be accurately discriminated by a combination of RS and ORS. In vivo experiments are needed to further assess the value of optical spectroscopy techniques. PMID- 22934845 TI - SIRT1 as a novel potential treatment target for vascular aging and age-related vascular diseases. AB - Aging is one of the greatest risk factors in vascular diseases (VDs). During aging, there are structural and functional changes in the vasculature, including dilated lumen, altered intimal-medial thickness (IMT), vascular stiffness, endothelial dysfunction, increased endothelial apoptosis, matrix metalloproteinase (MMP) dysregulation, increased expression of inflammatory molecules, aggravated oxidative stress and shortened telomere length. These changes leave the body more susceptible to primary hypertension, stroke and coronary artery disease. Molecules that suppress these age-related changes would provide an excellent medical intervention for VDs. Mammalian Sir2 (SIRT1, a NAD+ dependent deacetylase), previously shown to extend the lifespan of lower organisms, is a promising target molecule to influence some aspects of vascular aging. In this review, we summarized roles of SIRT1 in various pathophysiological processes of vascular aging and proposed that SIRT1 and its activators can become novel therapeutic targets for age-related VDs. PMID- 22934847 TI - Glutaminase isoenzymes as key regulators in metabolic and oxidative stress against cancer. AB - Cancer cells require a robust supply of reduced nitrogen to produce nucleotides, non-essential amino acids and a high cellular redox activity. Glutamine provides a major substrate for respiration as well as nitrogen for the production of proteins, hexosamines, and macromolecules. Therefore, glutamine is one of key molecules in cancer metabolism during cell proliferation. The notion of targeting glutamine metabolism in cancer, originally rationalized by the number of pathways fed by this nutrient, has been reinforced by more recent studies demonstrating that its metabolism is regulated by oncogenes. Glutamine can exert its effects by modulating redox homeostasis, bioenergetics, nitrogen balance or other functions, including by being a precursor of glutathione, the major nonenzymatic cellular antioxidant. Glutaminase (GA) is the first enzyme that converts glutamine to glutamate, which is in turn converted to alpha-ketoglutarate for further metabolism in the tricarboxylic acid cycle. Different GA isoforms in mammals are encoded by two genes, Gls and Gls2. As each enzymatic form of GA has distinct kinetic and molecular characteristics, it has been speculated that the differential regulation of GA isoforms may reflect distinct functions or requirements in different tissues or cell states. GA encoded by Gls gene (GLS) has been demonstrated to be regulated by oncogenes and to support tumor cell growth. GA encoded by Gls2 gene (GLS2) reduces cellular sensitivity to reactive oxygen species associated apoptosis possibly through glutathione-dependent antioxidant defense, and therefore to behave more like a tumor suppressor. Thus, modulation of GA function may be a new therapeutic target for cancer treatment. PMID- 22934846 TI - ROCK1 & 2 perform overlapping and unique roles in angiogenesis and angiosarcoma tumor progression. AB - The serine/threonine protein kinase paralogs ROCK1 & 2 have been implicated as essential modulators of angiogenesis; however their paralog-specific roles in endothelial function are unknown. shRNA knockdown of ROCK1 or 2 in endothelial cells resulted in a significant disruption of in vitro capillary network formation, cell polarization, and cell migration compared to cells harboring non targeting control shRNA plasmids. Knockdowns led to alterations in cytoskeletal dynamics due to ROCK1 & 2-mediated reductions in actin isoform expression, and ROCK2-specific reduction in myosin phosphatase and cofilin phosphorylation. Knockdowns enhanced cell survival and led to ROCK1 & 2-mediated reduction in caspase 6 and 9 cleavage, and a ROCK2-specific reduction in caspase 3 cleavage. Microarray analysis of ROCK knockdown lines revealed overlapping and unique control of global transcription by the paralogs, and a reduction in the transcriptional regulation of just under 50% of VEGF responsive genes. Finally, paralog knockdown in xenograft angiosarcoma tumors resulted in a significant reduction in tumor formation. Our data reveals that ROCK1 & 2 exhibit overlapping and unique roles in normal and dysfunctional endothelial cells, that alterations in cytoskeletal dynamics are capable of overriding mitogen activated transcription, and that therapeutic targeting of ROCK signaling may have profound impacts for targeting angiogenesis. PMID- 22934848 TI - MicroRNA targeting as a therapeutic strategy against glioma. AB - Glioblastoma multiforme (GBM), the most common and aggressive form of primary brain tumor, presents a dismal prognosis. Current standard therapies are only able to improve patient survival by a few months. The search for alternative approaches in glioblastoma treatment, together with the recent discovery of a new class of small RNA molecules that are capable of regulating gene expression, prompted a race for a deeper and thorough understanding of how these molecules work. Today, it is known that microRNAs are involved in many cellular processes that are altered in GBM tumors, such as angiogenesis, invasion, cell proliferation and apoptosis. Research in this area is now gathering efforts to translate these findings into clinically relevant therapies that could improve the diagnosis and outcome of GBM patients. In this review, we discuss the use of microRNAs as potential diagnostic, prognostic and therapeutic tools against glioblastoma. We will also assess the current challenges and future perspectives of microRNA-based therapies, with a special focus on why this promising therapeutic approach is not yet in the clinic and how to overcome this limitation. PMID- 22934849 TI - Somatostatin, somatostatin analogs and somatostatin receptor dynamics in the biology of cancer progression. AB - The pharmacological effects (i.e., inhibition of endocrine secretion and cell proliferation) mediated by the hormone somatostatin (SRIF) are derived from its universal high-affinity binding to five different G proteincoupled receptors (GPCRs), named sst1-5. However, SRIF has a half-life of less than 3 min, whereas the available mono- and bi-specific SRIF preferential analogs show prolonged half life and increased potency. These compounds may control tumor development, cell proliferation and metastatization by direct actions, including cell division arrest in G0/G1 phase (i.e., induction of cyclin-dependent kinase inhibitor p27(kip1) or p21(Cip1)), induction of apoptosis (i.e., induction of p53 and Bax) and suppression of cell invasion. Along with these direct actions on the biology of cancer progression, in vivo SRIF analogs may also regulate tumor growth through indirect actions, by suppressing the secretion of growth-promoting hormones and growth factors and angiogenesis. Interestingly, when ssts are co expressed, they may interact forming homo- or heterodimers, also with other GPCRs such as type 2 dopamine receptor and the MU-opioid receptor 1, altering their original pharmacological and functional properties. Dimers can be not only constitutive, but perhaps also ligandpromoted: hence, compounds with high affinity for different ssts isoforms may be used to achieve effects elicited by specific dimers. Future developments in the knowledge of ssts dynamics upon SRIF and SRIF analogs binding in neoplastic tissues may allow the full elucidation of the pathophysiological role of this system and the exploitation of the therapeutic potential of its modulation. PMID- 22934850 TI - Past, present and future strategies of immunotherapy in gynecological malignancies. AB - Recently, the combining of different drugs has greatly improved response and survival rates in gynecological malignancies. Results are however far from being satisfactory. Treatments used in case of advanced or recurrent disease offer limited results in terms of long-term responses. The urgent need for new and more effective treatments has prompted researchers to investigate and propose new therapeutic strategies. One of the most interesting approaches that are being explored is constituted by immunotherapy. Currently, immunotherapeutic strategies include vaccination with peptide, viral vectors, carbohydrates and antiidiotypic antibodies. In addition, cell based immunotherapy has been adopted in vitro activated lymphocytes and dendritic cells. Most experience has been acquired in ovarian cancer and cervical cancer. Little has been investigated in endometrial and rare gynecologic neoplasms.The clinical experiences and results achieved with immunotherapy in this setting of patients have been reviewed and the future avenues that are currently being explored have also been discussed. PMID- 22934851 TI - MiRNA-29: a microRNA family with tumor-suppressing and immune-modulating properties. AB - MicroRNAs (miRNAs) are ubiquitously expressed small, non-coding RNAs that negatively regulate gene expression at a post-transcriptional level. So far, over 1000 miRNAs have been identified in human cells and their diverse functions in normal cell homeostasis and many different diseases have been thoroughly investigated during the past decade. MiR-29, one of the most interesting miRNA families in humans to date, consists of three mature members miR-29a, miR-29b and miR-29c, which are encoded in two genetic clusters. Members of this family have been shown to be silenced or down-regulated in many different types of cancer and have subsequently been attributed predominantly tumor-suppressing properties, albeit exceptions have been described where miR-29s have tumor-promoting functions. MiR-29 targets expression of diverse proteins like collagens, transcription factors, methyltransferases and others, which may partake in abnormal migration, invasion or proliferation of cells and may favor development of cancer. Furthermore, members of the miR-29 family can be activated by interferon signaling, which suggests a role in the immune system and in host pathogen interactions, especially in response to viral infections. In this review, we summarize current knowledge on the genomic organization and regulation of the miR-29 family and we provide an overview of its implication in cancer suppression and promotion as well as in host immune responses. The numerous remarkable properties of these miRNAs and their often altered expression patterns might make the miR-29 family promising biomarkers and therapeutic targets for various diseases in future. PMID- 22934852 TI - Hyperglycemia, hypoglycemia and dementia: role of mitochondria and uncoupling proteins. AB - Diabetes mellitus is one of the most prevalent chronic diseases. Since glucose is the main fuel of the brain, its levels should be maintained within a narrow range to ensure normal brain function. Indeed, the literature shows that uncontrolled blood glucose levels, whether too high or too low, impact brain structure and function potentiating cognitive impairment. Uncoupling proteins (UCPs) are a family of mitochondrial anion carrier proteins located on the inner mitochondrial membrane, and their primary function is to leak protons from the intermembrane space into the mitochondrial matrix. The specific role of neuronal UCPs has been widely discussed and although there is no general agreement, there is a strong conviction that these proteins may be involved in the defense against mitochondrial reactive oxygen species (ROS) production and, consequently, protecting against oxidative damage. The generation of ROS is increasingly recognized as playing an important role in diabetes, neurodegenerative disorders and aging where mitochondria are both sources and targets of these reactive species. This review examines the neurodegenerative events associated with diabetes, highlighting the role of hyperglycemia and/or hypoglycemia on cognitive function. The role of mitochondria, neuronal UCPs and their impact in central nervous system will be elucidated. Finally, we will discuss neuronal UCPs as possible therapeutic targets for the treatment of diabetes-associated central complications and neurodegenerative diseases, namely Alzheimer's and Parkinson's diseases. PMID- 22934854 TI - Formulation and evaluation of microemulsion-based in situ ion-sensitive gelling systems for intranasal administration of curcumin. AB - The purpose of our study was to develop a microemulsion-based in situ ion sensitive gelling system for intranasal administration of curcumin. A new microemulsion composition for curcumin was optimized with the simple lattice design. And the microemulsion-based in situ ion-sensitive gelling system consisted of Capryol 90 as oil phase, Solutol HS15 as surfactant, Transcutol HP as cosurfactant and 0.3% DGG solution as water phase. The physicochemical properties such as morphology, droplet size distribution, zeta value and the in vitro release were investigated. In addition, the histological section studies on the reaction between the obtained formulation and nasal mucosa showed that the microemulsion-based in situ ion-sensitive gelling system could not produce obvious damage to nasal mucosa. The pharmacokinetics results showed that the absolute bioavailability of curcumin in the microemulsion-based in situ ion sensitive gelling system was 55.82% by intranasal administration. And the brain targeting index (BTI) was 6.50, and in the tissue distribution experiment, the value of (AUC(brain)/AUC(blood)) following intranasal administration was higher than that following intravenous administration, suggesting that the obvious brain targeting property by nasal delivery be attributed to a direct nose-to-brain drug transport. It can be concluded that the microemulsion-based in situ gelling as an effective and safe vehicle could greatly enhance the in vivo absorption and facilitate the delivery of curcumin to brain by intranasal administration. PMID- 22934853 TI - Beads-on-a-string structure of long telomeric DNAs under molecular crowding conditions. AB - The structure and stability of long telomeric DNAs, (T(2)AG(3))(n) (n = 4-20), were studied under dilute and molecular crowding conditions in the presence of Na(+) and K(+). Structural analysis showed that the long telomeric DNAs formed intramolecular G-quadruplexes under all conditions. In the presence of Na(+), the telomeric DNAs formed an antiparallel G-quadruplex under both dilute and molecular crowding conditions. However, in the presence of K(+), molecular crowding induced a conformational change from mixed to parallel. These results are consistent with numerous structural studies for G-quadruplex units under molecular crowding conditions. Thermodynamic analysis showed that G-quadruplexes under the molecular crowding conditions were obviously more stable than under dilute condition. Interestingly, this stabilization effect of molecular crowding was reduced for the longer telomeric DNAs, indicating that the G-quadruplex structure of long telomeric DNAs is not as stable under molecular crowding conditions, as implied from the large stabilization of isolated G-quadruplex units as previously reported. Moreover, a hydration study revealed that upon structure folding, the interior of a G-quadruplex unit was dehydrated, whereas the linker between two units was more hydrated. It is thus possible to propose that the linkers between G-quadruplex units are ordered structures but not random coils, which could have an important influence on the stability of the entire structure of long telomeric DNAs. These results are significant to elucidate the biological characteristics of telomeres, and can aid in the rational design of ligands and drugs targeting the telomere and related proteins. PMID- 22934855 TI - The Manley ventilator. PMID- 22934856 TI - Combined spinal-epidural (CSE) and its modifications--75 years on. PMID- 22934857 TI - Stroke volume variation as a predictor of fluid responsiveness in patients undergoing airway pressure release ventilation. AB - We investigated the effectiveness of stroke volume variation (SVV) shown by the Vigileo-FloTracTM system (Edwards Lifesciences, Irvine, CA) to predict fluid responsiveness in patients undergoing airway pressure release ventilation (APRV). All 80 patients mechanically ventilated in the intensive care unit of our hospital from April to November 2010 were included in this study. After starting APRV, Ringer's lactate solution was administered for 30 minutes. Haemodynamic variables including heart rate, mean arterial pressure, cardiac index (CI), stroke volume index (SVI) and SVV were measured before and after volume loading. SVV before volume loading was significantly correlated with absolute change in SVV (DeltaSVV) and percentage change in stroke volume index (DeltaSVI) after volume loading (DeltaSVV: P<0.05, r2=0.534; DeltaSVI: P<0.05, r2=0.217). Of the 80 patients, 38 (47.5%) were responders to intravascular volume expansion (increase in CI>=15%) and 42 (52.5%) were non-responders (increase in CI<15%). Receiver operating characteristic (ROC) curves were generated for SVV and central venous pressure by varying the discriminating threshold of the variable and areas under the ROC curves were calculated. The areas under the ROC curves were 0.793 for SVV (95% confidence interval: 0.709-0.877) and 0.442 for central venous pressure (95% confidence interval: 0.336-0.549), which were significantly different (P<0.05). The optimal threshold value of SVV to discriminate between responders and nonresponders was 14% (sensitivity: 78.9%; specificity: 64.3%). We found that SVV was able to predict fluid responsiveness in patients undergoing APRV with acceptable levels of sensitivity and specificity. PMID- 22934858 TI - Long thoracic nerve block in video-assisted thoracoscopic wedge resection for pneumothorax. AB - We hypothesised that relaxation of the serratus anterior muscle by long thoracic nerve (LTN) block could help pain relief after video-assisted thoracoscopic surgery. Patients undergoing thoracoscopic wedge resection for pneumothorax were randomly assigned to control or LTN block. LTN block was performed before induction of general anaesthesia. Pain was evaluated using a visual analogue scale before anaesthesia induction (T0), on arrival to the post-anaesthetic care unit (PACU) (T1), every ten minutes after arrival in the PACU for 30 minutes (T2, T3 and T4) and one hour and 24 hours after discharge from the PACU (T5 and T6). Visual analogue scale scores from T1 to T5 in the block group were lower than the control group (T1: 36+/-11 vs 48+/-14 [P=0001], T2: 36+/-11 vs 51+/-15 [P<0.001], T3: 35+/-vs 52+/-15 [P<0.001], T4: 30+/-7 vs 45+/-17 [P<0.001] and T5: 26+/-5 vs 32+/-5 [P<0.001]). Total intravenous patient-controlled analgesia bolus dose (alfentanil 75 ug/ml) during PACU stay (1.6+/-1.2 vs 3.9+/-2.0 ml, P<0.001) and one hour after discharge from the PACU (0.5+/-0.8 vs 1.7+/-1.2 ml, P<0.001) in the LTN group was significantly lower than the control group. Total intravenous patient-controlled analgesia bolus dose from 1-24 hours after discharge from the PACU was similar between groups (P=0197). These findings indicate that LTN block reduced pain after video-assisted thoracoscopic surgery from end-of-surgery to one hour after discharge from the PACU. PMID- 22934859 TI - Comparison between conventional and protective one-lung ventilation for ventilator-assisted thoracic surgery. AB - Recent papers suggest protective ventilation (PV) as a primary ventilation strategy during one-lung ventilation (OLV) to reduce postoperative pulmonary morbidity. However, data regarding the advantage of the PV strategy in patients with normal preoperative pulmonary function are inconsistent, especially in the case of minimally invasive thoracic surgery. Therefore we compared conventional OLV (VT 10 ml/kg, FiO2 1.0, zero PEEP) to protective OLV (VT 6 ml/kg, FiO2 0.5, PEEP 5 cmH2O) in patients with normal preoperative pulmonary function tests undergoing video-assisted thoracic surgery. Oxygenation, respiratory mechanics, plasma interleukin-6 and malondialdehyde levels were measured at baseline, 15 and 60 minutes after OLV and 15 minutes after restoration of two-lung ventilation. PaO2 and PaO2/FiO2 were higher in conventional OLV than in protective OLV (P<0.001). Interleukin-6 and malondialdehyde increased over time in both groups (P<0.05); however, the magnitudes of increase were not different between the groups. Postoperatively there were no differences in the number of patients with PaO2/FiO2<300 mmHg or abnormalities on chest radiography. Protective ventilation did not provide advantages over conventional ventilation for video-assisted thoracic surgery in this group of patients with normal lung function. PMID- 22934860 TI - Association between perioperative glucose levels and adverse outcomes in infants receiving open-heart surgery with cardiopulmonary bypass for congenital heart disease. AB - There is no consensus that hyperglycaemia is an independent predictor of morbidity-mortality in children. This retrospective observational study aimed to assess the association between abnormal perioperative glucose levels and adverse outcomes in infants receiving open-heart surgery with cardiopulmonary bypass. The records of a total of 233 infants who underwent cardiopulmonary bypass for a variety of congenital cardiac procedures between January and December 2010 were reviewed. The blood glucose levels, demographic and perioperative information were recorded. Patients who experienced complications (n=91) were compared with those who did not (n=142). We found both intraoperative and postoperative glucose levels increased compared to the preoperative values (P<0.001). Thirty patients (12.8%) experienced hyperglycaemia and 15 patients (6.4%) experienced at least one episode of hypoglycaemia during surgery. Within the first two days after surgery, 12 (5.2%) patients experienced hyperglycaemia and 32 (13.7%) became hypoglycaemic in the paediatric intensive care unit. However, the abnormal perioperative glucose levels were not associated with increased adverse outcomes. After adjusting for other potential variables, lower weight at surgery, longer surgery time and hospital length-of-stay are the independent predictors of morbidity-mortality. Our findings suggest that perioperative hyperglycaemia and mild transient hypoglycaemia do not appear to be detrimental to infants with congenital heart disease, although we did not assess neurological outcomes. Nevertheless, due to the limitations of the retrospective design of this study and its limited power, more thorough clinical randomised controlled trials are needed. PMID- 22934861 TI - Effect of preoperative education on behaviour of children during induction of anaesthesia: a randomised clinical trial of efficacy. AB - In this randomised prospective study we aimed to evaluate whether preoperative anaesthetic education delivered to children on the day of surgery reduces anxiety behaviour during induction of anaesthesia. One hundred children, six to 15 years of age, undergoing general anaesthesia for ambulatory surgery were allocated at random to a preoperative education group (n=50) or a control group (n=50). The main outcomes were behaviour score, self-reporting of satisfaction score and identification of the stage when children felt most fearful. Data from all 100 participants were analysed. There was no difference in behaviour score at induction or satisfaction score between the groups. Eighteen percent in the intervention group reported no fear preoperatively vs 10% in the control group. Intravenous induction failed in nine out of 38 children in the intervention group (23.7%) compared to five out of 40 in the control group (12.5%). When intravenous induction failed, eight out of nine (89%) of the intervention group remained co operative during gas induction compared to two out of five (40%) of the control group. Preoperative education delivered on the day of surgery did not reduce anxiety behaviour in children during intravenous induction of anaesthesia, but did reduce anxiety during subsequent inhalational induction. PMID- 22934862 TI - Mediated interruptions of anaesthesia providers using predictions of workload from anaesthesia information management system data. AB - Perioperative interruptions generated electronically from anaesthesia information management systems (AIMS) can provide useful feedback, but may adversely affect task performance if distractions occur at inopportune moments. Ideally such interruptions would occur only at times when their impact would be minimal. In this study of AIMS data, we evaluated the times of comments, drugs, fluids and periodic assessments (e.g. electrocardiogram diagnosis and train-of-four) to develop recommendations for the timing of interruptions during the intraoperative period. The 39,707 cases studied were divided into intervals between: 1) enter operating room; 2) induction; 3) intubation; 4) surgical incision; and 5) end surgery. Five-minute intervals of no documentation were determined for each case. The offsets from the start of each interval when >50% of ongoing cases had completed initial documentation were calculated (MIN50). The primary endpoint for each interval was the percentage of all cases still ongoing at MIN50. Results were that the intervals from entering the operating room to induction and from induction to intubation were unsuitable for interruptions confirming prior observational studies of anaesthesia workload. At least 13 minutes after surgical incision was the most suitable time for interruptions with 92% of cases still ongoing. Timing was minimally affected by the type of anaesthesia, surgical facility, surgical service, prone positioning or scheduled case duration. The implication of our results is that for mediated interruptions, waiting at least 13 minutes after the start of surgery is appropriate. Although we used AIMS data, operating room information system data is also suitable. PMID- 22934863 TI - Blood culture collection in patients with acute kidney injury receiving renal replacement therapy: an observational study. AB - Critically ill patients receiving renal replacement therapy (RRT) for acute kidney injury (AKI) have high reported intensive care unit (ICU) mortality. Blood culture (BC) collection practices in this population have to date been poorly characterised, specifically in regards to the influence of RRT on the clinical triggers for such an investigation. Utilising our electronic clinical information system, we conducted a retrospective observational study of patients admitted to a 30-bed tertiary level ICU and requiring RRT over a four-year period. Patients with a history of chronic kidney disease, prior RRT or ICU length-of-stay (LOS)<48 hours were excluded. Two hundred and thirty-one patients treated with RRT for AKI were identified. The observed median [interquartile range] BC collection rate in those having them drawn was 18 [11-32] per 100 patient days, although 42% of the cohort had no BC drawn during their ICU stay. Application of RRT in the 24 hours prior to initial BC collection was associated with lower body temperatures, higher white cell counts and greater use of vasopressor therapy. Bloodstream infection (identified from the first BC) was associated with greater ICU and in-hospital mortality. We also observed a predominance of candidaemia in this cohort, despite the absence of neutropenia. This study provides unique data describing BC collection rates in a cohort of critically ill patients receiving RRT for AKI and at high risk of dying. Further study of temperature alteration, detection of bloodstream infection and outcome in patients receiving RRT is now warranted. PMID- 22934864 TI - Accuracy of recorded body temperature of critically ill patients related to measurement site: a prospective observational study. AB - Accurate measurement of body temperature is an important indicator of the status of critically ill patients and is therefore essential. While axillary temperature is not considered accurate, it is still the conventional method of measurement in Asian intensive care units. There is uncertainty about the accuracy of thermometers for the critically ill. We compared the accuracy and precision of bladder, axillary and tympanic temperature measurements in critically ill patients. A total of 73 critically ill patients admitted to the intensive care unit of a teaching hospital were prospectively enrolled. Every four hours, we measured body temperature at three sites (bladder, axillary and tympanic). If the patient had received an indwelling pulmonary artery catheter, blood temperature was also recorded and this was compared with bladder, axillary and tympanic temperature readings. For all patients, axillary and tympanic temperature readings were compared with bladder temperature readings. Accuracy and precision were analysed using Bland-Altman analysis. When blood temperature data was available, the mean difference between blood and bladder temperature readings was small (0.02+/-0.21 degrees C). Compared with bladder temperature, mean difference for axillary temperature was -0.33+/-0.55 degrees C and for tympanic temperature it was -0.51+/-1.02 degrees C. For critically ill patients, recorded axillary temperature was closer to bladder temperature than tympanic temperature. PMID- 22934865 TI - Repeated intrathecal administration of ropivacaine causes neurotoxicity in rats. AB - Previous studies have shown that ropivacaine is the least neurotoxic local anaesthetic. Most of the data derive from short-term ropivacaine injection into the subarachnoid space. Intrathecal administration for a prolonged period, and the histological changes and behavioural effects of repeated intrathecal administration, have not previously been investigated. We studied the possible neurotoxicity of intrathecal injection of ropivacaine in a rat model. Rats received 0.12 ml/kg body weight of ropivacaine at concentrations of 0.5 or 1%, or normal saline only, via an implanted intrathecal catheter at 90-minute intervals for 12 hours. On days 1, 3, 5, 7, 14 and 28, the spinal cord was examined by light and electron microscopy at the L3 level. We assessed sensory thresholds to noxious stimulation, behavioural change and protein kinase B immunoreactivity for possible neuronal injury within the spinal cord. Ropivacaine 1% induced thermal hyperalgesia and mechanical allodynia, neuronal injury characterised by tissue oedema, proliferation of glial cells, neuronal morphology changes and degeneration and protein kinase B expression. There were no significant differences in motor function as a result of different concentrations of ropivacaine. Repeated intrathecal injection of ropivacaine 1% can induce neurotoxicity in rats. Our data suggests that expression of protein kinase B might be involved in this neurotoxicity. PMID- 22934866 TI - Predictors of severity in deep neck infections admitted to the intensive care unit. AB - A retrospective study was performed on adult patients admitted for surgical drainage of deep neck infections and admitted to the intensive care unit (ICU) during a period of 52 months. Severe infection was defined as septic shock/severe sepsis, mediastinitis, empyema or necrotising fasciitis. Complicated course was defined as ICU stay >8 days, reintubation, tracheostomy, renal replacement therapy, critical illness, myopathy or mortality. Chi-square or Fisher's exact test were used to assess differences and the significance level was controlled for multiple comparisons applying Bonferroni's correction. Fifty-four patients were studied. Variables associated with severe infection (43%) were abscess location (retropharyngeal [52 vs 7%; P<0.001] or multiple [52 vs 13%; P=0.002]), Acute Physiology and Chronic Health Evaluation II>7 (78 vs 13%; P<0.001), Simplified Acute Physiology Score II>29 (73 vs 21%; P<0.001) and first ICU day Sequential Organ Failure Assessment score>2 (77 vs 21%; P<0.001). Variables associated with complicated course (56%) were: parapharyngeal location (60 vs 8%; P<0.001)], Acute Physiology and Chronic Health Evaluation II>7 (67 vs 14%; P=0.001), Simplified Acute Physiology Score II>29 (62 vs 18%; P=0.002) and Sequential Organ Failure Assessment score>2 (68 vs 17%; P<0.001). Serious complications occur frequently in patients with deep neck infections surgically drained and admitted to the ICU. Higher severity scores are associated with both severe infection and a complicated course. Retropharyngeal and parapharyngeal locations are associated with severe infection and a complicated course respectively. PMID- 22934867 TI - A novel multimedia workshop on portable cardiac critical care ultrasonography: a practical option for the busy intensivist. AB - We aimed to assess the role of a short duration multimedia workshop to improve the knowledge and skills in cardiac critical care ultrasonography. Thirty critical care physicians participated in the cardiac critical care ultrasonography workshop. Two weeks prior to hands-on training, a three-hour web based didactic lecture was provided to learners. Hands-on training consisted of a two-hour examination on models without pathology and a 30-minute debriefing with instructors. Pre- and post-workshop knowledge tests were conducted online using 30 multiple choice questions. Pre- and post-workshop skill tests were video captured for evaluation by two reviewers to whom data were masked. Scores were based on 34 predetermined checklist items including learner performance, instrumentation and adequacy of ultrasound images. Learners' confidence levels on image acquisition were assessed using a ten-point Likert scale. A short duration multimedia, hands-on workshop improved intensivists' knowledge, skills and confidence levels on cardiac critical care ultrasonography image acquisition. Further studies are needed to assess the sustainability of observed improvements. This module may be a practical option for the acquisition and maintenance of cardiac critical care ultrasonography knowledge and skills. PMID- 22934868 TI - Therapeutic hypothermia following out-of-hospital cardiac arrest (OHCA): an audit of compliance at a large Australian hospital. AB - Therapeutic hypothermia (TH) is now largely considered the standard of care for patients following out-of-hospital cardiac arrest caused by ventricular arrhythmias, although the effective implementation of TH for individual patients can be challenging. This study aimed to document the effectiveness of TH when it is used at the discretion of treating physicians and not under the auspices of a research trial or protocol. A retrospective review of intensive care unit admissions over a four-year period detected 43 patients appropriate for TH. In the emergency department, only 20% of patients had TH commenced. Forty-four percent of patients required angiography in the cardiac catheterisation laboratory. It took, on average, 595 minutes for patients to reach their goal temperature, which was not reached at all in 13% of patients. Nineteen patients (44%) had a positive neurological outcome while 24 patients (56%) either died or had a poor neurological outcome. Without the control of a hospital protocol it was apparent that the implementation of TH in patients with an out-of-hospital cardiac arrest in our institution was inadequate. We recommend that TH is undertaken within the framework of a protocol that encompasses all the relevant departments. PMID- 22934869 TI - A survey of anaesthetists' understanding of Australian mandatory reporting laws. AB - Australian mandatory reporting laws for healthcare practitioners were introduced nationally in July 2010. We distributed an online survey to specialist anaesthetists and anaesthesia trainees in our institution with the aim of assessing anaesthetists' awareness, understanding and interpretation of the new laws. One hundred and three completed responses were received (response rate 67%). The majority of respondents were aware of their professional (85%) and legal (68%) reporting obligations. Respondents were most likely to report conduct relating to alcohol intoxication or sexual misconduct (75%) and least likely to report a colleague with an impairment that may be placing the public at risk of harm (12%). Consultant anaesthetists were more likely than trainees to report students (P=0.002), junior colleagues (P=0.01) and senior colleagues (P=0.03). Some anaesthetists believed the laws would deter them from seeking medical help themselves if they were impaired (39%). Mandatory reporting laws aim to improve patient safety while being fair to doctors who are reported and protecting those who report. Our survey indicates that there are differences among anaesthetists about the type of conduct they would report and their perception of the consequences of making a report. PMID- 22934870 TI - Enhanced Needle Visualization: advantages and indications of an ultrasound software package. AB - The ultrasound software package Enhanced Needle Visualization (ENV) has been reported to provide improved ultrasound imaging of needles even at steep insertion angles. ENV has three settings: shallow, medium and steep. However, the angles are unknown. We examined the advantages and indications of ENV in an in vitro study. A 22-gauge needle was inserted into pork meat using the in-plane technique. The needle was positioned at zero, 30, 45 and 60 degree angles, and 1, 2, 3 and 4 cm in-depth from the probe. The ultrasound visibility in each ENV setting was objectively evaluated and graded as 'not visible', 'poor', 'visible', 'good' and 'excellent' in ascending order. At zero degrees we found no advantage of ENV. At 30 degrees, the needle exhibited better visibility with 'good' or above grade in the shallow setting at all depths and in the medium setting at depths of 1, 2 and 3 cm than in the off position. At 45 degrees, needle visibility significantly increased from 'not visible' in the off position to 'visible' or above in the steep settings at depths of 1, 2 and 3 cm. At 60 degrees the objective visibility was 'not visible' in the off position and significantly increased to 'poor' in the steep setting. We recommend selecting the shallow setting for needles with an insertion angle of 30 degrees and the steep setting for 45 degrees within the advantageous area. This technique may allow safer ultrasound procedures for various unprecedented approaches. PMID- 22934871 TI - Anaphylaxis to muscle relaxants: an audit of ten years of allergy testing at the Royal Adelaide Hospital. AB - We audited patients with anaphylaxis to muscle relaxants during anaesthesia referred to the Department of Anaesthesia at the Royal Adelaide Hospital between the start of 2000 and the end of 2009. Of the 220 patients tested during this period, 43 had a positive intradermal test to the muscle relaxant given during their anaesthetic. The majority of these were to rocuronium and suxamethonium. Where rocuronium was the index agent, 65% of patients cross-reacted with another relaxant and 29% of patients with suxamethonium as their index agent demonstrated cross-reaction with another relaxant. PMID- 22934872 TI - Contribution of morphine and morphine-6-glucuronide to respiratory depression in a child. AB - A morphine plasma concentration/respiratory rate relationship has been described for both adults and children although that of its metabolite, morphine-6 glucuronide, remains uncertain. We describe this relationship in a child with end stage renal failure who received repeat morphine administration over two days. An EMAX model for additive morphine and morphine-6-glucuronide respiratory effects described respiratory rate better than models describing either alone. Failure to clear morphine-6-glucuronide renally led to respiratory depression episodes occurring later than those predicted by modelling morphine levels only. These findings support the use of alternative analgesics (e.g. fentanyl) that are cleared by non-renal pathways and have no active metabolites in patients with end stage renal disease. PMID- 22934873 TI - The tyranny of distance: telemedicine for the critically ill in rural Australia. AB - A case of severe sepsis with multi-organ failure needing complex support was deemed too ill for transfer to a major centre. Telemedicine allowed direct patient review, collaborative advice and collegial support with maintained healthcare standards while avoiding long distance transfer from his home and family. PMID- 22934874 TI - Anaesthesia for neonatal circumcision. PMID- 22934876 TI - Unusual cause of airway obstruction associated with the reinforced endotracheal tube in a prone patient. PMID- 22934877 TI - Bradycardia and hypertension: an unusual presentation of an intravascular epidural test dose during combined spinal and epidural anaesthesia. PMID- 22934878 TI - Combination therapy with high-frequency oscillatory ventilation, neuromuscular blockade, inhaled nitric oxide and prone position in acute respiratory distress syndrome with refractory hypoxaemia. PMID- 22934879 TI - Surgical stress increases circulating endothelial microparticles in the elderly. PMID- 22934880 TI - Serum lactate dehydrogenase as an early marker of posterior reversible encephalopathy syndrome. PMID- 22934881 TI - Use of combination of rocuronium and sugammadex in heart transplant recipients. PMID- 22934882 TI - Acute life-threatening airway obstruction with pseudomembrane formation after percutaneous dilational tracheostomy. PMID- 22934883 TI - Influence of major cardiopulmonary surgery on serum levels of procalcitonin and other inflammatory markers. AB - Procalcitonin is a marker of significant bacterial infection. With Food and Drug Administration approval of a new high-sensitive procalcitonin assay in the United States, we felt it would be important to assess its normal elevation and time characteristics, as compared to other inflammatory markers in patients undergoing routine cardiac surgery. This is a prospective observational study including consecutive patients after routine cardiac surgery. Blood was sampled preoperatively, immediately postoperatively and daily until discharge or to postoperative day five for measurement of blood markers of infection. Patients were classified into different groups based on the type of surgery (on-pump and off-pump) and progression of recovery (complicated and uncomplicated). Patients after coronary artery bypass grafting off-pump (n=61) had significantly lower mean (0.90 vs 1.13 ug/l, P=0.006) and peak (2.09 vs 2.35 ug/l, P=0.002) procalcitonin levels in the postoperative course compared to patients with either on-pump valve surgery alone, on-pump coronary artery bypass grafting alone (n=28) or valve surgery with coronary artery bypass grafting (n=16). In addition, mean and peak procalcitonin levels were significantly higher (P=0.004 and P=0.002 respectively) in the 60 patients with a complicated course. This study provides insights into 'normal' kinetics of a new high-sensitive procalcitonin assay after different types of cardiac surgery, and in patients with and without a complicated postoperative course. Our results suggest that using a single procalcitonin level to guide antibiotic therapy decisions during the early period after major cardiac surgery may not be useful and that monitoring its kinetic may be the preferred strategy. PMID- 22934884 TI - Impaired emotional processing in a patient with a left posterior insula-SII lesion. AB - The present case-report investigated the influence of a lesion in the left posterior insula-SII cortices on the processing of emotions. MB and 16 normal controls explicitly rated the valence and the intensity of both facial expressions and emotional words. In addition, they had to perform a number comparison task and a lexical decision task without focusing their attention on emotional components of stimuli. MB identified the valence of emotional words as well as the control group. Nevertheless, she provided higher intensity scores for disgusted words and her responses in the lexical decision task were significantly delayed for these stimuli. In addition, MB's response times were not differently influenced by the presence of irrelevant emotional faces. However, she explicitly identified fewer facial expressions of disgust and she assessed them as significantly less intense. This pattern of results contributes to highlight the psychological and behavioral disorders observed after a left posterior insular stroke. PMID- 22934885 TI - Ultimate detectability of volatile organic compounds: how much further can we reduce their ambient air sample volumes for analysis? AB - To understand the ultimately lowest detection range of volatile organic compounds (VOCs) in air, application of a high sensitivity analytical system was investigated by coupling thermal desorption (TD) technique with gas chromatography (GC) and time-of-flight (TOF) mass spectrometry (MS). The performance of the TD-GC/TOF MS system was evaluated using liquid standards of 19 target VOCs prepared in the range of 35 pg to 2.79 ng per MUL. Studies were carried out using both total ion chromatogram (TIC) and extracted ion chromatogram (EIC) mode. EIC mode was used for calibration to reduce background and to improve signal-to-noise. The detectability of 19 target VOCs, if assessed in terms of method detection limit (MDL, per US EPA definition) and limit of detection (LOD), averaged 5.90 pg and 0.122 pg, respectively, with the mean coefficient of correlation (R(2)) of 0.9975. The minimum quantifiable mass of target analytes, when determined using real air samples by the TD-GC/TOF MS, is highly comparable to the detection limits determined experimentally by standard. In fact, volumes for the actual detection of the major aromatic VOCs like benzene, toluene, and xylene (BTX) in ambient air samples were as low as 1.0 mL in the 0.11-2.25 ppb range. It was thus possible to demonstrate that most target compounds including those in low abundance could be reliably quantified at concentrations down to 0.1 ppb at sample volumes of less than 10 mL. The unique sensitivity of this advanced analytical system can ultimately lead to a shift in field sampling strategy with smaller air sample volumes facilitating faster, simpler air sampling (e.g., use of gas syringes rather than the relative complexity of pumps or bags/canisters), with greatly reduced risk of analyte breakthrough and minimal interference, e.g., from atmospheric humidity. The improved detection limits offered by this system can also enhance accuracy and measurement precision. PMID- 22934886 TI - Sex-specific estimates of dispersal show female philopatry and male dispersal in a promiscuous amphibian, the alpine salamander (Salamandra atra). AB - Amphibians display wide variations in life-history traits and life cycles that should prove useful to explore the evolution of sex-biased dispersal, but quantitative data on sex-specific dispersal patterns are scarce. Here, we focused on Salamandra atra, an endemic alpine species showing peculiar life-history traits. Strictly terrestrial and viviparous, the species has a promiscuous mating system, and females reproduce only every 3 to 4 years. In the present study, we provide quantitative estimates of asymmetries in male vs. female dispersal using both field-based (mark-recapture) and genetic approaches (detection of sex-biased dispersal and estimates of migration rates based on the contrast in genetic structure across sexes and age classes). Our results revealed a high level of gene flow among populations, which stems exclusively from male dispersal. We hypothesize that philopatric females benefit from being familiar with their natal area for the acquisition and defence of an appropriate shelter, while male dispersal has been secondarily favoured by inbreeding avoidance. Together with other studies on amphibians, our results indicate that a species' mating system alone is a poor predictor of sex-linked differences in dispersal, in particular for promiscuous species. Further studies should focus more directly on the proximate forces that favour or limit dispersal to refine our understanding of the evolution of sex-biased dispersal in animals. PMID- 22934888 TI - Nitrogen partitioning in oak leaves depends on species, provenance, climate conditions and soil type. AB - Climate-tolerant tree species and/or provenances have to be selected to ensure the high productivity of managed forests in Central Europe under the prognosticated climate changes. For this purpose, we studied the responses of saplings from three oak species (i.e. Quercus robur, Q. petraea and Q. pubescens) and provenances of different climatic origin (i.e. low or high rainfall, low or high temperature habitats) with regard to leaf nitrogen (N) composition as a measure of N nutrition. Saplings were grown in model ecosystems on either calcareous or acidic soil and subjected to one of four treatments (control, drought, air warming or a combination of drought and air warming). Across species, oak N metabolism responded to the influence of drought and/or air warming with an increase in leaf amino acid N concentration at the expense of structural N. Moreover, provenances or species from drier habitats were more tolerant to the climate conditions applied, as indicated by an increase in amino acid N (comparing species) or soluble protein N (comparing provenances within a species). Furthermore, amino acid N concentrations of oak leaves were significantly higher on calcareous compared to acidic soil. From these results, it can be concluded that seeds from provenances or species originating from drier habitats and - if available - from calcareous soil types may provide a superior seed source for future forest establishment. PMID- 22934887 TI - Mass spectrometry (LC-MS/MS) identified proteomic biosignatures of breast cancer in proximal fluid. AB - We have begun an early phase of biomarker discovery in three clinically important types of breast cancer using a panel of human cell lines: HER2 positive, hormone receptor positive and HER2 negative, and triple negative (HER2-, ER-, PR-). We identified and characterized the most abundant secreted, sloughed, or leaked proteins released into serum free media from these breast cancer cell lines using a combination of protein fractionation methods before LC-MS/MS mass spectrometry analysis. A total of 249 proteins were detected in the proximal fluid of 7 breast cancer cell lines. The expression of a selected group of high abundance and/or breast cancer-specific potential biomarkers including thromobospondin 1, galectin 3 binding protein, cathepsin D, vimentin, zinc-alpha2-glycoprotein, CD44, and EGFR from the breast cancer cell lines and in their culture media were further validated by Western blot analysis. Interestingly, mass spectrometry identified a cathepsin D protein single-nucleotide polymorphism (SNP) by alanine to valine replacement from the MCF-7 breast cancer cell line. Comparison of each cell line media proteome displayed unique and consistent biosignatures regardless of the individual group classifications, demonstrating the potential for stratification of breast cancer. On the basis of the cell line media proteome, predictive Tree software was able to categorize each cell line as HER2 positive, HER2 negative, and hormone receptor positive and triple negative based on only two proteins, muscle fructose 1,6-bisphosphate aldolase and keratin 19. In addition, the predictive Tree software clearly identified MCF-7 cell line overexpresing the HER2 receptor with the SNP cathepsin D biomarker. PMID- 22934889 TI - Phage display generation of a novel human anti-CD1A monoclonal antibody with potent cytolytic activity. AB - CD1A is a cell surface protein expressed on Langerhans cells and cortical thymocytes that could potentially be used as an immunotherapeutic target in Langerhans Cell Histiocytosis (LCH), the cortical subtype of T-cell acute lymphocytic leukaemia (T-ALL) and other CD1A-positive tumours. The monoclonal antibody (mAb) CR2113 was selected from a panel of six fully human mAbs isolated from a semi-synthetic phage display library, based on specificity and avidity against cells expressing CD1 antigen variants. CR2113 recognized CD1A in T-ALL cell lines and patient samples. Confocal microscopy revealed that the CR2113-CD1A complex was internalized at 37 degrees C. Furthermore, while CR2113 induced moderate complement-dependent cytotoxicity (CDC), potent antibody-dependent cell cytotoxicity (ADCC) activity was observed against CD1A expressing cell lines as well as T-ALL cell lines and T-ALL patient samples. In vivo experiments showed that CR2113 as a naked antibody has modest but specific anti-tumour activity against CD1A-expressing tumours. CR2113 is a high-affinity human anti-CD1A mAb with significant ADCC activity. These properties make CR2113 a candidate for clinical diagnostic imaging and therapeutic targeting of LCH as well as potential use in other clinical applications. PMID- 22934890 TI - Synthesis of the tetracyclic core (ABCE rings) of daphenylline. AB - A concise synthesis of the tetracyclic core (ABCE rings) of daphenylline has been accomplished involving a benzobicyclo[3.3.1] lactam as the key intermediate. This bridged bicyclic intermediate was efficiently constructed via a Bronsted acid promoted intramolecular Friedel-Crafts type Michael addition of a delta-benzyl alpha,beta-unsaturated delta-lactam. PMID- 22934892 TI - Localization of single-cell current sources based on extracellular potential patterns: the spike CSD method. AB - Traditional current source density (tCSD) calculation method calculates neural current source distribution of extracellular (EC) potential patterns, thus providing important neurophysiological information. While the tCSD method is based on physical principles, it adopts some assumptions, which can not hold for single-cell activity. Consequently, tCSD method gives false results for single cell activity. A new, spike CSD (sCSD) method has been developed, specifically designed to reveal CSD distribution of single cells during action potential generation. This method is based on the inverse solution of the Poisson-equation. The efficiency of the method is tested and demonstrated with simulations, and showed, that the sCSD method reconstructed the original CSD more precisely than the tCSD. The sCSD method is applied to EC spatial potential patterns of spikes, measured in cat primary auditory cortex with a 16-channel chronically implanted linear probe in vivo. Using our method, the cell-electrode distances were estimated and the spatio-temporal CSD distributions were reconstructed. The results suggested, that the new method is potentially useful in determining fine details of the spatio-temporal dynamics of spikes. PMID- 22934893 TI - Have mental health education programs influenced the mental health literacy of those with major depression and suicidal ideation? A comparison between 1998 and 2008 in South Australia. AB - Mental health literacy is the knowledge and beliefs about mental disorders that aid their recognition, management, or prevention and is considered to be an important determinant of help-seeking. This has relevance in suicide prevention, as depression, the clinical condition most frequently associated with suicidality, has been the target of community and professional education programs designed to enhance mental health literacy. In this study, whether such programs have influenced help-seeking attitudes and behavior in those who are depressed and suicidal was considered. The results indicate that despite intensive community education programs over the last two decades, there has been little change in those who are depressed and suicidal in terms of their attitudes toward treatment seeking and, more importantly, their treatment-seeking behavior. These results draw into question the value of current community education programs for those most vulnerable to suicidal behavior. PMID- 22934894 TI - Changes in time of sowing, flowering and maturity of cereals in Europe under climate change. AB - The phenological development of cereal crops from emergence through flowering to maturity is largely controlled by temperature, but also affected by day length and potential physiological stresses. Responses may vary between species and varieties. Climate change will affect the timing of cereal crop development, but exact changes will also depend on changes in varieties as affected by plant breeding and variety choices. This study aimed to assess changes in timing of major phenological stages of cereal crops in Northern and Central Europe under climate change. Records on dates of sowing, flowering, and maturity of wheat, oats and maize were collected from field experiments conducted during the period 1985-2009. Data for spring wheat and spring oats covered latitudes from 46 to 64 degrees N, winter wheat from 46 to 61 degrees N, and maize from 47 to 58 degrees N. The number of observations (site-year-variety combinations) varied with phenological phase, but exceeded 2190, 227, 2076 and 1506 for winter wheat, spring wheat, spring oats and maize, respectively. The data were used to fit simple crop development models, assuming that the duration of the period until flowering depends on temperature and day length for wheat and oats, and on temperature for maize, and that the duration of the period from flowering to maturity in all species depends on temperature only. Species-specific base temperatures were used. Sowing date of spring cereals was estimated using a threshold temperature for the mean air temperature during 10 days prior to sowing. The mean estimated temperature thresholds for sowing were 6.1, 7.1 and 10.1 degrees C for oats, wheat and maize, respectively. For spring oats and wheat the temperature threshold increased with latitude. The effective temperature sums required for both flowering and maturity increased with increasing mean annual temperature of the location, indicating that varieties are well adapted to given conditions. The responses of wheat and oats were largest for the period from flowering to maturity. Changes in timing of cereal phenology by 2040 were assessed for two climate model projections according to the observed dependencies on temperature and day length. The results showed advancements of sowing date of spring cereals by 1-3 weeks depending on climate model and region within Europe. The changes were largest in Northern Europe. Timing of flowering and maturity were projected to advance by 1-3 weeks. The changes were largest for grain maize and smallest for winter wheat, and they were generally largest in the western and northern part of the domain. There were considerable differences in predicted timing of sowing, flowering and maturity between the two climate model projections applied. PMID- 22934895 TI - History-dependent depolymerization of actin filaments. AB - Depolymerizing cytoskeletal filaments are involved in cell division, cell motility, and other cellular functions. Understanding the dynamics of depolymerization is as important as understanding the dynamics of polymerization. We study nonequilibrium depolymerization of actin filaments using a simple two state model. We show that the polymerization history influences the dynamics of depolymerization as well as the length fluctuations during depolymerization. We also simulate depolymerization under different experimentally feasible conditions. Under conditions of constant concentration, we show that the depolymerization happens in two regimes. Under the conditions of mass conservation, the depolymerization can have three regimes. PMID- 22934897 TI - National registration: a maturing professional accountability for occupational therapy. PMID- 22934896 TI - Transplantation of adipose-derived stem cells is associated with neural differentiation and functional improvement in a rat model of intracerebral hemorrhage. AB - AIMS: To examine whether transplantation of adipose-derived stem cells (ADSCs) induces neural differentiation and improves neural function in a rat intracerebral hemorrhage (ICH) model. METHODS: Adipose-derived stem cells cells were isolated from inguinal fat pad of rat. ICH was induced by injection of collagenase type IV into the right basal ganglia of rat. Forty-eight hours after ICH, ADSCs cells (10 MUL of 2-4 * 10(7) cells/mL) were injected into the right lateral cerebral ventricle. The differentiation of ADSCs was detected in vitro and in vivo. The neural function was evaluated with Zea Longa 5-grade scale at day 1, 3, 7, 14, or 28. RESULTS: Our data demonstrated that ADSCs differentiated into cells that shared the similarities of neurons or astrocytes in vitro. Transplantation of ADSCs decreased cell apoptosis and the transplanted ADSCs were able to differentiate into neuron-like and astrocyte-like cells around the hematoma, accompanied with upregulation of vascular endothelial growth factor expression and improvement of neural function. CONCLUSIONS: Our data suggest that transplantation of ADSCs could be a therapeutic approach for ICH stroke. PMID- 22934898 TI - The use of botulinum toxin type A in the management of adult-onset focal spasticity: a survey of Australian allied health professionals. AB - BACKGROUND: Recently, the European Journal of Neurology published international consensus statements for the assessment, treatment and aftercare associated with the use of botulinum neurotoxin type A. This survey examined current allied health practice in relation to botulinum neurotoxin type A use in Australia in the light of these guidelines. METHODS: An electronic questionnaire was distributed to members of neurology groups of the Australian Physiotherapy Association and Occupational Therapy Australia. The questionnaire explored assessment processes used, familiarity with pharmaceutical benefits scheme indications for botulinum neurotoxin type A use, goal setting and outcome measurement, follow-up therapy and access to spasticity management services. RESULTS: The 123 survey respondents (81 from the Australian Physiotherapy Association - response rate 16.2%, 42 from Occupational Therapy Australia - response rate 6.4%) reported that focal spasticity was a major problem for which botulinum neurotoxin type A was a primary intervention. The Tardieu scale was more frequently used than the modified Ashworth scale (82% vs. 48%). Most therapists (76.3%) reported being confident diagnosing spasticity and its functional implications (84.2%), but fewer were confident discussing referral for botulinum neurotoxin type A with doctors (56.1%). Goals were set in conjunction with the client (93.6%). Barriers to injection and adjunctive therapy (motor training etc.) included waiting times for botulinum neurotoxin type A injection, access to specialist adjunctive therapists and referral for treatment. CONCLUSIONS: Allied health practitioners in Australia report clinical practice to be closely aligned with international guidelines for the use of botulinum neurotoxin type A in adult spasticity. Therapist confidence in advocating for botulinum neurotoxin type A injection, consistent use of objective measures of spasticity and treatment outcomes and barriers to providing adjunctive therapy need to be addressed. PMID- 22934899 TI - Project-based fieldwork: perspectives of graduate entry students and project sponsors. AB - BACKGROUND/AIM: This article builds on an earlier viewpoint regarding the need for project-focussed fieldwork. It presents the findings of an evaluative study into the value of project placements undertaken by final year graduate entry master's students as part of a capstone subject. The authors argue that provision of project placements enable impending graduates to develop and implement macro level strategies to develop prevention, resource and service development skills often required of contemporary occupational therapy practitioners. METHODS: A qualitative approach is adopted. Student cohorts from 2005 and 2006 completed open-ended, written questionnaires, and agency project sponsors were interviewed to obtain their perspectives of the project placement experience. RESULTS: Despite some concern that project placements might be undertaken at the expense of 'clinical' placements these findings reveal that projects managed by students were perceived by services to add great value enabling them to advance important priorities. Students and sponsors highlighted a range of positive learning outcomes, including the ability to work collaboratively with supervisors and develop advanced communication skills and political acumen. The success of such placements depends on supportive supervision from academic staff. CONCLUSIONS AND SIGNIFICANCE OF THE STUDY: The findings promote project placements as a highly authentic aspect of work integrated learning enabling learners to draw together a range of attributes that support the ability to manage complex issues that have occupational relevance at a macro level. In addition, such experiences help learners to develop agency and political acumen both increasingly important capabilities for the contemporary workplace. PMID- 22934900 TI - Revisiting 1:1 and 2:1 clinical placement models: student and clinical educator perspectives. AB - AIM: A recent systematic review suggests that more comparative research is required on the effectiveness of clinical placement models. This study explored perspectives of clinical educators and students who had participated in both the 1:1 (one student supervised by one clinical educator) and 2:1 (two students supervised by one clinical educator) models of clinical education across occupational therapy and physiotherapy programmes in Ireland. METHODS: Qualitative data using a descriptive approach were gathered through individual semi-structured interviews with a convenience sample of 12 students and eight clinical educators. Transcripts were analysed using thematic content analysis. RESULTS: Three main themes emerged: learning opportunities and experiences; organisation and planning; relationships. Although clinical educators felt that the 2:1 model offered greater learning experiences than the 1:1 model, it presented organisational challenges. Students preferred the 2:1 model earlier in their clinical experience due to the benefits of peer learning, whereas the 1:1 model was favoured in the latter stages to demonstrate individual autonomy. Relationships forged during placement were significant, from the student's perspectives, but differed between models. Clinical educator and student perspectives indicated that learning from other members of the multidisciplinary team had a positive effect on learning within both models. CONCLUSION: Each clinical placement model requires specific organisational and planning skills to be effective. An awareness of individual student learning is essential to avoid dissatisfaction with the learning and assessment process on a 2:1 model. Recently established clinical education teams in Ireland may have a role to play in developing effective clinical learning. PMID- 22934901 TI - Evidence-based practice in occupational therapy services for children with autism spectrum disorders in Victoria, Australia. AB - BACKGROUND: The current practice of occupational therapy services provided for children with autism spectrum disorders in Victoria, Australia was investigated - specifically, practice in terms of the theories, assessments and intervention strategies utilised. Identification of professional development needs was also explored. The purpose was to identify how occupational therapy practice may have changed over the last decade and to explore what additional developments are required in the field. METHOD: A self-administered survey was mailed to 322 registered members of Occupational Therapy Australia Limited, Victoria Branch. RESULTS: A valid response rate of 20.5% was obtained. The majority of the participants worked in private practice, and had between one and five years of work experience. Theories, assessments and interventions that are associated with or based on, sensory integration and/or processing approaches are highly utilised by the participants in their service delivery with children with autism spectrum disorders. Participants indicated that they felt they needed training and courses around sensory integration. CONCLUSIONS: We concluded that there were few changes in occupational therapy practice related to the selection of theoretical models, assessments and interventions by the participants in this study over the last decade. It is essential for occupational therapists not to neglect the goals of providing occupation-based interventions to children with autism spectrum disorders by focusing only on sensory-based approaches. An urgent need for occupation-based approaches to working with children with autism spectrum disorders and their families is required. PMID- 22934891 TI - The composition of phyllosphere fungal assemblages of European beech (Fagus sylvatica) varies significantly along an elevation gradient. AB - Little is known about the potential effect of climate warming on phyllosphere fungi, despite their important impact on the dynamics and diversity of plant communities. The structure of phyllosphere fungal assemblages along elevation gradients may provide information about this potential effect, because elevation gradients correspond to temperature gradients over short geographic distances. We thus investigated variations in the composition of fungal assemblages inhabiting the phyllosphere of European beech (Fagus sylvatica) at four sites over a gradient of 1000 m of elevation in the French Pyrenees Mountains, by using tag encoded 454 pyrosequencing. Our results show that the composition of fungal assemblages varied significantly between elevation sites, in terms of both the relative abundance and the presence-absence of species, and that the variations in assemblage composition were well correlated with variations in the average temperatures. Our results therefore suggest that climate warming might alter both the incidence and the abundance of phyllosphere fungal species, including potential pathogens. For example, Mycosphaerella punctiformis, a causal agent of leaf spots, showed decreasing abundance with elevation and might therefore shift to higher elevations in response to warming. PMID- 22934902 TI - How mental health occupational therapists address issues of diet with their clients: a qualitative study. AB - BACKGROUND: Poor diet is a contributing factor to the high rates of obesity and related comorbidities in people with severe mental illness, and dietary change is a key treatment strategy. Providing healthy lifestyle interventions is a recognised role for occupational therapists. However, the existing literature fails to elucidate boundaries of this role. To begin to address this gap in the literature, this study explored the attitudes, actions and beliefs of mental health occupational therapists about providing diet-related interventions. METHODS: Semi-structured interviews were conducted with mental health occupational therapists working in one Area Health Service in New South Wales. Purposive sampling was used. Data were analysed using Constructivist Grounded Theory methods, where meaning is co-constructed by, and the theory ultimately grounded in the experiences of, the participant and researcher. RESULTS: The participants felt confident providing clients with interventions to promote diet related skill development and providing general healthy eating education to support this development. However, they were not comfortable providing clients with specific dietary advice. Participants identified a need for further training and support to enhance their effectiveness in providing healthy eating education and highlighted the need for more dietitians in mental health services. CONCLUSIONS: The occupational therapists in this study identified clear boundaries of their role in providing diet-related interventions for people with severe mental illness. Suggestions for improvement in this area included further training for occupational therapists as well as increased access to dietitians for those services that lie outside the occupational therapy role. PMID- 22934903 TI - Impact of the Learn to Play program on play, social competence and language for children aged 5-8 years who attend a specialist school. AB - INTRODUCTION: The aim of this study was to investigate the change in the relationship between play, language and social skills of children aged 5-8 years pre and post participation in the 'Learn to Play' program. The Learn to Play program is a child led play based intervention aimed at developing self-initiated pretend play skills in children. METHODS: All 19 participants attended a specialist school, with 10 of the 19 children having a diagnosis of autism. The play, language and social skills of the children were assessed at baseline and at follow up. Children were assessed using the Child-Initiated Pretend Play Assessment, the Preschool Language Scale and the Penn Interactive Peer Play Scale. Follow up data collection occurred after the children had been participating in the Learn to Play program for 1 hour twice a week for 6 months. RESULTS: After 6 months in the program, typical indicators of play accounted for an increase of 47.3% in shared variance with social interaction and an increase of 36% in shared variance for social connection. For language, object substitution ability accounted for 50% of the shared variance, which was an increase of 27% from baseline. CONCLUSION: The 'Learn to Play' program was associated with increases in children's language and social skills over a 6-month period within a special school setting, indicating the Learn to Play program is an effective intervention for children with developmental disabilities. This paper presents an example of how the Learn to Play program can be adapted into a classroom setting. PMID- 22934904 TI - Enhancing occupational therapists' confidence and professional development through a community of practice scholars. AB - INTRODUCTION: An important professional issue for occupational therapy is the need to develop and maintain high-quality occupational therapy services. Clearly, a strong educational foundation is necessary, but not sufficient, for meeting this goal. Occupational therapists need to engage in ongoing education, professional development and critique of their theory and practice to ensure they meet best practice standards. One way that practitioners can do this, is to form practitioner communities with a focus on scholarship: a 'community of practice scholars'. METHODS: Using the framework of action research, three occupational therapy academics worked collaboratively with 25 occupational therapy practitioners over a period of 12 months. During monthly teleconference meetings, the research group discussed, critiqued and reflected upon their practice. Transcripts of the final month's teleconferences, which focussed on evaluation of the community of practice scholars, were qualitatively analysed. FINDINGS: Two major themes are presented. The first theme, promotion of scholarship, describes that involvement in the community of practice scholars assisted participants to think more critically about their practice and to consider ways in which their practice might be improved. The second theme, promoting professional confidence, passion and cohesion, articulates that the support offered by the group helped the participants to feel an increased sense of confidence in their practice. CONCLUSION: It is proposed that communities of practice scholars have considerable potential for providing professional development opportunities for occupational therapists. In addition, such communities may lead to occupational therapists feeling more supported and experiencing increased satisfaction in their work. PMID- 22934905 TI - Test-retest reliability of computerised hand dynamometry in adults with acquired brain injury. AB - BACKGROUND/AIM: The ability to objectively and reliably measure hand performance over time is critical to monitor patient performance and evaluate treatment efficacy. Current spasticity measures are subjective in nature and fail to capture the complexity of the multi-faceted upper motor neuron syndrome. This study examined the test-retest reliability of dynamic computerised hand dynamometry for simultaneously measuring multiple aspects of positive and negative features of the upper motor neuron syndrome during an active grasp and release task. METHODS: Community-living adults with upper motor neuron syndrome following acquired brain injury attending metropolitan spasticity clinics for management of upper limb spasticity (N = 36; mean age 50 years +/-15) and control participants (N = 27, mean age 40 years +/-12) completed a computerised hand dynamometry protocol across two testing occasions 5 weeks apart. Objective measurement of Isometric Force, Cycle Duration and Isometric Grip Work, Force Velocity, was completed during a repeated grasp and release test protocol with a computerised hand dynamometer to evaluate the reliability and reproducibility of hand performance. RESULTS: Kendall Coefficient of Concordance W scores ranged from W = 0.69-0.98 for motor elements of grasp and release, including Isometric Force, Cycle Duration, Isometric Grip Work and Force Velocity. CONCLUSIONS: The investigated dynamic computerised hand dynamometry protocol showed fair/good to excellent levels of test-retest reliability in control participants and in subjects with upper motor neuron syndrome following acquired brain injury. PMID- 22934906 TI - Frailty: a concept under-utilised by occupational therapists. PMID- 22934907 TI - Evidence supports the effectiveness of occupational therapy interventions in improving components of recovery for adults with serious mental illness. PMID- 22934908 TI - Cognitive remediation has global cognitive and functional benefits for people with schizophrenia when combined with psychiatric rehabilitation. PMID- 22934909 TI - Synthesis of p-xylene from ethylene. AB - As oil supplies dwindle, there is a growing need to develop new routes to chemical intermediates that utilize alternative feedstocks. We report here a synthesis of para-xylene, one of the highest volume chemicals derived from petroleum, using only ethylene as a feedstock. Ethylene is an attractive alternative feedstock, as it can be derived from renewable biomass resources or harnessed from large domestic shale gas deposits. The synthesis relies on the conversion of hexene (from trimerization of ethylene) to 2,4-hexadiene followed by a Diels-Alder reaction with ethylene to form 3,6-dimethylcyclohexene. This monoene is readily dehydrogenated to para-xylene uncontaminated by the ortho and meta isomers. We report here a selective synthesis of para-xylene, uncontaminated by the ortho or meta isomers, using ethylene as the sole feedstock. PMID- 22934910 TI - Prevalence of low back pain among peasant farmers in a rural community in South South Nigeria. AB - INTRODUCTION: This study was undertaken to assess the prevalence and predominant causes of low back pain (LBP) among peasant farmers in Ebubu community in South south Nigeria. METHODS: This was a community based cross-sectional study of 310 consenting, adult, full-time farmers, recruited using a two-stage cluster sampling scheme developed by WHO. Specially trained community health extension workers interviewed participants using a pre-tested questionnaire designed by the authors to solicit information on defined LBP. Socio-demographic characteristics were also obtained. A clinical history was recorded, including: duration of LBP and mode of onset, pain severity, knowledge of LBP causes and care-seeking practices. Participants' BMI were calculated. Data were entered into Microsoft Excel and analyzed using the Statistical Package for Social Sciences v15 (www.spss.com). RESULTS: Of the 310 apparently healthy farmers (age range 18-58 years [mean 36.71+/-8.98]; 132 males) sampled, 208 had LBP (67.10%). Low back pain was more prevalent in the 31-40 years age group (49.04%), females (50.96%), those who were non-obese (68.95%) or tall (73.2%) and those who had practiced farming for a long duration. Severe LBP was significantly (p<0.05) linked to aging (51-60 years group), low BMI and those above average height (1.60 m). CONCLUSION: This study indicates that LBP is a prevalent health problem among rural peasant farmers. It was more prevalent in the middle-aged groups, and among females, the non-obese and tall individuals, and those who had been farming for a long duration. Severe LBP was linked to aging, high BMI and those above average height. PMID- 22934911 TI - Characterization of the native and denatured herceptin by enzyme linked immunosorbent assay and quartz crystal microbalance using a high-affinity single chain fragment variable recombinant antibody. AB - Herceptin/Trastuzumab is a humanized IgG1kappa light chain antibody used to treat some forms of breast cancer. A phage-displayed recombinant antibody library was used to obtain a single chain fragment variable (scFv, designated 2B4) to a linear synthetic peptide representing Herceptin's heavy chain CDR3. Enzyme linked immunosorbent assays (ELISAs) and piezoimmunosensor/quartz crystal microbalance (QCM) assays were used to characterize 2B4-binding activity to both native and heat denatured Herceptin. The 2B4 scFv specifically bound to heat denatured Herceptin in a concentration dependent manner over a wide (35-220.5 nM) dynamic range. Herceptin denatures and forms significant amounts of aggregates when heated. UV-vis characterization confirms that Herceptin forms aggregates as the temperature used to heat Herceptin increases. QCM affinity assay shows that binding stoichiometry between 2B4 scFv and Herceptin follows a 1:2 relationship proving that 2B4 scFv binds strongly to the dimers of heat denatured Herceptin aggregates and exhibits an affinity constant of 7.17 * 10(13) M(-2). The 2B4 based QCM assay was more sensitive than the corresponding ELISA. Combining QCM with ELISA can be used to more fully characterize nonspecific binding events in assays. The potential theoretical and clinical implications of these results and the advantages of the use of QCM to characterize human therapeutic antibodies in samples are also discussed. PMID- 22934912 TI - Factors contributing to extended activity times during the provision of wheeled mobility devices. AB - PURPOSE: A secondary analysis was performed on data from a recent time-motion study documenting the type and duration of activities performed during the provision of wheeled mobility and seating devices. The objective of this analysis was to report factors that were most associated with activities having extended durations. METHOD: Activities were categorized as occurring during the visit preparation, pre-delivery, delivery or follow-up phases of equipment provision. Extended activities were defined as activities at or exceeding the 75th percentile, corresponding to activities exceeding 37.5 min. Logistic regression and Odd Ratio calculations were used to identify factors that were associated with extended encounters with clients. RESULTS: Extended activities were more likely to be associated with Group 4 power chairs, ultra-lightweight wheelchairs and seating systems comprised of a combination of technologies, such as those with postural supports or using made-to measure or custom-molded techniques. CONCLUSIONS: Wheelchair and seating system type were more predictive of extended activities compared to diagnostic categories. This result leads us to posit that functional needs - rather than diagnosis - impacts the duration of client encounters and the complexity of the equipment prescribed to the user. The results also indicate that more complex equipment were more likely to require extended encounters than less complex devices in their respective groupings. PMID- 22934913 TI - 20-Year survival after radical prostatectomy as initial treatment for cT3 prostate cancer. AB - Study Type--Therapy (case series) Level of Evidence 4. What's known on the subject? and What does the study add? Despite a lack of randomised controlled trials, most men with locally advanced prostate cancer are recommended to undergo external beam radiotherapy (EBRT), often combined with long-term androgen deprivation therapy (ADT). Many of these men are not offered radical prostatectomy (RP) by their treating urologist. Additionally, it is know that EBRT with long-term ADT does provide good cancer control (88% at 10 years). We have previously published intermediate-term follow-up of a large series of men treatment with RP for cT3 prostate cancer. We report long-term follow-up of a large series of men treated with RP as primary treatment for cT3 prostate cancer. Our study shows that with long-term follow-up RP provides excellent oncological outcomes even at 20 years. While most men do require a multimodal treatment approach, many men can be managed successfully with RP alone. OBJECTIVE: * To present long-term survival outcomes after radical prostatectomy (RP) for patients with cT3 prostate cancer, as the optimal treatment for patients with clinical T3 prostate cancer is debated. PATIENTS AND METHODS: * We identified 843 men who underwent RP for cT3 tumours between 1987 and 1997. * Survival was estimated using the Kaplan-Meier method. * Cox proportional hazards regression models were used to evaluate the association of clinicopathological features with outcome RESULTS: * The median (range) postoperative follow-up was 14.3 (0.1-23.5) years. * Down-staging to pT2 disease occurred in 26% (223/843) at surgery. * Local recurrence-free, systemic progression-free and cancer-specific survival for men with cT3 prostate cancer after RP was 76%, 72%, and 81%, respectively, at 20 years. * On multivariate analysis, increasing RP Gleason score (hazard ratio [HR] 1.8; P = 0.01), non-diploid chromatin content (HR 1.8; P = 0.01), positive surgical margins (HR 2.1; P = 0.007), and seminal vesicle invasion (HR 2.1; P = 0.005) were associated with a significant risk of prostate cancer death, while a more recent year of surgery was associated with a decreased risk of cancer specific mortality (HR 0.88; P = 0.01) CONCLUSIONS: * RP affords accurate pathological staging and may be associated with durable cancer control for cT3 prostate cancer, with 20 years of follow-up presented here. * RP as part of a multimodal treatment strategy therefore remains a viable treatment option for patients with cT3 tumours. PMID- 22934914 TI - Differences in liquor prices between control state-operated and license-state retail outlets in the United States. AB - AIMS: This study aims to compare the average price of liquor in the United States between retail alcohol outlets in states that have a monopoly ('control' states) with those that do not ('licence' states). DESIGN: A cross-sectional study of brand-specific alcohol prices in the United States. SETTING: We determined the average prices in February 2012 of 74 brands of liquor among the 13 control states that maintain a monopoly on liquor sales at the retail level and among a sample of 50 license-state liquor stores, using their online-available prices. MEASUREMENTS: We calculated average prices for 74 brands of liquor by control versus license state. We used a random-effects regression model to estimate differences between control and license state prices-overall and by alcoholic beverage type. We also compared prices between the 13 control states. FINDINGS: The overall mean price for the 74 brands was $27.79 in the license states [95% confidence interval (CI): $25.26-30.32] and $29.82 in the control states (95% CI: $26.98-32.66). Based on the random-effects linear regression model, the average liquor price was approximately $2 lower (6.9% lower) in license states. CONCLUSIONS: In the United States monopoly of alcohol retail outlets appears to be associated with slightly higher liquor prices. PMID- 22934915 TI - Editorial: New approaches in the treatment of multiple myeloma: from target-based agents to the new era of microRNAs (dedicated to the memory of Prof. Salvatore Venuta). PMID- 22934916 TI - Clozapine as a potential treatment for refractory impulsive, compulsive, and punding behaviors in Parkinson's disease. AB - There have been emerging cases of medication refractory obsessions, impulsivity, compulsivity, and/or punding in Parkinson's disease. These cases have proven difficult to treat, even for the experienced clinician. We report several medication refractory cases with a positive response to treatment with clozapine. PMID- 22934917 TI - Residents' experiences of encounters with relatives and significant persons: a hermeneutic study. AB - The aim of this study was to explore and interpret the meaning of residents' experiences of encounters with their relatives and other significant persons in nursing homes. Twelve residents in three different nursing homes in a western Sweden municipality were interviewed. The method used was hermeneutical text analysis. Three themes emerged in the interpretation of the text: being pleased, being someone, and being inconvenient. These themes were also described through seven subthemes: to be happy to have someone, to make someone else happy, going back in life, to be together in a community, not being alone, to be disconnected, and to be a burden. The study concludes that it is important for nurses in nursing homes to develop a deeper insight into what various social contacts can mean for residents. To develop this knowledge, it is important that nurses in nursing homes can be educated, and supported by clinical supervision, in relation to residents' experiences of encounters with relatives and other significant persons. PMID- 22934918 TI - Charge-transfer-induced spin transitions in crystals containing cyanide-bridged Co-Fe clusters: role of intra- and intercluster interactions. AB - A theoretical model has been developed to explain at the electronic level the charge-transfer-induced spin transition (CTIST) in crystals based on cyano bridged binuclear Fe-Co clusters. The CTIST is considered as a cooperative phenomenon (phase transformation) driven by the long-range electron-deformational interaction via the acoustic phonons field that is taken into account within the mean field approach. The model for CTIST includes also the metal-metal electron transfer and intracluster magnetic exchange. The conditions that favor the CTIST are discussed. The qualitative explanation of the experimental data is given. PMID- 22934920 TI - Superparamagnetic iron oxide nanoparticles (SPIONs): synthesis and surface modification techniques for use with MRI and other biomedical applications. AB - Superparamagnetic iron oxide nanoparticles (SPIONs) comprise a fundamental technology class within the emerging field of nanomedicine, and have been extensively researched for cancer imaging and therapy. This review article will discuss the chemistry and design considerations associated with the synthesis of SPIONs and their incorporation into pharmaceutical formulations. Specific synthesis methods discussed include coprecipitation, thermal decomposition, microemulsion and solvothermal synthesis, as well as surface treatments and encapsulations to improve the nanoparticle biocompatibility and efficacy. Emerging applications of novel particle designs as MRI contrast agents are also discussed. PMID- 22934919 TI - Correlated discharges in the primate prefrontal cortex before and after working memory training. AB - The correlation of discharges between single neurons can provide information about the computations and network properties of neuronal populations during the performance of cognitive tasks. In recent years, dynamic modulation of neuronal correlations by attention has been revealed during the execution of behavioral tasks. Much less is known about the influence of learning and performing a task itself. We therefore sought to quantify the correlated firing of simultaneously recorded pairs of neurons in the prefrontal cortex of naive monkeys that were only required to fixate, and to examine how this correlation was altered after they had learned to perform a working memory task. We found that the trial-to trial correlation of discharge rates between pairs of neurons (noise correlation) differed across neurons depending on their responsiveness and selectivity for stimuli, even before training in a working memory task. After monkeys had learned to perform the task, correlated firing decreased overall, although the effects varied according to the functional properties of the neurons. The greatest decreases were observed on comparison of populations of neurons that exhibited elevated firing rates during the trial events and those that had more similar spatial and temporal tuning. Greater decreases in noise correlation were also observed for pairs comprising one fast spiking neuron (putative interneuron) and one regular spiking neuron (putative pyramidal neuron) than pairs comprising regular spiking neurons only. Our results demonstrate that learning and performance of a cognitive task alters the correlation structure of neuronal firing in the prefrontal cortex. PMID- 22934921 TI - Assimilate transport in phloem sets conditions for leaf gas exchange. AB - Carbon uptake and transpiration in plant leaves occurs through stomata that open and close. Stomatal action is usually considered a response to environmental driving factors. Here we show that leaf gas exchange is more strongly related to whole tree level transport of assimilates than previously thought, and that transport of assimilates is a restriction of stomatal opening comparable with hydraulic limitation. Assimilate transport in the phloem requires that osmotic pressure at phloem loading sites in leaves exceeds the drop in hydrostatic pressure that is due to transpiration. Assimilate transport thus competes with transpiration for water. Excess sugar loading, however, may block the assimilate transport because of viscosity build-up in phloem sap. Therefore, for given conditions, there is a stomatal opening that maximizes phloem transport if we assume that sugar loading is proportional to photosynthetic rate. Here we show that such opening produces the observed behaviour of leaf gas exchange. Our approach connects stomatal regulation directly with sink activity, plant structure and soil water availability as they all influence assimilate transport. It produces similar behaviour as the optimal stomatal control approach, but does not require determination of marginal cost of water parameter. PMID- 22934922 TI - Exposure to prescription drugs labeled for risk of adverse effects of suicidal behavior or ideation among 100 Air Force personnel who died by suicide, 2006 2009. AB - Prescription drugs for many indications are labeled with warnings for potential risk of suicidal ideation or behavior. Exposures to prescription drugs labeled for adverse effects of suicidal behavior or ideation among 100 Air Force personnel who died by suicide between 2006 and 2009 are described. Air Force registry data were linked to administrative prescription data. Descriptive statistics illustrate utilization: 89 personnel had a prescription history, 35 filled at least one prescription labeled with a warning, 26 had antidepressants on hand at death, and 2 died by drug overdose. Most airmen were not exposed to any prescriptions labeled for risk of suicidal ideation or behavior prior to death by suicide. PMID- 22934923 TI - The interconnections between obesity, thyroid function, and autoimmunity: the multifold role of leptin. AB - BACKGROUND: There is increasing evidence that changes in thyroid function are associated with obesity, a condition associated with a chronic low-grade state of inflammation. Meanwhile, recent data have disclosed a relation between obesity and thyroid autoimmunity, with the adipocyte hormone leptin appearing to be the key factor linking these two conditions. SUMMARY: Leptin has variably been implicated in thyroid function, while recent findings suggest that leptin resistance may mitigate leptin deficiency and enhance autoimmunity in obese subjects via mechanisms operating independently of thyroid function. The development of resistance to the weight-lowering effects of leptin in obesity might well be initiated by activation of inflammatory signaling, which substantially contributes to the derangement of immune response and propagation of autoimmunity in susceptible individuals. CONCLUSIONS: Regulation of inflammasome-derived cytokines in obesity is an important step in controlling the trigger of thyroid autoimmunity. The clarification of the pathways may offer innovative therapeutic targets in obesity and thyroid autoimmunity. PMID- 22934924 TI - Single-molecule fluorescence resonance energy transfer shows uniformity in TATA binding protein-induced DNA bending and heterogeneity in bending kinetics. AB - TATA binding protein (TBP) is a key component of the eukaryotic RNA polymerase II transcription machinery that binds to TATA boxes located in the core promoter regions of many genes. Structural and biochemical studies have shown that when TBP binds DNA, it sharply bends the DNA. We used single-molecule fluorescence resonance energy transfer (smFRET) to study DNA bending by human TBP on consensus and mutant TATA boxes in the absence and presence of TFIIA. We found that the state of the bent DNA within populations of TBP-DNA complexes is homogeneous; partially bent intermediates were not observed. In contrast to the results of previous ensemble studies, TBP was found to bend a mutant TATA box to the same extent as the consensus TATA box. Moreover, in the presence of TFIIA, the extent of DNA bending was not significantly changed, although TFIIA did increase the fraction of DNA molecules bound by TBP. Analysis of the kinetics of DNA bending and unbending revealed that on the consensus TATA box two kinetically distinct populations of TBP-DNA complexes exist; however, the bent state of the DNA is the same in the two populations. Our smFRET studies reveal that human TBP bends DNA in a largely uniform manner under a variety of different conditions, which was unexpected given previous ensemble biochemical studies. Our new observations led to us to revise the model for the mechanism of DNA binding by TBP and for how DNA bending is affected by TATA sequence and TFIIA. PMID- 22934925 TI - Nanodosimetry of (125)I Auger electrons. AB - PURPOSE: The nanodosimetric description of the radiation action of Auger electrons on nitrogen targets of nanometric size is presented. MATERIALS AND METHODS: Experimental microdosimetry at nanometer scale for Auger electrons has been accomplished with the set-up called Jet Counter. This consists of a pulse operated valve which injects an expanding nitrogen jet into an interaction chamber where a gaseous sensitive volume of cylindrical shape is created. The ionization cluster size distributions (ICSD) created by Auger electrons emitted by (125)I while crossing a nanometer-sized volume have been measured. RESULTS: The ICSD for the sensitive volumes corresponding to 3 and 12 nm in diameter (in unit density 1 g/cm(3)) irradiated by electrons emitted by a (125)I source were collected and compared with the corresponding Monte Carlo (MC) simulation. The preliminary results of the experiments with Auger electrons of (125)I interacting with a nitrogen jet having nanometric size comparable to a deoxyribonucleic acid (DNA) and nucleosome, showing the discrete spectrum of ICSD with extended cluster size, are described. CONCLUSIONS: The presented paper describes for the first time the nanodosimetric experiments with Auger electrons emitted by (125)I. A set of the new descriptors of the radiation quality describing the radiation effect at nanometer level is proposed. The ICSD were determined for the first time for an Auger emitter of (125)I. PMID- 22934926 TI - FeCl3.6H2O-catalyzed intramolecular allylic amination: synthesis of substituted dihydroquinolines and quinolines. AB - A facile and efficient method to synthesize 2- or 4-substituted 1,2 dihydroquinolines and quinolines catalyzed by FeCl(3).6H(2)O (2 mol %) was described. The iron-catalyzed intramolecular allylic amination of 2-aminophenyl-1 en-3-ols proceeded smoothly to afford 13 1,2-dihydroquinoline and 8 quinoline derivatives under mild reaction conditions with good to excellent yields (up to 96%). PMID- 22934928 TI - One-step access to luminescent pentaaryldiazaboroles via C-C double bond formation from imidoylstannanes. AB - A series of pentaaryl-substituted diazaboroles have been prepared for the first time by a novel strategy based on the C-C double bond formation from imidoylstannane reagents in the presence of dibromophenylboranes. The aryl substituents on the 4,5-position of the planar C(2)N(2)B core have substantial effects on their electronic structures. All the new diazaboroles are luminescent both in solution and in the solid state. DFT calculations indicate the 4,5-C-aryl substituents have significant contributions to the LUMOs. PMID- 22934927 TI - PGE2 maintains the tone of the guinea pig trachea through a balance between activation of contractile EP1 receptors and relaxant EP2 receptors. AB - BACKGROUND AND PURPOSE: The guinea pig trachea (GPT) is commonly used in airway pharmacology. The aim of this study was to define the expression and function of EP receptors for PGE(2) in GPT as there has been ambiguity concerning their role. EXPERIMENTAL APPROACH: Expression of mRNA for EP receptors and key enzymes in the PGE(2) pathway were assessed by real-time PCR using species-specific primers. Functional studies of GPT were performed in tissue organ baths. KEY RESULTS: Expression of mRNA for the four EP receptors was found in airway smooth muscle. PGE(2) displayed a bell-shaped concentration-response curve, where the initial contraction was inhibited by the EP(1) receptor antagonist ONO-8130 and the subsequent relaxation by the EP(2) receptor antagonist PF-04418948. Neither EP(3) (ONO-AE5-599) nor EP(4) (ONO-AE3-208) selective receptor antagonists affected the response to PGE(2). Expression of COX-2 was greater than COX-1 in GPT, and the spontaneous tone was most effectively abolished by selective COX-2 inhibitors. Furthermore, ONO-8130 and a specific PGE(2) antibody eliminated the spontaneous tone, whereas the EP(2) antagonist PF-04418948 increased it. Antagonists of other prostanoid receptors had no effect on basal tension. The relaxant EP(2) response to PGE(2) was maintained after long-term culture, whereas the contractile EP(1) response showed homologous desensitization to PGE(2), which was prevented by COX inhibitors. CONCLUSIONS AND IMPLICATIONS: Endogenous PGE(2), synthesized predominantly by COX-2, maintains the spontaneous tone of GPT by a balance between contractile EP(1) receptors and relaxant EP(2) receptors. The model may be used to study interactions between EP receptors. PMID- 22934929 TI - Why renal nurses cope so well with their workplace stressors. AB - BACKGROUND: Previous studies have found significant stressors experienced by nurses working in haemodialysis units yet renal nurses appear to report less burnout than other nurses. OBJECTIVES: This study aims to undertake an inductive process to better understand the stressors and the coping strategies used by renal nurses that may lead to resilience. METHOD: Sixteen haemodialysis nurses from a metropolitan Australian hospital and two satellite units participated in open-ended interviews. Data were analysed from a grounded theory methodology. Measures of burnout and resilience were also obtained. RESULTS: Two major categories of stressors emerged. First, due to prolonged patient contact, family like relationships developed that lead to the blurring of boundaries. Second, participants experienced discrimination from both patients and staff. Despite these stressors, the majority of participants reported low burnout and moderately high-to-high levels of resilience. The major coping strategy that appeared to promote resilience was emotional distancing, while emotional detachment appeared to promote burn-out. CONCLUSION: Assisting nurses to use emotional distancing, rather than emotional detachment strategies to engender a sense of personal achievement may promote resilience. PMID- 22934931 TI - Ear diseases and other risk factors for hearing impairment among adults: an epidemiological study. AB - OBJECTIVE: To investigate the prevalence of ear diseases, other otological risk factors potentially affecting hearing, and noise exposure among adults. Furthermore, subject-related factors possibly associated with hearing impairment (HI), i.e. handedness, eye color, and susceptibility to sunburn, were studied. DESIGN: A cross-sectional, unscreened, population-based, epidemiological study among adults. STUDY SAMPLE: The subjects (n = 850), aged 54-66 years, were randomly sampled from the population register. A questionnaire survey, an otological examination, and pure-tone audiometry were performed. RESULTS: Chronic middle-ear disease (both active and inactive) was the most common ear disease with a prevalence of 5.3%, while the prevalence of otosclerosis was 1.3%, and that of Meniere's disease, 0.7%. Noise exposure was reported by 46% of the subjects, and it had no effect on hearing among those with no ear disease or other otological risk factors for HI. Dark eye color and non-susceptibility to sunburn were associated with HI among noise-exposed subjects. CONCLUSIONS: Common ear diseases and other otological risk factors constitute a major part of the etiologies of HI among adults. Contrary to previous studies, noise exposure turned out to have only marginal effect on hearing among those with no otological risk factors. PMID- 22934930 TI - A randomized controlled comparison of NAL and DSL prescriptions for young children: hearing-aid characteristics and performance outcomes at three years of age. AB - OBJECTIVE: To determine the influence of choice of prescription and other child-, family- and intervention-related factors on speech, language, and functional performance of hearing-impaired children by three years of age. DESIGN AND STUDY SAMPLE: A randomized controlled design was implemented as part of a population based, longitudinal study on outcomes of children with hearing impairment (LOCHI) in Australia. Two hundred and eighteen children were randomly assigned to either the NAL or the DSL prescription for first fitting of hearing aids. Their performance outcomes were evaluated. RESULTS: Prescriptive targets were closely matched in children's hearing aids. There were no significant differences in children's language, speech production, or functional performance between prescriptions. Parents' ratings of children's device usage and loudness discomfort were not significantly different between prescription groups. Functional performance within the first year of fitting together with degree of hearing loss, presence of additional disabilities, and maternal education explained 44% of variation in language ability of children by three years of age. CONCLUSIONS: There was no significant association between choice of hearing-aid prescription and variance in children's outcomes at three years of age. In contrast, additional disability, maternal educational level, and early functional performance were significant predictive factors of children's outcomes. PMID- 22934932 TI - Effect of contralateral acoustic stimulation on cochlear tuning measured using stimulus frequency and distortion product OAEs. AB - OBJECTIVE: To study whether a change in cochlear tuning, measured using OAEs, could be detected due to contralateral activation of the efferent system using broadband noise. DESIGN: Cochlear tuning measures based on SFOAE phase gradients and SFOAE-2TS 'Q' were used to test this hypothesis. SFOAE magnitude and phase gradient were measured using a pure-tone sweep from 1248 to 2496 Hz at 50 dB SPL. 2TS curves of SFOAE were recorded with a suppressor frequency swept from 1120 to 2080 Hz at 50 dB SPL. DPOAE f2-sweep phase gradient was also obtained to allow comparisons with the literature. All three assays were performed across with- and no-CAS conditions. STUDY SAMPLE: Twenty-two young, normal-hearing adults. RESULTS: CAS did not produce a statistically significant change in the tuning metric in any of the OAE methods used, despite producing significant reductions in the OAE magnitude. CONCLUSION: It is unknown whether this insensitivity to CAS is due to an insensitivity of these three measures to cochlear mechanical tuning. The results suggest that any changes in tuning induced by CAS that may occur are small and difficult to detect using the OAE measurement paradigms used here. PMID- 22934933 TI - A replication study on proposed candidate genes in Meniere's disease, and a review of the current status of genetic studies. AB - OBJECTIVE: Multiple candidate genes have been presented for Meniere's disease (MD), but to date no positive replications have been reported. We review here all the previously proposed candidate genes for MD and report our results on the analysis of six such genes, AQP2, KCNE1, KCNE3, HCFC1, COCH, and ADD1. STUDY SAMPLE: A well-defined sample set of 38 sporadic and 21 familial Finnish MD patients. DESIGN: Mutation analysis, case-control study, and review of literature. RESULTS: A polymorphism rs1805127 in the potassium channel gene, KCNE1, was associated with MD in sporadic (p = 0.011), but not familial patients (p = 0.62). In addition, we identified four novel unique variations in the KCNE1 gene. PolyPhen and Mutation Taster analyses indicated that at least one of the variations c.259T > C; p.Trp87Arg is probably damaging to the coded protein. CONCLUSIONS: Our review of the reported candidate genes shows that the current understanding of the genetic factors contributing to the development of MD is limited, and that the study of its etiology would benefit greatly from more comprehensive genetic knowledge. PMID- 22934934 TI - "Smoking cessation for pregnancy and beyond: a virtual clinic," an innovative web based training for healthcare professionals. AB - This article provides an overview of an interactive online training designed for healthcare professionals to hone their skills in assisting pregnant women to quit smoking and to remain quit postpartum. The curriculum teaches a best practice approach for smoking cessation, the 5A's, and is based on current clinical recommendations. The program offers five interactive case simulations and comprehensive discussions of patient visits, short lectures on relevant topics from leading experts, interviews with real patients who have quit, and a dedicated website of pertinent links and office resources. The training is accredited for up to 4.5 hours of continuing education credits. To access the training, please visit www.smokingcessationandpregnancy.org. PMID- 22934935 TI - Enhancing surface enhanced Raman scattering (SERS) detection of propranolol with multiobjective evolutionary optimization. AB - Colloidal-based surface-enhanced Raman scattering (SERS) is a complex technique, where interaction between multiple parameters, such as colloid type, its concentration, and aggregating agent, is poorly understood. As a result SERS has so far achieved limited reproducibility. Therefore the aim of this study was to improve enhancement and reproducibility in SERS, and to achieve this, we have developed a multiobjective evolutionary algorithm (MOEA) based on Pareto optimality. In this MOEA approach, we tested a combination of five different colloids with six different aggregating agents, and a wide range of concentrations for both were explored; in addition we included in the optimization process three laser excitation wavelengths. For this optimization of experimental conditions for SERS, we chose the beta-adrenergic blocker drug propranolol as the target analyte. The objective functions chosen suitable for this multiobjective problem were the ratio between the full width at half-maximum and the half-maximum intensity for enhancement and correlation coefficient for reproducibility. To analyze a full search of all the experimental conditions, 7785 experiments would have to be performed empirically; however, we demonstrated the search for acceptable experimental conditions of SERS can be achieved using only 4% of these possible experiments. The MOEA identified several experimental conditions for each objective which allowed a limit of detection of 2.36 ng/mL (7.97 nM) propranolol, and this is significantly lower (>25 times) than previous SERS studies aimed at detecting this beta-blocker. PMID- 22934936 TI - Maternal and newborn healthcare providers in rural Tanzania: in-depth interviews exploring influences on motivation, performance and job satisfaction. AB - INTRODUCTION: Major improvements in maternal and neonatal health (MNH) remain elusive in Tanzania. The causes are closely related to the health system and overall human resource policy. Just 35% of the required workforce is actually in place and 43% of available staff consists of lower-level cadres such as auxiliaries. Staff motivation is also a challenge. In rural areas the problems of recruiting and retaining health staff are most pronounced. Yet, it is here that the majority of the population continues to reside. A detailed understanding of the influences on the motivation, performance and job satisfaction of providers at rural, primary level facilities was sought to inform a research project in its early stages. The providers approached were those found to be delivering MNH care on the ground, and thus include auxiliary staff. Much of the previous work on motivation has focused on defined professional groups such as physicians and nurses. While attention has recently broadened to also include mid-level providers, the views of auxiliary health workers have seldom been explored. METHODS: In-depth interviews were the methodology of choice. An interview guideline was prepared with the involvement of Tanzanian psychologists, sociologists and health professionals to ensure the instrument was rooted in the socio-cultural setting of its application. Interviews were conducted with 25 MNH providers, 8 facility and district managers, and 2 policy-makers. RESULTS: Key sources of encouragement for all the types of respondents included community appreciation, perceived government and development partner support for MNH, and on-the-job learning. Discouragements were overwhelmingly financial in nature, but also included facility understaffing and the resulting workload, malfunction of the promotion system as well as health and safety, and security issues. Low-level cadres were found to be particularly discouraged. Difficulties and weaknesses in the management of rural facilities were revealed. Basic steps that could improve performance appeared to be overlooked. Motivation was generally referred to as being fair or low. However, all types of providers derived quite a strong degree of satisfaction, of an intrinsic nature, from their work. CONCLUSIONS: The influences on MNH provider motivation, performance and satisfaction were shown to be complex and to span different levels. Variations in the use of terms and concepts pertaining to motivation were found, and further clarification is needed. Intrinsic rewards play a role in continued provider willingness to exert an effort at work. In the critical area of MNH and the rural setting many providers, particularly auxiliary staff, felt poorly supported. The causes of discouragement were broadly divided into those requiring renewed policy attention and those which could be addressed by strengthening the skills of rural facility managers, enhancing the status of their role, and increasing the support they receive from higher levels of the health system. Given the increased reliance on staff with lower-levels of training in rural areas, the importance of the latter has never been greater. PMID- 22934937 TI - Association between chronic kidney disease and urinary calculus by stone location: a population-based study. AB - Study Type--Disease prevalence study (cohort design) Level of Evidence 2a. What's known on the subject? and What does the study add? Several studies have estimated the potential association of urinary calculus (UC) with chronic kidney disease (CKD). However, previous literature focusing on this issue tended to evaluate the impact of kidney stones alone on incident CKD, with no studies having been conducted investigating the association between CKD and stone formation in other portions of the urological system. We found that patients with CKD were consistently more likely than comparison subjects to have been previously diagnosed with kidney calculus (odds ratio [OR] 2.10, 95% confidence interval [CI] 1.95-2.27), ureter calculus (OR 1.68, 95% CI 1.51-1.85), bladder calculus (OR 1.49, 95% CI 1.13-1.98), and unspecified calculus (OR 1.89, 95% CI 1.74 2.06). We concluded that there was an association between CKD and UC regardless of stone location. OBJECTIVE: * To explore the association of chronic kidney disease (CKD) with prior kidney calculus, ureter calculus, and bladder calculus using a population-based dataset in Taiwan. Several studies have estimated the potential association of urinary calculus (UC) with CKD. However, previous literature focusing on this issue tended to evaluate the impact of kidney stones alone on incident CKD, with no studies having been conducted investigating the association between CKD and stone formation in other portions of the urological system. PATIENTS AND METHODS: * We identified 21,474 patients who received their first-time diagnosis of CKD between 2001 and 2009. * The 21,474 controls were frequency-matched with cases for sex, age group, and index year. * We used conditional logistic regression analyses to compute the odds ratio (OR) and corresponding 95% confidence interval (CI) as an estimation of association between CKD and having been previously diagnosed with UC. RESULTS: * The results show that compared with controls, the OR of prior UC for cases was 1.91 (95% CI 1.81-2.01, P < 0.001) after adjusting for potential confounders. * Furthermore, cases were consistently more likely than controls to have been previously diagnosed with kidney calculus (OR 2.10, 95% CI 1.95-2.27), ureter calculus (OR 1.68, 95% CI 1.51-1.85), bladder calculus (OR 1.49, 95% CI 1.13-1.98), and unspecified UC (OR 1.89, 95% CI 1.74-2.06). CONCLUSION: * We concluded that there was an association between ckd and UC regardless of stone location. PMID- 22934938 TI - Single point mutation in Vibrio cholerae cytolysin compromises the membrane pore formation mechanism of the toxin. AB - Vibrio cholerae cytolysin (VCC) belongs to the family of beta-barrel pore-forming protein toxins. VCC is secreted by the bacteria as water-soluble monomers, which upon binding to target eukaryotic cells form transmembrane heptameric beta-barrel channels. High-resolution 3D structures are described both for the water-soluble monomeric form and the transmembrane oligomeric pore; albeit that our understanding of the mechanistic details of the membrane pore-formation process remains incomplete. Here, we report the characterization of a nonfunctional VCC variant harboring a single point mutation of Ala425Val positioned within a potential membrane-interacting loop in the VCC structure. The mutation appears to affect interaction of the toxin with erythrocytes as well as cholesterol containing liposome membrane, without affecting the oligomerization ability of the membrane-bound toxin molecules. The membrane-bound oligomers formed by this VCC mutant do not appear to represent the functional pore assembly of the toxin; rather, such assembly could be considered as being trapped in an abortive, nonfunctional oligomeric state. Our results suggest that the Ala425Val mutation in VCC critically compromises its cholesterol-dependent membrane-interaction mechanism and also abrogates the process of functional membrane pore formation by the toxin. PMID- 22934940 TI - Differential diagnosis between schizophrenia and autism in adulthood: a case report. AB - The clinical distinction between autism spectrum disorders (ASD), also called pervasive developmental disorders (PDD), and schizophrenia is often difficult to make. Here we describe a case of an adult patient presenting with a diagnosis of schizophrenia based on a history of functional deterioration and presumed persecutory delusions. A psychiatric and psychological assessment conducted from a developmental perspective, in association with direct observation and neuropsychological evaluation for intellectual disabilities and autism, led to a diagnosis of PDD not otherwise specified, with revision of the initial diagnosis of schizophrenia. PMID- 22934939 TI - Multiscale analysis of compartment models with dispersal. AB - The characterization of the population dynamics of animal populations and dispersal provides the underlying setting of this article. Novel results emerge from our exploration of the role of disease in this context. We focus on the study of the impact of dispersal on the dynamics of populations that account for (a) induced Allee effects; (b) disease dynamics; and (c) spatial heterogeneity, using deterministic and stochastic models. Specifically, the models incorporate disease-driven effects on the individuals' competitive ability to acquire resources as well as on their ability to move or reproduce. The results bring to the forefront the role of initial conditions and patch quality as well as 'topological' structure or connectivity landscape structure (the physical space where individuals move, reproduce, get sick, die, or compete for resources). The emphasis is placed on the dynamics of populations when disease is an important selective force. This article surveys the appropriate literature while including original research. PMID- 22934941 TI - Nampt/Visfatin/PBEF: a functionally multi-faceted protein with a pivotal role in malignant tumors. AB - Nampt/Visfatin/PBEF is a primary, rate-limiting enzyme involved in NAD+ biosynthesis, which serves as a pivotal substance for proteins, and is required for cell growth, survival, DNA replication and repair and energy metabolism. Growing researches have elucidated that it is a pleiotropic protein that functions not only as an enzyme, but also as an adipocytokin, a growth factor, and a cytokine. Additionally, accumulated evidences indicate that Nampt is correlated to various malignant tumors, and complicated mechanisms are proposed to be involved in the carcinogenesis, progression, invasion and metastasis of it, including regulation of energy metabolism and genome instability, promotion of proliferation, angiogenesis, and tumor-promoting inflammation, resistance in cell death and avoidance of immune destruction. APO866 and CHS-828 are recognized inhibitors of Nampt, known to block the intracellular and extracellular NAD+ synthesis pathway. Both of them are currently in clinical trials for the treatment of various malignant tumors and have been shown to represent novel promising antitumor chemotherapeutic agents. PMID- 22934943 TI - A generalized model and high throughput data analysis system for functional modulation of receptor-agonist systems suitable for use in drug discovery. AB - Positive allosteric modulators (PAMs) of receptors represent a class of pharmacologic agents having the desirable property of acting only in the presence of cognate ligands. Discovery and optimization of the structure activity relationships of PAMs is complicated by the requirement of a second ligand to manifest their action, and by the need to quantify both affinity and intrinsic efficacy. Multivariate regression analysis is a statistical method capable of simultaneously obtaining affinity and intrinsic efficacy parameters from curve fits of multiple agonist dose-response functions generated in the presence of varying concentrations of PAMs. Capitalizing on the advantages of multivariate regression analysis for PAM optimization requires a theoretical framework and a system that facilitates efficient flow of information from data generation through data analysis, storage, and retrieval. We describe here the experimental design, mathematical model and informatics workflow enabling a multivariate regression approach for rapidly obtaining affinity and intrinsic efficacy values for PAMs in a drug discovery setting. PMID- 22934944 TI - An overview of computational life science databases & exchange formats of relevance to chemical biology research. AB - Databases and exchange formats describing biological entities such as chemicals and proteins, along with their relationships, are a critical component of research in life sciences disciplines, including chemical biology wherein small information about small molecule properties converges with cellular and molecular biology. Databases for storing biological entities are growing not only in size, but also in type, with many similarities between them and often subtle differences. The data formats available to describe and exchange these entities are numerous as well. In general, each format is optimized for a particular purpose or database, and hence some understanding of these formats is required when choosing one for research purposes. This paper reviews a selection of different databases and data formats with the goal of summarizing their purposes, features, and limitations. Databases are reviewed under the categories of 1) protein interactions, 2) metabolic pathways, 3) chemical interactions, and 4) drug discovery. Representation formats will be discussed according to those describing chemical structures, and those describing genomic/proteomic entities. PMID- 22934945 TI - New informatics and automated infrastructure to accelerate new leads discovery by high throughput screening (HTS). AB - The Lankenau Institute for Medical Research Chemical Genomics Center, Inc. has developed a new (patents issued and pending) Nanotube Automated Repository System (NARS) for dynamic storage of millions of 'single-shot' samples stored in a new monolithic microtiter-storage tube plate of our own design we call 'nanotubes.' We have integrated the NARS with customized software to efficiently access up to 10,000,000 samples stored continuously frozen (-20 degrees C) in a dehumidified enclosure and sealed in a new microtiter NARS plate that is SBS compliant. Additional software was developed to analyze HTS data from orthogonally pooled compound libraries. Following 'de-convolution' of pooled HTS data, the software designates confirmatory retest samples to be 'cherry-picked' using the NARS. The application of a new, fully-integrated infrastructure for new leads discovery is described in detail. Other applications for our technologies and new infrastructure are discussed. PMID- 22934946 TI - Compound ranking based on a new mathematical measure of effectiveness using time course data from cell-based assays. AB - The half maximal inhibitory concentration (IC50) has several limitations that make it unsuitable for examining a large number of compounds in cytotoxicity studies, particularly when multiple exposure periods are tested. This article proposes a new approach to measure drug effectiveness, which allows ranking compounds according to their toxic effects on live cells. This effectiveness measure, which combines all exposure times tested, compares the growth rates of a particular cell line in the presence of the compound with its growth rate in the presence of DMSO alone. Our approach allows measuring a wider spectrum of toxicity than the IC50 approach, and allows automatic analyses of a large number of compounds. It can be easily implemented in linear regression software, provides a comparable measure of effectiveness for each investigated compound (both toxic and non-toxic), and allows statistically testing the null hypothesis that a compound is non-toxic versus the alternative that it is toxic. Importantly, our approach allows defining an automated decision rule for deciding whether a compound is significantly toxic. As an illustration, we describe the results of a cellbased study of the cytotoxicity of 24 analogs of novobiocin, a C terminal inhibitor of heat shock protein 90 (Hsp90); the compounds were ranked in order of cytotoxicity to a panel of 18 cancer cell lines and 1 normal cell line. Our approach may also be a good alternative to computing the half maximal effective concentration (EC50) in studies searching for compounds that promote cell growth. PMID- 22934947 TI - Recent trends and applications in 3D virtual screening. AB - Virtual screening (VS) is becoming an increasingly important approach for identifying and selecting biologically active molecules against specific pharmaceutically relevant targets. Compared to conventional high throughput screening techniques, in silico screening is fast and inexpensive, and is increasing in popularity in early-stage drug discovery endeavours. This paper reviews and discusses recent trends and developments in three-dimensional (3D) receptor-based and ligand-based VS methodologies. First, we describe the concept of accessible chemical space and its exploration. We then describe 3D structural ligand-based VS techniques, hybrid approaches, and new approaches to exploit additional knowledge that can now be found in large chemogenomic databases. We also briefly discuss some potential issues relating to pharmacokinetics, toxicity profiling, target identification and validation, inverse docking, scaffold hopping and drug re-purposing. We propose that the best way to advance the state of the art in 3D VS is to integrate complementary strategies in a single drug discovery pipeline, rather than to focus only on theoretical or computational improvements of individual techniques. Two recent 3D VS case studies concerning the LXR-beta receptor and the CCR5/CXCR4 HIV co-receptors are presented as examples which implement some of the complementary methods and strategies that are reviewed here. PMID- 22934948 TI - The chemometric study and quantitative structure retention relationship modeling of liquid chromatography separation of ziprasidone components. AB - Optimization of the experimental conditions of a novel HPLC method for determination of the impurity levels with ziprasidone (in bulk substance and pharmaceutical dosage forms) was performed with use of Multi-Layer Perceptron (MLP) Artificial Neural Networks (ANN) and Response Surface Plots. The obtained experimental conditions were further used to test a set of 20 reversed-phase columns for their selectivity towards ziprasidone components by use of the principal component analysis (PCA) and hierarchical clustering analysis (HCA). The obtained HPLC retention times of ziprasidone and its impurities (Imp I-V) along with the computed molecular parameters of the examined compounds were further used in the Quantitative Structure Retention Relationship (QSRR) study. The performed QSRR study has selected the LogD(pH 1.5), LogD(pH 2.5), LogD(pH 4.0), LogP, MS, and SAS parameters as descriptors of the chromatographic behavior of ziprasidone components. The developed QSRR model can be very useful in the tR prediction for the ziprasidone derivatives (impurities, degradation products, and metabolites). As the performed LC-MS study of the test solution has confirmed that the unknown impurity (t(R): 11.270 min) in the test solution is the TS1, one from two candidates predicted by QSRR (TS1 and TS5), the high prediction potential of the created QSRR models has been proved. PMID- 22934949 TI - Predicting coupling specificity of GPCRs based on the optimization of the coupling regions. AB - Prediction of promiscuous coupling between G-protein coupling receptors (GPCRs) and various G-proteins is one of the challenges for current research. In this article, a novel method that based on the optimization of the coupling regions is proposed. The cross validation results demonstrate that it can achieve an average accuracy of over 80% for promiscuous coupling prediction. The results further suggest that the optimized coupling regions may be important for the processes of signal transduction pathways. PMID- 22934951 TI - Identification of novel NaV1.7 antagonists using high throughput screening platforms. AB - Congenital Insensitivity to Pain (CIP) is a loss of function mutation resulting in a truncated NaV1.7 protein, suggesting a pivotal role in pain signaling and rendering it an important pharmaceutical target for multiple pain conditions. The structural homology in the NaV-channel family makes it challenging to design effective analgesic compounds without inducing for example cardiotoxicity or seizure liabilities. An additional approach to structural isoform selectivity is to identify compounds with use- or state-dependent profiles, i.e. inhibition efficacy based on the gating of the ion channel. In general nerve cells in damaged or inflamed tissue are more depolarized and electrically active compared to healthy nerve cells in for instance the heart. This observation has led to the design of two types of screening protocols emulating the voltage condition of peripheral neurons or cardiac tissue. The two voltage protocols have been developed to identify both use- and state-dependent antagonists. In this paper we describe an attempt to merge the two different protocols into one to increase screening efficacy, while retaining relevant state- and use-dependent pharmacology. The new protocol is constructed of two stimulation pulses and a slow voltage ramp for simultaneous assessment of resting and state-dependent block. By comparing all protocols we show that the new protocol indeed filter compounds for state-dependence and increase the prediction power of selecting use dependent compounds. PMID- 22934950 TI - A simple method for analyzing actives in random RNAi screens: introducing the "H Score" for hit nomination & gene prioritization. AB - Due to the numerous challenges in hit identification from random RNAi screening, we have examined current practices with a discovery of a variety of methodologies employed and published in many reports; majority of them, unfortunately, do not address the minimum associated criteria for hit nomination, as this could potentially have been the cause or may well be the explanation as to the lack of confirmation and follow up studies, currently facing the RNAi field. Overall, we find that these criteria or parameters are not well defined, in most cases arbitrary in nature, and hence rendering it extremely difficult to judge the quality of and confidence in nominated hits across published studies. For this purpose, we have developed a simple method to score actives independent of assay readout; and provide, for the first time, a homogenous platform enabling cross comparison of active gene lists resulting from different RNAi screening technologies. Here, we report on our recently developed method dedicated to RNAi data output analysis referred to as the BDA method applicable to both arrayed and pooled RNAi technologies; wherein the concerns pertaining to inconsistent hit nomination and off-target silencing in conjugation with minimal activity criteria to identify a high value target are addressed. In this report, a combined hit rate per gene, called "H score", is introduced and defined. The H score provides a very useful tool for stringent active gene nomination, gene list comparison across multiple studies, prioritization of hits, and evaluation of the quality of the nominated gene hits. PMID- 22934952 TI - Classification of active and weakly active ST inhibitors of HIV-1 integrase using a support vector machine. AB - Using a support vector machine (SVM), two computational models were built to predict whether a compound is an active or weakly active strand transfer (ST) inhibitor based on a dataset of 1257 ST inhibitors of HIV-1 integrase. The model built with MACCS fingerprints gave a prediction accuracy of 91.82% and a Matthews Correlation Coeffiient (MCC) of 0.73 on test set, and the model built with 40 MOE descriptors gave a prediction accuracy of 93.64% and an MCC of 0.79 on test set. Some molecular properties such as electrostatic properties, van der Waals surface area, hydrogen bond properties and the number of fluorine atoms are important factors influencing the interactions between the inhibitor and the integrase. Some scaffolds like beta-diketo acid and its derivatives, naphthyridine carboxamide or the isosteric of it and pyrimidionones may play crucial rule to the activity of the HIV-1 integrase inhibitors. PMID- 22934953 TI - A highly efficient green synthesis of N-alkyl 2-[(2-oxo-2-aryl ethyl) amino] benzamide derivatives from reaction of isatoic anhydride, primary amines and 2 bromoacethophenone. AB - N-alkyl 2-[(2-oxo-2-aryl ethyl)amino] benzamide derivatives have been synthesized in high yields. This involves three-component reaction of isatoic anhydride, primary amines in the presence of 2-bromoacethophenone derivatives. The reaction workup is simple and the products can be easily separated from the reaction mixture. PMID- 22934954 TI - Sonochemical synthesis of silica and silica sulfuric acid nanoparticles from rice husk ash: a new and recyclable catalyst for the acetylation of alcohols and phenols under heterogeneous conditions. AB - Silica nanoparticles were synthesized from rice husk ash at room temperature by sonochemical method. The feeding rate of percipiteting agent and time of sonication were investigated. The nanostructure of the synthesized powder was realized by the FE-SEM photomicrograph, FT-IR spectroscopy, XRD and XRF analyses. These analytical observations have revealed that the nano-sized amorphous silica particles are formed and they are spheroidal in shape. The average particle size of the silica powders is found to be around 50 nm. The as-synthesized silica nanoparticles were subsequently modified with chlorosulfonic acid and prepared silica sulfuric acid nanoparticles, which were employed as an efficient catalyst for the acylation of alcohols and phenols with acetic anhydride in excellent yields under solvent-free conditions at room temperature. This reported method is simple, mild, and environmentally viable and catalyst can be simply recovered and reused over 9 times without any significant loss of its catalytic activity. PMID- 22934955 TI - Persistent decrease in multiple components of the perineuronal net following status epilepticus. AB - In the rodent model of temporal lobe epilepsy, there is extensive synaptic reorganization within the hippocampus following a single prolonged seizure event, after which animals eventually develop epilepsy. The perineuronal net (PN), a component of the neural extracellular matrix (ECM), primarily surrounds inhibitory interneurons and, under normal conditions, restricts synaptic reorganization. The objective of the current study was to explore the effects of status epilepticus (SE) on PNs in the adult hippocampus. The aggrecan component of the PN was studied, acutely (48 h post-SE), sub-acutely (1 week post-SE) and during the chronic period (2 months post-SE). Aggrecan expressing PNs decreased by 1 week, likely contributing to a permissive environment for neuronal reorganization, and remained attenuated at 2 months. The SE-exposed hippocampus showed many PNs with poor structural integrity, a condition rarely seen in controls. Additionally, the decrease in the aggrecan component of the PN was preceded by a decrease in hyaluronan and proteoglycan link protein 1 (HAPLN1) and hyaluronan synthase 3 (HAS3), which are components of the PN known to stabilize the connection between aggrecan and hyaluronan, a major constituent of the ECM. These results were replicated in vitro with the addition of excess KCl to hippocampal cultures. Enhanced neuronal activity caused a decrease in aggrecan, HAPLN1 and HAS3 around hippocampal cells in vivo and in vitro, leaving inhibitory interneurons susceptible to increased synaptic reorganization. These studies are the foundation for future experiments to explore how loss of the PN following SE contributes to the development of epilepsy. PMID- 22934958 TI - The moderating effect of the negative impact of recent life events on the relation between intrinsic religiosity and death ideation in older adults. AB - Researchers tested the hypothesis that the negative impact of recent life events would moderate the relationship between intrinsic religiosity and death ideation in older adults. Participants (n = 272) completed assessments of death ideation, intrinsic religiosity, and negative impact of recent life events. We confirmed the presence of concurrent moderation and found that older adults with greater negative impact of recent life events and high intrinsic religiosity reported greater death ideation. These relatively surprising findings may be due to reduced fear of death in intrinsically religious older adults, an explanation consistent with previous research. PMID- 22934959 TI - Evidence for point transformations in photoactive molecular crystals by the photoinduced creation of diffuse diffraction patterns. AB - Time-resolved diffuse X-ray scattering is one powerful method for monitoring the progression from the creation of local structural changes inside a crystalline material up to the transformation of the whole crystalline bulk. In this work, we study the mechanism of phototransformation of a molecular crystal by time resolved diffuse X-ray scattering. Here, an optical excitation source, like a pulsed laser, initiates structural transformations which are monitored by X-ray scattering techniques. We have studied the dimerization process of the molecular switch alpha-styrylpyrylium (trifluoromethanesulfonate) TFMS, in particular for understanding whether cooperative effects influence the changes of the structure in the bulk and its periodicity. Upon illumination with optical light, alpha styrylpyrylium TFMS instantaneously photoswitches. Depending on the optical fluence, X-ray diffuse planes are observed prior to phototransformation of the bulk. In the early stages of transformation, the analysis reveals systems of randomly distributed islands of product clusters with gradual growth in size and amount. The degree of transformation follows the optical excitation profile, i.e., the spatial absorption of the laser beam. In the present studies, no influence of cooperativity on the photodimerization process has been found. PMID- 22934960 TI - Competition of silene/silylene chemistry with free radical chain reactions using 1-methylsilacyclobutane in the hot-wire chemical vapor deposition process. AB - The gas-phase reaction chemistry of using 1-methylsilacyclobutane (MSCB) in the hot-wire chemical vapor deposition (CVD) process has been investigated by studying the decomposition of MSCB on a heated tungsten filament and subsequent gas-phase reactions in a reactor. Three pathways exist to decompose MSCB on the filament to form ethene/methylsilene, propene/methylsilylene, and methyl radicals. The activation energies for forming propene and methyl radical, respectively, are determined to be 68.7 +/- 1.3 and 46.7 +/- 2.5 kJ.mol(-1), which demonstrates the catalytic nature of the decomposition. The secondary gas phase reactions in the hot-wire CVD reactor are characterized by the competition between a free radical chain reaction and the cycloaddition of silene reactive species produced either from the primary decomposition of MSCB on the filament or the isomerization of silylene species. At lower filament temperatures of 1000 1100 degrees C and short reaction time (t <= 15 min), the free radical chain reaction is equally important as the silene chemistry. With increasing filament temperature and reaction time, silene chemistry predominates. PMID- 22934962 TI - Characterization of a paramagnetic, mononuclear Pt(III)-alkyl complex intermediate in carbon-halogen bond coupling reactions. AB - Addition of Br(2) or I(2) to 14-electron, cationic Pt(II)-alkyl complexes led to the formation of the corresponding carbon-halogen Pt(II) coupling products. Low temperature experiments with Br(2) allowed us to isolate and characterize crystallographically a very unusual mononuclear, paramagnetic Pt(III)-alkyl intermediate with a seesaw structure that can be further oxidized to a transient Pt(IV) species before reductive carbon-halogen coupling reaction takes place. PMID- 22934961 TI - A systematic review and meta-analysis of alcohol consumption and injury risk as a function of study design and recall period. AB - BACKGROUND: It is well established that alcohol consumption is associated with an increased risk of injury. This systematic review and meta-analysis addresses important methodological issues commonly encountered in the alcohol and injury field by delineating the effect of study design and alcohol consumption recall period on effect size magnitude and by conducting gender-specific analyses. METHODS: We performed meta-analyses using random-effect models. Data sources were peer-reviewed studies on alcohol and injury from 1970 to 2009 from MEDLINE, PsychInfo, and on-line journals. Case-control or case-crossover emergency department (ED) studies reporting injury risk from alcohol consumption 6 hours before injury were included. RESULTS: The overall odds of injury were 2.799 (2.214 to 3.538, p < 0.001). For case-crossover studies, the odds were 3.815 (2.646 to 5.499, p < 0.001); for ED case-control studies, the odds were 1.977 (1.385 to 2.821, p < 0.001); and for population case-control designs, the odds were 3.145 (1.583 to 6.247, p < 0.005). The "usual frequency" recall period yielded an odds ratio of 4.235 (2.541 to 7.057, p < 0.001), compared to 2.320 (1.789 to 3.008, p < 0.001) for all other methods. There were significant differences in odds ratio magnitude when comparing studies by design and recall period. Females had higher odds of injury than males, 2.285 (1.361 to 3.836, p < 0.005) versus 1.071 (0.715 to 1.605, p = 0.737). CONCLUSIONS: Study design and alcohol consumption recall period have significant effects on effect size magnitude in estimating the risk of injury from alcohol consumption 6 hours prior to injury. For the "usual frequency" case-crossover design, significant moderator effects were found, resulting in overestimates of injury risk from alcohol. ED case-crossover designs tend to overestimate risk, and ED case-control designs tend to underestimate. We provide recommendations for future ED research. PMID- 22934963 TI - Hybrid nanocluster plasmonic resonator for immunological detection of hepatitis B virus. AB - Approximately 88% of the world population lives in regions with intermediate to high incidence of Hepatitis B virus (HBV), yet current serological and DNA-based detection methods have limited sensitivity and convenience. Here, we describe a preassembled plasmonic resonance nanocluster for HBV detection. The gold nanoparticle acceptors (AuNPs), with HBV surface antigen (HBsAg) epitope, and quantum dot (QD) donors with Fab antibody, are assembled into an immuno-mediated 3D-oriented complex with enhanced energy transfer and fluorescence quenching. The coherent plasmonic resonance between Au and QD nanoparticles is exploited to achieve improved donor-acceptor resonance within the nanocluster, which in the presence of HBV viral particles is disassembled in a highly specific manner. The nanocluster provides high detection specificity and sensitivity of HBV, with a sensitivity limit down to 1-100 viral particles per microliter and to attomolar levels of HBsAg. This general platform could be used to establish multiplex diagnostic assays for a variety of other microbial pathogens. PMID- 22934964 TI - Sulfiredoxin redox-sensitive interaction with S100A4 and non-muscle myosin IIA regulates cancer cell motility. AB - Sulfiredoxin (Srx) is a redox active protein that participates in the reduction of oxidized cysteine residues. Here we identify a novel function of Srx through its specific binding to S-glutathionylated S100A4 affecting its interaction with non-muscle myosin (NMIIA), thereby modulating the effect of S100A4 on NMIIA function and impacting cell adhesion and migration. Srx forms a complex with S100A4 (and has stronger affinity for S-glutathionylated S100A4), regulates its activity, and mediates redox regulation of the interaction of S100A4 with NMIIA. The consequence of this regulation is microfilament remodeling and altered cellular motility and adhesion. Srx-overexpressing cells had reduced levels of adhesion, decreased levels of Tyr(397)-phosphorylated focal adhesion kinase, and increased cell motility in wound healing assays. These results describe a novel redox-sensitive role for Srx in mediating complex protein interactions with plausible consequences for cancer cell motility. PMID- 22934965 TI - Silkworms can be used as an animal model to screen and evaluate gouty therapeutic drugs. AB - In the past few decades, the mouse has been used as a mammalian model for hyperuricemia and gout, which has increased not only in prevalence, but also in clinical complexity, accentuated in part by a dearth of novel advances in treatments for hyperuricemia and gouty arthritis. However, the use of mice for the development of gouty therapeutic drugs creates a number of problems. Thus, identification and evaluation of the therapeutic effects of chemicals in an alternative animal model is desirable. In the present study, the effects of gouty therapeutic drugs on lowering the content of uric acid and inhibiting activity of xanthine oxidase were evaluated by using a silkworm model, Bombyx mori L. (Lepidoptera: Bombycidae). The results showed that the effectiveness of oral administration of various gouty therapeutic drugs to 5(th) instar silkworms is consistent with results for human. The activity of xanthine oxidase of silkworm treated with allopurinol was lower, and declined in a dose-dependent manner compared with control silkworms, while sodium bicarbonate failed at inhibiting the activity of xanthine oxidase. The concentration of uric acid in the both hemolymph and fat body declined by 90 and 95% at six days post-administration with 25 mg/mL of allopurinol, respectively (p < 0.01), while the concentration of uric acid in both the hemolymph and fat body also declined by 81 and 95% at six days post-administration with 25 mg/mL of sodium bicarbonate, respectively (p < 0.01). Moreover, the epidermis of silkworm treated with allopurinol or sodium bicarbonate became transparent compared with the negative control group. These results suggest that silkworm larva can be used as an animal model for screening and evaluation of gouty therapeutic drugs. PMID- 22934966 TI - Spontaneous coronary artery dissection--a mimic. AB - Spontaneous coronary artery dissection (SCAD) is a rare but potentially life threatening condition if it goes unrecognized. Symptoms can range from chest pain to sudden cardiac death. We present a case of 33 year-old female marathon runner who presented to emergency department (ED) complaining of sudden onset of non positional, constant, pleuritic chest discomfort. She was eventually found to have spontaneous dissection of coronary artery. The mimicking nature of SCAD is presented in this article. We conclude that spontaneous coronary dissection, although still challenging due to its mimicking nature, should be considered in the differential diagnosis of chest pain and associated myocardial injury. PMID- 22934967 TI - Predictor of event-free survival in patients with myocardial infarction. AB - BACKGROUND AND PURPOSE: The incidence of cardiovascular events remains high in patients with myocardial infarction (MI) despite advances in current therapies. New and better methods for identifying patients at high risk of recurrent cardiovascular events are needed. This study aimed to analyze the clinical predictors of cardiovascular events in patients with MI. METHODS: The prospective cohort study consisted of 123 men and women aged between 31 and 80 years who had suffered a previous myocardial infarction (MI) 3-12 months before the examinations. The exclusion criteria were known diabetes mellitus and chronic inflammatory disease. Patients were followed up over 6.03 +/- 1.36 years for CV death, recurrent MI, stroke and unstable angina pectoris. Plasma levels of high sensitivity C-reactive protein (hs-CRP), total cholesterol and triglycerides were measured at the baseline. Echocardiography was performed. RESULTS: hs-CRP was significantly higher (P < 0.05) and left ventricular ejection fraction (LVEF) was borderline significantly lower (P = 0.057) in patients with CV events compared with those without CV events. In multivariate statistical analysis and after adjustment for age, sex, total cholesterol, smoking, and other baseline characteristics, hs-CRP > 3 mg/l, (RR: 6.23, 95%CI: 1.47-26.39; P < 0.01) and LVEF (RR: 0.94, 95%CI: 0.88-1.00; P < 0.05) remain as independent predictors of CV events. CONCLUSIONS: In this study population with previous MI an elevated hs CRP > 3 mg/l and left ventricular dysfunction were significant predictors of CV death, recurrent MI, stroke and unstable angina pectoris, independent of baseline characteristics and medical treatment. Data from the study suggest that hs-CRP levels >= 3 mg/l and baseline ejections fraction can be used to stratify individuals at high risk of adverse CV events from patients with stable and asymptomatic coronary artery disease (CAD). PMID- 22934969 TI - Approach to construct polysubstituted 1,2-dihydronaphtho[2,1-b]furans and their aerobic oxidative aromatization. AB - Triarylaminium salt was disclosed as an efficient initiator for the novel Friedel Crafts alkylation/annulation cascade reaction between chalcone epoxides and 2 naphthols to construct polysubstituted 1,2-dihydronaphtho[2,1-b]furans. The DDQ/NaNO(2)/O(2) catalytic system was first applied to the aerobic oxidative aromatization of heterocycles, and a simple and efficient one-pot tandem FC alkylation/annulation/aerobic oxidative aromatization procedure was also developed for the synthesis of complex naphtho[2,1-b]furans. PMID- 22934970 TI - Beyond genotype to phenotype: why the phenotype of an individual cannot always be predicted from their genome sequence and the environment that they experience. AB - One promise of personalized medicine is that it will be possible to make useful predictions about the phenotypes of individuals from their complete genome sequences (e.g. concerning their susceptibility to disease). However, to what extent is knowledge about an individual's genotype, together with information about the environment that they have experienced, sufficient to predict phenotypic variation? In the present review, we argue that, although the 'typical' phenotypic outcome of an individual's genome can be predicted, it is much more difficult to predict the actual outcome for a particular individual. We highlight three reasons for this. First, the outcome of mutations can be influenced by random (stochastic) processes. Second, genetic variation present in one generation can influence phenotypic traits in the next generation, even if individuals do not inherit this variation. Third, the environment experienced by one generation can influence phenotypic variation in the next generation. These contributions to phenotypic variation have long been appreciated by quantitative geneticists, although they have only recently been studied at the molecular level. Taken together, they mean that, in many cases, the genotypes of individuals and the environment that they experience may not be sufficient to determine their phenotypes. A more comprehensive genotype-to-phenotype model will be required to make accurate predictions about the biology of individuals. PMID- 22934971 TI - Improvement of Iranian nurses' competence through professional portfolio: a quasi experimental study. AB - The aim of the study was to determine the effect of a portfolio-based professional development program on nurses' competence in a university hospital in Iran. A pre-test/post-test, controlled, quasi-experimental design was used. From the university hospital's 18 general wards, four wards were randomly selected. Two wards were randomly allocated as the experimental group (35 subjects) and two wards as the control group (38 subjects). Nurses in the experimental group participated in a 12-month portfolio-based professional development program and nurses in the control group participated in the routine professional development programs of their wards. The data were collected by the Nurse Competence Scale and were analyzed using descriptive statistics and independent and paired t-tests. After intervention, the average nurses' competence in the experimental group increased significantly (P < 0.001) but these changes in the control group were not significant (P = 0.08). This study shows that the professional portfolio is an effective tool for improving nurses' competence. The professional portfolios help nurses update their knowledge, skills, and competence towards their full role as nurses. PMID- 22934972 TI - Apoptosis-associated speck-like protein containing a CARD (ASC) expression profiles in familial Mediterranean fever (FMF) patients with different MEFV mutation patterns. AB - OBJECTIVES: The inflammasome complex and the inflammatory pathway have been implicated in the pathogenesis of the most common autoinflammatory disorder, familial Mediterranean fever (FMF). Pyrin, the protein product of the FMF gene MEFV, interacts with the inflammasome complex adaptor protein ASC/PYCARD (apoptosis-associated speck-like protein with a CARD). Pyrin and ASC can both function as either inducers or suppressors of the cellular inflammatory response. We aimed to characterize ASC-induced gene expression profiles in FMF patients with different MEFV mutation patterns. METHODS: A total of 165 Caucasian patients with clinical and molecular FMF diagnoses were enrolled in the study. ASC gene expression was quantified by real-time quantitative reverse transcriptase polymerase chain reaction (qRT-PCR). RESULTS: ASC mRNA expression was increased in the MEFV mutation-positive group compared to the mutation-negative group (p = 0.001). The fold changes of ASC expression in the M694V homozygous (p = 0.02), M694V heterozygous (p = 0.012), compound heterozygous (p = 0.002), and R202Q/P369S/R408Q (p = 0.00) groups relative to the MEFV mutation-negative group were +2.4, +2.7, +3, and +3.4, respectively. qRT-PCR did not reveal a significant difference in ASC mRNA expression levels among the MEFV mutation-positive groups (p > 0.05). CONCLUSION: ASC mRNA expression was up-regulated in patients carrying MEFV mutations independent of mutation type. There was no significant relationship between specific MEFV genotypes and the level of ASC expression in the patient group analysed. Thus, the findings of this work may suggest a crucial relationship between mutant MEFV/pyrin and remarkable ASC up-regulation in FMF inflammation. PMID- 22934973 TI - Effects of local delivery of tetradecylthioacetic acid within the injured coronary vessel wall. AB - OBJECTIVES: Inflammation is involved in cell proliferation and collagen deposition causing vessel wall remodeling and restenosis after plain balloon angioplasty. Local drug delivery of bioactive agents that reduce the incidence of adverse wall remodeling is of considerable interest concerning treatment strategies for coronary vessel disease and could alter the need of repeated revascularization. DESIGN: In this study, 34 domestic pigs undergoing coronary balloon injury were randomly assigned to Tetradecylthioacetic acid (TTA) or placebo delivered locally. After four weeks, vessel wall collagen density, inflammatory markers and lipid fractions were assessed as well as cell proliferation. RESULTS: Collagen particle count was lower after TTA compared to placebo, 177 +/- 11 n/area versus 225 +/- 13 n/area (p = 0.007). Interleukin-2 (IL-2) concentration was reduced, 1.6 +/- 0.02 pg/ml versus 2.6 +/- 0.5 pg/ml, (p = 0.01). The anti-inflammatory index was increased after TTA, 46.28 +/- 12.1 versus 34.66 +/- 4.5, (p = 0.025). There were no differences between TTA and placebo with regard to cell proliferation. CONCLUSIONS: Local delivery of TTA reduced the local inflammatory response and collagen accumulation. Local balloon delivery of TTA into the vessel wall may represent an alternative antiproliferative strategy for preventing restenosis, in particular for vessels with obstructive disease not available for stent implantation. PMID- 22934974 TI - Interplay of foot-and-mouth disease virus, antibodies and plasmacytoid dendritic cells: virus opsonization under non-neutralizing conditions results in enhanced interferon-alpha responses. AB - Foot-and-mouth disease virus (FMDV) is a highly infectious member of the Picornaviridae inducing an acute disease of cloven-hoofed species. Vaccine induced immune protection correlates with the presence of high levels of neutralizing antibodies but also opsonising antibodies have been proposed as an important mechanism of the immune response contributing to virus clearance by macrophages and leading to the production of type-I interferon (IFN) by plasmacytoid dendritic cells (pDC). The present study demonstrates that the opsonising antibody titres mediating enhanced IFN-alpha responses in pDC were similar to neutralizing titres, when antigenically related viruses from the same serotype were employed. However, sera cross-reacted also with non-neutralized isolates of multiple serotypes, when tested in this assay. Both uncomplexed virus and immune complexed virus stimulated pDC via Toll-like receptor 7. An additional finding of potential importance for strain-specific differences in virulence and/or immunogenicity was that pDC activation by FMDV strongly differed between viral isolates. Altogether, our results indicate that opsonising antibodies can have a broader reactivity than neutralizing antibodies and may contribute to antiviral responses induced against antigenically distant viruses. PMID- 22934975 TI - Veterinary Quarterly ranks 30/143 in the top 25% of Veterinary Sciences category. PMID- 22934976 TI - Microfluidic generation of droplets with a high loading of nanoparticles. AB - Microfluidic approaches for controlled generation of colloidal clusters, for example, via encapsulation of colloidal particles in droplets, have been used for the synthesis of functional materials including drug delivery carriers. Most of the studies, however, use a low concentration of an original colloidal suspension (<10 wt %). Here we demonstrate microfluidic approaches for directly making droplets with moderate (10-25 wt %) and high (>60 wt %) particle concentrations. Three types of microfluidic devices, PDMS flow-focusing, PDMS T-junction, and microcapillary devices, are investigated for direct encapsulation of a high concentration of polystyrene (PS) nanoparticles in droplets. In particular, it is shown that PDMS devices fabricated by soft lithography can generate droplets from a 25 wt % PS suspension, whereas microcapillary devices made from glass capillary tubes are able to produce droplets from a 67 wt % PS nanoparticle suspension. When the PS concentration is between 0.6 and 25 wt %, the size of the droplets is found to change with the oil-to-water flow rate ratio and is independent of the concentration of particles in the initial suspensions. Drop sizes from ~12 to 40 MUm are made using flow rate ratios Q(oil)/Q(water) from 20 to 1, respectively, with either of the PDMS devices. However, clogging occurs in PDMS devices at high PS concentrations (>25 wt %) arising from interactions between the PS colloids and the surface of PDMS devices. Glass microcapillary devices, on the other hand, are resistant to clogging and can produce droplets continuously even when the concentration of PS nanoparticles reaches 67 wt %. We believe that our findings indicate useful approaches and guidelines for the controlled generation of emulsions filled with a high loading of nanoparticles, which are useful for drug delivery applications. PMID- 22934977 TI - Enterobacteriaceae that produce extended-spectrum beta-lactamases and AmpC beta lactamases in the community: the tip of the iceberg? AB - Escherichia coli remains one of the most frequent causes of nosocomial and community-acquired bacterial infections including urinary tract infections, enteric infections, and systemic infections in humans. Extra-intestinal pathogenic E. coli or ExPEC had emerged during the 2000s as an important player in the resistance to antibiotics, especially to the cephalosporins and fluoroquinolones. Most importantly among ExPEC, is the increasing recognition of isolates producing "newer beta-lactamases" that consist of plasmidmediated AmpC beta-lactamases (e.g. CMY), extended-spectrum beta-lactamases (e.g. CTX-M), and carbapenemases (e.g. NDM, KPC and OXA-48). Since the mid 2000's, E. coli that produce CTX-M enzymes (especially CTX-M-15), have emerged worldwide as important causes of community-associated urinary tract (UTIs) and blood stream infections. Community-associated acquisition and infections due to enterobacteria with plasmid-mediated AmpC beta-lactamases are a relatively recent phenomenon and have been described in Canada and USA. Empiric antibiotic coverage for these resistant organisms should be considered in community patients presenting with sepsis involving the urinary tract especially if a patient recently traveled to a high risk area. If this emerging public health threat is ignored, it is possible that the medical community may be forced in the near future to use the carbapenems as the first choice for the empirical treatment of serious infections associated with urinary tract infections originating from the community. PMID- 22934978 TI - Complex encounters: nanoparticles in whole blood and their uptake into different types of white blood cells. AB - AIM: A whole blood assay for evaluating the uptake of nanoparticles into white blood cells in order to close the gap between basic studies in cell culture and pharmacokinetic studies in animals was developed. MATERIALS & METHODS: After drawing peripheral blood into standard blood collection vials with different anticoagulants, amino- and carboxy-functionalized polymeric styrene nanoparticles were added and uptake was evaluated by flow cytometry. RESULTS: By counterstaining surface markers of leukocytes (e.g., monocytes, neutrophil granulocytes, B or T lymphocytes), investigations of different cell types can be conducted in a single run by flow cytometry. The authors demonstrated that anticoagulation should be done with heparin, and not EDTA, in order to prevent hampering of uptake mechanisms. CONCLUSION: By using heparinized whole blood, the authors demonstrated differences and usefulness of this assay for screening cellular uptake as it should occur in the bloodstream. Nevertheless, animal studies are warranted for final assessment of the nanoparticles. PMID- 22934979 TI - Metallofullerol nanoparticles with low toxicity inhibit tumor growth by induction of G0/G1 arrest. AB - AIMS: [Gd@C(82)(OH)(22)](n) is a new type of nanoparticle with potent antineoplastic activity and low toxicity compared with traditional drugs. In this study, we explored, for the first time, the effect of [Gd@C(82)(OH)(22)](n) on the cell cycle using human breast cancer MCF-7 and human umbilical vein endothelial ECV304 cell lines by flow cytometry. METHODS: Cell viability was assessed through CCK-8 assay, and MCF-7 tumor-bearing mice were examined after 2 weeks of treatment with [Gd@C(82)(OH)(22)](n). Cell cycle-related gene expression was detected by microarray and confirmed by real-time PCR and RNAi. RESULTS: Cell viability studies confirmed that [Gd@C(82)(OH)(22)](n) inhibits breast cancer effectively with very low toxicity. Flow cytometric data and microarray results reveal that [Gd@C(82)(OH)(22)](n) mediates G0/G1 arrest in both cell lines by regulating the expression of several genes, such as cyclin D2, cyclin E and CDK4, among others, in the related cell cycle. CONCLUSION: Results further demonstrated that [Gd@C(82)(OH)(22)](n) could inhibit tumor growth by inducing tumor cell and vein endothelial cell G0/G1 arrest, which may explain the low toxicity of [Gd@C(82)(OH)(22)](n). PMID- 22934980 TI - Novel electrochemical methodology for activity estimation of alkaline phosphatase based on solubility difference. AB - We propose a novel electrochemical detection system for alkaline phosphatase (ALP) activity using the difference in water and oil solubilities between the substrate, ferrocene ethyl phosphate ester (FcEtOPO(3)(2-)), and the enzymatic product, ferroceneethanol (FcEtOH). In this system, water droplets containing ALP and FcEtOPO(3)(2-) were placed on a Pt disk microelectrode and surrounded by a mineral oil. By the ALP-catalyzed reaction, FcEtOPO(3)(2-) was converted to FcEtOH, which was then transferred to the mineral oil from the water droplets with FcEtOPO(3)(2-) remaining in the water droplets. After partitioning FcEtOH from the water droplets, FcEtOPO(3)(2-) was detected at the Pt disk microelectrode to estimate the ALP activity. Using this novel system, the ALP activity of embryoid bodies was successfully detected. We believe that the present system will be widely applicable to ALP-based bioassays. PMID- 22934981 TI - Recurrent evolution of dependent colony foundation across eusocial insects. AB - The spectacular success of eusocial insects can be attributed to their sophisticated cooperation, yet cooperation is conspicuously absent during colony foundation when queens are alone. Selection against this solitary stage has led to a dramatically different strategy in thousands of eusocial insect species in which colonies are started by groups of nestmates and the benefits of sociality are retained continuously. Dependent colony foundation (DCF) evolved recurrently multiple times across the ants, bees, and wasps, though its prevalence in termites remains unclear. We review adaptations at both the colony level (reproductive investment shifts from sexuals to workers) and the individual level (wingless queens evolve in ants), and other consequences for life history (invasiveness, parasite transmission). Although few studies have focused on DCF, the accumulated data from anecdotal reports, supported by indirect information including morphology, population genetics, and colony demographics, make it clear that this strategy is more diverse and widespread than is usually recognized. PMID- 22934982 TI - The impact of molecular data on our understanding of bee phylogeny and evolution. AB - Our understanding of bee phylogeny has improved over the past fifteen years as a result of new data, primarily nucleotide sequence data, and new methods, primarily model-based methods of phylogeny reconstruction. Phylogenetic studies based on single or, more commonly, multilocus data sets have helped resolve the placement of bees within the superfamily Apoidea; the relationships among the seven families of bees; and the relationships among bee subfamilies, tribes, genera, and species. In addition, molecular phylogenies have played an important role in inferring evolutionary patterns and processes in bees. Phylogenies have provided the comparative framework for understanding the evolution of host-plant associations and pollen specialization, the evolution of social behavior, and the evolution of parasitism. In this paper, we present an overview of significant discoveries in bee phylogeny based primarily on the application of molecular data. We review the phylogenetic hypotheses family-by-family and then describe how the new phylogenetic insights have altered our understanding of bee biology. PMID- 22934984 TI - Discovery of novel scaffolds for Rho kinase 2 inhibitor through TRFRET-based high throughput screening assay. AB - Recent advances in basic and clinical studies have identified Rho kinase (ROCK) as an important target potentially implicated in a variety of cardiovascular diseases and ROCK inhibitors were considered as a pharmacological strategy to prevent and treat cardiovascular diseases. To screen the small molecule compound library against ROCK, a high throughput screening (HTS) campaign was carried out using immobilized metal affinity for phosphochemicals (IMAP)-based time-resolved fluorescence resonance energy transfer (TR-FRET) assay. Z' value and signal to background (S/B) ratio were achieved at 0.76 and 5.27 for the pilot library screening of the most diverse set consisting of 15,040 compounds with a reasonable reconfirmation rate. From this screening campaign, four novel scaffolds, such as 3- nitropyridine, 4-methoxy-1,3,5,-triazine, naphthalene-1,4 dione, and 2,3-dihydro-1H-pyrrolo[2,3-b]quinoxaline, were yielded. Particularly, we found that 3-nitropyridine derivatives possess potent inhibitory activity and selectivity for ROCK. Our findings provide important information for the design of novel ROCK inhibitor. PMID- 22934985 TI - The role of the dorsal thalamus in visual processing and object selection: a case of an attentional system in amphibians. AB - In amphibians, the midbrain tectum is regarded as the visual centre for object recognition but the functional role of forebrain centres in visual information processing is less clear. In order to address this question, the dorsal thalamus was lesioned in the salamander Plethodon shermani, and the effects on orienting behaviour or on visual processing in the tectum were investigated. In a two alternative-choice task, the average number of orienting responses toward one of two competing prey or simple configural stimuli was significantly decreased in lesioned animals compared to that of controls and sham-lesioned animals. When stimuli were presented during recording from tectal neurons, the number of spikes on presentation of a stimulus in the excitatory receptive field and a second salient stimulus in the surround was significantly reduced in controls and sham lesioned salamanders compared to single presentation of the stimulus in the excitatory receptive field, while this inhibitory effect on the number of spikes of tectal neurons was absent in thalamus-lesioned animals. In amphibians, the dorsal thalamus is part of the second visual pathway which extends from the tectum via the thalamus to the telencephalon. A feedback loop to the tectum is assumed to modulate visual processing in the tectum and to ensure orienting behaviour toward visual objects. It is concluded that the tectum-thalamus telencephalon pathway contributes to the recognition and evaluation of objects and enables spatial attention in object selection. This attentional system in amphibians resembles that found in mammals and illustrates the essential role of attention for goal-directed visuomotor action. PMID- 22934987 TI - Theoretical investigations of the reactions of phosphino disilenes and their derivatives with an E?E (E = C, Si, Ge, Sn, and Pb) double bond. AB - The potential energy surfaces for the reactions of phosphino dimetalalkenes featuring an E?E double bond, Rea-E?E, where E = group 14 elements, were investigated using density functional theory (B3LYP/LANL2DZ). Three types of chemical reactions (i.e., the rearrangement reaction, the transition metal complexation reaction, and the [2 + 2] cycloaddition with a diazene) were used to study the reactivity of the Rea-E?E molecules. The theoretical findings reveal that the smaller the singlet-triplet splitting (DeltaE(st)) of the Rea-E?E, the lower are its activation barriers and, in turn, the more rapid are its chemical reactions. Theoretical observations suggest that the relative reactivity increases in the order Rea-C?C < Rea-Si?Si < Rea-Ge?Ge < Rea-Sn?Sn < Rea-Pb?Pb. In other words, the smaller the atomic weight of the group 14 atom (E), the smaller is the atomic radius of E and the more stable is its phosphino Rea-E?E to chemical reaction. It is thus predicted that the phosphino Rea-C?C and Rea-Si?Si molecules should be stable and readily synthesized and isolated at room temperature, since they are quite inert to chemical reaction. The computational results are in good agreement with the available experimental observations. The theoretical results obtained in this work allow a number of predictions to be made. PMID- 22934986 TI - Probing the modulation of acute ethanol intoxication by pharmacological manipulation of the NMDAR glycine co-agonist site. AB - BACKGROUND: Stimulating the glycine(B) binding site on the N-methyl-d-aspartate ionotropic glutamate receptor (NMDAR) has been proposed as a novel mechanism for modulating behavioral effects of ethanol (EtOH) that are mediated via the NMDAR, including acute intoxication. Here, we pharmacologically interrogated this hypothesis in mice. METHODS: Effects of systemic injection of the glycine(B) agonist, d-serine, the GlyT-1 glycine transporter inhibitor, ALX-5407, and the glycine(B) antagonist, L-701,324, were tested for the effects on EtOH-induced ataxia, hypothermia, and loss of righting reflex (LORR) duration in C57BL/6J (B6) and 129S1/SvImJ (S1) inbred mice. Effects of the glycine(B) partial agonist, d cycloserine (DCS), the GlyT-1 inhibitor, N-[3-(4'-fluorophenyl)-3-(4' phenylphenoxy)propyl]sarcosine (NFPS), and the glycine(B) antagonist, 5,7 dichlorokynurenic (DCKA), on EtOH-induced LORR duration were also tested. Interaction effects on EtOH-induced LORR duration were examined via combined treatment with d-serine and ALX-5407, d-serine and MK-801, d-serine and L 701,324, as well as L-701,324 and ALX-5407, in B6 mice, and d-serine in GluN2A and PSD-95 knockout mice. The effect of dietary depletion of magnesium (Mg), an element that interacts with the glycine(B) site, was also tested. RESULTS: Neither d-serine, DCS, ALX-5407, nor NFPS significantly affected EtOH intoxication on any of the measures or strains studied. L-701,324, but not DCKA, dose-dependently potentiated the ataxia-inducing effects of EtOH and increased EtOH-induced (but not pentobarbital-induced) LORR duration. d-serine did not have interactive effects on EtOH-induced LORR duration when combined with ALX-5407. The EtOH-potentiating effects of L-701,324, but not MK-801, on LORR duration were prevented by d-serine, but not ALX-5407. Mg depletion potentiated LORR duration in B6 mice and was lethal in a large proportion of S1 mice. CONCLUSIONS: Glycine(B) site activation failed to produce the hypothesized reduction in EtOH intoxication across a range of measures and genetic strains, but blockade of the glycine(B) site potentiated EtOH intoxication. These data suggest endogenous activity at the glycine(B) opposes EtOH intoxication, but it may be difficult to pharmacologically augment this action, at least in nondependent subjects, perhaps because of physiological saturation of the glycine(B) site. PMID- 22934988 TI - Solar photo-Fenton process for the treatment of colored soft drink wastewater: decolorization, mineralization and COD removal of oolong tea effluent. AB - The decolorization and mineralization of dark-brown-colored oolong tea effluent by the solar photo-Fenton process has been examined. The solar photo-Fenton process for a fine day achieved 92% decolorization after 60 min and 94% mineralization after 80 min. For a cloudy day, about 88% decolorization and 85% mineralization were obtained after 290 min. For reference the UV light photo Fenton process was also conducted. Very similar degradation efficiencies were found between the solar and UV light photo-Fenton processes. However, the intrinsic low cost associated with abundant solar energy turned out to be more efficient in treating oolong tea effluent as compared with UV light. The decolorization and mineralization profiles under the different light intensities could be unified with the accumulated light energy instead of with irradiation time. This implies that the solar photo-Fenton process should be designed and operated on the basis of the accumulated energy rather than the reaction time. The COD removal was 99.3% after 75 min under the fine condition. This removal rate for a fine day was approximately twice as fast than that for a cloudy day and comparable to that by the UV light irradiation. The results obtained in this study suggest that the solar photo-Fenton process offers a promising technology for decolorization and degradation of oolong tea effluent. PMID- 22934989 TI - Removal of low concentrations of phenanthrene, fluoranthene and pyrene from urban wastewater by membrane bioreactors technology. AB - The fate and removal of phenanthrene (Phen), fluoranthene (F) and pyrene (Py) in urban wastewater treatment by membrane bioreactor (MBR) with low influent polycyclic aromatic hydrocarbons (PAHs) concentration were studied. A full experimental ultrafiltration MBR with a pre-denitrification configuration and capacity to treat 20 m(3)/d was employed. The system was operated with real urban wastewater, to which a concentration of PAHs was added. A constant purge was achieved in order to obtain 12 d of sludge retention time and the hydraulic retention time was 34 h. Concentration of PAHs was determined by Gas Chromatography and Mass Spectrometry with Twister, and mass balance on the MBR system were calculated. Data were supplemented by respirometric analyses, isolation of PAHs degrading microorganisms and bench-scale experiments. All effluent samples presented concentrations of PAHs, with removal levels of 91% and 92% for F and Py respectively, while for Phen performance did not surpass 82%. In spite of the high hydrophobicity of the tested compounds, their accumulation in the biomass was scarce and the sludge presented a low PAH concentration. The experiments reveal that PAHs removal is mainly due to air stripping, with biodegradation and adsorption making an insignificant contribution. PMID- 22934990 TI - Removal of BPA model compounds and related substances by means of column chromatography using Octolig(r). AB - Octolig(r), a polyethylenediimine ligand covalently attached to high-surface area silica gel, was used to study the removal of phenolic compounds from aqueous samples by column chromatography. Model phenolic compounds of Bisphenol A (BPA), 4-isopropylphenol and 4-(t-butyl) phenol, were selected for this study due to their similarities in pKa and log P values. The percent removal of these compounds by Octolig(r) was 26 +/- 2 and 22 +/- 2, respectively. Furthermore, the three isomers of nitrophenol were investigated as well as additional phenolic compounds, such as amoxicillin and five phenolic dyes. These compounds have a pKa range of 2-10.2. The compounds that have pKa values less than 8.3 were able to be completely removed by Octolig(r), yet compounds with pKa values of 8.3 and higher resulted in approximately 20-26% removal. PMID- 22934991 TI - Ozone degradation of alkylbenzene sulfonate in aqueous solutions using a stirred tank reactor with recirculation. AB - The degradation of linear alkylbenzene sulfonates (LAS) in aqueous solutions by ozone has been investigated. The ozonation process was performed in a stirred tank reactor with recirculation which simulates the clean-in-place process used in many industrial facilities. The gas-liquid mass transfer of ozone in a buffer solution at different temperatures (25-55 degrees C) was also studied in the same device, revealing that ozone decomposition can be considered negligible under the experimental conditions assayed. The effect of the initial LAS concentration, temperature, and ozone concentration on the concentration of homologues and total LAS were analysed as a function of time. Both concentrations diminished with time, this effect being more significant when higher temperatures were assayed. The relative proportion of homologues shows that the homologues of higher chain length are degraded in a greater proportion than are the homologues with shorter chain lengths. PMID- 22934992 TI - The apparent solubility of aluminum (III) in Hanford high-level waste. AB - The solubility of aluminum in Hanford nuclear waste impacts on the processability of the waste by a number of proposed treatment options. For many years, Hanford staff has anecdotally noted that aluminum appears to be considerably more soluble in Hanford waste than the simpler electrolyte solutions used as analogues. There has been minimal scientific study to confirm these anecdotal observations, however. The present study determines the apparent solubility product for gibbsite in 50 tank samples. The ratio of hydroxide to aluminum in the liquid phase for the samples is calculated and plotted as a function of total sodium molarity. Total sodium molarity is used as a surrogate for ionic strength, because the relative ratios of mono-, di- and trivalent anions are not available for all of the samples. These results were compared to the simple NaOH NaAl(OH)(4)-H(2)O system, and the NaOH-NaAl(OH)(4)-NaCl-H(2)O system data retrieved from the literature. The results show that gibbsite is apparently more soluble in the samples than in the simple systems whenever the sodium molarity is greater than 2M. This apparent enhanced solubility cannot be explained solely by differences in ionic strength. The change in solubility with ionic strength in simple systems is small compared to the difference between aluminum solubility in Hanford waste and the simple systems. The reason for the apparent enhanced solubility is unknown, but could include kinetic or thermodynamic factors that are not present in the simple electrolyte systems. Any kinetic explanation would have to explain why the samples are always supersaturated whenever the sodium molarity is above 2M. Real waste characterization data should not be used to validate thermodynamic solubility models until it can be confirmed that the apparent enhanced gibbsite solubility is a thermodynamic effect and not a kinetic effect. PMID- 22934993 TI - Plant tissue analysis for explosive compounds in phytoremediation and phytoforensics. AB - Plant tissue analysis methods were evaluated for six explosive compounds to assess uptake and phytoforensic methods development to quantify explosives in plant to obtain the plant data for the evaluation of explosive contamination in soil and groundwater. Four different solvent mixtures containing acetonitrile or methanol were tested at variable extraction ratios to compare the extraction efficiency for six explosive compounds: 2,4,6-trinitrotoluene (TNT), pentaerythritoltetranitrate (PETN), hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX), octahydro-1,3,5,7-tetranitro-1,3,5,7-tetrazocine (HMX), 2-amino-4,6 dinitrotoluene (2ADNT), and 2,4-Dinitroanisole (DNAN), in Laurel Willow (Salix pentandra) stem and range grass Big Bluestem (Andropogon gerardii) using LC MS/MS. Plant tissues were spiked with 500 ng/g of explosives and extracted using ultrasonically-assisted solvent extraction. With the ratio of fresh plant mass to solvent volume of 1:20 for willow and 1:40 for big bluestem grass, results indicated that all explosives in willow except HMX were extracted at higher than 73.3% by using 20 mL of methanol, 50:50 (v/v) methanol:water, or acetonitrile, whereas HMX was extracted with the highest recovery of 61.3% by 20 mL of acetonitrile. In big bluestem grass, the most effective solvents were 20 mL of either methanol or 50:50 (v/v) methanol:water for PETN extraction with a recovery of higher than 101.2% and 20 mL of 50:50 (v/v) methanol:water for HMX, RDX, TNT, 2ADNT, and DNAN extraction with a recovery of 83.8%, 104.4%, 97.5%, 80.7%, and 108.2%, respectively. However, unlike methanol and acetonitrile, 50:50 (v/v) methanol:water provided no problem of leading or split peak in chromatogram; therefore, it was preferred in the test and performed a method validation. Results indicated that 50:50 (v/v) methanol:water provided good repeatability and recovery and method detection limits at 0.5-20 ng/g fresh weight or 8.8-61.3 ng/g dry weight. Overall, results suggested that solvent extraction efficiency of explosives in plant was influenced by plant species and solvent used, and method presented here was believed to provide the preliminary data with respect to the analysis of simultaneous explosives in plants with LC-MS/MS. PMID- 22934994 TI - Environmental contamination of ready meals by polychlorinated biphenyls (PCBs). AB - The level of polychlorinated biphenyls (PCBs) contamination in ready meals was investigated to determine exposure compared to other foodstuffs. Chilled ready meals from nine categories (ambient, Chinese, Indian, Traditional UK, Italian, American Tex-Mex, Vegetarian and Organic), and three samples within each category were Soxhlet extracted in triplicate with hexane for 24 h, followed by a clean-up on deactivated silica gel. The cleaned extracts were concentrated to 1 ml under N(2) gas and analyzed on gas chromatography mass spectrometry (GC-MS) for 7 target PCBs (congeners 28, 52, 101, 118, 153, 138, and 180). Individual congener concentrations ranged from non-detectable to 0.40 ng g(-1) (wet weight). The cumulative concentration of all congeners (SigmaPCBs) ranged between 0.20 and 1.00 ng g(-1) (wet weight). These values translate into exposure levels of less than 1 MUg kg(-1)day(-1) for reference men and women of 70 and 57 kg, respectively. This preliminary study demonstrates that ready meals, like many other foods, are contaminated by PCBs and may represent an important route of human exposure given contemporary changes in consumer food choice. Even though low levels of contamination were observed, long-term exposure for population groups consuming a high volume of ready meals may have cause for concern regarding chronic health risks. PMID- 22934995 TI - Antibacterial effect of phosphates and polyphosphates with different chain length. AB - The aim of this study was to monitor the antibacterial effect of seven phosphate salts on selected strains of Gram-negative and Gram-positive bacteria, which could be considered responsible for food-borne diseases (Bacillus cereus, Bacillus subtilis, Enterococcus faecalis, Micrococcus luteus, Staphylococcus aureus, Citrobacter freundii, Escherichia coli, Proteus mirabilis, Salmonella enterica ser. Enteritidis and Pseudomonas aeruginosa). For these purposes, phosphates differing in chain length were used. The tested concentrations were in the range of 0.1-2.0% (wt v(-1)) applied at the model conditions. In the majority of cases the visible inhibitory effect on the growth of observed microorganisms could be seen. Due to the chemical structure of salts and their dissociation both the pH values of cultivation broth and similarly the growth characteristics of bacterial strains were affected. The inhibition of above mentioned bacteria was apparently supported by this dissociation. Phosphates obviously made the development of most Gram-positive bacteria impossible. Especially Micrococcus luteus was extremely sensitive to the presence of these substances. On the other hand, Gram-negative bacteria seemed to be resistant to the phosphate incidence. The exemption clause from the tested salts was represented by a high alkaline trisodium phosphate. It should be pointed out that generally the most significant antibacterial effects were shown by polyphosphates HEXA68 and HEXA70, trisodium phosphate undecahydrate, tetrasodium pyrophosphate and finally trisodium phosphate. By comparing the inhibitory effects of various phosphate salts can be concluded that the antibacterial activity was not determined only by the condensation degree but there was also proved the dependence on pH values. PMID- 22934996 TI - Contents and mass balances of cadmium and arsenic in a wastewater-fed fish pond of Hoang Mai, Hanoi, Vietnam. AB - Wastewater-fed aquatic production has been practiced since the 1960s in peri urban Hanoi. Wastewater is used as a cheap and reliable source of both water and nutrients but there is a risk that it may lead to accumulation of potentially toxic elements (PTEs) in the production systems and produce and thereby constitute a food safety risk. This study investigates the cadmium (Cd) and arsenic (As) concentrations in water, sediment, plant and fish of a wastewater fed-fish pond in Hoang Mai district, Hanoi, Vietnam. Cd concentrations in the water were lower than the Vietnamese quality guidelines (0.8-1.8 MUg Cd/L) for protection of aquatic life but As concentrations in inlet and outlet water of 44.3 and 21.3 MUg/L, respectively both were higher that the guidelines (20 MUg As/L) and may cause toxicity to fish in the pond and the surrounding vegetable farms using the outlet water for irrigation. The concentrations of Cd and As in fish and Cd in water spinach did not constitute a food safety risk. However, As concentrations in water spinach may be of concern. A mass balance estimate for the fish pond showed that about 12% of the incoming As accumulate in suspended particular matters, 40% settle down to the sediment, less than 0.1% accumulate in the fish and water spinach and 48% overflow with the pond effluent. The concentrations of Cd were too low to make a mass balance for the fish pond. PMID- 22934998 TI - Vinyl chloride removal from an air stream by biotrickling filter. AB - A biofiltration process was used for degradation of vinyl chloride as a hazardous material in the air stream. Three biotrickling filters in series-parallel allowing uniform feed and moisture distribution all over the bed were used. Granular activated carbon mixed with compost was employed as carrier bed. The biological culture consisted of mixture of activated sludge from PVC wastewater treatment plant. Concurrent flow of gas and liquid was used in the bed. Results indicated that during the operation period of 110 days, the biotrickling bed was able to remove over 35% of inlet vinyl chloride. Maximum elimination capacity was calculated to be 0.56 g.m(-3).hr(-1). The amount of chlorine accumulated in the circulating liquid due to the degradation of vinyl chloride was measured to be equal to the vinyl chloride removed from the air stream. PMID- 22934997 TI - Isolation and molecular identification of landfill bacteria capable of growing on di-(2-ethylhexyl) phthalate and deteriorating PVC materials. AB - Waste materials containing Di-(2-ethylhexyl) phthalate (DEHP), a suspected endocrine disruptor and reasonably anticipated human carcinogen, are typically disposed of in landfills. Despite this, very few studies had been conducted to isolate and identify DEHP-degrading bacteria in landfill leachate. Therefore, this study was conducted to isolate and characterize bacteria in landfill leachate growing on DEHP as the sole carbon source and deteriorating PVC materials. Four strains LHM1, LHM2, LHM3 and LHM4, not previously reported as DEHP-degraders, were identified via 16S rRNA gene sequence. Gram-positive strains LHM1 and LHM2 had a greater than 97% similarity with Chryseomicrobium imtechense MW 10(T) and Lysinibacillus fusiformis NBRC 15717(T), respectively. Gram-negative strains LHM3 and LHM4 were related to Acinetobacter calcoaceticus DSM 30006(T) (90.7% similarity) and Stenotrophomonas pavanii ICB 89(T) (96.0% similarity), respectively. Phylogenetic analysis also corroborated these similarities of strains LHM1 and LHM2 to the corresponding bacteria species. Strains LHM2 and LHM4 grew faster than strains LHM1 and LHM3 in the enrichment where DEHP was the sole carbon source. When augmented to the reactors with PVC shower curtains containing DEHP, strains LHM1 and LHM2 developed greater optical densities in the solution phase and thicker biofilm on the surfaces of the shower curtains. PMID- 22934999 TI - Degradation of 1-(2-chlorobenzoyl)-3-(4-chlorophenyl) urea by nanoscale zerovalent iron under aerobic and anaerobic conditions. AB - The goal of present study was to investigate the applicability of nanoscale zerovalent iron (NZVI) on the degradation of 1-(2-chlorobenzoyl)-3-(4 chlorophenyl) urea (CCU) under aerobic and anaerobic conditions, respectively. The experimental results showed that NZVI could effectively degrade CCU, but the removal efficiencies were different under these two different conditions. The best removal efficiencies for CCU were 90.2 and 75.8% under aerobic and anaerobic conditions, respectively. The highly oxidative hydroxyl radicals and reductively hydrogen would account for the rapid degradation of CCU under aerobic and anaerobic conditions, respectively. The experimental results also showed that surfactant Tween 20 significantly inhibited the degradation of CCU under aerobic conditions. However it markedly enhanced the degradation of CCU under anaerobic condition. PMID- 22935001 TI - Drosophila insulin-like peptide-6 (dilp6) expression from fat body extends lifespan and represses secretion of Drosophila insulin-like peptide-2 from the brain. AB - Reduced insulin/IGF signaling extends lifespan in diverse species, including Drosophila melanogaster where the genome encodes seven insulin-like peptides (dilp1-7). Of these, reduced dilp2 expressed in the brain has been associated with longevity assurance when over-expression of dfoxo in fat bodies extends lifespan. Here, we show that the insulin-regulated transcription factor dFOXO positively modulates dilp6 mRNA in adult fat body. Over-expression of dilp6 in adult fat body extends lifespan and increases longevity-associated metabolic phenotypes. Adult fat body dilp6 expression represses dilp2 and dilp5 mRNA in the brain, and the secretion of DILP2 into the hemolymph. The longevity benefit of expressing dfoxo in fat body, and the nonautonomous effect of fat body dfoxo upon brain dilp expression, is blocked by simultaneously repressing dilp6 by RNAi in fat body. dilp6 thus appears to bridge dFOXO, adipose tissue and brain endocrine function to regulate Drosophila longevity. PMID- 22935002 TI - Moisture source and diet affect development and reproduction of Orius thripoborus and Orius naivashae, two predatory anthocorids from Southern Africa. AB - The effect of moisture source and diet on the development and reproduction of the pirate bugs, Orius thripoborus (Hesse) and Orius naivashae (Poppius) (Hemiptera: Anthocoridae) was examined in the laboratory. Both species had been collected in and around sugarcane fields in South Africa. Supplementing eggs of the flour moth Ephestia kuehniella (Zeller) (Lepidoptera: Pyralidae) with a green bean pod as a moisture source yielded better nymphal survival and faster development, as compared with free water encapsulated in Parafilm, suggesting that the predators may extract extra nutrients from the bean pod. The impact of two factitious foods and moist honey bee pollen on developmental and reproductive parameters of both predators was also investigated. The overall performance of both Orius species on E. kuehniella eggs and cysts of brine shrimp, Artemia franciscana Kellogg (Crustacea: Artemiidae) was better than on pollen. Nonetheless, a pollen diet alone allowed 66 and 78% of the nymphs of O. thripoborus and O. naivashae, respectively, to reach adulthood. Overall, developmental and reproductive performance of O. thripoborus on the tested diets was superior to that of O. naivashae. The implications of these findings for the mass production of these predators and their potential role in biological control programs in southern Africa are discussed. PMID- 22935003 TI - Endolysins of Bacillus anthracis bacteriophages recognize unique carbohydrate epitopes of vegetative cell wall polysaccharides with high affinity and selectivity. AB - Bacteriophages express endolysins which are the enzymes that hydrolyze peptidoglycan resulting in cell lysis and release of bacteriophages. Endolysins have acquired stringent substrate specificities, which have been attributed to cell wall binding domains (CBD). Although it has been realized that CBDs of bacteriophages that infect Gram-positive bacteria target cell wall carbohydrate structures, molecular mechanisms that confer selectivity are not understood. A range of oligosaccharides, derived from the secondary cell wall polysaccharides of Bacillus anthracis, has been chemically synthesized. The compounds contain an alpha-d-GlcNAc-(1->4)-beta-d-ManNAc-(1->4)-beta-d-GlcNAc backbone that is modified by various patterns of alpha-d-Gal and beta-d-Gal branching points. The library of compounds could readily be prepared by employing a core trisaccharide modified by the orthogonal protecting groups N(alpha)-9 fluorenylmethyloxycarbonate (Fmoc), 2-methylnaphthyl ether (Nap), levulinoyl ester (Lev) and dimethylthexylsilyl ether (TDS) at key branching points. Dissociation constants for the binding the cell wall binding domains of the endolysins PlyL and PlyG were determined by surface plasmon resonance (SPR). It was found that the pattern of galactosylation greatly influenced binding affinities, and in particular a compound having a galactosyl moiety at C-4 of the nonreducing GlcNAc moiety bound in the low micromolar range. It is known that secondary cell wall polysaccharides of various bacilli may have both common and variable structural features and in particular differences in the pattern of galactosylation have been noted. Therefore, it is proposed that specificity of endolysins for specific bacilli is achieved by selective binding to a uniquely galactosylated core structure. PMID- 22935005 TI - Comparative structural and functional analysis of two octaheme nitrite reductases from closely related Thioalkalivibrio species. AB - Octaheme nitrite reductase from the haloalkaliphilic bacterium Thioalkalivibrio paradoxus was isolated and characterized. A comparative structural and functional analysis of two homologous octaheme nitrite reductases from closely related Thioalkalivibrio species was performed. It was shown that both enzymes have similar catalytic properties, owing to high structural similarity. Both enzymes are characterized by specific structural features distinguishing them from pentaheme cytochrome c nitrite reductases, such as the Tyr-Cys bond in the active site, the hexameric structure resulting in the formation of a void space inside the hexamer, and the product channel that opens into the void interior space of the hexamer. It is suggested that these specific structural features are responsible for the higher nitrite reductase activity, the greater preference for nitrite than for sulfite as a substrate, and the wider pH range of the catalytic activity of octaheme nitrite reductases than of pentaheme homologs. DATABASE: Nucleotide sequence data are available in the GenBank database under the accession number HQ665012.1. Structural data are available in the RCSB Protein Data Bank database under the accession numbers 3SXQ and 3TTB STRUCTURED DIGITAL ABSTRACT: TvPaR and TvPaR bind by x-ray crystallography (View interaction). PMID- 22935004 TI - Mechanistic studies on CymD: a tryptophan reverse N-prenyltransferase. AB - The prenyltransferase CymD catalyzes the reverse N-prenylation of tryptophan using dimethylallyl diphosphate (DMAPP) in the biosynthesis of the cyclic peptides cyclomarin and cyclomarazine. The mechanism is of interest because a non nucleophilic indole nitrogen must be alkylated in this process. Three mechanisms were initially considered, including (A) a direct addition of a carbocation to the nitrogen, (B) an addition of a carbocation to C-3 followed by an aza-Cope rearrangement, and (C) deprotonation of the indole followed by an S(N)2' addition to DMAPP. The use of 4-fluorotryptophan and 6-fluorotryptophan revealed that the reaction kinetics are only modestly affected by these substitutions, consistent with the notion that positive charge does not accumulate on the indole ring during catalysis. When (E)-3-(fluoromethyl)-2-buten-1-yl diphosphate was used in place of DMAPP, the maximal rate was reduced by a factor of 100, consistent with the development of positive charge on the dimethylallyl moiety. Positional isotope exchange (PIX) experiments show that the reaction with Trp proceeds without isotopic scrambling of the label in the starting material [1-(18)O]DMAPP. However, in the case of 4-fluorotryptophan, significant isotopic scrambling is observed (v(PIX)/v(rxn) = 1.1). This is consistent with a mechanism involving a discrete carbocation intermediate. Finally, a significant solvent kinetic isotope effect of 2.3 was observed in D(2)O, indicating that a proton transfer step is rate-limiting. Taken together, these observations support a mechanism that is a hybrid of mechanisms A and C. Ionization of DMAPP generates a dimethylallyl carbocation, and deprotonation of the indole nitrogen accompanies or precedes the nucleophilic attack. PMID- 22935006 TI - Effects of exercise and tea catechins on muscle mass, strength and walking ability in community-dwelling elderly Japanese sarcopenic women: a randomized controlled trial. AB - AIM: To investigate the effects of exercise and/or tea catechin supplementation on muscle mass, strength and walking ability in elderly Japanese women with sarcopenia. METHODS: A total of 128 women aged over 75 years were defined as sarcopenic and randomly assigned into four groups: exercise and tea catechin supplementation (n = 32), exercise (n = 32), tea catechin supplementation (n = 32) or health education (n = 32). The exercise group attended a 60-min comprehensive training program twice a week and the tea catechin supplementation group ingested 350 mL of a tea beverage fortified with catechin daily for 3 months. Body composition was determined by bioelectrical impedance analysis. Interview data and functional fitness measurements, such as muscle strength, balance and walking ability, were collected at baseline and after the 3-month intervention. RESULTS: There were significant group * time interactions observed in timed up & go (P < 0.001), usual walking speed (P = 0.007) and maximum walking speed (P < 0.001). The exercise + catechin group showed a significant effect (odds ratio 3.61, 95% confidence interval 1.05-13.66) for changes in the combined variables of leg muscle mass and usual walking speed compared with the health education group. CONCLUSIONS: The combination of exercise and tea catechin supplementation had a beneficial effect on physical function measured by walking ability and muscle mass. PMID- 22935007 TI - The effect of increasing external degrees of freedom on force production and neuromuscular stabilisation. AB - Evidence suggests that during interaction with different environmental dynamics the necessity to stabilise the involved joints leads to altered efficiency in force transmission to the surroundings and a specific orchestration of motor control strategies. However, little is known about the modalities of the changes associated with altered environmental dynamics. In 29 healthy participants, electromyographic (EMG) signals from four muscles of the right leg (M. peroneus longus, M. tibialis anterior, M. vastus medialis, M. gastrocnemius medialis) and three dimensions of force (Fx, Fy, Fz) were recorded. The participants were to exert force against an external object by performing a unilateral leg extension task with the task being influenced by either 0, 1 or 3 mechanical degrees of freedom. We hypothesised that the ankle stabilising muscles would increase their activities with increasing degrees of freedom (DoF), and that increasing external degrees of freedom results in decreased muscle force exerted during the movement task. The progressive change in the type of mechanical interaction from stable to unstable caused a loss of the ability to apply force in movement direction (Fz) which was accompanied by a reduction of Fy and Fx force dimensions. These reductions corresponded to maximum losses of 23% for Fz, 33% for Fx and 41% for Fy in the three degrees of freedom condition (all P < 0.001). Next, the individual muscles showed specific tuning effects, depending on the type of mechanical interaction. Our results suggest that the loss of the ability to exert force effectively against the external object is due to the neuromuscular stabilisation process of the involved joints. The change of the degrees of freedom conditions allowed for assessment of movement- or stabilisation-related adjustments of the motor system. PMID- 22935008 TI - Dominant factors governing the rate capability of a TiO2 nanotube anode for high power lithium ion batteries. AB - Titanium dioxide (TiO(2)) is one of the most promising anode materials for lithium ion batteries due to low cost and structural stability during Li insertion/extraction. However, its poor rate capability limits its practical use. Although various approaches have been explored to overcome this problem, previous reports have mainly focused on the enhancement of both the electronic conductivity and the kinetic associated with lithium in the composite film of active material/conducting agent/binder. Here, we systematically explore the effect of the contact resistance between a current collector and a composite film of active material/conducting agent/binder on the rate capability of a TiO(2) based electrode. The vertically aligned TiO(2) nanotubes arrays, directly grown on the current collector, with sealed cap and unsealed cap, and conventional randomly oriented TiO(2) nanotubes electrodes were prepared for this study. The vertically aligned TiO(2) nanotubes array electrode with unsealed cap showed superior performance with six times higher capacity at 10 C rate compared to conventional randomly oriented TiO(2) nanotubes electrode with 10 wt % conducting agent. On the basis of the detailed experimental results and associated theoretical analysis, we demonstrate that the reduction of the contact resistance between electrode and current collector plays an important role in improving the electronic conductivity of the overall electrode system. PMID- 22935009 TI - Association between glomerular filtration rate and 1,25-dihydroxyvitamin D in cardiac surgery. AB - BACKGROUND: Renal impairment is a risk factor for poor clinical outcome in cardiac surgical patients and low circulating levels of the vitamin D hormone 1,25-dihydroxyvitamin D (1,25[OH](2)D) may contribute to this risk. METHODS: We investigated the association between glomerular filtration rate (GFR) and 1,25(OH)(2)D in 151 heart transplant recipients and 59 other cardiac surgical patients in postoperative week 1 and at postoperative month 1. GFR estimates (eGFR) were calculated from cystatin C (CysC) and serum creatinine (SCr)-based formulas. RESULTS: With both formulas, linear models provided a better fit between eGFR and circulating 1,25(OH)(2)D than nonlinear models. Nonetheless, the association between 1,25(OH)(2)D and eGFR in the early postoperative period was stronger with the CysC-based formula (r = 0.560; P <0.001) than with the SCr based equation (r = 0.386; P <0.001). CysC-eGFR and SCr-eGFR displayed considerably lack of agreement in the early postoperative period, especially in heart transplant recipients. CONCLUSIONS: There is a relatively close association between CysC-eGFR and circulating 1,25(OH)(2)D in cardiac surgical patients. Data underline the importance of preserved kidney function in cardiac surgery for adequate circulating 1,25(OH)(2)D levels. The SCr-based formula is probably too imprecise for estimating GFR in the early postoperative period correctly. PMID- 22935010 TI - Intramolecular cyclization manifolds of 4-alkylpyridines bearing ambiphilic side chains: construction of spirodihydropyridines or benzylic cyclization via anhydrobase intermediates. AB - 4-Alkylpyridines possessing nucleophilic beta-dicarbonyl side chains have been converted to spirodihydropyridines upon treatment with ethyl chloroformate and sub-stoichiometric amounts of Ti(O(i)Pr)(4). Alternatively, inclusion of mild base in the reaction medium was found to facilitate generation of anhydrobase intermediates. Subsequent aldol-like condensations with electrophilic side chain moieties followed by hydrolysis delivered benzylically cyclized pyridines in good yield. In situ hydrogenation of cyclized anhydrobase intermediates afforded 4 substituted piperidines. PMID- 22935012 TI - Theoretical prediction of high pressure methane adsorption in porous aromatic frameworks (PAFs). AB - The adsorption isotherms of methane in four micro- and mesoporous materials, based on the diamond structure with (poly)phenyl chains inserted in all the C-C bonds, have been simulated with Grand Canonical Monte Carlo technique. The pressure range was extended above 250 bar and the isotherms were computed at 298, 313, and 353 K, to explore the potentiality of these materials for automotive applications, increasing the capacity of high-pressure tanks or storing a comparable amount of gas at much lower pressure. The force field employed in the simulations was optimized to fit the correct behavior of the free gas in all the pressure range and to reproduce the methane-phenyl interactions computed at high quantum mechanical level (post Hartree-Fock). All the examined materials showed a high affinity for methane, ensuring a larger storage of gas than simple compression in all the conditions: two samples exceeded the target proposed by U.S. Department of Energy for methane storage in low-pressure fuel tanks (180 cm(3) (STP)/cm(3) at 35 bar and room temperature). PMID- 22935011 TI - Risk factor assessment for problematic use of opioids for chronic pain. AB - Opioid analgesics provide effective treatment for noncancer pain, but many health providers have concerns about cognitive effects, tolerance, dependence, and addiction. Misuse of opioids is prominent in patients with chronic pain and early recognition of misuse risk could help providers offer adequate patient care while implementing appropriate levels of monitoring to reduce aberrant drug-related behaviors. Many persons with chronic pain also have significant medical and psychiatric comorbidities that affect treatment decisions. Neuropsychologists can play an important role in the identification of psychological and social dysfunction and in matching personal characteristics to effective interventions as part of a multidisciplinary approach to pain management. The assessment of different domains using semi-structured interviews, sensory and neuropsychological testing, and standardized self-report measures permits identification of somatosensory, emotional, cognitive, behavioral, and social issues in order to facilitate treatment planning. In this review we discuss opioid abuse and misuse issues that often arise in the treatment of patients with chronic pain, and present an overview of assessment and treatment strategies that can be effective in improving outcomes associated with the use of prescription opioids for pain. Finally we briefly discuss the effect of opiate analgesics on cognition and review some intervention strategies for chronic pain patients. PMID- 22935013 TI - Evaluating different fixation protocols for spectral cytopathology, part 2: cultured cells. AB - Spectral cytopathology (SCP) is a robust and reproducible diagnostic technique that employs infrared spectroscopy and multivariate statistical methods, such as principal component analysis to interrogate unstained cellular samples and discriminate changes on the biochemical level. In the past decade, SCP has taken considerable strides in its application for disease diagnosis. Cultured cell lines have proven to be useful model systems to provide detailed biological information to this field; however, the effects of sample fixation and storage of cultured cells are still not entirely understood in SCP. Conventional cytopathology utilizes fixation and staining methods that have been established and widely accepted for nearly a century and are focused on maintaining the morphology of a cell. Conversely, SCP practices must implement fixation protocols that preserve the sample's biochemical composition and maintain its spectral integrity so not to introduce spectral changes that may mask variance significant to disease. It is not only necessary to evaluate the effects on fixed exfoliated cells but also fixed cultured cells because although they are similar systems, they exhibit distinct differences. We report efforts to study the effects of fixation methodologies commonly used in traditional cytopathology and SCP including both fixed and unfixed routines applied to cultured HeLa cells, an adherent cervical cancer cell line. Data suggest parallel results to findings in Part 1 of this series for exfoliated cells, where the exposure time in fixative and duration of sample storage via desiccation contribute to minor spectral changes only. The results presented here reinforce observations from Part 1 indicating that changes induced by disease are much greater than changes observed as a result of alternate fixation methodologies. Principal component analysis of HeLa cells fixed via the same conditions and protocols as exfoliated cells (Part 1) yield nearly identical results. More importantly, the overall conclusion is that it is necessary that all samples subjected to comparative analysis should be prepared identically because although changes are minute, they are present. PMID- 22935014 TI - Is there any association between impaired health-related quality of life and non adherence to medical therapy in inflammatory bowel disease? AB - OBJECTIVES: Inflammatory bowel diseases (IBD) have a huge impact on the patients' lives and require continuous medication and long-term medical follow-up. The Short Form Health Survey (SF-36) is a commonly used questionnaire measuring health-related quality of life (HRQOL). Our aim was to evaluate whether HRQOL influences medication adherence and vice versa in IBD patients, and to find relationships between demographic parameters, therapeutic modalities and non adherence or HRQOL. PATIENTS AND METHODS: Five hundred ninety-two IBD patients treated at six Hungarian tertiary centers were enrolled. Patients completed the SF-36 questionnaire and a medication adherence report scale during their visits. The associations between demographic parameters, HRQOL, different kinds of therapies and non-adherence were analyzed. RESULTS: The most affected dimension was physical functioning and least affected were the social functions. About 42.7% of the patients revealed their HRQOL to be acceptable. About 74.6% of the patients believed that the prescribed medications actually improved their HRQOL. Diarrhea was the most common and most severe symptom during the course of the disease. Non-adherence was reported in 13.4% of the patients. 'Forgetting to take the medication' was the main reason for non-adherence in 67.6% of the cases. Medication adherence was significantly higher among nonsmoker patients, and also in the case of immunomodulator therapy. There was no association between the sum of HRQOL and different subscores and non-adherence. CONCLUSION: Inflammatory bowel disease is associated with low HRQOL, which is not affected by drug therapy. The impaired quality of life in IBD is mainly influenced by the disease itself. PMID- 22935017 TI - Indigenous and invasive fruit fly diversity along an altitudinal transect in Eastern Central Tanzania. AB - The relative abundance of indigenous and invasive frugivorous fruit flies (Diptera: Tephritidae) was evaluated spatially and temporally along an altitudinal transect between 581-1650 m in the Uluguru Mountains near Morogoro, Tanzania. The polyphagous invasive fruit fly Bactrocera invadens Drew, Tsuruta, and White and the indigenous fruit fly Ceratitis rosa Karsch show a similar temporal pattern, but are largely separated spatially, with B. invadens being abundant at lower elevation and C. rosa predominant at higher elevation. The polyphagous indigenous C. cosyra (Walker) coincides with B. invadens but shows an inverse temporal pattern. The cucurbit feeders B. cucurbitae (Coquillett) and Dacus bivittatus (Bigot) show a similar temporal pattern, but the former is restricted to lower elevations. Host availability and climatic differences seem to be the determining factors to explain the differences in occurrence and abundance in time and space. PMID- 22935015 TI - A novel transcript is up-regulated by fasting in the hypothalamus and enhances insulin signalling. AB - A transcript of unknown function, regulated by fasting and feeding, was identified by microarray analysis. The transcript is up-regulated in the fasting state. An 1168-bp cDNA was cloned from rat hypothalamus and sequenced. This sequence is consistent with adipogenesis down-regulating transcript 3 (AGD3) (also known as human OCC-1) mRNA. A protein sequence identical to AGD3 was determined by mass spectrometry. In the rat brain, AGD3 mRNA is distributed in the arcuate nucleus, ventromedial hypothalamus, amygdaloid nuclei, hippocampus, and somatic cortex. Double in situ hybridisation showed that AGD3 mRNA is co localised with pro-opiomelanocortin and neuropeptide Y in arcuate nucleus neurones. AGD3 binds with insulin receptor substrate 4 and increases insulin stimulated phospho-Akt and regulates AMP-activated protein kinase and mammalian target of rapamycin downstream target S6 kinase phosphorylation. PMID- 22935018 TI - Reactivity-based detection of copper(II) ion in water: oxidative cyclization of azoaromatics as fluorescence turn-on signaling mechanism. AB - An oxidative cyclization reaction transforms nonemissive azoanilines into highly fluorescent benzotriazoles. We have found that introduction of multiple electron donating amino groups onto a simple o-(phenylazo)aniline platform dramatically accelerates its conversion to the emissive polycyclic product. Notably, this chemistry can be effected by MUM-level concentrations of copper(II) ion in water (pH = 6-8) at room temperature to elicit >80-fold enhancement in the green emission at lambda(em) = 530 nm. Comparative kinetic and electrochemical studies on a series of structural analogues have established that the accelerated reaction rates correlate directly with a systematic cathodic shift in the oxidation onset potential of the azo precursors. In addition, single-crystal X ray crystallographic analysis on the most reactive derivative revealed the presence of a five-membered ring intramolecular hydrogen-bonding network. An enhanced contribution of the quinoid-type resonance in such conformation apparently facilitates the mechanistically required proton transfer step, which, in conjunction with electron transfer at lower oxidation potential, contributes to a rapid cyclization reaction triggered by copper(II) ion in water. PMID- 22935019 TI - Systems biology and biomechanical model of heart failure. AB - Heart failure is seen as a complex disease caused by a combination of a mechanical disorder, cardiac remodeling and neurohormonal activation. To define heart failure the systems biology approach integrates genes and molecules, interprets the relationship of the molecular networks with modular functional units, and explains the interaction between mechanical dysfunction and cardiac remodeling. The biomechanical model of heart failure explains satisfactorily the progression of myocardial dysfunction and the development of clinical phenotypes. The earliest mechanical changes and stresses applied in myocardial cells and/or myocardial loss or dysfunction activate left ventricular cavity remodeling and other neurohormonal regulatory mechanisms such as early release of natriuretic peptides followed by SAS and RAAS mobilization. Eventually the neurohormonal activation and the left ventricular remodeling process are leading to clinical deterioration of heart failure towards a multi-organic damage. It is hypothesized that approaching heart failure with the methodology of systems biology we promote the elucidation of its complex pathophysiology and most probably we can invent new therapeutic strategies. PMID- 22935020 TI - Frequency domain mapping of atrial fibrillation - methodology, experimental data and clinical implications. AB - The concept of dominant frequency (DF) has been used as a way to express local atrial activation rate during atrial fibrillation (AF). The rotor theory explaining the pathophysiology of AF is widely based upon spatial distribution of DF in the atria. Using frequency domain analysis to represent the rate of atrial activation by DF can avoid some of the limitations of time domain analysis of signals during AF. Understanding the concept of DF is of utmost importance to the proper use and interpretation of frequency domain analysis in AF. The current review focuses on the basic principles and methodology of frequency domain analysis using the Fourier transform during different types of AF. It also provides an update of the published experimental and clinical data on frequency domain analysis in light of the rotor theory for AF maintenance. PMID- 22935021 TI - Antiplatelet and antithrombin strategies in acute coronary syndrome: state-of-the art review. AB - Antiplatelet and antithrombotic agents significantly alter the clinical course of patients with acute coronary syndrome (ACS) and hence form the bedrock of the management pathway of this closely related continuum of coronary pathologies. The contemporary therapeutic armamentarium for the treatment of ACS now reflects the many technical and pharmacological advances that took place over the last two decades. In the original 1996 American College of Cardiology/ American Heart Association (ACC/AHA) guidelines for the management of acute myocardial infarction, only one antiplatelet agent (Aspirin) and one anticoagulant (unfractionated heparin) were recommended as class I therapies. Since then many newer agents have been developed and approved for routine clinical use in ACS patients. Recent research has focussed on improving efficacy on one hand and reducing bleeding complications on the other. This review focuses on the mechanism, efficacy, safety profile and clinical trial evidence of P2 Y12 receptor antagonist antiplatelet agents, glycoprotein IIb/IIIa receptor inhibitors (GPI), protease-activated receptor-1 (PAR-1) inhibitors, thrombin inhibitor bivalirudin and Factor Xa inhibitors fondaparinaux and rivaroxaban. PMID- 22935023 TI - GFP-like fluorophores as DNA labels for studying DNA-protein interactions. AB - GFP-like 3,5-difluoro-4-hydroxybenzylideneimidazolinone (FBI) and 3,5 bis(methoxy)-4-hydroxy-benzylideneimidazolinone (MBI) labels were attached to dCTP through a propargyl linker, and the resulting labeled nucleotides (dC(MBI)TP and dC(FBI)TP) were used for a facile enzymatic synthesis of oligonucleotide or DNA probes by polymerase-catalyzed primer extension. The MBI/FBI-labeled DNA probes exerted low fluorescence that was increased 2-3.2 times upon binding of a protein. The concept was demonstrated on sequence-specific binding of p53 to dsDNA and on nonspecific binding of single strand binding protein to an oligonucleotide. The FBI label was also used for a time-resolved experiment monitoring a single-nucleotide incorporation followed by primer extension by Vent(exo-) polymerase. PMID- 22935022 TI - Induced pluripotent stem cells and their potential for basic and clinical sciences. AB - Induced pluripotent stem (iPS) cells, are a type of pluripotent stem cell derived from adult somatic cells. They have been reprogrammed through inducing genes and factors to be pluripotent. iPS cells are similar to embryonic stem (ES) cells in many aspects. This review summarizes the recent progresses in iPS cell reprogramming and iPS cell based therapy, and describe patient specific iPS cells as a disease model at length in the light of the literature. This review also analyzes and discusses the problems and considerations of iPS cell therapy in the clinical perspective for the treatment of disease. PMID- 22935024 TI - Alterations in antibody subclass immune reactivity to trophoblast-derived fetal fibronectin and alpha2-macroglobulin in women with recurrent pregnancy loss. AB - PROBLEM: Increasing evidence supports the involvement of complex antibody mediated immunologic events at the decidua-trophoblast interface. Our objective is to define the humoral immune responses of pregnant women with a history of recurrent pregnancy loss (RPL) compared with gestation-age-matched and non pregnant controls in terms of trophoblast-derived antigenic targets and IgG subclasses. METHOD OF STUDY: Immunoprecipitation and Western immunoblotting were performed to characterize IgG subclass reactivity to Sw.71 trophoblast-derived fetal fibronectin and alpha-2-macroglobulin, using serum obtained from first trimester pregnant RPL subjects, gestation-age-matched controls, and non-pregnant controls. RESULTS: Using a generalized linear model, sera from women with a history of RPL exhibited increased IgG(3) immunoreactivity to trophoblast-derived fetal fibronectin and alpha-2-macroglobulin compared with controls (P < 0.001 and P < 0.001, respectively). CONCLUSION: IgG(3) reactivity in women with RPL may play a significant role in aberrant immune-regulatory mechanisms in early pregnancy. Further investigations into the role of autoantibodies against trophoblast-derived proteins in implantation and pregnancy are warranted. PMID- 22935025 TI - Incidence of postconcussion symptoms in psychiatric diagnostic groups, mild traumatic brain injury, and comorbid conditions. AB - The constellation of physical, cognitive, and emotional symptoms, collectively known as postconcussion syndrome (PCS), is not uniquely associated with concussion, making the etiology of chronic postconcussion symptoms controversial. The current study compared percentages of individuals meeting symptom-based criteria for PCS in a population-based sample of veterans composed of subgroups with various psychiatric diagnoses, a history of mild traumatic brain injury (MTBI), and healthy controls. Participants were identified from 4462 randomly sampled male U.S. Army veterans who served during the Vietnam era. Only 32% of veterans with a history of MTBI met DSM-IV symptom criteria for PCS as compared to 40% of those diagnosed with post-traumatic stress disorder (PTSD), 50% with generalized anxiety disorder (GAD), 57% with major depressive disorder (MDD), and 91% with somatization disorder. Results were consistent with existing literature showing that the PCS symptoms are not unique to concussion, and also provide important base-rate information for neuropsychologists practicing in both clinical and personal injury forensic settings. PMID- 22935027 TI - Diagnosis and management of gallbladder calculus disease. AB - BACKGROUND: The number and rate of cholecystectomy are increasing worldwide, although indications for operative treatment remain empirical, and several issues in the understanding of the condition are not concisely outlined. Our intention is to summarize and interpret current opinion regarding the indications and timing of cholecystectomy in calculous gallbladder disease. METHODS: Publications concerned with gallstone disease and related topics were searched for in MEDLINE using PubMed and summarized according to clinical scenarios with an emphasis on recent research. RESULTS: Only one randomized controlled trial has investigated the management (conservative vs. surgery) of patients with acute cholecystitis and several have compared early with deferred surgery. Two RCTs have examined treatment of uncomplicated, symptomatic gallstone disease. Apart from these, the overwhelming majority of publications are retrospective case series. CONCLUSIONS: Recent literature confirms that cholecystectomy for an asymptomatic or incidental gallstone is not justified. Symptomatic, uncomplicated gallstone disease may be classified into four severity groups based on severity and frequency of pain attacks, which may guide indication for cholecystectomy. Most patients below the age of 70 seem to prefer operative treatment. Acute cholecystitis may be treated with early operation if reduction of hospital days is an issue. Patients older than 70 years with significant comorbidities may forego surgical treatment without undue hazard. Symptoms following cholecystectomy remain in 25% or more and recent evidence suggest these are caused by a functional gastrointestinal disorder. PMID- 22935026 TI - Crystal structure of the Marburg virus GP2 core domain in its postfusion conformation. AB - Marburg virus (MARV) and Ebola virus (EBOV) are members of the family Filoviridae ("filoviruses") and cause severe hemorrhagic fever with human case fatality rates of up to 90%. Filovirus infection requires fusion of the host cell and virus membranes, a process that is mediated by the envelope glycoprotein (GP). GP contains two subunits, the surface subunit (GP1), which is responsible for cell attachment, and the transmembrane subunit (GP2), which catalyzes membrane fusion. The GP2 ectodomain contains two heptad repeat regions, N-terminal and C-terminal (NHR and CHR, respectively), that adopt a six-helix bundle during the fusion process. The refolding of this six-helix bundle provides the thermodynamic driving force to overcome barriers associated with membrane fusion. Here we report the crystal structure of the MARV GP2 core domain in its postfusion (six helix bundle) conformation at 1.9 A resolution. The MARV GP2 core domain backbone conformation is virtually identical to that of EBOV GP2 (reported previously), and consists of a central NHR core trimeric coiled coil packed against peripheral CHR alpha-helices and an intervening loop and helix-turn-helix segments. We previously reported that the stability of the MARV GP2 postfusion structure is highly pH-dependent, with increasing stability at lower pH [Harrison, J. S., Koellhoffer, J. K., Chandran, K., and Lai, J. R. (2012) Biochemistry51, 2515 2525]. We hypothesized that this pH-dependent stability provides a mechanism for conformational control such that the postfusion six-helix bundle is promoted in the environments of appropriately mature endosomes. In this report, a structural rationale for this pH-dependent stability is described and involves a high density array of core and surface acidic side chains at the midsection of the structure, termed the "anion stripe". In addition, many surface-exposed salt bridges likely contribute to the stabilization of the postfusion structure at low pH. These results provide structural insights into the mechanism of MARV GP2 mediated membrane fusion. PMID- 22935028 TI - Effects of sports massage and intermittent cold-water immersion on recovery from matches by basketball players. AB - The aim of this study was to compare the effects of intermittent cold-water immersion and massage on perceptual and performance markers of recovery by basketball players after competitive matches. Eight men (age 23 +/- 3 years; stature 190.5 +/- 8.9 cm; body mass 90.3 +/- 9.6 kg; body fat 12.8 +/- 4.8%) and eight women (age 22 +/- 2 years; stature 179.0 +/- 8.5 cm; body mass 77.6 +/- 9.2 kg; body fat 22.5 +/- 6.6%) basketball players participated. Massage, cold-water immersion or control were applied immediately after competitive matches, followed by assessments of perceptual measures of recovery and physical performance, countermovement jump and repeated-sprint ability 24 h after intervention. There was lower perception of fatigue overall and in the legs immediately after the massage and cold-water immersion condition (P < 0.001; eta2(P) = 0.91). Furthermore, women had a lower perception of fatigue in cold-water immersion than massage at any testing time (P < 0.001; eta2(P) = 0.37). Jump performance was greater after cold-water immersion than the control condition (P = 0.037, eta2(P) = 0.37). There was no effect of any of the recovery interventions on repeated sprint measures (P at best 0.067, eta2(P) at best 0.68). The results suggest that both massage and cold-water immersion improve perceptual measures of recovery. Furthermore, cold-water immersion improves jump performance although neither such immersion nor massage had an effect on repeated-sprint ability. This suggests that, overall, cold-water immersion is more useful than massage in the recovery from basketball matches, especially in women. PMID- 22935029 TI - Stacking of 2D electron gases in Ge probed at the atomic level and its correlation to low-temperature magnetotransport. AB - Stacking of two-dimensional electron gases (2DEGs) obtained by delta-doping of Ge and patterned by scanning probe lithography is a promising approach to realize ultrascaled 3D epitaxial circuits, where multiple layers of active electronic components are integrated both vertically and horizontally. We use atom probe tomography and magnetotransport to correlate the real space 3D atomic distribution of dopants in the crystal with the quantum correction to the conductivity observed at low temperatures, probing if closely stacked delta layers in Ge behave as independent 2DEGs. We find that at a separation of 9 nm the stacked-2DEGs, while interacting, still maintain their individuality in terms of electron transport and show long phase coherence lengths (~220 nm). Strong vertical electron confinement is crucial to this finding, resulting in an interlayer scattering time much longer (~1000 * ) than the scattering time within the dopant plane. PMID- 22935030 TI - Flow reduction in microchannels coated with a polymer brush. AB - We report on the design of microchannels made of glass capillary coated with polymer brushes elaborated by the so-called "grafting-from" technique. We present measurements of velocity profiles for pressure-driven flows of water in such "hairy" capillaries. We show that the flow reduction induced by the presence of the brush is unexpectedly greater than what could be anticipated from simple geometric arguments on the reduction of the effective capillary diameter or from predictions by models describing the brush layer as a poro-elastic boundary. PMID- 22935032 TI - Oral and maxillofacial osteosarcoma in dogs: a review. AB - Osteosarcoma in dogs is a heterogeneous disease entity with regard to its histologic, clinical and biologic behaviour. Differences in behaviour are associated with tumour location. Oral and maxillofacial osteosarcomas are typically reported as a component of the broader classifications of axial osteosarcoma or osteosarcoma of flat bones to differentiate them from appendicular osteosarcoma. Similar to human oral and maxillofacial osteosarcoma, in dogs, these also appear to have less aggressive behaviour than appendicular osteosarcoma. Ideally, local control is achieved with wide surgical resection that results in tumour-free margins. Failure of local control is the most common contributor to poor prognosis. Chemotherapy and radiation treatment are reported to have variable outcomes. The aim of this article is to review the literature on oral and maxillofacial osteosarcoma in dogs in comparison to appendicular and axial osteosarcoma. Similarities and differences between oral and maxillofacial osteosarcoma in humans are addressed. PMID- 22935031 TI - The role of PML ubiquitination in human malignancies. AB - Tumor suppressors are frequently downregulated in human cancers and understanding of the mechanisms through which tumor cells restrict the expression of tumor suppressors is important for the prognosis and intervention of diseases. The promyelocytic leukemia (PML) protein plays a critical role in multiple tumor suppressive functions, such as growth inhibition, apoptosis, replicative senescence, suppression of oncogenic transformation, and inhibition of migration and angiogenesis. These tumor suppression functions are recapitulated in several mouse models. The expression of PML protein is frequently downregulated in diverse types of human tumors and this downregulation often correlates with tumor progression. Recent evidence has emerged that PML is aberrantly degraded in various types of tumors through ubiquitination-dependent mechanisms. Here, we summarize our current understanding of the PML ubiquitination/degradation pathways in human cancers. We point out that multiple pathways lead to PML ubiquitination and degradation. Furthermore, the PML ubiquitination processes are often dependent on other types of posttranslational modifications, such as phosphorylation, prolylisomerization, and sumoylation. Such feature indicates a highly regulated nature of PML ubiquitination in different cellular conditions and cell contexts, thus providing many avenues of opportunity to intervene PML ubiquitination pathways. We discuss the potential of targeting PML ubiquitination pathways for anti-cancer therapeutic strategies. PMID- 22935033 TI - Is the mealtime experience in nursing homes understood? A qualitative study. AB - AIM: The aim of the present study was to explore the significance of the mealtime experience among residents of nursing homes in Spain. METHODS: A qualitative phenomenological approach was followed. An initial purposeful sampling of Spanish residents in for-profit nursing homes in the southern area of Madrid was carried out. A theoretical sampling was also implemented in order to gain a more in-depth understanding of dependence. Inclusion criteria for nursing home residents were: age (60 years or older) and lack of any cognitive impairment. Data were collected using unstructured and semistructured interviews. Data collection was concluded once theoretical saturation was reached, and the data were analysed using the Giorgi proposal. RESULTS: A total of 26 residents with a mean age of 83 years were included. Three main themes that describe the significance of meals in nursing homes emerged from the data: (i) timing of the meals - mealtimes serve as a point of reference for organizing activities in the nursing home and orient the residents during the day; (ii) table allocation - table allocation depends on the judgment of the personnel, the behavior of each resident and on the input from the residents that use a table; and (iii) the meals themselves - food is experienced as a privilege, as a sign of autonomy and normality, and as an indicator of personal identity. CONCLUSION: Understanding the social significance of meals for residents in nursing homes would provide deeper insight into resident expectations. This will in turn help to improve service and quality of life for residents. PMID- 22935034 TI - Design of a "turn-off/turn-on" biosensor: understanding carbohydrate-lectin interactions for use in noncovalent drug delivery. AB - A low-cost and highly sensitive biosensor system is designed to investigate carbohydrate-lectin interactions. This combination of glyco-gold nanoparticles and boronic acid biosensor system opens a way to study noncovalent drug delivery. PMID- 22935035 TI - The 2nd Hungarian National Growth Study (2003-2006). AB - BACKGROUND: Secular changes in the pattern of growth and maturation have been analysed by many regional surveys in Hungary during the last century. The first representative Hungarian National Growth Study was carried out between 1980-1983. AIM: The main objectives of the 2nd Hungarian National Growth Study (2003-2006) were to construct reference data of the most important indicators of body development and nutritional status in Hungarian children (aged 3-18 years, n = 25 278); to analyse the influence of nutrition, habitual physical activity and socio economic background factors on body development; to study secular changes in the pattern of development in Hungary in the last 20 years; and to analyse the relationship between body development and psychic health. SUBJECTS AND METHODS: Anthropometric dimensions and proportions, sexual maturity status, body composition, nutritional status and body shape were used for body developmental estimation. Some indicators of psychic health were also investigated. RESULTS: Reference centiles and data of all absolute body dimensions, some relative body dimensions and the pattern of eating and habitual physical activity have been constructed. CONCLUSION: Secular changes in the growth and maturation pattern are still taking place in the Hungarian population; sexual maturation in boys has shifted to a younger age. PMID- 22935036 TI - Direct trace-elemental analysis of urine samples by laser ablation-inductively coupled plasma mass spectrometry after sample deposition on clinical filter papers. AB - Collection of biological fluids on clinical filter papers shows important advantages from a logistic point of view, although analysis of these specimens is far from straightforward. Concerning urine analysis, and particularly when direct trace elemental analysis by laser ablation-inductively coupled plasma mass spectrometry (LA-ICPMS) is aimed at, several problems arise, such as lack of sensitivity or different distribution of the analytes on the filter paper, rendering obtaining reliable quantitative results quite difficult. In this paper, a novel approach for urine collection is proposed, which circumvents many of these problems. This methodology consists on the use of precut filter paper discs where large amounts of sample can be retained upon a single deposition. This provides higher amounts of the target analytes and, thus, sufficient sensitivity, and allows addition of an adequate internal standard at the clinical lab prior to analysis, therefore making it suitable for a strategy based on unsupervised sample collection and ulterior analysis at referral centers. On the basis of this sampling methodology, an analytical method was developed for the direct determination of several elements in urine (Be, Bi, Cd, Co, Cu, Ni, Sb, Sn, Tl, Pb, and V) at the low MUg L(-1) level by means of LA-ICPMS. The method developed provides good results in terms of accuracy and LODs (<=1 MUg L(-1) for most of the analytes tested), with a precision in the range of 15%, fit-for-purpose for clinical control analysis. PMID- 22935038 TI - Postpartum corticosterone administration reduces dendritic complexity and increases the density of mushroom spines of hippocampal CA3 arbours in dams. AB - Postpartum depression (PPD) affects approximately 15% of mothers after giving birth. A complete understanding of depression during the postpartum period has yet to be established, although disruptions in the hypothalamic-pituitary-adrenal axis and stress during the postpartum may be involved. To model these components in rats, we administered high corticosterone (CORT) postpartum, which increases immobility in the forced swim test (FST), and reduces maternal care, body weight and hippocampal cell proliferation in dams. The hippocampus is altered in response to chronic stress, exposure to high glucocorticoids and in major depression in humans. In the present study, we examined whether high CORT reduced dendritic complexity and spines in the CA3 region of the hippocampus. Additionally, housing complexity was manipulated so that dams and litters were housed either with tubes (complex) or without tubes (impoverished) to investigate the consequences of new animal care regulations. Dams received 40 mg/kg/day of CORT or oil starting on day 2 postpartum for 23 days. Maternal behaviours were assessed on postpartum days 2-8 and dams were tested using the FST on days 21 and 22. Dams were killed on day 24 and brains were processed for Golgi impregnation. Pyramidal cells in the CA3 subfield were traced using a camera lucida and analysed for branch points and dendritic complexity, as well as spine density and type on both basal and apical arbours. As previously established, high CORT postpartum reduced maternal care and increased immobility in the FST, which is a measure of depressive-like behaviour. High CORT postpartum reduced the complexity of basal arbours and increased mushroom spines on both apical and basal dendrites. Housing complexity had no effect on spines of CA3 pyramidal cells but modest effects on cell morphology. These data show that chronic high CORT in postpartum females alters hippocampal morphology and may provide insight regarding the neurobiological consequences of high stress or CORT during the postpartum period, as well as be relevant for postpartum stress or depression. PMID- 22935039 TI - The localization and regulation of proprotein convertase subtilisin/kexin (PCSK) 6 in human ovary. AB - PROBLEM: The aim of this study is to evaluate the expression and regulation of proprotein convertase subtilisin/kexin (PCSK) 6, which is known to be an important factor in the production of bone morphogenetic protein (BMP) cytokines in human ovary. METHOD OF STUDY: The localization of PCSK 6 protein in normal human ovaries was examined by immunohistochemistry. Human granulosa cells (GC), obtained from 34 patients undergoing ovarian stimulation for in vitro fertilization, were cultured with BMP-2, BMP-6, BMP-7, BMP-15, growth differentiation factor (GDF)-9, and activin-A with or without FSH. PCSK 6 mRNA expression level was evaluated by quantitative real-time reverse transcription and polymerase chain reaction (RT-PCR). RESULTS: An immunohistochemistry study revealed that GC expressed PCSK 6 throughout follicular development, beginning in the primary follicle stage, while oocytes expressed PCSK 6 from the primordial follicle stage onwards. An in vitro study demonstrated that BMP-2, BMP-6, BMP-7, and BMP-15, not activin-A and GDF-9, decreased PCSK 6 gene expression in human GC. FSH induced PCSK 6 mRNA in the presence of activin-A or GDF-9. GDF-3, which is an inhibitor of BMP cytokines, also induced PCSK 6 mRNA expression. CONCLUSIONS: PCSK 6, which is a critical factor to produce BMP cytokines, was suppressed with BMP stimulation in human GC, suggesting the presence of a negative feedback system in the follicular development process. PMID- 22935040 TI - Differential expression of HSP90alpha and heme oxygenase in cord blood RBC during preeclampsia. AB - Preeclampsia is a multisystem disorder with profound implications on both mother and fetus. Analysis of umbilical cord blood red blood cell (RBC) changes shall depict the fetal response to pregnancy-specific complications like preeclampsia. This study aims to analyze the regulation relationship between HSP90alpha and heme oxygenase-2 (HO-2) in cord blood RBC during preeclampsia. The lipid hydroperoxide (LHP) and 3-nitrotyrosine (3-NT) levels were measured as stress markers in cord blood RBC of both subjects. The impact of stress on RBC was assessed by measuring the level of membrane bound enzymes and assessing the changes in cord blood RBC. The expression of HSP90alpha and HO-2 were analyzed by enzyme-linked immunosorbent assay (ELISA) and immunohistochemistry analysis, respectively. There was significant increase in the level of LHP (p < 0.01), 3-NT (p < 0.05), HSP90alpha (p < 0.01) with decrease in the expression of HO-2 (p < 0.05) in cord blood RBC of preeclamptic subjects compared to normotensive subjects. Similarly, the membrane damage in preeclamptic RBC was assessed by spectrophotometrically and found to be increased by 41.7%, along with increase in number of nucleated RBC. The antiproliferative effect of carbon monoxide under stress might decrease the expression of HO-2 under conditions when there is an increasing need for RBC. The role of HSP90alpha level in cord blood RBC is discussed with reference to nitrative stress in preeclampsia. This study concludes the increased expression of nucleated RBC, HSP90alpha and corresponding decreased expression of HO-2 in such hypoxic condition may play a protective role; to prevent cord blood RBC against stress induced damage during preeclampsia. PMID- 22935041 TI - Postglacial species displacement in Triturus newts deduced from asymmetrically introgressed mitochondrial DNA and ecological niche models. AB - BACKGROUND: If the geographical displacement of one species by another is accompanied by hybridization, mitochondrial DNA can introgress asymmetrically, from the outcompeted species into the invading species, over a large area. We explore this phenomenon using the two parapatric crested newt species, Triturus macedonicus and T. karelinii, distributed on the Balkan Peninsula in south eastern Europe, as a model. RESULTS: We first delimit a ca. 54,000 km(2) area in which T. macedonicus contains T. karelinii mitochondrial DNA. This introgression zone bisects the range of T. karelinii, cutting off a T. karelinii enclave. The high similarity of introgressed mitochondrial DNA haplotypes with those found in T. karelinii suggests a recent transfer across the species boundary. We then use ecological niche modeling to explore habitat suitability of the location of the present day introgression zone under current, mid-Holocene and Last Glacial Maximum conditions. This area was inhospitable during the Last Glacial Maximum for both species, but would have been habitable at the mid-Holocene. Since the mid-Holocene, habitat suitability generally increased for T. macedonicus, whereas it decreased for T. karelinii. CONCLUSION: The presence of a T. karelinii enclave suggests that T. karelinii was the first to colonize the area where the present day introgression zone is positioned after the Last Glacial Maximum. Subsequently, we propose T. karelinii was outcompeted by T. macedonicus, which captured T. karelinii mitochondrial DNA via introgressive hybridization in the process. Ecological niche modeling suggests that this replacement was likely facilitated by a shift in climate since the mid-Holocene. We suggest that the northwestern part of the current introgression zone was probably never inhabited by T. karelinii itself, and that T. karelinii mitochondrial DNA spread there through T. macedonicus exclusively. Considering the spatial distribution of the introgressed mitochondrial DNA and the signal derived from ecological niche modeling, we do not favor the hypothesis that foreign mitochondrial DNA was pulled into the T. macedonicus range by natural selection. PMID- 22935042 TI - A randomized trial of protein supplementation compared with extra fast food on the effects of resistance training to increase metabolism. AB - OBJECTIVE: To prospectively evaluate the effects of resistance training combined with increased energy intake or protein-supplementation on lean body-mass, resting metabolic-rate (RMR) and cardiovascular risk factors. METHODS: Twenty four healthy males (aged 19-32 years) performed resistance exercise for 12 weeks aiming for at least 1 hour training-sessions 3 times a week. The participants were randomized to consume extra protein (33 g whey protein/day) or a meal of fast-food/day (1350 kcal, 41 g protein). Body-composition was measured with Dual Energy X-ray Absorptiometry (DEXA) and RMR by indirect calorimetry. Fasting blood samples were drawn before and after the 3-month training period and after 12 months. RESULTS: The body weight increased from 75.1 +/- 6.9 kg to 78.7 +/- 7.2 kg (p < 0.0001), without differences between the groups. RMR increased from 1787 +/- 143 kcal/24 h to 1954 +/- 187 kcal/24 h (p < 0.0001, N = 24), which was more than expected from the increase in lean body-mass (increase from 59.7 +/- 4.3 kg to 61.8 +/- 4.1 kg p = 0.004). Fasting serum-insulin levels increased in the fast food group compared with the extra-protein group (p = 0.03). ApoB increased from 0.691 +/- 0.14 g/L to 0.768 +/- 0.17 g/L, p = 0.004, in the fast-food group only. Long-term follow up after 12 months showed that RMR, body weight, total fat and lean body-masses did not differ from baseline (n = 19). CONCLUSIONS: Resistance training for 12 weeks increased RMR and lean body-mass similarly when based on either an increased energy-intake or protein supplement. However, the increase in RMR was higher than expected from the increase in lean body-mass. Thus resistance training could potentially decrease the risk of obesity by induction of increased RMR. PMID- 22935043 TI - Growth, body composition and metabolic profile of 8-year-old children exposed to metformin in utero. AB - OBJECTIVES: To investigate the possible long-term effects of metformin exposure on growth and development of the offspring born to mothers with polycystic ovary syndrome (PCOS). The drug passes through the placenta and can potentially influence the fetus. PATIENTS AND METHODS: This is a follow-up study of a randomized, controlled trial on PCOS women, randomized to metformin or placebo in pregnancy. Out of 37 children aged 7-9 years, 25 agreed to participate. Primary outcome measures were growth, body composition and metabolic parameters. RESULTS: There were no differences in height, weight or body composition between those exposed to metformin and those exposed to placebo. We found a higher fasting glucose level in the metformin group (4.93 mmol/L vs. 4.60 mmol/L, p = 0.04). In the metformin group there was a trend towards higher systolic blood pressure (106 mmHg vs. 101 mmHg, p = 0.05) and a lower LDL cholesterol level (2.42 mmol/L vs. 2.99 mmol/L, p = 0.07). CONCLUSION: Metformin exposure during fetal life does not seem to influence growth and body composition at the age of 8 years. A higher fasting glucose level and a possible higher systolic blood pressure and lower LDL cholesterol level in the metformin group may be coincidental and should be further explored. PMID- 22935044 TI - Unbound iron binding capacity (UIBC) as a test for empty iron stores--results from the HUNT Study. AB - BACKGROUND: When s-iron and s-transferrin are used to diagnose empty iron stores, the measurements are usually combined in the calculation of s-transferrin saturation. This may not be the best way to utilize the information in s-iron and s-transferrin, as s-transferrin alone has a better diagnostic accuracy than s transferrin saturation. We suggest that unbound iron binding capacity (UIBC), which is s-total iron binding capacity (2 times s-transferrin) minus s-iron could be used for diagnosing empty iron stores. METHODS: To test this hypothesis, we used ROC curve analysis to compare the diagnostic accuracy of s-iron, s transferrin, s-transferrin saturation and s-UIBC in diagnosing empty iron stores in 3029 women of childbearing age. Empty iron stores were defined as s-ferritin less than 10 MUg/L or less than 15 MUg/L. RESULTS: At both definitions of empty iron stores s-UIBC had a better diagnostic accuracy than the other tests, with area under the ROC curve of 0.80-0.87. This was also the trend in a subpopulation of 172 anemic women, where the area under the ROC curve of s-UIBC was 0.92. CONCLUSION: When diagnosing empty iron stores calculation of s-UIBC is a better way to utilize the information in s-iron and s-transferrin than is calculation of s-transferrin saturation. PMID- 22935045 TI - Stability of testosterone measured in male archival serum samples by two different methods. AB - OBJECTIVE: To investigate testosterone stability in archival serum samples stored for etiological cancer research, and compare two methods for testosterone measurements. DESIGN AND MEASUREMENTS: Four sets of 130 serum samples were randomly selected from male blood donors, aged 40-49 years at the time of blood draw. The sets had been stored at -25 degrees C for 1 month, 4, 17 and 29 years, respectively, and were analyzed for testosterone, sex hormone binding globuline, follicle stimulating hormone, luteinizing hormone, sodium, albumin and cotinine. Testosterone was measured by two methods, an electrochemiluminescence immunoassay, and a liquid chromatography tandem mass spectrometry method. RESULTS: The mean level of testosterone in the samples with the longest storage time (29 years) was substantially higher than that of the fresh samples. The two techniques gave approximately equal results for testosterone values in the range 5-27.5 nmol/L, close to normal range. CONCLUSIONS: The high mean levels of testosterone in the oldest samples suggest a downward trend over the last three decades, as any degradation during storage would tend to give the opposite result. For archival serum samples, both electrochemiluminescence immunoassay and liquid chromatography tandem mass spectrometry are applicable methods for measurement of testosterone within the expected reference range. PMID- 22935046 TI - A high carbohydrate diet induces the beneficial effect of the CC genotype of hepatic lipase C-514T polymorphism on the apoB100/apoAI ratio only in young Chinese males. AB - Both diet and genetic background have profound effects on plasma lipid profiles. It was hypothesized that a high carbohydrate (high-CHO) diet could affect the ratios of serum lipids and apolipoproteins (apo) differently in subjects with different genotypes of the C-514T hepatic lipase rs1800588 polymorphism. Fifty six healthy university students were given a stabilization diet of 54.1% carbohydrate for 7 days, followed with a high-CHO diet of 70.1% carbohydrate for 6 days. Body composition, serum lipids, apolipoproteins and the hepatic lipase C 514T rs1800588 polymorphism were analyzed. The ratios of serum lipids and apolipoproteins were calculated afterwards. At baseline, females have significantly lower waist circumference (WC) (CC genotype: p = 0.049; T carriers: p = 0.015) and waist-to-hip ratio (WHR) (CC genotype: p = 0.019; T carriers: p = 0.000) than males. When compared with those before the high-CHO diet, the body mass index (BMI) (p = 0.043) and WC (p = 0.048) were significantly decreased in the male T carriers, the TG/HDL-C ratios were significantly increased in females (CC genotype: p = 0.047; T carriers: p = 0.003). The TC/HDL-C ratios were significantly decreased in males (CC genotype: p = 0.000; T carriers: p = 0.003). And the LDL-C/HDL-C ratios were significantly decreased in all subjects (males with the CC genotype: p = 0.001; male T carriers: p = 0.000; females with the CC genotype: p = 0.018; female T carriers: p = 0.006). However, the apoB100/apoAI ratio was only significantly decreased in male CC genotype after the high-CHO diet (p = 0.005). PMID- 22935047 TI - Semi-automated quantification of methylmalonic acid in human serum by LC-MS/MS. AB - BACKGROUND: Methylmalonic acid (MMA), a sensitive biomarker of functional vitamin B12 deficiency, is commonly determined by gas chromatography-mass spectrometry (GC-MS) or liquid chromatography-tandem mass spectrometry (LC-MS/MS) methods using manual extraction and derivatization of MMA to reduce polarity prior to separation. METHODS: In the present study we introduce a semi-automated extraction on a strong anion exchanger, HPLC separation on a BEH-amide column to separate serum MMA from its abundant isoform, succinic acid, followed by MS/MS detection and quantification. RESULTS: The extraction of MMA plus internal standard provides full recovery and the method is linear between 0.03 MUmol/L and 20.0 MUmol/L (r(2) = 1.0) with intra-and inter-assay imprecision of 2.2%. Agreement with other laboratories has been demonstrated in external proficiency testing. Compared to both conventional GC-MS and LC-MS/MS methods, the correlation is r(2) > 0.99. CONCLUSIONS: The use of robotic pipetting, elimination of derivatization and improved separation by the BEH-amide column combined with HILIC chromatographic conditions significantly improve sample throughput compared to conventional methods. Using a single pipetting robot and LC-MS/MS instrument, this method is currently performing 180 analyses per day from 10 regional hospitals and several additional distant sites. PMID- 22935048 TI - AlphaLISA versus ELISA-based detection of interleukin 18 in healthy subjects and patients with end-stage renal disease. AB - BACKGROUND: Interleukin 18 (IL-18) is an important pro-inflammatory cytokine investigated in end-stage renal disease (ESRD) and several autoimmune and inflammatory diseases. The quantitative colorimetric sandwich ELISA test kit from MBL is the most frequently used ELISA kit for IL-18 detection. Recently, a new bead-based proximity assay named AlphaLISA was developed. The aim of this study was to compare the performance of these two kits and to evaluate aspects of sample handling on IL-18 measurements. METHODS: Measurements of IL-18 were performed on plasma samples from 11 ESRD-patients in regular haemodialysis treatment and 10 healthy volunteers. RESULTS: We found a significant difference between assays corresponding to a factor of 6.4 (6.0; 6.7), p < 0.0001. Agreement was excellent with intra-class correlation coefficient 0.95. MBL had lower inter assay variation, batch-to-batch variation and day-to-day variation. Spiking with recombinant IL-18 resulted in a mean recovery of 91 +/- 7 (MBL) vs. 135 +/- 17% (AlphaLISA), p < 0.0001. Both kits performed equally well when linearity was investigated. IL-18 was stable over a period of 424 days when plasma samples were stored at - 80 degrees C. When blood samples were stored at room temperature mean IL-18 concentration changed significantly between 0, 1, 6, and 24 hours after sampling (p = 0.0213). No significant change was found with storage at 5 degrees C. Severe haemolysis affected IL-18 measurements, whereas repeated freezing and thawing showed no effect. Mean IL-18 concentration was significantly higher in ESRD-patients compared to healthy subjects regardless of assay. CONCLUSION: Assay performance was best with the MBL-kit, although AlphaLISA was less time consuming when measuring plasma IL-18. PMID- 22935049 TI - Validation of the patients' perceived involvement in care scale among patients with chronic pain. AB - AIM: The aim of this study was to evaluate the psychometric properties of the Icelandic version of the Modified Patients' Perceived Involvement in Care Scale (M-PICS), I-PICS, an instrument measuring patients' perceptions of pain-related communication with health care providers (HCP). METHODS: The M-PICS was translated into Icelandic according to standard procedures for forward and backward translation. The questionnaire consisted of 20 items measuring four constructs: (i) the degree to which the HCP was perceived as controlling the information-exchange process; (ii) to what extent patients sought or shared information with their HCP; (iii) patients' perceived encouragement to raise questions and discuss their symptoms with their health care provider and (iv) patients' perceived participation in decision-making during the health care visit. The response options for each item ranged from one to five on a 5-point Likert scale, where higher scores indicated higher endorsement. RESULTS: One hundred and forty-nine participants with pain lasting longer than three months (77.2% women; mean age, 49.9 years) completed the questionnaire. To examine the construct validity of the I-PICS, a confirmatory factor analysis was performed, specifying four factors in congruence with the theoretical underpinnings of the original modified scale (M-PICS). Of the 20 items, 19 were retained, and the I PICS factor structure was for the most part identical to the M-PICS, with the exception of three items that moved between factors and one item that did not fall decisively on one specific factor. Internal consistency (alpha) for the four factors ranged from 0.74 to 0.86 and was 0.86 for the total scale. The mean score on the total I-PICS was 2.67 on a one to five scale, ranging from 1.21 to 4.28 (possible range, 1-5). CONCLUSION: This study supports the four-factor structure of the M-PICS and that the I-PICS is a valid and reliable instrument for assessing patient-HCP communication. PMID- 22935051 TI - Transcriptional profiling of Haemophilus parasuis SH0165 response to tilmicosin. AB - The Haemophilus parasuis respiratory tract pathogen poses a severe threat to the swine industry despite available antimicrobial therapies. To gain a more detailed understanding of the molecular mechanisms underlying H. parasuis response to tilmicosin treatment, microarray technology was applied to analyze the variation in gene expression of isolated H. parasuis SH0165 treated in vitro with subinhibitory (0.25 MUg/ml) and inhibitory (8 MUg/ml) concentrations. Tilmicosin treatment induced differential expression of 405 genes, the encoded products of which are mainly involved in the heat shock response, protein synthesis, and intracellular transportation. The subinhibitory and inhibitory concentrations of tilmicosin induced distinctive gene expression profiles of shared and unique changes, respectively. These changes included 302 genes mainly involved in protein export and the phosphotransferase system to sustain cell growth, and 198 genes mainly related to RNA polymerase, recombination, and repair to inhibit cell growth. In silico analysis of functions related to the differentially expressed genes suggested that adaptation of H. parasuis SH0165 to tilmicosin involves modulation of protein synthesis and membrane transport. Collectively, the genes comprising each transcriptional profile of H. parasuis response to tilmicosin provide novel insights into the physiological functions of this economically significant bacterium and may represent targets of future molecular therapeutic strategies. PMID- 22935050 TI - Important risk factors and attributable risk of vertebral fractures in the population-based Tromso study. AB - BACKGROUND: Vertebral fractures, the most common type of osteoporotic fractures, are associated with increased risk of subsequent fracture, morbidity, and mortality. The aim of this study was to examine the contribution of important risk factors to the variability in vertebral fracture risk. METHODS: Vertebral fracture was ascertained by VFA method (DXA, GE Lunar Prodigy) in 2887 men and women, aged between 38 and 87 years, in the population-based Tromso Study 2007/2008. Bone mineral density (BMD; g/cm2) at the hip was measured by DXA. Lifestyle information was collected by questionnaires. Multivariable logistic regression model, with anthropometric and lifestyle factors included, was used to assess the association between each or combined risk factors and vertebral fracture risk. Population attributable risk was estimated for combined risk factors in the final multivariable model. RESULTS: In both sexes, age (odds ratio [OR] per 5 year increase: 1.32; 95% CI 1.19-1.45 in women and 1.21; 95% CI 1.10 1.33 in men) and BMD (OR per SD decrease: 1.60; 95% CI 1.34-1.90 in women and1.40; 95% CI 1.18-1.67 in men) were independent risk factors for vertebral fracture. At BMD levels higher than 0.85 g/cm2, men had a greater risk of fracture than women (OR 1.52; 95% CI 1.14-2.04), after adjusting for age. In women and men, respectively, approximately 46% and 33% of vertebral fracture risk was attributable to advancing age (more than 70 years) and low BMD (less than 0.85 g/cm2), with the latter having a greater effect than the former. CONCLUSIONS: These data confirm that age and BMD are major risk factors for vertebral fracture risk. However, in both sexes the two factors accounted for less than half of fracture risk. The identification of individuals with vertebral fracture is still a challenge. PMID- 22935053 TI - How close can one approach the Dirac point in graphene experimentally? AB - The above question is frequently asked by theorists who are interested in graphene as a model system, especially in context of relativistic quantum physics. We offer an experimental answer by describing electron transport in suspended devices with carrier mobilities of several 10(6) cm(2) V(-1) s(-1) and with the onset of Landau quantization occurring in fields below 5 mT. The observed charge inhomogeneity is as low as ~10(8) cm(-2), allowing a neutral state with a few charge carriers per entire micrometer-scale device. Above liquid helium temperatures, the electronic properties of such devices are intrinsic, being governed by thermal excitations only. This yields that the Dirac point can be approached within 1 meV, a limit currently set by the remaining charge inhomogeneity. No sign of an insulating state is observed down to 1 K, which establishes the upper limit on a possible bandgap. PMID- 22935052 TI - Enhancing breast milk production with Domperidone in mothers of preterm neonates (EMPOWER trial). AB - BACKGROUND: The use of mother's own breast milk during initial hospitalization has a positive impact not only in reducing potential serious neonatal morbidities but also contribute to improvements in neurodevelopmental outcomes. Mothers of very preterm infants struggle to maintain a supply of breast milk during their infants' prolonged hospitalization. Galactogogues are medications that induce lactation by exerting its effects through oxytocin or prolactin enhancement. Domperidone is a potent dopamine D2 receptor antagonist which stimulates the release of prolactin. Small trials have established its ability in enhancing breast milk production. EMPOWER was designed to determine the safety and efficacy of domperidone in mothers experiencing an inadequate milk supply. METHODS/DESIGN: EMPOWER is a multicenter, double masked, randomized controlled phase-II trial to evaluate the safety and effectiveness of domperidone in those mothers identified as having difficulty in breast milk production. Eligible mothers will be randomized to one of two allocated groups: Group A: domperidone 10 mg orally three times daily for 28 days; and Group B: identical placebo 10 mg orally three times daily for 14 days followed by domperidone 10 mg orally three times daily for 14 days. The primary outcome will be determined at the completion of the first 2-week period; the second 2-week period will facilitate answering the secondary questions regarding timing and duration of treatment. To detect an estimated 30% change between the two groups (from 40% to 28%, corresponding to an odds ratio of 0.6), a total sample size of 488 mothers would be required at 80% power and alpha=0.05. To account for a 15% dropout, this number is increased to 560 (280 per group). The duration of the trial is expected to be 36-40 months. DISCUSSION: The use of a galactogogue often becomes the measure of choice for mothers in the presence of insufficient breast milk production, particularly when the other techniques are unsuccessful. EMPOWER is designed to provide valuable information in guiding the practices for this high-risk group of infants and mothers. The results of this trial will also inform both mothers and clinicians about the choices available to increase and maintain sufficient breast milk. TRIAL REGISTRATION: Clinical Trials.gov Identifier: NCT01512225. PMID- 22935054 TI - Multi-scale agent-based brain cancer modeling and prediction of TKI treatment response: incorporating EGFR signaling pathway and angiogenesis. AB - BACKGROUND: The epidermal growth factor receptor (EGFR) signaling pathway and angiogenesis in brain cancer act as an engine for tumor initiation, expansion and response to therapy. Since the existing literature does not have any models that investigate the impact of both angiogenesis and molecular signaling pathways on treatment, we propose a novel multi-scale, agent-based computational model that includes both angiogenesis and EGFR modules to study the response of brain cancer under tyrosine kinase inhibitors (TKIs) treatment. RESULTS: The novel angiogenesis module integrated into the agent-based tumor model is based on a set of reaction-diffusion equations that describe the spatio-temporal evolution of the distributions of micro-environmental factors such as glucose, oxygen, TGFalpha, VEGF and fibronectin. These molecular species regulate tumor growth during angiogenesis. Each tumor cell is equipped with an EGFR signaling pathway linked to a cell-cycle pathway to determine its phenotype. EGFR TKIs are delivered through the blood vessels of tumor microvasculature and the response to treatment is studied. CONCLUSIONS: Our simulations demonstrated that entire tumor growth profile is a collective behaviour of cells regulated by the EGFR signaling pathway and the cell cycle. We also found that angiogenesis has a dual effect under TKI treatment: on one hand, through neo-vasculature TKIs are delivered to decrease tumor invasion; on the other hand, the neo-vasculature can transport glucose and oxygen to tumor cells to maintain their metabolism, which results in an increase of cell survival rate in the late simulation stages. PMID- 22935055 TI - Femoroplasty: a new option for femur metastasis. AB - Bone metastases are very frequent in patients with cancer and usually are located in the patient's long bones and spine. Various approaches to pain relief and stability to the affected bone have been used. The aim of the study is to report our experience with a new minimally invasive percutaneous technique in patients with bone metastases located in the head, neck, and proximal femur. The technique is performed under fluoroscopic guidance through the application of polymethylmethacrylate bone cement. Our descriptive, retrospective, longitudinal case series included 15 patients who underwent femoroplasty. All patients reported pain reduction and improved mobility, with no complications observed. The femoroplasty procedure caused pain relief by stabilizing the bone through the consolidation of the microfractures because of bone metastases. PMID- 22935056 TI - Design and optimization of a chronotherapeutic dosage form for treatment of nocturnal acid breakthrough. AB - OBJECTIVE: Present work focuses on the use of tamarind gum to develop a drug delivery system making combined use of floating and pulsatile principles, for the chrono-prevention of nocturnal acid breakthrough. METHOD: The desired aim was achieved by fabricating a floating delivery system bearing time - lagged coating of Tamarindus indica seed polymer for the programmed release of Famotidine. Response Surface METHODology was the statistical tool that was employed for experiment designing, mathematical model generation and optimization study. A 32 full factorial design was used in designing the experiment. % weight ratio of tamarind gum to ethyl cellulose in the coating combination and the coating weight were the independent variables, whereas the lag time for drug release and the cumulative % drug release in 330 minutes were the observed responses. KEY FINDINGS: Results revealed that both the coating composition and the coating weight significantly affected the release of drug from the dosage form. CONCLUSION: The optimized formulation prepared according to the computer generated software, Design-Expert(r) deciphered response which were in close proximity with the experimental responses, thus confirming the robustness and accuracy of the predicted model for the utilization of natural polymer like tamarind gum for the chronotherapeutic treatment of nocturnal acid breakthrough. PMID- 22935057 TI - 109Pd labeled 5,10,15,20-tetrakis[4-carboxymethyleneoxyphenyl]porphyrin: a potential agent for targeted tumor therapy. AB - AIM: Radiolabeled porphyrin derivatives could be envisaged as potential agents for targeted tumor therapy owing to the inherent tumor accumulation property exhibited by porphyrins. However, to achieve adequately high tumor accumulation and retention therein along with fast clearance from all non-target organs, an optimum balance between the hydrophilicity and lipophilicity must be achieved. Based on our prior experiences of working with (109)Pd-labeled porphyrins with variable lipophilicity and hydrophilicity, we have envisioned a suitable porphyrin derivative which could be expected to have the required balance between lipophilicity and hydrophilicity when complexed with (109)Pd. Towards this, 5,10,15,20- tetrakis[4-carboxymethyleneoxyphenyl]porphyrin (PHBEPH) was synthesized, radiolabeled with (109)Pd and its biological behavior in small animal model was studied. EXPERIMENTAL: The porphyrin derivative was synthesized and characterized following the reported procedure and radiolabeled with (109)Pd [E beta(max) = 1.12 MeV, E gamma = 88 keV (3.6%), T1/2 = 13.7 h], which was produced by the thermal neutron bombardment on enriched (98% in (108)Pd) metallic Pd target at a flux of 3x1013 n/cm2.s for 3 d. Biological behavior of the radiolabeled agent was studied by biodistribution studies in Swiss mice bearing fibrosarcoma tumors. RESULTS: (109)Pd was produced with a specific activity of ~1.85 GBq/mg (50 mCi/mg) and radionuclidic purity of 100%. (109)Pd complex of the synthesized porphyrin derivative was prepared with excellent radiochemical purity ( > 98%) and the complex was observed to exhibit Log P value of -1.29. Biodistribution studies revealed good tumor uptake [(3.55+/-0.49)% injected activity (IA)/g] within 30 min post-injection (p.i.) and retention therein till 24 h [(2.56+/-0.25)% IA)/g], upto which the study was continued. The complex exhibited fast clearance from the non-target organs with favorable tumor/blood and tumor/muscle ratios [(5.09+/-0.18)% and (284.44+/-3.25)% at 24 h p.i.]. CONCLUSION: The complex exhibited good uptake and retention in the tumor along with encouraging target to non-target ratio. Preliminary biological studies indicated the promising attributes of the agent towards its use for targeted radiotherapy. PMID- 22935058 TI - Mechanistic insight into patterned supported lipid bilayer self-assembly. AB - Patterned supported lipid bilayers (SLBs) provide a model system for studying fluid lipid bilayers and transmembrane proteins in an array format. SLB arrays self-assemble on patterned self-assembled monolayers (SAMs) consisting of hexadecanethiol and glycol-terminated regions. While the mechanism of SLB formation on glass has been studied extensively, the formation of SLBs on other substrates is not necessarily well understood. Moreover, SLB arrays on patterned SAMs represent an intriguing system, since lipid vesicles do not adhere to glycol terminated monolayers. Here, we utilize surface plasmon resonance imaging (SPRi) and kinetic analysis to examine the mechanism of SLB formation on the glycol terminated regions of patterned SAMs and supported lipid monolayer (SLM) formation on alkyl-terminated regions of patterned SAMs. We determine that vesicles rupture to form a patterned SLB through a two-step mechanism that is dependent upon vesicle attachment at the interface of the two regions of the patterned monolayer. PMID- 22935059 TI - Lack of efficacy of tocilizumab in severe axial refractory spondyloarthritis: a report of 5 patients. PMID- 22935060 TI - Antenatal glucocorticoids supplementation and central nervous system development. AB - Maternal antenatal therapy with glucocorticoids (GC) is routinely used to prevent lung immaturity. The potential harmful effects on other organs, including in particular the central nervous system (CNS), are still controversial. In the present review we aimed to investigate: i) the beneficial and detrimental effects of antenatal GC treatment in both human and animal models; ii) the potential usefulness of biochemical markers such as calcium binding proteins (S100B, synaptophysin) and cytoskeletal protein of neurons and dendrites (MAP2) in the perinatal period, and iii) whether the assessment of brain markers in different biological fluids could constitute a promising tool for the monitoring of CNS function and/or developmental in fetuses and newborns whose mothers assumed GC antenatally. PMID- 22935062 TI - Drug metabolizing enzymes in the perinatal and neonatal period: differences in the expression and activity. AB - Physiological changes occurring perinatally and in the first month of life can affect the answer to a pharmacological treatment and the individual response to a drug in terms of efficacy and toxicity is highly variable in the neonatal population. Among potential causes for such variability, differences in drug metabolism may have a great impact. This article aims to review qualitative and quantitative differences in drug metabolizing enzymes in neonates, since both phase I and phase II metabolic pathways are immature at birth and subject to maturational changes in the first period of extrauterine life. Moreover, clinical implications will be discussed. PMID- 22935063 TI - Paracetamol (acetaminophen) efficacy and safety in the newborn. AB - Neonates can perceive pain, therefore an adequate analgesic therapy is a major issue not only from an ethical perspective but also to improve short- and long term outcome. Fever during the neonatal period requires hospitalization and needs a treatment with an antipyretic agent because of the high risk of severe complications. Paracetamol (acetaminophen), the most commonly prescribed drug in paediatric patients for its analgesic and antipyretic effects, is the only agent recommended for use as an antipyretic in the newborn and has been recently proposed as a supplement therapy to opioids for postoperative analgesia. This article aims to give an updated overview on the use of paracetamol in newborns by presenting its pharmacological profile (mechanism of action, pharmacokinetics), recommendations for dosing regimens (oral or rectal administration: 25-30 mg/kg/day in preterm neonates of 30 weeks' gestation, 45 mg/kg/day in preterm neonates of 34 weeks' gestation, 60 mg/kg/day in term neonates; i.v. administration: indicatively 20-40 mg/kg/day depending on gestational age, with some differences among various guidelines) and clinical uses (more commonly as analgesic/antipyretic by oral or rectal route, but also i.v. in anaesthesia for postoperative analgesia and painful procedures in Neonatal Intensive Care Units). Moreover, drug tolerability is discussed in the light of its potential hepatotoxicity and the unique characteristics of the newborn patient. By analyzing the available literature and the dosing guidelines, a mismatch exists between the current clinical use of paracetamol and the recommendations, suggesting a cautious approach particularly in extremely preterm neonates. PMID- 22935064 TI - Clinical and pharmacological aspects of immunoprophylaxis for respiratory syncytial virus infection in high-risk infants. AB - Respiratory syncytial virus (RSV) is the leading cause of respiratory tract infection in infants and young children throughout the world. Although preterm birth has been considered for years the major risk factor for severe disease and hospitalization, recent findings indicate that prematurity is not a necessary condition, but one of the independent risk factors for severe RSV infection, together with chronic lung diseases, congenital heart disease and immunodeficiency. Furthermore, over 50% of infants hospitalized for RSV infections during the first year of life are healthy, full-term newborns, suggesting that other environmental and individual factors may be involved. Unfortunately, there is still no specific therapy against RSV infection and therefore prophylactic measures seem to be the only intervention to avoid disease complications. No safe and effective RSV vaccine is available for the prevention of serious RSV infection. Therefore, in addition to hygienic measures, the only approach is passive immunoprophylaxis with humanized monoclonal anti-RSV antibodies, such as palivizumab that have been developed for clinical use. Because of the high cost of these antibodies, a better definition of the individual risk profile for severe RSV infection and timing of administration is needed for optimal effectiveness and careful use of limited health care resources. In this article, we have reviewed the clinical and pharmacological aspects of immunoprophylaxis with monoclonal antibodies for preventing RSV infection in high-risk infants. PMID- 22935065 TI - Echinocandins for the nursery: an update. AB - As the incidence rates of neonatal invasive fungal infection (IFI) have been increasing over the last years, research efforts have been addressed towards identifying both effective preventative strategies, and efficacious and well tolerated antifungal drugs. Historically, the first options in treatment of neonatal IFI have been -and currently are- fluconazole and amphotericin B. However, these two drugs carry limitations both in efficacy and in putative toxicity. Recently, new therapeutic alternatives have drawn the neonatologists' attention. Echinocandins are a new class of antifungal drugs with characteristics that might better meet the needs of this particular population of patients. Caspofungin, Micafungin and Anidulafungin have inherent good activities both against biofilms, and against natively fluconazole-resistent strains of Candida spp, thus overcoming two of the major weaknesses of the commonly used antifungal drugs in nurseries. Caspofungin and Micafungin have been recently studied in neonatal populations. The kinetics and appropriate dosing of this agent in premature and term infants have been described, but ongoing further studies are needed to better address this area. Extrapolation of data from randomized trials conducted in pediatric and adult patients showed through a subgroup analysis that both Caspofungin and Micafungin are effective and well tolerated also in neonates. Further studies properly designed for neonatal populations will better address long-term safety and echological issues related to Echinocandin use in neonates. PMID- 22935066 TI - The neonatal kidney: implications for drug metabolism and elimination. AB - The kidney is a major organ for drug elimination. The function of the neonatal kidney is markedly immature with a reduction of renal blood flow, of glomerular filtration and of active tubular secretion, even in healthy, term infants. Maturation of renal function in particular of glomerular filtration rate is gestational age and postnatal age-dependant. Moreover, many neonatal pathological conditions such as preterm birth, sepsis or perinatal asphyxia can also affect renal function. These developmental changes have a major impact on drug metabolism and elimination. Alterations in renal clearance can influence significantly both drugs efficacy and toxicity. Moreover, nephrogenesis is a still ongoing process in a number of premature infants before 36 wks postconceptional age. Drugs and toxic factors that may alter the constitution of the congenital nephron number endowment during this period may have long term consequences on arterial pressure and renal function at adulthood. PMID- 22935067 TI - Pharmacokinetics, pharmacodynamics and clinical use of valganciclovir in newborns with symptomatic congenital cytomegalovirus infection. AB - Congenital cytomegalovirus infection is the most common cause of nonhereditary sensorineural hearing loss and an important cause of psychomotor retardation. Newborns suffering from symptomatic congenital cytomegalovirus infection have been typically treated with i.v. ganciclovir (GCV). Nowadays valganciclovir (V GCV), a mono-valyl ester pro-drug of GCV, is available as an oral syrup. The existing literature demonstrated that V-GCV is well absorbed from the gastrointestinal tract and is rapidly converted into GCV in the intestinal wall and liver. The mechanism of antiviral action is the same that has been described for GCV. All these characteristics make this formulation particularly suitable for the symptomatic congenitally infected newborns. In neonates, V-GCV oral formulation proved stable and constant GVC plasma concentrations, in the suggested therapeutic range. The syrup demonstrated to be clinically effective and well tolerated and to be appropriate for a prolonged post-discharge therapy avoiding the discomfort of hospitalization, reducing the risk for nosocomial infections and decreasing the cost for the National Health Service. This article reviews all the available literature about V-GCV syrup in the treatment of newborns and infants with congenital CMV infection with the regard to pharmacokinetics, pharmacodynamic properties and clinical use, focussing on new data and on our experience. PMID- 22935069 TI - Why we need proper PBPK models to examine intestine and liver oral drug absorption. AB - Intestinal transporters and enzymes are factors that can influence the absorption of orally administrated drugs. Compartmental models are no longer adequate to describe the sequential handling of drugs and metabolites by the intestine and liver during oral drug absorption, especially when intestinal removal is substantial relative to the liver, and when induction/inhibition elicits different extents of change for identical intestinal and hepatic enzymes or transporters. In this review, we described PBPK models for the intestine (with differential flow patterns: traditional model, TM, and segregated flow model, SFM, and QGut model) as well as semi- or whole bodyphysiological- based pharmacokinetic (PBPK) models to describe the impact of the flow pattern, and the intestinal transporters and enzymes and their attendant heterogeneities on intestinal (FI or FG) and oral (Fsys) bioavailability. The modeling efforts have led to a refinement in providing mechanistic insight on the accurate prediction of drug and metabolite profiles for DDI, pharmacogenomics, age factors and disease conditions. PMID- 22935070 TI - A review on noscapine, and its impact on heme metabolism. AB - This review introduces the Noscapine, which is being used as an antitussive drug for a long time has been recently discovered as a novel tubulin-binding, anti angiogenic anticancer drug that causes cell cycle arrest and induces apoptosis in cancer cells both in vitro as well as in vivo. Noscapine is a multifunctional molecule i.e. it possesses various functional moieties. We maneuvered various amenable sites and have synthesized analogs, which might prove to be more efficacious and less cytotoxic. Moreover, development of oral controlled release anticancer formulation of noscapine is severely hampered due to short biological half-life (<2-h), poor absorption, low aqueous solubility, and extensive first pass metabolism, thereby requiring large doses for effective treatment. PMID- 22935071 TI - Yeast as a humanized model organism for biotransformation-related toxicity. AB - High drug attrition rates due to toxicity, the controversy of experimental animal usage, and the EU REACH regulation demanding toxicity profiles of a high number of chemicals demonstrate the need for new, in vitro toxicity models with high predictivity and throughput. Metabolism by cytochrome P450s (P450s) is one of the main causes of drug toxicity. As some of these enzymes are highly polymorphic leading to large differences is metabolic capacity, isotype-specific test systems are needed. In this review, we will discuss the use of yeast expressing (mammalian) P450s as a powerful, additional model system in drug safety. We will discuss the various cellular model systems for bioactivation-related toxicity and subsequently describe the properties of yeast as a model system, including the endogenous bioactivation enzymes present, the heterologous expression of (mammalian) P450s and the application of yeasts expressing heterologous P450s and/or other biotransformation enzymes in toxicity studies. All major human drug metabolizing P450s have been successfully expressed in yeast and various mutagenicity tests have been performed with these humanized yeast strains. The few examples of non-mutagenic toxicity studies with these strains and of the combination of P450s with phase II or other human enzymes show the potential of yeast as a model system in metabolism-related toxicity studies. The wide variety of genome-wide screens available in yeast, combined with its well-annotated genome, also facilitate follow-up studies on the genes involved in toxicity. Unless indicated otherwise "yeast" will refer to baker's yeast Saccharomyces cerevisiae. PMID- 22935068 TI - Triazole use in the nursery: fluconazole, voriconazole, posaconazole, and ravuconazole. AB - Invasive fungal infections in infants admitted to the neonatal intensive care unit are common and often fatal. The mainstay of therapy against invasive fungal infections is antifungal agents. Over the last two decades, the development and approval of these drugs evolved tremendously, and the azole class emerged as important agents in the treatment and prevention of invasive fungal infections. Among the azoles, fluconazole has been used extensively due to its favorable pharmacokinetics, excellent activity against Candida spp, and safety profile. This drug has been well studied in children, but data for its use in infants are largely limited to Candida prophylaxis studies. Voriconazole, a second generation triazole, has excellent activity against Candida and Aspergillus spp. However, data on its use in neonates are extremely limited. Posaconazole and ravuconazole are the newest agents of the triazole family. The antimicrobial spectrum of posaconazole is similar to voriconazole, but with additional activity against zygomycetes. Experience with posaconazole in children is very limited, and there are no reports of its use in infants. Ravuconazole is not approved for use by the FDA, but studies in animals and humans show that it is often fungicidal and has favorable pharmacokinetics. In conclusion, the management of invasive fungal infections has progressed greatly over the last two decades with the azole antifungals playing a significant role. Related to this class, future research is needed in order to better assess dosing, safety, schedules and areas of use of these agents in infants admitted to the neonatal intensive care unit. PMID- 22935072 TI - Decidual stromal cells as regulators of T-cell access to the maternal-fetal interface. AB - A recent study in the journal Science offers insights into the mechanism behind feto-maternal tolerance, as evidenced by changes in the immuno-logical environment of the uterus and decidua. They also provide a rich area of research for the understanding of the regulation of the immune system in other complicated medical conditions, including cancer and pregnancies affected by infection or autoimmunity. PMID- 22935073 TI - IL-7Ralpha and L-selectin, but not CD103 or CD34, are required for murine peanut induced anaphylaxis. AB - BACKGROUND: Allergy to peanuts results in severe anaphylactic responses in affected individuals, and has dramatic effects on society and public policy. Despite the health impacts of peanut-induced anaphylaxis (PIA), relatively little is known about immune mechanisms underlying the disease. Using a mouse model of PIA, we evaluated mice with deletions in four distinct immune molecules (IL7Ralpha, L-selectin, CD34, CD103), for perturbed responses. METHODS: PIA was induced by intragastric sensitization with peanut antigen and cholera toxin adjuvant, followed by intraperitoneal challenge with crude peanut extract (CPE). Disease outcome was assessed by monitoring body temperature, clinical symptoms, and serum histamine levels. Resistant mice were evaluated for total and antigen specific serum IgE, as well as susceptibility to passive systemic anaphylaxis. RESULTS: PIA responses were dramatically reduced in IL7Ralpha-/- and L-selectin-/ mice, despite normal peanut-specific IgE production and susceptibility to passive systemic anaphylaxis. In contrast, CD34-/- and CD103-/- mice exhibited robust PIA responses, indistinguishable from wild type controls. CONCLUSIONS: Loss of L-selectin or IL7Ralpha function is sufficient to impair PIA, while CD34 or CD103 ablation has no effect on disease severity. More broadly, our findings suggest that future food allergy interventions should focus on disrupting sensitization to food allergens and limiting antigen-specific late-phase responses. Conversely, therapies targeting immune cell migration following antigen challenge are unlikely to have significant benefits, particularly considering the rapid kinetics of PIA. PMID- 22935074 TI - General and oral health-related quality of life among caregivers of Parkinson's disease patients. AB - AIM: The aim of the present study was to evaluate the general and oral health related quality of life among caregivers of patients with Parkinson's disease. METHODS: A representative sample (n = 80, 19 men and 61 women) of caregivers from Sao Jose dos Campos, Brazil, answered Oral Health Impact Profile (OHIP-14) and Medical Outcomes Study 36-Item Short Form (SF-36) questionnaires, as well as another questionnaire regarding caregivers' characteristics and caring activities. RESULTS: The OHIP-14 average score was 2.56. The SF-36 average score for the domain of physical function was 87.4; for role-physical function, 85.0; for bodily pain, 62.9; for general health, 76.6; for vitality, 80.0; for social function, 88.4; for role-emotional function, 83.8; and for mental health, 85.3. All domains of the SF-36 also showed negative correlations with OHIP-14 in the entire sample, but this correlation could not be observed among lower educated caregivers. There were significant differences between formal and informal caregivers for OHIP-14 and for the majority of SF-36 domains. CONCLUSIONS: Most caregivers were female, the mean scores for SF-36 and OHIP-14 were adequate, and formal caregivers had better results for the SF-36 and OHIP-14 when compared with informal caregivers. PMID- 22935075 TI - Unilateral pitting edema of the leg as a manifestation of Graves' disease: a case report. AB - INTRODUCTION: Graves' hyperthyroidism has a number of well-recognized but relatively rare extrathyroid manifestations such as thyroid acropachy, pretibial myxedema, and congestive heart failure. CASE PRESENTATION: A 38-year-old Caucasian woman presented to the out-patient clinic with symptoms of hyperthyroidism lasting for approximately five months. Remarkably, she had developed pitting edema of her left leg four months before. She had gone through a conventional assessment, but the reason for the edema was not revealed. At presentation to the endocrinology clinic, the skin of both legs was of normal color and pitting edema on her left leg was of a diffuse nature and spread from her toes to two thirds of her leg. The skin surface of her left leg was smooth and had no elevations or discoloration, whereas her right leg appeared normal. Based on signs and symptoms of thyrotoxicosis and suppressed thyroid-stimulating hormone level (less than 0.001mIU/L, local reference of 0.4 to 4), treatment of 10mg of thiamazole three times a day was started. Additional blood tests revealed marked Graves' hyperthyroidism with elevated free T4 and anti-thyroid receptor antibodies. Within a month, the free T4 level was normalized and the edema was completely cleared and never reappeared during the treatment course of 12 months. CONCLUSIONS: To the best of our knowledge, this is the first description of unilateral treatment-responsive leg edema as a manifestation of Graves' hyperthyroidism. However, the pathophysiological mechanism underlying this case of edema remains unclear. PMID- 22935076 TI - Morphology and function in the Cambrian Burgess Shale megacheiran arthropod Leanchoilia superlata and the application of a descriptive matrix. AB - BACKGROUND: Leanchoilia superlata is one of the best known arthropods from the middle Cambrian Burgess Shale of British Columbia. Here we re-describe the morphology of L. superlata and discuss its possible autecology. The re description follows a standardized scheme, the descriptive matrix approach, designed to provide a template for descriptions of other megacheiran species. RESULTS: Our findings differ in several respects from previous interpretations. Examples include a more slender body; a possible hypostome; a small specialised second appendage, bringing the number of pairs of head appendages to four; a further sub-division of the great appendage, making it more similar to that of other megacheirans; and a complex joint of the exopod reflecting the arthropod's swimming capabilities. CONCLUSIONS: Different aspects of the morphology, for example, the morphology of the great appendage and the presence of a basipod with strong median armature on the biramous appendages indicate that L. superlata was an active and agile necto-benthic predator (not a scavenger or deposit feeder as previously interpreted). PMID- 22935077 TI - Willingness and ability to pay for unexpected dental expenses by Finnish adults. AB - BACKGROUND: Since 2002, adults have been able to choose oral health care services in the public sector or in the private sector in Finland. Though various subsidies for care exist in both sectors, the Public Dental Service (PDS) is a cheaper option for the patient but, on the other hand, there are no waiting lists for private care. The aim of this study was to assess middle-aged adults' use of dental services, willingness to pay (WTP) and ability to pay (ATP) for unexpected, urgent dental treatment. METHODS: Postal questionnaires on use of dental services were sent to a random sample of 1500 47-59 year old adults living in three large municipalities in the Helsinki region. The initial response rate was 65.8%. Two hypothetical scenarios were presented: "What would be the highest price you would be prepared to pay to have a lost filling replaced immediately, or, at the latest, the day after losing the filling?" and " How much could you pay for unexpected dental expenses at two weeks notice, if you suddenly needed more comprehensive treatment?" Logistic regression analysis was used to analyse factors related to WTP and ATP. RESULTS: Most respondents (89.6%) had visited a dentist recently and a majority (76.1%) had used private services. For immediate replacement of a lost filling, almost all respondents (93.2%) were willing to pay the lower price charged in the PDS and 46.2% were willing to pay the private fee. High income and no subjective need for dental treatment were positively associated with the probability of paying a higher price. Most respondents (93.0%) were able to pay a low fee, EUR 50 and almost half (41.6%) at least EUR 300 for unexpected treatment at short notice. High income and male sex were associated with high ATP. CONCLUSION: There was a strong and statistically significant relationship between income and WTP and ATP for urgent dental care, indicating that access to publicly provided services improved equity for persons with low income. PMID- 22935079 TI - Toroidal plasmonic eigenmodes in oligomer nanocavities for the visible. AB - Plasmonics has become one of the most vibrant areas in research with technological innovations impacting fields from telecommunications to medicine. Many fascinating applications of plasmonic nanostructures employ electric dipole and higher-order multipole resonances. Also magnetic multipole resonances are recognized for their unique properties. Besides these multipolar modes that easily radiate into free space, other types of electromagnetic resonances exist, so-called toroidal eigenmodes, which have been largely overlooked historically. They are strongly bound to material structures and their peculiar spatial structure renders them practically invisible to conventional optical microscopy techniques. In this Letter, we demonstrate toroidal modes in a metal ring formed by an oligomer of holes. Combined energy-filtering transmission electron microscopy and three-dimensional finite difference time domain analysis reveal their distinct features. For the study of these modes that cannot be excited by optical far-field spectroscopy, energy-filtering transmission electron microscopy emerges as the method of choice. Toroidal moments bear great potential for novel applications, for example, in the engineering of Purcell factors of quantum optical emitters inside toroidal cavities. PMID- 22935078 TI - Tenofovir, emtricitabine, and tenofovir diphosphate in dried blood spots for determining recent and cumulative drug exposure. AB - Tenofovir (TFV) disoproxil fumarate (TDF)+/-emtricitabine (FTC) are widely used for HIV treatment and chemoprophylaxis, but variable adherence may lead to suboptimal responses. Methods that quantify adherence would allow for interventions to improve treatment and prevention outcomes. Our objective was to characterize the pharmacokinetics of TFV-diphosphate (TFV-DP) and FTC triphosphate (FTC-TP) in red blood cells (RBCs) and peripheral blood mononuclear cells (PBMCs); to extend the RBC analysis to dried blood spots (DBSs); and to model how RBC/DBS monitoring could inform recent and cumulative drug exposure/adherence. Blood samples were collected from 17 HIV-negative adults at 5 visits over a 30-day pharmacokinetics study of daily oral TDF/FTC. Dosing was discontinued on day 30 and blood was collected on days 35, 45, and 60 during the washout period. Plasma/RBCs/PBMCs/DBSs were all quantified by liquid chromatography/tandem mass spectrometry. DBSs were paired with RBCs and plasma for comparisons. The median (interquartile range) RBC TFV-DP half-life was 17.1 (15.7-20.2) versus 4.2 (3.7-5.2) days in PBMCs. At steady state, TFV-DP was 130 fmol/10(6) RBCs versus 98 fmol/10(6) PBMCs. FTC-TP was not quantifiable in most RBC samples. TFV-DP in RBCs versus DBSs yielded an r(2)=0.83. TFV-DP in DBSs was stable at -20 degrees C. Simulations of TFV-DP in RBCs/DBSs, when dosed from one to seven times per week, demonstrated that each dose per week resulted in an average change of approximately 19 fmol/10(6) RBCs and 230 fmol/punch. TFV and FTC in plasma versus DBSs was defined by y=1.4x; r(2)=0.96 and y=0.8x; r(2)=0.99, respectively. We conclude that DBSs offer a convenient measure of recent (TFV/FTC) and cumulative (TFV-DP in RBCs) drug exposure with potential application to adherence monitoring. PMID- 22935081 TI - The necessary distinction between methodology and philosophical assumptions in healthcare research. AB - Methodological discussions within healthcare research have traditionally described a methodological dichotomy between qualitative and quantitative methods. The aim of this article is to demonstrate that such a dichotomy presents unnecessary obstacles for good research design and is methodologically and philosophically unsustainable. The issue of incommensurability is not a question of method but rather a question of the philosophical premises underpinning a given method. Thus, transparency on the philosophical level is important for validity and consistency as well as for attempts to integrate or establish an interface to other research. I argue that it is necessary to make a distinction between methodology and philosophical assumptions and to ensure consistency in these correlations. Furthermore, I argue that the question of incommensurability is best answered at this basic philosophical level. The complexity of health care calls for methodological pluralism and creativity that utilises the strength of both qualitative and quantitative approaches. Transparency and consistency on the philosophical level can facilitate new mixed methods research designs that may be promising methodological assets for healthcare research. I believe we are ill served by fortified positions that continue to uphold old battle lines. Empirical research begins in the field of practice and requires a certain amount of pragmatism. However, this pragmatism must be philosophically informed. PMID- 22935080 TI - Psychiatric aspects of chronic palliative care: waiting for death. AB - This article emphasizes the shifting paradigm of palliative care from cancer patients to vital organ failure in chronic diseases. It offers a view about a type of palliative care for patients reaching the pre-terminal phase of a chronic illness. Unlike cancer patients, time is not as sharply delineated and physical pain is not a major factor, but psychological distress is often a major component of the clinical condition. Starting from the perspective of a psychiatric consultant on medical and surgical wards, I present short clinical vignettes to introduce a discussion about psychological manifestations in patients with chronic vital organ failure. The objective is to help patients find meaning to the last stage of their life. To that effect, four key sensitive areas are presented for clinicians to assess end-of-life coping: pressure on character organization, the management of hope, mourning problems, and ill health as a screen for psychological distress. PMID- 22935082 TI - Pro-fibrotic processes in human lung fibroblasts are driven by an autocrine/paracrine endothelinergic system. AB - BACKGROUND AND PURPOSE: Since endothelin (ET) may act as pro-fibrotic mediator, expression and release of ET isoforms, their receptors and potential pro-fibrotic ET effects were studied in human lung fibroblasts. EXPERIMENTAL APPROACH: MRC-5 and primary human lung fibroblasts (phLFb) were cultured. Expression of prepro-ET isoforms was determined by qPCR and release of ET-1 by elisa. ET receptor function was analysed by real-time measurement of dynamic mass redistribution (DMR). Incorporation of [(3) H]-thymidine was determined as measure of proliferation and that of [(3) H]-proline for collagen synthesis. Phospho-p42/44 MAP kinase was determined by Western blot. KEY RESULTS: ET-1 is the predominant ET in human lung fibroblasts (hLF), and TGF-beta caused a further, selective and sustained up-regulation of ET-1 resulting in increased extracellular ET-1 accumulation. hLFb express mRNA encoding ET-A and ET-B receptors. Expression of both receptors was confirmed at protein level. ET-1 induced marked DMR signals, an effect that involved ET-A and ET-B receptors. Stimulatory effects of ET-1 on hLFb proliferation and collagen synthesis were mediated exclusively via ET-A receptors. ET-1, again via ET-A receptors, induced rapid activation of ERK MAPK, shown to be a crucial cellular signal in ET-1-induced collagen synthesis. ET-1 induced activation of ERK and collagen synthesis was, in contrast to corresponding effect of a muscarinic agonist, largely insensitive to pertussis toxin. CONCLUSIONS AND IMPLICATIONS: hLFb are endowed with all elements necessary to build a functional autocrine/paracrine endothelinergic system, which appears to drive pro-fibrotic airway and lung remodelling processes, effects for which only ET-A, but not ET-B receptors appear to be of significance. PMID- 22935083 TI - The effect of fenofibrate on lymphocyte release of proinflammatory cytokines and systemic inflammation in simvastatin-treated patients with atherosclerosis and early glucose metabolism disturbances. AB - This study was designed to investigate whether fibrates produce lymphocyte suppressing and systemic anti-inflammatory effects in statin-treated pre-diabetic patients. The study included 47 atherosclerotic patients with the concomitant presence of impaired fasting glucose and impaired glucose tolerance already receiving simvastatin treatment (40 mg daily) who were allocated to one of two groups treated for 90 days with, respectively, fenofibrate (200 mg daily) or placebo. Plasma lipids, glucose homoeostasis markers, plasma high-sensitivity C reactive protein as well as lymphocyte release of pro-inflammatory cytokines were determined on the allocation day and after 90 days of therapy. Compared with placebo, fenofibrate reduced lymphocyte release of interleukin-2, interferon gamma and tumour necrosis factor-alpha, which was accompanied by a reduction in plasma C-reactive protein levels. The results obtained indicate that fenofibrate inhibits lymphocyte secretory function and reduces low-grade inflammation in patients with both impaired fasting glucose and impaired glucose tolerance. Our findings suggest that the combined treatment with simvastatin and fenofibrate may be a better treatment option than simvastatin alone in this group of patients, particularly in those who are at high risk for cardiovascular events. PMID- 22935084 TI - Non-pharmacological interventions to reduce the risk of diabetes in people with impaired glucose regulation: a systematic review and economic evaluation. AB - BACKGROUND: The prevalence of type 2 diabetes mellitus (T2DM) is increasing in the UK and worldwide. Before the onset of T2DM, there are two conditions characterised by blood glucose levels that are above normal but below the threshold for diabetes. If screening for T2DM in introduced, many people with impaired glucose tolerance (IGT) will be found and it is necessary to consider how they should be treated. The number would depend on what screening test was used and what cut-offs were chosen. OBJECTIVE: To review the clinical effectiveness and cost-effectiveness of non-pharmacological interventions, including diet and physical activity, for the prevention of T2DM in people with intermediate hyperglycaemia. DATA SOURCES: Electronic databases, MEDLINE (1996 2011), EMBASE (1980-2011) and all sections of The Cochrane Library, were searched for systematic reviews, randomised controlled trials (RCTs) and other relevant literature on the effectiveness of diet and/or physical activity in preventing, or delaying, progression to T2DM.The databases were also searched for studies on the cost-effectiveness of interventions. REVIEW METHODS: The review of clinical effectiveness was based mainly on RCTs, which were critically appraised. Subjects were people with intermediate hyperglycaemia, mainly with IGT. Interventions could be diet alone, physical activity alone, or the combination. For cost effectiveness analysis, we updated the Sheffield economic model of T2DM. Modelling based on RCTs may not reflect what happens in routine care so we created a 'real-life' modelling scenario wherein people would try lifestyle change but switch to metformin after 1 year if they failed. RESULTS: Nine RCTs compared lifestyle interventions (predominantly dietary and physical activity advice, with regular reinforcement and frequent follow-up) with standard care. The primary outcome was progression to diabetes. In most trials, progression was reduced, by over half in some trials. The best effects were seen in participants who adhered best to the lifestyle changes; a scenario of a trial of lifestyle change but a switch to metformin after 1 year in those who did not adhere sufficiently appeared to be the most cost-effective option. LIMITATIONS: Participants in the RCTs were volunteers and their results may have been better than in general populations. Even among the volunteers, many did not adhere. Some studies were not long enough to show whether the interventions reduced cardiovascular mortality as well as diabetes. The main problem is that we know what people should do to reduce progression, but not how to persuade most to do it. CONCLUSION: In people with IGT, dietary change to ensure weight loss, coupled with physical activity, is clinically effective and cost-effective in reducing progression to diabetes. FUNDING: The National Institute for Health Research Health Technology Assessment programme. PMID- 22935086 TI - Transcutaneous electrical nerve stimulation for phantom pain and stump pain in adult amputees. AB - Following amputation, 50% to 90% of individuals experience phantom and/or stump pain. Transcutaneous electrical nerve stimulation (TENS) may prove to be a useful adjunct analgesic intervention, although a recent systematic review was unable to judge effectiveness owing to lack of quality evidence. The aim of this pilot study was to gather data on the effect of TENS on phantom pain and stump pain at rest and on movement. Ten individuals with a transtibial amputation and persistent moderate-to-severe phantom and/or stump pain were recruited. Inclusion criteria was a baseline pain score of >=3 using 0 to 10 numerical rating scale (NRS). TENS was applied for 60 minutes to generate a strong but comfortable TENS sensation at the site of stump pain or projected into the site of phantom pain. Outcomes at rest and on movement before and during TENS at 30 minutes and 60 minutes were changes in the intensities of pain, nonpainful phantom sensation, and prosthesis embodiment. Mean (SD) pain intensity scores were reduced by 1.8 (1.6) at rest (P < 0.05) and 3.9 (1.9) on movement (P < 0.05) after 60 minutes of TENS. For five participants, it was possible to project TENS sensation into the phantom limb by placing the electrodes over transected afferent nerves. Nonpainful phantom sensations and prosthesis embodiment remained unchanged. This study has demonstrated that TENS has potential for reducing phantom pain and stump pain at rest and on movement. Projecting TENS sensation into the phantom limb might facilitate perceptual embodiment of prosthetic limbs. The findings support the delivery of a feasibility trial. PMID- 22935085 TI - SNP microarray analyses reveal copy number alterations and progressive genome reorganization during tumor development in SVT/t driven mice breast cancer. AB - BACKGROUND: Tumor development is known to be a stepwise process involving dynamic changes that affect cellular integrity and cellular behavior. This complex interaction between genomic organization and gene, as well as protein expression is not yet fully understood. Tumor characterization by gene expression analyses is not sufficient, since expression levels are only available as a snapshot of the cell status. So far, research has mainly focused on gene expression profiling or alterations in oncogenes, even though DNA microarray platforms would allow for high-throughput analyses of copy number alterations (CNAs). METHODS: We analyzed DNA from mouse mammary gland epithelial cells using the Affymetrix Mouse Diversity Genotyping array (MOUSEDIVm520650) and calculated the CNAs. Segmental copy number alterations were computed based on the probeset CNAs using the circular binary segmentation algorithm. Motif search was performed in breakpoint regions (inter-segment regions) with the MEME suite to identify common motif sequences. RESULTS: Here we present a four stage mouse model addressing copy number alterations in tumorigenesis. No considerable changes in CNA were identified for non-transgenic mice, but a stepwise increase in CNA was found during tumor development. The segmental copy number alteration revealed informative chromosomal fragmentation patterns. In inter-segment regions (hypothetical breakpoint sides) unique motifs were found. CONCLUSIONS: Our analyses suggest genome reorganization as a stepwise process that involves amplifications and deletions of chromosomal regions. We conclude from distinctive fragmentation patterns that conserved as well as individual breakpoints exist which promote tumorigenesis. PMID- 22935087 TI - Tandem duplication of KIT exon 11 influences the proteome of canine mast cell tumours. AB - Mutations with permanent activation of the stem cell factor receptor KIT have been identified as one potential cause for canine cutaneous mast cell tumours (MCTs). The exact changes in global gene expression patterns associated with permanent activation of KIT in these tumours are unknown. The present study compares, by the use of two dimensional difference gel electrophoresis and matrix assisted laser desorption/ionization time-of-flight mass spectrometry, the proteomes of canine MCTs, with and without KIT exon 11 tandem duplication. Fifteen differentially expressed proteins were identified in mutated MCTs. These are mainly involved in cytoskeleton structure and cell motility (ACTR2, ACTB and CAPPA1), cell signalling (ARHGDIA) and lipid metabolism (ALOX15 and ACSBG4), or are serum proteins. The results therefore support the notion that KIT mutation is associated with changes in the proteome of affected cells with a major effect on the composition of the cytoskeletal proteome and cell motility proteins. No overlaps were identified when the results were compared with a recent study on the proteomic differences between low- and high-grade tumours, suggesting that KIT-mutated tumours may be regarded as a separate entity of high-grade tumours with potential relevance to therapeutic strategies. PMID- 22935088 TI - Iron overload syndrome in the black rhinoceros (Diceros bicornis): microscopical lesions and comparison with other rhinoceros species. AB - The African black rhinoceros (Diceros bicornis) has adapted to a low iron diet during evolution and is thus prone to iron overload in captivity, which is associated with a number of serious disorders. A S88T polymorphism in the HFE gene has been suggested as a potential genetic basis of increased iron uptake in the black rhinoceros, while the Indian rhinoceros is thought to be unaffected by iron overload in captivity. In the present study, the histopathology and distribution of iron accumulations in five black rhinoceroses with iron overload syndrome were characterized and compared with three Indian rhinoceroses (Rhinoceros unicornis) and one African white rhinoceros (Ceratotherium simum). At necropsy examination, iron storage in black rhinoceroses was not associated with gross lesions. Microscopically, the most consistent and highest degree of iron load was found in the spleen, liver, small intestine and lung. There was minimal fibrosis and single cell necrosis in the liver. Endocrine organs, lymph nodes, heart and kidney were less often and less markedly affected. Unexpectedly, Indian rhinoceroses also showed iron load in the spleen and smaller amounts in organs similar to the black rhinoceros except for in the heart, while the white rhinoceros had only minor detectable iron storage in intestine, liver and lung. Sequence analysis confirmed the HFE S88T polymorphism in black but not in Indian rhinoceroses. The results indicate that Indian rhinoceroses may also be affected by iron storage in captivity, although in a milder form than the black rhinoceros, and therefore challenge the relevance of the S88T polymorphism in the HFE gene of black rhinoceroses as the underlying cause for iron overload. PMID- 22935089 TI - Extensive myenteric ganglionitis in a case of equine chronic intestinal pseudo obstruction associated with EHV-1 infection. AB - A 7-year-old male trotter horse with a history of recurrent colic displayed clinical findings consistent with chronic intestinal pseudo-obstruction (CIP). At laparotomy, an impaction of the descending colon associated with marked atrophy of the right dorsal colon was found. The horse was humanely destroyed and tissues collected at necropsy examination revealed diffuse enteric ganglionitis comprising an infiltrate of CD3(+) T lymphocytes and plasma cells. At all levels of the intestinal tract the number of myenteric ganglia and of normal ganglion cells was decreased significantly. There were chromatolytic or necrotic neurons and the amount of connective tissue surrounding ganglia was increased. Immunohistochemical studies demonstrated slightly reduced expression of neuron specific enolase and a moderate increase in expression of S100 and glial fibrillary acidic protein in a sample of right dorsal colon taken during the necropsy examination compared with a biopsy sample taken from the same location. Immunolabelling and semi-nested polymerase chain reaction for equine herpesvirus (EHV)-1 performed on the gut were positive, supporting an aetiological relationship between EHV-1 infection and the enteric ganglionitis. PMID- 22935091 TI - A case of Takayasu's arteritis associated with familial Mediterranean fever. PMID- 22935090 TI - Protein expression profiling of inflammatory mediators in human temporal lobe epilepsy reveals co-activation of multiple chemokines and cytokines. AB - Mesial temporal lobe epilepsy (mTLE) is a chronic and often treatment-refractory brain disorder characterized by recurrent seizures originating from the hippocampus. The pathogenic mechanisms underlying mTLE remain largely unknown. Recent clinical and experimental evidence supports a role of various inflammatory mediators in mTLE. Here, we performed protein expression profiling of 40 inflammatory mediators in surgical resection material from mTLE patients with and without hippocampal sclerosis, and autopsy controls using a multiplex bead-based immunoassay. In mTLE patients we identified 21 upregulated inflammatory mediators, including 10 cytokines and 7 chemokines. Many of these upregulated mediators have not previously been implicated in mTLE (for example, CCL22, IL-7 and IL-25). Comparing the three patient groups, two main hippocampal expression patterns could be distinguished, pattern I (for example, IL-10 and IL-25) showing increased expression in mTLE + HS patients compared to mTLE-HS and controls, and pattern II (for example, CCL4 and IL-7) showing increased expression in both mTLE groups compared to controls. Upregulation of a subset of inflammatory mediators (for example, IL-25 and IL-7) could not only be detected in the hippocampus of mTLE patients, but also in the neocortex. Principle component analysis was used to cluster the inflammatory mediators into several components. Follow-up analyses of the identified components revealed that the three patient groups could be discriminated based on their unique expression profiles. Immunocytochemistry showed that IL-25 IR (pattern I) and CCL4 IR (pattern II) were localized in astrocytes and microglia, whereas IL-25 IR was also detected in neurons. Our data shows co-activation of multiple inflammatory mediators in hippocampus and neocortex of mTLE patients, indicating activation of multiple pro- and anti epileptogenic immune pathways in this disease. PMID- 22935092 TI - Courtship behaviour of Phlebotomus papatasi the sand fly vector of cutaneous leishmaniasis. AB - BACKGROUND: The sand fly Phlebotomus papatasi is an Old World vector of Leishmania major, the etiologic agent of zoonotic cutaneous leishmaniasis. This study describes the courtship behaviour of P. papatasi and compares it with that of Lutzomyia longipalpis, the New World vector of visceral leishmaniasis. Understanding the details of courtship behaviour in P. papatasi may help us to understand the role of sex pheromones in this important vector. RESULTS: P. papatasi courtship was found to start with the female touching the male, leading him to begin abdomen bending and wing flapping. Following a period of leg rubbing and facing, the male flaps his wings while approaching the female. The female then briefly flaps her wings in response, to indicate that she is willing to mate, thereby signaling the male to begin copulation. Male P. papatasi did not engage in parading behaviour, which is performed by male L. longipalpis to mark out individual territories during lekking (the establishment and maintenance of mating aggregations), or wing-flap during copulation, believed to function in the production of audio signals important to mate recognition. In P. papatasi the only predictor of mating success for males was previous copulation attempts and for females stationary wing-flapping. By contrast, male L. longipalpis mating success is predicted by male approach-flapping and semi-circling behaviour and for females stationary wing-flapping. CONCLUSIONS: The results show that there are important differences between the mating behaviours of P. papatasi and L. longipalpis. Abdomen bending, which does not occur in L. longipalpis, may act in the release of sex pheromone from an as yet unidentified site in the male abdomen. In male L. longipalpis wing-flapping is believed to be associated with distribution of male pheromone. These different behaviours are likely to signify significant differences in how pheromone is used, an observation that is consistent with field and laboratory observations. PMID- 22935094 TI - A template for reliable assessment of resident operative performance: assessment intervals, numbers of cases and raters. AB - BACKGROUND: Operative performance rating (OPR) instruments have been developed to assess operative performance (OP). To guide program implementation, this study determined: 1) Appropriate intervals for OP progress decisions, 2) Number of OPRs and raters required per interval to achieve reproducible results. METHODS: 21 surgeons rated 897 OPs (3 procedures) by 36 residents. Six-month PGY intervals were compared to determine length of stable operative performance intervals. Variance component analyses established rating factor importance. Generalizability analyses and decision studies determined number of OPRs required for reproducible OP decisions (reliabilities = 0.80). RESULTS: Resident OPRs are stable across single PGY years. 2.3 OPRs/resident/month provided a dependable basis for annual or semi-annual resident OP decisions. Results were similar for all procedures and training years. Rater idiosyncrasies accounted for most score variation (63% when interaction effects involving rater idiosyncrasies were included). Resident ability was the next most important source of variation (12%). Procedure was a less important source (5%). CONCLUSION: Annual resident OP decisions are supported. 2.3 OPRs per month provide a dependable basis for judging resident OP. These numbers are sufficient regardless of training year or procedure mix though efforts should be made to balance procedure mix. Multiple raters should rate each resident to control for rater idiosyncrasies. PMID- 22935095 TI - Racial disparity and their impact on hepatocellular cancer outcomes in inner-city New Orleans. AB - BACKGROUND: The role of socioeconomic factors that affect survival, particularly for hepatocellular cancer (HCC), has yet to be fully analyzed. This study attempts to elucidate those racial and socioeconomic factors that affect differences in survival for patients with HCC. METHODS: In a retrospective cohort study of 206 patients with HCC diagnosed in an inner-city urban center from 2003 to 2011, outcomes by race (African Americans versus white) were analyzed. Additional attention was paid to socioeconomic factors. Continuous variables were compared with the Student t-test, and categorical variables were compared with the chi(2) or Fisher exact test. Multivariate analysis was conducted using a logistic regression model. Patient death and survival data were analyzed with Kaplan-Meier and Cox proportional hazards. RESULTS: Comparison of 138 white and 68 African-American patients revealed that African-American patients were more likely to present with larger tumor size at the time of diagnosis (4.7 vs 3.7 cm; P < .05). African-American patients were also more likely to be intravenous drug users (25.4% vs 11.6%; P < .05) and have cirrhosis from hepatitis C (81% vs 60%; P < .01). African-American patients were less likely to have private insurance compared with white patients (68% vs 92%; P < .01). Despite these findings in our inner-city practice, there was no difference in liver transplantation rates or survival rates between the 2 groups. CONCLUSION: Despite presentation with less favorable tumor characteristics, African-American patients are able to achieve survival that is comparable with their white counterparts when treated in a program that is attuned to the challenges faced by their specific population. PMID- 22935093 TI - Novel multiregion hybridization assay for the identification of the most prevalent genetic forms of the human immunodeficiency virus type 1 circulating in Portugal. AB - The most efficient method for HIV-1 genetic characterization involves full-genome sequencing, but the associated costs, technical features, and low throughput preclude it from being routinely used for the analysis of large numbers of viral strains. Multiregion hybridization assays (MHA) represent an alternative for a consistent genetic analysis of large numbers of viral strains. Classically, MHA rely on the amplification by real-time PCR of several regions scattered along the HIV-1 genome, and on their characterization with clade-specific TaqMan probes (also known as hydrolysis probes). In this context, the aim of our study was the development of a technical variant of an MHA (vMHA(B/G/02)) for genotyping the most prevalent genetic forms of HIV-1 circulating in Portugal. Different sets of primers were designed for universal and clade-specific amplifications of several sections of the viral genome: gag, pol(Pr), pol(RT), vpu, env(gp120), and env(gp41). vMHA(B/G/02) was implemented using a real-time PCR-based approach, with detection dependent on the use of SYBR Green I. As an alternative, a technically less demanding strategy based on conventional PCR and agarose gel analysis of the reaction products was also developed. This method performed with overall good sensitivity and specificity (>91%) when a convenience sample of 45 plasma-derived HIV-1 strains was analyzed. Apart from the detection of subtype B, G, CRF02_AG, and CRF14_BG viruses, several unique B/G recombinant were also detected. Curiously, recombinant viruses including CRF02_AG sequences were not detected in the group of samples analyzed. PMID- 22935096 TI - Host cues induce egg hatching and pre-parasitic foraging behaviour in the mosquito parasitic nematode, Strelkovimermis spiculatus. AB - The responses of eggs in diapause and the infective stage of the nematode, Strelkovimermis spiculatus, to larvae of its host, Culex pipiens pipiens, were investigated in the laboratory. The results indicated that the presence of the host induced the egg hatching. The hatching rate increased when larger numbers of host larvae were present. Second instar mosquito larvae induced significantly higher hatching rates than any other stages. These findings explain how S. spiculatus synchronizes its life cycle with its host life cycle and population dynamics to increase its fitness when the natural habitat is constantly covered by water. Direct exposure of the nematode eggs to host larvae resulted in consumption of as many as 20 eggs per host. The eggs consumed caused 0-70% host mortality depending on the number consumed, which indicated an infection path other than cuticle penetration although it may represent a rare situation in nature. The result of host cue assays showed that the combination of chemical cues and physical vibration induced the highest egg hatching, which may increase the chance of host availability after hatching. However, once hatched, the nematodes ignored vibrations and used only chemical cues for host location. These findings suggest that eggs hatch synchronously with the most susceptible mosquito stage and with peak mosquito larval density. PMID- 22935097 TI - Fitness benefits of a division of labour in parasitic trematode colonies with and without competition. AB - A reproductive division of labour has recently been discovered within polyembryonic colonies of two species of parasitic trematodes infecting snail hosts. In these colonies, one morph expands the colony through asexual reproduction while the other morph never reproduces. As in other polyembryonic species using a division of labour (parasitoid wasps, one species of sea anemone), the non-reproducing morph appears specialized for defense against competing colonies. In this study, we first assessed competition between Philophthalmus sp. (which possesses reproducing and non-reproducing morphs) and the most common co-infecting species, Maritrema novaezealandensis, by quantifying colony success within snail hosts. Colonies of either species that did not compete within their host were more successful (i.e., produced more transmission stages) than colonies that were competing in a shared host. Second, we cultured individuals of both species in vitro, alone or together, to study the interaction more closely and to measure any advantage obtained by the colony from the non reproducing morphs. This was done by manipulating the presence and abundance of M. novaezealandensis as well as the presence of the non-reproducing 'defensive' morph. Philophthalmus sp. colonies with both reproducing and non-reproducing morphs but without M. novaezealandensis were most successful. This implies the non-reproducing morphs provide a fitness benefit to Philophthalmus sp. colonies even in the absence of competition, although the nature of this advantage remains unclear. PMID- 22935099 TI - Walnut consumption protects rats against cisplatin-induced neurotoxicity. AB - Walnut is extensively used in traditional medicine for treatment of various ailments. It is described as an anticancer, anti-inflammatory, blood purifier and antioxidant agent. In this study, we investigated whether or not Walnut could protect neurons against cisplatin-induced neurotoxicity in rats. Dietary walnut (6%) was assessed for its neuroprotective effects through the alteration in performance of hippocampus- and cerebellum-related behaviors following chronic cisplatin treatment (5 mg/kg/week for 5 consecutive weeks) in male rats. We also evaluated the effect of cisplatin and walnut administration on nociception. We showed that exposure of adolescent rats to cisplatin resulted in significant decrease in explorative behaviors and memory retention. Walnut consumption improved memory and motor abilities in cisplatin treated rats, while walnut alone did not show any significant changes in these abilities compared to saline. Cisplatin increased latency of response to nociception, and walnut reversed this effect of cisplatin. We conclude that walnuts in the diet following anticancer drugs such as cisplatin might have a protective effect against cisplatin-induced disruptions in motor and cognitive function. However, further studies are needed to elucidate the exact mechanisms of this protective effect of walnut and to explore underlying mechanisms. PMID- 22935098 TI - Ahrd Cyp1a2(-/-) mice show increased susceptibility to PCB-induced developmental neurotoxicity. AB - Polychlorinated biphenyls (PCBs) are developmental neurotoxicants that produce cognitive and behavioral changes in children exposed during gestation and lactation. Coplanar PCBs bind the aryl hydrocarbon receptor (AHR) and can be sequestered in liver by cytochrome P450 1A2 (CYP1A2). The AHR is a ligand activated transcription factor which increases expression of the CYP1 family, including CYP1A2. Our previous work examining genetic susceptibility to developmental PCB neurotoxicity showed that Ahr(b)Cyp1a2(-/-) mice with the high affinity Ahr(b) allele and lacking CYP1A2 were most susceptible while Ahr(b)Cyp1a2(+/+) and poor-affinity Ahr(d)Cyp1a2(+/+) mice were resistant. To follow up, a fourth line of mice was generated with the Ahr(d)Cyp1a2(-/-) genotype and compared with the background strain Ahr(b)Cyp1a2(+/+). Dams received a PCB mixture or the corn oil vehicle at gestational Day 10 (GD10) and postnatal Day 5 (PND5). Offspring were tested at PND60 in open field locomotor, acoustic startle with pre-pulse inhibition (PPI), novel object recognition and Morris water maze. Locomotor activity was increased in PCB-treated Ahr(b)Cyp1a2(+/+) mice, but no differences were seen in control vs. PCB-treated Ahr(d)Cyp1a2(-/-) mice. PCB-treated Ahr(d)Cyp1a2(-/-) mice had a higher baseline startle response and significantly reduced pre-pulse inhibition at the 74dB level compared with corn oil-treated controls (P<0.05). PCB-treated Ahr(d)Cyp1a2(-/-) mice had impairments in novel objective recognition (P<0.05) and during all three hidden platform phases of Morris water maze (P<0.01). Combined with our previous findings, these results indicate Cyp1a2 genotype is more important in susceptibility to PCB-induced deficits in learning and memory, but Ahr genotype appears more important when assessing acoustic startle-PPI and locomotor activity. PMID- 22935100 TI - Evaluating the impact of a novel restricted reimbursement policy for quinolone antibiotics: a time series analysis. AB - BACKGROUND: Publicly-funded drug plans often use prior authorization policies to limit drug prescribing. To guide physician prescribing of a class of antibiotics with broad antimicrobial activity (quinolone antibiotics) in accordance with new prescribing guidelines, Alberta's provincial health ministry implemented a new mechanism for formulary restriction entitled the optional special authorization (OSA) program. We conducted an observational study to determine the impact of this new formulary restriction policy on antimicrobial prescription rates as well as any clinical consequences. METHODS: Quinolone antibiotic use, and adherence with quinolone prescribing guidelines, was assessed before and after implementation of the OSA program in patients with common outpatient infections using an administrative data cohort and a chart review cohort, respectively. At the same time this policy was implemented to limit quinolone prescribing, two new quinolone antibiotics were added to the formulary. Using administrative data, we analysed a total of 397,534 unique index visits with regard to overall antibiotic utilization, and through chart review, we analysed 1681 charts of patients with infections of interest to determine the indications for quinolone usage. RESULTS: Using segmented regression models adjusting for age, sex and physician enrollment in the OSA program, there was no statistically significant change in the monthly rate of all quinolone use (-3.5 (95% CI -5.5, 1.4) prescriptions per 1000 index visits) following implementation of the OSA program (p = 0.74). There was a significant level change in the rate of quinolone antibiotic use for urinary tract infection (-33.6 (95% CI: -23.8, -43.4) prescriptions and upper respiratory tract infection (-16.1 (95%CI: -11.6, -20.6) prescriptions per 1000 index visits. Among quinolone prescriptions identified on chart review, 42.5% and 58.5% were consistent with formulary guidelines before and after the implementation of the OSA program, respectively (p = 0.002). There was no change in hospitalization, mortality or use of physician services after implementation of the OSA program. CONCLUSIONS: Despite the addition of two new quinolone antibiotics to the formulary, we found that there was no change in the use of quinolones after implementation of a new formulary restriction policy for outpatients with common outpatient infections. PMID- 22935101 TI - ncDNA and drift drive binding site accumulation. AB - BACKGROUND: The amount of transcription factor binding sites (TFBS) in an organism's genome positively correlates with the complexity of the regulatory network of the organism. However, the manner by which TFBS arise and accumulate in genomes and the effects of regulatory network complexity on the organism's fitness are far from being known. The availability of TFBS data from many organisms provides an opportunity to explore these issues, particularly from an evolutionary perspective. RESULTS: We analyzed TFBS data from five model organisms - E. coli K12, S. cerevisiae, C. elegans, D. melanogaster, A. thaliana and found a positive correlation between the amount of non-coding DNA (ncDNA) in the organism's genome and regulatory complexity. Based on this finding, we hypothesize that the amount of ncDNA, combined with the population size, can explain the patterns of regulatory complexity across organisms. To test this hypothesis, we devised a genome-based regulatory pathway model and subjected it to the forces of evolution through population genetic simulations. The results support our hypothesis, showing neutral evolutionary forces alone can explain TFBS patterns, and that selection on the regulatory network function does not alter this finding. CONCLUSIONS: The cis-regulome is not a clean functional network crafted by adaptive forces alone, but instead a data source filled with the noise of non-adaptive forces. From a regulatory perspective, this evolutionary noise manifests as complexity on both the binding site and pathway level, which has significant implications on many directions in microbiology, genetics, and synthetic biology. PMID- 22935103 TI - Global brain atrophy is associated with physical performance and the risk of falls in older adults with cognitive impairment. AB - AIM: Falls are common in patients with cognitive disorder. The purpose of this study was to determine whether global brain atrophy is associated with cognitive function, physical performance and fall incidents in older adults with mild cognitive disorder. METHODS: A total of 31 older adults with mild cognitive disorders (mean age 78.9 +/- 7.3 years) were studied, and 10 of them had experienced falls and the others had not in the past 1 year. Cognitive function and physical performance were measured in these patients. Global brain atrophy was determined by the Voxel-Based Specific Regional Analysis System for Alzheimer's Disease software. RESULTS: Fallers showed significantly worse scores than the non-fallers in the Global Brain Atrophy Index, Clock Drawing Test (CDT), Verbal Fluency Test (animal), maximum walking time and Timed Up & Go (TUG) Test. The Global Brain Atrophy Index was correlated with the Verbal Fluency Test (animal; r = -0.522), the Verbal Fluency Test with letter (ka; r = -0.337), CDT (r = -0.547), TUG (r = 0.276) and Five Chair Stands Test (r = 0.303) by age adjusted correlation analyses. Stepwise regression analysis showed that the Global Brain Atrophy Index (beta = 1.265, 95% CI 1.022-1.567) was a significant and independent determinant of falls (R(2) = 0.356, P = 0.003). CONCLUSION: Global brain atrophy might be indicated as one of the risk factors for falls in older adults with mild cognitive disorders. PMID- 22935102 TI - Opsin evolution and expression in arthropod compound eyes and ocelli: insights from the cricket Gryllus bimaculatus. AB - BACKGROUND: Opsins are key proteins in animal photoreception. Together with a light-sensitive group, the chromophore, they form visual pigments which initiate the visual transduction cascade when photoactivated. The spectral absorption properties of visual pigments are mainly determined by their opsins, and thus opsins are crucial for understanding the adaptations of animal eyes. Studies on the phylogeny and expression pattern of opsins have received considerable attention, but our knowledge about insect visual opsins is still limited. Up to now, researchers have focused on holometabolous insects, while general conclusions require sampling from a broader range of taxa. We have therefore investigated visual opsins in the ocelli and compound eyes of the two-spotted cricket Gryllus bimaculatus, a hemimetabolous insect. RESULTS: Phylogenetic analyses place all identified cricket sequences within the three main visual opsin clades of insects. We assign three of these opsins to visual pigments found in the compound eyes with peak absorbances in the green (515 nm), blue (445 nm) and UV (332 nm) spectral range. Their expression pattern divides the retina into distinct regions: (1) the polarization-sensitive dorsal rim area with blue- and UV-opsin, (2) a newly-discovered ventral band of ommatidia with blue- and green opsin and (3) the remainder of the compound eye with UV- and green-opsin. In addition, we provide evidence for two ocellar photopigments with peak absorbances in the green (511 nm) and UV (350 nm) spectral range, and with opsins that differ from those expressed in the compound eyes. CONCLUSIONS: Our data show that cricket eyes are spectrally more specialized than has previously been assumed, suggesting that similar adaptations in other insect species might have been overlooked. The arrangement of spectral receptor types within some ommatidia of the cricket compound eyes differs from the generally accepted pattern found in holometabolous insect taxa and awaits a functional explanation. From the opsin phylogeny, we conclude that gene duplications, which permitted differential opsin expression in insect ocelli and compound eyes, occurred independently in several insect lineages and are recent compared to the origin of the eyes themselves. PMID- 22935104 TI - In silico drug repositioning: what we need to know. AB - Drug repositioning, exemplified by sildenafil and thalidomide, is a promising way to explore alternative indications for existing drugs. Recent research has shown that bioinformatics-based approaches have the potential to offer systematic insights into the complex relationships among drugs, targets and diseases necessary for successful repositioning. In this article, we propose the key bioinformatics steps essential for discovering valuable repositioning methods. The proposed steps (repurposing with a purpose, repurposing with a strategy and repurposing with confidence) are aimed at providing a repurposing pipeline, with particular focus on the proposed Drugs of New Indications (DNI) database, which can be used alongside currently available resources to improve in silico drug repositioning. PMID- 22935105 TI - Henipavirus-related sequences in fruit bat bushmeat, Republic of Congo. PMID- 22935106 TI - Study on TRPV1-mediated mechanism for the hypersecretion of mucus in respiratory inflammation. AB - Transient receptor potential vanilloid 1 (TRPV1) is sensitized by the high affinity TrkA receptor, which promotes pro-inflammatory cytokine production and mediates mucus hypersecretion in bronchial epithelial cells. The purpose of this study was to investigate the mechanism of TRPV1-mediated mucus hypersecretion and respiratory inflammation. Firstly, using Western blot analysis we found that epidermal growth factor receptor (EGFR) and TRPV1 were highly co-expressed in human bronchial epithelial cells (HBE16) with HNE and capsaicin co-treated, the levels of pro-inflammatory cytokines and MUC5AC were also highly co-expressed; however, TRPV1 receptor expression was low in these cells with only HNE stimulation, which demonstrated that sensitization of TRPV1 was not increased in HBE16 cells treated with HNE alone. Secondly, the EGF receptor antagonist (AG1478) and the TrkA receptor inhibitor (K252a) significantly inhibited TRPV1 sensitivity and the expression of MUC5AC and pro-inflammatory cytokines. Furthermore, the PI3K inhibitor LY294002, the PKC inhibitor bisindoylmaleimide (BIM) and the TRPV1 antagonist capsazepine completely abrogated the EGF sensitizing effect. Furthermore, the hypoxia-inducible factor (HIF-1alpha) inhibitor 2-methoxyestradiol (2-ME2) decreased the activity of PKC by a specific pathway. These findings strongly suggest that TRPV1 sensitization influences the hypersecretion of mucus and inflammatory cytokines, is associated with the PI3K and PKC signaling pathways and is involved HIF-1alpha activity. PMID- 22935108 TI - The future of community-centred health services in Australia: 'When too many beds are not enough'. AB - The authors welcome a constructive debate on the future of community-centred health services. Therefore, we have written this piece in response to an article published by Cunningham in the previous edition of the Australian Health Review (Cunningham, Australian Health Review 2012; 36: 121-124), which was a very limited analysis and misleading critique of our previous contribution to this journal (Rosen et al. Australian Health Review 2010; 34: 106-115). The focus here is necessarily brief and does not stand in for a detailed analysis of the evidence base. The aim instead, is to draw attention back to the broader political economic and social dimensions of how the retreat from community health services has affected clinical care. We also outline a response to a longstanding assumption, or belief, that too many hospital beds are not enough and may never be enough. How we understand the problem of resource allocation in healthcare shapes the remedies that are considered realistic. We explain that the reasons for the systematic underdevelopment of community health services are complex, historical, and largely relate to political and economic factors, but they are still amenable to change. PMID- 22935107 TI - Peripheral administration of prokineticin 2 potently reduces food intake and body weight in mice via the brainstem. AB - BACKGROUND AND PURPOSE: Prokineticin 2 (PK2) has recently been shown to acutely reduce food intake in rodents. We aimed to determine the CNS sites and receptors that mediate the anorectic effects of peripherally administered PK2 and its chronic effects on glucose and energy homeostasis. EXPERIMENTAL APPROACH: We investigated neuronal activation following i.p. administration of PK2 using c-Fos like immunoreactivity (CFL-IR). The anorectic effect of PK2 was examined in mice with targeted deletion of either prokineticin receptor 1 (PKR1) or prokineticin receptor 2 (PKR2), and in wild-type mice following administration of the PKR1 antagonist, PC1. The effect of IP PK2 administration on glucose homeostasis was investigated. Finally, the effect of long-term administration of PK2 on glucose and energy homeostasis in diet-induced obese (DIO) mice was determined. KEY RESULTS: I.p. PK2 administration significantly increased CFL-IR in the dorsal motor vagal nucleus of the brainstem. The anorectic effect of PK2 was maintained in mice lacking the PKR2 but abolished in mice lacking PKR1 and in wild-type mice pre-treated with PC1. DIO mice treated chronically with PK2 had no changes in glucose levels but significantly reduced food intake and body weight compared to controls. CONCLUSIONS AND IMPLICATIONS: Together, our data suggest that the anorectic effects of peripherally administered PK2 are mediated via the brainstem and this effect requires PKR1 but not PKR2 signalling. Chronic administration of PK2 reduces food intake and body weight in a mouse model of human obesity, suggesting that PKR1-selective agonists have potential to be novel therapeutics for the treatment of obesity. PMID- 22935109 TI - Sleep Faster! (Somebody else needs your blanket...). AB - One of the elements of the health reform plan, as agreed to by Australian state and federal governments, is to introduce a 4-h National Access Target, to reduce emergency department (ED) waiting times. This article highlights the flawed rationale behind the 4-h rule, the UK experience of this rule and discusses the potential dangers it poses to Australian patients. An alternative solution proposed is the separation of elective and emergency surgical streams to reduce the variability in demand for inpatient services. PMID- 22935110 TI - Achieving waiting list reform: a pilot program integrating waiting time, category and patient factors. AB - Equity in resource allocation is central to the tenet of social justice in health care. The management of surgical waiting lists is of critical importance to clinicians, patients and regulators. In most hospital environments, the basic process has remained unchanged for decades. Patients are assigned to one of three urgency-related categories. Clinicians consequently administer three competing patient pools. The basis by which patients are selected for treatment may be difficult to define. The specific clinical circumstances of each patient are often unreported and may be unknown to those administering the list. Waiting list bias is also recognised. This may reflect clinician advocacy, pressure to meet category timeframe restrictions or perceived training requirements. In this environment, it is difficult to demonstrate propriety in care. We report the implementation of a pilot program to redesign waiting list management within a South Australian public hospital unit. This allows assemblage of patients into a single list. Overall priority is determined by balancing clinical acuity and waiting time. The determination of acuity takes into account both the primary category and the specific characteristics of each patient that are relevant to their intended procedure. Uniquely, the process is applicable to lists containing patients with dissimilar conditions. This paper reviews the limitations of current approaches in meeting reasonable community expectations. The principles and social justification underpinning this reform are introduced. Finally, the benefits offered by the program are discussed and interim results are reported. PMID- 22935111 TI - Is cancer care dependant on informal carers? AB - Over the past half century, medical care has become less institutionalised, more autonomous, equitable and less costly. This has led to a shift from hospital based delivery to community care. This paper examines the experiences of Canberra based carers following this shift using interview data from a longitudinal qualitative study of 32 informal carers of a spouse with cancer. Cancer patients experienced poorly coordinated care. When carers observed the effects of errors and miscommunication on patients, they felt compelled to coordinate patient care. Interview data suggest that informal carers of cancer patients are relied upon to manage patient care at home and in hospitals, but are not supported in undertaking this responsibility. This implies that carers should be a far more central focus in cancer care reform strategies. PMID- 22935112 TI - A model-based evaluation of collaborative care in management of patients with type 2 diabetes in Australia: an initial report. AB - OBJECTIVES: To analyse the short- and long-term costs and benefits of alternative models of primary care for the management of patients with type 2 diabetes in Australia. The models of care reflect differential uptake of primary care-based incentive programs, including reminder systems and involvement of practice nurses in management. This paper describes our study protocol and its progress. METHODS: We are undertaking an observational study using a cluster sample design that links retrospective patient data from a range of sources to estimate costs and intermediate outcomes (such as the level of glycosylated haemoglobin (HbA1c)) over a 3-year time horizon. We use the short-term data as a basis to estimate lifetime costs and benefits of alternative models of care using a decision analytic model. INITIAL REPORT: We recruited 15 practices from a metropolitan area (Adelaide) and allocated them to three models of care. Three hundred and ninety-nine patients agreed to participate. We use multilevel analysis to evaluate the association between different models of care and patient-level outcomes, while controlling for several covariates. DISCUSSION/CONCLUSIONS: Given the large amount of funding currently used to maintain primary care-based incentives in general practices in Australia, the results of this study generate the knowledge required to promote investment in the most cost-effective incentives. PMID- 22935113 TI - Incorporating educative environments into the holistic care of paediatric patients. AB - Hospital settings can, and should, create educative spaces and learning opportunities as part of their holistic care for young patients. The purpose of this paper is to examine the evidence for creating high quality, child-centred learning environments within paediatric settings. We explore the impact of physical spaces on learning; the literature on developmental stages of learning for children and young people as it relates to learning environments; and the literature on learning in out-of-school settings, particularly as this applies to children who are separated from their daily communities. As all paediatric settings can create opportunities for the ongoing educational development of their patients, this paper presents a way forward for this approach to holistic care. PMID- 22935114 TI - Federal budget 2012/13. PMID- 22935115 TI - Oral health - if not for everyone then for whom? PMID- 22935116 TI - Reflections on the role of less-than-comprehensive (exclusionary) private health insurance hospital products in the Australian healthcare system. AB - The number of people in Australia that are currently covered by a hospital private health insurance product continues to rise every quarter. In September 2010, for the first time since the introduction of the public universal social insurance scheme, Medicare, more than 10million persons in Australia are covered by private health insurance. Although the number of persons covered by private health insurance continues to grow, the quality and level of cover that members are holding is changing significantly. In an effort to limit premium rises and to reduce the benefits paid for treatment, private health insurers have introduced, and moved a large number of existing members to, less-than-comprehensive private health insurance policies. These policies, known as 'exclusionary' policies, are changing the dynamics of private health insurance in Australia. After examining the emergence and prevalence of these products, this commentary gives three different examples to illustrate how such products are changing the nature of private health insurance in Australia and are now set to create a series of policy issues that will require future attention. PMID- 22935117 TI - Safe timing for an urgent Caesarean section: what is the evidence to guide policy? AB - OBJECTIVE: To determine, from the evidence, what is the optimum decision to delivery (DDI) intervals in emergency Caesarean sections (CS). The aim of the study was to help guide policy in maternity services and identify issues relating to DDI and safe practice in maternity care. METHOD: A systematic review of the literature was undertaken. Assessment of the quality of eligible papers was undertaken using the Critical Appraisal Skills Program (CASP) rating. RESULTS: There is no strong evidence that a DDI of 30 min or less is associated with improved outcomes for babies or mothers. Some evidence suggests that a DDI of greater than 30 min but less than 75 min confers benefit, but these findings were confounded by the indications for the emergency CS. CONCLUSION: Urgent CS should occur as soon as possible, but there is insufficient evidence to support a definite time frame, such as 30 min. A consistency of approach and nomenclature in describing the urgency of CS is necessary, which would enable criteria for further audit regarding DDI. Staff training should be addressed to improve transfer systems for CS. Antenatal risk assessment and congruence with role delineation and service delivery capacity is important. PMID- 22935118 TI - Governance, management and clinical risk. PMID- 22935119 TI - A framework to improve evidence-informed decision-making in health service management. AB - OBJECTIVE: The objective of this paper is to present and provide justification for a framework to improve evidence-informed management decision-making among health service managers. Three research questions informed the study: How have different perspectives influenced how evidence has been defined? What are the barriers to the practice of evidence-informed decision-making (EIDM)? What are the factors that may encourage the application of evidence to guide management decision-making processes? METHODS: A literature review was conducted to identify studies that examined the practice of EIDM among health service managers. Information relevant to the three research questions was collectively analysed, compared and contrasted based on their relevance to the EIDM process. CONCLUSION: Several factors have played different but significant roles in affecting the practice of EIDM among health service managers. Although interaction between these factors is complex, the framework developed in this paper may guide the development of strategies to encourage and improve the utilisation of evidence in management decision-making process. PMID- 22935120 TI - How best to measure health workforce turnover and retention: five key metrics. AB - OBJECTIVE: This article identifies, critically appraises and illustrates the use of five key workforce turnover and retention metrics that are well suited for use by Australian rural health workforce planners. These are crude turnover (separation) rates, stability rates, survival probabilities, median survival and Cox proportional hazard ratios. Examples of their calculation are presented using actual data obtained from payroll records in Australian rural and remote health services. CONCLUSION: The use of this small number of metrics as a 'workforce measurement package' can help overcome many of the limitations evident when a single measure is reported in isolation, by providing a more comprehensive picture of turnover and retention patterns. We suggest that health services themselves can calculate the simplest measures, whereas regional and centralised health authorities with higher levels of expertise undertake survival analysis and comparisons of compiled data. IMPLICATIONS: These key metrics can be used routinely to measure baseline levels of health worker turnover and retention, to quantify important determinants of turnover and retention, and importantly, to make valid comparisons. This enables areas for improvement to be better targeted using appropriate retention strategies, and changes resulting from retention interventions to be evaluated effectively. PMID- 22935121 TI - International medical graduates' reflections on facilitators and barriers to undertaking the Australian medical council examination. AB - OBJECTIVE: In Australia, 25% of international medical graduates (IMGs) make up the medical workforce. Concern is expressed in the literature about the lack of awareness and knowledge of issues that impinge on IMGs' education. Although there is literature alluding to difficulties IMGs face with undertaking the Australian Medical Council (AMC) examination, there is little research detailing this experience. We therefore explored IMGs' reflections on facilitators and barriers in undertaking the AMC examination. METHODS: After ethics approval, in-depth telephone interviews were conducted with 30 IMGs selected from a hospital in Queensland. Data were coded and analysed using thematic analysis principles. Results. Two facilitating themes were identified: ability to sit for the first part of the examination in country of origin; and having access to resources such as bridging courses and study groups. Three themes represented barriers: not understanding procedural steps; financial issues; and lack of information on examination content and standards. CONCLUSION: The themes provide new insights and add depth to existing literature that can be used to improve procedural processes and education for IMGs towards successful outcomes in the AMC examination. PMID- 22935122 TI - Rural Undergraduate Support and Coordination, Rural Clinical School, and Rural Australian Medical Undergraduate Scholarship: rural undergraduate initiatives and subsequent rural medical workforce. AB - BACKGROUND: This study examined postgraduate work after an undergraduate clinical year spent in the Rural Clinical School of Western Australia (RCSWA), compared with 6 weeks Rural Undergraduate Support and Coordination (RUSC)-funded rural experience in a 6-year undergraduate medical course. Rural background, sex and Rural Australian Medical Undergraduate Scholarship (RAMUS)-holding were taken into account. Methods. University of Western Australia undergraduate data were linked by hand with postgraduate placements to provide a comprehensive dataset on the rural exposure history of junior medical practitioners working in Western Australia between 2004 and 2007. RESULTS: Participation in the RCSWA program was associated with significantly more postgraduate year one rural work than RUSC placement alone (OR=1.5, CI 0.97-2.38). The RCSWA workforce effect increased at postgraduate year two (OR=3.0, CI 1.6484 to 5.5935 relative to RUSC). Rural origin practitioners who chose the RCSWA program were more likely than other rural-origin practitioners to take rural rotations in both postgraduate years. RAMUS holders' choice in relation to the RCSWA program predicted later rural work. There were no effects of sex. CONCLUSIONS: Rural initiatives, in particular the Rural Clinical School program, are associated with postgraduate rural choices. The real impact of these data rely on the translation of early postgraduate choices into long-term work commitments. PMID- 22935123 TI - Effecting change using careplans: experience from two fractured neck of femur pathways. AB - OBJECTIVE: To use a qualitative track of the effects of two fractured neck of femur careplans (1 & 2) implemented at the Ipswich Emergency Department in 2002 and 2003 in order to comment on the reasons for comparative successes and failures as instruments for change in clinical practice. Careplan 1 was initiated by local clinicians in 2002, rescinded in 2003 to make way for the system wide careplan 2, then informally restituted in 2004 after careplan 2 was withdrawn. Careplan 2 did not articulate specific ED management plans. METHOD: Biennial retrospective chart audits of two newly introduced evidence-based clinical practices over time was used to track changes from careplan 1. These were the use of regional anaesthesia by medical staff, and the compliance with indwelling urinary catheter insertion by nursing staff. RESULTS: Elements of careplan 1 continued despite lack of promotion. There has been significant increase in nerve block (2.8% to 27%) and indwelling catheter insertion (26% to 75%) from 2000 to 2009. Formal use of careplan 1 has declined to 13-20% in 2009. Careplan 2 was withdrawn for review in 2004. CONCLUSIONS: Careplans are one way to effect lasting changes in clinical behaviours which may persist beyond their implementation and promotion phases. For acceptance, corporate plans should incorporate local practices. For longevity, local plans should comply with the corporate vision of continuity of care, but local investment in the plan will facilitate uptake. PMID- 22935124 TI - Breakaway technique training as a means of increasing confidence in managing aggression in neuroscience nursing. AB - OBJECTIVE: The objective of this paper was to evaluate breakaway technique training with neuroscience nursing staff as a measure of increased confidence and safety in managing aggression. METHODS: A quasi experimental design was used in a sample of neuroscience nursing staff (n=31), participating in 2*1h breakaway technique workshops. The workshops consisted of supervised skills training in safe breakaway techniques. A pre- and postintervention-matched questionnaire measuring confidence and safety around managing aggressive patients, and exposure to and confidence in dealing with breakaways, was self administered. RESULTS: Statistically significant increases in confidence and safety in working with aggressive patients, and confidence levels for safe breakaways were reported. Qualitative comments demonstrated a desire for ongoing skills workshops. CONCLUSIONS: This study provides early evidence of the importance of incorporating breakaway training into existing training programs which aim to minimise and manage aggression and violence in generalist settings. PMID- 22935125 TI - The effect of context on performance of an acute medical unit: experience from an Australian tertiary hospital. AB - OBJECTIVE: To ascertain the improvements in length of stay and discharge rates following the opening of an acute medical unit (AMU). METHODS: Retrospective cohort study of all patients admitted under general medicine from June-November 2008. Main outcome measures were length of stay in hospital and in the emergency department (ED). RESULTS: The length of time spent in the emergency department for those admitted to the AMU was significantly shorter than those admitted directly to a medical ward (6.83h v. 9.40h, P<0.0001). A trend towards shorter hospital length of stay continued after the AMU opened compared with the same period in the previous year (5.15 days (2.49, 11.57 CI) v. 5.66 days (2.76, 11.52 CI)). However, the number of ward transfers for a patient and the need to wait for a nursing home bed or public rehabilitation affected length of stay much more than the AMU. CONCLUSION: An AMU was successful in decreasing ED length of stay and contributed to decreasing hospital length of stay. However, we suggest that local context is crucially important in tailoring an AMU to obtain maximal benefit, and that AMUs are not a 'one size fits all' solution. PMID- 22935126 TI - Access to same day, next day and after-hours appointments: the views of Australian general practitioners. AB - OBJECTIVE: To evaluate factors associated with the availability of same or next day appointments and after-hours access reported by Australian general practitioners (GPs). METHODS: Secondary analysis of a survey of primary care practitioners conducted by the Commonwealth Fund in 2009 in 11 countries. Analysis of factors likely to be associated with reported availability of same or next day appointments and after-hours access. FINDINGS: Of 1016 Australian GPs, 78.8% reported that most patients in their practice had access to an appointment on the same or next day and 50% that their practice had arrangements for after hours access. Access to same or next day care was better in practices where practitioners reported larger numbers of patients seen per GP per week and reviewed their performance against annual targets, but worse in rural areas and practices routinely reviewing outcomes data. Arrangements for after-hours care were more common among GPs who were planning to retire in the next 5 years; worked in practices with high electronic functioning information systems; and received and reviewed clinical outcome data and incentives for performance. CONCLUSIONS: Improving after-hours access requires a comprehensive approach which includes incentives, improvements to information management and organised systems of care with review of data on clinical outcomes. PMID- 22935127 TI - Medical Assessment Units and the older patient: a retrospective case-control study. AB - OBJECTIVE: To evaluate the effect of a Medical Assessment Unit (MAU) on older patients. METHODS: Retrospective case-control study of patients 65 years and above admitted to the MAU (study group) and the general medical wards (control group) in Bankstown-Lidcombe Hospital from 1 October 2008 to 31 March 2009 with four most common Diagnosis-Related Groups (DRG) ('falls and gait disorder', 'chronic obstructive pulmonary disease (COPD)', 'other major respiratory diseases and 'cellulitis'). MAIN OUTCOME MEASURES: Length of stay (LOS) in Emergency Department (ED) and in the hospital, mortality, readmissions within 1 month, and discharge destination. RESULTS: Eighty-nine patients were studied; 47 in the MAU group and 42 in the non-MAU group. The MAU cohort was significantly older (84.1 +/- 7.9 years v. 80.4 +/- 7.8 years, respectively, P=0.03); and had shorter ED LOS (4.9 +/- 3.0h v. 6.5 +/- 2.8h, P=0.012). Overall hospital LOS did not differ except for patients with 'cellulitis', (5.7 +/- 4.9 days for MAU cohort v. 14.8 +/- 6.8 days for non-MAU cohort, P=0.022). There was no significant difference in mortality, readmission rate or discharge destination. Conclusions. The MAU can be an effective service model for older patients. More research is required to confirm this and to define the key elements that are essential for its effectiveness. PMID- 22935128 TI - Unplanned return visits to emergency in a regional hospital. AB - OBJECTIVE: The aim of this study was to determine the patient characteristics associated with unplanned return visits, using routinely collected hospital data, to assist in developing strategies to reduce their occurrence. METHODS: Emergency department data from a regional hospital were analysed using univariate and multivariate methods to determine the influence of clinical, service usage and demographic patient characteristics on unplanned return visits. RESULTS: Around 80% of the 16000 patients attending emergency presented on only one occasion in a year. Five per cent of patients presented with an unplanned return visit. Older patients, those with minor and low urgency conditions and with non-psychotic mental health conditions, those presenting during winter and after hours were significantly more likely to present as unplanned return visits. CONCLUSION: Although patient characteristics associated with unplanned return visits have been identified, the reasons underpinning the unplanned return visit rate, such as patient service preference and attitudes, need to be more fully investigated. PMID- 22935129 TI - Survival from breast cancer: an analysis of Australian data by surgeon case load, treatment centre location, and health insurance status. AB - OBJECTIVE: Early invasive breast cancer data from the Australian National Breast Cancer Audit were used to compare case fatality by surgeon case load, treatment centre location and health insurance status. METHOD: Deaths were traced to 31 December 2007, for cancers diagnosed in 1998-2005. Risk of breast cancer death was compared using Cox proportional hazards regression. RESULTS: When adjustment was made for age and clinical risk factors: (i) the relative risk of breast cancer death (95% confidence limit) was lower when surgeons' annual case loads exceeded 20 cases, at 0.87 (0.76, 0.995) for 21-100 cases and 0.83 (0.72, 0.97) for higher case loads. These relative risks were not statistically significant when also adjusting for treatment centre location (P >= 0.15); and (ii) compared with major city centres, inner regional centres had a relative risk of 1.32 (1.18, 1.48), but the risk was not elevated for more remote sites at 0.95 (0.74, 1.22). Risk of death was not related to private insurance status. CONCLUSION: Higher breast cancer mortality in patients treated in inner regional than major city centres and in those treated by surgeons with lower case loads requires further study. PMID- 22935130 TI - Detection of type 2 diabetes: what role for associated risk and protective factors and socioeconomic status? AB - OBJECTIVES: This study explored associations between demographic, socioeconomic, behavioural risk, and health factors (study factors) and detection of type 2 diabetes. METHODS: A secondary analysis of data extracted from the AusDiab study was undertaken. Participants were classified as known diabetes (KDM), newly detected diabetes (NDDM), impaired fasting glucose (IFG), impaired glucose tolerance (IGT), or normal according to results of a glucose tolerance test. RESULTS: The weighted prevalence of diabetes was 6.9%; 49.6% of participants with diabetes (NDDM+KDM) were classified as NDDM. Although study factors were associated with diabetes prevalence, most were not associated with proportion of diabetic participants classified as NDDM. Among participants with diabetes, NDDM was more likely among those who spoke English at home, were in good general health and did not report past history of cardiovascular disease. CONCLUSIONS; Although a range of personal and socioeconomic factors are associated with diabetes prevalence, these factors are not similarly associated with prior detection of diabetes. These findings highlight the importance of systematic approaches to screening for diabetes risk focussed on the whole population, with selective screening based on multi-factorial assessment of diabetes risk using the AUSDRISK Assessment Tool. PMID- 22935131 TI - Imaging features of primary extranodal histiocytic sarcoma: report of two cases and a review of the literature. AB - Histiocytic sarcoma is an extremely rare and aggressive malignancy of bone marrow origin that occurs in lymph nodes, skin, and the gastrointestinal tract. We report on the imaging features of two cases of primary histiocytic sarcoma, one in the retroperitoneum causing a tumor-bowel fistula and another with primary bone involvement. PMID- 22935132 TI - Anaplasma phagocytophilum in horses and ticks in Tunisia. AB - BACKGROUND: Anaplasma phagocytophilum , the causative agent of granulocytic anaplasmosis, affects several species of wild and domesticated mammals, including horses. We used direct and indirect methods to compare and evaluate exposure to A. phagocytophilum in horses in northern Tunisia. METHODS: Serum from 60 horses was tested by IFA for antibodies to A. phagocytophilum , and whole blood was tested for A. phagocytophilum 16S rRNA gene using a nested-PCR. To examine the risk of A. phagocytophilum transmission, 154 ticks that had been collected from horses were examined for the presence of A. phagocytophilum by nested-PCR targeting 16S rRNA gene. RESULTS: This is the first time that A. phagocytophilum has been detected in horses in Tunisia, with an overall seroprevalence of 40/60 (67%). Six of the seroreactive samples (10%) had an IFA titer of 1:80, 14 (23%) of 1:160, 8 (13%) of 1:320 and 12 (20%) a titer 1 >= 640. The seroprevalence revealed no significant regional and sex differences. In contrast, a significant difference was observed between breeds. Eight (13%) of the horses were positive for A. phagocytophilum in the PCR, with no significant breed and age differences. Hyalomma marginatum was a predominant tick species (130/154), and 3 were infected by A. phagocytophilum (a prevalence of 2.3%). The concordance rate of A. phagocytophilum detection between IFA and PCR had a k value of -0.07. CONCLUSIONS: The results presented in this study suggest that horses infested by ticks in Tunisia are exposed to A. phagocytophilum. PMID- 22935133 TI - PELICAN: A quality of life instrument for childhood asthma: study protocol of two randomized controlled trials in primary and specialized care in the Netherlands. AB - BACKGROUND: Asthma is one of the major chronic health problems in children in the Netherlands. The Pelican is a paediatric asthma-related quality of life instrument for children with asthma from 6-11 years old, which is suitable for clinical practice in primary and specialized care. Based on this instrument, we developed a self-management treatment to improve asthma-related quality of life. The Pelican intervention will be investigated in different health care settings. Results of intervention studies are often extrapolated to other health care settings than originally investigated. Because of differences in organization, disease severity, patient characteristics and care provision between health care settings, extrapolating research results could lead to unnecessary health costs without the desired health care achievements. Therefore, interventions have to be investigated in different health care settings when possible. This study is an example of an intervention study in different health care settings. In this article, we will present the study protocol of the Pelican study in primary and specialized care. METHOD/DESIGN: This study consists of two randomized controlled trials to assess the effectiveness of the Pelican intervention in primary and specialized care. The trial in primary care is a multilevel design with 170 children with asthma in 16 general practices. All children in one general practices are allocated to the same treatment group. The trial in specialized care is a multicentre trial with 100 children with asthma. Children in one outpatient clinic are randomly allocated to the intervention or usual care group. In both trials, children will visit the care provider four times during a follow up of nine months. This study is registered and ethically approved. DISCUSSION: This article describes the study protocol of the Pelican study in different health care settings. If the Pelican intervention proves to be effective and efficient, implementation in primary and specialized care for paediatric asthma in the Netherlands will be recommended. TRIAL REGISTRATION: This study is registered by clinicaltrial.gov (NCT01109745). PMID- 22935134 TI - Impact of the use of musculoskeletal ultrasound by rheumatologists in patients with shoulder and hand complaints compared with traditional clinical care. AB - OBJECTIVES: To compare the routine use of musculoskeletal ultrasonography (MSUS) with traditional clinical care in daily practice at shoulder and hand level. METHODS: An observational study was performed in four rheumatology departments. Within each department, 2 rheumatologists were selected; one rheumatologist used MSUS, and the other followed traditional rheumatology care. Consecutive patients with nontraumatic pain, hand numbness or disability, or pain and/or limitations in the shoulder were selected. We collected information regarding the clinical and MSUS diagnoses, changes in diagnosis and treatment following MSUS, local injections, the rheumatologist's satisfaction and the use of health care resources. A descriptive analysis was performed. RESULTS: A total of 168 patients were analysed, with 104 and 64 patients in the MSUS and traditional care groups, respectively. MSUS led to a diagnosis and therapeutic change in 53 (52%) and 55 patients (54%), respectively. The rate of local injection was 47% in the MSUS group (73% unexpected, 61% performed using US) compared with 21% in the traditional group (p=0.001). According to the rheumatologists, MSUS was useful in 72 cases (71%) and extremely useful in 20 cases (20%), and the rheumatologists reported a higher satisfaction with their patient evaluations (p<0.001). The MSUS group required fewer additional tests (38% vs. 81%, respectively, p<0.001), fewer medical visits (46% vs. 84%, p<0.001), and lower direct costs (11 vs. 30 euros, p<0.001) than the traditional care group. CONCLUSIONS: Compared with traditional care, the routine use of MSUS in rheumatology practice at hand and shoulder level can lead to important improvements in care, thereby reducing the number of additional tests and medical visits. PMID- 22935136 TI - Privacy by Design at Population Data BC: a case study describing the technical, administrative, and physical controls for privacy-sensitive secondary use of personal information for research in the public interest. AB - Population Data BC (PopData) is an innovative leader in facilitating access to linked data for population health research. Researchers from academic institutions across Canada work with PopData to submit data access requests for projects involving linked administrative data, with or without their own researcher-collected data. PopData and its predecessor-the British Columbia Linked Health Database-have facilitated over 350 research projects analyzing a broad spectrum of population health issues. PopData embeds privacy in every aspect of its operations. This case study focuses on how implementing the Privacy by Design model protects privacy while supporting access to individual-level data for research in the public interest. It explores challenges presented by legislation, stewardship, and public perception and demonstrates how PopData achieves both operational efficiencies and due diligence. PMID- 22935135 TI - Differential pH-dependent cellular uptake pathways among foamy viruses elucidated using dual-colored fluorescent particles. AB - BACKGROUND: It is thought that foamy viruses (FVs) enter host cells via endocytosis because all FV glycoproteins examined display pH-dependent fusion activities. Only the prototype FV (PFV) glycoprotein has also significant fusion activity at neutral pH, suggesting that its uptake mechanism may deviate from other FVs. To gain new insights into the uptake processes of FV in individual live host cells, we developed fluorescently labeled infectious FVs. RESULTS: N terminal tagging of the FV envelope leader peptide domain with a fluorescent protein resulted in efficient incorporation of the fluorescently labeled glycoprotein into secreted virions without interfering with their infectivity. Double-tagged viruses consisting of an eGFP-tagged PFV capsid (Gag-eGFP) and mCherry-tagged Env (Ch-Env) from either PFV or macaque simian FV (SFVmac) were observed during early stages of the infection pathway. PFV Env, but not SFVmac Env, containing particles induced strong syncytia formation on target cells. Both virus types showed trafficking of double-tagged virions towards the cell center. Upon fusion and subsequent capsid release into the cytosol, accumulation of naked capsid proteins was observed within four hours in the perinuclear region, presumably representing the centrosomes. Interestingly, virions harboring fusion defective glycoproteins still promoted virus attachment and uptake, but failed to show syncytia formation and perinuclear capsid accumulation. Non-fused or non fusogenic viruses are rapidly cleared from the cells by putative lysosomal degradation. Monitoring the fraction of viruses containing both Env and capsid signals as a function of time demonstrated that PFV virions fused within the first few minutes, whereas fusion of SFVmac virions was less pronounced and observed over the entire 90 minutes measured. CONCLUSIONS: The characterized double-labeled FVs described here provide new mechanistic insights into FV early entry steps, demonstrating that productive viral fusion occurs early after target cell attachment and uptake. The analysis highlights apparent differences in the uptake pathways of individual FV species. Furthermore, the infectious double labeled FVs promise to provide important tools for future detailed analyses on individual FV fusion events in real time using advanced imaging techniques. PMID- 22935137 TI - Adiponectin through its biphasic serum level is a useful biomarker during transition from diastolic dysfunction to systolic dysfunction - an experimental study. AB - BACKGROUND: Adiponectin is reported to relate with cardiovascular diseases, we sought to examine whether adiponectin is associated with disease progression of heart failure from hypertension in rats in comparison with other known biomarkers and echocardiographic parameters. Spontaneously hypertensive rats (SHR, n = 35), aged 1 month, were used and followed up to 18 months. High frequency echocardiography was performed both at baseline and every 3 months thereafter. Moreover, serum levels of N-terminal pro-natriuretic peptide (NT-proBNP) and interleukin-6 (IL-6) as well as serum level and tissue expression of adiponectin were determined at the same time as echocardiography. RESULTS: The results clearly demonstrated time-dependent progression of hypertension and heart dysfunction as evidenced by gradually increased left ventricular mass index, NT proBNP, IL-6 as well as gradually decreased cardiac function as assessed by echocardiography. Meanwhile, tissue and serum adiponectin decreased from 3 months and reached plateau until 12 months in parallel with decreasing of cardiac diastolic function. Thereafter, adiponectin levels increased prior to occurrence of systolic dysfunction. Adiponectin concentration is inversely related with NT proBNP, IL-6 and E/E' (correlation coefficient (r) = -0.756 for NT-proBNP, p < 0.001, -0.635 for IL-6, p = 0.002, and -0.626 for E/E', p = 0.002, respectively) while positively correlated with E/A and E'/A' (r = 0.683 for E/A, p = 0.001, 0.671 for E'/A', p = 0.001, respectively). No difference for adiponectin distribution among visceral adipose tissues was found. CONCLUSION: Adiponectin through its biphasic serum level is a useful biomarker during transition from diastolic dysfunction to systolic dysfunction. PMID- 22935138 TI - The impact of random frequency-dependent mutations on the average population fitness. AB - BACKGROUND: In addition to selection, the process of evolution is accompanied by stochastic effects, such as changing environmental conditions, genetic drift and mutations. Commonly it is believed that without genetic drift, advantageous mutations quickly fixate in a halpoid population due to strong selection and lead to a continuous increase of the average fitness. This conclusion is based on the assumption of constant fitness. However, for frequency dependent fitness, where the fitness of an individual depends on the interactions with other individuals in the population, this does not hold. RESULTS: We propose a mathematical model that allows to understand the consequences of random frequency dependent mutations on the dynamics of an infinite large population. The frequencies of different types change according to the replicator equations and the fitness of a mutant is random and frequency dependent. To capture the interactions of different types, we employ a payoff matrix of variable size and thus are able to accommodate an arbitrary number of mutations. We assume that at most one mutant type arises at a time. The payoff entries to describe the mutant type are random variables obeying a probability distribution which is related to the fitness of the parent type. CONCLUSIONS: We show that a random mutant can decrease the average fitness under frequency dependent selection, based on analytical results for two types and simulations for n types. Interestingly, in the case of at most two types the probabilities to increase or decrease the average fitness are independent of the concrete probability density function. Instead, they only depend on the probability that the payoff entries of the mutant are larger than the payoff entries of the parent type. PMID- 22935140 TI - Expression of constitutively active FoxO3 in murine forebrain leads to a loss of neural progenitors. AB - Inactivation of FoxO proteins by phosphorylation is the result of a number of stimuli, including the insulin/IGF pathway. We were interested in the consequence of blunting this pathway by employing transgenic mice with tetracycline controllable conditional expression of a constitutively active allele of FOXO3 under the control of the forebrain-specific CaMKIIalpha promoter. Although transgene-expressing mice were viable, brain weight was reduced by 30% in adult animals. Brains showed an isocortex compression with normal cortical layering, and a size reduction in regions known to depend on adult neurogenesis, i.e., the olfactory bulbs and the dentate gyrus. On postnatal activation of the transgene, adult neurogenesis was also severely affected. Investigating the molecular basis of this phenotype, we observed enhanced apoptosis starting from embryonic day E10.5 and a subsequent loss of progenitors in the ventricular/subventricular zones, but not in the isocortex or the striatum of adult mice. The enhanced apoptosis was accompanied by increased expression of PIK3IP1, which we identified as a direct transcriptional target of FOXO3. Transfection of Pik3ip1 into differentiating neural progenitors resulted in a significant reduction of viable cells. We therefore conclude that neural progenitors are particularly vulnerable to FOXO3-induced apoptosis, which is mediated by PIK3IP1, a negative PI3 kinase regulator. PMID- 22935139 TI - Normalization of a chromosomal contact map. AB - BACKGROUND: Chromatin organization has been increasingly studied in relation with its important influence on DNA-related metabolic processes such as replication or regulation of gene expression. Since its original design ten years ago, capture of chromosome conformation (3C) has become an essential tool to investigate the overall conformation of chromosomes. It relies on the capture of long-range trans and cis interactions of chromosomal segments whose relative proportions in the final bank reflect their frequencies of interactions, hence their spatial proximity in a population of cells. The recent coupling of 3C with deep sequencing approaches now allows the generation of high resolution genome-wide chromosomal contact maps. Different protocols have been used to generate such maps in various organisms. This includes mammals, drosophila and yeast. The massive amount of raw data generated by the genomic 3C has to be carefully processed to alleviate the various biases and byproducts generated by the experiments. Our study aims at proposing a simple normalization procedure to minimize the influence of these unwanted but inevitable events on the final results. RESULTS: Careful analysis of the raw data generated previously for budding yeast S. cerevisiae led to the identification of three main biases affecting the final datasets, including a previously unknown bias resulting from the circularization of DNA molecules. We then developed a simple normalization procedure to process the data and allow the generation of a normalized, highly contrasted, chromosomal contact map for S. cerevisiae. The same method was then extended to the first human genome contact map. Using the normalized data, we revisited the preferential interactions originally described between subsets of discrete chromosomal features. Notably, the detection of preferential interactions between tRNA in yeast and CTCF, PolII binding sites in human can vary with the normalization procedure used. CONCLUSIONS: We quantitatively reanalyzed the genomic 3C data obtained for S. cerevisiae, identified some of the biases inherent to the technique and proposed a simple normalization procedure to analyse them. Such an approach can be easily generalized for genomic 3C experiments in other organisms. More experiments and analysis will be necessary to reach optimal resolution and accuracies of the maps generated through these approaches. Working with cell population presenting highest levels of homogeneity will prove useful in this regards. PMID- 22935141 TI - A regulatory circuit of miR-148a/152 and DNMT1 in modulating cell transformation and tumor angiogenesis through IGF-IR and IRS1. AB - Dysregulation of microRNAs is a common feature in human cancers, including breast cancer (BC). Here we describe the epigenetic regulation of miR-148a and miR-152 and their impact on BC cells. Due to the hypermethylation of CpG island, the expression levels of both miR-148a and miR-152 (miR-148a/152) are decreased in BC tissues and cells. DNMT1, the DNA methyltransferase 1 for the maintenance methylation, is aberrantly up-regulated in BC and its overexpression is responsible for hypermethylation of miR-148a and miR-152 promoters. Intriguingly, we found that DNMT1 expression, which is one of the targets of miR-148a/152, is inversely correlated with the expression levels of miR-148a/152 in BC tissues. Those results lead us to propose a negative feedback regulatory loop between miR 148a/152 and DNMT1 in BC. More importantly, we demonstrate that IGF-IR and IRS1, often overexpressed in BC, are two novel targets of miR-148a/152. Overexpression of miR-148a or miR-152 significantly inhibits BC cell proliferation, colony formation, and tumor angiogenesis via targeting IGF-IR and IRS1 and suppressing their downstream AKT and MAPK/ERK signaling pathways. Our results suggest a novel miR-148a/152-DNMT1 regulatory circuit and reveal that miR-148a and miR-152 act as tumor suppressors by targeting IGF-IR and IRS1, and that restoration of miR 148a/152 expression may provide a strategy for therapeutic application to treat BC patients. PMID- 22935143 TI - Molecular mechanisms of the cardiovascular protective effects of polyphenols. AB - Epidemiological studies have reported a greater reduction in cardiovascular risk and metabolic disorders associated with diets rich in polyphenols. The antioxidant effects of polyphenols are attributed to the regulation of redox enzymes by reducing reactive oxygen species production from mitochondria, NADPH oxidases and uncoupled endothelial NO synthase in addition to also up-regulating multiple antioxidant enzymes. Although data supporting the effects of polyphenols in reducing oxidative stress are promising, several studies have suggested additional mechanisms in the health benefits of polyphenols. Polyphenols from red wine increase endothelial NO production leading to endothelium-dependent relaxation in conditions such as hypertension, stroke or the metabolic syndrome. Numerous molecules contained in fruits and vegetables can activate sirtuins to increase lifespan and silence metabolic and physiological disturbances associated with endothelial NO dysfunction. Although intracellular pathways involved in the endothelial effects of polyphenols are partially described, the molecular targets of these polyphenols are not completely elucidated. We review the novel aspects of polyphenols on several targets that could trigger the health benefits of polyphenols in conditions such as metabolic and cardiovascular disturbances. PMID- 22935142 TI - The apelin receptor inhibits the angiotensin II type 1 receptor via allosteric trans-inhibition. AB - BACKGROUND AND PURPOSE: The apelin receptor (APJ) is often co-expressed with the angiotensin II type-1 receptor (AT1) and acts as an endogenous counter-regulator. Apelin antagonizes Ang II signalling, but the precise molecular mechanism has not been elucidated. Understanding this interaction may lead to new therapies for the treatment of cardiovascular disease. EXPERIMENTAL APPROACH: The physical interaction of APJ and AT1 receptors was detected by co-immunoprecipitation and bioluminescence resonance energy transfer (BRET). Functional and pharmacological interactions were measured by G-protein-dependent signalling and recruitment of beta-arrestin. Allosterism and cooperativity between APJ and AT1 were measured by radioligand binding assays. KEY RESULTS: Apelin, but not Ang II, induced APJ : AT1 heterodimerization forced AT1 into a low-affinity state, reducing Ang II binding. Likewise, apelin mediated a concentration-dependent depression in the maximal production of inositol phosphate (IP(1) ) and beta-arrestin recruitment to AT1 in response to Ang II. The signal depression approached a limit, the magnitude of which was governed by the cooperativity indicative of a negative allosteric interaction. Fitting the data to an operational model of allosterism revealed that apelin-mediated heterodimerization significantly reduces Ang II signalling efficacy. These effects were not observed in the absence of apelin. CONCLUSIONS AND IMPLICATIONS: Apelin-dependent heterodimerization between APJ and AT1 causes negative allosteric regulation of AT1 function. As AT1 is significant in the pathogenesis of cardiovascular disease, these findings suggest that impaired apelin and APJ function may be a common underlying aetiology. LINKED ARTICLE: This article is commented on by Goupil et al., pp. 1101-1103 of this issue. To view this commentary visit http://dx.doi.org/10.1111/bph.12040. PMID- 22935144 TI - Perceptions of and barriers to use of generic medications in a rural African American population, Alabama, 2011. AB - INTRODUCTION: Using generic medications for chronic diseases provides efficacy similar to that of brand-name medication use, but at a lower price, potentially enhancing adherence. However, previous studies show that disadvantaged people, who may particularly benefit from cost savings, have low trust of generics and increased reluctance to switch to generics. The rural South includes areas of high poverty and minority communities whose members are at high risk for poor health outcomes; however, whether such beliefs exist in these communities has not been reported. We sought to obtain qualitative insight into beliefs about generic medication use among African Americans in the rural South. METHODS: Investigators conducted 4 focus groups with 30 community members from Alabama's Black Belt area. Transcribed discussions were analyzed and common themes identified. RESULTS: Participants were primarily unemployed middle-aged women, one-fourth of whom were uninsured and more than half of whom had a high school education or less. Barriers to generic medication use included perceptions that generics are less potent than brand-name medications, require higher doses, and, therefore, result in more side effects; generics are not "real" medicine; generics are for minor but not serious illnesses; the medical system cannot be trusted; and poor people are forced to "settle" for generics. CONCLUSION: Although education about generics could rectify misinformation, overcoming views such as mistrust of the medical system and the sense of having to settle for generics because of poverty may be more challenging. Policy makers and providers should consider these perspectives when working to increase generic drug use in these populations. PMID- 22935145 TI - Parents' perceptions of skin cancer threat and children's physical activity. AB - INTRODUCTION: Sun exposure is a major risk factor for skin cancer, but without physical activity, children are at risk of childhood obesity. The objective of this study was to explore relationships between parental perceptions of skin cancer threat, sun protection behaviors, physical activity, and body mass index (BMI) in children. METHODS: This is a cross-sectional analysis nested within the Colorado Kids Sun Care Program sun safety intervention trial. In summer 2007, parent telephone interviews provided data on demographics, perceptions of skin cancer threat, sun protection behaviors, and physical activity. Physical examinations provided data on phenotype, freckling, and BMI. Data from 999 Colorado children born in 1998 were included in analysis. We used analysis of variance, Spearman's rho (rho) correlation, and multivariable linear regression analysis to evaluate relationships with total amount of outdoor physical activity. RESULTS: After controlling for sex, race/ethnicity, skin color, and sun protection, regression analysis showed that each unit increase in perceived severity of nonmelanoma skin cancer was associated with a 30% increase in hours of outdoor physical activity (P = .005). Hours of outdoor physical activity were not related to perceived severity of melanoma or perceived susceptibility to skin cancer. BMI-for-age was not significantly correlated with perceptions of skin cancer threat, use of sun protection, or level of physical activity. CONCLUSION: The promotion of sun safety is not likely to inhibit physical activity. Skin cancer prevention programs should continue to promote midday sun avoidance and sun protection during outdoor activities. PMID- 22935147 TI - NDV-induced apoptosis in absence of Bax; evidence of involvement of apoptotic proteins upstream of mitochondria. AB - BACKGROUND: Recently it was shown that following infection of HeLa cells with Newcastle disease virus (NDV), the matrix (M) protein binds to Bax and subsequently the intrinsic pathway of apoptosis is activated. Moreover, there was very little alteration on mRNA and protein levels of Bax and Bcl-2 after infection with NDV. FINDING: In order to further investigate the role of members of the Bcl-2 family, Bax-knockout and wild-type HCT116 cells were infected with NDV strain AF2240. Although both cells underwent apoptosis through the activation of the intrinsic pathway and the release of cytochrome c from mitochondria, the percentage of dead Bax-knockout cells was significantly lower than wt cells (more than 10% at 48 h post-infection). In a parallel experiment, the effect of NDV on HT29 cells, that are originally Bcl-2-free, was studied. Apoptosis in HT29 cells was associated with Bax redistribution from cytoplasm to mitochondria, similar to that of HeLa and wt HCT116 cells. CONCLUSION: Although the presence of Bax during NDV-induced apoptosis contributes to a faster cell death, it was concluded that other apoptotic protein(s) upstream of mitochondria are also involved since cancer cells die whether in the presence or absence of Bax. Therefore, the classic Bax/Bcl-2 ratio may not be a major determinant in NDV-induced apoptosis. PMID- 22935146 TI - Somatic symptoms beyond those generally associated with a whiplash injury are increased in self-reported chronic whiplash. A population-based cross sectional study: the Hordaland Health Study (HUSK). AB - BACKGROUND: Chronic whiplash leads to considerable patient suffering and substantial societal costs. There are two competing hypothesis on the etiology of chronic whiplash. The traditional organic hypothesis considers chronic whiplash and related symptoms a result of a specific injury. In opposition is the hypothesis that chronic whiplash is a functional somatic syndrome, and related symptoms a result of society-induced expectations and amplification of symptoms. According to both hypotheses, patients reporting chronic whiplash are expected to have more neck pain, headache and symptoms of anxiety and depression than the general population. Increased prevalence of somatic symptoms beyond those directly related to a whiplash neck injury is less investigated. The aim of this study was to test an implication derived from the functional hypothesis: Is the prevalence of somatic symptoms as seen in somatization disorder, beyond symptoms related to a whiplash neck injury, increased in individuals self-reporting chronic whiplash? We further aimed to explore recall bias by comparing the symptom profile displayed by individuals self-reporting chronic whiplash to that among those self-reporting a non-functional injury: fractures of the hand or wrist. We explored symptom load, etiologic origin could not be investigated in this study. METHODS: Data from the Norwegian population-based "Hordaland Health Study" (HUSK, 1997-99); N = 13,986 was employed. Chronic whiplash was self reported by 403 individuals and fractures by 1,746. Somatization tendency was measured using a list of 17 somatic symptoms arising from different body parts and organ systems, derived from the research criteria for somatization disorder (ICD-10, F45). RESULTS: Chronic whiplash was associated with an increased level of all 17 somatic symptoms investigated (p<0.05). The association was moderately strong (group difference of 0.60 standard deviation), only partly accounted for by confounding. For self-reported fractures symptoms were only slightly elevated. Recent whiplash was more commonly reported than whiplash-injury a long time ago, and the association of interest weakly increased with time since whiplash (r = 0.016, p = 0.032). CONCLUSIONS: The increased prevalence of somatic symptoms beyond symptoms expected according to the organic injury model for chronic whiplash, challenges the standard injury model for whiplash, and is indicative evidence of chronic whiplash being a functional somatic syndrome. PMID- 22935148 TI - ABA signaling in guard cells entails a dynamic protein-protein interaction relay from the PYL-RCAR family receptors to ion channels. AB - Plant hormone abscisic acid (ABA) serves as an integrator of environmental stresses such as drought to trigger stomatal closure by regulating specific ion channels in guard cells. We previously reported that SLAC1, an outward anion channel required for stomatal closure, was regulated via reversible protein phosphorylation events involving ABA signaling components, including protein phosphatase 2C members and a SnRK2-type kinase (OST1). In this study, we reconstituted the ABA signaling pathway as a protein-protein interaction relay from the PYL/RCAR-type receptors, to the PP2C-SnRK2 phosphatase-kinase pairs, to the ion channel SLAC1. The ABA receptors interacted with and inhibited PP2C phosphatase activity against the SnRK2-type kinase, releasing active SnRK2 kinase to phosphorylate, and activate the SLAC1 channel, leading to reduced guard cell turgor and stomatal closure. Both yeast two-hybrid and bimolecular fluorescence complementation assays were used to verify the interactions among the components in the pathway. These biochemical assays demonstrated activity modifications of phosphatases and kinases by their interaction partners. The SLAC1 channel activity was used as an endpoint readout for the strength of the signaling pathway, depending on the presence of different combinations of signaling components. Further study using transgenic plants overexpressing one of the ABA receptors demonstrated that changing the relative level of interacting partners would change ABA sensitivity. PMID- 22935149 TI - Gene expression profile suggests that pigs (Sus scrofa) are susceptible to Anaplasma phagocytophilum but control infection. AB - BACKGROUND: Anaplasma phagocytophilum infects a wide variety of hosts and causes granulocytic anaplasmosis in humans, horses and dogs and tick-borne fever in ruminants. Infection with A. phagocytophilum results in the modification of host gene expression and immune response. The objective of this research was to characterize gene expression in pigs (Sus scrofa) naturally and experimentally infected with A. phagocytophilum trying to identify mechanisms that help to explain low infection prevalence in this species. RESULTS: For gene expression analysis in naturally infected pigs, microarray hybridization was used. The expression of differentially expressed immune response genes was analyzed by real time RT-PCR in naturally and experimentally infected pigs. Results suggested that A. phagocytophilum infection affected cytoskeleton rearrangement and increased both innate and adaptive immune responses by up regulation of interleukin 1 receptor accessory protein-like 1 (IL1RAPL1), T-cell receptor alpha chain (TCR alpha), thrombospondin 4 (TSP-4) and Gap junction protein alpha 1 (GJA1) genes. Higher serum levels of IL-1 beta, IL-8 and TNF-alpha in infected pigs when compared to controls supported data obtained at the mRNA level. CONCLUSIONS: These results suggested that pigs are susceptible to A. phagocytophilum but control infection, particularly through activation of innate immune responses, phagocytosis and autophagy. This fact may account for the low infection prevalence detected in pigs in some regions and thus their low or no impact as a reservoir host for this pathogen. These results advanced our understanding of the molecular mechanisms at the host-pathogen interface and suggested a role for newly reported genes in the protection of pigs against A. phagocytophilum. PMID- 22935150 TI - Different protein expression patterns associated with polycystic ovary syndrome in human follicular fluid during controlled ovarian hyperstimulation. AB - Polycystic ovary syndrome (PCOS) is one of the most common causes of anovulatory infertility, affecting 5-10% of females during their reproductive life. Currently the pathology of PCOS is largely unknown. To identify the differential protein expression in follicular fluids from PCOS and normal subjects during controlled ovarian hyperstimulation, we performed an initial proteomic study including two dimensional gel electrophoresis (2DE) analysis and mass spectroscopy, and confirmed results by western blot. Thirty-two protein spots were shown to be significantly differentially expressed between PCOS and normal follicular fluids, of which 20 unique proteins were identified to be associated with cellular metabolism and physiological processes; 13 of these proteins were upregulated while seven were downregulated in PCOS follicular fluids. Western blotting analyses confirmed the differential expressions for three randomly selected proteins, i.e. upregulated alpha1-antitrypsin, apolipoprotein A-I and transferrin in follicular fluid from PCOS patients than normal controls. Furthermore, semiquantitative reverse transcription-polymerase chain reaction (RT-PCR) analyses revealed that mRNA levels of serine palmitoyltransferase 2, serine/threonine-protein kinase male germ cell-associated kinase (MAK) and DNA damage-regulated autophagy modulator protein 2 decreased significantly in granulosa cells of PCOS patients compared with normal samples. These results increase our understanding of PCOS and the identified genes may serve as candidate biomarkers to develop diagnostic and therapeutic tools. PMID- 22935151 TI - The fibroblast growth factor family: involvement in the regulation of folliculogenesis. AB - Several growth factors have been identified as local regulators of follicle development and ovulation. Fibroblast growth factor (FGF) family members are potent mitogens and are involved in cell differentiation, cell migration and angiogenesis in many tissues and organs. In addition to FGF-2, which is the most studied FGF, other important members are FGF-1, -5, -7, -8, -9 and -10. A number of studies have indicated that FGFs play important roles in regulating the initiation of primordial follicle growth, oocyte and follicle survival, granulosa and theca cell proliferation and differentiation, corpus luteum formation, steroidogenesis and angiogenesis. The purpose of this review is to highlight the importance of the FGFs on mammalian female reproduction, providing a better understanding of the roles of this family in ovarian physiology and female fertility. PMID- 22935152 TI - Effects of progesterone and RU486 on the development and expression of adult male sexual behaviour and gene expression in the amygdala and preoptic area of the hypothalamus. AB - The number of progesterone receptors is greater in the male than female neonatal rat hypothalamus. The aims of the present study were to determine developmental effects of progesterone on the expression of adult male sexual behaviour and whether changes in behaviour were reflected by altered gene expression within the hypothalamic preoptic area (POA) or medial amygdala. Male rats were treated with progesterone (40 ug kg(-1), i.p.), the progesterone receptor antagonist RU486 (40 ug kg(-1), i.p.) or an equal volume of vehicle (10% ethanol, 90% corn oil) on postnatal Days 1-5. Treatment with either progesterone or RU486 inhibited (P <= 0.07) the initial expression of consummatory sexual behaviour at 10.5 weeks of age without influencing growth or serum concentrations of testosterone. Sexual interest, as measured by latency to exhibiting mounting behaviour or the number of mounts achieved, was not influenced by treatment with either progesterone or RU486. The effects of treatment with progesterone or RU486 on sexual behaviour were diminished by experience. Microarray analysis of the POA indicated 61 genes that were upregulated and 49 that were downregulated (P <= 0.01) following RU486 treatment of male rats. However, the altered expression of selected genes was not confirmed by real-time reverse transcription-polymerase chain reaction. The expression of targeted genes within the amygdala was not influenced by treatment with either progesterone or RU486. Neonatal treatment with RU486, but not progesterone, decreased testes weight (P=0.02) without affecting testes morphology. The results indicate that altering the progesterone environment during a critical developmental period affects the expression of behaviour, but that changes in behaviour are not mirrored by the altered expression of selected genes. PMID- 22935153 TI - Fetal growth restriction in hypothyroidism is associated with changes in proliferative activity, apoptosis and vascularisation of the placenta. AB - The objective of this study was to evaluate fetal weight, histomorphometric changes and proliferative activity, apoptosis and angiogenesis of the placenta in rats with hypothyroidism. Thirty-six adult female rats were divided into two groups with 18 animals each: control and hypothyroidism. Hypothyroidism was induced by daily administration of propylthiouracil (1 mg/animal). The administration began five days before becoming pregnant and the animals were sacrificed at 14 or 19 days of gestation. The control group received a placebo. The number and weight of fetuses and the rate of fetal death was determined, as well as the morphometric characteristics, the immunohistochemical expression of cell division control protein 47 (CDC)-47 and vascular endothelial growth factor (VEGF) and the number of apoptotic cells in the placental disk. The data were analysed by Mann-Whitney U test. Hypothyroidism reduced the weight of fetuses and of the uterus and placenta (P<0.05), altered the thickness of the placental labyrinth and spongiotrophoblast (P<0.05), increased the population of glycogen cells in the spongiotrophoblast (P<0.05), interfered with the vascular development of the placental labyrinth and decreased VEGF expression (P<0.05), reduced the expression of CDC-47 and cellularity and increased the apoptotic rate in the placental disk (P<0.05). We conclude that hypothyroidism affects fetal weight by altering the proliferative activity, apoptosis and vascularisation of the placenta. PMID- 22935154 TI - Determination of anti-Mullerian hormone concentrations in blood as a tool to select Holstein donor cows for embryo production: from the laboratory to the farm. AB - High between-animal variability in the number of embryos produced by multiple ovulation and embryo transfer (MOET) and ovum pick-up and in vitro production (OPU-IVP) methods remains a major limit to the development of embryo biotechnologies in cattle. The measurement of anti-Mullerian hormone (AMH) endocrine concentrations in cows can help to predict their follicular and ovulatory responses to gonadotrophin treatment. The present study aimed to provide practical information for a simple prognostic method based on AMH measurement in Holstein cows. Accurate AMH concentrations could be measured with ELISA in blood or plasma. In cows undergoing repeated OPU protocols over 1 year, the AMH concentrations measured in plasma samples collected before each gonadotrophin treatment were found to be highly repeatable and were tightly correlated with follicular responses. From data obtained at both an experimental station and farm settings, it was possible to propose AMH cut-off values to identify low-responding cows. Gonadotrophin-stimulated cows producing fewer than 15 large follicles at oestrus and fewer than 10 embryos in MOET protocols could be discarded efficiently with plasma AMH concentrations below 87 and 74 pg mL( 1), respectively. In conclusion, we propose a prognostic method based on a single AMH measurement to improve the results of embryo biotechnologies. PMID- 22935155 TI - Impaired mitochondrial function in murine oocytes is associated with controlled ovarian hyperstimulation and in vitro maturation. AB - The present study was designed to determine whether controlled ovarian hyperstimulation (COH) and in vitro maturation (IVM), two common clinical procedures in human IVF treatment, have an impact on mitochondrial DNA (mtDNA) copy number and mitochondrial function in oocytes. Matured mouse oocytes recovered following COH, IVM and natural cycles (NC), which simulated those treatments in human clinic IVF treatment. The copies of mtDNA, the activity of mitochondria as determined by inner mitochondrial membrane potential and oocyte adenosine trisphosphate (ATP) content, pattern of mitochondrial distribution, reactive oxygen species (ROS) levels and the integrity of the cytoskeleton were evaluated in oocytes. Significant differences were detected between COH and NC groups in all measures, except the pattern of mitochondrial distribution and ROS levels. There were also significant differences detected between IVM and NC treatment groups in the copies of mitochondrial DNA, the level of ROS and the integrity of the cytoskeleton in oocytes. In conclusion, the results of this investigation indicate that non-physiological COH and IVM treatments inhibit mtDNA replication, alter mitochondrial function and increase the percentage of abnormal cytoskeleton and ROS production. Damage related to the mitochondria may partly explain the low efficiency of IVF and high rate of embryonic loss associated with these clinical procedures. PMID- 22935156 TI - Identification and immunolocalisation of melatonin MT(1) and MT(2) receptors in Rasa Aragonesa ram spermatozoa. AB - The reproductive seasonality of sheep suggests that melatonin receptors may be present in ram spermatozoa. The present study confirms the presence of melatonin MT(1) and MT(2) receptors. The MT(1) receptor was detected using immunocytochemistry, with four sperm subpopulations identified based on the following labelling patterns: (1) one small subpopulation with labelling over the entire head and tail; (2) one of two main subpopulations that exhibited reactivity at the equatorial, post-acrosomal, neck and tail regions; (3) another main subpopulation with equatorial and tail labelling only; and (4) a subpopulation in which staining was detected only in the tail. Immunocytochemistry revealed the presence of the melatonin MT(2) receptor, with intense staining on the acrosome, post-acrosomal region and neck and tail regions of all cells, but not in the equatorial region. Western blot identification of ram protein extracts revealed a 39-kDa band compatible with both MT(1) and MT(2) receptors, a 75-kDa band compatible with MT(1)/MT(2) heterodimerisation, a 32-kDa band compatible with MT(1) receptor activation and a double band of 45-55 kDa that is compatible with MT(2) receptor homodimerisation or heterodimerisation with other G-proteins. In conclusion, we provide evidence of the presence of MT(1) and MT(2) receptors in ram spermatozoa, although the biochemical pathway triggered by these receptors and their function in terms of fertility remains to be elucidated. PMID- 22935157 TI - Effect of asynchronous transfer on bovine embryonic development and relationship with early cycle uterine proteome profiles. AB - The uterus provides the nurturing environment that supports the growth of the early preimplantation bovine conceptus. To determine critical time points of uterine influence, in vitro-produced Day 7 blastocysts were transferred into synchronous (Day 7) uteri and asynchronous uteri (Days 5 or 9). Embryo growth was evaluated 7 and 15 days after transfer and compared with that of embryos generated by AI. Conceptuses recovered from asynchronous Day 9 transfers were fourfold larger than synchronous transfer or gestational Day 14 AI conceptuses; by 15 days after transfer, differences were less marked. Two-dimensional gel electrophoresis was used to compare the histotroph protein composition of uterine luminal flushings (ULF) on Days 5 and 9 after oestrous to determine any protein differences that would promote embryo growth. The ULF were collected by serially flushing the uteri of the same heifers and mature cows at different times of the cycle. Ten proteins that differed in abundance between Day 5 and 9 were identified by mass spectrometry. Three, namely phosphoserine aminotransferase 1, purine nucleoside phosphorylase and aldose reductase, were verified by western blot analysis as more abundant on Day 9 (P<0.002). Myostatin was present in only in Day 9 ULF, whereas tissue inhibitor of matrix metalloproteinase 2 (TIMP2) and legumain were only detected in Day 14 ULF. Although mature cows had lower progesterone concentrations on Days 5 and 14 (P<0.05) and tended to have less TIMP2 than heifer groups, no other protein differences were detected. Thus, the embryo growth-enhancing environment on Day 9 was associated with temporal changes in the expression of several proteins of the histotroph. PMID- 22935158 TI - Neonatal immunisation against a novel gonadotrophin-releasing hormone construct delays the onset of gonadal growth and puberty in bull calves. AB - The aim of the present study was to investigate the effect of the neonatal immunisation of bull calves against a novel gonadotrophin-releasing hormone (GnRH) construct, comprised of GnRH coupled to the glycoprotein D subunit of the bovine herpes virus-1 (GnRH-BHV1 gD), on endocrine status, reproductive organ development and carcass quality. Eighteen bull calves received either GnRH construct (n=9) or saline (control; n=9) at 2, 6 and 13.5 weeks of age. Blood samples were taken to determine antibody titres against GnRH, FSH and testosterone (T) concentrations and LH pulse characteristics, with testicular circumference monitored monthly. Immunisation reduced LH pulse amplitude (P<0.05) and T concentrations (P<0.05), particularly at the peak in anti-GnRH titres after the second booster at 16 weeks of age (P<0.001), but not when titres fell. Despite antibody titres decreasing after 16 weeks, immunisation reduced testicular size between 16 to 57 weeks of age (P<0.05), provoking an 8-week delay in puberty onset, defined as testicular circumference >=14 cm. In conclusion, neonatal immunisation induced a significant immune response against GnRH, provoking a temporary endocrine disturbance that had a long-term effect on testicular development, delaying the onset of puberty. These results support the hypothesis that a developmental window exists during testicular development, such that disturbance of the endocrine drive to the gonads during this period results in a longer-term impairment of gonadal function. PMID- 22935159 TI - Association between melatonin receptor 1A (MTNR1A) gene polymorphism and the reproductive performance of Mediterranean Italian buffaloes. AB - A melatonin receptor 1A (MTNR1A) gene polymorphism in adult buffaloes has been reported to affect reproductive seasonality. Consequently, the aim of the present study was to assess whether this polymorphism can affect age at first conception and the interval between first and second calving in Mediterranean Italian buffaloes. The allelic frequency of the C and T alleles was 0.44 and 0.56, respectively, whereas the genotypic frequency was 26% for C/C, 40% for C/T and 34% for T/T. The average age at first mating was approximately 20 months, whereas that at calving was approximately 32 months. The largest number of calvings of primiparous buffaloes was recorded between June and October. No associations between genotype, first mating and subsequent calving date were found. The duration from first to second calving was longer in buffaloes with the C/C genotype compared with those with the T/T and C/T genotypes (P<0.01). The period of calving for buffaloes with the C/C genotype was mainly from July to September, whereas that for buffaloes with the T/T genotype was largely from March to May. The MTNR1A gene had no effect on the age of first conception in Mediterranean Italian buffaloes. Rather, the association between the T/T genotype and reproductive activity during days with a long photoperiod indicates that this polymorphism may be considered a genetic marker to identify buffaloes that are able to reproduce out of the breeding season. PMID- 22935160 TI - Characterisation of an in vitro system to study maternal communication with spermatozoa. AB - In vivo, gamete maturation, fertilisation and early embryonic development take place inside the oviduct. Several studies have indicated that local responses towards gametes and embryos are generated by the maternal reproductive tract. However, no defined in vitro model currently exists to allow detailed and systematic investigation of maternal communications with gametes and embryos. Therefore, we characterised an in vitro model based on the interaction of boar spermatozoa with an immortalised porcine oviduct epithelial cell line to evaluate different factors that may affect this model. The factors tested were sperm viability, source of spermatozoa, cell passage effect and the effect of reproductive and non-reproductive epithelial cells in the interaction with spermatozoa. After 24 h of co-incubation, RNA was extracted and used to synthesise cDNA for quantitative real-time PCR. Alteration in the expression of genes such as adrenomedullin, heat-shock 70-kDa protein 8 and prostaglandin E synthase was considered as the end point of this assay. The results showed that sperm viability and cell passage number had an effect on oviductal gene expression in response to spermatozoa. Oviductal cells showed significant alterations in gene expression when compared with non-reproductive epithelial cells. The simple in vitro system described here has potential application for further studies in our understanding of mechanisms involved in maternal interactions with spermatozoa. PMID- 22935161 TI - The effects of season and devil facial tumour disease on the reproductive physiology of the male Tasmanian devil (Sarcophilus harrisii). AB - Devil facial tumour disease (DFTD) is the cause of the rapid decline of wild Tasmanian devils. Female devils are seasonal breeders with births peaking during autumn (i.e. March) but the degree of reproductive seasonality in male devils is unknown. The objective of this study was to examine the potential effects of season and DFTD on reproductive function in male devils (n=55). Testicular (1.90+/-0.23 g) and epididymal (0.90+/-0.06 g) weights were maximal during autumn and spring (P<0.05), whereas prostate (3.71+/-0.74 g) and Cowper's gland (0.68+/ 0.22; 0.52+/-0.21 g) weights peaked during autumn (P<0.001). The motility of spermatozoa from the cauda epididymides extracted post-mortem was similar (P>0.05) across season and disease state (31.5+/-13.1% total motility). Testicular and epididymal weights were no different between animals displaying late or early-stage DTFD signs or disease-free animals (P>0.1). The accessory sex glands were larger in late-stage DFTD animals than in animals with early-stage disease signs or which were disease-free (P<0.01) but effects of season on this result can't be excluded. Serum testosterone concentrations peaked during summer (0.25+/-0.18 ng mL(-1)) but values were not different from the preceding and subsequent seasons (P>0.05), nor influenced by disease stage (P>0.1). Seasonal and DFTD-related changes in serum cortisol concentrations were not evident (P>0.1). Male devil reproduction does not appear to be restricted by season nor inhibited by DFTD. PMID- 22935162 TI - Development and evaluation of electroejaculation techniques in the Tasmanian devil (Sarcophilus harrisii). AB - Electroejaculation (EEJ) has been used successfully to collect samples suitable for genome resource banking from a variety of endangered wildlife species. Ejaculates can also be used to evaluate the reproductive potential of individuals and provide information on seminal characteristics to aid in the development of sperm cryopreservation techniques. Electroejaculation techniques used for marsupial and eutherian species were tested on Tasmanian devils (n=35). Spermic ejaculates were collected in 54% (19/35) of EEJ attempts. Spermic ejaculates were low in volume (3.9+/-6.5*10(2) uL, range 10-3000 uL) and contained low numbers of spermatozoa (3.3+/-7.8*10(3) spermatozoa per ejaculate, range 6-33000). The osmolality and pH of presumptive urine-free ejaculates were 389+/-130 mOsm kg(-1) (range 102-566) and 7.0+/-0.9 (range 6.0-8.0), respectively. Prostatic bodies were observed in 79% (26/33) of ejaculates. Episodic fluctuations in serum testosterone concentrations were not detected during the EEJ procedure (P>0.05). Increases observed in serum cortisol concentrations during EEJ were less (P<0.05) than those observed after an adrenalcorticotropic hormone challenge and diurnal variation suggested that cortisol concentrations are greater during the day than at night (P<0.05). This information can be used to provide range values for the future examination of basic endocrine responses and the adrenal-pituitary axis of this species. This study also demonstrated that spermatozoa-rich devil electroejaculates are more difficult to obtain and poorer in quality than those of other marsupials. PMID- 22935163 TI - Vocal fold composition and early glottic carcinoma infiltration. AB - BACKGROUND: Current imaging techniques provide only limited information pertaining to the extent of infiltration of laryngeal carcinomas into vocal fold tissue layers. Therefore, it is needed to seek the contribute to the body of knowledge surrounding examination and characterization in laryngeal carcinoma infiltration. METHODS: Excised larynges were collected from 30 male laryngectomy patients with an average age of 43.5 years (ranging 36 to 55 years) and history of smoking (>= 10 years) exhibiting T1, T2, or subglottal (normal vocal fold) carcinomas. Vocal folds were preserved via freezing or immersion in paraffin. The depth of the mucosa, submucosa, and muscular layers in both normal vocal folds and tumor tissues of afflicted vocal folds was measured. RESULTS: The average depths of the mucosa, submucosa, and muscular layers in normal vocal folds were 0.15 +/- 0.06 mm, 2.30 +/- 0.59 mm, and 2.87 +/- 0.88 mm, respectively. Infiltration measurements of T1 tumors showed a depth of 1.62 +/- 0.51 mm and 1.32 +/- 0.49 mm in frozen sections and paraffin-embedded samples, respectively. Similarly, T2 tumors showed a depth of 2.87 +/- 0.68 mm and 2.58 +/- 0.67 mm in frozen sections and paraffin-embedded samples, respectively. T1 and T2 tumors occupied 24.8 +/- 10 and 48.5 +/- 15 percent of the normal vocal fold depth, respectively. CONCLUSION: This data provides a baseline for estimating infiltration of laryngeal carcinomas in vocal fold tissue layers, of particular interest to surgeons. This information may be used to assess typical depths of infiltration, thus allowing for more appropriate selection of surgical procedures based on individual patient assessment. PMID- 22935164 TI - Blind spots at oncological CT: lessons learned from PET/CT. AB - Improved accuracy in oncological computed tomography (CT) could lead to a decrease in morbidity and improved survival for oncology patients. Visualization of metabolic activity using the glucose analogue [(18)F]fluorodeoxyglucose (FDG) in combination with the high anatomic resolution of CT in an integrated positron emission tomography (PET)/CT examination has the highest sensitivity and specificity for the detection of primary and metastatic lesions. However, PET/CT costs are high and patient access is limited; thus CT remains the primary imaging modality in oncology patients. We have noted that subtle lesions are more easily detected on CT by radiologists with PET/CT experience. We aimed to provide a brief review of the literature with comparisons of multi-detector computed tomography (MDCT) and PET/CT in primary and metastatic disease with an emphasis on findings that may be overlooked on MDCT in cancer of the breast, lung, colon, and ovaries, and in melanoma, as well as thrombosis in oncology patients. We further reviewed our experience for illustrative comparisons of PET/CT and MDCT studies. Experience in interpreting conventional CT scans alongside PET/CT can help the reader develop an appreciation for the subtle appearance of some lesions on CT that might otherwise be missed. This could improve detection rates, reduce errors, and improve patient management. PMID- 22935165 TI - Skewed TGFbeta/Smad signalling pathway in T cells in patients with Behcet's disease. AB - OBJECTIVES: Behcet's disease (BD) is a multi-systemic inflammatory disease, characterised by recurrent oral aphthosis, genital ulcers, skin lesions and uveitis. We have reported excessive Th1 cell activity in patients with BD. More recently, Th17 cells were suggested to associate with several autoimmune diseases. This study was designed to investigate the role of Th17 related cytokines and signalling molecules in patients with BD. METHODS: We examined mRNA expressions of Th1 and Th17 related cytokines and related signalling molecules in PBMC of 12 patients with BD and 14 normal controls (NC) using quantitative RT PCR. We studied expressions of the Th17 related cytokines in other four BD patients' skin lesions by immunofluorescence. RESULTS: Major Th17 related cytokines were not detected in unstimulated PBMC in patients with BD. After stimulation, mRNA expressions of TGFbeta receptor type 1, IL-12 receptor beta2 and suppressor of cytokine signalling protein (SOCS) 1 on PBMC were significantly enhanced in patients with BD, as compared with NC (p<0.05). mRNA expression of RORC, a key transcription factor for Th17 cell differentiation, was comparable between BD and NC. CD4+ T cells infiltrating into BD skin lesion expressed TGFbeta1 much more than those infiltrating into non-Behcet's disease erythema nodosum. CONCLUSIONS: These findings suggest that TGFbeta/Smad signalling pathway of T cells is overactive in patients with BD. PMID- 22935167 TI - Helping the in-group feels better: children's judgments and emotion attributions in response to prosocial dilemmas. AB - Five- to 13-year-old European American children (N = 76) predicted characters' decisions, emotions, and obligations in prosocial moral dilemmas. Across age, children judged that characters would feel more positive emotions helping an unfamiliar child from the racial in-group versus out-group (African American), happier ignoring the needs of a child from the racial out-group versus in-group, and greater obligation to help a child from the racial in-group versus out-group. Situations varied by whether the race of the needy child matched versus mismatched that of the focal character. With increasing age, children attributed more positive emotions to people who sacrifice their own desires to help needy others as well as became more discriminating about the situations that call for altruistic action. PMID- 22935166 TI - Antioxidant status and its association with elevated depressive symptoms among US adults: National Health and Nutrition Examination Surveys 2005-6. AB - We examined the relationship of elevated depressive symptoms with antioxidant status. Cross-sectional data from the National Health and Nutrition Examination Surveys 2005-6 on US adults aged 20-85 years were analysed. Depressive symptoms were measured using the Patient Health Questionnaire with a score cut-off point of 10 to define 'elevated depressive symptoms'. Serum antioxidant status was measured by serum levels of carotenoids, retinol (free and retinyl esters), vitamin C and vitamin E. The main analyses consisted of multiple logistic and zero-inflated Poisson regression models, taking into account sampling design complexity. The final sample consisted of 1798 US adults with complete data. A higher total serum carotenoid level was associated with a lower likelihood of elevated depressive symptoms with a reduction in the odds by 37 % overall with each sd increase in exposure, and by 34 % among women (P< 0.05). A dose-response relationship was observed when total serum carotenoids were expressed as quartiles (Q4 (1.62-10.1 MUmol/l) v. Q1 (0.06-0.86 MUmol/l): OR 0.41; 95 % CI 0.23, 0.76, P< 0.001; P for trend = 0.035), though no significant associations were found with the other antioxidant levels. Among carotenoids, beta-carotene (men and women combined) and lutein+zeaxanthins (women only, after control for dietary lutein+zeaxanthin intake and supplement use) had an independent inverse association with elevated depressive symptoms among US adults. None of the other serum antioxidants had a significant association with depressive symptoms, independently of total carotenoids and other covariates. In conclusion, total carotenoids (mainly beta-carotene and lutein+zeaxanthins) in serum were associated with reduced levels of depressive symptoms among community-dwelling US adults. PMID- 22935168 TI - Schizophrenia symptoms and functioning in patients receiving long-term treatment with olanzapine long-acting injection formulation: a pooled analysis. AB - BACKGROUND: This analysis of pooled data evaluates treatment outcomes of patients with schizophrenia receiving maintenance treatment with olanzapine long-acting injection (OLAI) by means of a categorical approach addressing the symptomatic and functional status of patients at different times. METHODS: Patients were grouped into 5 categories at baseline, 6 months, and 12 months. Shifts between categories were assessed for individual patients and factors associated with improvement were analyzed. 1182 patients from 3 clinical trials were included in the current analysis. RESULTS: At baseline, 434 (36.8%) patients had minimal Positive and Negative Syndrome Scale (PANSS) symptoms but seriously impaired Heinrich Carpenter's Quality of Life Scale (QLS) functioning; 303 (25.6%) had moderate to severe symptoms and seriously impaired function; 208 (17.6%) had mild to moderate symptoms but good functioning, and 162 (13.7%) had minimal symptoms and good functioning. Baseline category was significantly associated with Clinical Global Impression--Severity (CGI-S), extrapyramidal symptoms, working status, age, and number of previous episodes. The majority of all patients starting OLAI treatment maintained or improved (62% at 6 months and 52% at 12 months) their symptom and functioning levels on OLAI maintenance treatment. Less than 8% of the patients showed worsening of symptoms or functioning. An improvement in category was associated with high PANSS positive and low CGI-S scores at baseline. CONCLUSIONS: We present evidence that a composite assessment of schizophrenic patients including symptom severity and functioning is helpful in the evaluation of maintenance treatment outcomes. This approach could also be useful for the assessment of treatment options in clinical practice.The trials from which data are reported here were registered on clinicaltrials.gov as NCT00088491, NCT00088465, and NCT00320489. PMID- 22935169 TI - Microbial diversity and anaerobic hydrocarbon degradation potential in an oil contaminated mangrove sediment. AB - BACKGROUND: Mangrove forests are coastal wetlands that provide vital ecosystem services and serve as barriers against natural disasters like tsunamis, hurricanes and tropical storms. Mangroves harbour a large diversity of organisms, including microorganisms with important roles in nutrient cycling and availability. Due to tidal influence, mangroves are sites where crude oil from spills farther away can accumulate. The relationship between mangrove bacterial diversity and oil degradation in mangrove sediments remains poorly understood. RESULTS: Mangrove sediment was sampled from 0-5, 15-20 and 35-40 cm depth intervals from the Surui River mangrove (Rio de Janeiro, Brazil), which has a history of oil contamination. DGGE fingerprinting for bamA, dsr and 16S rRNA encoding fragment genes, and qPCR analysis using dsr and 16S rRNA gene fragment revealed differences with sediment depth. CONCLUSIONS: Analysis of bacterial 16S rRNA gene diversity revealed changes with depth. DGGE for bamA and dsr genes shows that the anaerobic hydrocarbon-degrading community profile also changed between 5 and 15 cm depth, and is similar in the two deeper sediments, indicating that below 15 cm the anaerobic hydrocarbon-degrading community appears to be well established and homogeneous in this mangrove sediment. qPCR analysis revealed differences with sediment depth, with general bacterial abundance in the top layer (0-5 cm) being greater than in both deeper sediment layers (15-20 and 35-40 cm), which were similar to each other. PMID- 22935170 TI - Clinical overlap between fibromyalgia tender points and enthesitis sites in patients with spondyloarthritis who present with inflammatory back pain. AB - OBJECTIVES: To assess the extent of coexistence of inflammatory back pain (IBP) with fibromyalgia (FM) features in patients with spondyloarthritis (SpA), and to assess the degree of overlap of FM tender points (TeP) and enthesitis sites (ES) in patients with SpA. METHODS: We evaluated 61 consecutive patients who presented with IBP. Anterior and posterior anatomic diagrams were used as an aid to record assessments of TeP typically seen in FM and ES. RESULTS: Of the patients assessed (n=61), 60 patients (97.9%) fulfilled criteria for IBP (male: female=17:43 (28.3%:71.7%); mean age=47.9 years (SD=11.5) and were included in the analysis. Of those who returned the questionnaire (n=47 (78.3%), 76.6% had onset of symptoms at <=40 years (mean age=33.5+/-12.5 years), 87.2% had back pain of >=3 months duration, 91.5% had morning stiffness (mean duration=70+/-66 minutes), and 60% showed improvement of pain with exercise. Eating disorders were reported by 21.3% of subjects, and stress was identified as a disease trigger by 40.4% of the respondents. Other symptoms related to FM were reported by 68.1% of the interviewed subjects. Of the 60 patients assessed, 18 (30%) fulfilled the clinical criteria for FM (at least 11 out of 18 TeP). Using regression analysis, a significant correlation was identified between FM TeP and ES. CONCLUSIONS: One third of patients with IBP fulfilled the criteria for FM. There is a significant degree of overlap between FM TeP and ES in patients with IBP. PMID- 22935171 TI - Two types of nanoparticle-based bio-barcode amplification assays to detect HIV-1 p24 antigen. AB - BACKGROUND: HIV-1 p24 antigen is a major viral component of human immunodeficiency virus type 1 (HIV-1) which can be used to identify persons in the early stage of infection and transmission of HIV-1 from infected mothers to infants. The detection of p24 is usually accomplished by using an enzyme-linked immunosorbent assay (ELISA) with low detection sensitivity. Here we report the use of two bio-barcode amplification (BCA) assays combined with polymerase chain reaction (PCR) and gel electrophoresis to quantify HIV-1 p24 antigen. METHOD: A pair of anti-p24 monoclonal antibodies (mAbs) were used in BCA assays to capture HIV-1 p24 antigen in a sandwich format and allowed for the quantitative measurement of captured p24 using PCR and gel electrophoresis. The first 1 G12 mAb was coated on microplate wells or magnetic microparticles (MMPs) to capture free p24 antigens. Captured p24 in turn captured 1D4 mAb coated gold nanoparticle probes (GNPs) containing double-stranded DNA oligonucleotides. One strand of the oligonucleotides was covalently immobilized whereas the unbound complimentary bio barcode DNA strand could be released upon heating. The released bio-barcode DNA was amplified by PCR, electrophoresed in agarose gel and quantified. RESULTS: The in-house ELISA assay was found to quantify p24 antigen with a limit of detection (LOD) of 1,000 pg/ml and a linear range between 3,000 and 100,000 pg/ml. In contrast, the BCA-based microplate method yielded an LOD of 1 pg/ml and a linear detection range from 1 to 10,000 pg/ml. The BCA-based MMP method yielded an LOD of 0.1 pg/ml and a linear detection range from 0.1 to 1,000 pg/ml. CONCLUSIONS: When combined with PCR and simple gel electrophoresis, BCA-based microplate and MMPs assays can be used to quantify HIV-1 p24 antigen. These methods are 3-4 orders of magnitude more sensitive than our in-house ELISA-based assay and may provide a useful approach to detect p24 in patients newly infected with HIV. PMID- 22935173 TI - Current strategies for the protection, regeneration, and replacement of cochlear hair cells. AB - Sensorineural hearing loss, which is often caused by degeneration of hair cells in the auditory epithelium, is permanent because lost hair cells cannot be replaced in mammals. In recent years, important progress has been made in understanding the mechanisms involved in hair cell damage and, more importantly, the reasons why hair cells cannot be regenerated spontaneously in mammals. The knowledge of the factors implicated in hair cell fate determination and of the mechanisms of hair cell regeneration in birds could help in the effort to find a treatment for hearing loss. Although cochlear implant technology is advanced, it still provides only moderate hearing capacity in sensorineural deaf individuals. Inducible stem cells and molecular therapies are appealing alternatives to the cochlear implant as they hold the promise of a cure. It is important to develop a safe and effective means to deliver stem cells or genes to the correct sites to stimulate regeneration in the right place. This review aims to synthesize the present knowledge in the field of sensorineural hearing loss, focusing on the mechanisms involved in hair cell development and regeneration, with the specific purpose of identifying new therapeutic strategies. Despite tremendous progress in this field, most of the concepts discussed in this review are still in the experimental stage. PMID- 22935174 TI - Management of goitre and small nodule disease by Canadian otolaryngologists. AB - OBJECTIVE: To describe current management practices among Canadian otolaryngologists for small thyroid nodule disease and nodules in the context of goitre. METHODS: An online survey was e-mailed to all active members of the Canadian Society of Otolaryngology-Head and Neck Surgery (CSOHNS). The responses were anonymous. Information was gathered on practice demographics and individual practices pertaining to diagnostic workup, surgical management, and follow-up of patients with goitre and small nodule disease. RESULTS: A total of 113 surveys were returned from 431 active CSOHNS members (26% response). The majority of respondents were less than 40 years (54%), resided in Ontario or Quebec (63%), and described their practice as academic (65%). Management of a small thyroid nodule following fine-needle aspiration cytology results reported as benign, nondiagnostic, abnormal, or papillary thyroid cancer was inconsistent. Papillary thyroid cancer was managed by total thyroidectomy (59%), total thyroidectomy plus level VI neck dissection (38%), hemithyroidectomy plus level VI neck dissection (2%), and hemithyroidectomy (1%). Management of goitre was not uniform. Symptomatic goitre management included discharge from practice (6%), follow-up with serial ultrasonography (12%), hemithyroidectomy (15%), and total thyroidectomy (66%). Practice demographics had a significant effect on intraoperative techniques, such as the use of an electromyographic nerve monitor. CONCLUSION: There was a lack of consensus among Canadian otolaryngologists regarding treatment of small thyroid nodules and nodules in the context of goitre. Canadian guidelines for management of small nodule disease may standardize care. PMID- 22935172 TI - HtrA1 expression associated with the occurrence and development of esophageal cancer. AB - BACKGROUND: The purposes of this study were to measure both the mRNA and protein expression levels of high-temperature requirement serine peptidase 1 (HtrA1) in human esophageal cancer tissues and their adjacent, comparatively normal esophageal tissues. METHODS: The expression levels of HtrA1 mRNA and protein in both tissue types were measured by semi-quantitative RT-PCR (reverse transcription-polymerase chain reaction) and Western blotting. The clinical and pathological correlation between HtrA1 expression levels and the occurrence and development of esophageal cancer was analyzed. RESULTS: The expression levels of HtrA1 mRNA and protein in esophageal carcinoma were significantly lower than the levels expressed in their adjacent normal esophageal tissue (p < 0.05). The more highly undifferentiated esophageal tumor cells expressed lower HtrA1 mRNA and protein expression levels (p < 0.05). Patients with tumors in early pathological stages (I-II) had significantly higher HtrA1 mRNA and protein expression levels than did patients with tumors in mid-to-late pathological stages (III-IV) (p < 0.05). Patients with positive lymph node metastasis had significantly lower HtrA1 mRNA and protein expression levels than did patients with lymph node-negative disease (p < 0.05). CONCLUSIONS: HtrA1 expression is associated with the occurrence and development of esophageal cancer. PMID- 22935175 TI - Idiopathic vocal cord paralysis in the radiated neck: a harbinger for malignant peripheral nerve sheath tumour. AB - OBJECTIVE: Patients with previous neck external beam radiotherapy (XRT) diagnosed with idiopathic vocal cord paralysis (VCP) can harbour sinister pathology. A case series of such patients found to have vagal malignant peripheral nerve sheath tumours (MPNSTs) is presented and combined with a literature review. Management and survival outcomes are analyzed. DESIGN: Case series and systematic literature review. SETTING: Academic tertiary care cancer centre. METHODS: The University of Alberta's head and neck mass database was gleaned for vagal XRT-induced MPNSTs (2001-2011). Charts were reviewed for patient and tumour demographics, diagnostic methods, pathology, treatment, and survival. A systematic literature review identified similar patients. MAIN OUTCOME MEASURES: Kaplan-Meier estimated actuarial survival rates were the primary outcome. Secondary outcomes included the mean time from XRT to presentation and to tumour recurrence as well as a summary of patient/tumour characteristics, diagnostic methods, and treatment options. RESULTS: Two institutional and seven additional literature-wide cases were found. The median age was 34 years, the median time from XRT to MPNST was 22 years, and all patients were surgically treated. The median time from surgery to recurrence was 2.5 years. Estimated 2- and 5-year survival rates were 71% and 54%, respectively. CONCLUSION: XRT-induced MPNST can present as idiopathic VCP two decades post-XRT. Treatment is surgical and offers acceptable survival. PMID- 22935176 TI - Effects of hepatocyte growth factor on wound healing of rabbit maxillary sinus mucosa. AB - OBJECTIVE: The purpose of this study was to investigate the effects of hepatocyte growth factor (HGF) on healing of the sinonasal mucosa. METHODS: A 6 mm wound was created in the bilateral maxillary sinuses of 16 New Zealand White rabbits, and 8 mm diameter absorbable gelatin sponge with 25 MUL HGF (case) and 25 MUL saline (control) were randomly assigned to each side for wound treatment. On the third and seventh days after the procedure, the average decreased diameter was recorded. On the seventh day, the medial wall of the maxillary sinus was taken for histologic analysis (including scanning electron microscopy of two rabbits). The maximal thickness of fibrous tissue and no epithelium coverage of the wound were detected. In the second, third, and fourth weeks, another 3 rabbits were randomly selected for photographs under a scanning electron microscope. RESULTS: On the third and seventh days after injury, the average decreased diameters were 2.05 +/- 0.56 mm and 1.56 +/- 0.80 mm, 3.90 +/- 0.76 mm, and 3.29 +/- 0.70 mm on the case and control sides, respectively. On day 7 after injury, the maximal thickness of fibrous tissue was 324.8 +/- 93.1 MUm and 432.8 +/- 106.3 MUm, and the wound without epithelium coverage was 345.7 +/- 114.6 MUm and 508.6 +/- 157.2 MUm on case and control sides, respectively, and there were significant differences (p < .05). CONCLUSIONS: HGF can promote wound healing and ciliogenesis and inhibit fibrosis in the maxillary sinus mucosa, especially in the first 3 days. This finding suggests that HGF plays a potential role in reepithelialization and cilium hyperplasia. PMID- 22935177 TI - Middle turbinate resection versus preservation in patients with chronic rhinosinusitis accompanying nasal polyposis: baseline disease burden and surgical outcomes between the groups. AB - OBJECTIVE: To evaluate baseline disease burden and surgical outcomes between middle turbinate resection and preservation groups consisting of patients diagnosed with chronic rhinosinusitis accompanying nasal polyposis (NP). STUDY DESIGN: Prospective, nonrandomized study. METHODS: The preoperative disease burden (extent of NP, Lund-Mackay scores, and subjective symptom scores) was evaluated using nasal endoscopy, computed tomography, and questionnaires. Objective and subjective surgical outcomes were assessed 12 months postoperatively based on endoscopic findings, the Sino-Nasal Outcome Test 20 (SNOT-20), and a visual analogue scale (VAS). RESULTS: The extent of NP, Lund Mackay scores, and VAS scores for the two main symptoms were significantly greater in the resection group than in the preservation group. The preservation group had better objective outcomes. Preoperative SNOT-20 and VAS scores were improved significantly at 12 months postoperatively in both groups, and the improvement did not differ significantly between the groups. CONCLUSIONS: The middle turbinate resection group had greater baseline disease burden (severe polyposis, more extensive disease, and poorer symptom scores) than the preservation group. This may be the reason for the poorer objective surgical outcome in the resection group despite more radical surgery. However, the subjective outcomes were successful regardless of the middle turbinate resection or preservation. PMID- 22935178 TI - Systematic evaluation of obstructive sleep apnea websites on the internet. AB - OBJECTIVE: To determine the quality and comprehensiveness of the websites on the Internet with information directed toward patients with obstructive sleep apnea (OSA). DESIGN: Systematic evaluation of websites on the Internet with information on OSA. SETTING: World Wide Web. METHODS: The search engine Google was queried with the term "obstructive sleep apnea." The first 50 results were evaluated. Only websites written in English and containing original information were reviewed. MAIN OUTCOME MEASURES: A data quality score (DQS) was generated by evaluating each website for the presence of 67 points of information relating to OSA. Each website was also evaluated using a Global Quality Score (GQS), the DISCERN instrument, the Flesch-Kincaid reading grade level, date of the last update, and sources of funding. RESULTS: Thirty-four websites met the inclusion criteria. The average DQS was 36 points (range 17-57). The average GQS was 2.9 (range 1-5). The average DISCERN score was 3.3 (range 1.9-4.7). The average reading grade level was 11.0 (range 5.0-15.8). Twenty-six websites (76%) provided authorship information. Twenty-five websites (74%) displayed a date of the last update. Of these, 12 websites were not updated within the past 2 years. Twenty websites (59%) provided a source of funding. CONCLUSIONS: There is a heterogeneous mixture of websites with varying quality on the Internet with information regarding OSA. Health care providers should be cognizant of the variety of information available for patients and be prepared to direct patients toward the high-quality information sources. PMID- 22935179 TI - Efficacy of radiofrequency turbinate reduction: evaluation by computed tomography and acoustic rhinometry. AB - BACKGROUND: Radiofrequency ablation (RFA) of the inferior turbinates is a popular surgical intervention that aims to reduce turbinate volume. However, in a few studies, the amount of volume loss was analyzed objectively. OBJECTIVE: The aim of this study was to investigate the effects of RFA on the inferior turbinate by comparing its volume before and 6 weeks after surgery via computed tomography (CT) and the change in minimal cross-sectional areas (MCAs) via acoustic rhinometry objectively. METHODS: Eighteen patients who underwent RFA with the diagnosis of isolated bilateral inferior turbinate hypertrophy were enrolled in the study. All patients were evaluated pre- and postoperatively with paranasal CT and acoustic rhinometry quantitatively for the assessment of inferior turbinate volume decrement and nasal cavity volume increment. Also, the subjective relief of obstructive symptoms was assessed with a visual analogue scale. RESULTS: There were significant reductions in volume for both right and left turbinates in the tomographic evaluation (p = .007 and .004, respectively). Acoustic rhinometry revealed nonsignificant increments for both MCA1 and MCA2 values except MCA2 of the right side. We also indicated a statistically significant correlation between the mean volume reduction in CT and improvement in mean MCA2 volume (2 to 5 cm from the nostril) obtained from acoustic rhinometric data in 36 turbinates (r = .337, p = .044). CONCLUSION: We showed that the use of RFA was highly effective in both reducing turbinate volume (demonstrated by radiologic findings and rhinometric analysis) and improving obstructive symptoms in patients with an isolated inferior turbinate. PMID- 22935180 TI - Tympanocentesis results of a Canadian pediatric myringotomy population, 2008 to 2010. AB - OBJECTIVE: This study was completed to evaluate the middle ear microbiology of a pediatric population with chronic otitis media with effusion and to determine if there has been a change in the spectrum of microorganisms or their antibiotic susceptibility in the modern age of antibiotic therapy. DESIGN: Retrospective chart review. SETTING: A Canadian academic pediatric otolaryngology practice. METHODS: This study includes all consecutive patients under the care of one pediatric otolaryngologist undergoing myringotomy and tube placement between the dates of September 2008 and August 2010. Tympanocentesis was performed on each middle ear immediately following the myringotomy, and the specimen was sent for microbiologic analysis. MAIN OUTCOME MEASURES: Culture results and sensitivities were compared to previous similar studies. RESULTS: A total of 246 children (average age of 4 +/- 3 years) and 506 ears had culture results as follows: normal flora, 47%; no growth, 35%; Haemophilus influenzae, 9%; Streptococcus pneumoniae, 4%; Moraxella catarrhalis, 3%; and Staphylococcus aureus, 2%. Ten of the 11 S. aureus cultures were methicillin resistant. The rate of pathogenicity decreased from 36.5% in children aged < 4 years to 15.3% in children aged 4+ years (p = .001). CONCLUSION: H. influenzae continues to lead as the most common pathogen; however, S. aureus is increasing in frequency. Pathogenicity decreases with age and appears to be lower in children with a cleft palate. PMID- 22935181 TI - Congenital tracheal stenosis managed conservatively: systematic review of the literature. AB - OBJECTIVE: Congenital tracheal stenosis (CTS) is challenging. Its natural history and epidemiology are poorly described. Information is scarce on cases not undergoing surgery. METHODS: A retrospective review of patients with CTS in one pediatric otolaryngology practice was performed. A Medline search of English publications from 1966 to 2008 was conducted using the terms "CTS," "management of CTS," and "slide tracheoplasty." RESULTS: Four patients were diagnosed over 5.5 years. Diagnosis was achieved within 4 months of life in three and at 13 years of age in one. Three children presented with difficulty to ventilate in the neonatal intensive care unit. One was diagnosed with asthma early in life. Other congenital abnormalities were encountered in three patients. One child required a tracheostomy due to respiratory failure, for reasons other than CTS. None required surgical repair, and conservative management was pursued. Three patients were followed for 5 years. Our search yielded 20 relevant reports from 1996 to 2008. All were retrospective case series. A total of 310 patients with a mean age of 17.14 months (+/- 24.10) were used in our analysis. The male to female ratio of those reported was 1.7:1. The mean follow-up was 5.1 years. Thirty-five to 43% of patients had no qualified indications for their surgical management. Mortality and complication rates make tracheal repair a significant undertaking. Little is reported on the long-term outcomes, swallowing functions, and quality of life of patients repaired who did not require immediate interventions. CONCLUSION: There is a need to identify specific indications for surgery and a stratification of successful candidates by various disease-related factors. If the difficulties weaning from assisted ventilation or coping with growth and activity requirements are circumvented, children may be managed conservatively. PMID- 22935182 TI - Primary low-grade angiosarcoma of the cervical lymph node. PMID- 22935183 TI - Nasopharygeal carcinoma presenting predominantly as an intracranial mass. PMID- 22935184 TI - Cervical neuropathic ulceration: description of a cervical analogy to trigeminal trophic syndrome. PMID- 22935185 TI - Odontogenic keratocyst and ectopic tooth of the left maxillary sinus. PMID- 22935186 TI - Bilateral chylothorax following neck dissection: case report and systematic review of the literature. PMID- 22935187 TI - Retropharyngeal angiofibroma. PMID- 22935188 TI - Extraosseous ewing sarcoma of the tonsil. PMID- 22935189 TI - Necrotizing vasculitis resulting in necrosis of the entire oral tongue. PMID- 22935190 TI - Serum leptin, resistin, visfatin and adiponectin levels in tumor necrosis factor receptor-associated periodic syndrome (TRAPS). AB - OBJECTIVES: The aims of our study were to evaluate serum leptin, resistin, visfatin and adiponectin levels in patients with tumour necrosis factor receptor associated periodic syndrome (TRAPS), in comparison to healthy controls, and to correlate their levels to parameters of disease activity and/or severity. METHODS: Serum leptin, resistin, visfatin and adiponectin levels were obtained from 14 TRAPS patients carrying mutations involving cysteine residues, from 16 TRAPS patients carrying other mutations, and from 16 healthy controls. Demographic, clinical and laboratory parameters, including amyloidosis were entered for each patient. Comparisons between groups as well as reciprocal comparisons have been evaluated. RESULTS: Serum leptin, resistin, visfatin and adiponectin did not significantly differ among the 3 groups. Patients carrying cysteine residues mutations showed lower visfatin serum levels than patients carrying other mutations (p<0.02). Serum leptin significantly correlated with the number of attacks/year (multiple R=0.32, multiple adjusted R2= 0.19, p <0.03). Serum adiponectin levels significantly correlated with the presence of amyloidosis (multiple R=0.79, multiple adjusted R2=0.57, p<0.03). Adiponectin values were a significant predictor for amyloidosis (AUC 0.75, 95 CI: 0.56-0.94, p<0.03), with a predicting cut-off value set at 23.16 pg/ml, the predictive positive value was 53.8%. Visfatin serum levels resulted respectively related to leptin (rs=0.42, r2=0.18, p<0.02) and to resistin (rs=0.57, r2=0.32, p<0.01) serum levels; whilst leptin and resistin serum levels did not reciprocally correlate. CONCLUSIONS: Although a prospective design study and larger cohort are mandatory, adipokines serum levels and their correlations with parameters of disease activity and/or severity seem to show a baseline pattern in TRAPS patients. PMID- 22935191 TI - Mar, a MITE family of hAT transposons in Drosophila. AB - BACKGROUND: Miniature inverted-repeat transposable elements (MITEs) are short, nonautonomous DNA elements flanked by subterminal or terminal inverted repeats (TIRs) with no coding capacity. MITEs were originally recognized as important components of plant genomes, where they can attain extremely high copy numbers, and are also found in several animal genomes, including mosquitoes, fish and humans. So far, few MITEs have been described in Drosophila. RESULTS: Herein we describe the distribution and evolution of Mar, a MITE family of hAT transposons, in Drosophilidae species. In silico searches and PCR screening showed that Mar distribution is restricted to the willistoni subgroup of the Drosophila species, and a phylogenetic analysis of Mar indicates that this element may have originated prior to the diversification of these species. Most of the Mar copies in D. willistoni present conserved target site duplications and TIRs, indicating recent mobilization of these sequences. We also identified relic copies of potentially full-length Mar transposon in D. tropicalis and D. willistoni. The phylogenetic relationship among transposases from the putative full-length Mar and other hAT superfamily elements revealed that Mar is placed into the recently determined Buster group of hAT transposons. CONCLUSION: On the basis of the obtained data, we can suggest that the origin of these Mar MITEs occurred before the subgroup willistoni speciation, which started about 5.7 Mya. The Mar relic transposase existence indicates that these MITEs originated by internal deletions and suggests that the full-length transposon was recently functional in D. willistoni, promoting Mar MITEs mobilization. PMID- 22935192 TI - Neoplastic stomach lesions and their mimickers: spectrum of imaging manifestations. AB - This review illustrates a wide spectrum of gastric neoplasms with emphasis on imaging findings helpful in characterizing various gastric neoplasms. Both the malignant and benign neoplasms along with focal gastric masses mimicking tumour are illustrated. Moreover, imaging clues to reach an accurate diagnosis are emphasized. PMID- 22935193 TI - The gut microbiome of kittens is affected by dietary protein:carbohydrate ratio and associated with blood metabolite and hormone concentrations. AB - High-protein, low-carbohydrate (HPLC) diets are common in cats, but their effect on the gut microbiome has been ignored. The present study was conducted to test the effects of dietary protein:carbohydrate ratio on the gut microbiota of growing kittens. Male domestic shorthair kittens were raised by mothers fed moderate-protein, moderate-carbohydrate (MPMC; n 7) or HPLC (n 7) diets, and then weaned at 8 weeks onto the same diet. Fresh faeces were collected at 8, 12 and 16 weeks; DNA was extracted, followed by amplification of the V4-V6 region of the 16S rRNA gene using 454 pyrosequencing. A total of 384 588 sequences (average of 9374 per sample) were generated. Dual hierarchical clustering indicated distinct clustering based on the protein:carbohydrate ratio regardless of age. The protein:carbohydrate ratio affected faecal bacteria. Faecal Actinobacteria were greater (P< 0.05) and Fusobacteria were lower (P< 0.05) in MPMC-fed kittens. Faecal Clostridium, Faecalibacterium, Ruminococcus, Blautia and Eubacterium were greater (P< 0.05) in HPLC-fed kittens, while Dialister, Acidaminococcus, Bifidobacterium, Megasphaera and Mitsuokella were greater (P< 0.05) in MPMC-fed kittens. Principal component analysis of faecal bacteria and blood metabolites and hormones resulted in distinct clusters. Of particular interest was the clustering of blood TAG with faecal Clostridiaceae, Eubacteriaceae, Ruminococcaceae, Fusobacteriaceae and Lachnospiraceae; blood ghrelin with faecal Coriobacteriaceae, Bifidobacteriaceae and Veillonellaceae; and blood glucose, cholesterol and leptin with faecal Lactobacillaceae. The present results demonstrate that the protein:carbohydrate ratio affects the faecal microbiome, and highlight the associations between faecal microbes and circulating hormones and metabolites that may be important in terms of satiety and host metabolism. PMID- 22935194 TI - A genome-wide association study of autism incorporating autism diagnostic interview-revised, autism diagnostic observation schedule, and social responsiveness scale. AB - Efforts to understand the causes of autism spectrum disorders (ASDs) have been hampered by genetic complexity and heterogeneity among individuals. One strategy for reducing complexity is to target endophenotypes, simpler biologically based measures that may involve fewer genes and constitute a more homogenous sample. A genome-wide association study of 2,165 participants (mean age = 8.95 years) examined associations between genomic loci and individual assessment items from the Autism Diagnostic Interview-Revised, Autism Diagnostic Observation Schedule, and Social Responsiveness Scale. Significant associations with a number of loci were identified, including KCND2 (overly serious facial expressions), NOS2A (loss of motor skills), and NELL1 (faints, fits, or blackouts). These findings may help prioritize directions for future genomic efforts. PMID- 22935195 TI - The comparative effectiveness of statin therapy in selected chronic diseases compared with the remaining population. AB - BACKGROUND: Total cholesterol (TC) concentration is the most commonly used measure of statin efficacy in the UK. This study aimed to evaluate the effectiveness of statins in lowering TC, cardiovascular events (CV) and mortality five common chronic diseases (chronic obstructive pulmonary disease (COPD), osteoarthritis (OA), rheumatoid arthritis (RA), chronic kidney disease (CKD), and diabetes mellitus (DM)) and to compare effectiveness with the rest of the population not recorded as having these diseases. METHODS: A population-based cohort study was conducted in Tayside population who had at least two TC measurements between 1993 and 2007. There were 12,140 patients with chronic diseases and 9,481 patients in the rest of the population not recorded as having these chronic diseases. The main outcomes were TC change from baseline, CV events and all-cause mortality. RESULTS: Statin-associated TC reductions varied from 15% to 28% with baseline value of between 5.1 and 5.9 mmol/L in the primary prevention (PP) and from 7% to 23% with baseline value of 4.5 to 5.2 mmol/L in the secondary prevention (SP) among chronic diseases patients. In the rest of the population, TC reductions with statins were 31% in PP and 28% in SP with baselines of 6.3 mmol/L and 5.3 mmol/L, respectively (test of heterogeneity with chronic disease groups: p < 0.001). A notional reduction of 0.5 mmol/L in TC predicted variable reductions in incident CV events of 30% in RA, 19% in CKD, and 20% in DM, and recurrent CV events by 62% in COPD, 16% in CKD, and 19% in DM. The corresponding figures for the rest of population were 12% for incident CV events and 17% for the recurrent CV events, respectively. Risk reductions for all-cause mortality varied from 20% to 36% in PP and from 18% to 40% in SP, except in OA or RA patients in the chronic diseases and 11% in PP and 16% in the rest of population (test of heterogeneity: p > 0.05). CONCLUSIONS: The effectiveness of statins in common chronic diseases varied. With the exception of diabetes, statins tends to be less effective in patients with the chronic diseases compared with the rest of the study population. Changes in TC with statins appear not to correlate well with the changes in cardiovascular events and all-cause mortality. PMID- 22935197 TI - Long-term follow-up of sporadic inclusion body myositis treated with intravenous immunoglobulin: a retrospective study of 16 patients. AB - OBJECTIVES: Previous studies of intravenous immunoglobulin (IVIG) treatment in sporadic inclusion body myositis (sIBM) have yielded conflicting results. Here, we have undertaken a retrospective assessment of the long-term effects of IVIG in our sIBM cohort. METHODS: Sixteen sIBM patients, treated with a mean of 10 IVIG infusions and followed up for a mean period of 23 months, were identified. Six sIBM patients treated with other drugs were used as an internal control group. Serial data on manual muscle testing (MMT), laboratory parameters and patients' subjective assessment were collected. RESULTS: Serial MMT scores were available in 14 IVIG treated patients. Two of these patients improved more than 20% in MMT from baseline up to the third IVIG infusion. One of six patients in the control group showed a similar MMT improvement during the first six months. Improved swallowing function was reported by three IVIG-treated patients, but none of the controls. The serum levels of creatine kinase fell more than 20 % after the first IVIG infusion in 7/16 IVIG-treated patients, but this improvement was not sustained during the follow-up period. CONCLUSIONS: IVIG treatment appears to have short-term beneficial effects on muscle strength and dysphagia in some few sIBM patients, but these effects are not sustained over time. PMID- 22935196 TI - A putative role for amino acid permeases in sink-source communication of barley tissues uncovered by RNA-seq. AB - BACKGROUND: The majority of nitrogen accumulating in cereal grains originates from proteins remobilised from vegetative organs. However, interactions between grain filling and remobilisation are poorly understood. We used transcriptome large-scale pyrosequencing of flag leaves, glumes and developing grains to identify cysteine peptidase and N transporter genes playing a role in remobilisation and accumulation of nitrogen in barley. RESULTS: Combination of already known and newly derived sequence information reduced redundancy, increased contig length and identified new members of cysteine peptidase and N transporter gene families. The dataset for N transporter genes was aligned with N transporter amino acid sequences of rice and Arabidopsis derived from Aramemnon database. 57 AAT, 45 NRT1/PTR and 22 OPT unigenes identified by this approach cluster to defined subgroups in the respective phylogenetic trees, among them 25 AAT, 8 NRT1/PTR and 5 OPT full-length sequences. Besides, 59 unigenes encoding cysteine peptidases were identified and subdivided into different families of the papain cysteine peptidase clade. Expression profiling of full-length AAT genes highlighted amino acid permeases as the group showing highest transcriptional activity. HvAAP2 and HvAAP6 are highly expressed in vegetative organs whereas HvAAP3 is grain-specific. Sequence similarities cluster HvAAP2 and the putative transporter HvAAP6 together with Arabidopsis transporters, which are involved in long-distance transfer of amino acids. HvAAP3 is closely related to AtAAP1 and AtAAP8 playing a role in supplying N to developing seeds. An important role in amino acid re-translocation can be considered for HvLHT1 and HvLHT2 which are specifically expressed in glumes and flag leaves, respectively. PCA and K-means clustering of AAT transcript data revealed coordinate developmental stages in flag leaves, glumes and grains. Phloem-specific metabolic compounds are proposed that might signal high grain demands for N to distantly located plant organs. CONCLUSIONS: The approach identified cysteine peptidases and specific N transporters of the AAT family as obviously relevant for grain filling and thus, grain yield and quality in barley. Up to now, information is based only on transcript data. To make it relevant for application, the role of identified candidates in sink-source communication has to be analysed in more detail. PMID- 22935198 TI - Spatiotemporal dynamics of re-innervation and hyperinnervation patterns by uninjured CGRP fibers in the rat foot sole epidermis after nerve injury. AB - The epidermis is innervated by fine nerve endings that are important in mediating nociceptive stimuli. However, their precise role in neuropathic pain is still controversial. Here, we have studied the role of epidermal peptidergic nociceptive fibers that are located adjacent to injured fibers in a rat model of neuropathic pain. Using the Spared Nerve Injury (SNI) model, which involves complete transections of the tibial and common peroneal nerve while sparing the sural and saphenous branches, mechanical hypersensitivity was induced of the uninjured lateral (sural) and medial (saphenous) area of the foot sole. At different time points, a complete foot sole biopsy was taken from the injured paw and processed for Calcitonin Gene-Related Peptide (CGRP) immunohistochemistry. Subsequently, a novel 2D-reconstruction model depicting the density of CGRP fibers was made to evaluate the course of denervation and re-innervation by uninjured CGRP fibers. The results show an increased density of uninjured CGRP-IR epidermal fibers on the lateral and medial side after a SNI procedure at 5 and 10 weeks. Furthermore, although in control animals the density of epidermal CGRP-IR fibers in the footpads was lower compared to the surrounding skin of the foot, 10 weeks after the SNI procedure, the initially denervated footpads displayed a hyper-innervation. These data support the idea that uninjured fibers may play a considerable role in development and maintenance of neuropathic pain and that it is important to take larger biopsies to test the relationship between innervation of injured and uninjured nerve areas. PMID- 22935199 TI - Balancing selected medication costs with total number of daily injections: a preference analysis of GnRH-agonist and antagonist protocols by IVF patients. AB - BACKGROUND: During in vitro fertilization (IVF), fertility patients are expected to self-administer many injections as part of this treatment. While newer medications have been developed to substantially reduce the number of these injections, such agents are typically much more expensive. Considering these differences in both cost and number of injections, this study compared patient preferences between GnRH-agonist and GnRH-antagonist based protocols in IVF. METHODS: Data were collected by voluntary, anonymous questionnaire at first consultation appointment. Patient opinion concerning total number of s.c. injections as a function of non-reimbursed patient cost associated with GnRH agonist [A] and GnRH-antagonist [B] protocols in IVF was studied. RESULTS: Completed questionnaires (n = 71) revealed a mean +/- SD patient age of 34 +/- 4.1 yrs. Most (83.1%) had no prior IVF experience; 2.8% reported another medical condition requiring self-administration of subcutaneous medication(s). When out of-pocket cost for [A] and [B] were identical, preference for [B] was registered by 50.7% patients. The tendency to favor protocol [B] was weaker among patients with a health occupation. Estimated patient costs for [A] and [B] were $259.82 +/ 11.75 and $654.55 +/- 106.34, respectively (p < 0.005). Measured patient preference for [B] diminished as the cost difference increased. CONCLUSIONS: This investigation found consistently higher non-reimbursed direct medication costs for GnRH-antagonist IVF vs. GnRH-agonist IVF protocols. A conditional preference to minimize downregulation (using GnRH-antagonist) was noted among some, but not all, IVF patient sub-groups. Compared to IVF patients with a health occupation, the preference for GnRH-antagonist was weaker than for other patients. While reducing total number of injections by using GnRH-antagonist is a desirable goal, it appears this advantage is not perceived equally by all IVF patients and its utility is likely discounted heavily by patients when nonreimbursed medication costs reach a critical level. PMID- 22935201 TI - Epigenetic dysregulation of secreted frizzled-related proteins in myeloproliferative neoplasms complements the JAK2V617F-mutation. AB - BACKGROUND: Secreted frizzled-related proteins (SFRPs) are antagonists of the Wnt signaling pathway, which plays a central role in stem cell maintenance and differentiation of stem cells and hematopoietic progenitors. Epigenetic downregulation of SFRPs by promoter hypermethylation has been described to be involved in the pathogenesis of hematopoietic malignancies. There is an association between aberrant Wnt signaling and the established cancer stem cell concept. In contrast to BCR-ABL1-positive chronic myeloid leukemia CML, BCR-ABL1 negative myeloproliferative neoplasms (Ph-MPN) are characterized by the frequent occurrence of an autoactivating mutation in the JAK2 tyrosine kinase (JAK2V617F) or other mutations in the JAK-STAT pathway. However, pathogenetic mechanisms of JAK2 mutated or unmutated Ph-MPN remain not completely understood. We determined the promoter methylation status of SFRP-1, -2, -4, and -5 in 57 MPN patient samples by methylation-specific polymerase chain reaction (PCR) (MSP). JAK2V617F was assessed by allele-specific PCR. RESULTS: Aberrant methylation among primary MPN samples was 4% for SFRP-1, 25% for SFRP-2, 2% for SFRP-4, and 0% for SFRP-5. Hypermethylation of SFRP-2, which was the most frequently hypermethylated gene in our study, could not be correlated to any specific MPN subtype. However, we detected a significant correlation between SFRP-2 methylation and presence of a JAK2V617F mutation (P = 0.008). None of the 10 CML samples showed any SFRP methylation. CONCLUSIONS: Our data indicate that epigenetic dysregulation of the Wnt signaling pathway is a common event in MPN with aberrant methylation of at least one SFRP being detected in 25% of the primary patient samples and in 30% if only accounting for Ph-MPN. A significant correlation between SFRP-2 methylation and presence of JAK2V617F in our data supports the hypothesis that epigenetic dysregulation may be a complementary mechanism to genetic aberrations. Aberrant methylation of crucial stem cell maintenance genes seems to contribute to disease pathogenesis in Ph-MPN. PMID- 22935200 TI - Comparative study of elderly-onset rheumatoid arthritis and young-onset rheumatoid arthritis in a Colombian population: clinical, laboratory and HLA-DRB1 findings. AB - OBJECTIVES: Elderly-onset rheumatoid arthritis (EORA) is considered to have different features in relation to young-onset rheumatoid arthritis (YORA). However, results from different evaluated populations worldwide have been inconsistent and in Colombia there are no known descriptions of the differences between these pathologies. The aim of this paper is to compare the clinical, laboratory and immunogenetic features in a Colombian population suffering with EORA and YORA. METHODS: EORA (>=65, n=104) and YORA (<65, n=96) patients were compared regarding clinical, laboratory and HLA-DRB1 alleles features. A control group without rheumatoid arthritis over 65 (n=179) was used to compare the HLA DRB1 alleles. All patients met the ACR/1987 criteria for rheumatoid arthritis and the clinimetric index was calculated. RESULTS: The gender ratio (female/male) was 1.8:1 in EORA. In both groups, the main onset pattern of disease was an insidious polyarticular onset (p=0.35). EORA was characterised by more distal-proximal joint involvement in comparison to YORA (p=0.0007). In EORA, the rheumatoid factor and anti-cyclic citrullinated peptide (anti-CCP) antibodies frequency was close to 50%, lower than in YORA (63%). In both groups, the DAS28 and HAQ-DI score was higher than 6 and 1, respectively. The HLA-DRB1*0403 and *1402 frequency was significantly higher in EORA than in YORA. Also, the shared epitope (p=0.0392), HLA-DRB1*01 (p=0.0068) and *0101 (p=0.0151) were associated with an anti-CCP positivity and the HLA-DRB1*0403 is protective for the anti-CCP presence in EORA (p=0.0201). CONCLUSIONS: EORA is characterised by a different clinical presentation and HLA-DRB1 alleles with respect to YORA. HLA-DRB1*0403 and *1402 are significantly more frequent in EORA compared to YORA. PMID- 22935202 TI - Associations of plasma phospholipid fatty acids with plasma homocysteine in Chinese vegetarians. AB - The association of plasma phospholipid (PL) fatty acid composition with plasma homocysteine (Hcy) in Chinese vegetarians is not understood. The main aim of the present study was to investigate the plasma PL fatty acid status, and its association with plasma Hcy in Chinese vegetarians and omnivores. A total of 103 male vegetarians and 128 male omnivores were recruited in Linyin Temple, Hangzhou. Plasma Hcy and PL fatty acid concentrations were determined by standard methods. Compared with omnivores, plasma PL n-3 PUFA (P< 0.001), 22 : 6n-3 (P< 0.001), 22 : 5n-6 (P= 0.021), 22 : 2n-6 (P< 0.001) and SFA (P= 0.017) were significantly lower, while plasma PL n-6 PUFA (P= 0.007) and total PUFA (P< 0.001) were significantly higher in vegetarians. The prevalence of hyperhomocysteinaemia (HHcy) in vegetarians (26.47 %) was significantly higher than that in omnivores (13.28 %). In vegetarians, plasma PL 22 : 6n-3 (r - 0.257, P= 0.046) was significantly negatively associated with plasma Hcy. In omnivores, plasma PL 18 : 1n-7 (r 0.237, P= 0.030) was significantly positively associated with plasma Hcy. Plasma PL 22 : 6n-3 (r - 0.217, P= 0.048) was negatively associated with plasma Hcy in omnivores. Plasma PL SFA were positively associated with the prevalence of HHcy. It would seem appropriate for vegetarians to increase their dietary n-3 PUFA and decrease dietary SFA, and thus reduce the risk of HHcy. PMID- 22935203 TI - Ultrasonographic predictors for the development of joint damage in rheumatoid arthritis patients: a single joint prospective study. AB - OBJECTIVES: This paper aims to evaluate if any ultrasonographic aspect of metacarpo-phalangeal (MCP) joint can be predictors for the development of new joint damage, at single joint level, in rheumatoid arthritis (RA) patients. METHODS: Two hundred and forty MCP joints of 24 patients with RA were prospectively evaluated both clinically and by ultrasound (US) at time 0, at six months and 12 months, in order to collect the following variables: presence of synovial hypertrophy and power-Doppler (PD) vascularisation both graded on a semiquantitative (0-3) scale, and the number and dimension of bone erosions. X ray examinations were carried out at time 0 and at 12 months and lesions were graded using the Sharp/van der Heijde (S/vdH) method at single joint level. Potential prognostic determinants for joint damage obtained at the first examination and during follow-up were entered in a conditional logistic regression analysis. RESULTS: Fifteen out of seventeen (88%) of the new eroded joints on x-rays examination had persistent PD vascularity and 14/17 (82%) had persistent synovial thickening (p=0.001 and p=0.02, vs. non-eroded joints, respectively). In multiple conditional logistic regression analysis, the most important factor associated with the development of radiological joint damage was the presence of a synovial PD score >=2 on two or more US evaluations (OR 8.51 [95%CI 1.84-39.48] for Rx new erosions and OR 8.30 [95%CI 1.97-38.9] for increased S/vdH local joint score). Both baseline synovial score >=2 and presence of Rx erosions were also significantly associated with the development of radiological joint damage. Two predictive models for x-ray erosions and total single joint level S/vdH damage score were constructed consisting of 2 baseline plus one longitudinal variable with a ROC AUC of 0.916 (95%CI 0.867-0.965) and 0.886 (95%CI 0.814-0.957). CONCLUSIONS: At the single joint level, the presence of US determined synovial thickness and PD signal at baseline and the persistent PD signal over time have relevant prognostic value for the development of articular damage in the same MCP joints of RA patients. PMID- 22935205 TI - Advances in therapeutic vaccines for pancreatic cancer. AB - Pancreatic cancer is one of the most difficult-to-treat cancers. Despite surgical resection, radiation and/or chemotherapy, greater than 94% of people with pancreatic cancer do not survive beyond 5 years. In fact, median survival after diagnosis of metastatic pancreatic cancer is 4.5 months. The majority of patients are diagnosed with nonresectable, metastatic disease, and chemotherapy only extends their median survival by less than 2 months with only 18% of those treated surviving beyond 1 year. Despite the severity of their disease, most patients exhibit tumor specific cellular immunity to their pancreatic cancer antigens. Obviously their immunity is ineffective in preventing tumor growth. Recent studies have demonstrated that the tumor microenvironment may hold the key to determining the nature of the tumors' ability to escape from immune attack. Preliminary clinical trials have suggested that blocking these escape mechanisms may result in survival benefit to the patients, and phase I and II clinical trials with tumor vaccines have led to some survival benefits. Perhaps combining therapies directed against immune escape mechanisms with tumor vaccines will result in even greater survival benefit for patients with pancreatic cancer. While therapeutic vaccines for pancreatic cancers have been reviewed previously (Plate, 2011), updates on recent preliminary reports of two clinical vaccine trials are worthy of our attention. PMID- 22935204 TI - Molecular correlates and prognostic significance of SATB1 expression in colorectal cancer. AB - BACKGROUND: Special AT-rich sequence-binding protein 1 (SATB1) is a global gene regulator that has been reported to confer malignant behavior and associate with poor prognosis in several cancer forms. SATB1 expression has been demonstrated to correlate with unfavourable tumour characteristics in rectal cancer, but its association with clinical outcome in colorectal cancer (CRC) remains unclear. In this study, we examined the prognostic impact of SATB1 expression in CRC, and its association with important molecular characteristics; i.e. beta-catenin overexpression, microsatellite instability (MSI) screening status, and SATB2 expression. METHODS: Immunohistochemical expression of SATB1 and beta-catenin was assessed in tissue microarrays with tumours from 529 incident CRC cases in the prospective population-based Malmo Diet and Cancer Study, previously analysed for SATB2 expression and MSI screening status. Spearmans Rho and Chi-Square tests were used to explore correlations between SATB1 expression, clinicopathological and investigative parameters. Kaplan Meier analysis and Cox proportional hazards modelling were used to explore the impact of SATB1 expression on cancer specific survival (CSS) and overall survival (OS). RESULTS: SATB1 was expressed in 222 (42%) CRC cases and negative, or sparsely expressed, in adjacent colorectal mucosa (n = 16). SATB1 expression was significantly associated with microsatellite stable tumours (p < 0.001), beta-catenin overexpression (p < 0.001) and SATB2 expression (p < 0.001). While not prognostic in the full cohort, SATB1 expression was significantly associated with poor prognosis in SATB2 negative tumours (HR = 2.63; 95% CI 1.46-4.71; p(interaction) = 0.011 for CSS and HR = 2.31; 95% CI 1.32-4.04; p(interaction) = 0.015 for OS), remaining significant in multivariable analysis. CONCLUSIONS: The results of this study demonstrate that SATB1 expression in CRC is significantly associated with beta catenin overexpression, microsatellite stability and SATB2 expression. Furthermore, SATB1 expression is a factor of poor prognosis in SATB2 negative tumours. Altogether, these data indicate an important role for SATB1 in colorectal carcinogenesis and suggest prognostically antagonistic effects of SATB1 and SATB2. The mechanistic basis for these observations warrants further study. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1922643082772076. PMID- 22935206 TI - Tracking the seed and tending the soil: evolving concepts in metastatic breast cancer. AB - Metastasis, the process whereby cancer cells spread from their primary site of origin and grow in adjacent or distant sites, is the primary cause of death in cancer patients. The last 30 years has witnessed significant progress in decreasing cancer mortality rates--largely as a result of improved screening and prevention, practical applications of cancer genomics, and less toxic, more targeted therapies. Despite these improvements, metastasis relentlessly drives mortality. The pervasive mortality from metastasis highlights the shortcomings of traditionally accepted hypotheses on the metastatic process. Historically, metastasis has been described as a unidirectional process, whereby cancer cells leave a primary tumor and seed metastasis in regional lymph nodes or distant sites. This anatomically based hypothesis has dictated much of our medical, and in particular, surgical approach to treating cancers. Alternatively, recent research indicates that metastasis is a multidirectional process whereby cancer cells can seed distant sites as well as the primary tumor itself. The multidirectional pathway of cancer cells, termed "self-seeding," has been corroborated in several experimental and clinical models. This review will evaluate the "self-seeding" hypothesis with attention both to the "seed" (cancer cells) as well as the "soil" (premetastatic niche). Increasingly, the role of the microenvironment surrounding metastases appears essential to the survival of metastatic colonies. The self-seeding model depends not only on the inherent mobility of cancer cells, but also on the supporting non-cancerous cells which enable circulating tumors cells to migrate to and survive in distant sites. The recognition that some of these non-cancerous cells include key components of the immune system has re-ignited the field of immunotherapy in cancer. One particular area of immunotherapy research, tumor entrained neutrophils, will be reviewed in more depth. Ultimately, understanding the dynamic interplay between cancer cells and the metastatic niche offers fertile ground for progress both in the treatment and prevention of metastasis. PMID- 22935207 TI - Clostridium difficile: an emerging pathogen in children. AB - Clostridium difficile is emerging as an important enteric pathogen in children. Historically considered as an asymptomatic colonizer of the gastrointestinal tract, C. difficile infection (CDI) has not been well-studied in pediatric populations. While asymptomatic carriage remains high among infants, recent epidemiological surveillance has demonstrated a rise in the prevalence of CDI in both healthcare and community settings, particularly in children 1-5 years of age. The pathogenesis of pediatric CDI, including the factors underlying the absence of toxin-mediated effects among colonized infants, remains ill-defined. Studies suggest that traditional adult CDI risk factors such as antibiotic and healthcare exposure may not be as important for children who acquire CDI in the community. As recognition of the significant impact of CDI in children increases, the pressing need for deepening our understanding of this disease and identifying optimal therapeutic and preventative strategies is becoming apparent. PMID- 22935208 TI - Effects of AFP gene silencing on apoptosis and proliferation of a hepatocellular carcinoma cell line. AB - Alpha fetoprotein (AFP) is an oncoembryonal protein that is highly expressed in the majority of hepatocellular carcinomas. Previous studies have shown that AFP may be involved in multiple cell growth regulating, differentiating, and immunosuppressive activities. We investigated the effects of AFP gene silencing by siRNA on apoptosis and proliferation of hepatocellular carcinoma cell line EGHC-9901, which highly expresses AFP and may serve as an ideal model for investigation of AFP functions. siRNA expressing plasmid targeting the AFP gene was first established and subsequently transfected into hepatocellular carcinoma cell line EGHC-9901; cells were then divided into three groups: siRNA-afp, transfected with AFP-siRNA; siRNA-beta-actin, transfected with siRNA-beta-actin as the positive group; and vector control, transfected with empty vector as the blank control group. After G418 positive clone selection for a couple of weeks, Western blot and RT (reverse transcription)-PCR assay demonstrated that AFP expression was almost completely inhibited by siRNA-afp, which indicates that siRNA expressing plasmid targeting the AFP gene has been successfully established. Furthermore, MTT (methyl thiazolyl tetrazelium) assay showed that cells transfected with siRNA-afp proliferated at a significantly lower speed than the other two groups and flat plate clone formation assay also witnessed less clones with diameters of more than 75 MUm in siRNA-afp immunofluorescence indicating that the apoptosis rate of cells transfected with siRNA-afp was significantly higher than the other two groups. Furthermore, flow cytometry manifested approximately 20% more cells of siRNA-afp within G1 phase than those of the negative group, indicating that inhibition of AFP expression may cause G1 phase arrest. Finally, Western blot and RT-PCR assay demonstrated that siRNA-afp induced a higher expression of caspase-3 than the other two groups whereas there was no difference in expression of caspase-8, caspase-9, and Bcl-2 between the three groups. PMID- 22935209 TI - Cervical cancer: prevention and treatment. AB - Cervical cancer is the commonest cancer cause of death among women in developing countries and efforts to prevent the disease using newer approaches and HPV vaccination need to be explored. Detection of cervical cancer at an early stage is associated with excellent survival but most women in developing countries present with advanced and often untreatable disease, with very poor survival. The ratio between incidence and mortality from cervical cancer remains very high, largely due to lack of access to appropriate anti-cancer therapies in developing countries. In developed countries with functional screening programs, cervical cancer has been rendered a relatively rare disease. Ongoing efforts to refine the characteristics of screening tests continue, as does implementation of current HPV vaccines for the primary prevention of cervical cancer. PMID- 22935210 TI - Update in liver transplantation. AB - Successful transplant outcomes require optimal patient selection and timing. Currently the major limitation facing liver transplant centers is the shortage of organs. The limited availability of organs has led to long waiting periods for liver transplantation and consequently many patients become seriously ill or die while on the waiting list. This has major implications in the selection of patients, as well as the timing of transplant, for optimal use of these scarce organs. Indications and contraindications have changed slightly over the years and will be reviewed in this article. Timing for transplantation has changed more dramatically in recent years since major changes to organ allocation systems have been undertaken to provide clinicians with a better way to prioritize patients for liver transplant. PMID- 22935211 TI - Network medicine approaches to the genetics of complex diseases. AB - Complex diseases are caused by perturbations of biological networks. Genetic analysis approaches focused on individual genetic determinants are unlikely to characterize the network architecture of complex diseases comprehensively. Network medicine, which applies systems biology and network science to complex molecular networks underlying human disease, focuses on identifying the interacting genes and proteins which lead to disease pathogenesis. The long biological path between a genetic risk variant and development of a complex disease involves a range of biochemical intermediates, including coding and non coding RNA, proteins, and metabolites. Transcriptomics, proteomics, metabolomics, and other -omics technologies have the potential to provide insights into complex disease pathogenesis, especially if they are applied within a network biology framework. Most previous efforts to relate genetics to -omics data have focused on a single -omics platform; the next generation of complex disease genetics studies will require integration of multiple types of -omics data sets in a network context. Network medicine may also provide insight into complex disease heterogeneity, serve as the basis for new disease classifications that reflect underlying disease pathogenesis, and guide rational therapeutic and preventive strategies. PMID- 22935212 TI - Sentinel node studies in truncal melanoma: does an increased number of draining basins correlate with an increased risk of lymph metastasis? AB - OBJECTIVES: To assess whether an association exists between drainage to multiple basins and lymphatic metastasis in patients with truncal melanoma. METHODS: We retrospectively reviewed 227 patients with primary malignant melanoma between January 2006 and December 2009. All patients received an intradermal injection of (99m)Tc-nanocolloid and lymphoscintigraphy followed by sentinel node biopsy. Pre staging histology with Breslow thickness from excision biopsy was also obtained. RESULTS: 82/227 (36%) patients with primary truncal melanoma were identified. Nodal histology was positive for metastatic disease in 27/82 (32.9%) patients. Of these 27, 15 had 1 basin of drainage, 7 had 2 basins of drainage and 5 had 3 basins of drainage. Of the 55 node-negative patients, 35 had 1 basin, 18 had 2 basins and 2 had 3 basins of drainage. We found no significant correlation with sentinel node positivity and those that had >=2 drainage basins. Breslow thickness was available in 65/82(79.2%) patients. Sentinel node biopsy was positive in 6/28 patients who had <1.5 mm thickness, 8/14 who had a 1.5-3.9 mm thickness and 9/23 who had >=4 mm thickness. There was a significant correlation between Breslow thickness of >=4 mm and nodal positivity (P = 0.03). CONCLUSION: This study demonstrates no association between multiple drainage basins and sentinel node histology. Sentinel lymph node status did correlate with Breslow thickness. PMID- 22935213 TI - Reliance on social security benefits by Swedish patients with ill-health attributed to dental fillings: a register-based cohort study. AB - BACKGROUND: Some people attribute their ill health to dental filling materials, experiencing a variety of symptoms. Yet, it is not known if they continue to financially support themselves by work or become reliant on different types of social security benefits. The aim of this study was to analyse reliance on different forms of social security benefits by patients who attribute their poor health to dental filling materials. METHODS: A longitudinal cohort study with a 13-year follow up. The subjects included were 505 patients attributing their ill health to dental restorative materials, who applied for subsidised filling replacement. They were compared to a cohort of matched controls representing the general population (three controls per patient). Annual individual data on disability pension, sick leave, unemployment benefits, and socio-demographic factors was obtained from Statistics Sweden. Generalized estimating equations were used to test for differences between cohorts in number of days on different types of social security benefits. RESULTS: The cohort of dental filling patients had a significantly higher number of days on sick leave and disability pension than the general population. The test of an overall interaction effect between time and cohort showed a significant difference between the two cohorts regarding both sick leave and disability pension. In the replacement cohort, the highest number of sick-leave days was recorded in the year they applied for subsidised replacement of fillings. While sick leave decreased following the year of application, the number of days on disability pension increased and peaked at the end of follow-up. CONCLUSIONS: Ill health related to dental materials is likely to be associated with dependence on social security benefits. Dental filling replacement does not seem to improve workforce participation. PMID- 22935216 TI - Language spoken at home and parental birthplace moderate the association of race/ethnicity and distorted weight perception. AB - Distorted weight perception (DWP), specifically overestimating weight status, is common in adolescents and may lead to eating disorders. The authors examined the role of acculturation proxies as effect modifiers of the relationship between race/ethnicity and DWP in a diverse adolescent population. Analysis of the 2005 California Health Interview Survey showed that of 2955 adolescents with underweight or healthy weight status, 10.6% reported DWP. Latino adolescents had increased odds of DWP compared with white adolescents (adjusted odds ratio [aOR] = 3.02; 95% confidence interval [CI] = 2.00, 4.57). Latinos who spoke English and other language(s) at home (aOR = 3.38; 95% CI = 2.11, 5.41) and Latino (aOR = 5.00; 95% CI = 2.34, 10.72) and Asian (aOR = 3.10, 95% CI = 1.15, 8.35) adolescents who spoke no English at home had increased odds of DWP compared with white, English-only speakers. Latino adolescents had increased odds (aOR = 3.98, 95% CI = 2.45, 6.47) of DWP if neither parent was US born. Assessing acculturation proxies may help identify adolescents at risk of DWP. PMID- 22935215 TI - Obesity does not aggravate vitrification injury in mouse embryos: a prospective study. AB - BACKGROUND: Obesity is associated with poor reproductive outcomes, but few reports have examined thawed embryo transfer in obese women. Many studies have shown that increased lipid accumulation aggravates vitrification injury in porcine and bovine embryos, but oocytes of these species have high lipid contents (63 ng and 161 ng, respectively). Almost nothing is known about lipids in human oocytes except that these cells are anecdotally known to be relatively lipid poor. In this regard, human oocytes are considered to be similar to those of the mouse, which contain approximately 4 ng total lipids/oocyte. To date, no available data show the impact of obesity on vitrification in mouse embryos. The aim of this study was to establish a murine model of maternal diet-induced obesity and to characterize the effect of obesity on vitrification by investigating the survival rate and embryo developmental competence after thawing. METHODS: Prospective comparisons were performed between six-eight-cell embryos from obese and normal-weight mice and between fresh and vitrified embryos. Female C57BL/6 mice were fed standard rodent chow (normal-weight group) or a high-fat diet (obese group) for 6 weeks. The mice were mated, zygotes were collected from oviducts and cultured for 3 days, and six-eight-cell embryos were then selected to assess lipid content in fresh embryos and to evaluate differences in apoptosis, survival, and development rates in response to vitrification. RESULTS: In fresh embryos from obese mice, the lipid content (0.044 vs 0.030, P<0.01) and apoptosis rate (15.1% vs.9.3%, P<0.05)were significantly higher, the survival rate (83.1% vs. 93.1%, P<0.01) on day 5 was significantly lower, and embryo development was notably delayed on days 3-5 compared with the normal-weight group. After vitrification, no significant difference was found between thawed embryos from obese and normal-weight mice in apoptosis, survival, and development rates on days 4 and 5. In both groups, pre- and post-vitrification embryo apoptosis, survival, and development rates were similar. CONCLUSIONS: This study demonstrated that differences in survival and developmental rates between embryos from obese and normal-weight mice were eliminated after vitrification. Thus, maternal obesity does not aggravate vitrification injury, but obesity alone greatly impairs pre-implantation embryo survival and development. PMID- 22935217 TI - Bisphosphonates use in children. AB - Bisphosphonates are synthetic analogues of pyrophosphate that inhibit bone resorption by their action on osteoclasts. In recent years, bisphosphonates have been used in children for treatment of a growing number of disorders associated primarily with generalized or localized osteoporosis, genetic and acquired metabolic bone diseases, heterotopic calcifications in soft tissues, and for hypercalcemia. In this review, the authors address the role of and experience with bisphosphonate therapy in disorders of childhood. PMID- 22935214 TI - Intraspecific sequence comparisons reveal similar rates of non-collinear gene insertion in the B and D genomes of bread wheat. AB - BACKGROUND: Polyploidization is considered one of the main mechanisms of plant genome evolution. The presence of multiple copies of the same gene reduces selection pressure and permits sub-functionalization and neo-functionalization leading to plant diversification, adaptation and speciation. In bread wheat, polyploidization and the prevalence of transposable elements resulted in massive gene duplication and movement. As a result, the number of genes which are non collinear to genomes of related species seems markedly increased in wheat. RESULTS: We used new-generation sequencing (NGS) to generate sequence of a Mb sized region from wheat chromosome arm 3DS. Sequence assembly of 24 BAC clones resulted in two scaffolds of 1,264,820 and 333,768 bases. The sequence was annotated and compared to the homoeologous region on wheat chromosome 3B and orthologous loci of Brachypodium distachyon and rice. Among 39 coding sequences in the 3DS scaffolds, 32 have a homoeolog on chromosome 3B. In contrast, only fifteen and fourteen orthologs were identified in the corresponding regions in rice and Brachypodium, respectively. Interestingly, five pseudogenes were identified among the non-collinear coding sequences at the 3B locus, while none was found at the 3DS locus. CONCLUSION: Direct comparison of two Mb-sized regions of the B and D genomes of bread wheat revealed similar rates of non-collinear gene insertion in both genomes with a majority of gene duplications occurring before their divergence. Relatively low proportion of pseudogenes was identified among non-collinear coding sequences. Our data suggest that the pseudogenes did not originate from insertion of non-functional copies, but were formed later during the evolution of hexaploid wheat. Some evidence was found for gene erosion along the B genome locus. PMID- 22935219 TI - Hirschsprung disease in the older child: diagnostic strategies. AB - BACKGROUND: Hirschsprung disease is usually diagnosed in patients who are younger than 1 year; but in some individuals it is found later in childhood. OBJECTIVE: This retrospective study is focused on clinical signs and symptoms of Hirschsprung disease in older children. MATERIALS AND METHODS: Patients with Hirschsprung disease were included in the study if they were older than 14 months at the time of diagnosis. RESULTS: Ten patients older than 14 months were diagnosed with Hirschsprung disease; 7 were males and 3 females. In all, 60% had a positive history of recurrent gastrointestinal infection with vomiting and hospitalization. In 6 patients, the final diagnosis was delayed because of unspecific findings in contrast enema. Rectal biopsy confirmed the diagnosis in all patients. CONCLUSION: Contrast enema is not a specific method for diagnosing Hirschsprung disease. Rectal biopsy alone confirms the diagnosis and provides a clear indication for surgery. PMID- 22935218 TI - Efforts to identify at-risk children for blood lead screening in pediatric clinics--Clark County, Nevada. AB - BACKGROUND: Childhood lead poisoning continues to be a public health problem; however, lead screening rates remain low in many areas. Our objective is to increase screening in pediatric clinics, while testing a questionnaire for its predictability of elevated blood lead levels (BLLs). METHODS: Participants were approached at pediatric clinics in Las Vegas, Nevada. A brief questionnaire assessed the child's potential exposure to lead and a blood sample was collected from each child. RESULTS: Of 564 children tested, 35 had detectable BLLs. Two questions from the questionnaire demonstrated significant differences in proportions (Fisher's exact test: P < .05) of affirmative/negative responses, for the 35 participants with detectable BLLs. CONCLUSION: The questionnaire failed to identify reliable associations between detectable BLLs and affirmative responses, limiting its use as an in-office tool. More research is recommended to identify and alleviate barriers to childhood lead screening in the clinical setting and to develop more applicable risk assessment tools. PMID- 22935220 TI - Predictors of attrition from a clinical pediatric obesity treatment program. AB - OBJECTIVE: To assess the predictors of attrition from a clinical pediatric obesity treatment program. METHODS: We evaluated 2- through 20-year-old patients first seen at the Duke University Healthy Lifestyles Program between October 2006 and December 2008. We assessed the predictors of early dropout (not returning for any follow-up visits within 1 year) and of noncompletion (not attending at least 6 visits within 1 year after entry). RESULTS: The sample included 983 patients. In adjusted analyses, non-white non-Hispanic children were more likely to be early dropouts than white non-Hispanic children (odds ratio [OR] = 1.46, 95% confidence interval [CI] = 1.03-2.07). Non-white non-Hispanic children were more likely to be noncompleters than white non-Hispanic (OR = 1.56, 95% CI = 1.03 2.36) and Hispanic children (OR = 2.56, 95% CI = 1.34-4.90). CONCLUSIONS: Race/ethnicity predicted patient attrition. Investigation into this association and program modification are needed to reduce attrition in certain racial/ethnic groups. PMID- 22935221 TI - Risk of African swine fever introduction into the European Union through transport-associated routes: returning trucks and waste from international ships and planes. AB - BACKGROUND: The uncontrolled presence of African swine fever (ASF) in Russian Federation (RF) poses a serious risk to the whole European Union (EU) pig industry. Although trade of pigs and their products is banned since the official notification in June 2007, the potential introduction of ASF virus (ASFV) may occur by other routes, which are very frequent in ASF, and more difficult to control, such as contaminated waste or infected vehicles. This study was intended to estimate the risk of ASFV introduction into the EU through three types of transport routes: returning trucks, waste from international ships and waste from international planes, which will be referred here as transport-associated routes (TAR). Since no detailed and official information was available for these routes, a semi-quantitative model based on the weighted combination of risk factors was developed to estimate the risk of ASFV introduction by TAR. Relative weights for combination of different risk factors as well as validation of the model results were obtained by an expert opinion elicitation. RESULTS: Model results indicate that the relative risk for ASFV introduction through TAR in most of the EU countries (16) is low, although some countries, specifically Poland and Lithuania, concentrate high levels of risk, the returning trucks route being the analyzed TAR that currently poses the highest risk for ASFV introduction into the EU. The spatial distribution of the risk of ASFV introduction varies importantly between the analyzed introduction routes. Results also highlight the need to increase the awareness and precautions for ASF prevention, particularly ensuring truck disinfection, to minimize the potential risk of entrance into the EU. CONCLUSIONS: This study presents the first assessment of ASF introduction into the EU through TAR. The innovative model developed here could be used in data scarce situations for estimating the relative risk associated to each EU country. This simple methodology provides a rapid and easy to interpret results on risk that may be used for a target and cost-effective allocation of resources to prevent disease introduction. PMID- 22935222 TI - The citrus flavanone naringenin suppresses CYP1B1 transactivation through antagonising xenobiotic-responsive element binding. AB - Exposure to environmental toxicants or exogenous oestrogen increases the risk of cancer. Some toxicants such as polycyclic aromatic hydrocarbons (PAH) undergo biotransformation to become genotoxic agents. Cytochrome p450 (CYP) 1B1 is an enzyme catalysing this transformation. Consumption of fruit and vegetables is considered to be protective against carcinogenesis, and naringenin can be found abundantly in citrus fruits. In the present study, the effect of naringenin on the regulation of CYP1B1 was investigated in MCF-7 cells. Enzyme inhibition assays revealed that naringenin inhibited CYP1B1 at or above 5 MUm but not CYP1A1 activity. Quantitative PCR analysis also demonstrated that 1 MUm-naringenin reduced CYP1B1 mRNA expression induced by 7,12-dimethylbenz(alpha)anthracene (DMBA). Further study illustrated that the suppression was at the transcriptional level. Since previous studies have shown that oestrogen response element (ERE) and xenobiotic-responsive element (XRE) are functional binding sequences in the promoter region of CYP1B1, interference of DNA binding on these two elements was pursued. Employing reporter gene assays as well as the electromobility shift assay, we verified that naringenin counteracted DMBA-induced XRE binding at - 1675. These results supported the notion that fruit consumption could be a protective measure against PAH biotransformation. PMID- 22935223 TI - The in vivo rat skin photomicronucleus assay: phototoxicity and photogenotoxicity evaluation of six fluoroquinolones. AB - An in vivo photomicronucleus test (MNT) using rat skin, the target organ for photoirritancy and carcinogenicity, was recently described. The assay was evaluated using fluoroquinolone (FQ) antibiotics with varying degrees of phototoxic potency (i.e. sparflocacin [SPFX], lomefloxacin [LOFX], ciprofloxacin [CIFX], levofloxacin [LEFX], gemifloxacin [GEFX] and gatifloxacin [GAFX]) using a solar simulator producing both UVA and UVB (ratio 23:1). Experiments were performed at The Netherlands Organisation for Applied Scientific Research (TNO) and GlaxoSmithKline (GSK) to investigate interlaboratory variability, including evaluation of phototoxicity (clinical signs), micronucleus induction and histopathology. The potency of micronuclei (MN) formation in rat skin induced by the FQs was SPFX = LOFX > CIFX = LEFX, however, MN induction was only statistically significant for SPFX and LOFX. In both laboratories, GEFX and GAFX did not increase the MN frequencies compared to the irradiated vehicle control. Signs of phototoxicity, including clinical and histopathological changes, were observed with SPFX and LOFX to a similar degree as the positive control, 8 methoxypsoralen. In addition, there were some clinical signs of phototoxicity seen with CIFX, LEFX, GEFX and GAFX, but not always in both laboratories for CIFX, GEFX and GAFX and when observed, these were considered only mild. Of these, only LEFX also showed histopathological changes. In all studies, photogenotoxic potency correlated with photocarcinogenic potential and moreover, photogenotoxicity was not observed in the absence of phototoxicity. The results of the TNO/GSK study indicate that the in vivo rat skin photoMNT may be a promising tool for detection of photoclastogencity and photoirritancy in the skin/eye in the same animal. Given the association between the MNT and cancer, the skin photoMNT may also provide a promising tool for the early detection of photocarcinogenesis and help bridge the gap in the existing photosafety testing paradigm. PMID- 22935224 TI - Topoisomerase IIalpha levels and G2 radiosensitivity in T-lymphocytes of women presenting with breast cancer. AB - Previous studies from our laboratory have identified a link between intracellular topoisomerase IIalpha (topo IIalpha) levels and chromosomal radiosensitivity, as measured by the frequencies of chromatid breaks in the so-called G2-assay. Lower topo IIalpha levels were associated with reduced chromosomal radiosensitivity in cultured human cells. These findings supported a model, in which it is proposed that such chromatid breaks are the result of radiation-induced errors made by topoisomerase IIalpha during decatenation of chromatids. Studies from our and other laboratories, using the G2-assay, have shown that phytohaemagglutinin (PHA) stimulated peripheral blood T-lymphocytes from 40% of female breast cancer cases show elevated chromatid break frequencies when exposed to a small standard dose of ionizing radiation, i.e. elevated above the 90th percentile of a group of female control samples. In the present study we have used a modified G2-assay to test whether elevated frequency of chromatid breaks in breast cancer cases is linked with elevated intracellular topo IIalpha level in PHA-stimulated T lymphocytes, and also whether there is a general correlation between chromosomal radiosensitivity and topo IIalpha level. Our results confirm previous studies that 40% of breast cancer cases show elevated radiosensitivity as compared with controls. Also, the mean chromatid break frequency in breast cancer cases was significantly higher than in controls (P = 0.0001). We found that the mean topo IIalpha level in the cohort of breast cancer cases studied was significantly raised, as compared with controls (P = 0.0016), which could indicate a genetic propensity towards a raised intracellular production of topo IIalpha in these individuals. There was no direct correlation between chromosomal radiosensitivity and topo IIalpha level for individual samples either in the breast cancer cohort or in controls. However, a comparison between control and breast cancer samples shows a higher mean topo IIalpha level in breast cancer samples that correlates with the elevated mean chromatid break frequency seen in these patient samples. We found no meaningful correlations between either chromatid break frequency or topo IIalpha level and either tumour grade or hormone status. We conclude that elevated intracellular topo IIalpha level is likely to be a significant factor in determining the chromosomal response of stimulated T-lymphocytes from certain breast cancer cases. PMID- 22935225 TI - Elevated serum osteopontin levels in idiopathic retroperitoneal fibrosis. AB - OBJECTIVES: To investigate the role of serum osteopontin concentrations for monitoring idiopathic retroperitoneal fibrosis. METHODS: In 22 patients with idiopathic retroperitoneal fibrosis serum concentrations of osteopontin were measured by an enzyme-linked immunosorbant assay and related to retrospectively gathered clinical data, contrast enhanced magnetic resonance imaging studies, and laboratory parameters. Patients with secondary causes, an inflammatory abdominal aortic aneurysm, and immunoglobulin G4-associated idiopathic retroperitoneal fibrosis were excluded. Twenty-two healthy volunteers served as controls. RESULTS: Serum osteopontin concentrations of patients with idiopathic retroperitoneal fibrosis were elevated compared to healthy controls (p=0.017) and correlated with the transverse diameter of the periaortic cuff as determined by imaging studies (rho=0.549; p=0.008). Patients presenting with a diameter greater than 10mm had higher osteopontin concentrations than patients with smaller diameters (p=0.004). Increased inflammatory activity as determined by the presence of contrast enhancement in imaging studies (p<0.001) and the presence of typical symptoms (p=0.013) were associated with higher osteopontin concentrations. CONCLUSIONS: Serum osteopontin concentrations were elevated in patients with idiopathic retroperitoneal fibrosis. Increased concentrations correlated with the presence of clinical symptoms and extended disease or activity parameters on magnetic resonance imaging. PMID- 22935226 TI - Mumps virus inhibits migration of primary human macrophages toward a chemokine gradient through a TNF-alpha dependent mechanism. AB - Macrophages are an important cell type for regulation of immunity, and can play key roles in virus pathogenesis. Here we address the effect of infection of primary human macrophages with the related paramyxoviruses Parainfluenza virus 5 (PIV5) and Mumps virus (MuV). Monocyte-derived macrophages infected with PIV5 or MuV showed very little cytopathic effect, but were found to be defective in migration toward a gradient of chemokines such as macrophage colony stimulating factor (MCSF) and vascular endothelial growth factor (VEGF). For MuV infection, the inhibition of migration required live virus infection, but was not caused by a loss of chemokine receptors on the surface of infected cells. MuV-mediated inhibition of macrophage chemotaxis was through a soluble factor released from infected cells. MuV infection enhanced secretion of TNF-alpha, but not macrophage inhibitory factor (MIF). Antibody inhibition and add-back experiments demonstrated that TNF-alpha was both necessary and sufficient for MuV-mediate chemotaxis inhibition. PMID- 22935228 TI - A filtration method for rapid preparation of conjugates for immunoassay. AB - Modification of protein and other biopolymers by labeling them with small or macromolecules has become a very powerful research tool in biochemistry, molecular biology, diagnostics, and therapeutics. However, current methodologies available for their preparations are not straightforward and take several hours of incubation time. In this paper, we describe a new filtration-assisted technique for covalent conjugation between the reactive functional groups of two different molecules (small or macromolecules). Compared to the current method, this new approach significantly reduces the total reaction time from several hours to just a few minutes. The technique has been used for the preparation of conjugates of a small molecule to a protein such as biotin-BSA conjugate or small molecules to a small molecule such as biotin-tyramine conjugate or protein protein conjugation such as antibody-horseradish peroxidase conjugate. The procedure consists of filtering the reaction mixture multiple times through membrane micropores with the help of two syringes, which make the cross filtration process less laborious. The method saves time, allows conjugation of less than 1mg protein and produces conjugates better than those obtained by the current methods. Although the present technique has been applied on some common conjugation methods, it provides a potentially general method, and may further be expanded for the synthesis of several other macromolecular conjugates. PMID- 22935227 TI - Immune response and tolerability of varicella vaccine in children and adolescents with systemic lupus erythematosus previously exposed to varicella-zoster virus. AB - OBJECTIVES: The aim of the present paper is to evaluate the immune response and tolerability of varicella vaccine in children and adolescents with systemic lupus erythematosus previously exposed to varicella-zoster virus. METHODS: We performed a prospective and controlled study on a group of 54 SLE patients that were chosen at random to be or not to be vaccinated (28 were vaccinated and 26 were not). Twenty-eight healthy controls, of matching age and sex were also vaccinated. All were submitted to a questionnaire, physical evaluation and laboratory assays: lymphocyte immune-phenotyping by flow cytometry, plasma varicella zoster virus (VZV) serology by ELISA and in vitro interferon gamma (IFNgamma) production by T cells after stimulus with VZV antigen. They were evaluated before vaccination and at 30, 45, 180 and 360 days afterwards. RESULTS: We did not observe any differences in the frequency of adverse events in both vaccinated groups. At study entry, all individuals were seropositive for VZV antibodies. The serum VZV antibody titres similarly increased after vaccination. The frequency of flares and the SLEDAI score were also similar among the patients. Thirty days after vaccination the production of IFNgamma specific to VZV was lower in the SLE group compared to healthy controls. In the follow-up we observed 4 cases of herpes zoster in the SLE unvaccinated group, but no zoster in the vaccinated group. CONCLUSIONS: The varicella vaccine was well tolerated in SLE group, who had pre existing immunity to varicella. The varicella vaccine immunogenicity measurement by serum antibody titres was appropriate. The incidence of HZ was lower in the vaccinated lupus group. PMID- 22935229 TI - Altered sodium channel-protein associations in critical illness myopathy. AB - BACKGROUND: During the acute phase of critical illness myopathy (CIM) there is inexcitability of skeletal muscle. In a rat model of CIM, muscle inexcitability is due to inactivation of sodium channels. A major contributor to this sodium channel inactivation is a hyperpolarized shift in the voltage dependence of sodium channel inactivation. The goal of the current study was to find a biochemical correlate of the hyperpolarized shift in sodium channel inactivation. METHODS: The rat model of CIM was generated by cutting the sciatic nerve and subsequent injections of dexamethasone for 7 days. Skeletal muscle membranes were prepared from gastrocnemius muscles, and purification and biochemical analyses carried out. Immunoprecipitations were performed with a pan-sodium channel antibody, and the resulting complexes probed in Western blots with various antibodies. RESULTS: We carried out analyses of sodium channel glycosylation, phosphorylation, and association with other proteins. Although there was some loss of channel glycosylation in the disease, as assessed by size analysis of glycosylated and de-glycosylated protein in control and CIM samples, previous work by other investigators suggest that such loss would most likely shift channel inactivation gating in a depolarizing direction; thus such loss was viewed as compensatory rather than causative of the disease. A phosphorylation site at serine 487 was identified on the NaV 1.4 sodium channel alpha subunit, but there was no clear evidence of altered phosphorylation in the disease. Co immunoprecipitation experiments carried out with a pan-sodium channel antibody confirmed that the sodium channel was associated with proteins of the dystrophin associated protein complex (DAPC). This complex differed between control and CIM samples. Syntrophin, dystrophin, and plectin associated strongly with sodium channels in both control and disease conditions, while beta-dystroglycan and neuronal nitric oxide synthase (nNOS) associated strongly with the sodium channel only in CIM. Recording of action potentials revealed that denervated muscle in mice lacking nNOS was more excitable than control denervated muscle. CONCLUSION: Taken together, these data suggest that the conformation/protein association of the sodium channel complex differs in control and critical illness myopathy muscle membranes; and suggest that nitric oxide signaling plays a role in development of muscle inexcitability. PMID- 22935231 TI - First do no harm: counting the cost of chasing drug efficacy. PMID- 22935230 TI - Harnessing genomics to identify environmental determinants of heritable disease. AB - Next-generation sequencing technologies can now be used to directly measure heritable de novo DNA sequence mutations in humans. However, these techniques have not been used to examine environmental factors that induce such mutations and their associated diseases. To address this issue, a working group on environmentally induced germline mutation analysis (ENIGMA) met in October 2011 to propose the necessary foundational studies, which include sequencing of parent offspring trios from highly exposed human populations, and controlled dose response experiments in animals. These studies will establish background levels of variability in germline mutation rates and identify environmental agents that influence these rates and heritable disease. Guidance for the types of exposures to examine come from rodent studies that have identified agents such as cancer chemotherapeutic drugs, ionizing radiation, cigarette smoke, and air pollution as germ-cell mutagens. Research is urgently needed to establish the health consequences of parental exposures on subsequent generations. PMID- 22935232 TI - Childhood Philadelphia-chromosome-positive B-lymphoblastic leukaemia. PMID- 22935233 TI - Ayurveda: alternative or complementary? PMID- 22935234 TI - Circulating tumour cells in early breast cancer. PMID- 22935235 TI - Circulating tumour cells in early breast cancer. PMID- 22935237 TI - Epilepsy meets cancer: when, why, and what to do about it? AB - The lifetime risk of having epileptic seizures is profoundly increased in patients with cancer: about 20% of all patients with systemic cancer may develop brain metastases. These patients and those with primary brain tumours have a lifetime risk of epilepsy of 20-80%. Moreover, exposure to chemotherapy or radiotherapy to the brain, cancer-related metabolic disturbances, stroke, and infection can provoke seizures. The management of epilepsy in patients with cancer includes diagnosis and treatment of the underlying cerebral pathological changes, secondary prophylaxis with antiepileptic drugs, and limiting of the effect of epilepsy and its treatment on the efficacy and tolerability of anticancer treatments, cognitive function, and quality of life. Because of the concern of drug-drug interactions, the pharmacological approach to epilepsy requires a multidisciplinary approach, specifically in a setting of rapidly increasing choices of agents both to treat cancer and cancer-associated epilepsy. PMID- 22935238 TI - Real-time tumour tracking in particle therapy: technological developments and future perspectives. AB - A key challenge in radiation oncology is accurate delivery of the prescribed dose to tumours that move because of respiration. Tumour tracking involves real-time target localisation and correction of radiation beam geometry to compensate for motion. Uncertainties in tumour localisation are important in particle therapy (proton therapy, carbon-ion therapy) because charged particle beams are highly sensitive to geometrical and associated density and radiological variations in path length, which will affect the treatment plan. Target localisation and motion compensation methods applied in x-ray photon radiotherapy require careful performance assessment for clinical applications in particle therapy. In this Review, we summarise the efforts required for an application of real-time tumour tracking in particle therapy, by comparing and assessing competing strategies for time-resolved target localisation and related clinical outcomes in x-ray radiation oncology. PMID- 22935239 TI - Targeted gene delivery by free-tissue transfer in oncoplastic reconstruction. AB - Surgery is the most effective curative treatment for various tumour types. Despite a current preference for conservative surgery, radical excision retains a clearly defined role in modern management of locoregional disease. Extirpative defects are reconstructed routinely using free-tissue transfer from a distant donor site. Although these free flaps currently provide no direct therapeutic benefit, advances in gene-delivery techniques offer the possibility to genetically modify flaps to produce potent targeted treatments with greater anatomical control. Several promising therapeutic strategies, including virus directed enzyme prodrug therapy, genetic radionuclide therapy, and free-flap radioprotection, have the potential to extend the role of the free flap beyond its immediate goal of restoring form and function to patients, but challenges exist. Work to translate therapeutic free-tissue transfer from preclinical study to clinical use is in progress. PMID- 22935240 TI - Anterior resection syndrome. AB - Up to 80% of patients with rectal cancer undergo sphincter-preserving surgery. It is widely accepted that up to 90% of such patients will subsequently have a change in bowel habit, ranging from increased bowel frequency to faecal incontinence or evacuatory dysfunction. This wide spectrum of symptoms after resection and reconstruction of the rectum has been termed anterior resection syndrome. Currently, no precise definition or causal mechanisms have been established. This disordered bowel function has a substantial negative effect on quality of life. Previous reviews have mainly focused on different colonic reconstructive configurations and their comparative effects on daily function and quality of life. The present Review explores the potential mechanisms underlying disturbed functions, as well as current, novel, and future treatment options. PMID- 22935242 TI - Radiographers and trainee radiologists reporting accident radiographs: a comparative plain film-reading performance study. AB - AIM: To compare the diagnostic accuracy and clinical validity of reporting radiographers with that of trainee radiologists whom they have recently joined in reporting emergency room radiographs at Bispebjerg University Hospital. MATERIALS AND METHODS: Plain radiographs of the appendicular skeleton from 1000 consecutive emergency room patients were included in the study: 500 primarily reported by radiographers and 500 by trainee radiologists. The final reporting was subsequently undertaken by a consultant radiologist in consensus with an orthopaedic surgeon. Two observers classified reports as either true positive/negative or false positive/negative based on the final report, which was considered the reference standard. To evaluate the severity of incorrect primary reports, errors were graded into three categories concerning clinical impact and erroneous reports graded as the most severe category were subsequently analysed. Mann-Whitney and Chi-squared tests were used to compare differences and associations between radiographers versus trainee radiologists regarding film reporting. RESULTS: The sensitivity for correct diagnosis was 99% for reporting radiographers and 94% for trainee radiologists. The specificity was found to be 97% for reporting radiographers and 99% for trainee radiologists. Radiographers missed significantly fewer fractures (n = 2) than trainee radiologists (n = 14; p = 0.006) but had a higher, but not significant, degree of over-calling. No significant difference was found between groups regarding clinical impact of incorrect reporting. CONCLUSION: Trained radiographers report accident radiographs of the extremities with high accuracy and constitute a qualified resource to help meet increasing workload and demands in quality standards. PMID- 22935241 TI - A pragmatic cluster randomised trial evaluating three implementation interventions. AB - BACKGROUND: Implementation research is concerned with bridging the gap between evidence and practice through the study of methods to promote the uptake of research into routine practice. Good quality evidence has been summarised into guideline recommendations to show that peri-operative fasting times could be considerably shorter than patients currently experience. The objective of this trial was to evaluate the effectiveness of three strategies for the implementation of recommendations about peri-operative fasting. METHODS: A pragmatic cluster randomised trial underpinned by the PARIHS framework was conducted during 2006 to 2009 with a national sample of UK hospitals using time series with mixed methods process evaluation and cost analysis. Hospitals were randomised to one of three interventions: standard dissemination (SD) of a guideline package, SD plus a web-based resource championed by an opinion leader, and SD plus plan-do-study-act (PDSA). The primary outcome was duration of fluid fast prior to induction of anaesthesia. Secondary outcomes included duration of food fast, patients' experiences, and stakeholders' experiences of implementation, including influences. ANOVA was used to test differences over time and interventions. RESULTS: Nineteen acute NHS hospitals participated. Across timepoints, 3,505 duration of fasting observations were recorded. No significant effect of the interventions was observed for either fluid or food fasting times. The effect size was 0.33 for the web-based intervention compared to SD alone for the change in fluid fasting and was 0.12 for PDSA compared to SD alone. The process evaluation showed different types of impact, including changes to practices, policies, and attitudes. A rich picture of the implementation challenges emerged, including inter-professional tensions and a lack of clarity for decision-making authority and responsibility. CONCLUSIONS: This was a large, complex study and one of the first national randomised controlled trials conducted within acute care in implementation research. The evidence base for fasting practice was accepted by those participating in this study and the messages from it simple; however, implementation and practical challenges influenced the interventions' impact. A set of conditions for implementation emerges from the findings of this study, which are presented as theoretically transferable propositions that have international relevance. TRIAL REGISTRATION: ISRCTN18046709--Peri-operative Implementation Study Evaluation (POISE). PMID- 22935243 TI - Effects of computer-assisted oral anticoagulant therapy. AB - BACKGROUND: Computer-assistance and self-monitoring lower the cost and may improve the quality of anticoagulation therapy. The main purpose of this clinical investigation was to use computer-assisted oral anticoagulant therapy to improve the time to reach and the time spent within the therapeutic target range compared to traditional oral anticoagulant therapy by physicians. METHODS: 54 patients were randomized equally into 3 groups. Patients in two groups used CoaguChek(r) systems to measure international normalized ratio (INR) values and had dosages of anticoagulation treatment calculated in a computer system by an algorithm specific to each group. The third group received traditional anticoagulation treatment by physicians. The obtained INR values were compared regarding the time to reach, and the time spent within, the therapeutic target range, corresponding to INR values from 2 to 3. RESULTS: Patients randomized to computer-assisted anticoagulation and the CoaguChek(r) system reached the therapeutic target range after 8 days compared to 14 days by prescriptions from physicians (p = 0.04). Time spent in the therapeutic target range did not differ between groups. The median INR value measured throughout the study from all patients by CoaguChek(r) at 2.5 (2.42-2.62) was lower than measured by a hospital-based Clinical and Biochemical Laboratory at 2.6 (2.45-2.76), (p = 0.02). CONCLUSIONS: The therapeutic target range was reached faster by the use of computer-assisted anticoagulation treatment than prescribed by physicians, and the total time spent within the therapeutic target range was similar. Thus computer-assisted oral anticoagulant therapy may reduce the cost of anticoagulation therapy without lowering the quality. INR values measured by CoaguChek(r) were reliable compared to measurements by a clinical and biochemical laboratory. PMID- 22935244 TI - Maternal concentrations of polyfluoroalkyl compounds during pregnancy and fetal and postnatal growth in British girls. AB - BACKGROUND: Prenatal exposures to polyfluoroalkyl compounds (PFCs) may be associated with adverse changes in fetal and postnatal growth. OBJECTIVE: We explored associations of prenatal serum concentrations of perfluorooctane sulfonate (PFOS), perfluorooctanoate (PFOA), and perfluorohexane sulfonate (PFHxS) with fetal and postnatal growth in girls. METHODS: We studied a sample of 447 singleton girls and their mothers participating in the Avon Longitudinal Study of Parents and Children (ALSPAC). Data on weight and length were obtained at birth and at 2, 9, and 20 months. Serum samples were obtained in 1991-1992, from mothers during pregnancy. We explored associations between prenatal PFC concentrations and weight at birth as well as longitudinal changes in weight-for age SD scores between birth and 20 months. RESULTS: PFOS (median, 19.6 ng/mL), PFOA (median, 3.7 ng/mL), and PFHxS (median, 1.6 ng/mL) were detected in 100% of samples. On average, girls born to mothers with prenatal concentrations of PFOS in the upper tertile weighed 140 g less [95% confidence interval (CI): -238, -42] at birth than girls born to mothers with concentrations in the lower tertile in adjusted models. Similar patterns were seen for PFOA (-133 g; 95% CI: -237, -30) and PFHxS (-108 g; 95% CI: -206, -10). At 20 months, however, girls born to mothers with prenatal concentrations of PFOS in the upper tertile weighed 580 g more (95% CI: 301, 858) when compared with those in the lower tertile. No differences in weight were found for PFOA and PFHxS. CONCLUSIONS: Girls with higher prenatal exposure to each of the PFCs examined were smaller at birth than those with lower exposure. In addition, those with higher exposure to PFOS were larger at 20 months. PMID- 22935245 TI - Prevalence and socio-demographic correlates of the compliance with the physical activity guidelines in children and adolescents in Germany. AB - BACKGROUND: Regular physical activity (PA) is a prerequisite for normal growth and maturation, health, and fitness of children and adolescents. Because of the growing evidence of the health benefits of regular PA, several national and international public health organisations have established PA guidelines. The purpose of this study was to assess the percentage of children and adolescents in Germany who meet the PA guideline of 60 minutes of moderate-to-vigorous PA each day and to evaluate socio-demographic correlates of compliance with the PA guideline. METHODS: The sample consists of 4,529 children and adolescents aged between 4 and 17 years who lived and were registered in the Federal Republic of Germany between 2003 and 2006. The compliance with the PA guideline was assessed using a widely accepted screening measure. Socioeconomic status, immigration background and residential area were assessed using a parent questionnaire. RESULTS: Overall, 13.1% of girls and 17.4% of boys complied with the national guideline of 60 minutes of moderate-to-vigorous PA daily. While compliance was significantly lower in older participants of both gender groups, the steepest decrease in compliance was observed for age groups around the transition time from primary to secondary school. Logistic regression revealed that socioeconomic status and a migration background were significant predictors for compliance in girls and residential area for compliance in boys. CONCLUSIONS: Programs and policy action addressing the problem of decreasing compliance with PA guideline with increasing age are warranted. The transition from primary school to secondary school seems to be a critical stage in life with respect to PA behaviour. Therefore, specific interventions should aim at restructuring and reorganising their daily and physical activities during this transition. PMID- 22935246 TI - Prospective study of the use of healthcare resources and economic costs in patients with fibromyalgia after treatment in routine medical practice. AB - OBJECTIVES: To estimate the burden and to prospectively analyse resources utilisation and costs in a cohort of treated patients with fibromyalgia (FM) in daily practice. METHODS: Prospective, observational, multicentre, 3-month study in 232 patients with FM according to the ACR criteria (98% women, 47 years), with no concomitant systemic diseases, followed in rheumatology units. The control group consisted of 110 subjects without FM or any other systemic condition, paired by age and gender. Clinical assessment, use of healthcare resources and treatments, out-of-pocket expenses, occupational status, days off work, and calculation of lost workdays equivalents were recorded. RESULTS: Patients had worse clinical status, four times the control group's healthcare costs, twelve times its indirect costs and six times its total costs. After the treatment, there was significant clinical improvement in the patient group, the healthcare costs were significantly reduced in all components except for drugs costs, which increased (p<0.001), and out-of-pocket expenses, which remained unaltered. Indirect costs were reduced (p<0.05) in the FM group only, mainly due to fewer days off work. The patient group presented a significantly greater variation in montly total costs than the controls; -?193.75 +/- 781.9 vs. -?26.22 +/- 402.7, p=0.006. The patients who most reduced their healthcare costs were actively employed. CONCLUSIONS: Treated patients with FM in daily practice improved their clinical status and were accompanied by a significant reduction in the cost of the illness. The extra cost of drugs is substantially compensated for by less use of other healthcare resources and fewer days off work. PMID- 22935247 TI - Production of engineered long-life and male sterile Pelargonium plants. AB - BACKGROUND: Pelargonium is one of the most popular garden plants in the world. Moreover, it has a considerable economic importance in the ornamental plant market. Conventional cross-breeding strategies have generated a range of cultivars with excellent traits. However, gene transfer via Agrobacterium tumefaciens could be a helpful tool to further improve Pelargonium by enabling the introduction of new genes/traits. We report a simple and reliable protocol for the genetic transformation of Pelargonium spp. and the production of engineered long-life and male sterile Pelargonium zonale plants, using the pSAG12::ipt and PsEND1::barnase chimaeric genes respectively. RESULTS: The pSAG12::ipt transgenic plants showed delayed leaf senescence, increased branching and reduced internodal length, as compared to control plants. Leaves and flowers of the pSAG12::ipt plants were reduced in size and displayed a more intense coloration. In the transgenic lines carrying the PsEND1::barnase construct no pollen grains were observed in the modified anther structures, which developed instead of normal anthers. The locules of sterile anthers collapsed 3-4 days prior to floral anthesis and, in most cases, the undeveloped anther tissues underwent necrosis. CONCLUSION: The chimaeric construct pSAG12::ipt can be useful in Pelargonium spp. to delay the senescence process and to modify plant architecture. In addition, the use of engineered male sterile plants would be especially useful to produce environmentally friendly transgenic plants carrying new traits by preventing gene flow between the genetically modified ornamentals and related plant species. These characteristics could be of interest, from a commercial point of view, both for pelargonium producers and consumers. PMID- 22935248 TI - Strength of perceptual experience predicts word processing performance better than concreteness or imageability. AB - Abstract concepts are traditionally thought to differ from concrete concepts by their lack of perceptual information, which causes them to be processed more slowly and less accurately than perceptually-based concrete concepts. In two studies, we examined this assumption by comparing concreteness and imageability ratings to a set of perceptual strength norms in five separate modalities: sound, taste, touch, smell and vision. Results showed that concreteness and imageability do not reflect the perceptual basis of concepts: concreteness ratings appear to be based on two different intersecting decision criteria, while imageability ratings are visually biased. Analysis of lexical decision and word naming performance showed that maximum perceptual strength (i.e., strength in the dominant perceptual modality) consistently outperformed both concreteness and imageability ratings in accounting for variance in response latency and accuracy. We conclude that so-called concreteness effects in word processing emerge from the perceptual strength of a concept's representation and discuss the implications for theories of conceptual representation. PMID- 22935249 TI - Observations on house fly larvae midgut ultrastructure after Brevibacillus laterosporus ingestion. AB - The pathological and histopathological course caused by Brevibacillus laterosporus on house fly larvae has been investigated conducting observations on insect behavior and midgut ultrastructure. After dissection and fixation, gut tissues were analyzed under transmission electron microscopy (TEM) in order to compare in vivo-treated and non-treated (control) fly specimens. Treated larvae showed extensively reduced feeding and growth rate, then became sluggish and died within 72 h. A progressive midgut epithelium deterioration was observed in treated larvae, compared to the control. Ultrastructural changes consisted of microvilli disruption, cytoplasm vacuolization and general disorganization, endoplasmic reticulum deformation, mitochondria alteration. Deterioration became progressively more dramatic until the infected cells released their content into the gut lumen. Disruption was associated also with midgut muscular sheath and connective tissue. These ultrastructural changes are similar to those widely described for other entomopathogenic bacteria, such as Bacillus thuringiensis, against different insect species. The rapid disruption of cellular fine structure supports a hypothesis based on an interaction of toxins with the epithelial cell membranes reminiscent of the specific B. thuringiensis delta-endotoxins mechanism of action on other insect targets. PMID- 22935251 TI - Collaborating through association partnerships and association leadership. PMID- 22935250 TI - Hydration biomarkers in free-living adults with different levels of habitual fluid consumption. AB - Little is known about the impact of habitual fluid intake on physiology. Specifically, biomarkers of hydration status and body water regulation have not been adequately explored in adults who consume different fluid volumes in everyday conditions, without prolonged exercise or environmental exposure. The purpose of the present study was to compare adults with habitually different fluid intakes with respect to biomarkers implicated in the assessment of hydration status, the regulation of total body water and the risk of kidney pathologies. In the present cross-sectional study, seventy-one adults (thirty-two men, thirty-nine women, age 25-40 years) were classified according to daily fluid intake: thirty-nine low drinkers (LD; <= 1.2 litres/d) and thirty-two high drinkers (HD; 2-4 litres/d). During four consecutive days, urinary parameters (first morning urine (FMU) on day 1 and subsequent 24 h urine (24hU) collections), blood parameters, and food and beverage intake were assessed. ANOVA and non-parametric comparisons revealed significant differences between the LD and HD groups in 24hU volume (1.0 (se 0.1) v. 2.4 (se 0.1) litres), specific gravity (median 1.023 v. 1.010), osmolality (767 (se 27) v. 371 (se 33) mOsm/kg) and colour (3.1 (se 0.2) v. 1.8 (se 0.2)). Similarly, in the FMU, the LD group produced a smaller amount of more concentrated urine. Plasma cortisol, creatinine and arginine vasopressin concentrations were significantly higher among the LD. Plasma osmolality was similar between the groups, suggesting physiological adaptations to preserve plasma osmolality despite low fluid intake. The long-term impact of adaptations to preserve plasma osmolality must be examined, particularly in the context of renal health. PMID- 22935252 TI - The multigenerational perioperative nursing workforce: a celebration for labor day. PMID- 22935253 TI - Workplace safety equals patient safety. PMID- 22935254 TI - Intraoperatively acquired pressure ulcers and perioperative normothermia: a look at relationships. AB - The risk of developing an intraoperatively acquired pressure ulcer (IAPU), which is recognized as a significant complication of deep tissue injury occurrence, is associated with duration of surgery and patient positioning. There is a strong association between hypothermia, tissue viability, and surgical site infections; however, the relationship between hypothermia and pressure ulcers has not been fully explored. We examined the incidence of pressure ulcers in surgical patients and determined that there is a relationship between maintaining perioperative normothermia and a reduction in IAPU development. We used a retrospective, explanatory, nonexperimental design, and we fit a binary logistic model to the data. This study shows that patients at higher risk for developing an IAPU include those who are critically ill, have a low Braden Scale skin assessment score, are thin, and are male with at least a 1 degrees F (1.8 degrees C) drop in temperature. These are important risks for perioperative nurses to take into account during care of surgical patients. More perioperative research is needed to identify ways to reduce risk, provide close assessment of high-risk patients, and implement the identified risk-reduction strategies. PMID- 22935255 TI - The Braden Q+P: a pediatric perioperative pressure ulcer risk assessment and intervention tool. AB - Pressure ulcers continue to be a personally and financially expensive complication of surgery and hospitalization. The effects of anesthesia, immobilization during surgery, and use of multiple medical devices all place the surgical patient at high risk for pressure-related skin injury. As part of a comprehensive pressure ulcer prevention initiative, nurses in the cardiac and main ORs at Children's Hospital Boston, Massachusetts, became concerned that current pressure ulcer risk assessment tools did not adequately capture the intense but short-term risk posed in the operating and procedural suites. A team, formed to investigate this matter, developed a tool to guide nursing assessment of patient risk and to plan nursing interventions to prevent pressure ulcers. Results after implementation of the Braden Q+P tool appear to show improvement in preventing pressure ulcers. Increased awareness of pressure ulcer prevention, a hospital focus on skin care, and nursing education about pressure ulcers supported this improvement. PMID- 22935256 TI - Risk factors associated with incorrect surgical counts. AB - Incorrect surgical counts after surgery are a perplexing problem for nurses working in the perioperative environment. To determine factors associated with an incorrect surgical count, this cross-sectional, correlational study examined explanatory variables (eg, patient and nurse characteristics, intraoperative circumstances, staff involvement) by using data abstracted from perioperative medical records and primary data collected from perioperative nurses. In the final multivariate analysis, six variables were significantly associated with an incorrect surgical count: a higher surgical risk, a lower body mass index, a complicated procedure, an unplanned procedure, an increased number of perioperative personnel involved, and an increased number of specialty teams involved. PMID- 22935257 TI - Medication errors, routines, and differences between perioperative and non perioperative nurses. AB - Despite efforts to reduce the incidence of perioperative medication errors, these errors continue to be a problem. We examined written accounts from 16 nurses who discussed medication errors in the perioperative environment and 11 nurses who provided additional information about perioperative errors, nursing education, and the state of health care. Preoperative medication errors were the most frequently reported perioperative medication errors. Other reported errors involved intraoperative medication administration, IV sedation, and "close call" events. Reasons for errors included production pressure, complacency, and failure to follow established routines. We also identified evidence of self-blame and lack of understanding between nursing units and specialty areas. We compared attitudes and opinions of nurses working in perioperative settings with those of nurses working in non-perioperative areas and found both similarities and differences in the perceptions of medication errors and why they occur. PMID- 22935258 TI - Implementing AORN recommended practices for minimally invasive surgery: part I. AB - This article focuses on the patient safety aspects of the revised AORN "Recommended practices for minimally invasive surgery" (MIS). Key considerations include ensuring proper fluid management practices, assessing patients for risk factors related to MIS, implementing precautions for electrosurgery, planning for risks related to MIS, and assessing patients postoperatively for potential complications related to MIS. Collaboration and collegiality among members of the surgical team are essential for ensuring all pertinent aspects of care are recognized and considered. PMID- 22935259 TI - Preventing multidrug-resistant gram-negative organisms in surgical patients. AB - Multidrug-resistant gram-positive infections have consumed the attention of health care organizations as well as the media, but recently multidrug-resistant gram-negative organisms (MDR-GNOs) have become more and more prevalent. Limited treatment options are available for MDR-GNO infections; thus, prevention is key. Patients who are at high risk for developing infections must be identified, and specialized prevention interventions must be developed for their care. Surgical patients are one subset of patients at high risk for developing MDR-GNOs. Advanced practice nurses must support nurses and other health care personnel in preventing MDR-GNO infections. Education should include active surveillance, contact precautions, cohorting patients and staff members, unit closures, reinforced hand hygiene practices, and environmental cleaning tailored to the care of surgical patients in regard to their preoperative, intraoperative, and postoperative care. PMID- 22935260 TI - Role of the chaplain on the medical-surgical team. PMID- 22935262 TI - Do not disturb! PMID- 22935264 TI - A rare cause of hematochezia: colon mucormycosis. PMID- 22935263 TI - Cardiac mass in Behcet's disease. AB - Cardiac mass is a rare manifestation of Behcet's disease (BD). Intracardiac thrombosis, endomyocardiofibrosis, endocardial fibroelastosis, inflammatory mass and cystic change have been reported as different entities of cardiac mass in BD. Here we presented 6 cases of this rare manifestation of BD. The clinical and pathological features were reviewed. PMID- 22935265 TI - Acute graft-versus-host disease of bowel. PMID- 22935266 TI - Synchronous mandibular and giant parieto-occipital skull metastasis from hepatocellular carcinoma. PMID- 22935267 TI - Cat's-eye stone. PMID- 22935268 TI - Multimorbidity and comorbidity in the Dutch population - data from general practices. AB - BACKGROUND: Multimorbidity is increasingly recognized as a major public health challenge of modern societies. However, knowledge about the size of the population suffering from multimorbidity and the type of multimorbidity is scarce. The objective of this study was to present an overview of the prevalence of multimorbidity and comorbidity of chronic diseases in the Dutch population and to explore disease clustering and common comorbidities. METHODS: We used 7 years data (2002-2008) of a large Dutch representative network of general practices (212,902 patients). Multimorbidity was defined as having two or more out of 29 chronic diseases. The prevalence of multimorbidity was calculated for the total population and by sex and age group. For 10 prevalent diseases among patients of 55 years and older (N = 52,014) logistic regressions analyses were used to study disease clustering and descriptive analyses to explore common comorbid diseases. RESULTS: Multimorbidity of chronic diseases was found among 13% of the Dutch population and in 37% of those older than 55 years. Among patients over 55 years with a specific chronic disease more than two-thirds also had one or more other chronic diseases. Most disease pairs occurred more frequently than would be expected if diseases had been independent. Comorbidity was not limited to specific combinations of diseases; about 70% of those with a disease had one or more extra chronic diseases recorded which were not included in the top five of most common diseases. CONCLUSION: Multimorbidity is common at all ages though increasing with age, with over two-thirds of those with chronic diseases and aged 55 years and older being recorded with multimorbidity. Comorbidity encompassed many different combinations of chronic diseases. Given the ageing population, multimorbidity and its consequences should be taken into account in the organization of care in order to avoid fragmented care, in medical research and healthcare policy. PMID- 22935270 TI - Assisting people with disabilities improves their collaborative pointing efficiency through the use of the mouse scroll wheel. AB - This study provided that people with multiple disabilities can have a collaborative working chance in computer operations through an Enhanced Multiple Cursor Dynamic Pointing Assistive Program (EMCDPAP, a new kind of software that replaces the standard mouse driver, changes a mouse wheel into a thumb/finger poke detector, and manages mouse actions). The study used an ABAB design to evaluate whether four people (two pairs) with multiple disabilities, who have very limited voluntary muscle control and cannot use a standard mouse, would be able to improve their collaborative pointing performance using their finger poke ability with a mouse wheel through EMCDPAP software. The data showed that both pairs of participants improved their collaborative pointing efficiency through the use of the EMCDPAP software during the intervention phase. The practical and developmental implications of the findings are discussed. PMID- 22935269 TI - The relationship between the prefrontal activation during a verbal fluency task and stress-coping style in major depressive disorder: a near-infrared spectroscopy study. AB - This study aimed to identify coping styles used by patients with major depressive disorder (MDD) in comparison with those used by healthy controls, and to explore their association with prefrontal hemodynamic response related to a cognitive task. Regional hemodynamic changes were monitored during a verbal fluency task (VFT) using a 52-channel near-infrared spectroscopy (NIRS) apparatus in 26 MDD patients in depressive state and 30 matched healthy controls, and their correlation with coping styles assessed by Coping Inventory for Stressful Situations (CISS) were examined. We found the Emotion-oriented coping style was significantly higher, whereas the Task-oriented coping and Avoidance-oriented coping style were lower in the MDD group compared with controls. Emotion-oriented coping style positively correlated with subjective assessment of depression severity. Regional hemodynamic changes were significantly smaller in the MDD group than in the control group in prefrontal and temporal regions, and positively correlated with Task-oriented coping (adaptive coping) in the bilateral ventrolateral and dorsolateral prefrontal cortex, and the midline fronto-polar and bilateral orbitofrontal cortex regions. These findings suggest coping styles may be considered an important source of knowledge for patients who struggle with the illness and for mental health professionals who work with MDD patients, and that hemodynamic response in the ventrolateral and dorsolateral prefrontal cortex, midline fronto-polar, and orbitofrontal cortex regions during a VFT may reflect the adaptive coping (Task-oriented coping) style in MDD patients in depressive state. PMID- 22935271 TI - The convergent validity of the Questions About Behavioral Function scale and functional analysis for problem behavior displayed by individuals with autism spectrum disorder. AB - Only a few studies have compared the convergent validity of the Questions About Behavioral Function (QABF) scale to the results of functional analyses (FA). In the current study, six participants who emitted problem behaviors participated in either a brief, or a no-interaction-series FA, while each participant's parent completed the QABF. The results of the study showed that for five participants, the QABF and the FA identified the same non-social function. For one participant, the QABF and FA identified potentially dual functions. Based on our findings, we suggest that the QABF could be embedded within a five-step functional assessment protocol. PMID- 22935272 TI - Global suicide mortality rates - a light at the end of the tunnel? PMID- 22935274 TI - Simultaneous nephrectomy and coronary artery bypass grafting through extended sternotomy. AB - BACKGROUND: The advances in surgical techniques, resuscitation and anesthesiology support over the last years have allowed simultaneous thoracic and abdominal operations to be made for cancer and concomitant severe heart vessel disease relieving the patient from several diseases simultaneously and achieving long lasting remission or cure. CLINICAL CASE: A simultaneous nephrectomy and coronary artery bypass grafting procedure through extended sternotomy is reported. A 63 year-old man with severe coronary artery disease was found to have renal carcinoma. DIAGNOSIS: Postoperative pathological investigation of the tumor revealed the presence of renal cell carcinoma pT3a N0 M0, G2. Coronarography revealed advanced three-vessel coronary artery disease. TREATMENT: We successfully performed a simultaneous curative surgery for renal carcinoma and coronary artery bypass graft surgery under cardiopulmonary bypass using a novel technique of extended sternotomy. Simultaneous surgery thus appears to be a beneficial and safe approach for the treatment of coronary artery disease and resectable renal cancer in carefully selected patients. PMID- 22935275 TI - Mislabeling controlled clinical trials (CCTs) as "randomized clinical trials (RCTs)" in dental specialty journals. AB - OBJECTIVES: This study aimed to investigate whether studies published in dental journals with the highest impact factor, representing the 5 major dental specialties and titled as randomized clinical trials (RCTs) are truly RCTs. A second objective was to explore the association of journal type and other publication characteristics on correct classification. METHODS: The American Journal of Orthodontics and Dentofacial Orthopedics (AJODO), the British Journal of Oral and Maxillofacial Surgery (BJOMS), the International Journal of Prosthodontics (IJP), the Journal of Clinical Periodontology (JCP), and the Journal of Endodontics (JOE) were hand searched for clinical trials labeled in the title as randomized from 1979 to July 2011. The data were analyzed using descriptive statistics, and univariable and multivariable examination of statistical associations via ordinal logistic regression modeling (proportional odds model). RESULTS: A total of 222 trials were identified. From the included trials, 88 (39.64%) were considered to be RCTs, 107 (48.20%) were considered to be of unclear status, and 27 (12.16%) were not considered as RCTs. In the multivariable analysis among the included variables, journal type, involvement of statistician, year of publication, multicenter trial, and number of authors were significant predictors of correctly classifying a study as an RCT versus no RCT and of unclear status. CONCLUSIONS: This study indicates the need for clear and accurate reporting of clinical trials and the need for educating investigators on RCT methodology. PMID- 22935276 TI - Is the evidence supporting dental procedures strong? A survey of Cochrane systematic reviews in oral health. AB - BACKGROUND: Every day a large number and variety of dental procedures are performed in clinical dental practice. There is, however, no information on the overall quality of evidence supporting these procedures. The objective of this study was to assess whether several common dental procedures are based on sound evidence. METHODS: All Cochrane systematic reviews (CSR) published in dentistry were surveyed. The authors' conclusions about the quality of evidence supporting a specific clinical treatment were used as the measure of outcome. The evidence was considered adequate if the authors did not clearly state the evidence was weak in the conclusions while also suggesting some evidence of the effectiveness of the therapy. RESULTS: Of 120 CSRs assessed, in only 26 (22.0% of the reviews) was the quality of evidence regarded as adequate for supporting clinical decisions, although some methodological limitations were identified in the full text of these reviews. Moreover, the authors of most reviews reported weak or unavailable evidence. CONCLUSIONS: On the basis of CSRs, the overall quality of evidence can be regarded as low or nonexistent for most of the dental procedures assessed. The information reported may guide future research. PMID- 22935277 TI - Scaling and root planing performed on pregnant women with mild to moderate periodontal disease is not efficacious in reducing preterm birth, low birth weight, or other poor pregnancy outcomes. PMID- 22935278 TI - Tooth loss may be associated with increased circulatory mortality. PMID- 22935279 TI - There is limited evidence to support the association between severe mental illness and poor oral health. PMID- 22935280 TI - Extended antibiotic therapy may reduce risk of infection following orthognathic surgery. PMID- 22935281 TI - The partial removal of carious tissue may arrest caries progression in primary teeth. PMID- 22935282 TI - Among patients undergoing third molar extraction, amoxicillin administration preoperatively or postoperatively is likely to be more efficacious than placebo in preventing postoperative complications. PMID- 22935283 TI - Toothbrushing may reduce risk of metabolic syndrome. PMID- 22935284 TI - Gingival blood glucose may screen for type 2 diabetes in patients with periodontal disease. PMID- 22935285 TI - Assessing for dry mouth in patients with orofacial pain may be beneficial, but study does not provide evidence. PMID- 22935286 TI - Periodontal treatment combined with tongue cleaning reduces oral malodor among patients with periodontitis, whereas for patients with gingivitis, tongue cleaning alone is sufficient. PMID- 22935287 TI - Chemotherapy or radiation therapy carries a greater risk of stroke if it is not accompanied by surgery in patients younger than 55 with head and neck cancer. PMID- 22935288 TI - Screening for international normalized ratio in the dental office may provide useful information to prevent both hemorrhagic and thromboembolic events. PMID- 22935289 TI - Panoramic radiography is sensitive and specific for detection of calcified carotid arteries when compared with the screening test of color Doppler ultrasound. PMID- 22935290 TI - People with HIV may be more likely to seek preventive dental care if financial barriers to care are removed, are actively taking HIV medications, and are satisfied with their overall oral health. PMID- 22935291 TI - The association between periodontitis and high C-reactive protein in adults with chronic kidney disease is not clearly established. PMID- 22935292 TI - Dental x-rays and risk of meningioma; the jury is still out. PMID- 22935294 TI - Response to Bretz review J Evid Base Dent Pract 2011;11:194-195. PMID- 22935295 TI - Generic anti-drug antibody assay with drug tolerance in serum samples from mice exposed to human antibodies. AB - Knowledge of the anti-drug antibody (ADA) status is necessary in early research studies. Because specific assay materials are sparse and time is pressing, a generic assay format with drug tolerance for detection of ADAs in serum samples from mice exposed to immunoglobulin G (IgG) or antigen-binding fragments (Fabs) is highly desirable. This article describes a generic immune complex assay in the sandwich enzyme-linked immunosorbent assay (ELISA) format based on (i) transformation of free ADAs to immune complexes by preincubation with excess drug, (ii) the use of a murine anti-human Fab constant domain Fab as capture reagent, (iii) detection of the immune complexes by a peroxidase-labeled rabbit anti-murine Fc antibody, and (iv) ADA-positive control conjugates consisting of human Fab and murine IgG. Results of the experiments suggest that the generic immune complex assay for mouse serum samples was at least equivalent to specific ADA immune assays and even superior regarding drug tolerance. The generic immune complex assay confers versatility as it detects ADAs in complex with full-length IgG as well as with Fabs independent of the target specificity in mouse serum samples. These features help to save the sparse amounts of specific antibodies available in early research and development and speed up drug candidate selection. PMID- 22935297 TI - Towards parsimony in habit measurement: testing the convergent and predictive validity of an automaticity subscale of the Self-Report Habit Index. AB - BACKGROUND: The twelve-item Self-Report Habit Index (SRHI) is the most popular measure of energy-balance related habits. This measure characterises habit by automatic activation, behavioural frequency, and relevance to self-identity. Previous empirical research suggests that the SRHI may be abbreviated with no losses in reliability or predictive utility. Drawing on recent theorising suggesting that automaticity is the 'active ingredient' of habit-behaviour relationships, we tested whether an automaticity-specific SRHI subscale could capture habit-based behaviour patterns in self-report data. METHODS: A content validity task was undertaken to identify a subset of automaticity indicators within the SRHI. The reliability, convergent validity and predictive validity of the automaticity item subset was subsequently tested in secondary analyses of all previous SRHI applications, identified via systematic review, and in primary analyses of four raw datasets relating to energy-balance relevant behaviours (inactive travel, active travel, snacking, and alcohol consumption). RESULTS: A four-item automaticity subscale (the 'Self-Report Behavioural Automaticity Index'; 'SRBAI') was found to be reliable and sensitive to two hypothesised effects of habit on behaviour: a habit-behaviour correlation, and a moderating effect of habit on the intention-behaviour relationship. CONCLUSION: The SRBAI offers a parsimonious measure that adequately captures habitual behaviour patterns. The SRBAI may be of particular utility in predicting future behaviour and in studies tracking habit formation or disruption. PMID- 22935298 TI - Control of Allergic Rhinitis and Asthma Test (CARAT) can be used to assess individual patients over time. AB - BACKGROUND: The Control of Allergic Rhinitis and Asthma Test (CARAT10) has been proposed as the first tool to implement the Allergic Rhinitis and its Impact on Asthma initiative guidelines in clinical practice. To serve this purpose, it must have adequate properties to assess the control of an individual over time. This study aimed to prospectively assess the test-retest reliability, responsiveness and longitudinal validity of CARAT10. METHODS: Adults with asthma and allergic rhinitis were enrolled at 4 outpatient clinics of Portuguese central hospitals. At each of the two visits, 4 to 6 weeks apart, patients filled out CARAT10 and additional questionnaires, followed by a medical evaluation blinded to the questionnaires' answers. RESULTS: From the 62 patients included, 51 patients completely filled out CARAT10 at both visits. The test-retest reliability, computed as an intra-class correlation coefficient, was 0.82. Regarding responsiveness, a significant change (p = 0.002) of CARAT10 score in clinically unstable patients was observed (95%CI -5.08; -1.31) and the Guyatt's responsiveness index was 1.54. As for the longitudinal validity assessment, the correlation coefficients of the changes of CARAT10 scores with those of ACQ5 and symptoms VAS ranged from 0.49 to 0.65, while with the physician assessment of control they ranged from 0.31 to 0.41. CONCLUSION: CARAT10 has good test-retest reliability, responsiveness and longitudinal validity. It can be used to assess control of allergic rhinitis and asthma, both to compare groups in clinical studies and to evaluate individual patients in clinical practice. PMID- 22935296 TI - Simultaneous and sensitive detection of six serotypes of botulinum neurotoxin using enzyme-linked immunosorbent assay-based protein antibody microarrays. AB - Botulinum neurotoxins (BoNTs), produced by Clostridium botulinum, are a group of seven (A-G) immunologically distinct proteins and cause the paralytic disease botulism. These toxins are the most poisonous substances known to humans and are potential bioweapon agents. Therefore, it is necessary to develop highly sensitive assays for the detection of BoNTs in both clinical and environmental samples. In the current study, we have developed an enzyme-linked immunosorbent assay (ELISA)-based protein antibody microarray for the sensitive and simultaneous detection of BoNT serotypes A, B, C, D, E, and F. With engineered high-affinity antibodies, the BoNT assays have sensitivities in buffer ranging from 1.3fM (0.2pg/ml) to 14.7fM (2.2pg/ml). Using clinical and food matrices (serum and milk), the microarray is capable of detecting BoNT serotypes A to F to similar levels as in standard buffer. Cross-reactivity between assays for individual serotype was also analyzed. These simultaneous, rapid, and sensitive assays have the potential to measure botulinum toxins in a high-throughput manner in complex clinical, food, and environmental samples. PMID- 22935299 TI - Long-term clinical course of patients carrying the Q703K mutation in the NLRP3 gene: a case series. AB - BACKGROUND: Cryopyrin-associated periodic syndromes (CAPS) comprise a spectrum of apparently distinct, rare, autosomal dominant autoinflammatory disorders of increasing severity caused by NLRP3 gene mutations. The Q703K allele is a variant of unknown pathogenetic significance, and has been considered to be both a clinically unremarkable polymorphism and a low- penetrance mutation. OBJECTIVES: To analyse the long-term clinical course in a cohort of patients presenting with periodic fever attacks and carrying the Q703K mutation in the NLRP3 gene. METHODS: Seven Caucasian patients (mean age 37.3+/-8.5 years, 2 males and 5 females) were identified as carriers of the Q703K mutation among 71 patients with CAPS-like symptoms. RESULTS: The mean age at disease onset was 25.58+/-16.08 years and the mean disease duration was 12.28+/-8.36. The mean number of febrile episodes was 7.56+/-6.48 and the mean duration of fever attacks was 6.66+/-4.71 days. Six out of 7 patients had a low grade fever, while 1 patient had no fever episodes. All patients were characterised by symptoms consistent with recurrent inflammatory syndrome. Six patients out of 7 presented skin lesions, 4/7 arthralgia, 4/7 myalgia, 4/7 conjunctivitis, 3/7 headache. All patients also complained of severe fatigue. In 4/7 patients symptoms were triggered or worsened by generalised cold exposure. CONCLUSIONS: We suggest that patients carrying the low-penetrance Q703K mutation in the NLRP3 gene may present with FCAS-like symptoms. However, given the high frequency of healthy carriers, the role of additional, still unknown genetic and/or environmental modifiers is conceivable. PMID- 22935300 TI - Benign mullerian papilloma of the cervix. PMID- 22935301 TI - Hysteroscopic diagnosis of endometrial vascular dystrophy. PMID- 22935302 TI - Small bowel obstruction after hysterectomy to treat benign disease. AB - STUDY OBJECTIVE: To estimate the incidence of small bowel obstruction (SBO) after hysterectomy performed because of benign indications and to compare the incidence of SBO after laparoscopic, vaginal, and abdominal hysterectomy. DESIGN: Single center retrospective analysis of all hysterectomies performed to treat benign disease over 9 years (Canadian Task Force classification II-2). SETTING: University-affiliated tertiary medical center. PATIENTS: The study included 3229 women who underwent hysterectomy performed because of benign indications. INTERVENTIONS: International Classification of Diseases, 9th revision, codes were applied to eligible patients' medical records to identify those who potentially had an SBO. Again, the electronic medical record was reviewed to confirm the occurrence of SBO. The Fisher exact test was used to evaluate the relationship between SBO and categorical variables, and the Wilcoxon rank sum test was performed to evaluate the relationship between SBO and continuous variables. MEASUREMENTS AND MAIN RESULTS: During the 9-year study, 3229 women with benign disease underwent hysterectomy: 38.3% abdominal, 39.3% vaginal, and 22.3% laparoscopic. Seventeen of 3229 women (0.53%; 95% confidence interval, 0.32-0.86) who underwent hysterectomy were identified as having an SBO. Among hysterectomy types, the incidence of SBO was not statistically significant for abdominal hysterectomy (9 of 17), vaginal hysterectomy (5 of 17), or laparoscopic hysterectomy (3 of 17) (p = .58). There were no differences in demographic data between patients with and without SBO. Incidence rates for SBO were calculated on the basis of hysterectomy route. CONCLUSION: The incidence of SBO after hysterectomy performed because of benign indications is low. The hysterectomy route does not seem to affect risk of SBO. PMID- 22935303 TI - Value of magnetic resonance imaging in diagnosis of adenomyosis and myomas of the uterus. AB - STUDY OBJECTIVE: To estimate the diagnostic performance of magnetic resonance imaging (MRI) in detection of myomas and adenomyosis of the uterus. DESIGN: Prospective cohort observational study (Canadian Task Force classification II-2). SETTING: Department of obstetrics and gynecology, tertiary academic hospital. PATIENTS: One hundred fifty-three consecutive women with an enlarged uterus accompanied by gynecologic symptoms and/or with an asymptomatic pelvic mass. INTERVENTION: Total abdominal hysterectomy. All patients underwent MRI before the operation. MEASUREMENTS AND MAIN RESULTS: The sensitivity, specificity, positive, and negative predictive value of MRI for the diagnosis of uterine pathology was calculated using histologic findings as the standard criterion for final diagnosis. Receiver operating characteristics curves were constructed to describe the diagnostic performance of MRI. In the diagnosis of myomas, MRI demonstrated sensitivity of 94.1%, specificity of 68.7%, PPV of 95.7%, and NPV of 61.1%. In the diagnosis of adenomyosis, MRI demonstrated sensitivity of 46.1%, specificity of 99.1%, PPV of 92.3%, and NPV of 88.5%. The area under the curve (AUC) for the diagnostic performance of MRI in the detection of myomas and adenomyosis was 0.81 and 0.73, respectively. Uterine sarcoma was diagnosed in 5 patients; in these cases, MRI demonstrated sensitivity of 60.0%, specificity of 99.2%, PPV of 75.0%, and NPV of 98.4%. The AUC for MRI in the diagnosis of uterine sarcomas was 0.80. CONCLUSIONS: MRI exhibits a high AUC for the diagnosis of both adenomyosis and myomas. The PPV of MRI in the diagnosis of adenomyosis and myomas of the uterus is high as well. MRI seems to be a useful technique in everyday clinical practice in the diagnostic approach of these common conditions, enabling clinicians to select the most appropriate management. PMID- 22935304 TI - Accuracy of assessment of tubal patency with selective pertubation at office hysteroscopy compared with laparoscopy in infertile women. AB - STUDY OBJECTIVE: To estimate the accuracy of the assessment of tubal patency using selective pertubation with office hysteroscopy compared with laparoscopy in infertile women. METHOD: Selective pertubation with office hysteroscopy was also performed in 35 infertile patients prior to their scheduled laparoscopy and chromohydrotubation as part of infertility evaluation. We compared the findings of the two methods. RESULTS: Hysteroscopic tubal assessment had a 82.9% accuracy with the laparoscopic dye method taken as reference, with a positive predictive value of 87.5%, and a negative predictive value of 76.7%. No complication or failure occurred. CONCLUSION: Selective pertubation with office hysteroscopy is a useful method for the assessment of tubal patency. As a minimal invasive office procedure it can be offered as a first line method for the evaluation of the uterine cavity and the tubes in infertile women. PMID- 22935305 TI - Assessment of transvaginal hysterotomy combined with medication for cesarean scar ectopic pregnancy. AB - The objective of this retrospective study was to explore a novel surgical technique, transvaginal hysterotomy combined with methotrexate injection, for treatment of cesarean scar ectopic pregnancy in 12 patients. All patients underwent the operation. Mean (SD; 95% CI) operative time was 21.6 (7.3; 17.0 26.2) minutes, and intraoperative blood loss was 90.8 (59.6; 52.9-128.7) mL. Postoperative ultrasonography confirmed removal of the pregnancy sac. The length of hospital stay was 7.4 (3.7; 5.0-9.8) days. The first normal postoperative menstrual period was at 28.3 (5.6; 24.7-31.9) days after surgery. The serum beta human chorionic gonadotropin concentration returned to normal at 15.8 (6.3; 11.8 19.8) days. We conclude that surgical removal of the ectopic sac via transvaginal hysterotomy combined with methotrexate injection during the operation is a potentially good new approach to treatment of cesarean scar ectopic pregnancy. The efficacy and safety of the technique need further confirmation in future studies. PMID- 22935306 TI - Should diagnostic hysteroscopy be performed before in vitro fertilization-embryo transfer? AB - The role of routine uterine cavity evaluation before an in vitro fertilization embryo transfer (IVF-ET) cycle has not been uniformly accepted. Published trials have demonstrated a relatively high incidence of cavitary abnormalities diagnosed at outpatient hysteroscopy in patients with previous IVF-ET cycle failure, the correction of which markedly improves outcomes. The value of performing this procedure before an initial cycle in patients without previous implantation failure has not been definitively confirmed in prospective randomized trials, but would seem logical in an effort to minimize the number of cycles a patient must undergo. The incidence of cavitary abnormalities in this population varies. One large series has reported a 22.9% incidence of endometrial cavitary abnormalities diagnosed at pre-cycle office hysteroscopy in this patient group. Hysterosalpingography and baseline transvaginal ultrasonography are insufficiently sensitive alternatives. Sonohysterography with infusion of saline solution, in particular with 3-dimensional technology, may be a reasonable alternative to diagnostic hysteroscopy, although relatively few well-designed trials have addressed this issue. There are an insufficient number of prospective randomized trials to clearly demonstrate that surgical removal of all abnormalities improves IVF-ET outcome. However, investigators suggest a benefit for resection of submucosal leiomyomas, adhesions, and at least a subset of polyps. Appropriately designed trials are required before a definitive recommendation can be made. PMID- 22935307 TI - Early abdominal pregnancy complicated by parasitic dermoid cyst: diagnosis by diffusion-weighted magnetic resonance imaging and management by laparoendoscopic single-site surgery. AB - A 26-year-old primigravida patient was referred with suspicion of ectopic pregnancy 39 days after her last menstrual period. Her serum beta-human chorionic gonadotropin value was 3812 mIU/mL. As we suspected the existence of ectopic pregnancy with bilateral dermoid cysts, laparoendoscopic single-site surgery was performed. After dissection of dense pelvic adhesion, cystectomy was performed for a left ovarian dermoid cyst. Although there was a right ovary at the correct position, a parasitic dermoid cyst firmly attached to the peritoneal surface of cul-de-sac was identified. After excision of the parasitic dermoid cyst, early abdominal pregnancy tissue implanted in the peritoneal hollow of right deep pararectal space was identified under the guidance of diffusion-weighted magnetic resonance imaging and was excised. With systemic administration of methotorexate, the postoperative course was uneventful. PMID- 22935308 TI - Caution: laparoscopic biopsy of a large pelvic mass may result in disaster. AB - Anterior sacral meningocele is a rare cause of a pelvic mass. Herein the authors describe the case of a young patient presenting with chronic pelvic pain undergoing diagnostic laparoscopy. She was found to have a retrorectal mass confirmed as an anterior sacral meningocele on subsequent MRI. The authors explore the case, describe a method of intraoperative management to minimize the risk of severe complications and include a discussion of the differential diagnosis. Central to this is an emphasis on advocating a cautious approach when confronted with an incidental unknown pelvic mass, as deleterious consequences may occur from biopsy of such a lesion. PMID- 22935309 TI - Atypical presentation of a vaginal epithelial inclusion cyst. AB - Vaginal masses can have numerous different presentations and causes. Physicians can often make an empiric diagnosis of these masses on the basis of their clinical presentation and location. Most of these diagnoses are correct, with the rare exception of the occasional urethral diverticulum or hydrocele. In this case report, we discuss the initial diagnosis of a suspected infected Bartholin gland duct cyst that was in fact a 10 * 8 * 7.5-cm epithelial inclusion cyst that extended through the ischiorectal fossa and down to the gluteal region, requiring extensive dissection. Also presented is a detailed description of the anatomical landmarks encountered at dissection through the vaginal sidewall and ischiorectal fossa. PMID- 22935310 TI - Low-invasive lymphatic surgery and lymphatic imaging for completely healed intractable pudendal lymphorrhea after gynecologic cancer treatment. AB - Lower limb lymphedema and an accompanying lymphatic fistula (lymphorrhea) occur as complications after gynecologic surgery to treat cancer. Herein, we report the case of a 68-year-old woman who underwent resection and radiotherapy because of uterine cervical cancer (stage 2a) 20 years previously. Left lower limb and pudendal lymphedema and continuous lymphorrhea developed soon after surgery. Conservative treatment was administered; however, the edema increased, and a pudendal lymphatic fistula and cellulitis developed repeatedly. Lymphovascular anastomosis (LVA) and lymph vessel ligation were performed after preoperative evaluation via lymphoscintigraphy and indocyanine green (ICG) lymphography. A radioisotope injected into the first interdigit pedal region flowed into the pudendal region via the inguinal lymph nodes at preoperative lymphoscintigraphy. Linear patterns were observed up to the half level of the crus, and stardust patterns occurred over the lower abdominal and pudendal regions at ICG lymphography. During surgery, ICG lymphography was also used to identify the site of the fistula. With the patient under local anesthesia, LVA was applied in the half crus and left inguinal regions, followed by ligation and division of lymph vessels flowing into the fistula. The region around the fistula was excised as a 1 * 3-cm tissue block. As of 5 months after surgery, no recurrence of lymphatic fistula or exacerbation of lymphedema has occurred. This case shows the effectiveness of preoperative ICG lymphography and lymphoscintigraphy followed by treatment via lymph vessel ligation and LVA for curative resolution of a lymphatic fistula. PMID- 22935311 TI - Laparoscopic management for Seprafilm-induced sterile peritonitis with paralytic ileus: report of 2 cases. AB - Postoperative adhesions after abdominopelvic surgery can be prevented with the use of mechanical barriers such as Seprafilm membranes. However, this procedure is not without complications. Herein are reported 2 cases of Seprafilm-associated sterile peritonitis after gynecologic surgical procedures. Both patients had symptoms that mimicked intraabdominal abscess formation soon after the initial surgery (1 patient had delivered via cesarean section, and the other had undergone total hysterectomy because of adenomyosis). However, laparoscopic examinations in these 2 patients revealed only gel-like hydrated Seprafilm without evidence of infection. Symptoms resolved after the abdominal cavity was thoroughly irrigated and the Seprafilm residue was completely removed. Both patients had an uneventful recovery. Previous reports suggested that Seprafilm related complications were most commonly observed in patients who underwent gynecologic debulking surgery because Seprafilm might react with the large area of the injured peritoneum and induce a strong inflammatory response. However, our experience showed that such complications could also be observed in patients who underwent nondebulking surgery. A laparoscopic approach should be considered the treatment of choice under these conditions to avoid unnecessary laparotomy. PMID- 22935312 TI - Use of intraoperative fluoroscopy during laparotomy to identify fragments of retained Essure microinserts: case report. AB - In previous case-reports of Essure microinsert perforation, the microinsert was successfully removed at laparoscopy. Herein is discussed the scenario of persistent pelvic pain over several years after an apparently successful laparoscopic retrieval of a perforating right-sided microinsert. In the interim, the patient underwent 2 unsuccessful exploratory laparotomy procedures in an attempt to retrieve additional microinsert fragments that had perforated the uterus. Successful management of Essure microinsert perforation in this patient ultimately required use of intraoperative fluoroscopy. Surgeons performing laparoscopy or laparotomy to retrieve Essure microinserts that have perforated should be aware that these are not always visible to the naked eye, and there should be a low threshold to use intraoperative fluoroscopy to ensure that all perforating fragments have been removed. PMID- 22935313 TI - Management of cesarean heterotopic pregnancy with transvaginal ultrasound-guided potassium chloride injection and gestational sac aspiration, and review of the literature. AB - Cesarean scar pregnancy is one of the rarest forms of ectopic pregnancy, located in the scar from a previous cesarean section. There are few reports of such pregnancies, and there is no consensus about the best management. Herein is reported a case of cesarean heterotopic pregnancy, diagnosed at 6 weeks' gestation and successfully treated via transvaginal ultrasound-guided potassium chloride injection and gestational sac aspiration, with preservation of the intrauterine pregnancy. PMID- 22935314 TI - Assessing DRG cost accounting with respect to resource allocation and tariff calculation: the case of Germany. AB - The purpose of this paper is to analyze the German diagnosis related groups (G DRG) cost accounting scheme by assessing its resource allocation at hospital level and its tariff calculation at national level. First, the paper reviews and assesses the three steps in the G-DRG resource allocation scheme at hospital level: (1) the groundwork; (2) cost-center accounting; and (3) patient-level costing. Second, the paper reviews and assesses the three steps in G-DRG national tariff calculation: (1) plausibility checks; (2) inlier calculation; and (3) the "one hospital" approach. The assessment is based on the two main goals of G-DRG introduction: improving transparency and efficiency. A further empirical assessment attests high costing quality. The G-DRG cost accounting scheme shows high system quality in resource allocation at hospital level, with limitations concerning a managerially relevant full cost approach and limitations in terms of advanced activity-based costing at patient-level. However, the scheme has serious flaws in national tariff calculation: inlier calculation is normative, and the "one hospital" model causes cost bias, adjustment and representativeness issues. The G-DRG system was designed for reimbursement calculation, but developed to a standard with strategic management implications, generalized by the idea of adapting a hospital's cost structures to DRG revenues. This combination causes problems in actual hospital financing, although resource allocation is advanced at hospital level. PMID- 22935315 TI - A study on inhibition of inflammation via p75TNFR signaling pathway activation in mice with traumatic brain injury. AB - OBJECTIVE: To investigate the effects of and mechanisms underlying the activation of the p75 tumor necrosis factor receptor (p75TNFR) signaling pathway in inflammatory responses in mice with traumatic brain injury. METHODS: We first generated hybridomas that produced antibodies specific for p75TNFR, by inoculating BALB/c mice with antigenic peptides derived from mouse p75TNFR, which is critical to the binding of tumor necrosis factor-alpha (TNF-alpha) and p75TNFR. The isotype, epitope, titer, specificity, and affinity constant of monoclonal antibodies (mAbs) were determined using commercial kits and enzyme linked immunosorbent assay. We then screened the agonist antibody via L929 cytotoxicity assay. The levels of inflammatory factors were detected in C57BL/6 mice with traumatic brain injury and then the mice were injected with either saline (control) or p75TNFR agonist mAb. Furthermore, we investigated the effects of p75TNFR agonist mAb on p38MAPK and nuclear factor-kappaB signals. RESULTS: Seven mAbs against p75TNFR were generated. Among them, the mAb D8F2 could markedly enhance the cytotoxicity of TNF-alpha on L929 cells. In a traumatic brain injury model, D8F2 could inhibit the levels of inflammatory factors and downregulate RNA transcription of these factors by suppressing the activation of p38 mitogen-activated protein kinase and nuclear factor-kappaB. CONCLUSION: The mAb D8F2 could inhibit posttraumatic inflammatory responses effectively. In this study, we developed an agonist anti-mouse p75TNFR mAb, which may be used in the future to devise new strategies for the clinical treatment of inflammation after trauma. PMID- 22935317 TI - Pyrethroid resistance in Anopheles gambiae from the rubber cultivated area of Niete, South Region of Cameroon. AB - Anti-vector intervention remains the most effective way of controlling malaria. Although in Cameroon and elsewhere focus is on the use of long-lasting insecticidal nets and indoor residual spraying, the efficacy of both methods greatly depends on the continuing susceptibility of the vectors to the insecticides used. The emergence and spread of insecticide resistance in the major malaria vectors constitute a huge challenge to control programmes. Consequently, routine monitoring and evaluation of vector resistance status to insecticides are mandatory for early detection of resistance should it arise, and effectively planning future anti-vector interventions especially in areas reputed for routine application in agriculture. The WHO bioassay kit was used to determine the susceptibility status of Anopheles gambiae s.l. populations to seven insecticides belonging to four classes (organochlorine, organophosphate, carbamate and pyrethroids) in Niete, an area of intense rubber cultivation in southern forested Cameroon. Species and molecular forms of An. gambiae s.l. as well as the presence of knock down resistance (kdr) mutations were determined using polymerase chain reaction (PCR) techniques. All Anopheles tested was identified as An. gambiae s.s. and of the M molecular form. Based on WHO classification, while the mosquitoes were fully (100%) susceptible to malathion and bendiocarb, resistance was confirmed to DDT and the pyrethroids, permethrin and lambda-cyhalothrin. The other pyrethroids (deltamethrin and cyfluthrin) showed signs of developing resistance. Resistance to DDT and pyrethroids is indicative of existing cross resistance mechanisms between these insecticides. The increase in knockdown times was greater than twofold that of the reference susceptible strain, suggesting the possible involvement of kdr mutations, also confirmed in this study. The findings highlight the need for constant evaluation, re-evaluation and monitoring of the insecticides for malaria vector control in Cameroon. However, bendiocarb and malathion can be used and may require alternation or combination with insecticides of other classes to better manage the occurrence and spread of resistance in Niete. PMID- 22935316 TI - DNA 'barcoding' of Schistosoma mansoni across sub-Saharan Africa supports substantial within locality diversity and geographical separation of genotypes. AB - Schistosoma mansoni is a widespread human helminth and causes intestinal schistosomiasis in 54 countries, mainly across Africa but also in Madagascar, the Arabian Peninsula and the neotropics. The geographical range of this parasite relies on the distribution of certain species of freshwater pulmonate snails of the genus Biomphalaria. Whilst S. mansoni is known to exhibit high population diversity the true extent of this diversity is still to be fully elucidated as sampling of this taxon progressively accrues. Here a DNA 'barcoding' approach is taken using sequence analysis of a 450bp region within the mitochondrial cox1 gene to assess the genetic diversity within a large number of S. mansoni larval stages collected from their natural human hosts across sub-Saharan Africa. Five hundred and sixty one individual parasite samples were examined from 22 localities and 14 countries. Considerable within-species diversity was found with 120 unique haplotypes splitting geographically into five discrete lineages. The highest diversity was found in East Africa with samples forming three of the five lineages. Less diversity was found in the Far and Central Western regions of Africa with haplotypes from the New World showing a close affinity to the Far Western African S. mansoni populations supporting the hypothesis of a colonisation of South America via the West African slave trade. The data are discussed in relation to parasite diversity and disease epidemiology. PMID- 22935318 TI - Prevalence of Opisthorchis viverrini infection in humans and fish in Kratie Province, Cambodia. AB - Opisthorchis viverrini is a medically important foodborne parasite in the Indochina Peninsula. In Cambodia, the prevalence of this trematode has been reported in Takeo Province, but not in other areas. In this study, we investigated the prevalence of O. viverrini infection among people in seven riparian villages along the Mekong River, Kratie Province. We also examined the status of metacercarial infection in fish hosts. Fecal specimens were collected from 2101 residents and schoolchildren, and were examined by the Kato-Katz technique. The average O. viverrini egg positive rate was 4.6%, with the highest prevalence found in Roka Kandal A village (10.4%) followed by Talous village (5.9%). In these villages, adult residents showed higher prevalences (19.4% and 9.0%, respectively) than schoolchildren (6.4% and 1.4%, respectively). O. viverrini adult worms were recovered from 2 egg-positive cases (18 and 4 specimens) after praziquantel treatment and purgation. In addition, three of seven freshwater fish species caught near the villages were positive for O. viverrini metacercariae. A total of 367 metacercariae were harvested from 19 infected fish (metacercarial density; 19 per fish). The species of the metacercariae was confirmed through adult worm recovery by experimental infection to hamsters. The results provide evidence that the surveyed areas of Kratie Province, Cambodia, are endemic for O. viverrini infection. PMID- 22935319 TI - Effects of astaxanthin supplementation on chemically induced tumorigenesis in Wistar rats. AB - BACKGROUND: Astaxanthin (ASTA) is a fat-soluble xanthophyll with powerful antioxidant functions. It is extracted from e.g. salmon, an important food source for certain human populations known to have a reduced risk of tumor development. It is possible that ASTA plays a role in cancer chemoprevention in such populations. The purpose of this study was to investigate the effects of dietary ASTA on chemically induced mammary tumorigenesis using N-methyl-N-nitroso-urea (MNU) in immature Wistar rats. METHODS: Thirty-six 37 days old juvenile female Wistar rats were at random allocated to 4 groups of which Groups 1 and 2 received a single dose of 55 mg MNU/kg body weight. The effects of ASTA was evaluated by giving rats of Groups 2 and 4 a dose of 50 mg ASTA/kg/day for the entire duration of the study. Group 3 rats received feed added alimentary oil.Necropsy and histopathological examinations were carried out on each rat 14 months after the administration of MNU. Haematological values and antioxidative status were determined. Oxidative stress was evaluated by monitoring superoxide dismutase (SOD) and glutathione peroxidase (GPx) activities in hepatic tissue. Lipid peroxidation and carbonylation of proteins was determined in protein extracts from the liver. RESULTS: Tumor development occurred only in rats of Groups 1 and 2, i.e. MNU exposed animals. Frequency of tumor development in general and average number of tumors per animal were insignificant between these two groups. Mammary gland tumors developed in equal frequencies in Group 1 and 2 rats, respectively. Although only rather few tumors were found in the mammary glands, a substantial number of other tumors were found in Group 1 and 2 rats, but at equal rates.Biochemical analyses showed significant higher levels of GPx, malondialdehyde and dinitrophenylhydrazine in Group 1 rats that for rats in all other groups thus indicating protective effects of ASTA on MNU induced hepatic oxidative stress. CONCLUSIONS: Supplementation with ASTA did not reduce tumorigenesis induced by MNU in Wistar rats. However, supplementation with ASTA seemed to have anti-inflammatory effects. PMID- 22935320 TI - Macro-AST: misleading finding in an adolescent with MCAD-deficiency. AB - BACKGROUND: MCAD-deficiency is the most common inborn error of fatty acid oxidation now included in many newborn screening programms using MS/MS. During prolonged catabolic episodes, patients may suffer from metabolic decompensation with dysfunction of liver, skeletal- and heart muscle as well as brain. In anabolism, neither clinical symptoms nor biochemical signs of organ dysfunction occur. CASE PRESENTATION: We report a female patient with MCAD-deficiency in whom at the age of 11 years isolated AST-elevation was found without any clinical or biochemical signs of organ dysfunction. We showed by polyethylene glycol precipitation that macro-AST formation was responsible for this biochemical finding. AST was probably complexed with immunoglobulins possibly related to an allergic disposition. Macro-AST formation is not a special feature of MCAD deficiency but rather a non-specific, coincidental finding which also occurs in healthy individuals. The general practitioner consulted by the patient before coming to our outpatient clinic for inborn errors of metabolism was worried that isolated AST-elevation indicated cell damage in MCAD-deficiency. He ordered further diagnostic tests like ultrasound, ECG and echocardiography without any pathology. CONCLUSION: In isolated AST-elevation, macro-AST has to be considered in order to avoid unnecessary, costly and invasive evaluation. This is not only true for healthy persons but for patients with chronic diseases like MCAD as well. PMID- 22935321 TI - Consumption of blueberries with a high-carbohydrate, low-fat breakfast decreases postprandial serum markers of oxidation. AB - We sought to determine whether consumption of blueberries could reduce postprandial oxidation when consumed with a typical high-carbohydrate, low-fat breakfast. Participants (n 14) received each of the three treatments over 3 weeks in a cross-over design. Treatments consisted of a high blueberry dose (75 g), a low blueberry dose (35 g) and a control (ascorbic acid and sugar content matching that of the high blueberry dose). Serum oxygen radical absorbance capacity (ORAC), serum lipoprotein oxidation (LO) and serum ascorbate, urate and glucose were measured at fasting, and at 1, 2 and 3 h after sample consumption. The mean serum ORAC was significantly higher in the 75 g group than in the control group during the first 2 h postprandially, while serum LO lag time showed a significant trend over the 3 h for both blueberry doses. Changes in serum ascorbate, urate and glucose were not significantly different among the groups. To our knowledge, this is the first report that has demonstrated that increased serum antioxidant capacity is not attributable to the fructose or ascorbate content of blueberries. In summary, a practically consumable quantity of blueberries (75 g) can provide statistically significant oxidative protection in vivo after a high-carbohydrate, low-fat breakfast. Though not tested directly, it is likely that the effects are due to phenolic compounds, either directly or indirectly, as they are a major family of compounds in blueberries with potential bioactive activity. PMID- 22935322 TI - Evaluating feasibility, reach and potential impact of a text message family planning information service in Tanzania. AB - BACKGROUND: The objective of this research was to evaluate the feasibility, reach and potential behavioral impact of providing automated family planning information via mobile phones to the general public in Tanzania. STUDY DESIGN: Data from users of the Mobile for Reproductive Health (m4RH) program were collected during the 10-month pilot period. First, contraceptive methods queried by each user were electronically logged by the mobile phone system. Second, four text questions assessing gender, age, promotion point and potential family planning impact were sent to every user. RESULTS: During the pilot period, 2870 unique users accessed m4RH in Tanzania, resulting in 4813 queries about specific contraceptive methods. Among those responding to text questions, 56% were female and approximately 60% were 29 or younger years in age. A variety of changes in family planning use were mentioned after using m4RH, with reported changes consistent with where users are in their reproductive life cycle. CONCLUSIONS: Reaching younger people, women and men of reproductive age with family planning information delivered via mobile phone is recommended. PMID- 22935323 TI - Emergency contraceptive pills as a backup for lactational amenorrhea method (LAM) of contraception: a randomized controlled trial. AB - BACKGROUND: The use of breastfeeding as a method of birth spacing occasionally ends in "unplanned pregnancy." This is due to unexpected expiration of one or more of the lactation amenorrhea method (LAM) prerequisites. The current study tests a new concept that the in-advance provision of single packet of progestogen emergency contraception (EC) pills during the postpartum LAM counseling may decrease the incidence of unplanned pregnancy during breastfeeding. STUDY DESIGN: This was a registered two-armed randomized controlled trial (NCT 01111929). Women intending to breastfeed and to postpone pregnancy for 1 year or more were approached. They received adequate postpartum contraceptive counseling. Women intending to use LAM were randomly assigned to one of two groups. The LAM-only group received the proper LAM counseling and did not receive counseling about EC. The LAM-EC group received counseling for both LAM and EC with in-advance provision of one packet of EC pills. They were advised to use these pills if one of the prerequisites of LAM expires and sexual relation has occurred before the initiation of another regular contraceptive protection. All the participants were advised that they need to use another regular method upon expiration of any of the LAM prerequisites. RESULTS: Eligible women were 1158 parturients randomized into two equal groups. Forty-four percent of the women provided with EC used them. Significantly more women in the LAM-EC group initiated regular contraception within or shortly after the first 6 months postpartum when compared with those in the LAM-only group (30.5% vs. 7.3%, respectively; p=.0004). Pregnancy occurred in 5% of the LAM-only group as compared with 0.8% in the LAM EC group (p=.005). Minimal side effects were reported after EC use. CONCLUSION: In-advance provision of EC pills can increase the rate of initiation of regular contraception once one or more of the prerequisites of LAM expire. Consequently, the use of EC pills as a temporary backup of LAM can decrease the incidence of unplanned pregnancy during breastfeeding. The use of progestogen EC pill during lactation is safe and tolerable. PMID- 22935324 TI - Team-based learning: a novel approach to medical student education in family planning. AB - BACKGROUND: Medical schools are increasingly using team-based learning (TBL). We compared medical student satisfaction and understanding of key concepts in family planning following TBL and traditional lectures. STUDY DESIGN: During the OB/GYN clinical rotation orientation, third year medical students completed a pretest in family planning. Students in the odd-numbered clerkships participated in TBL, and students in the even-numbered clerkships participated in lectures. Both groups of students completed a posttest and satisfaction survey. RESULTS: A total of 130 students participated in this study. Sixty-nine students were in the TBL group, and 61 students were in the lecture group. The TBL group reported higher scores when asked if the learning style was a valuable experience (p=.045), helped them learn the course material (p=.01) and improved problem-solving skills (p=.04). Both groups gained significant amount of knowledge (p<.001) as calculated by the Student's paired t test. The change in scores was not significantly different between the groups (p=.73), as calculated using the Student's unpaired t test. CONCLUSION: As a learning strategy for family planning, TBL resulted in high student satisfaction. This is the first study to evaluate this innovative teaching style for medical student education in family planning. PMID- 22935325 TI - Fragmin/protamine microparticles to adsorb and protect HGF and to function as local HGF carriers in vivo. AB - The clinical efficacy of hepatocyte growth factor (HGF) in tissue repair can be greatly enhanced by high affinity, biocompatible drug carriers that maintain the bioactivity and regulate release at the target site. We produced 0.5-3.0 MUm fragmin (low molecular weight heparin)/protamine microparticles (F/P MPs) as carriers for the controlled release of HGF. F/P MPs immobilized more than 3 MUg of HGF per mg of MPs and gradually released the absorbed HGF into the medium with a half-release time of approximately 5 days. Compared with HGF alone, HGF containing F/P MPs substantially enhanced the mitogenic effect of HGF on cultured human microvascular endothelial cells, by prolonging the biological half-life, and its conjugation to F/P MPs protected HGF from heat and proteolytic inactivation. F/P MPs disappeared 8 days after subcutaneous injection in mice, suggesting that they are rapidly biodegraded. Furthermore, the number of large (diameter >=200 MUm or containing >= 100 erythrocytes) and medium (diameter 20 200 MUm or containing 10-100 erythrocytes) lumen capillaries 8 days after injection of HGF-containing F/P MPs was significantly higher than that after injection of HGF or F/P MPs alone. Furthermore, the number of small (diameter <= 20 MUm or containing 1-10 erythrocytes) lumen capillaries was significantly higher 4 days after injection of HGF-containing F/P MPs. This increased angiogenic activity of HGF in vivo is probably due to both sustained local release and protection against biodegradation by the F/P MPs. Thus, F/P MPs may be useful and safe HGF carriers that facilitate cell proliferation and vascularization at sites of tissue damage. PMID- 22935326 TI - Injectable chitosan hyaluronic acid hydrogels for cartilage tissue engineering. AB - Injectable cartilaginous constructs that can form gels in tissue defects have many advantages in tissue engineering applications. In this study we created an injectable hydrogel consisting of methacrylated glycol chitosan (MeGC) and hyaluronic acid (HA) by photocrosslinking with a riboflavin photoinitiator under visible light. A minimum irradiation time of 40s was required to produce stable gels for cell encapsulation with 87-90% encapsulated chondrocyte viability. Although increasing the irradiation time from 40 to 600 s significantly enhanced the compressive modulus of the hydrogels up to 11 or 17 kPa for MeGC or MeGC/HA, respectively, these conditions reduced the encapsulated cell viability to 60-65%. The majority of chondrocytes encapsulated in MeGC hydrogels after 300 s irradiation maintained a rounded shape with a high cell viability of ~80-87% over a 21 day culture period. The incorporation of HA in MeGC hydrogels increased the proliferation and deposition of cartilaginous extracellular matrix by encapsulated chondrocytes. These findings demonstrate that MeGC/HA composite hydrogels have the potential for cartilage repair. PMID- 22935327 TI - Two observations suggesting that we die in ventricular systole. PMID- 22935328 TI - Role of an ideomotor mechanism in number processing. AB - The ideomotor principle predicts that the anticipation of expected sensory consequences precedes and controls voluntary goal-directed movements. Recent studies have revealed that an ideomotor mechanism could also support the link between finger movements and number processing. However, it is unknown whether such a mechanism is devoted to number processing per se, that is, without associated movement. In three experiments, we tested whether the ideomotor mechanism was also involved in a verbal number production task without associated goal-directed and motor dimensions. We tested this hypothesis in a response effect (R-E) paradigm generally used to assess the ideomotor mechanisms. The results of Experiment 1 revealed a compatibility effect both in a stimulus response task and an R-E task, suggesting the involvement of an ideomotor mechanism during number processing. More importantly, Experiment 2 revealed that performance in a motor imagery task correlated with the R-E compatibility effect, whereas performance in a visual imagery task did not, suggesting a distinct motor imagery contribution to R-E compatibility. Finally, Experiment 3 showed a strong R-E compatibility effect in a verbal word production task, but the correlations with motor or visual imagery tasks were not observed. Altogether, these findings suggest that ideomotor mechanisms play a specific and functional role in number processing. PMID- 22935329 TI - Synchronization can influence trust following virtual interaction. AB - Synchronization has recently received attention as a form of interpersonal interaction that may affect the affiliative relationships of those engaged in it. While there is evidence to suggest that synchronized movements lead to increased affiliative behavior (Hove & Risen, 2009; Valdesolo & DeSteno, 2011; Wiltermuth & Heath, 2009), the influence of other interpersonal cues has yet to be fully controlled. The current study controls for these features by using computer algorithms to replace human partners. By removing genuine interpersonal interaction, it also tests whether sounds alone can influence affiliative relationships, when it appears that another human agent has triggered those sounds. Results suggest that subjective experience of synchrony had a positive effect on a measure of trust, but task success was a similarly good predictor. An objective measure of synchrony was only related to trust in conditions where participants were instructed to move at the same time as stimuli. PMID- 22935330 TI - Modulation of auditory attention by training: evidence from dichotic listening. AB - We studied the effects of training on auditory attention in healthy adults with a speech perception task involving dichotically presented syllables. Training involved bottom-up manipulation (facilitating responses from the harder-to-report left ear through a decrease of right-ear stimulus intensity), top-down manipulation (focusing attention on the left-ear stimuli through instruction), or their combination. The results showed significant training-related effects for top-down training. These effects were evident as higher overall accuracy rates in the forced-left dichotic listening (DL) condition that sets demands on attentional control, as well as a response shift toward left-sided reports in the standard DL task. Moreover, a transfer effect was observed in an untrained auditory-spatial attention task involving bilateral stimulation where top-down training led to a relatively stronger focus on left-sided stimuli. Our results indicate that training of attentional control can modulate the allocation of attention in the auditory space in adults. Malleability of auditory attention in healthy adults raises the issue of potential training gains in individuals with attentional deficits. PMID- 22935331 TI - Determinants of antiretroviral therapy adherence in northern Tanzania: a comprehensive picture from the patient perspective. AB - BACKGROUND: To design effective, tailored interventions to support antiretroviral therapy (ART) adherence, a thorough understanding of the barriers and facilitators of ART adherence is required. Factors at the individual and interpersonal level, ART treatment characteristics and health care factors have been proposed as important adherence determinants. METHODS: To identify the most relevant determinants of adherence in northern Tanzania, in-depth interviews were carried out with 61 treatment-experienced patients from four different clinics. The interviews were ad-verbatim transcribed and recurrent themes were coded. RESULTS: Coding results showed that the majority of patients had basic understanding of adherence, but also revealed misconceptions about taking medication after alcohol use. Adherence motivating beliefs were the perception of improved health and the desire to live like others, as well as the desire to be a good parent. A de-motivating belief was that stopping ART after being prayed for was an act of faith. Facilitators of adherence were support from friends and family, and assistance of home based care (HBC) providers. Important barriers to ART adherence were the use of alcohol, unavailability of food, stigma and disclosure concerns, and the clinics dispensing too few pills. Strategies recommended by the patients to improve adherence included better Care and Treatment Centre (CTC) services, recruitment of patients to become Home Based Care ( HBC) providers, and addressing the problem of stigma through education. CONCLUSION: This study underscores the importance of designing tailored, patient centered adherence interventions to address challenges at the patient, family, community and health care level. PMID- 22935332 TI - Preliminary trial of postural strategy training using a personal transport assistance robot for patients with central nervous system disorder. AB - OBJECTIVE: To examine the efficacy of postural strategy training using a personal transport assistance robot (PTAR) for patients with central nervous system disorders. DESIGN: Single-group intervention trial. SETTING: Rehabilitation center at a university hospital. PARTICIPANTS: Outpatients (N=8; 5 men, 3 women; mean age, 50+/-13y) with a gait disturbance (mean time after onset, 34+/-29mo) as a result of central nervous system disorders were selected from a volunteer sample. INTERVENTIONS: Two methods of balance exercise using a PTAR were devised: exercise against perturbation and exercise moving the center of gravity. The exercises were performed twice a week for 4 weeks. MAIN OUTCOME MEASURES: Preferred and tandem gait speeds, Functional Reach Test, functional base of support, center of pressure (COP), muscle strength of lower extremities, and grip strength were assessed before and after the completion of the exercise program. After the exercise program, enjoyment of exercise was investigated via a visual analog scale questionnaire. RESULTS: After the program, statistically significant improvements were noted for tandem gait speeds (P=.009), Functional Reach Test (P=.003), functional base of support (P=.014), and lower extremity muscle strength (P<.001-.042). On the other hand, preferred gait speeds (P=.151), COP (P=.446-.714), and grip power (P=.584) did not change. Finally, subjects rated that this exercise was more enjoyable than traditional balance exercises. CONCLUSIONS: Dynamic balance and lower extremity muscle strength were significantly improved in response to postural strategy training with the PTAR. These results suggest that postural strategy training with the PTAR may contribute to fall prevention of patients with a balance disorder. PMID- 22935333 TI - BAP1 cancer syndrome: malignant mesothelioma, uveal and cutaneous melanoma, and MBAITs. AB - BACKGROUND: BRCA1-associated protein 1 (BAP1) is a tumor suppressor gene located on chromosome 3p21. Germline BAP1 mutations have been recently associated with an increased risk of malignant mesothelioma, atypical melanocytic tumors and other neoplasms. To answer the question if different germline BAP1 mutations may predispose to a single syndrome with a wide phenotypic range or to distinct syndromes, we investigated the presence of melanocytic tumors in two unrelated families (L and W) with germline BAP1 mutations and increased risk of malignant mesothelioma. METHODS: Suspicious cutaneous lesions were clinically and pathologically characterized and compared to those present in other families carrying BAP1 mutations. We then conducted a meta-analysis of all the studies reporting BAP1-mutated families to survey cancer risk related to the germline BAP1 mutation (means were compared using t-test and proportions were compared with Pearson chi2 test or two-tailed Fisher's exact test). RESULTS: Melanocytic tumors: of the five members of the L family studied, four (80%) carried a germline BAP1 mutation (p.Gln684*) and also presented one or more atypical melanocytic tumors; of the seven members of W family studied, all carried a germline BAP1 mutation (p.Pro147fs*48) and four of them (57%) presented one or more atypical melanocytic tumors, that we propose to call "melanocytic BAP1 mutated atypical intradermal tumors" (MBAITs). Meta-analysis: 118 individuals from seven unrelated families were selected and divided into a BAP1-mutated cohort and a BAP1-non-mutated cohort. Malignant mesothelioma, uveal melanoma, cutaneous melanoma, and MBAITs prevalence was significantly higher in the BAP1 mutated cohort (p <= 0.001). CONCLUSIONS: Germline BAP1 mutations are associated with a novel cancer syndrome characterized by malignant mesothelioma, uveal melanoma, cutaneous melanoma and MBAITs, and possibly by other cancers. MBAITs provide physicians with a marker to identify individuals who may carry germline BAP1 mutations and thus are at high risk of developing associated cancers. PMID- 22935334 TI - Differences in the osteoarthritic synovial fluid composition and rheology between patients with or without flare: a pilot study. AB - OBJECTIVES: To study the influence of the inflammatory status (flare or not) on hyaluronic acid (HA) and protein composition and on the intrinsic viscosity of the synoviol fluid (SF) from patients with knee osteoarthritis (KOA). METHODS: Patients with KOA were classified as having flare (F+) when they fulfilled the 4 following clinical criteria: 1) sudden aggravation of knee pain, 2) whose beginning was identifiable, 3) causing nocturnal awakenings 4) with clinical evidence of knee effusion. Patients were classified F- (no flare) if they do not fulfill any of the 3 first criteria. Forty-four SF were obtained by arthrocentesis and assayed using steric exclusion chromatography, which allows HA to be separated from the proteins and to determine both molecular weight (Mw) and concentration (C) of both HA and proteins. SF rheology was determined using a rheometer at 25 degrees C using a cone and plate geometry. Steady-state viscosity was determined in Pa.s, as a function of the shear rate at 1s-1. Correlations between ( Pa.s) and HA and Pr (Mw, C and Mw x C) were calculated. RESULTS: Among the 44 assayed SF, 25 were classified F- and 19 F+. There were statistically significant differences between F- and F+ for most of the studied variables: HA concentration and Mw (p=0.01 and 0.001 respectively), protein concentration and Mw (p=0.02 and 0.001 respectively), product Mw x C of the proteins (p<0.0001) and viscosity eta (p=0.0005). The product [(Mw xC) HA x (MwxC) proteins] was highly discriminating between F+ and F- (p<0.0001). The steady state viscosity was highly related to HA concentration (p= 0.0002) and HA Mw (p=0.01) and was negatively correlated with (Mw x C) proteins (p=0.0005), protein concentration (p=0.0007) and protein Mw (p=0.03). CONCLUSIONS: This pilot study shows significant differences of SF composition in patients having a flare-up compared to that of patients who do not have flare. These differences relate to both protein and HA composition and suggest that SF analysis makes possible to distinguish patients with and without flare-up. PMID- 22935336 TI - Oscillating microbial dynamics driven by small populations, limited nutrient supply and high death rates. AB - Predicting and controlling the behaviour of microbial ecosystems demands a fundamental understanding of the factors controlling their dynamics. In the natural environment microbes typically live in small local populations with limited and unpredictable nutrient supply and high death rates. Here, we show that these conditions can produce oscillations in microbial population dynamics, even for a single population. For a large population, with deterministic growth dynamics, our model predicts transient (damped) oscillations. For a small population, demographic noise causes these oscillations to be sustained indefinitely. We show that the same mechanism can produce sustained stochastic oscillations in a two-species, nutrient-cycling microbial ecosystem. Our results suggest that oscillatory population dynamics may be a common feature of small microbial populations in the natural environment, even in the absence of complex interspecies interactions or spatial structuring. PMID- 22935337 TI - Omega-3 polyunsaturated fatty acid profiling using fingertip-prick whole blood does not require overnight fasting before blood collection. AB - Fatty acid profiling through the rapid analysis of capillary blood collected by fingertip prick could enable economical screening for omega-3 polyunsaturated fatty acid (PUFA) status, although the typical requirement of fasting prior to sample collection may limit application. We hypothesize that moderate changes in omega-3 biomarkers determined from fingertip-prick blood will occur and correspond to omega-3 PUFA content of the meals. Eight participants consumed a single breakfast with high fat, high fat with omega-3 functional foods, and low fat and low fat with fish oil capsules in a cross-over design. The fatty acid composition of fingertip-prick blood total lipid and venous blood erythrocyte total lipid, plasma total lipid, plasma triacylglycerol, and plasma phospholipids were analyzed at baseline and 1, 2, 3 and 4 hours after each single breakfast consumption. Omega-3 blood biomarkers; % of omega-3 highly unsaturated fatty acid (HUFA) in total HUFA, weight % of eicosapentaenoic acid+docosahexaenoic acid, weight % of eicosapentaenoic acid+omega-3 docosapentaenoic acid+docosahexaenoic acid, and the ratio of total omega-6 PUFA to total omega-3 PUFA in fingertip prick blood, did not change from baseline during the postprandial period (P > .05). However, meal type yielded lower (P < .05) % omega-3 HUFA in total HUFA in the low fat meal (22.8 +/- 3.9) as compared with the low fat with omega-3 (24.2 +/- 3.9) and, the high fat (23.8 +/- 4) meals. The ratio of total omega-6 PUFA to total omega-3 PUFA was generally higher in meals without omega-3 compared with omega-3. In conclusion, determinations of omega-3 status by fingertip-prick blood sampling may not require prior overnight fasting. PMID- 22935335 TI - The comparative responsiveness of the patient self-report questionnaires and composite disease indices for assessing rheumatoid arthritis activity in routine care. AB - OBJECTIVES: This paper aims to evaluate the internal and external responsiveness of the patient self-report questionnaires, comparatively to the traditional composite indices to assess the activity of rheumatoid arthritis (RA) in everyday practice. METHODS: One hundred and ninety-one RA out-patients completed the clinical arthritis activity (PRO-CLARA) index, the rheumatoid arthritis disease activity index (RADAI), the routine assessment of patient index data (RAPID3), and the patient activity score (PAS). Simultaneously, the disease activity score 28 joints based on CRP (DAS28-CRP) and ESR (DAS28-ESR), the simplified disease activity index (SDAI), the clinical disease activity index (CDAI), and the mean overall index for RA (MOI-RA) were computed for each patient. Sensitivity to change was assessed after 6 months of treatment with disease-modifying anti rheumatic drugs or biologics. Internal responsiveness was evaluated with the effect size (ES) and standardised response mean (SRM). External responsiveness was investigated by receiver operating characteristic (ROC), in categories of respondents, stratified according to the response on an item on change in overall health. In addition, change scores were compared by calculating correlation coefficients. RESULTS: No significant differences in internal and external responsiveness were found between self-report questionnaires and composite indices. The internal responsiveness of the self-report questionnaires and composite measures was wide, with SRM and ES ranging from 1.03 (RADAI) to 1.80 (DAS28-ESR) and higher than that of the each individual measures. The responsiveness of the PRO-CLARA was equal to the DAS28-ESR, DAS28-CRP, SDAI or MOI-RA, but better than the CDAI. The RADAI and PAS were less responsive than the PRO-CLARA and RAPID3. The area under ROC curve of the PRO-CLARA gives identical results to those provided by other comparator composite indices. The score changes of all combinations were highly correlated (p<0.0001). CONCLUSIONS: The self-report questionnaires showed comparable internal and external responsiveness to the composite activity scores and allow for the detection of rheumatoid disease activity. They appear suitable for clinical decision making, epidemiologic research and clinical trials. Further longitudinal studies are needed to validate these encouraging results. PMID- 22935338 TI - Acute, quercetin-induced reductions in blood pressure in hypertensive individuals are not secondary to lower plasma angiotensin-converting enzyme activity or endothelin-1: nitric oxide. AB - Quercetin (Q) reduces blood pressure (BP) in hypertensive individuals, but the mechanism is unknown. We hypothesized that acute Q aglycone administration reduces BP in hypertensive men by decreasing angiotensin-converting enzyme (ACE) activity and/or by lowering the ratio of circulating endothelin-1 (ET-1) to nitric oxide and that these alterations will improve endothelial function. Using a double-blind, placebo-controlled, crossover design Q or placebo (P) was administered to normotensive men (n = 5; 24 +/- 3 years; 24 +/- 4 kg/m(2)) and stage 1 hypertensive men (n = 12; 41 +/- 12 years; 29 +/- 5 kg/m(2)). As anticipated, ingesting 1095 mg Q did not affect BP in normotensive men but resulted in maximal plasma Q (2.3 +/- 1.8 MUmol/L) at approximately 10 hours, with Q returning to baseline concentrations (0.4 +/- 0.08 MUmol/L) by approximately 17 hours. Results from this study provided rationale for determining end-points of interest in stage 1 hypertensive men 10 hours after ingesting Q or P. In stage 1 hypertensive individuals, plasma Q increased(0.6 +/- 0.4 vs. 0.05 +/- 0.02 MUmol/L), and mean BP decreased (103 +/- 7 vs 108 +/- 7 mm Hg; both P < .05) 10 hours after Q vs P, respectively. Plasma ACE activity (16 +/ 10 vs 18 +/- 10 U/L), ET-1 (1.6 +/- 0.9 vs 1.6 +/- 0.8 pg/ml), nitrites (57.0 +/ 3.0 vs 56.7 +/- 2.6 MUmol/L), and brachial artery flow-mediated dilation (6.2 +/ 2.9 vs. 6.3 +/- 3.2%) were unaffected by Q. A single dose of Q aglycone reduces BP in hypertensive men through a mechanism that is independent of changes in ACE activity, ET-1, or nitric oxide bioavailability and without affecting vascular reactivity. PMID- 22935339 TI - Enhanced vascular function after acute fat-rich snacking in healthy males. AB - Diets high in fat are associated with vascular dysfunction. Frequent snacking may exacerbate this problem by extending the postprandial state. We hypothesized that repeated fat-rich mixed snacks would impair peripheral endothelial function and increase oxidative stress, a purported causal factor. Second, we hypothesized that feeding a quantity of snack based on the subject's body size would not cause different effects from feeding a fixed or constant size snack. A crossover design was used where 10 healthy males followed 2 repeated-snack regimens (fixed and variable based on body surface area), 1 week apart. Each regimen consisted of 2 snacks, fed 4 hours apart (0 and 4 hours). Markers of vascular function (reactive hyperemia index [RHI]), oxidative stress, and antioxidant capacity were measured before and after each snack. Peripheral vascular function improved from fasting to 2 hours after snack 1 (RHI(2h-0h), P = .010), but the change before and after snack 2, RHI(6h-4h), was negative (P = .026), indicating reduced endothelial function after repeated snacking. The oxidative stress marker changed over time (P = .043), increasing after snack 1 and decreasing before snack 2, with no change after snack 2. The antioxidant marker increased 2 hours after each snack (P = .003). Responses to fixed snacks over time were not different from variable snacks, although power was low; the effect size was large for antioxidant capacity, medium for oxidative stress, and small for RHI. Snacking after fasting resulted in a transiently improved peripheral vascular response that disappeared with a second snack. Antioxidant capacity appeared to help limit oxidative stress from repeated snacking in these healthy male subjects. PMID- 22935340 TI - Duplicate portion sampling combined with spectrophotometric analysis affords the most accurate results when assessing daily dietary phosphorus intake. AB - The assessment of daily dietary phosphorus (P) intake is a major concern in human nutrition because of its relationship with Ca and Mg metabolism and osteoporosis. Within this context, we hypothesized that several of the methods available for the assessment of daily dietary intake of P are equally accurate and reliable, although few studies have been conducted to confirm this. The aim of this study then was to evaluate daily dietary P intake, which we did by 3 methods: duplicate portion sampling of 108 hospital meals, combined either with spectrophotometric analysis or the use of food composition tables, and 24-hour dietary recall for 3 consecutive days plus the use of food composition tables. The mean P daily dietary intakes found were 1106 +/- 221, 1480 +/- 221, and 1515 +/- 223 mg/d, respectively. Daily dietary intake of P determined by spectrophotometric analysis was significantly lower (P < .001) and closer to dietary reference intakes for adolescents aged from 14 to 18 years (88.5%) and adult subjects (158.1%) compared with the other 2 methods. Duplicate portion sampling with P analysis takes into account the influence of technological and cooking processes on the P content of foods and meals and therefore afforded the most accurate and reliable P daily dietary intakes. The use of referred food composition tables overestimated daily dietary P intake. No adverse effects in relation to P nutrition (deficiencies or toxic effects) were encountered. PMID- 22935341 TI - The lipid accumulation product is highly related to serum alanine aminotransferase level in male adults. AB - Studies confirm that the lipid accumulation product (LAP), which is based on the waist circumference and fasting serum triglycerides, is highly related to cardiovascular and metabolic diseases. Nonalcoholic fatty liver disease is a hepatic manifestation of metabolic syndrome and closely correlated with the alanine aminotransferase (ALT) elevation. Abdominal obesity and dyslipidemia are the important risk factors for nonalcoholic fatty liver disease. Our aim was to examine the correlation between the LAP and ALT in apparently healthy adults. We conducted a cross-sectional study of 587 adults. The blood pressure, anthropometric measurements, fasting and postload glucose, insulin, fasting lipid profile, and liver enzymes were measured. The LAP was calculated. For each gender, the subjects were divided into 3 groups according to the ALT level. The correlation between the LAP and ALT was analyzed. The LAP increased progressively across the ALT tertiles. A Pearson correlation analysis demonstrated that the LAP positively associated with the ALT in men and women (both P < .05) but independently related to the ALT only in men. Furthermore, after adjusting for the other confounding factors, the subjects in the upper quartile of LAP was 3.61 times more likely to show ALT elevation compared with those in the lower quartiles in men. In addition, in men, the LAP was considered as the best marker to predict increased ALT. Our findings suggested that the LAP was independently correlated with the ALT but only in men. The LAP was the main risk marker and might be superior to other variables in recognizing increased ALT. PMID- 22935342 TI - Fructose consumption during pregnancy and lactation induces fatty liver and glucose intolerance in rats. AB - Nutritional insults during pregnancy and lactation are health risks for mother and offspring. Both fructose (FR) and low-protein (LP) diets are linked to hepatic steatosis and insulin resistance in nonpregnant animals. We hypothesized that dietary FR or LP intake during pregnancy may exacerbate the already compromised glucose homeostasis to induce gestational diabetes and fatty liver. Therefore, we investigated and compared the effects of LP or FR intake on hepatic steatosis and insulin resistance in unmated controls (CTs) and pregnant and lactating rats. Sprague-Dawley rats were fed a CT, or a 63% FR, or an 8% LP diet. Glucose tolerance test at day 17 of the study revealed greater (P < .05) blood glucose at 10 (75.6 mg/dL vs 64.0 +/- 4.8 mg/dL) minutes and 20 (72.4 mg/dL vs 58.6 +/- 4.0 mg/dL) minutes after glucose dose and greater area under the curve (4302.3 mg?dL(-1)?min(-1) vs 3763.4 +/- 263.6 mg?dL(-1)?min(-1)) for FR-fed dams compared with CT-fed dams. The rats were euthanized at 21 days postpartum. Both the FR- and LP-fed dams had enlarged (P < .05) livers (9.3%, 7.1% body weight vs 4.8% +/- 0.2% body weight) and elevated (P < .05) liver triacylglycerol (216.0, 130.0 mg/g vs 19.9 +/- 12.6 mg/g liver weight) compared with CT-fed dams. Fructose induced fatty liver and glucose intolerance in pregnant and lactating rats, but not unmated CT rats. The data demonstrate a unique physiological status response to diet resulting in the development of gestational diabetes coupled with hepatic steatosis in FR-fed dams, which is more severe than an LP diet. PMID- 22935343 TI - Fructan extracts from wheat stem and barley grain stimulate large bowel fermentation in rats. AB - The benefits of inulin-type fructans for bowel health are well established, but less so for other fructan sources. In vitro data suggest that fructans extracted from cereals are readily fermented and produce favorable short-chain fatty acid profiles; however, whether this occurs in vivo is unknown. We hypothesized that in rats, fructans extracted from wheat stem and barley grain would have similar effects on fermentation as oligofructose (OF). Fifty-six male Sprague-Dawley rats were randomly assigned to 1 of 7 dietary treatments that contained either 2% or 5% fructan, provided by a barley grain fructan extract (BGFE), a wheat stem fructan extract, or OF or no added fructan (control). The duration of the feeding study was 14 days. Rats fed diets containing 5% fructan had higher cecal digesta weights; larger acetate, propionate, and total short-chain fatty acid pools; and lower pHs in comparison with the control group. In addition, only the 5% OF and 5% BGFE groups increased cecal butyrate pools, and 5% BGFE was the only group in which colonic digesta pH was lower than that of the control. Diets containing 2% fructan did not affect any of these fermentation end points. Whereas bifidobacteria numbers in cecal digesta of 2% and 5% OF were higher than that in the control group, they were not different from those in rats fed diets containing BGFE and wheat stem fructan extract. Barley grain and wheat stem fructans produced similar large bowel fermentation patterns to OF when fed to rats at 5% of the diet. PMID- 22935344 TI - An inhibitory effect of resveratrol in the mitotic clonal expansion and insulin signaling pathway in the early phase of adipogenesis. AB - Resveratrol is known as a potent antiobesity compound that acts partly through inhibition of adipogenesis. However, the direct targets responsible for its antiadipogenic action are unclear. Our hypothesis is that resveratrol inhibits adipogenesis through modulation of mitotic clonal expansion (MCE) and cell signaling pathways in the early phase of differentiation. To test this, we examined the effects of resveratrol on MCE and insulin signaling pathway in the early phase of adipogenesis in murine preadipocytes. We observed that the antiadipogenic action of resveratrol is largely limited to the early phase of adipogenesis. Specifically, the presence of resveratrol in the first 24 hours of adipogenesis was required for its antiadipogenic effect. During the first 24 hours of adipogenesis, resveratrol impaired the progression of MCE by suppressing the cell cycle entry of preadipocytes to G2/M phase, and expression of cell cycle regulators cyclin A and cyclin-dependent kinase 2. Concomitantly, resveratrol inhibited insulin signaling pathway in the early phase of adipogenesis. Furthermore, we revealed an inhibitory effect of resveratrol on insulin receptor (IR) activity, and this is likely through a direct physical interaction between resveratrol and IR. The antiadipogenic effect of resveratrol is through inhibition of the MCE and IR-dependent insulin signaling pathway in the early phase of adipogenesis. PMID- 22935345 TI - Genistein promotes insulin action through adenosine monophosphate-activated protein kinase activation and p70 ribosomal protein S6 kinase 1 inhibition in the skeletal muscle of mice fed a high energy diet. AB - Genistein (GEN), a soy isoflavone, exerts insulin-sensitizing actions in animals; however, the underlying mechanisms have not been determined. Because GEN is a known activator of adenosine monophosphate-activated protein kinase (AMPK), we hypothesize that GEN activates insulin signaling through AMPK activation. To test this hypothesis, a high fat-high fructose diet (HFFD)-fed mice model of insulin resistance was administered GEN, and the insulin signaling pathway proteins in the skeletal muscle were examined. Hyperglycemia and hyperinsulinemia observed in HFFD-fed mice were significantly lowered by GEN. GEN increased insulin-stimulated tyrosine phosphorylation of insulin receptor-beta and insulin receptor substrate (IRS) 1 but down-regulated IRS-1 serine phosphorylation in the skeletal muscle of HFFD-fed mice. Furthermore, GEN treatment improved muscle IRS-1-associated phospatidylinositol-3 kinase expression, phosphorylation of Akt at Ser(473), and translocation of glucose transporter subtype 4. Phosphorylation of AMPK at Thr(172) and acetyl coenzyme A carboxylase (ACC) at Ser(79) was augmented, whereas phosphorylation of p70 ribosomal protein S6 kinase 1 at Thr(389) was significantly decreased after GEN treatment in the skeletal muscle of HFFD-fed mice. These results suggest that GEN might improve insulin action in the skeletal muscle by targeting AMPK. PMID- 22935346 TI - Aqueous extract of tamarind seeds selectively increases glucose transporter-2, glucose transporter-4, and islets' intracellular calcium levels and stimulates beta-cell proliferation resulting in improved glucose homeostasis in rats with streptozotocin-induced diabetes mellitus. AB - Tamarindus indica Linn. has been in use for a long time in Asian food and traditional medicine for different diseases including diabetes and obesity. However, the molecular mechanisms of these effects have not been fully understood. In view of the multidimensional activity of tamarind seeds due to their having high levels of polyphenols and flavonoids, we hypothesized that the insulin mimetic effect of aqueous tamarind seed extract (TSE) might increase glucose uptake through improvement in the expression of genes of the glucose transporter (GLUT) family and sterol regulatory element-binding proteins (SREBP) 1c messenger RNA (mRNA) in the liver. Daily oral administration of TSE to streptozotocin (STZ)-induced (90 mg/kg intraperitoneally) type 2 diabetic male Wistar rats at different doses (120 and 240 mg/kg body weight) for 4 weeks showed positive correlation with intracellular calcium and insulin release in isolated islets of Langerhans. Tamarind seed extract supplementation significantly improved the GLUT-2 protein and SREBP-1c mRNA expression in the liver and GLUT-4 protein and mRNA expression in the skeletal muscles of diabetic rats. The elevated levels of serum nitric oxide (NO), glycosylated hemoglobin level (hemoglobin (A1c)) and tumor necrosis factor alpha (TNF-alpha) decreased after TSE administration. Immunohistochemical findings revealed that TSE abrogated STZ induced apoptosis and increased beta-cell neogenesis, indicating its effect on islets and beta-cell mass. In conclusion, it was found that the antidiabetic effect of TSE on STZ-induced diabetes resulted from complex mechanisms of beta cell neogenesis, calcium handling, GLUT-2, GLUT-4, and SREBP-1c. These findings show the scope for formulating a new herbal drug for diabetes therapy. PMID- 22935347 TI - Impact speed and a pedestrian's risk of severe injury or death. AB - This study estimates the risk of severe injury or death for pedestrians struck by vehicles using data from a study of crashes that occurred in the United States in years 1994-1998 and involved a pedestrian struck by a forward-moving car, light truck, van, or sport utility vehicle. The data were weighted to correct for oversampling of pedestrians who were severely injured or killed. Logistic regression was used to adjust for potential confounding related to pedestrian and vehicle characteristics. Risks were standardized to represent the average risk for a pedestrian struck by a car or light truck in the United States in years 2007-2009. Results show that the average risk of a struck pedestrian sustaining an injury of Abbreviated Injury Scale 4 or greater severity reaches 10% at an impact speed of 17.1miles per hour (mph), 25% at 24.9mph, 50% at 33.0mph, 75% at 40.8mph, and 90% at 48.1mph. The average risk of death reaches 10% at an impact speed of 24.1mph, 25% at 32.5mph, 50% at 40.6mph, 75% at 48.0mph, and 90% at 54.6mph. Risks varied by age. For example, the average risk of death for a 70 year-old pedestrian struck at any given speed was similar to the average risk of death for a 30-year-old pedestrian struck at a speed 11.8mph faster. PMID- 22935348 TI - Stenting of the vertebral artery origin with ostium dilation: technical note. AB - Endovascular treatment of vertebral artery (VA) origin stenosis typically requires placement of the proximal end of the stent within the lumen of the subclavian artery or aorta to provide complete coverage of the ostial lesion. This configuration may complicate subsequent endovascular access into the stented VA. We describe a technique modification of VA origin stenting and angioplasty with a monorail angioplasty balloon system designed specifically for dilation of the ostial origin which may be helpful in conforming the proximal portion of the stent to the VA origin. Simplified endovascular access to the VA origin after angioplasty is demonstrated. PMID- 22935349 TI - Utilization of CT perfusion patient selection for mechanical thrombectomy irrespective of time: a comparison of functional outcomes and complications. AB - BACKGROUND: Patient selection for acute ischemic stroke has been largely driven by time-based criteria, although emerging data suggest that image-based criteria may be useful. The purpose of this study was to directly compare outcomes of patients treated within a traditional time window with those treated beyond this benchmark when CT perfusion (CTP) imaging was used as the primary selection tool. METHODS: A prospectively collected database of all patients with acute ischemic stroke who received intra-arterial therapy at the Medical University of South Carolina was retrospectively analyzed, regardless of time from symptom onset. At presentation, CTP maps were qualitatively assessed. Selected patients underwent intra-arterial therapy. Functional outcome according to the modified Rankin scale (mRS) score at about 90 days was documented. RESULTS: 140 patients were included in the study. The median time from symptom onset to groin access was 7.0 h. Overall, 28 patients (20%) had bleeding complications, but only 10 (7.1%) were symptomatic. The average National Institute of Health Stroke Scale (NIHSS) score for patients treated <= 7 h from symptom onset was 17.3 and 30.2% had a mRS score of 0-2 at 90 days. Patients treated >7 h from symptom onset had an average NIHSS score of 15.1 and 45.5% achieved a mRS score of 0-2 at 90 days (p=0.104). Patients in the two groups had similar rates of symptomatic intracerebral hemorrhage (8.5% and 5.8%, respectively; p=0.745). CONCLUSIONS: No difference was found in the rates of good functional outcome between patients treated <= 7 h and those treated >7 h from symptom onset. These data suggest that imaging-based patient selection is a safe and viable methodology. PMID- 22935350 TI - Endovascular management of spinal arteriovenous malformations. AB - Spinal arteriovenous malformations (sAVMs) are rare vascular lesions whose natural history remains incompletely defined. Several classification schemes for sAVMs have evolved based on an improved understanding of the anatomic characteristics as well as pathophysiologic behavior of these arteriovenous shunts. Advances in endovascular technology have inspired the adoption of interventional techniques both as stand-alone treatment and as part of a multi modality management paradigm for sAVMs. Further refinements in liquid embolic agents as well as improved microcatheter navigability will contribute to an ever expanding role for endovascular intervention in the management of these lesions. PMID- 22935351 TI - Urinary N-acetyl-beta-D glucosaminidase as a surrogate marker for renal function in autosomal dominant polycystic kidney disease: 1 year prospective cohort study. AB - BACKGROUND: Renal failure is one of the most serious complications associated with autosomal dominant polycystic kidney disease (ADPKD). To date, early markers have failed to predict renal function deterioration at the early stages. This 1 year prospective study evaluated N-acetyl-beta-D-glucosaminidase (NAG) as a new surrogate marker for renal function in ADPKD. METHODS: A total of 270 patients were enrolled in the study, and we measured urinary NAG, beta2-microglobulin, neutrophil gelatinase-associated lipocalin (NGAL) and kidney injury molecule-1 (KIM-1) prospectively for 1 year to compare their predictive values for renal function. RESULTS: Baseline urinary NAG/Cr was negatively correlated with estimated glomerular filtration rate (GFR) (r2 = 0.153, P < 0.001) and positively correlated with total kidney volume (TKV) (r2 = 0.113, P < 0.001). Among other biomarkers, urinary NAG/Cr better discriminated patients with decreased renal function from those with conserved renal function, showing the largest area under the curve (AUC 0.794). Immunohistochemical study revealed strong staining along the cyst-lining epithelial cells as well as the nearby compressed tubular epithelial cells. However, both single and repeated measurements of urinary NAG/Cr failed to predict renal function decline in 1 year. CONCLUSIONS: Urinary NAG/Cr may be a useful surrogate marker for renal function in ADPKD patients. PMID- 22935352 TI - Reproduction in porcine circovirus type 2 (PCV2) seropositive gilts inseminated with PCV2b spiked semen. AB - BACKGROUND: Since 1999, field evidence of transplacental infection by porcine circovirus type 2 (PCV2) and reproductive failure has been reported in pigs. The objective of this study was to evaluate the clinical and pathological consequences of PCV2 infection in conventional PCV2-seropositive gilts by insemination with PCV2b-spiked semen. RESULTS: Six PCV2 seropositive gilts were inseminated with PCV2b-supplemented semen (infected) and three animals with semen and cell culture medium (controls). Only three out of the six infected animals were pregnant by ultrasonography on day 29 after insemination, while two out of the three controls were pregnant. One control gilt aborted on day 23 after insemination but not due to PVC2. Viraemia was demonstrated in four out of six infected and in one control gilt that became infected with PCV2a. Anti-PCV2 antibody titres showed dynamic variations in the infected group throughout the study. Among infected gilts, the animal with the lowest anti-PCV2 titre (1/100) at the beginning of the experiment and another that reached a similar low value during the experiment showed evident seroconversion over time and had also PCV2 positive foetuses. One placenta displayed mild focal necrosis of the chorionic epithelium positively stained by immunohistochemistry for PCV2 antigen. CONCLUSIONS: PCV2-seropositive gilts can be infected with PCV2 after intrauterine exposure and low maternal antibody titre may increase the probability of a foetal infection. PMID- 22935353 TI - Optic ataxia affects the lower limbs: evidence from a single case study. AB - Optic ataxia represents a spatial impairment of visually guided reaching following bilateral or unilateral damage to the posterior parietal cortex that is independent of purely motor or visual deficits. Research to date has focused on reaching actions performed with the upper limbs but has neglected to explore whether or not optic ataxia affects the lower limbs, that is, whether it is effector-specific. We asked patient M.H., who suffers from unilateral optic ataxia from left hemispheric damage, and eight age-matched controls, to perform leg movements by stepping down from a wooden block towards a visually presented target. Steps were performed using the left or the right leg, in conditions of central fixation or free viewing. Patient M.H. performed significantly worse than controls. His errors in step accuracy were most pronounced when stepping into the visual periphery (during central fixation), particularly while using the contralesional right foot towards the contralesional right hemispace. This behaviour is consistent with M.H.'s impairments in optic ataxia previously recorded for reaching and grasping actions with the upper limbs. The lesion affecting M.H.'s brain is quite large, encompassing functional areas associated with visuomotor transformations performed with different effectors such as arm and eye (superior parietal-occipital cortex and medial intraparietal sulcus). Our data suggest that optic ataxia is not completely effector-specific, and that neurons encoding visuomotor transformations for both arm and leg are probably both affected by the damage. Our results support the notion that lesions affecting the medial portion of the left posterior parietal cortex similarly affect different effectors (arm and leg) when visually guided actions are directed towards the same contralesional hemispace. In addition they may help explain why patients with optic ataxia have been reported to have difficulties in certain aspects of visually guided locomotion. PMID- 22935355 TI - Understanding overeating and obesity. AB - The combination of economic and biological factors is likely to result in overeating in the current environment of cheap and readily available food. This propensity is shown using a "dual decision" approach where choices reflect the interaction of a "deliberative" system, operating as in standard economic models, and an "affective" system that responds rapidly to stimuli without considering long-term consequences. This framework is characterized by excess food consumption and body weight, in that individuals prefer both ex-ante and ex-post to eat and weigh less than they actually do, with weight loss attempts being common but often unsuccessful or only partially successful. As in the standard model, weight is related to prices. However, another potentially important reason for rising obesity is that food producers have incentives to engineer products to stimulate the affective system so as to encourage overeating. Data from several sources are used to investigate predictions of the dual decision model, with the evidence providing broad support for at least some irrationality in food consumption. Most importantly, there is little indication that the large secular increases in body mass index have been accompanied by corresponding growth in utility-maximizing weight. One result is that efforts to reduce weight have become more common as obesity has increased. PMID- 22935356 TI - Simulators and the simulation environment: getting the balance right in simulation-based surgical education. AB - INTRODUCTION: Simulation occupies a central position in surgical education. It offers a safe environment for trainees to develop and improve their skills through sustained deliberate self-practice and appropriate feedback. This review explores the role of simulators and the simulation environment in light of educational theory to promote effective learning. DATA SOURCES: Information was obtained from peer-reviewed publications, books and online material. CONCLUSION: A simplistic perspective frames simulation as a means of gaining technical skills on basic models by offering a safe alternative to carrying out procedures on real patients. Although necessary, that aspect of simulation requires greater depth to satisfy the growing demand for alternatives to traditional clinical learning. A more realistic view should frame simulation as a means to gaining mastery within a complex clinical world. In order to strike the balance on simulating an ideal clinical scenario, alignment of the simulator and the simulation environment in the appropriate context appears crucial. PMID- 22935354 TI - Probing ion channel activity of human islet amyloid polypeptide (amylin). AB - Interactions of human islet amyloid polypeptide (hIAPP or amylin) with the cell membrane are correlated with the dysfunction and death of pancreatic islet beta cells in type II diabetes. Formation of receptor-independent channels by hIAPP in the membrane is regarded as one of the membrane-damaging mechanisms that induce ion homeostasis and toxicity in islet beta-cells. Here, we investigate the dynamic structure, ion conductivity, and membrane interactions of hIAPP channels in the DOPC bilayer using molecular modeling and molecular dynamics simulations. We use the NMR-derived beta-strand-turn-beta-strand motif as a building block to computationally construct a series of annular-like hIAPP structures with different sizes and topologies. In the simulated lipid environments, the channels lose their initial continuous beta-sheet network and break into oligomeric subunits, which are still loosely associated to form heterogeneous channel conformations. The channels' shapes, morphologies and dimensions are compatible with the doughnut-like images obtained by atomic force microscopy, and with those of modeled channels for Abeta, the beta(2)-microglobulin-derived K3 peptides, and the beta-hairpin-based channels of antimicrobial peptide PG-1. Further, all channels induce directional permeability of multiple ions across the bilayers from the lower to the upper leaflet. This similarity suggests that loosely associated beta-structure motifs can be a general feature of toxic, unregulated channels. In the absence of experimental high-resolution atomic structures of hIAPP channels in the membrane, this study represents a first attempt to delineate some of the main structural features of the hIAPP channels, for a better understanding of the origin of amyloid toxicity and the development of pharmaceutical agents. PMID- 22935357 TI - Macroscopic and pathological assessment of methylene blue and normal saline on postoperative adhesion formation in a rat cecum model. AB - BACKGROUND: Adhesion formation after abdominal surgery is a major cause of postoperative bowel obstruction, infertility, and chronic abdominal pain. In this study, we evaluated the effect of normal saline and methylene blue (MB) on postoperative adhesion formation in a rat cecum model. METHODS: A total of 30 Wistar female rats in 2 treatment and 1 control groups underwent midline laparotomy and standardized abrasion of the visceral peritoneum. Normal saline and methylene blue were administrated intraperitoneally at the end of the surgical procedure in 2 treatment groups. Fourteen days after surgery, a re laparotomy was performed for macroscopic and pathological assessment. RESULTS: The adhesion grade and extent of the normal saline group was lower than control and MB groups in macroscopic assessment (P<0.05 for both). A comparison of adhesion stages in pathological assessment showed increment in abdominal adhesion by usage methylene blue 1% and demonstrated significant difference between MB and 2 other groups (P<0.05). CONCLUSIONS: Administrated normal saline individually reduce the adhesion grade near cecum. Conversely, usage of methylene blue 1% may unpredictably increase risk of adhesion formation. PMID- 22935358 TI - Nuclear microsatellites for Pinus pinea (Pinaceae), a genetically depauperate tree, and their transferability to P. halepensis. AB - PREMISE OF THE STUDY: Pinus pinea is one of the few widespread plant species that are also genetically depauperate. It is also an important commercial species with high market value seeds. A deeper knowledge of the existing population genetic variation was needed. METHODS AND RESULTS: Twelve nuclear microsatellites were isolated from genomic and cDNA sequences and screened for variability in 729 individuals from 33 natural populations. Low level of genetic variability was confirmed with average expected heterozygosity of 0.11. Hardy-Weinberg equilibrium expectations were not met in only ~10% of the possible locus/population combinations. All loci were in linkage equilibrium, and the frequency of null alleles was very low (<=1% in 332 out of 396 locus/population combinations). Nine out of the 12 microsatellites were successfully transferred to P. halepensis. CONCLUSIONS: Despite low polymorphism, these new markers will be useful to resolve population structure and hold potential for seed origin identification and traceability. PMID- 22935359 TI - Isolation and characterization of a first set of polymorphic microsatellite markers in saffron, Crocus sativus (Iridaceae). AB - PREMISE OF THE STUDY: Twelve novel polymorphic microsatellite loci were developed and characterized from a repeat-enriched genomic library of Crocus sativus to study population and conservation genetics of this economically and medically important species. METHODS AND RESULTS: The microsatellite loci were isolated using a modified Fast Isolation by AFLP of Sequences COntaining repeats (FIASCO) method. The average number of alleles per locus was 2.6. The observed and expected heterozygosities varied from 0.07 to 0.92 and 0.1 to 0.58, respectively. Polymorphic information content value ranged from 0.09 to 0.55 with an average of 0.34. Four out of twelve loci showed significant departures from Hardy-Weinberg equilibrium. CONCLUSIONS: The microsatellite markers reported here will be useful for evaluating genetic diversity and will likely serve as an ideal resource for use in marker-assisted breeding programs, germplasm analysis, and varietal identification. PMID- 22935360 TI - Development of microsatellite markers for Anadenanthera colubrina var. cebil (Fabaceae), a native tree from South America. AB - PREMISE OF THE STUDY: Microsatellite primers were developed in the native legume tree Anadenanthera colubrina var. cebil to study the genetic diversity and genetic structure in natural populations in Argentina. METHODS AND RESULTS: Nine microsatellite markers were identified using a genomic library enriched for tandemly repeated motifs, eight of which markers were polymorphic. The polymorphism of these markers was assessed by investigating 20 individuals for fragment polymorphism; three to 13 alleles were observed for each locus. Observed and expected heterozygosities ranged from 0.300 to 1.000 and from 0.463 to 0.900, respectively. CONCLUSIONS: These results confirm that these primers will be useful for investigating the genetic diversity and genetic structure of natural populations of A. colubrina var. cebil in future studies. PMID- 22935361 TI - Strategies for cell shape control in tip-growing cells. AB - PREMISE OF THE STUDY: Despite the large diversity in biological cell morphology, the processes that specify and control cell shape are not yet fully understood. Here we study the shape of tip-growing, walled cells, which have evolved a polar mode of cell morphogenesis leading to characteristic filamentous cell morphologies that extend only apically. METHODS: We identified the relevant parameters for the control of cell shape and derived scaling laws based on mass conservation and force balance that connect these parameters to the resulting geometrical phenotypes. These laws provide quantitative testable relations linking morphological phenotypes to the biophysical processes involved in establishing and modulating cell shape in tip-growing, walled cells. KEY RESULTS AND CONCLUSIONS: By comparing our theoretical results to the observed morphological variation within and across species, we found that tip-growing cells from plant and fungal species share a common strategy to shape the cell, whereas oomycete species have evolved a different mechanism. PMID- 22935362 TI - Gene expression assays for actin, ubiquitin, and three microsatellite-encoding genes in Helianthus annuus (Asteraceae). AB - PREMISE OF THE STUDY: The "tuning knob" model of King et al. (Endeavor 21: 36-40, 1997) postulates that microsatellite mutations can alter phenotypes in a stepwise fashion. Some proposed mechanisms involve regulation of gene expression. To study the effect of microsatellites harbored in untranslated regions on gene expression in Helianthus annuus, we have developed TaqMan assays for three microsatellite encoding genes, and two constitutively expressed genes, actin and ubiquitin, to serve as standards. METHODS AND RESULTS: All five TaqMan assays yielded strong log-linear relationships between cycle threshold (C(T)) values and cDNA concentrations (R(2) = 0.98-0.99). Standard curves were based on five concentrations for each of five individuals. Efficiencies ranged from 0.83 to 1.03. CONCLUSIONS: The developed tools will allow for relative quantification of gene expression across individuals. Genotyping these loci will allow for testing the "tuning knob" hypothesis. Further, the actin and ubiquitin assays should be generally applicable to gene expression studies in H. annuus. PMID- 22935363 TI - Development of chromosome-arm-specific microsatellite markers in Triticum aestivum (Poaceae) using NGS technology. AB - PREMISE OF THE STUDY: The aim of this study was to assess the feasibility of developing chromosome-arm-specific microsatellite markers in wheat on a large scale based on chromosome survey sequences obtained with next-generation sequencing (NGS) technology. METHODS AND RESULTS: The Illumina Hi Seq2000 sequencing platform was used to sequence DNA of isolated wheat chromosome-arm 7DL. The data were assembled and microsatellite loci were identified computationally. In total, 16315 microsatellites were identified from 161061 assembled contigs. Thirty-three markers were randomly selected for validation across 20 diverse wheat cultivars. Two nulli-tetrasomic stocks were also screened to validate the specificity of the newly developed markers. CONCLUSIONS: This is the first study on identification of chromosome-arm-specific microsatellite markers using NGS technology. These new chromosome-arm-specific markers will facilitate saturation of the 7DL genetic map, and their availability will support genetic mapping and positional cloning in wheat. PMID- 22935364 TI - The plastid genome of the mycoheterotrophic Corallorhiza striata (Orchidaceae) is in the relatively early stages of degradation. AB - PREMISE OF THE STUDY: Plastid genomes of nonphotosynthetic, mycoheterotrophic plants represent apt systems in which to study effects of relaxed evolutionary constraints. The few mycoheterotrophic angiosperm plastomes sequenced to date display drastic patterns of degradation/reduction relative to those of photosynthetic relatives. The goal of this study was to focus on a mycoheterotrophic orchid hypothesized to be in the "early" stages of plastome degradation, to provide perspective on this process. METHODS: Short-read sequencing was used to generate a complete plastome sequence for Corallorhiza striata var. vreelandii, a mycoheterotrophic orchid, to investigate the extent of plastome degradation. Patterns of nonsynonymous/synonymous mutations were also assessed, and comparisons were made between Corallorhiza and other heterotrophic plant lineages. KEY RESULTS: Corallorhiza yielded a plastome of 137505 bp, with several photosynthesis-related genes either lost or pseudogenized. Members of all major photosynthesis complexes, except ATP-synthase genes, were affected. "Housekeeping" genes were intact, despite the loss of a single tRNA. Intact photosynthesis genes (excluding atp genes) together displayed elevated nonsynonymous changes, while housekeeping genes did not. CONCLUSIONS: The Corallorhiza plastome is not drastically reduced in overall size (~6% reduction relative to that of photosynthetic Oncidium), but displays a pattern congruent with a loss of photosynthetic function. Comparing Corallorhiza with other heterotrophs allows some emergent evolutionary patterns to be inferred, but these remain as hypotheses to be tested, especially at lower taxonomic levels, and in lineages illustrating transitions from autotrophy to heterotrophy. The independent, unique processes of plastome modification among mycoheterotrophic lineages illustrate the urgency of their conservation. PMID- 22935366 TI - Agreement of bioelectrical impedance with dual-energy X-ray absorptiometry and MRI to estimate changes in body fat, skeletal muscle and visceral fat during a 12 month weight loss intervention. AB - The aim of the present study was to analyse the agreement of bioelectrical impedance analysis (BIA) compared with dual-energy X-ray absorptiometry (DXA) and MRI in estimating body fat, skeletal muscle and visceral fat during a 12-month weight loss intervention. A total of nineteen obese adults (twelve females, seven males) aged 20.2-48.6 years, mean BMI 34.6 (SE 0.6) kg/m2, participated in the study. Body fat, skeletal muscle and visceral fat index were measured by BIA (Omron BF-500; Omron Medizintechnik) and compared with DXA (body fat and skeletal muscle) at baseline, 5 and 12 months, and with MRI (visceral fat) at baseline and 5 months. The subjects lost 8.9 (SE 1.8) kg (9.0 (SE 1.7) %) of body weight during the 12-month intervention. BIA, as compared to DXA, accurately assessed loss of fat (7.0 (SE 1.5) v. 7.0 (SE 1.4) kg, P= 0.94) and muscle (1.0 (SE 0.2) v. 1.4 (SE 0.3) kg, P= 0.18). While body fat was similar by the two methods, skeletal muscle was underestimated by 1-2 kg using BIA at each time point. Compared to MRI, BIA overestimated visceral fat, especially in males. BIA and DXA showed high correlations for kg fat, both cross-sectionally and longitudinally (r 0.91-0.99). BIA, compared with DXA and MRI, detected kg muscle and visceral fat more accurately cross-sectionally (r 0.77-0.87 and r 0.40-0.78, respectively) than their changes longitudinally (r 0.24-0.61 and r 0.46, respectively). BIA is at its best when assessing the amount or changes in fat mass. It is a useful method for measuring skeletal muscle, but limited in its ability to measure visceral fat. PMID- 22935365 TI - The alcohol industry lobby and Hong Kong's zero wine and beer tax policy. AB - BACKGROUND: Whereas taxation on alcohol is becoming an increasingly common practice in many countries as part of overall public health measures, the Hong Kong Special Administrative Region Government is bucking the trend and lowered its duties on wine and beer by 50 percent in 2007. In 2008, Hong Kong removed all duties on alcohol except for spirits. The aim of this paper is to examine the case of Hong Kong with its history of changes in alcohol taxation to explore the factors that have driven such an unprecedented policy evolution. METHODS: The research is based on an analysis of primary documents. Searches of official government documents, alcohol-related industry materials and other media reports on alcohol taxation for the period from 2000 to 2008 were systematically carried out using key terms such as "alcohol tax" and "alcohol industry". Relevant documents (97) were indexed by date and topic to undertake a chronological and thematic analysis using Nvivo8 software. RESULTS: Our analysis demonstrates that whereas the city's changing financial circumstances and the Hong Kong Special Administrative Region Government's strong propensity towards economic liberalism had, in part, contributed to such dramatic transformation, the alcohol industry's lobbying tactics and influence were clearly the main drivers of the policy decision. The alcohol industry's lobbying tactics were two-fold. The first was to forge a coalition encompassing a range of catering and trade industries related to alcohol as well as industry-friendly lawmakers so that these like-minded actors could find common ground in pursuing changes to the taxation policy. The second was to deliberately promote a blend of ideas to garner support from the general public and to influence the perception of key policy makers. CONCLUSIONS: Our findings suggest that the success of aggressive industry lobbying coupled with the absence of robust public health advocacy was the main driving force behind the unparalleled abolition of wine and beer duties in Hong Kong. Strong public health alliance and advocacy movement are needed to counteract the industry's continuing aggressive lobby and promotion of alcoholic beverages. PMID- 22935367 TI - Sodium dodecyl sulfate-modified electrochemical paper-based analytical device for determination of dopamine levels in biological samples. AB - We report the development of an electrochemical paper-based analytical device (ePAD) for the selective determination of dopamine (DA) in model serum sample. The ePAD device consists of three layers. In the top layer, SU-8 photoresist defines a hydrophilic sample application spot on the filter paper. The middle layer was made from transparency film and contained two holes, one for sample preconcentration and the other for the surfactant to allow transfer to the third layer. A screen-printed carbon electrode formed the bottom layer and was used for electrochemical measurements. In the absence of the anionic surfactant, sodium dodecyl sulfate (SDS), the oxidation peaks of DA, ascorbic acid (AA) and uric acid (UA) overlapped. With the addition of SDS, the DA oxidation peak shifted to more negative values and was clearly distinguishable from AA and UA. The oxidation potential shift was presumably due to preferential electrostatic interactions between the cationic DA and the anionic SDS. Indeed, whilst the SDS modified paper improved the DA current five-fold, the non-ionic Tween-20 and cationic tetradecyltrimethylammonium bromide surfactants had no effect or reduced the current, respectively. Furthermore, only the SDS-modified paper showed the selective shift in oxidation potential for DA. DA determination was carried out using square-wave voltammetry between -0.2 and 0.8 V vs. Ag/AgCl, and this ePAD was able to detect DA over a linear range of 1-100 MUM with a detection limit (S/N=3) of 0.37 MUM. The ePAD seems suitable as a low cost, easy-to-use, portable device for the selective quantitation of DA in human serum samples. PMID- 22935368 TI - An overview of the analytical characterization of nanostructured drug delivery systems: towards green and sustainable pharmaceuticals: a review. AB - The analytical characterization of drug delivery systems prepared by means of green manufacturing technologies using CO(2) as a processing fluid is here reviewed. The assessment of the performance of nanopharmaceuticals designed for controlled drug release may result in a complex analytical issue and multidisciplinary studies focused on the evaluation of physicochemical, morphological and textural properties of the products may be required. The determination of the drug content as well as the detection of impurities and solvent residues are often carried out by chromatography. Assays on solid state samples relying on X-ray, vibrational and nuclear magnetic resonance spectroscopies are of great interests to study the composition and structure of pharmaceutical forms. The morphology and size of particles are commonly checked by microscopy and complementary chemical information can be extracted in combination with spectroscopic accessories. Regarding the thermal behavior, calorimetric and thermogravimetric techniques are applied to assess the thermal transitions and stability of the samples. The evaluation of drug release profiles from the nanopharmaceuticals can be based on various experimental set-ups depending on the administration route to be considered. Kinetic curves showing the evolution of the drug concentration as a function of time in various physiological conditions (e.g., gastric, plasmatic or topical) are recorded commonly by UV-vis spectroscopy and/or chromatography. Representative examples are commented in detail to illustrate the characterization strategies. PMID- 22935369 TI - Surfactant media for constant-current coulometry. Application for the determination of antioxidants in pharmaceuticals. AB - Effect of surfactant presence on electrochemical generation of titrants has been evaluated and discussed for the first time. Cationic (1-dodecylpyridinium and cetylpyridinium bromide), anionic (sodium dodecyl sulfate) and nonionic (Triton X100 and Brij((r)) 35) surfactants as well as nonionic high molecular weight polymer (PEG 4000) do not react with the electrogenerated bromine, iodine and hexacyanoferrate(III) ions. The electrogenerated chlorine chemically interact with Triton X100 and Brij((r)) 35. The allowable range of surfactants concentrations providing 100% current yield has been found. Chain-breaking low molecular weight antioxidants (ascorbic acid, rutin, alpha-tocopherol and retinol) were determined by reaction with the electrogenerated titrants in surfactant media. Nonionic and cationic surfactants can be used for the determination of antioxidants by reaction with the electrogenerated halogens. On contrary, cationic surfactants gives significantly overstated results of antioxidants determination with electrogenerated hexacyanoferrate(III) ions. The use of surfactants in coulometry of alpha-tocopherol and retinol provides their solubilization and allows to perform titration in water media. Simple, express and reliable coulometric approach for determination of alpha-tocopherol, rutin and ascorbic acid in pharmaceuticals using surfactant media has been developed. The relative standard deviation of the measurements does not exceed of 5%. PMID- 22935370 TI - Electroanalytical measurements without electrolytes: conducting polymers as probes for redox titration in non-conductive organic media. AB - Electroanalytical methods have been applied only in conducting media. An application of conducting polymers allows to overcome this limitation. If such material is in electrochemical equilibrium with dissolved redox active species, its electrical conductivity depends on the redox potential of these species. Therefore, conductometric measurements with conducting polymers can provide about the same information as classical redox electrodes. The approach was applied for redox titration. Equivalent points obtained by this titration in aqueous and organic electrolytes were identical. Then the approach was applied for determination of bromine number by redox titration in non-conducting organic phase. PMID- 22935371 TI - Visible light induced photoelectrochemical biosensing based on oxygen-sensitive quantum dots. AB - A visible light induced photoelectrochemical biosensing platform based on oxygen sensitive near-infrared quantum dots (NIR QDs) was developed for detection of glucose. The NIR QDs were synthesized in an aqueous solution, and characterized with scanning electron microscopy and X-ray photoelectron spectroscopy. The as prepared NIR QDs were employed to construct oxygen-sensitive photoelectrochemical biosensor on a fluorine-doped tin oxide (FTO) electrode. The oxygen dependency of the photocurrent was investigated at as-prepared electrode, which demonstrated the signal of photocurrent is suppressed with the decreasing of oxygen. Coupling with the consumption of oxygen during enzymatic reaction, a photoelectrochemical strategy was proposed for the detection of substrate. Using glucose oxidase (GOx) as a model enzyme, that is, GOx was covalently attached to the surface of CdTe QDs, the resulting biosensor showed the sensitive response to glucose. Under the irradiation of visible light of a wavelength at 505 nm, the proposed photoelectrochemical method could detect glucose ranging from 0.1 mM to 11 mM with a detection limit of 0.04 mM. The photoelectrochemical biosensor showed a good performance with high upper detection limit, acceptable stability and accuracy, providing an alternative method for monitoring biomolecules and extending the application of near-infrared QDs. PMID- 22935372 TI - Thin layer coulometric determination of nitrate in fresh waters. AB - A nitrate ion-selective electrode (ISE) employing a permeable tubular membrane impregnated with a conventional ISE cocktail has been used successfully in the coulometric analysis of nitrate in fresh waters. The liquid ISE membrane comprising a nitrate ionophore [tridodecylmethylammonium nitrate (TDMAN)], lipophilic electrolyte [tetradodecyl-ammoniumtetrakis(4-chlorophenyl)borate (ETH 500)] and plasticizer [bis(3-ethyl-hexyl)sebacate (DOS)] was supported on a porous polypropylene tube. Coulometric analysis with the tubular membrane ISE showed that nitrate could be detected in the range 10-100 MUM with a precision of 2.3% relative standard deviation (RSD), limit of detection of 1.1 MUM and relative accuracy of 4.4% compared to a certified reference material (CRM) Lake sample. PMID- 22935374 TI - Determination of amino acids in selenium-enriched yeast by gas chromatography mass spectrometry after microwave assisted hydrolysis. AB - A simple, rapid microwave digestion procedure for protein hydrolysis preceding the determination of amino acids in yeast using gas chromatography-mass spectrometry (GC-MS) is described. Protein hydrolysis was performed in a focused microwave using 4M methanesulfonic acid (MAS). Amino acids were derivatized with methyl chlorofomate (MCF) and extracted into chloroform prior to GC-MS analysis. The microwave parameters, including power, temperature and heating time, were optimized. It was found that temperature and heating time were the most influential factors. A total of 17 amino acids were determined in selenium enriched yeast with use of standard addition calibration. Limits of detection and quantitation (LODs/LOQs) of the amino acids measured were in the sub-nmol range, suitable for monitoring of amino acids in yeast and other food products. PMID- 22935373 TI - Label-free electrochemical impedance detection of kinase and phosphatase activities using carbon nanofiber nanoelectrode arrays. AB - We demonstrate the feasibility of a label-free electrochemical method to detect the kinetics of phosphorylation and dephosphorylation of surface-attached peptides catalyzed by kinase and phosphatase, respectively. The peptides with a sequence specific to c-Src tyrosine kinase and protein tyrosine phosphatase 1B (PTP1B) were first validated with ELISA-based protein tyrosine kinase assay and then functionalized on vertically aligned carbon nanofiber (VACNF) nanoelectrode arrays (NEAs). Real-time electrochemical impedance spectroscopy (REIS) measurements showed reversible impedance changes upon the addition of c-Src kinase and PTP1B phosphatase. Only a small and unreliable impedance variation was observed during the peptide phosphorylation, but a large and fast impedance decrease was observed during the peptide dephosphorylation at different PTP1B concentrations. The REIS data of dephosphorylation displayed a well-defined exponential decay following the Michaelis-Menten heterogeneous enzymatic model with a specific constant, k(cat)/K(m), of (2.1+/-0.1)*10(7) M(-1)s(-1). Consistent values of the specific constant was measured at PTP1B concentration varying from 1.2 to 2.4 nM with the corresponding electrochemical signal decay constant varying from 38.5 to 19.1s. This electrochemical method can be potentially used as a label-free method for profiling enzyme activities in fast reactions. PMID- 22935375 TI - A specific Tween-80-Rhodamine S-MWNTs phosphorescent reagent for the detection of trace calcitonin. AB - The present study proposed a simple sensitive and specific immunoassay for the quantification of calcitonin (CT) in human serum with water-soluble multi-walled carbon nanotubes (MWNTs). The COOH group of MWNTs could react with the NH group of rhodamine S (Rhod.S) molecules to form Rhod.S-MWNTs, which could emit room temperature phosphorescence (RTP) on acetate cellulose membrane (ACM) and react with Tween-80 to form micellar compound. Tween-80-Rhod.S-MWNTs (TRM), as a phosphorescent labelling reagent, could dramatically enhance the RTP signal of the system. The developed TRM phosphorescent reagent was used to label anti calcitonin antibody (Ab(CT)) to form the TRM-Ab(CT) labelling product, which could take high specific immunoreaction with CT, and the DeltaI(p) (= I(p2) I(p1), I(p2) and I(p1) were the phosphorescence intensity of the test solution and the blank sample, respectively) of the system was linear to the content of CT. Hence, a new solid substrate room temperature phosphorescence immunoassay (SSRTPIA) was established for the determination of CT in human serum. This sensitive (limit of quantification (LOQ) was 8.0*10(-14) g mL(-1)), accurate, selective and precise method has been applied to determine CT in human serum and predict primary osteoporosis and fractures, with the results in good agreement with those obtained by chemiluminescence immunoassay (CLIA). Simultaneously, the structure of MWNTs was characterized with scanning electron microscopy (SEM) and infrared spectroscopy (IR), and the reaction mechanisms of both labelling Ab(CT) with TRM and SSRTPIA for the determination of trace CT were discussed. PMID- 22935376 TI - Computational and experimental study on the influence of the porogen on the selectivity of 4-nitrophenol molecularly imprinted polymers. AB - In molecular imprinting the porogen plays a decisive role, as it not only affects the physical properties of the resulting polymer including its porosity, the specific surface area, and the swelling behavior, but also governs the stability of the prepolymerization complex, which in turn decisively determines the recognition properties of the resulting molecularly imprinted polymer (MIP). In this study, the influence of the porogen on the selectivity of MIPs was investigated. Therefore, bulk MIPs against 4-nitrophenol using 4-vinylpyridine (4 VP) as functional monomer and ethylene glycol dimethacrylate (EDMA) as crosslinker were prepared in acetonitrile and chloroform. The recognition properties of both MIPs were evaluated during chromatographic studies using the respective porogenic solvents as mobile phase for both MIPs. Along with the characterization of the morphology of the obtained polymers via SEM and BET analysis, the beneficial nature of chloroform as porogen for imprinting 4-NP was experimentally demonstrated and verified by findings obtained from complementary molecular dynamics simulations. Moreover, the application of chloroform as mobile phase for the MIP prepared in acetonitrile and vice versa clearly demonstrated the dependence of the resulting recognition properties on the selection of the mobile phase. PMID- 22935377 TI - A chemiluminescence array sensor based on graphene-magnetite-molecularly imprinted polymers for determination of benzenediol isomers. AB - A chemiluminescence (CL) array sensor for determination of benzenediol isomers simultaneously using the system of luminol-NaOH-H(2)O(2) based on a graphene magnetite-molecularly imprinted polymer (GM-MIP) is described. Use of graphene in the GM-MIP thus prepared is helpful to improve the adsorption capacity, while use of magnetite nanoparticles can facilitate the isolation of GM-MIP at end of their synthesis, and rendering easier the use of the polymers in the array sensor. The adsorption performance and properties were characterized. The GM-MIP was used to increase the selectivity in CL analysis. In addition, the sensor was reusable and of good selectivity and adsorption capacity. The array sensor was finally used for the determination of hydroquinone, resorcinol and catechol in waste water samples simultaneously. PMID- 22935378 TI - Highly sensitive detection of nitroaromatic explosives using an electrospun nanofibrous sensor based on a novel fluorescent conjugated polymer. AB - An electrospun nanofibrous explosive sensor was first constructed based on a newly developed fluorescent conjugated polymer P containing heteroatom polycyclic units. Electrospinning by doping polymer P as a fluorescent probe in a polystyrene supporting matrix afforded a fluorescence nanofibrous film with unique porous structures, and effectively avoided the aggregation of polymer P. The novel explosive sensor exhibited stable fluorescence property, satisfactory reversibility with less than 5% loss of signal intensity after four quenching regeneration cycles, and good reproducibility among three batches with a relative standard deviation of 2.8%. Such fabricated sensor also showed remarkable sensitivity toward a series of trace nitroaromatic explosive vapors, including picric acid (parts-per-trillion level) and 2,4,6-trinitrotoluene vapor (parts-per billion level), as well as good selectivity with less than 10% response to typical interferents. Therefore, the present strategy extends the application of different kinds of conjugated polymers for the construction of optical chemosensors. PMID- 22935379 TI - Ultrasensitive optical detection of trinitrotoluene by ethylenediamine-capped gold nanoparticles. AB - This study found that 1,2-ethylenediamine (EDA) as a primary amine could be modified onto the surface of citrate-stabilized gold nanoparticles (Au NPs), and the EDA-capped Au NPs were successfully used as an ultrasensitive optical probe for TNT detection. The strong donor-acceptor (D-A) interactions between EDA and trinitrotoluene (TNT) at the Au NP/solution interface induced significant aggregation of the EDA-capped Au NPs, and enabled to easily realize the direct colorimetric detection of ultratrace TNT. The results showed that such a color change was readily seen by the naked eye, and the colorimetric detection could be down to 400 pM level of TNT with excellent discrimination against other nitro compounds. UV-vis absorption spectroscopy was used to examine the TNT-induced changes in local surface plasmon resonance (LSPR) of EDA-capped Au NPs, and a new LSPR band at ca. 630 nm arose along with the addition of TNT, which produced a detection limit of TNT down to ca. 40 pM. Furthermore, dynamic light scattering measurements evidenced the ultratrace TNT-induced small changes in the size of the EDA-capped Au NPs, and realized the quick and accurate detection of TNT in 0.4 pM level. These results demonstrated the ultrahigh sensitivity of this optical probe for TNT detection. Moreover, this optical probe is sample, stable, low-cost, and these excellent properties make it quite promising for infield and rapid detection of TNT. PMID- 22935380 TI - A novel stacking method of repetitive large volume sample injection and sweeping MEKC for determination of androgenic steroids in urine. AB - In this research, a novel stacking capillary electrophoresis method, repetitive large volume sample injection and sweeping MEKC (rLVSI-sweeping MEKC) were developed to analyze the presence of three androgenic steroids considered as sport doping drugs, testosterone (T), epitestosterone (E) and epitestosterone glucuronide (EG) in urine. This method provides better sensitivity enhancement than the traditional large volume sample stacking-sweeping strategies due to sensitivity enhancement by repetitive injections. This multiple sampling method enhances sensitivity of monitoring of urine samples by UV detection (254 nm). Firstly, the phosphate buffer was filled into an uncoated fused silica capillary and the samples were injected into the capillary at 10 psi for 20s, and then stacked at -10 kV for 1 min using phosphate buffer containing SDS. The above injecting and stacking steps were repeated five times. Finally, separation was performed at -20 kV, using phosphate buffer containing methanol, SDS and (2 hydroxypropyl)-beta-cyclodextrin. Method validation showed that calibration plots were linear (r>=0.997) over a range of 5-200 ng mL(-1) for T, 20-200 ng mL(-1) for E and 0.5-500 ng mL(-1) for EG. The limits of detection were 1.0 ng mL(-1) for T, 5.0 ng mL(-1) for E and 200.0 pg mL(-1) for EG. When evaluating precision and accuracy, values of RSD and RE in intra-day (n=3) and inter-day (n=5) analysis were found to be less than 10.0%. Compared with the simple LVSS sweeping, which is also a stacking strategy, this method further improves sensitivity up to 25 folds (~2500 folds with MEKC without preconcentration). This method was applied to monitor 10 athletes' urine, and did not detect any analyte. The novel stacking method was feasible for monitoring of doping by sportsmen. PMID- 22935381 TI - Influence of TNF-alpha blockers on the oral prevalence of opportunistic microorganisms in ankylosing spondylitis patients. AB - OBJECTIVES: To compare the oral prevalence and antimicrobial susceptibility of candida spp., staphylococci, enterobacteriaceae, and pseudomonas spp. from ankylosing spondylitis (AS) patients receiving conventional and anti-TNF-alpha therapy. METHODS: The study included 70 AS patients, diagnosed according to the modified New York criteria (1984). The volunteers were divided into 2 groups: a biological group (AS BioG) (n=35) (on anti-TNF-alpha therapy) and a conventional group (AS ConvG) (n=35). The control group (ContG) (n=70) was made up of healthy individuals matched for age, gender, and oral conditions. After clinical examination, oral rinse samples were collected and plated in specific culture media. The number of colony-forming units per milliliter (cfu/ml) was obtained, and isolates were identified using the API system. Antimicrobial susceptibility tests were performed according to the NCCLS guidelines. Prevalence and counts of microorganisms were statistically compared between the 3 groups, using the Mann Whitney and Chi-square tests. Significance level was set at 5%. RESULTS: In both the AS BioG and the AS ConvG, staphylococci counts were higher than that in the ContG (p<0.0001). Candida albicans and staphylococcus epidermidis were the most commonly found species in all the groups. Serratia marcescens and klebsiella oxytoca were more prevalent in the AS BioG and the AS ConvG, respectively. Two candida isolates (2.8%) from the AS BioG and 5 (10.8%) from the AS ConvG were resistant to amphotericin B and 5-fluorocytosine. A low percentage of staphylococci isolates was resistant to amoxicillin, ciprofloxacin, and doxycycline. CONCLUSIONS: Higher counts of staphylococci were observed in both AS groups, regardless of the current therapy, age, sex, and oral conditions. Anti TNF-alpha therapy could not be correlated with increased counts of microorganisms. PMID- 22935383 TI - Metabolic cardiovascular risk burden and atherosclerosis in African black and Caucasian women with rheumatoid arthritis: a cross-sectional study. AB - OBJECTIVES: The impact of metabolic risk factors on atherosclerotic cardiovascular disease (ACVD) in patients with rheumatoid arthritis (RA) from developing populations is currently unknown. We examined the relationships of the metabolic syndrome (MetS) and its components with carotid artery atherosclerosis in African women with rheumatoid arthritis (RA) from a developing black and developed Caucasian population. METHODS: We assessed the associations of the National Cholesterol Education Program Adult Treatment Panel III (NCEP-ATPIII) defined MetS and its criteria with high resolution B-mode ultrasound determined common carotid artery intima-media thickness (cIMT) and carotid artery plaque in multivariable regression models in 104 black and 93 Caucasian women with RA. RESULTS: The MetS prevalence was 30.8% in black compared to 9.7% in Caucasian women with RA (adjusted odds ratio [95% confidence interval]=10.11 [1.76-58.03] [p=0.009]). Population origin impacted on the relationships of metabolic risk factors with atherosclerosis. In Caucasian women, the MetS was associated with cIMT (p=0.036) and MetS triglycerides and the number of MetS criteria were each associated with both cIMT (p=0.01 and p=0.028, respectively) and plaque (p=0.049 and p=0.02, respectively); by contrast, in black women, MetS blood pressure was related to cIMT (p=0.04). CONCLUSIONS: A high overall metabolic cardiovascular risk burden as disclosed by markedly prevalent MetS in women with RA from developing groups of black African descent was not associated with atherosclerosis. This calls for systematic rigorous cardiovascular risk management irrespective of metabolic risk factor profiles in African black women with RA. PMID- 22935382 TI - Trastuzumab anti-tumor efficacy in patient-derived esophageal squamous cell carcinoma xenograft (PDECX) mouse models. AB - BACKGROUND: Trastuzumab is currently approved for the clinical treatment of breast and gastric cancer patients with HER-2 positive tumors, but not yet for the treatment of esophageal carcinoma patients, whose tumors typically show 5 ~ 35% HER-2 gene amplification and 0 ~ 56% HER-2 protein expression. This study aimed to investigate the therapeutic efficacy of Trastuzumab in patient-derived esophageal squamous cell carcinoma xenograft (PDECX) mouse models. METHODS: PDECX models were established by implanting patient esophageal squamous cell carcinoma (ESCC) tissues into immunodeficient (SCID/nude) mice. HER-2 gene copy number (GCN) and protein expression were determined in xenograft tissues and corresponding patient EC samples by FISH and IHC analysis. Trastuzumab anti-tumor efficacy was evaluated within these PDECX models (n = 8 animals/group). Furthermore, hotspot mutations of EGFR, K-ras, B-raf and PIK3CA genes were screened for in the PDECX models and their corresponding patient's ESCC tissues. Similarity between the PDECX models and their corresponding patient's ESCC tissue was confirmed by histology, morphology, HER-2 GCN and mutation. RESULTS: None of the PDECX models (or their corresponding patient's ESCC tissues) harbored HER-2 gene amplification. IHC staining showed HER-2 positivity (IHC 2+) in 2 PDECX models and negativity in 3 PDECX models. Significant tumor regression was observed in the Trastuzumab-treated EC044 HER-2 positive model (IHC 2+). A second HER-2 positive (IHC 2+) model, EC039, harbored a known PIK3CA mutation and showed strong activation of the AKT signaling pathway and was insensitive to Trastuzumab treatment, but could be resensitised using a combination of Trastuzumab and AKT inhibitor AZD5363. In summary, we established 5 PDECX mouse models and demonstrated tumor regression in response to Trastuzumab treatment in a HER-2 IHC 2+ model, but resistance in a HER-2 IHC 2+/PIK3CA mutated model. CONCLUSIONS: This study demonstrates Trastuzumab-induced tumor regressions in HER-2 positive tumors, and highlights PIK3CA mutation as a potential resistance mechanism to Trastuzumab treatment in pre-clinical patient-derived EC xenograft models. PMID- 22935385 TI - In reply to Yu. PMID- 22935386 TI - In regard to Hindie et al. PMID- 22935387 TI - In Regard to Machtay et al. PMID- 22935384 TI - Gene targeting in ischemic heart disease and failure: translational and clinical studies. AB - Alternative and innovative targeted strategies hold relevance in improving the current treatments for ischemic heart disease (IHD). One potential treatment modality, gene targeting, may provide a unique alternative to current IHD therapies. The principal function of gene targeting in IHD is to augment the expression of an endogenous gene through amplification of an exogenous gene, delivered by a plasmid or a viral vector to enhance myocardial perfusion, and limit the long-term sequelae. The initial clinical studies of gene targeting in IHD were focused upon induction of angiogenic factors and the outcomes were equivocal. Nevertheless, significant advancements have been made in viral vectors, mode of delivery, and potentially relevant targets for IHD. Several of these advancements, particularly with a focus on translational large animal studies, are the focus of this review. The development of novel vectors with prolonged transduction efficiency and minimal inflammation, coupled with hybrid perfusion-mapping delivery devices, and improving the safety of vector use and efficacy of gene systems are but a few of the exciting progresses that are likely to proceed to clinical studies in the near future. PMID- 22935389 TI - In regard to Yang et al. PMID- 22935391 TI - In reply to Zagar and Marks. PMID- 22935392 TI - In reply to Hannoun-Levi et al. PMID- 22935393 TI - In Reply to O'Sullivan et al. PMID- 22935394 TI - The power of radiation biophysics-let's use it. PMID- 22935395 TI - Combining physical and biologic parameters to predict radiation-induced lung toxicity in patients with non-small-cell lung cancer treated with definitive radiation therapy. AB - PURPOSE: To investigate the plasma dynamics of 5 proinflammatory/fibrogenic cytokines, including interleukin-1beta (IL-1beta), IL-6, IL-8, tumor necrosis factor alpha (TNF-alpha), and transforming growth factor beta1 (TGF-beta1) to ascertain their value in predicting radiation-induced lung toxicity (RILT), both individually and in combination with physical dosimetric parameters. METHODS AND MATERIALS: Treatments of patients receiving definitive conventionally fractionated radiation therapy (RT) on clinical trial for inoperable stages I-III lung cancer were prospectively evaluated. Circulating cytokine levels were measured prior to and at weeks 2 and 4 during RT. The primary endpoint was symptomatic RILT, defined as grade 2 and higher radiation pneumonitis or symptomatic pulmonary fibrosis. Minimum follow-up was 18 months. RESULTS: Of 58 eligible patients, 10 (17.2%) patients developed RILT. Lower pretreatment IL-8 levels were significantly correlated with development of RILT, while radiation induced elevations of TGF-beta1 were weakly correlated with RILT. Significant correlations were not found for any of the remaining 3 cytokines or for any clinical or dosimetric parameters. Using receiver operator characteristic curves for predictive risk assessment modeling, we found both individual cytokines and dosimetric parameters were poor independent predictors of RILT. However, combining IL-8, TGF-beta1, and mean lung dose into a single model yielded an improved predictive ability (P<.001) compared to either variable alone. CONCLUSIONS: Combining inflammatory cytokines with physical dosimetric factors may provide a more accurate model for RILT prediction. Future study with a larger number of cases and events is needed to validate such findings. PMID- 22935396 TI - Short sleep duration is associated with carotid intima-media thickness among men in the Coronary Artery Risk Development in Young Adults (CARDIA) Study. AB - BACKGROUND AND PURPOSE: Carotid intima-media thickness (CIMT) is a subclinical marker of cardiovascular disease. Recent studies suggest that shorter sleep duration is a risk factor for cardiovascular disease, but there is limited evidence regarding this association using high-quality, objective assessments of sleep. The aim of this study is to determine whether sleep duration is associated with CIMT. METHODS: The study used an observational cohort consisting of 617 black and white middle-aged healthy participants (37-52 years; 58% female) in the Coronary Artery Risk Development in Young Adults (CARDIA) Study. Multivariable adjusted linear regression analyses were performed. Sleep duration was measured using wrist actigraphy monitors. CIMT was calculated using the average of 20 measurements of the mean common carotid, bulb, and internal CIMT, which was assessed using ultrasound images. RESULTS: After adjusting for covariates, 1 hour of longer sleep duration was associated with 0.026 mm less CIMT among men (P=0.02; 95% CI, -0.047 to -0.005) and 0.001 mm less CIMT among women (P=0.91; 95% CI, -0.020 to 0.022). Segment-specific analyses indicated that the carotid bulb was a key driver of the observed association. CONCLUSIONS: Shorter objectively assessed sleep duration was associated with greater CIMT among men but not women. PMID- 22935397 TI - 30-Day risk-standardized mortality and readmission rates after ischemic stroke in critical access hospitals. AB - BACKGROUND AND PURPOSE: The critical access hospital (CAH) designation was established to provide rural residents with local access to emergency and inpatient care. CAHs, however, have poorer short-term outcomes for pneumonia, heart failure, and myocardial infarction compared with other hospitals. We assessed whether 30-day risk-standardized mortality rates (RSMRs) and risk standardized readmission rates (RSRRs) after ischemic stroke differ between CAHs and non-CAHs. METHODS: The study included all fee-for-service Medicare beneficiaries 65 years of age or older with a primary discharge diagnosis of ischemic stroke (International Classification of Diseases, 9th revision codes 433, 434, 436) in 2006. Hierarchical generalized linear models calculated hospital-level RSMRs and RSRRs, adjusting for patient demographics, medical history, and comorbid conditions. Non-CAHs were categorized by hospital volume quartiles and the RSMR and RSRR posterior probabilities in comparison with CAHs were determined using linear regression with Markov chain Monte Carlo simulation. RESULTS: There were 10 267 ischemic stroke discharges from 1165 CAHs and 300 114 discharges from 3381 non-CAHs. The RSMRs of CAHs were higher than non-CAHs (11.9%+/- 1.4% vs 10.9%+/- 1.7%; P<0.001), but the RSRRs were comparable (13.7%+/ 0.6% vs 13.7%+/- 1.4%; P=0.3). The RSMRs for the 2 higher volume quartiles of non-CAHs were lower than CAHs (posterior probability of RSMRs higher than CAHs=0.007 for quartile 3; P<0.001 for quartile 4), but there were no differences for lower volume hospitals; RSRRs did not vary by annual hospital volume. CONCLUSIONS: CAHs had higher RSMRs compared with non-CAHs, but readmission rates were similar. The observed differences may be partly explained by patient characteristics and annual hospital volume. PMID- 22935398 TI - White matter lesion severity in mild acute ischemic stroke patients and functional outcome after 1 year. AB - BACKGROUND AND PURPOSE: To determine if severity of visually assessed white matter disease is associated with disability after ischemic stroke. METHODS: In this Berlin "Cream & Sugar" substudy, all first ischemic stroke patients who received magnetic resonance imaging and completed follow-up between January 2009 and December 2010, were enrolled. Severity of white matter disease was assessed on fluid-attenuated inversion recovery or T2-weighted sequences using the Wahlund and Fazekas visual scales. Functional outcome was assessed after 1 year using the modified Rankin Scale (follow-up [FU] modified Rankin Scale [mRS]). RESULTS: Of 101 patients (37% female; median age, 67 years; interquartile range, 54-75; National Institutes of Health Stroke Scale score, 1; interquartile range, 0-2), median FU mRS was 1 (interquartile range, 0-2). Binary logistical regression adjusted for age (at 5-year intervals), acute National Institutes of Health Stroke Scale scores, fasting glucose, insulin, glycosylated hemoglobin, creatinine, C-reactive protein quartiles, waist circumference, and systolic blood pressure revealed that Fazekas scores of 2 and 3 independently associated with FU mRS (Fazekas score 2: adjusted odds ratio, 8.4; 95% confidence interval, 2.35 30.09; P=0.001; Fazekas score 3: adjusted odds ratio, 4.2; 95% confidence interval, 1.04-16.96; P=0.044). Wahlund scores>10 were significantly associated with FU mRS when fasting glucose levels were removed from the regression analysis (adjusted odds ratio, 12.17; 95% confidence interval, 1.91-77.54; P=0.008). CONCLUSIONS: Severe white matter disease defined by standard criteria in acute ischemic stroke patients is associated with disability at 1 year and can be assessed quickly using visual rating scales. CLINICAL TRIAL REGISTRATION INFORMATION: URLs: http://www.clinicaltrials.gov and https://eudract.ema.europa.eu. Unique identifiers: NCT 01378468 and 2009-010356 97. PMID- 22935399 TI - Long-term rate of change in memory functioning before and after stroke onset. AB - BACKGROUND AND PURPOSE: Memory impairment is a predictor and a consequence of stroke, but memory decline is common even in healthy elderly individuals. We compared the long-term trajectory of memory functioning before and after stroke with memory change in stroke-free elderly individuals. METHODS: Health and Retirement Study participants aged 50 years and older (n=17 340) with no stroke history at baseline were interviewed biennially up to 10 years for first self reported or proxy-reported stroke (n=1574). Age-, sex-, and race-adjusted segmented linear regression models were used to compare annual rates of change in a composite memory score before and after stroke among 3 groups: 1189 stroke survivors; 385 stroke decedents; and 15 766 cohort members who remained stroke free. RESULTS: Before stroke onset, individuals who later survived stroke had significantly (P<0.001) faster average annual rates of memory decline (-0.143 points per year) than those who remained stroke-free throughout follow-up (-0.101 points per year). Stroke decedents had even faster prestroke memory decline ( 0.212 points per year). At stroke onset, memory declined an average of -0.369 points among stroke survivors, comparable with 3.7 years of age-related decline in stroke-free cohort members. After stroke, memory in stroke survivors continued to decline at -0.142 points per year, similar to their prestroke rates (P=0.93). Approximately 50% of the memory difference between stroke survivors soon after stroke and age-matched stroke-free individuals was attributable to prestroke memory. CONCLUSIONS: Although stroke onset induced large decrements in memory, memory differences were apparent years before stroke. Memory declines before stroke, especially among those who did not survive the stroke, were faster than declines among stroke-free adults. PMID- 22935400 TI - Educational history is an independent predictor of cognitive deficits and long term survival in postacute patients with mild to moderate ischemic stroke. AB - BACKGROUND AND PURPOSE: Poststroke cognitive decline and white matter lesions (WML) are related to poor poststroke survival. Whether cognitive reserve as reflected by educational history associates with cognitive decline, recurrent strokes, and poststroke mortality independent of WML is not known. METHODS: A total of 486 consecutive acute mild/moderate ischemic stroke patients subjected to comprehensive neuropsychological assessment (n=409) and magnetic resonance imaging (n=395) 3 months poststroke were included in the study and followed-up for up to 12 years. Odds ratios (OR) for logistic and hazard ratios for Cox regression analyses are reported (OR and hazard ratio<=1 indicates a beneficial effect). RESULTS: Long educational history (per tertile) was associated with lower frequency of executive dysfunction in models adjusted for age, sex, marital status, and stroke severity (OR, 0.75; P<0.05) but not when adding WML as a covariate. In contrast, educational history was independently associated with less memory impairment (OR, 0.67; P<0.01), aphasia (OR, 0.69; P<0.05), visuospatial and constructive deficits (OR, 0.70; P<0.05), Mini-Mental State Examination score<25 (OR, 0.53; P<0.0001), and dementia (OR, 0.66; P<0.01). In Cox regression analysis, educational history was not associated with recurrent strokes, but it associated independently with favorable poststroke survival (hazard ratio, 0.86; P<0.05). CONCLUSIONS: Long educational history associates with less poststroke cognitive deficits, dementia, and favorable long-term survival independent of age, gender, marital status, stroke severity, and WML in patients with mild/moderate ischemic stroke. This supports the hypothesis that educational history as a proxy indicator of cognitive reserve protects against deficits induced by acute stroke. PMID- 22935401 TI - Prevention of vascular cognitive impairment. PMID- 22935402 TI - Impairments in cognitive function and brain connectivity in severe asymptomatic carotid stenosis. AB - BACKGROUND AND PURPOSE: Severe asymptomatic carotid stenosis has been associated with cognitive impairment, but it is unknown whether this association is attributable to effects on brain connectivity. We present cognitive network abnormalities in a group of patients at a presymptomatic stage. METHODS: Seventeen patients with >= 70% asymptomatic stenosis of unilateral internal carotid artery were compared with 26 healthy controls utilizing a comprehensive neuropsychological battery, the dizziness handicap inventory, and multimodality neuroimaging including diffusion tensor imaging and resting-state functional connectivity magnetic resonance imaging. Longitudinally, assessments were completed in a subgroup of 10 patients at 3 months after carotid artery stenting. RESULTS: Compared with the healthy controls, the patients had worse dizziness scores, poorer memory, complex visuo-spatial performances, and lower whole-brain mean fractional anisotropy. The Scheltens scores of leukoaraiosis/infarction were not different between groups. Their seed-based functional connectivity magnetic resonance imaging showed marked decrements of interhemispheric and intrahemispheric, ipsilaterally to carotid stenosis, functional connectivity in the frontoparietal network. In the default mode network, the intrahemispheric functional connectivity was bilaterally impaired. Importantly, the disrupted mean fractional anisotropy in the patients significantly correlated with the attention and verbal memory functions. After successful carotid artery stenting, small but measurable increments of the mean fractional anisotropy and little functional connectivity in the default mode network ipsilateral-to-carotid artery stenting were noted. CONCLUSIONS: We identified for the first time distinct patterns of network disruption that correlate with cognitive fragility in patients with asymptomatic carotid stenosis. Brain connectivity may provide early and useful biomarkers for brain ischemia and reperfusion. PMID- 22935403 TI - Dramatic recovery in acute ischemic stroke is associated with arterial recanalization grade and speed. AB - BACKGROUND AND PURPOSE: Dramatic recovery (DR) is a predictor of stroke outcome among others. However, after successful recanalization, systematic favorable outcome is not the rule. We sought to analyze the impact of recanalization on DR in patients with acute ischemic stroke eligible for any revascularization strategies (either intravenous or endovascular). METHODS: We analyzed data collected between April 2007 and May 2011 in our prospective clinical registry. All patients with acute ischemic stroke with National Institutes of Health Stroke Scale>=10 at admission and an identification of arterial status before treatment were included. DR was defined as National Institutes of Health Stroke Scale<=3 at 24 hours or a decrease of >=10 points within 24 hours. RESULTS: DR occurred in 75 of 255 patients with acute ischemic stroke (29.4%). Patients with persistent occlusion had a low DR rate (11.1%) than those with no documented occlusion (36.5%) and those with occlusion followed by recanalization (35.3%; both P<0.001). Among patients with recanalization monitored by angiography, DR was higher among patients with complete recanalization than among those with partial recanalization (46.8% versus 14.3%; P<0.001) and increased with tertiles of time to recanalization (Ptrend=0.002). In multivariable logistic regression analysis, grade and time to recanalization appeared independently associated with DR; the adjusted ORs were 4.17 (95% CI, 1.61-10.77) for complete recanalization and 1.24 (95% CI, 1.04-1.48) for each 30-minute time decrease. Patients with versus without DR more frequently had modified Rankin Scale<=1 (67.6% versus 9.0%; P<0.001) and less frequently had hemorrhage (17.3% versus 33.9%; P=0.024). CONCLUSIONS: DR is strongly associated with favorable clinical outcome and is dependent on complete recanalization and time to recanalization. PMID- 22935404 TI - D-limonene rich volatile oil from blood oranges inhibits angiogenesis, metastasis and cell death in human colon cancer cells. AB - AIMS: To identify the chemical constituents of volatile oil from blood orange (Citrus sinensis (L) Osbeck) and understand the possible mechanisms of inhibition of colon cancer cell proliferation. MAIN METHODS: Volatile oil was obtained from blood oranges by hydro-distillation. Nineteen compounds were identified by GC-MS and d-limonene was found to be the major component. The blood orange volatile oil was formulated into an emulsion (BVOE) and examined for its effects on viability of colon cancer cells. In addition, experiments were performed to understand the possible mechanism of proliferation inhibition, angiogenesis and metasasis by BVOE. KEY FINDINGS: BVOE exhibited dose-dependent inhibition of cell proliferation and induced apoptosis in the colon cancer cells, as confirmed by flow cytometry. Immunoblotting of colon cancer cells treated with BVOE shows dose dependent induction of Bax/Bcl2) and inhibition of vascular endothelial growth factor (VEGF). Furthermore, treatment of serum starved SW480 and HT-29 cells with 100MUg/ml BVOE suggested the inhibition of VEGF and markers associated with inhibition of angiogenesis. The antiangiogenic activity of BVOE was also confirmed by inhibition of in vitro tube formation in human umbilical vein endothelial cells. Dose-dependent anti-metastasis activity and blockage of vascular endothelial growth factor receptor 1 (VEGFR1) binding following treatment with BVOE were confirmed by cell migration assays and immunoblots to detect decreased expression of matrix metalloproteinases (MMP-9). SIGNIFICANCE: The results of this study provide persuasive evidence of the apoptotic and anti angiogenesis potential of BVOE in colon cancer cells. The extent of induction of apoptosis and inhibition of angiogenesis suggest that BVOE may offer great potential for prevention of cancer and may be appropriate for further studies. PMID- 22935405 TI - Liposome-encapsulated hemoglobin (hemoglobin-vesicle) is not transferred from mother to fetus at the late stage of pregnancy in the rat model. AB - AIMS: Liposome-encapsulated hemoglobin (hemoglobin vesicles: HbV; diameter 250 nm) is reconstructed from human hemoglobin and developed as an artificial oxygen carrier for use as a transfusion alternative. Previous studies using rodent models closely investigated the safety of daily repeated infusions (DRI) of HbV and reported that the reticuloendothelial system was physiologically capable of degrading HbV to maintain plasma clinical chemistry within normal ranges. The present study examined the effect of DRI of HbV on the pregnant rat mother and fetal development, focusing on placental transfer of HbV in pregnancy. MAIN METHODS: Pregnant rats intravenously received HbV bolus injections at 2 ml/kg/day for the last 7 consecutive days till term. The cumulative infusion volume (14 ml/kg) was equal to 25% of the whole blood volume (56 ml/kg). KEY FINDINGS: Maternal DRI of HbV had no obvious side effects on the pregnant mother or on fetal development. Maternal vital signs, plasma clinical chemistry, and blood gas parameters were overall normal after DRI of HbV. In addition, maternal/fetal transfer of HbV was limited to the placenta and HbV did not reach the fetus. Histopathological examination with human hemoglobin antibody detected HbV accumulation in the maternal spleen, liver, kidney, and placenta, but not in the fetuses. These results were also confirmed by a pharmacokinetic study using (125)I-labeled HbV. SIGNIFICANCE: This safety study of HbV use in the pregnant mother and fetus will contribute to a possible application of HbV as a potential treatment for fetal hypoxia by supplying oxygen through the placenta. PMID- 22935406 TI - Varicella zoster virus vasculopathy: a treatable form of rapidly progressive multi-infarct dementia after 2 years' duration. AB - We describe an extraordinarily protracted case of varicella zoster virus (VZV) multifocal vasculopathy in a man who presented initially with ischemic optic neuropathy and then suffered 4 episodes of stroke manifesting as multi-infarct dementia over a 2-year period. Brain magnetic resonance imaging (MRI) and angiography (MRA) revealed cortical and subcortical infarctions as well as vasculitic occlusion and stenosis. The patient was treated with corticosteroids and later with cyclophosphamide. More than 2 years after the onset of neurological disease, two cerebrospinal fluid (CSF) examinations revealed the presence of anti-VZV IgG antibody with reduced serum-to-CSF ratios of anti-VZV IgG compared with ratios for total IgG and albumin, indicative of intrathecal synthesis of anti-VZV IgG. After definitive diagnosis, immunosuppressive drugs were discontinued and he was treated with intravenous acyclovir; both mental status and gait improved and no further episodes of neurological dysfunction ensued. The favorable outcome in this patient indicates that VZV vasculopathy can be treated successfully even after 26 months. VZV must be considered as a possible cause of neurological disease in any patient with idiopathic multifocal vasculopathy. PMID- 22935407 TI - Fatigue in multiple sclerosis - a brief review. AB - Fatigue is the most common and debilitating symptom in multiple sclerosis (MS) and is believed to be distinctly different from fatigue seen in other chronic conditions. It can affect a patient's mood, sleep and have a detrimental effect on their quality of life. In the recent years much literature has emerged in an attempt to elucidate the potential causes and treatment of this common symptom. This review article aims to examine the most recent theories on the pathophysiology of fatigue in MS as well as its association with sleep and depression. We describe the pharmacological and non-pharmacological approaches to its treatment and propose a multidisciplinary, patient enabled and individualised manner to the management of fatigue in MS. PMID- 22935408 TI - Gender differences in motor and non-motor symptoms among Sardinian patients with Parkinson's disease. AB - BACKGROUND: Parkinson's disease (PD) occurs more frequently in men than in women and a higher risk for PD development in males compared with females has been hypothesized, suggesting gender may be a significant factor in the development and progression of parkinsonism. To date, gender differences in non-motor symptoms are under-reported. OBJECTIVE: To assess gender differences in motor and non-motor symptoms among Sardinian PD patients. METHODS: One hundred fifty-six (91 male and 65 female) consecutive Sardinian PD outpatients were included in this analysis. Modified Hoehn and Yahr scale and UPDRS were used to assess motor symptoms, while non-motor disturbances were evaluated with the non-motor symptoms scale (NMSS). Presence of depression, anxiety and other iatrogenic behavioral disorders was also investigated. In order to determine how gender differences could be specific to PD, 132 age-matched normal controls were assessed with the NMSS. RESULTS: Women were more likely than men to present with tremor as initial symptom (p<.025) and worse UPDRS instability score (p<.02). NMSS score in females was significantly higher than that in males (p<.018). A significantly higher severity in cardiovascular (p<0.002), sleep/fatigue (p<.018) and mood/apathy (p<.001) domains was observed in female PD patients, while the sexual dysfunction domain was reported with a significantly higher score in male patients (p<.017). Fatigue (p<.03), lack of motivation (p<.015) and sadness (p<.009) were observed significantly more frequent in females, while altered interest in sex was noted as more common in males (p<.001). Frequency of depression (p<.011) and anxiety (p<.001) was significantly higher in females, while male patients had increased frequency of compulsive sexual behaviors (p<.05). There was a significantly higher frequency of non-motor symptoms in eight domains in both male and female PD patients compared with controls (p<.001, for all comparisons, with the exception of urinary disturbances in females: p<.004). Only sexual dysfunctions were not significantly higher in male and female PD patients compared with controls. DISCUSSION: The present study highlights the role of gender differences associated with the occurrence of motor and non-motor disorders and our findings indicate that spectrum and severity of non-motor symptoms may present with different gender distribution in PD patients, suggesting a possible sex-related effect. PMID- 22935409 TI - A rare case of tuberculosis of the midfoot. AB - Despite the increasing prevalence of tuberculosis in developed countries, tuberculous osteomyelitis of the foot remains an uncommon complication. The relative rarity of such a diagnosis means that delays are often incurred before clinicians can correctly identify the pathogen and therefore instigate appropriate chemotherapy. The authors present a case of midfoot pain secondary to tuberculous osteomyelitis. PMID- 22935410 TI - Irreducible dislocation of all the lesser metatarsophalangeal joints of the foot: a case report. AB - We report a case of irreducible dorsal dislocation of all the lesser metatarsophalangeal joints of the foot following injury at sport. Plantar plate prevented reduction at all the joints, which necessitated an open reduction and stabilization with K-wire. This report highlights the necessity of prompt open reduction and reviews the mechanism of injury and complex anatomy at metatarsophalangeal joint. PMID- 22935411 TI - Reconstruction of complex osteochondral lesions of the talus with cylindrical sponge allograft and particulate juvenile cartilage graft: provisional results with a short-term follow-up. AB - Osteochondral lesions of the talus can be a challenging injury to treat for even the most experienced foot and ankle surgeon. Although the advances in imaging have made the diagnosis of chondral lesions more accurate, surgeons are still struggling to find ways to reliably treat advanced lesions with subchondral bone damage. This article looks at the use of allograft bone and particulate juvenile cartilage in patients with advanced subchondral bone damage and osteochondral lesions of the talus. PMID- 22935412 TI - Plantar heel pain due to vascular leiomyoma (angioleiomyoma). AB - The differential diagnosis of heel pain is extensive. The plantar heel pain is usually due to mechanical etiology, including plantar fasciitis, calcaneal spur, stress fracture, and nerve entrapment. Tumor is a rare cause of plantar heel pain. We present a case of chronic plantar heel pain with a vascular leiomyoma at the heel pad. PMID- 22935413 TI - A retrospective comparison of first metatarsophalangeal joint arthrodesis using a locked plate and compression screw technique. AB - INTRODUCTION: The historic primary treatment for end-stage first metatarsophalangeal (MTP) joint arthritis has been fusion. Traditionally, this has been accomplished by metaphyseal apposition between the proximal phalanx and metatarsal using crossed compression screws. Recently, locked plates have been introduced that help support this technique by offering added stability. We present our experience with 45 first MTP fusions in 45 feet using a locked plate and compression screw. METHODS: A retrospective review of 45 patients who met the study criteria with a hallux rigidus correction using a locked plate with a compression screw was performed. Charts and radiographs were independently reviewed by 2 authors not involved in the index procedures to assess outcomes. RESULTS: There was a 93% fusion rate (42/45 feet) with 3 nonunions. The mean time to union was 51.1 days (range = 29-116 days, SD = 24.4). The mean patient age was 58.1 years (range = 29-80 years, SD = 10.1). The mean time to partial weight bearing was 7.0 days (range = 0-53 days, SD = 13.8) and the mean time to full weight bearing was 62.0 days (range = 29-57 days, SD = 17.9). DISCUSSION: We report on the results of first MTP fusion using a compression screw and locked plate technique. The results show that this is an effective means of creating a first MTP joint arthrodesis. PMID- 22935415 TI - The large conductance calcium-activated K(+) channel interacts with the small GTPase Rab11b. AB - The transduction of sound by the receptor or hair cells of the cochlea leads to the activation of ion channels found in the basal and lateral regions of these cells. Thus, the processing of these transduced signals to the central nervous system is tied to the regulation of baso-lateral ion channels. The large conductance calcium-activated potassium or BK channel was revealed to interact with the small GTPase, Rab11b, which is one of many Rabs found in various endosomal pathways. Immunoelectron microscopy showed the colocalization of these two proteins in receptor cells and auditory neurons. Using Chinese hamster ovary cells as a heterologous expression system, Rab11b increased or decreased BK expression, depending on the overexpression or RNAi knockdown of Rab, respectively. Additional mutation analyses, using a yeast two-hybrid assay, suggested that this GTPase moderately interacts within a region of BK exclusive of the N- or C-terminal tails. These data suggest that this small GTPase regulates BK in a slow recycling process through the endocytic compartment and to the plasmalemma. PMID- 22935416 TI - Role of ERp46 in beta-cell lipoapoptosis through endoplasmic reticulum stress pathway as well as the protective effect of exendin-4. AB - Endoplasmic reticulum (ER) stress is considered as a key factor in free fatty acid (FFA)-induced apoptosis. ERp46, a new member of the thioredoxin family, is highly expressed in pancreatic beta-cells and plays an important role in glucose toxicity. In this study we examined the potential role of ERp46 in palmitic acid (PA)-induced cell apoptosis and the protective role of exendin-4, a long-acting agonist of the hormone glucagon-like peptide-1 (GLP-1) receptor. The glucose sensitive mouse beta-pancreatic cell line, betaTC6, was used to investigate the mechanisms of PA-induced apoptosis. Our results showed that ERp46 expression was reduced in a dose- and time-dependent manner after PA treatment. Furthermore, inhibition of ERp46 expression by small interfering (si)RNA-mediated silencing enhanced the ER stress response via three separate pathways and increased betaTC6 cell apoptosis rates. Moreover, exendin-4 reduced the ER stress response and levels of apoptosis in NC transfected cells after PA treatment, but not in cells transfected with ERp46siRNA. In conclusion, ERp46 plays a protective role in PA induced cell apoptosis by decreasing the ER stress response and might be a novel target for anti-diabetic drugs. Exendin-4 might protect against betaTC6 cell lipoapoptosis in part by activating ERp46 signaling pathway. PMID- 22935417 TI - Mitochondrial modulation of store-operated Ca(2+) entry in model cells of Alzheimer's disease. AB - Mitochondrial malfunction and calcium dyshomeostasis are early pathological events considered as important features of the Alzheimer's disease (AD) brain. Recent studies have suggested mitochondrion as an active regulator of Ca(2+) signaling based on its calcium buffering capacity. Herein, we investigated the mitochondrial involvement in the modulation of store-operated calcium entry (SOCE) in neural 2a (N2a) transgenic AD model cells. Results showed that SOCE was significantly depressed in N2a cells transfected with wild-type human APP695 (N2a APPwt) compared with empty vector control (N2a WT) cells. Pharmacological manipulation with mitochondrial function blockers, such as FCCP, RuR, or antimycin A/oligomycin, could inhibit mitochondrial calcium handling, and then impair SOCE pathway in N2a WT cells. Furthermore, mitochondria of N2a APPwt cells exhibited more severe swelling in response to Ca(2+), which is an indication of mitochondrial membrane permeability transition (MPT), than the wild-type controls. Additionally, treatment with cyclosporin A, a potent inhibitor of cyclophilin D, which can block MPT, could significantly restore the attenuated SOCE in N2a APPwt cells. Therefore, inhibition of cyclophilin D might be a therapeutic strategy for Alzheimer's disease. PMID- 22935414 TI - Oxidized phospholipids impair pulmonary antibacterial defenses: evidence in mice exposed to cigarette smoke. AB - Patients with COPD are associated with poor pulmonary anti-bacterial innate defenses, which increase the risk for frequent acute exacerbations caused by bacterial infection. Despite elevated numbers of phagocytes (macrophages and neutrophils), airways of patients with COPD show stable bacterial colonization. A defect in the phagocytic ability of alveolar macrophages (AMs) is one of the primary reasons for failure to clear the invading bacteria in airways of smokers and COPD patients and also in mice exposed to cigarette smoke (CS). Oxidative stress, as a result of CS exposure is implicated; however, the factors or mediators that inhibit phagocytic activity of AMs in lungs of smokers remain unclear. In the current study, we provide evidence that accumulation of oxidized phospholipids (Ox-PLs) mediate inhibition of phagocytic function of AMs in CS exposed mice. Mice exposed to 6months of CS showed impaired bacterial phagocytosis and clearance by AMs and elevated levels of Ox-PLs in bronchoalveolar lavage fluid (BALF), compared to mice exposed to room air. Intratracheal instillation of oxidized 1-palmitoyl-2-arachidonoyl-sn-glycero-3 phosphorylcholine (OX-PAPC) inhibited phagocytic activity of AMs and impaired pulmonary bacterial clearance in mice. In vitro studies demonstrated that exposure of J774 macrophages to OX-PAPC inhibited bacterial phagocytosis and clearance. However, pre-treatment of OX-PAPC with the monoclonal antibody EO6, which specifically binds to oxidized phospholipid but not native phospholipid, abolished OX-PAPC induced inhibition of bacterial phagocytosis and clearance. Incubation of BALF retrieved from CS-exposed mice impaired bacterial phagocytosis by J774 macrophages, which was abolished by pre-treatment of BALF with the EO6 antibody. In conclusion, our study shows that Ox-PLs generated following chronic CS exposure could play a crucial role in inhibiting phagocytic function of AMs and thus impair pulmonary anti-bacterial innate defenses in CS-exposed mice. Therapeutic approaches that augment pulmonary antioxidant defenses could be beneficial in reducing oxidative stress-driven impairment of phagocytosis by AMs in smokers and COPD patients. PMID- 22935418 TI - Engagement of T-cell antigen receptor and CD4/CD8 co-receptors induces prolonged STAT activation through autocrine/paracrine stimulation in human primary T cells. AB - Signal transducer and activator of transcription (STAT) proteins are key signaling molecules in response to cytokines and in regulating T cell biology. However, there are contradicting reports on whether STAT is involved in T-cell antigen receptor (TCR) signaling. To better define the role of STAT in TCR signaling, we activated the CD4/CD8-associated Lck kinase by co-crosslinking TCR and CD4/CD8 co-receptors in human peripheral blood T cells. Sequential STAT1, STAT3 and STAT5 activation was observed 1 h after TCR stimulation suggesting that STAT proteins are not the immediate targets in the TCR complex. We further identified interferon-gamma as the key cytokine in STAT1 activation upon TCR engagement. In contrast to transient STAT activation in cytokine response, this autocrine/paracrine-induced STAT activation was sustained. It correlated with the absence of two suppressors of cytokine signaling (SOCS) proteins, SOCS3 and cytokine-inducible SH2 containing protein that are negative feedback regulators of STAT signaling. Moreover, enforced expression of SOCS3 inhibited tyrosine phosphorylation of zeta-associated protein kinase of 70 kD in TCR-stimulated human Jurkat T cells. This is the first report demonstrating delayed and prolonged STAT activation coordinated with the loss of SOCS expression in human primary T cells after co-crosslinking of TCR and CD4/CD8 co-receptors. PMID- 22935419 TI - NFAT5 regulates the canonical Wnt pathway and is required for cardiomyogenic differentiation. AB - While nuclear factor of activated T cells 5 (NFAT5), a transcription factor implicated in osmotic stress response, is suggested to be involved in other processes such as migration and proliferation, its role in cardiomyogenesis is largely unknown. Here, we examined the role of NFAT5 in cardiac differentiation of P19CL6 cells, and observed that it was abundantly expressed in undifferentiated P19CL6 cells, and its protein expression was significantly downregulated by enhanced proteasomal degradation during DMSO-induced cardiomyogenesis. Expression of a dominant negative mutant of NFAT5 markedly attenuated cardiomyogenesis, which was associated with the inhibition of mesodermal differentiation. TOPflash reporter assay revealed that the transcriptional activity of canonical Wnt signaling was activated prior to mesodermal differentiation, and this activation was markedly attenuated by NFAT5 inhibition. Pharmacological activation of canonical Wnt signaling by [2'Z, 3'E]-6 bromoindirubin-3'-oxime (BIO) restored Brachyury expression in NFAT5DN-expressing cells. Inhibition of NFAT5 markedly attenuated Wnt3 and Wnt3a induction. Expression of Dkk1 and Cerberus1, which are secreted Wnt antagonists, was also inhibited by NFAT5 inhibition. Thus, endogenous NFAT5 regulates the coordinated expression of Wnt ligands and antagonists, which are essential for cardiomyogenesis through the canonical Wnt pathway. These results demonstrated a novel role of NFAT5 in cardiac differentiation of stem cells. PMID- 22935420 TI - Activation of epsilonPKC reduces reperfusion arrhythmias and improves recovery from ischemia: optical mapping of activation patterns in the isolated guinea-pig heart. AB - Pervious biochemical and hemodynamic studies have highlighted the important role of epsilonPKC in cardioprotection during ischemic preconditioning. However, little is known about the electrophysiological consequences of epsilonPKC modulation in ischemic hearts. Membrane permeable peptide epsilonPKC selective activator and inhibitor were used to investigate the role of epsilonPKC modulation in reperfusion arrhythmias. METHODS: Protein transduction domain from HIV-TAT was used as a carrier for peptide delivery into intact Langendorff perfused guinea pig hearts. Action potentials were imaged and mapped (124 sites) using optical techniques and surface ECG was continuously recorded. Hearts were exposed to 30 min stabilization period, 15 min of no-flow ischemia, followed by 20 min reperfusion. Peptides (0.5 MUM) were infused as follows: (a) control (vehicle-TAT peptide; TAT-scrambled psiepsilonRACK peptide); (b) epsilonPKC agonist (TAT-psiepsilonRACK); (c) epsilonPKC antagonist (TAT-epsilonV1). RESULTS: Hearts treated with epsilonPKC agonist psiepsilonRACK had reduced incidence of ventricular tachycardia (VT, 64%) and fibrillation (VF, 50%) compared to control (VT, 80%, P<0.05) and (VF, 70%, P < 0.05). However, the highest incidence of VT (100%, P < 0.05) and VF (80%) occurred in hearts treated with epsilonPKC antagonist peptide epsilonV1 compared to control and to epsilonPKC agonist psiepsilonRACK. Interestingly, at 20 min reperfusion, 100% of hearts treated with epsilonPKC agonist psiepsilonRACK exhibited complete recovery of action potentials compared to 40% (P < 0.05) of hearts treated with epsilonPKC antagonist peptide, epsilonV1 and 65% (P < 0.5) of hearts in control. At 20 min reperfusion, maps of action potential duration from epsilonPKC agonist psiepsilonRACK showed minimal dispersion (48.2 +/- 9 ms) compared to exacerbated dispersion (115.4 +/- 42 ms, P < 0.05) in epsilonPKC antagonist and control (67 +/- 20 ms, P<0.05). VT/VF and dispersion from hearts treated with scrambled agonist or antagonist peptides were similar to control. CONCLUSION: The results demonstrate that epsilonPKC activation by psiepsilonRACK peptide protects intact hearts from reperfusion arrhythmias and affords better recovery. On the other hand, inhibition of epsilonPKC increased the incidence of arrhythmias and worsened recovery compared to controls. The results carry significant therapeutic implications for the treatment of acute ischemic heart disease by preconditioning mimicking agents. PMID- 22935421 TI - Genetic analysis of the SIRT1 gene promoter in myocardial infarction. AB - Myocardial infarction (MI) is a restrictive phenotype of coronary artery disease. To date, a group of genes and genetic loci have been associated to MI. However, the genetic causes and underlying molecular mechanisms for MI remain largely unknown. SIRT1, one of highly conserved NAD-dependent class III deacetylases, has been involved in several cellular processes and implicated in human diseases. Autophagy is one of major cellular degradative pathways, which plays important roles in lipid metabolism. Recent studies have shown that SIRT1 deacetylates autophagy-related genes, and the expressions of autophagic genes are altered in MI patients. Accordingly, we hypothesized that SIRT1 may be linked to the MI pathogenesis. In this study, the SIRT1 gene promoter were genetically analyzed in large cohorts of MI patients (n = 327) and controls (n = 358). The results showed that six single-nucleotide polymorphisms and 14 sequence variants were identified. Among these, five novel heterozygous variants (g.69643743Ins, g.69643840Ins, g.69643903G > C, g.69644235G > C and g.69644353G > T) and one single-nucleotide polymorphism (rs35706870) were identified in MI patients, but in none of controls. Moreover, five novel heterozygous variants (g.69643672G > A, g.69644226C > T, g.69644278A > G, g.69644408G > A and g.69644408G > T) were only found in controls. The rest variants were found in MI patients and controls with similar frequencies. Taken together, the variants identified in MI patients may alter the transcriptional activities of SIRT1 gene promoter, which may change SIRT1 levels, contributing to the MI pathogenesis as a risk factor. PMID- 22935422 TI - Molecular docking of bisphenol A and its nitrated and chlorinated metabolites onto human estrogen-related receptor-gamma. AB - A xenoestrogen and known endocrine disruptor, bisphenol A (BPA) binds the human estrogen-related receptor-gamma (ERRgamma) with high affinity (Kd ~ 5.5 nM). It is likely that BPA undergoes oxidative biotransformation by hypochlorite/hypochlorous acid ((-)OCl/HOCl) and peroxynitrite (PN) and the products formed in these reactions may serve as secondary estrogens and contribute to the toxicodynamics of BPA. Therefore, in the present study we have examined the formation of chlorinated and nitrated BPA in reactions of BPA with ( )OCl/HOCl and PN(+CO(2)) performed around the neutral pH. We have identified four major products in these reactions and they include 3-chloro-BPA (CBPA), 3,3' dichloro-BPA (DCBPA), 3-nitro-BPA (NBPA) and 3,3'-dinitro-BPA (DNBPA). Towards understanding the toxicodynamics and estrogenic activity of BPA in biological systems, we have performed molecular docking of BPA, CBPA, DCBPA, DNBPA and NBPA onto the ERRgamma using AutoDock 4.2 software and compared the binding energies with those of estradiol, the natural ligand. Based on the genetic algorithm, the three best conformations were selected and averaged for each ligand and a detailed analysis of molecular interactions based on free energies of binding (kcal/mol) was computed. The results indicate the following rank order of binding to ERRgamma: BPA (-8.78 +/- 0.06) > CBPA (-8.53 +/- 0.41) > NBPA (-7.36 +/- 0.74) > DCBPA (-5.24 +/- 0.17) > DNBPA (-4.95 +/- 0.78) > estradiol (-4.94 +/- 1.04). The docking studies revealed that the OH group of one of the phenyl rings forms a hydrogen bond with Glu275/Arg316, while the OH group of other phenyl ring was bound to Asp346. These results suggest that both BPA and its putative chlorinated and nitrated metabolites have strong binding affinity compared to estradiol. PMID- 22935423 TI - A new method for establishing stable cell lines and its use for large-scale production of human guanylyl cyclase-B receptor and of the extracellular domain. AB - Guanylyl cyclase-B receptor (GC-B) is a membrane receptor that induces intracellular accumulation of cGMP when a specific ligand, C-type natriuretic peptide (CNP), binds to the extracellular ligand-binding domain (ECD). Despite of its medical and biological importance, characterization of GC-B is hampered by limited amounts of protein obtainable. To circumvent this problem, a method was developed for rapidly and semi-automatically establishing stable cell lines specialized for large-scale production. This method, utilizing a bicistronic expression vector for co-expressing a green fluorescent protein and FACS-based selection of high-expressing cells, is generally applicable. It worked particularly well with the ECD and yielded highly purified ECD at 1 mg/l of culture medium by affinity chromatography using modified CNPs. Measurements of ligand-binding and guanylyl cyclase activities for various natriuretic peptides showed that, as expected, CNP is by far the most potent agonist of GC-B with IC(50) of ~7.5 nM. This value is at least an order of magnitude larger than that reported earlier but similar to that established with the guanylyl cyclase-A receptor for its ligand, atrial natriuretic peptide. The methods developed here will be useful, at the least, for characterizing other members of the guanylyl cyclase receptor family. PMID- 22935424 TI - Endoplasmic reticulum (ER) stress inhibitor salubrinal protects against ceramide induced SH-SY5Y cell death. AB - In the present study, we examined the mechanisms of ceramide-induced cell death in SH-SY5Y human neuroblastoma cells. Our results demonstrate a significant endoplasmic reticulum (ER) stress response in SH-SY5Y cells after short-chain ceramide (C6) treatment. Administration of ceramide (C6) to SH-SY5Y human neuroblastoma cells caused apoptotic cell death, which was inhibited by ER stress inhibitor salubrinal. Further, ceramide-induced cell death reduced significantly in stable SH-SY5Y cells expressing C/EBP homologous protein (CHOP) shRNA. Salubrinal inhibited ceramide-induced inositol-requiring enzyme 1alpha (IRE1alpha)/apoptosis signal regulating kinase 1 (ASK1)/c-Jun N-terminal kinase (JNK) phosphorylation. Taken together, these data suggest that ceramide-induced SH-SY5Y cell death may be linked to the ER stress-regulated intrinsic pathway, and proposed the potential protective effects of salubrinal. PMID- 22935425 TI - Characteristics of petroleum contaminants and their distribution in Lake Taihu, China. AB - BACKGROUND: Taihu Lake is a typical plain eutrophic shallow lake. With rapidly economic development of the lake area, the petroleum products and oil wastewater produced in various processes have been inevitably discharged into Taihu Lake. As the major fresh water resource in the economically developed region of Yangtze River Delta, the water quality and environmental condition of Taihu Lake have the direct bearing on the natural environment and sustainable development of economy in this region. For this reason we carried out the study to explore the composition, distribution characteristics and sources of petroleum contaminants in Taihu Lake. The aim of this study was to provide the basis for standard management and pollution control of the Taihu Lake environment. RESULTS: The result showed that water samples from near industrial locations were of relatively higher petroleum contaminants concentrations. The oil pollutants concentrations in different areas of Lake Taihu ranged from 0.106 mg/L to 1.168 mg/L, and the sequence of total contents distribution characteristics of petroleum pollutants from high to low in different regions of Taihu Lake was: "Dapu", "Xiaomeikou", "Zhushan Bay", "Lake center", "Qidu". The results showed that total concentrations of n-alkanes and PAHs ranged from 0.045 to 0.281 mg/L and from 0.011 to 0.034 mg/L respectively. In the same region, the concentrations of hydrocarbon pollutants in the surface and bottom of the lake were higher than that in the middle. CONCLUSION: This paper reached a conclusion that the petroleum contaminants in Taihu Lake mainly derived from petroleum pollution caused by human activities as indicated by OEP, bimodal distribution, CPI, Pr/Ph ratio, the LMW/HMW ratio and other evaluation indices for sources of n-alkanes and polycyclic aromatic hydrocarbons (PAHs). PMID- 22935426 TI - [Abstracts of the 11th Congress of the French Society of Vascular Medicine, 2012, Lyon, France]. PMID- 22935427 TI - Surface anatomical profile of the cerebral cortex in obsessive-compulsive disorder: a study of cortical thickness, folding and surface area. AB - BACKGROUND: Studying the distribution of anatomical abnormalities over the entire cortical surface can help to identify key neural circuits implicated in generating symptoms of neuropsychiatric disorders. There is a significant inconsistency among studies investigating the neuroanatomy of obsessive compulsive disorder (OCD) because of the confounding influence of co-morbid depression and medication use and the lack of unbiased estimation of whole-brain morphometric changes. It is also unknown whether the distinct surface anatomical properties of thickness, surface area and gyrification, which collectively contribute to grey matter volume (GMV), are independently affected in OCD. Method The cortical maps of thickness, gyrification and surface areal change were acquired from 23 unmedicated OCD patients and 20 healthy controls using an unbiased whole-brain surface-based morphometric (SBM) method to detect regional changes in OCD. Subcortical structures were not assessed in this study. RESULTS: Patients showed a significant increase in the right inferior parietal cortical thickness. Significant increases in gyrification were also noted in the left insula, left middle frontal and left lateral occipital regions extending to the precuneus and right supramarginal gyrus in OCD. Areal contraction/expansion maps revealed no significant regional differences between the patients and controls. In patients, gyrification of the insula significantly predicted the symptom severity measured using Yale-Brown Obsessive-Compulsive Scale (YBOCS). CONCLUSIONS: An alteration in the cortical surface anatomy is an important feature of OCD seen in unmedicated samples that relates to the severity of the illness. The results underscore the presence of a neurodevelopmental aberration underlying the pathophysiology of OCD. PMID- 22935430 TI - [Basic consideration on the security checking of sick travelers at airports]. AB - The authorities guarantee the safety of passengers during air travel by strict ground security measures. All of these measures are restrictive and can affect the health status of both healthy and ill travelers. Patients who are in critical condition or confined to a stretcher and have to be repatriated by stretcher on a regular flight, must pass the airport security check as well. But the developers of security system should take into account the medical safety of patients during the procedure. The relevant medical principles are painfully missing not only in Hungary, but unfortunately also at most international airports. On the basis of principles reviewed in the present publication, an unambiguous, professionally reconciled regulation is necessary that would serve as a guideline for airport management and authorities, as well as for the involved medical personnel. Although setting principles into practice requires a different solution at each airport, yet, passenger safety and patient safety have to be harmonized as soon as possible. PMID- 22935429 TI - [Physiological and pathophysiological role of the circadian clock system]. AB - It has been well known for ages that in living organisms the rhythmicity of biological processes is linked to the ~ 24-hour light-dark cycle. However, the exact function of the circadian clock system has been explored only in the past decades. It came to light that the photosensitive primary "master clock" is situated in the suprachiasmatic photosensitive nuclei of the special hypothalamic region, and that it is working according to ~24-hour changes of light and darkness. The master clock sends its messages to the peripheral "slave clocks". In many organs, like pancreatic beta-cells, the slave clocks have autonomic functions as well. Two essential components of the clock system are proteins encoded by the CLOCK and BMAL1 genes. CLOCK genes are in interaction with endonuclear receptors such as peroxisoma-proliferator activated receptors and Rev erb-alpha, as well as with the hypothalamic-pituitary-adrenal axis, regulating the adaptation to stressors, energy supply, metabolic processes and cardiovascular system. Melatonin, the product of corpus pineale has a significant role in the functions of the clock system. The detailed discovery of the clock system has changed our previous knowledge about the development of many diseases. The most explored fields are hypertension, cardiovascular diseases, metabolic processes, mental disorders, cancers, sleep apnoe and joint disorders. CLOCK genes influence ageing as well. The recognition of the periodicity of biological processes makes the optimal dosing of certain drugs feasible. The more detailed discovery of the interaction of the clock system might further improve treatment and prevention of many disorders. PMID- 22935431 TI - [Intrathecal methotrexate chemotherapy for leptomeningeal carcinomatosis]. AB - Lung and breast cancer can give meningeal metastases. Clinical manifestations of leptomeningeal carcinomatosis include all forms of defect of the central nervous system depending on the localization of carcinomatous foci. Diagnosis is based on the detection of carcinomatous cells by the cytological examination of the cerebrospinal fluid. Without treatment the prognosis is limited to only some weeks or months. In case the meningeal carcinomatosis is related to breast cancer, intrathecal methotrexate chemotherapy may allow a significant survival benefit and improve the quality of life in about half of the patients. PMID- 22935432 TI - [The role of intestinal alkaline phosphatase in pediatric inflammatory bowel and celiac diseases]. AB - Intestinal alkaline phosphatase enzyme plays a pivotal role in the maintenance of intestinal mucosal barrier integrity with the detoxification capacity of lipopolysaccharide, the ligand of Toll-like receptor 4. The inappropriate immune responses and the damage of the mucosal barrier may contribute to the initiation of inflammatory bowel and celiac diseases. In the inflamed colonic mucosa of children with inflammatory bowel disease and in the duodenal mucosa of newly diagnosed children with celiac disease, the decreased intestinal alkaline phosphatase and increased Toll-like receptor 4 protein expression may generate enhanced lipopolysaccharide activity, which may strengthen tissue damaging processes. The enhancement of intestinal alkaline phosphatase activity in an animal model of colitis and in therapy resistant, adult patients with ulcerative colitis reduced the symptoms of intestinal inflammation. In accordance with these results, the targeted intestinal administration of the enzyme in the two examined disorders may be a supplemental therapeutic option in the future. PMID- 22935433 TI - [QUALICOPC -- primary care study on quality, costs and equity in European countries: the Hungarian branch]. AB - The importance of primary care has already been recognized in the developed countries, where the structure and function of primary care is very heterogeneous. In the QUALICOPC study, the costs, quality and equity of primary care systems will be compared in the 34 participating countries. Representative samples of primary care practices were recruited in Hungary. An evaluation with questionnaire was performed in 222 practices on the work circumstances, conditions, competency and financial initiatives. Ten patients in each practice were also questioned by independent fieldworkers. In this work, the methodology and Hungarian experience are described. The final results of the international evaluation will be analyzed and published later. It is expected that data obtained from the QUALICOPC study may prove to be useful in health service planning and may be shared with policy makers. PMID- 22935435 TI - Prognostic relevance of melanoma antigen D1 expression in colorectal carcinoma. AB - BACKGROUND: Melanoma antigen D1 (MAGED1) is a member of the type II melanoma antigen (MAGE) family. The down-regulation of MAGED1 expression has been shown in breast carcinoma cell lines and in glioma stem cells and may play an important role in apoptosis and anti-tumorigenesis. However, there is no report on its clinical role in colorectal cancer (CRC). METHODS: We examined the expression of MAGED1 by qPCR in colorectal cancer tissues and their adjacent non-tumorous tissues taken from 6 cases and performed Western blotting and IHC analyses. In addition, we analyzed MAGED1 expression in 285 clinicopathologically characterized colorectal cancer patients. RESULTS: MAGED1 expression was significantly down-regulated in colorectal cancer tissues compared with adjacent non-tumorous tissues and was associated with clinical stage (p < 0.001), T classification (p = 0.001), N classification (p < 0.001), M classification (p < 0.001) and pathologic differentiation (p = 0.002). Patients with lower MAGED1 expression had a shorter survival time than those with higher MAGED1 expression. Univariate and multivariate analyses indicated that MAGED1 expression was an independent prognostic factors (p < 0.001). CONCLUSIONS: MAGED1 may serve as a novel prognostic biomarker of human colorectal cancer. PMID- 22935436 TI - Conservation of functionally important global motions in an enzyme superfamily across varying quaternary structures. AB - The alpha-d-phosphohexomutase superfamily comprises enzymes involved in carbohydrate metabolism that are found in all kingdoms of life. Recent biophysical studies have shown for the first time that several of these enzymes exist as dimers in solution, prompting an examination of the oligomeric state of all proteins of known structure in the superfamily (11 different proteins; 31 crystal structures) via computational and experimental analyses. We find that these proteins range in quaternary structure from monomers to tetramers, with 6 of the 11 known structures being likely oligomers. The oligomeric state of these proteins not only is associated in some cases with enzyme subgroup (i.e., substrate specificity) but also appears to depend on domain of life, with the two archaeal proteins existing as higher-order oligomers. Within the oligomers, three distinct interfaces are observed, one of which is found in both archaeal and bacterial proteins. Normal mode analysis shows that the topological arrangement of the oligomers permits domain 4 of each protomer to move independently as required for catalysis. Our analysis suggests that the advantages associated with protein flexibility in this enzyme family are of sufficient importance to be maintained during the evolution of multiple independent oligomers. This study is one of the first showing that global motions may be conserved not only within protein families but also across members of a superfamily with varying oligomeric structures. PMID- 22935437 TI - Characteristics of patients with rheumatoid arthritis in clinical remission: the many aspects of DAS28 remission. AB - OBJECTIVES: The aim of this study was to observe the clinical characteristics, including the extent of foot and ankle involvement, of Korean patients with rheumatoid arthritis (RA) in remission, defined as Disease Activity Score in 28 joints (DAS28) <2.6. METHODS: Data from a registry of RA patients who visited a rheumatology clinic of a university-affiliated hospital and who were regularly evaluated with DAS28, including the ankle and foot metatarsophalangeal (MTP) joints were enrolled. Patients who were treated with disease-modifying anti rheumatic drugs for at least three months and who were in DAS28 remission were included in this study. RESULTS: Two hundred and thirteen episodes of DAS28 remission were observed in 147 patients. The mean DAS28 value at the time of remission was 1.84 (range, 0.14-2.59). The mean numbers of swollen joints and tender joints (of the 28 joints examined for DAS28) at the time of remission was 0.4 (range, 0-6) and 1.5 (range, 0-13), respectively. Overall, 11.7% and 38% of the patients in clinical remission had foot MTP/ankle swollen and tender joints, respectively. Additionally, 7% and 8.9%, respectively, of the patients in clinical remission had foot MTP/ankle swollen and tender joints without any involvement of the 28 joints included in the DAS28. CONCLUSIONS: Our results show that RA patients in DAS28 remission frequently have residual disease activity in the ankle and foot joints. Given that fore-foot disease activity can lead to joint damage and disability with respect to weight-bearing activities, these joints should be included in the clinical examination. PMID- 22935438 TI - Downward migration of radiocaesium in organic soils across a transect in Scotland. AB - Following the accident at the Chernobyl nuclear power plant in 1986, radioactive materials including (137)Cs were distributed over large parts of the former Soviet Union and Europe. Due to the relatively long physical half-life of (137)Cs (30.1 y) measurable activity concentrations can still be observed in the natural environment. We have determined the depth distribution of (137)Cs from the testing of nuclear weapons in the atmosphere and Chernobyl, in eight highly organic soils along an approximately east to west transect across the Central Highlands of Scotland. The (137)Cs activity concentrations in the soil profiles, corrected for radioactive decay to May 1986, were between 2.8 and 14.4 kBq m(-2). There were differences in the pattern of distribution of (137)Cs in the soil profiles. The mean migration depth of (137)Cs in the soil profiles was 12.2 cm with a range between 8.2 and 17.4 cm. Quantitative mineralogical analysis of the ash obtained after heating the soil to 400 degrees C indicated that clay minerals alone did not have a prime role in controlling the migration of (137)Cs down the profile. PMID- 22935439 TI - Simulations about self-absorption of tritium in titanium tritide and the energy deposition in a silicon Schottky barrier diode. AB - Simulations on the self-absorption of tritium electrons in titanium tritide films and the energy deposition in a silicon Schottky barrier diode are carried out using the Geant4 radiation transport toolkit. Energy consumed in each part of the Schottky radiovoltaic battery is simulated to give a clue about how to make the battery work better. The power and energy-conversion efficiency of the tritium silicon Schottky radiovoltaic battery in an optimized design are simulated. Good consistency with experiments is obtained. PMID- 22935440 TI - Relatively high-protein or 'low-carb' energy-restricted diets for body weight loss and body weight maintenance? AB - BACKGROUND: 'Low-carb' diets have been suggested to be effective in body weight (BW) management. However, these diets are relatively high in protein as well. OBJECTIVE: To unravel whether body-weight loss and weight-maintenance depends on the high-protein or the 'low-carb' component of the diet. DESIGN: Body-weight (BW), fat mass (FM), blood- and urine-parameters of 132 participants (age=50 +/- 12 yr; BW=107 +/- 20 kg; BMI=37 +/- 6 kg/m(2); FM=47.5 +/- 11.9 kg) were compared after 3 and 12 months between four energy-restricted diets with 33% of energy requirement for the first 3 months, and 67% for the last 9 months: normal-protein normal-carbohydrate (NPNC), normal-protein low-carbohydrate (NPLC); high-protein normal-carbohydrate (HPNC), high-protein low-carbohydrate (HPLC); 24h N-analyses confirmed daily protein intakes for the normal-protein diets of 0.7 +/- 0.1 and for the high-protein diets of 1.1 +/- 0.2g/kg BW (p<0.01). RESULTS: BW and FM decreased over 3 months (p<0.001): HP (-14.1 +/- 4 kg; -11.9 +/- 1.7 kg) vs. NP ( 11.5 +/- 4 kg; -9.3 +/- 0.7 kg) (p<0.001); LC (-13.5 +/- 4 kg; -11.0 +/- 1.2 kg) vs. NC (-12.3 +/- 3 kg; -10.3 +/- 1.1 kg) (ns). Diet * time interaction showed HPLC (-14.7 +/- 5 kg; -11.9 +/- 1.6 kg) vs. HPNC (-13.8 +/- 3 kg; -11.9 +/- 1.8 kg) (ns); NPLC (-12.2 +/- 4 kg; -10.0 +/- 0.8 kg) vs. NPNC (-10.7 +/- 4 kg; -8.6 +/- 0.7 kg) (ns); HPLC vs. NPLC (p<0.001); HPNC vs. NPNC (p<0.001). Decreases over 12 months (p<0.001) showed HP (-12.8 +/- 4 kg; -9.1 +/- 0.8 kg) vs. NP (-8.9 +/- 3 kg; -7.7 +/- 0.6 kg) (p<0.001); LC (-10.6 +/- 4 kg; -8.3 +/- 0.7 kg) vs. NC (11.1 +/- 3 kg; 9.3 +/- 0.7 kg) (ns). Diet * time interaction showed HPLC (-11.6 +/- 5 kg ; -8.2 +/- 0.7 kg) vs. HPNC (-14.1 +/- 4 kg; -10.0 +/- 0.9 kg) (ns); NPNC (-8.2 +/- 3 kg; -6.7 +/- 0.6 kg) vs. NPLC (-9.7 +/- 3 kg; -8.5 +/- 0.7 kg) (ns); HPLC vs. NPLC (p<0.01); HPNC vs. NPNC (p<0.01). HPNC vs. all other diets reduced diastolic blood pressure more. Relationships between changes in BW, FM, FFM or metabolic parameters and energy percentage of fat in the diet were not statistically significant. Metabolic profile and fat-free-mass were improved following weight-loss. CONCLUSION: Body-weight loss and weight-maintenance depends on the high-protein, but not on the 'low-carb' component of the diet, while it is unrelated to the concomitant fat-content of the diet. PMID- 22935441 TI - Association between sedentary behaviour and socioeconomic factors, diet and lifestyle among the Balearic Islands adolescents. AB - BACKGROUND: Many different factors influenced food habits and physical activity patterns of adolescents in a complex interactive way. The aim of this study was to assess association between sedentary behaviour and socioeconomic factors, diet and lifestyle among the Balearic Islands adolescents. METHODS: A cross-sectional survey (n = 1961; 12-17 years old) was carried out. Physical activity was assessed using the International Physical Activity Questionnaire for adolescents (IPAQ-A). Sedentary behaviour was defined as <300 min/week of moderate and vigorous physical activity. Anthropometric measurements, body image, socio economic and lifestyle determinants, food consumption, and adherence to the Mediterranean diet were assessed. RESULTS: The prevalence of sedentary behaviour was 37.1% (22.0% boys, 50.8% girls). Active boys consumed frequently breakfast cereals and fresh fruit; active girls yogurt, cheese, breakfast cereals, and fresh fruit; and sedentary girls high fat foods and soft drinks. Sedentary behaviour of girls was directly associated to age, and time spent on media screen and homework, and inversely related to adherence to Mediterranean diet, and body composition. Sedentary behaviour of boys was inversely related to adherence to the Mediterranean diet, and the desire to remain the same weight. CONCLUSIONS: The prevalence of sedentary behaviour among Balearic Islands adolescents is high, mainly among girls. Age, sex, parental educational and profession levels, body size dissatisfaction, and poor quality diet are important factors of physical activity practice among adolescents. PMID- 22935443 TI - New perspectives in the treatment of leg ulcers. PMID- 22935442 TI - No detection of occult HBV-DNA in patients with various rheumatic diseases treated with anti-TNF agents: a two-year prospective study. AB - OBJECTIVES: The widespread use of tumour necrosis factor (TNF)-targeted therapies in patients with rheumatic, digestive and dermatologic diseases has been associated with reports of reactivation of HBV replication and ensuing hepatitis flares both in asymptomatic HBsAg carriers and in subjects with occult HBV infection. The aim of our work was to investigate in a two-year prospective study the potential for HBV reactivation in patients with inflammatory joint diseases undergoing anti-TNF treatment from a southern Mediterranean area. METHODS: Fifty seven consecutive outpatients attending the Academic Unit of Rheumatology at the University of Palermo (12 with rheumatoid arthritis, 17 with psoriatic arthritis and 28 with ankylosing spondylitis) were enrolled in the study. HBV-DNA was tested by a standard quantitative assay in HBsAg-positive subjects and by an ad hoc highly sensitive PCR in HBsAg-negative patients performed at baseline and then every six months on the anti-TNF agent. RESULTS: Occult HBV-DNA was never detected in the 54 HBsAg negative subjects, regardless of their anti HBs/HBc status. All HBsAg positive patients, who were started on prophylactic lamivudine, remained HBV-DNA undetectable throughout the anti-TNF treatment. CONCLUSIONS: Even in an area of previously high HBV endemicity, where occult HBV infection is likely to have a high prevalence, treatment of rheumatological patients with anti TNF drugs is safe in terms of its potential to reactivate HBV. Prophylaxis with lamivudine is sufficient to prevent reactivation in HBsAg carriers. PMID- 22935444 TI - China collaborative study on dialysis: a multi-centers cohort study on cardiovascular diseases in patients on maintenance dialysis. AB - BACKGROUND: Cardiovascular disease (CVD) is the main cause of death in patients on chronic dialysis. The question whether dialysis modality impacts cardiovascular risk remains to be addressed. China Collaborative Study on Dialysis, a multi-centers cohort study, was performed to evaluate cardiovascular morbidity during maintenance hemodialysis (HD) and peritoneal dialysis (PD). METHOD: The cohort consisted of chronic dialysis patients from the database of 9 of the largest dialysis facilities around China. The inclusion period was between January 1, 2005, and December 1, 2010. Cardiovascular morbidity was defined as the presence of clinically diagnosed ischemic heart disease, heart failure, peripheral vascular disease, and/or stroke. The patients who had cardiovascular morbidity before initiation of dialysis were excluded. Data collection was based on review of medical record. RESULT: A total of 2,388 adult patients (1,775 on HD and 613 on PD) were enrolled. Cardiovascular morbidity affected 57% patients and was comparable between HD and PD patients. However, clinically diagnosed ischemic heart disease and stroke was more prevalent in PD than HD patients. When the patients were stratified by age or dialysis vintage, the cardiovascular morbidity was significantly higher in PD than HD among those aged 50 years or older, or those receiving dialysis over 36 months. Multivariate analysis revealed that the risk factors for cardiovascular morbidity had different pattern in PD and HD patients. Hyperglycemia was the strongest risk factor for cardiovascular morbidity in PD, but not in HD patients. Hypertriglyceridemia and hypoalbuminemia were independently associated with CVD only in PD patients. CONCLUSIONS: Cardiovascular morbidity during chronic dialysis was more prevalent in PD than HD patients among those with old age and long-term dialysis. Metabolic disturbance related risk factors were independently associated with CVD only in PD patients. Better understanding the impact of dialysis modality on CVD would be an important step for prevention and treatment. PMID- 22935445 TI - The influence of preoperative serum anticholinergic activity and other risk factors for the development of postoperative cognitive dysfunction after cardiac surgery. AB - OBJECTIVE: Patients undergoing cardiac surgery are at risk for postoperative cognitive dysfunction (POCD). Evaluating preoperative risk factors represents 1 possible way to minimize the postoperative risk of cognitive dysfunction. We investigated marked deterioration in cholinergic neurotransmission as 1 such potential risk factor for transient and long-lasting POCD. Serum anticholinergic activity (SAA) has already been described as a risk factor for developing delirium in an elderly study population. However, the role of SAA for long lasting POCD is unknown. METHODS: Following local ethics board approval and written informed consent, we recruited a cohort of patients aged >= 55 years undergoing cardiac surgery. Before surgery, levels of SAA were measured and a battery of neuropsychologic tests (NPTs) was applied. S100 calcium binding protein beta concentration was measured intraoperatively. Pre-, intra-, and postoperative patient-specific characteristics were recorded. The NPTs were repeated 3 months after hospital discharge to evaluate 3-month POCD. A group of nonsurgical patients (n = 34) was recruited as control subjects to adjust NPT scores, using reliable methods for the change index. Logistic multivariate regression was used to evaluate independent predictors of POCD. RESULTS: One hundred fifty-four patients were screened before surgery, and 117 completed the second NPT. POCD was identified in 25.6% of patients. In contrast to intraoperatively increased S100 calcium binding protein beta, preoperative SAA was not associated with POCD following adjustment for covariates. CONCLUSIONS: Preoperatively increased SAA did not predict POCD 3 months after cardiac surgery. PMID- 22935446 TI - New ascending aortic aneurysm model in rats reproduces main structural features of degenerative ascending thoracic aortic aneurysms in human beings. AB - OBJECTIVES: The singularity of the ascending aorta regarding mechanisms driving aneurysm formation requires the development of specific animal models. We investigated if adventitial elastase application results in ascending aorta aneurysms in rats. METHODS: Adult Lewis rats (n = 26) were anesthetized, their ascending aortas measured by transthoracic ultrasound, and exposed via median sternotomy. Elastase or saline was applied on the ascending aortic adventitia. Ascending aorta diameters were monitored by ultrasound at 10 and 30 days, when the animals were killed. Wall area was measured on orcein stained sections. Matrix metalloproteinase-2 and matrix metalloproteinase-9 levels were quantified on gelatin zymography. RESULTS: Following elastase application, ascending aortic diameter increased at 10 and 30 days follow-up by 38% and 44%, respectively (P = .004). Despite thinning of the media secondary to vascular dilation, standardized medial area was not different between elastase-treated aortas and controls. Standardized total wall area had a significant increase in treated aortas compared with controls. Active matrix metalloproteinase-2 was significantly increased at 30 days in treated aortas, whereas active matrix metalloproteinase-9 was no different from controls. CONCLUSIONS: Elastase application on rat ascending aortic adventitia produced aneurysms, creating a reproducible model. Aortic wall remodeling evolved toward an increase in total wall area, reproducing the main structural features of this disease in human beings. PMID- 22935447 TI - The beta-catenin/TCF complex as a novel target of resveratrol in the Wnt/beta catenin signaling pathway. AB - Wnts are secreted glycolipoproteins that play important roles in the regulation of embryonic development and tissue homeostasis. Binding of Wnt to receptors and co-receptors causes inactivation of the beta-catenin destruction complex, which leads to the stabilization and nuclear translocation of beta-catenin to initiate Wnt-responsive gene expression after associating with TCF in the nucleus. As its deregulation results in serious human diseases, especially cancers, the Wnt signaling pathway serves as a promising platform for screening anti-cancer drugs. Resveratrol was selected based on its ability to inhibit the beta-catenin/TCF mediated transcriptional activity. Resveratrol, a natural phytoalexin found in a variety of plants, possesses health-promoting properties including anti-aging, anti-inflammatory, anti-oxidant, anti-cancer, cardioprotective and neuroprotective activities. We found that resveratrol indeed exhibited dose dependent suppression of Wnt signaling, reduced the expression of Wnt target genes such as cyclin D1 and conductin, and inhibited the growth of Wnt-stimulated cells and Wnt-driven colorectal cancer cells. Further studies indicated that resveratrol functions downstream of GSK3beta. Treatment with resveratrol did not alter the amount of beta-catenin and its distribution in the cytoplasm and nucleus, suggesting that resveratrol did not affect the accumulation and nuclear targeting of beta-catenin. In contrast, co-immunoprecipitation and in vitro binding analyses substantiated that resveratrol was capable of disrupting the binding between beta-catenin and TCF4, contributing to the decreased Wnt signaling. Our discoveries not only reveal a novel target of resveratrol in the Wnt signaling pathway but also show the potential of therapy with harmless resveratrol in colorectal cancer and other Wnt-related diseases. PMID- 22935448 TI - Development of chemical inhibitors of the SARS coronavirus: viral helicase as a potential target. AB - Severe acute respiratory syndrome (SARS) was the first pandemic in the 21st century to claim more than 700 lives worldwide. However, effective anti-SARS vaccines or medications are currently unavailable despite being desperately needed to adequately prepare for a possible SARS outbreak. SARS is caused by a novel coronavirus, and one of its components, a viral helicase, is emerging as a promising target for the development of chemical SARS inhibitors. In the following review, we describe the characterization, family classification, and kinetic movement mechanisms of the SARS coronavirus (SCV) helicase-nsP13. We also discuss the recent progress in the identification of novel chemical inhibitors of nsP13 in the context of our recent discovery of the strong inhibition of the SARS helicase by natural flavonoids, myricetin and scutellarein. These compounds will serve as important resources for the future development of anti-SARS medications. PMID- 22935449 TI - Metabolomics and its potential in drug development. AB - Metabolomics is the global and unbiased survey of the complement of small molecules (say, <1 kDa) in a biofluid, tissue, organ or organism and measures the end-products of the cellular metabolism of both endogenous and exogenous substrates. Many drug candidates fail during Phase II and III clinical trials at an enormous cost to the pharmaceutical industry in terms of both time lost and of financial resources. The constantly evolving model of drug development now dictates that biomarkers should be employed in preclinical development for the early detection of likely-to-fail candidates. Biomarkers may also be useful in the preselection of patients and through the subclassification of diseases in clinical drug development. Here we show with examples how metabolomics can assist in the preclinical development phases of discovery, pharmacology, toxicology, and ADME. Although not yet established as a clinical trial patient prescreening procedure, metabolomics shows considerable promise in this regard. We can be certain that metabolomics will join genomics and transcriptomics in lubricating the wheels of clinical drug development in the near future. PMID- 22935450 TI - Function, diversity and therapeutic potential of the N-terminal domain of human chemokine receptors. AB - Chemokines and their receptors play fundamental roles in many physiological and pathological processes such as leukocyte trafficking, inflammation, cancer and HIV-1 infection. Chemokine-receptor interactions are particularly intricate and therefore require precise orchestration. The flexible N-terminal domain of human chemokine receptors has regularly been demonstrated to hold a crucial role in the initial recognition and selective binding of the receptor ligands. The length and the amino acid sequences of the N-termini vary considerably among different receptors but they all show a high content of negatively charged residues and are subject to post-translational modifications such as O-sulfation and N- or O glycosylation. In addition, a conserved cysteine that is most likely engaged in a receptor-stabilizing disulfide bond delimits two functionally distinct parts in the N-terminus, characterized by specific molecular signatures. Structural analyses have shown that the N-terminus of chemokine receptors recognizes a groove on the chemokine surface and that this interaction is stabilized by high affinity binding to a conserved sulfotyrosine-binding pocket. Altogether, these data provide new insights on the chemokine-receptor molecular interplay and identify the receptor N-terminus-binding site as a new target for the development of therapeutic molecules. This review presents and discusses the diversity and function of human chemokine receptor N-terminal domains and provides a comprehensive annotated inventory of their sequences, laying special emphasis on the presence of post-translational modifications and functional features. Finally, it identifies new molecular signatures and proposes a computational model for the positioning and the conformation of the CXCR4 N-terminus grafted on the first chemokine receptor X-ray structure. PMID- 22935451 TI - Hybrid repair of a very late, post-aortic coarctation surgery thoracic aneurysm: a case report. AB - INTRODUCTION: Local aneurysms after surgical repair of coarctation of the aorta occur mainly in patients surgically treated by Dacron patch plasty during adulthood. The management of these patients is always problematic, with frequent complications and increased mortality rates. Percutaneous stent-graft implantation avoids the need for surgical reintervention. CASE PRESENTATION: We report a case involving the hybrid treatment by stent-graft implantation and transposition of the left subclavian artery to the left common carotid artery of an aneurysmal dilatation of the thoracic aorta that occurred in a 64-year-old Caucasian man, operated on almost 40 years earlier with a Dacron patch plasty for aortic coarctation. Our patient presented to our facility for evaluation with back pain and shortness of breath after minimal physical effort. A physical examination revealed stony dullness to percussion of the left posterior thorax, with no other abnormalities. The results of chest radiography, followed by contrast-enhanced computed tomography and aortography, led to a diagnosis of giant aortic thoracic aneurysm. Successful treatment of the aneurysm was achieved by percutaneous stent-graft implantation combined with transposition of the left subclavian artery to the left common carotid artery. His post-procedural recovery was uneventful. Three months after the procedure, computed tomography showed complete thrombosis of the excluded aneurysm, without any clinical signs of left lower limb ischemia or new onset neurological abnormalities. CONCLUSIONS: Our patient's case illustrates the clinical outcomes of surgical interventions for aortic coarctation. However, the very late appearance of a local aneurysm is rather unusual. Management of such cases is always difficult. The decision-making should be multidisciplinary. A hybrid approach was considered the best solution for our patient. PMID- 22935453 TI - Diode laser for treatment of symptomatic hemorrhoid: a short term clinical result of a mini invasive treatment, and one year follow up. AB - Hemorrhoid is protrusion of plexus or blood vessels in the anal canal. The hemorrhoid may cause symptoms that are: bleeding, pain, prolaps, itching, soilage of feces, and psychologic discomfort. There are many methods for treatment of hemorrhoid like, medical therapy, cryo-therapy, rubber band ligation, sclerotherapy, laser, and surgery. All methods have some complication in postoperative period and recurrence. THE AIM OF THE STUDY: Was to evaluate Diode laser for treatment of hemorrhoid. MATERIAL AND METHODS: This study included patients who suffer from the hemorrhoid. Cases with fistula and fissure had been omitted. Patients with hemorrhoid in grade 2, 3, 4 and mixed were treated with diode laser. Follow up was done 1,7,14, 30, 90, and 360 days laser therapy. RESULTS: In this study, 341 patients with hemorrhoid treated with diode laser were included. Results of follow-up were as follows: need for analgesia in hospital stay and home was very low total complication was seen in 12 patient (3.51%), edema in 8 patient (2.34%), hemorrhage and abscess each of them in 2 patient (0.58%), stricture and recurrence was zero after one year. CONCLUSIONS: All methods used for hemorrhoid treatment has advantages, disadvantages, and limitations. But treatment of hemorrhoid by Diode laser, which is done by skilled surgeon has several advantages over other treatments. This advantages include, less operation time, less pain and bleeding, allow quick healing of piles, no stricture, and minimal recurrence after operation. PMID- 22935452 TI - Persistence of cognitive impairment and its negative impact on psychosocial functioning in lithium-treated, euthymic bipolar patients: a 6-year follow-up study. AB - BACKGROUND: Previous cross-sectional studies report that cognitive impairment is associated with poor psychosocial functioning in euthymic bipolar patients. There is a lack of long-term studies to determine the course of cognitive impairment and its impact on functional outcome. Method A total of 54 subjects were assessed at baseline and 6 years later; 28 had DSM-IV TR bipolar I or II disorder (recruited, at baseline, from a Lithium Clinic Program) and 26 were healthy matched controls. They were all assessed with a cognitive battery tapping into the main cognitive domains (executive function, attention, processing speed, verbal memory and visual memory) twice over a 6-year follow-up period. All patients were euthymic (Hamilton Rating Scale for Depression score lower than 8 and Young mania rating scale score lower than 6) for at least 3 months before both evaluations. At the end of follow-up, psychosocial functioning was also evaluated by means of the Functioning Assessment Short Test. RESULTS: Repeated measures multivariate analysis of covariance showed that there were main effects of group in the executive domain, in the inhibition domain, in the processing speed domain, and in the verbal memory domain (p<0.04). Among the clinical factors, only longer illness duration was significantly related to slow processing (p=0.01), whereas strong relationships were observed between impoverished cognition along time and poorer psychosocial functioning (p<0.05). CONCLUSIONS: Executive functioning, inhibition, processing speed and verbal memory were impaired in euthymic bipolar out-patients. Although cognitive deficits remained stable on average throughout the follow-up, they had enduring negative effects on psychosocial adaptation of patients. PMID- 22935454 TI - Endoscopic treatment of the choledocholithiasis--effectiveness, safety and limitations of the method. AB - Endoscopic Retrograde Cholangio-Pancreatography (ERCP) is accepted referred method of treatment of the choledocholithiasis. THE AIM OF THE STUDY: Evaluation of efficacy and safety of the endoscopic treatment of the biliary tract stones. MATERIAL AND METHODS: Results of 3309 Endoscopic Retrograde Cholangio Pancreatography (ERCP) carried out in Division of Endoscopy of the General Surgery Department in the period 2000 - 2010. The retrospective analysis of the indications, process, findings and final results of 1698 ERCP and Endoscopic Sphincterotomy (ES) was performed with intention to treat of the biliary tract stones. RESULTS: The 883 (52%)patients with coexisted gall-bladder and biliary tract stones were the principal group. The second group included 580 (34.2%) patients with residual choledocholithiasis after cholecystectomy and biliary tract surgery. Moreover ERCP, ES and endoscopic evacuation of biliary stones have been urgently carried out in 159 (9.4%) cases with acute biliary pancreatitis. Lastly ERCP with re-sphincterotomy and removal of the stones was performed in 75 (4.4%) patients with recurrent choledocholithiasis. The procedure was effective in 1561 (92%) patients. When removal of the stones was not possible, decompression of the biliary tract by implantation of the plastic stent was done in 63 (3.7%) cases. Ineffective procedure was noted in 74 (4.3%) patients. The most commonly observed complication was acute pancreatitis. Because of: post ES bleeding, acute haemmorhagic and necrotic pancreatitis, impacted Dormia basket and peripapillary duodenal perforation 10 patients (0.5%) had to be operated. Two patients (0.1%) died. CONCLUSIONS: 1. Endoscopic treatment of choledocholithiasis is highly effective but risk factors of complications with urgency an intensive conservative management and surgical intervention have to be considered. 2. After ES, if surgical evacuation of the stones have to be carry out, post operative biliary tract drainage (by T tube) is not necessary. PMID- 22935455 TI - Vascular endothelial growth factor and survivin immunostaining in gastric adenocarcinoma. AB - Two molecules - vascular endothelial growth factor involved in new vessels formation and survivin - antiapoptotic protein, reported to be associated with worse prognosis in various malignancies have been chosen for the study. Both are potential target for novel therapies. THE AIM OF THE STUDY: Was to determine the immunostaining of VEGF and survivin in gastric carcinoma and to analyse their relationship to the selected clinicopathological features and survival. MATERIAL AND METHODS: Formalin-fixed, paraffin-embedded sections from 41 gastric adenocarcinomas were used for immunohistochemical reaction with monoclonal antibodies against vascular endothelial growth factor and survivin. The results were compared with selected clinicopathological features and survival. RESULTS: Positive immunohistochemical reaction for vascular endothelial growth factor and survivin was revealed in 24 (58,53%) and 30 (73,17%), gastric carcinomas respectively. Vascular endothelial growth factor-negative gastric carcinomas were significantly more common in cases without metastases to regional lymph nodes and distant organs and in less advanced cases. Similar, distant metastases were also statistically less common in survivin-negative carcinomas. The differences in immunohistochemical reactions for survivin between less and more advanced cases almost reach statistical significance. The only factors significantly influenced 1, 2 and 3-year survival were vascular endothelial growth factor and survivin status. Statistically significant higher percentage of survival was noted in patients with vascular endothelial growth factor- and survivin-negative tumors. CONCLUSIONS: It seems that vascular endothelial growth factor and survivin play role in local invasion and spread of gastric adenocarcinoma and negatively influences survival. However, further studies are required to assess their true usefulness in the clinical practice. PMID- 22935457 TI - Intraoperative difficulties and the reasons for conversion in patients treated with laparoscopic colorectal tumors. AB - THE AIM OF THE STUDY: Was an evaluation of conversion causes and intraoperative difficulties in patients treated with laparoscopic surgery due to colorectal tumours on the basis of authors' own material. MATERIAL AND METHODS: in the period 2009-2012 160 patients were operated on because of large bowel cancer, 79 women and 81 men. Average age of patients was 66 years. The conversion was recognized as desuflation of peritoneal cavity, trocars removal and making laparotomy. RESULTS: The conversion was made in 22 cases (13,7%). More in men (16.1%) than in women. The conversion was made twice as likely in T3 and T4 tumors than in T1 and T2. CONCLUSIONS: The main cause of conversion in laparoscopic operations of colorectal cancer is local tumor progression. PMID- 22935456 TI - Prevalence of Cryptosporidium sp. in patients with colorectal cancer. AB - Parasitic protozoans of the Cryptosporidium genus are intracellular intestinal parasites of mammals, causing cryptosporidiosis. Clinically, cryptosporidiosis manifests as chronic diarrhoea. Individuals with immune disorders, including those with neoplasms, are at risk of symptomatic invasion. THE AIM OF THE STUDY: Was the evaluation of Cryptosporidium sp. prevalence in patients with diagnosed colorectal cancer. MATERIAL AND METHODS: The studied group encompassed 87 patients with diagnosed colorectal cancer, undergoing surgery at the Department of General and Oncological Surgery, Pomeranian Medical University, in the years 2009-2010. Immunoenzymatic tests for Cryptosporidium sp. on faeces samples were performed with the use of commercial test kit, ProSpecT((r))Cryptosporidium Microplate Assay (Remel Inc). RESULTS: The presence of Cryptosporidium sp. was found in 12.6% of studied patients with colorectal cancer. The performed statistical analysis did not reveal any correlation between Cryptosporidium sp. infection and gender, age, neoplasm advancement stage as per Astler-Coller scale, neoplasm differentiation grade, or neoplastic tumour localisation in relation to the splenic flexure. CONCLUSIONS: There was found high prevalence of Cryptosporidium sp. in patients with colorectal cancer. It was comparable to the prevalence reported for patients with immune deficiency. PMID- 22935458 TI - Lack of association between the 135G/C RAD51 gene polymorphism and the risk of colorectal cancer among Polish population. AB - One of the major causes of carcinogenesis is loss of genome stability. RAD51 in process of homologous recombination (HR) played crucial role in maintenance integrity of genome through initiate of DNA double strand breaks repair. Presence of single nucleotide polymorphism (SNP) in RAD51 gene could change the capacity of DNA repair and altered the response to damaging agents. Research on potential impact of genetic variability on development and progression CRC may contribute to setting new genetic markers or/and determined individual susceptibility to CRC.The aim of the study. This study was designed to evaluate the effect of 135 G/C (rs1801320) RAD51 polymorphism located in the 5' untraslated region on the risk and progression of CRC.Material and methods. The subjects consisted of histologically confirmed colorectal cancer (n = 200) and controls (n = 200) with lack of previous history of cancer. The distribution of genotypes was determined by restriction fragment length polymorphism PCR (RFLP - PCR). Statistical analysis was based on multivariate regression model.Results and conclusion. Our study reveal no significance association of 135 G/C RAD51 polymorphism with occurrence and progression of colorectal cancer. PMID- 22935459 TI - A rare case of Hodkin's lymphoma of the mediastinum imitating retrosternal goiter -retrospective analysis of the diagnostic process. AB - Primary extranodal sites of development of lymphoid neoplasms are rare and concern about 5% of patients with Hodgkin's lymphoma. Extranodal development is more common in non Hodgkin's lymphoma and may reach 33%. A 27-year-old woman was diagnosed by a cardiologist for a short breath. On the physical examination no other abnormalities were observed. Echocardiography, performed by cardiologist, revealed a large tumor, overlaying the right ventricle and compressing the pulmonary trunk. Chest X-ray, ultrasound and CT-scan confirmed diagnosis. In fine needle aspiration clear, lucid fluid was obtained. Scintygraphy of the neck and thorax showed accumulation of the marker in the properly placed but enlarged thyroid gland. Patient was qualified for surgical treatment - cervicotomy and sternothomy were performed. The histopatological exam of the tumor revealed Hodgkin's lymphoma of the mediastinum (classical subtype NS-1). Following the surgery, adjuvant therapy was instituted. After the treatment PET-CT-scan did not show any kind of non-physiological radiomarker's accumulation in the monitored regions of the body and in in three-years follow-up the patient shows no signs of recurrence. PMID- 22935460 TI - The use of a pedunculated, extended latissimus dorsi flap in primary and secondary breast reconstruction procedures--case report. AB - The extended latissimus dorsi flap (LD) is used in breast reconstruction since the 70's. LD flap is often used in corrective surgery in cases of unsatisfactory cosmetic results after breast-conserving therapy. In our department LD flap has several uses. In addition to free microvascular flaps - which applies in breast reconstructive surgery is routine, there are clinical situations where the use of pedicled LD flap is justified. The main indications for its use are: the inability to apply microvascular flap, the general condition (diabetes, advanced atherosclerosis), smoking, previous surgery of abdominal wall, abdominal obesity, patient preferences. Approximately 30% of patients after breast reconstruction require corrective procedures. Group which uses extended LD flap account for 24 patients. In 16 cases it was used for elective breast reconstruction. In the remaining eight cases it was used in the corrective procedures symmetry and shape of the previously reconstructed breast. Based on our own experience it can be concluded that the LD flap with an alternative to microvascular techniques. Complication rate when using the LD flap is relatively low and includes: seroma and slight motor disability of the shoulder girdle. PMID- 22935461 TI - Effective cancer treatment by multidisciplinary teams. PMID- 22935462 TI - Assessment of intramyocardial hemorrhage by T1-weighted cardiovascular magnetic resonance in reperfused acute myocardial infarction. AB - BACKGROUND: Intramyocardialhemorrhage (IMH) reflects severe reperfusion injury in acute myocardial infarction. Non-invasive detection of IMH by cardiovascular magnetic resonance (CMR) may serve as a surrogate marker to evaluate the effect of preventive measures to reduce reperfusion injury and hence provide additional prognostic information. We sought to investigate whether IMH could be detected by CMR exploiting the T1 shortening effect of methemoglobin in an experimental model of acute myocardial infarction. The results were compared to T2-weighthed short tau inversion recovery (T2-STIR), and T2*-weighted(T2*W) sequences. METHODS AND RESULTS: IMH was induced in ten 40 kg pigs by 50-min balloon occlusion of the mid LAD followed by reperfusion. Between 4-9 days (average 4.8) post-injury, the left ventricular myocardium was assessed by T1-weigthed Inversion Recovery(T1W-IR), T2 STIR, and T2*W sequences. All CMR images were matched to histopathology and compared with the area of IMH. The difference between the size of the IMH area detected on T1W-IR images and pathology was -1.6 +/- 11.3% (limits of agreement, 24%-21%), for the T2*W images the difference was -0.1 +/- 18.3% (limits of agreement, -36.8%-36.6%), and for T2-STIR the difference was 8.0 +/- 15.5% (limits of agreement, -23%-39%). By T1W IR the diagnostic sensitivity of IMH was 90% and specificity 70%, for T2*W imaging the sensitivity was 70% and specificity 50%, and for T2-STIR sensitivity for imaging IMH was 50% and specificity 60%. CONCLUSION: T1-weigthed non-contrast enhanced CMR detects IMH with high sensitivity and specificity and may become a diagnostic tool for detection of IMH in patients with myocardial infarction. PMID- 22935464 TI - Progression of myocardial fibrosis assessed with cardiac magnetic resonance in hypertrophic cardiomyopathy. AB - OBJECTIVES: This study sought to assess the rate of progression of fibrosis by 2 consecutive cardiac magnetic resonance (CMR) examinations and its relation with clinical variables. BACKGROUND: In hypertrophic cardiomyopathy (HCM) myocardial fibrosis, detected by late gadolinium enhancement (LGE), is associated to a progressive ventricular dysfunction and worse prognosis. METHODS: A total of 55 HCM patients (37 males; mean age 43 +/- 18 years) underwent 2 CMR examinations (CMR-1 and CMR-2) separated by an interval of 719 +/- 410 days. Extent of LGE was measured, and the rate of progression of LGE (LGE-rate) was calculated as the ratio between the increment of LGE (in grams) and the time (months) between the CMR examinations. RESULTS: At CMR-1, LGE was detected in 45 subjects, with an extent of 13.3 +/- 15.2 g. At CMR-2, 53 (96.4%) patients had LGE, with an extent of 24.6 +/- 27.5 g. In 44 patients, LGE extent increased significantly (>=1 g). Patients with apical HCM had higher increments of LGE (p = 0.004) and LGE-rate (p < 0.001) than those with other patterns of hypertrophy. The extent of LGE at CMR 1 and the apical pattern of hypertrophy were independent predictors of the increment of LGE. Patients with worsened New York Heart Association functional class presented higher increase of LGE (p = 0.031) and LGE-rate (p < 0.05) than those with preserved functional status. CONCLUSIONS: Myocardial fibrosis in HCM is a progressive and fast phenomenon. LGE increment, related to a worse clinical status, is more extensive in apical hypertrophy than in other patterns. PMID- 22935463 TI - Low-dose tacrolimus in treating lupus nephritis refractory to cyclophosphamide: a prospective cohort study. AB - OBJECTIVES: This study aims to assess the efficacy and safety of low-dose tacrolimus therapy in patients with refractory lupus nephritis (LN) who were resistant to cyclophosphamide (CYC). METHODS: A total of 26 LN patients (4 men and 22 women) with persistent proteinuria who were resistant to CYC treatment (>8 g in less than 6 months) were enrolled. Tacrolimus was initiated at 2 mg/day (if patient weight <60 kg) or 3mg/day (if patient weight >=60 kg), administered in two divided doses. Prospective data on daily proteinuria, serum albumin level, and serologic lupus activity were collected for 6 months. RESULTS: Mean age at baseline was 29.36+/-9.45 years. Mean urinary protein significantly decreased from 6.91+/-4.50 g at baseline to 1.11+/-1.10 g at 6 months (p<0.001). Mean serum album level significantly increased from 25.56+/-7.94 g/L at baseline to 38.12+/ 2.42 g/L at 6 months (p<0.001). Mean systemic lupus erythematosus disease activity index (SLEDAI) score decreased from 11.42+/-6.74 at baseline to 3.61+/ 2.73 at 6 months (p<0.001). Complete or partial response was observed in 88.46% of patients receiving tacrolimus therapy at 6 months. Twenty-one patients achieved partial or complete remission in two months. There was no significant difference among tacrolimus levels for patients with complete, partial, or no response. The effective dosage in this study was 2-3 mg/day for patients with complete or partial response to tacrolimus. Tacrolimus was well tolerated at the administered dose, though one patient developed severe lung infection. CONCLUSIONS: Our results suggested tacrolimus at low dosage and serum level to be potentially effective and safe for treatment in patients with LN resistant to sufficient CYC therapy. A tacrolimus dosage of 2-3 mg daily appears to be effective and safe. PMID- 22935465 TI - Hypertrophic cardiomyopathy: refining the lens of cardiac magnetic resonance to evaluate late gadolinium enhancement. PMID- 22935466 TI - The year in atherothrombosis. PMID- 22935467 TI - Large cardiac lipoma with pseudoaneurysmal appearance. PMID- 22935468 TI - President's page: Lifelong learning in the digital age. PMID- 22935469 TI - Potential treatment influences and mechanisms related to asymmetric dimethylarginine control in heart failure. PMID- 22935471 TI - Intermittent mechanical tricuspid valve obstruction recognized by central venous pressure tracing and confirmed by transesophageal echocardiography. PMID- 22935472 TI - Reproducibility and accuracy of robot-assisted laparoscopic fertility sparing radical trachelectomy. AB - OBJECTIVE: To assess the accuracy and reproducibility of robot-assisted laparoscopic abdominal fertility sparing radical trachelectomy in women with early stage cervical cancer. METHODS: Relevant prospective clinical data from 13 consecutive women planned for robotic radical trachelectomy between 2007 and 2012 were compared with retrospective data from 12 consecutive women planned for vaginal radical trachelectomy between 2000 and 2007. The first follow up on all women included a similar vaginal ultrasonographic measurement of the remaining cervical length and the position of the cerclage, enabling a direct comparison. Peri- and postoperative clinical data were evaluated. RESULTS: The remaining cervical length was equal between the robotic and vaginal procedures (mean 11 mm, range 8-13 mm; mean 11 mm, range 5-19 mm respectively, p=0.92). The distance from the cerclage to the inner cervical os was significantly shorter and less variable in the robot group (robot mean 2mm, range of 1-4mm, vaginal mean 4mm, range 2-7 mm, p=0.003). Rejection of the cerclage (n=3) and/or cervical stenosis (n=3) was diagnosed in four women, all of whom in the vaginal group, between one and 13 months after surgery. CONCLUSIONS: Robotic trachelectomy is equally reproducible and accurate as the vaginal trachelectomy in terms of the remaining cervical length and results in a significantly more precise placement of the cerclage. PMID- 22935473 TI - Mediators of cognitive-behavioral therapy for insomnia: a review of randomized controlled trials and secondary analysis studies. AB - The examination of treatment mechanisms in randomized controlled trials (RCTs) has considerable implications for research and clinical practice. Insomnia is a highly prevalent and distressing disorder, associated with many adverse outcomes. Although extensive work has focused on the cognitive-behavioral treatment of insomnia (CBT-I), few studies have directly examined the mechanisms of this intervention. CBT-I is a short-term, multi-component treatment that has demonstrated strong efficacy in treating insomnia. The purpose of the present study is: (a) to investigate if CBT-I works in accordance with its proposed mechanisms, and (b) to evaluate how the field is progressing in its understanding of these processes. This study comprehensively reviewed CBT-I RCTs for their inclusion of mediator variables. Secondary analysis studies were also surveyed for relevant mediator variables. Results demonstrated that 21 RCTs (39% of the total RCTs) and 11 secondary analysis studies examined at least one of the proposed mediators. Results of this review highlight that, although CBT-I appears to be targeting the hypothesized sleep processes, more research is needed to better understand whether CBT-I works in accordance with its theorized mechanisms. Inclusion of mediational analyses in future RCTs and secondary analysis studies would allow for further refinement of CBT-I and improved treatment outcomes. PMID- 22935474 TI - Vitamin D and lung disease. AB - The classic role of vitamin D in the regulation of calcium and phosphate metabolism, and its effects on bone health, are well established. More recently a critical role in immunity and respiratory health has been proposed. This arises from evidence for the capacity to generate the active metabolite, 1alpha,25 dihydroxyvitamin D3 (1,25(OH)D3), locally in many tissues beyond the kidney; expression of the vitamin D receptor (VDR) in immune and structural cells not involved in calcium-phosphate homeostasis; and control by 1,25(OH)D3 of the transcription of genes associated with numerous different biological processes through its nuclear VDR. Abnormalities in the vitamin D axis, including a high prevalence of vitamin D insufficiency worldwide, now appear important in a wide range of pulmonary diseases including viral and bacterial respiratory infection, asthma, chronic obstructive pulmonary disease, and cancer. Actions of vitamin D on innate immune responses, for example, production of antimicrobial peptides and autophagy, and on adaptive immune responses, for example, promoting regulatory lymphocytes, are believed to underpin these associations. PMID- 22935475 TI - New cell for asthma: enter the myeloid. PMID- 22935476 TI - Supporting teachers and children in schools: the effectiveness and cost effectiveness of the Incredible Years teacher classroom management programme in primary school children: a cluster randomised controlled trial, with parallel economic and process evaluations. AB - BACKGROUND: Childhood antisocial behaviour has high immediate and long-term costs for society and the individual, particularly in relation to mental health and behaviours that jeopardise health. Managing challenging behaviour is a commonly reported source of stress and burn out among teachers, ultimately resulting in a substantial number leaving the profession. Interventions to improve parenting do not transfer easily to classroom-based problems and the most vulnerable parents may not be easily able to access them. Honing teachers' skills in proactive behaviour management and the promotion of socio-emotional regulation, therefore, has the potential to improve both child and teacher mental health and well-being and the advantage that it might potentially benefit all the children subsequently taught by any teacher that accesses the training. METHODS/DESIGN: Cluster randomised controlled trial (RCT) of the Incredible Years teacher classroom management (TCM) course with combined economic and process evaluations.One teacher of children aged 4-9 years, from 80 schools in the South West Peninsula will be randomised to attend the TCM (intervention arm) or to "teach as normal" (control arm). The primary outcome measure will be the total difficulties score from the Strengths and Difficulties Questionnaire (SDQ) completed by the current class teachers prior to randomisation, and at 9, 18 and 30 months follow-up, supplemented by parent SDQs. Secondary measures include academic attainment (teacher report supplemented by direct measurement in a sub-sample), children's enjoyment of school, and teacher reports of their professional self-efficacy, and levels of burn out and stress, supplemented by structured observations of teachers classroom management skills in a subsample. Cost data for the economic evaluation will be based on parental reports of services accessed. Cost effectiveness, using the SDQ as the measure of effect, will be examined over the period of the RCT and over the longer term using decision analytic modelling. The process evaluation will use quantitative and qualitative approaches to assess fidelity to model, as well as explore Head teacher and teachers' experiences of TCM and investigate school factors that influence the translation of skills learnt to practice. DISCUSSION: This study will provide important information about whether the Teacher Classroom Management course influences child and teacher mental health and well-being in both the short and long term. It will also provide valuable insights into factors that may facilitate or impede any impact.The trial has been registered with ISCTRN (Controlled Trials Ltd) and assigned an ISRCTN number ISRCTN84130388. (http://www.controlled trials.com/isrctn/search.html?srch=ISRCTN84130388&sort=3&dir=desc&max=10). PMID- 22935477 TI - Effect of mycophenolic acid on trans-plasma membrane electron transport and electric potential in virus-infected plant tissue. AB - Mycophenolic acid (MPA) is an inosine monophosphate dehydrogenase inhibitor whose antiviral mechanism of action is supposed to interfere with NAD(+)/NADH conversion. Its effects on trans-plasma membrane electron transport (t-PMET) and on trans-plasma membrane electric potential (t-PMEP), which are involved in the NAD(+)/NADH conversion, were investigated using microelectrochemical techniques in tobacco plants infected by Cucumber mosaic virus. In these tests, ferricyanide (Fe(3+)) was used as electron acceptor in assays performed with intact cells; ferricyanide is converted to ferrocyanide (Fe(2+)) by one-electron reduction, and the rate of this reduction can be monitored in order to investigate the effects on t-PMET or t-PMEP. Considering tests on t-PMEP, MPA treatment of samples induced membrane depolarization and this effect was greater in healthy samples compared to infected ones. In any case, complete repolarization was achieved, indicating no irreversible damage to the membrane due to MPA administration. Moreover, in samples pre-treated with MPA, the extent of depolarization caused by Fe(3+) administration was lower than in samples without pre-treatment but the MPA effect was not related to virus infection. With regard to tests on t-PMET, MPA caused a reduction in Fe(3+)/Fe(2+) conversion compared to untreated plants. However, infected samples were less sensitive to MPA treatment, which may be due to the concurrent entry of MPA within the symplast that, as indicated by t-PMEP tests, was lower in infected samples. In conclusion, MPA interferes with membrane activity linked to NAD(+)/NADH conversion, acting differently in infected or healthy samples during drug uptake by cells. PMID- 22935479 TI - Leaving dualisms behind: felt thinking and the social. Commentary of John Cromby, 'beyond belief'. AB - From a metatheoretical critical perspective wary of theoretical dualisms, this commentary endorses Cromby's integrative proposal on the fusion of thought and affect. The proposal is discussed in relation to the current 'turn to affect' in the social sciences and to recent work in feminist theory. Specific arguments on the relation of cognition and discourse are appraised critically. PMID- 22935478 TI - Hydrogen peroxide is involved in the cold acclimation-induced chilling tolerance of tomato plants. AB - Cold acclimation increases plant tolerance to a more-severe chilling and in this process an accumulation of H(2)O(2) in plants is often observed. To examine the role of H(2)O(2) in cold acclimation in plants, the accumulation of H(2)O(2), antioxidant metabolism, the glutathione redox state, gas exchange and chlorophyll fluorescence were analyzed after cold acclimation at 12/10 degrees C and during the subsequent chilling at 7/4 degrees C in tomato (Solanum lycopersicum) plants. Cold acclimation modestly elevated the levels of H(2)O(2), the gene expression of respiratory burst oxidase homolog 1 (Rboh1) and NADPH oxidase activity, leading to the up-regulation of the expression and activity of antioxidant enzymes. In non-acclimated plants chilling caused a continuous rise in the H(2)O(2) content, an increase in the malondialdehyde (MDA) content and in the oxidized redox state of glutathione, followed by reductions in the CO(2) assimilation rate and the maximum quantum yield of photosystem II (F(v)/F(m)). However, in cold-acclimated plants chilling-induced photoinhibition, membrane peroxidation and reductions in the CO(2) assimilation rate were significantly alleviated. Furthermore, a treatment with an NADPH oxidase inhibitor or H(2)O(2) scavenger before the plants subjected to the cold acclimation abolished the cold acclimation-induced beneficial effects on photosynthesis and antioxidant metabolism, leading to a loss of the cold acclimation-induced tolerance against chilling. These results strongly suggest that the H(2)O(2) generated by NADPH oxidase in the apoplast of plant cells plays a crucial role in cold acclimation induced chilling tolerance. PMID- 22935480 TI - Understanding the biopsychosocial aspects of HIV disclosure among HIV-positive gay men in Scotland. AB - This study presents an interpretative phenomenological analysis of the experiential accounts of HIV-positive gay men. Participants took part in open ended interviews. Three key-related recurrent themes are presented: 'Disclosure, deliberation and the abject other'; 'Disclosure, care and the valued other' and 'Disclosure and intimate citizenship'. These highlight the complex, situated and mindful ways in which disclosure occurs. They stand in contrast to the understandings of HIV status disclosure as a 'health behaviour' deracinated from its social, relational and emotional dimensions. We explore the findings in relation to contemporary HIV prevention (with its increasing biomedical slant) and in relation to a biopsychosocial framework. PMID- 22935481 TI - Associations between kidney function and subclinical cardiac abnormalities in CKD. AB - Heart failure is a common consequence of CKD, and it portends high risk for mortality. However, among patients without known heart failure, the associations of different stages of estimated GFR (eGFR) with changes in cardiac structure and function are not well described. Here, we performed a cross-sectional analysis to study these associations among 3487 participants of the Chronic Renal Insufficiency Cohort Study. We estimated GFR using cystatin C. The prevalence of left ventricular hypertrophy (LVH) assessed by echocardiography was 32%, 48%, 57%, and 75% for eGFR categories >=60, 45-59, 30-44, and <30 ml/min per 1.73 m(2), respectively. In fully adjusted multivariable analyses, subjects with eGFR levels of <30 ml/min per 1.73 m(2) had twofold higher odds of LVH (OR=2.20, 95% CI=1.40-3.40; P<0.001) relative to subjects with eGFR>=60 ml/min per 1.73 m(2). This reduction in kidney function also significantly associated with abnormal LV geometry but not diastolic or systolic dysfunction. An eGFR of 30-44 ml/min per 1.73 m(2) also significantly associated with LVH and abnormal LV geometry compared with eGFR>=60 ml/min per 1.73 m(2). In summary, in this large CKD cohort, reduced kidney function associated with abnormal cardiac structure. We did not detect significant associations between kidney function and systolic or diastolic function after adjusting for potential confounding variables. PMID- 22935484 TI - Determination of the aggregation number and charge of ionic surfactant micelles from the stepwise thinning of foam films. AB - The stepwise thinning (stratification) of liquid films, which contain micelles of an ionic surfactant, depends on the micelle aggregation number, N(agg), and charge, Z. Vice versa, from the height of the step and the final film thickness one can determine N(agg), Z, and the degree of micelle ionization. The determination of N(agg) is based on the experimental fact that the step height is equal to the inverse cubic root of the micelle concentration. In addition, Z is determined from the final thickness of the film, which depends on the concentration of counterions dissociated from the micelles in the bulk. The method is applied to micellar solutions of six surfactants, both anionic and cationic: sodium dodecylsulfate (SDS), cetyl trimethylammonium bromide (CTAB), cetylpyridinium chloride (CPC), sodium laurylethersulfates with 1 and 3 ethylene oxide groups (SLES-1EO and SLES-3EO), and potassium myristate. The method has the following advantages: (i) N(agg) and Z are determined simultaneously, from the same set of experimental data; (ii) N(agg) and Z are determined for each given surfactant concentration (i.e. their concentration dependence is obtained), and (iii) N(agg) and Z can be determined even for turbid solutions, like those of carboxylates, where the micelles coexist with acid-soap crystallites, so that the application of other methods is difficult. The results indicate that the micelles of greater aggregation number have a lower degree of ionization, which can be explained with the effect of counterion binding. The proposed method is applicable to the concentration range, in which the films stratify and the micelles are spherical. This is satisfied for numerous systems representing scientific and practical interest. PMID- 22935483 TI - Mechanisms of anemia in CKD. AB - Anemia is a common feature of CKD associated with poor outcomes. The current management of patients with anemia in CKD is controversial, with recent clinical trials demonstrating increased morbidity and mortality related to erythropoiesis stimulating agents. Here, we examine recent insights into the molecular mechanisms underlying anemia of CKD. These insights hold promise for the development of new diagnostic tests and therapies that directly target the pathophysiologic processes underlying this form of anemia. PMID- 22935485 TI - Bone mass and vitamin D in patients with systemic sclerosis from two Spanish regions. AB - OBJECTIVES: To study the bone mass in patients with scleroderma (SSc) from two different Spanish regions and to evaluate the prevalence of vitamin D deficiency and insufficiency in this population and its possible relation to bone mineral density (BMD). METHODS: Disease, bone mineral density related variables and vitamin D were collected from all patients. Statistical analysis was carried out using the SPSS 17 statistics software for Windows. A p<0.05 was considered significant. RESULTS: A Z-score <-1 was found in 21.9% of the control population and 43% of SSc patients. The prevalence of osteopenia/osteoporosis was 50% in the control population and 77% in SSc (p<0.0001). We did not find differences between the prevalence of low BMD in the south (79%) and in the north of Spain (76.3%); but patients from the north had lower levels of vitamin D (27.4+/-16.2 ng/dL vs. 20.7+/-11.0 ng/dl; p<0.031). Low levels of vitamin D (<30ng/ml) were found in 69 patients out of 90, ten of them with insufficiency (<10ng/ml). Eighty-four point six percent of the patients with low levels of vitamin D (<30ng/ml) had LBMD compared whith 66.7% of those with normal levels (p=0.073). CONCLUSIONS: The prevalence of osteoporosis/osteopenia in Spanish patient with SSc is very high. Although there are a high prevelence of vitamin D deficiency, we could not demonstrate a relationship of vitamin D deficiency with low mineral density. PMID- 22935482 TI - Measurable urinary albumin predicts cardiovascular risk among normoalbuminuric patients with type 2 diabetes. AB - Micro- or macroalbuminuria is associated with increased cardiovascular risk factors among patients with type 2 diabetes, but whether albuminuria within the normal range predicts long-term cardiovascular risk is unknown. We evaluated the relationships between albuminuria and cardiovascular events in 1208 hypertensive, normoalbuminuric patients with type 2 diabetes from the BErgamo NEphrologic Diabetes Complication Trial (BENEDICT), all of whom received angiotensin converting enzyme inhibitor (ACEI) therapy at the end of the trial and were followed for a median of 9.2 years. The main outcome was time to the first of fatal or nonfatal myocardial infarction; stroke; coronary, carotid, or peripheral artery revascularization; or hospitalization for heart failure. Overall, 189 (15.6%) of the patients experienced a main outcome event (2.14 events/100 patient years); 24 events were fatal. Albuminuria independently predicted events (hazard ratio [HR], 1.05; 95% confidence interval [CI], 1.02-1.08). Second-degree polynomial multivariable analysis showed a continuous nonlinear relationship between albuminuria and events without thresholds. Considering the entire study population, even albuminuria at 1-2 MUg/min was significantly associated with increased risk compared with albuminuria <1 MUg/min (HR, 1.04; 95% CI, 1.02 1.07). This relationship was similar in the subgroup originally randomly assigned to non-ACEI therapy. Among those originally receiving ACEI therapy, however, the event rate was uniformly low and was not significantly associated with albuminuria. Taken together, among normoalbuminuric patients with type 2 diabetes, any degree of measurable albuminuria bears significant cardiovascular risk. The association with risk is continuous but is lost with early ACEI therapy. PMID- 22935487 TI - Real-time modelling used for outbreak management during a cholera epidemic, Haiti, 2010-2011. AB - The emergence of epidemic cholera in post-earthquake Haiti portended a public health disaster of uncertain magnitude. In order to coordinate relief efforts in an environment with limited healthcare infrastructure and stretched resources, timely and realistic projections of the extent of the cholera outbreak were crucial. Projections were shared with Government and partner organizations beginning 5 days after the first reported case and were updated using progressively more advanced methods as more surveillance data became available. The first projection estimated that 105 000 cholera cases would occur in the first year. Subsequent projections using different methods estimated up to 652 000 cases and 163 000-247 000 hospitalizations during the first year. Current surveillance data show these projections to have provided reasonable approximations of the observed epidemic. Providing the real-time projections allowed Haitian ministries and external aid organizations to better plan and implement response measures during the evolving epidemic. PMID- 22935486 TI - An open-label, sequential, dose-finding study of peginesatide for the maintenance treatment of anemia in chronic hemodialysis patients. AB - BACKGROUND: Peginesatide is a peptide-based erythropoiesis-stimulating agent that was designed and engineered to stimulate specifically the erythropoietin receptor dimer that governs erythropoiesis. The primary objective of this phase 2 dose finding study was to determine the once-monthly peginesatide dosing strategy that would maintain hemoglobin within +/-1.0 g/dL of baseline values after conversion from epoetin alfa; the safety of peginesatide was evaluated concurrently. METHODS: Chronic hemodialysis patients on stable regimens of epoetin alfa were sequentially assigned to cohorts that differed on (1) how the peginesatide starting dose was determined (using a single epoetin alfa-to-peginesatide dose conversion ratio or a tiered, weight-based or absolute-dose conversion table) and on (2) whether or not a 1-week erythropoiesis-stimulating agent-free interval was used. Peginesatide doses were titrated to maintain hemoglobin levels within +/ 1.0 g/dL from baseline. RESULTS: A total of 164 patients were enrolled and received intravenous peginesatide every 4 weeks for up to 6 doses; the duration of the study including follow-up was <=29 weeks. Overall, the proportion of patients with hemoglobin levels within +/-1.0 g/dL of baseline increased over the course of the study from 39% (Weeks 2-13) to 54% (Weeks 18-25). Cohorts that used tiered dose conversion tables trended towards having more stable peginesatide doses than did those cohorts that used a single dose conversion ratio. Moreover, cohorts that used an erythropoiesis-stimulating agent-free interval did not have the substantial initial increase in hemoglobin levels that was seen in those cohorts that did not use such an interval. In this study, the safety profile of peginesatide was consistent with those of marketed erythropoiesis-stimulating agents. CONCLUSIONS: The results of this study were used to guide the dosing regimens used subsequently in phase 3 studies. Once-monthly peginesatide is feasible in hemodialysis patients. TRIAL REGISTRATION: ClinicalTrials.gov registration: NCT00228449. PMID- 22935488 TI - A two-dimensional coordination polymer containing a two-dimensional zinc carboxylate layer constructed from helical chains: poly[(MU4-benzene-1,2 dicarboxylato)zinc(II)]. AB - The title compound, [Zn(C(8)H(4)O(4))](n), consists of one Zn(II) cation and one benzene-1,2-dicarboxylate dianion (BDC(2-)) as the building unit. The Zn(II) cation is four-coordinated by four carboxylate O atoms from four dianionic BDC(2 ) ligands in a distorted tetrahedral geometry. The Zn(II) cations are linked by the BDC(2-) ligands to generate a structure featuring two-dimensional zinc carboxylate layers containing left- and right-handed helical chains. The two dimensional layers are stacked along the a direction. The thermal stability of the title compound has been studied. PMID- 22935489 TI - rac-1-[(2-Methoxyethyl)sulfanyl]-2-[(2-methoxyethyl)sulfinyl]benzene and its PdCl2 complex. AB - As an extension of recent findings on the recovery of palladium with dithioether extractants, single crystals of the chelating vicinal thioether sulfoxide ligand rac-1-[(2-methoxyethyl)sulfanyl]-2-[(2-methoxyethyl)sulfinyl]benzene, C(12)H(18)O(3)S(2), (I), and its square-planar dichloridopalladium complex, rac dichlorido{1-[(2-methoxyethyl)sulfanyl]-2-[(2-methoxyethyl)sulfinyl]benzene kappa(2)S,S'}palladium(II), [PdCl(2)(C(12)H(18)O(3)S(2))], (II), have been synthesized and their structures analysed. The molecular structure of (II) is the first ever characterized involving a dihalogenide-Pd(II) complex in which the palladium is bonded to both a thioether and a sulfoxide functional group. The structural and stereochemical characteristics of the ligand are compared with those of the analogous dithioether compound [Traeger et al. (2012). Eur. J. Inorg. Chem. pp. 2341-2352]. The sulfinyl O atom suppresses the electron-pushing and mesomeric effect of the S-C-C-S unit in ligand (I), resulting in bond lengths significantly different than in the dithioether reference compound. In contrast, in complex (II), those bond lengths are nearly the same as in the analogous dithioether complex. As observed previously, there is an interaction between the central Pd(II) atom and the O atom that is situated above the plane. PMID- 22935490 TI - Binary salt of a palladium(II) complex with (phosphonomethyl)phosphonic (medronic) acid comprising 'handbell-like' [Pd{MU-CH2(PO3)2}]3 units. AB - The asymmetric unit of the title compound, dipotassium bis[hexaaquanickel(II)] tris(MU(2)-methylenediphosphonato)tripalladium(II) hexahydrate, K(2)[Ni(H(2)O)(6)](2)[Pd(3){CH(2)(PO(3))(2)}(3)].6H(2)O, consists of half a {[Pd{CH(2)(PO(3))(2)}](3)}(6-) anion [one Pd atom (4e) and a methylene C atom (4e) occupy positions on a twofold axis] in a rare 'handbell-like' arrangement, with K(+) and [Ni(H(2)O)(6)](2+) cations to form the neutral complex, completed by three solvent water molecules. The {[Pd{CH(2)(PO(3))(2)}](3)}(6-) units exhibit close Pd...Pd separations of 3.0469 (4) A and are packed via intermolecular C-H...Pd hydrogen bonds. The [KO(9)] and [NiO(6)] units are assembled into sheets coplanar with (011) and stacked along the [100] direction. Within these sheets there are [K(4)Ni(4)O(8)] and [K(2)Ni(2)O(4)] loops. Successive alternation of the sheets and [Pd{CH(2)(PO(3))(2)}](3) units parallel to [001] produces the three-dimensional packing, which is also supported by a dense network of hydrogen bonds involving the solvent water molecules. PMID- 22935491 TI - 1,1'-Methylenedipyridinium tetrachloridocuprate(II) and bis[tetrachloridoaurate(III)] hybrid salts by X-ray powder diffraction. AB - In order to explore the potential propensity of the 1,1'-methylenedipyridinium dication to form organic-inorganic hybrid ionic compounds by reaction with the appropriate halide metal salt, the organic-inorganic hybrid salts 1,1' methylenedipyridinium tetrachloridocuprate(II), (C(11)H(12)N(2))[CuCl(4)], (I), and 1,1'-methylenedipyridinium bis[tetrachloridoaurate(III)], (C(11)H(12)N(2))[AuCl(4)](2), (II), were obtained by treatment of 1,1' methylenedipyridinium dichloride with CuCl(2) and Na[AuCl(4)], respectively. Both hybrid salts were isolated as pure compounds, fully characterized by multinuclear NMR spectroscopy and their molecular structures confirmed by powder X-ray diffraction studies. The crystal structures consist of discrete 1,1' methylenedipyridinium dications and [CuCl(4)](2-) and [AuCl(4)](-) anions for (I) and (II), respectively. As expected, the dications form a butterfly shape; the Cu(II) centre of [CuCl(4)](2-) has a distorted tetrahedral configuration and the Au(III) centre of [AuCl(4)](-) shows a square-planar coordination. The ionic species of (I) and the dication of (II) each have twofold axial symmetry, while the two [AuCl(4)](-) anions are located on a mirror-plane site. Both crystal structures are stabilized by intermolecular C-H...Cl hydrogen bonds and also by Cl...pi interactions. It is noteworthy that, while the average intermolecular centroid-centroid pyridinium ring distance in (I) is 3.643 (8) A, giving strong evidence for noncovalent pi-pi ring interactions, for (II), the shortest centroid centroid distance between pyridinium rings of 5.502 (9) A is too long for any significant pi-pi ring interactions, which might be due to the bulk of the two [AuCl(4)](-) anions. PMID- 22935492 TI - The weakly coordinating perchlorate group in bis(N,N'-dimethylethylenediamine kappa2N,N')bis(perchlorato-kappaO)copper(II) studied at 100, 250 and 400 K. AB - The crystal structure of the title compound, [Cu(ClO(4))(2)(C(4)H(12)N(2))(2)], (I), is reported at 100, 250 and 400 K. The Cu(II) cation in this complex is coordinated in a distorted octahedral mode characteristic of Jahn-Teller systems. The coordination of the perchlorate ligands via longer, and presumably weaker, axial Cu-O distances varies significantly as a function of temperature. One of the Cu-O distances increases between 100 and 250 K, and one of the Cu-O-Cl angles expands between 250 and 400 K. At all temperatures, the complex forms a two dimensional N-H...O hydrogen-bond network in the (001) plane. PMID- 22935493 TI - MU-4,4'-Bipyridine-kappa2N:N'-bis[tetraaqua(4,4'-bipyridine kappaN)dimanganese(II)] bis(4-aminobenzoate) bis(perchlorate)-4,4'-bipyridine water (1/2/4): a supramolecular system constructed by pi-pi and hydrogen-bond interactions. AB - The title dinuclear manganese compound, [Mn(2)(C(10)H(8)N(2))(3)(H(2)O)(8)](C(7)H(6)NO(2))(2)(ClO(4))(2).2C(10)H(8)N(2).4 (2)O, (I), has an inversion center located midway between the Mn(II) ions. Each Mn(II) ion has a distorted octahedral coordination environment, defined by two mutually cis N atoms from two different 4,4'-bipyridine (4,4'-bipy) ligands and four O atoms from four water molecules. The asymmetric unit contains cationic [Mn(4,4'-bipy)(1.5)(H(2)O)(4)](2+), one isolated 4,4'-bipy molecule, one 4 aminobenzoate ion, one disordered perchlorate ion and two uncoordinated water molecules. In the dinuclear manganese cationic unit, one 4,4'-bipy acts as a bidentate bridging ligand between two Mn(II) ions, while the other two act only as monodentate terminal ligands, giving rise to a 'Z-type' [Mn(2)(4,4' bipy)(3)(H(2)O)(8)] host unit. These host units are linked to each other via face to-face pi-pi stacking interactions between monodentate terminal 4,4'-bipy ligands, generating a zigzag chain. The corners of these chains, defined by Mn(OH)(4) units, are surrounded by the solvent water molecules and the carboxylate O atoms of the 4-aminobenzoate ions, and all of these are connected to each other via strong O-H...O hydrogen-bond interactions, leading to a three dimensional grid network with a large cavity running along the b axis of the unit cell. The isolated 4,4'-bipy molecules, the 4-aminobenzoate and perchlorate anions and the water molecules are encapsulated in the cavities by numerous hydrogen-bond interactions. PMID- 22935494 TI - Tris(1,10-phenanthroline-kappa2N,N')iron(II) bis(2,4,5-tricarboxybenzoate) monohydrate and tris(2,2'-bipyridine-kappa2N,N')iron(II) 2,5-dicarboxybenzene-1,4 dicarboxylate-benzene-1,2,4,5-tetracarboxylic acid-water (1/1/2). AB - The title compounds, tris(1,10-phenanthroline-kappa(2)N,N')iron(II) bis(2,4,5 tricarboxybenzoate) monohydrate, [Fe(C(12)H(8)N(2))(3)](C(10)H(5)O(8))(2).H(2)O, (I), and tris(2,2'-bipyridine-kappa(2)N,N')iron(II) 2,5-dicarboxybenzene-1,4 dicarboxylate-benzene-1,2,4,5-tetracarboxylic acid-water (1/1/2), [Fe(C(10)H(8)N(2))(3)](C(10)H(4)O(8)).C(10)H(6)O(8).2H(2)O, (II), were obtained during an attempt to synthesize a mixed-ligand complex of Fe(II) with an N containing ligand and benzene-1,2,4,5-tetracarboxylic acid via a solvothermal reaction. In both mononuclear complexes, each Fe(II) metal ion is six-coordinated in a distorted octahedral manner by six N atoms from three chelating 1,10 phenanthroline or 2,2'-bipyridine ligands. In compound (I), the Fe(II) atom lies on a twofold axis in the space group C2/c, whereas (II) crystallizes in the space group P2(1)/n. In both compounds, the uncoordinated carboxylate anions and water molecules are linked by typical O-H...O hydrogen bonds, generating extensive three-dimensional hydrogen-bond networks which surround the cations. PMID- 22935495 TI - A novel one-dimensional Co(II) coordination polymer: catena poly[[hexaaquacobalt(II)] [[diaquabis(sulfato-kappaO)cobalt(II)]-MU-4,4' bipyridine-kappa2N:N'] [[triaqua(sulfato-kappaO)cobalt(II)]-MU-4,4'-bipyridine kappa2N:N']]. AB - The title compound, {[Co(H(2)O)(6)][Co(SO(4))(C(10)H(8)N(2))(H(2)O)(3)][Co(SO(4))(2)(C(10)H(8)N(2))(H 2)O)(2)]}(n), contains three crystallographically unique Co(II) centres, all of which are in six-coordinated environments. One Co(II) centre is coordinated by two bridging 4,4'-bipyridine (4,4'-bipy) ligands, one sulfate ion and three aqua ligands. The second Co(II) centre is surrounded by two N atoms of two 4,4'-bipy ligands and four O atoms, i.e. two O atoms from two monodentate sulfate ions and two from water molecules. The third Co(II) centre forms part of a hexaaquacobalt(II) ion. In the crystal structure, there are two different one dimensional chains, one being anionic and the other neutral, and adjacent chains are arranged in a cross-like fashion around the mid-point of the 4,4'-bipy ligands. The structure features O-H...O hydrogen-bonding interactions between sulfate anions and water molecules, resulting in a three-dimensional supramolecular network. PMID- 22935496 TI - Hydrogen bonding in cyclic imides and amide carboxylic acid derivatives from the facile reaction of cis-cyclohexane-1,2-carboxylic anhydride with o- and p anisidine and m- and p-aminobenzoic acids. AB - The structures of the open-chain amide carboxylic acid rac-cis-2-[(2 methoxyphenyl)carbamoyl]cyclohexane-1-carboxylic acid, C(15)H(19)NO(4), (I), and the cyclic imides rac-cis-2-(4-methoxyphenyl)-3a,4,5,6,7,7a-hexahydroisoindole 1,3-dione, C(15)H(17)NO(3), (II), chiral cis-3-(1,3-dioxo-3a,4,5,6,7,7a hexahydroisoindol-2-yl)benzoic acid, C(15)H(15)NO(4), (III), and rac-cis-4-(1,3 dioxo-3a,4,5,6,7,7a-hexahydroisoindol-2-yl)benzoic acid monohydrate, C(15)H(15)NO(4).H(2)O, (IV), are reported. In the amide acid (I), the phenylcarbamoyl group is essentially planar [maximum deviation from the least squares plane = 0.060 (1) A for the amide O atom] and the molecules form discrete centrosymmetric dimers through intermolecular cyclic carboxy-carboxy O-H...O hydrogen-bonding interactions [graph-set notation R(2)(2)(8)]. The cyclic imides (II)-(IV) are conformationally similar, with comparable benzene ring rotations about the imide N-C(ar) bond [dihedral angles between the benzene and isoindole rings = 51.55 (7) degrees in (II), 59.22 (12) degrees in (III) and 51.99 (14) degrees in (IV)]. Unlike (II), in which only weak intermolecular C-H...O(imide) hydrogen bonding is present, the crystal packing of imides (III) and (IV) shows strong intermolecular carboxylic acid O-H...O hydrogen-bonding associations. With (III), these involve imide O-atom acceptors, giving one-dimensional zigzag chains [graph-set C(9)], while with the monohydrate (IV), the hydrogen bond involves the partially disordered water molecule which also bridges molecules through both imide and carboxy O-atom acceptors in a cyclic R(4)(4)(12) association, giving a two-dimensional sheet structure. The structures reported here expand the structural database for compounds of this series formed from the facile reaction of cis-cyclohexane-1,2-dicarboxylic anhydride with substituted anilines, in which there is a much larger incidence of cyclic imides compared to amide carboxylic acids. PMID- 22935497 TI - An optically resolved crystal of thiomalate: (S)-1-phenylethanaminium (R) thiomalate. AB - The asymmetric unit of the optically resolved title salt, C(8)H(12)N(+).C(4)H(5)O(4)S(-), contains a 1-phenylethanaminium monocation and a thiomalate (3-carboxy-2-sulfanylpropanoate) monoanion. The absolute configurations of the cation and the anion are determined to be S and R, respectively. In the crystal, cation-anion N-H...O hydrogen bonds, together with anion-anion O-H...O and S-H...O hydrogen bonds, construct a two-dimensional supramolecular sheet parallel to the ab plane. The two-dimensional sheet is linked with the upper and lower sheets through C-H...pi interactions to stack along the c axis. PMID- 22935498 TI - Rietveld refinement of the cocrystal 2,4-dihydroxybenzoic acid-N'-(propan-2 ylidene)nicotinohydrazide (1/1). AB - A further example of using a covalent-bond-forming reaction to alter supramolecular assembly by modification of hydrogen-bonding possibilities is presented. This concept was introduced by Lemmerer, Bernstein & Kahlenberg [CrystEngComm (2011), 13, 55-59]. The title structure, C(9)H(11)N(3)O.C(7)H(6)O(4), which consists of a reacted niazid molecule, viz. N' (propan-2-ylidene)nicotinohydrazide, and 2,4-dihydroxybenzoic acid, was solved from powder diffraction data using simulated annealing. The results further demonstrate the relevance and utility of powder diffraction as an analytical tool in the study of cocrystals and their hydrogen-bond interactions. PMID- 22935499 TI - 3,4,6-Tri-O-acetyl-1,2-O-[1-(exo-ethoxy)ethylidene]-beta-D-mannopyranose 0.11 hydrate. AB - The title compound, C(16)H(24)O(10).0.11H(2)O, is a key intermediate in the synthesis of 2-deoxy-2-[(18)F]fluoro-D-glucose ((18)F-FDG), which is the most widely used molecular-imaging probe for positron emission tomography (PET). The crystal structure has two independent molecules (A and B) in the asymmetric unit, with closely comparable geometries. The pyranose ring adopts a (4)C(1) conformation [Cremer-Pople puckering parameters: Q = 0.553 (2) A, theta = 16.2 (2) degrees and phi = 290.4 (8) degrees for molecule A, and Q = 0.529 (2) A, theta =15.3 (3) degrees and phi = 268.2 (9) degrees for molecule B], and the dioxolane ring adopts an envelope conformation. The chiral centre in the dioxolane ring, introduced during the synthesis of the compound, has an R configuration, with the ethoxy group exo to the mannopyranose ring. The asymmetric unit also contains one water molecule with a refined site-occupancy factor of 0.222 (8), which bridges between molecules A and B via O-H...O hydrogen bonds. PMID- 22935500 TI - Novel pseudopolymorph of the active metabolite of perindopril. AB - The dimethyl sulfoxide hemisolvate of perindoprilat [systematic name: (1S)-2-((S) {1-[(2S,3aS,7aS)-2-carboxyoctahydro-1H-indol-1-yl]-1-oxopropan-2 yl}azaniumyl)pentanoate dimethyl sulfoxide hemisolvate], C(17)H(28)N(2)O(5).0.5C(2)H(6)OS, an active metabolite of perindopril, has been synthesized, structurally characterized by single-crystal X-ray diffraction and compared with its ethanol disolvate analogue [Pascard et al. (1991). J. Med. Chem. 34, 663-669]. Both compounds crystallize in the orthorhombic P2(1)2(1)2(1) space group in the same zwitterionic form, with a protonated alanine N atom and an anionic carboxylate group at the n-alkyl chain. The three structural units present in the unit cell (two zwitterions and the solvent molecule) are held together by a rich system of O-H...O, N-H...O and C-H...O hydrogen-bond contacts. PMID- 22935501 TI - Pseudopolymorphs of chelidamic acid and its dimethyl ester. AB - Different tautomeric and zwitterionic forms of chelidamic acid (4-hydroxypyridine 2,6-dicarboxylic acid) are present in the crystal structures of chelidamic acid methanol monosolvate, C(7)H(5)NO(5).CH(4)O, (Ia), dimethylammonium chelidamate (dimethylammonium 6-carboxy-4-hydroxypyridine-2-carboxylate), C(2)H(8)N(+).C(7)H(4)NO(5)(-), (Ib), and chelidamic acid dimethyl sulfoxide monosolvate, C(7)H(5)NO(5).C(2)H(6)OS, (Ic). While the zwitterionic pyridinium carboxylate in (Ia) can be explained from the pK(a) values, a (partially) deprotonated hydroxy group in the presence of a neutral carboxy group, as observed in (Ib) and (Ic), is unexpected. In (Ib), there are two formula units in the asymmetric unit with the chelidamic acid entities connected by a symmetric O H...O hydrogen bond. Also, crystals of chelidamic acid dimethyl ester (dimethyl 4 hydroxypyridine-2,6-dicarboxylate) were obtained as a monohydrate, C(9)H(9)NO(5).H(2)O, (IIa), and as a solvent-free modification, in which both ester molecules adopt the hydroxypyridine form. In (IIa), the solvent water molecule stabilizes the synperiplanar conformation of both carbonyl O atoms with respect to the pyridine N atom by two O-H...O hydrogen bonds, whereas an antiperiplanar arrangement is observed in the water-free structure. A database study and ab initio energy calculations help to compare the stabilities of the various ester conformations. PMID- 22935502 TI - The supramolecular architecture of tris(naphthalene-1,5-diaminium) bis(5 aminonaphthalen-1-aminium) octakis[hydrogen (5-carboxypyridin-3-yl)phosphonate]. AB - The asymmetric unit of the title compound, 3C(10)H(12)N(2)(2+).2C(10)H(11)N(2)(+).8C(6)H(5)NO(5)P(-), contains one and a half naphthalene-1,5-diaminium cations, in which the half-molecule has inversion symmetry, one 5-aminonaphthalen-1-aminium cation and four hydrogen (5 carboxypyridin-3-yl)phosphonate anions. The crystal structure is layered and consists of hydrogen-bonded anionic monolayers between which the cations are arranged. The acid monoanions are organized into one-dimensional chains along the [101] direction via hydrogen bonds established between the phosphonate sites. (C)O-H...N(py) hydrogen bonds (py is pyridine) crosslink the chains to form an undulating (010) monolayer. The cations serve both to balance the charge of the anionic network and to connect neighbouring layers via multiple hydrogen bonds to form a three-dimensional supramolecular architecture. PMID- 22935503 TI - Melaminium (2-carboxyethyl)(phenyl)phosphinate monohydrate. AB - Cocrystallization of melamine (1,3,5-triazine-2,4,6-triamine, ma) with (2 carboxyethyl)(phenyl)phosphinic acid (H(2)L) from water affords the title compound, C(3)H(7)N(6)(+).C(9)H(10)O(4)P(-).H(2)O or (maH)(HL).H(2)O, (I). The phosphinic acid H atom of each H(2)L molecule is transferred to a melamine molecule. Structural analysis reveals that there are two types of secondary building units in the crystal structure, namely cationic [(maH(+))(2)](infinity) ribbons and anionic {[(HL)(2)(H(2)O)(2)](2-)}(infinity) layers, the combination of which through hydrogen-bond and electrostatic interactions, generates a large scale two-dimensional layered structure. The thick layer is sandwich-like, with the central [(maH(+))(2)](infinity) ribbons being further stabilized by pi-pi stacking interactions. It is also worthy of note that two conformational isomeric R(6)(5)(24) hydrogen-bond ring motifs can be identified in the {[(HL)(2)(H(2)O)(2)](2-)}(infinity) layer. PMID- 22935504 TI - A three-component cocrystal: benzoyl(hydroxyimino)acetonitrile-18-crown-6-water (2/1/4). AB - In the title compound, 2C(9)H(6)N(2)O(2).C(12)H(24)O(6).4H(2)O, the 18-crown-6 (1,4,7,10,13,16-hexaoxacyclooctadecane) molecule resides across a centre of inversion. The adduct exists as a molecular hydrogen-bonded complex featuring integration of two kinds of synthons, viz. [(18-crown-6)(H(2)O)(4)] [O...O = 2.8645 (18)-2.9014 (18) A] and an oxime/aqua ensemble, PhC(O)C(CN)NOH...OH(2) [O...O = 2.5930 (18) A]. The reliability of the oxime/aqua motif, sustained by the highly acidic cyanooxime, is an essential factor in the construction of multicomponent cocrystals and the accommodation of oxime species in macrocyclic hosts. The supramolecular structure is generated by the alternation of hydrophilic [(18-crown-6)(H(2)O)(4)] layers and bilayers of benzoyl(hydroxyimino)acetonitrile molecules, resulting in stacking interactions between the phenyl and cyano groups of 3.666 (2) A. PMID- 22935505 TI - 1,3-Ninhydrin dihydrazone featuring an R4(4)(12) motif with 4 symmetry and comprising only N and H atoms. AB - In the title compound [systematic name: (1Z,3Z)-1,3-dihydrazinylidene-1H-inden 2(3H)-one], C(9)H(8)N(4)O, isolated molecules possess approximate noncrystallographic C(2v) symmetry and their cis conformation and planarity are assisted by a pair of short intramolecular N-H...O hydrogen bonds. Each molecule is asymmetrically involved in an extensive three-dimensional network of N-H...O and N-H...N hydrogen bonds, and the structure also exhibits weaker pi-pi and C=O...C interactions. The structure features an R(4)(4)(12) motif consisting solely of N and H atoms and possessing crystallographic 4 symmetry. PMID- 22935506 TI - 2-Ethyl-6-methylpyridin-3-ol and its salt bis(2-ethyl-3-hydroxy-6 methylpyridinium) succinate. AB - The title compounds, C(8)H(11)NO, (I), and 2C(8)H(12)NO(+).C(4)H(4)O(4)(2-), (II), both crystallize in the monoclinic space group P2(1)/c. In the crystal structure of (I), intermolecular O-H...N hydrogen bonds combine the molecules into polymeric chains extending along the c axis. The chains are linked by C H...pi interactions between the methylene H atoms and the pyridine rings into polymeric layers parallel to the ac plane. In the crystal structure of (II), the succinate anion lies on an inversion centre. Its carboxylate groups interact with the 2-ethyl-3-hydroxy-6-methylpyridinium cations via intermolecular N-H...O hydrogen bonds with the pyridine ring H atoms and O-H...O hydrogen bonds with the hydroxy H atoms to form polymeric chains, which extend along the [101] direction and comprise R(4)(4)(18) hydrogen-bonded ring motifs. These chains are linked to form a three-dimensional network through nonclassical C-H...O hydrogen bonds between the pyridine ring H atoms and the hydroxy-group O atoms of neighbouring cations. pi-pi interactions between the pyridine rings and C-H...pi interactions between the methylene H atoms of the succinate anion and the pyridine rings are also present in this network. PMID- 22935507 TI - Reinterpretation of the monohydrate of clarithromycin from X-ray powder diffraction data as a trihydrate. AB - Noguchi, Fujiki, Iwao, Miura & Itai [Acta Cryst. (2012), E68, o667-o668] recently reported the crystal structure of clarithromycin monohydrate from synchrotron X ray powder diffraction data. Voids in the crystal structure suggested the possible presence of two more water molecules. After successful location of the two additional water molecules, the Rietveld refinement still showed minor problems. These were resolved by noticing that one of the chiral centres in the molecule had been inverted. The corrected crystal structure of clarithromycin trihydrate, refined against the original data, is now reported. Dispersion corrected density functional theory calculations were used to check the final crystal structure and to position the H atoms. PMID- 22935508 TI - Frequent oral ulceration during early disease may predict a severe disease course in males with Behcet's syndrome. AB - OBJECTIVES: The numbers and recurrence rates of mucocutaneous manifestations can be highly variable among patients with Behcet's syndrome (BS) but it is not known whether these differences influence the disease course at the long-term. METHODS: We evaluated the outcome of 30 patients that made up the placebo arm of a 6 months controlled trial of thalidomide and looked at the relation between the frequencies of mucocutaneous manifestations during the trial and the development of major organ involvement necessitating immunosuppressives during the post-trial period. RESULTS: Fifteen (50%) patients had received immunosuppresives for major organ involvement during the post-trial period. Patients receiving immunosuppressive treatment were significantly younger at the onset of BS compared to those who did not (24.5+/-5 vs. 29.7+/-3.8 SD years; p=0.003). The mean number of oral ulcers recorded throughout the trial was significantly higher among patients using immunosuppressives compared to those who did not (2.09+/ 0.96 vs. 1.43+/-0.8; p=0.029). This significance disappeared when adjusted for age of onset of BS (p=0.16). ROC curve analysis showed that having 10 or more ulcers during 6 months has a sensitivity of 86.7% and a specificity of 53% for the subsequent necessity of immunosuppressive use. The same association was not true for genital ulcers, follicular lesions and erythema nodosum. CONCLUSIONS: These findings on a limited number of patients suggest that frequent occurrence of oral ulceration during the initial years of the disease may predict the development of major organ involvement in men with BS. PMID- 22935510 TI - Butyrylcholinesterase radioligands to image Alzheimer's disease brain. AB - Butyrylcholinesterase (BuChE) is found to have a brain distribution pattern that is distinct from that of acetylcholinesterase (AChE). Neurons containing BuChE are particularly located in the amygdala, hippocampal formation and the thalamus, structures involved in the normal functions of cognition and behavior that typically become compromised in Alzheimer's disease (AD). Progress of this disease is thought to result, at least in part, from the accumulation of beta amyloid (Abeta) plaques and neurofibrillary tangles (NFTs) in the brain. These structures characteristically become associated with cholinesterase activity, and are major determinants of AD diagnosis post-mortem. Early definitive AD diagnosis in the living brain could greatly facilitate specific timely treatment of the disorder and the search for novel drugs to preempt progress of this disease. Radioligands have been developed to detect deposition of Abeta plaques in the brain; however, since many cognitively normal individuals also exhibit Abeta plaque deposition, this approach has inherent disadvantages for definitive AD diagnosis during life. The association of BuChE with Abeta plaques appears to be a characteristic of AD. This has prompted the search for radioligands that target BuChE in association with Abeta plaques that accumulate in cortical grey matter, a region normally with very little of this enzyme activity. A number of BuChE radioligands have been synthesized and preliminary testing indicates that some such radioligands enter the brain and accumulate in regions known to contain BuChE. Radioligands targeting unusual BuChE activity in the brain may represent a means for early diagnosis and treatment monitoring of AD. PMID- 22935509 TI - Undersampled cine 3D tagging for rapid assessment of cardiac motion. AB - BACKGROUND: CMR allows investigating cardiac contraction, rotation and torsion non-invasively by the use of tagging sequences. Three-dimensional tagging has been proposed to cover the whole-heart but data acquisition requires three consecutive breath holds and hence demands considerable patient cooperation. In this study we have implemented and studied k-t undersampled cine 3D tagging in conjunction with k-t PCA reconstruction to potentially permit for single breath hold acquisitions. METHODS: The performance of undersampled cine 3D tagging was investigated using computer simulations and in-vivo measurements in 8 healthy subjects and 5 patients with myocardial infarction. Fully sampled data was obtained and compared to retrospectively and prospectively undersampled acquisitions. Fully sampled data was acquired in three consecutive breath holds. Prospectively undersampled data was obtained within a single breath hold. Based on harmonic phase (HARP) analysis, circumferential shortening, rotation and torsion were compared between fully sampled and undersampled data using Bland Altman and linear regression analysis. RESULTS: In computer simulations, the error for circumferential shortening was 2.8 +/- 2.3% and 2.7 +/- 2.1% for undersampling rates of R = 3 and 4 respectively. Errors in ventricular rotation were 2.5 +/- 1.9% and 3.0 +/- 2.2% for R = 3 and 4. Comparison of results from fully sampled in-vivo data acquired with prospectively undersampled acquisitions showed a mean difference in circumferential shortening of -0.14 +/- 5.18% and 0.71 +/- 6.16% for R = 3 and 4. The mean differences in rotation were 0.44 +/- 1.8 degrees and 0.73 +/- 1.67 degrees for R = 3 and 4, respectively. In patients peak, circumferential shortening was significantly reduced (p < 0.002 for all patients) in regions with late gadolinium enhancement. CONCLUSION: Undersampled cine 3D tagging enables significant reduction in scan time of whole heart tagging and facilitates quantification of shortening, rotation and torsion of the left ventricle without adding significant errors compared to previous 3D tagging approaches. PMID- 22935512 TI - Post-translational regulation of FOXO. AB - The Forkhead box O (FOXO) family transcription factors play critical roles in a series of cellular processes, including the cell cycle, cell death, metabolism, and oxidative stress resistance. FOXO proteins are subject to several post translational modifications, which are closely related to their activity. In this paper, we review the post-translational modifications of FOXOs and their biological functions. PMID- 22935511 TI - Effects of anti-cocaine vaccine and viral gene transfer of cocaine hydrolase in mice on cocaine toxicity including motor strength and liver damage. AB - In developing an vivo drug-interception therapy to treat cocaine abuse and hinder relapse into drug seeking provoked by re-encounter with cocaine, two promising agents are: (1) a cocaine hydrolase enzyme (CocH) derived from human butyrylcholinesterase and delivered by gene transfer; (2) an anti-cocaine antibody elicited by vaccination. Recent behavioral experiments showed that antibody and enzyme work in a complementary fashion to reduce cocaine-stimulated locomotor activity in rats and mice. Our present goal was to test protection against liver damage and muscle weakness in mice challenged with massive doses of cocaine at or near the LD50 level (100-120 mg/kg, i.p.). We found that, when the interceptor proteins were combined at doses that were only modestly protective in isolation (enzyme, 1mg/kg; antibody, 8 mg/kg), they provided complete protection of liver tissue and motor function. When the enzyme levels were ~400-fold higher, after in vivo transduction by adeno-associated viral vector, similar protection was observed from CocH alone. PMID- 22935513 TI - De novo achondroplasia causing four consecutive unsuccessful pregnancies: a case report. AB - INTRODUCTION: The incidence of achondroplasia is very low, and the birth of two or more consecutive babies with achondroplasia to unaffected parents is a rarity. We report a rare case of recurrent achondroplasia in babies of unaffected parents. CASE PRESENTATION: A 29-year-old Nigerian Igbo woman who has had three consecutive dead achondroplastic babies presented at a gestational age of 31 weeks with a two-hour history of drainage of liquor and vaginal bleeding. Neither she nor her husband had features of achondroplasia. Fundal height was compatible with the gestational age. Fetal heart activity was present. An abdominal ultrasound examination showed a viable fetus with short long bones, oligohydramnios, and a fundal placenta with a small retroplacental blood clot. Our patient was stabilized and had an emergency Cesarean section for grade 1 abruptio placentae. A live male baby with Apgar scores of 4 at one minute and 5 at 10 minutes was delivered. The baby had classic features of achondroplasia and died shortly after birth. CONCLUSIONS: To the best of our knowledge, this is the first reported case of recurrent achondroplasia in siblings of unaffected parents in Nigeria. Management is challenging, and the outcomes of future pregnancies appear bleak. However, proper counseling and follow-up are needed. There is also a need to establish preconception clinics and facilities for prenatal genetic diagnosis and gene therapy in developing countries. PMID- 22935514 TI - Invited commentary: the 21st century epidemiologist--a need for different training? AB - The accompanying paper by Ogino et al. (Am J Epidemiol. 2012;176(8):659-667) cogently suggests a need for including modern approaches like molecular pathological epidemiology (MPE) in our research. However, Ogino et al. make an assumption that epidemiology has previously not included pathology or modern technologies in epidemiologic studies and that there is a unique need for the specialty of MPE. The new molecular pathology is yet another technique that can improve epidemiologic investigations. There is a long tradition of combining good pathology with epidemiologic research, especially in studies of cardiovascular disease. Large epidemiologic studies have successfully integrated specialty expertise in a collaborative and mutually beneficial approach to test specific hypotheses. The author is concerned that MPE techniques, whether they involve metabolomics, genomics, proteomics, or microarrays, will come to drive epidemiologic studies without any specific hypothesis-testing or unique population characteristics. The epidemiologist would then become little more than a collector of study subjects and a distributor of the various specimens to the laboratories. PMID- 22935515 TI - Patterns of 12-year change in physical activity levels in community-dwelling older women: can modest levels of physical activity help older women live longer? AB - Few studies have addressed changes in physical activity participation over time among the elderly. The authors hypothesized that there were distinct trajectories of physical activity level over time and identifiable predictors of such trajectories, as well as that the maintenance of regular physical activity, even below recommended levels, was associated with lower mortality risk. Using longitudinal data (1994-2009) from 433 initially high-functioning older women aged 70-79 years at baseline, a joint latent class and survival mixture model identified 4 activity trajectory classes: always active (16.6%), fast declining (19.2%), stable moderate (32.3%), and always sedentary (31.9%). Obesity, coronary artery disease, chronic obstructive pulmonary disease, depressive symptoms, low self-efficacy, mobility disability, and low energy were associated with sedentary behavior and/or a fast decline in activity. Women in the fast declining and always sedentary classes had hazard ratios for death of 2.34 (95% confidence interval: 1.20, 4.59) and 3.34 (95% confidence interval: 1.72, 6.47), respectively, compared with the always active class; no mortality difference was found between the stable moderate and always active groups (hazard ratio = 1.24, 95% confidence interval: 0.63, 2.47). Our findings suggest that physical activity does not have to be vigorous to be beneficial and that the gain may be the greatest among women who reported the lowest levels of activity. PMID- 22935516 TI - Ogino et Al. Respond to "the 21st century epidemiologist". PMID- 22935518 TI - Inhibin beta E is upregulated by drug-induced endoplasmic reticulum stress as a transcriptional target gene of ATF4. AB - Inhibins and activins are gonadal peptide hormones of the transforming growth factor-beta super family with important functions in the reproductive system. By contrast, the recently identified inhibin betaE subunit, primarily expressed in liver cells, appears to exert functions unrelated to the reproductive system. Previously shown downregulation of inhibin betaE in hepatoma cells and anti proliferative effects of ectopic inhibin betaE overexpression indicated growth regulatory effects of inhibin betaE. We observed a selective re-expression of the inhibin betaE subunit in HepG2 hepatoblastoma cells, MCF7 breast cancer cells, and HeLa cervical cancer cells under endoplasmic reticulum stress conditions induced by tunicamycin, thapsigargin, and nelfinavir. Analysis of XPB1 splicing and ATF4 activation revealed that inhibin betaE re-expression was associated with induction of the endoplasmic reticulum stress reaction by these drugs. Transfection of an ATF4 expression plasmid specifically induced inhibin betaE expression in HeLa cells and indicates inhibin betaE as a hitherto unidentified target gene of ATF4, a key transcription factor of the endoplasmic reticulum stress response. Therefore, the inhibin betaE subunit defines not only a new player but also a possible new marker for drug-induced endoplasmic reticulum stress. PMID- 22935517 TI - Interdisciplinary education to integrate pathology and epidemiology: towards molecular and population-level health science. AB - In recent decades, epidemiology, public health, and medical sciences have been increasingly compartmentalized into narrower disciplines. The authors recognize the value of integration of divergent scientific fields in order to create new methods, concepts, paradigms, and knowledge. Herein they describe the recent emergence of molecular pathological epidemiology (MPE), which represents an integration of population and molecular biologic science to gain insights into the etiologies, pathogenesis, evolution, and outcomes of complex multifactorial diseases. Most human diseases, including common cancers (such as breast, lung, prostate, and colorectal cancers, leukemia, and lymphoma) and other chronic diseases (such as diabetes mellitus, cardiovascular diseases, hypertension, autoimmune diseases, psychiatric diseases, and some infectious diseases), are caused by alterations in the genome, epigenome, transcriptome, proteome, metabolome, microbiome, and interactome of all of the above components. In this era of personalized medicine and personalized prevention, we need integrated science (such as MPE) which can decipher diseases at the molecular, genetic, cellular, and population levels simultaneously. The authors believe that convergence and integration of multiple disciplines should be commonplace in research and education. We need to be open-minded and flexible in designing integrated education curricula and training programs for future students, clinicians, practitioners, and investigators. PMID- 22935519 TI - Transient receptor potential ankyrin 1 activation enhances hapten sensitization in a T-helper type 2-driven fluorescein isothiocyanate-induced contact hypersensitivity mouse model. AB - Some chemicals contribute to the development of allergies by increasing the immunogenicity of other allergens. We have demonstrated that several phthalate esters, including dibutyl phthalate (DBP), enhance skin sensitization to fluorescein isothiocyanate (FITC) in a mouse contact hypersensitivity model, in which the T-helper type 2 (Th2) response is essential. On the other hand, some phthalate esters were found to activate transient receptor potential ankyrin 1 (TRPA1) cation channels on sensory neurons. We then found a positive correlation between the enhancing effects of several types of phthalate esters on skin sensitization to FITC and their ability to activate TRPA1. Here we examined the involvement of TRPA1 in sensitization to FITC by using TRPA1 agonists other than phthalate esters. During skin sensitization to FITC, the TRPA1 agonists (menthol, carvacrol, cinnamaldehyde and DBP) augmented the ear-swelling response as well as trafficking of FITC-presenting dendritic cells to draining lymph nodes. We confirmed that these TRPA1 agonists induced calcium influx into TRPA1-expressing Chinese hamster ovary (CHO) cells. We also found that TRPA1 antagonist HC-030031 inhibited DBP-induced calcium influx into TRPA1-expressing CHO cells. After pretreatment with this antagonist upon skin sensitization to FITC, the enhancing effect of DBP on sensitization was suppressed. These results suggest that TRPA1 activation will become a useful marker to find chemicals that facilitate sensitization in combination with other immunogenic haptens. PMID- 22935521 TI - Monitoring strategies for drill cutting discharge in the vicinity of cold-water coral ecosystems. AB - Cold-water coral reefs represent some of the most biodiverse and biomass rich ecosystems in the marine environment. Despite this, ecosystem functioning is still poorly understood and the susceptibility of key species to anthropogenic activities and pollutants is unknown. In European waters, cold-water corals are often found in greatest abundance on the continental margin, often in regions rich in hydrocarbon reserves. In this viewpoint paper we discuss some of the current strategies employed in predicting and minimizing exposure of cold-water coral reef ecosystems on the Norwegian margin to waste materials produced during offshore drilling operations by the oil and gas industry. In the light of recent in situ and experimental research conducted with the key reef species Lophelia pertusa, we present some possible improvements to these strategies which may be utilized by industry and managers to further reduce the likelihood of exposure. We further highlight important outstanding research questions in this field. PMID- 22935520 TI - Polycyclic aromatic hydrocarbons as skin carcinogens: comparison of benzo[a]pyrene, dibenzo[def,p]chrysene and three environmental mixtures in the FVB/N mouse. AB - The polycyclic aromatic hydrocarbon (PAH), benzo[a]pyrene (BaP), was compared to dibenzo[def,p]chrysene (DBC) and combinations of three environmental PAH mixtures (coal tar, diesel particulate and cigarette smoke condensate) using a two stage, FVB/N mouse skin tumor model. DBC (4nmol) was most potent, reaching 100% tumor incidence with a shorter latency to tumor formation, less than 20 weeks of 12-O tetradecanoylphorbol-13-acetate (TPA) promotion compared to all other treatments. Multiplicity was 4 times greater than BaP (400 nmol). Both PAHs produced primarily papillomas followed by squamous cell carcinoma and carcinoma in situ. Diesel particulate extract (1 mg SRM 1650b; mix 1) did not differ from toluene controls and failed to elicit a carcinogenic response. Addition of coal tar extract (1 mg SRM 1597a; mix 2) produced a response similar to BaP. Further addition of 2 mg of cigarette smoke condensate (mix 3) did not alter the response with mix 2. PAH-DNA adducts measured in epidermis 12 h post initiation and analyzed by 32P post-labeling, did not correlate with tumor incidence. PAH dependent alteration in transcriptome of skin 12 h post initiation was assessed by microarray. Principal component analysis (sum of all treatments) of the 922 significantly altered genes (p<0.05), showed DBC and BaP to cluster distinct from PAH mixtures and each other. BaP and mixtures up-regulated phase 1 and phase 2 metabolizing enzymes while DBC did not. The carcinogenicity with DBC and two of the mixtures was much greater than would be predicted based on published Relative Potency Factors (RPFs). PMID- 22935522 TI - Impacts of dredged material disposal on macrobenthic invertebrate communities: A comparison of structural and functional (secondary production) changes at disposal sites around England and Wales. AB - Although the impacts of dredged material disposal in the marine environment have been well studied, there is currently a limited understanding of the associated impacts on benthic function. This study compares macrofaunal structural and functional (based on secondary production estimates) responses to dredged material disposal at 14 sites across the coast of England and Wales. Disposal resulted in significant reductions of total secondary production at seven sites; no sites exhibited significant increases in production estimates. These seven sites were generally those which displayed significant structural impacts. There was no clear relationship between multivariate structural changes and taxonomic contribution to total production, indicating that a lack of change in the former (regarded as a sensitive indicator of change) does not always signify a lack of a significant functional impact. The need to evaluate functional changes, in addition to structural impacts, with respect to dredged material disposal site monitoring is discussed. PMID- 22935523 TI - Razorbills (Alca torda) as bioindicators of mercury pollution in the southwestern Mediterranean. AB - Levels of mercury (Hg) were analyzed in the tissues of 50 Razorbills (Alca torda), from the Mediterranean area, which had drowned in fishing nets. The mercury distribution pattern in tissues was similar to those of other studies (liver > feather vane > kidney > muscle > brain > feather shaft), with mercury concentrations of 2.85 +/- 0.90, 2.66 +/- 1.60, 2.23 +/- 0.87, 1.54 +/- 0.54, 1.48 +/- 0.54 and 1.30 +/- 0.76 mg/kg (dry weight), respectively. It could be considered that Razorbills in the southwestern Mediterranean were chronically exposed to relatively low levels of MeHg, probably below 0.5 ppm, via dietary intake. We have proposed prediction equations for brain and kidney Hg concentrations using feather shafts as non-invasive samples. This work provides a solid understanding of Razorbill Hg exposure both in their wintering and breeding grounds, and shows that this species can be useful for assessing marine environmental health in the Mediterranean area. PMID- 22935524 TI - Adjuvanticity of epimedium polysaccharide-propolis flavone on inactivated vaccines against AI and ND virus. AB - The purpose of this research was to compare the activities of different dose of epimedium polysaccharide-propolis flavone adjuvant (EPA). The inactivated avian influenza (AI) and Newcastle disease (ND) vaccine containing three doses of EPA were prepared. In AI vaccine vaccination experiment, 300 14-day-old chickens were randomly divided into 6 groups and inoculated with three EPA-AI vaccines taking oil adjuvant (OA), non-adjuvant (NA) vaccines and physiological saline as controls, repeated at 28-day-old. The lymphocyte proliferation and serum antibody titer were determined. In ND vaccine vaccination experiment, 300 14-day-old chickens were grouped, treated with three EPA-ND vaccines, and determined same to AI vaccine vaccination experiment; at 42-day-old the chickens were challenged with NDV. On D(15) after challenged, the immune protective effect was observed. The results showed that EPA could significantly promote lymphocyte proliferation and enhance serum antibody titer against AI and ND, and reduce the morbidity of chickens challenged with NDV after vaccinated with ND vaccine, especially the effect of medium dose was better than that of non-adjuvant and oil adjuvant. These results indicated that EPA could enhance the immune effect of inactivated AI vaccine and ND vaccine and would be expected as a new-type adjuvant. PMID- 22935525 TI - Comparison of outcomes in adults with congenitally corrected transposition with situs inversus versus situs solitus. AB - The long-term outcome of patients with congenitally corrected transposition of the great arteries is mainly determined by progressive morphologically tricuspid valve regurgitation, heart block, atrial arrhythmias, and/or systemic ventricular dysfunction. Situs abnormalities have been reported in <=34% of cases, but whether clinical differences exist between a situs inversus and situs solitus arrangement has not yet been studied. The clinical records of 38 adults with congenitally corrected transposition of the great arteries (mean age 40 +/- 15 years) followed for a mean period of 7.4 years were reviewed. Of these 38 patients, 8 presented with situs inversus and 30 with situs solitus. No significant differences were found between the 2 groups in age, gender, ventricular septal defect, pulmonary tract stenosis, previous surgical repair, or duration of follow-up. However, none of the patients with situs inversus presented with an Ebstein-like anomaly of the morphologically tricuspid valve and none developed nonoperative-related complete atrioventricular block compared to 15 (50%; p = 0.013) and 11 (42%; p = 0.032) of the patients with situs solitus, respectively. At follow-up, 2 patients with situs inversus (25%) presented with sustained atrial arrhythmia, severe tricuspid regurgitation, or severe systemic right ventricular systolic dysfunction compared to 22 (73%) of 30 those with situs solitus (p = 0.034). No patient with situs inversus presented with cardiac death or severe heart failure compared to 12 (40%) of 30 with situs solitus (p = 0.038). In conclusion, Ebstein-like anomaly or spontaneous complete atrioventricular block are rare in patients with congenitally corrected transposition of the great arteries with situs inversus, and late complications are uncommon. The long-term outcome of patients with situs inversus was significantly better than that for patients with situs solitus. PMID- 22935526 TI - Impact of Clopidogrel loading dose in patients with chronic kidney disease undergoing primary percutaneous coronary intervention for ST-segment elevation myocardial infarction. AB - The optimal loading dose of clopidogrel in patients with chronic kidney disease who undergo primary percutaneous coronary intervention for ST-segment elevation myocardial infarction has not been investigated. The aim of this study was to assess the impact of clopidogrel loading dose on clinical outcomes in this setting. A total of 1,457 patients with CKD (estimated glomerular filtration rate <60 ml/min/1.73 m(2)) were evaluated according to clopidogrel loading dose: 600 mg (n = 861) versus 300 mg (n = 596). In-hospital complications, including major bleeding and clinical outcomes at 1 and 12 months, were compared between the 2 groups. The in-hospital major bleeding rate was similar (0.8% vs 0.2%, p = 0.09). Also, there were no differences in major adverse cardiac event rates, including death, recurrent myocardial infarction, target lesion revascularization, and stent thrombosis, at 1 month (15.6% vs 16.4%, p = 0.70) and 12 months (19.0% vs 21.3%, p = 0.32). On multivariate analysis, a 600-mg loading dose of clopidogrel was not an independent predictor of 1-month (odds ratio 1.13, 95% confidence interval 0.49 to 2.57, p = 0.78) and 12-month (odds ratio 0.89, 95% confidence interval 0.52 to 1.51, p = 0.66) major adverse cardiac events. After propensity score-matched analysis, these results were unchanged. In conclusion, a 600-mg loading dose of clopidogrel was not effective in reducing 1- and 12-month major adverse cardiac events in patients with chronic kidney disease who underwent primary percutaneous coronary intervention for ST-segment elevation myocardial infarction, but this dose did not increase the in-hospital major bleeding rate. PMID- 22935527 TI - Renal function and effect of statin therapy on cardiovascular outcomes in patients undergoing coronary revascularization (from the CREDO-Kyoto PCI/CABG Registry Cohort-2). AB - Although statin therapy is essential for secondary cardiovascular prevention, the therapeutic effect of statins on cardiovascular outcomes in patients with advanced chronic kidney disease (CKD) after coronary revascularization has not been fully elucidated. In the CREDO-Kyoto Registry Cohort-2, 14,706 patients who underwent first coronary revascularization were divided into 4 strata based on estimated glomerular filtration rate (eGFR) or status of hemodialysis (HD). Patients in each stratum were further divided into 2 groups based on statin therapy at discharge: non-CKD stratum (eGFR >=60 ml/min/1.73 m(2)), 8,959 patients (statin, n = 4,747; no statin, n = 4,212); mild CKD stratum (eGFR >=30 to <60 ml/min/1.73 m(2)), 4,567 patients (statin, n = 2,135; no statin, n = 2,432); severe CKD stratum (eGFR <30 ml/min/1.73 m(2)), 608 patients (statin, n = 229; no statin, n = 379); and HD stratum, 572 patients (statin, n = 117; no statin, n = 455). Median follow-up duration was 956 days (interquartile range 699 to 1,245). Adjusted risk for major adverse cardiovascular events (MACEs; composite of cardiovascular death, myocardial infarction, or stoke) was significantly lower in the statin group than in the no-statin group in the non CKD (hazard ratio 0.8, 95% confidence interval 0.68 to 0.95, p = 0.01) and mild CKD (hazard ratio 0.69, 95% confidence interval 0.56 to 0.84, p = 0.0002) strata. However, a significant association of statin therapy and lower risk for MACEs was not seen in the severe CKD (hazard ratio 0.91, 95% confidence interval 0.6 to 1.38, p = 0.65) and HD (hazard ratio 1.04, 95% confidence interval 0.64 to 1.69, p = 0.87) strata. In conclusion, statin therapy was associated with significantly lower risk for MACEs in patients with non-CKD and mild CKD undergoing coronary revascularization. However, therapeutic benefits of statins were not apparent in patients with severe CKD and HD. PMID- 22935528 TI - Modulation of smooth muscle cell phenotype: the other side of the story. PMID- 22935529 TI - Could plugging the oxidation-mediated Ca2+ leak stem the tide of the atrial fibrillation epidemic? PMID- 22935531 TI - How to chew up cells: lessons for the atherosclerotic plaque. PMID- 22935530 TI - Metabolic remodeling in the hypertrophic heart: fuel for thought. PMID- 22935532 TI - Helen Blau: she thinks like a cell. Interview by Ruth Williams. PMID- 22935533 TI - Lost in transgenesis: a user's guide for genetically manipulating the mouse in cardiac research. AB - The advent of modern mouse genetics has benefited many fields of diseased-based research over the past 20 years, none perhaps more profoundly than cardiac biology. Indeed, the heart is now arguably one of the easiest tissues to genetically manipulate, given the availability of an ever-growing tool chest of molecular reagents/promoters and "facilitator" mouse lines. It is now possible to modify the expression of essentially any gene or partial gene product in the mouse heart at any time, either gain or loss of function. This review is designed as a handbook for the nonmouse geneticist and/or junior investigator to permit the successful manipulation of any gene or RNA product in the heart, while avoiding artifacts. In the present review, guidelines, pitfalls, and limitations are presented so that rigorous and appropriate examination of cardiac genotype phenotype relationships can be performed. This review uses examples from the field to illustrate the vast spectrum of experimental and design details that must be considered when using genetically modified mouse models to study cardiac biology. PMID- 22935537 TI - TiO2-doped phosphate glass microcarriers: a stable bioactive substrate for expansion of adherent mammalian cells. AB - Scalable expansion of cells for regenerative cell therapy or to produce large quantities for high-throughput screening remains a challenge for bioprocess engineers. Laboratory scale cell expansion using t-flasks requires frequent passaging that exposes cells to many poorly defined bioprocess forces that can cause damage or alter their phenotype. Microcarriers offer a potential solution to scalable production, lending themselves to cell culture processes more akin to fermentation, removing the need for frequent passaging throughout the expansion period. One main problem with microcarrier expansion, however, is the difficulty in harvesting cells at the end of the process. Therefore, therapies that rely on cell delivery using biomaterial scaffolds could benefit from a microcarrier expansion system whereby the cells and microcarriers are transplanted together. In the current study, we used bioactive glass microcarriers doped with 5% TiO2 that display a controlled rate of degradation and conducted experiments to assess biocompatibility and growth of primary fibroblast cells as a model for cell therapy products. We found that the microcarriers are highly biocompatible and facilitate cell growth in a gradual controlled manner. Therefore, even without additional biofunctionalization methods, Ti-doped bioactive glass microcarriers offer potential as a cell expansion platform. PMID- 22935534 TI - Role of phospholipid oxidation products in atherosclerosis. AB - There is increasing clinical evidence that phospholipid oxidation products (Ox PL) play a role in atherosclerosis. This review focuses on the mechanisms by which Ox-PL interact with endothelial cells, monocyte/macrophages, platelets, smooth muscle cells, and HDL to promote atherogenesis. In the past few years major progress has been made in identifying these mechanisms. It has been recognized that Ox-PL promote phenotypic changes in these cell types that have long-term consequences for the vessel wall. Individual Ox-PL responsible for specific cellular effects have been identified. A model of the configuration of bioactive truncated Ox-PL within membranes has been developed that demonstrates that the oxidized fatty acid moiety protrudes into the aqueous phase, rendering it accessible for receptor recognition. Receptors and signaling pathways for individual Ox-PL species are now determined and receptor independent signaling pathways identified. The effects of Ox-PL are mediated both by gene regulation and transcription independent processes. It has now become apparent that Ox-PL affects multiple genes and pathways, some of which are proatherogenic and some are protective. However, at concentrations that are likely present in the vessel wall in atherosclerotic lesions, the effects promote atherogenesis. There have also been new insights on enzymes that metabolize Ox-PL and the significance of these enzymes for atherosclerosis. With the knowledge we now have of the regulation and effects of Ox-PL in different vascular cell types, it should be possible to design experiments to test the role of specific Ox-PL on the development of atherosclerosis. PMID- 22935538 TI - Needle metabolome, freezing tolerance and gas exchange in Norway spruce seedlings exposed to elevated temperature and ozone concentration. AB - Northern forests are currently experiencing increasing mean temperatures, especially during autumn and spring. Consequently, alterations in carbon sequestration, leaf biochemical quality and freezing tolerance (FT) are likely to occur. The interactive effects of elevated temperature and ozone (O(3)), the most harmful phytotoxic air pollutant, on Norway spruce (Picea abies (L.) Karst.) seedlings were studied by analysing phenology, metabolite concentrations in the needles, FT and gas exchange. Sampling was performed in September and May. The seedlings were exposed to a year-round elevated temperature (+1.3 degrees C), and to 1.4* ambient O(3) concentration during the growing season in the field. Elevated temperature increased the concentrations of amino acids, organic acids of the citric acid cycle and some carbohydrates, and reduced the concentrations of phenolic compounds, some organic acids of the shikimic acid pathway, sucrose, cyclitols and steroids, depending on the timing of the sampling. Although growth onset occurred earlier at elevated temperature, the temperature of 50% lethality (LT(50)) was similar in the treatments. Photosynthesis and the ratio of photosynthesis to dark respiration were reduced by elevated temperature. Elevated concentrations of O(3) reduced the total concentration of soluble sugars, and tended to reduce LT(50) of the needles in September. These results show that alterations in needle chemical quality can be expected at elevated temperatures, but the seedlings' sensitivity to autumn and spring frosts is not altered. Elevated O(3) has the potential to disturb cold hardening of Norway spruce seedlings in autumn, and to alter the water balance of the seedling through changes in stomatal conductance (g(s)), while elevated temperature is likely to reduce g(s) and consequently reduce the O(3)-flux inside the leaves. PMID- 22935539 TI - Impact of smoking cessation on the risk of subarachnoid haemorrhage: a nationwide multicentre case control study. AB - BACKGROUND AND PURPOSE: Subarachnoid haemorrhage (SAH) is the most devastating cerebrovascular disease. Cigarette smoking is one of the established risk factors for SAH, but the risk of SAH has not been properly elucidated in relation to smoking cessation. METHODS: We performed a nationwide multicentre case control study involving 33 hospitals in Korea. A total of 426 SAH cases and 426 age and sex matched controls were enrolled. We obtained detailed information on lifestyle, medical history and, in particular, smoking habits from participants using structured questionnaires. RESULTS: 148 SAH patients (37.4%) were current smokers compared with 103 (24.2%) controls, giving an adjusted OR of 2.84 (95% CI, 1.63 to 4.97) after controlling for possible confounders. Based on cumulative dose of smoking (pack years), the risk of SAH was found to increase in a dose responsive fashion. Smoking cessation (>=5 years) caused a reduction in SAH to 59% (p<0.05). However, participants with a history of heavy smoking (>=20 cigarettes per day) had a 2.3 times increased risk of SAH compared with participants who had never smoked (p<0.05). CONCLUSIONS: We have demonstrated that cigarette smoking increases the risk of SAH, but smoking cessation decreases the risk in a time dependent manner, although this beneficial effect may be diminished in previous heavy smokers. To forestall tragic SAH events, our results call for more global and vigorous efforts for people to stop smoking. PMID- 22935535 TI - AMP-activated protein kinase regulation and biological actions in the heart. AB - AMP-activated protein kinase (AMPK) is a stress-activated kinase that functions as a cellular fuel gauge and master metabolic regulator. Recent investigation has elucidated novel molecular mechanisms of AMPK regulation and important biological actions of the AMPK pathway that are highly relevant to cardiovascular disease. Activation of the intrinsic AMPK pathway plays an important role in the myocardial response to ischemia, pressure overload, and heart failure. Pharmacological activation of AMPK shows promise as a therapeutic strategy in the treatment of heart disease. The purpose of this review is to assess how recent discoveries have extended and in some cases challenged existing paradigms, providing new insights into the regulation of AMPK, its diverse biological actions, and therapeutic potential in the heart. PMID- 22935540 TI - Developing a nutrition intervention in children's centres: exploring views of parents in rural/urban settings in the UK. AB - OBJECTIVE: The present study explored parents' requirements for healthy eating support prior to the development of a tailored intervention. DESIGN: A cross sectional study of parents attending children's centres. SETTING: Children's centres in Cornwall (rural south-west England) and Islington (urban London borough). SUBJECTS: A total of 261 parents (94.2% female) of pre-school children (aged 2-5 years) completed a questionnaire on factors influencing food choice, and preferences for and views on healthy eating support. RESULTS: Parents reported that health, taste, freshness and quality were the most important factors influencing their food choices for their pre-school children. The importance of individual factors varied according to level of educational attainment. Over a third (38 %) of parents said they wanted more advice on healthy eating for children. Less educated parents showed the greatest interest in learning more about several aspects: what a 'healthy diet' means, how to prepare and cook healthy food, how to understand food labels, budgeting for food, examples of healthy food and snacks for children, appropriate portion sizes for children and ways to encourage children to eat well. CONCLUSIONS: There was demand for healthy eating support among parents of pre-school children, especially those who are less educated, in one rural and one urban area of England PMID- 22935541 TI - Can misfit dislocations be located above the interface of InAs/GaAs (001) epitaxial quantum dots? AB - InAs/GaAs(001) quantum dots grown by droplet epitaxy were investigated using electron microscopy. Misfit dislocations in relaxed InAs/GaAs(001) islands were found to be located approximately 2 nm above the crystalline sample surface, which provides an impression that the misfit dislocations did not form at the island/substrate interface. However, detailed microscopy data analysis indicates that the observation is in fact an artefact caused by the surface oxidation of the material that resulted in substrate surface moving down about 2 nm. As such, caution is needed in explaining the observed interfacial structure. PMID- 22935542 TI - A population-based study on the association between acute renal failure (ARF) and the duration of polypharmacy. AB - BACKGROUND: Because of the rapid growth in elderly population, polypharmacy has become a serious public health issue worldwide. Although acute renal failure (ARF) is one negative consequence of polypharmacy, the association between the duration of polypharmacy and ARF remains unclear. We therefore assessed this association using a population-based database. METHODS: Data were collected from the Taiwan National Health Insurance Research Database (NHIRD) from 2003 through 2006. The case group included patients hospitalized for ARF during 2006, but not admitted due to trauma, surgery, burn trauma, car accident, transplantation, or infectious diseases; the control group included patients hospitalized without ARF. The cumulative number of days of polypharmacy (defined as more than 5 prescriptions per day) for 1 year prior to admission was determined, with patients further subdivided into 4 categories: less than 30 days, 31-90 days, 91 180 days, and over 181 days. The dependent variable was ARF, and the control variables were age, gender, comorbidities in patients hospitalized for ARF, stay in ICUs during ARF hospitalization and site of operation for prior admissions within one month of ARF hospitalization. RESULTS: Of 20,790 patients who were admitted to hospitals for ARF in 2006, 12,314 (59.23 %) were male and more than 60 % were older than 65 years. Of patients with and without ARF, 16.14 % and 10.61 %, respectively, received polypharmacy for 91-180 days and 50.22 % and 24.12 %, respectively, for over 181 days. A statistical model indicated that, relative to patients who received polypharmacy for less than 30 days, those who received polypharmacy for 31-90, 91-180 and over 181 days had odds ratios of developing ARF of 1.33 (p<0.001), 1.65 (p<0.001) and 1.74 (p<0.001), respectively. CONCLUSIONS: We observed statistically significant associations between the duration of polypharmacy and the occurrence of ARF. PMID- 22935544 TI - Adipocytokines in primary antiphospholipid syndrome: potential markers of low grade inflammation, insulin resistance and metabolic syndrome. AB - OBJECTIVES: This study was undertaken to evaluate a possible association of adipocytokines with metabolic syndrome (MetS), inflammation and other cardiovascular risk factors in primary antiphospholipid syndrome (PAPS). METHODS: Fifty-six PAPS patients and 72 controls were included. Adiponectin, leptin, visfatin, resistin, plasminogen activator inhibitor-1 (PAI-1), lipoprotein (a), glucose, ESR, CRP, uric acid and lipid profiles were measured. The presence of MetS was determined as defined by the International Diabetes Federation (IDF), and insulin resistance was rated using the homeostasis model assessment (HOMA) index. RESULTS: Concentrations of leptin were higher [21.5 (12.9-45.7) ng/mL] in PAPS patients than in the controls [12.1 (6.9-26.8) ng/mL), p=0.001]. In PAPS patients, leptin and PAI-1 levels were positively correlated with BMI (r=0.61 and 0.29), HOMA-IR (r=0.71 and 0.28) and CRP (r=0.32 and 0.36). Adiponectin levels were negatively correlated with BMI (r=-0.28), triglycerides (r=-0.43) and HOMA IR (r=-0.36) and positively correlated with HDL-c (r=0.37) and anti-beta2GPI IgG (r=0.31). The presence of MetS in PAPS patients was associated with higher levels of leptin (p=0.002) and PAI-1 (p=0.03) levels and lower levels of adiponectin (p=0.042). Variables that independently influenced the adiponectin concentration were the triglyceride levels (p<0.001), VLDL-c (P=0.002) and anti-beta2GPI IgG (p=0.042); the leptin levels were BMI (p<0.001), glucose (p=0.046), HOMA-IR (p<0.001) and ESR (p=0.006); and the PAI-1 levels were CRP (p=0.013) and MetS (p=0.048). CONCLUSIONS: This study provides evidence that adipocytokines may be involved in low-grade inflammation, insulin resistance and MetS in PAPS patients. PMID- 22935545 TI - A new DPYD genotyping assay for improving the safety of 5-fluorouracil therapy. AB - BACKGROUND: Chemotherapeutic use of 5-fluorouracil (5FU) is compromised by 10-20% of patients developing severe toxicity. Recently described genetic variation in dihydropyrimidine dehydrogenase (DPYD) has been shown to be a major predictor of 5FU toxicity. Here, we describe a new genotyping assay for routine clinical use that covers all the major DPYD risk variants. METHODS: Genomic regions targeting DPYD risk variants (c.1129-5923C>G, c.1679T>G/A, c.1905+1G>A, c.2846A>T) and additional markers (c.234-123G>C, c.496A>G, c.775A>G) were amplified in a multiplex PCR reaction. The subsequent steps including allele-specific primer extension, hybridization of the primers to a microarray, scanning of the array, and data analysis were automated within the INFINITI(r) Analyzer (AutoGenomics). The assay was validated by analyzing 107 blood samples obtained from patients previously re-sequenced for the DPYD. RESULTS: The genotypes obtained with the developed assay were 100% concordant with the re-sequencing. The procedure is suitable for routine clinical use since the results are obtained within one day. For heterozygous risk variant carriers (~7% of Europeans), the treatment can be adjusted by 5FU dose reduction, whereas carriers of two risk alleles should be treated with an alternative therapy. CONCLUSIONS: The developed assay provides a novel tool to improve the safety of commonly used 5FU-based chemotherapies. PMID- 22935543 TI - Anterior cingulate cortex and cognitive control: neuropsychological and electrophysiological findings in two patients with lesions to dorsomedial prefrontal cortex. AB - Whereas neuroimaging studies of healthy subjects have demonstrated an association between the anterior cingulate cortex (ACC) and cognitive control functions, including response monitoring and error detection, lesion studies are sparse and have produced mixed results. Due to largely normal behavioral test results in two patients with medial prefrontal lesions, a hypothesis has been advanced claiming that the ACC is not involved in cognitive operations. In the current study, two comparably rare patients with unilateral lesions to dorsal medial prefrontal cortex (MPFC) encompassing the ACC were assessed with neuropsychological tests as well as Event-Related Potentials in two experimental paradigms known to engage prefrontal cortex (PFC). These included an auditory Novelty Oddball task and a visual Stop-signal task. Both patients performed normally on the Stroop test but showed reduced performance on tests of learning and memory. Moreover, altered attentional control was reflected in a diminished Novelty P3, whereas the posterior P3b to target stimuli was present in both patients. The error-related negativity, which has been hypothesized to be generated in the ACC, was present in both patients, but alterations of inhibitory behavior were observed. Although interpretative caution is generally called for in single case studies, and the fact that the lesions extended outside the ACC, the findings nevertheless suggest a role for MPFC in cognitive control that is not restricted to error monitoring. PMID- 22935546 TI - Mechanisms driving pre- and post-stressor repetitive negative thinking: metacognitions, cognitive avoidance, and thought control. AB - BACKGROUND AND OBJECTIVES: Repetitive negative thinking (RNT) is common to multiple emotional disorders and occurs before, during, and following a stressor. One replicated difference between common forms of RNT such as worry and rumination is temporal orientation towards a stressor, with worry being more future-oriented and rumination more past-oriented. Different mechanisms may drive RNT at these different time points. The aim of Study 1 was to examine whether previously demonstrated relationships between post-stressor RNT and mechanisms theorized to drive engagement in RNT, including metacognitive beliefs, cognitive avoidance strategies, and thought control strategies, would be replicated with anticipatory (pre-stressor) RNT. The aim of Study 2 was to replicate these associations in a new sample that completed measures of both pre- and post stressor RNT. METHOD: Participants in Study 1 (N = 175) completed the RNT-L in anticipation of a stressor, along with measures of metacognitive beliefs, cognitive avoidance strategies, and thought control strategies. Participants in Study 2 (N = 91) completed the measures both before and after a stressor. RESULTS: Pre- and post-stressor RNT were significantly correlated with all three mechanism measures. Metacognitive beliefs that RNT is uncontrollable and dangerous, and the thought control strategy of punishment, were most consistently and uniquely associated with RNT at both time-points. LIMITATIONS: Replication with clinical samples and with reference to a broader array of stressors is required. The correlational design precluded causal conclusions. CONCLUSIONS: Common and possibly some distinct mechanisms drive RNT before and after a stressor. PMID- 22935547 TI - Traumatic asphyxia due to blunt chest trauma: a case report and literature review. AB - INTRODUCTION: Crush asphyxia is different from positional asphyxia, as respiratory compromise in the latter is caused by splinting of the chest and/or diaphragm, thus preventing normal chest expansion. There are only a few cases or small case series of crush asphyxia in the literature, reporting usually poor outcomes. CASE PRESENTATION: We present the case of a 44-year-old Caucasian man who developed traumatic asphyxia with severe thoracic injury and mild brain edema after being crushed under heavy auto vehicle mechanical parts. He remained unconscious for an unknown time. The treatment included oropharyngeal intubation and mechanical ventilation, bilateral chest tube thoracostomies, treatment of brain edema and other supportive measures. Our patient's outcome was good. Traumatic asphyxia is generally under-reported and most authors apply supportive measures, while the final outcome seems to be dependent on the length of time of the chest compression and on the associated injuries. CONCLUSION: Treatment for traumatic asphyxia is mainly supportive with special attention to the re establishment of adequate oxygenation and perfusion; treatment of the concomitant injuries might also affect the final outcome. PMID- 22935548 TI - A qualitative examination of health and health care utilization after the September 11th terror attacks among World Trade Center Health Registry enrollees. AB - BACKGROUND: Many individuals who have 9/11-related physical and mental health symptoms do not use or are unaware of 9/11-related health care services despite extensive education and outreach efforts by the World Trade Center (WTC) Health Registry (the Registry) and various other organizations. This study sought to evaluate Registry enrollees' perceptions of the relationship between physical and mental health outcomes and 9/11, as well as utilization of and barriers to 9/11 related health care services. METHODS: Six focus groups were conducted in January 2010 with diverse subgroups of enrollees, who were likely eligible for 9/11 related treatment services. The 48 participants were of differing race/ethnicities, ages, and boroughs of residence. Qualitative analysis of focus group transcripts was conducted using open coding and the identification of recurring themes. RESULTS: Participants described a variety of physical and mental symptoms and conditions, yet their knowledge and utilization of 9/11 health care services were low. Participants highlighted numerous barriers to accessing 9/11 services, including programmatic barriers (lack of program visibility and accessibility), personal barriers such as stigmatization and unfamiliarity with 9/11-related health problems and services, and a lack of referrals from their primary care providers. Moreover, many participants were reluctant to connect their symptoms to the events of 9/11 due to lack of knowledge, the amount of time that had elapsed since 9/11, and the attribution of current health symptoms to the aging process. CONCLUSIONS: Knowledge of the barriers to 9/11-related health care has led to improvements in the Registry's ability to refer eligible enrollees to appropriate treatment programs. These findings highlight areas for consideration in the implementation of the new federal WTC Health Program, now funded under the James Zadroga 9/11 Health and Compensation Act (PL 111-347), which includes provisions for outreach and education. PMID- 22935549 TI - Effect of completion-time windows in the analysis of health-related quality of life outcomes in cancer patients. AB - BACKGROUND: We examined if cancer patients' health-related quality of life (HRQoL) scores on the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 are affected by the specific time point, before or during treatment, at which the questionnaire is completed, and whether this could bias the overall treatment comparison analyses. PATIENTS AND METHODS: A 'completion time window' variable was created on three closed EORTC randomised control trials in lung (non-small cell lung cancer, NSCLC) and colorectal cancer (CRC) to indicate when the QLQ-30 was completed relative to chemotherapy cycle dates, defined as 'before', 'on' and 'after'. HRQoL mean scores were calculated using a linear mixed model. RESULTS: Statistically significant differences (P<0.05) were observed on 6 and 5 scales for 'on' and 'after' comparisons in the NSCLC and two group CRC trial, respectively. As for the three-group CRC trial, several statistical differences were observed in the 'before' to 'on' and the 'on' to 'after' comparisons. For all three trials, including the 'completion-time window' variable in the model resulted in a better fit, but no substantial changes in the treatment effects were noted. CONCLUSIONS: We showed that considering the exact timing of completion within specified windows resulted in statistical and potentially clinically significant differences, but it did not alter the conclusions of treatment comparison in these studies. PMID- 22935550 TI - Siphon regeneration capacity is compromised during aging in the ascidian Ciona intestinalis. AB - The ascidian Ciona intestinalis has a short life span and powerful regeneration capacities. The regeneration of the oral siphon (OS) involves wound healing, blastema formation, cell proliferation, and replacement of 8 oral pigment organs (OPO), the latter via differentiation and migration of stem/precursor cells from localized niches in the siphon. The restoration of OPO pattern during OS regeneration occurs with a high degree of accuracy through three successive cycles of amputation. It is shown here that oral siphons of the largest and oldest members of a wild Ciona population do not completely regenerate their siphons after amputation. The loss of regeneration capacity was accompanied by reduced cell proliferation. In contrast to arrested OS outgrowth, the stem/precursor cells responsible for OPO replacement "over-differentiate" after OS amputation in the oldest animals, the typical number of OPO is increased from 8 to 12-16, and malformed OPO are produced. Also in contrast to younger animals, the oldest animals of the population show arrested OPO development after two consecutive cycles of amputation and regeneration. We conclude that there is a size and age threshold in Ciona after which the regenerative capacity of the OS is compromised due to effects of aging on cell proliferation. PMID- 22935552 TI - The impact of MEFV gene identification on FMF: an appraisal after 15 years. PMID- 22935551 TI - Impaired adaptability of in vivo mitochondrial energetics to acute oxidative insult in aged skeletal muscle. AB - Periods of elevated reactive oxygen species (ROS) production are a normal part of mitochondrial physiology. However, little is known about age-related changes in the mitochondrial response to elevated ROS in vivo. Significantly, ROS-induced uncoupling of oxidative phosphorylation has received attention as a negative feedback mechanism to reduce mitochondrial superoxide production. Here we use a novel in vivo spectroscopy system to test the hypothesis that ROS-induced uncoupling is diminished in aged mitochondria. This system simultaneously acquires (31)P magnetic resonance and near-infrared optical spectra to non invasively measure phosphometabolite and O(2) concentrations in mouse skeletal muscle. Using low dose paraquat to elevate intracellular ROS we assess in vivo mitochondrial function in young, middle aged, and old mice. Oxidative phosphorylation was uncoupled to the same degree in response to ROS at each age, but this uncoupling was associated with loss of phosphorylation capacity and total ATP in old mice only. Using mice lacking UCP3 we demonstrate that this in vivo uncoupling is independent of this putative uncoupler of skeletal muscle mitochondria. These data indicate that ROS-induced uncoupling persists throughout life, but that oxidative stress leads to mitochondrial deficits and loss of ATP in aged organisms that may contribute to impaired function and degeneration. PMID- 22935554 TI - Foods contributing to sodium intake and urinary sodium excretion in a group of Australian women. AB - OBJECTIVES: To identify food sources of Na in a group of community-dwelling women in Adelaide, South Australia. A secondary aim was to measure Na excretion in this group. DESIGN: Survey. SETTING: Community setting, Adelaide, South Australia. SUBJECTS: Seventy healthy women (mean age 48.6 (SD 8.1) years, mean BMI 28.6 (SD 6.3) kg/m2) living in metropolitan Adelaide, South Australia and participating in a validation study of an FFQ. Dietary intake was derived from two 4 d weighed food records. Foods from the 4 d weighed food records were grouped according to foods or food groups to establish contributors to Na intake. Na excretion was measured in two 24 h urine samples. Completeness of urine collections was verified using creatinine excretion. RESULTS: Bread alone contributed 19.0% of Na intake, with an overall contribution from the breads and cereals group of 32.5%. Meat products contributed 14.4% of intake, the dairy and eggs group (excluding cheese) 9.6% and combination dishes (e.g. pizza, quiche, sandwiches and stir fry dishes) 8.4%. Na excretion was 126 (SD 42) mmol/d, i.e. approximately 7.6 (SD 2.5) g salt/d. Seventy per cent of participants (n 48) had Na excretion >=100 mmol/d (146 (SD 34) mmol/d). CONCLUSIONS: Effective Na reduction could be achieved by reducing the amount in staple foods such as bread and meat products. PMID- 22935553 TI - Autoimmune encephalitis in children. AB - The causes of encephalitis are numerous, and extensive investigations for infectious agents and other etiologies are often negative. The discovery that many of these encephalitis are immune mediated has changed the approach to the diagnosis and treatment of these disorders. Moreover, the broad spectrum of symptoms including, psychosis, catatonia, alterations of behavior and memory, seizures, abnormal movements, and autonomic dysregulation usually requires a multidisciplinary treatment approach. This review focuses in several forms of encephalitis that occur in children, and for which an autoimmune etiology has been demonstrated (eg, anti-N-methyl-d-aspartate receptor encephalitis) or is strongly suspected (eg, Rasmussen encephalitis, limbic encephalitis, opsoclonus myoclonus). The authors also review several disorders that may be immune mediated, such as the rapid onset obesity with hypothalamic dysfunction, hypoventilation and autonomic dysregulation (ROHHAD) syndrome and some encephalopathies with fever and status epilepticus. Recognition of novel immune mediated encephalitis is important because some of these disorders are highly responsive to immunotherapy. PMID- 22935555 TI - A high leucine diet mitigates cardiac injury and improves survival after acute myocardial infarction. AB - OBJECTIVE: Evidence suggests that branched chain amino acids (BCAAs) are beneficial in treating human disease. It is unknown, however, what impact BCAAs have on outcomes in acute myocardial infarction (MI). This study was performed to test the hypothesis that the specific BCAA leucine mitigates cardiac injury and improves survival post-MI. MATERIALS/METHODS: 11-12 week old male C57BL/6 mice were subjected to experimental MI or sham procedure, and provided regular chow (RC; 1.5% leucine) or a high leucine diet (HLD; 5% leucine), and followed for 31/2 or 28 days. All mice were studied by echocardiography and cardiac catheterization, and all hearts were collected for histologic measurements of hypertrophy, fibrosis and apoptosis. Inflammation, hypertrophic gene expression, signal transduction, and glucose, palmitate and leucine metabolism were also measured in 31/2day hearts. RESULTS: Except for increased leucine and decreased glucose oxidation, an HLD had no effect on measured outcomes in sham mice. With MI, cardiac structure, function, and survival were significantly improved with an HLD. At 31/2days post-MI, an HLD increased cardiac hypertrophic signaling and decreased inflammation. Cardiac leucine oxidation was decreased in RC mice post MI, but significantly increased with an HLD. These changes in metabolism were accompanied by a significant increase in cardiac ATP content in the HLD group. Finally, at both 31/2 and 28 days post-MI, an HLD increased compensatory hypertrophy, and attenuated cardiac fibrosis and apoptosis. CONCLUSIONS: An HLD increases compensatory hypertrophy, attenuates fibrosis and apoptosis, and positively modulates oxidative metabolism to improve cardiac structure, function, and survival post-MI. PMID- 22935556 TI - Gonadotropin-releasing hormone agonist may minimize premature ovarian failure in young women undergoing autologous stem cell transplantation. AB - OBJECTIVE: To compare the rate of premature ovarian failure (POF) after stem cell transplantation (SCT) in young women receiving GnRH-agonist (GnRH-a) in conjunction with gonadotoxic chemotherapy. DESIGN: Prospective, nonrandomized study. SETTING: Tertiary university hospital. PATIENT(S): Ninety-five women received conditioning chemotherapy, with or without GnRH-a before SCT. Complete information was available for only 83 patients. INTERVENTION(S): Conditioning chemotherapy, with or without GnRH-a before SCT. MAIN OUTCOME MEASURE(S): Cyclic ovarian function (COF) or POF after SCT. RESULT(S): There were no significant differences in age, chemotherapy treatment, or diagnoses between the study and control groups. In the GnRH-a group, 38.3% (18/47) patients resumed COF, compared with 11.1% (4/36) for patients who did not receive GnRH-a. Patients who resumed COF were on average 3.7 years (median, 3 years) younger at the time of transplantation than those who experienced POF. GnRH-a had a significant effect on long-term COF in patients with lymphomas (66.7% [14/21] for GnRH-a group vs. 18.2% [2/11] for control) but not for leukemia patients. CONCLUSION(S): GnRH-a cotreatment in conjunction with conditioning chemotherapy before SCT may significantly decrease the gonadotoxicity and POF from 82% to 33% in lymphoma but not in leukemia patients. PMID- 22935558 TI - Shoulder adaptations among pitchers and position players over the course of a competitive baseball season. AB - OBJECTIVE: To determine if throwing arm shoulder range of motion (ROM) and scapular kinematic differences exist between baseball pitchers and position players over the course of a baseball season. DESIGN: Prospective cohort. SETTING: Professional baseball athletic training room. PARTICIPANTS: Sixteen asymptomatic professional baseball pitchers and 16 position players. INDEPENDENT VARIABLES: Preseason glenohumeral (GH) posterior tightness and scapular position. MAIN OUTCOME MEASURES: Throwing arm GH horizontal adduction ROM and GH internal rotation bilateral asymmetry ROM, as well as bilateral differences in forward scapular posture and throwing arm scapular upward rotation at rest, 60, 90, and 120 degrees of humeral elevation were measured. These measurements were taken before and at the conclusion of a 140-game baseball season. RESULTS: Analyses of covariances showed no significant differences in GH horizontal adduction or internal rotation asymmetry ROM between groups over the course of the season. However, the pitchers developed significantly less scapular upward rotation at 60 degrees (P = 0.007) and 90 degrees (P = 0.006) of humeral elevation compared with the position players during the season. Forward scapular posture (P = 0.23) and scapular upward rotation at 0 degrees (P = 0.93) and 120 degrees (P = 0.29) of humeral elevation were not significantly different between groups. CONCLUSIONS: These results suggest that baseball position players develop more scapular upward rotation over the course of a competitive season than pitchers. This discrepancy may increase the pitchers' risk of injury and may partially explain their higher incidence of shoulder injury compared with position players. Therefore, pitchers may benefit from strengthening exercises and stretches aimed at increasing scapular upward rotation throughout the competitive baseball season. PMID- 22935557 TI - Micronutrients intake is associated with improved sperm DNA quality in older men. AB - OBJECTIVE: To investigate whether lifestyle factors such as increased dietary intake of micronutrients reduce the risks of sperm DNA damage, and whether older men benefit more than younger men. DESIGN: Cross-sectional study design with equalized assignments into age groups. SETTING: National laboratory and university. PATIENT(S): Nonclinical group of 22-80-year-old nonsmoking men (n = 80) who reported no fertility problems. MAIN OUTCOME MEASURE(S): Sperm DNA damage measured by alkaline and neutral DNA electrophoresis (i.e., sperm Comet assay). RESULT(S): Sociodemographics, occupational exposures, medical and reproductive histories, and lifestyle habits were determined by questionnaire. The average daily dietary and supplement intake of micronutrients (vitamin C, vitamin E, b carotene, zinc, and folate) was determined using the 100-item Modified Block Food Frequency Questionnaire (FFQ). Men with the highest intake of vitamin C had approximately 16% less sperm DNA damage (alkaline sperm Comet) than men with the lowest intake, with similar findings for vitamin E, folate, and zinc (but not beta-carotene). Older men (>44 years) with the highest vitamin C intake had approximately 20% less sperm DNA damage compared with older men with the lowest intake, with similar findings for vitamin E and zinc. The older men with the highest intake of these micronutrients showed levels of sperm damage that were similar to those of the younger men. However, younger men (<44 years) did not benefit from higher intakes of the micronutrients surveyed. CONCLUSION(S): Men with higher dietary and supplement intake of certain micronutrients may produce sperm with less DNA damage, especially among older men. This raises the broader question of how lifestyle factors, including higher intakes of antioxidants and micronutrients, might protect somatic as well as germ cells against age associated genomic damage. PMID- 22935559 TI - Severe Bradycardia: Patient Outfoxed by Lady's Glove. PMID- 22935560 TI - The great "infiltrator": an uncommon cause of hepatitis. PMID- 22935561 TI - Association of response to hepatitis B vaccination and survival in dialysis patients. AB - BACKGROUND: The status of immunocompromised patients is well recognized in end stage renal disease (ESRD). As described recently, this acquired immune dysfunction in the uremic milieu may be one of the main pathogenic factors for mortality in ESRD. The aim of this study was to determine the relationship between the immune response following a hepatitis B vaccination (HBV vaccination) and the survival of maintenance dialysis patients. METHODS: A total of 156 patients (103 on hemodialysis and 53 on continuous ambulatory peritoneal dialysis) were recruited. After receiving a full dose of the HBV vaccination, all patients were followed up for to 5 years to evaluate the association of patient survival, cause of mortality, and immune response. RESULTS: The response rate to the hepatitis B vaccination was 70.5%. There was no significant association between the immune response and the 5-year survival rate (p =0.600) or between the post-vaccination anti-HBs titers and the 5-year survival rate (p = 0.201). The logistic prediction model with the coefficient as non-response following HBV vaccination, diabetes mellitus, old age, and low albumin level could significantly predict infection-cause mortality (sensitivity = 0.842, specificity = 0.937). CONCLUSION: There was no significant association between the immune response to HBV vaccination and the 5-year survival rate. However, non-response following HBV vaccination might be associated with infection-cause mortality in dialysis patients. PMID- 22935562 TI - A natural-transmission model of bovine tuberculosis provides novel disease insights. PMID- 22935563 TI - Macroautophagy-aided elimination of chromatin: sorting of waste, sorting of fate? AB - How tumor cells process damaged or unwanted DNA is a matter of much interest. Recently, Rello-Varona et al. (Cell Cycle 2012; 11:170-76) reported the involvement of macroautophagy (hereon autophagy) in the elimination of micronuclei (MN) from osteosarcoma cells. Prior to that, diminution of whole nuclei from multinucleated TP53-mutant tumor cells was described. Here, we discuss these two kinds of chromatin autophagy evoked after genotoxic stress in the context of the various biological processes involved: (1) endopolyploidy and the ploidy cycle; (2) the timing of DNA synthesis; (3) DNA repair; (4) chromatin:nuclear envelope interactions; and (5) cytoplasmic autophagy. We suggest that whereas some MN can be reunited with the main nucleus (through interactions with envelope-limited chromatin sheets) and participate in DNA repair, failure of repair serves as a signal for the chromatin autophagy of MN. In turn, autophagy of whole sub-nuclei in multi-nucleated cells appears to favor de-polyploidization, mitigation of aneuploidy with its adverse effects, thereby promoting the survival fitness of descendents and treatment resistance. Thus, both kinds of chromatin autophagy provide tumor cells with the opportunity to repair DNA, sort and resort chromatin, reduce DNA content, and enhance survival. PMID- 22935565 TI - Urinary ketone is associated with the heart failure severity. AB - OBJECTIVES: To test the hypothesis that urinary metabolites characterizing heart failure (HF) are associated with the magnitude of echocardiographic measurements and ultimately the severity of HF. DESIGN/METHODS: Patients with systolic HF (n=46) and control subjects (n=32) participated in this study. Patients with type 2 diabetes mellitus were excluded. Echocardiographic measurements were performed, and selected urinary metabolites were quantified. RESULTS: Urinary levels of acetate (p<0.05), acetone (p<0.01), cytosine (p<0.001), methylmalonate (p<0.001), and phenylacetylglycine (p<0.01) were significantly higher, while 1 methylnicotinamide (p<0.05) were significantly lower in HF patients than in controls. There were significant differences in E/E' (p<0.05), urinary levels of acetate (p<0.005), acetoacetate (p<0.05), acetone (p<0.05) and ketones (p<0.01) according to the New York Heart Association (NYHA) classification in HF patients. Multiple linear regression analysis revealed that urinary ketones were found to be independent factors for both left ventricular ejection fraction and E/E' after adjusting for confounders. CONCLUSION: Our results showed that urinary levels of ketone bodies are associated with the magnitude of echocardiographic parameters. PMID- 22935566 TI - Serum S100B protein is associated with depressive symptoms in patients with end stage renal disease. AB - OBJECTIVES: Depression is associated with a poorer prognosis in patients with end stage renal disease (ESRD). Increasing evidence indicates that glial pathology and blood-brain-barrier (BBB) dysfunction are involved in the pathophysiology of depression. S100B, a protein expressed in astro- and oligodendroglia in the human brain is considered a biomarker of depression. Our objective was to investigate the relationship between S100B and depressive symptoms in patients undergoing hemodialysis (HD). DESIGN AND METHODS: Seventy-eight Korean patients undergoing chronic HD without significant neurological issues participated in a cross sectional observation study. Depressive symptoms were assessed with the Beck Depression Inventory-II (BDI-II), and serum S100B levels were measured using blood samples obtained prior to a mid-week HD session. RESULTS: The mean age of patients was 59.0 years, and the mean dialysis duration was 51.7 months. About 45% of patients undergoing HD met criteria for depression (BDI-II>=20). Serum S100B levels were significantly higher in patients with depression compared with patients without depression (115.1+/-45.4 vs. 66.1+/-35.3 pg/mL, p<0.001). S100B (r=0.556, p<0.001) and high-sensitivity C-reactive protein (hs-CRP; r=0.422, p<0.001) and beta2-microglobulin (r=0.391, p<0.001) levels were positively correlated with BDI-II scores. A multivariate regression analysis showed that both S100B and hs-CRP were significantly associated with BDI-II scores. CONCLUSIONS: The results showed a close association between S100B and depressive symptoms in patients undergoing HD. However, the mechanisms underlying this relationship are currently unknown and warrant further investigation. PMID- 22935567 TI - Anti-tumour necrosis factor alpha therapy and increased risk of de novo psoriasis: is it really a paradoxical side effect? AB - OBJECTIVES: Tumour necrosis factor (TNF) alpha inhibitors (infliximab, etanercept, adalimumab) revolutionised the treatment of autoimmune diseases such as rheumatoid arthritis (RA), ankylosing spondylitis (AS), Crohn's disease (CD) and plaque psoriasis. During these treatments, cutaneous adverse effects may occur like eczema, lupus, alopecia areata or psoriasis, which represents a paradoxical adverse effect. The aim of this study was to collect and to analyse characteristics and outcomes of psoriasis induced by anti-TNF alpha treatments. METHODS: A search in the French Pharmacovigilance Database was performed between January 2002 and September 2009 using the following terms 'infliximab', 'etanercept', 'adalimumab' combined with the term 'psoriasis'. A literature review was performed utilising PubMed Database and Google scholar using permutations of the following terms 'infliximab', 'etanercept', 'adalimumab', 'tumour necrosis factor-alpha inhibitor' combined with 'psoriasis', 'palmoplantar pustular psoriasis', palmoplantar pustulosis'. Certolizumab pegol and golimumab were approved only recently and so were not included in the search. RESULTS: We found 57 cases in the French Pharmacovigilance Database and 184 cases in the literature. It appeared that the eruptions are most often pustular lesions and occur mainly on palms and/or soles (33.3% in the French Pharmacovigilance Database and 42.9% in the literature), while palmoplantar pustular psoriasis represents only 1.7% of the psoriatic patients. The three anti-TNF-alpha are involved in the psoriasis induction. Half the cases appeared with infliximab. The patients affected by this adverse effect are mostly women aged between 40-50 years old. The time of onset of psoriasis is highly variable. Those patients treated for their psoriasis with TNF-alpha inhibitor developed a psoriasis induced by the treatment with a different localisation and a different morphology from the initial psoriasis while other patients had a recurrence of this side effect with two different TNF-alpha antagonists, then the psoriasis developed with the 2nd anti-TNF alpha is of the same type as the psoriasis developed with the first molecule. CONCLUSIONS: This suggests that psoriasis occurring during anti-TNF alpha therapy are de novo psoriasis and not an aggravation of a pre existing psoriasis. To this day several hypotheses have been proposed to explain the mechanism of action. The occurrence of this adverse effect may call into question the continuation of the treatment which is nevertheless effective. PMID- 22935568 TI - Conditional targeting of tumor necrosis factor receptor-associated factor 6 reveals opposing functions of Toll-like receptor signaling in endothelial and myeloid cells in a mouse model of atherosclerosis. AB - BACKGROUND: Previous studies implicated Toll-like receptor signaling as a critical pathogenic pathway in atherosclerosis, but the cell-specific mechanisms by which Toll-like receptors act to control atherosclerotic plaque development remain poorly understood. METHODS AND RESULTS: To study the cell-specific role of tumor necrosis factor receptor-associated factor 6 (TRAF6) in atherosclerosis, we generated ApoE(-/-) mice with endothelial cell- or myeloid cell-specific TRAF6 deficiency using Cre/LoxP-mediated gene targeting. Endothelial TRAF6 deficiency reduced atherosclerosis in female ApoE(-/-) mice by inhibiting nuclear factor kappaB-dependent proinflammatory gene expression and monocyte adhesion to endothelial cells. In contrast, myeloid cell-specific TRAF6 deficiency caused exacerbated atherosclerosis, with larger plaques containing more necrotic areas in both male and female ApoE(-/-) mice. TRAF6-deficient macrophages showed impaired expression of the antiinflammatory and atheroprotective cytokine interleukin-10, elevated endoplasmic reticulum stress, increased sensitivity to oxidized low-density lipoprotein-induced apoptosis, and reduced capacity to clear apoptotic cells. Thus, the reduced antiinflammatory properties, coupled with increased sensitivity to apoptosis and impaired efferocytosis capacity of TRAF6 deficient macrophages, result in exacerbated atherosclerosis development in TRAF6(MYKO)/ApoE(-/-) mice. CONCLUSION: Toll-like receptor-mediated TRAF6 signaling acts in endothelial cells to promote atherosclerosis but displays atheroprotective, antiinflammatory and prosurvival functions in myeloid cells. PMID- 22935569 TI - A prospective, randomized clinical trial of hemodynamic support with Impella 2.5 versus intra-aortic balloon pump in patients undergoing high-risk percutaneous coronary intervention: the PROTECT II study. AB - BACKGROUND: Although coronary artery bypass grafting is generally preferred in symptomatic patients with severe, complex multivessel, or left main disease, some patients present with clinical features that make coronary artery bypass grafting clinically unattractive. Percutaneous coronary intervention with hemodynamic support may be feasible for these patients. Currently, there is no systematic comparative evaluation of hemodynamic support devices for this indication. METHODS AND RESULTS: We randomly assigned 452 symptomatic patients with complex 3 vessel disease or unprotected left main coronary artery disease and severely depressed left ventricular function to intra-aortic balloon pump (IABP) (n=226) or Impella 2.5 (n=226) support during nonemergent high-risk percutaneous coronary intervention. The primary end point was the 30-day incidence of major adverse events. A 90-day follow-up was required, as well, by protocol. Impella 2.5 provided superior hemodynamic support in comparison with IABP, with maximal decrease in cardiac power output from baseline of -0.04+/-0.24 W in comparison with -0.14+/-0.27 W for IABP (P=0.001). The primary end point (30-day major adverse events) was not statistically different between groups: 35.1% for Impella 2.5 versus 40.1% for IABP, P=0.227 in the intent-to-treat population and 34.3% versus 42.2%, P=0.092 in the per protocol population. At 90 days, a strong trend toward decreased major adverse events was observed in Impella 2.5-supported patients in comparison with IABP: 40.6% versus 49.3%, P=0.066 in the intent-to treat population and 40.0% versus 51.0%, P=0.023 in the per protocol population, respectively. CONCLUSIONS: The 30-day incidence of major adverse events was not different for patients with IABP or Impella 2.5 hemodynamic support. However, trends for improved outcomes were observed for Impella 2.5-supported patients at 90 days. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00562016. PMID- 22935570 TI - Complete locked-in syndrome: what's in a name? PMID- 22935571 TI - Being completely locked-in: neurophenomenology and the ethical challenge posed. PMID- 22935572 TI - Self-awareness and health-related quality of life after traumatic brain injury. AB - OBJECTIVE: To investigate the relations among self-awareness (SA), impaired SA, and health-related quality of life (HRQOL) after traumatic brain injury (TBI). PARTICIPANTS: One hundred forty-one adults hospitalized with TBI and their significant others from a cross-sectional multicenter study. Using Glasgow Coma Scale classification, 32 participants had severe injuries, 29 moderate, 44 mild, and 25 complicated mild TBI. MEASURES: Patient Competency Rating Scale for Neurorehabilitation; Short Form-36 Health Survey; Cognitive Quality of Life; Quality Of Life after Brain Injury; Hospital Anxiety and Depression Scale; Profile of Mood States; Glasgow Outcome Scale Extended. METHOD: Patient Competency Rating Scale for Neurorehabilitation ratings made by participants and their significant others were used to assess SA and discrepancies between the 2 ratings were used to define impaired SA. RESULTS: Significant associations were identified between SA and HRQOL, anxiety, depression, and severity of injury. Participants with and without impaired SA differed in cognitive HRQOL and leisure activities. Using multiple regression, no direct predictors of SA were identified, although interaction effects were observed. CONCLUSION: After TBI, lower SA is associated with higher estimates of HRQOL, particularly in the cognitive domain. Although the associations are modest, the assessment of SA should play a role in the interpretation of reported HRQOL after TBI. PMID- 22935573 TI - Predictors of inpatient and outpatient healthcare utilization in veterans with traumatic brain injury. AB - OBJECTIVE: Traumatic brain injury (TBI) can place a significant financial and resource burden on healthcare systems. This study examined predictors of outpatient and inpatient healthcare utilization in veterans with a history of TBI. METHODS: A secondary analysis was conducted on data from 1565 veterans with TBI and 1565 veterans without TBI seen for healthcare services at the VA Palo Alto Health Care System between 2000 and 2010. Patterns and predictors of outpatient and inpatient medical and psychiatric care were examined. RESULTS: Veterans with TBI utilized significantly more services compared with the control group. The TBI group was seen for more than 160 000 outpatient services and was almost 9 times more likely to be hospitalized than the control group. Although psychiatric disorders were more prevalent in the TBI group and associated with increased medical and mental health utilization within the TBI group, they did not account fully for the significant group differences. CONCLUSIONS: Veterans with a history of TBI have much greater healthcare needs than veterans without TBI, likely because of non-TBI-related factors. Increased monitoring and early intervention treatments may be warranted for certain at-risk veterans with the goal of minimizing their need for long-term or extensive healthcare services in the future. PMID- 22935574 TI - Adolescents' internalizing problems following traumatic brain injury are related to parents' psychiatric symptoms. AB - BACKGROUND: A small body of previous research has demonstrated that pediatric traumatic brain injury (TBI) increases risk for internalizing problems, but findings have varied regarding their predictors and correlates. METHODS: We examined the level and correlates of internalizing symptoms in 130 teens who had sustained a complicated mild to severe TBI within the past 1 to 6 months. Internalizing problems were measured via both maternal- and paternal-report Child Behavior Checklist. We also measured family functioning, parent psychiatric symptoms, and postinjury teen neurocognitive function. RESULTS: Mean parental ratings of internalizing problems were within the normal range. Depending on informant, 22% to 26% of the sample demonstrated clinically elevated internalizing problems. In multiple and binary logistic regression models, only parent psychiatric symptoms consistently provided unique prediction of teen internalizing symptoms. For maternal but not paternal report, female gender was associated with greater internalizing problems. CONCLUSION: Parent and teen emotional problems are associated following adolescent TBI. Possible reasons for this relationship, including the effects of TBI on the family unit, are discussed. PMID- 22935575 TI - Ventilatory anaerobic thresholds of individuals recovering from traumatic brain injury compared with noninjured controls. AB - OBJECTIVE: The purpose of this study was to compare the peak aerobic capacities and ventilatory anaerobic thresholds (VAT) of individuals with a traumatic brain injury (TBI) to age- and gender-matched controls. METHODS: Nineteen participants that previously suffered a mild to moderate TBI and 19 apparently healthy controls volunteered as subjects. Traumatic brain injury and healthy controls were matched for age and gender and were similar in weight and body mass index. Volunteers performed a maximal graded treadmill test to volitional failure where oxygen consumption ((Equation is included in full-text article.)O2), carbon dioxide production ((Equation is included in full-text article.)CO2, ventilation ((Equation is included in full-text article.)E, and heart rate were measured continuously. From metabolic and ventilatory data, VAT was measured using a previously described method. VAT and peak exercise responses of participants with a TBI were compared with healthy controls. RESULTS: The (Equation is included in full-text article.)O2, and (Equation is included in full-text article.)CO2 at VAT and peak exercise were lower for TBI compared with healthy controls. (Equation is included in full-text article.)E was also lower for TBI at VAT and peak exercise. Heart rate was lower for TBI at VAT; however, TBI had similar heart rate to healthy controls at peak exercise. CONCLUSIONS: The VAT and peak exercise capacities of participants with a TBI were below the metabolic demands of many routine daily activities. The data suggest that therapeutic interventions for individuals with a TBI should include targeted exercise prescriptions to improve cardiorespiratory fitness. PMID- 22935576 TI - Extra-pulmonary tuberculosis developing at sites of previous trauma. AB - We describe five individuals in whom extra-pulmonary tuberculosis appeared to localise at a site of previous blunt injury. We review other similar case reports where preceding trauma was blunt and non-penetrating, and discuss a possible mechanism involving transport of mycobacteria in monocytes to sites of injury during "latent" tuberculosis infection. This challenges the conventional model proposed for mycobacteria dissemination in tuberculosis disease. PMID- 22935577 TI - Recombinant human TSH versus thyroid hormone withdrawal. PMID- 22935578 TI - Comparative evaluation of 18F-labeled glutamic acid and glutamine as tumor metabolic imaging agents. AB - (18)F-labeled (2S,4R)-4-fluoro-l-glutamine (4F-GLN) has demonstrated high uptake in tumor cells that undergo high growth and proliferation. Similar tumor targeting properties have also been observed for (18)F-labeled (2S,4R)-4-fluoro-l glutamate (4F-GLU), suggesting that both are useful imaging agents. A new labeling procedure facilitates the preparation of (18)F-(2S,4R)4F-GLN and (18)F (2S,4R)4F-GLU with confirmed radiochemical and enantiomeric purity. Here, we report the preparation and comparative evaluation of (18)F-(2S,4R)4F-GLN and (18)F-(2S,4R)4F-GLU as tumor metabolic imaging agents. METHODS: Uptake of enantiomerically pure (18)F-(2S,4R)4F-GLN and (18)F-(2S,4R)4F-GLU was determined in 3 tumor cell lines (9L, SF188, and PC-3) at selected time points. The in vitro cell uptake mechanism was evaluated by inhibition studies in 9L cells. In vivo biodistribution and PET studies were performed on male F344 rats bearing 9L tumor xenografts. RESULTS: In vitro cell uptake studies showed that (18)F-(2S,4R)4F-GLN displayed higher uptake than (18)F-(2S,4R)4F-GLU. Amino acid transport system ASC (alanine-serine-cysteine-preferring; in particular, its subtype ASCT2 [SLC1A5 gene]) and system X(c)(-) (SLC7A11 gene) played an important role in transporting (18)F-(2S,4R)4F-GLN and (18)F-(2S,4R)4F-GLU, respectively, across the membrane. After being transported into cells, a large percentage of (18)F-(2S,4R)4F-GLN was incorporated into protein, whereas (18)F-(2S,4R)4F-GLU mainly remained as the free amino acid in its original form. In vivo studies of (18)F-(2S,4R)4F-GLN in the 9L tumor model showed a higher tumor uptake than (18)F-(2S,4R)4F-GLU, whereas (18)F-(2S,4R)4F-GLU had a slightly higher tumor-to-background ratio than (18)F (2S,4R)4F-GLN. Imaging studies showed that both tracers had fast accumulation in 9L tumors. Compared with (18)F-(2S,4R)4F-GLU, (18)F-(2S,4R)4F-GLN exhibited prolonged tumor retention reflecting its incorporation into intracellular macromolecules. CONCLUSION: Differences in uptake and metabolism in tumor cells were found between (18)F-(2S,4R)4F-GLN and (18)F-(2S,4R)4F-GLU. Both agents are potentially useful as metabolic tracers for tumor imaging. PMID- 22935579 TI - Influence of HIV infection on the clinical presentation and outcome of adults with acute community-acquired pneumonia in Yaounde, Cameroon: a retrospective hospital-based study. AB - BACKGROUND: The impact of HIV infection on the evolution of acute community acquired pneumonia (CAP) is still controversial. The aim of this study was to investigate possible differences in the clinical presentation and in-hospital outcomes of patients with CAP with and without HIV infection in a specialised service in Yaounde. METHODS: Medical files of 106 patients (51 men) aged 15 years and above, admitted to the Pneumology service of the Yaounde Jamot Hospital between January 2008 and May 2012, were retrospectively studied. RESULTS: Sixty two (58.5%) patients were HIV infected. The median age of all patients was 40 years (interquartile range: 31.75-53) and there was no difference in the clinical and radiological profile of patients with and without HIV infection. The median leukocyte count (interquartile range) was 14,600/mm3 (10,900-20,600) and 10,450/mm3 (6,400-16,850) respectively in HIV negative and HIV positive patients (p = 0.002). Median haemoglobin level (interquartile range) was 10.8 g/dl (8.9 12) in HIV negative and 9.7 g/dl (8-11.6) in HIV positive patients (p = 0.025). In-hospital treatment failure on third day (39.5% vs. 25.5.1%, p = 0.137) and mortality rates (9% vs. 14.5%, p = 0.401) were similar between HIV negative and HIV positive patients. CONCLUSION: Clinical and radiological features as well as response to treatment and in hospital fatal outcomes are similar in adult patients hospitalised with acute community-acquired pneumonia in Yaounde. In contrast, HIV infected patients tend to be more anaemic and have lower white cell counts than HIV negative patients. Larger prospective studies are needed to consolidate these findings. PMID- 22935580 TI - Overestimation of carboplatin doses is avoided by radionuclide GFR measurement. AB - BACKGROUND: Glomerular filtration rate (GFR) is used in the calculation of carboplatin dose. Glomerular filtration rate is measured using a radioisotope method (radionuclide GFR (rGFR)), however, estimation equations are available (estimated GFR (eGFR)). Our aim was to assess the accuracy of three eGFR equations and the subsequent carboplatin dose in an oncology population. PATIENTS AND METHODS: Patients referred for an rGFR over a 3-year period were selected; eGFR was calculated using the Modification of Diet in Renal Disease (MDRD), Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) and Cockcroft-Gault (CG) equations. Carboplatin doses were calculated for those patients who had received carboplatin chemotherapy. Bias, precision and accuracy were examined. RESULTS: Two hundred and eighty-eight studies met the inclusion/exclusion criteria. Paired t-tests showed significant differences for all three equations between rGFR and eGFR with biases of 12.3 (MDRD), 13.6 (CKD-EPI) and 7.7 ml min( 1) per 1.73 m(2) (CG). An overestimation in carboplatin dose was seen in 81%, 87% and 66% of studies using the MDRD, CKD-EPI and CG equations, respectively. CONCLUSION: The MDRD and CKD-EPI equations performed poorly compared with the reference standard rGFR; the CG equation showed smaller bias and higher accuracy in our oncology population. On the basis of our results we recommend that the rGFR should be used for accurate carboplatin chemotherapy dosing and where unavailable the use of the CG equation is preferred. PMID- 22935581 TI - Association between treatment effects on disease progression end points and overall survival in clinical studies of patients with metastatic renal cell carcinoma. AB - BACKGROUND: The relationship between progression-free survival and time to progression (PFS/TTP) and overall survival (OS) has been demonstrated in a variety of solid tumours but not in metastatic renal cell carcinoma (mRCC). METHODS: A systematic literature search was conducted to identify controlled trials of cytokine or targeted therapies for mRCC reporting information on treatment effects on PFS/TTP and OS for one or more comparison. The associations between treatment effects on PFS/TTP and OS were analysed using linear regression. RESULTS: Thirty-one studies representing 10943 patients, 75 treatment groups, and 41 comparisons were identified. The correlation coefficient between the negative log of the hazard ratio (HR) for PFS/TTP (-ln HR(PFS/TTP)) vs the negative log of the HR for OS (-ln HR(OS)) was 0.80 (P<0.0001). In linear regression, the coefficient on -ln HR(PFS/TTP) vs -ln HR(OS) was 0.64 (95% confidence interval (CI): 0.470.81; R(2)=0.63), suggesting each 10% relative risk reduction (RRR) for PFS/TTP was associated with a 6% RRR for OS. A 1-month gain in median PFS/TTP was associated with a 1.17-month gain in median OS (95% CI: 0.59,1.76; R(2)=0.28). CONCLUSION: In trials of treatments for mRCC, treatment effects on PFS/TTP are strongly associated with treatment effects on OS. PMID- 22935582 TI - Does tumour biology determine surgical success in the treatment of epithelial ovarian cancer? A systematic literature review. AB - BACKGROUND: Ovarian cancer is the most lethal gynaecological cancer. Progression free and overall survival is significantly related to surgical success and residual disease volume. It is unclear whether this survival advantage is due to an intrinsic biological element of the tumour cells which enables successful surgery and improved prognosis, or alternatively the number of tumour sustaining cells remaining irrespective of differences in biology. METHODS: A systematic review of the literature was performed identifying studies that have investigated the association between biomarkers and surgical outcomes. We attempted validation of these results using The Cancer Genome Atlas ovarian cancer data sets. RESULTS: Thirty studies were identified of which sixteen determined protein expression, eight gene expression and one DNA methylation in association with surgical debulking. Individualised linear models adjusting for batch, stage and age identified only expression of the genes MTDH and insulin-like growth factor-1 receptor (IGF1R) to be significantly associated with debulking surgery (P<0.05, false discovery rate (FDR)<5%), although in the case of IGF1R this was in the opposite direction to previous findings. CONCLUSION: The majority of studies are limited by design, include heterogeneous samples and lack adjustment for major confounding factors. High quality detailed clinical annotations should be routinely collected in future to more accurately evaluate biomarkers of surgical outcome. PMID- 22935583 TI - Safety, tolerability, pharmacokinetics and pharmacodynamics of AZD8055 in advanced solid tumours and lymphoma. AB - BACKGROUND: This study assessed the safety, tolerability, pharmacokinetics and pharmacodynamics of the first-in-class dual mammalian target of rapamycin complex (mTORC)1/mTORC2 inhibitor, AZD8055. METHODS: Patients with advanced solid malignancies or lymphomas were recruited into this phase I, open-label, dose escalation study of AZD8055 starting at 10 mg twice-daily oral dosing (BID). RESULTS: Forty-nine patients received AZD8055. Dose-limiting toxicities were reported at 40 mg (n=1), 90 mg (n=1) and 120 mg (n=3) BID; all were grade 3 rises in transaminases, reversible in all patients, apart from one who had liver metastases. The maximum tolerated dose was defined as 90 mg BID. The most frequent adverse events assessed to be related to AZD8055 were increased alanine aminotransferase (22%), increased aspartate aminotransferase (22%) and fatigue (16%). AZD8055 was rapidly absorbed (median t(max) ~0.5 h) and exposure increased with increasing doses. Seven patients had stable disease for >= 4 months. Partial metabolic responses, assessed by fluorodeoxyglucose positron emission tomography, were observed at >= 40 mg BID (n=8 at day 35). CONCLUSION: The maximum tolerated dose for AZD8055 is 90 mg BID. Apart from elevated transaminases, which occurred at most dose levels, the drug had an acceptable toxicity profile; however, no RECIST responses were seen. PMID- 22935584 TI - Oxaliplatin/capecitabine vs oxaliplatin/infusional 5-FU in advanced colorectal cancer: the MRC COIN trial. AB - BACKGROUND: COIN compared first-line continuous chemotherapy with the same chemotherapy given intermittently or with cetuximab in advanced colorectal cancer (aCRC). METHODS: Choice between oxaliplatin/capecitabine (OxCap) and oxaliplatin/leucovorin (LV)/infusional 5-FU (OxFU) was by physician and patient choice and switching regimen was allowed. We compared OxCap with OxFU and OxCap+cetuximab with OxFU+cetuximab retrospectively in patients and examined efficacy, toxicity profiles and the effect of mild renal impairment. RESULTS: In total, 64% of 2397 patients received OxCap(+/- cetuximab). Overall survival, progression free survival and overall response rate were similar between OxCap and OxFU but rate of radical surgeries was higher for OxFU. Progression free survival was longer for OxFU+cetuximab compared with OxCap+cetuximab but other efficacy measures were similar. Oxaliplatin/LV/infusional 5-FU (+/- cetuximab) was associated with more mucositis and infection whereas OxCap(+/- cetuximab) caused more gastrointestinal toxicities and palmar-plantar erythema. In total, 118 patients switched regimen, mainly due to toxicity; only 16% came off their second regimen due to intolerance. Patients with creatinine clearance (CrCl) 50 80 ml min(-1) on OxCap(+/- cetuximab) or OxFU+cetuximab had more dose modifications than those with better renal function. CONCLUSIONS: Overall, OxFU and OxCap are equally effective in treating aCRC. However, the toxicity profiles differ and switching from one regimen to the other for poor tolerance is a reasonable option. Patients with CrCl 50-80 ml min(-1) on both regimens require close toxicity monitoring. PMID- 22935585 TI - Novel targeted therapies for eosinophilic disorders. AB - Hypereosinophilic syndromes (HESs) are a diverse group of conditions characterized by clinical manifestations attributable to eosinophilia and eosinophilic infiltration of tissues. HESs are chronic disorders with significant morbidity and mortality. Although the availability of targeted chemotherapeutic agents, including imatinib, has improved quality of life and survival in some patients with HESs, additional agents with increased efficacy and decreased toxicity are sorely needed. The purpose of this review is to provide an overview of eosinophil biology with an emphasis on potential targets of pharmacotherapy and to provide a summary of potential eosinophil-targeting agents, including those in development, in clinical trials, or approved for other disorders. PMID- 22935587 TI - Workshop report from the National Institutes of Health Taskforce on the Research Needs of Eosinophil-Associated Diseases (TREAD). AB - BACKGROUND: Eosinophils are blood cells that are often found in high numbers in the tissues of allergic conditions and helminthic parasite infections. The pathophysiologic roles that eosinophils may serve in other human "eosinophil associated" diseases remain obscure. OBJECTIVE: National Institutes of Health (NIH) Institutes and the Office of Disease Prevention assembled an international taskforce of clinical and basic scientists with the charge to propose and prioritize unmet research needs in eosinophil-associated diseases. METHODS: The taskforce used an organ system approach to identify the different and common themes of eosinophil cell involvement in these diseases. In early 2012, a draft document was circulated for review. The document was amended and the prioritizations were set at a NIH-organized workshop in June 2012. RESULTS: The taskforce identified significant research needs. These needs cross disease entities but some are disease specific. There are substantial shortcomings to the various preclinical animal models, as well as significant gaps in our epidemiologic, pathophysiologic, diagnostic, prognostic, and therapeutic knowledge. The taskforce recognized that recent efforts by patient advocacy groups have played instrumental roles in improving the identification and characterization of these disorders. However, communications among the eosinophil interested communities, for example, governmental funding and regulatory agencies, and industry and clinician scientists need to be more comprehensive. CONCLUSIONS: Significant efforts are required to address our knowledge gaps to improve the outcomes of eosinophil-associated diseases. NIH Institutes, other federal agencies, lay organizations, and the pharmaceutical industry should consider the taskforce's recommendations in their future research activities. PMID- 22935588 TI - Working with the US Food and Drug Administration: progress and timelines in understanding and treating patients with eosinophilic esophagitis. PMID- 22935590 TI - Serum periostin as a marker of T(H)2-dependent eosinophilic airway inflammation. PMID- 22935586 TI - Human versus mouse eosinophils: "that which we call an eosinophil, by any other name would stain as red". AB - The respective life histories of human subjects and mice are well defined and describe a unique story of evolutionary conservation extending from sequence identity within the genome to the underpinnings of biochemical, cellular, and physiologic pathways. As a consequence, the hematopoietic lineages of both species are invariantly maintained, each with identifiable eosinophils. This canonical presence nonetheless does not preclude disparities between human and mouse eosinophils, their effector functions, or both. Indeed, many books and reviews dogmatically highlight differences, providing a rationale to discount the use of mouse models of human eosinophilic diseases. We suggest that this perspective is parochial and ignores the wealth of available studies and the consensus of the literature that overwhelming similarities (and not differences) exist between human and mouse eosinophils. The goal of this review is to summarize this literature and in some cases provide experimental details comparing and contrasting eosinophils and eosinophil effector functions in human subjects versus mice. In particular, our review will provide a summation and an easy-to-use reference guide to important studies demonstrating that although differences exist, more often than not, their consequences are unknown and do not necessarily reflect inherent disparities in eosinophil function but instead species-specific variations. The conclusion from this overview is that despite nominal differences, the vast similarities between human and mouse eosinophils provide important insights as to their roles in health and disease and, in turn, demonstrate the unique utility of mouse-based studies with an expectation of valid extrapolation to the understanding and treatment of patients. PMID- 22935591 TI - Crosstalk of regulatory T cells and tolerogenic dendritic cells prevents contact allergy in subjects with low zone tolerance. AB - BACKGROUND: Allergic contact dermatitis is one of the most common occupational diseases. A main protective mechanism in those who do not develop allergic contact dermatitis is tolerance induction by repeated exposure to low doses of contact allergen, which is termed low zone tolerance (LZT). The mechanisms that determine the tolerance induction in subjects with LZT are still elusive. OBJECTIVE: We performed analysis of the role of CD4(+)CD25(+) forkhead box protein 3 (FOXP3)-positive regulatory T (Treg) cells and dendritic cells (DCs) in mice with LZT. METHODS: Mechanisms of tolerance induction were analyzed in a murine model of LZT by using FOXP3 and IL-10 reporter mice, as well as mice that allow the selective depletion of Treg cells or DCs. RESULTS: Depletion of CD4(+)CD25(+)FOXP3(+) Treg cells during tolerance induction completely abolishes the development of LZT, resulting in a pronounced contact hypersensitivity response. Adoptive transfer experiments, depletion studies, and use of cell type specific deficient mice revealed that IL-10 production is critical for the suppressor function of Treg cells in mice with LZT and that tolerogenic CD8(+)CD11c(+) DCs located in the skin-draining lymph nodes are essential for LZT. In the absence of Treg cells, DCs did not develop tolerogenic functions, indicating that activated IL-10(+) Treg cells might imprint the tolerogenic DC phenotype. Cell communication analysis revealed that the education of tolerogenic DCs might involve a direct interaction with Treg cells mediated by gap junctions. Subsequently, induction of tolerogenic CD11c(+) DCs leads to the generation of hapten-specific CD8(+) Treg cells, which protect against contact hypersensitivity. CONCLUSIONS: Our data demonstrate critical interactions between CD4(+)CD25(+)FOXP3(+) Treg cells and tolerogenic CD8(+)CD11c(+) DCs during the induction of LZT. PMID- 22935592 TI - The adult with chronic cough. PMID- 22935593 TI - Cigarette smoking influences the clinical and occupational outcome of patients with tibial shaft fractures. PMID- 22935595 TI - Effect of both deposition temperature and indium doping on the properties of sol gel dip-coated SnO2 films. AB - Using indium chloride as an In source, In-doped SnO(2) films were fabricated by sol-gel method through dip-coating on borofloat glass substrates. The undoped SnO(2) films were deposited in air between 400 and 600 degrees C to get optimum deposition temperature in terms of crystal quality and hence In-doped SnO(2) films were deposited in air at 600 degrees C. The effect of both deposition temperature and In content on structural, morphological, optical and electrical properties was investigated. The crystalline structure and orientation of the films were investigated by X-ray diffraction (XRD) and surface morphology was studied by a field emission scanning electron microscope (FESEM). The compositional analysis of the films was confirmed by energy dispersive X-ray spectrometer (EDS). The absorption band edge of the SnO(2) films shifted from 3.88 to 3.66 eV with In content. The van der Pauw method was used to measure the sheet resistance of the films. The sheet resistance was affected significantly by deposition temperature and In content. PMID- 22935596 TI - Synthesis, characterization, equilibrium study and biological activity of Cu(II), Ni(II) and Co(II) complexes of polydentate Schiff base ligand. AB - Schiff base ligand, 1,4-bis[(2-hydroxybenzaldehyde)propyl]piperazine (BHPP), and its Cu(II), Ni(II) and Co(II) metal complexes were synthesized and characterized by elemental analysis, magnetic susceptibility, molar conductance and spectral (IR and UV-vis) studies. The ground state of BHPP ligand was investigated using the BUILDER module of MOE. Metal complexes are formed in the 1:1 (M:L) ratio as found from the elemental analysis and found to have the general formula [ML].nH(2)O, where M=Co(II), Ni(II) and Cu(II), L=BHPP. In all the studied complexes, the (BHPP) ligand behaves as a hexadentate divalent anion with coordination involving the two azomethine nitrogen's, the two nitrogen atoms of piperazine ring and the two deprotonated phenolic OH-groups. The magnetic and spectral data indicates octahedral geometry of metal(II) complexes. The ligand and their metal chelates have been screened for their antimicrobial activities using the disc diffusion method against the selected bacteria and fungi. They were found to be more active against Gram-positive than Gram-negative bacteria. Protonation constants of (BHPP) ligand and stability constants of its Cu(2+), Co(2+) and Ni(2+) complexes were determined by potentiometric titration method in 50% DMSO-water solution at ionic strength of 0.1 M sodium nitrate. It has been observed that the protonated Schiff base ligand (BHPP) have four protonation constants. The divalent metal ions Cu(2+), Ni(2+) and Co(2+) form 1:1 complexes. PMID- 22935594 TI - Sarcopenia, obesity, and natural killer cell immune senescence in aging: altered cytokine levels as a common mechanism. AB - Human aging is characterized by both physical and physiological frailty. A key feature of frailty, sarcopenia is the age-associated decline in skeletal muscle mass, strength, and endurance that characterize even the healthy elderly. Increases in adiposity, particularly in visceral adipose tissue, are almost universal in aging individuals and can contribute to sarcopenia and insulin resistance by increasing levels of inflammatory cytokines known collectively as adipokines. Aging also is associated with declines in adaptive and innate immunity, known as immune senescence, which are risk factors for cancer and all cause mortality. The cytokine interleukin-15 (IL-15) is highly expressed in skeletal muscle tissue and declines in aging rodent models. IL-15 inhibits fat deposition and insulin resistance, is anabolic for skeletal muscle in certain situations, and is required for the development and survival of natural killer (NK) lymphocytes. We review the effect that adipokines and myokines have on NK cells, with special emphasis on IL-15. We posit that increased adipokine and decreased IL-15 levels during aging constitute a common mechanism for sarcopenia, obesity, and immune senescence. PMID- 22935597 TI - Comparative analysis of the retinal microvasculature visualized with fluorescein angiography and the retinal function imager. AB - PURPOSE: To assess the visualization of the retinal microvasculature with intravenous fluorescein angiography (IVFA) compared to the Retinal Function Imager (RFI). DESIGN: Multicenter, retrospective, observational case series. METHODS: Seven normal eyes and 26 eyes with various ocular diseases were imaged with both IVFA and the RFI. The ability to assess vessel loops, vertical collateral vessels, the size of the foveal avascular zone (FAZ), and degree of vessel branching were compared between IVFA and RFI images. RESULTS: The RFI visualized a greater number of vessel loops (1.3 vs 0.4 per eye) and vertical collateral vessels (4.42 vs 0.97 per eye) than IVFA. On average, higher order of vessel branching was seen with the RFI compared to IVFA (5.2 vs 4.6). The foveal avascular zone (FAZ) was more clearly delineated using the RFI and was significantly smaller when measured on RFI (0.35 vs 0.75 mm(2)). CONCLUSIONS: RFI, a noninvasive retinal imaging instrument, revealed vessel loops, vertical collateral vessels, the area of the FAZ, and order of vessel branching in greater detail than IVFA. This instrument may be helpful in understanding dynamic retinal vascular changes in a number of common ocular diseases, as well as in normal eyes. PMID- 22935598 TI - Wide-field retinal imaging in the management of noninfectious posterior uveitis. AB - PURPOSE: To determine whether the use of ultra wide-field imaging changes the management or determination of disease activity in patients with noninfectious posterior uveitis. DESIGN: Prospective, observational case series. METHODS: setting: Divisions of Retina and Ocular Immunology at single academic medical center. patient population: Total of 43 patients with noninfectious posterior uveitis seen by 4 investigators at the Wilmer Eye Institute. procedures: Each patient underwent standard clinical examination, followed by ultra wide-field scanning laser ophthalmoscope (SLO) imaging and angiography. Investigators successively determined disease activity and management decisions based on clinical examination, examination plus simulated 30- or 60-degree fluorescein angiography (FA) (obtained by physically narrowing the field of view of the wide field images), examination plus ultra wide-field SLO images, and examination plus wide-field FA. main outcome measures: The primary outcome was the percentage of patients whose management changed based on the availability of wide-field imaging, compared with standard examination and imaging. The secondary outcome was detection of disease activity with and without wide-angle imaging. RESULTS: Management was altered in 7 of 43 patients (16%) based on examination and limited FA, whereas 21 of 43 patients (48%) had management change with the use of the ultra wide-field imaging and angiography (P < .001). Disease activity was detected in 22 of 43 patients (51%) based on examination and simulated conventional imaging, and in 27 of 43 (63%) with wide-field imaging (P = .27). CONCLUSIONS: The index study, with several design limitations, has suggested that ultra wide-field imaging may alter management decisions compared to standard-of care imaging and clinical examination. Additional studies, including longitudinal evaluations, are needed to determine whether these findings, or the subsequent management alterations, may improve patient outcomes. PMID- 22935599 TI - Childhood pterygium: a descriptive study of 19 cases presented to a tertiary eye care center. AB - PURPOSE: To describe the demographic features, clinical characteristics, and management in cases of childhood pterygium. DESIGN: Observational case series. METHODS: A retrospective review was done of 19 children (total 26 eyes) under the age of 16 years, consecutively presenting with pterygium and evaluated at a single tertiary care center between January 2000 and August 2011. The main outcome measures were clinical features, associated ocular or systemic diseases, approach towards its management, and histopathology of operated cases. RESULTS: Of the 19 patients, 10 were girls and 9 were boys. The mean age at presentation was 10.63 +/- 3.48 years (range 2-15 years). Seven patients (37%) had bilateral involvement. None of the cases had familial history. The median refractive astigmatism was found to be -0.5 diopter cylinder. All the eyes had primary pterygium, except 1, which was recurrent. The majority of the eyes (85%) were managed conservatively. Four eyes (15%) required surgery, where pterygium excision with conjunctival-limbal autograft with fibrin glue application was done. The follow-up of surgical cases ranged from 5 to 38 months (median 6 months). One operated case recurred 1 year after surgery. CONCLUSION: Development of pterygium is a possibility in younger age groups. No specific predisposing factors, either environmental or familial, were identified as contributing to childhood pterygium. The majority of the cases required conservative management. PMID- 22935600 TI - Histologic development of the human fovea from midgestation to maturity. AB - PURPOSE: To describe the histologic development of the human central retina from fetal week (Fwk) 22 to 13 years. DESIGN: Retrospective observational case series. METHODS: Retinal layers and neuronal substructures were delineated on foveal sections of fixed tissue stained in azure II-methylene blue and on frozen sections immunolabeled for cone, rod, or glial proteins. Postmortem tissue was from 11 eyes at Fwk 20-27; 8 eyes at Fwk 28-37; 6 eyes at postnatal 1 day to 6 weeks; 3 eyes at 9 to 15 months; and 5 eyes at 28 months to 13 years. RESULTS: At Fwk 20-22 the fovea could be identified by the presence of a single layer of cones in the outer nuclear layer. Immunolabeling detected synaptic proteins, cone and rod opsins, and Muller glial processes separating the photoreceptors. The foveal pit appeared at Fwk 25, involving progressive peripheral displacement of ganglion cell, inner plexiform, and inner nuclear layers. The pit became wider and shallower after birth, and appeared mature by 15 months. Between Fwk 25 and Fwk 38, all photoreceptors developed more distinct inner and outer segments, but these were longer on peripheral than foveal cones. After birth the foveal outer nuclear layer became much thicker as cone packing occurred. Cone packing and neuronal migration during pit formation combined to form long central photoreceptor axons, which changed the outer plexiform layer from a thin sheet of synaptic pedicles into the thickest layer in the central retina by 15 months. Foveal inner and outer segment length matched peripheral cones by 15 months and was 4 times longer by 13 years. CONCLUSIONS: These data are necessary to understand the marked changes in human retina from late gestation to early adulthood. They provide qualitative and quantitative morphologic information required to interpret the changes in hyper- and hyporeflexive bands in pediatric spectral-domain optical coherence tomography images at the same ages. PMID- 22935601 TI - Effect of timolol on refractive outcomes in eyes with myopic regression after laser in situ keratomileusis: a prospective randomized clinical trial. AB - PURPOSE: To compare the effects of timolol on refractive outcomes in eyes with myopic regression after laser in situ keratomileusis (LASIK) with a control matched group. DESIGN: Prospective, randomized, parallel-controlled, double masked clinical trial. A computer-generated randomization list based on random block permutation (length 4 to 8) was used for treatment allocation. METHODS: setting: Basir Eye Center, Tehran, Iran. PATIENT POPULATION: Of 124 eyes with myopic regression after LASIK using Technolas 217-Z, 45 eyes in each group were analyzed. INTERVENTION: Patients were randomly assigned into either Group 1, who received timolol 0.5% eye drops, or Group 2, who received artificial tears for 6 months. MAIN OUTCOME MEASURE: Spherical equivalent (SE) at 6 months posttreatment. RESULTS: In Group 1, SE improved from -1.48 +/- 0.99 diopter (D) before treatment to -0.88 +/- 0.91 D and -0.86 +/- 0.93 D 6 months after treatment and 6 months after timolol discontinuation, respectively (P < .001). In Group 2, it was -1.57 +/- 0.67 D, -1.83 +/- 0.76 D, and -1.91 +/- 0.70 D, respectively (P < .001). SE was significantly better in Group 1 6 months after treatment and 6 months after discontinuation of treatment (P < .001 for both comparisons). There was a 0.26 D decrease in SE improvement every 4 months after the surgery in the Group 1 (P < .001). CONCLUSIONS: Timolol application is effective for the treatment of myopic regression after LASIK compared with control group. Its effects last for at least 6 months after its discontinuation. PMID- 22935603 TI - Using the health-care matrix to teach and improve patient safety culture in an OB/GYN residency training program. AB - OBJECTIVE: To assess the utility of health-care matrix in teaching patient safety in terms of the Institute of Medicine Aims for health-care improvement and Accreditation Council for Graduate Medical Education competencies. METHODS: As part of residency education, health-care matrix conference is held monthly. A multidisciplinary team is invited. Residents choose cases and develop a draft matrix under faculty supervision. The matrix is presented, and consensus action plan is generated after discussion. Approximately 2 years after initiation of the program, residents completed an anonymous 15-item survey. RESULTS: The study included 26 health-care matrix conferences from 2007 to 2009. Main reasons for residents' selection of cases were management issues (42%), bleeding complications (35%), and medication errors (23%). Major contributors to patient safety concerns by Institute of Medicine Aims were timeliness (65%), and those by Accreditation Council for Graduate Medical Education competencies were system issues (77%), medical knowledge (69%), and communication issues (66%).Residents agreed that the program was useful. No resident thought that the program should be cancelled. Only 39% feel their communication skills were improved, 48% felt that preparation was time consuming, and 29% felt awkward presenting errors of superiors. Review of action plans developed after each matrix showed that implementation of recommendations was initiated in 92% of the cases. CONCLUSIONS: The health-care matrix curriculum can be used to teach patient safety culture, assess system processes, and improve patient care. This report highlights the importance of system issues, timeliness, medical knowledge, and communication for patient safety concerns. PMID- 22935602 TI - Predictor of poor coronary collaterals in chronic kidney disease population with significant coronary artery disease. AB - BACKGROUND: Coronary collateral circulation plays an important role to protect myocardium from ischemia, preserve myocardial contractility and reduce cardiovascular events. Chronic kidney disease (CKD) is associated with poor coronary collateral development and cardiovascular outcome. However, limited research investigates the predictors for collateral development in the CKD population. METHODS: We evaluated 970 consecutive patients undergoing coronary angiography and 202 patients with CKD, defined as a glomerular filtration rate less than 60 ml/min/1.73 m2, were finally analyzed. The collateral scoring system developed by Rentrop was used to classify patients into poor (grades 0 and 1) or good (grades 2 and 3) collateral group. RESULTS: The patients with poor collateral (n = 122) had a higher incidence of hypertension (82% vs 63.8%, p = 0.005), fewer diseased vessels numbers (2.1 +/- 0.9 vs 2.6 +/- 0.6, p < 0.001) and a trend to be diabetic (56.6% vs. 43.8%, p = 0.085) or female sex (37.7% vs. 25.0%, p = 0.067). Multivariate analysis showed hypertension (odd ratio (OR) 2.672, p = 0.006), diabetes (OR 1.956, p = 0.039) and diseased vessels numbers (OR 0.402, p < 0.001) were significant predictors of poor coronary collaterals development. Furthermore, hypertension and diabetes have a negative synergistic effect on collateral development (p = 0.004 for interaction). CONCLUSIONS: In the CKD population hypertension and diabetes might negatively influence the coronary collaterals development. PMID- 22935604 TI - Duplication of surgical site marking. AB - Wrong-site surgery is a devastating complication, and its avoidance requires uncompromising vigilance. The Joint Commission on Accreditation of Healthcare Organizations has labeled wrong-site surgery as a sentinel event and requires marking the surgical site before initiating an operation. We present a case involving the duplication of a preprocedure mark. A complete review of the patient's medical record averted disaster, but the case emphasizes the need for constant attentiveness by all members of the procedural team. PMID- 22935606 TI - Treatment with paliperidone in children with behavior disorders previously treated with risperidone: an open-label trial. AB - OBJECTIVES: Paliperidone is the main active metabolite of risperidone, with certain pharmacokinetic and tolerability characteristics that suggest it may be used in special groups, such as children. Our purpose is to document the clinical experience with the use of paliperidone in children with severe behavior problems that were partially refractory to treatment with risperidone and psychological treatment. MATERIALS AND METHODS: This is a prospective 16-week open-label study of paliperidone in 18 patients (mean age, 13.4 years) with severe and excessive irritability in the context of generalized developmental disorders or attention deficit/hyperactivity disorder. Patients who had exhibited an inadequate response to treatment with risperidone (1.5-2 mg/d) over a treatment period of 6 months were treated with paliperidone at 3 mg/d. Symptom severity at the beginning of the study and in response to paliperidone were rated with the Clinical Global Impression (CGI) scale and Overt Aggression Scale. RESULTS: A significant difference was documented between the mean score before treatment and the score after the drug intervention with paliperidone. There was a noticeable clinical improvement in 50% of the cases, as reflected in the CGI. Severity of aggressive behavior, as assessed by the Overt Aggression Scale, decreased significantly after paliperidone treatment: mean (SD), 2.7 (0.92) before treatment versus 1.5 (0.60) after treatment. This compound was safe and well tolerated. CONCLUSION: Half of the patients clearly responded to paliperidone extended release. Tolerance to this treatment was distinctly better than to risperidone. These preliminary results lay the foundation for further research into the use of paliperidone to treat pediatric disruptive behavior disorders within the context of randomized, double-blind, controlled clinical trials. PMID- 22935607 TI - A single polyprobe for detecting simultaneously eight pospiviroids infecting ornamentals and vegetables. AB - The spread of viroids belonging to the genus Pospiviroid (family Pospiviroidae), recorded recently in ornamentals and vegetables in several European countries, calls for fast, efficient and sensitive detection methods. Based on bioinformatics analyses of sequence identity among all pospiviroids, a digoxigenin-labeled polyprobe (POSPIprobe) was developed that, when tested by dot blot and Northern-blot hybridization, detected Potato spindle tuber viroid, Citrus exocortis viroid, Columnea latent viroid, Mexican papita viroid, Tomato planta macho viroid, Tomato apical stunt viroid, Pepper chat fruit viroid and Chrysanthemum stunt viroid. The end-point detection limits of the POSPIprobe ranged from 5(-2) to 5(-4), and from 5(-1) to 5(-3) for nucleic acid preparations obtained by phenol extraction and silica-capture, respectively, similar to those of single probes. Based on sequence identity, the POSPIprobe is expected to detect also the two pospiviroid species not tested in this study (Tomato chlorotic dwarf viroid and Iresine viroid-1). Dot-blot assays with the POSPIprobe were validated by testing 68 samples from tomato, chrysanthemum and argyranthemum infected by different pospiviroids as revealed by RT-PCR, thus confirming the potential of this polyprobe for quarantine, certification and survey programs. PMID- 22935608 TI - Impact of TNF-blocking agents on male sperm characteristics and pregnancy outcomes in fathers exposed to TNF-blocking agents at time of conception. AB - OBJECTIVES: Published data were analysed to determine if the use of tumour necrosis factor (TNF) blocking agents in male patients during time of conception is associated with an increased risk of fetal abnormalities or complications during pregnancy. Moreover, we were interested in the impact of TNFblocking agents on sperm quality characteristics. METHODS: We performed a systematic literature review (Medline, online archives of Annual European Congress of Rheumatology and the American College of Rheumatology). One-hundred and thirty nine Articles of potentially relevant reports were identified and screened for retrieval and nine articles were included in the final analysis. RESULTS: Overall, there were sixty cases, where expectant fathers used TNFblocking agents shortly before conception. The outcomes of the pregnancies are documented in twenty-eight events. We did not find any documentation of miscarriages or physical abnormities associated with TNF blocking treatment and paternity; however, we did find documentation evidence that sperm motility and vitality even may improve under TNF-blocking therapy. This improvement may be caused by a decrease in disease activity. CONCLUSIONS: Published data suggest that TNF blocking therapy in male patients during time of conception does not increase the risk of adverse pregnancy outcome. In addition TNF-blocking therapy does not appear to reduce male fertility. PMID- 22935609 TI - The secrets of the Bcl-2 family. AB - The Bcl-2 family of proteins is formed by pro- and antiapoptotic members. Together they regulate the permeabilization of the mitochondrial outer membrane, a key step in apoptosis. Their complex network of interactions both in the cytosol and on mitochondria determines the fate of the cell. In the past 2 decades, the members of the family have been identified and classified according to their function. Several competing models have been proposed to explain how the Blc-2 proteins orchestrate apoptosis signaling. However, basic aspects of the action of these proteins remain elusive. This review is focused on the biophysical mechanisms that are relevant for their action in apoptosis and on the challenging gaps in our knowledge that necessitate further exploration to finally understand how the Bcl-2 family regulates apoptosis. PMID- 22935610 TI - The prolyl-isomerase Pin1 activates the mitochondrial death program of p53. AB - In response to intense stress, the tumor protein p53 (p53) tumor suppressor rapidly mounts a direct mitochondrial death program that precedes transcription mediated apoptosis. By eliminating severely damaged cells, this pathway contributes to tumor suppression as well as to cancer cell killing induced by both genotoxic drugs and non-genotoxic p53-reactivating molecules. Here we have explored the role had in this pathway by the prolyl-isomerase Pin1 (peptidylprolyl cis/trans isomerase, NIMA-interacting 1), a crucial transducer of p53's phosphorylation into conformational changes unleashing its pro-apoptotic activity. We show that Pin1 promotes stress-induced localization of p53 to mitochondria both in vitro and in vivo. In particular, we demonstrate that upon stress-induced phosphorylation of p53 on Ser46 by homeodomain interacting protein kinase 2, Pin1 stimulates its mitochondrial trafficking signal, that is, monoubiquitination. This pathway is induced also by the p53-activating molecule RITA, and we demonstrate the strong requirement of Pin1 for the induction of mitochondrial apoptosis by this compound. These findings have significant implications for treatment of p53-expressing tumors and for prospective use of p53-activating compounds in clinics. PMID- 22935611 TI - 14-3-3-regulated Ca(2+)-dependent protein kinase CPK3 is required for sphingolipid-induced cell death in Arabidopsis. AB - In eukaryotic cells, sphingoid long chain bases (LCBs) such as sphingosine or phytosphingosine (PHS) behave as second messengers involved in various processes including programmed cell death (PCD). In plants, induction of PCD by LCBs has now been described, but the signalling pathway is still enigmatic. Using Arabidopsis, we identify new key steps in this pathway. We demonstrate that PHS induces activation of the calcium-dependent kinase CPK3, which phosphorylates its binding partners, the 14-3-3 proteins. This phosphorylation leads to the disruption of the complex and to CPK3 degradation. Using cpk3 knockout lines, we demonstrate that CPK3 is a positive regulator of LCB-mediated PCD. These findings establish 14-3-3-regulated CPK3 as a key component of the LCB pathway leading to PCD in plants. PMID- 22935612 TI - Identification of factors that function in Drosophila salivary gland cell death during development using proteomics. AB - Proteasome inhibitors induce cell death and are used in cancer therapy, but little is known about the relationship between proteasome impairment and cell death under normal physiological conditions. Here, we investigate the relationship between proteasome function and larval salivary gland cell death during development in Drosophila. Drosophila larval salivary gland cells undergo synchronized programmed cell death requiring both caspases and autophagy (Atg) genes during development. Here, we show that ubiquitin proteasome system (UPS) function is reduced during normal salivary gland cell death, and that ectopic proteasome impairment in salivary gland cells leads to early DNA fragmentation and salivary gland condensation in vivo. Shotgun proteomic analyses of purified dying salivary glands identified the UPS as the top category of proteins enriched, suggesting a possible compensatory induction of these factors to maintain proteolysis during cell death. We compared the proteome following ectopic proteasome impairment to the proteome during developmental cell death in salivary gland cells. Proteins that were enriched in both populations of cells were screened for their function in salivary gland degradation using RNAi knockdown. We identified several factors, including trol, a novel gene CG11880, and the cop9 signalsome component cop9 signalsome 6, as required for Drosophila larval salivary gland degradation. PMID- 22935613 TI - Planar cell polarity effector gene Intu regulates cell fate-specific differentiation of keratinocytes through the primary cilia. AB - Genes involved in the planar cell polarity (PCP) signaling pathway are essential for a number of developmental processes in mammals, such as convergent extension and ciliogenesis. Tissue-specific PCP effector genes of the PCP signaling pathway are believed to mediate PCP signals in a tissue- and cell type-specific manner. However, how PCP signaling controls the morphogenesis of mammalian tissues remains unclear. In this study, we investigated the role of inturned (Intu), a tissue-specific PCP effector gene, during hair follicle formation in mice. Tissue specific disruption of Intu in embryonic epidermis resulted in hair follicle morphogenesis arrest because of the failure of follicular keratinocyte to differentiate. Targeting Intu in the epidermis resulted in almost complete loss of primary cilia in epidermal and follicular keratinocytes, and a suppressed hedgehog signaling pathway. Surprisingly, the epidermal stratification and differentiation programs and barrier function were not affected. These results demonstrate that tissue-specific PCP effector genes of the PCP signaling pathway control the differentiation of keratinocytes through the primary cilia in a cell fate- and context-dependent manner, which may be critical in orchestrating the propagation and interpretation of polarity signals established by the core PCP components. PMID- 22935614 TI - Induction of autophagy and senescence by knockdown of ROC1 E3 ubiquitin ligase to suppress the growth of liver cancer cells. AB - Regulator of Cullins-1 (ROC1) or RING box protein-1 (RBX1) is an essential RING component of Cullin-RING ligase (CRL). Our previous studies showed that ROC1 is required for the growth of several cancer cell lines while ROC1 siRNA silencing inactivates CRL, leading to cell cycle arrest, cell senescence and/or apoptosis. However, it is completely unknown whether ROC1 knockdown triggers autophagic response by inactivating CRL. Moreover, the role of ROC1 in liver cancer remains elusive. In this study, we reported that ROC1 knockdown significantly inhibited the growth of liver cancer cells by sequentially and independently inducing autophagy and p21-dependent cell senescence. Mechanism analysis revealed that ROC1 silencing triggered autophagy by inhibition of mammalian target of rapamycin (mTOR) activity due to accumulation of mTOR-inhibitory protein Deptor, a substrate of CRL. Consistently, Deptor knockdown significantly blocked autophagy response upon ROC1 silencing. Biologically, autophagy response upon ROC1 silencing was a survival signal, and blockage of autophagy pathway sensitized cancer cells to apoptosis. Finally, we demonstrated that ROC1 was overexpressed in hepatocellular carcinomas, which is associated with poor prognosis of liver cancer patients. These findings suggest that ROC1 is an appealing drug target for liver cancer and provide a proof-of-concept evidence for a novel drug combination of ROC1 inhibitor and an autophagy inhibitor for effective treatment of liver cancer by enhancing apoptosis. PMID- 22935615 TI - hnRNP Q regulates translation of p53 in normal and stress conditions. AB - The responses to numerous stress signals are important for cellular growth and survival. The p53 tumor-suppressor protein is stabilized under stress conditions and induces transcription of several genes to regulate cell cycle and apoptosis. Regarding p53 protein accumulation, inhibition of proteasomal degradation of p53 protein, which is mainly mediated by Mdm2, has received much attention. Here, we demonstrate that regulation of translation initiation is also crucial for p53 protein accumulation. Furthermore, we report that heterogeneous nuclear ribonucleoprotein (hnRNP) Q binds to the 5'-untranslated region (UTR) of mouse p53 mRNA and regulates translation efficiency of p53 and apoptosis progression. We also suggest that changes in cytosolic hnRNP Q levels contribute to cell cycle dependent translational differences in p53 mRNA. PMID- 22935616 TI - Noncanonical control of C. elegans germline apoptosis by the insulin/IGF-1 and Ras/MAPK signaling pathways. AB - The insulin/IGF-1 pathway controls a number of physiological processes in the nematode worm Caenorhabditis elegans, including development, aging and stress response. We previously found that the Akt/PKB ortholog AKT-1 dampens the apoptotic response to genotoxic stress in the germline by negatively regulating the p53-like transcription factor CEP-1. Here, we report unexpected rearrangements to the insulin/IGF-1 pathway, whereby the insulin-like receptor DAF-2 and 3-phosphoinositide-dependent protein kinase PDK-1 oppose AKT-1 to promote DNA damage-induced apoptosis. While DNA damage does not affect phosphorylation at the PDK-1 site Thr350/Thr308 of AKT-1, it increased phosphorylation at Ser517/Ser473. Although ablation of daf-2 or pdk-1 completely suppressed akt-1-dependent apoptosis, the transcriptional activation of CEP-1 was unaffected, suggesting that daf-2 and pdk-1 act independently or downstream of cep-1 and akt-1. Ablation of the akt-1 paralog akt-2 or the downstream target of the insulin/IGF-1 pathway daf-16 (a FOXO transcription factor) restored sensitivity to damage-induced apoptosis in daf-2 and pdk-1 mutants. In addition, daf-2 and pdk-1 mutants have reduced levels of phospho-MPK-1/ERK in their germ cells, indicating that the insulin/IGF-1 pathway promotes Ras signaling in the germline. Ablation of the Ras effector gla-3, a negative regulator of mpk-1, restored sensitivity to apoptosis in daf-2 mutants, suggesting that gla-3 acts downstream of daf-2. In addition, the hypersensitivity of let-60/Ras gain-of function mutants to damage-induced apoptosis was suppressed to wild-type levels by ablation of daf-2. Thus, insulin/IGF-1 signaling selectively engages AKT-2/DAF 16 to promote DNA damage-induced germ cell apoptosis downstream of CEP-1 through the Ras pathway. PMID- 22935617 TI - Palladium-catalyzed asymmetric synthesis of 2-pyrrolidinones with a quaternary carbon stereocenter. AB - A palladium-catalyzed asymmetric synthesis of 2-pyrrolidinones with a quaternary stereocenter at the 3-position has been achieved by the reaction of gamma methylidene-delta-valerolactones with alkyl isocyanates. High enantioselectivity has been realized by employing a newly synthesized chiral phosphoramidite ligand. PMID- 22935619 TI - Dynamic covalent assembly of stimuli responsive vesicle gels. AB - We describe the reversible formation of stimuli-responsive vesicle gels from polymerised dynamic covalent surfactants, by simple mixing of soluble surfactant precursors in water under ambient conditions. PMID- 22935618 TI - X-chromosome inactivation in monkey embryos and pluripotent stem cells. AB - Inactivation of one X chromosome in female mammals (XX) compensates for the reduced dosage of X-linked gene expression in males (XY). However, the inner cell mass (ICM) of mouse preimplantation blastocysts and their in vitro counterparts, pluripotent embryonic stem cells (ESCs), initially maintain two active X chromosomes (XaXa). Random X chromosome inactivation (XCI) takes place in the ICM lineage after implantation or upon differentiation of ESCs, resulting in mosaic tissues composed of two cell types carrying either maternal or paternal active X chromosomes. While the status of XCI in human embryos and ICMs remains unknown, majority of human female ESCs show non-random XCI. We demonstrate here that rhesus monkey ESCs also display monoallelic expression and methylation of X linked genes in agreement with non-random XCI. However, XIST and other X-linked genes were expressed from both chromosomes in isolated female monkey ICMs indicating that ex vivo pluripotent cells retain XaXa. Intriguingly, the trophectoderm (TE) in preimplantation monkey blastocysts also expressed X-linked genes from both alleles suggesting that, unlike the mouse, primate TE lineage does not support imprinted paternal XCI. Our results provide insights into the species-specific nature of XCI in the primate system and reveal fundamental epigenetic differences between in vitro and ex vivo primate pluripotent cells. PMID- 22935620 TI - Misoprostol as first-line treatment for incomplete abortion at a secondary-level health facility in Nigeria. AB - OBJECTIVE: To determine the feasibility of introducing misoprostol as first-line treatment for incomplete abortion at a secondary-level health facility. METHODS: An open-label prospective study was conducted in a secondary-level health facility in Nigeria. Eligible women diagnosed with incomplete abortion received 400-MUg sublingual misoprostol as first-line treatment. Nurse-midwives took the lead in diagnosis, counseling, treatment, and assessment of final outcome. The primary outcome was the proportion of women who completed the abortion process. RESULTS: Complete evacuation was achieved in 83 of 90 (92.2%) eligible women. The most common adverse effects were abdominal pain/cramps (58 [64.4%]), heavy bleeding (21 [23.3%]), spotting (15 [16.7%]), and fever/chills (11 [12.2%]). More than 90% of women reported that the procedure was satisfactory, that pain and adverse effects were tolerable, and that bleeding was acceptable. Eighty-four (93.3%) and 86 (95.6%) women, respectively, would use the method in the future and recommend it to friends. CONCLUSION: Misoprostol is an effective, safe, and acceptable method for treating incomplete abortion. It can be successfully used as first-line treatment by nurse-midwives. Success rates over 90% are consistent with findings from previous studies in which drug administration was controlled solely by physicians. PMID- 22935621 TI - Sublingual [corrected] misoprostol as first-line care for incomplete abortion in Burkina Faso. AB - OBJECTIVE: To explore 400-MUg sublingual misoprostol as primary treatment in lower-level facilities with no previous experience providing postabortion care. METHODS: Women presenting with incomplete abortion were offered a single dose of 400-MUg sublingual misoprostol. Incomplete abortion was defined as uterine size consistent with fewer than 12 weeks of gestation, open cervical os, and reports of past or present history of vaginal bleeding. Women returned to the clinic 1 week after misoprostol administration for follow-up. At that time, they were discharged if the uterine evacuation was a success or were offered a second follow-up visit or surgical completion if still incomplete. RESULTS: One-hundred women received misoprostol; outcome data were unavailable for 1 woman. Complete uterine evacuation was achieved for 97 (98.0%) women. Satisfaction was high, with nearly all women indicating that they were "satisfied" (n=57 [57.6%]) or "very satisfied" (n=41 [41.4%]) with their experience. Adverse effects were considered "tolerable" by 72 of 97 (74.2%) women. Ninety-seven of 99 (98.0%) participants indicated that they would choose misoprostol for incomplete abortion care in the future and 95 of 97 (97.9%) stated that they would recommend it to a friend. CONCLUSION: Misoprostol is a viable option for treatment of incomplete abortion at mid-level facilities. PMID- 22935622 TI - Epidemiological characteristics of HIV-infected women with and without a history of criminal justice involvement in South Carolina. AB - The circumstances that lead to incarceration may potentiate the HIV/AIDS epidemic and this has become an emerging public health concern. In the United States and in most jurisdictions, HIV prevalence in the correctional setting is higher among female inmates than male inmates. This dichotomy is not fully understood and few studies have focused on women in the South. Using data from the South Carolina (SC) electronic HIV/AID Reporting System, the SC Law Enforcement Criminal History database, and a public access website of the SC Department of Corrections, the authors describe the epidemiological characteristics and correctional history of a population of HIV-infected women in SC diagnosed between January 1, 1996, and December 31, 2005. PMID- 22935623 TI - Perceptions and influences of a state prison smoking ban. AB - Prison smoking bans are increasingly common. It is important to consider how those who are incarcerated respond to these bans and to the subsequent development of contraband tobacco markets. Since there are high rates of smoking in individuals who become incarcerated, along with high rates of chronic illnesses that are exacerbated by smoking, it is critical to examine whether there are health promoting changes in perceptions of and intentions toward smoking and other health behaviors that can be maintained on release to the community. Interviews with incarcerated men experiencing a prison smoking ban revealed their responses to being smoke-free, reactions to the presence of contraband smoking, and the influences of this experience on their intentions to smoke following release. PMID- 22935624 TI - Use and interpretation of diagnostic vaccination in primary immunodeficiency: a working group report of the Basic and Clinical Immunology Interest Section of the American Academy of Allergy, Asthma & Immunology. AB - A major diagnostic intervention in the consideration of many patients suspected to have primary immunodeficiency diseases (PIDDs) is the application and interpretation of vaccination. Specifically, the antibody response to antigenic challenge with vaccines can provide substantive insight into the status of human immune function. There are numerous vaccines that are commonly used in healthy individuals, as well as others that are available for specialized applications. Both can potentially be used to facilitate consideration of PIDD. However, the application of vaccines and interpretation of antibody responses in this context are complex. These rely on consideration of numerous existing specific studies, interpolation of data from healthy populations, current diagnostic guidelines, and expert subspecialist practice. This document represents an attempt of a working group of the American Academy of Allergy, Asthma & Immunology to provide further guidance and synthesis in this use of vaccination for diagnostic purposes in consideration of PIDD, as well as to identify key areas for further research. PMID- 22935627 TI - Pentagonal tiling with buckybowls: pentamethylcorannulene on Cu(111). AB - We present scanning tunnelling microscopy studies and first principles calculation on the 2D crystallization of pentagonal pentamethylcorannulene on a Cu(111) surface under ultrahigh vacuum in the temperature range of 50 K to 400 K. The observed 2D crystal phases and their packing densities are compared to tiling options of hard pentagons. Temperature change-induced reversible phase transitions reveal entropic effects in 2D crystallization. Only inclusion of dispersion interactions into density functional theory yields structures observed experimentally at low temperatures. PMID- 22935625 TI - Tumor suppression by small molecule inhibitors of translation initiation. AB - Translation initiation factors are over-expressed and/or activated in many human cancers and may contribute to their genesis and/or progression. Removal of physiologic restraints on translation initiation causes malignant transformation. Conversely, restoration of physiological restrains on translation initiation reverts malignant phenotypes. Here, we extensively characterize the anti-cancer activity of two small molecule inhibitors of translation initiation: #1181, which targets the eIF2?GTP?Met-tRNAi ternary complex, and 4EGI-1, which targets the eIF4F complex. In vitro, both molecules inhibit translation initiation, abrogate preferentially translation of mRNAs coding for oncogenic proteins, and inhibit proliferation of human cancer cells. In vivo, both #1181 and 4EGI-1 strongly inhibit growth of human breast and melanoma cancer xenografts without any apparent macroscopic- or microscopic-toxicity. Mechanistically, #1181 phosphorylates eIF2alpha while 4EGI-1 disrupts eIF4G/eIF4E interaction in the tumors excised from mice treated with these agents. These data indicate that inhibition of translation initiation is a new paradigm in cancer therapy. PMID- 22935626 TI - Design, methods and demographic findings of the DEMINVALL survey: a population based study of Dementia in Valladolid, Northwestern Spain. AB - BACKGROUND: This article describes the rationale and design of a population-based survey of dementia in Valladolid (northwestern Spain). The main aim of the study was to assess the epidemiology of dementia and its subtypes. Prevalence of anosognosia in dementia patients, nutritional status, diet characteristics, and determinants of non-diagnosed dementia in the community were studied. The main sociodemographic, educational, and general health status characteristics of the study population are described. METHODS: Cross-over and cohort, population-based study. A two-phase door-to-door study was performed. Both urban and rural environments were included. In phase 1 (February 2009 - February 2010) 28 trained physicians examined a population of 2,989 subjects (age: >= 65 years). The seven minute screen neurocognitive battery was used. In phase 2 (May 2009 - May 2010) 4 neurologists, 1 geriatrician, and 3 neuropsychologists confirmed the diagnosis of dementia and subtype in patients screened positive by a structured neurological evaluation. Specific instruments to assess anosognosia, the nutritional status and diet characteristics were used. Of the initial sample, 2,170 subjects were evaluated (57% female, mean age 76.5 +/- 7.8, 5.2% institutionalized), whose characteristics are described. 227 persons were excluded for various reasons. Among those eligible were 592 non-responders. The attrition bias of non responders was lower in rural areas. 241 screened positive (11.1%). DISCUSSION: The survey will explore some clinical, social and health related life-style variables of dementia. The population size and the diversification of social and educational backgrounds will contribute to a better knowledge of dementia in our environment. PMID- 22935628 TI - Integrated analysis for a carbon- and water-constrained future: an assessment of drip irrigation in a lettuce production system in eastern Australia. AB - The Australian Government is meeting the challenge of water scarcity and climate change through significant on-farm infrastructure investment to increase water use efficiency and productivity, and secure longer term water supplies. However, it is likely that on-farm infrastructure investment will alter energy consumption and therefore generate considerable greenhouse gas (GHG) emissions, suggesting potential conflicts in terms of mitigation and adaptation policies. In particular, the introduction of a price on carbon may influence the extent to which new irrigation technologies are adopted. This study evaluated trade-offs between water savings, GHG emissions and economic gain associated with the conversion of a sprinkler (hand shift) irrigation system to a drip (trickle) irrigation system for a lettuce production system in the Lockyer Valley, one of the major vegetable producing regions in Australia. Surprisingly, instead of trade-offs, this study found positive synergies - a win-win situation. The conversion of the old hand-shift sprinkler irrigation system to a drip irrigation system resulted in significant water savings of almost 2 ML/ha, as well as an overall reduction in GHG emissions. Economic modelling, at a carbon price of $ 30/t CO(2)e, indicated that there was a net benefit of adoption of the drip irrigation system of about $ 4620/ML/year. We suggest priority should be given, in the implementation of on-farm infrastructure investment policy, to replacing older inefficient and energy-intensive sprinkler irrigation systems such as hand shift and roll-line. The findings of the study support the use of an integrated approach to avoid possible conflicts in designing national climate change mitigation and adaptation policies, both of which are being developed in Australia. PMID- 22935629 TI - Does the bathing water classification depend on sampling strategy? A bootstrap approach for bathing water quality assessment, according to Directive 2006/7/EC requirements. AB - Data on the 95th and 90th percentiles of bacteriological quality indicators are used to classify bathing waters in Europe, according to the requirements of Directive 2006/7/EC. However, percentile values and consequently, classification of bathing waters depend both on sampling effort and sample-size, which may undermine an appropriate assessment of bathing water classification. To analyse the influence of sampling effort and sample size on water classification, a bootstrap approach was applied to 55 bacteriological quality datasets of several beaches in the Balearic Islands (Spain). Our results show that the probability of failing the regulatory standards of the Directive is high when sample size is low, due to a higher variability in percentile values. In this way, 49% of the bathing waters reaching an "Excellent" classification (95th percentile of Escherichia coli under 250 cfu/100 ml) can fail the "Excellent" regulatory standard due to sampling strategy, when 23 samples per season are considered. This percentage increases to 81% when 4 samples per season are considered. "Good" regulatory standards can also be failed in bathing waters with an "Excellent" classification as a result of these sampling strategies. The variability in percentile values may affect bathing water classification and is critical for the appropriate design and implementation of bathing water Quality Monitoring and Assessment Programs. Hence, variability of percentile values should be taken into account by authorities if an adequate management of these areas is to be achieved. PMID- 22935632 TI - Predictors of end-stage renal disease and recurrence of lupus activity after initiation of dialysis in patients with lupus nephritis. AB - OBJECTIVES: The present paper aims at identifying the predictors of end-stage renal disease (ESRD) and at determining the long-term outcome of ESRD patients according to renal replacement modality in Korean patients with lupus nephritis (LN). METHODS: Between 1985 and 2010, 321 Korean patients with LN were enrolled in this study. We analysed the clinical and laboratory indices, the treatment responses and the biopsy findings. The events of interest were estimated by the Kaplan-Meier method and the risk factors were assessed by univariate and multivariate Cox proportional hazards regression analyses. RESULTS: The median follow-up time after the diagnosis of LN was 84 months. During follow-up, twenty nine patients evolved to ESRD. Renal survival rate at 5 and 10 years after LN onset was 95.9% and 91.1%, respectively. Deteriorated renal function (estimated glomerular filtration rate <60 ml/min/1.73m2) at LN onset (hazard ratio: 9.223) was found to be an independent risk factor for the development of ESRD. Recurrence of lupus nephritis in renal allograft and flare-ups of lupus activity were not observed among the patients undergoing kidney transplantation (KT) (n=11). In contrast, those with maintenance dialysis (n=18) developed 13 episodes of lupus flare in 10 patients and 5 died of either infection (n=2) or lupus flare (n=3). CONCLUSIONS: The impaired renal function at baseline is an independent predictor of ESRD in Korean patients with LN. The benefits of KT on the control of lupus activity and survival should be emphasised. PMID- 22935630 TI - l-theanine attenuates abstinence signs in morphine-dependent rhesus monkeys and elicits anxiolytic-like activity in mice. AB - l-theanine, 2-amino-4-(ethylcarbamoyl) butyric acid, an amino acid found in green tea (Camellia sinensis), is sold in the United States as a dietary supplement to reduce stress and improve cognition and mood. The observations that l-theanine has been shown to inhibit caffeine's stimulatory effects and that caffeine produces precipitated withdrawal signs in opioid-addicted monkeys and some opioid withdrawal signs in some normal monkeys, suggest that l-theanine may suppress opioid withdrawal signs. Additionally, l-theanine produces anxiolytic effects in humans indicating that it has anti-anxiety properties. Thus, in these studies we determined whether l-theanine attenuates opioid-withdrawal signs in morphine dependent rhesus monkeys, a model for spontaneous opioid withdrawal in human opioid addicts. We also evaluated whether l-theanine decreases anxiety-like behavior in mice, using the elevated plus maze and marble burying assays. l theanine significantly attenuated designated opioid withdrawal signs, including fighting, rigid abdominal muscles, vocalizing on palpation of abdomen, pacing, retching, wet-dog shakes, and masturbation. It had a relatively quick onset of action that persisted for at least 2.5h. l-theanine also produced anxiolytic-like effects in the elevated plus maze and the marble burying assay in naive mice at doses that did not significantly affect motor behavior. The results of these studies suggest that l-theanine may be useful in the pharmacotherapy of treating opioid withdrawal as well as anxiety-associated behaviors. PMID- 22935633 TI - Metabolic signals and food intake. Forty years of progress. AB - The Columbia Appetitive Seminar, which began in 1972, has been a huge success in bringing together scholars interested in appetitive behavior, stimulating research and new ideas, and encouraging collaborations. At the time of the Seminar's inception, predominant views were that energy derived acutely from the utilization of glucose was a primary causative factor in determining the initiation (hunger) and offset (satiation) of meals; and that specific nuclei in the hypothalamus controlled unique aspects of motivated behaviors, such as stimulating water intake or creating a feeling of satiety. Over the ensuing 40 years, these views have given way to models of appetitive behavior utilizing complex interacting neural circuits responding to diverse signals emanating from the gastrointestinal tract, the external environment, cognitive, learned and social factors, and many more. Pivotal reports include the 1973 demonstration that cholecystokinin reduces meal size, and the discovery of leptin in 1994. PMID- 22935635 TI - Generalists matter for public health. PMID- 22935634 TI - Effect of 9p21 genetic variation on coronary heart disease is not modified by other risk markers. The Atherosclerosis Risk in Communities (ARIC) Study. AB - OBJECTIVE: To determine whether the 9p21 SNP association with coronary heart disease is modified by other classical or novel risk markers. METHODS: The 9p21 SNP (rs10757274) and multiple risk markers were measured in the Atherosclerosis Risk in Communities Study, and incident coronary disease events were ascertained. Effect modification (interaction) of the 9p21 SNP with risk markers was tested in Cox proportional hazard regression models. RESULTS: The incidence rates of coronary heart disease per 1000 person-years were 14.4, 17.0, and 18.7 for AA, AG, and GG genotypes, yielding hazard ratios of 1.0, 1.20 (95% CI = 1.07-1.36), and 1.34 (95% CI = 1.16-1.53). There was no meaningful evidence of an interaction (all p-interaction > 0.04) between 9p21 SNP and any of 14 other risk markers for coronary heart disease. These included novel markers not previously explored for 9p21 interaction (e.g., cardiac troponin T and N-terminal pro-brain natriuretic peptide). CONCLUSION: Our study extends evidence that the 9p21 SNP association with coronary heart disease is not modified by classical or novel risk markers. Our findings therefore rule out additional plausible pathways by which 9p21 might have increased coronary heart disease risk. PMID- 22935636 TI - Cutaneous analgesia after subcutaneous injection of memantine and amantadine and their systemic toxicity in rats. AB - The purpose of the study is to find subcutaneous equianalgesic doses of memantine, amantadine and bupivacaine and use these doses to quantify the cardiovascular and central nervous system toxicity of these agents after intravenous administration. Memantine, amantadine and bupivacaine, a local anesthetic, in a dose-related fashion were determined for cutaneous analgesia by a block of the cutaneous trunci muscle reflex in rats, and equipotent doses were calculated. Following rapid intravenous infusion of equianalgesic bupivacaine, memantine, amantadine and saline (vehicle) in rats, we observed the onset time of seizure, apnea and impending death, and monitored mean arterial blood pressure and heart rate. Memantine and amantadine elicited dose-dependent cutaneous analgesia. At the 50% effective dose (ED(50)), the rank of potencies was bupivacaine [1.8 (1.7-2.0)]>memantine [19.1 (17.6-21.8)]>amantadine [36.1 (32.0 40.3)] (P<0.05). On ED(25), ED(50) and ED(75) basis, the duration caused by bupivacaine was similar to that caused by memantine or amantadine. At equianalgesic doses, the infusion time of memantine or amantadine required to induce seizure, impending death, and apnea was longer than that of bupivacaine during rapid intravenous infusion (P<0.01). The decreasing slope in mean arterial blood pressure and heart rate was slower with memantine and amantadine when compared with bupivacaine at equivalent doses (P<0.01). Our data showed that memantine and amantadine (i) were equal to bupivacaine at producing durations of cutaneous analgesia but (ii) were less likely than bupivacaine to cause cardiovascular and central nervous system toxicity. PMID- 22935637 TI - Bradykinin- and lipopolysaccharide-induced bradykinin B2 receptor expression, interleukin 8 release and "nitrosative stress" in bronchial epithelial cells BEAS 2B: role for neutrophils. AB - Bradykinin-induced interleukin (IL)-8 release should potentially activate neutrophils releasing myeloperoxidase (MPO) and subsequently generating "nitrosative stress". We studied bradykinin-induced expression of bradykinin B(2) receptor and bradykinin- and lipopolysaccharide (LPS)-induced IL-8 release, MPO (marker of neutrophil activation) and 3-nitrotyrosine (3-NT; marker of "nitrosative stress") production in human bronchial epithelial cells BEAS-2B alone or in co-culture with human neutrophils. We evaluated B(2) receptor protein expression in BEAS-2B cells by immunostainings and Western blot analysis, and measured respectively bradykinin- or LPS-induced IL-8 release in BEAS-2B cells and bradykinin- and/or LPS-induced MPO and 3-NT production in BEAS-2B cells co cultured with human neutrophils by ELISA. In addition, we evaluated bradykinin- and/or LPS-induced 3-NT formation in BEAS-2B cells co-cultured with human neutrophils by immunocytochemistry. Bradykinin up-regulates B(2) receptor expression (P<0.05) and stimulate IL-8 release (P<0.001) in BEAS-2B cells. Either the selective bradykinin B(2) receptor antagonist HOE 140 or the selective bradykinin B(1) receptor antagonist Lys-(des-Arg(9), Leu(8))-bradykinin alone halved IL-8 release and the combination of both drugs suppressed this effect. In BEAS-2B cells co-cultured with human neutrophils bradykinin increased MPO release and 3-NT production compared to BEAS-2B cells with human neutrophils (P<0.001), and the addition of LPS in BEAS-2B cells with human neutrophils and bradykinin induced a further dramatically increase of MPO release and 3-NT formation (P<0.001). Bradykinin and LPS provoked "nitrosative stress", potentially mediated by IL-8, in bronchial epithelium co-cultured with neutrophils suggesting a role for bradykinin in the amplification of chronic airway inflammation via production of "nitrosative stress". PMID- 22935638 TI - Autophagy vitalizes the pathogenicity of pathogenic fungi. AB - Plant pathogenic fungi utilize a series of complex infection structures, in particular the appressorium, to gain entry to and colonize plant tissue. As a consequence of the accumulation of huge quantities of glycerol in the cell the appressorium generates immense intracellular turgor pressure allowing the penetration peg of the appressorium to penetrate the leaf cuticle. Autophagic processes are ubiquitous in eukaryotic cells and facilitate the bulk degradation of macromolecules and organelles. The study of autophagic processes has been extended from the model yeast Saccharomyces cerevisiae to pathogenic fungi such as the rice blast fungus Magnaporthe oryzae. Significantly, null mutants for the expression of M. oryzae autophagy gene homologs lose their pathogenicity for infection of host plants. Clarification of the functions and network of interactions between the proteins expressed by M. oryzae autophagy genes will lead to a better understanding of the role of autophagy in fungal pathogenesis and help in the development of new strategies for disease control. PMID- 22935639 TI - Ligand substituents effect on 10Dq. AB - Reaction of 5,6-dihydro-5,6-epoxy-1,10-phenanthroline (L) with Ni(ClO(4))(2).6H(2)O in methanol in 3:1M proportion at room temperature yields [NiL(3)](ClO(4))(2).2H(2)O. The X-ray crystal structure of the cation NiL(3)(2+) has been determined. Aminolysis of the three epoxide rings in NiL(3)(2+) by 4 substituted anilines in boiling water without any Lewis acid catalyst gives a family of Ni(II) complexes with octahedral NiL(6)(2+) core. In these complexes, crystal field splitting 10Dq varies from 11601 to 15798 cm(-1) in acetonitrile. The variation in 10Dq is found to be satisfactorily linear (r(2)=0.951) with the Hammett sigma(R) parameter of the substituent on the anilino fragment. 10Dq increases with the increase in the electron donation ability of the substituent. PMID- 22935640 TI - Influence of the nitrogen content on the optical properties of CNx films. AB - Polycrystalline carbon nitride thin films were prepared by electrolysis of methanol-urea solution at different concentrations of urea to methanol and applied voltage 800 volts for 10h. Grazing incidence X-ray diffraction (GIXRD) revealed that the crystalline structure of carbon nitride films at moderate nitrogen content changed from amorphous phase to polycrystalline alpha-C(3)N(4), and beta-C(3)N(4) phases. The optical transmission analysis of the films revealed that the band gap value for indirect allowed transitions increased with increasing nitrogen content, while the associated phonon energy value showed the opposite behavior. The refractive index and the extinction coefficient of the samples deposited with different concentrations were determined as a function of wavelength. The refractive index decreases with increasing both nitrogen content and crystallinity. The refractive index dispersion for the investigated samples is discussed in terms of the single oscillator model and oscillator parameters. PMID- 22935641 TI - Studies on growth and spectral characterization of diglycine fumarate monohydrate single crystals. AB - Single crystals of organic optical material, diglycine fumarate monohydrate (DGFM) has been synthesized and grown from solution by slow evaporation solution growth method. Purity of synthesized materials was increased by continuous recrystallization. The lattice parameters of the grown crystals are observed by X ray diffraction method and the crystal system of grown crystal is identified as monoclinic. The optical transparency range has been investigated by UV-Vis-NIR spectroscopy method in the range between 190 and 1,100 nm. The presence of different modes of vibrations is analyzed using FT-IR technique. The carbon and hydrogen atmosphere in molecular structure of DGFM is investigated using FT-NMR method. The thermogravimetrrc analysis (TGA), differential thermal analysis (DTA) and differential scanning calorimetry (DSC) analysis shows that the grown crystal has very good thermal stability up to 263 degrees C. The Kurtz-Perry powder SHG test has done for grown crystals. PMID- 22935642 TI - Artificial metalloenzymes via encapsulation of hydrophobic transition-metal catalysts in surface-crosslinked micelles (SCMs). AB - Encapsulation of a hydrophobic rhodium catalyst in crosslinked micelles allowed nonpolar substrates to react in water with unusual selectivity. PMID- 22935643 TI - MicroRNA analysis: is it ready for prime time? PMID- 22935644 TI - Charged particle's flux measurement from PMMA irradiated by 80 MeV/u carbon ion beam. AB - Hadrontherapy is an emerging technique in cancer therapy that uses beams of charged particles. To meet the improved capability of hadrontherapy in matching the dose release with the cancer position, new dose-monitoring techniques need to be developed and introduced into clinical use. The measurement of the fluxes of the secondary particles produced by the hadron beam is of fundamental importance in the design of any dose-monitoring device and is eagerly needed to tune Monte Carlo simulations. We report the measurements carried out with charged secondary particles produced from the interaction of a 80 MeV/u fully stripped carbon ion beam at the INFN Laboratori Nazionali del Sud, Catania, with a poly-methyl methacrylate target. Charged secondary particles, produced at 90 degrees with respect to the beam axis, have been tracked with a drift chamber, while their energy and time of flight have been measured by means of a LYSO scintillator. Secondary protons have been identified exploiting the energy and time-of-flight information, and their emission region has been reconstructed backtracking from the drift chamber to the target. Moreover, a position scan of the target indicates that the reconstructed emission region follows the movement of the expected Bragg peak position. Exploiting the reconstruction of the emission region, an accuracy on the Bragg peak determination in the submillimeter range has been obtained. The measured differential production rate for protons produced with E(Prod)(kin) > 83 MeV and emitted at 90 degrees with respect to the beam line is dN(P)/(dN(C)dOmega) (E(Prod)(kin) > 83 MeV, theta = 90 degrees ) = (2.69 +/- 0.08(stat) +/- 0.12(sys)) * 10-4 sr-1. PMID- 22935645 TI - Factors influencing intention to undergo whole genome screening in future healthcare: a single-blind parallel-group randomised trial. AB - OBJECTIVE: This study investigated the effect of biased information on beliefs about, and intention to undergo, whole genome sequencing (WGS) screening; and predictors of intention. METHODS: A single-blind parallel-group randomised trial was conducted in Australia, in 2011. Using Excel, 216 participants with English proficiency and no genetic testing experience were randomly allocated (1:1): a neutral information pamphlet or a biased version omitting screening limitations. Measures included: screening intention; Protection Motivation Theory (PMT) constructs; consideration of future consequences (CFC); uncertainty avoidance (UA); anticipated regret (AR). RESULTS: Intention decreased from pre to post manipulation (p<.001, eta(2)=.07, 95% CIs [4.41, 4.86], [3.99, 4.44], respectively). Biased participants (n=106) had higher response efficacy beliefs than neutral participants (n=102) (p<.001, eta(2)=.04, 95% CIs [4.80, 5.10], [4.49, 4.79] respectively), but equal intention. The model explained 36.2% of the variance in intention; response efficacy (p<.001), response costs (p<.001), self efficacy (p=.024), and UA (p=.019) were predictors. CONCLUSION: This is the first study investigating factors influencing anticipated WGS screening uptake. Omitting screening limitations may bias beliefs about screening efficacy and benefits. Uptake may be driven by perceived benefits and costs, self-efficacy beliefs, and uncertainty avoidance. PMT appears to be an appropriate psychosocial model for this setting. PMID- 22935646 TI - Integrating environmental gap analysis with spatial conservation prioritization: a case study from Victoria, Australia. AB - Gap analysis is used to analyse reserve networks and their coverage of biodiversity, thus identifying gaps in biodiversity representation that may be filled by additional conservation measures. Gap analysis has been used to identify priorities for species and habitat types. When it is applied to identify gaps in the coverage of environmental variables, it embodies the assumption that combinations of environmental variables are effective surrogates for biodiversity attributes. The question remains of how to fill gaps in conservation systems efficiently. Conservation prioritization software can identify those areas outside existing conservation areas that contribute to the efficient covering of gaps in biodiversity features. We show how environmental gap analysis can be implemented using high-resolution information about environmental variables and ecosystem condition with the publicly available conservation prioritization software, Zonation. Our method is based on the conversion of combinations of environmental variables into biodiversity features. We also replicated the analysis by using Species Distribution Models (SDMs) as biodiversity features to evaluate the robustness and utility of our environment-based analysis. We apply the technique to a planning case study of the state of Victoria, Australia. PMID- 22935647 TI - Physical loss and modification of Southern Great Plains playas. AB - Playas are the primary wetland system in the Southern Great Plains (SGP) of North America providing critical stopover habitats for migratory birds in the Western Hemisphere. Collectively, these wetlands form the keystone ecosystem in this region supporting biodiversity for North America and provide habitat for native plants and animals that are essential for maintenance of international biological diversity along with other local and regional ecological services. Large-scale landscape changes in this region, primarily as a result of agriculturally-based anthropogenic impacts, threaten playas with functional loss and physical extinction. These impacts are not considered in current estimates of the number of extant functional playas, leading to biased estimates by groups or agencies extrapolating research or monitoring results, conducting conservation planning, and modeling impacts of future climate change. Using a combination of stochastic and empirical data, we identified impacts to playas and playa watersheds and quantified the extent and rate of these impacts relative to physical loss. Only 0.2% of playas had no wetland or watershed modification and we conservatively estimate that 17% of playas recently existing on the landscape no longer are represented by an apparent depression. With the inclusion of sediment volume estimates where >=100% of the volume of original differentiated playa soil has been filled, 60% or 16,855 playas have been physically lost from the SGP despite a continued presence of a depression. Data also show that small playas are being lost more rapidly than larger ones; the average size (+/-SE) of extant playas has increased from 7.5 +/- 0.47 to 8.5 +/- 0.55 ha. The reduced ecological condition of 95.3% of playas remaining on the landscape exceeds historical predictions of a maximum 85% of playas ever being modified. Given the results of this study these changes can now be accounted for, resulting in more informed management and conservation of playas and bring awareness to the urgency of implementation of effective conservation measures for playas and the species that depend on this keystone ecosystem. PMID- 22935648 TI - Comprehensive integration of genetic and environmental determinants to increase knowledge of the allergic diseases. PMID- 22935649 TI - Current world literature. PMID- 22935651 TI - Structure and function of endosomes in plant cells. AB - Endosomes are a heterogeneous collection of organelles that function in the sorting and delivery of internalized material from the cell surface and the transport of materials from the Golgi to the lysosome or vacuole. Plant endosomes have some unique features, with an organization distinct from that of yeast or animal cells. Two clearly defined endosomal compartments have been studied in plant cells, the trans-Golgi network (equivalent to the early endosome) and the multivesicular body (equivalent to the late endosome), with additional endosome types (recycling endosome, late prevacuolar compartment) also a possibility. A model has been proposed in which the trans-Golgi network matures into a multivesicular body, which then fuses with the vacuole to release its cargo. In addition to basic trafficking functions, endosomes in plant cells are known to function in maintenance of cell polarity by polar localization of hormone transporters and in signaling pathways after internalization of ligand-bound receptors. These signaling functions are exemplified by the BRI1 brassinosteroid hormone receptor and by receptors for pathogen elicitors that activate defense responses. After endocytosis of these receptors from the plasma membrane, endosomes act as a signaling platform, thus playing an essential role in plant growth, development and defense responses. Here we describe the key features of plant endosomes and their differences from those of other organisms and discuss the role of these organelles in cell polarity and signaling pathways. PMID- 22935652 TI - Vernalization - a cold-induced epigenetic switch. AB - Growth and development are modulated by environmental signals in many organisms. These signals are often perceived at one stage and 'remembered' until later in development. An increasingly well-understood example of this process in plants is provided by vernalization, which refers to the acquisition of the ability to flower after prolonged exposure to cold. In Arabidopsis thaliana, vernalization involves downregulation and epigenetic silencing of the gene encoding the floral repressor FLOWERING LOCUS C (FLC). This epigenetic silencing is quantitative and increases with the duration of exposure to cold. Vernalization involves a Polycomb-based switching mechanism, with localized nucleation of silencing during periods of cold, and spreading of the silencing complex over the whole gene after the exposure to cold. A number of characteristics of vernalization have recently been elaborated on through the use of mathematical modelling. This has revealed the importance of chromatin dynamics for the switching mechanism and has shown that the quantitative nature of the process is due to cell-autonomous switching of an increasing proportion of cells. The principles derived from vernalization are likely to be widely relevant to epigenetic reprogramming in many organisms. PMID- 22935653 TI - The in vivo function of mammalian cell and tissue polarity regulators--how to shape and maintain the epidermal barrier. AB - The establishment and maintenance of cell and tissue polarity is crucial for a range of biological processes, such as oriented division, migration, adhesion and barrier function. The molecular pathways that regulate cell and tissue polarity have been extensively studied in lower organisms as well as in mammalian cell culture. By contrast, relatively little is still known about how polarization regulates the in vivo formation and homeostasis of mammalian tissues. Several recent papers have identified crucial roles for mammalian polarity proteins in a range of in vivo processes, including stem cell behavior, cell fate determination, junction formation and maintenance and organ development. Using the epidermis of the skin as a model system, this Commentary aims to discuss the in vivo significance of cell and tissue polarity in the regulation of mammalian tissue morphogenesis, homeostasis and disease. Specifically, we discuss the mechanisms by which the molecular players previously identified to determine polarity in vitro and/or in lower organisms regulate epidermal stratification; orient cell division to drive cell fate determination within the epidermal lineage; and orient hair follicles. We also describe how altered polarity signaling contributes to skin cancer. PMID- 22935655 TI - Directed assembly of nanoscale Co(II)-substituted {Co9[P2W15]3} and {Co14[P2W15]4} polyoxometalates. AB - Herein we report two structurally intriguing Co(ii)-substituted polyoxometalates, a {Co(9)[P(2)W(15)](3)} and {Co(14)[P(2)W(15)](4)} (compounds 1 and 2) that are formed from the same building blocks under subtly different conditions. Compound 1 displays a structure previously predicted but never before realised, whilst compound 2 is the first Co-containing Dawson-based single-molecule magnet and has a unique cruciform structure. PMID- 22935656 TI - Delayed diagnosis of leukemia and association with morbid-mortality in children in Pernambuco, Brazil. AB - The objectives of this study were to describe the interval between symptom onset and diagnosis of acute leukemia, to assess risk factors for delayed diagnosis, and its effect on early morbid-mortality and event-free survival (EFS). Records of children aged 1 month to 18 years diagnosed with acute leukemia were reviewed for clinical, demographic, and health care provider factors, and for time to diagnosis. Of 288 patients diagnosed, 55% had a delay in diagnosis. The median time to diagnosis was 31 days. There were significant associations between the diagnostic delay and the distance from the tertiary care hospital (P=0.04), initial consultation in an outpatient clinic (P=0.04), presenting symptoms of bone/joint pain (P=0.04), family with more than 3 children (P=0.02), birth order of third or greater (P=0.009), paternal age <30 years (P=0.03), and paternal education <8 years (P=0.008). There was no association between delayed diagnosis and early morbid-mortality or EFS at 5 years. Initial consultation in an outpatient setting, presenting symptoms of bone/joint pain, and birth order of third or greater remained statistically significant in multivariate analyses, but the delay did not have an impact on early morbid-mortality or EFS. Education of primary care providers in atypical presentations of acute leukemia may decrease the diagnostic delay. PMID- 22935657 TI - A case of osteosarcoma in a patient with pycnodysostosis. AB - Pycnodysostosis is a rare sclerosing bone dystrophy. The main clinical features are short stature and oral and maxillofacial abnormalities such as a large head, a small and underdeveloped face with prominent nose and eyes, irregular dentition, small hands and feet with dystrophic nails, and trunk deformities such as scoliosis. The differential diagnosis is established with other skeletal dysplasias such as osteopetrosis, cleidocranial dysplasia, and idiopathic acro osteolysis. Since its first description in 1962 by Maroteaux and Lamy, about 100 cases have been published, some of these with uncommon features. We describe the case of a 22-year-old European man with pycnodysostosis who developed a chondroblastic osteosarcoma of the right femur. No case of bone cancer in this sclerosing bone disease had been described so far. PMID- 22935654 TI - Actin nucleators in the nucleus: an emerging theme. AB - Actin is an integral component of the cytoskeleton, forming a plethora of macromolecular structures that mediate various cellular functions. The formation of such structures relies on the ability of actin monomers to associate into polymers, and this process is regulated by actin nucleation factors. These factors use monomeric actin pools at specific cellular locations, thereby permitting rapid actin filament formation when required. It has now been established that actin is also present in the nucleus, where it is implicated in chromatin remodelling and the regulation of eukaryotic gene transcription. Notably, the presence of typical actin filaments in the nucleus has not been demonstrated directly. However, studies in recent years have provided evidence for the nuclear localisation of actin nucleation factors that promote cytoplasmic actin polymerisation. Their localisation to the nucleus suggests that these proteins mediate collaboration between the cytoskeleton and the nucleus, which might be dependent on their ability to promote actin polymerisation. The nature of this cooperation remains enigmatic and it will be important to elucidate the physiological relevance of the link between cytoskeletal actin networks and nuclear events. This Commentary explores the current evidence for the nuclear roles of actin nucleation factors. Furthermore, the implication of actin associated proteins in relaying exogenous signals to the nucleus, particularly in response to cellular stress, will be considered. PMID- 22935658 TI - Regression of mesenchymal hamartoma of the liver with sarcoma chemotherapy. AB - We present a young patient with metastatic Ewing sarcoma that had hepatic lesions. As we were unaware of hepatic metastases in Ewing sarcoma, liver biopsy was performed. The pathologic findings were diagnostic of mesenchymal hamartoma of the liver. Surprisingly, the combined chemotherapy for metastatic sarcoma resulted in almost complete resolution of the hamartoma in the liver. This option may be useful in extreme cases when resection is not feasible. PMID- 22935659 TI - Characteristics and prognosis of B-cell lymphoma in HIV-infected children in the HAART era. AB - Chronic HIV infection leads to increased risk of non-Hodgkin B-cell lymphoma. However, only few recent data are available about their current management and prognosis in HIV-infected children since the advent highly active antiretroviral therapy (HAART). This multicenter retrospective study describes the 12 cases of B cell non-Hodgkin lymphoma diagnosed in HIV-infected children in France between 1996 and 2009. All children had moderate to severe immunosuppression and high viral load at the time of diagnosis. Nine children had extracerebral primary sites and 3 had a primary central nervous system lymphoma. Eight patients had Burkitt lymphoma; 4 had diffuse large B-cell lymphoma. Concomitantly with HAART, all children with extracerebral lymphoma received intensive chemotherapy according to LMB protocol, those with primary central nervous system lymphoma received high-dose methotrexate. No toxicity-related deaths occurred. Ten patients entered complete remission (CR), 2 died of tumor progression despite a second line of therapy. No relapses occurred after CR (median follow-up, 72 mo). Thus, prognosis of patients unresponsive to first-line lymphoma treatment remains poor, but relapse seems to be rare when CR is achieved. Children without severe comorbidities can tolerate intensive chemotherapy with a mandatory HAART treatment, taking into account drug interactions. PMID- 22935660 TI - Transient neonatal cyanosis associated with a new Hb F variant: Hb F viseu. AB - Neonatal cyanosis in healthy newborns can be associated either with methemoglobin due to cytochrome b5 reductase deficiency or to M-hemoglobin, a group of hemoglobin variants resulting from mutations in the globin chain genes. We report the clinical case of a neonate with cyanosis and normal cardiac and respiratory function. At birth the hematological parameters were normal; however, the methemoglobinemia was 16%. Spontaneously, the cyanosis gradually decreased and by the fifth month of age the methemoglobin level was normal. A heterozygous Ggamma globin gene (HBG2) missense mutation 87 C-A (Leu28Met) was identified. His father, with a history of transfusion in the neonatal period, is heterozygous for the same mutation. This hemoglobin variant, not previously described, was called Hb F Viseu and is the sixth Ggamma-chain variant reported in association with neonatal cyanosis. PMID- 22935661 TI - Shwachman-Diamond syndrome: diarrhea, no longer required? AB - Exocrine pancreatic insufficiency and diarrhea have been hallmarks in the diagnosis of Shwachman-Diamond syndrome (SDS). We report 2 cases of genetically confirmed SDS in patients who presented with an unusual phenotype. Patient #1 presented with pancytopenia without other system involvement, while patient #2 presented with severe neutropenia, anemia, and a bifid thumb. Neither patient had diarrhea or malabsorption. Both patients had the classic heterozygous mutations c183_184 TA>CT and c.258+2 T>C in the Shwachman-Bodian-Diamond syndrome gene. Incomplete phenotypes may be more common than previously recognized in bone marrow failure syndromes; gastrointestinal symptoms should not be considered a prerequisite for SDS. PMID- 22935662 TI - Increased production of nitric oxide by phagocytic stimulated neutrophils in patients with chronic granulomatous disease. AB - Chronic granulomatous disease (CGD) is an inherited disorder in which phagocytic leukocytes fail to generate superoxide (O(2)(-)) and antimicrobial oxidants. Patients with CGD develop recurrent and often life-threatening infections due to catalase-positive microorganisms. We attempted to measure the production of nitric oxide and reactive oxygen species in polymorphonuclear neutrophils (PMNs) from patients with CGD using a flow cytometry technique. Venous blood was obtained from 5 male patients with X-linked CGD and from 10 healthy volunteers. The nitric oxide production by PMNs after phagocytosis was measured using diaminofluorescein-2 diacetate, a fluorescent indicator of intracellular nitric oxide production. After erythrocytes were hypotonically lysed, the cell pellet was applied to a cytofluorometer. Although the production of hydrogen peroxide by PMNs from patients with CGD was almost absent, nitric oxide production was detected at nearly half the level as was seen in the PMNs from healthy volunteers (CGD vs. healthy volunteers=140.1+/-28.6 vs. 256.4+/-10.3, mean fluorescence intensity; P<0.01). In conclusion, we demonstrated that human PMNs produces nitric oxide after phagocytic stimulation. Also nitric oxide production after phagocytic stimulation by PMNs of patients with CGD is observed although its amount is lower than that observed on healthy control. Despite the fact that CGD patients cannot produce H(2)O(2) which is essential for intracellular bacteriocidal process after phagocytosis, our data suggested that the phylactic effect in PMNs induced by nitric oxide could be at least partially related to the survival of patients with CGD. PMID- 22935663 TI - Wilms tumor and a duplex collecting system: a case report and review of literature. AB - Wilms tumor (WT) is described as a component of many different clinical conditions and genetic syndromes. However, the simultaneous occurrence of WT and a duplex collecting system is extremely rare. We report a case of a 4-year-old boy diagnosed with WT and a left duplex collecting system. The patient underwent a left radical nephrectomy. The histologic examination diagnosed it to be a case of WT with favorable histology. The patient received the chemotherapy regimen for stage 1 WT and was in complete remission during the follow-up period of 2 years. Further investigations are required for assessing the need for screening of WT in children with genitourinary malformations. PMID- 22935664 TI - Successful response to cidofovir of adenovirus hepatitis during chemotherapy in a child with hepatoblastoma. AB - BACKGROUND: Adenoviral infections are endemic in the pediatric population. Most of these infections are mild and self-limited in immunocompetent individuals. Although in profoundly immunocompromised hosts after solid organ or stem cell transplantation, adenovirus may cause fulminant hepatitis or other life threatening infections, this is a rare complication in patients receiving standard chemotherapy. OBSERVATION: We report a case of severe adenovirus hepatitis in a 7-month-old child receiving induction chemotherapy for hepatoblastoma who fully recovered after treatment with cidofovir. CONCLUSIONS: To our knowledge, this is the first report documenting recovering of severe adenoviral hepatitis in a nontransplanted immunocompromised host. PMID- 22935665 TI - Sinonasal teratocarcinosarcoma in an adolescent male. AB - Sinonasal teratocarcinosarcoma is an extremely rare and aggressive neoplasm with <100 cases described in the literature and only 3 reported pediatric cases. We describe a 15-year-old male with a case of sinonasal teratocarcinosarcoma with extension to the cribriform plate. He presented with epistaxis, nasal obstruction, and frontal headaches and was treated with resection and postoperative chemoradiation. He is currently doing well without evidence of recurrence 45 months after therapy. PMID- 22935666 TI - Pulmonary tuberculosis mimicking metastasis in a patient with osteosarcoma. AB - Pulmonary metastasis even at diagnosis or during treatment is an important problem in osteosarcoma treatment and treatment modality varies in patients with metastasis. Metastasectomy and aggressive induction chemotherapy are the 2 most well-known treatment options. However, reactivation of pulmonary tuberculosis can be a problem in developing countries, where the prevalence of tuberculosis is high. Here, we described a patient with osteosarcoma with pulmonary tuberculosis reactivation mimicking metastasis. PMID- 22935667 TI - Intraocular lens opacification mimicking the appearance of a congenital lamellar cataract. PMID- 22935668 TI - Parental smoking and childhood refractive error: the STARS study. AB - PURPOSE: To assess the relationship between parental smoking and childhood refractive errors in Singapore Chinese children aged 6-72 months recruited through the STrabismus, Amblyopia, and Refractive errors in Singaporean children study. METHODS: A total of 4164 children were recruited, with a positive response rate of 72.3% (n=3009). Cycloplegic refraction measurements were obtained from all children by trained eye professionals. Parents underwent an interviewer administered questionnaire with information on demographics, lifestyle, and parental smoking history being obtained. RESULTS: Spherical equivalent readings were obtained for 87.7% of the children. In all, 52.1% were male (n=1375). The overall prevalence of myopia (at least -0.5 D) was 11.0%. Overall, 37.1% of the fathers interviewed gave a history of smoking. Among the mothers interviewed, 9.2% gave a history of smoking, 6.6% had smoked during the child's life, and 2.2% had smoked during the pregnancy. Maternal history of ever smoking, smoking during child's life, and smoking during pregnancy were associated with decreased odds ratio (OR) of childhood myopia (OR 0.50 (P=0.01), OR 0.39 (P=0.01), and OR 0.3 (P=0.14), respectively). Paternal history of smoking was associated with decreased OR of childhood myopia (OR of 0.72 (P=0.02)). CONCLUSION: In light of this finding of an inverse association between parental smoking and childhood myopia, further studies are suggested to better understand the role of nicotinic acetylcholine receptor pharmacology in ocular development. This may pave the way for the development of targeted treatment strategies for prevention of myopia. PMID- 22935669 TI - The effects of intraocular silicone oil placement prior to iodine 125 brachytherapy for uveal melanoma: a clinical case series. AB - PURPOSE: To investigate the role of silicone oil as an adjunct to iodine 125 ((125)I) brachytherapy in attenuating radiation dose and reducing radiation retinopathy. METHODS: A 16-mm COMS plaque loaded with (125)I seeds was simulated in vitro on an eye model containing silicone oil as a vitreous substitute using BrachyDose. The radiation dose ratio of silicone oil vs water to ocular structures was calculated at angles subtended from the centre of the eye. Silicone oil was then used in three choroidal melanoma patients who underwent 23 gauge vitrectomy, silicone oil placement, and (125)I brachytherapy. RESULTS: Silicone oil reduced the ocular radiation dose in vitro to 65%. Radiation dose ratios on the retina increased from 0.45 to 0.99 when moving from points diametrically opposed to the plaque's central axis. In 10-24 months' follow-up, no patients have developed radiation retinopathy. Each patient required silicone oil removal and experienced cataract progression, and one also developed a retinal detachment. CONCLUSIONS: This study confirms that silicone oil attenuates radiation dose in vitro, and may protect against radiation retinopathy clinically in patients, however it requires extensive surgical interventions. Further studies in only very selected populations using silicone oil as an adjunct to (125)I brachytherapy will best elucidate its role in shielding radiation retinopathy. PMID- 22935670 TI - A standardised technique for locating periocular lesions and biopsy sites. PMID- 22935671 TI - Patterns of adherence to NICE glaucoma guidance in two different service delivery models. AB - PURPOSE: To assess adherence patterns to the UK National Institute of Health and Clinical Excellence (NICE) guidelines on glaucoma management (2009) in a tertiary referral centre shared care setting and in a district general hospital (DGH) setting. METHOD: We performed a retrospective case note analysis of 200 patients from two centres between January and June 2010. The two centres involved were a consultant-guided teaching hospital optometry-led shared care setting (setting 1) and a consultant-led DGH clinic setting (setting 2). The main outcome measures were compliance with eight of the main NICE guidelines on glaucoma diagnosis and management (2009). RESULTS: Both centres showed good adherence to the guidelines regarding the choice of initial treatment (96% vs 100%, settings 1 and 2, respectively) and arranging appropriate monitoring intervals (92% vs 86%). However, significant differences were seen when assessing whether an optic disc image was obtained at the initial visit (74% vs 10%), whether an appropriate initial assessment was performed (96% vs 58%), whether patients' review interval complied with the NICE guidance regardless of hospital cancellations (92% vs 66%), and whether concordance with medication was checked (88% vs 24%) (settings 1 and 2, respectively, P<0.01-Fisher's exact test). CONCLUSION: Our study provides evidence to suggest that a hospital-based shared care service with trained optometrists using assessment sheets compares favourably to non specialist glaucoma care delivered by ophthalmologists. PMID- 22935672 TI - Variable coordination of a chiral diphosphine containing an amidinium/NHC group within its backbone: MU-P,P', kappa2-P,P' and kappa3-P,C,P' coordination modes. AB - A diphosphine ligand (1.HPF(6)), which is a potential precursor to a PC(NHC)P pincer, with a backbone containing two phenylene groups and a central bicyclic 4 aza-2-azoniabicyclo[3.2.1]oct-2-ene unit has been synthesised and coordinated to Pd(II) and Pt(II) to give trans-[M(kappa(2)-P,P'-)Cl(2)]PF(6) where M = Pd (2) or Pt (3a). Single-crystal structure determinations of 2 and 3a show the complexes to be isostructural with the diphosphine coordinated in a trans-spanning fashion and the amidinium unit being protonated and non-coordinated. 2 and 3a react with CH(3)I to give the dimers trans-[Pd(2)(MU-1.H)(2)I(4)](PF(6))(2), 6, and trans [Pt(2)(MU-1.H)(2)I(4)](PF(6))(2), 7, as the major products. This bridging mode of coordination of [1.H](+) is also seen in trans-[Rh(2)(MU-1.H)(1,5 COD)(2)Cl(2)]PF(6), 4, and [Pt(2)(MU-kappa(2)-1.H)(dvdms)]PF(6), 5. Upon treatment with KO(t)Bu complexes and undergo deprotonation at the amidinium carbon to give trans-[M(kappa(3)-P,C,P'-1)Cl]PF(6) where M = Pd (8), and Pt (9). The related trans-[Rh(kappa(3)-P,C,P'-1)(CO)]PF(6) (10) is prepared directly from 1.HPF(6) and Rh(acac)(CO)(2): this and the palladium and platinum complexes 8 and 9 are isolated as isomeric mixtures as a consequence of a conformational isomerism. In situ deprotonation of 1.HPF(6) followed by addition of Ag(CF(3)SO(3)) gave S(Ag)-[Ag(kappa(3)-P,C,P'-1)(CF(3)SO(3))], 11. Some preliminary studies of the reactivity of 2 and 8 in Suzuki-type reactions are reported and the Pt(0) system has been shown to be an active hydrosilylation catalyst. PMID- 22935673 TI - Prevalence of periodontitis in adults in the United States: 2009 and 2010. AB - This study estimated the prevalence, severity, and extent of periodontitis in the adult U.S. population, with data from the 2009 and 2010 National Health and Nutrition Examination Survey (NHANES) cycle. Estimates were derived from a sample of 3,742 adults aged 30 years and older, of the civilian non-institutionalized population, having 1 or more natural teeth. Attachment loss (AL) and probing depth (PD) were measured at 6 sites per tooth on all teeth (except the third molars). Over 47% of the sample, representing 64.7 million adults, had periodontitis, distributed as 8.7%, 30.0%, and 8.5% with mild, moderate, and severe periodontitis, respectively. For adults aged 65 years and older, 64% had either moderate or severe periodontitis. Eighty-six and 40.9% had 1 or more teeth with AL >= 3 mm and PD >= 4 mm, respectively. With respect to extent of disease, 56% and 18% of the adult population had 5% or more periodontal sites with >= 3 mm AL and >= 4 mm PD, respectively. Periodontitis was highest in men, Mexican Americans, adults with less than a high school education, adults below 100% Federal Poverty Levels (FPL), and current smokers. This survey has provided direct evidence for a high burden of periodontitis in the adult U.S. population. PMID- 22935674 TI - The prevalence of periodontitis in the US: forget what you were told. PMID- 22935675 TI - ALDH-positive lung cancer stem cells confer resistance to epidermal growth factor receptor tyrosine kinase inhibitors. AB - Molecular targeting therapeutics, such as EGFR tyrosine kinase inhibitors (TKIs), are important treatment strategies for lung cancer. Currently, the major challenge confronting targeted cancer therapies is the development of resistance. Cancer stem cells (CSCs) represent a rare population of undifferentiated tumorigenic cells responsible for tumor initiation, maintenance and spreading. Resistance to conventional chemotherapeutic drugs is a common characteristic of CSCs. However, the issue of whether CSCs contribute to EGFR TKI resistance in lung cancer is yet to be established. In the current study, we explored the association of ALDH1A1 expression with EGFR TKI resistance in lung cancer stem cells. ALDH1A1-positive lung cancer cells displayed resistance to gefitinib, compared to ALDH1A1-negative lung cancer cells. Moreover, PC9/gef cells (gefitinib-resistant lung cancer cells) presented a higher proportion of ALDH1A1 positive cells, compared to PC9 cells (gefitinib-sensitive lung cancer cells). Clinical sample studies were consistent with results from cell culture model systems showing that lung cancer cells with resistance to EGFR TKI and chemotherapy drugs contain significantly increased proportions of ALDH1A1 positive cells. These findings collectively suggest that ALDH1A1 positivity in cancer stem cells confers resistance to EGFR TKI in lung cancer. PMID- 22935677 TI - Proapoptotic miltefosine nanovesicles show synergism with paclitaxel: Implications for glioblastoma multiforme therapy. AB - Hexadecylphosphocholine (HePC) or miltefosine based proapoptotic lipid nanovesicles encapsulating paclitaxel for synergistic anticancer effect of paclitaxel and miltefosine in chemoresistant human glioblastoma multiforme (U-87 MG) overexpressing multidrug resistance 1 (MDR1) gene product P-glycoprotein (P gp), were developed in this study. The nanovesicles had 100-200nm size and a negative zeta potential (~-25mV) and optimized for miltefosine content based on their physiochemical properties. With a high encapsulation efficiency of 94%, the nanovesicles showed sustained release of paclitaxel in nasal fluid and triggered release in the cerebrospinal fluid. Synergistic action of paclitaxel and miltefosine was observed with a low IC50 of 162+/-5nM. The nanovesicle also overcame drug resistance and showed ATP dependent uptake via clathrin mediated pathway in glioblastoma cells. An improved therapeutic efficacy in comparison to Taxol(r), the current clinical formulation of paclitaxel was observed. Efficient brain uptake of the nanovesicles upon intranasal administration was observed in vivo and the nanovesicles were also found to be able to cross blood brain barrier. These studies therefore suggest the therapeutic potential of proapoptotic lipid nanovesicles and their feasibility for intranasal administration in the treatment of chemoresistant glioblastoma. PMID- 22935676 TI - Withaferin A-induced apoptosis in human breast cancer cells is associated with suppression of inhibitor of apoptosis family protein expression. AB - The present study provides novel insight into the mechanism of apoptosis induction by withaferin A (WA), which is a bioactive constituent of an Ayurvedic medicine plant (Withania somnifera). Exposure of MDA-MB-231 and MCF-7 human breast cancer cells to WA resulted in suppression of XIAP, cIAP-2, and Survivin protein levels. The WA-induced apoptosis was significantly attenuated by ectopic expression of XIAP, Survivin, and cIAP-2 in both cells. However, the WA-mediated inhibition of MDA-MB-231 xenograft growth in vivo was associated with suppression of Survivin protein level only. These results indicate important contribution of Survivin suppression in WA-induced apoptosis. PMID- 22935678 TI - A new jasmonic acid stereoisomeric derivative induces apoptosis via reactive oxygen species in human prostate cancer cells. AB - With the aim of identifying novel agents with antigrowth and pro-apoptotic activity on prostate cancer cells, in the present study, we evaluated the effect of a (-)-jasmonic acid derivative, the 3-hydroxy-2(S)-(2Z-butenyl)-cyclopentane 1(S)-acetic acid, obtained by biotransformation, on cell growth in androgen sensitive (LNCaP) and androgen-insensitive (DU-145) human prostate cancer cells. The results obtained show that the new compound was able to inhibit the growth of both prostate cancer cells. In addition, our data seem to indicate that the apoptosis evocated by this new molecule, at least in part, appears to be associated with an increase of reactive oxygen species (ROS) production. PMID- 22935679 TI - Polyisoprenoyl gemcitabine conjugates self assemble as nanoparticles, useful for cancer therapy. AB - A series of new polyisoprenoyl prodrugs of gemcitabine, which can be formulated as nanoassemblies are described. These prodrugs were designed to improve gemcitabine efficacy and to overcome the limitations due to the systemic toxicity of this anticancer compound. In vitro biological assessment showed that these polyisoprenoyl gemcitabine nanoassemblies displayed notable cytotoxicity on several cancer cell lines, including murine melanoma cell line B16F10, human pancreatic carcinoma cell line MiaPaCa-2, human lung carcinoma cell line A549 and human breast adenocarcinoma cell line MCF7. Interestingly, it was observed that the anticancer efficacy of these nanoassemblies was dependant on the size of polyisoprenoyl moiety. The polyisoprenoyl prodrug of gemcitabine containing three isoprene units (2d) was the more active on all the cancer cell lines tested. The antitumor efficacy of the nanoassemblies (NAs) constructed with the most active prodrug 2d was further evaluated on a human pancreatic (MiaPaCa-2) carcinoma xenograft model in mice. The prodrug 2d NAs showed an increased antitumor efficacy as compared to free gemcitabine or to squalene-gemcitabine (SQ-gem, 2a) nanoassemblies. Interestingly, MiaPaCa-2 tumors that did not respond to gemcitabine were inhibited by 76% after treatment with prodrug 2d NAs, whereas SQ gem-treated MiaPaCa-2 tumor xenografts decreased only by 41% compared to saline or to gemcitabine-treated mice. Together, these findings demonstrated that the modulation of the length of nanoassemblies polyisoprenoyl moiety made tumor cells more sensitive to gemcitabine treatment without flagrant toxicity, thus providing a significant improvement in the drug therapeutic index. PMID- 22935680 TI - Hyaluronan grafted lipid-based nanoparticles as RNAi carriers for cancer cells. AB - RNA interference (RNAi), a natural cellular mechanism for RNA-guided regulation of gene expression could in fact become new therapeutic modality if an appropriate efficient delivery strategy that is also reproducible and safe will be developed. Numerous efforts have been made for the past eight years to address this challenge with only mild success. The majority of these strategies are based on cationic formulations that condense the RNAi payload and deliver it into the cell cytoplasm. However, most of these formulations also evoke adverse effects such as mitochondrial damage, interfering with blood coagulation cascade, induce interferon response, promote cytokine induction and activate the complement. Herein, we present a strategy that is devised from neutral phospholipids and cholesterol that self-assembled into lipid-based nanoparticles (LNPs). These LNPs were then coated with the glycosaminoglycan, hyaluronan (HA). HA-LNPs bound and internalized specifically into cancer cells compared with control, non-coated particles. Next, loaded with siRNAs against the multidrug resistance extrusion pump, p-glycoprotein (P-gp), HA-LNPs efficiently and specifically reduced mRNA and P-gp protein levels compared with control particles and with HA-LNPs loaded with control, non-targeted siRNAs. In addition, no cellular toxicity or cytokine induction was observed when these particles were cultured with human Peripheral Blood Mononuclear Cells (PBMCs). The HA-LNPs may offer an alternative approach to cationic lipid-based formulations for RNAi delivery into cancer cells in an efficient and safe manner. PMID- 22935681 TI - Double "plug and play" templates technology for photo controllable drug release polyelectrolyte multilayers. AB - An approach for the generation of photo controllable drug release polyelectrolyte multilayers is developed by combining double "plug and play" (PnP) templates technology and host-guest chemistry. These multilayers exhibited a reversible drug loading and release achieved by the photoinduced isomerization. PMID- 22935682 TI - From multi-residue screening to target analysis of pharmaceuticals in water: development of a new approach based on magnetic sector mass spectrometry and application in the Nairobi River basin, Kenya. AB - This paper presents the development and application of a new multi-residue analytical method providing the first data on the environmental occurrence of human pharmaceuticals in Africa, particularly the Nairobi River basin (Kenya). Based on pharmaceutical consumption data available for the Nairobi region, 43 'priority' pharmaceutically active ingredients (PAIs) were selected for this study. On the basis of magnetic sector high-resolution mass spectrometry, a new methodology involving both full-scan screening and selective target analysis has been developed to investigate the presence of the defined priority PAIs. Subsequent analysis of the corresponding standard compounds provided the full confirmation and indicative concentrations (low ng/L-high MUg/L) of 10 human PAIs in the Nairobi River. The detected compounds belong to different classes, i.e. antibiotics, analgesic/anti-inflammatory and anti-epileptic drugs, antimalarials and antiretrovirals. Ibuprofen, paracetamol, sulfamethoxazole and zidovudine showed to be the most concentrated PAIs (about 10-30 MUg/L). The concentration of the antiretrovirals (lamivudine, zidovudine and nevirapine) is clearly higher than those reported in the literature, although environmental data on this class of PAIs are still very limited. To the best of our knowledge, this is the first study that provides evidence of detection of lamivudine in surface water. The presented unique data on the occurrence of selected PAIs in the aquatic environment of Africa clearly show that the high prevalence of specific diseases like HIV/AIDS infection in developing countries might result in a different pattern of PAIs in environmental waters compared to the more developed regions. PMID- 22935683 TI - Epigenetic control of epithelial-to-mesenchymal transition and cancer metastasis. AB - Epithelial-mesenchymal transition (EMT) is vital for morphogenesis during embryonic development and is also critical for the conversion of early stage tumors into invasive malignancies. Several key inducers of EMT are transcription factors that repress the expression of E-cadherin, whose loss is a hallmark of EMT. Epigenetic regulation encompasses three types of changes: DNA methylation, histone modifications, and microRNAs, each of which has been shown to play a key role in controlling epithelial-mesenchymal transition and cancer metastasis. As we gain deeper understanding of epigenetic mechanisms controlling EMT processes and orchestrating all the metastatic steps, we broaden the therapeutic potentials of epigenetic drugs, such as DNA demethylating drugs and histone deacetylase/demethylase inhibitors, which can act upon metastasis-related genes, restoring their expression and biological functions. PMID- 22935684 TI - [Breast cancer screening: current status]. AB - The currently available scientific evidence attests that mammographic screening and quality treatment have been able to reduce mortality attributable to breast cancer. Although screening is not without risks, population-based screening has clear advantages over opportunistic detection. Following the Council of the European Union's "Recommendations on cancer screening", all the regional Autonomous Communities in Spain have screening programs that, in general, follow the same guidelines. The "European guidelines for quality assurance in breast cancer screening and diagnosis" serve as a reference that provides an overview of all aspects of screening. To achieve the foreseen objectives for the reduction of the morbidity and mortality attributable to breast cancer, screening programs must fulfill the established quality criteria and guarantee that patients have access to the best treatment options. PMID- 22935685 TI - [Mazabraud's syndrome, an uncommon association of intramuscular myxoma with fibrous dysplasia]. PMID- 22935686 TI - [Cerebral hydatid cyst]. PMID- 22935687 TI - [SFE Toulouse 2012]. PMID- 22935688 TI - Photoexcitation of mass/charge selected hemin+, caught in helium nanodroplets. AB - We report on a method by which mass/charge selected ions are picked up from a linear ion trap by liquid helium droplets. The size distributions of the doped droplets are measured via acceleration experiments. Depending on the source temperature, droplet sizes ranging from tens of thousands to several million helium atoms are obtained. Droplets doped with hemin, an iron containing porphyrin molecule, in the charge state +1 are then investigated using laser spectroscopy. It is observed that excitation with UV/VIS light can lead to ejection of the ion from the droplet. For doped droplets with a median size of ~150,000 helium atoms, the absorption of two photons at 380 nm is needed for ejection to become efficient. When droplets become smaller, the ejection efficiency is observed to strongly increase. Monitoring the ejection yield as a function of excitation wavelength can be used to obtain the optical spectrum of hemin(+). Compared to the spectrum of free gas-phase hemin(+) at room temperature, the here obtained spectrum is slightly narrower and shifted to the blue. PMID- 22935689 TI - Beyond finite elements: a comprehensive, patient-specific neurosurgical simulation utilizing a meshless method. AB - To be useful in clinical (surgical) simulations, a method must use fully nonlinear (both geometric and material) formulations to deal with large (finite) deformations of tissues. The method must produce meaningful results in a short time on consumer hardware and not require significant manual work while discretizing the problem domain. In this paper, we showcase the Meshless Total Lagrangian Explicit Dynamics Method (MTLED) which meets these requirements, and use it for computing brain deformations during surgery. The problem geometry is based on patient-specific MRI data and includes the parenchyma, tumor, ventricles and skull. Nodes are distributed automatically through the domain rendering the normally difficult problem of creating a patient-specific computational grid a trivial exercise. Integration is performed over a simple, regular background grid which does not need to conform to the geometry boundaries. Appropriate nonlinear material formulation is used. Loading is performed by displacing the parenchyma surface nodes near the craniotomy and a finite frictionless sliding contact is enforced between the skull (rigid) and parenchyma. The meshless simulation results are compared to both intraoperative MRIs and Finite Element Analysis results for multiple 2D sections. We also calculate Hausdorff distances between the computed deformed surfaces of the ventricles and those observed intraoperatively. The difference between previously validated Finite Element results and the meshless results presented here is less than 0.2mm. The results are within the limits of neurosurgical and imaging equipment accuracy (~1 mm) and demonstrate the method's ability to fulfill all of the important requirements for surgical simulation. PMID- 22935691 TI - Australian Critical Care receives impact factor. PMID- 22935690 TI - Stone comminution correlates with the average peak pressure incident on a stone during shock wave lithotripsy. AB - To investigate the roles of lithotripter shock wave (LSW) parameters and cavitation in stone comminution, a series of in vitro fragmentation experiments have been conducted in water and 1,3-butanediol (a cavitation-suppressive fluid) at a variety of acoustic field positions of an electromagnetic shock wave lithotripter. Using field mapping data and integrated parameters averaged over a circular stone holder area (R(h)=7 mm), close logarithmic correlations between the average peak pressure (P(+(avg))) incident on the stone (D=10 mm BegoStone) and comminution efficiency after 500 and 1000 shocks have been identified. Moreover, the correlations have demonstrated distinctive thresholds in P(+(avg)) (5.3 MPa and 7.6 MPa for soft and hard stones, respectively), that are required to initiate stone fragmentation independent of surrounding fluid medium and LSW dose. These observations, should they be confirmed using other shock wave lithotripters, may provide an important field parameter (i.e., P(+(avg))) to guide appropriate application of SWL in clinics, and facilitate device comparison and design improvements in future lithotripters. PMID- 22935692 TI - Study on probe current dependence of the intensity distribution in annular dark field images. AB - The intensity profile of atomic columns in annular dark field (ADF) images was quantitatively investigated for a silicon (001) crystal using a cold field emission source in an aberration corrected scanning transmission electron microscope. The intensity distribution at the atomic column in the annular dark field image was blurred by increasing the probe current from 10 to 40 pA, which was quantitatively well fit by a simulated distribution convolved by Gaussian envelopes with area proportional to the probe current. The blur of the ADF images was primarily determined by the size of the cold field emission source. PMID- 22935693 TI - Synthesis of selenium-containing polysaccharides and evaluation of antioxidant activity in vitro. AB - Selenium (Se) is an essential trace element for human beings and many other forms of life. Organic Se from natural foods has higher bioavailability and is safer than inorganic Se species. In the present study, selenium-containing derivatives of Artemisia sphaerocephala polysaccharide with the highest Se content of 1703 MUg/g were synthesized using H(2)SeO(3)/HNO(3) and BaCl(2) as a catalyst. The effects of the ratio of HNO(3) concentration and reaction temperature were investigated. Results of Raman and (13)C NMR spectroscopy indicated that C-6 substitution was predominant in selenized polysaccharide. A sharp decrease in M(w) was observed in the selenized reaction due to the acid environment. The in vitro antioxidant results suggest that selenium-containing polysaccharide should be applied as a novel selenium source in dietary supplements, with potent antioxidant properties. PMID- 22935694 TI - Preparation of regenerated silk fibroin/silk sericin fibers by coaxial electrospinning. AB - The coaxial electrospinning using the regenerated silk fibroin (SF) and silk sericin (SS) aqueous solutions as the core and shell spinning dopes, respectively, was carried out to prepare regenerated SF/SS composite fibers with components and core-shell structure similar to the natural silkworm silks. It was found from the scanning electron microscope (SEM) and transmission electron microscope (TEM) results that the core dope (SF aqueous solution) flow rate (Q(c)) and the applied voltage (V) had some effects on the morphology of the composite fiber. With an increase in Q(c), the diameter nonuniformity and eccentricity of the core fiber became serious, while the increasing V played an inverse role. In this work, the suitable Q(c) for the fiber formation with better electrospinnability was about 6 MUL/min, and the corresponding optimum V was 40 kV. Moreover, the results from Raman spectra analysis, modulated differential scanning calorimetry (MDSC), thermogravimetry (TG) measurement and mechanical property test showed that, compared with the pure SF fiber, the coaxially electrospun SF/SS fiber had more beta-sheet conformation, better thermostability and mechanical properties. This was probably because that SS played significant roles in dehydrating SF molecules and inducing the conformational transition of SF to beta-sheet structure. PMID- 22935695 TI - Does crystal or gel matter to stereochemistry of a reaction? Silver complexation promoted solid-state [2+2] reaction of an unsymmetrical olefin. AB - Head-to-tail and head-to-head [2+2] photodimerization of an unsymmetrical olefin containing benzimidazole and pyridyl groups was achieved by irradiating Ag(I) complexed olefin in crystalline state and gel state, respectively, in stereoselective manner. The [2+2] reaction indicates that the molecular arrangement in a gel is different from that of a xerogel. PMID- 22935696 TI - CDK inhibitors (p16/p19/p21) induce senescence and autophagy in cancer-associated fibroblasts, "fueling" tumor growth via paracrine interactions, without an increase in neo-angiogenesis. AB - Here, we investigated the compartment-specific role of cell cycle arrest and senescence in breast cancer tumor growth. For this purpose, we generated a number of hTERT-immortalized senescent fibroblast cell lines overexpressing CDK inhibitors, such as p16(INK4A), p19(ARF) or p21(WAF1/CIP1). Interestingly, all these senescent fibroblast cell lines showed evidence of increased susceptibility toward the induction of autophagy (either at baseline or after starvation), as well as significant mitochondrial dysfunction. Most importantly, these senescent fibroblasts also dramatically promoted tumor growth (up to ~2-fold), without any comparable increases in tumor angiogenesis. Conversely, we generated human breast cancer cells (MDA-MB-231 cells) overexpressing CDK inhibitors, namely p16(INK4A) or p21(WAF1/CIP1). Senescent MDA-MB-231 cells also showed increased expression of markers of cell cycle arrest and autophagy, including beta-galactosidase, as predicted. Senescent MDA-MB-231 cells had retarded tumor growth, with up to a near 2-fold reduction in tumor volume. Thus, the effects of CDK inhibitors are compartment-specific and are related to their metabolic effects, which results in the induction of autophagy and mitochondrial dysfunction. Finally, induction of cell cycle arrest with specific inhibitors (PD0332991) or cellular stressors [hydrogen peroxide (H(2)O(2)) or starvation] indicated that the onset of autophagy and senescence are inextricably linked biological processes. The compartment-specific induction of senescence (and hence autophagy) may be a new therapeutic target that could be exploited for the successful treatment of human breast cancer patients. PMID- 22935697 TI - Recognition mechanism of p63 by the E3 ligase Itch: novel strategy in the study and inhibition of this interaction. AB - The HECT-containing E3 ubiquitin ligase Itch mediates the degradation of several proteins, including p63 and p73, involved in cell specification and fate. Itch contains four WW domains, which are essential for recognition on the target substrate, which contains a short proline-rich sequence. Several signaling complexes containing these domains have been associated with human diseases such as muscular dystrophy, Alzheimer's or Huntington's diseases. To gain further insight into the structural determinants of the Itch-WW2 domain, we investigated its interaction with p63. We assigned, by 3D heteronuclear NMR experiments, the backbone and side chains of the uniformly (13)C-(15)N-labeled Itch-WW2. In vitro interaction of Itch-WW2 domain with p63 was studied using its interactive p63 peptide, pep63. Pep63 is an 18-mer peptide corresponding to the region from 534 551 residue of p63, encompassing the PPxY motif that interacts with the Itch-WW domains, and we identified the residues involved in this molecular recognition. Moreover, here, a strategy of stabilization of the conformation of the PPxY peptide has been adopted, increasing the WW-ligand binding. We demonstrated that cyclization of pep63 leads to an increase of both the biological stability of the peptide and of the WW-ligand complex. Stable metal-binding complexes of the pep63 have been also obtained, and localized oxidative damage on Itch-WW2 domain has been induced, demonstrating the possibility of use of metal-pep63 complexes as models for the design of metal drugs to inhibit the Itch-WW-p63 recognition in vivo. Thus, our data suggest a novel strategy to study and inhibit the recognition mechanism of Itch E3-ligase. PMID- 22935698 TI - Combined inhibition of Wee1 and Hsp90 activates intrinsic apoptosis in cancer cells. AB - Heat shock protein 90 (Hsp90) is an essential, evolutionarily conserved molecular chaperone. Cancer cells rely on Hsp90 to chaperone mutated and/or activated oncoproteins, and its involvement in numerous signaling pathways makes it an attractive target for drug development. Surprisingly, however, the impact of Hsp90 inhibitors on cancer cells is frequently cytostatic in nature, and efforts to enhance the antitumor activity of Hsp90 inhibitors in the clinic remain a significant challenge. In agreement with previous data obtained using Wee1 siRNA, we show that dual pharmacologic inhibition of Wee1 tyrosine kinase and Hsp90 causes cancer cells to undergo apoptosis in vitro and in vivo. Gene expression profiling revealed that induction of the intrinsic apoptotic pathway by this drug combination coincided with transcriptional downregulation of Survivin and Wee1, an outcome not seen in cells treated separately with either agent. At the translational level, expression of these two proteins, as well as activated Akt, was completely abrogated. These data support the hypothesis that Wee1 inhibition sensitizes cancer cells to Hsp90 inhibitors; they establish combined Wee1/Hsp90 inhibition as a novel therapeutic strategy; and they provide a mechanistic rationale for enhancing the pro-apoptotic activity of Hsp90 inhibitors. PMID- 22935700 TI - What limits meiotic crossovers? PMID- 22935699 TI - Identification of an estrogen-regulated circadian mechanism necessary for breast acinar morphogenesis. AB - Altered estrogen receptor alpha (ERA) signaling and altered circadian rhythms are both features of breast cancer. By using a method to entrain circadian oscillations in human cultured cells, we recently reported that the expression of key clock genes oscillates in a circadian fashion in ERA-positive breast epithelial cells but not in breast cancer cells, regardless of their ERA status. Moreover, we reported that ERA mRNA oscillates in a circadian fashion in ERA positive breast epithelial cells, but not in ERA-positive breast cancer cells. By using ERA-positive HME1 breast epithelial cells, which can be both entrained in vitro and can form mammary gland-like acinar structures in three-dimensional (3D) culture, first we identified a circuit encompassing ERA and an estrogen-regulated loop consisting of two circadian clock genes, PER2 and BMAL1. Further, we demonstrated that this estrogen-regulated circuit is necessary for breast epithelial acinar morphogenesis. Disruption of this circuit due to ERA-knockdown, negatively affects the estrogen-sustained circadian PER2-BMAL1 mechanism as well as the formation of 3D HME1 acini. Conversely, knockdown of either PER2 or BMAL1, by hampering the PER2-BMAL1 loop of the circadian clock, negatively affects ERA circadian oscillations and 3D breast acinar morphogenesis. To our knowledge, this study provides the first evidence of the implication of an ERA-circadian clock mechanism in the breast acinar morphogenetic process. PMID- 22935702 TI - Rejuvenating regeneration: metformin activates endogenous adult stem cells. PMID- 22935701 TI - Familial partial lipodystrophy, mandibuloacral dysplasia and restrictive dermopathy feature barrier-to-autointegration factor (BAF) nuclear redistribution. AB - Prelamin A processing impairment is a common feature of a restricted group of rare genetic alterations/disorders associated with a wide range of clinical phenotypes. Changes in histone posttranslational modifications, alterations in non-histone chromatin proteins and chromatin disorganization have been specifically linked to impairment of specific, distinct prelamin A processing steps, but the molecular mechanism involved in these processes is not yet understood . In this study, we show that the accumulation of wild-type prelamin A detected in restrictive dermopathy (RD), as well as the accumulation of mutated forms of prelamin A identified in familial partial lipodystrophy (FPLD) and mandibuloacral dysplasia (MADA), affect the nuclear localization of barrier-to autointegration factor (BAF), a protein able to link lamin A precursor to chromatin remodeling functions. Our findings, in accordance with previously described results, support the hypothesis of a prelamin A involvement in BAF nuclear recruitment and suggest BAF-prelamin A complex as a protein platform usually activated in prelamin A-accumulating diseases. Finally, we demonstrate the involvement of the inner nuclear membrane protein emerin in the proper localization of BAF-prelamin A complex. PMID- 22935703 TI - Identification of a novel function of the clathrin-coated structure at the plasma membrane in facilitating GM-CSF receptor-mediated activation of JAK2. AB - It is well known that ligand binding to the high-affinity GM-CSF receptor (GMR) activates JAK2. However, how and where this event occurs in a cellular environment remains unclear. Here, we demonstrate that clathrin- but not lipid raft-mediated endocytosis is crucial for GMR signaling. Knockdown expression of clathrin heavy chain or intersectin 2 (ITSN2) attenuated GMR-mediated activation of JAK2, whereas inhibiting clathrin-coated pits or plagues to bud off the membrane by the dominant-negative mutant of dynamin enhanced such event. Moreover, unlike the wild-type receptor, an ITSN2-non-binding mutant of GMR defective in targeting to clathrin-coated pits or plagues [collectively referred to as clathrin-coated structures (CCSs) here] failed to activate JAK2 at such locations. Additional experiments demonstrate that ligand treatment not only enhanced JAK2/GMR association at CCSs, but also induced a conformational change of JAK2 which is required for JAK2 to be activated by CCS-localized CK2. Interestingly, ligand-independent activation of the oncogenic mutant of JAK2 (JAK2V617F) also requires the targeting of this mutant to CCSs. But JAK2V617F seems to be constitutively in an open conformation for CK2 activation. Together, this study reveals a novel functional role of CCSs in GMR signaling and the oncogenesis of JAK2V617F. PMID- 22935704 TI - The stress-activated protein kinases p38alpha/beta and JNK1/2 cooperate with Chk1 to inhibit mitotic entry upon DNA replication arrest. AB - Accurate DNA replication is crucial for the maintenance of genome integrity. To this aim, cells have evolved complex surveillance mechanisms to prevent mitotic entry in the presence of partially replicated DNA. ATR and Chk1 are key elements in the signal transduction pathways of DNA replication checkpoint; however, other kinases also make significant contributions. We show here that the stress kinases p38 and JNK are activated when DNA replication is blocked, and that their activity allows S/M, but not G 2/M, checkpoint maintenance when Chk1 is inhibited. Activation of both kinases by DNA replication inhibition is not mediated by the caffeine-sensitive kinases ATR or ATM. Phosphorylation of MKK3/6 and MKK4, p38 and JNK upstream kinases was also observed upon DNA replication inhibition. Using a genetic approach, we dissected the p38 pathway and showed that both p38alpha and p38beta isoforms collaborate to inhibit mitotic entry. We further defined MKK3/6 and MK2/3 as the key upstream and downstream elements in the p38 signaling cascade after replication arrest. Accordingly, we found that the stress signaling pathways collaborate with Chk1 to keep cyclin B1/Cdk1 complexes inactive when DNA replication is inhibited, thereby preventing cell cycle progression when DNA replication is stalled. Our results show a complex response to replication stress, where multiple pathways are activated and fulfill overlapping roles to prevent mitotic entry with unreplicated DNA. PMID- 22935706 TI - DEC1 and MIC-1: new players of p53-dependent cell fate decision. PMID- 22935707 TI - Drosha mediates destabilization of Lin28 mRNA targets. AB - Lin28 plays important roles in development, stem cell maintenance, oncogenesis and metabolism. As an RNA-binding protein, it blocks the biogenesis primarily of let-7 family miRNAs and also promotes translation of a cohort of mRNAs involved in cell growth, metabolism and pluripotency, likely through recognition of distinct sequence and structural motifs within mRNAs. Here, we show that one such motif, shared by multiple Lin28-responsive elements (LREs) present in Lin28 mRNA targets also participates in a Drosha-dependent regulation and may contribute to destabilization of its cognate mRNAs. We further show that the same mutations in the LREs known to abolish Lin28 binding and stimulation of translation also abrogate Drosha-dependent mRNA destabilization, and that this effect is independent of miRNAs, uncovering a previously unsuspected coupling between Drosha-dependent destabilization and Lin28-mediated regulation. Thus, Lin28 dependent stimulation of translation of target mRNAs may, in part, serve to compensate for their intrinsic instability, thereby ensuring optimal levels of expression of genes critical for cell viability, metabolism and pluripotency. PMID- 22935705 TI - Glutamine depletion and glucose depletion trigger growth inhibition via distinctive gene expression reprogramming. AB - Glutamine (Gln) and glucose (Glc) represent two important nutrients for proliferating cells, consistent with the observations that oncogenic processes are associated with enhanced glycolysis and glutaminolysis. Gln depletion and Glc depletion have been shown to trigger growth arrest and eventually cell death. Solid tumors often outgrow the blood supply, resulting in ischemia, which is associated with hypoxia and nutrient insufficiency. Whereas oxygen-sensing and adaptive mechanisms to hypoxia have been well-studied, how cells directly sense and respond to Gln and Glc insufficiency remains unclear. Using mRNA profiling techniques, we compared the gene expression profiles of acute Gln-depleted cells, Glc-depleted cells and cells adapted to Gln depletion. Here we report the global changes of the gene expression in those cells cultured under the defined nutrient conditions. Analysis of mRNA profiling data revealed that Gln and Glc depletion triggered dramatic gene expression reprogramming. Either Gln or Glc deletion leads to changes of the expression of cell cycle genes, but these conditions have distinctive effects on transcription regulators and gene expression profiles. Moreover, Gln and Glc depletion triggered distinguishable ER-stress responses. The gene expression patterns support that Gln and Glc have distinctive metabolic roles in supporting cell survival and proliferation, and cells use different mechanisms to sense and respond to Gln and Glc insufficiency. Our mRNA profiling database provides a resource for further investigating the nutrient-sensing mechanisms and potential effects of Glc and Gln abundance on the biological behaviors of cells. PMID- 22935708 TI - Cdk7: open questions beyond the prevailing model. PMID- 22935709 TI - Increased tRNA modification and gene-specific codon usage regulate cell cycle progression during the DNA damage response. AB - S-phase and DNA damage promote increased ribonucleotide reductase (RNR) activity. Translation of RNR1 has been linked to the wobble uridine modifying enzyme tRNA methyltransferase 9 (Trm9). We predicted that changes in tRNA modification would translationally regulate RNR1 after DNA damage to promote cell cycle progression. In support, we demonstrate that the Trm9-dependent tRNA modification 5 methoxycarbonylmethyluridine (mcm(5)U) is increased in hydroxyurea (HU)-induced S phase cells, relative to G(1) and G(2), and that mcm(5)U is one of 16 tRNA modifications whose levels oscillate during the cell cycle. Codon-reporter data matches the mcm(5)U increase to Trm9 and the efficient translation of AGA codons and RNR1. Further, we show that in trm9Delta cells reduced Rnr1 protein levels cause delayed transition into S-phase after damage. Codon re-engineering of RNR1 increased the number of trm9Delta cells that have transitioned into S-phase 1 h after DNA damage and that have increased Rnr1 protein levels, similar to that of wild-type cells expressing native RNR1. Our data supports a model in which codon usage and tRNA modification are regulatory components of the DNA damage response, with both playing vital roles in cell cycle progression. PMID- 22935711 TI - p85beta increases phosphoinositide 3-kinase activity and accelerates tumor progression. PMID- 22935710 TI - VDAC3 regulates centriole assembly by targeting Mps1 to centrosomes. AB - Centrioles are duplicated during S-phase to generate the two centrosomes that serve as mitotic spindle poles during mitosis. The centrosomal pool of the Mps1 kinase is important for centriole assembly, but how Mps1 is delivered to centrosomes is unknown. Here we have identified a centrosome localization domain within Mps1 and identified the mitochondrial porin VDAC3 as a protein that binds to this region of Mps1. Moreover, we show that VDAC3 is present at the mother centriole and modulates centriole assembly by recruiting Mps1 to centrosomes. PMID- 22935712 TI - Signaling dynamics and embryonic development. PMID- 22935714 TI - Direct Repair of the Pars Interarticularis Defect in Spondylolysis. AB - STUDY DESIGN:: This is a retrospective study analyzing the results of Buck's operation for spondylolysis. OBJECTIVE:: To analyze the results of Buck's method as a treatment for symptomatic spondylolysis clinically and radiographically. And propose a new classification system of spondylolysis. SUMMARY OF BACKGROUND DATA:: 50 defects of 25 patients was classified into 4 subtypes and the bone fusion rate of each subgroups was analyzed. MATERIALS AND METHODS:: From March 1992 to March 2008, 50 defects of 25 patients with symptomatic spondylolysis were treated with Buck's method of direct repair. Surgical indication was (1) under 30 years of age, (2) with intractable low back pain without sciatica who did not response to conservative treatment for over 6 months, (3) without disc degeneration in lumbar MRI, (4) without instability in lateral flexion-extension view. Twenty males and five females with an average age of 21.2 years were followed up for an average 5 years 1 month. Clinical assessment using the Kirkaldy-Willis Criteria and radiographic assessment using the simple radiography and bone SPECT were performed. The pars interarticularis defects were classified into 4 subtypes in accordance with radiographical and intraoperative findings. RESULTS:: Clinically, there were 13 "Excellent", 9 "Good", 1 "Fair", and 2 "Poor" cases. 22 cases achieved Good to Excellent results. Radiographically, a total of 36 (72%) of the 50 defects showed union. There were no loosening of screws, but two patients showed screw breakages and nonunion postoperatively. There were no cases of postoperative complications except two cases of screw breakages. Pars interarticularis defects were classified into 4 subtypes- simple, atrophic, hypertrophic, and defect (gap) type. CONCLUSIONS:: It is suggested that Buck's operation, one of the method of treatment of spondylolysis is simple and has low complication rates. It is our conclusion that Buck's operation, which is a method of treatment for spondylolysis and mild spondylolisthesis when performed selectively in younger patients, can provide satisfactory results. PMID- 22935713 TI - Orc2 protects ORCA from ubiquitin-mediated degradation. AB - Origin recognition complex (ORC) is highly dynamic, with several ORC subunits getting posttranslationally modified by phosphorylation or ubiquitination in a cell cycle-dependent manner. We have previously demonstrated that a WD repeat containing protein ORC-associated (ORCA/LRWD1) stabilizes the ORC on chromatin and facilitates pre-RC assembly. Further, ORCA levels are cell cycle-regulated, with highest levels during G(1), and progressively decreasing during S phase, but the mechanism remains to be elucidated. We now demonstrate that ORCA is polyubiquitinated in vivo, with elevated ubiquitination observed at the G(1)/S boundary. ORCA utilizes lysine-48 (K48) ubiquitin linkage, suggesting that ORCA ubiquitination mediates its regulated degradation. Ubiquitinated ORCA is re localized in the form of nuclear aggregates and is predominantly associated with chromatin. We demonstrate that ORCA associates with the E3 ubiquitin ligase Cul4A Ddb1. ORCA is ubiquitinated at the WD40 repeat domain, a region that is also recognized by Orc2. Furthermore, Orc2 associates only with the non-ubiquitinated form of ORCA, and Orc2 depletion results in the proteasome-mediated destabilization of ORCA. Based on the results, we suggest that Orc2 protects ORCA from ubiquitin-mediated degradation in vivo. PMID- 22935715 TI - Symmetrically medial bony gutters for open-door laminoplasty. AB - STUDY DESIGN: Observational cohort study. OBJECTIVE: The authors modified open door laminoplasty in a manner that creates a bony gutter symmetrically and more medially away from the medial border of the lateral mass. SUMMARY OF BACKGROUND DATA: Cervical laminoplasty is becoming popular, but there was no definite position of bony gutter in performing open-door laminoplasty. METHODS: All of the patients underwent our modified open-door laminoplasty with medial bony gutters. The bony gutter on the open side was made 3 mm medially apart from the medial border of the lateral mass, and an opposite gutter on the hinge side was drilled symmetrically to that on the open side while preserving the ventral cortex. The lamina was kept elevated using titanium miniplates bridging the lamina and facet joint on the open side. On the computed tomography, distance of the bony gutters and the cross-sectional area were measured from C4 to C6. RESULTS: This study included consecutive 61 patients (46 men and 15 women; mean age, 61.6 y old). The average distance of the right bony gutter was 3.43 mm and that of left bony gutter was 3.35 mm. The average cross-sectional area of preoperative and postoperative computed tomography was 189.9 and 281.8 mm in all patients, respectively. In all patients, although bony gutter was placed medially, the spinal canal area was expanded significantly (P < 0.0001). Postoperative C5 palsy developed in one of the 61 patients (1.6%). Compared with patients without C5 palsy, the right bony gutter was placed much closer to the medial border of the lateral mass in a patient with C5 palsy in whom we opened the lamina on the right side. CONCLUSIONS: Our modified open-door laminoplasty with symmetrically and medially placed bony gutters produced low incidence of postoperative C5 palsy with effective expansion of the spinal canal area. PMID- 22935716 TI - Return of research results from genomic biobanks: cost matters. PMID- 22935717 TI - Am I a control?: Genotype-driven research recruitment and self-understandings of study participants. AB - PURPOSE: Genotype-driven research recruitment complicates traditional study roles and may leave those recruited worried about unwelcome surprises from their DNA. This study investigated the ways that individuals experience genotype-driven recruitment, and conceptualize their roles as research participants. METHODS: Individual interviews were conducted with the participants of a genotype-driven study on cystic fibrosis. The eligibility criteria included the presence of one of two genetic variants. We interviewed 24 of these participants: 9 had cystic fibrosis and 15 had been selected from a biobank as "healthy volunteers." RESULTS: Participants with cystic fibrosis expressed no concerns about the eligibility criteria and saw themselves as part of a close-knit research community. However, biobank participants were unsure about why they had been selected and how they should think about themselves relative to the study. They sometimes reacted with anxiety to genetic information that they perceived to connect them with cystic fibrosis. CONCLUSION: Being recruited for a study on the basis of one's genotype may raise uncertainties about the meaning and implications of the genotypic information. People without the disease under study may require especially clear and detailed explanations of what researchers already know about their genetic makeup, in terms of future risk for themselves or their children. PMID- 22935718 TI - Women's and health professionals' preferences for prenatal tests for Down syndrome: a discrete choice experiment to contrast noninvasive prenatal diagnosis with current invasive tests. AB - PURPOSE: To compare the preferences of women and health professionals for key attributes of noninvasive prenatal diagnosis for Down syndrome relative to current invasive tests. METHODS: A questionnaire incorporating a discrete choice experiment was used to obtain participants' stated preference for diagnostic tests that varied according to four attributes: accuracy, time of test, risk of miscarriage, and provision of information about Down syndrome only or Down syndrome and other conditions. Women and health professionals were recruited from five maternity services in England and a patient support group. RESULTS: Questionnaires from 335 women and 181 health professionals were analyzed. Safe tests, conducted early in pregnancy, with high accuracy and information about Down syndrome and other conditions were preferred. The key attribute affecting women's preferences for testing was no risk of miscarriage, whereas for health professionals it was accuracy. CONCLUSIONS: Policies for implementing noninvasive prenatal diagnosis must consider the differences between women's and health professionals' preferences to ensure the needs of all stakeholders are met. Women's strong preference for tests with no risk of miscarriage demonstrates that consideration for safety of the fetus is paramount in decision making. Effective pretest counseling is therefore essential to ensure women understand the possible implications of results. PMID- 22935719 TI - Genomic analysis of pediatric cataract in Saudi Arabia reveals novel candidate disease genes. AB - BACKGROUND: Pediatric cataract is an important preventable blinding disease. Previous studies have estimated 10-25% of cases to be genetic in etiology. METHODS: In an effort to characterize the genetics of cataract in our population, we have conducted a comprehensive clinical and genomic analysis (including autozygome and exome analysis) on a series of 38 index patients. RESULTS: Pediatric cataract is genetic in at least 79% of the study families. Although crystallins accounted for most of the mutant alleles, mutations in other genes were encountered, including recessive mutations in genes that usually cause the disease in a dominant manner. In addition, several novel candidate genes (MFSD6L, AKR1E2, RNLS, and CYP51A1) were identified. CONCLUSION: Pediatric cataract is typically a genetic disease, usually autosomal recessive, in Saudi Arabia. Although defining a specific cataract phenotype can sometimes predict the genetic cause, genomic analysis is often required to unravel the causative mutation given the marked genetic heterogeneity. The identified novel candidate genes require independent confirmation in future studies. PMID- 22935720 TI - A systematic analysis of small supernumerary marker chromosomes using array CGH exposes unexpected complexity. AB - PURPOSE: A small supernumerary marker chromosome is often seen in patients with developmental disorders. Prior to array-based comparative genomic hybridization markers were rarely genotyped end to end. In this study, a valid genotype-to phenotype correlation was possible because the supernumerary marker chromosomes were fully characterized by array-based comparative genomic hybridization in a genome-wide analysis. METHODS: Ten consecutive de novo small supernumerary marker chromosome cases were systematically genotyped using G-banding, C-banding, AgNOR staining, whole-genome array-based comparative genomic hybridization, and fluorescence in situ hybridization. RESULTS: Among 10 small supernumerary marker chromosome cases studied, 4 (40%) were not identified by array-based comparative genomic hybridization because of low-level mosaicism or because they lacked euchromatin. One case (10%) was a simple pericentromeric marker extending from 5p13.3 to 5q11.2. Five (50%) markers showed unexpected complexity. Two cases had markers that were derivative acrocentric (AgNOR+) chromosomes with the euchromatin from chromosomes 18p or 19p. Each of the other three cases with complex markers had unusual characteristics including a marker from noncontiguous segments of chromosome 19q, a highly complex rearrangement involving a chromosome 20 homolog as well as the small supernumerary marker chromosome, and a mosaic duplication of a proximal 8p marker. CONCLUSION: Small supernumerary marker chromosomes are frequently complex on the basis of our small sample. Whole-genome array-based comparative genomic hybridization characterization of the small supernumerary marker chromosome provided informed genetic counseling. PMID- 22935721 TI - Age-specific Parkinson disease risk in GBA mutation carriers: information for genetic counseling. AB - PURPOSE: We sought to estimate age-specific risk of Parkinson disease in relatives of patients with Gaucher disease, who are obligate carriers of GBA mutations and who were not ascertained by family history of Parkinson disease. METHODS: A validated family history of Parkinson disease questionnaire was administered to 119 patients with Gaucher disease who were evaluated at the Mount Sinai School of Medicine from 2009 to 2012; the ages of their parents, siblings, and children, history of Parkinson disease, age at onset of Parkinson disease, and ethnic background were obtained. Kaplan-Meier survival curves were used to estimate age-specific Parkinson disease penetrance among parents of patients with Gaucher disease, who are obligatory GBA mutation carriers. RESULTS: Two participants with Gaucher disease were affected by Parkinson disease (5.4% of those who were 60 years or older). Of the 224 informative parents of patients with Gaucher disease, 11 had Parkinson disease (4.9%). Among the parents (obligatory carriers), cumulative risk of Parkinson disease by ages 65 and 85 was estimated to be 2.2% +/-2.1% and 10.9% +/-7.2%, respectively. CONCLUSION: We provide useful age-specific estimates of Parkinson disease penetrance in patients with Gaucher disease and GBA heterozygous carriers for genetic counseling. Although GBA mutations may increase the risk for PD, the vast majority of patients with Gaucher disease and heterozygotes may not develop the disease. Further studies are needed to identify what modifies the risk of Parkinson disease in GBA mutation carriers. PMID- 22935722 TI - The effects of learning about one's own genetic susceptibility to alcoholism: a randomized experiment. AB - PURPOSE: Increased accessibility of direct-to-consumer personalized genetic reports raises the question: how are people affected by information about their own genetic predispositions? METHODS: Participants were led to believe that they had entered a study on the genetics of alcoholism and sleep disorders. Participants provided a saliva sample purportedly to be tested for the presence of relevant genes. While awaiting the results, they completed a questionnaire assessing their emotional state. They subsequently received a bogus report about their genetic susceptibility and completed a questionnaire about their emotional state and items assessing perceived control over drinking, relevant future drinking-related intentions, and intervention-related motivation and behavior. RESULTS: Participants who were led to believe that they had a gene associated with alcoholism showed an increase in negative affect, decrease in positive affect, and reduced perceived personal control over drinking. Reported intentions for alcohol consumption in the near future were not affected; however, individuals were more likely to enroll in a "responsible drinking" workshop after learning of their alleged genetic susceptibility. CONCLUSION: The first complete randomized experiment to examine the psychological and behavioral effects of receiving personalized genetic susceptibility information indicates some potential perils and benefits of direct-to-consumer genetic tests. PMID- 22935725 TI - Facile synthesis and versatile topological transformation of mono-cleavable symmetric starlike terpolymers. AB - A straightforward strategy involving a RAFT process and ring-opening polymerization was used to construct symmetric reduction-responsive amphiphilic A(2m)B(2n)C(2) (m~n~ 3) starlike terpolymers with precise microstructure, which could be efficiently converted into thiol-functionalized telechelic stars, degraded A(m)B(n)C miktoarm stars and comblike-linear multiblock copolymers via postmodification. PMID- 22935724 TI - Identification and mechanosensitivity of viscerofugal neurons. AB - Enteric viscerofugal neurons are interneurons with cell bodies in the gut wall; they project to prevertebral ganglia where they provide excitatory synaptic drive to sympathetic neurons which control intestinal motility and secretion. Here, we studied the mechanosensitivity and firing of single, identified viscerofugal neurons in guinea-pig distal colon. Flat sheet preparations of gut were set up in vitro and conventional extracellular recordings made from colonic nerve trunks. The nicotinic agonist, 1,1-dimethyl-4-phenylpiperazinium iodide (DMPP) (1mM), was locally pressure ejected onto individual myenteric ganglia. In a few ganglia, DMPP promptly evoked firing in colonic nerves. Biotinamide filling of colonic nerves revealed that DMPP-responsive sites corresponded to viscerofugal nerve cell bodies. This provides a robust means to positively identify viscerofugal neuron firing. Of 15 single units identified in this way, none responded to locally-applied capsaicin (1 MUM). Probing with von Frey hairs at DMPP-responsive sites reliably evoked firing in all identified viscerofugal neurons (18/18 units tested; 0.8-5 mN). Circumferential stretch of the preparation increased firing in all 14/14 units (1-5 g, p<0.05). Both stretch and von Frey hair responses persisted in Ca(2+)-free solution (6 mM Mg(2+), 1mM EDTA), indicating that viscerofugal neurons are directly mechanosensitive. To investigate their adequate stimulus, circular muscle tension and length were independently modulated (BAY K8644, 1 MUM and 10 MUM, respectively). Increases in intramural tension without changes in length did not affect firing. However, contraction-evoked shortening, under constant load, significantly decreased firing (p<0.001). In conclusion, viscerofugal neuron action potentials contribute to recordings from colonic nerve trunks, in vitro. They provide a significant primary afferent output from the colon, encoding circumferential length, largely independent of muscle tension. All viscerofugal neurons are directly mechanosensitive, although they have been reported to receive synaptic inputs. In short, viscerofugal neurons combine interneuronal function with length-sensitive mechanosensitivity. PMID- 22935726 TI - Methods in DNA replication. PMID- 22935727 TI - Use of the isopycnic plots in designing operations of supercritical fluid chromatography. V. Pressure and density drops using mixtures of carbon dioxide and methanol as the mobile phase. AB - The drops of pressure and density along chromatographic columns of different characteristics, eluted with different mixtures of carbon dioxide and methanol was mapped as functions of the column outlet pressure and the operating temperature. This paper extends an earlier report reporting the extent of the pressure and density drops along chromatographic columns eluted with neat CO(2)[1]. It illustrates the similarities and differences in the pressure and density profiles along columns operated with mixed mobile phases and with neat CO(2). Numerical calculations of the pressure and density drops along columns packed with particles of different sizes, under different operating conditions (temperature, outlet pressure, and flow rate), provide important insights regarding the extent of the pressure and density drops under these operating conditions. PMID- 22935728 TI - Matrix effects and recovery calculations in analyses of pharmaceuticals based on the determination of beta-blockers and beta-agonists in environmental samples. AB - In recent years substantial progress has been made in analytical methods for determining pharmaceutical residues in environmental samples. Although much work has attempted to establish the influence of sample matrix complexity on results through the determination of matrix effects (ME), extraction efficiency (EE) and absolute recovery of analytes (AR), comparison of these parameters is very complicated because different authors use different methods to obtain them. Moreover, there are few literature data describing the influence of aqueous matrices (tap water and waste water) on results obtained with GC-MS methods. For these reasons, the main aims of the present study were: (1) to critically review the determination of matrix effects and recovery parameters using the two most common techniques for analyzing drugs in environmental samples: gas and liquid chromatography coupled with mass spectrometry or tandem mass spectrometry (GC-MS, GC-MS/MS and LC-MS, LC-MS/MS); (2) to postulate a uniform method for determining ME, EE and AR using GC techniques; (3) to investigate the influence of different aqueous matrices on the solid-phase extraction, derivatization and final determination of drugs using GC. beta-Blockers and beta-agonists, drugs commonly found in the environment, were chosen as model compounds for this investigation. The values of ME, EE and AR obtained were compared with analogous (or similar) data obtained by other researchers using LC-MS measurements. All the results confirmed that GC-MS analyses are much less sensitive to the complexity of sample matrices than LC-MS, so GC-MS measurements appear to be a very good alternative to LC-MS methods of determining pharmaceutical residues in environmental samples. PMID- 22935723 TI - Circadian and sleep disorders in Parkinson's disease. AB - Impaired sleep and alertness, initially recognized by James Parkinson in his famous monograph "An Essay on the Shaking Palsy" in 1817, is one of the most common and disabling nonmotor symptoms of Parkinson's disease (PD). It is only recently, however, that sleep disturbances in PD have received the attention of medical and research community. Dopamine, the major neurotransmitter implicated in the pathogenesis of PD, plays a pivotal role in the regulation of sleep and circadian homeostasis. Sleep dysfunction affects up to 90% of patients with PD, and may precede the onset of the disease by decades. Sleep dysfunction in PD may be categorized into disturbances of overnight sleep and daytime alertness. Etiology of impaired sleep and alertness in PD is multifactorial. Co-existent primary sleep disorders, medication side effects, overnight re-emergence of motor symptoms, and primary neurodegeneration itself, are main causes of sleep disruption and excessive daytime sleepiness among patients with PD. Increasing body of evidence suggests that the circadian system becomes dysregulated in PD, which may lead to poor sleep and alertness. Treatment options are limited and frequently associated with unwanted side effects. Further studies that will examine pathophysiology of sleep dysfunction in PD, and focus on novel treatment approaches are therefore very much needed. In this article we review the role of dopamine in regulation of sleep and alertness and discuss main sleep and circadian disturbances associated with PD. PMID- 22935730 TI - Differential effects of nicotine treatment and ethanol self-administration on CYP2A6, CYP2B6 and nicotine pharmacokinetics in African green monkeys. AB - In primates, nicotine is metabolically inactivated in the liver by CYP2A6 and possibly CYP2B6. Changes in the levels of these two enzymes may affect nicotine pharmacokinetics and influence smoking behaviors. This study investigated the independent and combined effects of ethanol self-administration and nicotine treatment (0.5 mg/kg b.i.d. s.c.) on hepatic CYP2A6 and CYP2B6 levels (mRNA, protein, and enzymatic activity), in vitro nicotine metabolism, and in vivo nicotine pharmacokinetics in monkeys. CYP2A6 mRNA and protein levels and in vitro coumarin (selective CYP2A6 substrate) and nicotine metabolism were decreased by nicotine treatment but unaffected by ethanol. CYP2B6 protein levels and in vitro bupropion (selective CYP2B6 substrate) metabolism were increased by ethanol but unaffected by nicotine treatment; CYP2B6 mRNA levels were unaltered by either treatment. Combined ethanol and nicotine exposure decreased CYP2A6 mRNA and protein levels, as well as in vitro coumarin and nicotine metabolism, and increased CYP2B6 protein levels and in vitro bupropion metabolism, with no change in CYP2B6 mRNA levels. Chronic nicotine resulted in higher nicotine plasma levels achieved after nicotine administration, consistent with decreased CYP2A6. Ethanol alone, or combined with nicotine, resulted in lower nicotine plasma levels by a mechanism independent of the change in these enzymes. Thus, nicotine can decrease hepatic CYP2A6, reducing the metabolism of its substrates, including nicotine, whereas ethanol can increase hepatic CYP2B6, increasing the metabolism of CYP2B6 substrates. In vivo nicotine pharmacokinetics are differentially affected by ethanol and nicotine, but when both drugs are used in combination the effect more closely resembles ethanol alone. PMID- 22935729 TI - Diastereoselective discrimination of lysine-alanine-alanine peptides by zwitterionic cinchona alkaloid-based chiral selectors using electrospray ionization mass spectrometry. AB - Electrospray ionization-mass spectrometry (ESI-MS) was used to investigate stereoselective interactions between seven zwitterionic alkylsulfonate-modified cinchona alkaloid chiral selectors and biologically relevant lysine-alanine alanine tripeptide and alanine-alanine dipeptide selectands in modified methanolic solutions. Ion intensities from full scan mass spectra were used to assess degrees of association, the ratios of which were used to calculate selectivities for different selector-selectand pairs. The results support prior work on similar systems using HPLC, in that binding is mediated in these systems primarily through the quinuclidine amine on the selector and the C-terminal carboxylate of the peptide. N(alpha)- and N(alpha), N(E)-acetylated forms of the tripeptide were used to study the relative contribution to binding imparted by the presence of multiple basic amines on the tripeptide with the selectors; this was not previously investigated by HPLC. The ability of the sulfonate group on the selector to reach and preferentially interact with the N(E)-amine on the side chain of lysine was revealed. Overall, in acidic methanol conditions (0.5% acetic acid), degrees of association ranged from 1.5% to 17%, and selectivities ranged from non-selective to a 5.5:1 preference for binding one peptide stereoisomer over another with a given chiral selector. In sodium acetate (100 MUM)-modified methanol solutions, significant changes in degrees of association (ranging from 4% to 25%) and selectivities (ranging from non-selective to 4.2:1 preference) were observed. These mass spectrometry experiments help to clarify the chiral recognition mechanism for these selectors and suggest that retention and selectivity could be further modulated in HPLC experiments through the utilization of alkali salt-containing mobile phases. PMID- 22935731 TI - Preclinical characterization of ABT-348, a kinase inhibitor targeting the aurora, vascular endothelial growth factor receptor/platelet-derived growth factor receptor, and Src kinase families. AB - ABT-348 [1-(4-(4-amino-7-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)thieno[3,2-c]pyridin 3-yl)phenyl)-3-(3-fluorophenyl)urea] is a novel ATP-competitive multitargeted kinase inhibitor with nanomolar potency (IC(50)) for inhibiting binding and cellular autophosphorylation of Aurora B (7 and 13 nM), C (1 and 13 nM), and A (120 and 189 nM). Cellular activity against Aurora B is reflected by inhibition of phosphorylation of histone H3, induction of polyploidy, and inhibition of proliferation of a variety of leukemia, lymphoma, and solid tumor cell lines (IC(50) = 0.3-21 nM). In vivo inhibition of Aurora B was confirmed in an engrafted leukemia model by observing a decrease in phosphorylation of histone H3 that persisted in a dose-dependent manner for 8 h and correlated with plasma concentration of ABT-348. Evaluation of ABT-348 across a panel of 128 kinases revealed additional potent binding activity (K(i) < 30 nM) against vascular endothelial growth factor receptor (VEGFR)/platelet-derived growth factor receptor (PDGFR) families and the Src family of cytoplasmic tyrosine kinases. VEGFR/PDGFR binding activity correlated with inhibition of autophosphorylation in cells and inhibition of vascular endothelial growth factor (VEGF)-stimulated endothelial cell proliferation (IC(50) <= 0.3 nM). Evidence of on-target activity in vivo was provided by the potency for blocking VEGF-mediated vascular permeability and inducing plasma placental growth factor. Activity against the Src kinase family was evident in antiproliferative activity against BCR-ABL chronic myeloid leukemia cells and cells expressing the gleevec-resistant BCR-ABL T315I mutation. On the basis of its unique spectrum of activity, ABT-348 was evaluated and found effective in representative solid tumor [HT1080 and pancreatic carcinoma (MiaPaCa), tumor stasis] and hematological malignancy (RS4;11, regression) xenografts. These results provide the rationale for clinical assessment of ABT-348 as a therapeutic agent in the treatment of cancer. PMID- 22935733 TI - Encapsulated ionic liquids (ENILs): from continuous to discrete liquid phase. AB - Encapsulated ionic liquid (ENIL) material was developed, consisting of ionic liquid (IL) introduced into carbon submicrocapsules. ENILs contain >85% w/w of IL but discretized in submicroscopic encapsulated drops, drastically increasing the surface contact area with respect to the neat fluid. ENIL materials were here tested for gas separation processes, obtaining a drastic increase in mass transfer rate. PMID- 22935732 TI - Mnx1: a gatekeeper of beta cell fate. AB - A full understanding of embryonic endocrine pancreas development will be key to the establishment of islet replacement strategies. In particular, it is important to identify molecular pathways that establish the correct balance of specific endocrine pancreatic islet cell types. Recently, our work in the zebrafish has revealed that the correct ratio of alpha and beta cell fates depends on the homeodomain transcription factor Mnx1 (Hb9); in the absence of functional Mnx1, beta cell precursors give rise to alpha cells. ( 1) Our study suggests that mnx1 may function in beta cell precursors to suppress the alpha cell fate. Here we consider how Mnx1 may interact with other endocrine-specific transcription factors to specify beta cells. Our work emphasizes the vital importance of Mnx1 for beta cell development, and suggests that identifying Mnx1 transcriptional targets in beta cell precursors may provide important new information of direct relevance to stem cell-based protocols to cure diabetes. PMID- 22935734 TI - What drives the clustering of membrane-bound Ras? AB - The dynamic assembly and lateral organization of Ras proteins on the plasma membrane has been the focus of much research in recent years. It has been shown that different isoforms of Ras proteins share a nearly identical catalytic domain, yet form distinct and non-overlapping nanoclusters. Though this difference in the clustering behavior of Ras proteins has been attributed largely to their different C terminal lipid modification, its precise physical basis was not determined. Recently, we used computer simulations to study the mechanism by which the triply lipid-modified membrane-anchor of H-ras, and its partially de lipidated variants, form nanoclusters in a model lipid bilayer. We found that the specific nature of the lipid modification is less important for cluster formation, but plays a key role for the domain-specific distribution of the nanoclusters. Here we provide additional details on the interplay between bilayer structure perturbation and peptide-peptide association that provide the physical driving force for clustering. We present some thoughts about how enthalpic (i.e., interaction) and entropic effects might regulate nanocluster size and stability. PMID- 22935735 TI - Reducing muscle temperature drop after warm-up improves sprint cycling performance. AB - PURPOSE: This study aimed to determine the effect of passive insulation versus external heating during recovery after a sprint-specific warm-up on thigh muscle temperature and subsequent maximal sprint performance. METHODS: On three separate occasions, 11 male cyclists (age = 24.7 +/- 4.2 yr, height = 1.82 +/- 0.72 m, body mass = 77.9 +/- 9.8 kg; mean +/- SD) completed a standardized 15-min intermittent warm-up on a cycle ergometer, followed by a 30-min passive recovery period before completing a 30-s maximal sprint test. Muscle temperature was measured in the vastus lateralis at 1, 2, and 3 cm depth before and after the warm-up and immediately before the sprint test. Absolute and relative peak power output was determined and blood lactate concentration was measured immediately after exercise. During the recovery period, participants wore a tracksuit top and (i) standard tracksuit pants (CONT), (ii) insulated athletic pants (INS), or (iii) insulated athletic pants with integrated electric heating elements (HEAT). RESULTS: Warm-up increased Tm by approximately 2.5 degrees C at all depths, with no differences between conditions. During recovery, Tm remained elevated in HEAT compared with INS and CONT at all depths (P < 0.001). Both peak and relative power output were elevated by 9.6% and 9.1%, respectively, in HEAT compared with CONT (both P < 0.05). The increase in blood lactate concentration was greater (P < 0.05) after sprint in HEAT (6.3 +/- 1.8 mmol.L(-1)) but not INS (4.0 +/- 1.8 mmol.L(-1)) versus CONT (4.1 +/- 1.9 mmol.L(-1)). CONCLUSIONS: Passive heating of the thighs between warm-up completion and performance execution using pants incorporating electrically heated pads can attenuate the decline in Tm and improve sprint cycling performance. PMID- 22935736 TI - Dynamic visual acuity in baseball players is due to superior tracking abilities. AB - PURPOSE: Dynamic visual acuity (DVA) is defined as the ability to discriminate the fine parts of a moving object. DVA is generally better in baseball players than that in nonplayers. Although the better DVA of baseball players has been attributed to a better ability to track moving objects, it might be derived from the ability to perceive an object even in the presence of a great distance between the image on the retina and the fovea (retinal error). However, the ability to perceive moving visual stimuli has not been compared between baseball players and nonplayers. METHODS: To clarify this, we quantitatively measured abilities of eye movement and visual perception using moving Landolt C rings in baseball players and nonplayers. RESULTS: Baseball players could achieve high DVA with significantly faster eye movement at shorter latencies than nonplayers. There was no difference in the ability to perceive moving object's images projected onto the retina between baseball players and nonplayers. CONCLUSIONS: These results suggest that the better DVA of baseball players is primarily due to a better ability to track moving objects with their eyes rather than to improved perception of moving images on the retina. This skill is probably obtained through baseball training. PMID- 22935737 TI - Dopamine transporter shown by SPECT in patients with periodic leg movement after acute physical exercise. AB - PURPOSE: This study aimed to evaluate dopamine transporter (DAT) density in patients with periodic leg movement (PLM) shown by [(99mt)Tc]TRODAT-1 single photon emission computed tomography (SPECT) imaging and to determine the influence of acute physical exercise (maximal exercise test [MET]) on DAT densities. METHODS: Sixteen healthy male volunteers between 45 and 65 yr of age were selected to participate in the study. Each subject (eight subjects in the control group and eight subjects in the patients with PLM experimental group) underwent baseline polysomnography (PSG) to evaluate sleep patterns and PLM index values. After obtaining PSG baselines, SPECT baselines were determined using [(99mt)Tc]TRODAT-1, a selective DAT imaging ligand. Subsequently, the volunteers performed the MET in the morning, followed by a SPECT 2 h later and PSG that night to assess the effect of acute physical exercise on DAT and sleep patterns. RESULTS: The baseline SPECT results showed marginally significantly lower DAT densities in the striatal region of the experimental group. After the MET, no significant differences were observed between groups. The results also showed a significant reduction in the PLM index in the experimental group and a significantly increased percentage of stage 1 non-REM sleep in both groups after MET. CONCLUSIONS: Our results show that patients with PLM had a marginally lower DAT density in the left putamen region compared with the control group. Although the effect of acute physical exercise (MET) reduced PLM symptoms, the results suggest that this improvement was not due to DAT availability. PMID- 22935738 TI - Prospective BMI category change associated with cardiovascular fitness change. AB - PURPOSE: The objective of this study was to test the relationship of change in body mass index (BMI) percentile score group (from sixth to eighth grade) with change in cardiovascular fitness (CVF), baseline BMIz-score, and CVF. METHODS: Children (3998 (92%)) in the HEALTHY trial provided complete data at the beginning of sixth and end of eighth grades. Height and weight were assessed according to standardized protocol. CVF was measured using the 20-m shuttle run. Changes in BMI percentile were categorized into five groups: increased a BMI category, stayed obese, stayed overweight, stayed at a healthy weight, and decreased a BMI category. Data were analyzed separately by sex, controlling for race, parental education, change in pubertal stage, and baseline BMIz-score and CVF. RESULTS: Youth (male and female) who lowered their BMI group or remained in the healthy or overweight groups had significantly larger increases in CVF than those in the stayed obese or increased a BMI category groups. However, these relationships accounted for a small percentage of variance (i.e., weak relationship). Staying obese was associated with the highest baseline BMIz-score, with the second highest among those who decreased a BMI category. BMI category change accounted for the most variance in baseline BMIz-score. CONCLUSIONS: Changes in BMI categories were substantially more strongly related to sixth-grade values of BMIz-score than to CVF changes. Because preexisting adiposity may inhibit adiposity change, changes in CVF and adiposity should be attempted before middle school. PMID- 22935739 TI - Effect of aerobic interval training and caffeine on blood platelet function. AB - PURPOSE: Hyperactive platelets contribute to the thrombotic response in humans, and exercise transiently increases platelet function. Caffeine is routinely used by athletes as an ergogenic aid, but the combined effect of exercise and caffeine on platelet function has not been investigated. METHODS: Twelve healthy males were randomly assigned to one of four groups and undertook four experimental trials of a high-intensity aerobic interval training (AIT) bout or rest with ingestion of caffeine (3 mg.kg(-1)) or placebo. AIT was 8 * 5 min at approximately 75% peak power output (approximately 80% VO2peak) and 1-min recovery (approximately 40% peak power output, approximately 50% VO2peak) intervals. Blood/urine was collected before, 60, and 90 min after capsule ingestion and analyzed for platelet aggregation/activation. RESULTS: AIT increased platelet reactivity to adenosine diphosphate (placebo 30.3%, caffeine 13.4%, P < 0.05) and collagen (placebo 10.8%, caffeine 5.1%, P < 0.05) compared with rest. Exercise placebo increased adenosine diphosphate-induced aggregation 90 min postingestion compared with baseline (40.5%, P < 0.05), but the increase when exercise was combined with caffeine was small (6.6%). During the resting caffeine protocol, collagen-induced aggregation was reduced (-4.3%, P < 0.05). AIT increased expression of platelet activation marker PAC-1 with exercise placebo (P < 0.05) but not when combined with caffeine. CONCLUSION: A single bout of AIT increases platelet function, but caffeine ingestion (3 mg.kg(-1)) does not exacerbate platelet function at rest or in response to AIT. Our results provide new information showing caffeine at a dose that can elicit ergogenic effects on performance has no detrimental effect on platelet function and may have the potential to attenuate increases in platelet activation and aggregation when undertaking strenuous exercise. PMID- 22935740 TI - Aerobic fitness affects cortisol responses to concurrent challenges. AB - PURPOSE: Studies have demonstrated that a combination of mental and physical challenge can elicit exacerbated state anxiety, effort sense, and cortisol responses above that of a single stimulus. However, an analysis of the effects of aerobic fitness on the responses of cortisol to concurrent mental and physical stress between below average and above average fitness individuals has not been conducted. This study examined the effects of a combination of acute mental challenges and physical stress on psychological and cortisol responses between eight individuals of below average fitness (low fit (LF), VO2max = 36.58 +/- 3.36 mL.kg(-1).min(-1)) and eight individuals of above average fitness (high fit (HF), VO2max = 51.18 +/- 2.09 mL.kg(-1).min). METHODS: All participants completed two experimental conditions. An exercise-alone condition (EAC) consisted of cycling at 60% VO2max for 37 min, and a dual-challenge condition (DCC) included concurrent participation in a mental challenge for 20 min while cycling. RESULTS: The DCC resulted in increases in state anxiety (P = 0.018), perceived overall workload (P = 0.001), and exacerbated cortisol responses (P = 0.04). Furthermore, LF participants had a greater overall cortisol response in the DCC compared with the EAC (DCC = 346.83 +/- 226.92; EAC = -267.46 +/- 132.32; t7 = 2.49, P = 0.04), whereas HF participants demonstrated no difference between conditions (DCC = 38.91 +/- 147.01; EAC = -324.60 +/- 182.78; t7 = 1.68, P = 0.14). DISCUSSION: LF individuals seem to demonstrate unnecessary and unfavorable responses to the DCC compared with HF individuals, particularly concerning cortisol. The exacerbated cortisol responses in LF individuals have implications for harmful consequences such as increased risk of cardiovascular disease. PMID- 22935741 TI - Amorphous ternary cyclodextrin nanocomposites of telmisartan for oral drug delivery: improved solubility and reduced pharmacokinetic variability. AB - Despite of advancements in dosage form design and use of multifunctional excipients, improvement in dissolution characteristics of molecules like Telmisartan (TEL) having exceedingly pH dependent and poor solubility profile is still challenging. The present research work explores an innovative particle engineering approach which synergistically coalesce two principally different solubility enhancement strategies namely ternary beta-cyclodextrin complexation and top-down nanonization in a unit process. The research was aimed to improve solubility and reduce in vivo variability in pharmacokinetic parameters of TEL irrespective to physiological pH conditions. Ternary beta-cyclodextrin nanocomposites of TEL were prepared with high pressure homogenization using meglumine as ternary component. TEL nanocomposites were thoroughly characterized for particle size, surface topology, surface charge, inclusion complexation, crystalinity, dissolution and in vivo pharmacokinetic performance in male wistar rats at fed and fasted state. TEL nanocomposites exhibited average particle size of 698 +/- 23 nm. Remarkable improvement in in vitro dissolution characteristics in multimedia and biorelevant media was observed in comparison with plain drug and marketed formulation. Results of in vivo pharmacokinetic studies revealed that, nanocomposites effectively bypass variation in pharmacokinetic parameters at fed and fasted states with 346%, 315%, 301% and 321% increase in relative bioavailability compared to marketed formulation and pure TEL in fed and fasted conditions respectively. PMID- 22935742 TI - Development of ICD-10-TM ontology for a semi-automated morbidity coding system in Thailand. AB - OBJECTIVES: The International Classification of Diseases and Related Health Problems, 10th Revision, Thai Modification (ICD-10-TM) ontology is a knowledge base created from the Thai modification of the World Health Organization International Classification of Diseases and Related Health Problems, 10th Revision. The objectives of this research were to develop the ICD-10-TM ontology as a knowledge base for use in a semi-automated ICD coding system and to test the usability of this system. METHODS: ICD concepts and relations were identified from a tabular list and alphabetical indexes. An ICD-10-TM ontology was defined in the resource description framework (RDF), notation-3 (N3) format. All ICD-10 TM contents available as Microsoft Word documents were transformed into N3 format using Python scripts. Final RDF files were validated by ICD experts. The ontology was implemented as a knowledge base by using a novel semi-automated ICD coding system. Evaluation of usability was performed by a survey of forty volunteer users. RESULTS: The ICD-10-TM ontology consists of two main knowledge bases (a tabular list knowledge base and an index knowledge base) containing a total of 309,985 concepts and 162,092 relations. The tabular list knowledge base can be divided into an upper level ontology, which defines hierarchical relationships between 22 ICD chapters, and a lower level ontology which defines relations between chapters, blocks, categories, rubrics and basic elements (include, exclude, synonym etc.) of the ICD tabular list. The index knowledge base describes relations between keywords, modifiers in general format and a table format of the ICD index. In this research, the creation of an ICD index ontology revealed interesting findings on problems with the current ICD index structure. One problem with the current structure is that it defines conditions that complicate pregnancy and perinatal conditions on the same hierarchical level as organ system diseases. This could mislead a coding algorithm into a wrong selection of ICD code. To prevent these coding errors by an algorithm, the ICD-10 TM index structure was modified by raising conditions complicating pregnancy and perinatal conditions into a higher hierarchical level of the index knowledge base. The modified ICD-10-TM ontology was implemented as a knowledge base in semi automated ICD-10-TM coding software. A survey of users of the software revealed a high percentage of correct results obtained from ontology searches (>95%) and user satisfaction on the usability of the ontology. CONCLUSION: The ICD-10-TM ontology is the first ICD-10 ontology with a comprehensive description of all concepts and relations in an ICD-10-TM tabular list and alphabetical index. A researcher developing an automated ICD coding system should be aware of The ICD index structure and the complexity of coding processes. These coding systems are not a word matching process. ICD-10 ontology should be used as a knowledge base in The ICD coding software. It can be used to facilitate successful implementation of ICD in developing countries, especially in those countries which do not have an adequate number of competent ICD coders. PMID- 22935743 TI - Construction of a plasmid for expression of rat platelet-derived growth factor C and its effects on proliferation, migration and adhesion of endothelial progenitor cells. AB - Endothelial progenitor cells (EPCs) play a key role in restoring endothelial function and enhancing angiogenesis. Platelet-derived growth factor C (PDGF-C) is a newly discovered member of the PDGF family that binds to the PDGFR-alpha homodimer and the PDGFR-alpha/beta heterodimer. Currently, the biological effects of PDGF-C on EPCs proliferation, migration and adhesion are not well understood. In this study, the full-length coding sequence (CDS) region for the PDGF-C gene was obtained by reverse transcriptase-polymerase chain reaction (RT-PCR). The amplified PDGF-C product was digested and inserted into the pMD 19-T simple vector and then subcloned into a pIRES2-EGFP plasmid to construct the pIRES2-EGFP PDGF-C eukaryotic expression vector. After it was transfected to EPCs, the expression of PDGF-C protein in EPCs was verified by Western blotting analysis. Finally, we investigated the effects of PDGF-C protein overexpression on EPCs proliferation, migration and adhesion. In conclusion, we constructed a recombinant eukaryotic expression vector containing the complete CDS region of PDGF-C and expressed the full-length and functional PDGF-C protein successfully. Furthermore, PDGF-C promoted EPCs proliferation, migration and adhesion. This offers promise for the development of new therapeutic strategies for improving neovascularization and repair of blood vessel endothelium in patients with ischemic heart disease or peripheral arterial occlusive disease. PMID- 22935744 TI - Experimental and theoretical studies of plasmon-molecule interactions. AB - Plasmon-molecule interactions are widely believed to involve photo-induced interferences between the localized excitation of individual electrons in molecules and the large collective excitation of conduction electrons in metal particles. The intrinsic multi-scale characteristics of plasmon-molecule interactions not only offer great opportunities for realizing precise top-down control of the optical properties of individual molecules, but also allow for accurate bottom-up manipulation of light polarization and propagation as a result of molecular excitation. However, the temporal and spatial complexity of plasmon molecule experiments severely limits our interpretation and understanding of interactions that have important applications in dye-sensitized solar cells, single-molecule detectors, photoconductive molecular electronics, all-optical switching and photo-catalytic water splitting. This review aims to outline recent progress in experimental practice and theory for probing and exploiting the subtle coupling between discrete molecular orbitals and continuous metallic bands. For each experimental technique or theoretical model, the fundamental mechanisms and relevant applications are discussed in detail with specific examples. In addition, the experimental validation of theoretical models and the computational design of functional devices are both highlighted. Finally, a brief summary is presented together with an outlook for potential future directions of this emerging interdisciplinary research field. PMID- 22935745 TI - Coagulation response in dogs with and without systemic inflammatory response syndrome - preliminary results. AB - The impact of systemic inflammatory response syndrome (SIRS) on all phases of coagulation is largely unknown in dogs. Fifty-six healthy dogs (controls) and 25 diseased dogs were included. Based on physical and hematological examination, dogs were classified as "no-SIRS" (n=7) or "SIRS" (n=18). Evaluated coagulation variables included platelets, coagulation times, fibrinogen, antithrombin (AT), FVIII, protein C, protein S, activated protein C (APC)-ratio, calculated from aPTT with and without presence of APC, and kaolin-activated thrombelastography (TEG). Overall, no-SIRS and SIRS were characterized by hypocoaguable state (P<0.001 compared to controls) i.e., prolonged coagulation times, decreased AT (median 59 U/L and 89 U/L versus 126 U/L), and FVIII (median 19 U/L and 70 U/L versus 102 U/L). In no-SIRS and SIRS, APC-ratio was significantly lower than in the controls (median 1.1 and 2.0 versus 2.5, P<0.01, P<0.001). Severe coagulopathies may be present in critically ill dogs without concurrent SIRS. APC resistance is a frequent finding in severely diseased dogs. PMID- 22935746 TI - Effects of sleep bruxism on functional and occlusal parameters: a prospective controlled investigation. AB - This study was conducted to verify the results of a preceding retrospective pilot study by means of a prospective controlled investigation including a larger sample size. Therefore, the aim of this clinical investigation was to analyze the relationship between sleep bruxism and several functional and occlusal parameters. The null hypothesis of this study was that there would be no differences among sleep bruxism subjects and non-sleep bruxism controls regarding several functional and occlusal parameters. Fifty-eight sleep bruxism subjects and 31 controls participated in this study. The diagnosis sleep bruxism was based on clinical criteria of the American Academy of Sleep Medicine. Sixteen functional and occlusal parameters were recorded clinically or from dental study casts. Similar to the recently published retrospective pilot study, with a mean slide of 0.77 mm (s.d., 0.69 mm) in the sleep bruxism group and a mean slide of 0.4 mm (s.d., 0.57 mm) in the control group, the evaluation of the mean comparison between the two groups demonstrated a larger slide from centric occlusion to maximum intercuspation in sleep bruxism subjects (Mann-Whitney U test; P=0.008). However, following Bonferroni adjustment, none of the 16 occlusal and functional variables differed significantly between the sleep bruxism subjects and the non-sleep bruxism controls. The present study shows that the occlusal and functional parameters evaluated do not differ between sleep bruxism subjects and non-sleep bruxism subjects. However, as the literature reveals a possible association between bruxism and certain subgroups of temporomandibular disorders, it appears advisable to incorporate the individual adaptive capacity of the stomatognathic system into future investigations. PMID- 22935747 TI - Chemical composition of Galla chinensis extract and the effect of its main component(s) on the prevention of enamel demineralization in vitro. AB - To determine the chemical composition of Galla chinensis extract (GCE) by several analysis techniques and to compare the efficacy of GCE and its main component(s) in inhibition of enamel demineralization, for the development of future anticaries agents, main organic composition of GCE was qualitatively determined by liquid chromatography-time of flight-mass spectrometry (LC-TOF-MS) and quantified by high-performance liquid chromatography-diode array detector (HPLC DAD). Inorganic ions were tested by inductively coupled plasma-atomic emission spectroscopy and F was especially measured by ion chromatography. Then, bovine enamel blocks were randomly divided into four treatment groups and were subjected to a pH-cycling regime for 12 times. Each cycle included 5-min applications with one of four treatments: 4 g?L(-1) GCE solution, 4 g?L(-1) gallic acid (GA) solution, 1 g?L(-1) NaF solution (positive control), deionized water (DDW, negative control), and then 60-min application in pH 5.0 acidic buffer and 5-min application in neutral buffer. Acidic buffers were retained for calcium analysis. The main organic composition of GCE were GA and its isomer, and, to a lesser extent, small molecule gallotannins. The content of GA in GCE was 71.3%+/-0.2% (w/w). Inorganic ions were present in various amounts, of which Ca was (136+/ 2.82) ug?g(-1), and Zn was (6.8+/-0.1) ug?g(-1). No F was detected in GCE. In pH cycling, GA showed an effect similar to GCE in inhibiting enamel demineralization (P>0.05). GA was found to be the main effective, demineralization inhibiting component of GCE and could be a promising agent for the development of anticaries agents. PMID- 22935748 TI - Low-grade myofibroblastic sarcoma of the palate. AB - Low-grade myofibroblastic sarcoma (LGMS) is a rare, malignant tumor with myofibroblastic differentiation. Despite it being classified as a distinct entity by the World Health Organization, a few cases were reported in the oral and maxillofacial region. Here, a LGMS developed on the palate of a 73-year-old man who presented with a 1-cm tumor on the posterior border of the palate. Based on the histological and immunohistochemical features, a diagnosis of LGMS was established. The tumor was resected, and no recurrence was observed over 2 years. Although the tongue is the most preferred site for LGMS, it may occur in any region of the oral cavity. PMID- 22935749 TI - Magnetite nanorod thermotropic liquid crystal colloids: synthesis, optics and theory. AB - We have developed a facile method for preparing magnetic nanoparticles which couple strongly with a liquid crystal (LC) matrix, with the aim of preparing ferronematic liquid crystal colloids for use in magneto-optical devices. Magnetite nanoparticles were prepared by oxidising colloidal Fe(OH)(2) with air in aqueous media, and were then subject to alkaline hydrothermal treatment with 10 mol dm(-3) NaOH at 100 degrees C, transforming them into a polydisperse set of domain magnetite nanorods with maximal length ~500 nm and typical diameter ~20 nm. The nanorods were coated with 4-n-octyloxybiphenyl-4-carboxylic acid (OBPh) and suspended in nematic liquid crystal E7. As compared to the conventional oleic acid coating, this coating stabilizes LC-magnetic nanorod suspensions. The suspension acts as a ferronematic system, using the colloidal particles as intermediaries to amplify magnetic field-LC director interactions. The effective Frederiks magnetic threshold field of the magnetite nanorod-liquid crystal composite is reduced by 20% as compared to the undoped liquid crystal. In contrast with some previous work in this field, the magneto-optical effects are reproducible on time scales of months. Prospects for magnetically switched liquid crystal devices using these materials are good, but a method is required to synthesize single magnetic domain nanorods. PMID- 22935750 TI - Sequential native peptide ligation strategies for total chemical protein synthesis. AB - Total chemical synthesis of proteins is usually achieved by assembling unprotected peptide segments using site-specific and chemoselective native peptide ligation methods. Access to large proteins often requires the assembly of at least three segments due to the current limits of solid phase synthesis of individual peptide segments. The aim of this tutorial review is to present the basic concepts and challenges underlying the design of sequential peptide ligation strategies using solution or solid phase chemistry. A special emphasis is given to C-to-N and N-to-C three-segment assembly strategies, which potentially give access to proteins composed of up to 150 amino acid residues. PMID- 22935751 TI - A combinatorial approach toward smart libraries of discontinuous epitopes of HIV gp120 on a TAC synthetic scaffold. AB - We describe rapid and convenient access to smart libraries of protein surface discontinuous epitope mimics. Up to three different cyclic peptides, representing discontinuous epitopes in HIV-gp120, were conjugated to a triazacyclophane scaffold molecule via CuAAC. In this way protein mimics for use as synthetic vaccines and beyond will become available. PMID- 22935752 TI - Managing food allergy in childhood. AB - PURPOSE OF REVIEW: This study reviews the newest developments on experimental therapies for the treatment of food allergy. RECENT FINDINGS: Epitope studies and microarray technology promise to improve the accuracy of diagnostic testing and may allow the prediction of reaction severity and the likelihood of allergy resolution. The regular ingestion of small amounts of food in oral immunotherapy (OIT) has been shown to dramatically increase reaction thresholds. However, a subset of patients have developed significant gastrointestinal symptoms requiring discontinuation of the treatment. A similar treatment given sublingually has appeared safer than OIT, but has also shown a less robust effect. Ingestion of extensively heated foods seems to accelerate the natural resolution of milk and egg allergy. The injectable anti-IgE therapy omalizumab has been shown to benefit in conjunction with OIT and preliminary data has suggested that it may also be effective as monotherapy. The Chinese herbal formula FAHF-2 has been shown to suppress anaphylaxis from single and multiple food allergies in mice, and early human studies have shown that it is well tolerated. SUMMARY: Improved testing should allow more accurate diagnosis of food allergy. For these patients, treatments are on the horizon, but further studies are needed to determine long term safety and efficacy. PMID- 22935753 TI - Radiation exposure in children with inflammatory bowel disease. AB - PURPOSE OF REVIEW: Radiation exposure due to medical imaging has grown exponentially over the past two decades and the awareness has increased in the last few years with a number of articles in scientific publications and lay press. Radiation increases the risk of cancer and is particularly a concern in children. Limiting radiation exposure is most important in children, who are more sensitive to radiation, and specifically in children with a chronic lifelong disease such as inflammatory bowel disease (IBD). RECENT FINDINGS: Children with IBD and specifically Crohn's disease demonstrate high exposure to ionizing radiation due to medical imaging. The yearly rate of medical imaging radiation exposure may seem small at approximately 3-5 mSv/year, which is only slightly higher than typical background radiation (3 mSv/year). However, this extra yearly radiation exposure to children with a lifelong chronic disease may increase the risk of cancer. Additionally, recent literature suggests that some children with more severe disease are exposed to high radiation doses within the first few years of diagnosis. Imaging modalities that do not utilize radiation, such as MRI and ultrasonography, have demonstrated utility in diagnosing and managing IBD and are particularly important for children. SUMMARY: Pediatricians caring for children with chronic diseases should consider radiation exposure and limit exposure when possible. Future quality outcome benchmarks should include limiting exposure to radiation in children with chronic diseases. PMID- 22935754 TI - 'Shovel-Ready' applications of stem cell advances for pediatric heart disease. AB - PURPOSE OF REVIEW: The past decade has seen remarkable advances in the field of stem cell biology. Many new technologies and applications are passing the translational phase and likely will soon be relevant for the clinical pediatric cardiologist. RECENT FINDINGS: This review will focus on two advances in basic science that are now translating into clinical trials. The first advance is the recognition, characterization, and recent therapeutic application of resident cardiac progenitor cells (CPCs). Early results of adult trials and scattered case reports in pediatric patients support expanding CPC-based trials for end-stage heart failure in pediatric patients. The relative abundance of CPCs in the neonate and young child offers greater potential benefits in heart failure treatment than has been realized to date. The second advance is the technology of induced pluripotent stem cells (iPSCs), which reprograms differentiated somatic cells to an undifferentiated embryonic-like state. When iPSCs are differentiated into cardiomyocytes, they model a patient's specific disease, test pharmaceuticals, and potentially provide an autologous source for cell-based therapy. SUMMARY: The therapeutic recruitment and/or replacement of CPCs has potential for enhancing cardiac repair and regeneration in children with heart failure. Use of iPSCs to model heart disease holds great potential to gain new insights into diagnosis, pathophysiology, and disease-specific management for genetic-based cardiovascular diseases that are prevalent in pediatric patients. PMID- 22935755 TI - Screening for critical congenital heart disease: advancing detection in the newborn. AB - PURPOSE OF REVIEW: Screening for critical congenital heart disease (CCHD) using pulse oximetry was added to the recommended uniform screening panel through an endorsement by the Health and Human Services Secretary in September 2011. As organizations on both the macrolevels and microlevels consider implementation, research efforts and professional endorsements have been completed, providing important guidance moving forward. RECENT FINDINGS: Screening for CCHD has been endorsed by the American Heart Association, American College of Cardiology, March of Dimes and American Academy of Pediatrics. In addition, strategies for best practice regarding implementation and a screening protocol for well babies are now available. Screening for CCHD as a complement to existing mechanisms has been added without need for additional staff, associated with improved detection, and shown to be cost effective with an incremental cost-effectiveness ratio of L24 000. Hospitals in Wisconsin assessed their readiness and reported that all had pulse oximetry equipment onsite and 74.4% had access to same-day neonatal echocardiography. Infants in neonatal care units need further consideration, as there were reports of CCHD missed. SUMMARY: CCHD screening is easily implemented in community hospitals, and is cost effective, and some states may be better prepared for implementation than previously hypothesized. PMID- 22935756 TI - An update on hereditary angioedema. AB - PURPOSE OF REVIEW: To review and update the management and understanding of hereditary angioedema (HAE), while integrating insights into pediatric subtleties that exist in practice. RECENT FINDINGS: Major advances have recently been made in HAE treatment. Ecallantide (a kallikrein inhibitor approved for use in the United States in December 2009) and icatibant (a selective bradykinin B2 receptor antagonist approved for use in the United States in August 2011) represent novel subcutaneous therapies for acute HAE exacerbations. Recombinant human C1 esterase inhibitor (C1INH) serves as a promising future alternative to current mainstay acute and prophylactic treatment with plasma-derived C1INH. Recent guidelines have outlined new algorithms for short-term and long-term prophylaxis against HAE exacerbations. SUMMARY: The evolving standard of care for HAE management involves not only treatment of acute exacerbations but also individualized patient preference-sensitive short-term and long-term prophylaxis. Updated international consensus guidelines provide useful protocols, whereas recent clinical reviews have raised awareness of HAE. Further advances will likely focus on improving patient access to convenient acute and prophylactic treatment with C1INH. PMID- 22935757 TI - Pediatric cardiology: moving into a new era of diagnosis and therapeutic intervention. PMID- 22935758 TI - New imaging modalities to assess cardiac function: not just pretty pictures. AB - PURPOSE OF REVIEW: The following review will focus on the current advances in both echocardiography and cardiovascular MRI (CMRI) in the assessment of cardiac function. RECENT FINDINGS: The assessment of cardiac function in pediatric patients and in congenital heart disease (CHD) patients has dramatically improved over the last several years. The advancement of transthoracic echocardiography with tissue Doppler imaging, speckle tracking, and three-dimensional echocardiography has enabled strain assessment and the ability to estimate ventricular volumes in these complex patients. In the last few decades, CMRI has become an imaging modality that is now part of the standard tools used for cardiac assessment. With superb two-dimensional and three-dimensional resolution, CMRI allows clear delineation of cardiac and extracardiac structures as well as accurate and reproducible assessment of ventricular volume and function. The most recent and robust contributions of CMRI are its ability to provide characterization of the myocardium and the development of new measurements of global and regional myocardial mechanics and function. SUMMARY: Recent advances in echocardiography and CMRI allow a better understanding of myocardial mechanics and composition as well as accurate assessment of ventricular volume and global and regional function in the complex and unique anatomy often found in CHD patients. PMID- 22935759 TI - The determination and interpretation of the therapeutic index in drug development. AB - A key part of drug discovery and development is the characterization and optimization of the safety and efficacy of drug candidates to identify those that have an appropriately balanced safety-efficacy profile for a given indication. The therapeutic index (TI)--which is typically considered as the ratio of the highest exposure to the drug that results in no toxicity to the exposure that produces the desired efficacy--is an important parameter in efforts to achieve this balance. Various types of safety and efficacy data are generated in vitro and in vivo (in animals and in humans), and these data can be used to predict the clinical TI of a drug candidate at an early stage. However, approaches to systematically and quantitatively compare these types of data and to apply this knowledge more effectively are needed. This article critically discusses the various aspects of TI determination and interpretation in drug development for both small molecule drugs and biotherapeutics. PMID- 22935760 TI - A survey on visual information search behavior and requirements of radiologists. AB - OBJECTIVES: The main objective of this study is to learn more on the image use and search requirements of radiologists. These requirements will then be taken into account to develop a new search system for images and associated meta data search in the Khresmoi project. METHODS: Observations of the radiology workflow, case discussions and a literature review were performed to construct a survey form that was given online and in paper form to radiologists. Eye tracking was performed on a radiology viewing station to analyze typical tasks and to complement the survey. RESULTS: In total 34 radiologists answered the survey online or on paper. Image search was mentioned as a frequent and common task, particularly for finding cases of interest for differential diagnosis. Sources of information besides the Internet are books and discussions with colleagues. Search for images is unsuccessful in around 25% of the cases, stopping the search after around 10 minutes. The most common reason for failure is that target images are considered rare. Important additions for search requested in the survey are filtering by pathology and modality, as well as search for visually similar images and cases. Few radiologists are familiar with visual retrieval but they desire the option to upload images for searching similar ones. CONCLUSIONS: Image search is common in radiology but few radiologists are fully aware of visual information retrieval. Taking into account the many unsuccessful searches and time spent for this, a good image search could improve the situation and help in clinical practice. PMID- 22935761 TI - [Epidural analgesia for Nissen surgery in a child using a caudal approach]. PMID- 22935762 TI - Towards state-of-the-art anesthesia for fetal surgery: obstacles and opportunities. PMID- 22935763 TI - [Is postoperative epidural analgesia worthwhile actually?]. PMID- 22935764 TI - [Postoperative hepatic herniation]. PMID- 22935765 TI - Saharan dust, particulate matter and cause-specific mortality: a case-crossover study in Barcelona (Spain). AB - BACKGROUND: Studies measuring health effects of Saharan dust based on large particulate matter (PM) fraction groups may be masking some effects. Long distant transport reduces the amount of heavier and larger particles in the Saharan air masses increasing the relative contribution of smaller particles that may be more innocuous. This study investigates the association between different PM fractions and daily mortality during Saharan and non-Saharan days in Barcelona, Spain. METHODS: We collected daily PM(1), PM(2.5-1) and PM(10-2.5) fractions, and cause specific mortality (cardiovascular, respiratory and cerebrovascular) between March 2003 and December 2007. Changes of effects between Saharan and non-Saharan dust days were assessed using a time-stratified case-crossover design. RESULTS: During non-Saharan dust days we found statistically significant (p<0.05) effects of PM(10-2.5) for cardiovascular (odds ratio for increase of an interquartile range, OR=1.033, 95% confidence interval: 1.006-1.060) and respiratory mortality (OR=1.044, 95% CI: 1.001-1.089). During Saharan dust days strongest cardiovascular effects were found for the same fraction (OR=1.085, 95% CI: 1.017 1.158) with an indication of effect modification (p=0.111). Effects of PM(2.5-1) during Saharan dust days were about the double than in non-dust days for cardiovascular and respiratory mortality, but these differences were not statistically significant. CONCLUSION: Our results using independent fractions of PMs provide further evidence that the effects of short-term exposure to PM during Saharan dust days are associated with both cardiovascular and respiratory mortality. A better understanding of which of the different PM size fractions brought by Saharan dust is more likely to accelerate adverse effects may help better understand mechanisms of toxicity. PMID- 22935767 TI - Realizing the IOM future of nursing research within clinical practice. PMID- 22935766 TI - Prenatal exposure to pesticide ingredient piperonyl butoxide and childhood cough in an urban cohort. AB - RATIONALE: Previously we reported that airborne concentrations of cis-permethrin, but not trans-permethrin, measured during pregnancy in an inner city pediatric cohort was associated with cough by age 5. However, the effect of subsequent exposures to both permethrins during early childhood, and to piperonyl butoxide (PBO, a synergist for residential pyrethroid insecticides) remains to be elucidated. We hypothesized that prenatal and age 5-6 year measures of PBO and permethrins would be associated with cough at age 5-6 years in this cohort. Further, we explored the associations between these pesticide measures and wheeze, asthma, seroatopy, and fractional exhaled nitric oxide (FeNO). METHODS: PBO and permethrins were measured in personal air during the third trimester of pregnancy and indoor residential air at age 5-6 years (n=224). Health outcome questionnaires were administered to the mothers of 5-6 year old children. Indoor allergen specific and total immunoglobulin (Ig) E production was measured from sera collected at age 5, and FeNO was measured at 5-6 years. The hypotheses were tested using regression models adjusting for common confounders. RESULTS: Noninfectious cough was reported among 14% of children at age 5-6 years. Measures of prenatal PBO, but not age 5-6 year PBO or permethrins, increased the odds of cough [OR (95% CI): 1.27 (1.09-1.48), p<0.01; n=217]. No significant associations were found for other measured health outcomes. CONCLUSIONS: Prenatal PBO exposure was associated with childhood cough. It is unclear whether the observed effect is due mainly to PBO itself or residential pyrethroids of which PBO is an indicator. PMID- 22935768 TI - Building empowering work environments that foster civility and organizational trust: testing an intervention. AB - BACKGROUND: Creating supportive and empowering workplace conditions is important, not only because these conditions are related to improved nurse health and well being but also because they are important for retaining top performing nurses. The current nursing shortage emphasizes the need to create such conditions. OBJECTIVES: The aim of this study was to examine the impact of a workplace intervention (Civility, Respect, and Engagement in the Workplace [CREW]) on nurses' empowerment, experiences of supervisor and coworker incivility, and trust in nursing management. METHODS: Registered nurses (Time 1, n = 755; Time 2, n = 573) working in 41 units across five hospitals in two provinces completed measures of workplace empowerment, supervisor and coworker incivility, and trust in management before and after a 6-month intervention. Eight units participated in the intervention, and 33 units were control groups. Multilevel modeling was used to test the impact of the intervention. RESULTS: A significant interaction of time by intervention was found for the access to support and resources empowerment structures, total empowerment, supervisor incivility, and trust in management. DISCUSSION: Compared with the control group, nurses who experienced the intervention program reported significant improvements in empowerment, supervisor incivility, and trust in management. Despite methodological challenges experienced in this study, the CREW process appears to be a promising intervention approach to enhance quality of nursing work environments, which may contribute to the retention of the nursing workforce. PMID- 22935769 TI - Clinical nurse leader impact on microsystem care quality. AB - BACKGROUND: The current fragmented healthcare system, characterized by a lack of collaborative, patient-centered care processes, creates significant barriers to providing quality patient care. The clinical nurse leader (CNL) is theorized to provide clinical leadership at the point-of-practice to maintain cross disciplinary collaborative processes that lead to integrated quality care. OBJECTIVES: The aim of this study was to assess the impact of CNL integration into an acute care microsystem on care quality, as measured by patient satisfaction with care. METHODS: A short interrupted time series design was used to measure patient satisfaction with multiple aspects of care 10 months before and 12 months after integration of the CNL role on a progressive care unit, compared with a control unit. Data were obtained from Press Ganey surveys, and analysis was completed using a publicly available program for short time series data streams. RESULTS: Clinical nurse leader implementation was correlated with significantly improved patient satisfaction with admission processes (r = + .63, p = .02) and nursing care (r = +.75, p = .004), including skill level (r = .83, p = .003) and keeping patients informed (r = .70, p = .003). There was no significant correlation with improved patient satisfaction with physician care (r = .31, p = .14) or discharge processes (r = .33, p = .23) postimplementation. Control data showed no significant changes in patient satisfaction measures throughout the study time frame. DISCUSSION: The positive correlation between CNL mediated collaborative care processes and improvements in patient satisfaction with care quality provides empirical evidence of outcomes achievable through CNL implementation. Research is needed to explore the full range of achievable outcomes and to determine the specific processes by which these outcomes are realized. PMID- 22935770 TI - Applicability of a keratinocyte gene signature to predict skin sensitizing potential. AB - There is a need to replace animal tests for the identification of skin sensitizers and currently many alternative assays are being developed that have very promising results. In this study a gene signature capable of very accurate identification of sensitizers was established in the HaCaT human keratinocyte cell line. This signature was evaluated in a separate study using six chemicals that are either local lymph node (LLNA) false-positive or false-negative chemicals in addition to nine sensitizers and four non-sensitizers. Similar studies do not apply these more difficult to classify chemicals, which show the true potential for human predictions of an assay. Although the gene signature has improved prediction accuracy compared to the LLNA, the misclassified compounds were comparable between the two assays. Gene profiling also showed a sensitizer specific response of the Nrf2-keap1 and Toll-like receptor signaling pathways. After exposure to non-sensitizing chemicals that induce either of the pathways the signature misclassified all Nrf2-inducers, while the Toll-like receptor ligands were correctly classified. In conclusion, we confirm that keratinocyte based prediction assays may provide essential information on the properties of compounds. Furthermore, chemical selection is critical for assessment of the performance of in vitro alternative assays. PMID- 22935771 TI - FRET- and PET-based sensing in a single material: expanding the dynamic range of an ultra-sensitive nitroaromatic explosives assay. AB - A polyethylenimine polymer derivatized with pyrene moieties suitable for the fluorescence-based detection of nitroaromatic explosives (NAC) in aqueous systems is described. The system exhibits an exceptionally wide dynamic sensing range of 7 orders of magnitude (from 33 ppt to 225 ppm TNT or Tetryl). This broad range was achieved by the combination of FRET and PET sensing mechanisms in a single material. The sensing material is suitable for a paper strip assay. Simplicity, selectivity, and the wide dynamic range suggest this material for explosives detection in the field. PMID- 22935772 TI - Urinary tract infection concordance with positive blood and cerebrospinal fluid cultures in the neonatal intensive care unit. AB - OBJECTIVE: Urinary tract infections (UTI) are common in the neonatal intensive care unit (NICU). Blood, urine and cerebrospinal fluid (CSF) cultures are frequently obtained to evaluate for infection. We sought to determine the concordance between positive urine cultures and blood or CSF cultures. STUDY DESIGN: Infants <121 days of age with a UTI admitted to 322 NICUs managed by the Pediatrix Medical Group from 1997 to 2010 were identified. UTIs were defined by isolation of a single pathogenic organism in a urine sample obtained by catheterization or suprapubic tap. The UTI was concordant if the same organism was identified in the blood or CSF within 3 days of the urine culture. RESULT: Of 5681 infants with a urine culture, 984 had 1162 UTIs. In total, 976 UTIs (84%) had a blood culture collected within 3 days, and 127 (13%) were concordant. Of the 1162 UTIs, 77 (7%) had a CSF culture collected within 3 days, and 2 (3%) were concordant. CONCLUSION: Collection of a urine culture in infants evaluated for late-onset sepsis is important. Concordance was observed in 13% of blood cultures and 3% of CSF cultures. These findings may be related to the initiation of empirical antimicrobial therapy before evaluation for disseminated infection or poor blood culture sensitivity. PMID- 22935773 TI - Changes in regional tissue oxygenation saturation and desaturations after red blood cell transfusion in preterm infants. AB - OBJECTIVE: The study investigated the ability of near-infrared spectroscopy (NIRS) to detect subgroups of preterm infants who benefit most from red blood cell (RBC) transfusion in regard to cerebral/renal tissue oxygenation (i) and the number of general oxygen desaturation below 80% (SaO(2) <80%) (ii). STUDY DESIGN: Cerebral regional (crSO(2)) and peripheral regional (prSO(2)) NIRS parameters were recorded before, during, immediately after and 24 h after transfusion in 76 infants. Simultaneously, SaO(2) <80% were recorded by pulse oximetry. To answer the basic question of the study, all preterm infants were divided into two subgroups according to their pretransfusion crSO(2) values (<55% and >=55%). This cutoff was determined by a k-means clustering analysis. RESULT: crSO(2) and prSO(2) increased significantly in the whole study population. A stronger increase (P<0.0005) of both was found in the subgroup with pretransfusion crSO(2) values <55%. Regarding the whole population, a significant decrease (P<0.05) of episodes with SaO(2) <80% was observed. The subgroup with crSO(2) baselines <55% had significant (P<0.05) more episodes with SaO(2) <80% before transfusion. During and after transfusion, the frequency of episodes with SaO(2) <80% decreased more in this group compared with the group with crSO(2) baselines >=55%. CONCLUSION: NIRS measurement is a simple, non-invasive method to monitor regional tissue oxygenation and the efficacy of RBC transfusion. Infants with low initial NIRS values benefited most from blood transfusions regarding SaO(2) <80%, which may be important for their general outcome. PMID- 22935774 TI - Failure of early nasal continuous positive airway pressure in preterm infants of 26 to 30 weeks gestation. AB - OBJECTIVE: To identify variables associated with early nasal continuous positive airway pressure (ENCPAP) failure in preterm neonates less than 30 weeks gestational age. STUDY DESIGN: Multicenter prospective study including 131 preterm newborns, over a period of 2 years. Patients and respiratory variables were assessed using univariate analysis. RESULT: Variables associated with ENCPAP failure were: the need of resuscitation with a FiO(2)>0.30; a CPAP pressure of 6.4+/-1.2 cm H(2)O; the need of a FiO(2) of 0.40 in the first 4 h of life; male gender maintaining the need of a FiO(2)>0.25 in the first 4 h of life; and respiratory distress syndrome with criteria for surfactant administration. CONCLUSION: The need for oxygen in resuscitation and maintained in first hours of life, male gender, a CPAP pressure over 5 cm H(2)O and surfactant need are predictors of ENCPAP failure in preterm neonates 26 to 30 weeks gestational age. PMID- 22935775 TI - CAPE suppresses VEGFR-2 activation, and tumor neovascularization and growth. AB - The growth and metastasis of human solid tumors and the development of conditions such as diabetic retinopathy, rheumatoid arthritis, inflammatory psoriasis, and others are regulated by the balance between angiogenic stimulators and inhibitors released in the angiogenic-pathological microenvironment. Vascular endothelial growth factor (VEGF), an angiogenic factor, is a potent endothelial-specific mitogen that activates endothelial cells in pathological angiogenesis. Recently, we demonstrated that caffeic acid phenethyl ester (CAPE) inhibits tumor growth, invasion, and metastasis. However, the precise molecular mechanism underlying the inhibitory effect of CAPE on VEGF-mediated angiogenesis remains unknown. Here, we show that CAPE suppressed VEGF-induced proliferation, tube formation, migration, the formation of actin stress fibers and loss of VE-cadherin at cell-cell contacts in endothelial cells, indicating the inhibition of VEGF-mediated VEGF receptor-2 (VEGFR-2) and its downstream signal activation in vitro. CAPE blocked VEGF-stimulated neovascularization in the Matrigel plugs assay, and reduced vascular permeability in mouse skin capillaries in vivo. CAPE inhibited the growth and neovascularization of primary tumor cells in C57BL/6 and BALB/c mice inoculated with Lewis lung carcinoma, colon carcinoma, and melanoma cells. These results suggest that CAPE negatively modulates VEGF-induced angiogenesis by suppressing VEGFR-2 activation, and might be a therapeutic avenue for anti angiogenesis. PMID- 22935776 TI - Working throughout the night: beyond 'sleepiness'--impairments to critical decision making. AB - By the end of the first night on a 12h night-shift, wakefulness may have lasted up to 24h since the previous sleep. Although most work situations requiring critical decisions are foreseen and effectively resolved by well trained staff, such wakefulness can produce impairments in dealing with unexpected challenging situations involving uncertainty, change, distractions and capacity to evaluate risks. Also compromised can be the ability to engage in and keep abreast of protracted negotiations undertaken throughout the night. These effects, which are not just 'sleepiness', seem due to deteriorations with 'supervisory executive functions' of the prefrontal cortex; a region that appears particularly vulnerable to prolonged wakefulness. Recent research findings are presented to support this case, and some evidence-based recommendations made about practical countermeasures. PMID- 22935777 TI - When time is space: evidence for a mental time line. AB - Time and space are tightly linked in the physical word. Recently, several lines of evidence have suggested that the mental representation of time might be spatial in nature. For instance, time-space interactions have been described as a strong preference to associate the past with the left space and the future with the right space. Here we review the growing evidence of interactions between time and space processing, systematized according to the type of interaction being investigated. We present the empirical findings supporting the possibility that humans represent the subjective time flow on a spatially oriented "mental time line" that is accessed through spatial attention mechanisms. The heterogeneous time-space interactions are then compared with the number-space interactions described in the numerical cognition literature. An alternative hypothesis, which maintains a common system for magnitude processing, including time, space, and number, is also discussed. Finally, we extend the discussion to the more general issue of how the representation of these concepts might be grounded into the cortical circuits that support spatial attention and sensorimotor transformations. PMID- 22935778 TI - Fluorescence in situ hybridization (FISH) signal analysis using automated generated projection images. AB - Fluorescence in situ hybridization (FISH) tests provide promising molecular imaging biomarkers to more accurately and reliably detect and diagnose cancers and genetic disorders. Since current manual FISH signal analysis is low-efficient and inconsistent, which limits its clinical utility, developing automated FISH image scanning systems and computer-aided detection (CAD) schemes has been attracting research interests. To acquire high-resolution FISH images in a multi spectral scanning mode, a huge amount of image data with the stack of the multiple three-dimensional (3-D) image slices is generated from a single specimen. Automated preprocessing these scanned images to eliminate the non useful and redundant data is important to make the automated FISH tests acceptable in clinical applications. In this study, a dual-detector fluorescence image scanning system was applied to scan four specimen slides with FISH-probed chromosome X. A CAD scheme was developed to detect analyzable interphase cells and map the multiple imaging slices recorded FISH-probed signals into the 2-D projection images. CAD scheme was then applied to each projection image to detect analyzable interphase cells using an adaptive multiple-threshold algorithm, identify FISH-probed signals using a top-hat transform, and compute the ratios between the normal and abnormal cells. To assess CAD performance, the FISH-probed signals were also independently visually detected by an observer. The Kappa coefficients for agreement between CAD and observer ranged from 0.69 to 1.0 in detecting/counting FISH signal spots in four testing samples. The study demonstrated the feasibility of automated FISH signal analysis that applying a CAD scheme to the automated generated 2-D projection images. PMID- 22935779 TI - Multispectral enhancement method to increase the visual differences of tissue structures in stained histopathology images. AB - In this paper we proposed a multispectral enhancement scheme in which the spectral colors of the stained tissue-structure of interest and its background can be independently modified by the user to further improve their visualization and color discrimination. The colors of the background objects are modified by transforming their N-band spectra through an NxN transformation matrix, which is derived by mapping the representative samples of their original spectra to the spectra of their target colors using least mean square method. On the other hand, the color of the tissue structure of interest is modified by modulating the transformed spectra with the sum of the pixel's spectral residual-errors at specific bands weighted through an NxN weighting matrix; the spectral error is derived by taking the difference between the pixel's original spectrum and its reconstructed spectrum using the first M dominant principal component vectors in principal component analysis. Promising results were obtained on the visualization of the collagen fiber and the non-collagen tissue structures, e.g., nuclei, cytoplasm and red blood cells (RBC), in a hematoxylin and eosin (H&E) stained image. PMID- 22935780 TI - [Hans-Werner Altmann. 07 June 1916 to 31 July 2011]. PMID- 22935781 TI - [Report of the working group cytopathology. On the occasion of the 96th annual congress of the German Society of Pathology in Berlin]. PMID- 22935784 TI - Enlarging the big-bubble during deep anterior lamellar keratoplasty. AB - PURPOSE: During big-bubble deep anterior lamellar keratoplasty, a bubble that is not large enough can be formed. Further air injection can result in the rupture of the posterior lamella, necessitating conversion to penetrating keratoplasty. We describe some techniques to safely enlarge the big-bubble in such a circumstance. METHODS: In cases in which a white-margin bubble forms that has extended to the trephination margin, the bubble is collapsed and the margins are extended by blunt dissection. For cases of an undersized clear-margin bubble, the bubble is enlarged by gentle injection of a cohesive ophthalmic viscosurgical device into the bubble cavity. RESULTS: Using these techniques, big-bubbles were safely extended beyond the trephination margin for both white- and clear-margin bubbles. CONCLUSIONS: An undersized big-bubble can safely be extended using blunt dissection for white-margin bubbles and ophthalmic viscosurgical device injection for clear-margin bubbles. PMID- 22935783 TI - [New approaches in progressive kidney diseases]. AB - Renal fibrosis, i.e. the replacement of functional tissue with scar tissue, represents the pathological correlate for chronic kidney disease (CKD). A great number of renal diseases lead to CKD and thereby to renal fibrosis. Therefore, renal fibrosis represents an excellent treatment option for patients with CKD. Here we discuss the problems with the preclinical identification and testing of potential factors and therapeutic approaches for renal fibrosis as well as obstacles in the translation of these results to clinical practice. We present the preclinical evidence for the role of novel molecules involved in renal fibrosis, e.g. platelet-derived growth factors (PDGF), C5a or peroxisome proliferator-activated receptor-alpha (PPAR-alpha). PMID- 22935785 TI - Automatic correction of gaps in cerebrovascular segmentations extracted from 3D time-of-flight MRA datasets. AB - OBJECTIVES: Exact cerebrovascular segmentations are required for several applications in today's clinical routine. A major drawback of typical automatic segmentation methods is the occurrence of gaps within the segmentation. These gaps are typically located at small vessel structures exhibiting low intensities. Manual correction is very time-consuming and not suitable in clinical practice. This work presents a post-processing method for the automatic detection and closing of gaps in cerebrovascular segmentations. METHODS: In this approach, the 3D centerline is calculated from an available vessel segmentation, which enables the detection of corresponding vessel endpoints. These endpoints are then used to detect possible connections to other 3D centerline voxels with a graph-based approach. After consistency check, reasonable detected paths are expanded to the vessel boundaries using a level set approach and combined with the initial segmentation. RESULTS: For evaluation purposes, 100 gaps were artificially inserted at non-branching vessels and bifurcations in manual cerebrovascular segmentations derived from ten Time-of-Flight magnetic resonance angiography datasets. The results show that the presented method is capable of detecting 82% of the non-branching vessel gaps and 84% of the bifurcation gaps. The level set segmentation expands the detected connections with 0.42 mm accuracy compared to the initial segmentations. A further evaluation based on 10 real automatic segmentations from the same datasets shows that the proposed method detects 35 additional connections in average per dataset, whereas 92.7% were rated as correct by a medical expert. CONCLUSION: The presented approach can considerably improve the accuracy of cerebrovascular segmentations and of following analysis outcomes. PMID- 22935787 TI - Effects of PTH [1-34] on synoviopathy in an experimental model of osteoarthritis preceded by osteoporosis. AB - PURPOSE: Synoviopathy contributes to cartilage degradation in osteoarthritis (OA). Intermittent parathyroid hormone (PTH) [1-34] administration inhibits terminal differentiation of human chondrocytes and prevents cartilage damage. We aimed to determine whether PTH [1-34] could modify synovial changes in experimental OA preceded by osteoporosis (OP). METHODS: Twenty osteoporosis (OP) rabbits underwent knee surgery to induce OA. They were administered either saline vehicle or PTH for 10 weeks. Ten healthy rabbits were used as controls. Following sacrifice, synovial changes were assessed by Krenn synovitis score, immunohistochemistry for macrophages (RAM-11), B and T lymphocytes, type I collagen, parathyroid hormone 1 receptor (PTH1R), and anti-proliferating cell nuclear antigen (PCNA). Synovial mRNA levels of Col1A1, IL-1beta, cyclooxygenase 2 (COX-2), matrix-degrading metalloproteinases (MMP-9, MMP-13), and monocyte chemotactic protein-1 (MCP-1), as well as protein expression of PTH1R were also determined. Cartilage damage was analyzed by Mankin score. RESULTS: OPOA + vehicle rabbits showed an increase in synovitis score vs controls (P = 0.003), mainly due to synovial hyperplasia and fibrosis, while PTH reduced these changes (P = 0.017). Mankin and Krenn scores were well correlated in all groups (r = 0.629, P = 0.012). Immunostaining for RAM-11 and B lymphocytes was increased (P <= 0.05), whereas PTH1R protein levels tended to be higher in OPOA + vehicle animals vs controls. PTH did not modify RAM-11 staining or PTH1R levels; however, it restored PTH1R localization to the vicinity of synovial vessels. PTH also decreased type I collagen, MCP-1, and MMP-13 expression (P < 0.05), as well as PCNA staining compared to vehicle-treated OPOA rabbits. CONCLUSIONS: In our model of OA aggravated by previous OP, synoviopathy correlated well with cartilage damage. Intermittent PTH [1-34] administration ameliorated both hyperplasia and fibrosis. PMID- 22935786 TI - In vivo reduction or blockade of interleukin-1beta in primary osteoarthritis influences expression of mediators implicated in pathogenesis. AB - OBJECTIVE: Diminish interleukin-1beta (IL-1beta) signaling in a model of primary osteoarthritis by RNA interference-based transcript reduction or receptor blockade, and quantify changes incurred on transcript expression of additional mediators. METHODS: Knees of Hartley guinea pigs were collected at 120 and 180 days of age following injection with viral vectors (N = 4/treatment group/date) at 60 days. Two groups received either adeno-associated viral serotype 5 vector containing a knockdown sequence (TV), or adenoviral vector encoding for IL-1 receptor antagonist protein (Ad-IRAP); treatments were contrasted with opposite knees administered corresponding vector controls. A third group evaluated TV relative to saline-only injected knees. Chondropathy and immunohistochemistry findings were compared to untreated guinea pigs. Transcript expression levels in cartilage were calculated using the comparative CT (2(-DeltaDeltaCT)) method and analyzed by one-way analysis of variance (ANOVA) with pairwise comparisons using Tukey 95% confidence intervals. RESULTS: Vector transduction was confirmed at both harvest dates. TV and Ad-IRAP, relative to vector controls, significantly decreased IL-1beta. Inflammatory mediators [tumor necrosis factor-alpha (TNF alpha), IL-8, interferon-gamma (IFN-gamma)], and catabolic matrix metalloproteinase 13 (MMP13) were also decreased, while anabolic transforming growth factor-beta1 (TGF-beta1) was increased. IL-1beta was also decreased by TV vs saline, with a decrease in MMP13 and increase TGF-beta1; TNF-alpha, IL-8, and IFN-gamma were transiently increased. CONCLUSIONS: This work confirmed that a reduction in IL-1beta signaling was accomplished by either method, resulting in decreased expression of three inflammatory mediators and one catabolic agent, and increased expression of an anabolic molecule. Thus, evidence is provided that IL 1beta serves a role in vivo in spontaneous osteoarthritis and that these translational tools may provide beneficial disease modification. PMID- 22935788 TI - Mechanical injury of bovine cartilage explants induces depth-dependent, transient changes in MAP kinase activity associated with apoptosis. AB - OBJECTIVE: To characterize mitogen activated protein (MAP) kinase activity and chondrocyte apoptosis in an in vitro model of cartilage mechanical injury as a function of tissue depth and time post-injury. DESIGN: Mechanically injured osteochondral explants were assessed for cell viability, MAP kinase and caspase-3 activity over 15 days using immunofluorescence microscopy and Western blot. Zonal distributions of cell viability and apoptosis were quantified in the presence of specific mitogen activated protein kinase inhibitors. RESULTS: Viability rapidly decreased post-injury, most significantly in the superficial zone, with some involvement of the middle and deep zones, which correlated with increased caspase 3 activity. Transient and significant increases in extracellular-regulated protein kinase (ERK) activity were observed in middle and deep zones at 1 and 6 days post-injury, while c-Jun-amino terminal protein kinase activity increased in the deep zone at 1 and 6 days compared to uninjured controls. Changes in p38 activity were particularly pronounced, with significant increases in all three zones 30 min post-injury, but only in the middle and deep zones after 1 and 6 days. Inhibition of ERK and p38 increased chondrocyte viability which correlated with decreased apoptosis. CONCLUSIONS: Spatiotemporal patterns of MAP kinase signalling in cartilage after mechanical injury strongly correlate with changes in cell viability and chondrocyte apoptosis. Importantly, these signals may be pro-survival or pro-apoptotic depending on zonal location and time post-injury. These data yield mechanistic insights which may improve the diagnosis and treatment of cartilage injuries. PMID- 22935789 TI - Down's syndrome and Alzheimer's disease: towards secondary prevention. AB - A public-private partnership to establish biomarkers of dementia in Down's syndrome could aid the development of preventive therapies for the dementia associated with both Down's syndrome and Alzheimer's disease, based on the apparent common pathogenic role of amyloid precursor protein in the two conditions. PMID- 22935790 TI - Sting of Alzheimer's failures offset by upcoming prevention trials. PMID- 22935791 TI - Europe sets out to reform its clinical trial rules. PMID- 22935793 TI - Regulatory watch: pioneering gene therapy on brink of approval. PMID- 22935794 TI - Trial watch: HIV integrase inhibitor-based regimen beats market leader. PMID- 22935795 TI - Patent watch: extra exclusivity for new medical uses. PMID- 22935796 TI - Mark McClellan. Interview by Asher Mullard. PMID- 22935797 TI - The pharmaceutical market for obesity therapies. PMID- 22935798 TI - Cancer: Passenger deletions create cancer-specific Achilles heel. PMID- 22935799 TI - Vaccination: Oral vaccine induces genitorectal immunity. PMID- 22935805 TI - Shouldn't enantiomeric purity be included in the 'minimum information about a bioactive entity'? PMID- 22935807 TI - Temporal bone histopathology case of the month: Malignant peripheral nerve sheath tumor arising within vestibular schwannoma. PMID- 22935808 TI - Cochlear implantation in patients profoundly deafened after head injury. AB - OBJECTIVE: There is very little information in the literature regarding outcomes of cochlear implantation in patients profoundly deafened after head injury. The aim of this study was to assess outcomes in this group of patients. STUDY DESIGN: Retrospective case review. SETTING: The Manchester Cochlear Implant Programme, University of Manchester. PATIENTS: Profoundly deafened patients after head injury who proceeded to cochlear implantation for auditory rehabilitation. MAIN OUTCOME MEASURES: Mean age and duration of deafness at implantation. Preimplantation and postimplantation speech perception outcomes were measured using Bench Kowel Bamford (BKB) sentences in quiet and noise, City University of New York sentences with lip reading and Arthur Boothroyd words scoring the percentage phonemes correct. RESULTS: Twenty patients received 23 cochlear implants. Mean age at implantation was 51 years (standard deviation, 12 yr). Mean duration of deafness at implantation was 12 years (range, 1-30 yr).Preimplantation BKB score in quiet of 0%. Mean postimplantation BKB score in quiet was 64% (range, 0%-100%) and in noise was 61% (range, 0%-97%). Three were nonusers, and 1 required reimplantation. There was a moderately negative correlation between outcome and age at implantation (r = -0.41, p < 0.05) and between outcome and duration of deafness (r = -0.52, p < 0.05). CONCLUSION: Cochlear implantation is an effective method for hearing rehabilitation in profoundly deafened patients after head injury. However, negative factors, such as significant injury to the central auditory pathway, basal turn obliteration, long duration of deafness, and nonauditory stimulation, should be considered in the preoperative assessment of these patients. PMID- 22935803 TI - Leptin revisited: its mechanism of action and potential for treating diabetes. AB - Since the discovery of leptin in 1994, we now have a better understanding of the cellular and molecular mechanisms underlying its biological effects. In addition to its established anti-obesity effects, leptin exerts antidiabetic actions that are independent of its regulation of body weight and food intake. In particular, leptin can correct diabetes in animal models of type 1 and type 2 diabetes. In addition, long-term leptin replacement therapy improves glycaemic control, insulin sensitivity and plasma triglycerides in patients with severe insulin resistance due to lipodystrophy. These results have spurred enthusiasm for the use of leptin therapy to treat diabetes. Here, we review the current understanding of the glucoregulatory functions of leptin, emphasizing its central mechanisms of action and lessons learned from clinical studies, and discuss possible therapeutic applications of leptin in the treatment of type 1 and type 2 diabetes. PMID- 22935804 TI - Autophagy modulation as a potential therapeutic target for diverse diseases. AB - Autophagy is an essential, conserved lysosomal degradation pathway that controls the quality of the cytoplasm by eliminating protein aggregates and damaged organelles. It begins when double-membraned autophagosomes engulf portions of the cytoplasm, which is followed by fusion of these vesicles with lysosomes and degradation of the autophagic contents. In addition to its vital homeostatic role, this degradation pathway is involved in various human disorders, including metabolic conditions, neurodegenerative diseases, cancers and infectious diseases. This article provides an overview of the mechanisms and regulation of autophagy, the role of this pathway in disease and strategies for therapeutic modulation. PMID- 22935809 TI - Third-generation bisphosphonates for treatment of sensorineural hearing loss in otosclerosis. AB - OBJECTIVE: To evaluate hearing outcomes in patients treated with third generation bisphosphonates for otosclerosis-related sensorineural hearing loss (SNHL). HYPOTHESIS: Otosclerosis is a disease of abnormal bone remodeling in the otic capsule. In recent years, third generation bisphosphonates, with more powerful anti-resorptive properties and increased bone affinity, have demonstrated effectiveness in the treatment of osteoporosis and other metabolic bone diseases. We hypothesized that newer generation bisphosphonates, such as risedronate and zoledronate, would be effective in slowing the progression of SNHL in patients with otosclerosis. STUDY DESIGN: Retrospective review. SETTING: Tertiary referral center, ambulatory care. INTERVENTIONS: Risedronate or zoledronate administration. MAIN OUTCOME MEASURES: Bone conduction pure tone threshold averages (PTAs) and word recognition (WR) scores were examined for each ear before and after bisphosphonate treatment. Criteria for significant change were defined as greater than 10 decibels in PTA or between 4% and 18% in WR based on binomial variance. RESULTS: All 10 patients had audiometric progression of SNHL in the pretreatment monitoring interval and 12 ears met criteria for significant progression. All 10 patients (19 ears) showed at least no significant progression of SNHL (i.e., stabilization) at an average follow-up of 13 months. Two patients (3 ears) showed improvement by defined audiometric criteria. There were no major complications. CONCLUSION: Treatment with zoledronate or risedronate stabilized progressive SNHL related to otosclerosis in this small group of patients. Further evaluation of third-generation bisphosphonate treatments is warranted. PMID- 22935810 TI - Hearing outcomes after surgical plugging of the superior semicircular canal by a middle cranial fossa approach. AB - OBJECTIVE: To determine postoperative hearing outcomes after surgical plugging via middle cranial fossa approach for superior semicircular canal dehiscence syndrome (SCDS). STUDY DESIGN: Clinical review. SETTING: Tertiary care medical center. PATIENTS: Forty-three cases of SCDS based on history, physical examination, vestibular function testing, and computed tomography imaging confirming the presence of a dehiscence. All patients underwent surgical plugging of the superior semicircular canal via middle cranial fossa approach. INTERVENTION: Pure tone audiometry was performed preoperatively and at 7 days and at least 1 month postoperatively. MAIN OUTCOME MEASURES: Change in air-bone gap (ABG) and pure tone average (PTA). RESULTS: Preoperative average ABG across 0.25, 0.5, 1, and 2 kHz was 16.0 dB (standard deviation [SD], 7.5 dB). At 7 days postoperatively, average ABG was 16.5 dB (SD, 11.1; p = 0.42), and at greater than 1 month was 8.1 dB (SD, 8.4; p < 0.001). 53% (95% confidence interval, 33 69) of affected ears had greater than 10 dB increase in their 4-frequency (0.5, 1, 2, and 4 kHz) PTA measured by bone-conduction (BC) threshold 7 days postoperatively and 25% (95% confidence interval, 8-39) at greater than 1 month postoperatively. Mean BC PTA of affected ears was 8.4 dB hearing loss (HL) (SD, 10.4) preoperatively. Compared with baseline, this declined to 19.2 dB HL (SD, 12.6; p < 0.001) at 7 days postoperatively and 16.4 dB HL (SD, 18.8; p = 0.01) at greater than 1 month. No significant differences in speech discrimination score were noted (F = 0.17). CONCLUSION: Low-frequency air-bone gap decreases after surgical plugging and seems to be due to both increased BC thresholds and decreased AC thresholds. Surgical plugging via a middle cranial fossa approach in SCDS is associated with mild high-frequency sensorineural hearing loss that persists in 25% but no change in speech discrimination. PMID- 22935811 TI - Rapid cVEMP and oVEMP responses elicited by a novel head striker and recording device. AB - OBJECTIVE: To develop a reliable, easy to use bedside, office, or field system that allows the rapid measurement of cervical and ocular vestibular evoked myogenic potentials (cVEMP and oVEMP) using a bone-conduction stimulus. STUDY DESIGN: Prospective bioengineering design and proof of concept of the test system with saccular and utricular otolith response studies in human subjects. SETTING: Private practice, tertiary neurotology referral center. SUBJECTS: Twenty healthy adult controls without history of auditory or vestibular dysfunction and 5 preoperative and postoperative patients with confirmed superior canal dehiscence (SCD) participated. INTERVENTIONS: The subjects underwent auditory stimuli-based cVEMP and oVEMP studies using a commercially available system as well as testing with a novel bone-conduction cVEMP and oVEMP head striker system. MAIN OUTCOME MEASURES: Duration of each study, healthy subject and patient comfort, reproducibility, latency, and amplitude of auditory and striker evoked cVEMP and oVEMP responses. RESULTS: The mean age of the healthy controls was 43.8, with a range of 19 to 69 years (10 male and 10 female subjects). The mean age of the SCD patient group was 46, with a range of 25 to 54 years; all female subjects. Although the cVEMP responses were similar using either the auditory or head strike stimuli, the healthy subjects preferred the latter, but the SCD patients became more symptomatic. The oVEMP data showed more consistent responses using the striker system. A statistically significant reduction in latency for the striker-evoked cVEMP occurred compared with the auditory cVEMP evoked response in the 5 SCD preoperative patients. All normalized postoperatively. CONCLUSION: Recording the cVEMP and oVEMP responses using the striker system was much more rapid than with auditory stimuli and was more comfortable for the healthy subjects. The striker system and the acoustic method elicited strong otolithic receptor dysfunction symptoms in all SCD patients; however, they preferred the shorter striker studies. The striker system, because of the statistically shorter latency of p13 during the striker evoked cVEMP, which normalized after SCD closure, suggests that this method may be useful in identifying SCD patients before imaging studies. In addition, based on our biomechanical data, the striker was able to reliably produce a consistent and defined head striker impact. PMID- 22935812 TI - Particle repositioning maneuver versus Brandt-Daroff exercise for treatment of unilateral idiopathic BPPV of the posterior semicircular canal: a randomized prospective clinical trial with short- and long-term outcome. AB - OBJECTIVE: To compare the outcome and probability of recurrence in a series of patients with unilateral idiopathic benign paroxysmal positional vertigo of the posterior canal (PC-BPPV) that were randomly treated by Brandt-Daroff exercise (B D exercise) or by particle repositioning maneuver (PRM). STUDY DESIGN: Randomized prospective clinical trial. SETTING: Tertiary referral center. PATIENTS: Patients were included in this study if they complained of vertigo and had been diagnosed as having unilateral idiopathic PC-BPPV for at least 1 week before Dix-Hallpike maneuver (DHM), remained for 30 days in the randomly assigned treatment, and had at least 48 months' follow-up. INTERVENTION: Forty-one patients were treated with a single PRM and 40 patients by B-D exercise. MAIN OUTCOME MEASURE: Resolution of benign paroxysmal positional nystagmus on the DHM. The probability of recurrence was also studied. RESULTS: At Day 7, DHM was negative in 80.5% of the PRM-treated patients and in 25% of those treated by B-D exercise (p < 0.001). At Month 1, the differences between both treatment groups remained statistically significant (92.7% in PRM versus 42.5% in the B-D exercise had a negative DHM; p < 0.001). The variable that influenced that DHM became negative was the PRM (RR = 4.8; 95% confidence interval, 2.5-9.2; p < 0.001). The number of recurrences in PRM and B D exercise were 0.56 +/- 0.8 and 0.48 +/- 0.8, respectively (p = 0.48). The recurrence rate at 48 months was 35.5% (15/41) in B-D exercise and 36.6% (9/31) in the PRM group (p = 0.62). Although the time interval until the first recurrence was similar (p = 0.44), patients included in the PRM group showed a significantly longer time interval between the first and second recurrence (p = 0.04). CONCLUSION: PRM is more effective treatment and as safe as B-D exercise in the short term for unilateral and idiopathic PC-BPPV, and although it does not reduce the probability of recurrence in the 4-year follow-up period compared with B-D exercise, it may delay the second recurrence's onset in those patients who had already experienced a single recurrence. Our study supports the use of PRM as the treatment of choice in unilateral and idiopathic PC-BPPV, although exercise may be also considered as an alternative treatment in selected cases. PMID- 22935814 TI - Metastasizing middle ear carcinoid: an unusual case report, with focus on ultrastructural and immunohistochemical findings. AB - BACKGROUND: There are only 4 unequivocal cases of metastasizing middle ear carcinoid previously reported. OBJECTIVE: To present a case of metastasizing middle ear carcinoid, to review previously reported cases, and to discuss the clinical nature of this tumor, which is similar to "orthotopic" carcinoids bearing definite metastatic potential. STUDY DESIGN: Case report. PATIENT, INTERVENTION, RESULTS: We present a 72-year-old woman who developed ipsilateral parotid gland and cervical lymph node metastases 8 and 11 months after surgical removal of a primary middle ear lesion. She subsequently required 2 revision procedures and radiotherapy for local recurrences. Her case was complicated by nonsurgically induced permanent facial nerve paralysis, the cause of which remains obscure. At the end of the 8-year follow-up, the patient was alive with locally, recurrent tumor eroding the cranial base and invading the posterior intracranial fossa but with no signs of metastases. MAIN OUTCOME MEASURES: Light microscopy and immunohistochemical analysis. CONCLUSION: Considering the reported high rate of recurrence and their consequent metastases, a middle ear carcinoid should be classified as a neuroendocrine low-grade carcinoma. PMID- 22935813 TI - Auditory abilities after cochlear implantation in adults with unilateral deafness: a pilot study. AB - OBJECTIVE: This pilot study examined speech recognition, localization, temporal and spectral discrimination, and subjective reports of cochlear implant (CI) recipients with unilateral deafness. STUDY DESIGN: Three adult male participants with short-term unilateral deafness (<5 yr) participated. All had sudden onset of severe-to-profound hearing loss in 1 ear, which then received a CI, and normal or near normal hearing in the other ear. Speech recognition in quiet and noise, localization, discrimination of temporal and spectral cues, and a subjective questionnaire were obtained over several days. Listening conditions were CI, normal hearing (NH) ear, and bilaterally (CI and NH). RESULTS: All participants had open-set speech recognition and excellent audibility (250-6,000 Hz) with the CI. Localization improved bilaterally compared with the NH ear alone. Word recognition in noise was significantly better bilaterally than with the NH ear for 2 participants. Sentence recognition in various noise conditions did not show significant bilateral improvement; however, the CI did not hinder performance in noise even when noise was toward the CI side. The addition of the CI improved temporal difference discrimination for 2 participants and spectral difference discrimination for all participants. Participants wore the CI full time, and subjective reports were positive. CONCLUSION: Overall, the CI recipients with unilateral deafness obtained open-set speech recognition, improved localization, improved word recognition in noise, and improved perception of their ability to hear in everyday life. A larger study is warranted to further quantify the benefits and limitations of cochlear implantation in individuals with unilateral deafness. PMID- 22935815 TI - Rehabilitation of central facial paralysis with hypoglossal-facial anastomosis. AB - OBJECTIVE: To evaluate the ability of hypoglossal-facial nerve anastomosis to reanimate the face in patients with complete nuclear (central) facial nerve palsy. STUDY DESIGN: Retrospective case series. SETTING: Tertiary academic medical center. PATIENTS: Four patients with complete facial nerve paralysis due to lesions of the facial nucleus in the pons caused by hemorrhage due to arteriovenous or cavernous venous malformations, stroke, or injury after tumor resection. INTERVENTION: All patients underwent end-to-end hypoglossal-facial nerve anastomosis. MAIN OUTCOME MEASURES: Facial nerve function using the House Brackmann (HB) scale and physical and social/well-being function using the facial disability index. RESULTS: The mean age of the patients was 53.3 years (range, 32 73). There were 3 female and 1 male patients. All patients had preoperative facial function HB VI/VI. With a minimum of 12 months' follow-up after end-to-end hypoglossal-facial anastomosis, 75% of patients regained function to HB grade III/VI, and 25% had HB grade IV/VI. Average facial disability index scores were 61.25 for physical function and 78 for social/well-being, comparable to results from complete hypoglossal-facial anastomosis after peripheral facial nerve palsy after acoustic neuroma resection. CONCLUSION: Patients with nuclear facial paralysis who undergo end-to-end hypoglossal-facial nerve anastomosis achieve similar degrees of reanimation compared with those with peripheral facial nerve palsies. This raises the intriguing possibility that reinnervation may also be of benefit in patients with the vastly more common facial dysfunction because of cortical stroke or injury. PMID- 22935816 TI - A case of pneumolabyrinth induced by Eustachian tube air inflation. AB - OBJECTIVES: Here, we report a case of pneumolabyrinth induced by Eustachian tube air inflation (ETAI) with a catheter and present evidence that multiple air bubbles entered the perilymphatic space through a preexisting oval window fistula. SETTING: Tertiary referral center. PATIENT: Sixty-six-year-old woman. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Air bubbles in the perilymphatic space revealed by cone beam computed tomography (CT) volume rendering imaging. RESULTS: The patient was referred to us because of vertigo, unsteadiness, and right hearing loss after ETAI using a Eustachian tube catheter. On Day 2, an audiogram showed right total deafness, and the perilymphatic space could not be identified on T2-weighted magnetic resonance imaging. A high-resolution cone beam CT scan obtained on Day 3 showed multiple air bubbles in the labyrinth. The volume rendering images clearly revealed a larger air bubble in the vestibule inside the footplate of the stapes and small air bubbles in the horizontal semicircular canal, superior semicircular canal, and basal and second turns of the cochlea. This finding indicates that the air bubbles entered the perilymphatic space through an oval widow fistula caused by a sudden elevation in intratympanic air pressure. Two months later, the air bubbles had disappeared, and the patient's high tone hearing had improved slightly. CONCLUSION: ETAI can cause a pneumolabyrinth if the intratympanic pressure rises beyond a certain critical level. In this situation, volume rendering imaging of high-resolution cone beam CT can be used to quantify and identify the air bubbles present. The images taken in this study suggest that air bubbles entered the perilymphatic space through a perilymphatic fistula. PMID- 22935817 TI - Activation of PDGFR and EGFR promotes the acquisition of a stem cell-like phenotype in schwannomas. AB - OBJECTIVES: Vestibular schwannomas (VS) are benign tumors that arise from unregulated growth of Schwann cells. Both benign and malignant tumors are believed to contain tumor stem cells that are hypothesized to originate from dysregulation of tumor suppressors and oncogenes. We aimed to determine if schwannoma cells express stem cell genes and markers and if activation of the proto-oncogenes epidermal growth factor receptor and platelet-derived growth factor receptor would regulate the stem cell properties of these cells. METHODS: Immunohistochemical staining was used to determine the expression of stem cell genes in archived VS tissue, immunofluorescence was used to investigate the expression in cell lines, and Western blot analysis was used to measure PDGFR expression in vestibular schwannoma tissue. Upon activation of PDGFR or EGFR in schwannoma cell lines using specific ligands, flow cytometry was used to quantify the side population (SP), stem cell genes were measured using quantitative PCR, and tumorsphere-forming ability was determined. RESULTS: Stem cell genes are expressed in vestibular schwannoma tissue and schwannoma cell lines. Activation of both EGFR and PDGFR resulted in increase in the induction of the expression of the stem cell genes Oct-4 and Nanog and marked increase in tumorsphere-forming ability, but only PDGFR activation resulted in an increase in the side population in JS1 cells. CONCLUSION: Dysregulation of EGFR and PDGFR promotes the acquisition of a stem cell-like phenotype in schwannnoma cells that may be critical in vestibular schwannoma tumorigenesis. PMID- 22935818 TI - Long-term control of CMV retinitis in a patient with idiopathic CD4+ T lymphocytopenia. AB - Cytomegalovirus (CMV) retinitis with idiopathic CD4(+) T lymphocytopenia (ICL) is rare and difficult to control. We report a first case for long-term control of CMV retinitis with ICL using interleukin-2 (IL-2) therapy and succeeded in discontinuation of anti-CMV therapy. A 49-year-old Japanese woman was diagnosed with ICL based on low CD4(+) count (72/MUl), negative for HIV-1 and -2 antibodies, and absence of any defined immunodeficiency diseases or immunosuppressive therapy. PCR test of the aqueous humor in the right eye was suggestive of CMV retinitis. She was treated with systemic ganciclovir, but after several relapses of CMV retinitis, rhegmatogenous retinal detachment appeared in the right eye and she became blind in that eye. Three years later, she developed CMV retinitis in the left eye. Although she received systemic and focal anti-CMV treatments, the retinitis showed no improvement. Finally, retinal detachment occurred, and she underwent vitrectomy. IL-2 was injected to increase CD4(+) counts. Because of hyperpyrexia, blepharedema, central scotoma, and color anomaly, we changed to low-dose IL-2 therapy with no side effects. Finally, we succeeded in increasing the CD4(+) count to more than 200/MUl after discontinuation of low-dose IL-2 therapy. CMV retinitis never recurred after discontinuation of anti-CMV therapy, with good visual acuity of 20/20 in the left eye. She developed blindness of the first affected right eye, whereas the visual acuity of the left eye remains excellent more than 12 years after the onset of CMV retinitis through the combined use of anti-CMV therapy, IL-2 therapy, and vitrectomy. PMID- 22935819 TI - Outer-diameter narrowing of the internal carotid and middle cerebral arteries in moyamoya disease detected on 3D constructive interference in steady-state MR image: is arterial constrictive remodeling a major pathogenesis? AB - BACKGROUND: To obtain information on affected vessels in moyamoya disease (MMD), we analyzed the vascular morphological characteristics of MMD using three dimensional (3D) constructive interference in steady-state (CISS) magnetic resonance imaging (MRI). METHODS: The population of this 3D-CISS MRI study consisted of 51 patients with MMD: 16 patients with atherosclerotic middle cerebral artery (MCA) stenosis or occlusion, 42 MRI control patients, and 28 control digital subtraction angiography (DSA) patients. We measured the outer diameters of the terminal portion of the internal carotid artery (ICA) and the proximal portion of the MCA (M1 portion). We evaluated the inner diameter as the relative value (%) obtained from magnified DSA images and analyzed these data. RESULTS: The outer diameters of the ICA and M1 portions were significantly smaller in the MMD group than in the other two groups, while the M1 outer diameter of the atherosclerosis group was not significantly different compared to the control (ICA: MMD, 2.61 +/- 0.46 mm vs. control, 4.04 +/- 0.50 mm and M1: MMD, 1.92 +/- 0.43 mm vs. control, 3.34 +/- 0.54 mm vs. atherosclerosis, 3.45 +/- 0.56 mm). Furthermore, in MMD patients, the outer diameter was unrelated to the progression of the luminal stenosis grade estimated by DSA. CONCLUSIONS: This is the first report that the outer diameters of both the ICA and M1 decrease in MMD patients. Our findings suggest that the vascular constrictive changes of the affected arteries are an important phenomenon reflecting MMD pathology. PMID- 22935820 TI - EC-IC bypass for stroke: is there a future perspective? PMID- 22935821 TI - Expression of HOXD3 correlates with shorter survival in patients with invasive breast cancer. AB - Hox genes encode a family of homeodomain-containing transcription factors that determine cellular identity during development and which are also expressed in some types of cancer. The HOXD3 gene, a member of the Hox gene family, has been demonstrated to be expressed in several tumor cell lines, which exhibit enhanced invasion and metastasis through coordinate expression of metastasis-associated factors. However, the clinical impact of HOXD3 in breast cancer remains unclear. In the current study, we examined the expression of HOXD3 and integrin beta3 by immunohistochemical staining in patients with invasive breast cancer. We found that HOXD3 expression was significantly frequent in high histopathological grade and hormone-receptor negative breast cancer patients. The expression of HOXD3 was closely associated with integrin beta3 expression. Furthermore, patients with high HOXD3 expression levels in their breast tumors had significantly shorter survival times than patients in which HOXD3 was weakly expressed in breast tumors. Univariate and multivariate analyses confirmed that increased HOXD3 expression was an independent and significant factor in predicting poor prognosis for patients with breast cancer. In conclusion, HOXD3 expression is a significant unfavorable prognostic factor for patients with invasive breast cancer and as such is a potentially useful prognostic marker for breast cancer. PMID- 22935822 TI - Live-cell subcellular measurement of cell stiffness using a microengineered stretchable micropost array membrane. AB - Forces are increasingly recognized as major regulators of cell structure and function, and the mechanical properties of cells, such as cell stiffness, are essential to the mechanisms by which cells sense forces, transmit them to the cell interior or to other cells, and transduce them into chemical signals that impact a spectrum of cellular responses. Here we reported a new whole-cell cell stiffness measurement technique with a subcellular spatial resolution. This technique was based on a novel cell stretching device that allowed for quantitative control and real-time measurements of mechanical stimuli and cellular biomechanical responses. Our strategy involved a microfabricated array of silicone elastomeric microposts integrated onto a stretchable elastomeric membrane. Using a computer-controlled vacuum, this micropost array membrane (mPAM) was activated to apply equibiaxial cell stretching forces to adherent cells attached on the tops of the microposts. The micropost top positions before and after mPAM stretches were recorded using fluorescence microscopy and further utilized to quantify local cell stretching forces and cell area increments. A robust computation scheme was developed and implemented for subcellular quantifications of cell stiffness using the data of local cell stretching forces and cell area increments generated from mPAM cell stretch assays. Our cell stiffness studies using the mPAM revealed strong positive correlations among cell stiffness, cellular traction force, and cell spread area, and illustrated the important functional roles of actin polymerization and myosin II-mediated cytoskeleton contractility in regulating cell stiffness. Collectively, our work reported a new approach for whole-cell stiffness measurements with a subcellular spatial resolution, which would help likely explain the complex biomechanical functions and force-sensing mechanisms of cells and design better materials for cell and tissue engineering and other applications in vivo. PMID- 22935823 TI - Pineal arylalkylamine N-acetyltransferase (Aanat) gene expression as a target of inflammatory mediators in the chicken. AB - Previously, we demonstrated that experimental peritonitis in chickens was attenuated by treatment with exogenous melatonin, while the developing inflammation decreased pineal AANAT activity. This suggested the existence of a bidirectional relationship between the activated immune system and pineal gland function. The aim of the present study was to identify the step(s) in the chicken pineal melatonin biosynthetic pathway that are affected by inflammation. Peritonitis was evoked by i.p. injection of thioglycollate solution, either 2h after the start, or 2h before the end of the light period, and the animals were sacrificed 4h later. The effect of inflammation on the expression of genes encoding enzymes participating in melatonin biosynthesis in the pineal gland, i.e. tryptophan hydroxylase 1 (Tph1), dopa decarboxylase (Ddc), arylalkylamine N acetyltransferase (Aanat) and acetylserotonin O-methyltransferase (Asmt), was evaluated by qPCR. The pineal and serum melatonin concentration as well as the content of its precursors in the pineal gland were measured, along with the activity of the relevant biosynthetic enzymes. Developing peritonitis caused an increase in the pineal levels of the Tph1 mRNA during the night and the Asmt mRNA during the day, while nocturnal Aanat transcription was reduced. Both the pineal and serum melatonin level and the pineal content of N-acetylserotonin (NAS) were decreased during the night in birds with peritonitis. The amount and activity of pineal AANAT were significantly reduced, while the activity of HIOMT was increased under these experimental conditions. These results indicate that the observed decrease in MEL biosynthesis in chickens with developing inflammation is a result of transcriptional downregulation of the Aanat gene, followed by reduced synthesis and activity of the encoded enzyme. PMID- 22935824 TI - Ghrelin-induced growth hormone release from goldfish pituitary cells is nitric oxide dependent. AB - Ghrelin (GRLN) is an important neuroendocrine regulator of growth hormone (GH) release in vertebrates. Previous studies show goldfish (g)GRLN(19)-induced GH from the goldfish pituitary involves voltage sensitive Ca(2+) channels, increases in intracellular Ca(2+) and the PKC signalling pathway. We set out to examine the role of the nitric oxide (NO) pathway in gGLRN(19)-induced GH release from primary cultures of goldfish pituitary cells using pharmacological regulators in cell column perifusion systems. The NO scavenger PTIO abolished gGRLN(19)-induced GH release and co-treatment with the NO donor SNP and GRLN did not produce additive GH release responses. Nitric oxide synthase (NOS) inhibitors 1400 W and 7-Ni abolished GRLN-induced GH release while treatment with another NOS inhibitor, AGH, had no significant effect. Taken together, these results demonstrate that the NOS/NO is an integral component of gGRLN(19)-induced signalling within the goldfish pituitary cells, and given the relative specificity of AGH for inducible NOS and endothelial NOS isoforms, suggests that neuronal NOS is the likely NOS isoform utilized in goldfish somatotropes by this physiological regulator. PMID- 22935825 TI - Detection of HPV E7 oncoviral protein in cervical lesions by a new antibody. AB - The availability of a new E7 mAb-based immunohistochemistry (IHC) detection assay, Cervimax, allowed for the first time reliable testing of the E7 protein marker in formalin-fixed and paraffin-embedded tissues from cervical lesions. E7 specific IHC staining patterns were compared with those patterns of cervical cancer biomarkers, including the viral capsid protein L1 and the surrogate biomarkers p16INK4A, p53, hTERT, ubiquitin, and Ki67. The use of a tissue microarray of 138 cervical tissue cores from different pathologic stages allowed for a first profiling of the various markers in comparison with E7. Cervimax staining patterns closely overlap with those from p16INK4A and human telomerase reverse transcriptase (hTERT) in IHC staining for high-grade cervical intraepithelial neoplasia and squamous cell carcinoma. In squamous cell carcinoma, E7 immunostaining matched better to hTERT and ubiquitin profiles. On the contrary, the pattern of E7 and L1 were different in all the squamous lesions. The nuclear staining of E7 significantly discriminates between low-grade cervical intraepithelial neoplasia and high-grade cervical intraepithelial neoplasia in the basal, parabasal, and superficial layers. The results obtained in the presented pilot study suggest E7 as a valid candidate biomarker for all the stages of the malignant progression of cervical cancer; however, more extensive studies are needed to confirm the causal effect of the oncoprotein E7 in the diagnosis of human papillomavirus-induced diseases. These results also suggest that the diagnostic interpretation of cervical lesions could be increased by the combination of E7 and L1 staining in the evaluation of risk of progression, because related to different phases of viral integration. PMID- 22935826 TI - Salivary gland-like tumors of the breast express basal-type immunohistochemical markers. AB - BACKGROUND: Salivary gland-like tumors represent approximately 2% of primary breast carcinomas. These special histologic subtypes are characteristically negative for ER, PR, and HER2 (triple negative), and include adenoid cystic carcinoma, mucoepidermoid carcinoma, acinic cell carcinoma, and polymorphous low grade adenocarcinoma. Approximately 75% of triple-negative breast carcinomas belong to the basal-like subtype by gene expression profiling. Immunohistochemical panels that include basal-like markers such as EGFR, CK5/6, p cadherin, p63, and c-kit provide useful surrogates to gene expression arrays for classification of triple-negative breast cancers into the basal-like subtype. The purpose of this study was to explore the expression of these markers in salivary gland-like tumors of the breast. DESIGN: Excisional specimens from 10 untreated invasive triple-negative mammary carcinomas with salivary gland-like morphologies were evaluated for the immunohistochemical expression of EGFR, CK5/6, p-cadherin, p63, and c-kit using formalin-fixed, paraffin-embedded tissue and the L-SAB detection method. RESULTS: On the basis of morphology, 5 carcinomas were classified as adenoid cystic, 3 as mucoepidermoid, and 2 as polymorphous low grade. All of the adenoid cystic carcinomas, mucoepidermoid carcinomas, and polymorphous low-grade adenocarcinomas showed strong and diffuse expression of CK5/6, p-cadherin, and p63. EGFR was expressed weakly in adenoid cystic carcinomas and polymorphous low grade, whereas mucoepidermoid carcinomas had a stronger expression. C-kit was expressed in adenoid cystic carcinomas and low grade polymorphous, but only weakly positive in mucoepidermoid carcinomas. CONCLUSIONS: Adenoid cystic, mucoepidermoid, and polymorphous low-grade carcinomas of the breast express immunohistochemical markers that characterize the intrinsic basal-like subtype of breast cancer. PMID- 22935829 TI - [Integrated care of chronic obstructive pulmonary disease exacerbations: primary care and specialised care working together]. PMID- 22935827 TI - Mesenchymal Hamartoma of the Liver in Older Children: An Adult Variant or a Different Entity? Report of a Case With Review of the Literature. AB - Mesenchymal hamartoma of the liver (MHL) is an uncommon benign hepatic tumor typically affecting children under 2 years of age. Only 5% of MHL occur after 5 years and are very rarely observed in adults. According to age, MHL may differ in their morphologic features. We report a case of an 11-year-old boy with MHL, resembling a malignant lesion from a clinical point of view, characterized by unusual histologic features: a prominent myxoid stroma, with a minimal ductular component, and absent cystic spaces. The present case and others reported in older children or adults demonstrate that these lesions may represent a potential diagnostic pitfall when occurring outside their classic clinical context especially because of their peculiar histologic findings. Moreover, it may be hypothesized that variation in morphology might be related to different evolutive stages of the cell of origin. To support this hypothesis, we therefore studied the presence of components of the Notch pathway inside and outside the lesion. Their absence inside the tumor and, in contrast, the expression of Notch2 and HES1 evident in overrepresented bile ducts present at the periphery might explain not only the lack of bile ducts, but also indicate a more adult phenotype compared with classic pediatric MHL, which show more bile ducts and liver trabeculae embedded in the mesenchymal matrix. PMID- 22935828 TI - A simple way to improve immunoreactivity of prostate needle biopsies fixed in Bouin's solution to AMACR. PMID- 22935830 TI - [Contraceptive methods used by immigrant populations and conditions that influence the choice in a health area in Zaragoza]. AB - BACKGROUND: The percentage of women immigrants in Spain has increased in these last years, resulting in the emergence of specific needs related to sexual and reproductive health. The objective of this article was to define the contraceptive methods used by immigrant women and the determining factors that influence their choice. To estimate the use of emergency post-coital contraception and prevalence of abortion. METHODS: A descriptive cross-sectional study using a survey was carried out in the first quarter of 2011 at the "Centro de Salud Delicias Sur" in Zaragoza, Spain. The target population were immigrant women of childbearing age between 15 and 45 years who attended the clinic. Non probability sampling was used. RESULTS: The mean age was 29.35 years (95% confidence interval (CI) = 27.95 to 30.75 years). The majority country of origin was Ecuador. Almost half the women were single and worked in paid employment. The educational level was considered as average. The average duration of residence in Spain was 5.68 years (95% CI = 4.99 to 6.37 years) and 42% of them (95% CI = 32.62 to 51.83) did not use any contraceptive method. The most used contraceptive method was the condom, followed by oral hormonal contraceptives. More than half of the women had been informed in Primary Care. Almost one third (32%) (95% CI = 23.42 to 41.60) of the women had a history of abortion. More than 19% of women (95% CI = 12.46 to 28.10) had used the emergency contraceptive method. CONCLUSION: Contraceptive methods were not used by 42% of women. The alert indicators on the failure of preventive measures in sexual health are still too high. PMID- 22935831 TI - [Concordance analysis of referrals from Primary Care to Mental Health]. AB - APPROACH: Proper coordination between Primary Care (PC) and Mental Health Units (MHU) is needed, and referrals between the two systems are an important issue. We attempt to analyse various aspects on the variation between referrals from PC to MHU in the Burgos area. METHODOLOGY: Descriptive cross-sectional study, including all first-time referral patients from PC to MHU in Burgos in 2006: 1132 referrals. RESULTS: Waiting time for the first consultation with the specialist was less than 30 days in 38% of cases, and between 30 and 45 days in 36.1% of the case. The agreement between Family Doctors (FD) requests (psychiatry/clinical psychology) and the specialist performing first consultation was very high (Kappa Index 0.784). The most common diagnosis in PC were anxiety disorders (29%) and depression disorders (25%). The most common diagnosis in MHU were adaptation disorders (26%), anxiety disorders (21%), and depression disorders (19%). Diagnostic agreement between Primary care and Specialist care was low (Kappa Index 0.342). Specialists judged referrals appropriate or very appropriate in 72.4% of the cases, and deemed the information in the referral form to be adequate in 56.7% of the cases. As regards the referral type (ordinary, preferential or urgent), the agreement between PC and Mental Health specialists was very low (Kappa Index 0.179). In 75.9% of referrals, psychiatrist and clinical psychologist indicated not having had previous contact with the primary care physician. Almost half (47.7%) of referred patients indicated previous pharmacological treatment in PC. CONCLUSIONS: The degree of agreement between PC and MHU was very high in terms of specialist requested and attending specialist (psychiatry/clinical psychologist), was low in terms of diagnostic agreement, and it was very low in terms of referral type. This suggests a need to reinforce the relationship between both care systems. PMID- 22935832 TI - [Do we adequately prescribe antiplatelet treatment to type 2 diabetic patients?]. AB - OBJECTIVE: To estimate how many type 2 diabetic patients receive antiplatelet therapy according to the American Diabetes Association (ADA) guidelines on primary and secondary prevention. DESIGN: A descriptive, cross-sectional study based on information in medical records. A random sample of 170 type 2 diabetics seen in an urban Health Centre was studied. MEASUREMENTS: The data collected including, age, sex, antiplatelet therapy according to the ADA, antiplatelet therapy indicated, cardiovascular risk factors, cardiovascular disease, and other clinical parameters. RESULTS: Of the subjects analysed, 56.9% were males, and the mean age was 67.8 years. The majority of patients (71.2%) were on primary prevention, and 44.4% of the diabetics were receiving adequate antiplatelet therapy according to the ADA. Among the subjects on secondary prevention, 90.9% received adequate antiplatelet therapy, while only 25.7% of those on primary prevention received it, which was significant. The most used antiplatelet drug was acetylsalicylic acid (ASA). CONCLUSIONS: A large proportion of diabetes on primary prevention does not receive adequate antiplatelet therapy, according to the ADA. However, patients on secondary prevention receive sufficient antiplatelet treatment. The benefits of ASA in reducing cardiovascular disease are well documented in patients with cardiovascular disease. On the other hand, the role of antiplatelet therapy in diabetics on primary prevention is not clear and is the subject of discussion. From 2006 to 2011, the ADA has modified the recommendation level of primary prevention antiplatelet therapy, thus decreasing the percentage of patients that may be given antiplatelet therapy with ASA, to the extent that it increases the cardiovascular risk calculation required for its indication. PMID- 22935833 TI - [Primary prevention with aspirin]. AB - The benefit of acetylsalicylic acid and other antiplatelet drugs in secondary prevention is well established, however it use in primary prevention continues to be controversial. On the one hand, the benefit obtained is very near the potential damage arising from its use (mainly gastrointestinal bleeding), and on the other, the net benefit is less, given that its aim is to prevent the occurrence of vascular events in situations with a lower baseline risk. Antiplatelet treatment with aspirin in primary prevention has been evaluated in clinical trials and several meta-analyses, comparing its efficacy with a placebo, and with results noted for their heterogeneity. The mechanisms of action of different antiplatelet drugs, as well as the existing evidence with aspirin in primary prevention, the directions for its use by different Scientific Societies, and the cost/benefit of the intervention are reviewed. PMID- 22935834 TI - [Easily implemented cognitive behaviour techniques in Primary Care (part 1)]. AB - Cognitive behavioural therapy has shown to be very effective for treating the vast majority of mental health disorders. We comment on those techniques that can be easily used in the Primary Care setting. PMID- 22935835 TI - [Consensus on integrated care of acute exacerbations of chronic obstructive pulmonary disease (ATINA-EPOC). Part I]. PMID- 22935836 TI - [Consensus on integrated care of acute exacerbations of chronic obstructive pulmonary disease (ATINA-EPOC). Part II]. PMID- 22935837 TI - [Electrical alternans, electrocardiogram pattern in the diagnosis of a severe heart disease]. AB - Electrical alternans is a broad term that describes alternate-beat variation in the direction, amplitude and duration of any component of the ECG wave-form. It is associated with cardiac tamponade, serious ventricular arrhythmias, and sudden death. We present the clinical case of a 77-year-old female with electrical alternans, from which a diagnosis of cardiac tamponade was established. PMID- 22935838 TI - [Anti-fungal resistant hypopigmented macules in an adolescent]. AB - Progressive macular hypomelanosis of the trunk is a disease of unknown origin that often goes unrecognized in the clinical setting. We present an adolescent with this condition initially diagnosed as tinea versicolor. She was asymptomatic, with hypopigmented macules located on the trunk and with no previous history of inflammation, infection or injury. Progressive macular hypomelanosis is a common disorder that has frequently been misdiagnosed, probably because it is often considered a post-inflammatory hypopigmentation or pityriasis versicolor. PMID- 22935839 TI - [Thromboprophylaxis during immobilization of non-surgical traumatic injury in the lower limb. An outpatient perspective]. AB - Thromboprophylaxis with low molecular weight heparin is efficient, effective and generates savings in health costs in hospitals. However, outside hospitals, there are situations of apparent risk of thrombosis, where there seems to be no such consensus. This occurs in traumatic lower limb injuries which are not undergoing surgery and need a period of immobilization. These are processes with multidisciplinary interventions (Emergency, Family Physicians and Traumatology), although during outpatient follow up it is not easy to find criteria for using thromboprophylaxis. We report a case of a pulmonary embolism, with unusual symptoms, in an ambulatory patient with a fractured fibula and metatarsal, who was being treated with Bemiparin. As we shall see, this is a rare complication, but it shows the importance of proper risk assessment of thromboembolic disease in these patients. We emphasize the accompanying tomographic images for their clarity and eloquence. PMID- 22935840 TI - [Trans fats: a time bomb?]. PMID- 22935841 TI - [Preeclampsia and vascular risk. A view shared by primary care and nephrology]. PMID- 22935842 TI - [Pyogenic granuloma]. PMID- 22935843 TI - Advanced magnetic resonance imaging biomarkers of cerebral metastases. AB - There are a number of magnetic resonance imaging techniques available for use in the diagnosis and management of patients with cerebral metastases. This article reviews these techniques, in particular, the advanced imaging methodologies from which quantitative parameters can be derived, the role of these imaging biomarkers have in distinguishing metastases from primary central nervous system tumours and tumour mimics, and metrics that may be of value in predicting the origin of the primary tumour. PMID- 22935844 TI - L-carnitine treatment in incident hemodialysis patients: the multicenter, randomized, double-blinded, placebo-controlled CARNIDIAL trial. AB - BACKGROUND: L-carnitine levels decrease rapidly and steadily with duration of hemodialysis, and carnitine depletion can impair response to recombinant human erythropoietin (rHuEPO). The study hypothesis was that L-carnitine supplementation during the first year of hemodialysis would improve this response. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: From October 2006 through March 2010, this multicenter, randomized, double-blinded study assigned 92 incident hemodialysis patients to receive placebo or 1 g of intravenous L carnitine after each dialysis session for 1 year. The primary outcome measure compared the groups for rHuEPO resistance index (EPO-RI), defined as weekly rHuEPO doses (IU/kg body weight divided by hemoglobin level) (g/dl). RESULTS: In the L-carnitine group, carnitine concentration increased from a mean +/- SD of 79 +/- 51 umol/L to 258 +/- 137 umol/L; in the placebo group, it declined from 68 +/ 25 umol/L to 53 +/- 24 umol/L (interaction group * time, P<0.001). Carnitine deficiency affected about 30% of the patients in the placebo group during the study period. EPO-RI varied from 15.8 +/- 11.3 to 9.5 +/- 5.8 IU/kg per g/dl in the placebo group and from 20.6 +/- 12.8 to 15.6 +/- 15.9 IU/kg per g/dl in the L carnitine group, for a mean variation of -3.94 +/- 12.5 IU/kg per g/dl and -2.98 +/- 15.5 IU/kg per g/dl, respectively (P=0.7). After adjustment for baseline characteristics, the EPO-RI course was similar in each group (difference between groups, P=0.10; interaction group * time, P=0.9). CONCLUSIONS: Carnitine levels decrease by about 11% +/- 33% during the first year of hemodialysis. Treatment of incident hemodialysis patients with L-carnitine does not improve their response to rHuEPO. PMID- 22935845 TI - Dietary acid load and metabolic acidosis in renal transplant recipients. AB - BACKGROUND AND OBJECTIVES: Acidosis is prevalent among renal transplant recipients (RTRs) and adversely affects cardiometabolic processes. Factors contributing to acidosis are graft dysfunction and immunosuppressive drugs. Little is known about the potential influence of diet on acidosis in RTRs. This study examined the association of metabolic acid load with acidosis and with cardiovascular risk factors in RTRs and aimed to identify dietary factors associated with acidosis. DESIGN, PARTICIPANTS, SETTING, & MEASUREMENTS: 707 RTRs were included. Metabolic acid load was assessed by measuring 24-hour urinary net acid excretion (NAE; i.e., titratable acid + ammonium - bicarbonate). Acidosis was defined as serum [HCO(3)(-)] < 24 mmol/L. BP and insulin resistance, reflected by hemoglobin A1c, were among cardiovascular risk factors. Diet was assessed with food-frequency questionnaires. Linear regression analysis was applied to investigate association between NAE and acidosis and between dietary factors and acidosis. RESULTS: Mean age +/- SD was 53 +/- 13 years; 57% of patients were male. Acidosis was present in 31% of RTRs. NAE was associated with acidosis (serum HCO(3)(-): beta=-0.61; serum pH: beta=-0.010; both P<0.001). Patients with high intake of animal protein (i.e., from meat, cheese, and fish) and low intake of fruits and vegetables had significantly lower serum HCO(3)(-) and serum pH. No associations were observed between NAE and cardiovascular risk factors, such as hypertension and insulin resistance. CONCLUSIONS: In addition to conventional factors contributing to acidosis, diet might influence acid-base homeostasis in RTRs. Higher intake of fruits and vegetables and lower animal protein intake is associated with less acidosis in RTRs. PMID- 22935846 TI - Onco-nephrology: what the nephrologist needs to know about cancer and the kidney. PMID- 22935848 TI - Regional outbreak of CTX-M-2 beta-lactamase-producing Proteus mirabilis in Japan. AB - Proteus mirabilis is a common cause of urinary tract infection. Wild-type P. mirabilis strains are usually susceptible to penicillins and cephalosporins, but occurrences of P. mirabilis producing extended-spectrum beta-lactamases (ESBLs) have been recently reported. Here, we surveyed the prevalence of cefotaxime resistance among P. mirabilis strains at seven different hospitals in Kanagawa Prefecture, Japan, and investigated their molecular epidemiology to explain the mechanism of their spread. The prevalence of cefotaxime resistance among P. mirabilis increased annually, from 10.1 % in 1998 to 23.1 % in 2003, and increased drastically in 2004, exceeding 40 %. We collected 105 consecutive and non-duplicate cefotaxime-resistant P. mirabilis isolates (MIC 16 to >256 ug ml( 1)) from these hospitals from June 2004 to May 2005 and characterized their profile. PCR and sequence analysis revealed that all resistant strains produced exclusively CTX-M-2 beta-lactamase. PFGE analysis identified 47 banding patterns with 83 % or greater similarity. These results indicated that a regional outbreak of P. mirabilis producing CTX-M-2 beta-lactamase has occurred in Japan and suggest that the epidemic spread occurred within and across hospitals and communities by extended clonal strains. Plasmid analysis revealed that 44.8 % of plasmids harboured by bla(CTX-M-2) isolates had common profiles, encoding ISEcp1, IS26 and Int1, and belonged to incompatibility group T. Spread of the resistant isolates in Japan resulted from dissemination of narrow-host-range plasmids of the IncT group encoding bla(CTX-M-2). These findings indicate the rapidly developing problem of treating the species to prevent dissemination of ESBL producers. PMID- 22935847 TI - Relationship between ambulatory BP and clinical outcomes in patients with hypertensive CKD. AB - BACKGROUND AND OBJECTIVES: Abnormal ambulatory BP (ABP) profiles are commonplace in CKD, yet the prognostic value of ABP for renal and cardiovascular outcomes is uncertain. This study assessed the relationship of baseline ABP profiles with CKD progression and subsequent cardiovascular outcomes to determine the prognostic value of ABP beyond that of clinic BP measurements. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Between 2002 and 2003, 617 African Americans with hypertensive CKD treated to a clinic BP goal of <130/80 mmHg were enrolled in this prospective, observational study. Participants were followed for a median of 5 years. Primary renal outcome was a composite of doubling of serum creatinine, ESRD, or death. The primary cardiovascular outcome was a composite of myocardial infarction, hospitalized congestive heart failure, stroke, revascularization procedures, cardiovascular death, and ESRD. RESULTS: Multivariable Cox proportional hazard analysis showed that higher 24-hour systolic BP (SBP), daytime, night-time, and clinic SBP were each associated with subsequent renal (hazard ratio, 1.17-1.28; P<0.001) and cardiovascular outcomes (hazard ratio, 1.22-1.32; P<0.001). After controlling for clinic SBP, ABP measures were predictive of renal outcomes in participants with clinic SBP <130 mmHg (P<0.05 for interaction). ABP predicted cardiovascular outcomes with no interaction based on clinic BP control. CONCLUSIONS: ABP provides additional information beyond that of multiple clinic BP measures in predicting renal and cardiovascular outcomes in African Americans with hypertensive CKD. The primary utility of ABP in these CKD patients was to identify high-risk individuals among those patients with controlled clinic BP. PMID- 22935849 TI - PCR detection of co-infection with Mycobacterium tuberculosis and Mycobacterium avium in AIDS patients with meningitis. PMID- 22935850 TI - Mapping the genetic diversity within major clonal complexes of meticillin resistant Staphylococcus aureus utilizing genome-wide fluorescent amplified fragment length polymorphism markers. AB - The genetic diversity between major meticillin-resistant Staphylococcus aureus (MRSA) lineages was probed using fluorescent amplified fragment length polymorphism (FAFLP) as a random genome sampling tool. Genomic DNA was digested with endonucleases BglII and Csp6I and a subset of the restricted fragments were amplified using the primer pair BglII+A and Csp6I+0. Sixty-seven FAFLP profiles consisting of 46-68 amplified fragments ranging in size from 50 to 600 bp were exhibited amongst the 71 isolates analysed. Cluster analysis of FAFLP data revealed concordance with spa typing and MLST clonal complexes (CC), with isolates of each CC grouping in the same FAFLP cluster. Furthermore, FAFLP could differentiate subtypes within the homogeneous CC22 isolates and also between MLST sequence types 8 and 239. The discriminatory power of FAFLP was 0.998 compared to values of 0.975 and 0.909 for spa typing and MLST, respectively. Thus, FAFLP analysis proved to be a rapid, reproducible and high-resolution tool that displayed the microheterogeneity within MRSA lineages. Using FAFLP data, lineage specific fragments were identified and sequenced; these encoded toxins, antibiotic resistance determinants and bacteriophage resistance factors. Lineage specific sequence variations were observed, which may provide insights into the evolution and fitness of successful lineages. This will also aid in the development of rapid and high-throughput diagnostic PCR-based assays for the identification of MRSA lineages in resource-poor settings. PMID- 22935851 TI - Enhancing L2 students' listening transcription ability through a focus on morphological awareness. AB - Morphological awareness (MA), defined as the ability to understand the morphemic structure of the words, has been reported to affect various aspects of second language performance including reading comprehension ability, spelling performance, etc. But the concept has been far less treated with reference to l2 listening. Against this background, this study investigated the link between MA and listening transcription ability of Iranian pre-university students. To this aim, 40 pre-university students participated in the study and were assigned to control and experimental groups. Prior to giving any instruction regarding the morphological character of English words, the two groups were given three short listening passages to transcribe as pre-tests. The results of the independent samples t test run for the purpose of comparing the means of the two groups in the pre-test revealed no significant difference between the two groups in their listening transcription ability. The experimental group, then, received five 1-h sessions briefing them on the morphological realization of English words. The two groups were then given three short listening passages to transcribe as their as post-tests. The results of the independent-samples t tests attested to the significant difference between the two groups; thus, supporting the relationship between MA and listening transcription ability. PMID- 22935853 TI - The effects of stabilizing exercises on pain and disability of patients with lumbar segmental instability. AB - BACKGROUND DATA: Lumbar segmental instability (LSI) is one of the subgroups of non-specific chronic low back pain. Pain, functional disability and reduced muscle endurance are common in such patients. OBJECTIVE: The aim of this study was to determine the effects of stabilization exercise on pain, functional disability and muscle endurance in patients with LSI. METHODS: A randomized clinical trial was carried out on 30 patients who had LSI aged between 18-45 years. They were divided into two groups; the control group underwent routine exercise only while the experimental group performed routine exercise plus stabilization training for 8 weeks. Both had 3 months follow-up. The variables included pain intensity, functional disability and flexion and extension range of motion and flexor, extensor and lateral flexor muscles endurance which were evaluated 3 times; before, post treatment and after three months. The data were analyzed using repeated measurement ANOVA. RESULTS: The results revealed that after treatment, the trunk muscle endurance and flexion range of motion increased significantly and the pain intensity and functional disability decreased significantly in both groups; however the rate of improvement was significantly higher in the experimental group. The process of decreasing pain intensity and functional disability in addition to increasing muscle endurance time %was were significantly faster in the experimental group during the three months follow up. CONCLUSION: Regarding the positive effects of stabilizing exercises with routine exercises in reduction of pain intensity, increasing functional ability and muscle endurance, it is recommended to use this method in treatment of patients with lumbar segmental instability. PMID- 22935854 TI - Effect of stretching program in an industrial workplace on hamstring flexibility and sagittal spinal posture of adult women workers: a randomized controlled trial. AB - OBJECTIVES: To determine the effect of a stretching program performed in the workplace on the hamstring muscle extensibility and sagittal spinal posture of adult women. MATERIAL AND METHODS: Fifty-eight adult women volunteers (mean age of 44.23 +/- 8.87 years) from a private fruit and vegetable company were randomly assigned to experimental (n=27) or control (n=31) groups. The experimental group performed three exercises of hamstrings stretching of 20 seconds per exercise, three sessions a week for a period of 12 weeks. The control group did not participate in any hamstring stretching program. Hamstring flexibility was evaluated through the passive straight leg raise test and toe-touch test, performed both before and after the stretching program. Thoracic and lumbar curvatures and pelvic inclination were measured in relaxed standing and toe-touch test with a Spinal Mouse. RESULTS: Significant increases (p < 0.01) in toe-touch score and straight leg raise angle (in both legs) were found in the experimental group during post-test, while the control group showed a non-significant decrease for both toe-touch score and straight leg raise test. A significant decrease in thoracic curve and significant increase in pelvic inclination were found in the toe-touch test for the experimental group (p <0.05). However, no significant changes were found in standing posture for any group. CONCLUSIONS: Hamstring stretching exercises performed in the working place are effective for increasing hamstring muscle extensibility. This increase generates a more aligned thoracic curve and more anterior pelvic inclination when maximal trunk flexion is performed. PMID- 22935855 TI - Multiplying linear dimension techniques may predict the cross-sectional area of multifidus muscle at all levels of lumbar spine. AB - OBJECTIVE: This study was designed to find out the relationship between the multiplied linear dimensions (MLD) measurement and the cross-sectional area (CSA) measurement of the lumbar multifidus muscle. METHODS: Sixty healthy female subjects participated in this study. The CSA of the lumbar multifidus muscle from L2 to L5 was bilaterally measured by tracing around the muscle margins with an on screen cursor. The linear dimensions including lateral dimension (LD), anteroposterior dimension (APD) and MLD of the muscles were also calculated at the same levels of lumbar vertebrae. RESULTS: The linear regression between CSA and MLD for each vertebral level was significant (r=0.89 to 0.97, p<0.0001). In addition, there was significant correlation between CSA and APD (r=0.69 to 0.87, p<0.05). CONCLUSIONS: MLD method can be used to predict the CSA of the lumbar multifidus muscle. The method described for assessing the multifidus muscle is a potentially valuable, quick and easy way to evaluate muscle size at different levels of the lumbar vertebrae in clinical practice. PMID- 22935856 TI - A review of activity monitors as a new technology for objectifying function in lumbar spinal stenosis. AB - The purpose of this review article is to introduce the concept of activity monitoring, and to discuss the application of accelerometry in rehabilitation research and clinical practice using lumbar spinal stenosis as a model. Function is a complex concept, and changes in function have historically been challenging to measure. The International Classification of Functioning (ICF) defines two distinct components of function: capacity and performance. Capacity, the ability to perform a given task in a controlled environment can be measured through any number of existing functional measures. Performance, defined as activities performed on a day to day basis in the context of real life is challenging to measure, yet important in identifying the impact of pathology on real life. Recent advances in technology have allowed us to begin to measure performance, using activity monitors (accelerometers). Activity monitoring has the potential to change our concepts of outcomes, and as a result, expand our ideas about appropriateness of interventions in rehabilitation. Researchers and clinicians might benefit from using the new technology of activity monitors to measure the impact of intervention and to assess function. Therefore, this review will discuss the concept of activity monitoring and highlight potential uses for activity monitors in spine research and clinical care. PMID- 22935857 TI - Effect of scapular elevation taping on scapular depression syndrome: a case report. AB - OBJECTIVE: This report describes the application of scapular elevation taping (SET) using kinesio tape to elevate the scapula and treat upper trapezius (UT) muscle tenderness in a patient with scapular depression syndrome. METHODS: The patient was a 22-year-old man who had scapular depression and severe tenderness of the right UT. We performed SET for 2 months, 4 days a week, for an average of 9 h each day, to provide scapular elevation. RESULTS: At the last assessment, the right superior angle of the scapula and the lateral border of the acromion were slightly elevated compared with the spinous process of the second thoracic vertebra. A chest X-ray showed that the right coracoid process was higher compared to the initial level and that the level of the first ribs was similar on both sides. The pressure-pain threshold in the UT increased from 1 to 8 kg and the tenderness at 3 kg, assessed on a numeric rating scale, decreased from 6 to 0. No tenderness occurred when carrying a bag with the right hand or slinging a bag over the right shoulder. CONCLUSION: Continuous application of SET may be used as a supplementary method for scapular elevation and reduction in patients with UT tenderness. PMID- 22935858 TI - Comparing the efficacy of mature mud pack and hot pack treatments for knee osteoarthritis. AB - OBJECTIVE: The objective of this study is to compare the efficacy of mature mud pack and hot pack therapies on patients with knee osteoarthritis. DESIGN: This study was designed as a prospective, randomized-controlled, and single-blinded clinical trial. Twenty-seven patients with clinical and radiologic evidence of knee osteoarthritis were randomly assigned into two groups and were treated with mature mud packs (n 15) or hot packs (n=12). Patients were evaluated for pain [based on the visual analog scale (VAS)], function (WOMAC, 6 min walking distance), quality of life [Short Form-36 (SF-36)], and serum levels of tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), and insulin-like growth factor-1 (IGF-1) at baseline, post-treatment, and 3 and 6~months after treatment. RESULTS: The mud pack group shows a significant improvement in VAS, pain, stifness, and physical function domains of WOMAC. The difference between groups of pain and physical activity domains is significant at post-treatment in favor of mud pack. For a 6 min walking distance, mud pack shows significant improvement, and the difference is significant between groups in favor of mud pack at post-treatment and 3 and 6 months after treatment. Mud pack shows significant improvement in the pain subscale of SF-36 at the third month continuing until the sixth month after the treatment. Significant improvements are found for the social function, vitality/energy, physical role disability, and general health subscales of SF-36 in favor of the mud pack compared with the hot pack group at post-treatment. A significant increase is detected for IGF-1 in the mud pack group 3 months after treatment compared with the baseline, and the difference is significant between groups 3 months after the treatment. CONCLUSION: Mud pack is a favorable option compared with hotpack for pain relief and for the improvement of functional conditions in treating patients with knee osteoarthritis. PMID- 22935859 TI - Translation and validation of the Arab version of the fear avoidance beliefs questionnaire. AB - OBJECTIVE: Determine the reliability and validity of the fear avoidance beliefs questionnaire (FABQ) translated into Arabic. METHODS: The FABQ work and physical activity subscales (FABQ-W and FABQ-PA) were translated and culturally adapted into Arabic using the back-translation procedure. Forty-eight subjects with acute low back pain (LBP) and 63 subjects with chronic LBP, whose native language was Arabic, completed a demographic questionnaire, the FABQ, a pain intensity numerical scale, the Modified Oswestry Disability Index (MOSW), and the SF-36 questionnaire. Thirty patients completed the FABQ a second time 3-7 days later. RESULTS: FABQ-W and FABQ-PA showed good internal consistencies (alpha=0.90 and 0.81 respectively). Test-retest reliability was moderate to high (ICC (1,1) of 0.63 and 0.83 for the FABQ-W and FABQ-PA, respectively). Pain intensity correlated with FABQ-W only for subjects with acute pain (rho 0.41), and with the FABQ-PA only for subjects with chronic pain (rho 0.47). Significant differences between patients with acute and chronic pain were found. Correlations between the FABQ and the MOSW were moderate (rho between 0.40-0.42). Correlations between the FABQ subscales and the SF-36 questionnaire were stronger for subjects with chronic pain. A high ceiling effect was demonstrated for the FABQ-PA, in particular for patients with chronic LBP. CONCLUSIONS: The Arabic version of the FABQ has acceptable psychometric properties. However, the results of the physical activity subscale should be interpreted with caution due to a strong ceiling effect. PMID- 22935860 TI - Reliability of upper limb tension test 1 in normal subjects and patients with carpal tunnel syndrome. AB - BACKGROUND AND OBJECTIVE: Tension tests or neurodynamic techniques assess the mobility of the peripheral nerves and provide a guide for planning and managing physiotherapy treatments of entrapment syndromes such as carpal tunnel syndrome (CTS). One of the upper limb tension tests (ULTT) is ULTT1 that evaluates the efficacy of physiotherapy treatment. It has been shown to be a valid test but its reliability has not been investigated for CTS. Therefore, it is not known if the ULTT1 helps in diagnosing CTS and assessing CTS treatments. The purpose of this study was to determine the reliability of the ULTT1 in CTS. MATERIAL AND METHODS: In order to determine the reliability of the ULTT1, we tested 23 healthy subjects and 12 subjects with CTS on two separate test days. Outcome measure for this study was elbow extension. RESULTS: Inter subject elbow extensions were not significantly different between the two test days. Also, the coefficient of correlation +/- SEM in healthy and CTS subjects were 0.89 +/- 1.23 degrees and 0.84 +/- 3.67 degrees, respectively. CONCLUSION: From the above results, we conclude that the ULTT1 is highly reliable and can be used in diagnosis as well as the management of CTS. PMID- 22935861 TI - Groundwater quality in Imphal West district, Manipur, India, with multivariate statistical analysis of data. AB - The aim of this paper was to analyze the groundwater quality of Imphal West district, Manipur, India, and assess its suitability for drinking, domestic, and agricultural use. Eighteen physico-chemical variables were analyzed in groundwater from 30 different hand-operated tube wells in urban, suburban, and rural areas in two seasons. The data were subjected to uni-, bi-, and multivariate statistical analysis, the latter comprising cluster analysis (CA), principal component analysis (PCA), and factor analysis (FA). Arsenic concentrations exceed the Indian standard in 23.3% and the WHO limit in 73.3% of the groundwater sources with only 26.7% in the acceptable range. Several variables like iron, chloride, sodium, sulfate, total dissolved solids, and turbidity are also beyond their desirable limits for drinking water in a number of sites. Sodium concentrations and sodium absorption ratio (SAR) are both high to render the water from the majority of the sources unsuitable for agricultural use. Multivariate statistical techniques, especially varimax rotation of PCA data helped to bring to focus the hidden yet important variables and understand their roles in influencing groundwater quality. Widespread arsenic contamination and high sodium concentration of groundwater pose formidable constraints towards its exploitation for drinking and other domestic and agricultural use in the study area, although urban anthropogenic impacts are not yet pronounced. PMID- 22935863 TI - Etiology of community-acquired pneumonia in hospitalized children in northern Taiwan. AB - BACKGROUND: Pneumonia is the leading reason for hospitalization in children. The heptavalent pneumococcal conjugate vaccine was introduced in Taiwan in October 2005. There has been no comprehensive study of the etiology of childhood community-acquired pneumonia (CAP), either in the pre- or postpneumococcal conjugate vaccine era, in Taiwan. METHODS: From August 2001 to July 2002, consecutive children admitted to a teaching hospital with radiologically confirmed CAP were prospectively enrolled. The following were considered indicative of infection when positive: blood or pleural effusion bacterial culture or urinary Streptococcus pneumoniae antigen test (Binax NOW), direct immunofluorescent antigen test for Chlamydia species and viruses, virus isolation and identification and viral, mycoplasmal or chlamydial serologic tests. RESULTS: A total of 209 children were included, and 102 children (48.8%) were male. Patients' ages ranged from 7 months to 16 years with a median of 4 years and 3 months. The combined tests identified at least 1 etiologic agent in 85.6% of all cases, including typical bacterial pathogens in 88 cases (42.1%; 86 S. pneumoniae, 1 methicillin-resistant Staphylococcus aureus and 1 Mycobacterium tuberculosis), Mycoplasma pneumoniae in 77 cases (36.8%), Chlamydia species in 24 cases (11.5%), viral etiology in 86 cases (41.1%) and mixed viral-bacterial infections in 69 cases (33%). Children with S. pneumoniae infection were significantly younger than those with Mycoplasma pneumoniae infection (P = 0.0055) or unknown etiology (P = 0.0140). CONCLUSION: S. pneumoniae, Mycoplasma pneumoniae and viruses were equally common etiologic agents of childhood CAP in Taiwan. Frequent coinfection increased the difficulty of both predicting the responsible organisms and choosing empiric antibiotics for the management of pediatric CAP. PMID- 22935862 TI - Visible-light-induced photocatalytic reduction of Cr(VI) with coupled Bi2O3/TiO2 photocatalyst and the synergistic bisphenol A oxidation. AB - Coupled Bi2O3/TiO2 photocatalysts were fabricated by sol-gel and hydrothermal methods and characterized using various spectroscopy techniques. Photocatalytic reduction of Cr(VI) in aqueous solution, together with the synergistic effect of photodegradation of bisphenol A (BPA), was investigated using these coupled Bi2O3/TiO2 under visible-light irradiation. Coupling of Bi2O3 inhibited the phase transformation from anatase to rutile and extended absorption region to visible light. Bi ions did not enter TiO2 lattice and were more likely to bond with oxygen atoms to form Bi2O3 on the surface of TiO2. Photovoltage signals in visible range revealed the effective interfacial charge transfer between Bi2O3 and TiO2. Two percent Bi2O3/TiO2 exhibited the highest photocatalytic activity of visible-light-induced reduction of Cr(VI). The addition of BPA effectively increased the photocatalytic reduction of Cr(VI). Simultaneously, the presence of Cr(VI) promoted the degradation of BPA, which was demonstrated by the investigation of TOC removal yield and generated intermediates. A possible mechanism of photocatalytic reduction of Cr(VI) and degradation of BPA in Bi2O3/TiO2 system was proposed. The synergistic effect, observed between reduction of Cr(VI) and degradation of BPA, provides beneficial method for environmental remediation and purification of the complex wastewater. PMID- 22935864 TI - Risk factors for salmonella gastroenteritis in children less than five years of age in Taiwan. AB - BACKGROUND: Nontyphoid Salmonella spp. have been among the most common pathogens of acute gastroenteritis in children in Taiwan. However, the principal sources of transmission remain poorly defined. METHODS: A matched case-control study was conducted from January 2009 to October 2010. Cases were children aged 2-60 months who were hospitalized at 3 medical centers in Taiwan because of diarrhea and found to have culture-proven nontyphoidal Salmonella infection. Controls were healthy children or children with acute diseases other than gastroenteritis and matched to cases by age, gender, study site and enrollment date. RESULTS: A total of 396 cases and 930 matched controls were included for analysis. Multivariate analysis using conditional logistic regression identified contact with household members having diarrhea (matched odds ratio [mOR], 17.9; 95% confidence interval [CI]: 8.82-36.34; P < 0.0001), consumption of instant powdered milk (mOR, 2.04; 95% CI: 1.05-3.94; P = 0.0344), visits to health-care facilities (mOR, 1.66; 95% CI: 1.12-2.48; P = 0.0126) and consumption of purchased groundwater (mOR, 1.50; 95% CI: 1.06-2.11; P = 0.0214) within 1 week preceding enrollment as independent factors associated with increased risk of salmonellosis. Hand washing before meals (P = 0.0311), breastfeeding (P = 0.0370), consumption of chicken (P = 0.0019) and consumption of food prepared by caregivers (P = 0.0011) were protective against Salmonella infection. CONCLUSIONS: The principal transmission routes of Salmonella infection in Taiwanese children are person-to-person, waterborne and environmental contacts. The possibility of powdered milk and groundwater contamination of Salmonella cannot be excluded and requires further investigation. PMID- 22935865 TI - Nonvirologic algorithms for predicting HIV infection among HIV-exposed infants younger than 12 weeks of age. AB - BACKGROUND: Early initiation of antiretroviral therapy has been shown to reduce mortality among perinatally HIV-infected infants, but availability of virologic testing remains limited in many settings. METHODS: We collected cross-sectional data from mother-infant pairs in three primary care clinics in Lusaka, Zambia, to develop predictive models for HIV infection among infants younger than 12 weeks of age. We evaluated algorithm performance for all possible combinations of selected characteristics using an iterative approach. In primary analysis, we identified the model with the highest combined sensitivity and specificity. RESULTS: Between July 2009 and May 2011, 822 eligible HIV-infected mothers and their HIV-exposed infants were enrolled; of these, 44 (5.4%) infants had HIV diagnosed. We evaluated 382,155,260 different characteristic combinations for predicting infant HIV infection. The algorithm with the highest combined sensitivity and specificity required 5 of the following 7 characteristic thresholds: infant CD8 percentage >22; infant CD4 percentage <=44; infant weight for-age Z score <=0; infant CD4 <=1600 cells/uL; infant CD8 >2200 cells/uL; maternal CD4 <=600 cells/uL; and mother not currently using antiretroviral therapy for HIV treatment. This combination had a sensitivity of 90.3%, specificity of 78.4%, positive predictive value of 22.4%, negative predictive value of 99.2% and area under the curve of 0.844. CONCLUSION: Predicting HIV infection in HIV-exposed infants in this age group is difficult using clinical and immunologic characteristics. Expansion of polymerase chain reaction capacity in resource-limited settings remains urgently needed. PMID- 22935866 TI - Abnormal newborn screens and acylcarnitines in HIV-exposed and ARV-exposed infants. AB - BACKGROUND: Antiretroviral drugs (ARV), specifically nucleoside analogs, are toxic to mitochondrial oxidative phosphorylation. Other metabolic pathways, such as fatty acid oxidation, organic acid metabolism and amino acid metabolism, are dependent on normal oxidative phosphorylation but remain unexamined as potential points of ARV toxicity. METHODS: We analyzed newborn screening data from New York and compared proportions of abnormal newborn metabolic screens in HIV antibody screen-positive and HIV screen-negative neonates. Subsequently, we compared acylcarnitine levels in ARV-exposed (n = 16) and ARV-unexposed (n = 14) HIV exposed infants to assess for dysfunctional fatty and organic acid metabolism. RESULTS: : The rate of abnormal newborn metabolic screens in HIV screen-positive infants was higher than that in the general population (2.2% versus 1.2%; P = 0.00025), most of which were for disorders of mitochondria-related metabolism. Abnormal acylcarnitine levels occurred more frequently in ARV-exposed compared with ARV-unexposed infants (43% versus 0%; P = 0.02). CONCLUSIONS: A higher proportion of positive metabolic screens in HIV screen-positive neonates suggests that HIV or ARV exposure is associated with dysfunctional intermediary metabolism in newborns. Abnormal acylcarnitine levels were more frequent in ARV-exposed infants, suggesting that ARV may perturb normal fatty acid oxidation in some infants. Studies designed to validate and determine the clinical significance of these findings are warranted. PMID- 22935867 TI - Paradoxical Mycobacterium tuberculosis meningitis immune reconstitution inflammatory syndrome in an HIV-infected child. AB - Immune reconstitution inflammatory syndrome occurs in a subset of HIV-infected individuals as the immune system recovers secondary to antiretroviral therapy. An exaggerated and uncontrolled inflammatory response to antigens of viable or nonviable organisms is characteristic, with clinical deterioration despite improvement in laboratory indicators. We describe a fatal case of Mycobacterium tuberculosis meningitis immune reconstitution inflammatory syndrome in an HIV infected child and review the literature. PMID- 22935868 TI - Association between IgG subclasses against Toxoplasma gondii and clinical signs in newborns with congenital toxoplasmosis. AB - BACKGROUND: The aim of this study was to evaluate the association between clinical signs of congenital toxoplasmosis and IgG subclasses found in newborns participating in the Minas Gerais State Neonatal Screening Program. METHODS: Neonates with confirmed congenital toxoplasmosis underwent standardized ophthalmologic evaluation, neuroimaging studies and hearing assessment, as well as enzyme-linked immunosorbent assay testing for total IgG and its subclasses (IgG1, IgG2, IgG3 and IgG4) against soluble (STAg) and recombinant (rSAG1 and rMIC3) antigens of Toxoplasma gondii. RESULTS: Newborns with congenital toxoplasmosis but without ocular lesions were more likely to present anti-rMIC3 total IgG when compared with those newborns with active or cicatricial retinochoroidal lesions. Detection of anti-rMIC3 IgG2 and IgG4 was associated with presence of retinochoroidal lesions and intracranial calcifications, with higher mean reactivity index values than unaffected newborns with congenital toxoplasmosis. Anti-STAg IgG3 was associated with newborns without neurologic damage. CONCLUSIONS: Specific subclasses of IgG antibodies reacting with recombinant antigens of T. gondii may serve as biomarkers of neurologic and ocular changes in newborns with congenital toxoplasmosis. PMID- 22935869 TI - Acute neuromuscular weakness in a boy with a facial abscess contaminated with Clostridium botulinum. AB - Wound botulism arising from skin and soft tissue infection is rare in children, most cases being reported in adult intravenous drug users. Cranial nerve palsies are the primary presenting sign, followed by descending neuromuscular weakness. Diagnosis relies on isolation of either toxigenic Clostridium botulinum species or toxin from wound or blood samples. We present an unusual case of wound botulism in a pediatric patient with the intent to inform the reader and improve the time to diagnosis in such cases. PMID- 22935870 TI - Completeness of reporting in randomized controlled trials of 3 vaccines: a review of adherence to the CONSORT checklist. AB - BACKGROUND: Clear reporting of randomized controlled trials (RCTs) of vaccines is important for understanding results and assessing their validity. The CONsolidated Standards of Reporting Trials (CONSORT) statement provides guidance to help authors reporting RCTs. The objective was to assess the completeness of reporting of RCTs of vaccines based on the CONSORT 2010 checklist. METHODS: We collected data about items required by the CONSORT checklist or specific to trials of vaccines. We used publications of RCTs identified in 3 systematic reviews of pneumococcal polysaccharide, pneumococcal conjugate and rotavirus vaccines. We included the first journal publication that reported clinical, carriage or immunological data for each trial and summarized results descriptively. RESULTS: We included 70 publications from 19 journals. Of these, 14 publications (20%) stated in the title that the trial was randomized and 26 publications (37%) nominated at least 1 primary outcome. The method for generating the random allocation sequence was fully reported in 24 publications (34%), the method of allocation concealment in 9 publications (13%) and 30 publications (43%) included a flow diagram. Trial registration numbers were reported in all articles published in 2010 to 2011. Actual age at vaccination was reported in 20% of trials of childhood schedules. Eleven of 19 journals endorsed the CONSORT statement. CONCLUSIONS: The reporting of RCTs of vaccines is incomplete, with important methodological details missing from most reports. Journals could play a leading role in implementing changes. Improved reporting would make publications of vaccine trials easier to find, the findings easier to interpret and aid the incorporation of findings into policy. PMID- 22935871 TI - The use of intravenous colistin among children in the United States: results from a multicenter, case series. AB - BACKGROUND: A rapid increase in multidrug-resistant Gram-negative infections has led to a reemergence of colistin use globally. Although it is well described among adults, colistin use and its associated toxicities in children are poorly understood. We report findings from the largest case series of pediatric colistin use to date. METHODS: We queried pediatric infectious diseases specialists from the Emerging Infections Network to identify members who had prescribed intravenous colistin within the past 7 years. We collected relevant demographic and clinical data. Bivariate analyses and multivariable logistic regression were performed. RESULTS: Two hundred twenty-nine pediatric infectious diseases specialists completed the survey (84% response); 22% had prescribed colistin to children. Among respondents, 92 cases of colistin use from 25 institutions were submitted. The most commonly targeted organisms were multidrug-resistant Pseudomonas (67.4%), multidrug-resistant Acinetobacter -baumanii (11.9%), carbapenemase-producing Enterobacteriaceae (13.0%) and extended-spectrum beta lactamase producing Enterobacteriaceae (5.4%). Development of resistance to colistin was observed in 20.5% of patients. Additional antimicrobial therapy was administered to 84% of patients, and 22% of children experienced nephrotoxicity (not associated with dosage or interval of colistin prescribed). Renal function returned to baseline in all patients. Children aged >=13 years had approximately 7 times the odds of developing nephrotoxicity than younger children, even after controlling for receipt of additional nephrotoxic agents (odds ratio 7.16; 95% confidence interval: 1.51-14.06; P = 0.013). Four children exhibited reversible neurotoxicity. CONCLUSIONS: Most pediatric infectious diseases specialists have no experience prescribing colistin. Colistin use in children has been associated primarily with nephrotoxicity and, to a lesser extent, neurotoxicity, both of which are reversible. Emergence of resistance to colistin is concerning. PMID- 22935872 TI - Risk factors and outcomes of carbapenem-resistant Acinetobacter baumannii bacteremia in neonatal intensive care unit: a case-case-control study. AB - BACKGROUND: Carbapenem-resistant Acinetobacter baumannii (CRAB) has emerged as a serious threat among critically ill neonates. METHODS: We performed a case-case control study in a Thai neonatal intensive care unit to identify risk factors and outcomes for CRAB bacteremia. Case group (CG) I was defined as cases with CRAB (n = 14), and CG II was defined as cases with carbapenem-susceptible A. baumannii (n = 38) bacteremia. The control group (n = 44) was selected from all patients admitted before and after 3 days that CG I was identified, but had no infection. RESULTS: The mean gestational age and birth weight of CG I, II and control were 33.5, 35.2 and 35.2 weeks and 1856.5, 2273.9 and 2309.5 g, respectively. By multivariate analysis, CG I was more likely to have had an umbilical artery catheter (adjusted odds ratio = 29.30; P = 0.019) whereas CG II was more likely exposed to ceftazidime (adjusted odds ratio = 5.19; P = 0.046) and aminoglycosides (adjusted odds ratio = 35.59; P = 0.002). There was a significant difference in history of cefoperazone/sulbactam (21.4% versus 0%; P = 0.01) and imipenem use (35.7% versus 0%; P < 0.001) among CG I compared with control. Crude mortality in CG I was higher than CG II (42.9% versus 13.2%; odds ratio = 5.0; P = 0.02). CONCLUSION: Our cohort of neonatal CRAB bacteremia is characterized by a very high mortality. Infection-control interventions inclusive of strict adherence to infection-control process for central vascular line placement and maintenance as well as antimicrobial stewardship program are essential to help reduce CRAB bacteremia. PMID- 22935874 TI - Morphology-based features for adaptive mitosis detection of in vitro stem cell tracking data. AB - OBJECTIVES: The cultivation of adherently growing cell populations is a major task in the field of adult stem cell production used for drug discovery and in the field of regenerative medicine. To assessthe quality of a cell population, a crucial event is the mitotic cell division: the precise knowledge of these events enables the reconstruction of lineages and accurate proliferation curves as well as a detailed analysis of cell cycles. To serve in an autonomous cell farming framework, such a detector requires to work reliably and unsupervised. METHODS: We introduce a mitosis detector that is using a maximum likelihood (ML) estimator based on morphological cell features (cell area, brightness, length, compactness). It adapts to the 3 phases of cell growth (lag, log and stationary phase). As a concurrent model, we compared ML with kernel SVMs using linear, quadratic and Gaussian kernel functions. All approaches are evaluated for their ability to distinguish between mitotic and non-mitotic events. The large, publicly available benchmark data CeTReS (reference data set A with >240,000 segmented cells, >2,000 mitotic events) is used for this evaluation. RESULTS: The adaptive (unsupervised) ML approach clearly outperforms previously published non adaptive approaches and the linear SVM. Furthermore, it robustly reaches a performance comparable to quadratic and Gaussian SVM. CONCLUSIONS: The proposed simple and label free adaptive variant might be the method of choice when it comes to autonomous cell farming. Hereby, it is essential to have reliable and unsupervised mitosis detection that covers all phases of cell growth. PMID- 22935873 TI - Density interactions among Streptococcus pneumoniae, Haemophilus influenzae and Staphylococcus aureus in the nasopharynx of young Peruvian children. AB - Streptococcus pneumoniae, Haemophilus influenzae and Staphylococcus aureus are commonly carried in the nasopharynx of young children, and have been speculated to interact with each other. Although earlier studies used cultures alone to assess these interactions, the addition of real-time quantitative polymerase chain reaction (qPCR) provides further insight into these interactions. We compared results of culture and qPCR for the detection of these 3 bacteria in 446 nasopharynx samples collected from 360 healthy young children in a prospective cohort study in the Peruvian Andes. Patterns of concurrent bacterial colonization were studied using repeated measures logistic regression models with generalized estimating equations. Spearman correlation coefficients were used to assess correlations among bacterial densities. At a bacterial density <10 colony forming units/mL measured by qPCR, culture detected significantly less carriers (P < 0.0001) for all 3 pathogens, than at a bacterial density >10 colony forming units/mL. In addition, there was a positive association between S. pneumoniae and H. influenzae colonization measured by both culture (odds ratio [OR] 3.11-3.17, P < 0.001) and qPCR (OR 1.95-1.97, P < 0.01). The densities of S. pneumoniae and H. influenzae, measured by qPCR, were positively correlated (correlation coefficient 0.32, P < 0.001). A negative association was found between the presence of S. pneumoniae and Staphylococcus aureus in carriage with both culture (OR 0.45, P = 0.024) and qPCR (OR 0.61, P < 0.05). The impact of density on detection by culture and the observed density-related interactions support use of qPCR in additional studies to examine vaccine effects on diverse bacterial species. PMID- 22935875 TI - Preparation of porosity-controlled calcium carbonate by thermal decomposition of volume content-variable calcium carboxylate derivatives. AB - We demonstrate a novel approach for synthesizing porosity-controlled calcium carbonate by one-step thermal decomposition of various calcium carboxylate derivatives as well as their mixtures with different molar ratios. By varying the volume content of calcium in the calcium compounds or mixtures, the resulting porous calcium carbonate exhibits distinct porosity and structures that are very promising for various applications. PMID- 22935878 TI - Targeting activated mineralocorticoid receptor: Occam's razor revisited. AB - Activation of mineralocorticoid receptors (MRs) classically has been associated with electrolyte transport, but we now know that MR activation can also lead to tissue inflammation and fibrosis. Aldosterone consistently activates MR, but under selected circumstances, endogenous glucocorticoids such as cortisol and corticosterone can also trigger MR. Tissue-specific safeguards such as the enzyme 11beta-hydroxysteroid dehydrogenase limit glucocorticoid-induced MR activation, while the presence of reactive oxygen species may enhance the ability for glucocorticoid-induced MR activation even in the absence of aldosterone. PMID- 22935879 TI - Searching for new care models for chronic kidney disease. AB - Chronic kidney disease is associated with increased death risk. The estimated size of this high-risk population is too large for effective care to be delivered by nephrologists alone and will require models of care delivery that include partnerships with primary-care physicians and incorporate physician extenders. Studies show that some of these care models provide outcomes similar to those seen with nephrologists as sole providers; whether they are cost-effective or improve satisfaction with care remains to be demonstrated. PMID- 22935880 TI - The risks of vascular access. AB - Fatal vascular access hemorrhage is considered a rare complication of hemodialysis (HD). Ellingson et al. indicate otherwise, and their data suggest that it causes 0.4-1.6% of deaths in US HD patients. It is more common with grafts than fistulas, and many victims have had previous access hemorrhages. The widespread presumption that a fistula is the best, and a cuffed catheter the worst, access for HD patients needs reassessment, particularly in older, sicker patients. PMID- 22935881 TI - The alternative Iranian model of living renal transplantation. AB - The experience of the Iranian model should be carefully considered by those who suggest a pilot trial of a regulated market in organ sales. Mahdavi-Mazdeh's candid report makes clear that a fixed price as the basis of regulation is not possible. Iran is proceeding with an independent program of deceased organ donation in cities such as Shiraz. Mahdavi-Mazdeh's report is encouraging for the prospect of a revitalized expansion of deceased donation. PMID- 22935883 TI - Digital manifestations of tertiary hyperparathyroidism. PMID- 22935884 TI - The case ? a challenging case of severe rickets. PMID- 22935885 TI - Phagocytes mediate targeting of iron oxide nanoparticles to tumors for cancer therapy. AB - Nanotechnology has great potential to produce novel therapeutic strategies that target malignant cells through the ability of nanoparticles to get access to and be ingested by living cells. However its specificity for accumulation in tumors, which is the key factor that determines its efficacy, has always been a challenge. Here we tested a novel strategy to target and treat ovarian cancer, a representative peritoneal cancer, using iron oxide nanoparticles (IONPs) and an alternating magnetic field (AMF). Peritoneal tumors in general are directly accessible to nanoparticles administered intraperitoneally (IP), as opposed to the more commonly attempted intravenous (IV) administration. In addition, tumor associated immunosuppressive phagocytes, a predominant cell population in the tumor microenvironment of almost all solid tumors, and cells that are critical for tumor progression, are constantly recruited to the tumor, and therefore could possibly function to bring nanoparticles to tumors. Here we demonstrate that tumor-associated peritoneal phagocytes ingest and carry IONPs specifically to tumors and that these specifically delivered nanoparticles can damage tumor cells after IONP-mediated hyperthermia generated by AMF. This illustrates therapeutic possibilities of intraperitoneal (IP) injection of nanoparticles and subsequent ingestion by tumor-associated phagocytes, to directly impact tumors or stimulate antitumor immune responses. This approach could use IONPs combined with AMF as done here, or other nanoparticles with cytotoxic potential. Overall, the data presented here support IP injection of nanoparticles to utilize peritoneal phagocytes as a delivery vehicle in association with IONP-mediated hyperthermia as therapeutic strategies for ovarian and other peritoneal cancers. PMID- 22935886 TI - The impact of prostate biopsy on urinary symptoms, erectile function, and anxiety. AB - Transrectal ultrasound-guided prostate needle biopsy (PB) is considered the gold standard for the diagnosis of prostate cancer. Recently, lower urinary tract symptoms and erectile dysfunction have been reported following PB. We reviewed the literature on PB and these symptoms and summarized known findings between these conditions and other variables, such as periprostatic nerve block, saturation biopsy, serial biopsies, and psychological factors associated with PB and cancer. A PubMed search was performed using keywords "prostate biopsy," "complications," "erectile dysfunction," "lower urinary tract symptoms," "anxiety," and "quality of life." Eleven key papers are discussed and personal experience is drawn upon. Based upon available evidence, PB appears to be associated with short-term exacerbation of urinary symptoms in some men, as well as associated with anxiety and temporary erectile dysfunction, without a distinct relationship to periprostatic nerve block or the number of cores biopsied. Additional studies are warranted to determine the definitive etiology of these symptoms and to determine if interventions could reduce patient morbidity. In the interim, patients should be educated and counseled about these risks before undergoing PB. PMID- 22935887 TI - Intestinal transplantation: a review. AB - Parenteral nutrition is a life-saving therapy for patients with intestinal failure. Intestinal transplantation is now recognized as a treatment for patients who develop complications of parenteral nutrition and in whom attempts at intestinal rehabilitation have failed. Patients with parenteral nutrition related liver disease will require a liver graft typically part of a multivisceral transplant. Isolated intestinal transplants are more commonly performed in adults while multivisceral transplants are most commonly performed in infants. Isolated intestinal transplants have the best short-term outcome, with over 80 % survival at 1 year. Patients requiring multivisceral transplants have a high rate of attrition with a 1 year survival less than 70 %. Prognostic factors for a poor outcome include patient hospitalization at the time of transplant and donor age greater than 40 years while systemic sepsis and acute rejection are the major determinant of early postoperative outcome. For patients surviving the first year the outcome of transplantation of the liver in addition to intestine affords some survival advantage though long-term outcome does not yet match other abdominal organs. Outcomes for intestinal retransplantation are poor as a result of immunology and patient debility. Overall intestinal transplantation continues to develop and is a clear indication with cost and quality of life advantages in patients with intestinal failure that do not remain stable on parenteral nutrition. PMID- 22935888 TI - A case of primary signet-ring cell/histiocytoid carcinoma of the eyelid: immunohistochemical comparison with the normal sweat gland and review of the literature. AB - Primary signet-ring cell/histiocytoid carcinomas of the eyelid are extremely rare tumors considered to originate from sweat glands. Here, we report the case of a 72-year-old man diagnosed with primary signet-ring cell/histiocytoid carcinoma of the eyelid and present immunohistochemical analyses of the eyelid apocrine gland (Moll gland) and apocrine and eccrine sweat glands of perineum and axilla. Widespread infiltration of tumor cells with signet-ring cell or histiocytoid appearance was observed in his left eyelid, orbit, and periocular lesion. Tumor cells expressed mucins and showed immunoreactivity that was similar to that of the Moll gland: MUC6(+), GlcNAcalpha1->4Gal->R(-), MUC2(-), MUC5AC(-), GCDFP15(+), CD15(+), S100(-), CK7(+), CK20(-), ER(+), PgR (+), HER2(-), E cadherin(+), p63(-), PSA(-), and TTF-1(-). The tumor cells differed from those of perineal and axillary apocrine and eccrine sweat glands, which were MUC6(-). The Moll gland was ER(-) and PgR(-), whereas perineal and axillar apocrine sweat glands were ER(+) and PgR(+), and perineal and axillary eccrine sweat glands were ER(+) and PgR(-). The tumor showed characteristics similar to that of the eyelid Moll gland, which is demonstrated to be an apocrine gland with a protein expression distinct from that of other apocrine glands. MUC6 and GCDFP15 expression are useful in identifying the Moll gland immunophenotype and GCDFP15, ER and PgR expression are useful in distinguishing primary eyelid signet ring/histocytoid carcinoma from gastrointestinal malignancies. PMID- 22935889 TI - Granuloma annulare associated with cutaneous marginal zone lymphoma: a case linking a hematologic malignancy with granulomatous dermatitis. AB - Granuloma annulare and other granulomatous disorders have been reported to be associated with internal malignancies, primarily T-cell lymphomas, whereas very few reports of granulomatous disorders in association with B-cell lymphoma exist in the literature. We report a case of marginal zone lymphoma, a cutaneous B-cell lymphoma that occurred concomitantly with refractory granuloma annulare. This case highlights the importance of considering both B- and T-cell dyscrasias in the case of refractory or extensive granulomatous lesions and the importance of histopathologic examination in the evaluation of these lesions. PMID- 22935890 TI - Widespread atypical vascular lesions of the skin after whole-body electron beam therapy: expanding the clinical spectrum. AB - Atypical vascular lesion of the skin is an uncommon usually benign condition, thus far reported almost exclusively from mammary skin after radiotherapy for carcinoma of the breast. Some clinical and histological overlap exists with early angiosarcoma, which can also occur on irradiated skin. The lesions are divided into vascular and lymphatic types, the first representing a higher risk for development of angiosarcoma and the latter being more common. This article reports a rare case of widespread, progressive, vascular-type atypical vascular lesion after repeated whole-body electron beam irradiation administered as treatment for mycosis fungoides. PMID- 22935891 TI - Cellular angiolipoma: a clinicopathological and immunohistochemical study of 12 cases. AB - Cellular angiolipoma is a rare variant of angiolipoma. To date, only a few reports have been published in the literature. In this report, we analyzed a series of 12 cases to further evaluate this entity. Seven patients were men and 5 were women, aged from 23 to 62 years (average, 39 years). Clinically, the lesions occurred predominantly in the subcutaneous tissue of the extremities and trunk wall, usually as part of multiple small tender nodules. In 5 cases, cellular angioloipoma coexisted with the conventional angiolipoma. Histologically, the tumor differed from its conventional counterpart by containing densely cellular areas that occupied more than 90% of the tumors. By comparison, adipocytic component accounted only for a minimal portion (<10%). CD31 and CD34 immunostainings highlighted the rich vasculature in the cellular areas. In conclusion, the clinical and morphological overlaps between the cellular angiolipoma and its conventional counterpart indicate that they lie within the same spectrum of a single entity. PMID- 22935892 TI - Epithelioid histiocytic infiltrate caused by Mycobacterium scrofulaceum infection: a potential mimic of various neoplastic entities. AB - Mycobacterium scrofulaceum is a slow-growing atypical mycobacterium that is ubiquitous within our environment found in the water and soil. Most commonly, it manifests as the organism responsible for lymphadenitis in children. In adults, infection by this organism is rare and usually occurs in the setting of local or systemic host immunosuppression. We herein report a case of a 45-year-old woman who presented with a large subcutaneous nodule over her right upper arm. She had been on low dose oral prednisone for 17 years for systemic lupus erythematosus without complication. A biopsy of the nodule revealed a diffuse dermal infiltrate of epithelioid histiocytes laden with acid-fast bacilli mimicking a fibrohistiocytic neoplasm. Treatment with clarithromycin monotherapy resulted in clinical remission. Consideration of atypical mycobacterial infection is warranted in fibrohistiocytic proliferations of the skin especially within immunosuppressed patients. PMID- 22935894 TI - [Physiology and pathophysiology of wound healing of wound defects]. AB - Understanding wound healing involves more than simply stating that there are the three phases of inflammation, proliferation and maturation. Wound healing is a complex series of actions, reactions and interactions among cells and mediators in a sequential and simultaneously ongoing temporal process within a spatial frame. At first this article will attempt to provide a concise summary of the events, cellular components and main influential mediators of wound healing over time. Secondly, the pathophysiology of chronic non-healing wounds is described where an imbalance of stimulating and inhibiting factors causes failure of healing. The most relevant extrinsic and intrinsic determinants are described and related to the cellular and molecular level of disturbed wound healing. A basic understanding of wound healing is a prerequisite for any prophylactic or therapeutic maneuver to maintain or re-establish wound equilibrium to give a satisfactory healing trajectory. PMID- 22935895 TI - [Wound dressings. Overview and classification]. AB - Wound dressing and wound management are key words in current wound treatment. An unmanageably high number of products causes more confusion than clarification. Under continuous cost pressure in healthcare services, the choice of adequate wound management for long-term wound treatment, especially concerning chronic wounds, is crucial. This article presents an overview of the available wound dressings. PMID- 22935896 TI - [Hydroactive stage-adapted wound management]. AB - The treatment of subacute and chronic wounds is not only a major medical challenge but because of demographic developments and the concurrent increase in predisposing diseases, such as diabetes mellitus and arterial occlusive disease is also a relevant socioeconomic challenge. The principle of modern, moist wound care can now be regarded as established. In daily practice there are nevertheless significant treatment problems which are, among other things due to the vast variety of products available. As evidence-based guidelines for the treatment of chronic wounds were until recently lacking and many question were left unanswered, standards of care represent an appropriate means of orientation. In addition to improved quality of care in this way costs can also be reduced. Furthermore, criteria can be illustrated by which the selection of appropriate wound dressings can be facilitated and established. PMID- 22935897 TI - [Vacuum assisted closure therapy. Management of a severe blast injury to the lower limb]. AB - This article reports the case of a 23-year-old woman who sustained severe soft tissue injuries with open fractures of the left distal femur, the left proximal tibia, a subtotal amputation of the left foot with injuries to the anterior and posterior tibial artery due to a bomb blast. When the patient was transferred to our hospital 17 days after the trauma, all primarily closed wounds were severely infected. The fractures were treated by external fixateur and k-wire fixation. After debridement and initiation of negative pressure therapy the anterior tibial artery was reconstructed after 3 days and partial wound closure by a rectus abdominis muscle flap was achieved after 19 days. After almost total wound closure was accomplished open reduction internal fixation (ORIF) was performed for the distal femur fracture and a modification of the external fixateur for the tibial and foot fractures. The negative pressure therapy is an important component for treatment of complex soft tissue injuries and open fractures; however, it must be embedded in an interdisciplinary treatment plan with well defined treatment goals. PMID- 22935898 TI - [Treatment of fingertip amputation with semiocclusive dressing]. AB - BACKGROUND: Finger injuries are particularly challenging with respect to function and aesthetics. Flap surgery of the hand is technically demanding and can cause large defects if incorrectly performed. METHOD: Semiocclusive dressing, as described by Mennen and Wiese in 1993 is a simple and well-established method for treating fingertip amputations and soft tissue defects. The method is based on the principle of a moist chamber and is a good conservative option for treating these defects with respect to both function and aesthetics. PMID- 22935900 TI - [Effects of minimum volume regulations. Orthopedic and trauma-specific implications]. PMID- 22935899 TI - [Subscapularis tendon lesions. Anatomy, diagnosis and importance of arthroscopic treatment]. AB - The subscapularis tendon is involved in up to 43% of arthroscopically treated rotator cuff lesions. Due to the close anatomic relationship, participation of the long head of the biceps and supraspinatus tendon is common. Subscapularis tendon lesions are often not primary diagnosed correctly. Using specific clinical tests and modern sectional imaging, the percentage of correct diagnoses can be increased. Convincing clinical results, advantages of minimally invasive surgery, and superior visualization compared to the open approach argue for arthroscopic treatment of subscapularis lesions. Awareness of the footprint allows anatomic reconstruction. In case of planned open treatment, arthroscopy should precede as particularly articular-sided lesions might be missed otherwise. PMID- 22935901 TI - Fat deposition decreases diffusion parameters at MRI: a study in phantoms and patients with liver steatosis. AB - PURPOSE: Assess the effect of fat deposition on the MRI diffusion coefficients in lipid emulsion-based phantoms and patients with proven isolated liver steatosis. MATERIALS AND METHODS: Diffusion-weighted MRI with 11 b values from 0-500 s/mm(2) was performed in phantoms (fat fractions 0-18 %) with and without fat suppression and in 19 patients with normal liver (n = 14) or isolated liver steatosis (n = 5) proven by histopathology. The apparent, pure and perfusion-related diffusion coefficients and the perfusion fraction were measured. Spearman correlation coefficient and Mann-Whitney U test were used for comparisons. RESULTS: A strong correlation between the apparent and pure diffusion coefficients and fat fractions was seen in phantoms. The pure diffusion coefficient decreased significantly in patients with liver steatosis (0.96 +/- 0.16 * 10(-3) mm(2)/s versus 1.18 +/- 0.09 * 10(-3) mm(2)/s in normal liver, P = 0.005), whereas the decrease in apparent diffusion coefficient did not reach statistical significance (1.26 +/- 0.25 * 10(-3) mm(2)/s versus 1.41 +/- 0.14 * 10(-3) mm(2)/s in normal liver, P = 0.298). CONCLUSIONS: Fat deposition decreases the apparent and pure diffusion coefficients in lipid emulsion-based phantoms and patients with isolated liver steatosis proven by histopathology. PMID- 22935902 TI - MRI-guided focused ultrasound (MRgFUS) to treat facet joint osteoarthritis low back pain--case series of an innovative new technique. AB - OBJECTIVE: To evaluate the safety and efficacy of magnetic resonance-guided focused ultrasound (MRgFUS) to treat facet joint osteoarthritis pain. METHODS: Patients with a positive response to facet joint interventions were recruited from Pain and Spinal Clinics. Treatments were performed at the levels of pain according to symptomatology, previous invasive treatment and MRI grading of facet joint osteoarthritis. Both safety and efficacy data were collected. Pain palliation was evaluated using a validated pain numerical rating scale (NRS), Oswestry disability questionnaire (ODQ), Brief Pain Inventory (BPI) and the EuroQol (EQ-5D) health state score RESULTS: Eighteen patients were treated. There were no major adverse events. At 6/12 we found a reduction in both the NRS (average/worst) pain scores (60.2 %/51.2 %). This was associated with 45.9 % improvement in the ODQ score and 61.9 % reduction in the BPI interference score. We observed an improvement in the EuroQol (EQ-5D) health state score based on UK coefficients of +0.379 (0.317 to 0.696). CONCLUSIONS: Our phase I observational pilot study has evaluated an innovative new technique that is both non-invasive and radiation free. It is the first description of this procedure in the literature. In all patients the technique was safe, free of complications, effective and well tolerated. KEY POINTS: Magnetic resonance-guided focused ultrasound offers non-invasive therapy for facet joint pain. MRgFUS appears to be an effective and safe thermal ablation technique for facet joint pain. Real-time image control and thermal feedback minimise complications. MRgFUS allows outpatient management of facet joint osteoarthritic low back pain. PMID- 22935903 TI - Basilar membrane responses to tones and tone complexes: nonlinear effects of stimulus intensity. AB - The mammalian inner ear combines spectral analysis of sound with multiband dynamic compression. Cochlear mechanics has mainly been studied using single-tone and tone-pair stimulation. Most natural sounds, however, have wideband spectra. Because the cochlea is strongly nonlinear, wideband responses cannot be predicted by simply adding single-tone responses. We measured responses of the gerbil basilar membrane to single-tone and wideband stimuli and compared them, while focusing on nonlinear aspects of the response. In agreement with previous work, we found that frequency selectivity and its dependence on stimulus intensity were very similar between single-tone and wideband responses. The main difference was a constant shift in effective sound intensity, which was well predicted by a simple gain control scheme. We found expansive nonlinearities in low-frequency responses, which, with increasing frequency, gradually turned into the more familiar compressive nonlinearities. The overall power of distortion products was at least 13 dB below the overall power of the linear response, but in a limited band above the characteristic frequency, the power of distortion products often exceeded the linear response. Our results explain the partial success of a "quasilinear" description of wideband basilar membrane responses, but also indicate its limitations. PMID- 22935905 TI - The glacial pace of scientific publishing: why it hurts everyone and what we can do to fix it. PMID- 22935906 TI - Sense and antisense in biotech: the first antisense DNA company. PMID- 22935907 TI - A procedure for assessing intervention fidelity in experiments testing educational and behavioral interventions. AB - An intervention's effectiveness is judged by whether it produces positive outcomes for participants, with the randomized experiment being the gold standard for determining intervention effects. However, the intervention-as-implemented in an experiment frequently differs from the intervention-as-designed, making it unclear whether unfavorable results are due to an ineffective intervention model or the failure to implement the model fully. It is therefore vital to accurately and systematically assess intervention fidelity and, where possible, incorporate fidelity data in the analysis of outcomes. This paper elaborates a five-step procedure for systematically assessing intervention fidelity in the context of randomized controlled trials (RCTs), describes the advantages of assessing fidelity with this approach, and uses examples to illustrate how this procedure can be applied. PMID- 22935904 TI - Alternative Wnt pathways and receptors. AB - In addition to activating beta-catenin/TCF transcriptional complexes, Wnt proteins can elicit a variety of other responses. These are often lumped together under the denominator "alternative" or "non-canonical" Wnt signaling, but they likely comprise distinct signaling events. In this article, I discuss how the use of different ligand and receptor combinations is thought to give rise to these alternative Wnt-signaling responses. Although many of the biochemical details remain to be resolved, it is evident that alternative Wnt signaling plays important roles in regulating tissue morphogenesis during embryonic development. PMID- 22935908 TI - Cyst with a mural nodule tumor of the brain. AB - The purpose of this article is to illustrate the imaging findings of lesions that present as cyst with a mural nodule tumor (CMNT). CMNT is a subtype pattern of intra-axial enhancement in central nervous system tumors, typical of a variety of brain neoplasms, including, as the most common, hemangioblastoma, pilocytic astrocytoma, ganglioglioma and pleomorphic xanthoastrocytoma and as less common tanycytic ependymoma, intraparenchymal schwannoma, desmoplastic infantile ganglioglioma and cystic metastasis. A retrospective design was chosen given the rarity of CMNT. Relevant cases were obtained retrospectively to review the different lesions that can present with the appearance of CMNT. PMID- 22935910 TI - Child- and state-level characteristics associated with preventive dental care access among U.S. children 5-17 years of age. AB - The objectives of this study is to identify factors associated with lack of preventive dental care among U.S. children and state-level factors that explain variation in preventive dental care access across states. We performed bivariate analyses and multilevel regression analyses among 68,350 children aged 5-17 years using the 2007 National Survey of Children's Health data and relevant state-level data. Odds ratios (ORs) for child- and state-level variables were calculated to estimate associations with preventive dental care. We calculated interval odds ratios (IOR), median odds ratios (MOR), and intraclass correlation coefficients (ICC) to quantify variation in preventive dental care across states. Lack of preventive dental care was associated with various child-level factors. For state level factors, a higher odds of lack of preventive dental care was associated with a higher percentage of Medicaid-enrolled children not receiving dental services (OR = 1.30, 95 % confidence interval (CI): 1.15-1.47); higher percentage of children uninsured (OR = 1.48, 95 % CI: 1.29-1.69); lower dentist-to population ratio (OR = 1.36, 95 % CI: 1.03-1.80); and lower percentage of dentists submitting Medicaid/State Children's Health Insurance Program claims (OR = 1.04, 95 % CI: 1.01-1.06). IORs for the first three state-level factors did not contain one, indicating that these state-level characteristics were important in understanding variation across states. Lack of preventive dental care varied by state (MOR = 1.40). The state-level variation (ICC = 3.66 %) accounted for a small percentage of child- and state-level variation combined. Child- and state level characteristics were associated with preventive dental care access among U.S. children aged 5-17 years. State-level factors contribute to variation in dental care access across states and need to be considered in state-level planning. PMID- 22935911 TI - Smoking status and factors associated with smoking of first-time mothers during pregnancy and postpartum: findings from the Healthy Beginnings Trial. AB - This study aimed to investigate smoking status and factors associated with smoking among first-time mothers and their partners during pregnancy and postpartum. A prospective cohort study with 201 first-time mothers was conducted using data from the Healthy Beginnings Trial, undertaken in one of the most socially and economically disadvantaged areas of south-western Sydney, Australia in 2007-2010. Smoking status of the mothers and their partner and smoke-free home status were assessed at 30-36 weeks of pregnancy, and also at 6, 12 and 24 months postpartum. Multivariable two-level logistic random-intercept models were conducted. Smoking rates of the first-time mothers were 17.6 % during pregnancy and 22.5 % postpartum. The likelihood of being a current smoker among the mothers significantly increased after giving birth, with an adjusted odds ratio of 3.96 (95 % CI 1.3-12.1) at 6 months, 6.19 (95 % CI 1.84-30.9) at 12 months, and 6.58 (95 % CI 1.86-23.23) at 24 months postpartum. Mothers' smoking status was significantly inversely associated with educational level and positively associated with their partner's smoking status. In addition, mothers who breastfed their child were significantly less likely to be a smoker, with an adjusted odds ratio of 0.10 (95 % CI 0.02-0.68). Although pregnancy may act as a motivator to quit smoking, it is of concern that maternal smoking rate increased after giving birth. Smoking cessation programs should not only focus on smoking in pregnancy, but also address other risk factors, particularly in postpartum women and their partners. PMID- 22935912 TI - Multiple child care arrangements and common communicable illnesses in children aged 3 to 54 months. AB - The study examined the relationship between the number of concurrent child care arrangements and children's incidence of communicable illnesses throughout the first 41/2 years of life, and whether this association is mediated by the total number of children across care settings. Within-child fixed effects regression models were used to relate changes in the numbers of concurrent nonparental arrangements to changes in children's illnesses using longitudinal data from the NICHD's Study of Early Child Care and Youth Development (N = 1,265). 52 % of children attended multiple child care arrangements at least once from 3 to 54 months. Increases in the number of arrangements were associated with a 15 % increase in respiratory problems among children 3-54 months of age, and a 25 % increase in otitis media among children 36-54 months. Associations were smaller among African American children compared to European American and other-race children. Findings suggest that the number of peers with which a child comes into contact at child care mediates the association between increases in number of arrangements and increases in reported respiratory problems. Children attending multiple child care arrangements prior to kindergarten entry experience slightly more contemporaneous communicable diseases, relative to attending single nonparental arrangements, through exposure to more peers. PMID- 22935909 TI - Development of artemisinin compounds for cancer treatment. AB - Artemisinin contains an endoperoxide moiety that can react with iron to form cytotoxic free radicals. Cancer cells contain significantly more intracellular free iron than normal cells and it has been shown that artemisinin and its analogs selectively cause apoptosis in many cancer cell lines. In addition, artemisinin compounds have been shown to have anti-angiogenic, anti-inflammatory, anti-metastasis, and growth inhibition effects. These properties make artemisinin compounds attractive cancer chemotherapeutic drug candidates. However, simple artemisinin analogs are less potent than traditional cancer chemotherapeutic agents and have short plasma half-lives, and would require high dosage and frequent administration to be effective for cancer treatment. More potent and target-selective artemisinin-compounds are being developed. These include artemisinin dimers and trimers, artemisinin hybrid compounds, and tagging of artemisinin compounds to molecules that are involved in the intracellular iron delivery mechanism. These compounds are promising potent anticancer compounds that produce significantly less side effect than traditional chemotherapeutic agents. PMID- 22935914 TI - Photothermal-assisted fabrication of iron fluoride-graphene composite paper cathodes for high-energy lithium-ion batteries. AB - A facile route that combines co-assembly and photothermal reduction was developed to synthesize free-standing, flexible FeF(3)-graphene papers. The papers contain well-dispersed FeF(3) nanoparticles and open diffusion channels in a porous, electrically conducting network of graphene sheets, and demonstrate promising applications as cathodes in high-energy density Li-ion batteries. PMID- 22935913 TI - Temporal relationship between intimate partner violence and postpartum depression in a sample of low income women. AB - To estimate whether there is a temporal association between Postpartum Depression (PPD) and intimate partner violence (IPV), and to assess the potential role of social support on this relationship. A cross-sectional study was conducted between January 2006 and March 2007 with 701 low income women who received prenatal and postpartum care in primary health care units of the public sector in Sao Paulo, Brazil. The Self-Report Questionnaire (SRQ-20) was used to assess the presence of PPD. Structured standardized questionnaires were used to assess IPV and social support. The prevalence of PPD was estimated with a 95 % confidence interval. Crude and adjusted prevalence ratios were calculated using Poisson regression to examine the association between PPD and exposure variables. Values of p < 0.05 were considered statistically significant. The prevalence of PPD was 27.9 % (95 %CI 24.6:31.2). The prevalence of psychological IPV was 38.6 %, physical IPV 23.4 %, and sexual IPV 7.1 %. The multivariate analysis showed that PPD was strongly associated with current psychological and physical/sexual violence, after controlling for confounding factors, and less so with past (prenatal or lifetime) IPV. Presence of social support was an independent protective factor for PPD. Identifying and addressing intimate partner violence, including psychological violence, in the postpartum period should be considered as part of a comprehensive approach to caring for new mothers. PMID- 22935915 TI - Association study of susceptibility genes for late-onset Alzheimer's disease in the Japanese population. AB - APOE is an established susceptibility gene for late-onset Alzheimer's disease (LOAD). Recent genome-wide association studies have identified many additional susceptibility genes for LOAD in populations of European descent. However, there is little information on whether or not genetic variants in these genes are associated with other ethnicities. To investigate the association of seven genes identified by genome-wide association studies, we carried out a case-control study using 825 LOAD cases and 2934 controls in the Japanese population. For the APOE gene, APOE-epsilon4 carriers had a 4.54-fold higher risk than APOE-epsilon4 noncarriers after adjusting for age and sex (P=4.6*10(-27)). For other genes, the single-nucleotide polymorphism in the PICALM gene was significantly associated with LOAD (P=0.02, odds ratio=1.23). There was no significant interaction between PICALM and APOE-epsilon4 carrier status (P for interaction=0.68). Our data indicate that PICALM is also a susceptibility gene for LOAD in the Japanese population. PMID- 22935916 TI - Association between a COMT polymorphism and clinical response to risperidone treatment: a pharmacogenetic study. AB - A total of 130 Chinese schizophrenic patients (45 male, 85 female) were enrolled in the study. Clinical efficacy was determined using Brief Psychiatric Rating Scale (BPRS) scores. We genotyped 10 single-nucleotide polymorphisms (SNPs) of the catechol-O-methyl transferase gene (COMT) in our patients and re-examined them for association with changes in BPRS scores after 8 weeks of risperidone monotherapy. COMT is one of the genes that confer susceptibility to schizophrenia, both because of its role in neurotransmitter metabolism and because of its location in the high-risk schizophrenia-related region 22q11. Recent studies also found that COMT functional polymorphisms influenced individual response to antipsychotic medication. Our aim in this study was to explore the influence of COMT polymorphisms on pharmacological response to risperidone in the Chinese population. Statistical analysis revealed a significant association between an upstream COMT SNP, rs9606186, and scores reduction of BPRS in all patients and in the male subgroup but not in the female subgroup (allele analysis: P=0.055 for all, P=0.012 for male patients; genotype analysis: P=0.046 for all, P=0.020 for male patients, uncorrected, odds ratio=3.95). The COMT gene polymorphism, SNP rs9606186, is associated with risperidone therapy efficiency in the Chinese population. This association exhibited a sexually dimorphic difference, which may shed light on the genetics of COMT and its enzymatic sex-dependent mechanism. PMID- 22935917 TI - Analysis of Stathmin gene variation in patients with panic disorder and agoraphobia. PMID- 22935918 TI - No association between genetic polymorphisms of the NDUFS7 gene and schizophrenia in Han Chinese. AB - Accumulating evidence suggests that mitochondrial dysfunction contributes toward the pathogenesis of psychiatric diseases. NADH dehydrogenase Fe-S protein 7 (NDUFS7), a subunit of respiratory chain complex I, has been reported recently to be associated with bipolar disorder. To test whether this gene can confer a wide variety of psychiatric disorders, we carried out a case-control association analysis of three tagging single-nucleotide polymorphisms (rs2074896, rs2074897, and rs2074898) in the NDUFS7 gene by sequencing 330 Han Chinese patients with schizophrenia and 330 well-matched healthy controls. We found no significant difference in the frequency distributions of alleles, genotypes, and haplotypes between the cases and the controls, indicating no active role of this gene in schizophrenia. PMID- 22935919 TI - Expression changes and regulation of AR and IGF-1 in PC3 prostate cancer cells treated with sexual hormones and flutamide. AB - The study aims to investigate the changes and regulation of androgen receptor and insulin-like growth factor-1 in the PC3 prostate cells treated with 5alpha dihydrotestosterone, estrone, and flutamide. The PC3 cells were cultured and treated with 5alpha-dihydrotestosterone, estrone, and flutamide. Immunocytochemistry and Western blot were used to detect the expression of androgen receptor and insulin-like growth factor-1. The androgen receptor expression was analyzed by Western blot and optic density scan in the presence or absence of various kinase inhibitors. The statistical calculations were performed with the statistics-analyzing software package SPSS 13.0. A P <0.05 was considered statistically significant. The concentrations of 5alpha dihydrotestosterone and flutamide could almost not change the expression of androgen receptor and insulin-like growth factor-1 in PC3. But, the concentrations of estrone could increase the expression of androgen receptor and insulin-like growth factor-1 when PC3 cells are exposed to the studied concentration at various times. The expression of androgen receptor was regulated by the inhibitor of signal pathways of PI3, MEK1/2, and JUK. The expressions of androgen receptor and insulin-like growth factor-1 were influenced by estrone and were not influenced by 5alpha-dihydrotestosterone and flutamide in PC3 cells. And, the expression of androgen receptor was regulated by multiple signal pathways. PMID- 22935920 TI - CD74: a potential novel target for triple-negative breast cancer. AB - The expression status of CD74 in breast cancer stem cells and its clinical implications was evaluated in order to lay a foundation for managing breast cancer. Five hundred and eighty breast cancer specimens were enrolled in the study. The relationship between the CD74 protein and clinicopathological parameters as well as prognosis was subsequently determined. In total, 468 (80.69 %) of the 580 breast cases showed CD74-positive expression. After universal analysis, CD74 was observed to be related to lymph node metastasis and triple negative breast cancer (P = 0.01 and 0.001). Moreover, CD74 expression has a line correlation with lymph node metastasis and triple-negative breast cancer (P = 0.02 and 0.001). Furthermore, periostin was shown to attain a significantly more distant liver metastasis and worse disease-specific survival than those with none or low-expressed CD74 protein (P = 0.001). In the Cox regression test, CD74 protein was detected as an independent prognostic factor (P = 0.001). CD74 is consistently expressed in triple-negative subgroups of breast cancer and might be a new potential marker for triple-negative breast cancer. PMID- 22935921 TI - Iron transportation across the placenta. AB - According to the classification of placental types among animals, the transfer of iron through the placenta can occur via: absorption connected to transferin through the outer surface of the trophoblast in direct contact with circulating maternal blood; absorption of the erythrocytes by the chorionic epithelium in direct contact with accumulation of blood extravased from haemotophagous areas; absorption by the chorionic epithelium in direct contact with iron enriched secretions from the endometrial glands and absorption by extravasations of the blood in the maternal-fetal surface and the subsequent phagocytosis of the erythrocytes by trophoblast cells described in bovine, small ruminants, canine and feline. The function of erythrophagocytosis observed after the extravasation of blood in the maternal-fetal interface is undefined in several species. Possibly, the iron is transferred to the fetus through the trophoblastic erythrophagocytosis in the hemophogous area of the placenta and also in the endometrial glands. In this literature survey, new methods of studies regarding placental transfer involving iron and other nutrients necessary for survival and maintenance of embryonic fetus to birth are proposed. PMID- 22935922 TI - Hematological parameters of Iranian cichlid Iranocichla hormuzensis: Coad, 1982 (Perciformes) in Mehran river. AB - This study describes the hematological parameters in Iranocichla hormuzensis, an Iranian freshwater cichlid important as ornamental and food fish. Forty fish were captured with seine net at Mehran river Hormozgan province, Iran. Blood was used to determine the total counts of red blood cells (RBC) and white blood cells (WBC), hematocrit, mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC) and morphometric data of erythrocytes. The Iranian fish showed lower RBC and WBC values than the other cichlids (Oreochromis niloticus, O. aureus, O. mossambicus, O. hybrid, Cichlasoma dimerus and Cichla monoculus). Hematocrit did not vary among the species, but MCV, MCH and MCHC in I. hormuzensis were higher than those for O. niloticus, O. aureus, O. hybrid, C. dimerus and C. monoculus. These differences may be related to different life habit of fish. This study suggests that I. hormuzensis is well acclimated to the environment being the first report for its hematology. It is also suggested high efficiency in oxygen transportation, and an efficient inflow of oxygen by the gills, indicating the welfare of fish on this environment. PMID- 22935923 TI - Leaf anatomy and its contribution to the systematics of Aechmea subgenus Macrochordion (de Vriese) Baker (Bromeliaceae). AB - The leaf anatomy of the species Aechmea subgenus Macrochordion was analyzed to obtain valuable data on their taxonomic delimitation and to identify anatomical adaptations to their respective habitats and habits. All leaves of these species are hypostomatic, and present: peltate trichomes on both surfaces; stomata sunk in epidermal depressions; small epidermal cells with thick walls and inclusions of silica bodies; a mechanical hypodermis; an aquiferous parenchyma; chlorenchyma with fibrous clusters and air channels; and vascular bundles surrounded by a parenchymatic sheath and a cap of fibers. The results are evaluated within an adaptive and taxonomic context. Variations in hypodermic thickening, amount of water parenchyma, position of the air channels and shape of the cells filling the air channels are useful for delimiting groups of species, strengthening the relationships suggested by their external morphology. PMID- 22935924 TI - Minireview: regulation of gap junction dynamics by nuclear hormone receptors and their ligands. AB - Gap junctions are plasma membrane channels comprising connexin proteins that mediate intercellular permeability and communication. The presence, composition, and function of gap junctions can be regulated by diverse sets of physiological signals. Evidence from many hormone-responsive tissues has shown that connexin expression, modification, stability, and localization can be targeted by nuclear hormone receptors and their ligands through both transcriptional and nontranscriptional mechanisms. The focus of this review is to discuss molecular, cellular, and physiological studies that directly link receptor- and ligand triggered signaling pathways to the regulation of gap junction dynamics. PMID- 22935926 TI - Mild cognitive impairment: a subset of minor neurocognitive disorder? AB - The field of aging and dementia is increasingly preoccupied with identification of the asymptomatic phenotype of Alzheimer disease (AD). A quick glance at historical landmarks in the field indicates that the agenda and priorities of the field have evolved over time. The initial focus of research was dementia. In the late 1980s and 1990s, dementia researchers reported that some elderly persons are neither demented nor cognitively normal. Experts coined various terms to describe the gray zone between normal cognitive aging and dementia, including mild cognitive impairment. Advances made in epidemiologic, neuroimaging, and biomarkers research emboldened the field to seriously pursue the avenue of identifying asymptomatic AD. Accurate "diagnosis" of the phenotype has also evolved over time. For example, the American Psychiatric Association's Diagnostic and Statistical Manual of Mental Disorders (DSM-5) Task Force is contemplating to use the terms major and minor neurocognitive disorders. The six papers published in this edition of the journal pertain to mild cognitive impairment, which is envisaged to become a subset of minor neurocognitive disorders. These six studies have three points in common: 1) All of them are observational studies; 2) they have generated useful hypotheses or made important observations without necessarily relying on expensive biomarkers; and 3) Based on the new National Institute on Aging and the Alzheimer's Association guidelines, all the studies addressed the symptomatic phase of AD. Questionnaire-based observational studies will continue to be useful until such a time that validated biomarkers, be it chemical or neuroimaging, become widely available and reasonably affordable. PMID- 22935928 TI - Kinetic analysis, expression pattern, and production of a recombinant fungal protease inhibitor of tasar silkworm Antheraea mylitta. AB - Antheraea mylitta, a tasar silk-producing insect of Saturniidae family, expresses a fungal protease inhibitor named as A. mylitta fungal protease inhibitor-1 (AmFPI-1). AmFPI-1 inhibits alkaline protease of Aspergillus oryzae but its mechanism of action is not known. To understand the mode of inhibition of AmFPI-1 against the fungal protease, it was purified from the hemolymph of A. mylitta larvae and inhibitory activity against A. oryzae protease was studied. Kinetic analysis of purified AmFPI-1 on alkaline protease of A. oryzae showed that AmFPI 1 acts as a canonical-type competitive inhibitor with equilibrium dissociation constant (K ( i )) of 60 nM. Expression of AmFPI-1 in different body tissues of fifth instar A. mylitta larvae was determined by real-time PCR, and the highest expression was observed in fat body followed by integument, silk gland, and gut, indicating that AmFPI-1 has pleiotropic functions including protection from invading fungi. The cDNA of AmFPI-1 was expressed in Escherichia coli, and recombinant His-tagged fusion protein was purified by Ni-NTA chromatography. Recombinant AmFPI-1 showed inhibitory activity against A. oryzae protease and suggested its use in various biological applications to prevent proteolysis. PMID- 22935929 TI - Inpatient payment rule for 2013 ups hospital payments: still no funding for advanced pharmacy residencies. PMID- 22935930 TI - Fairview MTM services support accountable care. PMID- 22935931 TI - Integrated pharmacy practice helps reduce heart failure readmission rate. PMID- 22935933 TI - Effective use of a clinical decision-support system to advance antimicrobial stewardship. PMID- 22935934 TI - Clinical training of pharmacy administration residents. PMID- 22935935 TI - Assessment of community pharmacy residents' opinions regarding training beyond postgraduate year 1 residency. PMID- 22935936 TI - Vilazodone's comparative merits yet to be demonstrated. PMID- 22935937 TI - Vilazodone: a novel antidepressant. AB - PURPOSE: The pharmacology and pharmacokinetics of the antidepressant vilazodone (approved for U.S. marketing in 2011) are reviewed, with an emphasis on efficacy and safety data from Phase III clinical trials. SUMMARY: Vilazodone (marketed as Viibryd by Forest Pharmaceuticals) is a dual-acting serotonergic agent that combines the antidepressant effects of a selective serotonin-reuptake inhibitor (SSRI) with partial serotonin (5-HT)(1A)-receptor agonist activity. In two published eight-week Phase III trials involving a total of 878 adults with major depressive disorder (MDD), vilazodone use was found to yield significant symptomatic improvements relative to placebo use, as determined by mean changes from baseline in scores on the Hamilton Depression Rating Scale and other widely used clinical assessment instruments. Vilazodone hydrochloride therapy should be initiated at a dosage of 10 mg once daily and incrementally adjusted over 14 days to the recommended target daily dose of 40 mg; for optimal bioavailability and effectiveness, it should be taken after a light or high-fat meal. The adverse effects most commonly reported in clinical trials of vilazodone were diarrhea, nausea, vomiting, and insomnia. CONCLUSION: Vilazodone is an efficacious and safe new antidepressant for the treatment of MDD. Its relatively high cost and adverse effect profile, as well as a lack of data demonstrating that vilazodone can produce long-term MDD remission and offer significant advantages over the current standard of care, may limit the usefulness of vilazodone in clinical practice. PMID- 22935938 TI - Direct thrombin inhibitors for management of heparin-induced thrombocytopenia in patients receiving renal replacement therapy: comparison of clinical outcomes. AB - PURPOSE: The clinical outcomes of patients receiving renal replacement therapy (RRT) and treated with direct thrombin inhibitors (DTIs) for the management of heparin-induced thrombocytopenia (HIT) were compared. METHODS: A retrospective evaluation of clinical outcomes of patients receiving RRT with a presumed diagnosis of HIT treated with lepirudin, argatroban, or bivalirudin was conducted. Inpatients at the University of Pittsburgh Medical Center from January 1, 1995, through March 1, 2008, were included if they were receiving either continuous or intermittent RRT and argatroban, bivalirudin, or lepirudin; were exposed to heparin within the preceding 100 days (including a heparin-treated pulmonary artery catheter) or had a documented heparin allergy; and had at least one of following: (1) an absolute platelet count of <150,000 cells/MUL, (2) a decline in platelets of >50% from baseline before exposure to heparin, or (3) a documented diagnosis of thrombocytopenia. The primary outcome assessed was a triple composite endpoint of thrombosis, hemorrhage, and inhospital mortality. A secondary assessment compared the pharmacodynamic relationship between activated partial thromboplastin time and the triple composite. RESULTS: For the primary endpoint, there was no statistically significant difference observed among DTIs. In patients receiving RRT, a lack of a previous heparin allergy, the degree of International Normalized Ratio elevation, and lower serum albumin were significantly correlated with increased morbidity and the occurrence of the composite endpoint. CONCLUSION: No differences in adverse events or other clinical outcomes were observed in this retrospective evaluation of DTI use in patients receiving RRT with presumed HIT. PMID- 22935939 TI - Cost-benefit and cost-savings analyses of antiarrhythmic medication monitoring. AB - PURPOSE: The economic impact of pharmacist-managed antiarrhythmic drug therapy monitoring on an academic medical center's electrophysiology (EP) program was investigated. METHODS: Data were collected for the initial two years of patient visits (n = 816) to a pharmacist-run clinic for antiarrhythmic drug therapy monitoring. A retrospective cost analysis was conducted to assess the direct costs associated with three appointment models: (1) a clinic office visit only, (2) a clinic visit involving electrocardiography and basic laboratory tests, and (3) a clinic visit including pulmonary function testing and chest x-rays in addition to electrocardiography and laboratory testing. A subset of patient cases (n = 18) were included in a crossover analysis comparing pharmacist clinic care and usual care in an EP physician clinic. The primary endpoints were the cost benefits and cost savings associated with pharmacy-clinic care versus usual care. A secondary endpoint was improvement of overall EP program efficiency. RESULTS: The payer mix was 61.6% (n = 498) Medicare, 33.2% (n = 268) managed care, and 5.2% (n = 42) other. Positive contribution margins were demonstrated for all appointment models. The pharmacist-managed clinic also yielded cost savings by reducing overall patient care charges by 21% relative to usual care. By the second year, the pharmacy clinic improved EP program efficiency by scheduling an average of 24 patients per week, in effect freeing up one day per week of EP physician time to spend on other clinical activities. CONCLUSION: Pharmacist monitoring of antiarrhythmic drug therapy in an out-patient clinic provided cost benefits, cost savings, and improved overall EP program efficiency. PMID- 22935940 TI - Creating pharmacy staffing-to-demand models: predictive tools used at two institutions. AB - PURPOSE: The creation and implementation of data-driven staffing-to-demand models at two institutions are described. SUMMARY: Predictive workload tools provide a guideline for pharmacy managers to adjust staffing needs based on hospital volume metrics. At Abbott Northwestern Hospital, management worked with the department's staff and labor management committee to clearly outline the productivity monitoring system and the process for reducing hours. Reference charts describing the process for reducing hours and a form to track the hours of involuntary reductions for each employee were created to further enhance communication, explain the rationale behind the new process, and promote transparency. The University of Minnesota Medical Center-Fairview, found a strong correlation between measured pharmacy workload and an adjusted census formula. If the daily census and admission report indicate that the adjusted census will provide enough workload for the fully staffed department, no further action is needed. If the census report indicates the adjusted census is less than the breakeven point, staff members are asked to leave work, either voluntarily or involuntarily. The opposite holds true for days when the adjusted census is higher than the breakeven point, at which time additional staff are required to synchronize worked hours with predicted workload. CONCLUSION: Successful staffing-to- demand models were implemented in two hospital pharmacies. Financial savings, as indicated by decreased labor costs secondary to reduction of staffed shifts, were approximately $42,000 and $45,500 over a three-month period for Abbott Northwestern Hospital and the University of Minnesota Medical Center-Fairview, respectively. Maintenance of 100% productively allowed the departments to continue to replace vacant positions and avoid permanent staff reductions. PMID- 22935941 TI - Evaluation of appropriate serologic testing for suspected heparin-induced thrombocytopenia. AB - PURPOSE: The predictive value of clinical "4-T's" scoring in patient selection for serologic testing to confirm suspected heparin-induced thrombocytopenia (HIT) was evaluated. METHODS: In a chart review-based study at a large hospital, all adult inpatients who underwent enzyme-linked immunosorbent assay (ELISA) testing for HIT-antibody detection during a two-year period were identified. Scoring of the 4 T's (degree of thrombocytopenia, timing of symptom onset, presence of thrombosis or other sequelae, and other potential causes) was retrospectively performed on a random sample of cases (n = 70) by three pharmacist investigators. Based on the 4-T's scores, the probability of HIT confirmation via ELISA testing was classified as low, intermediate, or high; by comparing those classifications with documented ELISA results, the positive predictive value of 4-T's scoring was calculated. Interrater variability in 4-T's scoring was also assessed. RESULTS: 4 T's scoring of the 70 randomly selected cases indicated low, intermediate, and high probabilities of HIT confirmation via ELISA testing in 52, 17, and 1 case, respectively. Negative ELISA results were documented in the records of 37 patients in the low-probability group; the 4-T's scoring system was calculated to have an adjusted negative predictive value of 77.3%. The calculation of Gwet's agreement coefficient indicated substantial agreement in 4-T's scoring by the three raters. CONCLUSION: The study results suggest that among patients whose 4 T's scores indicate a low probability of HIT, the results of subsequent ELISA testing for HIT antibodies are likely to be negative in about 8 of 10 cases. PMID- 22935942 TI - Teaching clinical problem solving: a preceptor's guide. AB - PURPOSE: Instructional methods to help pharmacists succeed in their growing role in practice-based teaching are discussed, with an emphasis on techniques for fulfilling the four key preceptor roles. SUMMARY: The American Society of Health System Pharmacists (ASHP) and other organizations advocate ongoing efforts to develop the teaching skills of clinician-educators serving as preceptors to pharmacy students and residents. The broad model of teaching clinical problem solving recommended by ASHP emphasizes the creative and flexible application of the four major preceptor roles: (1) direct instruction, (2) modeling, (3) coaching, and (4) facilitating. A variety of teaching methods used in the fields of medicine and nursing that can also be adopted by practice-based pharmacy educators are presented; in particular, the advantages and disadvantages of various case-presentation formats (e.g., One-Minute Preceptor, SNAPPS, patient witnessed teaching, "Aunt Minnie," "think-aloud") are reviewed. Other topics discussed include the appropriate use of questioning as an educational tool, strategies for providing constructive feedback, teaching learners to self evaluate their skills and progress, and integrating residents into teaching activities. CONCLUSION: The ASHP-recommended approach to teaching clinical problem-solving skills can be applied within the educational frameworks provided by schools of pharmacy as well as pharmacy residency programs. A wide range of validated teaching strategies can be used to tailor learning experiences to individual learner needs while meeting overall program goals and objectives. PMID- 22935943 TI - Robotics in acute care hospitals. PMID- 22935944 TI - Application of the concept of "moral luck" in a case involving a pharmacist. PMID- 22935945 TI - Antigenic and genetic characterization of a European avian-like H1N1 swine influenza virus from a boy in China in 2011. AB - Cross-species transmission of influenza A viruses from swine to human occurs occasionally. In 2011, an influenza A H1N1 virus, A/Jiangsu/ALS1/2011 (JS/ALS1/2011), was isolated from a boy who suffered from severe pneumonia in China. The virus is closely related antigenically and genetically to avian-like swine H1N1 viruses that have recently been circulating in pigs in China and that were initially detected in European pig populations in 1979. The isolation of JS/ALS1/2011 provides additional evidence that swine influenza viruses can occasionally infect humans and emphasizes the importance of reinforcing influenza virus surveillance in both pigs and humans. PMID- 22935946 TI - The relationship between victimization and substance use among homeless and runaway female adolescents. AB - Each year, thousands of female adolescents run away from home due to sexual abuse, yet they continue to be victims of sexual assault once on the street. To date, few studies have examined how various forms of victimization are related to different types of substance use. The purpose of this article is to investigate the relationship between street exposure, childhood abuse, and different forms of street victimization with alcohol and marijuana use among 137 homeless and runaway female adolescents. Results from path analysis revealed that child sexual abuse was positively linked to trading sex and sexual and physical victimization. In addition, those who have traded sex experienced greater physical victimization, and who have spent more time away from home, used alcohol more frequently. Moreover, trading sex and experiencing more types of sexual victimization were positively linked to more frequent marijuana usage. Age, age at first run, longest time away from home, sexual abuse, and trading sex had significant indirect effects on alcohol and/or marijuana use. Together, these factors accounted for 27% of the variance in alcohol use and 37% of the variance in marijuana use. PMID- 22935947 TI - Domestic violence in India: insights from the 2005-2006 national family health survey. AB - This article assesses the prevalence and risk factors of domestic violence in India. The study uses the 2005-2006 India National Family Health Survey-III (NFHS III) and focuses on the 69,484 ever-married women ages 15 to 49 from all regions, who were administered the domestic violence module. The results show that 31% of respondents experienced physical violence in the past 12 months before the survey; the corresponding figure for sexual violence was 8.3%. The multivariate logistic regression results show key determinants of physical and sexual violence. Some of the most salient findings are that urban residence, household wealth, affiliation with Christian religious denominations, wife's age at marriage and education are associated with lower risk of physical and sexual violence. In contrast, being employed and being the wife of a man who drank alcohol increased the odds of experiencing both physical and sexual violence. Moreover, respondents who believed that wife-beating was justified under certain circumstances were more likely to experience domestic violence. These results and significant regional differences observed in this study suggest that gender role conditioning and cultural norms both contribute to domestic violence. Interventions, therefore, need to go beyond the institutional and legal levels to include cultural capital, which addresses partner and relationship issues. PMID- 22935948 TI - Child-to-parent violence: emotional and behavioral predictors. AB - Child-to-parent violence (CPV) includes acts committed by a child to intentionally cause physical, psychological, or financial pain to a parent. Available data indicate increasing rates of CPV in Spain, which have been attributed to a tendency toward more permissive parenting styles and changes in the power cycles within the families. The primary aim of this study was to assess the predictive role of some behavioral and emotional characteristics of adolescents who perpetrate CPV. A total of 1,072 adolescents (601 girls) filled out measures of CPV, proactive and reactive aggression, depressive symptoms, and substance abuse at Time 1, and measures of CPV 6 months later. The results showed that CPV was predicted by proactive, but not by reactive, aggression. This finding supports an instrumental role for CPV, which should be understood in the context of permissibility and lack of limits within the family. Depression and substance abuse also predicted the increase of CPV over time. Moreover, there were no sex differences in the prevalence of physical CPV, but verbal CPV was more predominant among girls. Although there were sex differences in some of the risk factors for CPV, the predictive model linking these risks to CPV was similar for boys and girls. Findings of this study suggest a psychological profile that combines internalizing problems and an instrumental use of violence in adolescents who perpetrate CPV. These characteristics are important for interventions. PMID- 22935949 TI - Analysis of 16 years of homicides and suicides involving the use of weapons recorded at the Milan Medicolegal Bureau. AB - The criminal use of weapons is a very topical issue in the industrialized countries and worldwide, and a reconsideration of the legislation governing their possession is warranted. We retrospectively analyzed the homicides and suicides involving the use of firearms and piercing and/or cutting weapons recorded at the Medicolegal Bureau in Milan from January 1, 1993, to December 31, 2008. First we considered the clinical histories of the deceased and the circumstantial details of their deaths, then we examined the data relating to the cause of death recorded in the autopsy reports. Our case series consisted of 414 homicides (54.2%) and 350 suicides (45.8%). Firearms were responsible for more deaths (64%) than piercing and/or cutting weapons (36%). The firearms involved were legally licensed in 40% of cases (suicides) and illegal in 22% (homicides). Our findings suggest the need to review the criteria considered for the issue of firearms licenses, in Italy at least. PMID- 22935950 TI - Women's reactions to interpersonal violence research: a longitudinal study. AB - This study assessed women's immediate and long-term reactions to completing self report measures of interpersonal violence. College women completed surveys at the beginning and end of a 2-month academic quarter for course credit. Results showed that 7.7% of participants experienced immediate negative emotional reactions to research participation. Greater immediate negative reactions were related to interpersonal victimization and psychological distress variables. Attrition from the study over the 2-month follow-up was not predicted by participants' immediate negative emotional reactions to the research or anticipation of future distress. Of the participants who returned for the follow-up, 2.1% of participants reported experiencing distress over the interim period as a result of their initial participation in the study. These long-term reactions were bivariately related to a number of victimization, psychological distress, and reaction variables measured at the first study session. However, in the regression analyses, only immediate negative emotional reactions to the research and anticipation of future distress predicted long-term negative emotional reactions. PMID- 22935952 TI - Prevalence and risk factors for domestic violence among pregnant women in northern Nigeria. AB - Many women experience domestic violence during pregnancy. The magnitude and risk factors for domestic violence during pregnancy are not well documented in many countries, including Nigeria. Using interviewer- administered questionnaires the authors investigated predictors of domestic violence during current pregnancy among women presenting for antenatal care at a tertiary care facility in northern Nigeria (n = 400). A total of 29 of 392 respondents (7.4%) experienced domestic violence during the current pregnancy. Of those who experienced violence, the majority (58.6%) reported being physically assaulted. Sexual violence was reported by only 4 respondents (13.8%). Financial and domestic issues were the major triggers of domestic violence. After adjusting for potential confounders, it was found that victims' educational attainment and occupation remained significant predictors of domestic violence. Higher educational attainment of women and their engagement in economic activity outside the home were associated with a decreased risk for domestic violence. There is a need for preventive, protective, and redress mechanisms to guard against domestic violence in Nigeria. PMID- 22935951 TI - Mediating links between maternal childhood trauma and preadolescent behavioral adjustment. AB - Structural equation modeling was used to simultaneously examine maternal psychological distress and social support as mediators linking maternal childhood trauma (MCT) to both maternal and child-reported behavior at 9 years of age in 231 birth mother-child dyads, who were primarily poor, urban, and African American. One half of the mothers (n = 116) reported a history of childhood abuse and neglect. Although MCT was associated with both increased maternal psychological distress and limited social support at 6 years, the pathway to child behavior ratings at 9 years was informant dependent. MCT influenced maternal ratings of her child's behavior, with some effects mediated through psychological distress. MCT indirectly influenced children's self-perception of behavior through maternal experience of social support. Maternal ratings and child self-ratings of child behavior problems were moderately correlated. No significant gender interaction was found. Findings suggest a need for understanding trauma histories in the lives of mothers who seek assistance for parenting and child behavior problems, especially in urban low income communities. Interventions targeting both increasing maternal social support and reducing psychological distress may promote competency and resiliency among children for whom MCT poses a risk to optimal development. PMID- 22935953 TI - Perception of slipperiness and prospective risk of slipping at work. AB - OBJECTIVES: Falls are a leading cause of injury at work, and slipping is the predominant cause of falling. Prior research has suggested a modest correlation between objective measures (such as coefficient of friction, COF) and subjective measures of slipperiness (such as worker perceptions) in the workplace. However, the degree of association between subjective measures and the actual risk of slipping at the workplace is unknown. This study examined the association between perception of slipperiness and the risk of slipping. METHODS: 475 workers from 36 limited-service restaurants participated in a 12-week prospective cohort study. At baseline, demographic information was collected, participants rated floor slipperiness in eight areas of the restaurant, and work environment factors, such as COF, were measured. Restaurant-level and area-level mean perceptions of slipperiness were calculated. Participants then reported their slip experience at work on a weekly basis for the next 12 weeks. The associations between perception of slipperiness and the rate of slipping were assessed. RESULTS: Adjusting for age, gender, body mass index, education, primary language, mean COF, use of slip resistant shoes, and restaurant chain, each 1-point increase in mean restaurant level perception of slipperiness (4-point scale) was associated with a 2.71 times increase in the rate of slipping (95% CI 1.25 to 5.87). Results were similar for area-level perception within the restaurant (rate ratios (RR) 2.92, 95% CI 2.41 to 3.54). CONCLUSIONS: Perceptions of slipperiness and the subsequent rate of slipping were strongly associated. These findings suggest that safety professionals, risk managers and employers could use aggregated worker perceptions of slipperiness to identify slipping hazards and, potentially, to assess intervention effectiveness. PMID- 22935954 TI - Impact of occupational mechanical exposures on risk of lateral and medial inguinal hernia requiring surgical repair. AB - OBJECTIVES: We undertook a register-based cohort study to evaluate exposure response relations between cumulative occupational mechanical exposures, and risk of lateral and medial inguinal hernia repair. METHODS: Among all men born in Denmark between 1938 and 1988, we established a cohort comprising those aged 18 65 years of age, who had at least 1 year of full-time employment between 1993 and 2007. Using information from a Job Exposure Matrix based on expert judgement and year-by-year information on Danish International Standard Classification of Occupations codes for each individual since 1993, we established time-varying cumulative estimates of exposure to daily lifting activities and standing/walking. Cumulative exposures for lagged 5-year time windows were expressed in a way that corresponds to the pack-year concept of smoking (ton years, frequent-heavy-lifting years, and standing-years). First-time inguinal hernia repairs in the period 1998-2008 were identified in the Danish Hernia Database. We used a logistic regression technique equivalent to survival analysis, adjusting for age, socioeconomic status, region of residence and calendar year. RESULTS: Within the cohort of 1 545 987 men, we identified 22 926 lateral, 15 877 medial and 1592 pantaloon or unspecified first-time inguinal hernia repairs. The risk of lateral hernia repair increased with ton-years, frequent-heavy-lifting-years, and standing-years, with ORs of up to around 1.4. The exposures correlated, but standing-years remained as the most robust risk factor after adjustment for lifting exposures. In general, the risk of medial hernia repair was unrelated to the exposures. CONCLUSIONS: Our findings suggest an increased risk of lateral inguinal hernia repair in relation to occupational mechanical exposures and a preventive potential of around 15% of all cases. PMID- 22935955 TI - Prospective randomised comparison of Marsh and Schnider pharmacokinetic models for propofol during induction of anaesthesia in elective cardiac surgery. AB - CONTEXT: Haemodynamic stability during induction is a cornerstone of cardiac anaesthesia. The evaluation of pharmacokinetic models for propofol during induction is lacking. OBJECTIVE: To compare haemodynamics during cardiac anaesthesia induction with two pharmacokinetic models. DESIGN: Randomised controlled trial. SETTING: Department of Cardiothoracic Surgery, Sao Joao Hospital; July to December 2010. PATIENTS: Ninety consecutive elective adult cardiac surgical patients. INTERVENTION: Random assignment to effect-site target controlled infusion by Marsh (n = 45) or Schnider (n = 45) pharmacokinetic models with an equilibration constant of 1.2 min(-1) adapted to Marsh's model. Invasive blood pressure measurements, propofol dose, and bispectral index (BIS) were recorded. After an initial target concentration of 1.5 MUg ml(-1), concentrations were upward-titrated in 0.5 MUg ml(-1) increments until the BIS was <50. RESULTS: No differences were observed between Marsh and Schnider models in required propofol dose (0.99 +/- 0.26 vs. 0.93 +/- 0.31 mg kg(-1), P = 0.322), decrease in mean blood pressure (25 +/- 13 vs. 22 +/- 14%, P = 0.192) or the need for vasopressors (20 vs. 24%, P = 0.800), but the use of the Marsh model resulted in a lower predicted effect-site concentration (2.3 +/- 0.4 vs. 2.7 +/- 0.6 MUg ml( 1), P = 0.006) and shorter time to induction (296 +/- 59 vs. 338 +/- 87 s, P = 0.024). There was a greater decrease in mean blood pressure in older patients (>60 years; 29 +/- 10 vs. 22 +/- 11%, P = 0.004) irrespective of model, but obese (BMI >=30 kg m(-2)) and nonobese patients did not differ. MAIN OUTCOME MEASURES: Decrease in mean blood pressure. CONCLUSION: In effect-site targeting with a 1.2 min(-1) equilibration constant, Marsh's model is comparable to Schnider's during induction of anaesthesia. PMID- 22935956 TI - The pharmacokinetics of a high intravenous dose of paracetamol after caesarean delivery: the effect of gestational age. AB - CONTEXT: Pregnancy affects intravenous paracetamol pharmacokinetics, but there are no studies on covariates of intravenous paracetamol pharmacokinetics around delivery. OBJECTIVES: To document the impact of gestational age at delivery on pharmacokinetics of a high intravenous dose of paracetamol. DESIGN: Pharmacokinetic study in women shortly after caesarean delivery. This study is an alternative analysis of a previously published study, using the same cohort but with added participants. SETTING: Single, tertiary perinatal care centre. PATIENTS: Of 36 patients recruited, pharmacokinetics analysis was performed in 34. Shortly following caesarean delivery, women received a loading dose (2 g) of intravenous paracetamol and four (at 1, 2, 4 and 6 h) plasma samples were collected. Of these 36 women, 28 had already been reported, but without further discrimination between preterm and term delivery, or any other covariate. Individual pharmacokinetic profiles were calculated assuming a linear one compartment model with instantaneous input, first-order output. Covariates of between individual variability (preterm vs. term, maternal disease vs. healthy, twin vs. singleton pregnancy) of individual pharmacokinetics within this cohort were explored (Mann-Whitney U-test). MAIN OUTCOME MEASURES: Individual paracetamol pharmacokinetics. RESULTS: Mean (SD) paracetamol clearance was 22.4 l h(-1) (9.3) or - when corrected for body surface area - 11.5 l h(-1) m(-2) (4.0). No significant effects of twin pregnancy (n = 8) or maternal co-morbidity (n = 3) were observed, but mean clearance after preterm delivery (n = 12, <37 weeks gestational age) was significantly higher [13.8 (5.7) vs. 10.2 l h(-1) m(-2) (1.9), P = 0.028] compared with term delivery (n = 22). Similarly, there was a difference in mean distribution volume [0.83 (0.25) vs. 0.69 l kg(-1) (0.1), P = 0.037], resulting in the absence of differences in median elimination half-life [112 (28) vs. 119 min (19)]. CONCLUSION: Women who underwent a preterm caesarean delivery had a higher paracetamol clearance compared with term delivery. These pharmacokinetic differences illustrate the relevance of performing pharmacokinetic studies at delivery. We encourage clinicians to perform similar studies for other drugs administered in this group. TRIAL REGISTRATION: EudraCT 2010-020164-37. PMID- 22935957 TI - Anaesthesia and orphan disease: sugammadex in a patient with Huntington's disease undergoing thyroid lobectomy. PMID- 22935959 TI - A secure and rapid method for orotracheal intubation of laboratory rats utilising handy instruments. AB - CONTEXT: Tracheal intubation of anaesthetised rats for laboratory experiments remains an essential yet challenging procedure. OBJECTIVE: We aimed to investigate whether tracheal intubation can be safely and securely accomplished in laboratory rats employing only handy instruments and with minimal experience. DESIGN: The feasibility and safety of a modified orotracheal intubation method was evaluated in rats undergoing open-chest surgery as part of another research protocol, and compared with an existing technique. SETTING: The study was carried out in a tertiary medical centre-affiliated animal laboratory. ANIMALS: Eighty five rats weighing 250 to 350 g anaesthetised with intraperitoneal pentobarbital (60 mg kg(-1)). INTERVENTIONS: Orotracheal intubation was performed on 35 animals (group Jou) using a previously reported technique and then on another 50 rats (group New) using the modified method employing a 3-ml syringe-derived intubation wedge, a 0.025-inch guidewire and a 16-gauge 45-mm-long intravenous catheter. MAIN OUTCOME MEASURES: The time for completion, the number of attempts and the incidence of difficulties and complications were recorded. The intubated tracheas were subsequently examined macroscopically and microscopically to determine position of the intubation catheter and the integrity of epithelial lining. RESULTS: Compared with the previous technique, the new method was completed more rapidly (1 +/- 0.2 vs. 5 +/- 2.4 min; P < 0.001), more smoothly (difficulties encountered in 8 vs. 74%; P < 0.001), with greater overall success (100 vs. 86%; P=0.022) and with fewer attempts [1 (1 to 1) vs. 2 (2 to 4); P < 0.001) for the new and Jou techniques, respectively, and with a lower incidence of procedure related complications. Postmortem analysis confirmed there was no microscopic injury to the tracheal epithelial lining with the new technique in contrast to 57% in those using the Jou technique (P < 0.001). CONCLUSION: Tracheal intubation for laboratory rats can be securely and safely completed with the modified method employing a short learning curve and easily available devices. PMID- 22935958 TI - The influence of haemodialysis on haemodynamic measurements using transpulmonary thermodilution in patients with septic shock: an observational study. AB - CONTEXT: Patients with sepsis frequently present with acute renal failure requiring intermittent renal replacement therapy and haemodynamic monitoring. To date, the effect of haemodialysis on PiCCO monitoring has not been determined. OBJECTIVE: To determine the effect of haemodialysis on the measurement of haemodynamic variables using transpulmonary thermodilution. DESIGN: Prospective observational study. SETTING: Medical ICU in a university hospital. PATIENTS: Thirty patients with sepsis and acute renal failure undergoing intermittent haemodialysis. INTERVENTIONS: None. MAIN OUTCOME MEASURES: Cardiac index, global end-diastolic volume index and extravascular lung water index measured with or without haemodialysis. RESULTS: Significant correlations were found for all variables measured with and without haemodialysis (r = 0.55 to 0.91, P < 0.01). Measurements of cardiac index without and with haemodialysis were significantly different [4.71 vs. 4.18 lmin(-1)m(-2), difference -0.54 (SD 0.70), 95% confidence interval (CI) -0.80 to -0.28; P < 0.01], as were values of global end diastolic volume index without and with haemodialysis [864.8 vs. 775.3 ml m(-2), difference -89.5 (SD 191.8), 95% CI -161.2 to -17.9; P = 0.02]. Measurements of extravascular lung water index without and with haemodialysis did not differ significantly [10.3 vs. 10.0 ml kg(-1), difference -0.3 (SD 2.0), 95% CI -1.1 to 0.5; P = 0.42]. CONCLUSION: Although significant correlations were found for cardiac index, global end-diastolic volume index and extravascular lung water index with and without haemodialysis, cardiac index and global end-diastolic volume index were significantly reduced during haemodialysis, but not extravascular lung water index, when measured by the PiCCO system in patients with septic shock. Although differences were small, the variability of within patient differences may be clinically important and care should be taken in relying solely on such measurements. PMID- 22935960 TI - N-Acetylcysteine inhibits platelet-monocyte conjugation in patients with type 2 diabetes with depleted intraplatelet glutathione: a randomised controlled trial. AB - AIMS/HYPOTHESIS: The aim of this study was to determine whether oral dosing with N-acetylcysteine (NAC) increases intraplatelet levels of the antioxidant, glutathione (GSH), and reduces platelet-monocyte conjugation in blood from patients with type 2 diabetes. METHODS: In this placebo-controlled randomised crossover study, the effect of oral NAC dosing on platelet-monocyte conjugation and intraplatelet GSH was investigated in patients with type 2 diabetes (eligibility criteria: men or post-menopausal women with well-controlled diabetes (HbA(1c) < 10%), not on aspirin or statins). Patients (n = 14; age range 43-79 years, HbA(1c) = 6.9 +/- 0.9% [52.3 +/- 10.3 mmol/mol]) visited the Highland Clinical Research Facility, Inverness, UK on day 0 and day 7 for each arm of the study. Blood was sampled before and 2 h after oral administration of placebo or NAC (1,200 mg) on day 0 and day 7. Patients received placebo or NAC capsules for once-daily dosing on the intervening days. The order of administration of NAC and placebo was allocated by a central office and all patients and research staff involved in the study were blinded to the allocation until after the study was complete and the data fully analysed. The primary outcome for the study was platelet-monocyte conjugation. RESULTS: Oral NAC reduced platelet-monocyte conjugation (from 53.1 +/- 4.5% to 42.5 +/- 3.9%) at 2 h after administration and the effect was maintained after 7 days of dosing. Intraplatelet GSH was raised in individuals with depleted GSH and there was a negative correlation between baseline intraplatelet GSH and platelet-monocyte conjugation. There were no adverse events. CONCLUSIONS/INTERPRETATION: The NAC-induced normalisation of intraplatelet GSH, coupled with a reduction in platelet-monocyte conjugation, suggests that NAC might help to reduce atherothrombotic risk in type 2 diabetes. FUNDING: Chief Scientist Office (CZB/4/622), Scottish Funding Council, Highlands & Islands Enterprise and European Regional Development Fund. TRIAL REGISTRATION: isrctn.org ISRCTN89304265. PMID- 22935961 TI - Mechanisms of modified LDL-induced pericyte loss and retinal injury in diabetic retinopathy. AB - AIMS/HYPOTHESIS: In previous studies we have shown that extravasated, modified LDL is associated with pericyte loss, an early feature of diabetic retinopathy (DR). Here we sought to determine detailed mechanisms of this LDL-induced pericyte loss. METHODS: Human retinal capillary pericytes (HRCP) were exposed to 'highly-oxidised glycated' LDL (HOG-LDL) (a model of extravasated and modified LDL) and to 4-hydroxynonenal or 7-ketocholesterol (components of oxidised LDL), or to native LDL for 1 to 24 h with or without 1 h of pretreatment with inhibitors of the following: (1) the scavenger receptor (polyinosinic acid); (2) oxidative stress (N-acetyl cysteine); (3) endoplasmic reticulum (ER) stress (4 phenyl butyric acid); and (4) mitochondrial dysfunction (cyclosporin A). Oxidative stress, ER stress, mitochondrial dysfunction, apoptosis and autophagy were assessed using techniques including western blotting, immunofluorescence, RT PCR, flow cytometry and TUNEL assay. To assess the relevance of the results in vivo, immunohistochemistry was used to detect the ER stress chaperon, 78 kDa glucose-regulated protein, and the ER sensor, activating transcription factor 6, in retinas from a mouse model of DR that mimics exposure of the retina to elevated glucose and elevated LDL levels, and in retinas from human participants with and without diabetes and DR. RESULTS: Compared with native LDL, HOG-LDL activated oxidative and ER stress in HRCP, resulting in mitochondrial dysfunction, apoptosis and autophagy. In a mouse model of diabetes and hyperlipidaemia (vs mouse models of either condition alone), retinal ER stress was enhanced. ER stress was also enhanced in diabetic human retina and correlated with the severity of DR. CONCLUSIONS/INTERPRETATION: Cell culture, animal, and human data suggest that oxidative stress and ER stress are induced by modified LDL, and are implicated in pericyte loss in DR. PMID- 22935963 TI - Obituary. PMID- 22935964 TI - ExpertDiscovery and UGENE integrated system for intelligent analysis of regulatory regions of genes. AB - The task of automatic extraction of the hierarchical structure of eukaryotic gene regulatory regions is in the junction of the fields of biology, mathematics and information technologies. A solution of the problem involves understanding of sophisticated mechanisms of eukaryotic gene regulation and applying advanced data mining technologies. In the paper the integrated system, implementing a powerful relation mining of biological data method, is discussed. The system allows taking into account prior information about the gene regulatory regions that is known by the biologist, performing the analysis on each hierarchical level, searching for a solution from a simple hypothesis to a complex one. The integration of ExpertDiscovery system into UGENE toolkit provides a convenient environment for conducting complex research and automating the work of a biologist. For demonstration, the system has been applied for recognition of SF1, SREBP, HNF4 vertebrate binding sites and for the analysis the human gene regulatory regions that promote liver-specific transcription. PMID- 22935962 TI - Moderate alcohol consumption is associated with improved insulin sensitivity, reduced basal insulin secretion rate and lower fasting glucagon concentration in healthy women. AB - AIMS/HYPOTHESIS: Moderate alcohol consumption is associated with a reduced risk of type 2 diabetes with a stronger effect in women. As the underlying mechanisms remain poorly characterised, we investigated its relationship with insulin resistance, insulin secretion, clearance of insulin and glucagon concentration. METHODS: One-thousand two-hundred and seventy-six non-diabetic individuals from the RISC (relationship between insulin sensitivity and cardiovascular disease) study without high alcohol consumption were studied; all had a euglycaemic hyperinsulinaemic clamp and an OGTT with assessment of insulin sensitivity, secretion and clearance. RESULTS: Alcohol consumption was positively associated with insulin sensitivity in women (beta = 0.15, p ( trend ) = 0.005) and in men (beta = 0.07, p ( trend ) = 0.07) after controlling for age, centre, waist, smoking and physical activity. In women, this association persisted after adjustment for adiponectin but was attenuated after controlling for HDL cholesterol, suggesting that part of the protection is related to a higher HDL cholesterol concentration. Higher alcohol consumption was associated with lower basal insulin secretion in women only (beta = -0.10, p ( trend ) = 0.004) and this association persisted after adjustment for insulin sensitivity. In men, increasing alcohol consumption was associated with enhanced insulin clearance and increased fasting NEFA concentrations, independently of insulin sensitivity. Fasting glucagon decreased with increasing alcohol in women only (abstainers 9.2 +/- 4.4; <28 g/week 8.6 +/- 4.0; 28-64 g/week 8.1 +/- 3.7; >64 g/week 7.5 +/- 3.1 pmol/l; p ( trend ) = 0.01). CONCLUSIONS/INTERPRETATION: Light-to-moderate alcohol consumption was associated in healthy women with enhanced insulin sensitivity, reduced basal insulin secretion rate and lower fasting plasma glucagon concentration, providing consistent mechanisms for the reduced risk of diabetes. PMID- 22935965 TI - Computer System for Analysis of Molecular Evolution Modes (SAMEM): analysis of molecular evolution modes at deep inner branches of the phylogenetic tree. AB - SAMEM (System for Analysis of Molecular Evolution Modes), a web-based pipeline system for inferring modes of molecular evolution in genes and proteins (http://pixie.bionet.nsc.ru/samem/), is presented. Pipeline 1 performs analyses of protein-coding gene evolution; pipeline 2 performs analyses of protein evolution; pipeline 3 prepares datasets of genes and/or proteins, performs their primary analysis, and builds BLOSUM matrices; pipeline 4 checks if these genes really are protein-coding. Pipeline 1 has an all-new feature, which allows the user to obtain K(R)/K(C) estimates using several different methods. An important feature of pipeline 2 is an original method for analyzing the rates of amino acid substitutions at the branches of a phylogenetic tree. The method is based on Markov modeling and a non-parametric permutation test, which compares expected and observed frequencies of amino acid substitutions, and infers the modes of molecular evolution at deep inner branches. PMID- 22935966 TI - Haploid evolutionary constructor: new features and further challenges. AB - In this paper we consider the recent advances in methodology for modeling of prokaryotic communities evolution and new features of the software package "Haploid evolutionary constructor" (http://evol-constructor.bionet.nsc.ru). We show the principles of building complex computer models in our software tool. These models describe several levels of biological organization: genetic, metabolic, population, ecological. New features of the haploid evolutionary constructor include the modeling of gene networks and phage infections. PMID- 22935967 TI - Towards a virtual C. elegans: a framework for simulation and visualization of the neuromuscular system in a 3D physical environment. AB - The nematode C. elegans is the only animal with a known neuronal wiring diagram, or "connectome". During the last three decades, extensive studies of the C. elegans have provided wide-ranging data about it, but few systematic ways of integrating these data into a dynamic model have been put forward. Here we present a detailed demonstration of a virtual C. elegans aimed at integrating these data in the form of a 3D dynamic model operating in a simulated physical environment. Our current demonstration includes a realistic flexible worm body model, muscular system and a partially implemented ventral neural cord. Our virtual C. elegans demonstrates successful forward and backward locomotion when sending sinusoidal patterns of neuronal activity to groups of motor neurons. To account for the relatively slow propagation velocity and the attenuation of neuronal signals, we introduced "pseudo neurons" into our model to simulate simplified neuronal dynamics. The pseudo neurons also provide a good way of visualizing the nervous system's structure and activity dynamics. PMID- 22935968 TI - ANDVisio: a new tool for graphic visualization and analysis of literature mined associative gene networks in the ANDSystem. AB - The ANDVisio tool is designed to reconstruct and analyze associative gene networks in the earlier developed Associative Network Discovery System (ANDSystem) software package. The ANDSystem incorporates utilities for automated extraction of knowledge from Pubmed published scientific texts, analysis of factographic databases, also the ANDCell database containing information on molecular-genetic events retrieved from texts and databases. ANDVisio is a new user's interface to the ANDCell database stored in a remote server. ANDVisio provides graphic visualization, editing, search, also saving of associative gene networks in different formats resulting from user's request. The associative gene networks describe semantic relationships between molecular-genetic objects (proteins, genes, metabolites and others), biological processes, and diseases. ANDVisio is provided with various tools to support filtering by object types, relationships between objects and information sources; graph layout; search of the shortest pathway; cycles in graphs. PMID- 22935969 TI - Impact of sex hormonal changes on tension-type headache and migraine: a cross sectional population-based survey in 2,600 women. AB - Sex hormones have some implications on headaches. The objective of the study was to investigate the effects of hormonal changes comparatively on tension-type headache (TTH) and migraine, in a population-based sample. A nationwide face-to face prevalence study was conducted using a structured electronic questionnaire. 54.3 % of the migraineurs reported that the probability of experiencing headache during menstruation was high, whereas 3.9 % had headache only during menstruation. Forward logistic regression analysis revealed that menstruation was a significant trigger for migraine in comparison to TTH. On the other hand, nearly double the number of TTH sufferers reported "pure menstrual headache" compared to migraineurs (p = 0.02). Menstrual headaches caused significantly higher MIDAS grades. One-third of the definite migraineurs reported improvement during pregnancy and oral contraceptives significantly worsened migraine. Menopause had a slight improving effect on migraine compared to TTH. Sex hormonal changes have major impacts particularly on migraine; however, the effects of hormonal fluctuations on TTH should not be underestimated. PMID- 22935970 TI - Characteristics of referred muscle pain to the head from active trigger points in women with myofascial temporomandibular pain and fibromyalgia syndrome. AB - Our aim was to compare the differences in the prevalence and the anatomical localization of referred pain areas of active trigger points (TrPs) between women with myofascial temporomandibular disorder (TMD) or fibromyalgia (FMS). Twenty women (age 46 +/- 8 years) with TMD and 20 (age 48 +/- 6 years) with FMS were recruited from specialized clinic. Bilateral temporalis, masseter, sternocleidomastoid, upper trapezius, and suboccipital muscles were examined for TrPs. TrPs were identified by palpation and considered active when the pain reproduced familiar pain symptom experienced by the patient. The referred pain areas were drawn on anatomical maps, digitalized and also measured. A new analysis technique based on a center of gravity (COG) method was used to quantitative estimate of the localization of the TrP referred pain areas. Women with FMS exhibited larger areas of usual pain symptoms than women with myofascial TMD (P < 0.001). The COG coordinates of the usual pain on the frontal and posterior pain maps were located more superior in TMD than in FMS. The number of active TrPs was significantly higher in TMD (mean +/- SD 6 +/- 1) than in FMS (4 +/- 1) (P = 0.002). Women with TMD exhibited more active TrPs in the temporalis and masseter muscles than FMS (P < 0.01). Women with FMS had larger referred pain areas than those with TMD for sternocleidomastoid and suboccipital muscles (P < 0.001). Significant differences within COG coordinates of TrP referred pain areas were found in TMD, the referred pain was more pronounced in the orofacial region, whereas the referred pain in FMS was more pronounced in the cervical spine. This study showed that the referred pain elicited from active TrPs shared similar patterns as usual pain symptoms in women with TMD or FMS, but that distinct differences in TrP prevalence and location of the referred pain areas could be observed. Differences in location of referred pain areas may help clinicians to determine the most relevant TrPs for each pain syndrome in spite of overlaps in pain areas. PMID- 22935972 TI - Basal cell carcinoma of the vulva: a case series. AB - AIMS: To review the diagnostic features and characteristics of an uncommon tumour, basal cell carcinoma (BCC) of the vulva. METHODS: The clinical and pathological details of six vulvar BCCs were reviewed. Four of the BCCs arose in isolation, one was combined with vulvar Paget's disease and another was intimately associated with a poorly differentiated squamous cell carcinoma. RESULTS: The average age of the six patients was 76 years (75 years for 'isolated' BCC; 78 years for BCC 'mixed' with other lesions). The duration of symptoms averaged 13 months in 'isolated' BCC but 24 months in 'mixed' BCC. Vulvar pruritus was the most common presenting complaint in the four cases of 'isolated' BCC. The initial biopsies included shave (* 2) or punch biopsies (* 4). Definitive surgery included excisional biopsy (* 2) or a wide local excision (* 3). In the five assessable tumours, the maximum tumour diameter averaged 19.8 mm (range 11-36 mm). In the sixth patient the BCC was contiguous with a 70 mm, unresectable, poorly differentiated squamous cell carcinoma which was treated by radiotherapy alone. CONCLUSIONS: : Although the histological diagnosis of vulvar BCC was straightforward in some of our cases, others presented difficulties due to non-representative initial biopsies, insufficient clinical information or contiguity with lesions of greater clinical significance such as Paget's disease or squamous cell carcinoma. PMID- 22935971 TI - The molecular basis for neuroimmune receptor signaling. AB - Many of the receptors which are responsible for the responses to the common drugs of abuse belong to the G protein-coupled receptor (GPCR) family. In this special issue of the Journal of Neuroimmune Pharmacology a collection of papers is presented which deals with signaling events that are important for the function of these receptors. Because these receptors are expressed by both neuronal and immune cells, and because these receptors play a complex role in regulating function in both the nervous and immune systems, a more complete understanding of the regulation of expression of these receptors is essential. Moreover, once these receptors are expressed and activated, a complex series of signaling events are initiated that can have substantial significance. We have only a limited understanding of these signaling events, but with more complete information, we may be able to control the undesirable and/or desirable consequences of receptor activation by drugs of abuse. PMID- 22935973 TI - Altered IkappaBalpha expression promotes NF-kappaB activation in monocytes from primary Sjogren's syndrome patients. AB - AIMS: To study the importance of IkappaBalpha in NF-kappaB signal transduction, we analysed the IkappaBalpha expression in monocytes from Sjogren's syndrome (SS) patients versus healthy controls. METHODS: Monocytes were obtained from the peripheral blood of 30 SS patients and 23 healthy subjects. IkappaBalpha expression was studied by semiquantitative reverse transcriptase polymerase chain reaction (RT-PCR), real-time PCR, immunoblotting, flow cytometry and enzyme linked immunosorbent assay (ELISA). RESULTS: Analysis of the gene and protein expression profiles of SS monocytes revealed a down-regulation of IkappaBalpha, and in all the Sjogren's syndrome cases examined, serum IkappaBalpha levels were significantly decreased in comparison with controls. CONCLUSIONS: Our findings clearly demonstrate changes in the levels of IkappaBalpha in SS monocytes, suggesting that the attenuated expression of IkappaBalpha could contribute to the deregulation of NF-kappaB pathways in the SS pathogenesis. Decreased expression of IkappaBalpha may specifically amplify cytokines production and inflammatory response linked to Sjogren's syndrome. PMID- 22935974 TI - Mitogen-activated protein kinase pathway in osteosarcoma. AB - AIMS: The MAPK pathway has been shown to contribute to the prognostic role and drug resistance in many cancers. In addition, the MAPK pathway was found to play a role in the aggressive behaviour of osteosarcoma (OS). We hypothesised that the expression of the MAPK pathway components may be of value in predicting the prognosis of patients with OS. METHODS: We evaluated the expression of pan-Ras, Raf-1, pMEK1/2 and pERK1/2 in 61 OS samples using immunohistochemistry and evaluated their effect on event free survival (EFS) and overall survival (OVS). RESULTS: pan-Ras, Raf-1, pMEK1/2 and pERK1/2 were found to be expressed in seven (11%), 36 (59%), 36 (59%) and 30 (49%) of 61 samples, respectively. Patients groups whose tumours expressed Raf-1, pMEK1/2 or pERK1/2 had a poorer clinical outcome than the group whose tumours did not express those antibodies. In addition, positive pMEK1/2 expression was associated with shorter EFS and OVS, irrespective of other prognostic factors. CONCLUSIONS: Our results further support the findings that aberrant expression of the MAPK pathway components may be the underlying mechanism behind OS, which results in more aggressive clinical behaviour. Furthermore, there may be a decrease in EFS and OVS in OS patients who have tumours that stain positively for pMEK. PMID- 22935975 TI - Utility of RhoC and ZAG protein expression as biomarkers for prediction of PSA failure following radical prostatectomy for high grade prostate cancer. AB - AIMS: To assess the prognostic utility of semi-quantiative expression of RhoC protein in whole prostates from patients who had radical prostatectomies for high grade prostate cancer (PCa). METHODS: Subjects who had surgery >55 months previously with primary Gleason pattern 4 PCa were identified from practice records, archival tissues were retrieved for review and RhoC immunohistochemistry, and ZAG expression was also assessed as a control. RESULTS: Eighty-nine subjects were included in the study; 57 had a rising prostate specific antigen (PSA) post-operatively ('cases') and 32 did not ('controls'). By univariate analysis, expression of both RhoC and ZAG proteins was greater in controls than cases, but this was significant only for ZAG. By multivariate analysis, Gleason variables (patterns and score), extraprostatic extension and decreased RhoC staining all contributed to predicting PSA failure (p < 0.05). ZAG expression was inversely correlated with Gleason pattern and hence was not independently predictive in our multivariate model. CONCLUSIONS: Increased RhoC expression predicted a good outcome after radical prostatectomy. ZAG staining also correlated with a favourable outcome but was not independently predictive due to its relationship with Gleason pattern. PMID- 22935976 TI - The effect of monoclonal antibody cetuximab (C225) in combination with tyrosine kinase inhibitor gefitinib (ZD1839) on colon cancer cell lines. AB - AIMS: The epidermal growth factor receptor (EGFR) is abnormally activated in many tumours. Two different categories of compounds targeting EGFR, monoclonal antibodies (mAbs) and low molecular weight tyrosine kinase inhibitors (TKIs), which target extracellular and intracellular domains of the receptor, respectively, have shown antitumour activity. We decided to explore whether the combined administration of cetuximab, a mAb, and gefitinib, a TKI, had superior antitumour activity than either agent given alone. METHODS: We studied the effects of cetuximab alone, gefitinib alone and the combination of cetuximab and gefitinib in two colon cancer cell lines, HT-29 and LoVo. The effects of these two agents on cell proliferation and induction of apoptosis were evaluated. RESULTS: Dose-dependent activity of cetuximab alone or gefitinib alone or the combination was observed for both colon cancer cell lines. In addition, the combined treatment with cetuximab and gefitinib resulted in a synergistic and more pronounced growth effect on cell proliferation and induction of apoptosis than either single-agent treatment. CONCLUSIONS: Our findings suggest that combined treatment with distinct EGFR inhibitory agents can augment the antitumour response over that realised with a single EGFR inhibitor. New and tempting treatment strategies on the EGFR target consisting of a double hit with a mAb and a TKI may improve the therapeutic ratio for colorectal cancer in future clinical trials. PMID- 22935977 TI - Reduced expression of Raf-1 kinase inhibitory protein in renal cell carcinoma: a significant prognostic marker. AB - AIMS: Renal cell carcinoma (RCC) is the third most common urological malignancy. Raf-1 kinase inhibitor protein (RKIP) has emerged as a significant metastatic suppressor and useful prognostic marker for a variety of human cancers. The aims of this study were to evaluate RKIP expression in RCC patients, and to determine the association of this protein with metastasis and its prognostic significance. METHODS: Immunohistochemical staining for RKIP was performed for 310 cases of various types of RCC. We investigated whether RKIP expression correlated with clinicopathological parameters and patient outcomes. RESULTS: The tubules of normal kidney showed consistently strong cytoplasmic and membranous RKIP immunoreactivity. RKIP expression was significantly reduced in 42.2% of RCC cases (negative 24.5%, weakly positive 17.7%). Reduced RKIP expression was significantly related to presence of distant metastasis (p < 0.001), higher disease stage (p = 0.004), larger tumour size (p = 0.005), and sarcomatoid subtype (p = 0.001). Univariate analysis showed that reduced RKIP expression was significantly associated with poor overall survival and disease-free survival (p = 0.0014 and 0.0001, respectively). The multivariate analysis revealed that reduced RKIP expression was an independent predictor of poor prognosis for overall patient survival (p = 0.035). CONCLUSION: Our results strongly suggested that reduced RKIP expression is associated with tumour progression and metastasis. Therefore, we concluded that RKIP expression is a significant prognostic marker for patients with RCC. PMID- 22935978 TI - Vaginal carriage rate of streptococcal pyogenes in 1600 pregnant women. PMID- 22935979 TI - Is there a need for expert opinion for biopsy diagnosis of difficult cases of malignant mesothelioma? PMID- 22935980 TI - Incidental finding of a common polymorphism (Asp1260Glu) and a previously unreported mutation of factor VIII (Asp588Val), resulting in moderate haemophilia A. PMID- 22935981 TI - Endocrine mucin producing sweat gland carcinoma: a clinicopathological analysis of three cases. PMID- 22935982 TI - Dabigatran: laboratory monitoring. PMID- 22935983 TI - Comparison of Vitek MS (MALDI-TOF) to standard routine identification methods: an advance but no panacea. PMID- 22935984 TI - A case of mesothelial/monocytic incidental cardiac excrescence (MICE) associated with squamous cell carcinoma of lung. PMID- 22935985 TI - A spectrum of oncocytic lesions in the parotid gland of a patient with sarcoidosis. PMID- 22935986 TI - Expressional analysis of NOLA1, NOLA2, NOLA3 and DKC1, the core proteins in H/ACA riboproteins, in gastric and colorectal cancers. PMID- 22935987 TI - Is CD20 positive plasma cell myeloma a unique clinicopathological entity? A study of 40 cases and review of the literature. AB - AIMS: A number of clinicopathological features have been attributed to the CD20 positive subset of plasma cell myeloma (PCM). CD20 is an appealing therapeutic target given the success with monoclonal antibody regimens in a spectrum of B cell lymphomas. To date, a small number of reports have described CD20 PCM as a unique subset, and these are not conclusive, especially taking into consideration reporting bias. This study aims to further identify the clinicopathological features of CD20 PCM. METHODS: A retrospective analysis of all newly diagnosed PCM between 2003 and 2010 was undertaken. Trephine material was retrieved and reviewed for CD20, and for positive cases an extended immunohistochemical (IHC) panel including cyclin D1 was subsequently performed. RESULTS: The review of our 40 cases and those described in the literature demonstrated that these are heterogeneous with regard to clinical features, morphology, biochemical features, immunophenotype, and cytogenetics. CONCLUSION: Based on our study and review of the literature, CD20 PCM cases represent a heterogeneous disease and not a unique clinicopathological entity. PMID- 22935988 TI - Sigma-1R agonist improves motor function and motoneuron survival in ALS mice. AB - Amyotrophic lateral sclerosis is a neurodegenerative disorder characterized by progressive weakness, muscle atrophy, and paralysis due to the loss of upper and lower motoneurons (MNs). Sigma-1 receptor (sigma-1R) activation promotes neuroprotection after ischemic and traumatic injuries to the central nervous system. We recently reported that sigma-1R agonist (PRE-084) improves the survival of MNs after root avulsion injury in rats. Moreover, a mutation of the sigma-1R leading to frontotemporal lobar degeneration/amyotrophic lateral sclerosis (ALS) was recently described in human patients. In the present study, we analyzed the potential therapeutic effect of the sigma-1R agonist (PRE-084) in the SOD1(G93A) mouse model of ALS. Mice were daily administered with PRE-084 (0.25 mg/kg) from 8 to 16 weeks of age. Functional outcome was assessed by electrophysiological tests and computerized analysis of locomotion. Histological, immunohistochemical analyses and Western blot of the spinal cord were performed. PRE-084 administration from 8 weeks of age improved the function of MNs, which was manifested by maintenance of the amplitude of muscle action potentials and locomotor behavior, and preserved neuromuscular connections and MNs in the spinal cord. Moreover, it extended survival in both female and male mice by more than 15 %. Delayed administration of PRE-084 from 12 weeks of age also significantly improved functional outcome and preservation of the MNs. There was an induction of protein kinase C-specific phosphorylation of the NR1 subunit of the N-methyl-D aspartate (NMDA) receptor in SOD1(G93A) animals, and a reduction of the microglial reactivity compared with untreated mice. PRE-084 exerts a dual therapeutic contribution, modulating NMDA Ca(2+) influx to protect MNs, and the microglial reactivity to ameliorate the MN environment. In conclusion, sigma-1R agonists, such as PRE-084, may be promising candidates for a therapeutical strategy of ALS. PMID- 22935990 TI - Idiopathic chylothorax: pathophysiology, diagnosis, and thoracic duct imaging. AB - Idiopathic chylothorax is a debilitating disease that can lead to respiratory and metabolic compromise and fibrosing pleuritis. Previous investigation has provided theories for the etiology of this poorly understood disease. This article provides an overview of the pathophysiology and diagnosis of chylothorax. Thoracic duct imaging, including minimally invasive techniques, is also discussed, as it is frequently performed in the perioperative period. A companion article reviews nonsurgical and surgical techniques for treating and managing idiopathic chylothorax in dogs and cats. PMID- 22935991 TI - Idiopathic chylothorax in dogs and cats: nonsurgical and surgical management. AB - Idiopathic chylothorax is a debilitating disease that can lead to respiratory and metabolic compromise and fibrosing pleuritis. Several treatment options are available once a diagnosis has been made. Although large-scale studies on the outcome of treatment for idiopathic chylothorax are lacking, long-term resolution of clinical signs is possible. Pathophysiology, diagnosis, and thoracic duct imaging are discussed in a companion article. This article provides an overview of nonsurgical and surgical management techniques for idiopathic chylothorax in dogs and cats. PMID- 22935989 TI - Non-pharmacological treatment of insomnia. AB - Insomnia is one of the most common sleep disorders, which is characterized by nocturnal symptoms of difficulties initiating and/or maintaining sleep, and by daytime symptoms that impair occupational, social, or other areas of functioning. Insomnia disorder can exist alone or in conjunction with comorbid medical and/or psychiatric conditions. The incidence of insomnia is higher in women and can increase during certain junctures of a woman's life (e.g., pregnancy, postpartum, and menopause). This article will focus on an overview of cognitive behavioral therapy for insomnia, evidence of effectiveness for this treatment when insomnia disorder is experienced alone or in parallel with a comorbidity, and a review with promising data on the use of cognitive behavioral therapy for insomnia when present during postpartum and menopause. PMID- 22935992 TI - Brachycephalic airway syndrome: management. AB - Brachycephalic airway syndrome (BAS) is a group of primary and secondary abnormalities that result in upper airway obstruction. Several of these abnormalities can be addressed medically and/or surgically to improve quality of life. This article reviews potential complications, anesthetic considerations, recovery strategies, and outcomes associated with medical and surgical management of BAS. PMID- 22935993 TI - Intestinal ischemia-reperfusion injury in horses: pathogenesis and therapeutics. AB - This article discusses the potential role of oxidative injury to the intestinal tract of horses and the therapeutic approaches that have been investigated to decrease cellular damage secondary to ischemia-reperfusion (IR) injury. Equine colic is a major concern for horse owners and veterinary practitioners. Strangulating and obstructive lesions of the small and large intestines commonly require intervention in patients via exploratory celiotomy. However, the application of information from experimentally induced IR injury in horses to clinical cases of naturally occurring equine colic is not clear. Thus, while the exact mechanisms and clinical significance of intestinal IR are being defined and may be matters of academic debate, a review of the available information may provide knowledge of potential underlying pathophysiologic mechanisms contributing to intestinal injury in equine colic. This information may allow clinicians to offer additional therapeutic strategies for horses with strangulating obstruction of the small or large intestine. Further clinical study of the therapeutic options for horses with naturally occurring disease is warranted. PMID- 22935994 TI - Mechanisms of oxidative injury in equine disease. AB - Oxygen is essential to aerobic life, but it is also associated with the production of highly reactive compounds that can pose danger to physiologic systems when the oxygen concentration is excessive. Reactive oxygen species (ROS) are required for normal physiologic processes, but when produced in excess, they can overwhelm endogenous antioxidants, resulting in significant cellular damage and, eventually, cell death. Ischemic events can initiate numerous pathophysiologic mechanisms leading to increased production of ROS, loss of cellular energy production, and lipid peroxidation. Although reperfusion is a necessary step in cellular recovery from ischemia, it can be deleterious by leading to the generation of even more ROS and stimulating the accumulation of neutrophils. Both of these processes may contribute to irreversible cell death and, ultimately, organ failure. This article reviews oxygen metabolism, ischemia, and reperfusion injury and how these processes may occur in equine disorders. PMID- 22935996 TI - Photoisomerization-induced stable liquid crystalline cubic blue phase. AB - We have succeeded in obtaining a photoinduced liquid crystalline cubic BP in a mixture of photoinactive and photoresponsive bent-core mesogens. The UV stimulus can convert N* to cubic BP through photoisomerization of the azobenzene linkages included in the photoresponsive bent-core molecule. PMID- 22935997 TI - Non-heme iron as ferrous sulfate does not interact with heme iron absorption in humans. AB - The absorption of heme iron has been described as distinctly different from that of non-heme iron. Moreover, whether heme and non-heme iron compete for absorption has not been well established. Our objective was to investigate the potential competition between heme and non-heme iron as ferrous sulfate for absorption, when both iron forms are ingested on an empty stomach. Twenty-six healthy nonpregnant women were selected to participate in two iron absorption studies using iron radioactive tracers. We obtained the dose-response curve for absorption of 0.5, 10, 20, and 50 mg heme iron doses, as concentrated red blood cells. Then, we evaluated the absorption of the same doses, but additionally we added non-heme iron, as ferrous sulfate, at constant heme/non-heme iron molar ratio (1:1). Finally, we compare the two curves by a two-way ANOVA. Iron sources were administered on an empty stomach. One factor analysis showed that heme iron absorption was diminished just by increasing total heme iron (P < 0.0001). The addition of non-heme iron as ferrous sulfate did not have any effect on heme iron absorption (P = NS). We reported evidence that heme and non-heme iron as ferrous sulfate does not compete for absorption. The mechanism behind the absorption of these iron sources is not clear. PMID- 22935998 TI - A versatile metal-organic framework for carbon dioxide capture and cooperative catalysis. AB - A multi-functional MOF was constructed from Cu paddlewheel motifs and a judiciously designed novel ligand bearing carboxylate, pyridine, and amide groups. exhibits selective adsorption of CO(2) over CH(4) and excellent catalytic activity in a tandem one-pot deacetalization-Knoevenagel condensation reaction as a cooperative catalyst. PMID- 22935995 TI - Mechanisms of psychostimulant-induced structural plasticity. AB - Psychostimulants robustly induce alterations in neuronal structural plasticity throughout brain reward circuits. However, despite our extensive understanding of how these circuits modulate motivated behavior, it is still unclear whether structural plasticity within these regions drives pathological behavioral responses in addiction. Although these structural changes have been subjected to an exhaustive phenomenological characterization, we still have a limited understanding of the molecular mechanisms regulating their induction and the functional relevance of such changes in mediating addiction-like behavior. Here we have highlighted the known molecular pathways and intracellular signaling cascades that regulate psychostimulant-induced changes in neuronal morphology and synaptic restructuring, and we discuss them in the larger context of addiction behavior. PMID- 22935999 TI - Amyloid-beta metabolism in Niemann-Pick C disease models and patients. AB - Niemann-Pick type C (NPC) is a progressive neurodegenerative lysosomal disease with altered cellular lipid trafficking. The metabolism of amyloid-beta (Abeta) - previously mainly studied in Alzheimer's disease - has been suggested to be altered in NPC. Here we aimed to perform a detailed characterization of metabolic products from the amyloid precursor protein (APP) in NPC models and patients. We used multiple analytical technologies, including immunoassays and immunoprecipitation followed by mass spectrometry (IP-MS) to characterize Abeta peptides and soluble APP fragments (sAPP-alpha/beta) in cell media from pharmacologically (U18666A) and genetically (NPC1 ( -/- ) ) induced NPC cell models, and cerebrospinal fluid (CSF) from NPC cats and human patients. The pattern of Abeta peptides and sAPP-alpha/beta fragments in cell media was differently affected by NPC-phenotype induced by U18666A treatment and by NPC1 ( /- ) genotype. U18666A treatment increased the secreted media levels of sAPP alpha, AbetaX-40 and AbetaX-42 and reduced the levels of sAPP-beta, Abeta1-40 and Abeta1-42, while IP-MS showed increased relative levels of Abeta5-38 and Abeta5 40 in response to treatment. NPC1 ( -/- ) cells had reduced media levels of sAPP alpha and Abeta1-16, and increased levels of sAPP-beta. NPC cats had altered CSF distribution of Abeta peptides compared with normal cats. Cats treated with the potential disease-modifying compound 2-hydroxypropyl-beta-cyclodextrin had increased relative levels of short Abeta peptides including Abeta1-16 compared with untreated cats. NPC patients receiving beta-cyclodextrin had reduced levels over time of CSF Abeta1-42, AbetaX-38, AbetaX-40, AbetaX-42 and sAPP-beta, as well as reduced levels of the axonal damage markers tau and phosphorylated tau. We conclude that NPC models have altered Abeta metabolism, but with differences across experimental systems, suggesting that NPC1-loss of function, such as in NPC1 ( -/- ) cells, or NPC1-dysfunction, seen in NPC patients and cats as well as in U18666A-treated cells, may cause subtle but different effects on APP degradation pathways. The preliminary findings from NPC cats suggest that treatment with cyclodextrin may have an impact on APP processing pathways. CSF Abeta, sAPP and tau biomarkers were dynamically altered over time in human NPC patients. PMID- 22936000 TI - Web-based digital gene expression atlases for the mouse. AB - Over the past 15 years the publicly available mouse gene expression data determined by in situ hybridization have dramatically increased in scope and spatiotemporal resolution. As a consequence of resources and tools available in the post-genomic era, full transcriptomes in the mouse brain and in the mouse embryo can be studied. Here we introduce and discuss seven current databases (MAMEP, EMBRYS, GenePaint, EURExpress, EuReGene, BGEM, and GENSAT) that grant access to large collections of expression data in mouse. We review the experimental focus, coverage, data assessment, and annotation for each of these databases and the implementation of analytic tools and links to other relevant databases. We provide a user-oriented summary of how to interrogate each database. PMID- 22936001 TI - Overview of new developments in and the future of cryopreservation in the laboratory mouse. AB - The large-scale mutagenesis programmes underway around the world are generating thousands of novel GA mouse strains that need to be securely archived. In parallel with advances in mutagenesis, the procedures used to cryopreserve mouse stocks are being continually refined in order to keep pace with demand. Moreover, the construction of extensive research infrastructures for systematic phenotyping is fuelling demand for these novel strains of mice and new approaches to the distribution of frozen and unfrozen embryos and gametes are being developed in order to reduce the dependency on the transportation of live mice. This article highlights some contemporary techniques used to archive, rederive, and transport mouse strains around the world. PMID- 22936002 TI - An assessment of cultural values and resident-centered culture change in U.S. nursing facilities. AB - BACKGROUND: Culture change initiatives propose to improve care by addressing the lack of managerial supports and prevalent stressful work environments in the industry; however, little is known about how culture change facilities differ from facilities in the industry that have not chosen to affiliate with the resident-centered care movements. PURPOSE: The aim of this study was to evaluate representation of organizational culture values within a random sample of U.S. nursing home facilities using the competing values framework and to determine whether organizational values are related to membership in resident-centered culture change initiatives. DESIGN AND METHODS: We collected reports of cultural values using a well-established competing values framework instrument in a random survey of facility administrators and directors of nursing within all states. We received responses from 57% of the facilities that were mailed the survey. Directors of nursing and administrators did not differ significantly in their reports of culture and facility measures combined their responses. FINDINGS: Nursing facilities favored market-focused cultural values on average, and developmental values, key to innovation, were the least common across all nursing homes. Approximately 17% of the facilities reported that all cultural values were strong within their facilities. Only high developmental cultural values were linked to participation in culture change initiatives. Culture change facilities were not different from non-culture change facilities in the promotion of employee focus as organizational culture, as emphasized in group culture values. Likewise, culture change facilities were also not more likely to have hierarchical or market foci than non-culture change facilities. PRACTICE IMPLICATIONS: Our results counter the argument that culture change facilities have a stronger internal employee focus than facilities more generally but do show that culture change facilities report stronger developmental cultures than non-culture change facilities, which indicates a potential to be innovative in their strategies. Facilities are culturally ready to become resident centered and may face other barriers to adopting these practices. PMID- 22936003 TI - Microfabricated mimics of in vivo structural cues for the study of guided tumor cell migration. AB - Guided cell migration plays a crucial role in tumor metastasis, which is considered to be the major cause of death in cancer patients. Such behavior is regulated in part by micro/nanoscale topographical cues present in the parenchyma or stroma in the form of fiber-like and/or conduit-like structures (e.g., white matter tracts, blood/lymphatic vessels, subpial and subperitoneal spaces). In this paper we used soft lithography micromolding to develop a tissue culture polystyrene platform with a microscale surface pattern that was able to induce guided cell motility along/through fiber-/conduit-like structures. The migratory behaviors of primary (glioma) and metastatic (lung and colon) tumors excised from the brain were monitored via time-lapse microscopy at the single cell level. All the tumor cells exhibited axially persistent cell migration, with percentages of unidirectionally motile cells of 84.0 +/- 3.5%, 58.3 +/- 6.8% and 69.4 +/- 5.4% for the glioma, lung, and colon tumor cells, respectively. Lung tumor cells showed the highest migratory velocities (41.8 +/- 4.6 MUm h(-1)) compared to glioma (24.0 +/- 1.8 MUm h(-1)) and colon (26.7 +/- 2.8 MUm h(-1)) tumor cells. This platform could potentially be used in conjunction with other biological assays to probe the mechanisms underlying the metastatic phenotype under guided cell migration conditions, and possibly by itself as an indicator of the effectiveness of treatments that target specific tumor cell motility behaviors. PMID- 22936004 TI - Characteristics of retained subretinal perfluoro-n-octane on optical coherence tomography. PMID- 22936005 TI - Intranasal insulin ameliorates tau hyperphosphorylation in a rat model of type 2 diabetes. AB - Recent studies have demonstrated that insulin plays important roles in the brain, including regulation of glucose metabolism and modulation of learning and memory. We have found dysregulation of brain insulin signaling in both Alzheimer's disease (AD) and type 2 diabetes (T2D), which correlates to hyperphosphorylation of tau, a key abnormal tau modification leading to neurofibrillary tangles. Here, we investigated tau phosphorylation and the two key components of the insulin signaling pathway, protein kinase B (AKT) and glycogen synthase kinase-3beta (GSK 3beta), in a rat model of T2D produced by a high protein, high glucose, and high fat diet followed by intraperitoneal injection of streptozocin. We found tau hyperphosphorylation, decreased AKT activation, and GSK-3beta over-activation in T2D rat brains. Intranasal insulin treatment for four weeks normalized AKT and GSK-3beta, as well as reduced tau hyperphosphorylation in T2D rat brains, whereas four-week treatments with subcutaneous insulin had minimal effects on brain GSK 3beta and tau phosphorylation. These results suggest decreased brain insulin signaling and tau hyperphosphorylation in the rat model of T2D and demonstrate the efficacy of intranasal insulin treatment to reverse these brain abnormalities. Our findings provide further mechanism by which T2D increases the risk for AD and also support the potential use of intranasal insulin for the treatment of AD. PMID- 22936007 TI - Treatment of Alzheimer's disease with the GSK-3 inhibitor tideglusib: a pilot study. AB - This pilot, double-blind, placebo-controlled, randomized, escalating dose trial explored the safety and efficacy of tideglusib, an inhibitor of glycogen synthase kinase-3, in Alzheimer's disease (AD) patients. Thirty mild-moderate AD patients on cholinesterase inhibitor treatment were administered escalating doses (400, 600, 800, 1,000 mg) of tideglusib or placebo (ratio 2 : 1) for 4, 4, 6, and 6 weeks, respectively. The primary objective was to evaluate the safety and tolerability of tideglusib with strict criteria for drug escalation or withdrawal. Mini-Mental Status Examination (MMSE), Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog+), word fluency, Geriatric Depression Scale (GDS), and a final Global Clinical Assessment (GCA) were assessed as secondary objectives. Treatment was well tolerated. Adverse events were as frequent in active and placebo groups, except for some moderate, asymptomatic, and fully reversible increases (>2.5 * ULN) of serum transaminases in 6 active cases (p = 0.001). Tideglusib produced positive trends in MMSE, ADAS-cog, GDS, and GCA without statistical significance in this small sample. Responders in MMSE were significantly higher in the active group (p = 0.05). Patients escalated up to 1000 mg/day had a benefit of 1.68 points in the MMSE and 4.72 points in the ADAS cog+ when compared to placebo. This small pilot study provides valuable safety and efficacy estimates for the treatment of AD patients with tideglusib, currently being confirmed in a larger clinical trial. Due to escalating doses and the small sample size, this trial provides insufficient evidence to support or reject a benefit of tideglusib in AD. PMID- 22936006 TI - Intracellular degradation of misfolded tau protein induced by geldanamycin is associated with activation of proteasome. AB - Misfolded, N- and C-terminally truncated tau protein is the primary constituent of neurofibrillary tangles in brains of patients afflicted with Alzheimer's disease (AD). Intracellular accumulation of misfolded and truncated tau leads to generation of cytotoxic intermediates; transgenic expression of truncated tau leads to neurological deficits, neurofibrillary degeneration, and premature death of animals. Since no cure for AD or other tauopathies is available yet, we tested the possibility for prevention of pathogenic events elicited by tau, via inhibition of its intracellular accumulation. Using a cell model conditionally expressing truncated and misfolding-prone tau protein, we showed that pathogenic forms of tau are degraded via the proteasome. We have also observed that chymotrypsin-like activity of the proteasome was significantly suppressed (a decrease of ~29.12% in comparison to control cells; p < 0.001) as a consequence of truncated tau expression. Interestingly, the activity of the proteasome was enhanced by geldanamycin, a natural inhibitor of Hsp90. This activation resulted in accelerated degradation of misfolded tau. We suggest that non-toxic inhibitors of Hsp90, especially those which can activate the proteasome, are good candidates for the development of molecules that efficiently counteract the damaging effects of pathologically misfolded proteins. PMID- 22936008 TI - Longitudinal stability evaluation of biomarkers and their correlation in cerebrospinal fluid and plasma from patients with Alzheimer's disease. AB - There is an increasing demand for biomarkers in clinical treatment trials to demonstrate target engagement and to support disease modification claims. To be able to detect treatment related effects, a prerequisite is that the levels of the biomarker are stable over time or that the change over time is known. In the present study, the stability of alpha- and beta-cleaved soluble amyloid-beta protein precursor (sAbetaPPalpha and sAbetaPPbeta), Abeta1-40 together with the phosphorylated form of neurofilament heavy/medium (pNfH/M) in cerebrospinal fluid (CSF) was analyzed in a cohort of 51 patients with Alzheimer's disease. In addition, the stability of Abeta1-40, Abeta1-42, and sAbetaPPbeta in plasma was explored. Plasma and CSF was sampled at baseline and after 6-months follow up, and all patients were on stable treatment with acetylcholinesterase inhibitors. During this 6-month longitudinal follow-up, we saw a small, but consistent and statistically significant increase in CSF levels of sAbetaPPbeta (103% of baseline levels) and a statistically significant decrease in the CSF levels of pNfH/M (91% of baseline levels). The mean level of the CSF biomarkers were very stable between baseline and endpoint, with within-patients coefficients of variation (CVs) of 5.84-17.3%, while the variability was larger for the plasma biomarkers, with CVs of 14.1-42.3%. This stability suggests that these biomarkers may have the potential to detect and monitor biochemical changes induced by disease-modifying drugs. PMID- 22936009 TI - The role of HDAC6 in Alzheimer's disease. AB - The expression of histone deacetylase 6 (HDAC6)--a versatile enzyme with a known role in epigenetics--increases significantly in the hippocampus and other relevant brain regions in both patients with Alzheimer's disease (AD) and animal models of AD. However, when and how HDAC6 expression increases during the course of AD progression remains unclear. Whether HDAC6 overexpression is an underlying cause of AD or a condition resulting from AD is controversial. Mounting evidence suggests that increased HDAC6 expression contributes to AD-associated neurodegeneration, although beneficial effects have also been identified. This review article addresses recent research on HDAC6 structure and function, and highlights the potential detrimental and protective roles of HDAC6 overexpression in AD. We hope to shed light on whether HDAC6 overexpression is associated with AD etiopathogenesis or whether it rescues AD-associated neurodegeneration compensatorily. Furthermore, we discuss new evidence showing that HDAC6 may be a therapeutic target for AD. PMID- 22936010 TI - Comparison of two analytical platforms for the clinical qualification of Alzheimer's disease biomarkers in pathologically-confirmed dementia. AB - Combined analysis of the Alzheimer's disease (AD) biomarkers amyloid-beta(1-42) (Abeta(1-42)), total tau (T-tau), and hyperphosphorylated tau (P-tau(181P)) in cerebrospinal fluid (CSF) reduces the uncertainty associated with clinical dementia diagnosis. The present study evaluated the diagnostic accuracy of the CSF biomarker concentrations obtained with a multi-analyte Luminex assay (INNO BIA AlzBio3) in comparison to single-analyte ELISA tests (INNOTEST). Data from 66 pathologically-confirmed dementia patients (51 AD and 15 non-AD) and 95 controls were included. Cut-off values were determined for each individual biomarker determined using both methods for different diagnostic challenges (dementia controls; AD-controls; AD-non-AD). Comparing the diagnostic accuracy of individual cut-off values between INNO-BIA and INNOTEST, no relevant differences could be identified. Logistic regression was used in addition to identify the best combination of predictor variables (biomarkers). Discrimination of dementia patients from controls using Abeta(1-42) and T-tau yielded a diagnostic accuracy of 0.87 and 0.90 for INNO-BIA and INNOTEST, respectively. Discriminating AD patients from controls, the diagnostic accuracy was 0.90 and 0.93 for INNO-BIA and INNOTEST, respectively. Optimal discrimination of AD and non-AD patients was achieved by combining Abeta(1-42) and P-tau(181P) (diagnostic accuracy = 0.86). In conclusion, which AD biomarkers or combination thereof are most informative is dependent on the differential diagnosis, but the clinical value of these markers in each of the differential diagnoses is independent of the method by which concentrations are determined. Since the clinical value of the ELISA (INNOTEST) and Luminex (INNO-BIA) tests is comparable, further research to select the most suitable analytical platform for routine CSF biomarker measurements is needed. PMID- 22936011 TI - Insulin and Alzheimer's disease: untangling the web. AB - The recognition of Alzheimer's disease (AD) as a heterogeneous disorder that results from incremental pathological changes in dynamic organismic systems is essential to move beyond the unidimensional approaches to prevention and therapy that have proven largely ineffective to date. Biological systems related to insulin metabolism are arguably the most critical regulators of longevity and corporeal aging. Our work has focused on identifying the relationship of the insulin network to brain aging, and determining the mechanisms through which insulin dysregulation promotes AD pathological processes. Candidate mechanisms include the effects of insulin on amyloid-beta, cerebral glucose metabolism, vascular function, lipid metabolism, and inflammation/oxidative stress. It is likely that different nodes of the insulin network are perturbed for subgroups of AD patients, or that for some subgroups, pathways independent of insulin are critical pathogenetic factors. New methods from systems network analyses may help to identify these subgroups, which will be critical for devising tailored prevention and treatment strategies. In the following review, we will provide a brief description of the role of insulin in normal brain function, and then focus more closely on recent evidence regarding the mechanisms through which disruption of that role may promote AD pathological processes. Finally, we will discuss the implications of this area for AD therapeutics and prevention. PMID- 22936012 TI - Enhanced phase synchronization of blood flow oscillations between heated and adjacent non-heated sacral skin. AB - The study of skin microcirculation may be used to assess risk for pressure ulcers. It is observed that local heating causes an increase in blood flow of not only the heated skin, but also in the adjacent non-heated skin. The underlying physiological mechanism of this indirect vasodilation of the non-heated skin remains unclear. We hypothesized that blood flow oscillations (BFO) in the adjacent non-heated skin area synchronize with BFO in the heated skin, thus inducing a vasodilatory response. We investigated BFO in the heated and adjacent non-heated skin (12.1 +/- 1.2-cm distance) on the sacrum in 12 healthy participants. The ensemble empirical mode decomposition (EEMD) was used to decompose blood flow signals into a set of intrinsic mode functions (IMFs), and the IMFs with power spectra over the frequency range of 0.0095-0.02, 0.02-0.05, and 0.05-0.15 Hz were chosen as the characteristic components corresponding to metabolic, neurogenic, and myogenic regulations, respectively. Then, the instantaneous phase of the characteristic components was calculated using the Hilbert transform. From the time series of phase difference between a pair of characteristic components, the epochs of phase synchronization were detected. The results showed that myogenic and neurogenic BFO exhibited self-phase synchronization during the slower vasodilation of the heated skin. In the non heated skin, the degree of synchronization of BFO is associated with the changes in blood flow. PMID- 22936013 TI - Chemoimmunotherapy with GA101 plus chlorambucil in patients with chronic lymphocytic leukemia and comorbidity: results of the CLL11 (BO21004) safety run in. PMID- 22936014 TI - Genome-wide profiling of methylation identifies novel targets with aberrant hypermethylation and reduced expression in low-risk myelodysplastic syndromes. AB - Gene expression profiling signatures may be used to classify the subtypes of Myelodysplastic syndrome (MDS) patients. However, there are few reports on the global methylation status in MDS. The integration of genome-wide epigenetic regulatory marks with gene expression levels would provide additional information regarding the biological differences between MDS and healthy controls. Gene expression and methylation status were measured using high-density microarrays. A total of 552 differentially methylated CpG loci were identified as being present in low-risk MDS; hypermethylated genes were more frequent than hypomethylated genes. In addition, mRNA expression profiling identified 1005 genes that significantly differed between low-risk MDS and the control group. Integrative analysis of the epigenetic and expression profiles revealed that 66.7% of the hypermethylated genes were underexpressed in low-risk MDS cases. Gene network analysis revealed molecular mechanisms associated with the low-risk MDS group, including altered apoptosis pathways. The two key apoptotic genes BCL2 and ETS1 were identified as silenced genes. In addition, the immune response and micro RNA biogenesis were affected by the hypermethylation and underexpression of IL27RA and DICER1. Our integrative analysis revealed that aberrant epigenetic regulation is a hallmark of low-risk MDS patients and could have a central role in these diseases. PMID- 22936015 TI - Effect of sulfhydryl modification on rat kidney basolateral plasma membrane transport function. AB - Transport processes are the hallmark of functioning kidney. Various nephrotoxicants disrupt the transport processes to manifest nephrotoxicity. Of several nephrotoxicants, mercuric chloride (HgCl(2)) depletes the reduced glutathione (GSH) in kidney and has been observed to affect the in vitro p aminohippurate (PAH) transport by basolateral (BL) membrane vesicles. The role of renal nonprotein sulfhydryls such as, reduced GSH has been demonstrated to affect the PAH transport by BL membrane vesicles. The role of protein sulfhydryls in transport process of PAH by BL membrane is not known. Due to mercury mediated effects on sulfhydryls, the effects of protein-sulfhydryls (-SH) modifying reagents in the current study were investigated on PAH transport by BL membrane. It was observed that modification of -SH by p-chloromercuribenzoate sulphate (pCMBS), and mercuric chloride (HgCl(2)) decreased while recovering the protein SH with dithiothreitol treatment provided protection against the effects of pCMBS, and HgCl(2) on PAH transport by BL membrane vesicles. PMID- 22936017 TI - Room-temperature synthesis of soluble, fluorescent carbon nanoparticles from organogel precursors. AB - Carbon nanoparticles were obtained at room temperature by irradiating an organogel made from a 1,8-diaryloctatetrayne derivative in chloroform. During the topochemical polymerization, the morphology of the gel changes from fibers to soluble, yellow fluorescent nanoparticles in high yield. Analyses suggest that the resulting nanoparticles are made of amorphous graphitic carbon. PMID- 22936016 TI - Drug delivery patterns for different stenting techniques in coronary bifurcations: a comparative computational study. AB - The treatment of coronary bifurcation lesions represents a challenge for the interventional cardiologists due to the lower rate of procedural success and the higher risk of restenosis. The advent of drug-eluting stents (DES) has dramatically reduced restenosis and consequently the request for re-intervention. The aim of the present work is to provide further insight about the effectiveness of DES by means of a computational study that combines virtual stent implantation, fluid dynamics and drug release for different stenting protocols currently used in the treatment of a coronary artery bifurcation. An explicit dynamic finite element model is developed in order to obtain realistic configurations of the implanted devices used to perform fluid dynamics analysis by means of a previously developed finite element method coupling the blood flow and the intramural plasma filtration in rigid arteries. To efficiently model the drug release, a multiscale strategy is adopted, ranging from lumped parameter model accounting for drug release to fully 3-D models for drug transport to the artery. Differences in drug delivery to the artery are evaluated with respect to local drug dosage. This model allowed to compare alternative stenting configurations (namely the Provisional Side Branch, the Culotte and the Inverted Culotte techniques), thus suggesting guidelines in the treatment of coronary bifurcation lesions and addressing clinical issues such as the effectiveness of drug delivery to lesions in the side branch, as well as the influence of incomplete strut apposition and overlapping stents. PMID- 22936018 TI - The impact of successful manual thrombus aspiration on in-stent restenosis after primary PCI: angiographic and clinical follow-up. AB - OBJECTIVES: This study sought to investigate the impact of successful manual thrombus aspiration on angiographic in-stent restenosis and clinical outcome in patients treated by bare metal stent implantation for ST-segment elevation acute myocardial infarction. BACKGROUND: There are very limited data on the impact of manual thrombus aspiration on the occurrence of in-stent restenosis after bare metal stent implantation. METHODS: This was a prospective, randomized, single center study. Patients (N=60) presenting within 12 h of ST-segment elevation acute myocardial infarction symptom onset were randomized to primary percutaneous coronary intervention (PCI) with (N=30) or without (N=30) upfront manual thrombus aspiration using the Export aspiration catheter. All patients underwent control coronary angiography after 6 months. RESULTS: Baseline, clinical, and angiographic preprocedural findings did not differ between the two groups. Patients who underwent successful manual thrombus aspiration had significantly higher minimal lumen diameter after 6 months (2.25+/-0.90 vs. 1.63+/-0.76, P=0.005), significantly lower percentage diameter stenosis (28.81 vs. 45.03%, P=0.017), and significantly lower late lumen loss (0.73+/-0.84 vs. 1.18+/-0.79, P=0.035). There was a trend for lower rate of major adverse cardiocerebrovascular events such as death, myocardial reinfarction, stroke, and target lesion revascularization in the same group of patients (16.67 vs. 26.67%, P=0.347). CONCLUSION: Successful upfront manual thrombus aspiration during primary PCI showed beneficial effects on the reduction of in-stent restenosis after bare metal stent implantation compared with standard PCI. PMID- 22936019 TI - Impact of preinterventional plaque composition and eccentricity on late-acquired incomplete stent apposition after sirolimus-eluting stent implantation: an intravascular ultrasound radiofrequency analysis. AB - OBJECTIVES: The present study aimed to investigate differences in plaque morphology and components in between the target coronary artery lesion with and without late-acquired incomplete stent apposition (LISA) using radiofrequency analysis (virtual histology) of intravascular ultrasound data. BACKGROUND: Incomplete stent apposition is frequently observed in patients with very late stent thrombosis after sirolimus-eluting stent implantation. METHODS: The study group consisted of 70 coronary artery lesions in 43 patients who underwent elective coronary stenting for stable angina pectoris. Virtual histology intravascular ultrasound was performed at the implantation of stent and 12-month follow-up. LISA was defined as a separation of stent struts from the intimal surface of the arterial wall that had not been present at the time of stent implantation. The plaque eccentricity index (EI) was calculated as (lumen radius+maximal plaque thickness)/(lumen radius+minimal plaque thickness). RESULTS: At 12-month follow-up, LISA occurred in 15 plaques (LISA group). Compared with the non-LISA group, the LISA group had significantly longer stents, a higher EI, smaller amount of fibro-fatty component (7.7+/-4.2 vs. 12.5+/-7.0%, P=0.01) and larger amount of necrotic core component (16.6+/-9.8 vs. 11.1+/-6.4%, P=0.06). Multivariate logistic regression analysis revealed that amount of necrotic core and plaque EI were independent positive predictors for LISA (odds ratio=1.4, 95% confidence interval=1.1-1.6, P=0.04 and 11.2, 1.9-64.9, P<0.01, respectively). CONCLUSION: Plaques with increased amounts of necrotic core and higher eccentricity are associated with subsequent LISA after sirolimus-eluting stent implantation. PMID- 22936020 TI - Predictive value of red cell distribution width in intrahospital mortality and postintervention thrombolysis in myocardial infarction flow in patients with acute anterior myocardial infarction. AB - OBJECTIVES: Recent studies have reported a strong independent association between increased red cell distribution width (RDW) and the risk of adverse outcomes in patients with heart failure, stable coronary disease, and acute coronary syndromes. However, in this study we aimed to determine the impact of an elevated RDW level on the postinterventional thrombolysis in myocardial infarction (TIMI) flow and intrahospital mortality in patients with acute anterior myocardial infarction (AMI). METHODS: A total of 763 patients with acute AMI undergoing a primary percutaneous coronary intervention were evaluated retrospectively. Upon admission, the RDW level was measured by an automated complete blood count. Postinterventional TIMI flow and intrahospital mortality was documented for all patients from hospital registries. The patients were classified according to the RDW level. RDW more than 14.8% was defined as elevated RDW. All groups were compared statistically according to the preinterventional characteristics. RESULTS: Elevated RDW was found to be an independent predictor of increased intrahospital mortality in multivariate regression analysis (hazard ratio: 3.677, 95% confidence interval: 1.228-11.008, P=0.02). Other independent predictors for intrahospital mortality were diabetes mellitus (hazard ratio: 6.743, 95% confidence interval: 1.941-23.420, P=0.003), smoking (hazard ratio: 6.779, 95% confidence interval: 1.505-30.534, P=0.013), and creatinine more than 0.8 mg/dl (hazard ratio: 7.982, 95% confidence interval: 1.759-36.211, P=0.007). However, there were no independent predictors for TIMI including elevated RDW. CONCLUSION: A high admission RDW level in patients with acute AMI undergoing a primary percutaneous coronary intervention was associated with an increased risk for intrahospital cardiovascular mortality, but was not associated with worse postinterventional TIMI flow. PMID- 22936021 TI - Ischemia-modified albumin in stable coronary atherosclerotic heart disease: clinical diagnosis and risk stratification. AB - OBJECTIVES: Ischemia-modified albumin (IMA), a new serum biomarker of myocardial ischemia, has been introduced in the diagnosis of acute coronary syndrome. However, few studies have been carried out in patients with stable coronary atherosclerotic heart disease (CHD). We aimed to evaluate the value of IMA in the diagnosis of stable CHD and to determine the correlation between IMA levels and the severity of myocardial ischemia. METHODS: A total of 129 patients with diagnosed CHD who had signed an informed consent form were enrolled. Patients were willing to undergo coronary angiography, which was the gold standard for the diagnosis of CHD. IMA was detected by the albumin cobalt binding test before coronary angiography. RESULTS: The mean IMA level of the non-CHD group was 67.68 +/- 29.61 U/ml and that of the CHD group was 90.24 +/- 29.61 U/ml. In the CHD group, the mean IMA levels of the one-branch lesion group, the two-branch lesion group, and the three-branch lesion group were 79.87 +/- 18.37, 98.10 +/- 23.39, and 98.06 +/- 33.47 U/ml, respectively. IMA levels and the number of diseased coronary arteries were significantly correlated (P<0.01, r=0.299). When the cut off threshold derived from the receiver operating characteristics curve was determined to be 93.07 U/ml, the sensitivity of admission IMA for a final diagnosis of CHD was 0.49, the specificity was 0.90, the negative predictive value was 0.45, and the positive predictive value was 0.91. Logistic regression analysis showed that IMA (P=0.000, b=2.056, odds ratio=7.815) was an independent predictor of CHD. CONCLUSION: IMA showed a high specificity and predictive value in the diagnosis of CHD. In addition, IMA was a strong and independent predictor of CHD. IMA levels and the number of diseased coronary arteries were significantly correlated. PMID- 22936022 TI - beta-Pinene inhibited germination and early growth involves membrane peroxidation. AB - beta-Pinene, an oxygenated monoterpene, is abundantly found in the environment and widely occurring in plants as a constituent of essential oils. We investigated the phytotoxicity of beta-pinene against two grassy (Phalaris minor, Echinochloa crus-galli) and one broad-leaved (Cassia occidentalis) weeds in terms of germination and root and shoot growth. beta-Pinene (0.02-0.80 mg/ml) inhibited the germination, root length, and shoot length of test weeds in a dose-response manner. The inhibitory effect of beta-pinene was greater in grassy weeds and on root growth than on shoot growth. beta-Pinene (0.04-0.80 mg/ml) reduced the root length in P. minor, E. crus-galli, and C. occidentalis over that in the control by 58-60, 44-92, and 26-85 %, respectively. In contrast, shoot length was reduced over the control by 45-97 % in P. minor, 48-78 % in E. crus-galli, and 11-75 % in C. occidentalis at similar concentrations. Further, we examined the impact of beta-pinene on membrane integrity in P. minor as one of the possible mechanisms of action. Membrane integrity was evaluated in terms of lipid peroxidation, conjugated diene content, electrolyte leakage, and the activity of lipoxygenases (LOX). beta-Pinene (>=0.04 mg/ml) enhanced electrolyte leakage by 23-80 %, malondialdehyde content by 15-67 %, hydrogen peroxide content by 9-39 %, and lipoxygenases activity by 38-383 % over that in the control. It indicated membrane peroxidation and loss of membrane integrity that could be the primary target of beta-pinene. Even the enhanced (9-62 %) activity of protecting enzymes, peroxidases (POX), was not able to protect the membranes from beta-pinene (0.04 0.20 mg/ml)-induced toxicity. In conclusion, our results show that beta-pinene inhibits root growth of the tested weed species through disruption of membrane integrity as indicated by enhanced peroxidation, electrolyte leakage, and LOX activity despite the upregulation of POX activity. PMID- 22936023 TI - Cloning and functional characterization of 3-hydroxy-3-methylglutaryl coenzyme A reductase gene from Withania somnifera: an important medicinal plant. AB - Withania somnifera (L.) Dunal is one of the most valuable medicinal plants synthesizing a large number of pharmacologically active secondary metabolites known as withanolides, the C28-steroidal lactones derived from triterpenoids. Though the plant has been well characterized in terms of phytochemical profiles as well as pharmaceutical activities, not much is known about the biosynthetic pathway and genes responsible for biosynthesis of these compounds. In this study, we have characterized the gene encoding 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGR; EC 1.1.1.34) catalyzing the key regulatory step of the isoprenoid biosynthesis. The 1,728-bp full-length cDNA of Withania HMGR (WsHMGR) encodes a polypeptide of 575 amino acids. The amino acid sequence homology and phylogenetic analysis suggest that WsHMGR has typical structural features of other known plant HMGRs. The relative expression analysis suggests that WsHMGR expression varies in different tissues as well as chemotypes and is significantly elevated in response to exposure to salicylic acid, methyl jasmonate, and mechanical injury. The functional color assay in Escherichia coli showed that WsHMGR could accelerate the biosynthesis of carotenoids, establishing that WsHMGR encoded a functional protein and may play a catalytic role by its positive influence in isoprenoid biosynthesis. PMID- 22936025 TI - A geostatistical methodology for the optimal design of space-time hydraulic head monitoring networks and its application to the Valle de Queretaro aquifer. AB - This paper presents a new methodology for the optimal design of space-time hydraulic head monitoring networks and its application to the Valle de Queretaro aquifer in Mexico. The selection of the space-time monitoring points is done using a static Kalman filter combined with a sequential optimization method. The Kalman filter requires as input a space-time covariance matrix, which is derived from a geostatistical analysis. A sequential optimization method that selects the space-time point that minimizes a function of the variance, in each step, is used. We demonstrate the methodology applying it to the redesign of the hydraulic head monitoring network of the Valle de Queretaro aquifer with the objective of selecting from a set of monitoring positions and times, those that minimize the spatiotemporal redundancy. The database for the geostatistical space-time analysis corresponds to information of 273 wells located within the aquifer for the period 1970-2007. A total of 1,435 hydraulic head data were used to construct the experimental space-time variogram. The results show that from the existing monitoring program that consists of 418 space-time monitoring points, only 178 are not redundant. The implied reduction of monitoring costs was possible because the proposed method is successful in propagating information in space and time. PMID- 22936024 TI - CD64 distinguishes macrophages from dendritic cells in the gut and reveals the Th1-inducing role of mesenteric lymph node macrophages during colitis. AB - Dendritic cells (DCs) and monocyte-derived macrophages (MPhis) are key components of intestinal immunity. However, the lack of surface markers differentiating MPhis from DCs has hampered understanding of their respective functions. Here, we demonstrate that, using CD64 expression, MPhis can be distinguished from DCs in the intestine of both mice and humans. On that basis, we revisit the phenotype of intestinal DCs in the absence of contaminating MPhis and we delineate a developmental pathway in the healthy intestine that leads from newly extravasated Ly-6C(hi) monocytes to intestinal MPhis. We determine how inflammation impacts this pathway and show that T cell-mediated colitis is associated with massive recruitment of monocytes to the intestine and the mesenteric lymph node (MLN). There, these monocytes differentiate into inflammatory MPhis endowed with phagocytic activity and the ability to produce inducible nitric oxide synthase. In the MLNs, inflammatory MPhis are located in the T-cell zone and trigger the induction of proinflammatory T cells. Finally, T cell-mediated colitis develops irrespective of intestinal DC migration, an unexpected finding supporting an important role for MLN-resident inflammatory MPhis in the etiology of T cell mediated colitis. PMID- 22936026 TI - Insulin resistance can impair reduction on carotid intima-media thickness in obese adolescents. AB - BACKGROUND: The atherosclerotic process at the endothelial level begins in early ages and seems to be associated with obesity and its comorbidities as insulin resistance. OBJECTIVE: The aim of this study was to verify the influence of insulin resistance on inflammatory and subclinical markers of atherosclerosis in obese adolescents. METHODS: Sixty-six post-pubescent obese adolescents were divided in two groups according to homeostasis model assessment of insulin resistance (HOMA-IR) measurement: with insulin resistance (IR) n=39 and without insulin resistance (NIR) n=27, and submitted to an interdisciplinary intervention over the course of 1 year. Common carotid artery intima-media thickness (cIMT), visceral and subcutaneous adipose tissue was determined by ultrasound. Body composition, blood pressure, HOMA-IR, lipid profile and adipokines concentrations [leptin, adiponectin, and plasminogen activator inhibitor type (PAI-1)] were analyzed before and after the therapy. RESULTS: Both groups presented significant improvements in body composition, inflammatory state (reduction of leptin and PAI 1 concentration; increasing of plasma adiponectin) and reduction of cIMT. Only NIR group showed positive correlation between changes in visceral fat (?Visceral) and changes in cIMT (? cIMT) (r = 0.42; p < 0.05). Simple linear regression analyze revealed ?Visceral to be an independent predictor to reduction of cIMT in this group (R2 adjusted = 0.14, p = 0.04). The final values of cIMT remained significantly higher in IR group when compared to NIR group. CONCLUSION: The presence of insulin resistance can impair changes in cIMT leading to early development of atherosclerosis in obese adolescents submitted to an interdisciplinary intervention.. PMID- 22936027 TI - Accuracy of the GRACE and TIMI scores in predicting the angiographic severity of acute coronary syndrome. AB - BACKGROUND: The accuracy of the GRACE and TIMI scores in predicting coronary disease extension in patients with non-ST-elevation acute coronary syndromes (ACS) has not been established. OBJECTIVE: To assess the hypothesis that the GRACE and TIMI risk scores satisfactorily predict coronary disease extension in patients withnon-ST-elevation ACS undergoing coronary angiography. METHODS: Individuals meeting the objective criteria for ACS and undergoing coronary angiography during hospitalization were consecutively assessed. Angiographic coronary disease was described as follows: quantification of coronary disease extension by using Gensini score; presence of any coronary artery obstruction (> 70% or > 50% when affecting left main coronary artery); and presence of severe disease (three-vessel disease or affecting the left main coronary artery). RESULTS: Of 112 patients assessed, a positive correlation of the Gensini score was observed with the GRACE (p = 0.017) and TIMI (p = 0.02) scores, but that association was weak (r = 0.23 and r = 0.27; respectively). The GRACE score could predict neither obstructive coronary disease (area under the ROC curve = 0.57; 95% CI = 0.46 - 0.69), nor severe coronary disease (ROC = 0.59; 95% CI = 0.48 - 0.70). The TIMI score proved to be a modest predictor of coronary disease (ROC = 0.65; 95% CI = 0.55 - 0.76) and of severe coronary disease (ROC = 0.66; 95% CI = 0.56 - 0.76). CONCLUSION: (1) There is a positive association between the values of the TIMI or GRACE scores and the extension of coronary artery disease in patients with ACS; (2) however, the degree of that association is not sufficient to make those scores accurate predictors of coronary angiography results. PMID- 22936028 TI - Lack of tight association between quality of life and exercise capacity in pulmonary arterial hypertension. AB - BACKGROUND: In pulmonary arterial hypertension (PAH) health-related quality of life (HRQOL) has been investigated over the short-term (weeks) but little is known about patient's perspective over the medium and long term. OBJECTIVE: To analyze how patients on specific PAH therapies do over one year of observation in terms of HRQOL, and to investigate if possible associations between the exercise capacity (EC) and HRQOL persist over the medium term. METHODS: Thirty-four patients on PAH therapies (bosentan and/or sildenafil) were enrolled (age 14 to 58 years, median 35.5 years, functional class II or III), and evaluated at baseline, and 3, 6, 9 and 12 months subsequently using the six-minute walk test and the SF-36 HRQOL questionnaire. RESULTS: The six minute walked distance did not change over the follow-up (387-432 meters, median values, p=0.2775), the same for the functional class and peripheral oxygen saturation. The SF-36 scores also remained stable, with physical health always worse than mental health. Of 40 possible associations between EC and HRQOL, only 12 were significant (30%, p<0.05). Prediction of severely depressed HRQOL based on a walked distance of <235 meters was >90% specific but <43% sensitive. CONCLUSION: Patients with PAH who remain stable in terms of EC also seem to do so in terms of HRQOL. However, EC and HRQOL are not consistently tied over time, and should be analyzed as different perspectives in the individual patient. PMID- 22936029 TI - Prognostic value of endothelial function in patients with atherosclerosis: systematic review. AB - Analysis of flow-mediated vasodilation (FMV) of the brachial artery by use of ultrasound allows assessing endothelial function, and provides pathophysiological, diagnostic and prognostic information. This systematic review was aimed at assessing the literature level of evidence of the predictive capacity of endothelial function, measured through brachial artery FMV by use of ultrasound, regarding cardiovascular events in individuals with atherosclerosis. The MEDLINE, SCIELO and LILACS databases were searched, and prospective cohort studies on human beings about the prognostic value of endothelial function, measured by use of brachial artery FMV in individuals with peripheral or coronary atherosclerosis, were selected. Studies with clear methodological biases were excluded. The final selection consisted of 15 studies. Of the 13 studies that on univariate analysis showed statistical significance of the FMV method to predict cardiovascular events, 12 showed independent predictive capacity on multivariate analysis. None of the studies reviewed described the incremental predictive value of FMV to the traditional predictive models, such as the Framingham score. Results of three studies have suggested that the method adds prognostic value to isolated markers such as ankle-brachial index (ABI), diabetes, and high sensitivity C-reactive protein (hsCRP). In conclusion, brachial artery FMV predicts cardiovascular risk, but its incremental predictive value to clinical prognostic models has not been established. In addition, solid evidence supporting its use in routine clinical practice to predict cardiovascular risk still lacks. PMID- 22936030 TI - Correlation between serum cystatin C and markers of subclinical atherosclerosis in hypertensive patients. AB - BACKGROUND: Serum cystatin C (s-CC), an endogenous marker of kidney function, has also been proposed as a cardiovascular risk marker. However, it is unknown whether it is a direct marker of atherosclerosis, independently of kidney function. OBJECTIVE: The aim of this study was to correlate s-CC with two surrogate markers of subclinical atherosclerosis. METHODS: This is a cross sectional study involving 103 middle-aged (57.49 +/- 11.7 years) hypertensive outpatients, being 60 female (58.25%), most with preserved kidney function. S-CC was correlated with carotid intima media thickness (IMT) and flow-mediated dilation of brachial artery (FMD), both assessed by ultrasound, as well as with measured creatinine clearance and established cardiovascular risk factors. RESULTS: S-CC was neither significantly correlated with IMT (r = -0.024; p = 0.84) nor with FMD (r = -0.050 and p = 0.687) and no significant association was observed with conventional risk factors and inflammatory markers. In univariate analysis, s-CC was correlated with measured creatinine clearance (r = -0,498; p < 0,001), age (r = 0,408; p < 0,001), microalbuminuria (r = 0,291; p = 0,014), uric acid (r = 0,391; p < 0,001), ratio E/e' (r = 0,242; p = 0,049) and Framingham score (r = 0,359; p = 0,001). However, after multiple regression analysis, only the association with measured creatinine clearance remained significant (r = 0,491; p < 0,001). CONCLUSION: In middle-aged hypertensive outpatients, s-CC correlated with measured creatinine clearance, as expected, but no association was observed with markers of atherosclerosis neither with established cardiovascular risk factors. PMID- 22936031 TI - Simplified International Index of Erectile Function (IIEF-5) and coronary artery disease in hypertensive patients. AB - BACKGROUND: Erectile Dysfunction (ED) is associated with increased risk of coronary artery disease (CAD). OBJECTIVE: To evaluate the association between ED, determined by the Simplified International Index of Erectile Function (IIEF-5) and CAD. METHODS: This was a cross-sectional cohort study that evaluated 263 hypertensive patients (55 [50-61] years). ED was assessed through the IIEF-5 and CAD by the history of previous myocardial revascularization and/or coronary angiography. RESULTS: The IIEF-5 correlated with creatinine clearance [CrCl] (Rho = 0.23, p <0.001) and age (Rho = -0.22, p <0.001). Forty-two patients had CAD, and IIEF-5 was able to discriminate them (area under the ROC curve = 0.63, p = 0.006). Patients were divided into two groups: IIEF-5 < 20 (n = 140) and IIEF-5 > 20 (n = 123); those with lower IIEF-5 scores were older (57 [52-61] vs. 54 [45 60] years, p = 0.002), had higher prevalence of CAD (22% vs. 9%, p = 0.004), smoking (64% vs. 47%, p = 0.009) and use of calcium channel inhibitors (65% vs. 43.%, p = 0.001), as well as lower CrCl (67.3 [30.8 to 88.6] vs. 82.6 [65.9 - 98.2] ml/min, p <0.001). The IIEF-5 < 21 was associated with increased risk of CAD in the logistic regression, both univariate (RR = 2.89 [95%CI: 1.39 - 6.05]), and after adjusting for age, diabetes, CrCl, smoking, mean arterial pressure and use of antihypertensive drugs (RR = 2.59 [95% CI: 1.01 - 6.61]). CONCLUSION: The IIEF-5 is associated with the diagnosis of CAD and its use can add information to cardiovascular risk staging in hypertensive patients. PMID- 22936032 TI - Chronic stress improves the myocardial function without altering L-type Ca+2 channel activity in rats. AB - BACKGROUND: Chronic stress is associated with cardiac remodeling; however the mechanisms have yet to be clarified. OBJECTIVE: The purpose of this study was test the hypothesis that chronic stress promotes cardiac dysfunction associated to L-type calcium Ca2+ channel activity depression. METHODS: Thirty-day-old male Wistar rats (70 - 100 g) were distributed into two groups: control (C) and chronic stress (St). The stress was consistently maintained at immobilization during 15 weeks, 5 times per week, 1h per day. The cardiac function was evaluated by left ventricular performance through echocardiography and by ventricular isolated papillary muscle. The myocardial papillary muscle activity was assessed at baseline conditions and with inotropic maneuvers such as: post-rest contraction and increases in extracellular Ca2+ concentration, in presence or absence of specific blockers L-type calcium channels. RESULTS: The stress was characterized for adrenal glands hypertrophy, increase of systemic corticosterone level and arterial hypertension. The chronic stress provided left ventricular hypertrophy. The left ventricular and baseline myocardial function did not change with chronic stress. However, it improved the response of the papillary muscle in relation to positive inotropic stimulation. This function improvement was not associated with the L-type Ca2+ channel. CONCLUSION: Chronic stress produced cardiac hypertrophy; however, in the study of papillary muscle, the positive inotropic maneuvers potentiated cardiac function in stressed rats, without involvement of L-type Ca2+ channel. Thus, the responsible mechanisms remain unclear with respect to Ca2+ influx alterations. PMID- 22936033 TI - Genome drafts of four phytoplasma strains of the ribosomal group 16SrIII. AB - By applying a coverage-based read selection and filtration through a healthy plant dataset, and a post-assembly contig selection based on homology and linkage, genome sequence drafts were obtained for four phytoplasma strains belonging to the 16SrIII group (X disease clade), namely Vaccinium Witches' Broom phytoplasma (647 754 nt in 272 contigs), Italian Clover Phyllody phytoplasma strain MA (597 245 nt in 197 contigs), Poinsettia branch-inducing phytoplasma strain JR1 (631 440 nt in 185 contigs) and Milkweed Yellows phytoplasma (583 806 nt in 158 contigs). Despite assignment to different 16SrIII subgroups, the genomes of the four strains were similar, comprising a highly conserved core (92 98 % similar in their nucleotide sequence among each other over alignments about 500 kb in length) and a minor strain-specific component. As far as their protein complement was concerned, they did not differ significantly in their basic metabolism potential from the genomes of other wide-host-range phytoplasmas sequenced previously, but were distinct from strains of other species, as well as among each other, in genes encoding functions conceivably related to interactions with the host, such as membrane trafficking components, proteases, DNA methylases, effectors and several hypothetical proteins of unknown function, some of which are likely secreted through the Sec-dependent secretion system. The four genomes displayed a group of genes encoding hypothetical proteins with high similarity to a central domain of IcmE/DotG, a core component of the type IVB secretion system of Gram-negative Legionella spp. Conversely, genes encoding functional GroES/GroEL chaperones were not detected in any of the four drafts. The results also indicated the significant role of horizontal gene transfer among different 'Candidatus Phytoplasma' species in shaping phytoplasma genomes and promoting their diversity. PMID- 22936034 TI - Absence of O antigen suppresses Shigella flexneri IcsA autochaperone region mutations. AB - The Shigella flexneri IcsA (VirG) protein is a polarly distributed autotransporter protein. IcsA functions as a virulence factor by interacting with the host actin regulatory protein N-WASP, which in turn activates the Arp2/3 complex, initiating actin polymerization. Formation of F-actin comet tails allows bacterial cell-to-cell spreading. Although various accessory proteins such as periplasmic chaperones and the beta-barrel assembly machine (BAM) complex have been shown to be involved in the export of IcsA, the IcsA translocation mechanism remains to be fully elucidated. A putative autochaperone (AC) region (amino acids 634-735) located at the C-terminal end of the IcsA passenger domain, which forms part of the self-associating autotransporter (SAAT) domain, has been suggested to be required for IcsA biogenesis, as well as for N-WASP recruitment, based on mutagenesis studies. IcsA(i) proteins with linker insertion mutations within the AC region have a significant reduction in production and are defective in N-WASP recruitment when expressed in smooth LPS (S-LPS) S. flexneri. In this study, we have found that the LPS O antigen plays a role in IcsA(i) production based on the use of an rmlD (rfbD) mutant having rough LPS (R-LPS) and a novel assay in which O antigen is depleted using tunicamycin treatment and then regenerated. In addition, we have identified a new N-WASP binding/interaction site within the IcsA AC region. PMID- 22936036 TI - Pretransplant neurological presentation and severe posttransplant brain injury in patients with acute liver failure. AB - BACKGROUND: Alterations in the central nervous system in patients with acute liver failure (ALF) present unique challenges in the perioperative period. In this retrospective study, we examined pretransplant neurological presentation and the incidence, clinical presentation, and risk factors associated with severe posttransplant brain injury (BI) in ALF patients undergoing orthotopic liver transplantation (OLT). METHODS: After institutional review board approval, ALF patients who underwent OLT between 2004 and 2010 at our center were reviewed. Pretransplant neurological presentation and severe posttransplant BI were examined. Risk factors for the latter were identified. RESULTS: During the study period, 90 (67 adults and 23 children) ALF patients underwent primary OLT. Preoperatively, all patients developed encephalopathy, 6 had seizure activity, 32 had radiological evidence of cerebral edema, and 11 had severe cerebral edema. After OLT, 7 patients developed severe posttransplant BI. Of these 7 patients, 4 had brain death, and 3 had irreversible injury that precluded them from living independently. Severe pretransplant cerebral edema and a higher posttransplant international normalized ratio (odds ratios and 95% confidence intervals: 50.2, 5.8-433.5 [P<0.001] and 3.1, 1.1-8.8 [P=0.031], respectively) were risk factors associated with severe posttransplant BI. CONCLUSIONS: Pretransplant neurological complications were prevalent, and severe posttransplant BI occurred at a rate of 7.8% and was significantly associated with severe pretransplant cerebral edema and postoperative international normalized ratio. Our findings support the use of pretransplant computed tomography. If severe pretransplant cerebral edema is confirmed, efforts should be made to aggressively control intracranial pressure and select a proper donor to minimize the risk of severe posttransplant BI and futile transplantation. PMID- 22936035 TI - Improving T cell responses to modified peptides in tumor vaccines. AB - Immune recognition and elimination of cancerous cells is the primary goal of cancer immunotherapy. However, obstacles including immune tolerance and tumor induced immunosuppression often limit beneficial immune responses. Vaccination is one proposed intervention that may help to overcome these issues and is an active area of study in cancer immunotherapy. Immunizing with tumor antigenic peptides is a promising, straight-forward vaccine strategy hypothesized to boost preexisting antitumor immunity. However, tumor antigens are often weak T cell agonists, attributable to several mechanisms, including immune self-tolerance and poor immunogenicity of self-derived tumor peptides. One strategy for overcoming these mechanisms is vaccination with mimotopes, or peptide mimics of tumor antigens, which alter the antigen presentation and/or T cell activation to increase the expansion of tumor-specific T cells. Evaluation of mimotope vaccine strategies has revealed that even subtle alterations in peptide sequence can dramatically alter antigen presentation and T cell receptor recognition. Most of this research has been performed using T cell clones, which may not be accurate representations of the naturally occurring antitumor response. The relationship between clones generated after mimotope vaccination and the polyclonal T cell repertoire is unclear. Our work with mimotopes in a mouse model of colon carcinoma has revealed important insights into these issues. We propose that the identification of mimotopes based on stimulation of the naturally responding T cell repertoire will dramatically improve the efficacy of mimotope vaccination. PMID- 22936037 TI - Diagnostic significance of peritubular capillary basement membrane multilaminations in kidney allografts: old concepts revisited. AB - BACKGROUND: Injury to peritubular capillaries and capillary basement membrane multilamination (PTCL) is a hallmark of antibody-mediated chronic renal allograft rejection. However, the predictive diagnostic value of PTCL is incompletely studied. METHODS: We analyzed the diagnostic significance of PTCL and propose diagnostic strategies. We evaluated 360 diagnostic native and 187 transplant kidney specimens by electron microscopy (terminology: PTCL-C, severe; PTCL subgroup C3, very severe multilamination; see Materials and Methods for definitions). RESULTS: PTCL was not pathognomonic for any specific disease. PTCL C/C3 was rare in native kidneys (C, 6%; C3, 1%), associated mainly with late thrombotic microangiopathy (C: 78%; C3: 11% of cases). In allografts, PTCL-C/C3 was significantly more common, especially in specimens more than 24 months after transplantation (C, 47%; C3, 31%). PTCL-C/C3 was found in acute (C, 20%; C3, 7%) and chronic T-cell rejection (C, 67%; C3, 29%), calcineurin inhibitor toxicity (C, 36%; C3, 18%), or C4d(+) specimens (C, 61%; C3, 50%) with odds ratios between 4 and 36. PTCL-C3 was more predominant in cases with antibody-mediated injury. Highest odds ratios (81-117) for PTCL-C/C3 were noted in combined injuries, that is, mixed chronic T-cell and concurrent chronic antibody-mediated rejection. Positive predictive values of PTCL-C and C3 are the following: all rejection types, 89% and 93%; all Banff chronic rejection types, 69% and 71%; and chronic presumptive antibody rejection, 37% and 49%, respectively. Corresponding negative predictive values of C and C3 for different Banff rejection categories are between 50% and 94%. CONCLUSIONS: The presence of PTCL-C3 is a helpful adjunct finding to diagnose rejection-induced tissue injury but cannot precisely predict the Banff rejection category. Conversely, the absence of PTCL-C3 is helpful in excluding chronic, Banff category II antibody-mediated rejection. PMID- 22936038 TI - Early changes of hypothalamic angiotensin II receptors expression in gestational protein-restricted offspring: effect on water intake, blood pressure and renal sodium handling. AB - The current study examines changes in the postnatal hypothalamic angiotensin receptors by maternal protein restriction (LP), and its impact on in uteri programming of hypertension in adult life. The data show that LP male pup body weight was significantly reduced when compared to that of control (NP) pups. Also, immunoblotting analysis demonstrated a significantly decreased expression of type 1 AngII receptors (AT1R) in the entire hypothalamic tissue extract of LP rats at 12 days of age compared to age-matched NP offspring. Conversely, the expression of the type 2 AngII (AT2R) receptors in 12-day- and 16-week-old LP hypothalamus was significantly increased. The current data show the influence of central AngII administration on water consumption in a concentration-dependent fashion, but also demonstrate that the water intake response to AngII was strikingly attenuated in 16-week-old LP. These results may be related to decreased brain arginine vasopressin (AVP) expression appearing in maternal protein-restricted offspring. The present investigation shows an early decrease in fractional urinary sodium excretion in maternal protein-restricted offspring. The decreased fractional sodium excretion was accompanied by a fall in proximal sodium excretion and occurred despite unchanged creatinine clearance. These effects were associated with a significant enhancement in arterial blood pressure in the LP group, but the precise mechanism of these phenomena remains unknown. PMID- 22936039 TI - Investigations into mild electric foot shock stress-induced cognitive enhancement: possible role of angiotensin neuropeptides. AB - This study was designed to investigate the role of angiotensin neuropeptides in mild electric foot shock stress-induced cognitive enhancement in mice. Mild stress was induced by applying mild electric foot shocks of 0.15 mA intensity for 0.5 s. The stress-induced alteration in cognition was assessed using a Morris water maze test. The animals were subjected to mild electric foot shocks 5 min before we recorded escape latency time (ELT), an index of learning, during the first 4 days of a 5-day trial in the Morris water maze. The time spent in target quadrant (TSTQ), an index of retrieval, was noted on the fifth day without prior administration of electric foot shock. The angiotensin-converting enzyme inhibitor lisinopril (5, 10 and 20 mg/kg), and telmisartan (1, 2 and 5 mg/kg), an angiotensin II receptor blocker, were employed to assess the role of angiotensin neuropeptides. The application of mild electric shocks significantly decreased ELT and increased TSTQ, indicating enhancement in stress-induced learning and memory. However, administration of lisinopril and telmisartan significantly attenuated the stress-induced decrease in ELT and increase in TSTQ. It may be concluded that mild electric foot shock-induced stress triggers the release of angiotensin neuropeptides that may be responsible for memory enhancement. PMID- 22936040 TI - HHN celebrates 30 years! Re-membering the herstory of Home Healthcare. PMID- 22936041 TI - Institute for Preventive Foot Health a sponsor of National Limb Loss Awareness Month April 2012. PMID- 22936042 TI - No place like home: a history of nursing and home care in the U.S. PMID- 22936043 TI - Returning home: historical influences on home healthcare in Canada. AB - In this article, the historical context of home healthcare in early 20th century Canada is examined with an emphasis on key events and groups that shaped nursing in the home as the primary form of healthcare. Ways in which home healthcare evolved are also addressed, including the movement from an emphasis on the home as the point of care for both preventative and curative services, to the separation of healthcare functions into public health, treatment of illness and injury, and pregnancy care-each with its own practitioners and regulators as hospital-based systems became the desirable norm. We conclude that the nature and status of home-based nursing evolved in response to public expectations of what comprised "best care" and who was responsible for providing (and funding) it. At a certain level, the home offered independent-minded nurses a level of autonomy and inscrutability unparalleled in hospital-based settings. As hospitals took preeminence as preferred sites for healthcare, the same geographic, cultural, and economic barriers that complicated access to hospitals also provided nurses unique opportunities in the home as relatively autonomous caregivers. PMID- 22936044 TI - Nutrition and depression in the community-based oldest-old. AB - The number of older adults continues to increase in all healthcare settings. The majority of older adults are living in the community. Most are dealing with at least one chronic physical illness or mental health concern. Nutritional status and depression, key indicators of overall health, have a complex and interdependent relationship. Clinicians must understand factors that affect nutrition and depression to promote positive health outcomes and enhance the overall quality of life for the oldest-old in the community. PMID- 22936046 TI - Polypharmacy in older adults at home: what it is and what to do about it- implications for home healthcare and hospice. AB - Polypharmacy--the use of more medications than are clinically indicated--is a problem that affects many older adults. Adults aged 65 years and older make up approximately 13% of the population, but they consume nearly one third of all prescriptions dispensed. Older adults are more prone to adverse drug reactions and drug-drug interactions due to physiological changes and multiple comorbidities. The harmful effects that may be caused by the inappropriate use of medications include but are not limited to: side effects, drug interactions, and high drug costs. Polypharmacy may lead to a decrease in quality of life. With an increase in specialization across medicine, many patients see multiple prescribers and may fill medications at multiple pharmacies. This can contribute to the problem of polypharmacy. Periodic medication reviews and effective and constant communication between healthcare providers and patients can help to identify potentially inappropriate medications, which is essential in aiding to reduce polypharmacy. PMID- 22936048 TI - Are we ensuring that our clinicians have the "right skills" for the 21st century? PMID- 22936049 TI - Looking back: home healthcare then and now--a personal experience. PMID- 22936050 TI - Measles immunometrics. PMID- 22936051 TI - Hematopoietic overexpression of the transcription factor Erg induces lymphoid and erythro-megakaryocytic leukemia. AB - The transcription factor encoded by the E-twenty-six (ETS)-related gene, ERG, is an essential regulator of hematopoietic stem cell function and a potent human oncoprotein. Enforced expression of ERG in murine hematopoietic cells leads to the development of a well-characterized lymphoid leukemia and a less well-defined non lymphoid disease. To clarify the latter, we generated murine bone marrow chimeras with enforced Erg expression in engrafted hematopoietic progenitor cells. As expected, these mice developed lymphoid leukemia. However, the previously reported non lymphoid disease that developed was shown to be a uniform, transplantable leukemia with both erythroid and megakaryocytic characteristics. In vivo, this disease had the overall appearance of an erythroleukemia, with an accumulation of immature erythroblasts that infiltrated the bone marrow, spleen, liver, and lung. However, when stimulated in vitro, leukemic cell clones exhibited both erythroid and megakaryocytic differentiation, suggesting that transformation occurred in a bipotential progenitor. Thus, in mice, Erg overexpression induces the development of not only lymphoid leukemia but also erythro-megakaryocytic leukemia. PMID- 22936052 TI - Interdisciplinary approaches to understanding disease emergence: the past, present, and future drivers of Nipah virus emergence. AB - Emerging infectious diseases (EIDs) pose a significant threat to human health, economic stability, and biodiversity. Despite this, the mechanisms underlying disease emergence are still not fully understood, and control measures rely heavily on mitigating the impact of EIDs after they have emerged. Here, we highlight the emergence of a zoonotic Henipavirus, Nipah virus, to demonstrate the interdisciplinary and macroecological approaches necessary to understand EID emergence. Previous work suggests that Nipah virus emerged due to the interaction of the wildlife reservoir (Pteropus spp. fruit bats) with intensively managed livestock. The emergence of this and other henipaviruses involves interactions among a suite of anthropogenic environmental changes, socioeconomic factors, and changes in demography that overlay and interact with the distribution of these pathogens in their wildlife reservoirs. Here, we demonstrate how ecological niche modeling may be used to investigate the potential role of a changing climate on the future risk for Henipavirus emergence. We show that the distribution of Henipavirus reservoirs, and therefore henipaviruses, will likely change under climate change scenarios, a fundamental precondition for disease emergence in humans. We assess the variation among climate models to estimate where Henipavirus host distribution is most likely to expand, contract, or remain stable, presenting new risks for human health. We conclude that there is substantial potential to use this modeling framework to explore the distribution of wildlife hosts under a changing climate. These approaches may directly inform current and future management and surveillance strategies aiming to improve pathogen detection and, ultimately, reduce emergence risk. PMID- 22936054 TI - Systematic analysis of human lysine acetylation proteins and accurate prediction of human lysine acetylation through bi-relative adapted binomial score Bayes feature representation. AB - Lysine acetylation is a reversible post-translational modification (PTM) which has been linked to many biological and pathological implications. Hence, localization of lysine acetylation is essential for deciphering the mechanism of such implications. Whereas many acetylated lysines in human proteins have been localized through experimental approaches in wet lab, it still fails to reach completion. In the present study, we proposed a novel feature extraction approach, bi-relative adapted binomial score Bayes (BRABSB), combined with support vector machines (SVMs) to construct a human-specific lysine acetylation predictor, which yields, on average, a sensitivity of 83.91%, a specificity of 87.25% and an accuracy of 85.58%, in the case of 5-fold cross validation experiments. Results obtained through the validation on independent data sets show that the proposed approach here outperforms other existing lysine acetylation predictors. Furthermore, due to the fact that global analysis of human lysine acetylproteins, which would ultimately facilitate the systematic investigation of the biological and pathological consequences associated with lysine acetylation events, remains to be resolved, we made an attempt to systematically analyze human lysine acetylproteins, demonstrating their diversity with respect to subcellular localization as well as biological process and predominance by "binding" in terms of molecular function. Our analysis also revealed that human lysine acetylproteins are significantly enriched in neurodegenerative disorders and cancer pathways. Remarkably, lysine acetylproteins in mitochondria are significantly related to neurodegenerative disorders and those in the nucleus are instead significantly involved in pathways in cancers, all of which might ultimately provide novel global insights into such pathological processes for the therapeutic purpose. The web server is deployed at http://www.bioinfo.bio.cuhk.edu.hk/bpbphka. PMID- 22936053 TI - Promoter hypermethylation in primary squamous cell carcinoma of the oral cavity and oropharynx: a study of a Brazilian cohort. AB - Epigenetic silencing of cancer-related genes plays an important role in oral/oropharyngeal squamous cell carcinoma (OSCC). We evaluated promoter hypermethylation of 4 cancer-related genes in OSCCs of a Brazilian cohort and determined its relationship with exposure to alcohol, tobacco, HPV infection and clinicopathological parameters. CDKN2A (cyclin-dependent kinase inhibitor 2A or p16), SFN (stratifin or 14-3-3 sigma), EDNRB (endothelin receptor B) and RUNX3 (runt-related transcript factor-3) had their methylation patterns evaluated by MSP analysis in OSCC tumors (n = 45). HPV detection was carried out by PCR/RFLP. Aberrant methylation was detected in 44/45 (97.8 %) OSCC; 24.4 % at CDKN2A, 77.8 % at EDNRB, 17.8 % at RUNX3 and 97.8 % at SFN gene. There was no significant association between methylation patterns and clinical parameters. HPV (subtype 16) was detected in 3 out of 45 patients (6 %). Our findings indicate that HPV infection is uncommon and methylation is frequent in Brazilian OSCCs, however, EDNRB and SFN gene methylation are not suitable OSCC biomarkers due to indistinct methylation in tumoral and normal samples. In contrast, CDKN2A and RUNX3 genes could be considered differentially methylated genes and potential tumor markers in OSCCs. PMID- 22936055 TI - Planning safe anesthesia: the role of collective resources management. AB - OBJECTIVE: Anticipation and planning are essential steps of risk management but the mechanisms of planning behavior are incompletely understood, especially the factors including collective work. The aim of this research is to understand how anesthetists plan safe solution to perform anesthesia. METHODS: A study based on interviews was conducted in two French hospitals. Data processing focused on the main decisions made by 20 anesthetists during two simulated pre-anesthetic consultation. The main decisions made have been identified and the decision criteria have been analyzed. RESULTS: To ensure patient safety, all anesthetists do not plan the same solution. The rejection or the selection of solutions by each physician rests on two types of criteria: the assessment of risks for the patient and the assessment of resources available to handle the situation. For the latter, the knowledge on the individual skills of each and the adoption of "local benchmark practices" play an essential role. CONCLUSION: Ultra safe performance in highly variable systems cannot be achieved only through standardization but also through the possibility and ability of the subjects to adapt their practices to their own skills and to that of their colleagues. The conditions for the development of this "adaptative safety" are discussed. PMID- 22936056 TI - Quality of evidence in drug compendia supporting off-label use of typical and atypical antipsychotic medications. AB - Public and private payers use drug compendia to make coverage determinations, yet the quality of evidence they contain has received little scrutiny. We examined compendia citations regarding antipsychotic drugs, an important drug class given their substantial costs and widespread use. Nearly three-fold as many off-label indications were recommended for atypical as for typical agents, a difference that did not appear to be due to differences in quality of evidence for typical and atypical off-label indications. Given the important role that compendia play in evidence synthesis, coverage decisions, and ultimately, prescription utilization, these data suggest greater efforts are needed to improve the quality of evidence and transparency of evidence evaluations compendia contain. PMID- 22936057 TI - Adverse effects of aromatherapy: a systematic review of case reports and case series. AB - AIM: This systematic review was aimed at critically evaluating the evidence regarding the adverse effects associated with aromatherapy. METHOD: Five electronic databases were searched to identify all relevant case reports and case series. RESULTS: Forty two primary reports met our inclusion criteria. In total, 71 patients experienced adverse effects of aromatherapy. Adverse effects ranged from mild to severe and included one fatality. The most common adverse effect was dermatitis. Lavender, peppermint, tea tree oil and ylang-ylang were the most common essential oils responsible for adverse effects. CONCLUSION: Aromatherapy has the potential to cause adverse effects some of which are serious. Their frequency remains unknown. Lack of sufficiently convincing evidence regarding the effectiveness of aromatherapy combined with its potential to cause adverse effects questions the usefulness of this modality in any condition. PMID- 22936058 TI - Patient safety incidents from acupuncture treatments: a review of reports to the National Patient Safety Agency. AB - BACKGROUND: Acupuncture is frequently employed to treat chronic pain syndromes or other chronic conditions. Nevertheless, there is a growing literature on adverse events (AEs) from treatments including pneumothorax, cardiac tamponade and spinal cord injury. Acupuncture is provided in almost all NHS pain clinics and by an increasing number of GP's and physiotherapists. Considering acupuncture's popularity, its safety has become an important public health issue. OBJECTIVES: To evaluate the harm caused to patients through acupuncture treatments within NHS organisations. METHODS: The National Reporting and Learning System (NRLS) database was searched for incidents reported from 1st January 2009 to 31st December 2011. The free text fields of all reports received from all healthcare settings and specialties were searched for the keyword 'acupuncture'. All relevant incidents were reviewed to provide a qualitative theme of the harm to patients. RESULTS: 468 patient safety incidents were identified; 325 met our inclusion criteria for analysis. Adverse events reported include retained needles (31%), dizziness (30%), loss of consciousness/unresponsive (19%), falls (4%), Bruising or soreness at needle site (2%), Pneumothorax (1%) and other adverse reactions (12%). The majority (95%) of the incidents were categorised as low or no harm. CONCLUSIONS: A number of AEs are recorded after acupuncture treatments in the NHS but the majority is not severe. However, miscategorisation and under reporting may distort the overall picture. Acupuncture practitioners should be aware of, and be prepared to manage, any significant harm from treatments. PMID- 22936059 TI - Pesticide poisoning in Palestine: a retrospective analysis of calls received by Poison Control and Drug Information Center from 2006-2010. AB - BACKGROUND AND OBJECTIVE: The agricultural industry is the largest economic sector in Palestine and is characterized by extensive and unregulated use of pesticides. The objective of this study was to analyze phone calls received by the Poison Control and Drug Information Center (PCDIC) in Palestine regarding pesticide poisoning. METHODS: All phone calls regarding pesticide poisoning received by the PCDIC from 2006 to 2010 were descriptively analyzed. Statistical Package for Social Sciences (SPSS version 16) was used in statistical analysis and to create figures. RESULTS: A total of 290 calls regarding pesticide poisoning were received during the study period. Most calls (83.8%) were made by physicians. The average age of reported cases was 19.6 +/- 15 years. Pesticide poisoning occurred mostly in males (56.9%). Pesticide poisoning was most common (75, 25.9%) in the age category of 20-29.9 years. The majority (51.7%) of the cases were deliberate self-harm while the remaining was accidental exposure. The majority of phone calls (250, 86.2%) described oral exposure to pesticides. Approximately one third (32.9%) of the cases had symptoms consistent with organophosphate poisoning. Gastric lavage (31.7%) was the major decontamination method used, while charcoal was only utilized in 1.4% of the cases. Follow up was performed in 45.5% of the cases, two patients died after hospital admission while the remaining had positive outcome. CONCLUSION: Pesticide poisoning is a major health problem in Palestine, and the PCDIC has a clear mission to help in recommending therapy and gathering information. PMID- 22936063 TI - Combined analysis of KRAS and PIK3CA mutations, MET and PTEN expression in primary tumors and corresponding metastases in colorectal cancer. AB - Metastasis is the main cause of mortality in patients with colorectal cancer. However, most of the targeted therapies and predictive molecular biomarkers were developed based mainly on primary tumors. The current study was conducted to determine the degree of discordance between potential predictive and/or prognostic molecular markers in primary colorectal tumors and corresponding metastases, as this could have an impact on the efficacy of targeted therapies in the advanced colorectal cancer. KRAS, PIK3CA and BRAF mutations were determined by Sanger sequencing and mutant-enriched polymerase chain reaction (PCR) assays in 83 paired samples, MET gene copy number by quantitative PCR in 59, MET expression by immunohistochemistry in 73 and nuclear and cytoplasmic expression of PTEN by immunohistochemistry in 78 and 71 pairs, respectively. A certain degree of discordance between primary tumors and corresponding metastases was demonstrated for all examined biomarkers except BRAF mutations. PIK3CA exon 9 mutations in primary tumors and loss of PTEN nuclear expression in metastases correlated with KRAS mutations. KRAS wild-type status in primary tumors was associated with loss of PTEN cytoplasmic expression and high gene copy number of MET. Survival and clinical data were available for 68 patients. The multiple regression analysis revealed that the right-sided tumor localization and overexpression of MET were associated with shorter overall survival. PMID- 22936064 TI - TdT expression in acute myeloid leukemia with minimal differentiation is associated with distinctive clinicopathological features and better overall survival following stem cell transplantation. AB - The diagnostic criteria for acute myeloid leukemia (AML), not otherwise specified, with minimal differentiation (AML-M0, French-American-British classification), have been refined in the 2008 World Health Organization (WHO) classification. Terminal deoxynucleotidyl transferase (TdT) expression in AML-M0 has been proposed by others as a surrogate for RUNX1 (runt-related transcription factor 1) mutations, a mutation associated with distinct gene expression profiles in AML-M0. In this study, we investigated the significance of TdT expression in AML-M0 cases defined using the 2008 WHO classification criteria. Demographic, laboratory and clinical information were obtained from the hospital medical records. Statistical analysis was performed using Student's t-test, log-rank test and Fisher's exact test. The study group included 30 AML-M0 patients (male:female=19:11; median age: 60 years). In all, 10 cases of AML-M0 were positive for TdT(+) and 20 cases were negative for TdT(-). Patients with TdT+ AML M0 had higher peripheral blood and bone marrow blast counts compared to patients with TdT- AML-M0 (P=0.01). TdT expression in AML-M0 was not associated with a distinct immunophenotype. Monoclonal IgH and TCR gene rearrangements were frequent, but independent of TdT expression in AML-M0. TdT expression in AML-M0 correlated with trisomy 13 and inversely correlated with aberrations of chromosomes 5 and 17. Among six patients with AML-M0 who received a stem cell transplant, overall survival was significantly longer for the three TdT+ patients compared with the three TdT- patients (P=0.03). In the TdT+AML-M0 subgroup, the three patients with stem cell transplant had better overall survival compared with five patients who did not receive stem cell transplant (P=0.01). We conclude that AML-M0, as currently defined in the 2008 WHO classification, can be divided into two groups based on TdT expression. Although there is a need to assess a greater number of patients, our results suggest that TdT positivity in AML-M0 identifies a subset of patients with a better prognosis after stem cell transplant. PMID- 22936065 TI - Chemokine receptors in gastric MALT lymphoma: loss of CXCR4 and upregulation of CXCR7 is associated with progression to diffuse large B-cell lymphoma. AB - Chemokine receptors have a crucial role in the development and progression of lymphoid neoplasms. To determine the chemokine receptor expression profile in gastric mucosa-associated lymphoid tissue (MALT) lymphoma, we performed an expression analysis of 19 chemokine receptors at mRNA levels by using real-time RT-PCR, as well as of five chemokine receptors--CCR8, CCR9, CXCR4, CXCR6 and CXCR7--by immunohistochemistry on human tissue samples of Helicobacter pylori associated gastritis, gastric MALT lymphoma and gastric extranodal diffuse large B-cell lymphoma originating from MALT lymphoma (transformed MALT lymphoma). Following malignant transformation from H. pylori-associated gastritis to MALT lymphoma, an upregulation of CCR7, CXCR3 and CXCR7, and a loss of CXCR4 were detected. The transformation of gastric MALT lymphomas to gastric extranodal diffuse large B-cell lymphoma was accompanied by upregulation of CCR1, CCR5, CCR7, CCR8, CCR9, CXCR3, CXCR6, CXCR7 and XCR1. Remarkably, CXCR4 expression was exclusively found in nodal marginal B-cell lymphomas and nodal diffuse large B cell lymphomas but not at extranodal manifestation sites, ie, in gastric MALT lymphomas or gastric extranodal diffuse large B-cell lymphomas. Furthermore, the incidence of bone marrow infiltration (16/51 with bone marrow involvement vs 35/51 with bone marrow involvement; Spearman rho=0467 P<0.001) positively correlated with CXCR4 expression. CXCL12, the ligand of CXCR4 and CXCR7, was expressed by epithelial, endothelial and inflammatory cells, MALT lymphoma cells and was most strongly expressed by extranodal diffuse large B-cell lymphoma cells, suggesting at least in part an autocrine signaling pathway. Our data indicate that CXCR4 expression is associated with nodal manifestation and a more advanced stage of lymphomas and hence, might serve as useful clinical prognostic marker. PMID- 22936066 TI - MicroRNAs as prognostic markers in indolent primary cutaneous B-cell lymphoma. AB - Indolent primary cutaneous B-cell lymphoma is a group of malignant lymphomas comprising marginal zone B-cell lymphoma and centrofollicular B-cell lymphoma. Relapse rate of these tumors is close to 40%, and identifying those patients who are likely to progress remains a challenge. The aim of this study was to characterize the microRNA (miRNA) expression profile of a series of primary cutaneous B-cell lymphomas and correlate with histological and clinical findings. We studied a series of 68 patients with primary cutaneous B-cell lymphomas (30 cutaneous marginal-zone B-cell lymphomas and 38 primary cutaneous centrofollicular lymphomas). A set of 11 miRNAs associated with the differentiation stage of B cells was quantified by real-time PCR, using RNA extracted from formalin-fixed, paraffin-embedded tissue diagnostic samples. Relevant clinical variables were retrieved in a subset of 57 patients (28 cutaneous marginal zone B-cell lymphomas and 29 primary cutaneous centrofollicular lymphomas). miR-150 was upregulated in cutaneous marginal zone B cell lymphomas relative to primary cutaneous centrofollicular lymphoma samples (false discovery rate <0.05). miR-155 and miR-150 expression levels were associated with progression-free survival in a univariate Cox regression analysis (P<0.1). After stratification by histological subtype, low-expression levels of miR-155 and miR-150 were both associated with shorter progression-free survival only in primary cutaneous marginal zone B-cell lymphomas cases (log-rank test, P<0.05). In summary, miRNA expression analysis can be used as a tool for diagnosis and outcome prognosis in indolent primary cutaneous B-cell lymphoma. PMID- 22936067 TI - The cancer-testis antigen NY-ESO-1 is highly expressed in myxoid and round cell subset of liposarcomas. AB - Liposarcomas are a heterogenous group of fat-derived sarcomas, and surgery with or without chemoradiation therapy remains the main stay of treatment. NY-ESO-1 is a cancer-testis antigen expressed in various cancers where it can induce both cellular and humoral immunity. Immunotherapy has shown promise in clinical trials involving NY-ESO-1-expressing tumors. Gene expression studies have shown upregulation of the gene for NY-ESO-1, CTAG1B, in myxoid and round cell liposarcomas. Herein, we evaluated the expression of NY-ESO-1 among liposarcoma subtypes by quantitative real-time PCR, western blot analysis, and immunohistochemistry. Frozen tissue for quantitative real-time PCR and western blot analysis was obtained for the following liposarcoma subtypes (n=15): myxoid and round cell (n=8); well-differentiated (n=4), and dedifferentiated (n=3). Formalin-fixed paraffin-embedded blocks were obtained for the following liposarcoma subtypes (n=44): myxoid and round cell (n=18); well-differentiated (n=10); dedifferentiated (n=10); and pleomorphic (n=6). Full sections were stained with monoclonal antibody NY-ESO-1, and staining was assessed for intensity (1-3+), percentage of tumor positivity, and location. In all, 7/8 (88%) and 16/18 (89%) myxoid and round cell expressed CTAG1B and NY-ESO-1 by quantitative real-time PCR and immunohistochemistry, respectively. Western blot correlated with mRNA expression levels. By immunohistochemistry, 94% (15/16) of positive cases stained homogenously with 2-3+ intensity. Also, 3/6 (50%) pleomorphic liposarcomas demonstrated a range of staining: 1+ intensity in 50% of cells; 2+ intensity in 5% of cells; and 3+ intensity in 90% of cells. One case of dedifferentiated liposarcoma showed strong, diffuse staining (3+ intensity in 75% of cells). Our study shows that both CTAG1B mRNA and protein are overexpressed with high frequency in myxoid and round cell liposarcoma, enabling the potential use of targeted immunotherapy in the treatment of this malignancy. PMID- 22936068 TI - Vascular plant species richness along environmental gradients in a cool temperate to sub-alpine mountainous zone in central Japan. AB - In order to clarify how vegetation types change along the environmental gradients in a cool temperate to sub-alpine mountainous zone and the determinant factors that define plant species richness, we established 360 plots (each 4 * 10 m) within which the vegetation type, species richness, elevation, topographic position index (TPI), slope inclination, and ground light index (GLI) of the natural vegetation were surveyed. Mean elevation, TPI, slope inclination, and GLI differed across vegetation types. Tree species richness was negatively correlated with elevation, whereas fern and herb species richness were positively correlated. Tree species richness was greater in the upper slope area than the lower slope area, whereas fern and herb species richness were greater in the lower slope area. Ferns and trees species richness were smaller in the open canopy, whereas herb species richness was greater in the open canopy. Vegetation types were determined firstly by elevation and secondary by topographic configurations, such as topographic position, and slope inclination. Elevation and topography were the most important factors affecting plant richness, but the most influential variables differed among plant life-form groups. Moreover, the species richness responses to these environmental gradients greatly differed among ferns, herbs, and trees. PMID- 22936069 TI - Adaptation to (non)valent task disturbance. AB - The cognitive system adapts to disturbances caused by task-irrelevant information. For example, interference due to irrelevant spatial stimulation (e.g., the spatial Simon effect) typically diminishes right after a spatially incongruent event. These adaptation effects reflect processes that help to overcome the impact of task-irrelevant information. Interference with (or interruption of) task processing can also result from valent (i.e., positive or negative) stimuli, such as in the "affective Simon" task. In the present study, we tested whether the resolution of valence-based task disturbances generalizes to the resolution of other cognitive (spatial) types of interference, and vice versa. Experiments 1 and 2 explored the interplay of adaptation effects triggered by spatial and affective interference. Incongruent spatial information modified the spatial Simon effect but not affective interference effects, whereas incongruent affective information modified affective interference effects to some extent, but not spatial Simon effects. In Experiment 3, we investigated the interplay of adaptation effects triggered by spatial interference and by the interruption of task processing from valent information that did not overlap with the main task ("emotional Stroop" effect). Again we observed domain-specific adaptation for the spatial Simon effect but found no evidence for cross-domain modulations. We assume that the processes used to resolve task disturbance from irrelevant affective and spatial information operate in largely independent manners. PMID- 22936070 TI - Critical comments and questions to the publication "Getgood A, Collins B, Slynarski K, Kurowska E, Parker D, Engebretsen L, MacDonald PB, Litchfield R 2011 Short-term safety and efficacy of a novel high tibial osteotomy system: a case controlled study. Knee Surg Sports Traumatol Arthrosc". PMID- 22936071 TI - Experimental visualization of lithium conduction pathways in garnet-type Li7La3Zr2O12. AB - The evolution of the Li-ion displacements in the 3D interstitial pathways of the cubic garnet-type Li(7)La(3)Zr(2)O(12), cubic Li(7)La(3)Zr(2)O(12), was investigated with high-temperature neutron diffraction (HTND) from RT to 600 degrees C; the maximum-entropy method (MEM) was applied to estimate the Li nuclear-density distribution. Temperature-driven Li displacements were observed; the displacements indicate that the conduction pathways in the garnet framework are restricted to diffusion through the tetrahedral sites of the interstitial space. PMID- 22936072 TI - Effect of taurine on ischemia-reperfusion injury. AB - Taurine is an abundant beta-amino acid that regulates several events that dramatically influence the development of ischemia-reperfusion injury. One of these events is the extrusion of taurine and Na+ from the cell via the taurine/Na+ symport. The loss of Na+ during the ischemia-reperfusion insult limits the amount of available Na+ for Na+/Ca2+ exchange, an important process in the development of Ca2+ overload and the activation of the mitochondrial permeability transition, a key process in ischemia-reperfusion mediated cell death. Taurine also prevents excessive generation of reactive oxygen species by the respiratory chain, an event that also limits the activation of the MPT. Because taurine is an osmoregulator, changes in taurine concentration trigger "osmotic preconditioning," a process that activates an Akt-dependent cytoprotective signaling pathway that inhibits MPT pore formation. These effects of taurine have clinical implications, as experimental evidence reveals potential promise of taurine therapy in preventing cardiac damage during bypass surgery, heart transplantation and myocardial infarction. Moreover, severe loss of taurine from the heart during an ischemia-reperfusion insult may increase the risk of ventricular remodeling and development of heart failure. PMID- 22936073 TI - Selective constraint on human pre-mRNA splicing by protein structural properties. AB - Alternative splicing (AS) is a major mechanism of increasing proteome diversity in complex organisms. Different AS transcript isoforms may be translated into peptide sequences of significantly different lengths and amino acid compositions. One important question, then, is how AS is constrained by protein structural requirements while peptide sequences may be significantly changed in AS events. Here, we address this issue by examining whether the intactness of three dimensional protein structural units (compact units in protein structures, namely protein units [PUs]) tends to be preserved in AS events in human. We show that PUs tend to occur in constitutively spliced exons and to overlap constitutive exon boundaries. Furthermore, when PUs are located at the boundaries between two alternatively spliced exons (ASEs), these neighboring ASEs tend to co-occur in different transcript isoforms. In addition, such PU-spanned ASE pairs tend to have a higher frequency of being included in transcript isoforms. ASE regions that overlap with PUs also have lower nonsynonymous-to-synonymous substitution rate ratios than those that do not overlap with PUs, indicating stronger negative selection pressure in PU-overlapped ASE regions. Of note, we show that PUs have protein domain- and structural orderness-independent effects on messenger RNA (mRNA) splicing. Overall, our results suggest that fine-scale protein structural requirements have significant influences on the splicing patterns of human mRNAs. PMID- 22936074 TI - Codons support the maintenance of intrinsic DNA polymer flexibility over evolutionary timescales. AB - Despite our long familiarity with how the genetic code specifies the amino acid sequence, we still know little about why it is organized in the way that it is. Contrary to the view that the organization of the genetic code is a "frozen accident" of evolution, recent studies have demonstrated that it is highly nonrandom, with implications for both codon assignment and usage. We hypothesize that this inherent nonrandomness may facilitate the coexistence of both sequence and structural information in DNA. Here, we take advantage of a simple metric of intrinsic DNA flexibility to analyze mutational effects on the four phosphate linkages present in any given codon. Application of a simple evolutionary neutral model of substitution to random sequences, translated with alternative genetic codes, reveals that the standard code is highly optimized to favor synonymous substitutions that maximize DNA polymer flexibility, potentially counteracting neutral evolutionary drift toward stiffer DNA caused by spontaneous deamination. Comparison to existing mutational patterns in yeast also demonstrates evidence of strong selective constraint on DNA flexibility, especially at so-called "silent" sites. We also report a fundamental relationship between DNA flexibility, codon usage bias, and several important evolutionary descriptors of comparative genomics (e.g., base composition, transition/transversion ratio, and nonsynonymous vs. synonymous substitution rate). Recent advances in structural genomics have emphasized the role of the DNA polymer's flexibility in both gene function and whole genome folding, thereby implicating possible reasons for codons to facilitate the multiplexing of both genetic and structural information within the same molecular context. PMID- 22936075 TI - Evolution of domain architectures and catalytic functions of enzymes in metabolic systems. AB - Domain architectures and catalytic functions of enzymes constitute the centerpieces of a metabolic network. These types of information are formulated as a two-layered network consisting of domains, proteins, and reactions-a domain protein-reaction (DPR) network. We propose an algorithm to reconstruct the evolutionary history of DPR networks across multiple species and categorize the mechanisms of metabolic systems evolution in terms of network changes. The reconstructed history reveals distinct patterns of evolutionary mechanisms between prokaryotic and eukaryotic networks. Although the evolutionary mechanisms in early ancestors of prokaryotes and eukaryotes are quite similar, more novel and duplicated domain compositions with identical catalytic functions arise along the eukaryotic lineage. In contrast, prokaryotic enzymes become more versatile by catalyzing multiple reactions with similar chemical operations. Moreover, different metabolic pathways are enriched with distinct network evolution mechanisms. For instance, although the pathways of steroid biosynthesis, protein kinases, and glycosaminoglycan biosynthesis all constitute prominent features of animal-specific physiology, their evolution of domain architectures and catalytic functions follows distinct patterns. Steroid biosynthesis is enriched with reaction creations but retains a relatively conserved repertoire of domain compositions and proteins. Protein kinases retain conserved reactions but possess many novel domains and proteins. In contrast, glycosaminoglycan biosynthesis has high rates of reaction/protein creations and domain recruitments. Finally, we elicit and validate two general principles underlying the evolution of DPR networks: 1) duplicated enzyme proteins possess similar catalytic functions and 2) the majority of novel domains arise to catalyze novel reactions. These results shed new lights on the evolution of metabolic systems. PMID- 22936077 TI - Hierarchical nanotubular titanium nitride derived from natural cellulose substance and its electrochemical properties. AB - Hierarchical nanotubular TiN was prepared by magnesiothermic reduction of titania replicas of a cellulose substance (filter paper), which possessed high surface area (31.4 m(2) g(-1)), and was demonstrated to be a promising electrode material due to its electrochemical performances. PMID- 22936076 TI - Adapting the Iconic Pain Assessment Tool Version 2 (IPAT2) for adults and adolescents with arthritis pain through usability testing and refinement of pain quality icons. AB - OBJECTIVES: To evaluate usability and pain iconography of the Iconic Pain Assessment Tool Version 2 (IPAT2), a self-report instrument that combines word descriptors and representative images (icons) to assess pain quality, intensity, and location, among adults and adolescents with arthritis. METHODS: Adults with inflammatory arthritis and adolescents with juvenile idiopathic arthritis partook in a single, semistructured, audio-recorded interview to evaluate: (1) the concreteness (object representativeness) and semantic distance (pain representativeness) of the IPAT2 iconography; (2) participants' current pain; and (3) perceptions and likes/dislikes of the IPAT2. Quantitative data were summarized descriptively and a line-by-line coding analysis identified key concepts from interview transcripts. The criterion for icon acceptability was mean and median ratings >=5.0 for concreteness, semantic distance, and satisfaction for describing arthritis pain. RESULTS: The sample was comprised of 15 adults (87% female, mean 57 y) and 15 adolescents (67% female, mean age 15 y). The IPAT2 was reported to be easy to use and understand, well liked, quick to complete, and perceived as potentially valuable for communicating arthritis pain to health care providers. The median time needed to complete a single pain record, after 5-minute demonstration, was 2.3 minutes and 1.4 minutes for the adults and adolescents, respectively. All pain quality icons met or exceeded the criterion for acceptability. DISCUSSION: All a priori objectives for the IPAT2 were achieved in this sample of rheumatology outpatients. With its unique blend of pain quality descriptors and representative images, the IPAT2 may importantly aid the assessment of pain in adults and adolescents with arthritis. PMID- 22936078 TI - Familial breast cancer: less emotional distress in adult daughters if they provide emotional support to their affected mother. AB - Associations of characteristics of the cancer context (residence with the mother, age at mother's cancer diagnosis or death, recency of mother's diagnosis or death) and the familial cancer experience (engagement in caregiving, emotional support receipt and provision during the mother's illness) with psychological adjustment were studied cross-sectionally in women at high risk for breast cancer (n = 147). Characteristics of the cancer context and engagement in caregiving for the mother's illness were not associated with psychological adjustment. Adult daughters who reported that they had provided emotional support to her mother (p = .023) and who received emotional support themselves during the mother's illness (p = .038) evidenced lower depressive symptoms. Furthermore, time since the mother's cancer diagnosis moderated effects of emotional support provision on intrusive thoughts such that daughters whose mothers were diagnosed with cancer no more than 5 years previously (but not more distally) reported lower intrusive thoughts when they provided emotional support to their mothers as compared to daughters who did not (p = .003). Effects were not moderated by whether the mother had died from cancer. Although relationships of support receipt and support provision with depressive symptoms may also be attributed to trait related behaviour linked to better psychological adjustment, the finding that intrusive thoughts were higher in daughters who were not emotionally supportive during their mother's recent cancer diagnosis is likely to be more context specific. PMID- 22936079 TI - Emergency neurological life support: intracranial hypertension and herniation. AB - Sustained intracranial hypertension and acute brain herniation are "brain codes," signifying catastrophic neurological events that require immediate recognition and treatment to prevent irreversible injury and death. As in cardiac arrest, evidence supports the organized implementation of a stepwise management algorithm. Because there are multiple etiologies and many treatments that can potentially reverse cerebral herniation, intracranial hypertension and herniation was chosen as an Emergency Neurological Life Support (ENLS) protocol. PMID- 22936080 TI - Subependymal nodules and giant cell tumours in tuberous sclerosis complex patients: prevalence on MRI in relation to gene mutation. AB - PURPOSE: The purpose of this study was to estimate the association among the presence of subependymal nodules (SENs), subependymal giant cell tumours (SGCTs) and gene mutation in tuberous sclerosis complex (TSC) patients. METHODS: Clinical records and images of 81 TSC patients were retrospectively reviewed by two neuroradiologists in consensus. All patients were assessed for gene mutations and were categorized as TSC1 or TSC2 mutation carriers, or no-mutations-identified (NMI) patients. They underwent a brain magnetic resonance imaging (MRI) using 0.1 mmol/kg of gadobutrol. Any enhancing SEN >= 1 cm and placed near the foramen of Monro was considered SGCT. Two MRI follow-up exams for each patient with SGCT were evaluated to assess tumour growth using Wilcoxon and chi-squared tests. RESULTS: Of 81 patients, 44 (54%) were TSC2 mutation carriers, 20 (25%) TSC1 and 17 (21%) NMI. Nine (11%) had a unilateral and three (4%) a bilateral SGCT. Fifty of 81 patients (62%) showed at least one SEN. None of the 31 patients without SEN showed SGCTs, whilst 12 (24%) of the 50 patients with at least one SEN showed SGCTs (p = 0.003). The association between the presence of SGCT or SEN and gene mutation was not significant (p = 0.251 and p = 0.187, respectively). At follow up, the median SGCT diameter increased from 14 to 15 mm (p = 0.017), whilst the median SGCT volume increased from 589 to 791 mm(3) (p = 0.006). CONCLUSIONS: TSC patients with SENs are more likely to present with SGCT than those without SENs, in particular for TSC2 mutation carriers. The SGCT growth rate may be missed if based on the diameter instead of on the volume. PMID- 22936081 TI - An unusual case of primary central nervous system germinoma with meningeal dissemination. AB - PURPOSE: Central nervous system germinomas often extend or disseminate into the ventricular and subarachnoid space. We present a case of primary central nervous system germinoma consisting mainly of meningeal dissemination, which is extremely unusual. CASE REPORT: A 16-year-old boy presented with pure germinoma, manifesting as anorexia and headache for 10 days. Radiological examinations revealed a large mass lesion in the posterior fossa and a small mass lesion on the pineal lobule with thickening of the tentorium cerebelli and falx. The patient underwent partial removal of the infratentorial tumor via open surgery. Intraoperative findings indicated extension of the dural and supracerebellar mass lesions into the epiarachnoid space. Three chemotherapy courses comprising ifosfamide, etoposide, and cisplatin were administered after the surgery. Craniospinal irradiation was administered subsequently. The adjuvant therapy had a complete response. CONCLUSION: Central nervous system germinoma cells may have similar compatibility to meningeal components as they do to cerebrospinal fluid or the ventricular system. If there is a possibility of the tumor extending into the subdural space during surgical intervention or other events, a range of postdiagnostic irradiation should be considered to cover a wider range. PMID- 22936082 TI - Quantitative immunohistochemical analysis of duodenal ghrelin cells after sleeve gastrectomy in Wistar rats. AB - PURPOSE: Sleeve gastrectomy (SG) removes substantial part of the gastric mucosa, which produces ghrelin. This reduction is expected to force other organs, such as the duodenum, to compensate by increasing the number of ghrelin-producing cells. The purpose of this study was to evaluate whether this response occurs. METHODS: Twelve adult male, Wistar rats underwent SG and were reoperated 30 or 60 days after the initial surgery. During the second surgery, a segment of the duodenum was resected to count ghrelin cells using immunohistochemistry. In six animals, SG was not performed, and the duodenal segment served as a control for ghrelin cell counts. The ghrelin cell index (GCI), which is the number of ghrelin cells divided by the number of villi in each segment, was measured and used in statistical analysis by one-way analysis of variance (ANOVA). RESULTS: There were increases in the absolute numbers of cells 30 and 60 days after SG, but statistical analysis by ANOVA showed no significant difference between the groups. CONCLUSION: A compensatory increase in the number of duodenal immunopositive ghrelin cells did not occur as a response to sleeve gastrectomy. PMID- 22936083 TI - Do opioid receptors play a role in the pathogenesis of the inflammatory response in acute pancreatitis? AB - PURPOSE: To investigate the effect of the opioid blocker naltrexone in the inflammatory response in acute pancreatitis (AP). METHODS: Acute pancreatitis was induced in anesthetized male Wistar rats by retrograde injection of 2.5% sodium taurocholate diluted in 0.5ml saline into the main pancreatic duct. Animals were randomized to the following experimental groups: Control Group (n=9): animals received an intraperitoneal injection of saline solution (0.5ml), 15 minutes before the induction of AP. Naltrexone Group (n=9): animals received an intraperitoneal injection of naltrexone 0.5ml (15 mg/kg), 15 minutes before induction of AP. Peritoneal levels of TNF-alpha and serum levels of IL-6 and amylase were determined The volume of the ascitic fluid was also evaluated. Myeloperoxidase (MPO) activities were analyzed in homogenates of pulmonary tissue. RESULTS: There were no significant differences in the ascitic fluid volume, nor in TNF-a and IL-6 levels in the naltrexone group compared to controls. Treatment with naltrexone did not affect the lung MPO activity compared to control group. CONCLUSIONS: The opioid receptors don't play an important role in the pathogenesis of the inflammatory response in acute pancreatitis. If opioids affect leukocytes inflammatory signaling, there are no major implications in the pathogenesis of acute pancreatitis. PMID- 22936084 TI - Anti toxic effect of broccoli extract on stannous dichloride toxicity. AB - PURPOSE: Since Technetium-99m ((99m)Tc) has favorable physical and chemical characteristics, it is widely used radioisotope in Nuclear Medicine. However, stannous dichloride (SnCl(2)) has been widely used as a reducing agent in labeling procedure of pharmaceutical with radionuclide, it has been realized that SnCl(2) have genotoxic and cytotoxic effects on biological systems. In previous studies, it has been shown that some herbal extract can reduce genotoxic and cytotoxic effects of SnCl(2). In the present study, it is aimed to evaluate the effect of the broccoli extract on the survival of E. coli ATCC 25922 strain against to toxic effects of SnCl(2). METHODS: Broccoli was extracted with methanol extraction. HPLC and TLC analysis of broccoli extract were performed. Then antitoxicity and dose response assays were performed on bacterial strain. RESULTS: The broccoli extract had dose dependent protective effect against SnCl(2) toxic effect on E. coli. CONCLUSIONS: The consumption of broccoli may alter the stannous dichloride toxicity. Broccoli extract may use as a new protective strategies against the toxic effect of SnCl(2) on patients who were taken (99m)Tc radiopharmaceuticals. PMID- 22936085 TI - Protective effect of N-acetylcysteine on kidney as a remote organ after skeletal muscle ischemia-reperfusion. AB - PURPOSE: To investigate whether N-acetylcysteine has a protective effect against renal injury as a remote organ after skeletal muscle ischemia-reperfusion in rats. METHODS: Twenty Wistar male rats were divided randomly into two experimental groups: group ischemia-reperfusion (group I) and group ischemia reperfusion + N-acetylcysteine (group II). After ketamine and xylazine anesthesia, femoral artery was exposed. All animals were undergone 2h of ischemia by occlusion femoral artery and 24h of reperfusion. Rats that were treated with N acetylcysteine given IV at a dose of 150 mg/kg(-1), immediately before reperfusion. After 24h of reperfusion, the blood samples were collected and submitted for evaluation of plasmatic urea, creatinine values and then rats were euthanized and left kidney harvested for histopathological analysis under light microscopy. RESULTS: The urea (35+/-7.84 mg.dL(-1)), creatinine (1.46+/-0.47 mg.dL(-1)) values were significantly lower in group II (P=0.000). Renal histopathologic study in group I showed extensive distal and proximal tubular cells necrosis and sloughing of epithelial cells into the tubular lumen, cast formation in tubule and glomerul, glomerul fibrosis and hemorrhage. Histopathologically, there was a significant difference (p=0.037) between two groups. CONCLUSION: The N-acetylcysteine was able to decrease renal injury induced by skeletal muscle ischemia reperfusion in rats. PMID- 22936086 TI - L-arginine in the ischemic phase protects against liver ischemia-reperfusion injury. AB - PURPOSE: To investigate the effects of intravenous L-arginine (LG) infusion on liver morphology, function and proinflammatory response of cytokines during the early phase of ischemia-reperfusion injury (IRI). METHODS: Thirty rabbits were subjected to 60 minutes of hepatic ischemia and 120 minutes of reperfusion. An intravenous injection of saline or L-arginine was administered five minutes before the ischemia and five minutes before initiating the reperfusion and at the 55th and 115th minutes after the ischemia. Samples were collected for histological analysis of the liver and measurements of the serum AST, ALT and LDH and the cytokines IL-6 and TNF-alpha. RESULTS: It was observed a significant reduction of sinusoidal congestion, cytoplasmic vacuolization, infiltration of polymorphonuclear leukocyte, nuclear pyknosis, necrosis and steatosis in liver tissue, as well as AST, ALT and LDH after injection of LG in the ischemia (p <0.001). Lower levels of IL-6 and TNF-alpha were associated with LG infusion during ischemia. Higher levels these proteins were observed in animals receiving LG during reperfusion. CONCLUSION: L-arginine protects the liver against ischemia/reperfusion injury, mainly when is administered during the ischemic phase. PMID- 22936087 TI - Use of 2-octyl cyanoacrylate adhesive in rat liver induced lesion. AB - PURPOSE: To evaluate the healing process of rat traumatic liver lesion corrected with the use of 2-octyl cyanoacrylate adhesive, compared to the use of biologically absorbable chromed catgut thread suture. METHODS: Thirty mail adult rats were divided into two groups (15 per group) according to the used method for liver lesion correction as follows: adhesive group (AG), and catgut group (CG); each group being divided into three subsets of five animals (7th, 14th, and 21st day), respectively, according to post-surgery evaluation. All animals were submitted to homogeneous lesion applying synthetic bonding to AG and using chromed catgut suture to CG for lesion correction. Macroscopic and microscopic parameters of healing processes were evaluated. RESULTS: Both groups of animals showed excellent abdominal wall healing, with no evidence of infection, and no abdominal cavity peritonitis or abscess. The presence of adherence was observed in both groups with no statistically significant difference. As to macroscopic evaluation, there was statistically significant difference with respect to specific factors of clinical inflammation (ischemic inflammation and giant celular inflammatory reaction) between animals evaluated on the 10th day (ischemic necrosis and giant cellular inflammatory reaction) among animals evaluated on the 14th day (A14 versus C14). CONCLUSION: Applying 2-octyl cyanoacrylate adhesive for correcting rat liver lesion does not change healing process when compared to the use of chromed catgut stitch. PMID- 22936088 TI - Evaluation of peritoneal reinfection after fecal peritonitis. AB - PURPOSE: To investigate the role of a previous abdominal infection on peritonitis. METHODS: Twenty-seven adult female Wistar rats were submitted to fecal peritonitis by an intraperitoneal injection of a solution of rat feces. The animals were divided into three groups (n = 9 each): Group 1 - control - intraperitoneal injection of an amount of fecal solution known to be lethal (10 ml/kg), Group 2 - reinfection - intraperitoneal injection of an amount of fecal solution known not to be lethal (2 ml/kg) followed by an injection of fecal solution (10 ml/kg) 30 days later, Group 3 - late reinfection - intraperitoneal injection of 2 ml/kg feces followed by an injection of 10 ml/kg four months later. RESULTS: All animals in Group 1 died within seven days after injection of the fecal solution. In contrast, in the pre-infected Group 2 only one animal died 24 hours after injection of the fecal solution (10 ml/kg). In Group 3, eight of the nine animals in each subgroup died over a period of seven days. The difference in survival time between groups 1, 2 and 3 was for p = 0.0042 (logrank test). CONCLUSIONS: Milder peritoneal sepsis due to fecal infection raises the organic resistance to a new more intense fecal contamination occuring after a short period of time. However, this protection did not persist over a prolonged period of time. PMID- 22936089 TI - Growth inhibition of Walker carcinosarcoma 256 with alcoholic extract of green tea leaves (Camellia sinensis). AB - PURPOSE: To evaluate the antitumor activity of alcoholic extracts of green tea (Camella sinensis). METHODS: Four groups of six Wistar rats were inoculated intramuscularly with 10(6) Walker tumor cells/mL. During 10 days, the animals received by gavage either 0.9% saline solution (Group I; negative control), solution containing 20 mg/Kg of tamoxifen (Group II; positive control), solution containing 0.07 g/Kg alcoholic extract of C. sinensis (Group III), or solution containing 0.14 g/Kg alcoholic extract of C. sinensis (Group IV). Following euthanasia on the tenth day, the tumor, liver, kidneys and spleen were excised and weighed, and tumor volume and tumor growth inhibition were quantified. RESULTS: The average weight of the animals was greater in Group IV than in Group II (p=0.0107). Tumor weight was smaller in Group IV than in Group I (p=0.0062), but did not differ from Group II. Tumor volume was smaller in Groups II and IV than in Group I (p=0.0131). Tumor growth inhibition was observed in Groups II (44.67% +/- 32.47), III (16.83% +/- 53.02) and IV (66.4% +/- 25.82) (p>0.05). The groups did not differ with regard to the weight of the excised organs. CONCLUSION: Alcoholic extracts of green tea have antitumor activity. PMID- 22936090 TI - Comparison of effects of unfractionated heparin and low molecular weight heparin on skin wound healing of rats. AB - PURPOSE: To compare the effects of unfractionated heparin (UH) and a low molecular weight heparin (LMWH) on skin wound healing of rats. METHODS: Forty eight male Sprague-Dawley rats underwent 8mm full thickness dorsal skin wounds and were randomly assigned to three equal groups. In experimental group A, heparin sodium was injected at a concentration of 1000U/kg. In experimental group B, enoxaparin was injected at a concentration of 1mg/kg. Physiologic saline (0.5ml) was administered to the control group. Injections were made subcutaneously, once daily, for seven days. At 7th and 10th days tissue samples were taken from all rats. Histologic examination of these tissues was made under light microscope and scored. RESULTS: Histological examination showed a significant difference between the 7th and 10th day groups in wound healing. It was observed that wound healing of LMWH injected group is better. This difference is statistically significant at 10th day. CONCLUSIONS: Daily administration of single doses of unfractionated heparin and a low molecular weight heparin improves wound healing positively. Low molecular weight heparin induces wound healing more than unfractionated heparin. PMID- 22936091 TI - Expression of RANTES, eotaxin-2, ICAM-1, LFA-1 and CCR-3 in chronic rhinosinusitis patients with nasal polyposis. AB - PURPOSE: To compare gene expression of the chemokines RANTES and eotaxin-2, its receptor, CCR-3, adhesion molecule ICAM-1 and its receptor LFA-1 in eosinophilic polyps and in control normal nasal mucosa. METHODS: Gene expression was quantified by Real Time PCR in polyps (n=35) and in healthy nasal mucosa (n=15). RESULTS: Eosinophilic polyps showed a higher expression of eotaxin-2 and RANTES, but not of CCR-3, ICAM-1 or LFA-1 compared to control nasal mucosa. CONCLUSION: Eosinophilic polyps present greater expression of eotaxin-2 and RANTES, but not of CCR-3, ICAM-1 or LFA-1 compared to control nasal mucosa. PMID- 22936092 TI - Evaluation of anatomical and functional changes esophageal stump of patients with advanced megaesophagus submitted to subtotal laparoscopic esophagectomy. AB - PURPOSE: Evaluate anatomical and functional changes of the esophageal stump and gastric fundus of patients with advanced megaesophagus, submitted to laparoscopic subtotal esophagectomy. METHODS: Twenty patients with advanced megaesophagus, previously submitted to a videolaparoscopic subtotal esophagectomy, were evaluated. Were conducted: radiological evaluation of the stump esophagus with transposed stomach, electromanometric, endoscopic examination and histopathology of the esophageal stump and gastric fundus, without making gastric tube or pyloroplasty. RESULTS: It was observed that the average height and pressure of the anastomosis, in the electromanometric evaluation, were 23.45cm (+/-1.84cm) and 7.55mmHg (+/-5.65mmHg). In patients with megaesophagus III, the pressure of the anastomosis was 10.91mmHg (+/-6.33mmHg), and pressure from the UES, 31.89mmHg (+/-14.64mm Hg), were significantly higher than those in grade IV. The pathological evaluation detected mild esophagitis in 35% of patients, moderate in 20% and acanthosis glicogenica in 45%. The examination of the gastric fundus showed that 50% of patients were infected with Helicobacter pylori. Chronic gastritis occurred in 95% of the patients. CONCLUSIONS: The laparoscopic esophagectomy shown to be effective in the treatment of advanced achalasia. The cervical level anastomosis protects the esophageal stump from the aggression resulted from gastric reflux after the esophagectomy. PMID- 22936093 TI - Progress in animal experimentation ethics: a case study from a Brazilian medical school and from the international medical literature. AB - PURPOSE: This study describes in Brazil and in the global biomedical community the time course of the development of animal research welfare guidelines. METHODS: The database of the Ethics Committee of the Faculty of Medicine of Ribeirao Preto (EC/FMRP-USP), Brazil, was surveyed since its inception in 2002 as the regulations became more stringent to provide better protection of animal research welfare at this institution. Medline database was evaluated to identify the number of publications in the period between 1968 and 2008 that used research animals and were in compliance with established ethics guidelines. RESULTS: The EC/FMRP-USP evaluated 979 projects up until 2009. Most of the applications came from Department of Physiology and the most frequently requested species was the rat. In 2004, national research funding agencies started to request prior approval from institutional review ethics committees prior to application review and this requirement became federal law in Brazil in 2008. The analysis of international publications revealed a relative reduction in studies involving research animals (18% in 1968 to 7.5% in 2008). CONCLUSIONS: The present work showed that in the last four decades major changes occurred in the guidelines dictating use of research animals occurred and they are being adopted by developing countries. Moreover, animal welfare concern in the scientific community preceded the introduction of journal guidelines for this purpose. Furthermore, in Brazil it was anticipated that laws were needed to protect animal research welfare from being not upheld. PMID- 22936094 TI - Feasibility of intravenous flat panel detector CT angiography for intracranial arterial stenosis. AB - BACKGROUND AND PURPOSE: I.v. FDCT angiography is an emerging technology for the detection of intracranial vascular disease. This study was conducted to determine the feasibility of i.v. FDCT in estimating major atherosclerotic intracranial arterial stenosis with DSA as the reference. MATERIALS AND METHODS: DSA and i.v. FDCT were performed simultaneously in patients with transient ischemic attack or acute cerebral infarction. The degree and length of stenosis were measured. The stenotic vessels were categorized into 4 groups by the grade of stenosis: normal (<30%), mild (30%-49%), moderate (50%-69%), or severe (>70%). The vessels of the normal group were excluded from analysis to reduce spectrum bias. Measurement of vessels was recorded by using an electric ruler by a qualified endovascular neurosurgeon and a neuroradiologist. RESULTS: Eight hundred forty-two vessel segments in 69 patients were calculated. Mild (n = 56), moderate (n = 47) and severe stenosis (n = 46) groups were analyzed. I.v. FDCT had a sensitivity of 97.6%, specificity of 96.9%, and negative predictive value of 96.9% for detecting >=50% stenosis and respective values of 91.9%, 98.2%, and 97.4% for depicting >=70% stenosis. The difference of stenotic length between the 2 tests was not significant as an increase in the severity of stenosis (Spearman rank correlation test; r = -0.12, P = .13). CONCLUSIONS: I.v. FDCT can be a feasible alternative as a noninvasive method for evaluating stenosis of the major intracranial arteries. PMID- 22936095 TI - Resting-state fMRI: a review of methods and clinical applications. AB - SUMMARY: Resting-state fMRI measures spontaneous low-frequency fluctuations in the BOLD signal to investigate the functional architecture of the brain. Application of this technique has allowed the identification of various RSNs, or spatially distinct areas of the brain that demonstrate synchronous BOLD fluctuations at rest. Various methods exist for analyzing resting-state data, including seed-based approaches, independent component analysis, graph methods, clustering algorithms, neural networks, and pattern classifiers. Clinical applications of resting-state fMRI are at an early stage of development. However, its use in presurgical planning for patients with brain tumor and epilepsy demonstrates early promise, and the technique may have a future role in providing diagnostic and prognostic information for neurologic and psychiatric diseases. PMID- 22936096 TI - Combined diffusion and perfusion MR imaging as biomarkers of prognosis in immunocompetent patients with primary central nervous system lymphoma. AB - BACKGROUND AND PURPOSE: ADC derived from DWI has been shown to correlate with PFS and OS in immunocompetent patients with PCNSL. The purpose of our study was to confirm the validity of ADC measurements as a prognostic biomarker and to determine whether rCBV measurements derived from DSC perfusion MR imaging provide prognostic information. MATERIALS AND METHODS: Pretherapy baseline DWI and DSC perfusion MR imaging in 25 patients with PCNSL was analyzed before methotrexate based induction chemotherapy. Contrast-enhancing tumor was segmented and coregistered with ADC and rCBV maps, and mean and minimum values were measured. Patients were separated into high or low ADC groups on the basis of previously published threshold values of ADC(min) < 384 * 10(-6) mm(2)/s. High and low rCBV groups were defined on the basis of receiver operating curve analysis. High and low ADC and rCBV groups were analyzed independently and in combination. Multivariate Cox survival analysis was performed. RESULTS: Patients with ADC(min) values < 384 * 10(-6) mm(2)/s or rCBV(mean) values < 1.43 had worse PFS and OS. The patient cohort with combined low ADC(min)-low rCBV(mean) had the worst prognosis. No other variables besides ADC and rCBV significantly affected survival. CONCLUSIONS: Our study reinforces the validity of ADC values as a prognostic biomarker and provides the first evidence of low tumor rCBV as a novel risk factor for adverse prognosis in immunocompetent patients with PCNSL. PMID- 22936097 TI - Spinal arteriovenous metameric syndrome: angioarchitecture and their prognosis. PMID- 22936098 TI - When dealing with unruptured aneurysms, what do low morbidity and mortality mean? PMID- 22936100 TI - Negative priming for target selection with saccadic eye movements. AB - We conducted a series of experiments to determine whether negative priming is used in the process of target selection for a saccadic eye movement. The key questions addressed the circumstances in which the negative priming of an object takes place, and the distinction between spatial and object-based effects. Experiment 1 revealed that after fixating a target (cricket ball) amongst an array of semantically related distracters, saccadic eye movements in a subsequent display were faster to the target than to the distracters or new objects, irrespective of location. The main finding was that of the facilitation of a recent target, not the inhibition of a recent distracter or location. Experiment 2 replicated this finding by using silhouettes of objects for selection that is based on feature shape. Error rates were associated with distracters with high target-shape similarity; therefore, Experiment 3 presented silhouettes of animals using distracters with low target-shape similarity. The pattern of results was similar to that of Experiment 2, with clear evidence of target facilitation rather than the inhibition of distracters. Experiment 4 and 5 introduced a distracter together with the target into the probe display, to generate a level of competitive selection in the probe condition. In these circumstances, clear evidence of spatial inhibition at the location of the previous distracters emerged. We discuss the implications for our understanding of selective attention and consider why it is essential to supplement response time data with the analysis of eye movement behaviour in spatial negative priming paradigms. PMID- 22936099 TI - Effects of magnitude and magnitude predictability of postural perturbations on preparatory cortical activity in older adults with and without Parkinson's disease. AB - The goal of this study was to identify whether impaired cortical preparation may relate to impaired scaling of postural responses of people with Parkinson's disease (PD). We hypothesized that impaired scaling of postural responses in participants with PD would be associated with impaired set-dependent cortical activity in preparation for perturbations of predictable magnitudes. Participants performed postural responses to backward surface translations. We examined the effects of perturbation magnitude (predictable small vs. predictable large) and predictability of magnitude (predictable vs. unpredictable-in-magnitude) on postural responses (center-of-pressure (CoP) displacements) and on preparatory electroencephalographic (EEG) measures of contingent negative variation (CNV) and alpha and beta event-related desynchronization (ERD). Our results showed that unpredictability of perturbation magnitude, but not the magnitude of the perturbation itself, was associated with increased CNV amplitude at the CZ electrode in both groups. While control participants scaled their postural responses to the predicted magnitude of the perturbation, their condition-related changes in CoP displacements were not correlated with condition-related changes in EEG preparatory activity (CNV or ERD). In contrast, participants with PD did not scale their postural responses to the predicted magnitude of the perturbation, but they did demonstrate greater beta ERD in the condition of predictably small-magnitude perturbations and greater beta ERD than the control participants at the CZ electrode. In addition, increased beta ERD in PD was associated with decreased adaptability of postural responses, suggesting that preparatory cortical activity may have a more direct influence on postural response scaling for people with PD than for control participants. PMID- 22936101 TI - Colorimetric photonic hydrogel aptasensor for the screening of heavy metal ions. AB - We have developed a robust method for the visual detection of heavy metal ions (such as Hg(2+) and Pb(2+)) by using aptamer-functionalized colloidal photonic crystal hydrogel (CPCH) films. The CPCHs were derived from a colloidal crystal array of monodisperse silica nanoparticles, which were polymerized within the polyacrylamide hydrogel. The heavy metal ion-responsive aptamers were then cross linked in the hydrogel network. During detection, the specific binding of heavy metal ions and cross-linked single-stranded aptamers in the hydrogel network caused the hydrogel to shrink, which was detected as a corresponding blue shift in the Bragg diffraction peak position of the CPCHs. The shift value could be used to estimate, quantitatively, the amount of the target ion. It was demonstrated that our CPCH aptasensor could screen a wide concentration range of heavy metal ions with high selectivity and reversibility. In addition, these aptasensors could be rehydrated from dried gels for storage and aptamer protection. It is anticipated that our technology may also be used in the screening of a broad range of metal ions in food, drugs and the environment. PMID- 22936102 TI - Cryptococcus laurentii biofilms: structure, development and antifungal drug resistance. AB - A great number of fungal infections are related to biofilm formation on inert or biological surfaces, which are recalcitrant to most treatments and cause human mortality. Cryptococcus laurentii has been diagnosed as the aetiological pathogen able to cause human infections mainly in immunosuppressed patients and the spectrum of clinical manifestations ranges from skin lesions to fungaemia. The effect of temperature, pH and surface preconditioning on C. laurentii biofilm formation was determined by 2, 3-bis (2-methoxy-4-nitro-5-sulfophenyl)-5 [(phenylamino) carbonyl]-2H-tetrazolium hydroxide (XTT) reduction assay. Scanning electron microscopic (SEM) analysis of C. laurentii biofilms demonstrated surface topographies of profuse growth and dense colonization with extensive polymeric substances around the cells. In this study, we determined the activity of amphotericin B, itraconazole and fluconazole against C. laurentii free-living cells and biofilms. The activity of antifungals tested was greater against free living cells, but sessile cells fell into the resistant range for these antifungal agents. Extracellular polymeric substances (EPS), comprising the matrix of C. laurentii biofilms, were isolated by ultrasonication. Fourier transform infrared spectroscopy (FT-IR) was performed with ethanol-precipitated and dried samples. Also, the multielement analysis of the EPS was performed by inductively coupled plasma optical emission spectroscopy (ICP-OES). PMID- 22936103 TI - Prevalence of dermatomycosis in a Brazilian tertiary care hospital. AB - A total of 233 specimens obtained from suspected cases of dermatomycosis from 189 patients were examined for causative fungi from December 2009 to May 2010 in a tertiary care hospital in the city of Belo Horizonte, state of Minas Gerais, southeastern Brazil. Yeast and fungal isolates obtained from specimens were regarded as conclusive diagnosis of mycoses in 82 cases (35.19 %), with the exception of two patients with pityriasis versicolor (2.4 %), in which the diagnosis was made only by direct examination plus clinical diagnostics of individuals. Forty-four subjects (23.28 %) were infected in more than one anatomical site. There was a higher occurrence on female patients (146, 77.2 %) than male (43, 22.8 %). Most of the infected patients were aged between 41 and 70 years (68.29 %). There were no statistically significant differences between occurrence of fungal infection and gender, presence of secondary disease and contact with animals. The largest number of examined material occurred in samples from toenails, which resulted in 50 % of positive cultures. Candida species were the most frequent group causing dermatomycosis in many anatomical sites, mainly in toenails and fingernails. Candida parapsilosis was the most representative (40.24 %) among all agents causing dermatomycosis of toenails and fingernails, followed by Candida tropicalis (20.73 %) and Trichophyton rubrum (10.98 %). Among the dermatophytes, Trichophyton genus represented over 80 % of the isolates, with T. rubrum representing 64.29 %, T. interdigitale (T. mentagrophytes) (21.43 %) and Microsporum gypseum (14.29 %). PMID- 22936104 TI - Enhanced stability and activity of temozolomide in primary glioblastoma multiforme cells with cucurbit[n]uril. AB - Temozolomide (TMZ) is the primary chemotherapeutic agent for treatment of glioblastoma multiforme (GBM) yet it has a fast rate of degradation under physiological conditions to the 'active' MTIC, which has poor penetration of the blood-brain barrier and cellular absorption. Herein we have demonstrated binding of TMZ within the cavity of nano-container cucurbit[7]uril, resulting in a decreased rate of drug degradation. Prolonging the lifetime of the TMZ under physiological conditions through encapsulation dramatically improved the drug's activity against primary GBM cell lines as more TMZ could be absorbed by the cells before degradation. This work can potentially lead to increases in the drug's propensity for crossing the blood-brain barrier and absorption into the GBM cells, thereby increasing the efficacy of this chemotherapy. PMID- 22936105 TI - SPaM: a combined self-paced reading and masked-priming paradigm. AB - In this article, we validate an experimental paradigm, SPaM, that we first described elsewhere (Luke & Christianson, Memory & Cognition 40:628-641, 2012). SPaM is a synthesis of self-paced reading and masked priming. The primary purpose of SPaM is to permit the study of sentence context effects on early word recognition. In the experiment reported here, we show that SPaM successfully reproduces results from both the self-paced reading and masked-priming literatures. We also outline the advantages and potential uses of this paradigm. For users of E-Prime, the experimental program can be downloaded from our lab website, http://epl.beckman.illinois.edu/. PMID- 22936106 TI - Sensory experience ratings for over 5,000 mono- and disyllabic words. AB - Sensory experience ratings (SERs) reflect the extent to which a word evokes a sensory and/or perceptual experience in the mind of the reader. Juhasz, Yap, Dicke, Taylor, and Gullick (Quarterly Journal of Experimental Psychology 64:1683 1691, 2011) demonstrated that SERs predict a significant amount of variance in lexical-decision response times in two megastudies of lexical processing when a large number of established psycholinguistic variables are controlled for. Here we provide the SERs for the 2,857 monosyllabic words used in the Juhasz et al. study, as well as newly collected ratings on 3,000 disyllabic words. New analyses with the combined set of words confirmed that SERs predict a reliable amount of variance in the lexical-decision response times and naming times from the English Lexicon Project (Balota, Yap, Cortese, Hutchison, Kessler, Loftus, & Treiman, Behavior Research Methods 39:445-459, 2007) when a large number of surface, lexical, and semantic variables are statistically controlled for. The results suggest that the relative availability of sensory/perceptual information associated with a word contributes to lexical-semantic processing. PMID- 22936107 TI - Motion-induced blindness measured objectively. AB - During central fixation, a moving pattern of nontargets induces repeated temporary blindness to even salient peripheral targets: motion-induced blindness (MIB). Hitherto, behavioral measures of MIB have relied on subjective judgments. Here, we offer an objective alternative that builds on earlier findings regarding the effects of MIB on the detectability of physical target offsets. We propose a small modification of regular MIB displays: Following a variable duration (lead time), one of the targets is physically removed. Subjects are to respond immediately afterward. We hypothesize that illusory target offsets, caused by MIB, are mistaken for physical target offsets and that errors should thus increase with lead time. Indeed, for both nonsalient and salient targets, we found that detection accuracy for physical target offsets dramatically decreased with lead time. We conclude that target offset detection accuracy is a valid objective measure of MIB. With our method, effects of guessing are minimal, and the fitting of psychometric functions is straightforward. In principle, a staircase extension--for more efficient data collection--is also possible. PMID- 22936108 TI - Characteristics of federally licensed firearms retailers and retail establishments in the United States: initial findings from the firearms licensee survey. AB - Firearms have widely supported legitimate purposes but are also frequently used in violent crimes. Owners and senior executives of federally licensed firearms dealers and pawnbrokers are a potentially valuable source of information on retail commerce in firearms, links between legal and illegal commerce, and policies designed to prevent the firearms they sell from being used in crimes. To our knowledge, there has been no prior effort to gather such information. In 2011, we conducted the Firearms Licensee Survey on a probability sample of 1,601 licensed dealers and pawnbrokers in the United States believed to sell 50 or more firearms per year. This article presents details of the design and execution of the survey and describes the characteristics of the respondents and their business establishments. The survey was conducted by mail, using methods developed by Dillman and others. Our response rate was 36.9 % (591 respondents), similar to that for other establishment surveys using similar methods. Respondents had a median age of 54; 89 % were male, 97.6 % were White, and 98.1 % were non-Hispanic. Those who held licenses under their own names had been licensed for a median of 18 years. A large majority of 96.3 % agreed that "private ownership of guns is essential for a free society"; just over half (54.9 %) believed that "it is too easy for criminals to get guns in this country." A match between the job and a personal interest in the shooting sports was the highest-ranking reason for working as a firearms retailer; the highest-ranking concerns were that "there are too many 'gun control' regulations" and that "the government might confiscate my guns." Most respondents (64.3 %) were gun dealers, with significant variation by region. Residential dealers accounted for 25.6 % of all dealers in the Midwest. Median annual sales volume was 200 firearms for both dealers and pawnbrokers. Dealers appeared more likely than pawnbrokers to specialize; they were more likely to rank in the highest or lowest quartile on sales of handguns, inexpensive handguns, and tactical rifles. Sales of inexpensive handguns and sales to women were more common among pawnbrokers. Internet sales were reported by 28.3 % of respondents and sales at gun shows by 14.3 %. A median of 1 % of sales were denied after purchasers failed background checks; firearm trace requests equaled <1 % of annual sales. Trace frequency was directly associated with the percentage of firearm sales involving handguns, inexpensive handguns, and sales to women. Frequency of denied sales was strongly and directly associated with frequency of trace requests (p < 0.0001). These results are based on self-report but are consistent with those from studies using objective data. PMID- 22936109 TI - Molecular characterization of novel trispecific ErbB-cMet-IGF1R antibodies and their antigen-binding properties. AB - Therapeutic antibodies are well established drugs in diverse medical indications. Their success invigorates research on multi-specific antibodies in order to enhance drug efficacy by co-targeting of receptors and addressing key questions of emerging resistance mechanisms. Despite challenges in production, multi specific antibodies are potentially more potent biologics for cancer therapy. However, so far only bispecific antibody formats have entered clinical phase testing. For future design of antibodies allowing even more targeting specificities, an understanding of the antigen-binding properties of such molecules is crucial. To this end, we have generated different IgG-like TriMAbs (trispecific, trivalent and tetravalent antibodies) directed against prominent cell surface antigens often deregulated in tumor biology. A combination of surface plasmon resonance and isothermal titration calorimetry techniques enables quantitative assessment of the antigen-binding properties of TriMAbs. We demonstrate that the kinetic profiles for the individual antigens are similar to the parental antibodies and all antigens can be bound simultaneously even in the presence of FcgammaRIIIa. Furthermore, cooperative binding of TriMAbs to their antigens was demonstrated. All antibodies are fully functional and inhibit receptor phosphorylation and cellular growth. TriMAbs are therefore ideal candidates for future applications in various therapeutic areas. PMID- 22936110 TI - Novel pyranopyrazoles: synthesis and theoretical studies. AB - A series of pyranopyrazoles, namely, 7-(2-aminoethyl)-3,4-dimethyl-1-phenyl-1H pyrazolo[3,4-b]pyridin-6(7H)-one (2), (Z)-3,4-dimethyl-1-(4-((4 nitrobenzylidene)amino)phenyl)pyrano[2,3-c]pyrazol-6(1H)-one (5), 1-(4-(3,4 dimethyl-6-oxopyrano[2,3-c]pyrazol-1(6H)-yl)phenyl)-3-(naphthalen-1-yl)urea (6), (Z)-ethyl 4-((3,4-dimethyl-6-oxo-1,6-dihydropyrano[2,3-c]pyrazol-5 yl)diazenyl)benzoate (8) and 3,4-dimethyl-N-(naphthalen-1-yl)-6-oxopyrano[2,3 c]pyrazole-1(6H)-carboxamide (9) were synthesized and characterized by means of their UV-VIS, FT-IR, 1H-NMR and 13C-NMR spectral data. Density Functional Theory calculations of the synthesized pyranopyrazoles were performed using molecular structures with optimized geometries. Molecular orbital calculations have provided detail description of the orbitals, including spatial characteristics, nodal patterns, and the contributions of individual atoms. PMID- 22936111 TI - A comparison of fruit chemical characteristics of two wild grown Rubus species from different locations of Croatia. AB - The main focus of our study was to investigate differences in nutritional (dry matter, soluble solids content, total acidity and pH value) and bioactive values (ascorbic acid, total anthocyanins, total phenols, and non-flavonoids content) of wild grown raspberry (Rubus idaeus) and blackberry (Rubus discolor) genotypes harvested from native populations in Croatia. The average total acidity ranged from 0.93 to 1.72% in R. discolor and 1.57 to 1.91% in R. idaeus. Ascorbic acid was found between 22.34 mg and 45.00 mg 100 g-1 in R. idaeus, while it was between 30.64 mg and 33.09 mg 100 g-1 in R. discolor genotypes. A great variability in total anthocyanins was detected in roatian wild blackberry and raspberry genotypes, ranging from 2,226 to 2,367 mg kg-1 for blackberries and 279 to 582 mg kg-1 for raspberries, indicating wild blackberries are particularly rich in anthocyanins. On the basis of these results, it can be concluded that investigated wild growing fruit species have a great potential in nutritive research, as well as in biodiversity research. It is necessary to carry out further investigation and evaluation of wild growing fruit species to utilize them in the most appropriate way, as well as conservation of interesting accessions in the gene banks. PMID- 22936112 TI - Cloning, phylogenetic analysis and 3D modeling of a putative lysosomal acid lipase from the camel, Camelus dromedarius. AB - Acid lipase belongs to a family of enzymes that is mainly present in lysosomes of different organs and the stomach. It is characterized by its capacity to withstand acidic conditions while maintaining high lipolytic activity. We cloned for the first time the full coding sequence of camel's lysosomal acid lipase, cLIPA using RT-PCR technique (Genbank accession numbers JF803951 and AEG75815, for the nucleotide and aminoacid sequences respectively). The cDNA sequencing revealed an open reading frame of 1,197 nucleotides that encodes a protein of 399 aminoacids which was similar to that from other related mammalian species. Bioinformatic analysis was used to determine the aminoacid sequence, 3D structure and phylogeny of cLIPA. Bioinformatics analysis suggested the molecular weight of the translated protein to be 45.57 kDa, which could be decreased to 43.16 kDa after the removal of a signal peptide comprising the first 21 aminoacids. The deduced cLIPA sequences exhibited high identity with Equus caballus (86%), Numascus leucogenys (85%), Homo sapiens (84%), Sus scrofa (84%), Bos taurus (82%) and Ovis aries (81%). cLIPA shows high aminoacid sequence identity with human and dog-gastric lipases (58%, and 59% respectively) which makes it relevant to build a 3D structure model for cLIPA. The omparison confirms the presence of the catalytic triad and the oxyanion hole in cLIPA. Phylogenetic analysis revealed that camel cLIPA is grouped with monkey, human, pig, cow and goat. The level of expression of cLIPA in five camel tissues was examined using Real Time-PCR. The highest level of cLIPA transcript was found in the camel testis (162%), followed by spleen (129%), liver (100%), kidney (20.5%) and lung (17.4%). PMID- 22936113 TI - Genetic analysis of Cydia pomonella (Lepidoptera: Tortricidae) populations with different levels of sensitivity towards the Cydia pomonella granulovirus (CpGV). AB - Microsatellite (simple sequence repeats, SSR) and mitochondrial DNA markers were used to assess the structure of European codling moth populations showing different levels of susceptibility towards one of the most important biocontrol agents used in apple production, the Cydia pomonella granulovirus CpGV-M. In 638 C. pomonella individuals from 33 different populations a total of 92 different alleles were scored using six SSR loci. The global estimate of genetic differentiation for all 33 populations was not significantly different from zero, thus indicating a lack of genetic differentiation. AMOVA analysis revealed a very weak but significant variance among C. pomonella populations from different geographic regions, however, no significant variation was evident between CpGV-M resistant or susceptible C. pomonella populations. Sequence analysis of a fragment of the cytochrome oxidase subunit 1 in eight C. pomonella populations resulted in 27 haplotypes, which were grouped in two distinct clusters. Again, no genetic differentiation between CpGV-M resistant and susceptible codling moth populations was detectable. In addition, Structure analysis using microsatellites and association tests with mtDNA haplotypes found neither population-level nor individual correlations associated with CpGV-M resistance. Accordingly, this lack of population structure does not allow discriminating between one or several, separate origins of CpGV-M resistance. PMID- 22936115 TI - [Value(s) of age]. PMID- 22936114 TI - Composition of two Spanish common dry beans (Phaseolus vulgaris), 'Almonga' and 'Curruquilla', and their postprandial effect in type 2 diabetics. AB - BACKGROUND: Legume consumption has been associated with a lower risk of developing type 2 diabetes. However, the type of legume is a modifier of its effect. Two Spanish dry bean varieties-white ('Almonga') and cream ('Curruquilla')-were analyzed and used in a postprandial study in type 2 diabetics to assess glucose, insulin and triacylglycerol in blood. RESULTS: 'Curruquilla' variety had higher total galactoside (stachyose, mainly), trypsin inhibitors and lectin content than 'Almonga'. The canning liquid was discarded prior to the analysis and the bean consumption by the subjects. The canning process reduced the total alpha-galactoside content (>50%), practically eliminated trypsin inhibitors, and no lectin content was found. After bean consumption, maximum glucose was obtained at 60 min and was three times lower than that in bread. After bean intake, maximum insulin was produced 60 min with 'Almonga' and occurred later (90 min) with 'Curruquilla' and bread. After 'Almonga' intake, the area under the curve response of triglycerides was 14% lower compared to bread (P = 0.013). CONCLUSIONS: 'Almonga' and 'Curruquilla' are similar in the content of the nutritional but not in that of the antinutritional components. Both beans showed similar effects on blood glucose and insulin in type 2 diabetics and marked differences compared to those of bread in terms of magnitude and time course, but only 'Almonga' rendered a significant reduction in the triglyceridemic response. PMID- 22936117 TI - Impact of intimate partner violence on anxiety and depression amongst women in Ile-Ife, Nigeria. AB - Research into intimate partner violence in the Nigerian environment has been limited. The objective of this study was to determine, amongst a sample of women attending the Enuwa Primary Health Care Center, Ile-Ife, the association between intimate partner violence and anxiety/depression. A descriptive cross-sectional study was conducted amongst 373 women who attended the antenatal clinic and welfare units of a primary health centre in Ile-Ife using the Composite Abuse Scale, the Hospital Anxiety and Depression Scale and a socio-demographic scale as instruments. Slightly over a third (36.7 %) reported intimate partner violence within the past year, 5.6 % had anxiety and 15.5 % were depressed. Anxiety and depression in the respondents were significantly associated with intimate partner violence. Women were ten times more likely to report being depressed and 17 times more likely to report anxiety if they were in violent relationships. This research has shown that the magnitude of intimate partner violence within the study population is comparable to those found in the developing countries. There are significant associations between intimate partner violence, anxiety and depression amongst the study population and this fact undoubtedly has implications for the mental health of the Nigerian woman. PMID- 22936121 TI - 1,2,4,5-Tetrakis(phenylsulfonyl)benzene: a novel quadruped host with D2 symmetry having ordered sulfolane and cycloheptanone guests. AB - The title tetrasulfone 1, in common with higher members of the multi-armed aromatic hosts, forms host-guest complexes with polar guest molecules. In the sulfolane and cycloheptanone complexes the host molecule possesses an abab conformation with exact C(2,) and approximate D(2) symmetry with deviations owing to crystal packing forces. The conformation of the well-ordered cycloheptanone molecule, which normally undergoes facile pseudorotation, is unambiguously defined in the voids of the crystalline inclusion compound. PMID- 22936118 TI - Comparative pharmacokinetic study of paclitaxel and docetaxel in streptozotocin induced diabetic rats. AB - The pharmacokinetics of paclitaxel and docetaxel were compared in diabetic rats induced by streptozotocin (DMIS rats) and the impact of altered expression of cytochrome P450 3A (Cyp3A) and P-glycoprotein (P-gp) in the diabetic state. The pharmacokinetics of paclitaxel and docetaxel were determined after intravenous (5 mg/kg) and oral (30 and 40 mg/kg, respectively) administration to both groups and the mRNA expression levels of Cyp3A isozymes and Mdr1a and Mdr1b in the liver and small intestine were determined in control and DMIS rats. After intravenous administration, the AUC and clearance of paclitaxel and docetaxel were not significantly different in DMIS vs control rats. After oral administration, the AUC and C(max) of paclitaxel in DMIS rats were significantly greater than those in the control rats, whereas those of docetaxel was not changed significantly. The mRNA expression levels of hepatic Cyp3A1, Cyp3A9 and Mdr1b were significantly increased in DMIS compared with the control rats. In the intestine, Cyp3A62 expression decreased in the DMIS rats compared with the controls. Thus the pharmacokinetic changes of taxanes observed in the DMIS rats were attributed to changes in P-gp and Cyp3A, predominant factors that control the absorption of paclitaxel and docetaxel, respectively. It seemed that there were different susceptibilities to intestinal P-gp and Cyp3A between the two taxanes. PMID- 22936120 TI - Quercetin attenuates cell apoptosis in focal cerebral ischemia rat brain via activation of BDNF-TrkB-PI3K/Akt signaling pathway. AB - Many studies have demonstrated that apoptosis play an important role in cerebral ischemic pathogenesis and may represent a target for treatment. Neuroprotective effect of quercetin has been shown in a variety of brain injury models including ischemia/reperfusion. It is not clear whether BDNF-TrkB-PI3K/Akt signaling pathway mediates the neuroprotection of quercetin, though there has been some reports on the quercetin increased brain-derived neurotrophic factor (BDNF) level in brain injury models. We therefore first examined the neurological function, infarct volume and cell apoptosis in quercetin treated middle cerebral artery occlusion (MCAO) rats. Then the protein expression of BDNF, cleaved caspase-3 and p-Akt were evaluated in either the absence or presence of PI3K inhibitor (LY294002) or tropomyosin receptor kinase B (TrkB) receptor antagonist (K252a) by immunohistochemistry staining and western blotting. Quercetin significantly improved neurological function, while it decreased the infarct volume and the number of TdT mediated dUTP nick end labeling positive cells in MCAO rats. The protein expression of BDNF, TrkB and p-Akt also increased in the quercetin treated rats. However, treatment with LY294002 or K252a reversed the quercetin induced increase of BDNF and p-Akt proteins and decrease of cleaved caspase-3 protein in focal cerebral ischemia rats. These results demonstrate that quercetin can decrease cell apoptosis in the focal cerebral ischemia rat brain and the mechanism may be related to the activation of BDNF-TrkB-PI3K/Akt signaling pathway. PMID- 22936122 TI - Determination of optimal cholecalciferol treatment in renal transplant recipients using a population pharmacokinetic approach. AB - PURPOSE: No information on optimal cholecalciferol dosing in kidney transplant patients is currently available because the time-course of serum 25-hydroxy vitamin D [25(OH)D] concentration has never been investigated. The aim of this study was to investigate 25(OH)D pharmacokinetics in renal transplant recipients and to determine the optimal dosage scheme allowing 25(OH)D concentrations to be maintained between 30-80 ng/mL during the first year post-transplantation. METHODS: Four months after renal transplantation, 49 patients received four oral doses of 100,000 IU cholecalciferol every 2 weeks (intensive phase), then every 2 months until 1 year after transplantation (maintenance phase). A control group of 47 transplanted patients was not supplemented but underwent blood sampling. In the treated group, 74 samples were collected before the first cholecalciferol administration and 119 thereafter. Two blood samples per patient were collected in the control group. Serum 25(OH)D concentrations were analyzed using a population approach. The turnover of 25(OH)D was modeled using a one-compartment model with first-order formation and elimination and basal concentration. RESULTS: The mean population parameter estimates and the associated between subject variability were: formation rate constant (k(f)), 0.11 day(-1); clearance (CL/F), 2.5 L/day (0.42); central volume of distribution (V(C)/F), 237 L; basal concentration (C(0)),12.82 ng/mL (0.41). Based on these values, in order to maintain 25(OH)D concentrations between 30 and 80 ng/mL, cholecalciferol dosing should be six successive administrations of 100,000 IU at 2-week intervals, followed by 100,000 IU once a month until the end of the first year. CONCLUSIONS: We present here the first pharmacokinetic model describing the time-course of 25(OH)D. We propose an optimal and practical scheme for the treatment of vitamin D insufficiency after renal transplantation. Taking into account the numerous effects of vitamin D on health, this scheme could help clinicians improve the care of kidney recipients. PMID- 22936123 TI - First European case of convulsions related to analytically confirmed use of the synthetic cannabinoid receptor agonist AM-2201. AB - PURPOSE: There is increasing reported use of synthetic cannabinoid receptor agonists (SCRA) across Europe. To date, there is limited information on the acute toxicity (harm) related to the use of these products. We describe here a case in which an individual developed convulsions related to the use of the SCRA AM-2201. CASE REPORT: A 20 year old male smoked a "Spice" (SCRA-containing) product called "Black Mamba," and rapidly after smoking, he had a generalised self-terminating tonic-clonic convulsion. After a 2 h observation period in the Emergency Department (ED), he self-discharged against medical advice. Subsequent analysis of urine collected at the time of presentation to the ED detected metabolites of AM-2201; no other drugs were detected on extensive analytic screening. DISCUSSION: This is the first case of convulsions related to the use of SCRA described in Europe, and the first case of convulsions related to the use the SCRA AM-2201 confirmed by analysis of biological samples. It is important for emergency physicians, clinical toxicologists and clinical pharmacologists managing those presenting with acute toxicity related to the use of SCRA to analytically confirm the exact compound(s) involved, to enable accurate description of the acute toxicity associated with individual SCRA. PMID- 22936124 TI - Predominant prevalence of arterial thrombosis in Japanese patients with antiphospholipid syndrome. AB - OBJECTIVE: To study the clinical and immunological manifestations of antiphospholipid syndrome (APS) in the Japanese population by a single-centre registration. METHODS: In this retrospective cohort study, 141 consecutive patients with APS, fulfilling the Sydney revised Sapporo criteria for definite APS, who visited our autoimmune clinic from 1988 to 2010, were recruited and followed up. All the patients were interviewed and underwent a general physical examination by qualified rheumatologists on the day of blood sampling. RESULTS: The population comprised 119 woman and 22 men with a mean age at diagnosis of 44 years (range 9-79 years). Seventy patients (49.6%) had primary APS, and 71 (50.4%) had systemic lupus erythematosus. The prevalence of thrombosis was 85.8 per cent, arterial thrombosis was found in 93 patients (66.0%) and venous thrombosis was found in 46 patients (32.6%). The most common thrombosis was cerebral infarction [86/141 (61.0%)] followed by deep vein thrombosis [33/141 (23.4%)]. Among 70 pregnant women, 45 (64.3%) had obstetric complications. Lupus anticoagulant was detected in 116 patients (82.3%), anticardiolipin antibodies in 83 (58.9%), anti-beta2 glycoprotein I antibodies in 73 (51.8%) and phosphatidylserine-dependent antiprothrombin antibodies in 98 (69.5%). CONCLUSION: High prevalence of arterial thrombosis was noted in Japanese patients with APS. The profile of heterogeneous and complex clinical manifestations was substantiated in Japanese patients with APS. PMID- 22936125 TI - Fatigue in patients with systemic lupus erythematosus: the role of dehydroepiandrosterone sulphate. AB - Fatigue is a major problem in systemic lupus erythematosus (SLE), but the physiological substrate of this fatigue is largely unclear. To examine if low levels of dehydroepiandrosterone (DHEA) and its sulphate DHEAS play a role in SLE fatigue, we compared: 1) DHEAS levels and fatigue between 60 female patients with SLE with low disease activity (31 using, 29 not using prednisone) and 60 age matched healthy women, and 2) fatigue between patients with SLE with low and normal DHEAS levels. Serum DHEAS levels were determined with an Advantage Chemiluminescense System. The Multidimensional Fatigue Inventory (MFI) was used to assess fatigue. Patients were more fatigued (p <= 0.001) than healthy women and more often had below-normal DHEAS levels (p < 0.001). Patients using prednisone with low and normal DHEAS levels reported a similar level of fatigue (p >= 0.39). Patients with low DHEAS levels not using prednisone reported less fatigue than those with normal DHEAS levels (p <= 0.03). Thus, our results indicate that low DHEAS levels in SLE are not - or even inversely - related to fatigue. After our previous finding that DHEA administration does not reduce fatigue, this result further indicates that low serum DHEA(S) levels alone do not offer an explanation for SLE fatigue. PMID- 22936126 TI - Benefits of a self-management program in low-income African-American women with systemic lupus erythematosus: results of a pilot test. AB - Minorities with systemic lupus erythematosus (SLE) are at high risk of poor disease outcomes and may face challenges in effectively self-managing multiple health problems. The Chronic Disease Self-Management Program (CDSMP) is an evidence-based intervention that improves the health of people with chronic illnesses. Although the CDSMP is offered by organizations throughout the United States and many countries around the world, it has not been tested among SLE patients. We pilot tested the benefits of the CDSMP in low-income African American patients with SLE. CDSMP workshops were delivered to 49 African American women with SLE who received medical care at a public lupus clinic in Atlanta, Georgia, US. We compared pre-post CDSMP changes (from baseline to 4 months after the start of the intervention) in health status, self-efficacy and self management behaviors using self-reported measures. Additionally, we assessed health care utilization changes using electronic administrative records in the 6 month periods before and after the intervention. We observed significant improvements post-intervention in the SF-36 physical health component summary (mean change = 2.4, p = 0.032); self-efficacy (mean change = 0.5, p = 0.035); and several self-management behaviors: cognitive symptoms management (mean change = 0.3, p = 0.036); communication with physicians (mean change = 0.4, p = 0.01); and treatment adherence (mean change = 0.4, p = 0.01). The median number of outpatient visits decreased from 3 to 1 (p < .0001). The CDSMP is a promising intervention for low-income African Americans with SLE. It is an inexpensive program with growing availability around the world that should be further evaluated as a resource to improve patient-centered outcomes and decrease health service utilization among SLE patients. PMID- 22936127 TI - Project: otorhinolaryngology trails. PMID- 22936128 TI - Filiform papillae do not have taste buds. PMID- 22936130 TI - Acoustic stimulation effect on temporal processing skills in elderly subjects before and after hearing aid fitting. AB - Aging can alter temporal processing and affect speech perception. AIM: To compare temporal processing auditory processing in elderly subject to and new hearing aid users. MATERIALS AND METHODS: The study included 60 elderly patients with bilateral sensorineural hearing loss. The procedures selected were the Duration Pattern Tests (DPT) and gaps in noise (GIN) test were used to analyze the responses of correct identification, and the temporal acuity threshold before and after the fitting of hearing aids. STUDY DESIGN: clinical and experimental research with non-probability sample of convenience. RESULTS: There was no statistically significant difference between the responses from GI and GII individuals. The elderly users of hearing aids had a lower gap detection threshold, greater recognition of gaps and of discrimination of the duration pattern in relation to when they were only potential users. CONCLUSION: There was a deterioration in temporal processing skills, regardless of hearing loss degrees. Thus, the effect of acoustic stimulation by the use of a hearing aid improved resolution and temporal ordering. PMID- 22936131 TI - Intellectual and school performance evaluation of children submitted to tonsillectomy and adenotonsillectomy before and after surgery. AB - Several studies have demonstrated the impact of obstructive sleep disorders on the quality of life of children. However, few studies address school and intellectual performances of children who have undergone tonsillectomy or adenotonsillectomy, indicating the benefits of these surgeries. OBJECTIVE: To evaluate and compare the learning and intellectual performances of children submitted to tonsillectomy or adenotonsillectomy, before and after surgery. MATERIALS AND METHODS: 83 children between the ages of 7 and 11 were evaluated by a psychologist employing a longitudinal and descriptive study in the pre and post surgery groups. The first evaluation was performed just before surgery, and the second and third evaluations one and six months after the surgical procedure. The social-demographic form, Raven's Colored Progressive Matrices Test and the School Performance Test were used. RESULTS: The group of children in this study presented a statistically significant evolution in their intellectual performance evaluations (p < 0.05) and also school performance evaluations in writing, mathematics and reading sub-tests (p < 0.001). CONCLUSION: Based on our findings we concluded that tonsillectomy or adenotonsillectomy performed in children with obstructive respiratory disorders produce a positive impact on intellectual and school learning development. PMID- 22936132 TI - Videofluoroscopic evaluation of mastication and swallowing in individuals with TMD. AB - To study mastication and swallowing disorders in patients with temporomandibular disorders (TMD). OBJECTIVE: To investigate mastication and swallowing disorders in patients with severe TMD referred to surgery. MATERIALS AND METHODS: Clinical and experimental study involving ten individuals with TMD submitted to deglutition videofluoroscopy. These patients did not have posterior teeth, mastication pain and food replacement in favor of pasty consistence food. The assessment of the oral and pharyngeal phases approached the following aspects: side of onset and preferential side for chewing, premature escape, remains of food residues in the oral cavity or in the pharyngeal recesses, number of necessary swallowing efforts, laryngeal penetration and/or tracheal aspiration. RESULTS: During mastication and the oral phase we observed tongue compensatory movements upon chewing (n = 7; 70%), premature escape (n = 4; 40%), food remains in the cavity after swallowing (n = 5; 50%) and an excessive number of deglutition efforts (n = 5; 50%). On the pharyngeal phase we observed food remains in the valleculae (n = 6; 60%), in the pyriform sinuses (n = 4; 40%); laryngeal penetration (n = 1; 10%) and tracheal aspiration (n = 4; 40%). CONCLUSION: TMD patients may have alterations in their chewing and swallowing patterns, with laryngeal penetration and/or tracheal aspiration. The study indicates the need for a multidisciplinary assessment because of dysphagia in TMD patients. PMID- 22936133 TI - Electroglottography of speakers of Brazilian Portuguese through Objective Multiparameter Vocal Assessment (EVA). AB - EVA was designed to study various speech production parameters. OBJECTIVE: This paper aims to define the mean values for electroglottography tests of Brazilian Portuguese speakers on EVA. MATERIALS AND METHOD: The voices of 20 men and 20 women without voice-related complaints were analyzed through electroglottography so as to obtain reference values for normality. CASE STUDY: this is a descriptive cross-sectional study. RESULTS: The mean values for normal male voices were: F0 = 127.77 Hz; F0 coefficient of variation = 2.51%; absolute jitter = 1.707 Hz; relative average perturbation = 0.0083; jitter factor = 1.34%; jitter ratio = 13.45%; QF = 0.447. The values for female voices were: F0 = 204.87 Hz; F0 coefficient of variation = 1.58%; absolute jitter = 3.30Hz; relative average perturbation = 0.0102; jitter factor = 1.60%; jitter ratio = 16.23%; QF= 0.443. Wave type for the entire sample was categorized as tilted pulse. CONCLUSION: Statistically significant differences were found for gender on parameters average FO and absolute jitter. While using acoustic analysis software, users must be based on parameters inherent to the software program when analyzing the collected data. PMID- 22936134 TI - The role of maxillary sinus puncture on the diagnosis and treatment of patients with hospital-acquired rhinosinusitis. AB - Rhinosinusitis is one of the most common causes of fever of unknown origin in critically ill patients and should be systematically searched. OBJECTIVE: This study aims to evaluate the diagnostic and therapeutic effect of maxillary sinus puncture performed at the bedside in patients with infective rhinosinusitis hospitalized in an Intensive Care Unit of a high complexity care hospital. MATERIALS AND METHODS: This retrospective study looks into patients on mechanical ventilation with fever of unknown origin and signs of rhinosinusitis on CT images who were submitted to inferior meatus maxillary sinus puncture. RESULTS: The total study sample consisted of 27 patients (70.3% male; mean age 45.3 years). The most common Intensive Care Unit admission diagnoses were head trauma and stroke. CT scans revealed the maxillary (85.2%) and sphenoid (74.1%) sinuses were the most involved paranasal sinuses. Middle meatus purulent drainage was seen in 30.7% of the nasal cavities. Fever was reduced in 70.4% of the patients after puncture (p < 0.001). The most commonly found organisms in sinus aspirates were Pseudomonas aeruginosa and Acinetobacter baumannii. CONCLUSION: Maxillary sinus puncture performed at the bedside of the patients is an important diagnostic and therapeutic tool for critically ill patients. PMID- 22936135 TI - The sphenopalatine artery: a surgical challenge in epistaxis. AB - Knowledge on the anatomy of the sphenopalatine artery (SPA) and its branches is fundamental for the success of the endoscopic treatment of posterior epistaxis. However, the complex anatomical variations seen in the irrigation of the nasal cavity poses a significant surgical challenge. OBJECTIVE: This paper aims to describe the endoscopic anatomy of the SPA in human cadavers. MATERIALS AND METHODS: This is a contemporary cross-sectional cohort study carried out between April 2010 and August 2011. The presence of the ethmoidal crest on the lamina perpendicular to the palatine bone and the location of the principal sphenopalatine foramen (PSF) and the accessory sphenopalatine foramen (ASF) were analyzed in 28 cadavers, and the branches emerging from the foramens were counted. RESULTS: Fifty-six nasal fossae were analyzed. The ethmoidal crest was present in 96% of the cases and was located anteriorly to the PSF in most cases. The PSF was located in the transition area between the middle and the superior meatus in all cases. The ASF was seen in 12 cases. Most nasal fossae (n = 12) presented a single bilateral arterial trunk emerging from the PSF. In other cases, three (n = 8) or two (n = 5) arterial trunks emerged bilaterally from the PSF. In most cases, the SPA emerged as a single trunk from the ASP. CONCLUSIONS: The anatomy of the SPA is highly variable. The success of the treatment for severe epistaxis relies heavily on adequate knowledge of the possible anatomical variations of the sphenopalatine artery. PMID- 22936136 TI - The histological rarity of thyroid cancer. AB - Thyroid cancer is the most common endocrine cancer, accounting for about 1% of all cancers. Sarcomas, lymphomas and metastases to the thyroid gland are rare and only with a handful of descriptions in the literature. OBJECTIVE: To describe rare histological types of thyroid cancer found in a reference center. METHODS: Medical chart review from admitted patients diagnosed with thyroid cancer in the period from 1977 to 2010. Demographic, diagnostic, therapeutic and histopathological information were collected. RESULTS: 3,018 records of patients admitted with thyroid disease were reviewed. Among the cases diagnosed with rare tumors there was a predominance of: anaplastic carcinoma: 22 cases (0.7%), followed by 11 cases of medullary carcinoma (0.36%); 2 cases of sarcoma (0.07%), 2 cases of lymphoma (0.07%) and one case of metastatic carcinoid tumor (0.03%). There were more females diagnosed (57%) as well as Caucasians (84%). The most frequent clinical presentation was a palpable thyroid nodule. All patients with lymphoma, sarcoma and anaplastic carcinoma died. CONCLUSION: Sarcomas, lymphomas and thyroid metastases are uncommon and tend to worse outcomes. PMID- 22936137 TI - Disabling hearing loss prevalence in Juiz de Fora, Brazil. AB - Data on the prevalence of disabling hearing loss (DHL) in Brazil is scarce, which impacts healthcare professionals' knowledge on the extent of the problem. OBJECTIVES: This study aimed at estimating DHL prevalence in the municipality of Juiz de Fora, Minas Gerais, to identify individual-related variables and find risk areas. MATERIALS AND METHODS: This was a descriptive sectional population study held from January to October of 2009. We randomly selected 349 households with 1,050 individuals who with ages ranging between 4 days and 95 years. The data collection instruments were: WHO structured questionnaire, ENT examination and laboratory tests. Chi-square and Poison regression models were used for analyses. RESULTS: DHL prevalence was estimated at 5.2% (95% CI = 3.1 to 7.3) which was classified as moderate in 3.9% (95% CI = 0.001 to 0.134), severe in 0.9% (95% CI = 0.001 to 0.107) and profound in 0.4% (95% CI = 0.001 to 0.095). We found correlation between DHL and tinnitus; age over 60 years and low educational level. CONCLUSIONS: Our data obtained pointed to the need to create hearing health programs targeted to specific risk groups, promoting quality of life for hearing impaired patients. PMID- 22936138 TI - Expression of calcium binding protein S100 A7 (psoriasin) in laryngeal carcinoma. AB - Many studies have reported increased expression of S100 A7 (psoriasin) in neoplastic lesions. Among them are studies on breast carcinoma, bladder squamous cell carcinoma, skin tumors and oral cavity squamous cell carcinoma. The expression of S100 A7 has not been described for laryngeal cancer. OBJECTIVE: This study aims to identify the expression of the calcium-binding protein S100 A7 and its correlation with squamous cell carcinomas of the larynx. MATERIAL AND METHODS: Specimens from 63 patients were submitted to immunohistochemistry testing with antibody S100 A7. Results were classified and compared. RESULTS: The group with highly differentiated tumors had the highest treatment failure scores. Moderately differentiated tumors had higher treatment failure scores than poorly differentiated tumors. Higher scores were predominantly seen on stages I and II in moderately differentiated tumors, whereas score distribution was more homogeneous in advanced stage disease (III and IV). Regarding failure in treatment, the group scoring zero (3/4 complications: 75%) differed significantly from the remaining groups (13/59: 22%). CONCLUSIONS: S100 A7 marker was expressed in 93.7% of laryngeal cancer cases, with higher positive correlation rates in more differentiated tumors and significantly lower rates of treatment failure. Scores had no impact on survival rates. PMID- 22936139 TI - Epidemiological study of HPV in oral mucosa through PCR. AB - The Human Papillomavirus (HPV) belongs to the Papillomaviridae family and has a capsid and a single DNA strand. Its infection occurs mainly through sexual intercourse, having an important tropism for skin and mucosal cells. AIM: To evaluate the HPV presence in normal oral mucosa of asymptomatic subjects and; in parallel, to correlate social behavioral habits with the virus. MATERIALS AND METHODS: Contemporary cohort cross-sectional study. The HPV was found by PCR, using general primers MY09/11 in 125 oral mucosa samples submitted to DNA extraction and PCR to search for the beta-globin gene in order to assess the quality of the extracted DNA. In parallel, we carried out a study of behavioral issues associated with the patients. RESULTS: All the samples had a positive diagnosis of the beta-hemoglobin gene. HPV was diagnosed in 23.2% of the samples analyzed. CONCLUSION: The virus was present in 29 of the 125 patients, without them having any clinical-pathological manifestation associated with the HPV. As to the social behavior of the patients, we concluded that oral sex is statistically correlated to the virus, and besides the HPV has been statistically more present in female patients. PMID- 22936140 TI - A comparison between neural response telemetry via cochleostomy or the round window approach in cochlear implantation. AB - There are two techniques for cochlear implant (CI) electrode placement: cochleostomy and the round window (RW) approach. OBJECTIVE: This study aims to compare neural response telemetry (NRT) results immediately after surgery to check for possible differences on auditory nerve stimulation between these two techniques. MATERIALS AND METHODS: This is a prospective cross-sectional study. Twenty-three patients were enrolled. Six patients underwent surgery by cochleostomy and 17 had it through the RW approach. RESULTS: Mean charge units (MCU) for high frequency sounds: patients submitted to the RW approach had a mean value of 190.4 (+/- 29.2) while cochleostomy patients averaged 187.8 (+/- 32.7); p = 0.71. MCU for mid frequency sounds: patients submitted to the RW approach had a mean value of 192.5 (+/- 22) while cochleostomy patients averaged 178.5 (+/- 18.5); p = 0.23. MCU for low frequency sounds: patients submitted to the RW approach had a mean value of 183.3 (+/- 25) while cochleostomy patients averaged 163.8 (+/- 19.3); p = 0.19. CONCLUSION: This study showed no differences in the action potential of the distal portion of the auditory nerve in patients with multichannel cochlear implants submitted to surgery by cochleostomy or through the RW approach, using the implant itself to generate stimuli and record responses. Both techniques equally stimulate the cochlear nerve. Therefore, the choice of approach can be made based on the surgeon's own preference and experience. PMID- 22936141 TI - Normal values for the Rhinoplasty Outcome Evaluation (ROE) questionnaire. AB - Rhinoplasty Outcome Evaluation (ROE) is an easy-to-use questionnaire that allows comprehensive assessment of rhinoplasty-related patient satisfaction. However, normal values for this questionnaire are not known. OBJECTIVE: To translate and cross-culture adapt the Rhinoplasty Outcome Evaluation questionnaire to Brazilian Portuguese and to establish normality parameters. MATERIALS AND METHODS: Cross sectional study with ROE administration to 62 patients waiting for rhinoplasty or septorhinoplasty (Cases) and 100 volunteer subjects without desire or need for nasal surgery (Controls). Assessment of possible sensitivity and specificity cutoffs. RESULTS: The cases' mean score was 6.6 or 27.5% (SD 3.18; min 0; max 15) and controls' mean score was 17.94 or 74.75% (SD 3.91; min 7; max 24). The best cutoff was 12 or 50%, with 95.16% sensitivity and 95% specificity. CONCLUSION: At the zero-to-24 score of the Brazilian Portuguese ROE, we found 12 as the best cutoff, with 95.16% of sensitivity and 95% of specificity. PMID- 22936142 TI - Reliability of radiographic parameters in adenoid evaluation. AB - The assessment of adenoids by x-ray imaging has been the topic of heated debate, but few studies have looked into the reliability of most existing radiographic parameters. OBJECTIVE: This study aims to verify the intra-examiner and inter examiner reproducibility of the adenoid radiographic assessment methods. MATERIALS AND METHODS: This is a cross-sectional case series study. Forty children of both genders aged between 4 and 14 were enrolled. They were selected based on complaints of nasal obstruction or mouth breathing and suspicion of pharyngeal tonsil hypertrophy. Cavum x-rays and orthodontic teleradiographs were assessed by two examiners in quantitative and categorical terms. RESULTS: All quantitative parameters in both x-ray modes showed excellent intra and inter examiner reproducibility. Relatively better performance was observed in categorical parameters used in cavum x-ray assessment by C-Kurien, C-Wang, C Fujioka, and C-Elwany over C-Cohen and C-Ysunza. As for orthodontic teleradiograph grading systems, C-McNamara has been proven to be more reliable than C-Holmberg. CONCLUSION: Most instruments showed adequate reproducibility levels. However, more research is needed to properly determine the accuracy and viability of each method. PMID- 22936143 TI - Hair cell alteration prevalence rates in students of a school in Distrito Federal. AB - Exposure to loud music is increasing among young people, and so could be the number of hearing impairment cases in this population. Otoacoustic emission tests are sensitive in capturing the effects of exposure to noise, and allow the detection of early cochlear disorders. OBJECTIVE: This study aims to look into the prevalence rates of injuries to outer hair cells in a population of students through otoacoustic emission testing. MATERIALS AND METHOD: One-hundred and thirty-four subjects were submitted to transient evoked and distortion product otoacoustic emission tests. Subjects were assessed on a "pass/fail" scale. This is a cross-sectional descriptive study on prevalence rates. RESULTS: More than four fifths (80.6%) of the 134 subjects had altered transient otoacoustic emissions, most of whom were males; 97.8% had altered distortion product otoacoustic emissions and 79.9% had altered test results in both transient evoked and distortion product OAEs; most were males; 94.0% reported they used earphones; and 82.8% stated they frequented places where loud music was played. CONCLUSION: The high prevalence rates of altered test results seem to indicate the presence of early cochlear disorders in the studied subjects. A significant number of subjects reported exposure to loud music, a habit that may be conducive to the onset of cochlear disorders. PMID- 22936144 TI - Sensorineural hearing loss in acromegalic patients under treatment. AB - Acromegaly is a rare endocrine disease. Few studies have evaluated its association with hearing loss (HL) and the results are conflicting. AIM: To evaluate the prevalence and features of HL in a group of patients being treated for acromegaly. To analyze peripheral and central auditory transmission. METHODS: Cross-sectional study. A group of 34 patients with acromegaly were submitted to metabolic evaluation, tonal audiometry and brainstem auditory evoked potentials. HL was considered when pure tone average was > 25 DBHL for low frequencies (250, 500, 1000 and 2000 Hz) or high frequencies (3000, 4000, 6000 and 8000 Hz). The patients were divided in group A (with HL) and B (without HL). RESULTS: Twelve patients (35.3%) had sensorineural HL (Group A), being 8 bilateral and 4 unilateral. No one had mixed or conductive HL. The prevalence of diabetes/impaired glucose tolerance was similar between the groups. The frequencies 3000, 4000, 6000 and 8000 Hz were the most affected and with a similar pattern in both ears. CONCLUSION: sensorineural HL was found in 38.9% of cases. Neither clinical nor metabolic differences were noted between the groups, as well as in regards to peripheral and central auditory transmission. PMID- 22936145 TI - The usefulness of a pectoralis major myocutaneous flap in preventing salivary fistulae after salvage total laryngectomy. AB - Salvage laryngectomy in patients treated with organ preservation protocols is associated with high rates of postoperative complications. The use of non irradiated tissue flaps in pharyngeal reconstruction could reduce the incidence of these complications. OBJECTIVE: This study aims to evaluate the usefulness of the pectoralis major myocutaneous flap in preventing salivary fistulae during the postoperative period of salvage total laryngectomy (TL). MATERIALS AND METHOD: This retrospective study enrolled 31 patients operated between April of 2006 and May of 2011. All patients had advanced cancer at the time of the salvage procedure and had been treated with chemoradiotherapy or radiotherapy alone. Pharyngeal reconstruction was performed using pectoralis major myocutaneous flap in 19 cases (61%); primary wound closure occurred in 12 patients (39%). RESULTS: Salivary fistulae occurred in 16% of the patients who received the flap and in 58% of the patients with primary closure of the pharynx (p < 0.02). No statistically significant differences were noted between the groups with respect to the mean time for fistula formation, reintroduction of an oral diet, or use of a nasoenteric tube for feeding. CONCLUSION: The pectoralis major myocutaneous flap was found to reduce the incidence of salivary fistulae in salvage laryngectomy procedures. PMID- 22936146 TI - Study of the noise spectrum on high frequency thresholds in workers exposed to noise. AB - Noise level can be quantified and qualified based on sound characteristics such as intensity, type of spectrum, duration and distribution of the noise exposure during one's working hours. OBJECTIVE: To assess noise spectrum and the audiometric configuration of workers. MATERIALS AND METHODS: Contemporary cross sectional cohort carried out in the Federal District - Brazil. We did an environmental analysis (spectral analysis) of the noise in companies from different industries, with audiological assessment of 347 workers. RESULTS: The spectral analysis revealed peaks at different frequencies for each industry investigated (8 kHz-metallurgical, 4 kHz-stone Works and 2 kHz-wood works). We noticed that the frequencies of 14 kHz and 16 kHz had significant differences between the various industries, with a greater prevalence of the metallurgical. CONCLUSION: The use of noise pressure measuring device, coupled to a frequency analyzer and high frequency audiometric assessment yielded an early detection of hearing damage, helping better organize preventive measures. PMID- 22936147 TI - Long term outcome of otosclerosis surgery. AB - The treatment of otosclerosis is eminently surgical. Good immediate results have been well documented when stapedotomy or stapedectomy are chosen. OBJECTIVES: This study aims to assess long term audiometric performance after otosclerosis surgery. MATERIALS AND METHODS: this retrospective study enrolled stapedotomy and partial stapedectomy patients seen at our service with proven hearing improvement after surgery. Forty-one patients (47 ears) accepted the invitation to be reassessed. Audiometry results before and immediately after surgery were compared. RESULTS: the median late follow-up was 11 years. To this date, 49% of the patients had normal hearing or mild dysacusis. Preoperative, postoperative, and late postoperative bone and air pure tone averages were 64.4 and 27.0 dB, 35.6 and 22.3 dB, and 44.1 and 29.5 dB respectively. CONCLUSION: Otosclerosis surgery offers good long term results. Despite the worsening of thresholds, the level of hypacusis ten years after surgery is lower than the levels observed before surgery. PMID- 22936148 TI - From nystagmus to the air and water caloric tests. AB - The caloric test is an important tool for the assessment of labyrinthine function. OBJECTIVE: To compare the nystagmus response in the caloric tests with air at 50oC and 24oC and with water at 44oC and 30oC. STUDY DESIGN: Randomized crossover clinical trial. MATERIALS AND METHODS: 40 healthy individuals were submitted to a neurotological evaluation, including caloric tests with air at 50oC and 24oC and water at 44oC and 30oC. RESULTS: Comparing the air and water caloric tests, there were no significant differences among the post-caloric nystagmus slow-phase velocity in relation to the stimulation order, between ears and between the values of unilateral weakness and directional preponderance. The slow-phase velocity values were higher with water (p = 0.008, p < 0.001), and cold stimulation produced stronger responses (p < 0.001). CONCLUSION: Comparing 50oC and 24oC air caloric test and 44oC and 30oC water caloric test, we observed similar slow-phase velocity values for both ears, higher responses in the cold temperature and in the test with water, and similar results of unilateral weakness or directional preponderance for post-caloric nystagmus in both tests. PMID- 22936149 TI - P300 latency and amplitude in Alzheimer's disease: a systematic review. AB - The P300 plays a key role as a method for monitoring and evaluating dementia, including Alzheimer's disease. OBJECTIVE: The goal of this study was to search for articles which analyzed P300 latency and amplitude values in Alzheimer's disease. METHODS: We searched in the following databases: Web of Science, Pub Med, Psyc Info, Medline, Biological Abstracts and Scielo using the following keywords: speed of information processing, processing speed, information processing, aged, older, elderly, older people, alzheimer dementia, alzheimer disease, Alzheimer and cross-references of selected articles. RESULTS: We found eight studies matching the inclusion criteria. These studies showed that there is a consensus on a P300 latency increase of elderly patients with Alzheimer's disease compared with subjects without the disease. However, it appears that, with respect to the P300 amplitude, there is still no consensus; however, it may be related to different methodological variables adopted in the reviewed studies. CONCLUSION: There is a need to standardize the variables involved in P300 measurement for senior citizens with Alzheimer's disease in order to be able to compare P300 latency and amplitude values for this population. PMID- 22936150 TI - Isolated congenital cholesteatoma of the mastoid process: a case report. PMID- 22936151 TI - Exuberant pyogenic granuloma in extragingival site. PMID- 22936152 TI - Malignant paranasal sinus schwannoma. PMID- 22936153 TI - Inflammatory myofibroblastic tumor of the temporal bone. PMID- 22936154 TI - Mandibular asymmetry: literature review and case report. PMID- 22936157 TI - Peak oxygen uptake prediction from a moderate, perceptually regulated, 1-km treadmill walk in male cardiac patients. AB - PURPOSE: To determine whether a moderate 1-km treadmill walking test (1KTWT) could be used to predict peak oxygen uptake VO(2)peak) in patients with cardiovascular disease. METHODS: One hundred seventy-eight male patients, aged 38 to 83 years, completed a VO(2)peak treadmill test and a 1KTWT using a self regulated intensity of 11 to 13 of 20 on the Borg scale. Multivariable regression analysis was used to develop equations for predicting VO(2)peak in a development group (n = 110), both for subjects prescribed and not prescribed a beta-blocking agent (BB/NBB, 66/44). These equations were then applied to a cross-validation and reproducibility group (n = 68, BB/NBB, 37/31), who completed the protocol twice within 2 weeks. RESULTS: Analysis from 1KTWT in the development group showed that age, body mass index, walking speed, and heart rate were the most potent predictors of VO(2)peak. Measured and predicted VO(2)peak were not significantly different, and were strongly associated among both the NBB (r = 0.81, P < .0001) and BB (r = 0.69, P < .0001) groups, with a mean residual of approximately 1.0 mL.kg(-1).min(-1). When applied to the cross-validation and reproducibility group, the equations similarly yielded strong associations (r = 0.64, P < 0.001 and r = 0.71, P < 0.001 for the NBB and BB groups, respectively), with no significantly differences between measured and predicted VO(2)peak. Mean test-retest differences for measured and predicted VO(2)peak were between 0.1 and -0.5 mL.kg(-1).min(-1). CONCLUSIONS: Equations developed from the 1KTWT accurately predicted VO(2)peak in patients with cardiovascular disease. The model may represent a valid, low cost, and simple tool for indirect estimations of cardiorespiratory fitness in an outpatient setting. PMID- 22936161 TI - Feeding currents of the upside down jellyfish in the presence of background flow. AB - The upside-down jellyfish (Cassiopea spp.) is an ideal organism for examining feeding and exchange currents generated by bell pulsations due to its relatively sessile nature. Previous experiments and numerical simulations have shown that the oral arms play an important role in directing new fluid into the bell from along the substrate. All of this work, however, has considered the jellyfish in the absence of background flow, but the natural environments of Cassiopea and other cnidarians are dynamic. Flow velocities and directions fluctuate on multiple time scales, and mechanisms of particle capture may be fundamentally different in moving fluids. In this paper, the immersed boundary method is used to simulate a simplified jellyfish in flow. The elaborate oral arm structure is modeled as a homogenous porous layer. The results show that the oral arms trap vortices as they form during contraction and expansion of the bell. For constant flow conditions, the vortices are directed gently across the oral arms where particle capture occurs. For variable direction flows, the secondary structures change the overall pattern of the flow around the bell and appear to stabilize regions of mixing around the secondary mouths. PMID- 22936158 TI - An investigation of the benefits of stress management within a cardiac rehabilitation population. AB - PURPOSE: Research describing whether stress management can improve clinical outcomes for patients in cardiac rehabilitation (CR) has yielded equivocal findings. METHODS: The present investigation retrospectively examined the incremental impact of exercise and stress management (n = 188), relative to exercise only (n = 1389), on psychosocial and physical health outcomes following a 12-week CR program. RESULTS: Participation in stress management and exercise was associated with greater reductions in waist circumference and systolic blood pressure, relative to exercise alone, for patients with baseline clinical elevations on these measures. The stress management group had more depressive symptoms (as measured by the Hospital Anxiety and Depression Scale; t[1] = 3.81, P < .001) and lower physical quality of life (as measured by the 12-Item Short Form Health Survey Physical Component; t[1] = 3.00, P = .003) than the exercise only group at baseline, but there were no differences between the groups at 12 weeks in terms of depressive symptoms (t[1] = 1.74, P = .082) or physical quality of life (t[1] = 1.56, P = .120). CONCLUSION: These findings suggest that stress management may offer additional benefits in selected patients over and above exercise in CR. PMID- 22936162 TI - The Coherent X-ray Imaging Data Bank. PMID- 22936163 TI - Evolutionary diagnosis method for variants in personal exomes. PMID- 22936164 TI - Neonatal desensitization does not universally prevent xenograft rejection. PMID- 22936166 TI - Pulling on single molecules. PMID- 22936167 TI - Evaluating protein interactions through cross-linking mass spectrometry. PMID- 22936168 TI - Deconstructing myelination: it all comes down to size. PMID- 22936169 TI - Biobanks, consent and claims of consensus. PMID- 22936170 TI - Imaging without lenses: achievements and remaining challenges of wide-field on chip microscopy. AB - We discuss unique features of lens-free computational imaging tools and report some of their emerging results for wide-field on-chip microscopy, such as the achievement of a numerical aperture (NA) of ~0.8-0.9 across a field of view (FOV) of more than 20 mm(2) or an NA of ~0.1 across a FOV of ~18 cm(2), which corresponds to an image with more than 1.5 gigapixels. We also discuss the current challenges that these computational on-chip microscopes face, shedding light on their future directions and applications. PMID- 22936171 TI - Broad-range real-time PCR assay for detection of bacterial DNA in ocular samples from infectious endophthalmitis. AB - BACKGROUND: To evaluate a broad-range real-time polymerase chain reaction (PCR) targeting the bacterial 16S rRNA gene for detection of bacterial DNA in infectious endophthalmitis. METHODS: The bacterial 16S rRNA gene was measured by quantitative real-time PCR. For the assay, bacterial DNA was prepared from 12 Gram-positive and 4 Gram-negative strains. To determine the optimum method for DNA extraction, four extraction procedures were selected by using DNA extraction program cards with and without the use of lysozyme. To evaluate PCR sensitivity, PCR fragments were amplified from Staphylococcus aureus and Escherichia coli DNA. RESULTS: DNA extraction using the Bacteria card((r)) without enzymes resulted in detection of all the tested strains at concentrations >= 10(7) copies/mL. Extraction with the Bacteria card((r)) with lysozyme resulted in detection of all the tested strains at concentrations >= 10(6) copies/mL, indicative of no significant difference between the two procedures. DNA extraction using the Virus card((r)), both with and without enzymes, resulted in reduced efficiency of detection of all strains compared with use of the Bacteria card((r)). The PCR could detect as few as 1-10 colony-forming units (CFU) in diluted vitreous samples per reaction, and all tested bacterial species known to cause endophthalmitis were detected. CONCLUSIONS: Bacterial 16S-specific PCR can comprehensively detect the main causative bacteria of clinically suspected endophthalmitis. PMID- 22936172 TI - Ultrahigh quantum efficiency of CuO nanoparticle decorated In2Ge2O7 nanobelt deep ultraviolet photodetectors. AB - Although there has been significant progress in the fabrication and performance optimization of 1-D nanostructure-based deep-ultraviolet photodetectors, it is still a challenge to develop an effective device with high performance characteristics, such as high photocurrent-dark current ratio and high quantum efficiency. Herein, an efficient and simple method to fabricate high performance CuO nanoparticle decorated In(2)Ge(2)O(7) nanobelt deep-ultraviolet photodetectors is presented. A CuO coated In(2)Ge(2)O(7) nanobelt based photodetector showed very high responsivity (7.34 * 10(5) A W(-1)) and high quantum efficiency (3.5 * 10(6)). The underlying mechanism is proposed to be the formation of p-n heterojunctions between decorated nanoparticles and nanobelts, which enhances the spatial separation of photogenerated electrons and holes. This study opens up a new horizon for creation of novel photodetectors with high quantum efficiency. PMID- 22936174 TI - Anorexia/cachexia of chronic diseases: a role for the TGF-beta family cytokine MIC-1/GDF15. AB - Anorexia/cachexia is a common and currently mostly untreatable complication of advanced cancer. It is also a feature of a number of chronic diseases and can also occur as part of the normal ageing process. Over recent years, two different, but sometimes overlapping, processes have been identified to mediate anorexia/cachexia: those that act primarily on muscle reducing its mass and function, and processes that decrease nutrition leading to loss of both fat and muscle. In the case of at least some cancers, the latter process is sometimes driven by marked overexpression of macrophage inhibitory cytokine-1/growth differentiation factor 15 (MIC-1/GDF15). MIC-1/GDF15 is a transforming growth factor beta (TGF-beta) family cytokine that is found in the serum of all normal individuals at an average concentration of about 0.6 ng/ml. Its increased expression in both cancers and other diseases can result in 10-100-fold or more elevation of its serum levels. In experimental animals, serum MIC-1/GDF15 levels at the lower end of this range induce anorexia by direct actions of the circulating cytokine on feeding centres in the brain. Mice with tumours overexpressing MIC-1/GDF15 display decreased food intake, loss of lean and fat mass and cachexia. That this process also mediates anorexia/cachexia in humans is suggested by the fact that there is a direct correlation between the degree of serum MIC-1/GDF15 elevation and the amount of cancer-related weight loss, the first such relationship demonstrated. Further, in experimental animals, weight loss can be reversed by neutralisation of tumour-produced MIC-1/GDF15 with a specific monoclonal antibody, suggesting the possibility of effective therapy of patients with the devastating complication of anorexia/cachexia. PMID- 22936175 TI - Controllable synthesis of a non-interpenetrating microporous metal-organic framework based on octahedral cage-like building units for highly efficient reversible adsorption of iodine. AB - A novel non-interpenetrating metal-organic framework IFMC-15 was successfully constructed based on octahedral cage-like building units and its outstanding performance in reversible adsorption of iodine was investigated. PMID- 22936173 TI - The N's and O's of Drosophila glycoprotein glycobiology. AB - The past 25 years have seen significant advances in understanding the diversity and functions of glycoprotein glycans in Drosophila melanogaster. Genetic screens have captured mutations that reveal important biological activities modulated by glycans, including protein folding and trafficking, as well as cell signaling, tissue morphogenesis, fertility, and viability. Many of these glycan functions have parallels in vertebrate development and disease, providing increasing opportunities to dissect pathologic mechanisms using Drosophila genetics. Advances in the sensitivity of structural analytic techniques have allowed the glycan profiles of wild-type and mutant tissues to be assessed, revealing novel glycan structures that may be functionally analogous to vertebrate glycans. This review describes a selected set of recent advances in understanding the functions of N-linked and O-linked (non-glycosaminoglycan) glycoprotein glycans in Drosophila with emphasis on their relatedness to vertebrate organisms. PMID- 22936176 TI - Malaria infection alters the expression of B-cell activating factor resulting in diminished memory antibody responses and survival. AB - Malaria is a major cause of morbidity worldwide with reports of over 200-500 million infected individuals and nearly 1 million deaths each year. Antibodies have been shown to play a critical role in controlling the blood stage of this disease; however, in malaria-endemic areas antibody immunity is slow to develop despite years of exposure to Plasmodium spp. the causative parasite. Using rodent Plasmodium yoelii YM, we provide evidence that malarial infections result in a decrease in the proportion of DCs that express the B-cell survival factor, BAFF, resulting in a decreased ability of these DCs to support memory B-cell differentiation into antibody secreting cells (ASCs) and/or the survival of ASCs. Further, compared with infected WT mice, ASC numbers were significantly increased in malaria-infected transgenic mice that either overexpressed BAFF or mice with BAFF-independent B-cell survival (B-cell-restricted TRAF3 deletion). Remarkably, BAFF-overexpressing mice were protected from lethal malaria infections, indicating the significance of the role BAFF plays in determining the outcome of malaria infections. These findings describe a previously unappreciated mechanism by which Plasmodium spp. can depress the generation of protective antibody responses. PMID- 22936177 TI - Human beta-cell killing by autoreactive preproinsulin-specific CD8 T cells is predominantly granule-mediated with the potency dependent upon T-cell receptor avidity. AB - The end-stage immunopathology of type 1 diabetes resulting in beta-cell destruction appears to be strongly dominated by cytotoxic CD8 T lymphocytes (CD8 T cells). However, the mechanism of cytotoxicity used by autoreactive CD8 T cells in the human setting remains unknown. Using type 1 diabetes patient-derived preproinsulin-specific CD8 T-cell clones recognizing either an HLA-A2 (A*0201) or HLA-A24 (A*2402)-restricted epitope (peptide of preproinsulin [PPI](15-24), ALWGPDPAAA; or PPI(3-11), LWMRLLPLL), we assessed the use of conventional mediators of cytotoxicity in the destruction of human beta-cells in vitro compared with virus-specific cytotoxic CD8 T-cell clones. We show that PPI specific CD8 T-cell clones are mainly reliant upon cytotoxic degranulation for inducing beta-cell death. Furthermore, we find that in comparison with virus specific CD8 T cells, there are differences in the killing potency of PPI specific CD8 T cells that are not due to cell-intrinsic differences, but rather are mediated by differences in strength of signaling by peptide-HLA ligands. The study highlights the regulation of beta-cell killing as a potential point for therapeutic control, including the possibility of blocking autoreactive CD8 T cell function without impacting upon general immune competence. PMID- 22936178 TI - Enhanced Nrf2 activity worsens insulin resistance, impairs lipid accumulation in adipose tissue, and increases hepatic steatosis in leptin-deficient mice. AB - The study herein determined the role of nuclear factor erythoid 2-related factor 2 (Nrf2) in the pathogenesis of hepatic steatosis, insulin resistance, obesity, and type 2 diabetes. Lep(ob/ob)-Keap1-knockdown (KD) mice, which have increased Nrf2 activity, were generated. Markers of obesity and type 2 diabetes were measured in C57Bl/6J, Keap1-KD, Lep(ob/ob), and Lep(ob/ob)-Keap1-KD mice. Lep(ob/ob)-Keap1-KD mice exhibited less lipid accumulation, smaller adipocytes, decreased food intake, and reduced lipogenic gene expression. Enhanced Nrf2 activity impaired insulin signaling, prolonged hyperglycemia in response to glucose challenge, and induced insulin resistance in Lep(ob/ob) background. Nrf2 augmented hepatic steatosis and increased lipid deposition in liver. Next, C57Bl/6J and Keap1-KD mice were fed a high-fat diet (HFD) to determine whether Keap1 and Nrf2 impact HFD-induced obesity. HFD-induced obesity and lipid accumulation in white adipose tissue was decreased in Keap1-KD mice. Nrf2 activation via Keap1-KD or sulforaphane suppressed hormone-induced differentiation and decreased peroxisome proliferator-activated receptor-gamma, CCAAT/enhancer-binding protein alpha, and fatty acid-binding protein 4 expression in mouse embryonic fibroblasts. Constitutive Nrf2 activation inhibited lipid accumulation in white adipose tissue, suppressed adipogenesis, induced insulin resistance and glucose intolerance, and increased hepatic steatosis in Lep(ob/ob) mice. PMID- 22936180 TI - Statement of Retraction. Blockade of receptor for advanced glycation end products in a model of type 1 diabetic leukoencephalopathy. Diabetes. 19 November 2012 [Epub ahead of print]. PMID- 22936179 TI - A potential role for dendritic cell/macrophage-expressing DPP4 in obesity-induced visceral inflammation. AB - Dipeptidyl peptidase-4 (DDP4) inhibitors target the enzymatic degradation of incretin peptides and represent a major advance in the treatment of type 2 diabetes. DPP4 has a number of nonenzymatic functions that involve its interaction with adenosine deaminase (ADA) and other extracellular matrix proteins. Here, we assessed the nonenzymatic role of DPP4 in regulating dendritic cell (DC)/macrophage-mediated adipose inflammation in obesity. Both obese humans and rodents demonstrated increased levels of DPP4 expression in DC/macrophage cell populations from visceral adipose tissue (VAT). The DPP4 expression increased during monocyte differentiation to DC/macrophages and with lipopolysaccharide (LPS)-induced activation of DC/macrophages. The DPP4 colocalized with membrane-bound ADA on human DCs and enhanced the ability of the latter to stimulate T-cell proliferation. The DPP4 interaction with ADA in human DC/macrophages was competitively inhibited by the addition of exogenous soluble DPP4. Knockdown of DPP4 in human DCs, but not pharmacologic inhibition of their enzymatic function, significantly attenuated the ability to activate T cells without influencing its capacity to secrete proinflammatory cytokines. The nonenzymatic function of DPP4 on DC may play a role in potentiation of inflammation in obesity by interacting with ADA. These findings suggest a novel role for the paracrine regulation of inflammation in adipose tissue by DPP4. PMID- 22936181 TI - Responsiveness of 'Conference' pears to 1-methylcyclopropene: the role of harvest date, orchard location and year. AB - BACKGROUND: In some pear varieties like 'Conference', 1-methylcyclopropene (1 MCP) treatment often impairs the ripening process indefinitely and the pears remain 'evergreen'. To better understand this behaviour, the influence of the harvest date, orchard location and year on the effectiveness of 1-MCP treatment was investigated. RESULTS: Pear softening was inhibited by 1-MCP treatment and the effectiveness of the treatment depended on harvest date, orchard location and year. Differences in the rate of softening in 1-MCP-treated pears depended mainly on the fruit physiological maturity at the moment of 1-MCP treatment. Accordingly, the combination of the Streif index and ethylene production at harvest appeared to be able to predict the evergreen behaviour. Treated pears with a low Streif index (<0.8) and high ethylene production at harvest (>=0.23 uL kg(-1) h(-1)) maintain significantly high firmness but did soften during shelf life, reaching acceptable eating quality. CONCLUSION: Evergreen behaviour was mainly influenced by the initial fruit maturity and especially by the ability of the fruit to produce ethylene at the moment of treatment. More mature fruit were able to overcome the inhibition by 1-MCP, and the solution to prevent evergreen behaviour therefore lies in the adequate determination of harvest maturity. PMID- 22936182 TI - Atovaquone ameliorate gastrointestinal toxoplasmosis complications in a pregnancy model. AB - BACKGROUND: Toxoplasma is an important source of foodborne hospitalization with no safe and effective therapy against chronic or congenital Toxopalsmosis. Atovaquone is a drug of choice but not approved for use in congenital Toxoplasmosis. We hypothesized atovaquone to be safe and effective against feto maternal Toxoplasmosis. MATERIAL/METHODS: Programmed pregnant mice were i.p. infected with 50-2400 Tachyzoites from Type II strain (clone PTG). Dams were treated daily with atovaquone or sham and monitored for pain, and complications. RESULTS: Dams developed pain related abdominal hypersensitivity (allodynia) to mechanical stimuli in a Tachyzoites dose dependent manner. Infected dams were anemic and exhibited ascities and severe hepatitis (score 3.6+/-0.01 on scale 0- normal to 4--severe) with influx of inflammatory and plasma cells, multinucleated dysplastic hepatocytes and necrosis. In addition, dams expressed mild to severe pancreatitis with mononuclear cell invasion, loss of islets and necrosis. This was consistent with splenomegaly (X3 Fold), and massive infiltration of epithelioid cells and loss of germinal structure. Colon became significantly shortened in length (p<0.01) with semi-normal content. Pathological manifestation included, shortening of crypts with numerous microabscess formations, infiltration of lymphocytes, and macrophages. The severe clinical complications led to abortion (50%), early birth (25%) or still birth (25%) consistent with the high dose of Tachyzoites inoculation. Atovaquone treatment partially but significantly protected the dams from the severity of hepatitis, splenomegaly, colitis, myocarditis, and pain related responses as well as fetal demise. CONCLUSIONS: This is a valuable model for therapeutic evaluation of feto-maternal Toxoplasmosis and gastrointestinal complications. Atovaquone protects dams and their fetuses against some infectious/inflammatory aspects of the disease. PMID- 22936183 TI - A 6-week training program increased muscle antioxidant system in elderly diabetic fatty rats. AB - BACKGROUND: It is widely accepted that oxidative stress is associated with the physiopathology of type 2 diabetes mellitus. In fact, it has been pointed out as a therapeutic target in T2DM. Fortunately, several papers have reported that long term training programs improved the antioxidant system in young and adult diabetic rats. Accordingly, this study was designed to assess the influence of a shorter training program in elderly diabetic fatty rats. MATERIAL/METHODS: Study subjects were 24 male homozygous Zucker diabetic fatty rats (Gmi, fa/fa) aged 18 weeks with an average weight of 370-450 g. After a 2-week period of environmental adaptation, animals were randomly distributed into the Exercised Group (n=12) that performed a 6-week swimming training protocol and the Sedentary Group (n=12). Animals were sacrificed under anesthesia 24 h after the last exercise session. Serum metabolic profile was determined. Total antioxidant status (TAS), MnSOD expression, glutathione status and ROS generation were assayed in gastrocnemius muscle. RESULTS: When compared with controls, exercised rats significantly improved their metabolic profile. Total antioxidant status (0.19+/ 0.002 vs. 0.13+/-0.002 ug/mg protein; p<0.001) and MnSOD expression (8471+/-90 vs. 6258+/-102 U/ug protein; p=0.003) were also increased in exercised rats. CONCLUSIONS: A 6-week swimming training program improved the antioxidant system in elderly fatty diabetic rats. Fortunately, this improvement was enough to reduce oxidative damage, expressed as protein oxidation. A major finding of this study was that our training protocol lasted just 6 weeks, in contrast to longer protocols previously published. PMID- 22936184 TI - Differential expression patterns of estrogen receptor (ER)-beta splice variants between papillary thyroid cancer and nodular thyroid goiter. AB - BACKGROUND: The aim of this study was to investigate the expression patterns of estrogen receptor (ER) beta1 (wild-type ERbeta) and ERbeta2 (ERbetacx) in papillary thyroid cancer (PTC) and nodular thyroid goiter (NTG), and to explore the reasons for the higher incidence of PTC in women of reproductive age. MATERIAL/METHODS: ERbeta1 and ERbeta2 expression was examined immunohistochemically on paraffin-embedded thyroid tissues from 106 patients with PTC and 30 patients with NTG. RESULTS: There was significant difference in the subcellular localization of ERbeta1 (P<0.001), but not in the positive percentage, between PTC and NTG specimens. No significant difference was found in the positive percentage or the subcellular distribution of ERbeta2 expression between PTC and NTG specimens. Both nuclear and nucleocytoplasmic ERbeta1 expressions were significantly lower in PTC lesions than in NTG tissue (P<0.001 and P<0.05, respectively), while ERbeta2 expression was significantly higher in the former than the latter (P<0.05). ERbeta1 expression in reproductive-aged (18~45 years) female patients with PTC was lower than that in age-matched male patients (P<0.05), while ERbeta2 expression had the opposite expression profile (P<0.05). There was no significant difference in ERbeta1 and ERbeta2 expression between reproductive-aged and advanced reproductive-aged (>45 years) female patients with PTC. CONCLUSIONS: This preliminary study indicates that the expression patterns of ERbeta1 and ERbeta2 differ between malignant PTC lesions and benign NTG tissue, and their expression might be involved in the female predominance of PTC during the reproductive years. The clinical and biological significance of these results await further investigation. PMID- 22936185 TI - Bacterial superinfection in zoonotic cutaneous leishmaniasis. AB - BACKGROUND: Zoonotic Cutaneous Leishmaniasis (ZCL) is a polymorphic disease. It is generally accepted that bacterial superinfection may play a role in the clinical appearance of the lesions and may delay or prevent the healing process. However, the pattern of bacterial pathogens involved has rarely been investigated. MATERIAL/METHODS: The aim of this study was to identify the bacterial species contaminating the suspected ZCL and their susceptibility to commonly used antibiotics. Microscopic examination of stained smears and cultures were used to differentiate ZCL from non-ZCL lesions in a rural area north of Isfahan, Iran from July to December 2009. Bacteria were isolated from the lesions and identified and antibiotic susceptibility was determined by standard microbiological techniques. RESULTS: The results show that 602 (68%) of 855 patients were positive for ZCL, of which 83.4% with volcano-shape, 8.8% psoriasiform, 6.6% popular form and 1.2% with other atypical forms of ZCL. The bacteria were isolated from 66.8% of ZCL (70% of volcano-shape, 60% of psoriasiform and 25% of popular form) and 64.7% of non-ZCL lesions. The most common species were Staphylococcus aureus (41.7%) and S. epidermidis (28%) followed by Bacillus sp. Streptococcus pyogenes, Escherichia coli, Klebsiella sp., Proteus sp., Enterobacter sp. and Pseudomonas aeroginosa. Ciprofloxacin, Erythromycin, Cefazolin and Clindamycin were the most effective antibiotics. CONCLUSIONS: Bacterial superinfection appears to be very common in ZCL, but its prevalence is not different from that of non-ZCL lesions and it has little effect on the clinical appearance of anthroponotic cutaneous Leishmaniasis (ACL). Local lesion care and management of bacterial superinfection must be considered in the treatment of ZCL. PMID- 22936186 TI - Acute histological changes of the lung after experimental Fontan circulation in a swine model. AB - BACKGROUND: Histological changes of the lungs were studied after the establishment of a modified total cavopulmonary connection (TCPC) without the use of cardiopulmonary bypass (CPB) or other means of temporary bypass on a swine model. MATERIAL/METHODS: 8 open chest-anesthetized pigs Landrace x Large White pigs (mean weight 43kg, mean age 4.5 months) underwent TCPC by the use of an appropriate size Y-shaped conduit connecting the superior and inferior caval veins (end-to-end anastomosis) to the pulmonary trunk (end-to-side anastomosis). After sternotomy, a wedge resection of the lung parenchyma was performed at baseline. Hemodynamic stability was sustained after TCPC establishment and 2 hours later another wedge resection of the lung was performed (from the same anatomic area). Histological studies were conducted by hematoxylin and eosin staining. RESULTS: All samples (n=8) at baseline were consistent with normal lung parenchyma. After the establishment of TCPC, all samples (n=8) revealed moderate mononuclear infiltration adjacent to pulmonary alveoli and bronchioles, findings compatible with bronchiolitis. CONCLUSIONS: In a normal swine model, 2 hours after the establishment of Fontan circulation without the use of CPB, pathologic examination of the lungs revealed bronchiolitis. Further research is needed to clarify these findings and the potential implications to the Fontan circulation, either immediate or long-term. PMID- 22936187 TI - A low-dose atorvastatin and losartan combination directly improves aortic ring relaxation and diminishes ischaemic-reperfusion injury in isolated rat hearts. AB - BACKGROUND: The cardiovascular pleiotropic effects of statins and angiotensin receptor blockers (ARBs) could be of interest for innovative preventive approaches. We aimed to investigate whether low-dose atorvastatin and losartan, separately not possessing protective cardiovascular pleiotropic effects, express them when combined. MATERIAL/METHODS: Forty-five adult male Wistar rats were anaesthetized and their thoracic aortas and hearts were isolated. Relaxation of aortic rings, coronary flow rate and the extent of myocardial ischaemic reperfusion injury were measured. Different concentrations (0.01, 0.1, 1.0 uM) of atorvastatin and losartan added to a perfusion medium were first tested. The separate drugs, which were ineffective, were then combined at the same concentrations and the concentration was tested in the same model. RESULTS: Low concentrations of atorvastatin or losartan (0.1 and 1 uM, respectively) produced no effects in isolated aorta. However, surprisingly, when these drug concentrations were combined, a significantly improved endothelium-dependent relaxation of the thoracic aorta was observed. Similarly, when combining individually ineffective concentrations of atorvastatin or losartan (0.01 and 0.1 uM, respectively), significantly increased coronary flow and a decreased extent of myocardial injury were observed. By using a nitric oxide-synthase inhibitor, we demonstrated that the vasodilatory effects obtained were nitric oxide dependent. The degree of effectiveness by the combination was comparable to that obtained by 10-fold (atorvastatin) or 100-fold (losartan) higher concentrations of the separate drugs. CONCLUSIONS: Our results revealed that remarkable additive/synergistic effects exist between low-doses of a statin (atorvastatin) and an ARB (losartan), resulting in important cardiovascular protection. This new concept could be valuable in cardiovascular prevention. PMID- 22936188 TI - The impact of a low cost wheelchair on the quality of life of the disabled in the developing world. AB - BACKGROUND: People with disabilities in the developing world do not have equal and adequate access to education, employment, or medical care. Their physical or mental condition, compounded by a lack of financial and technological resources, imposes a burden on both the family and the State. A wheelchair is a form of assistive technology which eases that burden for many. This study examines the impact of a simple, donated chair on the health, quality of life, and function of a subject population. MATERIAL/METHODS: Surveys were administered to 519 disabled recipients of a semi-rigid depot style wheelchair in 3 different countries at the time they received their chair and again after 12 months of use. Surveys evaluated physical and emotional health, functional independence, and lifestyle. RESULTS: On initial reports, 46.6% of subjects said they never left home, 52.3% were hospitalized one or more days/month, 70.3% reported daily pain, and 48.7% reported a negative mood state. Following 12 months of using the wheelchair, both the reported overall health rating and mood state increased by 20%; pain was significantly diminished. Although some areas in the ICF function measure improved more than others, the overall reported level of independence rose by 11%. CONCLUSIONS: A representative sample of the disabled in 3 countries of the world is socially isolated, in poor health, and with limited function. Receipt of a simple, depot style wheelchair significantly improved their quality of life, health indicators, and the ICF function measure following 12 months of use. PMID- 22936189 TI - Surgical sentinel lymph node biopsy in early breast cancer. Could it be avoided by performing a preoperative staging procedure? A pilot study. AB - BACKGROUND: The aim of this pilot trial was to study the feasibility of sentinel node percutaneous preoperative gamma probe-guided biopsy as a valid preoperative method of assessment of nodal status compared to surgical sentinel lymph node biopsy. MATERIAL/METHODS: This prospective study enrolled 10 consecutive patients without evidence of axillary lymph node metastases at preoperative imaging. All patients underwent sentinel node occult lesion localization (SNOLL) using radiotracer intradermic injection that detected a "hot spot" corresponding to the sentinel node in all cases. Gamma probe over the skin detection with subsequent ultrasonographically guided needle biopsy of the sentinel node were performed. The percutaneous needle core histopathological diagnosis was compared to the results of the surgical biopsy. RESULTS: Preoperative sentinel node identification was successful in all patients. CONCLUSIONS: The combination of preoperative gamma probe sentinel node detection and ultrasound-guided biopsy could represent a valid alternative to intraoperative sentinel node biopsy in clinically and ultrasonographically negative axillary nodes, resulting in shorter duration of surgery and lower intraoperative risks. PMID- 22936190 TI - Effect of a human-type communication robot on cognitive function in elderly women living alone. AB - BACKGROUND: Considering the high prevalence of dementia, it would be of great value to develop effective tools to improve cognitive function. We examined the effects of a human-type communication robot on cognitive function in elderly women living alone. MATERIAL/METHODS: In this study, 34 healthy elderly female volunteers living alone were randomized to living with either a communication robot or a control robot at home for 8 weeks. The shape, voice, and motion features of the communication robot resemble those of a 3-year-old boy, while the control robot was not designed to talk or nod. Before living with the robot and 4 and 8 weeks after living with the robot, experiments were conducted to evaluate a variety of cognitive functions as well as saliva cortisol, sleep, and subjective fatigue, motivation, and healing. RESULTS: The Mini-Mental State Examination score, judgement, and verbal memory function were improved after living with the communication robot; those functions were not altered with the control robot. In addition, the saliva cortisol level was decreased, nocturnal sleeping hours tended to increase, and difficulty in maintaining sleep tended to decrease with the communication robot, although alterations were not shown with the control. The proportions of the participants in whom effects on attenuation of fatigue, enhancement of motivation, and healing could be recognized were higher in the communication robot group relative to the control group. CONCLUSIONS: This study demonstrates that living with a human-type communication robot may be effective for improving cognitive functions in elderly women living alone. PMID- 22936191 TI - Respiratory pressures and expiratory peak flow rate of patients undergoing coronary artery bypass graft surgery. AB - BACKGROUND: To evaluate clinical and laboratorial parameters that predict decreased respiratory function in patients subjected to coronary artery bypass graft surgery (CABG). MATERIAL/METHODS: This was a prospective study evaluating 61 patients subjected to CABG with cardiopulmonary bypass, median sternotomy, and under mechanical ventilation for up to 24 h. One day before surgery, clinical information was recorded. Maximal inspiratory (MIP) and expiratory (MEP) pressures, and expiratory peak flow rate (EPFR) values were assessed 1 day before surgery and on the fifth postoperative day. Student's t test, 2-way ANOVA, Pearson's linear correlation, and logistic regression were used for statistical analysis. RESULTS: Patients were 63+/-10 years old, 67% males. Arterial hypertension was found in 75.4% of the patients, diabetes in 31.2%, dyslipidemia in 63.9%, tabagism in 25%, and chronic obstructive pulmonary disease (COPD) in 16.4%. Previous myocardial infarction was found in 67%. Preoperative hemoglobin levels were 12.8+/-1.71 g/dL. Older individuals had lower preoperative MEP and EPFR values. Preoperatively, positive association was found between hemoglobin levels and maximal respiratory pressures and EPFR values. Patients with both class III angina and COPD presented higher reductions in pulmonary pressures between the preoperative period and the 5th postoperative day. CONCLUSIONS: Older age and low hemoglobin levels are associated with preoperative low maximal respiratory pressures and EPFR. The combination of severe angina and COPD results in higher postoperative reduction of maximal respiratory pressures for patients who underwent CABG. PMID- 22936192 TI - Inhaled corticosteroids used for the control of asthma in a "real-life" setting do not affect linear growth velocity in prepubertal children. AB - BACKGROUND: Recent guidelines recommend inhaled corticosteroids as the first-line treatment for persistent asthma. However, long-term corticosteroid treatment in children has raised concerns about potential growth rate deceleration. We aimed to assess the association of growth velocity with the use of inhaled corticosteroids in prepubertal children with asthma in a "real-life" setting. MATERIAL/METHODS: This study included 844 children aged 4-9.5 years coming to the hospital for regular check-ups between October 2006 and February 2009 for asthma with/without allergic rhinitis and no other known constraints of growth. Out of the 844 children, 790 had all data needed for analysis--245 children were not treated with ICS, 545 children received ICS (fluticasone, budesonide) with/without INCS (fluticasone, mometasone or budesonide). During the study period, 48 children with/without ICS received short SCS courses. RESULTS: Mean (SE) height at the first check-up was 123.1 (0.31) cm; range (100.0-147.8 cm). Mean (SE) linear growth velocity (LGV) of the included children was 0.185 (0.0035) mm/day between 2 check-ups. No significant difference was found in LGV between the group not treated with ICS (0.180 mm/day+/-0.0055) and the group treated with ICS (0.187+/-0.0044 mm/day). Also, there was no statistical difference between subgroups according to additional therapy with INCS and SCS. No significant correlation was found for LGV and daily dose of ICS (r=0.086, p>0.05). CONCLUSIONS: In our retrospective study using electronic hospital database, ICS and combined use of corticosteroids did not show any association with LGV in prepubertal asthmatic children in a "real-life" setting. PMID- 22936193 TI - In vivo influence of extract from Aronia melanocarpa on the erythrocyte membranes in patients with hypercholesterolemia. AB - BACKGROUND: Hypercholesterolemia increases cholesterol concentration in erythrocyte membranes, which results in decrease of membrane fluidity and decreases the deformability of red blood cells. The fruits of Arona melanocarpa contains many of polyphenols and other compounds that have beneficial health effects. MATERIAL/METHODS: The aim of the study was to estimate the influence of 2-month supplementation of extract from Aronia melanocarpa (100 mg Aronox, three times per day) on cholesterol concentration, lipid peroxidation, membrane fluidity, level of thiol groups and activity of ATPase in erythrocytes from patients with hypercholesterolemia. The study involved 25 patients with hypercholesterolemia without pharmacological treatment and 20 healthy individuals as a control group. Blood samples were collected before, and after 1 and 2 months of Aronia administration. RESULTS: The 2-month Aronia supplementation resulted in a decrease of cholesterol concentration (by 22%) and a decrease of lipid peroxidation (by 40%), and an increase of membrane fluidity. No statistically significant increase of the concentration of thiol groups and of ATPase activity were observed. CONCLUSIONS: Our study shows that supplementation of extract from Aronia melanocarpa has a beneficial effect on rheological properties of erythrocytes. PMID- 22936194 TI - Ketamine, propofol and low dose remifentanil versus propofol and remifentanil for ERCP outside the operating room: is ketamine not only a "rescue drug"? AB - BACKGROUND: Endoscopic retrograde cholangiopancreatography ERCP is a painful and long procedure requiring transient deep analgesia and conscious sedation. An ideal anaesthetic that guarantees a rapid and smooth induction, good quality of maintenance, lack of adverse effects and rapid recovery is still lacking. This study aimed to compare safety and efficacy of a continuous infusion of low dose remifentanil plus ketamine combined with propofol in comparison to the standard regimen dose of remifentanil plus propofol continuous infusion during ERCP. MATERIAL/METHODS: 322 ASAI-III patients, 18-85 years old and scheduled for planned ERCP were randomized. Exclusion criteria were a predictable difficult airway, drug allergy, and ASA IV-V patients. We evaluated Propofol 1 mg/kg/h plus Remifentanil 0.25 ug/kg/min (GR) vs. Propofol 1 mg/kg/h plus Ketamine 5 ug/kg/min and Remifentanil 0.1 ug/kg/min (GK). Main outcome measures were respiratory depression, nausea/vomiting, quality of intraoperative conditions, and discharge time. P<=0.05 was statistically significant (95% CI). RESULTS: Respiratory depression was observed in 25 patients in the GR group compared to 9 patients in the GK group (p=0.0035). ERCP was interrupted in 9 cases of GR vs. no cases in GK; patients ventilated without any complication. Mean discharge time was 20+/-5 min in GK and 35+/-6 min in GR (p=0.0078) and transfer to the ward delayed because of nausea and vomiting in 30 patients in GR vs. 5 patients in GK (p=0.0024). Quality of intraoperative conditions was rated highly satisfactory in 92% of GK vs. 67% of GR (p=0.028). CONCLUSIONS: The drug combination used in GK confers clinical advantages because it avoids deep sedation, maintains adequate analgesia with conscious sedation, and achieves lower incidence of postprocedural nausea and vomiting with shorter discharge times. PMID- 22936195 TI - Inferior performance on selected neuropsychological tests in abstinent schizophrenia patients who have used cannabis. AB - BACKGROUND: A substantial proportion of patients with schizophrenia have co morbid psychoactive substance use, which can influence their cognitive functions. The aim of this study was to assess cognitive functioning in abstinent schizophrenia patients with various previous patterns of psychoactive substance use. MATERIAL/METHODS: The study was performed on a group of 80 schizophrenia patients (74 men, 6 women), aged 18-40 (mean 25) years, of whom in 40 a co-morbid psychoactive substance abuse was diagnosed. The latter group was subdivided, based on their predominant type of substance (opioid, amphetamine, or cannabis). All patients were examined during clinical improvement, and patients with comorbid substance use were also examined after a 6-week period of detoxification in a therapeutic community. A battery of neuropsychiatric tests was used, which included subtests of Trail Making test, Stroop test and Verbal Fluency test. RESULTS: No significant differences in clinical factors and cognitive functioning between the 2 examined groups were found. However, when the patients were divided according to their pattern of substance use, it turned out that the group of patients who used cannabis, despite the shortest duration of disease and that of addiction, and highest percentage of using atypical antipsychotics, performed worse on all cognitive tests, significantly so on Stroop and Fluency tests, compared to the groups with predominant opioid or amphetamine use. CONCLUSIONS: Abstinent schizophrenic patients who previously used cannabis have worse cognitive functioning compared to other schizophrenic patients with comorbid substance use. The possible role of previous cannabis use or cannabis withdrawal in this phenomenon is discussed. PMID- 22936196 TI - Effect of hepatitis B virus infection on right and left ventricular functions. AB - BACKGROUND: In this study we examined right and left ventricular systolic functions in hepatitis B virus (HBV) patients. MATERIAL/METHODS: The study included 50 HBsAg-positive patients (mean age; 33+/-13 years) and 50 other persons (mean age; 28+/-11 years) as a control group. Transthoracic echocardiography was performed in all the participants. Right and left ventricle systolic parameters were compared between these 2 groups. RESULTS: In the group of the patients with HBsAg positivity, the right ventricular fractional area change (RV FAC), tricuspid annular plane excursion (TAPSE) and RV myocardial systolic velocity (St) values were lower than in the control group (33+/-11 vs. 52+/-13%, p=0.001; 14.6+/-1.1 vs. 22.2+/-2.4 mm, p<0.001; 8.6+/-1.2 vs. 15.8+/ 2.3 cm/s, p<0,001, respectively); the right atrium (RA) and RV diameters were higher than in controls (5.1+/-1.2 vs. 3.7+/-0.5 cm, p<0.001; 4.9+/-0.8 vs. 3.4+/ 0.5 cm p<0.001, respectively); and systolic pulmonary artery pressure was higher than in control (39.3+/-9.5 vs. 22+/-8.4 mmHg, p<0.001). CONCLUSIONS: The findings showed that HBV infection may be associated with right ventricular systolic dysfunction and pulmonary hypertension. PMID- 22936197 TI - Evaluation of arteriovenous fistulas made with the diamond-shaped anastomosis technique. AB - BACKGROUND: Obtaining vascular access suitable for long-term use in hemodialysis patients is of utmost importance. In these patients, autogenous methods are generally used for access. There are various techniques for obtaining autogenous access in hemodialysis patients. MATERIAL/METHODS: Our objective was to evaluate the outcomes of the "diamond-shaped anastomosis" technique used as a surgical technique during the creation of arteriovenous fistulas in patients with chronic renal failure. We randomly selected and retrospectively examined 67 patients on whom the "diamond-shaped anastomosis" technique had been performed. RESULTS: We found an 89% patency rate in the 67 randomly selected patients on whom we applied this technique in the early stage (first 6 months). CONCLUSIONS: Maintaining fistula patency in the early postoperative period is important in fistula functioning. The diamond-shaped anastomosis is a simple technique with proven efficiency. This method can be applied in all situations and contributes to postoperative early stage latency. PMID- 22936199 TI - Short and long term mortality rates associated with first pregnancy outcome: population register based study for Denmark 1980-2004. AB - BACKGROUND: There is a growing interest in examining death rates associated with different pregnancy outcomes for time periods beyond one year. Previous population studies, however, have failed to control for complete reproductive histories. In this study we seek to eliminate the potential confounding effect of unknown prior pregnancy history by examining mortality rates associated specifically with first pregnancy outcome alone. We also examine differences in mortality rates associated with early abortion and late abortions (after 12 weeks). MATERIAL/METHOD: Medical records for the entire population of women born in Denmark between 1962 and 1991 and were alive in 1980, were linked to death certificates. Mortality rates associated with first pregnancy outcomes (delivery, miscarriage, abortion, and late abortion) were calculated. Odds ratios examining death rates based on reproductive outcomes, adjusted for age at first pregnancy and year of women's births, were also calculated. RESULTS: A total of 463,473 women had their first pregnancy between 1980 and 2004, of whom 2,238 died. In nearly all time periods examined, mortality rates associated with miscarriage or abortion of a first pregnancy were higher than those associated with birth. Compared to women who delivered, the age and birth year adjusted cumulative risk of death for women who had a first trimester abortion was significantly higher in all periods examined, from 180 days (OR=1.84; 1.11 <95% CI <3.71) through 10 years (1.39; 1.22 <95% CI <1.61), as was the risk for women who had abortions after 12 weeks from one year (OR=4.31; 2.18 <95% CI <8.54) through 10 years (OR=2.41; 1.56 <95% CI <2.41). For women who miscarried, the risk was significantly higher for cumulative deaths through 4 years (OR=1.75; 1.34 <95% CI <2.27) and at 10 years (OR=1.48; 1.18 <95% CI <1.85). CONCLUSIONS: Compared to women who delivered, women who had an early or late abortion had significantly higher mortality rates within 1 through 10 years. A lesser effect may also be present relative to miscarriage. Recommendations for additional research are offered. PMID- 22936198 TI - A step towards the discrimination of beta-lactamase-producing clinical isolates of Enterobacteriaceae and Pseudomonas aeruginosa by MALDI-TOF mass spectrometry. AB - BACKGROUND: Matrix-Assisted Laser-Desorption/Ionization Time of Flight Mass Spectrometry (MALDI-TOF MS) has already proven to be a powerful tool for species identification in microbiological laboratories. As adequate and rapid screening methods for antibiotic resistance are crucially needed, the present study investigated the discrimination potential of MALDI-TOF MS among extended-spectrum beta-lactamase (ESBL) or metallo-beta-lactamases- (MBL) producing and the nonproducing strains of Escherichia coli (n=19), Klebsiella pneumoniae (n=19), and Pseudomonas aeruginosa (n=38), respectively. MATERIAL/METHODS: We used a MALDI-TOF MS protocol, usually applied for species identification, in order to integrate a screening method for beta-lactamases into the routine species identification workflow. The acquired spectra were analyzed by visual inspection, statistical similarity analysis and support vector machine (SVM) classification algorithms. RESULTS: Neither visual inspection nor mathematical similarity analysis allowed discrimination between spectra of beta-lactamase-producing and the nonproducing strains, but classification within a species by SVM-based algorithms could achieve a correct classification rate of up to 70%. CONCLUSIONS: This shows that MALDI-TOF MS has definite potential to discriminate antibiotic resistant strains due to ESBL and MBL production from nonproducing strains, but this performance is not yet sufficiently reliable for routine microbiological diagnostics. PMID- 22936200 TI - Maternal and neonatal outcomes of macrosomic pregnancies. AB - BACKGROUND: To compare maternal and neonatal outcomes of term macrosomic and adequate for gestational age (AGA) pregnancies. MATERIAL/METHODS: A retrospective analysis was performed on all term singleton macrosomic (birth weight >=4000 g) and AGA (birth weight >10th percentile and <4000 g) pregnancies delivered at our hospital between 2004 and 2008. Data collected included maternal age, gestational age at delivery, mode of delivery, birth weight, fetal gender, maternal and neonatal complications. Comparisons were made between macrosomic and AGA pregnancies and between different severities of macrosomia (4000-4250 g, 4250 4500 g and >=4500 g). RESULTS: The study population comprised of 34,685 pregnancies. 2077 neonates had birth weight >=4000 g. Maternal age and gestational age at delivery were significantly higher for macrosomic neonates. Significantly more macrosomic neonates were born by cesarean section, and were complicated with shoulder dystocia, neonatal hypoglycemia, and had longer hospitalization period (both in vaginal and cesarean deliveries). Specifically, the odds ratio (OR) relative to AGA pregnancies for each macrosomic category (4000-4250 g, 4250-4500 g and >=4500 g) of shoulder dystocia was 2.37, 2.24, 7.61, respectively, and for neonatal hypoglycemia 4.24, 4.41, 4.15, respectively. The risk of post partum hemorrhage was statistically increased when birth weight was >4500 g (OR=5.23) but not for birth weight between 4000-4500 g. No differences were found in the rates of extensive perineal lacerations between AGA and the different macrosomic groups. CONCLUSIONS: Macrosomia is associated with increased rate of cesarean section, shoulder dystocia, neonatal hypoglycemia, and longer hospitalization, but not associated with excessive perineal tears. Increased risk of PPH was found in the >4500 g group. PMID- 22936201 TI - Factors that favor the occurrence of cough in patients treated with ramipril--a pharmacoepidemiological study. AB - BACKGROUND: Dry cough is a common cause for the discontinuation of ramipril treatment. The aim of this pharmacoepidemiological study was to assess the incidence of ramipril-related cough among the Polish population and to characterize patients at risk of experiencing the adverse effect of cough during ramipril treatment. MATERIAL/METHODS: This was a prospective observational study involving 10,380 patients treated with ramipril for a period of no longer than 8 weeks, consisting of 3 visits: baseline, first follow-up (after 4-8 weeks) and second follow-up visit (after 4-8 weeks of cessation of ramipril, conducted only for evaluating coughing patients). RESULTS: The incidence of ramipril-related cough was 7.1%. Logistic regression analysis identified female sex (OR=1.35), cigarette smoking (OR=2.50), chronic obstructive pulmonary disease (OR=1.70), asthma (OR=1.60) and previous history of tuberculosis (OR=6.20) to be significantly and independently associated with the onset of ramipril-related cough. Coughing subsided within a period of 2-20 days after ramipril was discontinued. In all patients reporting the appearance of cough within the first 5 days after therapy initiation, the adverse effect subsided after therapy discontinuation. If cough appeared within 6-10 days, it subsided after discontinuation in 81.6% of subjects. Cough persisted in 30.4% of those reporting later onset. CONCLUSIONS: 1. Female sex, cigarette smoking, COPD, asthma, and previous history of tuberculosis increase the risk of ramipril-related cough. 2. The later the cough occurs during treatment, the less often the drug is the causative agent and the cough and also less likely to disappear after discontinuation of ramipril. PMID- 22936203 TI - Future MS care: a consensus statement of the MS in the 21st Century Steering Group. AB - The "MS in the 21st Century" initiative was established with the purpose of (1) defining how multiple sclerosis (MS) treatment and standards of care should look in the 21st century; (2) developing a minimum standard of care across the world; and (3) motivating the broad MS community to align standards of care and challenge the current treatment paradigm. The aim was to develop a consensus statement to reach and influence the broader MS community. An expert steering group from Europe and Canada-consisting of neurologists, patient advocates, a pharmacoepidemiologist/pharmacoeconomist, and representatives from national MS centers-participated in a series of workshop-driven meetings between February 2011 and 2012. After three phases of discussions, the steering group identified that the overall vision for future care of MS should be full access to personalized treatment, with reimbursement, to achieve freedom from disease. They constructed seven overall principles that support this vision: personalized care, patient engagement, commitment to research, regulatory body education and reimbursement issues, new endpoints in clinical trials, more therapy options, and MS centers of excellence. This consensus statement outlines the key aspects of the seven principles that need to be addressed. The "MS in the 21st Century Steering Group" hopes that this consensus statement acts as a call to action for healthcare providers and decision-makers to address simultaneously the overarching principles that will guide patient management in order to improve outcomes for people with MS. PMID- 22936202 TI - Gorlin-Goltz syndrome--a medical condition requiring a multidisciplinary approach. AB - Gorlin-Goltz syndrome is a rare genetic condition showing a variable expressiveness. It is inherited in a dominant autosomal way. The strongest characteristic of the disease includes multiple basal cell carcinomas, jaw cysts, palmar and plantar pits, skeletal abnormalities and other developmental defects. Owing to the fact that the condition tends to be a multisystemic disorder, familiarity of various medical specialists with its manifestations may reduce the time necessary for providing a diagnosis. It will also enable them to apply adequate methods of treatment and secondary prevention. In this study, we present symptoms of the disease, its diagnostic methods and currently used treatments. We searched 2 scientific databases: Medline (EBSCO) and Science Direct, for the years 1996 to 2011. In our search of abstracts, key words included nevoid basal cell carcinoma syndrome and Gorlin-Goltz syndrome. We examined 287 studies from Medline and 80 from Science Direct, all published in English. Finally, we decided to use 60 papers, including clinical cases and literature reviews. Patients with Gorlin-Goltz syndrome need particular multidisciplinary medical care. Knowledge of multiple and difficult to diagnose symptoms of the syndrome among professionals of various medical specialties is crucial. The consequences of the disease pose a threat to the health and life of patients. Therefore, an early diagnosis creates an opportunity for effective prevention and treatment of the disorder. Prevention is better than cure. PMID- 22936204 TI - Evaluation of serum lipid levels in children. AB - This study aimed to establish reference values for serum levels of total cholesterol, triglycerides, low-density lipoprotein cholesterol (LDL-C), and high density lipoprotein cholesterol (HDL-C) in children. The study included samples from 4,102 healthy children (2,003 boys and 2,099 girls) ages 1-18 years. The serum levels of total cholesterol, triglycerides, and HDL-C were determined using the Advia 2400 autoanalyzer. The LDL-C levels were calculated using the Friedewald equation. The mean, standard deviation, and 5th, 10th, 25th, 50th, 75th, 90th, and 95th percentile values of the biochemical parameters for boys and girls were detected. The total cholesterol and HDL-C levels were higher among the girls than among the boys in 15- to 18-year-old group. No significant difference was found for the other serum lipid levels among any of the age groups. This study provided pediatric reference intervals for the lipid parameters for children. PMID- 22936205 TI - Configuration space partitioning and matrix buildup scaling for the vibrational configuration interaction method. AB - The accurate computation of anharmonic vibrational states for medium to large molecules is a requirement for the detailed understanding of nonlinear multidimensional infrared spectra and the dynamical information encoded in them. The vibrational configuration interaction (VCI) method constitutes a particularly promising tool in this respect. It is generally hampered though by its unfavorable scaling with respect to system size. We analyze the scaling behavior of several well-known as well as some new approximate VCI schemes in detail, which are complementary to the class of configuration selection schemes developed recently. We find that the combination of a configuration space partitioning, possibly based on configuration selection, with energetic thresholding and resonance screening provides an efficient scheme for the reduction of computational effort involved in VCI calculations while at the same time maintaining sufficient accuracy for the vibrational energies. PMID- 22936206 TI - Do dynamic strengthening and aerobic capacity exercises reduce pain and improve functional outcomes and strength in people with established rheumatoid arthritis? PMID- 22936207 TI - Impact of exercise training on adverse event risk and quality of life in patients with heart failure. PMID- 22936208 TI - Results of Tonnis-type acetabuloplasty in patients with developmental hip dysplasia. AB - AIM: The aim of this prospective study was to evaluate the outcome of open reduction and Tonnis acetabuloplasty as the first method of treating developmental dysplasia of the hip (DDH) in children in early childhood at walking age. MATERIALS AND METHODS: Between 2005 and 2009, 34 hips of 34 children were operated on with the aforementioned method. Mean age was 25.6 (range 12-44) months, and mean follow-up was 3.6 years. During the follow-up period ,the hips were evaluated using the acetabular index and for development of avascular necrosis and redislocation. Functional evaluation was also conducted. RESULTS: Clinically, 97.3 % of patients had excellent and good results. The acetabular angle decreased from 45 degrees preoperatively to 21 degrees early postoperatively and at the last follow-up had improved to 18 degrees . In two hips, type 2 avascular necrosis developed. Hip instability was not observed, and no additional surgery was performed. CONCLUSION: Tonnis acetabuloplasty is a powerful tool to increase primary stability of the hip when acetabular coverage is inadequate in DDH. Besides its acute correction ability, when performed properly, it has no unwanted effects on acetabular growth. As an isolated procedure or as a part of combined open reduction and/or femoral osteotomy, Tonnis type acetabuloplasty is a safe and effective method. PMID- 22936209 TI - Rapid destruction of the humeral head due to bone fragility: report of two cases. PMID- 22936210 TI - Conformity of behaviors among medical students: impact on performance of knee arthrocentesis in simulation. AB - Although the development of collaborative relationships is considered a requirement for medical education, the functioning of these relationships may be impaired by a well-documented social-psychological phenomenon known as group conformity. The authors hypothesized that students would insert a needle into an incorrect location relative to the patella when performing a knee arthrocentesis if they believed that their peers had also inserted a needle in the same incorrect location. This was a randomized controlled study conducted in 2011 with 60 medical students (24 male; 40.0 %) who were randomly assigned to either using a knee model that had a skin with holes left by peers inserting needles in the wrong location, or a knee with no marks in the skin. Each student's aspiration site was measured with a fibreglass ruler to determine whether it was correctly located within the superior third, 1 cm medial to the patella. The researchers determined that students who used the marked skin were more likely to insert the needle in the incorrect location compared to those who used the clean skin (n = 31, 86.11 vs. n = 14, 58.33 %), Fisher's exact test (1) = 5.93, p < 0.05, Cramer's phi = 0.31. This study demonstrates incorrect performance of the knee arthrocentesis procedure in simulation when students use a damaged model, which may be due to conformity. It suggests that further research on the impact of conformity in medical education is warranted. PMID- 22936211 TI - Poisoning in young children. PMID- 22936212 TI - Accurately administering oral medication to children isn't child's play. AB - OBJECTIVE: Parents administer oral medications with various measuring devices including metal teaspoons, calibrated spoons and oral syringes. We aimed to determine which was the most accurate. DESIGN: Self-controlled, non-randomised, experimental study. SETTING: Caregivers attending paediatric outpatient clinics. METHODOLOGY: Caregivers measured 5 ml of 120 mg/5 ml paracetamol suspension using a 5.0 ml metal teaspoon, 5.0 ml calibrated spoon and 5.0 ml oral syringe. Samples were weighed and converted to mls. MAIN OUTCOME MEASURES: The mean volume and variance of volumes were measured for each device. RESULTS: We recruited 277 caregivers (98% parents). Volumes measured ranged from 0.83-6.52 ml. Accuracy did not vary with caregivers' age, gender, instrument preference, number and age of children. The mean volumes measured with the oral syringe (95% CI 5.09 to 5.17 ml) and metal spoon (95% CI 3.90 to 4.08 ml) were significantly different to the desired 5 ml volume (p<0.0001), dissimilar to the mean volume measured using the calibrated spoon (95% CI 4.91 to 5.09 ml, p=0.99). The variance of volumes measured with the oral syringe (SD 0.348 ml) was significantly smaller (p<0.0001) than that measured using a calibrated spoon (SD 0.762 ml) or metal spoon (SD 0.749 ml). CONCLUSIONS: The calibrated spoon was the most accurate producing a mean volume of 5 ml, while the oral syringe had the smallest variance. The increased variability of calibrated or metal spoons may result in under or overdosing especially when administering drugs with a narrow therapeutic window. Health care professionals must make a case-by-case decision regarding which device is preferable depending on the medication in question. Parental education could improve measuring accuracy. PMID- 22936214 TI - Quantitative benefit-risk assessment using only qualitative information on utilities. AB - BACKGROUND: Utilities of pertinent clinical outcomes are crucial variables for assessing the benefits and risks of drugs, but numerical data on utilities may be unreliable or altogether missing. We propose a method to incorporate qualitative information into a probabilistic decision analysis framework for quantitative benefit-risk assessment. OBJECTIVE: To investigate whether conclusive results can be obtained when the only source of discriminating information on utilities is widely agreed upon qualitative relations, for example, ''sepsis is worse than transient headache'' or ''alleviation of disease is better without than with complications.'' METHOD: We used the structure and probabilities of 3 published models that were originally evaluated based on the standard metric of quality adjusted life years (QALYs): terfenadine versus chlorpheniramine for the treatment of allergic rhinitis, MCV4 vaccination against meningococcal disease, and alosetron for irritable bowel syndrome. For each model, we identified clinically straightforward qualitative relations among the outcomes. Using Monte Carlo simulations, the resulting utility distributions were then combined with the previously specified probabilities, and the rate of preference in terms of expected utility was determined for each alternative. RESULTS: Our approach conclusively favored MCV4 vaccination, and it was concordant with the QALY assessments for the MCV4 and terfenadine versus chlorpheniramine case studies. For alosetron, we found a possible unfavorable benefit-risk balance for highly risk-averse patients not identified in the original analysis. CONCLUSION: Incorporation of widely agreed upon qualitative information into quantitative benefit-risk assessment can provide for conclusive results. The methods presented should prove useful in both population and individual-level assessments, especially when numerical utility data are missing or unreliable, and constraints on time or money preclude its collection. PMID- 22936215 TI - Identifying ChIP-seq enrichment using MACS. AB - Model-based analysis of ChIP-seq (MACS) is a computational algorithm that identifies genome-wide locations of transcription/chromatin factor binding or histone modification from ChIP-seq data. MACS consists of four steps: removing redundant reads, adjusting read position, calculating peak enrichment and estimating the empirical false discovery rate (FDR). In this protocol, we provide a detailed demonstration of how to install MACS and how to use it to analyze three common types of ChIP-seq data sets with different characteristics: the sequence-specific transcription factor FoxA1, the histone modification mark H3K4me3 with sharp enrichment and the H3K36me3 mark with broad enrichment. We also explain how to interpret and visualize the results of MACS analyses. The algorithm requires ~3 GB of RAM and 1.5 h of computing time to analyze a ChIP-seq data set containing 30 million reads, an estimate that increases with sequence coverage. MACS is open source and is available from http://liulab.dfci.harvard.edu/MACS/. PMID- 22936216 TI - Culturing pyramidal neurons from the early postnatal mouse hippocampus and cortex. AB - The ability to culture and maintain postnatal mouse hippocampal and cortical neurons is highly advantageous, particularly for studies on genetically engineered mouse models. Here we present a protocol to isolate and culture pyramidal neurons from the early postnatal (P0-P1) mouse hippocampus and cortex. These low-density dissociated cultures are grown on poly-L-lysine-coated glass substrates without feeder layers. Cultured neurons survive well, develop extensive axonal and dendritic arbors, express neuronal and synaptic markers, and form functional synaptic connections. Further, they are highly amenable to low- and high-efficiency transfection and time-lapse imaging. This optimized cell culture technique can be used to culture and maintain neurons for a variety of applications including immunocytochemistry, biochemical studies, shRNA-mediated knockdown and live imaging studies. The preparation of the glass substrate must begin 5 d before the culture. The dissection and plating out of neurons takes 3-4 h and neurons can be maintained in culture for up to 4 weeks. PMID- 22936217 TI - Primary culture and immortalization of human fallopian tube secretory epithelial cells. AB - Primary human fallopian tube secretory epithelial cell (FTSEC) cultures are useful for studying normal fallopian tube epithelial biology, as well as for developing models of fallopian tube disease, such as cancer. Because of the limited ability of primary human FTSECs to proliferate in vitro, it is necessary to immortalize them in order to establish a cell line that is suitable for long term culture and large-scale in vitro experimentation. This protocol describes the isolation of FTSECs from human fallopian tube tissue, conditions for primary FTSEC culture and techniques for establishing immortal FTSEC lines. The entire process, from primary cell isolation to establishment of an immortal cell line, may take up to 2 months. Once established, immortal FTSECs can typically be maintained for at least 30 passages. PMID- 22936219 TI - A direct reaction approach for the synthesis of zeolitic imidazolate frameworks: template and temperature mediated control on network topology and crystal size. AB - The direct acid-base reaction between ZnO/CoO/Co(OH)(2) and imidazolic ligands under moderate heating (100-160 degrees C), in a closed vessel, leads to the generation of the corresponding zinc/cobalt-imidazolates in a high yield (87-97%) in which network topology is controlled by the addition of small amounts of structure directing agents. Moreover, the fine tuning of the thermal process at the synthetic stage permits us to increase the crystal size, and even to grow X ray quality single crystals. PMID- 22936220 TI - CBC and SBAIT: adding to multiply. PMID- 22936218 TI - Evidence for a multi-dimensional latent structural model of externalizing disorders. AB - Strong associations between conduct disorder (CD), antisocial personality disorder (ASPD) and substance use disorders (SUD) seem to reflect a general vulnerability to externalizing behaviors. Recent studies have characterized this vulnerability on a continuous scale, rather than as distinct categories, suggesting that the revision of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) take into account the underlying continuum of externalizing behaviors. However, most of this research has not included measures of disorders that appear in childhood [e.g., attention-deficit/hyperactivity disorder (ADHD) or oppositional defiant disorder (ODD)], nor has it considered the full range of possibilities for the latent structure of externalizing behaviors, particularly factor mixture models, which allow for a latent factor to have both continuous and categorical dimensions. Finally, the majority of prior studies have not tested multidimensional models. Using lifetime diagnoses of externalizing disorders from participants in the Fast Track Project (n = 715), we analyzed a series of latent variable models ranging from fully continuous factor models to fully categorical mixture models. Continuous models provided the best fit to the observed data and also suggested that a two-factor model of externalizing behavior, defined as (1) ODD+ADHD+CD and (2) SUD with adult antisocial behavior sharing common variance with both factors, was necessary to explain the covariation in externalizing disorders. The two-factor model of externalizing behavior was then replicated using a nationally representative sample drawn from the National Comorbidity Survey-Replication data (n = 5,692). These results have important implications for the conceptualization of externalizing disorders in DSM-5. PMID- 22936221 TI - Evaluation of the quality of trauma care service through the study of deaths in a tertiary hospital. AB - OBJECTIVE: To characterize deaths from trauma in a tertiary hospital and evaluate the quality of care provided to these victims. METHODS: This was a retrospective study in a referral center for trauma in the period of one year. Through the methodology Trauma Score - Injury Severity Score and the review of medical records, preventable, potentially avoidable and non-preventable deaths were identified and studied. RESULTS: Seventy-five patients were included in the study. There was a predominance of deaths in young, male victims of traffic accidents. The mean Revised Trauma Score, Injury Severity Score and Trauma Score Injury Severity Score were 5.60, 30.7 and 62.2%, respectively. The rate of deaths considered avoidable was 61.3%, potentially avoidable, 24%, and unavoidable, 14.7%. CONCLUSION: The study sample had epidemiological features similar to other studies, except for the high rate of avoidable deaths and the high values of the Revised Trauma Score. There were difficulties in obtaining data from medical records, medical imaging and autopsy findings. The quality of care provided to trauma victims in the institution proved unsatisfactory because of problems in collecting and storing data. PMID- 22936222 TI - Experience of two first level hospitals in the southwest region of Colombia on the implementation of the Panamerican Trauma Society International Trauma Registry. AB - OBJECTIVE: To describes the experience in the implementation of a TRS in two hospitals in Cali, Colombia. METHODS: The TRS includes prehospitalary, during hospitalization and discharging status information of each patient. Each hospital has an electronic data capture strategy. A three month Pilot-period descriptive analysis is presented. RESULTS: 3293 patients has been registered, 1626 (49.4%) from the Public hospital and 1613 (50.6%) from the Private one. 67.2% were men; the mean age +/-SD was 30.5+/-20 years; 30.5% were less than 18 years. The overall mortality rate was 3.5%. The most frequent consulting cause were falls (33.7%); 11.6% of injuries are secondary to fire gunshot, and this group where mortality rate was 62%. CONCLUSION: It was determined the needing for the TRS implementation and the mechanisms to provide continuity. The registry becomes an information source for the investigation developing. It was identified the causes of consult, morbidity and death due to trauma that will allow a better planning of the emergency services and of the regional trauma system in order to optimize and reduce the attention costs. Based on optimal information system it will be able to present the necessary adjusts to redesign the Trauma and Emergencies Attention System in the Colombian South-West. PMID- 22936223 TI - Evaluation of the mortality due to external causes. AB - OBJECTIVE: External causes have become an important public health problem due to their high mortality, morbidity, costs, the loss of potential years of life and the impact for individuals, their families and society. The aim of this study was to analyze the characteristics of fatal victims of trauma in a microregion from Sao Paulo State. METHOD: This was a retrospective, transverse, exploratory and descriptive study. The Coroner's Office (IML) of Catanduva - SP - provided 511 medical records of the victims of external causes from 2008-2011. It was performed a survey and a review of those records and the data retrieved regarded gender, age, intentionality and mechanism of external cause. RESULTS: The mortality predominance was on male individuals (77.9% of the cases - p<0.001). Deaths classified as non intentional represented 66.9%, where as the intentional ones represented 33.1% (p<0.0001). Accidents caused by land transports were responsible for 45.6% of cases, being the main cause for the deaths analyzed. On second place there were suicides (16%), followed by the homicides (13.9%). CONCLUSION: The results of the present study were different from the profiles found in some other Brazilian studies, approaching to the reality of the developed countries, considering non-intentionality as preponderant and the main causes were accidents by land transports, suicides and homicides, respectively. Improvements should be done to assure the quality of information in the documentation of Forensic Physicians, since the lack of information in the Death Certificate was one of the difficulties found by the authors. PMID- 22936224 TI - Epidemiological analysis of 210 cases of surgically treated traumatic extradural hematoma. AB - OBJECTIVE: To assess the epidemiology, clinical and radiological presentation of patients with traumatic extradural hematoma (EDH) undergoing neurosurgical procedures. METHODS: We performed a chart review of 210 patients admitted to the emergency department with EDH diagnosed by CT scan and surgically treated between August 1998 and January 2008. Variables analyzed were: age, gender, clinical and radiological presentation, mechanism of injury and neurological status at discharge from hospital. RESULTS: In 49.2% trauma mechanism was fall; 89.2% of patients were male, 49.7% of cases had a Glasgow Coma Scale (GCS) between 13 and 15; 61% of patients had age between 20 and 49 years; the location of EDH was the temporo-parietal and temporal in 26.5% and 19.6% of the cases, respectively; 32.8% had associated intracranial lesions, with skull fractures seen in around 45% of cases; 76.2% of surgically treated patients were discharged with minimal or no neurologic deficit. CONCLUSION: We observed that, in the study population, EDH appears more often in males, in the fourth decade of life, and is more related to falls. On admission, GCS was observed between 13 and 15 and it is appropriate to mention the involvement of the temporo-parietal region in most cases. We believe that knowledge of the epidemiology of traumatic epidural hematoma can assist in developing public health measures aimed at prevention and early identification of this disease in the population. PMID- 22936225 TI - Retrospective study of heart injuries occurred in Manaus - Amazon. AB - OBJECTIVE: To evaluate the forms of treatment employed to heart injuries and the main aspects related to their morbidity and mortality. METHODS: A retrospective study of 102 patients with cardiac injuries treated in the two emergency rooms in Manaus (Dr. John Lucio Pereira Machado Emergency Hospital and August 28 County Emergency Hospital) from January 1998 to June 2006. RESULTS: Of the 102 patients, 95.1% were men; mean age was 27 years; stab wounds accounted for 81.4% of cases and gunshot wounds for 18.6%; cardiorrhaphy was performed in 98.1% of cases. The heart chambers affected were: Right Ventricle (RV): 43.9% (36.2% isolated and 7.7% associated with other chambers); Left Ventricle (LV): 37.2%; Right Atrium (RA): 8.5%; and Left Atrium (LA): 10.4%; specific mortalities were of 21%, 23%, 22% and 45%, respectively. The mortality injuries to two associated chambers was 37.5%, 20% being for RA + RV, 100% for RV + LV, and zero for RV + LA. The lung accounted for 33.7% of the 89 associated lesions. Mean time of surgery and hospital stay were 121 minutes and 8.2 days, respectively. About 22.5% of patients displayed 41 complications. The mortality rate was 28.4%. Lesions grade IV and V corresponded to 55% and 41% of cases, with specific mortality of 26% and 15%, respectively. All patients with grade injuries VI died. CONCLUSION: Cardiac stab wounds were associated with lower mortality, cardiac lesions grade IV were associated with higher mortality and a shorter operative time was associated with greater severity and mortality. PMID- 22936226 TI - Plain chest radiographs for the diagnosis of post-traumatic diaphragmatic hernia. AB - OBJECTIVE: To describe changes in the radiographic examination of the chest in patients with post-traumatic diaphragmatic hernia (PTDH) confirmed intra operatively. METHODS: Between January 1990 and August 2008 45 patients with PTDH were treated. We analyzed demographic data, cause of injury, changes in chest radiography (CXR), extent and location of the diaphragmatic lesion and herniated organs. We described the radiographic findings most frequently identified by surgeons and radiologists. RESULTS: CXR was performed on 32 patients, predominantly male (27 cases, 84.4%) and the mean age was 34 years. The most common cause of injury was blunt trauma (25 cases, 78.1%). Radiographic examination of the chest showed changes suggestive of PTDH in 26 cases (81.3%). During exploratory laparotomy, left PTDH was found in 28 cases (87.5%) and right in four (12.5%). The most frequently herniated organ was the stomach. CONCLUSION: The study showed that CXR is very useful in the initial diagnostic approach to PTDH. The difficulty is that diaphragmatic injuries, particularly after penetrating trauma, may initially go unnoticed, and without changes in the CXR images, diagnosis is made difficult. PMID- 22936227 TI - Non operative management of gunshot wounds on the right thoracoabdomen. AB - OBJECTIVE: To analyze the results after the implementation of the non-operative management (NOM) of the right upper thoracoabdominal gunshot injuries protocol. METHODS: Prospective study. From January 2005 to December 2011, 115 patients were included into this study. Criteria for inclusion were gunshot wound to the right thoracoabdominal region, haemodynamic stability, no signs of peritonitis, and realized CT scan. The data collected were analysed by the software EXCEL. RESULTS: Among the 115 patients included in our study, the mean age was 25.8 years old (range, 14-78 years old), of whom 95.6% were male, 62.6% had thoracoabdominal injuries and 37.4% had exclusively abdominal injuries. The averages of trauma scores were RTS 7.7, ISS 14.8 and TRISS 97%. One hundred and nine patients (94.8%) had liver injury, 72 (62.6%) had diaphragm and lung injury, 28 (24.4%) had renal injury. Complications were present in 12 (10.5%) patients, 7 of these related to the thorax. The NOM failure happened in 4 (3.5%) patients, 2 of them due to bile peritonitis, 1 related to bleeding and 1 the laparotomy was unnecessary. The mean hospital stay was 9.4 days. There were 2 deaths due to associated gunshot brain injury. Sixty seven patients (58.3%) were presented in the follow-up after 2 months of trauma. The CT scan showed injury scar in 58 patients (86.5%). CONCLUSION: NOM of the penetrating right thoracoabdominal injuries must be seen with caution. The NOM of right thoracoabdominal gunshot injuries is safe only in selected cases, followed by well-defined protocols and when performed in places that have adequate infrastructure. PMID- 22936228 TI - Predictors of abdominal injuries in blunt trauma. AB - OBJECTIVE: To identify predictors of abdominal injuries in victims of blunt trauma. METHOD: retrospective analysis of trauma protocols (collected prospectively) of adult victims of blunt trauma in a period of 15 months. Variables were compared between patients with abdominal injuries (AIS>0) detected by computed tomography or/and laparotomy (group I) and others (AIS=0, group II). Student's t, Fisher and qui-square tests were used for statistical analysis, considering p<0.05 as significant. RESULTS: A total of 3783 cases were included, with a mean age of 39.1 +/- 17.7 years (14-99), 76.1% being male. Abdominal injuries were detected in 130 patients (3.4%). Patients sustaining abdominal injuries had significantly lower mean age (35.4 + 15.4 vs. 39.2 + 17.7), lower mean systolic blood pressure on admission (114.7 + 32.4 mmHg vs. 129.1 + 21.7 mmHg), lower mean Glasgow coma scale (12.9 + 3.9 vs. 14.3 + 2.0), as well as higher head AIS (0.95 + 1.5 vs. 0.67 + 1.1), higher thorax AIS (1.10 + 1.5 vs. 0.11 + 0.6) and higher extremities AIS (1.70 +/- 1.8 vs. 1.03 +/- 1.2). Patients sustaining abdominal injuries also presented higher frequency of severe injuries (AIS>3) in head (18.5% vs. 7.9%), thorax (29.2% vs. 2.4%) and extremities (40.0% vs. 13.7%). The highest odds ratios for the diagnosis of abdominal injuries were associated flail chest (21.8) and pelvic fractures (21.0). CONCLUSION: Abdominal injuries were more frequently observed in patients with hemodynamic instability, changes in Glasgow coma scale and severe lesions to the head, chest and extremities. PMID- 22936229 TI - Epidemiological evaluation of abdominal trauma victims submitted to surgical treatment. AB - OBJECTIVE: To evaluate the profile and outcome of victims of abdominal injuries who underwent laparotomy in the Emergency Hospital of the state of Sergipe (HUSE). METHODS: This was an observational, descriptive longitudinal study with prospective approach, through interviews of 100 patients with abdominal trauma who underwent surgery and evaluation of their medical records. The study period was from September to November of 2011 in the area of trauma care of the HUSE. RESULTS: the most affected individuals were male, mulattos, aged 25-49 years, with low education, single, Catholic, with an income of 1-2 minimum wages. There was a predominance of trauma in the urban areas, at night and on weekends. The most frequent cause of trauma was the attempted of murder associated with the use of alcohol and illicit drugs, and the most frequent mechanism, stabbing. The pain was the most frequent symptom. The most affected region was the upper abdomen and liver was the most affected organ. The hospital stay averaged 4-10 days. Most patients were discharged without sequelae. There were 2 deaths. CONCLUSION: In the HUSE, the association of abdominal trauma with men under the influence of alcohol and illegal drugs was striking, reflecting the context of interpersonal violence in current society. Despite the magnitude of the traumas, the outcome was satisfactory, although deaths, occurred, demonstrating the importance of keeping a trained surgical team in emergency hospitals. PMID- 22936230 TI - Blunt hepatic trauma: comparison between surgical and nonoperative treatment. AB - OBJECTIVE: To examine the outcomes of blunt hepatic trauma, and compare surgical and non-surgical treatment in patients admitted with hemodynamic stability and with no obvious indications of laparotomy. METHODS: This is a retrospective study of cases admitted to a university teaching hospital between the years 2000 and 2010. Patients undergoing surgical treatment were divided into two groups: (a) all patients undergoing surgical treatment, and (b) patients with obvious need for surgery. RESULTS: In this period, 120 patients were admitted with blunt hepatic trauma. Sixty five patients (54.1%) were treated non-operatively and fifty five patients were operated upon. Patients treated non-operatively had better physiologic conditions on admission, demonstrated less severe injuries (except the grade of hepatic injury), received less blood components and had lower morbidity and mortality than the patients operated upon. Patients who underwent non-operative treatment had a lower need for blood transfusion but higher rates of complications and mortality than the patients operated upon. Patients who were operated upon, with no obvious indications for surgery, had higher rates of complication and mortality than patients not operated upon. CONCLUSION: A non-operative approach resulted in lower complications, a lower need for blood transfusions and lower mortality. PMID- 22936231 TI - Damage control surgery: it's evolution over the last 20 years. AB - In less than twenty years, what began as a concept for the treatment of exsanguinating truncal trauma patients has become the primary treatment model for numerous emergent, life threatening surgical conditions incapable of tolerating traditional methods. Its core concepts are relative straightforward and simple in nature: first, proper identification of the patient who is in need of following this paradigm; second, truncation of the initial surgical procedure to the minimal necessary operation; third, aggressive, focused resuscitation in the intensive care unit; fourth, definitive care only once the patient is optimized to tolerate the procedure. These simple underlying principles can be molded to a variety of emergencies, from its original application in combined major vascular and visceral trauma to the septic abdomen and orthopedics. A host of new resuscitation strategies and technologies have been developed over the past two decades, from permissive hypotension and damage control resuscitation to advanced ventilators and hemostatic agents, which have allowed for a more focused resuscitation, allowing some of the morbidity of this model to be reduced. The combination of the simple, malleable paradigm along with better understanding of resuscitation has proven to be a potent blend. As such, what was once an almost lethal injury (combined vascular and visceral injury) has become a survivable one. PMID- 22936232 TI - Complicated diverticular disease: the changing paradigm for treatment. AB - The term "complicated" diverticulitis is reserved for inflamed diverticular disease complicated by bleeding, abscess, peritonitis, fistula or bowel obstruction. Hemorrhage is best treated by angioembolization (interventional radiology). Treatment of infected diverticulitis has evolved enormously thanks to: 1) laparoscopic colonic resection followed or not (Hartmann's procedure) by restoration of intestinal continuity, 2) simple laparoscopic lavage (for peritonitis +/- resection). Diverticulitis (inflammation) may be treated with antibiotics alone, anti-inflammatory drugs, combined with bed rest and hygienic measures. Diverticular abscesses (Hinchey Grades I, II) may be initially treated by antibiotics alone and/or percutaneous drainage, depending on the size of the abscess. Generalized purulent peritonitis (Hinchey III) may be treated by the classic Hartmann procedure, or exteriorization of the perforation as a stoma, primary resection with or without anastomosis, with or without diversion, and last, simple laparoscopic lavage, usually even without drainage. Feculent peritonitis (Hinchey IV), a traditional indication for Hartmann's procedure, may also benefit from primary resection followed by anastomosis, with or without diversion, and even laparoscopic lavage. Acute obstruction (nearby inflammation, or adhesions, pseudotumoral formation, chronic strictures) and fistula are most often treated by resection, ideally laparoscopic. Minimal invasive therapeutic algorithms that, combined with less strict indications for radical surgery before a definite recurrence pattern is established, has definitely lead to fewer resections and/or stomas, reducing their attendant morbidity and mortality, improved post-interventional quality of life, and less costly therapeutic policies. PMID- 22936233 TI - Profile of brazilian dissertations and theses on trauma: a documentary research. AB - OBJECTIVE: To characterize the dissertations and theses available in the Bank of Theses of the Coordination for the Improvement of Higher Education Personnel (CAPES) that deal with trauma. METHODS: This is a documentary research on the characterization of Brazilian theses and dissertations that deal with trauma, available at the CAPES Theses Database. Data collection was carried out in March 2012, by master's degree students and PhDs, following a research protocol. RESULTS: A total of 411 dissertations and theses about trauma were analyzed. We elucidated considerations on the following aspects of the selected studies: academic level, location of conduction of the work, author's training, methodological design, theme and type of trauma. CONCLUSION: The significant amount of studies analyzed reveals the importance of trauma in the current scenario, the expansion of graduate programs and researchers being in line with the theme that alarmingly affects the national and international epidemiology. PMID- 22936234 TI - Analysis of the YouTube videos on basic life support and cardiopulmonary resuscitation. AB - OBJECTIVE: To analyze the videos on the YouTube video sharing site, noting which points addressed in the videos related to CPR and BLS, based on the 2010 Guidelines for the American Heart Association (AHA). METHODS: This was an exploratory, quantitative and qualitative research performed in the YouTube sharing site, using as keywords the expressions in Portuguese equivalent to the Medical Subject Headings (MeSH) "Cardiopulmonary Resuscitation" and "Basic Life Support" for videos that focused on the basic life support. RESULTS: The research totaled 260 videos over the two searches. Following the exclusion criteria, 61 videos remained. These mostly are posted by individuals and belong to the category Education. Moreover, most of the videos, despite being added to the site after the publication of the 2010 AHA Guidelines, were under the older 2005 guidelines. CONCLUSION: Although the video-sharing site YouTube is widely used today, it lacks videos about CPR and BLS that comply to the most recent AHA recommendations, which may negatively influence the population that uses it. PMID- 22936235 TI - Emergency room volunteer internship: an instrument for quality in medical training. AB - OBJECTIVE: To analyze the influence of medical student's voluntary internship at the Emergency Room of the Workers Hospital (ER-HT) in the choice of medical specialty and its importance during graduation. METHODS: A questionnaire was given to doctors and medical students that performed internships at ER-HT for e" 500 hours, from March 2000 until March 2012. RESULTS: A total of 765 medical students and doctors performed e" 500 hours of practical activities at ER-HT and 390 answered the questionnaire - 37,9% chose surgical specialties and 24,1% clinical. Internship was crucial in choosing a career for 82,3%, and was a positive influence for 83,8%. Regarding the increment in interpersonal relationship, grade e" 8 was given by 61% of the participants for relationship with other professionals, 71% for relationship with colleagues and 63% for relationship with patients. The internship increased self-confidence for 92% and 75% reported an increase in technical knowledge. The training was considered useful and necessary for medical education to 80% of participants. CONCLUSION: Contribution provided by ER internships is undeniable for medical education and often influences students on choosing their medical specialties. The situations faced by students during these activities enable the development of intelligence in areas other than purely technical, which reflects in their medical practice. PMID- 22936236 TI - [Management of retained hemothoraces after chest tube thoracostomy for trauma]. PMID- 22936237 TI - Combined intra-arterial infusion and systemic chemoradiotherapy for stage IV squamous cell carcinoma of the mandibular gingiva. AB - PURPOSE: The purpose of this study was to show the effectiveness of combining intra-arterial infusion and systemic chemotherapy with concurrent radiotherapy for treatment of stage IV mandibular gingival cancer. MATERIALS AND METHODS: A total of 23 patients with mandibular gingival cancer were treated with either docetaxel by intra-arterial infusion followed by systemic chemoradiotherapy with cisplatinum and 5-fluorouracil as a monthly regimen, or with docetaxel and cisplatinum by intra-arterial infusion followed by systemic chemoradiotherapy with 5-fluorouracil as a weekly or biweekly regimen. Tumor responses, locoregional control, overall survival, disease-specific survival, and adverse events were evaluated. RESULTS: Of the 23 patients enrolled in the study, 22 completed the treatment. With regard to clinical stages, 82 % were diagnosed as IVA and 18 % IVB. Complete and partial response was observed in 82 and 18 %, respectively. Five-year overall survival, disease-specific survival, and locoregional control were 51, 70, and 72 %, respectively. No statistically significant difference was seen between the monthly regimen and the weekly plus biweekly regimen, although the latter resulted in longer survival and 88 % control. CONCLUSION: Combined intra-arterial infusion and systemic chemoradiotherapy may be an effective treatment for patients with stage IV mandibular gingival cancer. PMID- 22936238 TI - Quality of care in accredited and nonaccredited hospitals: perceptions of nurses in the Eastern Province, Saudi Arabia. AB - BACKGROUND: Although Saudi Arabia is one of the first countries in the Eastern Mediterranean Region to implement healthcare accreditation standards, little is known about its impact on nurse assessment of the provision of healthcare. OBJECTIVE: The main objectives of this study were to determine the quality of healthcare services provided by accredited and nonaccredited hospitals on the basis of the views of nurses. In addition, this study aimed to explore the potential contributing factors affecting the quality of care. METHODS: A cross sectional study was carried out at one accredited and another nonaccredited hospital at Al-Khobar city, Saudi Arabia. A questionnaire was used to assess nurses' perceptions of the quality of healthcare provided in the target hospitals on a five-point Likert scale tool. A total of 164 nurses were surveyed. MAIN OUTCOME MEASURES: Quality of healthcare services and the potential contributing factors affecting the quality of care. RESULTS: The most highly rated scales by nurses were 'education & training' (mean=4.09), followed by 'quality management' (mean=3.96) at the accredited hospital compared with 'use of data' (mean=3.56) and 'strategic quality planning' (mean=3.56) at the nonaccredited hospital. For both hospitals, the lowest scores were assigned to the 'reward' (mean=2.78 and 3.06 by nurses at accredited and nonaccredited hospitals, respectively). Nurses' rating for all scales was higher in the accredited compared with the nonaccredited hospital, except for the reward scale. The difference was statistically significant for all scales, except human resource utilization (P<=0.02). In accredited hospitals and for different scales, nurses with 4-6 years of experience, Saudi nurses, and those aged 30-35 years had significantly higher agreement scores than their counterparts. For the accredited hospitals, the predictors of good-quality results were leadership, commitment and support (P=0.019), and strategic quality planning (P=0.007). For nonaccredited hospitals, predictors of good quality results were leadership, commitment, and support (P=0.001). CONCLUSION: As perceived by nurses in study hospitals, accredited hospitals perform favorably compared with nonaccredited hospitals in almost all quality scales. Thus, accreditation can be considered a tool for improving hospital quality. The most important determinants of quality in healthcare were leadership, commitment and support, and strategic quality planning. PMID- 22936239 TI - Impact of medical curriculum on conceptualization of professionalism by residents at a University Hospital, Jeddah, Saudi Arabia. AB - BACKGROUND: The quality of healthcare outcomes and patient satisfaction are affected by communication skills and professionalism of the physician. Medical curricula have substantial influence on physicians' perception of professionalism. OBJECTIVES: The aim of this study was to determine the impact of medical curriculum on the values of the residents at King Abdulaziz University Hospital, Jeddah, Saudi Arabia, and their opinions on professionalism and to identify the sources that they describe as most influential in shaping their views. METHODS: This cross sectional study was conducted in 2010/2011. A modified version of the questionnaire designed by Blue and colleagues was distributed among the target group (n=201). Psychometric analysis of the survey tool showed that it was precise and had construct validity. RESULTS: The return rate was 76.6%. The overall means of the attitudes of both male and female residents toward the attributes of professionalism were low. Attitude toward professionalism showed an insignificant difference between male and female residents. Self-reflection ranked first among all studied attributes. Most male (80%) and female (76.7%) residents believed that working with consultants, specialists, and senior residents in the hospital was the main source of their opinions on professionalism. They considered basic science studies and the other extracurricular courses they attended to be the least helpful in developing their opinions. CONCLUSION AND RECOMMENDATIONS: Residents at King Abdulaziz University Hospital feel underserved in the area of developing their values toward professionalism during the preclinical years, relying to some extent on their experiences during their clinical years and mainly on their interactions with consultants, colleagues, and hospital staff to develop their sense of professionalism. Given the recent changes in the curriculum adopted by the university, it is recommended to assess the attitudes of the students under the new curriculum toward professionalism and to compare them with those of students under the traditional curriculum. PMID- 22936240 TI - Risk factors of perinatal and neonatal mortality in Alexandria, Egypt. AB - BACKGROUND: Egypt has already achieved the goal of reducing the under-five mortality rate (U5MR) by two-thirds. However, one of the challenges that Egypt currently faces is how to reduce the perinatal and neonatal mortality (PM, NM). This study aimed to identify the social and biomedical risk factors contributing toward PM and NM in Alexandria, Egypt. PARTICIPANTS AND METHODS: A case-control design was used. Cases were 150 mothers whose index pregnancy terminated in perinatal (from the 28th week of pregnancy to less than 7 days after birth) and neonatal deaths (from the seventh day to less than the 28th day after birth). They were selected from the antenatal clinic and neonatal care unit of ElShatby University hospital for Obstetrics and gynecology. Controls were 150 mothers with live births ranging in age from 28 days up to 2 months selected from the outpatient clinics of ElShatby University Hospital for Pediatrics. RESULTS: Stepwise logistic regression analysis indicated a higher risk of PM/NM among very young or very old mothers (OR=4.1 and 6.46, respectively), those who had previous PM/NM [odds ratio (OR)=12.7; 95% confidence interval (CI): 5.04-29.54], grand multiparous (OR=2.23; 95% CI: 1.50-5.42), those with infrequent antenatal visits (OR=3.88; 95% CI: 2.26-6.65), and mothers with complications during the index pregnancy (OR=9.21; 95% CI: 3.40-24.95). CONCLUSION: This study confirms the evidence of a positive association between PM/NM and maternal age, obstetric history, and utilization of healthcare services. Appropriate age at marriage and pregnancy, spacing of and limiting the number of births, and improving antenatal, natal, and postnatal care are priority actions that can reduce PM/NM in Alexandria. PMID- 22936241 TI - Prevalence of hearing impairment and its correlates among a group of hospitalized chronically ill elderly patients in Alexandria, Egypt. AB - BACKGROUND: Hearing impairment (HI) is one of the most common health problems among the elderly. The major risk factors for HI include aging, exposure to noise, chronic morbidities, and ototoxic drugs. Although the relation between HI and chronic morbidities among the elderly is well documented, it often receives minimal attention. The aim of this study was to determine the prevalence of HI and its correlates among a group of hospitalized chronically ill elderly patients in Alexandria, Egypt. PARTICIPANTS AND METHODS: A descriptive cross-sectional study was carried out on 370 chronically ill elderly patients in the internal medicine wards of Alexandria Main University Hospital. A structured pre-coded interview schedule was used to collect data on sociodemographic characteristics and medical history. A questionnaire for screening for HI in the elderly was also used. RESULTS: The majority of elderly patients (78.6%) complained of HI. HI was prevalent among all elderly patients aged 90 years and older. It was also more prevalent among women (82.2%), among single and divorced elderly patients (95.7 and 91.7%, respectively), among those who were illiterate or could only read and write (93.2%), among all skilled workers, and among housewives (82.2%). HI was also most prevalent among elderly patients who lived alone (82.6%), hypertensive elders (87.6%), and elderly patients taking analgesics (85.4%). CONCLUSION AND RECOMMENDATIONS: Hypertension and the intake of a number of medications were significantly associated with HI. It is recommended to use screening procedures for the identification of individuals with HI and to refer them for further audiologic evaluation. PMID- 22936242 TI - Research practices and publication obstacles among interns at King Abdulaziz University Hospital, Jeddah, Saudi Arabia, 2011-2012. AB - BACKGROUND: Medical students can play a vital role in health research at any institute. Moreover, scientific publication by medical students is a strong indicator of students' knowledge, skills and attitudes towards scientific research. Very little information exists, however, on this matter in Saudi Arabia. SUBJECTS AND METHODS: This cross-sectional study was conducted to assess the publication practices of medical interns who graduated from King Abdulaziz University Faculty of Medicine and to investigate barriers to conducting and publishing research during their medical studies. A questionnaire was distributed to 394 interns and 249 (63.2%) responded. RESULTS: About 31% of the responding interns started research during their undergraduate study years. About 12% discontinued their research, whereas only 7% submitted their research for publication. Only 3.2% of the interns had their research papers published and 3.2% had their research paper accepted for publication; 2% had research papers under revision. Interns had positive attitudes towards research, although only a few of them had submitted their papers for publication. Furthermore, interns expressed the need for training in research design, scientific paper writing and publication practice. They recommended devoting slots in medical school curriculum, in addition to other extracurricular training workshops, to teach and train students on such practices and also to provide more convenient opportunities for student participation in conferences. CONCLUSION AND RECOMMENDATIONS: Interns in King Abdulaziz University Faculty of Medicine have a positive attitude towards research; however, few students submit papers for publication. Lack of time and training in research methods were the main obstacles cited by the interns for conducting and publishing research. Interns welcome training in research, scientific writing and publication practice. These requirements will be issued to the main curriculum committee at the faculty of medicine and recommendations on possible actions will be discussed with the administration. PMID- 22936243 TI - Adherence to and outcome of isoniazid chemoprophylaxis among household contact children of adults having pulmonary tuberculosis in Alexandria, Egypt. AB - BACKGROUND: Current international guidelines recommend 6-9 months of isoniazid (INH) preventive chemotherapy to prevent the development of active tuberculosis (TB) in susceptible children exposed to Mycobacterium tuberculosis. However, this is dependent on good adherence, as shown by previous studies. OBJECTIVES: This study was conducted to describe the outcome of screening of contact children aged 5 years or less with household exposure to an adult pulmonary TB index case to determine the prevalence and possible risk factors of infection among contact children and to determine the extent and outcome of adherence of contact children to unsupervised INH chemoprophylaxis for 6 months. METHODS: A descriptive facility-based cross-sectional study was conducted from March 2009 to August 2010. Research settings were three of the National TB control program chest dispensaries (primary care facilities) in Alexandria, Egypt. Facility-based TB treatment registers of the previous 3 months were used to identify all new adult pulmonary TB cases. All children aged 5 years or less living in the same house as the index cases were identified and screened for TB. The contact children were given unsupervised INH preventive chemotherapy once active TB was excluded. Adherence to and outcome of preventive chemotherapy were followed up. Preventive chemotherapy consisted of unsupervised INH monotherapy for 6 months with monthly collection of tablets from the clinic. Adherence was documented after completion of the 6-month preventive treatment period. Adherence was considered reasonable if tablets were collected for more than 4 months, poor if collected for 2-4 months, and very poor if collected for less than 2 months. OUTCOME MEASURES: (a) Prevalence of infection and disease and the possible risk factors among contacts. (b) The extent and outcome of adherence to unsupervised INH chemoprophylaxis among contact children. (c) Factors behind poor adherence. RESULTS: In total, 197 adult TB index cases from 187 households were identified. In all, 297 children aged 5 years or less experienced household exposure, of whom 252 (84.9%) were fully evaluated. Tuberculin test was positive in 136 of the 252 child contacts (54.0%), of whom 130 were contacts of sputum-positive patients and six were contacts of sputum-negative patients. The important risk factors for transmission of TB infection were younger age, male sex, severe malnutrition, absence of BCG vaccination, contact with a sputum-positive adult who was a source case, household overcrowding, and exposure to environmental tobacco smoke. Thirty-three children were diagnosed and treated for TB at the baseline screening and 217 received preventive INH chemotherapy. Of the children who received preventive chemotherapy, only 36 (16.6%) completed at least 4 months of unsupervised INH monotherapy. During the subsequent follow-up period, eight children developed TB (secondary attack rate for TB disease was 3.7%), of whom four received no preventive chemotherapy and four were poorly adherent. CONCLUSION: The prevalence of TB infection and clinical disease among children in household contact with adult patients is high, and risk is significantly increased because of child contact, index patients and environmental factors. Adherence to 6 months of unsupervised INH chemoprophylaxis was very poor. PMID- 22936244 TI - Epidemiology of nosocomial infections and mortality following congenital cardiac surgery in Cairo University, Egypt. AB - BACKGROUND: Nosocomial infections (NI) have been associated with significant morbidity and attributed mortality, as well as increased healthcare costs. Relatively few data on congenital cardiac surgical ICU NI have been reported from developing countries. Little is known about the epidemiology of NI following congenital cardiac surgery in Egypt. The aims of the present study were: (a) to estimate the incidence rate and types of NI among children admitted to Pediatric Surgical Cardiac ICU in Cairo University Children's Hospital (Egypt) and (b) to estimate the mortality rate related to congenital cardiac surgery and identify its contributing risk factors. PARTICIPANTS AND METHODS: A follow-up study in the period between 1 January 2009 and 1 January 2010 included all patients admitted to the Pediatric Surgical Cardiac ICU in Cairo University, Abo El Reesh Children's Specialized Hospital (Egypt). Data were collected for each patient during the preoperative, intraoperative, and postoperative periods. Certain infection control procedures were carried out in certain months. RESULTS: Of 175 patients, NI were identified in 119 (68%). Poor hand hygiene was associated with increased NI in certain months of the study duration. NI were significantly higher at a younger age [median 9 (5-30) months, P<0.03]. Mortality was found in 54 patients, that is, 31% of the study population. Mortality was significantly observed with younger age, higher complexity score for congenital cardiac lesions, prolonged cardiopulmonary bypass and ischemic times, NI, prolonged mechanical ventilation, prolonged central line insertion, and the use of total parenteral nutrition. Mortality among the NI patients was found in 44 of 119 (37%). On carrying out a multivariate analysis, Acute Physiology and Chronic Health Evaluation II score [P<0.001, odds ratio (OR) 1.13, 95% confidence interval (CI) 1-1.2], age (P<0.001, OR 0.3, 95% CI 0.2-0.4), and prolonged duration of mechanical ventilation (P<0.03, OR 2.8, 95% CI 1.1-7.2) were identified as risk factors of mortality. CONCLUSION AND RECOMMENDATIONS: NI rate and subsequent mortality were high among cases followed up during the period from 1 January 2009 to 1 January 2010 in the University Children's Hospital (Cairo, Egypt). Early surgical interference, enforcement of proper infection control practices, especially hand hygiene, can reduce NI and trials for early extubation from mechanical ventilation might improve outcome following congenital cardiac surgery in pediatrics. PMID- 22936245 TI - Increased expression of TRPV1 in the cortex and hippocampus from patients with mesial temporal lobe epilepsy. AB - Transient receptor potential vanilloid type-1 (TRPV1) is a ligand-gated nonselective cation channel that has been well characterized in peripheral pain pathway. Recent evidence from animal models of temporal lobe epilepsy (TLE) has supported the important role of TRPV1 in epileptogenesis. In this study, we investigated the expression and cellular distribution of TRPV1 in the temporal cortex (CTX) and hippocampus (HPC) from 26 patients with mesial TLE (MTLE) compared with 12 histologically normal samples. Reverse transcription-PCR and Western blotting revealed up-regulated mRNA and protein levels of TRPV1 in the MTLE group versus the control group. Immunohistochemistry data demonstrated that TRPV1 was mainly distributed in the cell bodies and dendrites of neurons. Double labeled immunofluorescence further revealed that TRPV1 was localized on NeuN positive neurons and GFAP-positive astrocytes, but not on HLA-positive microglia. In addition, its co-localization with glutamate and gamma-aminobutyric acid (GABA) indicated that TRPV1 was distributed on both glutamatergic and GABAergic neurons. Moreover, nerve growth factor, a sensitizing factor for TRPV1, was showed a higher expression pattern in MTLE patients. Taken together, our findings suggest that the overexpression and distribution patterns of TRPV1 might be involved in the pathogenesis and epileptogenesis of human MTLE. PMID- 22936247 TI - Gold nanoparticles confined in the interconnected carbon foams with high temperature stability. AB - Gold nanoparticle-carbon foam composites with highly-dispersed gold nanoparticles confined in the cavities were prepared. The gold nanoparticles are effectively separated from each other by permeable carbon shells, which show high temperature stability and were fully accessible to the substrate. PMID- 22936246 TI - TGFbeta1 treatment reduces hippocampal damage, spontaneous recurrent seizures, and learning memory deficits in pilocarpine-treated rats. AB - Studies have demonstrated the neuroprotective activity of transforming growth factor beta-1 (TGFbeta1), protecting neurons against different kinds of insults. However, the role of exogenous TGFbeta1 in the neuronal damage following status epilepticus (SE) and the related spontaneous recurrent seizures (SRS) is unknown. The present study aimed to determine the effect of intranasal TGFbeta1 administration on SRS and cognitive function following lithium-pilocarpine induced SE and associated hippocampal damage. We found that intranasal TGFbeta1 significantly attenuated the hippocampal insults marked by hematoxylin and eosin, terminal deoxynucleotidyl transferase dUTP nick end labeling, and Fluoro-Jade B staining by 24, 48, and 72 h after SE was induced. The expression of the apoptosis-suppressing protein, Bcl-2, was elevated, whereas the expression of the apoptosis-promoting proteins, Bax and Caspase-3, was suppressed in TGFbeta1 treated rats compared to rats without TGFbeta1 treatment by 24, 48, and 72 h following induction of SE. The seizure number, severity, and duration of SRS over a 1-month period of monitoring starting 15 days after SE induction as well as the cognitive deficits detected 45 days after SE induction were significantly reduced in TGFbeta1-treated rats compared to those without TGFbeta1 treatment. Our results indicate that intranasal delivery of TGFbeta1 immediately after SE induction not only protected against SRS but also improved cognitive function. The anti-epileptogenic properties of TGFbeta1 may be related to its effect of neuroprotection or to its effect of apoptosis pathway changes. PMID- 22936248 TI - High-fidelity promoter profiling reveals widespread alternative promoter usage and transposon-driven developmental gene expression. AB - Many eukaryotic genes possess multiple alternative promoters with distinct expression specificities. Therefore, comprehensively annotating promoters and deciphering their individual regulatory dynamics is critical for gene expression profiling applications and for our understanding of regulatory complexity. We introduce RAMPAGE, a novel promoter activity profiling approach that combines extremely specific 5'-complete cDNA sequencing with an integrated data analysis workflow, to address the limitations of current techniques. RAMPAGE features a streamlined protocol for fast and easy generation of highly multiplexed sequencing libraries, offers very high transcription start site specificity, generates accurate and reproducible promoter expression measurements, and yields extensive transcript connectivity information through paired-end cDNA sequencing. We used RAMPAGE in a genome-wide study of promoter activity throughout 36 stages of the life cycle of Drosophila melanogaster, and describe here a comprehensive data set that represents the first available developmental time-course of promoter usage. We found that >40% of developmentally expressed genes have at least two promoters and that alternative promoters generally implement distinct regulatory programs. Transposable elements, long proposed to play a central role in the evolution of their host genomes through their ability to regulate gene expression, contribute at least 1300 promoters shaping the developmental transcriptome of D. melanogaster. Hundreds of these promoters drive the expression of annotated genes, and transposons often impart their own expression specificity upon the genes they regulate. These observations provide support for the theory that transposons may drive regulatory innovation through the distribution of stereotyped cis-regulatory modules throughout their host genomes. PMID- 22936249 TI - A second-generation assembly of the Drosophila simulans genome provides new insights into patterns of lineage-specific divergence. AB - We create a new assembly of the Drosophila simulans genome using 142 million paired short-read sequences and previously published data for strain w(501). Our assembly represents a higher-quality genomic sequence with greater coverage, fewer misassemblies, and, by several indexes, fewer sequence errors. Evolutionary analysis of this genome reference sequence reveals interesting patterns of lineage-specific divergence that are different from those previously reported. Specifically, we find that Drosophila melanogaster evolves faster than D. simulans at all annotated classes of sites, including putatively neutrally evolving sites found in minimal introns. While this may be partly explained by a higher mutation rate in D. melanogaster, we also find significant heterogeneity in rates of evolution across classes of sites, consistent with historical differences in the effective population size for the two species. Also contrary to previous findings, we find that the X chromosome is evolving significantly faster than autosomes for nonsynonymous and most noncoding DNA sites and significantly slower for synonymous sites. The absence of a X/A difference for putatively neutral sites and the robustness of the pattern to Gene Ontology and sex-biased expression suggest that partly recessive beneficial mutations may comprise a substantial fraction of noncoding DNA divergence observed between species. Our results have more general implications for the interpretation of evolutionary analyses of genomes of different quality. PMID- 22936251 TI - A one-pot regioselective synthesis of benzo[d]imidazo[2,1-b]thiazoles. AB - Benzo[d]imidazo[2,1-b]thiazole analogues were synthesized via a one-pot metal free procedure. A series of benzene and pyridine substrates were employed to the methodology. The desired products were generated in moderate to good yields. The effect of substituent group had also been studied. PMID- 22936250 TI - Time series community genomics analysis reveals rapid shifts in bacterial species, strains, and phage during infant gut colonization. AB - The gastrointestinal microbiome undergoes shifts in species and strain abundances, yet dynamics involving closely related microorganisms remain largely unknown because most methods cannot resolve them. We developed new metagenomic methods and utilized them to track species and strain level variations in microbial communities in 11 fecal samples collected from a premature infant during the first month of life. Ninety six percent of the sequencing reads were assembled into scaffolds of >500 bp in length that could be assigned to organisms at the strain level. Six essentially complete (~99%) and two near-complete genomes were assembled for bacteria that comprised as little as 1% of the community, as well as nine partial genomes of bacteria representing as little as 0.05%. In addition, three viral genomes were assembled and assigned to their hosts. The relative abundance of three Staphylococcus epidermidis strains, as well as three phages that infect them, changed dramatically over time. Genes possibly related to these shifts include those for resistance to antibiotics, heavy metals, and phage. At the species level, we observed the decline of an early-colonizing Propionibacterium acnes strain similar to SK137 and the proliferation of novel Propionibacterium and Peptoniphilus species late in colonization. The Propionibacterium species differed in their ability to metabolize carbon compounds such as inositol and sialic acid, indicating that shifts in species composition likely impact the metabolic potential of the community. These results highlight the benefit of reconstructing complete genomes from metagenomic data and demonstrate methods for achieving this goal. PMID- 22936252 TI - Acute social stress increases biochemical and self report markers of stress without altering spatial learning in humans. AB - OBJECTIVES: Spatial learning is shown to be influenced by acute stress in both human and other animals. However, the intricacies of this relationship are unclear. Based on prior findings we hypothesized that compared to a control condition, a social stress condition would not affect spatial learning performance despite elevated biochemical markers of stress. METHODS: The present study tested the effects of social stress in human males and females on a subsequent spatial learning task. Social stress induction consisted of evaluative stress (the Trier Social Stress Test, TSST) compared to a placebo social stress. RESULTS: Compared to the placebo condition, the TSST resulted in significantly elevated cortisol and alpha amylase levels at multiple time points following stress induction. In accord, cognitive appraisal measures also showed that participants in the TSST group experienced greater perceived stress compared to the placebo group. However, there were no group differences in performance on a spatial learning task. CONCLUSION: Our findings suggest that unlike physiological stress, social stress does not result in alterations in spatial learning in humans. It is possible that moderate social evaluative stress in humans works to prevent acute stress-mediated alterations in hippocampal learning processes.. PMID- 22936253 TI - Altered dopamine D1 and D2 receptor mRNA expression in mesencephalon from mice exposed to repeated treatments with methamphetamine and cannabinoid CB1 agonist methanandamide. AB - OBJECTIVES: In our previous studies we found that both acute administration of CB1 receptor agonist methanandamide and repeated methanandamide pre-treatment prior to methamphetamine challenge dose elicited increase in the CB1 receptor mRNA expression in the mouse mesencephalon. As a reciprocal cross-talk is reported between the cannabinoid CB1 and dopamine receptors, that are highly co localized on brain neurones, we targeted possible changes in relative expression of dopamine D1 and D2 receptor mRNA in mesencephalon in mice sensitized by repeated treatments to methamphetamine stimulatory effects and cross-sensitized to methamphetamine by cannabinoid CB1 receptor agonist methanandamide pre treatment. METHODS: To confirm development of behavioural sensitization or cross sensitization, respectively, we observed changes in locomotion using the open field test. Mice were treated repeatedly with either methamphetamine or methamphetamine after repeated pre-treatment with methanandamide. After each measurement of locomotion one third of animals were sacrificed and the brain was stored. RNA was isolated from the midbrain and used for reverse transcription and subsequent real-time PCR. RESULTS AND CONCLUSION: As in many of our earlier studies with the same dosage regimen we found in the behavioural part both development of sensitization to methamphetamine stimulatory effects after repeated treatment and cross-sensitization to them by pre-treatment with cannabinoid receptor CB1 agonist methanandamide. Real-time PCR analyses showed an increase in D1 receptor mRNA expression after the first dose of methamphetamine (that persisted also after the last dose of methamphetamine) and after the first dose of methanandamide (which also persisted after the methamphetamine challenge dose). In opposite a significant decrease in D2 receptor mRNA expression both after the first dose of methamphetamine and methanandamide (that persisted also after the methamphetamine challenge doses) was registered. Thus, our results suggest that both methamphetmine and methanandamide treatment can provoke changes in dopamine receptor density in mouse mesenpcephalon, the increase in D1 and decrease in D2 receptor subtypes. PMID- 22936254 TI - Changes in attenuation characteristics of axial system of pregnant drivers detected by the TVS method. AB - OBJECTIVES: During a longer car drive there are changes in rheological properties of driver's or passenger's connective tissues taking place as a consequence of monotonous and vibration load. These changes show more among the pregnant drivers, whose motion system is under heavier demands due to pregnancy. To asses these changes we have used the TVS (transfer vibration through the spine) method. METHODS: The TVS is based on application of gamma excitation pulses with half length 5 ms and then harmonic excitation continuously periodically changing from 5 Hz to 160 Hz on C7 and L5 vertebrae. This wave is transferred along the axial system and the acceleration of all the spinous tips of the vertebrae, along which the waves spread between C7 and S1, is detected by accelerometric sensors. The measurement was carried out on three drivers before and after a 4-hours driving. The same measurements of wave transfer along the spine with just one pregnant woman were carried out in th 16th, 26th and 32nd week of pregnancy. Consequently we constructed a simplified model of the spine in order to analyze gathered data by discovering elementary properties of the measured system. RESULTS: After both vibration and physical load there is a more significant dampening of the spinal tissues apparent, i.e. lower acceleration amplitude and the tissues resonance frequency also shifts towards the lower frequencies. On the other hand after long lasting relaxation on a bed an opposite tendency showed, the acceleration amplitude was higher, tissues were relaxed and dampening was lower. The same tendency manifested among the pregnant women. The influence of progressing pregnancy on the spinal segment transfer function showed through a shifting of peaks above 20Hz. Their size also changes monotonously. An absorption area moves towards higher frequencies, rigidity of axial system connections grows. CONCLUSION: The results say that drivers, including pregnant women, show changes in mechanical properties of examined tissues before and after vibration or other type of load. Or conversely before and after relaxation on a bed. Results of this work will be further analyzed, verified and evaluation procedures will be improved. We expect to find dependencies between excitation and resonance frequencies during the transfer via the axial system, the rheological properties of the axial system components and the physical nature of the load of the axial system. They are then going to be applicable for the prevention of injuries of the axial system, physiotherapy practices in the rehabilitation of post-operative conditions, the dosage of training loads of athletes, in determining the effects of job stress regimes and their prevention. PMID- 22936255 TI - Chronomedicine: an old concept's fledging? A selective literature search. AB - Chronomedicine may be conceptualized as dealing with the prevention, causation, diagnosis, and treatment of diseases in humans with a particular focus on the role "time" [Greek: chronos] plays in our physiology, endocrinology, metabolism and behavior at many organizational levels. While it has been used as a term and somewhat pursued as a discipline for decades, it appears that chronomedicine has captured a broader interest as a promising specialty only more recently. This commentary addresses roots of chronomedicine in the 1900s and perspectives for chronomedicine in the 21st century. Classical terms of chronobiology, e.g., Zeitgeber, melatonin and circadian, may be traced back to Aschoff, Lerner, and Halberg, respectively, but who actually coined the term "chronomedicine" and used it first in a publication remains unclear. Importantly, it could be(come) rather straightforward to transfer abundant insights gained from chronobiology to strategies in chronomedicine as animal models have been increasingly developed to understand human health and disease. Perspectively, chronomedicine should comprise "clinical chronomedicine" (individual-based) and "preventive chronomedicine" (population-based). Overall, due to the "maturing" of chronomedicine as a field, the near future might bring a section dedicated to chronomedicine in existing journals, or even a "Journal of Chronomedicine" as vectors of ideas and research. PMID- 22936256 TI - Direct contribution of obesity to oxidative damage to macromolecules. AB - BACKGROUND: Obesity constitutes a common modifiable risk factor for certain non communicable diseases (NCDs) associated with enhanced oxidative stress. OBJECTIVES AND METHODS: The aim of the study was to examine serum concentrations of malondialdehyde + 4-hydroxyalkenals (MDA+4-HDA), as an index of lipid peroxidation (LPO), and 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) concentration in peripheral blood lymphocytes, as an index of nuclear DNA damage, in overweight and obese adult patients. LPO and 8-oxodG, as well as clinical and laboratory parameters, which are frequently affected by obesity, were evaluated in 58 overweight and obese adult patients, and in 20 healthy volunteers. RESULTS: Both LPO and 8-oxodG levels were increased in overweight and obese patients, with further increase observed with the increasing body mass index (BMI). LPO correlated positively with body mass, BMI, waist circumference, hip circumference, waist:hip ratio, systolic or diastolic blood pressure, glucose, C reactive protein and ferritin concentrations. 8-oxodG correlated positively with body mass, BMI, hip circumference and triglyceride concentration, whereas it correlated negatively with iron concentration. Expectedly, positive correlation between LPO and 8-oxodG was also found. CONCLUSIONS: BMI constituted the only independent determinant (predictor) of LPO in overweight and obese patients. Consistently, LPO did constitute the only independent determinant of obesity. Overweight and obesity in adults are directly associated with increased oxidative damage to macromolecules. PMID- 22936257 TI - Expression of metalloproteinases 1, 2, 7, 9, and 12 in human cytotrophoblastic cells from normal and preeclamptic placentas. AB - OBJECTIVES: Preeclampsia is a specific pregnancy disorder which could be due, at least in part, to impaired invasion of trophoblastic cells. Since matrix metalloproteinases (MMPs) are the predominant proteases involved in trophoblastic invasion, we investigated and compared expression of MMP-1, 2, 7, 9 and 12 of cytotrophoblastic cells (CTB) purified from preeclamptic (PE) placentas to control CTB. MATERIAL AND METHODS: In order to evaluate invasive properties of cells, purified CTB were seeded on collagen-coated insert following boyden chamber principle and matrix metalloproteinases (MMPs) expression was evaluated by qPCR. RESULTS: Our results showed that PE CTB are less invasive than control CTB in vitro. In parallel, expression of MMPs, except for MMP-2, tends to be decreased in PE CTB compared to control CTB. CONCLUSION: At the exception of MMP 2, this study confirms the importance of MMPs in development of PE. PMID- 22936258 TI - Ghrelin concentration is correlated with IGF-I/IGFBP-3 molar ratio but not with GH secretion in children with short stature. AB - OBJECTIVES: In children with growth hormone deficiency (GHD) and neurosecretory dysfunction (NSD) ghrelin concentrations are significantly higher than in children with idiopathic short stature (ISS), however the correlation between serum ghrelin and growth hormone (GH) is not observed. The aim of the study was to compare ghrelin concentrations with IGF-I/IGFBP3 molar ratio in children with short stature due to different etiology. MATERIAL: Analysis comprised 136 children (58 girls and 78 boys), aged 3.86-16.82 years with short stature (below 2.0 SD); in 21 of them GHD was diagnosed, in 23 - NSD and 92 - ISS. In each child, fasting ghrelin, insulin-like growth factor type I (IGF-I) and its binding protein type 3 (IGFBP-3) concentrations were measured. The results were analysed separately in younger and in older children. Depending on IGF-I/IGFBP-3 molar ratio, children were divided into two (2) groups: with lower IGF-I/IGFBP-3 and with higher IGF-I/IGFBP-3 ratio value. RESULTS: Both in younger and in the older age groups, ghrelin concentration was significantly higher in children with lower IGF-I/IGFBP-3 ratio than in children with higher IGF-I/IGFBP-3 value (1937.3+/ 1232.4 vs 1365.3+/-632.1 pg/ml in younger children and 1205.4+/-548.8 vs 867.4+/ 282.9 pg/ml in older children). The negative correlation between ghrelin and IGF I/IGFBP-3 ratio was observed in both age groups. Not only children with GHD and NSD, but also as much as 39% out of all children with ISS were qualified into the subgroups with lower IGF-I/IGFBP-3 ratio. CONCLUSIONS: Ghrelin secretion is elevated in children with lower IGF-I/IGFBP-3 ratio. It seems that lower bioactivity of IGF-I is stimulating factor for ghrelin synthesis. PMID- 22936259 TI - Historic discovery of natural thermodynamic cause of cancer. AB - The essence of life is best manifested in cell, which, when brought to the edge of its existence in the actual environment may and sometimes must self-organise into an entirely different cell (neoplasm), but it must enhance dissipation of matter and energy in its closest environment. This phenomenon has been described before as self-organisation of dissipative structures in physics, chemistry and even sociology. Each neoplastic cell is such a dissipative system - with its clonal growth, the cell causes increasing disorganisation of the body, in consequence leading to neoplastic disease. The only adequate cause of formation of neoplasms is an internal dissipathogenic cellular state, which is clinically identify as preneoplastic ones at the level of morphology or molecular biology but also biophysics. Two general directions for therapy of neoplastic diseases arise from the thermodynamic essence of neogenesis: the direct one - targeting neoplasms, and the indirect one - leading to normalisation or sufficient alteration of their environment. The greatest disappointment in the fight against neoplasm was the discovery of its thermodynamic cause in a natural self organisation of biological dissipative structures. It is this dissipation that causes the signs and symptoms of neoplastic diseases ending with destruction of the body if the treatment comes too late and/or is insufficient, limited only to removal of neoplastic lesions without the always necessary elimination and/or prevention of preneoplastic (dissipathogenic) states. PMID- 22936260 TI - Nontrophoblastic placental tumors. AB - The aim of the study was to investigate potential influence of placental tumors on fetal outcome. The study comprised 10 cases of placental tumors. The analysis included the sonographic assessment of the tumor, signs of fetal anemia, as well as signs of hemodynamic disturbances or heart failure, and intrauterine treatment. The fetal hemodynamic was examined on the basis of Doppler blood flow in the umbilical artery and vein, middle cerebral artery, and ductus venous. The evaluation of fetal heart included the measurement of heart size, blood flow through cardiac valves and the assessment of fetal heart function based on cardiovascular score. The fetal outcome was also assessed according to birthweight, gestational age at delivery, pH, Ap score at 5th minute, abnormal neurological development and the need of intrauterine therapy. Ten cases of placental tumors were prenatally detected from 1999 to 2011. Among them 7 cases of hypoechogenic, non-vascularized cysts were identified and these neither effected the hemodynamics nor complicated fetal outcome. The vascularized tumors (chorioangioma) were the cause of severe anemia and hemodynamic disturbances and these led to fetal cardiac heart failure. In all cases of vascularized tumors from 2-3 intrauterine transfusion were performed. Rich vascularized tumors (chorioangioma) may cause hemodynamic disturbances and fetal heart failure. This may require intrauterine treatment and may result in abnormal fetal outcome and neurological development. PMID- 22936261 TI - Polymorphisms of apolipoprotein E gene and cognitive functions of postmenopausal women, measured by battery of computer tests - Central Nervous System Vital Signs. AB - OBJECTIVES: Apolipoprotein E (APOE) gene belongs to the group of genes increasing the risk of the Alzheimer's disease (AD) development. The purpose of the study was the analysis of cognitive functions in postmenopausal women having different polymorphisms of APOE gene; battery of computer tests - Central Nervous System Vital Signs (CNS-VS) were employed. METHODS: The women were qualified into the examined group on the grounds of clinical symptoms (minimum 2 years after the last menstruation), as well as on the basis of FSH concentration. At the qualification stage, a short test - Montreal Scale of Cognitive Function Assessment (MoCA) was conducted. The assessment of cognitive functions was made with the use of diagnostic CNS-Vital Signs equipment. Genomic DNA isolation was extracted from human whole blood. Multiplex PCR reactions have been performed in a single reaction tube with six (6) primers, consisting of 2 common primers and 4 specific primers [2 - for each of 2 single nucleotide polymorphism (SNP) sites]. RESULTS AND CONCLUSIONS: About half of the examined postmenopausal women were placed below average in the majority of the examined cognitive functions. The biggest impairments occurred in the field of processing speed, and the smallest - in the field of verbal and visual memory. Polymorphisms of APOE gene were considerably linked with the level of results of the majority of cognitive functions among postmenopausal women, as measured by battery of computer tests - CNS-VS. The presence of epsilon2/epsilon3 polymorphism of APOE gene impacted positively the obtained results of cognitive functions, whereas the presence of epsilon3/epsilon4, or epsilon4/epsilon4 polymorphisms worsened the obtained results. PMID- 22936262 TI - Primary motor cortex inhibition in spinal cord injuries. AB - OBJECTIVES AND METHODS: Excitability changes in the primary motor cortex in 17 spinal-cord injured (SCI) patients and 10 controls were studied with paired-pulse transcranial magnetic stimulation. The paired pulses were applied at inter stimulus intervals (ISI) of 2 ms and 15 ms while motor evoked potentials (MEP) were recorded in the biceps brachii (Bic), the abductor pollicis brevis (APB) and the tibialis anterior (TA) muscles. RESULTS: The study revealed a significant decrease in cortical motor excitability in the first weeks after SCI concerning the representation of both the affected muscles innervated from spinal segments below the lesion, and the spared muscles rostral to the lesion. In the patients with motor-incomplete injury, but not in those with motor-complete injury, the initial cortical inhibition of affected muscles was temporarily reduced 2-3 months following injury. The degree of inhibition in cortical areas representing the spared muscles was observed to be smaller in patients with no voluntary TA activity compared to patients with some activity remaining in the TA. Surprisingly, motor-cortical inhibition was observed not only at ISI 2 ms but also at ISI 15 ms. The inhibition persisted in patients who returned for a follow up measurement 2-3 years later. CONCLUSION: The present data showed different evaluation of cortical excitability between patients with complete and incomplete spinal cord lesion. Our results provide more insight into the pathophysiology of SCI and contribute to the ongoing discussion about the recovery process and therapy of SCI patients. PMID- 22936263 TI - Regional cerebellar metabolism (18FDG PET) predicts the clinical outcome of the short-term inpatient treatment of alcohol addiction. AB - OBJECTIVES: The acute and maintenance treatment of alcohol addiction represents the clinical challenge. The aims of our study were to evaluate the influence of alcohol consumption on regional brain metabolism and the predictive value of PET by means of the duration and quality of remission which followed the sub-acute treatment. METHODS: PET investigation with 18 fluoro-deoxyglucose (18FDG) were performed in detoxified patients with alcohol dependence at the end of short-term treatment. Abstinence was evaluated in patients during the one year follow-up period. RESULTS: We detected the positive correlation between 18FDG uptake in the cerebellar vermis (FWE, p<0.05) and duration of abstinence within one year. DISCUSSION: Our findings support the assumption that the cerebellum would be involved in the maintenance of abstinence in alcohol dependent subjects. Cerebellar connections with cortical areas critical for addiction such as frontal, parietal, temporal regions would mediate the influence of the cerebellum on emotional systems related to addiction. CONCLUSIONS: Our study is the first to document that the cerebellum and particularly the vermis is involved in the clinical outcome in terms of abstinence during one year. Our findings support the role of the cerebellum in addiction and the possibility to predict therapeutic outcome. PMID- 22936264 TI - Role of dehydroepiandrosterone and cortisol in nociceptive sensitivity to thermal pain in anorexia nervosa and healthy women. AB - OBJECTIVES: Anorexia nervosa (AN) patients represent a natural model of relationship between changed hormonal level and pain perception due to lower level of sex hormones and consistently described increased pain threshold. As the adrenal stress steroid hormones (cortisol and DHEA) are known to be also changed in AN (and share a common precursor), our study was aimed to analyze the association between these hormones and pain perception in AN patients and control healthy women. METHODS: The pain threshold latencies to radiant heat stimuli were measured in 20 DSM-IV diagnosed patients with AN and in 21 healthy women. Blood samples were collected in the morning hours and analyses of the plasma levels of dehydroepiandrosterone (DHEA), its conjugated sulfate ester (DHEA-S) and cortisol were implemented. RESULTS: Thermal pain threshold was higher in AN than in healthy women and correlated negatively with the level of DHEA and positively with cortisol/DHEA(S) ratio. No significant correlation between thermal pain and hormones was found in healthy women. If both groups were pooled together, the rest pain threshold correlated negatively with DHEA-S (r=-0.42, p=0.008). CONCLUSION: We showed for the first time that sensitivity to thermal pain in women is dependent on DHEA-S and on cortisol/DHEA(S) ratio in patients with AN. PMID- 22936265 TI - The hypothalamus mediates the effect of cerebellar fastigial nuclear glutamatergic neurons on humoral immunity. AB - OBJECTIVES: We explored effect of glutamatergic neurons in the fastigial nucleus (FN), one of three cerebellar nuclei, on humoral immunity and revealed that this effect was mediated by the hypothalamus via FN-hypothalamic glutamatergic transmission. METHODS: Rats were immunized with bovine serum albumin (BSA). On the third day after the immunization, 6-diazo-5-oxo-L-norleucine (DON), an inhibitor of glutaminase for glutamate synthesis, was microinjected in bilateral FN and D,L-threo-beta-hydroxyaspartic acid (THA), an inhibitor of glutamate transporters on plasma membrane, was microinjected in both sides of lateral hypothalamic area (LHA). Glutamate content in the hypothalamus was examined by high-performance liquid chromatography (HPLC). Flow cytometry and enzyme-linked immunosorbent assay (ELISA) were used to measure B lymphocyte percentage in mononuclear cells of peripheral blood and levels of anti-BSA IgM and IgG antibodies in the serum, respectively. RESULTS: DON injection in bilateral FN reduced B lymphocyte percentage and anti-BSA IgM and IgG levels, and simultaneously decreased glutamate content in the hypothalamus. Combined treatment with DON in the FN and with THA in the LHA elevated B cell number and anti-BSA IgM and IgG levels and increased hypothalamic glutamate content compared with DON treatment alone. However, combined treatment with DON in the FN and with THA in the ventrolateral thalamic nuclei (VL) did not significantly alter DON dependent changes in B cell number and antibody levels, although the co-treatment altered DON-dependent glutamate content in the thalamus. CONCLUSION: Cerebellar FN glutamatergic neurons participate in modulation of humoral immunity and this effect is mediated by the hypothalamus via FN-hypothalamic glutamatergic transmission. PMID- 22936266 TI - The influence of clonidine on oral ketamine-midazolam premedication in intellectually disabled patients indicated for dental procedures: double-blind comparison of two sedation regimes. AB - BACKGROUND: Dental procedures on intellectually disabled patients represent a clinical challenge. The oral administration of sedating drugs can remediate the problems with cooperation and enable the medical procedures to take place. Standard guidelines are lacking for oral sedation of the intellectually disabled. OBJECTIVE: To compare two oral combinations of sedating drugs in terms of time to the onset and achievement of full sedation, vital signs, behavioral measures and safety. METHODS: In a group of 29 intellectually disabled patients we compared two oral combinations for analgosedation: ketamine (5 mg/kg) - clonidine 2 ug/kg midazolam 0.3 mg/kg (N=17) or ketamine 5 mg/kg - midazolam 0.3 mg/kg (N= 12 patients). Drugs were dissolved in a sweet drink. RESULTS: Full sedation was achieved within 25 min. in 27 patients and serious side effects were not detected. Clonidine in combination with ketamine and midazolam did not exert any significant effect by means of the onset of sedation, time to the achievement of full sedation, vital signs and behavioral measures of sedation (Vancouver Interaction and Calmness Scale) and agitation (Pittsburgh Agitation Scale). CONCLUSIONS: Our study is the first to document that oral administration of ketamine and midazolam in low doses represents a safe and effective method of premedication in intellectually disabled patients indicated for dental procedures. Clonidine co-administration did not exert any substantial benefit and should be left out in this clinical setting. PMID- 22936267 TI - The prevalence of thyroid nodular disease in patients with increased titers of anti-thyroidal peroxidase antibodies. AB - OBJECTIVES: The aim of our study was to evaluate the possible association between autoimmunity and thyroid nodular disease (TND). DESIGN AND SETTING: We conducted a study on 58 patients who were treated in outpatient setting at the Department of Endocrinology, Metabolism and Internal Medicine. Serum samples were analyzed for TSH concentration and anti-TPO antibodies titers. Thyroid ultrasonography was performed in each subject in order to evaluate volume of the gland, and the number and size of nodules. RESULTS: TND occurred in 70% of anti-TPO positive subjects and in 57.9% of anti-TPO negative subjects, but statistical analysis did not demonstrate a significant concordance between the presence of anti-TPO antibodies and prevalence of TND (p>0.05). We showed that the mean (0.82 vs 0.75; p=0.49), minimal (0.2 vs 0.3; p=0.89) and maximal (2.7 vs 2.4; p=0.49) diameters of a nodule were similar in both groups. Solely in anti-TPO positive patients, anti-TPO titers positively correlated with the number of nodules (p=0.04). CONCLUSION: Our results favor the role of autoimmunity in TND development although associations between thyroid nodules and thyroid autoimmunity are complicated and may be the subject of much controversy. Increased anti-TPO may influence the number of nodules rather than the presence of TND itself. PMID- 22936268 TI - Transient psychosis due to caregiver burden in a patient caring for severely demented spouses. AB - OBJECTIVES: Caring for demented people has been associated with negative effect on caregiver health. One or more severe stress factors can precipitate brief reactive psychosis. METHODS: A 59-year-old Caucasian married woman with no prior psychosis has been caring for her severely demented husband for more than 3 years. She was treated for anxiety disorder and reaction to severe stress in our clinic for 1 year. RESULTS: Five days after husband's nursing home placement our patient developed the abnormal thought, that someone might tell her neighbours of her laziness and failures. She believed that she was under constant surveillance. These ideas grew rapidly into delusions and hallucinations. She was diagnosed as having transient psychosis with associated acute stress and was treated with risperidone. The psychosis lasted for two months. CONCLUSION: Careful differential diagnosis is necessary in the cases of transient psychosis. Psychotic symptoms in overloaded individuals may be more common than was previously thought. PMID- 22936269 TI - Isolation and characterization of pepsin-solubilized collagen from the integument of sea cucumber (Stichopus vastus). AB - BACKGROUND: Sea cucumber (Stichopus vastus) is considered an underutilized resource, since only its stomach and intestines are eaten raw as salad in a few countries and the remaining parts, especially the integument rich in collagen, is discarded. Hence a valuable by-product having potential nutraceutical and pharmaceutical applications is wasted. In the present investigation, pepsin solubilized collagen (PSC) from the integument of S. vastus was isolated, purified and characterized. RESULTS: Sodium dodecyl sulfate-polyacrylamide gel electrophoretic analysis showed that the purified collagen was of type I, consisting of three alpha1 chains of approximately 122 kDa each. The peptide map of PSC digested by V8 protease was different from that of calf skin type I collagen. Fourier transform infrared spectroscopy revealed that the triple helical structure was well preserved in isolated collagen. The denaturation temperature of PSC was 21.23 degrees C and showed good gel-forming capability at pH 6.5 and 300 mmol L-1 NaCl. CONCLUSION: It is inferred that the collagen isolated from S. vastus integument has potential for use as an alternative to land-based mammalian collagen in food, nutraceuticals and pharmaceutical industries. PMID- 22936270 TI - Pancreatic and biliary secretion are both altered in cystic fibrosis pigs. AB - The pancreas, liver, and gallbladder are commonly involved in cystic fibrosis (CF), and acidic, dehydrated, and protein-rich secretions are characteristic findings. Pancreatic function studies in humans have been done by sampling the jejunal fluid. However, it has been difficult to separately study the function of pancreatic and biliary systems in humans with CF, because jejunal fluid contains a mixture of bile and pancreatic fluids. In contrast, pancreatic and biliary ducts open separately into the porcine intestine; therefore, biliary and pancreatic fluid can be individually analyzed in CF pigs. We studied newborn wild type (WT) and CF pigs and found that CFTR was localized to the pancreatic ducts. We collected bile and pancreatic fluid and analyzed pancreatic enzymes with activity assays and immunoblot. Pancreatic enzyme expression was significantly decreased in CF compared with WT pigs. The volume and pH of pancreatic fluid were significantly lower and protein concentration was >5-fold higher in CF pigs. Secretin stimulation increased pancreatic fluid volume and pH in WT, but not CF, pigs. Baseline bile volume did not differ between WT and CF pigs, but volume did not increase in response to secretin in CF pigs. Bile pH was lower and protein concentration was twofold higher in CF pigs. These results indicate that pancreatic and biliary secretions are altered in CF pigs. Abnormal pancreatic and biliary secretion in CF may have important implications in disease pathogenesis. PMID- 22936271 TI - Differential signal pathway activation and 5-HT function: the role of gut enterochromaffin cells as oxygen sensors. AB - The chemomechanosensory function of the gut enterochromaffin (EC) cell enables it to respond to dietary agents and mechanical stretch. We hypothesized that the EC cell, which also sensed alterations in luminal or mucosal oxygen level, was physiologically sensitive to fluctuations in O(2). Given that low oxygen levels induce 5-HT production and secretion through a hypoxia inducible factor 1alpha (HIF-1alpha)-dependent pathway, we also hypothesized that increasing O(2) would reduce 5-HT production and secretion. Isolated normal EC cells as well as the well-characterized EC cell model KRJ-I were used to examine HIF signaling (luciferase-assays), hypoxia transcriptional response element (HRE)-mediated transcription (PCR), signaling pathways (Western blot), and 5-HT release (ELISA) during exposure to different oxygen levels. Normal EC cells and KRJ-I cells express HIF-1alpha, and transient transfection with Renilla luciferase under HRE control identified a hypoxia-mediated pathway in these cells. PCR confirmed activation of HIF-downstream targets, GLUT1, IGF2, and VEGF under reduced O(2) levels (0.5%). Reducing O(2) also elevated 5-HT secretion (2-3.2-fold) as well as protein levels of HIF-1alpha (1.7-3-fold). Increasing O(2) to 100% inhibited HRE mediated signaling, transcription, reduced 5-HT secretion, and significantly lowered HIF-1alpha levels (~75% of control). NF-kappaB signaling was also elevated during hypoxia (1.2-1.6-fold), but no significant changes were noted in PKA/cAMP. We concluded that gut EC cells are oxygen responsive, and alterations in O(2) levels differentially activate HIF-1alpha and tryptophan hydroxylase 1, as well as NF-kappaB signaling. This results in alterations in 5-HT production and secretion and identifies that the chemomechanosensory role of EC cells extends to oxygen sensing. PMID- 22936272 TI - Cell-specific effects of luminal acid, bicarbonate, cAMP, and carbachol on transporter trafficking in the intestine. AB - Changes in intestinal luminal pH affect mucosal ion transport. The aim of this study was to compare how luminal pH and specific second messengers modulate the membrane traffic of four major ion transporters (CFTR, NHE3, NKCC1, and NBCe1) in rat small intestine. Ligated duodenal, jejunal, and ileal segments were infused with acidic or alkaline saline, 8-Br-cAMP, or the calcium agonist carbachol in vivo for 20 min. Compared with untreated intestine, lumen pH was reduced after cAMP or carbachol and increased following HCO(3)(-)-saline. Following HCl-saline, lumen pH was restored to control pH levels. All four secretory stimuli resulted in brush-border membrane (BBM) recruitment of CFTR in crypts and villi. In villus enterocytes, CFTR recruitment was coincident with internalization of BBM NHE3 and basolateral membrane recruitment of the bicarbonate transporter NBCe1. Both cAMP and carbachol recruited NKCC1 to the basolateral membrane of enterocytes, while luminal acid or HCO(3)(-) retained NKCC1 in intracellular vesicles. Luminal acid resulted in robust recruitment of CFTR and NBCe1 to their respective enterocyte membrane domains in the upper third of the villi; luminal HCO(3)(-) induced similar membrane changes lower in the villi. These findings indicate that each stimulus promotes a specific transporter trafficking response along the crypt villus axis. This is the first demonstration that physiologically relevant secretory stimuli exert their actions in villus enterocytes by membrane recruitment of CFTR and NBCe1 in tandem with NHE3 internalization. PMID- 22936273 TI - Cocaine- and amphetamine-regulated transcript is the neurotransmitter regulating the action of cholecystokinin and leptin on short-term satiety in rats. AB - Vagal CCK-A receptors (CCKARs) and leptin receptors (LRbs) interact synergistically to mediate short-term satiety. Cocaine- and amphetamine-regulated transcript (CART) peptide is expressed by vagal afferent neurons. We sought to demonstrate that this neurotransmitter regulates CCK and leptin actions on short term satiety. We also examined the signal transduction pathways responsible for mediating the CART release from the nodose ganglia (NG). ELISA studies coupled with gene silencing of NG neurons by RNA interference elucidated intracellular signaling pathways responsible for CCK/leptin-stimulated CART release. Feeding studies followed by gene silencing of CART in NG established the role of CART in mediating short-term satiety. Immunohistochemistry was performed on rat NG neurons to confirm colocalization of CCKARs and LRbs; 63% of these neurons contained CART. Coadministration of CCK-8 and leptin caused a 2.2-fold increase in CART release that was inhibited by CCK-OPE, a low-affinity CCKAR antagonist. Transfection of cultured NG neurons with steroid receptor coactivator (SRC) or phosphatidylinositol 3-kinase (PI3K) small-interfering RNA (siRNA) or STAT3 lentiviral short hairpin RNA inhibited CCK/leptin-stimulated CART release. Silencing the expression of the EGR-1 gene inhibited the CCK/leptin-stimulated CART release but had no effect on CCK/leptin-stimulated neuronal firing. Electroporation of NG with CART siRNA inhibited CCK/leptin stimulated c-Fos expression in rat hypothalamus. Feeding studies following electroporation of the NG with CART or STAT3 siRNA abolished the effects of CCK/leptin on short-term satiety. We conclude that the synergistic interaction of low-affinity vagal CCKARs and LRbs mediates CART release from the NG, and CART is the principal neurotransmitter mediating short-term satiety. CART release from the NG involves interaction between CCK/SRC/PI3K cascades and leptin/JAK2/PI3K/STAT3 signaling pathways. PMID- 22936274 TI - Skin rejuvenation by microneedle fractional radiofrequency treatment in Asian skin; clinical and histological analysis. AB - BACKGROUND: For skin rejuvenation, microneedle fractional radiofrequency (RF) is a recently developed minimally invasive method for delivering RF energy directly into the skin using microneedle. OBJECTIVE: We evaluated efficacy and safety of microneedle fractional RF for skin rejuvenation in Asian skin and also conducted immunohistochemical analysis before and after treatment. PATIENTS AND METHODS: Twenty-five females (mean age 54.2, Fitzpatrick skin phototypes III-IV) received three consecutive fractional RF treatment at 4-week intervals. Outcome assessments included standardized photography, physician's global assessment, patient's satisfaction scores, objective biophysical measurements, and histologic analysis including immunohistochemical staining. RESULTS: All patients showed clinical improvement on physician's global assessment and patient's satisfaction scores. Among objective biophysical measurements, improvement in hydration and skin roughness was noticed. Histologic examination revealed marked increase in dermal thickness, dermal collagen content and dermal fibrillin content. Side effects were minimal. LIMITATIONS: The limitations are the small number of patients and lack of long-term follow-up. CONCLUSION: Microneedle fractional RF is a safe and effective skin rejuvenation method in Asians. PMID- 22936275 TI - The role of PKCepsilon-dependent signaling for cardiac differentiation. AB - Protein kinase Cepsilon (PKCepsilon) exerts a well-known cardio-protective activity in ischemia-reperfusion injury and plays a pivotal role in stem cell proliferation and differentiation. Although many studies have been performed on physiological and morphological effects of PKCepsilon mis-expression in cardiomyocytes, molecular information on the role of PKCepsilon on early cardiac gene expression are still lacking. We addressed the molecular role of PKCepsilon in cardiac cells using mouse cardiomyocytes and rat bone marrow mesenchymal stem cells. We show that PKCepsilon is modulated in cardiac differentiation producing an opposite regulation of the cardiac genes NK2 transcription factor related, locus 5 (nkx2.5) and GATA binding protein 4 (gata4) both in vivo and in vitro. Phospho-extracellular regulated mitogen-activated protein kinase 1/2 (p-ERK1/2) levels increase in PKCepsilon over-expressing cells, while pkcepsilon siRNAs produce a decrease in p-ERK1/2. Indeed, pharmacological inhibition of ERK1/2 rescues the expression levels of both nkx2.5 and gata4, suggesting that a reinforced (mitogen-activated protein kinase) MAPK signaling is at the basis of the observed inhibition of cardiac gene expression in the PKCepsilon over expressing hearts. We demonstrate that PKCepsilon is critical for cardiac cell early gene expression evidencing that this protein is a regulator that has to be fine tuned in precursor cardiac cells. PMID- 22936276 TI - Effects of androgen deprivation therapy and bisphosphonate treatment on bone in patients with metastatic castration-resistant prostate cancer: results from the University of Washington Rapid Autopsy Series. AB - Qualitative and quantitative bone features were determined in nondecalcified and decalcified bone from 20 predetermined bone sites in each of 44 patients who died with castration-resistant prostate cancer (CRPC), some of which received bisphosphonate treatment (BP) in addition to androgen-deprivation therapy (ADT). Thirty-nine of the 44 patients (89%) had evidence of bone metastases. By histomorphometric analysis, these bone metastases were associated with a range of bone responses from osteoblastic to osteolytic with a wide spectrum of bone responses often seen within an individual patient. Overall, the average bone volume/tissue volume (BV/TV) was 25.7%, confirming the characteristic association of an osteoblastic response to prostate cancer bone metastasis when compared with the normal age-matched weighted mean BV/TV of 14.7%. The observed new bone formation was essentially woven bone, and this was a localized event. In comparing BV/TV at metastatic sites between patients who had received BP treatment and those who had not, there was a significant difference (28.6% versus 19.3%, respectively). At bone sites that were not invaded by tumor, the average BV/TV was 10.1%, indicating significant bone loss owing to ADT that was not improved (11%) in those patients who had received BPs. Surprisingly, there was no significant difference in the number of osteoclasts present at the metastatic sites between patients treated or not treated with BPs, but in bone sites where the patient had been treated with BPs, giant osteoclasts were observed. Overall, 873 paraffin-embedded specimens and 661 methylmethacrylate-embedded specimens were analyzed. Our results indicate that in CRPC patients, ADT induces serious bone loss even in patients treated with BP. Furthermore, in this cohort of patients, BP treatment increased BV and did not decrease the number of osteoclasts in prostate cancer bone metastases compared with bone metastases from patients who did not receive BP. PMID- 22936277 TI - Evaluation of optic nerve head using a newly developed stereo retinal imaging technique by glaucoma specialist and non-expert-certified orthoptist. AB - PURPOSE: To evaluate the reproducibility and interexaminer consistency in analyzing the optic disc parameters using a newly fundus stereoscopic camera, and their correlation with parameters of the Heidelberg Retina Tomograph II (HRT II) was also examined. METHODS: This study examined 53 eyes of 53 healthy volunteers (mean age, 21.8 y). Fifty-five eyes of 55 glaucoma patients (mean age, 59.3 y) were also involved. A Nonmyd WX retinal camera was used for stereoscopic fundus imaging. The diagnostic parameters for the optic nerve head analyses were examined under the following conditions: (1) the intraexaminer reproducibility was determined by a certified orthoptist (CO) with 1 year's experience, with the appropriate coefficient of variation in 8 healthy eyes; and (2) the interexaminer consistency of the diagnostic parameters by both glaucoma specialist and CO was examined in 45 healthy eyes and 55 glaucomatous eyes. By subgroup analysis, the healthy eyes were classified into 2 groups based on the degree of myopia, the optic disc of glaucomatous eye was classified into 4 types: focal ischemic, generalized enlargement, myopic, and senile sclerotic, and also classified into 3 stages (early, moderate, and severe) by Hodapp-Anderson-Parrish scale. (3) The correlation of parameters common to Nonmyd WX and HRT II was examined in 18 eyes of randomly selected patients. RESULTS: The results were as follows: (1) Mean coefficient of variation of 2.6% to 17.6%, with volume parameters considerably lower than the other parameters. (2) In both groups, a high or moderate degree of consistency was obtained (r=0.40 to 0.99; P=0.032 to <0.0001), except only the upper rim width in healthy subjects (r=0.28; P=0.137). In particular, good consistency was obtained in healthy eye with >-3 D of myopia, in glaucoma patients with the generalized type of optic disc and severe glaucomatous stage. (3) A strong correlation with HRT II was obtained only in the cup area and the disc area by both specialist and CO (r=0.75 to 0.90; P=0.0003 to <0.0001). CONCLUSIONS: Our studies indicated that most of the parameters were highly reproducible and consistent, and less difference was found between the results obtained by an experienced glaucoma specialist and a non-expert CO in patients with deep cupping and severe eye, but the examiner needs a clear understanding of the criteria for the rim and the cup. PMID- 22936278 TI - Predictors and outcomes of ocular hypertension after open-globe injury. AB - PURPOSE: Evaluate predictors and outcomes of ocular hypertension after open-globe injury. PATIENTS AND METHODS: This is a retrospective, case-control study reviewing records of consecutive patients with open-globe injuries treated at Massachusetts Eye and Ear Infirmary between February 1999 and January 2007. Of 658 patients treated, 382 had at least 2 months of follow-up and sufficient data to be included. Main outcome measures are visual acuity, intraocular pressure (IOP), and type of glaucoma intervention employed. RESULTS: Sixty-five (17%) patients developed ocular hypertension defined as IOP>=22 mm Hg at >1 visit or requiring treatment. Increased age (P<0.001), hyphema (0.025), lens injury (P<0.0001), and zone II injury (P=0.0254) are risk factors for developing ocular hypertension after open-globe injury. Forty-eight (74%) patients with ocular hypertension were treated medically, 8 (12%) underwent filtering or glaucoma drainage device surgery, 5 (8%) had IOP normalization with observation, while 4 (6%) required anterior chamber washout with no other glaucoma surgery. Patients with ocular hypertension had an average maximum IOP=33.4 mm Hg at a median follow up of 21 days, with most patients maintaining normal IOP at all follow-up time points. Visual acuity improved over time with median acuity of hand motions preoperatively, and 20/60 at 12 and 36 months. CONCLUSIONS: Ocular hypertension is a significant complication after open-globe injury that sometimes requires surgical intervention. Predictive factors can alert physicians to monitor for elevated IOP in the first month after trauma. Most patients with traumatic ocular hypertension had improved visual acuity and IOP normalization over time. PMID- 22936279 TI - Survey on vision-related quality of life and self-management among patients with glaucoma. AB - PURPOSE: The aim of the study was to investigate the vision-related quality of life in glaucoma patients and identify the possible predictors for outcomes. METHODS: A total sample of 167 subjects with glaucoma was recruited using a convenience sampling strategy. The National Eye Institute Visual Function Questionnaire (NEI-VFQ-25) and the Glaucoma Self-Management Questionnaire were used for assessing vision-related quality of life and self-management behavior, respectively. The demographic and disease-related data were also collected. RESULTS: Regarding the vision-related quality of life, the lowest scores were for general health (32.78+/-23.59), followed by general vision (46.35+/-19.52). The highest score was for the dimension of color vision (89.02+/-20.76). Multiple linear regression analysis demonstrated that self-management behavior, positive glaucoma family history, and binocular visual acuity were predictors of vision related quality of life in this patient group. CONCLUSIONS: The current study indicates that vision-related quality of life in glaucoma patients is at a moderate level in China. Self-management behavior is an important predictor. Demographic data may not increase the explanatory effect. Future research should focus on how to integrate self-management skills into routine nursing practice for patients with glaucoma. PMID- 22936280 TI - Deepening of the upper eyelid sulcus caused by 5 types of prostaglandin analogs. AB - PURPOSE: Upper eyelid sulcus deepening has recently been reported as an adverse effect of prostaglandin (PG) eye drop use. However, no data are available regarding the frequency of upper eyelid sulcus deepening caused by different types of PG eye drops. We used 5 types of PG eye drops in Japanese subjects and examined the frequency of appearance of upper eyelid sulcus deepening in these subjects. PATIENTS AND METHODS: The study included 250 patients (250 eyes) diagnosed with primary open-angle glaucoma or ocular hypertension. Five healthy patients were included as controls. One eye of each patient was treated with one of the following PG eye drops for >3 months: latanoprost, travoprost, tafluprost, bimatoprost, and isopropyl unoprostone. A single-lens reflex camera was used to photograph the open eyelids. Three ophthalmologists independently judged the appearance of the deepened upper eyelid sulcus in the photographs of the 250 patients and 5 controls by comparing the right and left eyes. A subjective self reported symptom questionnaire was also administered. RESULTS: Upper eyelid sulcus deepening was objectively (photograph) and subjectively (questionnaire) noted in 24.0% and 12.0%, 50.0% and 24.0%, 18.0% and 10.0%, 60.0% and 40.0%, and 8.0% and 10.0% of the patients in the latanoprost, travoprost, tafluprost, bimatoprost, and unoprostone groups, respectively. It occurred more frequently (objectively and subjectively) in the bimatoprost group than in the latanoprost, the tafluprost, and the unoprostone groups (P<0.001). CONCLUSION: Upper eyelid sulcus deepening frequently occurred with bimatoprost usage, and this effect should be sufficiently elucidated before starting bimatoprost treatment. PMID- 22936281 TI - Potential for ultrasound in occult submucous cleft palate? PMID- 22936283 TI - Physicochemical interactions in solid dosage forms. AB - Complete characterization and mechanistic understanding of physicochemical interactions in solid dosage forms are not only important for consistent manufacturability, stability, and bioavailability of the drug product, but are also expected under the quality-by-design paradigm of drug development. Lack of this understanding can impact successful and timely development, scale-up, and commercial manufacture of dosage forms. This article highlights the stability and bioavailability implications of physicochemical interactions in dosage forms citing a couple of examples where such interactions necessitated the recall of commercial drug products. PMID- 22936282 TI - Inner ear anomalies seen on CT images in people with Down syndrome. AB - BACKGROUND: Although dysplasia of inner ear structures in Down syndrome has been reported in several histopathological studies, the imaging findings have not been widely studied. OBJECTIVE: To evaluate the prevalence and clinical significance of inner ear anomalies detected on CT images in patients with Down syndrome. MATERIALS AND METHODS: The temporal bone CT images of patients with Down syndrome were assessed for inner ear anomalies; clinical notes and audiograms were reviewed for hearing loss. Logistic regression models were employed to identify which CT findings were associated with sensorineural hearing loss (SNHL). RESULTS: Inner ear anomalies were observed in 74.5% (38/51) of patients. Malformed bone islands of lateral semicircular canal (LSCC), narrow internal auditory canals (IACs), cochlear nerve canal stenoses, semicircular canal dehiscence (SCCD), and enlarged vestibular aqueducts were detected in 52.5% (53/101), 24.5% (25/102), 21.4% (21/98), 8.8% (9/102) and 2% (2/101) of patients' ears, respectively. IAC stenosis had the highest odds ratio (OR = 5.37, 95% CI: 1.0-28.9, P = 0.05) for SNHL. CONCLUSION: Inner ear anomalies occurred in 74.5% of our population, with malformed (<3 mm) bone island of LSCC being the most common (52.5%) anomaly. Narrow IAC was seen in 24.5% of patients with Down syndrome and in 57.1% of ears with SNHL. High-resolution CT is a valuable for assessing the cause of hearing loss in people with Down syndrome. PMID- 22936284 TI - Patient activation in schizophrenia: insights from stories of illness and recovery. AB - Using a mixed-methods approach, we sought a deeper understanding of patient activation in 46 participants with schizophrenia. We qualitatively examined narratives for themes related to patient activation and divided the sample based on the mental health version of the patient activation measure. Participants high in patient activation described acceptance, control over illness, a wide range of activities that help them, and highlighted collaborative treatment experiences. The groups did not differ in understanding the cause of illness, what makes symptoms worse, or things they were proud of. Active management of schizophrenia mirrors physical health activation in several ways. PMID- 22936287 TI - Attitudes of Portuguese health professionals toward adverse drug reaction reporting. AB - BACKGROUND: Adverse drug reactions are a major public health problem. Underreporting is an important limitation of all reporting systems, partially due to attitudes of health professionals. OBJECTIVE: This study sought: (1) to evaluate the reproducibility of a questionnaire on attitudes to and knowledge of adverse drug reaction (ADR) reporting among physicians, nurses and pharmacists: and (2) to compare the attitudes and knowledge of these three groups of health professionals. METHODS: This study targeted a sample of physicians (n = 30), nurses (n = 30) and pharmacists (n = 20) in the central region of Portugal. A structured questionnaire was administered to each health professional twice, at an interval of 2-4 weeks. Most attitudes were based on Inman's 'seven deadly sins' and measured using a continuous visual analog scale (VAS), with answers scored from 0 (total disagreement) to 10 (total agreement). Questionnaire reproducibility was determined using the intraclass correlation coefficient (ICC). RESULTS: The response rate was 100 %. Attitudes that registered the highest ICCs were Complacency (the belief that really serious ADRs are well documented by the time a drug is marketed) (physicians, ICC 0.84; nurses, ICC 0.70; pharmacists, ICC 0.99), and Diffidence (the belief that one would only report an ADR if one were sure that it was related to the use of a particular drug) (physicians, ICC 0.73; nurses, ICC 0.65; pharmacists, ICC 0.98). In most cases, there were no differences among the three groups of professionals in terms of attitudes and knowledge. CONCLUSIONS: The Horizontal continuous VAS is reliable to detect the knowledge and attitudes about ADRs. PMID- 22936286 TI - Photoperiod-gonadotropin mismatches induced by treatment with acyline or FSH in Siberian hamsters: impacts on ovarian structure and function. AB - Many seasonal breeders time their reproductive efforts to specific times of the year to ensure adequate resources for the production and care of young. For long day (LD) breeders, females born before the summer solstice (LDs) reach sexual maturity quickly and often breed that same year, whereas females born after the summer solstice (short days (SDs)) may delay reproductive development to the following spring when environmental conditions are favorable for reproduction. In Siberian hamsters, development in SD is associated with structural and functional differences in the ovary compared with females held in LD, including a greater number of primordial follicles and an abundance of hypertrophied granulosa cells (HGCs), which are immunoreactive for anti-Mullerian hormone. The goal of this study was to determine whether SD-induced gonadotropin suppression is responsible for these phenotypic differences. Gonadotropin levels were suppressed in LD hamsters using the GNRH antagonist acyline. Conversely, to determine whether the SD ovarian phenotype is completely reversed by gonadotropin stimulation, recombinant human FSH (rhFSH) was administered. Our treatments were successful in mimicking FSH concentrations of the opposite photoperiod, but they did not produce a comparable change in the ovarian phenotype. Most notable was the lack of HGCs in the ovaries of acyline-treated LD females. Similarly, HGCs were maintained in the ovaries of SD females treated with rhFSH. Our data suggest that gonadotropins alone do not account for the SD ovarian phenotype. Future studies will determine whether SD-induced changes in other factors underlie these phenotypic changes. PMID- 22936288 TI - Characteristics, management, and depression outcomes of primary care patients who endorse thoughts of death or suicide on the PHQ-9. AB - BACKGROUND: With increasing emphasis on integrating behavioral health services, primary care providers play an important role in managing patients with suicidal thoughts. OBJECTIVE: To evaluate whether Patient Health Questionnaire-9 (PHQ-9) Item 9 scores are associated with patient characteristics, management, and depression outcomes in a primary care-based mental health program. DESIGN: Observational analysis of data collected from a patient registry. PARTICIPANTS: Eleven thousand fifteen adults enrolled in the Mental Health Integration Program (MHIP). INTERVENTIONS: MHIP provides integrated mental health services for safety net populations in over 100 community health centers across Washington State. Key elements of the team-based model include: a disease registry; integrated care management; and organized psychiatric case review. MAIN MEASURES: The independent variable, suicidal ideation (SI), was assessed by PHQ-9 Item 9. Depression severity was assessed with the PHQ-8. Outcomes included four indicators of depression treatment process (care manager contact, psychiatric case review, psychotropic medications, and specialty mental health referral), and two indicators of depression outcomes (50 % reduction in PHQ-9 score and PHQ-9 score < 10). KEY RESULTS: SI was common (45.2 %) at baseline, with significantly higher rates among men and patients with greater psychopathology. Few patients with SI (5.4 %) lacked substantial current depressive symptoms. After adjusting for age, gender, and severity of psychopathology, patients with SI received follow-up earlier (care manager contact HR = 1.05, p < 0.001; psychiatric review HR = 1.02, p < 0.05), and were more likely to receive psychotropic medications (OR = 1.11, p = 0.001) and specialty referral (OR = 1.23, p < 0.001), yet were less likely to achieve a PHQ-9 score < 10 (HR = 0.87, p < 0.001). CONCLUSIONS: Suicidal thoughts are common among safety-net patients referred by primary care providers for behavioral health care. Scores on Item 9 of the PHQ-9 are easily obtainable in primary care, may help providers initiate conversations about suicidality, and serve as useful markers of psychiatric complexity and treatment-resistance. Patients with positive scores should receive timely and comprehensive psychiatric evaluation and follow-up. PMID- 22936289 TI - Paced respiration for vasomotor and other menopausal symptoms: a randomized, controlled trial. AB - BACKGROUND: Paced respiration has been internationally recommended for vasomotor symptom management, despite limited empirical evidence. OBJECTIVE: To evaluate efficacy of a paced respiration intervention against breathing control and usual care control for vasomotor and other menopausal symptoms. DESIGN: A 16-week, 3 group, partially blinded, controlled trial with 2:2:1 randomization and stratification by group (breast cancer, no cancer), in a Midwestern city and surrounding area. PARTICIPANTS: Two hundred and eighteen randomized women (96 breast cancer survivors, 122 menopausal women without cancer), recruited through community mailings and registries (29 % minority). INTERVENTIONS: Training, home practice support, and instructions to use the breathing at the time of each hot flash were delivered via compact disc with printed booklet (paced respiration intervention) or digital videodisc with printed booklet (fast shallow breathing control). Usual care control received a letter regarding group assignment. MAIN MEASURES: Hot flash frequency, severity, and bother (primary); hot flash interference in daily life, perceived control over hot flashes, and mood and sleep disturbances (secondary). Intervention performance, adherence, and adverse events were assessed. KEY RESULTS: There were no significant group differences for primary outcomes at 8-weeks or 16-weeks post-randomization. Most intervention participants did not achieve 50 % reduction in vasomotor symptoms, despite demonstrated ability to correctly do paced respiration and daily practice. Statistically significant differences in secondary outcomes at 8 and 16 weeks were small, not likely to be clinically relevant, and as likely to favor intervention as breathing control. CONCLUSIONS: Paced respiration is unlikely to provide clinical benefit for vasomotor or other menopausal symptoms in breast cancer survivors or menopausal women without cancer. PMID- 22936290 TI - Bending the arc of the health care universe through systems improvement. PMID- 22936292 TI - Controlling HIV/AIDS: the obstacles and opportunities ahead. PMID- 22936291 TI - Experiencing the culture of academic medicine: gender matters, a national study. AB - BACKGROUND: Energized and productive faculty are critical to academic medicine, yet studies indicate a lack of advancement and senior roles for women. OBJECTIVE: Using measures of key aspects of the culture of academic medicine, this study sought to identify similarity and dissimilarity between perceptions of the culture by male and female faculty. DESIGN: The C - Change Faculty Survey was used to collect data on perceptions of organizational culture. PARTICIPANTS: A stratified random sample of 4,578 full-time faculty at 26 nationally representative US medical colleges (response rate 52 %). 1,271 (53 %) of respondents were female. MAIN MEASURES: Factor analysis assisted in the creation of scales assessing dimensions of the culture, which served as the key outcomes. Regression analysis identified gender differences while controlling for other demographic characteristics. KEY RESULTS: Compared with men, female faculty reported a lower sense of belonging and relationships within the workplace (T = 3.30, p < 0.01). Self-efficacy for career advancement was lower in women (T = 4.73, p < 0.001). Women perceived lower gender equity (T = -19.82, p < 0.001), and were less likely to believe their institutions were making changes to address diversity goals (T = -9.70, p < 0.001). Women were less likely than men to perceive their institution as family-friendly (T = -4.06, p < 0.001), and women reported less congruence between their own values and those of their institutions (T = -2.06, p < 0.05). Women and men did not differ significantly on levels of engagement, leadership aspirations, feelings of ethical/moral distress, perception of institutional commitment to faculty advancement, or perception of institutional change efforts to improve support for faculty. CONCLUSIONS: Faculty men and women are equally engaged in their work and share similar leadership aspirations. However, medical schools have failed to create and sustain an environment where women feel fully accepted and supported to succeed; how can we ensure that medical schools are fully using the talent pool of a third of its faculty? PMID- 22936293 TI - [Abstracts of 8th Moxifloxacin Research Workshop. November 17-18, 2012. Leverkusen, Germany]. PMID- 22936294 TI - Convergent synthesis of conjugated 1,2-disubstituted E-allylic alcohols from two aldehydes and methylenetriphenylphosphorane. AB - beta-Lithiooxyphosphonium ylides, made in situ from an aldehyde and methylenetriphenylphosphorane, react with a second aldehyde to form E-allylic alcohols. alpha-Branching and alpha,beta-unsaturation in the second aldehyde, together with the lack of further substitution on the phosphorane carbon play important roles in selectivity. A range of these aldehydes, in addition to aromatic aldehydes as the second aldehyde also provided synthetically useful access to E-allylic alcohols. PMID- 22936295 TI - Application of host-specific source-tracking tools for rapid identification of fecal contamination in fresh produce by humans and livestock. AB - BACKGROUND: Fecal contamination in fresh produce is a public health concern because it may contain human pathogens. We introduced host-specific quantitative real-time polymerase chain reaction (qPCR) assays for the rapid detection and identification of fecal contamination sources from humans and farm animals (cow, pig, chicken) in fresh produce. Each composite fecal sample was spiked on lettuce at two contamination levels (0.2 mg or 2 mg feces g-1), followed by qPCR assays for detecting each host-specific genetic marker: BoBac (cow); PF163 (pig); CP3-49 (chicken); and HF183 and gyrB (human). Two commercial DNA extraction kits were compared to evaluate DNA recovery yields and removal of PCR inhibition. Sketa2 assay was conducted to assess the presence of PCR inhibition in the contaminated lettuce. RESULTS: All the qPCR assays yielded reliable detection from contaminated lettuce (2 mg feces g-1), where their target gene numbers were 1.5 5.0 * 103 (HF183), 0.8-2.2 * 103 (gyrB), 0.6-1.6 * 103 (BoBac), 1.6-3.0 * 103 (CP3-49) and 1.1-2.2 * 103 (PF163) copies g-1 of lettuce. Among the two extraction kits, QIAamp DNA Stool Kit resulted in 2-3 times higher sensitivity and 20% less PCR inhibition than the PowerFoodTM kit. CONCLUSION: This study provides information on the optimized host-specific qPCR assay in identifying sources of fecal contamination in fresh produce and is useful for tracking the contamination source and improving agricultural practice. PMID- 22936296 TI - Aryl-linked imidazolidin-2-ones as non-peptidic beta-strand mimetics. AB - We describe the design and synthesis of a non-peptidic beta-strand mimetic composed of alternating aryl and imidazolidin-2-one rings that can be adapted to display diverse side-chains. Solid- and solution-phase data together with calculations suggest that the desired conformation for side-chain mimicry is readily accessible and well-populated. PMID- 22936297 TI - Biocarbon-coated LiFePO4 nucleus nanoparticles enhancing electrochemical performances. AB - We report a simple, inexpensive green biomimetic way for developing the high performance LiFePO(4) for high-power lithium-ion batteries. Biocarbon-coated LiFePO(4) nucleus nanoparticles are synthesized by using yeast cells as both a structural template and a biocarbon source. PMID- 22936298 TI - Randomized controlled clinical trial on the three-dimensional accuracy of fast set impression materials. AB - OBJECTIVES: The use of fast-setting impression materials with different viscosities for the one-stage impression technique demands precise working times when mixing. We examined the effect of varying working time on impression precision in a randomized clinical trial. MATERIALS AND METHODS: Focusing on tooth 46, three impressions were made from each of 96 volunteers, using either a polyether (PE: Impregum Penta H/L DuoSoft Quick, 3 M ESPE) or an addition-curing silicone (AS: Aquasil Ultra LV, Dentsply/DeTrey), one with the manufacturer's recommended working time (used as a reference) and two with altered working times. All stages of the impression-taking were subject to randomization. The three-dimensional precision of the non-standard working time impressions was digitally analyzed compared to the reference impression. Statistical analysis was performed using multivariate models. RESULTS: The mean difference in the position of the lower right first molar (vs. the reference impression) ranged from +/-12 MUm for PE to +19 and -14 MUm for AS. Significantly higher mean values (+62 to 40 MUm) were found for AS compared to PE (+21 to -26 MUm) in the area of the distal adjacent tooth. CONCLUSIONS: Fast-set impression materials offer high precision when used for single tooth restorations as part of a one-stage impression technique, even when the working time (mixing plus application of the light- and heavy-body components) diverges significantly from the manufacturer's recommended protocol. CLINICAL RELEVANCE: Best accuracy was achieved with machine mixed heavy-body/light-body polyether. Both materials examined met the clinical requirements regarding precision when the teeth were completely syringed with light material. PMID- 22936300 TI - Migratory insertion reactions of nickel and palladium sigma-alkyl complexes with a phosphinito-imine ligand. AB - Ligand exchange reactions have been used for the synthesis of metallacyclic complexes of Ni and Pd of the type [M[upper bond 1 start](CH(2)CMe(2)-o C(6)[upper bond 1 end]H(4))(P-N)], where P-N is the phosphinito-imine ligand P(iPr)(2)OC(Me)[double bond, length as m-dash]N(2,6-C(6)H(3)(iPr)(2). The protic acid [H(OEt(2))(BAr'(4))] (Ar' = 3,5-C(6)H(3)(CF(3))(2)) selectively cleaves one of the two sigma metal-carbon bonds, affording cationic monoalkyl complexes. Nickel monoalkyls stabilized with Et(2)O or MeCN ligands are thermally unstable and spontaneously undergo a decomposition process that ultimately leads to the breakdown of the phosphinito-imine ligand. In contrast, cationic alkylpalladium derivatives are thermally very stable, allowing the isolation of a formally unsaturated monoalkyl complex stabilized by an intramolecular pi-arene interaction. Although monoalkynickel and -palladium phosphinito-imine derivatives are inactive as ethylene polymerization or copolymerization catalysts, they readily experience migratory insertion reactions. A palladium chelate arising from the successive insertion of CO and ethylene has been isolated and characterized. PMID- 22936299 TI - Three-dimensional analysis of tooth dimensions in the MSX1-missense mutation. AB - OBJECTIVES: A novel, 3D technique to measure the differences in tooth crown morphology between the MSX1 cases and non-affected controls was designed to get a better understanding of dental phenotype-genotype associations. MATERIALS AND METHODS: Eight Dutch subjects from a single family with tooth agenesis, all with an established nonsense mutation c.332 C > A, p. Ser 111 Stop in exon 1 of MSX1, were compared with unaffected controls regarding several aspects of tooth crown morphology of incisor and molar teeth. A novel method of quantitative three dimensional analysis was used to detect differences. RESULTS: Statistically significant shape differences were observed for the maxillary incisor in the MSX1 family compared with the controls on the following parameters: surface area, buccolingual dimension, squareness, and crown volume (P <= 0.002). Molar crown shape was unaffected. CONCLUSIONS: A better understanding of dental phenotype genotype associations may contribute to earlier diagnosis of some multiple anomaly congenital syndromes involving dental anomalies. CLINICAL RELEVANCE: A "shape database" that includes associated gene mutations resulting from developmental syndromes may facilitate the genetic identification of hypodontia cases. PMID- 22936301 TI - Silver nanoparticle-induced oxidative stress, genotoxicity and apoptosis in cultured cells and animal tissues. AB - Silver nanoparticles (AgNPs) have emerged as an important class of nanomaterials for a wide range of industrial and medical applications. However, the unique properties of AgNPs could potentially lead to unexpected hazards to both human health and the well being of the environment. Possible mechanisms of AgNP-induced toxicity include the stimulation of oxidative stress, genotoxicity and apoptosis. In this study, a number of previous studies are therefore summarized that demonstrate oxidative stress-, genotoxicity- and apoptosis-related changes brought about by AgNPs in cultured cells and animal tissues. The physicochemical properties of AgNPs that are involved in encouraging such changes are also discussed. PMID- 22936302 TI - Generation and evaluation of the efficacy of rhesus monkey soluble cytotoxic T lymphocyte-associated antigen-4 in the allogeneic mixed lymphocyte reaction. AB - Cytotoxic T lymphocyte-associated antigen-4 (CTLA-4; CD152) is a transmembrane protein that is structurally similar to CD28. As CTLA-4 has a much higher binding affinity to B7 than CD28, several approaches using soluble CTLA-4 have been tried to down-regulate T cell activity by blocking the interaction between CD28 and B7. We constructed soluble rhesus monkey CTLA-4 immunoglobulin (CTLA-4Ig) containing a critical binding site to B7 combined with a constant Ig heavy chain region in a mammalian system. Flow cytometry analyses indicated that soluble rhesus monkey CTLA-4Ig bound to rhesus monkey CD86 (B7.2). Moreover, soluble rhesus monkey CTLA 4Ig more effectively blocked the rhesus monkey-rhesus monkey allogeneic mixed lymphocyte reaction compared with that of humans. These results indicate that soluble rhesus monkey CTLA-4Ig may be useful in preclinical trials in a rhesus monkey model. PMID- 22936304 TI - Anion-responsive diguanidinium-based chiral organogelators. AB - The chiral bicyclic diguanidinium chloride 1 forms gels in aromatic apolar solvents. The gels were characterized at different levels of organization, from the macroscopic to the molecular level by using microscopy, spectroscopy, and powder X-ray diffraction. The dependency on chirality has been highlighted by circular dichroism and electron microscopy. Furthermore, the gel has been shown to be effectively responsive to anionic stimuli, thus allowing the reversible control of the organic-phase gelation in contact with different salted aqueous solutions. PMID- 22936303 TI - Metabolic shifts: a fitness perspective for microbial cell factories. AB - Performance of industrial microorganisms as cell factories is limited by the capacity to channel nutrients to desired products, of which optimal production usually requires careful manipulation of process conditions, or strain improvement. The focus in process improvement is often on understanding and manipulating the regulation of metabolism. Nonetheless, one encounters situations where organisms are remarkably resilient to further optimization or their properties become unstable. Therefore it is important to understand the origin of these apparent limitations to find whether and how they can be improved. We argue that by considering fitness effects of regulation, a more generic explanation for certain behaviour can be obtained. In this view, apparent process limitations arise from trade-offs that cells faced as they evolved to improve fitness. A deeper understanding of such trade-offs using a systems biology approach can ultimately enhance performance of cell factories. PMID- 22936305 TI - Overexpression of tobacco osmotin (Tbosm) in soybean conferred resistance to salinity stress and fungal infections. AB - Salinity and fungal diseases are the two significant constraints limiting soybean productivity. In order to address these problems, we have transformed soybean cv. Pusa 16 via somatic embryogenesis with salinity induced and apoplastically secreted pathogenesis-related tobacco osmotin (Tbosm) gene using Agrobacterium mediated genetic transformation. Integration of Tbosm in randomly selected five GUS assay-positive independently transformed soybean plants was confirmed by polymerase chain reaction (PCR) and Southern hybridization. Reverse transcriptase PCR (RT-PCR) and Western blotting confirmed that the Tbosm was expressed in three of the five transformed soybean plants. Further the Western blotting revealed that the truncated osmotin protein accumulated more in apoplastic fluid. The transformed (T(1)) soybean plants survived up to 200 mM NaCl, whereas non transformed (NT) plants could withstand till 100 mM and perished at 150 mM NaCl. The biochemical analysis revealed the T(1) soybean plants accumulated higher amount of proline, chlorophyll, APX, CAT, SOD, DHAR, MDHAR, and RWC than NT plants. Leaf gas exchange measurements revealed that T(1) soybean plants maintained higher net photosynthetic rate, CO(2) assimilation, and stomatal conductance than NT plants. The three T(1) soybean plants expressing the osmotin gene also showed resistance against three important fungal pathogens of soybean- Microsphaera diffusa, Septoria glycines and Phakopsora pachyrhizi. The T(1) soybean plants produced 32-35 soybean pods/plant containing 10.3-12.0 g of seeds at 200 mM NaCl, whereas NT plant produced 28.6 soybean pods containing 9.6 g of seeds at 100 mM NaCl. The present investigation clearly shows that expression of Tbosm enhances salinity tolerance and fungal disease resistance in transformed soybean plants. PMID- 22936306 TI - Mind-body CAM interventions: current status and considerations for integration into clinical health psychology. AB - OBJECTIVE: Complementary and alternative medicine (CAM) is increasingly used for treating myriad health conditions and for maintaining general health. The present article provides an overview of current CAM use with a specific focus on mind body CAM and its efficacy in treating health conditions. METHOD: Characteristics of CAM users are presented, and then evidence regarding the efficacy of mind-body treatments (biofeedback, meditation, guided imagery, progressive muscle relaxation, deep breathing, hypnosis, yoga, tai chi, and qi gong) is reviewed. RESULTS: Demographics associated with CAM use are fairly well-established, but less is known about their psychological characteristics. Although the efficacy of mind-body CAM modalities for health conditions is receiving a great deal of research attention, studies have thus far produced a weak base of evidence. Methodological limitations of current research are reviewed. Suggestions are made for future research that will provide more conclusive knowledge regarding efficacy and, ultimately, effectiveness of mind-body CAM. Considerations for clinical applications, including training and competence, ethics, treatment tailoring, prevention efforts, and diversity, conclude the article. CONCLUSIONS: Integration of CAM modalities into clinical health psychology can be useful for researchers taking a broader perspective on stress and coping processes, illness behaviors, and culture; for practitioners seeking to incorporate CAM perspectives into their work; and for policy makers in directing healthcare resources wisely. PMID- 22936308 TI - Metabolic changes detected by ex vivo high resolution 1H NMR spectroscopy in the striatum of 6-OHDA-induced Parkinson's rat. AB - Parkinson's disease (PD) is a neurodegenerative disorder characterized by the progressive loss of the dopaminergic neurons; however, its crucial mechanism of the metabolic changes of neurotransmitters remains ambiguous. The pathological mechanism of PD might involve cerebral metabolism perturbations. In this study, ex vivo proton nuclear magnetic resonance ((1)H NMR) was used to determine the level changes of 13 metabolites in the bilateral striatum of 6-hydroxydopamine (6 OHDA)-induced PD rats. The results showed that, in the right striatum of 6-OHDA induced PD rats, increased levels of glutamate (Glu) and gamma-aminobutyric acid (GABA) concomitantly with decreased level of glutamine (Gln) were observed compared to the control. Whereas, in the left striatum of 6-OHDA-induced PD rats, increased level of Glu with decreased level of GABA and unchanged Gln were observed. Other cerebral metabolites including lactate, alanine, creatine, succinate, taurine, and glycine were also found to have some perturbations. The observed metabolic changes for Glu, Gln, and GABA are mostly likely the result of a shift in the steady-state equilibrium of the Gln-Glu-GABA metabolic cycle between astrocytes and neurons. The altered Gln and GABA levels are most likely as a strategy to protect neurons from Glu excitotoxic injury after striatal dopamine depletion. Changes in energy metabolism and tricarboxylic acid cycle might be involved in the pathogenesis of PD. PMID- 22936309 TI - hERG ion channel pharmacology: cell membrane liposomes in porous-supported lipid bilayers compared with whole-cell patch-clamping. AB - The purpose of this study was to obtain functional hERG ion channel protein for use in a non-cell-based ion channel assay. hERG was expressed in Sf9 insect cells. Attempts to solubilise the hERG protein from Sf9 insect cell membranes using non-ionic detergents (NP40 and DDM) were not successful. We therefore generated liposomes from the unpurified membrane fraction and incorporated these into porous Teflon-supported bilayer lipid membranes. Macroscopic potassium currents (1 nA) were recorded that approximated those in whole-cell patch clamping, but the channels were bidirectional in the bilayer lipid membrane (BLM). Currents were partially inhibited by the hERG blockers E4031, verapamil, and clofilium, indicating that the protein of interest is present at high levels in the BLM relative to endogenous channels. Cell liposomes produced from Sf9 insect cell membranes expressing voltage-gated sodium channels also gave current responses that were activated by veratridine and inhibited by saxitoxin. These results demonstrate that purification of the ion channel of interest is not always necessary for liposomes used in macro-current BLM systems. PMID- 22936310 TI - Measurement of distress in Chinese inpatients with lymphoma. AB - PURPOSE: The aim of this study was to assess the levels and sources of distress in patients with lymphoma. This study also focused on the influence of factors of the level of distress and the cutoff score using the Distress Thermometer (DT) relative to the Hospital Anxiety and Depression Scale (HADS). METHOD: DT and HADS were used to estimate the psychological status of 323 eligible lymphoma patients. The DT was evaluated against the HADS for its sensitivity and specificity. RESULTS: One hundred and ninety-three (59.7%) lymphoma patients experienced overall distress on the HADS, with 137 (42.4%) experiencing anxiety and 114 (35.3%) suffering from depression. There were 199 (61.6%) and 163 (50.5%) patients with distress score >= 4 and >= 5, respectively. DT was significantly correlated with the HADS-total (T) (r=0.820, p<0.001), HADS-depression (D) (r=0.763, p<0.001), and HADS-anxiety (A) (r=0.738, p<0.001). The consistency of the DT and HADS was favorable (coherence index=0.6030, p<0.01) when the cutoff score was 5 for the DT. Referring to the cutoff of 15 on HADS, 5 on DT yielded optimal specificity (0.869, p<0.001) and sensitivity (0.756, p<0.001). In multiple logistic regression analysis, patients with 'B symptoms' were more likely to have a distress score >= 5 [OR=4.512, p<0.05, 95% CI 1.953-10.467]. CONCLUSION: DT is efficacious for screening for anxiety and depression in lymphoma patients. PMID- 22936307 TI - alpha-Synuclein and neuronal cell death. AB - Parkinson's disease (PD) is a progressive neurodegenerative disorder affecting ~1 % of people over the age of 65. Neuropathological hallmarks of PD are prominent loss of dopaminergic (DA) neurons in the substantia nigra and formation of intraneuronal protein inclusions termed Lewy bodies, composed mainly of alpha synuclein (alphaSyn). Missense mutations in alphaSyn gene giving rise to production of degradation-resistant mutant proteins or multiplication of wild type alphaSyn gene allele can cause rare inherited forms of PD. Therefore, the existence of abnormally high amount of alphaSyn protein is considered responsible for the DA neuronal death in PD. Normally, alphaSyn protein localizes to presynaptic terminals of neuronal cells, regulating the neurotransmitter release through the modulation of assembly of soluble N-ethylmaleimide-sensitive factor attachment protein receptor complex. On the other hand, of note, pathological examinations on the recipient patients of fetal nigral transplants provided a prion-like cell-to-cell transmission hypothesis for abnormal alphaSyn. The extracellular alphaSyn fibrils can internalize to the cells and enhance intracellular formation of protein inclusions, thereby reducing cell viability. These findings suggest that effective removal of abnormal species of alphaSyn in the extracellular space as well as intracellular compartments can be of therapeutic relevance. In this review, we will focus on alphaSyn-triggered neuronal cell death and provide possible disease-modifying therapies targeting abnormally accumulating alphaSyn. PMID- 22936311 TI - Giant cell tumor occurring in familial Paget's disease of bone: report of clinical characteristics and linkage analysis of a large pedigree. AB - Neoplastic degeneration represents a rare but serious complication of Paget's disease of bone (PDB). Although osteosarcomas have been described in up to 1% of PDB cases, giant cell tumors are less frequent and mainly occur in patients with polyostotic disease. We recently characterized a large pedigree with 14 affected members of whom four developed giant cell tumors at pagetic sites. The high number of affected subjects across multiple generations allowed us to better characterize the clinical phenotype and look for possible susceptibility loci. Of interest, all the affected members had polyostotic PDB, but subjects developing giant cell tumors showed an increased disease severity with a reduced clinical response to bisphosphonate treatment and an increased prevalence of bone pain, deformities, and fractures. Together with an increased occurrence of common pagetic complications, affected patients of this pedigree also evidenced a fivefold higher prevalence of coronary artery disease with respect to either the unaffected family members or a comparative cohort of 150 unrelated PDB cases from the same geographical area. This association was further enhanced in the four cases with PDB and giant cell tumors, all of them developing coronary artery disease before 60 years of age. Despite the early onset and the severe phenotype, PDB patients from this pedigree were negative for the presence of SQSTM1 or TNFRSF11A mutations, previously associated with enhanced disease severity. Genome wide linkage analysis identified six possible candidate regions on chromosomes 1, 5, 6, 8, 10, and 20. Because the chromosome 8 and 10 loci were next to the TNFRSF11B and OPTN genes, we extended the genetic screening to these two genes, but we failed to identify any causative mutation at both the genomic and transcription level, suggesting that a different genetic defect is associated with PDB and potentially giant cell tumor of bone in this pedigree. PMID- 22936313 TI - Pharmacokinetics, biotransformation, and mass balance of edoxaban, a selective, direct factor Xa inhibitor, in humans. AB - This study determined the mass balance and pharmacokinetics of edoxaban in humans after oral administration of [14C]edoxaban. After oral administration of 60 mg (as active moiety) of [14C]edoxaban to six healthy male subjects, serial blood/plasma and urinary and fecal samples were collected for up to 168 h postdose. All samples were analyzed for total radioactivity by liquid scintillation counting and for concentrations of edoxaban and four metabolites in plasma, urine, and fecal samples by either high-performance liquid chromatography/tandem mass spectrometry method using multiple reaction modes, or a liquid chromatography radiometric method. The mean recovery of radioactivity was >97% of the administered radioactive dose, with 62.2% eliminated in feces and 35.4% in urine. Unchanged edoxaban accounted for the majority of radioactivity, with 49.1 and 23.8% of the dose as parent observed in feces and urine, respectively. Unchanged edoxaban was the most abundant species in plasma, with a mean area under the curve (AUC)(0-infinity) of 1596 ng . h/ml. The next most abundant species was metabolite M4, with a mean AUC(0-infinity) 147 ng . h/ml. The mass balance of edoxaban was well described, with unchanged edoxaban as the most abundant component of total radioactivity. Edoxaban is eliminated through multiple pathways, but each accounts for only a small amount of overall elimination. PMID- 22936315 TI - Predictability of metabolism of ibuprofen and naproxen using chimeric mice with human hepatocytes. AB - Prediction of human drug metabolism is important for drug development. Recently, the number of new drug candidates metabolized by not only cytochrome P450 (P450) but also non-P450 has been increasing. It is necessary to consider species differences in drug metabolism between humans and experimental animals. We examined species differences of drug metabolism, especially between humans and rats, for ibuprofen and (S)-naproxen as nonsteroidal anti-inflammatory drugs, which are metabolized by P450 and UDP-glucuronosyltransferase, sulfotransferase, and amino acid N-acyltransferase for taurine conjugation in liver, using human chimeric mice (h-PXB mice) repopulated with human hepatocytes and rat chimeric mice (r-PXB mice) transplanted with rat hepatocytes. We performed the direct comparison of excretory metabolites in urine between h-PXB mice and reported data for humans as well as between r-PXB mice and rats after administration of ibuprofen and (S)-naproxen. Good agreement for urinary metabolites (percentage of dose) was observed not only between humans and h-PXB mice but also between rats and r-PXB mice. Therefore, the metabolic profiles in humans and rats reflected those in h-PXB mice and r-PXB mice. Our results indicated that h-PXB mice should be helpful for predicting the quantitative metabolic profiles of drugs mediated by P450 and non-P450 in liver, and r-PXB mice should be helpful for evaluation of species differences in these metabolic enzymes. PMID- 22936314 TI - Inhibition of bupropion metabolism by selegiline: mechanism-based inactivation of human CYP2B6 and characterization of glutathione and peptide adducts. AB - Selegiline, the R-enantiomer of deprenyl, is used in the treatment of Parkinson's disease. Bupropion, an antidepressant, often used to treat patients in conjunction with selegiline, is metabolized primarily by CYP2B6. The effect of selegiline on the enzymatic activity of human cytochrome CYP2B6 in a reconstituted system and its effect on the metabolism of bupropion were examined. Selegiline was found to be a mechanism-based inactivator of the 7-ethoxy-4 (trifluoromethyl)coumarin O-deethylation (7-EFC) activity of CYP2B6 as well as bupropion metabolism. The inactivations were time-, concentration-, and NADPH dependent and were characterized by K(I) values of 0.14 and 0.6 MUM, k(inact) values of 0.022 and 0.029 min-1, and t(1/2) values of 31.5 and 24 min, respectively. In standard inhibition assays, selegiline increased the K(m) of CYP2B6 for bupropion from 10 to 92 MUM and decreased the k(cat) by ~50%. The reduced carbon-monoxide difference spectrum revealed over a 50% loss in the cytochrome P450 spectrum in the inactivated sample, with no loss in heme, and there was ~70% loss in enzyme activity. Trapping of the reactive metabolite using GSH led to the identification of a GSH-selegiline conjugate with a m/z 528 that could be explained by hydroxylation of selegiline followed by the addition of glutathione to the propargyl moiety after oxygenation to form the ketene intermediate. Liquid chromatography-tandem mass spectrometry analysis of the labeled protein following digestion with trypsin revealed the peptide 64DVFTVHLGPR73 as the peptide modified by the reactive metabolite of selegiline and the site of adduct formation is Asp64. PMID- 22936316 TI - HLA and non-HLA polymorphisms in renal transplantation. AB - Despite progress made in the field of immunosuppression, graft rejection remains a major cause of morbidity and mortality of patients after solid organ transplantation. There are several genetic causes which could influence the outcome of renal transplantation. One of the main determining factors of success in renal transplantation is human leukocyte antigen (HLA) compatibility between donor and recipient, particularly at HLA-A, HLA-B and HLA-DR loci. HLA compatibility remains an essential immunological barrier, despite modern immunosuppressive treatments. There is also evidence that natural killer (NK) cell alloreactivity contributes to the immune response which modulates the outcome of renal transplantation. However, the clinical impact of combinations of KIR genes (family of NK cell receptors) and their HLA ligands in donor and recipient still remains to be clearly established. Furthermore, cytokines are involved in the immune reaction against the renal transplant, but the implication of the genetic polymorphism of cytokines is strongly debated. Therefore, while HLA compatibility remains a primordial component for any renal transplantation, it would be premature to use the two other genetic aspects as criteria for organ allocation and as prognostic factors. PMID- 22936317 TI - The Western model of integrative oncology: the contribution of Chinese medicine. AB - Western integrative oncology (IO) combines conventional mainstream medicine with complementary and alternative medicine (CAM) for the care of cancer patients. Since it includes patient orientation and the holistic approach of many CAM options, IO offers not only preventive measures, but also a wide spectrum of treatment modalities for all stages of illness, from the acute phases through the rehabilitation period. Many therapeutic methods of IO are supported by scientific evidence, for example, dietary and nutritional counseling, exercise, and mind body medicine, among others. IO also includes therapeutic interventions of traditional Chinese medicine (TCM). At present acupuncture, qigong, and foot massage play an important role in the Western care of cancer patients. However, unlike in China, in Western countries herbal remedies are usually only used during those periods in which chemotherapy is not applied in order to avoid herb drug interactions. Instead, acupuncture is widely used to manage the side-effects that often accompany chemotherapy. This paper focuses on the role of Chinese medicine in Western IO and reviews the scope and limitations of IO in the care of cancer patients today. The future challenges of IO will also be discussed in this paper. PMID- 22936318 TI - Integrative oncology meets immunotherapy: new prospects for combination therapy grounded in Eastern medical knowledge. AB - As cancer rates rise globally, standard care is being questioned; new approaches involving immune therapies are emerging. With this shift comes a corresponding shift in the use and potential of herbal medicines and extracts. The focus of this article, which has evolved from a presentation at the Second Beijing International Symposium on Integrative Medicine (BISIM May 19-20, 2012), is particularly on Chinese medicine, but is generalizable to Eastern medicine more broadly and to other herbal traditions. Until recently, herbal and related treatments have been used as adjuvants to conventional care - for reducing side effects, enhancing cytotoxicity, and sometimes, undesirably counteracting the efficacy of chemotherapy and radiation. Now, in the context of a new class of immune-based cancer therapies, herbal and other complementary modalities are looked at as enhancers of the body's immunity. PMID- 22936319 TI - The treatment of non-small cell lung cancer by interstitial I-125 seeds implantation combined with chemotherapy and Chinese medicine. AB - OBJECTIVE: To investigate the effects of brachytherapy with computed tomography guided percutaneous radioactive I-125 seeds interstitial implantation (ISI) synchronized chemotherapy and Chinese medicine (CM) for the treatment of advanced stage of non-small cell lung cancer (NSCLC). METHODS: Ninety patients diagnosed with NSCLC by biopsy were randomly assigned to three groups: the synchronized therapy group (A), the chemotherapy plus CM-treated group (B), and the chemotherapy-treated group (C); a 2-month course of treatment was administered to them all. The effectiveness of treatment was evaluated based on tumor size, tumor markers (carcinoembryonic, squamous cell carcinoma-associated antigen, and cytokeratin 19 fragment), clinical symptoms, and quality of life (QOL) in patients. RESULTS: The total effective rates of Groups A to C were 83.33%, 46.67%, and 43.33%, respectively. The tumor markers were reduced obviously in Group A, showing signifificant difference compared with those in the other two groups. Additionally, QOL was elevated and cancer-related symptoms were alleviated more signifificant in Group A than those in Group C (all P<0.05). CONCLUSION: The synchronized therapy of I-125 implantation with chemotherapy and CM was a safe therapeutic method and can be regarded as a new mode for treatment of advanced-stage NSCLC. PMID- 22936320 TI - Effect of Yisui Shengxue Granule () on the oxidative damage of erythrocytes from patients with hemoglobin H disease. AB - OBJECTIVE: To investigate the effect of Yisui Shengxue Granule (, YSSXG), a complex Chinese medicine, on the oxidative damage of erythrocytes from patients with hemoglobin H (HbH) disease. METHODS: Twenty-two patients with HbH disease and 22 healthy volunteers were observed. YSSXG was given to patients with HbH disease for 3 months. Before and after the 3-month treatment, blood parameters [hemoglobin (Hb), red blood cells (RBCs), and reticulocyte percent (Ret)] were examined; inclusion bodies in erythrocytes were observed by transmission electron microscopy (TEM); activities of antioxidant defense enzymes [superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and catalase (Cat)] and erythrocyte membrane malondialdehyde (MDA) concentrations were determined. RESULTS: In patients with HbH disease, measured values of RBC and Hb obtained from the first to the third months after treatment with YSSXG were significantly higher than before treatment (P<0.01). Measured values of Ret from the second to the third months after treatment were significantly lower than before treatment (P<0.05 and P<0.01, respectively). Prior to treatment with YSSXG, TEM images of RBCs showed the presence of numerous inclusion bodies. After treatment with YSSXG, the amount and volume of inclusion bodies decreased. Treatment with YSSXG also led to a significant increase in SOD activity (P<0.01), a decrease in Cat activity (P<0.01), and no significant differences in GSHPx activity (P>0.05) or MDA concentration (P>0.05). However, compared with the healthy counterparts, SOD, GSH Px, and Cat activities presented at high levels (P<0.01) both before and after treatment. CONCLUSIONS: YSSXG could improve the degree of hemolysis and anemia in patients with HbH disease. The mechanism may be related to its antioxidative effects, which could elevate the activity of total SOD in erythrocytes and efficiently inhibit the oxidative precipitation of beta-globin chains. PMID- 22936321 TI - Induction of apoptosis in human Hep3B hepatoma cells by norcantharidin through a p53 independent pathway via TRAIL/DR5 signal transduction. AB - OBJECTIVE: To investigate the inhibitory activities of norcantharidin (NCTD), a demethylated analogue of cantharidin, on Hep3B cells (a human hepatoma cell line) with deficiency of p53. METHODS: The survival rate of the Hep3B cells after treating with NCTD was measured by MTT assay. Cell cycle of treated cells was analyzed by flow cytometry, and DNA fragmentation was observed by electrophoresis. The influence of inhibitors for various caspases and anti-death receptors antibodies on the NCTD-induced apoptosis in the cells was determined. RESULTS: NCTD treatment resulted in growth inhibition of Hep3B cells in a dose- and time-dependent manner. Cell cycle analysis of the cells after treatment with NCTD for 48 h shows that NCTD induced G(2)M phase arrest occurs at low concentration ([Symbol: see text] 25 MUmol/L) but G(0)G(1) phase arrest at high concentration (50 MUmol/L). The addition of both caspase-3 and caspase-10 inhibitors completely inhibited DNA fragmentation. Addition of anti-TRAIL/DR5 antibody significantly inhibited DNA fragmentation. CONCLUSION: NCTD may inhibit the proliferation of Hep3B cells by arresting cell cycle at G(2)M or G(0)G(1) phase, and induce cells apoptosis via TRAIL/DR5 signal transduction through activation of caspase-3 and caspase-10 by a p53-independent pathway. PMID- 22936322 TI - Effect of Huannao Yicong prescription [See Text] extract on beta-amyloid precursor protein metabolic signal transduction-related protein in brain tissue of dementia model transgenic mouse. AB - OBJECTIVE: To observe the effect of Huannao Yicong Prescription (, HNYC, a Chinese medical compound) extract on beta-amyloid precursor protein (APP) metabolic signal transduction related protein kinase C (PKC), tyrosine amyloid protein kinase (TrKA), and glycogen synthase kinase-3 (GSK-3) in brain tissue of transgenic mouse dementia model induced by APP. METHODS: Sixty dementia model transgenic 3-month-old mice induced by APP695V717I were randomly allocated in four groups: the model group (A), the Donepezil (0.65*10(-3) g.kg(-1).(-1)) treated group (B), and the two HNYC-treated groups (C and D) with high dosage (2.8 g.kg(-1).(-1)) and low dosage (1.4 g.kg(-1).(-1)) of HNYC extract, respectively, 15 mice in each group. Besides, a normal control group was set up with 15 C57BL/6J mice with the same age and genetic background as the model mice. The drugs for treatment were administered once a day by dissolving in equal volume distilled water through gastric infusion, continued for 6 months, to mice in group A and to normal control group equal-volume distilled water was administered instead. Spatial learning and memory capacity of mice were observed by Morris water maze; their one-time escape response memory capacity was tested by diving platform; and changes of PKC, TrkA, and GSK-3 levels in hippocampus and cortex of brain were detected by Western blotting. RESULTS: HNYC extract showed significant effects on increasing the time of model mice for swimming through the flat roof and the swimming time and path in the fourth quadrant P<0.05 or P<0.01). Diving platform test showed that the latent times in Groups B and C were longer than that in Group A significantly (P <0.05 and P<0.01). Compared with the normal control group, PKC and TrkA protein expression levels in hippocampus and cortex of model mice's brain lowered significantly (P<0.01), while GSK-3 protein expression increased significantly (P<0.01); compared with Group A (the model group), hippocampal and cortical levels of PKC protein expression in the intervened groups (B-D) as well as those of TrkA in Group C were higher (P<0.01 or P<0.05), while hippocampal levels of GSK-3 in intervened groups were lower (P<0.01). CONCLUSION: HNYC extract could obviously increase the protein expressions of PKC and TrkA and decrease the expression of GSK-3 protein in brain tissue of transgenetic mice model of dementia, and regulate APP metabolic signal transduction path, and thus to suppress the production of Abeta, which is one of the dominant mechanisms for improving learning/memory capacity of dementia model animals. PMID- 22936323 TI - A strategy for detecting absorbed bioactive compounds for quality control in the water extract of rhubarb by ultra performance liquid chromatography with photodiode array detector. AB - OBJECTIVE: To detect absorbed bioactive compounds of the water extract whose pharmacodynamic effect was craniocerebral protection for quality control assessment. METHODS: Anthraquinones in water extract of rhubarb (WER), in cerebrospinal fluid (CSF) of patients with traumatic brain injury (TBI) and in ipsilateral cortex of TBI rats following oral WER were respectively explored by ultra performance liquid chromatography with photodiode array detector (UPLC-PDA) method developed in the present study. The effects of anthraquinones absorbed into injured cortex on superoxidase dismutase (SOD) activity in TBI rats were detected. The antioxidative anthraquinones absorbed into target organ were evaluated for quality control of WER. RESULTS: Anthraquinones in WER were aloe emodin, rhein, emodin, chrysophanol, and physcion. Only the last anthraquinone was found in CSF and in ipsilateral cortex under this chromatographic condition. Physcion increased SOD activity in TBI rats significantly. CONCLUSIONS: Physcion was the main active compound of rhubarb against craniocerebral injury via antioxidant pathway. According to our strategy, the exploration of physcion suggested the possibility of a novel quality control of WER in treating TBI injury. PMID- 22936324 TI - Analysis on interrelation between electroacupuncture-induced cumulative analgesic effect and hypothalamic cholinergic activities in chronic neuropathic pain rats. AB - OBJECTIVE: To observe the effects of repeated electroacupuncture (EA) of Zusanli (ST36)- Yanglingquan (GB34) on hypothalamic acetylcholinesterase (AchE) and vesicular acetylcholine (ACh) transporter (VAChT) activities and choline acetyltransferase (ChAT) mRNA and muscarinic M1 receptor (M1R) mRNA expression in chronic constrictive injury (CCI) and/or ovariectomy (OVX) rats so as to reveal its underlying mechanism in cumulative analgesia. METHODS: A total of 103 female Wistar rats were randomly divided into normal control (n =15), CCI (n =15), CCI+EA2d (n =15), CCI+EA2W (n =15), OVX+CCI =13), OVX+CCI+EA2d (n =15), and OVX+CCI+EA2W groups (n =15). CCI model was established by ligature of the unilateral sciatic nerve with surgical suture. Memory impairment model was established by removal of the bilateral ovaries. Morris water test was conducted to evaluate the OVX rats' memory learning ability, and the thermal pain threshold (PT) of the bilateral paws was detected the next morning after EA. EA (2/15 Hz, 1 mA) was applied to bilateral ST36-GB34 for 30 min, once daily for 2 days or 2 weeks, respectively. Hypothalamic AChE activity was detected by histochemistry, VAChT immunoactivity was determined by immunohistochemistry, and ChAT mRNA and M1R mRNA expressions were assayed by reverse transcription-polymerase chain reaction (RT-PCR). RESULTS: In comparison with the normal control group, the AChE activity in hypothalamic arcuate nucleus (ARC) and supraoptic nucleus (SON) regions of CCI group, AChE activity in paraventricular nucleus (PVN), ARC, and SON regions of OVX+CCI group, and hypothalamic muscarinic M1R mRNA expression levels in both CCI and OVX+CCI groups were down-regulated significantly (P <0.05). Compared with the CCI group, the AChE activities in hypothalamic ARC and SON regions of CCI+EA2d and CCI+EA2W groups and PVN region of CCI+EA2W group and hypothalamic ChAT mRNA and M1R mRNA expression levels in CCI+EA2W group were up regulated considerably (P <0.05). In comparison with the OVX+CCI group, the AChE activities in PVN, ARC, and SON regions and the expressions of hypothalamic ChAT mRNA and VAChT in ARC region of OVX+CCI+EA2W group were up-regulated remarkably (P <0.05). The effects in rats of CCI+EA2W group were evidently superior to those of OVX+CCI+EA2d group in up-regulating AChE activities in PVN, ARC, and SON regions, VAChT immunoactivity in ARC region, and expression levels of hypothalamic ChAT mRNA and M1R mRNA (P <0.05). Similar situations were found in OVX+CCI rats after EA2W. It suggested a cumulative effect after repeated EA of ST36-GB34. Comparison between CCI+EA2W and OVX+CCI+EA2W groups showed that the effects in rats of the former group were evidently better than those of the latter group in up-regulating AChE activity in ARC and SON regions and the expressions of hypothalamic ChAT mRNA and M1 mRNA (P <0.05), suggesting a reduction of EA2W effects after OVX. CONCLUSION: Repeated EA can significantly up regulate AChE and VAChT activities and ChAT mRNA and M1R mRNA expressions in the hypothalamus of CCI and OVX+CCI rats, which may contribute to the cumulative analgesic effects of repeated EA and be closely related to the animals' neuromemory ability. PMID- 22936325 TI - Effect of formula compatibility on the pharmacokinetics of components from Dachengqi Decoction [See Text] in rats. AB - OBJECTIVE: To investigate the effect of prescription compatibility on the pharmacokinetics of components from Dachengqi Decoction (DCQD, ) in rats. METHODS: Twenty-four male rats were randomly and equally divided into the DCQD group, Dahuang (Radix et Rhizoma Rhei, Polygonaceae) group, Houpo (Magnolia officinalis Rehd., Magnoliaceae) group, and Zhishi (Fructus Aurantii Immaturus, Rutaceae) group. The blood samples were collected before dosing and subsequently at 10, 15, 20, 30, 45 min, 1, 2, 4, 8, and 12 h following gavage. The levels of aloe-emodin, rhein, emodin, chrysophanol, honokiol, magnolol, hesperidin, and naringin in rat serum were quantified using a liquid chromatography tandem mass spectrometry (LC-MS/MS) method for pharmacokinetic study. RESULTS: The area under the curve (AUC), mean retention time (MRT), the peak concentration (C(max)) of aloe-emodin, rhein, emodin, and chrysophanol in the DCQD group were significantly different compared with the Dahuang group (P <0.05, respectively). The mean plasma concentration, C(max), and the absorption of Dahuang's component in the DCQD group were obviously lower at each time point than those in the Dahuang group, while the elimination process of Dahuang's component was obviously delayed (P <0.05). Half-lives of aloe-emodin, chrysophanol, and rhein were also extended in the DCQD group (P <0.05, respectively). In the DCQD group, the mean plasma concentration, AUC, C(max) and absorption of honokiol, and magnolol were significantly lower (P <0.01, respectively) at each time point than those in the Houpo group, while the drug distribution half-life time (T(1/2alpha)), the drug eliminated half-life time (T(1/2beta)), MRT, and time of peak concentration (T(max)) were significantly delayed (P <0.05, respectively). Pharmacokinetic parameters of hesperidin and naringin in the Zhishi group were not significantly different as compared with the DCQD group (P >0.05, respectively), while the MRT of naringin was significantly longer. CONCLUSIONS: The compatibility in Chinese medicine could affect the drug's pharmacokinetics in DCQD, which proves that the prescription compatibility principle of Chinese medicine formulations has its own pharmacokinetic basis. PMID- 22936326 TI - The progress of the research on cardio-vascular effects and acting mechanism of polydatin. AB - Rhizoma Polygoni Cuspidati, a Chinese herbal drug, has actions of dispelling dampness, alleviating jaundice, clearing heat, subsiding toxin, activating blood, and removing stasis. Polydatin (PD), one of its chief active ingredients, has been proved by modern pharmacological studies to possess extensive cardiovascular pharmacological activity, showing marked effects on protecting cardio-myocyte, dilating blood vessel, antagonizing platelet aggregation, thrombosis, and atherosclerosis. The progress of the research on cardiovascular pharmacological actions and the acting mechanism of PD was reviewed in this paper. PMID- 22936327 TI - Immunological functions of steryl glycosides. AB - Steryl glycosides, sterols glycosylated at the 3beta-hydroxy group, have been widely found in plants, algae, and fungi, but are rare in bacteria and animals. Glycosylation of sterols is known to modify properties of the cell membrane and confer resistance against stresses by freezing or heat-shock on cells. Furthermore, accumulating evidence obtained from recent research suggests important biological functions of steryl glycosides, including regulation of host defenses against pathogens, lipid metabolism, and developmental events. This review is focused on the immunological functions of steryl glycosides, such as modulation of host immune functions upon exposure to cholesteryl glycosides produced by pathogenic bacteria. PMID- 22936328 TI - Genome-wide analysis of lectin receptor-like kinase family from Arabidopsis and rice. AB - Lectin receptor-like kinases (LecRLKs) are class of membrane proteins found in higher plants that are involved in diverse functions ranging from plant growth and development to stress tolerance. The basic structure of LecRLK protein comprises of a lectin and a kinase domain, which are interconnected by transmembrane region. Here we have identified LecRLKs from Arabidopsis and rice and studied these proteins on the basis of their expression profile and phylogenies. We were able to identify 32 G-type, 42 L-type and 1 C-type LecRLKs from Arabidopsis and 72 L-type, 100 G-type and 1 C-type LecRLKs from rice on the basis of their annotation and presence of lectin as well kinase domains. The whole family is rather intron-less. We have sub-grouped the gene family on the basis of their phylogram. Although on the basis of sequence the members of each group are closely associated but their functions vary to a great extent. The interacting partners and coexpression data of the genes revealed the importance of gene family in physiology and stress related responses. An in-depth analysis on gene-expression suggested clear demarcation in roles assigned to each gene. To gain additional knowledge about the LecRLK gene family, we searched for previously unreported motifs and checked their importance structurally on the basis of homology modelling. The analysis revealed that the gene family has important roles in diverse functions in plants, both in the developmental stages and in stress conditions. This study thus opens the possibility to explore the roles that LecRLKs might play in life of a plant. PMID- 22936329 TI - Versatile approach to alpha-alkoxy carbamate synthesis and stimulus-responsive alcohol release. AB - A series of alpha-alkoxy carbamates that cleave under mild conditions to release alcohols has been synthesized through a multicomponent process. The relationship between structural features in these compounds and the rate of alcohol release in the presence of basic hydrogen peroxide has been studied. The preparation of carbamates that cleave under other conditions has been demonstrated. PMID- 22936332 TI - Fampridine improves severe dysarthria in secondary-progressive multiple sclerosis. PMID- 22936330 TI - Effects of high hydrostatic pressure on physicochemical and functional properties of walnut (Juglans regia L.) protein isolate. AB - BACKGROUND: Walnut (Juglans regia L.) is a good source of protein that has potential application in new product formation and fortification. The main objectives of this study were to investigate the effects of high hydrostatic pressure (HHP) treatment (300-600 MPa 20 min) on physicochemical and functional properties of walnut protein isolate (WPI) using various analytical techniques at room temperature. RESULTS: The results showed significant modification of solubility, free sulfhydryl content and surface hydrophobicity with increased levels of HHP treatment, indicating partial denaturation and aggregation of proteins. Differential scanning calorimetry and fluorescence spectrum analyses demonstrated that HHP treatment resulted in gradual unfolding of protein structure. Emulsifying activity index was significantly (P < 0.05) increased after HHP treatment at 400 MPa, but significantly decreased (P < 0.05) relative to the untreated WPI with further increase in pressure. HHP treatment at 300-600 MPa significantly decreased emulsion stability index. Additionally, HHP-treated walnut proteins showed better foaming properties and in vitro digestibility. CONCLUSION: These results suggest that HHP treatment could be applied to modify the properties of walnut proteins by appropriate of pressure levels, which will help in using walnut protein as a potential food ingredient. PMID- 22936333 TI - Neuropathic pruritus (itch) in neuromyelitis optica. AB - BACKGROUND: Neuropathic pruritus (itch) is an uncommon, but well described, symptom in neurology. There are itch-specific neurons in the dorsal horn of the spinal cord. We noted excessive pruritus in patients with neuromyelitis optica (NMO). OBJECTIVE: We aimed to explore the characteristics of pruritus in NMO patients. METHODS: We reviewed case records of a well-defined cohort of 45 serial aquaporin-4 antibody-positive patients visiting the national NMO service. All patients were interviewed. RESULTS: Of the 45 antibody-positive NMO patients, 44 had myelitis and 12 of those 44 (27.3%) patients reported pruritus within a week of other symptoms of transverse myelitis with central cord involvement. In three patients, pruritus was the first symptom of a relapse, while in one case, pruritus was the very first symptom of the index episode of NMO. CONCLUSION: Neuropathic pruritus seems to be a common, but under-recognised symptom of myelitis associated with NMO. PMID- 22936334 TI - Training in MS: influence of two different endurance training protocols (aquatic versus overland) on cytokine and neurotrophin concentrations during three week randomized controlled trial. AB - BACKGROUND: The influences of exercising on cytokine response, fatigue and cardiorespiratory values are important aspects of rehabilitation in persons with multiple sclerosis (PwMS). Exercise performed within these programs is often practised in water but the effects of immersion on PwMS have not been systematically investigated. OBJECTIVE: The objective of this study is to determine differences in cytokine and neurotrophin concentrations, fatigue and cardiorespiratory values in response to 3 week endurance training conducted on a cycle ergometer or an aquatic bike. METHODS: A randomized controlled clinical trial was conducted in 60 MS patients (Expanded Disability Status Scale range 1.0 6.5). Resting serum levels of brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), Interleukin-6, soluble receptor of IL-6 and tumor necrosis factor alpha, and concentrations in response to cardiopulmonary exercise test (CPET), fatigue and cardiorespiratory values were determined at entry and discharge. Subjects performed daily 30 minute training at 60% of VO2max. RESULTS: Cytokines and neurotrophins showed no significant differences between groups over the training intervention. Within the water group BDNF resting and post-CPET concentrations (p<0.05) showed a significant increase and NGF tended to increase after the training intervention. Short-term effects on BDNF (CEPT) tended to increase at the start and significantly thereafter (p<0.05). No changes occurred in the land group. Other cytokines and fatigue scores remained unchanged over the training period. Cardiorespiratory values improved significantly over time within both groups. CONCLUSION: This study indicates that aquatic training activates BDNF regulation and can be an effective training method during rehabilitation in PwMS. PMID- 22936335 TI - Optic neuritis interferes with optical coherence tomography and magnetic resonance imaging correlations. AB - BACKGROUND: Retinal nerve fibre layer (RNFL) thinning is associated with brain atrophy in multiple sclerosis (MS). An influence of optic neuritis is well documented but sparsely investigated. Recently, the retinal ganglion cell layer (GCL) has been shown to provide superior information regarding visual function and retinal neurodegeneration as compared with RNFL. OBJECTIVE: To investigate the association of white and grey matter brain volume with peripapillary RNFL and macular GCL in MS patients with and without a history of optic neuritis. METHODS: 63 patients with relapsing-remitting MS were included in a two-centre cross sectional prospective study. All patients underwent retinal examination with spectral domain optical coherence tomography and 1.5 T MRI for determination of normalized brain volume (NBV), white matter volume (NWMV) and grey matter volume (NGMV). RESULTS: Both RNFL and GCL were associated with NBV, NWMV and NGMV in eyes without previous optic neuritis. This association is disrupted in the case of NGMV following optic neuritis. CONCLUSIONS: Both RNFL and GCL as parameters of neuro-axonal damage are comparably linked to whole brain as well as white and grey matter atrophy. An event of optic neuritis interferes with this relation, adding further damage to the optic nerve and disrupting especially an association with grey matter. PMID- 22936336 TI - Development of a chronic noncancer oral reference dose and drinking water screening level for sulfolane using benchmark dose modeling. AB - Sulfolane is a widely used industrial solvent that is often used for gas treatment (sour gas sweetening; hydrogen sulfide removal from shale and coal processes, etc.), and in the manufacture of polymers and electronics, and may be found in pharmaceuticals as a residual solvent used in the manufacturing processes. Sulfolane is considered a high production volume chemical with worldwide production around 18 000-36 000 tons per year. Given that sulfolane has been detected as a contaminant in groundwater, an important potential route of exposure is tap water ingestion. Because there are currently no federal drinking water standards for sulfolane in the USA, we developed a noncancer oral reference dose (RfD) based on benchmark dose modeling, as well as a tap water screening value that is protective of ingestion. Review of the available literature suggests that sulfolane is not likely to be mutagenic, clastogenic or carcinogenic, or pose reproductive or developmental health risks except perhaps at very high exposure concentrations. RfD values derived using benchmark dose modeling were 0.01-0.04 mg kg(-1) per day, although modeling of developmental endpoints resulted in higher values, approximately 0.4 mg kg(-1) per day. The lowest, most conservative, RfD of 0.01 mg kg(-1) per day was based on reduced white blood cell counts in female rats. This RfD was used to develop a tap water screening level that is protective of ingestion, viz. 365 ug l(-1). It is anticipated that these values, along with the hazard identification and dose response modeling described herein, should be informative for risk assessors and regulators interested in setting health-protective drinking water guideline values for sulfolane. PMID- 22936337 TI - Development and characterization of an aptamer binding ligand of fractalkine using domain targeted SELEX. AB - Fractalkine (FKN) is a unique cell surface protein with potential as a therapeutic target because of its role in inflammatory diseases and cancer. We developed an aptamer, named FKN-S2, with a dissociation constant of 3.4 +/- 0.7 nM that is specific to the chemokine domain of fractalkine. PMID- 22936338 TI - Bilateral spontaneous rupture of the flexor digitorum superficialis and the flexor digitorum profundus in a diabetic patient. AB - Closed flexor tendon rupture is an unusual condition that has been described in association with distinct underlying disease processes. Several theories have been implicated in the pathogenesis, including labor-associated forceful usage, gender, and age. The effect of diabetes on the native tendon tissue is not yet fully understood; however, the metabolic perturbations of diabetes have been shown to result in detrimental changes to the musculoskeletal system. We report an unusual case of bilateral spontaneous rupture of the flexor digitorum superficialis and flexor digitorum profundus in a 58-year-old woman with Type 2 diabetes mellitus. The clinical course, radiographic findings, and the biomechanical factors and mechanisms through which diabetes may affect the native tendon are presented. PMID- 22936340 TI - Plasmacytoid dendritic cells play a key role in promoting atherosclerosis in apolipoprotein E-deficient mice. AB - OBJECTIVE: Clinical studies have identified that reduced numbers of circulating plasmacytoid dendritic cells (pDCs) act as a predictor of cardiovascular events in coronary artery disease and that pDCs are detectable in the shoulder region of human atherosclerotic plaques, where rupture is most likely to occur. Results from animal models are controversial, with pDCs seen to inhibit or promote lesion development depending on the experimental settings. Here, we investigated the role of pDCs in atherosclerosis in apolipoprotein E-deficient mice. METHODS AND RESULTS: We demonstrated that the aorta and spleen of both apolipoprotein E deficient and C57BL/6 mice displayed similar numbers of pDCs, with similar activation status. In contrast, assessment of antigen uptake/presentation using the Ealpha/Y-Ae system revealed that aortic pDCs in apolipoprotein E-deficient(-) mice were capable of presenting in vivo systemically administered antigen. Continuous treatment of apolipoprotein E-deficient mice with anti-mouse plasmacytoid dendritic cell antigen 1 (mPDCA-1) antibody caused specific depletion of pDCs in the aorta and spleen and significantly reduced atherosclerosis formation in the aortic sinus (by 46%; P<0.001). Depletion of pDCs also reduced macrophages (by 34%; P<0.05) and increased collagen content (by 41%; P<0.05) in aortic plaques, implying a more stable plaque phenotype. Additionally, pDC depletion reduced splenic T-cell activation and inhibited interleukin-12, chemokine (C-X-C motif) ligand 1, monokine induced by interferon gamma, interferon gamma-induced protein 10, and vascular endothelium growth factor serum levels. CONCLUSIONS: These results identify a critical role for pDCs in atherosclerosis and suggest a potential role for pDC targeting in the control of the pathology. PMID- 22936341 TI - 25-hydroxyvitamin d levels and risk of ischemic heart disease, myocardial infarction, and early death: population-based study and meta-analyses of 18 and 17 studies. AB - OBJECTIVE: We tested the hypothesis that reduced plasma 25-hydroxyvitamin D associates with increased risk of ischemic heart disease, myocardial infarction, and early death. METHODS AND RESULTS: We measured baseline plasma 25 hydroxyvitamin D in 10 170 women and men from the Danish general population without vitamin D-fortified food. During 29 years of follow-up, 3100 persons developed ischemic heart disease, 1625 myocardial infarction, and 6747 died. Decreasing plasma 25-hydroxyvitamin D levels were associated with increasing risk of ischemic heart disease, myocardial infarction, and early death as a function of seasonally adjusted percentile categories (P for trend, 2*10(-4)-3*10(-53)). Comparing individuals with plasma 25-hydroxyvitamin D levels at the 1st to 4th percentile with individuals with levels at the 50th to 100th percentile, the multivariable adjusted risk was increased by 40% (95% CI, 14%-72%) for ischemic heart disease, by 64% (25%-114%) for myocardial infarction, by 57% (38%-78%) for early death, and by 81% (40%-135%) for fatal ischemic heart disease/myocardial infarction. In the meta-analyses of 18 and 17 studies, risk of ischemic heart disease and early death were increased by 39% (25%-54%) and 46% (31%-64%) for lowest versus highest quartile of 25-hydroxyvitamin D level. CONCLUSIONS: We observed increasing risk of ischemic heart disease, myocardial infarction, and early death with decreasing plasma 25-hydroxyvitamin D levels. These findings were substantiated in meta-analyses. PMID- 22936342 TI - Hepatocyte growth factor inhibits lipopolysaccharide-induced oxidative stress via epithelial growth factor receptor degradation. AB - OBJECTIVE: Lipopolysaccharide (LPS) triggers sepsis and systemic inflammatory response syndrome, which results in multiple organ failure. Our recent reports demonstrated that hepatocyte growth factor (HGF) attenuated angiotensin II induced oxidative stress via epithelial growth factor receptor (EGFR) degradation in vascular smooth muscle cells. Here, we examined whether HGF can protect against systemic inflammatory response syndrome induced by LPS and investigated the mechanism. METHODS AND RESULTS: HGF inhibited the increase in the expression of vascular cell adhesion molecule-1 and EGFR by LPS in vitro. HGF inhibited colocalization of EGFR and Src homology domain 2-containing inositol 5' phosphatase 2. Furthermore, HGF inhibited reactive oxygen species production. We also injected LPS into HGF transgenic mice with increased HGF serum concentration and their littermates. HGF transgenic mice reduced LPS-induced vascular cell adhesion molecule-1 and reactive oxygen species compared with control, accompanied by significant EGFR degradation. Furthermore, HGF transgenic mice significantly improved survival in the LPS injection model. CONCLUSIONS: The present study revealed inhibition of LPS-induced vascular cell adhesion molecule 1 expression by HGF via the degradation of EGFR. We demonstrated that HGF regulated Src homology domain 2-containing inositol 5'-phosphatase 2 recruitment to EGFR and inhibited LPS-induced inflammation via EGFR degradation. This effect of HGF may be useful for the treatment of inflammatory disease. PMID- 22936344 TI - A versatile molecular beacon-like probe for multiplexed detection based on fluorescence polarization and its application for a resettable logic gate. AB - A versatile molecular beacon (MB)-like probe was developed for multiplexed detection based on fluorescence polarization by target-induced allosteric effect and furthermore for resettable logic gate operation. PMID- 22936343 TI - Feedback regulation of cholesterol uptake by the LXR-IDOL-LDLR axis. AB - Inducible degrader of the low-density lipoprotein receptor (IDOL) is an E3 ubiquitin ligase that mediates the ubiquitination and degradation of the low density lipoprotein receptor (LDLR). IDOL expression is controlled at the transcriptional level by the cholesterol-sensing nuclear receptor liver X receptor (LXR). In response to rising cellular sterol levels, activated LXR induces IDOL production, thereby limiting further uptake of exogenous cholesterol through the LDLR pathway. The LXR-IDOL-LDLR mechanism for feedback inhibition of cholesterol uptake is independent of and complementary to the sterol regulatory element-binding protein pathway. Since the initial description of the LXR-IDOL pathway, biochemical studies have helped to define the structural basis for both IDOL target recognition and LDLR ubiquitin transfer. Recent work has also suggested links between IDOL and human lipid metabolism. PMID- 22936345 TI - High Prevalence of Hypertension and Other Cardiometabolic Risk Factors in US- and Caribbean-Born Blacks with Chest Pain Syndromes. AB - BACKGROUND: Caribbean-born blacks (CBB) have been reported to have lower coronary artery disease mortality rates than US-born blacks (UBB). We assessed whether CBB have a lower prevalence of cardiometabolic risk factors compared to UBB. METHODS: Non-Hispanic blacks (n = 275) hospitalized for chest pain who were prospectively enrolled in our Cardiovascular Outcomes Research Group (CORG) study provided clinical and demographic data. RESULTS: The study cohort comprised 45% (n = 125) UBB with a mean age of 61 +/- 16 years and 55% (n = 150) CBB with a mean age of 63 +/- 11 years. Myocardial infarction was diagnosed in 33% of UBB and 36% of CBB. CBB had a lower rate of previous myocardial infarction (14 vs. 24%; p = 0.04). They also smoked less (16 vs. 35%; p = 0.001) and were less likely to have first-degree relatives with coronary artery disease (24 vs. 41%; p = 0.018). However, they had a similarly high prevalence of hypertension (99 vs. 98%; p = 0.99), diabetes (58 vs. 48%; p = 0.11), dyslipidemia (53 vs. 42%; p = 0.08), and obesity (34 vs. 40%; p = 0.29) as UBB. CONCLUSION: A very high prevalence of hypertension exists in non-Hispanic blacks hospitalized for chest pain. CBB and UBB have a similar prevalence of cardiometabolic profile in our study population. Besides smoking, other factors contributing to lower CHD mortality reported for CBB need to be further explored. PMID- 22936346 TI - Lanthanides in molecular magnetism: so fascinating, so challenging. AB - Due to their usual large magnetic moments and large magnetic anisotropy lanthanide ions are investigated for the search of Single Molecule Magnets with high blocking temperature. However, the low symmetry crystal environment, the complexity of the electronic states or the non-collinearity of the magnetic anisotropy easy-axes in polynuclear systems make the rationalization of the magnetic behaviour of lanthanide based molecular systems difficult. In this perspective article we expose a methodology in which the use of additional characterization techniques, like single crystal magnetic measurements or luminescence experiments, complemented by relativistic ab initio calculations and a suitable choice of spin Hamiltonian models, can be of great help in order to overcome such difficulties, representing an essential step for the rational design of lanthanide based Single Molecule Magnets with enhanced physical properties. PMID- 22936347 TI - Donor-induced helical inversion of 1,1'-binaphthyl connecting with two molybdenum complexes. AB - An atropisomeric biaryl molecule with a given absolute configuration could present two opposite helical conformations through the rotation around C-C single bond. To the best of our knowledge, the biaryl system is the simplest helical inversion model apart from stereomutation between two enantiomers. Herein, we first report such true helical inversion phenomena of biaryl compounds. Two [Mo(VI)O(2)(L)]-type complexes, in which L is a tridentate dioxoanionic pyridine O,N,O-ligand, are coalesced on the 2,2',3,3'-positions of an (R)-1,1'-binaphthyl unit and an intramolecular dioxo bridge is formed by two Mo=O???Mo interactions. Exterior strong donors can coordinate to molybdenum to interrupt this dioxo bridge and inversions from negative to positive chirality are explicitly observed by circular dichroism spectroscopy, consistent with single-crystal X-ray diffraction analyses. PMID- 22936348 TI - Carbon nanotube functionalization with carboxylic derivatives: a DFT study. AB - Chemical functionalization of a single-walled carbon nanotube (CNT) with different carboxylic derivatives including -COOX (X=H, CH3, CH2NH2, CH3Ph, CH2NO2, and CH2CN) has been theoretically investigated in terms of geometric, energetic, and electronic properties. Reaction energies have been calculated to be in the range of -0.23 to -7.07 eV. The results reveal that the reaction energy is increased by increasing the electron withdrawing character of the functional groups so that the relative magnitude order is -CH2NO2>-CH2CN>-H>-CH2Ph>-CH3> CH2NH2. The chemical functionalization leads to an increase in HOMO/LUMO energy gap of CNT by about 0.32 to 0.35 eV (except for -H). LUMO, HOMO, and Fermi level of the CNT are shifted to lower energies especially in the case of -CH2NO2 and CH2CN functional groups. Therefore, it leads to an increment in work function of the tube, impeding the field electron emission. PMID- 22936349 TI - Tuning sub-10 nm single-phase NaMnF3 nanocrystals as ultrasensitive hosts for pure intense fluorescence and excellent T1 magnetic resonance imaging. AB - We report ultrasensitive sub-10 nm NaMnF(3) nanocrystals codoped with Yb(3+), Er(3+)/Tm(3+) ions, and their intense pure red and near-infrared upconversion emissions in the presence of Mn(2+). The nanocrystals showed excellent T(1) contrast in 7 T MRI, implying their potential as single-phase contrast agents for fluorescent deep tissue and MR imaging. PMID- 22936350 TI - Tumor architecture exerts no bias on nuclear grading in breast cancer diagnosis. AB - We recently reported that nuclear grading in prostate cancer is subject to a strong confirmation bias induced by the tumor architecture. We now wondered whether a similar bias governs nuclear grading in breast carcinoma. An unannounced test was performed at a pathology conference. Pathologists were asked to grade nuclei in a PowerPoint presentation. Circular high power fields of 27 invasive ductal carcinomas were shown, superimposed over low power background images of either tubule-rich or tubule-poor carcinomas. We found (a) that diagnostic reproducibility of nuclear grades was poor to moderate (weighed kappa values between 0.07 and 0.54, 27 cases, 44 graders), but (b) that nuclear grades were not affected by the tumor architecture. We speculate that the categorized grading in breast cancer, separating tubule formation, nuclear pleomorphism, and mitotic figure counts in a combined three tier score, prevents the bias that architecture exerts on nuclear grades in less well-controlled situations. PMID- 22936351 TI - Long-term outcome of children with acute cerebellitis. AB - BACKGROUND: Acute cerebellitis (AC) is characterized by cerebellar symptoms and magnetic resonance imaging (MRI) changes primarily confined to the cerebellum. OBJECTIVE: To analyze the neurological and cognitive long-term outcome of children with AC. METHODS: Children with AC diagnosed by typical clinical features and MRI findings were included in this retrospective study. Medical charts were reviewed and neurological deficits were assessed by neurological examination or by the expanded disability status scale telephone interview. Cognitive outcome was evaluated with a parental questionnaire (Kognitive Probleme bei Kindern und Jugendlichen). RESULTS: A total of 11 children (6 boys, 5 girls; age range: 3 years to 14 years and 10 months) were included. Of them, six children had a severe disease manifestation including mental status changes and neurological symptoms. Of the rest, two children had a moderate and three children had a mild form of AC. MRI of the cerebellum was obtained in the acute phase revealing signal alterations with different patterns. The average follow-up period was 4 years and 4 months. A complete recovery was observed in five children. Neurological sequelae were reported in five children ranging from ataxia to mild tremor. Cognitive deficits were found in six patients. The affected areas of cognition did include spatial visualization ability, language skills, and concentration. CONCLUSION: Neurological and cognitive sequelae are common in children with AC and underline the role of the cerebellum in cognition. PMID- 22936353 TI - An outline of desensitization in pentameric ligand-gated ion channel receptors. AB - Pentameric ligand-gated ion channel (pLGIC) receptors exhibit desensitization, the progressive reduction in ionic flux in the prolonged presence of agonist. Despite its pathophysiological importance and the fact that it was first described over half a century ago, surprisingly little is known about the structural basis of desensitization in this receptor family. Here, we explain how desensitization is defined using functional criteria. We then review recent progress into reconciling the structural and functional basis of this phenomenon. The extracellular-transmembrane domain interface is a key locus. Activation is well known to involve conformational changes at this interface, and several lines of evidence suggest that desensitization involves a distinct conformational change here that is incompatible with activation. However, major questions remain unresolved, including the structural basis of the desensitization-induced agonist affinity increase and the mechanism of pore closure during desensitization. PMID- 22936354 TI - Inactivation of anoctamin-6/Tmem16f, a regulator of phosphatidylserine scrambling in osteoblasts, leads to decreased mineral deposition in skeletal tissues. AB - During vertebrate skeletal development, osteoblasts produce a mineralized bone matrix by deposition of hydroxyapatite crystals in the extracellular matrix. Anoctamin6/Tmem16F (Ano6) belongs to a conserved family of transmembrane proteins with chloride channel properties. In addition, Ano6 has been linked to phosphatidylserine (PS) scrambling in the plasma membrane. During skeletogenesis, Ano6 mRNA is expressed in differentiating and mature osteoblasts. Deletion of Ano6 in mice results in reduced skeleton size and skeletal deformities. Molecular analysis revealed that chondrocyte and osteoblast differentiation are not disturbed. However, mutant mice display increased regions of nonmineralized, Ibsp expressing osteoblasts in the periosteum during embryonic development and increased areas of uncalcified osteoid postnatally. In primary Ano6(-/-) osteoblasts, mineralization is delayed, indicating a cell autonomous function of Ano6. Furthermore, we demonstrate that calcium-dependent PS scrambling is impaired in osteoblasts. Our study is the first to our knowledge to reveal the requirement of Ano6 in PS scrambling in osteoblasts, supporting a function of PS exposure in the deposition of hydroxyapatite. PMID- 22936352 TI - The Akt-associated microRNAs. AB - As master gene regulators, microRNAs are involved in diverse cellular pathways. It is well known that microRNAs are often dysregulated in many types of cancer and other human diseases. In cancer, microRNAs may function as oncogenes or tumor suppressors. Interestingly, recent evidence suggests that microRNA-mediated gene regulation interconnects with the Akt pathway, forming an Akt-microRNA regulatory network. MicroRNAs and Akt in this network work together to exert their cellular functions. Thus, a better understanding of this Akt-microRNA regulatory network is critical to successful targeting of the PI3K/Akt pathway for cancer therapy. We review recent advances in the understanding of how microRNAs affect Akt activity as well as how microRNAs are regulated through the Akt pathway. We also briefly discuss the clinical implication of gene regulation mediated through Akt associated microRNAs. PMID- 22936355 TI - The next generation of complex lung genetic studies. AB - Common genetic risk variants identified by genome-wide association studies have explained a small portion of disease heritability in complex diseases. It is becoming apparent that each gene/locus is heterogeneous and that multiple rare independent risk alleles across the population contribute to disease risk. Next generation sequencing technologies have reached the maturity and low cost necessary to perform whole genome, whole exome, and targeted region sequencing to identify all rare risk alleles across a population, a task that is not possible to achieve by genotyping. Design of whole genome, whole exome, and targeted sequencing projects to identify disease variants for complex lung diseases requires four main steps: library preparation, sequencing, sequence data analysis, and statistical analysis. Although data analysis approaches are still evolving, a number of published studies have successfully identified rare variants associated with complex disease. Despite many challenges that lie ahead in applying these technologies to lung disease, rare variants are likely to be a critical piece of the puzzle that needs to be solved to understand the genetic basis of complex lung disease and to use this information to develop better therapies. PMID- 22936358 TI - Maturity-dependent chilling tolerance regulated by the antioxidative capacity in postharvest cucumber (Cucumis sativus L.) fruits. AB - BACKGROUND: The aim of the present study was to reveal the effect of fruit maturity on the chilling tolerance of cucumber (Cucumis sativus L.) fruit and the oxidative and antioxidative mechanisms involved. Chinese mini-cucumber (cv. Hangcui-1) fruits were harvested at four developmental stages: Immature (3-8 days after anthesis (DAA)), Mature (9-16 DAA), Breaker (17-22 DAA) and Yellow (35-40 DAA). All fruits were stored at 2 degrees C for 9 days and rewarmed at 20 degrees C for 2 days. RESULTS: The chilling injury index declined with advancing fruit maturity. High superoxide anion radical production rate and hydrogen peroxide content were observed in Immature fruits after cold storage and rewarming. Under chilling stress, superoxide dismutase showed an early response. Fruits at earlier maturity stages exhibited higher catalase, ascorbate peroxidase and monodehydroascorbate reductase activities and glutathione content as well as its redox state, and lower peroxidase, dehydroascorbate reductase and glutathione reductase activities and ascorbate content as well as its redox state. CONCLUSION: Fruits at the earlier developmental stage are more susceptible to chilling injury, which is related to increased oxidative stress. High peroxidase activity and ascorbate content and maintenance of the latter's redox state appear critical to the chilling tolerance of cucumber fruits at later developmental stages. PMID- 22936356 TI - Inflammatory and oxidative stress responses of healthy young adults to changes in air quality during the Beijing Olympics. AB - RATIONALE: Unprecedented pollution control actions during the Beijing Olympics provided a quasi-experimental opportunity to examine biologic responses to drastic changes in air pollution levels. OBJECTIVES: To determine whether changes in levels of biomarkers reflecting pulmonary inflammation and pulmonary and systemic oxidative stress were associated with changes in air pollution levels in healthy young adults. METHODS: We measured fractional exhaled nitric oxide, a number of exhaled breath condensate markers (H(+), nitrite, nitrate, and 8 isoprostane), and urinary 8-hydroxy-2-deoxyguanosine in 125 participants twice in each of the pre- (high pollution), during- (low pollution), and post-Olympic (high pollution) periods. We measured concentrations of air pollutants near where the participants lived and worked. We used mixed-effects models to estimate changes in biomarker levels across the three periods and to examine whether changes in biomarker levels were associated with changes in pollutant concentrations, adjusting for meteorologic parameters. MEASUREMENTS AND MAIN RESULTS: From the pre- to the during-Olympic period, we observed significant and often large decreases (ranging from -4.5% to -72.5%) in levels of all the biomarkers. From the during-Olympic to the post-Olympic period, we observed significant and larger increases (48-360%) in levels of these same biomarkers. Moreover, increased pollutant concentrations were consistently associated with statistically significant increases in biomarker levels. CONCLUSIONS: These findings support the important role of oxidative stress and that of pulmonary inflammation in mediating air pollution health effects. The findings demonstrate the utility of novel and noninvasive biomarkers in the general population consisting largely of healthy individuals. PMID- 22936357 TI - Acellular normal and fibrotic human lung matrices as a culture system for in vitro investigation. AB - RATIONALE: Extracellular matrix (ECM) is a dynamic tissue that contributes to organ integrity and function, and its regulation of cell phenotype is a major aspect of cell biology. However, standard in vitro culture approaches are of unclear physiologic relevance because they do not mimic the compositional, architectural, or distensible nature of a living organ. In the lung, fibroblasts exist in ECM-rich interstitial spaces and are key effectors of lung fibrogenesis. OBJECTIVES: To better address how ECM influences fibroblast phenotype in a disease-specific manner, we developed a culture system using acellular human normal and fibrotic lungs. METHODS: Decellularization was achieved using treatment with detergents, salts, and DNase. The resultant matrices can be sectioned as uniform slices within which cells were cultured. MEASUREMENTS AND MAIN RESULTS: We report that the decellularization process effectively removes cellular and nuclear material while retaining native dimensionality and stiffness of lung tissue. We demonstrate that lung fibroblasts reseeded into acellular lung matrices can be subsequently assayed using conventional protocols; in this manner we show that fibrotic matrices clearly promote transforming growth factor-beta independent myofibroblast differentiation compared with normal matrices. Furthermore, comprehensive analysis of acellular matrix ECM details significant compositional differences between normal and fibrotic lungs, paving the way for further study of novel hypotheses. CONCLUSIONS: This methodology is expected to allow investigation of important ECM-based hypotheses in human tissues and permits future scientific exploration in an organ- and disease-specific manner. PMID- 22936359 TI - Successful surgical resection of leiomyoma obstructing the trachea. AB - We report a case of 51-year-old woman with a severely airway-obstructing leiomyoma who underwent successful tracheal resection. A preoperative tumor biopsy was avoided not to cause any risk of suffocation. At surgery, an endotracheal intubation distal to the tumor was achieved with a bronchoscopic guidance. A segmental resection of the trachea with a primary end-to-end anastomosis was performed via a half-splitting median sternotomy. Negative surgical margins for tumor were confirmed intraoperatively. Final pathological diagnosis was a primary tracheal leiomyoma. Definitive surgical resection is a treatment of choice for such airway-obstructing, wide-based leiomyoma. Although a bronchoscopic removal of the tumor is an alternative choice, the risks of suffocation, positive surgical margins, and perforation of the trachea need to be carefully discussed if it is considered. PMID- 22936360 TI - An LED-based fluorometer for chlorophyll quantification in the laboratory and in the field. AB - The chlorophyll content is an important experimental parameter in agronomy and plant biology research. In this report, we explore the feasibility of determining total concentration of extracts containing chlorophyll a and chlorophyll b by chlorophyll fluorescence. We found that an excitation at 457 nm results in the same integrated fluorescence emission for a molecule of chlorophyll a and a molecule of chlorophyll b. The fluorescence yield induced by 457 nm is therefore proportional to total molar chlorophyll concentration. Based on this observation, we designed an instrument to determine total chlorophyll concentrations. A single light emitting diode (LED) is used to excite chlorophyll extracts. After passing through a long-pass filter, the fluorescence emission is assessed by a photodiode. We demonstrate that this instrument facilitates the determination of total chlorophyll concentrations. We further extended the functionality of the instrument by including LEDs emitting at 435 and 470 nm wavelengths, thereby preferentially exciting chlorophyll a and chlorophyll b. This instrument can be used to determine chlorophyll a and chlorophyll b concentrations in a variety of organisms containing different ratios of chlorophylls. Monte-Carlo simulations are in agreement with experimental data such that a precise determination of chlorophyll concentrations in carotenoid-containing biological samples containing a concentration of less than 5 nmol/mL total chlorophyll can be achieved. PMID- 22936361 TI - Hemodynamic monitoring development: helpful technology or expensive luxury? PMID- 22936363 TI - Spectroscopic studies on the photochemical decarboxylation mechanisms of synthetic pyrethroids. AB - A novel radical trapping technique combined with a fluorescence spectroscopic analysis has been employed to investigate the radical intermediates produced by photodecarboxylation of four synthetic pyrethroids: fenvalerate (SMD), fenpropathrin (DTL), cyphenothrin (GKL), and cypermethrin (AGT). Under photoirradiation at >290 nm, all pyrethroids underwent direct photolysis via homolytic cleavage of the carbon-oxygen bonds in the ester groups. The consumed amount of a nitroxide free radical, as a trapping agent for the intermediate radical of a pyrethroid, was determined by ESR, which was the measure of the reaction yield of a photochemically generated alpha-cyano-3-phenoxybenzyl radical common to all pyrethroids. The reactivities of the pyrethroids studied was in the sequence of SMD >> DTL > GKL > AGT. Furthermore, nanosecond transient absorption spectroscopy demonstrated that geminate recombination of the radical pair within a solvent cage is the main deactivation route of the photochemically generated alpha-cyano-3-phenoxybenzyl radical common for all pyrethroids studied. PMID- 22936362 TI - Cardiac involvement in mitochondrial DNA disease: clinical spectrum, diagnosis, and management. AB - Mitochondrial disease refers to a heterogenous group of genetic disorders that result from dysfunction of the final common pathway of energy metabolism. Mitochondrial DNA mutations affect key components of the respiratory chain and account for the majority of mitochondrial disease in adults. Owing to critical dependence of the heart on oxidative metabolism, cardiac involvement in mitochondrial disease is common and may occur as the principal clinical manifestation or part of multisystem disease. Recent advances in our understanding of the clinical spectrum and genetic aetiology of cardiac involvement in mitochondrial DNA disease have important implications for cardiologists in terms of the investigation and multi-disciplinary management of patients. PMID- 22936365 TI - Enantioselective zinc-mediated conjugate addition of terminal alkynes to enones. AB - Zinc for conjugate alkynylation: The enantioselective conjugate addition of terminal alkynes to 2-arylidene-1,3-diketones in the presence of diethylzinc and a catalytic amount of (R)-VANOL has been developed. The reaction can be applied to different aromatic and heteroaromatic alkynes and enones, giving the expected products in good yield and with enantiomeric excesses up to 91%. The products can be enantiomerically enriched up to 99% ee by crystallization (see scheme). PMID- 22936367 TI - Novel bipolar host materials based on 1,3,5-triazine derivatives for highly efficient phosphorescent OLEDs with extremely low efficiency roll-off. AB - Recently, bipolar host materials have attracted considerable attention because they can achieve balanced charge injection/transport in phosphorescent organic light emitting diodes (PhOLEDs) and consequently obtain excellent device performance. In this work, two bipolar host materials, namely, 3-(4,6-diphenyl 1,3,5-triazin-2-yl)-9-phenyl-9H-carbazole (DPTPCz) and 3-(4,6-diphenoxy-1,3,5 triazin-2-yl)-9-phenyl-9H-carbazole (DPOTPCz), have been designed, synthesized and characterized. With high triplet energy levels of 2.78 and 2.86 eV for DPTPCz and DPOTPCz, respectively, two compounds are considered promising bipolar host materials for PhOLEDs. Blue and green PhOLEDs based on these two new compounds show excellent performances. The phosphorescent devices based on DPTPCz exhibit maximum external quantum efficiencies of 14.4% (for blue device) and 21.2% (for green device), and maintain high efficiencies of 11.9% and 20.0% even at a high luminance of 10,000 cd m(-2). PMID- 22936366 TI - A tyrosine kinase inhibitor-induced myocardial degeneration in rats through off target phosphodiesterase inhibition. AB - PF-04254644 is a selective kinase inhibitor of mesenchymal epithelial transition factor/hepatocyte growth factor receptor with known off-target inhibitory activity against the phosphodiesterase (PDE) family. Rats given repeated oral doses of PF-04254644 developed a mild to moderate myocardial degeneration accompanied by sustained increase in heart rate and contractility. Investigative studies were conducted to delineate the mechanisms of toxicity. Microarray analysis of Sprague-Dawley rat hearts in a 6 day repeat dose study with PF 04254644 or milrinone, a selective PDE3 inhibitor, revealed similar perturbation of the cyclic adenosine monophosphate (c-AMP) pathway. PDE inhibition and activation of c-AMP were further substantiated using PDE3B immunofluorescence staining and through a c-AMP response element reporter gene assay. The intracellular calcium and oxidative stress signaling pathways were more perturbed by treatment with PF-04254644 than milrinone. The rat cardiomyocytes calcium assay found a dose-dependent increase in intracellular calcium with PF-04254644 treatment. These data suggest that cardiotoxicity of PF-04254644 was probably due to activation of c-AMP signaling, and possibly subsequent disruption of intracellular calcium and oxidative stress signaling pathways. The greater response with PF-04254644 as compared with milrinone in gene expression and micro and ultrastructural changes is probably due to the broader panel of PDEs inhibition. PMID- 22936368 TI - Synthesis and catalytic application of palladium imidazol(in)ium-2 dithiocarboxylate complexes. AB - The palladium(II) dimer, [Pd(C,N-C(6)H(4)CH(2)NMe(2))Cl](2) reacts with two equivalents of the NHC.CS(2) zwitterionic ligands [NHC = IPr (1,3 diisopropylimidazol-2-ylidene), ICy (1,3-dicyclohexylimidazol-2-ylidene), IMes (1,3-bis(2,4,6-trimethylphenyl)imidazol-2-ylidene), IDip (1,3-bis(2,6 diisopropylphenyl)imidazol-2-ylidene), SIMes (1,3-bis(2,4,6 trimethylphenyl)imidazolin-2-ylidene)] in the presence of NH(4)PF(6), to yield the cationic products [Pd(C,N-C(6)H(4)CH(2)NMe(2))(S(2)C.NHC)](+). In a similar fashion, the compounds [Pd(C,N-bzq)(S(2)C.NHC)](+) (bzq = benzo[h]quinolinyl, NHC = ICy, IMes, IDip) are obtained from the corresponding dimer [Pd(C,N-bzq)Cl](2). The bis(phosphine) compounds [Pd(S(2)C.NHC)(PPh(3))(2)](2+) (NHC = ICy, IMes, IDip, SIMes) are obtained on treatment of [PdCl(2)(PPh(3))(2)] with NHC.CS(2) zwitterions in the presence of NH(4)PF(6). The reaction of [PdCl(2)(dppf)] with IMes.CS(2) and NH(4)PF(6) provides the complex [Pd(S(2)C.IMes)(dppf)](2+). The complexes [Pd(S(2)C.NHC)(PPh(3))(2)](PF(6))(2) (NHC = IMes, IDip) were active pre catalysts (1 mol% loading) for the conversion of benzo[h]quinoline to 10 methoxybenzo[h]quinoline in the presence of PhI(OAc)(2) and methanol. The intermediacy of [Pd(C,N-bzq)(S(2)C.NHC)](+) was supported by the high yield of 10 methoxybenzo[h]quinoline using [Pd(C,N-bzq)(S(2)C.IDip)](+) to promote the same reaction. Small amounts of 2,10-dimethoxybenzo[h]quinoline were also isolated from these reactions. Using [Pd(C,N-bzq)(S(2)C.IDip)](+) and N-chlorosuccinimide as the oxidant led to the formation of 10-chlorobenzo[h]quinoline in moderate yield from benzo[h]quinoline. The molecular structures of [Pd(S(2)C.IMes)(PPh(3))(2)](PF(6))(2) and [Pd(S(2)C.IMes)(dppf)](PF(6))(2) were determined crystallographically. PMID- 22936364 TI - Analysis of the C9orf72 gene in patients with amyotrophic lateral sclerosis in Spain and different populations worldwide. AB - A hexanucleotide repeat expansion in chromosome 9 open reading frame 72 (C9orf72) can cause amyotrophic lateral sclerosis (ALS) and/or frontotemporal dementia (FTD). We assessed its frequency in 781 sporadic ALS (sALS) and 155 familial ALS (fALS) cases, and in 248 Spanish controls. We tested the presence of the reported founder haplotype among mutation carriers and in 171 Ceph Europeans from Utah (CEU), 170 Yoruba Africans, 81 Han Chinese, and 85 Japanese subjects. The C9orf72 expansion was present in 27.1% of fALS and 3.2% of sALS. Mutation carriers showed lower age at onset (P = 0.04), shorter survival (P = 0.02), greater co-occurrence of FTD (P = 8.2 * 10(-5)), and more family history of ALS (P = 1.4 * 10(-20)), than noncarriers. No association between alleles within the normal range and the risk of ALS was found (P = 0.12). All 61 of the mutation carriers were tested and a patient carrying 28 hexanucleotide repeats presented with the founder haplotype. This haplotype was found in 5.6% Yoruba Africans, 8.9% CEU, 3.9% Japanese, and 1.6% Han Chinese chromosomes. PMID- 22936369 TI - Genetics and metabolic cardiomyopathies. AB - Metabolic disorders encompass a heterogeneous group of conditions that commonly affect the heart and contribute adversely to cardiovascular outcomes. As the heart is a metabolically active organ, inborn errors in metabolism (IEMs) often present with cardiac manifestations such as cardiomyopathy, arrhythmia, and valvular dysfunction. More than 40 IEMs are reported to cause cardiomyopathy, including fatty acid oxidation defects, glycogen, lysosomal and perioxisome storage diseases, mitochondrial cardiomyopathies, organic acidaemias, aminoacidopathies and congenital disorders of glycosylation. Studies suggest that IEM account for only 5% of cardiomyopathies; however, their diagnosis is imperative to enable the effective institution of disease-specific management strategies. This review describes the more common genetic defects that affect metabolic pathways and give rise to heart muscle disease. PMID- 22936370 TI - Advances in the differentiation of constrictive pericarditis and restrictive cardiomyopathy. AB - The diagnosis of constrictive pericarditis should be considered in any patient with unexplained right heart failure. The differentiation between constrictive pericarditis and restrictive cardiomyopathy is based on a combination of clinical presentation, history and imaging, and on occasion, on the basis of invasive hemodynamic studies or biopsy. Pertinent anatomic and physiologic findings on cardiac imaging modalities including echocardiography, computed tomography and cardiac magnetic resonance imaging are reviewed, and in many cases the diagnosis can be determined on the basis of imaging. Hemodynamic studies may clarify the diagnosis, and biopsy may find treatable causes of disease. PMID- 22936371 TI - Arrhythmogenic right ventricular cardiomyopathy. What is needed for a cure? AB - There have been major advances in recent years in the clinical setting of arrhythmogenic right ventricular cardiomyopathy, including new diagnostic criteria, a changing spectrum of the disease with even left dominant forms, the role of cardiac magnetic resonance and electroanatomic mapping, the expanding use of genetic screening and the existence of overlapping phenotypes. Moreover, early diagnosis at pre-participation screening with sports disqualification and risk stratification for the indication of ICD have been shown to be life-saving. In addition to traditional therapies targeting arrhythmias and congestive heart failure, an effective treatment of the disease could be based on the discovery of the molecular mechanisms involved in the pathobiology of the disease in order to block the onset and progression of cell death. PMID- 22936372 TI - Unusual mediastinal cystic lesions with air fluid level. AB - An air-fluid level within an enlarged mediastinal lymph node is unusual. We describe three patients who had mediastinal lymphadenopathy containing air-fluid levels. The differential diagnosis and approach are discussed. PMID- 22936373 TI - Digital pulp reconstruction with free neurovascular toe flaps. AB - Finger pulp defects are commonly encountered in clinical settings and their treatment remains a consistent challenge for plastic and hand surgeons. Reconstruction should restore, as much as possible, the contour of the pulp as well as discriminating sensibility. Following the prime reconstructive principle of replacing "like with like," the free neurovascular toe pulp flap seems to be the optimal choice for digital pulp reconstruction because of the natural similarity of the digital pulp both anatomically and physically. However, after about 30 years of experience with this procedure, it is still controversial because it is technically demanding, involves donor site morbidity, and its reliability is questionable. With other small free flaps available, the application of this flap has been challenged and reconsidered. In this review we specifically focus on the reconstruction of soft tissue defects of digital pulp using the free neurovascular toe flap, aiming to investigate its advantages and drawbacks and obtain a comprehensive understanding of this procedure. The latest reconstruction concerns and technical refinements are also discussed. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. PMID- 22936374 TI - e-Flap nipple reconstruction in amputation mammaplasty. AB - BACKGROUND: Although widely used in women who have gigantomastia, free nipple graft breast reduction has several disadvantages with respect to the nipple areola graft. In this report, we present the use of a nipple reconstruction method instead of free nipple grafting. METHOD: Free nipple reduction mammaplasty is performed according to the Wise pattern. The nipple is removed from the areola graft. Nipple reconstruction is done at the most proximal and projected part of the reduced breast, which corresponds to the future nipple site. Afterward, the reconstructed nipple is encircled with the areola graft. RESULTS: A total of 18 patients underwent breast reduction with nipple reconstruction and areola grafting between April 2007 and March 2010. The mean follow-up period was 8 months. With the proposed nipple reconstruction technique, the mean projections of the nipple at the end of the operation and at 6 months were 1.2 and 0.9 cm, respectively. CONCLUSION: The technique of using nipple reconstruction in amputation mammaplasty avoids the problems related to the nipple graft such as loss of projection, loss of sensation, or even total or partial loss of the nipple. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. PMID- 22936375 TI - "Inverted-Y": a modified vest-over-pants abdominoplasty pattern following bariatric surgery. AB - BACKGROUND: The post-bariatric surgery patient presents several challenges to the surgeon. Correction of skin and subcutaneous redundancy can be difficult, particularly in massive-weight-loss patients with horizontal laxity, upper abdominal or flank laxity, and "double-roll" deformities. The aim of our study was to propose our modification of the "vest-over-pants" abdominoplasty technique to exploit all the advantages of the Planas technique in bariatric surgery patients and to solve the problem of extreme epigastric skin redundancy in difficult abdominal contour cases. METHODS: Sixteen post-bariatric surgery patients (10 females and 6 males, nonsmokers) with moderate to severe epigastric skin laxity were enrolled in the study. They all had undergone a biliopancreatic diversion (BPD) by laparotomy and had undergone this body-contouring procedure from 2006 to 2010. RESULTS: After the inverted-Y abdominoplasty, 12 patients (75 %) had an uneventful recovery. On the other hand, one subject (6.25 %) had a seroma and four (25 %) had wound dehiscence and delayed wound healing. No skin necrosis was reported. In one patient (6.25 %) scar revision in areas that had delayed healing was performed. The addition of a vertical incision has not led to an increased rate of postoperative complications, but the rates are in line with the satisfactory results described with the Planas technique in bariatric surgery patients. In addition, various advantages have been observed compared to traditional vertical resection patterns. CONCLUSION: This case series has quantitative limitations and further investigations are needed. However, this study suggests that inverted-Y abdominoplasty could be a good compromise between the need to minimize complication rates and ensure an optimum aesthetic result and patient satisfaction rate in some abdominal defects in massive-weight-loss patients. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. PMID- 22936376 TI - Protocol for obtaining platelet-rich plasma (PRP), platelet-poor plasma (PPP), and thrombin for autologous use. AB - BACKGROUND: Plasma has been widely studied and used in many different situations to speed up healing with better tissue adherence and hemostasis. Research projects are now attempting to isolate platelet-rich plasma (PRP) and platelet poor plasma (PPP), making better use of their properties, particularly during operations and for wounds that are slow to heal. In view of the wide diversity of industrial machines and extraction protocols, together with the variety of industrially produced biologic glues, this article suggests an option for obtaining PRP, PPP, and human thrombin for autologous use. METHODS: A way of obtaining PRP, PPP, and thrombin is reproduced through a protocol defined and established by the authors. Autologous thrombin and plasma were obtained through the collection and successive centrifugation of ten whole blood samples, until the desired hemocomponents were isolated, followed by quantitative and qualitative analyses of the elements obtained. RESULTS: The mean platelet concentration obtained was 6.03 * 10(8) platelets/ml, with a mean thrombin concentration of 33.54 nM, both values compatible with reports in the literature when different protocols are applied. CONCLUSIONS: The protocol described is a good option for the preparation and application of PRP, PPP, and autologous thrombin, particularly as they can be obtained simultaneously, eliminating the possibilities of viral contamination and allergic reactions. Moreover, the cost of this procedure is low, it is easy to perform, and replicable. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. PMID- 22936377 TI - Multifrequency ultrasound-assisted liposuction: 5 years of experience. AB - BACKGROUND: The use of ultrasound in liposuction was first introduced by Kloehn. The ultrasound frequencies used in this technology have a high degree of selectivity for fat cells, thus reducing blood loss, postoperative edema, and ecchymosis and avoiding contour irregularities. The authors report their 5 years of experience with a multifrequency ultrasound generator and describe their series with the aim to focus attention on the problems linked with ultrasound use. METHODS: A total of 797 patients were selected to receive ultrasound assisted liposuction (UAL). Accurate preoperative planning was conducted for all the patients before admission to the surgical quarter. Liposuction was performed using general anesthesia for 538 patients (63 %), peripheral anesthesia for 220 patients (25.76 %), and local anesthesia for 96 patients (11.24 %). The ultrasound generator device was set by choosing the better working protocol (continuous or pulsed mode) according to the tissue characteristics, and the frequency test was performed. A photo of the patient was taken before surgery and at every follow-up visit to estimate the results and to have an objective evaluation of the outcome. The patient's opinion of the results also was recorded using a graduated scale. RESULTS: The results were excellent in 204 cases (25.4 %), good in 356 cases (44.6 %), moderate in 174 cases (22 %), and poor in 63 cases (8 %). CONCLUSIONS: For body contour improvement, UAL is an essential procedure. The introduction of multifrequency UAL, or rather the possibility of using the better working frequency during the treatment, allows better results, thus improving patient outcome. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. PMID- 22936378 TI - A minimally invasive gradual traction technique for inverted nipple correction. AB - BACKGROUND: An inverted nipple affects not only the aesthetic appearance of the breast but also breastfeeding. Most surgical procedures can cause injury to normal lactiferous ducts and sensory dysfunction. The authors present a simple, safe, and minimally invasive technique for treating inverted nipples. METHODS: A distracter was made using the distal end of a 5- or 10-ml disposable syringe. The length was 1.3-1.5 cm, and pinholes with a diameter of 1 mm were punctured at 3, 6, 9, and 12 o'clock at the apex of the distracter. The inverted nipple was pulled out, and two steel wires with a diameter of 0.6 mm were crossed through the nipple base and fixed to the external distracter. After surgery, the wires were tightened once per month. According to the severity of the nipple inversion, the distracter was removed after 4-6 months of traction. RESULTS: This method was used to correct 604 inverted nipples of 310 patients. The follow-up period ranged from 6 months to 2 years. No complications associated with surgery such as infection, depigmentation, sensory disturbance, or nipple necrosis occurred. The great majority of the patients (95.8 %) were satisfied with the aesthetic results. CONCLUSIONS: The described technique is minimally invasive, simple, safe, reliable, and low in cost. Satisfying aesthetic results can be achieved without destroying breastfeeding function or nipple sensation. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. PMID- 22936379 TI - In vitro N-acetyl-L-cysteine promotes proliferation and suppresses interleukin-8 expression in adipose-derived stem cells. AB - Adipose-derived stem cells (ADSCs) hold great promise for repair and regeneration of burn wounds by producing growth factors, but proinflammatory cytokines such as interleukin-8 (IL-8) released by ADSCs would potentially deepen the wound and inhibit healing. The reported research aimed to identify the effects of N-acetyl L-cysteine (NAC) on the proliferation, death, and IL-8 production of ADSCs. In the presence or absence of NAC, ADSC proliferation was examined using a CCK-8 Kit, and cell death was evaluated by flow cytometry analysis. Subsequently, IL-8 mRNA expression was detected by reverse transcriptase-polymerase chain reaction and protein production by enzyme-linked immunoassay. Findings showed that cell proliferation in the NAC-treated group was a significant 1.53-fold greater than in the control group, that the apoptosis rate of ADSCs decreased by 55.4 % compared with the control group, and that the necrosis rate decreased by 48.8 %. Additionally, the IL-8 mRNA expression decreased to 46.2 +/- 8.7 % that of the control group, and the IL-8 protein production decreased to 9.98 +/- 0.57 %. The authors believe that NAC might be helpful in burn wound repair and regeneration by stimulating the proliferation of ADSCs, inhibiting cell death, and suppressing IL-8 production. LEVEL OF EVIDENCE II: This journal requires that authors assign a level of evidence to each article. PMID- 22936380 TI - Computerized photogrammetry used to calculate the brow position index. AB - BACKGROUND: The orbital region is of vital importance to facial expression. Brow ptosis, besides having an impact on facial harmony, is a sign of aging. Various surgical techniques have been developed to increase the efficacy of brow-lift surgery. However, no consensus method exists for an objective measurement of the eyebrow position due to the curvature of the face. Therefore, this study aimed to establish a method for measuring the eyebrow position using computerized photogrammetry. METHODS: For this study, 20 orbital regions of 10 volunteers were measured by direct anthropometry using a digital caliper and by indirect anthropometry (computerized photogrammetry) using standardized digital photographs. Lines, points, and distances were defined based on the position of the anthropometric landmarks endocanthion and exocanthion and then used to calculate the brow position index (BPI). Statistical analysis was performed using Student's t test with a significance level of 5 %. RESULTS: The BPI values obtained by computerized photogrammetric measurements did not differ significantly from those obtained by direct anthropometric measurements (p > 0.05). The mean BPI was 84.89 +/- 10.30 for the computerized photogrammetric measurements and 85.27 +/- 10.67 for the direct anthropometric measurements. CONCLUSION: The BPI defined in this study and obtained by computerized photogrammetry is a reproducible and efficient method for measuring the eyebrow position. LEVEL OF EVIDENCE III: This journal requires that authors assign a level of evidence to each article. PMID- 22936381 TI - Synthetic hair implantation and squamous cell carcinoma of the scalp. PMID- 22936382 TI - Persistent improvement in lower eyelid-cheek contour after a transtemporal midface lift. AB - BACKGROUND: This study aimed to assess quantitative changes in lower-eyelid aesthetics after a transtemporal midface lift concomitant with transconjunctival blepharoplasty and lower-eyelid skin pinch. METHODS: The study enrolled 55 consecutive patients who underwent a transtemporal midface lift and concurrent transconjunctival blepharoplasty with lower-eyelid skin pinch. All the surgeries were performed over a 2-year period by the senior author (A.A.J.). Patient demographics and surgical details were recorded. Standardized digital photographs were taken at baseline and then 12 months postoperatively. These were analyzed to assess changes in the vertical height of the lower eyelid and compared using within-subject analysis. RESULTS: The study cohort consisted of 50 women with a mean age of 54 years (range, 28-76 years). Five patients were lost to follow-up evaluation. The mean vertical height of the lower eyelid was 11.8 mm preoperatively and 9.3 mm postoperatively, giving an average difference of 2.5 mm at the 12-month follow-up assessment. The changes in lower-eyelid height were statistically significant (p = 0.0002), and the lower eyelid-cheek contour was improved in all cases. No major complications occurred during the study period, and no revision surgery was performed. Lower-eyelid height changes did not vary significantly with patient age. CONCLUSIONS: Age-related changes to the midface are marked by increased vertical height of the lower eyelid and a concomitant appearance of infraorbital hollowing. Separation of the lower eyelid-cheek complex causes the typical double-contour deformity. To the authors' knowledge, no study to date has reported the long-term effect of a midface lift on lower eyelid aesthetics. The transtemporal midface lift not only repositions the malar fat pad but importantly also provides significant shortening of the lower eyelid at 12 months. This results in an improved midface contour. LEVEL OF EVIDENCE III: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 . PMID- 22936383 TI - Suction-assisted liposuction with a y-connector. AB - Liposuction appears to be one of the simplest aesthetic techniques to date, and its popularity has spread worldwide. The authors have been using a Y-connector that enables two plastic surgeons to work at the same with the same suction assisted liposuction (SAL) machine. For 12 patients whose liposuction procedures were performed using one-cannula SAL, the mean surgical time was 114 +/- 10.8 min, whereas for 11 patients whose liposuction procedures were performed with Y connector SAL, the mean surgical time was 62 +/- 7.8 min. This difference between the two groups is statistically significant (p < 0.05). The authors believe the Y connector may be a less tiring alternative for plastic surgeons who still think SAL is the gold standard for liposuction. LEVEL OF EVIDENCE V: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 . PMID- 22936384 TI - Observation of a transient intermediate in Soai's asymmetric autocatalysis: insights from 1H NMR turnover in real time. PMID- 22936385 TI - "The casual cruelty of our prejudices": on Walter Lippmann's theory of stereotype and its "obliteration" in psychology and social science. AB - Reflecting on his wartime government service, Walter Lippmann (1922) developed a theory of policy formulation and error. Introducing the constructs of stereotype, mental model, blind spots, and the process of manufacturing consent, his theory prescribed interdisciplinary social science as a tool for enhancing policy making in business and government. Lippmann used his influence with the Rockefeller foundations, business leaders, Harvard and the University of Chicago to gain support for this program. Citation analysis of references to "stereotype" and Lippmann reveals the rapid spread of the concept across the social sciences and in public discourse paralleled by obliteration by incorporation of the wider theory in behavioral science. "Stereotype" is increasingly invoked in anthropology, economics, and sociology though Lippmann and his wider theory ceased being cited decades ago. In psychology, citations are increasing but content analysis revealed blind spots and misconceptions about the theory and prescription. Studies of heuristics, biases, and organizational decision substantiate Lippmann's theory of judgment and choice. But his model for social science failed to consider the bounded rationality and blind spots of its practitioners. Policy formulation today is supported by research from narrow disciplinary silos not interdisciplinary science that reflects an awareness of history. PMID- 22936386 TI - BRCA1 and microRNAs: emerging networks and potential therapeutic targets. AB - BRCA1 is a well-known tumor suppressor implicated in familial breast and ovarian cancer. Since its cloning in 1994, numerous studies have established BRCA1's role in diverse cellular and biochemical processes, such as DNA damage repair, cell cycle control, and transcriptional regulation as well as ubiquitination. In addition, a number of recent studies have functionally linked this tumor suppressor to another important cellular regulator, microRNAs, which are short (19-22 nt) RNAs that were discovered in the nematode in 1993. Soon their presence and function were validated in mammals, and since then, the role of microRNAs has been actively investigated in almost all biological processes, including cancer. In this review, we will describe recent progress in the understanding of the BRCA1 function through microRNAs and the role of microRNAs in regulating BRCA1, with emphasis on the implication of these processes on the development and progression of cancer. We will also discuss the therapeutic potential of microRNA mimics or inhibitors of microRNAs to affect BRCA1 function. PMID- 22936387 TI - Sugar-hormone cross-talk in anthocyanin biosynthesis. AB - Anthocyanins, a class of flavonoids, are recognized for their diverse functions in plant development and beneficial effects on human health. Many of the genes encoding anthocyanin biosynthesis enzymes and the transcription factors that activate or repress them have been identified. Regulatory proteins that control anthocyanin biosynthesis by regulating the expression of different structural genes at the transcriptional and post-transcriptional levels are differentially modulated by environmental and biological factors such as light, temperature, sugar and hormones. This minireview summarizes the recent findings contributing to our understanding of the role of sugars and hormones in the modulation of the anthocyanin biosynthesis pathway with emphasis on the coordinated regulation of the critical transcriptional R2R3-MYB/bHLH/WD40 (MBW) complex in Arabidopsis. PMID- 22936388 TI - Isolation of a novel rmn1 gene genetically linked to spnab2 with respect to mRNA export in fission yeast. AB - In fission yeast, Schizosaccharomyces pombe, the spnab2 gene encodes an ortholog of the budding yeast nuclear abundant poly(A)(+) RNA-binding protein 2 (Nab2) that is an essential protein required for both mRNA biogenesis and nuclear export of mRNA to the cytoplasm. We have previously isolated three mutants (SLnab1-3) that showed synthetic lethality under the repressed condition of spnab2 expression. In this study, we isolated a novel rmn1 gene as a multicopy suppressor that complemented the defects in growth and mRNA export of SLnab1 mutant cells. The rmn1 gene contained three introns and encoded a 589 amino-acid protein with the RNA recognition motif (RRM) in the central region. The Deltarmn1 null mutant was viable but showed a s light mRNA export defect. However, its over expression caused a deleterious effect on growth accompanied by intense accumulation of poly(A)(+) RNA in the nucleus. The combination of Deltarmn1 with Deltaspnab2 or Deltaspmex67 also inhibited growth. In addition, Rmn1p was associated with Rae1p in vivo. These results suggest that rmn1 is a novel gene that is functionally linked to spnab2. PMID- 22936389 TI - Flavonoid oligoglycosides from Ophioglossum vulgatum L. having wound healing properties. AB - Two new glycosylated and acylated flavonols, viz. quercetin-3-O-[(6-caffeoyl) beta-glucopyranosyl (1 -> 3) alpha-rhamnopyranoside]-7-O-alpha-rhamnopyranoside (2), and kaempferol-3-O-[(6-caffeoyl)-beta-glucopyranosyl (1 -> 3) alpha rhamnopyranoside]-7-O-alpha-rhamnopyranoside (3), together with the known quercetin-3-O-methyl ether (1), were isolated from the aerial parts of the fern Ophioglossum vulgatum L. Their structures were established by means of 1D and 2D NMR spectra, as well as ESI-MS and ESI-HRMS spectra. Compounds 1-3 were all found to be active in scratch-wound healing assays on keratinocytes, with 3 being the most active one and showing maximum activity at 20 uM. PMID- 22936390 TI - Bridging history and social psychology: what, how and why. AB - This special issue aims to bridge history and social psychology by bringing together historians and social psychologists in an exercise of reading and learning from each other's work. This interdisciplinary exercise is not only timely but of great importance for both disciplines. Social psychologists can benefit from engaging with historical sources by being able to contextualise their findings and enrich their theoretical models. It is not only that all social and psychological phenomena have a history but this history is very much part of present-day and future developments. On the other hand historians can enhance their analysis of historical sources by drawing upon the conceptual tools developed in social psychology. They can "test" these tools and contribute to their validation and enrichment from completely different perspectives. Most important, as contributions to this special issue amply demonstrate, psychology's "historical turn" has the potential to shed a new light on striking, yet underexplored, similarities between contemporary public spheres and their pre modern counterparts. This issue thereby calls into question the dichotomy between traditional and de-traditionalized societies-a distinction that lies at the heart of many social psychology accounts of the world we live in. The present editorial will introduce and consider this act of bridging history and social psychology by focusing on three main questions: What is the bridge made of? How can the two disciplines be bridged? and Why we cross this interdisciplinary bridge? In the end a reflection on the future of this collaboration will be offered. PMID- 22936391 TI - Association of mammographic density with the proliferation marker Ki-67 in a cohort of patients with invasive breast cancer. AB - There is growing evidence that certain breast cancer (BC) risk factors specifically increase the risk for specific molecular tumor subtypes. Different molecular subtypes of BC can partly be described by analyzing proliferation in tumors. Very few data are available regarding the association of mammographic density (MD), as a BC risk factor, with proliferation. The aim of this study was to analyze the association between Ki-67 expression in BCs and MD. In this case only study, data on BC risk factors, hormone receptor expression, and MD were available for 1,975 patients with incident BC. MD was assessed as percentage mammographic density (PMD) using a semiautomated method by two readers for every patient. The association of the Ki-67 proliferation index and PMD was studied using multifactorial analyses of covariance (ANCOVA), with PMD as the target variable and including well-known factors that are also associated with MD such as age, parity, use of hormone replacement therapy (HRT), and body mass index (BMI). There were no significant differences in PMD between women with BC who had low and high Ki-67 values (P = 0.31). However, there were relevant differences in women with low BMI (P = 0.07), and in women using postmenopausal HRT (P = 0.06) as well as in women with low PR values (P = 0.07). In these subgroups, the Ki-67 expression index increased with decreasing PMD. Likewise PMD is correlated with BMI, parity status, and menopausal status stronger in patients with low proliferating tumors, and with progesterone receptor expression in patients with high proliferating tumors. MD correlates inversely with Ki-67 proliferation in BC tumors only in some subgroups of BC patients, defined by commonly known BC risk factors that are usually associated with MD as well. PMID- 22936394 TI - Three-component oxytrifluoromethylation of alkenes: highly efficient and regioselective difunctionalization of C=C bonds mediated by photoredox catalysts. PMID- 22936393 TI - A phoenix rising: who considers herself a "survivor" after a diagnosis of breast cancer? AB - PURPOSE: The purpose of this study is to investigate factors associated with patients' identification of themselves as survivors after a diagnosis of breast cancer. METHODS: A self-administered survey was deployed through the nonprofit organization Breastcancer.org . As part of a larger study, we collected data on treatment, mental health, perceived prognosis, concerns about recurrence, and the question, "Do you consider yourself a survivor of breast cancer?" RESULTS: Of the 629 survey respondents, 492 (78 %) considered themselves survivors of breast cancer. Factors independently associated with an affirmative response were (1) believing that one's prognosis was "very good" compared to others (p = <0.001), (2) recalling being told that treatment was curative (p = 0.04), (3) having better mental health (p = 0.002), and (4) having received chemotherapy (p = 0.01). CONCLUSIONS AND IMPLICATIONS FOR CANCER SURVIVORS: The disparate factors associated with the identification of oneself as a survivor-both the perception of having a very good prognosis and having received chemotherapy (reflecting high risk disease rather than a good prognosis)--are intriguing. Clinicians caring for women with breast cancer should be sensitive to the fact that not everyone considers herself a survivor. Addressing transitions at the end of treatment and during the follow-up period may be challenging for clinicians and patients alike. Awareness of the complexities of survivor identification may help clinicians in counseling their patients. PMID- 22936395 TI - Mycotoxicogenic fungal inhibition by innovative cheese cover with aromatic plants. AB - BACKGROUND: The use of aromatic plants and their extracts with antimicrobial properties may be compromised in the case of cheese, as some type of fungal starter is needed during its production. Penicillium verrucosum is considered a common cheese spoiler. The aim of this study was to evaluate the innovative use of certain aromatic plants as natural cheese covers in order to prevent mycotoxicogenic fungal growth (P. verrucosum). A collection of 12 essential oils (EOs) was obtained from various aromatic plants by solvent-free microwave extraction technology, and volatile characterisation of the EOs was carried out by gas chromatography/mass spectrometry. RESULTS: The most effective EOs against P. verrucosum were obtained from Anethum graveolens, Hyssopus officinalis and Chamaemelum nobile, yielding 50% inhibition of fungal growth at concentration values lower than 0.02 uL mL-1. All EOs showed high volatile heterogeneity, with alpha-phellandrene, pinocamphone, isopinocamphone, alpha-pinene, camphene, 1,8 cineole, carvacrol and trans-anethole being found to be statistically significant in the antifungal model. CONCLUSION: The use of these aromatic plants as natural covers on cheese can satisfactorily inhibit the growth of some mycotoxicogenic fungal spoilers. Among the volatile compounds present, alpha- and beta phellandrene were confirmed as the most relevant in the inhibition. PMID- 22936396 TI - Hypoxia-selective DNA interstrand cross-link formation by two modified nucleosides. AB - The clean crossed code: Two nitroimidazole-modified thymidines 1 a and 1 b were synthesized and incorporated into DNA oligomers. The 350 nm photolysis of 1 a and 1 b generated a 5-(2'-deoxyuridinyl)methyl radical that induced DNA interstrand cross-links (ICL; see scheme). A higher ICL yield was observed under hypoxic conditions than under aerobic conditions. PMID- 22936398 TI - Paclitaxel- and sirolimus-eluting stents in older patients with diabetes mellitus: results of a real-life multicenter registry. AB - BACKGROUND: Older patients and diabetes mellitus (DM) are rapidly increasing in Western world populations. The treatment of coronary artery disease in these patients is challenging because they are complex and at high risk. Performance of the two widely used drug-eluting stents (DES), i.e. sirolimus- (SES) and paclitaxel-eluting stent (PES), is understudied in this subset. AIM: We aimed to explore the impact of the first generation DES choice on mid term outcome in a large and unselected population of diabetic patients older than 65 years. METHODS AND RESULTS: From a multicenter registry of 2,429 diabetic patients treated with sirolimus- (SES) or paclitaxel-eluting stent (PES), 1,417 patients >=65 years old were analyzed overall and separately for groups aged 65-74 (67%) and >=75 (33%) years old. SES (55%) were compared to PES (45%) in terms of major adverse cardiac events, including all-cause death, myocardial infarction (MI) and target lesion revascularization (TLR) throughout 1-to-5 year follow-up (median time 24 months). We failed to find at the unadjusted and adjusted analyses statistically significant differences in term of outcome between the two DES, both in the overall cohort and in the two different aged subgroups, also regardless of the insulin treatment. CONCLUSIONS: In this real-life multicenter registry, PES and SES showed a comparable safety and efficacy profile in diabetic patients older than 65 years throughout 1-to-5 years follow-up. PMID- 22936397 TI - Vector integration in triple R gene transformants and the clustered inheritance of resistance against potato late blight. AB - Genetic transformation with resistance (R) genes is expected to enhance resistance durability against pathogens, especially for potato, a vegetatively propagated crop with tetrasomic inheritance and a long-term breeding program. In this study, 128 potato transformants were analysed for the presence of vector T DNA genes, borders and backbone sequences. They were harvested after transformation using a construct containing neomycin phosphotransferase II (nptII) and three R genes against potato late blight (Phytophthora infestans). Our analysis revealed that 45 % of the R gene-containing transformants possessed a low T-DNA copy number, without the integration of vector backbone and borders. The integration of vector backbone sequences was characterized using eight genes, and backbone gene tetA was selected for the early prediction of plants with backbone sequence integration. Three transformants, two plants harbouring one T DNA copy and one plant harbouring three T-DNA copies, were crossed with susceptible cv. Katahdin. Based on our results, we conclude that all four T-DNA genes were inherited as one cluster and segregated in a Mendelian fashion. The three T-DNA inserts from the transformant harbouring three T-DNA copies were statistically proven to be un-linked and inherited into the offspring plants independently. All of the R genes were functionally expressed in the offspring plants as in their parental transformants. This functional gene stacking has important implications towards achieving more durable resistance against potato late blight. PMID- 22936399 TI - Adult mesenchymal stem cells explored in the dental field. AB - During the last decade it was realized that stem cell-based therapies hold an enormous therapeutic potential, improving the life of patients with conditions ranging from neurodegenerative and traumatic diseases to regenerative medicine requiring replacement of complex structures such as bones and teeth. Based on their ability to regenerate and/or repair damaged tissue and eventually restore organ function, multiple types of stem/progenitor cells have been discovered. In the field of periodontal regeneration and tooth engineering, several types of adult multipotent mesenchymal stem cells from various sources are currently being investigated. These include the bone marrow stromal stem cells (BMSSCs), adipose derived stromal cells (ADSCs), dental pulp stem cells (DPSCs), dental follicle stem cells (DFSCs), stem cells from human exfoliated deciduous teeth (SHEDs), stem cells from the apical papilla (SCAP), periodontal ligament stem cells (PDLSCs), alveolar bone proper-derived stem cells, and gingival stem cells. The potential of these different MSCs as precursors for regenerative purposes in the dental field is discussed in this chapter. PMID- 22936400 TI - The impact of ligand reorganization on cerium(III) oxidation chemistry. PMID- 22936401 TI - Correlation between TGF-beta1 expression and proteomic profiling induced by severe acute respiratory syndrome coronavirus papain-like protease. AB - Severe acute respiratory syndrome (SARS) coronavirus (SARS-CoV) papain-like protease (PLpro), a deubiquitinating enzyme, demonstrates inactivation of interferon (IFN) regulatory factor 3 and NF-kappaB, reduction of IFN induction, and suppression of type I IFN signaling pathway. This study investigates cytokine expression and proteomic change induced by SARS-CoV PLpro in human promonocyte cells. PLpro significantly increased TGF-beta1 mRNA expression (greater than fourfold) and protein production (greater than threefold). Proteomic analysis, Western blot, and quantitative real-time PCR assays indicated PLpro upregulating TGF-beta1-associated genes: HSP27, protein disulfide isomerase A3 precursor, glial fibrillary acidic protein, vimentin, retinal dehydrogenase 2, and glutathione transferase omega-1. PLpro-activated ubiquitin proteasome pathway via upregulation of ubiquitin-conjugating enzyme E2-25k and proteasome subunit alpha type 5. Proteasome inhibitor MG-132 significantly reduced expression of TGF-beta1 and vimentin. PLpro upregulated HSP27, linking with activation of p38 MAPK and ERK1/2 signaling. Treatment with SB203580 and U0126 reduced PLpro-induced expression of TGF-beta1, vimentin, and type I collagen. Results point to SARS-CoV PLpro triggering TGF-beta1 production via ubiquitin proteasome, p38 MAPK, and ERK1/2-mediated signaling. PMID- 22936403 TI - Overcoming undernutrition with local resources in Africa, Asia and Latin America. AB - Even in the 21st century, undernutrition is a challenge to be overcome. In the year 2009, 1.02 billion people were reported as food insecure and 180 million children were undernourished. Food insecurity and undernutrition are more than a lack of food energy: they are not reflected countrywide by prevalence means; they are mostly not permanent but seasonal; they are mostly not caused by insufficient amounts of food being produced; and they first affect parents and later children. Food insecurity and undernutrition often manifest themselves as micronutrient deficiency. While undernutrition is still a challenge for global nutrition, a second challenge has arisen: preventing caloric overnutrition. In various countries, food pyramids or food circles have been plotted supporting nutrition education and illustrating the challenge. Such integrative approaches are desirable for all countries of the world, as in all countries, to a smaller or larger extent, undernutrition and caloric overnutrition are the problems of today and tomorrow. The International Assessment of Agriculture for Science Technology and Development (IAASTD) has paid attention to the inescapable interconnectedness of agriculture's different roles and functions in the world and in all societies. Overcoming undernutrition with local resources means first protecting and promoting the use of local resources against imports of low-priced processed foods from subsidised production in industrialised countries; second, it means developing education and training material for regional food production with a nutrition orientation; and third, the experiences of organic farming can contribute much to support farmers in developing countries in planting their indigenous varieties and applying integrated pest management strategies. PMID- 22936404 TI - Generation of a three-dimensional ultrastructural model of human respiratory cilia. AB - The ultrastructures of cilia and flagella are highly similar and well conserved through evolution. Consequently, Chlamydomonas is commonly used as a model organism for the study of human respiratory cilia. Since detailed models of Chlamydomonas axonemes were generated using cryoelectron tomography, disparities among some of the ultrastructural features have become apparent when compared with human cilia. Extrapolating information on human disease from the Chlamydomonas model may lead to discrepancies in translational research. This study aimed to establish the first three-dimensional ultrastructural model of human cilia. Tomograms of transverse sections (n = 6) and longitudinal sections (n = 9) of human nasal respiratory cilia were generated from three healthy volunteers. Key features of the cilium were resolved using subatomic averaging, and were measured. For validation of the method, a model of the well characterized structure of Chlamydomonas reinhardtii was simultaneously generated. Data were combined to create a fully quantified three-dimensional reconstruction of human nasal respiratory cilia. We highlight key differences in the axonemal sheath, microtubular doublets, radial spokes, and dynein arms between the two structures. We show a decreased axial periodicity of the radial spokes, inner dynein arms, and central pair protrusions in the human model. We propose that this first human model will provide a basis for research into the function and structure of human respiratory cilia in health and in disease. PMID- 22936402 TI - General olfactory sensitivity database (GOSdb): candidate genes and their genomic variations. AB - Genetic variations in olfactory receptors likely contribute to the diversity of odorant-specific sensitivity phenotypes. Our working hypothesis is that genetic variations in auxiliary olfactory genes, including those mediating transduction and sensory neuronal development, may constitute the genetic basis for general olfactory sensitivity (GOS) and congenital general anosmia (CGA). We thus performed a systematic exploration for auxiliary olfactory genes and their documented variation. This included a literature survey, seeking relevant functional in vitro studies, mouse gene knockouts and human disorders with olfactory phenotypes, as well as data mining in published transcriptome and proteome data for genes expressed in olfactory tissues. In addition, we performed next-generation transcriptome sequencing (RNA-seq) of human olfactory epithelium and mouse olfactory epithelium and bulb, so as to identify sensory-enriched transcripts. Employing a global score system based on attributes of the 11 data sources utilized, we identified a list of 1,680 candidate auxiliary olfactory genes, of which 450 are shortlisted as having higher probability of a functional role. For the top-scoring 136 genes, we identified genomic variants (probably damaging single nucleotide polymorphisms, indels, and copy number deletions) gleaned from public variation repositories. This database of genes and their variants should assist in rationalizing the great interindividual variation in human overall olfactory sensitivity (http://genome.weizmann.ac.il/GOSdb). PMID- 22936405 TI - Cigarette smoke-induced CXCR3 receptor up-regulation mediates endothelial apoptosis. AB - Endothelial monocyte-activating polypeptide II (EMAP II) and interferon-inducible protein (IP)-10 are proinflammatory mediators, which in addition to their chemokine activities, selectively induce apoptosis in endothelial cells and are up-regulated in the lungs of cigarette smoke-exposed humans. Previously, we showed that EMAP II is an essential mediator of cigarette smoke-induced lung emphysema in mice linking endothelial cell apoptosis with inflammation. Here we addressed the role of the CXCR3 receptor in EMAP II-induced and IP-10-induced apoptosis in endothelial cells and its regulation by cigarette smoke. We found that both neutralizing antibodies and small inhibitory RNA to CXCR3 abrogated EMAP II-induced and IP-10-induced endothelial caspase-3 activation and DNA fragmentation. CXCR3 receptor surface expression in human lung microvascular endothelial cells and in lung tissue endothelium was up-regulated by exposure to cigarette smoke. In tissue culture conditions, EMAP II-induced and IP-10-induced apoptosis was enhanced by preincubation with cigarette smoke extract. Interestingly, serum starvation also induced CXCR3 up-regulation and enhanced EMAP II-induced endothelial apoptosis. Signal transduction via p38 mitogen activated protein kinase activation was essential for CXCR3-induced cell death, but not for CXCR3 receptor up-regulation by cigarette smoke. In turn, protein nitration was required for CXCR3 receptor up-regulation by cigarette smoke and consequently for subsequent CXCR3-induced cell death. In conclusion, the concerted up-regulation of proinflammatory EMAP II, IP-10, and CXCR3 by cigarette smoke could sustain a cascade of cell death that may promote the alveolar tissue loss noted in human emphysema. PMID- 22936406 TI - "Development and evaluation of sodium alginate-polyacrylamide graft-co-polymer based stomach targeted hydrogels of famotidine". AB - In the present study, grafting technology has been used to develop novel grafted hydrogel beads as controlled drug delivery carriers. The chemical crosslinking and grafting of polyacrylamide onto sodium alginate has been found to be efficient method for the development of new polymeric carrier. The successful crosslinking has been confirmed by Fourier transformed infrared spectroscopy, thermogravimetric analysis, and elemental analysis. The polymeric network of sodium alginate-co-polyacrylamide (NaAlg-g-PAM) has been interlinked by covalent and hydrogen bonds which also strength the gel network. Simple ionotropic gelation method has been used for the preparation of NaAlg-g-PAM hydrogel beads. Its swelling and gelation were dependent on monomer and crosslinker concentrations. Entrapment of the drug moiety (famotidine; an antiulcer drug) within the grafted beads has been confirmed by X-ray powder diffraction and differential scanning calorimetry. More than 75% of drug loading in beads occurred with the increase of monomer and crosslinker concentration. In vitro drug release was found to be sustained up to the 12 h with 80% drug release. PMID- 22936407 TI - Understanding the oral mucosal absorption and resulting clinical pharmacokinetics of asenapine. AB - Absorption of drugs from the oral cavity into the mucosal tissues is typically a fast event. Dissolved drugs partition into the mucosal membranes and within minutes will reach equilibrium with drug in solution in the oral cavity. However, this does not always equate to rapid drug appearance in the systemic circulation. This has been attributed to slow partitioning out of the mucosal tissues and into the systemic circulation. Based on information from literature, physicochemical properties of asenapine, and clinical data, we conclude that for sublingually administered asenapine, the exposure is primarily a function of rapid partitioning into the mucosal membranes. This is followed by slow partitioning out of the mucosal tissues and into the systemic circulation, leading to a T (max) value of about 1 h. The bioavailability of asenapine at doses below the saturation solubility in the mouth does not change and is controlled primarily by mass transport equilibrium. At doses above the saturation solubility, the bioavailability becomes more dependent not only on the distribution equilibrium but also on contact time in the mouth because additional variables (e.g. dissolution rate of the drug) need to be accounted for. These explanations are consistent with oral cavity absorption models from the literature and can be used to accurately describe the clinical data for asenapine. PMID- 22936408 TI - Effect of processing parameters on the physical stability of silicone coatings. PMID- 22936409 TI - Impact of accelerometer wear time on physical activity data: a NHANES semisimulation data approach. AB - BACKGROUND: Current research practice employs wide-ranging accelerometer wear time criteria to identify a valid day of physical activity (PA) measurement. OBJECTIVE: To evaluate the effects of varying amounts of daily accelerometer wear time on PA data. METHODS: A total of 1000 days of accelerometer data from 1000 participants (age=38.7 +/- 14.3 years; body mass index=28.2 +/- 6.7 kg/m(2)) were selected from the 2005-2006 National Health and Nutrition Examination Study data set. A reference data set was created using 200 random days with 14 h/day of wear time. Four additional samples of 200 days were randomly selected with a wear time of 10, 11, 12 and 13 h/day(1). These data sets were used in day-to-day comparison to create four semisimulation data sets (10, 11, 12, 13 h/day) from the reference data set. Differences in step count and time spent in inactivity (<100 cts/min), light (100-1951 cts/min), moderate (1952-5724 cts/min) and vigorous (>=5725 cts/min) intensity PA were assessed using repeated-measures analysis of variance and absolute percent error (APE). RESULTS: There were significant differences for moderate intensity PA between the reference data set and semisimulation data sets of 10 and 11 h/day. Differences were observed in 10-13 h/day(1) for inactivity and light intensity PA, and 10-12 h/day for steps (all p values <0.05). APE increased with shorter wear time (13 h/day=3.9-14.1%; 12 h/day=9.9-15.2%, 11 h/day=17.1-35.5%; 10 h/day=24.6-40.3%). DISCUSSION: These data suggest that using accelerometer wear time criteria of 12 h/day or less may underestimate step count and time spent in various PA levels. PMID- 22936410 TI - Contribution of house and garden work to the association between physical activity and well-being in young, mid-aged and older women. AB - OBJECTIVE: Although physical activity occurs in leisure, transport, occupational and domestic domains of life, the contribution of house and garden work (HGW) to the association between total physical activity and well-being is not clear. The aim was to describe the contribution of HGW to total physical activity (TPA) in association with well-being in younger, mid-aged and older women. DESIGN: Younger (25-30 years), mid-aged (50-55 years) and older (76-81 years) participants in the Australian Longitudinal Study on Women's Health completed a mailed survey with questions about leisure, transport and house and garden activities. Well-being was assessed using the physical and mental components scores of the SF-36. Cross sectional associations between the physical activity variables and well-being were modelled using General Additive Modelling. RESULTS: Correlations between HGW and leisure/transport activity (LTA) were low (r<0.3, p<0.001). Positive curvilinear associations were found between LTA and physical and mental well being in all three cohorts, and between HGW and physical and mental well-being in mid-aged and older women. In the younger women, an inverse relationship was found between HGW and well-being. When HGW and LTA were summed (TPA), the associations between TPA and well-being were attenuated compared with those for LTA alone and well-being. CONCLUSIONS: In mid-aged and older women, relationships between HGW and well-being were similar to, but weaker than seen for LTA and well-being. In young women, well-being declined with increasing HGW. Summing HGW to LTA led to attenuated relationships, suggesting that domains of physical activity should not be summed when studying relationships with well-being. PMID- 22936411 TI - Biomechanical analysis of three tennis serve types using a markerless system. AB - PURPOSE: The tennis serve is commonly associated with musculoskeletal injury. Advanced players are able to hit multiple serve types with different types of spin. No investigation has characterised the kinematics of all three serve types for the upper extremity and back. METHODS: Seven NCAA Division I male tennis players performed three successful flat, kick and slice serves. Serves were recorded using an eight camera markerless motion capture system. Laser scanning was utilised to accurately collect body dimensions and data were computed using inverse kinematic methods. RESULTS: There was no significant difference in maximum back extension angle for the flat, kick or slice serves. The kick serve had a higher force magnitude at the back than the flat and slice as well as larger posteriorly directed shoulder forces. The flat serve had significantly greater maximum shoulder internal rotation velocity versus the slice serve. Force and torque magnitudes at the elbow and wrist were not significantly different between the serves. CONCLUSIONS: The kick serve places higher physical demands on the back and shoulder while the slice serve demonstrated lower overall kinetic forces. This information may have injury prevention and rehabilitation implications. PMID- 22936412 TI - Trauma care: not all countries are equal. PMID- 22936413 TI - Restructuring the finances of the greek health care system in the era of economic crisis. PMID- 22936414 TI - International Association for Trauma Surgery and Intensive Care (IATSIC): a historical vignette. AB - IATSIC was conceived in the mid-1980s by Martin Allgower. Its goal was to provide an international forum and to disseminate knowledge of trauma care globally. It has met and continues to meet this goal. IATSIC provides a forum for scholarly exchange and thus for elevating the global discussion of trauma. The organization propagates standards of care and provides courses for training surgeons and other healthcare professionals. Further, IATSIC continues to provide a solid foundation for quality practice and management of trauma by emphasizing not only the need to prioritize care of the injured worldwide, but also the knowledge, skills, tactics, and techniques needed to provide the care in a wide variety of environments around the globe. With the other specialty societies (IAES, IASMEN, ISDS, and BSI), it provides a substantial and sustaining underpinning for the ongoing activities of ISS/SIC. Martin Allgower died on October 27, 2007, but his vision lives on (Fig. 6). PMID- 22936415 TI - Synthesis of enantiomerically enriched imidazolidin-2-ones through asymmetric palladium-catalyzed alkene carboamination reactions. AB - Positive water effect: A catalyst composed of [Pd(2)(dba)(3)] (dba=dibenzylideneacetone) and (S)-Siphos-PE is effective for the enantioselective coupling of N-allyl ureas with aryl bromides to afford 4 substituted imidazolidin-2-ones. Added water leads to significantly improved enantioselectivities with electron-poor aryl halide substrates. It is suggested that the C-C bond-forming reductive elimination is the enantiodetermining step in these reactions. PMID- 22936416 TI - An angiographic technique for coronary fractional flow reserve measurement: in vivo validation. AB - Fractional flow reserve (FFR) is an important prognostic determinant in a clinical setting. However, its measurement currently requires the use of invasive pressure wire, while an angiographic technique based on first-pass distribution analysis and scaling laws can be used to measure FFR using only image data. Eight anesthetized swine were instrumented with flow probe on the proximal segment of the left anterior descending (LAD) coronary arteries. Volumetric blood flow from the flow probe (Qp), coronary pressure (Pa) and right atrium pressure (Pv) were continuously recorded. Flow probe-based FFR (FFRq) was measured from the ratio of flow with and without stenosis. To determine the angiography-based FFR (FFRa), the ratio of blood flow in the presence of a stenosis (QS) to theoretically normal blood flow (QN) was calculated. A region of interest in the LAD arterial bed was drawn to generate time-density curves using angiographic images. QS was measured using a time-density curve and the assumption that blood was momentarily replaced with contrast agent during the injection. QN was estimated from the total coronary arterial volume using scaling laws. Pressure-wire measurements of FFR (FFRp), which was calculated from the ratio of distal coronary pressure (Pd) divided by proximal pressure (Pa), were continuously obtained during the study. A total of 54 measurements of FFRa, FFRp, and FFRq were taken. FFRa showed a good correlation with FFRq (FFRa = 0.97 FFRq +0.06, r(2) = 0.80, p < 0.001), although FFRp overestimated the FFRq (FFRp = 0.657 FFRq + 0.313, r(2) = 0.710, p < 0.0001). Additionally, the Bland-Altman analysis showed a close agreement between FFRa and FFRq. This angiographic technique to measure FFR can potentially be used to evaluate both anatomical and physiological assessments of a coronary stenosis during routine diagnostic cardiac catheterization that requires no pressure wires. PMID- 22936417 TI - Assessment of parental disclosure of a 22q11.2 deletion syndrome diagnosis and implications for clinicians. AB - Most children with chromosome 22q11.2 deletion syndrome (22q11DS) have an IQ in the range that may allow them to be capable of understanding a genetic diagnosis despite mild intellectual disabilities. However, there are no publications that relate to the disclosure of a 22q11DS diagnosis to the affected child, or the factors that influence parents' disclosure to the child. A pilot study was conducted including eight semi-structured interviews with caregivers of children with 22q11DS, 10 to 17 years of age, to investigate the factors that influence how parents inform their children of the diagnosis. Six of eight participants had disclosed the diagnosis to the child, and most of these parents felt they could have benefited from additional advice from professionals to increase their confidence and success, as well as the child's comprehension of the information. Those who had not informed the child were uncertain about the words to use, how to initiate the conversation, or were concerned about the child's level of understanding. Our results demonstrate that genetics professionals should help prepare caregivers for conversations with their children about the diagnosis of 22q11DS, monitor the understanding of the diagnosis over time, and provide ongoing support. PMID- 22936418 TI - Transfer printing techniques for materials assembly and micro/nanodevice fabrication. AB - Transfer printing represents a set of techniques for deterministic assembly of micro-and nanomaterials into spatially organized, functional arrangements with two and three-dimensional layouts. Such processes provide versatile routes not only to test structures and vehicles for scientific studies but also to high performance, heterogeneously integrated functional systems, including those in flexible electronics, three-dimensional and/or curvilinear optoelectronics, and bio-integrated sensing and therapeutic devices. This article summarizes recent advances in a variety of transfer printing techniques, ranging from the mechanics and materials aspects that govern their operation to engineering features of their use in systems with varying levels of complexity. A concluding section presents perspectives on opportunities for basic and applied research, and on emerging use of these methods in high throughput, industrial-scale manufacturing. PMID- 22936419 TI - In vivo comet assay of multi-walled carbon nanotubes using lung cells of rats intratracheally instilled. AB - The genotoxicity of multi-walled carbon nanotubes (MWCNTs) was evaluated in vivo with comet assays using the lung cells of rats given MWCNTs. The MWCNTs were intratracheally instilled as a single dose at 0.2 or 1.0 mg kg(-1) or a repeated dose at 0.04 or 0.2 mg kg(-1) , once a week for 5 weeks, to male rats. The rats were sacrificed 3 or 24 h after the single instillation and were sacrificed 3 h after the last instillation in the repeated instillation groups. Histopathological examinations of the lungs revealed that MWCNTs caused inflammatory changes including the infiltration of macrophages and neutrophils after a single instillation and repeated instillation at both doses. In comet assays using rat lung cells, no changes in % Tail DNA were found in any group given MWCNTs. These findings indicate that MWCNTs do not have the potential to cause DNA damage in comet assays using the lung cells of rats given MWCNTs at doses causing inflammatory responses. PMID- 22936420 TI - Development and validation of a liquid chromatography-tandem mass spectrometry method for the simultaneous determination of acrivastine and pseudoephedrine in human plasma and its application in pharmacokinetics. AB - A specific, sensitive and accurate liquid chromatography-tandem mass spectrometry (LC-MS/MS) method has been developed for the simultaneous determination of acrivastine and pseudoephedrine in human plasma samples. Plasma samples were processed and analyzed on a Phenomenex Luna 3 MU CN 100A column (150 mm*2.0 mm) eluted with the mobile phase consisting of methanol and 0.01 mol/L ammonium acetate water solution containing 0.1% formic acid (45:55, v/v) at a flow rate of 0.2 mL/min. The analytes were detected by positive ion electrospray ionization in multiple reaction monitoring mode. The transitions of m/z 349->278, m/z 166->148 and m/z 256->167 were monitored for acrivastine, pseudoephedrine and diphenhydramine (IS), respectively. The method was specific and sensitive with a lower limit of quantitation (LLOQ) of 1.52 ng/mL for acrivastine and 8.13 ng/mL for pseudoephedrine. The method showed good linearity in the range of 1.52~606.0 0 ng/mL for acrivastine and 8.13~813.12 ng/mL for pseudoephedrine (r>=0.996). The mean recovery were ranged 91.82% ~ 98.46% for acrivastine and 90.77% ~ 92.05% for pseudoephedrine. Validation results, such as accuracy, precision and repeatability were within the required limits. The method was successfully applied in a pharmacokinetic study of the acrivastine and pseudoephedrine hydrochloride compound capsule in humans. PMID- 22936421 TI - Impaired quality of life in patients in long-term remission of Cushing's syndrome of both adrenal and pituitary origin: a remaining effect of long-standing hypercortisolism? AB - OBJECTIVE: The determinants that cause impaired quality of life (QOL) in patients in long-term remission of Cushing's syndrome (CS) are unknown. The aim of this study was to get more insight into the patient and disease characteristics related to impaired QOL in these patients. DESIGN: Cross-sectional study. METHODS: The QOL of 123 patients in remission of CS (age 52.2 +/- 12.0 years, 106 women, duration of remission 13.3 +/- 10.4 years, 80% pituitary CS), assessed with seven validated questionnaires, was compared with the QOL of an age- and sex matched control group (n=105). To investigate the influence of the aetiology of CS on QOL, patients in remission of pituitary and adrenal CS were compared. Furthermore, the influence of hormonal deficiencies, treatment strategy, duration of remission, gender and age on QOL was investigated. RESULTS: QOL in the total patient group and each patient subgroup was significantly worse on practically all dimensions of questionnaires compared with the control group (P<0.05), except for patients in remission of pituitary CS without hormonal deficiencies who had an impaired QOL on 50% of the QOL dimensions. Subgroup analysis revealed no difference in QOL between different patient groups, especially no difference between patients in remission of adrenal and pituitary CS. Female gender and a shorter duration of remission had a negative influence on QOL in the patient group. CONCLUSIONS: QOL remains impaired in patients in long-term remission of CS regardless of aetiology, presence of hormonal deficiencies and treatment strategies. More research is needed to establish the causes. PMID- 22936422 TI - What's all the fuss about? facts and figures about bone marrow failure and conditions. AB - The epidemiology of bone marrow failure conditions is not well understood. Although several population-based studies conducted in the last two decades have generated a wealth of information, it is still very challenging to interpret disease incidence and prevalence, particularly due to changes in disease classification, misdiagnosis of patients, frequent underreporting and use of different referent populations to calculate rates. Despite these limitations, the available epidemiologic data have revealed significant ethnic, geographic and clinical differences in disease biology that have implications for prevention and treatment strategies. With advances made in targeted therapies facilitated by identification of molecular biomarkers and increased use of curative bone marrow transplantation approach, the natural history of these disease entities is already changing. The epidemiology of these diseases seems to be the next frontier as knowledge gained about the risk factors and pathobiologic correlates could significantly help in designing patient-specific therapies with improved outcomes. PMID- 22936425 TI - Enaminone-based mimics of extended and hydrophilic alpha-helices. AB - Synthetic molecules capable of the mimicry of alpha-helices that are elongated and/or contain hydrophilic side chains have been largely elusive. However, the oligophenylenaminone structure can surmount both of these challenges (see scheme). PMID- 22936423 TI - Effects of saline stress on mineral composition, phenolic acids and flavonoids in leaves of artichoke and cardoon genotypes grown in floating system. AB - BACKGROUND: Cynara cardunculus is a species native to the Mediterranean basin. It includes globe artichoke and cultivated cardoon as well as their progenitor wild cardoon. The species is a source of biophenols, and its leaf extracts have been widely used in herbal medicine as hepatoprotectors and choleretics since ancient times. The aim of this study was to determine the effect of increasing the level of salinity in the nutrient solution (1 or 30 mmol L-1 NaCl) on biomass production, mineral composition, radical-scavenging activity, caffeoylquinic acids and flavonoids in three artichoke ('Romolo', 'Violetto di Provenza' and 'Violetto di Romagna') and three cultivated cardoon ('Bianco Avorio', 'Bianco Gigante Inerme' and 'Gigante di Romagna') cultivars grown in a floating system. RESULTS: Increased salinity in the nutrient solution decreased the leaf dry biomass and leaf number of artichoke and cultivated cardoon cultivars. Salinity reduced macro- and microelement accumulation in leaves (e.g. N, K, Ca, Mg, Fe, Mn and B) but improved their antioxidant activity, total polyphenols, chlorogenic acid, cynarin and luteolin. The cultivated cardoons, especially 'Bianco Avorio' and 'Gigante di Romagna', showed higher biomass and leaf number than those observed in artichoke genotypes. 'Violetto di Provenza' exhibited the highest content of chlorogenic acid, closely followed by 'Violetto di Romagna', whereas for cynarin content the highest values were recorded in 'Violetto di Provenza', 'Bianco Avorio' and 'Gigante di Romagna'. The highest content of luteolin was recorded in 'Gigante di Romagna' and 'Bianco Avorio', while the highest content of apigenin was observed in 'Gigante di Romagna'. CONCLUSION: The results showed that the floating system could be considered an effective tool to improve quality aspects through proper management of the salt concentration in the nutrient solution. They also suggest that specific cultivars should be selected to obtain the desired profile of bioactive compounds. PMID- 22936424 TI - Superantigen gene complement of Streptococcus pyogenes--relationship with other typing methods and short-term stability. AB - The profiling of the superantigen (SAg) encoding genes has been frequently used as a complementary typing method for group A streptococci (GAS), but a confusing gene nomenclature and a large diversity of primers used in screening has led to some conflicting results. The aim of this work was to develop a polymerase chain reaction (PCR) method capable of efficiently amplifying all the known allelic variants of these genes, and to evaluate the congruence of this methodology with other commonly used molecular typing methods. The presence of the 11 known SAg genes and two other exotoxin-encoding genes (speB and speF) was tested in a collection of 480 clinical GAS isolates, using two multiplex PCR reactions. The SAg gene profile was compared with other typing methods. Four naturally occurring deletions involving the genes speB, speF, and rgg were characterized, two of which were found among invasive isolates. The absence of the chromosomally encoded genes speG and smeZ was supported by Southern blot hybridization and associated with specific GAS lineages, while the presence of phage-encoded genes was more variable. Positive associations between SAg genes or between SAg profiles and emm types or pulsed-field gel electrophoresis (PFGE) clusters were observed. The results suggest that the SAg profile diversifies faster than other properties commonly used for molecular typing, such as emm type and multilocus sequence typing (MLST) sequence types (STs), and can be a useful complement in GAS molecular epidemiology. Still, the short-term stability of the SAg gene profile among prevalent genetic lineages may largely explain the observed associations between SAg genes. PMID- 22936428 TI - Metal-free catalytic olefin hydrogenation: low-temperature H2 activation by frustrated Lewis pairs. PMID- 22936427 TI - Management of patients with patent foramen ovale and cryptogenic stroke: a collaborative, multidisciplinary, position paper. AB - OBJECTIVES: To organize a common approach on the management of patent foramen ovale (PFO) and cryptogenic stroke that may be shared by different specialists. BACKGROUND: The management of PFO related to cryptogenic stroke is controversial, despite an increase in interventional closure procedures. METHODS: A consensus statement was developed by approaching Italian national cardiological, neurological, and hematological scientific societies. Task force members were identified by the president and/or the boards of each relevant scientific society or working group, as appropriate. Drafts were outlined by specific task force working groups. To obtain a widespread consensus, these drafts were merged and distributed to the scientific societies for local evaluation and revision by as many experts as possible. The ensuing final draft, merging all the revisions, was reviewed by the task force and finally approved by scientific societies. RESULTS: Definitions of transient ischemic attack and both symptomatic and asymptomatic cryptogenic strokes were specified. A diagnostic workout was identified for patients with candidate event(s) and patient foramen ovale to define the probable pathogenesis of clinical events and to describe individual PFO characteristics. Further recommendations were provided regarding medical and interventional therapy considering individual risk factors of recurrence. Finally, follow-up evaluation was appraised. CONCLUSIONS: Available data provided the basis for a shared approach to management of cryptogenic ischemic cerebral events and PFO among different Italian scientific societies. Wider international initiatives on the topic are awaited. PMID- 22936429 TI - Tract-based spatial statistics analysis of diffusion-tensor imaging data in pediatric- and adult-onset multiple sclerosis. AB - BACKGROUND: White matter (WM) microstructure may vary significantly in pediatric onset (PO) and adult-onset (AO) patients with multiple sclerosis (MS), a difference that could be explained by the effects of an inherent plasticity in the affected pediatric brains early in the disease, and a phenomenon that does not occur later in life. This hypothesis would support the observation that disease progression is much slower in POMS compared to AOMS patients. OBJECTIVES: To examine WM microstructure in the brain of adults with POMS and AOMS, using tract based spatial statistics (TBSS) analysis of diffusion-tensor imaging (DTI). METHODS: Adults with relapsing-remitting (RR) POMS, who were diagnosed before age of 18 years (n = 16), were compared with age-matched (AOA, n = 23) and disease duration-matched (AOD, n = 22) RR patients who developed MS after the age of 18 years. Scans were analyzed using the FSL software package (Oxford, UK) and statistics were performed using TBSS to evaluate WM microstructure between groups based on the mean fractional anisotropy (FA) values obtained from the DTI. RESULTS: Widespread cortical and deep WM area differences characterized by increased FA values were seen in the AOAMS compared with POMS group (P < 0.05, TFCE corrected). Significantly increased FA values of posterior WM areas were detected in the AODMS compared with POMS group (P < 0.05, TFCE corrected). CONCLUSION: Increased FA values in WM areas of the AOMS compared with the POMS patients suggest that diffuse WM microstructure changes are more attributable to age of onset than a simple function of disease duration and age. PMID- 22936430 TI - Control of Phytophthora nicotianae disease, induction of defense responses and genes expression of papaya fruits treated with Pseudomonas putida MGP1. AB - BACKGROUND: Biological control is a potential strategy to reduce post-harvest decay in several fruits. Little research has been carried out on the effects of endophytic bacterium on post-harvest blight caused by Phytophthora nicotianae in papaya. In this work, the biocontrol activity of Pseudomonas putida MGP1 on this disease and its possible mechanisms, including changes of defensive enzyme activities, total phenolic content and mRNA levels of two important genes, were investigated. RESULTS: Fruits treated with MGP1 showed a significant lower disease index and demonstrated increases in chitinase, beta-1,3-glucanase, phenylalanine ammonia-lyase, peroxidase, polyphenol oxidase and catalase activities and total phenolic content. In addition, the expression levels of pathogenesis related protein 1 gene (PR1) and non-expressor of PR1 gene (NPR1) in papaya fruits were elevated by MGP1 treatment. CONCLUSION The results indicated that papaya fruits were responsive to the endophytic bacterium Ps. putida, which could activate defensive enzymes and genes and thereby induce host disease resistance. PMID- 22936431 TI - Outcomes of resection of extra-adrenal pheochromocytomas/paragangliomas in the laparoscopic era: a comparison with adrenal pheochromocytoma. AB - INTRODUCTION: Laparoscopic adrenalectomy (LA) is the standard for removal of adrenal pheochromocytomas (pheos), but laparoscopic (LAP) resection of paragangliomas (PGs) is controversial. This study analyzes our results of resection of PGs in the LAP era. METHODS: A retrospective record review of all patients who underwent resection of intra-abdominal PGs from 1998 to 2011 was performed. Pre- and postoperative clinical, radiologic, biochemical, and pathologic data for LAP resection of PGs were compared with patients who underwent LA for adrenal pheo (LA pheo; n = 62). Statistical analysis was performed and data are reported as mean +/- SD. RESULTS: Fifteen patients had resection of PGs (6 OPEN, 9 LAP) and 62 had LA pheo. Most common PG locations were perirenal or renal hilum (n = 6) and para-aortic (n = 4). One LAP PG was converted to OPEN due to inflammation from a prior biopsy. Mean age of LAP PGs was 45.3 +/- 13.2 years, and mean tumor size was 3.3 +/- 2.1 cm. OPEN PGs were larger (5.1 vs. 3.3 cm), had shorter operative times (173 vs. 254 min), and longer hospitalization (5.7 vs. 2.6 days) and ICU stays (1.33 vs. 0.22 days) compared with LAP PGs (p <= 0.05). Compared with LA pheo, operative times for LAP PG were significantly longer (254 vs. 175 min, p = 0.001) but other outcomes were similar. Complications occurred in 5.9 % of LA pheos, 22 % of LAP PGs and 67 % of OPEN PGs. CONCLUSIONS: Patients with paragangliomas can safely benefit from LAP resection with outcomes similar to adrenal pheos. In the absence of a need for contiguous organ resection, LAP resection of paragangliomas seems to be the preferred surgical approach. PMID- 22936432 TI - Single-incision transumbilical levels 1 and 2 axillary lymph node dissection using a flexible endoscope in human cadaveric models. AB - BACKGROUND: The use of the flexible endoscope as a surgical platform potentially exposes a range of new surgical approaches and benefits yet to be fully defined. A new method using the flexible endoscope to undertake axillary dissection for breast cancer treatment is explored together with an investigation into its acceptability to the general public. METHODS: Endoscopic axillary dissection via a transumbilical approach using the flexible endoscope passed subcutaneously from the umbilicus is described for four human cadaveric axillas. A questionnaire, validated by clinicians, explored the general public's reaction to the approach and how it might be influenced by potentially serious morbidity such as an increased rate of cancer recurrence. RESULTS: All axillas were accessed successfully via the transumbilical approach. Levels 1 and 2 axillary dissection was attempted on four axillas. Scarring from previous axillary surgery prevented dissection in one case. In the remaining three cases, respectively 12, 11, and 14 lymph nodes were harvested. The operative times improved with each case, from 1080 to 390 min. A total of 127 people responded to the questionnaire, with 73 % preferring the described approach over the open and periareolar alternatives when morbidities were considered equivalent. When a hypothetical elevated risk of cancer recurrence was included with the transumbilical approach, one-fifth of the public still accepted the approach due to the likelihood of a superior cosmesis. CONCLUSION: The use of the flexible endoscope for oncologically safe levels 1 and 2 axillary dissection is possible and would be acceptable to the general public if it were clinically approved. However, significant challenges with the current endoscopic equipment and relevant instrumentation limit the potential of the technique. Technical innovation in terms of new instrument design with improved ergonomics will reduce long operating times and fatigue, thus ensuring surgical acceptance of the flexible endoscope. PMID- 22936433 TI - Consensus statement of the consortium for LESS cholecystectomy. AB - Many surgeons attempting Laparo-Endoscopic Single Site (LESS) cholecystectomy have found the operation difficult, which is inconsistent with our experience. This article is an attempt to promote a standardized approach that we feel surgeons with laparoscopic skills can perform safely and efficiently. This is a four-trocar approach consistent with the four incisions utilized in conventional laparoscopic cholecystectomy. After administration of general anesthesia, marcaine is injected at the umbilicus and a 12-mm vertical incision is made through the already existing anatomical scar of the umbilicus. A single four trocar port is inserted. A 5-mm deflectable-tip laparoscope is placed through the trocar at the 8 o'clock position, a bariatric length rigid grasper is inserted through the trocar at the 4 o'clock position (to grasp the fundus), and a rigid bent grasper is placed through the 10-mm port (to grasp the infundibulum). This arrangement of the instruments promotes minimal internal and external instrument clashing with simultaneous optimization of the operative view. This orientation allows retraction of the gallbladder in a cephalad and lateral direction, development of a window between the gallbladder and the liver which promotes the "critical view" of the cystic duct and artery, and provides triangulation with excellent visualization of the operative field. The operation is concluded with diaphragmatic irrigation of marcaine solution to minimize postoperative pain. Standardization of LESS cholecystectomy will speed adoption, reduce intraoperative complications, and improve the efficiency and safety of the approach. PMID- 22936434 TI - Technical and perioperative outcomes of minimally invasive esophagectomy in the prone position. AB - BACKGROUND: Minimally invasive esophagectomy (MIE) is performed through various approaches, including using video-assisted thoracoscopic surgery for mediastinal esophageal dissection. The prone technique allows for gravity-aided retraction of the lung. The aim of this study was to examine perioperative outcomes after prone MIE in relation to patient preoperative comorbidities. METHODS: A retrospective cohort study from our single tertiary-care center is presented. Between January 2007 and August 2010, a total of 42 patients underwent three-field prone MIE. The majority of patients were male (37 vs. 5 female), with an average age of 68 years (range = 37-87). The diagnoses for patients who underwent MIE were 35 adenocarcinoma, four Barrett's esophagus with high-grade dysplasia, two achalasia, and one squamous cell carcinoma. Neoadjuvant chemotherapy with or without radiotherapy was administered to 16 (38 %) patients. Preoperative comorbidities were quantified using the Modified Charlson Comorbidity Index; low risk was defined as a score of 0-2 (23 patients), moderate risk 3-4 (14 patients), and high risk 5 or higher (five patients). Postoperative complications were stratified using the Clavien Classification Scale; minor complications were grades 1 and 2 and major complications were grades 3-5. RESULTS: Median length of hospital stay was 8 days (range = 6-51) and median ICU stay was 2 days (range = 1 26). Average prone surgical time was 108 min (range = 67-198). Thirty-seven of 42 patients (88 %) were extubated on the day of operation. Postoperatively, all five high-risk patients had a complication, three of which were major. Eight of the 14 moderate-risk patients had a complication and three were major, and 17 of the 23 low-risk group had a complication with nine being major. There was a total of 15 major complications. Predominant complications were arrhythmias (15) and pneumonia (five), with four anastomotic leaks and two postoperative 30-day mortalities. CONCLUSIONS: This series supports using prone MIE. Despite a clinical pathway, including immediate extubation postoperatively, there is still a risk of pulmonary complications that appears to correlate with higher preoperative comorbidity scores. PMID- 22936435 TI - Practice gaps in gastrointestinal and endoscopic surgery (2011): a report from the Society of Gastrointestinal and Endoscopic Surgeons (SAGES) Continuing Education Committee. PMID- 22936436 TI - Omental patch repair effectively treats perforated marginal ulcer following Roux en-Y gastric bypass. AB - BACKGROUND: Marginal ulcer formation remains a significant complication of Roux en-Y gastric bypass (RYGB). Up to 1 % of all RYGB patients will develop free perforation of a marginal ulcer. Classically, this complication has required anastomotic revision; however, this approach is associated with significant morbidity. Several small series have suggested that omental patch repair may be effective. The aim of this study was to examine the management of perforated marginal ulcers following RYGB. METHODS: All patients who underwent operative intervention for perforated ulcers between 2003 and 2011 were reviewed. Those with a history of RYGB with perforation of a marginal ulcer were included in the analysis. Data collected included operative approach, operative time, blood loss, length of hospital stay, complications, smoking history, and steroid or NSAID use. RESULTS: From January 2003 to December 2011, a total of 1,760 patients underwent RYGB at our institution. Eighteen (0.85 %) developed perforation of a marginal ulcer. Three patients' original procedure was performed at another institution. Eight patients (44 %) had at least one risk factor for ulcer formation. Treatment included omental patch repair (laparoscopic, n = 7; open, n = 9) or anastomotic revision (n = 2). Compared to anastomotic revision, omental patch repair had shorter OR time (101 +/- 57 vs. 138 +/- 2 min), decreased estimated blood loss (70 +/- 72 vs. 250 +/- 71 mL), and shorter total length of stay (5.6 +/- 1.4 vs. 11.0 +/- 5.7 days). CONCLUSIONS: Perforated marginal ulcer represents a significant complication of RYGB. Patients should be educated to reduce risk factors for perforation, as prolonged proton pump inhibitor therapy may not prevent this complication in a patient with even just one risk factor. In our sample population we found laparoscopic or open omental patch repair to be a safe and effective treatment for this condition and it was associated with decreased operative time, blood loss, and length of stay. PMID- 22936437 TI - Single-incision laparoscopic splenectomy: preliminary experience in consecutive patients and comparison to standard laparoscopic splenectomy. AB - BACKGROUND: Since first being described in 2009, single-incision laparoscopic splenectomy has been described in a limited number of case reports and small case series. No studies have evaluated single-incision splenectomy in unselected patients, and outcomes of the procedure have not previously been compared to standard laparoscopy. METHODS: A retrospective review was conducted to evaluate all single-incision splenectomies performed by a single surgeon between June 2010 and June 2011. Additionally, patients who underwent standard laparoscopic splenectomy by surgeons in the same tertiary referral surgical oncology group were evaluated to serve as a control group. Demographic data, operative parameters, and postoperative outcomes were assessed. RESULTS: Eight patients underwent successful single-incision splenectomy during the study period without conversion to an open procedure or requiring additional ports. The median operative time was 92.5 min. There was 25 % morbidity and no mortality in the study group. Median length of stay was 4 days. Additionally, 18 patients who underwent standard laparoscopic splenectomy were evaluated for comparison. No significant differences were identified in the preoperative patient characteristics between the two groups. Single-incision splenectomy was associated with a shorter operative time (92.5 vs. 172 min, p = 0.003), lower conversion rate, equivalent length of stay, reduced mortality, similar morbidity, and comparable postoperative narcotic requirements. CONCLUSIONS: Single-incision splenectomy is feasible, safe, and efficient in an unselected patient population in the hands of an experienced laparoscopic surgeon. The single-incision technique is comparable to standard laparoscopic splenectomy in terms of operative time and perioperative outcomes. PMID- 22936438 TI - Demystifying sample-size calculation for clinical trials and comparative effectiveness research: the impact of low-event frequency in surgical clinical research. AB - BACKGROUND: Type II error, or not meeting sample-size requirement, has been identified as an issue in the surgical literature. The root of this problem is the low frequency of events in the majority of surgical clinical research. This exponentially increases the sample size needed to achieve statistical significance. METHODS: The methodology and mechanics of sample-size calculations are presented to demonstrate how sample-size requirements change based on baseline event rate and relative reduction in event rate. These concepts are then illustrated using real-life clinical scenarios. RESULTS: If a hypothetical baseline event rate is 1 % and the event rate in the experimental group is 0.5 % (therefore representing a 50 % reduction), then the total number of study patients required is 10,130. If the baseline event rate is 1 %, and the event rate in the experimental group is 0.9 % (a 10 % reduction), then the total number of study patients required is 299,410. CONCLUSIONS: Sample-size calculations are affected by the frequency of the event or events of interest. Given advances in clinical medicine, many clinical outcomes of interest occur at very low frequencies. These low frequencies exponentially increase the sample size required to find statistically significant differences, making randomized clinical trials difficult to conduct properly. Surgical clinical researchers should advocate for the establishment of robust, prospective, large, multi institutional clinical databases along with the establishment of proper outcomes research methodology as a way to augment randomized trials. PMID- 22936439 TI - Hepatectomy based on the tumor hemodynamics for hepatocellular carcinoma: a comparison among the hybrid and pure laparoscopic procedures and open surgery. AB - PURPOSE: This study was designed to evaluate the surgical parameters and treatment outcomes of tumor hemodynamics-based pure laparoscopic (PURE) and laparoscopy-assisted (HYBRID) hepatectomy for small hepatocellular carcinoma (HCC) compared with those of open hepatectomy. METHODS: Using a prospectively collected database from 1997 to 2011, we analyzed the data of 56 consecutive cases of laparoscopic hepatectomy for HCC (PURE, n = 24; HYBRID, n = 29; HALS, n = 3) from among 102 cases undergoing laparoscopic hepatectomy. We employed 27 cases treated by open hepatectomy during the same period as controls. RESULTS: PURE was associated with lesser blood loss, lower weight of the resected liver, and a shorter skin incision than HYBRID and open hepatectomy [median blood loss (mL): PURE 7, HYBRID 380, Open 450; P < 0.05]. On the other hand, HYBRID hepatectomy was associated with a longer operation time [operation time (min): HYBRID 232, Open 185; P = 0.0226]. The length of hospitalization in the cases treated by PURE and HYBRID hepatectomy was shorter than that in the cases treated by open hepatectomy [length of hospitalization (days): PURE 11, HYBRID 12, Open 17; P < 0.05]. One case each of transfusion and morbidity was recorded in this series. There was no significant difference of the overall (OS) or disease-free survival (DFS) between the patients treated by laparoscopic and open hepatectomy (3-year OS: 100 vs. 100 %; DFS 50 vs. 62 %, respectively). CONCLUSIONS: Neither the surgical parameters nor the treatment outcomes of hemodynamics-based laparoscopic hepatectomy were inferior to those of open hepatectomy. PMID- 22936441 TI - Synthesis of azepine derivatives by rhodium-catalyzed tandem 2,3 rearrangement/heterocyclization. PMID- 22936440 TI - Revisional surgery after failed laparoscopic adjustable gastric banding: a systematic review. AB - BACKGROUND: Laparoscopic adjustable gastric banding (LAGB) has emerged as one of the most commonly performed bariatric procedures worldwide. Unfortunately, revisional surgery is required in 20-30 % of cases. Several revisional strategies have been proposed, but there is no consensus regarding the best surgical option. This systematic review was designed to determine which revisional surgery (laparoscopic sleeve gastrectomy, laparoscopic Roux-en-Y gastric bypass, or laparoscopic biliopancreatic diversion with duodenal switch) is best suited to enhance weight loss following failed LAGB due to complications or inadequate weight loss. METHODS: EMBASE, MEDLINE, PsycINFO, and Cochrane Clinical Trials were searched using the most comprehensive timeline for each database. A total of 24 relevant articles were identified. Two investigators independently extracted data, and differences were resolved by consensus. The weighted means were calculated for weight loss measurements. RESULTS: A total of 106, 514, and 71 patients underwent conversion from LAGB to laparoscopic sleeve gastrectomy (LSG), laparoscopic Roux-en-Y gastric bypass (LRYGB), and laparoscopic biliopancreatic diversion and duodenal switch (BPDDS), respectively. Before revisional surgery, the weighted mean body mass index (BMI) was 38.8 (6.9), 43.3 (8.1), and 41.3 (7.2) kg/m(2) for the LSG, LRYGB, and BPDDS groups, respectively. The majority of data was reported at 12-24 months follow-up. The mean BMI within this interval was 28 (10.5), 32.2 (6.4), and 33 (5.7) kg/m(2) for the LSG, LRYGB, and BPDDS groups, respectively. In addition, the mean excess weight loss (EWL) was 22 % (2.8), 57.8 % (11.7), 47.1 % (14) for the LSG, LRYGB, and BPDDS groups, respectively. The EWL reached 78.4 % (35) in the BPPDS group after 2-year follow up. CONCLUSIONS: Failed LAGB is best managed with conversion to another bariatric procedure. Stable weight loss occurs with salvage LRYGB. Although results for revisional BPPDS appear promising, additional research, with higher methodological quality, is needed. PMID- 22936442 TI - Genetic trends for objectively measured and subjectively assessed traits in a Dorper sheep flock. AB - Genetic trends were constructed to monitor the genetic change for subjectively assessed and objectively measured traits using data emanating from complete records from the National Small Stock Improvement Scheme database and performance records accumulated by a single breeder over a period of 24 years. The objectively measured production traits considered were weaning weight, post weaning weight (PWW), yearling weight, average daily weight gain to weaning (ADGW), average daily weight gain during post-weaning phase (ADGPW) and average daily weight gain up to yearling age. The subjectively assessed traits (scored on a five-point scale) were conformation, fat distribution, size, type and colour. Direct genetic trends for live weight and growth traits (with the exception of ADGPW) were positive. All the objectively measured traits where maternal effects were significant, except PWW, registered small declines in maternal breeding values. The fastest genetic progress was attained by ADGW, which amounted to 0.29 % of the overall phenotypic mean per annum. Conformation and type exhibited positive but slow increments in direct breeding values at an equivalent annual rate amounting to 0.12 and 0.09 % of the overall phenotypic mean, respectively. Size demonstrated a negative genetic trend of -0.14 % of the overall phenotypic mean per annum. Genetic trends for fat distribution and colour were negligible. It was concluded that breeders should focus more on the performance recording of objective traits as they are likely to respond favourably to selection pressure. PMID- 22936443 TI - Hypoxia-induced factor-1alpha in endometrial carcinoma: a mini-review of current evidence. AB - Despite the well-established role of hypoxia in cancer biology, the literature on its effects on endometrial cancer is scarce; it mainly refers to experimental settings rather than patient-derived results. Herein, an overview of the hypoxia inducible factor 1alpha (HIF-1alpha) biology, focusing on endometrial cancer, is presented. The molecular mechanisms possibly involved in endometrial cancer progression are presented, followed by a systematic approach to the current literature on immunohistochemistry evaluation of HIF-1alpha expression in endometrial carcinoma. Since no consensus has been made regarding HIF-1alpha evaluation, the evidence of possible involvement of HIF-1alpha in endometrial carcinoma prognosis is weak. After a consensus has been made, properly powered studies may be able to clarify whether HIF-1alpha can act as a prognosticator in endometrial carcinoma. PMID- 22936444 TI - Tracking stem cell migration and survival in brain injury: current approaches and future prospects. AB - In recent years, stem cell-mediated therapies have gained considerable ground as potential treatments for a wide variety of brain pathologies including traumatic brain injury, stroke and neurodegenerative diseases. Despite extensive preclinical studies, many of these therapies have not been fully translated into viable clinical approaches. This is partly due to our inability to reliably track and monitor transplanted stem cells longitudinally over long periods of time in vivo. In this review, we discuss the predominant histological cell tracing methodologies, such as immunohistochemistry, and fluorescent cellular dyes and proteins, and compare them to emerging cellular imaging technologies. We show that advances in magnetic resonance imaging (MRI) have resulted in opportunities to use this technology to further our understanding of stem cell characteristics and behaviors in vivo. While MRI may not completely replace conventional cell tracking methods in pre-clinical, mechanistic work, it is clear that it has the potential to function as a powerful diagnostic tool for tracking stem cell migration and survival as well as for evaluating the efficacy of stem cell mediated therapies. PMID- 22936445 TI - The involvement of microRNAs in malignant transformation. AB - In the multiple steps in cancer progression, microRNAs (miRNAs) play significant roles in each stage. Reports of considerable differences in expression levels of miRNAs between normal and malignant tissues are understandable considering miRNAs are key regulators of gene expression. Dysregulation of miRNA expression levels in neoplasia occurs because many miRNAs are located in "fragile sites", which are frequently deleted in cancer. miRNAs are often down regulated in cancerous tissues and target oncogenic proteins are classified as tumour suppressor miRNAs, such as let-7. While, miRNAs that are frequently over-expression in neoplastic tissues compared to normal tissues and regulate tumour suppressor proteins are categorized as "oncomiRs". In this review, we summarize information about microRNAs involved in the emerging field of cancer stem cells, and microRNAs involved in breast cancer, an area of our expertise. The application of miRNAs to cancer therapeutics and diagnostics is emerging as an important field of gene therapy. The diverse nature of miRNAs in cancer is continually being elucidated to lead to the enigmatic treatment options for neoplastic disease. PMID- 22936446 TI - Promoter methylation of tumor-related genes in gastric carcinogenesis. AB - Aberrant promoter methylation and subsequent silencing of cancer-related genes has been recognized as an important pathway involved in gastric carcinogenesis. In fact, several factors are believed to contribute to its induction in gastric epithelia, including aging, diet, chronic inflammation and infection of Helicobacter pylori (H. pylori) and Epstein-Barr virus (EBV). However, the underling mechanisms are not completely identified, despite the belief that increased expression or activity of DNA methyltransferases (DNMTs), or decreased demethylation activity may contribute to the excessive methylation. A great number of genes with promoter methylation have been observed in gastric cancer (GC), among which p16INK4A (p16), Mut L homologue 1 (MLH1), Epithelial-cadherin (E-cadherin), Runt-related transcription factor 3 (RUNX3), adenomatous polyposis coli (APC), O(6)-methylguanine-DNA methyltransferase (MGMT), Ras association domain family 1A (RASSF1A) and Death-associated protein kinase (DAPK) have been extensively studied. Unlike the distinct methylation characterization in single genes, methylation analysis of multiple genes may provide more information in risk prediction, early detection, prognosis assessment and chemotherapy choice for GC. Specifically, particular monitoring and screening should be performed on those over 45 years old, with precancerous gastric disease or infection of H. pylori or EBV. As an alternative to tumor tissues, methylation detection in patient sera or gastric washes may also be used in risk prediction and early detection. However, what still poses a great challenge as well as a puzzle is the determination of the very genes that should be used in methylation analysis. Because epigenetic alterations are normally reversible, drugs or chemical compounds with demethylating activity, such as 5-aza-2'-deoxycytidine (5-aza-dC) could be used in the treatment of patients with multiple gene methylation. In view of the adverse effects of 5-aza-dC, DNMT-targeted strategy has been proposed and may prove to be more effective than demethylating agents. PMID- 22936447 TI - Claudin expression in breast cancer: high or low, what to expect? AB - The evaluation of claudins (CLDNs) expression pattern in tumours can be important to understand breast carcinogenesis. The study of CLDNs became more appealing since it was found that CLDN3 and CLDN4 are putative therapeutic targets for Clostridium perfrigens enterotoxin (CPE), as well as for monoclonal antibody based therapy. Moreover, the recently characterized CLDN-low molecular subgroup of breast tumours increased the interest in these molecules. Based on these facts, our aim was to explore the pattern of expression of CLDNs among a large series of invasive breast carcinomas. We also analysed the correlation between the combinatorial expression of CLDN3/CLDN4 and classical prognostic factors and biological markers. In addition, we also compared the characteristics of tumours with low expression of CLDN3, CLDN4 and CLDN7, assessed by immunohistochemistry (IHC), and the ones from CLDN-low subgroup of tumours previously defined by genomic assays. The combinatorial analysis of the expression of CLDN3/CLDN4 showed a significant association between high CLDN3/CLDN4 levels and triple negative tumours, as well as with worse patient outcome. This combined analysis may provide useful information for breast carcinomas, since these two CLDN members are putative therapeutic targets. Comparing tumours with low expression of CLDN3, CLDN4 and CLDN7 with tumours previously referred to as CLDN-low by genomic assays, we demonstrated that the single IHC evaluation of these three specific CLDNs is insufficient to identify the CLDN-low molecular subtype of breast tumours. The analysis of several other molecular markers, such as EMT (epithelial-to-mesenchymal transition) and CSC (cancer stem cell) markers should probably be added to improve the identification of this subgroup of tumours by IHC, which probably are enriched in carcinomas with metaplastic differentiation. PMID- 22936448 TI - Alloxan-induced hyperglycemia causes rapid-onset and progressive dental caries and periodontitis in F344 rats. AB - We have previously shown that diabetes increases dental caries, and periodontitis might be a secondary change resulting from dental caries in spontaneous diabetic rodent models. However, the lesions in these models were slow to manifest, and the intensity and frequency were mild and varied among individuals. The goal of this study was to confirm the reproducibility of caries development in chemically induced diabetic rats and investigate whether alloxan, which induces immediate and severe hyperglycemia in experimental animals, increases the lesions. Female F344 rats were examined 13 and 26 weeks after dosing of alloxan. Alloxan injection induced severe hyperglycemia in two-thirds of the rats. Progressive molar caries and periodontitis were already induced in all diabetic rats 13 weeks after dosing of alloxan, although the lesions were not observed in nondiabetic rats. Histopathologically, dental caries initially developed in the crown, then spread into the dental root, entered the periodontal connective tissue via the apical foramen, and progressed to periodontitis. In conclusion, alloxan-induced severe hyperglycemia is capable of causing rapid-onset and progressive dental caries and periodontitis in rats. PMID- 22936449 TI - Renal involvement in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL): report of a case with a six-year follow-up. AB - Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a disorder of the cerebral small blood vessels caused by a mutation in the NOTCH3 gene, which encodes a large transmembrane receptor NOTCH3. It is associated with systemic arteriopathy involving small arteries, besides the brain, in skin, spleen, liver, muscle, aorta and in the kidney. The key pathological finding is the accumulation of granular osmiophilic material (GOM) on degenerating vascular smooth muscle cells. In the kidney GOMs have been described only in a very limited number of CADASIL patients. We describe a genetically confirmed CADASIL patient with mild renal dysfunction and GOMs in the interlobular and juxtaglomerular arteries and, for the first time, also within the glomerulus, whose nephrology conditions remained stable, whereas the neurological manifestations markedly worsened over a six-year follow-up period. The reasons for this discrepancy are probably related to differences in the structure and function of brain and kidney blood vessels. PMID- 22936450 TI - Expression of cyclooxygenase-2 in invasive breast carcinomas and its prognostic impact. AB - Representative tumour sections from 468 patients with invasive breast cancer were immunostained for cyclooxygenase-2 (COX-2) and evaluated. The relationships between COX-2 expression, clinical outcome and various clinicopathological variables, including tumour vascularity and disseminated tumour cells (DTC) in the bone marrow were examined. COX-2 expression in invasive breast carcinoma cells was positively associated with oestrogen receptor and/or progesterone receptor positivity (p<0.001). Triple-negative tumours showed no/low COX-2 expression more frequently than other tumour types (p<0.001). Expression of COX-2 was not associated with breast cancer-specific survival (p=0.49, log-rank) or distant disease-free survival (p=0.67, log-rank) for all patients, including lymph node-negative, untreated patients (p>0.14, log-rank). There was also no significant association between COX-2 expression and histological grade, tumour size, nodal status, DTC in bone marrow, p53, HER2, or tumour vascularity. In conclusion, COX-2 expression in this series was associated with the presence of hormone receptors. Low COX-2 expression was observed in triple-negative breast carcinomas. PMID- 22936451 TI - Renal sinus pseudolymphoma in a patient with multiple carcinomas: a case report and a brief review of the literature. AB - The term pseudolymphoma refers to a heterogeneous group of benign reactive T-cell or B-cell lymphoproliferative processes of diverse causes that simulate lymphoma clinically and histologically but usually undergo spontaneous remission. Its pathogenesis is still unclear. The prognosis is good although some evidence suggests that pseudolymphoma may progress to lymphoma. Pseudolymphoma of the urinary tract is extremely rare. We herein report a case of pseudolymphoma of the renal sinus in a 70-year-old man, associated with a high grade urothelial carcinoma of the bladder and to a prostatic adenocarcinoma (Gleason score 6). A brief review of the literature is included. The kidney showed a well-defined, whitish soft mass which involved the renal sinus. Microscopically, the lesion of the renal sinus consisted of a proliferation of small to medium size lymphocytes (CD20 positive and Bcl-2 negative) sometimes arranged in hyperplastic follicular structures. The diagnosis was confirmed by molecular studies which showed an oligopolyclonal IgH rearrangement. To the best of our knowledge, this is the second case of pseudolymphoma with a complete molecular characterization ever described in the renal sinus and the first one associated with multiple urogenital carcinomas. PMID- 22936452 TI - A fluorescence-based demonstration of intestinal villi and epithelial cell in chickens fed dietary silicic acid powder including bamboo vinegar compound liquid. AB - This study investigates the combined effect of silicic acid and bamboo vinegar compound liquid (SPV) on the growth and intestinal histological alterations in poultry. Forty-eight 7-day-old male Sanuki Cochin chickens were fed a commercial mash diet supplemented with SPV at 0, 0.1, 0.2, and 0.3% level ad libitum for 112 days. Body weight gain tended to improve with increased concentrations of dietary SPV, although these results were not statistically significant (P<0.1). Tissue observation by light microscopy revealed that the jejunal villus height (P<0.01) and duodenal and jejunal villus area (P<0.05) increased in the 0.2 and 0.3% SPV groups, respectively, compared with the control. Cell mitosis within the duodenum and jejunum also increased in the 0.2 and 0.3% SPV groups. Scanning electron microscopy revealed a prominent increase in the number of protuberant cells on the villus apical surface of the duodenum and jejunum for the 0.2 and 0.3% SPV groups compared with the control. Poultry in the 0.3% SPV group had the highest body weight gain and hypertrophied histological alterations of intestinal villi. Fluorescent microscopic images of cell mitosis and protuberant cells in the duodenal crypt clearly confirmed positive reactions for the activator protein 2alpha (AP-2alpha) and proliferating cell nuclear antigen (PCNA), compared with the control. The present results indicate that dietary SPV stimulates adsorption by the epithelial cells, which activate cell proliferation and self-renewal and regulate the expression of cell cycle regulators AP-2alpha and PCNA, resulting in higher body weight gain. Thus, we can conclude that a concentration of 0.3% dietary SPV is ideal for promoting growth in poultry. PMID- 22936453 TI - Cimetidine-induced vascular cell apoptosis impairs testicular microvasculature in adult rats. AB - Cimetidine, an H2 receptor antagonist used for treatment of gastric ulcers, exerts antiandrogenic and antiangiogenic effects. In the testes cimetidine impairs spermatogenesis, Sertoli cells and peritubular tissue, inducing apoptosis in the myoid cells. Regarding the importance of histamine and androgens for vascular maintenance, the effect of cimetidine on the structural integrity of the testicular vasculature was evaluated. Adult male rats received cimetidine (CMTG) and saline (CG) for 50 days. The testes were fixed in buffered 4% formaldehyde and embedded in historesin and paraffin. In the PAS-stained sections, the microvascular density (MVD) and the vascular luminal area (VLA) were obtained. TUNEL method was performed for detection of cell death. Testicular fragments embedded in Araldite were analyzed under transmission electron microscopy. A significant decrease in the MVD and VLA and a high number of collapsed blood vessel profiles were observed in CMTG. Endothelial cells and vascular muscle cells were TUNEL-positive and showed ultrastructural features of apoptosis. These results indicate that cimetidine induces apoptosis in vascular cells, leading to testicular vascular atrophy. A possible antagonist effect of cimetidine on the H2 receptors and/or androgen receptors in the vascular cells may be responsible for the impairment of the testicular microvasculature. PMID- 22936454 TI - Relationship between B-cell-specific Moloney murine leukemia virus integration site 1 (BMI-1) and homologous recombination regulatory genes in invasive ductal breast carcinomas. AB - B-cell-specific Moloney murine leukemia virus integration site 1 (Bmi-1) is a Polycomb group protein that is able to induce telomerase activity, enabling the immortalization of epithelial cells. Immortalized cells are more susceptible to double-strand breaks (DSB), which are subsequently repaired by homologous recombination (HR). BRCA1 is among the HR regulatory genes involved in the response to DNA damage associated with the RAD51 protein, which accumulates in DNA damage foci after signaling H2AX, another important marker of DNA damage. Topoisomerase IIIbeta (topoIIIbeta) removes HR intermediates before chromosomal segregation, preventing damage to cellular DNA structure. In breast carcinomas positive for BMI-1 the role of proteins involved in HR remains to be investigated. The aim of this study was to evaluate the association between BMI-1 and homologous recombination proteins. Using tissue microarrays containing 239 cases of primary breast tumors, the expression of Bmi-1, BRCA-1, H2AX, Rad51, p53, Ki-67, topoIIIbeta, estrogen receptors (ER), progesterone receptors (PR), and HER-2 was analyzed by immunohistochemistry. We observed high Bmi-1 expression in 66 cases (27.6%). Immunohistochemical overexpression of BMI-1 was related to ER (p=0.004), PR (p<0.001), Ki-67 (p<0.001), p53 (p=0.003), BRCA-1 (p= 0.003), H2AX (p=0.024) and topoIIIbeta (p<0,001). Our results show a relationship between the expression of BMI-1 and HR regulatory genes, suggesting that Bmi-1 overexpression might be an important event in HR regulation. However, further studies are necessary to understand the mechanisms in which Bmi-1 could regulate HR pathways in invasive ductal breast carcinomas. PMID- 22936455 TI - Food insecurity among Cambodian refugee women two decades post resettlement. AB - Resettled refugees have high rates of chronic disease, which may be partially due to persistent food insecurity. This study describes food experiences on arrival in the U.S. and current food security status and examines characteristics related to food insecurity in a well-established refugee community. Focus groups and a survey assessed food security status and personal characteristics of Cambodian women in Lowell, MA, USA. Multivariate logistic regression was used to examine relationships with food insecurity. Current rates of food insecurity are high. In multivariate models, food insecurity was positively associated with being depressed and being widowed, and negatively associated with higher income and acculturation. Early arrivers (1980s) had difficulty in the U.S. food system on arrival, while later arrivers (1990s-2000s) did not. Refugee agencies should consider strategically devoting resources to ensure successful early transition to the U.S. food environment and long-term food security of refugees. PMID- 22936456 TI - Family history of prostate cancer in a black population. AB - Although family history of prostate cancer (PC) is an established risk factor for the disease, few studies have investigated this relationship among men with an African heritage. The Prostate Cancer in a Black Population (PCBP) study is a large, nationwide case-control study conducted in Barbados, West Indies from 2002 to 2011. In the PCBP study, a family history of PC in fathers or brothers was associated with a threefold increased risk of disease (OR = 3.04, 95 % CI (2.18, 4.22)) and a strong positive relationship was noted for the number of affected first degree relatives. Tumor grade did not generally influence the relationship between family history and PC. The magnitude of risks associated with having a father affected with the disease was slightly higher in the PCBP study compared to other populations. It remains unclear whether this finding is the result of an increased genetic susceptibility in African-Barbadian men. PMID- 22936457 TI - Propionyl-L-carnitine improves endothelial function, microcirculation and pain management in critical limb ischemia. AB - INTRODUCTION: Chronic critical limb ischemia (CLI) is a severe condition of hypo perfusion of lower limbs, which is associated with inflammation and a pro coagulative state. It is a disease at high risk of amputation and cardiovascular death. Propionyl-L-carnitine (PLC) is efficacious in improving pain free walking distance in peripheral arterial disease with claudication; it also exerts favorable effects on the arterial wall and on endothelial function. The purpose of this study was to evaluate the effects of PLC on microcirculation, endothelial function and pain relief in patients affected by CLI not suitable for surgical intervention. PATIENTS AND METHODS: We enrolled 48 patients with CLI. Patients were randomized into two groups: the first group was treated with PLC, the second was treated with saline solution. All of them underwent the following tests: laser Doppler flowmetry at the forefoot at rest and after ischemia, trans cutaneous oxygen partial pressure and carbon dioxide partial pressure at the forefoot at rest and after ischemia, endothelium dependent dilation of the brachial artery. All tests were repeated after treatments. Pain was assessed by visual analog pain scale. RESULTS: Endothelium dependent dilation increased after PLC (9.5 +/- 3.2 vs 4.9 +/- 1.4 %; p < 0.05). Post-ischemic peak flow with laser Doppler flow increased after PLC. TcPO2 increased, while TcPCO2 decreased after PLC; CO2 production decreased after PLC. VAS showed a significant reduction in pain perception after active treatment. CONCLUSIONS: In CLI patients, PLC can improve microcirculation (post ischemic hyperemia, TcPO2 and TcPCO2 production). PLC also enhances endothelium dependent dilation and reduces analgesic consumption and pain perception. PMID- 22936458 TI - Phosphodiesterase III inhibition increases cAMP levels and augments the infarct size limiting effect of a DPP-4 inhibitor in mice with type-2 diabetes mellitus. AB - PURPOSE: We assessed whether phosphodiesterase-III inhibition with cilostazol (Cil) augments the infarct size (IS)-limiting effects of MK0626 (MK), a dipeptidyl-peptidase-4 (DPP4) inhibitor, by increasing intracellular cAMP in mice with type-2 diabetes. METHODS: Db/Db mice received 3-day MK (0, 1, 2 or 3 mg/kg/d) with or without Cil (15 mg/kg/d) by oral gavage and were subjected to 30 min coronary artery occlusion and 24 h reperfusion. RESULTS: Cil and MK at 2 and 3 mg/kg/d significantly reduced IS. Cil and MK had additive effects at all three MK doses. IS was the smallest in the MK-3+Cil. MK in a dose dependent manner and Cil increased cAMP levels (p < 0.001). cAMP levels were higher in the combination groups at all MK doses. MK-2 and Cil increased PKA activity when given alone; however, PKA activity was significantly higher in the MK-2+Cil group than in the other groups. Both MK-2 and Cil increased myocardial levels of Ser(133) P-CREB, Ser(523) P-5-lipoxygenase, Ser(473)P-Akt and Ser(633) P-eNOS. These levels were significantly higher in the MK-2+Cil group. Myocardial PTEN (Phosphatase and tensin homolog on chromosome ten) levels were significantly higher in the Db/Db mice compared to nondiabetic mice. MK-2 and Cil normalized PTEN levels. PTEN levels tended to be lower in the combination group than in the MK and Cil alone groups. CONCLUSION: MK and Cil have additive IS-limiting effects in diabetic mice. The additive effects are associated with an increase in myocardial cAMP levels and PKA activity with downstream phosphorylation of Akt, eNOS, 5 lipoxygenase and CREB and downregulation of PTEN expression. PMID- 22936459 TI - Interferon-gamma-mediated tissue factor expression contributes to T-cell-mediated hepatitis through induction of hypercoagulation in mice. AB - Concanavalin A (Con A) treatment induces severe hepatitis in mice in a manner dependent on T cells, interferon (IFN)-gamma, and tumor necrosis factor (TNF). Treatment with the anticoagulant heparin protects against hepatitis, despite healthy production of IFN-gamma and TNF. Here, we investigated molecular and cellular mechanisms for hypercoagulation-mediated hepatitis. After Con A challenge, liver of wild-type (WT) mice showed prompt induction of Ifngamma and Tnf, followed by messenger RNA expression of tissue factor (TF) and plasminogen activator inhibitor-1 (PAI-1), which initiate blood coagulation and inhibit clot lysis, respectively. Mice developed dense intrahepatic fibrin deposition and massive liver necrosis. In contrast, Ifngamma(-/-) mice and Ifngamma(-/-) Tnf(-/ ) mice neither induced Pai1 or Tf nor developed hepatitis. In WT mice TF blockade with an anti-TF monoclonal antibody protected against Con A-induced hepatitis, whereas Pai1(-/-) mice were not protected. Both hepatic macrophages and sinusoidal endothelial cells (ECs) expressed Tf after Con A challenge. Macrophage depleted WT mice reconstituted with hematopoietic cells, including macrophages deficient in signal transducer and activator of transcription-1 (STAT1) essential for IFN-gamma signaling, exhibited substantial reduction of hepatic Tf and of liver injuries. This was also true for macrophage-depleted Stat1(-/-) mice reconstituted with WT macrophages. Exogenous IFN-gamma and TNF rendered T-cell null, Con A-resistant mice deficient in recombination-activating gene 2, highly susceptible to Con A-induced liver injury involving TF. CONCLUSIONS: Collectively, these results strongly suggest that proinflammatory signals elicited by IFN-gamma, TNF, and Con A in both hepatic macrophages and sinusoidal ECs are necessary and sufficient for the development of hypercoagulation-mediated hepatitis. PMID- 22936460 TI - Decreased expression of indoleamine 2,3-dioxygenase 1 in dendritic cells contributes to impaired regulatory T cell development in immune thrombocytopenia. AB - Along with their immunogenic role, dendritic cells (DCs) are also critical in maintaining tolerance to self-antigens by inducing regulatory T cells (Tregs) via the expression of the immunomodulatory enzyme indoleamine 2,3-dioxygenase 1 (IDO1). In turn, Tregs modulate the maturation and/or function of DCs. In immune thrombocytopenia (ITP), the interaction between DCs and Tregs has never been investigated although decreased number/function of Tregs as well as altered DCs have been described. Here, we ask whether, in ITP: (1) IDO1 expression/activity is decreased in mature DCs; (2) IDO1-mediated Treg generation is impaired; and (3) DC maturation is abnormally modulated by Tregs. We found that in ITP, DCs show reduced capability of upregulating the expression/activity of IDO1. This finding results in the reduced ability of mature DCs of converting T cells into Tregs. In turn, Tregs are characterized by decreased interleukin-10 production and show lower ability of inhibiting DC maturation. In conclusion, these data point out the role of IDO1 in the impaired regulatory T cell development of ITP patients and suggest that the cross-talk between Tregs and DCs is hampered and plays a pathogenetic role. PMID- 22936461 TI - Low-level laser therapy improves the inflammatory profile of rats with heart failure. AB - Following heart failure (HF), immune activation leads to an imbalance between pro inflammatory and anti-inflammatory cytokines. Low-level laser therapy (LLLT) has been used as an anti-inflammatory treatment in several disease conditions. However, the effect of LLLT on the skeletal muscle of rats with HF remains unclear. The present report aimed to evaluate the influence of LLLT on the inflammatory profile of rats with HF. The left coronary artery was ligated to induce HF and a sham operation was performed in the control groups. Male Wistar rats (n=49) were assigned to one of six groups: placebo sham rats (P-Sham; n=8), LLLT at a dose of 3 J/cm(2) sham rats (3 J/cm(2)-Sham; n=8), LLLT at a dose of 21 J/cm(2) sham rats (21 J/cm(2)-Sham; n=8), placebo HF rats (P-HF; n=9), LLLT at a dose of 3 J/cm(2) HF rats (3 J/cm(2)-HF; n=8), and LLLT at a dose of 21 J/cm(2) HF rats (21 J/cm(2)-HF; n=8). Four weeks after myocardial infarction or sham surgery, rats were subjected to LLLT (InGaAlP 660 nm, spot size 0.035 cm(2), output power 20 mW, power density 0.571 W/cm(2), energy density 3 or 21 J/cm(2), exposure time 5.25 s and 36.75 s) on the right gastrocnemius for 10 consecutive days. LLLT reduced plasma IL-6 levels (61.3 %; P<0.01), TNF-alpha/IL-10 (61.0 %; P<0.01) and IL-6/IL-10 ratios (77.3 %; P<0.001) and increased IL-10 levels (103 %; P<0.05) in the 21 J/cm(2)-HF group. Moreover, LLLT reduced the TNF-alpha (20.1 % and 21.3 %; both P<0.05) and IL-6 levels (54.3 % and 37.8 %; P<0.01 and P<0.05, respectively) and the IL-6/IL-10 ratio (59.7 % and 42.2 %; P<0.001 and P<0.05, respectively) and increased IL-10 levels (81.0 % and 85.1 %; both P<0.05) and the IL-10/TNF-alpha ratio (171.5 % and 119.8 %; P<0.001 and P<0.05, respectively) in the gastrocnemius in the 3 J/cm(2)-HF and 21 J/cm(2)-HF groups. LLLT showed systemic and skeletal muscle anti-inflammatory effects in rats with HF. PMID- 22936462 TI - Enhancing the molecular signature in molecule-nanoparticle networks via inelastic cotunneling. AB - Charge transport in networks of nanoparticles linked by molecular spacers is investigated. Remarkably, in the regime where cotunneling dominates, the molecular signature of a device is strongly enhanced. We demonstrate that the resistance ratio of identical networks with different molecular spacers increases dramatically, from an initial value of 50 up to 10(5) , upon entering the cotunneling regime. Our work shows that intrinsic molecular properties can be amplified through nanoscale engineering. PMID- 22936464 TI - Determination of fumonisins B1 and B2 in Chinese rice wine by HPLC using AQC precolumn derivatisation. AB - BACKGROUND: Fumonisins are a group of naturally occurring mycotoxins produced by various Fusarium species that commonly infect maize and other cereals, including sorghum and rice. In this study a sensitive and selective method was developed for the determination of fumonisins B1 and B2 (FB1 and FB2) in Chinese rice wine. The method is based on high-performance liquid chromatography and fluorescence detection following precolumn derivatisation with 6-aminoquinolyl-N hydroxysuccinimidyl carbamate (AQC). RESULTS: FB1 and FB2 in Chinese rice wine were extracted and purified using strong anion exchange cartridges and derivatised with AQC at room temperature. The AQC derivatives were stable for 5 days. Optimal fluorescence was obtained at an excitation wavelength of 246 nm and an emission wavelength of 390 nm. Chromatography was performed using a C18 column and gradient elution at 1 mL min-1 with methanol and 0.05 mol L-1 phosphate buffer at pH 4. The limit of detection was 6 ug L-1 for both FB1 and FB2. The method was successfully applied to the determination of FB1 and FB2 in Chinese rice wine, with recoveries of 87.5-94.5% being obtained. CONCLUSION: The established method was stable and sensitive for the determination of FB1 and FB2 in Chinese rice wine. PMID- 22936463 TI - A systematic review of antiretroviral adherence interventions for HIV-infected people who use drugs. AB - HIV-infected persons who use drugs (PWUDs) are particularly vulnerable for suboptimal combination antiretroviral therapy (cART) adherence. A systematic review of interventions to improve cART adherence and virologic outcomes among HIV-infected PWUDs was conducted. Among the 45 eligible studies, randomized controlled trials suggested directly administered antiretroviral therapy, medication-assisted therapy (MAT), contingency management, and multi-component, nurse-delivered interventions provided significant improved short-term adherence and virologic outcomes, but these effects were not sustained after intervention cessation. Cohort and prospective studies suggested short-term increased cART adherence with MAT. More conclusive data regarding the efficacy on cART adherence and HIV treatment outcomes using cognitive behavioral therapy, motivational interviewing, peer-driven interventions and the integration of MAT into HIV clinical care are warranted. Of great concern was the virtual lack of interventions with sustained post-intervention adherence and virologic benefits. Future research directions, including the development of interventions that promote long-term improvements in adherence and virologic outcomes, are discussed. PMID- 22936465 TI - Repeated measurements of in vitro fermentation of fibre-rich substrates using large intestinal microbiota of sows. AB - BACKGROUND: Fibrous ingredients for pig diets can be characterized by in vitro fermentation. In vitro fermentation methods often use a one-time measurement of gas production during the incubation of test substrates with one faecal inoculum. The representativeness of this approach can be questioned as measuring time and number of animals from which inoculum originates may influence fermentation results. An in vitro fermentation trial was conducted incubating three fibrous substrates with three inocula in five replicates (different fermentation runs) to test the influence of run and origin of inocula. RESULTS: Total gas production and maximal rate of gas production differed (P < 0.05) between fermentation runs, but less than substrates (P < 0.01). The ranking order between substrates remained similar for each run. Fermentation of cellulose led to higher coefficients of variation between inocula compared to the fast fermentable substrates oligofructose and soy pectin. Differences ranged from 2% for total gas production up to 25% for maximal rate of gas production. CONCLUSION: One fermentation run can provide representative results for substrate ranking. Using multiple inocula mixed from four faecal samples each leads to high coefficients of variation for slow fermentable substrates like cellulose. Future studies should examine the optimal number of animals for inocula preparation to decrease variation. PMID- 22936466 TI - Synthesis and characterization of a metallapyridyne complex. AB - Building bridges: The first m-metallapyridine and the first metallapyridyne were synthesized under mild reaction conditions. The two complexes are metal-bridged polycyclic metallabenzenoid aromatics, in which the transition-metal center is shared by both six-membered rings. The synthetic method permits the use of metallabenzene as a starting material to access higher pi-electron metallaaromatics. PMID- 22936468 TI - Analytical characterization of three hallucinogenic N-(2-methoxy)benzyl derivatives of the 2C-series of phenethylamine drugs. AB - This publication reports analytical properties of three new hallucinogenic substances identified in blotter papers seized from the drug market, namely 25D NBOMe [2-(2,5-dimethoxy-4-methylphenyl)-N-(2-methoxybenzyl)ethanamine], 25E-NBOMe [2-(4-ethyl-2,5-dimethoxyphenyl)-N-(2-methoxybenzyl)ethanamine] and 25G-NBOMe [2 (2,5-dimethoxy-3,4-dimethylphenyl)-N-(2-methoxybenzyl)ethanamine]. These substances are N-(2-methoxy)benzyl derivatives of the 2C-series of phenethylamine drugs. The applied procedure covered a variety of analytical methods, including gas chromatography with electron impact mass spectrometry (GC-EI-MS; without derivatization and after derivatization with trifluoroacetic anhydride (TFAA)), liquid chromatography-electrospray ionization-quadrupole time of flight mass spectrometry (LC-ESI-QTOF-MS), Fourier transform infrared spectroscopy (FTIR) and nuclear magnetic resonance (NMR), which made it possible to identify the active components unequivocally. The GC-MS spectra of analyzed compounds were very similar, with dominant ions observed at m/z = 150, 121, and 91. The remaining ions were analogous to those observed for parent substances, namely 2C-D, 2C-E, 2C-G, but their intensities were low. Derivatization allowed determination of molecular masses of the investigated substances. Their exact masses and chemical formulas were confirmed by LC-QTOF-MS experiments and the fragmentation patterns of these compounds following ESI were determined. The tandem mass spectrometry (MS/MS) experiments confirmed that the studied substances were N-(2 methoxy)benzyl derivatives of the 2C-series compounds. Final elucidation of the structures was performed by NMR spectroscopy. The substances were also characterized by FTIR spectroscopy to corroborate the identity of the compounds. PMID- 22936467 TI - What should we expect in a prognosis study in 2012? PMID- 22936469 TI - Rhodium-catalyzed direct C-H amination of benzamides with aryl azides: a synthetic route to diarylamines. AB - No muss, no fuss: A rhodium-catalyzed direct intermolecular C-H amination of benzamides and ketoximes using aryl azides as the amine source has been developed. The reaction exhibits a broad substrate scope with excellent functional-group tolerance, requires no external oxidants, releases N(2) as the only by-product, and produces diarylamines in high yields. PMID- 22936470 TI - Organocatalytic asymmetric fluorination/semipinacol rearrangement: an efficient approach to chiral beta-fluoroketones. AB - An asymmetric fluorination/semipinacol rearrangement of 2-oxa allylic alcohols, as catalyzed by cinchona-alkaloid derivatives, gives chiral beta-fluoro ketones with moderate to high levels of enantioselectivity (see scheme). Both enantiomers of the product could be obtained by using the appropriate catalyst. PMID- 22936471 TI - Postimplant complications with transcatheter closure of congenital perimembranous ventricular septal defects: a single-center, longitudinal study from 2002 to 2011. AB - BACKGROUND: Whether or not to close perimembranous VSDs (pmVSDs) by transcatheter techniques is controversial because of a high rate of complications as compared with surgical alternatives. OBJECTIVE: We report the short- and long-term follow up results of the use of several kinds of devices to close pmVSDs and the annual incidence of postimplant complications in our center. METHODS: From June 2002 to June 2011, 232 patients with pmVSD underwent attempted transcatheter closure; closure was successful in 209 cases (90.1%). Six types of occlusive devices were used. Patient age, defect size, device type, device size and its relation to defect size, and transcatheter and fluoroscopy time were analyzed for correlation with annual incidence of postimplant complications. RESULTS: There were no deaths during the follow-up period. Within 1 month after transcatheter closure, we found 91 adverse events (43.5%), but only 32 cases showed a trace amount of residual shunting. From 2002 to 2011, the annual incidence of postimplant complications gradually decreased, from 50% in 2002 to 17.6% in 2011. The use of Amplatzer occluder devices (r = 0.71, P = 0.033), double-disc symmetrical occluder devices (r = -0.68, P = 0.045), and transcatheter (r = 0.87, P = 0.003), and fluoroscopy time (r = 0.78, P = 0.02) were significantly correlated with the incidence of post-implant complications. CONCLUSIONS: Results of transcatheter closure of pmVSD in terms of postimplant complications are encouraging in our center. It seemed that eccentric Amplatzer and domestic occluder may be at rather higher risk for postimplant complications. The incidence of postimplant complications may be minimized by skilled maneuvers, excluding rather small patients, and selecting the appropriate kind of occlusive device. PMID- 22936472 TI - Effects of prior information on decoding degraded speech: an fMRI study. AB - Expectations and prior knowledge are thought to support the perceptual analysis of incoming sensory stimuli, as proposed by the predictive-coding framework. The current fMRI study investigated the effect of prior information on brain activity during the decoding of degraded speech stimuli. When prior information enabled the comprehension of the degraded sentences, the left middle temporal gyrus and the left angular gyrus were activated, highlighting a role of these areas in meaning extraction. In contrast, the activation of the left inferior frontal gyrus (area 44/45) appeared to reflect the search for meaningful information in degraded speech material that could not be decoded because of mismatches with the prior information. Our results show that degraded sentences evoke instantaneously different percepts and activation patterns depending on the type of prior information, in line with prediction-based accounts of perception. PMID- 22936473 TI - [Doctor-patient relationship]. PMID- 22936474 TI - [The doctor-patient relationship against the backdrop of patient-centered medicine. The conclusions of dialogical ethics]. AB - "Health" and "illness" are multilayered terms. The understanding of human health depends, apart from scientific aspects, on people's individual perceptions as well as on aspects of culture and world view. The ideal of patient-centered medicine requires that a physician does not merely have to establish an objectifiable diagnosis. Rather, a physician should also respect the patients' right to self-determination, their personal values, and their subjective view of health and illness. The philosophy of dialogue, which developed in the twentieth century, offers a conceptual background for this ideal. On an empirical basis, the successful communication between doctor and patient can be interpreted as a useful placebo phenomenon. Alternative medicine puts great emphasis on the doctor's attentive care. This also explains why the alternative branch of medicine has appealed to many patients. Therefore, science-oriented medicine should review methods in which the doctor's empathy and dialogue ability are crucial to treatment success. It is part of the physician's responsibility to appreciate the personal perspectives of patients, to respect them and, if necessary, to engage with them critically. PMID- 22936475 TI - [Patients' autonomy and patients' rights]. AB - Patient autonomy is a valuable asset. Under German law, the patient's right to self-determination is ensured by a corresponding duty of the physician to inform. Owing to various case laws of the courts over the last few decades, that duty, in all of its aspects (i.e., informing the patient about risks and benefits, about the diagnosis, about the course of treatment, about necessary patient compliance, and about potential treatment costs) has gained enormous jurisdictional and scientific attention as well as forensic importance. Established court practice has become highly elaborated and differentiated. Some precedents have, nevertheless, exceeded reasonable requirements for physicians, and moderation is advisable. The current plans concerning a Statute on the Protection of Patients' Rights in Germany aim at laying down the specific requirements for patients' informed consent, including what information has to be communicated and in what way. Such a goal is difficult, especially in light of regulatory techniques. The discussion about the statute seldom addresses the fact that the suitability of legal norms as a means for public guidance can be limited; in particular, they do not guarantee that a dialogue between patient and physician about risks and benefits will ensue on the basis of a partnership. Over-regulation can damage faith and confidence in the relationship between patients and physicians. PMID- 22936476 TI - [The changing role of physicians]. AB - Despite a very successful process of professionalisation during the past 150 years, today's physicians face several challenges urging them to adapt their traditional professional role and the patient-physician relationship inherent in this role. Among these challenges, a growing economic influence on physicians' practices, new demands from particular groups of patients (consumerism, role of the Internet etc.), and increasing inter-professional competition deserve special attention. New evidence of an association between a stressful work environment and physician's increased health risks provides additional support in favour of this notion. This contribution suggests potential directions of change of the physician's role by pointing to (a) a growing 'feminisation' of medicine, (b) an even stronger emphasis on patient needs and (c) extended teamwork and inter professional cooperation. PMID- 22936477 TI - [Patient-centered communication in the physician-patient relationship]. AB - As a result of increasing demands for more patient-centeredness in the German health care system, physician-patient communication has been subject to transformation. Physicians are being requested to take into account their patients' communicative needs, including information, shared decision making, and emotional support, more vigorously than they had been in the past. A cooperative model of the physician-patient relationship is considered most suitable for fulfilling these needs and for empowering patients to make informed decisions regarding their own health care. However, a large body of evidence exists particularly regarding communication between cancer patients and their doctors that shows that patients' needs are not adequately addressed or met. This potential for optimization is all the more important because targeting patients' needs during doctor-patient communication not only improves patients' satisfaction with the communication, quality of life, and well-being, but may also produce better treatment outcomes. PMID- 22936478 TI - [Placebo and the relationship between doctors and patients. Overview]. AB - In medicine, placebos are used both in scientific studies and for practical therapeutic purposes. In evidence-based medicine, the efficacy of treatment may be determined as the difference between the effects of the verum (the active study drug) and the placebo, the latter being a substance lacking specific action on the disease under consideration. However, the improvements in patients' conditions under placebo treatment may be substantial and comparable to those with verum. Genuine placebos predominate in clinical studies, while pseudoplacebos prevail in practical therapy. The term pseudoplacebo can also be applied to many procedures in complementary medicine, including homeopathic medicine (Buchel et al., Placebo in der Medizin, 2011). The comprehensive definition of placebo, as used in a report by the German Medical Association (Buchel et al., Placebo in der Medizin, 2011), states that a placebo effect may occur even when treating with verum. The placebo effect is modulated by the context of the treatment, by the expectations of the patients and the doctors, and by the success of the relationship between doctors and patients. A number of unspecific effects, e.g., spontaneous alleviation, statistical effects, variance with time, methodological errors, in addition to the placebo effect make up the total response that is called"placebo reaction." A complete list of the effectiveness of placebo for all important diseases is still lacking. Further, it is not possible to predict which patients will respond to placebo. Which characteristics of doctors are important (competence, empathy, communicative ability and partnership, trust) in order to achieve a placebo effect, particularly in addition to the verum effect measures of evidence-based medicine? Are there doctors who are better in this than others? Could the nocebo effect weaken the efficacy of treatment in evidence-based medicine? Since a placebo effect may occur in almost any standard therapy, information about placebos should be provided during medical education and continuing medical education (CME). The use of placebo in clinical studies is ethically justified and lawful in consenting patients if there is no other effective treatment available with which the test substance could be compared. For daily practical therapeutic purposes, placebos may be ethically acceptable and lawful if there is no effective therapy available, if the complaints are minor, if the patient expressly wishes treatment, and if there is a reasonable likelihood of success. However, an explanation of the expected benefits and risks must be provided to the patients. At present, there are two explanatory theories for the mechanism of action of placebo, namely, the associative and the mentalistic explanation (Buchel et al., Placebo in der Medizin, 2011). Interestingly, effects of placebo and of verum can be localized in the brain by physiological and anatomical techniques. With many open questions remaining, research on placebo is currently very active. These aspect and neurobiological findings in particular may facilitate for "scientifically" educated doctors to accept that ineffective materials, i.e., placebos, are in fact effective. PMID- 22936479 TI - [Gender (role) aspects in doctor-patient communication]. AB - Aspects of gender and gender roles are important factors influencing the interactions between physicians and their patients. On the one hand, gender roles have an impact on the behavior of the patients, such as in health care utilization or use of preventive examinations. On the other hand, gender issues influence doctors' actions with respect to communication, diagnosis, and treatment. Here, a gender bias may lead to misdiagnosis and inadequate treatment. In this paper certain pertinent aspects of gender roles in the doctor-patient relationship are discussed and illustrated by empirical findings. PMID- 22936480 TI - [Involving family members of chronically ill patients in physician-patient communication]. AB - Involving family members in the patient's treatment is central for coping with chronic diseases. The family's functioning and their involvement in the treatment process have a significant influence on compliance as well as on the patient's coping and quality of life. This article illustrates this broad topic through selected aspects. First, the importance of the family for the patient's coping and quality of life is highlighted in certain examples. Criteria for the family's involvement and important topics for the doctor's encounter with family members are introduced. Second, the necessities, problems, and consequences of doctor family communication are illustrated for the examples of stroke and dementia. Overall, there is only limited time to include the family in in-patient as well as out-patient care. As a result, physician-family communication is not integrated sufficiently in general care, even for chronic diseases. PMID- 22936481 TI - [Doctor-patient interaction: dealing with difficult situations]. AB - Good doctor-patient communication has a positive impact on patient satisfaction, adherence to treatment, health outcomes and well-being, and it has been linked to reduced anxiety, increased recall, and improved understanding. During the diagnostic phase and the course of the illness, patients exhibit a range of mood changes. These include sadness and worry, frustration and anger, uncertainty, fear of disease recurrence, difficulties in inter-personal relationships, changing roles, and concerns about body image. Medical consultations can be influenced by different expectations concerning the doctor-patient interaction, by individual roles and beliefs, and by a different understanding of health and well-being influenced by cultural and other factors not necessarily associated with the medical situation. Responding to anger and other difficult emotions, dealing with family meetings, or communicating via interpreters are often experienced as demanding situations by health care professionals. This article provides an overview of the difficult doctor-patient interactions and illustrates basic communication skills in responding to challenging situations. PMID- 22936482 TI - [The physician's role in various clinical contexts. Physician counseling on in vitro fertilization (IVF) and preimplantation genetic diagnosis (PGD)]. AB - The role of the physician in the context of in vitro fertilization and preimplantation genetic diagnosis has certain distinct characteristics. Involuntary childlessness by definition of the WHO is a disease with good treatment options. As it is not considered a medical emergency, the focus lies more on intensive information giving, education, and counseling. Because the diagnosis and treatment can be a medical and psychological strain for the couple, counseling should address both medical and psychological aspects. The physician needs to have detailed medical knowledge as well as good communication skills to be able to meet the specific needs of the couple. Moreover, the physician should point out the realistic success rates of treatment and should refer to alternatives, such as remaining childless, adoption, and sperm or egg donation. The concurrent inclusion of biological, psychological, social, and ethical aspects in terms of psychosomatic basic care (Psychosomatische Grundversorgung) seems to be useful. There is potential for conflicts, for example, due to the economic interests of the physician. On the other hand, the treatment can be a financial burden for the couple. Of importance are the physician's and the patient's moral concepts, especially concerning some aspects of therapy (sperm and egg donation, surrogacy). The expected welfare of the intended child should also be respected (e.g., higher risk of preterm birth in multiple pregnancies). Further possible conflicts in reproductive medicine arise because of the crossing of moral boundaries (oocyte donation for postmenopausal women, surrogacy, cloning of human beings). The framework of counseling is based on the guidelines of the German Medical Association (Bundesarztekammer) for assisted reproduction (2006). Preimplantation genetic diagnosis has special requirements from a medical and psychosocial point of view. PMID- 22936483 TI - [The physician's role in various clinical contexts. The physician's role in palliative care]. AB - The palliative care physician accompanies patients and their families in times of great disstress and potentially difficult medico-ethical decision making. The main objective of palliative care is the alleviation of pain and distressing symptoms in patients with progressive, incurable illness. By addressing physical problems and psychosocial as well as spiritual needs, palliative care aims at improving the quality of life of patients in order to help them to spend their remaining lifetime with as much autonomy as possible and in dignity. The concept of accompaniment in palliative care involves a multiprofessional team. Important factors in this approach are time, trust, professional, ethical, communicative, social, and emotional competencies and the attitude of physicians and other professionals. The physician is given responsibility by the patient. In accepting the role as a respondent to another individual's request for help, the physician can avoid the pitfalls of the obsolete paternalistic relationship model, or of one that is either merely autonomy based or of a provider-customer nature. PMID- 22936484 TI - [The role of caregivers in health care. Historical backgrounds and current conflict situations]. AB - As a result of recent demographic developments, there has been an increased demand for high-quality health care. Among the various health professions, caregiving represents the largest professional group, numbering approximately 820,000 caregivers. Despite its size, this group is failing to meet basic conditions in line with international standards that secure adequate care. This failing is primarily due to the special path that Germany took regarding healthcare at the end of the nineteenth century and on which it continues to this day. It manifests itself in a heteronomy to which the professional group is permanently subjected by lobbies and policies that view health care from a perspective whose primary aim is to reduce unemployment. The present lack of organization of caregivers has frustrated their political assertiveness; and not least because of this, many caregivers leave the profession early. The profession itself is grappling with its professional identity. The development of expert standards, research into care, ethical reflections, as well as the struggle for common professional training are positive signs in this ongoing debate and are reflected in the positive feedback received from patients. The interdisciplinary dialogue between caregivers and physicians is in need of improvement. The first signs of progress are evident within the framework of health care ethics committees. This dialogue would certainly benefit both the professional group as well as the patients. PMID- 22936485 TI - [Cross-cultural aspects of interaction and communication in mental health care. Barriers and recommendations for action]. AB - Mental health care for migrants is often impaired by a lack of policies and provisions in the respective institutions. This article focuses on "communication barriers" in psychosocial and psychotherapeutic settings, where personal communication is of great importance. Barriers that prevent migrants from using health care institutions include translation problems but also more complex misunderstandings based on divergent explanations regarding the causes, course, and adequate treatment of different disorders. The widely recommended intercultural opening of medical and psychosocial institutions involves using interpreters as cultural experts, reflecting on and mediating between divergent explanatory models, and avoiding cultural and ethnic stereotyping as well as encouraging an open, curious, and reflective professional attitude. With respect to institutional settings, rules for the financing of interpreters are as important as tackling barriers that limit migrants' access to medical and psychosocial institutions. PMID- 22936486 TI - [Physician-patient communication in medical education: can it be learned?]. AB - Based on a review of recent key articles, this paper demonstrates that many elements of physician-patient communication can be learned successfully during medical education. Methods of assessment and definition of success depend largely on the definition of teaching goals, which are usually based on the principles of a more egalitarian and non-paternalistic physician-patient communication. In this article another approach is suggested. Teaching objectives in patient-physician communication can also be deduced from the needs of clinical medicine, resulting in the following goals: students are able to gather relevant data from patients' history, they explicitly structure the consultation and the way they give information, they know how to respond to patients' emotions. The Objective Standardised Clinical Examination (OSCE) is discussed with its strengths and weaknesses. The inclusion of video-based feedback is presented as a teaching tool to improve students' self-reflection. Workplace-based assessment and Mini-CEX are promising educational tools that require a well-trained faculty, not only in the teaching and practice of communication but also in the art of giving constructive and yet honest feedback. PMID- 22936487 TI - [Customer and patient satisfaction. An appropriate management tool in hospitals?]. AB - Recently, the concept of patient satisfaction has been established as an essential part of the quality management of hospitals. Despite the concept's lack of theoretical and methodological foundations, patient surveys on subjective hospital experiences contribute immensely to the improvement of hospitals. What needs to be considered critically in this context is the concept of customer satisfaction for patients, the theoretical integration of empirical results, the reduction of false satisfaction indications and the application of risk-adjusted versus naive benchmarking of data. This paper aims to contribute to the theoretical discussion of the topic and to build a basis for planning methodologically sound patient surveys. PMID- 22936488 TI - [Indoor air guide values for ethylbenzene]. AB - The German Working Group on Indoor Guidelines of the Federal Environment Agency and the States' Health Authorities is issuing indoor air guide values to protect public health. No human studies are available for health evaluation of ethylbenzene in indoor air. In a well documented subchronic inhalation animal study assessed as reliable, ototoxic effects were observed (LOAECsubchronic = 870 mg/m3). The Working Group assessed a LAEC of 186 mg ethylbenzene/m3 for the endpoint ototoxicity. By applying a factor of 2 to extrapolate from subchronic to chronic exposure, an interspecies factor of 2.5, a factor of 10 for interindividual variability, and a factor of 2 to account for the higher respiratory rate of children compared to adults, a health hazard guide value (RW II) of 2 mg ethylbenzene/m3 is obtained. A precautionary guide value (RW I) of 0.2 mg ethylbenzene/m3 is recommended. PMID- 22936489 TI - [Indoor air guide values for C9-C15 alkylbenzenes]. AB - The German Ad-hoc Working Group on Indoor Guidelines of the Indoor Air Hygiene Committee and of the Supreme State Health Authorities is issuing indoor air guide values to protect public health. The data base of human studies is insufficient for the health evaluation of C9-C15-alkylbenzenes in indoor air. Therefore, indoor air guide values are based on animal studies with inhalation exposure to individual alkylbenzenes. The guide values are derived from a chronic inhalation study with isopropylbenzene in rats, in which toxic effects in the nasal respiratory epithelium were observed. A BMCL10 of 370 mg/m3 was calculated. Extrapolation to continuous exposure, applying an interspecies factor of 2.5, a factor of 10 for interindividual variability, and a factor of 2 to account for the higher respiratory rate of children compared to adults, a health hazard guide value (RW II) of 1 mg isopropylbenzene/m3 indoor air is obtained. A health precaution guide value of 0.1 mg isopropylbenzene/m3 indoor air is recommended. Same values were derived on the basis of toxic effects of trimethylbenzenes; the data base is insufficient for the derivation of specific indoor air guide values for higher alkyl benzenes. Therefore, the Ad-hoc Working Group is issuing the indoor air guide values for the sum of C9-C15 alkylbenzenes. PMID- 22936490 TI - [Substance monograph on bisphenol A (BPA) - reference and human biomonitoring (HBM) values for BPA in urine. Opinion of the Human Biomonitoring Commission of the German Federal Environment Agency (UBA)]. AB - Bisphenol A (BPA) is used for the production of polycarbonates and synthetic resins. Many of the items that contain BPA, for example polycarbonate bottles and coated cans, are commodities from which BPA can migrate into food and drinks, resulting in ubiquitous exposure of the population. Numerous animal studies and in vitro tests have shown that BPA acts as an "endocrine disruptor". Because of the still incomplete understanding of the complex and contradictory effects of BPA at doses below the NOAEL, the toxicological significance of recent findings is uncertain. The German HBM Commission takes notice that the risk assessment is currently in flux and that in the EU and other countries precautionary bans on BPA have been introduced. In the light of the extensive and growing body of literature, the Commission does not see itself in a position to resolve this controversy, nor to answer the question of the relevance of observed effects of low BPA doses on human health. The Commission has derived reference values (RV95) and TDI-based HBM I values for total BPA in urine. The RV95 values are 30 MUg/l for 3-5 year olds, 15 MUg/l for 6-14 year olds, and 7 MUg/l for 20-29 year olds. The HBM I value for children is 1.5 mg/l and 2.5 mg/l for adults, respectively. The Commission emphasizes that the HBM values will require immediate adjustment should the current TDI of 0.05 mg/kg bw/day be changed. For the practical application of HBM, the Commission recommends an assessment based on the RV95. Confirmed exceedance of the RV95 by repeat measurements should prompt a search for the possible source(s), following the ALARA principle. PMID- 22936492 TI - An arsenic fluorescent compound as a novel probe to study arsenic-binding proteins. AB - Arsenic-binding proteins are under continuous research. Their identification and the elucidation of arsenic/protein interaction mechanisms are important because the biological effects of these complexes may be related not only to arsenic but also to the arsenic/protein structure. Although many proteins bearing a CXXC motif have been found to bind arsenic in vivo, new tools are necessary to identify new arsenic targets and allow research on protein/arsenic complexes. In this work, we analyzed the performance of the fluorescent compound APAO-FITC (synthesized from p-aminophenylarsenoxide, APAO, and fluorescein isothiocyanate, FITC) in arsenic/protein binding assays using thioredoxin 1 (Trx) as an arsenic binding protein model. The Trx-APAO-FITC complex was studied through different spectroscopic techniques involving UV-Vis, fluorescence, atomic absorption, infrared and circular dichroism. Our results show that APAO-FITC binds efficiently and specifically to the Trx binding site, labeling the protein fluorescently, without altering its structure and activity. In summary, we were able to study a protein/arsenic complex model, using APAO-FITC as a labeling probe. The use of APAO-FITC in the identification of different protein and cell targets, as well as in in vivo biodistribution studies, conformational studies of arsenic-binding proteins, and studies for the design of drug delivery systems for arsenic anti-cancer therapies, is highly promising. PMID- 22936493 TI - Concepts and definitions for "supportive care," "best supportive care," "palliative care," and "hospice care" in the published literature, dictionaries, and textbooks. AB - PURPOSE: Commonly used terms such as "supportive care," "best supportive care," "palliative care," and "hospice care" were rarely and inconsistently defined in the palliative oncology literature. We conducted a systematic review of the literature to further identify concepts and definitions for these terms. METHODS: We searched MEDLINE, PsycInfo, EMBASE, and CINAHL for published peer-reviewed articles from 1948 to 2011 that conceptualized, defined, or examined these terms. Two researchers independently reviewed each citation for inclusion and then extracted the concepts/definitions when available. Dictionaries/textbooks were also searched. RESULTS: Nine of 32 "SC/BSC," 25 of 182 "PC," and 12 of 42 "HC" articles focused on providing a conceptual framework/definition. Common concepts for all three terms were symptom control and quality-of-life for patients with life-limiting illness. "SC" focused more on patients on active treatment compared to other categories (9/9 vs. 8/37) and less often involved interdisciplinary care (4/9 vs. 31/37). In contrast, "HC" focused more on volunteers (6/12 vs. 6/34), bereavement care (9/12 vs. 7/34), and community care (9/12 vs. 6/34). Both "PC" and "SC/BSC" were applicable earlier in the disease trajectory (16/34 vs. 0/9). We found 13, 24, and 17 different definitions for "SC/BSC," "PC," and "HC," respectively. "SC/BSC" was the most variably defined, ranging from symptom management during cancer therapy to survivorship care. Dictionaries/textbooks showed similar findings. CONCLUSION: We identified defining concepts for "SC/BSC," "PC," and "HC" and developed a preliminary conceptual framework unifying these terms along the continuum of care to help build consensus toward standardized definitions. PMID- 22936494 TI - Parental emotional functioning declines with occurrence of clinical complications in pediatric hematopoietic stem cell transplant. AB - PURPOSE: Parents' stress levels are high prior to their child's hematopoietic stem cell transplant (HSCT) and during transplant hospitalization, usually abating after discharge. Nevertheless, a subgroup of parents continues to experience frequent anxiety and mood disruption, the causes of which are not well understood. The purpose of this study was to assess whether clinical complications of HSCT could explain variation in parents' recovery of emotional functioning. METHODS: Pediatric HSCT recipients (n = 165) aged 5-18 and their parents were followed over the first year post-transplant. Health-related quality of life assessments and medical chart reviews were performed at each time period (baseline, 45 days, 3, 6, and 12 months). We tested the association between clinical complications [acute and chronic graft versus host disease (aGVHD and cGVHD), organ toxicity, and infection] and longitudinally measured parental emotional functioning, as assessed by the Child Health-Ratings Inventories. The models used maximum likelihood estimation with repeated measures. RESULTS: In adjusted analyses covering the early time period (45 days and 3 months), aGVHD grade >=2, intermediate or poor organ toxicity, and systemic infection were associated with decreases in mean parental emotional functioning of 5.2 (p = 0.086), 5.8 (p = 0.052), and 5.1 (p = 0.023) points, respectively. In the later time period (6 and 12 months), systemic infection was associated with a decrease of 20 points (p < 0.0001). cGVHD was not significantly associated. CONCLUSIONS: When children experience clinical complications after HSCT, parental emotional functioning can be impacted. Intervening at critical junctures could mitigate potential negative consequences for parents and their children. PMID- 22936495 TI - Health-related quality of life and inflammatory markers in malignant pleural mesothelioma. AB - PURPOSE: Malignant pleural mesothelioma (MPM) is a highly aggressive and symptomatic disease. We examined the relationship between health-related quality of life (HRQoL) and inflammatory markers, and the prognostic role of HRQoL in MPM patients. METHODS: MPM patients from two parallel phase II studies (thalidomide alone or thalidomide with chemotherapy) were included. HRQoL was assessed at baseline using the modified Lung Cancer Symptom Scale (LCSS). Baseline inflammatory markers and cytokines were measured. Spearman correlation was used to examine the relationship between inflammatory markers and HRQoL measures. The prognostic value of the HRQoL domains was examined using Cox proportional hazard model. RESULTS: Sixty-three patients were included: median age 61 years (range 44 79); 82% male; 77% Eastern Cooperative Oncology Group (ECOG) performance status 0 1; 44% epithelial histology subtype. Baseline systemic symptoms of anorexia and fatigue, the summation symptoms of overall symptomatic distress, interference with normal activity and global QoL and the aggregate score of total LCSS score were all associated with elevated neutrophil-to-lymphocyte ratio, C-reactive protein and vascular endothelial growth factor levels at baseline (rho >= 0.25; p < 0.05). Baseline anorexia, fatigue, cough, dyspnoea, pain, overall symptomatic distress, interference with normal activity, global QoL and total LCSS score were all significantly related to survival (p < 0.05) after adjusting for established prognostic factors (age, gender, histological subtype and performance status) and treatment effect. CONCLUSIONS: In conclusion, HRQoL seems to relate to a patient's systemic inflammatory status and is associated with survival in MPM patients. PMID- 22936496 TI - Analysis of the risk factors for myelosuppression after concurrent chemoradiotherapy for patients with advanced non-small cell lung cancer. AB - PURPOSE: Myelosuppression induced by concurrent chemotherapy and radiotherapy can be a significant problem in patients with non-small cell lung cancer (NSCLC), but its risk factors remain largely unknown. The objective of this study was to retrospectively evaluate clinical data obtained before chemoradiotherapy (CRT) to identify the risk factors for myelosuppression in patients with advanced NSCLC. METHODS: Between January 2007 and January 2012, 141 patients with advanced NSCLC were treated with curative intent according to the CRT protocol (50-70 Gy at 2 Gy/day with paclitaxel 135-175 mg/m(2) and carboplatin 100 mg/m(2) on days 1, 22, and 43). The endpoint of this survey was the occurrence of grade 3 or higher myelosuppression (neutropenia, leukopenia, thrombocytopenia, or anemia). Risk factors significantly related to myelosuppression were extracted using logistic regression analysis. RESULTS: Grade 3 or higher neutropenia, leukopenia, thrombocytopenia, or anemia occurred in 19.9, 16.3, 14.9, and 0% of the patients, respectively. According to the multivariate analysis, the risk factors included age, albumin, and body surface area (BSA) for neutropenia; performance status and bone metastases for leukopenia; and age, gender, and serum creatinine concentration for thrombocytopenia (p < 0.05). CONCLUSIONS: It was found that age, BSA, creatinine level, and female gender were the most important factors for CRT-induced myelosuppression in advanced NSCLC. By identifying these risk factors, medical staff can improve application of appropriate medical care to reduce the myelosuppression in advanced NSCLC patients treated by CRT. PMID- 22936498 TI - Effect of storage temperature on gentamicin release from antibiotic-coated bone chips. AB - Freezing is the most common method for storing bones until use in skeletal reconstruction. However, the effect of freezing on antibiotic delivery from antibiotic-coated bone has not been evaluated. In this study, we compared antibiotic delivery in vitro from gentamicin-coated human bone stored at different temperatures. Bone chips obtained from human femur heads were chemically cleaned and mixed with gentamicin sulfate. Samples were stored for 4 months at -20 degrees C, 4 months at -80 degrees C, or evaluated immediately without freezing. Antibiotic release from the bone chips was measured using Bacillus subtilis as an indicator strain. Zones of inhibition and rates of gentamicin release were similar in all three groups. Storage at -20 and -80 degrees C for bone allografts has no effect on gentamicin release from chemically cleaned bone chips. PMID- 22936497 TI - Use of reverse genetics to develop a novel marker porcine reproductive and respiratory syndrome virus. AB - Nucleocapsid (N) protein of porcine reproductive and respiratory syndrome virus (PRRSV) is the most abundant viral structural protein with high immunogenicity. Previously, the nonessential sequences for virus infectivity were identified at both N and C terminal ends of N protein. Here, by means of reverse genetics, a marker virus (v7APMa) was generated with a mutant N protein that differs from the wild-type strains (vAPRRS, type 2 PRRSV). v7APMa shows stable inheritance in cell culture and the virologic characteristics of the marker virus in vitro showed that v7APMa replicates well as its parental strain. In the pig model, the v7APMa marker virus induced a similar level of anti-N protein antibodies and robust antibodies against the marker peptide, from 14 days post infection. In addition, a peptide-based ELISA was developed to detect the specific antibodies for the introduced 7APMa peptide. This approach, using a rationally designed marker virus, provides a new potential mutant basis for further development of PRRSV novel vaccines. PMID- 22936500 TI - Highly enantioselective alkenylation of cyclic alpha,beta-unsaturated carbonyl compounds as catalyzed by a rhodium-diene complex: application to the synthesis of (S)-pregabalin and (-)-alpha-kainic acid. PMID- 22936499 TI - Characterization of lactose utilization and beta-galactosidase in Lactobacillus brevis KB290, the hetero-fermentative lactic acid bacterium. AB - Unlike dairy lactic acid bacteria, Lactobacillus brevis cannot ferment milk. We characterized the lactose utilization by L. brevis KB290. In a carbohydrate fermentation assay using API 50 CHL, we showed during 7 days L. brevis did not ferment lactose. L. brevis grew to the stationary phase in 2 weeks in MRS broth containing lactose as the carbon source. L. brevis slowly consumed the lactose in the medium. L. brevis hydrolyzed lactose and a lactose analog, o-nitrophenyl-beta D-galactopyranoside (ONPGal). This beta-galactosidase activity for ONPGal was not repressed by glucose, galactose, fructose, xylose, or maltose showing the microorganism may not have carbon catabolite repression. We purified the L. brevis beta-galactosidase using ammonium sulfate precipitation and several chromatographies. The enzyme's molecular weight is estimated at 72 and 37 kDa using SDS-PAGE analysis. The N-terminal amino acid sequence of the larger protein was 90 % similar to the sequence of the putative beta-galactosidase (YP_796339) and the smaller protein was identical to the sequence of the putative beta galactosidase (YP_796338) in L. brevis ATCC367. This suggests the enzyme is a heterodimeric beta-galactosidase. The specific activity of the purified enzyme for lactose is 55 U/mg. We speculate inhibition of lactose transport delays the lactose utilization in L. brevis KB290. PMID- 22936502 TI - Localisation of sentinel lymph nodes in patients with melanomas by planar lymphoscintigraphic and hybrid SPECT/CT imaging. AB - BACKGROUND: The aim of the study was to assess the role of planar lymphoscintigraphy and fusion imaging of SPECT/CT in sentinel lymph node (SLN) identification in patients with melanomas. MATERIAL AND METHODS: Planar and hybrid SPECT/low-dose CT lymphoscintigraphy were performed in 113 consecutive patients with melanomas (59 men, 54 women, mean age 57.6 with range 11-87 years, BMI 29.4 +/- 12.5). The radiopharmaceutical was injected around the tumour (Group A, 59 patients), or around the scar (Group B, 54 patients). Localisation of melanomas: head and neck 4, trunk 55, upper extremities 28, lower extremities 26. Planar and SPECT/CT images were interpreted separately by two nuclear medicine physicians. Abilities of these two techniques to image SLN were compared. RESULTS: SLNs were detected on lymphoscintigraphy comprising planar and SPECT-CT images in 108 (95.6%) study patients; there was failure to detect SLNs in the remaining 5 (4.4%) patients. Planar images identified 253 SLNs in 100 (88.5%) pts, with a mean of 2.2 +/- 1.7 (range 0-9 nodes) per patient. In the remaining 13 (11.5%) patients no SLNs were detected on planar images. On SPECT-CT images, 334 hot nodes were detected in 107 (94.7%) patients with a mean of 3.0 +/- 2.1 (range 0-9) nodes per patient. In the remaining 6 (5.3%) patients, SPECT-CT was negative. SPECT/CT visualised lymphatic drainage in 8 (7.1%) patients with non visualisation on planar imaging. CONCLUSIONS: In some patients with melanomas SPECT/CT improves detection of sentinel lymph nodes. It can image nodes not visible on planar scintigrams, exclude false positive uptake and exactly localize SLNs. PMID- 22936501 TI - Comparison of chromatographic methods for quality control of DMSA complexes with 99mTc and 188Re at (III) and (V) oxidation states. AB - BACKGROUND: The reliable method for determination of identity and radiochemical purity (RCP) is of great importance in radiopharmaceutical development. This is especially relevant when more than one form of radiometal/ligand complex can be formed during radiolabelling, such as complexes of 99mTc or 188Re with meso-2,3 dimercaptosuccinic acid (DMSA), where depending on the pH, metal can occur either at +3 or +5 oxidation state. The aim of our study was to evaluate possibilities for optimization of chromatographic systems leading to specific and reliable analytical method for determination of the identity and RCP of DMSA complexes with 99mTc or 188Re. MATERIAL AND METHODS: The commercial DMSA kits (POLATOM) were used for preparation of technetium-99m (III) and (V) complexes with DMSA. 99mTc(V)-DMSA complexes were prepared by addition of NaHCO3 to the kit vial prior to 99mTc-eluate to obtain pH ~8. 188Re(V)-DMSA was prepared either directly or using intermediate 188Re(III)-EDTA complex added to DMSA. RCP was evaluated by TLC using: ITLC-SG developed in methylethylketon, SG60 coated plates developed in: n-BuOH/H2O/CH3COOH and n-PrOH/H2O/CH3COOH systems, and in H2O. Comparative biodistribution studies were performed in normal Wistar rats. RESULTS: Using silica gel plates and n-PrOH, H2O and acetic acid in the developing solution, we observed that 99mTc/188Re(III)-DMSA and 99mTc/188Re(V)-DMSA complexes could be well separated from each other and from the impurities in the form of free pertechnetate/perrhenate. In vivo studies showed quite different biodistribution of 99mTc(III)- and 99mTc(V)-DMSA. The trivalent complex accumulated mainly in kidneys (>40%ID), while 99mTc(V)-DMSA revealed high excretion with urine and relatively high concentration in osseous tissue (ca. 2 %ID/g). Accumulation of this complex in kidneys was very low (ca. 2.5 %ID). Biodistribution pattern of 188Re(V)-DMSA prepared directly was almost identical to that of 99mTc(V)-DMSA. Biodistribution results of the 188Re preparation obtained using 188Re(III)-EDTA intermediate indicated that the preparation contained the mixture of penta- and trivalent 188Re complexes. The quite high accumulation of radioactivity in kidneys (23 %ID) gave evidence of the presence of 188Re(III)-DMSA in this preparation, what was also confirmed by the results of TLC analysis performed using silica gel plate and n-propanol/water/acetic acid as developing system. CONCLUSIONS: Based on our study, we have made recommendation on the suitable methods for investigations of RCP of DMSA complexes, i.e.: SG60 plates developed in the mixture of n-propanol/water/acetic acid, which enable determination of the tri- and pentavalent DMSA complexes, as well as, the pertechnetate/perrhenate impurity, and developed in water for determination of the colloidal residue. PMID- 22936503 TI - Recombinant human thyrotropin to help confirm lack of evidence of radiation induced differentiated thyroid cancer in young women seeking pregnancy. AB - BACKGROUND: Women with a history of differentiated thyroid carcinoma who are contemplating pregnancy may wish reassurance regarding apparent remission. However, the thyroid hormone withdrawal needed to obtain serum thyroglobulin testing (Tg) results in weeks-long biochemical and clinical hypothyroidism, which could increase miscarriage and fetal death rates if pregnancy occurred during withdrawal of thyroxine or soon thereafter. Recombinant human thyrotropin (rhTSH) elevates thyrotropin exogenously, allowing uninterrupted thyroid hormone therapy and avoids hypothyroidism. MATERIAL AND METHODS: Thirty female radiation-induced papillary thyroid carcinoma survivors who had undergone total- or near-total thyroidectomy and who were now seeking pregnancy (mean age 23.9 +/- 1.8 years), and who were considered cancer-free by local standards, underwent rhTSH-aided Tg testing to help confirm remission. At the time of rhTSH testing, mean follow-up after primary surgical treatment was 11.1 +/- 3.9 years, and all patients had negative neck ultrasonography, undetectable unstimulated serum Tg (< 0.2 ng/mL) and no interfering anti-Tg antibodies. However, based on T3, N1 or M1 status, 28/30 (93.3%) patients had high recurrence risk. RESULTS: rhTSH produced no serum Tg increase in 27/30 women (90.0%). Serum Tg increases to 0.4-0.9 ng/ml were observed in 3 women, but careful neck ultrasonography found no lymphadenopathy. Reassured about their remission, 14/30 women (46%) have become pregnant and delivered healthy children in the 3 years since rhTSH-aided testing. CONCLUSIONS: rhTSH-aided Tg testing is useful in confirming absence of tumor in female patients with a history of radiation-induced thyroid cancer who are seeking pregnancy, but who also have a high risk of thyroid cancer recurrence. PMID- 22936504 TI - Nuclear medicine in the diagnosis of benign thyroid diseases. AB - Thyroid gland has the unique ability to concentrate iodine. This phenomenon offers a perfect background for a wide range of diagnostic tests utilizing radioactive iodine nuclides of iodine and technetium. Despite the very good availability of ultrasonography and other imaging modalities, radionuclide methods are still inevitable in a various cases of thyroid disease. In this article, a comprehensive review of all these methods used in the diagnosis of benign thyroid diseases is presented. Iodine and technetium uptake tests are briefly described. Indications to thyroid scan in the context of iodine supply are also presented. Finally, the significance of thyroid findings in PET images is pointed out. The article is illustrated by some typical patterns of radionuclide thyroid images. PMID- 22936505 TI - Iodine-131 for therapy of thyroid diseases. Physical and biological basis. AB - Iodine-131 is successfully used in the treatment of hyperthyroidism and differentiated thyroid cancer. Thyroid is the critical organ for iodine. Iodine is taken up by the thyroid follicular cells. Radioactive isotope iodine-131 simultaneously emits two types of radiation: radiation beta minus (beta-) used for the treatment and gamma (gamma) used for diagnosis. Due to the penetration of beta particles in tissue, damaging effect of beta-radiation is restricted to thyroid cells. In this article, characteristic of iodine-131, mechanism of action and mechanism of tissue damage is presented. HIGH energy gamma-ray emission, contributes to the dose of both: patient's body and the personnel. In accordance with the principles of radiation protection, reducing exposure to ionizing radiation should be achieved by: use of proper shieldings, organization of work, appropriate distance from the radiation source and reducing the time of exposure. Treatment with I-131, depending on medical indications, may be carried out on stationary or outpatient basis. All activities conducted in the exposure to radiation must comply with the principles of radiation protection, in accordance with the applicable regulations, that are also presented in this article. PMID- 22936506 TI - Bone scan in metabolic bone diseases. Review. AB - Metabolic bone disease encompasses a number of disorders that tend to present a generalized involvement of the whole skeleton. The disorders are mostly related to increased bone turnover and increased uptake of radiolabelled diphosphonate. Skeletal uptake of 99mTc-labelled diphosphonate depends primarily upon osteoblastic activity, and to a lesser extent, skeletal vascularity. A bone scan image therefore presents a functional display of total skeletal metabolism and has valuable role to play in the assessment of patients with metabolic bone disorders. However, the bone scan appearances in metabolic bone disease are often non-specific, and their recognition depends on increased tracer uptake throughout the whole skeleton. It is the presence of local lesions, as in metastatic disease, that makes a bone scan appearance obviously abnormal. In the early stages, there will be difficulty in evaluating the bone scans from many patients with metabolic bone disease. However, in the more severe cases scan appearances can be quite striking and virtually diagnostic. PMID- 22936507 TI - Comparison between Impact factor, SCImago journal rank indicator and Eigenfactor score of nuclear medicine journals. AB - Despite its widespread acceptance in the scientific world, impact factor (IF) has been criticized recently on many accounts: including lack of quality assessment of the citations, influence of self citation, English language bias, etc. In the current study, we evaluated three indices of journal scientific impact: (IF), Eigenfactor Score (ES), and SCImago Journal rank indicator (SJR) of nuclear medicine journals. Overall 13 nuclear medicine journals are indexed in ISI and SCOPUS and 7 in SCOPUS only. Self citations, Citations to non-English articles, citations to non-citable items and citations to review articles contribute to IFs of some journals very prominently, which can be better detected by ES and SJR to some extent. Considering all three indices while judging quality of the nuclear medicine journals would be a better strategy due to several shortcomings of IF. PMID- 22936508 TI - Case report of a patient with initially inoperable well-differentiated midgut neuroendocrine tumor (WDNT)--PRRT and long-acting somatostatin analogs as the neoadjuvant therapy. AB - A 43-year-old man was admitted to Surgery Department because of abdominal pain, vomiting, weight loss and flushes. Computed tomography (CT) examination revealed upper and middle abdomen tumor of about 110 * 110 mm. Histopathological analysis of the tissues obtained during the exploratory laparotomy confirmed WDNT (well differentiated neuroendocrine tumor according to the WHO classification 2000). The patient received 5 doses of chemotherapy without any response. A positive result of 99mTc-[EDDA/Hynic] Octreotate scintigraphy (SRS) gave the possibility of PRRT (peptide receptor radionuclide therapy). The patient was treated with the total dose of 400 mCi of 90Y-DOTA-TATE. CT performed after the PRRT revealed regression of the tumor size to 72 * 94 mm. A decrease of CgA level and release of symptoms were also observed. Aiming at the removal of the considerable diminished tumor the patient was qualified for the second laparotomy. "Cytoreduction" surgery with partial excision of the tumor was performed. Additionally tumor-affected appendix was removed. The second focus of WDNT (according to the WHO classification 2000) with Ki67 < 1% was found in the appendix. Pathologists confirmed the above-mentioned lesions as independent (an extremely rare clinical situation). The following treatment with long-acting somatostatin analogs and 300 mCi of 90Y-DOTA-TATE resulted in further regression of the tumor size to 25 * 35 mm. Consecutive laparotomy is considered. If complete tumor removal might be achieved is an open question. The above case report shows the efficacy of combined therapy with the use of "hot" and "cold" somatostatin analogs not only in controlling the symptoms of the disease but also in obtaining tumor size regression making surgical intervention possible. Such a neoadjuvant therapy seems to be a promising tool in the management of patients with initially inoperable neuroendocrine tumors. PMID- 22936510 TI - Rate dependent left bundle branch block: the pattern of myocardial perfusion SPECT. AB - We report myocardial perfusion SPECT pattern in four subsequent patients with rate dependent left bundle branch block (LBBB). Three females and one male (aged 48, 51, 63 and 67 years) were studied. None of the patients had history of typical chest pain and all suffered from atypical chest pain or dyspnea on exertion. All patients were tested for baseline and serial heart rate, blood pressure, and electrocardiogram recordings. The exercise treadmill tests (ETT) were carried out under the strict supervision of a cardiologist, a nuclear medicine physician and close availability of an expert cardio-pulmonary resuscitation team and cardiac care unit within just few seconds. Maximal stress test (at least 85% of calculated heart rate, following development of LBBB) was achieved in all four patients according to standard Bruce protocol. No adverse cardiac events were noted and all ETT stress protocols terminated completely and safely. Myocardial perfusion SPECT imaging showed no evidence of reversible perfusion defects. The only patient with past history of exercise induced LBBB showed nonreversible perfusion defects in the septal and anteroseptal regions and mild LV cavity dilatation. The limited number of patients enrolled in our study does not allow us to draw a definite conclusion. Despite the presence of false positive defects in myocardial perfusion SPECT in patients with sustained LBBB, such a finding is not a consistent finding in patients with rate dependent or exercised-induced LBBB, unlike that which we expected to see. Maybe it is possible to continue ETT for those patients undergoing myocardial perfusion scintigraphy and developing rate dependent LBBB. PMID- 22936511 TI - Primary breast non-Hodgkin lymphoma. A report of an unusual case. AB - Although lymphomas are generally considered as tumors of lymph nodes about 25-40% arise at extranodal sites. We report a case of a 60 years old female who developed a right breast B-diffuse large cell non-Hodgkin lymphoma in 2005 treated by chemo/radio-therapy which relapsed at the same breast in 2007 and at the other breast in 2010. The patient underwent both radiologic and nuclear medicine studies. PMID- 22936512 TI - Concurrent papillary thyroid cancer and parathyroid adenoma as a rare condition: a case report. AB - Although the pathological relationship between parathyroid and thyroid diseases is common, an association between parathyroid adenoma and thyroid cancer is rare. Concomitant thyroid cancer in patients with primary hyperparathyroidism (pHPT) has been reported at varying frequencies. WE present here a 23-year-old man who had papillary thyroid carcinoma in the right thyroid lobe and a parathyroid adenoma in the left thyroid lobe, which were confirmed surgically. PMID- 22936513 TI - Scientific Meeting Report Radiosynovectomy--radionuclide treatment of synovitis in the peripheral joints. AB - On 25 February 2012, an interdisciplinary scientific meeting on the Radiosynovectomy of Peripheral Joints (RPJ) was held in a lecture hall of Nukleomed clinic in Warsaw. PMID- 22936514 TI - Gdynia Oncology Centre of the Polish Red Cross Maritime Hospital in Gdynia Nuclear Medicine Department. AB - A new Nuclear Medicine Department has been opened in Gdynia. In October 2011, the construction and procuring equipment for the Nuclear Medicine Department (NMD) of the Polish Red Cross Maritime Hospital in Gdynia-Redlowo was completed after several years of efforts. PMID- 22936515 TI - The opening ceremony of the Radiopharmaceuticals Production and Research Centre at the Heavy Ion Laboratory of the University of Warsaw, May 15, 2012. Followed by an International Conference PETRAD2012. AB - Two important events happened at the Heavy Ion Laboratory of the University of Warsaw in May this year. First, on May 15 the new Radiopharmaceuticals Production and Research Centre (RPRC) was inaugurated by the Rector Elect, Prof. Marcin Palys. The construction of this Centre, located on the premises of the Laboratory, was supported by grants from the Ministry of Sciences, International Atomic Energy Agency, Ministry of Health and European Structural Funds. PMID- 22936516 TI - On 4 June 2012, modern PET/CT scanner was officially opened at University Hospital--report from the opening ceremony; Krakow (Poland). AB - On the 4th of June, the PET/CT center has been opened in Cracow. That hybrid system has been installed in Nuclear Medicine Center which is part of Endocrinology Department of University Hospital. This is one of the sixteen PET/CT scanners operate in whole Poland and first public hybrid equipment in province of Malopolska. PMID- 22936517 TI - Postharvest management affects spearmint and calamint essential oils. AB - BACKGROUND: The objectives of this work were to evaluate the phytomass yield, essential oil (EO) content and EO yield of Mentha spicata L. var. rubra, M. spicata L. var. viridis and Calamintha nepeta Savi in Piedmont (Italy), and to study how postharvest management (hydrodistillation of EO from fresh, dehumidified or oven-dried herbs) can affect the EO content and profile of the three species. RESULTS: Mentha spicata L. var. rubra gave the greatest phytomass yield (1997 g m(-2)), which was statistically different from M. spicata L. var. viridis and C. nepeta. The highest EO yield was obtained from C. nepeta (3.75 g m(-2)), which was significantly different from the Mentha genus. Postharvest management significantly affected both the EO content and the EO profile of each species, with the dehumidifying process leading to a significantly higher EO content than the oven-drying process. The EO profile was different not only from species to species but also because of the postharvest management. CONCLUSION: The dehumidifying process is a relatively new postharvest technology that has shown positive results in terms of EO yield, and it can be applied to species which have a high EO value, after evaluation of the resulting EO profile. PMID- 22936518 TI - Psychotic depression--beyond the antidepressant/antipsychotic combination. AB - Psychotic depression is an identified subtype of major depression that has many features of a distinct psychiatric disorder. Recent studies support previous findings that psychotic depression is associated with a less favorable course of illness. Moreover, the presence of a single psychotic symptom appears to predict decreased responsiveness to antidepressant monotherapy. Recent studies also support biological differences between psychotic and non-psychotic depression. Previous findings of greater HPA axis dysregulation are supported by evidence of diminished cortisol suppression with the mineralocorticoid antagonist fludrocortisone in psychotic depression. Moreover, a functional neuroimaging study demonstrated greater activation in parahippocampal and tempoparietal regions in psychotic depression during a memory task. In support of several previous treatment studies, a recent meta-analysis of studies that compared an antidepressant-antipsychotic combination to antidepressants or antipsychotics alone found a therapeutic advantage with the combined treatment over monotherapy. A recent clinical trial suggests that mifepristone, a glucocorticoid antagonist, may be an effective adjunctive treatment for psychotic depression. PMID- 22936520 TI - Association between elevated plasma norepinephrine levels and cardiac wall motion abnormality in poor-grade subarachnoid hemorrhage patients. AB - Patients with aneurysmal subarachnoid hemorrhage (SAH) are frequently complicated by acute cardiac dysfunctions, including cardiac wall motion abnormality (WMA). Massive release of catecholamine into the systemic circulation after aneurysmal rupture is believed to result in WMA, and poor-grade SAH seems to be the most important risk factor. However, plasma catecholamine levels have rarely been measured in SAH patients with WMA, and previous studies indicated that the elevated levels might not necessarily predict WMA. The objective of this study is (1) to evaluate relationship between WMA and plasma catecholamine levels in poor grade SAH patients in the acute phase and (2) to clarify clinical characteristics of SAH patients with WMA. Among 142 poor-grade (World Federation of Neurosurgical Societies grades IV and V) SAH patients, 48 underwent both transthoracic ultrasound and measurement of plasma catecholamine levels within 24 h of SAH onset. They were divided into WMA+ (n = 23) and WMA- (n = 25) groups, and intergroup comparison was made on demographics, plasma catecholamine levels, and outcomes. Plasma norepinephrine levels were significantly higher in WMA+ group than in WMA- group (2,098.4 +/- 1,773.4 vs. 962.9 +/- 838.9 pg/mL, p = 0.02), and the former showed significantly worse outcomes 90 days after admission. There were no intergroup differences in the plasma levels of epinephrine. Plasma norepinephrine levels were inversely correlated with left ventricular ejection fraction. Multivariate logistic regression analysis revealed that increased plasma norepinephrine levels were predictive of WMA, although age, female sex, and grade V SAH were not. This retrospective study highlights the role of norepinephrine in pathogenesis of SAH-induced WMA. PMID- 22936521 TI - Unconventional nucleation and oriented growth of ZIF-8 crystals on non-polar surface. AB - Zeolitic imidazolate framework-8 (ZIF-8) crystals show unconventionally selective nucleation and oriented growth on a patterned self-assembled monolayer (SAM) surface. The growth selectivity and crystal orientation are also affected by the odd-even effect for SAMs. The oriented growth of the ZIF-8 crystals is found to result from fast crystallization of the nuclei triggered by the specific SAM surfaces. PMID- 22936519 TI - A coordinate-based meta-analytic model of trauma processing in posttraumatic stress disorder. AB - Posttraumatic stress disorder (PTSD) has a well-defined set of symptoms that can be elicited during traumatic imagery tasks. For this reason, trauma imagery tasks are often employed in functional neuroimaging studies. Here, coordinate-based meta-analysis (CBM) was used to pool eight studies applying traumatic imagery tasks to identify sites of task-induced activation in 170 PTSD patients and 104 healthy controls. In this way, right anterior cingulate (ACC), right posterior cingulate (PCC), and left precuneus (Pcun) were identified as regions uniquely active in PTSD patients relative to healthy controls. To further characterize these regions, their normal interactions, and their typical functional roles, meta-analytic connectivity modeling (MACM) with behavioral filtering was applied. MACM indicated that the PCC and Pcun regions were frequently co-active and associated with processing of cognitive information, particularly in explicit memory tasks. Emotional processing was particularly associated with co-activity of the ACC and PCC, as mediated by the thalamus. By narrowing the regions of interest to those commonly active across multiple studies (using CBM) and developing a priori hypotheses about directed probabilistic dependencies amongst these regions, this proposed model-when applied in the context of graphical and causal modeling-should improve model fit and thereby increase statistical power for detecting differences between subject groups and between treatments in neuroimaging studies of PTSD. PMID- 22936522 TI - Influence of some environmental factors on drupe maturation and olive oil composition. AB - BACKGROUND: Understanding the relationships between olive cultivars and the cultivation environment as well as optimising cultivation choices can lead to maximum expression of oil production in terms of both quantity and quality. For this purpose, samples of the Ortice olive cultivar grown in two different environments in southern Italy at altitudes of 500 and 50 m above sea level (a.s.l.) were harvested on various dates to monitor drupe maturation and determine the nutritional and chemical characteristics of the oils. RESULTS: Fruits grown at 50 m a.s.l. ripened about 10-15 days earlier than those grown at 500 m a.s.l. The oil obtained at 500 m a.s.l. was characterised by a higher content of total polyphenols and a higher content of oleic and stearic acids. CONCLUSION: The different heat accumulation related to the environment affected drupe development as well as the colouring trend and oil content. Consequently, the growth environment changed the content of Ortice oil fatty acids and polyphenols, while the flavour profile remained fairly stable in both environments, with the cultivar effect prevailing over the environment factor. PMID- 22936523 TI - PCDD/F release during benthic trawler-induced sediment resuspension. AB - Benthic trawling can cause the resuspension of large amounts of sediments. Such regular practice in the Grenland fjord system in the south of Norway has the potential to affect the fate, movement, and bioavailability of sediment associated polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs). A novel mode of exposing passive sampling devices consisting of towing semipermeable membrane devices attached to the trawl net was used to gauge in situ changes in the freely dissolved concentration of PCDD/Fs on benthic trawler-induced sediment resuspension. Significant accumulation of a number of PCDD/F congeners was observed despite the short (5 h) sampler exposure times. On average, a one order of magnitude increase in freely dissolved PCCD/F concentrations was seen within minutes of the sediment being resuspended. This observation was supported by similar changes in filtered PCDD/F concentrations measured by high-volume sampling prior to resuspension and in the sediment plume. PMID- 22936525 TI - Surface topology engineering of membranes for the mechanical investigation of the tubulin homologue FtsZ. PMID- 22936524 TI - Self-monitoring as a mediator of weight loss in the SMART randomized clinical trial. AB - BACKGROUND: Integral components of behavioral weight-loss treatment include self monitoring of diet and physical activity along with feedback to participants regarding their behaviors. While providing feedback has been associated with weight loss, no studies have examined the impact of feedback frequency on weight loss or the mediating role of self-monitoring adherence in this relationship. PURPOSE: This study examined the effect of participant feedback frequency on weight loss and determined if this effect was mediated by adherence to self monitoring in a behavioral weight-loss trial conducted in the USA. METHOD: Participants (N = 210) were randomly assigned to one of three self-monitoring methods with either no-daily feedback messages or daily feedback messages: (1) paper diary (PD), no-daily feedback; (2) personal digital assistant (PDA), no daily feedback; and (3) PDA, daily tailored feedback messages (PDA + FB). The Sobel test via bootstrapping examined the direct effect of feedback frequency on weight loss and the indirect effect through self-monitoring adherence. RESULTS: Receiving daily feedback messages significantly increased participants' self monitoring adherence. A significant effect of feedback frequency on weight loss was noted; however, after adjusting for self-monitoring adherence, the effect of feedback frequency on weight loss was no longer significant. Feedback frequency had a significant indirect effect on weight loss through self-monitoring adherence. CONCLUSION: Self-monitoring adherence mediated the effect of feedback frequency on weight loss. Increasing the frequency with which participants receive feedback could enhance self-monitoring adherence, a critical component of behavioral weight-loss treatment. PMID- 22936526 TI - Ischemic changes associated with a large patent arterial duct in small infants. AB - Infants with a large patent arterial duct (PDA) may develop signs of congestive heart failure secondary to pulmonary overcirculation. As the PVR decreases, the relative pulmonary blood flow (Qp :Qs ) increases and this may cause tachypnea, respiratory distress, failure to thrive, ventricular dysfunction and even ventilator dependency. The diastolic runoff from the systemic circulation may result in intestinal hypoperfusion resulting in necrotizing enterocolitis, and in severe cases, myocardial ischemia. Cardiac ischemia due to coronary steal is a recognized clinical entity. We present two cases of infants who developed coronary artery steal with the use of supplemental oxygen therapy during anesthesia induction for PDA occlusion. These cases highlight the importance of prudent use of supplemental oxygen therapy in infants with large PDAs. PMID- 22936527 TI - Comparative biochemical characterization and in silico analysis of novel lipases Lip11 and Lip12 with Lip2 from Yarrowia lipolytica. AB - Novel lipases lip11 and lip12 from Yarrowia lipolytica MSR80 were cloned and expressed in E. coli HB101 pEZZ18 system along with lip2. These enzymes were constitutively expressed as extracellular proteins with IgG tag. The enzymes were purified by affinity chromatography and analyzed by SDS-PAGE with specific activity of 314, 352 and 198 U/mg for Lip2, Lip11 and Lip12, respectively on olive oil. Biochemical characterization showed that all were active over broad range of pH 4.0-9.0 and temperature 20-80 degrees C with optima at pH 7 and 40 degrees C. All the three lipases were thermostable up to 80 degrees C with varying t(1/2). Activity on various substrates revealed that they were most active on oils > triacylglycerides > p-np-esters. Relatively Lip2 and Lip11 showed specificity for mid to long chain fatty acids, while Lip12 was mid chain specific. GC analysis of triolein hydrolysis by these lipases revealed that Lip2 and Lip11 are regioselective, while Lip12 is not. Effect of metal ions showed that Lip2 and Lip12 were activated by Ca2+ whereas Lip11 by Mg2+. All were thiol activated and inhibited by PMSF and N-bromosuccinimide. All were activated by non polar solvents and inhibited by polar solvents. Detailed sequence analysis and structural predictions revealed Lip11 and Lip12 shared 61 and 62 % homology with Lip2 (3O0D) and three dimensional superimposition revealed Lip2 was closer to Lip11 than to Lip12 as was observed during biochemical characterization. Finally, thermostability and substrate specificity has been explained on the basis of detailed amino acid analysis. PMID- 22936528 TI - Intraabdominal abscess caused by actinomycosis in a patient with mesenteric fibromatosis of the small intestine: report of a case. AB - A 38-year-old man presented to our Emergency Department with acute severe abdominal pain; 3 days after, a mesenteric mass had been detected by abdomino pelvic computed tomography. Emergency laparotomy revealed a mesenteric mass with focal surface rupture. Microscopically, the mesenteric mass was composed of fibroblast-like spindle cells with intervening marked collagen deposits. These spindle cells were positive for nuclear beta-catenin and negative for CD34, c kit, smooth muscle actin, and S-100 protein. We diagnosed the mesenteric lesion as deep fibromatosis, consistent with mesenteric fibromatosis (MF). Serial sections of the ruptured portion showed abscess formation with a peripheral radiating pattern of microcolonies, proven to be actinomycosis by Grocott's methenamine silver stain and gram staining. One glandular fragment was found in the adhered muscle layers and a foreign body reaction was seen within the abscess cavity. We speculate that MF involved the serosal adhesions between the adjacent bowel walls and the subsequent fibrous pulling might have created the connection between the bowel lumen and the bowel wall. This disrupted barrier led to the Actinomyces infection. To our knowledge, this is the first report of sporadic MF leading to the formation of an abscess cavity with rupture and actinomycosis. PMID- 22936529 TI - The relationships among licensed nurse turnover, retention, and rehospitalization of nursing home residents. AB - PURPOSE: Individuals receiving postacute care in skilled nursing facilities often require complex, skilled care provided by licensed nurses. It is believed that a stable set of nursing personnel is more likely to deliver better care. The purpose of this study was to determine the relationships among licensed nurse retention, turnover, and a 30-day rehospitalization rate in nursing homes (NHs). DESIGN AND METHODS: We combined two data sources: NH facility-level data (including characteristics of the facility, the market, and residents) and the Florida Nursing Home Staffing Reports (which provide staffing information for each NH) for 681 Florida NHs from 2002 to 2009. Using a two-way fixed effects model, we examined the relationships among licensed nurse turnover rates, retention rates, and 30-day rehospitalization rates. RESULTS: Results indicate that an NH's licensed nurse retention rate is significantly associated with the 30-day rehospitalization rate (est. = -.02, p = .04) controlling for demographic characteristics of the patient population, residents' preferences for hospitalization, and the ownership characteristics of the NH. The NHs experiencing a 10% increase in their licensed nurse retention had a 0.2% lower rehospitalization rate, which equates to 2 fewer hospitalizations per NH annually. Licensed nurse turnover is not significantly related to the 30-day rehospitalization rate. IMPLICATIONS: These findings highlight the need for NH administrators and policy makers to focus on licensed nurse retention, and future research should focus on the measures of staff retention for understanding the staffing/quality relationship. PMID- 22936530 TI - Treatment outcomes of a crisis intervention program for dementia with severe psychiatric complications: the Kansas bridge project. AB - PURPOSE: Although declines in memory and attention are hallmark symptoms of Alzheimer's disease (AD), noncognitive symptoms are prevalent. Over 80% of individuals will experience neuropsychiatric symptoms, which complicates symptom profiles. Research indicates a community-integrated response to dementia crisis can reduce negative consequences attributed to crisis including increased caregiver burden, increased health care costs, and premature institutionalizations. DESIGN AND METHODS: The Kansas Dementia Crisis Bridge Project is a multidisciplinary collaboration to provide direct support in critical situations to reduce psychiatric rehospitalizations. Coordinators provided counsel and dementia education to families throughout critical period of acute neuropsychiatric symptoms, facilitated professional involvement, and provided crisis prevention planning through crisis review. The Neuropsychiatric Inventory Questionnaire and Geriatric Depression Scale were used to measure the impact of neuropsychiatric symptoms and Bridge interventions on patient and caregivers. RESULTS: The Bridge project significantly reduced patient anxiety, depression, resistance to care, impulsive behavior, verbal outbursts, and wandering. Caregivers reported significantly reduced anxiety, apathy, resistance to care, and less distress over patient neuropsychiatric symptoms. Caregivers also reported increased confidence in managing difficult behaviors, and the project effectively reduced or resolved neuropsychiatric crisis. The project delayed nursing home placement for community-dwelling patients. IMPLICATIONS: Crisis support models like the Bridge project reduce strain on care-delivery systems by incorporating nonpharmacological interventions, assisting families with communication, and reducing family distress during symptom crises. Although much of AD research focuses on disease-modifying medical interventions, aging and care systems in the state must simultaneously move towards dependency-modifying care interventions. PMID- 22936531 TI - Obesity among Kuwaitis aged 50 years or older: prevalence, correlates, and comorbidities. AB - OBJECTIVES: Obesity is a serious global health problem. Our objectives are to assess the prevalence of overweight and obesity among elderly Kuwaitis aged 50 or older, examine their sociodemographic correlates, and analyze the association between obesity and its comorbidities. METHODS: A cross-sectional face-to-face interview survey using a structured questionnaire was conducted among 2,443 Kuwaiti men and women aged 50 or older. Height and weight were measured and body mass index (BMI) was calculated. RESULTS: About 81% respondents were overweight of whom 46% were obese. Mean BMI was 30.0 (31.2 for women and 28.1 for men). Multinomial logistic regression analysis revealed that relatively young elderly Kuwaitis (50-59) were 1.7 and 2.2 times more likely to be overweight and obese, respectively, compared with those aged 70 or older. Married individuals had 2.3 times higher risk to be overweight or obese than non-married individuals. Women were 3.6 times more likely to suffer from obesity than men. Overweight and obesity were found to be independent risk factors for hypertension (OR = 1.3 and 1.9, respectively), diabetes (OR = 1.4), and osteoarthritis (OR = 1.8 and 1.6, respectively). CONCLUSIONS: Prevalence of overweight and obesity is alarmingly high among elderly Kuwaitis. The associated disease burden is substantial. Stakeholders should address the problem and launch national extensive health promoting campaigns targeting perceptible lifestyle changes. PMID- 22936532 TI - The preferences for everyday living inventory: scale development and description of psychosocial preferences responses in community-dwelling elders. AB - PURPOSE OF THE STUDY: Assessing preferences for daily life is the foundation for person-centered care delivery. This study tested a new measure, the Preferences for Everyday Living Inventory (PELI), with a large sample of community-dwelling older adults. We sought to evaluate the tool's convergent and divergent validity, identify the most commonly held preferences within the sample, and explore relationships between gender and race and strength of preferences. DESIGN AND METHODS: Randomly selected African American and Caucasian home health agency clients (N = 437) were interviewed using the PELI. Respondents self-reported functional ability, physical health, affect, mental health, and five domains of psychosocial preferences. The study examined correlations among descriptive variables and preference items and used logistic regression to estimate relationships between gender and race and 55 PELI items and 10 descriptive covariates. RESULTS: The study found support for the PELI's construct validity, identified seniors' most strongly held preferences across domains, and revealed significant differences in preferences by gender and race. IMPLICATIONS: The PELI captures strongly held personal preferences and shows promise as a practical tool that allows providers to document client preferences and customize care accordingly. PMID- 22936533 TI - Renovating Alzheimer's: "constructive" reflections on the new clinical and research diagnostic guidelines. AB - The development of disease concepts for conditions such as Alzheimer's disease (AD) is an ongoing social process that evolves over time. The biomedical paradigm about AD that has informed our culture's understanding of brain aging for the past several decades is currently undergoing a major and timely renovation in the early 21st century. This evolution is reflected in new guidelines issued by the National Institute on Aging and Alzheimer's Association (NIA/AA) for the diagnosis of AD and related conditions that aim at helping researchers identify and eventually treat AD in its presymptomatic stages. The purpose of this article is to offer the scientific, clinical, and ethics communities a critical analysis of the implications of proposed guidelines and prompt deeper reflection about the lessons learned from these new efforts both in terms of their actual content and the cultural context in which they were issued and will be used. From a social constructivist perspective, we explore the gradual 100-year evolution of AD and summarize the proposed NIA/AA guidelines within this historical context, enumerating what we see as their main benefits and limitations. We then consider the potential implications of these guidelines in the clinical setting, and explore shifts in our cultural paradigm about brain aging that might be engendered by the logic of the guidelines. PMID- 22936534 TI - "We're not just sitting on the periphery": a staff perspective of physical activity in older adults with schizophrenia. AB - Targeted physical activity interventions to improve the poor physical function of older adults with schizophrenia are necessary but currently not available. Given disordered thought processes and institutionalization, it is likely that older adults with schizophrenia have unique barriers and facilitators to physical activity. It is necessary to consider the perspective of the mental health staff about barriers and facilitators to physical activity to design a feasible intervention. PURPOSE OF THIS STUDY: To describe the perceptions of mental health staff about barriers and facilitators to engage in physical activities that promote physical function among older adults with schizophrenia. DESIGN AND METHOD: We conducted qualitative interviews with 23 mental health staff that care for older adults with schizophrenia. The data were collected and analyzed with grounded theory methodology. RESULTS: The participants were interested in promoting physical activity with older adults with schizophrenia. Facilitators and barriers to physical activity identified were mental health, role models and rewards, institutional factors, and safety. IMPLICATIONS: In order to design successful physical activity interventions for this population, the intervention may need to be a routine part of the mental health treatment program and patients may need incentives to participate. Staff should be educated that physical activity may provide the dual benefit of physical and mental health treatment. PMID- 22936535 TI - Insights into the experiences of older workers and change: through the lens of selection, optimization, and compensation. AB - PURPOSE: The study examined the barriers faced, the goals selected, and the optimization and compensation strategies of older workers in relation to career change. METHOD: Thirty open-ended interviews, 12 in the United States and 18 in New Zealand, were conducted, recorded, transcribed verbatim, and analyzed for themes. RESULTS: Barriers to finding and maintaining work included task difficulty, problems with coworkers and management, lack of self-confidence, health/physical limitations, ageism, and stereotyping. Respondents' most frequently selected goals for a new career were the desire to help others, work satisfaction, and acquisition of learning. Seventy-five percent of respondents in paid employment had earning an income as a goal. Optimization strategies included drawing on past experience, assessing skills, seeking careers/organizations that fitted their values, and a willingness to accept lower pay or unpaid work. Attitudinal strategies included focus and persistence, optimism, and positive attitudes toward change. The compensation strategies reported were on-the-job training; help from coworkers, clients, or customers; friends and family social support; and professional networks. Management practices considered helpful were flexible work schedules, supervisors' patience, and formal recognition of the value of older workers. CONCLUSION: This qualitative study, using the SOC framework, showed that evaluating one's skills and values, being positive about change, and being part of a supportive work environment were key contributors to adaptive competence. PMID- 22936536 TI - Training of lay health educators to implement an evidence-based behavioral weight loss intervention in rural senior centers. AB - PURPOSE OF THE STUDY: Lay health educators (LHEs) offer great promise for facilitating the translation of evidence-based health promotion programs to underserved areas; yet, there is little guidance on how to train LHEs to implement these programs, particularly in the crucial area of empirically validated obesity interventions. DESIGN AND METHODS: This article describes experiences in recruiting, training, and retaining 20 LHEs who delivered a 12 month evidence-based behavioral lifestyle intervention (based on the Diabetes Prevention Program) in senior centers across a rural state. A mixed method approach was used which incorporated collecting the folllowing: quantitative data on sociodemographic characteristics of LHEs; process data related to training, recruitment, intervention implementation, and retention of LHEs; and a quantitative program evaluation questionnaire, which was supplemented by a qualitative program evaluation questionnaire. Descriptive statistics were calculated for quantitative data, and qualitative data were analyzed using content analysis. RESULTS: The training program was well received, and the LHEs effectively recruited participants and implemented the lifestyle intervention in senior centers following a structured protocol. IMPLICATIONS: The methods used in this study produced excellent long-term retention of LHEs and good adherence to intervention protocol, and as such may provide a model that could be effective for others seeking to implement LHE-delivered health promotion programs. PMID- 22936537 TI - China: awakening giant developing solutions to population aging. AB - As the world's most populous country with the largest aging population and a rapidly growing economy, China is receiving increased attention from both the Chinese government and the governments of other countries that face low fertility and aging problems. This unprecedented shift of demographic structure has repercussions for many aspects of development including economic growth, social welfare, elder care, and other public welfare issues in China. Balancing population aging and economic growth requires innovative strategies and represents both challenges and opportunities for China. PMID- 22936538 TI - Understanding nursing home worker conceptualizations about good care. AB - This study explored how direct care workers in nursing homes conceptualize good care and how their conceptualizations are influenced by external factors surrounding their work environment and the relational dynamics between them and residents. Study participants were drawn from a local service employees' union, and in-depth interviews were conducted. Data were analyzed using a grounded theory approach, and the results revealed that direct care workers equated good care, such as resident cleanliness, comfort, and happiness as a desirable outcome of care activities. Good care also meant affectionate, respectful, and patient attitudes of direct care workers toward residents in care delivery processes. Nursing home workers internalized the perspectives of residents and other professionals about what constitutes good care, and then drew their own conclusions about how to balance, combine, and compromise those diverse demands. It is important to communicate accurate and consistent messages about what comprises good nursing home care to nursing home workers and build a working environment where workers' conceptualizations about good care can be executed without organizational barriers. PMID- 22936539 TI - Long-term outcome for ADL following the health-promoting RCT--elderly persons in the risk zone. AB - PURPOSE: To examine independence in activities of daily living (ADL) at the 1- and 2-year follow-ups of the health-promoting study Elderly Persons in the Risk Zone. DESIGN AND METHOD: A randomized, three-armed, single-blind, and controlled study. A representative sample of 459 independent and community-dwelling older adults, 80 years and older, were included. A preventive home visit was compared with four weekly multiprofessional senior group meetings including a follow-up home visit. RESULTS: Analysis showed a significant difference in favor of the senior meetings in postponing dependence in ADL at the 1-year follow-up (odds ratio [OR] = 1.92, 95% confidence interval [CI] = 1.19-3.10) and also in reducing dependence in three (OR = 0.52, 95% CI = 0.31-0.86) and four or more ADL (OR = 0.40, 95% CI = 0.22-0.72) at the 2-year follow-up. A preventive home visit reduced dependence in two (OR = 0.40, 95% CI = 0.24-0.68) and three or more ADL (OR = 0.37, 95% CI = 0.17-0.80) after 1 year. IMPLICATIONS: A long-term evaluation of Elderly Persons in the Risk Zone showed that both senior meetings and a preventive home visit reduced the extent of dependence in ADL after 1 year. The senior meetings were superior to a preventive home visit since additional significant effects were seen after 2 years. To further enhance the long-term effects of the senior meetings and support the process of self-change in health behavior, it is suggested that booster sessions might be a good way of reinforcing the intervention. PMID- 22936540 TI - Reclaiming joy: pilot evaluation of a mental health peer support program for older adults who receive Medicaid. AB - PURPOSE: Stigma and lack of access to providers create barriers to mental health treatment for older adults living in the community. In order to address these barriers, we developed and evaluated a peer support intervention for older adults receiving Medicaid services. DESIGN AND METHODS: Reclaiming Joy is a mental health intervention that pairs an older adult volunteer with a participant (older adult who receives peer support). Volunteers receive training on the strengths based approach, mental health and aging, goal setting and attainment, community resources, and safety. Participant-volunteer pairs meet once a week for 10 weeks. Participants establish and work toward goals (e.g., better self-care, social engagement) that they feel would improve their mental health and well-being. Aging services agencies provide a part time person to manage the program, match volunteers and participants, and provide ongoing support. Outcomes evaluation for this pilot study included pre/postintervention assessments of participants. RESULTS: Thirty-two participants completed the intervention. Pre/postassessment group means showed statistically significant improvement for depression but not for symptoms of anxiety. Quality-of-life indicators for health and functioning also improved for participants with symptoms of both depression and anxiety. IMPLICATIONS: The Reclaiming Joy peer support intervention has potential for reducing depression and increasing quality of life in low-income older adults who have physical health conditions. It is feasible to administer and sustain the intervention through collaborative efforts with minimal program resources and a small amount of technical assistance. PMID- 22936541 TI - Ecological theatre and the evolutionary game: how environmental and demographic factors determine payoffs in evolutionary games. AB - In the standard approach to evolutionary games and replicator dynamics, differences in fitness can be interpreted as an excess from the mean Malthusian growth rate in the population. In the underlying reasoning, related to an analysis of "costs" and "benefits", there is a silent assumption that fitness can be described in some type of units. However, in most cases these units of measure are not explicitly specified. Then the question arises: are these theories testable? How can we measure "benefit" or "cost"? A natural language, useful for describing and justifying comparisons of strategic "cost" versus "benefits", is the terminology of demography, because the basic events that shape the outcome of natural selection are births and deaths. In this paper, we present the consequences of an explicit analysis of births and deaths in an evolutionary game theoretic framework. We will investigate different types of mortality pressures, their combinations and the possibility of trade-offs between mortality and fertility. We will show that within this new approach it is possible to model how strictly ecological factors such as density dependence and additive background fitness, which seem neutral in classical theory, can affect the outcomes of the game. We consider the example of the Hawk-Dove game, and show that when reformulated in terms of our new approach new details and new biological predictions are produced. PMID- 22936542 TI - The cellular and molecular mechanisms by which insulin influences breast cancer risk and progression. AB - Epidemiological studies have related hyperinsulinemia and type 2 diabetes to an increased breast cancer risk, an aggressive and metastatic phenotype, and a poor prognosis. Furthermore, diabetic retinopathy arises from pathological angiogenesis, which is also essential for breast cancer growth and metastasis. Insulin stimulates the proliferation of some human breast cancer cell lines in vitro by mechanisms that use both the phosphatidylinositol-3 kinase and the mitogen-activated protein kinase/Akt signaling pathways; it is also a cell survival (anti-apoptotic) agent and enhances tumor cell migration and invasive capacity. Hyperinsulinemia affects breast cancer cells via the endocrine system, but experimental studies suggest the importance of paracrine mechanisms operating by the effects of insulin on the secretion of adipokines from tumor-associated adipose tissue. In such a system, one adipokine, leptin, has stimulatory paracrine effects on breast cancer cell proliferation and survival, while a second, adiponectin, is inhibitory. Leptin, vascular endothelial growth factor, another insulin-regulated adipokine, and insulin itself also stimulate angiogenesis. Insulin has complex interactions with estrogens: it induces adipose stromal cell aromatase and tumor cell sex steroid hormone receptor expression and suppresses sex hormone-binding globulin, which may enhance estrogen synthesis and bioactivity with consequent promotion of estrogen-dependent breast cancer. All these actions influence the later steps in breast cancer development but genetic studies are also revealing connections between gene abnormalities related to type 2 diabetes and the initiation stage of breast carcinogenesis. Understanding the various mechanisms by which insulin participates in breast cancer cell biology provides opportunities for novel approaches to treatment. PMID- 22936543 TI - New developments in the medical treatment of Cushing's syndrome. AB - Cushing's syndrome (CS) is a severe endocrine disorder characterized by chronic cortisol excess due to an ACTH-secreting pituitary adenoma, ectopic ACTH production, or a cortisol-producing adrenal neoplasia. Regardless of the underlying cause, untreated CS is associated with considerable morbidity and mortality. Surgery is the primary therapy for all causes of CS, but surgical failure and ineligibility of the patient to undergo surgery necessitate alternative treatment modalities. The role of medical therapy in CS has been limited because of lack of efficacy or intolerability. In recent years, however, new targets for medical therapy have been identified, both at the level of the pituitary gland (e.g. somatostatin, dopamine, and epidermal growth factor receptors) and the adrenal gland (ectopically expressed receptors in ACTH independent macronodular adrenal hyperplasia). In this review, results of preclinical and clinical studies with drugs that exert their action through these molecular targets, as well as already established medical treatment options, will be discussed. PMID- 22936544 TI - Kruppel-like factor 5 in human breast carcinoma: a potent prognostic factor induced by androgens. AB - Kruppel-like factor 5 (intestinal) or Kruppel-like factor 5 (KLF5) is a zinc finger-containing transcription factor and involved in important biological processes including cell proliferation and differentiation. However, clinical significance of KLF5 protein has remained largely unknown in breast cancer. Therefore, in this study, we immunolocalized KLF5 in 113 human breast carcinoma cases. KLF5 immunoreactivity was frequently detected in the nuclei of breast carcinoma cells, and median value of the ratio of KLF5-positive carcinoma cells was 30% and was positively associated with the status of androgen receptor. KLF5 immunoreactivity was also significantly associated with increased risk of recurrence and worse clinical outcome in breast cancer patients by univariate analyses, and subsequent multivariate analyses demonstrated that KLF5 immunoreactivity was an independent prognostic factor for both disease-free and breast cancer-specific survival of the patients. We then examined possible regulation of KLF5 by androgen using MCF-7 breast carcinoma cells. KLF5 mRNA was induced by biologically active androgen 5alpha-dihydrotestosterone in a dose- and time-dependent manner in MCF-7 cells. In addition, results of transfection experiments demonstrated that proliferation activity of MCF-7 cells was significantly associated with the KLF5 expression level. These findings suggest that KLF5 is an androgen-responsive gene in human breast carcinomas and play important roles in the progression of breast carcinomas. KLF5 immunoreactivity is therefore considered a potent prognostic factor in human breast cancers. PMID- 22936545 TI - Fine-needle aspiration of gray zone lesions of the breast: fibroadenoma versus ductal carcinoma. AB - While breast lesions have characteristic cytological features, some lesions, particularly adenocarcinoma and fibroadenoma, may present with overlapping features causing erroneous diagnoses. The current study aimed to define significant cytomorphologic features predictive of fibroadenoma and adenocarcinoma, respectively. Further, we intended to evaluate the predictive characteristics for differentiation between gray zone lesions and to identify root causes contributing to misdiagnoses. First, direct smears prepared from 14 histology-confirmed fibroadenomas and 14 adenocarcinomas were reviewed and characteristics of commonly encountered morphologic features were assessed. We then retrospectively and blindly reviewed nine cytohistologic discrepant cases using the significant characteristic as a guideline, in order to assess whether these discrepant cases could be correctly categorized. Morphologic characteristics predictive of fibroadenoma included moderate cellularity, large, folded cellular sheets/aggregates, staghorn projections, smooth and round borders, monolayers, honeycomb arrangement, smaller nuclear size, and background bipolar cells. Predictive characteristics of adenocarcinoma included high cellularity, loose cohesive sheets/aggregates, pointed projections, irregular borders, larger nuclear size, irregular nuclear membrane, prominent nucleoli, and single atypical epithelial cells. Retrospective, blind review correctly re classified seven out of nine cytohistologic discrepant cases, including five false negative cases and two false positive cases. Root causes contributing to the misdiagnoses were large branching sheets of carcinoma mimicking folded sheets of fibroadenoma; fibroblasts mimicking myoepithelial cells; apocrine cells mimicking carcinoma cells; and not recognizing the loose myxoid matrix presenting as soap bubbles in fibroadenoma. In conclusion, this study identified significant characteristics that can assist in achieving accurate diagnosis in a subpopulation of breast aspirates that present with overlapping features. PMID- 22936546 TI - Anatomical classification of the shape and topography of the operated stomach. AB - The aim of the study was to present the classification of anatomical variants of the operated stomach, based on radiological and historical data. Different anatomical variants of the operated organ were found in 431 out of 2034 patients examined in the years 2006-2010. Four main groups were established: abnormal position along longitudinal (I) and horizontal axis (II), as well as abnormal shape (III) and stomach connections (IV). An additional group (V) encloses mixed forms that combine features of two or more of the main groups. The first group contains the partial and total translocation of the stomach into the thoracic cavity after the partial or total oesophagectomy. Depending on the applied surgical techniques used during the total oesophagectomy, the stomach could be located anteriorly or posteriorly to the pericardial sac. An elongated and gastrectatic form often with signs of pylorostenosis is visible in patients treated by vagotomy. The consequences of fundoplication included: lack of or narrow cardiac angle, and often a mild form of stomach cascade. The most common abnormal shape of the stomach was secondary to gastrectomy and gastric bending. The final organ shape depends on the type of applied surgical procedure that maintains physiological connection with the duodenum or an un-anatomical one, mostly with the jejunal loop. In banding, the body of the stomach forms an hourglass at the level of the artificial adjustable band, typically applied in surgical treatment of obesity (slim surgery). PMID- 22936547 TI - Ultrastructural aspects of acute pancreatitis induced by 2, 2'-azobis (2 amidinopropane) dihydrochloride (AAPH) in rats. AB - Pathophysiology of acute pancreatitis (AP) has not been clearly established; nevertheless, accumulating evidence implicates highly reactive oxygen species (ROS) as important mediators of exocrine tissue damage. In this study, we used a water-soluble radical initiator, 2,2 -azobis-(2-amidinopropane) dihydrochloride (AAPH), to investigate the consequences of oxidative stress insult to the rat pancreas. The detailed characterisation of acini ultrastructural changes in the early course (3, 6, 12, 24 h) of AAPH-induced pancreatitis (40 mg/1 kg body weight) was performed. Considerable damage to the mitochondria in acinar cells manifested by increased translucence of the matrix, partial destruction of cristae, and formation of myelin figures were noted. At the same time, focal dilation, degranulation of rough endoplasmic reticulum, and reduced number of zymogen granules was observed. The most prominent ultrastructural feature was accumulation of highly polymorphic cytoplasmic vacuoles in acinar cells. Double membrane-bound autophagosomes, different in size and shape, with sequestered organelles, autophagolysosomes, and large, empty, single-membrane-bound vacuoles were observed within the cytoplasm. The results indicate that intensive and impaired autophagy mediates pathological accumulation of vacuoles in acinar cells. The rat model of acute pancreatitis induced by AAPH is useful to investigate the early events of oxidative stress insult to the pancreas. PMID- 22936548 TI - Vascular architecture of the human uterine cervix, as assessed in light- and scanning electron microscopy. AB - BACKGROUND: The aim of this study was to visualise and describe the vasculature of the human uterine cervix. MATERIAL AND METHODS: The material for this study was obtained from women (age between 20 to 45 years) during autopsy. The material was collected not later than 24 h post-mortem. This study was performed using uteri from cadavers of menstruating nulliparas (33 uteri) and menstruating multiparas (27 uteri). Collected uteri were perfused via the afferent vessels with Mercox resin (for corrosion-casting and SEM assessment) or acrylic paint solution (light microscopy assessment). The research protocol was approved by the Jagiellonian University Ethics Committee (registry KBET/121/8/2007). RESULTS: In all cases bilateral cervical branches (1-4), originating from the uterine artery, were found. Both in the vaginal and supravaginal parts of the cervix, four distinct vascular zones were found. In the pericanalar zone ran small veins, responsible for draining the mucosal capillaries. Both in the muscular layer, as well as in the pericanalar zone, arterioles, and venules passed close to each other, often adjoining. CONCLUSIONS: This study does not confirm the existence of a single cervicovaginal artery, but shows that the vascular supply of the cervix comes from several vessels. It also introduces the idea of two systems, responsible for draining blood from the mucosal capillaries. Neither assessment in light microscopy nor in SEM revealed any differences between multiparas and nulliparas, regarding the vascular architecture of the cervix. PMID- 22936549 TI - Functional hand proportion is approximated by the Fibonacci series. AB - The debatable relationship of functional human hand proportion with the Fibonacci series has remained an obscure scientific enigma short of clinical interest. The main difficulty of proving such a relationship lies in defining what should constitute true functional proportion. In this study, we re-evaluate this unique relationship using hand flexion creases as anatomical surrogates for the functional axes of joint rotation. Standardised desktop photocopies of palmar views of both hands in full digital extension and abduction were obtained from 100 healthy male volunteers of Chinese ethnicity. The functional axes were represented by the distal digital crease (distal interphalangeal joint, DIPJ), proximal digital crease (proximal interphalangeal joint, PIPJ), as well as the midpoint between the palmar digital and transverse palmar creases (metacarpophalangeal joint, MCPJ). The ratio of DIPJ-Fingertip:PIPJ-DIPJ:MCPJ PIPJ (p3:p2:p1) was measured by two independent observers and represented as standard deviation about the mean, and then compared to the theoretical ratio of 1:1:2. Our results showed that, for the 2nd to 5th digits, the p2:p3 ratios were 0.97 +/- +/- 0.09, 1.10 +/- 0.10, 1.04 +/- 0.12, and 0.80 +/- 0.08, respectively; whilst the p1:p2 ratios were 1.91 +/- 0.17, 1.98 +/- 0.14, 1.89 +/ 0.16, and 2.09 +/- 0.24, respectively. When the data were analysed for all digits, they showed a combined p3:p2:p1 ratio of 1:0.98:2.01. In conclusion, our results suggest that functional human hand proportion, as defined by flexion creases, is approximated by the Fibonacci series. PMID- 22936550 TI - Development of the deep flexor tendons and lumbricalis muscle in the hand and foot: a histological study using human mid-term foetuses. AB - To revisit foetal development of the deep flexor tendons of the hand and foot, we examined the paraffin-embedded histology of 20 mid-term foetuses at 8-15 weeks of estimated gestational age (35-118 mm crown-rump length or CRL). At 8-9 weeks, in front of the metacarpal bones, the flexor pollicis longus and flexor digitorum profundus (FDP) muscles provided a plate-like, common tendon from which the lumbricalis muscles originated. However, in the foot, we had no evidence of such a common tendon. The flexor pollicis tendon was separated from the common tendon at 9-10 weeks possibly due to mechanical stress from the laterally growing thumb. Notably, at the lumbricalis muscle origins at 10-12 weeks, the FDP and flexor digitorum longus tendons remained undifferentiated and the primitive tenocytes were dispersed from them. The dispersed cells seemed to develop into an interface tissue between the lumbricalis muscle fibre and the deep tendon. In 3 of 5 specimens at 15 weeks, we found an excess number of the FDP tendons (5-7) in the proximal side of the lumbricalis muscle origin. However, the excess tendons dispersed in the lumbricalis muscle origin. The development of the lumbricalis muscle origin might follow the tendon splitting for four fingers. However, conversely, we hypothesised that the developing lumbricalis muscles re-arranged the deep flexor tendons to provide a configuration of one deep tendon per one finger (or toe). The quadrates plantae muscle seemed not to contribute on the re-arrangement. PMID- 22936551 TI - Anatomic study of infrapopliteal vessels. AB - The purpose of this project is to study and analyse the anatomical variations of the infrapopliteal vessels concerning their branching pattern. A reliable sample of one hundred formalin-fixed adult cadavers was dissected by the Anatomical Laboratory of Athens University. The variations can be classified in the following way: the normal branching of the popliteal artery was present in 90%. The remainder revealed variant branching patterns: hypoplastic or aplastic posterior tibial artery and the pedis arteries arising from the peroneal (3%); hypoplastic or aplastic anterior tibial artery (1.5%); and the dorsalis pedis formed by two equal branches, arising from the peroneal and the anterior tibial artery (2%). The variations were more frequent in females and in short-height individuals. Knowledge of these variations is rather important for any invasive technic concerning lower extremities. PMID- 22936552 TI - Left renal vein abnormalities detected during routine abdominal computed tomography imaging: clinico-radiological significance. AB - BACKGROUND: Preoperative knowledge of the presence of major venous anomalies facilitates the safe performance of aortic surgery. The purpose of the study was to estimate the incidence, as detected by abdominal computed tomography (CT), of major left renal vein anomalies related to the abdominal aorta in an adult population. MATERIAL AND METHODS: Seven hundred and fifty abdominal CT examinations were reviewed retrospectively for the presence of left renal vein anomalies. Eleven CT scans were excluded from the study because of technical or patient- -related factors. The course of the left renal vein was assessed on the CT slices to detect any anomalies. RESULTS: Left renal vein anomaly was detected in 23 (3.1%) of 739 cases. Seventeen (2.3%) of them were a retro-aortic, and six (0.8%) of them were a circumaortic left renal vein. CONCLUSIONS: It is important to detect left renal vein anomalies before retroperitoneal surgery or interventional procedures. These anomalies can be identified in routine abdominal CT examinations with a careful inspection. PMID- 22936553 TI - The relationship between the carrying angle and the distal extent of the 2nd and 4th fingertips. AB - The angle towards the lateral side between the arm and forearm when the forearm is in full extension and supination is defined as the carrying angle. It is well known that the 2nd finger is longer in women whereas the 4th finger is longer in men, due to in-utero hormonal effects. In the present study, the relationship between the carrying angle and the distal extent of the 2nd and 4th fingertips is studied. The findings reveal that the carrying angle was greater both in left and right sides in women than in men. In addition, while the distal extent of the 2nd fingertips was longer in women, the 4th fingertip was longer in men. There was a moderately positive correlation between the carrying angle and the distal fingertip lengths. Therefore, it could be suggested that the morphometric factors play role on the distal extent of the fingertips other than the hormonal effects. PMID- 22936554 TI - Age-related histopathological changes in the cardiac conducting system in the Turkish population: an evaluation of 202 autopsy cases. AB - BACKGROUND: Histopathological features of the cardiac conducting system (CCS) in the Turkish population have not been investigated previously. MATERIAL AND METHODS: We examined CCS of 202 autopsy heart specimens dissected between the years 2004 and 2005 in Bursa Forensic Medicine Institution. Of the 202 cases from all age groups, 154 were males and 48 were females. RESULTS: In our cases, an increase in fibrous and adipose tissue concordant with age, indicating an age related nature, were detected. Fibrous and fatty tissue infiltration appeared at the age of 35. Fatty infiltration started between the ages 20 and 34 years at the sinoatrial node (SAN). There was no relationship between obesity and fatty tissue infiltration in SAN and atrioventricular node (AVN). In 4 cases calcification and in 19 cases inflammation was observed. Amyloid accumulation was not present. In 7 cases myocardial infarction not involving CCS was seen. In 1 case fibroelastoma was detected. CONCLUSIONS: In the Turkish population age-related fibrosis and fatty infiltration in CCS appeared at the age of 35 years and increased with age. Fatty infiltration in the SAN started at a younger age than that reported in the literature. In cases where the cause of death could not be determined, we could not detect lethal pathological features. However, we think that examination of the CCS will improve the quality of autopsy diagnosis. PMID- 22936555 TI - Median nerve thenar motor branch anatomical variations. AB - BACKGROUND: The aim of this study was to determine the prevalence of the different types of median nerve thenar motor branch and to compare them with literature data. MATERIAL AND METHODS: This study was conducted using median nerves dissected from cadavers stored in a 10% solution of formaldehyde at the Department of Anatomy of Jagiellonian University Medical College (JUMC) and cadavers from the Department of Forensic Medicine JUMC. The research protocol was approved by the Jagiellonian University Ethics Committee (registry KBET/ /209/B/2002). RESULTS: The studied group comprised 8 (26.7%) women and 22 men (age between 23 and 92 years), yielding a total of 60 thenar motor branches (30 right vs. 30 left). Forty-seven (78.3%) nerves were classified as extraligamentous, 12 (20%) were subligamentous, and 1 (1.7%) was transligamentous. As for the side of origin of the thenar motor branch, in 45 (75%) cases it was the radial side and in 2 (3.33%) cases it was the ulnar side. CONCLUSIONS: The obtained results confirm that the extraligamentous type of thenar motor branch is the most common and that the ulnar origin of the thenar motor branch is the rarest. PMID- 22936556 TI - Clinical anatomy of the auriculotemporal nerve in the area of the infratemporal fossa. AB - The auriculotemporal nerve is a sensory branch extending from the posterior section of the mandibular nerve trunk. Its nerve roots form a short trunk, which gives off a number of branches, innervating: the temporomandibular joint, the temporal region, structures of the external ear: auricle, and external acoustic meatus, and the parotid gland. It also conducts excretory fibres to the buccal and labial glands. Anatomical relationships between the auriculotemporal nerve and the muscles of mastication, temporomandibular joint, and surrounding vessels in the area of the infratemporal fossa create favourable conditions for entrapment syndromes. Entrapment of the auriculotemporal nerve plays a role in the pathogenesis of temporomandibular joint pain syndromes, headaches, as well as pain symptoms or paraesthesias within the external acoustic meatus and auricle. The current study was performed on 16 specimens containing the infratemporal fossa. Some variations in the nerve roots of the auriculotemporal nerve were found and described as one-, two-, three-, four-, and five-root variants. The topography of the auriculotemporal nerve and its close relationship to the structures of the temporomandibular joint were described. Individually, the variable topography of the nerve course may play a role in the symptomatology of headaches and localisation of pain in the face regions and masticatory system. PMID- 22936557 TI - The incidence of infrapatellar plicae in the elderly Welsh population. AB - There are several studies reporting the incidence of suprapatellar, medial, and lateral plicae, but there is very limited information regarding the incidence of the infrapatellar plica. The purpose of our study was to record the incidence of infrapatellar plicae in the elderly Welsh population suffering from knee osteoarthritis. A prospective study was performed and 90 knees with severe osteoarthritis of the knee joint (Kellgren-Lawrence type III and IV) were investigated during total knee arthroplasty surgery. Documentation was performed at every total knee replacement surgery for the length of the study. Knee replacement was performed by one senior surgeon. Infrapatellar plica was investigated by a medial parapatellar approach and was classified into five types according to Kim's classification. The overall incidence of infrapatellar plicae was 37.7%. The most common type of plicae was the separate type (23.3%). There was no significant difference found between male and female patients. The fenestra type was the least common (2.22%). The incidence of infrapatellar plicae in the elderly Welsh population suffering from knee osteoarthritis was significantly lower when compared to a study that recorded the incidence of infrapatellar plica in young patients. Possibly, the degenerative changes of the knee joint can cause the resorption of the infrapatellar plica, thus decreasing its incidence in the elderly population. PMID- 22936558 TI - The location of the infraorbital foramen in human skulls, to be used as new anthropometric landmarks as a useful method for maxillofacial surgery. AB - BACKGROUND: The aim of the study was to determine the localisation of the infraorbital foramen in relation to chosen anthropometric landmarks as novel reference points: nasion, rhinion, and frontomalare orbitale, and to verify their symmetry. MATERIAL AND METHODS: Sixty-four sides of thirty-two human skulls were investigated. The distances between the infraorbital foramina and nasion, rhinion, and frontomalare orbitale, and the distances between two contralateral infraorbital foramens were measured. The symmetry was analysed and statistical analysis was performed. RESULTS: The mean distance and standard deviation (mean +/- SD) between the right infraorbital foramen and the nasion, rhinion, and right frontomalare orbitale were 45.23 +/- 3.20 mm, 39.84 +/- 1.72 mm, and 36.28 +/- 1.50 mm, respectively, and between the left infraorbital foramen and the nasion, rhinion, and left frontomalare orbitale were 44.38 +/- 2.76 mm, 38.88 +/- 2.01 mm, and 36.31 +/- 2.19 mm, respectively. CONCLUSIONS: The results presented in this study may be particularly helpful for surgery in patients with oedema of the infraorbital region when the other landmarks are difficult to localise. PMID- 22936559 TI - The role of ideational distress in the relation between persecutory ideations and reactive aggression. AB - BACKGROUND: People with schizophrenia are more likely to be violent than the people without it. Feeling driven to act on persecutory delusions may be one explanation for this, but it remains unclear why some should act on such delusions but some not. Acquisition of data from people who are very ill is problematic. Our study explores testing of hypotheses on similar ideational and behavioural associations among healthy recruits from the general population. AIMS: This study aims to test the effect of distress induced by persecutory ideas on any relationships between those ideas and aggressive behaviour, and the effect of gender. METHODS: Twenty-four men and 53 women from the general population participated in this study. The measures of aggressive behaviour were experimentally induced aggressive responding, self-reported aggressive behaviour in general, and self-reported reactive and proactive aggressive behaviours. RESULTS: Among men, persecutory ideation predicted reactive aggressive responding and aggressive style of behaviour only in those who experienced higher levels of persecutory ideational distress. Among women, with generally lower levels of aggression, the role of ideational distress was more complicated; Women in the low distress group responded with higher aggression on the task. Women in the higher distress group responded with higher aggressive style. For neither men nor women were there links between persecutory ideation and proactive aggression, regardless of distress. CONCLUSIONS: Ideational distress moderates the relation between persecutory ideation and aggression in different measures of aggression in men and women. IMPLICATIONS FOR PRACTICE AND/OR RESEARCH: Recognition of a relation between persecutory ideations and aggression is also important in the general population. Insight in the theory of acting upon delusions may lead to more accurate violence risk assessment. Facilitation of early detection of experienced delusional distress may lead to development of more specific psychotherapeutic interventions to manage violence risk. PMID- 22936560 TI - The role of the right hemisphere in metaphor comprehension: a meta-analysis of functional magnetic resonance imaging studies. AB - The role of the right hemisphere (RH) in metaphor comprehension is still controversial. Numerous neuroimaging studies have found that conventionality, sentential context, and task demand can influence the involvement of the RH in metaphor processing. The current meta-analysis used foci from 17 original functional magnetic resonance imaging studies to identify what factors modulate the involvement of the RH in metaphor processing. Activation likelihood estimation was used for quantification. We focused on the contrast of metaphorical meaning processing versus literal meaning processing and calculated the meta-analysis effects when (1) metaphorical meaning is conventional, (2) metaphorical meaning is novel, (3) metaphorical and literal meaning are presented in words, (4) metaphorical and literal meaning are presented in sentential context, (5) task is valence judgment, and (6) task is semantic relatedness judgment. The results indicated that the RH only showed significant effects in metaphor processing when the metaphorical meaning is novel, when metaphorical meaning is presented in sentential context, and when the task is semantic relatedness judgment. The effects were located in right fronto-temporal regions, including inferior frontal gyrus, middle frontal gyrus, insula, superior temporal gyrus, and middle temporal gyrus. These results suggest that conventionality, contextual complexity, and task demand can modulate the effect of figurativeness and influence the involvement of RH in metaphor comprehension. The main role of the RH in metaphor processing is related with activating broad semantic fields and integrating concepts that may have distant semantic relations, and hence provide support for the view that the RH is responsible for processing coarse semantic information in language comprehension. PMID- 22936561 TI - Infrared photodetectors based on CVD-grown graphene and PbS quantum dots with ultrahigh responsivity. AB - Infrared photodetectors based on single-layer CVD-grown graphene and PbS quantum dots, which are fabricated by solution processing, show ultrahigh responsivities of up to 10(7) A/W under infrared light illumination. The devices fabricated on flexible plastic substrates have excellent bending stability. The photoresponse is attributed to the field-effect doping in graphene films induced by negative charges generated in the quantum dots. PMID- 22936562 TI - Docetaxel in combination with estramustine and prednisolone for castration resistant prostate cancer. AB - BACKGROUND: The aim of this study was to investigate the efficacy and toxicity of docetaxel-based chemotherapy, and to investigate pretreatment factors that can predict overall survival (OS) in patients with castration-resistant prostate cancer (CRPC). METHODS: From June 2005 to July 2010, 70 patients with CRPC underwent docetaxel-based chemotherapy at Wakayama Medical University and related hospitals. Docetaxel was given at a dose of 70 mg/m(2) once every 3 weeks or 35 mg/m(2) twice every 3 weeks. Oral estramustine 560 mg was given concurrently for five consecutive days during weeks 1 and 2 of each cycle, and prednisolone 10 mg was given every day. Dexamethasone 8 mg was premedicated intravenously before docetaxel administration. RESULT: The patients received a median of four cycles of treatment (range 1-31). In the serum prostate-specific antigen response, 13 (18.6%) patients achieved a complete response and 29 (41.4%) achieved a partial response. Median OS and time to progression were 14 months and 6 months, respectively. Median follow-up period was 9.5 months. Two independent pretreatment risk factors that predicted OS were visceral metastasis including lymph node metastasis and anemia. Grade 3/4 neutropenia and anemia occurred in 25.7 and 8.6% of the patients, respectively. Four treatment-related deaths were seen during the observation period. CONCLUSION: The combination of docetaxel, estramustine and prednisolone was effective in Japanese patients with CRPC; however, this combination therapy should be carefully indicated to elderly and/or poor performance status patients due to its toxicity. Visceral metastasis and anemia were identified as independent risk factors which could predict OS. PMID- 22936563 TI - Combined chemotherapy with gemcitabine and carboplatin for metastatic urothelial carcinomas in patients with high renal insufficiency. AB - BACKGROUND: This was a retrospective study to evaluate the activity and toxicity of a combined chemotherapeutic regimen of gemcitabine and carboplatin (GCa) in patients with metastatic urothelial carcinomas (UCs) with special regard to patients with highly impaired renal function. METHODS: Eleven patients whose creatinine clearance was 30 ml/min or under and who had been diagnosed with metastatic UC were treated with GCa. The patient cohort comprised 4 males and 7 females, with a median age of 74 (range 67-84) years. The median follow-up was 19 (range 1-58) months. RESULTS: Five of the 11 patients (45%) showed an objective response, with 2 achieving a clinically complete response and 3 a partial response with GCa. The grade 3/4 toxicity of the regimen was primarily hematological, including anemia (55%), neutropenia (45%), and thrombocytopenia (45%). Four patients (36%) could not complete the treatment in total. Grade 3 pneumonitis was found in one patient, and the treatment was terminated. Grade 4 febrile neutropenia occurred in the patient on hemodialysis, and the patient was forced to discontinue the chemotherapy. Another 2 patients also called off the treatment due to a pulmonary adverse event and an elevation of serum creatinine, respectively. CONCLUSIONS: GCa appears to be effective for the treatment of metastatic UCs in patients with impaired renal function, but it is necessary to pay attention to the occurrence of severe adverse events. PMID- 22936564 TI - Improved survival of Japanese patients with human papillomavirus-positive oropharyngeal squamous cell carcinoma. AB - BACKGROUND: The prevalence of oropharyngeal carcinoma is rising in western Europe and the United States, where there appears to be a strong association between human papillomavirus (HPV) and oropharyngeal squamous cell carcinoma (OPSCC). However, such a correlation has not yet been fully evaluated in Japan. METHODS: We performed a retrospective analysis of the association between tumour HPV status and the demographic and clinicopathological parameters of 71 patients with OPSCC at Hokkaido University Hospital, Japan, between 1998 and 2009. The parameters included age, gender, survival, tumour subsite, tumour-node-metastasis (TNM) stage, smoking history, second primary tumour status, recurrence/residual disease at the primary site, and overall survival. HPV status was established by multiplex polymerase chain reaction (PCR) analysis. RESULTS: Of the 71 oropharyngeal cancers, 20 were positive for HPV-16, two for HPV-18, and one for HPV-58. Kaplan-Meier survival analysis showed improved overall survival rates in patients with HPV-positive tumours (p = 0.0038) compared with HPV-negative tumours. Of the 45 patients who received chemoradiotherapy, HPV-positive patients experienced better overall survival than HPV-negative patients (p = 0.0032). In a multivariate analysis, the survival benefit of HPV-positive patients was independent of age and T and N classification. CONCLUSIONS: HPV status is a significantly favourable prognostic factor in oropharyngeal cancer and could be used as a marker to optimize the treatment of patients with this type of cancer in Japan. PMID- 22936565 TI - Survivin expression can predict the effect of chemoradiotherapy for advanced lower rectal cancer. AB - BACKGROUND: Chemoradiotherapy (CRT) has been used to improve local control and survival in patients with advanced rectal carcinoma. However, a significant proportion of patients show poor response to adjuvant CRT. We thus investigated the usefulness of survivin expression as a predictive marker of the CRT response and its characteristics. METHODS: Forty-three patients with lower rectal cancer who underwent CRT were investigated. All patients received preoperative CRT consisting of TS-1 concurrent with 40 Gy of pelvic irradiation followed by curative resection. The relationship between clinical response, or pathological response, and the expression of survivin of pre-CRT biopsy specimens was evaluated by immunohistochemistry and compared with post-CRT expression. RESULTS: Positive expression of survivin was observed in 26 of 43 patients (60%) in pre CRT specimens. Survivin was positively expressed in 77% of stable disease cases, and 43% of partial response (p < 0.05). Regarding the correlation between pathological response and survivin expression, positive expression of survivin was recognized in 75% (18 of 24) of Grade 0 + 1 cases, 50% (7 of 14) of Grade 2 cases, and 20% (1 of 5) of Grade 3 cases. A reverse correlation was recognized between pathological responses and survivin expression (p < 0.05). There were differences in the tumor differentiation between the survivin-positive group and the negative group (p < 0.05). The expression concordance rate was 66% between pre- and post-CRT tissues. In post-CRT tissues, nuclear survivin expression disappeared completely and cytoplasmic expression increased, especially in responder cases. CONCLUSION: Survivin expression in biopsy could be an important predictive factor of preoperative CRT response. PMID- 22936566 TI - Transcriptional architecture and chromatin landscape of the core circadian clock in mammals. AB - The mammalian circadian clock involves a transcriptional feed back loop in which CLOCK and BMAL1 activate the Period and Cryptochrome genes, which then feedback and repress their own transcription. We have interrogated the transcriptional architecture of the circadian transcriptional regulatory loop on a genome scale in mouse liver and find a stereotyped, time-dependent pattern of transcription factor binding, RNA polymerase II (RNAPII) recruitment, RNA expression, and chromatin states. We find that the circadian transcriptional cycle of the clock consists of three distinct phases: a poised state, a coordinated de novo transcriptional activation state, and a repressed state. Only 22% of messenger RNA (mRNA) cycling genes are driven by de novo transcription, suggesting that both transcriptional and posttranscriptional mechanisms underlie the mammalian circadian clock. We also find that circadian modulation of RNAPII recruitment and chromatin remodeling occurs on a genome-wide scale far greater than that seen previously by gene expression profiling. PMID- 22936567 TI - Processing and subcellular trafficking of ER-tethered EIN2 control response to ethylene gas. AB - Ethylene gas is essential for many developmental processes and stress responses in plants. ETHYLENE INSENSITIVE2 (EIN2), an NRAMP-like integral membrane protein, plays an essential role in ethylene signaling, but its function remains enigmatic. Here we report that phosphorylation-regulated proteolytic processing of EIN2 triggers its endoplasmic reticulum (ER)-to-nucleus translocation. ER tethered EIN2 shows CONSTITUTIVE TRIPLE RESPONSE1 (CTR1) kinase-dependent phosphorylation. Ethylene triggers dephosphorylation at several sites and proteolytic cleavage at one of these sites, resulting in nuclear translocation of a carboxyl-terminal EIN2 fragment (EIN2-C'). Mutations that mimic EIN2 dephosphorylation, or inactivate CTR1, show constitutive cleavage and nuclear localization of EIN2-C' and EIN3 and EIN3-LIKE1-dependent activation of ethylene responses. These findings uncover a mechanism of subcellular communication whereby ethylene stimulates phosphorylation-dependent cleavage and nuclear movement of the EIN2-C' peptide, linking hormone perception and signaling components in the ER with nuclear-localized transcriptional regulators. PMID- 22936569 TI - Disulfide rearrangement triggered by translocon assembly controls lipopolysaccharide export. AB - The presence of lipopolysaccharide (LPS) on the cell surface of Gram-negative bacteria is critical for viability. A conserved beta-barrel membrane protein LptD (lipopolysaccharide transport protein D) translocates LPS from the periplasm across the outer membrane (OM). In Escherichia coli, this protein contains two disulfide bonds and forms the OM LPS translocon with the lipoprotein LptE. Here, we identified seven in vivo states on the oxidative-folding pathway of LptD. Proper assembly involved a nonfunctional intermediate containing non-native disulfides. Intermediate formation required the oxidase DsbA, and subsequent maturation to the active form with native disulfides was triggered by LptE. Thus, disulfide bond-dependent protein folding of LptD requires the proper assembly of a two-protein complex to promote disulfide bond rearrangement. PMID- 22936571 TI - Failure to report harms and adverse events in clinical trials: why does the problem continue? PMID- 22936570 TI - Analytical evaluation of two monovarietal virgin olive oils cultivated in the south of Tunisia: Jemri-Bouchouka and Chemlali-Tataouin cultivars. AB - BACKGROUND: The characterisation of virgin olive oils from two Tunisian cultivars, growing in the Tataouin zone, namely Jemri-Bouchouka, a rare olive cultivar, and Chemlali-Tataouin, was carried out. Several analytical parameters were evaluated; these include quality index, fatty acids, phenolic, chlorophyll, carotenoid, squalene, alpha-tocopherol compositions and oxidative stability. RESULTS: Jemri-Bouchouka olive oil had the highest value of oleic acid (74.50%) while Chemlali-Tataouin olive oil had the highest value of oleic acid (69.39 %) and also was characterized by a high percentage of palmitic acid (14.75 %) which makes this oil freeze at a low temperature [corrected]. On the other hand, Jemri Bouchouka oil was characterised by a low phenolic and alpha-tocopherol content (267.72 mg GAE kg-1 and 278.34 mg kg-1, respectively). Ten phenolic compounds were identified. The main phenols found in the two olive oils were oleuropein aglycon and pinoresinol. All phenolic compounds showed significant correlations with oxidative stability. CONCLUSION: The analytical parameters of virgin olive oil that were determined in this study were greatly influenced by cultivar. PMID- 22936572 TI - Case report: giant cardiac malignancy in a nine-year-old female. AB - PURPOSE: To describe the management of a giant cardiac malignancy initially diagnosed as an anterior mediastinal mass. CLINICAL FEATURES: A nine-year-old female with right facial swelling and chronic cough was diagnosed with a large right mediastinal mass. Intermittent ventricular and supraventricular arrhythmias were noted on admission electrocardiograms. Empiric corticosteroid and radiation therapy did not reduce the size of the tumour, and initial tissue biopsies were non-diagnostic. Due to worsening tamponade physiology and persistent arrhythmias, the patient was scheduled for tumour debulking with potential resection. Prior to surgery, a multidisciplinary team was assembled to delineate team member responsibilities and treatment algorithms. The procedure was performed under general anesthesia with spontaneous ventilation preserved during endotracheal intubation and invasive line placement. The team was prepared to provide extracorporeal mechanical support if needed. The child required inotropic and vasoactive medications after transitioning to positive pressure ventilation, but her hemodynamics improved with sternotomy. The lesion was identified as a malignant cardiac clear-cell tumour that was unresectable. Her sternum was left open, as attempted closure led to the re-creation of tamponade physiology. She underwent delayed sternal closure days later. After months of chemotherapy that resulted in significant tumour involution, she underwent successful surgical resection. CONCLUSION: Giant primary cardiac tumours may present similarly to large anterior mediastinal masses. The care of patients with these lesions requires an understanding of the risks associated with mediastinal masses as well as those unique to cardiac tumours. A multidisciplinary approach is critical to providing safe and effective care throughout this process. PMID- 22936568 TI - A high-coverage genome sequence from an archaic Denisovan individual. AB - We present a DNA library preparation method that has allowed us to reconstruct a high-coverage (30*) genome sequence of a Denisovan, an extinct relative of Neandertals. The quality of this genome allows a direct estimation of Denisovan heterozygosity indicating that genetic diversity in these archaic hominins was extremely low. It also allows tentative dating of the specimen on the basis of "missing evolution" in its genome, detailed measurements of Denisovan and Neandertal admixture into present-day human populations, and the generation of a near-complete catalog of genetic changes that swept to high frequency in modern humans since their divergence from Denisovans. PMID- 22936573 TI - Chemical composition and functional characterisation of commercial pumpkin seed oil. AB - BACKGROUND: Pumpkin (Cucurbita pepo L.) seed oil is a common product in Slovenia, Hungary and Austria and is considered a preventive agent for various pathologies, particularly prostate diseases. These properties are related to its high content of carotenoids and liposoluble vitamins. In this study the carotenoid (lutein and zeaxanthin), vitamin E (alpha- and gamma-tocopherol) and fatty acid contents of 12 samples of commercial pumpkin seed oil were investigated together with the composition of the volatile fraction resulting from the roasting process. RESULTS: The aromatic profile obtained from the commercial samples was directly related to the intensity of the roasting process of the crushed pumpkin seeds. The roasting temperature played a crucial role in the concentrations of volatile substances originating from Strecker degradation, lipid peroxidation and Maillard reaction. CONCLUSION: The findings suggest that high-temperature roasting leads to the production of an oil with intense aromatic characteristics, while mild conditions, generally employed to obtain an oil with professed therapeutic characteristics, lead to a product with minor characteristic pumpkin seed oil aroma. The nutraceutical properties of the product are confirmed by the high content of alpha- and gamma-tocopherol and carotenoids. PMID- 22936574 TI - Buildup of image quality in view-shared time-resolved 3D CE-MRA. AB - Time-resolved three-dimensional contrast-enhanced MR angiography often relies on view sharing of peripheral k-space data to enable acquisition of angiograms with both high spatial resolution and a rapid frame rate. It is typically assumed that k-space will be fully sampled during passage of the contrast bolus arterial phase. However, this is not the case when view sharing is incomplete, for example, at the leading edge of an enhancing vessel or if acquisition time is limited as in fluoroscopic tracking for multistation bolus chase MR angiography. Incomplete view sharing will degrade image quality, for example, by reducing vessel signal and sharpness and increasing undersampling artifacts. In this work, the evolution of angiogram quality with view sharing is quantitatively assessed in phantom experiments and in vivo contrast-enhanced MR angiography calf studies. It is demonstrated that there are multiple sets of sequence parameters that can yield a target image update time, but the choice of parameters can profoundly affect how image quality evolves with view sharing. A fundamental tradeoff between vessel signal and sharpness and its relationship to the sequence temporal footprint is investigated and discussed. PMID- 22936575 TI - Reductive cleavage of the Csp2-Csp3 bond of secondary benzyl alcohols: rhodium catalysis directed by N-containing groups. AB - Cutting loose: 1,1-Biarylmethanol substrates undergo reductive cleavage of the C C bond in the presence of a cationic Rh(III) catalyst and H(2) (see scheme; DG=directing group). Various functional groups are tolerated in the reaction system. Preliminary studies indicate that a five-membered rhodacycle intermediate, which then converts into a Rh(III) hydride species for the reduction, is involved in the catalytic cycle. PMID- 22936577 TI - Intracoronary imaging of coronary fibromuscular dysplasia with OCT and IVUS. AB - Fibromuscular dysplasia (FMD) is a segmental non-atherosclerotic, non inflammatory vasculopathy typically of small- to medium-muscular arteries. Coronary FMD (CFMD) is believed to be rare. However, we have found an association between spontaneous coronary artery dissection (SCAD) and FMD as the cause of myocardial infarction in ~25% of young women age <50 years. It is plausible that pre-existing CFMD predisposed these women to SCAD. Definitive diagnosis of CFMD entails autopsy that is obviously impractical, and prior angiographic description does not differentiate superimposed SCAD from obliterative arteriopathy of CFMD. Adjunctive intravascular ultrasound or optical coherence tomography may aid the diagnosis of CFMD and we report the first of such novel images. PMID- 22936576 TI - Role of functional brain imaging in understanding rheumatic pain. AB - Rheumatic pain and, in particular, rheumatoid arthritis, osteoarthritis and fibromyalgia, are common and debilitating chronic pain syndromes. Recently, human functional neuroimaging, for example EEG, fMRI, and PET has begun to reveal some of the crucial central nervous system mechanisms underlying these diseases. The purpose of this review is to summarise current knowledge on the brain mechanisms of rheumatic pain revealed by functional neuroimaging techniques. The evidence suggests that two mechanisms may be largely responsible for the clinical pain associated with these rheumatic diseases: abnormalities in the medial pain system and/or central nervous system sensitisation and inhibition. If we can understand how functioning of the central nociceptive system becomes altered, even in the absence of peripheral nociceptive input, by using functional neuroimaging techniques, in the future we may be able to develop improved, more effective treatments for patients with chronic rheumatic pain. PMID- 22936578 TI - White matter tract integrity of frontostriatal circuit in attention deficit hyperactivity disorder: association with attention performance and symptoms. AB - The frontostriatal circuit has been postulated to account for the core symptoms such as inattention in attention deficit/hyperactivity disorder (ADHD). This study investigated the white matter integrity of frontostriatal fiber tracts using diffusion spectrum imaging (DSI) tractography and its correlations with measures of multi-dimensional aspects of inattention based on psychiatric interview and attention tasks in 25 children with ADHD and 25 matched typically developing (TD) children. All the subjects were assessed with comprehensive psychiatric interviews and the Conner's Continuous Performance Test (CCPT). DSI data were acquired on a 3-Tesla MRI system. The frontostriatal fiber pathways were reconstructed by deterministic tractography, and generalized fractional anisotropy values were measured along individual targeted tracts to investigate alterations in microstructure integrity. Children with ADHD performed worse than TD children in the dimensions of focused attention, sustained attention, impulsivity, and vigilance of the CCPT, and showed impaired integrity in four bilateral frontostriatal tracts, namely the dorsolateral-caudate, medial prefrontal-caudate, orbitofrontal-caudate, and ventrolateral-caudate tracts, and in global white matter as well. The integrity of the left orbitofronto-caudate tract was associated with the symptom of inattention in children with ADHD, compatible with the attention deficit and motivational dysfunction theories in ADHD. The integrity of the frontostriatal tracts was associated with the attention performance only in TD children, suggestive of possible recruitment of tracts other than the frontostriatal tracts implicated in attention deficits in children with ADHD. In conclusion, our results demonstrate the functional involvement of the frontostriatal circuit with respect to clinical symptoms and attention performance. PMID- 22936580 TI - H.-C. Lin, D.-L. Ren, Q.-L. He, H. Peng, S.-K. Xie, D. Su, X.-X. Wang: Partial stapled hemorrhoidopexy versus circular stapled hemorrhoidopexy for grade III-IV prolapsing hemorrhoids: a two-year prospective controlled study. PMID- 22936581 TI - Splenic lobe/segment dearterialization. PMID- 22936582 TI - Functional luminal imaging probe: a new technique for dynamic evaluation of mechanical properties of the anal canal. AB - BACKGROUND: The muscle structures surrounding the anal canal are of major importance in maintaining continence but their anatomy and function vary along its length. Standard manometry does not provide detailed information about mechanical properties of the anal canal. A new functional luminal imaging probe (FLIP) has been developed for this purpose. The aim of our study was to investigate whether FLIP allows detailed evaluation of dynamic biomechanical properties along the length of the anal canal. METHODS: The in vitro validity and reproducibility of the FLIP system were tested. Fifteen healthy volunteers (age 32-65 years, mean 51 years), of whom 12 were females, were investigated. The integrity and dimensions of the anal sphincter apparatus were evaluated with endoanal ultrasonography and standard anal manometry. During standardized distensions with the FLIP, 16 cross-sectional areas of the anal canal were measured at 5-mm intervals. Distensibility of the following three segments was evaluated: upper anal canal (surrounded by the internal anal sphincter and the puborectalis muscle), mid-anal canal (surrounded by the internal anal sphincter and the external anal sphincter) and lower anal canal (surrounded by the external anal sphincter). Color contour plots were generated from the FLIP-based dynamic recordings of serial cross-sections. RESULTS: In vitro tests confirmed the validity and reproducibility of the FLIP system. The luminal geometry during distension and the biomechanical properties of the anal canal differed at the three levels. Both at rest and during squeeze the mid-anal canal was significantly less distensible than the upper (p < 0.01) and the lower (p < 0.05) anal canal. CONCLUSIONS: FLIP is a promising method for evaluation of the nonhomogeneous biomechanical properties along the length of the anal canal. PMID- 22936583 TI - The technical approach to laparoscopic colectomy in patients who have undergone prior abdominoplasty. AB - BACKGROUND: For those patients undergoing laparoscopic colorectal surgery who have had prior abdominoplasty, cosmetic outcome is important and the technical considerations for laparoscopy in post-abdominoplasty patients have not been previously addressed. The aim of the present study was to define the technical approach to the post-abdominoplasty patient undergoing laparoscopic colorectal surgery after abdominoplasty. METHODS: Utilizing the technical approach described, eleven patients underwent laparoscopy after prior abdominoplasty over a 7-year period. RESULTS: The majority of patients (10/11) felt their laparoscopic colorectal resection had no adverse effect on the aesthetics of their prior abdominoplasty. From a surgeon's standpoint, the only significant challenge was due to the loss of abdominal wall compliance. CONCLUSIONS: The surgical approach to laparoscopic colectomy in the post-abdominoplasty patient requires careful planning. Cosmetic outcome is a particularly important consideration for this subset of patients, and this should be appreciated by the operating surgeon. PMID- 22936585 TI - J.O. Larkin, P.A. Carroll, P.H. McCormick, B.J. Mehigan: Control of splenic bleeding during splenic flexure mobilisation by devascularisation of the inferior pole of the spleen. PMID- 22936584 TI - A new colonic lavage system to prepare the colon for colonoscopy: a retrospective study. AB - BACKGROUND: One of the most unpleasant and sometimes difficult elements of colonoscopic examination is the bowel preparation which is usually performed 6 or more hours prior to the examination ("early" preparation), causing many patients to refrain from undergoing this procedure. We present a novel technique for bowel preparation that begins approximately 30 min prior to the introduction of the colonoscope and eliminates the need for significant pre-procedure preparation. METHODS: The medical records of all consecutive patients who underwent colonoscopy without "early" preparation (CWEP) from May 2009 through June 2010 were retrospectively reviewed. The procedure was performed using a novel cleansing device, the "ColonoScoPrepTM", with which the colon is prepared about half an hour prior to insertion of the colonoscope. The only medication required is two to three bisacodyl tablets the night before. The quality of bowel preparation was graded as excellent, good, satisfactory, or poor, and patient satisfaction was assessed according to a prospective protocol. RESULTS: During this period, 125 patients underwent CWEP. Of these, 110 (89.4 %) patients had an excellent or good preparation, permitting complete colonoscopic examination unimpeded by fecal matter. In 11 patients, preparation was satisfactory, in 2 it was poor and in 2, colonoscopy was not completed due to unsatisfactory preparation. None of the patients suffered from abdominal pain or cramps during or after the CWEP and none had post-colonoscopy diarrhea. All patients were satisfied with the procedure. CONCLUSIONS: Despite the fact that the study is retrospective, CWEP appears safe and easy to perform. A prospective study comparing conventional bowel preparation and CWEP is now underway. PMID- 22936586 TI - Minimally invasive postoperative analgesia for pain relief after minimally invasive surgical procedures: the role of local anesthetic infusion. PMID- 22936587 TI - Raised intraocular pressure (IOP) and perioperative visual loss in laparoscopic colorectal surgery: a catastrophe waiting to happen? A systematic review of evidence from other surgical specialities. AB - BACKGROUND: Case reports of healthy patients experiencing total perioperative visual loss (POVL) after elective laparoscopic surgery, including colorectal resection, are appearing increasingly frequently in the literature. We reviewed the literature exploring the relationship between patient positioning and intraocular pressure (IOP) across all surgical specialties. This was then applied to the potential risk of developing POVL in patients undergoing laparoscopic colorectal surgery. METHODS: A systematic review of the relevant literature was performed to identify all studies exploring the relationship between intraocular pressure and patient positioning. RESULTS: Eight relevant studies on both elective patients and healthy non-anaesthetised volunteers in the spinal, neurosurgical and urological fields were identified which explore the changes in IOP according to patient positioning. These all reported significant rises in IOP in both head-down positioning and prone positioning, and the strongest effects were seen in those patients placed in combined head-down and prone position (such as prone jackknife). Rises in IOP were time-dependent in all studies. CONCLUSIONS: Patients undergoing laparoscopic colorectal surgery in a prolonged head-down position are likely to experience raised IOP and thus are at risk of POVL. Those having a laparoscopic abdominoperineal excision with prone positioning for the perineal component are probably those in the greatest danger. Surgeons need to be aware of this under-recognised but potentially catastrophic complication. PMID- 22936588 TI - Twenty-three-hour stay loop ileostomy closures: a pilot study. AB - BACKGROUND: In UK in 2010-2011, 4,463 ileostomy closures were performed (35,442 bed days) with a median inpatient stay of 5 days (Hospital Episode Statistics data). This seems anomalous when there are reports of 23-h stay colectomies. We present our early experience of 23-h discharge for loop ileostomy closures. METHODS: A specific patient journey/pathway for 23-h discharge following loop ileostomy closure was implemented at a single UK institution between August 2011 and April 2012. Follow-up was by telephone contact 24-48 h postdischarge and by routine outpatient appointment, and patients were also provided with a 24-h contact point in case of emergency. RESULTS: Twenty-three patients were included (18 male patients; median age, 63 years; range, 28-78 years). Fifteen were discharged within 23 h. The remaining 8 patients were all discharged within 48 h of surgery. Four patients were readmitted with superficial wound infection (1), slight wound discharge (1), Clostridium difficile diarrhoea (1) and an anastomotic leak 8 days after surgery (1). Median length of follow-up was 3 months (range, 1-10 months). CONCLUSIONS: A specific 23-h discharge protocol for loop ileostomy closures is feasible and safe. Improved primary care and out-of hours hospital support would have prevented both minor wound complications requiring readmission. The anastomotic leak presented at postoperative day 8 and would have occurred in the community even if a standard protocol was used. Additional patient information and support via stoma care have been introduced to build on our experience, and 23-h stay has been introduced as standard care. PMID- 22936589 TI - Impact of hepatic lymph node metastasis on survival of patients with synchronous resectable or unresectable liver metastases of colorectal cancer. AB - BACKGROUND: The goals of this retrospective study were to comprehensively evaluate the impact of hepatic lymph node (HLN) involvement on survival in patients with synchronous resectable or unresectable liver metastases from colorectal cancer and to highlight how to deal with such cases in the light of recent advances in chemotherapy. METHODS: The impact of HLN involvement on survival, along with various clinical, pathological, and therapeutic factors, was retrospectively evaluated in 61 patients with synchronous liver metastases from colorectal cancer (resectable, 26; unresectable, 35), undergoing resection of the primary tumor and histopathological evaluation between July 2000 and April 2008. RESULTS: The proportion with HLN metastasis was 11.5 % in resectable cases and 28.6 % in unresectable cases. On multivariate analysis using the Cox proportional hazards model, HLN metastasis (P < 0.001), along with non-resection of hepatic lesions (P < 0.001), larger metastatic tumor volume (P < 0.001), non-use of oxaliplatin-based chemotherapy (P < 0.001), involvement of 4 or more regional lymph nodes (P < 0.001), and excessive lymphatic invasion (P = 0.02), was identified as an independent risk factor for shorter survival. CONCLUSIONS: To establish a new therapeutic strategy for synchronous liver metastasis of colorectal cancer, the HLNs should be examined histologically in patients undergoing resection of their primary colon and rectal cancer. PMID- 22936590 TI - Transanal single-port laparoscopic total mesorectal excision in the treatment of rectal cancer. AB - Our objective was to report of our first experience with transanal total mesorectal excision (TME) of rectal cancer using single-port equipment, a pure natural orifice transluminal endoscopic surgery (NOTES) procedure, and to discuss the advantages and disadvantages of the technique. A patient with rectal cancer was selected according to preoperative evaluation criteria. Purse-string sutures were placed into the rectum distal to the tumor using the procedure of prolapse and hemorrhoids (PPH) anoscope. A full-thickness incision of the rectal wall was made circumferentially below the purse string and a three-channel cannula was inserted. The artificial orifice was insufflated. The entire mesorectum was dissected upward according to the principles of TME. Pneumoperitoneum was created by opening the rectouterine pouch. The sigmoid colon and its mesentery were dissected, and the inferior mesenteric vessels were ligated and divided. After dissection of a sufficient length of sigmoid colon, the PPH anoscope and the three-channel cannula were removed. The rectum and sigmoid colon were brought out through the anus. The tumor was resected. After removal of the specimens, a stapled end-to-end anastomosis was fashioned between the rectum and the sigmoid colon. Operative time was 300 min. The mesorectum was completely removed with negative distal and circumferential margin. The final pathological stage was pT3N1M0, with one positive lymph node (1/12). The patient recovered uneventfully after surgery. Pure-NOTES performed as transanal single-port laparoscopic TME for rectal cancer appears to be feasible and safe. PMID- 22936591 TI - Vertical transumbilical incision versus left lower transverse incision for specimen retrieval during laparoscopic colorectal surgery. AB - BACKGROUND: This study compared the short-term surgical outcomes of the vertical transumbilical incision with the left lower transverse incision for specimen retrieval in laparoscopic colorectal cancer surgery. METHODS: One hundred forty seven consecutive patients scheduled for laparoscopic surgery for sigmoid colon and rectal cancer between April 2010 and December 2010 were classified into one of the two groups according to the site of the minilaparotomy: a transumbilical incision group (n = 92) and a left lower transverse incision group (n = 55). RESULTS: Demographic data, operation time, estimated blood loss, frequency of transfusion, size of the tumor, number of harvested lymph nodes, distal resection margins, time to first flatus, and length of hospital stay were similar between the two groups. Postoperative pain scores were also similar between the two groups. The length of the minilaparotomy incision was shorter in the transumbilical group than the left lower transverse group at operation (mean, 4.6 vs. 6.2 cm, p = 0.000). The postoperative mean satisfaction score was higher in the transumbilical group, but this was not statistically significant (7.6 vs. 7.1, p = 0.224). Fourteen patients in the transumbilical group and 7 patients in the left lower transverse group developed wound-related complications (p = 0.810), including two cases of incisional hernia, both in the transumbilical group. High body mass index (>=25 kg/m(2)) and longer operative time (>=180 min) were risk factors for wound complications on univariate analysis. CONCLUSIONS: Transumbilical minilaparotomy in laparoscopic colorectal surgery is a good alternative approach with acceptable wound complications. PMID- 22936592 TI - Visual analogue scales for grading faecal incontinence and quality of life: their relationship with the Jorge-Wexner score and Rockwood scale. AB - BACKGROUND: The purpose of this study was to determine the probability of substituting two validated methods frequently used for scoring severity and quality of life of faecal incontinence (FI) by a single score represented in a visual analogue scale (VAS). METHODS: One hundred and three consecutive unselected patients affected by FI of different aetiologies were prospectively included in the study. Evaluation of the continence status and quality of life referred to the last month was scored by (1) Jorge-Wexner score, (2) Rockwood FIQL scale, (3) Visual Analogue Scale for Faecal Incontinence (VASFI), and (4) Visual Analogue Scale for Quality of Life (VASQL). Patients unable to respond accurately to one or more of the questionnaires were excluded. The Bland and Altman method was applied to evaluate the agreement between Jorge-Wexner and VASFI. Correlation between both the analogue scales (VASFI and VASQL) and each one with each of the four FIQL scale scores was first determined by an analysis of simple correlation with each subscale and thereafter by multiple regression analysis following the backward strategy. RESULTS: Comparison of VASFI with the Jorge-Wexner score shows that the two methods are neither concordant nor interchangeable, and in a given patient, the differences between both may fluctuate between 5.4 and -10.6 (95 % confidence interval). Correlation of VASFI and VASQL shows that the correlation between both the analogue scales is middling (r (2) = 0.543, beta coefficient -0.538). Correlation of VASFI and FIQL subscales shows that in simple regression analysis, VASFI correlates with lifestyle, coping/behaviour, and embarrassment, but after multiple regression analysis, VASFI correlates significantly only with embarrassment. Correlation of VASQL and FIQL subscales shows that in simple regression analysis, VASQL correlates with lifestyle, coping/behaviour, and embarrassment, but after multiple regression analysis, VASQL only correlates significantly with coping/behaviour. CONCLUSIONS: This study shows that a VAS for FI cannot replace the Jorge-Wexner score and a VAS for quality of life cannot substitute all the four subscales of FIQL. Severity of FI and its impact on quality of life expressed in a VAS only have a fair correlation, showing that they do not assess the same issues, which is also supported by the finding that VASFI correlates significantly only with the embarrassment subscale of FIQL. PMID- 22936593 TI - Unselected rectal cancer patients undergoing low anterior resection with defunctioning ileostomy can be safely managed within an Enhanced Recovery Programme. AB - BACKGROUND: An increasing body of evidence supports the application of the Enhanced Recovery Programme (ERP) to colorectal surgery. Some institutions have reported an association between ERP failure and low rectal cancer surgery. We present the results that we achieved by applying the ERP to low anterior resections for tumours within 6 cm of the anal verge, with a view to determining the validity and safety of applying the ERP to this patient group. METHODS: A multimodal ERP, based on Kehlet's model, was introduced in January 2007 and applied to all patients undergoing elective resections. Patients having a low anterior resection for a rectal cancer less than 6 cm from the anal verge between January 2007 and August 2011 were retrospectively identified from a prospectively maintained database. Individual patient record review was performed. RESULTS: Twenty consecutive patients (12 males) were identified. Median total postoperative length of stay (LOS), including readmission, was 8 days (mean 10.7, range 4-47 days), with 2 readmissions and no deaths. When surgery was uncomplicated, median LOS was 5 days (mean 5.8, range 4-12 days, n = 11), whereas LOS increased when a complication occurred, with a median of 12 days (mean 16.6, range 8-47 days, n = 9) [p = 0.001]. CONCLUSIONS: The ERP can safely be applied to this high-risk patient group. When no complication occurs, LOS of 5 days can be expected. When a complication is encountered, LOS is prolonged (12 days), but this is acceptable compared with the current national median LOS in the United Kingdom of 11 days for all rectal cancer surgery (at any height) with a stoma. PMID- 22936594 TI - Introduction of a tryptophan side chain into subsite +1 enhances transglycosylation activity of a GH-18 chitinase from Arabidopsis thaliana, AtChiC. AB - A tryptophan side chain was introduced into subsite +1 of family GH-18 (class V) chitinases from Nicotiana tabacum and Arabidopsis thaliana (NtChiV and AtChiC, respectively) by the mutation of a glycine residue to tryptophan (G74W-NtChiV and G75W-AtChiC). The specific activity toward glycol chitin of the two mutant enzymes was 70-71% of that of the wild type. Using chitin oligosaccharides, (GlcNAc)(n) (n = 4, 5 and 6), as the substrates, we found the transglycosylation reaction to be significantly enhanced in G74W-NtChiV and G75W-AtChiC when compared with the corresponding wild-type enzymes. The introduced tryptophan side chain might protect the oxazolinium ion intermediate from attack by a nucleophilic water molecule. The enhancement of transglycosylation activity was much more distinct in G75W-AtChiC than in G74W-NtChiV. Nuclear magnetic resonance titration experiments using the inactive double mutants, E115Q/G74W-NtChiV and E116Q/G75W-AtChiC revealed that the association constant of (GlcNAc)(5) was considerably larger for the latter. Amino acid substitutions at the acceptor binding site might have resulted in the larger association constant for G75W AtChiC, giving rise to the higher transglycosylation activity of G75W-AtChiC. PMID- 22936595 TI - Carbon nanotube based high resolution holograms. AB - Carbon nanotubes are used as the smallest possible scattering element for diffracting light in a highly controlled manner to produce a 2D image. An array of carbon nanotubes is elegantly patterned to produce a high resolution hologram. In response to incident light on the hologram, a high contrast and wide field of view CAMBRIDGE image is produced. PMID- 22936596 TI - Preparative isolation and purification of three stilbene glycosides from the tibetan medicinal plant Rheum tanguticum maxim. Ex Balf. by high-speed counter current chromatography. AB - INTRODUCTION: Stilbene glycosides are the primary constituents of Rheum tanguticum Maxim. ex Balf., to which different bioactivities has been attributed, including: anti-HIV, anti-oxidant, anti-tumour, anti-malarial, and anti-allergy activity. However, effective methods for the isolation and purification of stilbene glycosides, such as trans-rhapontin, cis-rhapontin and trans desoxyrhaponticin, from this herb are not currently available. OBJECTIVE: To develop an efficient method for the preparative isolation and purification of three stilbene glycosides from Rheum tanguticum Maxim. ex Balf. via high-speed counter-current chromatography (HSCCC). METHODS: A solvent system composed of chloroform:n-butanol:methanol:water (4:1:3:2, v/v/v/v) was developed for the separation. The upper phase was used as the stationary phase, and the lower phase was used as the mobile phase. The flow rate was 1.8 mL/min. The apparatus was controlled at 800 rpm and 25 degrees C, and the effluent was monitored at 280 nm. Chemical constituents were analysed by high-performance liquid chromatography (HPLC), and their structures were identified by 1H- and 13C-NMR. RESULTS: Under the optimised conditions, 25.5 mg trans-rhapontin, 16.0 mg cis-rhapontin and 20.5 mg trans-desoxyrhaponticin were separated from 80 mg crude sample; the isolates had purities of 99.6, 97.2 and 99.2%, respectively. CONCLUSION: A simple and efficient HSCCC method has been optimised for the preparative separation of stilbene glycosides from Rheum tanguticum Maxim. ex Balf. PMID- 22936597 TI - Quality parameters and antioxidant properties in organic and conventionally grown broccoli after pre-storage hot water treatment. AB - BACKGROUND: Demand for broccoli has increased due to its high content of bioactive compounds. However, broccoli is a perishable commodity with a short shelf life mainly due to dehydration, yellowing and losses of bioactive compounds. Thus, efficient treatments to preserve broccoli quality are needed. RESULTS: The effect of heat treatment on senescence and antioxidant compounds evolution during storage at 20 degrees C was evaluated in organic and conventionally grown broccoli. Senescence evolved quickly as manifested by floral head yellowing, which was higher in conventional than in organic broccolis, but senescence was significantly delayed by heat treatment. All organic acids, including ascorbic acid, were found at higher concentrations in organic than in conventional broccoli at harvest but decreased during storage in all broccolis. Phenolic concentration and antioxidant activity (in both hydrophilic and lipophilic fractions) also decreased during storage, although these decreases were higher in conventional than in organic broccolis, and no differences were found attributable to heat treatment. CONCLUSIONS: Heat treatment was effective in delaying broccoli senescence, manifested by chlorophyll retention. In addition, organic broccoli maintained higher concentrations of bioactive compounds (ascorbic acid and phenolics) and antioxidant potential during storage than conventional broccoli, with higher potential health beneficial effects. PMID- 22936598 TI - Development of a freeze-dried mixture of Nile tilapia (Oreochromis niloticus) croquette using a GA-based multiobjective optimisation. AB - BACKGROUND: The mechanically separated meat (MSM) of Nile tilapia is an example of a by-product that can be used in the development of new foods. The aim of this study was to optimise the mixture of different flours in the development of a freeze-dried mixture of fish croquette using Nile tilapia MSM. Flavour, texture and overall acceptance of seven formulations were evaluated by an acceptance test. A genetic algorithm (GA) with desirability functions was combined with a multiobjective optimisation of the response surface models. RESULTS: The combination of flours was chosen to minimise cost and maximise overall acceptance and fibre content. Overall acceptance showed a statistically significant correlation (P <= 0.05) with flavour (r = 0.67) and texture (r = 0.61). The GA based approach indicated that the highest overall acceptance was obtained when using wheat and rye flours in equal parts. This formulation had an overall acceptance of 7.52, a fibre content of 11.50 g kg-1 and a cost of US$2.21/kg. After 24 h of freeze-drying, the water activity of the mixture was 0.11. CONCLUSION: The GA-based approach was able to optimise the croquette formulation. The freeze-drying process contributed to the development of a value-added product with high quality and long shelf-life. PMID- 22936600 TI - Percutaneous embolization of a giant collateral vessel originating from the azygos vein via the inferior vena cava. AB - We present the case of a 45-year-old man with univentricular heart, small outlet chamber, and L-transposition of the great vessels. As an infant, the patient underwent multiple palliative surgical interventions. He presented with worsening dyspnea and fatigue and was found to have systemic oxygen saturation of 85% on 2 L of oxygen by nasal cannula, whereas he had chronically remained between 90 and 95% throughout most of adulthood. There was no evidence of significant valvular regurgitation or stenosis, nor was there an overt intracardiac shunt by echocardiography. Cardiac CT and cardiac MRI revealed a large serpiginous systemic to pulmonary venovenous collateral located behind the left atrium. The collateral drained into the lower right pulmonary vein as it entered the left atrium. The tributary veins to the "giant" collateral were determined by these images modalities. The patient underwent a percutaneous embolization of this giant venovenous collateral via a remnant supracardinal vein originating from the infrarenal inferior vena cava using two Amplatzer Vascular Plug II. Immediately after the procedure the patient's oxygen saturation increased to 90% on room air at rest. At 2 months follow-up the patient had a marked clinical improvement with oxygen saturation as high as 95% on room air while walking. Our case illustrates a successful embolization of a giant collateral via an embryological venous remnant connecting the IVC to the azygos system. PMID- 22936599 TI - Retrospective correction of physiological noise in DTI using an extended tensor model and peripheral measurements. AB - Diffusion tensor imaging is widely used in research and clinical applications, but this modality is highly sensitive to artefacts. We developed an easy-to implement extension of the original diffusion tensor model to account for physiological noise in diffusion tensor imaging using measures of peripheral physiology (pulse and respiration), the so-called extended tensor model. Within the framework of the extended tensor model two types of regressors, which respectively modeled small (linear) and strong (nonlinear) variations in the diffusion signal, were derived from peripheral measures. We tested the performance of four extended tensor models with different physiological noise regressors on nongated and gated diffusion tensor imaging data, and compared it to an established data-driven robust fitting method. In the brainstem and cerebellum the extended tensor models reduced the noise in the tensor-fit by up to 23% in accordance with previous studies on physiological noise. The extended tensor model addresses both large-amplitude outliers and small-amplitude signal changes. The framework of the extended tensor model also facilitates further investigation into physiological noise in diffusion tensor imaging. The proposed extended tensor model can be readily combined with other artefact correction methods such as robust fitting and eddy current correction. PMID- 22936602 TI - Soft Janus colloidal crystal film. AB - Two-faced character in a film: Soft "Janus" two-dimensional colloidal crystal films were made using polystyrene (PS) particles, on an air-water interface as a mold for a flexible polypyrrole layer. By removing the PS particles, an array of femtoliter-sized cups was produced. These two-dimensional colloidal crystal films can also be transferred onto substrates with curvature. PMID- 22936601 TI - alpha-Synuclein protects neurons from apoptosis downstream of free-radical production through modulation of the MAPK signalling pathway. AB - alpha-Synuclein is a pre-synaptic chaperone and its accumulation contributes to differential cell loss in Parkinson's disease. Cytoplasmic expression of alpha synuclein can directly modulate apoptotic pathways and contribute to cell survival, whereas induced over-expression of the protein causes oxidative stress through mitochondrial and cytosolic free-radical production. This study aimed to clarify the contribution of endogenous alpha-synuclein to oxidative stress and its association with cell death. Primary cortical neurons were derived from alpha synuclein knock-out (Snca-/-) and wild-type (C57BL/6; WT) mice and treated with in vitro models of oxidative-stress, complex I inhibition and excitotoxicity. Mitochondrial free radical production was determined in isolated mitochondria derived from each mouse strain. Snca-/- derived cortical cultures were more susceptible (P < 0.05) to oxidative-stress, but not excitotoxicity. This result was determined by significant increases in cell death (Propidium-Iodide staining) after 6 h treatment in Snca-/- (45 % +/- 2.7 SEM), relative to WT (33 % +/- 3.9 SEM) cultures. alpha-Synuclein also confers significant (P < 0.05) resistance to low-dose (5 nM) rotenone toxicity, with a twofold reduction in cell death in WT, compared with Snca-/- cortical neurons. The expression of alpha-synuclein had no effect on cortical glutathione levels, or the production of reactive oxygen intermediates in isolated mitochondria. These data indicate that endogenous levels of alpha-synuclein confer resistance to oxidative stress downstream of free radical production and scavenging. The current data suggest that alpha synuclein prevents cytochrome c release and apoptosis through inhibition of the MAPK signalling pathway. PMID- 22936604 TI - Objectifying the impact of incomplete revascularization by repeat angiographic risk assessment with the residual SYNTAX score after left main coronary artery percutaneous coronary intervention. AB - OBJECTIVES: We investigated the prognostic accuracy of a standardized quantification of incomplete revascularization after percutaneous coronary intervention (PCI) of the unprotected left main coronary artery (ULMCA) named residual SYNTAX score (rSS). BACKGROUND: Prognostic implications of coronary lesions left untreated after ULMCA PCI are confounded by the lack of a uniform definition of incomplete revascularization. METHODS: Baseline SYNTAX score (bSS), rSS, and the difference between bSS and rSS (DeltaSS ) were assessed in predicting the risk of 2-year cardiac mortality of 400 patients undergoing ULMCA PCI. RESULTS: The rSS and bSS showed comparable discrimination (rSS area under the curve [AUC] 0.72, 95% confidence interval [95% CI] 0.61-0.83; bSS AUC 0.73, 95% CI 0.62-0.84). Hosmer-Lemeshow statistics were 0.60 for rSS (P = 0.44) and 2.45 (P = 0.12) for bSS, reflecting better calibration ability of the rSS. The DeltaSS provided the worst discrimination and calibration characteristics (AUC 0.55; 95% CI 0.44-0.66; Hosmer-Lemeshow statistic 3.13, P = 0.08). The rSS was independently associated with the 2-year adjusted-risk of cardiac mortality (hazard ratio 1.07, 95% CI 1.03-1.12, P = 0.001). The risk information from both the rSS and bSS slightly improved the discrimination ability compared with risk information from each single risk assessment (AUC 0.74, 95% CI 0.62-0.86) with a net reclassification improvement of +14.2% and +13.6% over rSS and bSS alone, respectively. CONCLUSIONS: The rSS carries a prognostic value as independent predictor of 2-year cardiac mortality. Compared with a single assessment of the SYNTAX score, information coming from repeat assessment of the angiographic risk may improve the ability to discriminate and reclassify patients undergoing ULMCA PCI. PMID- 22936605 TI - Identification of the human medial temporal lobe regions on magnetic resonance images. AB - The medial temporal lobe (MTL) plays a key role in learning, memory, spatial navigation, emotion, and social behavior. The improvement of noninvasive neuroimaging techniques, especially magnetic resonance imaging, has increased the knowledge about this region and its involvement in cognitive functions and behavior in healthy subjects and in patients with various neuropsychiatric and neurodegenerative disorders. However, cytoarchitectonic boundaries are not visible on magnetic resonance images (MRI), which makes it difficult to identify precisely the different parts of the MTL (hippocampus, amygdala, temporopolar, perirhinal, entorhinal, and posterior parahippocampal cortices) with imaging techniques, and thus to determine their involvement in normal and pathological functions. Our aim in this study was to define neuroanatomical landmarks visible on MRI, which can facilitate the examination of this region. We examined the boundaries of the MTL regions in 50 post-mortem brains. In eight cases, we also obtained post-mortem MRI on which the MTL boundaries were compared with histological examination before applying them to 26 in vivo MRI of healthy adults. We then defined the most relevant neuroanatomical landmarks that set the rostro-caudal limits of the MTL structures, and we describe a protocol to identify each of these structures on coronal T1-weighted MRI. This will help the structural and functional imaging investigations of the MTL in various neuropsychiatric and neurodegenerative disorders affecting this region. PMID- 22936606 TI - Maintaining quality and bioactive compounds of broccoli by combined treatment with 1-methylcyclopropene and 6-benzylaminopurine. AB - BACKGROUND: Broccoli deteriorates very quickly after harvest at ambient temperature due to the loss of green colour and the consequent yellowing of florets. To search for an effective method to control quality deterioration, the effect of 1-methylcyclopropene (1-MCP) combined with 6-benzylaminopurine (6-BA) treatment on visual quality, antioxidant enzymes and bioactive compounds in broccoli florets were investigated. RESULTS: A combined treatment of 2.5 uL L-1 1 MCP and 200 mg L-1 6-BA significantly reduced the increase of lightness (L*) value, and retained a high level for the hue value (H) and chlorophyll content. Superoxide dismutase, ascobate peroxidase and catalase activities increased while the activity of peroxidase decreased during storage in treated samples in comparison with the controls. The combined treatment enhanced the biosynthesis of glucosinolate and the formation of the anticarcinogen sulforaphane, which improved the health benefit of broccoli. CONCLUSION: These results indicate that a combined treatment of 1-MCP and 6-BA could be a good candidate for maintaining the visual quality and enhancing the nutritional value in broccoli during storage at 15 degrees C. PMID- 22936608 TI - Volatile constituents of roasted tigernut oil (Cyperus esculentus L.). AB - BACKGROUND: Volatile compounds play a key role in determining the sensory appreciation of vegetable oils. In this study a systematic evaluation of odorants responsible for the characteristic flavour of roasted tigernut oil was carried out. RESULTS: A total of 75 odour-active volatiles were identified. From these, 13 aroma compounds showing high flavour dilution factors in the range of 16 to 128 were quantified by their odour activity values (OAVs). On the basis of high OAVs in oil, the following aroma compounds [vanillin (chocolate, sweet vanilla), 5-ethylfurfural (caramel, spicy), 2,3-dihydro-3,5-dihydroxy-6-methyl-4H-pyran-4 one (caramel), phenyl acetaldehyde (honey-like), ethanone, 1-(4-hydroxy-3 methoxyphenyl) (faint vanilla)] were elucidated as important contributors to the overall chocolate, sweet vanilla, butterscotch aroma of the oil. CONCLUSION: Odorants with high concentrations in the roasted tigernut oil such as 5 hydroxymethylfurfural, ethyl hexadecanoate, n-propyl-9,12-octadecadienoate gave relatively low OAVs, so their contributions to the overall orthonasal aroma impression of roasted tigernut oil can be assumed to be low. PMID- 22936607 TI - The PNT domain from Drosophila pointed-P2 contains a dynamic N-terminal helix preceded by a disordered phosphoacceptor sequence. AB - Pointed-P2, the Drosophila ortholog of human ETS1 and ETS2, is a transcription factor involved in Ras/MAP kinase-regulated gene expression. In addition to a DNA binding ETS domain, Pointed-P2 contains a PNT (or SAM) domain that serves as a docking module to enhance phosphorylation of an adjacent phosphoacceptor threonine by the ERK2 MAP kinase Rolled. Using NMR chemical shift, 15N relaxation, and amide hydrogen exchange measurements, we demonstrate that the Pointed-P2 PNT domain contains a dynamic N-terminal helix H0 appended to a core conserved five-helix bundle diagnostic of the SAM domain fold. Neither the secondary structure nor dynamics of the PNT domain is perturbed significantly upon in vitro ERK2 phosphorylation of three threonine residues in a disordered sequence immediately preceding this domain. These data thus confirm that the Drosophila Pointed-P2 PNT domain and phosphoacceptors are highly similar to those of the well-characterized human ETS1 transcription factor. NMR-monitored titrations also revealed that the phosphoacceptors and helix H0, as well as region of the core helical bundle identified previously by mutational analyses as a kinase docking site, are selectively perturbed upon ERK2 binding by Pointed-P2. Based on a homology model derived from the ETS1 PNT domain, helix H0 is predicted to partially occlude the docking interface. Therefore, this dynamic helix must be displaced to allow both docking of the kinase, as well as binding of Mae, a Drosophila protein that negatively regulates Pointed-P2 by competing with the kinase for its docking site. PMID- 22936609 TI - A synthetic two-spin quantum bit: g-engineered exchange-coupled biradical designed for controlled-NOT gate operations. AB - A quantum gate: A system of two coupled electron spins that is useful for simple quantum computing operations has been prepared by synthesis of a biradical 1 and co-crystallization with an isomorphous host molecule. The two weakly exchange coupled quantum bits (target qubit blue and control qubit red) span four electron spin states. The electron spin transition is denoted by two black arrows. PMID- 22936610 TI - Single labeled DNA FIT probes for avoiding false-positive signaling in the detection of DNA/RNA in qPCR or cell media. AB - Oligonucleotide hybridization probes that fluoresce upon binding to complementary nucleic acid targets allow the real-time detection of DNA or RNA in homogeneous solution. The most commonly used probes rely on the distance-dependent interaction between a fluorophore and another label. Such dual-labeled oligonucleotides signal the change of the global conformation that accompanies duplex formation. However, undesired nonspecific binding events and/or probe degradation also lead to changes in the label-label distance and, thus, to ambiguities in fluorescence signaling. Herein, we introduce singly labeled DNA probes, "DNA FIT probes", that are designed to avoid false-positive signals. A thiazole orange (TO) intercalator dye serves as an artificial base in the DNA probe. The probes show little background because the attachment mode hinders 1) interactions of the "TO base" in cis with the disordered nucleobases of the single strand, and 2) intercalation of the "TO nucleotide" with double strands in trans. However, formation of the probe-target duplex enforces stacking and increases the fluorescence of the TO base. We explored open-chain and carbocyclic nucleotides. We show that the incorporation of the TO nucleotides has no effect on the thermal stability of the probe-target complexes. DNA and RNA targets provided up to 12-fold enhancements of the TO emission upon hybridization of DNA FIT probes. Experiments in cell media demonstrated that false-positive signaling was prevented when DNA FIT probes were used. Of note, DNA FIT probes tolerate a wide range of hybridization temperature; this enabled their application in quantitative polymerase chain reactions. PMID- 22936611 TI - Open-chain unsaturated selanyl sulfides: stereochemical structure and stereochemical behavior of their 77Se-1H spin-spin coupling constants. AB - Stereochemical structure of nine Z-2-(vinylsulfanyl)ethenylselanyl organyl sulfides has been investigated by means of experimental measurements and second order polarization propagator approach calculations of their (1)H-(1)H, (13)C (1)H, and (77)Se-(1)H spin-spin coupling constants together with a theoretical conformational analysis performed at the MP2/6-311G** level. All nine compounds were shown to adopt the preferable skewed s-cis conformation of their terminal vinylsulfanyl group, whereas the favorable rotational conformations with respect to the internal rotations around the C-S and C-Se bonds of the internal ethenyl group are both skewed s-trans. Stereochemical trends of (77)Se-(1)H spin-spin coupling constants originating in the geometry of their coupling pathways and the selenium lone pair effect were rationalized in terms of the natural J-coupling analysis within the framework of the natural bond orbital approach. PMID- 22936612 TI - One-pot synthesis of spheres-on-sphere silica particles from a single precursor for fast HPLC with low back pressure. AB - Spheres-on-sphere (SOS) silica particles are prepared in a one-pot scalable synthesis from mercaptopropyltrimethoxysilane with hydrophilic polymer and cationic surfactant under alkaline conditions. The SOS particles exhibit solid core porous-shell properties. The fast separation of small molecules and proteins with low back pressure are demonstrated by high-performance liquid chromatography (HPLC) for the columns packed with SOS-particles. PMID- 22936613 TI - Alcohol septal ablation for obstructive hypertrophic cardiomyopathy: outcomes in young, middle-aged, and elderly patients. AB - OBJECTIVES: We compared the efficacy and safety of alcohol septal ablation (ASA) for obstructive hypertrophic cardiomyopathy (HCM) in young, middle-aged, and elderly patients. BACKGROUND: Intersociety guidelines suggest based on limited evidence that young patients with medically refractory symptoms of obstructive HCM should undergo surgical myectomy while elderly patients may be more appropriate for ASA. METHODS: Data for 360 patients undergoing 389 ASAs were prospectively collected and retrospectively analyzed according to age. RESULTS: Young (<45 years), middle-aged (45-64 years), and elderly (>=65 years) patients comprised 28, 40, and 32% of the study population, respectively. Young patients had thicker left ventricular septal walls at baseline, and elderly patients had more comorbidity and dyspnea. Resting, mean left ventricular outflow tract gradients (LVOTGs) were similar across the age groups at baseline (62, 66, and 68 mm Hg, respectively; P = NS for all comparisons). LVOTGs and dyspnea were significantly and similarly improved in all age groups immediately after ASA and through 12 months of follow-up (P < 0.001 for before and after comparisons; P = NS for intergroup comparisons). Complication rates were similar for young and middle-aged patients but higher for elderly patients (9.1 and 6.3% vs. 20.8%, respectively; P <= 0.016 for elderly vs. others). Mortality rates for young and middle-aged patients were lower than for elderly patients, but the differences were not statistically significant. CONCLUSIONS: Patients undergoing ASA had significant and similar improvements in LVOTGs and symptoms regardless of age. Procedural complications were increased in elderly patients, who had numerically but not statistically significantly higher mortality rates. PMID- 22936614 TI - Calorimetric and spectroscopic investigation of the interaction between the C terminal domain of Enzyme I and its ligands. AB - Enzyme I initiates a series of phosphotransfer reactions during sugar uptake in the bacterial phosphotransferase system. Here, we have isolated a stable recombinant C-terminal domain of Enzyme I (EIC) of Escherichia coli and characterized its interaction with the N-terminal domain of Enzyme I (EIN) and also with various ligands. EIC can phosphorylate EIN, but their binding is transient regardless of the presence of phosphoenolpyruvate (PEP). Circular dichroism and NMR indicate that ligand binding to EIC induces changes near aromatic groups but not in the secondary structure of EIC. Binding of PEP to EIC is an endothermic reaction with the equilibrium dissociation constant (K(D) ) of 0.28 mM, whereas binding of the inhibitor oxalate is an exothermic reaction with K(D) of 0.66 mM from calorimetry. The binding thermodynamics of EIC and PEP compared to that of Enzyme I (EI) and PEP reveals that domain-domain motion in EI can contribute as large as ~-3.2 kcal/mol toward PEP binding. PMID- 22936615 TI - Development of a protocol to solidify native and artificial oil bodies for long term storage at room temperature. AB - BACKGROUND: Oil bodies isolated from sesame seeds coalesced to form large oil drops when they were solidified in a drying process commonly used for food products. The aim of this study was to develop a protocol to solidify oil bodies for long-term storage at room temperature. RESULTS: On the basis of testing several excipients, the coalescence of oil bodies could be effectively prevented when they were combined with mannitol. Sizes of oil bodies appeared similar under a light microscope before and after powderisation in combination with 70% or more mannitol. Artificial oil bodies were successfully generated with sesame oil, phospholipid and recombinant sesame caleosin. Following the developed protocol, native and artificial oil bodies were stably solidified in tablets. Both native and artificial oil bodies dissolved from the tablets remained stable after an accelerated stress test under a condition of 75% humidity at 40 degrees C for 4 months. CONCLUSION: A protocol was successfully developed for the solidification of native and artificial oil bodies in stable powder and tablet forms. This successful protocol is very likely to expedite the utilisation of artificial oil bodies in their potential applications. PMID- 22936616 TI - An examination of adults on antipsychotic medication at risk for metabolic syndrome: a comparison with obese and eating disorder populations. AB - Little research has explored how eating disorders (ED) may be involved in the increased risk for metabolic syndrome in adults on antipsychotic medication. This pilot study compared participants on antipsychotic medication with obese and ED samples with respect to demographic and psychosocial factors. Participants (antipsychotic medication n = 12; obese n = 12; ED n = 12), were adults presenting to an outpatient psychiatry department (83.3% women; M age = 45.75 +/- 11.5). Analysis of variance, analysis of covariance and chi-square tests were used to compare the samples. Participants on antipsychotic medications had a significantly lower mean body mass index than the obese (p < .001) and ED (p < .05) samples, as well as significantly lower Restraint Total scores (p < .05) and subjective binge episode frequency (p < .05) than the ED sample. The lack of significant differences that occurred between the antipsychotic medication sample and two eating disorder samples significantly different from one another indicates that this population may have unique symptomology and treatment needs. PMID- 22936617 TI - Fiber supercapacitors utilizing pen ink for flexible/wearable energy storage. AB - A novel type of flexible fiber/wearable supercapacitor that is composed of two fiber electrodes - a helical spacer wire and an electrolyte - is demonstrated. In the carbon-based fiber supercapacitor (FSC), which has high capacitance performance, commercial pen ink is directly utilized as the electrochemical material. FSCs have potential benefits in the pursuit of low-cost, large-scale, and efficient flexible/wearable energy storage systems. PMID- 22936618 TI - Weak arene stabilization of bulky amido-germanium(II) and tin(II) monocations. PMID- 22936620 TI - Advances in quantitative FRET-based methods for studying nucleic acids. AB - Forster resonance energy transfer (FRET) is a powerful tool for monitoring molecular distances and interactions at the nanoscale level. The strong dependence of transfer efficiency on probe separation makes FRET perfectly suited for "on/off" experiments. To use FRET to obtain quantitative distances and three dimensional structures, however, is more challenging. This review summarises recent studies and technological advances that have improved FRET as a quantitative molecular ruler in nucleic acid systems, both at the ensemble and at the single-molecule levels. PMID- 22936619 TI - Plaque shift and distal embolism in patients with acute myocardial infarction: a volumetric intravascular ultrasound analysis from the HORIZONS-AMI trial. AB - BACKGROUNDS: Vessel expansion and axial plaque redistribution or distal plaque embolization contribute to the increase in lumen dimensions after stent implantation. METHODS AND RESULTS: Preintervention and postintervention grayscale volumetric intravascular ultrasound was used to study 43 de novo native coronary lesions treated with TAXUS or Express bare metal stents in the HORIZONS-AMI Trial. There was a decrease in lesion segment plaque + media (P + M) volume ( 19.5 +/- 22.2 mm(3) ) that was associated with a decrease in overall analysis segment (lesion plus 5 mm long proximal and distal reference segments) P + M volume (-17.5 +/- 21.0 mm(3) ) that was greater than the shift of plaque from the lesion to the proximal and distal reference segments (1.9 +/- 4.5 mm(3) , P < 0.0001). Overall analysis segment P + M volume decreased more in the angiographic thrombus (+) versus the thrombus (-) group (27.4 +/- 23.4 vs. -8.9 +/- 14.3 mm(3) , P = 0.003), whereas plaque shift to the reference segments showed no significant difference between the two groups (1.5 +/- 5.2 vs. 2.3 +/- 3.9 mm(3) , P = 0.590). Compared with the angiographic thrombus (-) group, patients in the thrombus (+) group more often developed no reflow (25% vs. 0%, P = 0.012) and had a higher preintervention CK-MB (P = 0.011), postintervention CK-MB (P < 0.001), and periprocedural (post-PCI minus pre-PCI) elevation of CK-MB (P = 0.001). CONCLUSIONS: In acute myocardial infarction lesions, there was a marked poststenting reduction in overall plaque volume that was significantly greater in patients with angiographic thrombus than without thrombus and may have explained a greater periprocedural rise in CK-MB. PMID- 22936621 TI - Influence of cultivation parameters on the composition of volatile compounds and physico-chemical characteristics of kiwi fruit. AB - BACKGROUND: The effect of four cultivation parameters (post-maturity harvest date, storage period at 0 degrees C and input of nitrogen or potassium fertilisers) on the physico-chemical characteristics and composition of volatile compounds in kiwi fruit (Actinidia deliciosa) were evaluated. Five physico chemical parameters were selected, namely, pH, total acidity, dry matter, conductivity and refractive index. To our knowledge, no published data are available concerning the influence of nitrogen or potassium fertilisers on the volatile compounds and physico-chemical parameters in kiwi fruit. RESULTS: Except for total acidity, these parameters were only weakly influenced by cultivation parameters. The concentrations of five main volatile compounds [hexanal, (E)-hex 2-enal, hexan-2-ol, ethyl butyrate and hexanol] were also measured using gas chromatography and gas chromatography-mass spectrometry. This work showed that the total content of volatile compounds decreased with post-maturity harvest date and storage period of 3 months. In contrast, the input levels of nitrogen and potassium had little effect on the concentrations of volatile components CONCLUSION: This study demonstrates a high degree of difference in the physiochemical parameters and volatile composition of kiwi fruit, depending on the harvest date, the time of storage and the input of fertilisers. PMID- 22936622 TI - Structural trends of 29Si-1H spin-spin coupling constants across double bond. AB - The calculations of geminal and vicinal (29)Si-(1)H spin-spin coupling constants across double bond in 15 alkenylmethylsilanes and alkenylchlorosilanes were carried out at the second-order polarization propagator approach level in a good agreement with experiment. Two structural trends, namely, (i) the geometry of the coupling pathway and (ii) the effect of the electrowithdrawing substituent, have been interpreted in terms of the natural J-coupling analysis within the framework of the natural bond orbital approach. Thus, the marked difference between cisoidal and transoidal (29)Si-(1)H spin-spin coupling constants across double bond was accounted for the delocalization contributions including bonding and antibonding Si-C and C-H orbitals, whereas the chlorine effect was explained in terms of the steric contributions including bonding Si-Cl orbitals. PMID- 22936623 TI - Absence of in vitro innate immunomodulation by insect-derived short proline-rich antimicrobial peptides points to direct antibacterial action in vivo. AB - Some antimicrobial peptides (AMPs) have been described to exert immunomodulatory effects, which may contribute to their in vivo antibacterial activity. Very recently, we could show that novel oncocin and apidaecin derivatives are potently antibacterially active in vivo. Therefore, we studied oncocin and apidaecin derivatives for their effects on murine dendritic cells (DC) and macrophages and compared them with well-known immunomodulatory activities of murine cathelicidin related antimicrobial peptide (CRAMP). To characterize the immunomodulatory activity of the peptides on key cells of the innate immune system, we stimulated murine DC and macrophages with the oncocin and apidaecin derivatives alone, or in combination with lipopolysaccharide (LPS). We analyzed the secretion of pro inflammatory cytokines, the expression of surface activation markers, and the chemotactic activity of the AMPs. In contrast to LPS, none of the oncocin and apidaecin derivatives alone has an influence on cytokine or surface marker expression by DC and macrophages. Furthermore, the tested oncocin and apidaecin derivatives do not modulate the immune response after LPS stimulation, whereas CRAMP shows a reduction of the LPS-mediated immune response as expected. All peptides tested are not chemotactic for DC. Together, lack of in vitro immunomodulatory effects by oncocin and apidaecin derivatives on key cells of the innate murine immune system suggests that their potent in vivo antibacterial activity relies on a direct antibacterial effect. This will simplify further pharmaceutical investigation and development of insect peptides as therapeutic compounds against bacterial infections. PMID- 22936624 TI - Solution structure of a tethered Lmo2(LIM2) /Ldb1(LID) complex. AB - LIM-only protein 2, Lmo2, is a regulatory protein that is essential for hematopoietic development and inappropriate overexpression of Lmo2 in T-cells contributes to T-cell leukemia. It exerts its functions by mediating protein protein interactions and nucleating multicomponent transcriptional complexes. Lmo2 interacts with LIM domain binding protein 1 (Ldb1) through the tandem LIM domains of Lmo2 and the LIM interaction domain (LID) of Ldb1. Here, we present the solution structure of the LIM2 domain of Lmo2 bound to Ldb1(LID) . The ordered regions of Ldb1 in this complex correspond well with binding hotspots previously defined by mutagenic studies. Comparisons of this Lmo2(LIM2) Ldb1(LID) structure with previously determined structures of the Lmo2/Ldb1(LID) complexes lead to the conclusion that modular binding of tandem LIM domains in Lmo2 to tandem linear motifs in Ldb1 is accompanied by several disorder-to-order transitions and/or conformational changes in both proteins. PMID- 22936625 TI - Orderly ultrathin films based on perylene/poly(N-vinyl carbazole) assembled with layered double hydroxide nanosheets: 2D fluorescence resonance energy transfer and reversible fluorescence response for volatile organic compounds. AB - Neutral poly(N-vinyl carbazole) (PVK) and perylene are coassembled within the interlayers of layered double hydroxide (LDH) nanosheets to form (perylene@PVK/LDH)(n) ultrathin films by the hydrogen-bond layer-by-layer assembly method. An efficient 2D fluorescence resonance energy transfer (FRET) process from PVK to perylene is demonstrated, and this FRET process can be inhibited/recovered reversibly by the adsorption/desorption of common volatile organic compounds (VOCs). PMID- 22936626 TI - Complex gadolinium-oxo clusters formed along concave protein surfaces. AB - Protein-bound contrast: The unusual observation of a heptanuclear gadolinium-oxo cluster on the surface of the cell-adhesion protein Flo5A establishes the basis for directed incorporation of poly-lanthanide clusters into biomolecules. The observed gadolinium cluster might serve as a paradigm for the design of protein based MRI contrast agents. PMID- 22936627 TI - A rapid and simple screening method of Cronobacter spp. in cell suspension and tofu. AB - BACKGROUND: Cronobacter spp. causes illnesses such as neonatal meningitis, sepsis and necrotising enterocolitis that can be fatal in infants and neonates. Thus it is of great concern to the food industry, which requires a simple and miniaturised method for the rapid detection of Cronobacter spp. in food. RESULTS: A simple and rapid method was developed for the quantitative estimation of Cronobacter spp. Cell suspension cultures and tofu inoculated with Cronobacter spp. as well as a mixed culture (Cronobacter spp. and other micro-organisms) were serially diluted twofold on microtitre plates. Kim and Rhee broth, containing salicin, was added to each well. After 16-18 h of incubation the colour of broth in the wells changed from purple to yellow owing to salicin fermentation by Cronobacter spp. Bacterial counts were predicted by analysing the end points (the last well number in a series of positive wells). The coefficients of determination (r(2)) between the conventional plating method and the current method had high degrees of correlation (0.954-0.963), suggesting that the latter method offers a reasonable quantification of Cronobacter spp. CONCLUSION: The simple method developed in this study could be used for the efficient and rapid screening of Cronobacter spp. in the food industry. PMID- 22936629 TI - 17O NMR studies of ortho-substituent effects in substituted phenyl tosylates. AB - (17)O NMR spectra for 35 ortho-, para-, and meta-substituted phenyl tosylates (phenyl 4-methylbenzenesulfonates), 4-CH(3)-C(6)H(4) SO(2)OC(6)H(4)-X, at natural abundance in acetonitrile at 50 degrees C were recorded. The (17)O NMR chemical shifts, delta((17)O), of the sulfonyl (SO(2)) and the single-bonded phenoxy (OPh) oxygens for para and meta derivatives correlated well with dual substituent parameter treatment using the Taft inductive, sigma(I), and resonance, sigmao(R), constants. The influence of ortho substituents on the sulfonyl oxygen and the single-bonded phenoxy oxygen chemical shifts, delta((17)O), was found to be nicely described by the Charton equation: delta((17)O)(ortho) = delta((17)O)(H) + rho(I)sigma(I) + rho(R)sigma degrees (R) + deltaE(s)(B) when the data treatment was performed separately for electron-donating +R substituents and electron attracting -R substituents. Electron-attracting meta and para substituents in the phenyl moiety caused deshielding while the electron-donating meta, para and ortho +R substituents produce shielding effects on the sulfonyl (SO(2)) and single bonded phenoxy (OPh) oxygens. The influence of ortho inductive and resonance effects in the case of +R substituents was found to be approximately twice higher than the corresponding influence from the para position. Due to the steric effect of ortho substituents a decrease in shielding of the oxygens at the sulfonyl group (deltaE(s)(B) > 0, E(s)(B) < 0) was detected. PMID- 22936628 TI - Echocardiographic predictors of single versus dual MitraClip device implantation and long-term reduction of mitral regurgitation after percutaneous repair. AB - OBJECTIVES: To describe predictors of the number of MitraClip devices implanted during percutaneous repair of mitral regurgitation (MR), and the long-term reduction in MR. BACKGROUND: In the EVEREST trials, one or two MitraClip devices were implanted to reduce MR, as needed. METHODS: Preprocedural transthoracic echocardiograms (TTE) and transesophageal echocardiograms (TEE) of 233 subjects who received 1 or 2 MitraClip devices in the EVEREST II Randomized Trial and High Risk Study were analyzed. TEEs were reviewed for etiology of MR and pathoanatomic features of the valve, valve apparatus, and the regurgitant jet. Follow-up MR was assessed by TTE postprocedure and at 12 months. RESULTS: Ninety-seven subjects (42%) had two MitraClip devices implanted. Subjects with quantitatively more severe MR were more likely to receive two devices [mean regurgitant volume (RV) 45.9 +/- 21.9 vs. 36.3 +/- 18.5 mL, P <0.001]. On multivariate analysis, increased anterior leaflet thickness (OR 1.7 per mm, P = 0.007) and greater baseline RV (OR 1.21 per 10 mL, P = 0.01) were associated with increased odds of implanting two devices. The frequency of 2+ MR or less at discharge was similar regardless of the number of devices implanted. After propensity matching, patients had quantitatively similar MR at twelve-month follow-up, regardless of whether one or two MitraClip devices were implanted (P = 0.6). CONCLUSIONS: Subjects with thicker anterior mitral leaflets and more severe MR were more likely to receive two MitraClip devices. Immediate and long-term reduction in MR was similar regardless of the number of devices implanted at the time of the procedure. PMID- 22936630 TI - Symmetry breaking in the self-assembly of partially fluorinated benzene-1,3,5 tricarboxamides. AB - The interplay of two subsequent aggregation processes results in a symmetry breaking phenomenon in an achiral self-assembling system. Partially fluorinated benzene-1,3,5-tricarboxamide molecules self-assemble into a racemic mixture of one-dimensional P- and M-helical aggregates, followed by bundling into optically active higher-order aggregates or fibers. PMID- 22936631 TI - Patterned superomniphobic-superomniphilic surfaces: templates for site-selective self-assembly. PMID- 22936632 TI - Time of methyl jasmonate application influences the development of 'Cripps Pink' apple fruit colour. AB - BACKGROUND: The effects of time and numbers of pre-harvest sprays of methyl jasmonate (MJ) on the development of red blush, export-grade fruit, accumulation of flavonoids in fruit skin and quality of 'Cripps Pink' apple were investigated in 2005 and 2006. In the first experiment during 2005, whole trees were sprayed once with 10 mmol L(-1) MJ at weekly intervals from 155 to 183 days after full bloom (DAFB). In second experiment during 2006, different numbers of sprays (0, 1, 2, 3, 4, 5 or 6) of 5 mmol L(-1) MJ were applied from 151 to 179 DAFB. RESULTS: A single spray of MJ (10 mmol L(-1)) at 169 DAFB resulted in the highest increase in the red blush, export-grade fruit, accumulation of anthocyanins, cyanidin 3-galactosides, chlorogenic acid, phloridzin, flavanols and flavonols in fruit skin as compared to all other treatments without affecting fruit quality. A single spray of 5 mmol L(-1) MJ at 186 DAFB was more effective in improving red blush, export-grade fruit and accumulation of anthocyanins in fruit skin as compared to its multiple applications. The exposed sides of fruit developed better colour than the shaded sides, regardless of time and numbers of MJ sprays. Time of a single spray of MJ is more effective than its multiple applications. CONCLUSIONS: A single pre-harvest spray of MJ (10 mmol L(-1)) at 169 DAFB or MJ (5 mmol L(-1)) at 186 DAFB was effective in improving the red blush and export grade fruit through accumulation of flavonoids in fruit skin without adversely affecting quality at harvest. PMID- 22936633 TI - Fluorescence study of energy transfer in PMMA polymers with pendant oligo phenylene-ethynylenes. AB - A spectroscopic characterization of polymers containing rigid pi-conjugated oligo(phenyleneethynylene) chromophores as well as oligo(phenyleneethynylene) and methyl methacrylate is presented. The polymers exhibit molar masses of up to 15,000 g mol(-1) and a degree of polymerization between 22 and 80. Emission measurements of the monomeric and polymeric species show that radiative as well as nonradiative rates are influenced by the degree of polymerization due to intramolecular interactions of chromophores pendant to the polymer backbone. Time resolved emission anisotropy measurements suggest that energy migrates within the polymers. Steady-state emission anisotropy measurements also point to energy migration. Additionally, two oligo(phenyleneethynylene)s with different sizes of the conjugated system are copolymerized in order to enable energy trapping due to energy transfer. The shortened energy-donor fluorescence lifetime within the donor-acceptor copolymers suggest energy transfer. Depending on the degree of polymerization, dispersion of the donor fluorescence lifetime is observed. PMID- 22936634 TI - Multimodality 3D-roadmap for cardiovascular interventions in congenital heart disease--a single-center, retrospective analysis of 78 cases. AB - BACKGROUND: Modern fluoroscopic angiography systems permit rendering of three dimensional volumetric data sets using rotational angiography (3D-RA). Along with magnetic resonance imaging (MRI) or multi-detector-row computed tomography (MDCT) data sets, they can be fused with live fluoroscopy images for roadmapping during therapeutic procedures, but the value of multimodality fused data sets has not been clarified. METHODS: In a pediatric cardiac catheterization laboratory, we analyzed 78 interventional cardiovascular procedures in which 3D models of 3D-RA, MRI, or MDCT were used for 3D-guidance. Accuracy of 2D-3D registration as well as overall procedural benefit was independently rated by two pediatric interventionalists. Fluoroscopy time, radiation dose, and contrast dye consumption were evaluated and, grouping a subgroup analysis, the parameters were compared between patients who underwent stenting of aortic coarctation with and without 3D-roadmapping. RESULTS: 3D-guiding was used in 78 cases, 75 of these cases were with accurate 2D-3D registration. 3D-roadmapping was rated superior to conventional biplane imaging in 74 cases. 3D-guidance was used in 64 cases to define the ideal C-arm angulation and in 60 cases for accurate device positioning. Median dose-area product in the total investigation was 706.3 MUGym(2) (104.8-7249.7 MUGym(2) ), 3.3 ml/kg (0.9-13.7 ml/kg) of contrast dye was used, and total fluoroscopy time was 14.5 min (2.9-68.1 min). Fluoroscopy time for 3D-guided stenting of aortic coarctation is significantly lower (8.35 versus 10.2 min; P = 0.04). CONCLUSION: 3D-image fusion with live fluoroscopy can be applied successfully in catheter-based interventions of congenital heart disease. 3D-guidance facilitates catheter manipulations and interventions, allows preselection of ideal projection angles, reduces fluoroscopic time and the number of control angiographies. PMID- 22936636 TI - The race for interferon-free HCV therapies: a snapshot by the spring of 2012. AB - After a decade of having been the standard of care (SOC) for the treatment of chronic HCV infection, PEGylated IFN (combined with ribavirin) is now at the verge of being complemented and then replaced by a combination of new DAAs and even some compounds interacting with host cell factors. Principal targets for the direct-acting antivirals (DAAs) are the protease NS3/4A, the protein NS5A, and the RNA-dependent RNA polymerase NS5B, which offers at least two target sites, the catalytic domain for nucleos(t)ides and several non-catalytic (allosteric) domains for the non-nucleoside type of NS5B inhibitors. Two PIs have already been approved, but many more NS3/4A, NS5A, and NS5B (up to 40!) inhibitors are in (pre)clinical development. The abundance of candidate anti-HCV drugs will, on the one hand, speed up their development but, on the other hand, complicate the choice of the most appropriate drug combination(s). PMID- 22936637 TI - Drug-drug interaction study to assess the effects of atorvastatin co administration on pharmacokinetics and anti-thrombotic properties of cilostazol in male Wistar rats. AB - Cilostazol (CLZ) and atorvastatin (ATV) are often co-prescribed to treat conditions such as peripheral arterial disease. In the present study, the drug drug interaction potential of multi-dose ATV co-administration with CLZ on both pharmacokinetics and the anti-thrombotic property of CLZ is demonstrated. The pharmacokinetic parameters of CLZ (6 mg/kg, twice daily) were determined in male Wistar rats after 7 days co-administration with ATV (5 mg/kg, once daily) in order to assess the interaction potential between CLZ and ATV on chronic treatment. In vitro metabolic inhibition and everted gut sac studies were conducted to elucidate the mechanism of this interaction. Pharmacodynamic drug drug interaction was evaluated on anti-thrombotic models including time to occlusion, platelet aggregation and rat tail bleeding time. A validated LC-MS/MS method was employed simultaneously to quantify both ATV and CLZ in rat plasma matrix. A statistically significant increase in systemic exposure (Css(max) by ~1.75 fold; AUC by ~3.0 fold) to CLZ was observed in ATV pre-treated rats. In vitro metabolism studies using liver microsomes (RLM and HLM) demonstrated statistically significant inhibition of CLZ metabolism when co-incubated with ATV. No change in apparent permeability of CLZ was observed in the presence of ATV. Atorvastatin showed a significant delay in artery occlusion time without altering CLZ's bleeding time and platelet aggregation profile. Collectively the results of these studies provide metabolic insight into the nature of drug-drug interaction between the selected drugs. Co-administration with ATV influences the pharmacokinetics and anti-thrombotic property of CLZ. A thorough clinical investigation is required before extrapolation of data to humans. PMID- 22936638 TI - Distance to hospital and utilization of surgical services in Haiti: do children, delivering mothers, and patients with emergent surgical conditions experience greater geographical barriers to surgical care? AB - BACKGROUND: An inverse relationship between healthcare utilization and distance to care has been previously described. The purpose of this study was to evaluate this effect related to emergency and essential surgical care in central Haiti. METHODS: We conducted a retrospective review of operative logbooks from the Clinique Bon Sauveur in Cange, Haiti, from 2008 to 2010. We used Geographic Information Systems to map the home locations of all patients. Spearman's correlation was used to determine the relationship between surgical utilization and distance, and a multivariate linear regression model identified characteristics associated with differences in distances traveled to care. RESULTS: The highest annual surgical utilization rate was 184 operations/100,000 inhabitants. We found a significant inverse correlation between surgical utilization rate and distance from residence to hospital (rs = -0.68, p = 0.02). The median distance from residence to hospital was 55.9 km. Pediatric patients lived 10.1% closer to the hospital than adults (p < 0.01), and distance from residence to hospital was not significantly different between men and women (p = 0.25). Patients who received obstetric or gynecologic surgery originated 7.8% closer to the hospital than patients seeking other operations (p < 0.01), and patients who received emergent surgical care originated 24.8% closer to the hospital than patients who received elective surgery (p < 0.01). CONCLUSIONS: Utilization of surgical services was low and inversely related to distance from residence to hospital in rural areas of central Haiti. Children and patients receiving obstetric, gynecologic or emergent surgery lived significantly closer to the hospital, and these groups may need special attention to ensure adequate access to surgical care. PMID- 22936639 TI - An RNA splicing enhancer that does not act by looping. AB - Out of the loop: Do the proteins bound to an enhancer site on pre-mRNA interact directly with the splice site by diffusion (looping), as is generally accepted, or does the intervening RNA play a role? By inserting a PEG linker between an enhancer sequence and alternative splice sites, the interaction of these two elements can be studied. Intervening RNA was essential for the enhancer activity, which rules out the looping model. PMID- 22936641 TI - Mononuclear water oxidation catalysts. AB - Recently, several mononuclear water oxidation catalysts have been reported, a breakthrough considering the dogma that at least two metal sites were required to oxidize water efficiently. In this Review various mononuclear catalysts which have been reported in the last five years are reviewed, as well as their implementation in prototype devices that allow dioxygen formation to be coupled to dihydrogen production will be discussed. PMID- 22936640 TI - Persistent hexavalent chromium exposure impaired the pubertal development and ovarian histoarchitecture in wistar rat offspring. AB - Hexavalent chromium (CrVI) is a highly toxic metal and a major environmental pollutant. Several studies indicate that CrVI exposure adversely affects reproductive function. We reported that maternal Cr exposure resulted in Cr accumulation in the reproductive organs of female offsprings. CrVI can cross the placental barrier and also can be passed through breastfeeding. The present investigation aimed to determine the persistent (in utero through puberal period) CrVI exposure-induced toxic effects on the reproductive functions of mother and the offspring. Induction of oxidative stress is one of the plausible mechanisms behind Cr-induced cellular deteriorations. Mother rats exposed to CrVI showed reduced reproductive outcome, while the offsprings showed higher accumulation of Cr in ovary, altered steroid, and peptide hormones. Specific activities of antioxidant enzymes were decreased and associated with increased levels of H2 O2 , and lipid peroxidation. CrVI exposure also damaged the ovarian histoarchitecture in various age groups studied. CrVI exposure also delayed the sexual maturation. Results from the present investigation suggest that CrVI exposure from in utero through puberal period significantly damaged the pubertal development through altered antioxidants, anemia, and altered hormone levels. These changes were associated with damaged ovarian histoarchitecture and extended estrous cycle in developing Wistar rats. PMID- 22936642 TI - Stress proneness in molecularly defined long QT syndrome: a study using temperament assessment by behavioural inhibition system scale. AB - The long QT syndrome (LQTS) is an inherited cardiac disorder that predisposes the mutation carrier to ventricular arrhythmias that can lead to sudden death. The objective of the present study was to replicate the previous finding in terms of stress-related temperament trait, i.e. behavioural inhibition system (BIS). The study subjects included 583 LQTS mutation carriers (256 symptomatic and 327 asymptomatic) from the Finnish LQTS registry and 79 healthy subjects randomly derived from the population-based sample of the Young Finns Study. Symptomatic and asymptomatic LQTS mutation carriers did not differ from each other on BIS (3.27 versus 3.24, p > 0.05), whereas LQTS mutation carriers scored higher on BIS than the comparison group derived from the representative population-based sample (3.25 versus 2.99, p = 0.003, eta2 = 0.014). BIS was significantly higher in women than in men (3.32 versus 3.06, p < 0.001, eta2 = 0.017). The results confirm our previous finding of higher stress proneness of LQTS mutation carriers. Their innate stress proneness may have relevance because it increases our understanding on the role of stress in the manifestation of symptoms. PMID- 22936643 TI - Conformer selection and intensified dynamics during catalytic turnover in chymotrypsin. PMID- 22936644 TI - Attachment of chloride anion to sugars: mechanistic investigation and discovery of a new dopant for efficient sugar ionization/detection in mass spectrometers. AB - A new method for efficient ionization of sugars in the negative-ion mode of electrospray mass spectrometry is presented. Instead of using strongly hydrophobic dopants such as dichloromethane or chloroform, efficient ionization of sugars has been achieved by using aqueous HCl solution for the first time. This methodology makes it possible to use hydrophilic dopants, which are more appropriate for chromatographic separation techniques with efficient sugar ionization and detection in mass spectrometry. The interaction between chloride anions and monosaccharides (glucose and galactose) was studied by DFT in the gas phase and by implementing the polarizable continuum model (PCM) for calculations in solution at the high B3LYP/6-31+G(d,p)//B3LYP/6-311+G(2d,p) level of theory. In all optimized geometries of identified [M+Cl](-) anions, a non-covalent interaction exists. Differences were revealed between monodentate and bidentate complex anions, with the latter having noticeably higher binding energies. The calculated affinity of glucose and galactose toward the chloride anion in the gas phase and their chloride anion binding energies in solution are in excellent agreement with glucose and galactose [M+Cl](-) experimental intensity profiles that are represented as a function of the chloride ion concentration. Density functional calculations of gas-phase affinities toward chloride anion were also performed for the studied disaccharides sucrose and gentiobiose. All calculations are in excellent agreement with the experimental data. An example is introduced wherein HCl was used to effectively ionize sugars and form chlorinated adduct anions to detect sugars and glycosylated metabolites (anthocyanins) in real biological systems (Vitis vinifera grape extracts and wines), whereas they would not have been easily detectable under standard infusion electrospray mass spectrometry conditions as deprotonated species. PMID- 22936645 TI - Determinants of road traffic crash fatalities across Indian States. AB - This article explores the determinants of road traffic crash fatalities in India. In addition to income, the analysis considers the sociodemographic population structure, motorization levels, road and health infrastructure and road rule enforcement as potential factors. An original panel data set covering 25 Indian states is analyzed using multivariate regression analysis. Time and state fixed effects account for unobserved heterogeneity across states and time. The rising motorization, urbanization and accompanying increase in the share of vulnerable road users, that is, pedestrians and two-wheelers, are the major drivers of road traffic crash fatalities in India. Among vulnerable road users, women form a particularly high-risk group. Higher expenditure per police officer is associated with a lower fatality rate. The results suggest that India should focus, in particular, on road infrastructure investments that allow the separation of vulnerable from other road users on improved road rule enforcement and should pay special attention to vulnerable female road users. PMID- 22936646 TI - Induction of oxidative stress and histological changes in liver by subacute doses of butyl cyclohexyl phthalate. AB - Phthalates are esters of phthalic acid and are mainly used as plasticizers in a wide variety of products and applications. There is no information on butyl cyclohexyl phthalate (BCP) toxicity. This study was performed to evaluate the histopathological effects and to determine oxidative stress inducing potential in liver by subacute exposure of BCP. The animals of the treatment groups were orally administered 100, 200, and 400 mg/kg/day BCP for 5 consecutive days per week during 28 days. As a result, no significant changes were observed in body weight gains, and absolute and relative liver weights of liver of BCP treated mice, when compared with control group. Although the degree of lipid peroxidation in the liver tissue of all BCP exposure groups were significantly higher than those of the control (p < 0.01), SOD and CAT activities in liver tissue of mice of 200 and 400 mg/kg exposure groups were significantly lower than those of the controls (p < 0.01). Moreover, BCP caused dose-dependent histological changes in the liver of mice such as congestions in vena centralis, an enlargement of the sinusoids, degeneration in hepatocytes, vacuole formations and presence of lipid droplets in hepatocytes, eosinophilic cytoplasm. While iNOS immunoreactivity was increased in all treatment groups, Type IV collagen and Connexin 43 immunoreactivities were decreased in all treatment groups compared with the control group. Significant decrease was observed in the number of TUNEL-positive liver cells of BCP treated mice. These results suggested that BCP exposure induces oxidative stress in liver and exposure of BCP during long time period could lead to hepatocarcinogenesis. PMID- 22936647 TI - Enantioselective oxidation of aldehydes catalyzed by alcohol dehydrogenase. AB - Teaching old dogs new tricks: Alcohol dehydrogenases (ADHs) may be established redox biocatalysts but they still are good for a few surprises. ADHs can be used to oxidize aldehydes, and this was demonstrated by the oxidative dynamic kinetic resolution of profens. In the presence of a suitable cofactor regeneration system, this reaction can occur with high selectivity. PMID- 22936648 TI - Water-vapor-assisted nanoimprinting of PEDOT:PSS thin films. AB - PEDOT:PSS thin films are successfully patterned using water-vapor-assisted nanoimprinting, a process compatible with organic electronic devices. The imprinted patterns are characterized via grazing-incident small-angle X-ray scattering and scanning electron microscopy. Superior pattern transfer quality of water-vapor assisted nanoimprinting over conventional thermal nanoimprinting is demonstrated. PMID- 22936649 TI - Stable dyes containing double acceptors without COOH as anchors for highly efficient dye-sensitized solar cells. AB - The electron acceptor 2-(1,1-dicyanomethylene) rhodanine is a promising alternative to cyanoacrylic acid as an anchoring group for organic dyes. For example, the RD-II-based dye-sensitized solar cell has an overall conversion efficiency of 7.11 % and long-term stability. PMID- 22936650 TI - Observable structures of small neutral and anionic gold clusters. AB - Since gold clusters have mostly been studied theoretically by using DFT calculations, more accurate studies are of importance. Thus, small neutral and anionic gold clusters (Au(n) and Au(n)(-) , n = 4-7) were investigated by means of coupled cluster with singles, doubles, and perturbative triple excitations [CCSD(T)] calculations with large basis sets, and some differences between DFT and CCSD(T) results are discussed. Interesting isomeric structures that have dangling atoms were obtained. Structures having dangling atoms appear to be stable up to n = 4 for neutral gold clusters and up to n = 7 for anionic clusters. The relative stabilities and electronic properties of some isomers and major structures are discussed on the basis of the CCSD(T) calculations. This accurate structure prediction of small gold clusters corresponding to experimental photoelectron spectral peaks is valuable in the field of atom-scale materials science including nanocatalysts. PMID- 22936651 TI - Cognitive effects of chemotherapy in breast cancer patients: a dose-response study. AB - OBJECTIVE: The purpose of this study was to determine if cognition progressively worsens with cumulative chemotherapy exposure. We reasoned that the demonstration of such a 'dose-response' relationship would help to establish whether cognitive changes are caused by neurotoxic effects of chemotherapy or whether they are due to other confounding factors such as mood and pre-treatment differences in cognition. METHODS: Sixty women with early stage breast cancer, aged 65 years or younger with no previous history of cancer or chemotherapy, were matched to 60 healthy women on age and education. Neuropsychological assessment was conducted after surgery but prior to commencing chemotherapy and then again following each chemotherapy cycle in patients and at yoked intervals in healthy controls. We used multilevel modeling to assess change over time in an overall cognitive summary score as well as domain-specific cognitive scores. RESULTS: After controlling for baseline performance, age, education, and mood, the chemotherapy group showed a significant progressive decline over time relative to a matched healthy control group in an overall cognitive summary score, as well as in working memory, processing speed, verbal memory, and visual memory scores. A linear model best fit the trajectory of cognitive change over the course of treatment in the chemotherapy group supporting a dose-response hypothesis. CONCLUSIONS: These results are in keeping with a dose-response relationship and provide the most compelling clinical evidence to date that cognitive decline is caused by chemotherapy exposure. PMID- 22936652 TI - Polymorphism M55V in gene encoding small ubiquitin-like modifier 4 (SUMO4) protein associates with susceptibility to type 1 (and type 2) diabetes. AB - BACKGROUND: The association between small ubiquitin-like modifier 4 (SUMO4) gene polymorphism and type 1 diabetes mellitus (T1DM) or type 2 diabetes mellitus (T2DM) has been investigated in several studies. We conducted a meta-analysis to evaluate the association of SUMO4 gene polymorphism with T1DM and T2DM susceptibility. METHODS: A meta-analysis was performed on the published studies before August 2011. The association of SUMO4 M55V polymorphism with T1DM and T2DM was evaluated. Meta-analysis was performed for genotypes AA versus GG, AA versus AG, AA versus AG + GG and A allele versus G allele in a fixed/random effect model. The combined odds ratio (OR) with 95% confidence interval (95% CI) was calculated to estimate the strength of the association. RESULTS: Sixteen case control studies including 9190 cases and 10 456 healthy controls were included. T1DM patients were divided into Asian and Caucasian subgroup. We detected a significant association of SUMO4 M55V polymorphism with T1DM in Asian population (A versus G: OR = 0.79, 95%CI = 0.72-0.86, p = 0.000) and a significant association of SUMO4 M55V polymorphism with T1DM in Caucasian population (A versus G: OR = 0.84, 95%CI = 0.73-0.97, p = 0.007). Included T2DM patients were all Asian. Meanwhile, a significant association of SUMO4 M55V polymorphism with T2DM was also found (A versus G: OR = 0.86, 95%CI = 0.79-0.94, p = 0.001). CONCLUSIONS: Our study demonstrates significant associations of SUMO4 M55V polymorphism with T1DM in Asian and Caucasian population and with T2DM in Asian population. PMID- 22936653 TI - Proteomic analysis of cerebrospinal fluid before and after intrathecal injection of steroid into patients with postherpetic pain. AB - Postherpetic neuralgia (PHN) is the most frequent complication of herpes zoster, and the risk of it increases with age. By comparing proteomes of the cerebrospinal fluid (CSF) before and after the treatment, it may be possible to identify proteins that play a role in PHN and to predict responses to various treatments. To address this issue, we enrolled eight outpatients with PHN over 55 years of age and treated them with intrathecal methylprednisolone and lidocaine four times every week, collecting CSF samples before the treatment at each visit. We used 2D DIGE to investigate differentially expressed proteins in the CSF before and after repetitive treatments individually. Of 145 differentially expressed spots, the levels of nine proteins were decreased by the treatment including lipocalin-type prostaglandin D synthase (L-PGDS), and five were increased by it. The time course of alterations in the L-PGDS concentration in the CSF of each patient, detected by a pairwise and sandwich ELISA by SPR constructed here was well correlated with that by 1DE Western blots with anti-L PGDS antibody, but was not related with that of the pain relief. The present study demonstrates that the real-time ELISA was precise and sensitive enough to measure L-PGDS in the CSF and that the steroid treatment decreased the L-PGDS concentration in CSF. PMID- 22936654 TI - Genetic incorporation of a metal-chelating amino acid as a probe for protein electron transfer. PMID- 22936655 TI - Altered microtubule equilibrium and impaired thrombus stability in mice lacking RanBP10. AB - The crucial function of blood platelets in hemostasis is to prevent blood loss by stable thrombus formation. This process is driven by orchestrated mechanisms including several signal transduction cascades and morphologic transformations. The cytoplasmic microtubule modulator RanBP10 is a Ran and beta1-tubulin binding protein that is essential for platelet granule release and mice lacking RanBP10 harbor a severe bleeding phenotype. In this study, we demonstrate that RanBP10 nullizygous platelets show normal adhesion on collagen and von Willebrand factor under flow conditions. However, using a ferric chloride-induced arterial thrombosis model, the formation of stable thrombi was significantly impaired, preventing vessel occlusion or leading to recanalization and thromboembolization. Delta-granule secretion was normal in mutant mice, whereas platelet shape change in aggregometry was attenuated. Lack of RanBP10 leads to increased beta1-tubulin protein, which drives alpha-monomers into polymerized microtubules. In mutant platelets agonists failed to contract the peripheral marginal band or centralize granules. Pretreatment of wild-type platelets with taxol caused microtubule stabilization and phenocopied the attenuated shape change in response to collagen, suggesting that RanBP10 inhibits premature microtubule polymerization of beta1-tubulin and plays a pivotal role in thrombus stabilization. PMID- 22936656 TI - Kruppel-like factor 7 overexpression suppresses hematopoietic stem and progenitor cell function. AB - Increased expression of Kruppel-like factor 7 (KLF7) is an independent predictor of poor outcome in pediatric acute lymphoblastic leukemia. The contribution of KLF7 to hematopoiesis has not been previously described. Herein, we characterized the effect on murine hematopoiesis of the loss of KLF7 and enforced expression of KLF7. Long-term multilineage engraftment of Klf7(-/-) cells was comparable with control cells, and self-renewal, as assessed by serial transplantation, was not affected. Enforced expression of KLF7 results in a marked suppression of myeloid progenitor cell growth and a loss of short- and long-term repopulating activity. Interestingly, enforced expression of KLF7, although resulting in multilineage growth suppression that extended to hematopoietic stem cells and common lymphoid progenitors, spared T cells and enhanced the survival of early thymocytes. RNA expression profiling of KLF7-overexpressing hematopoietic progenitors identified several potential target genes mediating these effects. Notably, the known KLF7 target Cdkn1a (p21(Cip1/Waf1)) was not induced by KLF7, and loss of CDKN1A does not rescue the repopulating defect. These results suggest that KLF7 is not required for normal hematopoietic stem and progenitor function, but increased expression, as seen in a subset of lymphoid leukemia, inhibits myeloid cell proliferation and promotes early thymocyte survival. PMID- 22936657 TI - Absence of LTB4/BLT1 axis facilitates generation of mouse GM-CSF-induced long lasting antitumor immunologic memory by enhancing innate and adaptive immune systems. AB - BLT1 is a high-affinity receptor for leukotriene B4 (LTB4) that is a potent lipid chemoattractant for myeloid leukocytes. The role of LTB4/BLT1 axis in tumor immunology, including cytokine-based tumor vaccine, however, remains unknown. We here demonstrated that BLT1-deficient mice rejected subcutaneous tumor challenge of GM-CSF gene-transduced WEHI3B (WGM) leukemia cells (KO/WGM) and elicited robust antitumor responses against second tumor challenge with WEHI3B cells. During GM-CSF-induced tumor regression, the defective LTB4/BLT1 signaling significantly reduced tumor-infiltrating myeloid-derived suppressor cells, increased the maturation status of dendritic cells in tumor tissues, enhanced their CD4(+) T-cell stimulation capacity and migration rate of dendritic cells that had phagocytosed tumor-associated antigens into tumor-draining lymph nodes, suggesting a positive impact on GM-CSF-sensitized innate immunity. Furthermore, KO/WGM mice displayed activated adaptive immunity by attenuating regulatory CD4(+) T subsets and increasing numbers of Th17 and memory CD44(hi)CD4(+) T subsets, both of which elicited superior antitumor effects as evidenced by adoptive cell transfer. In vivo depletion assays also revealed that CD4(+) T cells were the main effectors of the persistent antitumor immunity. Our data collectively underscore a negative role of LTB4/BLT1 signaling in effective generation and maintenance of GM-CSF-induced antitumor memory CD4(+) T cells. PMID- 22936658 TI - Combined treatment with lenalidomide and epoetin alfa in lower-risk patients with myelodysplastic syndrome. AB - The erythropoietic effects of lenalidomide are cytokine dependent, suggesting that the erythroid hematologic improvement (HI-E) rate may be augmented by combined treatment (CT) with recombinant human erythropoietin (rhu-EPO) in myelodysplastic syndrome (MDS). In the present study, we explored the benefits of CT and the relationship between lenalidomide pharmacokinetics and hematologic toxicity in transfusion-dependent patients with low- to intermediate-1-risk MDS who failed prior rhu-EPO. In stage I, patients received 10 or 15 mg/d of lenalidomide monotherapy. At week 16, erythroid nonresponders (NRs) were eligible for CT with rhu-EPO 40 000 U/wk. Among 39 patients, HI-E response rate to monotherapy was 86% (6 of 7) in del(5q) and 25% (8 of 32) in non-del(5q) patients (10 mg, 17.7%; 15 mg, 33.3%). Twenty-three patients proceeded to CT, with 6 (26.0%) achieving HI-E. In 19 non-del(5q) patients, 4 (21.1%) showed HI-E. Mean baseline serum EPO in non-del(5q) patients was lower in monotherapy and CT responders than in NR (not statistically significant). Thrombocytopenia was significantly correlated with lenalidomide area under the plasma concentration time curve (P = .0015), but severity of myelosuppression did not. The benefits of lenalidomide plus rhu-EPO are currently under investigation in a phase 3 Eastern Cooperative Oncology Group (ECOG)-sponsored intergroup study. This study is registered at www.clinicaltrials.gov as NCT00910858. PMID- 22936659 TI - Transcriptome sequencing in Sezary syndrome identifies Sezary cell and mycosis fungoides-associated lncRNAs and novel transcripts. AB - Sezary syndrome (SS) is an aggressive cutaneous T-cell lymphoma (CTCL) of unknown etiology in which malignant cells circulate in the peripheral blood. To identify viral elements, gene fusions, and gene expression patterns associated with this lymphoma, flow cytometry was used to obtain matched pure populations of malignant Sezary cells (SCs) versus nonmalignant CD4(+) T cells from 3 patients for whole transcriptome, paired-end sequencing with an average depth of 112 million reads per sample. Pathway analysis of differentially expressed genes identified mis regulation of PI3K/Akt, TGFbeta, and NF-kappaB pathways as well as T-cell receptor signaling. Bioinformatic analysis did not detect either nonhuman transcripts to support a viral etiology of SS or recurrently expressed gene fusions, but it did identify 21 SC-associated annotated long noncoding RNAs (lncRNAs). Transcriptome assembly by multiple algorithms identified 13 differentially expressed unannotated transcripts termed Sezary cell-associated transcripts (SeCATs) that include 12 predicted lncRNAs and a novel transcript with coding potential. High-throughput sequencing targeting the 3' end of polyadenylated transcripts in archived tumors from 24 additional patients with tumor-stage CTCL confirmed the differential expression of SC-associated lncRNAs and SeCATs in CTCL. Our findings characterize the SS transcriptome and support recent reports that implicate lncRNA dysregulation in human malignancies. PMID- 22936660 TI - The expanding role(s) of eosinophils in health and disease. AB - Surprisingly, the role(s) of eosinophils in health and disease is often summarized by clinicians and basic research scientists as a pervasive consensus opinion first learned in medical/graduate school. Eosinophils are rare white blood cells whose activities are primarily destructive and are only relevant in parasitic infections and asthma. However, is this consensus correct? This review argues that the wealth of available studies investigating the role(s) of eosinophils in both health and disease demonstrates that the activities of these granulocytes are far more expansive and complex than previously appreciated. In turn, this greater understanding has led to the realization that eosinophils have significant contributory roles in a wide range of diseases. Furthermore, published studies even implicate eosinophil-mediated activities in otherwise healthy persons. We suggest that the collective reports in the literature showing a role for eosinophils in an ever-increasing number of novel settings highlight the true complexity and importance of this granulocyte. Indeed, discussions of eosinophils are no longer simple and more often than not now begin with the question/statement "Did you know ...?" PMID- 22936661 TI - Structural insights into inhibition of the bivalent menin-MLL interaction by small molecules in leukemia. AB - Menin functions as a critical oncogenic cofactor of mixed lineage leukemia (MLL) fusion proteins in the development of acute leukemias, and inhibition of the menin interaction with MLL fusion proteins represents a very promising strategy to reverse their oncogenic activity. MLL interacts with menin in a bivalent mode involving 2 N-terminal fragments of MLL. In the present study, we reveal the first high-resolution crystal structure of human menin in complex with a small molecule inhibitor of the menin-MLL interaction, MI-2. The structure shows that the compound binds to the MLL pocket in menin and mimics the key interactions of MLL with menin. Based on the menin-MI-2 structure, we developed MI-2-2, a compound that binds to menin with low nanomolar affinity (K(d) = 22nM) and very effectively disrupts the bivalent protein-protein interaction between menin and MLL. MI-2-2 demonstrated specific and very pronounced activity in MLL leukemia cells, including inhibition of cell proliferation, down-regulation of Hoxa9 expression, and differentiation. Our results provide the rational and essential structural basis to design next generation of inhibitors for effective targeting of the menin-MLL interaction in leukemia and demonstrate a proof of concept that inhibition of complex multivalent protein-protein interactions can be achieved by a small-molecule inhibitor. PMID- 22936662 TI - Kininogen deficiency protects from ischemic neurodegeneration in mice by reducing thrombosis, blood-brain barrier damage, and inflammation. AB - Thrombosis and inflammation are hallmarks of ischemic stroke still unamenable to therapeutic interventions. High-molecular-weight kininogen (KNG) is a central constituent of the contact-kinin system which represents an interface between thrombotic and inflammatory circuits and is critically involved in stroke development. Kng(-/-) mice are protected from thrombosis after artificial vessel wall injury and lack the proinflammatory mediator bradykinin. We investigated the consequences of KNG deficiency in models of ischemic stroke. Kng(-/-) mice of either sex subjected to transient middle cerebral artery occlusion developed dramatically smaller brain infarctions and less severe neurologic deficits without an increase in infarct-associated hemorrhage. This protective effect was preserved at later stages of infarction as well as in elderly mice. Targeting KNG reduced thrombus formation in ischemic vessels and improved cerebral blood flow, and reconstitution of KNG-deficient mice with human KNG or bradykinin restored clot deposition and infarct susceptibility. Moreover, mice deficient in KNG showed less severe blood-brain barrier damage and edema formation, and the local inflammatory response was reduced compared with controls. Because KNG appears to be instrumental in pathologic thrombus formation and inflammation but dispensable for hemostasis, KNG inhibition may offer a selective and safe strategy for combating stroke and other thromboembolic diseases. PMID- 22936663 TI - Formation of a PKCzeta/beta-catenin complex in endothelial cells promotes angiopoietin-1-induced collective directional migration and angiogenic sprouting. AB - Angiogenic sprouting requires that cell-cell contacts be maintained during migration of endothelial cells. Angiopoietin-1 (Ang-1) and vascular endothelial growth factor act oppositely on endothelial cell junctions. We found that Ang-1 promotes collective and directional migration and, in contrast to VEGF, induces the formation of a complex formed of atypical protein kinase C (PKC)-zeta and beta-catenin at cell-cell junctions and at the leading edge of migrating endothelial cells. This complex brings Par3, Par6, and adherens junction proteins at the front of migrating cells to locally activate Rac1 in response to Ang-1. The colocalization of PKCzeta and beta-catenin at leading edge along with PKCzeta dependent stabilization of cell-cell contacts promotes directed and collective endothelial cell migration. Consistent with these results, down-regulation of PKCzeta in endothelial cells alters Ang-1-induced sprouting in vitro and knockdown in developing zebrafish results in intersegmental vessel defects caused by a perturbed directionality of tip cells and by loss of cell contacts between tip and stalk cells. These results reveal that PKCzeta and beta-catenin function in a complex at adherens junctions and at the leading edge of migrating endothelial cells to modulate collective and directional migration during angiogenesis. PMID- 22936665 TI - HIF-1alpha is a negative regulator of plasmacytoid DC development in vitro and in vivo. AB - Hypoxia-inducible factors (HIFs) regulate hematopoiesis in the embryo and maintain hematopoietic stem cell function in the adult. How hypoxia and HIFs contribute to hematopoietic lineage differentiation in the adult is ill defined. Here we provide evidence that HIF-1 limits differentiation of precursors into plasmacytoid dendritic cells (pDCs). Low oxygen up-regulated inhibitor of DNA binding 2 (ID2) and suppressed Flt3-L-induced differentiation of bone marrow cells to pDCs in wild-type but not HIF-1alpha(fl/fl) LysM-Cre bone marrow cells. Moreover, pDC differentiated normally in hypoxic ID2(-/-) bone marrow cultures. Finally, we observed elevated pDC frequencies in bone marrow, blood, and spleen of HIF-1alpha(fl/fl) LysM-Cre and ID2(-/-), but not HIF-2alpha(fl/fl) LysM-Cre mice. Our data indicate that the low oxygen content in the bone marrow might limit pDC development. This might be an environmental mechanism to restrict the numbers of these potentially autoreactive cells. PMID- 22936664 TI - Aging and neoteny in the B lineage. AB - Aging and the physiologic decline of tissues and cells were once thought to be irreversible. However, recent studies suggest that various tissues, especially parts of the hematopoietic system, can be rejuvenated. Here we review potential mechanisms for this process and how they may be used to reverse age-related disorders and aging in general. We propose the novel hypothesis that altering the homeostatic process during cellular depletion can reverse aging in the hematopoietic system. PMID- 22936667 TI - A metal-organic framework as attractive cryogenic magnetorefrigerant. AB - Magnetocaloric effect: A Gd(III)-based metal-organic framework (MOF) has an unprecedented large magnetocaloric effect around 2 K. It was shown to be an interesting magnetorefrigerant for ultralow-temperature applications, because it combines the advantages of molecular materials and the robustness of a framework with strong 3D chemical connections (see figure). PMID- 22936666 TI - Antitumor T-cell responses contribute to the effects of dasatinib on c-KIT mutant murine mastocytoma and are potentiated by anti-OX40. AB - Targeted and immune-based therapies are thought to eradicate cancer cells by different mechanisms, and these approaches could possibly complement each other when used in combination. In this study, we report that the in vivo antitumor effects of the c-KIT inhibitor, dasatinib, on the c-KIT mutant P815 mastocytoma tumor were substantially dependent on T cell-mediated immunity. We found that dasatinib treatment significantly decreased levels of Tregs while specifically enhancing tumor antigen-specific T-cell responses. We sought to further enhance this therapy with the addition of anti-OX40 antibody, which is known to provide a potent costimulatory signal to T cells. The combination of dasatinib and anti OX40 antibody resulted in substantially better therapeutic efficacy compared with either drug alone, and this was associated with enhanced accumulation of tumor antigen-specific T cells in the tumor microenvironment. Furthermore, the combination regimen inhibited the function of Tregs and also resulted in significantly up-regulated expression of the IFN-gamma-induced chemokines CXCL9, 10, and 11 in the tumor microenvironment, which provides a feasible mechanism for the enhanced intratumoral CTL infiltration. These studies delineate a strategy by which targeted therapy and immunotherapy may be combined to achieve superior antitumor responses in cancer patients. PMID- 22936668 TI - Changes in supportive care needs after first-line treatment for ovarian cancer: identifying care priorities and risk factors for future unmet needs. AB - OBJECTIVE: The objective of this paper is to determine changes in supportive care needs after first-line treatment for ovarian cancer and identify risk factors for future unmet needs. METHODS: Two hundred and nineteen women with ovarian cancer were asked to complete a baseline survey 6-12 months after diagnosis then follow up surveys every 6 months for up to 2 years. The validated Supportive Care Needs Survey-Short Form measured 34 needs across five domains. Logistic regression identified baseline variables associated with future needs. RESULTS: At baseline, standardized median scores (possible range 0-100, least-to-greatest need) within the psychological, system/information, physical, patient care and sexuality need domains were 25, 20, 15, 15 and 8, respectively. The most frequently reported moderate-to-high unmet needs at baseline were needing help with fear about cancer spreading (25%), concerns about worries of those close (20%), being informed about things to help get well (20%), uncertainty about future (19%) and lack of energy (18%). All except the item about being informed were still reported as unmet needs by >= 15% of women 2 years later. Median health system/information, patient care and sexuality need scores decreased over 2 years (p<0.05), whereas psychological and physical scores remained constant. Risk factors for having >= 1 moderate-to-high unmet overall, psychological or physical need 1-2 years after baseline included older age, advanced disease, unmet need, anxiety, depression, insomnia and less social support at baseline. CONCLUSION: Women with ovarian cancer report needing ongoing assistance to deal with psychological and physical needs over the first 2 years after first-line treatment. Targeting individuals at risk of future unmet needs should be prioritized. PMID- 22936669 TI - A genome-wide association study on a southern European population identifies a new Crohn's disease susceptibility locus at RBX1-EP300. AB - OBJECTIVE: Genome-wide association studies (GWAS) have identified multiple risk loci for Crohn's disease (CD). However, the cumulative risk exerted by these loci is low, and the likelihood that additional, as-yet undiscovered loci contribute to the risk of CD is very high. We performed a GWAS on a southern European population to identify new CD risk loci. DESIGN: We genotyped 620 901 genome markers on 1341 CD patients and 1518 controls from Spain. The top association signals representing new candidate risk loci were subsequently analysed in an independent replication cohort of 1365 CD patients and 1396 controls. RESULTS: We identified a genome-wide significant association on chromosome 22q13.2 in the intergenic region between the RBX1 and EP300 genes (single nucleotide polymorphism rs4820425, OR 1.27, 95% CI 1.17 to 1.38, p=3.42E-8). We also found suggestive evidence for the association of the IFNGR2 (21q22.11), FOXP2 (7q31), MACROD2 (20p12.1) and AIF1 (6p21.3) loci with CD risk. CONCLUSIONS: In this GWAS performed on a southern European cohort, we have identified a new risk locus for CD between RBX1 and EP300. This study demonstrates that using populations of different ancestry is a useful strategy to identify new risk loci for CD. PMID- 22936670 TI - Surface maturation scoring for oesophageal squamous intraepithelial neoplasia: a novel diagnostic approach inspired by first endomicroscopic 3-dimensional reconstruction. AB - OBJECTIVE: Loss of surface maturation and cytonuclear atypia have been regarded as the pathological 'gold standard' for the diagnosis of oesophageal squamous cell intraepithelial neoplasia. However, there has been no satisfactory endomicroscopic method similar to this pathological approach to detect surface maturation and screen for oesophageal squamous cell intraepithelial neoplasia. The aim of this study was to apply a 3-dimensional (3D) confocal endomicroscopic imaging technique to investigate the surface maturation of the oesophageal epithelium and develop new 2-dimensional confocal endomicroscopic criteria based on surface maturation. DESIGN: In the 3D reconstruction phase, intrapapillary capillary loops were reconstructed to demonstrate the stereo configuration of the oesophageal epithelium, and a novel surface maturation scoring (SMS) method for plane confocal images was developed based on the interpretation of the 3D microstructure. In the SMS diagnostic phase, 1214 patients were screened and confocal images from 64 non-invasive oesophageal lesions were independently evaluated using SMS and previous methods. RESULTS: We successfully obtained and interpreted 3D confocal images of the human oesophageal epithelium for the first time. The sensitivity (81.0%, 95% CI 58.1% to 94.6%) and specificity (90.7%, 95% CI 77.9% to 97.4%) of the newly established SMS were superior to previous confocal approaches in distinguishing squamous intraepithelial neoplasia from other non-invasive lesions. CONCLUSIONS: 3D confocal endomicroscopic imaging provides valuable insight into the stereo configuration of the human oesophageal epithelium. SMS is a novel and promising diagnostic method to distinguish neoplasia during ongoing endoscopy. PMID- 22936671 TI - New protease inhibitors and direct-acting antivirals for hepatitis C: interferon's long goodbye. PMID- 22936672 TI - Treatment of relapsing autoimmune pancreatitis with immunomodulators and rituximab: the Mayo Clinic experience. AB - BACKGROUND: There is a paucity of data on long-term management of type 1 autoimmune pancreatitis (AIP), a relapsing steroid-responsive disorder. OBJECTIVE: We describe our experience with treatment of relapses and maintenance of remission using steroid-sparing immunomodulators (IMs) and induction of remission using rituximab (RTX). METHODS: We obtained details of disease relapse and treatment in 116 type 1 AIP patients from clinic visits, medical records and telephone interviews. We compared relapse free survival in those treated with IMs versus those treated with steroids alone, assessed patients' response to RTX, and identified treatment-related complications. RESULTS: During a median follow-up of 47 months, 52/116 AIP patients experienced 76 relapse episodes. The first relapse was treated with another course of steroids in 24 patients, and with steroids plus IM in another 27 patients; subsequent relapse-free survival until a second relapse was similar in the two groups (p=0.23). 38 patients received an IM for >2 months; failure or intolerance of IM therapy occurred in 17 (45%). 12 patients with steroid or IM intolerance/resistance were treated with RTX, an antiCD20 antibody; 10 (83%) experienced complete remission and had no relapses while on maintenance therapy. Treatment-limiting side effects related to RTX were uncommon. CONCLUSIONS: In type 1 AIP relapses are common. Relapse-free survival is similar in those treated with steroids plus IM compared to those treated with steroids alone. Nearly half the patients on IMs will relapse during treatment. RTX is effective in the treatment of both IM resistant and steroid intolerant patients. PMID- 22936673 TI - Diagnostic accuracy of magnetic resonance colonography for the evaluation of disease activity and severity in ulcerative colitis: a prospective study. AB - OBJECTIVE: The aim of this study was to determine the diagnostic accuracy of magnetic resonance colonography (MRC) for the evaluation of disease activity and severity in patients with ulcerative colitis (UC) using endoscopy as the reference standard. METHODS: Fifty patients with UC underwent colonoscopy and MRC for the evaluation of disease activity. All patients were prospectively and consecutively included. Endoscopic activity was evaluated globally and on a segment basis using the modified Baron score (MBS), and also classified as absent, mild to moderate (inflammation without ulcers) or severe (presence of ulceration). MRC parameters evaluated in each segment were: wall thickness, pre- and post-contrast wall signal intensity, relative contrast enhancement (RCE), mural oedema, ulcers, enlarged lymph nodes and the comb sign. RESULTS: Independent predictors for endoscopic activity on a segment basis were RCE (p=0.006), presence of oedema (p=0.003), enlarged lymph nodes (p<0.001) and the comb sign (p<0.001). A segmental simplified MRC index (MRC-S) >= 1 detected endoscopic inflammation with high diagnostic accuracy (sensitivity 87%, specificity 88%, area under the curve (AUC) 0.95; p<0.001). MRC-S index >= 2 detected severe lesions with high sensitivity (83%) and specificity (82%) with an AUC of 0.91 (p<0.001). The MRC-S index strongly correlated with the MBS (r=0.81, p<0.001) and with the subjective assessment of the radiologists for the evaluation of disease severity (r=0.77, p<0.001). CONCLUSIONS: MRC has a high accuracy for the diagnosis of disease activity and severity in UC. PMID- 22936675 TI - Exploring life before IBD. PMID- 22936674 TI - CagA mediates epigenetic regulation to attenuate let-7 expression in Helicobacter pylori-related carcinogenesis. AB - OBJECTIVE: MicroRNAs (miRNAs) act as tumour suppressor genes or oncogenes in the regulation of multiple carcinogenic processes. Aberrant miRNA expression is reported in Helicobacter pylori (H pylori)-related gastritis and gastric cancer. The cytotoxin-associated gene A (CagA) of H pylori has a pathophysiologically important role in gastric carcinogenesis. A study was undertaken to evaluate the effect of CagA on miRNA expression and its regulatory mechanism. METHODS: The effect of CagA on miRNA expression was assessed by comprehensive miRNA microarray. The mechanisms of the in vitro and in vivo effects of CagA on histone modification and DNA methylation and the involvement of CagA-dysregulated signal transduction on let-7, an important representative miRNA in gastric carcinogenesis, were investigated. RESULTS: In in vitro experiments, CagA significantly attenuated let-7 expression leading to Ras pathway activation. CagA enhanced c-myc, DNA methyltransferase 3B (DNMT3B) and Enhancer of Zeste homologue 2 (EZH2) expression and attenuated miR-26a and miR-101 expression, which resulted in the attenuation of let-7 expression by histone and DNA methylation. Experiments performed in CagA transgenic mice revealed that c-myc, EZH2 and DNMT3B expression were enhanced and let-7 expression was attenuated to induce Ras oncoprotein expression in the stomach, with no associated inflammation. CONCLUSIONS: H pylori CagA induces aberrant epigenetic silencing of let-7 expression, leading to Ras upregulation. PMID- 22936676 TI - FTY720 preserved islet beta-cell mass by inhibiting apoptosis and increasing survival of beta-cells in db/db mice. AB - BACKGROUND: FTY720, an analogue of sphingosine-1-phosphate, has shown potential in the treatment of several autoimmune diseases, such as multiple sclerosis, type 1 diabetes and systemic lupus erythematosus. It prevents development or cure of autoimmune diabetes in animal models. Recently, we reported that FTY720 also prevents development of diabetes in db/db mice by beta-cell regeneration in vivo. This study investigated the effect of FTY720 on apoptosis in beta-cells in db/db mice treated with FTY720 16 weeks. METHODS: Six week old female db/db mice were divided into control and FTY720 groups. FTY720 (10 mg/kg) was orally administrated daily. Body weights and fasting glucose levels were measured once a week after overnight fasting. After 16 weeks of treatment, oral glucose and insulin tolerance tests were performed, serum insulin levels and insulin contents in pancreas were determined, and then all mice were subjected to physiological and histological analyses. RESULTS: FTY720-treated mice showed normal fasting glucose levels, improved glucose tolerance with normal insulin sensitivity and restored beta-cell function to produce and secret insulin. Pancreas histology revealed that FTY720 prevented islet damage and preserved beta-cell mass by inhibiting apoptosis and increasing beta-cell survival in pancreatic islets. CONCLUSIONS: We concluded that early intervention with FTY720 in db/db mice can prevent development of diabetes through preserving beta-cell mass by inhibiting apoptosis and increasing survival of islet beta-cells. PMID- 22936677 TI - Proteomic analysis of ganglioside-associated membrane molecules: substantial basis for molecular clustering. AB - Ganglioside GD3 is specifically expressed in human melanomas, and plays a role in the enhancement of malignant phenotypes of melanoma cells. To analyze the mechanisms by which GD3 enhances malignant properties and signals in melanomas, it is essential to clarify how GD3 interacts with membrane molecules on the cell membrane. In this study, we performed proteomics analysis of glycolipid-enriched microdomains (GEM) with current sucrose density gradient ultracentrifugation of Triton X-100 extracts and MS. We also examined GD3-associated molecules using enzyme-mediated activation of radical sources (EMARS) reaction combined with MS. Comparison of molecules identified as residents in GEM/rafts and those detected by EMARS reaction using an anti-GD3 antibody revealed that a relatively low number of molecules is recruited around GD3, while a number of membrane and secreted molecules was defined in GEM/rafts. These results suggested that EMARS reaction is useful to identify actually interacting molecules with gangliosides such as GD3 on the cell membrane, and many other microdomains than GD3 associating rafts exist. Representative examples of GD3-associated molecules such as neogenin and MCAM were shown. PMID- 22936678 TI - Evaluation of SDS depletion using an affinity spin column and IMS-MS detection. AB - While the use of detergents is necessary for a variety of protein isolation preparation protocols, they are not compatible with mass spectral analysis due to ion suppression and adduct formation. This manuscript describes optimization of detergent removal, using commercially available SDS depletion spin columns containing an affinity resin, providing for both increased protein recovery and thorough SDS removal. Ion mobility spectrometry coupled with mass spectrometry (IMS-MS) allowed for a concurrent analysis of both analyte and detergent. In the case of both proteins and peptides, higher detergent concentrations than previously reported provided an increase of sample recovery; however there was a limit as SDS was detected by IMS-MS at higher levels of SDS indicating incomplete detergent depletion. The results also suggest that optimal conditions for SDS removal are dependent on the sample concentration. Overall, this study provides a useful guide for proteomic studies where SDS is required for efficient sample preparation. PMID- 22936679 TI - Insulin resistance in multiple tissues in patients with type 1 diabetes mellitus on long-term continuous subcutaneous insulin infusion therapy. AB - BACKGROUND: The aim of this study was to determine whether insulin resistance is present in lean patients with uncomplicated type 1 diabetes mellitus on long-term continuous subcutaneous insulin infusion (CSII), compared with matched healthy controls. METHODS: We studied eight patients (four men and four women) with type 1 diabetes mellitus on continuous subcutaneous insulin infusion and eight healthy controls, matched for age, gender and body mass index. Insulin sensitivity was measured by hyperinsulinemic euglycemic clamp studies with infusion of [6,6-(2) H(2)] glucose. RESULTS: Endogenous glucose production did not differ in the basal state between patients and controls. However, endogenous glucose production was less suppressed during clamp conditions in patients compared with controls (64% vs 79%, p = 0.01), indicating decreased hepatic insulin sensitivity. During the clamp study, glucose disposal rate was ~38% lower in patients compared with controls (24.4 +/- 2.5 vs 39.7 +/- 5.6 umol/kgLBM/min, p = 0.04). Accordingly, the rate of infusion of glucose was ~51% lower in patients (17.7 +/- 2.8 vs 39.7 +/- 5.7 umol/kgLBM/min, p = 0.02). Finally, non-esterified fatty acids levels were ~2.5 times higher in patients during steady state clamp conditions (150 +/- 26 vs 58 +/- 4 pmol/L, p = 0.01), reflecting decreased insulin sensitivity of lipolysis. CONCLUSIONS: Insulin resistance is a prominent feature of lean patients with type 1 diabetes mellitus, despite long term and stable treatment with continuous subcutaneous insulin infusion. Insulin resistance in type 1 diabetes involves both lipolysis, hepatic and peripheral glucose metabolism. PMID- 22936680 TI - Epidithiol formation by an unprecedented twin carbon-sulfur lyase in the gliotoxin pathway. PMID- 22936681 TI - Cardiovascular magnetic resonance measurement of myocardial extracellular volume in health and disease. AB - OBJECTIVE: To measure and assess the significance of myocardial extracellular volume (ECV), determined non-invasively by equilibrium contrast cardiovascular magnetic resonance, as a clinical biomarker in health and a number of cardiac diseases of varying pathophysiology. DESIGN: Prospective study. SETTING: Tertiary referral cardiology centre in London, UK. PATIENTS: 192 patients were mainly recruited from specialist clinics. We studied patients with Anderson-Fabry disease (AFD, n=17), dilated cardiomyopathy (DCM, n=31), hypertrophic cardiomyopathy (HCM, n=31), severe aortic stenosis (AS, n=66), cardiac AL amyloidosis (n=27) and myocardial infarction (MI, n=20). The results were compared with those for 81 normal subjects. RESULTS: In normal subjects, ECV (mean (95% CI), measured in the septum) was slightly higher in women than men (0.273 (0.264 to 0.282 vs 0.233 (0.225 to 0.244), p<0.001), with no change with age. In disease, the ECV of AFD was the same as in normal subjects but higher in all other diseases (p<0.001). Mean ECV was the same in DCM, HCM and AS (0.280, 0.291, 0.276 respectively), but higher in cardiac AL amyloidosis and higher again in MI (0.466 and 0.585 respectively, each p<0.001). Where ECV was elevated, correlations were found with indexed left ventricular mass, end systolic volume, ejection fraction and left atrial area in apparent disease-specific patterns. CONCLUSIONS: Myocardial ECV, assessed non-invasively in the septum with equilibrium contrast cardiovascular magnetic resonance, shows gender differences in normal individuals and disease-specific variability. Therefore, ECV shows early potential to be a useful biomarker in health and disease. PMID- 22936682 TI - Industrial pharmaceutical drug research has done more for the health of people with MS than academic neurologists: yes. PMID- 22936683 TI - Industrial pharmaceutical drug research has done more for the health of people with MS than academic neurologists: no. PMID- 22936684 TI - Industrial pharmaceutical drug research has done more for the health of people with MS than academic neurologists: commentary. PMID- 22936688 TI - In vitro comparison of two different methods of cell washing. AB - The storage of red blood cells (RBC) results in increased concentrations of plasma free hemoglobin, potassium, glucose, and lactate, among other undesirable substances. These concentrations continue to increase as RBC products age and can cause deleterious effects to the patient. In the setting of cardiac surgery, the autotransfusion devices are routinely used to wash blood that is shed from the surgical site. These devices could also be used to wash stored RBC units obtained from the blood bank. The objective of this study was to compare the product created by washing a unit of RBCs with the AutoLog autotransfusion device in the operating room to the washed products from a standard cell washer in the blood bank. Eleven outdated RBC units (stored for >42 days at 4 degrees C) were split in half. One half was washed using the Medtronic AutoLog device; the other half was washed using the blood bank's Cobe 2991 Cell Processor. Analytes were measured on samples from the unwashed parent unit and from the washed daughter units. The parameters measured included hematocrit, free hemoglobin, lactate, lactate dehydrogenase (LDH), potassium, glucose, and pH. When compared to the original untreated RBCs, the glucose, lactate, and potassium levels were decreased when washed in an autotranfusion device. Additionally, the free hemoglobin and LDH levels were significantly lower with the Medtronic Autolog cell saver than in the COBE 2991 Cell Processor. Washing the RBC donor units in an autotransfusion device prior to transfusion can effectively attenuate the increases seen in glucose, potassium, free hemoglobin, and LDH associated with RBC storage lesion. PMID- 22936689 TI - Pancreatic beta-cell function and type 2 diabetes risk: quantify the causal effect using a Mendelian randomization approach based on meta-analyses. AB - The objective of the study is to quantify the causal effect of beta-cell function on type 2 diabetes by minimizing residual confounding and reverse causation. We employed a Mendelian randomization (MR) approach using TCF7L2 variant rs7903146 as an instrument for lifelong levels of beta-cell function. We first conducted two sets of meta-analyses to quantify the association of the TCF7L2 variant with the risk of type 2 diabetes among 55 436 cases and 106 020 controls from 66 studies by calculating pooled odds ratio (OR) and to quantify the associations with multiple direct or indirect measures of beta-cell function among 35 052 non diabetic individuals from 31 studies by calculating pooled mean difference. We further applied the method of MR to obtain the causal estimates for the effect of beta-cell function on type 2 diabetes risk based on findings from the meta analyses. The OR [95% confidence interval (CI)] was 0.87 (0.81-0.93) for each five unit increment in homeostasis model assessment of insulin secretion (HOMA %B) (P = 3.0 * 10(-5)). In addition, for measures based on intravenous glucose tolerance test, ORs (95% CI) associated with type 2 diabetes risk were 0.24 (0.08 0.74) (P = 0.01) and 0.14 (0.04-0.48) (P = 0.002) for per 1 standard deviation increment in insulin sensitivity index and disposition index, respectively. Findings from the present study lend support to a causal role of pancreatic beta cell function itself in the etiology of type 2 diabetes. PMID- 22936690 TI - Functional evaluation of genetic variation in complex human traits. AB - Genome-wide association studies and, more recently, next-generation sequencing studies have accelerated the investigation of complex human traits by providing a wealth of association data linking genetic variants to diseases and other phenotypic traits. These data promise to transform our understanding of the molecular pathways underlying complex human traits, but only if functional evaluation of the novel genetic variants is undertaken. Here, we review recent examples in which such functional evaluation has been attempted, with varying degrees of success, and we highlight new technological advances that should greatly enhance our ability to identify and dissect causal genotype-phenotype relationships. PMID- 22936692 TI - Can genetic associations change with age? CFH and age-related macular degeneration. AB - Genetic variation in the gene encoding complement factor H (CFH) on chromosome 1q31 has repeatedly been associated with an increased risk of age-related macular degeneration (AMD); however, previous studies have had inadequate numbers of participants across a sufficiently wide age range to determine whether the association varies by age. We conducted a genetic case-control study using data from 2294 cases and 2294 controls selected from the Melbourne Collaborative Cohort Study, matched on age, sex and region of origin. Four consistently replicated CFH single-nucleotide polymorphisms (SNPs) were genotyped: rs1061170 (Y402H), rs2274700, rs393955 and rs800292; their relationship with AMD prevalence was determined across the age range 48-86. A difference in genotype frequencies was seen across age groups, where the low-risk homozygote prevalence rose with each increasing age group. Associations with early AMD were strongly modified by age for three of the four SNPs (interaction P-value: 0.01-0.00003). An inverse association between the high-risk homozygote for each SNP and early AMD was observed in the younger age groups [odds ratios (OR) range 0.37-0.48 for age <55], reversing to a positive association with increasing age (OR 1.87-2.8 for age >75). The direction of associations for this gene change was from inverse to risk with increasing age. These findings have important implications for predictive models for AMD and potentially other age-related diseases which extrapolate risks from older cohorts, as they assume homogeneity of association by age, which might not exist. PMID- 22936691 TI - Chromatin and epigenetic regulation of pre-mRNA processing. AB - New data are revealing a complex landscape of gene regulation shaped by chromatin states that extend into the bodies of transcribed genes and associate with distinct RNA elements such as exons, introns and polyadenylation sites. Exons are characterized by increased levels of nucleosome positioning, DNA methylation and certain histone modifications. As pre-mRNA splicing occurs co-transcriptionally, changes in the transcription elongation rate or epigenetic marks can influence exon splicing. These new discoveries broaden our understanding of the epigenetic code and ascribe a novel role for chromatin in controlling pre-mRNA processing. In this review, we summarize the recently discovered interplay between the modulation of chromatin states and pre-mRNA processing with the particular focus on how these processes communicate with one another to control gene expression. PMID- 22936695 TI - An MBoC favorite: regulation of the vitellogenin receptor during Drosophila melanogaster oogenesis. PMID- 22936694 TI - Genome-wide association study identifies a new locus JMJD1C at 10q21 that may influence serum androgen levels in men. AB - Circulating androgen levels are often used as indicators of physiological or pathological conditions. More than half of the variance for circulating androgen levels is thought to be genetically influenced. A genome-wide association study (GWAS) has identified two loci, SHBG at 17p13 and FAM9B at Xp22, for serum testosterone (T) levels; however, these explain only a small fraction of inter individual variability. To identify additional genetic determinants of androgen levels, a GWAS of baseline serum T and dihydrotestosterone (DHT) levels was conducted in 3225 men of European ancestry from the REduction by DUtasteride of Prostate Cancer Events (REDUCE) study. Cross-validation was used to confirm the observed associations between the drug (n = 1581) and placebo (n = 1644) groups of REDUCE. In addition to confirming the associations of two known loci with serum T levels (rs727428 in SHBG: P = 1.26 * 10(-12); rs5934505 in FAM9B: P = 1.61 * 10(-8)), we identified a new locus, JMJD1C at 10q21 that was associated with serum T levels at a genome-wide significance level (rs10822184: P = 1.12 * 10(-8)). We also observed that the SHBG locus was associated with serum DHT levels (rs727428: P = 1.47 * 10(-11)). Moreover, two additional variants in SHBG [rs72829446, in strong linkage equilibrium with the missense variant D356N (rs6259), and rs1799941] were also independently associated with circulating androgen levels in a statistical scale. These three loci (JMJD1C, SHBG and FAM9B) were estimated to account for ~5.3 and 4.1% of the variance of serum T and DHT levels. Our findings may provide new insights into the regulation of circulating androgens and potential targets for androgen-based therapy. PMID- 22936693 TI - Immunochip analyses identify a novel risk locus for primary biliary cirrhosis at 13q14, multiple independent associations at four established risk loci and epistasis between 1p31 and 7q32 risk variants. AB - To further characterize the genetic basis of primary biliary cirrhosis (PBC), we genotyped 2426 PBC patients and 5731 unaffected controls from three independent cohorts using a single nucleotide polymorphism (SNP) array (Immunochip) enriched for autoimmune disease risk loci. Meta-analysis of the genotype data sets identified a novel disease-associated locus near the TNFSF11 gene at 13q14, provided evidence for association at six additional immune-related loci not previously implicated in PBC and confirmed associations at 19 of 22 established risk loci. Results of conditional analyses also provided evidence for multiple independent association signals at four risk loci, with haplotype analyses suggesting independent SNP effects at the 2q32 and 16p13 loci, but complex haplotype driven effects at the 3q25 and 6p21 loci. By imputing classical HLA alleles from this data set, four class II alleles independently contributing to the association signal from this region were identified. Imputation of genotypes at the non-HLA loci also provided additional associations, but none with stronger effects than the genotyped variants. An epistatic interaction between the IL12RB2 risk locus at 1p31and the IRF5 risk locus at 7q32 was also identified and suggests a complementary effect of these loci in predisposing to disease. These data expand the repertoire of genes with potential roles in PBC pathogenesis that need to be explored by follow-up biological studies. PMID- 22936696 TI - An MBoC favorite: CRB3 binds directly to Par6 and regulates the morphogenesis of the tight junctions in mammalian epithelial cells. PMID- 22936697 TI - An October call to arms: we are research! AB - The American Society for Cell Biology is targeting the first week of October 2012 (the week before Nobel Prize winners are announced) to launch the We Are Research initiative. The goal of this initiative is to mobilize practicing junior and senior scientists, including graduate students, postdocs, and other lab members, to make contact with their elected officials and neighbors and explain to them why Federal support and investment in biomedical research is vital to the health and economic welfare of the United States. This initiative is designed to illustrate how important people are to scientific research and to supply our representatives with reliable and accurate information in the form of letters, emails, telephone calls, and personal visits. PMID- 22936698 TI - The "study" role of past National Institutes of Health study sections. AB - The original National Institutes of Health (NIH) study sections had two missions. The review of grant applications was the enduring one that we all recognize. The second original function, less remembered today, was to stand ready to advise the NIH, and in fact the entire community in a given biomedical field, on the current state of that discipline, as well as to opine on what new vistas were arising and to suggest (or occasionally even launch) appropriate courses of action. The present contribution is intended to remind us of this lesser-known original function of NIH study sections. We might ponder whether today's study sections, although more overworked than Sisyphus, should again take up this second function. PMID- 22936699 TI - Evaluating how we evaluate. AB - Evaluation of scientific work underlies the process of career advancement in academic science, with publications being a fundamental metric. Many aspects of the evaluation process for grants and promotions are deeply ingrained in institutions and funding agencies and have been altered very little in the past several decades, despite substantial changes that have taken place in the scientific work force, the funding landscape, and the way that science is being conducted. This article examines how scientific productivity is being evaluated, what it is rewarding, where it falls short, and why richer information than a standard curriculum vitae/biosketch might provide a more accurate picture of scientific and educational contributions. The article also explores how the evaluation process exerts a profound influence on many aspects of the scientific enterprise, including the training of new scientists, the way in which grant resources are distributed, the manner in which new knowledge is published, and the culture of science itself. PMID- 22936700 TI - Agricultural exposures and farm-related injuries among adolescents in rural China. AB - This cross-sectional study explored the incidence of farm injuries and the relationship between agricultural exposures and injury among 2053 adolescents aged 13-19 years in Macheng, China. A comprehensive self-administered questionnaire was given to adolescents. The cumulative incidence rate of farm injury was 19.8%. Adolescents who were male, aged 10-15 years, left behind, working more days each month and living on the plains, reported higher rates. Specific agricultural exposures, such as large animals, pesticides and operating farm machinery were associated with higher injury rates. Prevention programmes are needed to reduce farm injuries. PMID- 22936701 TI - Cost benefit analysis of 20 mph zones in London. AB - Evidence suggests that 20 mph zones are an effective intervention to reduce casualties from road traffic crashes in urban areas. This analysis compares the costs of construction of the 20 mph zone intervention in high and low casualty areas in London to the value of casualties avoided over 5 and 10 year time horizons. Probabilistic sensitivity analyses were conducted to quantify uncertainty in the results associated with model parameters. Results indicate a net present value (NPV) of L18 947 (90% credible limits -L75 252 to L82 021 2005 prices) after 5 years and L67 306 (L-29 157 to L137 890) after 10 years when 20 mph zones are implemented in areas with one or more casualty per kilometre of road. Simulations from our model suggest that the 'threshold of casualties' where NPVs become positive using a 10 year time horizon is 0.7 casualties per kilometre. PMID- 22936702 TI - Genome-wide association analysis reveals 12q13.3-q14.1 as new risk locus for sarcoidosis. AB - Sarcoidosis is a systemic inflammatory disease of unknown aetiology, influenced by genetic and environmental factors. However, the loci so far identified for sarcoidosis explain only a part of its assumed heritability. To identify further susceptibility loci, we performed a genome-wide association analysis using the Affymetrix 6.0 Human GeneChip followed by validation and replication stages. After quality control, 637 cases, 1233 controls and 677 619 single-nucleotide polymorphisms (SNPs) were available for an initial screening. 99 SNPs were selected for validation in an independent study panel (1664 patients, 2932 controls). SNP rs1050045 was significantly associated with sarcoidosis (corrected p=0.0215) in the validation panel and yielded a p-value of 9.22 * 10(-8) (OR 1.24) in the meta-analysis of the screening and validation stage. A meta-analysis of three populations from Germany, the Czech Republic and Sweden confirmed this finding (p = 0.024; OR 1.14). Fine-mapping and mRNA expression studies pointed to osteosarcoma amplified 9 (OS9) as the most likely candidate for the underlying risk factor. The OS9 protein plays an important role in endoplasmic reticulum associated protein degradation and acts during Toll-like receptor induced activation of myeloid cells. Expression analyses of OS9 mRNA provide evidence for a functional mechanism underlying the detected association signal. PMID- 22936703 TI - The lectin-like domain of thrombomodulin hampers host defence in pneumococcal pneumonia. AB - The lectin-like domain of thrombomodulin (TM) plays an important regulatory role in sterile inflammatory conditions, but its role in severe Gram-positive infectious disease is unknown. Streptococcus pneumoniae is the most common cause of community-acquired pneumonia. The aim of this study was to determine the role of the lectin-like domain of TM in murine pneumococcal pneumonia. Wild-type (WT) mice and mice lacking the lectin-like domain of TM (TM(LeD/LeD)) were infected intranasally with viable S. pneumoniae and either observed in a survival study or euthanised 6, 24 or 48 h after infection. TM(LeD/LeD) mice had a markedly better survival in pneumococcal pneumonia when compared with WT mice. At 48 h post infection with S. pneumoniae, TM(LeD/LeD) mice had lower bacterial loads in blood and liver, and exhibited less pulmonary inflammation, as shown by having less lung histopathology, less neutrophil influx and lower cytokine and chemokine levels. Plasma levels of pro-inflammatory cytokines were also reduced in TM(LeD/LeD) mice after exposure to the infection. Deletion of the lectin-like domain of TM improves the host defence in pneumococcal pneumonia. The lectin-like domain of TM may have a differential role in response to Gram-positive or Gram negative bacteria. PMID- 22936704 TI - Major bleeding with vitamin K antagonist anticoagulants in pulmonary hypertension. AB - Vitamin K antagonists are advised in pulmonary arterial hypertension patients despite a lack of safety data. We reviewed major bleeding in three classes of pulmonary hypertension patients, all receiving vitamin K antagonists. Bleeding event rates were 5.4 per 100 patient-years for patients with idiopathic pulmonary arterial hypertension, 19 per 100 patient-years for connective tissue disease related pulmonary arterial hypertension patients and 2.4 per 100 patient-years for chronic thromboembolic pulmonary hypertension patients. Life tables analysis showed that event-free survival was worse in patients with connective tissue disease related pulmonary hypertension than in patients with idiopathic pulmonary arterial hypertension (Wilcoxon=12.8; p<0.001), and patients with chronic thromboembolic pulmonary hypertension (Wilcoxon=23.2; p<0.001). Patients with idiopathic pulmonary arterial hypertension suffered more events than patients with chronic thromboembolic pulmonary hypertension (Wilcoxon=7.2; p<0.01). Major bleeding was independent of age, sex, target international normalised ratio (INR) range, documented INR, vitamin K antagonist type, or right atrial pressure, but was associated with use of prostacyclin analogues. Major bleeding risk during vitamin K antagonist therapy differs among groups of patients with pulmonary hypertension. Further research regarding optimal anticoagulant therapy is needed, as well as risk-benefit analyses for pulmonary hypertension patients with a higher bleeding propensity. PMID- 22936706 TI - Smoking cessation strategies in patients with COPD. AB - Smoking cessation is the cornerstone of treatment of chronic obstructive pulmonary disease (COPD) patients. This systematic review evaluates the effectiveness of behavioural and pharmacological smoking cessation strategies in COPD patients. MEDLINE was searched from January 2002 to October 2011. Randomised controlled trials evaluating the effect of smoking cessation interventions for COPD patients, published in English, were selected. The methodological quality of included trials was assessed using the Delphi list by two reviewers independently. The relative risks of smoking cessation due to the intervention, compared with controls, were calculated. Eight studies met the inclusion criteria. Heterogeneity was observed for study population, the intervention strategy, the follow-up period and the outcome. According to the Delphi list methodological quality scores, five studies were considered to be of acceptable quality. Pharmacological therapy combined with behavioural counselling was more effective than each strategy separately. In COPD patients, the intensity of counselling did not seem to influence the results, nor did the choice of drug therapy make a difference. This systematic review makes clear that in COPD patients, pharmacological therapy combined with behavioural counselling is more effective than each strategy separately. Neither the intensity of counselling nor the type of anti-smoking drug made a difference. PMID- 22936705 TI - Impact of obesity on outcomes for patients hospitalised with pneumonia. AB - Obesity is an increasing problem in the USA, and research into the association between obesity and pneumonia has yielded conflicting results. Using Department of Veterans Affairs administrative data from fiscal years 2002-2006, we examined a cohort of patients hospitalised with a discharge diagnosis of pneumonia. Body mass index was categorised as underweight (<18.5 kg . m(-2)), normal (18.5-24.9 kg . m(-2), reference group), overweight (25-29.9 kg . m(-2)), obese (30-39.9 kg . m(-2)) and morbidly obese (>= 40 kg . m(-2)). Our primary analyses were multi level regression models with the outcomes of 90-day mortality, intensive care unit (ICU) admission, need for mechanical ventilation and vasopressor utilisation. The cohort comprised 18 746 subjects: 3% were underweight, 30% were normal, 36% were overweight, 27% were obese and 4% were morbidly obese. In the regression models, after adjusting for potential confounders, morbid obesity was not associated with mortality (OR 0.96, 95% CI 0.72-1.28), but obesity was associated with decreased mortality (OR 0.86, 95% CI 0.74-0.99). Neither obesity nor morbid obesity was associated with ICU admission, use of mechanical ventilation or vasopressor utilisation. Underweight patients had increased 90-day mortality (OR 1.40, 95% CI 1.14-1.73). Although obesity is a growing health epidemic, it appears to have little impact on clinical outcomes and may reduce mortality for veterans hospitalised with pneumonia. PMID- 22936707 TI - The TL,NO/TL,CO ratio in pulmonary function test interpretation. AB - The transfer factor of the lung for nitric oxide (T(L,NO)) is a new test for pulmonary gas exchange. The procedure is similar to the already well-established transfer factor of the lung for carbon monoxide (T(L,CO)). Physiologically, T(L,NO) predominantly measures the diffusion pathway from the alveoli to capillary plasma. In the Roughton-Forster equation, T(L,NO) acts as a surrogate for the membrane diffusing capacity (D(M)). The red blood cell resistance to carbon monoxide uptake accounts for ~50% of the total resistance from gas to blood, but it is much less for nitric oxide. T(L,NO) and T(L,CO) can be measured simultaneously with the single breath technique, and D(M) and pulmonary capillary blood volume (V(c)) can be estimated. T(L,NO), unlike T(L,CO), is independent of oxygen tension and haematocrit. The T(L,NO)/T(L,CO) ratio is weighted towards the D(M)/V(c) ratio and to alpha; where alpha is the ratio of physical diffusivities of NO to CO (alpha=1.97). The T(L,NO)/T(L,CO) ratio is increased in heavy smokers, with and without computed tomography evidence of emphysema, and reduced in the voluntary restriction of lung expansion; it is expected to be reduced in chronic heart failure. The T(L,NO)/T(L,CO) ratio is a new index of gas exchange that may, more than derivations from them of D(M) and V(c) with their in-built assumptions, give additional insights into pulmonary pathology. PMID- 22936708 TI - Oestradiol ameliorates monocrotaline pulmonary hypertension via NO, prostacyclin and endothelin-1 pathways. AB - Pulmonary hypertension continues to be a serious clinical problem with high mortality. As oestrogen is a potential vasodilator of the pulmonary circulation, this study examined the mechanisms by which 17beta-oestradiol improves monocrotaline (MCT)-induced pulmonary hypertension. Female Sprague-Dawley rats underwent bilateral ovariectomy or sham operations. The rats received MCT (50 mg.kg(-1)) and were treated with 17beta-oestradiol (1 mg.kg(-1) per day) for either 5 weeks or only from week 4 to week 5. Plasma 17beta-oestradiol concentrations were decreased in sham-operated, MCT-treated rats when compared with sham-operated rats (17.7 +/- 4.7 versus 50.3 +/- 15.4 pg.mL(-1); p=0.029). The 17beta-oestradiol anabolic enzyme cytochrome P450 (CYP)-19 was decreased by MCT treatment, while the catabolic enzymes CYP-1A1 and -1B1 were increased. Ovariectomised and MCT-treated rats had more severe pulmonary hypertension. 17beta-oestradiol suppressed pulmonary arterial smooth muscle cell proliferation and macrophage infiltration, and enhanced apoptosis by increasing nitric oxide (NO) and prostacyclin (prostaglandin (PG)I2) levels and reducing endothelin (ET) 1 levels. Phosphoinositide-3-kinase (PI3K) and Akt phosphorylations were markedly increased, but were inhibited by 17beta-oestradiol treatment in rats with pulmonary hypertension. Oestrogen deficiency may aggravate development of pulmonary hypertension. 17beta-oestradiol improved pulmonary hypertension via activation of the PI3K/Akt pathway to regulate NO, PGI2 and ET-1 expression. PMID- 22936709 TI - A potential role for insulin resistance in experimental pulmonary hypertension. AB - Patients with pulmonary arterial hypertension have increased prevalence of insulin resistance. We aimed to determine whether metabolic defects are associated with bone morphogenic protein receptor type 2 (Bmpr2) mutations in mice, and whether these may contribute to pulmonary vascular disease development. Metabolic phenotyping was performed on transgenic mice with inducible expression of Bmpr2 mutation, R899X. Phenotypic penetrance in Bmpr2(R899X) was assessed in a high-fat diet model of insulin resistance. Alterations in glucocorticoid responses were assessed in murine pulmonary microvascular endothelial cells and Bmpr2(R899X) mice treated with dexamethasone. Compared to controls, Bmpr2(R899X) mice showed increased weight gain and demonstrated insulin resistance as assessed by the homeostatic model assessment insulin resistance (1.0 +/- 0.4 versus 2.2 +/ 1.8) and by fat accumulation in skeletal muscle and decreased oxygen consumption. Bmpr2(R899X) mice fed a high-fat diet had strong increases in pulmonary hypertension penetrance (seven out of 11 versus three out of 11). In cell culture and in vivo experiments, Bmpr2 mutation resulted in a combination of constitutive glucocorticoid receptor activation and insensitivity. Insulin resistance is present as an early feature of Bmpr2 mutation in mice. Exacerbated insulin resistance through high-fat diet worsened pulmonary phenotype, implying a possible causal role in disease. Impaired glucocorticoid responses may contribute to metabolic defects. PMID- 22936711 TI - Riociguat for interstitial lung disease and pulmonary hypertension: a pilot trial. AB - We assessed the safety, tolerability and preliminary efficacy of riociguat, a soluble guanylate cyclase stimulator, in patients with pulmonary hypertension associated with interstitial lung disease (PH-ILD). In this open-label, uncontrolled pilot trial, patients received oral riociguat (1.0-2.5 mg three times daily) for 12 weeks (n=22), followed by an ongoing long-term extension (interim analysis at 12 months) in those eligible (n=15). Primary end-points were safety and tolerability. Secondary end-points included haemodynamic changes and 6 min walk distance (6MWD). Overall, 104 adverse events were reported, of which 25 were serious; eight of the latter were considered drug-related. After 12 weeks of therapy, mean cardiac output increased (4.4 +/- 1.5 L . min(-1) to 5.5 +/- 1.8 L . min(-1)), pulmonary vascular resistance (PVR) decreased (648 +/- 207 dyn . s( 1) . cm(-5) to 528 +/- 181 dyn . s(-1) . cm(-5)) and mean pulmonary artery pressure (mPAP) remained unchanged compared with baseline. Arterial oxygen saturation decreased but mixed-venous oxygen saturation slightly increased. The 6MWD increased from 325 +/- 96 m at baseline to 351 +/- 111 m after 12 weeks. Riociguat was well tolerated by most patients and improved cardiac output and PVR, but not mPAP. Further studies are necessary to evaluate the safety and efficacy of riociguat in patients with PH-ILD. PMID- 22936712 TI - The transpulmonary pressure gradient for the diagnosis of pulmonary vascular disease. AB - The transpulmonary pressure gradient (TPG), defined by the difference between mean pulmonary arterial pressure (P(pa)) and left atrial pressure (P(la); commonly estimated by pulmonary capillary wedge pressure: P(pcw)) has been recommended for the detection of intrinsic pulmonary vascular disease in left heart conditions associated with increased pulmonary venous pressure. In these patients, a TPG of >12 mmHg would result in a diagnosis of "out of proportion" pulmonary hypertension. This value is arbitrary, because the gradient is sensitive to changes in cardiac output and both recruitment and distension of the pulmonary vessels, which decrease the upstream transmission of P(la). Furthermore, pulmonary blood flow is pulsatile, with systolic P(pa) and mean P(pa) determined by stroke volume and arterial compliance. It may, therefore, be preferable to rely on a gradient between diastolic P(pa) and P(pcw). The measurement of a diastolic P(pa)/P(pcw) gradient (DPG) combined with systemic blood pressure and cardiac output allows for a step-by-step differential diagnosis between pulmonary vascular disease, high output or high left-heart filling pressure state, and sepsis. The DPG is superior to the TPG for the diagnosis of "out of proportion" pulmonary hypertension. PMID- 22936713 TI - Proteinase 3 activity in sputum from subjects with alpha-1-antitrypsin deficiency and COPD. AB - Chronic obstructive pulmonary disease (COPD) is associated with tissue damage believed to result from an imbalance between serine proteinases and their inhibitors. Although the role of neutrophil elastase (NE) has been studied, it is likely that other proteinases play a role. The importance of proteinase 3 (PR3) has not been established, as specific substrates have only recently been available. We studied clinically stable subjects with either alpha-1-antitrypsin (A1AT) deficiency or usual COPD with chronic bronchitis. Sol phase sputum was analysed for PR3 activity and concentration, NE activity and concentration, concentrations of airway inhibitors (A1AT, secretory leukoproteinase inhibitor and elafin) and markers of neutrophilic inflammation. 12 patients were also studied during exacerbations. PR3 activity was present in most sputum samples and greater than NE activity (which was largely undetectable) in both subject groups (A1AT deficiency median PR3 128 nM, interquartile range (IQR) 33-558 nM; NE 0 nM, IQR 0-0 nM; p=0.0043; COPD PR3 22 nM, IQR 0-103 nM; NE 0 nM, IQR 0-0 nM; p=0.015). PR3 activity was greater during exacerbations than in the stable state (p=0.037) and correlated with markers of neutrophilic inflammation. The regular identification of PR3 activity in sputum from stable subjects with A1AT deficiency or usual COPD suggests it may play a greater role in the pathophysiology than previously thought. PMID- 22936710 TI - Contact investigation for tuberculosis: a systematic review and meta-analysis. AB - Investigation of contacts of patients with tuberculosis (TB) is a priority for TB control in high-income countries, and is increasingly being considered in resource-limited settings. This review was commissioned for a World Health Organization Expert Panel to develop global contact investigation guidelines. We performed a systematic review and meta-analysis of all studies reporting the prevalence of TB and latent TB infection, and the annual incidence of TB among contacts of patients with TB. After screening 9,555 titles, we included 203 published studies. In 95 studies from low- and middle-income settings, the prevalence of active TB in all contacts was 3.1% (95% CI 2.2-4.4%, I(2)=99.4%), microbiologically proven TB was 1.2% (95% CI 0.9-1.8%, I(2)=95.9%), and latent TB infection was 51.5% (95% CI 47.1-55.8%, I(2)=98.9%). The prevalence of TB among household contacts was 3.1% (95% CI 2.1-4.5%, I(2)=98.8%) and among contacts of patients with multidrug-resistant or extensively drug-resistant TB was 3.4% (95% CI 0.8-12.6%, I(2)=95.7%). Incidence was greatest in the first year after exposure. In 108 studies from high-income settings, the prevalence of TB among contacts was 1.4% (95% CI 1.1-1.8%, I(2)=98.7%), and the prevalence of latent infection was 28.1% (95% CI 24.2-32.4%, I(2)=99.5%). There was substantial heterogeneity among published studies. Contacts of TB patients are a high-risk group for developing TB, particularly within the first year. Children <5 yrs of age and people living with HIV are particularly at risk. Policy recommendations must consider evidence of the cost-effectiveness of various contact tracing strategies, and also incorporate complementary strategies to enhance case finding. PMID- 22936715 TI - Vascular Disease: Diagnostic and Therapeutic Approaches. PMID- 22936716 TI - Is organizational justice associated with clinical performance in the care for patients with diabetes in primary care? Evidence from the improving Quality of care in Diabetes study. AB - BACKGROUND: Type 2 diabetes is an increasingly prevalent illness, and there is considerable variation in the quality of care provided to patients with diabetes in primary care. OBJECTIVES: The aim of this study was to explore whether organizational justice and organizational citizenship behaviour are associated with the behaviours of clinical staff when providing care for patients with diabetes. METHODS: The data were from an ongoing prospective multicenter study, the 'improving Quality of care in Diabetes' (iQuaD) study. Participants (N = 467) were clinical staff in 99 primary care practices in the UK. The outcome measures were six self-reported clinical behaviours: prescribing for glycaemic control, prescribing for blood pressure control, foot examination, giving advice about weight management, providing general education about diabetes and giving advice about self-management. Organizational justice perceptions were collected using a self-administered questionnaire. The associations between organizational justice and behavioural outcomes were tested using linear multilevel regression modelling. RESULTS: Higher scores on the procedural component of organizational justice were associated with more frequent weight management advice, self management advice and provision of general education for patients with diabetes. The associations between justice and clinical behaviours were not explained by individual or practice characteristics, but evidence was found for the partial mediating role of organizational citizenship behaviour. CONCLUSIONS: Quality improvement efforts aimed at increasing advice and education provision in diabetes management in primary care could target also perceptions of procedural justice. PMID- 22936714 TI - Inhaled therapies, azithromycin and Mycobacterium abscessus in cystic fibrosis patients. AB - Cystic fibrosis (CF) patients are at particularly high risk of developing lung disease caused by Mycobacterium abscessus complex (MABSC). Over the last 10 years, changes in CF treatment, with increasing use of inhaled therapies and low dose azithromycin, have been accompanied by an increase in the prevalence of MABSC infections in CF patients. There is therefore some concern about the role of new CF treatments in the emergence of MABSC infections. We addressed this issue by means of a case-control study including 30 MABSC-positive cases and 60 nontuberculous mycobacteria-negative CF controls matched for age, sex and centre. We also compared practices at the CF centres with the highest prevalence of MABSC with those at the other centres. No positive association was found between MABSC lung disease and the use of inhaled therapies or low-dose azithromycin in the 4 years preceding MABSC isolation. These treatments were not significantly more frequently used at the CF centres with the highest MABSC prevalence rates. In conclusion, there is no evidence for a link between M. abscessus complex lung disease and inhaled therapies or low-dose azithromycin in patients with CF. PMID- 22936717 TI - Inferring the evolutionary history of IncP-1 plasmids despite incongruence among backbone gene trees. AB - Plasmids of the incompatibility group IncP-1 can transfer and replicate in many genera of the Proteobacteria. They are composed of backbone genes that encode a variety of essential functions and accessory genes that have implications for human health and environmental remediation. Although it is well understood that the accessory genes are transferred horizontally between plasmids, recent studies have also provided examples of recombination in the backbone genes of IncP-1 plasmids. As a consequence, phylogeny estimation based on backbone genes is expected to produce conflicting gene tree topologies. The main goal of this study was therefore to infer the evolutionary history of IncP-1 plasmids in the presence of both vertical and horizontal gene transfer. This was achieved by quantifying the incongruence among gene trees and attributing it to known causes such as 1) phylogenetic uncertainty, 2) coalescent stochasticity, and 3) horizontal inheritance. Topologies of gene trees exhibited more incongruence than could be attributed to phylogenetic uncertainty alone. Species-tree estimation using a Bayesian framework that takes coalescent stochasticity into account was well supported, but it differed slightly from the maximum-likelihood tree estimated by concatenation of backbone genes. After removal of the gene that demonstrated a signal of intergroup recombination, the concatenated tree was congruent with the species-tree estimate, which itself was robust to inclusion/exclusion of the recombinant gene. Thus, in spite of horizontal gene exchange both within and among IncP-1 subgroups, the backbone genome of these IncP-1 plasmids retains a detectable vertical evolutionary history. PMID- 22936718 TI - Waxy phenotype evolution in the allotetraploid cereal broomcorn millet: mutations at the GBSSI locus in their functional and phylogenetic context. AB - Waxy mutants, in which endosperm starch contains ~100% amylopectin rather than the wild-type composition of ~70% amylopectin and ~30% amylose, occur in many domesticated cereals. The cultivation of waxy varieties is concentrated in east Asia, where there is a culinary preference for glutinous-textured foods that may have developed from ancient food processing traditions. The waxy phenotype results from mutations in the GBSSI gene, which catalyzes amylose synthesis. Broomcorn or proso millet (Panicum miliaceum L.) is one of the world's oldest cultivated cereals, which spread across Eurasia early in prehistory. Recent phylogeographic analysis has shown strong genetic structuring that likely reflects ancient expansion patterns. Broomcorn millet is highly unusual in being an allotetraploid cereal with fully waxy varieties. Previous work characterized two homeologous GBSSI loci, with multiple alleles at each, but could not determine whether both loci contributed to GBSSI function. We first tested the relative contribution of the two GBSSI loci to amylose synthesis and second tested the association between GBSSI alleles and phylogeographic structure inferred from simple sequence repeats (SSRs). We evaluated the phenotype of all known GBSSI genotypes in broomcorn millet by assaying starch composition and protein function. The results showed that the GBSSI-S locus is the major locus controlling endosperm amylose content, and the GBSSI-L locus has strongly reduced synthesis capacity. We genotyped 178 individuals from landraces from across Eurasia for the 2 GBSSI and 16 SSR loci and analyzed phylogeographic structuring and the geographic and phylogenetic distribution of GBSSI alleles. We found that GBSSI alleles have distinct spatial distributions and strong associations with particular genetic clusters defined by SSRs. The combination of alleles that results in a partially waxy phenotype does not exist in landrace populations. Our data suggest that broomcorn millet is a system in the process of becoming diploidized for the GBSSI locus responsible for grain amylose. Mutant alleles show some exchange between genetic groups, which was favored by selection for the waxy phenotype in particular regions. Partially waxy phenotypes were probably selected against-this unexpected finding shows that better understanding is needed of the human biology of this phenomenon that distinguishes cereal use in eastern and western cultures. PMID- 22936719 TI - The complex NOD-like receptor repertoire of the coral Acropora digitifera includes novel domain combinations. AB - Innate immunity in corals is of special interest not only in the context of self defense but also in relation to the establishment and collapse of their obligate symbiosis with dinoflagellates of the genus Symbiodinium. In innate immunity system of vertebrates, approximately 20 tripartite nucleotide oligomerization domain (NOD)-like receptor proteins that are defined by the presence of a NAIP, CIIA, HET-E and TP1 (NACHT) domain, a C-terminal leucine-rich repeat (LRR) domain, and one of three types of N-terminal effector domain, are known to function as the primary intracellular pattern recognition molecules. Surveying the coral genome revealed not only a larger number of NACHT- and related domain nucleotide-binding adaptor shared by APAF-1, R proteins, and CED-4 (NB-ARC) encoding loci (~500) than in other metazoans but also surprising diversity of domain combinations among the coral NACHT/NB-ARC-containing proteins; N-terminal effector domains included the apoptosis-related domains caspase recruitment domain (CARD), death effector domain (DED), and Death, and C-terminal repeat domains included LRRs, tetratricopeptide repeats, ankyrin repeats, and WD40 repeats. Many of the predicted coral proteins that contain a NACHT/NB-ARC domain also contain a glycosyl transferase group 1 domain, a novel domain combination first found in metazoans. Phylogenetic analyses suggest that the NACHT/NB-ARC domain inventories of various metazoan lineages, including corals, are largely products of lineage-specific expansions. Many of the NACHT/NB-ARC loci are organized in pairs or triplets in the Acropora genome, suggesting that the large coral NACHT/NB-ARC repertoire has been generated at least in part by tandem duplication. In addition, shuffling of N-terminal effector domains may have occurred after expansions of specific NACHT/NB-ARC-repeat domain types. These results illustrate the extraordinary complexity of the innate immune repertoire of corals, which may in part reflect adaptive evolution to a symbiotic lifestyle in a uniquely complex and challenging environment. PMID- 22936720 TI - Basal vertebrates clarify the evolutionary history of ciliopathy-associated genes Tmem138 and Tmem216. AB - Recently, Lee et al. (Lee JH, Silhavy JL, Lee JE, et al. (30 co-authors). 2012. Evolutionarily assembled cis-regulatory module at a human ciliopathy locus. Science (335:966-969.) demonstrated that mutation in either of the transmembrane protein encoding genes, TMEM138 or TMEM216, causes phenotypically indistinguishable ciliopathy. Furthermore, on the basis of the observation that their orthologs are linked in a head-to-tail configuration in other mammals and Anolis, but present on different scaffolds or chromosomes in Xenopus tropicalis and zebrafish, the authors concluded that the two genes were joined by chromosomal rearrangement at the evolutionary amphibian-to-reptile transition to form a functional module. We have sequenced these gene loci in a cartilaginous fish, the elephant shark, and found that the two genes together with a related gene (Tmem80) constitute a tandem cluster. This suggests that the two genes were already linked in the vertebrate ancestor and then rearranged independently in Xenopus and zebrafish. Analyses of the coelacanth and lamprey genomes support this hypothesis. Our study highlights the importance of basal vertebrates as critical reference genomes. PMID- 22936721 TI - Inference of genome duplications from age distributions revisited. AB - Whole-genome duplications (WGDs), thought to facilitate evolutionary innovations and adaptations, have been uncovered in many phylogenetic lineages. WGDs are frequently inferred from duplicate age distributions, where they manifest themselves as peaks against a small-scale duplication background. However, the interpretation of duplicate age distributions is complicated by the use of K(S), the number of synonymous substitutions per synonymous site, as a proxy for the age of paralogs. Two particular concerns are the stochastic nature of synonymous substitutions leading to increasing uncertainty in K(S) with increasing age since duplication and K(S) saturation caused by the inability of evolutionary models to fully correct for the occurrence of multiple substitutions at the same site. K(S) stochasticity is expected to erode the signal of older WGDs, whereas K(S) saturation may lead to artificial peaks in the distribution. Here, we investigate the consequences of these effects on K(S)-based age distributions and WGD inference by simulating the evolution of duplicated sequences according to predefined real age distributions and re-estimating the corresponding K(S) distributions. We show that, although K(S) estimates can be used for WGD inference far beyond the commonly accepted K(S) threshold of 1, K(S) saturation effects can cause artificial peaks at higher ages. Moreover, K(S) stochasticity and saturation may lead to confounded peaks encompassing multiple WGD events and/or saturation artifacts. We argue that K(S) effects need to be properly accounted for when inferring WGDs from age distributions and that the failure to do so could lead to false inferences. PMID- 22936723 TI - Voluntary resistance running with short distance enhances spatial memory related to hippocampal BDNF signaling. AB - Although voluntary running has beneficial effects on hippocampal cognitive functions if done abundantly, it is still uncertain whether resistance running would be the same. For this purpose, voluntary resistance wheel running (RWR) with a load is a suitable model, since it allows increased work levels and resultant muscular adaptation in fast-twitch muscle. Here, we examined whether RWR would have potential effects on hippocampal cognitive functions with enhanced hippocampal brain-derived neurotrophic factor (BDNF), as does wheel running without a load (WR). Ten-week-old male Wistar rats were assigned randomly to sedentary (Sed), WR, and RWR (to a maximum load of 30% of body weight) groups for 4 wk. We found that in RWR, work levels increased with load, but running distance decreased by about half, which elicited muscular adaptation for fast-twitch plantaris muscle without causing any negative stress effects. Both RWR and WR led to improved spatial learning and memory as well as gene expressions of hippocampal BDNF signaling-related molecules. RWR increased hippocampal BDNF, tyrosine-related kinase B (TrkB), and cAMP response element-binding (CREB) protein levels, whereas WR increased only BDNF. With both exercise groups, there were correlations between spatial memory and BDNF protein (r = 0.41), p-CREB protein (r = 0.44), and work levels (r = 0.77). These results suggest that RWR plays a beneficial role in hippocampus-related cognitive functions associated with hippocampal BDNF signaling, even with short distances, and that work levels rather than running distance are more determinant of exercise-induced beneficial effects in wheel running with and without a load. PMID- 22936722 TI - Subtle alterations in breathing and heart rate control in the 5-HT1A receptor knockout mouse in early postnatal development. AB - We hypothesized that absence of the 5-HT(1A) receptor would negatively affect the development of cardiorespiratory control. In conscious wild type (WT) and 5 HT(1A) receptor knockout (KO) mice, we measured resting ventilation (Ve), oxygen consumption (Vo(2)), heart rate (HR), breathing and HR variability, and the hypercapnic ventilatory response (HCVR) at postnatal day 5 (P5), day 15 (P15), and day 25 (P25). In KO mice compared with WT, we found a 17% decrease in body weight at only P5 (P < 0.01) and no effect on Vo(2). Ve was significantly (P < 0.001) lower at P5 and P25, but there was no effect on the HCVR. Breathing variability (interbreath interval), measured by standard deviation, the root mean square of the standard deviation (RMSSD), and the product of the major (L) and minor axes (T) of the Poincare first return plot, was 57% to 187% higher only at P5 (P < 0.001). HR was 6-10% slower at P5 (P < 0.001) but 7-9% faster at P25 (P < 0.001). This correlated with changes in the spectral analysis of HR variability; the low frequency to high frequency ratio was 47% lower at P5 but 68% greater at P25. The RMSSD and (L * T) of HR variability were ~2-fold greater at P5 only (P < 0.001; P < 0.05). We conclude that 5-HT(1A) KO mice have a critical period of potential vulnerability at P5 when pups hypoventilate and have a slower respiratory frequency and HR with enhanced variability of both, suggesting abnormal maturation of cardiorespiratory control. PMID- 22936724 TI - Synergistic stimulation of myogenesis by glucocorticoid and IGF-I signaling. AB - Muscle wasting is associated with poor prognosis in chronic obstructive pulmonary disease (COPD). Exercise stimulates muscle recovery, but its efficacy is variable, depending on the clinical condition and medical treatment. Systemic glucocorticoids, commonly administered in high doses during acute disease exacerbations or as maintenance treatment in end-stage disease, are known to contribute to muscle wasting. As muscle mass recovery involves insulin-like growth factor (IGF)-I signaling, which can be stimulated by anabolic steroids, the impact of glucocorticoids and the effect of simultaneous IGF-I stimulation by anabolic steroids on muscle recovery and growth were investigated. The effects of, and interactions between, glucocorticoid and IGF-I signaling on skeletal muscle growth were assessed in differentiating C2C12 myocytes. As proof of principle, we performed a post hoc analysis stratifying patients by glucocorticoid use of a clinical trial investigating the efficacy of anabolic steroid supplementation on muscle recovery in muscle-wasted patients with COPD. Glucocorticoids strongly impaired protein synthesis signaling, myotube formation, and muscle-specific protein expression. In contrast, in the presence of glucocorticoids, IGF-I synergistically stimulated myotube fusion and myofibrillar protein expression, which corresponded with restored protein synthesis signaling by IGF-I and increased transcriptional activation of muscle-specific genes by glucocorticoids. In COPD patients on maintenance glucocorticoid treatment, the clinical trial also revealed an enhanced effect of anabolic steroids on muscle mass and respiratory muscle strength. In conclusion, synergistic effects of anabolic steroids and glucocorticoids on muscle recovery may be caused by relief of the glucocorticoid-imposed blockade on protein synthesis signaling, allowing effective translation of glucocorticoid-induced accumulation of muscle-specific gene transcripts. PMID- 22936726 TI - Involvement of PGE2 and RANTES in Staphylococcus aureus-induced fever in rats. AB - This study investigated the involvement of prostaglandins and regulated on activation, normal T cell expressed and secreted (RANTES), in fever induced by live Staphylococcus aureus (no. 25923, American Type Culture Collection) injection in rats. S. aureus was injected intraperitoneally at 10(9), 10(10), and 2 * 10(10) colony-forming units (CFU)/cavity, and body temperature (T(b)) was measured by radiotelemetry. The lowest dose of S. aureus induced a modest transient increase in T(b), whereas the two higher doses promoted similar long lasting and sustained T(b) increases. Thus, the 10(10) CFU/cavity dose was chosen for the remaining experiments. The T(b) increase induced by S. aureus was accompanied by significant decreases in tail skin temperature and increases in PGE(2) levels in the cerebrospinal fluid (CSF) and hypothalamus but not in the venous plasma. Celecoxib (selective cyclooxygenase-2 inhibitor, 2.5 mg/kg po) inhibited the fever and the increases in PGE(2) concentration in the CSF and hypothalamus induced by S. aureus. Dipyrone (120 mg/kg ip) reduced the fever from 2.5 to 4 h and the PGE(2) increase in the CSF but not in the hypothalamus. S. aureus increased RANTES in the peritoneal exudate but not in the CSF or hypothalamus. Met-RANTES (100 MUg/kg iv), a chemokine (C-C motif) receptor (CCR)1/CCR5 antagonist, reduced the first 6 h of fever induced by S. aureus. This study suggests that peripheral (local) RANTES and central PGE(2) production are key events in the febrile response to live S. aureus injection. As dipyrone does not reduce PGE(2) synthesis in the hypothalamus, it is plausible that S. aureus induces fever, in part, via a dipyrone-sensitive PGE(2)-independent pathway. PMID- 22936725 TI - Pulmonary C-fiber activation attenuates respiratory-related tongue movements. AB - The functional impact of pulmonary C-fiber activation on upper airway biomechanics has not been evaluated. Here, we tested the hypothesis that pulmonary C-fiber activation alters the respiratory-related control of tongue movements. The force produced by tongue movements was quantified in spontaneously breathing, anesthetized adult rats before and after stimulation of pulmonary C fibers via intrajugular delivery of capsaicin (0.625 and 1.25 MUg/kg). Brief occlusion of the trachea was used to increase the respiratory drive to the tongue muscles, and hypoglossal (XII) nerve branches were selectively sectioned to denervate the protrusive and retrusive tongue musculature. Tracheal occlusion triggered inspiratory-related tongue retrusion in rats with XII nerves intact or following section of the medial XII nerve branch, which innervates the genioglossus muscle. Inspiratory-related tongue protrusion was only observed after section of the lateral XII branch, which innervates the primary tongue retrusor muscles. The tension produced by inspiratory-related tongue movement was significantly attenuated by capsaicin, but tongue movements remained retrusive, unless the medial XII branch was sectioned. Capsaicin also significantly delayed the onset of tongue movements such that tongue forces could not be detected until after onset of the inspiratory diaphragm activity. We conclude that altered neural drive to the tongue muscles following pulmonary C-fiber activation has a functionally significant effect on tongue movements. The diminished tongue force and delay in the onset of tongue movements following pulmonary C-fiber activation are potentially unfavorable for upper airway patency. PMID- 22936727 TI - Low-level mechanical stimulation is sufficient to improve tendon healing in rats. AB - Treatment of tendon injuries often involves immobilization. However, immobilization might not prevent mild involuntary isometric muscle contraction. The effect of weak forces on tendon healing is therefore of clinical interest. Studies of tendon healing with various methods for load reduction in rat Achilles tendon models show a consistent reduction in tendon strength by at least half, compared with voluntary cage activity. Unloading was not complete in any of these models, and the healing tendon was therefore still exposed to mild mechanical stimulation. By reducing the forces acting on the tendon even further, we now studied the effects of this mild stimulation. Rat Achilles tendons were transected and allowed to heal spontaneously under four different loading conditions: 1) normal cage activity; 2) calf muscle paralysis induced by botulinum toxin A (Botox); 3) tail suspension; 4) Botox and tail suspension, combined, to eliminate even mild stimulation. Healing was evaluated by mechanical testing after 8 days. Botox alone and suspension alone both reduced tendon callus size (transverse area), thereby impairing its strength compared with normal cage activity. The combination of Botox and suspension did not further reduce tendon callus size but drastically impaired the material properties of the tendon callus compared with each treatment alone. The peak force was only a fifth of that in the normal cage activity group. The results indicate that also the mild loading that occurs with either Botox or suspension alone stimulates tendon healing. This stimulation appears to affect mainly tissue quality, whereas stronger stimulation also increases callus size. PMID- 22936729 TI - Aortic function quantified: the heart's essential cushion. AB - Arterial compliance is mainly determined by the elasticity of proximal large conduit arteries of which the aorta is the largest contributor. Compliance forms an important part of the cardiac load and plays a role in organ (especially coronary) perfusion. To follow local changes in aortic compliance, as in aging, noninvasive determination of compliance distribution would be of great value. Our goal is to determine regional aortic compliance noninvasively in the human. In seven healthy individuals at six locations, aortic blood flow and systolic/diastolic area (DeltaA) was measured with MRI. Simultaneously brachial pulse pressure (DeltaP) was measured with standard cuff. With a transfer function we derived DeltaP at the same aortic locations as the MRI measurements. Regional aortic compliance was calculated with two approaches, the pulse pressure method, and local area compliance (DeltaA/DeltaP) times segment length, called area compliance method. For comparison, pulse wave velocity (PWV) from local flows at two locations was determined, and compliance was derived from PWV. Both approaches show that compliance is largest in the proximal aorta and decreases toward the distal aorta. Similar results were found with PWV-derived compliance. Of total arterial compliance, ascending to distal arch (segments 1-3) contributes 40% (of which 15% is in head and arms), descending aorta (segments 4 and 5) 25%, and "hip, pelvic and leg arteries" 20%. Pulse pressure method includes compliance of side branches and is therefore larger than the area compliance method. Regional aortic compliance can be obtained noninvasively. Therefore, this technique allows following changes in local compliance with age and cardiovascular diseases. PMID- 22936728 TI - Sustained postexercise increases in AS160 Thr642 and Ser588 phosphorylation in skeletal muscle without sustained increases in kinase phosphorylation. AB - Prior exercise by rats can induce a sustained increase in muscle Akt substrate of 160 kDa (AS160) phosphorylation on Thr(642) (pAS160(Thr642)). Because phosphorylation of AS160 on both AS160(Thr642) and AS160(Ser588) is important for insulin-stimulated glucose transport (GT), we determined if exercise would also induce a sustained increase in pAS160(Ser588) concomitant with persistently elevated pAS160(Thr642) and GT. Given that the mechanisms for sustained postexercise (PEX) effects on pAS160 were uncertain, we also studied the four kinases known to phosphorylate AS160 (Akt, AMPK, RSK, and SGK1). In addition, because the serine/threonine phosphatase(s) that dephosphorylate muscle AS160 were previously unidentified, we assessed the ability of four serine/threonine phosphatases (PP1, PP2A, PP2B, and PP2C) to dephosphorylate AS160. We also evaluated exercise effects on posttranslational modifications (Tyr(307) and Leu(309)) that regulate PP2A. In isolated epitrochlearis muscles from rats, GT at 3hPEX with insulin significantly (P < 0.05) exceeded SED controls. Muscles from 0hPEX vs. 0hSED and 3hPEX vs. 3hSED rats had greater pAS160(Thr642) and pAS160(Ser588). AMPK was the only kinase with greater phosphorylation at 0hPEX vs. 0hSED, and none had greater phosphorylation at 3hPEX vs. 3hSED. Each phosphatase was able to dephosphorylate pAS160(Thr642) and pAS160(Ser588) in cell free assays. Exercise did not alter posttranslational modifications of PP2A. Our results revealed: 1) pAMPK as a potential trigger for increased pAS160(Thr642) and pAS160(Ser588) at 0hPEX; 2) PP1, PP2A, PP2B, and PP2C were each able to dephosphorylate AS160; and 3) sustained PEX-induced elevations of pAS160(Thr642) and pAS160(Ser588) were attributable to mechanisms other than persistent phosphorylation of known AS160 kinases or altered posttranslational modifications of PP2A. PMID- 22936730 TI - Unchanged [3H]ouabain binding site content but reduced Na+-K+ pump alpha2-protein abundance in skeletal muscle in older adults. AB - Aging is associated with reduced muscle mass, weakness, and increased fatigability. In skeletal muscle, the Na(+)-K(+) pump (NKA) is important in regulating Na(+)-K(+) gradients, membrane excitability, and thus contractility, but the effects of aging on muscle NKA are unclear. We investigated whether aging is linked with reduced muscle NKA by contrasting muscle NKA isoform gene expression and protein abundance, and NKA total content in 17 Elderly (66.8 +/- 6.4 yr, mean +/- SD) and 16 Young adults (23.9 +/- 2.2 yr). Participants underwent peak oxygen consumption assessment and a vastus lateralis muscle biopsy, which was analyzed for NKA alpha(1)-, alpha(2)-, alpha(3)-, beta(1)-, beta(2)-, and beta(3)-isoform gene expression (real-time RT-PCR), protein abundance (immunoblotting), and NKA total content ([(3)H]ouabain binding sites). The Elderly had lower peak oxygen consumption (-36.7%, P = 0.000), strength ( 36.3%, P = 0.001), NKA alpha(2)- (-24.4%, 11.9 +/- 4.4 vs. 9.0 +/- 2.7 arbitrary units, P = 0.049), and NKA beta(3)-protein abundance (-23.0%, P = 0.041) than Young. The beta(3)-mRNA was higher in Elderly compared with Young (P = 0.011). No differences were observed between groups for other NKA isoform mRNA or protein abundance, or for [(3)H]ouabain binding site content. Thus skeletal muscle in elderly individuals was characterized by decreased NKA alpha(2)- and beta(3) protein abundance, but unchanged alpha(1) abundance and [(3)H]ouabain binding. The latter was likely caused by reduced alpha(2) abundance with aging, preventing an otherwise higher [(3)H]ouabain binding that might occur with a greater membrane density in smaller muscle fibers. Further study is required to verify reduced muscle NKA alpha(2) with aging and possible contributions to impaired exercise capability and daily living activities. PMID- 22936732 TI - HIV infection, lymphoid fibrosis, and disease. PMID- 22936731 TI - Divergent skeletal muscle respiratory capacities in rats artificially selected for high and low running ability: a role for Nor1? AB - Inactivity-related diseases are becoming a huge burden on Western society. While there is a major environmental contribution to metabolic health, the intrinsic properties that predispose or protect against particular health traits are harder to define. We used rat models of inborn high running capacity (HCR) and low running capacity (LCR) to determine inherent differences in mitochondrial volume and function, hypothesizing that HCR rats would have greater skeletal muscle respiratory capacity due to an increase in mitochondrial number. Additionally, we sought to determine if there was a link between the expression of the orphan nuclear receptor neuron-derived orphan receptor (Nor)1, a regulator of oxidative metabolism, and inherent skeletal muscle respiratory capacity. LCR rats were 28% heavier (P < 0.0001), and fasting serum insulin concentrations were 62% greater than in HCR rats (P = 0.02). In contrast, HCR rats had better glucose tolerance and reduced adiposity. In the primarily oxidative soleus muscle, maximal respiratory capacity was 21% greater in HCR rats (P = 0.001), for which the relative contribution of fat oxidation was 20% higher than in LCR rats (P = 0.02). This was associated with increased citrate synthase (CS; 33%, P = 0.009) and beta-hydroxyacyl-CoA (beta-HAD; 33%, P = 0.0003) activities. In the primarily glycolytic extensor digitum longus muscle, CS activity was 29% greater (P = 0.01) and beta-HAD activity was 41% (P = 0.0004) greater in HCR rats compared with LCR rats. Mitochondrial DNA copy numbers were also elevated in the extensor digitum longus muscles of HCR rats (35%, P = 0.049) and in soleus muscles (44%, P = 0.16). Additionally, HCR rats had increased protein expression of individual mitochondrial respiratory complexes, CS, and uncoupling protein 3 in both muscle types (all P < 0.05). In both muscles, Nor1 protein was greater in HCR rats compared with LCR rats (P < 0.05). We propose that the differential expression of Nor1 may contribute to the differences in metabolic regulation between LCR and HCR phenotypes. PMID- 22936733 TI - Treating myeloma: the future is already here! PMID- 22936734 TI - Suicidal T cells: a jump-start for the thymus. PMID- 22936735 TI - BTK inhibition in myeloma: targeting the seed and the soil. PMID- 22936736 TI - A drug that stops traffic at the nuclear border. PMID- 22936737 TI - Why not the liver instead of the kidney? PMID- 22936738 TI - Factors VIII and V swap fatty feet. PMID- 22936739 TI - Malignancies are the major cause of death in patients with adult onset common variable immunodeficiency. PMID- 22936740 TI - Seasonal and pandemic (A/H1N1 2009) MF-59-adjuvanted influenza vaccines in complete remission non-Hodgkin lymphoma patients previously treated with rituximab containing regimens. PMID- 22936741 TI - Massive expansion of maternal T cells in response to EBV infection in a patient with SCID-Xl. PMID- 22936742 TI - Second attempt to discontinue imatinib in CP-CML patients with a second sustained complete molecular response. PMID- 22936744 TI - Ending honorary authorship. PMID- 22936743 TI - Meta-analysis of 2040 sickle cell anemia patients: BCL11A and HBS1L-MYB are the major modifiers of HbF in African Americans. PMID- 22936748 TI - Ancient DNA. A crystal-clear view of an extinct girl's genome. PMID- 22936749 TI - Public health. Outbreak pattern stymies vaccine work. PMID- 22936750 TI - Research quality. Service offers to reproduce results for a fee. PMID- 22936751 TI - Astrobiology. In the hunt for the red planet's dirtiest secret. PMID- 22936752 TI - Immunology. The new view of complement. PMID- 22936753 TI - Immunology. Stalling sepsis? PMID- 22936754 TI - The scientific whaling loophole. PMID- 22936756 TI - Decoding cryptosystems. PMID- 22936755 TI - Iconic CO2 time series at risk. PMID- 22936758 TI - Comment on "Intensifying weathering and land use in Iron Age Central Africa". AB - Bayon et al. (Reports, 9 March 2012, p. 1219) interpreted unusually high aluminum potassium ratio values in an Atlantic sediment core as indicating anthropogenic deforestation around 2500 years before the present (B.P.). We argue that there is no terrestrial evidence for forest destruction by humans and that the third millennium B.P. rainforest crisis can be clearly attributed mostly to climatic change. PMID- 22936759 TI - Comment on "Intensifying weathering and land use in Iron Age Central Africa". AB - Bayon et al. (Reports, 9 March 2012, p. 1219) claim that the "rainforest crisis" in Central Africa centered around 2500 years before the present "was not triggered by natural climatic factors" and that it was caused by widespread deforestation resulting from the arrival of the Bantu colonists. However, there is a consensus among palaeoecologists that this landscape change and the related physical erosion it caused was due mainly to a shift to more seasonal rainfall regime. PMID- 22936761 TI - Climate change. Climate negotiators create an opportunity for scholars. PMID- 22936762 TI - Biochemistry. Spare the (elastic) rod. PMID- 22936763 TI - Chemistry. Vibrational excitation can control tropospheric chemistry. PMID- 22936764 TI - Cell biology. Beyond oil and water--phase transitions in cells. PMID- 22936765 TI - Ecology. Bad news for soil carbon sequestration? PMID- 22936766 TI - Development. Esophageal stem cells, where art thou? PMID- 22936767 TI - Cell Biology. Mitochondrial dynamics and apoptosis--the ER connection. PMID- 22936768 TI - Applied physics. Structured light meets structured matter. PMID- 22936769 TI - IBI* series winner. Discovering nanoscience. PMID- 22936771 TI - Interception of excited vibrational quantum states by O2 in atmospheric association reactions. AB - Bimolecular reactions in Earth's atmosphere are generally assumed to proceed between reactants whose internal quantum states are fully thermally relaxed. Here, we highlight a dramatic role for vibrationally excited bimolecular reactants in the oxidation of acetylene. The reaction proceeds by preliminary adduct formation between the alkyne and OH radical, with subsequent O(2) addition. Using a detailed theoretical model, we show that the product-branching ratio is determined by the excited vibrational quantum-state distribution of the adduct at the moment it reacts with O(2). Experimentally, we found that under the simulated atmospheric conditions O(2) intercepts ~25% of the excited adducts before their vibrational quantum states have fully relaxed. Analogous interception of excited-state radicals by O(2) is likely common to a range of atmospheric reactions that proceed through peroxy complexes. PMID- 22936770 TI - Mitochondrial fission, fusion, and stress. AB - Mitochondrial fission and fusion play critical roles in maintaining functional mitochondria when cells experience metabolic or environmental stresses. Fusion helps mitigate stress by mixing the contents of partially damaged mitochondria as a form of complementation. Fission is needed to create new mitochondria, but it also contributes to quality control by enabling the removal of damaged mitochondria and can facilitate apoptosis during high levels of cellular stress. Disruptions in these processes affect normal development, and they have been implicated in neurodegenerative diseases, such as Parkinson's. PMID- 22936772 TI - Probing the ultimate limits of plasmonic enhancement. AB - Metals support surface plasmons at optical wavelengths and have the ability to localize light to subwavelength regions. The field enhancements that occur in these regions set the ultimate limitations on a wide range of nonlinear and quantum optical phenomena. We found that the dominant limiting factor is not the resistive loss of the metal, but rather the intrinsic nonlocality of its dielectric response. A semiclassical model of the electronic response of a metal places strict bounds on the ultimate field enhancement. To demonstrate the accuracy of this model, we studied optical scattering from gold nanoparticles spaced a few angstroms from a gold film. The bounds derived from the models and experiments impose limitations on all nanophotonic systems. PMID- 22936773 TI - Biogenic potassium salt particles as seeds for secondary organic aerosol in the Amazon. AB - The fine particles serving as cloud condensation nuclei in pristine Amazonian rainforest air consist mostly of secondary organic aerosol. Their origin is enigmatic, however, because new particle formation in the atmosphere is not observed. Here, we show that the growth of organic aerosol particles can be initiated by potassium-salt-rich particles emitted by biota in the rainforest. These particles act as seeds for the condensation of low- or semi-volatile organic compounds from the atmospheric gas phase or multiphase oxidation of isoprene and terpenes. Our findings suggest that the primary emission of biogenic salt particles directly influences the number concentration of cloud condensation nuclei and affects the microphysics of cloud formation and precipitation over the rainforest. PMID- 22936774 TI - Radiative absorption enhancements due to the mixing state of atmospheric black carbon. AB - Atmospheric black carbon (BC) warms Earth's climate, and its reduction has been targeted for near-term climate change mitigation. Models that include forcing by BC assume internal mixing with non-BC aerosol components that enhance BC absorption, often by a factor of ~2; such model estimates have yet to be clearly validated through atmospheric observations. Here, direct in situ measurements of BC absorption enhancements (E(abs)) and mixing state are reported for two California regions. The observed E(abs) is small-6% on average at 532 nm-and increases weakly with photochemical aging. The E(abs) is less than predicted from observationally constrained theoretical calculations, suggesting that many climate models may overestimate warming by BC. These ambient observations stand in contrast to laboratory measurements that show substantial E(abs) for BC are possible. PMID- 22936776 TI - Arbuscular mycorrhizal fungi increase organic carbon decomposition under elevated CO2. AB - The extent to which terrestrial ecosystems can sequester carbon to mitigate climate change is a matter of debate. The stimulation of arbuscular mycorrhizal fungi (AMF) by elevated atmospheric carbon dioxide (CO(2)) has been assumed to be a major mechanism facilitating soil carbon sequestration by increasing carbon inputs to soil and by protecting organic carbon from decomposition via aggregation. We present evidence from four independent microcosm and field experiments demonstrating that CO(2) enhancement of AMF results in considerable soil carbon losses. Our findings challenge the assumption that AMF protect against degradation of organic carbon in soil and raise questions about the current prediction of terrestrial ecosystem carbon balance under future climate change scenarios. PMID- 22936775 TI - A gain-of-function polymorphism controlling complex traits and fitness in nature. AB - Identification of the causal genes that control complex trait variation remains challenging, limiting our appreciation of the evolutionary processes that influence polymorphisms in nature. We cloned a quantitative trait locus that controls plant defensive chemistry, damage by insect herbivores, survival, and reproduction in the natural environments where this polymorphism evolved. These ecological effects are driven by duplications in the BCMA (branched-chain methionine allocation) loci controlling this variation and by two selectively favored amino acid changes in the glucosinolate-biosynthetic cytochrome P450 proteins that they encode. These changes cause a gain of novel enzyme function, modulated by allelic differences in catalytic rate and gene copy number. Ecological interactions in diverse environments likely contribute to the widespread polymorphism of this biochemical function. PMID- 22936777 TI - How the cucumber tendril coils and overwinds. AB - The helical coiling of plant tendrils has fascinated scientists for centuries, yet the underlying mechanism remains elusive. Moreover, despite Darwin's widely accepted interpretation of coiled tendrils as soft springs, their mechanical behavior remains unknown. Our experiments on cucumber tendrils demonstrate that tendril coiling occurs via asymmetric contraction of an internal fiber ribbon of specialized cells. Under tension, both extracted fiber ribbons and old tendrils exhibit twistless overwinding rather than unwinding, with an initially soft response followed by strong strain-stiffening at large extensions. We explain this behavior using physical models of prestrained rubber strips, geometric arguments, and mathematical models of elastic filaments. Collectively, our study illuminates the origin of tendril coiling, quantifies Darwin's original proposal, and suggests designs for biomimetic twistless springs with tunable mechanical responses. PMID- 22936778 TI - Extreme bendability of DNA less than 100 base pairs long revealed by single molecule cyclization. AB - The classical view of DNA posits that DNA must be stiff below the persistence length [<150 base pairs (bp)], but recent studies addressing this have yielded contradictory results. We developed a fluorescence-based, protein-free assay for studying the cyclization of single DNA molecules in real time. The assay samples the equilibrium population of a sharply bent, transient species that is entirely suppressed in single-molecule mechanical measurements and is biologically more relevant than the annealed species sampled in the traditional ligase-based assay. The looping rate has a weak length dependence between 67 and 106 bp that cannot be described by the worm-like chain model. Many biologically important protein DNA interactions that involve looping and bending of DNA below 100 bp likely use this intrinsic bendability of DNA. PMID- 22936779 TI - Network context and selection in the evolution to enzyme specificity. AB - Enzymes are thought to have evolved highly specific catalytic activities from promiscuous ancestral proteins. By analyzing a genome-scale model of Escherichia coli metabolism, we found that 37% of its enzymes act on a variety of substrates and catalyze 65% of the known metabolic reactions. However, it is not apparent why these generalist enzymes remain. Here, we show that there are marked differences between generalist enzymes and specialist enzymes, known to catalyze a single chemical reaction on one particular substrate in vivo. Specialist enzymes (i) are frequently essential, (ii) maintain higher metabolic flux, and (iii) require more regulation of enzyme activity to control metabolic flux in dynamic environments than do generalist enzymes. Furthermore, these properties are conserved in Archaea and Eukarya. Thus, the metabolic network context and environmental conditions influence enzyme evolution toward high specificity. PMID- 22936780 TI - Synthesis of methylphosphonic acid by marine microbes: a source for methane in the aerobic ocean. AB - Relative to the atmosphere, much of the aerobic ocean is supersaturated with methane; however, the source of this important greenhouse gas remains enigmatic. Catabolism of methylphosphonic acid by phosphorus-starved marine microbes, with concomitant release of methane, has been suggested to explain this phenomenon, yet methylphosphonate is not a known natural product, nor has it been detected in natural systems. Further, its synthesis from known natural products would require unknown biochemistry. Here we show that the marine archaeon Nitrosopumilus maritimus encodes a pathway for methylphosphonate biosynthesis and that it produces cell-associated methylphosphonate esters. The abundance of a key gene in this pathway in metagenomic data sets suggests that methylphosphonate biosynthesis is relatively common in marine microbes, providing a plausible explanation for the methane paradox. PMID- 22936782 TI - Correlated trait-correlated method minus one analysis of the convergent and discriminant validities of the strengths and difficulties questionnaire. AB - This study used the correlated trait-correlated method minus one model to examine the convergent and discriminant validity of the scales of the Strengths and Difficulties Questionnaire (SDQ). The SDQ scales are emotional symptoms (ES), conduct problems (CP), hyperactivity (HY), peer problems (PP), and prosocial behaviors (PS). A total of 202 adolescents provided self-ratings and were also rated by their mothers and teachers. The findings indicated support for convergent validity for all five SDQ scales for all three respondents. Generally there was more convergence between mother-adolescent ratings than mother-teacher and adolescent-teacher ratings, especially for ES and PP. There was support for the discriminant validity between the traits in all scales, except between CP and HY. The findings are discussed in relation to the construct validity and clinical use of the SDQ. PMID- 22936783 TI - Neuropsychological testing in a rural African school-age population: evaluating contributions to variability in test performance. AB - This study investigated the psychometric properties of a number of neuropsychological tests adapted for use in sub-Saharan Africa. A total of 308 school-age children in a predominantly rural community completed the tests. These tests were developed to assess skills similar to those measured by assessments of cognitive development published for use in Western contexts. Culturally appropriate adaptations were made to enhance within-population variability. Internal consistency ranged from .70 to .84. Scores on individual tests were related to various background factors at the level of the child, household, and neighborhood. School experience was the most consistent predictor of outcome, accounting for up to 22.9% of the variance observed. Significant associations were identified to determine salient background characteristics that should be taken into account when measuring the discrete effects of disease exposure in similar sociocultural and economic settings. PMID- 22936781 TI - The shared antibiotic resistome of soil bacteria and human pathogens. AB - Soil microbiota represent one of the ancient evolutionary origins of antibiotic resistance and have been proposed as a reservoir of resistance genes available for exchange with clinical pathogens. Using a high-throughput functional metagenomic approach in conjunction with a pipeline for the de novo assembly of short-read sequence data from functional selections (termed PARFuMS), we provide evidence for recent exchange of antibiotic resistance genes between environmental bacteria and clinical pathogens. We describe multidrug-resistant soil bacteria containing resistance cassettes against five classes of antibiotics (beta lactams, aminoglycosides, amphenicols, sulfonamides, and tetracyclines) that have perfect nucleotide identity to genes from diverse human pathogens. This identity encompasses noncoding regions as well as multiple mobilization sequences, offering not only evidence of lateral exchange but also a mechanism by which antibiotic resistance disseminates. PMID- 22936784 TI - Kidney stones and kidney function loss: a cohort study. AB - OBJECTIVE: To investigate whether the presence of kidney stones increase the risk of end stage renal disease (ESRD) or other adverse renal outcomes. DESIGN: A registry cohort study using validated algorithms based on claims and facility utilisation data. Median follow-up of 11 years. SETTING: Alberta, Canada, between 1997 and 2009. PARTICIPANTS: 3,089,194 adult patients without ESRD at baseline or a history of pyelonephritis. Of these, 1,954,836 had outpatient serum creatinine measurements and were included in analyses of chronic kidney disease and doubling of serum creatinine level. EXPOSURE: One or more kidney stones during follow-up. MAIN OUTCOME MEASURES: Incident ESRD, development of stage 3b-5 chronic kidney disease (estimated glomerular filtration rate <45 mL/min/1.73 m(2)), and sustained doubling of serum creatinine concentration from baseline. RESULTS: 23,706 (0.8%) patients had at least one kidney stone, 5333 (0.2%) developed ESRD, 68,525 (4%) developed stage 3b-5 chronic kidney disease, and 6581 (0.3%) experienced sustained doubling of serum creatinine. Overall, one or more stone episodes during follow-up was associated with increased risk of ESRD (adjusted hazard ratio 2.16 (95% CI 1.79 to 2.62)), new stage 3b-5 chronic kidney disease (hazard ratio 1.74 (1.61 to 1.88)), and doubling of serum creatinine (hazard ratio 1.94 (1.56 to 2.43)), all compared with those without kidney stones during follow-up. The excess risk of adverse outcomes associated with at least one episode of stones seemed greater in women than in men, and in people aged <50 years than in those aged >= 50. However, the risks of all three adverse outcomes in those with at least one episode of stones were significantly higher than in those without stones in both sexes and age strata. The absolute increase in the rate of adverse renal outcomes associated with stones was small: the unadjusted rate of ESRD was 2.48 per million person days in people with one or more episodes of stones versus 0.52 per million person days in people without stones. CONCLUSION: Even a single kidney stone episode during follow-up was associated with a significant increase in the likelihood of adverse renal outcomes including ESRD. However, the increases were small in absolute terms. PMID- 22936785 TI - Risk of lung cancer associated with domestic use of coal in Xuanwei, China: retrospective cohort study. AB - OBJECTIVE: To estimate the risk of lung cancer associated with the use of different types of coal for household cooking and heating. SETTING: Xuanwei County, Yunnan Province, China. DESIGN: Retrospective cohort study (follow-up 1976-96) comparing mortality from lung cancer between lifelong users of "smoky coal" (bituminous) and "smokeless coal" (anthracite). PARTICIPANTS: 27,310 individuals using smoky coal and 9962 individuals using smokeless coal during their entire life. MAIN OUTCOME MEASURES: Primary outcomes were absolute and relative risk of death from lung cancer among users of different types of coal. Unadjusted survival analysis was used to estimate the absolute risk of lung cancer, while Cox regression models compared mortality hazards for lung cancer between smoky and smokeless coal users. RESULTS: Lung cancer mortality was substantially higher among users of smoky coal than users of smokeless coal. The absolute risks of lung cancer death before 70 years of age for men and women using smoky coal were 18% and 20%, respectively, compared with less than 0.5% among smokeless coal users of both sexes. Lung cancer alone accounted for about 40% of all deaths before age 60 among individuals using smoky coal. Compared with smokeless coal, use of smoky coal was associated with an increased risk of lung cancer death (for men, hazard ratio 36 (95% confidence interval 20 to 65); for women, 99 (37 to 266)). CONCLUSIONS: In Xuanwei, the domestic use of smoky coal is associated with a substantial increase in the absolute lifetime risk of developing lung cancer and is likely to represent one of the strongest effects of environmental pollution reported for cancer risk. Use of less carcinogenic types of coal could translate to a substantial reduction of lung cancer risk. PMID- 22936787 TI - Mean platelet volume as a diagnostic marker for cardiovascular disease: drawbacks of preanalytical conditions and measuring techniques. AB - After the first description of platelets more than a century ago, the knowledge about their origin and function grew continuously. The development of the impedance method as a completely automated assay allowed integrating mean platelet volume (MPV) measurement as a routine parameter of the complete blood count. This enabled us to focus more on the association of platelet function and size. Since then, many authors described MPV as a marker of platelet reactivity and risk factor for cardiovascular diseases. Hence, the preanalytical variability of this parameter is known from its introduction as standard laboratory value. Unfortunately no preanalytical standards have been implemented. This review shows the high variability in the literature with MPV as a risk factor for cardiovascular disease. After a brief description of the biology of platelets, we provide an in-depth survey of the measurement methods and their drawbacks. Finally, we propose a possible approach to standardization. PMID- 22936786 TI - Lifestyle, social factors, and survival after age 75: population based study. AB - OBJECTIVE: To identify modifiable factors associated with longevity among adults aged 75 and older. DESIGN: Population based cohort study. SETTING: Kungsholmen, Stockholm, Sweden. PARTICIPANTS: 1810 adults aged 75 or more participating in the Kungsholmen Project, with follow-up for 18 years. MAIN OUTCOME MEASURE: Median age at death. Vital status from 1987 to 2005. RESULTS: During follow-up 1661 (91.8%) participants died. Half of the participants lived longer than 90 years. Half of the current smokers died 1.0 year (95% confidence interval 0.0 to 1.9 years) earlier than non-smokers. Of the leisure activities, physical activity was most strongly associated with survival; the median age at death of participants who regularly swam, walked, or did gymnastics was 2.0 years (0.7 to 3.3 years) greater than those who did not. The median survival of people with a low risk profile (healthy lifestyle behaviours, participation in at least one leisure activity, and a rich or moderate social network) was 5.4 years longer than those with a high risk profile (unhealthy lifestyle behaviours, no participation in leisure activities, and a limited or poor social network). Even among the oldest old (85 years or older) and people with chronic conditions, the median age at death was four years higher for those with a low risk profile compared with those with a high risk profile. CONCLUSION: Even after age 75 lifestyle behaviours such as not smoking and physical activity are associated with longer survival. A low risk profile can add five years to women's lives and six years to men's. These associations, although attenuated, were also present among the oldest old (>= 85 years) and in people with chronic conditions. PMID- 22936788 TI - Copper modulates zinc metalloproteinase-dependent ectodomain shedding of key signaling and adhesion proteins and promotes the invasion of prostate cancer epithelial cells. AB - A disintegrin and metalloproteinases (ADAMs) and matrix metalloproteinases (MMPs) are zinc metalloproteinases (ZMPs) that catalyze the "ectodomain shedding" of a range of cell surface proteins including signaling and adhesion molecules. These "sheddases" are associated with the invasion and metastasis of a range of cancers. Increased serum and tumor tissue levels of copper are also observed in several cancers, although little is known about how the metal might promote disease progression at the molecular level. In the current study, we investigated whether copper might regulate the ectodomain shedding of two key cell surface proteins implicated in the invasion and metastasis of prostate cancer, the Notch ligand Jagged1 and the adhesion molecule E-cadherin, and whether the metal was able to influence the invasion of the prostate cancer epithelial cell line PC3. Physiological copper concentrations stimulated the ZMP-mediated proteolysis of Jagged1 and E-cadherin in cell culture models, whereas other divalent metals had no effect. Copper-mediated Jagged1 proteolysis was also observed following the pretreatment of cells with cycloheximide and in a cell-free membrane system, indicating a posttranslational mechanism of sheddase activation. Finally, the concentrations of copper that stimulated ZMP-mediated protein shedding also enhanced PC3 invasion; an effect that could be negated using a sheddase inhibitor or copper chelators. Collectively, these data implicate copper as an important factor in promoting prostate cancer cell invasion and indicate that the selective posttranslational activation of ZMP-mediated protein shedding might play a role in this process. PMID- 22936790 TI - N-myc and noncoding RNAs in neuroblastoma. AB - Neuroblastoma is a pediatric tumor of the sympathetic nervous system. Amplification and overexpression of the MYCN proto-oncogene occurs in approximately 20% of neuroblastomas and is associated with advanced stage disease, rapid tumor progression, and poor prognosis. MYCN encodes the transcriptional regulator N-myc, which has been shown to both up- and downregulate many target genes involved in cell cycle, DNA damage, differentiation, and apoptosis in neuroblastoma. During the last years, it has become clear that N-myc also modulates the expression of several classes of noncoding RNAs, in particular microRNAs. MicroRNAs are the most widely studied noncoding RNA molecules in neuroblastoma. They function as negative regulators of gene expression at the posttranscriptional level in diverse cellular processes. Aberrant regulation of miRNA expression has been implicated in the pathogenesis of neuroblastoma. While the N-myc protein is established as an important regulator of several miRNAs involved in neuroblastoma tumorigenesis, tumor suppressor miRNAs have also been documented to repress MYCN expression and inhibit cell proliferation of MYCN-amplified neuroblastoma cells. It is now becoming increasingly evident that N-myc also regulates the expression of long noncoding RNAs such as T-UCRs and ncRAN. This review summarizes the current knowledge about the interplay between N-myc and noncoding RNAs in neuroblastoma and how this contributes to neuroblastoma tumorigenesis. PMID- 22936789 TI - The essential role of Gialpha2 in prostate cancer cell migration. AB - Cell- and receptor-specific regulation of cell migration by Gi/oalpha-proteins remains unknown in prostate cancer cells. In the present study, oxytocin (OXT) receptor was detected at the protein level in total cell lysates from C81 (an androgen-independent subline of LNCaP), DU145 and PC3 prostate cancer cells, but not in immortalized normal prostate luminal epithelial cells (RWPE1), and OXT induced migration of PC3 cells. This effect of OXT has been shown to be mediated by Gi/oalpha-dependent signaling. Accordingly, OXT inhibited forskolin-induced luciferase activity in PC3 cells that were transfected with a luciferase reporter for cyclic AMP activity. Although mRNAs for all three Gialpha isoforms were present in PC3 cells, Gialpha2 was the most abundant isoform that was detected at the protein level. Pertussis toxin (PTx) inhibited the OXT-induced migration of PC3 cells. Ectopic expression of the PTx-resistant Gialpha2-C352G, but not wild type Gialpha2, abolished this effect of PTx on OXT-induced cell migration. The Gialpha2-targeting siRNA was shown to specifically reduce Gialpha2 mRNA and protein in prostate cancer cells. The Gialpha2-targeting siRNA eliminated OXT induced migration of PC3 cells. These data suggest that Gialpha2 plays an important role in the effects of OXT on PC3 cell migration. The Gialpha2 targeting siRNA also inhibited EGF-induced migration of PC3 and DU145 cells. Expression of the siRNA-resistant Gialpha2, but not wild type Gialpha2, restored the effects of EGF in PC3 cells transfected with the Gialpha2-targeting siRNA. In conclusion, Gialpha2 plays an essential role in OXT and EGF signaling to induce prostate cancer cell migration. PMID- 22936791 TI - Accounting for the role of habit in lifestyle intervention research. PMID- 22936792 TI - Patients' well-being: experience and actions in their preventing and handling of atrial fibrillation. AB - BACKGROUND: Atrial fibrillation (AF) influences the lives of patients in the form of worsened well-being. Patients' own experience of and how to handle AF is rarely investigated. These are important aspects for healthcare services to understand in order to support the well-being of patients with AF. AIM: To explore and describe critical incidents in which patients experience how AF affects their well-being and what actions they take to prevent and handle it. DESIGN AND METHODS: An explorative, descriptive design based on the critical incident technique (CIT) was used. Interviews were conducted with 25 patients (16 men and 9 women) with AF in a healthcare area in southern Sweden. RESULTS: Patients experienced discomfort and limitations in daily life. The actions they took were self-care related actions and healthcare related actions. CONCLUSION: AF affects well-being when it is uncomfortable and leads to pronounced limitations in daily life with the patients trying to maintain or restore well being through adapting and developing strategies for self-care. Patients base the handling of AF on their personal experience. PMID- 22936793 TI - Skin rash in a preterm infant. PMID- 22936794 TI - Association of systolic and diastolic blood pressure and all cause mortality in people with newly diagnosed type 2 diabetes: retrospective cohort study. AB - OBJECTIVE: To examine the effect of systolic and diastolic blood pressure achieved in the first year of treatment on all cause mortality in patients newly diagnosed with type 2 diabetes, with and without established cardiovascular disease. DESIGN: Retrospective cohort study. SETTING: United Kingdom General Practice Research Database, between 1990 and 2005. PARTICIPANTS: 126,092 adult patients (age >= 18 years) with a new diagnosis of type 2 diabetes who had been registered with participating practices for at least 12 months. MAIN OUTCOME MEASURE: All cause mortality. RESULTS: Before diagnosis, 12,379 (9.8%) patients had established cardiovascular disease (myocardial infarction or stroke). During a median follow-up of 3.5 years, we recorded 25,495 (20.2%) deaths. In people with cardiovascular disease, tight control of systolic (<130 mm Hg) and diastolic (<80 mm Hg) blood pressure was not associated with improved survival, after adjustment for baseline characteristics (age at diagnosis, sex, practice level clustering, deprivation score, body mass index, smoking, HbA(1c) and cholesterol levels, and blood pressure). Low blood pressure was also associated with an increased risk of all cause mortality. Compared with patients who received usual control of systolic blood pressure (130-139 mm Hg), the hazard ratio of all cause mortality was 2.79 (95% confidence interval 1.74 to 4.48, P<0.001) for systolic blood pressure at 110 mm Hg. Compared with patients who received usual control of diastolic blood pressure (80-84 mm Hg), the hazard ratios were 1.32 (1.02 to 1.78, P=0.04) and 1.89 (1.40 to 2.56, P<0.001) for diastolic blood pressures at 70-74 mm Hg and lower than 70 mm Hg, respectively. Similar associations were found in people without cardiovascular disease. Subgroup analyses of people diagnosed with hypertension and who received treatment for hypertension confirmed initial findings. CONCLUSION: Blood pressure below 130/80 mm Hg was not associated with reduced risk of all cause mortality in patients with newly diagnosed diabetes, with or without known cardiovascular disease. Low blood pressure, particularly below 110/75 mm Hg, was associated with an increased risk for poor outcomes. PMID- 22936796 TI - Believe in better. PMID- 22936795 TI - Low glycaemic index diet in pregnancy to prevent macrosomia (ROLO study): randomised control trial. AB - OBJECTIVE: To determine if a low glycaemic index diet in pregnancy could reduce the incidence of macrosomia in an at risk group. DESIGN: Randomised controlled trial. SETTING: Maternity hospital in Dublin, Ireland. PARTICIPANTS: 800 women without diabetes, all in their second pregnancy between January 2007 to January 2011, having previously delivered an infant weighing greater than 4 kg. INTERVENTION: Women were randomised to receive no dietary intervention or start on a low glycaemic index diet from early pregnancy. MAIN OUTCOMES: The primary outcome measure was difference in birth weight. The secondary outcome measure was difference in gestational weight gain. RESULTS: No significant difference was seen between the two groups in absolute birth weight, birthweight centile, or ponderal index. Significantly less gestational weight gain occurred in women in the intervention arm (12.2 v 13.7 kg; mean difference -1.3, 95% confidence interval -2.4 to -0.2; P=0.01). The rate of glucose intolerance was also lower in the intervention arm: 21% (67/320) compared with 28% (100/352) of controls had a fasting glucose of 5.1 mmol/L or greater or a 1 hour glucose challenge test result of greater than 7.8 mmol/L (P=0.02). CONCLUSION: A low glycaemic index diet in pregnancy did not reduce the incidence of large for gestational age infants in a group at risk of fetal macrosomia. It did, however, have a significant positive effect on gestational weight gain and maternal glucose intolerance. TRIAL REGISTRATION: Current Controlled Trials ISRCTN54392969. PMID- 22936797 TI - Overall sulfation of heparan sulfate from pancreatic islet beta-TC3 cells increases maximal fibril formation but does not determine binding to the amyloidogenic peptide islet amyloid polypeptide. AB - Islet amyloid, a pathologic feature of type 2 diabetes, contains the islet beta cell peptide islet amyloid polypeptide (IAPP) as its unique amyloidogenic component. Islet amyloid also contains heparan sulfate proteoglycans (HSPGs) that may contribute to amyloid formation by binding IAPP via their heparan sulfate (HS) chains. We hypothesized that beta-cells produce HS that bind IAPP via regions of highly sulfated disaccharides. Unexpectedly, HS from the beta-cell line beta-TC3 contained fewer regions of highly sulfated disaccharides compared with control normal murine mammary gland (NMuMG) cells. The proportion of HS that bound IAPP was similar in both cell lines (~65%). The sulfation pattern of IAPP bound versus non-bound HS from beta-TC3 cells was similar. In contrast, IAPP bound HS from NMuMG cells contained frequent highly sulfated regions, whereas the non-bound material demonstrated fewer sulfated regions. Fibril formation from IAPP was stimulated equally by IAPP-bound beta-TC3 HS, non-bound beta-TC3 HS, and non-bound NMuMG HS but was stimulated to a greater extent by the highly sulfated IAPP-bound NMuMG HS. Desulfation of HS decreased the ability of both beta-TC3 and NMuMG HS to stimulate IAPP maximal fibril formation, but desulfated HS from both cell types still accelerated fibril formation relative to IAPP alone. In summary, neither binding to nor acceleration of fibril formation from the amyloidogenic peptide IAPP is dependent on overall sulfation in HS synthesized by beta-TC3 cells. This information will be important in determining approaches to reduce HS IAPP interactions and ultimately prevent islet amyloid formation and its toxic effects in type 2 diabetes. PMID- 22936799 TI - The structural basis for a coordinated reaction catalyzed by a bifunctional glycosyltransferase in chondroitin biosynthesis. AB - Bifunctional chondroitin synthase K4CP catalyzes glucuronic acid and N acetylgalactosamine transfer activities and polymerizes a chondroitin chain. Here we have determined that an N-terminal region (residues 58-134) coordinates two transfer reactions and enables K4CP to catalyze polymerization. When residues 58 107 are deleted, K4CP loses polymerase activity while retaining both transfer activities. Peptide (113)DWPSDL(118) within this N-terminal region interacts with C-terminal peptide (677)YTWEKI(682). The deletion of either sequence abolishes glucuronic acid but not N-acetylgalactosamine transfer activity in K4CP. Both donor bindings and transfer activities are lost by mutating (677)YTWEKI(682) to (677)DAWEDI(682). On the other hand, acceptor substrates retain their binding to K4CP mutants. The characteristics of these K4CP mutants highlight different states of the enzyme reaction, providing an underlying structural basis for how these peptides play essential roles in coordinating the two glycosyltransferase activities for K4CP to elongate the chondroitin chain. PMID- 22936798 TI - The endoplasmic reticulum stress transducer BBF2H7 suppresses apoptosis by activating the ATF5-MCL1 pathway in growth plate cartilage. AB - BBF2H7 (box B-binding factor 2 human homolog on chromosome 7) is a basic leucine zipper transmembrane transcription factor that belongs to the cyclic AMP responsive element-binding protein (CREB)/activating transcription factor (ATF) family. This novel endoplasmic reticulum (ER) stress transducer is localized in the ER and is cleaved in its transmembrane region in response to ER stress. BBF2H7 has been shown to be expressed in proliferating chondrocytes in cartilage during the development of long bones. The target of BBF2H7 is Sec23a, one of the coat protein complex II components. Bbf2h7-deficient (Bbf2h7(-/-)) mice exhibit severe chondrodysplasia, with expansion of the rough ER in proliferating chondrocytes caused by impaired secretion of extracellular matrix (ECM) proteins. We observed a decrease in the number of proliferating chondrocytes in the cartilage of Bbf2h7(-/-) mice. TUNEL staining of the cartilage showed that apoptosis was promoted in Bbf2h7(-/-) chondrocytes. Atf5 (activating transcription factor 5), another member of the CREB/ATF family and an antiapoptotic factor, was also found to be a target of BBF2H7 in chondrocytes. ATF5 activated the transcription of Mcl1 (myeloid cell leukemia sequence 1), which belongs to the antiapoptotic B-cell leukemia/lymphoma 2 family, to suppress apoptosis. Finally, we found that the BBF2H7-ATF5-MCL1 pathway specifically suppressed ER stress-induced apoptosis in chondrocytes. Taken together, our findings indicate that BBF2H7 is activated in response to ER stress caused by synthesis of abundant ECM proteins and plays crucial roles as a bifunctional regulator to accelerate ECM protein secretion and suppress ER stress-induced apoptosis by activating the ATF5-MCL1 pathway during chondrogenesis. PMID- 22936800 TI - Clock genes influence gene expression in growth plate and endochondral ossification in mice. AB - We have previously shown transient promotion by parathyroid hormone of Period-1 (Per1) expression in cultured chondrocytes. Here we show the modulation by clock genes of chondrogenic differentiation through gene transactivation of the master regulator of chondrogenesis Indian hedgehog (IHH) in chondrocytes of the growth plate. Several clock genes were expressed with oscillatory rhythmicity in cultured chondrocytes and rib growth plate in mice, whereas chondrogenesis was markedly inhibited in stable transfectants of Per1 in chondrocytic ATDC5 cells and in rib growth plate chondrocytes from mice deficient of brain and muscle aryl hydrocarbon receptor nuclear translocator-like (BMAL1). Ihh promoter activity was regulated by different clock gene products, with clear circadian rhythmicity in expression profiles of Ihh in the growth plate. In BMAL1-null mice, a predominant decrease was seen in Ihh expression in the growth plate with a smaller body size than in wild-type mice. BMAL1 deficit led to disruption of the rhythmic expression profiles of both Per1 and Ihh in the growth plate. A clear rhythmicity was seen with Ihh expression in ATDC5 cells exposed to dexamethasone. In young mice defective of BMAL1 exclusively in chondrocytes, similar abnormalities were found in bone growth and Ihh expression. These results suggest that endochondral ossification is under the regulation of particular clock gene products expressed in chondrocytes during postnatal skeletogenesis through a mechanism relevant to the rhythmic Ihh expression. PMID- 22936801 TI - A phytoestrogen diarylheptanoid mediates estrogen receptor/Akt/glycogen synthase kinase 3beta protein-dependent activation of the Wnt/beta-catenin signaling pathway. AB - Estrogen promotes growth in many tissues by activating Wnt/beta-catenin signaling. Recently, ASPP 049, a diarylheptanoid isolated from Curcuma comosa Roxb., has been identified as a phytoestrogen. This investigation determined the involvement of Wnt/beta-catenin signaling in the estrogenic activity of this diarylheptanoid in transfected HEK 293T and in mouse preosteoblastic (MC3T3-E1) cells using a TOPflash luciferase assay and immunofluorescence. ASPP 049 rapidly activated T-cell-specific transcription factor/lymphoid enhancer binding factor mediated transcription activity and induced beta-catenin accumulation in the nucleus. Interestingly, the effects of ASPP 049 on the transcriptional activity and induction and accumulation of beta-catenin protein in the nucleus of MC3T3-E1 cells were greater compared with estradiol. Activation of beta-catenin in MC3T3 E1 cells was inhibited by ICI 182,780, suggesting that an estrogen receptor is required. In addition, ASPP 049 induced phosphorylations at serine 473 of Akt and serine 9 of GSK-3beta. Moreover, ASPP 049 also induced proliferation and expressions of Wnt target genes Axin2 and Runx2 in MC3T3-E1 cells. In addition, ASPP 049 increased alkaline phosphatase expression, and activity that was abolished by DKK-1, a blocker of the Wnt/beta-catenin receptor. Taken together, these results suggest that ASPP 049 from C. comosa induced osteoblastic cell proliferation and differentiation through ERalpha-, Akt-, and GSK-3beta-dependent activation of beta-catenin signaling. Our findings provide a scientific rationale for using C. comosa as a dietary supplement to prevent bone loss in postmenopausal women. PMID- 22936802 TI - Transmembrane and extracellular domains of syndecan-1 have distinct functions in regulating lung epithelial migration and adhesion. AB - Syndecan-1 is a cell surface proteoglycan that can organize co-receptors into a multimeric complex to transduce intracellular signals. The syndecan-1 core protein has multiple domains that confer distinct cell- and tissue-specific functions. Indeed, the extracellular, transmembrane, and cytoplasmic domains have all been found to regulate specific cellular processes. Our previous work demonstrated that syndecan-1 controls lung epithelial migration and adhesion. Here, we identified the necessary domains of the syndecan-1 core protein that modulate its function in lung epithelial repair. We found that the syndecan-1 transmembrane domain has a regulatory function in controlling focal adhesion disassembly, which in turn controls cell migration speed. In contrast, the extracellular domain facilitates cell adhesion through affinity modulation of alpha(2)beta(1) integrin. These findings highlight the fact that syndecan-1 is a multidimensional cell surface receptor that has several regulatory domains to control various biological processes. In particular, the lung epithelium requires the syndecan-1 transmembrane domain to govern cell migration and is independent from its ability to control cell adhesion via the extracellular domain. PMID- 22936803 TI - Ubiquitin E3 ligase A20 facilitates processing microbial product in nasal epithelial cells. AB - Microbial products play a role in the pathogenesis of allergic diseases; ubiquitin E3 ligase A20 (A20) is an important molecule in regulating inflammation in the body. The present study aims to elucidate the role of A20 in processing the absorbed microbial products in nasal epithelial cells. Human nasal mucosal specimens were collected from patients with or without chronic rhinitis and analyzed by immunohistochemistry. Human nasal epithelial cell line, RPMI2650 cell, was employed to assess the role of A20 in processing the absorbed staphylococcal enterotoxin B (SEB). The RPMI2650 cells absorbed SEB in the culture. The increase in A20 was observed in RPMI2650 cells in parallel to the absorption of SEB. A20 is a critical molecule in the degradation of SEB in the nasal epithelial cells by promoting the tethering of endosomes and lysosomes. A20 plays a critical role in processing of the absorbed SEB in nasal epithelial cells. PMID- 22936804 TI - Membrane-induced lever arm expansion allows myosin VI to walk with large and variable step sizes. AB - Myosin VI, the only known minus-ended actin filament-dependent motor, plays diverse cellular roles both as a processive motor and as a mechanical anchor. Although myosin VI has a short lever arm containing only one "IQ-motif" and a unique insertion for CaM binding, the motor walks with large and variable step sizes of ~30-36 nm. Here, we show that the previously predicted coiled-coil domain immediately following the IQ-motifs (referred to as the lever arm extension (LAE)) adopts a stable monomeric, three-helix bundle fold in solution. Importantly, the LAE can undergo reversible, lipid membrane-dependent conformational changes. Upon exposure to lipid membranes, the LAE adopts a partially extended rod shape, and the removal of lipids from the LAE converts it back into the compact helix bundle structure. Molecular dynamics simulations indicate that lipid membrane binding may initiate unfolding and thereby trigger the LAE expansion. This reversible, lipid membrane-dependent expansion of the LAE provides a mechanistic base for myosin VI to walk with large and variable step sizes. PMID- 22936805 TI - FAM20C plays an essential role in the formation of murine teeth. AB - FAM20C is highly expressed in bone and tooth. Previously, we showed that Fam20C conditional knock-out (KO) mice manifest hypophosphatemic rickets, which highlights the crucial roles of this molecule in promoting bone formation and mediating phosphate homeostasis. In this study, we characterized the dentin, enamel, and cementum of Sox2-Cre-mediated Fam20C KO mice. The KO mice exhibited small malformed teeth, severe enamel defects, very thin dentin, less cementum than normal, and overall hypomineralization in the dental mineralized tissues. In situ hybridization and immunohistochemistry analyses revealed remarkable down regulation of dentin matrix protein 1 (DMP1) and dentin sialophosphoprotein in odontoblasts, along with a sharply reduced expression of ameloblastin and amelotin in ameloblasts. Collectively, these data indicate that FAM20C is essential to the differentiation and mineralization of dental tissues through the regulation of molecules critical to the differentiation of tooth-formative cells. PMID- 22936806 TI - Ceramide glycosylation by glucosylceramide synthase selectively maintains the properties of breast cancer stem cells. AB - Cancer stem cells are distinguished from normal adult stem cells by their stemness without tissue homeostasis control. Glycosphingolipids (GSLs), particularly globo-series GSLs, are important markers of undifferentiated embryonic stem cells, but little is known about whether or not ceramide glycosylation, which controls glycosphingolipid synthesis, plays a role in modulating stem cells. Here, we report that ceramide glycosylation catalyzed by glucosylceramide synthase, which is enhanced in breast cancer stem cells (BCSCs) but not in normal mammary epithelial stem cells, maintains tumorous pluripotency of BCSCs. Enhanced ceramide glycosylation and globotriosylceramide (Gb3) correlate well with the numbers of BCSCs in breast cancer cell lines. In BCSCs sorted with CD44(+)/ESA(+)/CD24(-) markers, Gb3 activates c-Src/beta-catenin signaling and up-regulates the expression of FGF-2, CD44, and Oct-4 enriching tumorigenesis. Conversely, silencing glucosylceramide synthase expression disrupts Gb3 synthesis and selectively kills BCSCs through deactivation of c Src/beta-catenin signaling. These findings highlight the unexploited role of ceramide glycosylation in selectively maintaining the tumorous pluripotency of cancer stem cells. It speculates that disruption of ceramide glycosylation or globo-series GSL is a useful approach to specifically target BCSCs specifically. PMID- 22936807 TI - Novel IL27p28/IL12p40 cytokine suppressed experimental autoimmune uveitis by inhibiting autoreactive Th1/Th17 cells and promoting expansion of regulatory T cells. AB - IL-12 family cytokines are important in host immunity. Whereas some members (IL 12, IL-23) play crucial roles in pathogenesis of organ-specific autoimmune diseases by inducing the differentiation of Th1 and Th17 lymphocytes, others (IL 27 and IL-35) suppress inflammatory responses and limit tissue injury induced by these T cell subsets. In this study, we have genetically engineered a novel IL27p28/IL12p40 heterodimeric cytokine (p28/p40) that antagonizes signaling downstream of the gp130 receptor. We investigated whether p28/p40 can be used to ameliorate uveitis, a CNS inflammatory disease. Experimental autoimmune uveitis (EAU) is the mouse model of human uveitis and is mediated by Th1 and Th17 cells. We show here that p28/p40 suppressed EAU by inhibiting the differentiation and inflammatory responses of Th1 and Th17 cells while promoting expansion of IL 10(+)- and Foxp3(+)-expressing regulatory T cells. Lymph node cells from mice treated with p28/p40 blocked adoptive transfer of EAU to naive syngeneic mice by immunopathogenic T cells and suppressive effects of p28/p40 derived in part from antagonizing STAT1 and STAT3 pathways induced by IL-27 and IL-6. Interestingly, IL27p28 also suppressed EAU, but to a lesser extent than p28/p40. The inhibition of uveitogenic lymphocyte proliferation and suppression of EAU by p28/p40 and IL27p28 establish efficacy of single chain and heterodimeric IL-12 family cytokines in treatment of a CNS autoimmune disease. Creation of the biologically active p28/p40 heterodimeric cytokine represents an important proof-of-concept experiment, suggesting that cytokines comprising unique IL-12 alpha- and beta subunit pairing may exist in nature and may constitute a new class of therapeutic cytokines. PMID- 22936808 TI - Structural basis for intrinsic thermosensing by the master virulence regulator RovA of Yersinia. AB - Pathogens often rely on thermosensing to adjust virulence gene expression. In yersiniae, important virulence-associated traits are under the control of the master regulator RovA, which uses a built-in thermosensor to control its activity. Thermal upshifts encountered upon host entry induce conformational changes in the RovA dimer that attenuate DNA binding and render the protein more susceptible to proteolysis. Here, we report the crystal structure of RovA in the free and DNA-bound forms and provide evidence that thermo-induced loss of RovA activity is promoted mainly by a thermosensing loop in the dimerization domain and residues in the adjacent C-terminal helix. These determinants allow partial unfolding of the regulator upon an upshift to 37 degrees C. This structural distortion is transmitted to the flexible DNA-binding domain of RovA. RovA contacts mainly the DNA backbone in a low-affinity binding mode, which allows the immediate release of RovA from its operator sites. We also show that SlyA, a close homolog of RovA from Salmonella with a very similar structure, is not a thermosensor and remains active and stable at 37 degrees C. Strikingly, changes in only three amino acids, reflecting evolutionary replacements in SlyA, result in a complete loss of the thermosensing properties of RovA and prevent degradation. In conclusion, only minor alterations can transform a thermotolerant regulator into a thermosensor that allows adjustment of virulence and fitness determinants to their thermal environment. PMID- 22936809 TI - Resveratrol modulates interleukin-1beta-induced phosphatidylinositol 3-kinase and nuclear factor kappaB signaling pathways in human tenocytes. AB - Resveratrol, an activator of histone deacetylase Sirt-1, has been proposed to have beneficial health effects due to its antioxidant and anti-inflammatory properties. However, the mechanisms underlying the anti-inflammatory effects of resveratrol and the intracellular signaling pathways involved are poorly understood. An in vitro model of human tenocytes was used to examine the mechanism of resveratrol action on IL-1beta-mediated inflammatory signaling. Resveratrol suppressed IL-1beta-induced activation of NF-kappaB and PI3K in a dose- and time-dependent manner. Treatment with resveratrol enhanced the production of matrix components collagen types I and III, tenomodulin, and tenogenic transcription factor scleraxis, whereas it inhibited gene products involved in inflammation and apoptosis. IL-1beta-induced NF-kappaB and PI3K activation was inhibited by resveratrol or the inhibitors of PI3K (wortmannin), c Src (PP1), and Akt (SH-5) through inhibition of IkappaB kinase, IkappaBalpha phosphorylation, and inhibition of nuclear translocation of NF-kappaB, suggesting that PI3K signaling pathway may be one of the signaling pathways inhibited by resveratrol to abrogate NF-kappaB activation. Inhibition of PI3K by wortmannin attenuated IL-1beta-induced Akt and p65 acetylation, suggesting that p65 is a downstream component of PI3K/Akt in these responses. The modulatory effects of resveratrol on IL-1beta-induced activation of NF-kappaB and PI3K were found to be mediated at least in part by the association between Sirt-1 and scleraxis and deacetylation of NF-kappaB and PI3K. Overall, these results demonstrate that activated Sirt-1 plays an essential role in the anti-inflammatory effects of resveratrol and this may be mediated at least in part through inhibition/deacetylation of PI3K and NF-kappaB. PMID- 22936812 TI - Spanish government accused of "manipulating" drugs bill figures. PMID- 22936810 TI - Overexpression of vesicle-associated membrane protein (VAMP) 3, but not VAMP2, protects glucose transporter (GLUT) 4 protein translocation in an in vitro model of cardiac insulin resistance. AB - Cardiac glucose utilization is regulated by reversible translocation of the glucose transporter GLUT4 from intracellular stores to the plasma membrane. During the onset of diet-induced insulin resistance, elevated lipid levels in the circulation interfere with insulin-stimulated GLUT4 translocation, leading to impaired glucose utilization. Recently, we identified vesicle-associated membrane protein (VAMP) 2 and 3 to be required for insulin- and contraction-stimulated GLUT4 translocation, respectively, in cardiomyocytes. Here, we investigated whether overexpression of VAMP2 and/or VAMP3 could protect insulin-stimulated GLUT4 translocation under conditions of insulin resistance. HL-1 atrial cardiomyocytes transiently overexpressing either VAMP2 or VAMP3 were cultured for 16 h with elevated concentrations of palmitate and insulin. Upon subsequent acute stimulation with insulin, we measured GLUT4 translocation, plasmalemmal presence of the fatty acid transporter CD36, and myocellular lipid accumulation. Overexpression of VAMP3, but not VAMP2, completely prevented lipid-induced inhibition of insulin-stimulated GLUT4 translocation. Furthermore, the plasmalemmal presence of CD36 and intracellular lipid levels remained normal in cells overexpressing VAMP3. However, insulin signaling was not retained, indicating an effect of VAMP3 overexpression downstream of PKB/Akt. Furthermore, we revealed that endogenous VAMP3 is bound by the contraction-activated protein kinase D (PKD), and contraction and VAMP3 overexpression protect insulin stimulated GLUT4 translocation via a common mechanism. These observations indicate that PKD activates GLUT4 translocation via a VAMP3-dependent trafficking step, which pathway might be valuable to rescue constrained glucose utilization in the insulin-resistant heart. PMID- 22936811 TI - Complex regulation of voltage-dependent activation and inactivation properties of retinal voltage-gated Cav1.4 L-type Ca2+ channels by Ca2+-binding protein 4 (CaBP4). AB - Cav1.4 L-type Ca(2+) channels are crucial for synaptic transmission in retinal photoreceptors and bipolar neurons. Recent studies suggest that the activity of this channel is regulated by the Ca(2+)-binding protein 4 (CaBP4). In the present study, we explored this issue by examining functional effects of CaBP4 on heterologously expressed Cav1.4. We show that CaBP4 dramatically increases Cav1.4 channel availability. This effect crucially depends on the presence of the C terminal ICDI (inhibitor of Ca(2+)-dependent inactivation) domain of Cav1.4 and is absent in a Cav1.4 mutant lacking the ICDI. Using FRET experiments, we demonstrate that CaBP4 interacts with the IQ motif of Cav1.4 and that it interferes with the binding of the ICDI domain. Based on these findings, we suggest that CaBP4 increases Cav1.4 channel availability by relieving the inhibitory effects of the ICDI domain on voltage-dependent Cav1.4 channel gating. We also functionally characterized two CaBP4 mutants that are associated with a congenital variant of human night blindness and other closely related nonstationary retinal diseases. Although both mutants interact with Cav1.4 channels, the functional effects of CaBP4 mutants are only partially preserved, leading to a reduction of Cav1.4 channel availability and loss of function. In conclusion, our study sheds new light on the functional interaction between CaBP4 and Cav1.4. Moreover, it provides insights into the mechanism by which CaBP4 mutants lead to loss of Cav1.4 function and to retinal disease. PMID- 22936813 TI - Cancer patients rate London's hospitals the worst in England. PMID- 22936814 TI - Government hit squads to help hospitals make savings on PFI deals. PMID- 22936815 TI - Ifenprodil effects on GluN2B-containing glutamate receptors. AB - N-Methyl-d-aspartate (NMDA) receptors are glutamate- and glycine-gated channels that mediate fast excitatory transmission in the central nervous system and are critical to synaptic development, plasticity, and integration. They have a rich complement of modulatory sites, which represent important pharmacological targets. Ifenprodil is a well tolerated NMDA receptor inhibitor; it is selective for GluN2B-containing receptors and has neuroprotective effects. The mechanism by which ifenprodil inhibits NMDA receptor responses is not fully understood. The inhibition is incomplete and noncompetitive with other known NMDA receptor agonists or modulators, although reciprocal effects have been reported between ifenprodil potency and that of extracellular ligands including glutamate, glycine, zinc, protons, and polyamines. Recent structural studies revealed that ifenprodil binds to a unique site at the interface between the extracellular N termini of GluN1 and GluN2B subunits, supporting the view that interactions with other extracellular modulators are indirect. In this study, we examined how ifenprodil affects the gating reaction of NMDA receptors in conditions designed to minimize actions by contemporaneous ligands. We found that ifenprodil decreased NMDA receptor equilibrium open probability by raising an energetic barrier to activation and also by biasing the receptor toward low open probability gating modes. These results demonstrate intrinsic effects of ifenprodil on NMDA receptor stationary gating kinetics and provide means to anticipate how ifenprodil will affect receptor responses in defined physiological and pathological circumstances. PMID- 22936816 TI - Xenobiotics and loss of cell adhesion drive distinct transcriptional outcomes by aryl hydrocarbon receptor signaling. AB - The aryl hydrocarbon receptor (AhR) is a signal-regulated transcription factor, which is canonically activated by the direct binding of xenobiotics. In addition, switching cells from adherent to suspension culture also activates the AhR, representing a nonxenobiotic, physiological activation of AhR signaling. Here, we show that the AhR is recruited to target gene enhancers in both ligand [isopropyl 2-(1,3-dithietane-2-ylidene)-2-[N-(4-methylthiazol-2-yl)carbamoyl]acetate (YH439)]-treated and suspension cells, suggesting a common mechanism of target gene induction between these two routes of AhR activation. However, gene expression profiles critically differ between xenobiotic- and suspension activated AhR signaling. Por and Cldnd1 were regulated predominantly by ligand treatments, whereas, in contrast, ApoER2 and Ganc were regulated predominantly by the suspension condition. Classic xenobiotic-metabolizing AhR targets such as Cyp1a1, Cyp1b1, and Nqo1 were regulated by both ligand and suspension conditions. Temporal expression patterns of AhR target genes were also found to vary, with examples of transient activation, transient repression, or sustained alterations in expression. Furthermore, sequence analysis coupled with chromatin immunoprecipitation assays and reporter gene analysis identified a functional xenobiotic response element (XRE) in the intron 1 of the mouse Tiparp gene, which was also bound by hypoxia-inducible factor-1alpha during hypoxia and features a concatemer of four XRE cores (GCGTG). Our data suggest that this XRE concatemer site concurrently regulates the expression of both the Tiparp gene and its cis antisense noncoding RNA after ligand- or suspension-induced AhR activation. This work provides novel insights into how AhR signaling drives different transcriptional programs via the ligand versus suspension modes of activation. PMID- 22936817 TI - The paternal role in pre-eclampsia and giving birth to a small for gestational age infant; a population-based cohort study. AB - OBJECTIVE: To estimate the effect of partner change on risks of pre-eclampsia and giving birth to a small for gestational age infant. DESIGN: Prospective population study. SETTING: Sweden. PARTICIPANTS: Women with their first and second successive singleton births in Sweden between 1990 and 2006 without pregestational diabetes and/or hypertension (n=446 459). OUTCOME MEASURES: Preterm (<37 weeks) and term (>=37 weeks) pre-eclampsia, and giving birth to a small for gestational age (SGA) infant. Risks were adjusted for interpregnancy interval, maternal age, body mass index, height and smoking habits in second pregnancy, years of involuntary childlessness before second pregnancy, mother's country of birth, years of formal education and year of birth. Further, when we calculated risks of SGA we restricted the study population to women with non-pre eclamptic pregnancies. RESULTS: In women who had a preterm pre-eclampsia in first pregnancy, partner change was associated with a strong protective effect for preterm pre-eclampsia recurrence (OR 0.24; 95% CI 0.07 to 0.88). Similarly, partner change was also associated with a protective effect of recurrence of SGA birth (OR 0.75; 95% CI 0.67 to 0.84). In contrast, among women without SGA in first birth, partner change was associated with an increased risk of SGA in second pregnancy. Risks of term pre-eclampsia were not affected by partner change. CONCLUSIONS: There is a paternal effect on risks of preterm pre-eclampsia and giving birth to an SGA infant. PMID- 22936818 TI - Registration in a quality register: a method to improve end-of-life care--a cross sectional study. AB - OBJECTIVES: Structured methods to assess and support improvement in the quality of end-of-life care are lacking and need to be developed. This need is particularly high outside the specialised palliative care. This study examines whether participation in a national quality register increased the quality of end of-life care. DESIGN: This study is a cross-sectional longitudinal register study. SETTING: The Swedish Register of Palliative Care (SRPC) collects data about end-of-life care for deaths in all types of healthcare units all over Sweden. Data from all 503 healthcare units that had reported patients continuously to the register during a 3-year period were analysed. PRIMARY AND SECONDARY OUTCOME MEASURES: Data on provided care during the last weeks of life were compared year-by-year with logistic regression. PARTICIPANTS: The study included a total 30 283 patients. The gender distribution was 54% women and 46% men. A total of 60% of patients in the study had a cancer diagnosis. RESULTS: Provided end-of-life care improved in a number of ways. The prevalence of six examined symptoms decreased. The prescription of 'as needed' medications for pain, nausea, anxiety and death rattle increased. A higher proportion of patients died in their place of preference. The patient's next of kin was more often offered a follow-up appointment after the patient's death. No changes were seen with respect to providing information to the patient or next of kin. CONCLUSIONS: Participation in a national quality register covariates with quality improvements in end-of-life care over time. PMID- 22936819 TI - What happens to clinical training fellows? A retrospective study of the 20 years outcome of a Medical Research Council UK cohort. AB - OBJECTIVES: The Clinical Research Training Fellowship (CRTF) allows up to 3 years support for clinically qualified candidates to undertake specialised or further research training in biomedical sciences. CRTFs are perceived as a crucial step in the career development and progression of Clinical Academics but there are no published data to support this notion. We conducted an electronic survey of a large cohort of Medical Research Council (MRC) CRTFs followed for up to 20 years. DESIGN: Retrospective analysis of CRTF outcome data held with the MRC, UK. PARTICIPANTS: Two cohorts comprising 40 CRFTs awarded by the MRC in the year 1991 and 299 MRC CRTFs who were awarded a fellowship between 1993 and 2003. RESULTS: The MRC CRTF scheme built capacity in clinical academia across the UK with 40% of CRTFs progressing to a University professorship. Importantly, the CRTF scheme is also providing NHS consultants who remain research active. CONCLUSIONS: This is the first analysis of outcome of CRTFs in the UK and provides robust evidence of the importance of this capacity building mode of funding to underpin research excellence at the University-NHS interface. PMID- 22936820 TI - How often do US-based human subjects research studies register on time, and how often do they post their results? A statistical analysis of the Clinicaltrials.gov database. AB - CONTEXT: The Food and Drug Administration Modernization Act of 1997 (FDAMA) and the FDA Amendment Act of 2007 (FDAAA), respectively, established mandates for registration of interventional human research studies on the website clinicaltrials.gov (CTG) and for posting of results of completed studies. OBJECTIVE: To characterise, contrast and explain rates of compliance with ontime registration of new studies and posting of results for completed studies on CTG. DESIGN: Statistical analysis of publically available data downloaded from the CTG website. PARTICIPANTS: US studies registered on CTG since 1 November 1999, the date when the CTG website became operational, through 24 June 2011, the date the data set was downloaded for analysis. MAIN OUTCOME MEASURES: Ontime registration (within 21 days of study start); average delay from study start to registration; proportion of studies posting their results from within the group of studies listed as completed on CTG. RESULTS: As of 24 June 2011, CTG contained 54 890 studies registered in the USA. Prior to 2005, an estimated 80% of US studies were not being registered. Among registered studies, only 55.7% registered within the 21-day reporting window. The average delay on CTG was 322 days. Between 28 September 2007 and June 23 2010, 28% of intervention studies at Phase II or beyond posted their study results on CTG, compared with 8.4% for studies without industry funding (RR 4.2, 95% CI 3.7 to 4.8). Factors associated with posting of results included exclusively paediatric studies (adjusted OR (AOR) 2.9, 95% CI 2.1 to 4.0), and later phase clinical trials (relative to Phase II studies, AOR for Phase III was 3.4, 95% CI 2.8 to 4.1; AOR for Phase IV was 6.0, 95% CI 4.8 to 7.6). CONCLUSIONS: Non-compliance with FDAMA and FDAAA appears to be very common, although compliance is higher for studies sponsored by industry. Further oversight may be required to improve compliance. PMID- 22936821 TI - A prospective observational study of quality of diabetes care in a shared care setting: trends and age differences (ZODIAC-19). AB - OBJECTIVE: The Zwolle Outpatient Diabetes project Integrating Available Care (ZODIAC) study was initiated in 1998 to investigate the effects of shared care for patients with type 2 diabetes mellitus (T2DM) in the Netherlands, and to reduce the number of diabetes-related complications. Benchmarking the performance of diabetes care was and is an important aspect of this study. We aimed to investigate trends in diabetes care, within the ZODIAC study for a wide variety of quality indicators during a long follow-up period (1998-2008), with special interest for different age groups. DESIGN: Prospective observational cohort study. SETTING: Primary care, Zwolle, The Netherlands. PARTICIPANTS: Patients with T2DM. METHODS: A dataset of quality measures was collected annually during the patient's visit to the practice nurse or general practitioner. Linear time trends from 1998 to 2008 were estimated using linear mixed models in which we adjusted for age and gender. Age was included in the model as a categorical variable: for each follow-up year all participants were categorised into the categories <60, 60-75 and >75 years. Differences in trends between the age categories were investigated by adding an interaction term to the model. RESULTS: The number of patients who were reported to participate increased in the period 1998-2008 from 1622 to 27 438. All quality indicators improved in this study, except for body mass index. The prevalence albuminuria decreased in an 11-year period from 42% to 21%. No relevant differences between the trends for the three age categories were observed. During all years of follow-up, mean blood pressure and body mass index were the lowest and highest, respectively, in the group of patients <60 years (data not shown). CONCLUSIONS: Quality of diabetes care within the Dutch ZODIAC study, a shared care project, has considerably improved in the period 1998-2008. There were no relevant differences between trends across various age categories. PMID- 22936822 TI - The Olympic Regeneration in East London (ORiEL) study: protocol for a prospective controlled quasi-experiment to evaluate the impact of urban regeneration on young people and their families. AB - INTRODUCTION: Recent systematic reviews suggest that there is a dearth of evidence on the effectiveness of large-scale urban regeneration programmes in improving health and well-being and alleviating health inequalities. The development of the Olympic Park in Stratford for the London 2012 Olympic and Paralympic Games provides the opportunity to take advantage of a natural experiment to examine the impact of large-scale urban regeneration on the health and well-being of young people and their families. DESIGN AND METHODS: A prospective school-based survey of adolescents (11-12 years) with parent data collected through face-to-face interviews at home. Adolescents will be recruited from six randomly selected schools in an area receiving large-scale urban regeneration (London Borough of Newham) and compared with adolescents in 18 schools in three comparison areas with no equivalent regeneration (London Boroughs of Tower Hamlets, Hackney and Barking & Dagenham). Baseline data will be completed prior to the start of the London Olympics (July 2012) with follow-up at 6 and 18 months postintervention. Primary outcomes are: pre-post change in adolescent and parent mental health and well-being, physical activity and parental employment status. Secondary outcomes include: pre-post change in social cohesion, smoking, alcohol use, diet and body mass index. The study will account for individual and environmental contextual effects in evaluating changes to identified outcomes. A nested longitudinal qualitative study will explore families' experiences of regeneration in order to unpack the process by which regeneration impacts on health and well-being. ETHICS AND DISSEMINATION: The study has approval from Queen Mary University of London Ethics Committee (QMREC2011/40), the Association of Directors of Children's Services (RGE110927) and the London Boroughs Research Governance Framework (CERGF113). Fieldworkers have had advanced Criminal Records Bureau clearance. Findings will be disseminated through peer-reviewed publications, national and international conferences, through participating schools and the study website (http://www.orielproject.co.uk). PMID- 22936823 TI - Combined carbamazepine and pregabalin therapy in a rat model of neuropathic pain. AB - BACKGROUND: Carbamazepine and pregabalin have proven effects against neuropathic pain. Carbamazepine blocks voltage-dependent Na(+) channels, whereas pregabalin blocks voltage-dependent Ca(2+) channels. The authors hypothesized that the co administration of these drugs would synergistically reduce neuropathic pain. METHODS: Neuropathic pain was induced by L5 nerve ligation in Sprague-Dawley rats. To determine their ED(50) values, carbamazepine and pregabalin were orally administered at 0.3, 3, 10, or 30 mg kg(-1). The drugs were then co-administered at 0, 1/4*ED(50), 1/2*ED(50), 1.5*ED(50), and 2*ED(50) to determine the ED(50) and ED(75) values of the drugs in combination. Allodynia was determined using the von Frey hair test and dose-effect curves and isobolograms were used to investigate drug interactions. Levels of the acute reactive protein c-Fos in the dorsal horn were evaluated as an indicator of pathological nerve excitation. RESULTS: At ED(50) levels, carbamazepine and pregabalin did not exhibit synergism, but doses higher than ED(75) were found to be synergistic. The combination index was 0.18 (strong synergy) and dose reductions were 35.7-fold for carbamazepine and 6.8-fold for pregabalin when co-administered when compared with a single administration at ED(75). The percentage allodynia relief was only 60% for carbamazepine and 80% for pregabalin by single administration, whereas their co-administration relieved allodynia by 100%. Furthermore, treatment decreased c-Fos expression in the dorsal horn, but expressional differences between animals treated with carbamazepine plus pregabalin were not significantly different from those treated with single drug. CONCLUSIONS: Carbamazepine and pregabalin ameliorate neuropathic pain synergistically at higher doses. PMID- 22936824 TI - Relationship between approximate entropy and visual inspection of irregularity in the EEG signal, a comparison with spectral entropy. AB - BACKGROUND: Several measures have been developed to quantify the change in EEG from wakefulness to deep anaesthesia. Measures of signal complexity or entropy have been popular and even applied in commercial monitors. These measures quantify different features of the signal, however, and may therefore behave in an incomparable way when calculated for standardized EEG patterns. METHODS: Two measures widely studied for anaesthesia EEG analysis were considered: spectral entropy and approximate entropy. First, we generated surrogate signals which had the same spectral entropy as a prototype signal, the sawtooth wave. Secondly, EEG samples where rhythmic pattern caused a peak in the power spectrum in the alpha frequency band were modified by enhancing or suppressing the corresponding rhythm. RESULTS: We found that the value of spectral entropy does not, in general, correlate with the visual impression of signal regularity. Also, the two entropy measures interpret a standardized artificially modified EEG signal in opposite directions: spectral peak of increasing amplitude in the alpha-frequency band causes spectral entropy to increase but decreases approximate entropy when low frequencies are present in the signal. CONCLUSIONS: Spectral entropy and approximate entropy of EEG are two totally different measures. They change similarly in deepening anaesthesia due to an increase in slow activity. In some cases, however, they may change in opposite directions when the EEG signal properties change during anaesthesia. Failure to understand the behaviour of these measures can lead to misinterpretation of the monitor readings or study results if no reference to the raw EEG signal is taken. PMID- 22936825 TI - Icatibant and ACE inhibitor angioedema. AB - Icatibant is a selective bradykinin 2 receptor antagonist, currently licensed for use in hereditary angioedema. Its benefit in ACE inhibitor angioedema is yet to be fully established. A handful of preliminary case reports suggest that it may be of benefit in reducing both symptom severity and possible hospital or intensive care admission. To date, there are no case reports of the usage of Icatibant in the emergency department in the UK. Here we report our experience of Icatibant in a 62-year-old gentleman presenting with severe oral, pharyngeal and laryngeal oedema while on an ACE inhibitor. PMID- 22936826 TI - Longitudinal changes in ejection fraction in heart failure patients with preserved and reduced ejection fraction. AB - BACKGROUND: Heart failure (HF) can occur in patients with preserved (HFpEF, EF>=50%) or reduced (HFrEF, EF<50%) ejection fraction (EF), but changes in EF after HF diagnosis are not well described. METHODS AND RESULTS: Among a community cohort of incident HF patients diagnosed from 1984 to 2009 in Olmsted County, Minnesota, we obtained all EFs assessed by echocardiography from initial HF diagnosis until death or last follow-up through March 2010. Mixed effects models fit a unique linear regression line for each person using serial EF data. Compiled results allowed estimates of the change in EF over time in HFpEF and HFrEF. Among 1233 HF patients (48.3% male, mean age 75.0 years, mean follow-up 5.1 years), 559 (45.3%) had HFpEF at diagnosis. In HFpEF, on average, EF decreased by 5.8% over 5 years (P<0.001) with greater declines in older individuals and those with coronary disease. Conversely, EF increased in HFrEF (average increase 6.9% over 5 years, P<0.001). Greater increases were noted in women, younger patients, individuals without coronary disease, and those treated with evidence-based medications. Overall, 39% of HFpEF patients had an EF<50% and 39% of HFrEF patients had an EF>=50% at some point after diagnosis. Decreases in EF over time were associated with reduced survival whereas increases in EF were associated with improved survival. CONCLUSIONS: These data suggest that progressive contractile dysfunction may contribute to the pathophysiology of HFpEF. Prospective longitudinal studies are needed to confirm these observations and establish the mechanism and clinical relevance of decline in EF over time in HFpEF. PMID- 22936827 TI - Elevated levels of the mediator of catabolic bone remodeling RANKL in the bone marrow environment link chronic heart failure with osteoporosis. AB - BACKGROUND: Chronic heart failure (CHF) is associated with a 4-fold increased risk for osteoporotic fractures. Therefore, we sought to identify the pathophysiological link between chronic heart failure and catabolic bone remodeling. METHODS AND RESULTS: In a total cohort of 153 subjects (123 patients with CHF, 30 patients with coronary artery disease and preserved cardiac function) as well as mice with heart failure, bone marrow (BM) plasma levels of the catabolic receptor activator of NF-kappaB ligand (RANKL), and its antagonist, osteoprotegerin were measured. The osteoclast inducing activity of BM plasma was tested in cell culture. BM plasma levels of RANKL and of the ratio RANKL/osteoprotegerin were significantly elevated in patients with CHF. On multivariate regression analysis, parameters of severity and duration of heart failure were independent determinants of elevated BM plasma RANKL levels. BM plasma levels of RANKL were directly correlated with the systemic marker of bone turnover C-telopeptide of type 1 collagen (r=0.6; P<0.001). Alterations in BM plasma levels of RANKL/osteoprotegerin were confirmed in a mouse model of postinfarction heart failure. Stimulation of human mesenchymal cells with BM plasma obtained from CHF patients increased the formation of osteoclasts, and this effect was blocked by the RANKL inhibition. CONCLUSIONS: CHF is associated with a profound and selective elevation of the bone resorption stimulating RANKL within the BM microenvironment. These data for the first time disclose a direct pathophysiological pathway linking CHF with catabolic bone remodeling associated with an increased osteoporotic fracture risk. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifiers: NCT 00289822, NCT 00284713, NCT 00326989, NCT 00962364. PMID- 22936828 TI - The polyamines and their catabolic products are significant players in the turnover of nitrogenous molecules in plants. AB - Polyamines (PAs) are nitrogenous molecules which play a well-established role in most cellular processes during growth and development under physiological or biotic/abiotic stress conditions. The molecular mode(s) of PA action have only recently started to be unveiled, and comprehensive models for their molecular interactions have been proposed. Their multiple roles are exerted, at least partially, through signalling by hydrogen peroxide (H(2)O(2)), which is generated by the oxidation/back-conversion of PAs by copper amine oxidases and PA oxidases. Accumulating evidence suggests that in plants the cellular titres of PAs are affected by other nitrogenous compounds. Here, we discuss the state of the art on the possible nitrogen flow in PAs, their interconnection with nitrogen metabolism, as well as the signalling roles of PA-derived H(2)O(2) during some developmental processes and stress responses. PMID- 22936829 TI - The use of metabolomics integrated with transcriptomic and proteomic studies for identifying key steps involved in the control of nitrogen metabolism in crops such as maize. AB - Linking plant phenotype to gene and protein expression and also to metabolite synthesis and accumulation is one of the main challenges for improving agricultural production worldwide. Such a challenge is particularly relevant to crop nitrogen use efficiency (NUE). Here, the differences in leaf gene transcript, protein, and metabolite accumulation in maize subjected to long-term nitrogen (N)-deficient growth conditions at two important stages of plant development have been studied. The impact of N deficiency was examined at the transcriptomic, proteomic, and metabolomic levels. It was found that a number of key plant biological functions were either up- or down-regulated when N was limiting, including major alterations to photosynthesis, carbon (C) metabolism, and, to a lesser extent, downstream metabolic pathways. It was also found that the impact of the N deficiency stress resembled the response of plants to a number of other biotic and abiotic stresses, in terms of transcript, protein, and metabolite accumulation. The genetic and metabolic alterations were different during the N assimilation and the grain-filling period, indicating that plant development is an important component for identifying the key elements involved in the control of plant NUE. It was also found that integration of the three 'omics' studies is not straightforward, since different levels of regulation seem to occur in a stepwise manner from gene expression to metabolite accumulation. The potential use of these 'omics' studies is discussed with a view to improve our understanding of whole plant nitrogen economics, which should have applications in breeding and agronomy. PMID- 22936830 TI - Proteomic analysis of Mn-induced resistance to powdery mildew in grapevine. AB - Previous studies documented that metal hyperaccumulation armours plants with direct defences against pathogens. In the present study, it was found that high leaf Mn concentrations (<2500 ug g(-1)) induced grapevine resistance to powdery mildew [Uncinula necator (Schw.) Burr]. Manganese delayed pathogen spreading after powdery mildew (PM) inoculation, but did not directly inhibit pathogen growth on a long-term basis. It was postulated that the grapevine resistance resulted from the induction of protective mechanisms in planta. To test this hypothesis, the proteome profile was analysed by Difference Gel Electrophoresis (DIGE) methods to identify proteins that are putatively involved in pathogen resistance. A high Mn concentration caused little oxidative pressure in grapevine, but oxidative stress was deeply enhanced by PM stress. Except for a few proteins that were related to oxidative pressure and proteins specially regulated by Mn or PM, most of the detected proteins exhibited similar changes under excess Mn stress and under PM stress, suggesting that similar signalling processes mediate the responses to the two stresses. As well as PM stress, high leaf Mn concentration significantly enhanced salicylic acid concentration and increased the expression of proteins involved in ethylene and jasmonic acid synthesis. The proteins related to pathogen resistance were also enhanced by excess Mn, including a PR-like protein, an NBS-LRR analogue, and a JOSL protein, and this was accompanied by the increased activity of phenylalanine ammonia lyase. It was concluded that high leaf Mn concentration triggered protective mechanisms against pathogens in grapevine. PMID- 22936833 TI - Keeping the M in medical exemptions: protecting our most vulnerable children. PMID- 22936832 TI - Ectopic divisions in vascular and ground tissues of Arabidopsis thaliana result in distinct leaf venation defects. AB - Leaf venation patterns vary considerably between species and between leaves within a species. A mechanism based on canalization of auxin transport has been suggested as the means by which plastic yet organized venation patterns are generated. This study assessed the plasticity of Arabidopsis thaliana leaf venation in response to ectopic ground or procambial cell divisions and auxin transport inhibition (ATI). Ectopic ground cell divisions resulted in vascular fragments between major veins, whereas ectopic procambial cell divisions resulted in additional, abnormal vessels along major veins, with more severely perturbed lines forming incomplete secondary and higher-order venation. These responses imply limited vascular plasticity in response to unscheduled cell divisions. Surprisingly, a combination of ectopic ground cell divisions and ATI resulted in massive vascular overgrowth. It is hypothesized that the vascular overproduction in auxin transport-inhibited wild-type leaves is limited by simultaneous differentiation of ground cells into mesophyll cells. Ectopic ground cell divisions may negate this effect by providing undifferentiated ground cells that respond to accumulated auxin by differentiation into vascular cells. PMID- 22936831 TI - Proteomic analysis revealed nitrogen-mediated metabolic, developmental, and hormonal regulation of maize (Zea mays L.) ear growth. AB - Optimal nitrogen (N) supply is critical for achieving high grain yield of maize. It is well established that N deficiency significantly reduces grain yield and N oversupply reduces N use efficiency without significant yield increase. However, the underlying proteomic mechanism remains poorly understood. The present field study showed that N deficiency significantly reduced ear size and dry matter accumulation in the cob and grain, directly resulting in a significant decrease in grain yield. The N content, biomass accumulation, and proteomic variations were further analysed in young ears at the silking stage under different N regimes. N deficiency significantly reduced N content and biomass accumulation in young ears of maize plants. Proteomic analysis identified 47 proteins with significant differential accumulation in young ears under different N treatments. Eighteen proteins also responded to other abiotic and biotic stresses, suggesting that N nutritional imbalance triggered a general stress response. Importantly, 24 proteins are involved in regulation of hormonal metabolism and functions, ear development, and C/N metabolism in young ears, indicating profound impacts of N nutrition on ear growth and grain yield at the proteomic level. PMID- 22936834 TI - Medical exemptions to school immunization requirements in the United States- association of state policies with medical exemption rates (2004-2011). AB - All 50 US states allow medical exemptions from school entry immunization requirements. The extent to which medical exemptions are granted and the relationship with ease of obtaining these exemptions has not previously been examined in detail. We evaluated counts and rates of state-level medical exemptions to kindergarten entry requirements over 7 school years (2004-2005 through 2010-2011). During this period, 0.26%-0.41% of enrolled children received medical exemptions. In states with easier medical exemption criteria, medical exemption rates were significantly higher (adjusted incidence rate ratio: 6.4 [95% confidence interval: 2.7-15.6]). Routine evaluation of medical exemption rates is needed to ensure their appropriate use. PMID- 22936835 TI - Editorial: peer across the barrier--new live transmissions from the intestinal mucosa. PMID- 22936836 TI - Editorial: TRPV1: how thymocytes sense stress and respond with autophagy. PMID- 22936837 TI - Molecular support for the recognition of the Mycoblastus fucatus group as the new genus Violella (Tephromelataceae, Lecanorales). AB - The crustose lichen genus Mycoblastus in the Northern Hemisphere includes eight recognized species sharing large, simple ascospores produced 1-2 per ascus in strongly pigmented biatorine apothecia. The monophyly of Mycoblastus and the relationship of its various species to Tephromelataceae have never been studied in detail. Data from ITS rDNA and the genes coding for translation elongation factor 1-alpha and DNA replication licensing factor mini-chromosome maintenance complex 7 support the distinctness of Mycoblastus s. str. from the core of the Tephromelataceae, but recover M. fucatus and an undescribed Asian species as strongly supported within the latter group. We propose accommodating these two species in a new genus, Violella, which is characterized by its brownish inner ascospore walls, Fucatus-violet hymenial pigment granules and secondary chemistry, and discuss the position of Violella relative to Calvitimela and Tephromela. We describe the new species Violella wangii T. Sprib. & Goffinet to accommodate a new species with roccellic acid from Bhutan, China, India and the Russian Far East. We also exclude Mycoblastus indicus Awasthi & Agarwal from the genus Mycoblastus and propose for it the new combination Malmidea indica (Awasthi & Agarwal) Hafellner & T. Sprib. PMID- 22936838 TI - Balancing life with glycoconjugates: monitoring unfolded protein response mediated anti-angiogenic action of tunicamycin by Raman Spectroscopy. AB - Asparagine-linked protein glycosylation is a hallmark for glycoprotein structure and function. Its impairment by tunicamycin [a competitive inhibitor of N acetylglucosaminyl 1-phosphate transferase (GPT)] has been known to inhibit neo vascularization (i.e., angiogenesis) in humanized breast tumor due to an induction of ER stress-mediated unfolded protein response (UPR). The studies presented here demonstrate that (i) tunicamycin (i) inhibits capillary endothelial cell proliferation in a dose dependent manner; (ii) treated cells are incapable of forming colonies upon its withdrawal; and (iii) tunicamycin treatment causes nuclear fragmentation. Tunicamycin-induced ER stress-mediated UPR event in these cells was studied with the aid of Raman spectroscopy, in particular, the interpretation of bands at 1672, 1684 and 1694 cm(-1), which are characteristics of proteins and originate from C=O stretching vibrations of mono substituted amides. In tunicamycin-treated cells these bands decreased in area as follows: at 1672 cm(-1) by 41.85% at 3 h and 55.39% at 12 h; at 1684 cm(-1) by 20.63% at 3 h and 40.08% at 12 h; and also at 1994 cm(-1) by 33.33% at 3 h and 32.92% at 12 h, respectively. Thus, in the presence of tunicamycin, newly synthesized protein chains fail to arrange properly into their final secondary and/or tertiary structures, and the random coils they form had undergone further degradation. PMID- 22936839 TI - Early-Life Socioeconomic Status and the Prevalence of Breast Cancer in Later Life. AB - Knowledge of mechanisms linking early-life social environment and breast cancer remains limited. We explore direct and indirect effects of early-life socioeconomic status (SES) on breast cancer prevalence in later life. Using 50 year data from the Wisconsin Longitudinal Study (N = 4,275) and structural equation modeling, we found a negative direct effect of early-life SES, indicating that women from higher-SES family background had lower breast cancer prevalence than women from lower-SES families. Additionally, early-life SES has a positive indirect effect on breast cancer via women's adult SES and age at first birth. Were it not for their higher SES in adulthood and delayed childbearing, women from higher-SES families of origin would have had lower breast cancer prevalence than women from lower-SES families. Yet, early-life SES is associated positively with adult SES and age at first birth, and women's higher adult SES and delayed childbearing are related to higher breast cancer prevalence. PMID- 22936840 TI - Boldness behavior and stress physiology in a novel urban environment suggest rapid correlated evolutionary adaptation. AB - Novel or changing environments expose animals to diverse stressors that likely require coordinated hormonal and behavioral adaptations. Predicted adaptations to urban environments include attenuated physiological responses to stressors and bolder exploratory behaviors, but few studies to date have evaluated the impact of urban life on codivergence of these hormonal and behavioral traits in natural systems. Here, we demonstrate rapid adaptive shifts in both stress physiology and correlated boldness behaviors in a songbird, the dark-eyed junco, following its colonization of a novel urban environment. We compared elevation in corticosterone (CORT) in response to handling and flight initiation distances in birds from a recently established urban population in San Diego, California to birds from a nearby wildland population in the species' ancestral montane breeding range. We also measured CORT and exploratory behavior in birds raised from early life in a captive common garden study. We found persistent population differences for both reduced CORT responses and bolder exploratory behavior in birds from the colonist population, as well as significant negative covariation between maximum CORT and exploratory behavior. Although early developmental effects cannot be ruled out, these results suggest contemporary adaptive evolution of correlated hormonal and behavioral traits associated with colonization of an urban habitat. PMID- 22936841 TI - Nest site and weather affect the personality of harvester ant colonies. AB - Environmental conditions and physical constraints both influence an animal's behavior. We investigate whether behavioral variation among colonies of the black harvester ant, Messor andrei, remains consistent across foraging and disturbance situations and ask whether consistent colony behavior is affected by nest site and weather. We examined variation among colonies in responsiveness to food baits and to disturbance, measured as a change in numbers of active ants, and in the speed with which colonies retrieved food and removed debris. Colonies differed consistently, across foraging and disturbance situations, in both responsiveness and speed. Increased activity in response to food was associated with a smaller decrease in response to alarm. Speed of retrieving food was correlated with speed of removing debris. In all colonies, speed was greater in dry conditions, reducing the amount of time ants spent outside the nest. While a colony occupied a certain nest site, its responsiveness was consistent in both foraging and disturbance situations, suggesting that nest structure influences colony personality. PMID- 22936842 TI - Photorefractoriness and energy availability interact to permit facultative timing of spring breeding. AB - In seasonally breeding mammals, vernal reproductive development is not directly triggered by increases in day length, rather, an endogenous program of photorefractoriness to short winter days initiates spontaneous development in advance of spring. The transition to the reproductive phenotype is energetically demanding. How food availability in late winter and early spring impacts the onset and expression of photorefractoriness is not known. In this study, male Siberian hamsters were born into a simulated natural photoperiod, and at the winter solstice, they were subjected to a restricted feeding protocol in which a daily food ration was provided in an amount equal to ad libitum (AL) intake during the weeks preceding the solstice. Over the next several months, AL-fed control hamsters exhibited spontaneous recrudescence or spontaneous development. In contrast, vernal reproductive development was abolished in most food-rationed hamsters. In food-rationed hamsters that did exhibit recrudescence, conspicuous delays in the onset of gonadal development and decreases in the magnitude of growth were evident. In all hamsters, the termination of food rationing triggered rapid gonadal development. The data indicate that late winter/early spring increases in environmental food availability are required for the normal manifestation of photorefractoriness-induced reproductive development and suggest that a function of photorefractoriness may be merely to disinhibit the reproductive axis from photoperiodic suppression. Vernal gonadal development or recrudescence appears to be strongly affected by proximate energy availability. PMID- 22936843 TI - Wind selectivity and partial compensation for wind drift among nocturnally migrating passerines. AB - A migrating bird's response to wind can impact its timing, energy expenditure, and path taken. The extent to which nocturnal migrants select departure nights based on wind (wind selectivity) and compensate for wind drift remains unclear. In this paper, we determine the effect of wind selectivity and partial drift compensation on the probability of successfully arriving at a destination area and on overall migration speed. To do so, we developed an individual-based model (IBM) to simulate full drift and partial compensation migration of juvenile Willow Warblers (Phylloscopus trochilus) along the southwesterly (SW) European migration corridor to the Iberian coast. Various degrees of wind selectivity were tested according to how large a drift angle and transport cost (mechanical energy per unit distance) individuals were willing to tolerate on departure after dusk. In order to assess model results, we used radar measurements of nocturnal migration to estimate the wind selectivity and proportional drift among passerines flying in SW directions. Migration speeds in the IBM were highest for partial compensation populations tolerating at least 25% extra transport cost compared to windless conditions, which allowed more frequent departure opportunities. Drift tolerance affected migration speeds only weakly, whereas arrival probabilities were highest with drift tolerances below 20 degrees . The radar measurements were indicative of low drift tolerance, 25% extra transport cost tolerance and partial compensation. We conclude that along migration corridors with generally nonsupportive winds, juvenile passerines should not strictly select supportive winds but partially compensate for drift to increase their chances for timely and accurate arrival. PMID- 22936844 TI - 'It's not about money, it's about my health': determinants of participation and adherence among women in an HIV-HSV2 prevention trial in Johannesburg, South Africa. AB - High levels of adherence in clinical trials are essential for producing accurate intervention efficacy estimates. Adherence to clinical trial products and procedures is dependent on the motivations that drive participants. Data are presented to document reasons for trial participation and adherence to daily aciclovir for HSV-2 and HIV-1 genital shedding suppression among 300 HIV-1/HSV-2 seropositive women in South Africa. In-depth interviews after exit from the trial with 31 randomly selected women stratified by age and time since HIV diagnosis confirmed high levels of adherence measured during the trial. Main reasons for trial participation were related to seeking high-quality health care, which explains high levels of adherence in both study arms. Concerns that women would abuse reimbursements, fabricate data, and share or dump pills were not corroborated. Altruism is not a primary motivator in these settings where access to quality services is an issue. This study provides further evidence that good adherence of daily medication is possible in developing countries, particularly where study activities resonate with participants or fill an unmet need. PMID- 22936845 TI - Drug adherence to biologic DMARDS with a special emphasis on the benefits of subcutaneous abatacept. AB - Major advances in drug development have led to the introduction of biologic disease- modifying drugs for the treatment of rheumatoid arthritis, which has resulted in unprecedented improvement in outcomes for many patients. These agents have been found to be effective in reducing clinical signs and symptoms, improving radiological damage, quality of life, and functionality, and have also been found to have an acceptable safety profile. Despite this, drug adherence is unknown, which has huge health care and health-economic implications. Local and national guidelines exist for the use of biologics; however, its varied use is widespread. Although this may in part reflect differences in prescribing behavior, patient preference plays a key role. In this review we will explore the factors that contribute to patient preference for, and adherence to, biologic therapy for rheumatoid arthritis with emphasis on the subcutaneous preparation of abatacept, a T-cell costimulatory molecule blocker. Overall, subcutaneous administration is preferred by patients and this may well improve drug adherence. PMID- 22936846 TI - Impact of simultaneous pancreas-kidney transplantation: patients' perspectives. AB - BACKGROUND: Few qualitative studies of simultaneous pancreas-kidney transplantation (SPK Tx) have been published. The aims of this study were to explore from the perspective of patients, the experience of living with diabetes mellitus type 1 (T1DM), suffering from complications, and undergoing SPK Tx with good outcome; and to determine the impact of SPK Tx on patients and their social and cultural environment. METHODS: We performed a focused ethnographic study. Twenty patients were interviewed. Data were analyzed using content analysis and constant comparison following the method proposed by Miles and Huberman. RESULTS: A functioning SPK Tx allowed renal replacement therapy and insulin to be discontinued. To describe their new situation, patients used words and phrases such as "miracle", "being reborn" or "coming back to life". Although the complications of T1DM, its surgery and treatment, and associated psychological problems did not disappear after SPK Tx, these were minimized when compared with the pretransplantation situation. CONCLUSION: For patients, SPK Tx represents a recovery of their health and autonomy despite remaining problems associated with the complications of T1DM and SPK Tx. The understanding of patients' existential framework and their experience of disease are key factors for planning new intervention and improvement strategies. PMID- 22936847 TI - Upper limit of the normal range for thyroid-stimulating [corrected] hormone is higher with increasing age. PMID- 22936848 TI - Exploring barriers to optimal anticoagulation for atrial fibrillation: interviews with clinicians. AB - BACKGROUND: Warfarin, the most commonly used antithrombotic agent for stroke prophylaxis in atrial fibrillation (AF), requires regular monitoring, frequent dosage adjustments, and dietary restrictions. Clinicians' perceptions of barriers to optimal AF management are an important factor in treatment. Anticoagulation management for AF is overseen by both cardiology and internal medicine (IM) practices. Thus, gaining the perspective of specialists and generalists is essential in understanding barriers to treatment. We used qualitative research methods to define key issues in the prescription of warfarin therapy for AF by cardiology specialists and IM physicians. METHODS AND RESULTS: Clinicians were interviewed to identify barriers to warfarin treatment in a large Midwestern city. Interviews were conducted until thematic saturation occurred. Content analysis yielded several themes. The most salient theme that emerged from clinician interviews was use of characteristics other than the patient's CHADS(2) score to enact a treatment plan, such as the patient's social situation and past medication-taking behavior. Other themes included patient knowledge, real-world problems, breakdown in communication, and clinician reluctance. CONCLUSION: Warfarin treatment is associated with many challenges. The barriers identified by clinicians highlight the unmet need associated with stroke prophylaxis in AF and the opportunity to improve anticoagulation treatment in AF. Social and lifestyle factors were important considerations in determining treatment. PMID- 22936849 TI - Clinical confidence following an interprofessional educational program on eating disorders for health care professionals: a qualitative analysis. AB - There are an increasing number of educational programs to improve clinical competence and skills to treat mental disorders. For complex disorders there is also a focus on improving the quality of interprofessional work. This paper reports on interprofessional outputs of an educational program on eating disorders. A total of 207 professionals who completed the program were requested to describe up to 12 possible scenarios depicted as realistic prospects for their future work within this field. Analyzing the scenarios resulted in three categories of describing the participants' preferences: (1) interprofessional interventions and treatment; (2) the further development of competence; and (3) organization of the health care system. The findings showed that the participants were considering working across new lines in their current workplaces or crossing borders to new frontiers in the execution of competence. Our findings may be summarized into the concept of "clinical confidence." This concept has so far been understood as some kind of personal trait, disposition, or attitude. The present findings add nuances to this concept in terms of state-dependent encouragement, engagement, and a potential to act and to cross professional borders in order to better treat complex mental disorders. PMID- 22936850 TI - Efficacy of chlorhexidine gluconate ointment (Oronine H((r))) for experimentally induced comedones. AB - BACKGROUND: Oronine H((r)) ointment, which contains chlorhexidine gluconate as its active component, is a well known disinfectant, and has been widely used for treatment of acne in Japan. In this study, we investigated the inhibitory effect of this ointment on the formation of comedones induced by application of 50% oleic acid on the orifices of the external auditory canals of rabbits. METHODS: The application sites were observed with a dermatoscope, and the area of the hair pores was measured using an Image analysis software program. RESULTS: The chlorhexidine gluconate ointment inhibited comedone formation significantly more effectively than the liquid paraffin used as a control (P < 0.001). We also investigated the therapeutic effect of this ointment on comedones. After starting application of chlorhexidine gluconate ointment or liquid paraffin on the comedone area, the hair pore size was gradually decreased in the group treated with chlorhexidine gluconate ointment compared with the hair pore size at baseline. CONCLUSION: These results suggest that chlorhexidine gluconate ointment is effective for inhibiting comedone formation as well as for treating already formed comedones. Chlorhexidine gluconate ointment is a useful topical medicine for the treatment of early-stage acne and for preventing acne. PMID- 22936851 TI - Completeness of TNM cancer staging for melanoma in the Danish Cancer Registry, 2004-2009. AB - BACKGROUND: The purpose of this study was to investigate the completeness of TNM (Tumor, Node, Metastasis) staging of melanoma in the Danish Cancer Registry (DCR). METHODS: We identified 8762 patients with a first primary diagnosis of melanoma from the DCR between 2004 and 2009. We obtained information on level of comorbidity, defined according to the Charlson Comorbidity Index, through the Danish National Patient Register. We computed the completeness of TNM staging overall and by each stage component. Analyses were stratified by gender, age, year of diagnosis, and level of comorbidity. We designed an algorithm that categorized melanoma stage as localized, regional, distant, or unknown. Owing to knowledge on clinical coding practice, we allowed for categorization of tumors with certain missing stage components. RESULTS: The overall completeness of the TNM staging was 78.4% (95% confidence interval [CI] 77.5-79.3). Completeness varied little by gender and year of diagnosis. However, completeness decreased from 83.5% (95% CI 81.7-85.3) in patients aged 0-39 years to 68.7% (95% CI 65.7 71.6%) in patients 80 years or older, and from 80.3% (95% CI 79.4-81.3) among patients with a low level of comorbidity to 67.4% (95% CI 63.1-71.4) among patients with a high level of comorbidity. Using the algorithm, 87.3% of cases could be assigned to one of the defined stage categories. CONCLUSION: The overall completeness of the TNM registration for melanoma was fairly high but varied with age and level of comorbidity. Thus, data on TNM stage should be used with caution in epidemiological and other research. PMID- 22936852 TI - Completeness of breast cancer staging in the Danish Cancer Registry, 2004-2009. AB - BACKGROUND: The purpose of this study was to investigate the completeness of TNM (Tumor, Node, Metastasis) staging for breast cancer in the Danish Cancer Registry. METHODS: We identified 26,488 patients with a first diagnosis of breast cancer between 2004 and 2009 from the Danish Cancer Registry. We obtained information on comorbidity through the Danish National Patient Registry. We estimated the completeness of TNM registration in the Danish Cancer Registry and stratified the analysis by gender, age, year of cancer diagnosis, and comorbidity. We designed an algorithm categorizing breast cancer into localized, regional, distant, or unknown stage based on TNM codes. RESULTS: The overall completeness of TNM registration was 85.4%. The completeness varied little by gender and study year, but decreased from 91.3% in patients aged 0-39 years to 57.0% in patients aged 80 years or more, and from 87.9% among patients with a low level of comorbidity to 69.7% among patients with a high level of comorbidity. CONCLUSION: The completeness of the TNM registration varied substantially by age and level of comorbidity. Thus, depending on the outcome under study, stage specific analyses may yield biased results. The completeness of TNM should be considered in study designs using TNM information. PMID- 22936853 TI - Completeness of prostate cancer staging in the Danish Cancer Registry, 2004-2009. AB - OBJECTIVE: To investigate the completeness of TNM (Tumor-Node-Metastasis) staging for prostate cancer (PC) in the Danish Cancer Registry (DCR). METHODS: We identified 20,184 men registered with first-time PC in the DCR between 2004 and 2009. These patients were linked to the Danish National Patient Register to obtain data on comorbidity according to the Charlson Comorbidity Index (CCI). We calculated the completeness and corresponding 95% confidence intervals (CI) of TNM staging overall and by the individual components. We also defined a clinically-based algorithm classifying PC into four stage categories: localized, regional, distant, and unknown. RESULTS: The overall completeness of TNM staging was 34.2% (95% CI: 0.34-0.35). TNM completeness improved gradually over time reaching 41.2% in 2009. TNM completeness decreased substantially with age from 75.0% among patients 0-39 years to 11.3% among patients 80 years or older. Similarly, completeness decreased with increasing comorbidity level from 37.6% among patients with low CCI to 20.3% among those with high CCI. When classifying T1 cancer as a complete registration regardless of missing N or M stage, the overall TNM completeness increased to 48.7% (95% CI: 0.48-0.49). According to the clinically-based staging algorithm, 70.5% of PC cases could be categorized into a definite clinical stage. CONCLUSION: One-third of PC patients had a complete registration of all TNM components in the DCR. Although TNM completeness improved over time, older age and high comorbidity were consistently associated with missing TNM staging. Research and monitoring based on cancer registries such as the DCR should account for missing TNM staging. Failing to do so could otherwise lead to biased results of stage-specific analyses. PMID- 22936854 TI - Completeness of bladder cancer staging in the Danish Cancer Registry, 2004-2009. AB - OBJECTIVE: To investigate the completeness of tumor, node, and metastasis (TNM) staging for invasive bladder cancer in the Danish Cancer Registry (DCR). METHODS: From the DCR, we retrieved data on TNM stage, year of diagnosis, sex, and age of all-incident invasive bladder cancer patients between 2004 and 2009. Data on comorbidity was obtained from the Danish National Patient Register. We estimated the completeness of TNM registration in the DCR overall and stratified the analysis by sex, age, year of cancer diagnosis, and Charlson comorbidity score. Through knowledge of pathophysiology and clinical coding practice, we designed a clinically based algorithm that allowed tumors with certain missing TNM-stage components to be placed in localized, regional, distant, and unknown categories. RESULTS: The overall completeness of TNM staging for bladder cancer was 44.1% (95% confidence interval [CI]: 42.7-45.5). Completeness decreased from 60.9% (95% CI: 40.6-78.6) in patients aged 0-39 years to 25.5% (95% CI: 23.2-27.9) in patients aged 80 years or older. Among patients with a low level of comorbidity, completeness was 48.4% (95% CI: 46.6-50.3), decreasing to 34.0% (95% CI: 30.4 37.8) among those with a high level of comorbidity. The highest proportion of missing TNM data was found for registration of lymph node metastases. Defining T1 cancer as completely registered, regardless of missing N and M stage, increased TNM-registration completeness to 61.8%. When we applied a clinically based algorithm, only 29.6% of tumors had an unknown stage. CONCLUSION: The overall completeness of TNM staging for bladder cancer in the DCR was low, especially with increasing age and high level of comorbidity. Thus, restricting analyses to bladder cancer patients with complete data on stage may produce substantially selected study populations. Careful considerations should thus be made on handling missing data. PMID- 22936855 TI - Completeness of TNM staging of small-cell and non-small-cell lung cancer in the Danish cancer registry, 2004-2009. AB - OBJECTIVE: We examined the completeness of TNM staging of small-cell (SCLC) and nonsmall- cell (NSCLC) lung cancer in the national Danish Cancer Registry (DCR) and whether staging varied by year of diagnosis, gender, age, degree of comorbidity, or presence of histopathological diagnosis. METHODS: We identified all patients with SCLCs and NSCLCs registered in the DCR during 2004-2009 and examined the completeness of their TNM registrations. Completeness was defined as the number of recorded individuals with TNM divided by the total number of patients. Completeness was calculated for TNM, T, N, and M individually, overall, and by year of diagnosis, gender, age at diagnosis, and comorbidity. Data regarding comorbidity was obtained from the Danish National Patient Register (DNPR). We performed separate analyses for patients with a histopathologically verified diagnosis of NSCLC. Finally, we designed an algorithm to categorize tumors with missing TNM components as limited, extensive, or distant disease. RESULTS: Overall TNM staging completeness was 77.5% (95% confidence interval (CI): 76.1%-78.8%) for SCLC and 77.9% (95% CI: 77.3%-78.4%) for NSCLC. Completeness did not vary by gender and increased during the study period. The proportion of staged patients was lower among patients above 80 years of age or with medium to high levels of comorbidity. CONCLUSION: Overall TNM completeness for SCLC and NSCLC in the Danish Cancer Registry is high, but decreases with increasing levels of comorbidity and at ages greater than 80 years. Researchers should be aware of these potential sources of bias. PMID- 22936856 TI - Establishing a laboratory network of influenza diagnosis in Indonesia: an experience from the avian flu (H5N1) outbreak. AB - Indonesia has been part of the global influenza surveillance since the establishment of a National Influenza Center (NIC) at the National Institute of Health Research and Development (NIHRD) by the Indonesian Ministry of Health in 1975. When the outbreak of avian influenza A (H5N1) occurred, the NIC and US Naval Medical Research Unit 2 were the only diagnostic laboratories equipped for etiology confirmation. The large geographical area of the Republic of Indonesia poses a real challenge to provide prompt and accurate diagnosis nationally. This was the main reason to establish a laboratory network for H5N1 diagnosis in Indonesia. Currently, 44 laboratories have been included in the network capable of performing polymerase chain reaction testing for influenza A. Diagnostic equipment and standard procedures of biosafety and biosecurity of handling specimens have been adopted largely from World Health Organization recommendations. PMID- 22936857 TI - Body mass index, triglycerides, glucose, and blood pressure as predictors of type 2 diabetes in a middle-aged Norwegian cohort of men and women. AB - BACKGROUND: Obesity, hypertension, and hypertriglyceridemia are important risk factors for type 2 diabetes (T2D). We wanted to assess the risk associated with these three factors alone and in combination, and the relative importance of these and several other risk factors (eg, nonfasting glucose) as predictors of T2D. METHODS: Risk factors in a Norwegian population (n = 109,796) aged 40-45 years were measured in health studies in 1995-1999. Blood glucose-lowering drugs dispensed in 2004-2009 were used to estimate the incidence of T2D. Groups based on combinations of body mass index (BMI), diastolic blood pressure, and triglycerides were defined by using the 50% and 90% quantiles for each variable for men and women. The relative importance of BMI, triglycerides, total cholesterol, high-density lipoprotein cholesterol, glucose, blood pressure, and year of birth for predicting T2D was assessed using deviance from univariate and multivariate logistic regression models. Height, weight, and blood pressure were measured. All biomarkers were measured in nonfasting blood samples. RESULTS: In the various groups of BMI, triglycerides, and diastolic blood pressure, the incidence of T2D ranged from 0.5% to 19.7% in men and from 0.15% to 21.8% in women. BMI was the strongest predictor of incident T2D, followed by triglyceride levels in women and glucose levels in men. The inclusion of risk factors other than BMI, glucose, triglycerides, and blood pressure in multivariate models only marginally improved the prediction. CONCLUSION: BMI was the strongest predictor of type 2 diabetes. At defined levels of BMI, the incidence of T2D varied substantially with triglyceride levels and blood pressure. Thus, controlling triglycerides and blood pressure in middle-aged individuals should be targeted to prevent later onset of T2D. PMID- 22936858 TI - Increase in psychotropic drug use between 2006 and 2010 among adolescents in Norway: a nationwide prescription database study. AB - BACKGROUND: The purposes of this study were to investigate the prevalence of psychotropic (hypnotic, antidepressant, and anxiolytic) drug use among adolescents aged 15-16 years during the period 2006-2010 according to gender and subcategories of psychotropics, and to study psychotropic drug use over the period 2007-2010 among incident users in 2007. METHODS: This was a one-year prevalence and follow-up study based on information retrieved from the nationwide Norwegian prescription database for the period 2006-2010. The study population consisted of adolescents aged 15-16 years who had filled at least one prescription for a psychotropic drug in the study period. The main outcome measures were filling of hypnotic, antidepressant, and/or anxiolytic drug prescriptions. RESULTS: Overall use of psychotropic drugs increased from 13.9 to 21.5 per 1000 among boys and from 19.7 to 24.7 per 1000 among girls during the 2006- 2010 period. Hypnotic drugs, and melatonin in particular, accounted for most of the increase. For melatonin, the annual median amount dispensed was 180 defined daily doses through the period until 2010, at which time it decreased to 90 defined daily doses. In total, 16.4% of all incident psychotropic drug users in 2007 were still having prescriptions dispensed in 2010. CONCLUSION: This study shows an increase in hypnotic drugs dispensed for adolescents in Norway, mainly attributable to the increasing use of melatonin. The amount of melatonin dispensed indicates more than sporadic use over longer periods, despite melatonin only being licensed in Norway for use in insomnia for individuals aged 55 years or older. PMID- 22936859 TI - Signal detection to identify serious adverse events (neuropsychiatric events) in travelers taking mefloquine for chemoprophylaxis of malaria. AB - BACKGROUND: For all medications, there is a trade-off between benefits and potential for harm. It is important for patient safety to detect drug-event combinations and analyze by appropriate statistical methods. Mefloquine is used as chemoprophylaxis for travelers going to regions with known chloroquine resistant Plasmodium falciparum malaria. As such, there is a concern about serious adverse events associated with mefloquine chemoprophylaxis. The objective of the present study was to assess whether any signal would be detected for the serious adverse events of mefloquine, based on data in clinicoepidemiological studies. MATERIALS AND METHODS: We extracted data on adverse events related to mefloquine chemoprophylaxis from the two published datasets. Disproportionality reporting of adverse events such as neuropsychiatric events and other adverse events was presented in the 2 * 2 contingency table. Reporting odds ratio and corresponding 95% confidence interval [CI] data-mining algorithm was applied for the signal detection. The safety signals are considered significant when the ROR estimates and the lower limits of the corresponding 95% CI are >=2. RESULTS: Two datasets addressing adverse events of mefloquine chemoprophylaxis (one from a published article and one from a Cochrane systematic review) were included for analyses. Reporting odds ratio 1.58, 95% CI: 1.49-1.68 based on published data in the selected article, and 1.195, 95% CI: 0.94-1.44 based on data in the selected Cochrane review. Overall, in both datasets, the reporting odds ratio values of lower 95% CI were less than 2. CONCLUSION: Based on available data, findings suggested that signals for serious adverse events pertinent to neuropsychiatric event were not detected for mefloquine. Further studies are needed to substantiate this. PMID- 22936860 TI - Clinical use of antidepressant therapy and associated cardiovascular risk. AB - A number of different psychotropic agents have been associated with an increased risk of cardiovascular disease, and these relationships have been difficult to interpret due to the presence of confounding factors. Recently, there has been renewed interest in the potential for certain antidepressants to cause QT prolongation, which is a predisposing factor for arrhythmia. However, the optimum means of determining QT remains contentious due to discrepancies between methods that may be readily applied in a clinical setting versus more detailed techniques during regulatory assessment. A number of different pharmacological mechanisms might explain the occurrence of adverse cardiac effects, and these differ according to the type of antidepressant agent. Emerging data indicate that citalopram exhibits a dose-effect relationship for QT prolongation. Whereas cardiotoxicity is readily apparent in the context of intentional antidepressant overdose, the occurrence of cardiac effects as a result of therapeutic administration is less certain. Pre-existing cardiac disease and other factors that independently predispose to arrhythmia are important considerations. Therefore, clinical judgment is needed to evaluate the overall risk or benefit of a particular antidepressant in any patient. Close monitoring should be considered for those at greatest risk of QT prolongation and arrhythmia. PMID- 22936862 TI - Contamination of irrigation systems of dental units with Cryptosporidium species in Alexandria, Egypt: a neglected disinfection pitfall. AB - PURPOSE: To investigate the contamination of the dental irrigation systems with Cryptosporidium species in Alexandria, Egypt. METHODS: Forty water samples from all 20 working dental irrigation machines in a dental center in Alexandria were included in the study. Water samples were taken from the handpieces of dental irrigation machines in all studied units. After filtration through a membrane filter, water sample residues were stained using modified Ziehl-Neelsen staining and examined microscopically for Cryptosporidium spp. RESULTS: Cryptosporidium spp. was found as a contaminant in 27.5% of water samples taken from dental irrigation machines. CONCLUSION: This indicates a contamination by the public water supplies to which these dental irrigation machines are connected. This disinfection pitfall may pose an infection risk to those seeking dental care. PMID- 22936863 TI - A charismatic new species of green lacewing discovered in Malaysia (Neuroptera, Chrysopidae): the confluence of citizen scientist, online image database and cybertaxonomy. AB - An unusual new species of green lacewing (Neuroptera: Chrysopidae: Semachrysa jadesp. n.) is described from Selangor (Malaysia) as a joint discovery by citizen scientist and professional taxonomists. The incidental nature of this discovery is underscored by the fact that the species was initially photographed and then released, with images subsequently posted to an online image database. It was not until the images in the database were randomly examined by the professional taxonomists that it was determined that the species was in fact new. A subsequent specimen was collected at the same locality and is described herein along with another specimen identified from nearby Sabah. PMID- 22936861 TI - Advances in patient-controlled analgesia: the role of fentanyl ITS. AB - Effective pain relief is an essential component of a patient's peri-operative care package. Good analgesia has been shown to reduce the incidence of cardiovascular, respiratory and thrombo-embolic complications following surgery. Satisfactory analgesia facilitates early patient ambulation following surgery, which may reduce in-patient stay. Patient-controlled analgesia (PCA) systems are a well established standard therapy for acute post-operative pain; however some practical limitations limit their clinical utility. The fentanyl inotophoretic transdermal system (ITS) is a novel self-contained needle-free PCA device, which delivers boluses of fentanyl transdermally. This system has been shown to provide analgesia equivalent to conventional PCA modalities, with unique design features that may confer advantages to patients and staff, including facilitating patient mobilization in the post-operative phase. This review will discuss the technology of iontophoretic systems, the pharmacology of transdermal fentanyl delivery, and some practical implications of the fentanyl ITS. PMID- 22936864 TI - An aberrant species of Nipponocercyon from Sichuan, China (Coleoptera, Hydrophilidae, Sphaeridiinae). AB - A detailed examination of specimens of Cryptopleurum sichuanicum Ryndevich, 2005 from high altitudes of Sichuan Province, China, revealed that the species belongs in the genus Nipponocercyon Sato, 1963 previously endemic to Japan. The species is here transferred in Nipponocercyon, and Nipponocercyon sichuanicus (Ryndevich, 2005), comb. n. is redescribed and compared with Nipponocercyon shibatai Sato, 1963. The male genitalia of Nipponocercyon sichuanicus is described for the first time. An adapted diagnosis of Nipponocercyon is provided, and reasons for the inclusion of Nipponocercyon sichuanicus into Nipponocercyon and the general distribution of the genus are discussed. PMID- 22936865 TI - Five new species and three new females of the genus Endotricha Zeller from China (Lepidoptera, Pyralidae, Pyralinae). AB - Five new species of the genus Endotricha Zeller are described from China: Endotricha dentiprocessasp. n., Endotricha unicolorsp. n., Endotricha shafferisp. n., Endotricha convexasp. n. and Endotricha whalleyisp. n. Females of three species are described for the first time: Endotricha hoenei Whalley, 1963, Endotricha luteogrisalis Hampson, 1896 and Endotricha simipunicea Wang & Li, 2005. Photographs of the adults and both male and female genitalia are provided. PMID- 22936866 TI - Description of a new species of coral-inhabiting barnacle, Darwiniella angularis sp. n. (Cirripedia, Pyrgomatidae) from Taiwan. AB - The present study has identified a new species from the previously monotypic genus Darwiniella Anderson, 1992. Darwiniella angularissp. n. is similar to Darwiniella conjugatum (Darwin, 1854) in external shell morphology and arthropodal characters. Darwiniella conjugatum, however, has a sharper tergal spur and a less obvious adductor plate angle when compared to Darwiniella angularissp. n. Molecular analyses on mitochondrial DNA 12S rDNA and COI regions also support the morphological differences. Sequence divergences in 12S rDNA and COI between Darwiniella conjugatum and Darwiniella angularissp. n. are 5% and 13% respectively, which are equivalent to the inter-specific sequence divergences in other barnacles. Both Darwiniella species are common on Cyphastrea Milne-Edwards and Haime, 1848 corals and Darwiniella angularissp. n. is also collected from Astreopora de Blainville, 1830 corals in Taiwan. PMID- 22936867 TI - The preimaginal stages of Pnigalio gyamiensis Myartseva & Kurashev, 1990 (Hymenoptera, Eulophidae), a parasitoid associated with Chrysoesthia sexguttella (Thunberg) (Lepidoptera, Gelechiidae). AB - The larval instars of Pnigalio gyamiensis Myartseva and Kurashev are described in detail for the first time. This species is a larval-pupal ectoparasitoid of Chrysoesthia sexguttella (Thunberg) (Lepidoptera, Gelechiidae), which forms leaf mines in the plant Chenopodium album L. (Caryophyllales: Amaranthaceae). The female of Pnigalio gyamiensis lays a single egg on the skin of the host larva or nearby it, without any significant preference for a particular variant. The presence of long hairs on its body provides the newly-hatched first larval instar with high mobility. Some peculiarities in this parasitoid-host relationship are described. PMID- 22936868 TI - Austromesocypris bluffensis sp. n. (Crustacea, Ostracoda, Cypridoidea, Scottiinae) from subterranean aquatic habitats in Tasmania, with a key to world species of the subfamily. AB - Austromesocypris bluffensissp. n. is described and we report another species, Austromesocypris sp., both collected from subterranean aquatic habitats in Tasmania. This discovery adds a major taxonomic group to the already diverse invertebrate cave fauna of Tasmania, and is of interest because, globally, obligate subterranean aquatic species (stygobites) are poorly represented within the family Cyprididae. The genus Austromesocypris Martens, De Deckker & Rossetti, 2004 is otherwise known to comprise entirely "terrestrial or semi-terrestrial" species. The second species is not described because only juvenile specimens were collected. Both species stand apart from their congeners by the carapace shape, which is rectangular in Austromesocypris bluffensis and triangular and asymmetrical in the unnamed species. Another unique feature of the new species is the almost symmetrical uropodal rami. We also identify some broader systematic issues within the Scottiinae including the position of two New Zealand species, Scottia audax (Chapman, 1961) and Scottia insularis Chapman, 1963 in the genus, and point out their closer relationship to the Gondwana genera of Scottiinae, Austromesocypris and Mesocypris Daday, 1910, than to the Palearctic genus Scottia Brady & Norman, 1889, based on the morphology of the maxillula and mandibula. The identity of the Australian records of Scottia audax (Chapman, 1961), Austromesocypris australiensis (De Deckker, 1983) and the Boreal records of Scottia pseudobrowniana Kempf, 1971 are all considered doubtful. A key to the world species of Scottiinae is provided. PMID- 22936869 TI - Two new species and new record of Batricavus Yin & Li (Coleoptera, Staphylinidae, Pselaphinae) from China. AB - Two new species, Batricavus abdominalis Yin & Li, sp. n. and Batricavus hainanensis Yin & Li, sp. n. are described from Hainan, South China, with male habitus and major diagnostic features illustrated. Batricavus tibialis Yin & Li is newly recorded from Zhejiang, East China. Keys to both sexes of the genus are included. PMID- 22936870 TI - Two additional new species of the Stenus indubius group (Coleoptera, Staphylinidae) from China. AB - Two new species of the Stenus indubius group from China are described: Stenus huapingensissp. n. from Guangxi Province and Stenus zhujianqingisp. n. from Zhejiang Province. Habitus photos and illustrations of diagnostic characters of the new species and two described species, Stenus paradecens Tang & Li, 2005 and Stenus guniujiangense Tang & Li, 2005, are provided. PMID- 22936871 TI - Aphanius arakensis, a new species of tooth-carp (Actinopterygii, Cyprinodontidae) from the endorheic Namak Lake basin in Iran. AB - A new species of tooth-carp, Aphanius arakensissp. n., is described from the Namak Lake basin in Iran. The new species is distinguished by the congeners distributed in Iran by the following combination of characters: 10-12 anal fin rays, 28-32 lateral line scales, 10-13 caudal peduncle scales, 8-10 gill rakers, 12-19, commonly 15-16, clearly defined flank bars in males, a more prominent pigmentation along the flank added by relatively big blotches in the middle and posterior flank segments in females, a short but high antirostrum of the otolith that has a wide excisura, and a ventral rim with some small, drop-like processes, and 19 molecular apomorphies (17 transitions, two transversions) in the cytochrome b gene. It was suggested based on the phylogenetic analysis that the new species is sister to Aphanius sophiae from the Kor River and that Aphanius farsicus from the Maharlu Lake basin is sister to Aphanius arakensis plus Aphanius sophiae. A noticeable feature of the Aphanius diversity in Iran is the conservatism of the external morphology as well as morphometric and meristic characters, while distinctive differences are present in genetic characters, otolith morphology, and male color pattern. Transformation of the latter was probably driven by sexual selection. PMID- 22936872 TI - An extraordinary new family of spiders from caves in the Pacific Northwest (Araneae, Trogloraptoridae, new family). AB - The new spider genus and species Trogloraptor marchingtoni Griswold, Audisio & Ledford is described as the type of the new family Trogloraptoridae. The oblique membranous division of the basal segment of the anterior lateral spinnerets of Trogloraptor suggests that this haplogyne family is the sister group of the other Dysderoidea (Dysderidae, Oonopidae, Orsolobidae and Segestriidae). Trogloraptor is known only from caves and old growth forest understory in the Klamath-Siskiyou region of Oregon and California. PMID- 22936873 TI - The status of the genus Bostryx Troschel, 1847, with description of a new subfamily (Mollusca, Gastropoda, Bulimulidae). AB - The status of the genus Bostryx is discussed and, based on morphological and molecular data, restricted to a group of species related to Bostryx solutus, for which the new subfamily name Bostrycinae is introduced. PMID- 22936874 TI - Description of a new species of the genus Glenea from Tibet, China (Coleoptera, Cerambycidae, Lamiinae, Saperdini). AB - A new species, Glenea jinisp. n. is described from Tibet, China. It can be separated from other species of the genus Glenea Newman by the complicated black and ochre markings as well as characters of the genitalia. PMID- 22936875 TI - A study on the apterous genus Clytomelegena Pic, 1928 (Coleoptera, Disteniidae). AB - The genus Noeconia Murzin, 1988 is synonymized with Clytomelegena Pic, 1928. Clytomelegena kabakovi (Murzin, 1988), comb. n. is newly recorded from China (Guangxi Prov.). And Laos (Attapeu Prov.) is a new locality of this genus. Both sexes are apterous. Photographs and genitalic descriptions of Clytomelegena kabakovi are presented for the first time. PMID- 22936876 TI - A review of the species of Rhynchopsilopa Hendel from China (Diptera, Ephydridae). AB - Species of the shore-fly genus Rhynchopsilopa Hendel from China are reviewed. Four new species (Rhynchopsilopa guangdongensissp. n., Rhynchopsilopa huangkengensissp. n., Rhynchopsilopa jinxiuensissp. n., Rhynchopsilopa shixingensissp. n.) and two previously known species, Rhynchopsilopa longicornis (Okada) and Rhynchopsilopa magnicornis Hendel, are described or redescribed. A key to the species hitherto known from China is presented. PMID- 22936877 TI - A comparison of two common flight interception traps to survey tropical arthropods. AB - Tropical forests are predicted to harbor most of the insect diversity on earth, but few studies have been conducted to characterize insect communities in tropical forests. One major limitation is the lack of consensus on methods for insect collection. Deciding which insect trap to use is an important consideration for ecologists and entomologists, yet to date few study has presented a quantitative comparison of the results generated by standardized methods in tropical insect communities. Here, we investigate the relative performance of two flight interception traps, the windowpane trap, and the more widely used malaise trap, across a broad gradient of lowland forest types in French Guiana. The windowpane trap consistently collected significantly more Coleoptera and Blattaria than the malaise trap, which proved most effective for Diptera, Hymenoptera, and Hemiptera. Orthoptera and Lepidoptera were not well represented using either trap, suggesting the need for additional methods such as bait traps and light traps. Our results of contrasting trap performance among insect orders underscore the need for complementary trapping strategies using multiple methods for community surveys in tropical forests. PMID- 22936878 TI - A new species of the genus Helcogramma (Blenniiformes, Tripterygiidae) from Taiwan. AB - A new species of triplefin fish (Blenniiformes: Tripterygiidae), Helcogramma williamsi, is described from six specimens collected from southern Taiwan. This species is well distinguished from its congeners by possessing 13 second dorsal fin spines; third dorsal-fin rays modally 11; anal-fin rays modally 19; pored scales in lateral line 22-24; dentary pore pattern modally 5+1+5; lobate supraorbital cirrus; broad, serrated or palmate nasal cirrus; first dorsal fin lower in height than second; males with yellow mark extending from anterior tip of upper lip to anterior margin of eye and a whitish blue line extending from corner of mouth onto preopercle. Comparisons and a diagnostic key are provided for the species of Helcogramma now known from Taiwan: Helcogramma fuscipectoris, Helcogramma inclinata, Helcogramma striata, Helcogramma trigloides, and the newly recorded, Helcogramma rhinoceros. PMID- 22936879 TI - AED Trials in Newly Diagnosed Patients: Out With the Old Versus New, in With the New Versus New. PMID- 22936880 TI - Neonatal encephalopathy, MRI lesions, and later epilepsy: no harm, no foul? PMID- 22936881 TI - SUDEP: What Are the Risk Factors? Do Seizures or Antiepileptic Drugs Contribute to an Increased Risk? PMID- 22936882 TI - Like a circle in a spiral: stimulating the windmills of your mind. PMID- 22936883 TI - What is a seizure? Insights from human single-neuron recordings. PMID- 22936884 TI - Not all seizures are epilepsy also applies to the military. PMID- 22936885 TI - Long-term outcome after epilepsy surgery: relapsing, remitting disorder? PMID- 22936886 TI - Advances in epilepsy genetics and genomics. AB - Current and emerging technologies for mutation identification are changing the landscape of genetics and accelerating the pace of discovery. Application of high throughput genomic analysis to epilepsy will advance our understanding of the genetic contribution to common forms of epilepsy and suggest novel therapeutic strategies for improved treatment. PMID- 22936887 TI - Better resolution and fewer wires discover epileptic spiral waves. PMID- 22936888 TI - KCNQ2 Potassium Channel Epileptic Encephalopathy Syndrome: Divorce of an Electro Mechanical Couple? PMID- 22936889 TI - Reactive plasticity with a kainate receptor twist: rhythmic firing in granule cells breaks down the gate? PMID- 22936890 TI - Neuregulation: NRG1 Tames Interneurons and Epilepsy. PMID- 22936891 TI - Overcoming barriers to successful epilepsy management. PMID- 22936893 TI - Coupling mechanical deformations and planar cell polarity to create regular patterns in the zebrafish retina. AB - The orderly packing and precise arrangement of epithelial cells is essential to the functioning of many tissues, and refinement of this packing during development is a central theme in animal morphogenesis. The mechanisms that determine epithelial cell shape and position, however, remain incompletely understood. Here, we investigate these mechanisms in a striking example of planar order in a vertebrate epithelium: The periodic, almost crystalline distribution of cone photoreceptors in the adult teleost fish retina. Based on observations of the emergence of photoreceptor packing near the retinal margin, we propose a mathematical model in which ordered columns of cells form as a result of coupling between planar cell polarity (PCP) and anisotropic tissue-scale mechanical stresses. This model recapitulates many observed features of cone photoreceptor organization during retinal growth and regeneration. Consistent with the model's predictions, we report a planar-polarized distribution of Crumbs2a protein in cone photoreceptors in both unperturbed and regenerated tissue. We further show that the pattern perturbations predicted by the model to occur if the imposed stresses become isotropic closely resemble defects in the cone pattern in zebrafish lrp2 mutants, in which intraocular pressure is increased, resulting in altered mechanical stress and ocular enlargement. Evidence of interactions linking PCP, cell shape, and mechanical stresses has recently emerged in a number of systems, several of which show signs of columnar cell packing akin to that described here. Our results may hence have broader relevance for the organization of cells in epithelia. Whereas earlier models have allowed only for unidirectional influences between PCP and cell mechanics, the simple, phenomenological framework that we introduce here can encompass a broad range of bidirectional feedback interactions among planar polarity, shape, and stresses; our model thus represents a conceptual framework that can address many questions of importance to morphogenesis. PMID- 22936894 TI - Colesevelam hydrochloride: evidence for its use in the treatment of hypercholesterolemia and type 2 diabetes mellitus with insights into mechanism of action. AB - Colesevelam hydrochloride is a molecularly engineered, second-generation bile acid sequestrant demonstrating enhanced specificity for bile acids which has been approved for use as adjunctive therapy to diet and exercise as monotherapy or in combination with a beta-hydroxymethylglutaryl-coenzyme A reductase inhibitor for the reduction of elevated low-density lipoprotein cholesterol in patients with primary hypercholesterolemia. It is also the only lipid-lowering agent currently available in the United States which has been approved for use as adjunctive therapy in patients with type 2 diabetes mellitus whose glycemia remains inadequately controlled on therapy with metformin, sulfonylurea, or insulin. With the recent emphasis upon drug safety by the Food and Drug Administration and various consumer agencies, it is fitting that the role of nonsystemic lipid lowering therapies such as bile acid sequestrants - with nearly 90 years of in class, clinically safe experience - should be reexamined. This paper presents information on the major pharmacologic effects of colesevelam, including a discussion of recent data derived from both in vitro and in vivo rodent and human studies, which shed light on the putative mechanisms involved. PMID- 22936892 TI - Efficacy and safety of three antiretroviral regimens for initial treatment of HIV 1: a randomized clinical trial in diverse multinational settings. AB - BACKGROUND: Antiretroviral regimens with simplified dosing and better safety are needed to maximize the efficiency of antiretroviral delivery in resource-limited settings. We investigated the efficacy and safety of antiretroviral regimens with once-daily compared to twice-daily dosing in diverse areas of the world. METHODS AND FINDINGS: 1,571 HIV-1-infected persons (47% women) from nine countries in four continents were assigned with equal probability to open-label antiretroviral therapy with efavirenz plus lamivudine-zidovudine (EFV+3TC-ZDV), atazanavir plus didanosine-EC plus emtricitabine (ATV+DDI+FTC), or efavirenz plus emtricitabine tenofovir-disoproxil fumarate (DF) (EFV+FTC-TDF). ATV+DDI+FTC and EFV+FTC-TDF were hypothesized to be non-inferior to EFV+3TC-ZDV if the upper one-sided 95% confidence bound for the hazard ratio (HR) was <=1.35 when 30% of participants had treatment failure. An independent monitoring board recommended stopping study follow-up prior to accumulation of 472 treatment failures. Comparing EFV+FTC-TDF to EFV+3TC-ZDV, during a median 184 wk of follow-up there were 95 treatment failures (18%) among 526 participants versus 98 failures among 519 participants (19%; HR 0.95, 95% CI 0.72-1.27; p = 0.74). Safety endpoints occurred in 243 (46%) participants assigned to EFV+FTC-TDF versus 313 (60%) assigned to EFV+3TC ZDV (HR 0.64, CI 0.54-0.76; p<0.001) and there was a significant interaction between sex and regimen safety (HR 0.50, CI 0.39-0.64 for women; HR 0.79, CI 0.62 1.00 for men; p = 0.01). Comparing ATV+DDI+FTC to EFV+3TC-ZDV, during a median follow-up of 81 wk there were 108 failures (21%) among 526 participants assigned to ATV+DDI+FTC and 76 (15%) among 519 participants assigned to EFV+3TC-ZDV (HR 1.51, CI 1.12-2.04; p = 0.007). CONCLUSION: EFV+FTC-TDF had similar high efficacy compared to EFV+3TC-ZDV in this trial population, recruited in diverse multinational settings. Superior safety, especially in HIV-1-infected women, and once-daily dosing of EFV+FTC-TDF are advantageous for use of this regimen for initial treatment of HIV-1 infection in resource-limited countries. ATV+DDI+FTC had inferior efficacy and is not recommended as an initial antiretroviral regimen. TRIAL REGISTRATION: www.ClinicalTrials.gov NCT00084136. Please see later in the article for the Editors' Summary. PMID- 22936895 TI - Pancrelipase: an evidence-based review of its use for treating pancreatic exocrine insufficiency. AB - Pancreatic exocrine insufficiency (PEI) is often observed in patients with pancreatic diseases, including chronic pancreatitis, cystic fibrosis, and tumors, or after surgical resection. PEI often results in malnutrition, weight loss and steatorrhea, which together increase the risk of morbidity and mortality. Therefore, nutritional interventions, such as low-fat diets and pancreatic enzyme replacement therapy (PERT), are needed to improve the clinical symptoms, and to address the pathophysiology of pancreatic exocrine insufficiency. PERT with delayed-release pancrelipase is now becoming a standard therapy for pancreatic exocrine insufficiency because it significantly improves the coefficients of fat and nitrogen absorption as well as clinical symptoms, without serious treatment emergent adverse events. The major adverse events were tolerable gastrointestinal tract symptoms, such as stomach pain, nausea, and bloating. Fibrosing colonopathy, a serious complication, is associated with high doses of enzymes. Several pancrelipase products have been approved by the US Food and Drug Administration in recent years. Although many double-blind, placebo-controlled trials of pancrelipase products have been conducted in recent years, these studies have enrolled relatively few patients and have often been less than a few weeks in duration. Moreover, few studies have addressed the issue of pancreatic diabetes, a type of diabetes that is characterized by frequent hypoglycemia, which is difficult to manage. In addition, it is unclear whether PERT improves morbidity and mortality in such settings. Therefore, large, long-term prospective studies are needed to identify the optimal treatment for pancreatic exocrine insufficiency. The studies should also examine the extent to which PERT using pancrelipase improves mortality and morbidity. The etiology and severity of pancreatic exocrine insufficiency often differ among patients with gastrointestinal diseases or diabetes (type 1 and type 2), and among elderly subjects. Finally, although there is currently limited clinical evidence, numerous extrapancreatic diseases and conditions that are highly prevalent in the general population may also be considered potential targets for PERT and related treatments. PMID- 22936896 TI - The decision to fight or flee - insights into underlying mechanism in crickets. AB - Ritualized fighting between conspecifics is an inherently dangerous behavioral strategy, optimized to secure limited resources at minimal cost and risk. To be adaptive, potential rewards, and costs of aggression must be assessed to decide when it would be more opportune to fight or flee. We summarize insights into the proximate mechanisms underlying this decision-making process in field crickets. As in other animals, cricket aggression is enhanced dramatically by motor activity, winning, and the possession of resources. Pharmacological manipulations provide evidence that these cases of experience dependent enhancement of aggression are each mediated by octopamine, the invertebrate counterpart to adrenaline/noradrenaline. The data suggest that both physical exertion and rewarding aspects of experiences can activate the octopaminergic system, which increases the propensity to fight. Octopamine thus represents the motivational component of aggression in insects. For the decision to flee, animals are thought to assess information from agonistic signals exchanged during fighting. Cricket fights conform to the cumulative assessment model, in that they persist in fighting until the sum of their opponent's actions accumulates to some threshold at which they withdraw. We discuss evidence that serotonin, nitric oxide, and some neuropeptides may promote an insect's tendency to flee. We propose that the decision to fight or flee in crickets is controlled simply by relative behavioral thresholds. Rewarding experiences increase the propensity to fight to a level determined by the modulatory action of octopamine. The animal will then flee only when the accumulated sum of the opponent's actions surpasses this level; serotonin and nitric oxide may be involved in this process. This concept is in line with the roles proposed for noradrenaline, serotonin, and nitric oxide in mammals and suggests that basic mechanisms of aggressive modulation may be conserved in phylogeny. PMID- 22936897 TI - Emerging Roles of Alternative Pre-mRNA Splicing Regulation in Neuronal Development and Function. AB - Alternative pre-mRNA splicing has the potential to greatly diversify the repertoire of transcripts in multicellular organisms. Increasing evidence suggests that this expansive layer of gene regulation plays a particularly important role in the development and function of the nervous system, one of the most complex organ systems found in nature. In this review, we highlight recent studies that continue to emphasize the influence and contribution of alternative splicing regulation to various aspects of neuronal development in addition to its role in the mature nervous system. PMID- 22936899 TI - Experience-dependent plasticity in white matter microstructure: reasoning training alters structural connectivity. AB - Diffusion tensor imaging (DTI) techniques have made it possible to investigate white matter plasticity in humans. Changes in DTI measures, principally increases in fractional anisotropy (FA), have been observed following training programs as diverse as juggling, meditation, and working memory. Here, we sought to test whether three months of reasoning training could alter white matter microstructure. We recruited participants (n = 23) who were enrolled in a course to prepare for the Law School Admission Test (LSAT), a test that places strong demands on reasoning skills, as well as age- and IQ-matched controls planning to take the LSAT in the future (n = 22). DTI data were collected at two scan sessions scheduled three months apart. In trained participants but not controls, we observed decreases in radial diffusivity (RD) in white matter connecting frontal cortices, and in mean diffusivity (MD) within frontal and parietal lobe white matter. Further, participants exhibiting larger gains on the LSAT exhibited greater decreases in MD in the right internal capsule. In summary, reasoning training altered multiple measures of white matter structure in young adults. While the cellular underpinnings are unknown, these results provide evidence of experience-dependent white matter changes that may not be limited to myelination. PMID- 22936898 TI - Human stefin B normal and patho-physiological role: molecular and cellular aspects of amyloid-type aggregation of certain EPM1 mutants. AB - Epilepsies are characterized by abnormal electrophysiological activity of the brain. Among various types of inherited epilepsies different epilepsy syndromes, among them progressive myoclonus epilepsies with features of ataxia and neurodegeneration, are counted. The progressive myoclonus epilepsy of type 1 (EPM1), also known as Unverricht-Lundborg disease presents with features of cerebellar atrophy and increased oxidative stress. It has been found that EPM1 is caused by mutations in human cystatin B gene (human stefin B). We first describe the role of protein aggregation in other neurodegenerative conditions. Protein aggregates appear intraneurally but are also excreted, such as is the case with senile plaques of amyloid-beta (Abeta) that accumulate in the brain parenchyma and vessel walls. A common characteristic of such diseases is the change of the protein conformation toward beta secondary structure that accounts for the strong tendency of such proteins to aggregate and form amyloid fibrils. Second, we describe the patho-physiology of EPM1 and the normal and aberrant roles of stefin B in a mouse model of the disease. Furthermore, we discuss how the increased protein aggregation observed with some of the mutants of human stefin B may relate to the neurodegeneration that occurs in rare EPM1 patients. Our hypothesis (Ceru et al., 2005) states that some of the EPM1 mutants of human stefin B may undergo aggregation in neural cells, thus gaining additional toxic function (apart from loss of normal function). Our in vitro experiments thus far have confirmed that four mutants undergo increased aggregation relative to the wild type protein. It has been shown that the R68X mutant forms amyloid-fibrils very rapidly, even at neutral pH and forms perinuclear inclusions, whereas the G4R mutant exhibits a prolonged lag phase, during which the toxic prefibrillar aggregates accumulate and are scattered more diffusely over the cytoplasm. Initial experiments on the G50E and Q71P missense EPM1 mutants are described. PMID- 22936900 TI - The stressed eyewitness: the interaction of thematic arousal and post-event stress in memory for central and peripheral event information. AB - Both arousal during the encoding of stimuli and subsequent stress can affect memory, often by increasing memory for important or central information. We explored whether event-based (thematic) arousal and post-event stress interact to selectively enhance eyewitnesses' memory for the central aspects of an observed incident. Specifically, we argue that memory for stimuli should be enhanced when (1) the stimuli are encoded under arousal (vs. non-arousal), and (2) stress is experienced soon after the encoding episode. We designed an experiment that extended previous research by manipulating arousal without changing the stimulus material, distinguishing between central and peripheral event information, and using a dynamic, life-like event instead of static pictures. After watching a video depicting a burglary under high or low thematic arousal, psychosocial stress was induced or not induced by the Trier Social Stress Test (TSST). Salivary cortisol was measured at standard intervals. Consistent with our prediction, we found a significant post-event stress * thematic arousal * centrality interaction, indicating that the recognition advantage for central event items over peripheral event items was most pronounced under both high thematic arousal and post-event stress. Because stress was induced after encoding this interaction cannot be explained by possible differences at encoding, such as narrowed attention. The centrality effect of post-event stress under high thematic arousal was statistically mediated by the cortisol increase, which suggests a key role of the stress hormone. We discuss implications of our findings for psychological and neuroscientific theories of emotional memory formation. PMID- 22936901 TI - Electrophysiological evidence for adult age-related sparing and decrements in emotion perception and attention. AB - The present study examined adult age differences in processing emotional faces using a psychological refractory period paradigm. We used both behavioral and event-related potential (P1 component) measures. Task 1 was tone discrimination (fuzzy vs. pure tones) and Task 2 was emotional facial discrimination ("happy" vs. "angry" faces). The stimulus onset asynchrony (SOA) between the two tasks was 100, 300, and 900 ms. Earlier research observed larger age deficits in emotional facial discrimination for negative (angry) than for positive (happy) faces (Baena et al., 2010). Thus, we predicted that older adults would show decreased attentional efficiency in carrying out dual-task processing on the P1 (a component linked to amygdalar modulation of visual perception; Rotshtein et al., 2010). Both younger and older groups showed significantly higher P1 amplitudes at 100- and 300-ms SOAs than at the 900-ms SOA, and this suggests that both age groups could process Task 2 faces without central attention. Also, younger adults showed significantly higher P1 activations for angry than for happy faces, but older adults showed no difference. These results are consistent with the idea that younger adults exhibited amygdalar modulation of visual perception, but that older adults did not. PMID- 22936902 TI - Temporal-order judgment of visual and auditory stimuli: modulations in situations with and without stimulus discrimination. AB - Temporal-order judgment (TOJ) tasks are an important paradigm to investigate processing times of information in different modalities. There are a lot of studies on how temporal order decisions can be influenced by stimuli characteristics. However, so far it has not been investigated whether the addition of a choice reaction time (RT) task has an influence on TOJ. Moreover, it is not known when during processing the decision about the temporal order of two stimuli is made. We investigated the first of these two questions by comparing a regular TOJ task with a dual task (DT). In both tasks, we manipulated different processing stages to investigate whether the manipulations have an influence on TOJ and to determine thereby the time of processing at which the decision about temporal order is made. The results show that the addition of a choice RT task does have an influence on the TOJ, but the influence seems to be linked to the kind of manipulation of the processing stages that is used. The results of the manipulations indicate that the temporal order decision in the DT paradigm is made after perceptual processing of the stimuli. PMID- 22936903 TI - Isolating a cerebellar contribution to rapid visual attention using transcranial magnetic stimulation. AB - Patient and neuroimaging research have provided increasing support for a role of the posterior-lateral cerebellum in cognition, particularly attention. During rapid serial visual presentation, when two targets are presented in close temporal proximity (<500 ms), accuracy at detecting the second target (T2) suffers. This phenomenon is known as the attentional blink (AB), and in cerebellar lesion patients this effect is exaggerated. Damage to the cerebellum may thus disrupt the use of attentional resources during stimulus processing conditions that are temporally demanding. There are reciprocal connections between the cerebral cortex and the contralateral cerebellum, these connections allow for the possibility that lateralized functions in the cerebral cortex (such as language) remain lateralized in the cerebellum. The purpose of this study was to investigate the temporal characteristics of the cerebellar contribution to the AB and to functionally localize the contribution of the cerebellum to the AB using transcranial magnetic stimulation (TMS). We hypothesized that T2 accuracy would decrease after right cerebellar stimulation when the delay between the first target (T1) and T2 was short (120-400 ms) compared to long (720-960 ms). We used continuous theta burst stimulation (cTBS), a form of TMS, to transiently inhibit a focal population of neurons in the left and right posterior-lateral cerebellum of healthy participants (n = 45). Three groups of participants (n = 15) performed the AB before and after either sham, left, or right cerebellar stimulation. The results of this cTBS study support our hypothesis. During the short delay, participants in the right cTBS group showed a greater AB magnitude compared to both the left and sham cTBS groups (p < 0.05). No difference in T2 detection was found over long delays. The results provide further support for a cerebellar contribution to an integrated neural network recruited during temporally demanding attention-based tasks. PMID- 22936904 TI - Speed impairs attending on the left: comparing attentional asymmetries for neglect patients in speeded and unspeeded cueing tasks. AB - Visuospatial neglect after stroke is often characterized by a disengage deficit on a cued orienting task, in which individuals are disproportionately slower to respond to targets presented on the contralesional side of space following an ispilesional cue as compared to the reverse. The purpose of this study was to investigate the generality of the finding of a disengage deficit on another measure of cued attention, the temporal order judgment (TOJ) task, that does not depend upon speeded manual responses. Individuals with right hemisphere stroke with and without spatial neglect and older healthy controls (OHC) were tested with both a speeded RT cueing task and an unspeeded TOJ-with-cuing task. All stroke patients evidenced a disengage deficit on the speeded RT cueing task, although the size and direction of the bias was not associated with the severity of neglect. In contrast, few neglect patients showed a disengage deficit on the TOJ task. This discrepancy suggests that the disengage deficit may be related to task demands, rather than solely due to impaired attentional mechanisms per se. Further, the results of our study show that the disengage deficit is neither necessary nor sufficient for neglect to manifest. PMID- 22936905 TI - Emotional and cognitive processing of narratives and individual appraisal styles: recruitment of cognitive control networks vs. modulation of deactivations. AB - Research in psychotherapy has shown that the frequency of use of specific classes of words (such as terms with emotional valence) in descriptions of scenes of affective relevance is a possible indicator of psychological affective functioning. Using functional magnetic resonance imaging (MRI), we investigated the neural correlates of these linguistic markers in narrative texts depicting core aspects of emotional experience in human interaction, and their modulation by individual differences in the propensity to use these markers. Emotional words activated both lateral and medial aspects of the prefrontal cortex, as in previous studies of instructed emotion regulation and in consistence with recruitment of effortful control processes. However, individual differences in the spontaneous use of emotional terms in characterizing the stimulus material were prevalently associated with modulation of the signal in the perigenual cortex, in the retrosplenial cortex and precuneus, and the anterior insula/ventrolateral prefrontal cortex. Modulation of signal by the presence of these textual markers or individual differences mostly involved areas deactivated by the main task, thus further differentiating neural correlates of these appraisal styles from those associated with effortful control. These findings are discussed in the context of reports in the literature of modulations of deactivations, which suggest their importance in orienting attention and generation of response in the presence of emotional information. These findings suggest that deactivations may play a functional role in emotional appraisal and may contribute to characterizing different appraisal styles. PMID- 22936906 TI - Resting-state connectivity of the amygdala is altered following Pavlovian fear conditioning. AB - Neural plasticity in the amygdala is necessary for the acquisition and storage of memory in Pavlovian fear conditioning, but most neuroimaging studies have focused only on stimulus-evoked responses during the conditioning session. This study examined changes in the resting-state functional connectivity (RSFC) of the amygdala before and after Pavlovian fear conditioning, an emotional learning task. Behavioral results from the conditioning session revealed that participants learned normally and fMRI data recorded during learning identified a number of stimulus-evoked changes that were consistent with previous work. A direct comparison between the pre- and post-conditioning amygdala connectivity revealed a region of dorsal prefrontal cortex (PFC) in the superior frontal gyrus that showed a significant increase in connectivity following the conditioning session. A behavioral measure of explicit memory performance was positively correlated with the change in amygdala connectivity within a neighboring region in the superior frontal gyrus. Additionally, an implicit autonomic measure of conditioning was positively correlated with the change in connectivity between the amygdala and the anterior cingulate cortex (ACC). The resting-state data show that amygdala connectivity is altered following Pavlovian fear conditioning and that these changes are also related to behavioral outcomes. These alterations may reflect the operation of a consolidation process that strengthens neural connections to support memory after the learning event. PMID- 22936907 TI - Long-term sensory stimulation therapy improves hand function and restores cortical responsiveness in patients with chronic cerebral lesions. Three single case studies. AB - Rehabilitation of sensorimotor impairment resulting from cerebral lesion (CL) utilizes task specific training and massed practice to drive reorganization and sensorimotor improvement due to induction of neuroplasticity mechanisms. Loss of sensory abilities often complicates recovery, and thus the individual's ability to use the affected body part for functional tasks. Therefore, the development of additional and alternative approaches that supplement, enhance, or even replace conventional training procedures would be advantageous. Repetitive sensory stimulation protocols (rSS) have been shown to evoke sensorimotor improvements of the affected limb in patients with chronic stroke. However, the possible impact of long-term rSS on sensorimotor performance of patients with CL, where the incident dated back many years remains unclear. The particular advantage of rSS is its passive nature, which does not require active participation of the subjects. Therefore, rSS can be applied in parallel to other occupations, making the intervention easier to implement and more acceptable to the individual. Here we report the effects of applying rSS for 8, 36, and 76 weeks to the paretic hand of three long-term patients with different types of CL. Different behavioral tests were used to assess sensory and/or sensorimotor performance of the upper extremities prior, after, and during the intervention. In one patient, the impact of long-term rSS on restoration of cortical activation was investigated by recording somatosensory evoked potentials (SEP). After long-term rSS all three patients showed considerable improvements of their sensory and motor abilities. In addition, almost normal evoked potentials could be recorded after rSS in one patient. Our data show that long-term rSS applied to patients with chronic CL can improve tactile and sensorimotor functions, which, however, developed in some cases only after many weeks of stimulation, and continued to further improve on a time scale of months. PMID- 22936908 TI - Adaptive thresholding for reliable topological inference in single subject fMRI analysis. AB - Single subject fMRI has proved to be a useful tool for mapping functional areas in clinical procedures such as tumor resection. Using fMRI data, clinicians assess the risk, plan and execute such procedures based on thresholded statistical maps. However, because current thresholding methods were developed mainly in the context of cognitive neuroscience group studies, most single subject fMRI maps are thresholded manually to satisfy specific criteria related to single subject analyzes. Here, we propose a new adaptive thresholding method which combines Gamma-Gaussian mixture modeling with topological thresholding to improve cluster delineation. In a series of simulations we show that by adapting to the signal and noise properties, the new method performs well in terms of total number of errors but also in terms of the trade-off between false negative and positive cluster error rates. Similarly, simulations show that adaptive thresholding performs better than fixed thresholding in terms of over and underestimation of the true activation border (i.e., higher spatial accuracy). Finally, through simulations and a motor test-retest study on 10 volunteer subjects, we show that adaptive thresholding improves reliability, mainly by accounting for the global signal variance. This in turn increases the likelihood that the true activation pattern can be determined offering an automatic yet flexible way to threshold single subject fMRI maps. PMID- 22936909 TI - Does spike-timing-dependent synaptic plasticity couple or decouple neurons firing in synchrony? AB - Spike synchronization is thought to have a constructive role for feature integration, attention, associative learning, and the formation of bidirectionally connected Hebbian cell assemblies. By contrast, theoretical studies on spike-timing-dependent plasticity (STDP) report an inherently decoupling influence of spike synchronization on synaptic connections of coactivated neurons. For example, bidirectional synaptic connections as found in cortical areas could be reproduced only by assuming realistic models of STDP and rate coding. We resolve this conflict by theoretical analysis and simulation of various simple and realistic STDP models that provide a more complete characterization of conditions when STDP leads to either coupling or decoupling of neurons firing in synchrony. In particular, we show that STDP consistently couples synchronized neurons if key model parameters are matched to physiological data: First, synaptic potentiation must be significantly stronger than synaptic depression for small (positive or negative) time lags between presynaptic and postsynaptic spikes. Second, spike synchronization must be sufficiently imprecise, for example, within a time window of 5-10 ms instead of 1 ms. Third, axonal propagation delays should not be much larger than dendritic delays. Under these assumptions synchronized neurons will be strongly coupled leading to a dominance of bidirectional synaptic connections even for simple STDP models and low mean firing rates at the level of spontaneous activity. PMID- 22936910 TI - Invariant object recognition based on extended fragments. AB - Visual appearance of natural objects is profoundly affected by viewing conditions such as viewpoint and illumination. Human subjects can nevertheless compensate well for variations in these viewing conditions. The strategies that the visual system uses to accomplish this are largely unclear. Previous computational studies have suggested that in principle, certain types of object fragments (rather than whole objects) can be used for invariant recognition. However, whether the human visual system is actually capable of using this strategy remains unknown. Here, we show that human observers can achieve illumination invariance by using object fragments that carry the relevant information. To determine this, we have used novel, but naturalistic, 3-D visual objects called "digital embryos." Using novel instances of whole embryos, not fragments, we trained subjects to recognize individual embryos across illuminations. We then tested the illumination-invariant object recognition performance of subjects using fragments. We found that the performance was strongly correlated with the mutual information (MI) of the fragments, provided that MI value took variations in illumination into consideration. This correlation was not attributable to any systematic differences in task difficulty between different fragments. These results reveal two important principles of invariant object recognition. First, the subjects can achieve invariance at least in part by compensating for the changes in the appearance of small local features, rather than of whole objects. Second, the subjects do not always rely on generic or pre-existing invariance of features (i.e., features whose appearance remains largely unchanged by variations in illumination), and are capable of using learning to compensate for appearance changes when necessary. These psychophysical results closely fit the predictions of earlier computational studies of fragment-based invariant object recognition. PMID- 22936911 TI - Invariant recognition of visual objects: some emerging computational principles. PMID- 22936912 TI - Decoding semantics across fMRI sessions with different stimulus modalities: a practical MVPA study. AB - Both embodied and symbolic accounts of conceptual organization would predict partial sharing and partial differentiation between the neural activations seen for concepts activated via different stimulus modalities. But cross-participant and cross-session variability in BOLD activity patterns makes analyses of such patterns with MVPA methods challenging. Here, we examine the effect of cross modal and individual variation on the machine learning analysis of fMRI data recorded during a word property generation task. We present the same set of living and non-living concepts (land-mammals, or work tools) to a cohort of Japanese participants in two sessions: the first using auditory presentation of spoken words; the second using visual presentation of words written in Japanese characters. Classification accuracies confirmed that these semantic categories could be detected in single trials, with within-session predictive accuracies of 80-90%. However cross-session prediction (learning from auditory-task data to classify data from the written-word-task, or vice versa) suffered from a performance penalty, achieving 65-75% (still individually significant at p " 0.05). We carried out several follow-on analyses to investigate the reason for this shortfall, concluding that distributional differences in neither time nor space alone could account for it. Rather, combined spatio-temporal patterns of activity need to be identified for successful cross-session learning, and this suggests that feature selection strategies could be modified to take advantage of this. PMID- 22936913 TI - Toward on-chip, in-cell recordings from cultured cardiomyocytes by arrays of gold mushroom-shaped microelectrodes. AB - Cardiological research greatly rely on the use of cultured primary cardiomyocytes (CMs). The prime methodology to assess CM network electrophysiology is based on the use of extracellular recordings by substrate-integrated planar Micro Electrode Arrays (MEAs). Whereas this methodology permits simultaneous, long-term monitoring of the CM electrical activity, it limits the information to extracellular field potentials (FPs). The alternative method of intracellular action potentials (APs) recordings by sharp- or patch-microelectrodes is limited to a single cell at a time. Here, we began to merge the advantages of planar MEA and intracellular microelectrodes. To that end we cultured rat CM on micrometer size protruding gold mushroom-shaped microelectrode (gMMUEs) arrays. Cultured CMs engulf the gMMUE permitting FPs recordings from individual cells. Local electroporation of a CM converts the extracellular recording configuration to attenuated intracellular APs with shape and duration similar to those recorded intracellularly. The procedure enables to simultaneously record APs from an unlimited number of CMs. The electroporated membrane spontaneously recovers. This allows for repeated recordings from the same CM a number of times (>8) for over 10 days. The further development of CM-gMMUE configuration opens up new venues for basic and applied biomedical research. PMID- 22936915 TI - Perlecan and the blood-brain barrier: beneficial proteolysis? AB - The cerebral microvasculature is important for maintaining brain homeostasis. This is achieved via the blood-brain barrier (BBB), composed of endothelial cells with specialized tight junctions, astrocytes, and a basement membrane (BM). Prominent components of the BM extracellular matrix (ECM) include fibronectin, laminin, collagen IV, and perlecan, all of which regulate cellular processes via signal transduction through various cell membrane bound ECM receptors. Expression and proteolysis of these ECM components can be rapidly altered during pathological states of the central nervous system. In particular, proteolysis of perlecan, a heparan sulfate proteoglycan, occurs within hours following ischemia induced by experimental stroke. Proteolysis of ECM components following stroke results in the degradation of the BM and further disruption of the BBB. While it is clear that such proteolysis has negative consequences for the BBB, we propose that it also may lead to generation of ECM protein fragments, including the C terminal domain V (DV) of perlecan, that potentially have a positive influence on other aspects of CNS health. Indeed, perlecan DV has been shown to be persistently generated after stroke and beneficial as a neuroprotective molecule and promoter of post-stroke brain repair. This mini-review will discuss beneficial roles of perlecan protein fragment generation within the brain during stroke. PMID- 22936917 TI - Physiological Intracellular Crowdedness is Defined by the Perimeter-to-Area Ratio of Sub-Cellular Compartments. AB - The intracellular environment is known to be a crowded and inhomogeneous space. Such an in vivo environment differs from a well-diluted, homogeneous environment for biochemical reactions. However, the effects of both crowdedness and the inhomogeneity of environment on the behavior of a mobile particle have not yet been investigated sufficiently. As described in this paper, we constructed artificial reaction spaces with fractal models, which are assumed to be non reactive solid obstacles in a reaction space with crevices that function as operating ranges for mobile particles threading the space. Because of the homogeneity of the structures of artificial reaction spaces, the models succeeded in reproducing the physiological fractal dimension of solid structures with a smaller number of non-reactive obstacles than in the physiological condition. This incomplete compatibility was mitigated when we chose a suitable condition of a perimeter-to-area ratio of the operating range to our model. Our results also show that a simulation space is partitioned into convenient reaction compartments as an in vivo environment with the exact amount of solid structures estimated from TEM images. The characteristics of these compartments engender larger mean square displacement of a mobile particle than that of particles in smaller compartments. Subsequently, the particles start to show confined particle-like behavior. These results are compatible with our previously presented results, which predicted that a physiological environment would produce quick response and slow exhaustion reactions. PMID- 22936918 TI - Neurodevelopmental Genes Have Not Read The DSM Criteria: Or, Have They? PMID- 22936914 TI - Expression Profiling of Solute Carrier Gene Families at the Blood-CSF Barrier. AB - The choroid plexus (CP) is a highly vascularized tissue in the brain ventricles and acts as the blood-cerebrospinal fluid (CSF) barrier (BCSFB). A main function of the CP is to secrete CSF, which is accomplished by active transport of small ions and water from the blood side to the CSF side. The CP also supplies the brain with certain nutrients, hormones, and metal ions, while removing metabolites and xenobiotics from the CSF. Numerous membrane transporters are expressed in the CP in order to facilitate the solute exchange between the blood and the CSF. The solute carrier (SLC) superfamily represents a major class of transporters in the CP that constitutes the molecular mechanisms for CP function. Recently, we systematically and quantitatively examined Slc gene expression in 20 anatomically comprehensive brain areas in the adult mouse brain using high quality in situ hybridization data generated by the Allen Brain Atlas. Here we focus our analysis on Slc gene expression at the BCSFB using previously obtained data. Of the 252 Slc genes present in the mouse brain, 202 Slc genes were found at detectable levels in the CP. Unsupervised hierarchical cluster analysis showed that the CP Slc gene expression pattern is substantially different from the other 19 analyzed brain regions. The majority of the Slc genes in the CP are expressed at low to moderate levels, whereas 28 Slc genes are present in the CP at the highest levels. These highly expressed Slc genes encode transporters involved in CSF secretion, energy production, and transport of nutrients, hormones, neurotransmitters, sulfate, and metal ions. In this review, the functional characteristics and potential importance of these Slc transporters in the CP are discussed, with particular emphasis on their localization and physiological functions at the BCSFB. PMID- 22936916 TI - Integration of peroxisomes into an endomembrane system that governs cellular aging. AB - The peroxisome is an organelle that has long been known for its essential roles in oxidation of fatty acids, maintenance of reactive oxygen species (ROS) homeostasis and anaplerotic replenishment of tricarboxylic acid (TCA) cycle intermediates destined for mitochondria. Growing evidence supports the view that these peroxisome-confined metabolic processes play an essential role in defining the replicative and chronological age of a eukaryotic cell. Much progress has recently been made in defining molecular mechanisms that link cellular aging to fatty acid oxidation, ROS turnover, and anaplerotic metabolism in peroxisomes. Emergent studies have revealed that these organelles not only house longevity defining metabolic reactions but can also regulate cellular aging via their dynamic communication with other cellular compartments. Peroxisomes communicate with other organelles by establishing extensive physical contact with lipid bodies, maintaining an endoplasmic reticulum (ER) to peroxisome connectivity system, exchanging certain metabolites, and being involved in the bidirectional flow of some of their protein and lipid constituents. The scope of this review is to summarize the evidence that peroxisomes are dynamically integrated into an endomembrane system that governs cellular aging. We discuss recent progress in understanding how communications between peroxisomes and other cellular compartments within this system influence the development of a pro- or anti-aging cellular pattern. We also propose a model for the integration of peroxisomes into the endomembrane system governing cellular aging and critically evaluate several molecular mechanisms underlying such integration. PMID- 22936920 TI - Linear deterministic accumulator models of simple choice. AB - We examine theories of simple choice as a race among evidence accumulation processes. We focus on the class of deterministic race models, which assume that the effects of fluctuations in the parameters of the accumulation processes between-choice trials (between-choice noise) dominate the effects of fluctuations occurring while making a choice (within-choice noise) in behavioral data (i.e., response times and choices). The latter deterministic approximation, when combined with the assumption that accumulation is linear, leads to a class of models that can be readily applied to simple-choice behavior because they are computationally tractable. We develop a new and mathematically simple exemplar within the class of linear deterministic models, the Lognormal race (LNR). We then examine how the LNR, and another widely applied linear deterministic model, Brown and Heathcote's (2008) LBA, account for a range of benchmark simple-choice effects in lexical-decision task data reported by Wagenmakers et al. (2008). Our results indicate that the LNR provides an accurate description of this data. Although the LBA model provides a slightly better account, both models support similar psychological conclusions. PMID- 22936921 TI - Incidental learning of temporal structures conforming to a metrical framework. AB - Implicit learning of sequential structures has been investigated mostly for visual, spatial, or motor learning, but rarely for temporal structure learning. The few experiments investigating temporal structure learning have concluded that temporal structures can be learned only when coupled with another structural dimension, such as musical pitch or spatial location. In these studies, the temporal structures were without metrical organization and were dependent upon participants' response times (Response-to-Stimulus Intervals). In our study, two experiments investigated temporal structure learning based on Inter-Onset Intervals in the presence of an uncorrelated second dimension (ordinal structure) with metrically organized temporal structures. Our task was an adaptation of the classical Serial Reaction Time paradigm, using an implicit task in the auditory domain (syllable identification). Reaction times (RT) revealed that participants learned the temporal structures over the exposure blocks (decrease in RT) without a correlated ordinal dimension. The introduction of a test block with a novel temporal structure slowed RT and exemplified the typical implicit learning profile. Post-test results suggested that participants did not have explicit knowledge of the metrical temporal structures. These findings provide the first evidence of the learning of temporal structure with an uncorrelated ordinal structure, and set a foundation for further investigation of temporal cognition. PMID- 22936919 TI - Synesthesia, sensory-motor contingency, and semantic emulation: how swimming style-color synesthesia challenges the traditional view of synesthesia. AB - Synesthesia is traditionally regarded as a phenomenon in which an additional non standard phenomenal experience occurs consistently in response to ordinary stimulation applied to the same or another modality. Recent studies suggest an important role of semantic representations in the induction of synesthesia. In the present proposal we try to link the empirically grounded theory of sensory motor contingency and mirror system based embodied simulation/emulation to newly discovered cases of swimming style-color synesthesia. In the latter color experiences are evoked only by showing the synesthetes a picture of a swimming person or asking them to think about a given swimming style. Neural mechanisms of mirror systems seem to be involved here. It has been shown that for mirror sensory synesthesia, such as mirror-touch or mirror-pain synesthesia (when visually presented tactile or noxious stimulation of others results in the projection of the tactile or pain experience onto oneself), concurrent experiences are caused by overactivity in the mirror neuron system responding to the specific observation. The comparison of different forms of synesthesia has the potential of challenging conventional thinking on this phenomenon and providing a more general, sensory-motor account of synesthesia encompassing cases driven by semantic or emulational rather than pure sensory or motor representations. Such an interpretation could include top-down associations, questioning the explanation in terms of hard-wired structural connectivity. In the paper the hypothesis is developed that the wide-ranging phenomenon of synesthesia might result from a process of hyperbinding between "too many" semantic attribute domains. This hypothesis is supplemented by some suggestions for an underlying neural mechanism. PMID- 22936922 TI - About the Distinction between Working Memory and Short-Term Memory. AB - The theoretical concepts short-term memory (STM) and working memory (WM) have been used to refer to the maintenance and the maintenance plus manipulation of information, respectively. Although they are conceptually different, the use of the terms STM and WM in literature is not always strict. STM and WM are different theoretical concepts that are assumed to reflect different cognitive functions. However, correlational studies have not been able to separate both constructs consistently and there is evidence for a large or even complete overlap. The emerging view from neurobiological studies is partly different, although there are conceptual problems troubling the interpretation of findings. In this regard, there is a crucial role for the tasks that are used to measure STM or WM (simple and complex span tasks, respectively) and for the cognitive load reflected by factors like attention and processing speed that may covary between and within these tasks. These conceptual issues are discussed based on several abstract models for the relation between STM and WM. PMID- 22936923 TI - Do horses expect humans to solve their problems? AB - Domestic animals are highly capable of detecting human cues, while wild relatives tend to perform less well (e.g., responding to pointing gestures). It is suggested that domestication may have led to the development of such cognitive skills. Here, we hypothesized that because domestic animals are so attentive and dependant to humans' actions for resources, the counter effect may be a decline of self sufficiency, such as individual task solving. Here we show a negative correlation between the performance in a learning task (opening a chest) and the interest shown by horses toward humans, despite high motivation expressed by investigative behaviors directed at the chest. If human-directed attention reflects the development of particular skills in domestic animals, this is to our knowledge the first study highlighting a link between human-directed behaviors and impaired individual solving task skills (ability to solve a task by themselves) in horses. PMID- 22936924 TI - Receptor-Heteromer Investigation Technology and its application using BRET. AB - Receptor heteromerization has the potential to alter every facet of receptor functioning, leading to new pharmacological profiles with increased signaling diversity and regulation from that of the monomeric receptor, or indeed receptor homomer. An understanding of the molecular consequences of receptor heteromerization will provide new insights into the physiology and pathology mediated by receptors, expanding the possibilities for pharmacological discovery. Particularly advantageous approaches to investigate novel heteromer pharmacology utilize cell-based assay technologies that assess ligand-dependent functional responses specific to the receptor heteromer. Importantly, this allows for differentiation of heteromer-specific pharmacology from pharmacology associated with the co-expressed receptor monomers and homomers. The Receptor-Heteromer Investigation Technology (Receptor-HIT) successfully employs a proximity-based reporter system, such as bioluminescence resonance energy transfer (BRET), in a configuration that enables determination of such heteromer-specific pharmacology. Therefore, Receptor-HIT provides a simple, robust and versatile approach for investigating the elusive "biochemical fingerprint" of receptor heteromers. PMID- 22936925 TI - Hormone-stimulated modulation of endocytic trafficking in osteoclasts. AB - A precise control of vesicular trafficking is crucial not only for osteoclastic bone resorption, but also for the crosstalk between osteoclasts and osteoblasts, which regulates bone homeostasis. In addition to the release of growth factors and modulators, such as glutamate, flux through the intracellular trafficking routes could also provide the osteoclast with a monitoring function of its resorption activity. To establish the signaling pathways regulating trafficking events in resorbing osteoclasts, we used the bone conserving hormone calcitonin, which has the unique property of inducing osteoclast quiescence. Calcitonin acts through the calcitonin receptor and activates multiple signaling pathways. By monitoring trafficking of a fluorescent low molecular weight probe in mature, bone resorbing osteoclasts we show for the first time that calcitonin blocks endocytosis from the ruffled border by phospholipase C (PLC) activation. Furthermore, we identify a requirement for polyunsaturated fatty acids in endocytic trafficking in osteoclasts. Inhibition of PLC prior to calcitonin treatment restores endocytosis to 75% of untreated rates. This effect is independent of protein kinase C activation and can be mimicked by an increase in intracellular calcium. We thus define an essential role for intracellular calcium levels in the maintenance of endocytosis in osteoclasts. PMID- 22936926 TI - Effect of glycosphingolipids on osteoclastogenesis and osteolytic bone diseases. AB - Alterations in glycosphingolipid (GSL) production results in lysosomal storage disorders associated with neurodegenerative changes. In Gaucher's disease, the patients also develop osteoporosis that is ameliorated upon treatment for the underlying defect in GSL metabolism. The role of GSLs in osteoclast and osteoblast formation is discussed here as well as the potential therapeutic uses of already approved drugs that limit GSL production in bone loss disorders such as multiple myeloma and periodontal disease. PMID- 22936928 TI - Differential virus host-ranges of the Fuselloviridae of hyperthermophilic Archaea: implications for evolution in extreme environments. AB - An emerging model for investigating virus-host interactions in hyperthermophilic Archaea is the Fusellovirus-Sulfolobus system. The host, Sulfolobus, is a hyperthermophilic acidophile endemic to sulfuric hot springs worldwide. The Fuselloviruses, also known as Sulfolobus Spindle-shaped Viruses (SSVs), are "lemon" or "spindle"-shaped double-stranded DNA viruses, which are also found worldwide. Although a few studies have addressed the host-range for the type virus, Sulfolobus Spindle-shaped Virus 1 (SSV1), using common Sulfolobus strains, a comprehensive host-range study for SSV-Sulfolobus systems has not been performed. Herein, we examine six bona fide SSV strains (SSV1, SSV2, SSV3, SSVL1, SSVK1, SSVRH) and their respective infection characteristics on multiple hosts from the family Sulfolobaceae. A spot-on-lawn or "halo" assay was employed to determine SSV infectivity (and host susceptibility) in parallel challenges of multiple SSVs on a lawn of a single Sulfolobus strain. Different SSVs have different host-ranges with SSV1 exhibiting the narrowest host-range and SSVRH exhibiting the broadest host range. In contrast to previous reports, SSVs can infect hosts beyond the genus Sulfolobus. Furthermore, geography does not appear to be a reliable predictor of Sulfolobus susceptibility to infection by any given SSV. The ability for SSVs to infect susceptible Sulfolobus host does not appear to change between 65 degrees C and 88 degrees C (physiological range); however, very low pH appears to influence infection. Lastly, for the virus-host pairs tested the Fusellovirus-Sulfolobus system appears to exhibit host-advantage. This work provides a foundation for understanding Fusellovirus biology and virus-host coevolution in extreme ecosystems. PMID- 22936929 TI - A review of ammonia-oxidizing bacteria and archaea in Chinese soils. AB - Ammonia (NH(3)) oxidation, the first and rate-limiting step of nitrification, is a key step in the global Nitrogen (N) cycle. Major advances have been made in recent years in our knowledge and understanding of the microbial communities involved in ammonia oxidation in a wide range of habitats, including Chinese agricultural soils. In this mini-review, we focus our attention on the distribution and community diversity of ammonia-oxidizing bacteria (AOB) and ammonia oxidizing archaea (AOA) in Chinese soils with variable soil properties and soil management practices. The niche differentiation of AOB and AOA in contrasting soils have been functionally demonstrated using DNA-SIP (stable isotope probing) methods, which have shown that AOA dominate nitrification processes in acidic soils, while AOB dominated in neutral, alkaline and N-rich soils. Finally, we discuss the composition and activity of ammonia oxidizers in paddy soils, as well as the mitigation of the greenhouse gas nitrous oxide (N(2)O) emissions and nitrate leaching via inhibition of nitrification by both AOB and AOA. PMID- 22936927 TI - The second skin: ecological role of epibiotic biofilms on marine organisms. AB - In the aquatic environment, biofilms on solid surfaces are omnipresent. The outer body surface of marine organisms often represents a highly active interface between host and biofilm. Since biofilms on living surfaces have the capacity to affect the fluxes of information, energy, and matter across the host's body surface, they have an important ecological potential to modulate the abiotic and biotic interactions of the host. Here we review existing evidence how marine epibiotic biofilms affect their hosts' ecology by altering the properties of and processes across its outer surfaces. Biofilms have a huge potential to reduce its host's access to light, gases, and/or nutrients and modulate the host's interaction with further foulers, consumers, or pathogens. These effects of epibiotic biofilms may intensely interact with environmental conditions. The quality of a biofilm's impact on the host may vary from detrimental to beneficial according to the identity of the epibiotic partners, the type of interaction considered, and prevailing environmental conditions. The review concludes with some unresolved but important questions and future perspectives. PMID- 22936930 TI - Genome-Wide Analysis of Salicylate and Dibenzofuran Metabolism in Sphingomonas Wittichii RW1. AB - Sphingomonas wittichii RW1 is a bacterium isolated for its ability to degrade the xenobiotic compounds dibenzodioxin and dibenzofuran (DBF). A number of genes involved in DBF degradation have been previously characterized, such as the dxn cluster, dbfB, and the electron transfer components fdx1, fdx3, and redA2. Here we use a combination of whole genome transcriptome analysis and transposon library screening to characterize RW1 catabolic and other genes implicated in the reaction to or degradation of DBF. To detect differentially expressed genes upon exposure to DBF, we applied three different growth exposure experiments, using either short DBF exposures to actively growing cells or growing them with DBF as sole carbon and energy source. Genome-wide gene expression was examined using a custom-made microarray. In addition, proportional abundance determination of transposon insertions in RW1 libraries grown on salicylate or DBF by ultra-high throughput sequencing was used to infer genes whose interruption caused a fitness loss for growth on DBF. Expression patterns showed that batch and chemostat growth conditions, and short or long exposure of cells to DBF produced very different responses. Numerous other uncharacterized catabolic gene clusters putatively involved in aromatic compound metabolism increased expression in response to DBF. In addition, only very few transposon insertions completely abolished growth on DBF. Some of those (e.g., in dxnA1) were expected, whereas others (in a gene cluster for phenylacetate degradation) were not. Both transcriptomic data and transposon screening suggest operation of multiple redundant and parallel aromatic pathways, depending on DBF exposure. In addition, increased expression of other non-catabolic genes suggests that during initial exposure, S. wittichii RW1 perceives DBF as a stressor, whereas after longer exposure, the compound is recognized as a carbon source and metabolized using several pathways in parallel. PMID- 22936931 TI - MicroRNAs in HIV-1 infection: an integration of viral and cellular interaction at the genomic level. AB - The microRNA pathways govern complex interactions of the host and virus at the transcripts level that regulate cellular responses, viral replication and viral pathogenesis. As a group of single-stranded short non-coding ribonucleotides (ncRNAs), the microRNAs complement their messenger RNA (mRNA) targets to effect post-transcriptional or translational gene silencing. Previous studies showed the ability of human immunodeficiency virus 1 (HIV-1) to encode microRNAs which modify cellular defence mechanisms thus creating an environment favorable for viral invasion and replication. In corollary, cellular microRNAs were linked to the alteration of HIV-1 infection at different stages of replication and latency. As evidences further establish the regulatory involvement of both cellular and viral microRNA in HIV-1-host interactions, there is a necessity to organize this information. This paper would present current and emerging knowledge on these multi-dimensional interactions that may facilitate the design of microRNAs as effective antiretroviral reagents. PMID- 22936932 TI - Microbial biogeography of arctic streams: exploring influences of lithology and habitat. AB - Terminal restriction fragment length polymorphism and 16S rRNA gene sequencing were used to explore the community composition of bacterial communities in biofilms on sediments (epipssamon) and rocks (epilithon) in stream reaches that drain watersheds with contrasting lithologies in the Noatak National Preserve, Alaska. Bacterial community composition varied primarily by stream habitat and secondarily by lithology. Positive correlations were detected between bacterial community structure and nutrients, base cations, and dissolved organic carbon. Our results showed significant differences at the stream habitat, between epipssamon and epilithon bacterial communities, which we expected. Our results also showed significant differences at the landscape scale that could be related to different lithologies and associated stream biogeochemistry. These results provide insight into the bacterial community composition of little known and pristine arctic stream ecosystems and illustrate how differences in the lithology, soils, and vegetation community of the terrestrial environment interact to influence stream bacterial taxonomic richness and composition. PMID- 22936933 TI - Selective inhibitors of phosphoinositide 3-kinase delta: modulators of B-cell function with potential for treating autoimmune inflammatory diseases and B-cell malignancies. AB - The delta isoform of the p110 catalytic subunit (p110delta) of phosphoinositide 3 kinase is expressed primarily in hematopoietic cells and plays an essential role in B-cell development and function. Studies employing mice lacking a functional p110delta protein, as well as the use of highly-selective chemical inhibitors of p110delta, have revealed that signaling via p110delta-containing PI3K complexes (PI3Kdelta) is critical for B-cell survival, migration, and activation, functioning downstream of key receptors on B cells including the B-cell antigen receptor, chemokine receptors, pro-survival receptors such as BAFF-R and the IL-4 receptor, and co-stimulatory receptors such as CD40 and Toll-like receptors (TLRs). Similarly, this PI3K isoform plays a key role in the survival, proliferation, and dissemination of B-cell lymphomas. Herein we summarize studies showing that these processes can be inhibited in vitro and in vivo by small molecule inhibitors of p110delta enzymatic activity, and that these p110delta inhibitors have shown efficacy in clinical trials for the treatment of several types of B-cell malignancies including chronic lymphocytic leukemia (CLL) and non Hodgkin lymphoma (NHL). PI3Kdelta also plays a critical role in the activation, proliferation, and tissue homing of self-reactive B cells that contribute to autoimmune diseases, in particular innate-like B-cell populations such as marginal zone (MZ) B cells and B-1 cells that have been strongly linked to autoimmunity. We discuss the potential utility of p110delta inhibitors, either alone or in combination with B-cell depletion, for treating autoimmune diseases such as lupus, rheumatoid arthritis, and type 1 diabetes. Because PI3Kdelta plays a major role in both B-cell-mediated autoimmune inflammation and B-cell malignancies, PI3Kdelta inhibitors may represent a promising therapeutic approach for treating these diseases. PMID- 22936935 TI - Homeostasis of lymphocytes and monocytes in frequent blood donors. AB - Age-associated decline of immune function is believed to be mainly due to alterations of immune cells. However, longitudinal changes of human immune cells with age have not yet been adequately addressed. To test the hypothesis that regeneration of lymphocytes and monocytes is robust throughout most of adult life until advanced age, we examined six leukapheresis donors (3 young and 3 middle aged/old) who donated approximately 10% of their peripheral blood mononuclear cells (PBMC) every other month over 3-5 years. We found the number of both lymphocytes and monocytes were quite stable in the blood of all six donors. As expected, young donors had more T cell receptor excision circles (TRECs), CD31{}(+) cells (CD4 only) and longer telomeres in T cells than did the middle aged donors. Interestingly, more variation in TREC number, Vbeta usages, and telomere lengths were observed in young donors during the 3-5 years course of donation whereas the middle-aged/old donors showed a rather striking stability in these measurements. This may reflect a more prominent role of thymic output in T cell regeneration in young than in middle-aged/old donors. Together, these findings provide an in vivo glimpse into the homeostasis of lymphocytes and monocytes in the blood at different ages, and support the notion that regeneration of lymphocytes and monocytes is robust throughout adult life up to the early 70s. PMID- 22936934 TI - CXCR2: From Bench to Bedside. AB - Leukocyte recruitment to sites of infection or tissue damage plays a crucial role for the innate immune response. Chemokine-dependent signaling in immune cells is a very important mechanism leading to integrin activation and leukocyte recruitment. CXC chemokine receptor 2 (CXCR2) is a prominent chemokine receptor on neutrophils. During the last years, several studies were performed investigating the role of CXCR2 in different diseases. Until now, many CXCR2 inhibitors are tested in animal models and clinical trials and promising results were obtained. This review gives an overview of the structure of CXCR2 and the signaling pathways that are activated following CXCR2 stimulation. We discuss in detail the role of this chemokine receptor in different disease models including acute lung injury, COPD, sepsis, and ischemia-reperfusion-injury. Furthermore, this review summarizes the results of clinical trials which used CXCR2 inhibitors. PMID- 22936937 TI - Molecular Linkage Mapping and Marker-Trait Associations with NlRPT, a Downy Mildew Resistance Gene in Nicotiana langsdorffii. AB - Nicotiana langsdorffii is one of two species of Nicotiana known to express an incompatible interaction with the oomycete Peronospora tabacina, the causal agent of tobacco blue mold disease. We previously showed that incompatibility is due to the hypersensitive response (HR), and plants expressing the HR are resistant to P. tabacina at all stages of growth. Resistance is due to a single dominant gene in N. langsdorffii accession S-4-4 that we have named NlRPT. In further characterizing this unique host-pathogen interaction, NlRPT has been placed on a preliminary genetic map of the N. langsdorffii genome. Allelic scores for five classes of DNA markers were determined for 90 progeny of a "modified backcross" involving two N. langsdorffii inbred lines and the related species N. forgetiana. All markers had an expected segregation ratio of 1:1, and were scored in a common format. The map was constructed with JoinMap 3.0, and loci showing excessive transmission distortion were removed. The linkage map consists of 266 molecular marker loci defined by 217 amplified fragment length polymorphisms (AFLPs), 26 simple-sequence repeats (SSRs), 10 conserved orthologous sequence markers, nine inter-simple sequence repeat markers, and four target region amplification polymorphism markers arranged in 12 linkage groups with a combined length of 1062 cM. NlRPT is located on linkage group three, flanked by four AFLP markers and one SSR. Regions of skewed segregation were detected on LGs 1, 5, and 9. Markers developed for N. langsdorffii are potentially useful genetic tools for other species in Nicotiana section Alatae, as well as in N. benthamiana. We also investigated whether AFLPs could be used to infer genetic relationships within N. langsdorffii and related species from section Alatae. A phenetic analysis of the AFLP data showed that there are two main lineages within N. langsdorffii, and that both contain populations expressing dominant resistance to P. tabacina. PMID- 22936936 TI - PKC-theta-mediated signal delivery from the TCR/CD28 surface receptors. AB - Protein kinase C-theta (PKCtheta) is a key enzyme in T lymphocytes, where it plays an important role in signal transduction downstream of the activated T cell antigen receptor (TCR) and the CD28 costimulatory receptor. Interest in PKCtheta as a potential drug target has increased following recent findings that PKCtheta is essential for harmful inflammatory responses mediated by Th2 (allergies) and Th17 (autoimmunity) cells as well as for graft-versus-host disease (GvHD) and allograft rejection, but is dispensable for beneficial responses such as antiviral immunity and graft-versus-leukemia (GvL) response. TCR/CD28 engagement triggers the translocation of the cytosolic PKCtheta to the plasma membrane (PM), where it localizes at the center of the immunological synapse (IS), which forms at the contact site between an antigen-specific T cell and antigen-presenting cells (APC). However, the molecular basis for this unique localization, and whether it is required for its proper function have remained unresolved issues until recently. Our recent study resolved these questions by demonstrating that the unique V3 (hinge) domain of PKCtheta and, more specifically, a proline-rich motif within this domain, is essential and sufficient for its localization at the IS, where it is anchored to the cytoplasmic tail of CD28 via an indirect mechanism involving Lck protein tyrosine kinase (PTK) as an intermediate. Importantly, the association of PKCtheta with CD28 is essential not only for IS localization, but also for PKCtheta-mediated activation of downstream signaling pathways, including the transcription factors NF-kappaB and NF-AT, which are essential for productive T cell activation. Hence, interference with formation of the PKCtheta-Lck-CD28 complex provides a promising basis for the design of novel, clinically useful allosteric PKCtheta inhibitors. An additional recent study demonstrated that TCR triggering activates the germinal center kinase (GSK)-like kinase (GLK) and induces its association with the SLP-76 adaptor at the IS, where GLK phosphorylates the activation loop of PKCtheta, converting it into an active enzyme. This recent progress, coupled with the need to study the biology of PKCtheta in human T cells, is likely to facilitate the development of PKCtheta based therapeutic modalities for T cell-mediated diseases. PMID- 22936938 TI - We are good to grow: dynamic integration of cell wall architecture with the machinery of growth. AB - Despite differences in cell wall composition between the type I cell walls of dicots and most monocots and the type II walls of commelinid monocots, all flowering plants respond to the same classes of growth regulators in the same tissue-specific way and exhibit the same growth physics. Substantial progress has been made in defining gene families and identifying mutants in cell wall-related genes, but our understanding of the biochemical basis of wall extensibility during growth is still rudimentary. In this review, we highlight insights into the physiological control of cell expansion emerging from genetic functional analyses, mostly in Arabidopsis and other dicots, and a few examples of genes of potential orthologous function in grass species. We discuss examples of cell wall architectural features that impact growth independent of composition, and progress in identifying proteins involved in transduction of growth signals and integrating their outputs in the molecular machinery of wall expansion. PMID- 22936940 TI - Conserved Peptide Upstream Open Reading Frames are Associated with Regulatory Genes in Angiosperms. AB - Upstream open reading frames (uORFs) are common in eukaryotic transcripts, but those that encode conserved peptides occur in less than 1% of transcripts. The peptides encoded by three plant conserved peptide uORF (CPuORF) families are known to control translation of the downstream ORF in response to a small signal molecule (sucrose, polyamines, and phosphocholine). In flowering plants, transcription factors are statistically over-represented among genes that possess CPuORFs, and in general it appeared that many CPuORF genes also had other regulatory functions, though the significance of this suggestion was uncertain (Hayden and Jorgensen, 2007). Five years later the literature provides much more information on the functions of many CPuORF genes. Here we reassess the functions of 27 known CPuORF gene families and find that 22 of these families play a variety of different regulatory roles, from transcriptional control to protein turnover, and from small signal molecules to signal transduction kinases. Clearly then, there is indeed a strong association of CPuORFs with regulatory genes. In addition, 16 of these families play key roles in a variety of different biological processes. Most strikingly, the core sucrose response network includes three different CPuORFs, creating the potential for sophisticated balancing of the network in response to three different molecular inputs. We propose that the function of most CPuORFs is to modulate translation of a downstream major ORF (mORF) in response to a signal molecule recognized by the conserved peptide and that because the mORFs of CPuORF genes generally encode regulatory proteins, many of them centrally important in the biology of plants, CPuORFs play key roles in balancing such regulatory networks. PMID- 22936939 TI - Bundling actin filaments from membranes: some novel players. AB - Progress in live-cell imaging of the cytoskeleton has significantly extended our knowledge about the organization and dynamics of actin filaments near the plasma membrane of plant cells. Noticeably, two populations of filamentous structures can be distinguished. On the one hand, fine actin filaments which exhibit an extremely dynamic behavior basically characterized by fast polymerization and prolific severing events, a process referred to as actin stochastic dynamics. On the other hand, thick actin bundles which are composed of several filaments and which are comparatively more stable although they constantly remodel as well. There is evidence that the actin cytoskeleton plays critical roles in trafficking and signaling at both the cell cortex and organelle periphery but the exact contribution of actin bundles remains unclear. A common view is that actin bundles provide the long-distance tracks used by myosin motors to deliver their cargo to growing regions and accordingly play a particularly important role in cell polarization. However, several studies support that actin bundles are more than simple passive highways and display multiple and dynamic roles in the regulation of many processes, such as cell elongation, polar auxin transport, stomatal and chloroplast movement, and defense against pathogens. The list of identified plant actin-bundling proteins is ever expanding, supporting that plant cells shape structurally and functionally different actin bundles. Here I review the most recently characterized actin-bundling proteins, with a particular focus on those potentially relevant to membrane trafficking and/or signaling. PMID- 22936941 TI - The endoplasmic reticulum in plant immunity and cell death. AB - The endoplasmic reticulum (ER) is a highly dynamic organelle in eukaryotic cells and a major production site of proteins destined for vacuoles, the plasma membrane, or apoplast in plants. At the ER, these secreted proteins undergo multiple processing steps, which are supervised and conducted by the ER quality control system. Notably, processing of secreted proteins can considerably elevate under stress conditions and exceed ER folding capacities. The resulting accumulation of unfolded proteins is defined as ER stress. The efficiency of cells to re-establish proper ER function is crucial for stress adaptation. Besides delivering proteins directly antagonizing and resolving stress conditions, the ER monitors synthesis of immune receptors. This indicates the significance of the ER for the establishment and function of the plant immune system. Recent studies point out the fragility of the entire system and highlight the ER as initiator of programed cell death (PCD) in plants as was reported for vertebrates. This review summarizes current knowledge on the impact of the ER on immune and PCD signaling. Understanding the integration of stress signals by the ER bears a considerable potential to optimize development and to enhance stress resistance of plants. PMID- 22936942 TI - RNA trafficking in parasitic plant systems. AB - RNA trafficking in plants contributes to local and long-distance coordination of plant development and response to the environment. However, investigations of mobile RNA identity and function are hindered by the inherent difficulty of tracing a given molecule of RNA from its cell of origin to its destination. Several methods have been used to address this problem, but all are limited to some extent by constraints associated with accurately sampling phloem sap or detecting trafficked RNA. Certain parasitic plant species form symplastic connections to their hosts and thereby provide an additional system for studying RNA trafficking. The haustorial connections of Cuscuta and Phelipanche species are similar to graft junctions in that they are able to transmit mRNAs, viral RNAs, siRNAs, and proteins from the host plants to the parasite. In contrast to other graft systems, these parasites form connections with host species that span a wide phylogenetic range, such that a high degree of nucleotide sequence divergence may exist between host and parasites and allow confident identification of most host RNAs in the parasite system. The ability to identify host RNAs in parasites, and vice versa, will facilitate genomics approaches to understanding RNA trafficking. This review discusses the nature of host-parasite connections and the potential significance of host RNAs for the parasite. Additional research on host-parasite interactions is needed to interpret results of RNA trafficking studies, but parasitic plants may provide a fascinating new perspective on RNA trafficking. PMID- 22936943 TI - Comparative structure and biomechanics of plant primary and secondary cell walls. AB - Recent insights into the physical biology of plant cell walls are reviewed, summarizing the essential differences between primary and secondary cell walls and identifying crucial gaps in our knowledge of their structure and biomechanics. Unexpected parallels are identified between the mechanism of expansion of primary cell walls during growth and the mechanisms by which hydrated wood deforms under external tension. There is a particular need to revise current "cartoons" of plant cell walls to be more consistent with data from diverse approaches and to go beyond summarizing limited aspects of cell walls, serving instead as guides for future experiments and for the application of new techniques. PMID- 22936945 TI - A new definition of aging? PMID- 22936944 TI - Receptor-like kinase complexes in plant innate immunity. AB - Receptor-like kinases (RLKs) are surface localized, transmembrane receptors comprising a large family of well-studied kinases. RLKs signal through their transmembrane and juxtamembrane domains with the aid of various interacting partners and downstream components. The N-terminal extracellular domain defines ligand specificity, and RLK families are sub-classed according to this domain. The most studied of these subfamilies include those with (1) leucine-rich repeat (LRR) domains, (2) LysM domains (LYM), and (3) the Catharanthus roseus RLK1-like (CrRLK1L) domain. These proteins recognize distinct ligands of microbial origin or ligands derived from intracellular protein/carbohydrate signals. For example, the pattern-recognition receptor (PRR) AtFLS2 recognizes flg22 from flagellin, and the PRR AtEFR recognizes elf18 from elongation factor (EF-Tu). Upon binding of their cognate ligands, the aforementioned RLKs activate generic immune responses termed pattern-triggered immunity (PTI). RLKs can form complexes with other family members and engage a variety of intracellular signaling components and regulatory pathways upon stimulation. This review focuses on interesting new data about how these receptors form protein complexes to exert their function. PMID- 22936946 TI - A Question Never Comes Alone: Comments on 'What is Aging?'. PMID- 22936948 TI - Identification of DNA methylation biomarkers from Infinium arrays. AB - Epigenetic modifications of DNA, such as cytosine methylation are differentially abundant in diseases such as cancer. A goal for clinical research is finding sites that are differentially methylated between groups of samples to act as potential biomarkers for disease outcome. However, clinical samples are often limited in availability, represent a heterogeneous collection of cells or are of uncertain clinical class. Array-based methods for identification of methylation provide a cost-effective method to survey a proportion of the methylome at single base resolution. The Illumina Infinium array has become a popular and reliable high throughput method in this field and are proving useful in the identification of biomarkers for disease. Here, we compare a commonly used statistical test with a new intuitive and flexible computational approach to quickly detect differentially methylated sites. The method rapidly identifies and ranks candidate lists with greatest inter-group variability whilst controlling for intra-group variability. Intuitive and biologically relevant filters can be imposed to quickly identify sites and genes of interest. PMID- 22936947 TI - Posttranscriptional regulation of gene expression-adding another layer of complexity to the DNA damage response. AB - In response to DNA damage, cells activate a complex, kinase-based signaling network to arrest the cell cycle and allow time for DNA repair, or, if the extend of damage is beyond repair capacity, induce apoptosis. This signaling network, which is collectively referred to as the DNA damage response (DDR), is primarily thought to consist of two components-a rapid phosphorylation-driven signaling cascade that results in immediate inhibition of Cdk/cyclin complexes and a delayed transcriptional response that promotes a prolonged cell cycle arrest through the induction of Cdk inhibitors, such as p21. In recent years a third layer of complexity has emerged that involves potent posttranscriptional regulatory mechanisms that control the cellular response to DNA damage. Although much has been written on the relevance of the DDR in cancer and on the post transcriptional role of microRNAs (miRs) in cancer, the post-transcriptional regulation of the DDR by non-coding RNAs and RNA-binding proteins (RBPs) still remains elusive in large parts. Here, we review the recent developments in this exciting new area of research in the cellular response to genotoxic stress. We put specific emphasis on the role of RBPs and the control of their function through DNA damage-activated protein kinases. PMID- 22936949 TI - The Role of PPARgamma in Helicobacter pylori Infection and Gastric Carcinogenesis. AB - Peroxisome proliferator-activated receptor gamma (PPARgamma) is a nuclear receptor that is important in many physiological and pathological processes, such as lipid metabolism, insulin sensitivity, inflammation, cell proliferation, and carcinogenesis. Several studies have shown that PPARgamma plays an important role in gastric mucosal injury due to Helicobacter pylori (H. pylori). As H. pylori infection is the main etiologic factor in chronic gastritis and gastric cancer, understanding of the potential roles of PPARgamma in H. pylori infection may lead to the development of a therapeutic target. In this paper, the authors discuss the current knowledge on the role of PPARgamma in H. pylori infection and its related gastric carcinogenesis. PMID- 22936950 TI - Heart cells with regenerative potential from pediatric patients with end stage heart failure: a translatable method to enrich and propagate. AB - Background. Human cardiac-derived progenitor cells (hCPCs) have shown promise in treating heart failure (HF) in adults. The purpose of this study was to describe derivation of hCPCs from pediatric patients with end-stage HF. Methods. At surgery, discarded right atrial tissues (hAA) were obtained from HF patients (n = 25; hAA-CHF). Minced tissues were suspended in complete (serum-containing) DMEM. Cells were selected for their tissue migration and expression of stem cell factor receptor (hc-kit). Characterization of hc-kit(positive) cells included immunohistochemical screening with a panel of monoclonal antibodies. Results. Cells, including phase-bright cells identified as hc-kit(positive), spontaneously emigrated from hAA-CHF in suspended explant cultures (SEC) after Day 7. When cocultured with tissue, emigrated hc-kit(positive) cells proliferated, first as loosely attached clones and later as multicellular clusters. At Day 21~5% of cells were hc-kit(positive). Between Days 14 and 28 hc-kit(positive) cells exhibited mesodermal commitment (GATA-4(positive) and NKX2.5(positive)); then after Day 28 cardiac lineages (flk-1(positive), smooth muscle actin(positive), troponin-I(positive), and myosin light chain(positive)). Conclusions. C kit(positive) hCPCs can be derived from atrial tissue of pediatric patients with end-stage HF. SEC is a novel culture method for derivation of migratory hc kit(positive) cells that favors clinical translation by reducing the need for exogenously added factors to expand hCPCs in vitro. PMID- 22936951 TI - Dietary Patterns and Body Mass Index in Children with Autism and Typically Developing Children. AB - To determine whether dietary patterns (juice and sweetened non-dairy beverages, fruits, vegetables, fruits & vegetables, snack foods, and kid's meals) and associations between dietary patterns and body mass index (BMI) differed between 53 children with autism spectrum disorders (ASD) and 58 typically developing children, ages 3 to 11, multivariate regression models including interaction terms were used. Children with ASD were found to consume significantly more daily servings of sweetened beverages (2.6 versus 1.7, p=0.03) and snack foods (4.0 versus 3.0, p=0.01) and significantly fewer daily servings of fruits and vegetables (3.1 versus 4.4, p=0.006) than typically developing children. There was no evidence of statistical interaction between any of the dietary patterns and BMI z-score with autism status. Among all children, fruits and vegetables (p=0.004) and fruits alone (p=0.005) were positively associated with BMI z-score in our multivariate models. Children with ASD consume more energy-dense foods than typically developing children; however, in our sample, only fruits and vegetables were positively associated with BMI z-score. PMID- 22936952 TI - Advances in the diagnosis of anorexia nervosa and bulimia nervosa using brain imaging. AB - INTRODUCTION: Anorexia and bulimia nervosa are severe psychiatric disorders and the availability of brain imaging techniques hold promise that those techniques will be useful in clinical practice. AREAS COVERED: In this review I describe currently available brain imaging techniques and focus on the brain imaging methods functional magnetic resonance imaging (fMRI) and positron emission tomography (PET). Those techniques have helped describe alterations in brain circuitry in AN and BN that related to anxiety and reward processing. Novel computational models help further define brain function in relation to particular neurotransmitters. EXPERT OPINION: Brain imaging techniques are exciting methods to learn about brain function and progress has been made to identify in healthy populations brain circuits that code behaviors. These techniques have been used in AN and BN over the past decade and have improved our understanding of brain function in those disorders. Still, human brain imaging is not at a point yet where it could be used diagnostically. However, with the refinement of imaging hardware as well as improved models that describe brain function we will get closer to our aims to not only better understand the neurobiology of those disorders, but predict illness development, treatment response and long term prognosis. PMID- 22936953 TI - Gender Differences in the Fagerstrom Test for Nicotine Dependence in Korean Americans. AB - INTRODUCTION: This study was conducted to compare gender differences in the psychometric properties of the Fagerstrom Test for Nicotine Dependence (FTND). METHODS: The sample comprised 334 Korean immigrants (97 women and 237 men) who reported daily smoking for the past six months. Item-by-item responses and exploratory factor analyses (EFA) were compared by gender. Promax rotation was selected based on findings from previous studies suggesting correlated factors. RESULTS: Compared with men, women smoked fewer cigarettes per day, were more likely to smoke when ill in bed, and were less likely to smoke frequently in the morning. The entire sample and men within the sample had the same factor loading pattern, where three items (time to first cigarette, the cigarette most hate to give up, and smoke more frequently in the morning) were loaded on Factor 1 (morning smoking) and the remaining three items (difficult to refrain from smoking in public places, number of cigarettes smoked per day, and smoking even when ill in bed) on Factor 2 (daytime smoking). For women, however, neither the 1 nor 2-factor model fit the data well. CONCLUSIONS: For Korean American male smokers, the psychometric properties of the FTND were similar to those seen in other populations, but this was not the case with Korean American women. Clinicians may need to modify their interpretation of nicotine dependence severity if basing only on the FTND with Korean Women. The FTND assesses smoking patterns which has a cultural influence and other measures of nicotine dependence should be considered. PMID- 22936968 TI - Screen anti-influenza lead compounds that target the PA(C) subunit of H5N1 viral RNA polymerase. AB - The avian influenza (H5N1) viral RNA polymerase protein PA(C) was used as a target to screen nine chlorogenic acid derivatives for their polymerase inhibitor activity. Among them, seven compounds were PA(C) ligands, and four inhibited influenza RNA polymerase activity. These results aid in the design of anti influenza agents based on caffeoylquinic acid. PMID- 22936970 TI - Insights from classifying visual concepts with multiple kernel learning. AB - Combining information from various image features has become a standard technique in concept recognition tasks. However, the optimal way of fusing the resulting kernel functions is usually unknown in practical applications. Multiple kernel learning (MKL) techniques allow to determine an optimal linear combination of such similarity matrices. Classical approaches to MKL promote sparse mixtures. Unfortunately, 1-norm regularized MKL variants are often observed to be outperformed by an unweighted sum kernel. The main contributions of this paper are the following: we apply a recently developed non-sparse MKL variant to state of-the-art concept recognition tasks from the application domain of computer vision. We provide insights on benefits and limits of non-sparse MKL and compare it against its direct competitors, the sum-kernel SVM and sparse MKL. We report empirical results for the PASCAL VOC 2009 Classification and ImageCLEF2010 Photo Annotation challenge data sets. Data sets (kernel matrices) as well as further information are available at http://doc.ml.tu-berlin.de/image_mkl/(Accessed 2012 Jun 25). PMID- 22936969 TI - I223R mutation in influenza A(H1N1)pdm09 neuraminidase confers reduced susceptibility to oseltamivir and zanamivir and enhanced resistance with H275Y. AB - BACKGROUND: Resistance of pandemic A(H1N1)2009 (H1N1pdm09) virus to neuraminidase inhibitors (NAIs) has remained limited. A new mutation I223R in the neuraminidase (NA) of H1N1pdm09 virus has been reported along with H275Y in immunocompromised patients. The aim of this study was to determine the impact of I223R on oseltamivir and zanamivir susceptibility. METHODS: The NA enzymatic characteristics and susceptibility to NAIs of viruses harbouring the mutations I223R and H275Y alone or in combination were analyzed on viruses produced by reverse genetics and on clinical isolates collected from an immunocompromised patient with sustained influenza H1N1pdm09 virus shedding and treated by oseltamivir (days 0-15) and zanamivir (days 15-25 and 70-80). RESULTS: Compared with the wild type, the NA of recombinant viruses and clinical isolates with H275Y or I223R mutations had about two-fold reduced affinity for the substrate. The H275Y and I223R isolates showed decreased susceptibility to oseltamivir (246 fold) and oseltamivir and zanamivir (8.9- and 4.9-fold), respectively. Reverse genetics assays confirmed these results and further showed that the double mutation H275Y and I223R conferred enhanced levels of resistance to oseltamivir and zanamivir (6195- and 15.2-fold). In the patient, six days after initiation of oseltamivir therapy, the mutation H275Y conferring oseltamivir resistance and the I223R mutation were detected in the NA. Mutations were detected concomitantly from day 6-69 but molecular cloning did not show any variant harbouring both mutations. Despite cessation of NAI treatment, the mutation I223R persisted along with additional mutations in the NA and the hemagglutinin. CONCLUSIONS: Reduced susceptibility to both oseltamivir and zanamivir was conferred by the I223R mutation which potentiated resistance to both NAIs when associated with the H275Y mutation in the NA. Concomitant emergence of the I223R and H275Y mutations under oseltamivir treatment underlines the importance of close monitoring of treated patients especially those immunocompromised. PMID- 22936971 TI - Reward value determines memory consolidation in parasitic wasps. AB - Animals can store learned information in their brains through a series of distinct memory forms. Short-lasting memory forms can be followed by longer lasting, consolidated memory forms. However, the factors determining variation in memory consolidation encountered in nature have thus far not been fully elucidated. Here, we show that two parasitic wasp species belonging to different families, Cotesia glomerata (Hymenoptera: Braconidae) and Trichogramma evanescens (Hymenoptera; Trichogrammatidae), similarly adjust the memory form they consolidate to a fitness-determining reward: egg-laying into a host-insect that serves as food for their offspring. Protein synthesis-dependent long-term memory (LTM) was consolidated after single-trial conditioning with a high-value host. However, single-trial conditioning with a low-value host induced consolidation of a shorter-lasting memory form. For Cotesia glomerata, we subsequently identified this shorter-lasting memory form as anesthesia-resistant memory (ARM) because it was not sensitive to protein synthesis inhibitors or anesthesia. Associative conditioning using a single reward of different value thus induced a physiologically different mechanism of memory formation in this species. We conclude that the memory form that is consolidated does not only change in response to relatively large differences in conditioning, such as the number and type of conditioning trials, but is also sensitive to more subtle differences, such as reward value. Reward-dependent consolidation of exclusive ARM or LTM provides excellent opportunities for within-species comparison of mechanisms underlying memory consolidation. PMID- 22936972 TI - Vaccination with lipid core peptides fails to induce epitope-specific T cell responses but confers non-specific protective immunity in a malaria model. AB - Vaccines against many pathogens for which conventional approaches have failed remain an unmet public health priority. Synthetic peptide-based vaccines offer an attractive alternative to whole protein and whole organism vaccines, particularly for complex pathogens that cause chronic infection. Previously, we have reported a promising lipid core peptide (LCP) vaccine delivery system that incorporates the antigen, carrier, and adjuvant in a single molecular entity. LCP vaccines have been used to deliver several peptide subunit-based vaccine candidates and induced high titre functional antibodies and protected against Group A streptococcus in mice. Herein, we have evaluated whether LCP constructs incorporating defined CD4(+) and/or CD8(+) T cell epitopes could induce epitope specific T cell responses and protect against pathogen challenge in a rodent malaria model. We show that LCP vaccines failed to induce an expansion of antigen specific CD8(+) T cells following primary immunization or by boosting. We further demonstrated that the LCP vaccines induced a non-specific type 2 polarized cytokine response, rather than an epitope-specific canonical CD8(+) T cell type 1 response. Cytotoxic responses of unknown specificity were also induced. These non specific responses were able to protect against parasite challenge. These data demonstrate that vaccination with lipid core peptides fails to induce canonical epitope-specific T cell responses, at least in our rodent model, but can nonetheless confer non-specific protective immunity against Plasmodium parasite challenge. PMID- 22936973 TI - Measuring the maturity of the fast-spiking interneuron transcriptional program in autism, schizophrenia, and bipolar disorder. AB - BACKGROUND: Emerging evidence suggests that fast-spiking (FS) interneurons are disrupted in multiple neuropsychiatric disorders including autism, schizophrenia, and bipolar disorder. FS cells, which are the primary source of synaptic inhibition, are critical for temporally organizing brain activity, regulating brain maturation, and modulating critical developmental periods in multiple cortical systems. Reduced expression of parvalbumin, a marker of mature FS cells, has been reported in individuals with schizophrenia and bipolar disorder and in mouse models of schizophrenia and autism. Although these results suggest that FS cells may be immature in neuropsychiatric disease, this possibility had not previously been formally assessed. METHODS: This study used time-course global expression data from developing FS cells to create a maturation index that tracked with the developmental age of purified cortical FS cells. The FS cell maturation index was then applied to global gene expression data from human cortex to estimate the maturity of the FS cell developmental program in the context of various disease states. Specificity of the index for FS cells was supported by a highly significant correlation of maturation index measurements with parvalbumin expression levels that withstood correction for multiple covariates. CONCLUSIONS: Results suggest the FS cell developmental gene expression program is immature in autism, schizophrenia, and bipolar disorder. More broadly, the current study indicates that cell-type specific maturation indices can be used to measure the maturity of developmental programs even in data from mixed cell types such as those found in brain homogenates. PMID- 22936974 TI - Association between activity space exposure to food establishments and individual risk of overweight. AB - OBJECTIVE: Environmental exposure to food sources may underpin area level differences in individual risk for overweight. Place of residence is generally used to assess neighbourhood exposure. Yet, because people are mobile, multiple exposures should be accounted for to assess the relation between food environments and overweight. Unfortunately, mobility data is often missing from health surveys. We hereby test the feasibility of linking travel survey data with food listings to derive food store exposure predictors of overweight among health survey participants. METHODS: Food environment exposure measures accounting for non-residential activity places (activity spaces) were computed and modelled in Montreal and Quebec City, Canada, using travel surveys and food store listings. Models were then used to predict activity space food exposures for 5,578 participants of the Canadian Community Health Survey. These food exposure estimates, accounting for daily mobility, were used to model self-reported overweight in a multilevel framework. Median Odd Ratios were used to assess the proportion of between-neighborhood variance explained by such food exposure predictors. RESULTS: Estimates of food environment exposure accounting for both residential and non-residential destinations were significantly and more strongly associated with overweight than residential-only measures of exposure for men. For women, residential exposures were more strongly associated with overweight than non-residential exposures. In Montreal, adjusted models showed men in the highest quartile of exposure to food stores were at lesser risk of being overweight considering exposure to restaurants (OR = 0.36 [0.21-0.62]), fast food outlets (0.48 [0.30-0.79]), or corner stores (0.52 [0.35-0.78]). Conversely, men experiencing the highest proportion of restaurants being fast-food outlets were at higher risk of being overweight (2.07 [1.25-3.42]). Women experiencing higher residential exposures were at lower risk of overweight. CONCLUSION: Using residential neighbourhood food exposure measures may underestimate true exposure and observed associations. Using mobility data offers potential for deriving activity space exposure estimates in epidemiological models. PMID- 22936975 TI - Lung cancer mortality (1950-1999) among Eldorado uranium workers: a comparison of models of carcinogenesis and empirical excess risk models. AB - Lung cancer mortality after exposure to radon decay products (RDP) among 16,236 male Eldorado uranium workers was analyzed. Male workers from the Beaverlodge and Port Radium uranium mines and the Port Hope radium and uranium refinery and processing facility who were first employed between 1932 and 1980 were followed up from 1950 to 1999. A total of 618 lung cancer deaths were observed. The analysis compared the results of the biologically-based two-stage clonal expansion (TSCE) model to the empirical excess risk model. The spontaneous clonal expansion rate of pre-malignant cells was reduced at older ages under the assumptions of the TSCE model. Exposure to RDP was associated with increase in the clonal expansion rate during exposure but not afterwards. The increase was stronger for lower exposure rates. A radiation-induced bystander effect could be a possible explanation for such an exposure response. Results on excess risks were compared to a linear dose-response parametric excess risk model with attained age, time since exposure and dose rate as effect modifiers. In all models the excess relative risk decreased with increasing attained age, increasing time since exposure and increasing exposure rate. Large model uncertainties were found in particular for small exposure rates. PMID- 22936976 TI - Using liposomes as carriers for polyphenolic compounds: the case of trans resveratrol. AB - Resveratrol (3,5,4'-trihydroxy-trans-stilbene) is a polyphenol found in various plants, especially in the skin of red grapes. The effect of resveratrol on human health is the topic of numerous studies. In fact this molecule has shown anti cancer, anti-inflammatory, blood-sugar-lowering ability and beneficial cardiovascular effects. However, for many polyphenol compounds of natural origin bioavailability is limited by low solubility in biological fluids, as well as by rapid metabolization in vivo. Therefore, appropriate carriers are required to obtain efficient therapeutics along with low administration doses.Liposomes are excellent candidates for drug delivery purposes, due to their biocompatibility, wide choice of physico-chemical properties and easy preparation.In this paper liposome formulations made by a saturated phosphatidyl-choline (DPPC) and cholesterol (or its positively charged derivative DC-CHOL) were chosen to optimize the loading of a rigid hydrophobic molecule such as resveratrol.Plain and resveratrol loaded liposomes were characterized for size, surface charge and structural details by complementary techniques, i.e. Dynamic Light Scattering (DLS), Zeta potential and Small Angle X-ray Scattering (SAXS). Nuclear and Electron Spin magnetic resonances (NMR and ESR, respectively) were also used to gain information at the molecular scale.The obtained results allowed to give an account of loaded liposomes in which resveratrol interacted with the bilayer, being more deeply inserted in cationic liposomes than in zwitterionic liposomes. Relevant properties such as the mean size and the presence of oligolamellar structures were influenced by the loading of RESV guest molecules.The toxicity of all these systems was tested on stabilized cell lines (mouse fibroblast NIH-3T3 and human astrocytes U373-MG), showing that cell viability was not affected by the administration of liposomial resveratrol. PMID- 22936977 TI - Acutely decreased thermoregulatory energy expenditure or decreased activity energy expenditure both acutely reduce food intake in mice. AB - Despite the suggestion that reduced energy expenditure may be a key contributor to the obesity pandemic, few studies have tested whether acutely reduced energy expenditure is associated with a compensatory reduction in food intake. The homeostatic mechanisms that control food intake and energy expenditure remain controversial and are thought to act over days to weeks. We evaluated food intake in mice using two models of acutely decreased energy expenditure: 1) increasing ambient temperature to thermoneutrality in mice acclimated to standard laboratory temperature or 2) exercise cessation in mice accustomed to wheel running. Increasing ambient temperature (from 21 degrees C to 28 degrees C) rapidly decreased energy expenditure, demonstrating that thermoregulatory energy expenditure contributes to both light cycle (40 +/- 1%) and dark cycle energy expenditure (15 +/- 3%) at normal ambient temperature (21 degrees C). Reducing thermoregulatory energy expenditure acutely decreased food intake primarily during the light cycle (65 +/- 7%), thus conflicting with the delayed compensation model, but did not alter spontaneous activity. Acute exercise cessation decreased energy expenditure only during the dark cycle (14 +/- 2% at 21 degrees C; 21 +/- 4% at 28 degrees C), while food intake was reduced during the dark cycle (0.9 +/- 0.1 g) in mice housed at 28 degrees C, but during the light cycle (0.3 +/- 0.1 g) in mice housed at 21 degrees C. Cumulatively, there was a strong correlation between the change in daily energy expenditure and the change in daily food intake (R(2) = 0.51, p<0.01). We conclude that acutely decreased energy expenditure decreases food intake suggesting that energy intake is regulated by metabolic signals that respond rapidly and accurately to reduced energy expenditure. PMID- 22936978 TI - A novel porcine circovirus-like agent P1 is associated with wasting syndromes in pigs. AB - A novel porcine pathogen tentatively named P1, which was obtained from the sera of the pigs exhibiting clinical signs of postweaning multisystemic wasting syndrome (PMWS) experimentally caused the classical clinic signs and pathologic lesions of the disease in pigs by direct in vivo injection with P1 DNA plasmids. Twenty colostrum-fed (CF) pigs that were free of PCV2 and P1 at 1 month of age were randomly designated equally to two groups. Group 1 pigs were each injected with 400 ug of the cloned P1 plasmid DNA into the superficial inguinal lymph nodes and Group 2 were injected with same amount of the empty pSK vector DNA and served as controls. Viremias were positively detected in 8 of 10 P1 infected pigs from 14-21 days post-inoculation (dpi). The 8 infected animals showed pallor of skin and diarrhea. Gross lesions in the pigs euthanized on 35 dpi were similarly characterized by encephalemia, haemorrhage of the bladder mucosa, haemorrhage of the superficial inguinal lymph nodes, lung atrophy and haemorrhage. Histopathological lesions were arteriectasis and telangiectasia of the cavitas subarachnoidealis, interstitial pneumonia, mild atrophy of the cardiac muscle cells, histiocytic hyperplasia of the follicles in the tonsils, and haemorrhage of the inguinal lymph nodes. P1 DNA and antigens were confirmed by PCR and immunohistochemistry in the tissues and organs of the infected pigs, including the pancreas, bladders, testicles/ovaries, brains, lungs and liver. There were no obvious clinical signs and pathological lesions in the control pigs. This study demonstrated that P1 infection is one of the important pathologic agents on pig farms. PMID- 22936979 TI - Brain transcriptional responses to high-fat diet in Acads-deficient mice reveal energy sensing pathways. AB - BACKGROUND: How signals from fatty acid metabolism are translated into changes in food intake remains unclear. Previously we reported that mice with a genetic inactivation of Acads (acyl-coenzyme A dehydrogenase, short-chain), the enzyme responsible for mitochondrial beta-oxidation of C4-C6 short-chain fatty acids (SCFAs), shift consumption away from fat and toward carbohydrate when offered a choice between diets. In the current study, we sought to indentify candidate genes and pathways underlying the effects of SCFA oxidation deficiency on food intake in Acads-/- mice. METHODOLOGY/PRINCIPAL FINDINGS: We performed a transcriptional analysis of gene expression in brain tissue of Acads-/- and Acads+/+ mice fed either a high-fat (HF) or low-fat (LF) diet for 2 d. Ingenuity Pathway Analysis revealed three top-scoring pathways significantly modified by genotype or diet: oxidative phosphorylation, mitochondrial dysfunction, and CREB signaling in neurons. A comparison of statistically significant responses in HF Acads-/- vs. HF Acads+/+ (3917) and Acads+/+ HF vs. LF Acads+/+ (3879) revealed 2551 genes or approximately 65% in common between the two experimental comparisons. All but one of these genes were expressed in opposite direction with similar magnitude, demonstrating that HF-fed Acads-deficient mice display transcriptional responses that strongly resemble those of Acads+/+ mice fed LF diet. Intriguingly, genes involved in both AMP-kinase regulation and the neural control of food intake followed this pattern. Quantitative RT-PCR in hypothalamus confirmed the dysregulation of genes in these pathways. Western blotting showed an increase in hypothalamic AMP-kinase in Acads-/- mice and HF diet increased, a key protein in an energy-sensing cascade that responds to depletion of ATP. CONCLUSIONS: Our results suggest that the decreased beta-oxidation of short-chain fatty acids in Acads-deficient mice fed HF diet produces a state of energy deficiency in the brain and that AMP-kinase may be the cellular energy-sensing mechanism linking fatty acid oxidation to feeding behavior in this model. PMID- 22936980 TI - Structure of the Children's Revised Impact of Event Scale (CRIES) with children and adolescents exposed to debris flood. AB - AIM: PTSD symptoms were pervasive among children and adolescents after experiencing or exposure to traumatic events. Screening and diagnosis of PTSD symptoms is crucial in trauma-related research and practice. The 13-item Children's Revised Impact of Event Scale (CRIES) has been demonstrated to be a valid and reliable tool to achieve this goal. This study was designed to examine the psychometric properties of the 13-item CRIES in a sample of Chinese debris flood victims. METHODS: A total of 268 participants (145 girls, 123 boys) aged 8 18 years were recruited from an integral part of a service oriented project, supported by the Institute of Psychology, Chinese Academy of Sciences following the debris flood. The participants were given the 13-item CRIES 3 months after the debris flood. RESULTS: The results of confirmatory factor analysis indicated that a two-factor structure (intrusion+arousal vs avoidance) emerged as the model best fit in total sample, boys and girls subsamples, respectively. The scale was also demonstrated to have good internal consistency (Cronbach's alpha = 0.83). CONCLUSION: The study confirmed the good psychometric properties of the CRIES and its' applicability to Chinese children and adolescents. Moreover, these findings imply that the CRIES factor structure is stable across age, gender, and different types of trauma. PMID- 22936981 TI - No evidence of the effect of the interventions to combat health care fraud and abuse: a systematic review of literature. AB - BACKGROUND: Despite the importance of health care fraud and the political, legislative and administrative attentions paid to it, combating fraud remains a challenge to the health systems. We aimed to identify, categorize and assess the effectiveness of the interventions to combat health care fraud and abuse. METHODS: The interventions to combat health care fraud can be categorized as the interventions for 'prevention' and 'detection' of fraud, and 'response' to fraud. We conducted sensitive search strategies on Embase, CINAHL, and PsycINFO from 1975 to 2008, and Medline from 1975-2010, and on relevant professional and organizational websites. Articles assessing the effectiveness of any intervention to combat health care fraud were eligible for inclusion in our review. We considered including the interventional studies with or without a concurrent control group. Two authors assessed the studies for inclusion, and appraised the quality of the included studies. As a limited number of studies were found, we analyzed the data using narrative synthesis. FINDINGS: The searches retrieved 2229 titles, of which 221 full-text studies were assessed. We found no studies using an RCT design. Only four original articles (from the US and Taiwan) were included: two studies within the detection category, one in the response category, one under the detection and response categories, and no studies under the prevention category. The findings suggest that data-mining may improve fraud detection, and legal interventions as well as investment in anti-fraud activities may reduce fraud. DISCUSSION: Our analysis shows a lack of evidence of effect of the interventions to combat health care fraud. Further studies using robust research methodologies are required in all aspects of dealing with health care fraud and abuse, assessing the effectiveness and cost-effectiveness of methods to prevent, detect, and respond to fraud in health care. PMID- 22936982 TI - Early keratectomy in the treatment of moderate Fusarium keratitis. AB - PURPOSE: To evaluate the treatment outcomes and costs of early keratectomy in the management of moderate Fusarium keratitis. METHODOLOGY/PRINCIPAL FINDINGS: Consecutive cases of culture proven Fusarium keratitis treated at our hospital between January 2004 to December 2010 were included in this retrospective study. There were 38 cases of moderate keratitis with infiltrates between 3 to 6 mm in diameter and depth of infiltration not exceeding the inner 1/3 of the cornea. After excluding 5 patients with incomplete follow-up data, 13 patients who received early keratectomy within 1 week of admission were compared with a group of 20 patients treated medically. The significance of the association between early keratectomy and visual acuity, progression to perforation, secondary glaucoma and cataract formation, adjuvant therapy, hospitalization days and cost were assessed. There were no differences between the keratectomy and medication groups in regards to age, sex, presence of systemic diseases, and hypopyon formation on presentation. The early keratectomy group had a shorter hospital stay than the medical therapy group. Disease duration was significantly lower in the early keratectomy group (median: 29.0 vs. 54.5 days, P<0.001). Median hospitalization costs per patient were lower with early keratectomy (mean ward fee: 15175.4 vs. 44159.5 NTD, P<0.001; mean donor fee: 0 vs. 900.0 NTD, P<0.001), primarily because of reductions in hospital stay. More patients in the medication group developed perforations than in the keratectomy group (20% vs. 0%, respectively) and the perforation-free rate was higher in those with early keratectomy, but the results were not statistically significant. CONCLUSIONS/SIGNIFICANCE: Early keratectomy in moderate Fusarium keratitis may reduce length of hospital stay, hospital costs, and perforation rates. PMID- 22936983 TI - Exposure to heavy ion radiation induces persistent oxidative stress in mouse intestine. AB - Ionizing radiation-induced oxidative stress is attributed to generation of reactive oxygen species (ROS) due to radiolysis of water molecules and is short lived. Persistent oxidative stress has also been observed after radiation exposure and is implicated in the late effects of radiation. The goal of this study was to determine if long-term oxidative stress in freshly isolated mouse intestinal epithelial cells (IEC) is dependent on radiation quality at a dose relevant to fractionated radiotherapy. Mice (C57BL/6J; 6 to 8 weeks; female) were irradiated with 2 Gy of gamma-rays, a low-linear energy transfer (LET) radiation, and intestinal tissues and IEC were collected 1 year after radiation exposure. Intracellular ROS, mitochondrial function, and antioxidant activity in IEC were studied by flow cytometry and biochemical assays. Oxidative DNA damage, cell death, and mitogenic activity in IEC were assessed by immunohistochemistry. Effects of gamma radiation were compared to (56)Fe radiation (iso-toxic dose: 1.6 Gy; energy: 1000 MeV/nucleon; LET: 148 keV/um), we used as representative of high LET radiation, since it's one of the important sources of high Z and high energy (HZE) radiation in cosmic rays. Radiation quality affected the level of persistent oxidative stress with higher elevation of intracellular ROS and mitochondrial superoxide in high-LET (56)Fe radiation compared to unirradiated controls and gamma radiation. NADPH oxidase activity, mitochondrial membrane damage, and loss of mitochondrial membrane potential were greater in (56)Fe irradiated mice. Compared to gamma radiation oxidative DNA damage was higher, cell death ratio was unchanged, and mitotic activity was increased after (56)Fe radiation. Taken together our results indicate that long-term functional dysregulation of mitochondria and increased NADPH oxidase activity are major contributing factors towards heavy ion radiation-induced persistent oxidative stress in IEC with potential for neoplastic transformation. PMID- 22936984 TI - The B-MYB transcriptional network guides cell cycle progression and fate decisions to sustain self-renewal and the identity of pluripotent stem cells. AB - Embryonic stem cells (ESCs) are pluripotent and have unlimited self-renewal capacity. Although pluripotency and differentiation have been examined extensively, the mechanisms responsible for self-renewal are poorly understood and are believed to involve an unusual cell cycle, epigenetic regulators and pluripotency-promoting transcription factors. Here we show that B-MYB, a cell cycle regulated phosphoprotein and transcription factor critical to the formation of inner cell mass, is central to the transcriptional and co-regulatory networks that sustain normal cell cycle progression and self-renewal properties of ESCs. Phenotypically, B-MYB is robustly expressed in ESCs and induced pluripotent stem cells (iPSCs), and it is present predominantly in a hypo-phosphorylated state. Knockdown of B-MYB results in functional cell cycle abnormalities that involve S, G2 and M phases, and reduced expression of critical cell cycle regulators like ccnb1 and plk1. By conducting gene expression profiling on control and B-MYB deficient cells, ChIP-chip experiments, and integrative computational analyses, we unraveled a highly complex B-MYB-mediated transcriptional network that guides ESC self-renewal. The network encompasses critical regulators of all cell cycle phases and epigenetic regulators, pluripotency transcription factors, and differentiation determinants. B-MYB along with E2F1 and c-MYC preferentially co regulate cell cycle target genes. B-MYB also co-targets genes regulated by OCT4, SOX2 and NANOG that are significantly associated with stem cell differentiation, embryonic development, and epigenetic control. Moreover, loss of B-MYB leads to a breakdown of the transcriptional hierarchy present in ESCs. These results coupled with functional studies demonstrate that B-MYB not only controls and accelerates cell cycle progression in ESCs it contributes to fate decisions and maintenance of pluripotent stem cell identity. PMID- 22936985 TI - Rac-induced left ventricular dilation in thyroxin-treated ZmRacD transgenic mice: role of cardiomyocyte apoptosis and myocardial fibrosis. AB - The pathways inducing the critical transition from compensated hypertrophy to cardiac dilation and failure remain poorly understood. The goal of our study is to determine the role of Rac-induced signaling in this transition process. Our previous results showed that Thyroxin (T4) treatment resulted in increased myocardial Rac expression in wild-type mice and a higher level of expression in Zea maize RacD (ZmRacD) transgenic mice. Our current results showed that T4 treatment induced physiologic cardiac hypertrophy in wild-type mice, as demonstrated by echocardiography and histopathology analyses. This was associated with significant increases in myocardial Rac-GTP, superoxide and ERK1/2 activities. Conversely, echocardiography and histopathology analyses showed that T4 treatment induced dilated cardiomyopathy along with compensatory cardiac hypertrophy in ZmRacD mice. These were linked with further increases in myocardial Rac-GTP, superoxide and ERK1/2 activities. Additionally, there were significant increases in caspase-8 expression and caspase-3 activity. However, there was a significant decrease in p38-MAPK activity. Interestingly, inhibition of myocardial Rac-GTP activity and superoxide generation with pravastatin and carvedilol, respectively, attenuated all functional, structural, and molecular changes associated with the T4-induced cardiomyopathy in ZmRacD mice except the compensatory cardiac hypertrophy. Taken together, T4-induced ZmRacD is a novel mouse model of dilated cardiomyopathy that shares many characteristics with the human disease phenotype. To our knowledge, this is the first study to show graded Rac-mediated O(2).(-) results in cardiac phenotype shift in-vivo. Moreover, Rac mediated O(2).(-) generation, cardiomyocyte apoptosis, and myocardial fibrosis seem to play a pivotal role in the transition from cardiac hypertrophy to cardiac dilation and failure. Targeting Rac signaling could represent valuable therapeutic strategy not only in saving the failing myocardium but also to prevent this transition process. PMID- 22936986 TI - ZNF750 is expressed in differentiated keratinocytes and regulates epidermal late differentiation genes. AB - Disrupted skin barrier due to altered keratinocyte differentiation is common in pathologic conditions such as atopic dermatitis, ichthyosis and psoriasis. However, the molecular cascades governing keratinocyte terminal differentiation are poorly understood. We have previously demonstrated that a dominant mutation in ZNF750 leads to a clinical phenotype reminiscent of psoriasis and seborrheic dermatitis. Here we show that ZNF750 is a nuclear protein bearing a functional C terminal nuclear localization signal. ZNF750 was specifically expressed in the epidermal suprabasal layers and its expression was augmented during differentiation, both in human skin and in-vitro, peaking in the granular layer. Silencing of ZNF750 in Ca2+-induced HaCaT keratinocytes led to morphologically apparent arrest in the progression of late differentiation, as well as diminished apoptosis and sustained proliferation. ZNF750 knockdown cells presented with markedly reduced expression of epidermal late differentiation markers, including gene subsets of epidermal differentiation complex and skin barrier formation such as FLG, LOR, SPINK5, ALOX12B and DSG1, known to be mutated in various human skin diseases. Furthermore, overexpression of ZNF750 in undifferentiated cells induced terminal differentiation genes. Thus, ZNF750 is a regulator of keratinocyte terminal differentiation and with its downstream targets can serve in future elucidation of therapeutics for common diseases of skin barrier. PMID- 22936988 TI - Some clouds have a silver lining: paradoxes of anthropogenic perturbations from study cases on long-lived social birds. AB - In recent centuries and above all over the last few decades, human activities have generated perturbations (from mild to very severe or catastrophes) that, when added to those of natural origin, constitute a global threat to biodiversity. Predicting the effects of anthropogenic perturbations on species and communities is a great scientific challenge given the complexity of ecosystems and the need for detailed population data from both before and after the perturbations. Here we present three cases of well-documented anthropogenic severe perturbations (different forms of habitat loss and deterioration influencing fertility and survival) that have affected three species of birds (a raptor, a scavenger and a waterbird) for which we possess long-term population time series. We tested whether the perturbations caused serious population decline or whether the study species were resilient, that is, its population dynamics were relatively unaffected. Two of the species did decline, although to a relatively small extent with no shift to a state of lower population numbers. Subsequently, these populations recovered rapidly and numbers reached similar levels to before the perturbations. Strikingly, in the third species a strong breakpoint took place towards greater population sizes, probably due to the colonization of new areas by recruits that were queuing at the destroyed habitat. Even though it is difficult to draw patterns of resilience from only three cases, the study species were all long-lived, social species with excellent dispersal and colonization abilities, capable of skipping reproduction and undergoing a phase of significant long-term population increase. The search for such patterns is crucial for optimizing the limited resources allocated to conservation and for predicting the future impact of planned anthropogenic activities on ecosystems. PMID- 22936987 TI - Relaxin signals through a RXFP1-pERK-nNOS-NO-cGMP-dependent pathway to up regulate matrix metalloproteinases: the additional involvement of iNOS. AB - The hormone, relaxin, inhibits aberrant myofibroblast differentiation and collagen deposition by disrupting the TGF-beta1/Smad2 axis, via its cognate receptor, Relaxin Family Peptide Receptor 1 (RXFP1), extracellular signal regulated kinase (ERK)1/2 phosphorylation (pERK) and a neuronal nitric oxide (NO) synthase (nNOS)-NO-cyclic guanosine monophosphate (cGMP)-dependent pathway. However, the signalling pathways involved in its additional ability to increase matrix metalloproteinase (MMP) expression and activity remain unknown. This study investigated the extent to which the NO pathway was involved in human gene-2 (H2) relaxin's ability to positively regulate MMP-1 and its rodent orthologue, MMP-13, MMP-2 and MMP-9 (the main collagen-degrading MMPs) in TGF-beta1-stimulated human dermal fibroblasts and primary renal myofibroblasts isolated from injured rats; by gelatin zymography (media) and Western blotting (cell layer). H2 relaxin (10 100 ng/ml) significantly increased MMP-1 (by ~50%), MMP-2 (by ~80%) and MMP-9 (by ~80%) in TGF-beta1-stimulated human dermal fibroblasts; and MMP-13 (by ~90%), MMP 2 (by ~130%) and MMP-9 (by ~115%) in rat renal myofibroblasts (all p<0.01 vs untreated cells) over 72 hours. The relaxin-induced up-regulation of these MMPs, however, was significantly blocked by a non-selective NOS inhibitor (L nitroarginine methyl ester (hydrochloride); L-NAME; 75-100 uM), and specific inhibitors to nNOS (N-propyl-L-arginine; NPLA; 0.2-2 uM), iNOS (1400W; 0.5-1 uM) and guanylyl cyclase (ODQ; 5 uM) (all p<0.05 vs H2 relaxin alone), but not eNOS (L-N-(1-iminoethyl)ornithine dihydrochloride; L-NIO; 0.5-5 uM). However, neither of these inhibitors affected basal MMP expression at the concentrations used. Furthermore, of the NOS isoforms expressed in renal myofibroblasts (nNOS and iNOS), H2 relaxin only stimulated nNOS expression, which in turn, was blocked by the ERK1/2 inhibitor (PD98059; 1 uM). These findings demonstrated that H2 relaxin signals through a RXFP1-pERK-nNOS-NO-cGMP-dependent pathway to mediate its anti fibrotic actions, and additionally signals through iNOS to up-regulate MMPs; the latter being suppressed by TGF-beta1 in myofibroblasts, but released upon H2 relaxin-induced inhibition of the TGF-beta1/Smad2 axis. PMID- 22936989 TI - Contaminated small drinking water supplies and risk of infectious intestinal disease: a prospective cohort study. AB - BACKGROUND: This study sought to identify whether elevated risk of infectious intestinal disease (IID) exists in contaminated small water supply consumers compared with consumers drinking from small supplies complying with current standards and whether this effect is modified by age. METHODOLOGY AND PRINCIPAL FINDINGS: A prospective cohort study of 611 individuals receiving small supplies in England was conducted. Water supplies received sanitary inspection and examination for indicator bacteria and participants maintained a daily record of IID. Regression modeling with generalized estimating equations that included interaction terms between age and indicators of fecal pollution was performed. Crude IID prevalence was 9 . 3 days with symptoms/1000 person days (95%CI: 8 . 4, 10 . 1) and incidence was 3 . 2 episodes/1000 person days (95%CI, 2 . 7, 3 . 7) or 1 . 2 episodes per person year. Although there was no overall association between IID risk and indicator presence, there was strong interaction between age and indicator presence. In children under ten, relative risk (RR) of IID in those drinking from enterococci contaminated supplies was 4.8 (95%CI: 1.5, 15.3) for incidence and 8.9 (95%CI: 2.8, 27.5) for prevalence. In those aged 10 to 59, IID risk was lower but not statistically significant. CONCLUSIONS: Contaminated small water supplies pose a substantial risk of IID to young children who live in homes reliant on these supplies. By contrast older children and adults do not appear to be at increased risk. Health care professionals with responsibility for children living in homes provided by very small water supplies should make parents aware of the risk. PMID- 22936990 TI - Leu128(3.43) (l128) and Val247(6.40) (V247) of CXCR1 are critical amino acid residues for g protein coupling and receptor activation. AB - CXCR1, a classic GPCR that binds IL-8, plays a key role in neutrophil activation and migration by activating phospholipase C (PLC)beta through Galpha(15) and Galpha(i) which generates diacylglycerol and inositol phosphates (IPs). In this study, two conserved amino acid residues of CXCR1 on the transmembrane domain (TM) 3 and TM6, Leu128(3.43) (L128) and Val247(6.40) (V247), respectively, were selectively substituted with other amino acids to investigate the role of these conserved residues in CXCR1 activation. Although two selective mutants on Leu128, Leu128Ala (L128A) and Leu128Arg (L128R), demonstrated high binding affinity to IL 8, they were not capable of coupling to G proteins and consequently lost the functional response of the receptors. By contrast, among the four mutants at residue Val247 (TM6.40), replacing Val247 with Ala (V247A) and Asn (V247N) led to constitutive activation of mutant receptors when cotransfected with Galpha(15). The V247N mutant also constitutively activated the Galpha(i) protein. These results indicate that L128 on TM3.43 is involved in G protein coupling and receptor activation but is unimportant for ligand binding. On the other hand, V247 on TM6.40 plays a critical role in maintaining the receptor in the inactive state, and the substitution of V247 impaired the receptor constraint and stabilized an active conformation. Functionally, there was an increase in chemotaxis in response to IL-8 in cells expressing V247A and V247N. Our findings indicate that Leu128(3.43) and Val247(6.40) are critical for G protein coupling and activation of signaling effectors, providing a valuable insight into the mechanism of CXCR1 activation. PMID- 22936991 TI - BSim: an agent-based tool for modeling bacterial populations in systems and synthetic biology. AB - Large-scale collective behaviors such as synchronization and coordination spontaneously arise in many bacterial populations. With systems biology attempting to understand these phenomena, and synthetic biology opening up the possibility of engineering them for our own benefit, there is growing interest in how bacterial populations are best modeled. Here we introduce BSim, a highly flexible agent-based computational tool for analyzing the relationships between single-cell dynamics and population level features. BSim includes reference implementations of many bacterial traits to enable the quick development of new models partially built from existing ones. Unlike existing modeling tools, BSim fully considers spatial aspects of a model allowing for the description of intricate micro-scale structures, enabling the modeling of bacterial behavior in more realistic three-dimensional, complex environments. The new opportunities that BSim opens are illustrated through several diverse examples covering: spatial multicellular computing, modeling complex environments, population dynamics of the lac operon, and the synchronization of genetic oscillators. BSim is open source software that is freely available from http://bsim-bccs.sf.net and distributed under the Open Source Initiative (OSI) recognized MIT license. Developer documentation and a wide range of example simulations are also available from the website. BSim requires Java version 1.6 or higher. PMID- 22936992 TI - Drinking, substance use and the operation of motor vehicles by young adolescents in Canada. AB - BACKGROUND: Impaired driving is a recognized cause of major injury. Contemporary data are lacking on exposures to impaired driving behaviours and related injury among young adolescents, as well as inequities in these youth risk behaviours. METHODS AND FINDINGS: Cycle 6 (2009/10) of the Health Behaviour in School-Aged Children survey involved 26,078 students enrolled in 436 Canadian schools. We profiled cross-sectionally the reported use of alcohol, marijuana, or other illicit drugs by on-road and off-road vehicle operators when young adolescents (mean age 13.3 (+/- 1.6) years) were either driving or riding as a passenger. Comparisons were made across vulnerable subgroups. Multi-level logistic regression analyses were used to quantify the effects of the driving behaviours on risks for motor vehicle-related injury. Attributable risk fractions were also estimated. A total of 10% (+/- 3%) of participants reported recent operation of an on-road or off-road motor vehicle after consuming alcohol, marijuana, or other illicit drugs, while 21% (+/- 3%) reported riding as a passenger with a driver under the same conditions. Larger proportions of youth reporting these risk behaviours were males, and from older age groups, rural communities, and socio economically disadvantaged populations. The behaviours were consistently associated with increased risks for motor vehicle-related injury at the individual level (RR 2.35; 95% CI: 1.54 to 3.58 for frequent vs. no exposure as a driver; RR 1.68; 95% CI: 1.20 to 2.36 for frequent vs. no exposure as a passenger) and at the population level (Attributable Risk Fraction: 7.1% for drivers; 14.0% for passengers). The study was limited mainly by its reliance on self-reported data. CONCLUSION: Impaired driving is an important health priority among young adolescents in Canada. Inequities in the involvement of younger adolescents in these risk behaviours suggest the need for targeted interventions for specific subgroups such as youth from rural communities, and among socially disadvantaged populations. PMID- 22936994 TI - Microfabricated inserts for magic angle coil spinning (MACS) wireless NMR spectroscopy. AB - This article describes the development and testing of the first automatically microfabricated probes to be used in conjunction with the magic angle coil spinning (MACS) NMR technique. NMR spectroscopy is a versatile technique for a large range of applications, but its intrinsically low sensitivity poses significant difficulties in analyzing mass- and volume-limited samples. The combination of microfabrication technology and MACS addresses several well-known NMR issues in a concerted manner for the first time: (i) reproducible wafer-scale fabrication of the first-in-kind on-chip LC microresonator for inductive coupling of the NMR signal and reliable exploitation of MACS capabilities; (ii) improving the sensitivity and the spectral resolution by simultaneous spinning the detection microcoil together with the sample at the "magic angle" of 54.74 degrees with respect to the direction of the magnetic field (magic angle spinning - MAS), accompanied by the wireless signal transmission between the microcoil and the primary circuit of the NMR spectrometer; (iii) given the high spinning rates (tens of kHz) involved in the MAS methodology, the microfabricated inserts exhibit a clear kinematic advantage over their previously demonstrated counterparts due to the inherent capability to produce small radius cylindrical geometries, thus tremendously reducing the mechanical stress and tearing forces on the sample. In order to demonstrate the versatility of the microfabrication technology, we have designed MACS probes for various Larmor frequencies (194, 500 and 700 MHz) testing several samples such as water, Drosophila pupae, adamantane solid and LiCl at different magic angle spinning speeds. PMID- 22936993 TI - Mosquito feeding assays to determine the infectiousness of naturally infected Plasmodium falciparum gametocyte carriers. AB - INTRODUCTION: In the era of malaria elimination and eradication, drug-based and vaccine-based approaches to reduce malaria transmission are receiving greater attention. Such interventions require assays that reliably measure the transmission of Plasmodium from humans to Anopheles mosquitoes. METHODS: WE COMPARED TWO COMMONLY USED MOSQUITO FEEDING ASSAY PROCEDURES: direct skin feeding assays and membrane feeding assays. Three conditions under which membrane feeding assays are performed were examined: assays with i) whole blood, ii) blood pellets resuspended with autologous plasma of the gametocyte carrier, and iii) blood pellets resuspended with heterologous control serum. RESULTS: 930 transmission experiments from Cameroon, The Gambia, Mali and Senegal were included in the analyses. Direct skin feeding assays resulted in higher mosquito infection rates compared to membrane feeding assays (odds ratio 2.39, 95% confidence interval 1.94-2.95) with evident heterogeneity between studies. Mosquito infection rates in membrane feeding assays and direct skin feeding assays were strongly correlated (p<0.0001). Replacing the plasma of the gametocyte donor with malaria naive control serum resulted in higher mosquito infection rates compared to own plasma (OR 1.92, 95% CI 1.68-2.19) while the infectiousness of gametocytes may be reduced during the replacement procedure (OR 0.60, 95% CI 0.52-0.70). CONCLUSIONS: Despite a higher efficiency of direct skin feeding assays, membrane feeding assays appear suitable tools to compare the infectiousness between individuals and to evaluate transmission-reducing interventions. Several aspects of membrane feeding procedures currently lack standardization; this variability makes comparisons between laboratories challenging and should be addressed to facilitate future testing of transmission-reducing interventions. PMID- 22936995 TI - Estimating Plasmodium falciparum transmission rates in low-endemic settings using a combination of community prevalence and health facility data. AB - As some malaria control programs shift focus from disease control to transmission reduction, there is a need for transmission data to monitor progress. At lower levels of transmission, it becomes increasingly more difficult to measure precisely, for example through entomological studies. Many programs conduct regular cross sectional parasite prevalence surveys, and have access to malaria treatment data routinely collected by ministries of health, often in health management information systems. However, by themselves, these data are poor measures of transmission. In this paper, we propose an approach for combining annual parasite incidence and treatment data with cross-sectional parasite prevalence and treatment seeking survey data to estimate the incidence of new infections in the human population, also known as the force of infection. The approach is based on extension of a reversible catalytic model. The accuracy of the estimates from this model appears to be highly dependent on levels of detectability and treatment in the community, indicating the importance of information on private sector treatment seeking and access to effective and appropriate treatment. PMID- 22936996 TI - A survey of the FDA's AERS database regarding muscle and tendon adverse events linked to the statin drug class. AB - BACKGROUND: Cholesterol management drugs known as statins are widely used and often well tolerated; however, a variety of muscle-related side effects can arise. These adverse events (AEs) can have serious impact, and form a significant barrier to therapy adherence. Surveillance of post-marketing AEs is of vital importance to understand real-world AEs and reporting differences between individual statin drugs. We conducted a review of post-approval muscle and tendon AE reports in association with statin use, to assess differences within the drug class. METHODS: We analyzed all case reports from the FDA AE Reporting System (AERS) database linking muscle-related AEs to statin use (07/01/2005-03/31/2011). Drugs examined were: atorvastatin, simvastatin, lovastatin, pravastatin, rosuvastatin, and fluvastatin. RESULTS: Relative risk rates for rosuvastatin were consistently higher than other statins. Atorvastatin and simvastatin showed intermediate risks, while pravastatin and lovastatin appeared to have the lowest risk rates. Relative risk of muscle-related AEs, therefore, approximately tracked with per milligram LDL-lowering potency, with fluvastatin an apparent exception. Incorporating all muscle categories, rates for atorvastatin, simvastatin, pravastatin, and lovastatin were, respectively, 55%, 26%, 17%, and 7.5% as high, as rosuvastatin, approximately tracking per milligram potency (Rosuvastatin>Atorvastatin>Simvastatin>Pravastatin ~ Lovastatin) and comporting with findings of other studies. Relative potency, therefore, appears to be a fundamental predictor of muscle-related AE risk, with fluvastatin, the least potent statin, an apparent exception (risk 74% vs rosuvastatin). INTERPRETATION: AE reporting rates differed strikingly for drugs within the statin class, with relative reporting aligning substantially with potency. The data presented in this report offer important reference points for the selection of statins for cholesterol management in general and, especially, for the rechallenge of patients who have experienced muscle-related AEs (for whom agents of lower expected potency should be preferred). PMID- 22936997 TI - The niche factor syndecan-1 regulates the maintenance and proliferation of neural progenitor cells during mammalian cortical development. AB - Neural progenitor cells (NPCs) divide and differentiate in a precisely regulated manner over time to achieve the remarkable expansion and assembly of the layered mammalian cerebral cortex. Both intrinsic signaling pathways and environmental factors control the behavior of NPCs during cortical development. Heparan sulphate proteoglycans (HSPG) are critical environmental regulators that help modulate and integrate environmental cues and downstream intracellular signals. Syndecan-1 (Sdc1), a major transmembrane HSPG, is highly enriched in the early neural germinal zone, but its function in modulating NPC behavior and cortical development has not been explored. In this study we investigate the expression pattern and function of Sdc1 in the developing mouse cerebral cortex. We found that Sdc1 is highly expressed by cortical NPCs. Knockdown of Sdc1 in vivo by in utero electroporation reduces NPC proliferation and causes their premature differentiation, corroborated in isolated cells in vitro. We found that Sdc1 knockdown leads to reduced levels of beta-catenin, indicating reduced canonical Wnt signaling. Consistent with this, GSK3beta inhibition helps rescue the Sdc1 knockdown phenotype, partially restoring NPC number and proliferation. Moreover, exogenous Wnt protein promotes cortical NPC proliferation, but this is prevented by Sdc1 knockdown. Thus, Sdc1 in the germinal niche is a key HSPG regulating the maintenance and proliferation of NPCs during cortical neurogenesis, in part by modulating the ability of NPCs to respond to Wnt ligands. PMID- 22936998 TI - Phylogenomic resolution of paleozoic divergences in harvestmen (Arachnida, Opiliones) via analysis of next-generation transcriptome data. AB - Next-generation sequencing technologies are rapidly transforming molecular systematic studies of non-model animal taxa. The arachnid order Opiliones (commonly known as "harvestmen") includes more than 6,400 described species placed into four well-supported lineages (suborders). Fossil plus molecular clock evidence indicates that these lineages were diverging in the late Silurian to mid Carboniferous, with some fossil harvestmen representing the earliest known land animals. Perhaps because of this ancient divergence, phylogenetic resolution of subordinal interrelationships within Opiliones has been difficult. We present the first phylogenomics analysis for harvestmen, derived from comparative RNA-Seq data for eight species representing all suborders. Over 30 gigabases of original Illumina short-read data were used in de novo assemblies, resulting in 50-80,000 transcripts per taxon. Transcripts were compared to published scorpion and tick genomics data, and a stringent filtering process was used to identify over 350 putatively single-copy, orthologous protein-coding genes shared among taxa. Phylogenetic analyses using various partitioning strategies, data coding schemes, and analytical methods overwhelmingly support the "classical" hypothesis of Opiliones relationships, including the higher-level clades Palpatores and Phalangida. Relaxed molecular clock analyses using multiple alternative fossil calibration strategies corroborate ancient divergences within Opiliones that are possibly deeper than the recorded fossil record indicates. The assembled data matrices, comprising genes that are conserved, highly expressed, and varying in length and phylogenetic informativeness, represent an important resource for future molecular systematic studies of Opiliones and other arachnid groups. PMID- 22936999 TI - Semaphorin-3D and semaphorin-3E inhibit the development of tumors from glioblastoma cells implanted in the cortex of the brain. AB - Class-3 semaphorins are secreted axon guidance factors. Some of these semaphorins have recently been characterized as suppressors of tumor progression. To determine if class-3 semaphorins can be used to inhibit the development of glioblastoma-multiforme tumors, we expressed recombinant sema-3A, 3B, 3D, 3E, 3F or 3G in U87MG glioblastoma cells. Sema3A and sema3B expressing cells contracted and changed shape persistently while cells expressing other semaphorins did not. Sema3A and sema3F differed from other semaphorins including sema3B as they also inhibited the proliferation of the cells and the formation of soft agar colonies. With the exception of sema3G and sema3B, expression of these semaphorins in U87MG cells inhibited significantly tumor development from subcutaneously implanted cells. Strong inhibition of tumor development was also observed following implantation of U87MG cells expressing each of the class-3 semaphorins in the cortex of mouse brains. Sema3D and sema3E displayed the strongest inhibitory effects and their expression in U373MG or in U87MG glioblastoma cells implanted in the brains of mice prolonged the survival of the mice by more then two folds. Furthermore, most of the mice that died prior to the end of the experiment did not develop detectable tumors and many of the mice survived to the end of the experiment. Most of the semaphorins that we have used here with the exception of sema3D were characterized previously as inhibitors of angiogenesis. Our results indicate that sema3D also functions as an inhibitor of angiogenesis and suggest that the anti-tumorigenic effects are due primarily to inhibition of tumor angiogenesis. These results indicate that class-3 semaphorins such as sema3D and sema3E could perhaps be used to treat glioblastoma patients. PMID- 22937000 TI - The co-selection of fluoroquinolone resistance genes in the gut flora of Vietnamese children. AB - Antimicrobial consumption is one of the major contributing factors facilitating the development and maintenance of bacteria exhibiting antimicrobial resistance. Plasmid-mediated quinolone resistance (PMQR) genes, such as the qnr family, can be horizontally transferred and contribute to reduced susceptibility to fluoroquinolones. We performed an observational study, investigating the copy number of PMQR after antimicrobial therapy. We enrolled 300 children resident in Ho Chi Minh City receiving antimicrobial therapy for acute respiratory tract infections (ARIs). Rectal swabs were taken on enrollment and seven days subsequently, counts for Enterobacteriaceae were performed and qnrA, qnrB and qnrS were quantified by using real-time PCR on metagenomic stool DNA. On enrollment, we found no association between age, gender or location of the participants and the prevalence of qnrA, qnrB or qnrS. Yet, all three loci demonstrated a proportional increase in the number of samples testing positive between day 0 and day 7. Furthermore, qnrB demonstrated a significant increase in copy number between paired samples (p<0.001; Wilcoxon rank-sum), associated with non-fluoroquinolone combination antimicrobial therapy. To our knowledge, this is the first study describing an association between the use of non-fluoroquinolone antimicrobials and the increasing relative prevalence and quantity of qnr genes. Our work outlines a potential mechanism for the selection and maintenance of PMQR genes and predicts a strong effect of co-selection of these resistance determinants through the use of unrelated and potentially unnecessary antimicrobial regimes. PMID- 22937001 TI - The modulating effect of personality traits on neural error monitoring: evidence from event-related FMRI. AB - The present study investigated the association between traits of the Five Factor Model of Personality (Neuroticism, Extraversion, Openness for Experiences, Agreeableness, and Conscientiousness) and neural correlates of error monitoring obtained from a combined Eriksen-Flanker-Go/NoGo task during event-related functional magnetic resonance imaging in 27 healthy subjects. Individual expressions of personality traits were measured using the NEO-PI-R questionnaire. Conscientiousness correlated positively with error signaling in the left inferior frontal gyrus and adjacent anterior insula (IFG/aI). A second strong positive correlation was observed in the anterior cingulate gyrus (ACC). Neuroticism was negatively correlated with error signaling in the inferior frontal cortex possibly reflecting the negative inter-correlation between both scales observed on the behavioral level. Under present statistical thresholds no significant results were obtained for remaining scales. Aligning the personality trait of Conscientiousness with task accomplishment striving behavior the correlation in the left IFG/aI possibly reflects an inter-individually different involvement whenever task-set related memory representations are violated by the occurrence of errors. The strong correlations in the ACC may indicate that more conscientious subjects were stronger affected by these violations of a given task set expressed by individually different, negatively valenced signals conveyed by the ACC upon occurrence of an error. Present results illustrate that for predicting individual responses to errors underlying personality traits should be taken into account and also lend external validity to the personality trait approach suggesting that personality constructs do reflect more than mere descriptive taxonomies. PMID- 22937002 TI - Is prnt a pseudogene? Identification of ram Prt in testis and ejaculated spermatozoa. AB - A hallmark of prion diseases or transmissible spongiform encephalopaties is the conversion of the cellular prion protein (PrP(C)), expressed by the prion gene (prnp), into an abnormally folded isoform (PrP(Sc)) with amyloid-like features that causes scrapie in sheep among other diseases. prnp together with prnd (which encodes a prion-like protein designated as Doppel), and prnt (that encodes the prion protein testis specific--Prt) with sprn (shadow of prion protein gene, that encodes Shadoo or Sho) genes, constitute the "prion gene complex". Whereas a role for prnd in the proper functioning of male reproductive system has been confirmed, the function of prnt, a recently discovered prion family gene, comprises a conundrum leading to the assumption that ruminant prnt is a pseudogene with no protein expression. The main objective of the present study was to identify Prt localization in the ram reproductive system and simultaneously to elucidate if ovine prnt gene is transcribed into protein-coding RNA. Moreover, as Prt is a prnp-related protein, the amyloid propensity was also tested for ovine and caprine Prt. Recombinant Prt was used to immunize BALB/c mice, and the anti-Prt polyclonal antibody (APPA) immune response was evaluated by ELISA and Western Blot. When tested by indirect immunofluorescence, APPA showed high avidity to the ram sperm head apical ridge subdomain, before and after induced capacitation, but did not show the same behavior against goat spermatozoa, suggesting high antibody specificity against ovine-Prt. Prt was also found in the testis when assayed by immunohistochemistry during ram spermatogenesis, where spermatogonia, spermatocytes, spermatids and spermatozoa, stained positive. These observations strongly suggest ovine prnt to be a translated protein-coding gene, pointing to a role for Prt protein in the ram reproductive physiology. Besides, caprine Prt appears to exhibit a higher amyloid propensity than ovine Prt, mostly associated with its phenylalanine residue. PMID- 22937003 TI - A detailed modular analysis of heat-shock protein dynamics under acute and chronic stress and its implication in anxiety disorders. AB - Physiological and psychological stresses cause anxiety disorders such as depression and post-traumatic stress disorder (PTSD) and induce drastic changes at a molecular level in the brain. To counteract this stress, the heat-shock protein (HSP) network plays a vital role in restoring the homeostasis of the system. To study the stress-induced dynamics of heat-shock network, we analyzed three modules of the HSP90 network--namely trimerization reactions, phosphorylation-dephosphorylation reactions, and the conversion of HSP90 from an open to a closed conformation--and constructed a corresponding nonlinear differential equation model based on mass action kinetics laws. The kinetic parameters of the model were obtained through global optimization, and sensitivity analyses revealed that the most sensitive parameters are the kinase and phosphatase that drive the phosphorylation-dephosphorylation reactions. Bifurcation analysis carried out with the estimated kinetic parameters of the model with stress as bifurcation parameter revealed the occurrence of "mushroom", a type of complex dynamics in which S-shaped and Z-shaped hysteretic bistable forms are present together. We mapped the molecular events responsible for generating the mushroom dynamics under stress and interpreted the occurrence of the S-shaped hysteresis to a normal level of stress, and the Z-shaped hysteresis to the HSP90 variations under acute and chronic stress in the fear conditioned system, and further, we hypothesized that this can be extended to stress-related disorders such as depression and PTSD in humans. Finally, we studied the effect of parameter variations on the mushroom dynamics to get insight about the role of phosphorylation-dephosphorylation parameters in HSP90 network in bringing about complex dynamics such as isolas, where the stable steady states in a bistable system are isolated and separated from each other and not connected by an unstable steady state. PMID- 22937004 TI - Effects of altered catecholamine metabolism on pigmentation and physical properties of sclerotized regions in the silkworm melanism mutant. AB - Catecholamine metabolism plays an important role in the determination of insect body color and cuticle sclerotization. To date, limited research has focused on these processes in silkworm. In the current study, we analyzed the interactions between catecholamines and melanin genes and their effects on the pigmentation patterns and physical properties of sclerotized regions in silkworm, using the melanic mutant melanism (mln) silkworm strain as a model. Injection of beta alanine into mln mutant silkworm induced a change in catecholamine metabolism and turned its body color yellow. Further investigation of the catecholamine content and expression levels of the corresponding melanin genes from different developmental stages of Dazao-mln (mutant) and Dazao (wild-type) silkworm revealed that at the larval and adult stages, the expression patterns of melanin genes precipitated dopamine accumulation corresponding to functional loss of Bm iAANAT, a repressive effect of excess NBAD on ebony, and upregulation of tan in the Dazao-mln strain. During the early pupal stage, dopamine did not accumulate in Dazao-mln, since upregulation of ebony and black genes led to conversion of high amounts of dopamine into NBAD, resulting in deep yellow cuticles. Scanning electron microscope analysis of a cross-section of adult dorsal plates from both wild-type and mutant silkworm disclosed the formation of different layers in Dazao-mln owing to lack of NADA, compared to even and dense layers in Dazao. Analysis of the mechanical properties of the anterior wings revealed higher storage modulus and lower loss tangent in Dazao-mln, which was closely associated with the altered catecholamine metabolism in the mutant strain. Based on these findings, we conclude that catecholamine metabolism is crucial for the color pattern and physical properties of cuticles in silkworm. Our results should provide a significant contribution to Lepidoptera cuticle tanning research. PMID- 22937005 TI - Island evolution and systematic revision of Comoran snakes: why and when subspecies still make sense. AB - Species delimitation and species concepts have been a matter of debate among biodiversity researchers in the last decades, resulting in integrative taxonomy approaches and the use of modern species concepts, such as the phylogenetic, evolutionary or general lineage species concepts. The discussion of subspecies status and concepts has been addressed much less extensively, with some researchers completely refraining from recognizing subspecies. However, allopatric insular populations that are particularly differentiated have traditionally been assigned subspecies status. We studied the molecular phylogeny and morphology of endemic Comoran tree snakes of the genus Lycodryas. Taking an integrative taxonomic approach, we used the concept of independent lines of evidence to discriminate between evidence for specific and subspecific status. Molecular (mtDNA) and morphological data provided sufficient evidence to support four different taxa within Comoran Lycodryas. In a revision of this group, we propose two species, each with two subspecies. We present a discussion of the strong sexual dichromatism unique to Comoran Lycodryas within the genus and related genera that may be explained by sexual selection in combination with the absence of major predators. Then, we discuss the effects of insular evolution and the "island rule" on morphological traits in Comoran Lycodryas and in Liophidium mayottensis, another snake endemic to the Comoros. The absence of larger-bodied snakes may have promoted an increase in body size and the number of dorsal scale rows in these species. Finally, we discuss the subspecies concept, its applications and its significance for integrative taxonomy and for limiting taxonomic inflation. We emphasize that taxon descriptions should be based on an integrative approach using several lines of evidence, preferably in combination with statements on the underlying species concepts or operational criteria, to increase the objectivity and comparability of descriptions. PMID- 22937006 TI - Inducible microRNA-223 down-regulation promotes TLR-triggered IL-6 and IL-1beta production in macrophages by targeting STAT3. AB - MicroRNAs are small non-coding RNA molecules that regulate gene expression by either translational inhibition or mRNA degradation. MicroRNAs play pivotal roles in the regulation of both innate and adaptive immune responses, including TLR triggered inflammatory response. Here we reported that the expression of microRNA 223 (miR-223) was significantly decreased in murine macrophages during activation by lipopolysaccharide (LPS) or poly (I?C) stimulation. The inducible miR-223 down regulation resulted in the activation of signal transducer and activator of transcription 3 (STAT3), which is directly targeted by miR-223, thus promoting the production of pro-inflammatory cytokines IL-6 and IL-1beta, but not TNF alpha. Interestingly, IL-6 was found to be a main factor in inducing the decrease in miR-223 expression after LPS stimulation, which formed a positive feedback loop to regulate IL-6 and IL-1beta. Herein, our findings provide a new explanation characterizing the molecular mechanism responsible for the regulation of IL-6 production after TLR-triggered macrophage activation. PMID- 22937007 TI - HDAC6 inhibitor blocks amyloid beta-induced impairment of mitochondrial transport in hippocampal neurons. AB - Even though the disruption of axonal transport is an important pathophysiological factor in neurodegenerative diseases including Alzheimer's disease (AD), the relationship between disruption of axonal transport and pathogenesis of AD is poorly understood. Considering that alpha-tubulin acetylation is an important factor in axonal transport and that Abeta impairs mitochondrial axonal transport, we manipulated the level of alpha-tubulin acetylation in hippocampal neurons with Abeta cultured in a microfluidic system and examined its effect on mitochondrial axonal transport. We found that inhibiting histone deacetylase 6 (HDAC6), which deacetylates alpha-tubulin, significantly restored the velocity and motility of the mitochondria in both anterograde and retrograde axonal transports, which would be otherwise compromised by Abeta. The inhibition of HDAC6 also recovered the length of the mitochondria that had been shortened by Abeta to a normal level. These results suggest that the inhibition of HDAC6 significantly rescues hippocampal neurons from Abeta-induced impairment of mitochondrial axonal transport as well as mitochondrial length. The results presented in this paper identify HDAC6 as an important regulator of mitochondrial transport as well as elongation and, thus, a potential target whose pharmacological inhibition contributes to improving mitochondrial dynamics in Abeta treated neurons. PMID- 22937008 TI - Clonal expansion of both modern and ancient genotypes of Mycobacterium tuberculosis in southern Taiwan. AB - We present the first comprehensive analysis of Mycobacterium tuberculosis isolates circulating in the Kaohsiung region of southern Taiwan. The major spoligotypes found in the 224 isolates studied were Beijing lineages (n = 97; 43.3%), EAI lineages (n = 72; 32.1%) and Haarlem lineages (n = 18; 8.0%). By 24 MIRU-VNTR typing, 174 patterns were identified, including 24 clusters of 74 isolates and 150 unique patterns. The combination of spoligotyping and 12-MIRU VNTR revealed that 129 (57.6%) of the 224 isolates were clustered in 18 genotypes. Moreover, 63.6% (7/11) of infected persons younger than 30 years had a Beijing strain, which could suggest recent spread among younger persons by this family of TB strains in Kaohsiung. Among the 94 Beijing family (SIT1, SIT250 and SIT1674) isolates further analyzed for SNPs by mass spectrometry, the most frequent strain found was ST10 (n = 49; 52%), followed by ST22 (n = 17; 18%) and ST19 (n = 11; 12%). Among the EAI-Manila family isolates analyzed by region deletion-based subtyping, the most frequent strain found was RD type 1 (n = 63; 87.5%), followed by RD type 2 (n = 9; 12.5%). In our previous study, the proportion of modern Beijing strains (52.5%) in northern Taiwan was significantly higher than the proportion of EAI strains (11%). In contrast, in the present study, EAI strains comprised up to 32% of Beijing strains in southern Taiwan. In conclusion, both 'modern' (Beijing) and 'ancient' (EAI) M. tuberculosis strains are prevalent in the Kaohsiung region, perhaps suggesting that both strains are somehow more adapted to southern Taiwan. It will be interesting to investigate the dynamics of the lineage composition by different selection pressures. PMID- 22937009 TI - A putative gene sbe3-rs for resistant starch mutated from SBE3 for starch branching enzyme in rice (Oryza sativa L.). AB - Foods high in resistant starch (RS) are beneficial to prevent various diseases including diabetes, colon cancers, diarrhea and chronic renal or hepatic diseases. Elevated RS in rice is important for public health since rice is a staple food for half of the world population. A japonica mutant 'Jiangtangdao 1' (RS = 11.67%) was crossed with an indica cultivar 'Miyang 23' (RS = 0.41%). The mutant sbe3-rs that explained 60.4% of RS variation was mapped between RM6611 and RM13366 on chromosome 2 (LOD = 36) using 178 F(2) plants genotyped with 106 genome-wide polymorphic SSR markers. Using 656 plants from four F(3:4) families, sbe3-rs was fine mapped to a 573.3 Kb region between InDel 2 and InDel 6 using one STS, five SSRs and seven InDel markers. SBE3 which codes for starch branching enzyme was identified as a candidate gene within the putative region. Nine pairs of primers covering 22 exons were designed to sequence genomic DNA of the wild type for SBE3 and the mutant for sbe3-rs comparatively. Sequence analysis identified a missense mutation site where Leu-599 of the wild was changed to Pro 599 of the mutant in the SBE3 coding region. Because the point mutation resulted in the loss of a restriction enzyme site, sbe3-rs was not digested by a CAPS marker for SpeI site while SBE3 was. Co-segregation of the digestion pattern with RS content among 178 F(2) plants further supported sbe3-rs responsible for RS in rice. As a result, the CAPS marker could be used in marker-assisted breeding to develop rice cultivars with elevated RS which is otherwise difficult to accurately assess in crops. Transgenic technology should be employed for a definitive conclusion of the sbe3-rs. PMID- 22937010 TI - Development and fibronectin signaling requirements of the zebrafish interrenal vessel. AB - BACKGROUND: The early morphogenetic steps of zebrafish interrenal tissue, the teleostean counterpart of the mammalian adrenal gland, are modulated by the peri interrenal angioblasts and blood vessels. While an organized distribution of intra-adrenal vessels and extracellular matrix is essential for the fetal adrenal cortex remodeling, whether and how an intra-interrenal buildup of vasculature and extracellular matrix forms and functions during interrenal organogenesis in teleosts remains unclear. METHODOLOGY AND PRINCIPAL FINDINGS: We characterized the process of interrenal gland vascularization by identifying the interrenal vessel (IRV); which develops from the axial artery through angiogenesis and is associated with highly enriched Fibronectin (Fn) accumulation at its microenvironment. The loss of Fn1 by either antisense morpholino (MO) knockdown or genetic mutation inhibited endothelial invasion and migration of the steroidogenic tissue. The accumulation of peri-IRV Fn requires Integrin alpha5 (Itga5), with its knockdown leading to interrenal and IRV morphologies phenocopying those in the fn1 morphant and mutant. fn1b, another known fn gene in zebrafish, is however not involved in the IRV formation. The distribution pattern of peri-IRV Fn could be modulated by the blood flow, while a lack of which altered angiogenic direction of the IRV as well as its ability to integrate with the steroidogenic tissue. The administration of Fn antagonist through microangiography exerted reducing effects on both interrenal vessel angiogenesis and steroidogenic cell migration. CONCLUSIONS AND SIGNIFICANCE: This work is the first to identify the zebrafish IRV and to characterize how its integration into the developing interrenal gland requires the Fn-enriched microenvironment, which leads to the possibility of using the IRV formation as a platform for exploring organ-specific angiogenesis. In the context of other developmental endocrinology studies, our results indicate a highly dynamic interrenal-vessel interaction immediately before the onset of stress response in the zebrafish embryo. PMID- 22937011 TI - Size matters: concurrency and the epidemic potential of HIV in small networks. AB - BACKGROUND: Generalized heterosexual epidemics are responsible for the largest share of the global burden of HIV. These occur in populations that do not have high rates of partner acquisition, and research suggests that a pattern of fewer, but concurrent, partnerships may be the mechanism that provides the connectivity necessary for sustained transmission. We examine how network size affects the impact of concurrency on network connectivity. METHODOLOGY/PRINCIPAL FINDINGS: We use a stochastic network model to generate a sample of networks, varying the size of the network and the level of concurrency, and compare the largest components for each scenario to the asymptotic expected values. While the threshold for the growth of a giant component does not change, the transition is more gradual in the smaller networks. As a result, low levels of concurrency generate more connectivity in small networks. CONCLUSIONS/SIGNIFICANCE: Generalized HIV epidemics are by definition those that spread to a larger fraction of the population, but the mechanism may rely in part on the dynamics of transmission in a set of linked small networks. Examples include rural populations in sub-Saharan Africa and segregated minority populations in the US, where the effective size of the sexual network may well be in the hundreds, rather than thousands. Connectivity emerges at lower levels of concurrency in smaller networks, but these networks can still be disconnected with small changes in behavior. Concurrency remains a strategic target for HIV combination prevention programs in this context. PMID- 22937012 TI - Ethanol-induced face-brain dysmorphology patterns are correlative and exposure stage dependent. AB - Prenatal ethanol exposure is the leading preventable cause of congenital mental disability. Whereas a diagnosis of fetal alcohol syndrome (FAS) requires identification of a specific pattern of craniofacial dysmorphology, most individuals with behavioral and neurological sequelae of heavy prenatal ethanol exposure do not exhibit these defining facial characteristics. Here, a novel integration of MRI and dense surface modeling-based shape analysis was applied to characterize concurrent face-brain phenotypes in C57Bl/6J fetuses exposed to ethanol on gestational day (GD)7 or GD8.5. The facial phenotype resulting from ethanol exposure depended upon stage of insult and was predictive of unique patterns of corresponding brain abnormalities. Ethanol exposure on GD7 produced a constellation of dysmorphic facial features characteristic of human FAS, including severe midfacial hypoplasia, shortening of the palpebral fissures, an elongated upper lip, and deficient philtrum. In contrast, ethanol exposure on GD8.5 caused mild midfacial hypoplasia and palpebral fissure shortening, a shortened upper lip, and a preserved philtrum. These distinct, stage-specific facial phenotypes were associated with unique volumetric and shape abnormalities of the septal region, pituitary, and olfactory bulbs. By demonstrating that early prenatal ethanol exposure can cause more than one temporally-specific pattern of defects, these findings illustrate the need for an expansion of current diagnostic criteria to better capture the full range of facial and brain dysmorphology in fetal alcohol spectrum disorders. PMID- 22937013 TI - Risk factors for HIV and unprotected anal intercourse among men who have sex with men (MSM) in Almaty, Kazakhstan. AB - INTRODUCTION: Men who have sex with men (MSM) are at high risk for HIV infection. MSM in Central Asia, however, are not adequately studied to assess their risk of HIV transmission. METHODS: This study used respondent driven sampling methods to recruit 400 MSM in Almaty, the largest city in Kazakhstan, into a cross-sectional study. Participation involved a one-time interviewer-administered questionnaire and rapid HIV screening test. Prevalence data were adjusted for respondent network size and recruitment patterns. Multivariate logistic regression was used to investigate the association between HIV and selected risk factors, and unprotected anal intercourse (UAI) and selected risk factors. RESULTS: After respondent driven sampling (RDS) weighted analysis, 20.2% of MSM were HIV positive, and 69.0% had unprotected sex with at least one male partner in the last 12 months. Regression analysis showed that HIV infection was associated with unprotected receptive anal sex (AOR: 2.00; 95% CI: 1.04-3.84). Having unprotected anal intercourse with male partners, a measure of HIV risk behaviors, was associated with being single (AOR: 0.38; 95% CI: 0.23-0.64); very difficult access to lubricants (AOR: 11.08; 95% CI: 4.93-24.91); STI symptoms (AOR: 3.45; 95% CI: 1.42-8.40); transactional sex (AOR: 3.21; 95% CI: 1.66-6.22); and non injection drug use (AOR: 3.10; 95% CI: 1.51-6.36). CONCLUSIONS: This study found a high HIV prevalence among MSM in Almaty, and a population of MSM engaging in multiple high-risk behavior in Almaty. Greater access to HIV education and prevention interventions is needed to limit the HIV epidemic among MSM in Almaty. PMID- 22937014 TI - Quality of life, physical diseases, and psychological impairment among survivors 3 years after Wenchuan earthquake: a population based survey. AB - BACKGROUND: Few research studies have addressed the long-term effects caused by catastrophes, and no study has ever explored the life quality, physical diseases, and psychological impairment of earthquake survivors at the same time. This study seeks to reveal survivors' quality of life, physical diseases, and mental health. METHODS: A cross-sectional survey was conducted through multi-stage sampling approach three years after the Wenchuan earthquake. RESULTS: A total of 2525 subjects were interviewed. Symptoms of PTSD were reported by 8.8% of the respondents from the seriously affected areas and 0.5%, the less hit areas. Prevalence of chronic diseases was 39.2% and 22.1% respectively, and two-week prevalence rate, 24.9% and 12.7% respectively. In the multivariate analysis, two week prevalence, displacement, no regular income, receiving mental health support after the disaster, family members died or missing, injured due to the quake, and person who witnessed someone being killed or injured were independently associated with higher prevalence for symptoms of PTSD. Most subscales of SF-12 negatively correlated with age, chronic diseases, two-week prevalence, injured due to the disaster, home or property loss, and score of the 3-year PTSD symptoms, but positively correlated with higher education and higher household income. CONCLUSIONS: The rates of physical diseases and symptoms of PTSD were relatively high, and the quality of life was poor among victims in the hard-hit areas 3 years after the earthquake. Physical impairment correlated with symptom of PTSD, and both were negatively associated with quality of life. PMID- 22937015 TI - Optimization of cardiovascular stent against restenosis: factorial design-based statistical analysis of polymer coating conditions. AB - The objective of this study was to optimize the physicodynamic conditions of polymeric system as a coating substrate for drug eluting stents against restenosis. As Nitric Oxide (NO) has multifunctional activities, such as regulating blood flow and pressure, and influencing thrombus formation, a continuous and spatiotemporal delivery of NO loaded in the polymer based nanoparticles could be a viable option to reduce and prevent restenosis. To identify the most suitable carrier for S-Nitrosoglutathione (GSNO), a NO prodrug, stents were coated with various polymers, such as poly (lactic-co-glycolic acid) (PLGA), polyethylene glycol (PEG) and polycaprolactone (PCL), using solvent evaporation technique. Full factorial design was used to evaluate the effects of the formulation variables in polymer-based stent coatings on the GSNO release rate and weight loss rate. The least square regression model was used for data analysis in the optimization process. The polymer-coated stents were further assessed with Differential scanning calorimetry (DSC), Fourier transform infrared spectroscopy analysis (FTIR), Scanning electron microscopy (SEM) images and platelet adhesion studies. Stents coated with PCL matrix displayed more sustained and controlled drug release profiles than those coated with PLGA and PEG. Stents coated with PCL matrix showed the least platelet adhesion rate. Subsequently, stents coated with PCL matrix were subjected to the further optimization processes for improvement of surface morphology and enhancement of the drug release duration. The results of this study demonstrated that PCL matrix containing GSNO is a promising system for stent surface coating against restenosis. PMID- 22937016 TI - Systematic analysis of the physiological importance of deubiquitinating enzymes. AB - Deubiquitinating enzymes (DUBs) are proteases that control the post-translational modification of proteins by ubiquitin and in turn regulate diverse cellular pathways. Despite a growing understanding of DUB biology at the structural and molecular level, little is known about the physiological importance of most DUBs. Here, we systematically identify DUBs encoded by the genome of Drosophila melanogaster and examine their physiological importance in vivo. Through domain analyses we uncovered 41 Drosophila DUBs, most of which have human orthologues. Systematic knockdown of the vast majority of DUBs throughout the fly or in specific cell types had dramatic consequences for Drosophila development, adult motility or longevity. Specific DUB subclasses proved to be particularly necessary during development, while others were important in adults. Several DUBs were indispensable in neurons or glial cells during developmental stages; knockdown of others perturbed the homeostasis of ubiquitinated proteins in adult flies, or had adverse effects on wing positioning as a result of neuronal requirements. We demonstrate the physiological significance of the DUB family of enzymes in intact animals, find that there is little functional redundancy among members of this family of proteases, and provide insight for future investigations to understand DUB biology at the molecular, cellular and organismal levels. PMID- 22937017 TI - Distance from home to study clinic and risk of follow-up interruption in a cohort of HIV-1-discordant couples in Nairobi, Kenya. AB - BACKGROUND: Longitudinal studies of HIV-1-infected individuals or those at risk of infection are subject to missed study visits that may have negative consequences on the care of participants and can jeopardize study validity due to bias and loss of statistical power. Distance between participant residence and study clinic, as well as other socioeconomic and demographic factors, may contribute to interruptions in patient follow-up. METHODS: HIV-1-serodiscordant couples were enrolled between May 2007 and October 2009 and followed for two years in Nairobi, Kenya. At baseline, demographic and home location information was collected and linear distance from each participant's home to the study clinic was determined. Participants were asked to return to the study clinic for quarterly visits, with follow-up interruptions (FUI) defined as missing two consecutive visits. Cox proportional hazards regression was used to assess crude and adjusted associations between FUI and home-to-clinic distance, and other baseline characteristics. RESULTS: Of 469 enrolled couples, 64% had a female HIV 1-infected partner. Overall incidence of FUI was 13.4 per 100 person-years (PY), with lower incidence of FUI in HIV-1-infected (10.8 per 100 PY) versus uninfected individuals (16.1 per 100 PY) (hazard ratio [HR] = 0.66; 95% confidence interval [CI]: 0.50, 0.88). Among HIV-1-infected participants, those living between 5 and 10 kilometers (km) from the study clinic had a two-fold increased rate of FUI compared to those living <5 km away (HR = 2.17; 95% CI: 1.09, 4.34). Other factors associated with FUI included paying higher rent (HR = 1.67; 95% CI: 1.05, 2.65), having at least primary school education (HR = 1.96; 95% CI: 1.02, 3.70), and increased HIV-1 viral load (HR = 1.23 per log(10) increase; 95% CI: 1.01, 1.51). CONCLUSIONS: Home-to-clinic distance, indicators of socioeconomic status, and markers of disease progression may affect compliance with study follow-up schedules. Retention strategies should focus on participants at greatest risk of FUI to ensure study validity. PMID- 22937018 TI - "That pregnancy can bring noise into the family": exploring intimate partner sexual violence during pregnancy in the context of HIV in Zimbabwe. AB - BACKGROUND: Globally, studies report a high prevalence of intimate partner sexual violence (IPSV) and an association with HIV infection. Despite the criminalisation of IPSV and deliberate sexual HIV infection in Zimbabwe, IPSV remains common. This study explored women's and health workers' perspectives and experiences of sexuality and sexual violence in pregnancy, including in relation to HIV testing. METHODS: This qualitative study was part of a larger study of the dynamics of intimate partner violence and HIV in pregnancy in Zimbabwe. Key informant interviews were conducted with health workers and focus group discussions were held with 64 pregnant or nursing mothers attending antenatal and postnatal care clinics in low-income neighbourhoods of Harare, covering the major thematic areas of validated sexual violence research instruments. Thematic content analysis of audio-recorded and transcribed data was conducted. RESULTS: While women reported some positive experiences of sex in pregnancy, most participants commonly experienced coercive sexual practices. They reported that men failed to understand, or refused to accept, pregnancy and its associated emotional changes, and often forced painful and degrading sexual acts on them, usually while the men were under the influence of alcohol or illicit drugs. Men often refused or delayed HIV testing, and participants reported accounts of HIV positive men not disclosing their status to their partners and deliberately infecting or attempting to infect them. Women's passive acceptance of sexual violence was influenced by advice they received from other females to subordinate to their partners and to not deprive men of their conjugal sexual rights. CONCLUSIONS: Cultural and societal factors, unequal gender norms and practices, women's economic vulnerability, and men's failure to understand pregnancy and emotional changes, influence men to perpetrate IPSV, leading to high risk of HIV infection. PMID- 22937019 TI - A case-control study of peripheral blood mitochondrial DNA copy number and risk of renal cell carcinoma. AB - BACKGROUND: Low mitochondrial DNA (mtDNA) copy number is a common feature of renal cell carcinoma (RCC), and may influence tumor development. Results from a recent case-control study suggest that low mtDNA copy number in peripheral blood may be a marker for increased RCC risk. In an attempt to replicate that finding, we measured mtDNA copy number in peripheral blood DNA from a U.S. population based case-control study of RCC. METHODOLOGY/PRINCIPAL FINDINGS: Relative mtDNA copy number was measured in triplicate by a quantitative real-time PCR assay using DNA extracted from peripheral whole blood. Cases (n = 603) had significantly lower mtDNA copy number than controls (n = 603; medians 0.85, 0.91 respectively; P = 0.0001). In multiple logistic regression analyses, the lowest quartile of mtDNA copy number was associated with a 60% increase in RCC risk relative to the highest quartile (OR = 1.6, 95% CI = 1.1-2.2; P(trend) = 0.009). This association remained in analyses restricted to cases treated by surgery alone (OR (Q1) = 1.4, 95% CI = 1.0-2.1) and to localized tumors (2.0, 1.3-2.8). CONCLUSIONS/SIGNIFICANCE: Our findings from this investigation, to our knowledge the largest of its kind, offer important confirmatory evidence that low mtDNA copy number is associated with increased RCC risk. Additional research is needed to assess whether the association is replicable in prospective studies. PMID- 22937020 TI - Characterization of the rat oncostatin M receptor complex which resembles the human, but differs from the murine cytokine receptor. AB - Evaluation of a pathophysiological role of the interleukin-6-type cytokine oncostatin M (OSM) for human diseases has been complicated by the fact that mouse models of diseases targeting either OSM or the OSM receptor (OSMR) complex cannot fully reflect the human situation. This is due to earlier findings that human OSM utilizes two receptor complexes, glycoprotein 130 (gp130)/leukemia inhibitory factor receptor (LIFR) (type I) and gp130/OSMR (type II), both with wide expression profiles. Murine OSM on the other hand only binds to the gp130/OSMR (type II) receptor complex with high affinity. Here, we characterize the receptor usage for rat OSM. Using different experimental approaches (knock-down of the OSMR expression by RNA interference, blocking of the LIFR by LIF-05, an antagonistic LIF variant and stably transfected Ba/F3 cells) we can clearly show that rat OSM surprisingly utilizes both, the type I and type II receptor complex, therefore mimicking the human situation. Furthermore, it displays cross-species activities and stimulates cells of human as well as murine origin. Its signaling capacities closely mimic those of human OSM in cell types of different origin in the way that strong activation of the Jak/STAT, the MAP kinase as well as the PI3K/Akt pathways can be observed. Therefore, rat disease models would allow evaluation of the relevance of OSM for human biology. PMID- 22937021 TI - Reduced variability of ongoing and evoked cortical activity leads to improved behavioral performance. AB - Sensory responses of the brain are known to be highly variable, but the origin and functional relevance of this variability have long remained enigmatic. Using the variable foreperiod of a visual discrimination task to assess variability in the primate cerebral cortex, we report that visual evoked response variability is not only tied to variability in ongoing cortical activity, but also predicts mean response time. We used cortical local field potentials, simultaneously recorded from widespread cortical areas, to gauge both ongoing and visually evoked activity. Trial-to-trial variability of sensory evoked responses was strongly modulated by foreperiod duration and correlated both with the cortical variability before stimulus onset as well as with response times. In a separate set of experiments we probed the relation between small saccadic eye movements, foreperiod duration and manual response times. The rate of eye movements was modulated by foreperiod duration and eye position variability was positively correlated with response times. Our results indicate that when the time of a sensory stimulus is predictable, reduction in cortical variability before the stimulus can improve normal behavioral function that depends on the stimulus. PMID- 22937022 TI - Predictive modeling of spinner dolphin (Stenella longirostris) resting habitat in the main Hawaiian Islands. AB - Predictive habitat models can provide critical information that is necessary in many conservation applications. Using Maximum Entropy modeling, we characterized habitat relationships and generated spatial predictions of spinner dolphin (Stenella longirostris) resting habitat in the main Hawaiian Islands. Spinner dolphins in Hawai'i exhibit predictable daily movements, using inshore bays as resting habitat during daylight hours and foraging in offshore waters at night. There are growing concerns regarding the effects of human activities on spinner dolphins resting in coastal areas. However, the environmental factors that define suitable resting habitat remain unclear and must be assessed and quantified in order to properly address interactions between humans and spinner dolphins. We used a series of dolphin sightings from recent surveys in the main Hawaiian Islands and a suite of environmental variables hypothesized as being important to resting habitat to model spinner dolphin resting habitat. The model performed well in predicting resting habitat and indicated that proximity to deep water foraging areas, depth, the proportion of bays with shallow depths, and rugosity were important predictors of spinner dolphin habitat. Predicted locations of suitable spinner dolphin resting habitat provided in this study indicate areas where future survey efforts should be focused and highlight potential areas of conflict with human activities. This study provides an example of a presence-only habitat model used to inform the management of a species for which patterns of habitat availability are poorly understood. PMID- 22937024 TI - Female fitness optimum at intermediate mating rates under traumatic mating. AB - Traumatic mating behaviors often bear signatures of sexual conflict and are then typically considered a male strategy to circumvent female choice mechanisms. In an extravagant mating ritual, the hermaphroditic sea slug Siphopteron quadrispinosum pierces the integument of their mating partners with a syringe like penile stylet that injects prostate fluids. Traumatic injection is followed by the insertion of a spiny penis into the partner's gonopore to transfer sperm. Despite traumatic mating, field mating rates exceed those required for female fertilization insurance, possibly because costs imposed on females are balanced by direct or indirect benefits of multiple sperm receipt. To test this idea, we exposed animals to a relevant range of mating opportunity regimes and assessed the effects on mating behavior and proxies of female fitness. We find penis intromission duration to decrease with mating rates, and a female fecundity maximum at intermediate mating rates. The latter finding indicates that benefits beyond fertilization insurance can make higher mating rates also beneficial from a female perspective in this traumatically mating species. PMID- 22937023 TI - Changes in the infrared microspectroscopic characteristics of DNA caused by cationic elements, different base richness and single-stranded form. AB - BACKGROUND: The infrared (IR) analysis of dried samples of DNA and DNA polypeptide complexes is still scarce. Here we have studied the FT-IR profiles of these components to further the understanding of the FT-IR signatures of chromatin and cell nuclei. METHODOLOGY/PRINCIPAL FINDINGS: Calf thymus and salmon testis DNA, and complexes of histone H1, protamine, poly-L-lysine and poly-L arginine (histone-mimic macromolecules) with DNA were analyzed in an IR microspectroscope equipped with an attenuated total reflection diamond objective and Grams software. Conditions including polypeptides bound to the DNA, DNA base composition, and single-stranded form were found to differently affect the vibrational characteristics of the chemical groups (especially, PO(2)(-)) in the nucleic acid. The antisymmetric stretching (nu(as)) of the DNA PO(2)(-) was greater than the symmetric stretching (nu(s)) of these groups and increased in the polypeptide-DNA complexes. A shift of the nu(as) of the DNA PO(2)(-) to a lower frequency and an increased intensity of this vibration were induced especially by lysine-rich histones. Lysine richness additionally contributed to an increase in the vibrational stretching of the amide I group. Even in simple molecules such as inorganic phosphates, the vibrational characteristics of the phosphate anions were differently affected by different cations. As a result of the optimization of the DNA conformation by binding to arginine-rich polypeptides, enhancements of the vibrational characteristics in the FT-IR fingerprint could be detected. Although different profiles were obtained for the DNA with different base compositions, this situation was no longer verified in the polypeptide-DNA complexes and most likely in isolated chromatin or cell nuclei. However, the nu(as) PO(2)(-)/nu(s) PO(2)(-) ratio could discriminate DNA with different base compositions and DNA in a single-stranded form. CONCLUSIONS/SIGNIFICANCE: FT-IR spectral profiles are a valuable tool for establishing the vibrational characteristics of individualized chromatin components, such as DNA and DNA-polypeptide complexes in dried samples. PMID- 22937025 TI - Imagining one's own and someone else's body actions: dissociation in anorexia nervosa. AB - BACKGROUND: Patients with anorexia nervosa (AN) usually report feeling larger than they really are. This body overestimation appears to be related not only to the patient's body image but also to an abnormal representation of the body in action. In previous work on a body-scaled anticipation task, anorexic patients judged that they could not pass through a door-like aperture even when it was easily wide enough--suggesting the involvement of the body schema. In the present study, we sought to establish whether this erroneous judgment about action is specifically observed when it concerns one's own body or whether it is symptomatic of a general impairment in perceptual discrimination. METHODS: Twenty five anorexic participants and 25 control participants were presented with a door like aperture. They had to judge whether or not the aperture was wide enough for them to pass through (i.e. first-person perspective, 1PP) and for another person present in the testing room to pass through (i.e. third-person perspective, 3PP). RESULTS: We observed a higher passability ratio (i.e. the critical aperture size to shoulder width ratio) in AN patients for 1PP but not for 3PP. Moreover, the magnitude of the passability ratio was positively correlated not only with the extent of the patient's body and eating concerns but also with the body weight prior to disease onset. Our results suggest that body overestimation can affect judgments about the capacity for action but only when they concern the patient's own body. This could be related to impairments of the overall network involved in the emergence of the body schema and in one's own perspective judgments. CONCLUSION: Overestimation of the body schema might occur because the central nervous system has not updated the new, emaciated body, with maintenance of an incorrect representation based on the patient's pre-AN body dimensions. PMID- 22937026 TI - Investigation of hepatitis B virus and human immunodeficiency virus transmission among severely mentally ill residents at a long term care facility. AB - BACKGROUND: A high prevalence of hepatitis B virus (HBV) and human immunodeficiency virus (HIV) infections have been reported among persons with severe mental illness. In October, 2009, the Cook County Department of Public Health (CCDPH) initiated an investigation following notification of a cluster of HBV infections among mentally ill residents at a long term care facility (LTCF). METHODS: LTCF staff were interviewed and resident medical records were reviewed. Residents were offered testing for HBV, HCV, and HIV. Serum specimens from residents diagnosed with HBV or HIV infection were sent to the Centers for Disease Control and Prevention (CDC) for analysis. RESULTS: Eleven newly diagnosed HBV infections were identified among mentally ill residents at the LTCF. Of these 11 infections, 4 serum specimens were available for complete HBV genome sequencing; all 4 genomes were found to be closely related. Four newly diagnosed HIV infections were identified within this same population. Upon molecular analysis, 2 of 4 HIV sequences from these new infections were found to be nearly identical and formed a tight phylogenetic cluster. CONCLUSIONS: HBV and HIV transmission was identified among mentally ill residents of this LTCF. Continued efforts are needed to prevent bloodborne pathogen transmission among mentally ill residents in LTCFs. PMID- 22937027 TI - Both lethal and edema toxins of Bacillus anthracis disrupt the human dendritic cell chemokine network. AB - Bacillus anthracis, the agent of anthrax, produces two main virulence factors: a capsule and two toxins. Both lethal toxin (LT) and edema toxin (ET) paralyze the immune defense system. Here, we analyze the effects of LT and ET on the capacity of human monocyte-derived dendritic cells (MoDC) to produce proinflammatory chemokines. We show that both toxins disrupt proinflammatory chemokine production. LT has more pronounced effects than ET on CXCL8 production, which is correlated with impaired recruitment of neutrophils in vitro. Finally, we show that both toxins also differentially disrupt IL-12p70, IL-10, and TNF-alpha production. Taken together, these results demonstrate that both B. anthracis toxins alter MoDC functions and the activation of the innate immune system. PMID- 22937028 TI - Cell-free microRNA expression profiles in malignant effusion associated with patient survival in non-small cell lung cancer. AB - OBJECTIVE: MicroRNAs (miRNAs) expression is altered in cancer cells, and miRNAs could serve as diagnostic and prognostic biomarker for cancer patients. This study was designed to analyze circulating miRNAs expression in the malignant pleural effusion (MPE) and their association with patient survival in non-small cell lung cancer (NSCLC). METHODS: Pleural effusion from 184 patients with NSCLC and MPE were collected. MiRNA microarray and bioinformatics interpretation were used to evaluate miRNA expression profiles in 10 NSCLC patients with different survival prognosis. Associations were validated in 184 patients (randomly classified into training and validation set with equal number in each group) using quantitative RT-PCR. Risk scores were formulated based on the expression signature of miRNAs. Clinical data, such as patient survival, were collected for correlation analysis. RESULTS: Thirty-three miRNAs were found to be altered more than two-fold by microarray in malignant effusions between longer-survival and shorter-survival groups, and levels of five miRNAs (miRNA-93, miRNA-100, miRNA 134, miRNA-151 and miRNA-345) were significantly associated with overall survival. High expression of miR-100 and low expression of miRNA-93, miRNA-134, miRNA-151 and miRNA-345 were associated with poor survival in both the training and validation cohort. Patients with high risk scores had overall poor survival compared to the patients with low risk scores. Risk score was an independent predictor of patient survival. CONCLUSIONS: Expression patterns of miRNAs are systematically altered in MPE of patient with NSCLC. The five miRNA signature from the effusion may serve as a predictor for the overall survival of patients with lung cancers. PMID- 22937029 TI - General relationships between abiotic soil properties and soil biota across spatial scales and different land-use types. AB - Very few principles have been unraveled that explain the relationship between soil properties and soil biota across large spatial scales and different land-use types. Here, we seek these general relationships using data from 52 differently managed grassland and forest soils in three study regions spanning a latitudinal gradient in Germany. We hypothesize that, after extraction of variation that is explained by location and land-use type, soil properties still explain significant proportions of variation in the abundance and diversity of soil biota. If the relationships between predictors and soil organisms were analyzed individually for each predictor group, soil properties explained the highest amount of variation in soil biota abundance and diversity, followed by land-use type and sampling location. After extraction of variation that originated from location or land-use, abiotic soil properties explained significant amounts of variation in fungal, meso- and macrofauna, but not in yeast or bacterial biomass or diversity. Nitrate or nitrogen concentration and fungal biomass were positively related, but nitrate concentration was negatively related to the abundances of Collembola and mites and to the myriapod species richness across a range of forest and grassland soils. The species richness of earthworms was positively correlated with clay content of soils independent of sample location and land-use type. Our study indicates that after accounting for heterogeneity resulting from large scale differences among sampling locations and land-use types, soil properties still explain significant proportions of variation in fungal and soil fauna abundance or diversity. However, soil biota was also related to processes that act at larger spatial scales and bacteria or soil yeasts only showed weak relationships to soil properties. We therefore argue that more general relationships between soil properties and soil biota can only be derived from future studies that consider larger spatial scales and different land-use types. PMID- 22937030 TI - Application of intra-oral dental scanners in the digital workflow of implantology. AB - Intra-oral scanners will play a central role in digital dentistry in the near future. In this study the accuracy of three intra-oral scanners was compared. MATERIALS AND METHODS: A master model made of stone was fitted with three high precision manufactured PEEK cylinders and scanned with three intra-oral scanners: the CEREC (Sirona), the iTero (Cadent) and the Lava COS (3M). In software the digital files were imported and the distance between the centres of the cylinders and the angulation between the cylinders was assessed. These values were compared to the measurements made on a high accuracy 3D scan of the master model. RESULTS: The distance errors were the smallest and most consistent for the Lava COS. The distance errors for the Cerec were the largest and least consistent. All the angulation errors were small. CONCLUSIONS: The Lava COS in combination with a high accuracy scanning protocol resulted in the smallest and most consistent errors of all three scanners tested when considering mean distance errors in full arch impressions both in absolute values and in consistency for both measured distances. For the mean angulation errors, the Lava COS had the smallest errors between cylinders 1-2 and the largest errors between cylinders 1-3, although the absolute difference with the smallest mean value (iTero) was very small (0,0529 degrees ). An expected increase in distance and/or angular errors over the length of the arch due to an accumulation of registration errors of the patched 3D surfaces could be observed in this study design, but the effects were statistically not significant. CLINICAL RELEVANCE: For making impressions of implant cases for digital workflows, the most accurate scanner with the scanning protocol that will ensure the most accurate digital impression should be used. In our study model that was the Lava COS with the high accuracy scanning protocol. PMID- 22937031 TI - Tubulin-destabilizing agent BPR0L075 induces vascular-disruption in human breast cancer mammary fat pad xenografts. AB - BPR0L075, 6-methoxy-3-(3',4',5'-trimethoxy-benzoyl)-1H-indole, is a tubulin binding agent that inhibits tubulin polymerization by binding to the colchicine binding site. BPR0L075 has shown antimitotic and antiangiogenic activity in vitro. The current study evaluated the vascular-disrupting activity of BPR0L075 in human breast cancer mammary fat pad xenografts using dynamic bioluminescence imaging. A single dose of BPR0L075 (50 mg/kg, intraperitoneally (i.p.)) induced rapid, temporary tumor vascular shutdown (at 2, 4, and 6 hours); evidenced by rapid and reproducible decrease of light emission from luciferase-expressing orthotopic MCF7 and MDA-MB-231 breast tumors after administration of luciferin substrate. A time-dependent reduction of tumor perfusion after BPR0L075 treatment was confirmed by immunohistological staining of the perfusion marker Hoechst 33342 and tumor vasculature marker CD31. The vasculature showed distinct recovery within 24 hours post therapy. A single i.p. injection of 50 mg/kg of BPR0L075 initially produced plasma concentrations in the micromolar range within 6 hours, but subsequent drug distribution and elimination caused BPR0L075 plasma levels to drop rapidly into the nanomolar range within 24 h. Tests with human umbilical vein endothelial (HUVEC) cells and tumor cells in culture showed that BPR0L075 was cytotoxic to both tumor cells and proliferating endothelial cells, and disrupted pre-established vessels in vitro and ex vivo. In conclusion, BPR0L075 caused rapid, albeit, temporary tumor vascular shutdown and led to reduction of tumor perfusion in orthotopic human breast cancer xenografts, suggesting that this antimitotic agent may be useful as a vascular-disrupting cancer therapy. PMID- 22937033 TI - Molecular characterization of the Neuronatin gene in the porcine placenta. AB - Imprinted genes play important roles in placental and embryonic development. Neuronatin (NNAT), first identified as an imprinted gene in human and mouse brains, played important roles in neuronal differentiation in the brain and in glucose-mediated insulin secretion in pancreatic beta cells. In the pig, NNAT was reported to be imprinted in eleven tissues. Our previous microarray hybridization study showed that NNAT was differentially expressed in Yorkshire and Meishan pig placentas, but the imprinting status and function of NNAT in the placenta have not been investigated. We demonstrated for the first time that NNAT was monoallelically expressed in the placenta. Immunochemistry analysis showed that NNAT was located in the uterine luminal and glandular epithelium in placentas. We also confirmed the differential expression of NNAT in Meishan and Yorkshire pig placentas by qPCR. Using IPA software and the published literature, we created a model network of the possible relationships between NNAT and glucose transporter genes. A dual luciferase reporter assay demonstrated that the crucial promoter region of NNAT contained a CANNTG sequence in the +210 to +215 positions, which corresponded to the E-box. Our findings demonstrated important roles of NNAT in placenta function. PMID- 22937032 TI - Rapamycin regulates the expression and activity of Kruppel-like transcription factor 2 in human umbilical vein endothelial cells. AB - BACKGROUND: Although rapamycin has been reported to increase procoagulants and decrease anticoagulants in human umbilical vein endothelial cells (HUVECs), there is no significant difference in the incidence of stent thrombosis between patients with drug-eluting stents (DESs) and those with bare metal stents (BMSs). Kruppel-like transcription factor 2 (KLF2) has been identified as a key regulator of endothelial antithrombotic function. We hypothesized that rapamycin might induce the expression and activity of KLF2, thereby counteracting coronary endothelial dysfunction induced by DESs. METHODS AND RESULTS: Expression of KLF2, tissue factor (TF) and endothelial NO synthase (eNOS) were assessed in HUVECs treated with rapamycin at concentrations of 2, 20, 200 and 2000 ng/ml for 24 and 48 hours without or with thrombin. Rapamycin strongly induced the expression and activity of KLF2 in high dose groups (p<0.01). Compared with control group, the expression of TF was increased by rapamycin, which inhibited the expression of eNOS after treating for 24 hours (p<0.01). Furthermore, small-interfering RNA mediated knockdown of KLF2 strongly magnified the ability of rapamycin to induce TF and reduce eNOS accumulation in HUVECs. CONCLUSIONS: Rapamycin-dependent induction of KLF2 might partly counteract coronary endothelial dysfunction and thereby provided a novel molecular target to prevent stent thrombosis induced by DESs. PMID- 22937034 TI - Molecular relatedness of methicillin-resistant S. aureus isolates from staff, environment and pets at University Veterinary Hospital in Malaysia. AB - Methicillin-resistant Staphylococcus aureus (MRSA) has emerged as a problem in veterinary medicine and is no longer considered as a mere nosocomial pathogen. We studied the occurrence of MRSA in veterinary personnel, cats and dogs and the environmental premises in University Veterinary Hospital (UVH). We found the prevalence of MRSA as follows: UVH 2/28 (7.1%) staff, 8/100 (8%) of the pets [5/50 (10%) of the dogs and 3/50 (6%) of the cats)], and 9/28 (4.5%) of the environmental samples. Antibiotic sensitivity tests (AST) show multi-resistance characteristics of the MRSA and the minimum inhibitory concentration (MIC) values for the isolates ranged from 1.5 ug to >256 ug/ml. Molecular typing by using multi-locus sequence typing (MLST), staphylococcal protein A typing (spa typing) and pulsed-field gel electrophoresis (PFGE) was conducted and the results from MLST indicated that an isolate from a veterinary personnel (PG21), typed as ST1241 belonged to the same clonal complex (CC) as the two isolates from two dogs (DG16 and DG20), both being typed as ST59. The PFGE results revealed that the two isolates from two veterinary personnel, PG21 and PG16 belonged to closely related MRSA strains with isolates from dog (DG36) and from environmental surface (EV100) respectively. The fact that PFGE revealed close similarity between isolates from humans, a dog and environmental surfaces indicates the possibility for either of them to be the source of MRSA and the potential routes and risks of spread. PMID- 22937035 TI - Increased microglia/macrophage gene expression in a subset of adult and pediatric astrocytomas. AB - Glioblastoma (GBM) is a highly malignant brain tumor with a dismal prognosis. Gene expression profiling of GBM has revealed clinically relevant tumor subtypes, and this provides exciting opportunities to better understand disease pathogenesis. Results from an increasing number of studies demonstrate a role for the immune response in cancer progression, yet it is unclear how the immune response differs across tumor subtypes and how it affects outcome. Utilizing gene expression data from The Cancer Genome Atlas Project and the Gene Expression Omnibus database, we demonstrate an enrichment of immune response-related gene expression in the mesenchymal subtype of adult GBM (n = 173) and pediatric high grade gliomas (n = 53). In an independent cohort of pediatric astrocytomas (n = 24) from UCSF, we stratified tumors into subtypes and confirmed these findings. Using novel immune cell-specific gene signatures we demonstrate selective enrichment of microglia/macrophage-related genes in adult and pediatric GBM tumors of the mesenchymal subtype. Furthermore, immunostaining of adult GBM tumors showed significantly higher cell numbers of microglia/macrophages in mesenchymal versus non-mesenchymal tumors (p = 0.04). Interestingly, adult GBM tumors with the shortest survival had significant enrichment of microglia/macrophage-related genes but this was not true for pediatric GBMs. Consistent with an association with poor outcome, immune response-related genes were highly represented in an adult poor prognosis gene signature, with the expression of genes related to macrophage recruitment and activation being most strongly associated with survival (p<0.05) using CoxBoost multivariate modeling. Using a microglia/macrophage high gene signature derived from quantification of tumor-infiltrating cells in adult GBM, we identified enrichment of genes characteristic of CD4 T cells, granulocytes, and microglia/macrophages (n = 573). These studies support a role for the immune response, particularly the microglia/macrophage response, in the biology of an important subset of GBM. Identification of this subset may be important for future therapeutic stratification. PMID- 22937036 TI - Vitamin D, parathyroid hormone and their associations with hypertension in a Chinese population. AB - BACKGROUND: Conflicting reports support or refute an association between vitamin D deficiency with high levels of parathyroid hormone (PTH) and raised blood pressure or hypertension. OBJECTIVE: To explore the associations of serum vitamin D and PTH levels with blood pressure and risk of hypertension in a Chinese population. METHODS: A population-based cross-sectional study was conducted among 1,420 Chinese participants, aged 20-83 years, in 2010. Anthropometric phenotypes and blood pressure were evaluated. Serum lipids, 25-hydroxyvitamin D [25(OH)D] and PTH were measured. RESULTS: One thousand four hundred and twenty participants, including 566 women (39.9%), were evaluated in 2010. Four hundred and eighty seven were hypertensive (34.3%), of whom 214 (43.9%) received antihypertensive treatment. The median concentrations of serum 25(OH)D and PTH were 22.0 ng/ml and 2.83 pmol/l, respectively. Serum 25(OH)D and natural log of PTH levels were not independently associated with blood pressure in a multivariable adjusted linear regression analysis of 1,206 participants not receiving antihypertensive treatment (P>0.05). In logistic regression analyses, serum 25(OH)D levels were not associated with risk of hypertension in single and multiple regression models. One unit increments of natural log of PTH levels were significantly associated with risk of hypertension in the crude model (OR = 1.78, 95% confidence interval 1.38-2.28, P<0.0001) and model adjusted for age and sex (OR = 1.41, 95% confidence interval 1.08-1.83, P = 0.01). However, these associations were attenuated and became nonsignificant (OR = 1.29, 95% confidence interval 0.98-1.70, P = 0.07) after further adjustment for body mass index, current alcohol intake, current smoking, glomerular filtration rate and family history of hypertension. CONCLUSIONS: Serum vitamin D and PTH levels are not independently associated with blood pressure or risk of hypertension in a Chinese population. PMID- 22937037 TI - Robust expression and secretion of Xylanase1 in Chlamydomonas reinhardtii by fusion to a selection gene and processing with the FMDV 2A peptide. AB - Microalgae have recently received attention as a potential low-cost host for the production of recombinant proteins and novel metabolites. However, a major obstacle to the development of algae as an industrial platform has been the poor expression of heterologous genes from the nuclear genome. Here we describe a nuclear expression strategy using the foot-and-mouth-disease-virus 2A self cleavage peptide to transcriptionally fuse heterologous gene expression to antibiotic resistance in Chlamydomonas reinhardtii. We demonstrate that strains transformed with ble-2A-GFP are zeocin-resistant and accumulate high levels of GFP that is properly 'cleaved' at the FMDV 2A peptide resulting in monomeric, cytosolic GFP that is easily detectable by in-gel fluorescence analysis or fluorescent microscopy. Furthermore, we used our ble2A nuclear expression vector to engineer the heterologous expression of the industrial enzyme, xylanase. We demonstrate that linking xyn1 expression to ble2A expression on the same open reading frame led to a dramatic (~100-fold) increase in xylanase activity in cells lysates compared to the unlinked construct. Finally, by inserting an endogenous secretion signal between the ble2A and xyn1 coding regions, we were able to target monomeric xylanase for secretion. The novel microalgae nuclear expression strategy described here enables the selection of transgenic lines that are efficiently expressing the heterologous gene-of-interest and should prove valuable for basic research as well as algal biotechnology. PMID- 22937038 TI - Strand-specific RNA-seq reveals ordered patterns of sense and antisense transcription in Bacillus anthracis. AB - BACKGROUND: Although genome-wide transcriptional analysis has been used for many years to study bacterial gene expression, many aspects of the bacterial transcriptome remain undefined. One example is antisense transcription, which has been observed in a number of bacteria, though the function of antisense transcripts, and their distribution across the bacterial genome, is still unclear. METHODOLOGY/PRINCIPAL FINDINGS: Single-stranded RNA-seq results revealed a widespread and non-random pattern of antisense transcription covering more than two thirds of the B. anthracis genome. Our analysis revealed a variety of antisense structural patterns, suggesting multiple mechanisms of antisense transcription. The data revealed several instances of sense and antisense expression changes in different growth conditions, suggesting that antisense transcription may play a role in the ways in which B. anthracis responds to its environment. Significantly, genome-wide antisense expression occurred at consistently higher levels on the lagging strand, while the leading strand showed very little antisense activity. Intrasample gene expression comparisons revealed a gene dosage effect in all growth conditions, where genes farthest from the origin showed the lowest overall range of expression for both sense and antisense directed transcription. Additionally, transcription from both strands was verified using a novel strand-specific assay. The variety of structural patterns we observed in antisense transcription suggests multiple mechanisms for this phenomenon, suggesting that some antisense transcription may play a role in regulating the expression of key genes, while some may be due to chromosome replication dynamics and transcriptional noise. CONCLUSIONS/SIGNIFICANCE: Although the variety of structural patterns we observed in antisense transcription suggest multiple mechanisms for antisense expression, our data also clearly indicate that antisense transcription may play a genome-wide role in regulating the expression of key genes in Bacillus species. This study illustrates the surprising complexity of prokaryotic RNA abundance for both strands of a bacterial chromosome. PMID- 22937039 TI - Fc gamma receptor CD64 modulates the inhibitory activity of infliximab. AB - BACKGROUND: Tumor necrosis factor (TNF) is an important cytokine in the pathogenesis of inflammatory bowel disease (IBD). Anti-TNF antibodies have been successfully implemented in IBD therapy, however their efficacies differ among IBD patients. Here we investigate the influence of CD64 Fc receptor on the inhibitory activity of anti-TNFs in cells of intestinal wall. METHODS: Intestinal cell lines, monocytes/macrophages and peripheral blood mononuclear cells (PBMCs) were used as models. The efficacies of adalimumab, infliximab and certolizumab pegol were assessed by RT-PCR for target genes. Protein levels and localizations were examined by Western blotting and immunofluorescence. Antibody fragments were obtained by proteolytic digestion, immunoprecipitation and protein chip analysis. Knock-down of specific gene expression was performed using siRNAs. RESULTS: Infliximab had limited efficacy towards soluble TNF in cell types expressing Fc gamma receptor CD64. Both adalimumab and infliximab had lower efficacies in PBMCs of IBD patients, which express elevated levels of CD64. Infliximab-TNF complexes were more potent in activating CD64 in THP-1 cells than adalimumab, which was accompanied by distinct phospho-tyrosine signals. Blocking Fc parts and isolation of Fab fragments of infliximab improved its efficacy. IFN-gamma-induced expression of CD64 correlated with a loss of efficacy of infliximab, whereas reduction of CD64 expression by either siRNA or PMA treatment improved inhibitory activity of this drug. Colonic mRNA expression levels of CD64 and other Fc gamma receptors were significantly increased in the inflamed tissues of infliximab non responders. CONCLUSIONS: CD64 modulates the efficacy of infliximab both in vitro and ex vivo, whereas the presence of this receptor has no impact on the inhibitory activity of certolizumab-pegol, which lacks Fc fragment. These data could be helpful in both predicting and evaluating the outcome of anti-TNF therapy in IBD patients with elevated systemic and local levels of Fc receptors. PMID- 22937040 TI - The epidemiology of low- and high-energy distal radius fracture in middle-aged and elderly men and women in Southern Norway. AB - BACKGROUND: Distal radius is one of the most frequent sites for fractures in the elderly population. Despite this, there is a paucity of epidemiological data for distal radius fracture, in particular, distinguishing between high- and low energy fractures. Our aim was to study the epidemiology of high- and low-energy distal radius fracture in middle-aged and elderly men and women in Southern Norway, and search for associates with high- or low-energy distal radius fracture in this population. METHODOLOGY/PRINCIPAL FINDINGS: Patients with distal radius fractures aged >= 50 years were identified from all four hospitals in Southern Norway between 2004 and 2005. Age-adjusted and age-specific incidence rates for men and women were calculated, and potential associates with high- and low-energy distal radius fracture were explored both in univariate and multivariate analyses. A total of 799 individuals (118 men and 681 women) aged >= 50 years with low-energy and 84 (48 men and 36 women) with high-energy distal radius fracture were identified. The overall age-adjusted incidence rate per 10,000 person-years was 18.9 for men (low energy, 12.8 vs. high-energy, 6.1) and 75.1 for women (low energy, 71.1 vs. high energy, 4.0). In multivariate model, younger age, male gender, summer season, and living in a rural area were independently associated with an increased risk of high-energy fracture. CONCLUSION: An approximately fourfold higher age-adjusted incidence rate for distal radius fracture was found among women, when compared with men. However, the proportion of patients with high-energy distal radius fracture was approximately fivefold higher in men than in women. Our data suggest that younger age, male gender, summer seasons, and living in rural areas are independent risk factors for increased risk of high-energy distal radius fracture. PMID- 22937041 TI - Altered spontaneous activity in anisometropic amblyopia subjects: revealed by resting-state FMRI. AB - Amblyopia, also known as lazy eye, usually occurs during early childhood and results in poor or blurred vision. Recent neuroimaging studies have found cortical structural/functional abnormalities in amblyopia. However, until now, it was still not known whether the spontaneous activity of the brain changes in amblyopia subjects. In the present study, regional homogeneity (ReHo), a measure of the homogeneity of functional magnetic resonance imaging signals, was used for the first time to investigate changes in resting-state local spontaneous brain activity in individuals with anisometropic amblyopia. Compared with age- and gender-matched subjects with normal vision, the anisometropic amblyopia subjects showed decreased ReHo of spontaneous brain activity in the right precuneus, the left medial prefrontal cortex, the left inferior frontal gyrus, and the left cerebellum, and increased ReHo of spontaneous brain activity was found in the bilateral conjunction area of the postcentral and precentral gyri, the left paracentral lobule, the left superior temporal gyrus, the left fusiform gyrus, the conjunction area of the right insula, putamen and the right middle occipital gyrus. The observed decreases in ReHo may reflect decreased visuo-motor processing ability, and the increases in ReHo in the somatosensory cortices, the motor areas and the auditory area may indicate compensatory plasticity in amblyopia. PMID- 22937043 TI - Gaining perspective on what we've lost: the reliability of encoded anecdotes in historical ecology. AB - Historical data are essential in fisheries management and conservation, especially for species that suffered significant population declines prior to ecological data collection. Within the field of historical marine ecology, studies have relied on anecdotal evidence, such as written accounts by explorers and interviews of different generations of resource users, to demonstrate the former abundance of certain species and the extent of their ranges. Yet, do we all agree on how these anecdotes are interpreted? This study examines the way that different people interpret anecdotes extracted from historical narratives. We outsource a survey to 50 randomly selected people using Amazon Mechanical Turk (www.mturk.com) and ask them to 'code' historical anecdotes based on their perceived abundance of species. We perform intercoder reliability tests to show that people's perceptions of historical anecdotes are generally consistent. The results speak to the reliability of using people's perceptions to acquire quantitative data, and provide novel insights into the use of anecdotal evidence to inform historical ecology. PMID- 22937042 TI - NFkappaB in the development of endothelial activation and damage in uremia: an in vitro approach. AB - Impaired hemostasis coexists with accelerated atherosclerosis in patients with chronic kidney disease (CKD). The elevated frequency of atherothrombotic events has been associated with endothelial dysfunction. The relative contribution of the uremic state and the impact of the renal replacement therapies have been often disregarded. Plasma markers of endothelial activation and damage were evaluated in three groups of patients with CKD: under conservative treatment (predialysis), on hemodialysis, and on peritoneal dialysis. Activation of p38 MAPK and the transcription factor NFkappaB was assessed in endothelial cell (EC) cultures exposed to pooled sera from each group of patients. Most of the markers evaluated (VCAM-1, ICAM-1, VWF, circulating endothelial cells) were significantly higher in CDK patients than in controls, being significantly more increased in the group of peritoneal dialysis patients. These results correlated with the activation of both p38 MAPK and NFkappaB in EC cells exposed to the same sera samples, and also to the peritoneal dialysis fluids. Hemodialysis did not further contribute to the endothelial damage induced by the uremic state observed in predialysis patients, probably due to the improved biocompatibility of the hemodialysis technique in recent years, resulting in lower cellular activation. However, peritoneal dialysis seemed to exert a significant proinflammatory effect on the endothelium that could be related to the high glucose concentrations and glucose degradation products present in the dialysis fluid. Although peritoneal dialysis has been traditionally considered a more physiological technique, our results raise some doubts with respect to inflammation and EC damage. PMID- 22937044 TI - When is a species declining? Optimizing survey effort to detect population changes in reptiles. AB - Biodiversity monitoring programs need to be designed so that population changes can be detected reliably. This can be problematical for species that are cryptic and have imperfect detection. We used occupancy modeling and power analysis to optimize the survey design for reptile monitoring programs in the UK. Surveys were carried out six times a year in 2009-2010 at multiple sites. Four out of the six species--grass snake, adder, common lizard, slow-worm -were encountered during every survey from March-September. The exceptions were the two rarest species--sand lizard and smooth snake--which were not encountered in July 2009 and March 2010 respectively. The most frequently encountered and most easily detected species was the slow-worm. For the four widespread reptile species in the UK, three to four survey visits that used a combination of directed transect walks and artificial cover objects resulted in 95% certainty that a species would be detected if present. Using artificial cover objects was an effective detection method for most species, considerably increased the detection rate of some, and reduced misidentifications. To achieve an 85% power to detect a decline in any of the four widespread species when the true decline is 15%, three surveys at a total of 886 sampling sites, or four surveys at a total of 688 sites would be required. The sampling effort needed reduces to 212 sites surveyed three times, or 167 sites surveyed four times, if the target is to detect a true decline of 30% with the same power. The results obtained can be used to refine reptile survey protocols in the UK and elsewhere. On a wider scale, the occupancy study design approach can be used to optimize survey effort and help set targets for conservation outcomes for regional or national biodiversity assessments. PMID- 22937045 TI - Human papillomavirus mutational insertion: specific marker of circulating tumor DNA in cervical cancer patients. AB - INTRODUCTION: In most cases of cervical cancers, HPV DNA is integrated into the genome of carcinoma cells. This mutational insertion constitutes a highly specific molecular marker of tumor DNA for every patient. Circulating tumor DNA (ctDNA) is an emerging marker of tumor dynamics which detection requires specific molecular motif. To determine whether the sequence of the cell-viral junction could be used in clinical practice as a specific marker of ctDNA, we analyzed a series of cervical cancer patient serums. METHODS AND FINDINGS: Serum specimens of 16 patients diagnosed with HPV16/18-associated cervical cancer, and for which the viral integration locus had been previously localized, were analyzed. Sequential serum specimens, taken at different times during the course of the disease, were also available for two of these cases. ctDNA was found in 11 out of 13 patients with tumor size greater than 20 mm at diagnosis, and analysis of sequential serum specimens showed that ctDNA concentration in patients serum was related to tumor dynamics. CONCLUSIONS: We report that HPV mutational insertion constitutes a highly specific molecular marker of ctDNA in HPV-associated tumor patients. Using this original approach, ctDNA was detected in most cervical cancer patients over stage I and ctDNA concentration was found to reflect tumor burden. In addition to its potential prognostic and predictive value, HPV mutation insertion is likely to constitute a new molecular surrogate of minimal residual disease and of subclinical relapse in HPV-associated tumor. This is of major importance in the perspective of specific anti-HPV therapy. PMID- 22937046 TI - A multi-omics analysis of recombinant protein production in Hek293 cells. AB - Hek293 cells are the predominant hosts for transient expression of recombinant proteins and are used for stable expression of proteins where post-translational modifications performed by CHO cells are inadequate. Nevertheless, there is little information available on the key cellular features underpinning recombinant protein production in Hek293 cells. To improve our understanding of recombinant protein production in Hek293 cells and identify targets for the engineering of an improved host cell line, we have compared a stable, recombinant protein producing Hek293 cell line and its parental cell line using a combination of transcriptomics, metabolomics and fluxomics. Producer cultures consumed less glucose than non-producer cultures while achieving the same growth rate, despite the additional burden of recombinant protein production. Surprisingly, there was no indication that producer cultures compensated for the reduction in glycolytic energy by increasing the efficiency of glucose utilization or increasing glutamine consumption. In contrast, glutamine consumption was lower and the majority of genes involved in oxidative phosphorylation were downregulated in producer cultures. We observed an overall downregulation of a large number of genes associated with broad cellular functions (e.g., cell growth and proliferation) in producer cultures, and therefore speculate that a broad adaptation of the cellular network freed up resources for recombinant protein production while maintaining the same growth rate. Increased abundance of genes associated with endoplasmic reticulum stress indicated a possible bottleneck at the point of protein folding and assembly. PMID- 22937047 TI - A spectrum of pleiotropic consequences in development due to changes in a regulatory pathway. AB - Regulatory evolution has frequently been proposed as the primary mechanism driving morphological evolution. This is because regulatory changes may be less likely to cause deleterious pleiotropic effects than changes in protein structure, and consequently have a higher likelihood to be beneficial. We examined the potential for mutations in trans acting regulatory elements to drive phenotypic change, and the predictability of such change. We approach these questions by the study of the phenotypic scope and size of controlled alteration in the developmental network of the bacterium Myxococcus xanthus. We perturbed the expression of a key regulatory gene (fruA) by constructing independent in frame deletions of four trans acting regulatory loci that modify its expression. While mutants retained developmental capability, the deletions caused changes in the expression of fruA and a dramatic shortening of time required for completion of development. We found phenotypic changes in the majority of traits measured, indicating pleiotropic effects of changes in regulation. The magnitude of the change for different traits was variable but the extent of differences between the mutants and parental type were consistent with changes in fruA expression. We conclude that changes in the expression of essential regulatory regions of developmental networks may simultaneously lead to modest as well as dramatic morphological changes upon which selection may subsequently act. PMID- 22937048 TI - Golgi cell-mediated activation of postsynaptic GABA(B) receptors induces disinhibition of the Golgi cell-granule cell synapse in rat cerebellum. AB - In the cerebellar glomerulus, GABAergic synapses formed by Golgi cells regulate excitatory transmission from mossy fibers to granule cells through feed-forward and feedback mechanisms. In acute cerebellar slices, we found that stimulating Golgi cell axons with a train of 10 impulses at 100 Hz transiently inhibited both the phasic and the tonic components of inhibitory responses recorded in granule cells. This effect was blocked by the GABA(B) receptor blocker CGP35348, and could be mimicked by bath-application of baclofen (30 uM). This depression of IPSCs was prevented when granule cells were dialyzed with GDPbetaS. Furthermore, when synaptic transmission was blocked, GABA(A) currents induced in granule cells by localized muscimol application were inhibited by the GABA(B) receptor agonist baclofen. These findings indicate that postsynaptic GABA(B) receptors are primarily responsible for the depression of IPSCs. This inhibition of inhibitory events results in an unexpected excitatory action by Golgi cells on granule cell targets. The reduction of Golgi cell-mediated inhibition in the cerebellar glomerulus may represent a regulatory mechanism to shift the balance between excitation and inhibition in the glomerulus during cerebellar information processing. PMID- 22937049 TI - Prediction of disease-related interactions between microRNAs and environmental factors based on a semi-supervised classifier. AB - Accumulated evidence has shown that microRNAs (miRNAs) can functionally interact with a number of environmental factors (EFs) and their interactions critically affect phenotypes and diseases. Therefore, in-silico inference of disease-related miRNA-EF interactions is becoming crucial not only for the understanding of the mechanisms by which miRNAs and EFs contribute to disease, but also for disease diagnosis, treatment, and prognosis. In this paper, we analyzed the human miRNA EF interaction data and revealed that miRNAs (EFs) with similar functions tend to interact with similar EFs (miRNAs) in the context of a given disease, which suggests a potential way to expand the current relation space of miRNAs, EFs, and diseases. Based on this observation, we further proposed a semi-supervised classifier based method (miREFScan) to predict novel disease-related interactions between miRNAs and EFs. As a result, the leave-one-out cross validation has shown that miREFScan obtained an AUC of 0.9564, indicating that miREFScan has a reliable performance. Moreover, we applied miREFScan to predict acute promyelocytic leukemia-related miRNA-EF interactions. The result shows that forty nine of the top 1% predictions have been confirmed by experimental literature. In addition, using miREFScan we predicted and publicly released novel miRNA-EF interactions for 97 human diseases. Finally, we believe that miREFScan would be a useful bioinformatic resource for the research about the relationships among miRNAs, EFs, and human diseases. PMID- 22937050 TI - Survey of the diagnostic retooling process in national TB reference laboratories, with special focus on rapid speciation tests endorsed by WHO in 2007. AB - BACKGROUND: Successful integration of new diagnostics in national tuberculosis (TB) control programs, also called 'retooling', is highly dependent on operational aspects related to test availability, accessibility and affordability. This survey aimed to find out whether recommendations to use new diagnostics lead to successful retooling in high TB endemic countries, using immunochromatographic tests (ICTs) for TB culture speciation as a case study. ICTs are recommended to accurately confirm the presence of bacteria of the Mycobacterium tuberculosis complex in liquid culture isolates. METHODS AND FINDINGS: Questionnaires were sent to national TB reference laboratories (NRLs) in 42 high TB endemic countries to address their access to information on ICT implementation, logistics related to availability, accessibility and affordability of ICTs, and testing algorithms. Results from 16 responding countries indicated that half of the NRLs were aware of the contents of WHO guidance documents on liquid culture and ICT implementation, as well as their eligibility for a negotiated pricing agreement for ICT procurement. No major issues with availability and accessibility of ICTs were raised. When asked about testing algorithms, ICTs were not used as stand-alone or first test for TB culture identification as recommended by WHO. CONCLUSIONS: The low response rate was a limitation of this survey and together with NRLs managers' unawareness of global guidance, suggests a lack of effective communication between partners of the global laboratory network and NRLs. TB tests could become more affordable to high TB endemic countries, if the possibility to negotiate lower prices for commercial products is communicated to them more successfully. NRLs need additional guidance to identify where available technologies can be most usefully implemented and in what order, taking into account long-term laboratory strategies. PMID- 22937051 TI - Human-specific SNP in obesity genes, adrenergic receptor beta2 (ADRB2), Beta3 (ADRB3), and PPAR gamma2 (PPARG), during primate evolution. AB - Adrenergic-receptor beta2 (ADRB2) and beta3 (ADRB3) are obesity genes that play a key role in the regulation of energy balance by increasing lipolysis and thermogenesis. The Glu27 allele in ADRB2 and the Arg64 allele in ADRB3 are associated with abdominal obesity and early onset of non-insulin-dependent diabetes mellitus (NIDDM) in many ethnic groups. Peroxisome proliferator activated receptor gamma (PPARG) is required for adipocyte differentiation. Pro12Ala mutation decreases PPARG activity and resistance to NIDDM. In humans, energy-expense alleles, Gln27 in ADRB2 and Trp64 in ADRB3, are at higher frequencies than Glu27 and Arg64, respectively, but Ala12 in PPARG is at lower frequency than Pro12. Adaptation of humans for lipolysis, thermogenesis, and reduction of fat accumulation could be considered by examining which alleles in these genes are dominant in non-human primates (NHP). All NHP (P. troglodytes, G. gorilla, P. pygmaeus, H. agilis and macaques) had energy-thrifty alleles, Gly16 and Glu27 in ADRB2, and Arg64 in ADRB3, but did not have energy-expense alleles, Arg16, Gln27 and Trp64 alleles. In PPARG gene, all NHP had large adipocyte accumulating type, the Pro12 allele. CONCLUSIONS: These results indicate that a tendency to produce much more heat through the energy-expense alleles developed only in humans, who left tropical rainforests for savanna and developed new features in their heat-regulation systems, such as reduction of body hair and increased evaporation of water, and might have helped the protection of entrails from cold at night, especially in glacial periods. PMID- 22937052 TI - Live and non-live pregnancy outcomes among women with depression and anxiety: a population-based study. AB - BACKGROUND: Women taking antidepressant or anti-anxiety medications during early pregnancy have high risks of non-live pregnancy outcomes, although the contribution of the underlying illnesses to these risks remains unclear. We examined the impacts of antenatal depression and anxiety and of commonly prescribed treatments on the risks of non-live pregnancy outcomes. METHODS: We identified all pregnancies and their outcome (live birth, perinatal death, miscarriage or termination) among women aged 15-45 years between 1990 and 2009 from a large primary care database in the United Kingdom. Women were grouped according to whether they had no history of depression and anxiety, a diagnosis of such illness prior to pregnancy, illness during pregnancy and illness during pregnancy with use of medication (stratified by medication type). Multinomial logistic regression models were used to compare risks of non-live outcomes among these groups, adjusting for major socio-demographic and lifestyle characteristics. RESULTS: Among 512,574 pregnancies in 331,414 women, those with antenatal drug exposure showed the greatest increased risks for all non-live pregnancy outcomes, relative to those with no history of depression or anxiety, although women with prior (but not currently medicated) illness also showed modest increased risks. Compared with un-medicated antenatal morbidity, there was weak evidence of an excess risk in women taking tricyclic antidepressants, and stronger evidence for other medications. CONCLUSIONS: Women with depression or anxiety have higher risks of miscarriage, perinatal death and decisions to terminate a pregnancy if prescribed psychotropic medication during early pregnancy than if not. Although underlying disease severity could also play a role, avoiding or reducing use of these drugs during early pregnancy may be advisable. PMID- 22937054 TI - Quaternion-based discriminant analysis method for color face recognition. AB - Pattern recognition techniques have been used to automatically recognize the objects, personal identities, predict the function of protein, the category of the cancer, identify lesion, perform product inspection, and so on. In this paper we propose a novel quaternion-based discriminant method. This method represents and classifies color images in a simple and mathematically tractable way. The proposed method is suitable for a large variety of real-world applications such as color face recognition and classification of the ground target shown in multispectrum remote images. This method first uses the quaternion number to denote the pixel in the color image and exploits a quaternion vector to represent the color image. This method then uses the linear discriminant analysis algorithm to transform the quaternion vector into a lower-dimensional quaternion vector and classifies it in this space. The experimental results show that the proposed method can obtain a very high accuracy for color face recognition. PMID- 22937053 TI - Transferring the characteristics of naturally occurring and biased antibody repertoires to human antibody libraries by trapping CDRH3 sequences. AB - Antibody repertoires are characterized by diversity as they vary not only amongst individuals and post antigen exposure but also differ significantly between vertebrate species. Such plasticity can be exploited to generate human antibody libraries featuring hallmarks of these diverse repertoires. In this study, the focus was to capture CDRH3 sequences, as this region generally accounts for most of the interaction energy with antigen. Sequences from human as well as non-human sources were successfully integrated into human antibody libraries. Next generation sequencing of these libraries proved that the CDRH3 lengths and amino acid composition corresponded to the species of origin. Specific CDRH3 sequences, biased towards the recognition of a model antigen either by immunizing mice or by selecting with phage display, were then integrated into another set of libraries. From these antigen biased libraries, highly potent antibodies were more frequently isolated, indicating that the characteristics of an immune repertoire is transferrable via CDRH3 sequences into a human antibody library. Taken together, these data demonstrate that the properties of naturally or experimentally biased repertoires can be effectively harnessed for the generation of targeted human antibody libraries, substantially increasing the probability of isolating antibodies suitable for therapeutic and diagnostic applications. PMID- 22937055 TI - The hippocampus remains activated over the long term for the retrieval of truly episodic memories. AB - The role of the hippocampus in declarative memory consolidation is a matter of intense debate. We investigated the neural substrates of memory retrieval for recent and remote information using functional magnetic resonance imaging (fMRI). 18 young, healthy participants learned a series of pictures. Then, during two fMRI recognition sessions, 3 days and 3 months later, they had to determine whether they recognized or not each picture using the "Remember/Know" procedure. Presentation of the same learned images at both delays allowed us to track the evolution of memories and distinguish consistently episodic memories from those that were initially episodic and then became familiar or semantic over time and were retrieved without any contextual detail. Hippocampal activation decreased over time for initially episodic, later semantic memories, but remained stable for consistently episodic ones, at least in its posterior part. For both types of memories, neocortical activations were observed at both delays, notably in the ventromedial prefrontal and anterior cingulate cortices. These activations may reflect a gradual reorganization of memory traces within neural networks. Our data indicate maintenance and strengthening of hippocampal and cortico-cortical connections in the consolidation and retrieval of episodic memories over time, in line with the Multiple Trace theory (Nadel and Moscovitch, 1997). At variance, memories becoming semantic over time consolidate through strengthening of cortico cortical connections and progressive disengagement of the hippocampus. PMID- 22937056 TI - Variations of CHI3L1, levels of the encoded glycoprotein YKL-40 and prediction of fatal and non-fatal ischemic stroke. AB - BACKGROUND: Polymorphisms of CHI3L1 are associated with inter-individual YKL-40 levels and YKL-40 is associated with an increased mortality and is elevated in patients with cardiovascular disease. We investigated the association between single nucleotide polymorphisms (SNPs) of CHI3L1, serum YKL-40 levels and all cause and cardiovascular mortality and first-time incidence of myocardial infarction, ischemic heart disease (IHD) and stroke. METHODOLOGY/PRINCIPAL FINDINGS: 12 SNPs of CHI3L1 were genotyped and serum YKL-40 was measured in 2656 Danes representative of the general population. Median follow-up period was 15 (0 16) years. Admission data and deaths were ascertained from registers from the Danish National Board of Health. Fourth quartile YKL-40 levels were associated with an increased mortality risk of ischemic stroke (HR 2.44 (1.01-5.88), p = 0.041) and so were homozygotes of the minor allele of rs872129 (HR 9.35 (1.25 69.87, p = 0.022)). Both continuous YKL-40 levels and 4(th) quartile YKL-40 values (>85 ng/ml) were associated with all-cause mortality (HRs 1.22 (95% CI, 1.10-1.35), p<0.0001, and 1.40 (1.15-1.71), p<0.0001), an increased risk of first time stroke (HR 1.16 (1.01-1.33), p = 0.04, and 1.63 (1.23-2.16), p = 0.001) and a decreased risk of incidence of IHD (HR 0.77 (0.65-0.91), p = 0.002, and 0.61 (0.44-0.85), p = 0.003). CONCLUSIONS/SIGNFICANCE: High YKL-40 levels (>85 ng/ml) and rs872129 were associated with an increased mortality risk of ischemic stroke, but high YKL-40 levels were also inverse related with the risk of incidence of IHD. This could be a chance finding but could also elucidate that YKL-40 plays different roles in development of thromboembolisms versus the formation of local thrombosis. PMID- 22937057 TI - Gene isoform specificity through enhancer-associated antisense transcription. AB - Enhancers and antisense RNAs play key roles in transcriptional regulation through differing mechanisms. Recent studies have demonstrated that enhancers are often associated with non-coding RNAs (ncRNAs), yet the functional role of these enhancer:ncRNA associations is unclear. Using RNA-Sequencing to interrogate the transcriptomes of undifferentiated mouse embryonic stem cells (mESCs) and their derived neural precursor cells (NPs), we identified two novel enhancer-associated antisense transcripts that appear to control isoform-specific expression of their overlapping protein-coding genes. In each case, an enhancer internal to a protein coding gene drives an antisense RNA in mESCs but not in NPs. Expression of the antisense RNA is correlated with expression of a shorter isoform of the associated sense gene that is not present when the antisense RNA is not expressed. We demonstrate that expression of the antisense transcripts as well as expression of the short sense isoforms correlates with enhancer activity at these two loci. Further, overexpression and knockdown experiments suggest the antisense transcripts regulate expression of their associated sense genes via cis-acting mechanisms. Interestingly, the protein-coding genes involved in these two examples, Zmynd8 and Brd1, share many functional domains, yet their antisense ncRNAs show no homology to each other and are not present in non-murine mammalian lineages, such as the primate lineage. The lack of homology in the antisense ncRNAs indicates they have evolved independently of each other and suggests that this mode of lineage-specific transcriptional regulation may be more widespread in other cell types and organisms. Our findings present a new view of enhancer action wherein enhancers may direct isoform-specific expression of genes through ncRNA intermediates. PMID- 22937058 TI - Proteomic analysis reveals new cardiac-specific dystrophin-associated proteins. AB - Mutations affecting the expression of dystrophin result in progressive loss of skeletal muscle function and cardiomyopathy leading to early mortality. Interestingly, clinical studies revealed no correlation in disease severity or age of onset between cardiac and skeletal muscles, suggesting that dystrophin may play overlapping yet different roles in these two striated muscles. Since dystrophin serves as a structural and signaling scaffold, functional differences likely arise from tissue-specific protein interactions. To test this, we optimized a proteomics-based approach to purify, identify and compare the interactome of dystrophin between cardiac and skeletal muscles from as little as 50 mg of starting material. We found selective tissue-specific differences in the protein associations of cardiac and skeletal muscle full length dystrophin to syntrophins and dystrobrevins that couple dystrophin to signaling pathways. Importantly, we identified novel cardiac-specific interactions of dystrophin with proteins known to regulate cardiac contraction and to be involved in cardiac disease. Our approach overcomes a major challenge in the muscular dystrophy field of rapidly and consistently identifying bona fide dystrophin-interacting proteins in tissues. In addition, our findings support the existence of cardiac-specific functions of dystrophin and may guide studies into early triggers of cardiac disease in Duchenne and Becker muscular dystrophies. PMID- 22937059 TI - Observational study of QuantiFERON(r)-TB gold in-tube assay in tuberculosis contacts in a low incidence area. AB - BACKGROUND: QuantiFERON(r)-TB Gold in-Tube (QFT) assay is a recently developed test to assess latent tuberculosis infection in contagious tuberculosis (TB) contact subjects. To assess the QFT assay in recently exposed contacts of active tuberculosis patients in a French area with low TB incidence but high Bacille Calmette-Guerin coverage, and evaluate progression rates to TB disease. METHODOLOGY/PRINCIPAL FINDINGS: Between January 2007 and December 2009, 687 contacts of culture-confirmed tuberculosis cases underwent the QFT assay, with tuberculin skin test (TST) in 473, and a 34 months mean follow-up. Of 687 contacts, 148 were QFT positive, while 526 were negative and 13 indeterminate. QFT was positive in 35% of individuals with TST >= 10 mm, 47.5% with TST >= 15 mm or phlyctenular, but in 21% of cases in which two-step TST (M0 and M3) remained negative. Conversely, QFT was negative in 69% of cases with two-step TST showing conversion from negative to positive. All indeterminate QFT were associated with TST induration <10 mm in diameter. For 29 QFT-positive subjects, no chemoprophylaxis was given due to medical contraindications. Of the remaining 119 QFT-positive contacts, 97 accepted chemoprophylaxis (81.5%), and 79 (81.4%) completed the treatment. Two contacts progressed to TB disease: one subject was QFT positive and had declined chemoprophylaxis, while the other one was QFT negative. QFT positive predictive value for progression to TB was 1.96% (1/51) with a 99.8% (525/526) negative predictive value. CONCLUSIONS/SIGNIFICANCE: Our results confirm the safety of the QFT-based strategy for assessing the TB chemoprophylaxis indication, as only one contact developed TB disease out of 526 QFT-negative subjects. PMID- 22937060 TI - An effective strategy for a whole-cell biosensor based on putative effector interaction site of the regulatory DmpR protein. AB - INTRODUCTION AND RATIONALE: The detection of bioavailable phenol is a very important issue in environmental and human hazard assessment. Despite modest developments recently, there is a stern need for development of novel biosensors with high sensitivity for priority phenol pollutants. DmpR (Dimethyl phenol regulatory protein), an NtrC-like regulatory protein for the phenol degradation of Pseudomonas sp. strain CF600, represents an attractive biosensor regimen. Thus, we sought to design a novel biosensor by modifying the phenol detection capacity of DmpR by using mutagenic PCR. METHODS: Binding sites of 'A' domain of DmpR were predicted by LIGSITE, and molecular docking was performed by using GOLD to identify the regions where phenol may interact with DmpR. Total five point mutations, one single at position 42 (Phe-to-Leu), two double at 140 (Asp-to-Glu) and 143 (Gln-to-Leu), and two double at L113M (Leu-to- Met) and D116A (Asp-to- Ala) were created in DmpR by site-directed mutagenesis to construct the reporter plasmids pRLuc42R, pRLuc140p143R, and pRLuc113p116R, respectively. Luciferase assays were performed to measure the activity of luc gene in the presence of phenol and its derivatives, while RT-PCR was used to check the expression of luc gene in the presence of phenol. RESULTS: Only pRLuc42R and pRLuc113p116R showed positive responses to phenolic effectors. The lowest detectable concentration of phenol was 0.5 uM (0.047 mg/L), 0.1 uM for 2, 4-dimethylphenol and 2-nitrophenol, 10 uM for 2, 4, 6-trichlorophenol and 2-chlorophenol, 100 uM for 2, 4 dichlorophenol, 0.01 uM for 4-nitrophenol, and 1 uM for o-cresol. These concentrations were measured by modified luciferase assay within 3 hrs compared to 6-7 hrs in previous studies. Importantly, increased expression of luciferase gene of pRLuc42R was observed by RT-PCR. CONCLUSIONS: The present study offers an effective strategy to design a quick and sensitive biosensor for phenol by constructing recombinant bacteria having DmpR gene. PMID- 22937061 TI - The mitochondrial phosphate transporters modulate plant responses to salt stress via affecting ATP and gibberellin metabolism in Arabidopsis thaliana. AB - The mitochondrial phosphate transporter (MPT) plays crucial roles in ATP production in plant cells. Three MPT genes have been identified in Arabidopsis thaliana. Here we report that the mRNA accumulations of AtMPTs were up-regulated by high salinity stress in A. thaliana seedlings. And the transgenic lines overexpressing AtMPTs displayed increased sensitivity to salt stress compared with the wild-type plants during seed germination and seedling establishment stages. ATP content and energy charge was higher in overexpressing plants than those in wild-type A. thaliana under salt stress. Accordingly, the salt-sensitive phenotype of overexpressing plants was recovered after the exogenous application of atractyloside due to the change of ATP content. Interestingly, Genevestigator survey and qRT-PCR analysis indicated a large number of genes, including those related to gibberellin synthesis could be regulated by the energy availability change under stress conditions in A. thaliana. Moreover, the exogenous application of uniconazole to overexpressing lines showed that gibberellin homeostasis was disturbed in the overexpressors. Our studies reveal a possible link between the ATP content mediated by AtMPTs and gibberellin metabolism in responses to high salinity stress in A. thaliana. PMID- 22937062 TI - Enhanced vitellogenesis in a whitefly via feeding on a begomovirus-infected plant. AB - BACKGROUND: The MEAM1 (B biotype) Bemisia tabaci (Gennadius) is one of the most widespread and damaging whitefly cryptic species. Our previous studies discovered that the MEAM1 whitefly indirectly benefits from interactions with the tomato yellow leaf curl China virus (TYLCCNV) via accelerated ovarian development and increased fecundity. However, the physiological mechanism of begomoviruse infected plants acting on the reproduction of the insect vector was unknown. METHODOLOGY/PRINCIPAL FINDINGS: Biochemical and molecular properties of vitellogenin (Vg) and vitellin (Vt) were characterized in the MEAM1 whitefly. In addition, kinetics of Vt levels in ovary and Vg levels in hemolymph in different stages were detected using a sandwich ELISA. The level of hemolymph Vg increased rapidly after eclosion. A significantly higher level of hemolymph Vg and ovary Vt were observed in whiteflies feeding on virus-infected tobacco plants than those feeding on uninfected plants. In order to detect the levels of Vg mRNA transcription, complete vitellogenin (Vg) mRNA transcripts of 6474 bp were sequenced. Vg mRNA level in whiteflies feeding on virus-infected plants was higher than those feeding on uninfected plants. However, virus-infection of the whiteflies per se, as demonstrated using an artificial diet system, did not produce significant changes in Vg mRNA level. CONCLUSIONS/SIGNIFICANCE: In MEAM1 whitefly, increased levels of both vitellin and vitellogenin as well as increased transcription of Vg mRNA are associated with feeding on begomovirus-infected plants, thus providing a mechanism for accelerated vitellogenesis. We conclude that MEAM1 whitefly profits from feeding on begomovirus-infected plants for yolk protein synthesis and uptake, and thereby increases its fecundity. These results not only provide insights into the molecular and physiological mechanisms underlying the elevated reproduction of a whitefly species through its association with a begomovirus-infected plant, but also provide a better understanding of the molecular mechanisms related to whitefly reproduction. PMID- 22937063 TI - Measuring nepotism through shared last names: are we really moving from opinions to facts? AB - Nepotistic practices are detrimental for academia. An analysis of shared last names among academics was recently proposed to measure the diffusion of nepotism, the results of which have had a huge resonance. This method was thus proposed to orient the decisions of policy makers concerning cuts and funding. Because of the social relevance of this issue, the validity of this method must be assessed. Thus, we compared results from an analysis of Italian and United Kingdom academic last names, and of Italian last and given names. The results strongly suggest that the analysis of shared last names is not a measure of nepotism, as it is largely affected by social capital, professional networking and demographic effects, whose contribution is difficult to assess. Thus, the analysis of shared last names is not useful for guiding research policy. PMID- 22937064 TI - Comparison and temporal trends of three groups with cryptococcosis: HIV-infected, solid organ transplant, and HIV-negative/non-transplant. AB - BACKGROUND: The Infectious Disease Society of America (IDSA) 2010 Clinical Practice Guidelines for the management of cryptococcosis outlined three key populations at risk of disease: (1) HIV-infected, (2) transplant recipient, and (3) HIV-negative/non-transplant. However, direct comparisons of management, severity and outcomes of these groups have not been conducted. METHODOLOGY/PRINCIPAL FINDINGS: Annual changes in frequency of cryptococcosis diagnoses, cryptococcosis-attributable mortality and mortality were captured. Differences examined between severe and non-severe disease within the context of the three groups included: demographics, symptoms, microbiology, clinical management and treatment. An average of nearly 15 patients per year presented at Duke University Medical Center (DUMC) with cryptococcosis. Out of 207 study patients, 86 (42%) were HIV-positive, 42 (20%) were transplant recipients, and 79 (38%) were HIV-negative/non-transplant. HIV-infected individuals had profound CD4 lymphocytopenia and a majority had elevated intracranial pressure. Transplant recipients commonly (38%) had renal dysfunction. Nearly one-quarter (24%) had their immunosuppressive regimens stopped or changed. The HIV-negative/non transplant population reported longer duration of symptoms than HIV-positive or transplant recipients and 28% (22/79) had liver insufficiency or underlying hematological malignancies. HIV-positive and HIV-negative/non-transplant patients accounted for 89% of severe disease cryptococcosis-attributable deaths and 86% of all-cause mortality. CONCLUSIONS/SIGNIFICANCE: In this single-center study, the frequency of cryptococcosis did not change in the last two decades, although the underlying case mix shifted (fewer HIV-positive cases, stable transplant cases, more cases with neither). Cryptococcosis had a relatively uniform and informed treatment strategy, but disease-attributable mortality was still common. PMID- 22937065 TI - Characterization and differential gene expression between two phenotypic phase variants in Salmonella enterica serovar Typhimurium. AB - Salmonella enterica serovar Typhimurium strain 798 has previously been shown to undergo phenotypic phase variation. One of the phenotypes expresses virulence traits such as adhesion, while the other phenotype does not. Phenotypic phase variation appears to correlate with the ability of this strain to cause persistent, asymptomatic infections of swine. A new method to detect cells in either phenotypic phase was developed using Evans Blue-Uranine agar plates. Using this new assay, rates of phenotypic phase variation were obtained. The rate of phase variation from non-adhesive to adhesive phenotype was approximately 10(-4) per cell per generation while phase variation from the adhesive to the non adhesive phenotype was approximately 10(-6) per cell per generation. Two highly virulent S. Typhimurium strains, SL1344 and ATCC 14028, were also shown to undergo phase variation. However, while the rate from adhesive to non-adhesive phenotype was approximately the same as for strain 798, the non-adhesive to adhesive phenotype shift was 37-fold higher. Differential gene expression was measured using RNA-Seq. Eighty-three genes were more highly expressed by 798 cells in the adhesive phenotype compared to the non-adhesive cells. Most of the up-regulated genes were in virulence genes and in particular all genes in the Salmonella pathogenicity island 1 were up-regulated. When compared to the virulent strain SL1344, expression of the virulence genes was approximately equal to those up-regulated in the adhesive phenotype of strain 798. A comparison of invasive ability demonstrated that strain SL1344 was the most invasive followed by the adhesive phenotype of strain 798, then the non-adhesive phenotype of strain 798. The least invasive strain was ATCC 14028. The genome of strain 798 was sequenced and compared to SL1344. Both strains had very similar genome sequences and gene deletions could not readily explain differences in the rates of phase variation from non-adhesive to the adhesive phenotype. PMID- 22937066 TI - Kruppel-like factor 4, a tumor suppressor in hepatocellular carcinoma cells reverts epithelial mesenchymal transition by suppressing slug expression. AB - Kruppel-like factor 4 (KLF4) is a zinc-finger transcription factor that plays an important role in differentiation and pathogenesis. KLF4 has been suggested to act as an oncogene or tumor suppressor in different tumor types. However, the role of KLF4 in hepatocellular carcinoma (HCC) remains unclear. Here, we demonstrate that forced expression of Klf4 in murine HCC cell lines reduced anchorage-independent growth in soft agar as well as cell migration and invasion activities in vitro. Ectopic Klf4 expression impaired subcutaneous tumor growth and lung colonization in vivo. By contrast, Klf4 knockdown enhanced HCC cell migration. Interestingly, ectopic expression of Klf4 changed the morphology of murine HCC cells to a more epithelial phenotype. Associated with this, we found that expression of Slug, a critical epithelial mesenchymal transition (EMT) related transcription factor, was significantly down-regulated in Klf4-expressing cells. Chromatin immunoprecipitation (ChIP) and luciferase reporter assays showed that Klf4 is able to bind and repress the activity of the Slug promoter. Furthermore, ectopic Slug expression partially reverts the Klf4-mediated phenotypes. Consistent with a role as a tumor suppressor in HCC, analysis of the public microarray databases from Oncomine revealed reduced KLF4 expression in human HCC tissues in comparison with normal liver tissues in 3 out of 4 data sets. By quantitative reverse transcription-polymerase chain reaction (qRT-PCR), we found reduced KLF4 mRNA in 50% of HCC tissues. Importantly, an inverse correlation between the expression of KLF4 and SLUG was found in HCC tissues. Our data suggest that KLF4 acts as a tumor suppressor in HCC cells, in part by suppressing SLUG transcription. PMID- 22937068 TI - A metacommunity framework for enhancing the effectiveness of biological monitoring strategies. AB - Because of inadequate knowledge and funding, the use of biodiversity indicators is often suggested as a way to support management decisions. Consequently, many studies have analyzed the performance of certain groups as indicator taxa. However, in addition to knowing whether certain groups can adequately represent the biodiversity as a whole, we must also know whether they show similar responses to the main structuring processes affecting biodiversity. Here we present an application of the metacommunity framework for evaluating the effectiveness of biodiversity indicators. Although the metacommunity framework has contributed to a better understanding of biodiversity patterns, there is still limited discussion about its implications for conservation and biomonitoring. We evaluated the effectiveness of indicator taxa in representing spatial variation in macroinvertebrate community composition in Atlantic Forest streams, and the processes that drive this variation. We focused on analyzing whether some groups conform to environmental processes and other groups are more influenced by spatial processes, and on how this can help in deciding which indicator group or groups should be used. We showed that a relatively small subset of taxa from the metacommunity would represent 80% of the variation in community composition shown by the entire metacommunity. Moreover, this subset does not have to be composed of predetermined taxonomic groups, but rather can be defined based on random subsets. We also found that some random subsets composed of a small number of genera performed better in responding to major environmental gradients. There were also random subsets that seemed to be affected by spatial processes, which could indicate important historical processes. We were able to integrate in the same theoretical and practical framework, the selection of biodiversity surrogates, indicators of environmental conditions, and more importantly, an explicit integration of environmental and spatial processes into the selection approach. PMID- 22937067 TI - Hepatitis C virus translation preferentially depends on active RNA replication. AB - Hepatitis C virus (HCV) RNA initiates its replication on a detergent-resistant membrane structure derived from the endoplasmic reticulum (ER) in the HCV replicon cells. By performing a pulse-chase study of BrU-labeled HCV RNA, we found that the newly-synthesized HCV RNA traveled along the anterograde-membrane traffic and moved away from the ER. Presumably, the RNA moved to the site of translation or virion assembly in the later steps of viral life cycle. In this study, we further addressed how HCV RNA translation was regulated by HCV RNA trafficking. When the movement of HCV RNA from the site of RNA synthesis to the Golgi complex was blocked by nocodazole, an inhibitor of ER-Golgi transport, HCV protein translation was surprisingly enhanced, suggesting that the translation of viral proteins occurred near the site of RNA synthesis. We also found that the translation of HCV proteins was dependent on active RNA synthesis: inhibition of viral RNA synthesis by an NS5B inhibitor resulted in decreased HCV viral protein synthesis even when the total amount of intracellular HCV RNA remained unchanged. Furthermore, the translation activity of the replication-defective HCV replicons or viral RNA with an NS5B mutation was greatly reduced as compared to that of the corresponding wildtype RNA. By performing live cell labeling of newly synthesized HCV RNA and proteins, we further showed that the newly synthesized HCV proteins colocalized with the newly synthesized viral RNA, suggesting that HCV RNA replication and protein translation take place at or near the same site. Our findings together indicate that the translation of HCV RNA is coupled to RNA replication and that the both processes may occur at the same subcellular membrane compartments, which we term the replicasome. PMID- 22937070 TI - Coupling between intrinsic prefrontal HbO2 and central EEG beta power oscillations in the resting brain. AB - There is increasing interest in the intrinsic activity in the resting brain, especially that of ultraslow and slow oscillations. Using near-infrared spectroscopy (NIRS), electroencephalography (EEG), blood pressure (BP), respiration and heart rate recordings during 5 minutes of rest, combined with cross spectral and sliding cross correlation calculations, we identified a short lasting coupling (duration [Formula: see text] s) between prefrontal oxyhemoglobin (HbO2) in the frequency band between 0.07 and 0.13 Hz and central EEG alpha and/or beta power oscillations in 8 of the 9 subjects investigated. The HbO2 peaks preceded the EEG band power peaks by 3.7 s in 6 subjects, with moderate or no coupling between BP and HbO2 oscillations. HbO2 and EEG band power oscillations were approximately in phase with BP oscillations in the 2 subjects with an extremely high coupling (squared coherence [Formula: see text]) between BP and HbO2 oscillation. No coupling was identified in one subject. These results indicate that slow precentral (de)oxyhemoglobin concentration oscillations during awake rest can be temporarily coupled with EEG fluctuations in sensorimotor areas and modulate the excitability level in the brains' motor areas, respectively. Therefore, this provides support for the idea that resting state networks fluctuate with frequencies of between 0.01 and 0.1 Hz (Mantini et.al. PNAS 2007). PMID- 22937069 TI - Pseudotyped AAV vector-mediated gene transfer in a human fetal trachea xenograft model: implications for in utero gene therapy for cystic fibrosis. AB - BACKGROUND: Lung disease including airway infection and inflammation currently causes the majority of morbidities and mortalities associated with cystic fibrosis (CF), making the airway epithelium and the submucosal glands (SMG) novel target cells for gene therapy in CF. These target cells are relatively inaccessible to postnatal gene transfer limiting the success of gene therapy. Our previous work in a human-fetal trachea xenograft model suggests the potential benefit for treating CF in utero. In this study, we aim to validate adeno associated virus serotype 2 (AAV2) gene transfer in a human fetal trachea xenograft model and to compare transduction efficiencies of pseudotyping AAV2 vectors in fetal xenografts and postnatal xenograft controls. METHODOLOGY/PRINCIPAL FINDINGS: Human fetal trachea or postnatal bronchus controls were xenografted onto immunocompromised SCID mice for a four-week engraftment period. After injection of AAV2/2, 2/1, 2/5, 2/7 or 2/8 with a LacZ reporter into both types of xenografts, we analyzed for transgene expression in the respiratory epithelium and SMGs. At 1 month, transduction by AAV2/2 and AAV2/8 in respiratory epithelium and SMG cells was significantly greater than that of AAV2/1, 2/5, and 2/7 in xenograft tracheas. Efficiency in SMG transduction was significantly greater in AAV2/8 than AAV2/2. At 3 months, AAV2/2 and AAV2/8 transgene expression was >99% of respiratory epithelium and SMG. At 1 month, transduction efficiency of AAV2/2 and AAV2/8 was significantly less in adult postnatal bronchial xenografts than in fetal tracheal xenografts. CONCLUSIONS/SIGNIFICANCE: Based on the effectiveness of AAV vectors in SMG transduction, our findings suggest the potential utility of pseudotyped AAV vectors for treatment of cystic fibrosis. The human fetal trachea xenograft model may serve as an effective tool for further development of fetal gene therapy strategies for the in utero treatment of cystic fibrosis. PMID- 22937071 TI - Etiology and Incidence of viral and bacterial acute respiratory illness among older children and adults in rural western Kenya, 2007-2010. AB - BACKGROUND: Few comprehensive data exist on disease incidence for specific etiologies of acute respiratory illness (ARI) in older children and adults in Africa. METHODOLOGY/PRINCIPAL FINDINGS: From March 1, 2007, to February 28, 2010, among a surveillance population of 21,420 persons >5 years old in rural western Kenya, we collected blood for culture and malaria smears, nasopharyngeal and oropharyngeal swabs for quantitative real-time PCR for ten viruses and three atypical bacteria, and urine for pneumococcal antigen testing on outpatients and inpatients meeting a ARI case definition (cough or difficulty breathing or chest pain and temperature >38.0 degrees C or oxygen saturation <90% or hospitalization). We also collected swabs from asymptomatic controls, from which we calculated pathogen-attributable fractions, adjusting for age, season, and HIV status, in logistic regression. We calculated incidence by pathogen, adjusting for health-seeking for ARI and pathogen-attributable fractions. Among 3,406 ARI patients >5 years old (adjusted annual incidence 12.0 per 100 person-years), influenza A virus was the most common virus (22% overall; 11% inpatients, 27% outpatients) and Streptococcus pneumoniae was the most common bacteria (16% overall; 23% inpatients, 14% outpatients), yielding annual incidences of 2.6 and 1.7 episodes per 100 person-years, respectively. Influenza A virus, influenza B virus, respiratory syncytial virus (RSV) and human metapneumovirus were more prevalent in swabs among cases (22%, 6%, 8% and 5%, respectively) than controls. Adenovirus, parainfluenza viruses, rhinovirus/enterovirus, parechovirus, and Mycoplasma pneumoniae were not more prevalent among cases than controls. Pneumococcus and non-typhi Salmonella were more prevalent among HIV-infected adults, but prevalence of viruses was similar among HIV-infected and HIV-negative individuals. ARI incidence was highest during peak malaria season. CONCLUSIONS/SIGNIFICANCE: Vaccination against influenza and pneumococcus (by potential herd immunity from childhood vaccination or of HIV-infected adults) might prevent much of the substantial ARI incidence among persons >5 years old in similar rural African settings. PMID- 22937072 TI - The TT genotype of the STAT4 rs7574865 polymorphism is associated with high disease activity and disability in patients with early arthritis. AB - BACKGROUND: The number of copies of the HLA-DRB1 shared epitope, and the minor alleles of the STAT4 rs7574865 and the PTPN22 rs2476601 polymorphisms have all been linked with an increased risk of developing rheumatoid arthritis. In the present study, we investigated the effects of these genetic variants on disease activity and disability in patients with early arthritis. METHODOLOGY AND RESULTS: We studied 640 patients with early arthritis (76% women; median age, 52 years), recording disease-related variables every 6 months during a 2-year follow up. HLA-DRB1 alleles were determined by PCR-SSO, while rs7574865 and rs2476601 were genotyped with the Taqman 5' allelic discrimination assay. Multivariate analysis was performed using generalized estimating equations for repeated measures. After adjusting for confounding variables such as gender, age and ACPA, the TT genotype of rs7574865 in STAT4 was associated with increased disease activity (DAS28) as compared with the GG genotype (beta coefficient [95% confidence interval] = 0.42 [0.01-0.83], p = 0.044). Conversely, the presence of the T allele of rs2476601 in PTPN22 was associated with diminished disease activity during follow-up in a dose-dependent manner (CT genotype = -0.27 [-0.56- -0.01], p = 0.042; TT genotype = -0.68 [-1.64- -0.27], p = 0.162). After adjustment for gender, age and disease activity, homozygosity for the T allele of rs7574865 in STAT4 was associated with greater disability as compared with the GG genotype. CONCLUSIONS: Our data suggest that patients with early arthritis who are homozygous for the T allele of rs7574865 in STAT4 may develop a more severe form of the disease with increased disease activity and disability. PMID- 22937073 TI - Multiplex T-RFLP allows for increased target number and specificity: detection of Salmonella enterica and six species of Listeria in a single test. AB - A multiplex T-RFLP test was developed to detect and identify Salmonella enterica and all six species of Listeria inoculated into milk at minimal levels. Extensive in silico analysis was used to design a fifteen-primer, six-amplimer methodology and in vitro application showed target organism DNA, when amplified individually, yielded the predicted terminal restriction fragments (TRFs) following digestion. Non-target organisms were either not-amplified or yielded TRFs which did not interfere with target identification. Multiple target DNA analysis gave over 86% detection of total TRFs predicted, and this was improved to over 90% detection of total TRFs predicted when only two target DNA extracts were combined analysed. Co inoculation of milk with five strains each of the target species of S. enterica and L. monocytogenes, along with five strains of the non-target species E. coli was followed by enrichment in SEL medium for M-TRFLP analysis. This allowed for detection of both target species in all samples, with detection of one S. enterica and two Listeria TRFs in all cases, and detection of a second S. enterica TRF in 91% of cases. This was from an initial inoculum of <5 cfu per 25 ml milk with a background of competing E. coli present, and gave a result from sampling of under 20 hours. The ability to increase target species number without loss of sensitivity means that extensive screening can be performed at reduced cost due to a reduction in the number of tests required. PMID- 22937075 TI - Network selection: a method for ranked lists selection. AB - We consider the problem of finding the set of rankings that best represents a given group of orderings on the same collection of elements (preference lists). This problem arises from social choice and voting theory, in which each voter gives a preference on a set of alternatives, and a system outputs a single preference order based on the observed voters' preferences. In this paper, we observe that, if the given set of preference lists is not homogeneous, a unique true underling ranking might not exist. Moreover only the lists that share the highest amount of information should be aggregated, and thus multiple rankings might provide a more feasible solution to the problem. In this light, we propose Network Selection, an algorithm that, given a heterogeneous group of rankings, first discovers the different communities of homogeneous rankings and then combines only the rank orderings belonging to the same community into a single final ordering. Our novel approach is inspired by graph theory; indeed our set of lists can be loosely read as the nodes of a network. As a consequence, only the lists populating the same community in the network would then be aggregated. In order to highlight the strength of our proposal, we show an application both on simulated and on two real datasets, namely a financial and a biological dataset. Experimental results on simulated data show that Network Selection can significantly outperform existing related methods. The other way around, the empirical evidence achieved on real financial data reveals that Network Selection is also able to select the most relevant variables in data mining predictive models, providing a clear superiority in terms of predictive power of the models built. Furthermore, we show the potentiality of our proposal in the bioinformatics field, providing an application to a biological microarray dataset. PMID- 22937074 TI - Interaction of Mycobacterium tuberculosis RshA and SigH is mediated by salt bridges. AB - The alternate sigma factor sigH of Mycobacterium tuberculosis is expressed under stress and acts as a major regulator of several genes, including some other sigma factors and redox systems. While it is auto-regulated by its own promoter at the transcriptional level, its regulation at the post-translational level is through its cognate protein, an anti-sigma factor, RshA. Hither before RshA was believed to be a zinc-associated anti-sigma factor (ZAS) and the binding of RshA to SigH is redox dependent. Here, we show that RshA coordinates a [2Fe-2S] cluster using cysteines as ligands and native RshA has more affinity to [2Fe-2S] cluster than to zinc. Furthermore, we used amide hydrogen deuterium exchange mass spectrometry (HDX-MS), followed by site-directed mutagenesis in SigH and RshA, to elucidate the interaction mechanism of RshA and SigH and the potential role of metal ion clustering in SigH regulation. Three regions in SigH, comprising of residues 1 25, 58-69, 90-111, 115-132 and 157-196 and residues 35-57 of RshA show decreased deuterium exchange and reflect decreased solvent accessibility upon complexation with SigH. Of the three RshA mutants, created based on the HDX results, the RsHA E37A mutant shows stronger interaction with SigH, relative to WT RshA, while the H49A mutant abolishes interactions and the C(53)XXC(56)AXXA mutant has no effect on complexation with SigH. The D22A, D160A and E162 SigH mutants show significantly decreased binding to RshA and the E168A mutant completely abolished interactions with RshA, indicating that the SigH-RshA interaction is mediated by salt bridges. In addition, SigH-RshA interaction does not require clustering of metal ions. Based on our results, we propose a molecular model of the SigH-RshA interaction. PMID- 22937076 TI - Early systemic granulocyte-colony stimulating factor treatment attenuates neuropathic pain after peripheral nerve injury. AB - Recent studies have shown that opioid treatment can reduce pro-inflammatory cytokine production and counteract various neuropathic pain syndromes. Granulocyte colony-stimulating factor (G-CSF) can promote immune cell differentiation by increasing leukocytes (mainly opioid-containing polymorphonuclear (PMN) cells), suggesting a potential beneficial role in treating chronic pain. This study shows the effectiveness of exogenous G-CSF treatment (200 ug/kg) for alleviating thermal hyperalgesia and mechanical allodynia in rats with chronic constriction injury (CCI), during post-operative days 1-25, compared to that of vehicle treatment. G-CSF also increases the recruitment of opioid-containing PMN cells into the injured nerve. After CCI, single administration of G-CSF on days 0, 1, and 2, but not on day 3, relieved thermal hyperalgesia, which indicated that its effect on neuropathic pain had a therapeutic window of 0-48 h after nerve injury. CCI led to an increase in the levels of interleukin-6 (IL-6) mRNA and tumor necrosis factor-alpha (TNF-alpha) protein in the dorsal root ganglia (DRG). These high levels of IL-6 mRNA and TNF alpha were suppressed by a single administration of G-CSF 48-144 h and 72-144 h after CCI, respectively. Furthermore, G-CSF administered 72-144 h after CCI suppressed the CCI-induced upregulation of microglial activation in the ipsilateral spinal dorsal horn, which is essential for sensing neuropathic pain. Moreover, the opioid receptor antagonist naloxone methiodide (NLXM) reversed G CSF-induced antinociception 3 days after CCI, suggesting that G-CSF alleviates hyperalgesia via opioid/opioid receptor interactions. These results suggest that an early single systemic injection of G-CSF alleviates neuropathic pain via activation of PMN cell-derived endogenous opioid secretion to activate opioid receptors in the injured nerve, downregulate IL-6 and TNF-alpha inflammatory cytokines, and attenuate microglial activation in the spinal dorsal horn. This indicates that G-CSF treatment can suppress early inflammation and prevent the subsequent development of neuropathic pain. PMID- 22937077 TI - Expression and in situ localization of two major PR proteins of grapevine berries during development and after UV-C exposition. AB - In grapevine Vitis vinifera L. cv Pinot noir, the Pathogenesis-Related (PR) proteins CHI4D and TL3 are among the most abundant extractable PR proteins of ripe berries and accumulate during berry ripening from veraison until full maturation. Evidence was supplied in favor of the involvement of these two protein families in plant defense mechanisms and plant development. In order to better understand CHI4D and TL3 function in grapevine, we analyzed their temporal and spatial pattern of expression during maturation and after an abiotic stress (UV-C) by in situ hybridization (ISH) and immunohistolocalization. In ripening berries, CHI4D and TL3 genes were mainly expressed in the exocarp and around vascular bundles of the mesocarp. In UV-C exposed berries, CHI4D and TL3 gene expression was strongly induced before veraison. Corresponding proteins localized in the exocarp and, to a lesser extent, around vascular bundles of the mesocarp. The spatial and temporal accumulation of the two PR proteins during berry maturation and after an abiotic stress is discussed in relation to their putative roles in plant defense. PMID- 22937078 TI - Molecular identification of a rare subtype of Cryptosporidium hominis in infants in China. AB - Two Cryptosporidium isolates from separate infants suffering from diarrhea were obtained from a hospital in Zhengzhou, China and were genotyped by PCR amplification and sequence analysis of the small-subunit ribosomal RNA (rRNA) (SSU rRNA), 70-kDa heat shock protein (HSP70), and actin genes. Further subtyping was performed by PCR amplification and sequence analysis of the 60-kDa glycoprotein (gp60) gene. Both the isolates were identified as Cryptosporidium hominis subtype IdA21, a rare subtype previously found only in a human immunodeficiency virus-infected child in South Africa and another child in Jordan. PMID- 22937079 TI - Specific genomic regions are differentially affected by copy number alterations across distinct cancer types, in aggregated cytogenetic data. AB - BACKGROUND: Regional genomic copy number alterations (CNA) are observed in the vast majority of cancers. Besides specifically targeting well-known, canonical oncogenes, CNAs may also play more subtle roles in terms of modulating genetic potential and broad gene expression patterns of developing tumors. Any significant differences in the overall CNA patterns between different cancer types may thus point towards specific biological mechanisms acting in those cancers. In addition, differences among CNA profiles may prove valuable for cancer classifications beyond existing annotation systems. PRINCIPAL FINDINGS: We have analyzed molecular-cytogenetic data from 25579 tumors samples, which were classified into 160 cancer types according to the International Classification of Disease (ICD) coding system. When correcting for differences in the overall CNA frequencies between cancer types, related cancers were often found to cluster together according to similarities in their CNA profiles. Based on a randomization approach, distance measures from the cluster dendrograms were used to identify those specific genomic regions that contributed significantly to this signal. This approach identified 43 non-neutral genomic regions whose propensity for the occurrence of copy number alterations varied with the type of cancer at hand. Only a subset of these identified loci overlapped with previously implied, highly recurrent (hot-spot) cytogenetic imbalance regions. CONCLUSIONS: Thus, for many genomic regions, a simple null-hypothesis of independence between cancer type and relative copy number alteration frequency can be rejected. Since a subset of these regions display relatively low overall CNA frequencies, they may point towards second-tier genomic targets that are adaptively relevant but not necessarily essential for cancer development. PMID- 22937080 TI - Lactation-related microRNA expression profiles of porcine breast milk exosomes. AB - Breast milk is the primary source of nutrition for newborns, and is rich in immunological components. MicroRNAs (miRNAs) are present in various body fluids and are selectively packaged inside the exosomes, a type of membrane vesicles, secreted by most cell types. These exosomal miRNAs could be actively delivered into recipient cells, and could regulate target gene expression and recipient cell function. Here, we analyzed the lactation-related miRNA expression profiles in porcine milk exosomes across the entire lactation period (newborn to 28 days after birth) by a deep sequencing. We found that immune-related miRNAs are present and enriched in breast milk exosomes (p<10(-16), chi(2) test) and are generally resistant to relatively harsh conditions. Notably, these exosomal miRNAs are present in higher numbers in the colostrums than in mature milk. It was higher in the serum of colostrum-only fed piglets compared with the mature milk-only fed piglets. These immune-related miRNA-loaded exosomes in breast milk may be transferred into the infant body via the digestive tract. These observations are a prelude to in-depth investigations of the essential roles of breast milk in the development of the infant's immune system. PMID- 22937081 TI - Local-based semantic navigation on a networked representation of information. AB - The size and complexity of actual networked systems hinders the access to a global knowledge of their structure. This fact pushes the problem of navigation to suboptimal solutions, one of them being the extraction of a coherent map of the topology on which navigation takes place. In this paper, we present a Markov chain based algorithm to tag networked terms according only to their topological features. The resulting tagging is used to compute similarity between terms, providing a map of the networked information. This map supports local-based navigation techniques driven by similarity. We compare the efficiency of the resulting paths according to their length compared to that of the shortest path. Additionally we claim that the path steps towards the destination are semantically coherent. To illustrate the algorithm performance we provide some results from the Simple English Wikipedia, which amounts to several thousand of pages. The simplest greedy strategy yields over an 80% of average success rate. Furthermore, the resulting content-coherent paths most often have a cost between one- and threefold compared to shortest-path lengths. PMID- 22937082 TI - Eggspot number and sexual selection in the cichlid fish Astatotilapia burtoni. AB - Sexual selection on male coloration is one of the main mechanisms proposed to explain the explosive speciation rates in East African cichlid fish. True eggspots are color patterns characteristic of the most species-rich lineage of cichlids, the Haplochromini, and have been suggested to be causally related to the speciation processes. Eggspots are thought to have originated by sensory exploitation and subsequently gained several roles in sexual advertisement. However, for most of these functions the evidence is equivocal. In addition, the genetic architecture of this trait still is largely unknown. We conducted bidirectional selective breeding experiments for eggspot numbers in the model cichlid, Astatotilapia burtoni. After two generations, low lines responded significantly, whereas the high lines did not. Body size was both phenotypically and genotypically correlated with eggspot number and showed correlated response to selection. Males with higher numbers of eggspots were found to sire larger offspring. Despite the potential to act as honest indicators of fitness, the behavioral experiments showed no evidence of a role in either intra- or inter sexual selection. Visual-based female preference was instead explained by courtship intensity. The evolution of this trait has been interpreted in light of adaptive theories of sexual selection, however the present and published results suggest the influence of non-adaptive factors such as sensory exploitation, environmental constraints and sexual antagonism. PMID- 22937083 TI - GASP/WFIKKN proteins: evolutionary aspects of their functions. AB - Growth and differentiation factor Associated Serum Protein (GASP) 1 and 2 are proteins known to be involved in the control of myostatin activity at least in vitro. Most deuterostome GASPs share a modular organization including WAP, follistatin/kazal, IGc2, two kunitz, and NTR domains. Based on an exon shuffling model, we performed independent phylogenetic analyses on these modules and assessed that papilin is probably a sister sequence to GASP with a divergence date estimated from the last common ancestor to bilateria. The final organization was acquired by the addition of the FS domain in early deuterostomes. Our study revealed that Gasp genes diverged during the first round of genome duplication in early vertebrates. By evaluating the substitution rate at different sites on the proteins, we showed a better conservation of the follistatin/kazal domain of GASP1 than GASP2 in mammals, suggesting a stronger interaction with myostatin. We also observed a progressive increase in the conservation of follistatin and kunitz domains from the ancestor of Ciona to early vertebrates. In situ hybridization performed on mouse embryos showed a weak Gasp1 expression in the formed somites at 10.5 dpc and in limb buds from embryonic E10.0 to E12.5. Similar results were obtained for zebrafish embryos. We propose a synthetic view showing possible interactions between GASP1 and myostatin and highlighting the role of the second kunitz domain in preventing myostatin proteolysis. PMID- 22937084 TI - Calpain/SHP-1 interaction by honokiol dampening peritoneal dissemination of gastric cancer in nu/nu mice. AB - BACKGROUND: Honokiol, a small-molecular weight natural product, has previously been reported to activate apoptosis and inhibit gastric tumorigenesis. Whether honokiol inhibits the angiogenesis and metastasis of gastric cancer cells remains unknown. METHODOLOGY/PRINCIPAL FINDINGS: We tested the effects of honokiol on angiogenic activity and peritoneal dissemination using in vivo, ex vivo and in vitro assay systems. The signaling responses in human gastric cancer cells, human umbilical vascular endothelial cells (HUVECs), and isolated tumors were detected and analyzed. In a xenograft gastric tumor mouse model, honokiol significantly inhibited the peritoneal dissemination detected by PET/CT technique. Honokiol also effectively attenuated the angiogenesis detected by chick chorioallantoic membrane assay, mouse matrigel plug assay, rat aortic ring endothelial cell sprouting assay, and endothelial cell tube formation assay. Furthermore, honokiol effectively enhanced signal transducer and activator of transcription (STAT-3) dephosphorylation and inhibited STAT-3 DNA binding activity in human gastric cancer cells and HUVECs, which was correlated with the up-regulation of the activity and protein expression of Src homology 2 (SH2)-containing tyrosine phosphatase-1 (SHP-1). Calpain-II inhibitor and siRNA transfection significantly reversed the honokiol-induced SHP-1 activity. The decreased STAT-3 phosphorylation and increased SHP-1 expression were also shown in isolated peritoneal metastatic tumors. Honokiol was also capable of inhibiting VEGF generation, which could be reversed by SHP-1 siRNA transfection. CONCLUSIONS/SIGNIFICANCE: Honokiol increases expression and activity of SPH-1 that further deactivates STAT3 pathway. These findings also suggest that honokiol is a novel and potent inhibitor of angiogenesis and peritoneal dissemination of gastric cancer cells, providing support for the application potential of honokiol in gastric cancer therapy. PMID- 22937085 TI - Integration in working memory: a magnetic stimulation study on the role of left anterior prefrontal cortex. AB - Integration is a fundamental working memory operation, requiring the insertion of information from one task into the execution of another concurrent task. Previous neuroimaging studies have suggested the involvement of left anterior prefrontal cortex (L-aPFC) in relation to working memory integration demands, increasing during presentation of information to be integrated (loading), throughout its maintenance during a secondary task, up to the integration step, and then decreasing afterward (unloading). Here we used short bursts of 5 Hz repetitive Transcranic Magnetic Stimulation (rTMS) to modulate L-aPFC activity and to assess its causal role in integration. During experimental blocks, rTMS was applied (N = 10) over L-aPFC or vertex (control site) at different time-points of a task involving integration of a preloaded digit into a sequence of arithmetical steps, and contrasted with a closely matched task without integration demand (segregation). When rTMS was applied during the loading phase, reaction times during secondary task were faster, without significant changes in error rates. RTMS instead worsened performance when applied during information unloading. In contrast, no effects were observed when rTMS was applied during the other phases of integration, or during the segregation condition. These results confirm the hypothesis that L-aPFC is causally and selectively involved in the integration of information in working memory. They additionally suggest that pre-integration loading and post-integration unloading of information involving this area may be active and resource-consuming processes. PMID- 22937086 TI - Mtb-specific CD27low CD4 T cells as markers of lung tissue destruction during pulmonary tuberculosis in humans. AB - BACKGROUND: Effector CD4 T cells represent a key component of the host's anti tuberculosis immune defense. Successful differentiation and functioning of effector lymphocytes protects the host against severe M. tuberculosis (Mtb) infection. On the other hand, effector T cell differentiation depends on disease severity/activity, as T cell responses are driven by antigenic and inflammatory stimuli released during infection. Thus, tuberculosis (TB) progression and the degree of effector CD4 T cell differentiation are interrelated, but the relationships are complex and not well understood. We have analyzed an association between the degree of Mtb-specific CD4 T cell differentiation and severity/activity of pulmonary TB infection. METHODOLOGY/PRINCIPAL FINDINGS: The degree of CD4 T cell differentiation was assessed by measuring the percentages of highly differentiated CD27(low) cells within a population of Mtb- specific CD4 T lymphocytes ("CD27(low)IFN-gamma(+)" cells). The percentages of CD27(low)IFN gamma+ cells were low in healthy donors (median, 33.1%) and TB contacts (21.8%) but increased in TB patients (47.3%, p<0.0005). Within the group of patients, the percentages of CD27(low)IFN-gamma(+) cells were uniformly high in the lungs (>76%), but varied in blood (12-92%). The major correlate for the accumulation of CD27(low)IFN-gamma(+) cells in blood was lung destruction (r = 0.65, p = 2.7 * 10(-7)). A cutoff of 47% of CD27(low)IFN-gamma(+) cells discriminated patients with high and low degree of lung destruction (sensitivity 89%, specificity 74%); a decline in CD27(low)IFN-gamma(+)cells following TB therapy correlated with repair and/or reduction of lung destruction (p<0.01). CONCLUSIONS: Highly differentiated CD27(low) Mtb-specific (CD27(low)IFN-gamma(+)) CD4 T cells accumulate in the lungs and circulate in the blood of patients with active pulmonary TB. Accumulation of CD27(low)IFN-gamma(+) cells in the blood is associated with lung destruction. The findings indicate that there is no deficiency in CD4 T cell differentiation during TB; evaluation of CD27(low)IFN gamma(+) cells provides a valuable means to assess TB activity, lung destruction, and tissue repair following TB therapy. PMID- 22937087 TI - The development and application of a multiple gene co-silencing system using endogenous URA3 as a reporter gene in Ganoderma lucidum. AB - Ganoderma lucidum is one of the most important medicinal mushrooms; however, molecular genetics research on this species has been limited due to a lack of reliable reverse genetic tools. In this study, the endogenous orotidine 5' monophosphate decarboxylase gene (URA3) was cloned as a silencing reporter, and four gene-silencing methods using hairpin, sense, antisense, and dual promoter constructs, were introduced into G. lucidum through a simple electroporation procedure. A comparison and evaluation of silencing efficiency demonstrated that all of the four methods differentially suppressed the expression of URA3. Our data unequivocally indicate that the dual promoter silencing vector yields the highest rate of URA3 silencing compared with other vectors (up to 81.9%). To highlight the advantages of the dual promoter system, we constructed a co silencing system based on the dual promoter method and succeeded in co-silencing URA3 and laccase in G. lucidum. The reduction of the mRNA levels of the two genes were correlated. Thus, the screening efficiency for RNAi knockdown of multiple genes may be improved by the co-silencing of an endogenous reporter gene. The molecular tools developed in this study should facilitate the isolation of genes and the characterization of the functions of multiple genes in this pharmaceutically important species, and these tools should be highly useful for the study of other basidiomycetes. PMID- 22937089 TI - Analysis of differential miRNA expression in the duodenum of Escherichia coli F18 sensitive and -resistant weaned piglets. AB - Small RNA duodenal libraries were constructed for Escherichia coli F18-sensitive and -resistant weaned piglets in full-sib pair groups and sequenced using Illumina Solexa high-throughput sequencing technology. The identification of differentially expressed miRNAs provides the basis for improved database information on pig miRNAs, understanding the genetic basics of differences in resistance to E. coli F18 between local Chinese and exotic pig breeds, and finding new resistance markers for E. coli F18 infection. The duodenum of all individuals contained more than 90% of known swine miRNAs. A total of 58 differentially expressing miRNAs were identified, of which 46 were increased and 12 were decreased in E. coli F18-sensitive pigs. Of miRNAs with increased expression, ssc-miR-143 was most highly expressed, followed by ssc-let-7f, ssc miR-192, and ssc-miR-21. We identified a total of 2036 intersection target genes by comparing TargetScan data and previous gene expression profile results. Gene ontology and pathway analysis of intersection genes showed that differentially expressed miRNAs were mainly involved in the immune response and transcriptional regulation. Combining information on differential miRNA expression and their regulatory relationships with transcription factors, identified 12 candidate miRNA disease markers, including 11 miRNAs with increased expression, ssc-miR 143, ssc-let-7f, ssc-miR-30e, ssc-miR-148a, ssc-miR-148b, ssc-miR-181a, ssc-miR 192, ssc-miR-27b, ssc-miR-15b, ssc-miR-21, and ssc-miR-215, and one with decreased expression, ssc-miR-152. Quantitative real-time PCR analysis of candidate miRNA expression in a larger cohort of E coli F18-sensitive and resistant animals confirmed the high-throughput sequencing results. PMID- 22937088 TI - A toolbox for tuberculosis diagnosis: an Indian multicentric study (2006-2008): microbiological results. AB - BACKGROUND: The aim of this multicentric prospective study in India was to assess the value of several microbiological tools that contribute to the diagnosis of tuberculosis (TB) according to HIV status. METHODS: Standard microbiological tools on individual specimens were analyzed. RESULTS: Among the 807 patients with active TB, 131 were HIV-infected, 316 HIV-uninfected and 360 had HIV-unknown status. Among the 980 non-active TB subjects, 559 were at low risk and 421 were at high risk of M. tuberculosis (Mtb) exposure. Sensitivity of smear microscopy (SM) was significantly lower in HIV-infected (42.2%) than HIV-uninfected (75.9%) (p = 0.0001) and HIV-unknown pulmonary TB patients (61.4%) (p = 0.004). Specificity was 94.5% in non-TB patients and 100% in health care workers (HCW) and healthy family contacts. Automated liquid culture has significantly higher diagnostic performances than solid culture, measured by sensitivity (74.7% vs. 55.9%) (p = 0.0001) and shorter median time to detection (TTD) (12.0 vs. 34.0 days) (p = 0.0001). Specificity was 100% in HCW and cured-TB patients, but was lower in non-TB patients (89%) due to isolation of Mycobacteria other than tuberculosis (MOTT). TTD by both methods was related to AFB score. Contamination rate was low (1.4%). AccuProbe hybridization technique detected Mtb in almost all culture-positive specimens, but MOTT were found in 4.7% with a significantly higher frequency in HIV-infected (15%) than HIV-uninfected TB patients (0.5%) (p = 0.0007). Pre-test classification significantly increased the diagnostic value of all microbiological tests in pulmonary TB patients (p<0.0001) but to a lesser degree in extrapulmonary TB patients. CONCLUSIONS: Conventional microbiological tools led to results similar to those already described in India special features for HIV-infected TB patients included lower detection by SM and culture. New microbiological assays, such as the automated liquid culture system, showed increased accuracy and speed of detection. PMID- 22937090 TI - Eye movements and verbal report in a single case of visual neglect. AB - In this single case study, visuospatial neglect patient P1 demonstrated a dissociation between an intact ability to make appropriate reflexive eye movements to targets in the neglected field with latencies of <400 ms, while failing to report targets presented at such durations in a separate verbal detection task. In contrast, there was a failure to evoke the usually robust Remote Distractor Effect in P1, even though distractors in the neglected field were presented at above threshold durations. Together those data indicate that the tight coupling that is normally shown between attention and eye movements appears to be disrupted for low-level orienting in P1. A comparable disruption was also found for high-level cognitive processing tasks, namely reading and scene scanning. The findings are discussed in relation to sampling, attention and awareness in neglect. PMID- 22937091 TI - Epidemiology of functional diarrhea and comparison with diarrhea-predominant irritable bowel syndrome: a population-based survey in China. AB - BACKGROUND: The epidemiology of functional diarrhea and its impacts on Chinese remain unclear, and there are no data on the comparative epidemiology of functional diarrhea and diarrhea-predominant irritable bowel syndrome (IBS-D). This study was to explore the epidemiology of functional diarrhea and its impacts, and to identify its distinction from IBS-D. METHODS AND FINDINGS: A cross-sectional survey was conducted in 16078 respondents, who were interviewed under a randomized stratified multi-stage sampling design in five cities of China. All respondents completed the modified Rome II questionnaire, and the 36 item Short Form health survey (SF-36) was used for assessing health-related quality of life in 20% of the sample. Overall, 248 respondents (1.54%) had functional diarrhea and 277 (1.72%) had IBS-D. Functional diarrhea was positively associated with increasing age and body mass index (trend test P<0.05). The three most common symptoms for at least 3 weeks in the past months were loose, mushy or watery stools (n = 203, 81.85%), more than three bowel movements a day (n = 100, 40.32%) and having to rush to the toilet to have a bowel movement (n = 72, 29.03%). Meaningful impairment was observed in 5 of the 8 SF-36 domains in respondents with functional diarrhea. The demographics are mostly similar between the respondents with functional diarrhea and IBS-D; however, respondents with IBS D had more frequent symptoms of diarrhea and even lower scores in SF-36 domains than those with functional diarrhea. CONCLUSIONS: The prevalence of functional diarrhea in China is substantially lower than that in Western countries and relatively higher than that in other Asian countries. It impaired health-related quality of life, and respondents with IBS-D have even worse quality of life. Further population-based studies are needed to investigate the epidemiology of functional diarrhea and the differences between functional diarrhea and IBS-D. PMID- 22937092 TI - Aerial application of pheromones for mating disruption of an invasive moth as a potential eradication tool. AB - Biological invasions can cause major ecological and economic impacts. During the early stages of invasions, eradication is desirable but tactics are lacking that are both effective and have minimal non-target effects. Mating disruption, which may meet these criteria, was initially chosen to respond to the incursion of light brown apple moth, Epiphyas postvittana (LBAM; Lepidoptera: Tortricidae), in California. The large size and limited accessibility of the infested area favored aerial application. Moth sex pheromone formulations for potential use in California or elsewhere were tested in a pine forest in New Zealand where LBAM is abundant. Formulations were applied by helicopter at a target rate of 40 g pheromone per ha. Trap catch before and after application was used to assess the efficacy and longevity of formulations, in comparison with plots treated with ground-applied pheromone dispensers and untreated control plots. Traps placed at different heights showed LBAM was abundant in the upper canopy of tall trees, which complicates control attempts. A wax formulation and polyethylene dispensers were most effective and provided trap shut-down near ground level for 10 weeks. Only the wax formulation was effective in the upper canopy. As the pheromone blend contained a behavioral antagonist for LBAM, 'false trail following' could be ruled out as a mechanism explaining trap shutdown. Therefore, 'sensory impairment' and 'masking of females' are the main modes of operation. Mating disruption enhances Allee effects which contribute to negative growth of small populations and, therefore, it is highly suitable for area-wide control and eradication of biological invaders. PMID- 22937093 TI - Transcriptional profiling of midgut immunity response and degeneration in the wandering silkworm, Bombyx mori. AB - BACKGROUND: Lepidoptera insects have a novel development process comprising several metamorphic stages during their life cycle compared with vertebrate animals. Unlike most Lepidoptera insects that live on nectar during the adult stage, the Bombyx mori silkworm adults do not eat anything and die after egg laying. In addition, the midguts of Lepidoptera insects produce antimicrobial proteins during the wandering stage when the larval tissues undergo numerous changes. The exact mechanisms responsible for these phenomena remain unclear. PRINCIPAL FINDINGS: We used the silkworm as a model and performed genome-wide transcriptional profiling of the midgut between the feeding stage and the wandering stage. Many genes concerned with metabolism, digestion, and ion and small molecule transportation were down-regulated during the wandering stage, indicating that the wandering stage midgut loses its normal functions. Microarray profiling, qRT-PCR and western blot proved the production of antimicrobial proteins (peptides) in the midgut during the wandering stage. Different genes of the immune deficiency (Imd) pathway were up-regulated during the wandering stage. However, some key genes belonging to the Toll pathway showed no change in their transcription levels. Unlike butterfly (Pachliopta aristolochiae), the midgut of silkworm moth has a layer of cells, indicating that the development of midgut since the wandering stage is not usual. Cell division in the midgut was observed only for a short time during the wandering stage. However, there was extensive cell apoptosis before pupation. The imbalance of cell division and apoptosis probably drives the continuous degeneration of the midgut in the silkworm since the wandering stage. CONCLUSIONS: This study provided an insight into the mechanism of the degeneration of the silkworm midgut and the production of innate immunity-related proteins during the wandering stage. The imbalance of cell division and apoptosis induces irreversible degeneration of the midgut. The Imd pathway probably regulates the production of antimicrobial peptides in the midgut during the wandering stage. PMID- 22937094 TI - Multilocus sequence subtyping and genetic structure of Cryptosporidium muris and Cryptosporidium andersoni. AB - In this study, nine C. muris and 43 C. andersoni isolates from various animals in China were subtyped by a multilocus sequence typing (MLST) tool. DNA sequence analyses showed the presence of 1-2 subtypes of C. muris and 2-6 subtypes of C. andersoni at each of the four loci (MS1, MS2, MS3, and MS16), nine of which represented new subtypes. Altogether, two C. muris and 10 C. andersoni MLST subtypes were detected. Linkage disequilibrium analysis indicated although the overall population structure of the two parasites was clonal, the Chinese C. andersoni in cattle has an epidemic structure. Three and two clusters were produced in the C. muris and C. andersoni populations by Structure 2.3.3 analysis, with Chinese C. muris and C. andersoni substructures differing from other countries. Thus, this study suggested the prevalence of C. andersoni in China is not attributed to the introduction of dairy cattle. More studies involving more genetic loci and systematic sampling are needed to better elucidate the population genetic structure of C. muris and C. andersoni in the world and the genetic basis for the difference in host specificity among the two most common gastric parasites. PMID- 22937095 TI - A SINE-derived element constitutes a unique modular enhancer for mammalian diencephalic Fgf8. AB - Transposable elements, including short interspersed repetitive elements (SINEs), comprise nearly half the mammalian genome. Moreover, they are a major source of conserved non-coding elements (CNEs), which play important functional roles in regulating development-related genes, such as enhancing and silencing, serving for the diversification of morphological and physiological features among species. We previously reported a novel SINE family, AmnSINE1, as part of mammalian-specific CNEs. One AmnSINE1 locus, named AS071, showed an enhancer property in the developing mouse diencephalon. Indeed, AS071 appears to recapitulate the expression of diencephalic fibroblast growth factor 8 (Fgf8). Here we established three independent lines of AS071-transgenic mice and performed detailed expression profiling of AS071-enhanced lacZ in comparison with that of Fgf8 across embryonic stages. We demonstrate that AS071 is a distal enhancer that directs Fgf8 expression in the developing diencephalon. Furthermore, enhancer assays with constructs encoding partially deleted AS071 sequence revealed a unique modular organization in which AS071 contains at least three functionally distinct sub-elements that cooperatively direct the enhancer activity in three diencephalic domains, namely the dorsal midline and the lateral wall of the diencephalon, and the ventral midline of the hypothalamus. Interestingly, the AmnSINE1-derived sub-element was found to specify the enhancer activity to the ventral midline of the hypothalamus. To our knowledge, this is the first discovery of an enhancer element that could be separated into respective sub-elements that determine regional specificity and/or the core enhancing activity. These results potentiate our understanding of the evolution of retroposon-derived cis-regulatory elements as well as the basis for future studies of the molecular mechanism underlying the determination of domain specificity of an enhancer. PMID- 22937096 TI - Genomic alterations in breast cancer patients in betel quid and non betel quid chewers. AB - Betel Quid (BQ) chewing independently contributes to oral, hepatic and esophageal carcinomas. Strong association of breast cancer risk with BQ chewing in Northeast Indian population has been reported where this habit is prodigal. We investigated genomic alterations in breast cancer patients with and without BQ chewing exposure. Twenty six BQ chewers (BQC) and 17 non BQ chewer (NBQC) breast cancer patients from Northeast India were analyzed for genomic alterations and pathway networks using SNP array and IPA. BQC tumors showed significantly (P<0.01) higher total number of alterations, as compared with NBQC tumors, 48 +/- 17% versus 32 +/- 25 respectively. Incidence of gain in fragile sites in BQC tumors were significantly (P<0.001) higher as compared with NBQC tumors, 34 versus 23% respectively. Two chromosomal regions (7q33 and 21q22.13) were significantly (p<0.05) associated with BQC tumors while two regions (19p13.3-19p12 and 20q11.22) were significantly associated with NBQC tumors. GO terms oxidoreductase and aldo-keto reductase activity in BQC tumors in contrast to G-protein coupled receptor protein signaling pathway and cell surface receptor linked signal transduction in NBQC tumors were enriched in DAVID. One network "Drug Metabolism, Molecular Transport, Nucleic Acid Metabolism" including genes AKR1B1, AKR1B10, ETS2 etc in BQC and two networks "Molecular Transport, Nucleic Acid Metabolism, Small Molecule Biochemistry" and "Cellular Development, Embryonic Development, Organismal Development" including genes RPN2, EMR3, VAV1, NNAT and MUC16 etc were seen in NBQC. Common alterations (>30%) were seen in 27 regions. Three networks were significant in common regions with key roles of PTK2, RPN2, EMR3, VAV1, NNAT, MUC16, MYC and YWHAZ genes. These data show that breast cancer arising by environmental carcinogens exemplifies genetic alterations differing from those observed in the non exposed ones. A number of genetic changes are shared in both tumor groups considered as crucial in breast cancer progression. PMID- 22937097 TI - Involvement of microRNAs in regulation of osteoblastic differentiation in mouse induced pluripotent stem cells. AB - BACKGOROUND: MicroRNAs (miRNAs), which regulate biological processes by annealing to the 3'-untranslated region (3'-UTR) of mRNAs to reduce protein synthesis, have been the subject of recent attention as a key regulatory factor in cell differentiation. The effects of some miRNAs during osteoblastic differentiation have been investigated in mesenchymal stem cells, however they still remains to be determined in pluripotent stem cells. METHODOLOGY/PRINCIPAL FINDINGS: Bone morphogenic proteins (BMPs) are potent activators of osteoblastic differentiation. In the present study, we profiled miRNAs during osteoblastic differentiation of mouse induced pluripotent stem (iPS) cells by BMP-4, in which expression of important osteoblastic markers such as Rux2, osterix, osteopontin, osteocalcin, PTHR1 and RANKL were significantly increased. A miRNA array analysis revealed that six miRNAs including miR-10a, miR-10b, miR-19b, miR-9-3p, miR-124a and miR-181a were significantly downregulated. Interestingly, miR-124a and miR 181a directly target the transcription factors Dlx5 and Msx2, both of which were increased by about 80-and 30-fold, respectively. In addition, transfection of miR 124a and miR-181a into mouse osteo-progenitor MC3T3-E1 cells significantly reduced expression of Dlx5, Runx2, osteocalcin and ALP, and Msx2 and osteocalcin, respectively. Finally, transfection of the anti-miRNAs of these six miRNAs, which are predicted to target Dlx5 and Msx2, into mouse iPS cells resulted in a significant increase in several osteoblastic differentiation markers such as Rux2, Msx2 and osteopontin. CONCLUSIONS/SIGNIFICANCE: In the present study, we demonstrate that six miRNAs including miR-10a, miR-10b, miR-19b, miR-9-3p, miR 124a and miR-181a miRNAs, especially miR-124a and miR-181a, are important regulatory factors in osteoblastic differentiation of mouse iPS cells. PMID- 22937098 TI - Life history trade-offs and relaxed selection can decrease bacterial virulence in environmental reservoirs. AB - Pathogen virulence is usually thought to evolve in reciprocal selection with the host. While this might be true for obligate pathogens, the life histories of opportunistic pathogens typically alternate between within-host and outside-host environments during the infection-transmission cycle. As a result, opportunistic pathogens are likely to experience conflicting selection pressures across different environments, and this could affect their virulence through life history trait correlations. We studied these correlations experimentally by exposing an opportunistic bacterial pathogen Serratia marcescens to its natural protist predator Tetrahymena thermophila for 13 weeks, after which we measured changes in bacterial traits related to both anti-predator defence and virulence. We found that anti-predator adaptation (producing predator-resistant biofilm) caused a correlative attenuation in virulence. Even though the direct mechanism was not found, reduction in virulence was most clearly connected to a predator driven loss of a red bacterial pigment, prodigiosin. Moreover, life-history trait evolution was more divergent among replicate populations in the absence of predation, leading also to lowered virulence in some of the 'predator absent' selection lines. Together these findings suggest that the virulence of non obligatory, opportunistic bacterial pathogens can decrease in environmental reservoirs through life history trade-offs, or random accumulation of mutations that impair virulence traits under relaxed selection. PMID- 22937099 TI - Pentamers not found in the universal proteome can enhance antigen specific immune responses and adjuvant vaccines. AB - Certain short peptides do not occur in humans and are rare or non-existent in the universal proteome. Antigens that contain rare amino acid sequences are in general highly immunogenic and may activate different arms of the immune system. We first generated a list of rare, semi-common, and common 5-mer peptides using bioinformatics tools to analyze the UniProtKB database. Experimental observations indicated that rare and semi-common 5-mers generated stronger cellular responses in comparison with common-occurring sequences. We hypothesized that the biological process responsible for this enhanced immunogenicity could be used to positively modulate immune responses with potential application for vaccine development. Initially, twelve rare 5-mers, 9-mers, and 13-mers were incorporated in frame at the end of an H5N1 hemagglutinin (HA) antigen and expressed from a DNA vaccine. The presence of some 5-mer peptides induced improved immune responses. Adding one 5-mer peptide exogenously also offered improved clinical outcome and/or survival against a lethal H5N1 or H1N1 influenza virus challenge in BALB/c mice and ferrets, respectively. Interestingly, enhanced anti-HBsAg antibody production by up to 25-fold in combination with a commercial Hepatitis B vaccine (Engerix-B, GSK) was also observed in BALB/c mice. Mechanistically, NK cell activation and dependency was observed with enhancing peptides ex vivo and in NK-depleted mice. Overall, the data suggest that rare or non-existent oligopeptides can be developed as immunomodulators and supports the further evaluation of some 5-mer peptides as potential vaccine adjuvants. PMID- 22937101 TI - Probing the binding sites of antibiotic drugs doxorubicin and N-(trifluoroacetyl) doxorubicin with human and bovine serum albumins. AB - We located the binding sites of doxorubicin (DOX) and N-(trifluoroacetyl) doxorubicin (FDOX) with bovine serum albumin (BSA) and human serum albumins (HSA) at physiological conditions, using constant protein concentration and various drug contents. FTIR, CD and fluorescence spectroscopic methods as well as molecular modeling were used to analyse drug binding sites, the binding constant and the effect of drug complexation on BSA and HSA stability and conformations. Structural analysis showed that doxorubicin and N-(trifluoroacetyl) doxorubicin bind strongly to BSA and HSA via hydrophilic and hydrophobic contacts with overall binding constants of K(DOX-BSA) = 7.8 (+/- 0.7) * 10(3) M(-1), K(FDOX BSA) = 4.8 (+/- 0.5)* 10(3) M(-1) and K(DOX-HSA) = 1.1 (+/- 0.3)* 10(4) M(-1), K(FDOX-HSA) = 8.3 (+/- 0.6)* 10(3) M(-1). The number of bound drug molecules per protein is 1.5 (DOX-BSA), 1.3 (FDOX-BSA) 1.5 (DOX-HSA), 0.9 (FDOX-HSA) in these drug-protein complexes. Docking studies showed the participation of several amino acids in drug-protein complexation, which stabilized by H-bonding systems. The order of drug-protein binding is DOX-HSA > FDOX-HSA > DOX-BSA > FDOX>BSA. Drug complexation alters protein conformation by a major reduction of alpha-helix from 63% (free BSA) to 47-44% (drug-complex) and 57% (free HSA) to 51-40% (drug complex) inducing a partial protein destabilization. Doxorubicin and its derivative can be transported by BSA and HSA in vitro. PMID- 22937100 TI - Mechanism-based urinary biomarkers to identify the potential for aminoglycoside induced nephrotoxicity in premature neonates: a proof-of-concept study. AB - Premature infants are frequently exposed to aminoglycoside antibiotics. Novel urinary biomarkers may provide a non-invasive means for the early identification of aminoglycoside-related proximal tubule renal toxicity, to enable adjustment of treatment and identification of infants at risk of long-term renal impairment. In this proof-of-concept study, urine samples were collected from 41 premature neonates (<= 32 weeks gestation) at least once per week, and daily during courses of gentamicin, and for 3 days afterwards. Significant increases were observed in the three urinary biomarkers measured (Kidney Injury Molecule-1 (KIM-1), Neutrophil Gelatinase-associated Lipocalin (NGAL), and N-acetyl-beta-D glucosaminidase (NAG)) during treatment with multiple courses of gentamicin. When adjusted for potential confounders, the treatment effect of gentamicin remained significant only for KIM-1 (mean difference from not treated, 1.35 ng/mg urinary creatinine; 95% CI 0.05-2.65). Our study shows that (a) it is possible to collect serial urine samples from premature neonates, and that (b) proximal tubule specific urinary biomarkers can act as indicators of aminoglycoside-associated nephrotoxicity in this age group. Further studies to investigate the clinical utility of novel urinary biomarkers in comparison to serum creatinine need to be undertaken. PMID- 22937102 TI - A skeletal muscle ryanodine receptor interaction domain in triadin. AB - Excitation-contraction coupling in skeletal muscle depends, in part, on a functional interaction between the ligand-gated ryanodine receptor (RyR1) and integral membrane protein Trisk 95, localized to the sarcoplasmic reticulum membrane. Various domains on Trisk 95 can associate with RyR1, yet the domain responsible for regulating RyR1 activity has remained elusive. We explored the hypothesis that a luminal Trisk 95 KEKE motif (residues 200-232), known to promote RyR1 binding, may also form the RyR1 activation domain. Peptides corresponding to Trisk 95 residues 200-232 or 200-231 bound to RyR1 and increased the single channel activity of RyR1 by 1.49 +/- 0.11-fold and 1.8 +/- 0.15-fold respectively, when added to its luminal side. A similar increase in [(3)H]ryanodine binding, which reflects open probability of the channels, was also observed. This RyR1 activation is similar to activation induced by full length Trisk 95. Circular dichroism showed that both peptides were intrinsically disordered, suggesting a defined secondary structure is not necessary to mediate RyR1 activation. These data for the first time demonstrate that Trisk 95's 200 231 region is responsible for RyR1 activation. Furthermore, it shows that no secondary structure is required to achieve this activation, the Trisk 95 residues themselves are critical for the Trisk 95-RyR1 interaction. PMID- 22937103 TI - Circular permutation prediction reveals a viable backbone disconnection for split proteins: an approach in identifying a new functional split intein. AB - Split-protein systems have emerged as a powerful tool for detecting biomolecular interactions and reporting biological reactions. However, reliable methods for identifying viable split sites are still unavailable. In this study, we demonstrated the feasibility that valid circular permutation (CP) sites in proteins have the potential to act as split sites and that CP prediction can be used to search for internal permissive sites for creating new split proteins. Using a protein ligase, intein, as a model, CP predictor facilitated the creation of circular permutants in which backbone opening imposes the least detrimental effects on intein folding. We screened a series of predicted intein CPs and identified stable and native-fold CPs. When the valid CP sites were introduced as split sites, there was a reduction in folding enthalpy caused by the new backbone opening; however, the coincident loss in entropy was sufficient to be compensated, yielding a favorable free energy for self-association. Since split intein is exploited in protein semi-synthesis, we tested the related protein trans-splicing (PTS) activities of the corresponding split inteins. Notably, a novel functional split intein composed of the N-terminal 36 residues combined with the remaining C-terminal fragment was identified. Its PTS activity was shown to be better than current reported two-piece intein with a short N-terminal segment. Thus, the incorporation of in silico CP prediction facilitated the design of split intein as well as circular permutants. PMID- 22937104 TI - Zea mays Taxilin protein negatively regulates opaque-2 transcriptional activity by causing a change in its sub-cellular distribution. AB - Zea mays (maize) Opaque-2 (ZmO2) protein is an important bZIP transcription factor that regulates the expression of major storage proteins (22-kD zeins) and other important genes during maize seed development. ZmO2 is subject to functional regulation through protein-protein interactions. To unveil the potential regulatory network associated with ZmO2, a protein-protein interaction study was carried out using the truncated version of ZmO2 (O2-2) as bait in a yeast two-hybrid screen with a maize seed cDNA library. A protein with homology to Taxilin was found to have stable interaction with ZmO2 in yeast and was designated as ZmTaxilin. Sequence analysis indicated that ZmTaxilin has a long coiled-coil domain containing three conserved zipper motifs. Each of the three zipper motifs is individually able to interact with ZmO2 in yeast. A GST pull down assay demonstrated the interaction between GST-fused ZmTaxilin and ZmO2 extracted from developing maize seeds. Using onion epidermal cells as in vivo assay system, we found that ZmTaxilin could change the sub-cellular distribution of ZmO2. We also demonstrated that this change significantly repressed the transcriptional activity of ZmO2 on the 22-kD zein promoter. Our study suggests that a Taxilin-mediated change in sub-cellular distribution of ZmO2 may have important functional consequences for ZmO2 activity. PMID- 22937105 TI - Enantioselective cytotoxicity profile of o,p'-DDT in PC 12 cells. AB - BACKGROUND: The continued uses of dichlordiphenyltrichloroethane (DDT) for indoor vector control in some developing countries have recently fueled intensive debates toward the global ban of this persistent legacy contaminant. Current approaches for ecological and health risk assessment has ignored the chiral nature of DDT. In this study by employing an array of cytotoxicity related endpoints, we investigated the enantioselective cytotoxicity of o,p'-DDT. PRINCIPAL FINDINGS: we demonstrated for the first time that R-(-)-o,p'-DDT caused more neuron cell death by inducing more severe oxidative stress, which selectively imbalanced the transcription of stress-related genes (SOD1, SOD2, HSP70) and enzyme (superoxide dismutase and lactate dehydrogenase) activities, and greater cellular apoptosis compared to its enantiomer S-(+)-o,p'-DDT at the level comparable to malaria area exposure (parts per million). We further elucidated enantioselective modes of action using microarray combined with enzyme linked immunosorbent assay. The enantioselective apoptosis might involve three signaling pathways via caspase 3, tumor protein 53 (p53) and NF(k)B. CONCLUSIONS: Based on DDT stereochemistry and results reported for other chiral pesticides, our results pointed to the same directional enantioselectivity of chiral DDT toward mammalian cells. We proposed that risk assessment on DDT should consider the enantiomer ratio and enantioselectivities. PMID- 22937106 TI - "There are too many, but never enough": qualitative case study investigating routine coding of clinical information in depression. AB - BACKGROUND: We sought to understand how clinical information relating to the management of depression is routinely coded in different clinical settings and the perspectives of and implications for different stakeholders with a view to understanding how these may be aligned. MATERIALS AND METHODS: Qualitative investigation exploring the views of a purposefully selected range of healthcare professionals, managers, and clinical coders spanning primary and secondary care. RESULTS: Our dataset comprised 28 semi-structured interviews, a focus group, documents relating to clinical coding standards and participant observation of clinical coding activities. We identified a range of approaches to coding clinical information including templates and order entry systems. The challenges inherent in clearly establishing a diagnosis, identifying appropriate clinical codes and possible implications of diagnoses for patients were particularly prominent in primary care. Although a range of managerial and research benefits were identified, there were no direct benefits from coded clinical data for patients or professionals. Secondary care staff emphasized the role of clinical coders in ensuring data quality, which was at odds with the policy drive to increase real-time clinical coding. CONCLUSIONS: There was overall no evidence of clear-cut direct patient care benefits to inform immediate care decisions, even in primary care where data on patients with depression were more extensively coded. A number of important secondary uses were recognized by healthcare staff, but the coding of clinical data to serve these ends was often poorly aligned with clinical practice and patient-centered considerations. The current international drive to encourage clinical coding by healthcare professionals during the clinical encounter may need to be critically examined. PMID- 22937108 TI - Mild electrical stimulation and heat shock ameliorates progressive proteinuria and renal inflammation in mouse model of Alport syndrome. AB - Alport syndrome is a hereditary glomerulopathy with proteinuria and nephritis caused by defects in genes encoding type IV collagen in the glomerular basement membrane. All male and most female patients develop end-stage renal disease. Effective treatment to stop or decelerate the progression of proteinuria and nephritis is still under investigation. Here we showed that combination treatment of mild electrical stress (MES) and heat stress (HS) ameliorated progressive proteinuria and renal injury in mouse model of Alport syndrome. The expressions of kidney injury marker neutrophil gelatinase-associated lipocalin and pro inflammatory cytokines interleukin-6, tumor necrosis factor-alpha and interleukin 1beta were suppressed by MES+HS treatment. The anti-proteinuric effect of MES+HS treatment is mediated by podocytic activation of phosphatidylinositol 3-OH kinase (PI3K)-Akt and heat shock protein 72 (Hsp72)-dependent pathways in vitro and in vivo. The anti-inflammatory effect of MES+HS was mediated by glomerular activation of c-jun NH(2)-terminal kinase 1/2 (JNK1/2) and p38-dependent pathways ex vivo. Collectively, our studies show that combination treatment of MES and HS confers anti-proteinuric and anti-inflammatory effects on Alport mice likely through the activation of multiple signaling pathways including PI3K-Akt, Hsp72, JNK1/2, and p38 pathways, providing a novel candidate therapeutic strategy to decelerate the progression of patho-phenotypes in Alport syndrome. PMID- 22937107 TI - FunSAV: predicting the functional effect of single amino acid variants using a two-stage random forest model. AB - Single amino acid variants (SAVs) are the most abundant form of known genetic variations associated with human disease. Successful prediction of the functional impact of SAVs from sequences can thus lead to an improved understanding of the underlying mechanisms of why a SAV may be associated with certain disease. In this work, we constructed a high-quality structural dataset that contained 679 high-quality protein structures with 2,048 SAVs by collecting the human genetic variant data from multiple resources and dividing them into two categories, i.e., disease-associated and neutral variants. We built a two-stage random forest (RF) model, termed as FunSAV, to predict the functional effect of SAVs by combining sequence, structure and residue-contact network features with other additional features that were not explored in previous studies. Importantly, a two-step feature selection procedure was proposed to select the most important and informative features that contribute to the prediction of disease association of SAVs. In cross-validation experiments on the benchmark dataset, FunSAV achieved a good prediction performance with the area under the curve (AUC) of 0.882, which is competitive with and in some cases better than other existing tools including SIFT, SNAP, Polyphen2, PANTHER, nsSNPAnalyzer and PhD-SNP. The sourcecodes of FunSAV and the datasets can be downloaded at http://sunflower.kuicr.kyoto u.ac.jp/sjn/FunSAV. PMID- 22937109 TI - Atmospheric oxygen tension slows myoblast proliferation via mitochondrial activation. AB - BACKGROUND: Mitochondrial activity inhibits proliferation and is required for differentiation of myoblasts. Myoblast proliferation is also inhibited by the ~20% oxygen level used in standard tissue culture. We hypothesize that mitochondrial activity would be greater at hyperoxia (20% O(2)) relative to more physiological oxygen (5% O(2)). METHODOLOGY/PRINCIPAL FINDINGS: Murine primary myoblasts from isolated myofibres and conditionally immortalized H-2K myoblasts were cultured at 5% and 20% oxygen. Proliferation, assayed by cell counts, EdU labeling, and CFSE dilution, was slower at 20% oxygen. Expression of MyoD in primary myoblasts was delayed at 20% oxygen, but myogenicity, as measured by fusion index, was slightly higher. FACS-based measurement of mitochondrial activity indicators and luminometric measurement of ATP levels revealed that mitochondria exhibited greater membrane potential and higher levels of Reactive Oxygen Species (ROS) at 20% oxygen with concomitant elevation of intracellular ATP. Mitochondrial mass was unaffected. Low concentrations of CCCP, a respiratory chain uncoupler, and Oligomycin A, an ATP synthase inhibitor, each increased the rate of myoblast proliferation. ROS were investigated as a potential mechanism of mitochondrial retrograde signaling, but scavenging of ROS levels by N-acetyl cysteine (NAC) or alpha-Phenyl-N-tert-butylnitrone (PBN) did not rescue the suppressed rate of cell division in hyperoxic conditions, suggesting other pathways. Primary myoblasts from older mice showed a slower proliferation than those from younger adult mice at 20% oxygen but no difference at 5% oxygen. CONCLUSIONS/SIGNIFICANCE: These results implicate mitochondrial regulation as a mechanistic explanation for myoblast response to oxygen tension. The rescue of proliferation rate in myoblasts of aged mice by 5% oxygen suggests a major artefactual component to age-related decline of satellite cell proliferation in standard tissue culture at 20% oxygen. It lends weight to the idea that these age related changes result at least in part from environmental factors rather than characteristics intrinsic to the satellite cell. PMID- 22937110 TI - Validation of an instrument to measure older adults' expectations regarding movement (ERM). AB - BACKGROUND: Many individuals with Parkinson's disease are not diagnosed and treated. Attitudes about aging and related help-seeking may affect the timely diagnosis of Parkinson's disease. Our objectives were to develop measures of older adults' expectations regarding movement with aging, specifically related to parkinsonism, and their beliefs about seeking healthcare for the diagnosis and treatment of parkinsonism. METHODS: We established content and face validity from interviews with experts, review of the literature, and pre-testing with key informants. Two 9-item instruments resulted: Expectations Regarding Movement (ERM) and Healthcare Seeking Beliefs for parkinsonism (HSB). These instruments were administered to 210 older adults at senior centers to investigate internal consistency and construct validity. RESULTS: 192 (91%) of the older adults completed more than 90% of the survey. The mean age was 76; 17 (9%) reported parkinsonism. Both scales demonstrated good internal consistency (alpha = 0.90). Factor analysis supported construct validity of the ERM and HSB scores. Older age, lower education, worse self-reported health and African American race each were associated with lower ERM scores, but not HSB scores. CONCLUSION: The ERM, a brief measure of expectations regarding movement with aging, shows reliability and validity. This scale may be useful in identifying older adults at increased risk for under-identification of Parkinson's disease. Further work is needed to measure healthcare seeking for parkinsonism. PMID- 22937111 TI - Rod-driven OFF pathway responses in the distal retina: dark-adapted flicker electroretinogram in mouse. AB - PURPOSE: The rodent retina does not exhibit a positive OFF-response in the electroretinogram (ERG), which makes it difficult to evaluate its OFF-pathway functions in vivo. We studied the rod-driven OFF pathway responses by using a dark-adapted 10-Hz flicker ERG procedure in mouse. MATERIALS AND METHODS: Conventional ERGs and 10-Hz dark-adapted flicker ERGs were obtained in wild-type mice (C57BL/6), in mice with pure rod (cpfl1) or pure cone (rho(-/-)) function, and in nob1 mice which have a selective ON-pathway defect. To isolate the response from ON or OFF pathway, glutamate analogs 2-amino-4-phosphobutyric acid (APB, an ON pathway blocker) and cis-2, 3-piperidine-dicarboxylic acid (PDA, an OFF pathway blocker), were injected intravitreally. RESULTS: The amplitude intensity profile of the dark-adapted 10-Hz flicker ERG in the wild-type mice exhibits two peaks at middle and high light intensities. The two peaks represent rod- and cone-driven responses respectively. In APB-treated C57BL/6 mice and in nob1 mice, the dark-adapted ERG b-waves were absent. However, both rod- and cone driven OFF pathway responses were evident with flicker ERG recording. At middle light intensities that activate only rod system, the flicker ERG responses in saline-injected nob1 mice were similar to those in APB-injected cpfl1 mice and wild-type mice. These responses are sensitive to PDA. The amplitudes of these rod driven OFF pathway responses were approximately 20% of the total rod-driven flicker ERG responses. CONCLUSION: We demonstrate that the rod-OFF bipolar cell pathway is functional in the outer retina. The dark-adapted flicker ERG is practical for the evaluation of rod- and cone-driven responses, and the residual OFF pathway signals in subjects with ON pathway defects. PMID- 22937112 TI - Crystal structures of archaemetzincin reveal a moldable substrate-binding site. AB - BACKGROUND: Archaemetzincins are metalloproteases occurring in archaea and some mammalia. They are distinct from all the other metzincins by their extended active site consensus sequence HEXXHXXGXXHCX(4)CXMX(17)CXXC featuring four conserved cysteine residues. Very little is known about their biological importance and structure-function relationships. PRINCIPAL FINDINGS: Here we present three crystal structures of the archaemetzincin AfAmzA (Uniprot O29917) from Archaeoglobus fulgidus, revealing a metzincin architecture featuring a zinc finger-like structural element involving the conserved cysteines of the consensus motif. The active sites in all three structures are occluded to different extents rendering the enzymes proteolytically inactive against a large variety of tested substrates. Owing to the different ligand binding there are significant differences in active site architecture, revealing a large flexibility of the loops covering the active site cleft. CONCLUSIONS: The crystal structures of AfAmzA provide the structural basis for the lack of activity in standard proteolytic assays and imply a triggered activity onset upon opening of the active site cleft. PMID- 22937113 TI - The consistency of beneficial fitness effects of mutations across diverse genetic backgrounds. AB - Parallel and convergent evolution have been remarkably common observations in molecular adaptation but primarily in the context of the same genotype adapting to the same conditions. These phenomena therefore tell us about the stochasticity and limitations of adaptation. The limited data on convergence and parallelism in the adaptation of different genotypes conflict as to the importance of such events. If the effects of beneficial mutations are highly context dependent (i.e., if they are epistatic), different genotypes should adapt through different mutations. Epistasis for beneficial mutations has been investigated but mainly through measurement of interactions between individually beneficial mutations for the same genotype. We examine epistasis for beneficial mutations at a broader genetic scale by measuring the fitness effects of two mutations beneficial for the ssDNA bacteriophage ID11 in eight different, related genotypes showing 0.3 3.7% nucleotide divergence from ID11. We found no evidence for sign epistasis, but the mutations tended to have much smaller or no effects on fitness in the new genotypes. We found evidence for diminishing-returns epistasis; the effects were more beneficial for lower-fitness genotypes. The patterns of epistasis were not determined by phylogenetic relationships to the original genotype. To improve our understanding of the patterns of epistasis, we fit the data to a model in which each mutation had a constant, nonepistatic phenotypic effect across genotypes and the phenotype-fitness map had a single optimum. This model fit the data well, suggesting that epistasis for these mutations was due to nonlinearity in the phenotype-fitness mapping and that the likelihood of parallel evolution depends more on phenotype than on genotype. PMID- 22937114 TI - High prevalence of vitamin D deficiency in pregnant women: a national cross sectional survey. AB - An increasing number of studies suggest that vitamin D deficiency during pregnancy is associated with multiple adverse health outcomes in mothers, neonates and children. There are no representative country data available on vitamin D status of pregnant women in Europe. The aim of this study was to estimate the prevalence of vitamin D deficiency among Belgian pregnant women and to assess the determinants of vitamin D status in the first and third trimester of pregnancy. The women were selected via a multi-stage proportionate-to-size sampling design. Blood samples were collected and a questionnaire was completed face-to-face. 55 obstetric clinics were randomly selected and 1311 pregnant women participated in the study. The median serum 25-hydroxyvitamin D [25-(OH)D] concentration was significantly lower in the first trimester (20.4 ng/ml) than in third trimester (22.7 ng/ml). Of all women, 74.1% (95%CI = 71.8-76.5%) were vitamin D insufficient (25-(OH)D <30 ng/ml), 44.6% (95%CI = 41.9-47.3%) were vitamin D deficient (25-(OH)D <20 ng/ml), while 12.1% (95%CI = 10.3-13.8%) were severely vitamin D deficient (25-(OH)D <10 ng/ml). Of all women included, 62.0% reported taking vitamin D-containing multivitamins, of which only 24.2% started taking those before pregnancy. The risk of vitamin D deficiency (25-(OH)D <20 ng/ml) was significantly higher for less educated women and women who reported not going on holidays to sunny climates. The risk of severe vitamin D deficiency (25-(OH)D <10 ng/ml) decreased for women who reported alcohol consumption during pregnancy, decreased with more frequent use of sunscreen lotion and increased for smokers and women who reported preference for shadow. In conclusion, vitamin D deficiency is highly prevalent among pregnant women in Belgium and this raises concerns about the health consequences for the mother and the offspring. A targeted screening strategy to detect and treat women at high risk of severe vitamin D deficiency is needed in Belgium and in Europe. PMID- 22937115 TI - Berberine reduces fibronectin expression by suppressing the S1P-S1P2 receptor pathway in experimental diabetic nephropathy models. AB - The accumulation of glomerular extracellular matrix (ECM) is one of the critical pathological characteristics of diabetic renal fibrosis. Fibronectin (FN) is an important constituent of ECM. Our previous studies indicate that the activation of the sphingosine kinase 1 (SphK1)-sphingosine 1- phosphate (S1P) signaling pathway plays a key regulatory role in FN production in glomerular mesangial cells (GMCs) under diabetic condition. Among the five S1P receptors, the activation of S1P2 receptor is the most abundant. Berberine (BBR) treatment also effectively inhibits SphK1 activity and S1P production in the kidneys of diabetic models, thus improving renal injury. Based on these data, we further explored whether BBR could prevent FN production in GMCs under diabetic condition via the S1P2 receptor. Here, we showed that BBR significantly down-regulated the expression of S1P2 receptor in diabetic rat kidneys and GMCs exposed to high glucose (HG) and simultaneously inhibited S1P2 receptor-mediated FN overproduction. Further, BBR also obviously suppressed the activation of NF kappaB induced by HG, which was accompanied by reduced S1P2 receptor and FN expression. Taken together, our findings suggest that BBR reduces FN expression by acting on the S1P2 receptor in the mesangium under diabetic condition. The role of BBR in S1P2 receptor expression regulation could closely associate with its inhibitory effect on NF-kappaB activation. PMID- 22937116 TI - Technical and regulatory shortcomings of the TaqMan version 1 HIV viral load assay. AB - BACKGROUND: The lower limit of detection of the original Roche Amplicor HIV plasma viral load (pVL) assay (50 copies/mL) has defined HIV treatment success. The Amplicor assay, however, has been replaced by the Roche TaqMan assay(s). Changes to the limits of detection and calibration have not been validated for clinical utility. Sudden increases in the number of patients with detectable pVL have been reported following the introduction of the TaqMan version 1 assay. METHODS: Between October 2009 and April 2010 all routine pVL samples from British Columbia, Canada, with 40-250 copies/mL by TaqMan were re-tested by Amplicor (N = 1198). Subsequent short-term virological and resistance outcomes were followed in patients with unchanged therapy (N = 279; median 3.2 months follow-up). RESULTS: TaqMan and Amplicor values correlated poorly at low pVL values. Low-level pVL by TaqMan was not associated with impending short-term virological failure; only 17% of patients with 40-250 copies/mL by TaqMan had detectable pVL by Amplicor at follow-up. During the follow-up period only 20% of patients had an increase in pVL by TaqMan (median [IQR]: 80 [36-283] copies/mL). In addition, in ~2.4% of samples pVL was dramatically underestimated by TaqMan due to poor binding of the proprietary TaqMan primers. CONCLUSIONS: The replacement of Amplicor with the TaqMan assay has altered the previously accepted definition of HIV treatment failure without any evidence to support the clinical relevance of the new definition. Given the systematic differences in measurement in the low pVL range the British Columbia HIV treatment guidelines now use a threshold of >250 copies/mL by TaqMan to define treatment failure. PMID- 22937117 TI - Cutaneous papilloma and squamous cell carcinoma therapy utilizing nanosecond pulsed electric fields (nsPEF). AB - Nanosecond pulsed electric fields (nsPEF) induce apoptotic pathways in human cancer cells. The potential therapeutic effective of nsPEF has been reported in cell lines and in xenograft animal tumor model. The present study investigated the ability of nsPEF to cause cancer cell death in vivo using carcinogen-induced animal tumor model, and the pulse duration of nsPEF was only 7 and 14 nano second (ns). An nsPEF generator as a prototype medical device was used in our studies, which is capable of delivering 7-30 nanosecond pulses at various programmable amplitudes and frequencies. Seven cutaneous squamous cell carcinoma cell lines and five other types of cancer cell lines were used to detect the effect of nsPEF in vitro. Rate of cell death in these 12 different cancer cell lines was dependent on nsPEF voltage and pulse number. To examine the effect of nsPEF in vivo, carcinogen-induced cutaneous papillomas and squamous cell carcinomas in mice were exposed to nsPEF with three pulse numbers (50, 200, and 400 pulses), two nominal electric fields (40 KV/cm and 31 KV/cm), and two pulse durations (7 ns and 14 ns). Carcinogen-induced cutaneous papillomas and squamous carcinomas were eliminated efficiently using one treatment of nsPEF with 14 ns duration pulses (33/39 = 85%), and all remaining lesions were eliminated after a 2nd treatment (6/39 = 15%). 13.5% of carcinogen-induced tumors (5 of 37) were eliminated using 7 ns duration pulses after one treatment of nsPEF. Associated with tumor lysis, expression of the anti-apoptotic proteins Bcl-xl and Bcl-2 were markedly reduced and apoptosis increased (TUNEL assay) after nsPEF treatment. nsPEF efficiently causes cell death in vitro and removes papillomas and squamous cell carcinoma in vivo from skin of mice. nsPEF has the therapeutic potential to remove human squamous carcinoma. PMID- 22937118 TI - Body mass index and mortality in chronic obstructive pulmonary disease: a meta analysis. AB - BACKGROUND: The association between body mass index (BMI) and mortality in patients suffering from chronic obstructive pulmonary disease (COPD) has been a subject of interest for decades. However, the evidence is inadequate to draw robust conclusions because some studies were generally small or with a short follow-up. METHODS: We carried out a search in MEDLINE, Cochrane Central Register of Controlled Trials, and EMBASE database for relevant studies. Relative risks (RRs) with 95% confidence interval (CI) were calculated to assess the association between BMI and mortality in patients with COPD. In addition, a baseline risk adjusted analysis was performed to investigate the strength of this association. RESULTS: 22 studies comprising 21,150 participants were included in this analysis. Compared with patients having a normal BMI, underweight individuals were associated with higher mortality (RR = 1.34, 95% CI = 1.01-1.78), whereas overweight (RR = 0.47, 95% CI = 0.33-0.68) and obese (RR = 0.59, 95% CI = 0.38 0.91) patients were associated with lower mortality. We further performed a baseline risk-adjusted analysis and obtained statistically similar results. CONCLUSION: Our study showed that for patients with COPD being overweight or obese had a protective effect against mortality. However, the relationship between BMI and mortality in different classes of obesity needed further clarification in well-designed clinical studies. PMID- 22937120 TI - The effects of landscape variables on the species-area relationship during late stage habitat fragmentation. AB - Few studies have focused explicitly on the later stages of the fragmentation process, or "late-stage fragmentation", during which habitat area and patch number decrease simultaneously. This lack of attention is despite the fact that many of the anthropogenically fragmented habitats around the world are, or soon will be, in late-stage fragmentation. Understanding the ecological processes and patterns that occur in late-stage fragmentation is critical to protect the species richness in these fragments. We investigated plant species composition on 152 islands in the Thousand Island Lake, China. A random sampling method was used to create simulated fragmented landscapes with different total habitat areas and numbers of patches mimicking the process of late-stage fragmentation. The response of the landscape-scale species-area relationship (LSAR) to fragmentation per se was investigated, and the contribution of inter-specific differences in the responses to late-stage fragmentation was tested. We found that the loss of species at small areas was compensated for by the effects of fragmentation per se, i.e., there were weak area effects on species richness in landscapes due to many patches with irregular shapes and high variation in size. The study also illustrated the importance of inter-specific differences for responses to fragmentation in that the LSARs of rare and common species were differently influenced by the effects of fragmentation per se. In conclusion, our analyses at the landscape scale demonstrate the significant influences of fragmentation per se on area effects and the importance of inter-specific differences for responses to fragmentation in late-stage fragmentation. These findings add to our understanding of the effects of habitat fragmentation on species diversity. PMID- 22937119 TI - Human parainfluenza virus-associated respiratory tract infection among children and genetic analysis of HPIV-3 strains in Beijing, China. AB - The relevance of human parainfluenza viruses (HPIVs) to the epidemiology of acute respiratory infections (ARI) in China is unclear. From May 2008 to September 2010, 443 nasopharyngeal aspirates (NPAs) from hospitalized pediatric patients (age from 1 to 93 months) in Beijing were collected and screened for HPIVs and other common respiratory viruses by real-time RT-PCR. Sixty-two of 443 samples were positive for HPIVs with 4 positive for HPIV-2 and 58 positive for HPIV-3, indicating that HPIV-3 was the predominant virus present during the study period. A phylogenetic tree based on all the available HN (hemagglutinin-neuraminidase) sequences of HPIV-3 indicated that three distinct clusters (A,B, and C) were circulating with some temporal and regional clustering. Cluster C was further divided into sub-clusters, C1, C2, C3 and C4. HPIV-3 from Beijing isolates belonged to sub-cluster C3, and were grouped with the isolates from two Provinces of China and the neighboring country of Japan. Genetic analysis based on entire HN gene revealed that the HPIV-3 isolates from Beijing were highly similar with 97.2%-100% identity at the nucleotide level and these could be divided into two closely related lineages, C3a and C3b. These findings suggested that there was co circulation of multiple lineages of HPIV-3 in the Beijing region during the study period. This is the first study to describe the epidemiology and molecular characterization of HPIVs in China. PMID- 22937121 TI - Transcriptional profiling of bone marrow stromal cells in response to Porphyromonas gingivalis secreted products. AB - Periodontitis is an infectious inflammatory disease that destroys the tooth supporting (periodontal) tissues. Porphyromonas gingivalis is an oral pathogen highly implicated in the pathogenesis of this disease. It can exert its effects to a number of cells, including osteogenic bone marrow stromal cells which are important for homeostastic capacity of the tissues. By employing gene microarray technology, this study aimed to describe the overall transcriptional events (>2 fold regulation) elicited by P. gingivalis secreted products in bone marrow stromal cells, and to dissect further the categories of genes involved in bone metabolism, inflammatory and immune responses. After 6 h of challenge with P. gingivalis, 271 genes were up-regulated whereas 209 genes were down-regulated, whereas after 24 h, these numbers were 259 and 109, respectively. The early (6 h) response was characterised by regulation of genes associated with inhibition of cell cycle, induction of apoptosis and loss of structural integrity, whereas the late (24 h) response was characterised by induction of chemokines, cytokines and their associated intracellular pathways (such as NF-kappaB), mediators of connective tissue and bone destruction, and suppression of regulators of osteogenic differentiation. The most strongly up-regulated genes were lipocalin 2 (LCN2) and serum amyloid A3 (SAA3), both encoding for proteins of the acute phase inflammatory response. Collectively, these transcriptional changes elicited by P. gingivalis denote that the fundamental cellular functions are hindered, and that the cells acquire a phenotype commensurate with propagated innate immune response and inflammatory-mediated tissue destruction. In conclusion, the global transcriptional profile of bone marrow stromal cells in response to P. gingivalis is marked by deregulated homeostatic functions, with implications in the pathogenesis of periodontitis. PMID- 22937122 TI - Combination training in aging individuals modifies functional connectivity and cognition, and is potentially affected by dopamine-related genes. AB - BACKGROUND: Aging is a major co-risk factor in many neurodegenerative diseases. Cognitive enrichment positively affects the structural plasticity of the aging brain. In this study, we evaluated effects of a set of structured multimodal activities (Combination Training; CT) on cognitive performances, functional connectivity, and cortical thickness of a group of healthy elderly individuals. CT lasted six months. METHODOLOGY: Neuropsychological and occupational performances were evaluated before and at the end of the training period. fMRI was used to assess effects of training on resting state network (RSN) functional connectivity using Independent Component Analysis (ICA). Effects on cortical thickness were also studied. Finally, we evaluated whether specific dopamine related genes can affect the response to training. PRINCIPAL FINDINGS: Results of the study indicate that CT improves cognitive/occupational performances and reorganizes functional connectivity. Intriguingly, individuals responding to CT showed specific dopamine-related genotypes. Indeed, analysis of dopamine-related genes revealed that carriers of DRD3 ser9gly and COMT Val158Met polymorphisms had the greatest benefits from exposure to CT. CONCLUSIONS AND SIGNIFICANCE: Overall, our findings support the idea that exposure to a set of structured multimodal activities can be an effective strategy to counteract aging-related cognitive decline and also indicate that significant capability of functional and structural changes are maintained in the elderly. PMID- 22937123 TI - Selective expression of KCNS3 potassium channel alpha-subunit in parvalbumin containing GABA neurons in the human prefrontal cortex. AB - The cognitive deficits of schizophrenia appear to be associated with altered cortical GABA neurotransmission in the subsets of inhibitory neurons that express either parvalbumin (PV) or somatostatin (SST). Identification of molecular mechanisms that operate selectively in these neurons is essential for developing targeted therapeutic strategies that do not influence other cell types. Consequently, we sought to identify, in the human cortex, gene products that are expressed selectively by PV and/or SST neurons, and that might contribute to their distinctive functional properties. Based on previously reported expression patterns in the cortex of mice and humans, we selected four genes: KCNS3, LHX6, KCNAB1, and PPP1R2, encoding K(+) channel Kv9.3 modulatory alpha-subunit, LIM homeobox protein 6, K(+) channel Kvbeta1 subunit, and protein phosphatase 1 regulatory subunit 2, respectively, and examined their colocalization with PV or SST mRNAs in the human prefrontal cortex using dual-label in situ hybridization with (35)S- and digoxigenin-labeled antisense riboprobes. KCNS3 mRNA was detected in almost all PV neurons, but not in SST neurons, and PV mRNA was detected in >90% of KCNS3 mRNA-expressing neurons. LHX6 mRNA was detected in almost all PV and >90% of SST neurons, while among all LHX6 mRNA-expressing neurons 50% expressed PV mRNA and >44% expressed SST mRNA. KCNAB1 and PPP1R2 mRNAs were detected in much larger populations of cortical neurons than PV or SST neurons. These findings indicate that KCNS3 is a selective marker of PV neurons, whereas LHX6 is expressed by both PV and SST neurons. KCNS3 and LHX6 might be useful for characterizing cell-type specific molecular alterations of cortical GABA neurotransmission and for the development of novel treatments targeting PV and/or SST neurons in schizophrenia. PMID- 22937124 TI - Mechanisms of dietary response in mice and primates: a role for EGR1 in regulating the reaction to human-specific nutritional content. AB - BACKGROUND: Humans have a widely different diet from other primate species, and are dependent on its high nutritional content. The molecular mechanisms responsible for adaptation to the human diet are currently unknown. Here, we addressed this question by investigating whether the gene expression response observed in mice fed human and chimpanzee diets involves the same regulatory mechanisms as expression differences between humans and chimpanzees. RESULTS: Using mouse and primate transcriptomic data, we identified the transcription factor EGR1 (early growth response 1) as a putative regulator of diet-related differential gene expression between human and chimpanzee livers. Specifically, we predict that EGR1 regulates the response to the high caloric content of human diets. However, we also show that close to 90% of the dietary response to the primate diet found in mice, is not observed in primates. This might be explained by changes in tissue-specific gene expression between taxa. CONCLUSION: Our results suggest that the gene expression response to the nutritionally rich human diet is partially mediated by the transcription factor EGR1. While this EGR1 driven response is conserved between mice and primates, the bulk of the mouse response to human and chimpanzee dietary differences is not observed in primates. This result highlights the rapid evolution of diet-related expression regulation and underscores potential limitations of mouse models in dietary studies. PMID- 22937125 TI - Serum levels of TWEAK and scavenger receptor CD163 in type 1 diabetes mellitus: relationship with cardiovascular risk factors. a case-control study. AB - OBJECTIVE: To test the usefulness of serum concentrations of tumor necrosis factor-like weak inducer of apoptosis (sTWEAK) and soluble scavenger receptor CD163 (sCD163) as markers of subtle inflammation in patients with type 1 diabetes mellitus (T1DM) without clinical cardiovascular (CV) disease and to evaluate their relationship with arterial stiffness (AS). METHODS: Sixty-eight patients with T1DM and 68 age and sex-matched, healthy subjects were evaluated. Anthropometrical variables and CV risk factors were recorded. Serum concentrations of sTWEAK and sCD163 were measured. AS was assessed by aortic pulse wave velocity (aPWV). All statistical analyses were stratified by gender. RESULTS: T1DM patients showed lower serum concentrations of sTWEAK (Men: 1636.5 (1146.3-3754.8) pg/mL vs. 765.9 (650.4-1097.1) pg/mL; p<0.001. Women: 1401.0 (788.0-2422.2) pg/mL vs. 830.1 (562.6-1175.9) pg/mL; p = 0.011) compared with their respective controls. Additionally, T1DM men had higher serum concentrations of sCD163 (285.0 (247.7-357.1) ng/mL vs. 224.8 (193.3-296.5) ng/mL; p = 0.012) compared with their respective controls. sTWEAK correlated negatively with aPWV in men (r = -0.443; p<0.001). However, this association disappeared after adjusting for potential confounders. In men, the best multiple linear regression model showed that the independent predictors of sTWEAK were T1DM and WHR (R(2) = 0.640; p<0.001). In women, T1DM and SBP were the independent predictors for sTWEAK (R(2) = 0.231; p = 0.001). CONCLUSION: sTWEAK is decreased in T1DM patients compared with age and sex-matched healthy subjects after adjusting for classic CV risk factors, although sTWEAK levels may be partially influenced by some of them. Additionally, T1DM men have higher serum concentrations of sCD163. These results point out an association between the inflammatory system and CV risk in T1DM. PMID- 22937126 TI - Prediction of protein-protein interaction sites by random forest algorithm with mRMR and IFS. AB - Prediction of protein-protein interaction (PPI) sites is one of the most challenging problems in computational biology. Although great progress has been made by employing various machine learning approaches with numerous characteristic features, the problem is still far from being solved. In this study, we developed a novel predictor based on Random Forest (RF) algorithm with the Minimum Redundancy Maximal Relevance (mRMR) method followed by incremental feature selection (IFS). We incorporated features of physicochemical/biochemical properties, sequence conservation, residual disorder, secondary structure and solvent accessibility. We also included five 3D structural features to predict protein-protein interaction sites and achieved an overall accuracy of 0.672997 and MCC of 0.347977. Feature analysis showed that 3D structural features such as Depth Index (DPX) and surface curvature (SC) contributed most to the prediction of protein-protein interaction sites. It was also shown via site-specific feature analysis that the features of individual residues from PPI sites contribute most to the determination of protein-protein interaction sites. It is anticipated that our prediction method will become a useful tool for identifying PPI sites, and that the feature analysis described in this paper will provide useful insights into the mechanisms of interaction. PMID- 22937127 TI - Synchrotron ultraviolet microspectroscopy on rat cortical bone: involvement of tyrosine and tryptophan in the osteocyte and its environment. AB - Alcohol induced osteoporosis is characterized by a bone mass decrease and microarchitecture alterations. Having observed an excess in osteocyte apoptosis, we aimed to assess the bone tissue biochemistry, particularly in the osteocyte and its environment. For this purpose, we used a model of alcohol induced osteoporosis in rats. Bone sections of cortical bone were investigated using synchrotron UV-microspectrofluorescence at subcellular resolution. We show that bone present three fluorescence peaks at 305, 333 and 385 nm, respectively corresponding to tyrosine, tryptophan and collagen. We have determined that tyrosine/collagen and tryptophan/collagen ratios were higher in the strong alcohol consumption group. Tryptophan is related to the serotonin metabolism involved in bone formation, while tyrosine is involved in the activity of tyrosine kinases and phosphatases in osteocytes. Our experiment represents the first combined synchrotron UV microspectroscopy analysis of bone tissue with a quantitative biochemical characterization in the osteocyte and surrounding matrix performed separately. PMID- 22937128 TI - Utility of the plasma level of suPAR in monitoring risk of mortality during TB treatment. AB - OBJECTIVE: To investigate whether changes in the plasma level of soluble urokinase plasminogen activator receptor (suPAR) can be used to monitor tuberculosis (TB) treatment efficacy. DESIGN: This prospective cohort study included 278 patients diagnosed with active pulmonary TB and followed throughout the 8-month treatment period. RESULTS: Mortality during treatment was higher in the highest inclusion quartile of suPAR (23%) compared to the lowest three quartiles (7%), the risk ratio being 3.1 (95% CI 1.65-6.07). No association between early smear conversion and subsequent mortality or inclusion suPAR was observed. After 1 and 2 months of treatment, an increase in suPAR compared to at diagnosis was associated with a Mortality Rate Ratio (MRR) of 4.5 (95%CI: 1.45 14.1) and 2.1 (95%CI 0.62-6.82), respectively, for the remaining treatment period. CONCLUSIONS: The present study confirmed that elevated suPAR level at time of initiation of TB treatment is associated with increased risk of mortality. Furthermore, increased suPAR levels after one month of treatment was associated with increased risk of mortality during the remaining 7-month treatment period. PMID- 22937129 TI - Triphala and its active constituent chebulinic acid are natural inhibitors of vascular endothelial growth factor-a mediated angiogenesis. AB - Triphala churna (THL) is a combination of three fruits that has been used for many years in India for the treatment of various diseases. There are now reports which indicate that THL can inhibit growth of malignant tumors in animals. However, the mechanisms by which THL mediates its anti-tumor actions are still being explored. Because vascular endothelial growth factor-A (VEGF) induced angiogenesis plays a critical role in the pathogenesis of cancer, we therefore investigated whether tumor inhibitory effects of THL or its active constituents are through suppression of VEGF actions. We herein report that THL and chebulinic (CI) present in THL can significantly and specifically inhibit VEGF induced angiogenesis by suppressing VEGF receptor-2 (VEGFR-2) phosphorylation. These results are of clinical significance as these inexpensive and non-toxic natural products can be used for the prevention and treatment of diseases where VEGF induced angiogenesis has an important role. PMID- 22937130 TI - Programmable illumination and high-speed, multi-wavelength, confocal microscopy using a digital micromirror. AB - Confocal microscopy is routinely used for high-resolution fluorescence imaging of biological specimens. Most standard confocal systems scan a laser across a specimen and collect emitted light passing through a single pinhole to produce an optical section of the sample. Sequential scanning on a point-by-point basis limits the speed of image acquisition and even the fastest commercial instruments struggle to resolve the temporal dynamics of rapid cellular events such as calcium signals. Various approaches have been introduced that increase the speed of confocal imaging. Nipkov disk microscopes, for example, use arrays of pinholes or slits on a spinning disk to achieve parallel scanning which significantly increases the speed of acquisition. Here we report the development of a microscope module that utilises a digital micromirror device as a spatial light modulator to provide programmable confocal optical sectioning with a single camera, at high spatial and axial resolution at speeds limited by the frame rate of the camera. The digital micromirror acts as a solid state Nipkov disk but with the added ability to change the pinholes size and separation and to control the light intensity on a mirror-by-mirror basis. The use of an arrangement of concave and convex mirrors in the emission pathway instead of lenses overcomes the astigmatism inherent with DMD devices, increases light collection efficiency and ensures image collection is achromatic so that images are perfectly aligned at different wavelengths. Combined with non-laser light sources, this allows low cost, high-speed, multi-wavelength image acquisition without the need for complex wavelength-dependent image alignment. The micromirror can also be used for programmable illumination allowing spatially defined photoactivation of fluorescent proteins. We demonstrate the use of this system for high-speed calcium imaging using both a single wavelength calcium indicator and a genetically encoded, ratiometric, calcium sensor. PMID- 22937131 TI - Impact of nesting mortality on avian breeding phenology: a case study on the red backed shrike (Lanius collurio). AB - The seasonal timing of avian reproduction is supposed primarily to coincide with favourable feeding conditions. Long-term changes in avian breeding phenology are thus mostly scrutinized in relation to climatic factors and matching of the food supplies, while the role of nesting mortality is largely unexplored. Here we show that higher seasonal mean daily mortality rate leads to a shift in the distribution of breeding times of the successful nests to later dates in an an open-nesting passerine bird, the red-backed shrike Lanius collurio. The effect appeared to be strong enough to enhance or counteract the influence of climatic factors and breeding density on the inter-annual variation in mean hatching dates. Moreover, the seasonal distribution of reproductive output was shifted to larger, or smaller, broods early in the season when the nesting mortality increased, or decreased, respectively, during the season. We suggest that population level changes in timing of breeding caused by a general advancement of spring and of the food supplies might be altered by the seasonality in nesting mortality. Hence, we argue that consideration of nesting mortality is of major importance for understanding long-term trends in avian phenology, particularly in species capable of renesting. PMID- 22937132 TI - The protein kinase KIS impacts gene expression during development and fear conditioning in adult mice. AB - The brain-enriched protein kinase KIS (product of the gene UHMK1) has been shown to phosphorylate the human splicing factor SF1 in vitro. This phosphorylation in turn favors the formation of a U2AF(65)-SF1-RNA complex which occurs at the 3' end of introns at an early stage of spliceosome assembly. Here, we analyzed the effects of KIS knockout on mouse SF1 phosphorylation, physiology, adult behavior, and gene expression in the neonate brain. We found SF1 isoforms are differently expressed in KIS-ko mouse brains and fibroblasts. Re-expression of KIS in fibroblasts restores a wild type distribution of SF1 isoforms, confirming the link between KIS and SF1. Microarray analysis of transcripts in the neonate brain revealed a subtle down-regulation of brain specific genes including cys-loop ligand-gated ion channels and metabolic enzymes. Q-PCR analyses confirmed these defects and point to an increase of pre-mRNA over mRNA ratios, likely due to changes in splicing efficiency. While performing similarly in prepulse inhibition and most other behavioral tests, KIS-ko mice differ in spontaneous activity and contextual fear conditioning. This difference suggests that disregulation of gene expression due to KIS inactivation affects specific brain functions. PMID- 22937133 TI - Chronic ketamine administration modulates midbrain dopamine system in mice. AB - Ketamine is an anesthetic and a popular abusive drug. As an anesthetic, effects of ketamine on glutamate and GABA transmission have been well documented but little is known about its long-term effects on the dopamine system. In the present study, the effects of ketamine on dopamine were studied in vitro and in vivo. In pheochromocytoma (PC 12) cells and NGF differentiated-PC 12 cells, ketamine decreased the cell viability while increasing dopamine (DA) concentrations in a dose-related manner. However, ketamine did not affect the expression of genes involved in DA synthesis. In the long-term (3 months) ketamine treated mice, significant increases of DA contents were found in the midbrain. Increased DA concentrations were further supported by up-regulation of tyrosine hydroxylase (TH), the rate limiting enzyme in catecholamine synthesis. Activation of midbrain dopaminergic neurons could be related to ketamine modulated cortical-subcortical glutamate connections. Using western blotting, significant increases in BDNF protein levels were found in the midbrain, suggesting that perhaps BDNF pathways in the cortical-subcortical connections might contribute to the long-term ketamine induced TH upregulation. These data suggest that long-term ketamine abuse caused a delayed and persistent upregulation of subcortical DA systems, which may contribute to the altered mental status in ketamine abusers. PMID- 22937134 TI - Hand to mouth in a neandertal: right-handedness in Regourdou 1. AB - We describe and analyze a Neandertal postcranial skeleton and dentition, which together show unambiguous signs of right-handedness. Asymmetries between the left and right upper arm in Regourdou 1 were identified nearly 20 years ago, then confirmed by more detailed analyses of the inner bone structure for the clavicle, humerus, radius and ulna. The total pattern of all bones in the shoulder and arm reveals that Regourdou 1 was a right-hander. Confirmatory evidence comes from the mandibular incisors, which display a distinct pattern of right oblique scratches, typical of right-handed manipulations performed at the front of the mouth. Regourdou's right handedness is consistent with the strong pattern of manual lateralization in Neandertals and further confirms a modern pattern of left brain dominance, presumably signally linguistic competence. These observations along with cultural, genetic and morphological evidence indicate language competence in Neandertals and their European precursors. PMID- 22937136 TI - Colorimetric focus-forming assay with automated focus counting by image analysis for quantification of infectious hepatitis C virions. AB - Hepatitis C virus (HCV) infection is the leading cause of liver transplantation in Western countries. Studies of HCV infection using cell culture-produced HCV (HCVcc) in vitro systems require quantification of infectious HCV virions, which has conventionally been performed by immunofluorescence-based focus-forming assay with manual foci counting; however, this is a laborious and time-consuming procedure with potentially biased results. In the present study, we established and optimized a method for convenient and objective quantification of HCV virions by colorimetric focus-forming assay with automated focus counting by image analysis. In testing different enzymes and chromogenic substrates, we obtained superior foci development using alkaline phosphatase-conjugated secondary antibody with BCIP/NBT chromogenic substrate. We additionally found that type I collagen coating minimized cell detachment during vigorous washing of the assay plate. After the colorimetric focus-forming assay, the foci number was determined using an ELISpot reader and image analysis software. The foci number and the calculated viral titer determined by this method strongly correlated with those determined by immunofluorescence-based focus-forming assay and manual foci counting. These results indicate that colorimetric focus-forming assay with automated focus counting by image analysis is applicable as a more-efficient and objective method for quantification of infectious HCV virions. PMID- 22937135 TI - Prevalence of c-KIT mutations in gonadoblastoma and dysgerminomas of patients with disorders of sex development (DSD) and ovarian dysgerminomas. AB - Activating c-KIT mutations (exons 11 and 17) are found in 10-40% of testicular seminomas, the majority being missense point mutations (codon 816). Malignant ovarian dysgerminomas represent ~3% of all ovarian cancers in Western countries, resembling testicular seminomas, regarding chromosomal aberrations and c-KIT mutations. DSD patients with specific Y-sequences have an increased risk for Type II Germ Cell Tumor/Cancer, with gonadoblastoma as precursor progressing to dysgerminoma. Here we present analysis of c-KIT exon 8, 9, 11, 13 and 17, and PDGFRA exon 12, 14 and 18 by conventional sequencing together with mutational analysis of c-KIT codon 816 by a sensitive and specific LightCycler melting curve analysis, confirmed by sequencing. The results are combined with data on TSPY and OCT3/4 expression in a series of 16 DSD patients presenting with gonadoblastoma and dysgerminoma and 15 patients presenting pure ovarian dysgerminomas without DSD. c-KIT codon 816 mutations were detected in five out of the total of 31 cases (all found in pure ovarian dysgerminomas). A synonymous SNP (rs 5578615) was detected in two patients, one DSD patient (with bilateral disease) and one patient with dysgerminoma. Next to these, three codon N822K mutations were detected in the group of 15 pure ovarian dysgerminomas. In total activating c-KIT mutations were found in 53% of ovarian dysgerminomas without DSD. In the group of 16 DSD cases a N505I and D820E mutation was found in a single tumor of a patient with gonadoblastoma and dysgerminoma. No PDGFRA mutations were found. Positive OCT3/4 staining was present in all gonadoblastomas and dysgerminomas investigated, TSPY expression was only seen in the gonadoblastoma/dysgerminoma lesions of the 16 DSD patients. This data supports the existence of two distinct but parallel pathways in the development of dysgerminoma, in which mutational status of c-KIT might parallel the presence of TSPY. PMID- 22937137 TI - Over-expression of monoacylglycerol lipase (MGL) in small intestine alters endocannabinoid levels and whole body energy balance, resulting in obesity. AB - The function of small intestinal monoacylglycerol lipase (MGL) is unknown. Its expression in this tissue is surprising because one of the primary functions of the small intestine is to convert diet-derived MGs to triacylglycerol (TG), and not to degrade them. To elucidate the function of intestinal MGL, we generated transgenic mice that over-express MGL specifically in small intestine (iMGL mice). After only 3 weeks of high fat feeding, iMGL mice showed an obese phenotype; body weight gain and body fat mass were markedly higher in iMGL mice, along with increased hepatic and plasma TG levels compared to wild type littermates. The iMGL mice were hyperphagic and displayed reduced energy expenditure despite unchanged lean body mass, suggesting that the increased adiposity was due to both increased caloric intake and systemic effects resulting in a hypometabolic rate. The presence of the transgene resulted in lower levels of most MG species in intestinal mucosa, including the endocannabinoid 2 arachidonoyl glycerol (2-AG). The results therefore suggest a role for intestinal MGL, and intestinal 2-AG and perhaps other MG species, in whole body energy balance via regulation of food intake as well as metabolic rate. PMID- 22937138 TI - Crystal structures of three classes of non-steroidal anti-inflammatory drugs in complex with aldo-keto reductase 1C3. AB - Aldo-keto reductase 1C3 (AKR1C3) catalyses the NADPH dependent reduction of carbonyl groups in a number of important steroid and prostanoid molecules. The enzyme is also over-expressed in prostate and breast cancer and its expression is correlated with the aggressiveness of the disease. The steroid products of AKR1C3 catalysis are important in proliferative signalling of hormone-responsive cells, while the prostanoid products promote prostaglandin-dependent proliferative pathways. In these ways, AKR1C3 contributes to tumour development and maintenance, and suggest that inhibition of AKR1C3 activity is an attractive target for the development of new anti-cancer therapies. Non-steroidal anti inflammatory drugs (NSAIDs) are one well-known class of compounds that inhibits AKR1C3, yet crystal structures have only been determined for this enzyme with flufenamic acid, indomethacin, and closely related analogues bound. While the flufenamic acid and indomethacin structures have been used to design novel inhibitors, they provide only limited coverage of the NSAIDs that inhibit AKR1C3 and that may be used for the development of new AKR1C3 targeted drugs. To understand how other NSAIDs bind to AKR1C3, we have determined ten crystal structures of AKR1C3 complexes that cover three different classes of NSAID, N phenylanthranilic acids (meclofenamic acid, mefenamic acid), arylpropionic acids (flurbiprofen, ibuprofen, naproxen), and indomethacin analogues (indomethacin, sulindac, zomepirac). The N-phenylanthranilic and arylpropionic acids bind to common sites including the enzyme catalytic centre and a constitutive active site pocket, with the arylpropionic acids probing the constitutive pocket more effectively. By contrast, indomethacin and the indomethacin analogues sulindac and zomepirac, display three distinctly different binding modes that explain their relative inhibition of the AKR1C family members. This new data from ten crystal structures greatly broadens the base of structures available for future structure-guided drug discovery efforts. PMID- 22937139 TI - Zebrafish foxP2 zinc finger nuclease mutant has normal axon pathfinding. AB - foxP2, a forkhead-domain transcription factor, is critical for speech and language development in humans, but its role in the establishment of CNS connectivity is unclear. While in vitro studies have identified axon guidance molecules as targets of foxP2 regulation, and cell culture assays suggest a role for foxP2 in neurite outgrowth, in vivo studies have been lacking regarding a role for foxP2 in axon pathfinding. We used a modified zinc finger nuclease methodology to generate mutations in the zebrafish foxP2 gene. Using PCR-based high resolution melt curve analysis (HRMA) of G0 founder animals, we screened and identified three mutants carrying nonsense mutations in the 2(nd) coding exon: a 17 base-pair (bp) deletion, an 8bp deletion, and a 4bp insertion. Sequence analysis of cDNA confirmed that these were frameshift mutations with predicted early protein truncations. Homozygous mutant fish were viable and fertile, with unchanged body morphology, and no apparent differences in CNS apoptosis, proliferation, or patterning at embryonic stages. There was a reduction in expression of the known foxP2 target gene cntnap2 that was rescued by injection of wild-type foxP2 transcript. When we examined axon pathfinding using a pan axonal marker or transgenic lines, including a foxP2-neuron-specific enhancer, we did not observe any axon guidance errors. Our findings suggest that foxP2 is not necessary for axon pathfinding during development. PMID- 22937140 TI - Association of the European lactase persistence variant (LCT-13910 C>T polymorphism) with obesity in the Canary Islands. AB - BACKGROUND: European lactose tolerance genotype (LCT -13910 C>T, rs4988234) has been positively associated to body mass indexes (BMI) in a meta-analysis of 31,720 individuals of northern and central European descent. A strong association of lactase persistence (LP) with BMI and obesity has also been traced in a Spanish Mediterranean population. The aim of this study was to analyze a potential association of LP compared to lactase non-persistence (LNP) with BMI in inhabitants of the Canary Islands of Spain using Mendelian randomization. METHODS: A representative, randomly sampled population of adults belonging to the Canary Islands Nutrition Survey (ENCA) in Spain, aged 18-75 years (n = 551), was genotyped for the LCT - 13910 C>T polymorphism. Milk consumption was assessed by a validated questionnaire. Anthropometric variables were directly measured. WHO classification of BMI was used. RESULTS: LP individuals were significantly more obese than LNP subjects (chi(2) = 10.59; p<0.005). LP showed in a multivariate linear regression analysis showed a positive association of LP with BMI compared to LNP, (beta = 0.96; 95% CI: 0.08-1.85, p = 0.033). In a multinomial logistic regression analysis normal range weight LP subjects showed an odds ratio for obesity of 2.41; 95%CI 1.39-418, (p = 0.002) compared to LNP. CONCLUSIONS: The T 13910 of the allele LCT-13910 C>T polymorphism is positively associated with BMI. LP increases significantly the risk to develop obesity in the studied population. The LCT-13910 C>T polymorphism stands proxy for the lifetime exposure pattern, milk intake, that may increase susceptibility to obesity and to obesity related pathologies. PMID- 22937141 TI - Investigating the role of FGF18 in the cultivation and osteogenic differentiation of mesenchymal stem cells. AB - Fibroblast growth factor18 (FGF18) belongs to the FGF family and is a pleiotropic protein that stimulates proliferation in several tissues. Bone marrow mesenchymal stem cells (BMSCs) participate in the normal replacement of damaged cells and in disease healing processes within bone and the haematopoietic system. In this study, we constructed FGF18 and investigated its effects on rat BMSCs (rBMSCs). The proliferative effects of FGF18 on rBMSCs were examined using an MTS assay. To validate the osteogenic differentiation effects of FGF18, ALP and mineralization activity were examined as well as osteogenic differentiation-related gene levels. FGF18 significantly enhanced rBMSCs proliferation (p<0.001) and induced the osteogenic differentiation by elevating ALP and mineralization activity of rBMSCs (p<0.001). Furthermore, these osteogenic differentiation effects of FGF18 were confirmed via increasing the mRNA levels of collagen type I (Col I), bone morphogenetic protein 4 (BMP4), and Runt-related transcription factor 2 (Runx2) at 3 and 7 days. These results suggest that FGF18 could be used to improve bone repair and regeneration. PMID- 22937142 TI - Identification of a novel bat papillomavirus by metagenomics. AB - The discovery of novel viruses in animals expands our knowledge of viral diversity and potentially emerging zoonoses. High-throughput sequencing (HTS) technology gives millions or even billions of sequence reads per run, allowing a comprehensive survey of the genetic content within a sample without prior nucleic acid amplification. In this study, we screened 156 rectal swab samples from apparently healthy bats (n = 96), pigs (n = 9), cattles (n = 9), stray dogs (n = 11), stray cats (n = 11) and monkeys (n = 20) using a HTS metagenomics approach. The complete genome of a novel papillomavirus (PV), Miniopterus schreibersii papillomavirus type 1 (MscPV1), with L1 of 60% nucleotide identity to Canine papillomavirus (CPV6), was identified in a specimen from a Common Bent-wing Bat (M. schreibersii). It is about 7.5kb in length, with a G+C content of 45.8% and a genomic organization similar to that of other PVs. Despite the higher nucleotide identity between the genomes of MscPV1 and CPV6, maximum-likelihood phylogenetic analysis of the L1 gene sequence showed that MscPV1 and Erethizon dorsatum papillomavirus (EdPV1) are most closely related. Estimated divergence time of MscPV1 from the EdPV1/MscPV1 common ancestor was approximately 60.2-91.9 millions of years ago, inferred under strict clocks using the L1 and E1 genes. The estimates were limited by the lack of reliable calibration points from co divergence because of possible host shifts. As the nucleotide sequence of this virus only showed limited similarity with that of related animal PVs, the conventional approach of PCR using consensus primers would be unlikely to have detected the novel virus in the sample. Unlike the first bat papillomavirus RaPV1, MscPV1 was found in an asymptomatic bat with no apparent mucosal or skin lesions whereas RaPV1 was detected in the basosquamous carcinoma of a fruit bat Rousettus aegyptiacus. We propose MscPV1 as the first member of the novel Dyolambda-papillomavirus genus. PMID- 22937143 TI - DIDS prevents ischemic membrane degradation in cultured hippocampal neurons by inhibiting matrix metalloproteinase release. AB - During stroke, cells in the infarct core exhibit rapid failure of their permeability barriers, which releases ions and inflammatory molecules that are deleterious to nearby tissue (the penumbra). Plasma membrane degradation is key to penumbral spread and is mediated by matrix metalloproteinases (MMPs), which are released via vesicular exocytosis into the extracellular fluid in response to stress. DIDS (4,4'-diisothiocyanatostilbene-2,2'-disulphonic acid) preserves membrane integrity in neurons challenged with an in vitro ischemic penumbral mimic (ischemic solution: IS) and we asked whether this action was mediated via inhibition of MMP activity. In cultured murine hippocampal neurons challenged with IS, intracellular proMMP-2 and -9 expression increased 4-10 fold and extracellular latent and active MMP isoform expression increased 2-22 fold. MMP mediated extracellular gelatinolytic activity increased ~20-50 fold, causing detachment of 32.1+/-4.5% of cells from the matrix and extensive plasma membrane degradation (>60% of cells took up vital dyes and >60% of plasma membranes were fragmented or blebbed). DIDS abolished cellular detachment and membrane degradation in neurons and the pathology-induced extracellular expression of latent and active MMPs. DIDS similarly inhibited extracellular MMP expression and cellular detachment induced by the pro-apoptotic agent staurosporine or the general proteinase agonist 4-aminophenylmercuric acetate (APMA). Conversely, DIDS treatment did not impair stress-induced intracellular proMMP production, nor the intracellular cleavage of proMMP-2 to the active form, suggesting DIDS interferes with the vesicular extrusion of MMPs rather than directly inhibiting proteinase expression or activation. In support of this hypothesis, an antagonist of the V type vesicular ATPase also inhibited extracellular MMP expression to a similar degree as DIDS. In addition, in a proteinase-independent model of vesicular exocytosis, DIDS prevented stimulus-evoked release of von Willebrand Factor from human umbilical vein endothelial cells. We conclude that DIDS inhibits MMP exocytosis and through this mechanism preserves neuronal membrane integrity during pathological stress. PMID- 22937144 TI - GPU-FS-kNN: a software tool for fast and scalable kNN computation using GPUs. AB - BACKGROUND: The analysis of biological networks has become a major challenge due to the recent development of high-throughput techniques that are rapidly producing very large data sets. The exploding volumes of biological data are craving for extreme computational power and special computing facilities (i.e. super-computers). An inexpensive solution, such as General Purpose computation based on Graphics Processing Units (GPGPU), can be adapted to tackle this challenge, but the limitation of the device internal memory can pose a new problem of scalability. An efficient data and computational parallelism with partitioning is required to provide a fast and scalable solution to this problem. RESULTS: We propose an efficient parallel formulation of the k-Nearest Neighbour (kNN) search problem, which is a popular method for classifying objects in several fields of research, such as pattern recognition, machine learning and bioinformatics. Being very simple and straightforward, the performance of the kNN search degrades dramatically for large data sets, since the task is computationally intensive. The proposed approach is not only fast but also scalable to large-scale instances. Based on our approach, we implemented a software tool GPU-FS-kNN (GPU-based Fast and Scalable k-Nearest Neighbour) for CUDA enabled GPUs. The basic approach is simple and adaptable to other available GPU architectures. We observed speed-ups of 50-60 times compared with CPU implementation on a well-known breast microarray study and its associated data sets. CONCLUSION: Our GPU-based Fast and Scalable k-Nearest Neighbour search technique (GPU-FS-kNN) provides a significant performance improvement for nearest neighbour computation in large-scale networks. Source code and the software tool is available under GNU Public License (GPL) at https://sourceforge.net/p/gpufsknn/. PMID- 22937145 TI - Oxytocin increases heart rate variability in humans at rest: implications for social approach-related motivation and capacity for social engagement. AB - CONTEXT: Oxytocin (OT) plays a key regulatory role in human social behaviour. While prior studies have examined the effects of OT on observable social behaviours, studies have seldom examined the effects of OT on psychophysiological markers such as heart rate variability (HRV), which provides an index of individual's motivation for social behaviour. Furthermore, no studies have examined the impact of OT on HRV under resting conditions, which provides an index of maximal capacity for social engagement. OBJECTIVE: To examine the effects of OT on HRV measures in healthy male participants while at rest. OT was hypothesised to increase HRV, compared to placebo, and that the effects would be greatest for a non-linear measure of HRV (the detrended fluctuation scaling exponent). METHODS: Twenty-one male participants were recruited for this study. Participants were non-smokers, not on any medications and reported no history of psychiatric illness, neurological disorder, or any other serious medical condition (e.g. diabetes, cardiovascular disease). The study employed a randomised, placebo-controlled, within-subject, crossover, experimental design. MAIN OUTCOME MEASURES: HRV was calculated from electrocardiography under a standardized, 10-minute, resting state condition. RESULTS: As hypothesised, OT increased HRV and these effects were largest using the detrended fluctuation scaling exponent, a non-linear measure. These changes were observed in the absence of any change in state mood, as measured by the profile of mood states. Importantly, participants were unable to correctly guess which treatment they had been assigned at either of the two assessments. CONCLUSIONS: Together with the broader literature on OT and HRV, findings suggest that acute administration of OT may facilitate a fundamental psychophysiological feature of social behaviour, increasing capacity for social engagement. Findings also suggest that HRV changes may provide a novel biomarker of response to OT nasal spray that can be incorporated into research on response to treatment. PMID- 22937146 TI - Do bites of kissing bugs cause unexplained allergies? Results from a survey in triatomine-exposed and unexposed areas in southern california. AB - BACKGROUND: The bite of Triatominae can cause cutaneous allergic reactions and even anaphylaxis. Since the early 1980s, no population-based surveys have been done in Southern California, and none was ever carried out in inland Los Angeles or Riverside Counties. OBJECTIVES: To measure the frequency of insect sightings, bites and allergic reactions in a suburban area of eastern Los Angeles County and along with rural and urban sites in Riverside County. METHODS: A door-to-door survey was done in triatomine exposed and unexposed areas. Logistic regression modeling was used for the analysis, and study participants were asked to collect insects. RESULTS: Out of the 221 study participants in the exposed areas, 46 (20%) knew about the presence of Triatominae in their neighborhood. Fifteen (7%) persons reported triatomine sightings in their house during the month preceding the interview. Also, 15 (7%) participants reported ever being bitten by a triatomine. Ten (5%) participants collected either a Triatoma protracta Uhler and/or Paratriatoma hirsuta Barber in and around their house. Twenty-nine (13%) persons in the rural Riverside County reported symptoms compatible with allergy to triatomine bites. This was 4 times higher than in the urban control area where only 4 (3%) of 115 persons reported these symptoms. The association between living in a triatomine-exposed area and self-reported symptoms suggestive of allergies increased slightly when adjusted for the participant's sex and the age of their house (adjusted odds ratio: 5.1, 95% confidence interval: 1.2 to 22.0). Reporting these symptoms was associated with seeing Triatominae in the neighborhood and having been bitten. CONCLUSION: Allergies to triatomine bites could be a significant problem in inland Southern California. Further investigations, a diagnostic test and better information of persons living in triatomine-exposed areas are needed. PMID- 22937147 TI - The Mre11 nuclease is critical for the sensitivity of cells to Chk1 inhibition. AB - The Chk1 kinase is required for the arrest of cell cycle progression when DNA is damaged, and for stabilizing stalled replication forks. As a consequence, many Chk1 inhibitors have been developed and tested for their potential to enhance DNA damage-induced tumor cell killing. However, inhibition of Chk1 alone, without any additional exogenous agent, can be cytotoxic. Understanding the underlying mechanisms of this sensitivity is critical for defining which patients might respond best to therapy with Chk1 inhibitors. We have investigated the mechanism of sensitivity in U2OS osteosarcoma cells. Upon incubation with the Chk1 inhibitor MK-8776, single-stranded DNA regions (ssDNA) and double-strand breaks (DSB) begin to appear within 6 h. These DSB have been attributed to the structure specific DNA endonuclease, Mus81. The Mre11/Rad50/Nbs1 complex is known to be responsible for the resection of DSB to ssDNA. However, we show that inhibition of the Mre11 nuclease activity leads, not only to a decrease in the amount of ssDNA following Chk1 inhibition, but also inhibits the formation of DSB, suggesting that DSB are a consequence of ssDNA formation. These findings were corroborated by the discovery that Mre11-deficient ATLD1 cells are highly resistant to MK-8776 and form neither ssDNA nor DSB following treatment. However, once complimented with exogenous Mre11, the cells accumulate both ssDNA and DSB when incubated with MK-8776. Our findings suggest that Mre11 provides the link between aberrant activation of Cdc25A/Cdk2 and Mus81. The results highlight a novel role for Mre11 in the production of DSB and may help define which tumors are more sensitive to MK-8776 alone or in combination with DNA damaging agents. PMID- 22937149 TI - Resistance of soil-bound prions to rumen digestion. AB - Before prion uptake and infection can occur in the lower gastrointestinal system, ingested prions are subjected to anaerobic digestion in the rumen of cervids and bovids. The susceptibility of soil-bound prions to rumen digestion has not been evaluated previously. In this study, prions from infectious brain homogenates as well as prions bound to a range of soils and soil minerals were subjected to in vitro rumen digestion, and changes in PrP levels were measured via western blot. Binding to clay appeared to protect noninfectious hamster PrP(c) from complete digestion, while both unbound and soil-bound infectious PrP(Sc) proved highly resistant to rumen digestion. In addition, no change in intracerebral incubation period was observed following active rumen digestion of unbound hamster HY TME prions and HY TME prions bound to a silty clay loam soil. These results demonstrate that both unbound and soil-bound prions readily survive rumen digestion without a reduction in infectivity, further supporting the potential for soil-mediated transmission of chronic wasting disease (CWD) and scrapie in the environment. PMID- 22937148 TI - An alu-based phylogeny of lemurs (infraorder: Lemuriformes). AB - LEMURS (INFRAORDER: Lemuriformes) are a radiation of strepsirrhine primates endemic to the island of Madagascar. As of 2012, 101 lemur species, divided among five families, have been described. Genetic and morphological evidence indicates all species are descended from a common ancestor that arrived in Madagascar ~55 60 million years ago (mya). Phylogenetic relationships in this species-rich infraorder have been the subject of debate. Here we use Alu elements, a family of primate-specific Short INterspersed Elements (SINEs), to construct a phylogeny of infraorder Lemuriformes. Alu elements are particularly useful SINEs for the purpose of phylogeny reconstruction because they are identical by descent and confounding events between loci are easily resolved by sequencing. The genome of the grey mouse lemur (Microcebus murinus) was computationally assayed for synapomorphic Alu elements. Those that were identified as Lemuriformes-specific were analyzed against other available primate genomes for orthologous sequence in which to design primers for PCR (polymerase chain reaction) verification. A primate phylogenetic panel of 24 species, including 22 lemur species from all five families, was examined for the presence/absence of 138 Alu elements via PCR to establish relationships among species. Of these, 111 were phylogenetically informative. A phylogenetic tree was generated based on the results of this analysis. We demonstrate strong support for the monophyly of Lemuriformes to the exclusion of other primates, with Daubentoniidae, the aye-aye, as the basal lineage within the infraorder. Our results also suggest Lepilemuridae as a sister lineage to Cheirogaleidae, and Indriidae as sister to Lemuridae. Among the Cheirogaleidae, we show strong support for Microcebus and Mirza as sister genera, with Cheirogaleus the sister lineage to both. Our results also support the monophyly of the Lemuridae. Within Lemuridae we place Lemur and Hapalemur together to the exclusion of Eulemur and Varecia, with Varecia the sister lineage to the other three genera. PMID- 22937150 TI - Myocardin overexpression is sufficient for promoting the development of a mature smooth muscle cell-like phenotype from human embryonic stem cells. AB - BACKGROUND: Myocardin is thought to have a key role in smooth muscle cell (SMC) development by acting on CArG-dependent genes. However, it is unclear whether myocardin-induced SMC maturation and increases in agonist-induced calcium signalling are also associated with increases in the expression of non-CArG dependent SMC-specific genes. Moreover, it is unknown whether myocardin promotes SMC development from human embryonic stem cells. METHODOLOGY/PRINCIPAL: Findings The effects of adenoviral-mediated myocardin overexpression on SMC development in human ESC-derived embryoid bodies were investigated using immunofluorescence, flow cytometry and real time RT-PCR. Myocardin overexpression from day 10 to day 28 of embryoid body differentiation increased the number of smooth muscle alpha actin(+) and smooth muscle myosin heavy chain(+) SMC-like cells and increased carbachol-induced contractile function. However, myocardin was found to selectively regulate only CArG-dependent SMC-specific genes. Nevertheless, myocardin expression appeared to be sufficient to specify the SMC lineage. CONCLUSIONS/SIGNIFICANCE: Myocardin increases the development and maturation of SMC-like cells from human embryonic stem cells despite not activating the full repertoire of SMC genes. These findings have implications for vascular tissue engineering and other applications requiring large numbers of functional SMCs. PMID- 22937151 TI - Involvement of AMPA receptor GluR2 and GluR3 trafficking in trigeminal spinal subnucleus caudalis and C1/C2 neurons in acute-facial inflammatory pain. AB - To evaluate the involvement of trafficking of alpha-amino-3-hydroxy-5-methyl-4 isoxazolepropionic acid receptor (AMPAR) GluR2 and GluR3 subunits in an acute inflammatory orofacial pain, we analyzed nocifensive behavior, phosphorylated extracellular signal-regulated kinase (pERK) and Fos expression in Vi/Vc, Vc and C1/C2 in GluR2 delta7 knock-in (KI), GluR3 delta7 KI mice and wild-type mice. We also studied Vc neuronal activity to address the hypothesis that trafficking of GluR2 and GluR3 subunits plays an important role in Vi/Vc, Vc and C1/C2 neuronal activity associated with orofacial inflammation in these mice. Late nocifensive behavior was significantly depressed in GluR2 delta7 KI and GluR3 delta7 KI mice. In addition, the number of pERK-immunoreactive (IR) cells was significantly decreased bilaterally in the Vi/Vc, Vc and C1/C2 in GluR2 delta7 KI and GluR3 delta7 KI mice compared to wild-type mice at 40 min after formalin injection, and was also significantly smaller in GluR3 delta7 KI compared to GluR2 delta7 KI mice. The number of Fos protein-IR cells in the ipsilateral Vi/Vc, Vc and C1/C2 was also significantly smaller in GluR2 delta7 KI and GluR3 delta7 KI mice compared to wild-type mice 40 min after formalin injection. Nociceptive neurons functionally identified as wide dynamic range neurons in the Vc, where pERK- and Fos protein-IR cell expression was prominent, showed significantly lower spontaneous activity in GluR2 delta7 KI and GluR3 delta7 KI mice than wild-type mice following formalin injection. These findings suggest that GluR2 and GluR3 trafficking is involved in the enhancement of Vi/Vc, Vc and C1/C2 nociceptive neuronal excitabilities at 16-60 min following formalin injection, resulting in orofacial inflammatory pain. PMID- 22937152 TI - CFTR regulates early pathogenesis of chronic obstructive lung disease in betaENaC overexpressing mice. AB - BACKGROUND: Factors determining the onset and severity of chronic obstructive pulmonary disease remain poorly understood. Previous studies demonstrated that airway surface dehydration in betaENaC-overexpressing (betaENaC-Tg) mice on a mixed genetic background caused either neonatal mortality or chronic obstructive lung disease suggesting that the onset of lung disease was modulated by the genetic background. METHODS: To test this hypothesis, we backcrossed betaENaC-Tg mice onto two inbred strains (C57BL/6 and BALB/c) and studied effects of the genetic background on neonatal mortality, airway ion transport and airway morphology. Further, we crossed betaENaC-Tg mice with CFTR-deficient mice to validate the role of CFTR in early lung disease. RESULTS: We demonstrate that the C57BL/6 background conferred increased CFTR-mediated Cl(-) secretion, which was associated with decreased mucus plugging and mortality in neonatal betaENaC-Tg C57BL/6 compared to betaENaC-Tg BALB/c mice. Conversely, genetic deletion of CFTR increased early mucus obstruction and mortality in betaENaC-Tg mice. CONCLUSIONS: We conclude that a decrease or absence of CFTR function in airway epithelia aggravates the severity of early airway mucus obstruction and related mortality in betaENaC-Tg mice. These results suggest that genetic or environmental factors that reduce CFTR activity may contribute to the onset and severity of chronic obstructive pulmonary disease and that CFTR may serve as a novel therapeutic target. PMID- 22937154 TI - Hypoxia regulates CD44 and its variant isoforms through HIF-1alpha in triple negative breast cancer. AB - BACKGROUND: The CD44 transmembrane glycoproteins play multifaceted roles in tumor progression and metastasis. CD44 expression has also been associated with stem like breast cancer cells. Hypoxia commonly occurs in tumors and is a major cause of radiation and chemo-resistance. Hypoxia is known to inhibit differentiation and facilitates invasion and metastasis. Here we have investigated the effect of hypoxia on CD44 and two of its isoforms in MDA-MB-231 and SUM-149 triple negative human breast cancer cells and MDA-MB-231 tumors using imaging and molecular characterization. METHODS AND FINDINGS: The roles of hypoxia and hypoxia inducible factor (HIF) in regulating the expression of CD44 and its variant isoforms (CD44v6, CD44v7/8) were investigated in human breast cancer cells, by quantitative real-time polymerase chain reaction (qRT-PCR) to determine mRNA levels, and fluorescence associated cell sorting (FACS) to determine cell surface expression of CD44, under normoxic and hypoxic conditions. In vivo imaging studies with tumor xenografts derived from MDA-MD-231 cells engineered to express tdTomato red fluorescence protein under regulation of hypoxia response elements identified co-localization between hypoxic fluorescent regions and increased concentration of (125)I-radiolabeled CD44 antibody. CONCLUSIONS: Our data identified HIF-1alpha as a regulator of CD44 that increased the number of CD44 molecules and the percentage of CD44 positive cells expressing variant exons v6 and v7/8 in breast cancer cells under hypoxic conditions. Data from these cell studies were further supported by in vivo observations that hypoxic tumor regions contained cells with a higher concentration of CD44 expression. PMID- 22937155 TI - The first record of a trans-oceanic sister-group relationship between obligate vertebrate troglobites. AB - We show using the most complete phylogeny of one of the most species-rich orders of vertebrates (Gobiiformes), and calibrations from the rich fossil record of teleost fishes, that the genus Typhleotris, endemic to subterranean karst habitats in southwestern Madagascar, is the sister group to Milyeringa, endemic to similar subterranean systems in northwestern Australia. Both groups are eyeless, and our phylogenetic and biogeographic results show that these obligate cave fishes now found on opposite ends of the Indian Ocean (separated by nearly 7,000 km) are each others closest relatives and owe their origins to the break up of the southern supercontinent, Gondwana, at the end of the Cretaceous period. Trans-oceanic sister-group relationships are otherwise unknown between blind, cave-adapted vertebrates and our results provide an extraordinary case of Gondwanan vicariance. PMID- 22937153 TI - Brain networks of novelty-driven involuntary and cued voluntary auditory attention shifting. AB - In everyday life, we need a capacity to flexibly shift attention between alternative sound sources. However, relatively little work has been done to elucidate the mechanisms of attention shifting in the auditory domain. Here, we used a mixed event-related/sparse-sampling fMRI approach to investigate this essential cognitive function. In each 10-sec trial, subjects were instructed to wait for an auditory "cue" signaling the location where a subsequent "target" sound was likely to be presented. The target was occasionally replaced by an unexpected "novel" sound in the uncued ear, to trigger involuntary attention shifting. To maximize the attention effects, cues, targets, and novels were embedded within dichotic 800-Hz vs. 1500-Hz pure-tone "standard" trains. The sound of clustered fMRI acquisition (starting at t = 7.82 sec) served as a controlled trial-end signal. Our approach revealed notable activation differences between the conditions. Cued voluntary attention shifting activated the superior intra--parietal sulcus (IPS), whereas novelty-triggered involuntary orienting activated the inferior IPS and certain subareas of the precuneus. Clearly more widespread activations were observed during voluntary than involuntary orienting in the premotor cortex, including the frontal eye fields. Moreover, we found evidence for a frontoinsular-cingular attentional control network, consisting of the anterior insula, inferior frontal cortex, and medial frontal cortices, which were activated during both target discrimination and voluntary attention shifting. Finally, novels and targets activated much wider areas of superior temporal auditory cortices than shifting cues. PMID- 22937156 TI - Elevating SOX2 levels deleteriously affects the growth of medulloblastoma and glioblastoma cells. AB - Medulloblastomas and glioblastomas are devastating tumors that respond poorly to treatment. These tumors have been shown to express SOX2 and overexpression of SOX2 has been correlated with poor prognosis. Although knockdown of SOX2 impairs the growth and tumorigenicity of brain tumor cells, it was unclear how elevating SOX2 levels would affect their fate. Interestingly, studies conducted with neural stem cells have shown that small increases or decreases in the level of this transcription factor significantly alter their fate. Here, we report that elevating SOX2 3-fold above endogenous levels in U87 and U118 glioblastoma, and DAOY medulloblastoma cells significantly impairs their ability to proliferate. We extended these findings and determined that elevating SOX2 in DAOY cells remodels their cell-cycle profile by increasing the proportion of cells in the G1 compartment, and induces the expression of genes associated with differentiation. Furthermore, we show that elevating SOX2 leads to a dramatic induction of CD133 expression in DAOY cells, yet inhibits the ability of both CD133(+) and CD133(-) cells to form neurospheres. Together, these findings argue that SOX2 levels must be carefully controlled in glioblastomas and medulloblastomas to maintain their fate. Equally important, our data suggests that increases in the expression of SOX2 during brain tumor progression are likely to be linked closely with changes in other critical genes that work in concert with SOX2 to enhance the tumorigenicity of brain tumors. Importantly, we demonstrate that this is also likely to be true for other cancers that express SOX2. Moreover, these studies demonstrate the advantage of using inducible promoters to study the effects of SOX2 elevation, as compared to gene expression systems that rely on constitutive expression. PMID- 22937157 TI - Spermatogonial stem cell markers and niche in equids. AB - Spermatogonial stem cells (SSCs) are the foundation of spermatogenesis and are located in a highly dynamic microenvironment called "niche" that influences all aspects of stem cell function, including homing, self-renewal and differentiation. Several studies have recently identified specific proteins that regulate the fate of SSCs. These studies also aimed at identifying surface markers that would facilitate the isolation of these cells in different vertebrate species. The present study is the first to investigate SSC physiology and niche in stallions and to offer a comparative evaluation of undifferentiated type A spermatogonia (Aund) markers (GFRA1, PLZF and CSF1R) in three different domestic equid species (stallions, donkeys, and mules). Aund were first characterized according to their morphology and expression of the GFRA1 receptor. Our findings strongly suggest that in stallions these cells were preferentially located in the areas facing the interstitium, particularly those nearby blood vessels. This distribution is similar to what has been observed in other vertebrate species. In addition, all three Aund markers were expressed in the equid species evaluated in this study. These markers have been well characterized in other mammalian species, which suggests that the molecular mechanisms that maintain the niche and Aund/SSCs physiology are conserved among mammals. We hope that our findings will help future studies needing isolation and cryopreservation of equids SSCs. In addition, our data will be very useful for studies that aim at preserving the germplasm of valuable animals, and involve germ cell transplantation or xenografts of equids testis fragments/germ cells suspensions. PMID- 22937158 TI - A systematic review and meta-analysis of risk factors for sexual transmission of HIV in India. AB - BACKGROUND: Approximately 2.4 million people are living with HIV in India. This large disease burden, and potential for epidemic spread in some areas, demands a full understanding of transmission in that country. We wished to quantify the effects of key sexual risk factors for HIV infection for each gender and among high- and low-HIV risk populations in India. METHODOLOGY: We conducted a systematic review of sexual risk factors for HIV infection from 35 published studies. Risk factors analyzed were: male circumcision/religion, Herpes Simplex Virus 2, syphilis, gonorrhoea, genital ulcer, multiple sexual partners and commercial sex. Studies were included if they met predetermined criteria. Data were extracted and checked by two researchers and random-effects meta analysis of effects was conducted. Heterogeneity in effect estimates was examined by I(2) statistic. Publication bias was tested by Begg's test and funnel plots. Meta regression was used to assess effect modification by various study attributes. RESULTS: All risk factors were significantly associated with HIV status. The factor most strongly associated with HIV for both sexes was HSV-2 infection (OR(men): 5.87; 95%CI: 2.46-14.03; OR(women): 6.44; 95%CI: 3.22-12.86). The effect of multiple sexual partners was similar among men (OR = 2.46; 95%CI: 1.91 3.17,) and women (OR = 2.02; 95%CI: 1.43-2.87) and when further stratified by HIV risk group. The association between HSV-2 and HIV prevalence was consistently stronger than other STIs or self-reported genital ulcer. If the strong associations between HSV-2 and HIV were interpreted causally, these results implied that approximately half of the HIV infections observed in our study population were attributable to HSV-2 infection. CONCLUSIONS: The risk factors examined in our analysis should remain targets of HIV prevention programs. Our results confirm that sexual risk factors for HIV infection continue to be an important part of Indian HIV epidemic 26 years after it began. PMID- 22937159 TI - YY1-binding sites provide central switch functions in the PARP-1 gene expression network. AB - Evidence is presented for the involvement of the interplay between transcription factor Yin Yang 1 (YY1) and poly(ADP-ribose) polymerase-1 (PARP-1) in the regulation of mouse PARP-1 gene (muPARP-1) promoter activity. We identified potential YY1 binding motifs (BM) at seven positions in the muPARP-1 core promoter (-574/+200). Binding of YY1 was observed by the electrophoretic supershift assay using anti-YY1 antibody and linearized or supercoiled forms of plasmids bearing the core promoter, as well as with 30 bp oligonucleotide probes containing the individual YY1 binding motifs and four muPARP-1 promoter fragments. We detected YY1 binding to BM1 (-587/-558), BM4 (-348/-319) and a very prominent association with BM7 (+86/+115). Inspection of BM7 reveals overlap of the muPARP-1 translation start site with the Kozak sequence and YY1 and PARP-1 recognition sites. Site-directed mutagenesis of the YY1 and PARP-1 core motifs eliminated protein binding and showed that YY1 mediates PARP-1 binding next to the Kozak sequence. Transfection experiments with a reporter gene under the control of the muPARP-1 promoter revealed that YY1 binding to BM1 and BM4 independently repressed the promoter. Mutations at these sites prevented YY1 binding, allowing for increased reporter gene activity. In PARP-1 knockout cells subjected to PARP-1 overexpression, effects similar to YY1 became apparent; over expression of YY1 and PARP-1 revealed their synergistic action. Together with our previous findings these results expand the PARP-1 autoregulatory loop principle by YY1 actions, implying rigid limitation of muPARP-1 expression. The joint actions of PARP-1 and YY1 emerge as important contributions to cell homeostasis. PMID- 22937160 TI - Mitochondrial haplogroups H and J: risk and protective factors for ischemic cardiomyopathy. AB - BACKGROUND: Since mitochondria are the principal source of reactive oxygen species (ROS), these organelles may play an important role in ischemic cardiomyopathy (IC) development. The mitochondrial genome may influence this disease. The aim of the present study was to test the relationship between IC development and the impact of single nucleotide polymorphisms (SNPs) in mitochondrial DNA (mtDNA) defining the mitochondrial haplogroups in a population study. METHODOLOGY AND PRINCIPAL FINDINGS: Ten major European haplogroups were identified by using the single base extension technique and by polymerase chain reaction-restriction fragment length polymorphism. Frequencies and Odds Ratios for the association between IC patients (n = 358) and healthy controls (n = 423) were calculated. No convincing associations between classical risk factors for ischemic cardiomyopathy development and haplogroups were found. However, compared to healthy controls, the prevalence of haplogroup H was significantly higher in IC patients (40.0% vs 50.0%, p-value = 0.039) while the frequency of haplogroup J was significantly lower (11.1% vs 5.6%, p-value = 0.048). The analysis of the SNPs characterizing the European mtDNA haplogroups showed that the m.7028C allele (40.0% vs 50.0%, p-value = 0.005) and m.14766C allele (43.0% vs 54.2%, p-value = 0.002) were overrepresented in IC patients, meanwhile the m.10398G allele (19.8% vs 13.1%, p-value = 0.015) and m.4216C allele (22.2% vs 16.5%, p-value = 0.044) were found as protective factors against IC. CONCLUSIONS AND SIGNIFICANCE: Our results showed that the haplogroups H and J were found as a risk and protective factors for ischemic cardiomyopathy development, respectively. PMID- 22937161 TI - Focal adhesion kinase (FAK) mediates the induction of pro-oncogenic and fibrogenic phenotypes in hepatitis C virus (HCV)-infected cells. AB - Hepatitis C Virus (HCV) infection is one of the most common etiological factors involved in fibrosis development and its progression to hepatocellular carcinoma (HCC). The pivotal role of hepatic stellate cells (HCSs) and extracellular matrix (ECM) in fibrogenesis is now certainly accepted, while the network of molecular interactions connecting HCV is emerging as a master regulator of several biological processes including proliferation, inflammation, cytoskeleton and ECM remodeling. In this study, the effects of HCV proteins expression on liver cancer cells, both pro-invasive and pro-fibrogenic phenotypes were explored. As a model of HCV infection, we used permissive Huh7.5.1 hepatoma cells infected with JFH1 derived ccHCV. Conditioned medium from these cells was used to stimulate LX-2 cells, a line of HSCs. We found that the HCV infection of Huh7.5.1 cells decreased adhesion, increased migration and caused the delocalization of alpha actinin from plasma membrane to cytoplasm and increased expression levels of paxillin. The treatment of LX-2 cells, with conditioned medium from HCV-infected Huh7.5.1 cells, caused an increase in cell proliferation, expression of alpha smooth muscle actin, hyaluronic acid release and apoptosis rate measured as cleaved poly ADP-ribose polymerase (PARP). These effects were accompanied in Huh7.5.1 cells by an HCV-dependent increasing of FAK activation that physically interacts with phosphorylated paxillin and alpha-actinin, and a rising of tumor necrosis factor alpha production/release. Silencing of FAK by siRNA reverted all effects of HCV infection, both those directed on Huh7.5.1 cells, and those indirect effects on the LX-2 cells. Moreover and interestingly, FAK inhibition enhances apoptosis in HCV-conditioned LX-2 cells. In conclusion, our findings demonstrate that HCV, through FAK activation, may promote cytoskeletal reorganization and a pro-oncogenic phenotype in hepatocyte-like cells, and a fibrogenic phenotype in HSCs. PMID- 22937162 TI - Two novel heat-soluble protein families abundantly expressed in an anhydrobiotic tardigrade. AB - Tardigrades are able to tolerate almost complete dehydration by reversibly switching to an ametabolic state. This ability is called anhydrobiosis. In the anhydrobiotic state, tardigrades can withstand various extreme environments including space, but their molecular basis remains largely unknown. Late embryogenesis abundant (LEA) proteins are heat-soluble proteins and can prevent protein-aggregation in dehydrated conditions in other anhydrobiotic organisms, but their relevance to tardigrade anhydrobiosis is not clarified. In this study, we focused on the heat-soluble property characteristic of LEA proteins and conducted heat-soluble proteomics using an anhydrobiotic tardigrade. Our heat soluble proteomics identified five abundant heat-soluble proteins. All of them showed no sequence similarity with LEA proteins and formed two novel protein families with distinct subcellular localizations. We named them Cytoplasmic Abundant Heat Soluble (CAHS) and Secretory Abundant Heat Soluble (SAHS) protein families, according to their localization. Both protein families were conserved among tardigrades, but not found in other phyla. Although CAHS protein was intrinsically unstructured and SAHS protein was rich in beta-structure in the hydrated condition, proteins in both families changed their conformation to an alpha-helical structure in water-deficient conditions as LEA proteins do. Two conserved repeats of 19-mer motifs in CAHS proteins were capable to form amphiphilic stripes in alpha-helices, suggesting their roles as molecular shield in water-deficient condition, though charge distribution pattern in alpha-helices were different between CAHS and LEA proteins. Tardigrades might have evolved novel protein families with a heat-soluble property and this study revealed a novel repertoire of major heat-soluble proteins in these anhydrobiotic animals. PMID- 22937163 TI - Structural basis for the dsRNA specificity of the Lassa virus NP exonuclease. AB - Lassa virus causes hemorrhagic fever characterized by immunosuppression. The nucleoprotein of Lassa virus, termed NP, binds the viral genome. It also has an additional enzymatic activity as an exonuclease that specifically digests double stranded RNA (dsRNA). dsRNA is a strong signal to the innate immune system of viral infection. Digestion of dsRNA by the NP exonuclease activity appears to cause suppression of innate immune signaling in the infected cell. Although the fold of the NP enzyme is conserved and the active site completely conserved with other exonucleases in its DEDDh family, NP is atypical among exonucleases in its preference for dsRNA and its strict specificity for one substrate. Here, we present the crystal structure of Lassa virus NP in complex with dsRNA. We find that unlike the exonuclease in Klenow fragment, the double-stranded nucleic acid in complex with Lassa NP remains base-paired instead of splitting, and that binding of the paired complementary strand is achieved by "relocation" of a basic loop motif from its typical exonuclease position. Further, we find that just one single glycine that contacts the substrate strand and one single tyrosine that stacks with a base of the complementary, non-substrate strand are responsible for the unique substrate specificity. This work thus provides templates for development of antiviral drugs that would be specific for viral, rather than host exonucleases of similar fold and active site, and illustrates how a very few amino acid changes confer alternate specificity and biological phenotype to an enzyme. PMID- 22937164 TI - Xenogeneic graft-versus-host-disease in NOD-scid IL-2Rgammanull mice display a T effector memory phenotype. AB - The occurrence of Graft-versus-Host Disease (GvHD) is a prevalent and potentially lethal complication that develops following hematopoietic stem cell transplantation. Humanized mouse models of xenogeneic-GvHD based upon immunodeficient strains injected with human peripheral blood mononuclear cells (PBMC; "Hu-PBMC mice") are important tools to study human immune function in vivo. The recent introduction of targeted deletions at the interleukin-2 common gamma chain (IL-2Rgamma(null)), notably the NOD-scid IL-2Rgamma(null) (NSG) and BALB/c-Rag2(null) IL-2Rgamma(null) (BRG) mice, has led to improved human cell engraftment. Despite their widespread use, a comprehensive characterisation of engraftment and GvHD development in the Hu-PBMC NSG and BRG models has never been performed in parallel. We compared engrafted human lymphocyte populations in the peripheral blood, spleens, lymph nodes and bone marrow of these mice. Kinetics of engraftment differed between the two strains, in particular a significantly faster expansion of the human CD45(+) compartment and higher engraftment levels of CD3(+) T-cells were observed in NSG mice, which may explain the faster rate of GvHD development in this model. The pathogenesis of human GvHD involves anti-host effector cell reactivity and cutaneous tissue infiltration. Despite this, the presence of T-cell subsets and tissue homing markers has only recently been characterised in the peripheral blood of patients and has never been properly defined in Hu-PBMC models of GvHD. Engrafted human cells in NSG mice shows a prevalence of tissue homing cells with a T-effector memory (T(EM)) phenotype and high levels of cutaneous lymphocyte antigen (CLA) expression. Characterization of Hu-PBMC mice provides a strong preclinical platform for the application of novel immunotherapies targeting T(EM)-cell driven GvHD. PMID- 22937165 TI - Increased responsiveness of peripheral blood mononuclear cells to in vitro TLR 2, 4 and 7 ligand stimulation in chronic pain patients. AB - Glial activation via Toll-like receptor (TLR) signaling has been shown in animals to play an important role in the initiation and establishment of chronic pain. However, our ability to assess this central immune reactivity in clinical pain populations is currently lacking. Peripheral blood mononuclear cells (PBMCs) are an accessible source of TLR expressing cells that may mirror similarities in TLR responsiveness of the central nervous system. The aim of this study was to characterize the IL-1beta response to various TLR agonists in isolated PBMCs from chronic pain sufferers (on and not on opioids) and pain-free controls. Venous blood was collected from 11 chronic pain sufferers on opioids (>= 20 mg of morphine / day), 8 chronic pain sufferers not on opioids and 11 pain-free controls. PBMCs were isolated and stimulated in vitro with a TLR2 (Pam3CSK4), TLR4 (LPS) or TLR7 (imiquimod) agonist. IL-1beta released into the supernatant was measured with ELISA. Significantly increased IL-1beta expression was found in PBMCs from chronic pain sufferers (on and not on opioids) compared with pain-free controls for TLR2 (F((6, 277)) = 15, P<0.0001), TLR4 (F((8, 263)) = 3, P = 0.002) and TLR7 (F((2,201)) = 5, P = 0.005) agonists. These data demonstrate that PBMCs from chronic pain sufferers were more responsive to TLR agonists compared with controls, suggesting peripheral cells may have the potential to become a source of biomarkers for chronic pain. PMID- 22937166 TI - Genetic factors control nicotine self-administration in isogenic adolescent rat strains. AB - Adult cigarette smokers usually become dependent on cigarettes during adolescence. Despite recent advances in addiction genetics, little data delineates the genetic factors that account for the vulnerability of humans to smoke tobacco. We studied the operant nicotine self-administration (SA) behavior of six inbred strains of adolescent male rats (Fisher 344, Brown Norway, Dark Agouti, Spontaneous Hypertensive Rat, Wistar Kyoto and Lewis) and six selected F1 hybrids. All rats were trained to press a lever to obtain food starting on postnatal day (PN) 32, and then nicotine (0.03 mg/kg/infusion, i.v.) reinforcement was made available on PN41-42 (10 consecutive daily 2 h sessions). Of the 12 isogenic strains, Fisher rats self-administered the fewest nicotine infusions (1.45 +/- 0.36/d) during the last 3 d, while Lewis rats took the most nicotine (13.0 +/- 1.4/d). These strains sorted into high, intermediate and low self-administration groups in 2, 2, and 8 strains, respectively. The influence of heredity on nicotine SA (0.64) is similar to that reported for humans. Therefore, this panel of isogenic rat strains effectively models the overall impact of genetics on the vulnerability to acquire nicotine-reinforced behavior during adolescence. Separate groups of rats responded for food starting on PN41. The correlation between nicotine and food reward was not significant. Hence, the genetic control of the motivation to obtain nicotine is distinctly different from food reward, indicating the specificity of the underlying genetic mechanisms. Lastly, the behavior of F1 hybrids was not predicted from the additive behavior of the parental strains, indicating the impact of significant gene-gene interactions on the susceptibility to nicotine reward. Taken together, the behavioral characteristics of this model indicate its strong potential to identify specific genes mediating the human vulnerability to smoke cigarettes. PMID- 22937167 TI - Older men who use computers have lower risk of dementia. AB - OBJECTIVE: To determine if older men who use computers have lower risk of developing dementia. METHODS: Cohort study of 5506 community-dwelling men aged 69 to 87 years followed for up to 8.5 years. Use of computers measured as daily, weekly, less than weekly and never. Participants also reported their use of email, internet, word processors, games or other computer activities. The primary outcome was the incidence of ICD-10 diagnosis of dementia as recorded by the Western Australian Data Linkage System. RESULTS: 1857/5506 (33.7%) men reported using computers and 347 (6.3%) received a diagnosis of dementia during an average follow up of 6.0 years (range: 6 months to 8.5 years). The hazard ratio (HR) of dementia was lower among computer users than non-users (HR = 0.62, 95%CI = 0.47 0.81, after adjustment for age, educational attainment, size of social network, and presence of depression or of significant clinical morbidity). The HR of dementia appeared to decrease with increasing frequency of computer use: 0.68 (95%CI = 0.41-1.13), 0.61 (95%CI = 0.39-0.94) and 0.59 (95%CI = 0.40-0.87) for less than weekly, at least weekly and daily. The HR of dementia was 0.66 (95%CI = 0.50-0.86) after the analysis was further adjusted for baseline cognitive function, as measured by the Mini-Mental State Examination. CONCLUSION: Older men who use computers have lower risk of receiving a diagnosis of dementia up to 8.5 years later. Randomised trials are required to determine if the observed associations are causal. PMID- 22937168 TI - Genetic diversity increases insect herbivory on oak saplings. AB - A growing body of evidence from community genetics studies suggests that ecosystem functions supported by plant species richness can also be provided by genetic diversity within plant species. This is not yet true for the diversity resistance relationship as it is still unclear whether damage by insect herbivores responds to genetic diversity in host plant populations. We developed a manipulative field experiment based on a synthetic community approach, with 15 mixtures of one to four oak (Quercus robur) half-sib families. We quantified genetic diversity at the plot level by genotyping all oak saplings and assessed overall damage caused by ectophagous and endophagous herbivores along a gradient of increasing genetic diversity. Damage due to ectophagous herbivores increased with the genetic diversity in oak sapling populations as a result of higher levels of damage in mixtures than in monocultures for all families (complementarity effect) rather than because of the presence of more susceptible oak genotypes in mixtures (selection effect). Assemblages of different oak genotypes would benefit polyphagous herbivores via improved host patch location, spill over among neighbouring saplings and diet mixing. By contrast, genetic diversity was a poor predictor of the abundance of endophagous herbivores, which increased with individual sapling apparency. Plant genetic diversity may not provide sufficient functional contrast to prevent tree sapling colonization by specialist herbivores while enhancing the foraging of generalist herbivores. Long term studies are nevertheless required to test whether the effect of genetic diversity on herbivory change with the ontogeny of trees and local adaptation of specialist herbivores. PMID- 22937169 TI - Glucagon like peptide-1-induced glucose metabolism in differentiated human muscle satellite cells is attenuated by hyperglycemia. AB - BACKGROUND: Glucagon like peptide-1 (GLP-1) stimulates insulin secretion from the pancreas but also has extra-pancreatic effects. GLP-1 may stimulate glucose uptake in cultured muscle cells but the mechanism is not clearly defined. Furthermore, while the pancreatic effects of GLP-1 are glucose-dependent, the glucose-dependency of its extra-pancreatic effects has not been examined. METHODS: Skeletal muscle satellite cells isolated from young (22.5 +/- 0.97 yr), lean (BMI 22.5 +/- 0.6 kg/m(2)), healthy males were differentiated in media containing either 22.5 mM (high) or 5 mM (normal) glucose for 7 days in the absence or presence of insulin and/or various GLP-1 concentrations. Myocellular effects of GLP-1, insulin and glucose were assessed by western-blot, glucose uptake and glycogen synthesis. RESULTS: We firstly show that the GLP-1 receptor protein is expressed in differentiated human muscle satellite cells (myocytes). Secondly, we show that in 5 mM glucose media, exposure of myocytes to GLP-1 results in a dose dependent increase in glucose uptake, GLUT4 amount and subsequently glycogen synthesis in a PI3K dependent manner, independent of the insulin signaling cascade. Importantly, we provide evidence that differentiation of human satellite cells in hyperglycemic (22.5 mM glucose) conditions increases GLUT1 expression, and renders the cells insulin resistant and interestingly GLP-1 resistant in terms of glucose uptake and glycogen synthesis. Hyperglycemic conditions did not affect the ability of insulin to phosphorylate downstream targets, PKB or GSK3. Interestingly we show that at 5 mM glucose, GLP-1 increases GLUT4 protein levels and that this effect is abolished by hyperglycemia. CONCLUSIONS: GLP-1 increases glucose uptake and glycogen synthesis into fully differentiated human satellite cells in a PI3-K dependent mechanism potentially through increased GLUT4 protein levels. The latter occurs independently of the insulin signaling pathway. Attenuation of both GLP-1 and insulin-induced glucose metabolism by hyperglycemia is likely to occur downstream of PI3K. PMID- 22937171 TI - Factors that influence parental attitudes toward enrollment in type 1 diabetes trials. AB - AIMS: To assess parental attitudes towards type 1 diabetes clinical trials (T1DCTs) and factors that impact willingness to enroll their children with and without diabetes. METHODS: A cross-sectional survey of parents of children with type 1 diabetes was administered at an academic clinic and a diabetes educational event. RESULTS: Survey response rate was 36%. Of 166 participating parents, 76% were aware of T1DCTs. More parents reported willingness to enroll children with diabetes (47%) than unaffected children (36%). Only 18% recalled being asked to enroll their children, and of these, 60% agreed to enroll at least some of those times. Less than 30% were comfortable with placebos. Factors predicting willingness to enroll children with diabetes included healthcare provider trust, comfort with consent by proxy, low fear of child being a "guinea pig," and comfort with placebo. Factors predicting willingness to enroll unaffected children were provider trust, comfort with consent by proxy, comfort with placebo, and perceived ease of understanding T1DCT information. CONCLUSIONS: Parents report moderate willingness to enroll children in T1DCTs. Willingness is diminished by common trial methodologies. Although most parents recalled receiving trial-related information, significantly fewer recalled being asked to participate. Efforts to optimize effective communication around identified areas of parental concern may increase T1DCT participation. PMID- 22937170 TI - Therapeutic efficacy by targeting correction of Notch1-induced aberrants in uveal tumors. AB - There is a need for more effective treatments for uveal melanoma. The recombinant oncolytic adenovirus H101 replicates specifically in p53-depleted tumor cells, and has been approved for use by the Chinese State Food and Drug Administration. However, this treatment is associated with subsequent remission. Transfection of uveal melanoma cells with a small interfering RNA against Notch1 (siNotch1) effectively suppressed Notch1 expression, resulting in significant cell growth inhibition when combined with H101 treatment. Combined treatment with siNotch1 and H101 (H101-Notch1-siRNA) greatly enhanced apoptosis and cell cycle arrest in vitro as compared to treatment with H101 or siNotch1 alone. For in vivo treatments, the combined treatment of siNotch1 and H101 showed remarkable tumor growth inhibition and prolonged mouse survival in the OCM1 xenograft model. We predict that Notch pathway deregulation could be a feature of uveal melanoma, and could be a therapeutic target, especially if p53 is concurrently targeted. PMID- 22937173 TI - The scarlet letter of alkylation: a mini review of selective alkylating agents. AB - If there were a stigma scale for chemotherapy, alkylating agents would be ranked at the top of the list. The chemical term alkylation is associated with nonselective toxicity, an association that dates back to the use of nitrogen mustards during World War I as chemical warfare agents. That this stigma persists and extends to compounds that, through selectivity, attempt to "tame" the indiscriminate destructive potential of alkylation is the subject of this review. Selective alkylation, as it is referred to herein, constitutes an extremely nascent and dynamic field in oncology. The pharmacodynamic response to this selective strategy depends on a delicate kinetic balance between specificity and the rate and extent of binding. Three representative compounds are presented: RRx 001, 3-bromopyruvate, and TH-302. The main impetus for the development of these compounds has been the avoidance of the serious complications of traditional alkylating agents; therefore, it is the thesis of this review that they should not experience stigma by association. PMID- 22937172 TI - Transcriptomic analysis of acclimation to temperature and light stress in Saccharina latissima (Phaeophyceae). AB - Kelps, brown algae of the order Laminariales, dominate rocky shores and form huge kelp beds which provide habitat and nurseries for various marine organisms. Whereas the basic physiological and ecophysiological characteristics of kelps are well studied, the molecular processes underlying acclimation to different light and temperature conditions are still poorly understood. Therefore we investigated the molecular mechanisms underlying the physiological acclimation to light and temperature stress. Sporophytes of S. latissima were exposed to combinations of light intensities and temperatures, and microarray hybridizations were performed to determine changes in gene expression patterns. This first large-scale transcriptomic study of a kelp species shows that S. latissima responds to temperature and light stress with a multitude of transcriptional changes: up to 32% of genes showed an altered expression after the exposure experiments. High temperature had stronger effects on gene expression in S. latissima than low temperature, reflected by the higher number of temperature-responsive genes. We gained insights into underlying molecular processes of acclimation, which includes adjustment of the primary metabolism as well as induction of several ROS scavengers and a sophisticated regulation of Hsps. We show that S. latissima, as a cold adapted species, must make stronger efforts for acclimating to high than to low temperatures. The strongest response was caused by the combination of high temperatures with high light intensities, which proved most harmful for the alga. PMID- 22937174 TI - An integrated method for reproducible and accurate image-guided stereotactic cranial irradiation of brain tumors using the small animal radiation research platform. AB - Preclinical studies of cranial radiation therapy (RT) using animal brain tumor models have been hampered by technical limitations in the delivery of clinically relevant RT. We established a bioimageable mouse model of glioblastoma multiforme (GBM) and an image-guided radiation delivery system that facilitated precise tumor localization and treatment and which closely resembled clinical RT. Our novel radiation system makes use of magnetic resonance imaging (MRI) and bioluminescent imaging (BLI) to define tumor volumes, computed tomographic (CT) imaging for accurate treatment planning, a novel mouse immobilization system, and precise treatments delivered with the Small Animal Radiation Research Platform. We demonstrated that, in vivo, BLI correlated well with MRI for defining tumor volumes. Our novel restraint system enhanced setup reproducibility and precision, was atraumatic, and minimized artifacts on CT imaging used for treatment planning. We confirmed precise radiation delivery through immunofluorescent analysis of the phosphorylation of histone H2AX in irradiated brains and brain tumors. Assays with an intravenous near-infrared fluorescent probe confirmed that radiation of orthografts increased disruption of the tumor blood-brain barrier (BBB). This integrated model system, which facilitated delivery of precise, reproducible, stereotactic cranial RT in mice and confirmed RT's resultant histologic and BBB changes, may aid future brain tumor research. PMID- 22937175 TI - Diffuse optical spectroscopy evaluation of treatment response in women with locally advanced breast cancer receiving neoadjuvant chemotherapy. AB - The aim of this study was to investigate the potential of diffuse optical spectroscopy for monitoring of patients with locally advanced breast cancer (LABC) undergoing neoadjuvant chemotherapy. Fifteen women receiving treatment for LABC had the affected breast scanned before; 1 week, 4 weeks, and 8 weeks after treatment initiation; and before surgery. Optical properties related to tissue microstructure and biochemical composition were obtained. Clinical and pathologic tumor response was evaluated using whole-mount pathology after mastectomy. Patients who responded to treatment demonstrated an initial increase followed by a drop in optical parameters measured in the whole breast, whereas nonresponding patients demonstrated only a drop in the same parameters 1 week after treatment initiation. Responding patients demonstrated a significant increase of 17% +/- 7%, 8% +/- 8%, 10% +/- 7%, 11% +/- 11%, and 16% +/- 15% in deoxygenated hemoglobin, oxygenated hemoglobin, total hemoglobin concentrations, water percentage, and tissue optical index, 1 week after treatment initiation, respectively. In contrast, nonresponding patients had a decrease of 14% +/- 9%, 18% +/- 7%, 17% +/- 7%, 29% +/- 7%, and 32% +/- 9% in their corresponding optical parameters. Deoxygenated hemoglobin concentration (with 100% sensitivity, 83% specificity) and water percentage (with 75% sensitivity, 100% specificity) were found to be the best predictors of treatment response at 1 week after starting treatment. The results of this study suggest that optical parameters can be potentially used to predict and monitor patients' responses to neoadjuvant chemotherapy and can form a basis for the customization of treatments in which inefficacious treatments can be switched to more efficacious therapies. PMID- 22937176 TI - Angiogenic alterations associated with circulating neoplastic DNA in ovarian carcinoma. AB - OBJECTIVES: Forty percent of women with ovarian carcinoma have circulating free neoplastic DNA identified in plasma. Angiogenesis is critical in neoplastic growth and metastasis. We sought to determine whether circulating neoplastic DNA results from alterations in the balance of angiogenesis activators and inhibitors. METHODS: Sixty patients with invasive ovarian carcinomas with somatic TP53 mutations that had been characterized for circulating neoplastic DNA had carcinoma analyzed for microvessel density using immunohistochemistry with CD31 and for the expression of VEGF, ANGPT1, ANGPT2, PTGS2, PLAU, THBS1, CSF1, PIK3CA, HIF1A, IL8, MMP2, and MMP9 message by real-time quantitative polymerase chain reaction. The expression of each gene was calculated relative to GAPDH expression for each neoplasm. Patient plasma had been tested for circulating neoplastic DNA using a ligase detection reaction. RESULTS: MMP2 expression was significantly correlated with free plasma neoplastic DNA (P = .007). Microvessel density was not correlated with plasma neoplastic DNA or BRCA1/2 mutation status. The expression pattern of other angiogenic factors did not correlate with plasma neoplastic DNA but correlated with each other. BRCA1/2 mutated carcinomas had significantly different expression profiles of angiogenesis activators and inhibitors in comparison to sporadic carcinomas. CONCLUSIONS: MMP2 expression is associated with the presence of circulating neoplastic DNA in women with ovarian carcinoma. These data are consistent with the proinvasive properties of MMP2 and suggest that the presence of circulating neoplastic DNA indicates a more aggressive malignant phenotype. Carcinomas with germ line BRCA1/2 mutations had a lower angiogenic profile than those without mutations. PMID- 22937177 TI - Effects of MnDPDP and ICRF-187 on Doxorubicin-Induced Cardiotoxicity and Anticancer Activity. AB - Oxidative stress participates in doxorubicin (Dx)-induced cardiotoxicity. The metal complex MnDPDP and its metabolite MnPLED possess SOD-mimetic activity, DPDP and PLED have, in addition, high affinity for iron. Mice were injected intravenously with MnDPDP, DPDP, or dexrazoxane (ICRF-187). Thirty minutes later, mice were killed, the left atria were hung in organ baths and electrically stimulated, saline or Dx was added, and the contractility was measured for 60 minutes. In parallel experiments, 10 uM MnDPDP or MnPLED was added directly into the organ bath. The effect of MnDPDP on antitumor activity of Dx against two human tumor xenografts (MX-1 and A2780) was investigated. The in vitro cytotoxic activity was studied by co-incubating A2780 cells with MnDPDP, DPDP, and/or Dx. Dx caused a marked reduction in contractile force. In vivo treatment with MnDPDP and ICRF-187 attenuated the negative effect of Dx. When added directly into the bath, MnDPDP did not protect, whereas MnPLED attenuated the Dx effect by approximately 50%. MnDPDP or ICRF-187 did not interfere negatively with the anti tumor activity of Dx, either in vivo or in vitro. Micromolar concentrations of DPDP but not MnDPDP displayed an in vitro cytotoxic activity against A2780 cells. The present results show that MnDPDP, after being metabolized to MnPLED, protects against acute Dx cardiotoxicity. Both in vivo and in vitro experiments show that cardioprotection takes place without interfering negatively with the anticancer activity of Dx. Furthermore, the results suggest that the previously described cytotoxic in vivo activity of MnDPDP is an inherent property of DPDP. PMID- 22937178 TI - Expression of death receptor 6 by ovarian tumors in laying hens, a preclinical model of spontaneous ovarian cancer. AB - Tumor-associated neoangiogenesis and suppression of antitumor immunity are hallmarks of tumor development and progression. Death receptor 6 (DR6) has been reported to be associated with suppression of antitumor immunity and tumor progression in several malignancies. However, expression of DR6 by malignant ovarian epithelial tumors at an early stage is unknown. The goals of this study were to determine whether DR6 is expressed by malignant ovarian epithelial tumors at an early stage and to examine whether DR6 expression is associated with ovarian cancer (OVCA) progression in a laying hen model of spontaneous OVCA. Expression of DR6 was examined in normal and malignant ovaries, normal ovarian surface epithelial (OSE) cells, or malignant epithelial cells and in serum of 3 year-old hens. The population of microvessels expressing DR6 was significantly higher in hens with early-stage OVCA than hens with normal ovaries (P < .01) and increased further in late-stage OVCA. The results of this study showed that, in addition to microvessels, tumor cells in the ovary also express DR6 with a significantly higher intensity than normal OSE cells. Similar patterns of DR6 expression were also observed by immunoblot analysis and gene expression studies. Furthermore, DR6 was also detected in the serum of hens. In conclusion, DR6 expression is associated with OVCA development and progression in laying hens. This study may be helpful to examine the feasibility of DR6 as a useful surrogate marker of OVCA, a target for antitumor immunotherapy and molecular imaging and thus provide a foundation for clinical studies. PMID- 22937179 TI - Three-dimensional Telomere Signatures of Hodgkin- and Reed-Sternberg Cells at Diagnosis Identify Patients with Poor Response to Conventional Chemotherapy. AB - In classic Hodgkin lymphoma (HL) the malignant mononuclear Hodgkin (H) and multinuclear Reed-Sternberg (RS) cells are characterized by a distinct three dimensional nuclear telomere organization with shortening of the telomere length and the formation of telomeric aggregates. We asked if the severity of these telomere changes correlates with the clinical behavior of the disease. We retrospectively evaluated three-dimensional telomere organization by quantitative fluorescent in situ hybridization (Q-FISH) of diagnostic biopsies from 16 patients who were good responders and compared them with 16 diagnostic biopsies of 10 patients with refractory or relapsing HL (eight initial biopsies, four confirming progressions, and four confirming relapses). The H cells from patients with refractory/relapsing disease contained a significantly higher percentage of very small telomeres (P = .027) and telomere aggregates (P = .032) compared with H cells of patients entering rapid remission. These differences were even more significant (P = .002 and P = .013, respectively) when comparing the eight initial diagnostic biopsies of refractory/relapsing HL with diagnostic biopsies of eight patients with ongoing long-lasting remission (mean of 47 months). This specific three-dimensional telomere Q-FISH signature identifies these highly aggressive mononuclear H cells at the first diagnostic biopsy and thus may offer a new molecular marker to optimize initial treatment. PMID- 22937180 TI - Decreased skp2 expression is necessary but not sufficient for therapy-induced senescence in prostate cancer. AB - Therapy-induced senescence (TIS), a cytostatic stress response in cancer cells, is induced inefficiently by current anticancer agents and radiation. The mechanisms that mediate TIS in cancer cells are not well defined. Herein, we characterize a robust senescence response both in vitro and in vivo to the quinone diaziquone (AZQ), previously identified in a high-throughput senescence induction small-molecule screen. Using AZQ and several other agents that induce senescence, we screened a series of cyclin-dependent kinase inhibitors and found that p27(Kip1) was induced in all investigated prostate cancer cell lines. The ubiquitin-ligase Skp2 negatively regulates p27(Kip1) and, during TIS, is translocated to the cytoplasm before its expression is decreased in senescent cells. Overexpression of Skp2 blocks the effects of AZQ on senescence and p27(Kip1) induction. We also find that stable long-term short hairpin RNA knockdown of Skp2 decreases proliferation but does not generate the complete senescence phenotype. We conclude that Skp2 participates in regulating TIS but, alone, is insufficient to induce senescence in cancer cells. PMID- 22937181 TI - l-DOPA Decarboxylase (DDC) Expression Status as a Novel Molecular Tumor Marker for Diagnostic and Prognostic Purposes in Laryngeal Cancer. AB - l-DOPA decarboxylase (DDC) plays an essential role in the enzymatic synthesis of dopamine and alterations in its gene expression have been reported in several malignancies. Our objective was to analyze DDC messenger RNA (mRNA) and protein expression in laryngeal tissues and to evaluate the clinical implication of this molecule in laryngeal cancer. In this study, total RNA was isolated from 157 tissue samples surgically removed from 100 laryngeal cancer patients. A highly sensitive real-time polymerase chain reaction methodology based on SYBR Green I fluorescent dye was developed for the quantification of DDC mRNA levels. In addition, Western blot analysis was performed for the detection of DDC protein. DDC mRNA expression was revealed to be significantly downregulated in primary laryngeal cancer samples compared with their nonmalignant counterparts (P = .001). A significant negative association was also disclosed between DDC mRNA levels and TNM staging (P = .034). Univariate analysis showed that patients bearing DDC-positive tumors had a significantly decreased risk of death (hazard ratio = 0.23, P = .012) and local recurrence (hazard ratio = 0.32, P =.006), whereas DDC expression retained its favorable prognostic significance in the multivariate analysis. Kaplan-Meier curves further demonstrated that DDC-positive patients experienced longer overall and disease-free survival periods (P = .006 and P = .004, respectively). Moreover, DDC protein was detected in both neoplastic and noncancerous tissues. Therefore, our results suggest that DDC expression status could qualify as a promising biomarker for the future clinical management of laryngeal cancer patients. PMID- 22937182 TI - An interferon response gene expression signature is activated in a subset of medulloblastomas. AB - Recent evidence suggests that cytomegalovirus infection contributes to the development of medulloblastomas. Differential activation of antiviral expression programs in medulloblastomas has not been investigated yet. In this study, we assess the relevance of an antiviral transcriptional response in medulloblastomas. We analyzed a gene expression signature of type I interferon response in three public gene expression data sets of medulloblastomas. Interferon response genes were found to be significantly coordinately regulated in two independent studies. We distilled a signature of 10 interferon response genes from two data sets. This signature exhibited strongly significant gene versus-gene correlation of expression levels across samples in a third external medulloblastoma data set. Our medulloblastoma IFN signature identified a previously unrecognized patient subgroup partially overlapping the WNT and SHH subtypes proposed by others. We conclude that significant traces of differential activation of antiviral transcriptional response can be found in three independent medulloblastoma patient cohorts. This IFN activation signal often coincides with reduced proliferation scores. Our proposed 10-gene type I IFN response gene signature could help to assess antiviral states in further gene expression data sets of medulloblastomas or other cancers. PMID- 22937183 TI - [Serological analysis of toxoplasmosis during pregnancy: risk assessment and perspectives of prenatal screening at the University Hospital of Bobo Dioulasso in Burkina Faso]. PMID- 22937184 TI - Acute pseudo-septic arthritis following viscosuplementation of the knee. AB - A 70-year-old woman with a history of medial femoro-tibial compartment of knee osteoarthritis was admitted for acute arthritis six days after a second intra articular injection of Hyaluronic acid. The joint fluid was inflammatory, with no crystals, and laboratory tests showed marked inflammation leading to antibiotic treatment for suspected septic arthritis. The persistent symptoms and negative results of joint fluid and blood cultures led to discontinuation of the antibiotic therapy after 10 days. Anti-inflammatory with rehabilitation therapy of the knee relieved the symptoms, and the patient was discharged home 3 weeks after her admission. Aseptic arthritis induced by repeated Hyaluronic acid injection is the most likely diagnosis. Physicians should be conscious of this extremely severe complication. PMID- 22937185 TI - [Peritoneal dialysis in patients under twenty years: experience in a Moroccan university hospital]. PMID- 22937186 TI - [Frequency of severe anemia in children aged 2 months to 15 years at Mother and Child Centre of the Chantal Biya Foundation Yaounde, Cameroon]. PMID- 22937187 TI - [Vaginal localisation of Mansonella perstans: report of a case at the University Hospital of Bobo-Dioulasso, Burkina Faso]. PMID- 22937188 TI - Elevated plasma homocysteine in type 2 diabetes mellitus: a risk factor for cardiovascular diseases. AB - BACKGROUND: Elevated plasma total homocysteine (tHcy) concentration has been associated with an increased risk for cardiovascular events in type 2 diabetic individuals independent of conventional risk factors. Available study in Nigerian Africans is scare. METHODS: Seventy (30 males) and (40 females) type 2 diabetes mellitus, with age mean of 54 +/- 11.52 years were selected for this study and thirty apparently healthy volunteers were included as controls. The biochemical parameters and anthropometric indices were determined using standard procedures. RESULTS: Significant increases were obtained in body weight, body mass index (p<0.001) and waist circumference (p<0.012) when compared with the corresponding control values respectively. The fasting plasma glucose (p<0.01), tHcy (p<0.02), and triglyceride (p<0.03) were significantly higher in the diabetes group when compared with the corresponding control values. The plasma folic acid and vitamin B(12) (p<0.05) were significantly reduced compared to the control values. The tHcy (p<0.01) was significantly higher in the males when compared with the corresponding female value. Significant decrease was obtained in the plasma triglyceride (p<0.003) in the male patients when compared with the female patients. CONCLUSION: Our result showed increased plasma tHcy, triglyceride and waist circumference as well as decreased folic acid and vitamin B(12) in type 2 diabetes mellitus. These alterations are risk factors for premature CVD events. PMID- 22937189 TI - [Temporary detention of young women accused of illegal abortion or infanticide in Senegal]. PMID- 22937190 TI - [Rhupus syndrome: report of two cases]. PMID- 22937191 TI - [Contribution of endoscopy in portal hypertension in children: about 68 cases]. PMID- 22937192 TI - The impact of knowledge and attitudes on adherence to tuberculosis treatment: a case-control study in a Moroccan region. AB - BACKGROUND: Although tuberculosis (TB) care is provided free of charge in Morocco, a high number of patients voluntarily interrupt their treatment before the end. Treatment Default is a major obstacle in the fight against the disease. The purpose of this study was to describe the impact of knowledge and attitudes toward TB on treatment adherence. METHODS: Case-control study of 290 TB patients (85 defaulters and 205 controls). A defaulter was defined as a TB patient who interrupted treatment for two months or longer. Socio-demographic measurements, knowledge and attitude were collected by face to face anonymous questionnaire. Khi-square test was conducted to examine differences in TB attitudes and knowledge according to treatment adherence. RESULTS: The mean age of participants was 31.7 +/- 12.0 years. Monthly income was under 2000 MAD (180 ?) for 82% of them. Over sixty four percent were illiterate or had a basic educational level. Microbial cause was known by 17.2% respondents; 20.5% among adherent patients versus 9.4% (p=0.02). The fact that the disease is curable was more known by adherent patients: 99.0% versus 88.2% (p < 0.01). Eighty tree per cent of patients had been informed about treatment duration and consequences of not completing treatment: 89.0% among adherent patients versus 69.7% (p<0.001). The main reason evoked for defaulting was the sensation of being cured (72.9% of defaulters). CONCLUSION: This study shows a poor knowledge on TB especially among non adherent patients. This finding justifies the need to incorporate patient's education into current TB case management. PMID- 22937193 TI - Diet and non-Hodgkin's lymphoma risk. AB - BACKGROUND: The role of dietary factors in the epidemiology of Non-Hodgkin's lymphoma (NHL) remains largely undefined. Dietary habits may play a role in the etiology of NHL by influencing the immune system. METHODS: Dietary patterns and the risk of NHL were analyzed in a case control study; including 170 NHL cases and 190 controls. All subjects completed a validated food-frequency questionnaire. The dietary pattern was investigated separately and in nine nutritional groups. Crosstab tables were used to estimate the odds ratios (OR), and P(trend). RESULTS: Consumption of highest versus lowest quartile of proteins (OR, 8.088 P(trend)=0.000), fats (OR, 6.17 P(trend)=0.000) and sweets (OR, 8.806 P(trend)=0.000) were associated with a significantly increased NHL risk. The inverse association was found for fresh fruits (OR, 0.117 P(trend)=0.000) and vegetables (OR, 0.461 P(trend)=0.010). CONCLUSION: An association between dietary intake and the risk of NHL is biologically plausible due to immunosuppressive effects of fat and animal proteins, and antioxidant properties of vegetables and fruits. PMID- 22937194 TI - Evaluation of medical consultation letters at King Fahd Hospital, Al Hufuf, Saudi Arabia. AB - BACKGROUND: In surgical wards, it is of paramount importance to communicate with other health care providers, mostly physicians, referring patients to them for their consultation on any health conditions that affect pre-operative, operative and post-operative patient care. The purposes of this investigation were to assess the appropriateness of physician responses in medical consultation reports and compare physician responses when using these reports from different levels of health care providers. METHODS: This study was conducted in Al-Hufuf, Saudi Arabia. The researchers evaluated all the surgical consultation letters in the files during the period between March 2010 and March 2011. From the explored 234 files, only 200 consultation letters were chosen as there was a referral data plus consultation data in the same file. We evaluated the quality of consultation report included the ethical concerns towards colleagues and patient, consideration of patient safety in all opinions, comprehensive pertinent scientific information, addressing the patient's medical condition with putting possible differential diagnosis, conclusion and precise management plans suggested. RESULTS: The results showed that the specialists' consultation letters had the highest percentage of fulfillment of all the six items in the consultation report. There is no uniform existing consultation report form. CONCLUSION: Specialist form showed the highest number of mentioning the diagnosis. Consultant form showed the highest number of mentioning the concise aim of referral. The highest percentage of all categories mentioned all items in consultation report with a good level were the specialists. PMID- 22937195 TI - [Study of factors related to adherence to antiretroviral therapy among patients followed at HIV/AIDS Unit in the District Hospital of Dschang, Cameroon]. PMID- 22937196 TI - [The intracranial tuberculoma: report of 125 cases]. PMID- 22937197 TI - Periorbital edema as initial manifestation of chronic cutaneous lupus erythematosus. AB - Periorbital edema occurs frequently in dermatomyositis, but it has rarely been noted in systemic systemic lupus erythematosus. We describe a patient who developed bilateral periorbital edema and erythema as the sole manifestation of systemic lupus erythematosus. PMID- 22937198 TI - [Primary lymphoma of the breast: a case report]. PMID- 22937199 TI - Cholera epidemiology in Nigeria: an overview. AB - Cholera is an acute diarrhoeal infection caused by ingestion of food or water contaminated with the bacterium, Vibrio cholera. Choleragenic V. cholera O1 and O139 are the only causative agents of the disease. The two most distinguishing epidemiologic features of the disease are its tendency to appear in explosive outbreaks and its predisposition to causing pandemics that may progressively affect many countries and spread into continents. Despite efforts to control cholera, the disease continues to occur as a major public health problem in many developing countries. Numerous studies over more than a century have made advances in the understanding of the disease and ways of treating patients, but the mechanism of emergence of new epidemic strains, and the ecosystem supporting regular epidemics, remain challenging to epidemiologists. In Nigeria, since the first appearance of epidemic cholera in 1972, intermittent outbreaks have been occurring. The later part of 2010 was marked with severe outbreak which started from the northern part of Nigeria, spreading to the other parts and involving approximately 3,000 cases and 781 deaths. Sporadic cases have also been reported. Although epidemiologic surveillance constitutes an important component of the public health response, publicly available surveillance data from Nigeria have been relatively limited to date. Based on existing relevant scientific literature on features of cholera, this paper presents a synopsis of cholera epidemiology emphasising the situation in Nigeria. PMID- 22937200 TI - Pericardial cyst with right ventricular compression. AB - Pericardial cysts are infrequent and benign mediastinal lesions. While most pericardial cysts are asymptomatic, some patients may present with compression symptoms. We present the case of a 22-year-old man who presented with a right pericardial cyst that caused compression of the right ventricle. PMID- 22937201 TI - [Takayasu's arteritis and rheumatoid arthritis: a rare association - about an observation]. PMID- 22937202 TI - Gastrointestinal bleeding due to an erosion of the superior mesenteric artery: an exceptional fatal complication of pancreatic pseudocyst. AB - The erosion of a pancreatic pseudocyst into an adjacent artery is a rare and highly lethal complication of pancreatitis with reported death rates of 12% to 40%. The majority of patients had bleeding from the splenic artery, the gastroduodenal artery and the anterior pacreaticoduodenal artery. Exceptionally, some cases with bleeding from the superior mesenteric artery, or hepatic artery were reported. We report the case of a 50 year old patient having a cataclysmic upper gastrointestinal bleeding due to an erosion of the superior mesenteric artery by a pancreatic pseudocyst, and discuss contemporary methods in diagnosis and management of the condition. PMID- 22937203 TI - Genomic amplification and a role in drug-resistance for the KDM5A histone demethylase in breast cancer. AB - Lysine-specific demethylase 5A (KDM5A), an enzyme that removes activating H3K4 di and trimethylation marks, plays critical roles in controlling transcription and chromatin architecture, yet its biological functions largely remain uncharacterized, particularly in the context of human cancer. In the present study, we found that the KDM5A gene was significantly amplified and over expressed in various human tumors, including breast cancer. Reducing the expression of KDM5A by shRNA knockdown inhibited proliferation of KDM5A-amplified breast cancer cells. More importantly, we demonstrated that KDM5A over-expression was associated with breast cancer drug resistance. Furthermore, knockdown of KDM5A gene expression altered H3K4 methylation and induced upregulation of CDK inhibitors as well as genes mediating apoptotic cell death. Taken together, our study strongly links KDM5A histone demethylase activity to breast cancer proliferation and drug resistance, and suggests KDM5A is a potential target for breast cancer therapy. PMID- 22937204 TI - Salutary effects of a novel oxidative stress modulator on adenine-induced chronic progressive tubulointerstitial nephropathy. AB - BACKGROUND: Oxidative stress and inflammation promote the development and progression of chronic kidney disease. Oxidative stress is associated with depletion of tissue glutathione (GSH), the most abundant endogenous intracellular antioxidant, but degradation of oral GSH by digestive enzymes limits its therapeutic use. We hypothesized that GSH repletion with F1, a novel oral GSH precursor containing cystine as a cysteine carrier, would restore tissue GSH and attenuate oxidative stress and inflammation, and thereby reduce the severity of interstitial nephropathy in chronic renal failure (CRF). METHODS: Male Sprague Dawley rats (n=5-8) were assigned to 3 groups: Control (regular rat chow), CRF (rat chow containing 0.7% adenine), and F1-treated CRF (rat chow containing 0.7% adenine and F1, 0.5g/kg/day) for 2-weeks. Animals were switched to regular chow and euthanized after 2 additional weeks. RESULTS: Consumption of 0.7% adenine containing diet caused azotemia; severe kidney swelling; heavy tubular and glomerular damage; massive tubulointerstitial nephropathy; impaired urinary concentrating capacity; severe anemia; increased markers of oxidative stress, plasma oxidized glutathione disulfide (GSSG); reduced GSH/GSSG ratio and manganese superoxide dismutase; increased expression of inflammatory mediators (cyclooxygenase-2, cytoplasmic NF-kappaB, p-IkappaBalpha, nuclear NF-kappaB p65), and 3-nitrotyrosine, p<0.05. Co-treatment with F1 significantly attenuated tubulointerstitial inflammation and edema, improved urinary concentrating capacity, azotemia and anemia, and normalized markers of tissue oxidative and nitrosative stress, p<0.05. CONCLUSIONS: The novel oxidative stress modulator, F1, markedly attenuated oxidative stress indicators, inflammation, renal injury and dysfunction in the rat model of CRF. Studies to determine the effects of F1 in other models of acute and CRF are warranted. PMID- 22937206 TI - Single nucleotide polymorphisms of the adult intestinal stem cell marker Lgr5 in primary and metastatic colorectal cancer. AB - Morphological and clinical heterogeneity of advanced colorectal cancer is probably caused by genetic variability in putative cancer stem cell genes, including Lgr5. Here, we investigated 23 variants of the Lgr5 gene in normal tissue, primary tumors, lymph node metastases and distant metastases of stage III and stage IV colorectal cancer patients. These data were compared to results of immunohistochemical Lgr5 expression analysis and to prognostic clinical parameters. No differences were found comparing germline and somatic Lgr5 genotype in primary tumors, but additional Lgr5 gene alterations could be demonstrated in lymph node and distant metastases. Significant negative correlation was seen between Lgr5 allelic variation and Lgr5 protein expression (p=0.0394), which mainly can be attributed to the negative influence of non coding Lgr5 gene variations on Lgr5 protein expression (p=0.0166). Lgr5 gene variants could be found more frequently in primary tumors of stage III patients with increased time to recurrence, in distant metastases of patients with better survival and in lymph node metastases of patients with poorer survival compared to patients with Lgr5 wild type in primary and metastatic tissues, respectively. However, the analytic power of these prognostic data was low due to small sample size in the investigated groups. In conclusion, our data indicate that Lgr5 allelic variation affect Lgr5 protein expression in colorectal carcinomas. The somatic Lgr5 genotype seems to be relatively stable in primary tumors, but becomes vulnerable during the metastatic process of colorectal cancer. This instability has possibly prognostic importance, which has to be further evaluated by large cohort studies. PMID- 22937205 TI - The role of estrogen in the pathophysiology of tubal ectopic pregnancy. AB - 17beta-estradiol, acting through estrogen receptors alpha and beta, plays a fundamental role in the regulation of Fallopian tube cell homeostasis and in the modulation of normal tubal physiological processes. Fluctuations in E2 levels also play crucial roles in the initiation or progression of numerous human diseases. Fallopian tube malfunction often results in tubal ectopic pregnancy, which is one cause of maternal morbidity and mortality in women. Several factors have been proposed to be associated with increased risk of tubal ectopic pregnancy, but whether these factors are the cause of, or are merely symptoms of, such pregnancies remains unresolved due to the lack of knowledge in regards to the mechanisms by which embryos inadvertently implant in the Fallopian tube. This review summarizes recent findings, including data from our own laboratory, on E2 metabolism and estrogen receptor (ER) subtype expression within the Fallopian tube in humans and rodents. This review also outlines several important, unresolved questions in the field that, once addressed, could offer important clues into how E2/ER signaling contributes to the pathology of tubal function. A better understanding of the specific functions of estrogen receptor subtypes in vivo, as well as of the mechanism and consequences of receptor subtype interactions is critical to understanding their respective roles in Fallopian tube physiology and in the pathophysiology and etiology of tubal ectopic pregnancy. PMID- 22937207 TI - The MURDOCK Study: a long-term initiative for disease reclassification through advanced biomarker discovery and integration with electronic health records. AB - BACKGROUND: Facing critically low return per dollar invested on clinical research and clinical care, the American biomedical enterprise is in need of a significant transformation. A confluence of high-throughput "omic" technologies and increasing adoption of the electronic health record has fueled excitement for a new paradigm for biomedical research and practice. The ability to simultaneously measure thousands of molecular variables and assess their relationships with clinical data collected during the course of care could enable reclassification of disease not only by gross phenotypic observation but according to underlying molecular mechanism and influence of social determinants.In turn, this reclassification could enable development of targeted therapeutic interventions as well as disease prevention strategies at the individual and population levels. METHODS/DESIGN: The MURDOCK Study consists of distinct project "horizons" or stages. Horizon 1 entailed the generation and analysis of molecular data for existing large,clinically well-annotated cohorts in four disease areas. Horizon 1.5 involves creating and maintaining a 50,000-person,community volunteer registry for biomarker signature validation and prospective studies, including integration of environmental and social data. Horizon 2 leverages and prospectively recruits Horizon 1.5 volunteers, and extends the study to additional disease areas of interest. Horizon 3 will expand the study through regional, national,and international partnerships. DISCUSSION: The MURDOCK Study embodies a new model of team science investigation and represents a significant resource for translational research. The study team invites inquiries to form new collaborations to exploit the rich resources provided by these biospecimens and associated study data. PMID- 22937208 TI - HIV-1 Tat-induced microglial activation and neuronal damage is inhibited via CD45 modulation: A potential new treatment target for HAND. AB - Microglia become activated in humans subsequent to infection with HIV, and uncontrolled brain inflammation plays a key role in neuronal injury and and cognitive dysfunction during HIV infection. Various studies have shown a deleterious role for the HIV regulatory protein Tat in the development and maintenance of HIV-associated neurocognitive disorders (HAND). One cell surface receptor implicated in inhibiting microglial activation is the protein-tyrosine phosphatase (PTP), CD45. It is especially effective at inhibiting microglial activation because its action takes place far upstream from proinflammatory intracellular signaling mediators. To investigate the possible role of CD45 in microglial responsiveness to HIV-1 Tat protein, we treated BV-2 microglia with a tyrosine phosphatase inhibitor [potassium bisperoxo (1, 10-phenanthroline) oxovanadate (phen), 5 MUM] and HIV-1 Tat protein (700ng/ml). We found a synergistic pro-inflammatory microglial activation as supported by tumor necrosis factor-alpha (TNF-alpha) and interleukin 1-beta (IL-1beta) release, both of which were dependent on p44/42 mitogen-activated protein kinase (MAPK) activation. Stimulation of microglial CD45 by anti-CD45 antibody markedly inhibited these Tat or Tat/Phen effects via attenuation of p44/42 MAPK, suggesting CD45 negatively regulates microglial activation. As a validation of these findings in vivo, brains from transgenic mice deficient for CD45 through complete genetic ablation, or by CNS delivery of CD45shRNA, demonstrate markedly increased production of TNF alpha 24 hours after intracerebroventricular injection of HIV-Tat protein (5MUg/mouse) compared to control mice. This increased microglial activation was accompanied by astrogliosis and a significant loss of cortical neurons due to apoptosis in CD45 deficient animals. These results suggest therapeutic agents that activate CD45 PTP signaling may be effective in suppressing microglial activation associated with HAND. PMID- 22937209 TI - Post-insult valproic acid-regulated microRNAs: potential targets for cerebral ischemia. AB - Stroke is a devastating brain injury that is a leading cause of adult disability with limited treatment options. Using a rat model of middle cerebral artery occlusion (MCAO) to induce cerebral ischemia, we profiled microRNAs (miRNAs), small non-protein coding RNAs, in the ischemic cortex. Many miRNAs were confirmed by qPCR to be robustly upregulated 24 hours following MCAO surgery including miR 155, miR-297a, miR-466f, miR-466h, and miR-1224. In addition, we treated MCAO rats with valproic acid (VPA), a mood stabilizer and histone deacetylase inhibitor. This post-insult treatment was shown to improve neurological deficits and motor performance following MCAO. To provide mechanistic insight into the potential targets and pathways that may underlie these benefits, we profiled miRNAs regulated following this VPA treatment. Two promising post-insult VPA regulated candidates were miR-331 and miR-885-3p. miR-331 was also regulated by VPA pre-treatment in rat cortical neuronal cultures subjected to oxygen-glucose deprivation, an in vitro ischemic model. The predicted targets of these miRNAs analyzed by Ingenuity Pathway Analysis (IPA) identified networks involved in hematological system development, cell death, and nervous system development. These predicted networks were further filtered using IPA and showed significant associations with neurological diseases including movement disorders, neurodegenerative disorders, damage to cerebral cortex, and seizure disorders among others. Collectively, these data support common disease mechanisms that may be under miRNA control and provide exciting directions for further investigations aimed at elucidating the miRNA mechanisms and targets that may yield new therapies for neurological disorders. PMID- 22937210 TI - ImmunoPET and near-infrared fluorescence imaging of CD105 expression using a monoclonal antibody dual-labeled with (89)Zr and IRDye 800CW. AB - CD105 (endoglin) is an independent marker for poor prognosis in more than 10 solid tumor types. The goal of this study was to develop a CD105-specific agent for both positron emission tomography (PET) and near-infrared fluorescence (NIRF) imaging, which has potential clinical applications in the diagnosis and imaged guided resection of solid tumors. TRC105, a chimeric anti-CD105 monoclonal antibody, was conjugated to a NIRF dye (800CW) and p-isothiocyanatobenzyl desferrioxamine (Df-Bz-NCS) before (89)Zr-labeling. Another chimeric antibody, cetuximab, was used as an isotype-matched control. FACS analysis revealed no difference in CD105 binding affinity/specificity between TRC105 and Df-TRC105 800CW. Serial PET imaging revealed that the 4T1 tumor uptake of (89)Zr-Df-TRC105 800CW was 6.3 +/- 1.9, 12.3 +/- 1.3, and 11.4 +/- 1.1 %ID/g at 4, 24, and 48 h post-injection (p.i.) respectively (n = 3), higher than all organs starting from 24 h p.i., which provided excellent tumor contrast. Tumor uptake as measured by both in vivo and ex vivo NIRF imaging had a linear correlation with the %ID/g values obtained from PET, corroborated by biodistribution studies. Blocking experiments, control studies with (89)Zr-Df-cetuximab-800CW, and histology all confirmed the CD105 specificity of (89)Zr-Df-TRC105-800CW. In conclusion, herein we report dual-modality PET and NIRF imaging of CD105 expression in a breast cancer model, where CD105-specific uptake of (89)Zr-Df-TRC105-800CW in the tumor was observed. PMID- 22937211 TI - A hypermorphic SP1-binding CD24 variant associates with risk and progression of multiple sclerosis. AB - A large number of risk alleles have been identified for multiple sclerosis (MS). However, how genetic variations may affect pathogenesis remains largely unknown for most risk alleles. Through direct sequencing of CD24 promoter region, we identified a cluster of 7 new single nucleotide polymorphisms in the CD24 promoter. A hypermorphic haplotype consisting of 3 SNPs was identified through association studies consisting of 935 control and 764 MS patients (P=0.001, odds ratio 1.3). The variant is also associated with more rapid progression of MS (P=0.016, log rank test). In cells that are heterozygous for the risk allele, chromatin immunoprecipitation revealed that risk allele specifically bind to a transcription factor SP1, which is selectively required for the hypermorphic promoter activity of the variant. In MS patients, the CD24 transcript levels associate with the SP1-binding variant in a dose-dependent manner (P=7x10(-4)). Our data revealed a potential role for SP1-mediated transcriptional regulation in MS pathogenesis. PMID- 22937212 TI - Kruppel-like factor 8 emerges as an important regulator of cancer. AB - Kruppel-like factor 8 (KLF8) is a young member of the KLF transcription factor family proteins. It is highly overexpressed in several types of human cancers and regulates various cellular processes important for tumor progression. Increasing evidence has made KLF8 a new focus in cancer research and a potential target for cancer therapy. This review highlights the role of KLF8 in cancer by summarizing the up-to-date studies into its structure, function as a dual transcription factor, target genes and mechanisms of expression and modifications. PMID- 22937213 TI - Dysregulated lipid metabolism in cancer. AB - Alteration of lipid metabolism has been increasingly recognized as a hallmark of cancer cells. The changes of expression and activity of lipid metabolizing enzymes are directly regulated by the activity of oncogenic signals. The dependence of tumor cells on the dysregulated lipid metabolism suggests that proteins involved in this process are excellent chemotherapeutic targets for cancer treatment. There are currently several drugs under development or in clinical trials that are based on specifically targeting the altered lipid metabolic pathways in cancer cells. Further understanding of dysregulated lipid metabolism and its associated signaling pathways will help us to better design efficient cancer therapeutic strategy. PMID- 22937214 TI - Extrahepatic biliary cancer: New staging classification. AB - Tumor staging defines the point in the natural history of the malignancy when the diagnosis is made. The most common staging system for cancer is the tumor, node, metastases classification. Staging of cancers provides useful parameters in the determination of the extent of disease and prognosis. Cholangiocarcinoma are rare and refers to cancers that arise from the biliary epithelium. These tumors can occur anywhere along the biliary tree. These tumors have been previously divided into extrahepatic and intrahepatic lesions. Until recently the extrahepatic bile duct tumors have been considered as a single entity per American Joint Commission on Cancer (AJCC) staging classification. The most recent changes to the AJCC classification of bile duct cancers divide the tumors into two major categories: proximal and distal tumors. This practical classification is based on anatomy and surgical management. High quality cross-sectional computed tomography (CT) and/or magnetic resonance (MR) imaging of the abdomen are essential information to accurately stage this tumors. Imaging plays an important role in diagnosis, localization, staging and optimal management of cholangiocarcinoma. For example, it helps to localize the tumor to either perihilar or distal bile duct, both of which have different management. Further, it helps to accurately stage the disease and identify the presence of significant nodal and distant metastasis, which may preclude surgery. Also, it helps to identify the extent of local invasion, which has a major impact on the management. For example, extensive involvement of hepatic duct reaching up to second-order biliary radicals or major vascular encasement of portal vein or hepatic arteries precludes curative surgery and patient may be managed by palliative therapy. Further, imaging helps to identify any anatomical variations in the hepatic arterial or venous circulation and biliary ductal system, which is vital information for surgical planning. This review presents relevant clinical presentation and imaging acquisition and presentation for the accurate staging classification of bile duct tumors based on the new AJCC criteria. This will be performed with the assistance of anatomical diagrams and representative CT and MR images. The image interpretation must include all relevant imaging information for optimum staging. Detailed recommendations on the items required on the radiology report will be presented. PMID- 22937216 TI - Imaging investigation of pancreatic cystic lesions and proposal for therapeutic guidelines. AB - AIM: To propose a diagnostic algorithm for preoperatively predicting the need for surgical intervention. METHODS: The study included 56 patients (27 men and 29 women) with a final diagnosis of cystic pancreatic lesions. The following materials were used: ultrasonic equipment with 3.5 and 7 MHz linear, convex and biopsical transducers. Multidetector computed tomography (MDCT) investigations were performed using a 16-slice scanner. Images were obtained following the oral administration of 200 mL water and 100 mL intravenous iopamidol (300 mg/mL) administered by pump injector at a rate of 3 mL/s (40 and 60 s post-injection, respectively) using 0.5 mm detectors, reconstructed at 1 mm (pancreatic phase) or 2 mm (portal venous phase) increments. The table feed was 10 mm per rotation. Images were acquired in the pancreatic and portal venous phases of contrast enhancement. The "Chiba" needles 18, 20, 22, 23 G and an automatic aspiration system were used in conjunction with the following methods of guiding the interventional procedures: (1)"free-hand" biopsy and puncture method under ultrasound (US) or computed tomography (CT) control; (2) guiding method using biopsical transducer. RESULTS: All 56 patients in this study underwent at least two cuts imaging survey methods, such as US, CT or magnetic resonance imaging (MRI). The most common preoperative diagnostic examination was US scan - 56 patients (100%). MDCT studies were conducted in 49 (87.50%) and MRI in 13 (23.21%). More than half of patients surveyed (37) underwent some type of interventional procedure: 25-fine-needle aspiration and 29-fine needle aspiration biopsy (FNAB), as part of the examination. Thirty-four patients of all 56 patients underwent surgery because of histological evidence of malignancy after the FNAB for cystic lesions of the pancreas. Distal pancreatectomy with splenectomy was the most common operative approach in 13 patients, followed by Whipple resection in 11 and distal pancreatectomy without splenectomy in 7. Three patients were treated with total pancreatectomy due to the presence of a multifocal mucinous neoplasm. Comparing the diagnostic results of US examination with those of MDCT examination and histological verification true positive results were found in 31 patients, true negative in 11 patients, false positive in 5 and false negative in 9 patients. Accordingly we estimated the power of the diagnostic imaging methods for cystic lesions of the pancreas. A specificity of 68.75%, sensitivity of 79.48%, accuracy of 75.00%, positive predictive value of 86.11% and negative predictive value of 55% were obtained. The power increased after applying invasive procedures with immunohistochemical analysis of CEA and P 53 (Fig. 4). In 15 patients with cytological feature of malignant tumour cells, the tumour markers were positive. In our opinion the higher the percentage of reacting cells the higher the percent of malignancy. In patients with clear symptoms and/or clear imaging features of malignant or premalignant cystic neoplasm, the need for surgery was confirmed by histological verification in 34 (60.71%) of cases. CONCLUSION: By using the proposed algorithm, cystic mucinous tumors of the pancreas were detected and proper operative interventions would have been rendered with fewer diagnostic examinations. PMID- 22937217 TI - Hepatocellular carcinoma treated with transarterial chemoembolization: Evaluation with parametric contrast-enhanced ultrasonography. AB - AIM: To evaluate the response of hepatocellular carcinoma (HCC) to transarterial chemoembolization (TACE) using a simplified protocol of parametric contrast enhanced ultrasound (pCEUS). METHODS: Eighteen patients with HCC (18 target tumors, diameter: 2.8-12 cm) were evaluated before, and 20 d after TACE. The distribution and morphology of TACE-induced necrosis in these tumors precluded accurate evaluation by visual assessment or by simple measurements. For pCEUS, a 4.8 mL bolus of SonoVue (Bracco, Milan, Italy) was intravenously administered and analysis of tumor perfusion during the initial phase of enhancement (0-30 s post injection) was performed with dedicated software (Qontrast, Bracco, Milan, Italy). Time-intensity curves were plotted and three parameters were calculated: peak intensity (PI, in percentage %), time to peak (TTP in seconds, s) and area under the curve during wash-in (AUC-WI, in arbitrary units, a.u). Magnetic resonance imaging was the standard imaging modality for post-treatment evaluation. Changes in tumor size were recorded and response was assessed according to response evaluation criteria in solid tumors criteria. RESULTS: A statistically significant decrease in PI and AUC-WI was observed in the treated tumors post TACE; PIpre: 21.5% +/- 8.7% (mean +/- SD), PIpost: 12.7% +/- 6.7%, P < 0.001, AUC-WI pre: 17493 +/- 9563 a.u, AUC-WI post: 9585 +/- 5494 a.u, P < 0.001. A slight increase in TTP was noted post TACE, but this was not statistically significant; TTP pre: 13.1 +/- 4.3 s, TTP post: 13.6 +/- 4.2 s , P = 0.058). The changes in the aforementioned parameters were not accompanied by significant tumor shrinkage. CONCLUSION: pCEUS, even when limited to the study of the arterial phase of tumoral enhancement, can detect and quantify early perfusional changes in HCC post TACE. PMID- 22937215 TI - Progress in atherosclerotic plaque imaging. AB - Cardiovascular diseases are the primary cause of mortality in the industrialized world, and arterial obstruction, triggered by rupture-prone atherosclerotic plaques, lead to myocardial infarction and cerebral stroke. Vulnerable plaques do not necessarily occur with flow-limiting stenosis, thus conventional luminographic assessment of the pathology fails to identify unstable lesions. In this review we discuss the currently available imaging modalities used to investigate morphological features and biological characteristics of the atherosclerotic plaque. The different imaging modalities such as ultrasound, magnetic resonance imaging, computed tomography, nuclear imaging and their intravascular applications are illustrated, highlighting their specific diagnostic potential. Clinically available and upcoming methodologies are also reviewed along with the related challenges in their clinical translation, concerning the specific invasiveness, accuracy and cost-effectiveness of these methods. PMID- 22937218 TI - Inferior pancreaticoduodenal artery aneurysm treated with coil packing and stent placement. AB - Two cases with a pancreaticoduodenal arterial aneurysm accompanied with superior mesenteric artery (SMA) stenosis were previously described and both were treated surgically. However, for interventional treatment, securing a sufficient blood supply to the SMA should be a priority of treatment. We present the case of a 71 year-old male with a 20 mm diameter pancreaticoduodenal arterial aneurysm accompanied by SMA stenosis at its origin. The guidewire traverse from SMA to the aneurysm was difficult because of the tight SMA stenosis; however, the guidewire traverse from the celiac artery was finally successful and was followed by balloon angioplasty using a pull-through technique, leading to stent placement. Thereafter, coil packing through the SMA achieved eradication of the aneurysm without bowel ischemia. At the last follow-up computed tomography 8 mo later, no recurrence of the aneurysm was confirmed. The pull-through technique was useful for angioplasty for tight SMA stenosis in this case. PMID- 22937219 TI - Early anthropogenic transformation of the Danube-Black Sea system. AB - Over the last century humans have altered the export of fluvial materials leading to significant changes in morphology, chemistry, and biology of the coastal ocean. Here we present sedimentary, paleoenvironmental and paleogenetic evidence to show that the Black Sea, a nearly enclosed marine basin, was affected by land use long before the changes of the Industrial Era. Although watershed hydroclimate was spatially and temporally variable over the last ~3000 years, surface salinity dropped systematically in the Black Sea. Sediment loads delivered by Danube River, the main tributary of the Black Sea, significantly increased as land use intensified in the last two millennia, which led to a rapid expansion of its delta. Lastly, proliferation of diatoms and dinoflagellates over the last five to six centuries, when intensive deforestation occurred in Eastern Europe, points to an anthropogenic pulse of river-borne nutrients that radically transformed the food web structure in the Black Sea. PMID- 22937220 TI - Transition in the equilibrium distribution function of relativistic particles. AB - We analyze a transition from single peaked to bimodal velocity distribution in a relativistic fluid under increasing temperature, in contrast with a non relativistic gas, where only a monotonic broadening of the bell-shaped distribution is observed. Such transition results from the interplay between the raise in thermal energy and the constraint of maximum velocity imposed by the speed of light. We study the Bose-Einstein, the Fermi-Dirac, and the Maxwell Juttner distributions, and show that they all exhibit the same qualitative behavior. We characterize the nature of the transition in the framework of critical phenomena and show that it is either continuous or discontinuous, depending on the group velocity. We analyze the transition in one, two, and three dimensions, with special emphasis on twodimensions, for which a possible experiment in graphene, based on the measurement of the Johnson-Nyquist noise, is proposed. PMID- 22937221 TI - Hydrogen bond nanoscale networks showing switchable transport performance. AB - Hydrogen bond is a typical noncovalent bond with its strength only one-tenth of a general covalent bond. Because of its easiness to fracture and re-formation, materials based on hydrogen bonds can enable a reversible behavior in their assembly and other properties, which supplies advantages in fabrication and recyclability. In this paper, hydrogen bond nanoscale networks have been utilized to separate water and oil in macroscale. This is realized upon using nanowire macro-membranes with pore sizes ~tens of nanometers, which can form hydrogen bonds with the water molecules on the surfaces. It is also found that the gradual replacement of the water by ethanol molecules can endow this film tunable transport properties. It is proposed that a hydrogen bond network in the membrane is responsible for this switching effect. Significant application potential is demonstrated by the successful separation of oil and water, especially in the emulsion forms. PMID- 22937222 TI - Wet-spinning assembly of continuous, neat, and macroscopic graphene fibers. AB - Graphene is now the most attractive carbon-based material. Integration of 2D graphene sheets into macroscopic architectures such as fibers illuminates the direction to translate the excellent properties of individual graphene into advanced hierarchical ensembles for promising applications in new graphene-based nanodevices. However, the lack of effective, low-cost and convenient assembly strategy has blocked its further development. Herein, we demonstrate that neat and macroscopic graphene fibers with high mechanical strength and electrical conductivity can be fluidly spun from the common graphene oxide (GO) suspensions in large scale followed with chemical reduction. The curliness-fold formation mechanism of GO fiber has been proposed. This wet-spinning technique presented here facilitates the multifunctionalization of macroscopic graphene-based fibers with various organic or inorganic components by an easy-handle in situ or post synthesis approach, which builds the solid foundation to access a new family of advanced composite materials for the next practical applications. PMID- 22937224 TI - Evidence for a bacterial mechanism for group-specific social odors among hyenas. AB - Symbiotic microbes can benefit their animal hosts by enhancing the diversity of communication signals available to them. The fermentation hypothesis for chemical recognition posits that 1) fermentative bacteria in specialized mammalian scent glands generate odorants that mammals co-opt to communicate with one another, and 2) that variation in scent gland odors is due to underlying variation in the structure of bacterial communities within scent glands. For example, group specific social odors are suggested to be due to members of the same social group harboring more similar bacterial communities in their scent glands than do members of different social groups. We used 16S rRNA gene surveys to show that 1) the scent secretions of spotted hyenas are densely populated by fermentative bacteria whose closest relatives are well-documented odor producers, and that 2) these bacterial communities are more similar among hyenas from the same social group than among those from different groups. PMID- 22937223 TI - Pf155/RESA protein influences the dynamic microcirculatory behavior of ring-stage Plasmodium falciparum infected red blood cells. AB - Proteins exported by Plasmodium falciparum to the red blood cell (RBC) membrane modify the structural properties of the parasitized RBC (Pf-RBC). Although quasi static single cell assays show reduced ring-stage Pf-RBCs deformability, the parameters influencing their microcirculatory behavior remain unexplored. Here, we study the dynamic properties of ring-stage Pf-RBCs and the role of the parasite protein Pf155/Ring-Infected Erythrocyte Surface Antigen (RESA). Diffraction phase microscopy revealed RESA-driven decreased Pf-RBCs membrane fluctuations. Microfluidic experiments showed a RESA-dependent reduction in the Pf-RBCs transit velocity, which was potentiated at febrile temperature. In a microspheres filtration system, incubation at febrile temperature impaired traversal of RESA-expressing Pf-RBCs. These results show that RESA influences ring-stage Pf-RBCs microcirculation, an effect that is fever-enhanced. This is the first identification of a parasite factor influencing the dynamic circulation of young asexual Pf-RBCs in physiologically relevant conditions, offering novel possibilities for interventions to reduce parasite survival and pathogenesis in its human host. PMID- 22937225 TI - Connexin36 gap junction blockade is ineffective at reducing seizure-like event activity in neocortical mouse slices. AB - Despite much research, there remains controversy over the role of gap junctions in seizure processes. Many studies report anticonvulsant effects of gap junction blockade, but contradictory results have also been reported. The aim of this study was to clarify the role of connexin36 (Cx36) gap junctions in neocortical seizures. We used the mouse neocortical slice preparation to investigate the effect of pharmacological (mefloquine) and genetic (Cx36 knockout mice (Cx36KO)) manipulation of Cx36 gap junctions on two seizure models: low-magnesium artificial cerebrospinal fluid (ACSF) and aconitine perfusion in low-magnesium ACSF. Low-magnesium- (nominally zero) and aconitine- (230 nM) induced seizure like event (SLE) population activity was recorded extracellularly. The results were consistent in showing that neither mefloquine (25 MUM) nor genetic knockdown of Cx36 expression had anticonvulsant effects on SLE activity generated by either method. These findings call into question the widely held idea that open Cx36 gap junctions promote seizure activity. PMID- 22937226 TI - What Do Changes in Brain Perfusion Induced by Etomidate Suggest about Epilepsy in Human Patients? AB - Epilepsy is one of the major neurological disorders, affecting roughly 1-2% of the world's population, of which approximately 20-25% of patients are drug resistant. A variety of drugs have been used to activate and identify the epileptic area in patients during presurgical evaluation. We studied the cerebral blood flow (CBF) by single photon-emission computed tomography (SPECT) and bioelectrical brain activity responses to etomidate in 11 patients. Etomidate (0.1 mg/kg) was administered while patients were monitored by video electroencephalography with foramen ovale electrodes (FOEs). After etomidate administration, a brief period of high-frequency activity was observed, followed by a generalized, high-voltage delta pattern. Increased regional CBF was observed bilaterally in thalamus, putamen, and posterior hippocampus. Besides, the only interhemispheric difference was observed in the posterior hippocampus, where CBF decreased in the epileptic temporal lobe. Activation by etomidate induces a specific and repetitive response in the bioelectrical activity. In addition, CBF changes induced by etomidate may serve as a diagnostic tool in the near future. PMID- 22937227 TI - Evolution and prospects for intracranial pharmacotherapy for refractory epilepsies: the subdural hybrid neuroprosthesis. AB - Intracranial pharmacotherapy is a novel strategy to treat drug refractory, localization-related epilepsies not amenable to resective surgery. The common feature of the method is the use of some type of antiepileptic drug (AED) delivery device placed inside the cranium to prevent or stop focal seizures. This distinguishes it from other nonconventional methods, such as intrathecal pharmacotherapy, electrical neurostimulation, gene therapy, cell transplantation, and local cooling. AED-delivery systems comprise drug releasing polymers and neuroprosthetic devices that can deliver AEDs into the brain via intraparenchymal, ventricular, or transmeningeal routes. One such device is the subdural Hybrid Neuroprosthesis (HNP), designed to deliver AEDs, such as muscimol, into the subdural/subarachnoid space overlaying neocortical epileptogenic zones, with electrophysiological feedback from the treated tissue. The idea of intracranial pharmacotherapy and HNP treatment for epilepsy originated from multiple sources, including the advent of implanted medical devices, safety data for intracranial electrodes and catheters, evidence for the seizure-controlling efficacy of intracerebral AEDs, and further understanding of the pathophysiology of focal epilepsy. Successful introduction of intracranial pharmacotherapy into clinical practice depends on how the intertwined scientific, engineering, clinical, neurosurgical and regulatory challenges will be met to produce an effective and commercially viable device. PMID- 22937229 TI - ADAM23, a Gene Related to LGI1, Is Not Linked to Autosomal Dominant Lateral Temporal Epilepsy. AB - Autosomal dominant lateral temporal epilepsy (ADTLE) is an inherited epileptic syndrome characterized by ictal auditory symptoms or aphasia, negative MRI findings, and relatively benign evolution. Mutations responsible for ADLTE have been found in the LGI1 gene. The functions of the Lgi1 protein apparently are mediated by interactions with members of the ADAM protein family: it binds the postsynaptic receptor ADAM22 to regulate glutamate-AMPA currents at excitatory synapses and also the ADAM23 receptor to promote neurite outgrowth in vitro and dendritic arborization in vivo. Because alteration of each of these neuronal mechanisms may underlie ADLTE, ADAM22 and ADAM23 are candidate genes for this syndrome. In a previous work, we excluded a major role of ADAM22 in the aetiology of ADLTE. Here, we performed linkage analysis between microsatellite markers within or flanking the ADAM23 gene and ADLTE in 13 Italian families. The results exclude ADAM23 as major causative gene for ADLTE. PMID- 22937228 TI - Blood-brain barrier dysfunction in epileptogenesis of the temporal lobe. AB - Epilepsy of the temporal lobe (TLE) is the most common form of focal epilepsy, and in adults, it most frequently develops after injury. However, the mechanisms by which a normal functioning brain turns into an epileptic one still remain obscure. Recent studies point to vascular involvement and particularly blood brain barrier (BBB) dysfunction in the development of epilepsy. The BBB is a specialized structure which functions to control the neuronal extracellular milieu. BBB dysfunction is found in many diseases of the central nervous system, including stroke, traumatic injuries, tumors and infections. Interestingly, all these insults may initiate an epileptogenic process which eventually leads to spontaneous, recurrent seizures. This epileptogenic time frame usually lasts weeks, months, or even years in man, and days to weeks in rodents and may serve as a "window of opportunity" for the prevention of epilepsy. However, no prevention strategy exists, stressing the importance of research into the mechanisms of epileptogenesis. Here, we will underscore recent experiments suggesting that BBB dysfunction directly induces epileptogenesis. We will provide new evidence to support the hypothesis that BBB breakdown and specifically exposure of temporal lobe structures to the most common serum protein, albumin, is sufficient to induce epileptogenesis. PMID- 22937230 TI - Prognosis and outcome predictors in psychogenic nonepileptic seizures. AB - It is estimated that one in five patients referred to specialist epilepsy clinics for refractory seizures have psychogenic nonepileptic seizures (PNES). Despite the high prevalence, little is known about the prognosis of patients with PNES. In this paper we set out to systematically assess published original studies on the prognosis and outcome predictors of patients with PNES. Our literature search across the databases Medline, PsycINFO, and EMBASE generated 18 original studies meeting the search criteria. Prognosis was found to be poor in adults, but good in children. Predictors of poor outcome included the presence of coexisting epilepsy or psychiatric comorbidities, violent seizure phenomenology, dependent lifestyle, and poor relationships. Overall, too much reliance is placed on seizure remission as an outcome measurement for patients with PNES, and the impact of many of the outcome predictors requires evaluation using larger studies with longer followup. PMID- 22937231 TI - Surgical treatment for refractory epilepsy: review of patient evaluation and surgical options. AB - Treatment of epilepsy often imposes an exposure to various antiepileptic drugs and requires long-term commitment and compliance from the patient. Although many new medications are now available for the treatment of epilepsy, approximately 30% of epilepsy patients still experience recurrent seizures and many experience undesirable side effects. Treatment of epilepsy requires a multidisciplinary approach. For those patients with medically refractory seizures, surgical treatment has increased in prevalence as techniques and devices improve. With increased utilization, proper patient selection has become crucial in evaluating appropriateness of surgical intervention. Epilepsy syndromes in which surgery has shown to be effective include mesial temporal sclerosis, cortical dysplasia, many pediatric epilepsy syndromes, and vascular malformations. Monitoring in an epilepsy monitoring unit with continuous scalp or intracranial EEG is an important step in localization of seizure focus. MRI is the standard imaging technique for evaluation of anatomy. However, other imaging studies including SPECT and PET have become more widespread, often offering increased diagnostic value in select situations. In addition, as an alternative or adjunct to surgical resection, implantable devices such as vagus nerve stimulators, deep brain stimulators, and direct brain stimulators could be useful in seizure treatment. PMID- 22937232 TI - Neuroimaging in Animal Seizure Models with (18)FDG-PET. AB - Small animal neuroimaging has become increasingly available to researchers, expanding the breadth of questions studied with these methods. Applying these noninvasive techniques to the open questions underlying epileptogenesis is no exception. A major advantage of small animal neuroimaging is its translational appeal. Studies can be well controlled and manipulated, examining the living brain in the animal before, during, and after the disease onset or disease treatment. The results can also be compared to data collected on human patients. Over the past decade, we and others have explored metabolic patterns in animal models of epilepsy to gain insight into the circuitry underlying development of the disease. In this paper, we provide technical details on how metabolic imaging that uses 2-deoxy-2[(18)F]fluoro-D-glucose ((18)FDG) and positron emission tomography (PET) is performed and explain the strengths and limitations of these studies. We will also highlight recent advances toward understanding epileptogenesis through small animal imaging. PMID- 22937233 TI - Executive functions in chronic mesial temporal lobe epilepsy. AB - There is no consensus as to whether mesial temporal lobe epilepsy (MTLE) leads to executive function deficits. In this study, we adopted an extensive neuropsychological test battery and assessed different executive functions in chronic, unilateral MTLE. Performance of MTLE patients was compared with that of healthy peers and with normative data. Several MTLE patients had scores below cut off or below the 10th percentile of normative data. Scores of the whole patient group were overall in the average range of normative data. Relative to controls, MTLE patients performed poorly in tests of working memory, cognitive flexibility, categorical verbal fluency, set-shifting, categorization, and planning. These findings raise an important methodological issue as they suggest that executive function deficits in chronic MTLE may be individually variable and that their assessment should include different tests. Deficits in chronic MTLE are not limited to temporal lobe functions, such as memory, but may extend to extra temporal cognitive domains, such as executive functions. PMID- 22937234 TI - Characterization of the gene expression profile of human hippocampus in mesial temporal lobe epilepsy with hippocampal sclerosis. AB - One of the main putative causes of therapy refractory epilepsy in mesial temporal lobe epilepsy (MTLE) with hippocampal sclerosis is the overexpression of multidrug transporters (MDTs) at the blood-brain barrier (BBB). It steps up the removal of antiepileptic drugs (AEDs) out of the brain cells across the BBB resulting in a low concentration of AEDs within the target cells. Some of the mechanisms of AED resistance are most likely to be genetically determined. To obtain more information about the underlying pathophysiology of intractability in epilepsy, we compared the global gene expression profile of human hippocampus and hippocampal-derived microvascular endothelial cells from MTLE with HS patients and controls. At the level of MDT, a significant up-regulation was found for ABCB1 (P-gp), ABCB2, ABCB3, and ABCB4, which was mainly related to endothelial cells. The data on the MDT were validated and extended by quantitative RT-PCR. Surprisingly, inflammatory factors such as interleukins (IL-1alpha, IL-1beta, IL 6, and IL-18) and cytokines (TNF-alpha and TGF-beta1) were found to be up regulated in hippocampal parenchyma. The overexpression of P-gp, IL-1beta, and IL 6 was also confirmed by immunohistochemistry (IHC). Our results suggest that complex expression changes of ABC-transporters may play a decisive role in pharmacoresistance in MTLE. Further studies on the new and unexpected overexpression of inflammatory cytokines may unlock hitherto undiscovered pathways of the underlying pathophysiology of human MTLE. PMID- 22937235 TI - Gamma knife radiosurgery for mesial temporal lobe epilepsy. AB - Many patients with mesial temporal lobe epilepsy continue to have seizures despite medical therapy. For these patients, one recourse is surgical resection of the mesial temporal lobe, with its attendant risks. Noninvasive treatment with Gamma Knife radiosurgery is under active investigation as a possible alternative to open surgery. Accumulated evidence from multiple studies shows radiosurgery to be comparable in outcomes to surgical resection. A definitive randomized, controlled trial, the Radiosurgery or Open Surgery for Epilepsy (ROSE) trial, is currently underway, and further investigation of this promising treatment is crucial in our advancement of alternative therapies to treat refractory epilepsy. PMID- 22937236 TI - The ketogenic diet 2011: how it works. AB - Although the ketogenic diet (KD) has been widely accepted as a legitimate and successful therapy for epilepsy and other neurological disorders, its mechanism of action remains an enigma. The use of the KD causes major metabolic changes. The most significant of them seems to be the situation of chronic ketosis, but there are others as well, for instance, high level of polyunsaturated fatty acids (PUFAs). These "primary" influences lead to "secondary", in part adaptive, effects, for instance changes in mitochondrial density and gene expression. Clinically, the influences of the diet are considered as anticonvulsive and neuroprotective, although neuroprotection can also lead to prevention of seizures. Potential clinical implications of these mechanisms are discussed. PMID- 22937237 TI - Natural history of temporal lobe epilepsy: antecedents and progression. AB - Temporal lobe epilepsy represents the largest group of patients with treatment resistant/medically intractable epilepsy undergoing epilepsy surgery. The underpinnings of common forms of TLE in many instances begin in early life with the occurrence of an initial precipitating event. The first epileptic seizure often occurs after a variable latency period following this event. The precise natural history and progression following the first seizure to the development of TLE, its subsequent resolution through spontaneous remission or the development of treatment resistant epilepsy remain poorly understood. Our present understanding of the role played by these initial events, the subsequent latency to development of temporal lobe epilepsy, and the emergence of treatment resistance remains incomplete. A critical analysis of published data suggest that TLE is a heterogeneous condition, where the age of onset, presence or absence of a lesion on neuroimaging, the initial precipitating event, association with febrile seizures, febrile status epilepticus, and neurotropic viral infections influence the natural history and outcome. The pathways and processes through which these variables coalesce into a framework will provide the basis for an understanding of the natural history of TLE. The questions raised need to be addressed in future prospective and longitudinal observational studies. PMID- 22937238 TI - Validation of the Self-Assessment of Treatment Questionnaire among Patients with Postherpetic Neuralgia. AB - Introduction. A five-item Self-Assessment of Treatment (SAT) was developed to assess improvement and satisfaction with treatment associated with the application of a novel high concentration 8% capsaicin topical patch in clinical trials in patients with postherpetic neuralgia (PHN). This study evaluated the item performance and psychometric properties of the SAT. Methods. The SAT, Brief Pain Inventory, SF-36v2, Short-Form McGill Pain Questionnaire, and Patient and Clinician Global Impression of Change (PGIC; CGIC) scores were measured in two 12 week Phase 3 clinical trials. Factor analysis assessed the underlying factor structure, followed by examination of the reliability and validity of the multi item domain. Results. Pooled data from 698 patients completing SAT after 12 weeks of treatment were analyzed. A one-factor model combining three of the five items emerged as the optimal solution. Internal consistency reliability of this treatment efficacy factor was high (Cronbach's alpha = 0.89). Construct validity was demonstrated by moderate to high correlations with change in other study endpoints. SAT mean scores consistently discriminated between patient change groups defined by PGIC and CGIC. Conclusions. The measurement properties of the three-item version of SAT are valid and reliable for assessment of treatment with a high concentration capsaicin patch among patients with PHN. PMID- 22937239 TI - Using video self-modelled social stories to teach social skills to a young child with autism. AB - The present study investigated the effectiveness of combining Social Stories and Video Self-Modelling (VSM) to teach social skills to a three-year-old child with autism. A multiple-baseline across behaviors design revealed that video self modelled Social Stories were effective at improving all three target behaviors: greeting, inviting to play, and contingent responding. In addition, these behaviors successfully generalized across settings, toys, and communication partners. Concomitant behavior changes, namely, increased levels of communicative behavior and levels of social engagement were also observed. These results support the effectiveness of video self-modelled Social Stories and illustrate the potential of combined intervention techniques for remedying the social deficits faced by this population. PMID- 22937240 TI - The social cognitive evaluation battery for children with autism: a new tool for the assessment of cognitive and social development in children with autism spectrum disorders. AB - The Social Cognitive Evaluation Battery (SCEB) is a new instrument for the psychological evaluation of children with autism. The battery consists of 16 scales that measure different cognitive and socioemotional functions. This study reports the results of a reliability analysis and some elements of validation. Analyses are based on the observed performance of 100 children with autism and a convenience sample of 35 normal children. Validation is based on the examination of the structure of the relations between the 16 scale scores of the SCEB, their relations with other measurements, the correspondence between the theoretical developmental ages, and the observed chronological ages and the SCEB's sensitivity to specific disorders. The results show that this new instrument is useful and relevant for the psychological assessment of children with autism. PMID- 22937241 TI - Dysautonomia in autism spectrum disorder: case reports of a family with review of the literature. AB - Case histories of a mother and her two children are reported. The mother was a recovered alcoholic. She and her two children, both of whom had symptoms that are typical of autistic spectrum disorder, had dysautonomia. All had intermittently abnormal erythrocyte transketolase studies indicating abnormal thiamine pyrophosphate homeostasis. Both children had unusual concentrations of urinary arsenic. All had symptomatic improvement with diet restriction and supplementary vitamin therapy but quickly relapsed after ingestion of sugar, milk, or wheat. The stress of a heavy metal burden, superimposed on existing genetic or epigenetic risk factors, may be important in the etiology of autism spectrum disorder when in combination. Dysautonomia has been associated with several diseases, including autism, without a common etiology. It is hypothesized that oxidative stress results in loss of cellular energy and causes retardation of hard wiring of the brain in infancy, affecting limbic system control of the autonomic nervous system. PMID- 22937242 TI - Autism in developing countries: lessons from iran. AB - Most research into Autism Spectrum Disorders has been conducted in affluent English-speaking countries which have extensive professional support services. This paper describes a series of investigations that was undertaken in Iran, and these findings, together with reviews of research in other low-income countries, are used to identify key lessons in three areas of service provision of particular relevance to developing countries with scarce professional resources: first, the issues to be considered in establishing the prevalence of the condition nationally; second, identification of parental understanding of ASD and the impact it has on them as carers; third, the education and training that could be provided to families when professional supports are sparse. It is concluded that culturally sensitive, parental support strategies must be central to the planning and development of services. Moreover, future research should further elucidate the needs of families and evaluate the impact of culturally tailored interventions designed to promote the children's development and overall family quality of life. PMID- 22937243 TI - Increasing the understanding and demonstration of appropriate affection in children with asperger syndrome: a pilot trial. AB - The study was conducted to examine relationships between affectionate behavior in children with Asperger syndrome and variables likely to influence its expression (e.g., tactile sensitivity, social ability). It also evaluated the impact of a cognitive behavioral intervention that aimed to improve a child's understanding and expression of affection. Twenty-one children, aged 7 to 12 years, participated in the trial. The results showed significant correlations between measures of affection and tactile sensitivity and social ability. After attending the 5-week program, parents identified significant increases in the appropriateness of children's affectionate behavior both towards immediate family and people outside the immediate family, despite reporting no significant changes in their child's general difficulties with affectionate behavior. There was a significant improvement in children's understanding of the purpose of affection. The findings are discussed as well as the limitations of the study. PMID- 22937245 TI - Possible evidence for a fall in the prevalence of high-functioning pervasive developmental disorder with age? AB - A survey was undertaken to investigate the prevalence of high-functioning pervasive developmental disorder (HFPDD) in a community sample of teenagers and adults aged 13 and above in the city of Sheffield, UK. 112 possible and definite cases were found, of whom 65 (57%) had a previous diagnosis. The detected prevalence of possible or definite HFPDD was found to be 0.24 per 1000 of the population of Sheffield city aged 13 or over, but the prevalence by year of age fell from a maximum of 1.1 per 1000 in the group aged 13 to 14 years old (1 young adult in every 900 in this age group) to 0.03 per 1000 in the over 60s (1 person in every 38500 in this age group). The results of this study are preliminary and need follow-up investigation in larger studies. We suggest several explanations for the findings, including reduced willingness to participate in a study as people get older, increased ascertainment in younger people, and increased mortality. Another contributory factor might be that the prevalence of high functioning pervasive development disorder may decline with age. This raises the possibility that AS symptoms might become subclinical in adulthood in a proportion of people with HFPDD. PMID- 22937244 TI - Developing a Deeper Understanding of Autism: Connecting Knowledge through Literature Mining. AB - In the field of autism, an enormous increase in available information makes it very difficult to connect fragments of knowledge into a more coherent picture. We present a literature mining method, RaJoLink, to search for matched themes in unrelated literature that may contribute to a better understanding of complex pathological conditions, such as autism. 214 full text articles on autism, published in PubMed, served as a source of data. Using ontology construction, we identified the main concepts of what is already known about autism. Then, the RaJoLink method, based on Swanson's ABC model, was used to reveal potentially interesting, but not yet investigated, connections between different concepts in research. Among the more interesting concepts identified with RaJoLink in our study were calcineurin and NF-kappaB. Both terms can be linked to neuro-immune abnormalities in the brain of patients with autism. Further research is needed to provide stronger evidence about calcineurin and NF-kappaB involvement in autism. However, the analysis presented confirms that this method could support experts on their way towards discovering hidden relationships and towards a better understanding of the disorder. PMID- 22937246 TI - Associations between Parental Anxiety/Depression and Child Behavior Problems Related to Autism Spectrum Disorders: The Roles of Parenting Stress and Parenting Self-Efficacy. AB - Parents of children with autism spectrum disorders (ASDs) have been shown to experience increases in stress, depression, and anxiety, which are also associated with child behavior problems related to ASDs. Literature-examining potential mechanisms that underlie the relationship of child behavior problems and parental anxiety/depression in this population are scarce. The current study sought to examine the roles of parenting stress and parenting self-efficacy as mediators between child behavior problems and parental anxiety/depression. Using a sample of 134 mothers, these potential mediators were tested. Hypotheses were supported, indicating that parenting stress mediated the relationship between child behavior problems and decreased parenting self-efficacy, and decreased parenting self-efficacy in turn partially mediated the relationship between parenting stress and increased depression/anxiety. PMID- 22937247 TI - The molecular genetics of autism spectrum disorders: genomic mechanisms, neuroimmunopathology, and clinical implications. AB - Autism spectrum disorders (ASDs) have become increasingly common in recent years. The discovery of single-nucleotide polymorphisms and accompanying copy number variations within the genome has increased our understanding of the architecture of the disease. These genetic and genomic alterations coupled with epigenetic phenomena have pointed to a neuroimmunopathological mechanism for ASD. Model animal studies, developmental biology, and affective neuroscience laid a foundation for dissecting the neural pathways impacted by these disease generating mechanisms. The goal of current autism research is directed toward a systems biological approach to find the most basic genetic and environmental causes to this severe developmental disease. It is hoped that future genomic and neuroimmunological research will be directed toward finding the road toward prevention, treatment, and cure of ASD. PMID- 22937248 TI - Parent report of community psychiatric comorbid diagnoses in autism spectrum disorders. AB - We used a national online registry to examine variation in cumulative prevalence of community diagnosis of psychiatric comorbidity in 4343 children with autism spectrum disorders (ASD). Adjusted multivariate logistic regression models compared influence of individual, family, and geographic factors on cumulative prevalence of parent-reported anxiety disorder, depression, bipolar disorder, and attention deficit/hyperactivity disorder or attention deficit disorder. Adjusted odds of community-assigned lifetime psychiatric comorbidity were significantly higher with each additional year of life, with increasing autism severity, and with Asperger syndrome and pervasive developmental disorder-not otherwise specified compared with autistic disorder. Overall, in this largest study of parent-reported community diagnoses of psychiatric comorbidity, gender, autistic regression, autism severity, and type of ASD all emerged as significant factors correlating with cumulative prevalence. These findings could suggest both underlying trends in actual comorbidity as well as variation in community interpretation and application of comorbid diagnoses in ASD. PMID- 22937249 TI - Association of sensory processing and eating problems in children with autism spectrum disorders. AB - "Selective" or "picky eating" is a frequent problem in children with autism spectrum disorders (ASD). Many of these children do not treat sensory input, particularly olfactory, auditory, visual, and tactile information in the same manner as their typically developing peers of the same age. The purpose of this paper was to examine the relationship between problems of sensory processing and the number of eating problems in children with ASD. Of 95 children with ASD, 3 to 10 years of age, 65 percent showed a definite difference and 21 percent a probable difference in sensory processing on the total score of the Short Sensory Profile. These results were significantly related to an increase in the number of eating problems measured by the Eating Profile. These results could not be explained by age, sex, mental retardation, attention deficit disorder, or hyperactivity. Timely interventions focusing on the sensory components of eating must now be developed. PMID- 22937251 TI - Normal Gaze Cueing in Children with Autism Is Disrupted by Simultaneous Speech Utterances in "Live" Face-to-Face Interactions. AB - Gaze cueing was assessed in children with autism and in typically developing children, using a computer-controlled "live" face-to-face procedure. Sensitivity to gaze direction was assessed using a Posner cuing paradigm. Both static and dynamic directional gaze cues were used. Consistent with many previous studies, using photographic and cartoon faces, gaze cueing was present in children with autism and was not developmentally delayed. However, in the same children, gaze cueing was abolished when a mouth movement occurred at the same time as the gaze cue. In contrast, typical children were able to use gaze cues in all conditions. The findings indicate that gaze cueing develops successfully in some children with autism but that their attention is disrupted by speech utterances. Their ability to learn to read nonverbal emotional and intentional signals provided by the eyes may therefore be significantly impaired. This may indicate a problem with cross-modal attention control or an abnormal sensitivity to peripheral motion in general or the mouth region in particular. PMID- 22937250 TI - The broader autism phenotype and its implications on the etiology and treatment of autism spectrum disorders. AB - The presence of autism-related traits has been well documented in undiagnosed family members of individuals with autism spectrum disorder (ASD). The most common finding is mild impairments in social and communication skills that are similar to those shown by individuals with autism, but exhibited to a lesser degree. Termed the broader autism phenotype (BAP), these traits suggest a genetic liability for autism-related traits in families. Genetic influence in autism is strong, with identical twins showing high concordance for the diagnosis and related traits and approximately 20% of all ASD cases having an identified genetic mechanism. This paper highlights the studies conducted to date regarding the BAP and considers the implications of these findings for the etiology and treatment of ASD. PMID- 22937252 TI - An initial investigation of the generalization of a school-based social competence intervention for youth with high-functioning autism. AB - This study evaluated the impact of generalization of the Social Competence Intervention-Adolescent (SCI-A) curriculum in a school setting for individuals with high-functioning autism or Asperger's Syndrome (N = 6). This study examined to what degree the generalization of the SCI-A curriculum could be measured when delivered in a school setting. Across the six participants preliminary results suggest improvement on teacher reports of social skills and executive functioning. Some improvements were also evident in direct measures of facial expression recognition. Data collected in the nonintervention settings indicated that some generalization of social interaction skills may have occurred for all six participants. Future research directions are discussed. PMID- 22937253 TI - Hypothesis: the role of sterols in autism spectrum disorder. AB - A possible role for sterols in the development of autism spectrum disorder (ASD) has not been proven, but studies in disorders of sterol biosynthesis, chiefly Smith-Lemli-Opitz syndrome (SLOS), enable hypotheses on a causal relationship to be discussed. Advances in genetic technology coupled with discoveries in membrane physiology have led to renewed interest for lipids in the nervous system. This paper hypothesizes on the role of sterol dysfunction in ASD through the framework of SLOS. Impaired sonic hedgehog patterning, alterations in membrane lipid rafts leading to abnormal synaptic plasticity, and impaired neurosteroid synthesis are discussed. Potential therapeutic agents include the development of neuroactive steroid-based agents and enzyme-specific drugs. Future investigations should reveal the specific mechanisms underlying sterol dysfunction in neurodevelopmental disorders by utilizing advanced imaging and molecular techniques. PMID- 22937254 TI - Eye Movement Sequences during Simple versus Complex Information Processing of Scenes in Autism Spectrum Disorder. AB - Minshew and Goldstein (1998) postulated that autism spectrum disorder (ASD) is a disorder of complex information processing. The current study was designed to investigate this hypothesis. Participants with and without ASD completed two scene perception tasks: a simple "spot the difference" task, where they had to say which one of a pair of pictures had a detail missing, and a complex "which one's weird" task, where they had to decide which one of a pair of pictures looks "weird". Participants with ASD did not differ from TD participants in their ability to accurately identify the target picture in both tasks. However, analysis of the eye movement sequences showed that participants with ASD viewed scenes differently from normal controls exclusively for the complex task. This difference in eye movement patterns, and the method used to examine different patterns, adds to the knowledge base regarding eye movements and ASD. Our results are in accordance with Minshew and Goldstein's theory that complex, but not simple, information processing is impaired in ASD. PMID- 22937255 TI - Autism, context/noncontext information processing, and atypical development. AB - Autism has been attributed to a deficit in contextual information processing. Attempts to understand autism in terms of such a defect, however, do not include more recent computational work upon context. This work has identified that context information processing depends upon the extraction and use of the information hidden in higher-order (or indirect) associations. Higher-order associations underlie the cognition of context rather than that of situations. This paper starts by examining the differences between higher-order and first order (or direct) associations. Higher-order associations link entities not directly (as with first-order ones) but indirectly through all the connections they have via other entities. Extracting this information requires the processing of past episodes as a totality. As a result, this extraction depends upon specialised extraction processes separate from cognition. This information is then consolidated. Due to this difference, the extraction/consolidation of higher order information can be impaired whilst cognition remains intact. Although not directly impaired, cognition will be indirectly impaired by knock on effects such as cognition compensating for absent higher-order information with information extracted from first-order associations. This paper discusses the implications of this for the inflexible, literal/immediate, and inappropriate information processing of autistic individuals. PMID- 22937256 TI - Cognitive Skills of Young Children with and without Autism Spectrum Disorder Using the BSID-III. AB - Objective. The purpose of the study was to compare the cognitive skills of young children diagnosed with autism spectrum disorder (ASD) to same-aged peers referred for possible developmental delays or behavioral concerns using the Bayley Scales of Infant Development-Third Edition. Method. A retrospective chart review was conducted of 147 children ages 16 to 38 months who were referred to a diagnostic clinic for developmental evaluation. Children with ASD were compared to those without ASD with respect to cognition and language outcomes, both overall and by age. Results. While language skills in children with ASD were more significantly delayed than language skills in children without ASD, there was less discrepancy in the cognitive skills of children with and without ASD. Conclusion. Formal cognitive assessment of children with ASD can provide guidance for developmental expectations and educational programming. Cognitive skills of children with ASD may be underappreciated. PMID- 22937257 TI - Factors affecting age at initial autism spectrum disorder diagnosis in a national survey. AB - Entry into early intervention depends on both age of first parent concern (AOC) and age at initial autism spectrum disorder (ASD) diagnosis (AOD). Using data collected from a national online registry from 6214 children diagnosed with an ASD between 1994 and 2010 in the US, we analyzed the effect of individual, family, and geographic covariates on AOC and AOD in a multivariate linear regression model with random effects. Overall, no single modifiable factor associated with AOC or AOD emerged but cumulative variation in certain individual and family-based features, as well as some geographic factors, all contribute to AOC and AOD variation. A multipronged strategy is needed for targeted education and awareness campaigns to maximize outcomes and decrease disparities in ASD care. PMID- 22937258 TI - Decreased levels of EGF in plasma of children with autism spectrum disorder. AB - Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder estimated to affect 1 in 110 children in the U.S., yet the pathology of this disorder is not fully understood. Abnormal levels of several growth factors have been demonstrated in adults with ASD, including epidermal growth factor (EGF) and hepatocyte growth factor (HGF). Both of these growth factors serve important roles in neurodevelopment and immune function. In this study, concentrations of EGF and HGF were assessed in the plasma of 49 children with ASD aged 2-4 years old and 31 typically developing controls of a similar age as part of the Autism Phenome Project (APP). Levels of EGF were significantly reduced in the ASD group compared to typically developing controls (P = 0.003). There were no significant differences in HGF levels in young children with ASD and typically developing controls. EGF plays an important role in regulating neural growth, proliferation, differentiation and migration, and reduced levels of this molecule may negatively impact neurodevelopment in young children with ASD. PMID- 22937259 TI - Visual scanning in very young children with autism and their unaffected parents. AB - This study of gaze patterns in very young children with autism and their parents included 23 cases (with 16 fathers and 19 mothers) and 46 controls (with 14 fathers and 28 mothers). Children (mean age 3.3 +/- 1.5 years) with autism met DSM-IV and ADOS-G diagnostic criteria. The participants' gaze patterns were recorded while they viewed four simple movies that did not feature people. In children, severity of autism is related to spending more time watching irrelevant regions in one of the four movies. The mothers of children with autism showed an atypical pattern for three movies, whereas the fathers of children with autism did not show an atypical gaze pattern. The gaze pattern of the mothers was positively correlated with that of their children. The atypical viewing pattern of autistic individuals appears not to be restricted to people and social situations but is also seen in other situations, suggesting that there is a perceptual broad autism phenotype. PMID- 22937260 TI - Meditation as a potential therapy for autism: a review. AB - Autism is a chronic neurodevelopmental disorder of unknown cause that affects approximately 1-3 percent of children and four times more boys than girls. Its prevalence is global and its social impact is devastating. In autism, the brain is unable to process sensory information normally. Instead, simple stimuli from the outside world are experienced as overwhelmingly intense and strain the emotional centers of the brain. A stress response to the incoming information is initiated that destabilizes cognitive networks and short-circuits adequate behavioral output. As a result, the child is unable to respond adequately to stimulation and initiate social behavior towards family, friends, and peers. In addition, these children typically face immune-digestive disorders that heighten social fears, anxieties, and internal conflicts. While it is critical to treat the physical symptoms, it is equally vital to offer an evidence-based holistic solution that harmonizes both their emotional and physical well-being as they move from childhood into adult life. Here, we summarize evidence from clinical studies and neuroscience research that suggests that an approach built on yogic principles and meditative tools is worth pursuing. Desired outcomes include relief of clinical symptoms of the disease, greater relaxation, and facilitated expression of feelings and skills, as well as improved family and social quality of life. PMID- 22937262 TI - Oligodendrocytes in schizophrenia. PMID- 22937261 TI - Age-related increase in the number of oligodendrocytes is dysregulated in schizophrenia and mood disorders. AB - The postnatal maturation of the human prefrontal cortex is associated with substantial increase of number of oligodendrocytes. Previously, we reported decreased numerical density of oligodendrocytes in the prefrontal cortex in schizophrenia and mood disorders. To gain further understanding of the role oligodendrocytes in pathogenesis of schizophrenia and mood disorders, we examined the effect of the age on the number of oligodendrocytes in the prefrontal cortex in schizophrenia, bipolar disorder, and major depressive disorder. We revealed the age-related increase in numerical density of oligodendrocytes in layer VI and adjacent white matter of BA10 and BA 9 in normal controls but not in schizophrenia, bipolar disorder, and major depressive disorder. The absence of normal increase in the number of oligodendrocytes in gray and white matter with age in schizophrenia and mood disorders suggests that age-related process of oligodendrocyte increase is dysregulated in schizophrenia and mood disorders. PMID- 22937263 TI - Clinical Practice Associated with a Switch from and to Ziprasidone during Routine Inpatient Treatment of Patients with Schizophrenia. AB - Ziprasidone (ZIP) shows a low propensity for metabolic side effects but can prolong QTc time. It is unclear how these features translate into clinical reality. Charts of inpatients with schizophrenia and switched from (ZIP - , n = 27) or to ZIP (ZIP + , n = 24) were reviewed. Clinical data including documented switch reasons were anonymously analyzed. Comorbidity, body mass index (BMI) at admission, illness severity, side effects, illness duration, and length of stay were comparable in both groups. About 2/3 of ZIP+ were women (1/3 of ZIP - , P = 0.035); ZIP+ patients were younger (P = 0.017), had higher BMI values (P = 0.042), and received higher chlorpromazine equivalents before switch (P = 0.004) whereas ZIP doses were comparable (136 versus 141 mg/d). More patients in ZIP- versus ZIP+ were switched because of previous weight gain (P = 0.006) and depression (P = 0.085) whereas single reasons for ZIP- versus ZIP+ were mainly persisting positive symptoms (P = 0.089) and patients' choice (P = 0.10). The results of the naturalistic study corroborate controlled trials. PMID- 22937264 TI - Ultrastructural alterations of myelinated fibers and oligodendrocytes in the prefrontal cortex in schizophrenia: a postmortem morphometric study. AB - Schizophrenia is believed to result from altered neuronal connectivity and impaired myelination. However, there are few direct evidence for myelin abnormalities in schizophrenia. We performed electron microscopic study of myelinated fibers and oligodendrocytes and morphometric study of myelinated fibers in the prefrontal cortex in gray and white matters in schizophrenia and normal controls. Six types of abnormal fibers and ultrastructural alterations of oligodendrocytes were found in schizophrenia. No significant group differences in area density of myelinated fibers were found. Frequency of pathological fibers was increased significantly in gray matter in young and elderly schizophrenia patients and in patients with predominantly positive symptoms. In contrast, in white matter, frequency of altered fibers was increased significantly in elderly patients, in patients with predominantly negative symptoms, and correlated with illness duration. Progressive alterations of myelinated fibers in white matter might be followed by alterations of myelinated fibers in gray matter in schizophrenia. PMID- 22937265 TI - Randomized Controlled Trial of Clozapine and CBT for First-Episode Psychosis with Enduring Positive Symptoms: A Pilot Study. AB - Here we report the results of a pilot study investigating the relative and combined effects of a 12 week course of clozapine and CBT in first-episode psychosis patients with prominent ongoing positive symptoms following their initial treatment. Patients from our early psychosis service who met the inclusion criteria (n = 48) were randomized to one of four treatment groups: clozapine, clozapine plus CBT, thioridazine, or thioridazine plus CBT. The degree of psychopathology and functionality of all participants was measured at baseline then again at 6, 12 and 24 weeks, and the treatment outcomes for each group determined by statistical analysis. A substantial proportion (52%) of those treated with clozapine achieved symptomatic remission, as compared to 35% of those who were treated with thioridazine. Overall, those who received clozapine responded more rapidly to treatment than those receiving the alternative treatments. Interestingly, during the early treatment phase CBT appeared to reduce the intensity of both positive and negative symptoms and thus the time taken to respond to treatment, as well having as a stabilizing effect over time. PMID- 22937266 TI - Cannabinoids for the treatment of schizophrenia? A balanced neurochemical framework for both adverse and therapeutic effects of cannabis use. AB - Recent studies have found that cannabinoids may improve neuropsychological performance, ameliorate negative symptoms, and have antipsychotic properties for a subgroup of the schizophrenia population. These findings are in contrast to the longstanding history of adverse consequences of cannabis use, predominantly on the positive symptoms, and a balanced neurochemical basis for these opposing views is lacking. This paper details a review of the neurobiological substrates of schizophrenia and the neurochemical effects of cannabis use in the normal population, in both cortical (in particular prefrontal) and subcortical brain regions. The aim of this paper is to provide a holistic neurochemical framework in which to understand how cannabinoids may impair, or indeed, serve to ameliorate the positive and negative symptoms as well as cognitive impairment. Directions in which future research can proceed to resolve the discrepancies are briefly discussed. PMID- 22937267 TI - Abnormal behaviors and microstructural changes in white matter of juvenile mice repeatedly exposed to amphetamine. AB - Amphetamine (AMP) is an addictive CNS stimulant and has been commonly abused by adolescents and young adults, during which period brain white matter is still developing. This study was to examine the effect of a nonneurotoxic AMP on the white matter of juvenile mice. d-AMP (1.0 mg/kg) was given to young male C57BL/6 mice once a day for 21 days. The spatial working memory and locomotion of mice were measured at the end. Then, mice were sacrificed and their brains were processed for morphological analyses to examine the white matter structure and for Western blot analysis to measure three main proteins expressed in mature oligodendrocytes. AMP-treated mice displayed higher locomotion and spatial working memory impairment and showed lower levels of Nogo-A and GST-pi proteins in frontal cortex and lower MBP protein in the frontal cortex and hippocampus. They also had fewer mature oligodendrocytes and weak MBP immunofluorescent staining in the same two brain regions. But the striatum was spared. These results suggest that the late-developing white matter is vulnerable to AMP treatment which is able to increase striatal and cortical dopamine. Both the compromised white matter and increased dopamine may contribute to the observed behavioral changes in AMP-treated mice. PMID- 22937268 TI - Parietal lobes in schizophrenia: do they matter? AB - Objective. Despite observations that abnormal parietal lobe (PL) function is associated with psychotic-like experiences, our knowledge about the nature of PL involvement in schizophrenia is modest. The objective of this paper is to investigate the role of the PL in schizophrenia. Method. Medline databases were searched for English language publications using the following key words: parietal lobe, combined with schizophrenia, lesions, epilepsy, cognition, rare genetic disorders, MRI, fMRI, PET, and SPECT, respectively, followed by cross checking of references. Results. Imaging studies in childhood onset schizophrenia suggest that grey matter abnormalities start in parietal and occipital lobes and proceed to frontal regions. Although, the findings are inconsistent, several studies with patients at risk to develop schizophrenia indicate early changes in the PL. Conclusions. We want to propose that in a proportion of individuals with emerging schizophrenia structural and functional alterations may start in the PL and progress to frontal regions. PMID- 22937269 TI - Second generation antipsychotics improve sexual dysfunction in schizophrenia: a randomised controlled trial. AB - The impact of antipsychotic drug treatment on sexual function was investigated during a randomised trial comparing first generation antipsychotics (FGAs) to (nonclozapine) second generation antipsychotics (SGAs). Sexual function and quality of life were (rater-blind) assessed in 42 patients with DSM-IV schizophrenia (aged 18-65) using the self-report version of the Derogatis Interview for Sexual Function (DISF-SR) and the Heinrichs Quality of Life Scale (QLS), prior to, and 12 weeks following, a change in medication from an FGA drug to either an FGA or SGA drug. SGAs significantly improved sexual function compared to FGAs. Change in sexual function was associated with change in quality of life. Where impaired sexual functioning is a distressing adverse effect of treatment with an FGA agent, consideration should be given to switching to an SGA. PMID- 22937270 TI - Dissecting the Syndrome of Schizophrenia: Progress toward Clinically Useful Biomarkers. AB - The search for clinically useful biomarkers has been one of the holy grails of schizophrenia research. This paper will outline the evolving notion of biomarkers and then outline outcomes from a variety of biomarkers discovery strategies. In particular, the impact of high-throughput screening technologies on biomarker discovery will be highlighted and how new or improved technologies may allow the discovery of either diagnostic biomarkers for schizophrenia or biomarkers that will be useful in determining appropriate treatments for people with the disorder. History tells those involved in biomarker research that the discovery and validation of useful biomarkers is a long process and current progress must always be viewed in that light. However, the approval of the first biomarker screen with some value in predicting responsiveness to antipsychotic drugs suggests that biomarkers can be identified and that these biomarkers that will be useful in diagnosing and treating people with schizophrenia. PMID- 22937271 TI - Very low-dose risperidone in first-episode psychosis: a safe and effective way to initiate treatment. AB - Patients experiencing a first psychotic episode have high rates of extrapyramidal symptoms (EPSs) when treated with the doses of neuroleptics used in multiepisode or chronic schizophrenia. There is some evidence that lower doses may be equally, if not more, effective but less toxic in this population. Here, we report the results of a biphasic open label trial designed to assess the efficacy, safety, and tolerability of low-dose (2-4 mg/day) risperidone treatment in a group of 96 first-episode nonaffective psychosis patients. At the end of the trial, 62% of patients met the response criteria although approximately 80% had achieved a response at some time during the study. Reports of EPS remained low, and there were no dystonic reactions. We conclude that even at a dose of 2 mg/day, risperidone was highly effective in reducing acute symptomatology in a real world sample of young first-episode psychosis patients. PMID- 22937272 TI - Diffusion tensor imaging, structural connectivity, and schizophrenia. AB - A fundamental tenet of the "disconnectivity" theories of schizophrenia is that the disorder is ultimately caused by abnormal communication between spatially disparate brain structures. Given that the white matter fasciculi represent the primary infrastructure for long distance communication in the brain, abnormalities in these fiber bundles have been implicated in the etiology of schizophrenia. Diffusion tensor imaging (DTI) is a magnetic resonance imaging (MRI) technique that enables the visualization of white matter macrostructure in vivo, and which has provided unprecedented insight into the existence and nature of white matter abnormalities in schizophrenia. The paper begins with an overview of DTI and more commonly used diffusion metrics and moves on to a brief review of the schizophrenia literature. The functional implications of white matter abnormalities are considered, particularly with respect to myelin's role in modulating the transmission velocity of neural discharges. The paper concludes with a speculative hypothesis about the relationship between gray and white matter abnormalities associated with schizophrenia. PMID- 22937273 TI - First- and third-person perspectives in psychotic disorders and mood disorders with psychotic features. AB - Lack of insight, very frequent in schizophrenia, can be considered a deficit in Theory of Mind (ToM) performances, and is also found in other psychiatric disorders. In this study, we used the first- to third-person shift to examine subjects with psychotic and psychotic mood disorders. 92 patients were evaluated with SANS and SAPS scales and asked to talk about their delusions. They were asked to state whether they thought what they said was believable for them and for the interviewer. Two weeks later, 79 patients listened to a tape where their delusion was reenacted by two actors and were asked the same two questions. Some patients gained insight when using third-person perspective. These patients had lower SAPS scores, a lower score on SAPS item on delusions, and significant improvement in their SAPS delusion score at the second interview. Better insight was not related to a specific diagnostic group. PMID- 22937275 TI - Relationships between Brain Structure and Metabolic Changes in Schizophrenia Patients Treated with Olanzapine: A Voxel-Based Morphometric Study. AB - Introduction. Second-generation antipsychotics treatment is associated with weight gain and metabolic disturbances. Although much research has been done on the topic, the precise mechanisms underlying such side effects are still not well understood. Method. We followed over 16 weeks a group of 17 schizophrenia patients who were treated with olanzapine and monitored biometric, clinical, and metabolic data, including ghrelin and leptin levels. All patients had a structural cerebral magnetic resonance imaging examination during the first week of their followup and at the end of the study. Results. We found positive and negative significant correlations between grey matter volumes of several brain regions and variations of body weight as well as of ghrelin and leptin levels. The right frontal operculum, bilateral precuneus, and bilateral hippocampal regions were found to be significantly associated with those changes. Conclusion. Our results suggest associations between brain structure and metabolic variations in schizophrenia patients taking olanzapine. PMID- 22937274 TI - White matter abnormalities and animal models examining a putative role of altered white matter in schizophrenia. AB - Schizophrenia is a severe mental disorder affecting about 1% of the population worldwide. Although the dopamine (DA) hypothesis is still keeping a dominant position in schizophrenia research, new advances have been emerging in recent years, which suggest the implication of white matter abnormalities in schizophrenia. In this paper, we will briefly review some of recent human studies showing white matter abnormalities in schizophrenic brains and altered oligodendrocyte-(OL-) and myelin-related genes in patients with schizophrenia and will consider abnormal behaviors reported in patients with white matter diseases. Following these, we will selectively introduce some animal models examining a putative role of white matter abnormalities in schizophrenia. The emphasis will be put on the cuprizone (CPZ) model. CPZ-fed mice show demyelination and OLs loss, display schizophrenia-related behaviors, and have higher DA levels in the prefrontal cortex. These features suggest that the CPZ model is a novel animal model of schizophrenia. PMID- 22937276 TI - Balance, Falls-Related Self-Efficacy, and Psychological Factors amongst Older Women with Chronic Low Back Pain: A Preliminary Case-Control Study. AB - Objective. To investigate balance functions in older women and evaluate the association of the fear-avoidance beliefs model (FABM) factors with balance and mobility performance. Participants. Fifteen older women with CLBP was compared with age-matched pain-free controls (n = 15). Main Outcome Measures. Pain intensity, falls-related self-efficacy and intrinsic constructs in the FABM were evaluated. Postural steadiness (centre of pressure (COP)) and mobility functions were assessed. Linear relationships of FABM variables with COP and mobility score were estimated. Results. CLBP showed lower mobility score compared to controls. CLBP presented lower falls-related self-efficacy and it was associated with reduced mobility scores. FABM variables and falls-related self-efficacy were correlated with postural steadiness. Physical activity was reduced in CLBP, but no between-group difference was evident for knee extensor strength. No systematic linkages were observed between FABM variables with mobility score or postural steadiness. Conclusions. Back pain status affects balance and mobility functions in older women. Falls-related self-efficacy is lower in CLBP and is associated with reduced mobility. Disuse syndrome in CLBP elderly is partly supported by the results of this preliminary study. PMID- 22937278 TI - Rapid and significant reduction in size of pituitary adenoma in children treated with fractionated stereotactic radiation therapy: a case report. AB - Radiation treatment in the management of pituitary adenoma in children is still a controversy due to the great concern of late radiation effect. Stereotactic radiation therapy is the modern radiation technique that is more widely applicable in pituitary adenoma because of the ability to give highly conformal radiation to the target organ and to reduce the radiation dose to normal tissue. A 15-year-old boy presented with postradiation therapy recurrence pituitary macroadenoma. His vision was useful only on the left eye. MRI revealed the recurrent macroadenoma with severe invasion of optic apparatus. Since no any other treatment option was to be given to this patient, we decided to reirradiate the patient with conventional fractionated stereotactic radiation. At 3 months of followup, MRI showed that the tumor had an early and significant reduction in size without any sign of toxicity. PMID- 22937277 TI - Anesthesia and Intensive Care Management in a Pregnant Woman with PRES: A Case Report. AB - Posterior reversible encephalopathy syndrome (PRES) is a temporary condition that is diagnosed clinically, neurologically, and radiologically. Its symptoms vary, and nonspecific headaches, confusion, impairment of consciousness, nausea, vomiting, and visual impairment may occur. Acute hypertension often accompanies these symptoms. Patients can also suffer from convulsions, cortical visual impairment, and coma. Diagnosis can be difficult due to focal neurologic signs. Nevertheless, knowing the clinical risk factors can lead to the right diagnosis. It has been reported that this condition may also occur during organ transplantation, immunosuppressive treatment, and autoimmune diseases and chemotherapy, and also patients with eclampsia. In this paper, a 21-year-old, 31 week pregnant woman, who had been diagnosed with PRES and thanks to early diagnosis and treatment had fully recovered and discharged from the intensive care unit, is presented, and the relevant literature is discussed. PMID- 22937279 TI - Endometrioid adenocarcinoma metastatic to the thyroid, presenting like anaplastic thyroid cancer. AB - Metastasis of uterine cancer to the head and neck is extremely rare. We report what we believe to be the first documented case of endometrioid adenocarcinoma metastasizing to the thyroid gland. An 80-year-old woman was referred to the otolaryngology service with a rapidly growing neck mass. The mass appeared to originate from the thyroid gland. Her clinical presentation was consistent with anaplastic thyroid carcinoma. A tracheostomy was performed. An open biopsy established the diagnosis of moderately differentiated adenocarcinoma, consistent with a gynecologic primary. The patient had undergone a hysterectomy 5 years prior for endometrioid adenocarcinoma. The thyroid tumor histology and immunophenotype corresponded well with her prior endometrial carcinoma, indicating that the thyroid mass was a metastasis from the endometrial primary. Radiotherapy appears to offer good local disease control in this rare case of endometrioid adenocarcinoma metastatic to the thyroid. PMID- 22937280 TI - Challenges in management of primary hypoparathyroidism associated with autoimmune polyglandular syndrome type 1. AB - We report a case of autoimmune polyglandular syndrome type 1 (APS1) complicated by severe vascular insufficiency due to diffuse vascular calcification. APS1 is characterised clinically by multiple autoimmune conditions and development of at least two components of the triad of mucocutaneous candidiasis, hypoparathyroidism, and autoimmune adrenal insufficiency. We highlight the problems in current serum calcium monitoring methods and suggest that fluctuations in serum calcium concentrations due to difficulties treating hypoparathyroidism may have contributed to the vascular calcification seen in this case. PMID- 22937281 TI - Malignant Range Elevation of Serum Chromogranin A due to Inadvertent Use of Proton Pump Inhibitor in a Subject with Pancreatic Incidentaloma. AB - We present a case of highly elevated tenfold rise of serum chromogranin A in a young, morbidly obese, hypertensive female being investigated for pancreatic mass, weight loss, and elevated ESR. Following extensive noninvasive investigations, an ultrasound-guided pancreatic biopsy confirmed benign haemorrhagic cyst. A clue to the etiology of the hyperchromogranin A was the elevated serum gastrin level leading to suspicion of proton pump inhibitor administration confirmed by admittance to its use. Withdrawal of the medication led to dramatic resolution of the neuroendocrine tumor marker. PMID- 22937282 TI - Life-Threatening Hypocalcemia following Subtotal Parathyroidectomy in a Patient with Renal Failure and Previous Roux-en-Y Gastric Bypass Surgery. AB - Background. Roux-en-Y gastric bypass (RYGB) can result in calcium and vitamin D deficiency. Parathyroid surgery carries the risk of immediate and long-term hypocalcemia. Methods and Results. We describe a 54-year-old woman with history of end-stage renal disease and gastric bypass surgery who developed calciphylaxis requiring a 3.5-gland parathyroidectomy. Seven weeks later, she presented with weakness, perioral numbness, leg cramps, a positive Chvostek's sign, hypotension, prolonged QT-interval, and serum calcium of 5.4 mg/dL. Oral and intravenous calcium, calcitriol, and high calcium bath hemodialysis were given. She required 18 days of intravenous calcium and an outpatient maintenance regimen of calcitriol 6 mcg/day, calcium carbonate 8 grams/day, calcium citrate 1.2 grams/day, and ergocalciferol 50,000 IU/week. Conclusion. The patient's life threatening prolonged hypocalcemia and large requirements of calcium and calcitriol were due to a combination of malabsorption, hypoparathyroidism, and renal failure. Special considerations should be given to bariatric surgery patients undergoing neck exploration. PMID- 22937283 TI - Case of hypercalcemia secondary to hypervitaminosis a in a 6-year-old boy with autism. AB - Vitamin A intoxication secondary to over-the-counter nutritional supplements and from its use in acne treatment has been described. However, there have been very few case reports of chronic hypervitaminosis A leading to hypercalcemia in the pediatric population. This paper describes a boy with hypercalcemia secondary to chronic vitamin A intoxication in the context of vitamin A usage for therapy of autism. In addition to discontinuation of vitamin A, hyperhydration, and furosemide, the hypercalcemia in this patient required the use of prednisone and pamidronate to normalize the calcium. PMID- 22937284 TI - Primary hyperparathyroidism in pregnancy-a rare cause of life-threatening hypercalcemia: case report and literature review. AB - Objective. To report a case of primary hyperparathyroidism in a pregnant patient, report the obstetric and neonatal outcomes, and review the relevant literature. Results. A 29-year-old primigravida was successfully treated for PHP with minimally invasive resection of a parathyroid adenoma in the second trimester of pregnancy. A healthy baby girl was delivered at 37-week gestation with an unremarkable neonatal course. To the best of our knowledge, this is the second case report in the literature utilizing intraoperative PTH during a parathyroidectomy in a pregnant woman. Conclusions. Primary hyperparathyroidism is a rare life-threatening condition that can present during pregnancy. The diagnosis can be difficult to establish during pregnancy, given the nonspecific symptoms related to hypercalcemia. However, a better understanding of the condition, improved diagnostic studies, and well-organized multidisciplinary management decisions can significantly reduce the morbidity and mortality associated with the disease during pregnancy. This case report is presented to highlight the value of early diagnosis and appropriate management of PHP during pregnancy. PMID- 22937285 TI - Spontaneous Rupture, Disappearance, and Reaccumulation of a Rathke's Cleft Cyst. AB - Rathke's cleft cysts (RCCs) are benign epithelium-lined intrasellar cysts containing mucoid material and are believed to originate from the remnants of Rathke's pouch. Most are asymptomatic but may cause symptoms secondary to compression of adjacent structures such as visual disturbances and endocrinopathies, especially hypopituitary. Furthermore, inflammation such as an aseptic meningitis syndrome may be associated with these tumors, presumably resulting from leakage of cyst material into the subarachnoid space. We present a unique case of spontaneous rupture and complete disappearance of a known sella suprasellar cyst associated with a severe headache syndrome, followed by cyst reaccumulation requiring surgery. Although this phenomenon is well accepted, to our knowledge, this is the first report of the complete disappearance of a Rathke's cyst presenting with the classic syndrome. Furthermore, it was remarkable how quickly it recurred and became symptomatic, providing evidence that an "empty sella syndrome" may indeed need clinical follow-up. PMID- 22937286 TI - Scleredema diabeticorum in a patient with type 2 diabetes mellitus. AB - Background. Scleredema adultorum, a connective tissue disorder of unknown aetiology, is characterized by a thickening of the reticular dermis in the upper back of the body that may decrease the mobility of the affected tissues. It has been reported in diabetic patients with poor metabolic control. Therapeutic options are limited with generally poor results. Case Report. 53-year-old white male with type 2 diabetes mellitus was referred to our department for evaluation of incipient nephropathy and retinopathy. On examination, he presented erythematous, indurated, painless and ill-defined plaque on the skin of the upper back with limited movement of shoulders. A biopsy was done revealing scleredema. PUVA treatment and physiotherapy were started with the amelioration of mobility and acquiring some elasticity of the upper back. Discussion. The development of scleredema in diabetic patients has been related to prolonged exposure to chronic hyperglycaemia. Our patient has had diabetes for 20 years with an acceptable glucose control, however he developed the scleredema 10 years ago. Conclusions. Scleredema is a rare connective disorder that seems to appear most frequently in diabetic subjects. Good metabolic control seems not to preclude its development. PUVA treatment and physiotherapy are therapeutic options that seem to be of some help. PMID- 22937287 TI - A Case of Resistance to Thyroid Hormone with Chronic Thyroiditis: Discovery of a Novel Mutation (I54V). AB - Resistance to thyroid hormone (RTH) is a rare disorder characterized by variable tissue hyporesponsiveness to thyroid hormone, usually caused by mutations in the thyroid hormone receptor beta (TRbeta). It has been reported that the serum of patients with RTH is free of auto-antibodies against thyroglobulin (Tg) and thyroid peroxidase (TPO), except in rare cases where coincidental autoimmune thyroiditis is also present. We describe a 13-year-old girl with chronic thyroiditis and RTH. This patient had increased plasma free T3, free T4 at the upper limits with unsuppressed TSH. She had peripheral manifestations of thyroid hormone excess, hypertension and growth acceleration. Anti-TPO antibodies were positive. Sequence analysis of the TRbeta gene was performed and revealed a novel mutation I54V in exon 4. The same mutation was also found in the mother and two asymptomatic sisters. The clinical presentation of our patient is not habitual in RTH because growth retardation is frequently reported in this syndrome. The association between RTH and thyroiditis complicate the management of the hypothyroidism. PMID- 22937289 TI - Premature menarche associated with primary hypothyroidism in a 5.5-year-old girl. AB - Children with hypothyroidism generally have delayed pubertal development. Rare association with precocious puberty may occur especially in long standing untreated patients. The cardinal features of hypothyroidism induced pseudo precocious pubertal development include thelarche, galactorrhea and menarche. Other characteristics features are an absence of sexual hair and retardation of linear growth. Its manifestation as isolated menarche has been rarely reported. Recently, a five and half year old girl presented to us with history of one episode of vaginal bleeding. A pelvic ultrasonogram revealed multiple cysts in both ovaries and subsequent investigations led to a diagnosis of autoimmune hypothyroidism. PMID- 22937288 TI - An unusual case of myonecrosis. AB - Diabetic Myonecrosis is a rare complication of long-standing Diabetes Mellitus Type 1 and 2. The most likely affected areas are of proximal lower limbs, mostly the quadriceps muscle. The presenting features are myriad and a diagnostic conundrum for the physician. There has been previously mentioned, through few case reports, the classical presentation of diabetes-related muscle infarction. Here we present a patient of diabetic myonecrosis, in whom the initial presentation of diabetes mellitus was that of bilateral symmetric proximal upper limb predominant muscle infarction, which has never been reported before. PMID- 22937290 TI - Recurrent urosepsis and cardiogenic shock in an elderly patient with pheochromocytoma. AB - Pheochromocytomas are thought to be uncommon in the elderly. However, the prevalence is likely to be higher than reported, as older patients are less likely to be diagnosed due to absence of classical symptoms of sympathetic overactivity and confounding effects of aging, comorbidities, and medications. We describe a hypertensive elderly patient with incidentally diagnosed pheochromocytoma complicated by recurrent urosepsis, cardiomyopathy, and fatal myocardial infarction. Our case demonstrates that, in older hypertensive patients without classical symptoms, orthostatic hypotension and urinary retention, which are common in the elderly, may indicate catecholamine excess and that the deleterious cardiovascular consequences of catecholamine excess in the elderly are not prevented by pharmacological alpha- and beta-blockade. PMID- 22937291 TI - Asymptomatic severe hypocalcemia secondary to vitamin d deficiency in an elderly patient. AB - Objective. To describe an asymptomatic presentation of severe hypocalcemia secondary to vitamin D deficiency in an elderly patient. Methods. We describe the presentation and clinical course of an elderly woman with asymptomatic severe hypocalcemia referred to an endocrinology clinic for hyperparathyroidism. Results. The patient is an 83-year-old Caucasian woman who presented to an endocrinology clinic for evaluation of hyperparathyroidism, with an intact PTH of 462 pg/mL (normal range 14-72 pg/mL). The same lab report included a serum calcium of 5.2 mg/dL (normal range 8-10.5 mg/dL). She displayed no signs or symptoms of hypocalcemia. Given the extreme severity of hypocalcemia and her age, she was hospitalized. Vitamin D deficiency was suspected and was subsequently confirmed with undetectable serum levels. The patient remained asymptomatic throughout her hospital stay. Total and ionized calcium levels at discharge were 7.2 mg/dL and 1.03 mmol/L (normal range 1.1-1.4 mmol/L), respectively. Conclusion. Physicians should exercise prudent management with respect to the vitamin D status of the elderly patient, as certain patients may exhibit severe hypovitaminosis D and hypocalcemia without apparent clinical symptoms. PMID- 22937292 TI - Thyrotoxic Periodic Paralysis: Case Reports and an Up-to-Date Review of the Literature. AB - Objectives. To describe 2 cases of thyrotoxic periodic paralysis. Methods. We report of 2 cases of thyrotoxic periodic paralysis in 2 individuals from 2 different backgrounds with emphasis on their presentation and treatment. We also conducted a literature search to put together an update review of thyrotoxic periodic paralysis. Results. A 47-year-old Chinese and 28-year-old Caucasian male presented with profound yet reversible weakness associated with hypokalemia on admission bloods and thyrotoxicosis. Both were given definitive therapy to prevent recurrence of attacks with any future relapse of thyrotoxicosis. Conclusion. Thyrotoxic periodic paralysis (TPP) is a rare but potentially serious complication of thyrotoxicosis resulting in temporary but severe muscle weakness. Recent discovery of a novel mutation in the KCNJ18 gene which codes for an inwardly rectifying potassium channel and is controlled by thyroid hormones may provide greater insight into the pathogenesis of TPP. PMID- 22937293 TI - The coexistence of an intrasellar adenoma, lymphocytic hypophysitis, and primary pituitary lymphoma in a patient with acromegaly. AB - The concomitant presence of three histopathologically different entities in the pituitary gland is a rare occurrence. Most publications identify at least two distinct pathologies, mainly, a pituitary adenoma coexisting with a second intrasellar lesion. We present a case of a 71-year-old female referred for evaluation and treatment of acromegaly. Questioning revealed she was experiencing facial palsy, visual disturbances, and syncopal spells for several weeks. When laboratory evaluation showed elevated somatomedin (IGF-I) levels and an oral glucose tolerance test failed to demonstrate any suppression of her growth hormone (GH) values, an MRI of the pituitary revealed a sellar mass. A presumptive diagnosis of pituitary adenoma was established. The patient underwent transsphenoidal resection of the sellar mass, which proved to be a large B-cell lymphoma (Stage I-E) associated with areas of adenoma and lymphocytic hypophysitis. PMID- 22937294 TI - Insulin in the medical management of postprandial hypoglycemia in a patient with type 2 diabetes after gastric bypass surgery. AB - Objective. We evaluated a 47-year-old woman with a history of type 2 diabetes and severe obesity who developed postprandial hypoglycemia after undergoing Roux-en-Y gastric bypass surgery and losing 60% of her total body weight. We studied her insulin secretion and blood glucose dynamics and were able to tailor a therapeutic regimen involving insulin that eliminated episodes of hypoglycemia. Methods. We studied blood glucose levels during a prolonged fast, performed continuous glucose monitoring studies using a subcutaneous glucose sensor, and evaluated regional pancreatic insulin secretion using selective arterial calcium stimulation. Results. Continuous glucose monitoring revealed that the patient had early (1-2 hr) postprandial hyperglycemia followed by late (3-4 hr) postprandial hypoglycemia. Biochemical studies confirmed endogenous pancreatogenous insulin secretion as the cause of episodic hypoglycemia, but imaging studies and selective arterial calcium stimulation failed to localize an insulinoma. The patient was treated with preprandial doses of insulin aspart in order to attenuate the early postprandial hyperglycemia, and the late hypoglycemic episodes were avoided. Conclusion. We describe an interesting and novel nonsurgical approach to the prevention of postprandial hypoglycemia in a patient with noninsulinoma pancreatogenous hypoglycemia after gastric bypass. PMID- 22937295 TI - Improved diabetes control and pancreatic function in a type 2 diabetic after omeprazole administration. AB - A 43-year-old man with type 2 diabetes, opposed to insulin use and poorly responsive to oral agents added sequentially over 6 years, was placed on 40 mg omeprazole twice daily. A linear decline in daily fasting blood glucose was observed over the first two-month treatment, and his hemoglobin A1c was reduced from 11.9% to 8.2%, then sustained at 8.1% after four months. Glucose, insulin, and C-peptide response to a 2-hour glucose tolerance test were consistently improved across this time period, and calculated beta-cell mass increased by 67%. We believe these responses are consistent with activation or neogenesis of pancreatic beta cells, possibly through a gastrin-mediated mechanism. PMID- 22937296 TI - A rare form of melanoma masquerading as a diabetic foot ulcer: a case report. AB - Background. Acral lentiginous melanoma (ALM) is a less-common form of melanoma in US, and it accounts for about 5% of all diagnosed melanomas in US. ALM is often overlooked until it is well advanced because of the lesion's location and its atypical appearance in the early stages. We present a case of ALM initially presented as a diabetic foot ulcer. Case Report. An 81-year-old man initially presented to the primary care clinic with a right foot diabetic ulcer. There was a large plantar, dark-colored ulcer that bled easy. Initial excision biopsy revealed Clark's Level IV ALM. Subsequent definitive wide excision and sentinel node biopsy confirmed ALM with metastasis to inguinal lymph nodes (stage IIIb). The treatment included wide margin excision of the lesion with en bloc amputations of 4th and 5th toes, followed by adjuvant chemotherapy. Discussion. The development of ALM may potentially relate to diabetes as a reported higher prevalence of diabetes with ALM patients. Conclusion. The difficulty in early diagnosing of ALM remains as a formidable challenge particularly in diabetic patients who commonly develop plantar foot ulcers due to the diabetic neuropathy. This case reiterates the importance of a thorough foot exam in such patients. PMID- 22937297 TI - Severe hypothyroidism causing pre-eclampsia-like syndrome. AB - Objective. Analyzing and managing pre-eclampsia-like syndrome due to severe hypothyroidism. Methods. Presentation of a case of severe hypothyroidism due to Hashimoto's syndrome, associated with a severe early-onset preeclampsia-like syndrome, managed in our Gynecology Department. Results. Severe pre-eclampsia led to miscarriage at 24 weeks of gestational age in a 42-year-old woman, although we attempted to correct hypothyroidism with increasing doses of levothyroxine and liothyronine sodium. Conclusion. Recognizing pre-eclampsia-like syndrome caused by overt hypothyroidism from other forms of pregnancy-induced hypertension is essential for choosing the correct treatment. PMID- 22937298 TI - Ain't No Sunshine When She's Gone: Pseudohypoparathyroidism Discovered in an Adult. AB - An 18-year-old negroid woman presented with progressive cramps in both hands. She was Jamaican and had moved to The Netherlands 8 months before. On physical examination Trousseau's sign was positive. Laboratory analysis showed severe hypocalcaemia (1.17 mmol/L) and hyperphosphatemia (2.0 mmol/L). Urinary excretion of both calcium (0.8 mmol/day) and phosphate (5 mmol/day) was low, as is seen in hypoparathyroidism. However, the PTH level was increased (22.1 pmol/L), whereas 25-(OH)-vitamin D was low (31 nmol/L). An Ellsworth-Howard test showed only a fivefold increase in urinary phosphate excretion after administration of synthetic PTH, supporting the diagnosis pseudohypoparathyroidism. Upon treatment with calcium supplementation and alfacalcidol, her symptoms disappeared. Pseudohypoparathyroidism (PHP) is a rare hereditary disorder resembling hypoparathyroidism, although plasma PTH levels are elevated. PHP is caused by alterations in the PTH receptor, inducing target tissue resistance to PTH. This results in hypocalcaemia and hyperphosphatemia, while PTH levels are elevated. The diagnosis is confirmed by the Ellsworth-Howard test, which will show a 100 fold increase in phosphate excretion if the PTH receptor functions properly. Treatment is lifelong supplementation of calcium and alfacalcidol. In our patient, symptoms were probably evoked by the lack of sunlight in Dutch winter, decreasing vitamin D levels and thereby aggravating hypocalcaemia. PMID- 22937299 TI - Feminizing adrenal carcinoma presenting with heart failure and ventricular tachycardia. AB - We present a case of feminizing adrenal carcinoma with severe elevation in serum estradiol and otherwise unexplained congestive heart failure with ventricular arrhythmia and review the literature on feminizing adrenal tumors and the potential relationship between estrogen and cardiac problems. A 54-year-old man presented with congestive heart failure and ventricular arrhythmia. Imaging revealed a large adrenal mass. Hormonal evaluation revealed a very high serum level of estradiol, elevated DHEA-sulfate and androstenedione, and lack of cortisol suppression on a low-dose overnight dexamethasone suppression test. The patient underwent a left adrenalectomy with subsequent normalization of serum estradiol. Surgical pathology examination established adrenocortical carcinoma MacFarlane stage II. Upon 15-month followup, the patient continued to have a normal serum estradiol level, his cardiac function was significantly improved, and he had no further episodes of ventricular arrhythmia. To the best of our knowledge, the serum estradiol level that was detected in our case is the highest that has been reported. Further, we hypothesize that the very high serum concentration of estradiol in our case may have played a role in his cardiac presentation with congestive heart failure and arrhythmia, particularly as these problems resolved with normalization of his serum estradiol level. PMID- 22937300 TI - A New Three-Way Translocation t(4;11;7)(q21;q23;q22) in a Mixed-Phenotype Acute Leukemia. AB - A 68-year-old man was admitted to our hospital in September 2008 because of a left-sided chest pain. Bone marrow examination showed that 85.5% of leukemic cells were positive for myeloperoxidase (MPO) and were negative for esterase stain. Flow cytometric analysis (FCM) revealed the expression of CD19, CD79a, CD13, CD33, CD34, and HLA-DR on the blasts. Cytogenetic analysis of bone marrow cells using the G-banding technique demonstrated 47, XY, +X, t(4;11;7)(q21;q23;q22) in five of the 20 analyzed cells. The patient was diagnosed as having mixed biphenotypic acute leukemia according to the European Group for Immunologic Classification of Leukemia criteria. Mixed-phenotype acute leukemia is a rare, difficult to diagnose entity. Whether patients with mixed phenotype acute leukemia should be treated with regimens designed for acute myeloid leukemia, acute lymphoblastic leukemia, or both remains unclear. PMID- 22937301 TI - A success story leading us to think big! AB - Immune dysregulation is the hallmark of all autoimmune diseases. It is extremely interesting to study the associations and pathogenesis of the various autoimmune diseases, like the link between the AIHA and CLL. This link is well established and is based on the fact that there is loss of tolerance to the self-antigen, which in turn leads to immunebased hemolytic anemia. Around 30% of the patients with CLL are at the risk of developing AIHA, and 11% eventually develop AIHA. Whether there is any definite linkup between the corrupted immune system and "acute" leukemias/lymphomas is yet to be established. Needless to say, if there was an association between the pathogenesis of the ALLs and AIHA, it would be a landmark in the field of oncology as it would enforce early diagnosis and treatment for the disease which is much more aggressive and found in a comparatively younger age group (predominantly in children and a mean age of 40 years in adults) as compared to its chronic counterparts. The AIHA would serve as a "tip to the underlying iceberg" in these situations, warning us of the cryptic diagnosis. PMID- 22937302 TI - Prethymic cytoplasmic CD3 negative acute lymphoblastic leukemia or acute undifferentiated leukemia: a case report. AB - Acute undiffentiated leukemia (AUL) is an acute leukemia with no more than one membrane marker of any given lineage. Blasts often express HLA-DR, CD34, and/or CD38 and may be positive for terminal deoxynucleotidyl transferase (TdT). The expression of CD34, HLA-DR, and CD38 has been shown in pro-T-ALL, although in this case, blasts should also express CD7 and cyCD3. However, some cases of T-ALL without CD3 in the cytoplasm and all TCR chain genes in germ line configuration are reported, features that fit well with a very early hematopoietic cell. We report a case of acute leukemia CD34+/-HLADR+CD7+CD38+cyCD3- in which a diagnosis of AUL was considered. However the blasts were also positive for CD99 and TCR delta gene rearrangement which was found on molecular studies. Therefore a differential diagnosis between AUL and an early cyCD3 negative T-ALL was debated. PMID- 22937303 TI - Allografting for Bosutinib, Imatinib, Nilotinib, Dasatinib, and Interferon Resistant Chronic Myeloid Leukemia without ABL Kinase Mutation. AB - The current treatment of chronic phase chronic myeloid leukemia (CML) consists of oral tyrosine kinase inhibitors (TKIs). However, high-risk CML may present with an aggressive course which may result in blastic crisis or a "difficult-to manage" state with available treatments. The aim of this paper is to report a patient with complicated CML resistant to treatment and progressed despite the administration of bosutinib, imatinib mesylate, nilotinib, dasatinib, interferon alpha 2a, cytotoxic chemotherapy, and allogeneic hematopoietic stem cell transplantation. The striking point of this case story is that no Abl kinase domain mutation against TKIs has been detected during this very complicated disease course of CML. Meanwhile, challenging cases will always be present despite the hope and progress in CML in the TKI era. PMID- 22937304 TI - Successful Administration of Recombinant Human Soluble Thrombomodulin alpha (Recomodulin) for Disseminated Intravascular Coagulation during Induction Chemotherapy in an Elderly Patient with Acute Monoblastic Leukemia Involving the t(9;11)(p22;q23) MLL/AF9 Translocation. AB - Patients with acute myelogenous leukemia complicate with disseminated intravascular coagulation (DIC), not only at the time of the initially leukemia diagnosis, but also during induction chemotherapy. In Japan, recently, a recombinant human soluble thrombomodulin alpha (Recomodulin) has been introduced as a new type of anti-DIC agent for clinical use in patients with hematological cancer or infectious disease. We describe a 67-year-old female case in which 25,600 units of Recomodulin for 6 days were successfully administered for both initially complicating and therapy-induced DIC without any troubles of bleeding in an acute monoblastic leukemia (AML-M5a) patient with the MLL gene translocation. Furthermore, the levels of DIC biomarkers recovered rapidly after the Recomodulin treatment. Our case suggests that DIC control using Recomodulin is one of the crucial support-therapies during remission induction chemotherapy in patients with acute leukemia of which type tends to complicate extramedullary or extranodal infiltration having potential to onset DIC. PMID- 22937305 TI - Diffuse large B-cell lymphoma with calf muscle localization. AB - Although diffuse large B-cell lymphoma (DLBCL) usually occurs in the lymph nodes, approximately 30-40% of the time it can have an extranodal site of involvement and it can arise in nearly every body site such as intestine, bone, breast, liver, skin, lung, and central nervous system. Muscle involvement of DLBCL is especially uncommon, comprising 0.5% of extranodal NHL. We report a case of a 72 year-old man with extranodal DLBCL of a unique manifestation in the calf muscle, involving predominantly the gastrocnemius muscle. The patient achieved complete response and remained free of local recurrence or metastasis following diagnosis. PMID- 22937306 TI - Lymphocyte Rich Hodgkin's Lymphoma Presented with Warm Hemolytic Anemia: A Case Report and Literature Review. AB - Hodgkin's lymphoma accounts for ten percent of all lymphomas. In the United States, there are about 8000 new cases every year. This paper describes a case of lymphocyte-rich Hodgkin's lymphoma (LRHL) manifested by autoimmune hemolytic anemia (AIHA). A 27-year-old Israeli male presented with dizziness associated with one month of low-grade fevers and night sweats; he also complained of persistent cough, pruritus, and ten-pound weight lost during this time. The CBC revealed hemoglobin of 5.9 gm/dL, and direct Coomb's test detected multiple nonspecific antibodies consistent with the diagnosis of AIHA. Chest, abdomen, and pelvic CT scan showed mediastinal lymphadenopathy and splenomegaly. Lymph node biopsy revealed classic LRHL. AIHA resolved after completion of the first cycle of chemotherapy with adriamycin, bleomycin, vinblastine, and dacarbazine (ABVD); after six cycles, he went into complete remission. Although infrequent, AIHA can be responsible for the presenting symptoms of HL. PMID- 22937307 TI - Myelodysplastic syndrome and autoimmunity: a case report of an unusual presentation of myelodysplastic syndrome. AB - Myelodysplastic syndrome (MDS) commonly presents asymptomatically or with symptomatic cytopenias. However, autoimmune phenomena in association with MDS have been well described in several case reports and case series. Typically, these autoimmune phenomena take the form of vasculitides, arthritis, connective tissue diseases, pulmonary infiltrates, or polymyalgia rheumatica. We present the case of a woman with MDS (karyotype 46,XX,+1,der(1;7)(q10;p10)[20], that evolved with an additional trisomy 8 clone) and a novel spectrum of autoimmune diseases including acute fibrinous and organizing pneumonia (AFOP) and lacrimal gland pseudotumor. PMID- 22937308 TI - Hemorrhagic Cystitis due to BK Reactivation in a Young Female Treated for Hodgkin Disease. AB - Hodgkin's lymphoma is a disease with a high rate of curability under classic chemo-radiotherapy regimes. Complications due to chemotherapy could include viral reactivation due to chronic lymphopenia. BK virus (BKV) is a polyoma virus belonging to the Papovaviridae family with antibody seroprevalences in healthy populations varying from 60% to 80%. Initial infections are asymptomatic usually occur in early childhood, after which the viruses remain latent in the kidneys or urothelium. Reactivation of BKV occurs in individuals with severe immunosuppression during HIV infections, transplantation or, exceptionally, after classical chemotherapy. BKV incidence is approximately 0% to 5% in immunocompetent individuals. Reactivation is associated with nephropathy and haemorrhagic cystitis. Herein, we present a case of a haemorrhagic cystitis due to BKV reactivation in a patient with Hodgkin's disease treated with chemotherapy. PMID- 22937309 TI - Lenalidomide-Associated ITP. AB - Lenalidomide is a potent immunomodulatory agent being used increasingly for treatment of hematologic malignancies including multiple myeloma and myelodysplasia. The common toxicities of lenalidomide, including dose-limiting myelosuppression, are well described. However, the immunomodulatory properties of lenalidomide may give rise to unexpected autoimmune complications. Herein, we describe a case of immune thrombocytopenic purpura (ITP) associated with use of lenalidomide. PMID- 22937310 TI - CML Developing Three Years after Therapy Completion in a Child with Ph(-) Pre-B ALL. AB - We report a girl with a history of Ph(-) pre-B-ALL and three years of disease free survival admitting to our hospital for regular end of treatment checkup with an increased white blood cell count which in follow-up studies and molecular detection of BCR-ABL (p210) fusions gene had been diagnosed as a Ph(+) typical CML. The upcoming question in this case scenario is whether developed CML is a secondary leukemia due to previous ALL chemotherapy or just a relapse case of primary leukemia. PMID- 22937311 TI - Granulocytic Sarcoma by AML M4eo (inv16) after Allogeneic Stem Cell Transplantation without Bone Marrow Involvement. AB - Granulocytic sarcoma (GS) represents a rare type of extramedullar manifestation from the acute myeloid leukaemia (AML). We report the case of a patient with recurrences of AML M4eo leukaemia in the uterus and the small intestine at 3 and 5 years, respectively, after matched related peripheral blood stem cell transplantation (PBSCT). The patient underwent the withdrawal of immunosuppression, hysterectomy, and local irradiation at first relapse, as well as systemic chemotherapy and donor lymphocyte infusions at second recurrence, inducing a second and third complete remission, respectively. At year six after transplantation, the patient experienced disease progression by meningeosis leukaemia to which she succumbed despite intrathecal chemotherapy. Following allogeneic stem cell transplantation, awareness for atypical manifestations of granulocytic sarcoma appears prudent, the cellular immunotherapy should aim at immunological disease control. PMID- 22937312 TI - Treatment of Aggressive NK-Cell Leukemia: A Case Report and Review of the Literature. AB - Aggressive NK-cell leukemia is a rare malignancy with neoplastic proliferation of natural killer cells. It often presents with constitutional symptoms, a rapid declining clinical course, and a poor prognosis with a median survival of a few months. The disease is usually resistant to cytotoxic agents, and no treatment has emerged as the standard of care for these patients. We report a case of an 18 year-old male who obtains complete remission following two lines of combination chemotherapy. We describe in details our regimens for induction chemotherapy and perform a review of existing literature concerning treatment of aggressive NK cell leukemia. PMID- 22937313 TI - Keratitis-Ichthyosis-Deafness Syndrome, Atypical Connexin GJB2 Gene Mutation, and Peripheral T-Cell Lymphoma: More Than a Random Association? AB - Keratitis-ichthyosis-deafness (KID) syndrome is a rare congenital disorder characterized by skin lesions, neurosensorial hypoacusia, and keratitis, usually due to the c.148G -> A mutation involving the connexin 26 gene. We report on a KID patient who showed the atypical c.101T -> C mutation and developed a T-cell lymphoma so far never described in this group of patients. PMID- 22937314 TI - Secondary Leukemia in a non-Hodgkin's Lymphoma Patient Presenting as Myeloid Sarcoma of the Breast. AB - As defined by the World Health Organization classification of tumors of hematopoietic and lymphoid tissue, myeloid sarcoma (MS) is a tumor mass of myeloblasts or immature myeloid cells that can arise before, concurrent with, or following acute myeloid leukaemia. We describe a case of secondary leukemia presenting itself as MS of the breast in a patient previously treated for a non Hodgkin's Lymphoma. PMID- 22937315 TI - An unusual cause of anaemia of chronic disease: lisinopril-induced chronic inflammatory state. AB - We report the case of a patient with severe systemic symptoms (weight loss, malaise, and anorexia), eosinophilic oesophagitis, and raised inflammatory markers coinciding with the use of lisinopril. The onset of symptoms occurred after the administration of lisinopril and resolved shortly after cessation of the medication. Despite thorough investigation, no other cause of the systemic inflammation and anaemia of chronic disease was found. "Drug rash with eosinophilia and systemic symptoms" (DRESSs) syndrome describes a potentially serious multiorgan inflammatory response to certain classes of drugs; this includes the use of ACE inhibitors. Although this patient did not meet strict criteria for DRESSs, the subacute inflammatory syndrome with eosinophilic organ infiltration bears similar features. ACE inhibitors should be considered in the differential diagnosis in patients with nonspecific systemic inflammation and anaemia of chronic disease where no other cause is found. PMID- 22937316 TI - Erdheim-chester disease associated with marginal zone lymphoma and monoclonal proteinemia. AB - Erdheim-Chester disease (ECD) is a rare non-Langerhans cell histiocytosis. We report a fatal case of ECD with extensive cardiac involvement associated with a marginal zone lymphoma and monoclonal proteinemia in a young man. This is the first reported association of ECD with a monoclonal gammopathy or a lymphoma. PMID- 22937317 TI - Response of paroxysmal nocturnal hemoglobinuria clone with aplastic anemia to rituximab. AB - Paroxysmal nocturnal hemoglobinuria is caused by expansion of a hematopoietic stem cell clone with an acquired somatic mutation in the PIG-A gene. This mutation aborts the synthesis and expression of the glycosylphosphatidylinositol anchor proteins CD55 and CD59 on the surface of blood cells, thereby making them more susceptible to complement-mediated damage. A spectrum of disorders occurs in PNH ranging from hemolytic anemia and thrombosis to myelodysplasia, aplastic anemia and, myeloid leukemias. Aplastic anemia is one of the most serious and life-threatening complications of PNH, and a PNH clone is found in almost a third of the cases of aplastic anemia. While allogeneic bone marrow transplantation and T cell immune suppression are effective treatments for aplastic anemia in PNH, these therapies have significant limitations. We report here the first case, to our knowledge, of PNH associated with aplastic anemia treated with the anti-CD20 monoclonal antibody rituximab, which was associated with a significant reduction in the size of the PNH clone and recovery of hematopoiesis. We suggest that this less toxic therapy may have a significant role to play in treatment of PNH associated with aplastic anemia. PMID- 22937318 TI - Myelodysplastic Syndrome with t(1;7) Associated with Marked Dysmegakarypoiesis & Severe Thrombocytopenia: A Case Report and Review of the Literature. AB - We present the case of a 70-year-old woman who had a bone marrow examination performed to investigate marked thrombocytopenia in the context of a recent history of metastatic glucagonoma. Surprisingly this identified marked dysmegakaryopoiesis and fulfilled diagnostic criteria for refractory cytopenia with multilineage dysplasia, with a relatively uncommon associated cytogenetic lesion t(1;7). We present the case and review the literature of this cytogenetic lesion. PMID- 22937319 TI - Granulocytic sarcoma of the male breast in acute myeloblastic leukemia with concurrent deletion of 5q and trisomy 8. AB - We describe a unique case of Granulocytic Sarcoma (GS) in a male, who presented to us with a painless right breast mass without any prior history of Leukemia. GS is an extramedullary tumor of myeloproliferative precursors and may involve multiple sites of the body, but involvement of male breast is extremely rare. In the absence of clinical history or hematological abnormality, GS may be misdiagnosed, depending on the degree of myeloid differentiation present within the tumor. Often it is misdiagnosed as lymphoma. Diagnosis is made by finding eosinophilic myelocytes, myeloperoxidase, chloroacetate esterase staining, and lysozyme immunostain. Chemotherapy regimens similar to acute myeloid leukemia are recommended to treat GS. Recognition of this rare entity is important because early, aggressive chemotherapy can induce regression of the tumor and improve patient longevity. PMID- 22937320 TI - Multiple myeloma of the thyroid cartilage. AB - A 60-year-old male presented with hoarseness. His past medical history was remarkable for a plasmacytoma of the left maxillary sinus having been resected without systemic evidence of plasma cell myeloma (PCM), also known as multiple myeloma (MM), at the time. This maxillary sinus disease recurred and was treated with radiation. Workup for PCM was conducted. Treatment included melphalan and autologous stem cell transplant. Because of the therapeutic and prognostic implications, a Plasma cell neoplasm (PCN) in a neck mass must be carefully evaluated by clinical and pathological criteria in order to distinguish plasmacytoma from PCM. PCN involvement of the thyroid cartilage is very rare, with only 5 previously reported cases. PMID- 22937321 TI - Myelodysplastic syndrome with myelofibrosis transformed to a precursor B-cell acute lymphoblastic leukemia: a case report with review of the literature. AB - Myelodysplastic syndromes (MDS) comprise a group of heterogeneous clonal hematopoietic cell disorders characterized by cytopenias, bone marrow hypercellularity, and increased risk of transformation to acute leukemias. MDS usually transformed to acute myeloid leukemia, and transformation to acute lymphoblastic leukemia (ALL) is rare. Herein, we report a unique patient who presented with MDS with myelofibrosis. Two months after the initial diagnosis, she progressed to a precursor B-cell acute lymphoblastic leukemia. She was treated with induction therapy followed by allogenic stem cell transplantation. She was alive and doing well upon last followup. We have also reviewed the literature and discussed the clinicopathologic features of 36 MDS patients who progressed to ALL reported in the literature. PMID- 22937322 TI - Heparin-induced thrombocytopenia associated with massive intracardiac thrombosis: a case report. AB - A 60-years old patient was admitted to a community hospital with septic arthritis. He was treated with antibiotics and subcutaneous unfractionated heparin (UH) was used for venous thromboprophylaxis. After three days, he developed leg deep venous thrombosis and was treated with IV heparin. One day later, the patient developed pulmonary emboli, which was found using ventilation/perfusion scan. He was transferred to the University Hospital for further management. Upon arrival, antibiotic and intravenous UH were continued. Trans-Esophageal Echocardiogram showed a thrombus in the right atrium, a small portion of which extended to the left atrium through a patent foramen ovale. Another large thrombus was noted in the right ventricle, which extended to the pulmonary artery. Review of the patient's medical records revealed a halving of his platelet count three days following the heparin administration. Therefore, HIT seemed very likely. Intravenous UH was stopped and an emergency thrombectomy was performed. ELISA testing of HIT antibodies came negative. This made HIT diagnosis unlikely and the patient received dalteparin. A week later, as the platelet count declined again, HIT antibodies' testing using ELISA and C-14 serotonin release was repeated, and both assays were positive. Argatroban was restarted and the platelet count normalized. PMID- 22937323 TI - G-CSF-Associated Bone Marrow Necrosis in AML after Induction Chemotherapy. AB - Bone marrow necrosis (BMN) is defined as necrosis of the myeloid tissues and stroma without involvement of the cortical bone. We report a case of 66-year-old male with AML-M4 (FAB classification) who was given induction chemotherapy with cytarabine and daunorubicin. Filgrastim at 480 micrograms was administered on days 15-19 to shorten the duration of neutropenia. Consequently patient developed severe pelvic bone pain, leukoerythroblastosis, and severe leukocytosis. Repeat bone marrow aspiration and biopsy on day 21 confirmed bone marrow necrosis. These manifestations responded quickly to discontinuation of filgrastim. Subsequently, he recovered full myelopoiesis. We suggest that there may be more cases of BMN associated with G-CSF that are undiagnosed. PMID- 22937324 TI - Myelofibrosis associated with romiplostim treatment in a patient with immune thrombocytopenia. AB - Immune thrombocytopenia is characterized by antibody-mediated platelet destruction and insufficient platelet production resulting in isolated thrombocytopenia in the absence of underlying cause. Despite many treatment options, low-to-intermediate rates of remission and high rates of resistance to treatment are seen. Approximately 20% of patients do not attain a hemostatic platelet count after splenectomy or after first- and second-line medical approaches. A new option in these cases is treatment with romiplostim. Bone marrow (BM) fibrosis has been reported in clinical trials with romiplostim. We report a case with marked reticulin fibrosis of the BM, worsening of cytopenias and dyserythropoiesis, and atypical megakaryocytes, which did not reverse following cessation of the drug. Although this could represent idiopathic myelofibrosis, unrelated to therapy, the pretreatment biopsy demonstrating no fibrosis combined with the concordant timing of the drug and fibrosis suggests the treatment with romiplostim may be causative. PMID- 22937325 TI - Posaconazole-vincristine coadministration triggers seizure in a young female adult: a case report. AB - Coadministration of azoles and vincristine has been shown to increase vincristine neurotoxic effects due to the inhibition of cytochrome P450 (CYP) isoform 3A4, for which vincristine is a substrate. Despite the absence of any casual relationship between seizure and coadministration of azoles, few case reports of vincristine-induced seizure have been documented after coadministration of fluconazole or posaconazole in children. In this paper we are reporting the first young female adult who experienced generalized seizure after coadministration of posaconazole and vincristine. The 19-year-old female was diagnosed with acute lymphoblastic leukemia. She started induction phase of Berlin Frankfurt Muenster protocol along with posaconazole 200 mg three times daily as prophylactic antifungal therapy. Five days after the third vincristine dose, she developed generalized seizure accompanied by high blood pressure and SIADH. Her neurological exam/CT scan did not show any abnormality. In conclusion, this study reports a novel finding in the sense that all previous case reports pertaining to posaconazole-vincristine-induced seizure in literature involved children. Physicians should be made aware of this rare possible outcome to closely monitor their patients and take appropriate measures to prevent such possible adverse effect. PMID- 22937326 TI - Treatment of chronic myelomonocytic leukemia with 5-azacytidine: case reports. AB - Epigenetic therapy with hypomethylating agent (5-azacytidine; AZA) is common in the management of specific subtypes of myelodysplastic syndrome (MDS), but there are only few studies in chronic myelomonocytic leukemia (CMML) patients. In this paper our experience with 3 CMML patients treated with AZA is described. In one patient transfusion independency was observed after 4 treatment cycles; in one case a partial response was recorded, but a progression to acute myeloid leukemia (AML) after 13 AZA cycles has appeared. In one patient, AZA in reduced dosage was administered as a bridging treatment before allogeneic stem cell transplantation (ASCT), but in the control bone marrow aspirate (before ASCT) a progression to AML was recorded. Future studies are mandatory for evaluation of new molecular and clinical features which could predict the efficiency of hypomethylating agents in CMML therapy with respect to overall survival, event-free survival, quality-adjusted life year, and pharmacoeconomy. PMID- 22937327 TI - Successful treatment of fanconi anemia and T-cell acute lymphoblastic leukemia. AB - Fanconi anemia is associated with an increased risk of malignancy. Patients are sensitive to the toxic effects of chemotherapy. We report the case of a patient with Fanconi anemia who developed T-cell acute lymphoblastic leukemia. He experienced chemotherapy-related complications including prolonged neutropenia, grade IV vincristine neuropathy, and disseminated aspergillosis. He was successfully treated with modified dosing of cytarabine and intrathecal methotrexate followed by allogeneic bone marrow transplant. The aspergillosis was treated with systemic antifungal treatment and surgical resection. Now 30 months after bone marrow transplant the patient is without evidence of aspergillosis or leukemia. PMID- 22937328 TI - Cytogenetics findings in a histiocytic sarcoma case. AB - Histiocytic sarcoma (HS) is a neoplasm derived from histiocytes. Its diagnosis was not clear until its immunohistochemistry profile was correctly established. Not much is known about its genetic properties. We report a case of a 48-year-old male patient whose bone marrow was almost completely occupied by monomorphic medium size neoplastic cellularity. Its immunohistochemical profile was CD68(+), CD4(+), CD45(+) with negativity of other dendritic cells, and other lineage markers. Cytogenetic study showed 4 related clones: one with trisomy 8 and extra material on the short arms of chromosome 4; a second line with tetrasomy of chromosome 8, add(4)(p16); the third clone had the same alterations as the previous and deletion of chromosome 3 at q11; the fourth line had tetrasomy 8 and translocation t(3;5)(q25;q35). To our knowledge this is the first HS case showing chromosome 8 trisomy and tetrasomy and the other described alterations. PMID- 22937329 TI - Chronic Myeloid Leukemia with e19a2 BCR-ABL1 Transcripts and Marked Thrombocytosis: The Role of Molecular Monitoring. AB - While most patients with chronic myeloid leukemia (CML) express either e13a2 or e14a2 BCR-ABL1 transcripts, a significant minority expresses variant transcripts, of which e19a2 is the most common. Although considered to have a relatively favourable outcome, reported responses to tyrosine kinase inhibitor (TKI) therapy are variable with molecular monitoring in CML patients with e19a2 BCR-ABL1 transcripts rarely reported. A case of e19a2 BCR-ABL1 CML with marked thrombocytosis is described in which the value of molecular monitoring is emphasised during treatment interruptions, dose reductions, and changes. This case serves to demonstrate the requirement for prospective real-time quantitative PCR (RQ-PCR) assays for patients with variant BCR-ABL1 transcript types and standardisation of such assays to enable modern patient management. PMID- 22937330 TI - Successful Treatment of Posttransplant EBV-Associated Lymphoma and Plasmacytoma Solely Localized to the CNS. AB - Two patients with diabetic nephropathy were diagnosed with primary central nervous system posttransplant Epstein-Barr-virus-associated lymphoproliferative disorder (PTLD) 3 years after renal transplantation. The histological diagnoses of the isolated brain tumors were diffuse large B-cell lymphoma and plasmacytoma. Considerable co-morbidity precluded intensive chemotherapy. The first patient with lymphoid CD20+ PTLD had a partial resection of her tumor performed. She was treated with 4 weekly doses of rituximab, ganciclovir and prednisolone; the posttransplant immune suppression (tacrolimus) was reduced. After 4 weeks of treatment a magnetic resonance imaging (MRI) demonstrated complete regression of the CNS lesion. The patient continues to receive rituximab (every second month), valgangciclovir and low-dose prednisolone. Twenty-two months after initiation of therapy, she is still in complete remission. The second patient was only treated with craniospinal irradiation involving the medulla to the second cervical vertebra and valgangciclovir. Moreover, the posttransplant immune suppression was reduced. A new MRI two months after initiation of therapy showed a complete regression of the lesions in the CNS; this was again demonstrated by a MRI after 19 months. These 2 cases illustrate interesting alternative treatments of PTLD. To our knowledge, an EBV-associated PTLD of plasmacytic origin isolated to the CNS has never been described before. PMID- 22937331 TI - Inflammatory pseudotumor of the head presenting with hemiparesis and aphasia. AB - Inflammatory pseudotumor most commonly occurs in the orbit and produces orbital pseudotumor, but extension into brain parenchyma is uncommon. We report a case of inflammatory pseudotumor involving sphenoid sinus, cavernous sinus, superior orbital fissure, orbital muscle, and intracranial extension into left temporal lobe producing right hemiparesis and wernicke's aphasia. The patient improved clinically and radiologically with steroid administration. This paper provides an insight into the spectrum of involvement of inflammatory pseudotumor and the importance of early diagnosis of the benign condition. PMID- 22937332 TI - Neuropsychiatric Outcome of an Adolescent Who Received Deep Brain Stimulation for Tourette's Syndrome. AB - This case study followed one adolescent patient who underwent bilateral deep brain stimulation of the centromedian parafascicular complex (CM-Pf) for debilitating, treatment refractory Tourette's syndrome for a period of 1.5 years. Neurocognitive testing showed no significant changes between baseline and follow up assessments. Psychiatric assessment revealed positive outcomes in overall adaptive functioning and reduction in psychotropic medication load in this patient. Furthermore, despite significant baseline psychiatric comorbidity, this patient reported no suicidal ideation following electrode implantation. Deep brain stimulation is increasingly being used in children and adolescents. This case reports on the positive neurologic and neuropsychiatric outcome of an adolescent male with bilateral CM-Pf stimulation. PMID- 22937333 TI - Sporadic hemiplegic migraine with seizures and transient MRI abnormalities. AB - Hemiplegic migraines are characterised by attacks of migraine with aura accompanied by transient motor weakness. There are both familial and sporadic subtypes, which are now recognised as separate entities by the International Classification of Headache Disorders, edition II (ICHD-II). Sporadic hemiplegic migraine is a rare variant of migraine, We report a case of sporadic hemiplegic migraine and seizures with MRI features suggestive of cortical hyper intensity and edema on T2 and FLAIR images with no restriction pattern on diffusion and these changes completely resolving over time, suggesting that these changes are due prolonged neuronal depolarization and not of ischemic origin. PMID- 22937334 TI - A case of worsening deep cerebral venous sinus thrombosis managed by intrasinus thrombolysis. AB - Cerebral venous sinus thrombosis (CVST) is an uncommon condition with severe consequences. Although we do not know the exact incidence and prevalence of CVST, it is an important diagnosis. Over the past decade, it has been diagnosed more frequently due to greater awareness and availability of noninvasive diagnostic techniques. Furthermore, routine diagnostic neuroimaging has been used to monitor the clinical progress of these patients, especially in deteriorating cases. In order to decrease morbidity and mortality, an understanding of CVST treatment options is important. Treatment of extensive intracranial venous sinus thrombosis with intrasinus infusion of recombinant tissue plasminogen activator (rt-PA) is relatively controversial as there are no clear guidelines in regards to appropriate therapeutic management. We report a case of successful intrasinus thrombolysis of deep cerebral sinus thrombosis (DCST) resulting in rapid radiographic improvement associated with complete clinical recovery. PMID- 22937335 TI - Moya moya disease in a child: a case report. AB - We report a case of 8-year-old female child who was admitted at our hospital with complaints of transient ischemic attacks and left-sided hemiparesis. On MR angiography, the child was diagnosed to have Moya Moya disease. Moya Moya disease is a rare cause of cerebral stroke in children. The patient was treated conservatively and referred to a higher centre for specific neurosurgery. Neurosurgical revascularization process leads to favourable outcome. PMID- 22937336 TI - Meningioangiomatosis: a case report and literature review emphasizing diverse appearance on different imaging modalities. AB - Purpose. Meningioangiomatosis (MA) is a rare, benign lesion that commonly mimics other intracranial malformations in clinical presentation and appearance on imaging. The case presented and the literature review performed highlight the importance of combining MRI and CT results to better characterize intracranial lesions and including MA on the list of differential diagnoses of patients presenting with seizures. Methods. The case described is of a 19-year-old male with a 10-year history of worsening seizures refractory to multiple drug regimens. MRI revealed an atypical vascular malformation. The patient underwent surgical resection of the epileptogenic cortex. Results. Although the radiologic impression of the lesion was a vascular malformation, pathological examination revealed MA. A literature search performed highlights the variability of the appearance of MA on CT and MRI and suggests the utility of the T2 GRE sequence in illustrating the presence of calcification and, in a lesion with other characteristic features, the diagnosis of MA. Conclusion. MA can be a difficult diagnosis to make based on imaging findings alone. However, in a patient with a characteristic history and presentation, the presence of a calcified mass on CT and MRI brain susceptibility artifact on a T2 GRE sequence may suggest MA. PMID- 22937337 TI - Dopamine neurons in the ventral tegmental area: an autopsy case of disorganized type of schizophrenia. AB - The mesolimbic dopamine (DA) system has been associated with the pathogenesis of schizophrenia. Here, we examined DA-containing neuronal structures of the ventral tegmental area (VTA) of an autopsy case of disorganized type of schizophrenia (75 year-old female), using tyrosine hydroxylase (TH) immunohistochemistry. A free floating method using 50-MUm cryostat sections and three-dimensional imaging analyzer AxioVision were applied to observe the wide range structures of TH immunoreactive (-ir) neurons. TH-ir neuronal cell bodies in the VTA of the present case had irregular shape and various size, and TH-ir neuronal processes had irregular thickness and straightened shape or curved shape having many corners, when compared to a control autopsy case with no detectable neurological and psychiatric diseases (64-year-old male). The mechanisms underlying the morphological characteristics of DA neurons of the brains with schizophrenia should be elucidated epigenetically as well as genetically. PMID- 22937338 TI - Intracranial hemorrhage revealing pseudohypoparathyroidism as a cause of fahr syndrome. AB - Pseudohypoparathyroidism is an infrequently encountered disease. It is one of the causes of Fahr syndrome which also is a rare clinical entity caused by multiple diseases. A 4-year-old man hospitalized for sudden onset left hemiparesis and hypertension was diagnosed to have right thalamic and midbrain hemorrhage on plain CT scan of the head which also revealed co-existent extensive intracranial calcifications involving the basal ganglia and cerebellum bilaterally. General physical examination revealed features of Albright hereditary osteodystrophy, goitre, hypertension, left hemiparesis, and signs of cerebellar dysfunction. Laboratory findings suggested hypocalcemia, hyperphosphatemia along with high TSH, low FT(4), low FT(3), and high anti-TPO antibody. Though bilateral intracranial calcifications are usually encountered as an incidental radiological finding in the CT scan of brain, in this case, the patient admitted for thalamic and midbrain hemorrhage was on investigation for associated intracranial calcification, and goitre was also found to have coexisting pseudohypoparathyroidism and autoimmune hypothyroidism. PMID- 22937339 TI - A middle-aged woman with logopenic progressive aphasia as a precursor of Alzheimer's disease: case report and review of the literature. AB - PRIMARY PROGRESSIVE APHASIA IS A NEURODEGENERATIVE DISORDER THAT WAS RECENTLY CLASSIFIED INTO THREE TYPES: fluent (semantic), nonfluent, and logopenic. The logopenic variant is the least common one and is closely related to Alzheimer's disease in comparison to the other two variants that are closely related to frontotemporal dementia. We report the case of a middle-aged woman who presented to our center with progressive aphasia that was undiagnosed for two years. The patient's neurological evaluation including positron emission tomography is consistent with a logopenic variant of primary progressive aphasia. PMID- 22937340 TI - An unusual cause of pseudomedian nerve palsy. AB - We describe a patient who presented with an acute paresis of her distal right hand suggesting a peripheral median nerve lesion. However, on clinical examination a peripheral origin could not be verified, prompting further investigation. Diffusion-weighted magnetic resonance imaging revealed an acute ischaemic lesion in the hand knob area of the motor cortex. Isolated hand palsy in association with cerebral infarction has been reported occasionally. However, previously reported cases presented predominantly as ulnar or radial palsy. In this case report, we present a rather rare finding of an acute cerebral infarction mimicking median never palsy. PMID- 22937341 TI - Isolated central nervous system vasculitis associated with antiribonuclear protein antibody. AB - We describe the case of a young woman who was referred to a tertiary care center with unexplained subacute progressive encephalopathy preceded by long-standing severe headaches. Her extensive workup was remarkable for abnormal intracranial angiography suggestive of small- and medium-vessel vasculitis, persistently elevated protein in the cerebrospinal fluid and persistently high titers of antiribonuclear protein antibody. The patient showed a modest response to intravenous high-dose steroids. We propose that the patient's neurologic disease is secondary to immune-mediated central nervous system vasculitis, possibly as an initial manifestation of mixed connective tissue disease. PMID- 22937342 TI - CNS intravascular lymphoma: a case report. AB - Intravascular lymphoma is a rare but well-described entity. The clinical manifestations are heterogeneous. We report a case of a 59-year-old woman who presented initially with syncope followed by subacute cognitive decline that progressed to minimally conscious state. Shortly after the transfer to our tertiary center the patient died. Brain autopsy disclosed the diagnosis of B-cell intravascular lymphoma. We speculate that syncope could be the first manifestation of central nervous system intravascular lymphoma and should be considered in the differential diagnosis of unexplained syncope. In addition, we stress the importance of early brain biopsy in unexplained white matter disease. PMID- 22937343 TI - Malignant transformation six months after removal of intracranial epidermoid cyst: a case report. AB - Intracranial epidermoid cysts are uncommon benign tumors of developmental origin; malignant transformation of benign epidermoid cysts is rare, and their prognosis remains poor. We report a case of squamous cell carcinoma arising in the cerebellopontine angle. A 52-year-old man presented with left facial paralysis and cerebellar ataxia. He had undergone total removal of a benign epidermoid cyst six months previously. Postoperative magnetic resonance imaging of the brain revealed a heterogeneous and cystic lesion in the left cerebellopontine angle with hydrocephalus. The cyst wall was enhanced by gadolinium. He underwent ventricle-peritoneal shunt and removal again; the histopathological examination revealed a squamous cell carcinoma possibly arising from an underlying epidermoid cyst. This entity is being reported for its rarity. The presence of contrast enhancement at the site of an epidermoid cyst combined with an acute, progressive neurological deficit should alert the neurosurgeon to the possibility of a malignant transformation. PMID- 22937344 TI - Multiple dural tuberculomas presenting as leptomeningeal carcinomatosis. AB - Objective and Importance. We present the rare occurrence of multiple dural-based tuberculomas mimicking leptomeningeal carcinomatosis in a young immunocompetent patient. Clinical Presentation. A 36-year-old man presented with a 2-month history of generalized epileptic activity and altered perception. Neurological examination was remarkable for bilateral Babinski's sign. Cranial magnetic resonance imaging (MRI) revealed multiple dural-based enhancing lesions with cerebral edema. Intervention. A right frontal craniotomy was performed for diagnosis. Histological examination revealed multiple confluent necrotizing and nonnecrotizing granulomas with giant cells which was consistent with tuberculosis (TB), and the patient was placed on anti-TB therapy for 24 months. Conclusion. To the best of our knowledge isolated diffuse involvement of the dura mater by TB, mimicking leptomeningeal carcinomatosis, as the sole manifestation of disease has not been reported before. Since pachymeningeal TB is rarely suspected when atypical radiological appearance is combined with the absence of systemic disease, biopsy is inevitably required for diagnosis. PMID- 22937345 TI - Atypical Parkinsonism Revealing a Late Onset, Rigid and Akinetic Form of Huntington's Disease. AB - Huntington's disease (HD) is a rare hereditary neurodegenerative disorder characterized in over 90 percent of cases by chorea as the presenting motor symptom. We report a 54-year-old male who presented with Parkinsonism as the initial symptom of the disease. Genetic analysis revealed expansion of 40 CAG repeats, and brain MRI showed both severe caudate nuclei and cortical atrophy. Single-photon emission computed tomography (SPECT) imaging of the dopamine transporter showed nigrostriatal pathway degeneration. Here, we also describe his 2 years of clinical followup after ensuing dopaminergic stimulation. PMID- 22937346 TI - Primary Amoebic Meningoencephalitis in an Infant due to Naegleria fowleri. AB - Primary amoebic meningoencephalitis (PAM) caused by free-living amebae Naegleria fowleri is a rare and fatal condition. A fatal case of primary amoebic meningoencephalitis was diagnosed in a 5-month-old infant who presented with the history of decrease breast feeding, fever, vomiting, and abnormal body movements. Trophozoites of Naegleria fowleri were detected in the direct microscopic examination of CSF and infant was put on amphotericin B and ceftazidime. Patient condition deteriorated, and he was discharged against medical advice and subsequently expired. We also reviewed previously reported 8 Indian cases of primary amoebic meningoencephalitis (PAM) and observed that for the last 5 years, none of the patients responded to amphotericin B. Has an era of amphotericin B resistant Naegleria fowleri been emerged? Management strategy of PAM needs to be reviewed further. PMID- 22937347 TI - Suspected "t-cell-mediated" hypereosinophilic syndrome presenting with cerebral watershed infarcts. AB - We describe a case of suspected "T-cell-mediated" hypereosinophilic syndrome presenting with cerebral watershed infarcts. An extensive search for potential embolic sources was negative, supporting the hypothesis that cerebrovascular endothelial dysfunction could have caused the infarcts. PMID- 22937348 TI - Anti-glutamic Acid decarboxylase antibody-associated ataxia as an extrahepatic autoimmune manifestation of hepatitis C infection: a case report. AB - Extrahepatic immunological manifestations of hepatitis C virus (HCV) are well described. In addition, antiglutamic acid decarboxylase (GAD) antibody-associated cerebellar ataxia is well-established entity. However, there have been no reports in the literature of anti-GAD antibody-associated ataxia as an extrahepatic manifestation of HCV infection. We report the case of a young woman with chronic hepatitis C virus and multiple extrahepatic autoimmune diseases including Sjogren syndrome and pernicious anemia who presented with subacute midline cerebellar syndrome and was found to have positive antiglutamic acid decarboxylase (GAD) antibody in the serum and cerebrospinal fluid. An extensive diagnostic workup to rule out neoplastic growths was negative, suggesting the diagnosis of nonparaneoplastic antiglutamic acid decarboxylase antibody-associated cerebellar ataxia as an additional extrahepatic manifestation of hepatitis C virus infection. The patient failed to respond to high-dose steroids and intravenous immunoglobulin. Treatment with the monoclonal antibody rituximab stabilized the disease. We postulate that anti-GAD associated ataxia could be an extrahepatic manifestation of HCV infection. PMID- 22937349 TI - Role of adjuvant radiosurgery after thoracoscopic microsurgical resection of a spinal schwannoma. AB - Stereotactic radiosurgery to benign tumors of the spine has not been advocated as a primary treatment modality because of the favorable prognosis for these lesions after gross-total resection. There is even less evidence regarding its use as an adjuvant to neurosurgical resection of benign recurrent spinal disease. We describe the case of a 30-year-old man with a thoracic spinal schwannoma who had an interval increase of his lesion five months after thoracoscopic microsurgical resection. The patient opted for noninvasive stereotactic radiosurgery in lieu of additional surgical excision and has had stable disease 15 months after radiosurgical treatment with the linear accelerator (LINAC) system. In this setting, stereotactic radiosurgery provided a useful adjunct to thoracoscopic microsurgical resection. Future Class I and II evidence should be sought to evaluate the utility of stereotactic radiosurgery as a primary treatment modality or as an adjuvant for microneurosurgical resection of benign spinal lesions in patients who want noninvasive treatment after disease recurrence or who harbor medical comorbidities that would preclude them from being safe surgical candidates. PMID- 22937350 TI - Trigeminal Neuralgia due to Vertebrobasilar Dolichoectasia. AB - We presented a case of drug-resistant trigeminal neuralgia attributed to vertebrobasilar dolichoectasia, a rare condition characterized by enlargement, tortuosity, or elongation of intracranial arteries. Dolichoectatic vessels can cause dysfunction of cranial nerves through direct vascular compression. The relationships of vertebrobasilar dolichoectasia with the particularities of neurovascular conflict and images findings are discussed. PMID- 22937351 TI - Paroxysmal hypnogenic dyskinesia responsive to doxylamine: a case report. AB - Paroxysmal hypnogenic dyskinesia is a rare clinical entity characterized by intermittent dystonia and choreoathetoid movements that begin exclusively during sleep, often with consciousness preserved once the patient is awakened during the episodes. They occur almost every night and are often misdiagnosed as sleeping disorders. Paroxysmal hypnogenic dyskinesia is currently known to be a form of frontal lobe epilepsy, but not in all cases. We present a 19-year-old male patient with paroxysmal hypnogenic dyskinesia who responded to antihistamines. This supports an alternative theory from 1977 (before the cases had been adequately described) that the disorder lies in dysregulation in the basal ganglia. This description now appears similar to acute dystonic reactions such as extrapyramidal symptoms from antipsychotic medications, which also respond to antihistamines. PMID- 22937352 TI - Acute ischemic stroke secondary to iron deficiency anemia: a case report. AB - A rare case of acute ischemic stroke in a young patient with iron deficiency anemia (IDA) is reported. IDA has been suggested to have an association with stroke, but few cases have proven it thus far. Three physiological mechanisms explaining IDA to ischemic stroke include a hypercoagulable state secondary to IDA, thrombocytosis secondary to IDA, and anemic hypoxia induced by IDA. Our paper shows an example of a hypoxia-induced stroke secondary to IDA in a young woman with menorrhagia. Thrombus formation was ruled out as the Magnetic Resonance Angiogram (MRA) showed no evidence. As all other known causes for stroke were ruled out, the patient's IDA is a reasonable cause for her stroke. Iron deficiency decreases the amount of hemoglobin, which consequently decreases the amount of oxygen in the blood resulting in low-oxygen delivery to the brain. This causes hypoxic conditions in the brain, leading to death of brain tissue. Thus, we suggest a possible relationship between IDA and ischemic stroke in young adults. Considering IDA as one of the risk factors for ischemic stroke and treating with timely transfusions would be an important step one can take to prevent stroke. PMID- 22937353 TI - Cerebral edema associated with ventricular reservoirs in two patients: a case report. AB - Placement of ventricular reservoirs is a common practice to treat various tumors of the central nervous system (CNS). Ventricular catheter-reservoir-associated edema has been noted in the literature, but a thorough review of this literature identified no articles that examine this particular complication in neurooncology patients, specifically. We report two cases of ventricular catheter-reservoir associated edema in patients receiving treatment for CNS metastasis. PMID- 22937354 TI - An unusual case of bilateral agenesis of the cochlear nerves. AB - Imaging of the cochlea and internal auditory canals are increasingly important nowadays because of the growing number of cochlear implants being performed throughout the world. We report a case of a 4-year-old boy who was born deaf and was being evaluated in our service for possible cochlear implantation. Audiometry disclosed profound bilateral deafness. The magnetic resonance imaging revealed only two nerves in each inner auditory canal: one in the anterior superior quadrant, identified as the facial nerve, and one on the posterior quadrants, representing both the superior and inferior vestibular nerves. The semicircular canals were not seen and the vestibule had dysplastic morphology. The diagnosis was bilateral agenesis of the cochlear nerves and semicircular canals. PMID- 22937355 TI - Primary Non-Hodgkin's Lymphoma of the Scalp and Cranial Vault. AB - Primary Non-Hodgkin's Lymphoma of the cranial scalp and skull vault is a rare disease. We are describing a case of the same in a 50-year-old man. He was presented with a diffuse swelling in the left side scalp since 4 months of duration and progressively enlarging in size. On local Examination of the scalp, there was a diffuse swelling in the left parietal and occipital region of scalp. Imaging showed diffuse infiltration of the skull vault with extracranial soft tissue masses. Further investigations with CT scan chest, abdomen, and pelvis did not reveal any other evidence of systemic lymphoma. Biopsy of one of the scalp masses showed a small to intermediate cell B-cell lymphoma. Other nine previously reported cases of primary skull vault lymphoma were reviewed. PMID- 22937356 TI - Intracranial metastatic neuroblastoma treated with gamma knife stereotactic radiosurgery: report of two novel cases. AB - Intracranial metastasis of neuroblastoma (IMN) is associated with poor survival. No curative therapy for the treatment of IMN currently exists. Unfractionated radiotherapy may be beneficial in the treatment of IMN given the known radiosensitivity of neuroblastoma as well as its proclivity to metastasize as discrete lesions. We present two patients with IMN treated with Gamma Knife stereotactic radiosurgery (SRS). Single-fraction radiotherapy yielded temporary reduction of tumor burden and stability of disease in both patients. SRS may be a useful palliative tool in the treatment of IMN and expands the overall treatment options for this disease. PMID- 22937357 TI - Relowering of serum na for osmotic demyelinating syndrome. AB - We report a case in whom slow correction of hyponatremia (5 mmol/day for 3 days) induced central pontine myelinolysis (CPM). After the diagnosis was confirmed by imaging, we started to relower serum Na that completely recovered the sign and symptoms of CPM. Rapid correction of serum sodium is known to be associated with CPM. However, it may occur even after slow correction of hyponatremia. Currently, there is no standard therapy for CPM other than supportive therapy. Other therapy includes sterioid, plasmaphresis and IVIG, but these therapies have not been shown to be particularly effective. The pathophysiology of CPM is related to a relative dehydration of the brain during the correction of hyponatremia, resulting in cell death and demyelination, therefore gentle rehydration with lowering serum sodium may not be an unreasonable therapy. The present case provides supportive evidence that reinduction of hyponatremia is effective in treating CPM if started immediately after the diagnosis is suggested. The present case tells us that severe chronic hyponatremia must be managed with extreme care especially in patients with chronic debilitating illness and that relowering serum Na is a treatment of choice when CPM is suggested. PMID- 22937358 TI - Spinal cord stroke: acute imaging and intervention. AB - Spinal cord infarction is an uncommon disease and as such is often a diagnostic challenge for clinicians. It can vary in its onset, severity, outcome, and recovery from patient to patient. Treatment options for this relatively rare condition also remain elusive. Current consensus recommendations are antiplatelet therapy and the symptomatic management of associated complications such as paraplegia and thromboembolic disease. There are multiple studies in surgical literature of a variety of interventions and adjuncts used for reducing the risk of ischemic spinal cord neurological injury, seen most often in the setting of thoracoabdominal aortic repair operations. We report two cases of acute non surgical-related spinal cord infarcts, where early diagnosis was made and aggressive, early treatments instituted. With often devastating outcomes, we highlight the need for early detection and that interventions, commonly used in preventing neurological injury after high-risk aneurysm repairs, may be beneficial in treating and reducing the severity of disability in acute spinal cord stroke. PMID- 22937359 TI - Isolated cataplexy in the differential diagnosis of drop attacks: a case of successful clinical diagnosis and treatment. AB - Drop attacks are sudden spontaneous falls that are not accompanied by alteration of consciousness and are followed by immediate recovery. Cataplexy, which is usually associated with narcolepsy, is one of the causes of drop attacks. We report a patient with the rare condition of cataplexy without associated narcolepsy (isolated cataplexy). Isolated cataplexy should be included in the differential diagnosis when a patient presents with recurrent drop attacks and normal diagnostic test results. PMID- 22937360 TI - Glioblastoma presenting with steroid-induced pseudoregression of contrast enhancement on magnetic resonance imaging. AB - Corticosteroid-induced reduction in contrast enhancement on radiographic imaging is most commonly associated with lymphoma but has been reported in other entities, including glioma. This finding may represent a diagnostic dilemma. Concern that steroid-induced cytotoxicity obscures histological diagnosis of suspected lymphoma may lead to postponement of a biopsy. If glioma is not considered in the differential diagnosis, reduction in tumor contrast enhancement may be misinterpreted as disease regression rather than a transient radiographic change. We report a case of a patient with an enhancing right temporoparietal mass adjacent to the atrium of the lateral ventricle. After treatment with dexamethasone was started, the mass exhibited marked reduction in contrast enhancement, with symptom improvement. The clinical course suggested lymphoma, and surgery was not performed. Subsequent screening for extra-axial lymphoma was negative. Two weeks later, the patient developed worsening symptoms, and repeat T1-weighted imaging showed interval increase in size and enhancement. The findings suggested a possible diagnosis of malignant glioma. The patient underwent a stereotactic-guided craniotomy for excision of the right temporoparietal mass lesion. Final histological diagnosis was glioblastoma multiforme, World Health Organization grade IV. PMID- 22937361 TI - Granulocytic sarcoma presenting as atypical mastoiditis with facial paralysis: description of a case. AB - We describe a case of temporal granulocytic sarcoma in a 26-year-old patient after apparent molecular remission of an acute myeloid leukaemia. He complained of otodynia with hearing loss and facial paralysis on the right side. He was treated with chemotherapy and self-transplant haematopoietic stem cells. He was cured clinically, molecular remission of the haematological processes was achieved, and he remained asymptomatic for three years. Facial paralysis and hearing loss associated with temporal GS should be treated with chemotherapy. Aggressive surgery may complicate the clinical course of the disease and it should be avoided. PMID- 22937362 TI - Tracheostomal myiasis: a case report and review of the literature. AB - "Myiasis" is considered in Hindu mythology as "God's punishment for sinners." It is known to infest live human or animal tissue. Literature abounds with reports of myiasis affecting the nasal cavity, ear, nonhealing ulcers, exophytic malignant growth, and cutaneous tissue. But report of myiasis of the tracheal stoma is rare. Only a few cases of tracheal myiasis have been reported in literature. We report a case of tracheostomal myiasis in an elderly male. The species which had infested the stoma was identified as Chrysomya bezziana, an obligate parasite. This is to our knowledge the first case report of an obligate parasite (Chrysomya bezziana) infestation of the tracheostoma from India. PMID- 22937363 TI - Uncontrolled epistaxis secondary to traumatic pseudoaneurysm of the maxillary artery. AB - We describe a rare case of traumatic pseudoaneurysm of the maxillary artery following a fall. The patient presented with epistaxis that could not be controlled with anterior and posterior nasal packing. She was urgently taken to the angiography suite for evaluation and ultimately underwent embolization of a left maxillary artery pseudoaneurysm with 500-700 micron Contour PVA followed by coiling with two 3 mm Tornado coils. Bleeding subsided after embolization, and the patient suffered no neurologic sequelae. PMID- 22937364 TI - Nasopharyngeal actinomycosis. AB - Nasopharyngeal actinomycosis is a rarely encountered bacterial infection which usually occurs after nasal trauma or surgery. In some clinical cases, nasopharyngeal actinomycosis has appeared in patients without prior trauma, making diagnosis difficult. Here we present three such cases successfully treated with appropriate dosages of penicillin. One 16-year-old boy with no previous medical antecedents showed an important thickening of the posterior wall of the nasopharynx. A similar nasopharyngeal thickening was found in a 42-year-old woman exhibiting poor dental hygiene. In another 42-year-old woman, nasopharyngeal inflammation was accompanied by multiple right lymphoadenopathies. Like the first two patients, the woman had no prior trauma but did exhibit poor dental hygiene and teeth rottenness. In all three patients, actinomycosis diagnosis was confirmed by anaerobic microbial culturing of the biopsy specimen. Although diagnosis is delayed in patients with no prior trauma, treatment with antibiotics has greatly improved the prognosis for all forms of actinomycosis, and neither death nor deformity is common. PMID- 22937365 TI - Coinfection by Aspergillus and zygomycetes species in a case of acute rhinosinusitis. AB - Invasive mycotic infections can be effectively treated if rapid identification of fungus is obtained. We reported a case of coinfection by Aspergillus and Rhizopus sp. involving nose, paranasal sinuses, orbit, and brain in a 68-year-old known hypertensive male. He was presented to ENT OPD with history of fever and intermittent headache since fifteen days along with history of right-sided nasal obstruction and proptosis since seven days. CT scan of brain and paranasal sinuses showed findings of pansinusitis with cellulitic changes in right orbit. MRI confirmed the same along with features of intracranial extension with focal meningitis in right frontotemporal region. Laboratory parameters did not conclude much except for leucocytosis and hyponatremia. Patient was taken for endoscopic debridement from nose and paranasal sinuses, and tissue was sent for microbiological and histopathological examination. Minced tissue was processed, and after 48 hrs of incubation two types of growth were identified, one was yellowish, granular, and powdery consistent with Aspergillus sp., and another was cottony and woolly consistent with Rhizopus sp. LCB mount confirmed presence of Aspergillus flavus and Rhizopus arrhizus. Patient responded to therapy with IV amphotericin B and surgical debridement. On discharge patient's condition was good. PMID- 22937366 TI - Orbital cellulitis: a rare presentation of metastatic bronchial carcinoma. AB - Objective. We report a rare and unusual case of bronchial carcinoma presenting with symptoms of complications of sinonasal disease. Case Report. A 66-year-old lady was referred with a 1-week history of progressive ocular pain, chemosis, and visual disturbance. Computed tomography of the paranasal sinuses revealed frontal and ethmoidal sinus opacification with orbital involvement consistent with a diagnosis of orbital cellulitis secondary to sinusitis. Surgical exploration revealed that the sinuses and right orbit were filled with soft tissue and subsequent histopathological examination of the biopsies indicating metastases from an adenosquamous bronchial carcinoma. Further imaging revealed a large, asymptomatic, bronchial primary with deposits in the brain and liver. The advanced presentation of the disease limited treatment to best supportive care. Conclusion. Orbital cellulitis and sinonasal malignancies have a similar pattern of clinical presentation, posing a potential diagnostic pitfall. There are only two previously reported cases of metastatic lung carcinoma in the frontal sinus with 15 cases of sinonasal tract involvement reported overall. There are no reported cases of adenosquamous carcinoma in the sinonasal tract. PMID- 22937367 TI - Extramedullary plasmacytoma of the tonsil. AB - Plasma cell tumors are a diverse group of neoplasms characterized by monoclonal proliferation of plasma cells. Extramedullary plasmacytoma (EMP) is a rare form of localized plasma cell tumor that arises most often in the head and neck region. We present an unusual case of EMP of the palatine tonsil from a tertiary care university hospital. We discuss the histopathologic and radiologic evaluation as well as treatment of EMP. PMID- 22937368 TI - Intraosseous cavernous hemangioma of inferior turbinate: a rare case report. AB - Objectives. To investigate hemangiomas in the differential diagnosis of the nasal cavity neoplasms, even though it is an extremely rare mesenchymal tumor of the nasal cavity, and the world literature was reviewed. Case Report. A 57-year-old woman applied to our department with a 5-year history of left-sided nasal obstruction without history of epistaxis, nasal packaging, or facial trauma. Anterior rhinoscopic examination revealed a mass originating from inferior turbinate that completely obstructs the left nasal cavity. Paranasal computed tomography (CT) showed that the bony mass originated from the anterior part of the left inferior turbinate. Surrounding tissues were normal, and there was not any erosion or destruction. Mass was excised by the endoscopic approach. Histological diagnosis was reported as osseous cavernous hemangioma. Conclusion. Hemangiomas are a rare cause of intranasal masses. Its unusual site and masked presentation makes the differential diagnosis difficult. When a bony hard, well shaped mass was seen in the nasal cavity, the possibility of intraosseous hemangioma must be remembered. PMID- 22937370 TI - Squamous cell carcinoma of the external auditory canal: a case report. AB - Squamous cell carcinoma of the temporal bone and external auditory canal is a rare tumor with a reported incidence of between 1 to 6 cases per million population per year. Because squamous cell carcinoma of the temporal bone and auditory canal is so rare, developing an adequate tumor staging system and treatment has been difficult. We present a case of squamous cell carcinoma of the external auditory canal in 65-year-old Hispanic female who presented with a 6 month history of right ear pain, 3-month history of serosanguineous right ear drainage, and symptoms of facial paralysis. Due to the extensive spread of her tumor into the middle ear at the time of diagnosis, her tumor was deemed unresectable and she received palliative chemotherapy and radiation therapy and was sent to Alice Hospice and died several weeks later. PMID- 22937369 TI - Ewing's Sarcoma of the Zygomatic Arch Presenting in a 69-Year Old: An Unusual Case Report. AB - Objective. We report a rare case of Ewing's sarcoma of the zygomatic arch presenting in a 69-year-old patient. Method. Case report and a review of the world literature on Ewing's sarcoma incidence and management. Results. Ewing's sarcoma is a malignant round cell tumour of neuroectodermal origin that typically presents in the pelvis and long bones of children and adolescent boys. This report is the first to document the presentation of ewing's sarcoma of the zygomatic arch in a 69-year-old lady. Our patient underwent surgical excision and radiotherapy and at 4-year followup has no signs of recurrence or metastasis. Conclusion. To our knowledge this is the first case report to document Ewing's sarcoma of this location in a 69-year-old patient. This case report highlights the importance of diagnostic investigations in Ewing's sarcoma and discusses the management issues that this rare presentation raises. PMID- 22937371 TI - Lymphoepithelioma-like carcinoma of the salivary gland: is radiotherapy alone adequate? AB - Introduction. Lymphoepithelioma-like carcinoma (LELC) of the salivary gland is a rare tumor. Currently, surgery with or without radiotherapy is the recommended treatment for all salivary gland carcinomas. However, in contrast to other high grade salivary gland carcinomas, LELCs are considered radiosensitive. There are only a few published reports of radiotherapy alone for the treatment of salivary gland LELC. Case. We present two cases of LELC of the salivary gland. One was treated with surgery and postoperative radiotherapy, and the other was given a single cycle of chemotherapy and then radiotherapy. Currently, both patients have no evidence of disease. Conclusion. Radiotherapy as a single modality should be reevaluated. The role of systemic chemotherapy to gain systemic control should be addressed due to noteworthy metastatic disease. PMID- 22937372 TI - Benign lymphoid hyperplasia of the tongue base causing upper airway obstruction. AB - Severe benign lymphoid hyperplasia (LH) is unusual in the head and neck region, but the diagnosis of LH is of clinical importance as it may be confused with malignant lymphoma, both on clinical examination and pathologically. While the etiology is poorly understood, a number of previous theories exist, which are included here in the context of a literature review. In this paper we present a case of severe pharyngeal lymphoid hyperplasia causing airway obstruction and requiring tracheotomy and subsequent surgical debulking. PMID- 22937373 TI - Skull repair after major crush injury. AB - Reconstructive surgery after trauma of the head and neck is a wide field in ENT surgery. The repair of bony defects often requires implantation of engineered prostheses. We present the case of a 48-year-old male patient who had suffered a major crush injury to his head resulting in a complex bony defect. A computer assisted designed (CAD/CAM) Titanium implant was used for reconstruction. Direct prefabrication of the individually designed implant led to an excellent coverage of the bony defect and easy adaptation to the defect margins. Results. Treatment plan and surgery as well as implant design and manufacturing were performed in a multidisciplinary team. Skin expander implantation prior to reconstructive surgery ensured a tension-free closure. This team approach led to a satisfactory outcome for this patient. This case illustrates the necessity of a multidisciplinary approach for the optimum management of complex head and neck injuries. PMID- 22937374 TI - Giant plexiform schwannoma of the tongue. AB - We present the case of a 38-year-old woman that presented with a very slowly enlarging mass of the tongue. MRI revealed a large mass originating in the tongue base and extending to the supraglottic space. Biopsy of this tumor confirmed the diagnosis of schwannoma. An endaural approach allowed complete resection of the tumor. Definitive histopathological examination showed a plexiform schwannoma. Schwannoma or neurilemoma represents a benign tumor potentially affecting any nerve. The head and neck region is a relatively common location for schwannomas, but tongue schwannomas are considered to be rare and pose the problem of both clinical and histological differential diagnosis of tongue masses. PMID- 22937375 TI - A rare case of radiation-induced osteosarcoma of the ethmoid sinus. AB - Radiation therapy has been recognized as a useful modality of treatment in head and neck malignant tumors. However, radiation over 10 Gy may predispose to secondary tumors. Radiation-induced osteosarcoma of the ethmoid sinus is unusual. These tumors may present long after radiation with epistaxis. Computed tomography, magnetic resonance imaging, and biopsy are the modalities of diagnosis. We report a case of radiation-induced osteosarcoma of the ethmoid sinus 9 years after initial exposure. We describe the clinical presentation, the radiological findings, and the management. PMID- 22937376 TI - The fourth branchial complex anomaly: a rare clinical entity. AB - Fourth branchial pouch anomalies are rare congenital disorders of the neck and are a consequence of abnormal development of the branchial apparatus during embryogenesis. Failure to appropriately recognize these anomalies may result in misdiagnosis, insufficient treatment, and continued recurrence. Here, we present an unique presentation of two cases, describe their diagnosis, clinical course, and management, and review the literature regarding these interesting anomalies. PMID- 22937377 TI - Solitary neurofibroma of the floor of the mouth: a case report. AB - We present a case of a solitary neurofibroma of the floor of the mouth protruding into the submandibular region. A 51-year-old female presented with a 2-year history of swelling of the floor of the mouth. MRI revealed that the mass measuring 50 * 70 mm showed a homogenous, low signal intensity on a T1-weighted image and high signal intensity on a T2-weighted image. The tumor was completely removed through a cervical approach. Cases of a solitary neurofibroma originating from the floor of the mouth are extremely rare. PMID- 22937378 TI - Odontogenic keratocyst looks can be deceptive, causing endodontic misdiagnosis. AB - Odontogenic keratocyst (OKC) is the cyst arising from the cell rests of dental lamina. It can occur anywhere in the jaw, but commonly seen in the posterior part of the mandible. Radiographically, most OKCs are unilocular when presented at the periapex and can be mistaken for radicular or lateral periodontal cyst. When the cyst is multilocular and located at the molar ramus area, it may be confused to ameloblastoma. Lots of cases have been reported in the literature where OKC is associated with the nonvital tooth. So trauma could be one of the reasons in inducing this cyst. In our case, it was in the anterior region at the periapex of nonvital tooth having traumatic occlusion. Hence, the diagnosis of radicular cyst was made and endodontic treatment was done. PMID- 22937379 TI - A Rare Clinical Presentation of Intraoral Darier's Disease. AB - Darier's disease, also known as keratosis follicularis or dyskeratosis follicularis, is a rare disorder of keratinization. It is an autosomal dominant genodermatosis with high penetrance and variable expressivity. Its manifestation appears as hyperkeratotic papules primarily affecting seborrheic areas on the head, neck, thorax, and less frequently the oral mucosa. When oral manifestations are present, the palatal and alveolar mucosae are primarily affected. They usually asymptomatic and are discovered in routine dental examination. Histologically, the lesions present as suprabasal clefts in the epithelium with acantholytic and dyskeratotic cells represented by "corps ronds and grains." This paper reports a case of an adult male patient who presented with painful whitish lesions on buccal mucosa with crusty lips as the only clinical sign of Darier's disease. As this patient did not have skin lesions or family history, an intraoral biopsy confirmed the diagnosis of Darier's disease by a multidisciplinary team. PMID- 22937380 TI - Primary sarcoma of the specialised prostatic stroma: a case report and review of the literature. AB - Primary sarcoma tumours of the prostate are rare and are classified, according to their histology, as stromal tumours of uncertain malignant potential (STUMP) and stromal prostatic sarcoma (PS; low and high grade). We describe a case of a 71 year-old man that developed progressive urinary obstruction symptoms and was subjected to a transurethral prostatic resection (TURP). Histologically, there is a diffuse proliferation of epithelioid and spindle cells that showed rare atypical mitotic figures. Immunohistochemically, the neoplastic cells express diffusely CD34 and focally progesterone whereas no immunoreactivity was seen for cytocheratin, desmin, S-100, Bcl-2, chromogranin, CD117, and actin smooth muscle. A final diagnosis of low-grade prostatic stromal sarcoma (LG-PS) was made. This is a really rare neoplasm; in the literature, in fact, to our knowledge, only 6 cases are described and all of these were alive and free of disease at followup. Our patient too is free of disease at 15 months from the diagnosis. PMID- 22937381 TI - Xanthogranulomatous osteomyelitis presenting as swelling in right tibia. AB - Xanthogranulomatous osteomyelitis is a very rare form of chronic osteomyelitis which presents like a bone tumor. Three cases of xanthogranulomatous osteomyelitis have been described previously in the literature. We present a case of xanthogranulomatous osteomyelitis occurring in the distal part of tibia. This case presented as swelling in a 13-year-old boy. Simple curettage proved to be curative in the present case. PMID- 22937382 TI - Trisomy 19 and t(9;22) in a patient with acute basophilic leukemia. AB - We report a case of acute basophilic leukemia with two coexisting clonal abnormalities, t(9;22) and trisomy 19. The blast showed positive reaction with myeloperoxidase but negative reaction with chloroacetate esterase and acid phosphatase. Metachromatic features of the blast were observed with toluidine blue stain. Ultrastructure study showed the presence of azurophilic granules in basophils and blast mast cells. Conventional and molecular cytogenetic studies revealed, t(9;22) with BCR/ABL positive and trisomy 19 in all metaphase cells. To our knowledge, this paper here is the first to present acute basophilic leukemia with trisomy 19 and t(9;22). PMID- 22937383 TI - Hypophosphatemic rickets: presenting features of fanconi-bickel syndrome. AB - Fanconi-Bickel Syndrome (FBS) is a rare variety of glycogen storage disease (GSD). Characterized by massive hepatomegaly due to glycogen accumulation, severe hypophosphatemic rickets, and marked growth retardation due to proximal renal tubular dysfunction. We report a young boy presented as hypophosphatemic rickets with hepatomegaly and subsequently diagnosed as FBS. PMID- 22937384 TI - Extraskeletal chondrosarcoma of labium majus. AB - Extraskeletal myxoid chondrosarcoma (ESMC) is a rare tumor seen more often in men. It is seen to arise from soft tissue of lower extremity or buttocks. We report a case of soft tissue swelling of left labium majus in a 66-year-old female. Patient underwent wide excision with uneventful postoperative course. Histopathology of specimen confirmed it to be ESMC. Patient refused adjuvant therapy. Followup of 1 year has shown her to be disease- and symptom- free. Only two cases arising from vulva have been reported in literature . This is the third case and first from Indian subcontinent. A brief review of clinical features, diagnosis, treatment, and outcome of patients with extraskeletal chondrosarcoma is presented. PMID- 22937385 TI - Acute demyelination in a person with amphetamine abuse. AB - We report the case of a 31-year-old woman, admitted to the hospital for chest pain, dying a few days later from septic multiorgan failure, and showing at autopsy foci of acute demyelination in the occipital lobe. Gas chromatography/mass spectrometry analysis revealed the presence of amphetamine in the demyelinated area, which might be considered as the pathogenic agent, since other causes for demyelination could be excluded. This case represents the first report showing a demyelinating process due to a street drug. PMID- 22937386 TI - Tuberous sclerosis complex associated with papillary serous carcinoma of the peritoneum, lymphangioleiomyomatosis, and angiomyolipoma. AB - Tuberous sclerosis complex (TSC) is associated with benign and malignant tumors, including lymphangioleiomyomatosis (LAM) and angiomyolipoma (AML). We herein describe the TSC case of a 50-year-old woman having a papillary serous carcinoma of the peritoneum (PSCP), LAM, and AML. On microscopic examination, the PSCP cells showed a cuboidal to columnar shape, proliferated into the papillae, and infiltrated into the peritoneal cavity and anterior thoracic wall. On immunohistochemical evaluation, the tumor cells were positive for epithelial membrane antigen, human epidermal cytokeratins, and progesterone receptor, but negative for calretinin, carcinoembryonic antigen, MCF-7 cell line (Ber-EP4), and estrogen receptor. PMID- 22937387 TI - Atypical cutaneous fibrous histiocytoma: an unusual and misleading variant of fibrous histiocytoma. AB - Atypical fibrous histiocytoma is a distinctive variant of cutaneous fibrous histiocytoma, which is often mistaken histologically for sarcoma and which have a tendency to recur locally and a capacity to metastasize, although very rarely. We report a new case of atypical cutaneous fibrous histiocytoma in a 31-year-old man who presented with a recurrent polypoid nodule on the abdominal wall. The diagnosis was made on the basis of morphological and immunohistochemical findings. We discuss through this case and a review of the literature pathological and evolutive features and diagnostic difficulties of this entity. PMID- 22937389 TI - Unusual presentation of papillary microcarcinoma of thyroid as thigh mass. AB - An elderly otherwise healthy male presented with a mass in thigh. Fine needle aspiration cytology (FNAC) revealed features of papillary carcinoma of thyroid, suggesting secondary deposits. Later the patient was clinically evaluated. There was no obvious thyromegaly both clinically and sonologically. The patient was followed up. One month after initial presentation, he came with an enlarged cervical lymph node and a tiny nodule in thyroid. FNAC from both the thyroid and cervical lymph node showed identical features of papillary carcinoma. PMID- 22937388 TI - Epitheloid myxofibrosarcoma of the parotid gland. AB - Myxofibrosarcoma has been recently described as a distinct histological entity and commonly affects the extremities and trunk of the elderly. It is, however, rare in the head and neck (2.8%) region, and we are unaware of any reports of it presenting as a parotid mass. The epitheloid variant accounts for less than 3% of myxofibrosarcomas. We report a case of a 78/F presenting with an epitheloid myxofibrosarcoma in the parotid gland. The clinical presentation was of a parotid lump of 9-month duration, and the diagnosis was made following thorough histological assessment. We present what we believe to be the first reported case of a (epitheloid) myxofibrosarcoma affecting the parotid gland and highlight its diagnostic features and outcome of treatment. PMID- 22937390 TI - A case of angiomyolipoma arising in the tongue. AB - A 61-year-old woman was referred to our hospital with a mass in the left proglossis. The lesion was excised with a provisional diagnosis of hemangioma. The mass was well-demarcated and easily dissected with an ultrasonic surgical aspirator. The histopathologic diagnosis was angiomyolipoma arising in the tongue. There were no signs of recurrence at followup at 18 months. PMID- 22937391 TI - Extramedullary hematopoiesis: an unusual finding in subdural hematomas. AB - We present a case of a 59-year-old man who was found to have clusters of hyperchromatic, small, round nucleated cells within a subdural hematoma removed after a skull fracture. Immunohistochemistry study confirmed that the cells were hematopoietic components predominantly composed of normoblasts. In this paper, we describe the clinical and pathological findings. A brief review of published information on extramedullary hematopoiesis in subdural hematoma and the mechanisms of pathogenesis are also discussed. While extramedullary hematopoiesis is seen anecdotally by neuropathologists in chronic subdural hematomas, only a few cases are documented in the literature. Furthermore, extramedullary hematopoiesis in subdural hematoma can pose a diagnostic challenge for general pathologists who encounter subdural hematoma evacuations seldom in their surgical pathology practices. PMID- 22937392 TI - A case report on the surgical treatment of the huge inflammatory pseudotumor in the AIDS patient with hemophilic. AB - An HIV infected hemophilia patient with huge inflammatory pseudotumor was in severe ill condition. The operation of right hip joint amputation was performed on the patient with perioperative infusion of coagulation factor VIII and highly active antiretroviral therapy (HAART). The pathological found that Inflammatory cell infiltration, formation of folliculus lymphaticus, muscular fiber breakage, and fibrous tissue hyperplasy, necrosis in both soft tissue and bone were seen in inflammatory pseudotumour. The vital signs remained stable during the operation and patient's overall health condition improved significantly ten months after operation. With the infusion of coagulation factor VIII and HAART, HIV infected hemophilia patient can be safety operation and may get effective result. PMID- 22937393 TI - Biliary dyskinesia as a rare presentation of metastatic breast carcinoma of the gallbladder: a case report. AB - Background. Breast carcinoma is the most common malignancy in women worldwide. It is most commonly associated with metastases to the liver, lung, bone, and the brain. Invasive lobular carcinoma is a less common pathology with slightly higher metastases to the upper gastrointestinal tract. Invasive lobular carcinoma metastasis to the gallbladder is extremely rare. Method. In this paper we are presenting a case of a 67-year-old female with metastases of invasive lobular breast cancer to the gallbladder six years after her therapy. Conclusion. This case clearly signifies the nature of the micrometastatic foci of the invasive lobular carcinoma even many years after a successful treatment. PMID- 22937394 TI - A delayed diagnosis: conflicting investigation results should be challenged. AB - We present a case where a diagnosis of advanced HIV led to many other diagnoses but more importantly life-threatening multivariant Castleman's disease which is rare and was successfully treated. This case highlights the importance of questioning and challenging investigations when it does not fit with the clinical picture. Multidisciplinary teams are crucial and always seek expert advice if unsure. The much-quoted adage of "many symptoms and signs will fit one diagnosis" also bodes well in this case. PMID- 22937395 TI - Merkel cell carcinoma with lymphoepithelioma-like pattern: a case report of an exceedingly rare variant of merkel cell carcinoma with lymph node metastases at presentation. AB - Merkel cell carcinoma (MCC) or primary neuroendocrine carcinoma of the skin is a rare neoplasm with aggressive behavior. Primary lymphoepithelioma-like (LEL) carcinoma of the skin is a recently described exceptional tumor, with a relatively good prognosis, and is characterized by a neoplastic epithelial component associated with a dense lymphoid stroma. Rarely, MCC shows a marked lymphocytic host response or can even mimic a LEL carcinoma. We report a new case of MCC mimicking an LEL carcinoma in a 72-year-old male; the diagnosis of MCC was made on the basis of the morphology and immunohistochemical findings. We present through this case an exceptional pattern of MCC which can be misleading, and we insist on differential diagnoses. PMID- 22937396 TI - Laryngeal chondroma: a rare diagnosis in this localization. AB - Primary chondroid tumors of the larynx represent less than 1% of all laryngeal tumors. Most of them are chondromas and they often involve to the cricoid cartilage. A 31-year-old male patient applied to the oto-laryngology service with a history of dysphonia and dyspnea. Microlaryngoscopy revealed 2 cm sized, ill defined, covered with regular mucosa, porous, and hard mass on posterior surface of crycoid cartilage in subglottic area. Following the excision of the lesion, histopathologic examination revealed as chondroma. Two years later, local recurrence was detected and the diagnosis was again chondroma. There was no complaint of the patient in last 3 and half years of follow-up. Chondroma should carefully be differentiated from chondrosarcoma and the patients should be followed for possible recurrences. PMID- 22937397 TI - Morphologic heterogeneity in carcinosarcoma of the gallbladder: report of a rare cases. AB - Carcinosarcoma is a rare tumor composed of variable proportions of carcinomatous and sarcomatous elements and comprises less than one percent of all gallbladder malignancies. In most reported cases of carcinosarcoma of gallbladder, the epithelial component is adenocarcinoma. The mesenchymal component varies from homogenous sarcoma to more heterotopic elements like malignant bone, cartilage, and other mesenchymal tissues. We report a rare case of carcinosarcoma of the gallbladder in an 83-year-old male, with the carcinomatous component represented by undifferentiated carcinoma (spindle and giant cell type with osteoclastic giant cells) and the mesenchymal component seen as foci of chondrosarcoma. PMID- 22937398 TI - Serial murder of four victims, of both genders and different ethnicities, by an ordained baptist minister. AB - A case of a 61-year-old African-American male who sexually assaulted and murdered four individuals, of different ethnicities and both genders, is reported. The subject additionally engaged in sexual activity with each victim postmortem. Each murder is reviewed in detail, and the subjective state of the offender during the murders is commented upon. Psychological test data are reviewed. The subject met criteria for several Axis I disorders, including Bipolar I Disorder, Pedophilia, and Sexual Sadism, and met criteria for Axis II diagnoses of Narcissistic and Antisocial Personality disorder. He was additionally classified as a Psychopath, which, in combination with his Sexual Sadism, general psychiatric state, and exquisite sensitivity to humiliation, led to his decision to murder. PMID- 22937399 TI - Modified exposure and response prevention to treat the repetitive behaviors of a child with autism: a case report. AB - We report the case study of a school-aged child with autism whose repetitive behaviors were treated with a modified version of a technique routinely used in cognitive behavior therapy (i.e., exposure response prevention) to treat obsessive-compulsive disorder. A trained behavioral therapist administered the modified ERP treatment over the course of an intensive two-week treatment period with two therapy sessions occurring daily. The treatment was successful at decreasing the amount of child distress and cooccurring problem behavior displayed; however, the child's interest in the repetitive behavior eliciting stimulus (i.e., puzzles) remained. The case study demonstrates specific ways that exposure response prevention strategies can be adapted to the unique kinds of repetitive behaviors that present clinically in autism. A larger clinical trial is needed to substantiate these findings. PMID- 22937400 TI - Treatment complexities of a young woman suffering psychosis and pituitary adenoma. AB - This paper is a clinical description of the presentation, therapy, and pharmacological management of a 28-year-old woman who had nine admissions to a psychiatry ward, the last four within one year. It became clear that the treatments, which the patient had received concurrently for ten years for a pituitary adenoma and for psychotic symptoms, were counteractive. The case highlights the importance of the role of prolactin in psychosis and of an interdisciplinary team approach when patients present with complex symptoms. PMID- 22937401 TI - Extensive Deep Venous Thrombosis in a Patient with Neurolept Malignant Syndrome despite Being on Prophylaxis. AB - The risk of venous thromboembolism (VTE) in patients with Neuroleptic malignant syndrome (NMS) and those on antipsychotic medications is well established. We present here a case whereby the patient had NMS and developed extensive deep venous thrombosis (DVT) despite being on standard DVT Prophylaxis. Our case illustrates that empiric intravenous heparin for the initial few days after the onset of NMS may be considered in those with high risk of VTE, as in such patients standard DVT prophylaxis may not be sufficient. To standardize as to which patients with NMS would be at the highest risk of VTE while on standard DVT prophylaxis, the role of a standardized scoring system and a double-blind randomized trial in the future would probably be beneficial. PMID- 22937402 TI - Reducing Children's Media Viewing. AB - This case study evaluates the use of a Restrictive aide and the complementary use of parental mediation techniques to reduce media viewing among children. A family was provided a TV Token Timer, which involved a positive reward in exchange for participating in activities outside of watching television. Media viewing habits decreased from the baseline to the completion of the intervention at week 8 for both children. The parent reported high levels of Instructive mediation and positively evaluated the family's use of the TV Token Timer. PMID- 22937403 TI - Severe neuropsychiatric reaction in a deployed military member after prophylactic mefloquine. AB - Recent studies of military personnel who have deployed to Iraq and Afghanistan have reported a number of combat-related psychiatric disorders such as posttraumatic stress disorder, depression, and traumatic brain injury. This case report involves a 27-year-old male active-duty US military service member who developed severe depression, psychotic hallucinations, and neuropsychological sequelae following the prophylactic use of the antimalarial medication mefloquine hydrochloride. The patient had a recent history of depression and was taking antidepressant medications at the time of his deployment to the Middle East. Psychiatrists and other health care providers should be aware of the possible neuropsychiatric side effects of mefloquine in deployed military personnel and should consider the use of other medications for malaria prophylaxis in those individuals who may be at increased risk for side effects. PMID- 22937404 TI - Fregoli syndrome: an underrecognized risk factor for aggression in treatment settings. AB - Fregoli syndrome (FS) is commonly associated with verbal threats and aggressive behavior. We present a case of Fregoli syndrome leading to an assault. We discuss the possible underdiagnosis of FS, associated risk for aggression, and strategies to reduce that risk. PMID- 22937405 TI - Role of donepezil in autism: its conduciveness in psychopharmacotherapy. AB - A woman consulted psychiatric Out-Patient Department (OPD) for her 5-year and 2 month-old son presenting with typical autistic symptoms like social, behavioural, and communicational ineptitudeness. Subsequent treatment with Donepezil resulted in marked improvement in the aforementioned symptomatology. Recent studies in autistic child have shown diminished acetylcholine and nicotinic receptor activity, thus an acetylcholinergic enhancer, Donepezil, likely accounts for improvement in autistic symptoms. Evidently, the case report consolidates Donepezil role as a potentially useful agent in the treatment of cognitive and behavioural symptoms observed in this disorder. PMID- 22937406 TI - Chronic Tinnitus following Electroconvulsive Therapy. AB - A 43-year-old female with a 27-year history of obsessive-compulsive disorder and major depression had previously been treated with psychotherapy, antidepressant, and antipsychotic medications. Because these treatments were minimally effective and because the frequency and duration of her depressive episodes continued to increase, the patient was scheduled to undergo a series of electroconvulsive therapy (ECT) procedures. The patient received four ECT treatments during one month. Stimulating current was delivered to the right frontotemporal region of the head. Electroencephalographic seizures occurred during each of the ECT procedures. After the patient recovered from anesthesia, she complained of headaches, muscle pain, amnesia, and, after the fourth ECT, she reported a ringing sound in her right ear. Audiometric testing the day after the fourth ECT revealed a slight increase in threshold for 8000 Hz tones in her right ear. It is likely that current delivered during the fourth ECT treatment triggered the perception of tinnitus for this patient. The unique organization of this patient's central nervous and auditory systems combined with her particular pharmacological history might have predisposed her to developing tinnitus. PMID- 22937407 TI - Electroconvulsive therapy and corpus callosum aplasia: a 3-year followup. AB - Electroconvulsive Therapy (ECT) is a powerful treatment option in severe or chronic catatonic states and has been reported to be useful in oligophrenic patients. We report the followup medical history of a patient with corpus callosum aplasia (or agenesis) who was continuously treated with ECT over three years. First, he improved considerably after a series of ECT, but relapses of catatonia made a continuous, weekly ECT necessary. Due to the severity of the brain malformation, an add-on medication with benzodiazepines and second generation antipsychotics was necessary to treat catatonic symptoms. This case emphasises the benefits of long-term ECT in oligophrenic patients. PMID- 22937408 TI - Atypical creutzfeldt-jakob disease evolution after electroconvulsive therapy for catatonic depression. AB - We describe a case report of an 80-year-old woman who presented with symptomatology compatible with an episode of major depression with catatonia. After psychiatric admission, electroconvulsive therapy (ECT) was applied, but symptoms progressed with cognitive impairment, bradykinesia, widespread stiffness, postural tremor, and gait disturbance. After compatible magnetic resonance imaging (MRI), diffusion changes, and electroencephalogram (EEG) findings the case was reoriented to Creutzfeldt-Jakob disease (CJD). The genetic study found a methionine/valine heterozygosity at codon 129 of the prion protein gene PrP(Sc). On followup, a significant clinical recovery turned out. For this reason, EEG and MRI were repeated and confirmed the findings. The patient subsequently demonstrated progressive clinical deterioration and died 21 months later. The diagnosis was verified postmortem by neuropathology. The vCJD subtype MV2 is indeed characterized by early and prominent psychiatric symptoms and a prolonged disease duration however no frank clinical recovery has before been reported. PMID- 22937409 TI - Stable Bipolar Patient Switched to Mania following Clinical Doses of Prednisone. AB - We describe a stable bipolar female patient on medications that got switched into mania due to higher doses of prednisone prescribed for her severe sinusitis. PMID- 22937410 TI - Treatment dilemmas in a young man presenting with narcolepsy and psychotic symptoms. AB - Psychotic features can be present in both narcolepsy and psychosis, which can result in challenges in diagnosis and management. The prevalence of both conditions is low and the reports in young people are scarce. Our report illustrates the relevance of a thorough differential diagnosis as well as the need to explore treatment avenues based on the evidence available for both narcolepsy and psychosis symptoms to try and maximise the therapeutic impact. PMID- 22937411 TI - Addition of aripiprazole to the clozapine may be useful in reducing anxiety in treatment-resistant schizophrenia. AB - There exist many case reports and studies on the antipsychotic augmentation by aripirazole in partial responders to clozapine, the most seem to be finding a slight difference in the PANSS and CGI scores after the aripirazole addition. The results of our report are compatible with those of other studies but, we have found a considerable antianxiety action in both of the cases. The 5HT1A agonism of aripirazole could be hypothesized as mechanism contributing to this effect. PMID- 22937412 TI - Workplace inhalant abuse in adult female: brief report. AB - Inhalant abuse is the purposeful inhalation of intoxicating gases and vapors for the purpose of achieving an altered mental state. With its propensity for being yet an under-recognized form of substance use, being gateway to hard substances, cross-cultural penetration crossing socioeconomic boundaries, and causing significant morbidity and mortality in early ages, the prevention of inhalant misuse is a highly pertinent issue. This clinical report identifies a newer perspective in the emergence of inhalant abuse initiation. We report a case of an adult female with late onset of inhalant dependence developing at workplace and recommend for greater awareness, prevention, and management of this expanding substance abuse problem. PMID- 22937413 TI - Contingency management for patients with cooccurring disorders: evaluation of a case study and recommendations for practitioners. AB - Research indicates that contingency management (CM) has potential to improve a number of outcomes (e.g. substance use, treatment attendance, quality of life) among individuals with substance use and cooccurring disorders. However, multiple factors must be considered on a case-by-case basis in order to promote optimal treatment effects. The present study describes an individualized CM protocol for a US Veteran with substance dependence and cooccurring severe mental illness. CM targeted attendance at outpatient appointments and appropriate use of hospital resources. Effects of CM were assessed by comparing the 3-month baseline and CM periods. The CM intervention marginally reduced unnecessary hospital admissions, resulting in cost savings to the medical center of over $5,000 in three months for this individual. However, CM did not affect outpatient attendance. Several complications arose, highlighting challenges in using CM in populations with substance use and cooccurring disorders. Practical suggestions are offered for maximizing the effects of CM. PMID- 22937414 TI - Memantine as an augmentation therapy for anxiety disorders. AB - Objective. Glutamate, an excitatory neurotransmitter in the central nervous system (CNS), may play a role in the development of anxiety. Memantine partially blocks N-methyl-D-aspartate (NMDA) receptors' glutamate channels located in the CNS. This paper evaluates memantine as an augmentation therapy for treatment of anxiety. Methods. 15 consecutive partially responding anxious patients were treated with adjunctive memantine for 10 weeks. Memantine was dosed 5-20 mg/day. Result. Memantine augmentation resulted in clinically relevant reduction in anxiety symptoms when compared to baseline. Forty percent of patients achieved remission (HAM-A >= 7). Memantine improved sleep quality. Mean dose was 14 mg/d (range 5-20 mg/d). Typical adverse events included nausea and headache. Conclusion. The NMDA receptor antagonist memantine may be an effective augmentation therapy in patients with treatment-resistant anxiety. PMID- 22937415 TI - Management of agitation following aneurysmal subarachnoid hemorrhage: is there a role for Beta-blockers? AB - Introduction. Stroke is a leading cause of mortality and morbidity in the United States. About 20% of the stroke is hemorrhagic and about 50% of these is due to aneurysmal subarachnoid hemorrhage. A troublesome neuropsychiatric complication of subarachnoid hemorrhage is agitation/aggression. Case Presentation. A 45-year old man with no prior psychiatric history, sustained subarachnoid hemorrhage. After initial stabilization for 2 days, he underwent craniotomy and clipping of anterior cerebral communicating artery aneurysm. Treatment was continued with labetalol, nimodipine, and levetiracetam. Beginning postoperative day 4, patient developed episodes of confusion and agitation/aggression. Switching of Levetiracetam to valproate did not show any improvement. Psychiatry team tried to manage him with intense nursing intervention and different medications like olanzapine, valproate, lorazepam, and haloperidol. However, patient continued to be agitated and aggressive. Switching from labetalol to metoprolol resulted in dramatic improvement within 3 days. Discussion. Antipsychotics and benzodiazepines are often not sufficiently effective in the control of agitation/aggression in patients with traumatic brain injury and similar conditions. Our case report and the literature review including a cochrane review suggests that beta-blockers may be helpful in this situation. PMID- 22937416 TI - EMDR in Competition with Fate: A Case Study in a Chinese Woman with Multiple Traumas. AB - This paper described the application of eye movement desensitization reprocessing (EMDR) for addressing the posttraumatic stress disorder (PTSD) symptoms in a Chinese woman who had experienced multiple traumas in her childhood. EMDR is an integrative therapeutic intervention that uses a standardized eight-phase approach to treatment. It is also a proven, effective, and efficient treatment for trauma. In this client with multiple traumas, the etiological event that lay the foundation of her dysfunctional responses was reprocessed first. The successful resolution of this event allowed the positive treatment effects to transfer to other traumatic events of a similar theme. This case also illustrates the importance of identifying a culturally appropriate positive cognition (PC) in contributing to the success of the treatment. PMID- 22937417 TI - Differences in the Treatment Response to Antithyroid Drugs versus Electroconvulsive Therapy in a Case of Recurrent Catatonia due to Graves' Disease. AB - We reported a case which presented recurrent episodes of catatonia as a result of Graves' disease with hyperthyroidism. The patient showed different treatment response in each episodes; in the first episode, psychiatric and physical symptoms were resolved by a combination of antithyroid and anxiolytic therapies, while in the second episode, the combination therapy did not ameliorate her symptoms and ECT was indicated. We postulated that decreased CSF level of TTR and the resulting susceptibility to the derangement of peripheral thyroid function might be involved in this different treatment response. PMID- 22937418 TI - Hemicrania Continua Headache in a Veteran with Posttraumatic Stress Disorder and Major Depressive Disorder without Traumatic Brain Injury. AB - Hemicrania continua is a headache characterized by chronic unremitting unilateral pain associated with ipsilateral autonomic findings. This type of headache responds to high-flow oxygen and indomethacin. This case report describes a male veteran with posttraumatic stress disorder (PTSD) and major depressive disorder who suffers from comorbid hemicrania continua. The psychiatric symptoms were recalcitrant to psychopharmacological intervention. However, when the patient's hemicrania continua was treated appropriately, the patient's psychiatric symptoms also abated. This case demonstrates the need to address physical comorbidities that may exacerbate psychiatric disorders, such as PTSD. PMID- 22937419 TI - Autism in early childhood: an unusual developmental course-three case reports. AB - Autistic spectrum disorder (ASD) is typically characterized by either an emerging and gradual course or developmental regression in early childhood. The versatile clinical course is progressively acknowledged in recent years. Children with developmental disorders in general are referred to the Child Development Center for a multidisciplinary assessment, investigation, treatment and followup. We report three infants with an initial diagnosis of developmental delays, recovery of normal development following intervention in a multidisciplinary center, and subsequent regression into classic autism following their discharge from the program. An extensive medical workup was noncontributory. This unusual presentation, to our knowledge not reported previously, should be recognized by professionals involved in child development and psychiatry. PMID- 22937420 TI - Biperiden dependence: case report and literature review. AB - Anticholinergic drugs are frequently used in psychiatry for the prophylaxis and treatment of extrapiramidal symptoms caused by neuroleptics. Abuse of anticholinergic agents has been reported in patients with psychotic disorders, on treatment with neuroleptics, and polysubstance use disorders. We are reporting the case of a patient who presented with hypoactive delirium as a consequence of biperiden dependence. The clinician must pay special attention to detect anticholinergic misuse in patients presenting with delirium of unknown cause. PMID- 22937421 TI - Thymoma with coexisting undifferentiated pleomorphic sarcoma: a case report. AB - We report here a case of thymoma simultaneously associated with undifferentiated pleomorphic sarcoma. A 45-year-old male presented with axillary lump. Radiographic studies showed a mediastinal mass. On fine needle aspiration cytology and histopathological examination, a diagnosis of thymoma with coexisting undifferentiated pleomorphic sarcoma was made. Although thymomas are associated with many extrathymic malignancies, it's association with undifferentiated pleomorphic sarcoma is rare. This case is being reported on to reinforce that clinicians should bear in mind the possibility of extrathymic malignancies in patients with thymomas. PMID- 22937423 TI - Giant intrapulmonary teratoma: a rare case. AB - Teratomas are tumors composed of tissues derived from more than one germ cell line. Pulmonary teratomas are rare and commonly involve the upper lobe of the left lung. Criteria for pulmonary origin are the exclusion of a gonadal or other extragonadal primary site and origin entirely within the lung. We report a case of a giant pulmonary teratoma in a 2-year-old male child and review the relevant literature. PMID- 22937422 TI - A Case of Sarcoidosis with Unusual Radiographic Findings that Developed 5 Years after Silicone Augmentation Mammoplasty Complicated by Miliary Tuberculosis during Corticosteroid Treatment. AB - A 54-year-old woman with a past history of silicone augmentation mammoplasty was admitted with fever and dyspnea with diffuse interstitial shadows on computed tomography (CT). Although radiological findings were atypical, we diagnosed sarcoidosis by laboratory, microbiological, and bronchoalveolar lavage fluid analysis. Corticosteroids ameliorated the condition, but she had recurrent of fever and CT revealed miliary nodules while interstitial shadows disappeared. Liver biopsy showed that noncaseating granuloma and Ziehl-Neelsen stain was positive. We diagnosed miliary tuberculosis which developed during corticosteroid therapy. Antituberculotic therapy resulted in favorable outcome. Possibility exists that onset of sarcoidosis was induced by mammoplasty, namely, human adjuvant disease. PMID- 22937424 TI - Malignant rhabdoid tumor of the lung in the young adult: a case report. AB - Malignant rhabdoid tumor (MRT) is one of the most aggressive and lethal malignancies in pediatric oncology. Malignant rhabdoid tumor was initially described in 1978 as a rhabdomyosarcomatoid variant of a Wilms tumor because of its occurrence in the kidney and because of the resemblance of its cells to rhabdomyoblasts. The absence of muscular differentiation led Haas and colleagues to coin the term rhabdoid tumor of the kidney in 1981, Haas et al.. PMID- 22937425 TI - A young man with bilateral spontaneous pneumothorax. AB - Case. A 33-year-old male nonsmoker presented with sudden onset of dyspnoea and thoracic pain. Chest radiograph showed a left-sided pneumothorax. Few days later he developed a right-sided pneumothorax. He had a positive family history of pneumothorax. High-resolution computed tomography of the chest showed multiple pulmonary cysts predominantly located in the lower lung regions. We suspected Birt-Hogg-Dube syndrome (BHD). Conclusion. Birt-Hogg-Dube syndrome is a rare autosomal dominant inherited genodermatosis and characterised by clinical manifestations including hamartomas of the skin, renal tumors, and pulmonary cysts with spontaneous pneumothorax. BHD is probably underdiagnosed because of the wide variability in its clinical expression. It is important to recognize these patients because of the possibility of developing renal cancer. PMID- 22937426 TI - First Report of a Case of Pneumococcal Meningitis Which Did Not Respond to the Ceftriaxone Therapy despite the Isolated Organism Being Sensitive to This Antibiotic In Vitro. AB - A 60-year-old man presented with pneumococcal meningitis which did not respond to the ceftriaxone therapy, in spite of in-vitro susceptibility (minimal inhibitory concentration of 0.016 MUg/dLit) of the isolated organism to this antibacterial agent, although ceftriaxone is still the drug of choice for such pneumococcal meningitis. Review of published articles revealed no report of clinical resistance in organisms which were susceptible to the same antimicrobial agent in vitro. This alarming emergence of isolates with in vivo resistance should be considered and even could lead to a shift in the empirical antibiotic therapy for pneumococcal infections. PMID- 22937427 TI - Methaemoglobinemia Induced by MDMA? AB - Case. A 45-year-old man with a blank medical history presented at the emergency room with dizziness and cyanosis. Physical examination showed cyanosis with a peripheral saturation (SpO(2)) of 85%, he did not respond to supplemental oxygen. Arterial blood gas analysis showed a striking chocolate brown colour. Based on these data, we determined the arterial methaemoglobin concentration. This was 32%. We gave 100% oxygen and observed the patient in a medium care unit. The next day, patient could be discharged in good condition. Further inquiry about exhibitions and extensive history revealed that the patient used MDMA (3,4- methylenedioxymethamphetamine, the active ingredient of ecstasy). Conclusion. Acquired methaemoglobinemia is a condition that occurs infrequently, but is potentially life threatening. Different nutrients, medications, and chemicals can induce methaemoglobinemia by oxidation of haemoglobin. The clinical presentation of a patient with methaemoglobinemia is due to the impossibility of O(2) binding and transport, resulting in tissue hypoxia. Important is to think about methaemoglobin in a patient who presents with cyanosis, a peripheral saturation of 85% that fails to respond properly to the administration of O(2). Because methaemoglobin can be reduced physiologically, it is usually sufficient to remove the causative agent, to give O(2), and to observe the patient. PMID- 22937428 TI - Spontaneous resolution of massive spontaneous tubercular pneumothorax. AB - A 29-year-old female presented with complaints of fever and productive cough of three weeks duration. Pulmonary tuberculosis was diagnosed bacteriologically and she was prescribed antituberculosis drugs. During follow-up she developed massive pneumothorax, for which patient refused surgical management and was managed conservatively. After six months there was complete spontaneous resolution of pneumothorax. The unusual presentation and unexpected outcome prompted us to report this case. PMID- 22937429 TI - Investigating a case of recurrent pleural effusion. AB - We describe the case of a patient with long-standing Parkinson's disease and recurrent bilateral pleural effusions. The pleural fluid was an exudate, rich in normal lymphocytes, and the echocardiogram, chest computerized axial tomography, and immunological, microbiological and cytological studies were negative. The patient had been taking bromocriptine, which can be related to chronic pleural effusions. Using Pubmed, we found about 40 cases of pleuropulmonary changes or constrictive pericarditis that were related to bromocriptine. We decided to suspend this drug, with resolution of the pleural effusion and respiratory complaints for more than a year now. We discuss possible underlining mechanisms for this and emphasize the importance of collecting the past medical history and medication and of considering possible iatrogenic effects. PMID- 22937430 TI - Rapidly progressive lung cysts and pleural effusion: a case report. AB - Angiosarcoma is a rare but highly malignant tumor arising from vascular endothelial cells. Angiosarcoma commonly arises from the heart, liver, breast, and skin including the scalp. Angiosarcoma metastasizing to the lungs can present as either pneumothorax, hemothorax, or pleural effusions. They can rarely present as rapidly enlarging thin-walled pulmonary cysts. A review of the literature is included. PMID- 22937431 TI - Successful erlotinib treatment for a patient with gefitinib-related hepatotoxicity and lung adenocarcinoma refractory to intermittently administered gefitinib. AB - A 73-year-old Japanese man was histologically diagnosed with lung adenocarcinoma harboring an exon 19 deletion in the epidermal growth factor receptor. The patient was treated with gefitinib for 6 weeks until he developed substantially elevated hepatic enzyme levels that resulted in the discontinuation of gefitinib. Gefitinib was reintroduced with an intermittent treatment schedule after the transaminase levels normalized, but the patient's enzyme levels rose again, and the cancer progressed. Gefitinib was eventually replaced with erlotinib. There was stable disease for 7 weeks without any signs of liver toxicity. Thus, erlotinib may be a beneficial and well-tolerated treatment option for patients with gefitinib-related hepatotoxicity. PMID- 22937432 TI - Familial pulmonary capillary hemangiomatosis early in life. AB - Background. Pulmonary capillary hemangiomatosis (PCH) is a rare disease, especially in infancy. Four infants have been reported up to the age of 12 months. So far, no familial patients are observed at this age. Patients. We report three siblings, two female newborns and a foetus of 15-week gestation of unrelated, healthy parents suffering from histologically proven PCH. The first girl presented with increased O(2) requirements shortly after birth and patent ductus arteriosus (PDA). She subsequently developed progressive respiratory failure and pulmonary hypertension and died at the age of five months. The second girl presented with clinical signs of bronchial obstruction at the age of three months. The work-up showed a PDA-which was surgically closed-pulmonary hypertension, and bronchial wall instability with stenosis of the left main bronchus. Transient oxygen therapy was required with viral infections. The girl is now six years old and clinically stable without additional O(2) requirements. Failure to thrive during infancy and a somewhat delayed development may be the consequence of the disease itself but also could be attributed to repeated episodes of respiratory failure and a long-term systemic steroid therapy. The third pregnancy ended as spontaneous abortion. The foetus showed histological signs of PCH. Conclusion. Despite the differences in clinical course, the trias of PCH, PDA, and pulmonary hypertension in the two life born girls suggests a genetic background. PMID- 22937433 TI - A rare fungal infiltration of lungs in a healthy young girl. AB - Cunninghamella bertholletiae is an opportunistic fungal organism found in soil and is a rare cause of human disease. The few reported cases of C. bertholletiae have involved immune compromised hosts. We report a case of C. bertholletiae in an otherwise healthy patient presenting with persistent high-grade fever and pulmonary infiltration resistant to antibiotics. The organism is isolated through bronchoscopy and responded to broad spectrum antifungal. This is the first case of C. bertholletiae reported in the literature in an immune competent individual. PMID- 22937434 TI - A rare case of vanishing lung syndrome. AB - We describe here a rare case of Idiopathic Bullous Emphysema/Vanishing Lung Syndrome (VLS) in a 33-year-old male patient with a history of marijuana abuse who presents to the hospital with pleuritic chest pain thought to be due to pneumothorax based on the chest radiograph. This case emphasizes the need to obtain chest computed tomography in a relatively stable patient suspected of VLS to reduce the potential risk of overseeing a bronchopleural fistula. PMID- 22937435 TI - Leukocytoclastic vasculitis in a patient with type 1 cryoglobulinemia. AB - Cutaneous manifestations of type 1 cryoglobulinemia are usually related to vascular occlusion by noninflammatory thrombosis; rarely is leukocytoclastic vasculitis seen in type 1 cryoglobulinemia. We report the case of a 64-year-old male who presented with isolated cutaneous leukocytoclastic vasculitis that was initially attributed to essential mixed cryoglobulinemia after thorough diagnostic evaluation. A lack of adequate clinical response to therapy prompted further investigation, including cryoprecipitate electrophoresis and immunofixation, which revealed an IgM kappa monoclonal gammopathy consistent with type 1 cryoglobulinemia. A renewed search for an underlying malignancy led to the discovery of early Waldenstrom's macroglobulinemia. Although leukocytoclastic vasculitis is more characteristic of mixed cryoglobulinemia, it can be a presenting manifestation of type 1 cryoglobulinemia. PMID- 22937436 TI - Etanercept-induced myelopathy in a pediatric case of blau syndrome. AB - Blau syndrome is a rare autoinflammatory disorder within the group of pediatric granulomatous diseases. Mutations in nucleotide-binding oligomerization domain 2 (NOD2/CARD15) are responsible for this condition, which has an autosomal dominant pattern of inheritance and variable expressivity. The clinical picture includes arthritis, uveitis, skin rash, and granulomatous inflammation. Central nervous system involvement is seldom reported, although some isolated cases of seizures, neurosensorial hearing loss, and transient cranial nerve palsy have been described. Treatment consists of nonsteroidal anti-inflammatory drugs, corticosteroids, and immunosuppressive agents, among which anti-tumor-necrosis factor-alpha (TNF-alpha) biologic agents, such as etanercept, play an important role. Among the major adverse effects of TNF-alpha inhibitors, demyelinating disease, multiple sclerosis, and acute transverse myelitis have been reported in adults. We describe a case of pediatric Blau syndrome affected by etanercept induced myelopathy, manifesting as a clinical syndrome of transverse myelitis. The patient experienced rapid recovery after etanercept was discontinued. To our knowledge, this is the first such case reported in the literature and, possibly, the one with the latest onset, following 8 years of treatment. We discuss the etiopathogenic mechanisms of this reaction and possible explanations for the imaging findings. PMID- 22937437 TI - Morphoea with myositis: a rare association. AB - In this case, we describe an unusual presentation of a young woman with a rash typical of morphoea (confirmed on biopsy), who went on to develop myositis in an atypical distribution. Although the association of myositis with diffuse systemic sclerosis is well described, the link with localised scleroderma (morphoea) and myositis has not been described. PMID- 22937438 TI - Concurrence of juvenile idiopathic arthritis and multiple sclerosis. AB - We report a 21-year-old female patient known to have Juvenile idiopathic arthritis (JIA) who later developed multiple sclerosis (MS). The disease was documented on the brain and cerebral magnetic resonance imaging (MRI) and the visual evoked potential. Our case emphasizes the need to evaluate the symptoms and brain MRI carefully. The concurrence of MS and JIA is uncommon. The possible relationship between the 2 diseases was discussed. PMID- 22937439 TI - Serum cytokine concentrations in a patient with rheumatoid arthritis on etanercept therapy who subsequently developed pneumocystis pneumonia: a case report. AB - We report a rheumatoid arthritis patient who was treated with etanercept. Serum levels of tumor-necrosis-factor- (TNF-) alpha, soluble-tumor-necrosis-factor receptor- (sTNFR-) I and -II, interleukin- (IL-) 6, and IL-1 beta were measured by ELISA before and during the course of therapy. While the serum levels of IL-6 and IL-1 beta dropped rapidly following the initiation of therapy, the concentrations of TNF-alpha and sTNFR-II steadily increased to a plateau. Although significant clinical efficacy was observed, etanercept had to be discontinued when after 12 weeks of therapy the patient was found to have pneumocystis pneumonia. PMID- 22937440 TI - Disseminated tuberculosis mimicking ankylosing spondylitis. AB - Ankylosing spondylitis is a chronic inflammatory disorder affecting mainly the axial skeleton. Here we report a case of a man with a clinical suspicion of ankylosing spondylitis but with a persistence of increased inflammatory markers. In this case, (18)F-FDG-PET/CT revealed multiple hypermetabolic lesions in axial skeleton, lymph nodes, and the lung, suggestive of either disseminated tuberculosis or lymphoma. Histological analysis of the pulmonary lesion revealed mycobacterium tuberculosis. This case highlights, firstly, the importance of excluding other diagnoses in the presence of clinical picture of ankylosing spondylitis and high inflammatory markers and, secondly, the determining role of PET/CT. PMID- 22937441 TI - Chronic recurrent multifocal osteomyelitis with concomitant features of juvenile idiopathic arthritis. AB - We report a case of a 13-year-old girl with chronic recurrent multifocal osteomyelitis (CRMO) who developed severe arthritis in four different joints within the first year from the onset of the disease. Her multiple vertebrae lesions showed significant amelioration after a 2-month treatment with prednisolone. In parallel, the initial severe symmetrical arthritis of both knees showing overt synovitis and joint effusion, in the absence of lesions in the metaphyses of the femur or the tibia, responded remarkably well in intra articular triamcinolone hexacetonide injections. However, upon discontinuation of prednisolone, the patient developed severe arthritis of her right ankle and the proximal interphalangeal joint of her right middle finger. Thus, prednisolone was reinitiated combined with methotrexate, and the patient went into remission, which persists one year after prednisolone tapering. The appearance of arthritis in both knees in the absence of bone lesions and the emergence of severe arthritis of the ankle after remission of spinal bone lesions suggest that CRMO and juvenile idiopathic arthritis may coexist and be causally related. PMID- 22937442 TI - Association of Sweet's Syndrome and Systemic Lupus Erythematosus. AB - Sweet's syndrome is an acute febrile neutrophilic dermatosis which usually presents as an idiopathic disorder but can also be drug induced, associated with hematopoetic malignancies and myelodysplastic disorders, and more, infrequently, observed in autoimmune disorders. Sweet's syndrome has been reported in three cases of neonatal lupus, three cases of hydralazine-induced lupus in adults, and in nine pediatric and adult systemic lupus erythematosus (SLE) patients. We describe three additional adult cases of Sweet's associated with SLE and provide a focused review on nondrug-induced, nonneonatal SLE and Sweet's. In two of three new cases, as in the majority of prior cases, the skin rash of Sweet's paralleled underlying SLE disease activity. The pathogenesis of Sweet's remains elusive, but evidence suggests that cytokine dysregulation may be central to the clinical and pathological changes in this condition, as well as in SLE. Further research is needed to define the exact relationship between the two conditions. PMID- 22937443 TI - Cricoarytenoiditis as an initial manifestation of systemic lupus erythematosus. AB - Systemic lupus erythematosus (SLE) is a chronic inflammatory disease encompassing a broadened spectrum of clinical manifestations. Vocal cords involvement in SLE is not a frequent entity but can be life threatening if not treated. We hereby report the case of a patient presenting with cricoarytenoiditis and vocal cord dysfunction revealing SLE. PMID- 22937444 TI - Systemic Sclerosis and Multiple Cancers of the Female Genital Tract: Prolonged Survival following Current Treatment Strategies. AB - Background. Systemic sclerosis is a rare, chronic, multisystem, and autoimmune disease. There is an overall increased risk of malignancy in patients with systemic sclerosis. However, multiple cancers of the female genital tract in patients with SSc are a very rare event. Our aim is to present a case of SSc and multiple cancers of the female genital tract, with prolonged survival following current treatment strategies. Case. The patient, a 43-year-old nulliparous premenopausal Greek woman suffering from systemic sclerosis, presented with a history of abdominal pain and abnormal uterine bleeding. She underwent total abdominal hysterectomy with bilateral salpingo-oophorectomy, total omentectomy, appendectomy, and pelvic lymph node dissection. The histopathology revealed synchronous primary cancers of the endometrium and left ovary. The final diagnosis was stage Ib endometrial cancer endometrioid type and stage IIIc ovarian cancer endometrioid type. She underwent postoperative adjuvant chemotherapy and remains well without evidence of disease 89 months after initial surgery. Conclusion. Although our patient was diagnosed at advanced stage disease, prolonged survival may be related with radical surgery and postoperative adjuvant chemotherapy according to current treatment strategies. PMID- 22937445 TI - A patient of lupus presenting with myocarditis and overlapping autoimmune hepatitis. AB - Systemic lupus erythematosus has myriad presentations. Symptomatic myocarditis and/or symptomatic autoimmune hepatitis associated with lupus are rare at presentation. Here we report a young Asian girl, who presented to us with features of symptomatic myocarditis and overlapping autoimmune hepatitis. She was eventually diagnosed to be harboring systemic lupus erythematosus, in whom rigorous management led to gratuitous recovery. PMID- 22937446 TI - Reduced quadriceps motor-evoked potentials in an individual with unilateral knee osteoarthritis: a case report. AB - One male with unilateral osteoarthritis (OA) of the knee underwent testing of corticospinal (CS) excitability (as quantified from motor-evoked potentials (MEPs) in the rectus femoris (RF) using transcranial magnetic stimulation) and quadriceps muscle strength. Baseline data indicated reduced MEP amplitudes in the RF of the affected limb compared to the unaffected limb. Increases in RF MEP amplitudes from both limbs were observed immediately following a 30-minute exercise session focusing on muscle strengthening. Following an 8-week muscle strengthening intervention, the participant exhibited increased MEP amplitudes and muscle strength in the affected limb. These findings suggest that alterations in peripheral muscle function found in patients with knee OA may have an origin centrally within the motor cortex and that interlimb differences may be evident in those with unilateral disease. These findings also suggest that CS excitability may be improved following a muscle strengthening intervention. PMID- 22937447 TI - Report of a rare case of gorham-stout disease of both shoulders: bisphosphonate treatment and shoulder replacement. AB - Massive osteolysis known as Gorham-Stout disease is a rare idiopathic disorder typically affecting long bones in a unifocal pattern. Angiomatosis is strongly connected to the osteolysis. Weather angiomatosis is the cause or the result of osteolysis is subject of intense discussion (Kawasaki et al. (2003), Moller et al. (1999), Radhakrishnan and Rockson (2008)). There are about 200 cases described since 1955. Our patient is a 77-year-old female patient with osteolyses of both shoulders involving the proximal humerus, lateral clavicle, and the glenoid. Under bisphosphonate therapy, the progressive osteolysis stopped on the right side and showed progression on the left. With the patient complaining about severe rest pain and impaired function, we performed surgical reconstruction by implantation of total shoulder prosthesis three months after onset of symptoms. Our case shows a possibility of primary and early surgical reconstruction with good clinical outcome. PMID- 22937448 TI - Epididymo-orchitis as a presenting feature of relapsing polychondritis: a case report. AB - Relapsing polychondritis (RP) is a rare multisystem disease. It is characterized by recurrent inflammation of cartilaginous structures including the ears, nose, tracheo-bronchial tree and peripheral joints. Proteoglycan-rich structures such as the heart, eyes and blood vessels can also be affected. Systemic symptoms including fever, weight loss and lethargy are common. RP is difficult to diagnose as it presents in a wide variety of ways and there is no diagnostic test. Corticosteroids are the mainstay of treatment but other immunosuppressive drugs can be used in combination with steroids. We present an unusual presentation of RP. PMID- 22937449 TI - Generalized morphea after breast cancer radiation therapy. AB - We present a case of a 69-year-old woman who received external beam radiation for the treatment of breast cancer. Seven months later, she developed generalized morphea involving the area of irradiated skin of the breast as well as distant sites of the groin and distal lower extremity. Postirradiation morphea is an uncommon yet well-documented phenomenon, usually confined to the radiated site and the immediate surrounding tissue. To our knowledge, this is only the fourth reported case of morphea occurring distant from the radiation field. While most cases of postirradiation morphea have been shown to either resolve spontaneously or respond to topical corticosteroids, our patient required systemic therapy with methotrexate, which resulted in clinical improvement. With this paper, we hope to bring further awareness to this phenomenon and demonstrate a successful treatment response with the use of methotrexate in postirradiation generalized morphea. PMID- 22937450 TI - Lipid Storage Myopathy in Behcet's Disease: A Rare Cause of Elevated Serum Creatine Kinases Levels. AB - Muscular involvement in Behcet's disease is rare and there are only a few case reports in the literature. The causes of elevated muscle enzymes in a patient with Behcet's disease are many, including myositis, drug-induced myopathy, metabolic myopathy, and the disease itself. We herein have defined an algorithmic approach to a patient with Behcet's disease and elevated muscle enzymes and report a case of coexisting of lipid storage myopathy. PMID- 22937451 TI - Schnitzler's disease as an important differential diagnosis of chronic recurrent multifocal osteomyelitis: a case report. AB - Introduction. At first sight, chronic recurrent multifocal osteomyelitis (CRMO) and Schnitzler's disease are diagnoses of exclusion and can be similar in their manifestation. Methods. In this paper we present the reevaluation of the 13-year old diagnosis of chronic recurrent osteomyelitis of a 58-year-old man with chronic ostealgia, night sweat, and pruritic urticarial lesions on the extremities and trunk. For further examination, we performed blood analysis, bone and skin biopsies, CT scans, and magnetic resonance imaging. Results. Laboratory findings showed increased inflammation parameters. Magnetic resonance imaging (MRI) revealed a diffuse bone marrow infiltration. A bone and skin biopsy showed a sclerotic bone marrow involvement and a superficial dermal and perivascular infiltrate of neutrophils. Based on these findings, the diagnosis of Schnitzler's disease was made. Conclusion. Here, we want to present Schnitzler's disease as an important differential diagnosis to CRMO in adults presenting with signs suggestive of CRMO. PMID- 22937452 TI - Antiphospholipid antibody syndrome presenting with hemichorea. AB - A 25-year-old Bangladeshi lady presented to neurology with a three-month history of involuntary movements of her right arm, associated with loss of power. There was progression to the right leg, and she subsequently developed episodes of slurred speech and blurred vision. At the time of presentation, she was 12 weeks pregnant and the symptoms were reported to have started at conception. Past medical history was unremarkable apart from one first trimester miscarriage and there was no significant family history suggestive of a hereditary neurological condition. MRI of the head revealed no abnormalities but serology showed positive antinuclear antibodies (ANAs) at a titre of 1/400. Further investigations revealed strongly positive anticardiolipin antibodies (>120) and positive lupus anticoagulant antibodies. The patient had a second miscarriage at 19 weeks gestation strengthening the possibility that the chorea was related to antiphospholipid antibody syndrome and she was started on a reducing dose of Prednisolone 40 mg daily and aspirin 300 mg daily. Six months later, she had complete resolution of neurological symptoms. There are several reports of chorea as a feature of antiphospholipid syndrome, but no clear consensus on underlying pathophysiology. PMID- 22937453 TI - The coexistence of systemic lupus erythematosus and thyrotoxicosis: the diagnostic value of antihistone antibodies. AB - We report four female patients with Graves' disease with positive ANA antibodies and possibility for development of systemic lupus erythematosus. All four patients have been treated with antithyroid drugs. SLE symptoms have appeared from 4 to 12 months after the beginning of therapy with methysol in two of them. The third patient had no symptoms for SLE, but her ANA, anti-DNA, and antihistone antibodies had been positive at the time of the onset of thyrotoxicosis. The fourth patient had alopecia areata with positive ANA and antihistone antibodies. PMID- 22937454 TI - Successful treatment of a patient with giant cell vasculitis (horton arteritis) with tocilizumab a humanized anti-interleukin-6 receptor antibody. AB - Giant cell arteritis (GCA) is the most common form of systemic vasculitis in adults, affecting preferentially medium-large size arteries. Here we report a case of a female with a diagnosis of GCA based on temporal artery biopsy, successfully treated with tocilizumab, a humanized anti-interleukin-6 receptor antibody. PMID- 22937455 TI - Streptococcus agalactiae Septic Arthritis of the Shoulder and the Sacroiliac Joints: A Case Report. AB - Invasive group beta-streptococcal arthritis is being increasingly diagnosed as suggested by recent data. We report a case of a middle-aged lady from Sri Lanka who developed septic arthritis of the right shoulder and the left sacroiliac joint as well as an iliopsoas collection caused by Streptococcus agalactiae shortly after labor at Hamad General Hospital in Doha, Qatar. We conclude that Streptococcus agalactiae septic arthritis is rare. It can present with invasive disease in adults. It usually targets older females and immuno compromised patients especially those with risk factors for bacteraemia. Therefore a high index of suspicion is needed. Shoulder and sacroiliac joint affection is not uncommon for unknown reasons. Utilizing imaging modalities such as ultrasonography and magnetic resonance imaging is helpful. PMID- 22937456 TI - Dermatomyositis sine myositis with membranoproliferative glomerulonephritis. AB - Dermatomyositis (DM) is an autoimmune disease that is characterized by involvement of proximal musculature and skin. We report a 52-year-old woman with a 6-year history of dermatomyositis sine myositis, who developed lower extremity edema and proteinuria. Pathological examination of renal biopsy showed membranoproliferative glomerulonephritis. She received steroid, cyclophosphamide, and mycophenolate mofetil. Over the 9 to 10 months after the beginning of treatment, the proteinuria was improved. PMID- 22937457 TI - IgG4-Related Disease without Overexpression of IgG4: Pathogenesis Implications. AB - IgG4-related disease is a new disease group that affects multiple organs. It is characterized by high serum IgG4 and abundant infiltration of IgG4-bearing plasma cells in the affected organ. Here, we describe an intriguing case that suggested that IgG4-related disease might present without IgG4 overexpression or infiltration, at least during a relapse. A 47-year-old man had been diagnosed with systemic lupus erythematosus 15 years. He was admitted due to a pituitary mass, systemic lymphadenopathy, and multiple nodules in the lungs and kidneys. The serum IgG4 level was normal and histopathological examination of the pituitary mass showed abundant lymphocyte and plasma cell infiltration with very few IgG4-positive cells. When we examined specimens preserved from 15 years ago, we found high serum IgG4 levels and IgG4-bearing plasma cell infiltration. This resulted in a diagnosis of IgG4-related disease, and we considered the current episode to be a relapse without IgG4 overexpression. This case indicated that, to clarify the pathogenesis of IgG4-related disease, current cases should repeat specimen evaluations over the course of IgG4-related disease to define diagnostic markers. PMID- 22937458 TI - Polymyositis following Pandemic Influenza A (H1N1) and 2009-10 Seasonal Trivalent Vaccines. AB - Sporadic associations between inflammatory myopathies with vaccinations were described in the literature, raising the possible trigger value of vaccines in the development of these autoimmune disorders. Here, we reported the clinical history of 3 patients who developed polymyositis complicated by interstitial lung disease (2 cases) and dermatomyositis (1 case), after influenza A (H1N1) vaccination. PMID- 22937459 TI - Postmortem demonstration of the source of pulmonary thromboembolism: the importance of the autopsy. AB - Periprostatic or paravaginal venous thromboses are rarely considered clinically as sites of clot origin in patients with pulmonary thromboembolism. The majority of emboli have been demonstrated to originate in the veins of the legs. This report raises awareness of pelvic vein thrombosis as a potential source of pulmonary embolism that is rarely considered or detected clinically, and which usually requires postmortem examination for recognition. It also reviews the possible routes emboli may take to reach the lungs. PMID- 22937460 TI - Management of an unusual iliac fossa venous plexus. AB - Symptomatic iliac fossa and suprapubic varicosities are uncommon presentations in adults. Such presentations often point to acquired obstructive process to pelvic outflow or to the progression of venous insufficiency and reflux in the pelvic and gonadal veins. Less frequently, venous anomalies of the renal veins or IVC might be implicated. Furthermore, late presentations of congenital or acquired developmental abnormalities might become manifest. As this case illustrates, a thorough understanding of the underlying pathologic process and the anatomical derangement must be sought before any treatment is instituted. Unnecessary extirpation of these varicosities would simply have removed vital physiologic cross-pelvic collateral circulation from the lower extremity in the face of chronic iliac vein occlusion. PMID- 22937461 TI - Extra-abdominal fibromatosis (desmoid tumor): a rare tumor of the lower extremity arising from the popliteal fossa. AB - Aggressive fibromatosis is a rare soft tissue tumor. Although it lacks metastatic potential, it can grow aggressively in a locally infiltrating pattern. The tumors frequently recur after surgical excision, which remains the treatment of choice. Optional combinations of radiotherapy and/or chemotherapy have been used postoperatively for recurrent disease and/or inoperable cases. A palpable mass was detected in the popliteal fossa of the right lower extremity in a 48-year-old man. Magnetic resonance imaging showed a contrast-enhancing noncalcified lesion initially felt to represent a vascular tumor. An invasive mass adherent to the surrounding tissue was visualized intraoperatively and extensively debulked. The patient's postoperative course was uneventful. Histologic examination of the surgical specimen was consistent with an extra-abdominal desmoid tumor. After appropriate recognition, wide local excision may be the most appropriate treatment for fibromatosis of the extremity. However, the rarity of this tumor and the difficulty inherent in distinguishing it from similar-appearing tumors are necessitating histologic confirmation of the diagnosis. PMID- 22937463 TI - Emergency abdominal aortic aneurysm repair in a patient with failing heart: axillofemoral bypass using a centrifugal pump combined with levosimendan for inotropic support. AB - We describe the case of an 83-year-old patient requiring repair of a large symptomatic abdominal aortic aneurysm (AAA). The patient was known to have coronary artery disease (CAD) with symptoms and signs of significant myocardial dysfunction, left-heart failure, and severe aortic insufficiency. The procedure was performed with the help of both mechanical and pharmacological circulatory support. Distal perfusion was provided by an axillofemoral bypass with a centrifugal pump, with dobutamine and levosimendan administered as pharmacological inotropic support. The patient's hemodynamic status was monitored with continuous cardiac output monitoring and transesophageal echocardiography. No serious circulatory complications were recorded during the perioperative and postoperative periods. This paper suggests a potential novel approach to combined circulatory support in patients with heart failure, scheduled for open abdominal aortic aneurysm repair. PMID- 22937462 TI - Coronary anomaly and coronary artery fistula as cause of angina pectoris with literature review. AB - Coronary artery fistulas are rare anomalies of the coronary arteries that may sometimes cause symptoms by shunting blood flow away from the myocardial capillary network. We report the case of a 46-year old lady which shows the right coronary cusp giving rise to left main coronary artery called anomalous origin of a coronary artery (AOCA), and also a fistula between the left coronary artery and pulmonary artery. We describe our diagnostic approach and review the literature on the epidemiology, pathophysiology, the diagnostic modalities, and treatment options. PMID- 22937464 TI - A rare cause of cyanosis: hepatopulmonary syndrome caused by congenital extrahepatic portosystemic shunt. AB - A 19-year-old male patient presented cyanosis and dyspnoea because of the presence of multiple pulmonary arteriovenous fistulas resulting in oxygen desaturation. The CTA revealed that intestinal and splenic venous blood bypasses the liver and drains into the inferior vena cava. This is the first reported case of hepatopulmonary syndrome caused by congenital extrahepatic portosystemic shunt in which intestinal and splenic venous blood bypasses the liver and drains into the inferior vena cava. PMID- 22937465 TI - Intima sarcoma of the pulmonary artery mimicking takayasu disease. AB - Pulmonary artery intima sarcoma is an uncommon but fatal tumor, which often masquerades chronic thromboembolic pulmonary hypertension (CTEPH) and in the present case Takayasu arteritis. Pulmonary arterial pressure is mildly elevated in the presence of extensive proximal lesions. A parenchyma thin-walled cavitary lesion may be a sign of pulmonary extravasation of the tumor. PMID- 22937466 TI - Endovascular treatment of a giant aneurysm of the maxillary artery. AB - Aneurysms of the maxillary artery are rare and the majority of the literature refers to false aneurysms. We report the first case of what we believe to be a spontaneous true maxillary artery aneurysm and its endovascular management. PMID- 22937467 TI - Arterial thrombosis in patients with human immunodeficiency virus: two-case reports and review of the literature. AB - Thrombosis during HIV infection was commonly vein thrombosis. Arterial thrombosis is also more and more described. We report two cases detected in the Abidjan Cardiology Institute. Case Reports. Case 1: an HIV infected female presented with sudden loss of consciousness and right hemiplegia. She had been taking HAART regimen for five years. Neck vessels ultrasonography revealed thrombosis on left ICA. Anticoagulant treatment leads to reduction of symptoms and left ICA partial recanalization. Case 2: male HIV infected taking HAART therapy was admitted for an acute pain of left lower limb; examination showed a decrease of heat, sensitivity, and mobility of this limb with popliteal and tibial pulses abolished. Arterial ultrasonography and CT angiography showed occlusion on the lower third of superficial femoral artery and homolateral popliteal artery suggesting a thrombosis of this artery. He underwent a femorotibial bypass surgery and anticoagulant treatment. The outcome was good with reappearance of local heat of the limb and tibial pulses. Probable etiology is early carotid atherosclerosis associated with protein S deficiency in the first case and antiphospholipid syndrome in the second case. Conclusion. Arterial thrombosis might occur in HIV infection. Several etiological factors could be involved in the pathogeny of these arterial thromboses. PMID- 22937468 TI - Asymptomatic delayed coil migration from an intracranial aneurysm: a case report. AB - Objective. To describe asymptomatic delayed migration of a coil loop in a patient following successful coil embolization of an anterior communicating artery saccular aneurysm. Methods. A 24-year-old man with a ruptured anterior communicating artery saccular aneurysm underwent coil embolization with one helical ultrasoft coil. Results. A followup CT scan head and a cerebral angiogram one month following the procedure revealed distal migration of an intra aneurysmal coil loop into the left pericallosal artery. The patient, however, remained asymptomatic. Conclusion. Delayed migration of coil following embolization of an intracranial aneurysm is an extremely rare occurrence. An asymptomatic presentation, as in our patient, is even more unique. The stent-like configuration of the migrated spiral coil loop probably prevented complete occlusion of the blood vessel. PMID- 22937469 TI - Giant precordial T wave inversion in a patient with gastroenteritis. AB - Giant precordial T wave inversion (GPTI) on ECG may be the result of several pathologies, including myocardial ischemia, pulmonary edema, pulmonary embolism, subarachnoid hemorrhage, apical hypertrophy, and postpacing. We describe a case of a 75-year-old woman who developed GPTI after an episode of gastroenteritis. To our knowledge, this is the first report of this ECG pattern associated with gastroenteritis. PMID- 22937470 TI - Use of the stingray re-entry system in two complex cases of occluded superficial femoral arteries. AB - Totally occluded infrainguinal arterial disease presents formidable challenges to endovascular revascularization. A variety of devices have been made available to make the crossing of these lesions more amenable to endovascular techniques. We discuss the novel use of a device that has been developed for crossing occluded coronary arteries, the Stingray Re-Entry System. PMID- 22937471 TI - Coronary subclavian steal syndrome unamenable to angioplasty successfully managed with subclavian-subclavian bypass. AB - Purpose. Coronary-subclavian steal syndrome (CSSS) is defined as a reversal of flow in a previously constructed internal mammary artery (IMA) coronary conduit, producing myocardial ischemia. We present a case of CSSS which could not be ameliorated with endovascular therapy and necessitated a subclavian-subclavian bypass. Case Report. 80-year-old Caucasian male with history of CABG presented with syncope. He had absent left-sided radial pulse with blood pressure being 60/40 on left arm and 130/80 on the right. He underwent cardiac catheterization for NSTEMI which showed patent left internal mammary artery graft to left anterior descending coronary artery with retrograde flow, and diagnosis of coronary subclavian steal syndrome was made. Complete occlusion of proximal left subclavian artery was identified. Percutaneous angioplasty failed because of calcified plaque causing 100% occlusion. Carotid doppler showed bilateral carotid artery disease. He finally underwent subclavian-subclavian bypass which resolved his condition. Conclusion. Subclavian-subclavian bypass is a successful alternative to carotid-subclavian bypass for management of CSSS especially with concomitant critical carotid artery atherosclerotic disease. PMID- 22937472 TI - ObamaCare: Another step toward corporate socialized medicine in the US. PMID- 22937473 TI - Hemorrhage and risk of further hemorrhagic strokes following cerebral revascularization in Moyamoya disease: A review of the literature. AB - BACKGROUND: We sought to review the current literature with regards to future risks of hemorrhage following cerebral revascularization in Moyamoya disease (MMD). METHODS: We performed a comprehensive literature review using PubMed to inspect the available data on the risk of hemorrhage after revascularization in MMD. RESULTS: In this review, we identify the risk factors associated with hemorrhage in MMD both before and after cerebral revascularization. We included proposed pathophysiology of the hemorrhagic risk, role of the type of bypass performed, treatment options, and future needs for investigation. CONCLUSIONS: The published cases and series of MMD treatment do show a risk of hemorrhage after treatment with either direct or indirect bypass both in the immediate as well as long-term future. While there are no discernible patterns in the rate of these hemorrhages, there is Class III evidence for the predictive effect of multiple microbleeds on preoperative imaging. Also, whereas revascularization, both direct and indirect, has been shown to reduce ischemic complications from MMD, there is not an association with the risk of hemorrhage after the procedure. Further studies need to be performed to help evaluate what the risk factors are and how to counsel patients as to the long-term outlook of this disease process. PMID- 22937474 TI - Image-guided linear accelerator-based spinal radiosurgery for hemangioblastoma. AB - PURPOSE: To retrospectively review the efficacy and safety of image-guided linear accelerator-based radiosurgery for spinal hemangioblastomas. METHODS: Between August 2004 and September 2010, nine patients with 20 hemangioblastomas underwent spinal radiosurgery. Five patients had von Hipple-Lindau disease. Four patients had multiple tumors. Ten tumors were located in the thoracic spine, eight in the cervical spine, and two in the lumbar spine. Tumor volume varied from 0.08 to 14.4 cc (median 0.72 cc). Maximum tumor dimension varied from 2.5 to 24 mm (median 10.5 mm). Radiosurgery was performed with a dedicated 6 MV linear accelerator equipped with a micro-multileaf collimator. Median peripheral tumor dose and prescription isodose were 12 Gy and 90%, respectively. Image guidance was performed by optical tracking of infrared reflectors, fusion of oblique radiographs with dynamically reconstructed digital radiographs, and automatic patient positioning. Follow-up varied from 14 to 86 months (median 51 months). RESULTS: Kaplan-Meier estimated 4-year overall and solid tumor local control rates were 90% and 95%, respectively. One tumor progressed 12 months after treatment and a new cyst developed 10 months after treatment in another tumor. There has been no clinical or imaging evidence for spinal cord injury. CONCLUSIONS: Results of this limited experience indicate linear accelerator-based radiosurgery is safe and effective for spinal cord hemangioblastomas. Longer follow-up is necessary to confirm the durability of tumor control, but these initial results imply linear accelerator-based radiosurgery may represent a therapeutic alternative to surgery for selected patients with spinal hemangioblastomas. PMID- 22937475 TI - Effects of alpha-MSH on ischemia/reperfusion injury in the rat sciatic nerve. AB - BACKGROUND: Ischemia/reperfusion (I/R) causes the production of toxic free radicals and leads to pathological changes in nerve tissue. We investigated the effect of alpha-melanocyte stimulating hormone (alpha-MSH) in a rat model for sciatic nerve I/R and discuss the possible cytoprotective and antioxidant mechanism of alpha-MSH against ischemic fiber degeneration. METHODS: Experiments were performed using 42 adult male Wistar rats. Rats were divided into six experimental groups: control group, ischemia group, I/R groups, and alpha-MSH treated groups. Ischemia was produced by clamping of the femoral vessels. Immediately after ischemia that lasted 3 h, 75 MUg/kg of alpha-MSH was administered subcutaneously before reperfusion and the tissue malondialdehyde (MDA) level was evaluated as an indicator of lipid peroxidation in groups with different reperfusion periods. RESULTS: The reperfusion injury did not begin in the first hour of reperfusion after 3 h of ischemia, and MDA levels increased on the first day of reperfusion. During the first day, blood MDA levels were decreased in the alpha-MSH group compared to the control group. The tissue from animals pre-treated with alpha-MSH showed fewer morphological alterations. Myelin breakdown was significantly diminished after treatment with alpha-MSH, and the ultrastructural features of axons showed remarkable improvement. Two-way analysis of variance was used for comparing three or more groups. When a significant difference existed, the post-hoc multiple-comparison test was applied to demonstrate the differences. CONCLUSIONS: The results confirm that pre-treatment with alpha-MSH after ischemia protected the peripheral nerves against I/R injury. PMID- 22937476 TI - Magnetic resonance imaging is essential prior to spinal subarachnoid blockade for parturients with a history of brain tumor resection undergoing cesarean section. AB - BACKGROUND: Primary brain tumors are usually treated by surgical removal with the goal of complete resection within the constraints of preservation of neurological function. However, gross total resection may not mean complete tumor removal, and ongoing compression from a mass effect can lead to serious sequelae. Spinal subarachnoid blockade is contraindicated in patients with brain tumors or space occupying lesions. CASE DESCRIPTION: A 32-year-old full term parturient presented to Labor and Delivery for semi-urgent repeat cesarean section. Three months ago, she underwent resection of a benign brain tumor and recovered with no new neurological deficits. The neurosurgeon was consulted by the anesthesia team and stated that the tumor was completely extirpated. Since there was no postoperative magnetic resonance imaging (MRI) and the patient still had some neurological deficits, the anesthesia team decided to proceed with a general anesthetic using a rapid sequence induction and intubation. Mild hyperventilation to maintain an end-tidal CO(2) of 30 mmHg was selected and conservative fluid management was maintained. Postcesarean MRI revealed residual tumor compressing the brain stem and a loculated cyst. If a spinal subarachnoid blockade technique had been selected, the risk of uncal herniation, based on the postoperative MRI findings, may have been realized. CONCLUSIONS: The present case demonstrates the necessity of a comprehensive and thorough review prior to selecting the anesthetic approach to mange the patients with a history of brain tumor resection. Postoperative MR imaging should be performed to evaluate the extent of tumor resection and possible existence of residual tumor. PMID- 22937477 TI - Ependymomas of the filum terminale: The role of surgery and radiotherapy. AB - BACKGROUND: Ependymomas of the filum terminale (EFT) form a specific and relatively uncommon subtype of spinal cord ependymomas. Most series in the literature are small, spanning a large time period. Up to date no consensus has been reached about the optimal treatment of these lesions. Some authors promote postoperative radiotherapy for all cases, others advocate postoperative radiotherapy only when a subtotal resection is performed or when metastasis are apparent. METHODS: We performed a retrospective analysis of 22 patients with an EFT (mean age at diagnosis of 35.6 years). RESULTS: In all patients (9/22) with lesions smaller than 4.5 cm no metastases were present and a complete resection could be obtained. No adjuvant radiotherapy was performed and at latest follow they had an excellent outcome. In our series, these initial tumor characteristics were more important regarding prognosis than either histology or treatment related factors. For the larger tumors, total resection was obtained less frequently, more dissemination was diagnosed and a worse outcome was scored. Radiotherapy if indicated did lead to an acceptable disease control. CONCLUSION: In every case of EFT, an individual treatment protocol has to be outlined, but if an EFT is relatively small and can be resected completely, we would advocate to withhold radiotherapy. PMID- 22937478 TI - Spinal endodermal cyst resembling an arachnoid cyst in appearance: Pitfalls in intraoperative diagnosis of cystic lesions. AB - BACKGROUND: Surgical treatment of endodermal cysts requires total removal of the cyst wall during the first operation to prevent recurrence. Therefore, intraoperative pathological diagnosis plays an important role in determining the optimal surgical strategy. We present a rare case of a spinal endodermal cyst and discuss its diagnostic difficulty during the intraoperative pathological examination. CASE DESCRIPTION: An 18-year-old male presented with progressive paraparesis and precordial oppression. Magnetic resonance (MR) imaging revealed an intradural extramedullary cystic mass having the same signal intensity as cerebrospinal fluid (CSF) without gadolinium enhancement at the T1-T2 level. The preoperative diagnosis was an endodermal or arachnoid cyst. The patient underwent surgery. An intraoperative frozen section showed a cyst wall consisting of loose, thin, fibrous tissue intermittently covered by flattened epithelium. The diagnosis was an arachnoid cyst. Accordingly, partial resection of the cyst wall was performed to create CSF communication between the cyst and subarachnoid space. However, the postoperative pathological diagnosis from permanent sections was an endodermal cyst, which was lined with ciliated columnar epithelium that was immunopositive for cytokeratin and epithelial membrane antigen. Subsequent paraffin embedding and immunostaining of the intraoperative frozen sample also confirmed patchy cytokeratin expression by all flattened epithelial cells. The patient's cyst had refilled 10 months after surgery, and he subsequently underwent fenestration of the cyst wall and placement of a cyst-subarachnoid shunt. CONCLUSION: Examination of multiple samples from multiple sites or intraoperative immunostaining of frozen sections is recommended for accurate intraoperative diagnosis of endodermal cysts. PMID- 22937479 TI - Epilepsy due to a temporal ganglioglioma and its subsequent malignant transformation into a primitive neuroectodermal tumor. AB - BACKGROUND: Gangliogliomas (GGs) are rare brain tumors, and their malignant changes are still less frequent. In these cases, almost always the malignant component is the glial one. However, there are few cases in which the neuronal component exhibits malignant transformation. CASE DESCRIPTION: We described a case of a 14-year-old male patient who started with seizures and 5 years later, its frequency was almost daily despite being treated with several antiepileptic drugs. Magnetic resonance imaging showed a nonenhancing lesion located at the right inferior temporal gyri. He underwent surgery, and the tumor was completely removed. Histological diagnosis was GG. He had no seizures anymore, but 3 years later, the tumor recurred as a giant heterogeneously enhancing space-occupying mass within the right temporal lobe. A second surgical resection was performed. Histological diagnosis was a primitive neuroectodermal tumor (PNET). One month and a half later, the tumor has recurred again. He and his family decided not to undergo another operation, so he was referred to the radiotherapy department. CONCLUSION: As in this patient, GGs may recur as a primitive neuroectodermal tumor, likely because both types of neoplasm form part of the same heterogeneous group of brain tumors which contains neuronal components, but on the other side of the malignancy spectrum. PMID- 22937480 TI - Intramedullary neurenteric cyst associated with a tethered spinal cord: Case report and literature review. AB - BACKGROUND: Neurenteric cysts are benign tumors of the central nervous system (CNS) that represent 0.3% to 0.5% of all spinal cord tumors. They are usually extramedullary and found in the lower cervical and thoracic spine. Only 12.2% of neurenteric cysts are documented to be intramedullary. CASE DESCRIPTION: The authors report a case of a 35-year-old female that presented with progressive weakness and loss of coordination in her legs. Magnetic resonance imaging (MRI) showed an intramedullary cystic lesion in the thoracolumbar region and a low lying conus medullaris suggesting tethered cord. The patient was taken to the operating room for detethering of her spinal cord and resection of the lesion. Pathologic examination of the tissue confirmed the diagnosis of a neurenteric cyst. CONCLUSION: A search of the literature since the advent of MRI showed 29 published cases of intramedullary neurentic cysts. Of the 24 published cases with a follow-up MRI, the average recurrence rate was 25% with a mean follow up of 51 months. PMID- 22937481 TI - 3T magnetic resonance imaging testing of externally programmable shunt valves. AB - BACKGROUND: Exposure of externally programmable shunt-valves (EPS-valves) to magnetic resonance imaging (MRI) may lead to unexpected changes in shunt settings, or affect the ability to reprogram the valve. We undertook this study to examine the effect of exposure to a 3T MRI on a group of widely used EPS valves. METHODS: Evaluations were performed on first generation EPS-valves (those without a locking mechanism to prevent changes in shunt settings by external magnets other than the programmer) and second generation EPS-valves (those with a locking mechanisms). Fifteen new shunt-valves were divided into five groups of three identical valves each, and then exposed to a series of six simulated MRI scans. After each of the exposures, the valves were evaluated to determine if the valve settings had changed, and whether the valves could be reprogrammed. The study produced 18 evaluations for each line of shunt-valves. RESULTS: Exposure of the first generation EPS-valves to a 3T magnetic field resulted in frequent changes in the valve settings; however, all valves retained their ability to be reprogrammed. Repeated exposure of the second generation EPS-valves has no effect on shunt valve settings, and all valves retained their ability to be interrogated and reprogrammed. CONCLUSIONS: Second generation EPS-valves with locking mechanisms can be safely exposed to repeated 3T MRI systems, without evidence that shunt settings will change. The exposure of the first generation EPS-valves to 3T MRI results in frequent changes in shunt settings that necessitate re evaluation soon after MRI to avoid complications. PMID- 22937482 TI - Solitary cerebral metastasis from transitional cell carcinoma after a 14-year remission of urinary bladder cancer treated with gemcitabine: Case report and literature review. AB - BACKGROUND: Brain metastases are the most common adult brain tumors, frequently arising from primary tumors in the lung, breast, skin, kidneys, and colon. Transitional cell carcinoma (TCC), the most common type of urinary bladder cancer, is a rare cause of brain metastasis with an ominous prognosis. CASE DESCRIPTION: A 68-year-old female presented with right-sided paresis and focal motor seizures of her right upper and lower extremities 14 years after being diagnosed and treated for primary TCC of the urinary bladder with gemcitabine based chemotherapy. MRI imaging revealed a 3.1 * 3.1 * 2.7 cm heterogeneously enhancing mass located along the posterior aspect of the left frontal convexity. The lesion was accessed using a transsulcal approach and was surgically debulked along the motor cortex with motor strip mapping, followed by adjuvant whole-brain radiation therapy. Pathological examination confirmed metastatic carcinoma with features of TCC, a rare entity among metastatic brain tumors. CONCLUSION: Brain metastases may present several years later in patients with TCC of the urinary bladder who have been treated with surgery and chemotherapy. Chemotherapeutic agents that penetrate the blood-brain barrier, such as gemcitabine, may delay development of cerebral metastasis from primary TCC of the urinary bladder. PMID- 22937483 TI - "Hitting all the right markers to save a life" Solitary fibrous tumors of the central nervous system: Case series and review of the literature. AB - BACKGROUND: Solitary fibrous tumors (SFTs) of the central nervous system are uncommon. Their biological features remain largely unknown; hence, the clinical management and prognosis is often challenging due to the lack of comprehensive data. For this reason, we present two cases of large SFTs to illustrate a comprehensive review. METHODS: THIS WAS A RETROSPECTIVE ANALYSIS OF TWO PATIENTS: a 65-year-old male with a left parietooccipital lesion and a 70-year-old female with a right parietal convexity mass. RESULTS: Gross total resection was performed in the male patient with no recurrence 30 months after resection. The second patient received stereotactic radiosurgery for what was initially thought to be a parafalcine meningioma; however, continued growth 1 year later prompted an open resection, with pathology indicative of an SFT. The tumor recurred the following year requiring repeat resection. Unfortunately, due to the aggressive nature of the lesion, the patient eventually succumbed to tumor burden a year later. CONCLUSION: Based on the literature review, the sometimes observed aggressive growth pattern, and also, the potential for malignant transformation, we recommend complete resection of SFTs with close sequential follow-up. PMID- 22937484 TI - Stent-assisted coil emboilization of ruptured intracranial aneurysms: A retrospective multicenter review. AB - BACKGROUND: The purpose of this study is to retrospectively review our experience with stent-assisted embolization of patients with an acutely ruptured cerebral aneurysm. METHODS: Medical records and imaging were reviewed for 36 patients who underwent stent-assisted embolization of a ruptured cerebral aneurysm. RESULTS: Seventeen patients (47%) received a preprocedural loading dose of clopidogrel and five patients (14%) received an intraprocedural dose of clopidogrel. The remaining 14 patients (36%) were treated with antiplatelet therapy following the procedure. Six (17%) stent related intraprocedural thromboembolic complications were encountered; four of these resolved (one partial, three complete) following treatment with abciximab and/or heparin during the procedure. Five of the six thromboembolic events occurred in patients who were not pretreated with clopidogrel (P = 0.043). Two patients in this series (6%) had a permanent thrombotic complication resulting in mild hemiparesis in one patient, and hemianopsia in the second. No procedure related hemorrhagic complications occurred in any patient. One patient had a spontaneous parenchymal hemorrhage contralateral to the treated aneurysm discovered 10 days after treatment. Twenty eight patients (78%) had a Glasgow Outcome Score of 4 or better at discharge. Seven of 21 patients (33%) with angiographic follow-up required further treatment of the coiled aneurysm. CONCLUSION: Stent-assisted coil embolization is an option for treatment of ruptured wide neck ruptured aneurysms and for salvage treatment during unassisted embolization of ruptured aneurysms but complications and retreatment rates are higher than for routine clipping or coiling of cerebral aneurysms. Pretreatment with clopidogrel appears effective in reducing thrombotic complications without significant increasing risk of hemorrhagic complications. PMID- 22937485 TI - Effect of lesional differences in prolapsed leaflets on clinical outcomes in patients with mitral valve prolapse. AB - BACKGROUND: Mitral valve prolapse (MVP) is usually benign, although serious complications may occur. It remains unclear whether the region of prolapsed mitral leaflets might affect prognosis. The aim of this study was to investigate lesional differences of clinical courses of MVP. METHODS AND RESULTS: We retrospectively investigated 128 MVP patients who had been followed up for for a mean of 56.4 months. They were classified into prolapse of the anterior mitral leaflet (AML, n = 59), posterior mitral leaflet (PML, n = 47), or both leaflets (AML & PML, n = 22). Echocardiographic and clinical data were examined from medical records. Average time to clinical events; MV surgery, new onset of atrial fibrillation (AF), echocardiographic evidence of new chordal rupture, and worsening of mitral regurgitation severity were all significantly shorter in PML prolapse than in those with AML or AML & PML prolapses. Increases in the left ventricular dimensions and estimated pulmonary arterial systolic pressures were significantly larger in PML prolapse, compared with AML or AML & PML prolapses. A subanalysis of PML prolapse revealed that new chordal rupture tended to be more frequent in middle scallop prolapse (48%) compared with lateral and medial scallops (18%). In contrast, new onset of AF tended to occur in lateral and medial scallop prolapses (44%) compared with middle scallop prolapse (20%). CONCLUSIONS: PML prolapse patients had a poor outcome, compared with AML or AML & PML prolapse patients. Precise regional evaluation of the prolapsed leaflets may predict cardiac complications in MVP. PMID- 22937486 TI - Treatment of systemic hypertension. AB - Systemic hypertension is a major risk factor for cardiovascular disease and is present in 69% of patients with a first myocardial infarction, in 77% of patients with a first stroke, in 74% of patients with chronic heart failure, and in 60% of patients with peripheral arterial disease. Double-blind, randomized, placebo controlled trials have found that antihypertensive drug therapy reduces cardiovascular events in patients aged younger than 80 years and in patients aged 80 years and older in the Hypertension in the Very Elderly Trial. Although the optimal blood pressure treatment goal has not been determined, existing epidemiologic and clinical trial data suggest that a reasonable therapeutic blood pressure goal should be <140/90 mm Hg in patients younger than 80 years and a systolic blood pressure of 140-145 mm Hg if tolerated in patients aged 80 years and older. Non-pharmacologic lifestyle measures should be encouraged both to prevent development of hypertension and as adjunctive therapy in patients with hypertension. Angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, beta blockers, calcium channel blockers, and diuretics have all reduced cardiovascular events in randomized trials. The choice of specific drugs depends on efficacy, tolerability, presence of specific comorbidities, and cost. PMID- 22937488 TI - Choices in the use of ICD-9 codes to identify stroke risk factors can affect the apparent population-level risk factor prevalence and distribution of CHADS2 scores. AB - While developed for managing individuals with atrial fibrillation, risk stratification schemes for stroke, such as CHADS2, may be useful in population based studies, including those assessing process of care. We investigated how certain decisions in identifying diagnoses from administrative data affect the apparent prevalence of CHADS2-associated diagnoses and distribution of scores. Two sets of ICD-9 codes (more restrictive/ more inclusive) were defined for each CHADS2-associated diagnosis. For stroke/transient ischemic attack (TIA), the more restrictive set was applied to only inpatient data. We varied the number of years (1-3) in searching for relevant codes, and, except for stroke/TIA, the number of instances (1 vs. 2) that diagnoses were required to appear. The impact of choices on apparent disease prevalence varied by type of choice and condition, but was often substantial. Choices resulting in substantial changes in prevalence also tended to be associated with more substantial effects on the distribution of CHADS2 scores. PMID- 22937487 TI - Autoimmune diseases and venous thromboembolism: a review of the literature. AB - Venous thromboembolism (VTE) is major health problem and is sometimes complicated by lethal pulmonary embolism (PE). Disturbances of the coagulation and anticoagulation systems are important risk factors for VTE. Comparative studies suggest that coagulation and innate immunity have a shared evolutionary origin. It is therefore unsurprising that the immune and coagulation systems are linked, with many molecular components being important for both systems. Systemic inflammation modulates thrombotic responses by suppressing fibrinolysis, upregulating procoagulant, and downregulating anticoagulants, and autoimmune disorders such as systemic lupus erythematosus (SLE), inflammatory bowel disease (IBD), and Behcet's syndrome have been linked to an increased risk of VTE. Recent reports have further shown that a majority of autoimmune and immune-mediated disorders are linked to an increased risk of venous thrombosis, PE, or VTE. For instance, a Swedish nationwide study found that the risk of PE was increased in the first year after hospitalization for 33 different autoimmune disorders. Especially high risks were noted for several autoimmune diseases such as immune thrombocytopenic purpura, polyarteritis nodosa, polymyositis/dermatomyositis, ulcerative colitis, and SLE. Another study from England, also based on hospitalization data, found that immune-mediated disorders were associated with an increased risk of VTE compared with other medical causes of hospitalization. Multiple mechanisms may operate and disease-specific factors, such as cardiolipin antibodies, have been identified. However, inflammation by itself appears to change the hemostatic balance in a thrombogenic direction. Recent epidemiological studies, together with previous experimental and clinical studies, indicate that autoimmune disorders should not only be viewed as inflammatory disorders, but also hypercoagulable disorders. Research to identify thrombotic risk factors, elucidate the mechanisms involved, and investigate prophylactic regiments is needed. The present review describes the epidemiological, clinical, and experimental evidence for the connection between VTE and autoimmune and immune mediated disorders. PMID- 22937490 TI - Hypoxia inducible factor-1alpha-mediated gene activation in the regulation of renal medullary function and salt sensitivity of blood pressure. AB - Many enzymes that produce natriuretic factors such as nitric oxide synthase (NOS), hemeoxygenase-1 (HO-1) and cyclooxygenase-2 (COX-2) are highly expressed in the renal medulla. These enzymes in the renal medulla are up-regulated in response to high salt intake. Inhibition of these enzymes within the renal medulla reduces sodium excretion and increases salt sensitivity of arterial blood pressure, indicating that these enzymes play important roles in kidney salt handling and renal adaptation to high salt challenge. However, it remains a question what mechanisms mediate the activation of these enzymes in response to high salt challenge in the renal medulla. Interestingly, these enzymes are oxygen sensitive genes and regulated by transcription factor hypoxia-inducible factor (HIF)-1alpha. Our recent serial studies have demonstrated that: 1) High salt intake stimulates HIF-1alpha-mediated gene expression, such as NOS, HO-1 and COX 2, in the renal medulla, which may augment the production of different antihypertensive factors in the renal medulla, mediating renal adaptation to high salt intake and regulating salt sensitivity of arterial blood pressure. 2) HIF prolyl-hydroxylase 2 (PHD2), an enzyme that promotes the degradation of HIF 1alpha, is highly expressed in renal medulla. High salt intake suppresses the expression of PHD2 in the renal medulla, which increases HIF-1alpha-mediated gene expressions in the renal medulla, thereby participates in the control of salt sensitivity of blood pressure. 3) The high salt-induced inhibition in PHD2 and the consequent activation of HIF-1alpha in the renal medulla is not observed in Dahl salt sensitive hypertensive (Dahl/ss) rats. Correction of these defects in PHD2/HIF-1alpha-associated molecular adaptation in the renal medulla improves sodium excretion, reduces sodium retention and attenuates saltsensitive hypertension in Dahl/ss rats. In conclusion, PHD2 regulation of HIF-1alpha mediated gene activation in the renal medulla is an important molecular adaptation to high salt intake; impaired PHD2 regulation of HIF-1alpha-mediated gene activation in the renal medulla may be responsible for the salt-sensitive hypertension in Dahl/ss rats; correction of these defects may be used to as therapeutic strategies for the treatment of salt-sensitive hypertension. PMID- 22937491 TI - Impact of SYNTAX score on 1-year clinical outcomes in patients undergoing percutaneous coronary intervention for unprotected left main coronary artery. AB - SYNTAX score is an angiographic scoring system that was developed to quantify the number, complexity, and location of lesions in patients undergoing coronary revascularization. Up to now, the impact of SYNTAX score on clinical outcomes in patients undergoing percutaneous coronary intervention (PCI) for unprotected left main coronary artery (LMCA) lesions has not been fully examined. Therefore, we evaluate the usefulness of the SYNTAX score and identify the cutoff value of this score to predict 1-year clinical outcomes in patients undergoing PCI for unprotected LMCA lesions. This was a single-center retrospective study that included 49 consecutive patients undergoing elective PCI for unprotected LMCA lesions. We calculated the SYNTAX score and examined the correlations between this score and 1-year clinical outcomes. Major adverse cardiac events (MACE) occurred in 12 patients (24%): target lesion revascularization in 9 patients (18%), myocardial infarction in 2 (4%), and cardiac death in 1 (2%). The frequency of MACE was significantly higher in the intermediate (47%) or high score group (50%) than in the low score group (4%). Furthermore, the SYNTAX score was significantly higher in the MACE group than in the non-MACE group (31 vs. 22, p = 0.008). Receiver-operating characteristic curve showed that the SYNTAX score exhibited 83% sensitivity and 76% specificity for predicting the development of MACE at a cutoff value 26. These results demonstrate that the SYNTAX score could be a useful tool to predict 1-year clinical outcomes in patients undergoing elective PCI for unprotected LMCA lesions. PMID- 22937489 TI - New frontiers in heart hypertrophy during pregnancy. AB - During Pregnancy, heart develops physiological left ventricular hypertrophy as a result of the natural volume overload. Previously we have characterized the molecular and functional signature of heart hypertrophy during pregnancy. Cardiac hypertrophy during pregnancy is a complex process that involves many changes including in the signalling pathways, composition of extracellular matrix as well as the levels of sex hormones. This review summarises the recent advances and the new frontiers in the context of heart hypertrophy during pregnancy. In particular we focus on structural and extracellular matrix remodelling as well as signalling pathways in pregnancy-induced physiological heart hypertrophy. Emerging evidence shows that various microRNAs modulate key components of hypertrophy, therefore the role of microRNAs in the regulation of gene expression in pregnancy induced hypertrophy is also discussed. We also review the role of ubiquitin proteasome system, the major machinery for the degradation of damaged and misfolded proteins, in heart hypertrophy. The role of sex hormones in particular estrogen in cardiac remodeling during pregnancy is also discussed. We also review pregnancy-induced cardiovascular complications such as peripartum cardiomyopathy and pre-eclampsia and how the knowledge from the animal studies may help us to develop new therapeutic strategies for better treatment of cardiovascular diseases during pregnancy. Special emphasis has to be given to the guidelines on disease management in pregnancy. PMID- 22937492 TI - Protection of the ischemic myocardium during the reperfusion: between hope and reality. AB - The heart is an organ that requires an important energy input to ensure its contractile function. Myocardial ischemia happens when there is a deficiency of blood flow that is responsible for the passage from an aerobic to anaerobic metabolism. Myocardial ischemia results from an imbalance between inputs and the needs of nutrient and oxygen to the myocardium. The restoration of myocardial perfusion called reperfusion is a way to save the ischemic myocardium. However, although reperfusion is beneficial for the survival of the ischemic myocardium, it also induces a deleterious effect in addition to that of ischemic stress. Three decade ago, while several studies, strived to elucidate the protective effect of preconditioning, a phenomenon performed before ischemia and having a powerful protective effects against ischemia/reperfusion injury, very few have believed in the possibility of protecting the myocardium after ischemia (during reperfusion). Actually, both ischemic and pharmacological postconditioning as well as controlled reperfusion methods to protect the ischemic heart have proved effective in the reduction of damage related to ischemia/reperfusion. The possibility of protecting the myocardium during reperfusion opens a new area in the research against damage caused by ischemia/reperfusion because these methods are easily transferable in a clinic setting. PMID- 22937495 TI - Launching of international journal of burns and trauma. PMID- 22937494 TI - Impact of timing to coronary angiography in acute coronary syndrome on contemporary clinical practice. AB - Recent studies appear to suggest a correlation between timing to coronary angiography and clinical outcome among patients with acute coronary syndrome (ACS). We aim to study 12-month outcomes of ACS patients who are stratified according to early (<=24 hours), intermediate (>24 to <48 hours) and delayed (>=48 hours) coronary angiography. This is a prospective observational study of patients with ACS defined as either unstable angina pectoris or non-ST elevation myocardial infarction (MI) admitted between October 2008 and July 2009. Baseline clinical characteristics of age, gender, cardiovascular risk factors (diabetes mellitus, hypertension, dyslipidemia) and TIMI score were analyzed and adjusted for outcomes. The primary outcome was combined major adverse cardiovascular events (MACE) of death or non-fatal MI, as well as target vessel revascularization (TVR) up to 12 months. This study consisted of 642 patients (75% males, mean age 60+/-13) with median follow-up of 7 months and median TIMI score of 4. Over half (50.2%) were categorized as high-risk (TIMI score >=4). 281 patients (43.5%) had early angiography, 170 (26.5%) had angiography between >24 to <48 hours and 191(30%) patients had delayed angiography >=48 hours. In high risk patients, the primary outcome occurred in 10.9% of patients in the early group, as compared with 13.2% in intermediate group and 23.9% in delayed group (p=0.015) at six months. However, in low-risk patients (TIMI scores <4), there was no significant difference between the groups (7.1% vs. 3.4% vs. 5.9%, p=0.316) at six months. Compared to the intermediate and delayed groups, patients in the early group had lower overall MACE at 12 months (21% vs. 14% vs. 10%, p=0.006) that was largely related to a lower frequency of death at 12 months (11% vs. 7% vs. 4.6%, p=0.03). There were no differences in rates of TVR between the groups (4% vs. 7% vs. 3.5%, p=0.14). In this observational analysis, an early strategy to coronary angiography was associated with improved survival at one year while an early to intermediate strategy benefitted the subgroup of high-risk patients with significant reductions in cardiovascular events at six months. PMID- 22937493 TI - MicroRNAs in ischemia-reperfusion injury. AB - Ischemia-reperfusion injury (IRI) is a major causal factor of tissue injury in various clinical settings including myocardial infarction, stroke, and free microsurgical tissue transfer. MicroRNAs (miRNAs, miRs) are short, non-coding RNA molecules involved in post-transcriptional regulation of gene expression. During the last years they have emerged as regulators of IRI as well as ischemic preconditioning and ischemic postconditioning. Here we give an overview of the current literature and describe the potential use of miRNA-based therapeutics for the treatment and prevention of ischemia-reperfusion injury in the future. PMID- 22937496 TI - Nucleotide oligomerization domain 2 contributes to the innate immune response in THCE cells stimulated by Aspergillus fumigatus conidia. AB - AIM: To investigate the expression of nucleotide oligomerization domain 2 (NOD2) in the immortalized human corneal epithelial cell line (THCE), and its role in the innate immune response triggered by inactive Aspergillus fumigatus (Af) conidia. METHODS: The normal THCE cells were investigated as controls. After incubation with inactive Af conidia for 0.5, 2, 4, 6, and 8 hours, THCE cells were harvested, mRNA expression of NOD2 and receptor interacting protein 2 (RIP2) was detected by RT-PCR. Intracellular proteins including NOD2, NF-kappaB and proinflammatory cytokines such as TNF-alpha, IL-8, IL-6 in the cell supernatant were analyzed by ELISA. RESULTS: Our data indicate that NOD2 expressed in the normal THCE cells. After triggered by the inactive Af conidia, the expression of NOD2, RIP2 mRNA and the secretion of NOD2, NF-kappaB, TNF-alpha, IL-8, IL-6 both increased in a time-depended manner, and reached the peak point at 4, 6, 6, 4, 6, 6, 4 hours, respectively. And after pretreated with NOD2 neutralizing antibody, the expression of RIP2, NF-kappaB, TNF-alpha, IL-8 both decreased dramatically at the peak point, while the secretion of IL-6 changed little. CONCLUSION: The results of this study suggest that NOD2 exists and expresses in the THCE cells, and contributes to the innate immune responses triggered by inactive Af conidia by induction of proinflammatory cytokines such as TNF-alpha and IL-8 through the NF-kappaB pathway. PMID- 22937497 TI - Evaluation of novel decellularizing corneal stroma for cornea tissue engineering applications. AB - AIM: To develop a new decellularization method depended upon the natural corneal structure and to harvest an ideal scaffold with good biocompatibilities for corneal reconstruction. METHODS: The acellular cornea matrix (ACM) were prepared from de-epithelium fresh porcine corneas (DFPCs) by incubation with 100% fresh human sera and additional electrophoresis at 4 degrees C. Human corneal epithelial cells (HCEs) were used for the cytotoxicity tests of ACM. ACM were implanted into the Enhanced Green Fluorecence Protein (eGFP) transgenic mouse anterior chamber for evaluation of histocompatibility. RESULTS: HE and GSIB4 results showed fresh porcine cornea matrix with 100% human sera and electrophoresis could entirely decellularize stromal cell without reducing its transparency. ACM had no cytotoxic effect ex vivo. Animal test showed there was no rejection for one month after surgery. CONCLUSION: These results provide a decellularizing approach for the study of corneal tissue engineering and had the broader implications for the field of biological tissue engineering in other engineered organ or tissue matrix. PMID- 22937498 TI - Effect of recombinant human platelet-derived growth factor B on cat corneal endothelial cell viability mediated by adeno-associated virus. AB - AIM: To transduce recombinant human platelet-derived growth factor B(PDGF-B) gene adeno-associated virus(AAV) to in vitro cultured cat corneal endothelial cell (CEC) and observe the effect of the expressed PDGF-BB protein on the viability of cat CEC. METHODS: Cat cornea endothelium was torn under microscope and rapidly cultivated in DMEM to form single layer CEC and the passage 2 endothelial cells were used in this study. The recombinant human PDGF-B gene AAV was constructed and transduced into cat CEC directly. Three groups were as following: blank control group, AAV control group and recombinant AAV group. At 24 hours, 48 hours, and 5 days after transduction, total RNA was extracted from the CEC by Trizol and the expression of PDGF-B gene was detected by fluorescence quantitative polymerase chain reaction. Viability of the transduced CEC was detected at 48 hours after transduction by MTT assay. Cell morphology was observed under inverted phase contrast microscope. RESULTS: With the torn endothelium culture technique, we rapidly got single layer cat CEC. At 24 hours, 48 hours and 5 days after transduction, fluorescence quantitative polymerase chain reaction showed there was no significant difference of the expressed PDGF-B gene mRNA between blank control group and AAV control group (P>0.05). In contrast, there were significant differences between two control groups and recombinant AAV group (P<0.05). MTT assay showed that in recombinant AAV group, the expressed PDGF-BB protein could promote the viability of cat CEC. Morphology observation showed at 48 hours after transduction, cells in CEC-AAV-PDGF-B group proliferated into bigger scales in regular triangle to hexagon shape with distinct boundary, while the number of cells was significantly less in the two control groups. CONCLUSION: The recombinant AAV-PDGF-B expresses biological active PDGF-BB protein in cat CECs, which promotes the viability and proliferation of cells. PMID- 22937499 TI - Transplantation of tissue-engineered human corneal epithelium in limbal stem cell deficiency rabbit models. AB - AIM: To evaluate the biological functions of tissue-engineered human corneal epithelium (TE-HCEP) by corneal transplantation in limbal stem cell deficiency (LSCD) rabbit models. METHODS: TE-HCEPs were reconstructed with DiI-labeled untransfected HCEP cells and denuded amniotic membrane (dAM) in air-liquid interface culture, and their morphology and structure were characterized by hematoxylin-eosin (HE) staining of paraffin-sections, immunohistochemistry and electron microscopy. LSCD models were established by mechanical and alcohol treatment of the left eyes of New Zealand white rabbits, and their eyes were transplanted with TE-HCEPs with dAM surface outside by lamellar keratoplasty (LKP). Corneal transparency, neovascularization, thickness, and epithelial integrality of both traumatic and post transplantation eyes were checked once a week by slit-lamp corneal microscopy, a corneal pachymeter, and periodic acid Schiff (PAS) staining. At day 120 post surgery, the rabbits in each group were sacrificed and their corneas were examined by DiI label observation, HE staining, immunohistochemistry and electron microscopy. RESULTS: After cultured for 5 days on dAM, HCEP cells, maintaining keratin 3 expression, reconstructed a 6-7 layer TE-HCEP with normal morphology and structure. The traumatic rabbit corneas, entirely opaque, conjunctivalized and with invaded blood vessels, were used as LSCD models for TE-HCEP transplantation. After transplantation, obvious edema was not found in TE-HCEP-transplanted corneas which became more and more transparent, the invaded blood vessels reduced gradually throughout the monitoring period. The corneas decreased to normal thickness on day 25, while those of dAM eyes were over 575um in thickness during the monitoring period. A 4-5 layer of epithelium consisting of TE-HCEP originated cells attached tightly to the anterior surface of stroma was reconstructed 120 days after TE-HCEP transplantation, which was similar to the normal control eye in morphology and structure. In contrast, intense corneal edema, turbid, invaded blood vessels were found in dAM eyes, and no multilayer epithelium was found but only a few scattered conjunctiva-like cells appeared. CONCLUSION: The TE-HCEP, with similar morphology and structure to those of innate HCEP, could reconstruct a multilayer corneal epithelium with normal functions in restoring corneal transparency and thickness of LSCD rabbits after transplantation. It may be a promising HCEP equivalent for clinical therapy of corneal epithelial disorders. PMID- 22937500 TI - LMWH inhibits anterior chamber inflammation after extra capsular lens extraction through down regulation of bFGF content in aqueous humor. AB - AIM: To observe the changes of basic fibroblast growth factor (bFGF) content in anterior chamber before and after extra capsular lens extraction for investigating the mechanism of low molecular weight heparin (LMWH) inhibiting anterior chamber inflammation. METHODS: Eighty-four rabbits were randomly divided into control and experimental group, 42 rabbits in each group. Extra capsular lens extraction was done on unilateral eye in each rabbit. LMWH was perfused into anterior chamber by the concentration of 50U/mL at the end of operation in experimental group. The degrees of corneal edema, aqueous flare and fibrin were evaluated with slit lamp microscope on postoperative day 1, 3, 6, 15, 30, 45 and 60, respectively. Six eyes of each group were at each time point. Contents of bFGF in aqueous humor were determined by ELISA after animals were killed. Another six eyes were used for determining the base line level of bFGF in aqueous humor. RESULTS: The degrees of corneal edema, aqueous flare and fibrin in experimental group were significantly lighter than those in control group (P<0.01) on postoperative day 1, 3 and 6, respectively. No difference was showed between the two groups at other point time. Contents of bFGF in aqueous humor increased at the same time. bFGF content reached peak on postoperative day 1 in experimental group, while on postoperative day 6 in control group. Contents of bFGF in the two groups declined slowly after reaching peak. The bFGF content in control group were significantly higher than that in experimental group 1-30 days after surgery (P<0.05). No significant differences were shown between the two groups on postoperative day 45 and 60, respectively. CONCLUSION: Perfusion with LMWH by the concentration of 50U/mL can significantly reduce anterior chamber inflammation after extra capsular lens extraction in rabbits, which may be related to down regulation of bFGF content in aqueous humor. PMID- 22937501 TI - Molecular mechanism of the inhibition effect of Celecoxib on corneal collagen degradation in three dimensions. AB - AIM: To clarify the molecular mechanism of Celecoxib on corneal collagen degradation and corneal ulcer. METHODS: Rabbit corneal fibroblasts were harvested and suspended in serum-free MEM. Type I collagen, DMEM, collagen reconstitution buffer and corneal fibroblast suspension were mixed on ice. The resultant mixture solidify in an incubator, after which test reagents and plasminogen was overlaid and the cultures were returned to the incubator. The supernatants from collagen gel incubations were collected and the amount of hydroxyproline in the hydrolysate was measured. Immunoblot analysis of MMP1, 3 and TIMP1, 2 was performed. MMP2, 9 was detected by the method of Gelatin zymography. Cytotoxicity Assay was measured. RESULTS: Celecoxib inhibited corneal collagen degradation in a dose and time manner; Celecoxib inhibited the IL-1beta induced increases in proMMP1, 2, 3, 9 and active MMP1, 2, 3, 9 in a concentration-depended manner. Celecoxib can also inhibit the IL-1beta induced increases in the TIMP1, 2. CONCLUSION: Celecoxib can inhibit corneal collagen degradation induced by IL 1beta, this effect is the consequence of the reduction of MMP1, 2, 3, 9 and TIMP1, 2. The results of the present study provide new insight into Celecoxib in corneal ulcer treatment. PMID- 22937503 TI - Comparison of the effects of bevacizumab and ranibizumab injection on corneal angiogenesis in an alkali burn induced model. AB - AIM: To investigate the effects of bevacizumab and ranibizumab on corneal neovascularization in an alkali burn-induced model of corneal angiogenesis. METHODS: Fifteen Wistar albino rats were divided randomly into 3 groups after chemical cauterization of the cornea. The first group received a single dose of 0.1mL saline solution as a control group whereas second and third groups received a single dose of 2.5mg bevacizumab or 1mg ranibizumab by subconjunctival injection, respectively. After three weeks, the rat corneas were evaluated by biomicroscopy and corneal photographs were taken. The percentage of neovascularization area, length of the longest new vessel, corneal edema and corneal opacity scores were assessed. RESULTS: The analysis of digital photographs showed that the percentage of neovascularization area to the total corneal area, the length of the longest new vessel, corneal edema and opacity scores were significantly lower in both study groups compared to the control group (P<0.05). Additionally, the percentage of corneal neovascularization area, the length of the longest new vessel and corneal opacity score were less with bevacizumab than ranibizumab. CONCLUSION: Subconjunctival bevacizumab and ranibizumab treatments may be effective methods in reducing corneal neovascularization. Furthermore, bevacizumab is more effective than ranibizumab in the inhibition of corneal neovascularization. PMID- 22937502 TI - Effect of VEGF-targeted antisense gene therapy on retinoblastoma cell line SO RB50 in vitro and in vivo. AB - AIM: To evaluate the possibility of generation 4 polyamidoamine (G4PAMAM) dendrimers acting as the delivery system of vascular endothelial growth factor (VEGF) antisense oligodeoxynucleotides (VEGFASODN), and to investigate the anti tumor effect of G4PAMAM/VEGFASODN complex on the cultured cells and the mouse tumor xenograft model. METHODS: The transfection efficiency was assessed by Flow cytometry (FCM). Thiazolyl tetrazolium (MTT) assay was performed to determine the relative growth rate (RGR) of the cells after transfection. Then a mouse tumor xenograft model of human retinoblastoma was established. Different interventions were given to the mice by intratumoral injection and the tumor growth was monitored. The expression of VEGF mRNA was detected by reverse transcription PCR (RT-PCR), the expression of VEGF protein was determined by western blot analysis, and the microvessel density (MVD) was measured by immunohistochemistry (IHC) staining. RESULTS: G4PAMAM/VEGFASODN exhibited a high transfection rate in vitro, and the transfection rates of different doses of G4PAMAM/VEGFASODN groups increased with higher doses. This effect was accompanied by a dose-depended reduction in cell viability. The tumor growth in the tumor-bearing athymic mice was significantly inhibited in the G4PAMAM/VEGFASODN group. The expressions of VEGF mRNA and protein were obviously inhibited in the G4PAMAM/VEGFASODN group (P<0.05), and the MVD of the G4PAMAM/VEGFASODN group was lower than that of the other groups (P<0.05). CONCLUSION: VEGFASODN can be delivered into the cultured and transplanted retinoblastoma cells efficiently by G4PAMAM, suppress the expressions of VEGF mRNA and protein, and reduce the MVD of tumor tissues. The G4PAMAM/VEGFASODN complex has antitumor properties in vitro and in vivo. PMID- 22937504 TI - Magnetic resonance diffusion tensor imaging and diffusion tensor tractography of human visual pathway. AB - AIM: To investigate the visual pathway in normal subjects and patients with lesion involved by diffusion tensor imaging (DTI) and diffusion tensor tractography (DTT). METHODS: Thirty normal volunteers, 3 subjects with orbital tumors involved the optic nerve (ON) and 33 subjects with occipital lobe tumors involved the optic radiation (OR) (10 gliomas, 6 meningiomas and 17 cerebral metastases) undertook routine cranium magnetic resonance imaging (MRI), DTI and DTT. Visual pathway fibers were analyzed by DTI and DTT images. Test fractional anisotropy (FA) and mean diffusivity (MD) values in different part of the visual pathway. RESULTS: The whole visual pathway but optic chiasm manifested as hyperintensity in FA maps and homogenous green signal in the direction encoded color maps. The optic chiasm did not display clearly. There was no significant difference between the bilateral FA values and MD values of normal visual pathway but optic chiasm, which the FA values tested were much too low (all P>0.05). The ONs of subjects with orbital tumors were compressed and displaced. Only one subject had lower FA values and higher MD values. OR of 9 gliomas subjects were infiltrated, with displacement in 2 and disruption in 7 subjects. All OR in 6 meniongiomas subjects were displaced. OR in 17 cerebral metastases subjects all developed displacement while 7 of them had disruption also. CONCLUSION: MR-DTI is highly sensitive in manifesting visual pathway. Visual pathway can be analyzed quantitatively in FA and MD values. DTT supplies accurate three dimensional conformations of visual pathway. But optic chiasm's manifestation still needs to improve. PMID- 22937505 TI - Outcomes and possible risk factors associated with axis alignment and rotational stability after implantation of the Toric implantable collamer lens for high myopic astigmatism. AB - AIM: To assess the visual outcomes and possible risk factors associated with axis alignment and rotational stability after implantation of Toric implantable collamer lens (TICL) for the correction of high myopic astigmatism. METHODS: In this prospective, nonrandomized clinical study, 54 consecutive eyes of 29 patients with high myopic astigmatism received TICL implantation. To evaluate postoperative axis deviation from the intended axis, a digital anterior segment photograph was taken. The ultrasound biomicroscopy(UBM) was used to observe footplate-position. RESULTS: After mean follow-up of 8.6 months, mean manifest refractive cylinder (MRC) decreased 79.3% from (-1.88+/-1.49)D preoperatively to (0.39+/-0.61)D postoperatively. MRC within 1.00 D occurred in 68.5% (37/54) of eyes, whereas 48.1% (26/54) had MRC within 0.50 D. Mean manifest refraction spherical equivalent (MRSE) changed from (-12.08+/-4.22)D preoperatively to ( 0.41+/-0.61)D postoperatively. Uncorrected binocular vision of 20/20 or better occurred in 72.2% (39/54) of patients compared with binocular best-corrected visual acuity (BCVA) of 20/20 or better in 44.4% (24/54) preoperatively. The mean difference between intended and achieved TICL axes was (6.96+/-8.37) degrees . Footplates of TICLs were in the ciliary sulcus in 22 eyes (46.3%), below the ciliary sulcus in 32 eyes (53.7%). The angle of TICL rotation had significant correlation with the footplates-position (t=2.127; P=0.045) and the postoperative TICL vaulting (r=-0.516; P=0.000). CONCLUSION: The results of our study further support the safety, efficacy and predictability of TICL for the correct high myopic astigmatism. The footplate-position of TICL and vault value should be taken into consideration as two possible risks factors for TICL rotation. PMID- 22937506 TI - Clinical effect of improved viscocanalostomy for the treatment of primary congenital glaucoma. AB - AIM: To evaluate the clinical effect of improved viscocanalostomy in patients with primary congenital glaucoma. METHODS: Retrospective analysis of improved viscocanalostomy was performed on 51 eyes of 42 patients with primary congenital glaucoma. The outcome evaluation included postoperative intraocular pressure(IOP), corneal diameter, cup/disc ratio and complications. All patients were followed up at week 1, month 1, 3, 6 and 12. RESULTS: The results revealed that postoperative IOP was decreased from (38.57+/-13.61)mmHg to (10.53+/ 3.91)mmHg, (14.89+/-5.26)mmHg, (15.42+/-5.11)mmHg, (13.82+/-3.46)mmHg, (13.16+/ 5.29)mmHg at follow-up time of 1 week, 1, 3, 6, 12 months (P<0.001). The postoperative corneal diameter was decreased significantly (P=0.002); The mean cup/dish ratio wasn't significantly different (P=0.148) before and after the surgery, the cup/dish ratio of successful surgery was evidently decreased (preoperative 0.7+/-0.2, postoperative 0.6+/-0.3, P=0.007), but the complications like as unformed anterior chamber were not observed. The mean follow-up period was 12 months. CONCLUSION: Improved viscocanalostomy improves the clinical effects of the patients with primary congenital glaucoma, such as higher success rates, lower postoperative mean IOP and fewer complications. PMID- 22937507 TI - Outcomes of 957 preterm neonatal fundus examinations in a Guangzhou NICU through 2008 to 2011. AB - AIM: To take fundus examination in the preterm neonates to observe the common diseases and report the outcomes in a neonatal intensive care unit (NICU) in Guangzhou between May 2008 and May 2011. METHODS: Fundus examinations were performed with Retcam II in 957 prematures. RESULTS: There were 957 prematures in this study, including 666 males and 291 females, 2 triple births, 152 twins and 803 singletons. During the three years, 86 infants with any stage retinopathy of prematurity (ROP) (9.0%), 123 infants with retinal hemorrhage(12.9%), 10 infants with neonatal fundual jaundice(1.0%) and 3 babies with congenital choroidal coloboma (0.3%) were found. CONCLUSION: Early detection and prompt treatment of ocular disorders in neonates is important to avoid lifelong visual impairment. Examination of the eyes should be performed in the newborn period and at all well child visits. PMID- 22937508 TI - Refractive accuracy after intraocular lens implantation in pediatric cataract. AB - AIM: To analyze the factors that influence the prediction error (PE) after intraocular lens (IOL) implantation in pediatric cataract. METHODS: The medical records of cataract patients of no more than 14 years old who had primary IOL implantation were reviewed from 2006 to 2010. The PE, absolute value of PE (APE), and predictability between in different axial length, mean corneal curvature, corneal astigmatism, and age at the surgery were analyzed. RESULTS: Seventy-five children (119 eyes) were included, with a mean age of (5.09+/-2.54) years. At the follow-up of (1.19+/-0.69) months, the mean postoperative PE was (-0.22+/-1.12) D, and APE was (0.87+/-0.73)D. The PE in eyes with an axial length >20mm but <=22mm were significantly under-corrected than that in eyes with longer axis, and the APE in eyes with an axial length <=20mm was more obvious compared with the others. The correlations between PE and axial length, as well as corneal astigmatism, and between APE and axial length were significant. The predictability was significantly poorer in the eyes with an axial length <=20mm than the others. CONCLUSION: The axial length is closely related with the PE after IOL implantation in pediatric cataract patients, especially when it is <=20mm, PE is more significant. The formula that is more suitable to very short axial length should be explored. PMID- 22937509 TI - Comparison of the Schirmer I test with and without topical anesthesia for diagnosing dry eye. AB - AIM: To determine the value of Schirmer I test (S I t) without anesthesia and with topical anesthesia for diagnosing dry eye (DE). METHODS: Totally 220 eyes in 110 patients, male (44) and female (66), (39.56+/-12.67) years old diagnosed with DE were examined. S I t without anesthesia was performed firstly, and 15 minutes later, it was applied again in the same person after topical anesthesia with 0.5% proparacaine hydrochloride eye drops. The wetting strips counted <10mm per 5 minutes were defined positive, while <=5mm per 5 minutes were defined strong positive. RESULTS: The wetting length in S I t after topical anesthesia was significantly lower than that in S I t without anesthesia (P<0.001). The positive rate and strong positive rate of S I t after topical anesthesia were significantly higher than that of S I t without anesthesia (P<0.001). The positive rate and strong positive rate of S I t without anesthesia and the strong positive rate of S I t after topical anesthesia in patients with aqueous deficiency dry eye (ADDE) were significantly higher than those in total patients whereas those in patients with evaporative dry eye (EDE) were significantly lower than those in total patients (P<0.001). CONCLUSION: S I t after topical anesthesia with 0.5% proparacaine hydrochloride eye drops is more objective and reliable than that without anesthesia in reflecting the status of DE, and its diagnostic value in patients with ADDE was even higher, making itself a meaningful evidence for the diagnosis and treatment of DE. PMID- 22937510 TI - Efficacy and necessity of prophylactic vitrectomy for acute retinal necrosis syndrome. AB - AIM: To compare the efficacy of prophylactic vitrectomy for acute retinal necrosis syndrome(ARN) with routine treatment in Chinese patients, thereby investigate the necessity of prophylactic vitrectomy for ARN. METHODS: Thirty patients (37 eyes) were retrospectively included in this study. The eyes were divided into 2 groups by treatment, including routine treatment, which consisted of antiviral medication and vitrectomy after retinal detachment (RD) (n=21), and prophylactic vitrectomy, which consisted of antiviral medication and vitrectomy for the prevention of RD performed during the active inflammatory phase (n=16). The extent of necrosis was determined by fundus photographs at the time of presentation (for eyes with mild vitreous opacity) or the drawings in the operation records. Necrosis of the 37 eyes was divided into 3 grades, including peripheral, middle-peripheral and extensive. The follow-up period ranged from 8 to 57 months. Differences in visual acuity and necrosis between groups were identified using independent samples t-test. RESULTS: Necrosis was more extensive in the routine treatment group than in the prophylactic vitrectomy group (P<0.05). In the routine treatment group, conservative treatment improved necrosis and prevented RD in 6 eyes (29%). Seven eyes (33%) obtained anatomical success, but retinal redetachment occurred in 8 eyes (57%). There were also 5 eyes (24%) developed ocular hypotony or atrophy. Ten eyes (48%) achieved equal or increased visual acuity. In the prophylactic vitrectomy group, RD occurred in 2 eyes (13%). Twelve eyes (75%) were completely anatomically successful, and 10 eyes underwent silicone oil removal. Only one eye (6%) became ocular hypotony. Fourteen eyes (88%) achieved equal or increased visual acuity. The prophylactic vitrectomy group achieved better vision trends than the routine treatment group (P<0.05). Eyes with peripheral necrosis had better visual outcomes than those with mid-peripheral (P<0.05) or extensive (P<0.05) necrosis. However, there was no significant difference between eyes with mid-peripheral and extensive necrosis (P=0.3008) CONCLUSION: Prophylactic vitrectomy can prevent RD and improve the prognosis of ARN, making it an option for cases with rapidly progressing necrosis despite antiviral treatment and cases with moderate to extensive necrosis and severe vitreous opacity. PMID- 22937511 TI - Reconstruction of complex orbital fracture with titanium implants. AB - AIM: To evaluate the effectiveness and safety of complex orbital fracture reconstruction with titanium implants. METHODS: A retrospective review of 46 patients treated with complex orbital fractures reconstruction using titanium implants from January 2005 to December 2008 was conducted. The following data were recorded: age, gender, mechanism of injury, preoperative and postoperative orbital CT, visual acuity, diplopia, ocular motility and Hertel exophthalmometer. RESULTS: The most common cause was motor vehicle accident (47.8%), followed by industrial injury (30.4%). All patients had improved appearance after operation and CT scan at one week after operation showed the fracture defects of orbit and neighboring areas had been reconstructed. Forty-six cases had various degrees of enophthalmos before operation. Among them, 32 cases were completely corrected, 11 cases improved obviously and 3 cases had no improvement after operation. Thirty six patients with visual acuity >=20/60 revealed diplopia of various degrees, including 26 patients had diplopia in right ahead and/or reading positions. At the sixth month after operation, diplopia disappeared in five patients, 7 patients still had diplopia in right ahead and/or reading positions, 14 patients had diplopia in positions rather than right ahead and reading positions (<20 degrees ) and ten patients had diplopia only at peripheral gazing (>20 degrees ). All patients had various degrees of ocular motility disorders before operation. At the sixth month after operation, eyeball movement disorder disappeared in 9 patients, 31 patients showed improvement and 6 patients had no improvement. Complications of implant infection, rejection and displacement were not reported after operation. CONCLUSION: The application of titanium implants in the repair of complex orbital fractures greatly improves the appearance and functional results, which is a favorable material for plastic surgery of complex orbital fracture. PMID- 22937512 TI - Oxidative stress-elevated high gamma glutamyl transferase levels, and aging, intake of tropical food plants, migration and visual disability in Central Africans. AB - AIM: To investigate the independent pathogenic role of high serum gamma-glutamyl transferase (GGT) levels, sociodemographic data, dietary and environmental risk factors for visual disability (VD). METHODS: This was a case-control study, run in 200 black Congolese patients managed in Saint Joseph Hospital Ophthalmology Division from Kinshasa town. Logistic regression model was used to identify determinants of VD (n=58) among sex, age, cigarette smoking, alcohol abuse, rural urban migration, education levels, aging >=60 years, intake of red Beans, Safou fruit and Taro leaves, lipid profile, residence, socioeconomic status, and GGT. RESULTS: After adjusting for confounding factors, we identified migration (OR=3.7 95% CI: 1.2-11.3; P=0.023), low education level (OR=3.1 95% CI 1.1-8.5; P=0.026), no intake of Safou fruit (OR=34.2 95% CI 11.5-102; P<0.0001), age >= 60 years (OR=2.5 95% CI 1.01-6.5; P=0.049), and serum GGT >=10 U/L (OR=3.6 95% CI 1.3-9.6; P=0.012) as the significant and independent determinants of VD. CONCLUSION: VD appears as a major public health problem in Central Africa to be prevented or delayed by control of migration, lifestyle changes, antioxidant supplements, appropriate diet, nutrition education, and blocking of oxidative stress. PMID- 22937513 TI - Risk factors for clinically significant macular edema in a multi-ethnics population with type 2 diabetes. AB - AIM: To determine the risk factors of clinically significant macular edema (CSME) in patients with non-proliferative diabetic retinopathy (NPDR) in a multi-ethnics Malaysian population. METHODS: We performed a case control study in which 150 patients with bilateral NPDR and CSME in either eye were compared to 150 patients with bilateral NPDR and no CSME in both eyes. CSME and NPDR were graded according to Early Treatment of Diabetic Retinopathy Study criteria. Student's t-test, odds ratio and multiple logistic regression analysis were performed to analyze the duration of diabetes, body mass index (BMI), blood pressure(BP), total cholesterol, low density lipoprotein (LDL), high density lipoprotein (HDL), triglycerides (TG), fasting blood glucose (FBG), HbA1c, full blood count, serum creatinine and proteinuria between the two groups. RESULTS: Both groups were matched in terms of age, gender and ethnicity. Duration of diabetes, total serum cholesterol, serum LDL, FBG, HbA1c and serum creatinine were significantly higher in the CSME group (P<0.05). The hemoglobin, packed cell volume were significantly lower in the CSME group (p<0.05). There was no significant difference for serum HDL, TG, BMI, systolic and diastolic BP. Multiple logistic regression analysis showed that total serum cholesterol and HbA1c had significantly high odds of developing CSME. CONCLUSION: HbA1c and total cholesterol are the two most important risk factors associated with CSME in patients with NPDR. PMID- 22937514 TI - Corneal white-to-white distance and mesopic pupil diameter. AB - AIM: To study the relationship between corneal white-to-white (WTW) distance and mesopic pupil diameter. METHODS: This study is composed of 30 cases that underwent photorefractive keratotomy (PRK). Pupil size measurements were performed with Schwind ORK wavefront analyzer in mesopic conditions. WTW distance was measured with a measuring caliper. Also, A-scan ultrasound examination was performed in all patients. The relationship among the mesopic pupil diameter and age, sex, axial length, lens thickness, anterior chamber depth(ACD), horizontal WTW distance, vertical WTW distance, spherical equivalent, and average keratometry were analyzed with univariate and multivariate regression analysis. RESULTS: Mean pupil diameter was (6.39+/-0.80)mm (range: 3.70mm-7.73mm). Horizontal WTW distance measurements were between 11.00mm and 12.50mm and mean horizontal WTW distance was (11.79+/-0.43)mm. On the other hand, vertical WTW distances ranged between 10.00mm and 13.00mm, and their mean was (11.42+/ 0.72)mm. Bivariate correlation between pupil diameter and other variables showed that the axial length, ACD, spherical equivalent, and horizontal WTW distance had a moderate correlation with mesopic pupil diameter. Multiple regression analysis revealed that spherical equivalent and horizontal WTW distances were significantly associated with mesopic pupil diameter (R=0.598, R(2)=0.358 P=0.02). CONCLUSION: This study shows that mesopic pupil diameter is closely related to horizontal WTW distance. These two factors must be taken in consideration together in preoperative ablation zone planning. PMID- 22937515 TI - Characteristics and clinical presentations of pediatric retinoblastoma in North western Iran. AB - AIM: To report the characteristics and clinical presentations of retinoblastoma in a series of pediatric patients from Iran. METHODS: In this retrospective study, profiles of pediatric patients with retinoblastoma archived in a referral eye hospital in north-west of Iran during 7 years (n=40 patients with 57 eyes) were reviewed. Demographics, as well as the laterality, clinical manifestations and the types of treatment were the major endpoints. The Student's t test, Mann Whitney U-test, Chi-square or Fishers' Exact test was used for analysis where appropriate. RESULTS: There were 23 cases (57.7%) with unilateral and 17 cases (42.5%) with bilateral involvement. The male to female ratio was 1 to 1.4 with a mean admitting age of 24.0+/-11.3 (range: 5-62) months. The mean diagnosis delay was 7.4+/-9.6 months (range: 10 days to 13 months). The most common presenting sign was leukocoria (97.5%) followed by proptosis (7.5%), strabismus (7.5%), hyphema (5%), orbital cellulitis (5%) and glaucoma (2.5%). Enucleation was performed in 95.7% of the cases with unilateral involvement and at least one eye of the patients with bilateral disease. A second enucleation was performed in other 3 patients (17.6%) of the latter group. CONCLUSION: This is the first study evaluating a series of Iranian children with retinoblastoma. PMID- 22937516 TI - Treatment of moderate to severe keratoconus with 6-mm Intacs SK. AB - AIM: To evaluate the effect of Intacs SK corneal ring segment implant for treatment of patients with moderate to severe keratoconus, who have clear central cornea and cannot tolerate contact lens. METHODS: In this prospective, non comparative, interventional case series study performed in Dena Hospital, Shiraz, Iran, thirty-seven eyes of thirty-six patients with moderate to severe keratoconus, clear central cornea, and contact lens intolerance were enrolled and underwent Intacs SK corneal ring segment implantation. Preoperatively, uncorrected distance visual acuity (UCDVA), best-corrected distance visual acuity (BCDVA), central corneal thickness(CCT) and average keratometry (Av-K) were measured and compared with post-operative results at one week, one month, three months, and six months. RESULTS: Mean preoperative UCDVA and BCDVA were (1.32+/ 0.31)logMAR and (1.07+/-0.27)logMAR, respectively. Av-K was (52.13+/-0.39)D, and the CCT was (432+/-39.5)um. Post-operative examinations showed a clinically significant improvement in both UCDVA and BCDVA (P<0.001). There was also a significant effect based on the time of assessment on both UCDVA and BCDVA and both parameters had a continuous improvement during the follow-up period. Three months after operation there was a statistical significant reduction of Av-K (P=0.0001), but there were no significant changes in CCT (P=0.149). CONCLUSION: Intacs SK corneal ring segment implants seem to be a safe and effective treatment option for patients who have keratoconus, clear central cornea, and contact lens intolerance. PMID- 22937519 TI - Descemet membrane detachment after trabeculectomy. AB - Descemet's membrane detachment (DMD) can be a potentially serious complication of intraocular surgery or ocular trauma. The cause is not very clear. We are trying to remind an awareness of the spectrum of DMD resulting from trabeculectomy by presenting a case of extensive DMD after trabeculectomy which was successfully repaired. PMID- 22937517 TI - Optogenetics: a novel optical manipulation tool for medical investigation. AB - Optogenetics is a new and rapidly evolving gene and neuroengineering technology that allows optical control of specific populations of neurons without affecting other neurons in the brain at high temporal and spatial resolution. By heterologous expression of the light-sensitive membrane proteins, cell type specific depolarization or hyperpolarization can be optically induced on a millisecond time scale. Optogenetics has the higher selectivity and specificity compared to traditional electrophysiological techniques and pharmaceutical methods. It has been a novel promising tool for medical research. Because of easy handling, high temporal and spatial precision, optogenetics has been applied to many aspects of nervous system research, such as tactual neural circuit, visual neural circuit, auditory neural circuit and olfactory neural circuit, as well as research of some neurological diseases. The review highlights the recent advances of optogenetics in medical study. PMID- 22937520 TI - Ocular injuries by durian fruit. AB - AIM: To report various ocular injuries caused by durian fruit. METHODS: Three cases of ocular injuries were described in young patients, due to accidental fall of durian fruit on the forehead and face, while they were taking rest/sleeping /playing under the durian tree. RESULTS: The ocular injuries observed were lacerating injury of cornea with iris incarceration, hyphema, superficial penetrating injury of sclera and angle recession glaucoma in the right eye of first patient; lacerating injury of cornea with iris prolapse in the left eye of second patient; subconjunctival haemorrhage, traumatic mydriasis and superficial penetrating injury of sclera, commotion retinopathy and macular edema in the left eye of third patient. Vision improved to normal in all the eyes following surgical/ medical/optical treatment. CONCLUSION: Evidence of penetrating injury (because of thorns) and blunt injury (because of weight) can be seen in the eyes when durian fruit falls on the face. Vision can be recovered fully with immediate and appropriate treatment in these cases. The ocular injuries can be prevented by educating the public to wear protective metal frame wide goggles and not to sleep/take rest under the durian tree. PMID- 22937518 TI - TRPC6: an underlying target for human glaucoma. AB - Glaucoma is one of the leading causes of visual impairment and blindness worldwide. Of known risk factors for glaucoma, an increased in intraocular pressure is most highly correlated with glaucomatous damage. Irrespective of the cause, apoptosis of the retinal ganglion cells is the eventual outcome. It is widely accepted that glaucoma is a neurodegenerative disease that is strongly correlated with central nervous system disorders, such as Alzheimer's disease. These two disorders also share some similarities in pathogenic mechanisms. Recent studies suggest that the transient receptor potential canonical 6 channel could work together with brain-derived neurotrophic factor to promote neuron survival in brain and retina. In this study, we propose that transient receptor potential canonical 6 may contribute to the pathogenesis of human glaucoma and become a potential therapeutic target. PMID- 22937521 TI - Different outcomes of serpiginous choroiditis with or without ocular and systemic treatment. PMID- 22937522 TI - Treatment of complex traumatic retina detachment. PMID- 22937523 TI - Rosai-Dorfman disease of unilateral lacrimal gland in an elderly Chinese male. PMID- 22937524 TI - Role of T lymphocytes in tumor response to radiotherapy. AB - Over thirty years ago, Helen Stone and colleagues compared the effects of local tumor irradiation in immunocompetent and T cell deficient mice, providing the first evidence that tumor response to radiotherapy is impaired in the absence of a normal T cell repertoire. In the following three decades there has been an exponential growth in understanding T cells and the complex molecular mechanisms that regulate their activation, migration to tumors and effector functions. We now also know that tumor progression is intrinsically linked to the development of multiple immunosuppressive mechanisms that allow cancer cells to escape immune control. Recent evidence about the role of T cells in determining the prognosis and outcome of patients at any clinical stages of cancer has been instrumental in re-directing the concept of immunosurveillance and immunoediting from the realm of preclinical models to the reality of clinical observations. Importantly, cell death induced by standard anti-cancer therapies like chemotherapy and radiation has been demonstrated to involve the immune system and, in certain specific settings, enable a specific immune response. It is, therefore, not surprising that the last few years have seen an increase in investigations exploring how to harness the ability of radiation to induce anti-tumor immune responses. We will review here the experimental evidence that anti-tumor T cells are key players in tumor control achieved by radiotherapy. The effects of radiation on the tumor that have been shown to enhance the priming and effector phases of anti-tumor immunity will be discussed. Finally, we will highlight promising combinations of immune response modifiers that enhance T cell function with radiotherapy which are being tested in the clinic. PMID- 22937525 TI - Effects of ionizing radiation on the immune system with special emphasis on the interaction of dendritic and T cells. AB - Dendritic cells (DCs), as professional antigen-presenting cells, are members of the innate immune system and function as key players during the induction phase of adaptive immune responses. Uptake, processing, and presentation of antigens direct the outcome toward either tolerance or immunity. The cells of the immune system are among the most highly radiosensitive cells in the body. For high doses of ionizing radiation (HD-IR) both immune-suppressive effects after whole body irradiation and possible immune activation during tumor therapy were observed. On the other hand, the effects of low doses of ionizing radiation (LD-IR) on the immune system are controversial and seem to show high variability among different individuals and species. There are reports revealing that protracted LD-IR can result in radioresistance. But immune-suppressive effects of chronic LD-IR are also reported, including the killing or sensitizing of certain cell types. This article shall review the current knowledge of radiation-induced effects on the immune system, paying special attention to the interaction of DCs and T cells. PMID- 22937526 TI - Pediatric high grade glioma: a review and update on tumor clinical characteristics and biology. AB - High grade gliomas (HGG) are one of the most common central nervous system (CNS) tumors encountered in adults, but they only represent approximately 8-12% of all pediatric CNS tumors. Historically, pediatric HGG were thought to be similar to adult HGG since they appear histologically identical; however, molecular, genetic, and biologic data reveal that they are distinct. Similar to adults, pediatric HGG are very aggressive and malignant lesions with few patients achieving long-term survival despite a variety of therapies. Initial treatment strategies typically consist of a gross total resection (GTR) when feasible followed by focal radiotherapy combined with chemotherapy. Over the last few decades, a wealth of data has emerged from basic science and pre-clinical animal models helping to better define the common biologic, genetic, and molecular make up of these tumors. These data have not only provided a better understanding of tumor biology, but they have also provided new areas of research targeting molecular and genetic pathways with the potential for novel treatment strategies and improved patient outcomes. Here we provide a review of pediatric non brainstem HGG, including epidemiology, presentation, histology, imaging characteristics, treatments, survival outcomes, and an overview of both basic and translational research. An understanding of all relevant pre-clinical tumor models, including their strengths and pitfalls is essential in realizing improved patient outcomes in this population. PMID- 22937530 TI - Interfacial Janus gold nanoclusters as excellent phase- and orientation-specific dopamine sensors. AB - This investigation, following our recent report on the one-pot hemi-micellar interfacial synthesis of Janus gold nanoclusters and the inter-cluster electron coupling establishing insulator-metal transition in the oriented Janus monolayers [Langmuir, 2010, 26(17), 14047], was to fabricate modified electrodes for sensing dopamine, the neurotransmitter. With a detection limit in the sub-nanomolar range, the apparent electron transfer rate constants for dopamine detection signified an intricate Janus cluster 2D phase dependency. Surface pressure as a thermodynamic variable controlled the electronic communication between the clusters as a result of varied inter-cluster distance and size, ultimately reflecting on the sensitivity and detection limit for dopamine sensing. The non covalent nature of the ligands on the core metal clusters facilitated the overall electro-catalytic oxidation of dopamine. The notable feature of this precise work was that it established a more effective phase- and orientation-specific Janus cluster sensing than those reported through patterned gold nanowire based sensors. PMID- 22937527 TI - Does helminth activation of toll-like receptors modulate immune response in multiple sclerosis patients? AB - Multiple sclerosis (MS) is an inflammatory autoimmune demyelinating disease affecting the Central Nervous System (CNS), in which Th1 and Th17 cells appear to recognize and react against certain myelin sheath components. Epidemiological evidence has accumulated indicating steady increase in autoimmune disease incidence in developed countries. Reduced infectious disease prevalence in particular has been proposed as the cause. In agreement with this hypothesis, we recently demonstrated significantly better clinical and radiological outcome in helminth-infected MS patients, compared to uninfected ones. Parasite-driven protection was associated with regulatory T cell induction and anti-inflammatory cytokine secretion, including increased TGF-beta and IL-10 levels. Interestingly, surface expression of TLR2, on both B cells and dendritic cells (DC) was significantly higher in infected MS patients. Moreover, stimulation of myelin specific T cell lines with a TLR2 agonist induced inhibition of T cell proliferation, suppression of IFN-gamma, IL-12, and IL-17 secretion, as well as increase in IL-10 production, suggesting the functional responses observed correlate with TLR2 expression patterns. Furthermore, parasite antigens were able to induce TLR2 expression on both B cells and DCs. All functional effects mediated by TLR2 were abrogated when MyD88 gene expression was silenced; indicating helminth-mediated signaling induced changes in cytokine secretion in a MyD88-dependent manner. In addition, helminth antigens significantly enhanced co stimulatory molecule expression, effects not mediated by MyD88. Parasite antigens acting on MyD88 induced significant ERK kinase phosphorylation in DC. Addition of the ERK inhibitor U0126 was associated with dose-dependent IL-10 inhibition and reciprocal enhancement in IL-12, both correlating with ERK inhibition. Finally, cytokine effects and changes observed in co-stimulatory DC molecules after helminth antigen exposure were lost when TLR2 was silenced. Overall, the data described indicate that helminth molecules exert potent regulatory effects on both DCs and B cells from MS patients through TLR2 regulation. PMID- 22937529 TI - Electrokinetic focusing and separation of mammalian cells in conductive biological fluids. AB - Active manipulation of cells, such as trapping, focusing, and isolation, is essential for various bioanalytical applications. Herein, we report a hybrid electrokinetic technique for manipulating mammalian cells in physiological fluids. This technique applies a combination of negative dielectrophoretic force and hydrodynamic drag force induced by electrohydrodynamics, which is effective in conductive biological fluids. With a three-electrode configuration, the stable equilibrium positions of cells can be adjusted for separation and focusing applications. Cancer cells and white blood cells can be positioned and isolated into specific locations in the microchannel under both static and dynamic flow conditions. To investigate the sensitivity of the hybrid electrokinetic process, AC voltage, frequency, and bias dependences of the cell velocity were studied systematically. The applicability of the hybrid electrokinetic technique for manipulating cells in physiological samples is demonstrated by continuous focusing of human breast adenocarcinoma spiked in urine, buffy coats, and processed blood samples with 98% capture efficiency. PMID- 22937531 TI - Disposable electrochemical immunosensor for simultaneous assay of a panel of breast cancer tumor markers. AB - The multiplexed immunosensor array was fabricated on a carbon electrode array containing three graphite working electrodes, which was prepared with screen printed technology. This immunosensor was achieved using graphene (GR) to modify the immunosensor surface for accelerating electron transfer. The in situ synthesis of AuNPs on GR modified electrode surface aimed at the immobilization of capture antibody (Ab(1)). With a sandwich-type immunoreaction, the alkaline phosphatase (ALP)-labeled antibody (Ab(2)) functionalized Au cluster (AuCs)/GR was captured on the immunosensor surface to catalyze the hydrolysis of 3-indoxyl phosphate in substrate, which produced an indoxyl intermediate to reduce Ag ion. The silver deposition process was catalyzed by both ALP and AuCs/GR, which amplified the detection signal. The deposited silver was then measured by anodic linear sweep voltammetric stripping analysis in KCl solution. The increase of stripping peak currents was proportional to the logarithm value of the CA 153, CA 125 and CEA concentration in the range 5.0 * 10(-3) to 50 U mL(-1) for CA 153, 1.0 * 10(-3) to 100 U mL(-1) for CA 125, and 4.0 * 10(-3) to 200 ng mL(-1) for CEA, with a limit detection of 1.5 * 10(-3) U mL(-1) for CA 153, 3.4 * 10(-4) U mL(-1) for CA 125, and 1.2 * 10(-3) ng mL(-1) for CEA. The disposable immunosensor array and simple detection method for fast measurement of a panel of tumor markers avoided cross-talk and the need for deoxygenation for the electrochemical immunoassay, and showed significant clinical value for application in cancer screening, providing great potential for convenient point of-care testing and commercial application. PMID- 22937528 TI - Enteric pathogens through life stages. AB - Enteric infections and diarrheal diseases constitute pervasive health burdens throughout the world, with rates being highest at the two ends of life. During the first 2-3 years of life, much of the disease burden may be attributed to infection with enteric pathogens including Salmonella, rotavirus, and many other bacterial, viral, and protozoan organisms; however, infections due to Clostridium difficile exhibit steady increases with age. Still others, like Campylobacter infections in industrialized settings are high in early life (<2 years old) and increase again in early adulthood (called the "second weaning" by some). The reasons for these differences undoubtedly reside in part in pathogen differences; however, host factors including the commensal intestinal microbial communities, immune responses (innate and acquired), and age-dependant shifts likely play important roles. Interplay of these factors is illustrated by studies examining changes in human gut microbiota with inflammatory bowel disease and irritable bowel syndrome. Recent gut microbial surveys have indicated dramatic shifts in gut microbial population structure from infants to young adults to the elders. An understanding of the evolution of these factors and their interactions (e.g., how does gut microbiota modulate the "inflamm-aging" process or vice versa) through the human life "cycle" will be important in better addressing and controlling these enteric infections and their consequences for both quality and quantity of life (often assessed as disability adjusted life-years or "DALYs"). PMID- 22937532 TI - Solid probe assisted nanoelectrospray ionization mass spectrometry for biological tissue diagnostics. AB - To perform remote and direct sampling for mass spectrometry, solid probe assisted nanoelectrospray ionization (SPA-nanoESI) has been newly developed. After capturing the sample on the tip of the needle by sticking it to the biological tissue, the needle was inserted into the solvent-preloaded nanoESI capillary from the backside. NanoESI gave abundant ion signals for human kidney tissues and the liver of a living mouse. The method is easy to operate and versatile because any biological specimen could be sampled away from the mass spectrometer. Minimal invasiveness is another merit of this method. PMID- 22937533 TI - Proceedings of the 16th European Conference on Analytical Chemistry, September 2011, Belgrade, Serbia. PMID- 22937534 TI - Proceedings of the European Charcot Foundation Symposium A Reappraisal of Nutrition and Environment in Multiple Sclerosis, European Charcot Foundation Symposium, December 2-4, 2010, Fiuggi, Italy. PMID- 22937535 TI - Proceedings of the 38th International Congress on Electrocardiology, June 8-11, 2011, Kingston, Ontario, Canada. PMID- 22937536 TI - Proceedings of the 4th International Symposium on Kallikreins and Kallikrein Related Peptidases, September 2-4, 2011, Rhodes, Greece. PMID- 22937537 TI - Job satisfaction: Turbulent times. PMID- 22937538 TI - [Tigecycline: effectiveness and safety]. PMID- 22937539 TI - [Colonoscopy versus fecal immunochemical testing in colorectal-cancer screening]. PMID- 22937540 TI - [Colonoscopic polypectomy and long-term prevention of colorectal cancer deaths]. PMID- 22937541 TI - [Effect of a monoclonal antibody to PCSK9 on LDL cholesterol]. PMID- 22937542 TI - Purification and characterization of ribosomal proteins from the 30 S subunit of the extreme halophile Halobacterium marismortui. AB - Ribosomal proteins were extracted from 30 S subunits of Halobacterium marismortui under native conditions.Their separation was based on gel filtration and hydrophobic chromatography, performed at a concentration of 3.2 M KC1 to avoid denaturation. A total of nine proteins were isolated, purified and identified by partial amino-terminal sequences and two-dimension a gel electrophoresis. There is a high degree of sequence homology with 30 S proteins from H. cutirubrum, and also some with 30 (S) proteins of eubacteria.Proton NMR data indicate unfolding of the proteins in low salt. One of the proteins, however, retains its secondary structure at a salt concentration as low as 0.1 M NaCl, and even in 8 M urea. One reason for this outstanding stability could be the high proportion (50%) of beta structure in this protein as determined from circular dichroism measurements. In general, there is a higher beta-sheet content than for 30 S proteins from Escherichia coli. Measurements of Stokes radii indicate several of the proteins to have a rather elongated shape. One of these is a complex consisting of L3/L4 and L20, similar to the LI-complex from E. co&.The presence of this 50 S complex in the preparation of the small subunit suggests a location on the interface between the subunits. PMID- 22937543 TI - [Molecular mechanism of migraine headache]. PMID- 22937544 TI - Medicare program; hospital inpatient prospective payment systems for acute care hospitals and the long-term care hospital prospective payment system and fiscal year 2013 rates; hospitals' resident caps for graduate medical education payment purposes; quality reporting requirements for specific providers and for ambulatory surgical centers. final rule. AB - We are revising the Medicare hospital inpatient prospective payment systems (IPPS) for operating and capital-related costs of acute care hospitals to implement changes arising from our continuing experience with these systems. Some of the changes implement certain statutory provisions contained in the Patient Protection and Affordable Care Act and the Health Care and Education Reconciliation Act of 2010 (collectively known as the Affordable Care Act) and other legislation. These changes will be applicable to discharges occurring on or after October 1, 2012, unless otherwise specified in this final rule. We also are updating the rate-of-increase limits for certain hospitals excluded from the IPPS that are paid on a reasonable cost basis subject to these limits. The updated rate-of-increase limits will be effective for cost reporting periods beginning on or after October 1, 2012. We are updating the payment policies and the annual payment rates for the Medicare prospective payment system (PPS) for inpatient hospital services provided by long-term care hospitals (LTCHs) and implementing certain statutory changes made by the Affordable Care Act. Generally, these changes will be applicable to discharges occurring on or after October 1, 2012, unless otherwise specified in this final rule. In addition, we are implementing changes relating to determining a hospital's full-time equivalent (FTE) resident cap for the purpose of graduate medical education (GME) and indirect medical education (IME) payments. We are establishing new requirements or revised requirements for quality reporting by specific providers (acute care hospitals, PPS-exempt cancer hospitals, LTCHs, and inpatient psychiatric facilities (IPFs)) that are participating in Medicare. We also are establishing new administrative, data completeness, and extraordinary circumstance waivers or extension requests requirements, as well as a reconsideration process, for quality reporting by ambulatory surgical centers (ASCs) that are participating in Medicare. We are establishing requirements for the Hospital Value-Based Purchasing (VBP) Program and the Hospital Readmissions Reduction Program. PMID- 22937545 TI - Dr Khoo Oon Teik (1921-2012). PMID- 22937546 TI - Stereotactic core-cut breast biopsy. PMID- 22937547 TI - Prostate cryosurgery. PMID- 22937548 TI - General surgery. PMID- 22937549 TI - Photoselective vaporization of the prostate. PMID- 22937550 TI - Off-pump coronary artery bypass. PMID- 22937551 TI - [Why not use the word accident]. PMID- 22937552 TI - Heartsink - patient, doctor or consultation? AB - I recently participated in a registrar education discussion about 'heartsink' patients. What is a heartsink patient? O'Dowd appears to have coined the phrase and refers to patients who 'exasperate, defeat and overwhelm their doctors by their behaviour'. He implemented a plan to identify, discuss and actively manage the heartsink patients at his practice and his definition has led to a classification of typical trigger patients and guidelines on how to best manage these patients PMID- 22937553 TI - Gatekeeper, shopkeeper, scientist, coach? AB - Health Workforce Australia is proposing to further extend the list of practitioners who are eligible to prescribe to include physiotherapists, pharmacists and psychologists. PMID- 22937554 TI - Fitness to drive. PMID- 22937556 TI - Meeting RACGP QI&CPD requirements for CPR. PMID- 22937555 TI - COPD and pulmonary rehabilitation. PMID- 22937557 TI - [Antimicrobial dosing in critically ill patients requiring renal replacement therapy - maximize efficacy and minimize toxicity!]. PMID- 22937558 TI - [Study of the limbic system]. PMID- 22937559 TI - [Ethics in terminal care in the field of neurology]. PMID- 22937560 TI - [Educational program for neurology]. PMID- 22937561 TI - [Establishment of an economic foundation for neurologists in order to achieve progress in clinical neurology in Japan]. PMID- 22937562 TI - [Manpower in neurological care in rural and urban Japan]. PMID- 22937563 TI - [Prospects for application of aptamers in diagnostics of bacterial infections]. AB - Nucleic acid-based aptamers are widely accepted as promising tools for development of a plethora of diagnostic and therapeutic preparations, as well as means ofenvironmental monitoring. Aptamers can be regarded as fully synthetic analogs of antibodies. At the same time, certain properties ofaptamers render them superior to antibodies in terms of development of new diagnostic and monitoring systems that combine high sensitivity and specificity with high reproducibility and inexpensive manufacturing. In particular, the aptamers tailored to bind biomolecules and live cells can be employed in solving the problem of combining short analysis time with high sensitivity and specificity in detection of pathogenic bacteria. The present review summarizes the current state of the techniques developed for aptamer-based detection of bacteria and their components and discusses the potential of their practical application. PMID- 22937564 TI - [Characteristics of Vibrio cholerae Cef (CHO cell elongating factor): bioinformatics analysis and experimental data]. AB - Bioinformatics analysis of the primary and secondary structure of the Vibrio cholerae Cef (CHO cell elongating factor) protein was conducted. Similarity with triacylglycerol lipases and cytotonic toxins of other bacterial species was observed. Cef was predicted to be a heat-tolerant serine lipase with the Kunitz domain and leucine zipper. These data were confirmed experimentally. The Cefs of the two biotypes of V. cholerae O1, as well as O139 and nonO1/nonO139 serogroups, were purified from the recombinant Escherichia coli strains carrying corresponding cloned genes, and their physicochemical properties, biochemical and biological activities in vitro and in vivo were characterized. Biological activity against the cultured cells was not associated with estherase activity. Evidently, Cef is a bifunctional protein contributing both to pathogenicity of the cholera agent and to its competitive ability in different ecological niches. PMID- 22937565 TI - [Molecular-genetic analysis of the epidemical strains of the Vibrio cholerae El Tor isolated from the Siberian and maritime regions of Russia]. AB - The detection of the biotype-specificity, pathogenicity determinants, and sequencing of the ctxB gene and the ctxAB promoter was carried out for analysis of the Vibrio cholerae El Tor strains genome structure. The strains (n = 90) were isolated during cholera epidemic outbreaks in Siberia and the Far East. All toxigenic Vibrio cholerae El Tor strains were divided into two groups: the first group included strains isolated during 1970s: they had the genotype ctxB3+rstREl+rstRCl-rstC+TLC+tbr4. All epidemic dangerous El Tor biotype strains isolated in 1990s belonged to the second group. The strains were characterized as atypical variants because of classical genotype (ctxB1) ctxB gene harboring. The second group fell into three genotypes according to the set of genetic markers (ctxB, rstR, rstC, TLC, tbr). It was suggested that the set of genetic determinants could be used as a marker for epidemiological analysis of spreading of atypical ET strains. The comparative analysis of genome structure enables to suggest possible ways of pathogen evolution. PMID- 22937566 TI - [Identification of the differences in the genes responsible for methionine biosynthesis in Bacillus anthracis strains and phylogeny-related species]. AB - The comparative analysis of the gene sequences encoding the synthesis of enzymes responsible for the intermediary metabolism of methionine in Bacillus anthracis strains and in closely related bacterial species was carried out. Deletion of 42 nucleotides in the hom2 gene, which determines the homoserinedehydrogenase, is detected in all tested Bacillus anthracis strains. In the strains of other bacillar species hom2 gene mutation, which blocks up the tracts of methionine and threonine biosynthesis, was not identified. The single nucleotide polymorphism was determined in asd1, metX, and metH genes. It provides the identification of B. anthracis strains using sequencing technology. PMID- 22937567 TI - [Genotype diversity of the Bacillus anthracis strains isolated from the Caucasus region]. AB - The study of the genotypes of Bacillus anthracis strains isolated from the Caucasus region was performed using MLVA. Among 149 strains, 32 distinctive MLVA 8 genotypes belonging to Ala, A3a, A4 and B1 molecular diversity groups were identified. 9 genotypes were not described previously; 6 genotypes were not found in other geographic regions and could be considered as endemic for Caucasus. The majority of the identified genotypes are widespread not only in Caucasus, but also throughout Eurasia, Africa, and America. Molecular diversity of Caucasian isolates is comparable to the worldwide diversity. This represents historical relations of this region, proximity to ancient trade routes and intensity of the anthrax epizootic in Caucasus. The obtained results are of interest from the theoretical point of view, as well as for the application in epidemiological research of the anthrax outbreaks. PMID- 22937568 TI - [Use of multiple locus variable number tandem repeats analysis for the Brucella systematization]. AB - The methods of molecular-genetic differentiation to strain level acquire increasing significance in the current system of struggle with brucellosis. MLVA (multiple locus variable number tandem repeats analysis) was selected for molecular-genetic differentiation to strain level and simultaneous establishment of the genetic relationship of investigated Brucella strains. The goal of this work was MLVA typing of three pathogenic Brucella species strains with the analysis of stability of chosen loci, discrimination power and concordance to conventional phenotypic methods of the Brucella differentiation for use in systematization of brucellosis causing agents. MATERIALS AND METHODS: Twenty six Brucella strains representing reference (n = 15), vaccine (n = 2) and field strains of three pathogenic Brucella species were tested: B. melitensis (n = 3), B. abortus (n = 2), B. suis (n = 2), and isolates (n = 2) with unidentified taxonomic position using MLVA with 9 pairs primers on known variable loci of Brucella genome. The analysis of the stability of chosen loci, discrimination power on Hunter-Gaston discrimination index (HGDI) and consistency to phenotypic methods of identification was performed. RESULTS: MLVA was confirmed for the results of phenotypic methods of identification, stability of the chosen loci in majority reference, and vaccine strains with a high index of variability HGDI 0.9969 for all loci. A dendrogram was plotted on the basis of MLVA data on distributed Brucella strains in related clusters according to its taxonomic species and biovar positions and construction of 25 genotypes. B. melitensis strains formed cluster related to the reference strain of B. melitensis 63/9 biovar 2. Australian isolates of Brucella 83-4 and Brucella 83-6 isolated from rodents formed a cluster distant from other strains of Brucella. CONCLUSION: MLVA is a promising method for differentiation of Brucella strains with known and unresolved taxonomic status for their systematization and creation of MLVA genotype catalogue that will promote qualitative improvement of brucellosis surveillance system in Russia. PMID- 22937569 TI - Construction of baculovirus expression vector of miRNAs and its expression in insect cells. AB - MicroRNAs (miRNAs) are endogenous small non-protein coding RNAs that play important regulatory roles in animals and plants by binding to target transcripts for cleavage or translational repression. The miR-9a is very conservative in animals from flies to humans. Studies indicated that miR-9a is involved in the regulation of neurogenesis in animals. In our study, the baculovirus expression system was used to transcribe a recombinant vector containing miR-9a for further analysis the function ofmiR-9a. The sequence ofpre-miR-9a from silkworm DNA was first cloned into the donor pFastBac. The enhanced green fluorescent protein (EGFP) was used as reporter gene. The recombinant donor plasmid pFastBac-miR-9a was transformed into E.coli DH10Bac/AcNPV forming Bacmid-9a which was transfected into insect cells with cational lipofectin. The transcription of mature miR-9a was detected by Real-time PCR. The results show the recombinant Bacmid-9a was successfully constructed and effectively transcribed miR-9a in infected Sf21 insect cells. PMID- 22937570 TI - [Development of academic A.I. Strukov's ideas in the modem pathologic anatomy]. PMID- 22937571 TI - [Urothelial tumor of the urinary bladder: immunohistochemical features]. AB - Morphological and clinical characteristics of the urinary bladder cancers (UBC) are important diagnostics and prognostic criteria, however the possibilities of biopsy using/for prognosis of recidivation or efficiency of UBC treatment are limited. The most popular diagnostic and prognostic immunohistochemical markers are the regulators of cell cycle (P53, P21, Ki-67) and cytokeratins. In order to revealed immunohistochemical criteria, objectively reflected the malignancy of UBC, we studied the expression level of P53, proliferative index of Ki-67 and the malignant of UBC according to CK20 in the biopsy of 32 patients with superficial UBC. The immunohistochemical reaction with antibody to P53, CK20 and Ki-67 was carried out at paraffin slices. We detected differences of P53 expression levels at carcinomas with high and low malignancy rate. The expression levels of CK20 and the Ki-67 proliferative index were different between Ta and T1-T2 cancers (p = 0.006). Intensity of nuclear staining with P53 antibodies could be use for estimation of the UBC malignancy rate. Pathological type of CD20 expression and high percentage of Ki-67-positive staining nucleus are evidence of the invasive urothelial tumors. The using of P53, Ki-67 and CD20 could be recommended for pathohistological investigation of biopsy and surgical material of UBC to diagnostic objectification and prognosis of its clinical course. PMID- 22937572 TI - [Morphological features of the esophagogastric transition zone at fetuses and newborns]. AB - Morphological research of the esophagogastric transition mucosa at 35 fetuses and newborns was done. The esophagogastric transition was lined by high columnar epithelium and mucos glands. At fetuses of 22-24 week gestational age studied zone didn't have any glands. Histochemical features of the epithelium, particularly MUC5AC positive staining, corresponded to cardial type of the Barrett esophagus, defined at adults. We have revealed that mucosa of the esophagogastric transition has gastric origin and arises before birth. We found out the islets of columnar epithelium on the surface of the laminated pavement epithelium, indicated about its uneven development up to the birth. The sites of immature epithelium could be considered as transformation zones both of laminated pavement epithelium or columnar one. PMID- 22937573 TI - [Molecular and morphological aspects of endometrial receptivity disorders at chronic endometritis]. AB - The endometrial receptivity is a complex of structure-functional characteristics of endometrium with clear temporal and spatial constants, conditioning the ability of endometrium to the implantation. The aim of our research was a studying of morphological and molecular aspects of the endometrial receptivity disorders at chronic endometritis. The basic studied group included cases of chronic endometritis (CE) with unknown etiology (30 patients) and with CE under autoimmune thyroiditis (26 patients with presence of antithyroid antibodies- ATA). All patients had different disorders of reproductive function; some of them were infertile. More over 73% of all studied patients were of the 26-40 ages old. The control group was presented by endometrium of healthy surrogate mothers (10 cases). The research was done on the Pipelle biopsies of endometrium, which was taken in the secretory phase (the period of "implantation window"). For confirmation of the CE diagnosis, the endometrium of women with ATA was taken in the proliferative phase too. Morphological, immunohistochemical and statistical (nonparametric analysis of Mann-Whitney) methods were used. As the primary antibodies were used CD68, CD138, CD56, Ki-67, Apaf-1, LIE The structure analysis of pinopodes was carried out by stained paraffin slices (CytoViva Technologies Inc., Auburn, AL, USA) with using of the traditional and luminescent microscopy (the definition is over 100 nm). Structure and molecular changes of endometrium at CE include inflammatory infiltration, fibroblastic reactions and alteration of extracellular matrix; apoptosis of functional layer leading to its insusceptibility to the regulatory signals. Disorders of endometrial remodeling in the "implantation window" determine the result of implantation and can be reason of the infertility. The reduced receptivity at CE is characterized by decrease of mature pinopodes and low expression of LIF in the surface epithelium. PMID- 22937575 TI - [Immunomorphologic features of epithelial-stromal relationships at hyperplasia and endometrial carcinoma]. AB - The results of a immunomorphologic comprehensive study of epithelial-stromal relationships in the uterus hyperplasia and endometrial cancer suggest that the suppressor gene of cancer (PTEN) plays a key role in the process of neoplastic transformation of endometrial hyperplasia and adenocarcinoma development. For the first time the existence of two highly differentiated endometrial adenocarcinoma immunophenotype were detected The first one is a PTEN-negative endometrial aedenocarcinoma, characterized by an almost complete inhibition of tumor suppressor gene PTEN in the epithelium of the glands and stromal cell of the tumor The second type is a PTEN-positive endometrial adenocarcinoma, in which epithelial and stromal tumor suppressor gene PTEN activity has retained Based on these results we have formulated a hypothesis about the different types of endometrial hyperplasia morphogenesis and its possible transfer to cervical cancer associated with features of tumor suppressor gene PTEN. PMID- 22937574 TI - [Clinico-morphological and molecular-genetic characteristic of the miometrium with failure of the uterine scar after the Cesarean section at women with undifferentiated forms of connective tissue dysplasia]. AB - Connective tissue state, its strength, is actual problem especially in the moment of labor because the weakness of labor activity or accelerated labor can be in depending on its consistency and elasticity. In addition, connective tissue is very important in the involution of the uterus after labor or wounds healing. Clinico-morphological and molecular-genetic investigation of 90 patients with undifferentiated forms of connective tissue dysplasia (uCTD) has been done. Reparation of tissue at patients with uCTD had a number of peculiarities, such as fibromuscular scar formation by substitution mechanisms with the laminin deficiency in the basic capillar membrane and extracellular matrix, accumulation of III and IV types of collagen, low expression of VEGF in the stromal cell and polymorphism of the alpha estrogen receptor gene. This immunohistochemical changes correlated with focuses of connective tissue disorganization as mucoid swelling, fibrinoid changes and hyalinosis, as well pathology of the microvasculature, resulted in chronic ischemia of the tissue. The disorganization is connected with disturbed reparation as a result of the genetically determined polymorphism of alpha and beta estrogen receptors. uCTD in pregnant women is prognostically significant for selection of way of delivery. PMID- 22937576 TI - [Interconnection of the angiopathy and neuropathy development mechanism at patients with type II pancreatic diabetes]. AB - In the article we summarized literature data, covered genesis of angiopathy and neuropathy at patients with type II diabetes. In the genesis of disease different metabolic, immune, hypoxic, genetic and others factors, caused affection of arteries, microcirculation and the peripheral nervous system, play an important role. Increasing changes of the great and minute vessels are interconnected with diabetic neuropathy PMID- 22937577 TI - [Pneumocystic pneumonia]. AB - The article is devoted to short description of epidemiology, clinical and radiologic demonstration of pneumocystic pneumonia. The features of pathologicoanatomic changes at pneumocystic pneumonia are described. Own observation about combination of classic and scarce histological changes at this disease is in the article. PMID- 22937578 TI - [Causes of the people death from drunkenness and alcoholism]. AB - We analyzed causes of 1008 people death, who abused by alcohol. Among them 2 groups were separated out: people died due to drunkenness and due to alcoholism. The structure of the death was similar in the both groups, however depended on alcoholism stages. The major cause of the death in group of drunkenness people was acute heart insufficiency, less commonly--lung pathology, and very rarely- brain vessels pathology and liver cirrhosis. In group of people, who died due to alcoholism, lung pathology was the major cause of these deaths, acute heart insufficiency was occurred less commonly, and very rare brain pathology because of delirium tremens or alcohol withdrawal syndrome, as so liver cirrhosis with complications. Hemorrhagic pancreonecrosis after alcoholic excess was found out in both groups, but it was more often in people, who died due to drunkenness. Obtained results show importance of chronic alcoholism identification as a disease with several stages including drunkenness and alcoholism. PMID- 22937579 TI - [Morphological, immunohistochemical and radiological manifestation of lung tissue remodeling at lung sarcoidosis]. AB - Sarcoidosis is a group of diseases with chronic immune inflammation and granulomas formation in the lung, lymph nodes, and others organs. Under progress of disease remodeling of the lung tissue occurs and at 20-25% of patient with sarcoidosis lung fibrosis is developed. We studied biopsies from 50 patients with sarcoidosis and 10 biopsies of pathological intact lung tissue as a control group. Roentgenologic, morphologic and immunohistochemical methods with using of mono- and polyclonal antibody to MMP 1, 2, 9 and TIMP-1, PCNA, aSMA, apo-CAS were realized. The expression levels of growth factors, apoptosis, MMPs, TIMPs were different in various clinic-morphological courses of sarcoidosis. As a rule under sarcoidosis deep remodeling of lung tissue didn't occur in spite of granulomatous inflammation. Granulomatous process, alveolitis (bronchiolitis) and sclerotic changes resulted in alteration of the lung. Cells of sarcoidosis granulomas, produced low level of MMPs and TIMP can't induce evident fibrosis and so hypertension is absent or becomes apparent in the slight form. It apparently can be link with localization of pathologic process in lung tissue without any alterations in the bronchoalveolar zone. Alveolitis under sarcoidosis conditions is notable for low activity of inflammation and doesn't result in interstitial fibrosis developing. PMID- 22937580 TI - [Morphofunctional changes of BALB/c and C57BL/6 mice's immune system under chronic bacterial gram-negative endotoxicosis]. AB - Chronic endotoxicosis was modeled by subcutaneous injection of the sepharose in complex with LPS. In these conditions we have studied morphofunctional changes of the immune system of BALB/c and C57Bl/6 mice, which are characterized by the different types of the immune response (Th2 type is predominant in BALB/c, Th1- in C57Bl/6). In the 1st-7th day t in the serum of BALB/c mice the endotoxin level increased in 21.3 times, in C57Bl/6--in 20.6 times. The endotoxin antibodies significantly decreased in 1th-7th days, on the 14th day it increased in the serum of both mice's strains. Morphofunctional changes of the immune system after chronic endotoxicosis were different in BALB/c and C57BI/6 mice. On the 1th day after injection of LPS and sepharose, in the thymus of C57Bl/6 mice the cortex layer was exhausted because of cell death, in the thymus of BALB/c mice II-III stages of accidental involution were developed. On the 7-14th day after injection of LPS and sepharose in the spleen of C57Bl/6 mice T- and B-zones were hyperplastic, however in spleen of BALB/c mice only T-zone were enlarged. After LPS and sepharose injection changes of cytokine production synthesized by KonA activated splenic cells were found out. In both strains the level of proinflammatory cytokines--TNFalpha and IL-1beta decreased, as well the Th1 cytokine IL-2. The production o fTh2-cytokine - IL-4, significantly decreased only in C57BI/6 mice. We suggest that damaging effect of LPS injection is determined by predominant Th2 or Th2 types of the immune response. PMID- 22937581 TI - [Morphologic and functional heterogeneous changes of the urinary bladder different parts at rats with infravesical obstruction of the urinary tracts]. AB - Infravesical obstruction of the lower urinary tracts of 30 rats was carried out by the measured constriction of the urethral prevesical parts. Morphologic and functional changes of the urinary bladder different parts were studied in 1 week and in 3 months. Compensatory hypertrophy of the detrusor was accompanied increasing of hypertrophied, atrophic and native forms of leiomyocytes, as so their transformation into myofibroblasts with connective tissue formation between the muscle fibers mainly in the neck of urinary bladder Contractility of the detrusor decreased with their tonus increasing mainly in the neck of urinary bladder too. Weakening effect of adrenalin in 3 month after obstruction significantly decreased, while in the body and neck of urinary bladder it virtually disappeared. Blockade of alpha-adrenoreceptors after noradrenalin stimulation resulted in enchancement of the hypertrophic detrusor contraction when tonus of the urinary neck decreased. On the contrary, in the intact urinary bladder the similarly influence resulted in weakening of contraction. PMID- 22937582 TI - [Pathogenetic importance of helicobacter pylori infection]. AB - H. pylori are etiological factor of human acute and chronic gastritis. Depending on pathogenic factors of microorganism and polymorphism of human genes, chronic gastritis can be a cause for ulcerative enteritis of the duodenum or stomach, gastric adenocarcinoma and MALT-lymphoma development. We revealed genetic features of bacteria, determined the intensity of inflammation, such as pathogenic factors--cag, plastic region of the genome and adhesin coding genes. Epigenetic changes, for example the methylation of E-cadherin gene associated with H pylori, are crucial for carcinogenesis. Thereby, predisposition of chronic gastritis associated with H. pylori to ulcerative enteritis of the duodenum, ulcerative stomach disease or gastric adenocarcinoma depends on topography, the intensity of inflammation and changes of acid production in the stomach. PMID- 22937584 TI - [The new views to pseudotuberculosis pathology]. AB - For the first time the nature of cell damages under pseudotuberculosis as a generalized infection has been analyzed by positions of the modern knowledge about types of the cell death. The own and literature data have pointed to presence the apoptosis-induced effect of Yersinia pseudotuberculosis, a causative agent of this infection. In conclusion, the typical pathological changes for pseudotuberculosis infection such as granuloma formation with the central karyorrhexis could be appearance of apoptotic and secondary necrotic changes. PMID- 22937585 TI - Patients drive successful healthcare. PMID- 22937583 TI - [Autosomal-recessive renal cystic disease and congenital hepatic fibrosis: clinico-anatomic case]. AB - Clinico-anatomic observation of autosomal-recessive renal cystic disease and congenital hepatic fibrosis at two fetuses from the same family was done. Mutation of His3124Tyr in 58 exon of PKHD1 gene in heterozygous state was found out. The same pathomorphological changes in the epithelium of cystic renal tubules and bile ducts of the liver were noted. We suggest that the autopsy research of fetuses with congenital abnormalities, detected after prenatal ultrasonic screening, has high diagnostic importance. PMID- 22937586 TI - Member analysis of the Supreme Court's ACA ruling. PMID- 22937587 TI - ICD-10: low-impact first steps. PMID- 22937588 TI - MGMA Government Affairs Committee chair testifies on 7 steps the government should take regarding ICD-10 implementation. PMID- 22937589 TI - Fears of further payment disruptions cited in association testimony on HIPAA 5010. PMID- 22937590 TI - Wasted days and wasted nights. Meetings cost some physicians up to $49,000 annually. PMID- 22937591 TI - Tips for effective staff recruitment. PMID- 22937592 TI - Planning ahead for a bright future: Ohio-based group expands practice reach. PMID- 22937593 TI - What's your plan for managing your most valuable asset--employees? PMID- 22937594 TI - Changing times and tides of healthcare: swimming with the reform. PMID- 22937595 TI - Using company policies as a shield. PMID- 22937596 TI - Avoiding pitfalls. Integration survival techniques for the practice manager. PMID- 22937597 TI - Lateral violence: tools managers can use to help shift the culture. PMID- 22937598 TI - FDA proposes a UDI system for medical devices. PMID- 22937599 TI - Reducing variation in total knee replacements. PMID- 22937600 TI - Tying anesthesia salaries to on-time starts, turnovers. PMID- 22937601 TI - Fecal microbiota transplantation for treating recurrent Clostridium difficile infection. PMID- 22937602 TI - Lumens and endoscopes: meeting cleaning basics. PMID- 22937603 TI - [Gastrointestinal stromal tumor]. AB - Gastrointestinal stromal tumor, i.e., GIST is by far the most common mesenchymal tumor of the gastrointestinal tract. GIST has received special clinical attention, because it is one of the first solid tumors treated with tyrosine kinase inhibitors as targeted oncological therapy. Accordingly, accurate diagnosis of GIST has become clinically increasingly important. While GISTs were previously classified as gastrointestinal smooth muscle or Schwann cell tumors, they are now distinguished as a separate, specific tumor entity. Loss of succinate dehydrogenase complex is a newly understood pathogenesis for 5% of GIST, associated with early onset of disease. PMID- 22937604 TI - [Autism spectrum disorders in children and adolescents]. AB - Childhood autism, Asperger's syndrome and atypical autism together make up autism spectrum disorders (ASDs) with a prevalence of 0.6-0.7%. These disorders are defined by qualitative impairments in social interaction, qualitative abnormalities in communication, and by restricted, stereotyped, repetitive patterns of behaviour, interests and activities. Many children or adolescents with ASDs have sensory abnormalities, neurological disorders and additional disabilities of vision, hearing or ambulation. Psychiatric co-morbidity is common. Diagnostics and rehabilitation are implemented in multi-professional collaboration. Early recognition makes up the basis for early intervention that improves the prognosis. Screening of these disorders in well-baby clinics is being developed. PMID- 22937605 TI - [Fast-track treatment--second revolution of colorectal surgery]. AB - The fast-track treatment model can be regarded as the second revolution of colorectal surgery after the introduction of laparoscopic surgery. In the gastro surgical unit of the Central Hospital of Central Finland, results equivalent to international studies in colorectal surgery have been achieved by using fast track model. In a study setting, this treatment model has resulted in significant decrease of total treatment costs and speeded up discharge of the patients from the hospital. The fast-track treatment model requires both a motivated, trained medical team and a motivated patient. PMID- 22937606 TI - [Cognitive methods during medical consultation]. AB - An essential method of cognitive psychotherapy is a precise, situation-focused interview, during which interpretations, emotions and behavior are taken into account. This work mode is also suited for medical consultation. In cognitive psychology, schemes and modes are identified that may be helpful for analyzing the patient-doctor relationship. Empathy may improve patient outcome. Properly applied cognitive methods facilitate the evolution of empathy. PMID- 22937607 TI - [Treatment of infertility]. AB - Primary evaluation of infertility consists of confirmation of regular ovulation and capacity to produce functional spermatozoa, and exclusion of any anatomical barrier for infertility. If the sperm analysis is normal, clomiphene is the first line treatment in anovulatory women. Obese women suffering from polycystic ovary syndrome may be first offered metformin for 3-4 months before the addition of clomiphene. If ovulation cannot be induced with clomiphene, aromatase inhibitors, ovarian drilling gonadotrophin stimulation are the subsequent steps. If no response is obtained after 4-6 ovulatory cycles, intrauterine insemination and in vitro fertilisation should be offered. PMID- 22937608 TI - [Clinico-pathological conference report: sudden deterioration of general condition, hypokalemia and diabetes in an elderly man]. AB - An elderly man had been treated for prostate cancer with radiation and neoadjuvant hormonal therapy. One year after the cessation of radiation therapy, the PSA value was found to be elevated. A non-steroidal antiandrogen bicalutamide was initiated to the patient. Due to poor treatment response the drug was changed for the GnRH agonist leuprorelin acetate, which upon injection caused a sudden deterioration of the patient's general condition. He was delirious and in pain, and was diagnosed with leukocytosis, hypokalemia, hyperglycemia and metabolic alkalosis. The patient was referred to the endocrinological clinic for evaluation of the metabolic-endocrinological problems. He succumbed to disseminated prostate cancer. PMID- 22937609 TI - [Acute methemoglobinemia in a young girl]. AB - Methemoglobinemia is an acute and potentially life-threatening condition. It can be congenital but more often acquired. Suspected the diagnosis of this condition is straight forward. In methemoglobinemia red cells are unable to carry oxygen, because the iron of the heme is oxidised from Fe2+ to Fe3+. Symptoms are depended on the level of methemoglobinemia. Intravenous methylene blue is the treatment of choice. PMID- 22937610 TI - [Diuretics in pregnancy can do harm]. AB - We describe a case with severe pre-eclampsia with poor obstetric outcome. This patient developed oliguria and received multiple doses of furosemide which probably contributed to the poor outcome. This case presentation reminds of the risks associated with pre-eclampsia in which both blood volume and utero placental blood flow are already decreased. This condition was further worsened by diuretics. PMID- 22937611 TI - [Family policy has no effect on birth rate]. PMID- 22937612 TI - ["Caution summer" - accidents!]. PMID- 22937613 TI - [Varicella - chickenpox]. PMID- 22937614 TI - [Underestimated danger: scattered radiation generates greater uv exposure than direct sunlight]. PMID- 22937615 TI - [Working group of leading pediatric nurses holds their convention for the first time in a rehabilitation clinic]. PMID- 22937616 TI - [Stress management in intensive care: are certain personality types especially stress resistant?]. PMID- 22937617 TI - [Management of change processes in a neonatal department - introduction of development promoting nursing according to NIDCAP]. PMID- 22937618 TI - [Withdrawal symptoms in long-term conscious sedation exposure of pediatric intensive care patients]. PMID- 22937619 TI - [Cornerstones of a new nursing career regulation. Is health and pediatric nursing losing its basic education?]. PMID- 22937620 TI - [Out of sync rhythm: doctor visit in arrhythmias after common colds]. PMID- 22937621 TI - [Study: work intensification on the intensive care unit can have serious consequences]. PMID- 22937622 TI - [25 years pediatric home nursing in Hamburg]. PMID- 22937623 TI - [Congenital diaphragmatic hernia. Prenatal tracheal balloon occlusion as therapy option]. PMID- 22937624 TI - [Practical value for prospective FGKiKP: "theme evenings" have been well received]. PMID- 22937625 TI - [Never trays with grapefruit juice. Drugs can become inactive as a result of interactions - or cause an overdose]. PMID- 22937626 TI - [Lactose intolerance: when milk doesn't enliven, instead causes fatigue]. PMID- 22937627 TI - [Needles stable carbon isotope composition and traits of Pinus sylvestris var. mongolica in sparse wood grassland in south edge of Keerqin Sandy Land under the conditions of different precipitation]. AB - A comparative study was conducted on the needles stable carbon isotope composition (delta13 C), specific leaf area (SLA), and dry matter content (DMC) of 19-year-old Pinus sylvestris var. mongolica trees in a sparse wood grassland in the south edge of Keerqin Sandy Land under the conditions of extreme drought and extreme wetness, aimed to understand the water use of Pinus sylvestris under the conditions of extreme precipitation. The soil water content and groundwater level were also measured. In the dry year (2009), the soil water content in the grassland was significantly lower than that in the wet year (2010), but the delta13C values of the current year-old needles had no significant difference between the two years and between the same months of the two years. The SLA of the current year-old needles was significantly lower in the dry year than in the wet year, but the DMC had no significant difference between the two years. Under the conditions of the two extreme precipitations, the water use efficiency of the trees did not vary remarkably, and the trees could change their needles SLA to adapt the variations of precipitation. For the test ecosystem with a groundwater level more than 3.0 m, extreme drought could have no serious impact on the growth and survival of the trees. PMID- 22937628 TI - [Effects of habitat change on nutrient contents in Quercus variabilis seedlings]. AB - Quercus variabilis seedlings were collected from the habitats at different latitudes, and transplanted on the same experimental sites installed in the central part and southern and northern boundaries of China, where Q. variabilis has a natural distribution, aimed to study the effects of habitat change on the nutrient contents in the seedlings in their vigorous growth period. With habitat change, the various organs nitrogen (N) content and the stem phosphorous (P) content of the transplanted seedlings changed significantly, but the organs potassium (K) content and the leaf- and root P content had less change. In the experimental sites, the organ N content of the transplanted seedlings had significant positive correlation with the latitudes where the seedlings grew, the stem- and root P contents decreased with the increasing latitude, while the leaf N:P ratio had less change. The organ N and P contents of the transplanted seedlings growing in northern boundary decreased significantly, and the effect of the latitudes was more obvious. The leaf N:P ratio of all the seedlings transplanted from different altitudes increased to different degrees. It was concluded that the nutrient contents in different organs of Q. variabilis seedlings varied with latitude, and the seedlings had different responses to habitat change. PMID- 22937629 TI - [Correlations between wild Polygonatum odoratum quality and main ecological factors]. AB - By the methods of stepwise regression, principal component analysis, and grey relational grade analysis, this paper studied the correlations between the effective components (polysaccharides and water- and alcohol-soluble substances) contents and antioxidant activity of wild Polygonatum odoratum in different places and the ecological factors. Among the test ecological factors, the mean air temperature in January and in July, mean annual precipitation, frost-free period, and soil pH and total potassium were the main factors affecting the effective component contents of P. odoratum, with a contribution rate of 99.0%. As compared with soil factors, climatic factors made more contribution to the effective component contents. Soil total potassium was the key factor controlling the effective component contents, mean annual precipitation was the main decision factor, and mean air temperature in January was the main limiting factor. The plant polysaccharides and water-soluble substance contents were the key factors affecting the antioxidant activity of P. odoratum, and the capability of P. odoratum in excavating DPPH free radical increased with increasing contents of polysaccharides and water-soluble substances. PMID- 22937630 TI - [Geographic variation of seed morphological traits of Picea schrenkiana var. tianschanica in Tianshan Mountains, Xinjiang of Northwest China]. AB - Taking the Picea schrenkiana var. tianschanica forests at three sites with different longitudes (Zhaosu, Tianchi, and Qitai) in Tianshan Mountains as the objects, the cones were collected along an altitudinal gradient to analyze the variation of their seed morphological traits (seed scale length and width, seed scale length/width ratio, seed wing length and width, seed wing length/ width ratio, seed length and width, and seed length/width ratio). All the seed traits except seed width tended to decrease with increasing altitude. The seed traits except seed wing width, seed width, and seed length/width ratio all had significant negative correlations with altitude. Seed scale length and width and seed scale length/width ratio had significant positive correlations with longitude. Seed scale length, seed scale length/width ratio, and seed wing length/width ratio had significant negative correlations with slope degree. No significant correlations were observed between the seed traits except seed wing width and the slope aspect. Altitude was the main factor affecting the seed scale length, seed scale length/width ratio, and seed wing length/width ratio. PMID- 22937631 TI - [Effects of stumping on Calligonum mongolicum shelterbelt growth and soil moisture and salt distribution along Tarim Desert Highway, Xinjiang of Northwest China]. AB - In order to ensure the stability and sustainability of the Calligonum mongolicum shelterbelt along Tarim Desert Highway, the aged C. mongolicum was stumped to investigate its growth and soil moisture and salt distribution. After stumping twice, C. mongolicum grew rapidly in its height, crown width, maximum basal diameter, and sprout number. Three years after stumping, the average height of the sprouts exceeded the control (no stumping), and the crown width and maximum basal diameter was 92.0% and 73.0% of the control, respectively. The fresh mass of the branches and assimilating branches, their dry mass, and the total fresh mass and dry mass of the aboveground parts reached 80.0%, 115.0%, 80.0%, 116.0%, 93.5%, and 88.0% of the control, respectively. Four years after stumping, the aboveground biomass surpassed the control. Comparing with the control, stumping increased the soil moisture content significantly and decreased the soil salt concentration. It was suggested that, to stump the aged C. mongolicum repeatedly could increase the soil moisture content and decrease the soil salt concentration in root zone, and effectively promote the rejuvenation and renewing of C. mongolicum. PMID- 22937632 TI - [Dynamic changes of soil respiration in Citrus reticulata and Castanea henryi orchards in Wanmulin Nature Reserve, Fujian Province of East China]. AB - From January 2009 to December 2009, the soil respiration in the Citrus reticulata and Castanea henryi orchards in Wanmulin Nature Reserve was measured with Li 8100, aimed to characterize the dynamic changes of the soil respiration and its relationships with soil temperature and moisture in the two orchards. The monthly variation of the soil respiration in the orchards was single-peaked, with the peak appeared in July (3.76 micromol x m(-2) x s(-1)) ) and August (2.69 micromol x m(-2) x s(-1)). Soil temperature was the main factor affecting the soil respiration, and explained 73%-86% of the monthly variation of soil respiration. The average annual soil respiration rate was significantly higher in Citrus reticulata orchard than in Castanea henryi orchard, with the mean value being 2.68 and 1.55 micromol x m(-2) x s(-1), respectively. There was a significant positive correlation between the soil respiration rate and soil moisture content in Castanea henryi orchard, but less correlation in Citrus reticulata orchard. The Q10 value of the soil respiration in Citrus reticulata and Castanea henryi orchards was 1.58 and 1.75, and the annual CO2 flux was 10.01 and 5.77 t C x hm( 2) x a(-1), respectively. PMID- 22937633 TI - [Impacts of salt stress on the growth and physiological characteristics of Panicum virgatum seedlings]. AB - An experiment was conducted in an artificial climate chamber to study the growth and physiological characteristics of switchgrass (Panicum virgatum) seedlings exposed to 0, 50, 100, 150, and 200 mmol x L(-1) of NaCl solutions. With the increasing concentration of the NaCl, the seedling growth was obviously inhibited. The plant height decreased, leaves became smaller, photosynthetic leaf area and net photosynthetic rate reduced, and dry matter accumulation decreased significantly, presenting the general traits of glycophyte. Meanwhile, the seedlings also showed relatively high salt tolerance. After exposed to 200 mmol x L(-1) of NaCl for 30 days, the seedlings still survived, with the green leaf area per plant and net photosynthetic rate being 491.9 cm2 and 0.93 micromol CO2 x m( 2) x s(-1), respectively. In this experiment, the salt tolerance threshold for P. virgatum was 178.6 mmol L(-1) when taking 50% drop in biomass as the standard. PMID- 22937634 TI - [Effects of salt stress on physiological characters and salt-tolerance of Ulmus pumila in different habitats]. AB - Taking the Ulmus pumila seedlings from three different habitats (medium-, mild-, and non-saline soils) as test materials, an experiment was conducted to study their salt-tolerance thresholds and physiological characteristic under different levels (0, 2, 4, 6, 8, and 10 g X kg(-1)) of salt stress. With increasing level of the salt stress, the seedlings taken from medium- and mild- saline habitats had a lower increment of leaf membrane permeability, Na+ content, and Na+/K+ but a higher increment of leaf proline, soluble sugar, and K+ contents, and a lower decrement of leaf starch content, net photosynthetic rate, transpiration rate, intercellular CO2 concentration, and stomatic conductance, as compared with the seedlings taken from non-saline habitat. The salt-tolerance thresholds of the seedlings taken from different habitats were in the order of medium- saline habitat (7.76 g X kg(-1)) > mild- saline habitat (7.37 g X kg(-1)) > non-saline habitat (6.95 g X kg(-1)). It was suggested that the U. pumila seedlings in medium- and mild-saline habitats had a stronger adaptability to saline soil environment than the U. pumila seedlings in non-saline soil environment. PMID- 22937635 TI - [Measurement accuracy of granier calibration based on transpiration of Platycladus orientalis]. AB - In order to understand the accuracy of Granier' s thermal dissipation method in measuring tree water consumption, a comparative study was made from May to June, 2010. The sap flow density of potted Platycladus orientalis was measured with thermal dissipation probe, which was compared with the whole-plant gravimetric measurement. There were significant linear relationships (R2 > 0.825) between the sap flow velocity in both north and south directions of P. orientalis measured by thermal dissipation probe and the transpiration rate measured by gravimetric method. The average daily sap flux in the north and south directions of P. orientalis were 10.6% and 15.1% lower than the daily average transpiration of P. orientalis, respectively, but the differences were not significant. Therefore, Granier's method had high reliability in the measurement of P. orientalis transpiration at daily scale, though the large temperature fluctuation between day and night could result in a lower daily sap flux than daily transpiration. PMID- 22937636 TI - [Fire behavior of ground surface fuels in Pinus koraiensis and Quercus mongolica mixed forest under no wind and zero slope condition: a prediction with extended Rothermel model]. AB - A laboratory burning experiment was conducted to measure the fire spread speed, residual time, reaction intensity, fireline intensity, and flame length of the ground surface fuels collected from a Korean pine (Pinus koraiensis) and Mongolian oak (Quercus mongolica) mixed stand in Maoer Mountains of Northeast China under the conditions of no wind, zero slope, and different moisture content, load, and mixture ratio of the fuels. The results measured were compared with those predicted by the extended Rothermel model to test the performance of the model, especially for the effects of two different weighting methods on the fire behavior modeling of the mixed fuels. With the prediction of the model, the mean absolute errors of the fire spread speed and reaction intensity of the fuels were 0.04 m X min(-1) and 77 kW X m(-2), their mean relative errors were 16% and 22%, while the mean absolute errors of residual time, fireline intensity and flame length were 15.5 s, 17.3 kW X m(-1), and 9.7 cm, and their mean relative errors were 55.5%, 48.7%, and 24%, respectively, indicating that the predicted values of residual time, fireline intensity, and flame length were lower than the observed ones. These errors could be regarded as the lower limits for the application of the extended Rothermel model in predicting the fire behavior of similar fuel types, and provide valuable information for using the model to predict the fire behavior under the similar field conditions. As a whole, the two different weighting methods did not show significant difference in predicting the fire behavior of the mixed fuels by extended Rothermel model. When the proportion of Korean pine fuels was lower, the predicted values of spread speed and reaction intensity obtained by surface area weighting method and those of fireline intensity and flame length obtained by load weighting method were higher; when the proportion of Korean pine needles was higher, the contrary results were obtained. PMID- 22937637 TI - [Establishment of standard forest fuel models for Fenglin Natural Reserve, Heilongjiang Province, China]. AB - From the viewpoint of forest fire behavior, and based on the key parameters of fuels, three standard forest fuel models for the forests differed significantly in fuel characteristics and local environmental conditions in Fenglin Natural Reserve were established by using hierarchical cluster analysis. The three models were FL-I, FL-II, and FL-III for the broadleaved-Korean pine forest, spruce-fir forest, and poplar-birch forest, the representative forest types in the Reserve, respectively. According to the forest structure and composition, land cover type, and horizontal and vertical continuity, the three models FL-I , FL-II, and FL-III were similar to the models C-5, C-2, and D-1 in Canada CFBPS fuel classification system, respectively. The forest ground features and the horizontal and vertical characteristics of the three models established in this paper could help the investigators to identify the fuel types in fuel inventory. PMID- 22937638 TI - [Dynamic changes of vegetation net primary productivity in permafrost zone of Northeast China in 1982-2009 in response to global change]. AB - As one of the high-latitude cold regions, the permafrost zone of Northeast China (PZNC) is more sensitive to global change. Based on the AVHRR GIMMS NDVI and MODIS NDVI, and by using CASA model, this paper simulated the net primary productivity (NPP) in the PZNC from 1982 to 2009. In 1982-2009, the mean annual air temperature, annual solar radiation and sunshine duration, and atmospheric CO2 concentration and its annual increasing rate in the PZNC increased significantly while the annual precipitation had a significant decrease, and the annual NPP showed an up-and-down trend, with the turning point in 1998. The annual NPP had a high spatial heterogeneity, with an average of 623 g C X m(-2). Comparing with air temperature, the precipitation in growth season was the main factor affecting the NPP. Land use change altered land cover, and thus, the spatiotemporal characteristics of NPP. A significant positive correlation was observed between the NPP and atmospheric CO2 concentration. The impact of permafrost degradation on NPP differed with regional environment. The NPP had a significant positive correlation with the mean annual ground temperature, but a negative correlation with the annual maximum permafrost depth. PMID- 22937639 TI - [Ecological restoration effect of closed and half-closed degraded wetlands in Northwest Yunnan Plateau, Southwest China]. AB - Selecting the restoration site of Napahai, a representative degraded wetland in Northwest Yunnan Plateau, as test object, a comparative study was made on the changes of plant community species composition, water quality, and soil organic matter (OM) and total nitrogen (TN) contents within stream way, meadow, and lakeside before and after vegetation restoration, aimed to verify the effectiveness of integrated ecosystem restoration at catchment scale. In the early restoration period, the plants at the study site increased from 13 to 28 species, 12 to 22 genera, and 8 to 18 families, and the aboveground biomass increased from 318.56 g x m(-2) to 507.68 g x m(-2). The plant community structure and composition in lakeside and riverside had an obvious change before and after the vegetation restoration. Pollution-tolerant species diminished or disappeared, while the primary swamp communities of Sparganium stoloniferum and Batrachium bungei appeared after their disappearance for many years. After vegetation restoration, soil OM and TN contents increased from 28.85 g x kg(-1) and 0.79 g x kg(-1) to 50.26 g x kg(-1) and 1.45 g x kg(-1), respectively. The TN and TP contents and COD in the water decreased significantly, and their removal rates reached to 67.9%, 79.2%, and 71.2%, respectively. The transparency of water body increased to 179%, indicating that the structure and function of the wetland ecosystem had been substantially improved and restored. It was concluded that the vegetation restoration measures and technology used in closed or half-closed plateau wetland area were effective, PMID- 22937640 TI - [Spatial variability of soil nutrients and salinity in coastal saline-alkali land based on belt transect method]. AB - A north-south transect was established in the saline-alkali land of Yellow River old course at Diaokou of northern Yellow River Delta, Shandong Province of East China to analyze the spatial distribution characteristics of soil nutrients and salinity and related affecting factors by using geostatistics method. In the study area, the nugget/still of soil organic matter, total nitrogen (TN), available phosphorus (AP), and available potassium (AK) contents and soil salinity were 0.38, 0.40, 0.50, 0.32, and 0.34, respectively, which demonstrated that these five parameters were moderately spatial dependence. The soil organic matter and TN contents in this transect had a similar distribution pattern, soil AK content was highly correlated to soil salinity, while soil AP content presented a fluctuated distribution. According to the comprehensive analysis of soil organic matter content and salinity, this transect was classified into three types, i.e., high salinity and low fertility, high salinity and high fertility, and low salinity and high fertility. The spatial distribution pattern of the five soil parameters was closed related to the soil parental material, land use pattern, distance to sea, and road block. PMID- 22937641 TI - [Relationships between summer drought and strong typhoon events and pine wilt disease occurrence in East Asia]. AB - The occurrence and prevalence of pine wilt disease cause huge losses to Japan, China, and South Korea in East Asia, and have received concerns from many countries. By the methods of field observation and meteorological data analysis, this paper studied the characteristics of the occurrence and prevalence of pine wilt disease and their relations to the meteorological disaster events. In Japan, China and South Korea, the meteorological extreme events of persistent summer drought and strong typhoon could trigger the occurrence of pine wilt. In extremely dry and hot environment, pine trees often appeared energy metabolism imbalance and entire tree wilt. However, in the years with lower temperature and more rainfall, less or nearly no pine wilt event occurred. It was suggested that before the attack by pine wood nematode and its vectors, the vigor of the pines had already declined, and thus, pine wilt disease could be confined in the areas often hit by summer drought and strong typhoon events. In the areas with suitable natural environment characterized by less summer drought and strong typhoon events and no improperly enlarged pine planting, there would be little possibility of widespread occurrence of pine wilt disease. PMID- 22937642 TI - [Spatial distribution pattern of carabid assemblage in agricultural landscape of Miyun County, Beijing]. AB - By the method of pitfall trap sampling, an investigation was conducted on the carabid assemblage in four typical habitats (maize field, peanut field, orchard, and semi-natural woodland) in the agricultural landscape in Xitiange Village of Miyun County, Beijing. Among the four habitats, orchard had the highest alpha diversity of carabid assemblage, followed by woodland and maize field, and peanut field had the lowest one. The species composition of the assemblage in woodland, peanut field, and orchard had evident difference, but was similar to that in maize field to some extent. The number of the individuals of predatory and omnivorous carabid sub-assemblages was larger in orchard, and the predatory sub assemblage presented more distinct difference in its species turnover rate than the omnivore sub-assemblage among the habitats. This study showed that low intensively managed orchard habitat could sustain higher alpha-diversity of carabid assemblage than semi-natural woodland habitat, and the landscape with diversified habitats could benefit the beta-diversity of carabid assemblage and its predatory sub-assemblage. To attach importance to the conservation of diversified habitats and low-intensively managed farmland habitat would have significance for the conservation of carabid assemblage diversity and its pest control function in agricultural landscape. PMID- 22937643 TI - [Influence of soil salinization on soil animal community in an arid oasis of middle Heihe River basin]. AB - An investigation was conducted on the status of soil salinization and the structure of soil animal community across six land use/cover types in an arid oasis of middle Heihe River basin, and the methods of redundancy analysis, regression analysis, and path analysis were adopted to analyze the responses of the soil animal community under different land use/cover types and different management modes to the various status of soil salinization. The six land use/cover types were 21-year old shrub land without irrigation and fertilization, 28-year old poplar and 33-year-old pine plantations with irrigation, 27- and 100 year-old farmlands with irrigation and fertilization, and natural grassland, from which all the other five land use/cover types were converted. The results demonstrated that land cover change in the absence of management practices did not lead to a significant change in the abundance and group richness of the soil animal community, while land cover change in the presence of management practices resulted in a significant change in the soil animal community. The evolvement of the soil animal community structure was co-affected by soil pH, soluble salt content, and Na+, Cl, HCO3-, and Mg2+ concentrations, among which, soil soluble salt and Na had the greatest contribution, being the key affecting factors. The abundance and group richness of the soil animal community had significant negative exponential correlations with soil soluble salt content and Na+ concentration, and significant quadratic correlations with soil Mg2+ and HCO3- concentrations. The calculated ecological threshold values of soil Mg2+ and HCO3- concentrations for the abundance and group richness of the soil animal community were 38.7-39.4 mg x kg(-1) and 324.9-335.3 mg x kg(-1), at which, the abundance and group richness reached their peaks 40-43 individuals x m(-2) and 13-14 families x m(-2), respectively. When the Mg2+ and HCO3- concentrations increased further, the abundance and group richness decreased. PMID- 22937644 TI - [Effects of lead stress on the growth and reproduction of Spodoptera litura fabricius (Lepidoptera:Noctuidae)]. AB - Standard artificial diet was added with different concentration lead (Pb) to feed herbivorous insect Spodoptera litura larvae to study their growth and reproduction under the effects of Pb stress. With the increasing concentration Pb in the diet, the survival rate and body mass of the larvae at their different development stages (larvae, pupae, and adults) decreased. The minimum concentration of Pb which caused the significant decrease of the survival rate was 100 mg x kg(-1), and that caused a remarkable decrease of body mass was 50 mg x kg(-1). After fed with the diet containing 25-200 mg x kg(-1) of Pb, the duration of laying eggs was significantly shortened. With increasing concentration Pb in the diet, the oviposition rate and fecundity of female adults decreased significantly, the average mass of one thousand eggs was significantly less than that of the control, and the hatching rate of the eggs laid by adults was also decreased significantly. All the results suggested that Pb stress had significant inhibition effects on the growth and reproduction of S. litura. PMID- 22937645 TI - [Genetic characteristics associated with drought tolerance of plant height and thousand-grain mass of recombinant inbred lines of wheat]. AB - A total of 120 recombinant inbred lines (RIL) derived from Chinese winter wheat cultivars Longjian 19xQ9086 and the two parents were taken as test materials to study the quantitative genetics characteristics of their plant height at different development stages, thousand-grain mass, as well as the correlations between the two traits under rainfed (drought stress) and well-watered conditions, and evaluate the genetic variation of the RIL. Under the two water conditions, the target traits of the RIL showed substantial transgressive segregation and great sensitivity to water condition. The drought stress coefficient of the plant height was higher at jointing stage, being up to 0.851. There was a significant positive correlation between the plant height at different development stages and the thousand-grain mass, and comparing with that at other growth stages, the plant height at jointing stage had a higher correlation coefficient with the thousand-grain mass (R2DS = 0.32, R2WW = 0.28). The plant height at both jointing and flowering stages had significant positive and direct effect but negative and indirect gross effect on the thousand-grain mass, while the plant height at heading and maturing stages was in adverse. The target traits showed a lower heritability ranged from 0.27 to 0.60. The numbers of the gene pairs controlling the thousand-grain mass were 10 under rainfed and 13 under well-watered conditions, while those of the gene pairs controlling the plant height at different development stages were 3-7 under rainfed and 4-14 under well-watered conditions, respectively. According to the clustering of the drought stress coefficient of plant height, the RIL could be classified into five subgroups, showing the abundant variation of the RIL in their phe- notypes and in the sensitivity to water condition. It was considered that the test RIL were appropriate for the study of the quantitative genetics of wheat drought resistance. PMID- 22937646 TI - [Influence of different duration of waterlogging on the growth and C and N metabolism of soybean at seedling and flowering stages]. AB - A pot experiment with soybean cultivar Nannong 99-6 was conducted to study its growth and C and N metabolism at seedling and flowering stages under the stress of different duration of waterlogging. Waterlogging inhibited the soybean growth. The plant biomass, leaf area, leaf pigment content, and photosynthesis rate all decreased significantly, and the leaf malonyldialdehyde (MDA) content had a significant increase. The change ranges of the physiological indices increased with increasing waterlogging duration. After the release of the stress, the plants had some recovery. The recovery capability in treatment waterlogging for 10 d was stronger than that in the treatment waterlogging for 20 d. The leaf soluble C and N and key enzymes had different responses to waterlogging. Soluble sugar content and glutamine synthease and sucrose synthease activities all increased, but soluble protein content decreased. The influence of waterlogging on the plant biomass, leaf area, and MDA content was smaller at seedling stage than at flowering stage. It was suggested that the shorter the waterlogging duration was, the lesser damage the soybean plant suffered, and the stronger the recovery capability was. Soybean plant could recover itself after waterlogging for 10 d. PMID- 22937647 TI - [Effects of phosphorous fertilizers on phytoavailability of cadmium in its contaminated soil and related mechanisms]. AB - To explore an effective measure to ensure the safety of rice quality in cadmium (Cd)-contaminated farmland, a pot culture experiment was conducted to study the effects of of low Cd content (Cd < 0.2 mg x kg(-1)) phosphorous fertilizers with an application rate of 0.10 or 0.20 g P2O5 x kg(-1) on the phytoavailability of Cd in its contaminated p add y soil, with the related mechanisms discussed. Compared with no phosphorous fertilization, applying 0.10 P2O5 x kg(-1) of calcium magnesium phosphate (CMP) and monopotassium phosphate (MKP) increased soil pH and decreased soil available Cd content significantly, and CMP and calcium superphosphate (CSP) decreased the Cd accumulation in rice significantly. When the application rate was up to 0.20 g P2O5 x kg(-1), calcium hydrogen phosphate (CHP) increased the soil pH and decreased the soil available Cd content significantly, and CMP, MKP, and CHP decreased the DTPA-extractable soil Cd content by 11.8%, 9.8%, and 11.8%, and the NH4 OAc-extractable soil Cd content by 9.5%, 7.1%, and 7.1%, respectively. All test phosphorous fertilizers could significantly decrease the stem and leaf Cd contents, with a decrement of 24.9% 50.8%, and except CHP, the others could significantly decrease the Cd content of brown rice. With the application CMP and CSP, the Cd content of brown rice was close to the National Hygienic Standard for Grains (GB 2715-2005). Among the test phosphorous fertilizers, those can increase soil pH (CMP, MKP, and CHP) could significantly decrease the availability of soil Cd significantly, and those containing calcium (CMP and CSP) were more effective in decreasing the Cd accumulation in rice. The efficiency of the phosphorous fertilizers was mainly determined by their chemical properties. Alkaline calcium-containing phosphorous fertilizers were more effective in decreasing the Cd absorption and accumulation in rice plant in Cd-contaminated farmland. PMID- 22937648 TI - [Effects of nitrogen application period on the nitrogen metabolism key enzymes activities and antioxidant characteristics of high-yielding summer maize]. AB - Taking the high-yielding summer maize cultivars Denghai 661 (DH661) and Zhengdan 958 (ZD958) as test materials, a field experiment was conducted to study their grain yield, nitrogen use efficiency, key enzymes activities of nitrogen metabolism, and antioxidant enzymes activities under effects of different nitrogen application periods. One-dose nitrogen application at jointing stage was not beneficial to the increase of grain yield and the nitrogen accumulation in plant and grain, while split application in combination with application after anthesis increased the nitrogen accumulation in plant and grain significantly and increased the grain yield. When the nitrogen was applied at a ratio of 2:4:4 at jointing stage, 10-leaf stage, and 10 days after anthesis, the grain yield of DH661 was up to 14123.0 kg x hm(-2); when the nitrogen was applied at a ratio of 1:2:5:2 as the basal and at jointing stage, 10-leaf stage, and 10 days after anthesis, the grain yield of ZD958 was up to 14517.1 kg x hm(-2). These two nitrogen application modes increased the grain yield of DH661 and ZD958 by 14.5% and 17.5%, respectively, as compared with one-dose nitrogen application at jointing stage. Split nitrogen application before anthesis increased plant nitrate reductase activity significantly. In the 0-42 days after anthesis under split nitrogen application, the glutamine synthetase, glutamate synthase, and glutamate dehydrogenase activities of DH661 and ZD958 were averagely increased by 32.6%, 47.1% and 50.4%, and 14.5%, 61.8% and 25.6%, and the superoxide dismutase and catalase activities were increased by 22. 0% and 36.6%, and 13.4% and 62.0%, respectively, and the malondialdehyde content was decreased significantly, as compared with one-off nitrogen application. It was suggested that for the high yielding of summer maize, split application of nitrogen and appropriately increasing the nitrogen application ratio after anthesis could enhance the plant key nitrogen metabolism enzymes activities, delay leaf senescence, promote plant nitrogen uptake and its utilization, and increase grain yield. PMID- 22937649 TI - [Effects of exogenous gamma-aminobutyric acid on polyamine metabolism of melon seedlings under hypoxia stress]. AB - Taking melon cultivar 'Xiyu No. 1 ' as test material, a hydroponic experiment was conducted to investigate the effects of exogenous gamma-aminobutyric acid (GABA) on the seedlings polyamine metabolism under hypoxia stress. Compared with the control in normoxic treatment, the seedlings under hypoxia stress had significantly higher glutamic acid decarboxylase (GAD) activity and GABA content, and their polyamine synthesis enzymes activities all enhanced significantly, which led to a marked increase of polyamines contents. Meanwhile, the seedlings leaf- and root diamine oxidase (DAO) and polyamine oxidase (PAO) activities also had a significant increase. The increment of root arginine decarboxylase (ADC) activity was higher, which induced a higher content of free putrescine (Put) in roots, while the increment of leaf ornithine decarboxylase (ODC) and S adenosylmethionine decarboxylase (SAMDC) activities were higher, inducing a higher content of free spermidine (Spd) in leaves. The PBs-extractable DAO and PAO activies in roots were significantly lower than those in leaves, but the cell wall-bound PAO activity was in adverse. Under hypoxia stress, the addition of exogenous GABA increased the leaf- and root GABA and glutamic acid contents and decreased the GAD activity significantly. The increase of arginine, ornithine, and methionine contents promoted the activities of polyamines synthesis enzymes, which led to the significant increase of polyamines contents and the significant decrease of DAO and PAO activities. PMID- 22937650 TI - [Cadmium accumulation, subcellular distribution, and chemical forms in Vitis vinifera cv. chardonnay grapevine]. AB - A pot culture experiment was conducted to study the Cd absorption, Cd subcellular distribution, and Cd chemical forms in one-year old self-rooted Chardonnay and SO4 rootstock-grafted Chardonnay grapevine after root-irrigating with different concentration CdCl and CaCl2. In the grapevine, the absorbed Cd was mostly distributed in underground organs (root and rhizome). In treatment 4 mmol x L(-1) of CdCl2, 77.1% and 1.4% of the absorbed Cd in self-rooted Chardonnay were accumulated in underground organs and leaves, respectively, while 93.9% and 0.1% of the absorbed Cd in grafted Chardonnay were accumulated in the organs below graft position and in leaves, respectively. 5 mmol L(-1) of CaCl2 decreased the plant Cd absorption and accumulation, while 10 mmol x L(-1) of CaCl2 increased the plant Cd absorption and accumulation significantly. The Cd subcellular distribution in roots and leaves was in the order of cell wall > soluble fraction > organelle, and more than 50% of the Cd was accumulated in cell wall. In the roots, NaCl-extractable Cd had a major proportion, followed by HAc-extractable Cd, and water-extractable Cd. The contents of all the Cd chemical forms varied with the increasing concentration of Cd in the treatments. PMID- 22937651 TI - [Impacts of elevated atmospheric ozone concentration on flag leaf microscopic structure of wheat: a field study with FACE system]. AB - By using FACE (Free-Air Controlled Environment)-ozone system, a field plot experiment was conducted in 2008-2009 to study the effects of elevated ozone (O3) concentration on the flag leaf microscopic structure, chlorophyll content, and grain weight of wheat. Two treatments were installed, i. e., ambient O3 and 150% of ambient O3, and four winter varieties, i. e., Yannong 19, Yangmai 16, Jiaxin 002, and Yangfumai 2, were taken as the test materials. At anthesis, elevated O3 concentration had a slight damage to the flag leaf microscopic structure. The mesophyll cell and chloroplast structure began destroying, and the grana lamellae started breaking and loosing. Twenty-one days after anthesis, the differences in the leaf microscopic structure between the two treatments became significant. Under elevated O3, the flag leaf senescence was accelerated, with the endomembrane system disintegrated, grana lamella disappeared, and corpus adiposum inside chloroplast broken down, resulting in a significant decrease of the chlorophyll content, photosynthesis rate, and grain weight at maturing stage. Significant difference was observed among the test varieties in their responses to elevated O3. Jiaxin 002 was tolerant, while Yangfumai 2 was sensitive to the ozone stress. PMID- 22937652 TI - [Microbial community structure in strong aromatic liquor fermented grains characterized by PLFA fingerprints]. AB - Taking the nine common microbial strains in liquor-making process as test objects, this paper studied the characteristics of phospholipid fatty acid (PLFA), a characteristic component of the strains cell membrane, and the relationships between the detected amount of PLFA and the biomass of the strains. There existed significant differences in the PLFA fingerprints between test bacteria, actinomycetes, molds, and yeasts, and the PLFA fingerprint of each strain could be used as the basis to distinguish species and genus. Within a certain range of the strains biomass, the detected amount of total PLFA or 16:0 was linearly correlated with the biomass. After adding different biomass Gram positive (G+) bacteria, Gram negative (G-) bacteria, and fungi in fermented grains, a significant difference was observed in the relative amount of PLFA between experimental and control samples. It was suggested that the fingerprint of PLFA could quantitatively or semi-quantitatively characterize the microbial community structure and its dynamic variation in fermented grains. By detecting the PLFA profiles of fermented grains in various liquor industries and by analyzing the microbial community structure in the fermented grains, it was substantiated that PLFA fingerprinting was of general applicability. PMID- 22937653 TI - [Expression of Na+/H+ antiporter gene KsNHX1 in Kochia sieversiana under saline alkali stress]. AB - The 3 'cDNA fragment of KsNHX1 in Kochia sieversiana was obtained by RACE. The phylogenetic analysis of antiporters from different plant species indicated that the KsNHX1 was a gene encoding vacuolar Na+/H+ antiporter. By using semi quantitative RT-PCR, the expression profiles of the KsNHX1 under different saline alkali stresses were examined. It was observed that the transcript of KsNHX1 in leaves under the stress of 200 mmol x L(-1) for 2-24 h increased gradually with increasing duration, and the expression of KsNHX1 in roots, stems, leaves, and flowers under the stress of 200 mmol x L(-1) for 10 h was up-regulated. Under various NaCl concentrations, the expression of KsNHX1 in leaves was up-regulated, with the maximum under 160 mmol x L(-1) of NaCl. The expression of KsNHX1 in roots was also up-regulated under the stress of < 400 mmol x L(-1). Under various concentrations of Na2CO3, the expression of KsNHX1 in roots appeared the similar change patterns with those under corresponding concentrations of NaCl, but the expression of KsNHX1 in leaves was down-regulated except under 160 mmol x L(-1). The changes of the expression patterns implied that KsNHX1 played roles in maintaining the homeostasis of K+/Na+, which probably contributed to the saline alkali tolerance of Kochia sieversiana. PMID- 22937654 TI - [Identification of a new heterotrophic nitrobacterium strain Colloides sp. JZ1-1 and its nitrifying capability]. AB - A heterotrophic nitrobacterium strain JZ1-1 with higher nitrifying capability was isolated and mutagenized from an acclimated activated sludge. The JZ1-1 was identified as Colloides sp., according to its morphological and physiological features. The factors affecting the nitrifying capability of JZ1-1 were investigated, including medium carbon source, C/N ratio, pH value, dissolved oxygen, temperature, and ammonium nitrogen concentration. The optimal carbon source was sodium citrate, and the nitrification was favored when the C/N ratio was from 10 to 14, temperature was 30 degrees C, and pH value was 6-9 when cultured at a rotating speed of more than 150 r x min(-1). JZ1-1 could degrade ammonium nitrogen effectively when the initial concentration of ammonium nitrogen was from 100 mg x L(-1) to 500 mg x L(-1). JZ1-1 was stable after 5 generations of subculture. PMID- 22937655 TI - [Regulation strategies of regional land use management based on ecosystem services: a case study in Wanquan Town, Zhejiang Province of East China]. AB - Through the evaluation of the gains and losses of the key functions of regional ecological system under different management modes, various ecosystems functions and their spatial distribution patterns in Wanquan Town were analyzed. Based on different development needs, various scenarios were established and weighed. In 2009, the support function value supplied by the ecosystems in the Town was 58 million RMB, among which, oxygen release function ranked first (37 million RMB), and the regulation function value provided by the ecosystems was 1238 million RMB, among which, climate regulation ranked first (1127 million RMB). The total ecosystem services value was 1297 million RMB, being 1.46 times of the local GDP (888 million RMB) in the same year. Compared with that in 2002, the service function value of the ecosystems declined in 2009, with the largest decrements in climate regulation and water yield. Under policy scenario and protection scenario, the variation trends of the values of various ecosystems functions were basically the same. Except that the values of the functions oxygen release and nutrient cycling decreased, the values of the others increased obviously. Under protection scenario, the total ecosystem services value had a higher increment than that under policy scenario, especially for the water yield and carbon sequestration functions. It was suggested that protection scenario could be the optimal land use management mode for the socio-economic sustainable development of the Town. PMID- 22937656 TI - [Spatial distribution characteristics of urban potential population in Shenyang City based on QuickBird image and GIS]. AB - Population is the most active factor affecting city development. To understand the distribution characteristics of urban population is of significance for making city policy decisions and for optimizing the layout of various urban infrastructures. In this paper, the information of the residential buildings in Shenyang urban area was extracted from the QuickBird remote sensing images, and the spatial distribution characteristics of the population within the Third-Ring Road of the City were analyzed, according to the social and economic statistics data. In 2010, the population density in different types of residential buildings within the Third-Ring Road of the City decreased in the order of high-storey block, mixed block, mixed garden, old multi-storey building, high-storey garden, multi-storey block, multi-storey garden, villa block, shanty, and villa garden. The vacancy rate of the buildings within the Third-Ring Road was more than 30%, meaning that the real estate market was seriously overstocked. Among the five Districts of Shenyang City, Shenhe District had the highest potential population density, while Tiexi District and Dadong District had a lower one. The gravity center of the City and its five Districts was also analyzed, which could provide basic information for locating commercial facilities and planning city infrastructure. PMID- 22937657 TI - [Multi-gradients of land surface temperature in mountainous cities with rapid urbanization: a case study in central area of Chongqing City]. AB - By using TM/ETM+ and MODIS images, the land surface temperature (LST) and relative heat island intensity (RHII) of the central area of Chongqing City were extracted to analyze the distribution patterns of the LST and RHII along the multi-gradients of topography, population, and gross domestic product (GDP) as well as the potential quantitative relationships. The LST and RHII manifested a non-monotonically decreasing trend along the gradients of elevation and relief degree, respectively, both with a significant quadratic polynomial relationship. The maximum RHII appeared at 200-350 m elevation section due to the massive urban construction activities, and had significant linear relationships with the population density and the GDP per square kilometer. The RHII rose about 0.10 degrees C when the population density increased 1000 people per square kilometer, and rose about 0.08 degrees C when the GDP per square kilometer increased 10 million RMB Yuan. PMID- 22937658 TI - [Perception of residents in world heritage site to the effects of ecological migration: a case study of three migrant resettlement spots in Wulingyuan, Hunan Province of South-central China]. AB - Based on the investigation in three typical migrant resettlement spots in Wulingyuan Scenic Area, a demonstration analysis was conducted on the residents' perception to the effects of ecological migration on world heritage site. The residents in the 3 spots had great differences in the positive perception to the economic effects of ecological migration, but less differences in the perception to the negative indices. The residents had high identity with the positive socio cultural effects, but weak perception to the negative effects. The residents in the 3 resettlement spots had obvious differences in the perception to the effects on resources and environment, but mostly agreed that the negative psychological effects were not so obvious. The negative comments were given to the main migration policies. Age, educational level, monthly income, and proportion of tourism input were the main factors affecting the residents' perception, and the way of resettlement as well as the proportion of tourism input also had important effects on the residents' perception. Migration policy was the dominant factor affecting the integral perception of the residents to ecological migration. PMID- 22937659 TI - [Effects of riparian ecological restoration engineering with offshore wave elimination weir on restoration area's water quality]. AB - Riparian ecological restoration engineering with offshore wave-elimination weir is an engineering measure with piled wave-elimination weir some meters away from the shore. This measure can dissipate waves, promote sediment deposition, and create an artificial semi-closed bay to restore vegetation in a riparian area which has hard dam and destroyed vegetation. Three habitat gradient zones, i. e., emerged vegetation zone, submerged vegetation zone, and open water area, can be formed after this engineering. In June 2010-May 2011, a field investigation was conducted on the water quality in the three zones in an ecological restoration area of Gonghu Bay, Taihu Lake. The water body inside the weir generally had lower concentrations of nitrite and nitrate but higher concentrations of ammonium and total nitrogen than the water body outside the weir. The water phosphorus concentration inside the weir was lower than that outside the weir in autumn and winter, while an opposite trend was observed in spring and summer. The coefficients of variation of the water body' s nitrite and orthophosphate concentration inside the weir decreased, and the annual maximum values of the water nitrite, nitrate, and orthophosphate concentrations inside the weir were lower than those outside the weir. On the contrary, the coefficients of variation of the water body's ammonium and total nitrogen concentrations inside the weir increased, and the annual maximum values of the water ammonium and total nitrogen concentrations inside the weir were higher than those outside the weir. To some extent, the restoration engineering could exacerbate the deterioration of the water quality indices such as ammonium and total nitrogen in the restoration area by the end of growth season PMID- 22937660 TI - [Control effect of different covering patterns on indigenous nutrient release from sediment]. AB - A laboratory simulation experiment was conducted to study the release of sediment phosphorous and nitrogen under the effects of coating the sediment with plastic, clinoptilolite, calcite, quartz sand, and calcium nitrate, aimed to provide scientific basis and technical support to control the sediment nutrient release under the background of water environment pollution by different concentrations of nitrogen and phosphorus. The control efficacy of test coating materials for sediment total phosphorous release was in the order of plastic > calcium nitrate > clinoptilolite > calcite > quartz sand, and that for sediment total nitrogen release was in the order of clinoptilolite > plastic > calcite > quartz sand > calcium nitrate. As for the release of sediment NO(3-)-N, the control efficacy of test coating materials was calcium nitrate > quartz sand > clinoptilolite > calcite > plastic coating; whereas for the release of sediment NH(4+)-N, the sequence was calcium nitrate > plastic coating > clinoptilolite > calcite > quartz sand. Water temperature had definite relativity to the sediment nutrient release. With the increase of water temperature, the concentrations of water total phosphorous and nitrogen and NO(3-)-N increased, while the concentration of water NH(4+)-N presented a declining trend. PMID- 22937661 TI - [Applications of macroinvertebrate community index and quantitative macroinvertebrate community index in monitoring and assessing river water quality]. AB - This paper introduced the principles and applications of macroinvertebrate community index (MCI) and quantitative macroinvertebrate community index (QMCI) commonly used in New Zealand, and applied them to monitor and assess 53 sites in 40 rivers in Wellington region of the Country. Both MCI and QMCI were correlated with the rivers nutrients enrichment significantly, suggesting that it was possible to use the two indices to monitor and assess the nutrient pollution of water body. The MCI and QMCI could rapidly and easily assess water body quality, and the assessment showed that in Wellington region, the rivers water quality was overall good, but some of the rivers were poor in water quality. There was a significant correlation between MCI and QMCI, but, as compared with QMCI, MCI was better correlated with the rivers nutrients enrichment, and thus, recommended to be applied to assess water body quality. The aim of this paper was to introduce the related researchers in China how to use MCI and QMCI in monitoring and assessing water body quality, and gave some ideas on improving the development of biotic index with macroinvertebrates in rivers water quality assessment in China. PMID- 22937662 TI - [Residual level and ecological risk assessment of OCPs and PCBs in sediments of mudflat shellfish culturing areas in Ningbo, Zhejiang Province of East China]. AB - GC-ECD methods were adopted to determine the residual level of OCPs (including HCHs and DDTs) and PCBs in the surface sediments collected from mudflat shellfish culturing areas in Ningbo, with the sources of the OCPs and PCBs analyzed and the ecological risks of the residual OCPs and PCBs evaluated. The residual level of OCPs was 0.80-32.40 ng X g(-1), and that of PCBs was 3.20-33.33 ng X g(-1). The HCHs mainly came from long distance atmospheric transportation and historical residues, while the DDTs had new input at some sites, possibly coming from the application of dicofol. At most sites, there existed potential ecological risks of p, p'-DDT and DDTs, with strong indications in Qiangtou and Xidian where the residual level of p, p'-DDT was higher than the effect rang median (ERM), suggesting an ecological menace to the benthos. The residual PCBs at most sites were in low level ecological risk. PMID- 22937663 TI - [Construction of individual-based ecological model for Scomber japonicas at its early growth stages in East China Sea]. AB - By adopting FVCOM-simulated 3-D physical field and based on the biological processes of chub mackerel (Scomber japonicas) in its early life history from the individual-based biological model, the individual-based ecological model for S. japonicas at its early growth stages in the East China Sea was constructed through coupling the physical field in March-July with the biological model by the method of Lagrange particle tracking. The model constructed could well simulate the transport process and abundance distribution of S. japonicas eggs and larvae. The Taiwan Warm Current, Kuroshio, and Tsushima Strait Warm Current directly affected the transport process and distribution of the eggs and larvae, and indirectly affected the growth and survive of the eggs and larvae through the transport to the nursery grounds with different water temperature and foods. The spawning grounds in southern East China Sea made more contributions to the recruitment to the fishing grounds in northeast East China Sea, but less to the Yangtze estuary and Zhoushan Island. The northwestern and southwestern parts of spawning grounds had strong connectivity with the nursery grounds of Cheju and Tsushima Straits, whereas the northeastern and southeastern parts of the spawning ground had strong connectivity with the nursery grounds of Kyushu and Pacific Ocean. PMID- 22937664 TI - [Mechanisms of nitrous oxide emission during livestock manure aerobic composting]. AB - Aerobic composting is an effective way to treat and recycle livestock manure. However, the aerobic composting of livestock manure is a potential source of the greenhouse gas nitrous oxide (N2O), which closely relates to the global greenhouse effect and ozone depletion. With the expansion of livestock industry and the dramatic increasing yield of manure compost, the N2O emission during the aerobic composting has become a severe problem. The researches on the mechanisms of N2O emission during livestock manure composting have attracted increasing concerns. In this paper, the recent researches on the N2O generation approaches, emission dynamics, potential affecting factors, and microbiological mechanisms of N2O emission during livestock manure aerobic composting were reviewed, and the measures to control the N2O emission during composting process were summarized. Some perspectives for the future researches in this field were suggested. PMID- 22937665 TI - [Occurrence and ecological consequences of transgenic rice gene flow: a review]. AB - China is one of the origin centers of rice (Oryza sativa), with a distribution of abundant wild rice germplasm resources. Since the biosafety certificates were issued to Bt transgenic rice containing cry1Ac gene against lepidopteran pests, concerns are raised on the gene flow from transgenic rice to its wild relatives. This paper reviewed the occurrence of transgenic rice gene flow and its potential ecological consequences. Most studies suggested that transgenic rice could successfully hybridize with cultivated rice, wild rice (O. rufipogon), red rice (O. sativa f. spontanea), and barnyard grass (Echinochloa caudata), and the gene flow from transgenic rice had a lower occurrence frequency and was highly variable. Once the gene flow successfully occurred, the transgenes could introgress into a wild population within only a few generations because of the fitness advantage of transgenic rice due to the new selective traits of transgenes. When the transgenic plants invaded and persisted in a wild population, the dynamic changes of the mixed population would depend on the relative fitness and competition capability. To study the effects of the gene flow of transgenic rice and its long-term ecological consequences would have significance in rationally protecting and utilizing wild rice germplasm resources in China. PMID- 22937666 TI - [Research progress on plate mixed culture of lignocellulolytic microorganisms]. AB - Mixed culture of microorganisms has been widely used for the research of lignocellulose transformation and degradation, but the results of the mixed culture are largely affected by the interactions of different lignocellulolytic microorganisms. At present, the researches on these interactions are mainly based on plate mixed culture assay. For this assay, two types of plate were used, namely, basic medium plate and improved medium plate. The basic medium plate is mainly used for the study of colony morphology, mycelia color, exocellular volatile organic compounds, and exocellular enzyme activity, whereas the improved medium plate is used for comparative study, with the carbon sources replaced by natural lignocelloses. This paper summarized the present research status and advancement about the plate mixed culture of lignocellulolytic microorganisms, and put forward a prospect about the focuses of future research in this field. PMID- 22937667 TI - [Quantitative estimation of vegetation cover and management factor in USLE and RUSLE models by using remote sensing data: a review]. AB - Soil loss prediction models such as universal soil loss equation (USLE) and its revised universal soil loss equation (RUSLE) are the useful tools for risk assessment of soil erosion and planning of soil conservation at regional scale. To make a rational estimation of vegetation cover and management factor, the most important parameters in USLE or RUSLE, is particularly important for the accurate prediction of soil erosion. The traditional estimation based on field survey and measurement is time-consuming, laborious, and costly, and cannot rapidly extract the vegetation cover and management factor at macro-scale. In recent years, the development of remote sensing technology has provided both data and methods for the estimation of vegetation cover and management factor over broad geographic areas. This paper summarized the research findings on the quantitative estimation of vegetation cover and management factor by using remote sensing data, and analyzed the advantages and the disadvantages of various methods, aimed to provide reference for the further research and quantitative estimation of vegetation cover and management factor at large scale. PMID- 22937668 TI - [Use of emergency services by the aged]. PMID- 22937669 TI - [Older patients at the emergency department: current and future challenges]. AB - Emergency departments are and will be at the front line to face the forthcoming increased use of the health care system by the aging baby boomers cohort. Emergency department services will need to adjust on a quantitative as well as on a qualitative basis to manage the impact of these demographic changes. Various models of care have been developed to improve the care of older geriatric patients in the Emergency department that resulted in favorable results on functional, health, as well as health services utilization outcomes. Key components of these successful models have been identified that require a high level of integration between geriatric and emergency teams. PMID- 22937670 TI - [Older people admitted to the emergency department after a fall: what to do?]. AB - Falls in older people are frequent. Falls may lead to serious injuries and are associated with greater morbidity, mortality, and reduced overall functioning in the older population. Evidences exist regarding the beneficial effects of fall prevention programs. However, these interventions are rarely implemented in our health system. Older people admitted to the emergency department after a fall should get careful attention in order to initiate specific interventions to prevent new falls. This article provides a clinical assessment strategy to evaluate older persons after a fall and proposes an algorithm for discharge planning decision. PMID- 22937671 TI - [Comprehensive geriatric assessment in the emergency department: some usefull screening tools]. AB - Emergency department (ED) admissions of patients 75 years and older are consistently increasing. Older patients suffer from atypical symptomatology, spend more time, and are more at risk of adverse outcomes (early readmission, functional decline, institutionalization and death) than younger people. The identification of geriatric syndromes like cognitive decline can improve the management of such patients and decrease the rate of the outcomes. In ED, screening tools developed to detect these geriatric problems have to be quick, easy to use and to present a high sensibility. This article aims at reviewing the literature about the ED-validated screening tools that could be applied in practice. PMID- 22937672 TI - [Abdominal pain among elderly patients in the emergency department]. AB - With the population ageing, each physician will increasingly be confronted with older patients, who often suffer from multiple ailments. In such population, abdominal pain, though a frequent complaint, can present a real challenge as history and clinical examination may be misleading. This symptom is however the fourth most frequent ground for consultation in the emergency department and is often a major consumer of time and money. It therefore seems essential to address each case of abdominal pain in the elderly with methodology and bearing in mind at all times that the usual clinical signs may be missing or deceiving. Diagnosis of nonspecific abdominal pain often marks the end of the consultation once the worst has been excluded. PMID- 22937673 TI - [Trauma in the elderly]. AB - Older patients can suffer severe trauma, especially in home environment. In Switzerland, falls are the main cause of trauma mortality in patients older than 65. Low kinetics mecanisms can cause severe trauma. Undertriage is frequent in emergency rooms and could result in delayed mortality. Except for hip fractures and simple fractures of extremities, age more then 65 should be a criteria for admitting the patient in a trauma center and activating the trauma team. PMID- 22937674 TI - [Elderly patients in the emergency department: a selection of some recent publications]. AB - Geriatric patients presenting to the ED are at high risk of mortality as well as of cognitive or functional decline. Thus, ED is an ideal spot for interventions that can improve their outcome. In this article, we summarize six recent studies, regarding the utilization of prognostic evaluation scores in geriatric patients presenting to the ED, adverse drug reactions, the significance of elevated troponin in patients who have remained on the ground after a fall, the rationale of performing head CT in patients without focal neurologic findings after a fall, the ideal treatment of a proximal femoral fracture and the excessive use of urinary catheters in the ED. PMID- 22937675 TI - [Abdominal aortic aneurysms: diagnosis and endovascular therapy]. AB - Abdominal aortic aneurysms are a common condition whose prognosis without treatment is poor because of the lethality in case of breakage. An early diagnosis is thus necessary by screening or symptoms recognition. Surgery is not the only option then, continuous monitoring and medical treatment being sometimes possible. If curative treatment is undertaken, endovascular technique is an alternative to open surgical repair but its indications are not yet fully established and endovascular grafts have not the same longevity as open surgery. A review of the indications for endovascular repair in patients operated at the Geneva University Hospital has been used to illustrate the importance of individualized care for each patient. PMID- 22937676 TI - [Half of internal medicine residents are on the edge of burnout]. PMID- 22937677 TI - [Mycoplasma is bionic; writing with our eyes]. PMID- 22937678 TI - [AIDS: 30 years and we are we going?]. PMID- 22937679 TI - [Doctor Guillotin and the machine named after him (3)]. PMID- 22937680 TI - [The Federal Office of Statistics and the utopian idea of transparency]. PMID- 22937681 TI - Infectology in Bosnia and Herzegovina--new trends. PMID- 22937682 TI - Quality assesment of medical education at faculty of medicine of Sarajevo University. AB - INTRODUCTION: Goal of measurement of the quality assessment of students' satisfaction is identification of weak and outdated sections of medical education. By finding out the unnecessary aspects, it is possible to start with improvement of the educational system. METHODOLOGY: The survey was conducted on the sample of 108 students of the final year of the study of Medical faculty in Sarajevo in December 2011. Questionnaire has 24 process and outcome variables for the purpose of quality assessment of the education at the Medical faculty. RESULTS: The measurement of quality of realized lectures of final year of Medical faculty in Sarajevo with formatted questionnaires determined that above 90% students rated it very low with grades under 3 of possible 5, compared with average 3 in survey from 2008. Unpreparedness of independent service after finished medical education has raised to 70% of questioned students, compared to 53% in 2008. Ratio of educators and assistents to students was graded mostly with grades under 3 of possible 5 by more then 80% questioned participants. Students grading satisfaction with concept of preclinical training has peaked in low levels of grade 1 by 44% survey participants, what are similar results compared to 2008. The measurement of satisfaction with concept of clinical education determined even lower and embarassing values of 94% negative attitudes and opinions by questioned students, compared with 83% in 2008. Availability of modern technical equipment at Faculty of Medicine is very low rated with grades under 2 by 87% of students. DISCUSSION AND CONCLUSION: The problems and weak points in medical education of Faculty of Medicine University of Sarajevo have persisted during period of more then a decade what comparsion of survey results clearly show. There is urgent need of improving and reforming the educational system which will bring more practical clinical and preclincal work, patient student contact and interaction with bigger full attendance of educators and tutors, all supported by new modern technical and informational technologies. On this way the achievement of independent and patient oriented work after received medical education is granted for future generations of doctors. PMID- 22937683 TI - Clinical and epidemiological features of acute corrosive poisonings. AB - BACKGROUND: the ingestion of chemical agents, of caustic nature, represents a serious problem for clinical toxicology. If the ingestion doesn't cause death during the acute period, it will most often cause severe side effects in the upper gastrointestinal tract during the chronic phase. AIMS: The purpose of this study is to show the clinical, epidemiological and socio-economical characteristics seen in acute corrosive poisonings such as ingested caustic agents, causes for abuse and most consequential complications. MATERIAL AND METHODS: a ten year medical data was constructed and collected (2000-2009) from patients with acute corrosive poisonings who were hospitalized and treated in the University Clinic of toxicology and urgent internal medicine in Skopje, Republic of Macedonia. The variables included were: age, sex, type of poisonings and percentage of late post-corrosive complications. RESULTS: In the study, 735 patients files were analyzed, collected in a period often years. The mean age of patients is 32.9 +/- 15.6 years. Majority of patients ingested hydrochloric acid (HCl; n = 354; 48,16%). CONCLUSION: Demographic, diagnostic and therapeutic findings in acute corrosive poisonings are found to be similar to the findings observed in the referenced literature. Conclusively, women between 14 and 30 years old represent a high risk group; hydrochloric acid is the most often abused agent; and high percentage of post-corrosive complications are PMID- 22937684 TI - Socioeconomic and lifestyle determinants of obesity in a transitional southeast European population. AB - OBJECTIVE: We aimed to assess the prevalence and socioeconomic and behavioral correlates of obesity in adult population of Albania, a transitional country in the western Balkans. METHODS: A cross-sectional study was conducted in 2007-2009 in the Albanian capital, including a sex-stratified random sample of 997 Tirana residents aged 25-65 years (83% response). A structured interview included data on demographic and socioeconomic characteristics and lifestyle factors. Physical examination included measurement of height, weight, and hips and waist circumferences. Binary logistic regression was used to assess the association of obesity with covariates. RESULTS: Half of participants were overweight, and about 30% were obese (36% women and 24% men). Obesity was positively associated with age, but inversely related to education and economic level. Almost every day drinkers were more likely to be obese compared to non-drinkers (OR = 2.2, 95% CI = 1.4-2.9). Fat and carbohydrate intake were both positively associated with obesity (for fat intake OR [low-moderate vs. high intake] = 3.1, 95% CI = 2.0 4.2) and for carbohydrate intake OR [low-moderate vs. high intake] = 2.8; 95% CI = 1.9-3.3). CONCLUSIONS: Our findings indicate that overweight and obesity pose serious public health concerns in this post-communist country. Health professionals and policy makers should focus particularly on the modifiable risk factors as an effective means of controlling the burden of obesity in Albania. PMID- 22937685 TI - Therapeutic approach to chickenpox in children and adults--our experience. AB - INTRODUCTION: Chickenpox is highly contagious childhood disease which occurs as a result of varicella-zoster virus primary infection. Symptomatic therapy is usually adequate for chickenpox, but in some cases it requires combinations of antiviral drugs and antibiotics. OBJECTIVES: To present our expirience with chickenpox therapy in children and adult patients. MATERIAL AND METHODS: Study included 120 randomly chosen patients, 60 adults and 60 children, with confirmed chickenpox infection, hospitalised at Clinic for infectious diseases in Sarajevo. Observed period was 1st January 2005. to 30th June 2011. We compared used therapy and outcome of disease. RESULTS: We had 333 patients with confirmed chickenpox in mentioned period. Male sex prevailed. Antiviral (acyclovir) therapy was initiated in 8(13.5%) adults and 16(27%) children. Most frequently used antibiotic was Co Amoxiclav in a group of adults and Ceftriaxone in a group of children. DISCUSSION AND CONCLUSION: We use different terapeutical approaches to chickenpox according to the severity of the clinical picture and the existence of underlying diseases. Symptomatic treatment is indicated in all immunocompetent patients with no signs of complications. Use of corticosteroids remains open dillemma. Our therapeutical approcach followed by actual guidelines proved to be usefull. No death cases were recorded in these PMID- 22937686 TI - Osteoarticular manifestations of brucellosis. AB - INTRODUCTION: Osteoarticular manifestations of human brucellosis occur in 20-40% of patients while spondylodiscitis is the most severe form of the bone and joint structures involvements. AIM: The aim of this paper is tho show clinical and radiological caracteristics of osteoarticular forms of brucellosis, with special reference to spondylodiscitis. MATERIAL AND METHODS: The medical histories of 120 hospitalized patients at the Clinic for Infectious Diseases, Clinical Center of Sarajevo University, diagnosed with brucellosis, were analyzed. RESULTS: Osteoarticular manifestations had sixty-nine patients, representing 78.4% of all localized forms of the disease. Spondylodiscitis represents 40.6% of all osteoarticular manifestations of the disease. Nine patients (32.1%) had paravertebral and paraspinal abscess. Median diagnostic interval for spondylodiscitis (116 +/- 160 days) was almost twice prolonged compared to the arthritis and sacroilitis (p < 0.05). The most common radiological manifestations were erosions of the vertebral surface (67.8%). Computerized tomography confirmed inflammation in 85.2% of the patients, while magnetic resonance imaging (MRI) showed radiological alterations in all patients (100%). DISCUSSION AND CONCLUSION: Osteoarticular manifestations are the most common localised forms of brucellosis. The frequency of spondylodiscitis is in relation to duration of the diagnostic time. MRI shows a high degree of sensitivity to inflammatory changes of spine and "Pedro Pons' sign" is patognomic radiological alteration. PMID- 22937687 TI - Spermiogram part of population with the manifest orchitis during an ongoing epidemic of mumps. AB - INTRODUCTION: Incidence mumps infection has declined since the introduction of the inevitable MRP vaccination during the stage of childhood. In Bosnia and Herzegovina (BIH), from a period of February 2011 until today, there is an evident inclination of the recorded cases of the mumps infection. Orchitis usually occurs in between 3 to 10 days after the parotitis and is found with the post-puberty population. AIM: The aim of the study is to confirm the changes that occur during an early stage of the spermiogram and hormonal status, and after treated mumps orchitis, the patients treated in the Clinic for the Infectious Diseases. PATIENTS AND METHODS: Retrospectively, the analysis of 54 historical diseases was undertaken. During the research stage, the patients after being discharged have made an inquiry to our clinical consultancy units with final results of the spermiogram and hormone-FSH, LH and testosteron. The data analysis was processed with the SPSS program for Windows. RESULTS: the average length of the hospitalization period was in between 8 (medium) days, and average age M (mean) = 21,9 +/- 5,4 years. The speriogram of the treated patients was undertaken one month after the acute phase of the disease and has shown the following results: azoospermia with 14 patients (25,9%), oligospermia with 30 patients (55,6%) and normospermia with 10 patients (18,5%). During the hormonal status with 11 patients (20,4%), the results have shown the inclination of the value in FSH hormons, with 11 patients (20,4%), have shown the lesser value of the testosterons. CONCLUSION: The current study suggests that post-orhitis atrofia is expected within a period of 2-3 months after the infection, and thus, the monitoring on the patients' treatment would continue. The male infertility as a result of mumps ocrhitis is controversial and continues to be the thematic issue as well as the effect of orchitis on testicular endocrine function. Key words: epidemic, mumps PMID- 22937689 TI - Neoplasms in the clinical material of neurology clinic, Clinical Center of University of Sarajevo in the period 1990-2009. AB - INTRODUCTION: Brain tumors are a unique and heterogeneous group of tumors with which face a variety of specialties, mostly oncologists, neurologists and neurosurgeons. Due to their specific location all brain tumors are malignant, regardless of their malignant potential, because any expansion process within the skull, increased intracranial pressure and destruction of surrounding structures, which can cause neurological, quantitative disturbances of consciousness or death. GOAL: The goal of this study was to record neoplastic processes of the central nervous system in patients of Neurology Clinic, Clinical Center of Sarajevo University in the twenty-year period (January 1st 1990-December 31st 2009). The study was partly retrospective and partly prospective determined by three time periods. MATERIAL AND METHODS: We reviewed medical records and documentation of patients treated at Neurology Clinic, which has 102 beds. All patients' data were collected using a specially designed questionnaire for this study. RESULTS AND DISCUSSION: The number of secondary tumor process for the period 2000-2005 is greater than in the period 1990-1999, while in the period 2000-2009 is increasing (17.2%-30.3%). The male-female ratio is 52:48. During the first two monitoring period there were statistically significantly more men, and in the last monitoring period there were more women. The mean patient's age was 60 years. The most common symptom was hemiparesis for all observed periods evaluated with standard diagnostic tests: CT and MRI. CONCLUSION: We can conclude that CNS neoplasms in patients of Neurology Clinic, Clinical Center of Sarajevo University are present in the twenty-year period with total of 1.47%, and showed a decrease of 2.7% (1990-1999) to 0.47% for the period 2006-2009. PMID- 22937688 TI - Importance of quick test for screening of former drug users. AB - INTRODUCTION: Most frequent mode of transmission of HCV today is with intravenous drug use. Former intravenous (IV) drug users present population group more exposed to HCV infection. Longer period of substance abuse, common syringe, more sexual partners (drug users) represent independent, statistically significant risk factors in this population. Diagnosis of HCV infection is based on history, epidemiological data, and clinical presentation, blood tests, histopathological and virology investigation. Hepagnost C is fast immunochromatography test for qualitative detection of HCV antibodies in blood, serum or plasma. Sensitivity of this test compared to EIA is >99% and relative specificity 98,6%. MATERIAL AND METHODS: At Clinic for Infectious diseases (Hepatology Department) voluntary testing with Hepagnost C test was done for 22 former drug users. Results of this cross-sectional study are processed with SPSS program for Windows. RESULTS: Most of the subjects were male (95,5%), average age of 33 +/- 3,5 years with average length of drug usage of 10 (7-12,5) years. All positive (9/22) were tested with EIA test and HCV infection was confirmed (9/9), therefore positive predictive value for Hepagnost C is 100%. We investigated relative risk (RR) with IV drug usage. Higher risk for infection (1,7 times) was among IV. drug users. Odds ratio was 2,4 (chance for HCV in iv. drug users group is 2,4 times higher). Common syringes increase relative risk for 4,5 times, and Odds ratio for infection 9 times. CONCLUSIONS: Hepagnost C test of high sensitivity and specificity showed 100% prediction. It is simple, inexpensive and comfortable test with results within 15 minutes. Demographic characteristics of tested persons as well as statistical results do not deviate significantly from results in available literature. PMID- 22937690 TI - Role of early viral infections in development of multiple sclerosis. AB - INTRODUCTION: Multiple sclerosis is a chronic inflammatory, autoimmune, demyelinating, disease but also degeneration of axons, with mainly progressive course, causing greater or lesser degree of disability. In addition to genetic predisposition the environmental factors, with particular importance of early viral infection, have an essential role in the development of MS. These are called long-acting viruses that remain hidden in the body for years by encouraging latent immunological changes in the body, eventually resulting in autoimmune demyelination and the appearance of disease symptoms, which confirms the high titer of antibodies to certain viruses in patients with the MS. To first of all herpes simplex virus, Epstein Barr virus, cytomegalovirus and rubella virus. GOAL: Goal of this study is to analyze the incidence of early infection with rubella virus, herpes simplex, cytomegalovirus and Epstein-Barr, in MS patients using titers of IgG and IgM antibodies. MATERIAL AND METHODS: The study included patients treated at the Neurology Clinic in Sarajevo, with a diagnosis of multiple sclerosis (newly discovered) in the period January 2009-December 2011. To all patients beside history and neurological examination and tests to confirm the MS (brain MRI, evoked potentials and CSF examination) made serological tests for viruses, HSV, Rubella virus, cytomegalovirus and Ebstain Barr's virus, with reference to the previous parameters (old) and new viral infection. RESULTS: In this period there were 118 newly diagnosed multiple sclerosis from which 69.5% (82) female and 30.5% (36) male patients aged 23-56 years. IgG antibodies to herpes simplex virus was positive in 93.2% (110 patients) (72 F and 38 M and IgM only in 0.84% (1 patient). Ig G in Cytomegalovirus was positive in 86.44% (102 subjects, 71 females and 31 males), while IgM was negative in whole sample. IgG Rubella virus was positive in 61.01% (72 patients, 52 F and 20 M) and IgM was negative in all, while IgG in Ebstain Barr's virus was positive in 83% (98 patients). CONCLUSION: Early infection by herpes simplex virus, cytomegalovirus, Epstein-Barr and Rubella is present in patients with multiple sclerosis in a significant number so the conclusions is the fact that in the development of multiple sclerosis an important role early exposure to these viruses. Key words: early viral infection, multiple sclerosis. PMID- 22937691 TI - Ultrasound evaluation of uterine scar after Cesarean section and next birth. AB - INTRODUCTION: Cesarean section (Sectio Caesarea) is a surgical method for the completion of delivery. After various historical modifications of operative techniques, modern approach consists in the transverse dissection of the anterior wall of the uterus. The rate of vaginal birth after cesarean section was significantly reduced from year to year, and the rate of repeated cesarean section is increased during the past 10 years. Evaluation of scar thickness is done by ultrasound, but it is still debatable size of thick scar that would be guiding "cut-off value" for the completion of the delivery method. GOAL: The aim was to examine the most accurate ultrasonic method for assessing thickness scar on the uterus after previous cesarean delivery and determine the threshold thickness of scar that would allow the completion of birth vaginally. MATERIAL AND METHODS: Conducted is prospective study of 108 pregnant women aged 20-42 years, who had previously had a Caesarean section. Diagnostic accuracy in assessing the success of scar scale by evaluation of delivery (spontaneous or caesarean section). Measurements were carried out by 2D and 3D ultrasound machines in the 20, 38-40 week of gestation and 48 hours after birth. RESULTS: Tests have shown that there is a statistically significant difference in the rates of specificity (0.04), sensitivity (0.05), PPV (0.01) and NPV (0.01) between 2D and 3D ultrasound. Ultrasound images of uterine muscle scar after prior cesarean section are better by 3D methods. The marginal value, "cut-off value" thick scar, which provides the possibility of vaginal birth after previous incision was 3.5 mm. CONCLUSION: The study showed that ultrasound measurement of 3D ultrasound thick scar on the uterus after previous cesarean section has practical application in determining the mode of delivery among pregnant women who have previously given birth by Caesarean section. PMID- 22937692 TI - One hundred kidney transplantations in Tuzla. AB - INTRODUCTION: Kidney transplantation assures considerably better quality of life than the treatment of end-stage renal disease patients with dialysis. GOAL: Authors intended to present results of kidney transplantations that were performed for over 13 years in UCC Tuzla. EXAMINEES AND METHODS: Total of 100 transplantations have been done over 13 years. The gender and age structure have been presented, as well as number of transplantations per year, type of transplantation (living related donor, living unrelated donor, deceased donor), number and percentage of donors and results of transplantations expressed as survival of both the patient and transplanted kidney/ renal graft. We also wanted to presented other important events such as dates of introduction of certain drugs, dates of first cadaver transplantation, transplantation with desensitization protocols and dates of first living unrelated (spousal/emotional) transplantation. RESULTS: The survival of patients and renal grafts were demonstrated by Kaplan-Meier curve, and obtained results were fully in range of results recommended in other literature and by other authors. One-year survival of graft is 94%, with five-year survival being 75%. One-year survival of patients is 95%, and five-year survival of patients was 84%. DISCUSSION: Our results have been compared to those from other studies, gaining suggestions for transplantation improvement. CONCLUSION: Among all modifications of renal replacement therapy transplantation is by far the method of choice because, its well known advantages aside, it also has an economical advantage over chronic treatment with dialysis and it should therefore become interesting to healthcare systems. PMID- 22937693 TI - Staphylococcal sepsis and frequency of metastatic foci. AB - INTRODUCTION: Staphylococcal sepsis is one of the most serious bacterial infections in the world, in most cases accompanied by metastatic foci in various organ systems. OBJECTIVE: analyze the metastatic foci patients suffering from staphylococcal sepsis. PATIENTS AND METHODS: we analyzed the patients treated for staphylococcal sepsis during the ten year period. RESULTS: 67 patients were included, of which 45 (67,2%) with the outpatient acquired infection and 22 (32.8%) hospital acquired. Male was present in higher percentage 58.2% and the average age of patients was 39 years. Meticillin-sensitive strains are present in 73.1% and resistant isolates in 26.9%. Chi square test of independence showed a dependence isolated pathogens in relation to the place of infection p = 0,003. From the total number of metastatic foci, 39 was in the lung, 32 in the skin and subcutaneous tissue, 24 in the abdomen, 15 in the bones and joints, 11 heart and brain 2. CONCLUSION: The greatest number of metastases was in the lung. Significantly large number of patients had outpatient infection with predominance of meticillin sensitive strains while in hospital infections in a greater percentage were meticillin rezistent strains. Proven dependence of isolated pathogens in relation to the place of infection (outpatient/hospital). PMID- 22937694 TI - Cellulitis--epidemiological and clinical characteristics. AB - INTRODUCTION: Cellulitis is acute skin infection and/or infection of subcutaneous tissue, mostly caused by Streptococcus pyogenes and Staphylococcus aureus. Clinical preview is usually obvious and enough for diagnosis. Tretment is antimicrobial therapy. In recurrent cases a prophylaxis is very often needed. OBJECTIVES: Analysis some of the epidemiological and clinical characteristics of cellulitis. PATIENTS AND METHODS: Retrospective analysis of medical documentation of patients with clinical preview of cellulitis who were hospitalized in Clinic for infective diseases of Clinical Center of University of Sarajevo in last three years. RESULTS: In period of three years 123 patients were hospitalized with clinical preview of cellulitis in the broadest sense of the word. In 123 of cellulitises, 35/123 (28.45%) were erisipelases-superficial type and 88/123 (71,55%) were deep cellulitises. Men were more affected 56,09%, average of age was 50.22 years. Before hospitalization patients had ambulance treatment in average of 5.12 days, and hospitalization was long in average of 13.33 days. Risk factors wich contributes to the disease were found in 71.54% of cases. Due to localisation, skin disorders on lower limb were the most frequent 71.56%, cellulitis of upper limb were found in 12.19%, head and/or neck in 13.08%, trunk in 3.25%. Repetition of disease were found in 4.8% in patients wtih risk factors. Bacteremic isolats were confirmed in 27.64% of cases. In all patients empirical antibiotic treatment were started, in the 62.60% the first choice of medicine was antibiotic from the group of lincosamides. CONCLUSION: Cellulitis is very serious disease that can be prevented. PMID- 22937695 TI - Serratia marcescens meningitis following spinal anaesthesia and arthroscopy. AB - We present case of nosocomial bacterial meningitis, caused by Serratia marcescens (ESBL), occurred following spinal anaesthesia. Although very rare bacterial meningitis is serious complication of spinal anaesthesia and early diagnosis as well as effective treatment is extremely important. Previously healthy individual, admitted to Orthopaedic Department for routine arthroscopy, approximately within 24 hours after operation was performed complained of headache and fever. Infectious Diseases physician was consulted, lumbar puncture was performed and purulent meningitis was confirmed. Cerebrospinal fluid and blood cultures of patient confirmed Serratia marcescens (ESBL), resistant pathogen and important nosocomial agent. Patient was successfully treated. Cases of spinal meningitis caused by Serratia marcescens are rare. Local resistance pattern is important and should be always considered when starting therapy. Infection control team was appointed because of similar case of meningitis one month before in the same Department, and after investigation discovered Serratia in anaesthetic vial used in procedures. New measures and recommendations regarding infection control were implemented at Orthopaedic Department. Meningitis as a complication should always be considered as a possible differential diagnosis with patients after spinal anaesthesia complaining on headache and fever. Early diagnosis and early treatment is extremely important. Knowledge and practice of infection control measures is mandatory and should be always emphasized to performing staff. PMID- 22937696 TI - Diagnosis and treatment of chronic viral hepatitis B and C: doctrinary approach. AB - Association of Gastroenterologists and Hepatologists of Bosnia and Herzegovina based on the experiences of domestic and foreign centers operating in the field of hepatology and accepted guidelines of the European and the U.S. Association for Liver Diseases adopted the consensus for the diagnosis and treatment of chronic viral hepatitis B and C. The guidelines are intended for specialists in gastroenterology and hepatology, and infectious diseases physicians working in primary health care and family medicine, but also other physicians who are confronted with this disease in their practice, with the aim of facilitating and shortening the diagnostic and treatment protocols of patients with chronic viral hepatitis B and C. This ensures faster, more efficient, more rational and cost effective care of patients with hepatitis, with an emphasis on stopping the deterioration of liver disease to liver cirrhosis and eventually hepatocellular carcinoma. Key words: Chronic hepatitis B and PMID- 22937697 TI - [From persistence to symbiosis of microorganisms]. AB - Primary results of study of problem of microorganism persistence over the last 2 decades on 7 all-Russian conferences in Orenburg are examined in the article. Milestones of both fundamental research and practically significant studies are designated, the role of persistent potential of microorganisms in infectious pathology is evaluated. The emerging turn of studies from persistence to symbiosis is consonant with the idea of international project "Human microbiom" and allows to use the persistent potential of microorganisms as one of the instruments of resolving issues of infectology. PMID- 22937698 TI - [Model of chronic salmonellosis: parameters of infection and immune response in inbred mice genetically variable in susceptibility to salmonellosis]. AB - AIM: Study parameters of chronic infection and immune response in I/St and A/Sn line mice in the model of per oral infection of mice with Salmonella enterica serovar Typhimurium. MATERIALS AND METHODS: Studies were carried out in I/StSnEgYCit (I/St), A/JsnYCit (A/Sn) inbred line mice as well as their back crossing hybrids [I/StrxF1(I/StxA/Sn)]BC. Mice were infected per os by S. enterica serovar Typhimurium strain IE147 at a dose of 2 x 10(5) PFU per mice. The number of salmonellae was determined at days 3, 5 and 7, weeks 3 and 4 after the infection in various organs, the number of antibody producers--by cell EIA. Pathomorphologic changes in mice spleens were studied histologically by using hematoxylin and eosin staining. In offspring of back crossing [I/St x F1(I/St x A/Sn)]BCl segregation genetic analysis of sensitivity to salmonella infection trait and mapping of loci taking part in salmonella infection were carried out. RESULTS: The course of chronic salmonellosis in susceptible I/St line was characterized by the presence of more pronounced pathomorphologic changes in spleen and significantly higher microbial load in organs (approximately by 1000 times) when compared with A/Sn mice. Interlinear differences in susceptibility to infection correlated with differences in the type of early local and systemic immune response. In I/St mice a higher level of salmonella specific IgG2a-, IgG1- and IgA forming cells in spleen compared with A/Sn mice was detected which correlates with a pronounced splenomegaly and high concentration of salmonellae. On the contrary A/Sn mice demonstrated a higher level of salmonella specific IgA forming cells in Peyer patches that probably leads to protection of A/Sn line during per oral infection. Genetic analysis of susceptibility to salmonellosis trait inheritance showed the presence of its coupling with D9Mit89 locus of chromosome 9 on which previously Tbs2 locus was mapped that plays a role in the control of tuberculosis infection. CONCLUSION: There is a probability of the presence of general mechanisms of genetic control of tuberculosis and salmonella infections in A/Sn and I/St mice. PMID- 22937699 TI - [Contribution of L,D-carboxypeptidases in virulence of facultative intracellular pathogenic bacteria Listeria monocytogenes]. AB - AIM: Evaluate influence of mutation of Listeria monocytogenes genes coding murein tetrapeptide L,D-carboxypeptidase Lmo0028 and Lmo1638 on dynamics of infectious process and interaction of purified muropeptides with NOD1 receptor. MATERIALS AND METHODS: Wild type EGDe strain and recombinant strains GIMins1638 H GIMins0028 obtained on its basis by site-specific mutagenesis were used. Infectious process dynamics was studied on the model of intravenous infection of BALB/c mice. Ligand-receptor interaction activity of muropeptides isolated from recombinant and parent strains were assayed on HEK293-hNOD1 cell line expressing NOD1 receptor and containing in their genome beta-galactosidase reporter gene under the control of NF-kappaB dependent promoter expression. RESULTS: Lack of Lmo0028 decelerates reproduction of listerias in animal liver starting from 24 hours and at later terms after the infection whereas lack of Lmo1638 leads to increase of microbial load 6 and 24 hours after the infection with no influence on further infection. Differences in activation of NOD1 receptor by muropeptides isolated from recombinant and parent strains were not detected. CONCLUSION: Despite high homology murein-tetrapeptide L,D-carboxypeptidase Lmo0028 and Lmo1638 make a different contribution to the development of infectious process caused by L. monocytogenes in BALB/c line mice. Lack of differences in NOD1 receptor activation may be associated with compensation of enzymatic functions in strains with mutation in each of the genes owing to the presence of homologous protein. PMID- 22937700 TI - [Characteristic of early mucosal immune response in mice during intravaginal infection caused by Chlamydia muridarum]. AB - AIM: Comparison of features of recruitment to infection focus of cells mediating early immune reactions in intravaginally infected mice that had previously received or not received covinan (progesterone analogue). MATERIALS AND METHODS: A/Sn and BALB/c line mice were used in the study. C. muridarum strain Nigg infection was carried out intravaginally or intraperitoneally. For synchronization of sexual cycle a group of mice received subcutaneously a synthetic analogue of progesterone--proligeston (covinan) at a single dose of 33 mg/kg. Acute urogenital infection was evaluated by culture method. Quantitative determination of C. muridarum DNA (including study of persistence) was carried out by real time PCR. Subpopulation structure of cell population of peritoneal and vaginal lavage was evaluated by flow cytofluorometry. RESULTS: Intravaginal infection of mice that had not received covinan resulted in a pronounced recruitment of cells into vaginal cavity at 24 hours after the infection. Influx of neutrophils, dendritic cells and T-lymphocytes was especially pronounced. Prior administration of covinan practically nullified cell recruitment to infection focus though partial preservation of subpopulations of activated dendritic cells and CD8+ T-cells was observed. CONCLUSION: In mice with artificially induced by progesterone sensitivity to chlamydias the ability of recruitment to the infection focus of cells that mediate early immune reactions is reduced, that gives evidence on the importance of these reactions for infection outcome. PMID- 22937701 TI - [Influence of Chlamydia trachomatis type III secretion system on regulation of cytokine response]. AB - AIM: Develop in vitro model for studying production of cytokines by monocyte cells infected with Chlamydia trachomatis mediated by type III secretion system (TTSS). MATERIALS AND METHODS: Strain C. trachomatis L2/434/Bu was used in the experiments, culture of human monocytes U-937 was infected by this strain. Level of inflammatory cytokines was measured on flow analyzer Bio-Plex 200 (Bio-Rad Laboratories). Low molecular compound LHC-342 which belongs to the class of heterocyclic compounds was used as TTSS inhibitor. RESULTS: 24 hours after the infection with C. trachomatis culture 8 analyzed cytokines are induced in U-937 cells (IL-1beta, IL-4, IL-6, IL-8, IL-10, GM-CSF, IFN-gamma, TNFalpha). The most pronounced increase was observed for IL-8, GM-CSF and IFN-gamma. Introduction of TTSS inhibitor into the culture of infected cells suppressed chlamydia growth, but addition of FeSO4 restored the growth of chlamydiae. And activity associated with translocation of effector TTSS protein IncA to inclusion membrane was suppressed. Under the conditions of the obtained model of TTSS inhibition during intracellular development of C. trachomatis a significant decrease of 2 pro inflammatory cytokines--IL-6 and IL-1beta--was observed. CONCLUSION: Cytokine response plays a key role in the protective immune response in chlamydia infection but at the same time induces immunopathologic conditions. The data obtained give reasons to assume role of C. trachomatis TTSS in the induction of this component of immune response that requires further detailed studies. PMID- 22937702 TI - [New approaches to therapy of persistent infections: elimination of intracellular Chlamydai trachomatis by exposure to low temperature argon plasma]. AB - AIM: Study microbicidal activity of low temperature argon plasma (LTP) that is a stream of partially ionized argon having macroscopic temperature of the environment against Chlamydia trachomatis obligate intracellular parasites. Study viability of host cells in parallel. MATERIALS AND METHODS: McCoy line cells infected with C. trachomatis (Bu-434/L2 strain) were exposed to LTP obtained by using atmospheric pressure plasma SHF generator. Intracellular localization of chlamydiae was visualized by luminescent microscopy. RESULTS: Exposure of infected McCoy line cells resulted in the destruction of chlamydia inclusions and practically complete elimination of intracellular bacteria. At the same time LTP exposure did not result in immediate death of host cells, an insignificant reduction of the number of cells was observed 24 hours after the exposure to LTP. CONCLUSION: The effect of LTP for elimination of intracellular chlamydia without significant changes in viability of eukaryotic host cells was demonstrated. PMID- 22937704 TI - [Pathogenicity factors of enterococci of human intestinal microflora]. AB - AIM: Characteristic of pathogenicity factors of enterococci isolated from human feces. MATERIALS AND METHODS: Production of hemolysin, gelatinase and DNase was determined in 161 enterococci cultures. RESULTS: Hemolytic activity detected in 14.9 +/- 2.8% of the studied cultures was the most prevalent characteristic; 22 of 24 hemolytic strains belonged to E. faecalis species. Human erythrocyte lysis was also caused by E. faecium and E. durans cultures (1 strain each). Other pathogenicity factors were detected solely in E. faecalis species members. Enterococci proteolytic activity associated with gelatinase enzyme production manifested on various substrates--both gelatin and milk. This property was detected in 7.5 +/- 2.1% cultures. Deoxyribonuclease was detected in 1 (1.2 +/- 0.9%) E. faecalis strain. A number of E. faecalis cultures possessing hemolytic activity additionally hydrolyzed gelatin (22.7 +/- 8.9% strains) and DNA (4.5 +/- 4.4% isolates). CONCLUSION: Though pathogenicity factors occur in enterococci of intestine microflora relatively rarely, separate cultures with expression of 2 or more pathogenicity factors may be essential in the development of endogenous infections especially in immune compromised patients. PMID- 22937703 TI - [Species characteristic and persistent factors of Candida genus fungi isolated from various biotopes during infectious-inflammation diseases and intestine dysbiosis]. AB - AIM: Determine species composition and persistent properties of Candida genus fungi isolated from various biotopes of the human organism during infectious inflammation diseases and intestine dysbiosis. MATERIALS AND METHODS: 152 Candida genus fungi were isolated and identified from individuals with dysbioses and patients with infectious-inflammation diseases. Antilactoferrin and sIgA-protease activity of isolates was determined by enzyme immunoassay. RESULTS. C. albicans strain was shown to be the dominant species isolated from all the studied biotopes. Wide prevalence of the studied properties in Candida genus fungi and their dependence on species membership, isolation biotope, infectious process form, degree ofdysbiotic disorders in intestine was established. CONCLUSION: The data obtained expand the understanding of biological properties of Candida genus fungi that facilitate their prolonged survival in host organism. PMID- 22937705 TI - [Genetic characteristic of virulent potential of enterococci of human intestinal microbiota]. AB - AIM: Determine prevalence of genetic determinants of virulence among enterococci strains comprising human intestine microbiota. MATERIALS AND METHODS: 81 enterococci strains isolated from intestine of individuals during examination for dysbiosis were used in the study. Strain identification was performed by using multiplex PCR. Hemolytic and gelatinase activity was determined by dish method; genes coding virulence factor synthesis (gelE, sprE, cylM, cylB, cylA, esp)--by PCR. RESULTS: A wide set of genetic determinants of virulence was detected in E. faecalis strain microorganisms. CONCLUSION: Enterococcus genus microorganisms of human intestine microbiota that have virulence potential may become the reason for endogenous infection. The data obtained may be used for prognosis of risk of development of endogenous enterococci infections. PMID- 22937706 TI - [Influence of corynebacteria metabolites on antagonistic activity of H2O2 producing lactobacilli]. AB - AIM: Study combined influence of Corynebacterium genus bacteria metabolites and H2O2 producing lactobacilli on survival rate of Staphylococcus aureus, Escherichia coli and Lactobacillus acidophilus. MATERIALS AND METHODS: The ability to inhibit catalase of the test strains used and to reduce bactericidal effect of hydroxyl radical were determined in corynebacteria. H2O2 containing metabolites were obtained by cultivating lactobacilli in mineral medium, the amount of H2O2 was determined by oxidation of TMB by peroxidase. Bactericidal effect of lactobacilli metabolites for test strains treated by corynebacteria metabolites was evaluated by seeding results. Results. Inhibitio by corynebacteria metabolites of S. aureus catalase activity by 30-40% and E. coli catalase activ ity by 40-70% was shown. A reduction of bactericidal effect of hydroxyl radicals by corynebacteria metabolites by 30-35% for S. aureus, 38-42% for E. coli and 70-73% for L. acidophilus was noted. The enchantment of bactericidal effect of lactobacilli after treatment of the test strain by corynebacteria metabolites against S. aureus and E. coli manifested by reduction of the numbe of viable cells by 2-3 lg CFU. For L. acidophilus the bactericidal effect oflactobacilli metabolite in the same conditions reduced, and that led to the increase ofviability by 2-4 lg PFU. CONCLUSION: A conclusion on the possibility of regulation by associative bacteria the manifestations of antagonistic activity of H2O2 producing dominant microorganisms is made based on the data obtained. PMID- 22937707 TI - [Interaction of Bifidobacterium bifidum with members of normal microflora in human intestine microsymbiocenosis]. AB - AIM: Study the influence of exometabolites of B. bifidum on biological properties of bacteria that are the members of normoflora and their ability to interact with associative microsymbionts. MATERIALS AND METHODS: Bacterial strains that are members of the normal microflora of human intestine: B. bifidum, Lactobacillus acidophilus, Enterococcusfaecium and Escherichia coli lactose positive non hemolytic (lac "+"/hly "-") were used. As opportunistic microorganisms cultures of E. coli lactose negative hemolytic (lac "-"/hly "+"), Klebsiella pneumoniae and Staphylococcus aureus were used. Isolation and identification of microorganisms was performed by generally accepted methods according to guidances. In the first series of experiments influence of B. bifidum metabolites on biological properties of microorganisms that are members ofnormoflora was studied. In the second series--the influence of bifidobacteria supernatants on interrelations of B. bifidum, L. acidophilus and E. coli lac "+"/hly "-" with opportunistic associants. Growth properties (GP), biofilm formation (BFF) and anti-lysozyme activity (ALA) of microorganisms was studied photometrically. Optical density measurement were performed on ELx808 (BioTek, U.S.A.) photometer. The data obtained were treated by nonparametric method using Mann-Whitney criteria. RESULTS: B. bifidum supernatant was established to stimulate in 33.3 66.7% of cases or did not alter growth/reproduction, BFF and ALA of microorganisms that are characteristic for eubiosis of intestine including bacteria of the same species that could have implications for realization by bifidobacteria ofbiotope colonization resistance. Features of interaction ofexometabolites of bifidobacteria with microorganisms that are characteristic for eubiosis of human intestine consisting in enchantment or changes of effects of the influence of normoflora members on BFF of associants were revealed. The maximum enchantment of inhibitory effect of indigenous strains under the influence ofbifidobacteria was noted in associations E. coli lac "+"/hly "-" E. coli lac "-"/hly "+" as well as E. faecium--S. aureus. CONCLUSION: Thus, the data obtained may be used for detection of mechanisms of functioning of normal microsymbiocenosis in human associative symbiosis. PMID- 22937708 TI - [Renal calculus microflora in urolithiasis and search for agents of control of biofilms formed by uropathogenic bacteria]. AB - AIM: Study bacterial biofilms in native material (renal calculus) by electron microscopy method and developmeit of biofilm model by isolates in vitro on sterile calculi of various chemical composition. MATERIALS AND METHODS: Bacterial spectra of microflora of renal calculus lavages were studied, isolated pure cultures were identified up to species. Comparisons of urine microflora obtained before operation in patients with urolithiasis with microflora of removed renal calculi were carried out. RESULTS: Urease activity and genes coding pathogenicity factors were detected, and the ability to form biofilms by isolates was studied. Model of formation of biofilms in vitro on sterile renal calculi was developed and candidate agents reducing the biofilm forming ability were tested. CONCLUSION: Uropathogenic microorganisms infecting renal calculi and forming biofilms on them not only support chronic infection by increased resistance to therapy but also facilitate novel lithogenesis. PMID- 22937709 TI - [Persistent properties of microorganisms inhabiting highly mineralized water bodies]. AB - AIM: Study prevalence and intensity of persistent properties in bacteria inhabiting highly min eralized water bodies and determine their role in interaction with halophilous heterotrophic protozoa. MATERIALS AND METHODS: 300 bacteria strains and 3 cultures of heterotrophic protozo isolated from water bodies with mineralization of 2-350 g/l were studied. Antilysozyme (ALA) antihistone (AHA) activity of bacteria, protozoa lysozyme were evaluated by dish and photometric methods. Protozoa histones were evaluated cytochemically. Interaction of protozoa and Escherichia coli was evaluated by experimental co cultivation. RESULTS: Presence of lysozyme an histones was shown in halophilous heterotrophic protozoa. Prevalence of ALA and AHA in bacteria was shown to increase as water body mineralization decreases. Intensity of E. colielimination from brine was determined to depend on the bacteria ALA level and phagocytic activity of protozoa. Participation of halotolerant protozoa in formation of heterogeneity of bacterial population by ALA was shown. CONCLUSION: In biocenoses of highly mineralized water bodies functioning of lysozyme-antilysozyme, histone antihistone systems was shown. Bacteria with high persistent potential may impair sanitary parameters of highly mineralized water bodies, process of self purification of which depends directly on phagocytic activity of protozoa. PMID- 22937710 TI - [Influence of antimicrobial peptides of human thrombocytes on Staphylococcus aureus biofilm formation]. AB - AIM: Study the influence ofplatelet low molecular weight protein on S. aureus biofilm formation. MATERIALS AND METHODS: 20 clinical isolates of coagulase positive staphylococci (S. aureus) served as material. Preparation containing a mixture of antimicrobial peptides (fractions with molecular weight 60-70 kDa, 20 25 kDa and 5-10 kDa) obtained from human thrombocyte donors was used. Bio film formation (BFF) by staphylococci was studied photometrically, the degree of hydrophobicity was evaluated by separation of cell suspension in two-phase system liquid-liquid. The data obtained were treated by nonparametric method using Mann Whitney criteria. RESULTS: Platelet low molecular weight proteins (PLB) at concentration of 2 microg/ml reduced biofilm formation of S. aureus by 48.7 +/- 9.8% from initial values, increased hydrophobicity of plankton and biofilm cell fractions. Maximum inhibitory effect of the preparation containing platelet low molecular weight proteins was noted at concentration of 50 microg/ml. CONCLUSION: The data obtained on inhibition of staphylococci BFF by platelet low molecular weight protein open a perspective of further studies of PLB as a preparation suitable for control ofbiofilm of persistent microorganisms. PMID- 22937711 TI - [Significance of hydrobiont persistent properties for symbiotic interactions]. AB - Significance of symbiotic relations formed by associative symbiosis type for autochthonous and allochthonous microflora of natural water bodies is shown. Generality of symbiotic interaction mechanisms of symbionts in limnetic and halophilous communities provided by secreted factors of natural resistance from the side of the host, and by factors of persistence from the side of symbionts is proven based on a set of examples. Features of operation of lysozyme antilysozyme, histon-antihiston, hydrogen peroxide-catalase functional systems in symbiotic interactions of autotrophic and heterotrophic components of hydrobiocenosis with dominant and associative microflora are presented. Associative microflora of allochthonous origin was shown to actively use the ecologically formed system of interaction between hydrobionts that facilitates survival of these microorganisms and preservation of their persistent potential, and as a result leads to biocenosis disorders. The knowledge obtained open new possibilities and perspectives of research of sanitary and ecological aspects of vital activity of aquatic biocenoses. PMID- 22937712 TI - [Features of legionella biofilm formation in artificial and natural water systems]. AB - AIM: Study the ability to form monospecies and associative biofilms as a characteristic oflegionella strains and features of organization of natural legionella biofilms in potentially dangerous water systems. MATERIALS AND METHODS: Comparative evaluation ofthe ability of 28 strains of Legionella spp. to form biofilms was determined in water according to previously developed procedure. Samples from biofilm of industrial enterprise coolers and systems of hot water supply of public buildings (hotels, trade centers, hospitals) were studied. Biofilms were studied by scanning and transmission electron microscopy methods. RESULTS: Legionella strains are divided into 3 groups by the ability to form biofilms. L. pneumophila BLR-05 strain that has the most pronounced ability to form monospecies biofilm and persistence in association with Pseudomonas aeruginosa was detected. Formation of massive legionella biofilm in association with bacteria of other taxonomic groups was detected on protective antibacterial filters in the system of hot water supply of a department of a therapeutic prophylaxis institution in the course of 2-3 weeks. Legionella biofilms on the surface of coolers resemble an aggregate of fungi, bacteria and blue-green algae enclosed into matrix. CONCLUSION: The ability to form artificial monospecies and associative biofilm may be a useful characteristic of legionella strains for evaluation of their adhesion and be used to evaluate epidemiological significance of the isolated strains. Prevention of formation of natural legionella biofilms in potentially dangerous water systems is necessary as an essential component of modern strategy of legionellosis prophylaxis. PMID- 22937713 TI - [Persistence of biologically active components of gastrointestinal tract microflora]. AB - The article is dedicated to examination and analysis of materials on translocation of microflora and its products from intestine to the internal environment of the macroorganism and persistence of biologically active substances of microflora in the bloodstream. High frequency of translocation and persistence of intestine microflora and its components in system bloodstream is shown. Persistent biologically active substances of endogenous microorganisms take part in human physiology and pathology. PMID- 22937714 TI - [Toxoplasmosis in HIV infection: invasion reactivation criteria]. AB - Contemporary representation of toxoplasmosis reactivation criteria in HIV infection is generalized. Significance of the issue is justified: toxoplasmosis is a leading neurological pathology in AIDS with a high lethality percentage due to complexity of clinical confirmation and difficulties of laboratory confirmation of the start of reactivation. Clinical, instrumental, immunologic, molecular genetic invasion reactivation criteria are discussed in the article and analysis of their effectiveness is performed; their most feasible combinations are justified. Further system analysis of the cerebral toxoplasmosis reactivation criteria specified in the article in combination with search of new pathogen dissemination markers will allow to obtain important information that has both fundamental interest and important practical significance. PMID- 22937715 TI - [Burkholderia cepacia persistence in patients with mucoviscidosis]. AB - AIM: Study features of persistence of Burkholderia cepacia in mucoviscidosis patients. MATERIALS AND METHODS: In the period from 2008 to 2009, 56 B. cepacia strains isolated from children with mucoviscidosis were obtained. 114 medical histories of children with mucoviscidosis from various age groups were analyzed. The developed algorithm for identification and typing including phenotype and molecular biology methods was used to identify B. cepacia bacteria. Strain genotyping was carried out by RAPD-PCR with random oligonucleotide primer as well as pulse-electrophoresis. RESULTS: Persistence of associations ofmicroogranisms in 59.4% of cases was established to be the feature of persistent infection in mucoviscidosis. The feature of persistence of B. cepacia strains in patients with diagnosis ofmuco-viscidosis mixed form, severe course is persistence in association with Pseudomonas aeruginosa. B. cepacia bacteria that can persist in mucoviscidosis patients are characterized by resistance to many antibiotics. A prolonged (up to 1 year and 5 months) persistence of B. cepacia strains isolated from 1 patient was proven by using microflora monitoring of lower respiratory tract. CONCLUSION: B. cepacia bacteria may colonize lower respiratory tract of mucoviscidosis patients, persist for a long time and be transmitted between patients. PMID- 22937716 TI - [Persistence of Pseudomonas aeruginosa strains in patients of Federal Scientific Center of Transplantology and Artificial Organs]. AB - AIM: Study genetic diversity of P. aeruginosa strains persisting in patients of Federal Scientific Center of Transplantology and Artificial Organs, and main factors facilitating persistence of strains in the hospital. MATERIALS AND METHODS: 136 P. aeruginosa strains isolated from patients of the center for 3 years 6 months were genotyped by RAPD-PCR and MLST methods and studied for antibiotics resistance and presence of integrons. RESULTS: Genetic diversity of strains persisting in hospital was established. Strains of main genotypes ST235, ST446, ST598 were isolated from patients of various surgical departments. Patients were shown to be colonized by these strains during stay in reanimation and intensive therapy department (RITD) of the hospital. Strains of dominant genotype 235 were isolated from 47% of examined patients during more than 3 years. Only genotype 235 strains contained integron with cassettes of antibiotics resistance genes blaGES5 and aadA6 in the genome. CONCLUSION: The data obtained show that over the period of observation in the center 1 clone of P. aeruginosa that belonged to genotype 235 dominated. This clone was endemic for this hospital and in the process of prolonged persistence became more resistant to antibiotics. Colonization of patients with these strains occurs in RITD. This confirms the necessity of constant monitoring of hospital microflora for advance detection of potentially dangerous epidemic hospital strains able to cause hospital infections. PMID- 22937717 TI - [Unusual forms of persistence of Mycoplasma hominis in organism of infected humans]. AB - AIM: Study previously unknown forms of persistence of Mycoplasma hominis in host organism. MATERIALS AND METHODS: Culture method was used for detection of mycoplasmas. Identification was carried out by serological, electron microscopy methods, classic PCR and real time PCR; circulating immune complexes (CIC) were isolated by PEG precipitation. RESULTS: Classic micoplasma cultures could not be isolated from blood even once. At the same time "mini-colony" cultures composed of mini-cells that were hardly passaged but sometimes formed continuous layer of the same colonies were isolated from blood serum samples with high frequency. During reseeding for more than 1 year they never acquired classic form. Not only antigens of M. hominis but its DNA were shown to be present in CIC. Viable cells forming "mini-colonies" identical to those isolated from blood sera were isolated from circulating immune complexes. A system of evidence on identity of isolated M. hominis cultures is presented. Cultures had infectivity and an ability to persist in organs of experimentally infected mice. CONCLUSION: The isolated forms are apparently the result of adaptation of mycoplasmas to humoral immunity factors. PMID- 22937718 TI - [Destabilization of homeostasis of organism of burn patients as a marker of sepsis development, its complications and outcome]. AB - AIM: Detection in burn patients of markers of sepsis development, its complications and outcome. MATERIALS AND METHODS: Sera IL-6, TNF-alpha, IL-8, IL 1beta, IL-Ra, IL-18, INF-gamma, IL-10 and sTREM-1 cytokine levels of burn patients at days 3-6 and 10-17 after the burn were studied. RESULTS: Statistically significant cytokine parameters in blood sera that already at the early stages of the burn disease may be markers of the course severity and sepsis outcome were obtained. At day 3-6 after the injury high level of IL-10 in blood sera may act as a lethal outcome marker in burn patients, and by day 10-17 after the burn high level of IL-6 becomes determinative. Low level of IL-1beta may serve as a marker of complicated course of sepsis in patients with favorable outcome already at days 3-6 after the injury. CONCLUSION: Certain laboratory parameters of human organism homeostasis destabilization may be used as markers of sepsis development, its complications and outcome already in the initial period of burn disease in severe thermal injuries. PMID- 22937719 TI - [Production of cytokines by vaginal epitheliocytes in the process of interaction with dominant and associative microsymbionts]. AB - AIM: Study the expression of cytokines by vaginal epitheliocytes in the process of interaction with dominant and associative microsymbionts. MATERIALS AND METHODS: IL-8, IL-6, IL-1beta and TNFalpha expression in response to interaction with heat inactivated Lactobacillus spp., Staphylococcus aureus, Escherichia coli, Corynebacterium spp. or their secretory products in comparison with basal expression of cytokines by vaginal epitheliocytes was studied. Results. Lactobacilli secretory products were shown not to influence the expression of IL 8 and IL-1beta and moderately stimulated IL-6 and TNFalpha expression. Contact of epitheliocytes with heat inactivated lactobacilli increased secretion of IL-8, IL 6 and IL-1beta and reduced TNFalpha production. Secretory products of S. aureus and E. coli caused stimulation of IL-6, IL-1beta production and practically did not change the expression of IL-8 and TNFalpha. Contact of epitheliocytes with heat inactivated S. aureus sup pressed TNFalpha production and had no influence on IL-8, IL-6 and IL-1beta expression, contact with E. colistimulated TNFalpha and IL-1beta expression and suppressed IL-6 expression. Changes in cytokine expression during interaction of epitheliocytes with corynebacteria were largely similar to the results of interaction with lactobacilli except IL-6 production that was markedly stimulated by corynebacteria secretory products. Conclusion. In epithelial-bacterial interactions dominant and associative microorganisms have a differential effect on functional status of mucosal epitheliocytes manifesting in production of cytokines that could be the basis of mucosal immunity regulation. PMID- 22937720 TI - [Cytokine status of cervical mucus in women with transitory and persistent course of papillomavirus infection]. AB - AIM: Study the levels of cytokines in cervical mucus of women with transitory and persistent course of papillomavirus infection (PVI). MATERIALS AND METHODS: Material from 122 women was studied: 32 patients in control group, 68 patients with transitory course of PVI and 52 women with persistent course of PVI. The presence or absence of high risk HPV DNA was confirmed by real time PCR. High risk HPV DNA was determined in scrapes of epithelial cells of cervical canal. Quantitative determination of cytokines (IFN-alpha, IFN-gamma, IL-1beta, receptor antagonist IL-1, IL-2, IL-4, IL-8 and IL-10, TNFalpha in cervical mucus was performed by enzyme immunoassay. RESULTS: Transitory course of PVI was characterized by an increase of IFN-alpha and IFN-gamma, persistent course of PIV -by a decrease of IFN-alpha, IL-2 level was increased in both groups of patients with PVI. CONCLUSION: The outcome of PVI is controlled by interferon component of the immunity. Because of this during observation of patients with PVI the determination of IFN-alpha, IFN-gamma content in cervical mucus is an appropriate diagnostic procedure in clinical practice for the prognosis of risk of development of high risk PIV persistency. PMID- 22937721 TI - [Role of opportunistic infection causative agent in etiology of obstructive bronchitis and prolonged subfebrility in children]. AB - AIM: Determine the role of opportunistic infections causative agents in ethology of obstructive bronchitises and prolonged subfebrilities in children. MATERIALS AND METHODS: 56 children with the diagnosis of obstructive bronchitis and 46 children with the diagnosis of prolonged subfebrility were examined for the presence of herpes, mycoplasma and pneumocystic infections. EIA, IIF, rapid culture method, PCR were used. RESULTS: The highest number of cases of mixed infection was detected in children with HHV-6 infection. Mixed infection was diagnosed 6 times more frequently in children with obstructive bronchitis and 9 times in children with prolonged subfebrility. The number of children with pneumocystosis in combination with other infections was 2.4 and 2 times higher than with monoinfection; with CMV infection--4 and 2 times; with HSV infection--5 and 4 times; EBV infection--6 and 3.7 times. The only exception was mycoplasmosis detected in children with obstructive bronchitis where the difference between the number of mono and mixed infection cases was insignificant. CONCLUSION: The data obtained give evidence of wide spread of opportunistic infections. PMID- 22937722 TI - Remission of refractory Crohn's disease by high-dose cyclophosphamide and autologous peripheral blood stem cell transplantation. AB - BACKGROUND: Despite advances in immunosuppressive therapy, up to 10% of patients with severe Crohn's disease (CD) remain refractory to conventional treatment. Limited evidence from pilot trials suggests that high-dose immunosuppression and autologous peripheral blood stem cell transplantation (autoPBSCT) may induce remission in these patients, but there is substantial controversy regarding the safety and efficacy of this approach. AIM: To address this issue, a monocentre phase I/II trial of autoPBSCT was performed in patients with refractory CD in our hospital. METHODS: Here, we report on the outcome of 12 patients with refractory CD treated with autoPBSCT. Briefly, CD34(+) -selected PBSCs were harvested after mobilisation therapy with cyclophosphamide and granulocyte-colony stimulating factor. Later, immunoablative conditioning therapy with high-dose cyclophosphamide followed by autoPBSCT was applied and clinical and endoscopic responses were analysed after a mean follow-up of 3.1 years (range 0.5-10.3 years). RESULTS: PBSC harvest following mobilisation chemotherapy was successful in 11/12 patients and resulted in a clinical and endoscopic improvement in 7/12 patients. Subsequent conditioning and autoPBSCT were performed in nine patients and were relatively well tolerated. Among those, five patients achieved a clinical and endoscopic remission within 6 months after autoPBSCT. However, relapses occurred in 7/9 patients during follow-up, but disease activity could be controlled by low-dose corticosteroids and conventional immunosuppressive therapy. CONCLUSION: Immunoablation by cyclophosphamide and autologous peripheral blood stem cell transplantation is safe and effective to induce remission of refractory Crohn's disease, and should be further evaluated in randomised controlled trials. PMID- 22937723 TI - Continuing evolution of opioid use in primary care practice: implications of emerging technologies. AB - BACKGROUND: Primary care physicians, nurse practitioners, and nurses are often the first to evaluate patients with pain and many patients depend on these clinicians for pain relief. The growing evidence supporting use of opioids for appropriately selected patients means that primary care practitioners must be knowledgeable regarding ever-evolving pain-management strategies. SCOPE: This review summarizes core considerations in opioid prescribing in the primary care setting, the risks of undertreatment of pain, the challenges and barriers associated with prescribing opioids, identifying risk factors that may predict problematic use, and emerging formulation technologies expected to assist clinicians in better achieving effective pain control while minimizing risks for misuse or diversion. RESULTS: Primary care physicians face considerable challenges in optimizing pain management while minimizing potential for misuse, abuse and diversion. Opioid treatment decisions are based not only on the type of pain but also the patient's psychosocial history, including a screening for predicting aberrant behaviors and, in some patients, substance abuse. New opioid formulations are available to assist clinicians in achieving adequate patient relief while reducing risk of tampering and abuse. Primary care practitioners need to be aware of these new options and integrate them into clinical treatment decisions. CONCLUSIONS: The strategic use of new opioid formulations and better patient assessment may lead to more successful use of opioids in the management of pain, while limiting or lowering the risk of the development of an addiction problem, abuse or diversion. PMID- 22937724 TI - Assessing achievement and maintenance of glycemic control by patients initiating basal insulin. AB - OBJECTIVE: Describe characteristics of diabetic patients who initiated basal insulin and assess their glycemic control. RESEARCH DESIGN AND METHODS: Physician encounters in the General Electric EMR Database (2005-2010) were assessed for patients with type II diabetes (T2DM) who initiated basal insulin between February 2006 and August 2009, with initiation defined as no prescription record of insulin in prior 15 months. Patients were followed for an average 2.5 years after insulin initiation. The proportion and time to achieving HbA1c <= 7% ('goal') were assessed. Among patients who reached goal, the proportion and time to HbA1c increasing above 7% were analyzed. Cox proportional hazard models were estimated to identify predictors of HbA1c goal achievement and goal sustainability. RESULTS: Basal insulin initiators with T2DM (n = 13,373) were on average 60 years old, 50.5% were females, and 59.5% had HbA1c > 8%; 5840 (44%) patients reached goal within one year and 7699 (58%) reached goal during the ~2.5 year follow-up. Being older, white or male, lower baseline HbA1c values, and no OAD use before insulin initiation were associated with significantly higher rates of reaching goal. Among patients who reached goal, 57.6% could not sustain the goal. Being Hispanic, higher baseline HbA1c values, and baseline OAD use were associated with significantly lower rates of goal sustainment. CONCLUSION: A high proportion of T2DM patients did not have adequate glycemic control after initiating basal insulin. Various factors existing prior to insulin initiation were related to successful treatment of T2DM. Further research on how to improve glycemic control is encouraged. PMID- 22937725 TI - Postoperative analgesic requirements after subarachnoid or epidural anesthesia with ropivacaine 0.75% in cesarean section. A double-blind randomized trial. AB - OBJECTIVE: Postoperative analgesic requirements and pain scores were compared after subarachnoid versus epidural anesthesia with plain ropivacaine 0.75% for elective cesarean section. STUDY DESIGN: Ropivacaine 0.75% was randomly administered for subarachnoid or epidural anesthesia in 108 parturients, scheduled for cesarean section. Times for the sensory block to reach T4 level and to regress to T6 level were recorded. At 2, 4, 8 and 24 h postoperatively, pain scores at rest and cough, morphine consumption as well as patient satisfaction, incidence of headache, nausea and/or vomiting were measured. RESULTS: Median (min max) time for the sensory block to reach T4 was 7 (3-0) min versus 24 (16-73) min and to regress to T6 was 126 (70-332) min versus 200 (98-439) min in the subarachnoid and epidural groups, respectively (p=0.001). Although the subarachnoid had more analgesic consumption than the epidural group at 2 and 4 h postoperatively (7.3+/-4.7 vs. 1.8+/-2.4 mg, p=0.001 and 9+/-5.7 vs. 3.3+/-3.8 mg, p=0.001, respectively) no difference was observed at 8 or 24 h postoperatively (p=0.14 and p=0.38, respectively). VAS scores at rest and after cough (p=0.56, p=0.35, respectively), patient satisfaction (p=0.61), incidence of headache (p=1.0), nausea and/or vomiting (p=0.78) did not differ between the two groups. CONCLUSIONS: Postoperative pain, analgesic requirements, patient satisfaction and adverse effects did not differ when subarachnoid or epidural anesthesia with ropivacaine 0.75% was used for elective cesarean section. Nevertheless, subarachnoid provides faster onset and offset of the block, compared to epidural anesthesia. The key limitation of this study is the lack of postoperative serum ropivacaine measurements taken with concurrent pain score measurements. PMID- 22937726 TI - REACH coarse-grained simulation of a cellulose fiber. AB - A molecular level understanding of the structure, dynamics and mechanics of cellulose fibers can aid in understanding the recalcitrance of biomass to hydrolysis in cellulosic biofuel production. Here, a residue-scale REACH (Realistic Extension Algorithm via Covariance Hessian) coarse-grained force field was derived from all-atom molecular dynamics (MD) simulations of the crystalline Ibeta cellulose fibril. REACH maps the atomistic covariance matrix onto coarse grained elastic force constants. The REACH force field was found to reproduce the positional fluctuations and low-frequency vibrational spectra from the all-atom model, allowing elastic properties of the cellulose fibril to be characterized using the coarse-grained force field with a speedup of >20 relative to atomistic MD on systems of the same size. The calculated longitudinal/transversal Young's modulus and the velocity of sound are in agreement with experiment. The persistence length of a 36-chain cellulose microcrystal was estimated to be ~380 MUm. Finally, the normal-mode analysis with the REACH force field suggests that intrinsic dynamics might facilitate the deconstruction of the cellulose fibril from the hydrophobic surface. PMID- 22937727 TI - Cationic poly(N-isopropylacrylamide) block copolymer adsorption investigated by dual polarization interferometry and lattice mean-field theory. AB - A series of cationic diblock copolymers, poly(N-isopropylacrylamide)(48)-block poly((3-acrylamidopropyl)trimethylammonium chloride)(X), abbreviated as PNIPAAM(48)-b-PAMPTMA(+)(X) (X = 0, 6, 10, 14, and 20), has been synthesized, and their adsorption onto silicon oxynitride from aqueous solution has been investigated using dual polarization interferometry. The polymer adsorption was modeled by using a lattice mean-field theory, and a satisfactory consistency between theory and experiments was found in terms of surface excess and layer thickness. Both theory and experiments show that the adsorption is limited by steric repulsion for X < X(max) and by electrostatic interactions for X > X(max). Modeling demonstrates that significant surface charge regulation occurs due to adsorption. Both the nonionic and cationic block exhibit nonelectrostatic affinity to silicon oxynitride and thus contribute to the driving force for adsorption, and modeling is used for clarifying how changes in the nonelectrostatic affinity affects the surface excess. The segments of the nonionic and cationic blocks seem less segregated when both have a nonelectrostatic affinity for the surface compared to the case where the segments had no surface affinity. Adsorption kinetics was investigated experimentally. Two kinetic regimes were observed: the adsorption rate is initially controlled by the mass transfer rate to the surface and at higher coverage is limited by the attachment rate. PMID- 22937728 TI - Building-up remarkably stable magnesium porphyrin polymers self-assembled via bidentate axial ligands: synthesis, structure, surface morphology, and effect of bridging ligands. AB - A series of supramolecular architectures of magnesium tetranitrooctaethylporphyrins mediated by several bidentate axial ligands have been synthesized in excellent yields and structurally characterized. Six conjugated axial ligand with increasing chain lengths have been utilized in the present investigations in which the Mg...Mg nonbonding distance between successive ions also increases from 0.73 to 2.70 nm in the series. To the best of our knowledge, this is the first report where stable metallo-porphyrin polymers with such long spacers have been synthesized in one pot so easily. Linear one dimensional (1D) polymeric chains were observed in the X-ray structure of the six coordinated complexes in which porphyrin units are aligned parallel to each other to have so-called "shish kebab" like architectures to maintain offset-stacked overlap. However, after an optimum Mg...Mg nonbonding distance, these 1D chain do not continue, rather they form five-coordinated porphyrin dimers with "wheel-and axle" like architectures which are then self-aggregated by pi-pi interactions in a perpendicular manner to fill space created by large bridging ligands more effectively which consequently results in spherical structures. The structures of the molecules in solution and their surface patterns on highly ordered pyrolytic graphite (HOPG) have also been investigated. PMID- 22937729 TI - Parents' constructions of the sexual self-presentation and sexual conduct of adolescents: discourses of gendering and protecting. AB - In this paper, we explore the discourses on sexuality that a sample of parents drew upon when they talked about teenage sexual self-presentation and conduct. The sample consisted of 43 parents (32 mothers and 11 fathers) of young people aged 10-19 years. Data were gathered using in-depth interviews and were analysed using a strategy known as modified analytical induction. Findings indicated that while an acceptance the traditional heterosexual script permeated participants' accounts, and protective discourses in relation to young women were brought to bear, so, too, were protective discourses invoked in relation to young men. On the whole, young women tended to be cast as sexual subjects who chose to self sexualise and this was sometimes seen by participants as a threat to young men. We argue that the discourses that parents connoted were multiple and sometimes contradictory, and our analysis problematises the notion that conventional discourses singularly cast women as objects of male sexuality. However, the overall picture indicated that in parents' narratives, young women tended to be more heavily regulated and either viewed as needing protection from male sexual advances or castigated for encouraging them. PMID- 22937730 TI - Prostate cancer treatment: the times they are a' changin'. PMID- 22937731 TI - Species diversity, seasonal dynamics, and vertical distribution of litter dwelling thrips in an urban forest remnant of South China. AB - Litter-dwelling thrips are an important component of soil macroinvertebrates in tropical and subtropical regions. However, little is known about assemblage composition, seasonal abundance and vertical distribution of litter-dwelling thrips. A survey of forest litter-dwelling thrips and other soil macroinvertebrates was conducted in an urban forest remnant at Guangzhou, China during 2004-2005 and 2008-2009. A total of 835 Tullgren samples were collected during the study. Thysanoptera constituted 6.5% of total litter-dwelling macroinvertebrate individuals extracted, representing three families, 19 genera, and 25 species. Psalidothrips ascitus Ananthakrishnan (Thysanoptera: Phlaeothripidae) and Hyidiothrips guangdongensis Wang, Tong and Zhang represented 78.5% of all individuals of litter-dwelling thrips during the survey. Numbers of species and density of leaf-litter thrips fluctuated between different months. Density of litter thrips increased from March until October, reaching a maximum of 41.1 individuals/m2 followed by a decrease. In January and February only a few larval thrips were present. Species diversity gradually increased from July (four species) to December (10 species), and then declined rapidly. The vertical distribution showed that the leaf-litter thrips species richness and abundance decreased significantly with soil depth; they were found only in the litter layer and upper soil layer (0-5 cm in depth) and were entirely absent in deeper soil layers. The results suggest that litter-dwelling thrips are a common group of litter invertebrates with high species diversity in subtropical regions. These urban forest remnants should be given special consideration in forest conservation planning, because of their significance as refugia for the litter invertebrate assemblages, especially for leaf-litter thrips. PMID- 22937732 TI - Development of an early induction model of medulloblastoma in Ptch1 heterozygous mice initiated with N-ethyl-N-nitrosourea. AB - Mice heterozygous for the ptch1 gene (ptch1 mice) are known as a valuable model of medulloblastoma, a common brain tumor in children. To increase the incidence and reduce the time required for tumor development, allowing for evaluation of modifier effects on medulloblastoma in a short time, we attempted to develop an early induction model of medulloblastoma in ptch1 mice initiated with N-ethyl-N nitrosourea (ENU). Ptch1 mice and their wild-type littermates received a single intraperitoneal injection of ENU (10, 50 or 100 mg/kg) on postnatal day 1 (d1) or 4 (d4), and histopathological assessment of brains was conducted at 12 weeks of age. The width of the external granular layer (EGL), a possible origin of medulloblastoma, after injection of 100 mg ENU on d1 or d4 was measured in up to 21-day-old mice. Cerebellar size was apparently reduced at the 50 mg dose and higher regardless of genotype. Microscopically, early lesions of medulloblastomas occurred with a high incidence only in ptch1 mice receiving 10 mg on d1 or d4, but a significant increase was not observed in other groups. Persistent EGL cells and misalignment of Purkinje cells were increased dose-dependently. Although EGL was strikingly decreased after ENU injection, strong recovery was observed in mice of the d1-treated group. In summary, neonatal treatment with ENU is available for the induction of medulloblastoma in ptch1 mice, and 10 mg of ENU administered on d1 appeared to be an appropriate dose to induce medulloblastoma. PMID- 22937733 TI - The contribution of the ABCG2 C421A polymorphism to cancer susceptibility: a meta analysis of the current literature. AB - BACKGROUND: ABCG2, also known as BCRP, is a half ATP-binding cassette (ABC) transporter that localizes to plasma membranes. Recently, a number of studies have investigated the relationship between the C421A polymorphism in ABCG2 and cancer risk in multiple populations and various types of cancers; however, this relationship remains unclear. Therefore, we performed a meta-analysis to further explore this association. METHODS: The meta-analysis incorporated 10 studies involving a total of 3593 cases and 5875 controls. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated based on the date extracted from the studies to evaluate the strength of association. We also analyzed the heterogeneity and sensitivity of each report and the publication bias of the studies. RESULTS: Overall, our results showed that there appeared to be a significant association between the ABCG2 C421A polymorphism and decreased cancer susceptibility (heterozygote-AC versus CC: OR = 0.759, 95%CI = 0.620-0.930; dominant effects model-AA/AC versus CC: OR = 0.771, 95%CI = 0.634-0.938; additive effects model-A allele versus C allele: OR = 0.809, 95%CI = 0.687-0.952). Similarly, decreased cancer risk was also found after stratification of the SNP data by cancer type, ethnicity and source of controls in heterozygote model, dominant effects model and additive effects model. CONCLUSIONS: We found that the ABCG2 C421A polymorphism is a protective factor for developing cancer. The same relationship was found when the studies were stratified by cancer type, ethnicity and source of controls. PMID- 22937734 TI - Development of a food frequency questionnaire for Sri Lankan adults. AB - BACKGROUND: Food Frequency Questionnaires (FFQs) are commonly used in epidemiologic studies to assess long-term nutritional exposure. Because of wide variations in dietary habits in different countries, a FFQ must be developed to suit the specific population. Sri Lanka is undergoing nutritional transition and diet-related chronic diseases are emerging as an important health problem. Currently, no FFQ has been developed for Sri Lankan adults. In this study, we developed a FFQ to assess the regular dietary intake of Sri Lankan adults. METHODS: A nationally representative sample of 600 adults was selected by a multi stage random cluster sampling technique and dietary intake was assessed by random 24-h dietary recall. Nutrient analysis of the FFQ required the selection of foods, development of recipes and application of these to cooked foods to develop a nutrient database. We constructed a comprehensive food list with the units of measurement. A stepwise regression method was used to identify foods contributing to a cumulative 90% of variance to total energy and macronutrients. In addition, a series of photographs were included. RESULTS: We obtained dietary data from 482 participants and 312 different food items were recorded. Nutritionists grouped similar food items which resulted in a total of 178 items. After performing step wise multiple regression, 93 foods explained 90% of the variance for total energy intake, carbohydrates, protein, total fat and dietary fibre. Finally, 90 food items and 12 photographs were selected. CONCLUSION: We developed a FFQ and the related nutrient composition database for Sri Lankan adults. Culturally specific dietary tools are central to capturing the role of diet in risk for chronic disease in Sri Lanka. The next step will involve the verification of FFQ reproducibility and validity. PMID- 22937735 TI - Plasminogen activator inhibitor-1 promotes synaptogenesis and protects against abeta(1-42)-induced neurotoxicity in primary cultured hippocampal neurons. AB - Plasminogen activator inhibitor-1 (PAI-1) is a soluble factor that is released from astrocytes, the most abundant type of glial cell in the brain. PAI-1 was initially identified as inhibiting two types of plasminogen activators, that is, tissue-type plasminogen and urokinase activators that are known to lead to the proteolytic degradation of the extracellular matrix. Recently, PAI-1 was reported to mediate the neuroprotective activity of transforming growth factor-beta1 against N-methyl-D-aspartate receptor-mediated excitotoxicity and to be involved in angiogenesis following ischemic stroke, independently of the effects via the inhibition of tissue-type plasminogen and urokinase-type plasminogen activators. In this study, we examined whether PAI-1 influences synaptogenesis and neurotoxicity induced by amyloid beta peptide(1-42) (Abeta(1-42)) in rat primary hippocampal neurons. Using immunostaining, treatment with PAI-1 for 24 h was found to significantly upregulate synaptophysin, postsynaptic density-95, and the polysialylated form of neural cell adhesion molecule, compared to treatment with vehicle alone. In addition, PAI-1 has neuroprotective effects against Abeta(1-42) induced cytotoxicity in rat primary cultured hippocampal neurons. Taken together, our results suggest that PAI-1 has therapeutic potential in Alzheimer's disease by promoting synaptogenesis and by demonstrating neuroprotective effects against Abeta(1-42)-oligomer-induced neurotoxicity in rat primary cultured hippocampal neurons. PMID- 22937737 TI - Comparison of five equations for estimating resting energy expenditure in Chinese young, normal weight healthy adults. AB - BACKGROUND: Most resting energy expenditure (REE) predictive equations for adults were derived from research conducted in western populations; whether they can also be used in Chinese young people is still unclear. Therefore, we conducted this study to determine the best REE predictive equation in Chinese normal weight young adults. METHODS: Forty-three (21 male, 22 female) healthy college students between the age of 18 and 25 years were recruited. REE was measured by the indirect calorimetry (IC) method. Harris-Benedict, World Health Organization (WHO), Owen, Mifflin and Liu's equations were used to predictREE (REEe). REEe that was within 10% of measured REE (REEm) was defined as accurate. Student's t test, Wilcoxon Signed Ranks Test, McNemar Test and the Bland-Altman method were used for data analysis. RESULTS: REEm was significantly lower (P < 0.05 or P < 0.01) than REEe from equations, except for Liu's, Liu's-s, Owen, Owen-s and Mifflin in men and Liu's and Owen in women. REEe calculated by ideal body weight was significantly higher than REEe calculated by current body weight ( P < 0.01), the only exception being Harris-Benedict equation in men. Bland-Altman analysis showed that the Owen equation with current body weight generated the least bias. The biases of REEe from Owen with ideal body weight and Mifflin with both current and ideal weights were also lower. CONCLUSIONS: Liu's, Owen, and Mifflin equations are appropriate for the prediction of REE in young Chinese adults. However, the use of ideal body weight did not increase the accuracy of REEe. PMID- 22937738 TI - Perforating pilomatricoma with anetodermic epidermis in an adolescent with lymphoma. AB - Pilomatricoma is a benign neoplasm originating from primitive cells of the hair matrix. Occasionally the skin overlying pilomatricomas assumes peculiar clinical features, and anetodermic change of the skin overlying pilomatricomas is sometimes seen, but perforation in pilomatricoma is a rare event. We report a case of perforating pilomatricoma with anetoderma in an adolescent with lymphoma. PMID- 22937739 TI - A novel HLA-B*35 allele, B*35:189 with a new motif GGG at codon 35, identified by sequence-based typing in a Chinese potential donor. AB - B*35:189: one nucleotide change resulting in a new motif GGG at codon 35 in HLA B. PMID- 22937736 TI - Antibiotics for bronchiectasis exacerbations in children: rationale and study protocol for a randomised placebo-controlled trial. AB - BACKGROUND: Despite bronchiectasis being increasingly recognised as an important cause of chronic respiratory morbidity in both indigenous and non-indigenous settings globally, high quality evidence to inform management is scarce. It is assumed that antibiotics are efficacious for all bronchiectasis exacerbations, but not all practitioners agree. Inadequately treated exacerbations may risk lung function deterioration. Our study tests the hypothesis that both oral azithromycin and amoxicillin-clavulanic acid are superior to placebo at improving resolution rates of respiratory exacerbations by day 14 in children with bronchiectasis unrelated to cystic fibrosis. METHODS: We are conducting a bronchiectasis exacerbation study (BEST), which is a multicentre, randomised, double-blind, double-dummy, placebo-controlled, parallel group trial, in five centres (Brisbane, Perth, Darwin, Melbourne, Auckland). In the component of BEST presented here, 189 children fulfilling inclusion criteria are randomised (allocation-concealed) to receive amoxicillin-clavulanic acid (22.5 mg/kg twice daily) with placebo-azithromycin; azithromycin (5 mg/kg daily) with placebo amoxicillin-clavulanic acid; or placebo-azithromycin with placebo-amoxicillin clavulanic acid for 14 days. Clinical data and a paediatric cough-specific quality of life score are obtained at baseline, at the start and resolution of exacerbations, and at day 14. In most children, blood and deep nasal swabs are also collected at the same time points. The primary outcome is the proportion of children whose exacerbations have resolved at day 14. The main secondary outcome is the paediatric cough-specific quality of life score. Other outcomes are time to next exacerbation; requirement for hospitalisation; duration of exacerbation; and spirometry data. Descriptive viral and bacteriological data from nasal samples and blood markers will also be reported. DISCUSSION: Effective, evidence based management of exacerbations in people with bronchiectasis is clinically important. Yet, there are few randomised controlled trials (RCTs) in the neglected area of non-cystic fibrosis bronchiectasis. Indeed, no published RCTs addressing the treatment of bronchiectasis exacerbations in children exist. Our multicentre, double-blind RCT is designed to determine if azithromycin and amoxicillin-clavulanic acid, compared with placebo, improve symptom resolution on day 14 in children with acute respiratory exacerbations. Our planned assessment of the predictors of antibiotic response, the role of antibiotic-resistant respiratory pathogens, and whether early treatment with antibiotics affects duration and time to the next exacerbation, are also all novel. TRIAL REGISTRATION: Australia and New Zealand Clinical Trials Register (ANZCTR) number ACTRN12612000011886. PMID- 22937740 TI - Multiple biomarker tissue arrays: A computational approach to identifying protein protein interactions in the EGFR/ERK signalling pathway. AB - BACKGROUND: Many studies have demonstrated genetic and environmental factors that lead to renal cell carcinoma (RCC) and that occur during a protracted period of tumourigenesis. It appears suitable to identify and characterise potential molecular markers that appear during tumourigenesis and that might provide rapid and effective possibilities for the early detection of RCC. EGFR activation induces cell cycle progression, inhibition of apoptosis and angiogenesis, promotion of invasion/metastasis, and other tumour promoting activities. Over expression of EGFR is thought to play an important role in tumour initiation and progression of RCC because up-regulation of EGFR has been associated with high grade cancers and a worse prognosis. METHODS: Characterisation of the protein profile interacting with EGFR was performed using the following: an immunohistochemical (IHC) study of EGFR, a comprehensive computational study of EGFR protein-protein interactions, an analysis correlating the expression levels of EGFR with other significant markers in the tumourigenicity of RCC, and finally, an analysis of the utility of EGFR for prognosis in a cohort of patients with renal cell carcinoma. RESULTS: The cases that showed a higher level of this protein fell within the clear cell histological subtype (p = 0.001). The EGFR significance statistic was found with respect to a worse prognosis. In vivo significant correlations were found with PDGFR-beta, Flk-1, Hif1-alpha, proteins related to differentiation (such as DLL3 and DLL4 ligands), and certain metabolic proteins such as Glut5. In silico significant associations gave us a panel of 32 EGFR-interacting proteins (EIP) using the APID and STRING databases. CONCLUSIONS: This work summarises the multifaceted role of EGFR in the pathology of RCC, and it identifies EIPs that could help to provide mechanistic explanations for the different behaviours observed in tumours. PMID- 22937741 TI - Selective esterifications of primary alcohols in a water-containing solvent. AB - Oxyma and an oxyma derivative, (2,2-dimethyl-1,3-dioxolan-4-yl)methyl 2-cyano-2 (hydroxyimino)acetate (5b), displayed a remarkable effect on selective esterifications of primary alcohols. A wide range of carboxylic acids could be esterified with primary alcohols by using EDCI, NaHCO(3), and Oxyma or Oxyma derivative 5b in 5% H(2)O-CH(3)CN. Oxyma derivative 5b is particularly useful, since it could be removed after the reaction via a simple basic or an acidic aqueous workup procedure. PMID- 22937742 TI - Development of antioxidant packaging material by applying corn-zein to LLDPE film in combination with phenolic compounds. AB - Functional active packaging materials were successfully developed by incorporating antioxidant agents into corn-zein-laminated linear low-density polyethylene (LLDPE) film. The minimum effective concentrations of the active compounds (for example, thymol, carvacrol, eugenol) were determined and these compounds were then laminated into LLDPE films to develop corn-zein-laminated films with antioxidant agents. The release rate of antioxidant agents in gas and liquid media were determined along with the mechanical and water barrier properties of the films containing these compounds. Tensile strength and percentage elongation at break were reduced in the corn-zein-laminated LLDPE films when compared to typical LLDPE film. Furthermore, the ability of the corn zein-laminated films to repel moisture decreased by approximately 12.2%, but was improved by incorporating hydrophobic antioxidant compounds in the corn-zein layer. Examination of release kinetics in the gas and liquid phases verified that antioxidants were effectively released from the films and inhibited oxidation during testing. Finally, the films were used for fresh ground beef packaging, and effectively inhibited lipid oxidation and had a positive effect on the color stability of beef patties during storage. These results indicate that the developed antioxidant films are a novel active packaging material that can be effectively implemented by the food industry to improve the quality and safety of foods. PRACTICAL APPLICATION: Zein protein, a by-product of corn processing industry, was laminated into plastic films in combination with natural phenolic compounds to develop antioxidant packaging films. The films demonstrated their efficient release patterns of antioxidant compounds, which are suitable for packaging applications and food protection. PMID- 22937743 TI - Positive selection on NIN, a gene involved in neurogenesis, and primate brain evolution. AB - A long-held dogma in comparative neurobiology has been that the number of neurons under a given area of cortical surface is constant. As such, the attention of those seeking to understand the genetic basis of brain evolution has focused on genes with functions in the lateral expansion of the developing cerebral cortex. However, new data suggest that cortical cytoarchitecture is not constant across primates, raising the possibility that changes in radial cortical development played a role in primate brain evolution. We present the first analysis of a gene with functions relevant to this dimension of brain evolution. We show that NIN, a gene necessary for maintaining asymmetric, neurogenic divisions of radial glial cells (RGCs), evolved adaptively during anthropoid evolution. We explored how this selection relates to neural phenotypes and find a significant association between selection on NIN and neonatal brain size in catarrhines. Our analyses suggest a relationship with prenatal neurogenesis and identify the human data point as an outlier, possibly explained by postnatal changes in development on the human lineage. A similar pattern is found in platyrrhines, but the highly encephalized genus Cebus departs from the general trend. We further show that the evolution of NIN may be associated with variation in neuron number not explained by increases in surface area, a result consistent with NIN's role in neurogenic divisions of RGCs. Our combined results suggest a role for NIN in the evolution of cortical development. PMID- 22937745 TI - Anterior chamber parameters measured using the Pentacam Scheimpflug imaging device before and after cataract surgery in eyes with primary angle closure. PMID- 22937744 TI - The lavender plumage colour in Japanese quail is associated with a complex mutation in the region of MLPH that is related to differences in growth, feed consumption and body temperature. AB - BACKGROUND: The lavender phenotype in quail is a dilution of both eumelanin and phaeomelanin in feathers that produces a blue-grey colour on a wild-type feather pattern background. It has been previously demonstrated by intergeneric hybridization that the lavender mutation in quail is homologous to the same phenotype in chicken, which is caused by a single base-pair change in exon 1 of MLPH. RESULTS: In this study, we have shown that a mutation of MLPH is also associated with feather colour dilution in quail, but that the mutational event is extremely different. In this species, the lavender phenotype is associated with a non-lethal complex mutation involving three consecutive overlapping chromosomal changes (two inversions and one deletion) that have consequences on the genomic organization of four genes (MLPH and the neighbouring PRLH, RAB17 and LRRFIP1). The deletion of PRLH has no effect on the level of circulating prolactin. Lavender birds have lighter body weight, lower body temperature and increased feed consumption and residual feed intake than wild-type plumage quail, indicating that this complex mutation is affecting the metabolism and the regulation of homeothermy. CONCLUSIONS: An extensive overlapping chromosome rearrangement was associated with a non-pathological Mendelian trait and minor, non deleterious effects in the lavender Japanese quail which is a natural knockout for PRLH. PMID- 22937746 TI - Hypertriglyceridemic waist may explain ethnic differences in hypertension among patients with type 2 diabetes in Sweden. AB - BACKGROUND: Hypertension is common among persons with type 2 diabetes. The aim of this study was to analyze the association between ethnicity and hypertension prevalence after adjusting for age, sex, Hba1c, total cholesterol, elevated triglycerides and hypertriglyceridemic waist. The study population consisted of 354 primary health care patients diagnosed with type 2 diabetes (173 Assyrians/Syrians and 181 Swedes) residing in Sodertalje, Sweden. Unconditional logistic regression was used to analyze the data. RESULTS: Hypertension prevalence was higher among Swedes than Assyrians/Syrians, (77% versus 58%; p = 0.001). In the unadjusted logistic regression model, the odds ratio for hypertension in Swedes was twice as high than that in Assyrians/Syrians (OR = 2.44; 95% CI =1.54-3.86). In the age- and sex-adjusted model, odds ratio of hypertension was 2.25 (95% CI 1.41-3.60). After adjustments for total cholesterol was made, the odds ratio of hypertension decreased slightly to 1.73. When elevated triglycerides and hypertriglyceridemic waist were separately introduced, the odds ratio of hypertension was no longer significant between the ethnic groups (1.60 and 1.43 for triglycerides and hypertriglyceridemic waist respectively). In addition, advanced age - 60-69 years old (OR = 1.80, CI 95% 1.00-3.20) and >= 70 years old (OR = 2.88, CI 95% 1.40-5.93), elevated total cholesterol (OR = 1.48, CI 95% 1.12-1.95) and presents of hypertriglyceridemic waist (those with high WC and high TG) were significant confounding factors for the increased risk of hypertension independent of ethnicity. CONCLUSIONS: The crude differences in prevalence of hypertension between the Swedes and Assyrians/Syrians in our study population with type 2 diabetes were no longer significant when adjusting for high triglycerides levels or the presence of hypertriglyceridemic waist. PMID- 22937747 TI - Selenium inhibits renal oxidation and inflammation but not acute kidney injury in an animal model of rhabdomyolysis. AB - Acute kidney injury (AKI) is a manifestation of rhabdomyolysis (RM). Extracellular myoglobin accumulating in the kidney after RM promotes oxidative damage, which is implicated in AKI. AIM: To test whether selenium (Se) supplementation diminishes AKI and improves renal function. RESULTS: Dietary selenite increased Se in the renal cortex, as demonstrated by X-ray fluorescence microscopy. Experimental RM-stimulated AKI as judged by increased urinary protein/creatinine, clusterin, and kidney injury molecule-1 (KIM-1), decreased creatinine clearance (CCr), increased plasma urea, and damage to renal tubules. Concentrations of cholesterylester (hydro)peroxides and F2-isoprostanes increased in plasma and renal tissues after RM, while aortic and renal cyclic guanidine monophosphate (cGMP; marker of nitric oxide (NO) bioavailability) decreased. Renal superoxide dismutase-1, phospho-P65, TNFalpha gene, MCP-1 protein, and the 3-chloro-tyrosine/tyrosine ratio (Cl-Tyr/Tyr; marker of neutrophil activation) all increased after RM. Dietary Se significantly decreased renal lipid oxidation, phospho-P65, TNFalpha gene expression, MCP-1 and Cl-Tyr/Tyr, improved NO bioavailability in aorta but not in the renal microvasculature, and inhibited proteinuria. However, CCr, plasma urea and creatinine, urinary clusterin, and histopathological assessment of AKI remained unchanged. Except for the Se++ group, renal angiotensin-receptor-1/2 gene/protein expression increased after RM with parallel increases in MEK1/2 inhibitor-sensitive MAPkinase (ERK) activity. INNOVATION: We employed synchrotron radiation to identify Se distribution in kidneys, in addition to assessing reno-protection after RM. CONCLUSION: Se treatment has some potential as a therapeutic for AKI as it inhibits oxidative damage and inflammation and decreases proteinuria, albeit histopathological changes to the kidney and some plasma and urinary markers of AKI remain unaffected after RM. PMID- 22937748 TI - Identifying obesity indicators which best correlate with type 2 diabetes in a Chinese population. AB - BACKGROUND: Obesity has been shown to be a prognostic indicator of type 2 diabetes (T2D); however, the power of different obesity indicators in the detection of T2D remains controversial. This study evaluates the detecting power of body mass index (BMI), waist circumference (WC), waist-to-hip ratio (WHR) and waist-to-height ratio (WHTR) for the presence of T2D in undiagnosed diabetics among the Chinese population. METHODS: Individuals were selected from an ongoing large-scale population-based Beijing Community Pre-Diabetes (BCPD) study cohort. The oral glucose tolerance tests (OGTT) were performed to diagnose diabetes. A total of 220 new cases of T2D and 1,868 normal blood glucose subjects were analyzed. ROC curve analyses were used to compare the association of different obesity indicators with T2D and determine the optimal cut-off points of the best predictor for identifying T2D in men and women. RESULTS: All indicators positively correlated with presence of T2D in both men and women. In women, WC, WHR and WHTR were similar, but were better in identifying T2D when compared to BMI (P < 0.0001, P=0.0016 and P=0.0001, respectively). In men, WC, WHTR and BMI were similar, but WC and WHTR were better than WHR (P=0.0234, P=0.0101, respectively). For women, 86 cm was the optimal WC cut-off point, and its sensitivity and specificity were 0.714 and 0.616; for men, the optimal cut-off point was 90 cm, and its sensitivity and specificity were 0.722 and 0.571. CONCLUSION: Compared with BMI, WHR and WHTR, WC is a simple and accurate measure for predicting T2D in the Chinese population. PMID- 22937749 TI - The impact of sport and active recreation injuries on physical activity levels at 12 months post-injury. AB - The aim of this study was to evaluate the impact of serious sport and active recreation injury on 12-month physical activity levels. Adults admitted to hospital with sport and active recreation-related injuries, and captured by the Victorian Orthopaedic Trauma Outcomes Registry were recruited to the study. Changes between preinjury and 12 month post-injury physical activity was assessed using the short International Physical Activity Questionnaire (IPAQ). Independent demographic, injury, and hospital variables were assessed for associations with changes in physical activity levels, using multivariate linear regression. A total of 324 patients were recruited, of which 98% were followed up at 12 months. Mean short IPAQ scores decreased from 7650 METS (95% CI: 7180, 8120) preinjury to 3880 METS; (95% CI: 3530, 4250) post-injury, independent of functional recovery. Education level and occupation group were the only variables independently associated with changes in physical activity levels post-injury. These results highlighted that sport and active recreation injuries lead to significant reductions in physical activity levels. Hence, the prevention of sport and active recreation injuries is important when considering promotion of activity at a population level. PMID- 22937750 TI - Infarct healing is a dynamic process following acute myocardial infarction. AB - BACKGROUND: The role of infarct size on left ventricular (LV) remodeling in heart failure after an acute ST-segment elevation myocardial infarction (STEMI) is well recognized. Infarct size, as determined by cardiovascular magnetic resonance (CMR), decreases over time. The amount, rate, and duration of infarct healing are unknown. METHODS: A total of 66 patients were prospectively enrolled after reperfusion for an acute STEMI. Patients underwent a CMR evaluation within 1 week, 4 months, and 14 months after STEMI. RESULTS: Mean infarct sizes for the 66 patients at baseline (acute necrosis), early follow-up (early scar), and late follow-up (late scar) were 25 +/- 17 g, 17 +/- 12 g, and 15 +/- 11 g, respectively. Patients were stratified in tertiles, based on infarct size, with the largest infarcts having the greatest absolute decrease in mass at early and late scar. The percent reduction of infarct mass was independent of initial infarct size. There was an 8 g or 32% decrease in infarct mass between acute necrosis and early scar (p < 0.01) with a 2 g or 12% additional decrease in infarct mass between early and late scar (p < 0.01). CONCLUSIONS: Infarct healing is a continuous process after reperfusion for STEMI, with greatest reduction in infarct size in the first few months. The dynamic nature of infarct healing through the first year after STEMI indicates that decisions based on infarct size, and interventions to reduce infarct size, must take into consideration the time frame of measurement. PMID- 22937751 TI - Joining and leaving sex work: experiences of women in Kigali, Rwanda. AB - Although sex work can bring significant economic benefit there are serious downsides, not least vulnerability to adverse sexual health outcomes. Focus groups discussions and in-depth interviews were conducted with 70 female sex workers to explore the context in which they started sex work, their motivations to leave, and their experiences of trying to leave. The pathway to becoming a sex worker was underscored by poverty, with disruptive events leading to increasing vulnerability and increasingly difficult life choices. A sizeable minority of women became sex workers while working as house-girls, a position associated with financial, physical and sexual vulnerability. The majority of participants were still working as sex workers, citing financial reasons for not leaving. Motivations to leave sex work included experiencing a frightening incident, peer pressure and concerns about dependent children. Those who left often described a change in their financial circumstances that enabled them to leave. Some had left but had returned to sex work following a financial crisis or because they found their new life too hard. House-girls are particularly vulnerable and therefore an appropriate focus for prevention. Programmes assisting women to leave need to include financial safety nets so that a time of financial difficulty does not necessitate a return to sex work. PMID- 22937753 TI - Lack of association between the C276T polymorphism of the neuronal nitric oxide synthase gene and migraine. AB - A migraine attack is a spectacularly complex brain event that can produce a wide array of neurological and systemic symptoms. The molecular mechanisms and genetics of migraine have not yet been clarified. The objective of this study was to analyze the genotype distributions and allele frequencies for the C276T polymorphism of the neuronal nitric oxide synthase (nNOS) gene among the patients with migraine. The diagnosis of migraine was made clinically based on questionnaires. One hundred and twenty patients with migraine were genotyped for the C276T polymorphism of the nNOS gene and compared with 185 age-matched healthy controls. Genomic DNA from migraine patients and controls was analyzed by polymerase chain reaction (PCR). A PCR-restriction fragment-length polymorphism analysis of nNOS gene polymorphism was performed, and the results were compared. Neither genotype distributions nor the allele frequencies for the C276T polymorphism showed a significant difference between the groups. Additionally, there was no marked differences in genotype distribution or allele frequencies for the migraine without aura and migraine with aura subgroups when compared to control group. These results suggested that migraine of the Turkish population seemed to develop without any alterations in nNOS C276T polymorphism. Our data showed that there is no marked association between the C276T polymorphism of the nNOS gene and migraine. PMID- 22937752 TI - A glutathione-dependent detoxification system is required for formaldehyde resistance and optimal survival of Neisseria meningitidis in biofilms. AB - AIM: The glutathione-dependent AdhC-EstD formaldehyde detoxification system is found in eukaryotes and prokaryotes. It is established that it confers protection against formaldehyde that is produced from environmental sources or methanol metabolism. Thus, its presence in the human host-adapted bacterial pathogen Neisseria meningitidis is intriguing. This work defined the biological function of this system in the meningococcus using phenotypic analyses of mutants linked to biochemical and structural characterization of purified enzymes. RESULTS: We demonstrated that mutants in the adhC and/or estD were sensitive to killing by formaldehyde. Inactivation of adhC and/or estD also led to a loss of viability in biofilm communities, even in the absence of exogenous formaldehyde. Detailed biochemical and structural analyses of the esterase component demonstrated that S formylglutathione was the only biologically relevant substrate for EstD. We further showed that an absolutely conserved cysteine residue was covalently modified by S-glutathionylation. This leads to inactivation of EstD. INNOVATION: The results provide several conceptual innovations. They provide a new insight into formaldehyde detoxification in bacteria that do not generate formaldehyde during the catabolism of methanol. Our results also indicate that the conserved cysteine, found in all EstD enzymes from humans to microbes, is a site of enzyme regulation, probably via S-glutathionylation. CONCLUSION: The adhc-estD system protects against formaldehyde produced during endogenous metabolism. PMID- 22937754 TI - Endobronchial metastases from renal cell carcinoma: a late manifestation of the disease with an increasing incidence. PMID- 22937755 TI - Use of dental services throughout middle and early old ages: a prospective cohort study. AB - OBJECTIVES: Focusing on a Swedish 1942 birth cohort, this study describes the trend of dental health care utilization between age 50 and 65 and identifies major determinants of dental visiting habits using Andersen's model as adapted for dentistry as a theoretical framework. METHOD: In 1992, a census of 50 year olds in two counties of Sweden was invited to participate in a longitudinal questionnaire survey. Of the total population of 8888 subjects, 6346 responded (71%). Of the 6346 subjects who completed the 1992 survey, 4143 (65%) completed postal follow ups in 1997, 2002 and 2007. RESULTS: 83.3% and 3.2% of the cohort remained stable with respect to use and nonuse of regular dental care. Cochran's Q test revealed that the proportions reporting regular use decreased from 93% at age 50-87% at age 65 (P < 0.001). Generalized estimated equations revealed the following covariates; gender (females), country of birth (native born), marital status (married), perceived quality of dental care (good perceptions), dental care utilization as a child, remaining teeth and perceived oral problems. The influence of the variable time, functioning as a measure of period/ageing, maintained a statistically significant relationship with regular utilization after adjusting for all covariates in the model. CONCLUSION: Regular use of dental health care services decreased slightly but statistically significantly from age 50 to 65 and was most prevalent in socio-economically advantaged groups, among those with remaining own teeth, subjects who perceived oral problems and reported high quality dental care. The results have implications for planning of elderly dental health care and required dental workforce in Sweden and countries with similar welfare systems. PMID- 22937756 TI - Polymorphisms in the promoter of the CD14 gene and their associations with susceptibility to pulmonary tuberculosis. AB - Although the role of CD14 in recognizing Mycobacterium tuberculosis is well understood, the possible role of polymorphisms in susceptibility to develop tuberculosis remains unclear. This study evaluates whether there is an association of polymorphisms within the promoter of the CD14 gene with susceptibility to pulmonary tuberculosis. In a case-control study, we genotyped the eight known single nucleotide polymorphisms SNPs within the promoter of the CD14 gene of 698 Han Chinese subjects. Statistically significant differences between tuberculosis patients and healthy controls were found for G-1619A, T 1359G, A-1145G, and C-159T. The haplotype-GGGT, composed of these four SNPs, exhibited a significant association with the disease. Furthermore, expression levels of soluble CD14 were significantly higher in tuberculosis patients with the GGGT haplotype than with other haplotypes, while IgE expression levels were significantly reduced. Our results suggest that these four SNPs within the promoter of the CD14 gene are associated with susceptibility to pulmonary tuberculosis. PMID- 22937757 TI - Contribution of GATA1 dysfunction to multi-step leukemogenesis. AB - In mammals, hematopoietic homeostasis is maintained by a fine-tuned balance among the self-renewal, proliferation, differentiation and survival of hematopoietic stem cells and their progenies. Each process is also supported by the delicate balance of the expression of multiple genes specific to each process. GATA1 is a transcription factor that comprehensively regulates the genes that are important for the development of erythroid and megakaryocytic cells. Accumulating evidence supports the notion that defects in GATA1 function are intimately linked to hematopoietic disorders. In particular, the somatic mutation of the GATA1 gene, which leads to the production of N-terminally truncated GATA1, contributes to the genesis of transient myeloproliferative disorder and acute megakaryoblastic leukemia in infants with Down syndrome. Similarly, a mutation in the GATA1 regulatory region that reduces GATA1 expression is involved in the onset of erythroid leukemia in mice. In both cases, the accumulation of immature progenitor cells caused by GATA1 dysregulation underlies the pathogenesis of the leukemia. This review provides a summary of multi-step leukemogenesis with a focus on GATA1 dysfunction. PMID- 22937758 TI - Idiopathic acquired true leukonychia totalis. AB - Idiopathic acquired true leukonychia totalis is a rare nail disorder not associated with other abnormalities. We present a case in a 12-year-old Egyptian boy. PMID- 22937759 TI - Biomechanical profile of the cornea in primary congenital glaucoma. AB - PURPOSE: The aim of our study was to investigate the biomechanical properties of the cornea in primary congenital glaucoma (PCG) and to identify the potential ocular determinants, which affect the corneal biomechanical metrics. METHODS: Corneal hysteresis (CH), corneal resistance factor (CRF) and central corneal thickness (CCT) were measured in 26 patients with PCG (40 eyes) with the aid of ocular response analyser. In vivo laser-scanning confocal microscopy was used for the estimation of stromal keratocyte density (KD) and the evaluation of corneal endothelium. Twenty normal subjects (40 eyes) served as controls. Student's t test and Pearson's correlation coefficients were used for statistical analysis. p Values <0.05 were considered statistically significant. RESULTS: Corneal hysteresis, CRF and CCT were significantly reduced in patients with PCG (all p < 0.05). Corneal hysteresis and CRF negatively correlated with the corneal diameter in both groups (r(1) = -0.53, r(2) = -0.66, p < 0.001 for CH and r(1) = -0.61, r(2) = -0.69, p < 0.001 for CRF). Moreover, we identified a significant correlation between CH and CRF with CCT in both groups (r(1) = 0.51, r(2) = 0.48, p < 0.001 for CH and r(1) = 0.45, r(2) = 0.44, p < 0.001 for CRF). Mean KD was significantly reduced both in the anterior and posterior corneal stroma in patients with PCG (764 +/- 162 and 362 +/- 112 cells/mm(2) , respectively) compared with controls (979 +/- 208 and 581 +/- 131 cells/mm(2) , respectively) (p < 0.001). There was no significant correlation between the keratocyte density in anterior and/or posterior stroma and CH or CRF in any group (r(1) = 0.29, r(2) = 0.31, p < 0.06). Mean endothelial cell density was also significantly reduced in PCG group (2920 +/- 443 cells/mm(2) ) compared with control group (3421 +/- 360 cells/mm(2) ) (p < 0.001). Pleomorphism and polymegalism were significantly increased in corneal endothelium of patients with PCG. CONCLUSIONS: Our results showed a significant reduction in CH and CRF in PCG. Both CH and CRF were negatively correlated with corneal diameter. A significant correlation of CH and CRF with CCT was identified in both groups. Keratocyte density was decreased in PCG, but did not have a significant impact on CH and CRF. Mean endothelial density was also decreased in PCG. Our results suggest that reduced CCT and increased corneal diameter are major ocular determinants for the modified corneal biomechanical profile in PCG, while cellular alterations in corneal stroma and endothelium have no significant biomechanical impact. PMID- 22937760 TI - Acute liver failure following cleft palate repair: a case of therapeutic acetaminophen toxicity. AB - Background : Acetaminophen is a widely used analgesic and antipyretic agent in the pediatric population. While the hepatotoxic effects of the drug have been well recognized in cases of acute overdose and chronic supratherapeutic doses, the toxic effects of acetaminophen are rarely documented in cases where therapeutic guidelines are followed. Case : An 8-month-old boy underwent cleft palate repair and placement of bilateral myringotomy tubes. His anesthetic course was uneventful, consisting of maintenance with desflurane and fentanyl. He received acetaminophen for routine postoperative pain management and was tolerating liquids and discharged home on postoperative day 1. On day 3, the child was profoundly lethargic with multiple episodes of emesis and was taken to the emergency department. He suffered a 45-second tonic-clonic seizure in transport to the regional children's medical center, and initial laboratory results demonstrated acute hepatitis with AST 24,424 U/L, ALT 12,885 U/L, total bilirubin 3.1 mg/dL, and a serum acetaminophen level of 83 MUg/mL. Aggressive supportive measures including blood products and periprocedural fresh frozen plasma, piperacillin/tazobactam, and intravenous infusions of N-acetylcysteine, sodium phenylacetate and sodium benzoate, carnitine, and citrulline were administered. His metabolic acidosis and acute hepatitis began to correct by day 4, and he was discharged home without further surgical intervention on day 15. Conclusion : Although acetaminophen is an effective and commonly used analgesic in pediatric practice, hepatotoxicity is a potentially devastating complication. This report challenges the appropriateness of existing guidelines for acetaminophen administration and emphasizes the importance of close follow-up and hydration after even relatively minor surgery. PMID- 22937763 TI - Malignant transformation of Madelung's disease in a patient with a coincidental diagnosis of breast cancer: a case report. AB - Madelung's disease or multiple symmetric lipomatosis (MSL) is a rare disorder of unknown etiology which typically presents symmetrically subcutaneous accumulation of non-encapsulated adipose tissue which slowly grows around the neck, upper part of the arms, pelvis, back and thigh. This disease is also frequently associated with hepatopathy, glucose intolerance, hyperuricemia, and malignant tumors of the upper airways. Nevertheless, only one description of malignant transformation of Madelung's disease has been presented in literature. Here, we report a case of liposarcomatous transformation of Madelung's disease in a 59-year-old Italian woman with a coincidental diagnosis of breast cancer. VIRTUAL SLIDE: The virtual slide for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/3480884087499351. PMID- 22937762 TI - Maternal 3'UTRs: from egg to onset of zygotic transcription in Atlantic cod. AB - BACKGROUND: Zygotic transcription in fish embryos initiates around the time of gastrulation, and all prior development is initiated and controlled by maternally derived messenger RNAs. Atlantic cod egg and embryo viability is variable, and it is hypothesized that the early development depends upon the feature of these maternal RNAs. Both the length and the presence of specific motifs in the 3'UTR of maternal RNAs are believed to regulate expression and stability of the maternal transcripts. Therefore, the aim of this study was to characterize the overall composition and 3'UTR structure of the most common maternal RNAs found in cod eggs and pre-zygotic embryos. RESULTS: 22229 Sanger-sequences were obtained from 3'-end sequenced cDNA libraries prepared from oocyte, 1-2 cell, blastula and gastrula stages. Quantitative PCR revealed that EST copy number below 9 did not reflect the gene expression profile. Consequently genes represented by less than 9 ESTs were excluded from downstream analyses, in addition to sequences with low quality gene hits. This provided 12764 EST sequences, encoding 257 unique genes, for further analysis. Mitochondrial transcripts accounted for 45.9-50.6% of the transcripts isolated from the maternal stages, but only 12.2% of those present at the onset of zygotic transcription. 3'UTR length was predicted in nuclear sequences with poly-A tail, which identified 191 3'UTRs. Their characteristics indicated a more complex regulation of transcripts that are abundant prior to the onset of zygotic transcription. Maternal and stable transcripts had longer 3'UTR (mean 187.1 and 208.8 bp) and more 3'UTR isoforms (45.7 and 34.6%) compared to zygotic transcripts, where 15.4% had 3'UTR isoforms and the mean 3'UTR length was 76 bp. Also, diversity and the amount of putative polyadenylation motifs were higher in both maternal and stable transcripts. CONCLUSIONS: We report on the most pronounced processes in the maternally transferred cod transcriptome. Maternal stages are characterized by a rich abundance of mitochondrial transcripts. Maternal and stable transcripts display longer 3'UTRs with more variation of both polyadenylation motifs and 3'UTR isoforms. These data suggest that cod eggs possess a complex array of maternal RNAs which likely act to tightly regulate early developmental processes in the newly fertilized egg. PMID- 22937764 TI - Evaluation of a modified pH-shift process to reduce 2-methylisoborneol and geosmin in spiked catfish and produce a consumer acceptable fried catfish nugget like product. AB - Muddy and/or musty off-flavors in farmed-raised catfish occur as a result of the absorption of geosmin (GEO) and 2-methylisoborneol (MIB), compounds produced by algae. Previous research suggests the acid pH-shift method may be able to reduce off-flavors to produce a consumer acceptable product. The objective of this research was to evaluate application of the acid pH-shift method using a shaker sieve for protein recovery and to evaluate consumer acceptability of a resultant batter-coated fried nugget-like catfish product. Farm-raised catfish were either allowed to depurate (control) or treated with 1 ppb GEO or MIB. Fillets from each replicate were collected and ground and treated by the acid pH-shift process. Samples from all treatments and replicates were evaluated for residual GEO and MIB. In addition, batter-coated fried catfish samples were prepared for a consumer sensory evaluation. Results demonstrated that the pH-shift process decreased moisture, ash, and collagen content of catfish fillet tissue (P < 0.05). Flavor of control samples was preferred (P < 0.05). Texture of catfish samples treated by the pH-shift process was preferred (P < 0.05). Results demonstrate the pH-shift process can be utilized to reduce off-flavors and increase the acceptability of a processed catfish product. PRACTICAL APPLICATION: Use of a sieve as an economic alternative for the pH-shift process was evaluated for removing off-flavors from catfish. Difficulties were encountered with regard to protein recovery using the sieve and suggestions are made to, perhaps, make the process more applicable for a sieve-based recovery step. The process as described reduced off-flavors, but only 2-fold suggesting the process would work best on catfish near or just over off-flavor thresholds. Results also indicated the pH-shift process could be used to improve texture of a fried catfish product designed to be similar to chicken nuggets. PMID- 22937765 TI - Health-related quality of life among colorectal cancer patients in Malaysia: a study protocol. AB - BACKGROUND: Colorectal cancer is a major public health problem in Malaysia. However, it is also one of the most treatable cancers, resulting in significant numbers of survivors. Therefore, the impact of surviving treatment for colorectal cancer on health related quality of life is important for the patients, clinicians and policy makers, and may differ in different cultures and populations. The aim of this study was to validate the Malaysian versions of the European Organization for Research and Treatment of Cancer quality of life instruments among colorectal cancers patients. METHODS/DESIGN: This is a cross sectional multi centre study. Three hospitals were included, the University of Malaya Medical Centre, the Universiti Kebangsaan Malaysia Medical Centre and Hospital Tuanku Jaafar Seremban. Malaysian citizens and permanent residence were studied and demographic and clinical information obtained from hospital records. The European Organization for Research and Treatment of Cancer Quality of life Core 30, colorectal cancer CR29, and the colorectal cancer liver metastasis LMC 21 were used and an observer assessment of performance obtained with the Karnofsky Performance Scale. Questionnaires were translated into three most commonly spoken languages in Malaysia (Bahasa Malaysia, Chinese and Tamil), then administered, scored and analyzed following the developers' guidelines. Ethical approval was obtained from the participating centres. Tests of reliability and validity were performed to examine the validity of these instruments. CONCLUSION: The result of pilot testing shows that the use of the Malaysian versions of EORTC QLQ C30, CR29 instruments is feasible in our sample of colorectal cancer patients. Instructions for completion as well as questions were well understood except the questions on the overall quality of life, overall health status and sexual activity. Thus we anticipate obtaining good psychometric properties for the instruments at the end of the study. PMID- 22937766 TI - Sarcoidosis in a young child with Alagille syndrome: a case report. AB - We report a now 6-year-old African-American male with both Alagille syndrome and pediatric sarcoidosis. With a prior JAG1 mutation positive diagnosis of Alagille syndrome, he presented to the hospital with a subacute, predominantly respiratory febrile condition, eventually diagnosed as sarcoidosis. A liver biopsy revealed paucity of bile ducts and scattered epithelioid granulomas, while a skin biopsy showed granulomatous angiitis, a manifestation of sarcoidosis not yet reported in a pediatric patient. He has subsequently been treated with corticosteroids, mycophenolate mofetil, and infliximab with clinical response. Alagille syndrome and sarcoidosis have not yet been reported in the medical literature in the same patient to the best of our knowledge. We briefly review these two seemingly unrelated conditions and propose a possible common pathogenic mechanism. PMID- 22937767 TI - Reaching and engaging non-gay identified, non-disclosing Black men who have sex with both men and women. AB - Non-gay identified (NGI) Black men who have sex with both men and women (MSMW) and who use substances are at risk of acquiring and transmitting HIV to their partners. Homophobic community norms can discourage such men from disclosing their risk behaviour to female partners and others, including service providers. It is important to understand the dynamics of risk in this vulnerable population, but research is challenged by the men's need for secrecy. In this paper we report on successful efforts to recruit 33 non-disclosing, NGI Black MSMW for in-depth interviews concerning substance use, HIV risk and attitudes toward disclosing their risk behaviour. We employed targeted and referral sampling, with initial contacts and/or key informants drawn from several types of settings in New York City, including known gay venues, community organisations, neighbourhood networks and the Internet. Key informant gatekeepers and the ability to establish rapport proved central to success. Perceived stigma is a source of social isolation, but men are willing to discuss their risk behaviour when they trust interviewers to protect their privacy and engage with them in a non-judgemental manner. Findings imply that the most effective prevention approaches for this population may be those that target risk behaviours without focusing on disclosure of sexual identities. PMID- 22937768 TI - The injury mortality burden in Guinea. AB - BACKGROUND: The injury mortality burden of Guinea has been rarely addressed. The paper aimed to report patterns of injury mortality burden in Guinea. METHODS: We retrieved the mortality data from the Guinean Annual Health Statistics Report 2007. The information about underlying cause of deaths was collected based on Guinean hospital discharge data, Hospital Mortuary and City Council Mortuary data. The causes of death are coded in the 9th International Classification of Diseases (ICD-9). Multivariate Poisson regression was used to test the impacts of sex and age on mortality rates. The statistical analyses were performed using Statatm 10.0. RESULTS: In 2007, 7066 persons were reported dying of injuries in Guinea (mortality: 72.8 per 100,000 population). Transportation, fire/burn, falls, homicide and drowning were the five leading causes of fatal injuries for the whole population, accounting for 37%, 22%, 12%, 10% and 6% of total deaths, respectively. In general, age-specific injury causes displayed similar patterns of the whole population except that poisoning replaced falls as a leading cause among children under five years old. Males were at 30-50% more risk of dying from six commonest causes than females and old age groups had higher injury mortality rates than younger age groups. CONCLUSION: Transportation, fire/burn, falls, homicide, and drowning accounted for the majority of total injury mortality burden in Guinea. Males and old adults were high-risk population of fatal injuries and should be targeted by injury prevention. Lots of work is needed to improve weak capacities for injury control in order to reduce the injury mortality burden. PMID- 22937769 TI - National intensive care unit bed capacity and ICU patient characteristics in a low income country. AB - BACKGROUND: Primary health care delivery in the developing world faces many challenges. Priority setting favours HIV, TB and malaria interventions. Little is known about the challenges faced in this setting with regard to critical care medicine. The aim of this study was to analyse and categorise the diagnosis and outcomes of 1,774 patients admitted to a hospital intensive care unit (ICU) in a low-income country over a 7-year period. We also assessed the country's ICU bed capacity and described the challenges faced in dealing with critically ill patients in this setting. FINDINGS: A retrospective audit was conducted in a general ICU in a university hospital in Uganda. Demographic data, admission diagnosis, and ICU length of stay were recorded for the 1,774 patients who presented to the ICU in the period January 2003 to December 2009. Their mean age was 35.5 years. Males accounted for 56.5% of the study population; 92.8% were indigenous, and 42.9% were referrals from upcountry units. The average mortality rate over the study period was 40.1% (n = 715). The highest mortality rate (44%) was recorded in 2004 and the lowest (33.2%) in 2005. Children accounted for 11.6% of admissions (40.1% mortality). Sepsis, ARDS, traumatic brain injuries and HIV related conditions were the most frequent admission diagnoses. A telephonic survey determined that there are 33 adult ICU beds in the whole country. CONCLUSIONS: Mortality was 40.1%, with sepsis, head injury, acute lung injury and HIV/AIDS the most common admission diagnoses. The country has a very low ICU bed capacity. Prioritising infectious diseases poses a challenge to ensuring that critical care is an essential part of the health care package in Uganda. PMID- 22937770 TI - Spontaneous resolution of a mixed-ligand nickel(II) coordination polymer with achiral precursors. AB - Metal-center-driven spontaneous resolution of a chiral coordination polymer, [Ni(SDB)(BIX)](n) (1), from achiral precursors has been probed by single-crystal X-ray diffraction and circular dichroism spectroscopy. Enantiomorphs 1P and 1M showed a parallel interpenetrated 2D -> 3D chiral framework with (8(2).10) topology. Switching of the metal center under the same reaction parameters resulted in isostructural achiral and noninterpenetrating (4,4) grid-type sql networks [M(SDB)(BIX)](n), where M = Co(II), Zn(II), and Cd(II) for 2-4, respectively. PMID- 22937771 TI - Frictional properties of mixed fluorocarbon/hydrocarbon silane monolayers: a simulation study. AB - Because of small surface area to volume ratios nanoscale devices can exhibit dominant surface forces that can quickly degrade unlubricated contacting surfaces. While fluorinated materials have been widely used as lubricants, because of their low critical surface tension and high thermal and mechanical stability, fluorinated monolayer coatings, which are suitable for lubricating nanoscale devices, are less effective as lubricants. Although fluorinated monolayers are more stable than their hydrocarbon counterparts against elevated temperature and humidity, they are known to exhibit higher frictional forces. To overcome this issue, here we study mixed monolayers composed of both hydrocarbon and fluorocarbon chains. Hydrocarbon-based monolayers have been widely studied and shown to improve frictional properties and device life. To investigate the frictional behavior of mixed fluorocarbon/hydrocarbon monolayers, molecular dynamics simulations of pure hydrogenated and fluorinated chains and mixed fluorinated/hydrogenated chains on silica surfaces have been performed. The adhesion and friction between the nanoconfined monolayers as a function of normal load, chain length, and chemical composition of the monolayer coating have been investigated, and mixed fluorocarbon/hydrocarbon monolayers found to outperform both pure fluorocarbon and pure hydrocarbon monolayers. Surface coverage was found to have a significant effect on the performance of all systems studied with higher surface coverage resulting in lower frictional forces. The simulations also show that when the hydrocarbon chains in the monolayer are longer than the fluorocarbon chains, a liquidlike layer is formed by the longer hydrocarbon chains that protrudes above the shorter fluorocarbon chains and aids in friction reduction. A frictional load dependence is also seen in these mixed monolayer systems because of repulsive interactions between the fluorocarbon base layer and the hydrocarbon liquidlike layer. A chain length difference of eight carbons between the base layer and the liquidlike layer was found to provide the lowest friction, while both a larger (because of increased entanglement) and a smaller (insufficient atoms between the contacting base layers to form a liquidlike layer) chain length difference increased friction. PMID- 22937772 TI - Neuronal models in infinite-dimensional spaces and their finite-dimensional projections: Part II. AB - Application of comparison theorem is used to examine the validitiy of the "lumped parameter assumption" in describing the behavior of solutions of the continuous cable equation U(t) = DU(xx)+f(U) with the discrete cable equation dV(n)/dt = d*(V(n+1) - 2V(n) + V(n-1)) + f(V(n)), where f is a nonlinear functional describing the internal diffusion of electrical potential in single neurons. While the discrete cable equation looks like a finite difference approximation of the continuous cable equation, solutions of the two reveal significantly different behavior which imply that the compartmental models (spiking neurons) are poor quantifiers of neurons, contrary to what is commonly accepted in computational neuroscience. PMID- 22937773 TI - Chemical composition and antibacterial activity of the essential oils of Ferula vesceritensis Coss et Dur. leaves, endemic in Algeria. AB - BACKGROUND: The biological importance of members of genus Ferula promoted us to investigate the leaves of Ferula vesceritensis Coss et Dur. (endemic plant) previously not investigated. This study presents the chemical composition and antibacterial activities of the hydrodistilled oils. RESULTS: Volatile components of the leaves of F. vesceritensis have been studied by gas chromatography-mass spectrometry to afford 23 compounds. The major components were found to be 5,9 tetradecadiyne (24.72%), germacrene D (24.51%), farnesene (8.57%), and alpha bisabolene (8.57%). The antimicrobial activities of the essential oils were evaluated by disk diffusion method and tested against Gram-positive and Gram negative bacteria. The volatile oil showed a strong antibacterial activity against Staphylococcus aureus, Escherichia coli, and Klebsiella pneumonia. CONCLUSIONS: These results reinforce the previous studies showing that the genus Ferula is considered as a good source of essential oils. The results presented here can be considered as the first information on the antimicrobial properties of F. vesceritensis. PMID- 22937774 TI - ZSI 375 artificial urinary sphincter for male urinary incontinence: a preliminary study. AB - OBJECTIVE: To assess retrospectively the safety and efficacy of an artificial urinary sphincter, the ZSI 375 device (Zephyr Surgical Implants, Geneva, Switzerland), in male patients with moderate-to-severe stress urinary incontinence after a prostate or bladder intervention. PATIENTS AND METHODS: The ZSI 375 device is a one-piece device consisting of an adjustable cuff, moulded to fit around the urethra, which is connected by a tube to a pump and a pressure regulating tank. It has no abdominal reservoir. Patients underwent a perineal incision for cuff placement and an inguinal incision for pump and tank scrotal placement. Complications and pads used to manage incontinence were recorded. RESULTS: Between May 2009 and April 2011, 36 patients underwent ZSI 375 device placement. The median (range) follow-up was 15.4 (6-28) months. No patient experienced bladder overactivity, chronic urinary retention, or any other adverse effect after device activation. Complications leading to device removal arose in four patients (one case of erosion, three cases of infection). Social continence (0 or 1 pad/day) was achieved in 28/36 patients (78%) at 3 months and 26/36 patients (73%) at 6 months after device activation. In 12/14 patients for a sphincter closure pressure range of 60-70 cm H2O, in 3/3 patients for a range of 70-80 cm H2O and in 2/11 for a range of 90-100 cm, H2O social continence was achieved only after increasing the pressure of the cuff by trans-scrotal injection of saline. CONCLUSIONS: The ZSI 375 device is safe and effective but our follow-up may not have been long enough to identify all potential complications. Further research is needed to confirm these results and extend our investigation, for instance, to the peno-scrotal approach. PMID- 22937775 TI - Drug-induced lupus erythematosus with emphasis on skin manifestations and the role of anti-TNFalpha agents. AB - Drug-induced lupus erythematosus (DILE) is a lupus-like syndrome temporally related to continuous drug exposure which resolves upon drug discontinuation. There are currently no standard diagnostic criteria for DILE. Findings include skin manifestations, arthritis, serositis, anti-nuclear and anti-histone antibodies positivity. Similarly to idiopathic lupus erythematosus, DILE can be divided into systemic (SLE), subacute cutaneous (SCLE) and chronic cutaneous lupus (CCLE). Systemic DILE presents as a milder version of idiopathic SLE, and the drugs most frequently implicated are hydralazine, procainamide and quinidine. Anti-TNFalpha therapies are the latest class of medications found to be associated, although rarely, with a "lupus-like" syndrome, which is however clinically distinct from classical DILE. Drug-induced SCLE is the most common form of DILE. It is very similar to idiopathic SCLE in terms of clinical and serologic characteristics. The most commonly implicated drugs are antihypertensive drugs and terbinafine, but in recent years also proton pump inhibitors and chemotherapeutic agents have been associated. Drug-induced CCLE is very rare and usually caused by fluorouracil agents and NSAIDS, but some cases have induced by pantoprazole and anti-TNFalpha agents. PMID- 22937777 TI - Can financial insecurity and condescending treatment explain the higher prevalence of poor self-rated health in women than in men? A population-based cross-sectional study in Sweden. AB - INTRODUCTION: Women have in general poorer self-rated health than men. Both material and psychosocial conditions have been found to be associated with self rated health. We investigated whether two such factors, financial insecurity and condescending treatment, could explain the difference in self-rated health between women and men. METHODS: The association between the two factors and self rated health was investigated in a population-based sample of 35,018 respondents. The data were obtained using a postal survey questionnaire sent to a random sample of men and women aged 18-75 years in 2008. The area covers 55 municipalities in central Sweden and the overall response rate was 59%. Multinomial odds ratios for poor self-rated health were calculated adjusting for age, educational level and longstanding illness and in the final model also for financial insecurity and condescending treatment. RESULTS: The prevalence of poor self-rated health was 7.4% among women and 6.0% among men. Women reported more often financial insecurity and condescending treatment than men did. The odds ratio for poor self-rated health in relation to good self-rated health was 1.29 (95% CI: 1.17-1.42) for women compared to men when adjusted for age, educational level and longstanding illness. The association became, however, statistically non-significant when adjusted for financial insecurity and condescending treatment. CONCLUSION: The present findings suggest that women would have as good self-rated health as men if they had similar financial security as men and were not treated in a condescending manner to a larger extent than men. Longitudinal studies are, however, required to confirm this conclusion. PMID- 22937778 TI - Carbon-carbon bond cleavage in fluorescent pyronin analogues induced by yellow light. AB - A novel class of pyronin analogues, which undergoes a photochemically induced cleavage of the C-C bond in the presence of water in both solution and on a silica gel surface upon direct irradiation with visible light, is reported. The reaction course can be monitored by characteristic fluorescence of both the starting compound and the final product. This system could find useful applications in the field of photoremovable protecting groups or caged fluorophores. PMID- 22937776 TI - Integrated network analysis reveals a novel role for the cell cycle in 2009 pandemic influenza virus-induced inflammation in macaque lungs. AB - BACKGROUND: Annually, influenza A viruses circulate the world causing wide-spread sickness, economic loss, and death. One way to better defend against influenza virus-induced disease may be to develop novel host-based therapies, targeted at mitigating viral pathogenesis through the management of virus-dysregulated host functions. However, mechanisms that govern aberrant host responses to influenza virus infection remain incompletely understood. We previously showed that the pandemic H1N1 virus influenza A/California/04/2009 (H1N1; CA04) has enhanced pathogenicity in the lungs of cynomolgus macaques relative to a seasonal influenza virus isolate (A/Kawasaki/UTK-4/2009 (H1N1; KUTK4)). RESULTS: Here, we used microarrays to identify host gene sequences that were highly differentially expressed (DE) in CA04-infected macaque lungs, and we employed a novel strategy - combining functional and pathway enrichment analyses, transcription factor binding site enrichment analysis and protein-protein interaction data - to create a CA04 differentially regulated host response network. This network describes enhanced viral RNA sensing, immune cell signaling and cell cycle arrest in CA04 infected lungs, and highlights a novel, putative role for the MYC-associated zinc finger (MAZ) transcription factor in regulating these processes. CONCLUSIONS: Our findings suggest that the enhanced pathology is the result of a prolonged immune response, despite successful virus clearance. Most interesting, we identify a mechanism which normally suppresses immune cell signaling and inflammation is ineffective in the pH1N1 virus infection; a dyregulatory event also associated with arthritis. This dysregulation offers several opportunities for developing strain-independent, immunomodulatory therapies to protect against future pandemics. PMID- 22937779 TI - Clinical transplantation of ex vivo expanded autologous limbal epithelial cells using a culture medium with human serum as single supplement: a retrospective case series. AB - PURPOSE: Presently, our clinic is the only centre in Scandinavia that offers patients with corneal surface pathology including limbal stem cell deficiency (LSCD) transplantation of ex vivo expanded limbal epithelial cells (LECs). We here present clinical data of the first nine patients with LSCD who were transplanted with autologous LECs expanded in medium completely free of any animal-derived products and non-human/recombinant growth factors (including Cholera Toxin), and with autologous human serum as the only growth supplement. METHODS: We conducted a noncomparative retrospective study of patients with LSCD at our centre between 2009 and 2011. The diagnosis was based on history and clinical signs. A biopsy was taken from healthy limbus, and the epithelium was expanded on amniotic membrane (AM) in medium containing autologous serum and subsequently transplanted to the affected eye. RESULTS: Successful outcome was defined as relief of pain and photophobia and/or improved best corrected visual acuity (BCVA) and/or reestablishment of a stable corneal epithelium and regression of corneal vascularization. Five of the nine transplanted patients (55.6%) had an improvement in either subjective symptoms or objective findings (11- to 28-month follow-up). CONCLUSIONS: Our clinical study shows that patients with LSCD can be treated successfully with transplantation of LECs expanded ex vivo in a medium with autologous serum as the only growth supplement. The use of this novel culture system, which is devoid of animal-derived products and non human/recombinant growth factors (including Cholera Toxin), reduces the risks of inter-species disease transmission and host immune responses to xenogenic proteins, both obvious advantages for the patient. PMID- 22937780 TI - Opening the dialogue: what counts? PMID- 22937781 TI - Purpose, objectives, and outcome: tying the pieces together. AB - The fundamental intent of continuing nursing education is to improve the professional practice of nursing and the care provided to patients. Using a thoughtful process for developing a purpose and objectives for an activity and identifying the desired outcome(s) helps to ensure that the learning activity will be valuable for learners and achieve desired results. PMID- 22937782 TI - The nursing professional development series: addressing the learning needs of nurse educators. AB - This column discusses an education series specifically designed to advance the practice of those in nursing professional development. PMID- 22937783 TI - Technology and nursing education: an online toolkit for educators. AB - New tools that are free are available via the Internet and can successfully be used to create interactive and engaging courses designed to reach today's technologically savvy learners. PMID- 22937785 TI - Rapidly involuting congenital hemangioma associated with profound, transient thrombocytopenia. AB - Rapidly involuting congenital hemangioma (RICH) is an uncommon, often high-flow vascular tumor that presents at birth and involutes within the first year of life. It is clinically and histologically distinct from infantile hemangioma, kaposiform hemangioendothelioma, and tufted angioma, the latter two being associated with Kasabach-Merritt phenomenon. We present a female infant with RICH and profound, transient thrombocytopenia and review the extent and clinical course of thrombocytopenia in the context of congenital vascular tumors. PMID- 22937786 TI - Solvation effect on the NH stretching vibrations of solvated aminopyrazine, 2 aminopyridine, and 3-aminopyridine clusters. AB - The vibrational spectra of the hydrated and methanol-solvated aminopyrazine, 2 aminopyridine and 3-aminopyridine in supersonic jets have been measured in terms of IR-UV double-resonance spectroscopy. Comparing the IR spectrum of aminopyrazine with those of 2-aminopyridine and 3-aminopyridine clusters, we determine the solvation structure of aminopyrazine to be a similar cyclic structure as hydrated 2-aminopyridine clusters [Wu, et al., Phys. Chem. Chem. Phys. 2004, 6, 515]. In the case of monohydrated aminopyrazine cluster, one of the normal modes composed of the hydrogen-bonded OH and NH stretching local modes gives the anomalously weak IR intensity, which is ascribed to the cancellation of the dipole moment change between the OH and NH stretching local modes. The solvated 3-aminopyridine clusters forms the hydrogen-bond between the pyridyl nitrogen atom and the OH group, but the amino group is indirectly affected to induce slight blue shift of the NH(2) stretches. This phenomenon is explained by inductive effect where the electron withdrawing from the amino group upon the solvation results in a "quinoid-like" structure of the amino group. PMID- 22937787 TI - Is there an advantage of living over deceased donation in liver transplantation? AB - Living donor liver transplantation (LDLT) is a well-established strategy to decrease the mortality in the waiting list and recent studies have demonstrated its value even in patients with low MELD score. However, LDLT is still under a high level of scrutiny because of its technical complexity and ethical challenges as demonstrated by a decline in the number of procedures performed in the last decade in Western Countries. Many aspects make LDLT different from deceased donor liver transplantation, including timing of transplantation, procedure-related complications as well as immunological factors that may affect graft outcomes. Our review suggests that in selected cases, LDLT offers significant advantages over deceased donor liver transplantation and should be used more liberally. PMID- 22937788 TI - Association between TNF-delta 238G/A polymorphisms and the risk of ischemic stroke. AB - BACKGROUND: Stroke is the second highest cause of morbidity and functional disability around the world. In addition, it is the second most common cause of death worldwide [ 1 ]. However, the genetic pathology of stroke is still unclear. Published data on the association between TNF-a 238G/A polymorphisms and ischemic stroke risk are inconsistent and controversial. To provide a more robust estimate about TNF-a 238G/A polymorphisms on the risk of ischemic stroke, we conducted this meta-analysis. METHODS: We used the pooled odds ratios (ORs) with 95% confidence intervals (95%CIs) to investigate the relationship between TNF alpha238G/A polymorphisms and ischemic stroke. Publication bias was tested by Begg's test and inverted funnel plot, and Heterogeneity was checked by Cochran's Q statistic and the inconsistency index (I(2)). RESULTS: There are 7 studies that include 1,766 cases and 1,560 controls in this meta-analysis. The results indicated a significant association between TNF-alpha238G/A polymorphisms and ischemic stroke in overall analysis, Caucasian and Adult. However, statistical association was not observed in Juvenile and Asian. CONCLUSIONS: This meta analysis suggests that TNF-alpha238G/A polymorphisms increases the risk of ischemic stroke in Adult, Caucasian, and overall analysis. However, in Juvenile and Asian analysis, significant associations between TNF-alpha238G/A and ischemic stroke were not found. PMID- 22937789 TI - S-MDM4 mRNA overexpression indicates a poor prognosis and marks a potential therapeutic target in chronic lymphocytic leukemia. AB - The purpose of the present study was to investigate the prognostic significance of murine double minute 4 (MDM4) in chronic lymphocytic leukemia (CLL) and to characterize the role of MDM4 in the p53 pathway. Full-length MDM4 (FL-MDM4), a splicing variant of MDM4 (S-MDM4) and murine double minute 2 (MDM2) mRNA expressions were detected by quantitative PCR in 140 Chinese patients with CLL, and primary CLL cells were treated in vitro with either fludarabine or Nutlin-3 to explore the interaction between p53 status and MDM4 or MDM2 expression. A marked increase of FL-MDM4 and S-MDM4 expressions were observed in the CLL patients with p53 aberrations (deletion and/or mutation) (P = 0.024, P < 0.001). A high level of S-MDM4 mRNA expression was associated with short treatment free survival (TFS) (P = 0.004). FL-MDM4 expression was significantly decreased after fludarabine treatment (P = 0.001) but increased after Nutlin-3 treatment (P = 0.008) of primary CLL cells without p53 aberrations. Both S-MDM4 and MDM2 expressions were significantly increased after fludarabine treatment of CLL cells without p53 aberrations (P = 0.013 and P = 0.030). MDM2 overexpression also occurred in CLL cells with p53 wild type after Nutlin-3 treatment (P = 0.018). FL MDM4 and S-MDM4 overexpression are indicators of p53 aberrations in CLL patients, suggesting that those patients have a poor prognosis. FL-MDM4 inhibitory effects on p53 can be removed by MDM2-p53 and saved by Nutlin-3. PMID- 22937790 TI - Microscopic endometrial perivascular epithelioid cell nodules: a case report with the earliest presentation of a uterine perivascular epithelioid cell tumor. AB - Perivascular epithelioid cell (PEC) tumors (PEComas) are a family of related mesenchymal tumors composed of PECs which co-express melanocytic and smooth muscle markers. Although their distinctive histologic, immunohistochemical, ultrastructural, and genetic features have been clearly demonstrated, their histogenesis and normal counterpart remain largely unknown. Precursor lesions of PEComas have rarely been reported. We herein describe a tuberous sclerosis patient with microscopic PEC nodules in the endometrium of adenomyosis, pelvic endometriosis, an ovarian endometriotic cyst, and the endometrium of the uterine cavity. The nodules showed a mixture of spindle-shaped and epithelioid cells concentrically arranged around small arteries. The cells exhibited uniform nuclei, light eosinophilic cytoplasm, and immunoreactivity with HMB-45 and CD10. Some nodules revealed continuity with a PEComa in the myometrium. These findings support microscopic endometrial PEC nodules possibly being precursor lesions of uterine PEComas. The wide distribution of the nodules in the pelvis may be related to the multicentricity of PEComas in tuberous sclerosis patients. Owing to the immunoreactivity with CD10, microscopic endometrial PEC nodules may be misinterpreted as endothelial stromal cells unless melanocytic markers are stained. To the best of our knowledge, this is a case with the earliest manifestation of PEC lesions occurring in the endometrium. Virtual slides: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/9658280017862643. PMID- 22937791 TI - Are there gender-specific risk factors for suicidal activity among patients with schizophrenia and depression? AB - Are there gender-specific risk factors for suicidal activity among patients with schizophrenia and depression? A total of 74 schizophrenia patients (51 men, 23 women) and 77 unipolar nonpsychotic depressed patients (26 men, 51 women) from the Chicago Follow-up Study were studied prospectively at 2 years posthospitalization and again at 7.5 years. Poor early posthospital global functioning is significantly associated with later suicidal activity only for men in both our schizophrenia and depressive samples. Early display of psychotic symptoms is associated with later suicidal activity among male schizophrenia patients. Early cognitive impairment is not significantly associated with later suicidal activity for any of the four groups of patients. The study results must be seen as exploratory and will hopefully spur future research on this important topic. PMID- 22937792 TI - Ad libitum fluid intake leads to no leg swelling in male Ironman triathletes - an observational field study. AB - BACKGROUND: An association between fluid intake and limb swelling has been described for 100-km ultra-marathoners. We investigated a potential development of peripheral oedemata in Ironman triathletes competing over 3.8 km swimming, 180 km cycling and 42.2 km running. METHODS: In 15 male Ironman triathletes, fluid intake, changes in body mass, fat mass, skeletal muscle mass, limb volumes and skinfold thickness were measured. Changes in renal function, parameters of skeletal muscle damage, hematologic parameters and osmolality in both serum and urine were determined. Skinfold thicknesses at hands and feet were measured using LIPOMETER(r) and changes of limb volumes were measured using plethysmography. RESULTS: The athletes consumed a total of 8.6 +/- 4.4 L of fluids, equal to 0.79 +/- 0.43 L/h. Body mass, skeletal muscle mass and the volume of the lower leg decreased (p <0.05), fat mass, skinfold thicknesses and the volume of the arm remained unchanged (p >0.05). The decrease in skeletal muscle mass was associated with the decrease in body mass (p <0.05). The decrease in the lower leg volume was unrelated to fluid intake (p >0.05). Haemoglobin, haematocrit and serum sodium remained unchanged (p >0.05). Osmolality in serum and urine increased (p <0.05). The change in body mass was related to post-race serum sodium concentration ([Na+]) (r = -0.52, p <0.05) and post-race serum osmolality (r = 0.60, p <0.05). CONCLUSIONS: In these Ironman triathletes, ad libitum fluid intake maintained plasma [Na+] and plasma osmolality and led to no peripheral oedemata. The volume of the lower leg decreased and the decrease was unrelated to fluid intake. Future studies may investigate ultra-triathletes competing in a Triple Iron triathlon over 11.4 km swimming, 540 km cycling and 126.6 km running to find an association between fluid intake and the development of peripheral oedemata. PMID- 22937794 TI - Brentuximab vedotin in Hodgkin's lymphoma. AB - INTRODUCTION: Monoclonal antibodies (mAbs) directed against antigens expressed by tumor cells have become an effective therapeutic option in hematologic malignancies. Antibody-drug conjugates (ADC) utilize the targeting properties of mAbs to deliver cytotoxic agents inside the malignant cell. Brentuximab vedotin is a CD30-specific ADC with significant clinical activity in Hodgkin's lymphoma (HL). AREAS COVERED: CD30 is an ideal target for therapy due to its limited expression on normal tissues and the strong and uniform expression on malignant cells in classical Hodgkin's lymphoma (cHL). Early studies using unconjugated CD30 mAbs have demonstrated lack of objective responses in patients with recurrent cHL. Brentuximab vedotin is an ADC with significant clinical activity in patients with HL. Here, the authors review the biology of brentuximab vedotin, summarize available clinical data and discuss future treatment strategies. EXPERT OPINION: Brentuximab vedotin is a well-tolerated and highly active drug in patients with relapsed cHL. This novel agent has the potential to be incorporated in the standard management of the disease with significant therapeutic impact. PMID- 22937793 TI - Comparative genomics of the white-rot fungi, Phanerochaete carnosa and P. chrysosporium, to elucidate the genetic basis of the distinct wood types they colonize. AB - BACKGROUND: Softwood is the predominant form of land plant biomass in the Northern hemisphere, and is among the most recalcitrant biomass resources to bioprocess technologies. The white rot fungus, Phanerochaete carnosa, has been isolated almost exclusively from softwoods, while most other known white-rot species, including Phanerochaete chrysosporium, were mainly isolated from hardwoods. Accordingly, it is anticipated that P. carnosa encodes a distinct set of enzymes and proteins that promote softwood decomposition. To elucidate the genetic basis of softwood bioconversion by a white-rot fungus, the present study reports the P. carnosa genome sequence and its comparative analysis with the previously reported P. chrysosporium genome. RESULTS: P. carnosa encodes a complete set of lignocellulose-active enzymes. Comparative genomic analysis revealed that P. carnosa is enriched with genes encoding manganese peroxidase, and that the most divergent glycoside hydrolase families were predicted to encode hemicellulases and glycoprotein degrading enzymes. Most remarkably, P. carnosa possesses one of the largest P450 contingents (266 P450s) among the sequenced and annotated wood-rotting basidiomycetes, nearly double that of P. chrysosporium. Along with metabolic pathway modeling, comparative growth studies on model compounds and chemical analyses of decomposed wood components showed greater tolerance of P. carnosa to various substrates including coniferous heartwood. CONCLUSIONS: The P. carnosa genome is enriched with genes that encode P450 monooxygenases that can participate in extractives degradation, and manganese peroxidases involved in lignin degradation. The significant expansion of P450s in P. carnosa, along with differences in carbohydrate- and lignin-degrading enzymes, could be correlated to the utilization of heartwood and sapwood preparations from both coniferous and hardwood species. PMID- 22937796 TI - Risk factors and clinical presentation of craniocervical arterial dissection: a prospective study. AB - BACKGROUND: Craniocervical arterial dissection is a major cause of ischaemic stroke in young adults. The pathogenesis is not fully understood but is thought to be related to a combination of an intrinsic weakness in the arterial wall and an external trigger. Intrinsic susceptibility is thought to be a generalised arteriopathy, vascular anomaly or genetic predisposition. Proposed extrinsic factors include recent viral infection and minor mechanical trauma to the neck, including neck manipulation, which has raised concerns amongst manual practitioners in particular as to the appropriate screening of patients and avoidance of more vigorous therapeutic techniques. The presenting features of dissection may mimic a musculoskeletal presentation, creating a diagnostic dilemma for primary care practitioners. Early recognition is critical so that appropriate management can be commenced.The aims of this study are to prospectively investigate young patients <=55 years admitted to hospital with radiologically diagnosed craniocervical arterial dissection compared to matched controls with stroke but not dissection, to identify risk factors and early presenting clinical features, so these may be more readily identified by primary care practitioners. METHODS: Patients <= 55 years presenting to hospital with craniocervical arterial dissection and controls will have their medical records reviewed and be interviewed and questioned about possible risk factors, preceding events to admission such as recent neck trauma, and presenting clinical features including any preceding transient ischaemic features. Clinical assessment will include a connective tissue screening examination to identify subclinical connective tissue disorders. Radiology and blood screening will be reviewed for typical features and inflammatory markers. Functional outcome will be reviewed to determine the burden of the stroke. DISCUSSION: This study will provide descriptive and comparative data on intrinsic and extrinsic risk factors for craniocervical arterial dissection and outline the typical clinical presentation, including the nature of early presenting features which might assist practitioners to identify those patients for whom vigorous manual therapy of the neck is inappropriate and alert them to those for whom immediate urgent medical care should be sought. PMID- 22937795 TI - Non-invasive prenatal diagnostic test accuracy for fetal sex using cell-free DNA a review and meta-analysis. AB - BACKGROUND: Cell-free fetal DNA (cffDNA) can be detected in maternal blood during pregnancy, opening the possibility of early non-invasive prenatal diagnosis for a variety of genetic conditions. Since 1997, many studies have examined the accuracy of prenatal fetal sex determination using cffDNA, particularly for pregnancies at risk of an X-linked condition. Here we report a review and meta analysis of the published literature to evaluate the use of cffDNA for prenatal determination (diagnosis) of fetal sex. We applied a sensitive search of multiple bibliographic databases including PubMed (MEDLINE), EMBASE, the Cochrane library and Web of Science. RESULTS: Ninety studies, incorporating 9,965 pregnancies and 10,587 fetal sex results met our inclusion criteria. Overall mean sensitivity was 96.6% (95% credible interval 95.2% to 97.7%) and mean specificity was 98.9% (95% CI = 98.1% to 99.4%). These results vary very little with trimester or week of testing, indicating that the performance of the test is reliably high. CONCLUSIONS: Based on this review and meta-analysis we conclude that fetal sex can be determined with a high level of accuracy by analyzing cffDNA. Using cffDNA in prenatal diagnosis to replace or complement existing invasive methods can remove or reduce the risk of miscarriage. Future work should concentrate on the economic and ethical considerations of implementing an early non-invasive test for fetal sex. PMID- 22937797 TI - Recurrent orbital schwannomas: clinical course and histopathologic correlation. AB - BACKGROUND: Schwannomas are slow-growing typically encapsulated tumors composed of differentiated Schwann cells, the primary class of peripheral glial cells. Complete excision is the treatment of choice for orbital schwannomas that cause pain, disfigurement, diplopia, or optic neuropathy. The presence of multiple schwannomas in a single patient suggests possible association with neurofibromatosis type 2 (NF2) or schwannomatosis. CASE PRESENTATION: We present 2 patients who experienced recurrent orbital schwannoma without evidence for neurofibromatosis. The recurrence in one patient, a 59-year old man, occurred 6 years after complete excision of the initial tumor. This recurrence consisted of 2 independent tumors in the same orbit. The recurrence in the second patient, a 5 year-old girl, occurred multiple times within days to weeks of partial excisions until eventually a complete excision was performed. CONCLUSION: The clinical history, histopathologic features and particularly the intraoperative findings suggest that the 59 year old man suffers from orbital schwannomatosis, while the rapid recurrence in the second patient correlated with the cellular features of her plexiform schwannoma. Hence, the recurrence in each patient is linked to a different etiology, with implications for treatment and patient counseling given the difficulty in treating orbital schwannomatosis. To our knowledge, this is the first description of isolated orbital schwannomatosis. PMID- 22937799 TI - Detection of transcribed seal impressions using 3-D pressure traces. AB - Seals have been frequently used to certify that individuals or organizations have authorized or approved a document that bears these impressions. Much attention has been focused on the detection of forged seal impressions to expose and prevent seal-related frauds. This paper describes an image-processing technique that detects seal impressions transferred from a genuine document to a target document using transcription media. The proposed method utilizes a three dimensional (3-D) scanner to generate a pressure trace map of the suspect seal impression. After utilizing a noise-reduction algorithm to improve image quality, the pressure map is aligned with a 2-D image of the same seal impression. The pressure ratio, determined by comparing the pressure map and inked impression of a suspect seal, can be used to determine whether the seal is genuine or was transferred to the target document. The results show that the proposed technique successfully identified transcribed seal impressions with an error rate of <1%. PMID- 22937798 TI - Neuroprotection after stroke by targeting NOX4 as a source of oxidative stress. AB - SIGNIFICANCE: Stroke, a leading cause of death and disability, poses a substantial burden for patients, relatives, and our healthcare systems. Only one drug is approved for treating stroke, and more than 30 contraindications exclude its use in 90% of all patients. Thus, new treatments are urgently needed. In this review, we discuss oxidative stress as a pathomechanism of poststroke neurodegeneration and the inhibition of its source, type 4 nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX4), as a conceptual breakthrough in stroke therapy. RECENT ADVANCES: Among potential sources of reactive oxygen species (ROS), the NOXes stand out as the only enzyme family that is solely dedicated to forming ROS. In rodents, three cerebrovascular NOXes exist: the superoxide-forming NOX1 and 2 and the hydrogen peroxide-forming NOX4. Studies using NOX1 knockout mice gave conflicting results, which overall do not point to a role for this isoform. Several reports find NOX2 to be relevant in stroke, albeit to variable and moderate degrees. In our hands, NOX4 is, by far, the major source of oxidative stress and neurodegeneration on ischemic stroke. CRITICAL ISSUES: We critically discuss the tools that have been used to validate the roles of NOX in stroke. We also highlight the relevance of different animal models and the need for advanced quality control in preclinical stroke research. FUTURE DIRECTIONS: The development of isoform-specific NOX inhibitors presents a precious tool for further clarifying the role and drugability of NOX homologues. This could pave the avenue for the first clinically effective neuroprotectant applied poststroke, and even beyond this, stroke could provide a proof of principle for antioxidative stress therapy. PMID- 22937801 TI - Assignment of metal-ligand modes in Pt(II) diimine complexes relevant to solar energy conversion. AB - This work describes a comprehensive assignment of the vibrational spectra of the platinum(II) diimine bisthiolate and chloride complexes as a prototype structure for a diversity of Pt(II) diimine chromophores. The dynamics and energy dissipation pathways in excited states of light harvesting molecules relies largely on the coupling between the high frequency and the low frequency modes. As such, the assignment of the vibrational spectrum of the chromophore is of utmost importance, especially in the low-frequency region, below 500 cm(-1), where the key metal-ligand framework modes occur. This region is experimentally difficult to access with infrared spectroscopy and hence frequently remains elusive. However, this region is easily accessible with Raman and inelastic neutron scattering (INS) spectroscopies. Accordingly, a combination of inelastic neutron scattering and Raman spectroscopy with the aid of computational results from periodic-DFT and the mode visualizations, as well as isotopic substitution, allowed for an identification of the modes that contain significant contributions from Pt-Cl, Pt-S, and Pt-N stretch modes. The results also demonstrate that it is not possible to assign transition energies to "pure", localized modes in the low frequency region, as a consequence of the anticipated severe coupling that occurs among the skeletal modes. The use of INS has proved invaluable in identifying and assigning the modes in the lowest frequency region, and overall the results will be of assistance in analyzing the structure of the electronic excited state in the families of chromophores containing a Pt(diimine) core. PMID- 22937803 TI - Applied hydroformylation. PMID- 22937802 TI - Microcosmic mechanisms for protein incomplete release and stability of various amphiphilic mPEG-PLA microspheres. AB - The microcosmic mechanisms of protein (recombinant human growth hormone, rhGH) incomplete release and stability from amphiphilic poly(monomethoxypolyethylene glycol-co-D,L-lactide) (mPEG-PLA, PELA) microspheres were investigated. PELA with different hydrophilicities (PELA-1, PELA-2, and PELA-3) based on various ratios of mPEG to PLA were employed to prepare microspheres exhibiting a narrow size distribution using a combined double emulsion and premix membrane emulsification method. The morphology, rhGH encapsulation efficiency, in vitro release profile, and rhGH stability of PELA microspheres during the release were characterized and compared in detail. It was found that increasing amounts of PLA enhanced the encapsulation efficiency of PELA microspheres but reduced both the release rate of rhGH and its stability. Contact angle, atomic force microscope (AFM), and quartz crystal microbalance with dissipation (QCM-D) techniques were first combined to elucidate the microcosmic mechanism of incomplete release by measuring the hydrophilicity of the PELA film and its interaction with rhGH. In addition, the pH change within the microsphere microenvironment was monitored by confocal laser scanning microscopy (CLSM) employing a pH-sensitive dye, which clarified the stability of rhGH during the release. These results suggested that PELA hydrophilicity played an important role in rhGH incomplete release and stability. Thus, the selection of suitable hydrophilic polymers with adequate PEG lengths is critical in the preparation of optimum protein drug sustained release systems. This present work is a first report elucidating the microcosmic mechanisms responsible for rhGH stability and its interaction with the microspheres. Importantly, this research demonstrated the application of promising new experimental methods in investigating the interaction between biomaterials and biomacromolecules, thus opening up a range of exciting potential applications in the biomedical field including drug delivery and tissue regeneration. PMID- 22937800 TI - A computational framework for boosting confidence in high-throughput protein protein interaction datasets. AB - Improving the quality and coverage of the protein interactome is of tantamount importance for biomedical research, particularly given the various sources of uncertainty in high-throughput techniques. We introduce a structure-based framework, Coev2Net, for computing a single confidence score that addresses both false-positive and false-negative rates. Coev2Net is easily applied to thousands of binary protein interactions and has superior predictive performance over existing methods. We experimentally validate selected high-confidence predictions in the human MAPK network and show that predicted interfaces are enriched for cancer -related or damaging SNPs. Coev2Net can be downloaded at http://struct2net.csail.mit.edu. PMID- 22937804 TI - Stable bifurcations in semelparous Leslie models. AB - In this paper, we consider nonlinear Leslie models for the dynamics of semelparous age-structured populations. We establish stability and instability criteria for positive equilibria that bifurcate from the extinction equilibrium at R (0)=1. When the bifurcation is to the right (forward or super-critical), the criteria consist of inequalities involving the (low-density) between-class and within-class competition intensities. Roughly speaking, stability (respectively, instability) occurs if between-class competition is weaker (respectively, stronger) than within-class competition. When the bifurcation is to the left (backward or sub-critical), the bifurcating equilibria are unstable. We also give criteria that determine whether the boundary of the positive cone is an attractor or a repeller. These general criteria contribute to the study of dynamic dichotomies, known to occur in lower dimensional semelparous Leslie models, between equilibration and age-cohort-synchronized oscillations. PMID- 22937805 TI - Predicting the geographic distribution of a species from presence-only data subject to detection errors. AB - Several models have been developed to predict the geographic distribution of a species by combining measurements of covariates of occurrence at locations where the species is known to be present with measurements of the same covariates at other locations where species occurrence status (presence or absence) is unknown. In the absence of species detection errors, spatial point-process models and binary-regression models for case-augmented surveys provide consistent estimators of a species' geographic distribution without prior knowledge of species prevalence. In addition, these regression models can be modified to produce estimators of species abundance that are asymptotically equivalent to those of the spatial point-process models. However, if species presence locations are subject to detection errors, neither class of models provides a consistent estimator of covariate effects unless the covariates of species abundance are distinct and independently distributed from the covariates of species detection probability. These analytical results are illustrated using simulation studies of data sets that contain a wide range of presence-only sample sizes. Analyses of presence-only data of three avian species observed in a survey of landbirds in western Montana and northern Idaho are compared with site-occupancy analyses of detections and nondetections of these species. PMID- 22937806 TI - German S2k guidelines for the therapy of pathological scars (hypertrophic scars and keloids). PMID- 22937807 TI - Palladium-catalyzed C(sp2)-H cyanation using tertiary amine derived isocyanide as a cyano source. AB - An unprecedented palladium-catalyzed cyanation of aromatic C-H bonds by using tertiary amine derived isocyanide as a novel cyano source was developed. Cu(TFA)(2) was used as a requisite stoichiometric oxidant. Mechanistic studies suggest that a tertiary carbon cation-based intermediate is involved following the C-N bond breakage. PMID- 22937808 TI - How critical are the van der Waals interactions in polymer crystals? AB - van der Waals (vdW) interactions play a prominent role in polymer crystallization. However, density functional theory (DFT) computations that utilize conventional (semi)local exchange-correlation functionals are unable to account for vdW interactions adequately and hence lead to poor predictions of equilibrium structures, densities, cohesive energies, and bulk moduli of polymeric crystals. This study therefore applies two forms of dispersion corrections to DFT, using either the Grimme (DFT-D3/D2) or the Tkatchenko and Scheffler (DFT-TS) approaches. We critically evaluate the relative performance of these two approaches in predicting structural, energetic, and elastic properties for a wide range of polymer crystals and also compare it with conventional electron exchange-correlation functionals (LDA, PBE, and PW91). Our results show that although the conventional functionals either systematically underestimate (e.g., LDA) or overestimate (e.g., PBE and PW91) the lattice parameters that control the polymer interchain interactions in a crystal, the dispersion corrected functionals consistently provide a better prediction of the structural parameters. In a relative sense, however, the D3 and TS schemes are superior to the D2 approach owing to the environment-dependent atomic dispersion coefficients implicit in the D3 and TS treatments (we do note though that the D2 scheme already constitutes a significant improvement over the (semi)local functionals). Our results not only elucidate the importance of dispersion corrections in the accurate determination of the structural properties of the prototypical polymers considered but also provide a benchmark for comparing other procedures that might be used for including vdW interactions in such systems. PMID- 22937809 TI - Prognostic value of human papillomavirus and squamous cell carcinoma antigen in head and neck squamous cell carcinoma. AB - To clarify the synergistic influence of human papillomavirus (HPV) status and squamous cell carcinoma antigen (SCCA) mRNA expression on head and neck squamous cell carcinoma (HNSCC) prognosis, HPV DNA presence and SCCA1 and SCCA2 mRNA expression were determined by PCR and quantitative real-time RT-PCR, respectively, in 121 patients with primary HNSCC who were receiving curative treatment. HPV DNA was detected in 28.1% (34/121) of HNSCC cases, and only high risk types (HPV-16, HPV-33, HPV-35 and HPV-58) were observed. Positive HPV status showed a significantly better prognosis than negative HPV status (P = 0.022). An elevated SCCA2/SCCA1 mRNA ratio was an independent predictor of disease recurrence (P = 0.004). In addition, HPV-negative patients with a high SCCA2/SCCA1 ratio (>0.27) had a significantly lower recurrence-free survival rate than HPV-negative patients with a low SCCA2/SCCA1 ratio (P < 0.011). Our findings revealed that both HPV status and the SCCA2/SCCA1 mRNA ratio are independently associated with prognosis in HNSCC. Patients with both a HPV-negative status and a high SCCA2/SCCA1 ratio might need intensified treatment and rigorous follow up after treatment because of the high risk of recurrence. PMID- 22937810 TI - Network-based assessment of the selectivity of metabolic drug targets in Plasmodium falciparum with respect to human liver metabolism. AB - BACKGROUND: The search for new drug targets for antibiotics against Plasmodium falciparum, a major cause of human deaths, is a pressing scientific issue, as multiple resistance strains spread rapidly. Metabolic network-based analyses may help to identify those parasite's essential enzymes whose homologous counterparts in the human host cells are either absent, non-essential or relatively less essential. RESULTS: Using the well-curated metabolic networks PlasmoNet of the parasite Plasmodium falciparum and HepatoNet1 of the human hepatocyte, the selectivity of 48 experimental antimalarial drug targets was analyzed. Applying in silico gene deletions, 24 of these drug targets were found to be perfectly selective, in that they were essential for the parasite but non-essential for the human cell. The selectivity of a subset of enzymes, that were essential in both models, was evaluated with the reduced fitness concept. It was, then, possible to quantify the reduction in functional fitness of the two networks under the progressive inhibition of the same enzymatic activity. Overall, this in silico analysis provided a selectivity ranking that was in line with numerous in vivo and in vitro observations. CONCLUSIONS: Genome-scale models can be useful to depict and quantify the effects of enzymatic inhibitions on the impaired production of biomass components. From the perspective of a host-pathogen metabolic interaction, an estimation of the drug targets-induced consequences can be beneficial for the development of a selective anti-parasitic drug. PMID- 22937811 TI - Twins with neonatal pemphigus vulgaris born to a mother with pemphigus vulgaris: a case report. AB - Dichorionic diamniotic twins were born at 37 weeks of gestation by cesarean section to a 34-year-old primigravid Japanese woman because the first twin was in breech presentation. The mother had been diagnosed with pemphigus vulgaris prior to her pregnancy. In addition to a high antidesmoglein 3 autoantibody titer, flaccid bullae and erosions on both of the twins' lips and in their oral cavities at 13 days of age led to the diagnosis of neonatal pemphigus vulgaris. This case highlights the need for awareness that pemphigus vulgaris may not occur immediately after birth. PMID- 22937812 TI - Adolescent lipoprotein classifications according to National Health and Nutrition Examination Survey (NHANES) vs. National Cholesterol Education Program (NCEP) for predicting abnormal lipid levels in adulthood in a Middle East population. AB - BACKGROUND: To compare the predictive ability of adolescent lipoprotein classification using the National Examination Survey (NHANES) cut points and those of the National Cholesterol Education Program (NCEP) for predicting abnormal levels in adulthood. METHOD: From 1032 adolescents, aged 14-19 years, participants of the Tehran Lipid and Glucose Study, all lipid measures were determined at baseline and again after 6 years. Multivariable Odds Ratios (ORs) were calculated for borderline and high categories of lipids to predict dyslipidemia in adulthood, considering the normal level as a reference. Area under the receiving characteristics curve (AUC) was used to assess the predictive ability of each adolescent lipid classification. RESULT: Applying the NCEP classification, the prevalences of high total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), triglycerides and low high density lipoprotein cholesterol (HDL-C) in males were 12.1%, 12.9%, 26.1% and 34.2% respectively; in females the corresponding prevalences were 15.4%, 17.9%, 21.4% and 25.0%, respectively. Using NHANES cut points, the prevalence of high TC, LDL-C and triglycerides were lower, than those defined by NCEP; the ORs of high categories of lipids (defined by NHANES) were higher than ORs based on the NECP classification, except for HDL-C. For all lipid measures, both classifications had similar predictive abilities, except for TC/HDL-C, which had higher predictive power applying the NHANES classification rather than the NCEP one (AUC 71% vs. 68%, respectively). CONCLUSION: No differences were found between NCEP and NHANES classifications for prediction of adult dyslipidemia, except for TC/HDL-C. Because of their simple application, NCEP cut points can be used in clinical settings. PMID- 22937813 TI - Citation classics in suicide and life threatening behavior: a research note. AB - The number of citations a scholarly work receives is a common measure of its impact on the scientific literature; "citation classics" are the most highly cited works. The content of Suicide and Life-Threatening Behavior (SLTB) citation classics is described here. The impact of SLTB citation classics is compared to their counterparts in journals having published the most suicide papers. All data are from the ISI electronic venue on the Web of Science and refer to the number of citations the top 1% of works received in each of ten journals from 1975 through August 10, 2011. Among all ten journals, SLTB ranked first in the number of works on suicide. The principle theme of half of SLTB suicide classics was literature review. The median number of citations for SLTB citation classics (top 1%) was 121.5, with a range between 96 and 279 citations, but classics from generalized psychiatric journals received more citations as anticipated. Journal impact factors explained 73% of the variance in classic's citation counts across journals. On average, suicide classics received 30% more citations than all classics. Among a second group of five specialized suicide journals, however, SLTB ranked first in average 5-year impact. Although SLTB produced the highest number of suicide articles of any journal, SLTB's citation classics received fewer citations than suicide classics in high-impact/prestige, general journals. Future work is needed to assess what predicts which SLTB articles ultimately become citation classics. PMID- 22937814 TI - Eye movements during visual search in patients with glaucoma. AB - BACKGROUND: Glaucoma has been shown to lead to disability in many daily tasks including visual search. This study aims to determine whether the saccadic eye movements of people with glaucoma differ from those of people with normal vision, and to investigate the association between eye movements and impaired visual search. METHODS: Forty patients (mean age: 67 [SD: 9] years) with a range of glaucomatous visual field (VF) defects in both eyes (mean best eye mean deviation [MD]: -5.9 (SD: 5.4) dB) and 40 age-related people with normal vision (mean age: 66 [SD: 10] years) were timed as they searched for a series of target objects in computer displayed photographs of real world scenes. Eye movements were simultaneously recorded using an eye tracker. Average number of saccades per second, average saccade amplitude and average search duration across trials were recorded. These response variables were compared with measurements of VF and contrast sensitivity. RESULTS: The average rate of saccades made by the patient group was significantly smaller than the number made by controls during the visual search task (P = 0.02; mean reduction of 5.6% (95% CI: 0.1 to 10.4%). There was no difference in average saccade amplitude between the patients and the controls (P = 0.09). Average number of saccades was weakly correlated with aspects of visual function, with patients with worse contrast sensitivity (PR logCS; Spearman's rho: 0.42; P = 0.006) and more severe VF defects (best eye MD; Spearman's rho: 0.34; P = 0.037) tending to make less eye movements during the task. Average detection time in the search task was associated with the average rate of saccades in the patient group (Spearman's rho = -0.65; P < 0.001) but this was not apparent in the controls. CONCLUSIONS: The average rate of saccades made during visual search by this group of patients was fewer than those made by people with normal vision of a similar average age. There was wide variability in saccade rate in the patients but there was an association between an increase in this measure and better performance in the search task. Assessment of eye movements in individuals with glaucoma might provide insight into the functional deficits of the disease. PMID- 22937815 TI - Activation of retinal microglial cells is not associated with Muller cell reactivity in vitrectomized rabbit eyes. AB - PURPOSE: Vitrectomy is a frequently performed surgical intervention in ophthalmology to remove vitreous traction and opacities or to treat complicated retinal detachments and diabetic changes. However, there is lack of information about cellular responses in retinal tissue after a surgical intervention such as vitrectomy. Microglia cells, the immune competent cells of neuronal tissue, are involved in nearly all neuropathological changes and are additionally activated by neurosurgical interventions. For most neurodegenerative changes, it is described that microglia activation is generally accompanied by a reactive gliosis of macroglial cells. However, it is not known whether microglial cell activation is necessarily associated with macroglial cell gliosis or whether these processes are regulated separately. Furthermore, there is an ongoing debate about possible detrimental consequences of microglial cell activation for neurons in central neural and retinal tissue. METHODS: Using immunohistochemistry and whole-cell patch clamp experiments in a rabbit model of partial pars plana vitrectomy, we investigated micro- and macroglial cell reactivity after this intervention. RESULTS: Partial vitrectomy induced a massive microglia response characterized by morphological changes, intraretinal migration and proliferation of retinal microglial cells, respectively. Microglial cell reactivity was observed 2 days after the operation and was down-regulated after 7 days. Microglia reactivity was associated with neither a general Muller cell gliosis nor an obvious neuronal cell loss. Electrophysiological examinations revealed no significant changes of whole-cell currents and membrane potentials of Muller cells from healthy and vitrectomized eyes up to 3 weeks after operation. Only a small number of individual Muller glial cells expressed GFAP or reduced their inward currents as a sign of Muller cell gliosis. CONCLUSION: Vitrectomy induced a massive response of microglial cells. However, microglia activation and deactivation are effectively regulated and are not necessarily associated with macroglial (Muller) cell reactivity and with obvious detrimental effects to neurons. PMID- 22937816 TI - Middle cerebral artery Doppler and hemoglobin changes immediately following fetal transfusion. AB - OBJECTIVE: To determine the relationship between the change in middle cerebral artery peak systolic velocity (MCA-PSV) and the change in fetal Hemoglobin (Hb) immediately following intrauterine transfusion (IUT). MATERIALS AND METHODS: Study data included all IUTs performed for suspected fetal anemia from 2007-2011. RESULTS: Sixty-eight IUTs were performed for 23 pregnancies, demonstrating a statistically significant MCA-PSV decrease for up to four IUTs. Significant correlations between changes in Hb levels and MCA-PSV were not detected. CONCLUSION: MCA-PSV values were highly variable in the immediate post-operative period and did not correlate with the Hb change. PMID- 22937817 TI - The evidence of the rugoscopy effectiveness as a human identification method in patients submitted to rapid palatal expansion. AB - The objective of this study was to demonstrate the effectiveness of rugoscopy as a human identification method, even when the patient is submitted to rapid palatal expansion, which in theory would introduce doubt. With this intent, the Rugoscopic Identity was obtained for each subject using the classification formula proposed by Santos based on the intra-oral casts made before and after treatment from patients who were subjected to palatal expansion. The casts were labeled with the patients' initials and randomly arranged for studying. The palatine rugae kept the same patterns in every case studied. The technical error of the intra-evaluator measurement provided a confidence interval of 95%, making rugoscopy a reliable identification method for patients who were submitted to rapid palatal expansion, because even in the presence of intra-oral changes owing to the use of palatal expanders, the palatine rugae retained the biological and technical requirements for the human identification process. PMID- 22937818 TI - H2-induced copper and silver nanoparticle precipitation inside sol-gel silica optical fiber preforms. AB - Ionic copper- or silver-doped dense silica rods have been prepared by sintering sol-gel porous silica xerogels doped with ionic precursors. The precipitation of Cu or Ag nanoparticles was achieved by heat treatment under hydrogen followed by annealing under air atmosphere. The surface plasmon resonance bands of copper and silver nanoparticles have been clearly observed in the absorption spectra. The spectral positions of these bands were found to depend slightly on the particle size, which could be tuned by varying the annealing conditions. Hence, transmission electron microscopy showed the formation of spherical copper nanoparticles with diameters in the range of 3.3 to 5.6 nm. On the other hand, in the case of silver, both spherical nanoparticles with diameters in the range of 3 to 6 nm and nano-rods were obtained. PMID- 22937819 TI - A review of the United States experience with combined heart-liver transplantation. AB - Since first described by Starzl, combined heart and liver transplantation (CHLT) has been a relatively rare event, although utilization has increased in the past decade. This study was undertaken to review the United States experience with this procedure; UNOS data on CHLT was reviewed. CHLT was compared with liver transplantation alone and heart transplantation alone in terms of acute rejection within 12 months, graft survival, and patient survival. Survival was calculated according to Kaplan-Meier and Cox proportional hazards. Continuous variables were compared using Student's t-test and categorical variables with chi-squared. Between 1987 and 2010, there were 97 reported cases of CHLT in the United States. Amyloidosis was the most common indication for both heart (n = 26, 26.8%) and liver (n = 27, 27.8%) transplantation in this cohort. Liver graft survival in the CHLT cohort at 1, 5, and 10 years was 83.4%, 72.8%, and 71.0%, whereas survival of the cardiac allograft was 83.5%, 73.2%, and 71.5%. This was similar to graft survival in liver alone transplantation (79.4%, 71.0%, 65.1%; P = 0.894) and heart transplantation alone (82.6%, 71.9%, 63.2%; P = 0.341). CHLT is a safe and effective procedure, with graft survival rates similar to isolated heart and isolated liver transplantation. PMID- 22937820 TI - Rapid quantification of plant-powdery mildew interactions by qPCR and conidiospore counts. AB - BACKGROUND: The powdery mildew disease represents a valuable patho-system to study the interaction between plant hosts and obligate biotrophic fungal pathogens. Numerous discoveries have been made on the basis of the quantitative evaluation of plant-powdery mildew interactions, especially in the context of hyper-susceptible and/or resistant plant mutants. However, the presently available methods to score the pathogenic success of powdery mildew fungi are laborious and thus not well suited for medium- to high-throughput analysis. RESULTS: Here we present two new protocols that allow the rapid quantitative assessment of powdery mildew disease development. One procedure depends on quantitative polymerase chain reaction (qPCR)-based evaluation of fungal biomass, while the other relies on the quantification of fungal conidiospores. We validated both techniques using the powdery mildew pathogen Golovinomyces orontii on a set of hyper-susceptible and resistant Arabidopsis thaliana mutants and found that both cover a wide dynamic range of one to two (qPCR) and four to five (quantification of conidia) orders of magnitude, respectively. The two approaches yield reproducible results and are easy to perform without specialized equipment. CONCLUSIONS: The qPCR and spore count assays rapidly and reproducibly quantify powdery mildew pathogenesis. Our methods are performed at later stages of infection and discern mutant phenotypes accurately. The assays therefore complement currently used procedures of powdery mildew quantification and can overcome some of their limitations. In addition, they can easily be adapted to other plant-powdery mildew patho-systems. PMID- 22937821 TI - Seeing mathematics: perceptual experience and brain activity in acquired synesthesia. AB - We studied the patient JP who has exceptional abilities to draw complex geometrical images by hand and a form of acquired synesthesia for mathematical formulas and objects, which he perceives as geometrical figures. JP sees all smooth curvatures as discrete lines, similarly regardless of scale. We carried out two preliminary investigations to establish the perceptual nature of synesthetic experience and to investigate the neural basis of this phenomenon. In a functional magnetic resonance imaging (fMRI) study, image-inducing formulas produced larger fMRI responses than non-image inducing formulas in the left temporal, parietal and frontal lobes. Thus our main finding is that the activation associated with his experience of complex geometrical images emerging from mathematical formulas is restricted to the left hemisphere. PMID- 22937822 TI - ggbio: an R package for extending the grammar of graphics for genomic data. AB - We introduce ggbio, a new methodology to visualize and explore genomics annotations and high-throughput data. The plots provide detailed views of genomic regions, summary views of sequence alignments and splicing patterns, and genome wide overviews with karyogram, circular and grand linear layouts. The methods leverage the statistical functionality available in R, the grammar of graphics and the data handling capabilities of the Bioconductor project. The plots are specified within a modular framework that enables users to construct plots in a systematic way, and are generated directly from Bioconductor data structures. The ggbio R package is available at http://www.bioconductor.org/packages/2.11/bioc/html/ggbio.html. PMID- 22937823 TI - Botrytis cinerea mutants deficient in D-galacturonic acid catabolism have a perturbed virulence on Nicotiana benthamiana and Arabidopsis, but not on tomato. AB - D-Galacturonic acid is the most abundant monosaccharide component of pectic polysaccharides that comprise a significant part of most plant cell walls. Therefore, it is potentially an important nutritional factor for Botrytis cinerea when it grows in and through plant cell walls. The d-galacturonic acid catabolic pathway in B. cinerea consists of three catalytic steps converting d-galacturonic acid to pyruvate and l-glyceraldehyde, involving two nonhomologous galacturonate reductase genes (Bcgar1 and Bcgar2), a galactonate dehydratase gene (Bclgd1) and a 2-keto-3-deoxy-l-galactonate aldolase gene (Bclga1). Knockout mutants in each step of the pathway (DeltaBcgar1/DeltaBcgar2, DeltaBclgd1 and DeltaBclga1) showed reduced virulence on Nicotiana benthamiana and Arabidopsis thaliana leaves, but not on Solanum lycopersicum leaves. The cell walls of N. benthamiana and A. thaliana leaves were shown to have a higher d-galacturonic acid content relative to those of S. lycopersicum. The observation that mutants displayed a reduction in virulence, especially on plants with a high d-galacturonic acid content in the cell walls, suggests that, in these hosts, d-galacturonic acid has an important role as a carbon nutrient for B. cinerea. However, additional in vitro growth assays with the knockout mutants revealed that B. cinerea growth is reduced when d-galacturonic acid catabolic intermediates cannot proceed through the entire pathway, even when fructose is present as the major, alternative carbon source. These data suggest that the reduced virulence of d-galacturonic acid catabolism deficient mutants on N. benthamiana and A. thaliana is not only a result of the inability of the mutants to utilize an abundant carbon source as nutrient, but also a result of the growth inhibition by catabolic intermediates. PMID- 22937824 TI - Responses to pandemic ASO3-adjuvanted A/California/07/09 H1N1 influenza vaccine in human immunodeficiency virus-infected individuals. AB - BACKGROUND: Influenza infection may be more serious in human immunodeficiency virus (HIV)-infected individuals, therefore, vaccination against seasonal and pandemic strains is highly advised. Seasonal influenza vaccines have had no significant negative effects in well controlled HIV infection, but the impact of adjuvanted pandemic A/California/07/2009 H1N1 influenza hemaglutinin (HA) vaccine, which was used for the first time in the Canadian population as an authorized vaccine in autumn 2009, has not been extensively studied. OBJECTIVE: Assess vaccine-related effects on CD4(+) T cell counts and humoral responses to the vaccine in individuals attending the Newfoundland and Labrador Provincial HIV clinic. METHODS: A single dose of ArepanrixTM split vaccine including 3.75 MUg A/California/07/2009 H1N1 HA antigen and ASO3 adjuvant was administered to 81 HIV infected individuals by intramuscular injection. Plasma samples from shortly before, and 1-5 months after vaccination were collected from 80/81 individuals to assess humoral anti-H1N1 HA responses using a sensitive microbead-based array assay. Data on CD4(+) T cell counts, plasma viral load, antiretroviral therapy and patient age were collected from clinical records of 81 individuals. RESULTS: Overall, 36/80 responded to vaccination either by seroconversion to H1N1 HA or with a clear increase in anti-H1N1 HA antibody levels. Approximately 1/3 (28/80) had pre-existing anti-H1N1 HA antibodies and were more likely to respond to vaccination (22/28). Responders had higher baseline CD4(+) T cell counts and responders without pre-existing antibodies against H1N1 HA were younger than either non-responders or responders with pre-existing antibodies. Compared to changes in their CD4(+) T cell counts observed over a similar time period one year later, vaccine recipients displayed a minor, transient fall in CD4(+) T cell numbers, which was greater amongst responders. CONCLUSIONS: We observed low response rates to the 2009 pandemic influenza vaccine among HIV-infected individuals without pre-existing antibodies against H1N1 HA and a minor transient fall in CD4(+) T cell numbers, which was accentuated in responders. A single injection of the ArepanrixTM pandemic A/California/07/2009 H1N1 HA split vaccine may be insufficient to induce protective immunity in HIV-infected individuals without pre-existing anti-H1N1 HA responses. PMID- 22937825 TI - Common statistical mistakes. PMID- 22937828 TI - Toward state-to-state dynamics in ultracold collisions: lessons from high resolution spectroscopy of weakly bound molecular complexes. PMID- 22937829 TI - Inhibition of lymphatic metastasis in neuroblastoma by a novel neutralizing antibody to vascular endothelial growth factor-D. AB - Lymphatic spread is an important clinical determinant in the prognosis of many human cancers. The lymphangiogenic factor vascular endothelial growth factor-D (VEGF-D) is implicated in the promotion of lymphatic metastasis through the development of lymphatic vessels in some human cancers. In this study, we developed an anti-VEGF-D monoclonal antibody, cVE199, and investigated its in vitro properties, in vivo effects against tumors and possible target indications to evaluate its potential as a therapeutic antibody. The cVE199 molecule was revealed to have a specific binding reactivity against human VEGF-D, as well as a specific inhibitory activity against the binding of human VEGF-D to VEGFR-3. In addition, cVE199 was found to inhibit the biological activity of VEGF-D against lymphatic cells in vitro. Because we determined that a neuroblastoma cell line, SK-N-DZ, abundantly expressed VEGF-D, an in vivo efficacy study was performed using a xenograft model of SK-N-DZ. We found that cVE199 significantly decreased lymphatic metastasis of SK-N-DZ as well as lymphangiogenesis in primary lesions. Finally, we investigated VEGF-D expression in human neuroblastoma, finding that the molecule was expressed in 11 of 29 human neuroblastoma specimens (37.9%). In conclusion, we found that a novel anti-VEGF-D monoclonal antibody, cVE199, with specific reactivity against human VEGF-D, prevents lymphatic metastasis of neuroblastoma through the inhibition of lymphangiogenesis in an animal model. In addition, our results show that VEGF-D is expressed in some cases of human neuroblastomas, which suggests that cVE199 is a potential anti-metastasis therapeutic antibody in neuroblastoma treatment. PMID- 22937830 TI - High risk human papillomavirus and Epstein Barr virus in human breast milk. AB - BACKGROUND: Multiple viruses, including human immunodeficiency virus, Epstein Barr virus (EBV) and mouse mammary tumour virus have been identified in human milk. High risk human papillomavirus (HPV) sequences have been identified in breast cancer. The aim of this study is to determine if viral sequences are present in human milk from normal lactating women. FINDINGS: Standard (liquid) and in situ polymerase chain reaction (PCR) techniques were used to identify HPV and EBV in human milk samples from normal lactating Australian women who had no history of breast cancer.High risk human papillomavirus was identified in milk samples of 6 of 40 (15%) from normal lactating women - sequencing on four samples showed three were HPV 16 and one was HPV 18. Epstein Barr virus was identified in fourteen samples (33%). CONCLUSION: The presence of high risk HPV and EBV in human milk suggests the possibility of milk transmission of these viruses. However, given the rarity of viral associated malignancies in young people, it is possible but unlikely, that such transmission is associated with breast or other cancers. PMID- 22937831 TI - Impact of probiotics on the course of indirect hyperbilirubinemia and phototherapy duration in very low birth weight infants. AB - OBJECTIVE: To evaluate the efficacy of orally administered Saccharomyces boulardii (S. boulardii) on the course of hyperbilirubinemia and duration of treatment in very low birth weight (VLBW) infants. METHODS: Infants with a gestational age of <= 32 weeks and birth weight of <= 1500 g were enrolled. The infants in the study group were given S. boulardii with a dose of 250 mg once a day and the infants in the control group were fed without S. boulardii supplementation. The primary outcome measurements were duration of phototherapy and levels of total bilirubin at the end of phototherapy. RESULTS: A total of 179 infants (81 in the study group and 98 in the control group) were enrolled. The duration of phototherapy was shorter in the study group [1.9 +/- 0.86 vs. 2.6 +/- 0.9 days, p = 0.000)]. Feeding intolerance was significantly lower in the study group than in the control group (20.9% vs. 47.9%; p = 0.00). CONCLUSION: S. boulardii supplementation at a dose of 250 mg/day is safe for VLBW infants in the short term and effective in reducing the duration of phototherapy in VLBW infants. We suggest that it provides this effect by improving the feeding intolerance and suppressing the reabsorption of bilirubin into the enterohepatic circulation. PMID- 22937827 TI - Redox and reactive oxygen species regulation of mitochondrial cytochrome C oxidase biogenesis. AB - SIGNIFICANCE: Cytochrome c oxidase (COX), the last enzyme of the mitochondrial respiratory chain, is the major oxygen consumer enzyme in the cell. COX biogenesis involves several redox-regulated steps. The process is highly regulated to prevent the formation of pro-oxidant intermediates. RECENT ADVANCES: Regulation of COX assembly involves several reactive oxygen species and redox regulated steps. These include: (i) Intricate redox-controlled machineries coordinate the expression of COX isoenzymes depending on the environmental oxygen concentration. (ii) COX is a heme A-copper metalloenzyme. COX copper metallation involves the copper chaperone Cox17 and several other recently described cysteine rich proteins, which are oxidatively folded in the mitochondrial intermembrane space. Copper transfer to COX subunits 1 and 2 requires concomitant transfer of redox power. (iii) To avoid the accumulation of reactive assembly intermediates, COX is regulated at the translational level to minimize synthesis of the heme A containing Cox1 subunit when assembly is impaired. CRITICAL ISSUES: An increasing number of regulatory pathways converge to facilitate efficient COX assembly, thus preventing oxidative stress. FUTURE DIRECTIONS: Here we will review on the redox regulated COX biogenesis steps and will discuss their physiological relevance. Forthcoming insights into the precise regulation of mitochondrial COX biogenesis in normal and stress conditions will likely open future perspectives for understanding mitochondrial redox regulation and prevention of oxidative stress. PMID- 22937832 TI - An integer optimization algorithm for robust identification of non-linear gene regulatory networks. AB - BACKGROUND: Reverse engineering gene networks and identifying regulatory interactions are integral to understanding cellular decision making processes. Advancement in high throughput experimental techniques has initiated innovative data driven analysis of gene regulatory networks. However, inherent noise associated with biological systems requires numerous experimental replicates for reliable conclusions. Furthermore, evidence of robust algorithms directly exploiting basic biological traits are few. Such algorithms are expected to be efficient in their performance and robust in their prediction. RESULTS: We have developed a network identification algorithm to accurately infer both the topology and strength of regulatory interactions from time series gene expression data in the presence of significant experimental noise and non-linear behavior. In this novel formulism, we have addressed data variability in biological systems by integrating network identification with the bootstrap resampling technique, hence predicting robust interactions from limited experimental replicates subjected to noise. Furthermore, we have incorporated non-linearity in gene dynamics using the S-system formulation. The basic network identification formulation exploits the trait of sparsity of biological interactions. Towards that, the identification algorithm is formulated as an integer-programming problem by introducing binary variables for each network component. The objective function is targeted to minimize the network connections subjected to the constraint of maximal agreement between the experimental and predicted gene dynamics. The developed algorithm is validated using both in silico and experimental data-sets. These studies show that the algorithm can accurately predict the topology and connection strength of the in silico networks, as quantified by high precision and recall, and small discrepancy between the actual and predicted kinetic parameters. Furthermore, in both the in silico and experimental case studies, the predicted gene expression profiles are in very close agreement with the dynamics of the input data. CONCLUSIONS: Our integer programming algorithm effectively utilizes bootstrapping to identify robust gene regulatory networks from noisy, non-linear time-series gene expression data. With significant noise and non-linearities being inherent to biological systems, the present formulism, with the incorporation of network sparsity, is extremely relevant to gene regulatory networks, and while the formulation has been validated against in silico and E. Coli data, it can be applied to any biological system. PMID- 22937833 TI - Determining the use of prophylactic antibiotics in breast cancer surgeries: a survey of practice. AB - BACKGROUND: Prophylactic antibiotics (PAs) are beneficial to breast cancer patients undergoing surgery because they prevent surgical site infection (SSI), but limited information regarding their use has been published. This study aims to determine the use of PAs prior to breast cancer surgery amongst breast surgeons in Colombia. METHODS: An online survey was distributed amongst the breast surgeon members of the Colombian Association of Mastology, the only breast surgery society of Colombia. The scope of the questions included demographics, clinical practice characteristics, PA prescription characteristics, and the use of PAs in common breast surgical procedures. RESULTS: The survey was distributed amongst eighty-eight breast surgeons of whom forty-seven responded (response rate: 53.4%). Forty surgeons (85.1%) reported using PAs prior to surgery of which >60% used PAs during mastectomy, axillary lymph node dissection, and/or breast reconstruction. Surgeons reported they targeted the use of PAs in cases in which patients had any of the following SSI risk factors: diabetes mellitus, drains in situ, obesity, and neoadjuvant therapy. The distribution of the self-reported PA dosing regimens was as follows: single pre-operative fixed-dose (27.7%), single preoperative dose followed by a second dose if the surgery was prolonged (44.7%), single preoperative dose followed by one or more postoperative doses for >24 hours (10.6%), and single preoperative weight-adjusted dose (2.1%). CONCLUSION: Although this group of breast surgeons is aware of the importance of PAs in breast cancer surgery there is a discrepancy in how they use it, specifically with regards to prescription and timeliness of drug administration. Our findings call for targeted quality-improvement initiatives, such as standardized national guidelines, which can provide sufficient evidence for all stakeholders and therefore facilitate best practice medicine for breast cancer surgery. PMID- 22937834 TI - Infant categorization of path relations during dynamic events. AB - Fundamental to amassing a lexicon of relational terms (i.e., verbs, prepositions) is the ability to abstract and categorize spatial relations such as a figure (e.g., boy) moving along a path (e.g., around the barn). Three studies examine how infants learn to categorize path over changes in manner, or how an action is performed (e.g., running vs. crawling). Experiment 1 (n = 60) finds that 10- to 12-month-old English-learning infants categorize a figure's path. In Experiment 2 (n = 27) categorization is disrupted when the ground object is removed, suggesting the relation between figure and ground defines the path. Experiment 3 (n = 24) shows that language may be a mechanism guiding category formation. These studies suggest that English-learning infants can categorize path, a component lexicalized in the world's languages. PMID- 22937835 TI - The case for intraocular delivery of PPAR agonists in the treatment of diabetic retinopathy. AB - BACKGROUND: Systemic therapeutics targeting the peroxisome proliferator-activated receptors have been found to be beneficial in the treatment of diabetic retinopathy. In this paper, we provide a rationale for the use of these therapeutics as intraocular agents. In addition, we introduce the peroxisome proliferator-activated receptors and describe their functions in response to the drugs. DISCUSSION: Based on the evidence of large-scale clinical studies investigating the systemic administration of fenofibrate, this ligand for peroxisome proliferator-activated receptor-alpha is potentially a good candidate for intraocular delivery. Here, we describe the mechanisms by which it might be acting to improve diabetic retinopathy, its relative safety and we speculate on how it could be developed for intraocular delivery. SUMMARY: In this paper, we provide a rationale for the further investigation of peroxisome proliferator activated receptor-alpha agonists as intraocular agents for the treatment of diabetic retinopathy. PMID- 22937836 TI - Exserohilum infection in an immunocompromised neonate. AB - Invasive fungal infections in children have increased in recent years, coinciding with greater survival of preterm neonates and children with immunodeficiencies, more intense chemotherapy regimens, and greater use of stem cell and solid organ transplantation. We describe a case of an immunosuppressed neonate who developed cutaneous Exserohilum rostratum infection. PMID- 22937837 TI - Electrodeposition of polymer nanodots with controlled density and their reversible functionalization by polyhistidine-tag proteins. AB - We present a simple and rapid procedure for producing polymer-coated substrates that can be easily functionalized by ion-chelating proteins. The procedure consists of depositing 18 nm metal-chelating cyclam-modified polymer nanoparticles (cyclam-nps) onto a conductive substrate (an Indium Tin Oxide (ITO) electrode) from an aqueous dispersion of Cu(2+)-loaded cyclam-nps while being subjected to a direct current (DC) field. The density of deposited nps as measured by AFM is shown to be in direct correlation to the concentration of nps in the dispersion with deposition of the particles taking less than 5 s. Because of the functionalization of the nps with cyclam groups, they can be used as anchoring sites for 6-Histidine (6-His) tagged proteins through complexation with divalent metal ions. In this work 6-His Green Fluorescent Protein (6-His GFP) is used as a model protein. The characterization by fluorescence microscopy clearly shows that the protein affinity was ion dependent and that the 6-His GFP density can be controlled by np density, which is itself easily tunable. AFM observations confirmed the immobilization of 6-His GFP onto cyclam-nps and its subsequent removal by treatment with ethylenediaminetetraacetic acid (EDTA). PMID- 22937838 TI - Comparative study of aromaticity in tetraoxa[8]circulenes. AB - A detailed analysis of the local aromaticity in tetraoxa[8]circulene and its benzo-annelated derivates was performed by means of the energy effect (ef), multicenter delocalization indices (MCI), harmonic oscillator model of aromaticity (HOMA) index, nucleus independent chemical shifts (NICS), and ring current maps. According to the indices employed, the central ring of tetraoxa[8]circulene is antiaromatic, whereas the benzenoid and furanoid rings are aromatic. The calculated current density distribution in tetraoxa[8]circulenes showed that the "annulene within an annulene" model of aromaticity is not applicable for these compounds. It was found that the presence of benzo-annelated rings enhances (respectively diminishes) aromaticity (respectively antiaromaticity) of the five-membered (respectively eight-membered) rings in tetraoxa[8]circulenes. These effects are found to be proportional to the number of benzo-annelated rings. The observed regularities can be rationalized by means of the pairwise energy effect (pef) of cyclic conjugation. PMID- 22937839 TI - Advancing rheumatology in the Asian Pacific region: new challenges, new horizons. Abstracts of the 15th Congress of Asia Pacific League of Associations for Rheumatology. Amman, Jordan. September 10-14, 2012. PMID- 22937840 TI - 4,8-Sphingadienine and 4-hydroxy-8-sphingenine activate ceramide production in the skin. AB - BACKGROUND: Ingestion of glucosylceramide improves transepidermal water loss (TEWL) from the skin, but the underlying mechanism by which a small amount of dietary glucosylceramide can vastly improve skin conditions remains unclear. In a previous report, glucosylceramides were shown to be digested to sphingoids, which were shown to be absorbed through the intestinal epithelium. Based on these observations, we hypothesized that sphingoids are the key molecules facilitating endogenous ceramide production. In this study, we assessed the effect of 4,8 sphingadienine (d18:2) and 4-hydroxy-8-sphingenine (t18:1), derived from konjac glucosylceramide, on stimulating ceramide production. METHODS: Konjac glucosylceramide acidolysis was performed using hydrochloric acid; the resulting d18:2 and t18:1 were fractionated by column chromatography. Real-time quantitative RT-PCR was performed to assess the effect of d18:2 and t18:1 on gene expression in normal human epidermal keratinocytes, while their effect on the nuclear receptor, peroxisome proliferator-activated receptor (PPAR)gamma, was measured using a receptor-cofactor assay system. The effect of d18:2 and t18:1 on stimulating ceramide production was evaluated using HPTLC analysis in a 3 dimensional human skin model. RESULTS: We noted the upregulation of genes related to de novo ceramide synthesis as well as of those encoding the elongases of very long-chain fatty acids by d18:2 and t18:1, but not by glucosylceramide and 4 sphingenine. Both these sphingoids also facilitated the expression of PPARbeta/delta and PPARgamma; moreover, they also demonstrated ligand activity for PPARgamma. These results indicated that d18:2 and t18:1 promote the differentiation of keratinocytes. Analysis of the lipids within the 3-dimensional human skin model indicated that treatment with d18:2 and t18:1 not only upregulated gene expression but also increased ceramide production. CONCLUSIONS: The sphingoids d18:2 and t18:1 activated genes related to de novo ceramide synthesis and increased ceramide production, whereas glucosylceramide and 4 sphingenine could not. These results suggest that the effect of dietary glucosylceramides on the skin is mediated by d18:2 and t18:1. PMID- 22937842 TI - Electronic structure and bandgap of gamma-Al2O3 compound using mBJ exchange potential. AB - gamma-Al2O3 is a porous metal oxide and described as a defective spinel with some cationic vacancies. In this work, we calculate the electronic density of states and band structure for the bulk of this material. The calculations are performed within the density functional theory using the full potential augmented plan waves plus local orbital method, as embodied in the WIEN2k code. We show that the modified Becke-Johnson exchange potential, as a semi-local method, can predict the bandgap in better agreement with the experiment even compared to the accurate but much more expensive green function method. Moreover, our electronic structure analysis indicates that the character of the valence band maximum mainly originates from the p orbital of those oxygen atoms that are close to the vacancy. The charge density results show that the polarization of the oxygen electron cloud is directed toward aluminum cations, which cause Al and O atoms to be tightly connected by a strong dipole bond. PMID- 22937841 TI - Structural and conformational dynamics of self-assembling bioactive beta-sheet peptide nanostructures decorated with multivalent RNA-binding peptides. AB - Understanding the dynamic behavior of nanostructural systems is important during the development of controllable and tailor-made nanomaterials. This is particularly true for nanostructures that are intended for biological applications because biomolecules are usually highly dynamic and responsive to external stimuli. In this Article, we investigated the structural and conformational dynamics of self-assembling bioactive beta-sheet peptide nanostructures using electron paramagnetic resonance (EPR) spectroscopy. The model peptide nanostructures are characterized by the cross-beta spine of beta ribbon fibers and multiple RNA-binding bioactive peptides that constitute the shell of the nanostructures. We found first, that bioactive peptides at the shell of beta-ribbon nanostructure have a mobility similar to that of an isolated monomeric peptide. Second, the periphery of the cross-beta spine is more immobile than the distal part of surface-displayed bioactive peptides. Third, the rotational dynamics of short and long fibrils are similar; that is, the mobility is largely independent of the extent of aggregation. Fourth, peptides that constitute the shell are affected first by the external environment at the initial stage. The cross-beta spine resists its external environment to a certain extent and abruptly disintegrates when the perturbation reaches a certain degree. Our results provide an overall picture of beta-sheet peptide nanostructure dynamics, which should be useful in the development of dynamic self-assembled peptide nanostructures. PMID- 22937843 TI - An update on unilateral sporadic small vestibular schwannoma. AB - Advances in neuroimaging have increased the detection rate of small vestibular schwannomas (VSs, maximum diameter < 25 mm). Current management modalities include observation with serial imaging, stereotactic radiosurgery, and microsurgical resection. Selecting one approach over another invites speculation, and no standard management consensus has been established. Moreover, there is a distinct clinical heterogeneity among patients harboring small VSs, making standardization of management difficult. The aim of this article is to guide treating physicians toward the most plausible therapeutic option based on etiopathogenesis and the highest level of existing evidence specific to the different cohorts of hypothetical case scenarios. Hypothetical cases were created to represent 5 commonly encountered scenarios involving patients with sporadic unilateral small VSs, and the literature was reviewed with a focus on small VS. The authors extrapolated from the data to the hypothetical case scenarios, and based on the level of evidence, they discuss the most suitable patient-specific treatment strategies. They conclude that observation and imaging, stereotactic radiosurgery, and microsurgery are all important components of the management strategy. Each has unique advantages and disadvantages best suited to certain clinical scenarios. The treatment of small VS should always be tailored to the clinical, personal, and social requirements of an individual patient, and a rigid treatment protocol is not practical. PMID- 22937844 TI - Hearing preservation surgery for vestibular schwannoma: experience with the middle fossa approach. AB - OBJECT: In the early 1960s William F. House developed the middle fossa approach for the removal of small vestibular schwannomas (VSs) with the preservation of hearing. It is the best approach for tumors that extend laterally to the fundus of the internal auditory canal, although it does have the potential disadvantage of increased facial nerve manipulation, especially for tumors arising from the inferior vestibular nerve. The aim of this study was to monitor the hearing preservation and facial nerve outcomes of this approach. METHODS: A prospective database was constructed, and data were retrospectively reviewed. RESULTS: Between December 2004 and January 2012, 30 patients with small VSs underwent surgery via a middle fossa approach for hearing preservation. The patients consisted of 13 men and 17 women with a mean age of 46 years. Tumor size ranged from 7 to 19 mm. Gross-total resection was accomplished in 25 of 30 patients. Preoperative hearing was American Academy of Otolaryngology-Head and Neck Surgery (AAO-HNS) Class A in 21 patients, Class B in 5, Class C in 3, and undocumented in 1. Postoperatively, hearing was graded as AAO-HNS Class A in 15 patients, Class B in 7, Class C in 1, Class D in 2, and undocumented in 5. Facial nerve function was House-Brackmann (HB) Grade I in all patients preoperatively. Postoperatively, facial nerve function was HB Grade I in 28 patients, Grade III in 1, and Grade IV in 1. There were 3 complications: CSF leakage in 1 patient, superficial wound infection in 1, and extradural hematoma (asymptomatic) in 1. The overall hearing preservation rate of at least 73% and HB Grade I facial nerve outcome of 93% in this cohort are in keeping with other contemporary reports. CONCLUSIONS: The middle fossa approach for the resection of small VSs with hearing preservation is a viable and relatively safe option. It should be considered among the various options available for the management of small, growing VSs. PMID- 22937845 TI - A stepwise illustration of the translabyrinthine approach to a large cystic vestibular schwannoma. AB - Of the presigmoid approaches, the translabyrinthine approach is often used when a large exposure is needed to gain access to the cerebellopontine angle but when hearing preservation is not a concern. At the authors' institution, this approach is done with the aid of ENT/otolaryngology for temporal bone drilling and exposure. In the present article and video, the authors demonstrate the use of the translabyrinthine approach for resection of a large cystic vestibular schwannoma, delineating the steps of positioning, opening, temporal bone drilling, tumor resection, and closure. Gross-total resection was achieved in the featured case. The patient's postoperative facial function was House-Brackmann Grade II on the side ipsilateral to the tumor, although function improved with time. The translabyrinthine route to the cerebellopontine angle is an excellent approach for masses that extend toward the midline or anterior to the pons. Although hearing is sacrificed, facial nerve function is generally spared. PMID- 22937846 TI - Do cystic vestibular schwannomas have worse surgical outcomes? Systematic analysis of the literature. AB - OBJECT: The goal of this study was to perform a systematic quantitative comparison of the surgical outcomes between cystic vestibular schwannomas (CVSs) and solid vestibular schwannomas (SVSs). METHODS: A review of English-language literature published between 1990 and 2011 was performed using various search engines including PubMed, Google Scholar, and the Cochrane database. Only studies that reported surgical results of CVSs in comparison with SVSs were included in the analysis. The primary end point of this study was surgical outcomes, defined by the following: 1) facial nerve outcomes at latest follow-up; 2) mortality rates; or 3) non-facial nerve complication index. Secondary end points included extent of resection and brainstem adherence. RESULTS: Nine studies comprising 428 CVSs and 1287 SVSs were included in the study. The mean age of patients undergoing surgery was 48.3 +/- 6.75 and 47.1 +/- 9 years for CVSs and SVSs, respectively (p = 0.8). The mean tumor diameter for CVSs was 3.9 +/- 0.84 cm and that for SVSs was 3.7 +/- 1.2 cm (p = 0.7). There was no significant difference in the extent of resection among CVSs and SVSs (81.2% vs 80.7%, p = 0.87) Facial nerve outcomes were significantly better in the cohort of patients with SVSs than in those with CVSs (52.1% vs 39%, p = 0.0001). The perioperative mortality rates for CVSs and SVSs were not significantly different (3% and 3.8%, respectively; p = 0.6). No significant difference was noted between the cumulative non-facial nerve complication rate (including mortality) among patients with CVSs and SVSs (24.5% and 25.6%, respectively; p = 0.75) CONCLUSIONS: Facial nerve outcomes are worse in patients undergoing resection for CVSs than in patients undergoing resection for SVSs. There were no significant differences in the extent of resection or postoperative morbidity and mortality rates between the cohorts of patients with vestibular schwannomas. PMID- 22937847 TI - Extent of resection and early postoperative outcomes following removal of cystic vestibular schwannomas: surgical experience over a decade and review of the literature. AB - OBJECT: Vestibular schwannomas (VSs) are benign tumors of the eighth cranial nerve sheath, representing approximately 6%-8% of all newly diagnosed brain tumors, with an annual incidence of 2000-2500 cases in the US. Although most of these lesions are solid, cystic vestibular schwannomas (CVSs) compose 4%-20% of all VSs and are commonly larger at the time of presentation. The authors present their experience with the operative management of CVSs, including surgical approach, extent of resection, and postoperative facial nerve outcomes. The literature pertaining to clinical and histopathological differences between CVSs and their solid counterparts is reviewed. METHODS: The University of Southern California Department of Neurosurgery database was retrospectively reviewed to identify patients who had undergone resection of a VS between 2000 and 2010. One hundred seventy-nine patients with VS were identified. Patients with CVSs were the subject of the present analysis. Diagnosis of a CVS was made based on MRI findings. Clinical and neuroimaging data, including pre- and postoperative assessments and operative notes, were collected and reviewed. RESULTS: Twenty three patients, 14 men (61%) and 9 women (39%), underwent 24 operations for CVSs. These patients composed 12.8% of all cases of VS. Patient ages ranged from 28 to 78 years (mean 55 years), and the mean maximal tumor diameter was 3.6 cm (range 2.0-4.0 cm). Patients most frequently presented with headache, hearing loss, vertigo, and dizziness. Preoperative facial numbness was reported in 44% of patients. Among the 24 cases, 13 were treated with retrosigmoid craniotomy and 11 via a translabyrinthine approach. Complete resection was achieved in 11 patients (48%), subtotal resection (STR) in 8 patients (35%), and near-total resection (NTR) in 4 patients (17%). Facial nerve outcomes were available in all except one case. Good facial nerve outcomes (House-Brackmann [HB] Grades I-III) were achieved in 82% of the patients who had undergone either NTR or STR, as compared with 73% of patients who had undergone gross-total resection (GTR; p > 0.05, Fisher exact test). In comparison, 83% of patients with solid VSs had a good HB grade (p = 0.38, Fisher exact test), although this finding did not reach statistical significance. Complications included wound infection (2 patients), delayed CSF leakage (1 patient), and a delayed temporal encephalocele following a translabyrinthine approach and requiring surgical repair (1 patient). CONCLUSIONS: Cystic vestibular schwannoma represents a clinical and surgical entity separate from its solid counterpart, as demonstrated by its more rapid clinical course and early surgical outcomes. Facial nerve grades may correlate with the degree of tumor resection, trending toward poorer grades with more significant resections. Although GTR is recommended whenever possible, performing an STR when facial nerve preservation is in jeopardy to improve facial nerve outcomes is the preferred strategy at the authors' institution. PMID- 22937848 TI - Surgery for vestibular schwannomas: a systematic review of complications by approach. AB - OBJECT: Various studies report outcomes of vestibular schwannoma (VS) surgery, but few studies have compared outcomes across the various approaches. The authors conducted a systematic review of the available data on VS surgery, comparing the different approaches and their associated complications. METHODS: MEDLINE searches were conducted to collect studies that reported information on patients undergoing VS surgery. The authors set inclusion criteria for such studies, including the availability of follow-up data for at least 3 months, inclusion of preoperative and postoperative audiometric data, intraoperative monitoring, and reporting of results using established and standardized metrics. Data were collected on hearing loss, facial nerve dysfunction, persistent postoperative headache, CSF leak, operative mortality, residual tumor, tumor recurrence, cranial nerve (CN) dysfunction involving nerves other than CN VII or VIII, and other neurological complications. The authors reviewed data from 35 studies pertaining to 5064 patients who had undergone VS surgery. RESULTS: The analyses for hearing loss and facial nerve dysfunction were stratified into the following tumor categories: intracanalicular (IC), size (extrameatal diameter) < 1.5 cm, size 1.5-3.0 cm, and size > 3.0 cm. The middle cranial fossa approach was found to be superior to the retrosigmoid approach for hearing preservation in patients with tumors < 1.5 cm (hearing loss in 43.6% vs 64.3%, p < 0.001). All other size categories showed no significant difference between middle cranial fossa and retrosigmoid approaches with respect to hearing loss. The retrosigmoid approach was associated with significantly less facial nerve dysfunction in patients with IC tumors than the middle cranial fossa method was; however, neither differed significantly from the translabyrinthine corridor (4%, 16.7%, 0%, respectively, p < 0.001). The middle cranial fossa approach differed significantly from the translabyrinthine approach for patients with tumors < 1.5 cm, whereas neither differed from the retrosigmoid approach (3.3%, 11.5%, and 7.2%, respectively, p = 0.001). The retrosigmoid approach involved less facial nerve dysfunction than the middle cranial fossa or translabyrinthine approaches for tumors 1.5-3.0 cm (6.1%, 17.3%, and 15.8%, respectively; p < 0.001). The retrosigmoid approach was also superior to the translabyrinthine approach for tumors > 3.0 cm (30.2% vs 42.5%, respectively, p < 0.001). Postoperative headache was significantly more likely after the retrosigmoid approach than after the translabyrinthine approach, but neither differed significantly from the middle cranial fossa approach (17.3%, 0%, and 8%, respectively; p < 0.001). The incidence of CSF leak was significantly greater after the retrosigmoid approach than after either the middle cranial fossa or translabyrinthine approaches (10.3%, 5.3%, 7.1%; p = 0.001). The incidences of residual tumor, mortality, major non-CN complications, residual tumor, tumor recurrence, and dysfunction of other cranial nerves were not significantly different across the approaches. CONCLUSIONS: The middle cranial fossa approach seems safest for hearing preservation in patients with smaller tumors. Based on the data, the retrosigmoid approach seems to be the most versatile corridor for facial nerve preservation for most tumor sizes, but it is associated with a higher risk of postoperative pain and CSF fistula. The translabyrinthine approach is associated with complete hearing loss but may be useful for patients with large tumors and poor preoperative hearing. PMID- 22937849 TI - Technical nuances of resection of giant (> 5 cm) vestibular schwannomas: pearls for success. AB - Removal of vestibular schwannomas (VSs, or acoustic neuromas) remains one of the most challenging operations in neurosurgery. Giant or huge tumors (> 5 cm) heighten these challenges, and technical nuances play a special role in maximizing tumor resection while minimizing complications. In this article, the senior author describes his technical experience with microsurgical excision of giant VSs. The accompanying video further illustrates these details. PMID- 22937851 TI - Fascial sling technique for dural reconstruction after translabyrinthine resection of acoustic neuroma: technical note. AB - Reconstruction of presigmoid dural defects after resection of acoustic neuromas via the translabyrinthine approach is paramount to prevent postoperative CSF leakage. However, primary dural reapproximation and achieving a watertight closure of the dural defect in this anatomical region are quite difficult. Standard closure techniques after the translabyrinthine approach often involve packing an abdominal fat graft that plugs the dural defect and mastoidectomy cavity. This technique, however, may pose the risk of direct compression of the fat graft on the facial nerve and brainstem. Nonetheless, even with the evolution in dural repair techniques, postoperative CSF leaks can still occur and provide a route for infection and meningitis. In this report, the authors describe a novel dural "sling" reconstruction technique using autologous fascia lata to repair presigmoid dural defects created after translabyrinthine resection of acoustic neuromas. The fascia lata is sewn to the edges of the presigmoid dural defect to create a sling to suspend the fat graft within the mastoidectomy defect. A titanium mesh plate embedded in porous polyethylene is secured over the mastoidectomy defect to apply pressure to the fat graft. In the authors' experience, this has been a successful technique for dural reconstruction after translabyrinthine removal of acoustic neuromas to prevent postoperative CSF leakage. There were no cases of CSF leakage in the first 8 patients treated using this technique. The operative details and preliminary results of this technique are presented. PMID- 22937850 TI - Facial nerve outcomes after surgery for large vestibular schwannomas: do surgical approach and extent of resection matter? AB - OBJECT: The object of this study was to evaluate facial nerve outcomes in the surgical treatment of large vestibular schwannomas (VSs; >= 2.5 cm maximal or extrameatal cerebellopontine angle diameter) based on both the operative approach and extent of tumor resection. METHODS: A PubMed search was conducted of English language studies on the treatment of large VSs published from 1985 to 2011. Studies were then evaluated and included if they contained data regarding the size of the tumor, surgical approach, extent of resection, and postoperative facial nerve function. RESULTS: Of the 536 studies initially screened, 59 full text articles were assessed for eligibility, and 30 studies were included for analysis. A total of 1688 tumor resections were reported. Surgical approach was reported in 1390 patients and was significantly associated with facial nerve outcome (phi= 0.29, p < 0.0001). Good facial nerve outcomes (House-Brackmann Grade I or II) were produced in 62.5% of the 555 translabyrinthine approaches, 65.2% of the 601 retrosigmoid approaches, and 27.4% of the 234 extended translabyrinthine approaches. Facial nerve outcomes from translabyrinthine and retrosigmoid approaches were not significantly different from each other, but both showed significantly more good facial nerve outcomes, compared with the extended translabyrinthine approach (OR for translabyrinthine vs extended translabyrinthine = 4.43, 95% CI 3.17-6.19, p < 0.0001; OR for retrosigmoid vs extended translabyrinthine = 4.98, 95% CI 3.57-6.95, p < 0.0001). There were 471 patients for whom extent of resection was reported. There was a strong and significant association between degree of resection and outcome (phi= 0.38, p < 0.0001). Of the 80 patients receiving subtotal resections, 92.5% had good facial nerve outcomes, compared with 74.6% (n = 55) and 47.3% (n = 336) of those who received near-total resections and gross-total resections, respectively. In the 2 way comparison of good versus suboptimal/poor outcomes (House-Brackmann Grade III VI), subtotal resection was significantly better than near-total resection (OR = 4.21, 95% CI 1.50-11.79; p = 0.004), and near-total resection was significantly better than gross-total resection (OR = 3.26, 95% CI 1.71-6.20; p = 0.0002) in producing better facial nerve outcomes. CONCLUSIONS: In a pooled patient population from studies evaluating the treatment of large VSs, subtotal and near total resections were shown to produce better facial nerve outcomes when compared with gross-total resections. The translabyrinthine and retrosigmoid surgical approaches are likely to result in similar rates of good facial nerve outcomes. Both of these approaches show better facial nerve outcomes when compared with the extended translabyrinthine approach, which is typically reserved for especially large tumors. The reported literature on treatment of large VSs is extremely heterogeneous and minimal consistency in reporting outcomes was observed. PMID- 22937852 TI - Postoperative imaging of vestibular schwannomas. AB - Symptomatic vestibular schwannomas can be treated with resection (translabyrinthine, retrosigmoid [suboccipital], or middle cranial fossa approaches) or stereotactic radiosurgery. When appropriate, auditory brainstem stimulators can also be implanted in patients with current or impending hearing loss due to bilateral vestibular schwannomas. Imaging plays a prominent role in determining management following these procedures. In this article, the expected postoperative imaging appearances are depicted. The radiological features of complications are also reviewed, including recurrent tumor, fat graft necrosis, CSF leakage, infection, hydrocephalus, cerebral infarction, venous sinus thrombosis, hemorrhage, and temporal lobe and cerebellar contusions. PMID- 22937853 TI - The approach to the patient with incidentally diagnosed vestibular schwannoma. AB - With the increasing prevalence and decreasing cost of MRI scans, incidental discovery of vestibular schwannoma (VS) has become more common. Scarce literature exists regarding management of the tumors in those patients with incidentally discovered VSs, and clear guidelines for management do not exist. In this review, the authors examine the available literature for insights into management of incidentally diagnosed VS and provide an algorithm for their management. PMID- 22937854 TI - The impact of comorbidities, regional trends, and hospital factors on discharge dispositions and hospital costs after acoustic neuroma microsurgery: a United States nationwide inpatient data sample study (2005-2009). AB - OBJECT: Hospitalization cost and patient outcome after acoustic neuroma surgery depend on several factors. There is a paucity of data regarding the relationship between demographic features such as age, sex, race, insurance status, and patient outcome. Apart from demographic factors, there are several hospital related factors and regional issues that can affect outcomes and hospital costs. To the authors' knowledge, no study has investigated the issue of regional disparity across the country in terms of cost of hospitalization and discharge disposition. METHODS: The authors analyzed the Nationwide Inpatient Sample (NIS) database over the years 2005-2009. Several variables were analyzed from the database, including patient demographics, comorbidities, and surgical complications. Hospital variables, such as bedsize, rural/urban location, teaching status, federal or private ownership, and the region, were also examined. Patient outcome and increased hospitalization costs were the dependent variables studied. RESULTS: A total of 2589 admissions from 242 hospitals were analyzed from the NIS data over the years 2005-2009. The mean age was 48.99 +/- 13.861 years (+/- SD), and 304 (11.7%) of the patients were older than 65 years. The cumulative cost incurred by the hospitals from 2005 to 2009 was $948.77 million. The mean expenditure per admission was $76,365.09 +/- $58,039.93. The mean total charges per admission rose from $59,633.00 in 2005 to $97,370.00 in 2009. The factors that predicted most significantly with other than routine (OTR) disposition outcome were age older than 65 years (OR 2.22, 95% CI 1.411-3.518; p < 0.001), aspiration pneumonia (OR 16.085, 95% CI 4.974-52.016; p < 0.001), and meningitis (OR 11.299, 95% CI 3.126-40.840; p < 0.001). When compared with patients with Medicare and Medicaid, patients with private insurance had a protective effect against OTR disposition outcome. Higher comorbidities predicted independently for OTR disposition outcome (OR 1.409, 95% CI 1.072-1.852; p = 0.014). The West region predicted negatively for OTR disposition outcome. Large hospitals were independently associated with higher hospital charges (OR 4.269, 95% CI 3.106-5.867; p < 0.001). The West region had significantly higher (p < 0.001) mean hospital charges than the other regions. Patient factors such as meningitis and aspiration pneumonia were strong independent predictors of increased hospital charges (p < 0.001). Higher comorbidities (OR 1.297, 95% CI 1.036-1.624; p = 0.023) and presence of neurofibromatosis Type 2 (OR 2.341, 95% CI 1.479-3.707; p < 0.001) were associated with higher hospital charges. CONCLUSIONS: The authors' study shows that several factors can affect patient outcome and hospital charges for patients who have undergone acoustic neuroma surgery. Factors such as younger age, higher ZIP code income, less comorbidity, private insurance, elective surgery, and the West region predicted for better disposition outcome. However, the West region, higher comorbidities, and weekend admissions were associated with higher hospitalization costs. PMID- 22937855 TI - Incidental vestibular schwannomas: a review of prevalence, growth rate, and management challenges. AB - With the relatively recent increase in the use of MRI techniques, there has been a concurrent rise in the number of vestibular schwannomas (VSs) detected as incidental findings. These incidental VSs may be prevalent in up to 0.02%-0.07% of individuals undergoing MRI and represent a significant portion of all diagnosed VSs. The management of these lesions poses a significant challenge for practitioners. Most incidental VSs tend to be small and associated with minimal symptoms, permitting them to be managed conservatively at the time of diagnosis. However, relatively few indicators consistently predict tumor growth and patient outcomes. Furthermore, growth rates have been shown to vary significantly over time with a large variety of long-term growth patterns. Thus, early MRI screening for continued tumor growth followed by repeated MRI studies and clinical assessments throughout the patient's life is an essential component in a conservative management strategy. Note that tumor growth is typically associated with a worsening of symptoms in patients who undergo conservative management, and many of these symptoms have been shown to significantly impact the patient's quality of life. Specific indications for the termination of conservative management vary across studies, but secondary intervention has been shown to be a relatively safe option in most patients with progressive disease. Patients with incidental VSs will probably qualify for a course of conservative management at diagnosis, and regular imaging combined with the expectation that the tumor and symptoms may change at any interval is crucial to ensuring positive long-term outcomes in these patients. In this report, the authors discuss the current literature pertaining to the prevalence of incidental VSs and various considerations in the management of these lesions. It is hoped that by incorporating an understanding of tumor growth, patient outcomes, and management strategies, practitioners will be able to effectively address this challenging disease entity. PMID- 22937856 TI - Pitfalls in intraoperative nerve monitoring during vestibular schwannoma surgery. AB - Despite the widespread acceptance of intraoperative neurophysiological monitoring in skull base surgery over the last 2 decades, surgeon training in the technical and interpretive aspects of nerve monitoring has been conspicuously lacking. Inadequate fundamental knowledge of neurophysiological monitoring may lead to misinterpretations and an inability to troubleshoot system errors. Some surgeons perform both the technical and interpretive aspects of monitoring themselves while others enjoin coworkers (surgical residents, nurses, anesthetists, or a separate monitoring service) to perform the technical portion. Regardless, the surgeon must have a thorough understanding to avoid potential medical and legal pitfalls because poor monitoring is worse than no monitoring. A structured curriculum and protocol in both the technical and interpretive aspects of monitoring is recommended for all personnel involved in the monitoring process. This paper details the technical, interpretive, and surgical correlates necessary for optimal intraoperative nerve monitoring during vestibular schwannoma surgery with an emphasis on electromyographic monitoring for facial and recurrent laryngeal nerves. Just as the American Society of Anesthesiologists' 1986 "Standards for Basic Anesthetic Monitoring" became a useful tool for both patients and anesthesiologists, impending guidelines in intraoperative neurophysiological monitoring should likewise become an important instrument for optimizing intraoperative neurophysiological monitoring. PMID- 22937857 TI - Intraoperative neuromonitoring techniques in the surgical management of acoustic neuromas. AB - Unfavorable outcomes such as facial paralysis and deafness were once unfortunate probable complications following resection of acoustic neuromas. However, the implementation of intraoperative neuromonitoring during acoustic neuroma surgery has demonstrated placing more emphasis on quality of life and preserving neurological function. A modern review demonstrates a great degree of recent success in this regard. In facial nerve monitoring, the use of modern electromyography along with improvements in microneurosurgery has significantly improved preservation. Recent studies have evaluated the use of video monitoring as an adjunctive tool to further improve outcomes for patients undergoing surgery. Vestibulocochlear nerve monitoring has also been extensively studied, with the most popular techniques including brainstem auditory evoked potential monitoring, electrocochleography, and direct compound nerve action potential monitoring. Among them, direct recording remains the most promising and preferred monitoring method for functional acoustic preservation. However, when compared with postoperative facial nerve function, the hearing preservation is only maintained at a lower rate. Here, the authors analyze the major intraoperative neuromonitoring techniques available for acoustic neuroma resection. PMID- 22937858 TI - Neuroanatomical correlation of the House-Brackmann grading system in the microsurgical treatment of vestibular schwannoma. AB - Avoidance of facial nerve injury is one of the major goals of vestibular schwannoma (VS) surgery because functional deficits of the facial nerve can lead to physical, cosmetic, and psychological consequences for patients. Clinically, facial nerve function is assessed using the House-Brackmann grading scale, which also allows physicians to track the progress of a patient's facial nerve recovery. Because the facial nerve is a peripheral nerve, it has the ability to regenerate, and the extent of its functional recovery depends largely on the location and nature of its injury. In this report, the authors first describe the facial nerve anatomy, the House-Brackmann grading system, and factors known to be predictors of postoperative facial nerve outcome. The mechanisms and pathophysiology of facial nerve injury during VS surgery are then discussed, as well as factors affecting facial nerve regeneration after surgery. PMID- 22937859 TI - The newly diagnosed vestibular schwannoma: radiosurgery, resection, or observation? AB - OBJECT: Management recommendations for patients with smaller-volume or newly diagnosed vestibular schwannomas (< 4 cm(3)) need to be based on an understanding of the anticipated natural history of the tumor and the side effects it produces. The natural history can then be compared with the risks and benefits of therapeutic intervention using a minimally invasive strategy such as stereotactic radiosurgery (SRS). METHODS: The authors reviewed the emerging literature stemming from recent recommendations to "wait and scan" (observation) and compared this strategy with published outcomes after early intervention using SRS or results from matched cohort studies of resection and SRS. RESULTS: Various retrospective studies indicate that vestibular schwannomas grow at a rate of 0 3.9 mm per year and double in volume between 1.65 and 4.4 years. Stereotactic radiosurgery arrests growth in up to 98% of patients when studied at intervals of 10-15 years. Most patients who select "wait and scan" note gradually decreasing hearing function leading to the loss of useful hearing by 5 years. In contrast, current studies indicate that 3-5 years after Gamma Knife surgery, 61%-80% of patients maintain useful hearing (speech discrimination score > 50%, pure tone average < 50). CONCLUSIONS: Based on published data on both volume and hearing preservation for both strategies, the authors devised a management recommendation for patients with small vestibular schwannomas. When resection is not chosen by the patient, the authors believe that early SRS intervention, in contrast to observation, results in long-term tumor control and improved rates of hearing preservation. PMID- 22937860 TI - Surgical approaches for resection of vestibular schwannomas: translabyrinthine, retrosigmoid, and middle fossa approaches. AB - Surgical removal remains one of the key treatment modalities for vestibular schwannomas. A team approach between a neurotologist and a neurosurgeon offers the patient the expertise of both specialties and maximizes the chances for an optimal outcome. Vestibular schwannomas can typically be resected through 1 of 3 main surgical approaches: the translabyrinthine, the retrosigmoid, or the middle fossa approaches. In this report and videos, the authors describe and illustrate the indications and surgical techniques for the removal of these tumors. PMID- 22937861 TI - Acoustic neuromas. PMID- 22937863 TI - Monotherapy for vitiligo using a 308-nm xenon-chloride excimer laser: colorimetric assessment of factors that influence treatment efficacy. PMID- 22937862 TI - Comparison of bone marrow and adipose tissue-derived canine mesenchymal stem cells. AB - BACKGROUND: Bone marrow-derived mesenchymal stem cells (BM-MSCs) and adipose tissue-derived mesenchymal stem cells (AT-MSCs) are potential cellular sources of therapeutic stem cells. MSCs are a multipotent population of cells capable of differentiating into a number of mesodermal lineages. Treatment using MSCs appears to be a helpful approach for structural restoration in regenerative medicine. Correct identification of these cells is necessary, but there is inadequate information on the MSC profile of cell surface markers and mRNA expression in dogs. In this study, we performed molecular characterization of canine BM-MSCs and AT-MSCs using immunological and mRNA expression analysis. RESULTS: Samples were confirmed to be multipotent based on their osteogenic and adipogenic differentiation. And these cells were checked as stem cell, hematopoietic and embryonic stem cell (ESC) markers by flow cytometry. BM- and AT MSCs showed high expression of CD29 and CD44, moderate expression of CD90, and were negative for CD34, CD45, SSEA-3, SSEA-4, TRA-1-60, and TRA-1-81. SSEA-1 was expressed at very low levels in AT-MSCs. Quantitative real-time PCR (qRT-PCR) revealed expression of Oct3/4, Sox2, and Nanog in BM- and AT-MSCs. There was no significant difference in expression of Oct3/4 and Sox2 between BM-MSCs and AT MSCs. However, Nanog expression was 2.5-fold higher in AT-MSCs than in BM-MSCs. Using immunocytochemical analysis, Oct3/4 and Sox2 proteins were observed in BM- and AT-MSCs. CONCLUSION: Our results provide fundamental information to enable for more reproducible and reliable quality control in the identification of canine BM-MSCs and AT-MSCs by protein and mRNA expression analysis. PMID- 22937865 TI - Single amino acid residue in the M4 domain of GluN1 subunit regulates the surface delivery of NMDA receptors. AB - N-methyl-D-aspartate (NMDA) receptors are glutamate ion channels that are critically involved in excitatory synaptic transmission and plasticity. The functional NMDA receptor is a heterotetramer composed mainly of GluN1 and GluN2 subunits. It is generally thought that only correctly assembled NMDA receptors can pass the quality control checkpoint in the endoplasmic reticulum (ER) and are transported to the cell surface membranes. The molecular mechanisms underlying these processes remain poorly understood. Using chimeric and mutated GluN1 subunits expressed in heterologous cells, we identified a single amino acid residue within the fourth membrane domain (M4) of GluN1 subunit, L830, that regulates the surface number of NMDA receptors. Our experiments show that this residue is not critical for the interaction between GluN1 and GluN2 subunits or for the formation of functional receptors, but rather that it regulates the forward trafficking of the NMDA receptors. The surface expression of both GluN2A- and GluN2B-containing receptors is regulated by the L830 residue in a similar manner. We also found that the L830 residue is not involved in the trafficking of individually expressed GluN1 subunits. Our data reveal a critical role of the single amino acid residue within the GluN1 M4 domain in the surface delivery of functional NMDA receptors. PMID- 22937866 TI - Differences in awareness between persons with left and right hemispheric stroke. AB - AIM: The aim of this study was to investigate whether there are any differences in awareness of ability between persons with left and right hemispheric stroke. METHODS: The sample consisted of data from the Assessment of Awareness of Ability (A3) database, primarily consisting of clients admitted to occupational therapy services. In total the study included 183 data records from clients, 78 with left and 105 with right hemispheric stroke. Awareness of ability was assessed using the Assessment of Awareness of Ability (A3). Differences in awareness were investigated using t-tests, CI, effect size, and differential item functioning. RESULTS: No significant overall mean difference (t-test = 1.31, p = 0.19) in awareness between left and right hemispheric stroke was identified. However, significant differences (p < 0.05) were identified on three specific items included in the A3. In these cases, persons with right hemispheric stroke showed a more limited awareness. CONCLUSION: Persons with right hemispheric stroke have more pronounced problems with being aware of limitations in specific ADL performance skills compared with persons with left hemispheric stroke. PMID- 22937867 TI - A new route to a 2-phosphanaphthalene. AB - The reaction between methylenechlorophosphine-pentacarbonyltungsten and an isobenzofuran affords a [4 + 2] adduct whose oxygen bridge is broken by BBr(3), leading to a 2-phosphanaphthalene. PMID- 22937864 TI - A gene expression signature of emphysema-related lung destruction and its reversal by the tripeptide GHK. AB - BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a heterogeneous disease consisting of emphysema, small airway obstruction, and/or chronic bronchitis that results in significant loss of lung function over time. METHODS: In order to gain insights into the molecular pathways underlying progression of emphysema and explore computational strategies for identifying COPD therapeutics, we profiled gene expression in lung tissue samples obtained from regions within the same lung with varying amounts of emphysematous destruction from smokers with COPD (8 regions * 8 lungs = 64 samples). Regional emphysema severity was quantified in each tissue sample using the mean linear intercept (Lm) between alveolar walls from micro-CT scans. RESULTS: We identified 127 genes whose expression levels were significantly associated with regional emphysema severity while controlling for gene expression differences between individuals. Genes increasing in expression with increasing emphysematous destruction included those involved in inflammation, such as the B-cell receptor signaling pathway, while genes decreasing in expression were enriched in tissue repair processes, including the transforming growth factor beta (TGFbeta) pathway, actin organization, and integrin signaling. We found concordant differential expression of these emphysema severity-associated genes in four cross-sectional studies of COPD. Using the Connectivity Map, we identified GHK as a compound that can reverse the gene-expression signature associated with emphysematous destruction and induce expression patterns consistent with TGFbeta pathway activation. Treatment of human fibroblasts with GHK recapitulated TGFbeta-induced gene expression patterns, led to the organization of the actin cytoskeleton, and elevated the expression of integrin beta1. Furthermore, addition of GHK or TGFbeta restored collagen I contraction and remodeling by fibroblasts derived from COPD lungs compared to fibroblasts from former smokers without COPD. CONCLUSIONS: These results demonstrate that gene-expression changes associated with regional emphysema severity within an individual's lung can provide insights into emphysema pathogenesis and identify novel therapeutic opportunities for this deadly disease. They also suggest the need for additional studies to examine the mechanisms by which TGFbeta and GHK each reverse the gene-expression signature of emphysematous destruction and the effects of this reversal on disease progression. PMID- 22937868 TI - Trigeminal interpolaris/caudalis transition neurons mediate reflex lacrimation evoked by bright light in the rat. AB - Abnormal sensitivity to bright light can cause discomfort or pain and evoke protective reflexes such as lacrimation. Although the trigeminal nerve is probably involved, the mechanism linking luminance to somatic sensory nerve activity remains uncertain. This study determined the effect of bright light on second-order ocular neurons at the ventral trigeminal interpolaris/caudalis transition (Vi/Vc) region, a major termination zone for trigeminal sensory fibers that innervate the eye. Most Vi/Vc neurons (80.9%) identified by responses to mechanical stimulation of the ocular surface also encoded bright light intensity. Light-evoked neural activity displayed a long latency to activation (> 10 s) and required transmission through the trigeminal root ganglion. Light-evoked neural activity was inhibited by intravitreal injection of phenylephrine or l-N(G) nitro-arginine methyl ester (L-NAME), suggesting a mechanism coupled to vascular events within the eye. Laser Doppler flowmetry revealed rapid light-evoked increases in ocular blood flow that occurred prior to the increase in Vi/Vc neural activity. Synaptic blockade of the Vi/Vc region by cobalt chloride prevented light-evoked increases in tear volume, whereas blockade at the more caudal spinomedullary junction (Vc/C1) had no effect. In summary, Vi/Vc neurons encoded bright light intensity and were inhibited by drugs that alter blood flow to the eye. These results support the hypothesis that light-responsive neurons at the Vi/Vc transition region are critical for ocular-specific functions such as reflex lacrimation, whereas neurons at the caudal Vc/C1 junction region probably serve other aspects of ocular nociception. PMID- 22937870 TI - Functional genomics tools to decipher the pathogenicity mechanisms of the necrotrophic fungus Plectosphaerella cucumerina in Arabidopsis thaliana. AB - The analysis of the interaction between Arabidopsis thaliana and adapted (PcBMM) and nonadapted (Pc2127) isolates of the necrotrophic fungus Plectosphaerella cucumerina has contributed to the identification of molecular mechanisms controlling plant resistance to necrotrophs. To characterize the pathogenicity bases of the virulence of necrotrophic fungi in Arabidopsis, we developed P. cucumerina functional genomics tools using Agrobacterium tumefaciens-mediated transformation. We generated PcBMM-GFP and Pc2127-GFP transformants constitutively expressing the green fluorescence protein (GFP), and a collection of random T-DNA insertional PcBMM transformants. Confocal microscopy analyses of the initial stages of PcBMM-GFP infection revealed that this pathogen, like other necrotrophic fungi, does not form an appressorium or penetrate into plant cells, but causes successive degradation of leaf cell layers. By comparing the colonization of Arabidopsis wild-type plants and hypersusceptible (agb1-1 and cyp79B2cyp79B3) and resistant (irx1-6) mutants by PcBMM-GFP or Pc2127-GFP, we found that the plant immune response was already mounted at 12-18 h post inoculation, and that Arabidopsis resistance to these fungi correlated with the time course of spore germination and hyphal growth on the leaf surface. The virulence of a subset of the PcBMM T-DNA insertional transformants was determined in Arabidopsis wild-type plants and agb1-1 mutant, and several transformants were identified that showed altered virulence in these genotypes in comparison with that of untransformed PcBMM. The T-DNA flanking regions in these fungal mutants were successfully sequenced, further supporting the utility of these functional genomics tools in the molecular characterization of the pathogenicity of necrotrophic fungi. PMID- 22937869 TI - Identification of the Streptococcus mutans LytST two-component regulon reveals its contribution to oxidative stress tolerance. AB - BACKGROUND: The S. mutans LrgA/B holin-like proteins have been shown to affect biofilm formation and oxidative stress tolerance, and are regulated by oxygenation, glucose levels, and by the LytST two-component system. In this study, we sought to determine if LytST was involved in regulating lrgAB expression in response to glucose and oxygenation in S. mutans. RESULTS: Real time PCR revealed that growth phase-dependent regulation of lrgAB expression in response to glucose metabolism is mediated by LytST under low-oxygen conditions. However, the effect of LytST on lrgAB expression was less pronounced when cells were grown with aeration. RNA expression profiles in the wild-type and lytS mutant strains were compared using microarrays in early exponential and late exponential phase cells. The expression of 40 and 136 genes in early-exponential and late exponential phase, respectively, was altered in the lytS mutant. Although expression of comYB, encoding a DNA binding-uptake protein, was substantially increased in the lytS mutant, this did not translate to an effect on competence. However, a lrgA mutant displayed a substantial decrease in transformation efficiency, suggestive of a previously-unknown link between LrgA and S. mutans competence development. Finally, increased expression of genes encoding antioxidant and DNA recombination/repair enzymes was observed in the lytS mutant, suggesting that the mutant may be subjected to increased oxidative stress during normal growth. Although the intracellular levels of reaction oxygen species (ROS) appeared similar between wild-type and lytS mutant strains after overnight growth, challenge of these strains with hydrogen peroxide (H2O2) resulted in increased intracellular ROS in the lytS mutant. CONCLUSIONS: Overall, these results: (1) Reinforce the importance of LytST in governing lrgAB expression in response to glucose and oxygen, (2) Define a new role for LytST in global gene regulation and resistance to H2O2, and (3) Uncover a potential link between LrgAB and competence development in S. mutans. PMID- 22937871 TI - Validated TLC-densitometry method for the simultaneous analysis of pyrethroid insecticides in agricultural and domestic products. AB - BACKGROUND: Pyrethroids are widely used for the control of pests and insects, as pyrethroids are believed to pose little risk to human health and environment. However, exposure to the pyrethroids exceeding the label directions might adversely affect human health and environment. Hence a careful selection of environment friendly household product is required that must contain exactly the label claimed pyrethroids amount. RESULTS: A sensitive and robust TLC densitometric method for simultaneous quantification of commonly used synthetic pyrethroids including esbiothrin, alpha-cypermethrin and cis/trans permethrin in agricultural and domestic products has been developed and validated. TLC aluminum sheets, precoated with 0.2 mm thick layer of silica gel 60 F-254, were used for chromatographic process. Densitometric analysis of chromatoplates was carried out in absorbance mode at corresponding lambdamax of each pyrethroid. Equally valid common mobile phase for all pyrethroids consisted of hexane-dichloromethane ethylacetate-formic acid (8:1.5:0.4:0.1 v/v/v/v) which provided sharp and symmetrical peaks of esbiothrin, alpha-cypermethrin, trans-permethrin and cis permethrin, at Rf 0.31, 0.53, 0.6 and 0.65, respectively. Linear regression data for respective calibration curves showed a good linearity for all pyrethroids with r = 0.991-0.996. Limits of detection (LOD) and limits of quantification (LOQ) for all pyrethroids were found in the range of 1.6-2.8 and 4.9-8.5 ng/spot, respectively. CONCLUSIONS: The developed method is applicable for separating the mixture of pyrethroids and at the same time, it is also valid for separating their isomers. The method is reproducible, precise and accurate for the quantitative determination of pyrethroids in agricultural and domestic products. PMID- 22937872 TI - Fatal hepatitis E viral infection in pregnant women in Ghana: a case series. AB - BACKGROUND: Viral infections during pregnancy can pose serious threats to mother and fetus from the time of conception to the time of delivery. These lead to congenital defects, spontaneous abortion and even death. The definitive diagnosis and management of pregnancy-related viral infections may be challenging especially in less resourced countries. CASE PRESENTATION: We present clinical and laboratory responses to the diagnosis and management of three cases of fulminant hepatitis secondary to Hepatitis E viral infection in pregnancy.Case 1 was a 31-year-old Ghanaian woman who presented with a week's history of passing dark urine as well as yellowish discoloration of the eyes. She subsequently developed fulminant hepatitis secondary to Hepatitis E viral infection, spontaneously aborted at 24 weeks of gestation and later died.Case 2 was also a 31-year-old Ghanaian woman who was admitted with a four-day history of jaundice. She had low grade fever, but no history of abdominal pain, haematuria, pale stool or pruritus. She next developed fulminant hepatitis secondary to Hepatitis E viral infection. However, she did not miscarry but died at 28 weeks of gestation.Case 3 was a 17-year-old Ghanaian woman who was referred to the tertiary health facility on account of jaundice and anaemia. She had delivered a live male infant at maturity of 32 weeks but noticed she was jaundiced and had a presentation of active disease 3 days prior to delivery. The baby was icteric at birth and on evaluation, had elevated bilirubin (mixed type) with normal liver enzymes. Hepatitis E virus infection was confirmed in both mother and baby. However, the jaundice and the hepatomegaly resolved in mother and baby after 5 and 12 days respectively. CONCLUSION: To the best of our knowledge, these are the first documented cases of fatal fulminant hepatic failures resulting from HEV infection in Ghana. PMID- 22937873 TI - Health risk behaviors among young adults with spina bifida. AB - AIM: Persons with spina bifida who adopt unhealthy lifestyles could be at increased risk of adverse health outcomes because the presence of spina bifida may magnify this risk. We estimated overall and age-specific prevalence of selected health risk behaviors (HRBs) in young people with spina bifida and examined the association between HRBs and depression. METHOD: We performed analyses on data obtained from individuals with spina bifida (n=130; mean age 23y SD 4y 5mo; 64 males, 66 females; 64% lumbosacral lesion; 77% with shunt) who participated in a population-based survey conducted by the Arkansas Spinal Cord Commission in 2005. RESULTS: Compared with national estimates, young people with spina bifida tend to eat less healthy diets, do less exercise, and engage in more sedentary activities. Respondents were less likely to use substances (alcohol, tobacco, illegal drugs), which peaked among 25 to 31 year olds. About 90% saw a doctor in the previous year. Nearly one half reported mild or major depressive symptoms. In the logistic regression analysis after controlling for potential confounders (age, sex, ethnic group, education, employment, marital status, living arrangement, level of lesion, presence of shunt, mobility, self-rated health and healthcare utilization), major depressive symptoms were associated with current alcohol drinking (adjusted odds ratio: 4.74; 95% CI 1.18-19.04). INTERPRETATION: Young adults with spina bifida exhibit unhealthy behaviors that continue into their late 20s. The findings highlight the need to increase awareness of their health risk profiles in the spina bifida community and show opportunities for mental health and health risk screening and counseling by healthcare providers. PMID- 22937874 TI - Pregnancy loss and role of infant HIV status on perinatal mortality among HIV infected women. AB - BACKGROUND: HIV-infected women, particularly those with advanced disease, may have higher rates of pregnancy loss (miscarriage and stillbirth) and neonatal mortality than uninfected women. Here we examine risk factors for these adverse pregnancy outcomes in a cohort of HIV-infected women in Zambia considering the impact of infant HIV status. METHODS: A total of 1229 HIV-infected pregnant women were enrolled (2001-2004) in Lusaka, Zambia and followed to pregnancy outcome. Live-born infants were tested for HIV by PCR at birth, 1 week and 5 weeks. Obstetric and neonatal data were collected after delivery and the rates of neonatal (<28 days) and early mortality (<70 days) were described using Kaplan Meier methods. RESULTS: The ratio of miscarriage and stillbirth per 100 live births were 3.1 and 2.6, respectively. Higher maternal plasma viral load (adjusted odds ratio [AOR] for each log10 increase in HIV RNA copies/ml = 1.90; 95% confidence interval [CI] 1.10-3.27) and being symptomatic were associated with an increased risk of stillbirth (AOR = 3.19; 95% CI 1.46-6.97), and decreasing maternal CD4 count by 100 cells/mm3 with an increased risk of miscarriage (OR = 1.25; 95% CI 1.02-1.54). The neonatal mortality rate was 4.3 per 100 increasing to 6.3 by 70 days. Intrauterine HIV infection was not associated with neonatal morality but became associated with mortality through 70 days (adjusted hazard ratio = 2.76; 95% CI 1.25-6.08). Low birth weight and cessation of breastfeeding were significant risk factors for both neonatal and early mortality independent of infant HIV infection. CONCLUSIONS: More advanced maternal HIV disease was associated with adverse pregnancy outcomes. Excess neonatal mortality in HIV-infected women was not primarily explained by infant HIV infection but was strongly associated with low birth weight and prematurity. Intrauterine HIV infection contributed to mortality as early as 70 days of infant age. Interventions to improve pregnancy outcomes for HIV-infected women are needed to complement necessary therapeutic and prophylactic antiretroviral interventions. PMID- 22937875 TI - Poly-amido-saccharides: synthesis via anionic polymerization of a beta-lactam sugar monomer. AB - Enantiopure poly-amido-saccharides (PASs) with a defined molecular weight and narrow dispersity are synthesized using an anionic ring-opening polymerization of a beta-lactam sugar monomer. The PASs have a previously unreported main chain structure that is composed of pyranose rings linked through the 1- and 2 positions by an amide with alpha-stereochemistry. The monomer is synthesized in one-step from benzyl-protected D-glucal and polymerized using mild reaction conditions to give degrees of polymerization ranging from 25 to >120 in high yield. Computational modeling reveals how the monomer's structure and steric bulk affect the thermodynamics and kinetics of polymerization. Protected and deprotected polymers and model compounds are characterized using a variety of methods (NMR, GPC, IR, DLS, etc.). On the basis of circular dichroism, the deprotected polymer possesses a regular secondary structure in aqueous solution, which agrees favorably with the prediction of a helical structure using molecular modeling. Furthermore, we provide evidence suggesting that the polymers bind the lectin concanavalin A at the same site as natural carbohydrates, showing the potential of these polymers to mimic natural polysaccharides. PASs offer the advantages associated with synthetic polymers, such as greater control over structure and derivitization. At the same time, they preserve many of the structural features of natural polysaccharides, such as a stereochemically regular, rigid pyranose backbone, that make natural carbohydrate polymers important materials both for their unique properties and useful applications. PMID- 22937877 TI - Hypoglycaemia is associated with increased length of stay and mortality in people with diabetes who are hospitalized. AB - AIM: To study the length of stay and inpatient mortality of patients with diabetes who had an episode of hypoglycaemia in a non critical care setting at University Hospital Birmingham, UK. METHODS: Retrospective analysis of routinely available electronic data of 6374 admissions with a recording of either laboratory or point-of-care blood glucose value. Based on the lowest recorded blood glucose values, patients were categorized into a group without hypoglycaemia (> 3.9 mmol/l), a group with mild to moderate hypoglycaemia (2.3 3.9 mmol/l) and a group with severe hypoglycaemic (<= 2.2 mmol/l). Length of stay and inpatient mortality were compared between the three groups, adjusting for age, gender, ethnicity, deprivation, admission type, use of insulin and modified Charlson co-morbidity score. RESULTS: There were 148 admissions (2.3%) with severe hypoglycaemia (<= 2.2 mmol/l), 500 admissions (7.8%) with mild to moderate hypoglycaemia (2.2-3.9 mmol/l) and 5726 admissions with no recorded hypoglycaemic episode (> 3.9 mmol/l). After adjustment, length of stay, when compared with those without a recorded hypoglycaemic episode, was 1.51 (95% CI 1.35-1.68) times higher in the group with blood glucose values of 2.3-3.9 mmol/l and 2.33 (95% CI 1.91-2.84) higher in the group with blood glucose values <= 2.2 mmol/l. Adjusted odds ratio of inpatient mortality when compared with the group without hypoglycaemia was 1.62 (95% CI 1.16-2.27) in the group with blood glucose values of 2.3-3.9 mmol/l and 2.05 (95% CI 1.24-3.38) in the group with blood glucose values <= 2.2 mmol/l. CONCLUSION: Hypoglycaemia is associated with increased length of stay and inpatient mortality. Whilst causative evidence is lacking, our data are consistent with the need to avoid hypoglycaemia in our current and continued approach for optimal glycaemic control in people with diabetes admitted to hospital. PMID- 22937876 TI - Molecular epidemiology of bat lyssaviruses in Europe. AB - Bat rabies cases in Europe are principally attributed to two lyssaviruses, namely European bat lyssavirus type 1 (EBLV-1) and European bat lyssavirus type 2 (EBLV 2). Between 1977 and 2011, 961 cases of bat rabies were reported to Rabies Bulletin Europe, with the vast majority (>97%) being attributed to EBLV-1. There have been 25 suspected cases of EBLV-2, of which 22 have been confirmed. In addition, two single isolations of unique lyssaviruses from European insectivorous bats were reported in south-west Russia in 2002 (West Caucasian bat virus) and in Germany in 2010 (Bokeloh bat lyssavirus). In this review, we present phylogenetic analyses of the EBLV-1 and EBLV-2 using partial nucleoprotein (N) gene sequences. In particular, we have analysed all EBLV-2 cases for which viral sequences (N gene, 400 nucleotides) are available (n = 21). Oropharyngeal swabs collected from two healthy Myotis daubentonii during active surveillance programmes in Scotland and Switzerland also yielded viral RNA (EBLV 2). Despite the relatively low number of EBLV-2 cases, a surprisingly large amount of anomalous data has been published in the scientific literature and Genbank, which we have collated and clarified. For both viruses, geographical relationships are clearly defined on the phylogenetic analysis. Whilst there is no clear chronological clustering for either virus, there is some evidence for host specific relationships, particularly for EBLV-1 where more host variation has been observed. Further genomic regions must be studied, in particular for EBLV-1 isolates from Spain and the EBLV-2 isolates to provide support for the existence of sublineages. PMID- 22937878 TI - Protein and lipid oxidation in Parma ham during production. AB - Lipid oxidation adds to the characteristic flavor of dry-cured products, but the role of protein oxidation in the production of such meats is unknown. Lipid and protein oxidations in biceps femoris (BF) and semimembranosus (SM) muscles were evaluated throughout the production period of Parma ham (0-13 months). Lipid oxidation, determined as primary and secondary lipid oxidation products (POV and TBARS), and protein thiol loss commenced immediately without any lag phase and preceded the initiation of protein radicals and protein carbonyls, which increased after a lag phase of 3 months. TBARS reached a maximum value of 2.5 mg MDA/kg dry matter in SM after 1 month and leveled off at 1 mg MDA/kg dry matter in both SM and BF between 6 and 12 months. Loss in protein thiols proceeded similarly for SM and BF from initial ~50 to ~27 nmol/mg protein after 6 months and stayed constant. Gel electrophoresis showed that myosin was lost primarily by proteolytic degradation and not by polymerization through protein disulfides. Overall, oxidation accelerated during the first stages of production but stabilized toward the final stages of maturation. PMID- 22937879 TI - Colonic mucosal mediators from patients with irritable bowel syndrome excite enteric cholinergic motor neurons. AB - BACKGROUND: Mediators released in the mucosal milieu have been suggested to be involved in visceral hypersensitivity and abdominal pain in patients with irritable bowel syndrome (IBS). However, their impact on myenteric neurons remains unsettled. METHODS: Mucosal biopsies were obtained from the descending colon of patients with IBS and controls. Mucosal mast cells were identified immunohistochemically. The impact of spontaneously released mucosal mediators on guinea pig electrically stimulated longitudinal muscle myenteric plexus (LMMP) preparations was assessed in vitro by means of selective receptor antagonists and inhibitors. KEY RESULTS: Patients with IBS showed an increased mast cell count compared with controls. Application of mucosal mediators of IBS to LMMPs potentiated cholinergic twitch contractions, an effect directly correlated with mast cell counts. Enhanced contractions were inhibited by 50.3% with the prostaglandin D2 antagonist BW A868C, by 31.3% and 39% with the TRPV1 antagonists capsazepine and HC-030031, respectively, and by 60.5% with purinergic P2X antagonist pyridoxalphosphate-6-azophenyl-2',4'-disulfonic acid. Conversely, the serotonin1-4, histamine1-3, tachykinin1-3 receptor blockade, and serine protease inhibition had no significant effect. CONCLUSIONS & INFERENCES: Colonic mucosal mediators from patients with IBS excite myenteric cholinergic motor neurons. These effects were correlated with mast cell counts and mediated by activation of prostanoid receptors, TRPV1, and P2X receptors. These results support the role of mucosal inflammatory mediators and mast cell activation in altered motor function of IBS. PMID- 22937880 TI - Singly ionized double-donor complex in vertically coupled quantum dots. AB - The electronic states of a singly ionized on-axis double-donor complex (D2+) confined in two identical vertically coupled, axially symmetrical quantum dots in a threading magnetic field are calculated. The solutions of the Schrodinger equation are obtained by a variational separation of variables in the adiabatic limit. Numerical results are shown for bonding and antibonding lowest-lying artificial molecule states corresponding to different quantum dot morphologies, dimensions, separation between them, thicknesses of the wetting layers, and magnetic field strength. PMID- 22937881 TI - Biodegradable polymer (PLGA) coatings featuring cinnamaldehyde and carvacrol mitigate biofilm formation. AB - Biofilm-associated infections are one of the leading causes of death in the United States. Although infections may be treated with antibiotics, the overuse of antibiotics has led to the spread of antibiotic resistance. Many natural antimicrobial compounds derived from edible plants are safe for human use and target bacteria nonspecifically. Therefore, they may impair biofilm formation with less evolutionary pressure on pathogens. Here, we explore the use of two natural antimicrobial compounds, cinnamaldehyde (CA, from cinnamon) and carvacrol (CARV, from oregano), for biofilm prevention. We have fabricated and characterized films that incorporate CA and CARV into the biodegradable, FDA approved polymer poly(lactic-co-glycolic acid), PLGA. The addition of CA and CARV to PLGA films not only adds antimicrobial activity but also changes the surface properties of the films, making them more hydrophilic and therefore more resistant to bacterial attachment. An addition of 0.1% CA to a PLGA film significantly impairs biofilm development by Staphylococcus aureus, and 0.1% CARV in PLGA significantly decreases biofilm formation by both Escherichia coli and S. aureus. Pseudomonas aeruginosa, which is less susceptible to CA and CARV, was not affected by the addition of 0.1% CA or CARV to the PLGA coatings; however, P. aeruginosa biofilm was significantly reduced by 1.0% CA. These results indicate that both CA and CARV could potentially be used in low concentrations as natural additives in polymer coatings for indwelling devices to delay colonization by bacteria. PMID- 22937884 TI - Educational expectations of GP trainers. A EURACT needs analysis. AB - INTRODUCTION: In this background paper, we discuss the educational needs of family medicine teachers and trainers in the light of a EURACT (European Academy of Teachers in General Practice) project aimed at the development of a European framework for the professional development of general practice (GP) educators. BACKGROUND: There is evidence that the ideal GP educator would benefit from systematic training in teaching skills. Although international literature indicates that such skills training should be in supervision, feedback, assessment and educational management, it is not clear if these needs vary between trainers who teach general practice in different settings and environments. Needs assessment: Recently EURACT, in collaboration with partners from five EU countries and Turkey, set up a project aimed at the development of a comprehensive 'training the trainers' programme. The project included a baseline survey of perceived educational needs and wants among both novice and expert European GP educators. The survey demonstrated that the educational needs of GP educators did not vary much in the content areas in which training was required throughout Europe but did vary in the level and depth of knowledge needed; this depended on their experience and level of expertise as teachers. IMPLICATIONS: Based on the information gathered and experience gained from previous EURACT courses, a Leonardo da Vinci project has developed and launched a comprehensive programme with courses at three levels of participant expertise, to address the personal learning needs of GP educators. PMID- 22937882 TI - Effects of salivary protein flow and indigenous microorganisms on initial colonization of Candida albicans in an in vivo model. AB - BACKGROUND: Candida albicans is a dimorphic fungus that is part of the commensal microbial flora of the oral cavity. When the host immune defenses are impaired or when the normal microbial flora is disturbed, C. albicans triggers recurrent infections of the oral mucosa and tongue. Recently, we produced NOD/SCID.e2f1-/- mice that show hyposalivation, decrease of salivary protein flow, lack IgA and IgG in saliva, and have decreased NK cells. Our objective was to characterize C. albicans infection and biofilm formation in mice. METHODS: NOD/SCID.e2f1-/- mice were used as an animal model for C. albicans infection. C. albicans yeast and hyphal forms solutions were introduced in the oral cavity after disinfection by Chlorhexidine. RESULTS: The numbers of C. albicans colonized and decreased in a time-dependent manner in NOD/SCID.e2f1+/+ after inoculation. However, the colonization levels were higher in NOD/SCID.e2f1+/+ than NOD/SCID.e2f1-/- mice. In the mice fed 1% sucrose water before inoculation, C. albicans sample was highly contaminated by indigenous microorganisms in the oral cavity; and was not in the mice fed no sucrose water. The colonization of C. albicans was not influenced by the contamination of indigenous microorganisms. The hyphal form of C. albicans restricted the restoration of indigenous microorganisms. The decreased saliva in NOD/SCID.e2f1-/- did not increase the colonization of C. albicans in comparison to NOD/SCID.e2f1+/+ mice. We suggest that the receptor in saliva to C. albicans may not be sufficiently provided in the oral cavity of NOD/SCID.e2f1-/- mice. CONCLUSION: The saliva protein flow may be very important for C. albicans initial colonization, where the indigenous microorganisms do not affect colonization in the oral cavity. PMID- 22937883 TI - Identifying associations between pig pathologies using a multi-dimensional machine learning methodology. AB - BACKGROUND: Abattoir detected pathologies are of crucial importance to both pig production and food safety. Usually, more than one pathology coexist in a pig herd although it often remains unknown how these different pathologies interrelate to each other. Identification of the associations between different pathologies may facilitate an improved understanding of their underlying biological linkage, and support the veterinarians in encouraging control strategies aimed at reducing the prevalence of not just one, but two or more conditions simultaneously. RESULTS: Multi-dimensional machine learning methodology was used to identify associations between ten typical pathologies in 6485 batches of slaughtered finishing pigs, assisting the comprehension of their biological association. Pathologies potentially associated with septicaemia (e.g. pericarditis, peritonitis) appear interrelated, suggesting on-going bacterial challenges by pathogens such as Haemophilus parasuis and Streptococcus suis. Furthermore, hepatic scarring appears interrelated with both milk spot livers (Ascaris suum) and bacteria-related pathologies, suggesting a potential multi pathogen nature for this pathology. CONCLUSIONS: The application of novel multi dimensional machine learning methodology provided new insights into how typical pig pathologies are potentially interrelated at batch level. The methodology presented is a powerful exploratory tool to generate hypotheses, applicable to a wide range of studies in veterinary research. PMID- 22937885 TI - Scale up, optimization and stability analysis of Curcumin C3 complex-loaded nanoparticles for cancer therapy. AB - BACKGROUND: Nanoparticle based delivery of anticancer drugs have been widely investigated. However, a very important process for Research & Development in any pharmaceutical industry is scaling nanoparticle formulation techniques so as to produce large batches for preclinical and clinical trials. This process is not only critical but also difficult as it involves various formulation parameters to be modulated all in the same process. METHODS: In our present study, we formulated curcumin loaded poly (lactic acid-co-glycolic acid) nanoparticles (PLGA-CURC). This improved the bioavailability of curcumin, a potent natural anticancer drug, making it suitable for cancer therapy. Post formulation, we optimized our process by Reponse Surface Methodology (RSM) using Central Composite Design (CCD) and scaled up the formulation process in four stages with final scale-up process yielding 5 g of curcumin loaded nanoparticles within the laboratory setup. The nanoparticles formed after scale-up process were characterized for particle size, drug loading and encapsulation efficiency, surface morphology, in vitro release kinetics and pharmacokinetics. Stability analysis and gamma sterilization were also carried out. RESULTS: Results revealed that that process scale-up is being mastered for elaboration to 5 g level. The mean nanoparticle size of the scaled up batch was found to be 158.5+/-9.8 nm and the drug loading was determined to be 10.32+/-1.4%. The in vitro release study illustrated a slow sustained release corresponding to 75% drug over a period of 10 days. The pharmacokinetic profile of PLGA-CURC in rats following i.v. administration showed two compartmental model with the area under the curve (AUC0 infinity) being 6.139 mg/L h. Gamma sterilization showed no significant change in the particle size or drug loading of the nanoparticles. Stability analysis revealed long term physiochemical stability of the PLGA-CURC formulation. CONCLUSIONS: A successful effort towards formulating, optimizing and scaling up PLGA-CURC by using Solid-Oil/Water emulsion technique was demonstrated. The process used CCD-RSM for optimization and further scaled up to produce 5 g of PLGA-CURC with almost similar physicochemical characteristics as that of the primary formulated batch. PMID- 22937886 TI - The effects of therapeutic x-ray doses on mechanical, chemical and physical properties of poly methyl methacrylate. AB - AIM: The aim of this study was to investigate the effect of radiation doses very close to the human dose for oral cancers on mechanical, chemical and physical properties for poly methyl-methacrylate (PMMA). METHODS: PMMA samples were divided into four different groups: no irradiated group, 25-Gy irradiated group, 50-Gy irradiated group and 75-Gy irradiated group. Each group contained nine samples. After 24 h, a three-point loading test was applied to each PMMA groups. The transverse strength and the elastic modulus were calculated using the test results. The results were analyzed statistically by using one-way analysis of variance. The structural characterizations of the PMMA samples were carried out by a Fourier Transform Infrared (FTIR) spectrophotometer to evaluate the chemical structure differences. RESULTS: The transverse strength values of 25-Gy, 50-Gy and 75-Gy radiation groups were significantly higher than that of the no radiation group (p < 0.05). There was no significant difference among the elastic modulus values of the study groups (p > 0.05). The FTIR findings demonstrated that the irradiation process did not change the chemical structure of the PMMA polymeric materials. CONCLUSION: The therapeutic radiation doses increase the mechanical properties of the PMMA; however, the chemical and structural properties have no effect. When the findings of this study are taken into account, it can be said that patients can wear dentures during the radiotherapy. PMID- 22937887 TI - Systemic lupus erythematous presenting with hydroa vacciniforme-like eruption: mimicking Epstein-Barr virus-associated lymphoproliferative disorders. PMID- 22937888 TI - Nitric oxide (NO): a key player in the senescence of Medicago truncatula root nodules. AB - Nitric oxide (NO) is a signalling and defence molecule involved in diverse plant developmental processes, as well as in the plant response to pathogens. NO has also been detected at different steps of the symbiosis between legumes and rhizobia. NO is required for an optimal establishment of the Medicago truncatula Sinorhizobium meliloti symbiotic interaction, but little is known about the role of NO in mature nodules. Here, we investigate the role of NO in the late steps of symbiosis. Genetic and pharmacological approaches were conducted to modulate the NO level inside root nodules, and their effects on nitrogen fixation and root nodule senescence were monitored. An increase in endogenous NO levels led to a decrease in nitrogen fixation and early nodule senescence, characterized by cytological modifications of the nodule structure and the early expression of a specific senescence marker. By contrast, a decrease in NO levels led to a delay in nodule senescence. Together, our results strongly suggest that NO is a signal in developmental as well as stress-induced nodule senescence. In addition, this work demonstrates the pivotal role of the bacterial NO detoxification response in the prevention of early nodule senescence, and hence the maintenance of efficient symbiosis. PMID- 22937889 TI - Sarcoidosis in a 65-year-old woman presenting with a lung mass and pericardial effusion: a case report. AB - INTRODUCTION: Sarcoidosis is a multi-systemic disorder of unknown origin and most commonly affects the lungs. Diagnosis relies on the presence of non-caseating granulomas on histologic specimens. In high-resolution computed tomography, the most characteristic findings are peribronchovascular thickening, perilymphatic nodular distribution, and bilateral hilar adenopathy. Confluent nodular opacities or large masses are rare manifestations of the disease. It is well recognized that sarcoidosis can mimic infectious, malignant, and granulomatous conditions. Here, we report a case with a high initial index of suspicion for lung malignancy in terms of clinical, lung imaging, and endoscopic findings. CASE PRESENTATION: A 65-year-old Caucasian woman, lifelong non-smoker with an unremarkable medical history, presented with a 10-month history of progressive breathlessness, dry cough, fatigue, arthralgias, and mild weight loss. The only significant clinical finding was bilateral enlargement of auxiliary lymph nodes. High-resolution computed tomography revealed a soft tissue density mass at the right hilum which was surrounding and narrowing airways and vascular components, nodules with vascular distribution, enlarged mediastinal lymph nodes, and pericardial effusion. Our patient underwent a bronchoscopy, which revealed the presence of submucosal infiltration and narrowing of the right upper bronchus. Endobronchial biopsies showed non-caseating granulomas. As local sarcoid reactions with non caseating granulomas can be observed near tumors, our patient underwent video assisted thoracoscopy and surgical removal of an auxiliary lymph node, both of which confirmed the presence of non-caseating granulomas and the diagnosis of sarcoidosis. She was treated with steroids with improvement of clinical and imaging findings. However, while on a maintenance dose, she presented with a pleural effusion, which, after the diagnostic work-up, proved to be sarcoidosis related. Treatment with initially high doses of steroids plus a steroid-sparing agent led to resolution of the effusion. CONCLUSIONS: We report a case with a high initial index of suspicion for lung malignancy. Clinicians should always be aware that sarcoidosis enters the differential diagnosis of patients presenting with a lung mass that encases and narrows bronchial and vascular structures with associated pericardial effusion. Rarely, pleural effusion can be the presenting symptom of disease relapse despite maintenance treatment. PMID- 22937892 TI - The importance of metacommunity ecology for environmental assessment research in the freshwater realm. AB - Most bioassessment programs rest on the assumption that species have different niches, and that abiotic environmental conditions and changes therein determine community structure. This assumption is thus equivalent to the species sorting perspective (i.e. that species differ in their responses to environmental variation) in metacommunity ecology. The degree to which basing bioassessment on the species sorting perspective is reasonable is likely to be related to the spatial extent of a study and the characteristics of the organism groups (e.g. dispersal ability) with which the effects of anthropogenic changes are assessed. Recent findings in metacommunity research have stressed that community structure is determined not only by local abiotic environmental conditions but also by biotic interactions and dispersal-related effects. For example, dispersal limitation may prevent community structure recovery from the effects of a putative stressor, as organisms may not be able to disperse to all sites in a region. Mass effects (i.e. the presence of species in environmentally suboptimal sites due to high dispersal rates from environmentally suitable sites) may, in turn, obscure the effects of a stressor, as dispersal from source sites (e.g. an unaltered site) allows persistence at sink sites (e.g. an anthropogenically altered site). Better bioassessment should thus take both niche- and dispersal related processes simultaneously into consideration, which can be accomplished by explicitly modelling spatial location as a proxy for dispersal effects. Such an integrated approach should be included in bioassessment programs using general multivariate approaches, predictive modelling, and multimetric indices. PMID- 22937891 TI - Use of the ThinPrep Imaging System for internal quality control of cervical cytology. AB - OBJECTIVE: To audit the use of the ThinPrep Imaging System (TIS) for internal quality control (IQC) in the place of rapid review (RR), and to compare its performance with routine primary screening. METHOD: During 9 months, 16 462 ThinPrep slides were processed by TIS. Slides were initially reviewed using the TIS review scope, as recommended by the manufacturer: 22 fields of view were observed and, if considered abnormal, a full microscopic review was conducted using the review scope. Different biomedical scientists (BMSs), working on each procedure in rotation, performed batches of TIS-assisted quality control and routine primary screening independently on unmarked slides. Any slides with abnormalities detected by either method were referred to a consultant pathologist or advanced BMS practitioner for a final report. TIS results were compared with both previous records of RR and routine primary screening carried out on the same slides. We used the UK terminology in which 'dyskaryosis' is equivalent to squamous intraepithelial lesion (SIL) and borderline to atypical (including squamous and glandular cells). RESULTS: TIS preview detected significantly more high-grade dyskaryosis compared with RR during the previous 4 years: 2.0-4.2 compared with 0.1-1.8 detected per 1000 slides (P = 0.0001). TIS and routine screening were equivalent in sensitivity and specificity for the final cytology result, but BMSs were significantly more likely to classify slides as dyskaryotic rather than borderline when using TIS compared with routine screening. Referrals for potentially high-grade abnormalities detected by TIS-assisted IQC alone found 28 biopsies of at least cervical intraepithelial neoplasia grade 2 (CIN2+), whereas 15 CIN2+ biopsies were found on routine screening but missed using TIS. There was no significant change in the rates of inadequate tests, high- or low grade cytological abnormalities, or positive predictive value for CIN2+ when TIS was in use. CONCLUSIONS: Screening with TIS was more sensitive than RR for IQC, providing a rescreening method equivalent to routine primary screening in overall accuracy. PMID- 22937890 TI - Integrated community-directed intervention for schistosomiasis and soil transmitted helminths in western Kenya - a pilot study. AB - BACKGROUND: Schistosome and soil-transmitted helminth (STH) infections are recognized as major global public health problems, causing severe and subtle morbidity, including significant educational and nutritional effects in children. Although effective and safe drugs are available, ensuring access to these drugs by all those at risk of schistosomiasis and STHs is still a challenge. Community directed intervention (CDI) has been used successfully for mass distribution of drugs for other diseases such as onchocerciasis and lymphatic filariasis. A national control programme is yet to be instituted in Kenya and evidence for cost effective strategies for reaching most affected communities is needed. This study evaluated the effectiveness and feasibility of the CDI strategy in the control of schistosomiasis and STHs, in East Uyoma location, Rarieda district, a community of western Kenya that is highly endemic for both infections. RESULTS: Pre treatment prevalence of S. mansoni averaged 17.4% (range 5-43%) in the entire location. Treatment coverage in different villages ranged from 54.19 to 96.6% by community drug distributor (CDD) records. Assessment from a household survey showed coverage of 52.3 -91.9% while the proportion of homesteads (home compounds) covered ranged from 54.9-98.5%. Six months after one round of drug distribution, the prevalence levels of S. mansoni, hookworm and Trichuris trichura infections were reduced by 33.2%, 69.4% and 42.6% respectively. CONCLUSIONS: This study shows that CDI is an accepted and effective strategy in the mass treatment of schistosomiasis and STH infections in resource constrained communities in Kenya and may be useful in similar communities elsewhere. A controlled trial comparing CDI and school based mass drug administration to demonstrate their relative advantages is ongoing. PMID- 22937893 TI - Asbestos fiber burden in lung tissues of occupationally exposed workers. PMID- 22937894 TI - Febrile seizures and behavioural and cognitive outcomes in preschool children: the Generation R study. AB - AIM: General developmental outcome is known to be good in school-aged children who experienced febrile seizures. We examined cognitive and behavioural outcomes in preschool children with febrile seizures, including language and executive functioning outcomes. METHOD: This work was performed in the Generation R Study, a population-based cohort study in Rotterdam from early fetal life onwards. Information about the occurrence of febrile seizures was collected by questionnaires at the ages of 1, 2, and 3 years. At the age of 3 years, behaviour and emotion were assessed using the Child Behavior Checklist. Information on expressive language development was obtained by the Language Development Survey at the age of 2 years 6 months. To assess executive functioning, parents completed the Behaviour Rating Inventory of Executive Function - Preschool Version when their children were 4 years old. Final analyses were based on 3157 children. RESULTS: No associations were found between febrile seizures and the risk of behavioural problems or executive functioning. In contrast to single febrile seizures, recurrent febrile seizures were significantly associated with an increased risk of delayed vocabulary development (odds ratio 3.22, [95% confidence interval 1.30-7.94]). INTERPRETATION: Febrile seizures are not associated with problem behaviour or executive functioning in preschool children, but the results suggest that children with recurrent febrile seizures might be at risk for delayed language development. PMID- 22937895 TI - Taspoglutide, a once-weekly glucagon-like peptide 1 analogue, vs. insulin glargine titrated to target in patients with Type 2 diabetes: an open-label randomized trial. AB - AIMS: To compare the efficacy and safety of once-weekly taspoglutide with insulin glargine in patients with advanced Type 2 diabetes failing metformin and sulphonylurea combination therapy. METHODS: This open-label, parallel-group, multi-centre trial randomized 1049 patients continuing metformin 1:1:1 to taspoglutide 10 mg once weekly, taspoglutide 20 mg once weekly or insulin glargine once daily with forced titration to fasting plasma glucose <= 6.1 mmol/l. Sulphonylureas were discontinued before randomization. The primary endpoint was change in HbA(1c) after 24 weeks. RESULTS: After 24 weeks, least square mean changes from baseline in HbA(1c) in patients receiving taspoglutide 10 mg [-8 mmol/mol (se 1)] [-0.77% (se 0.05)] or taspoglutide 20 mg [-11 mmol/mol (se 1)] [-0.98% (se 0.05)] were non-inferior to insulin glargine [-9 mmol/mol (se 1)] [-0.84% (se 0.05)]; treatment difference of 0.07% (95% CI -0.06 to 0.21) and 0.14% (95% CI -0.28 to -0.01), for taspoglutide 10 and 20 mg, respectively, vs. insulin glargine. Taspoglutide was associated with more adverse events (mainly gastrointestinal) and significantly less hypoglycaemia than insulin glargine. CONCLUSIONS: Compared with insulin glargine, taspoglutide provided non-inferior HbA(1c) reductions associated with less hypoglycaemia, but more gastrointestinal adverse events. PMID- 22937896 TI - A review of simulation modelling approaches used for the spread of zoonotic influenza viruses in animal and human populations. AB - Increasing incidences of emerging and re-emerging diseases that are mostly zoonotic (e.g. severe acute respiratory syndrome, avian influenza H5N1, pandemic influenza) has led to the need for a multidisciplinary approach to tackling these threats to public and animal health. Accordingly, a global movement of 'One Health/One-Medicine' has been launched to foster collaborative efforts amongst animal and human health officials and researchers to address these problems. Historical evidence points to the fact that pandemics caused by influenza A viruses remain a major zoonotic threat to mankind. Recently, a range of mathematical and computer simulation modelling methods and tools have increasingly been applied to improve our understanding of disease transmission dynamics, contingency planning and to support policy decisions on disease outbreak management. This review provides an overview of methods, approaches and software used for modelling the spread of zoonotic influenza viruses in animals and humans, particularly those related to the animal-human interface. Modelling parameters used in these studies are summarized to provide references for future work. This review highlights the limited application of modelling research to influenza in animals and at the animal-human interface, in marked contrast to the large volume of its research in human populations. Although swine are widely recognized as a potential host for generating novel influenza viruses, and that some of these viruses, including pandemic influenza A/H1N1 2009, have been shown to be readily transmissible between humans and swine, only one study was found related to the modelling of influenza spread at the swine-human interface. Significant gaps in the knowledge of frequency of novel viral strains evolution in pigs, farm-level natural history of influenza infection, incidences of influenza transmission between farms and between swine and humans are clearly evident. Therefore, there is a need to direct additional research to the study of influenza transmission dynamics in animals and at the animal-human interface. PMID- 22937897 TI - Gestational diabetes mellitus diagnosed by screening or symptoms: does it matter? AB - OBJECTIVE: To investigate whether outcome differs between pregnancies complicated by gestational diabetes mellitus (GDM), which was either detected by risk-factor based screening when no clinical signs are apparent (screening-group) or due to clinical signs of hyperglycemia (e.g. accelerated fetal growth or hydramnios) (diagnosis-group). METHODS: A retrospective cohort of 249 patients with GDM treated between 2006 and 2009 were identified: 74 in the diagnosis-group and 175 in the screening-group. Fetal macrosomia was defined as an abdominal circumference (FAC) >90th percentile at the time of diagnosis of GDM. Large for gestational age (LGA) was defined as a birthweight >90th percentile, corrected for gestational age, parity and sex. RESULTS: GDM was diagnosed 4 weeks later in the diagnosis-group. At diagnosis of GDM, more infants in the diagnosis-group had a FAC >p90 and at birth more infants in this group were LGA. CONCLUSION: GDM diagnosed by screening is associated with a lower incidence of fetal and neonatal macrosomia than GDM diagnosed by clinical symptoms. A later diagnosis of GDM is more prevalent in presumed low-risk pregnancies. These results favour a policy of routine screening. PMID- 22937898 TI - Confinement of metal-organic polyhedra in silica nanopores. AB - Metal-organic polyhedra (MOPs) have been incorporated into silica nanopores for the first time. Three MOPs with identical geometries but different ligand functionality (namely tert-butyl, hydroxyl, and sulfonic groups) were employed. A typical mesoporous silica, SBA-15, with a two-dimensional hexagonal pore regularity was used as the host. In comparison with bulk MOPs, which prefer to aggregate, MOPs confined in silica nanopores can be well dispersed, making the active sites and pores in the MOPs accessible. These dispersed MOPs showed apparently superior H(2) adsorption capacity in comparison with aggregated bulk MOPs. Moreover, the thermal stability of the MOPs was enhanced upon their confinement in silica nanopores. PMID- 22937900 TI - Nutrient intake in patients with irritable bowel syndrome compared with the general population. AB - BACKGROUND: Food and diet are central issues that concern patients with irritable bowel syndrome (IBS). Few studies have thoroughly analyzed dietary intake in IBS. Our aims were to determine the nutrient intake in IBS patients in comparison to the general population, assess nutritional differences between IBS subgroups based on the predominant bowel habit or symptom severity, as well as to evaluate if their nutrient intake meet nutrition recommendations. METHODS: We included 187 IBS patients (mean 40.2 years; 139 women). They completed a 4-days food registration record, which was compared with an age-, and gender-matched control group (n = 374; 278 women) from a nation-wide dietary survey and with Nordic Nutrient Recommendations. KEY RESULTS: Daily nutrient intake in IBS patients was similar to the general population and met national nutrients recommendations. Irritable bowel syndrome patients had similar energy distribution from macronutrients compared to the control group, but the protein percentage tended to be higher. Irritable bowel syndrome patients also had significantly higher daily intake of vitamin E, folate, iron, vitamin C, and dietary fibers, as well as lower intake of vitamin A, riboflavin, calcium, and potassium. There was no association between nutrient intake and IBS subtypes or symptom severity. CONCLUSIONS & INFERENCES: Although many IBS patients state that they avoid food items, this does not seem to influence their intake of nutrients to any large extent. The observed minor differences in nutrient intake indicate a tendency toward higher intake of fruit and vegetables and a lower intake of meat and dairy products in IBS patients. PMID- 22937899 TI - Phylogenetic analysis of a gene cluster encoding an additional, rhizobial-like type III secretion system that is narrowly distributed among Pseudomonas syringae strains. AB - BACKGROUND: The central role of Type III secretion systems (T3SS) in bacteria plant interactions is well established, yet unexpected findings are being uncovered through bacterial genome sequencing. Some Pseudomonas syringae strains possess an uncharacterized cluster of genes encoding putative components of a second T3SS (T3SS-2) in addition to the well characterized Hrc1 T3SS which is associated with disease lesions in host plants and with the triggering of hypersensitive response in non-host plants. The aim of this study is to perform an in silico analysis of T3SS-2, and to compare it with other known T3SSs. RESULTS: Based on phylogenetic analysis and gene organization comparisons, the T3SS-2 cluster of the P. syringae pv. phaseolicola strain is grouped with a second T3SS found in the pNGR234b plasmid of Rhizobium sp. These additional T3SS gene clusters define a subgroup within the Rhizobium T3SS family. Although, T3SS 2 is not distributed as widely as the Hrc1 T3SS in P. syringae strains, it was found to be constitutively expressed in P. syringae pv phaseolicola through RT PCR experiments. CONCLUSIONS: The relatedness of the P. syringae T3SS-2 to a second T3SS from the pNGR234b plasmid of Rhizobium sp., member of subgroup II of the rhizobial T3SS family, indicates common ancestry and/or possible horizontal transfer events between these species. Functional analysis and genome sequencing of more rhizobia and P. syringae pathovars may shed light into why these bacteria maintain a second T3SS gene cluster in their genome. PMID- 22937902 TI - The role of dislocation-induced scattering in electronic transport in GaxIn1-xN alloys. AB - Electronic transport in unintentionally doped GaxIn1-xN alloys with various Ga concentrations (x = 0.06, 0.32 and 0.52) is studied. Hall effect measurements are performed at temperatures between 77 and 300 K. Temperature dependence of carrier mobility is analysed by an analytical formula based on two-dimensional degenerate statistics by taking into account all major scattering mechanisms for a two dimensional electron gas confined in a triangular quantum well between GaxIn1-xN epilayer and GaN buffer. Experimental results show that as the Ga concentration increases, mobility not only decreases drastically but also becomes less temperature dependent. Carrier density is almost temperature independent and tends to increase with increasing Ga concentration. The weak temperature dependence of the mobility may be attributed to screening of polar optical phonon scattering at high temperatures by the high free carrier concentration, which is at the order of 1014 cm-2. In our analytical model, the dislocation density is used as an adjustable parameter for the best fit to the experimental results. Our results reveal that in the samples with lower Ga compositions and carrier concentrations, alloy and interface roughness scattering are the dominant scattering mechanisms at low temperatures, while at high temperatures, optical phonon scattering is the dominant mechanism. In the samples with higher Ga compositions and carrier concentrations, however, dislocation scattering becomes more significant and suppresses the effect of longitudinal optical phonon scattering at high temperatures, leading to an almost temperature-independent behaviour. PMID- 22937901 TI - IMPROVDENT: improving dentures for patient benefit. A crossover randomised clinical trial comparing impression materials for complete dentures. AB - BACKGROUND: According to the UK Adult Dental Health Survey (2009) 15% of adults aged 65-74, 30% aged 75-84 and 47% aged >85 years are edentulous and require complete dentures. Patients' quality of life and nutrition status are affected by poor dentures. The quality of the dental impression is the most important issue for improving the fit and comfort of new dentures. There is paucity of RCT evidence for which impression material is best for complete dentures construction. This study aims to compare two impression materials for effectiveness and cost effectiveness. METHODS/DESIGN: IMPROVDENT is a double blind crossover trial comparing the use of alginate and silicone, two commonly used denture impression materials, in terms of patient preference and cost effectiveness. Eighty five edentulous patients will be recruited and provided with two sets of dentures, similar in all aspects except for the impression material used (alginate or silicone). Patients will try both sets of dentures for a two-week period, unadjusted, to become accustomed to the feel of the new dentures (habituation period). Patients will then wear each set of dentures for a period of 8 weeks (in random order) during which time the dentures will be adjusted for optimum comfort. Finally, patients will be given both sets of dentures for a further two weeks to wear whichever denture they prefer (confirmation period).Patients will be asked about quality of life and to rate dentures on function and comfort at the end of each trial period and asked which set they prefer at the end of the habituation period (unadjusted denture preference) and confirmation period (adjusted denture preference). A health economic evaluation will estimate incremental cost-effectiveness ratios of producing dentures from the two materials. A qualitative study will investigate the impact of dentures on behaviour and quality of life. FUNDING: IMPROVDENT is funded by NIHR RfPB (PB-PG-0408-16300). DISCUSSION: This trial aims to provide evidence on the costs and quality of dentures cast from two different commonly used impression materials; the intention is to significantly impact on the quality of denture production within NHS dentistry. TRIAL REGISTRATION: ISRCTN Register: ISRCTN01528038 UKCRN Portfolio ID: 8305. PMID- 22937903 TI - A formal enantioselective total synthesis of FR901483. AB - A formal enantioselective total synthesis of the potent immunosuppressant FR901483 (1) has been accomplished. Our approach features the use of chiron 6 as the starting material, the application of the one-pot amide reductive bisalkylation method to construct the chiral aza-quaternary center (dr = 9:1), regio- and diastereoselective intramolecular aldol reaction to build the bridged ring, and ring closing metathesis to form the 3-pyrrolin-2-one ring. PMID- 22937904 TI - Computational analysis of human OGA structure in complex with PUGNAc and NAG thiazoline derivatives. AB - The substitution of serine and threonine residues in nucleocytoplasmic proteins with 2-acetamido-2-deoxy-beta-D-glucopyranose (O-GlcNAc) residues is an essential post-translational modification found in many multicellular eukaryotes. O glycoprotein 2-acetamino-2-deoxy-beta-D-glucopyranosidase (O-GlcNAcase) hydrolyzes O-GlcNAc residues from post-translationally modified serine/threonine residues of nucleocytoplasmic protein. O-GlcNAc has been implicated in several disease states such as cancer, Alzheimer's disease, and type II diabetes. For this paper, a model of the human O-GlcNAcase (hOGA) enzyme based on the X-ray structures of bacterial Clostridium perfringens (CpNagJ) and Bacteroides thetaiotaomicrometer (BtOGA) homologues has been generated through molecular homology modeling. In addition, molecular docking, molecular dynamics (MD) simulations, and Linear Interaction Energy (LIE) were employed to determine the bind for derivatives of two potent inhibitors: O-(2-acetamido-2-deoxy-D glucopyranosylidene)amino-N-phenylcarbamate (PUGNAc) and 1,2-dideoxy-2'-methyl-R D-glucopyranoso-[2,1-d]-Delta2'-thiazoline (NAG-thiazoline), with hOGA. The results show that the binding free energy calculations using the Linear Interaction Energy (LIE) are correlated with inhibition constant values. Therefore, the model of the human O-GlcNAcase (hOGA) obtained here may be used as a target for rational design of new inhibitors. PMID- 22937906 TI - Subacute cutaneous lupus erythematosus after treatment with capecitabine. PMID- 22937905 TI - High-molecular-weight adiponectin and anthropometric variables among elementary schoolchildren: a population-based cross-sectional study in Japan. AB - BACKGROUND: Studies about the relationship between high-molecular-weight adiponectin (HMW-adn) and anthropometric variables among population-based elementary schoolchildren have been too limited, especially in Japan, where blood collection is not usually performed in the annual health examination at elementary schools. The objective of the present study was to investigate the relationship between HMW-adn and anthropometric variables (body mass index [BMI], percent body fat [%BF], waist circumference [WC], and waist-to-height ratio [WHtR]) among population-based elementary schoolchildren in Japan. METHODS: Subjects comprised all fourth-grade schoolchildren (9 or 10 years of age) in the town of Ina, Saitama Prefecture, Japan during 2005-2008 (N = 1675). After excluding 21 subjects because of refusal to participate or incomplete data, data from a total of 1654 subjects (846 boys and 808 girls) were analyzed. The height, weight, %BF, and WC of each subject were measured, while blood samples were drawn from the subjects to measure adiponectin levels (HMW-adn and total adiponectin). Childhood obesity was determined according to the age- and sex-specific cut-off points proposed by the International Obesity Task Force. Spearman's correlation coefficients between adiponectin levels and anthropometric variables were calculated for each sex. RESULTS: The anthropometric variables were negatively correlated with HMW-adn in both boys and girls. Correlation coefficients of HMW adn with anthropometric variables in the obesity group were consistently higher than those in the non-obesity group among both boys and girls. In addition, only WHtR was significantly correlated with HMW-adn regardless of sex and physique (obesity or non-obesity); the correlation coefficient was -0.386 among boys and 0.543 among girls in the obesity group, while it was -0.124 among boys and -0.081 among girls in the non-obesity group. CONCLUSIONS: HMW-adn was negatively correlated with anthropometric variables, while the correlation coefficients of HMW-adn with anthropometric variables in the obesity group were consistently higher than those in the non-obesity group. Moreover, only WHtR was significantly associated with HMW-adn regardless of sex and physique. The results of this study suggested that it is useful to monitor WHtR as a surrogate for HMW-adn among elementary school students, especially obese children. PMID- 22937907 TI - Sequence and comparative analysis of the MIP gene in Chinese straw mushroom, Volvariella volvacea. AB - The mitochondrial intermediate peptidase (MIP) gene is conserved in fungi. It is linked closely with the mating-type A (mtA) gene. In this study, a fragment of the MIP gene in Volvariella volvacea (Bull. ex Fr.) Singer was first cloned by homologue-based cloning technology. Subsequently, the entire MIP DNA sequence (PYd21-MIP) was obtained after the fragment was compared with the genomic data through BLAST analysis. The PYd21-MIP sequence appeared to be homologous with the MIP gene in other fungi. Phylogenetic analysis of PYd21-MIP and other MIP sequences from diverse fungi agreed with the current organism phylogeny. Analysis of protein domains by InterProScan software and motif searching demonstrated that PYd21-MIP encodes a homologous MIP protein. These data support the hypothesis that the PYd21-MIP protein is a Hog-MIP protein homologue from V. volvacea. PMID- 22937908 TI - Oral health care for patients with epidermolysis bullosa--best clinical practice guidelines. AB - OBJECTIVE: To provide the users with information on the current best practices for managing the oral health care of people living with EB. METHODS: A systematic literature search, in which the main topic is dental care in patients with Epidermolysis Bullosa, was performed. Consulted sources, ranging from 1970 to 2010, included MEDLINE, EMBASE, CINAHL, The Cochrane Library, DARE, and the Cochrane controlled trials register (CENTRAL). In order to formulate the recommendations of the selected studies the SIGN system was used. The first draft was analysed and discussed by clinical experts, methodologists and patients representatives on a two days consensus meeting. The resulting document went through an external review process by a panel of experts, other health care professionals, patient representatives and lay reviewers. The final document was piloted in three different centres in United Kingdom, Czech Republic and Argentina. RESULTS: The guideline is composed of 93 recommendations divided into 3 main areas: 1) Oral Care--access issues, early referral, preventative strategies, management of microstomia, prescriptions and review appointments 2) Dental treatment: general treatment modifications, radiographs, restorations, endodontics, oral rehabilitation, periodontal treatment, oral surgery and orthodontics, and 3) Anaesthetic management of dental treatment. CONCLUSIONS: A preventive protocol is today's dental management approach of choice. PMID- 22937909 TI - Proteaceae from severely phosphorus-impoverished soils extensively replace phospholipids with galactolipids and sulfolipids during leaf development to achieve a high photosynthetic phosphorus-use-efficiency. AB - Proteaceae species in south-western Australia occur on severely phosphorus (P) impoverished soils. They have very low leaf P concentrations, but relatively fast rates of photosynthesis, thus exhibiting extremely high photosynthetic phosphorus use-efficiency (PPUE). Although the mechanisms underpinning their high PPUE remain unknown, one possibility is that these species may be able to replace phospholipids with nonphospholipids during leaf development, without compromising photosynthesis. For six Proteaceae species, we measured soil and leaf P concentrations and rates of photosynthesis of both young expanding and mature leaves. We also assessed the investment in galactolipids, sulfolipids and phospholipids in young and mature leaves, and compared these results with those on Arabidopsis thaliana, grown under both P-sufficient and P-deficient conditions. In all Proteaceae species, phospholipid levels strongly decreased during leaf development, whereas those of galactolipids and sulfolipids strongly increased. Photosynthetic rates increased from young to mature leaves. This shows that these species extensively replace phospholipids with nonphospholipids during leaf development, without compromising photosynthesis. A considerably less pronounced shift was observed in A. thaliana. Our results clearly show that a low investment in phospholipids, relative to nonphospholipids, offers a partial explanation for a high photosynthetic rate per unit leaf P in Proteaceae adapted to P-impoverished soils. PMID- 22937910 TI - Characterizing the photoinduced switching process of a nitrospiropyran self assembled monolayer using in situ sum frequency generation spectroscopy. AB - Sum frequency generation (SFG) vibrational spectroscopy is employed to investigate the reversible, photoinduced spiro->merocyanine isomerization of a self-assembled monolayer, the result of attachment of nitrospiropyran to a gold surface using a dithiolane anchoring group. The attachment of these molecular "alligator clips" to spiropyran molecules provide an easily accessible method to self-assemble a robust monolayer of spiropyran on a gold surface, which allows photoswitching of the spiropyran units. Probing the symmetric and antisymmetric stretching modes of the nitro group allows the determination of the structural orientation of the charged moiety with respect to the surface normal as well as the isomerization rates under photoinduced switching conditions. The photoisomerization of the spiropyran SAM on the gold surface is much faster than the rates of switching spiropyrans in a solid crystalline form, and the rate of thermal relaxation of the opened to closed form in this study is found to be on the same time scale as the relaxation of spiropyran when present in solutions with polar solvents. PMID- 22937911 TI - Scrotal cutaneous verruciform xanthoma with monocyte chemoattractant protein-1 immunohistochemical study: a case report. AB - INTRODUCTION: Verruciform xanthoma is a rare, benign lesion characterized by hyperkeratosis and aggregates of foam cell macrophages. Here, we describe a case of verruciform xanthoma on the scrotum, in which the immunohistochemical localization of monocyte chemoattractant protein-1, a chemokine of the C-C or beta family that has been shown to induce the recruitment of monocytes for injured tissue, was analyzed to determine which cells release chemoattractants for macrophages. CASE PRESENTATION: A 75-year-old Japanese man with a well defined nodule on the left scrotum was admitted to the hospital. An excision biopsy revealed epidermal papillary proliferation with parakeratosis, hyperkeratosis, and infiltration of foam cell macrophages, whereby a pathological diagnosis of benign cutaneous verruciform xanthoma was made. Immunohistochemically, monocyte chemoattractant protein-1 was observed predominantly on cytokeratin AE1/AE3-positive differentiating keratinocytes in the prickle cell layer. However, while infiltrating macrophages were densely stained for monocyte chemoattractant protein-1, keratinocytes in the basal and parabasal layers were almost negative. CONCLUSIONS: We demonstrated that keratinocyte-derived monocyte chemoattractant protein-1 plays an important role in the establishment of particular histological features of verruciform xanthoma. However, in the present case, unlike in previous reports, monocyte chemoattractant protein-1 immunostaining in keratinocytes in the basal and parabasal layers was not prominent. We speculate that in the active phase of verruciform xanthoma, when continuous stimuli that release monocyte chemoattractant protein-1 from keratinocytes to the surrounding stromal area are present, the apparent immunostaining of monocyte chemoattractant protein-1 can be underestimated because of the void created by accelerated keratinocyte release from the cytoplasmic fraction. PMID- 22937912 TI - Using death certificates and medical examiner records for adolescent occupational fatality surveillance and research: a case study. AB - Death certificates and medical examiner records have been useful yet imperfect data sources for work-related fatality research and surveillance among adult workers. It is unclear whether this holds for work-related fatalities among adolescent workers who suffer unique detection challenges in part because they are not often thought of as workers. This study investigated the utility of using these data sources for surveillance and research pertaining to adolescent work related fatalities. Using the state of North Carolina as a case study, we analyzed data from the death certificates and medical examiner records of all work-related fatalities data among 11- to 17-year-olds between 1990-2008 (N = 31). We compared data sources on case identification, of completeness, and consistency information. Variables examined included those on the injury (e.g., means), occurrence (e.g., place), demographics, and employment (e.g., occupation). Medical examiner records (90%) were more likely than death certificates (71%) to identify adolescent work-related fatalities. Data completeness was generally high yet varied between sources. The most marked difference being that in medical examiner records, type of business/industry and occupation were complete in 72 and 67% of cases, respectively, while on the death certificates these fields were complete in 90 and 97% of cases, respectively. Taking the two sources together, each field was complete in upward of 94% of cases. Although completeness was high, data were not always of good quality and sometimes conflicted across sources. In many cases, the decedent's occupation was misclassified as "student" and their employer as "school" on the death certificate. Even though each source has its weaknesses, medical examiner records and death certificates, especially when used together, can be useful for conducting surveillance and research on adolescent work-related fatalities. However, extra care is needed by data recorders to ensure that occupation and employer are properly coded when dealing with adolescent worker deaths. PMID- 22937913 TI - Evaluation of C-reactive protein, haptoglobin and cardiac troponin 1 levels in brachycephalic dogs with upper airway obstructive syndrome. AB - BACKGROUND: Brachycephalic dogs have unique upper respiratory anatomy with abnormal breathing patterns similar to those in humans with obstructive sleep apnea syndrome (OSAS). The objective of this study was to evaluate the correlation between anatomical components, clinical signs and several biomarkers, used to determine systemic inflammation and myocardial damage (C-reactive protein, CRP; Haptoglobin, Hp; cardiac troponin I, cTnI), in dogs with brachycephalic upper airway obstructive syndrome (BAOS). RESULTS: Fifty brachycephalic dogs were included in the study and the following information was studied: signalment, clinical signs, thoracic radiographs, blood work, ECG, components of BAOS, and CRP, Hp and cTnI levels. A high proportion of dogs with BAOS (88%) had gastrointestinal signs. The prevalence of anatomic components of BAOS was: elongated soft palate (100%), stenotic nares (96%), everted laryngeal saccules (32%) and tracheal hypoplasia (29.1%). Increased serum levels of biomarkers were found in a variable proportion of dogs: 14% (7/50) had values of CRP > 20 mg/L, 22.9% (11/48) had values of Hp > 3 g/L and 47.8% (22/46) had levels of cTnI > 0.05 ng/dl. Dogs with everted laryngeal saccules had more severe respiratory signs (p<0.02) and higher values of CRP (p<0.044). No other statistical association between biomarkers levels and severity of clinical signs was found. CONCLUSIONS: According to the low percentage of patients with elevated levels of CRP and Hp, BAOS does not seem to cause an evident systemic inflammatory status. Some degree of myocardial damage may occur in dogs with BAOS that can be detected by cTnI concentration. PMID- 22937914 TI - Bluetongue serotype 2 and 9 modified live vaccine viruses as causative agents of abortion in livestock: a retrospective analysis in Italy. AB - The recent outbreak caused by Schmallenberg virus, which affected sheep, goats and cattle in Europe, highlighted the importance of having a robust surveillance plan capable of monitoring abortions and malformations in the livestock offspring. In this context, bluetongue viruses (BTVs) represented and represent one of the major threats to the European livestock industry. Aiming to improve the understanding on BTV cross placental transmission and serotype involvement, in this retrospective study foetal spleens and/or brains of 663 ovines, 429 bovines, 155 goats and 17 buffaloes were tested for the presence of BTV by virus isolation. BTV vaccine strains were isolated from 31 foetuses (2.4%; 95% CI: 1.7 3.4%): 24 (3.6%; 95% CI: 2.4-5.3%) from ovine foetal tissues; 6 (1.4%; 95% CI: 0.6-3.0%) from bovine foetal tissues and 1 (0.6%; 95% CI: 0.2-3.5%) from the spleen of a caprine foetus. All foetuses were from animals vaccinated with either BTV-2 or BTV-2, and BTV-9 modified live vaccines (MLVs) produced by Onderstepoort Biological Products (OBP), South Africa. Among the 31 isolated vaccine strains, serotype 9 (n = 28) was more frequently isolated (P < 0.05) than serotype 2 (n = 3). In two cases infectious vaccine strains were found in the foetal tissues 2 months after the vaccine administration. Other pathogens known to be causative agents of abortion in ruminants were not detected nor isolated. This study demonstrates, for the first time, that BTV-2 and BTV-9 vaccine strains are able to cross the placental barrier of sheep, cattle and goats. BTV-2 and BTV-9 vaccine strains are able to infect foetuses and cause abortions or malformations depending on the period of pregnancy at the time of vaccination. PMID- 22937915 TI - Area-under-the-HbA1c-curve above the normal range and the prediction of microvascular outcomes: an analysis of data from the Diabetes Control and Complications Trial. AB - AIMS: In the Diabetes Control and Complications Trial, mean updated HbA(1c) accounted for most of the differential risk of microvascular complications between intensive and conventional insulin therapy. We hypothesized, however, that a more precise measure of chronic hyperglycaemic exposure may be the incremental area-under-the-HbA(1c)-curve above the Diabetes Control and Complications Trial-standardized normal range for HbA(1c) (iAUC(HbA1c>norm)). METHODS: Using the Principal Diabetes Control and Complications Trial data set, we compared the following three measures of chronic glycaemic exposure for their capacity to predict retinopathy, nephropathy and neuropathy during the Diabetes Control and Complications Trial: mean updated HbA(1c), iAUC(HbA1c>norm), and total area-under-the-HbA(1c)-curve (tAUC(HbA1c)). For each outcome, models using each of these three glycaemic measures were compared in the following three ways: hazard or odds ratio, chi(2) statistic, and Akaike information criterion. RESULTS: The three glycaemic measures did not differ in their prediction of neuropathy. iAUC(HbA1c>norm) was modestly superior to mean updated HbA(1c) for predicting nephropathy (chi(2) P = 0.017, Akaike P = 0.032). In contrast, for predicting retinopathy, both iAUC(HbA1c>norm) (chi(2) P = 0.0005, Akaike P = 0.0005) and tAUC(HbA1c) (chi(2) P = 0.004, Akaike P = 0.004) were significantly better than mean updated HbA(1c). Varying its HbA(1c) threshold incrementally between 37 and 53 mmol/mol (5.5-7.0%), inclusive, did not improve the prediction of retinopathy by iAUC(HbA1c>threshold) beyond that of tAUC(HbA1c,) consistent with the concept of a continuous relationship between glycaemia and retinopathy, with no glycaemic threshold. CONCLUSIONS: Both iAUC(HbA1c>norm) and tAUC(HbA1c) were superior to mean updated HbA(1c) for predicting retinopathy. Optimal assessment of chronic glycaemic exposure as a determinant of retinopathic risk may require consideration of both the degree of hyperglycaemia and its duration. PMID- 22937916 TI - Serological and molecular survey of Leishmania parasites in apparently healthy dogs in the West Bank, Palestine. AB - BACKGROUND: Canine visceral leishmaniasis (CVL) is caused by Leishmania infantum in all Mediterranean countries. The Leishmania parasite is transmitted by the bite of a corresponding sand fly vector and primarily maintained in nature by wild and domestic reservoirs, including dogs, foxes and jackals. Infected dogs are the primary reservoir host in endemic regions and are the most significant risk disposing humans to infection. The present study aimed at assessing the prevalence of infection with Leishmania and identification of Leishmania infantum in domestic dogs in the West Bank, Palestine. METHODS: The infection rate among domestic dogs collected from seven districts in the Palestinian West Bank was investigated by examination of parasites in culture from the buffy coat using serological and molecular methods; based on ELISA, internal transcribed spacer 1 (ITS1) and cysteine protease (CPB) PCR. RESULTS: Out of 215 dogs examined for Leishmania, 36 (16.7%) were positive in at least one method. Twenty three animals (11.5%) were positive for Leishmania DNA, whereas, ELISA and culture revealed 16 (7.5%), and 4 (1.5%) respectively. CPB-PCR on one of three culture-positive isolates revealed Leishmania infantum as the causative agent for Leishmania infection in dogs. CONCLUSIONS: Our study showed that canine leishmania infection is prevalent with varying degrees in all the seven studied districts in Palestine despite the absence of human VL cases in 4 of these districts. The causative agent was confirmed to be Leishmania infantum. PMID- 22937917 TI - Insulin-stimulated phosphorylation of protein phosphatase 1 regulatory subunit 12B revealed by HPLC-ESI-MS/MS. AB - BACKGROUND: Protein phosphatase 1 (PP1) is one of the major phosphatases responsible for protein dephosphorylation in eukaryotes. Protein phosphatase 1 regulatory subunit 12B (PPP1R12B), one of the regulatory subunits of PP1, can bind to PP1cdelta, one of the catalytic subunits of PP1, and modulate the specificity and activity of PP1cdelta against its substrates. Phosphorylation of PPP1R12B on threonine 646 by Rho kinase inhibits the activity of the PP1c PPP1R12B complex. However, it is not currently known whether PPP1R12B phosphorylation at threonine 646 and other sites is regulated by insulin. We set out to identify phosphorylation sites in PPP1R12B and to quantify the effect of insulin on PPP1R12B phosphorylation by using high-performance liquid chromatography-electrospray ionization-tandem mass spectrometry. RESULTS: 14 PPP1R12B phosphorylation sites were identified, 7 of which were previously unreported. Potential kinases were predicted for these sites. Furthermore, relative quantification of PPP1R12B phosphorylation sites for basal and insulin treated samples was obtained by using peak area-based label-free mass spectrometry of fragment ions. The results indicate that insulin stimulates the phosphorylation of PPP1R12B significantly at serine 29 (3.02 +/- 0.94 fold), serine 504 (11.67 +/- 3.33 fold), and serine 645/threonine 646 (2.34 +/- 0.58 fold). CONCLUSION: PPP1R12B was identified as a phosphatase subunit that undergoes insulin-stimulated phosphorylation, suggesting that PPP1R12B might play a role in insulin signaling. This study also identified novel targets for future investigation of the regulation of PPP1R12B not only in insulin signaling in cell models, animal models, and in humans, but also in other signaling pathways. PMID- 22937918 TI - The neural crest- and placodes-derived afferent innervation of the mouse esophagus. AB - BACKGROUND: The mouse is an invaluable model for mechanistic studies of esophageal nerves, but the afferent innervation of the mouse esophagus is incompletely understood. Vagal afferent neurons are derived from two embryonic sources: neural crest and epibranchial placodes. We hypothesized that both neural crest and placodes contribute to the TRPV1-positive (potentially nociceptive) vagal innervation of the mouse esophagus. METHODS: Vagal jugular/nodose ganglion (JNG) and spinal dorsal root ganglia (DRG) neurons were retrogradely labeled from the cervical esophagus. Single cell RT-PCR was performed on the labeled neurons. KEY RESULTS: In the Wnt1Cre/R26R mice expressing a reporter in the neural crest derived cells we found that both the neural crest- and the placodes-derived vagal JNG neurons innervate the mouse esophagus. In the wild-type mouse the esophageal vagal JNG TRPV1-positive neurons segregated into two subsets: putative neural crest-derived purinergic receptor P2X(2) -negative/preprotachykinin-A (PPT-A) positive subset and putative placodes-derived P2X(2) -positive/PPTA-negative subset. These subsets also segregated by the expression of TrkA and GFRalpha(3) in the putative neural crest-derived subset, and TrkB in the putative placodes derived subset. The TRPV1-positive esophageal DRG neurons had the phenotype similar to the vagal putative neural crest-derived subset. CONCLUSIONS & INFERENCES: The TRPV1-positive (potentially nociceptive) vagal afferent neurons innervating the mouse esophagus originate from both neural crest and placodes. The expression profile of the receptors for neurotrophic factors is similar between the neural crest-derived vagal and spinal nociceptors, but distinct from the vagal placodes-derived nociceptors. PMID- 22937919 TI - Psychometric properties of the Confidence and Trust in Delivery Questionnaire (CTDQ): a pilot study. AB - BACKGROUND: Assessing expecting mother's opinions prior to birth draws a comprehensive picture for the caregivers about their emotional state and their expectations. Some questionnaires to cover these aspects do exist. This study aims to present the psychometric properties of a new instrument, the Confidence and Trust in Delivery Questionnaire (CDTQ) a short but reliable a self-report instrument that focuses on confidence and trust as meaningful dimensions for expectant mothers. METHODS: A pilot validation study of 221 women 6 weeks before childbirth was conducted in Germany between October 2007 and June 2008. To detect structural relations between the items, factor and reliability analyses were applied to the CTDQ items. Factor analysis was performed by means of principal components analysis and varimax rotation. Internal reliability was assessed by Cronbach's alpha. External validation was performed using the sense of coherence (SOC) scale. RESULTS: The CTDQ comprises of 11 items. We found a 4-factor structure. The internal consistency of the whole item pool (Cronbach's alpha = 0.79) and the 4 subscales [confidence in labor (alpha = 0.82); partner's support (alpha = 0.62); trust in medical competency (alpha = 0.68); being informed (alpha = 0.60)] can be regarded as sufficient or even excellent. The 4 factors explained 69.6% of total variance. Except for a high intercorrelation (0.70) between "partner's support" and "trust in medical competence", the subscales show low intercorrelations, indicating an adequate independence of the respective subscales. Regarding the external validity we found minor respective moderate correlations with the SOC scale. CONCLUSIONS: Our data suggest that the CTDQ is a useful instrument to assess confidence and trust in delivery. With 4 clinically relevant dimensions, the CTDQ is now open for further studies in the field of labor. PMID- 22937920 TI - Febrile seizures and behavioural and cognitive outcomes in preschool children: an old issue revisited. PMID- 22937921 TI - Unilateral linear capillaropathy limited to the upper extremity in an infant. PMID- 22937922 TI - Intersubband terahertz transitions in Landau level system of cascade GaAs/AlGaAs quantum well structures in strong tilted magnetic field. AB - The tunable terahertz intersubband Landau level transitions in resonant tunneling cascade quantum well structures are considered. The way of lifting the selection rule forbidding the inter-Landau level terahertz transitions of interest by applying a magnetic field tilted with respect to the structure layers is proposed. The importance of asymmetric structure design to achieve considerable values of transition dipole matrix elements is demonstrated. PMID- 22937924 TI - Angle inequality for judging the transition from Cassie-Baxter to Wenzel states when a water drop contacts bottoms of grooves between micropillars. AB - A specific criterion is often used to judge the transition from Cassie-Baxter wetting state to that of Wenzel. In this work, we examine the applicability of this specific criterion to the case of micropillars with circular or polygonal cross-sections. For this purpose, we derive an angle inequality. When this angle inequality is violated, the specific criterion holds for the corresponding micropillars. Otherwise, the specific criterion may not be applicable to such micropillars. These results are validated by pressing tests on six types of micropillars, which have circular, triangular, square, hexagonal, T-shaped, and star-like cross-sections. PMID- 22937923 TI - DNA binding specificity of ATAF2, a NAC domain transcription factor targeted for degradation by Tobacco mosaic virus. AB - BACKGROUND: Control of the host transcriptome represents a key battleground in the interaction of plants and pathogens. Specifically, plants have evolved complex defense systems that induce profound transcriptional changes in response to pathogen attack while pathogens have evolved mechanisms to subvert or disable these defenses. Several NAC transcription factors such as ATAF2 have been linked to plant defense responses, including those targeting viruses. The replication protein of Tobacco mosaic virus (TMV) has been shown to interact with and target the degradation of ATAF2. These findings suggest that the transcriptional targets of ATAF2 are involved in defense against TMV. RESULTS: To detect potential ATAF2 transcriptional targets, a genomic pull-down assay was utilized to identify ATAF2 promoter binding sequences. Subsequent mobility shift and DNA footprinting assays identified a 30-bp ATAF2 binding sequence. An in vivo GUS reporter system confirmed the function of the identified 30-bp binding sequence as an ATAF2 specific transcriptional activator in planta. Gel filtration studies of purified ATAF2 protein and mutagenesis studies of the 30-bp binding sequence indicate ATAF2 functions as a dimer. Computational analysis of interacting promoter sequences identified a corresponding 25-bp A/T-rich consensus sequence with repeating [GC]AAA motifs. Upon ATAF2 induction real-time qRT-PCR studies confirmed the accumulation of select gene transcripts whose promoters contain this consensus sequence. CONCLUSION: We report the identification of a cis regulatory binding sequence for ATAF2. Different from other known NAC protein binding sequences, the A/T-rich ATAF2 binding motif represents a novel binding sequence for NAC family proteins. Combined this information represents a unique tool for the identification of ATAF2 target genes. PMID- 22937925 TI - Flexible approach to stemona alkaloids: total syntheses of (-)-stemospironine and three new diastereoisomeric analogs. AB - Total syntheses of (-)-stemospironine and three new diastereoisomeric analogs have been completed through a flexible strategy devised for Stemona alkaloids. The azabicycle 7 is the pivotal intermediate, from which the sequence splits according to each particular target. The most remarkable differential feature for stemospironine is the installation of the spiranic gamma-lactone through an intramolecular Horner-Wadsworth-Emmons olefination. The configuration of the stereogenic center at C-11 was controlled by fine-tuning of the synthetic sequence. PMID- 22937926 TI - Brainstem gliomas. PMID- 22937927 TI - Oculomotor nerve palsy by posterior communicating artery aneurysms: influence of surgical strategy on recovery. AB - OBJECT: Resolution of oculomotor nerve palsy (ONP) after clipping of posterior communicating artery (PCoA) aneurysms has been well documented. However, whether additional decompression of the oculomotor nerve via aneurysm sac dissection or resection is superior to pure aneurysm clipping is the subject of much debate. Therefore, the objective in the present investigation was to analyze the influence of surgical strategy--specifically, clipping with or without aneurysm dissection--on ONP resolution. METHODS: Between June 1999 and December 2010, 18 consecutive patients with ruptured and unruptured PCoA aneurysms causing ONP were treated at the authors' institution. Oculomotor nerve palsy was evaluated on admission and at follow-up. The electronic database MEDLINE was searched for additional data in published studies of PCoA aneurysms causing ONP. Two reviewers independently extracted data. RESULTS: Overall, 8 studies from the literature review and 6 patients in the current series (121 PCoA aneurysms) met the study inclusion criteria. Ninety-four aneurysms were treated with simple aneurysm neck clipping and 27 with clipping plus aneurysm sac decompression. The surgical strategy, simple aneurysm neck clipping versus clipping plus oculomotor nerve decompression, had no effect on full ONP resolution on univariate (p = 0.5) and multivariate analyses. On multivariate analysis, patients with incomplete ONP at admission were more likely to have full resolution of the palsy than were those with complete ONP at admission (p = 0.03, OR = 4.2, 95% CI 1.1-16). CONCLUSIONS: Data in the present study indicated that ONP caused by PCoA aneurysms improves after clipping without and with oculomotor nerve decompression. The resolution of ONP is inversely associated with the initial severity of ONP. PMID- 22937928 TI - Effect of pregnancy on hemangioblastoma development and progression in von Hippel Lindau disease. AB - OBJECT: Prior cases suggest that pregnancy increases the development and progression of CNS hemangioblastomas and/or peritumoral cysts. To determine the effect of pregnancy on CNS hemangioblastomas and peritumoral cysts, the authors prospectively evaluated serial clinical and imaging findings in patients with von Hippel-Lindau (VHL) disease who became pregnant and compared findings during pregnancy to findings in the same patients when they were not pregnant as well as to findings from a cohort of VHL patients who did not become pregnant. METHODS: Female VHL disease patients enrolled in a prospective natural history study who were of reproductive age (16-35 years at study entrance) were included. Analysis of serial clinical and imaging findings was performed. RESULTS: Thirty-six consecutive female VHL disease patients harboring 177 hemangioblastomas were included (mean follow-up [+/- SD] 7.5 +/- 2.3 years). Nine patients (25%) became pregnant (pregnancy cohort). The mean rates of development of new hemangioblastomas and peritumoral cysts in these women during pregnancy (0.4 +/- 0.4 tumors/year; 0.1 +/- 0.2 cysts/year) did not differ significantly (p > 0.05) from the mean rates in the same group during nonpregnant periods (0.3 +/- 0.4 tumors/year; 0.1 +/- -0.1 cysts/year) or from the rate in the 27 patients who did not become pregnant (the no-pregnancy cohort: 0.3 +/- 0.5 tumors/year; 0.1 +/- 0.2 cysts/year). Hemangioblastoma growth rates were similar (p > 0.05) during pregnancy (mean 29.8% +/- 42.7% increase in volume per year) compared with during nonpregnant periods (41.4% +/- 51.4%) in the pregnancy cohort and the no pregnancy cohort (34.3% +/- 55.3%). Peritumoral cyst growth rates during pregnancy (571.0% +/- 887.4%) were similar (p > 0.05) to those of the no pregnancy cohort (483.9% +/- 493.9%), but the rates were significantly higher for women in the pregnancy cohort during nonpregnant periods (2373.6% +/- 3392.9%; p < 0.05 for comparison with no-pregnancy cohort). There was no significant difference (p > 0.05) in the need for resection or the mean age at resection between the pregnancy (28% of hemangioblastomas in cohort; mean patient age at resection 30.2 +/- 2.6 years) and no-pregnancy cohorts (19%; 32.3 +/- 5.6 years). CONCLUSIONS: Pregnancy is not associated with increased hemangioblastoma or peritumoral cyst development or progression in patients with VHL disease. PMID- 22937929 TI - Diffuse brainstem glioma: prognostic factors. AB - OBJECT: Brainstem gliomas were regarded as a single entity prior to the advent of MRI; however, several studies investigating MRI have recognized that these lesions are a heterogeneous group, and certain subgroups have a better prognosis for long-term survival. The aim of this study was to conduct a retrospective analysis of prognostic factors of patients with brainstem gliomas confirmed by histopathological diagnosis, particularly regarding assessment of whether histological grade, age, and MRI findings are prognostic factors for patient survival. METHODS: The study evaluated 100 patients diagnosed with brainstem glioma. There were 63 adults (40 men and 23 women; age range 18-75 years, mean 41 years) and 37 children (19 boys and 18 girls; age range 2-12 years, mean 6.9 years). RESULTS: The mean overall survival of this population, measured from the date of biopsy, was 57 months for diffuse low-grade glioma and 13.8 months for diffuse high-grade glioma (p < 0.001). The mean survival among patients with nonenhancing contrast lesions on MRI was 54.2 months, whereas for patients with enhancing lesions, it was 21.7 months (p < 0.001). Comparisons between the Kaplan Meier survival curves of adults and children revealed similar median survival periods of 25 and 16 months, respectively (p > 0.05). The multivariate analysis (Cox proportional hazards regression) revealed that only histological grade was a significant prognostic factor (p < 0.001). CONCLUSIONS: The study revealed that histological grade and MRI features were significant prognostic factors for survival in these patients, but in multivariate analysis, only histological grade remained a significant factor. PMID- 22937930 TI - Cognitive functioning early after surgery of gliomas in eloquent areas. AB - OBJECT: Patients with gliomas frequently have cognitive deficits, and surgery can exacerbate these deficits. Preoperative assessment is therefore crucial in patients undergoing surgery for glioma in eloquent areas, because the proximity of functional areas increases the risk of permanent postoperative cognitive disturbances. Although pre- and postoperative language and motor function in patients with glioma have been investigated frequently, data on good cognition studies are scarce. Most studies have focused on clinical neurological functioning or have only used brief neurological instruments. The authors investigated whether surgery for glioma in eloquent areas influences cognition early after surgery, by using an elaborate test protocol. METHODS: Twenty-eight patients with gliomas of the left hemisphere in language and nonlanguage areas were assessed before and 3 months after surgery with a comprehensive neuropsychological test protocol. The authors performed a correlation analysis between change in cognitive performance and tumor characteristics (that is, location, volume, pathological features, and histological grade) and between cognitive change and treatment-related factors (the extent of the resection and postoperative treatment with chemo- and radiotherapy). RESULTS: Both pre- and postoperatively, the mean performance of the patients was worse than the performance of the normal population in the language domain, the memory domain, and the executive functions (p < 0.05). Postoperatively, a decline was found in the language domain (t = 2.34, p = 0.027) and in the executive functions (t = 2.45, p = 0.022). However, cognitive change postsurgery was influenced by the location of the tumor; the decrease of cognitive score in the language domain was only observed in patients with tumors in or close to language areas (t = 2.33, p = 0.029). No effect on cognitive change was found for the other tumor characteristics and treatment-related factors. CONCLUSIONS: This study underlines the importance of the use of a neuropsychological test protocol before and after surgery in patients with glioma, because several tasks in the domains of language, memory, and executive functions appeared to deteriorate after surgery. Tumor resection in language areas increases the risk of cognitive deficits in the language domain postoperatively. PMID- 22937931 TI - Cranial nerve III palsy. PMID- 22937932 TI - Mannitol or saline. PMID- 22937933 TI - Hearing after Gamma Knife surgery. PMID- 22937934 TI - Longitudinal analysis of hearing before and after radiosurgery for vestibular schwannoma. AB - OBJECT: The aim of this study was to perform an accurate analysis of changes in hearing in patients with vestibular schwannoma (VS) who have undergone Gamma Knife surgery (GKS) and distinguish the impact of radiosurgery from the natural course of hearing deterioration due to the tumor itself. METHODS: This study was a retrospective review of prospectively collected patient data. A group of 154 patients with unilateral nonsurgically treated VS was conservatively monitored for more than 6 months and then treated with GKS between July 1997 and September 2005. They were followed up with serial clinical examination, MRI, and audiometry. The annual hearing decrease rate (AHDR) was measured before and after radiosurgery, and the possible prognostic factors for hearing preservation were investigated. RESULTS: The mean dose prescribed to the tumor margins was 12.1 Gy. The mean radiological follow-up period after GKS was 60 months (range 7-123 months). The tumor control rate was 94.8%, and 8 patients underwent subsequent intervention due to tumor progression. The mean audiological follow-up times before and after GKS were 22 and 52 months, respectively. The mean AHDRs before and after GKS were 5.39 dB/year (95% CI 3.31-7.47 dB/year) and 3.77 dB/year (95% CI 3.13-4.40 dB/year), respectively (p > 0.05). The mean pre- and post-GKS AHDRs in patients who initially had Gardner-Robertson (GR) Class I hearing were -0.57 dB/year (95% CI -2.95 to 1.81 dB/year) and 3.59 dB/year (95% CI 2.52-4.65 dB/year), respectively (p = 0.007). The mean pre- and post-GKS AHDRs in patients who initially had GR Class II hearing were 5.09 dB/year (95% CI 1.36-8.82 dB/year) and 4.98 dB/year (95% CI 3.86-6.10 dB/year), respectively (p > 0.05). A subgroup of 80 patients had both early and late post-intervention AHDR assessment (with early referring to the period from GKS to the assessment closest to the 2 year follow-up point and late referring to the period from that assessment to the most recent one); in these patients, the mean early post-GKS AHDR was 5.86 dB/year (95% CI 4.25-7.50 dB/year) and the mean late post-GKS AHDR was 1.86 dB/year (95% CI 0.77-2.96 dB/year) (p < 0.001). A maximum cochlear dose of less than 4 Gy was found to be the sole prognostic factor for hearing preservation. CONCLUSIONS: The present study demonstrated the absence of an increase in AHDR after radiosurgery as compared with the preoperative AHDR. There was even a trend indicating a reduction in the annual hearing loss after radiosurgery over the long term. To fully elucidate a possible protective effect of radiosurgery, longer-term follow-up with a larger group of patients will be required. PMID- 22937935 TI - Correlation between language function and the left arcuate fasciculus detected by diffusion tensor imaging tractography after brain tumor surgery. AB - OBJECT: Disturbance of the arcuate fasciculus in the dominant hemisphere is thought to be associated with language-processing disorders, including conduction aphasia. Although the arcuate fasciculus can be visualized in vivo with diffusion tensor imaging (DTI) tractography, its involvement in functional processes associated with language has not been shown dynamically using DTI tractography. In the present study, to clarify the participation of the arcuate fasciculus in language functions, postoperative changes in the arcuate fasciculus detected by DTI tractography were evaluated chronologically in relation to postoperative changes in language function after brain tumor surgery. METHODS: Preoperative and postoperative arcuate fasciculus area and language function were examined in 7 right-handed patients with a brain tumor in the left hemisphere located in proximity to part of the arcuate fasciculus. The arcuate fasciculus was depicted, and its area was calculated using DTI tractography. Language functions were measured using the Western Aphasia Battery (WAB). RESULTS: After tumor resection, visualization of the arcuate fasciculus was increased in 5 of the 7 patients, and the total WAB score improved in 6 of the 7 patients. The relative ratio of postoperative visualized area of the arcuate fasciculus to preoperative visualized area of the arcuate fasciculus was increased in association with an improvement in postoperative language function (p = 0.0039). CONCLUSIONS: The role of the left arcuate fasciculus in language functions can be evaluated chronologically in vivo by DTI tractography after brain tumor surgery. Because increased postoperative visualization of the fasciculus was significantly associated with postoperative improvement in language functions, the arcuate fasciculus may play an important role in language function, as previously thought. In addition, postoperative changes in the arcuate fasciculus detected by DTI tractography could represent a predicting factor for postoperative language dependent functional outcomes in patients with brain tumor. PMID- 22937936 TI - Von Hippel-Lindau disease and pregnancy. PMID- 22937937 TI - Paraneoplastic leukocytoclastic vasculitis as an initial presentation of malignant pleural mesothelioma: a case report. AB - INTRODUCTION: Vasculitis has been associated with malignancies, more commonly hematological rather than solid malignancies. Due to the rarity of these conditions and the lack of a temporal association, the relationship between vasculitis and malignancy remains unclear. Paraneoplastic vasculitis as a phenomenon of lung cancer has been described in the literature. To the best of our knowledge, this is the first case report of leukocytoclastic vasculitis being an initial presentation of malignant pleural mesothelioma. CASE PRESENTATION: We report the case of an 84-year old Greek man who presented to our facility with an erythematous, pruritic and purpuric rash affecting his limbs. This was biopsy proven to be leukocytoclastic vasculitis and treated conservatively with topical corticosteroids as well as oral prednisolone, with good results. Six months later, he was diagnosed as having malignant pleural mesothelioma. As he remained asymptomatic from his malignancy, no systemic chemotherapy was instituted. He had a recurrence of biopsy-proven leukocytoclastic vasculitis two months after he was diagnosed as having mesothelioma, which again settled with conservative measures. CONCLUSIONS: It is important to remain vigilant with regard to the association between leukocytoclastic vasculitis and malignancies. A diagnosis of vasculitis requires a search for malignancies as well as other possible etiologies. This is particularly of relevance when the vasculitis becomes chronic, recurrent or treatment is no longer effective. Should our patient have experienced refractory vasculitis, we would have instituted systemic chemotherapy to treat the underlying malignancy. PMID- 22937948 TI - Redox-modulated stepwise photochromism in a ruthenium complex with dual dithienylethene-acetylides. AB - Achieving stepwise photochromism in a combined molecule to access all of the possible ring-open/closed isomers is a challenge due to facile energy transfer from ring-open dithienylethene (DTE) to an adjacent ring-closed moiety that prohibits further photocyclization. The preparation, characterization, and photochromic properties of a bis(sigma-acetylide) bonded ruthenium(II) complex 2oo and its oxidized form 2oo(+) with two identical DTE-acetylides (L1o) are described. Stepwise and dual photochromic reactions are successfully achieved in both 2oo and 2oo(+), in which the ring-closing absorption band of 2oo(+) shows an obvious blue-shift relative to 2oo. It is demonstrated that stepwise photochromic reactions 2oo->2co->2cc are more facile than 2oo(+)->2co(+)->2cc(+). The lower electronic density at the reactive carbon atoms upon oxidation of Ru(II) to Ru(III) causes photocyclization to have more difficulty proceeding in oxidized species 2oo(+)/2co(+). Upon dual ring-closure, 2cc/2cc(+) exhibits significant electronic interaction between two identical ring-closed DTE units across trans Ru(dppe)(2) spacer. The interconversion processes among six states are unambiguously demonstrated by NMR, UV-vis-NIR, and IR spectroscopic, and electrochemical and computational studies. PMID- 22937950 TI - Hearing conservation and noise management practices in professional orchestras. AB - Hearing conservation and noise exposure management for professional orchestras is a difficult issue resistant to standard control measures as used in other industries with excessive noise problems. Although there has been a great deal of research into this area in terms of the audiological status of musicians and their exposure to noise, there are relatively few industry-specific strategies that can be adopted by an orchestra looking to address these issues. Australia does not have a uniform approach to hearing conservation management in its orchestras; however, each orchestra actively grapples with the challenges of balancing legal, practical, and artistic concerns. This study systematically investigated hearing conservation practices, noise exposure management, and audiological screening protocols in eight professional orchestras. The research involved personal interviews with staff at each orchestra, including inspection of venues and facilities. While all these orchestras were aware of the risks and were actively taking significant steps to reduce noise exposure, a range of approaches, with varying degrees of effectiveness and understanding of the issue, were found across the sector. There was limited evidence of educational programs for either the musicians at risk of excessive noise exposure or the staff responsible for devising and implementing control measures. In addition, the reported use of adequate personal hearing protection by musicians was poor. As Australia has recently introduced a national approach to workplace health and safety, a similar approach to noise and audiological management across the country's orchestral sector is proposed, drawn from existing research and practice. This will enable both consistent procedures and meaningful dialogue between the orchestras on the topics of hearing conservation, audiological monitoring, and educational practices. PMID- 22937949 TI - Pharmacokinetics and effect of intravenous meloxicam in weaned Holstein calves following scoop dehorning without local anesthesia. AB - BACKGROUND: Dehorning is a common practice involving calves on dairy operations in the United States. However, less than 20% of producers report using analgesics or anesthetics during dehorning. Administration of a systemic analgesic drug at the time of dehorning may be attractive to dairy producers since cornual nerve blocks require 10 - 15 min to take effect and only provide pain relief for a few hours. The primary objectives of this trial were to (1) describe the compartmental pharmacokinetics of meloxicam in calves after IV administration at 0.5 mg/kg and (2) to determine the effect of meloxicam (n = 6) or placebo (n = 6) treatment on serum cortisol response, plasma substance P (SP) concentrations, heart rate (HR), activity and weight gain in calves after scoop dehorning and thermocautery without local anesthesia. RESULTS: Plasma meloxicam concentrations were detectable for 50 h post-administration and fit a 2-compartment model with a rapid distribution phase (mean T(1/2alpha) = 0.22 +/- 0.087 h) and a slower elimination phase (mean T(1/2beta) = 21.86 +/- 3.03 h). Dehorning caused a significant increase in serum cortisol concentrations and HR (P < 0.05). HR was significantly lower in the meloxicam-treated calves compared with placebo-treated calves at 8 h (P = 0.039) and 10 h (P = 0.044) after dehorning. Mean plasma SP concentrations were lower in meloxicam treated calves (71.36 +/- 20.84 pg/mL) compared with control calves (114.70 +/- 20.84 pg/mL) (P = 0.038). Furthermore, the change in plasma SP from baseline was inversely proportional to corresponding plasma meloxicam concentrations (P = 0.008). The effect of dehorning on lying behavior was less significant in meloxicam-treated calves (p = 0.40) compared to the placebo-treated calves (P < 0.01). Calves receiving meloxicam prior to dehorning gained on average 1.05 +/- 0.13 kg bodyweight/day over 10 days post dehorning compared with 0.40 +/- 0.25 kg bodyweight/day in the placebo-treated calves (p = 0.042). CONCLUSIONS: To our knowledge, this is the first published report examining the effects of meloxicam without local anesthesia on SP, activity and performance of calves post-dehorning. These findings suggest that administration of meloxicam alone immediately prior to dehorning does not mitigate signs of acute distress but may have long term physiological, behavior and performance effects. PMID- 22937951 TI - Health risk behaviors in spina bifida: the need for clinical and policy action. PMID- 22937952 TI - Nicotiana attenuata alpha-DIOXYGENASE1 through its production of 2 hydroxylinolenic acid is required for intact plant defense expression against attack from Manduca sexta larvae. AB - Nicotiana attenuata alpha-DIOXYGENASE1 (alpha-DOX1) is an oxylipin-forming gene elicited during herbivory by fatty acid amino acid conjugates (FACs) contained in oral secretions of Manduca sexta. To understand the roles of Naalpha-DOX1 and its major product, 2-hydroxylinolenic acid (2-hydroxylinolenic acid), in N. attenuata's anti-herbivore defenses, we used a transgenic line specifically silenced in Naalpha-DOX1 expression (ir-alpha-dox1) and monitored 2-HOT production in M. sexta-damaged tissues and its role in influencing the production of direct defense compounds and resistance to this insect. Attack by M. sexta larvae amplified 2-HOT formation at the feeding sites; a reaction probably facilitated by Naalpha-DOX1's high pH optimum which allows 2-HOT formation to occur in the more alkaline conditions at the feeding sites or potentially in the insect mouth parts after the leaf tissue is ingested. Manduca sexta larvae performed better on ir-alpha-dox1 plants than on wild-type (WT) plants as a result of attenuated herbivory-specific JA and 2-HOT bursts as well as JA inducible well-established defenses (nicotine, caffeoylputrescine and trypsin proteinase inhibitors). Repeated applications of 2-HOT to wounds before insect feeding partly amplified JA-controlled defenses and restored the resistance of ir alpha-dox1 plants. We conclude that 2-HOT, produced by attack-activated alpha DOX1 activity, participates in defense activation during insect feeding. PMID- 22937953 TI - Cost identification of Nordic FLIRI, Nordic FLOX, XELIRI and XELOX in first-line treatment of advanced colorectal cancer in Sweden -- a clinical practice model approach. AB - INTRODUCTION: The role of health-related economy is crucial due to the finite healthcare resources. Intravenous (i.v.) regimes Nordic FLOX and Nordic FLIRI, and the partly oral alternatives XELIRI and XELOX are four commonly used chemotherapies in the first-line treatment of advanced colorectal cancer (CRC) in the Scandinavian countries, all with different costs. AIM: To describe and compare costs associated with four commonly used treatments for advanced CRC in clinical routine practice. An additional aim was to evaluate the theoretical cost impact of adverse effects associated with the therapies. MATERIAL AND METHODS: The retrospective study was carried out using observations and a clinical quality database of CRC patients treated with Nordic FLOX, Nordic FLIRI, XELIRI and XELOX as first line at an oncology clinic in Gothenburg, Sweden. The treatments are used in parallel in clinical practice. All patients treated from 2003 to 2009 were included. The clinical outcome of the therapies was equivalent; mean treatment time was 5.9-7.7 months. A clinical economic evaluation model was designed. All direct costs associated with the baseline treatment, administration of chemotherapy and drug costs were collected and evaluated. RESULTS: The maximum cost for the four treatments was estimated to be 72 000-75 000 SEK per patient for six months, of this approximately 8000 SEK was linked to treatment of toxicity. During six months the i.v. treatments could include 17 more outpatient visits per patient compared to the oral alternatives. During treatment at the clinic around 20% of the patients were hospitalised (XELOX excluded, because of few included patients). CONCLUSION: The results indicate that the four regimens are similar in terms of treatment costs. Different costs affect the total cost. The oral alternative makes it possible to treat additional patients with the same labour force resources. Treatment of adverse effects contributes to extensive resource use at the hospital. PMID- 22937954 TI - Haemangiopericytoma presenting with acute intracerebral haemorrhage--a case report and literature review. AB - BACKGROUND: Intracranial haemangiopericytoma (HPC), a rare malignant tumour, should be distinguished from meningioma and solitary fibrous tumour, which have been considered as separate entities since 1993, according to histopathology and clinical characteristics. METHODS: A PUBMED search for "Intracranial Haemangiopericytoma" yielded 176 articles, where 26 were of particular interest for this review article. CASE REPORT: Our patient, a 27-year-old man with HPC of grade III according to WHO, presents with an acute intracerebral haematoma, which is extremely rare. RESULTS: Surgery (total resection) is the primary treatment. Long-term close clinical and radiological follow-up is crucial due to the high rate of recurrence and tendency for development of metastasis. DISCUSSION: The effects of postoperative radiotherapy need further investigation. Besides neurosurgery, radiotherapy should always be considered in both patients with these highly malignant tumours (WHO grade III) and in patients with partial resection or inoperable cases (WHO grade II). PMID- 22937955 TI - Cladribine (2-chlorodeoxyadenosine) in frontline chemotherapy for adult Langerhans cell histiocytosis: A single-center study of seven cases. AB - BACKGROUND: Adult Langerhans cell histiocytosis is a rare disorder with diverse clinical manifestations and inconsistent treatment outcomes to conventional therapeutic regimens. Cladribine (2-chlorodeoxyadenosine) repeatedly proved effective in cases of relapsed multifocal and multisystem disease forms. In this retrospective study we present an analysis of cladribine in frontline systemic therapy. MATERIAL AND METHODS: A cohort of seven male patients with biopsy proved multisystem (six cases) and multifocal (one case) Langerhans cell histiocytosis received cladribine at a dose of 5 mg/m(2) subcutaneously (five cases) or by two hour intravenous infusion (two cases) over five consecutive days, every four weeks for a median of four courses (range 4-6). The treatment was enhanced with cyclophosphamide (300 mg intravenously on days 1-5 in cycles 4-6) and corticoids (dexamethasone 24 mg orally or methylprednisolone 250 mg intravenously on days 1 5 in cycles 4-6) in two patients, with radiotherapy (20 Gy on skin or bone lesions) in three patients and with photochemotherapy (psoralen plus ultraviolet A light, PUVA) on skin lesions in one patient. RESULTS: All patients achieved clinically relevant treatment response confirmed by positron emission tomography (PET). Durable complete remissions were maintained in six patients (86%), including two patients with hypophysis involvement, with the median follow-up of 37 months (range 15-94; 49.8 +/- 35.2 [ 6 ]). One patient had an aggressive, early relapsing disease requiring further treatment lines. The treatment-related toxicities consisted of transient bone marrow suppression affecting the leukocytes predominantly. Grade 3 lymphopenia occurred in five patients (71%) and grade 3 neutropenia in one patient (14%). CONCLUSION: Cladribine, both as a single agent as well as in combination with an alkylating cytostatic and corticoids, represents an effective treatment option with favorable toxicity profile for adult patients with multisystem or aggressive multifocal form of Langerhans cell histiocytosis. PMID- 22937956 TI - Gastroparesis on the rise: incidence vs awareness? AB - BACKGROUND: Recent reports provide a conflicting picture with a stable prevalence of gastroparesis (GP) in a population-based study, but a more than doubling in hospitalizations for gastroparesis within the last 10 years. We hypothesized that this apparent discrepancy is due to changes in disease recognition and coding rather than prevalence. METHODS: Using data from the Nationwide Inpatient Sample, Healthcare cost and utilization project, Agency for Healthcare Research and Quality, we examined time trends of resource utilization for GP and related disorders. KEY RESULTS: Between 1994 and 2009, annual hospitalizations for gastroparesis as primary diagnosis increased more than 18-fold from 918 to 16,736. In the same time frame, hospitalizations for not otherwise specified functional disorders of the stomach decreased by nearly 50% from 13,430 to 6480 per year. CONCLUSIONS & INFERENCES: Although hospitalizations rates and emergency encounters for gastroparesis have increased dramatically within the last 2 decades, there was a concomitant decrease in resource utilization for other functional disorders of the stomach, suggesting that increased awareness contributed to this trend, which represents a shift in diagnoses rather than a true difference in the incidence and/or prevalence of these illnesses. PMID- 22937958 TI - Communicating health rights to disadvantaged populations: challenges in developing a culture-centered approach for Ethiopian immigrants in Israel. AB - Knowing about one's health rights can be critical for obtaining equitable and appropriate health care. A model drawing on a culture-centered approach was used to develop and present health rights information materials for a disadvantaged cultural minority-the Ethiopian immigrant community in Israel. The model is based on the supposition that the design of health rights information materials should address both concerns and barriers identified by members of the cultural community and illustrate specific means to address them. Stories of community members' actual experiences served as the basis for several types of narratives presented in video clips, a photonovella, and an illustrated booklet. More than 100 people participated in the study in five focus groups and 50 personal interviews. Findings indicate participants felt the materials developed using this approach were informative and represented their concerns and cultural barriers to realizing these rights from their perspective and would help motivate them to realize their health rights. The analytic process, which involved members from the cultural community, resulted in the identification of dilemmas associated with the development of solution-oriented materials that draw on the culture-centered approach. These dilemmas pose additional theoretical challenges to the culture-centered approach. PMID- 22937957 TI - Electro-acupuncture on functional peripheral nerve regeneration in mice: a behavioural study. AB - BACKGROUND: The improvement of axonal regeneration is a major objective in the treatment of peripheral nerve injuries. The aim of this study was to evaluate the effects of electro-acupuncture on the functional recovery of sensorimotor responses following left sciatic nerve crush in mice. METHODS: Sciatic nerve crush was performed on seven week old female mice. Following the injury, the control group was untreated while the experimental group received an electro acupuncture application to the injured limb under isoflurane anesthesia at acupoints GB 30 and GB 34. Mechanical and heat sensitivity tests were performed to evaluate sensory recovery. Gait analysis was performed to assess sensorimotor recovery. RESULTS: Our results show that normal sensory recovery is achieved within five to six weeks with a two-week period of pain preceding the recovery to normal sensitivity levels. While electro-acupuncture did not accelerate sensory recovery, it did alleviate pain-related behaviour but only when applied during this period. Application before the development of painful symptoms did not prevent their occurrence. The analysis of gait in relation to the sensory tests suggests that the electro-acupuncture specifically improved motor recovery. CONCLUSIONS: This study demonstrates that electro-acupuncture exerts a positive influence on motor recovery and is efficient in the treatment of pain symptoms that develop during target re-innervation. PMID- 22937959 TI - Effectiveness and cost-effectiveness of web-based treatment for phobic outpatients on a waiting list for psychotherapy: protocol of a randomised controlled trial. AB - BACKGROUND: Phobic disorders are highly prevalent and constitute a considerable burden for patients and society. As patients wait for face-to-face psychotherapy for phobic disorders in outpatient clinics, this time can be used for guided self help interventions. The aim of this study is to investigate a five week internet based guided self-help programme of exposure therapy in terms of clinical effectiveness and impact on speed of recovery in psychiatric outpatients, as well as the cost-effectiveness of this pre-treatment waiting list intervention. METHODS/DESIGN: A randomised controlled trial will be conducted among 244 Dutch adult patients recruited from waiting lists of outpatient clinics for face-to face psychotherapy for phobic disorders. Patients suffering from at least one DSM IV classified phobic disorder (social phobia, agoraphobia or specific phobia) are randomly allocated (at a 1:1 ratio) to either a five-week internet-based guided self-help program followed by face-to-face psychotherapy, or a control group followed by face-to-face psychotherapy. Waiting list status and duration are unchanged and actual need for further treatment is evaluated prior to face-to face psychotherapy. Clinical and economic self-assessment measurements take place at baseline, post-test (five weeks after baseline) and at 3, 6, 9 and 12 months after baseline. DISCUSSION: Offering pre-treatment internet-based guided self help efficiently uses time otherwise lost on a waiting list and may increase patient satisfaction. Patients are expected to need fewer face-to-face sessions, reducing total treatment cost and increasing speed of recovery. Internet delivered treatment for phobias may be a valuable addition to psychotherapy as demand for outpatient treatment increases while budgets decrease. TRIAL REGISTRATION: Netherlands Trial Register NTR2233. PMID- 22937960 TI - Skin autofluorescence and risk of micro- and macrovascular complications in patients with Type 2 diabetes mellitus-a multi-centre study. AB - AIMS: Skin autofluorescence is a non-invasive marker of advanced glycation end product accumulation. In a previous study, skin autofluorescence correlated with and predicted micro- and macrovascular complications in Type 2 diabetes in a primary care setting. The present cross-sectional study aims to confirm the association between skin autofluorescence and diabetic complications in patients with Type 2 diabetes in a multi-centre secondary care setting. METHODS: We analysed 563 subjects with Type 2 diabetes mellitus from five Dutch hospitals. RESULTS: Median age was 64 years, median duration of diabetes 13 years and median HbA(1c) 58 mmol/mol (7.5%). Sixty-one per cent of patients had microvascular complications (38% nephropathy, 36% retinopathy, 35% neuropathy) and 42% had macrovascular complications. Median UK Prospective Diabetes Study 10 year risk for coronary events was 19%. Median skin autofluorescence was elevated compared with age-matched healthy control subjects: 2.77 (interquartile range 2.39-3.28) vs. 2.46 (2.08-2.84) arbitrary units. Skin autofluorescence was particularly increased in patients with complications: no complications, median 2.56 (2.26-2.90); microvascular complications, 2.79 (2.38-3.29); macrovascular complications, 2.85 (2.41-3.41); both micro- and macrovascular complications, 2.96 (2.56-3.60) arbitrary units, P < 0.001. Logistic regression analysis showed that age, duration of diabetes, renal function, gender, atrial fibrillation and skin autofluorescence were independently associated with macrovascular complications. Multiple regression analysis identified age, smoking, renal function, macrovascular complications and the number of microvascular complications as the determinants of skin autofluorescence. CONCLUSIONS: This study confirms that skin autofluorescence is increased in patients with Type 2 diabetes in a secondary care setting. Skin autofluorescence was associated with macrovascular complications in patients with diabetes and this association was independent of classical risk factors. PMID- 22937962 TI - Molecular and histopathological characterization of sheep-associated malignant catarrhal fever (SA-MCF) outbreak in beef cattle. AB - An outbreak of suspected malignant catarrhal fever (MCF) was investigated by molecular and histopathological assays. Of the 70 Holstein beef calf herds, 14 were affected by multiple clinical signs suggestive of MCF infection. These beef calves were housed next to sheep flocks. In the complete blood count, the 14 affected calves had severe anaemia with leucopaenia, lymphopaenia and neutropaenia. Upon PCR amplification using a hemi-nested PCR assay for the detection of the Ovine herpesvirus 2 (OvHV-2), bovine tissue samples from the mesenteric lymph nodes and spleen and ovine blood samples were shown to be positive with the expected PCR bands amplified. Direct sequencing of the hemi nested PCR product confirmed the identity of the causative virus as OvHV-2. The histopathological findings confirmed the clinical and laboratory diagnosis of MCF. Collective clinical, PCR and histopathological data confirmed the identity of this outbreak to be a sheep-associated malignant catarrhal fever (SA-MCF). PMID- 22937961 TI - Why is tick-borne encephalitis increasing? A review of the key factors causing the increasing incidence of human TBE in Sweden. AB - The highest annual incidence of human tick-borne encephalitis (TBE) in Sweden ever recorded by the Swedish Institute for Communicable Disease Control (SMI) occurred last year, 2011. The number of TBE cases recorded during 2012 up to 6th August 2012 indicates that the incidence for 2012 could exceed that of 2011. In this review of the ecology and epidemiology of TBE in Sweden our main aim is to analyse the possible reasons behind the gradually increasing incidence of human TBE during the last 20 years. The main TBE virus (TBEV) vector to humans in Sweden is the nymphal stage of the common tick Ixodes ricinus. The main mode of transmission and maintenance of TBEV in the tick population is considered to be when infective nymphs co-feed with uninfected but infectible larvae on rodents. In most locations the roe deer, Capreolus capreolus is the main host for the reproducing adult I. ricinus ticks. The high number of roe deer for more than three decades has resulted in a very large tick population. Deer numbers have, however, gradually declined from the early 1990s to the present. This decline in roe deer numbers most likely made the populations of small rodents, which are reservoir-competent for TBEV, gradually more important as hosts for the immature ticks. Consequently, the abundance of TBEV-infected ticks has increased. Two harsh winters in 2009-2011 caused a more abrupt decline in roe deer numbers. This likely forced a substantial proportion of the "host-seeking" ticks to feed on bank voles (Myodes glareolus), which at that time suddenly had become very numerous, rather than on roe deer. Thus, the bank vole population peak in 2010 most likely caused many tick larvae to feed on reservoir-competent rodents. This presumably resulted in increased transmission of TBEV among ticks and therefore increased the density of infected ticks the following year. The unusually warm, humid weather and the prolonged vegetation period in 2011 permitted nymphs and adult ticks to quest for hosts nearly all days of that year. These weather conditions stimulated many people to spend time outdoors in areas where they were at risk of being attacked by infective nymphs. This resulted in at least 284 human cases of overt TBE. The tick season of 2012 also started early with an exceptionally warm March. The abundance of TBEV-infective "hungry" ticks was presumably still relatively high. Precipitation during June and July was rich and will lead to a "good mushroom season". These factors together are likely to result in a TBE incidence of 2012 similar to or higher than that of 2011. PMID- 22937963 TI - Exciton properties in zincblende InGaN-GaN quantum wells under the effects of intense laser fields. AB - : In this work, we study the exciton states in a zincblende InGaN/GaN quantum well using a variational technique. The system is considered under the action of intense laser fields with the incorporation of a direct current electric field as an additional external probe. The effects of these external influences as well as of the changes in the geometry of the heterostructure on the exciton binding energy are discussed in detail. PMID- 22937964 TI - Mechanisms linking obesity, inflammation and altered metabolism to colon carcinogenesis. AB - Due to its prevalence, obesity is now considered a global epidemic. It is linked to increased risk of colorectal cancer, the third most common cancer and the second leading cause of death among adults in Western countries. Obese adipose tissue differs from lean adipose tissue in its immunogenic profile, body fat distribution and metabolic profile. Obese adipose tissue releases free fatty acids, adipokines and many pro-inflammatory chemokines. These factors are known to play a key role in regulating malignant transformation and cancer progression. Obese adipose tissue is infiltrated by macrophages that participate in inflammatory pathways activated within the tissue. Adipose tissue macrophages consist of two different phenotypes. M1 macrophages reside in obese adipose tissue and produce pro-inflammatory cytokines, and M2 macrophages reside in lean adipose tissue and produce anti-inflammatory cytokines, such as interleukin-10 (IL-10). The metabolic networks that confer tumour cells with their oncogenic properties, such as increased proliferation and the ability to avoid apoptosis are still not well understood. We review the interactions between adipocytes and immune cells that may alter the metabolism towards promotion of colorectal cancer. PMID- 22937966 TI - Global health and gerontological nursing. PMID- 22937965 TI - Quality of life among women with sexual dysfunction undergoing hemodialysis: a cross-sectional observational study. AB - BACKGROUND: Sexual function among women undergoing hemodialysis (HD) is under studied and there is no consensus about the effect of sexual dysfunction (SD) on their quality of life (QoL). We aimed to determine the prevalence of SD and to compare QoL between women undergoing maintenance HD with and without SD. METHODS: We included female end-stage renal disease (ESRD) patients undergoing HD during June 2011 in the only renal unit in the north of Ceara state, northeastern Brazil. The criteria for inclusion were age between 18 and 55, at least three months on dialysis and being sexually active. Women using antidepressant medication were excluded. We used the Female Sexual Function Index (FSFI), which evaluates six domains of sexual function, including desire, arousal, lubrication, orgasm, satisfaction and pain. The patients were classified as presenting SD if the total FSFI score was less than 26. For QoL evaluation, we used the validated Brazilian version of SF-36. This is a widely used 36-item questionnaire covering eight dimensions of QoL. Demographic data, time on dialysis, underlying etiology of ESRD, and laboratory measures were assessed in unit records. RESULTS: Of a total of 58 women, 46 (79.3%) presented SD. There were lower scores related to physical functioning (48.2 vs. 71.2; p = 0.007), bodily pain (45 vs. 67.5; p = 0.010), vitality (52.1 vs. 69.1; p = 0.026) and social functioning (57.2 vs. 76.1; p = 0.034) among women with SD compared to women without SD. Physical functioning and role-physical presented positive linear correlation with FSFI scores, respectively, r = 0.322 (p = 0.013) and r = 0.345 (p = 0.007). CONCLUSION: The prevalence of SD among women on HD is very high, reaching nearly 80%. Women on HD with SD had worse QoL, especially physical aspects of QoL, when compared to women without SD. Therefore, approaches aiming to improve QoL among women undergoing HD should be considered. PMID- 22937970 TI - Suitability of patch test allergens for standard series in Thai patients: ten year retrospective review of patch test results. PMID- 22937971 TI - Design, synthesis, and evaluation of novel cyclic phosphates of 5-aminosalicylic acid as cytochrome p450-activated prodrugs. AB - Four novel cyclic phosphates of the anti-inflammatory agent 5-aminosalicylic acid (5-ASA) were designed and synthesized as cytochrome P450 (CYP)-activated prodrugs. These prodrugs can be used for targeting into gut wall, since these types of cyclic phosphates are known to be activated mainly by CYP3A forms, which are expressed not only in the liver but also in the small intestine and to a lesser extent in the colon. The present study shows that aromatic ring activating substituents, like chlorine, are definitely needed to obtain the desired enzymatic cleavage of the cyclic phosphate prodrugs of 5-ASA. However, the position of the activating substituent has also a strong impact on the chemical stability, and therefore, an appropriate balance between the rates of prodrug bioactivation and chemical stability needs to be taken into consideration in future studies on cyclic phosphate prodrugs of 5-ASA. PMID- 22937973 TI - Gastric bronchogenic cyst presenting as a submucosal mass: a case report. AB - INTRODUCTION: Bronchogenic cysts are developmental anomalies of the primitive foregut which mostly occur in the lung. Gastric bronchogenic cysts are extremely rare; few cases have been reported in the literature and the diagnosis was often made following surgical resection. CASE PRESENTATION: A 40-year-old North African man was admitted to our hospital with a gastric submucosal mass. An endoscopic ultrasound revealed a unilocular cystic mass located in the muscular layer. Its content was echogenic suggestive of mucus. Magnetic resonance imaging confirmed the liquid nature of the cyst and showed a high ratio of proteins. Based on these observations, the diagnosis of bronchogenic cyst was confirmed. An endoscopic monitoring was decided rather than surgery because of the small size of the cyst and the absence of symptoms. CONCLUSION: Although gastric bronchogenic cysts are rare, they should be well known and considered in all differential diagnoses of gastric tumors. We report a new case of gastric bronchogenic cyst and highlight the contribution of morphological tests that currently allow a non-invasive diagnosis. PMID- 22937972 TI - Identification of white campion (Silene latifolia) guaiacol O-methyltransferase involved in the biosynthesis of veratrole, a key volatile for pollinator attraction. AB - BACKGROUND: Silene latifolia and its pollinator, the noctuid moth Hadena bicruris, represent an open nursery pollination system wherein floral volatiles, especially veratrole (1, 2-dimethoxybenzene), lilac aldehydes, and phenylacetaldehyde are of key importance for floral signaling. Despite the important role of floral scent in ensuring reproductive success in S. latifolia, the molecular basis of scent biosynthesis in this species has not yet been investigated. RESULTS: We isolated two full-length cDNAs from S. latifolia that show similarity to rose orcinol O-methyltransferase. Biochemical analysis showed that both S. latifolia guaiacol O-methyltransferase1 (SlGOMT1) &S. latifolia guaiacol O-methyltransferase2 (SlGOMT2) encode proteins that catalyze the methylation of guaiacol to form veratrole. A large Km value difference between SlGOMT1 (~10 MUM) and SlGOMT2 (~501 MUM) resulted that SlGOMT1 is 31-fold more catalytically efficient than SlGOMT2. qRT-PCR expression analysis showed that the SlGOMT genes are specifically expressed in flowers and male S. latifolia flowers had 3- to 4-folds higher level of GOMT gene transcripts than female flower tissues. Two related cDNAs, S. dioica O-methyltransferase1 (SdOMT1) and S. dioica O-methyltransferase2 (SdOMT2), were also obtained from the sister species Silene dioica, but the proteins they encode did not methylate guaiacol, consistent with the lack of veratrole emission in the flowers of this species. Our evolutionary analysis uncovered that SlGOMT1 and SlGOMT2 genes evolved under positive selection, whereas SdOMT1 and SdOMT2 genes show no evidence for selection. CONCLUSIONS: Altogether, we report the identification and functional characterization of the gene, SlGOMT1 that efficiently catalyzes veratrole formation, whereas another copy of this gene with only one amino acid difference, SlGOMT2 was found to be less efficient for veratrole synthesis in S. latifolia. PMID- 22937974 TI - Synthetic study of pyrrocidines: first entry to the decahydrofluorene core of pyrrocidines. AB - The first synthesis of decahydrofluorene core 4 of pyrrocidines was accomplished. The cis,trans-fused tricyclic ring system was stereoselectively constructed via Diels-Alder reaction using two Danishefsky dienes. PMID- 22937975 TI - Development and validation of a method for purification of mallein for the diagnosis of glanders in equines. AB - BACKGROUND: The allergic test of mallein is one of the most frequently used tests, together with the Complement Fixation Test (CFT), for the diagnosis of glanders in endemic areas. Mallein, a purified protein derivative (PPD), is produced similarly to PPD tuberculin and the end product is a primarily proteic antigen, which is only poorly purified. The immuno-allergic activity of mallein is believed to be due to a high molecular weight group of proteins present in the antigen. To improve the quality of the antigen, in terms of sensitivity and specificity, a new method of mallein production was developed, in which purification was accomplished by ultrafiltration in a Tangential Flow Filtration system (TFF). RESULTS: The TFF methodology efficiently separated the high and low molecular weight protein groups of mallein. The five TFF-purified malleins, produced from Burkholderia mallei strains isolated from clinical cases of glanders in Brazil, proved to be more potent than standard mallein in the induction of an allergic reaction in sensitized animals. Regarding specificity, two of the purified malleins were equivalent to the standard and three were less specific. CONCLUSION: Some of the TFF-purified malleins showed considerable potential to be used as an auxiliary test in the diagnosis of glanders. PMID- 22937976 TI - Natural latex sensitization and respiratory function among workers in latex glove factories: a pilot study. PMID- 22937977 TI - Patient-tailored self-management intervention for older adults with hypertension in a nursing home. AB - AIMS AND OBJECTIVES: This study was to evaluate the effects of a patient-tailored self-management intervention on (1) blood pressure control and (2) self-care behaviour, exercise self-efficacy and medication adherence among Korean older hypertensive patients in a nursing home. BACKGROUND: Little is known about whether a patient-tailored self-management for nursing home residents with hypertension is likely to advance the care of this growing population worldwide. DESIGN: A non-equivalent comparison group design. METHODS: Forty-seven patients (23 and 24 in the intervention and comparison groups, respectively) participated in the study. No one withdrew during the eight-week study period. Hypertensive patients in the intervention group received health education and tailored individual counselling for eight weeks to enhance the self-management. RESULTS: The mean age of patients was 77.4 years. Patients were on hypertensive medications for 11.8 years; only 36 of them took medications without assistance. The baseline comparisons of the patients with and without 8-week intervention did not differ for clinical and demographic variables and outcome measures. Blood pressure decreased when comparing the baseline to eight weeks later from baseline; moreover, blood pressure was significantly reduced only in patients who received the intervention. Self-care behaviour and exercise self-efficacy significantly increased over time only in those who were in the intervention group. However, no significant difference was observed in medication adherence between the two groups. CONCLUSIONS: Patient-tailored self-management intervention was a practical approach for decreasing blood pressure and increasing self-care behaviour in older hypertensive patients in a nursing home. Further studies are needed to validate these findings using a larger sample with long-term follow-up. RELEVANCE TO CLINICAL PRACTICE: A patient-tailored intervention is feasible not only to empower nursing home residents with hypertension for their care, but also to offer a qualified training and guidelines to nursing home staffs, expanding their professional competence in clinical practice. PMID- 22937978 TI - Effects of hydroxyapatite coating of cups used in hip revision arthroplasty. AB - BACKGROUND AND PURPOSE: Coating of acetabular revision implants with hydroxyapatite (HA) has been proposed to improve ingrowth and stability. We investigated whether HA coating of revision cups can reduce the risk of any subsequent re-revision. METHODS: We studied uncemented cups either with or without HA coating that were used at a primary acetabular revision and registered in the Swedish Hip Arthroplasty Register (SHAR). 2 such cup designs were identified: Harris-Galante and Trilogy, both available either with or without HA coating. These cups had been used as revision components in 1,780 revisions of total hip arthroplasties (THA) between 1986 and 2009. A Cox proportional hazards model including the type of coating, age at index revision, sex, cause of cup revision, cup design, the use of bone graft at the revision procedure, and the type of cup fixation at primary THA were used to calculate adjusted risk ratios (RRs with 95% CI) for re-revision for any reason or due to aseptic loosening. RESULTS: 71% of the cups were coated with HA and 29% were uncoated. At a mean follow-up time of 6.9 (0-24) years, 159 (9%) of all 1,780 cups had been re revised, mostly due to aseptic loosening (5%), dislocation (2%), or deep infection (1%). HA coating had no significant influence on the risk of re revision of the cup for any reason (RR = 1.4, CI: 0.9-2.0) or due to aseptic loosening (RR = 1.1, 0.6-1.9). In contrast, HA coating was found to be a risk factor for isolated liner re-revision for any reason (RR = 1.8, CI: 1.01-3.3). Age below 60 years at the index cup revision, dislocation as the cause of the index cup revision, uncemented cup fixation at primary THA, and use of the Harris Galante cup also increased the risk of re-revision of the cup. In separate analyses in which isolated liner revisions were excluded, bone grafting was found to be a risk factor for re-revision of the metal shell due to aseptic loosening (RR = 2.1, CI: 1.05-4.2). INTERPRETATION: We found no evidence to support the notion that HA coating improves the performance of the 2 studied cup designs in revision arthroplasty. In contrast, patient-related factors such as younger age and dislocation as the reason for cup revision, and technical factors such as the choice of revision cup were found to influence the risk of subsequent re-revision of the cup. The reason for inferior results after revision of uncemented cups is not known, but it is possible that these hips more often had pronounced bone loss at the index cup revision. PMID- 22937979 TI - Detection of the water-binding sites of the oxygen-evolving complex of Photosystem II using W-band 17O electron-electron double resonance-detected NMR spectroscopy. AB - Water binding to the Mn(4)O(5)Ca cluster of the oxygen-evolving complex (OEC) of Photosystem II (PSII) poised in the S(2) state was studied via H(2)(17)O- and (2)H(2)O-labeling and high-field electron paramagnetic resonance (EPR) spectroscopy. Hyperfine couplings of coordinating (17)O (I = 5/2) nuclei were detected using W-band (94 GHz) electron-electron double resonance (ELDOR) detected NMR and Davies/Mims electron-nuclear double resonance (ENDOR) techniques. Universal (15)N (I = 1/2) labeling was employed to clearly discriminate the (17)O hyperfine couplings that overlap with (14)N (I = 1) signals from the D1-His332 ligand of the OEC (Stich Biochemistry 2011, 50 (34), 7390-7404). Three classes of (17)O nuclei were identified: (i) one MU-oxo bridge; (ii) a terminal Mn-OH/OH(2) ligand; and (iii) Mn/Ca-H(2)O ligand(s). These assignments are based on (17)O model complex data, on comparison to the recent 1.9 A resolution PSII crystal structure (Umena Nature 2011, 473, 55-60), on NH(3) perturbation of the (17)O signal envelope and density functional theory calculations. The relative orientation of the putative (17)O MU-oxo bridge hyperfine tensor to the (14)N((15)N) hyperfine tensor of the D1-His332 ligand suggests that the exchangeable MU-oxo bridge links the outer Mn to the Mn(3)O(3)Ca open-cuboidal unit (O4 and O5 in the Umena et al. structure). Comparison to literature data favors the Ca-linked O5 oxygen over the alternative assignment to O4. All (17)O signals were seen even after very short (<=15 s) incubations in H(2)(17)O suggesting that all exchange sites identified could represent bound substrate in the S(1) state including the MU-oxo bridge. (1)H/(2)H (I = 1/2, 1) ENDOR data performed at Q- (34 GHz) and W-bands complement the above findings. The relatively small (1)H/(2)H couplings observed require that all the MU-oxo bridges of the Mn(4)O(5)Ca cluster are deprotonated in the S(2) state. Together, these results further limit the possible substrate water binding sites and modes within the OEC. This information restricts the number of possible reaction pathways for O-O bond formation, supporting an oxo/oxyl coupling mechanism in S(4). PMID- 22937980 TI - Low-level laser therapy and sodium diclofenac in acute inflammatory response induced by skeletal muscle trauma: effects in muscle morphology and mRNA gene expression of inflammatory markers. AB - Pharmacological therapy is widely used in the treatment of muscle injuries. On the other hand, low-level laser therapy (LLLT) arises as a promising nonpharmacological treatment. The aim of this study was to analyze the effects of sodium diclofenac (topical application) and LLLT on morphological aspects and gene expression of biochemical inflammatory markers. We performed a single trauma in tibialis anterior muscle of rats. After 1 h, animals were treated with sodium diclofenac (11.6 mg g(-1) of solution) or LLLT (810 nm; continuous mode; 100 mW; 3.57 W cm(-2) ; 1, 3 or 9 J; 10, 30 or 90 s). Histological analysis and quantification of gene expression (real-time polymerase chain reaction-RT-PCR) of cyclooxygenase 1 and 2 (COX-1 and COX-2) and tumor necrosis factor-alpha (TNF alpha) were performed at 6, 12 and 24 h after trauma. LLLT with all doses improved morphological aspects of muscle tissue, showing better results than injury and diclofenac groups. All LLLT doses also decreased (P < 0.05) COX-2 compared to injury group at all time points, and to diclofenac group at 24 h after trauma. In addition, LLLT decreased (P < 0.05) TNF-alpha compared both to injury and diclofenac groups at all time points. LLLT mainly with dose of 9 J is better than topical application of diclofenac in acute inflammation after muscle trauma. PMID- 22937981 TI - Bilateral versus unilateral cochlear implants in children: speech recognition, sound localization, and parental reports. AB - OBJECTIVE: To compare bilateral and unilateral speech recognition in quiet and in multi-source noise, and horizontal sound localization of low and high frequency sounds in children with bilateral cochlear implants. DESIGN: Bilateral performance was compared to performance of the implanted side with the best monaural speech recognition in quiet result. Parental reports were collected in a questionnaire. Results from the CI children were compared to binaural and monaural performance of normal-hearing peers. STUDY SAMPLE: Sixty-four children aged 5.1-11.9 years who were daily users of bilateral cochlear implants. Thirty normal-hearing children aged 4.8-9.0 years were recruited as controls. RESULTS AND CONCLUSIONS: Group data showed a statistically significant bilateral speech recognition and sound localization benefit, both behaviorally and in parental reports. The bilateral speech recognition benefit was smaller in quiet than in noise. The majority of subjects localized high and low frequency sounds significantly better than chance using bilateral implants, while localization accuracy was close to chance using unilateral implants. Binaural normal-hearing performance was better than bilateral performance in implanted children across tests, while bilaterally implanted children showed better localization than normal-hearing children under acute monaural conditions. PMID- 22937982 TI - Professor Dafydd Stephens 1942-2012. PMID- 22937983 TI - An uncommon case of random fire-setting behavior associated with Todd paralysis: a case report. AB - BACKGROUND: The association between fire-setting behavior and psychiatric or medical disorders remains poorly understood. Although a link between fire-setting behavior and various organic brain disorders has been established, associations between fire setting and focal brain lesions have not yet been reported. Here, we describe the case of a 24-year-old first time arsonist who suffered Todd's paralysis prior to the onset of a bizarre and random fire-setting behavior. CASE PRESENTATION: A case of a 24-year-old man with a sudden onset of a bizarre and random fire-setting behavior is reported. The man, who had been arrested on felony arson charges, complained of difficulties concentrating and of recent memory disturbances with leg weakness. A video-EEG recording demonstrated a close relationship between the focal motor impairment and a clear-cut epileptic ictal discharge involving the bilateral motor cortical areas. The SPECT result was statistically analyzed by comparing with standard SPECT images obtained from our institute (easy Z-score imaging system; eZIS). eZIS revealed hypoperfusion in cingulate cortex, basal ganglia and hyperperfusion in frontal cortex,. A neuropsychological test battery revealed lower than normal scores for executive function, attention, and memory, consistent with frontal lobe dysfunction. CONCLUSION: The fire-setting behavior and Todd's paralysis, together with an unremarkable performance on tests measuring executive function fifteen months prior, suggested a causal relationship between this organic brain lesion and the fire-setting behavior. The case describes a rare and as yet unreported association between random, impulse-driven fire-setting behavior and damage to the brain and suggests a disconnection of frontal lobe structures as a possible pathogenic mechanism. PMID- 22937984 TI - Temperature invariance of NaCl solubility in water: inferences from salt-water cluster behavior of NaCl, KCl, and NH4Cl. AB - The growth and stability of salt-water clusters have been experimentally studied in aqueous solutions of NaCl, KCl, and NH(4)Cl from dilute to near-saturation conditions employing dynamic light scattering and zeta potential measurements. In order to examine cluster stability, the changes in the cluster sizes were monitored as a function of temperature. Compared to the other cases, the average size of NaCl-water clusters remained almost constant over the studied temperature range of 20-70 degrees C. Information obtained from the temperature-dependent solution compressibility (determined from speed of sound and density measurements), multinuclear NMR ((1)H, (17)O, (35)Cl NMR), and FTIR were utilized to explain the cluster behavior. Comparison of NMR chemical shifts of saturated salt solutions with solid-state NMR data of pure salts, and evaluation of spectral modifications in the OH stretch region of saturated salt solutions as compared to that of pure water, provided important clues on ion pair-water interactions and water structure in the clusters. The high stability and temperature independence of the cluster sizes in aqueous NaCl shed light on the temperature invariance of its solubility. PMID- 22937985 TI - The importance of identity-by-state information for the accuracy of genomic selection. AB - BACKGROUND: It is commonly assumed that prediction of genome-wide breeding values in genomic selection is achieved by capitalizing on linkage disequilibrium between markers and QTL but also on genetic relationships. Here, we investigated the reliability of predicting genome-wide breeding values based on population wide linkage disequilibrium information, based on identity-by-descent relationships within the known pedigree, and to what extent linkage disequilibrium information improves predictions based on identity-by-descent genomic relationship information. METHODS: The study was performed on milk, fat, and protein yield, using genotype data on 35 706 SNP and deregressed proofs of 1086 Italian Brown Swiss bulls. Genome-wide breeding values were predicted using a genomic identity-by-state relationship matrix and a genomic identity-by-descent relationship matrix (averaged over all marker loci). The identity-by-descent matrix was calculated by linkage analysis using one to five generations of pedigree data. RESULTS: We showed that genome-wide breeding values prediction based only on identity-by-descent genomic relationships within the known pedigree was as or more reliable than that based on identity-by-state, which implicitly also accounts for genomic relationships that occurred before the known pedigree. Furthermore, combining the two matrices did not improve the prediction compared to using identity-by-descent alone. Including different numbers of generations in the pedigree showed that most of the information in genome-wide breeding values prediction comes from animals with known common ancestors less than four generations back in the pedigree. CONCLUSIONS: Our results show that, in pedigreed breeding populations, the accuracy of genome-wide breeding values obtained by identity-by-descent relationships was not improved by identity-by state information. Although, in principle, genomic selection based on identity-by state does not require pedigree data, it does use the available pedigree structure. Our findings may explain why the prediction equations derived for one breed may not predict accurate genome-wide breeding values when applied to other breeds, since family structures differ among breeds. PMID- 22937986 TI - Sleep disorders and their clinical significance in children with Down syndrome. AB - AIM: Our aim was to review basic aspects of sleep disorders in children with Down syndrome in the light of present-day findings of such disorders in children in general, including other groups of children with developmental disabilities. METHODS: A literature search of adverse developmental effects of sleep disturbance, types of sleep disturbance in children with Down syndrome, their aetiology, including possible contributions of physical and psychiatric comorbidities and medication effects, principles of assessment and diagnosis, and treatment issues, was carried out. RESULTS: Sleep disturbance is particularly common in children with developmental disorders including Down syndrome. Although there are just three basic sleep problems (sleeplessness or insomnia, excessive daytime sleepiness, and parasomnias) there are many possible underlying causes (sleep disorders), the nature of which dictates the particular treatment required. In children with Down syndrome, in addition to the same influences in other children, various comorbid physical and psychiatric conditions are capable of disturbing sleep. Possible adverse medication effects also need to be considered. INTERPRETATION: Screening for sleep disorders and their causes should be routine; positive findings call for detailed diagnosis. Management should acknowledge the likely multifactorial aetiology of the sleep disorders in Down syndrome. Successful treatment can be expected to alleviate significantly the difficulties of both child and family. PMID- 22937987 TI - Foot health education for people with rheumatoid arthritis - some patient perspectives. AB - BACKGROUND: Patient education is an important component of foot health management for people with rheumatoid arthritis (RA). The content and strategies for delivery require investigation in relation to the patients' needs. This study explores patients' experiences of foot health education, to inform how the patients' needs could be identified in clinical practice and inform effective education delivery. METHOD: A focus group was used to collect data. The dialogue was recorded digitally, transcribed verbatim and analysed using a structured thematic approach. Member checking and peer review added to credibility of the data.Six themes emerged; (i) content and purpose of patient education - what it should be, (ii) content of patient education - what it should not be, (iii) timing of information on foot health, (iv) method of delivery, (v) ability to engage with foot health education and (vi) the patient/practitioner relationship. CONCLUSIONS: This study identified aspects of patient education considered important by this group of patients in relation to content, timing and delivery, forming the basis for further research on clinical and patient focussed outcomes of patient education.Identifying health education needs and provision of supportive verbal and written information can foster an effective therapeutic relationship, supporting effective foot health education for people with RA. PMID- 22937988 TI - Limitations of the risk factor based approach in early neonatal sepsis evaluations. AB - AIM: Guidelines for detection of early neonatal sepsis employ a risk factor approach combined with laboratory parameters. In an era of increasing intrapartum antibiotic prophylaxis (IAP), we re-assessed the approach as a whole and each of the risk factors individually. METHOD: This retrospective study included infants with risk factors for sepsis or those treated with antibiotics or who had documented early sepsis. Safety of the protocol was assessed by the number of cases of either missed or partially treated late sepsis or meningitis and the sepsis-related mortality rate. Predictive value of each clinical and laboratory factor was calculated. RESULTS: Of the 22,215 neonates, 2096 were assessed. IAP among infants with risk factors rose from 68% in 2005 to 78% in 2008 (p = 0.001). A total of 1662 asymptomatic infants had risk factors, 635 received antibiotics and one (0.06%) had sepsis. A total of 434 symptomatic infants were treated with antibiotics and of these 234 had risk factors and 20 (4.6%) had sepsis. No cases of partially treated or missed sepsis were detected. Poor predictive value was found for all risk factors except prematurity and leukopenia. CONCLUSION: The risk factor based approach in asymptomatic infants cannot be justified. In hospital observation of asymptomatic infants for 2-3 days with antibiotic treatment being reserved only for symptomatic infants may be a reasonable alternative. PMID- 22937989 TI - European guidelines on management of restless legs syndrome: report of a joint task force by the European Federation of Neurological Societies, the European Neurological Society and the European Sleep Research Society. AB - BACKGROUND: Since the publication of the first European Federation of Neurological Societies (EFNS) guidelines in 2005 on the management of restless legs syndrome (RLS; also known as Willis-Ekbom disease), there have been major therapeutic advances in the field. Furthermore, the management of RLS is now a part of routine neurological practice in Europe. New drugs have also become available, and further randomized controlled trials have been undertaken. These guidelines were undertaken by the EFNS in collaboration with the European Neurological Society and the European Sleep Research Society. OBJECTIVES: To provide an evidence-based update of new treatments published since 2005 for the management of RLS. METHODS: First, we determined what the objectives of management of primary and secondary RLS should be. We developed the search strategy and conducted a review of the scientific literature up to 31 December 2011 (print and electronic publications) for the drug classes and interventions employed in RLS treatment. Previous guidelines were consulted. All trials were analysed according to class of evidence, and recommendations made according to the 2004 EFNS criteria for rating. RECOMMENDATIONS: Level A recommendations can be made for rotigotine, ropinirole, pramipexole, gabapentin enacarbil, gabapentin and pregabalin, which are all considered effective for the short-term treatment for RLS. However, for the long-term treatment for RLS, rotigotine is considered effective, gabapentin enacarbil is probably effective, and ropinirole, pramipexole and gabapentin are considered possibly effective. Cabergoline has according to our criteria a level A recommendation, but the taskforce cannot recommend this drug because of its serious adverse events. PMID- 22937990 TI - Molecular fingerprint-based artificial neural networks QSAR for ligand biological activity predictions. AB - In this manuscript, we have reported a novel 2D fingerprint-based artificial neural network QSAR (FANN-QSAR) method in order to effectively predict biological activities of structurally diverse chemical ligands. Three different types of fingerprints, namely, ECFP6, FP2 and MACCS, were used in FANN-QSAR algorithm development, and FANN-QSAR models were compared to known 3D and 2D QSAR methods using five data sets previously reported. In addition, the derived models were used to predict GPCR cannabinoid ligand binding affinities using our manually curated cannabinoid ligand database containing 1699 structurally diverse compounds with reported cannabinoid receptor subtype CB(2) activities. To demonstrate its useful applications, the established FANN-QSAR algorithm was used as a virtual screening tool to search a large NCI compound database for lead cannabinoid compounds, and we have discovered several compounds with good CB(2) binding affinities ranging from 6.70 nM to 3.75 MUM. To the best of our knowledge, this is the first report for a fingerprint-based neural network approach validated with a successful virtual screening application in identifying lead compounds. The studies proved that the FANN-QSAR method is a useful approach to predict bioactivities or properties of ligands and to find novel lead compounds for drug discovery research. PMID- 22937991 TI - Factorial validation of the Patient Assessment of Chronic Illness Care (PACIC) and PACIC short version (PACIC-S) among cardiovascular disease patients in the Netherlands. AB - OBJECTIVE: The Chronic Care Model (CCM) has achieved widespread acceptance and reflects the core elements of patient-centred care in chronic diseases such as cardiovascular diseases (CVD). In the Netherlands the extent to which CVD patients receive care congruent with the CCM is unknown. The main objectives of this study were to validate the 20-item Patient Assessment of Chronic Illness Care (PACIC) and the 11-item (PACIC-S) in the Netherlands among CVD patients and investigate the validity, reliability, and sensitivity to change of both instruments. METHODS: The Dutch version of the PACIC and PACIC-S were tested among 1484 CVD patients (out of 2760; response rate 54%) enrolled in Disease Management Programmes (DMPs) at T0 and 1167 respondents (out of 2545; response rate = 46%) at T1. Five hundred-eighty-five CVD patients filled in the questionnaire at both T0 and T1. We tested the instrument by means of structural equation modeling, and examined its construct validity, reliability and sensitivity to change. Reliability of the instrument was assessed by determining the statistical coherence of the scaled items. Internal consistency of the subscales was assessed by calculating Cronbach's alphas and correlations between the PACIC and PACIC-S. We investigated the sensitivity to change of the original PACIC and the PACIC-S with paired t-tests among CVD patients in DMPs who filled in the questionnaire at both T0 and T1 (N = 585). RESULTS: The confirmatory factor analyses revealed good indices of fit with the PACIC and PACIC-S. Internal consistency as represented by Cronbach's alphas were also good. Correlations between the PACIC and PACIC-S subscales were excellent: 0.98 at both T0 and T1. Paired t-tests results show that the PACIC and PACIC-S improved significantly over time (p < 0.01). CONCLUSIONS: The psychometric properties of the Dutch PACIC and PACIC-S were satisfactory and it is sensitive to change, rendering it a valid and reliable instrument for assessing chronic illness care among CVD patients. PMID- 22937992 TI - Single-photon emission from single InGaAs/GaAs quantum dots grown by droplet epitaxy at high substrate temperature. AB - The authors report single-photon emission from InGaAs quantum dots grown by droplet epitaxy on (100) GaAs substrates using a solid-source molecular beam epitaxy system at elevated substrate temperatures above 400 degrees C without post-growth annealing. High-resolution micro-photoluminescence spectroscopy exhibits sharp excitonic emissions with lifetimes ranging from 0.7 to 1.1 ns. The coherence properties of the emitted photons are investigated by measuring the first-order field correlation function. PMID- 22937993 TI - Heterobimetallic Pd-Sn catalysis: a Suzuki, tandem ring-closing sequence toward indeno[2,1-b]thiophenes and indeno[2,1-b]indoles. AB - Indeno[2,1-b]thiophene and indeno[1,2-b]indole motifs have been obtained in moderate to good yields from easily available substituted boronic acids, 2-bromo aryl/vinyl aldehydes, and nucleophiles such as arenes/heteroarenes and others using a catalytic combination of bimetallic "Pd-Sn" and AgPF(6). This formal three-component coupling involves a Suzuki reaction followed by nucleophile assisted tandem ring closure. The sequential synthesis of substituted heterocycle fused indenes, benzofluorene, and fluorenes was also accomplished. PMID- 22937994 TI - Successful management of allergy to the insulin excipient metacresol in a child with type 1 diabetes: a case report. AB - INTRODUCTION: Insulin allergy to human insulin preparations during the treatment of diabetes is suggested to occur at rates ranging from <1.0% to 2.4%. These reactions vary from mild localized reactions, which resolve with repeated exposure, to life-threatening anaphylaxis and death. The management of persistent insulin allergy in type 1 diabetes mellitus is particularly complicated because ongoing treatment with insulin is essential. CASE PRESENTATION: We present the case of a 12-year-old Caucasian girl with localized allergy to the insulin excipient metacresol, and the subsequent desensitization therapy using continuous subcutaneous insulin infusion with simultaneous intravenous insulin infusion. CONCLUSIONS: This is the first documented case of allergy to the metacresol component of insulin in the pediatric type 1 diabetes literature. We describe an approach to diagnosis and management of metacresol allergy in type 1 diabetes. PMID- 22937995 TI - Occupational exposures to noise resulting from the workplace use of personal media players at a manufacturing facility. AB - This study examined the contribution of noise exposures from personal media player (PMP) use in the workplace to overall employee noise exposures at a Colorado manufacturing facility. A total of 24 workers' PMP and background noise exposures were measured. Twelve PMP users worked in high-background-noise exposure (HBNE) areas, and 12 worked in low-background-noise exposure (LBNE) areas. The self-selected PMP listening level of each worker was measured using an ear simulator, and the background noise of each employee workstation was measured using a sound level meter. Workers' self-reported PMP duration of use, PMP listening exposure levels, and background noise levels were used to estimate the daily occupational noise exposures. Measured background noise levels averaged 81 dBA for HBNE workers and 59 dBA for LBNE workers. Measured, free-field equivalent listening exposure levels were significantly greater for HBNE workers (85 dBA) compared with LBNE workers (75 dBA) (p = 0.0006). Estimated mean daily noise exposures for both groups were below the ACGIH threshold limit value for noise of 85 dBA8-hr time weighted average (TWA), specifically 84 dBA TWA for HBNE workers and 72 dBA TWA for LBNE workers. Three of 12 (25%) HBNE workers had estimated exposures greater than 85 dBA TWA when only background noise was considered, yet when PMP use was also considered, 6 of 12 (50%) had estimated exposures greater than 85 dBA TWA, suggesting that PMP use doubled the number of overexposed workers. None of the LBNE workers had estimated exposures greater than 85 dBA TWA. The contribution of PMP use to overall noise exposures was substantially less among HBNE workers than LBNE workers due to the disproportionate selection of noise-attenuating headsets among HBNE workers compared with LBNE workers. It is recommended that the facility management either restrict workplace PMP use among HBNE workers or require output-limiting technology to prevent occupational noise-induced hearing loss. PMID- 22937996 TI - Health-related quality of life, anxiety and depression related to mammography screening in Norway. AB - AIM AND OBJECTIVES: To measure health-related quality of life, anxiety and depression ahead of mammography screening and to assess any differences in health related quality of life compared to reference population. BACKGROUND: The study of health-related quality of life among attendees prior to mammography screening has received little attention, and increased knowledge is needed to better understand the overall health benefits of participation. DESIGN: A two-group cross-sectional comparative study was performed. METHODS: The samples comprised 4,249 attendees to mammography screening and a comparison group of 943 women. We used the SF-36 Health Survey to assess health-related quality of life. Linear regression was used to study any differences between the groups with adjustment for age, level of education, occupation, having children and smoking status. Other normative data were also used. Anxiety and depression were assessed using the Hospital Anxiety and Depression Scale. RESULTS: Attendees scored statistically significant higher on the SF-36 than the comparison group but were in line with normative data. Attendees had anxiety mean 4.1 and depression mean 2.6. CONCLUSIONS: The majority of the attendees have a high health-related quality of life, low anxiety and depression ahead of screening. Anxiety and depression were less than shown in normative data from Norway. Despite a high health-related quality of life, low anxiety and depression among the majority, healthcare workers should pay special attention to the few women who are anxious and depressed, and have a lower health-related quality of life. Omitted from mammography screening may be women who are unemployed, have lower socioeconomic status, are anxious and are depressed. Further research should be performed with non-attendees and subgroups to improve the screening programme. RELEVANCE TO CLINICAL PRACTICE: It is important to identify which patients have the greatest need for support and caring in an organised mammography screening and who may be overlooked. PMID- 22937997 TI - Trends in prevalence, awareness, treatment, and control of hypertension, and the risk of mortality among middle-aged Lithuanian urban population in 1983-2009. AB - BACKGROUND: Arterial hypertension (AH) is a main risk factor for the risk from cardiovascular (CVD) and stroke mortality. Only few data was published on prevalence, awareness and management of AH in Lithuania. Development of objective approaches to the treatment and control of AH reduces the risk of mortality. The aim of this study was to evaluate time trends, the prevalence, awareness, treatment and control of AH and risk of mortality among Lithuanian urban population aged 45-64 years during the period of 1983-2009. METHODS: Time trends of AH and risk of mortality were examined in three MONICA health surveys in 1983, 1986, 1992, and in one health survey according to MONICA protocol in 2002 included randomly recruited of 2,218 men and 2,491 women. AH was defined as systolic blood pressure (BP) >=140 mmHg and/or diastolic BP of >=90 mmHg or current use of antihypertensive medication. The main outcome measures were all cause mortality, mortality from CVD, coronary heart disease (CHD) and stroke. The mean duration of follow-up was 11.8 +/- 9.2 years. All survey periods were age standardized to the year 2006 of Kaunas population. The estimates of hazard ratio and 95% confidence interval were based on the multivariate Cox proportional hazards regression. RESULTS: In men during 1983-2002 period hypertension prevalence was 52.1-58.7% and did not significantly change whereas in women decreased from 61.0 to 51.0%. There was a significant increase in hypertension awareness among hypertensive men and women (45.0 to 64.4% and 47.7 to 72.3%, respectively) and in treated hypertensives (55.4 to 68.3% in men and 65.6 to 86.2% in women). Adjusted Cox proportional hazard regression analyses revealed a strong dose-response association between blood-pressure level and all-cause, CVD, CHD and stroke-mortality risk in both men and women groups. CONCLUSION: In Lithuanian urban population the prevalence of hypertension remains high. Despite positive changes in hypertension awareness and treatment, hypertension control remains poor. A strong dose-response association between the level of BP and all cause, CVD, CHD and stroke mortality risk was indicated. PMID- 22937999 TI - Creating an attractive aging face. PMID- 22938000 TI - UVB irradiation down-regulates type XVI collagen expression in mouse and human skin. AB - BACKGROUND: Type XVI collagen is a member of the fibril-associated collagens with interrupted triple helices; however, its function or regulation remain unclear. AIMS: This study is to examine the effect of ultraviolet B (UVB) or photoaging on type XVI collagen expression in various cultured cells, mouse, and human skin. METHODS: The level of alpha1 (XVI) collagen mRNA was determined by quantitative real-time reverse transcriptase-polymerase chain reaction and the localization of type XVI collagen in normal human skins was detected by thealpha1 (XVI) collagen polypeptide antibody. RESULTS: Exposure of keratinocytes resulted in suppression of mRNA level in a dose- and time-dependent manner and in normal fibroblasts or organotypic cocultures was also inhibited. Expression level in hairless mouse skin was decreased by UVB exposure. Messenger RNA level of human skins in the sun protected area appeared to be greater than that in the sun-exposed area. Sun protected and sun-exposed normal skin taken from young subjects showed positive immunoreactivities with the anti-alpha1 (XVI) collagen antibody in the subepidermal region, whereas sun-exposed skin from elderly subjects exhibited negative immunoreaction. CONCLUSIONS: Reduction of type XVI collagen by UVB irradiation in vitro and in vivo may be related to the alteration of extracellular matrix in the photodamaged skin. PMID- 22937998 TI - Anti-proliferative effect of methanolic extract of Gracilaria tenuistipitata on oral cancer cells involves apoptosis, DNA damage, and oxidative stress. AB - BACKGROUND: Methanolic extracts of Gracilaria tenuistipitata (MEGT) were obtained from the edible red algae. Previously, we found that water extract of G. tenuistipitata was able to modulate oxidative stress-induced DNA damage and its related cellular responses. METHODS: In this study, the methanol extraction product MEGT was used to evaluate the cell growth inhibition in oral cancer cells and its possible mechanism was investigated. RESULTS: The cell viability of MEGT treated Ca9-22 oral cancer cell line was significantly decreased in a dose response manner (p < 0.05). The sub-G1 population and annexin V intensity of MEGT treated Ca9-22 cancer cells were significantly increased in a dose-response manner (p < 0.0005 and p < 0.001, respectively). The gammaH2AX intensities of MEGT-treated Ca9-22 cancer cells were significantly increased in a dose-response manner (p < 0.05). The reactive oxygen species (ROS) and glutathione (GSH) positive intensities of MEGT-treated Ca9-22 oral cancer cells were significantly increased and decreased, respectively, in a dose-response manner (p < 0.05). The DiOC2(3) intensity for mitochondrial membrane potential (MMP) of MEGT-treated Ca9 22 cancer cells was significantly decreased in a dose-response manner (p < 0.05). CONCLUSIONS: These results indicated that MEGT had apoptosis-based cytotoxicity against oral cancer cells through the DNA damage, ROS induction, and mitochondrial depolarization. Therefore, MEGT derived from the edible algae may have potential therapeutic effects against oral squamous cell carcinoma (OSCC). PMID- 22938001 TI - Hair weathering and hair capacitance mapping: a pilot study. AB - BACKGROUND: Currently, there is no reported objective method allowing confident assessment of hair hydration mapping. Thus, assessing hair moisture kinetics and versatility according to hair shaft damages and hair care products is difficult to perform. AIM: To explore a new method for assessing hair moisture. METHOD: A new method of hair capacitance mapping (HCM) is introduced for monitoring hair surface damage and hydration. This study was performed on intact and weathered hair locks. Samples were soaked in 10% solutions of regular shampoos or in tap water alone. HCM was performed using the SkinChip((r)) device based on a semiconductor image sensor technology. Time to complete water desorption from cuticular cells was recorded. RESULTS: Hair surface moisture was increased for <30 min after soaking in the shampoos or water alone. The method was sensitive enough to disclose a gradient of moisture from the base to the tip of the hair shafts. Weathered hairs lost their moisture more rapidly than intact hairs. CONCLUSION: Hair capacitance mapping appears to be a promising method in the assessment of the dynamics of hair surface moisture. PMID- 22938002 TI - Photo-damage protective effect of two facial products, containing a unique complex of Dead Sea minerals and Himalayan actives. AB - BACKGROUND: Skin appearance is badly affected when exposed to solar UV rays, which encourage physiological and structural cutaneous alterations that eventually lead to skin photo-damage. AIMS: To test the capability of two facial preparations, extreme day cream (EXD) and extreme night treatment (EXN), containing a unique complex of Dead Sea water and three Himalayan extracts, to antagonize biological effects induced by photo-damage. METHODS: Pieces of organ cultures of human skin were used as a model to assess the biological effects of UVB irradiation and the protective effect of topical application of two Extreme preparations. Skin pieces were analyzed for mitochondrial activity by MTT assay, for apoptosis by caspase 3 assay, and for cytokine secretion by solid phase ELISA. Human subjects were tested to evaluate the effect of Extreme preparations on skin wrinkle depth using PRIMOS and skin hydration by a corneometer. RESULTS: UVB irradiation induced cell apoptosis in the epidermis of skin organ cultures and increased their pro-inflammatory cytokine, tumor necrosis alpha (TNFalpha) secretion. Topical applications of both preparations significantly attenuated all these effects. Furthermore, in human subjects, a reduction in wrinkle depth and an elevation in the intense skin moisture were observed. CONCLUSIONS: The observations clearly show that EXD and EXN preparations have protective anti apoptotic and anti-inflammatory properties that can attenuate biological effects of skin photo-damage. Topical application of the preparations improves skin appearance by reducing its wrinkles depth and increasing its moisturizing impact. PMID- 22938003 TI - Reduction of facial wrinkles depth by sleeping on copper oxide-containing pillowcases: a double blind, placebo controlled, parallel, randomized clinical study. AB - BACKGROUND: Copper up-regulates the secretion of extracellular skin proteins and stabilizes the extracellular matrix once formed. As copper can be absorbed through intact skin, we reasoned that sleeping on pillowcases containing copper impregnated fibers would reduce skin wrinkles. OBJECTIVE: Demonstrate that sleeping on pillowcases containing copper-impregnated fibers reduce facial skin wrinkles. PATIENTS/METHODS: An 8-week, double blind, parallel, randomized study was carried out, in which healthy volunteers, aged 30-60, used either copper oxide-containing pillowcases (1% weight/weight) (test group, n = 30) or control pillowcases without copper (control group, n = 31). Skin conditions of the subjects were evaluated by visual grading by two expert graders and by 3D Image Analysis GFM PRIMOS((r)) at baseline (before treatment) and following 4 and 8 weeks of sleeping on the pillowcases. RESULTS: The use of the copper oxide containing pillowcase resulted in significant decrease of crow's feet after 4 (P = 0.01) and 8 (P = 0.002) weeks, but none was observed in the control group, as determined by the expert graders. On the basis of the 3D measurements, three roughness (R) parameters were improved after 4 and 8 weeks (P < 0.02) and the Rmax parameter at 8 weeks (P = 0.016) in the test group, but there were no changes in the R-parameters during the course of the study in the control group. The average reduction per month in the R-parameters was approximately 9%. No adverse reactions were observed or reported during the 8 weeks study. CONCLUSIONS: Sleeping on copper oxide-containing pillowcases results in reduction of wrinkles depth and overall improvement of skin appearance. PMID- 22938004 TI - Skin tightening induced by fractional CO(2) laser treatment: quantified assessment of variations in mechanical properties of the skin. AB - BACKGROUND: Certain authors have reported the efficacy of fractional resurfacing laser treatment in patients with photodamaged skin resulting in skin tightening of treated area. OBJECTIVE: To assess skin tightening after CO(2) fractional resurfacing laser treatment by measuring variations in mechanical properties in treated areas. Dermal elasticity was measured using suction applied with an in vivo skin elasticity meter (Cutometer((r))). METHODS: A prospective observational study was undertaken from January 2007 to August 2009. Laser treatment was performed with the SmartXide Dot((r)) (Deka((r)), Firenze, Italy) CO(2) fractional resurfacing device. Patients were offered quantified analysis using the Cutometer((r)) before and after treatment. RESULTS: Seventeen patients (61 areas treated) were included in the study. Median delay between before and after cutometric evaluations was 80 days. We found significant improvement in elastic (R2 +5.9%), viscoelastic (R8 -9.4%), fatigue (R3 and R9 -16.2% and -19.7%, respectively), and thickness (R0 -14.9%) parameters. These results are consistent with significant tightening and also elastic tissue improvement. CONCLUSIONS: It was possible to quantify skin tightening because of CO(2) fractional laser treatment using a noninvasive technique. PMID- 22938005 TI - Clinical efficacy of a serum integrating multiple cosmetic ingredients in the management of erythema of the face in aging skin. AB - BACKGROUND: Skin redness is a common cosmetic concern affecting predominantly fair-skin individuals and often leading to rosacea. On the basis of the current scientific knowledge of the physiological mechanisms underlying the problem, a complex and integral skin care serum (100RXED2025) was developed and tested clinically for efficacy. METHOD: Forty-five healthy men and women volunteers, age 30-65, were recruited. All subjects had fair skin (phototype I, II, or III) and presented some degree of skin redness with telangiectasia on the cheeks, the nose, or the nose sides, at baseline. In the course of this open label study, subjects applied the test product on their face, twice daily for 56 days. For each subject, skin redness was evaluated through colorimetric and visual analysis of photographs taken under cross-polarized light at T = 28 (week 4) and T = 56 (week 8), then compared to baseline measurements obtained at day 0. RESULTS: Forty-four volunteers completed the study. On visual evaluation, skin redness had decreased in average by 32.2% at T = 28 (P < 0.001) and by 48.0% at T = 56 (P < 0.001). Importantly, 91% of the subjects showed improvement of skin redness at T = 28, reaching 100% at T = 56. Colorimetric analysis gave an average reduction in redness of 11.6% at T = 28 (P < 0.001) and 13.7% at T = 56 (P < 0.001). CONCLUSION: The anti-redness efficacy of the test product was demonstrated after 28 days with further increase following 56 days of application. PMID- 22938006 TI - Marine-derived nutrient improves epidermal and dermal structure and prolongs the life span of reconstructed human skin equivalents. AB - INTRODUCTION: ImedeenTM is a cosmeceutical that provides nutrients to the skin. One of its active ingredients is the Marine ComplexTM (MC). AIM: The aim of this study was to evaluate whether MC affects skin morphogenesis differently in female and male human skin equivalents (HSEs). METHODS: Human skin equivalents were established with cells obtained from female or male donors between 30 and 45 years of age and cultured for seven or 11 weeks in the presence or absence of MC. Using immunohistochemistry, we examined early differentiation by keratin 10 expression, (hyper)proliferation by keratin 17 and Ki67, and basement membrane composition by laminin 332 and collagen type VII. In addition, the expression of collagen type I and the secretion of pro-collagen I were measured. RESULTS: Marine Complex strongly increased the number of Ki67-positive epidermal cells in female HSEs. In the dermis, MC significantly stimulated the amount of secreted pro-collagen I and increased the deposition of laminin 332 and collagen type VII. Furthermore, MC prolonged the viable phase of HSEs by slowing down its natural degradation. After 11 weeks of culturing, the MC-treated HSEs showed higher numbers of viable epidermal cell layers and a thicker dermal extracellular matrix compared with controls. In contrast, these effects were less pronounced in male HSEs. CONCLUSION: The MC nutrient positively stimulated overall HSE tissue formation and prolonged the longevity of both female and male HSEs. The ability of MC to stimulate the deposition of basement membrane and dermal components can be used to combat 2 human skin aging in vivo. PMID- 22938007 TI - Periorbital area rejuvenation using carbon dioxide therapy. AB - BACKGROUND: Different conservative and surgical approaches are used for periorbital region rejuvenation, but none of them is effective in the treatment of the medial third of the lower eyelid. OBJECTIVE: The present study is designed to assess the effectiveness of carboxytherapy in the treatment of wrinkles on the median and medial region of the lower eyelid and dark circles around the eyes. METHODS AND MATERIALS: From January 2008 to December 2010, 90 patients with moderate to severe periorbital wrinkles and/or dark circles underwent subcutaneous injections of CO(2) once a week for 7 weeks. Patients were assessed before and 2 months after the treatment through photographic documentation and the compilation of visual analog scales. RESULTS: At the end of the study period, patients reported a reduction of facial fine lines and wrinkles as well as a decrease in periorbital hyperpigmentation. A few side effects were observed but they were all transient and did not require discontinuation of treatment. CONCLUSION: Carbon dioxide therapy results as an effective noninvasive modality for the rejuvenation of the periorbital area. PMID- 22938008 TI - The Fabi-Bolton chest wrinkle scale: a pilot validation study. AB - Up until now, no objective scale has existed to evaluate chest wrinkles and assess the efficacy of treatment. This study was designed to validate a new photonumeric wrinkle assessment scale using standardized photographic methodology to obtain reference photographs. Multiple photographs from 28 volunteer subjects with varying degrees of chest wrinkles were evaluated by a study team of two independent physicians. Photographs of 16 subjects representing the full spectrum of chest wrinkle severity were selected and classified using the Fabi-Bolton (F B) 5-point wrinkle scale (1 = wrinkles absent; 2 = shallow but visible wrinkles; 3 = moderately deep wrinkles; 4 = deep wrinkles, with well-defined edges; 5 = wrinkles very deep with redundant folds). One representative photograph was chosen by study team consensus for each of the five scale points. A second, independent group of evaluators rated the randomly arranged photographs using the F-B wrinkle scale. The numeric results were then tabulated and compared. The F-B wrinkle scale provided a reproducible and effective method for assessing chest wrinkles with very little interrater variability. The F-B wrinkle scale is a reliable tool for the classification of chest wrinkles and evaluation of therapeutic and cosmetic interventions. PMID- 22938009 TI - A simple idea for approximating the volume of filler needed for chest-wall contour-defects. AB - Fillers can be used to correct contour-defects. Due to the irregularities of defects, estimating the volume of filler required can be difficult. This frequently results in surgeons taking a step-wise approach to filler-injection, usually occurring over different appointments. Using a patient with pectus excavatum as an example, we provide a simple tip as to estimating the volume of filler required. In this case, normal saline was poured into the chest-wall defect until the adequate level was reached (from the lateral aspect), while noting how much liquid was used. The patient then had a comparable volume of filler injected. PMID- 22938010 TI - Restylane persisting in lower eyelids for 5 years. AB - The authors report the case of a 58-year-old woman presenting with "puffiness" in her lower eyelids persisting for approximately 5 years. While dark, puffy eyelid circles following hyaluronic acid placement periorbitally are not uncommon, what is so unusual in our case is that it was noted 5 years after treatment with Restylane. It has been our experience that hyaluronic acid within periorbital tissues can result in a negative cosmetic outcome that can persist for years after the treatment. PMID- 22938012 TI - The Byzantine Empress Zoe Porphyrogenita and the quest for eternal youth. AB - The diachronically continuous struggle for eternal youth as represented by the Byzantine Empress Zoe Porphyrogenita (978-1050). The presentation of a beautiful empress, trying to keep her youth appearance until a prolonged age, applying on herself cosmetic essences and fragrances made in her personal laboratory into the imperial palace. The review of the relevant literature and the historical evidence derived from the historians and chroniclers of her era, as well as the surviving images of Zoe. The eye-witness chroniclers of the era describe her as blonde, with bright white skin, lack of wrinkles, and a very young girl appearance, preserving her beauty even into her 60s. All the historical sources agree that her main occupation was the manufacture of cosmetic essences, and for this purpose, she had installed a laboratory (myrepseion) in her private quarters, where she prepared various drugs and perfumes, spending much of her time for these activities. It is noteworthy that her first two husbands died under circumstances that aroused suspicions of Zoe's involvement in their deaths, as she had parallel love affairs. The best known image of Zoe is the mosaic panel in Saint Sophia, the cathedral Church of Constantinople and her representation has been long discussed, as she was 64 years old at the time of the scene apparently depicted in the panel, and maybe she took the opportunity of adding a more pleasing portrait of herself. The preservation of beauty is a timeless quest and cosmetic dermatology has its origins in antiquity and medieval times. PMID- 22938011 TI - Does massage postapplication improve moisturizer's efficacy? A 2-week regression study. AB - BACKGROUND: Combining massage with moisturizer application is a popular technique in beauty spa sessions. The subjective positive psychological effects of massage with moisturizer application in hand and face beauty treatment are documented by many people attending spa sessions. The aim of this study was to objectively evaluate the effect of local effleurage massage as an external intervention on moisturizer efficacy. METHODS: In a regression-type study of 2-week, twice-daily application followed by 1 week of regression, 13 female subjects applied "off the shelf" moisturizer twice daily on both forearms followed by 1 min superficial massage for one forearm randomized among subjects. The influence of massage after moisturizer application on skin barrier properties was evaluated by noninvasive measurements of transepidermal water loss (TEWL), skin capacitance, and skin elasticity at baseline, day 7, and day 14 during the treatment phase, and day 21 following a 1-week regression period, in which no moisturizer and no massage were performed on forearms. RESULTS: The tested "off the shelf" moisturizer in both "massage" and "no-massage" application protocols caused a comparable progressive improvement in skin hydration level and barrier permeability over the 2-week treatment period, which was maintained during the 1-week regression (no moisturizer) period. In addition, skin elasticity was similarly improved by both application protocols. CONCLUSION: In this long-term study, the daily performance of massage after moisturizer application was not an effective external intervention for enhancing moisturizer efficacy. PMID- 22938013 TI - Recurrent acute mastoiditis - a retrospective national study in Sweden. AB - CONCLUSIONS: Recurrences were seen in 5% of all patients with acute mastoiditis (AM). Mastoidectomy had been performed in the majority of the patients with recurrences at their first episode of AM. Compared with the group with a single episode of AM, the recurrent group exhibited more subperiosteal and ear canal abscesses, although they were not more severely ill. It appears from this study that previous mastoidectomy itself could predispose patients to recurrent AM (rAM), perhaps due to easier access to the mastoid cavity and/or due to a reduction in mucosal lining. OBJECTIVE: To retrospectively study the incidence and characteristics of rAM in Sweden. METHODS: Data from patients with rAM were reviewed and compared with data from patients with a single episode of AM during 1993-2007 in 33 ear, nose and throat departments in Sweden. RESULTS: Of 798 cases fulfilling the criteria for AM, 36 patients (5%) had experienced one or more recurrences, of which 4 patients (11%) had concurrent cholesteatoma. More than 50% of the patients had their first episode of AM before the age of 2 years. There was a highly significant difference between the two groups concerning the frequency of mastoidectomies and subperiosteal/retroauricular abscesses. However, other clinical characteristics, including severe complications, did not differ significantly. The majority of recurrences were treated conservatively with myringotomy and intravenous antibiotics, and also with aspiration/incision if a subperiosteal/retroauricular abscess was present. PMID- 22938015 TI - Analysis of DNA-guided self-assembly of microspheres using imaging flow cytometry. AB - Imaging flow cytometry was used to analyze the self-assembly of DNA-conjugated polystyrene microspheres. This technique enables quantitative analysis of the assembly process and thereby enables detailed analysis of the effect of structural and process variables on the assembly yield. In a demonstration of the potential of this technique, the influence of DNA strand base pair (bp) length was examined, and it was found that 50 bp was sufficient to drive the assembly of microspheres efficiently, forming not only dimers but also chainlike structures. The effect of stoichiometry on the yield was also examined. The analysis demonstrated that self-assembly of 50 bp microspheres can be driven nearly to completion by stoichiometric excess in a manner similar to Le Chatelier's principle in common chemical equilibrium. PMID- 22938014 TI - Hypoxia-induced DNA hypermethylation in human pulmonary fibroblasts is associated with Thy-1 promoter methylation and the development of a pro-fibrotic phenotype. AB - BACKGROUND: Pulmonary fibrosis is a debilitating and lethal disease with no effective treatment options. Understanding the pathological processes at play will direct the application of novel therapeutic avenues. Hypoxia has been implicated in the pathogenesis of pulmonary fibrosis yet the precise mechanism by which it contributes to disease progression remains to be fully elucidated. It has been shown that chronic hypoxia can alter DNA methylation patterns in tumour derived cell lines. This epigenetic alteration can induce changes in cellular phenotype with promoter methylation being associated with gene silencing. Of particular relevance to idiopathic pulmonary fibrosis (IPF) is the observation that Thy-1 promoter methylation is associated with a myofibroblast phenotype where loss of Thy-1 occurs alongside increased alpha smooth muscle actin (alpha SMA) expression. The initial aim of this study was to determine whether hypoxia regulates DNA methylation in normal human lung fibroblasts (CCD19Lu). As it has been reported that hypoxia suppresses Thy-1 expression during lung development we also studied the effect of hypoxia on Thy-1 promoter methylation and gene expression. METHODS: CCD19Lu were grown for up to 8 days in hypoxia and assessed for global changes in DNA methylation using flow cytometry. Real-time PCR was used to quantify expression of Thy-1, alpha-SMA, collagen I and III. Genomic DNA was bisulphite treated and methylation specific PCR (MSPCR) was used to examine the methylation status of the Thy-1 promoter. RESULTS: Significant global hypermethylation was detected in hypoxic fibroblasts relative to normoxic controls and was accompanied by increased expression of myofibroblast markers. Thy-1 mRNA expression was suppressed in hypoxic cells, which was restored with the demethylating agent 5-aza-2'-deoxycytidine. MSPCR revealed that Thy-1 became methylated following fibroblast exposure to 1% O2. CONCLUSION: These data suggest that global and gene-specific changes in DNA methylation may play an important role in fibroblast function in hypoxia. PMID- 22938016 TI - Letter from the editor. PMID- 22938017 TI - Recombinant porcine norovirus identified from piglet with diarrhea. AB - BACKGROUND: Noroviruses (NoVs) are members of the family Caliciviridae and are emerging enteric pathogens of humans and animals. Some porcine NoVs are genetically similar to human strains and are classified into GII, like most epidemic human NoVs. So far, PoNoV have been exclusively detected in fecal samples of adult pig without clinical signs. RESULTS: Result showed that 2 of the 12 evaluated fecal samples were positive for PoNoVs, one of which was positive for PoNoV alone, and the other was coinfected with porcine circovirus and PoNoV. Phylogenetic and recombination analysis showed that the PoNoV positive alone strain was a recombinant new genotype strain. Experimental infection of miniature pigs with fecal suspensions confirmed that this strain can cause gastroenteritis in piglets. CONCLUSION: This is the first report that recombinant new genotype PoNoV exised in pig herd of China, which cause diarrhea in pigs in nature condition. This find raised questions about the putative epidemiologic role of PoNoV. PMID- 22938018 TI - Load-distributing band improves ventilation and hemodynamics during resuscitation in a porcine model of prolonged cardiac arrest. AB - BACKGROUND: The use of mechanical cardiopulmonary resuscitation (CPR) has great potential for the clinical setting. The purpose of present study is to compare the hemodynamics and ventilation during and after the load-distributing band CPR, versus the manual CPR in a porcine model of prolonged cardiac arrest, and to investigate the influence of rescue breathing in different CPR protocols. METHODS: Sixty-four male pigs (n = 16/group), weighing 30 +/- 2 kg, were induced ventricular fibrillation and randomized into four resuscitation groups: continuous load-distributing band CPR without rescue ventilation (C-CPR), load distributing band 30:2 CPR (A-CPR), load-distributing band CPR with continuous rescue breathing (10/min) (V-CPR) or manual 30:2 CPR (M-CPR). Respiratory variables and hemodynamics were recorded continuously; blood gas was analyzed. RESULTS: Tidal volume produced by compressions in the A-, C- and V-CPR groups were significantly higher compared with the M-CPR group (all p < 0.05). Coronary perfusion pressure of the V-CPR group was significantly lower than the C-CPR group (p < 0.01), but higher than the M-CPR group. The increasing of lung dead space after restoration of spontaneous circulation was significantly greater in the M-CPR group compared with the A-, C- and V-CPR groups (p < 0.01). Blood pH gradually decreased and was lower in the M-CPR group than that in the A-, C- and V-CPR groups (p < 0.01). PaO2 of the A-, C- and V-CPR groups were significantly higher and PaCO2 were significantly lower compared with the M-CPR (both p < 0.05). Cerebral performance categories were better in the A-, C- and V-CPR groups compared with the M-CPR group (p < 0.0001). CONCLUSIONS: The load-distributing band CPR significantly improved respiratory parameters during resuscitation by augmenting passive ventilation, and significantly improved coronary perfusion pressure. The volume of ventilation produced by the load-distributing band CPR was adequate to maintain sufficient gas exchange independent of rescue breathing. PMID- 22938019 TI - A decision aid to assist decisions on disclosure of mental health status to an employer: protocol for the CORAL exploratory randomised controlled trial. AB - BACKGROUND: The UK Equality Act 2010 makes it unlawful for employers to ask health questions before making an offer of employment except in certain circumstances. While the majority of employers would prefer applicants to disclose a mental illness at the application stage, many people either wait until they have accepted the job and then disclose to an occupational health professional, or do not do so at all due to the anticipation of discrimination or a wish for privacy. However, non disclosure precludes the ability to request reasonable adjustments in the workplace or to make a claim of direct discrimination. Disclosure to employers is therefore a difficult decision. A recent pilot study by our group of the CORAL decision aid showed that it helped mental health service users clarify their needs and values regarding disclosure and led to reduction in decisional conflict. The present proof of concept trial aims to determine whether a full scale randomised controlled trial (RCT) is justifiable and feasible, and to optimise its design. METHODS: In this single blind exploratory RCT in London, a total of 80 participants (inclusion criteria: age >= 18 years, on the caseload of a specialist employment adviser working with people with mental illness; referred to the adviser either from primary care via Improving Access to Psychological Therapies or secondary mental health service; currently seeking or interested in either paid or voluntary employment, and a Decisional Conflict Scale score of 37.5 or greater and stage of decision score 1 5) will be recruited from vocational advice services. After completing a baseline assessment, participants will be randomly assigned to one of two conditions (1) Use of the CORAL Decision Aid (DA) in addition to treatment as usual or (2) Treatment as usual. Those allocated to the DA condition will be given it to read and complete, and the researcher will be present to record the time taken and any content that causes confusion. Intervention participants may keep the decision aid but are discouraged from showing it to other service users to avoid contamination. Follow up interviews will be conducted at 3 months. Primary outcomes are: (i) stage of decision making score; (ii) decisional conflict scores and (iii) employment related outcomes. Secondary analyses will identify predictors of disclosure and qualitative analysis will explore the impact of the intervention. DISCUSSION: A reduction in decisional conflict regarding disclosure leading to more effective job seeking activity could have significant economic consequences for people with mental illness in terms of employment rates and productivity. TRIAL REGISTRATION NUMBER: NCT01379014 (ClinicalTrials.gov Identifier). PMID- 22938021 TI - Retrospective analysis of 12 Korean patients with paraneoplastic pemphigus. AB - Paraneoplastic pemphigus (PNP) is a rare, life-threatening, autoimmune, mucocutaneous blistering disease associated with neoplasia. Both humoral and cellular immunity are involved in the pathogenesis of PNP. Characteristically, PNP has a diverse spectrum of clinical and immunopathological features. We retrospectively analyzed 12 Korean patients with PNP who were diagnosed between 1993 and 2011. We performed analysis of the clinical features, clinical outcomes, underlying neoplasia, histological features and laboratory findings. All of the patients except one had severe mucosal involvement. Two patients had only mucosal lesions but no cutaneous involvement was observed. Erythema multiforme or lichen planus-like eruptions rather than bullous lesions were more commonly observed skin rashes. The most common histological features were interface dermatitis and apoptotic keratinocytes. There were associated hematological-related neoplasms in 11 patients, with Castleman's disease (n = 4) as the most frequent. Twelve patients were followed for 5-148 months (mean, 43.0). The prognosis depended on the nature of the underlying neoplasm. Six patients died due to respiratory failure (n = 3), postoperative septicemia (n = 1), lymphoma (n = 1) and sarcomatosis (n = 1). The 2-year survival rate was 50.0%, and the median survival period after diagnosis was 21.0 months. Immunoblotting was performed in 12 patients and autoantibodies to plakins were detected in 11 patients. The results of this study demonstrated the clinical, histological and immunological diversity of PNP. Widely accepted diagnostic criteria that account for the diversity of PNP are needed. PMID- 22938020 TI - Anatomical, architectural, and biochemical diversity of the murine forelimb muscles. AB - We characterized the architecture, fiber type, titin isoform distribution, and collagen content of 27 portions of 22 muscles in the murine forelimb. The mouse forelimb was different from the human arm in that it had the extensor digitorum lateralis muscle and no brachioradialis muscle. Architecturally, the mouse forelimb differed from humans with regard to load bearing, having a much larger contribution from extensors than flexors. In mice, the extensor : flexor PCSA ratio is 2.7, whereas in humans it is only 1.4. When the architectural difference index was calculated, similarities became especially apparent between flexors and extensors of the distal forelimb, as well as pronators. Discriminant analysis revealed that biochemical measures of collagen, titin, and myosin heavy chain were all strong between-species discriminators. In terms of composition, when compared with similar muscles in humans, mice had, on average, faster muscles with higher collagen content and larger titin isoforms. This report establishes the anatomical and biochemical properties of mouse forelimb muscles. Given the prevalence of this species in biological studies, these data will be invaluable for studying the biological basis of mouse muscle structure and function. PMID- 22938022 TI - Conductance, a contrivance to explore ion association and solvation behavior of an ionic liquid (tetrabutylphosphonium tetrafluoroborate) in acetonitrile, tetrahydrofuran, 1,3-dioxolane, and their binaries. AB - Precise measurements on electrical conductance (Lambda) of solutions of an ionic liquid (IL) tetrabutylphosphonium tetrafluoroborate in acetonitrile (ACN), tetrahydrofuran (THF), and 1,3-dioxolane (1,3-DO) and their binary mixtures have been reported at 298.15 K. The conductance data have been analyzed by the Fuoss conductance equation (1978) in terms of the limiting molar conductance (Lambda(o)), the association constant (K(A)), and the association diameter (R) for ion-pair formation. The Walden product is obtained and discussed. However, the deviation of the conductometric curves (Lambda versus ?c) from linearity for the electrolyte in THF and 1,3-DO and their binary mixtures indicated triple-ion formation and therefore the corresponding conductance data have been analyzed by the Fuoss-Kraus theory of triple ions. The limiting ionic conductances (lambda(o)(+/-)) have been estimated from the appropriate division of the limiting molar conductivity value of tetrabutylammonium tetraphenylborate [Bu(4)NBPh(4)] as the "reference electrolyte" method along with a numerical evaluation of ion-pair and triple-ion formation constants (K(P) ~ K(A) and K(T)). The results have been discussed in terms of solvent properties and configurational theory. Ionic association in the limiting molar conductances as well as the single-ion conductivity values have been determined for the electrolyte in the solvent media. PMID- 22938023 TI - Downregulation of the lycopene epsilon-cyclase gene increases carotenoid synthesis via the beta-branch-specific pathway and enhances salt-stress tolerance in sweetpotato transgenic calli. AB - Lycopene epsilon-cyclase (LCY-epsilon) is involved in the first step of the alpha branch synthesis pathway of carotenoids from lycopene in plants. In this study, to enhance carotenoid synthesis via the beta-branch-specific pathway [which yields beta-carotene and abscisic acid (ABA)] in sweet potato, the expression of IbLCY-epsilon was downregulated by RNAi (RNA interference) technology. The RNAi IbLCY-epsilon vector was constructed using a partial cDNA of sweet potato LCY epsilon isolated from the storage root and introduced into cultured sweet potato cells by Agrobacterium-mediated transformation. Both semi-quantitative Reverse transcription polymerase chain reaction (RT-PCR) of carotenoid biosynthesis genes and high-performance liquid chromatography (HPLC) analysis of the metabolites in transgenic calli, in which the LCY- epsilongene was silenced, showed the activation of beta-branch carotenoids and its related genes. In the transgenic calli, the beta-carotene content was approximately 21-fold higher than in control calli, whereas the lutein content of the transgenic calli was reduced to levels undetectable by HPLC. Similarly, expression of the RNAi-IbLCY-epsilon transgene resulted in a twofold increase in ABA content compared to control calli. The transgenic calli showed significant tolerance of 200 mM NaCl. Furthermore, both the beta-branch carotenoids content and the expression levels of various branch specific genes were higher under salt stress than in control calli. These results suggest that, in sweet potato, downregulation of the epsilon-cyclization of lycopene increases carotenoid synthesis via the beta-branch-specific pathway and may positively regulate cellular defenses against salt-mediated oxidative stress. PMID- 22938024 TI - Crystal structure and DNA-binding mode of Klebsiella pneumoniae primosomal PriB protein. AB - PriB is a primosomal DNA replication protein required for the re-initiation of replication in bacteria. In this study, we investigated the gene expression of PriB in Klebsiella pneumoniae (KpPriB) and characterized the gene product through crystal structural and functional analyses. Quantitative polymerase chain reaction analysis (Q-PCR) indicated that the 104-aa priB was expressed in K. pneumoniae with a C(T) value of 22.4. The crystal structure of KpPriB (Protein Data Bank entry: 4APV) determined at a resolution of 2.1 A was similar to that of Escherichia coli PriB (EcPriB). KpPriB formed a single complex with single stranded DNA (ssDNA) of different lengths, suggesting a highly cooperative process. Structure-based mutational analysis revealed that substitution at K18, F42, R44, W47, K82, K84, or K89 but not R34 in KpPriB had a significant effect on both ssDNA and double-stranded DNA (dsDNA) binding. Based on these findings, the known ssDNA interaction sites of PriB were expanded to include R44 and F42, thus allowing nucleic acids to wrap around the whole PriB protein. PMID- 22938025 TI - Daptomycin efficacy in the central nervous system of a patient with disseminated methicillin-resistant Staphylococcus aureus infection: a case report. AB - INTRODUCTION: Staphylococcus aureus has emerged as a major nosocomial pathogen in the last decades and also represents the second most common pathogen isolated from patients in outpatient settings. Although methicillin-resistant S.aureus infections were traditionally limited to hospitals, community-associated cases of methicillin-resistant S.aureus infections have been reported. In our case, we observed an unexpected event during treatment. CASE PRESENTATION: A 60-year-old Caucasian man developed fever and multiple muscle and brain abscesses caused by Panton-Valentine leukocidin-negative community-associated methicillin-resistant S. aureus. CONCLUSION: Although our patient was given antimicrobials active against the isolated methicillin-resistant S. aureus strain, it was only after the introduction of daptomycin that his skin, soft tissue and muscle lesions and also brain manifestations improved. PMID- 22938026 TI - Unmet need for induction of labor in Africa: secondary analysis from the 2004 - 2005 WHO Global Maternal and Perinatal Health Survey (A cross-sectional survey). AB - BACKGROUND: Induction of labor is being increasingly used to prevent adverse outcomes in the mother and the newborn.This study assessed the prevalence of induction of labor and determinants of its use in Africa. METHODS: We performed secondary analysis of the WHO Global Survey of Maternal and Newborn Health of 2004 and 2005. The African database was analyzed to determine the use of induction of labor at the country level and indications for induction of labor. The un-met needs for specific obstetric indications and at country level were assessed. Determinants of use of induction of labor were explored with multivariate regression analysis. RESULTS: A total of 83,437 deliveries were recorded in the 7 participating countries. Average rate of induction was 4.4% with a range of 1.4 - 6.8%. Pre-labor rupture of membranes was the commonest indication for induction of labor. Two groups of women were identified: 2,776 women with indications had induction of labor while 7,996 women although had indications but labor was not induced.Induction of labor was associated with reduction of stillbirths and perinatal deaths [OR - 0.34; 95% CI (0.27 - 0.43)].Unmet need for induction of labor ranged between 66.0% and 80.2% across countries. Determinants of having an induction of labor were place of residence, duration of schooling, type of health facility and level of antenatal care. CONCLUSION: Utilization of induction of labor in health facilities in Africa is very low. Improvements in social and health infrastructure are required to reverse the high unmet need for induction of labor. PMID- 22938028 TI - Photovoltaic Ge/Si quantum dot detectors operating in the mid-wave atmospheric window (3 to 5 MUm). AB - : Ge/Si quantum dots fabricated by molecular-beam epitaxy at 500 degrees C are overgrown with Si at different temperatures Tcap, and effect of boron delta doping of Si barriers on the mid-infrared photoresponse was investigated. The photocurrent maximum shifts from 2.3 to 3.9 MUm with increasing Tcapfrom 300 degrees C to 750 degrees C. Within the sample set, we examined devices with different positions of the delta-doping layer with respect to the dot plane, different distances between the delta-doping layer and the dot plane d, and different doping densities pB. All detectors show pronounced photovoltaic behavior implying the presence of an internal inversion asymmetry due to the placing dopants in the barriers. The best performance was achieved for the device with Tcap = 600 degrees C, pB = 12 * 1011cm-2, and d = 5 nm in a photovoltaic regime. At a sample temperature of 90 K and no applied bias, a responsivity of 0.83 mA/W and detectivity of 8 * 1010 cm Hz1/2/W at lambda = 3.4 MUm were measured under normal incidence infrared radiation. PMID- 22938027 TI - Is there any role of thrombin activatable fibrinolysis inhibitor in the development of a hypercoagulable state in gastric cancer. AB - BACKGROUND: The purpose of this study was to investigate plasma levels of thrombin activatable fibrinolysis inhibitor (TAFI) and TAFI's relationship with coagulation markers (prothrombin fragment 1 + 2) in gastric cancer patients. METHODS: Thirty-three patients with gastric adenocarcinoma and 29 healthy control subjects were prospectively enrolled in the study. Patients who had a history of secondary malignancy, thrombosis related disease, oral contraceptive use, diabetes mellitus, chronic renal failure or similar chronic metabolic disease were excluded from the study. A fasting blood sample was drawn from patients to determine the plasma levels of TAFI and Prothrombin Fragment 1 + 2 (F 1 + 2). In addition, data on patient age, sex, body mass index (BMI) and stage of disease were recorded. The same parameters, except stage of disease, were also recorded for the control group. Subsequently, we assessed the difference in the levels of TAFI and F 1 + 2 between the patient and control groups. Moreover, we investigated the relation of TAFI and F 1 + 2 levels with age, sex, BMI and stage of disease in the gastric cancer group. RESULTS: There were no statistical differences in any demographic variables (age, gender and BMI) between the groups (Table 1). The mean plasma TAFI levels of the gastric cancer group (69.4 +/- 33.1) and control group (73.3 +/- 27.5) were statistically similar (P = 0.62). The mean plasma F 1 + 2 level in the gastric cancer group was significantly higher than for those in the control group (549.7 +/- 325.3 vs 151.9 +/- 67.1, respectively; P < 0.001). In the gastric cancer group, none of the demographic variables (age, gender and BMI) were correlated with either TAFI or F 1 + 2 levels. Also, no significant associations were found between the stage of the cancer and either TAFI or F 1 + 2 levels. CONCLUSION: In our study, TAFI levels of gastric cancer patients were similar to healthy subjects. The results of our study suggest that TAFI does not play a role in pathogenesis of the hypercoagulable state in gastric cancer patients. PMID- 22938029 TI - Low-calcium dialysate as a risk factor for decline in bone mineral density in peritoneal dialysis patients. AB - OBJECTIVE: Few studies have linked changes in bone mineral density (BMD) in peritoneal dialysis (PD) patients to the calcium concentration in peritoneal dialysate. MATERIAL AND METHODS: In total, 236 incident patients who underwent an annual BMD determination for 2 years were enrolled. The patients were divided into two groups: the standard calcium dialysate (SCD) group (n = 190; 1.75 mmol/l) and the low-calcium dialysate (LCD) group (n = 46; 1.25 mmol/l). RESULTS: There were no significant differences between the baseline demographics of the two groups, such as age, diabetes, calcium, phosphorus, alkaline phosphatase (ALP), intact parathyroid hormone (i-PTH) levels or variables related to BMD. Univariate and multivariate analyses [adjusted for age, gender and time-averaged 25(OH)-vitamin D] determined that the LCD group had higher time-averaged i-PTH and ALP and a greater decrease in bone mineral content, lumbar spine BMD, subtotal BMD and total BMD compared to the SCD group. CONCLUSION: LCD is associated with a more rapid decline in BMD, higher i-PTH and higher ALP in PD patients. It is suggested that LCD be avoided for PD patients at risk of osteoporosis and hyperparathyroidism. PMID- 22938030 TI - EC144 is a potent inhibitor of the heat shock protein 90. AB - Alkyne 40, 5-(2-amino-4-chloro-7-((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)-7H pyrrolo[2,3-d]pyrimidin-5-yl)-2-methylpent-4-yn-2-ol (EC144), is a second generation inhibitor of heat shock protein 90 (Hsp90) and is substantially more potent in vitro and in vivo than the first generation inhibitor 14 (BIIB021) that completed phase II clinical trials. Alkyne 40 is more potent than 14 in an Hsp90alpha binding assay (IC(50) = 1.1 vs 5.1 nM) as well as in its ability to degrade Her-2 in MCF-7 cells (EC(50) = 14 vs 38 nM). In a mouse model of gastric tumors (N87), 40 stops tumor growth at 5 mg/kg and causes partial tumor regressions at 10 mg/kg (po, qd * 5). Under the same conditions, 14 stops tumor growth only at 120 mg/kg, and does not induce partial regressions. Thus, alkyne 40 is approximately 20-fold more efficacious than 14 in mice. PMID- 22938031 TI - Is the lag screw sliding effective in the intramedullary nailing in A1 and A2 AO OTA intertrochanteric fractures? A prospective study of Sliding and None-sliding lag screw in Gamma-III nail. AB - OBJECT: To compare the Sliding with Non-sliding lag screw of a gamma nail in the treatment of A1 and A2 AO-OTA intertrochanteric fractures. MATERIALS AND METHODS: 80 patients were prospectively collected. In each group, AO/OTA 31-A were classified into group A. AO/OTA 31-A2.1 was classified as group B. We classified the A2.2 and A2.3 as group C. According to the set-screw locking formation of Gamma-III, the cases were randomly allocated to Sliding subgroup and Non-sliding subgroup in A, B and C groups. Follow-ups were performed 1, 3, 6 and 12 months postoperatively. RESULTS: In the Sliding group, the bone healing rate 3, 6, 12 months postoperatively reached 85.00%, 97.50%, 100% in group A, B and C. Meanwhile, in Non-sliding group, postoperatively, bone healing rate were 90.00%, 95.00% and 97.50% in group A, B and C, respectively. Both differences were not significant. Lower limb discrepancy between Sliding and Non-sliding pattern was significantly different in group C which represent fracture types of AO/OTA 31 A2.2 and A2.3 (0.573 +/- 0.019 mm in Non-sliding group, 0.955 mm +/- 0.024 mm in Sliding group, P < 0.001 ). Difference of sliding distance among the three groups was significant among group A, B and C: 0.48 mm +/- 0.04 mm, 0.62 mm +/- 0.07 mm and 0.92 mm +/- 0.04 mm (P < 0.001). Differences in average healing time and Harris scores also presented no significance in the three groups. CONCLUSIONS: As a result, we can conclude that the sliding distance is minimal in Gamma nails and it is related to the comminuted extent of the intertrochanteric area in A1 and A2 AO-OTA intertrochanteric fractures. For treating these kinds of fractures, the sliding of the lag screw of an Gamma nail does not improve any clinical results and in certain cases, such as highly comminuted A1 and A2 fractures, can therefore even benefit from a locked lag screw by tightening the set-screw. PMID- 22938032 TI - Characterization of neutralizing mouse-human chimeric and shuffling antibodies against botulinum neurotoxin A. AB - Mouse-human chimeric monoclonal antibodies that could neutralize botulinum neurotoxins were developed and an attempt was made to establish mouse hybridoma cell clones that produced monoclonal antibodies that neutralized botulinum neurotoxin serotype A (BoNT/A). Four clones (2-4, 2-5, 9-4 and B1) were selected for chimerization on the basis of their neutralizing activity against BoNT/A and the cDNA of the variable regions of their heavy (V(H)) and light chains (V(L)) were fused with the upstream regions of the constant counterparts of human kappa light and gamma 1 heavy chain genes, respectively. CHO-DG44 cells were transfected with these plasmids and mouse-human chimeric antibodies (AC24, AC25, AC94 and ACB1) purified to examine their binding and neutralizing activities. Each chimeric antibody exhibited almost the same capability as each parent mouse mAb to bind and neutralize activities against BoNT/A. From the chimeric antibodies against BoNT/A, shuffling chimeric antibodies designed with replacement of their V(H) or V(L) domains were constructed. A shuffling antibody (AC2494) that derived its V(H) and V(L) domains from chimeric antibodies AC24 and AC94, respectively, showed much higher neutralizing activity than did other shuffling antibodies and parent counterparts. This result indicates that it is possible to build high-potency neutralizing chimeric antibodies by selecting and shuffling V(H) and V(L) domains from a variety of repertoires. A shuffling chimeric antibody might be the best candidate for replacing horse antitoxin for inducing passive immunotherapy against botulism. PMID- 22938033 TI - Screening and identification of dietary oils and unsaturated fatty acids in inhibiting inflammatory prostaglandin E2 signaling in fat stromal cells. AB - BACKGROUND: The molecular mechanisms of dietary oils (such as fish oil) and unsaturated fatty acids, which are widely used by the public for anti inflammation and vascular protection, have not been settled yet. In this study, prostaglandin E(2) (PGE(2))-mediated calcium signaling was used to screen dietary oils and eight unsaturated fatty acids for identification of their anti inflammatory mechanisms. Isolated fat/stromal cells expressing endogenous PGE(2) receptors and an HEK293 cell line specifically expressing the recombinant human PGE(2) receptor subtype-1 (EP(1)) were cultured and used in live cell calcium signaling assays. The different dietary oils and unsaturated fatty acids were used to affect cell signaling under the specific stimulation of a pathological amount of inflammatory PGE(2). RESULTS: It was identified that fish oil best inhibited the PGE(2) signaling in the primary cultured stromal cells. Second, docosahexaenoic acid (DHA), found in abundance in fish oil, was identified as a key factor of inhibition of PGE(2) signaling. Eicosapentaenoic acid (EPA), another major fatty acid found in fish oil and tested in this study was found to have small effect on EP(1) signaling. The study suggested one of the four PGE(2) subtype receptors, EP(1) as the key target for the fish oil and DHA target. These findings were further confirmed by using the recombinant EP(1) expressed in HEK293 cells as a target. CONCLUSION: This study demonstrated the new mechanism behind the positive effects of dietary fish oils in inhibiting inflammation originates from the rich concentration of DHA, which can directly inhibit the inflammatory EP(1)-mediated PGE(2) receptor signaling, and that the inflammatory response stimulated by PGE(2) in the fat stromal cells, which directly related to metabolic diseases, could be down regulated by fish oil and DHA. These findings also provided direct evidence to support the use of dietary oils and unsaturated fatty acids for protection against heart disease, pain, and cancer resulted from inflammatory PGE(2). PMID- 22938034 TI - Pain management and satisfaction in postsurgical patients. AB - AIMS AND OBJECTIVES: To examine the relationship between patient satisfaction and the incidence of severe and enduring pain through a health board wide hospital satisfaction questionnaire. BACKGROUND: The incidence and management of acute postoperative pain and its relationship to patient satisfaction have been of great interest to clinicians over the last 20 years. Evidence suggests that despite many moves to address this problem with the advent of acute pain nurse specialists and dedicated pain teams, severe and enduring pain continues to be a problem. However, patients appear to report high satisfaction levels. DESIGN: The study design was a postal questionnaire the results of which were analysed statistically. METHODS: The postal questionnaire was sent to patients who had been discharged from acute hospitals in one health board in the previous two weeks. A total of three large acute hospitals were included. The data were analysed to produce descriptive statistics for all patients on the pain questions and then for patients with severe and enduring pain on the variables of age, gender, ethnic group, responses to pain questions and type of admission. RESULTS: Twenty-six percent of patients reported having pain all or most of the time. Patients suffering from severe and enduring pain were younger females. CONCLUSION: Acute postoperative pain continues to be a problem, although patients continue reporting moderate satisfaction levels. RELEVANCE TO CLINICAL PRACTICE: Acute postoperative pain is an ongoing issue for postsurgical patients. It is crucial to understand and recognise issues that can adversely contribute to increased pain severity. PMID- 22938035 TI - What explains willingness to pay for smoking-cessation treatments - addiction level, quit-rate effectiveness or the opening bid? AB - BACKGROUND: Several countries have now passed laws that place limitations on where smokers may smoke. A range of smoking-cessation treatments have become available, many of which have documented increased quit rates. Population surveys show that most smokers wish to quit, and most non-smokers would prefer to reduce the prevalence of smoking in society. The strengths of these preferences, however, as measured by their willingness to pay (WTP), have not yet been investigated. OBJECTIVE: This study aims to identify variables that explain variations in people's answers to WTP questions on smoking-cessation treatments. METHODS: A representative sample of the Norwegian population was asked their WTP in terms of an earmarked contribution to a public smoking-cessation programme. A sub-group of daily smokers was, in addition, asked about their WTP for a hypothetical treatment that would remove their urge to smoke. The impact of variation in the question format (different opening bids) on stated WTP was compared with that of factors suggested by economic theory, such as quit-rate effectiveness, degree of addiction as measured by the 12-item Cigarette Dependence Scale (CDS-12), and degree of peer group influence as measured by the proportion of one's friends who smoke. RESULTS: In both programmes, the most important determinant for explaining variations in WTP was the size of the opening bid. Differences in quit-rate effectiveness did not matter for people's WTP for the smoking-cessation programme. Addiction, and having a small proportion of friends who smoke, were positively associated with smokers' WTP to quit smoking. CONCLUSION: Variations in WTP were influenced more by how the question was framed in terms of differences in opening bids, than by variables reflecting the quality (effectiveness) and need (addiction level) for the good in question. While the WTP method is theoretically attractive, the findings that outcomes in terms of different quit rates did not affect WTP, and that WTP answers can be manipulated by the chosen opening bid, should raise further doubts on the ability of this method to provide valid and reliable answers that reflect true preferences for health and healthcare. PMID- 22938036 TI - Necrotizing enterocolitis after red blood cell transfusion in preterm infants with patent ductus arteriosus: a case series. AB - AIM: Both patent ductus arteriosus (PDA) and packed red blood cell (PRBC) transfusion are risk factors for necrotizing enterocolitis (NEC). The combination of PDA and PRBC transfusion may have a synergistic effect on the intestinal circulation. METHODS: We present four cases of NEC in very low birth weight (VLBW) infants within 14 h after PRBC transfusion. RESULTS: All infants were growing on full enteral feeding, and they all had a PDA. CONCLUSION: We are concerned that the simultaneous presence of a PDA and PRBC transfusion in VLBW infants may place the infant at even greater risk of NEC than each of these factors alone. PMID- 22938037 TI - Nutrigenetic screening strains of the mulberry silkworm, Bombyx mori, for nutritional efficiency. AB - The activity of sericulture is declining due the reduction of mulberry production area in sericulture practicing countries lead to adverse effects on silkworm rearing and cocoon production. Screening for nutrigenetic traits in silkworm, Bombyx mori L. (Lepidoptera: Bombycidae) is an essential prerequisite for better understanding and development of nutritionally efficient breeds/hybrids, which show less food consumption with higher efficiency conversion. The aim of this study was to identify nutritionally efficient polyvoltine silkworm strains using the germplasm breeds RMW(2), RMW(3), RMW(4), RMG(3), RMG(1), RMG(4), RMG(5), RMG(6) and APM(1) as the control. The 1(st) day of 5(th) stage silkworm larvae of polyvoltine strains were subjected to standard gravimetric analysis until spinning for three consecutive generations covering three different seasons on 19 nutrigenetic traits. Highly significant (p <= 0.001) differences were found among all nutrigenetic traits of polyvoltine silkworm strains in the experimental groups. The nutritionally efficient polvoltine silkworm strains were resulted by utilizing nutrition consumption index and efficiency of conversion of ingesta/cocoon traits as the index. Higher nutritional efficiency conversions were found in the polyvoltine silkworm strains on efficiency of conversion of ingesta to cocoon and shell than control. Comparatively smaller consumption index, respiration, metabolic rate with superior relative growth rate, and quantum of food ingesta and digesta requisite per gram of cocoon and shell were shown; the lowest amount was in new polyvoltine strains compared to the control. Furthermore, based on the overall nutrigenetic traits utilized as index or 'biomarkers', three polyvoltine silkworm strains (RMG(4), RMW(2), and RMW(3)) were identified as having the potential for nutrition efficiency conversion. The data from the present study advances our knowledge for the development of nutritionally efficient silkworm breeds/hybrids and their effective commercial utilization in the sericulture industry. PMID- 22938039 TI - Structural tissue organization in the beak of Java and Darwin's finches. AB - Birds are well known for occupying diverse feeding niches, and for having evolved diverse beak morphologies associated with dietary specialization. Birds that feed on hard seeds typically possess beaks that are both deep and wide, presumably because of selection for fracture avoidance, as suggested by prior studies. It follows then that birds that eat seeds of different size and hardness should vary in one or more aspects of beak morphology, including the histological organization of the rhamphotheca, the cellular interface that binds the rhamphotheca to the bone, and the organization of trabeculae in the beak. To explore this expectation we here investigate tissue organization in the rhamphotheca of the Java finch, a large granivorous bird, and describe interspecific differences in the trabecular organization of the beak across 11 species of Darwin's finches. We identify specializations in multiple layers of the horny beak, with the dermis anchored to the bone by Sharpey's fibers in those regions that are subjected to high stresses during biting. Moreover, the rhamphotheca is characterized by a tight dermo-epidermal junction through interdigitations of these two tissues. Herbst corpuscles are observed in high density in the dermis of the lateral aspect of the beak as observed in other birds. Finally, the trabecular organization of the beak in Darwin's finches appears most variable in regions involved most in food manipulation, with the density of trabeculae in the beak generally mirroring loading regimes imposed by different feeding habits and beak use in this clade. PMID- 22938038 TI - S-bacillithiolation protects conserved and essential proteins against hypochlorite stress in firmicutes bacteria. AB - AIMS: Protein S-bacillithiolations are mixed disulfides between protein thiols and the bacillithiol (BSH) redox buffer that occur in response to NaOCl in Bacillus subtilis. We used BSH-specific immunoblots, shotgun liquid chromatography (LC)-tandem mass spectrometry (MS/MS) analysis and redox proteomics to characterize the S-bacillithiolomes of B. subtilis, B. megaterium, B. pumilus, B. amyloliquefaciens, and Staphylococcus carnosus and also measured the BSH/oxidized bacillithiol disulfide (BSSB) redox ratio after NaOCl stress. RESULTS: In total, 54 proteins with characteristic S-bacillithiolation (SSB) sites were identified, including 29 unique proteins and eight proteins conserved in two or more of these bacteria. The methionine synthase MetE is the most abundant S-bacillithiolated protein in Bacillus species after NaOCl exposure. Further, S-bacillithiolated proteins include the translation elongation factor EF Tu and aminoacyl-tRNA synthetases (ThrS), the DnaK and GrpE chaperones, the two Cys peroxiredoxin YkuU, the ferredoxin-NADP(+) oxidoreductase YumC, the inorganic pyrophosphatase PpaC, the inosine-5'-monophosphate dehydrogenase GuaB, proteins involved in thiamine biosynthesis (ThiG and ThiM), queuosine biosynthesis (QueF), biosynthesis of aromatic amino acids (AroA and AroE), serine (SerA), branched chain amino acids (YwaA), and homocysteine (LuxS and MetI). The thioredoxin-like proteins, YphP and YtxJ, are S-bacillithiolated at their active sites, suggesting a function in the de-bacillithiolation process. S-bacillithiolation is accompanied by a two-fold increase in the BSSB level and a decrease in the BSH/BSSB redox ratio in B. subtilis. INNOVATION: Many essential and conserved proteins, including the dominant MetE, were identified in the S-bacillithiolome of different Bacillus species and S. carnosus using shotgun-LC-MS/MS analyses. CONCLUSION: S-bacillithiolation is a widespread redox control mechanism among Firmicutes bacteria that protects conserved metabolic enzymes and essential proteins against overoxidation. PMID- 22938040 TI - A predictive scoring instrument for tuberculosis lost to follow-up outcome. AB - BACKGROUND: Adherence to tuberculosis (TB) treatment is troublesome, due to long therapy duration, quick therapeutic response which allows the patient to disregard about the rest of their treatment and the lack of motivation on behalf of the patient for improved. The objective of this study was to develop and validate a scoring system to predict the probability of lost to follow-up outcome in TB patients as a way to identify patients suitable for directly observed treatments (DOT) and other interventions to improve adherence. METHODS: Two prospective cohorts, were used to develop and validate a logistic regression model. A scoring system was constructed, based on the coefficients of factors associated with a lost to follow-up outcome. The probability of lost to follow-up outcome associated with each score was calculated. Predictions in both cohorts were tested using receiver operating characteristic curves (ROC). RESULTS: The best model to predict lost to follow-up outcome included the following characteristics: immigration (1 point value), living alone (1 point) or in an institution (2 points), previous anti-TB treatment (2 points), poor patient understanding (2 points), intravenous drugs use (IDU) (4 points) or unknown IDU status (1 point). Scores of 0, 1, 2, 3, 4 and 5 points were associated with a lost to follow-up probability of 2,2% 5,4% 9,9%, 16,4%, 15%, and 28%, respectively. The ROC curve for the validation group demonstrated a good fit (AUC: 0,67 [95% CI; 0,65-0,70]). CONCLUSION: This model has a good capacity to predict a lost to follow-up outcome. Its use could help TB Programs to determine which patients are good candidates for DOT and other strategies to improve TB treatment adherence. PMID- 22938042 TI - Antiproliferative and cell apoptosis-inducing activities of compounds from Buddleja davidii in Mgc-803 cells. AB - BACKGROUND: Buddleja davidii is widely distributed in the southwestern region of China. We have undertaken a systematic analysis of B. davidii as a Chinese traditional medicine with anticancer activity by isolating natural products for their activity against the human gastric cancer cell line Mgc-803 and the human breast cancer cell line Bcap-37. RESULTS: Ten compounds were extracted and isolated from B. davidii, among which colchicine was identified in B. davidii for the first time. The inhibitory activities of these compounds were investigated in Mgc-803, Bcap-37 cells in vitro by MTT [3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide] assay, and the results showed that luteolin and colchicine had potent inhibitory activities against the growth of Mgc-803 cells. Subsequent fluorescence staining and flow cytometry analysis indicated that these two compounds could induce apoptosis in Mgc-803 cells. The results also showed that the percentages of early apoptotic cells (Annexin V+/PI-, where PI is propidium iodide) and late apoptotic cells (Annexin V+/PI+) increased in a dose- and time-dependent manner. After 36 h of incubation with luteolin at 20 MUM, the percentages of cells were approximately 15.4% in early apoptosis and 43.7% in late apoptosis; after 36 h of incubation with colchicine at 20 MUM, the corresponding values were 7.7% and 35.2%, respectively. CONCLUSIONS: Colchicine and luteolin from B. davidii have potential applications as adjuvant therapies for treating human carcinoma cells. These compounds could also induce apoptosis in tumor cells. PMID- 22938043 TI - Harden the chloroplast to protect the plant. AB - The chloroplast is the central switch of the plant's response to cold and light stress. The ability of many plant species to develop a cold tolerant phenotype is dependent on the presence of light and photosynthetic activity during low temperature growth. Light exposure at low temperature stimulates an over reduction of the plastoquinone pool as well as the accumulation of reactive oxygen species, and both metabolic conditions generate a retrograde signal controlling nuclear gene expression. At the same time the chloroplast is the target of many cold acclimation processes which are the results of the chloroplast-nucleus cross-talk. Often, the extent of cold acclimation of the chloroplast is tightly correlated with the overall plant tolerance to chilling and freezing temperatures, a finding suggesting that the chloroplast cold acclimation could be the rate limiting factor in the adaptation to low temperature. PMID- 22938041 TI - Single plasmonic nanoparticle tracking studies of solid supported bilayers with ganglioside lipids. AB - Single-particle tracking experiments were carried out with gold nanoparticle labeled solid supported lipid bilayers (SLBs) containing increasing concentrations of ganglioside (GM(1)). The negatively charged nanoparticles electrostatically associate with a small percentage of positively charged lipids (ethyl phosphatidylcholine) in the bilayers. The samples containing no GM(1) show random diffusion in 92% of the particles examined with a diffusion constant of 4.3(+/-4.5) * 10(-9) cm(2)/s. In contrast, samples containing 14% GM(1) showed a mixture of particles displaying both random and confined diffusion, with the majority of particles, 62%, showing confined diffusion. Control experiments support the notion that the nanoparticles are not associating with the GM(1) moieties but instead most likely confined to regions in between the GM(1) clusters. Analysis of the root-mean-squared displacement plots for all of the data reveals decreasing trends in the confined diffusion constant and diameter of the confining region versus increasing GM(1) concentration. In addition, a linearly decreasing trend is observed for the percentage of randomly diffusing particles versus GM(1) concentration, which offers a simple, direct way to measure the percolation threshold for this system, which has not previously been measured. The percolation threshold is found to be 22% GM(1) and the confining diameter at the percolation threshold only ~50 nm. PMID- 22938044 TI - Costs associated with long-term catheter care in nursing home patients. AB - OBJECTIVE: Approximately 8% of nursing home patients in Sweden have a long-term indwelling catheter. A catheter requires daily care and regular changes (basic care). Beyond this, significant numbers of patients are troubled by frequent complications necessitating acute catheter changes and/or rinses. The aim of this study was to calculate the costs associated with long-term indwelling catheters among patients at nursing homes. MATERIAL AND METHODS: All 366 patients with indwelling urinary catheters at 78 nursing homes were followed prospectively for 1 year and all catheter-related procedures, rinses, and changes were registered and the costs of the procedures calculated. RESULTS: The basic cost was calculated to be SEK 1157 per month and patient. The average monthly cost for acute interventions was estimated to range from SEK 169 in the quartile with few such events up to SEK 455 in the quartile with frequent acute interventions. Personnel accounted for over 90% of the costs associated with indwelling catheters. CONCLUSIONS: Basic catheter care was more cost intensive than acute interventions. This applied even for the 25% of subjects frequently troubled by complications requiring acute catheter changes or rinses. The cost of the catheters and material used in connection with catheter rinses/irrigations was low compared with the cost of the personnel undertaking the procedures. PMID- 22938045 TI - Body composition study by dual-energy x-ray absorptiometry in familial partial lipodystrophy: finding new tools for an objective evaluation. AB - BACKGROUND: Familial partial lipodystrophies (FPLD) are clinically heterogeneous disorders characterized by selective loss of adipose tissue, insulin resistance and metabolic complications. Until genetic studies become available for clinical practice, clinical suspicion and pattern of fat loss are the only parameters leading clinicians to consider the diagnosis. The objective of this study was to compare body composition by dual energy X-ray absorptiometry (DXA) in patients with FPLD and control subjects, aiming to find objective variables for evaluation of FPLD. METHODS: Eighteen female patients with partial lipodystrophy phenotype and 16 healthy controls, matched for body mass index, sex and age were studied. All participants had body fat distribution evaluated by DXA measures. Fasting blood samples were obtained for evaluation of plasma leptin, lipid profile and inflammatory markers. Genetic studies were carried out on the 18 patients selected that were included for statistical analysis. Thirteen women confirmed diagnosis of Dunnigan-type FPLD (FPLD2). RESULTS: DXA revealed a marked decrease in truncal fat and 3 folds decrease in limbs fat percentage in FPLD2 patients (p <0.001). Comparative analysis showed that ratio between trunk and lower limbs fat mass, characterized as Fat Mass Ratio (FMR), had a greater value in FLPD2 group (1.86 +/- 0.43 vs controls 0.93 +/- 0.10; p <0.001) and a improved accuracy for evaluating FPLD2 with a cut-off point of 1.2. Furthermore, affected women showed hypoleptinemia (FLPD2 4.9 +/- 2.0 vs controls 18.2 +/- 6.8; p <0.001), insulin resistance and a more aggressive lipid profile. CONCLUSION: In this study, assessment of body fat distribution by DXA permitted an objective characterization of FLPD2. A consistent pattern with marked fat reduction of lower body was observed in affected patients. To our knowledge this is the first time that cut-off values of objective variables were proposed for evaluation of FPLD2. PMID- 22938046 TI - What do we know about who does and does not attend general health checks? Findings from a narrative scoping review. AB - BACKGROUND: General and preventive health checks are a key feature of contemporary policies of anticipatory care. Ensuring high and equitable uptake of such general health checks is essential to ensuring health gain and preventing health inequalities. This literature review explores the socio-demographic, clinical and social cognitive characteristics of those who do and do not engage with general health checks or preventive health checks for cardiovascular disease. METHODS: An exploratory scoping study approach was employed. Databases searched included the British Nursing Index and Archive, Cumulative Index to Nursing and Allied Health Literature (CINAHL), Cochrane Database of Systematic Reviews (CDSR) and Database of Abstracts of Reviews of Effects (DARE), EMBASE, MEDLINE, PsycINFO and the Social Sciences Citation Index (SSCI). Titles and abstracts of 17463 papers were screened; 1171 papers were then independently assessed by two researchers. A review of full text was carried out by two of the authors resulting in 39 being included in the final review. RESULTS: Those least likely to attend health checks were men on low incomes, low socio-economic status, unemployed or less well educated. In general, attenders were older than non-attenders. An individual's marital status was found to affect attendance rates with non-attenders more likely to be single. In general, white individuals were more likely to engage with services than individuals from other ethnic backgrounds. Non-attenders had a greater proportion of cardiovascular risk factors than attenders, and smokers were less likely to attend than non-smokers. The relationship between health beliefs and health behaviours appeared complex. Non-attenders were shown to value health less strongly, have low self-efficacy, feel less in control of their health and be less likely to believe in the efficacy of health checks. CONCLUSION: Routine health check-ups appear to be taken up inequitably, with gender, age, socio-demographic status and ethnicity all associated with differential service use. Furthermore, non-attenders appeared to have greater clinical need or risk factors suggesting that differential uptake may lead to sub-optimal health gain and contribute to inequalities via the inverse care law. Appropriate service redesign and interventions to encourage increased uptake among these groups is required. PMID- 22938047 TI - Reducing power and iron chelating property of Terminalia chebula (Retz.) alleviates iron induced liver toxicity in mice. AB - BACKGROUND: The 70% methanol extract of Terminalia chebula Retz. fruit (TCME) was investigated for its in vitro iron chelating property and in vivo ameliorating effect on hepatic injury of iron overloaded mice. METHODS: The effect of fruit extract on Fe2+-ferrozine complex formation and Fe2+ mediated pUC-18 DNA breakdown was studied in order to find the in vitro iron chelating activity. Thirty-six Swiss Albino mice were divided into six groups of: blank, patient control and treated with 50, 100, 200 mg/kg b.w. of TCME and desirox (standard iron chelator drug with Deferasirox as parent compound). Evaluations were made for serum markers of hepatic damage, antioxidant enzyme, lipid per oxidation and liver fibrosis levels. The reductive release of ferritin iron by the extract was further studied. RESULTS: In vitro results showed considerable iron chelation with IC50 of 27.19 +/- 2.80 MUg/ml, and a significant DNA protection with [P]50 of 1.07 +/- 0.03 MUg/ml along with about 86% retention of supercoiled DNA. Iron dextran injection (i.p.) caused significant increase in the levels of the serum enzymes, viz., alanine aminotransferase (ALAT), aspartate aminotransferase (ASAT), alkaline phosphatase (ALP) and Bilirubin, which were subsequently lowered by oral administration of 200 mg/kg b.w. dose of the fruit extract by 81.5%, 105.88%, 188.08% and 128.31%, respectively. Similarly, treatment with the same dose of the extract was shown to alleviate the reduced levels of liver antioxidant enzyme superoxide dismutase, catalase, glutathione S-transferase and non-enzymatic reduced glutathione, by 49.8%, 53.5%, 35.4% and 11% respectively, in comparison to the iron overloaded mice. At the same time, the fruit extract effectively lowered the iron-overload induced raised levels of lipid per oxidation, protein carbonyl, hydroxyproline and liver iron by 49%, 67%, 67% and 26%, respectively, with oral treatment of 200 mg/kg b.w. dose of TCME. The fruit extract also showed potential activity for reductive release of ferritin iron. CONCLUSIONS: These findings suggest that Terminalia chebula extract may contain active substances capable of lessening iron overload induced toxicity, and hence possibly be useful as iron chelating drug for iron overload diseases. PMID- 22938048 TI - Biepicondylar fracture presenting with elbow dislocation: a case report. AB - INTRODUCTION: Biepicondylar fracture of the elbow is very rare, and to date there have only been three reports of this injury and its treatment in the English scientific literature. This case report evaluates the surgical internal fixation of a biepicondylar fracture of the elbow with an associated dislocation. CASE PRESENTATION: We report the case of a 15-year-old Turkish girl with a biepicondylar fracture dislocation of the left elbow. Open reduction and an internal fixation operation were applied. There were no complications. CONCLUSION: In these injuries, open reduction and internal fixation appear to be a good method to restore elbow stability and function. PMID- 22938050 TI - Characterization of hybrid cobalt-porous silicon systems: protective effect of the Matrix in the metal oxidation. AB - In the present work, the characterization of cobalt-porous silicon (Co-PSi) hybrid systems is performed by a combination of magnetic, spectroscopic, and structural techniques. The Co-PSi structures are composed by a columnar matrix of PSi with Co nanoparticles embedded inside, as determined by Transmission Electron Microscopy (TEM). The oxidation state, crystalline structure, and magnetic behavior are determined by X-Ray Absorption Spectroscopy (XAS) and Alternating Gradient Field Magnetometry (AGFM). Additionally, the Co concentration profile inside the matrix has been studied by Rutherford Backscattering Spectroscopy (RBS). It is concluded that the PSi matrix can be tailored to provide the Co nanoparticles with extra protection against oxidation. PMID- 22938049 TI - Exploration of novel 3-substituted azetidine derivatives as triple reuptake inhibitors. AB - Novel azetidines based on the 3-aryl-3-oxypropylamine scaffold were designed, synthesized, and evaluated as TRIs. Reduction of 1 followed by Swern oxidation and then Grignard reaction gave 3. The alkylation of 3 provided the corresponding azetidine derivatives 6, of which the two most promising, 6bd and 6be, were selected from 86 prepared analogues based on their biological profiles. Compound 6be showed activity in vivo in FST at 10 mg/kg IV or 20-40 mg/kg PO. PMID- 22938052 TI - Oviposition and larval habitat preferences of the saltwater mosquito, Aedes vigilax, in a subtropical mangrove forest in Queensland, Australia. AB - Our aim was to investigate the oviposition and larval habitats of the saltwater mosquito Aedes vigilax (Skuse) (Diptera: Culicidae) in a mangrove forest system in subtropical Queensland, Australia. Eggshells (indicators of oviposition) and larvae were sampled in three habitat classes that were depicted in a schematic model. Two classes were in depressions or basins, either with hummocks or dense pneumatophore substrates, both of which retained water after tidal flooding. The third class was in freely flushed mangroves that corresponded with more frequent tidal connections than the depression classes. ANOVA and Tukey-Kramer tests were used to analyze the data. The null hypotheses were rejected: the hummock class was a significant habitat based on both eggshell and larval data. The conclusion was that mosquito production in the mangrove system was distributed unevenly between habitat classes, and that the hummock class had conditions suited to the requirements of the immature stages of Ae. vigilax. This research has the potential to inform mosquito management strategies by focusing treatment on the problem habitats and underpinning habitat modifications including reducing water retention in the basins. PMID- 22938053 TI - Outcome of risk adapted therapy for relapsed/refractory acute lymphoblastic leukemia in children. AB - Results of second-line therapy for childhood acute lymphoblastic leukemia (ALL) remain suboptimal, particularly for high-risk groups identified using timing and site of relapse. We report results of prospectively collected data for pediatric patients with ALL who received risk adjusted second-line therapy. The 59 patients who failed first-line ALL therapy included 36 (61%) with bone marrow (BM), 13 (22.1%) with isolated extramedullary (EM) and 10 (16.9%) with BM + EM relapse. Some 51.8% patients were reinduced with high dose cytosine arabinoside (HDAraC) based and 48.2% with standard four-drug regimens. In all, 38/56 (67.9%) achieved a complete remission (CR) with second-line therapy; the overall CR rate was 78.6% and was not associated with CR1 duration (p =0.8). Three-year overall survival (OS) was 45.3%, and was 61.4% for those achieving a CR. No risk group benefited from HSCT over chemotherapy. Patients with isolated EM relapse beyond 18 months of CR1 and BM relapse beyond 12 months off-therapy had an excellent outcome (OS 91.7%), identifying a particularly good-risk cohort. Patients not in this category continue with poor outcome even following hematopoietic stem cell transplant. PMID- 22938051 TI - Outpatient management of severe early OHSS by administration of GnRH antagonist in the luteal phase: an observational cohort study. AB - BACKGROUND: Management of established severe OHSS requires prolonged hospitalization, occasionally in intensive care units, accompanied by multiple ascites punctures, correction of intravascular fluid volume and electrolyte imbalance. The aim of the present study was to evaluate whether it is feasible to manage women with severe OHSS as outpatients by treating them with GnRH antagonists in the luteal phase. METHODS: This is a single-centre, prospective, observational, cohort study. Forty patients diagnosed with severe OHSS, five days post oocyte retrieval, were managed as outpatients after administration of GnRH antagonist (0.25 mg) daily from days 5 to 8 post oocyte retrieval, combined with cryopreservation of all embryos. The primary outcome measure was the proportion of patients with severe OHSS, in whom outpatient management was not feasible. RESULTS: 11.3% (95% CI 8.3%-15.0%) of patients (40/353) developed severe early OHSS. None of the 40 patients required hospitalization following luteal antagonist administration and embryo cryopreservation. Ovarian volume, ascites, hematocrit, WBC, serum oestradiol and progesterone decreased significantly (P < 0.001) by the end of the monitoring period, indicating rapid resolution of severe OHSS. CONCLUSIONS: The current study suggests, for the first time, that successful outpatient management of severe OHSS with antagonist treatment in the luteal phase is feasible and is associated with rapid regression of the syndrome, challenging the dogma of inpatient management. The proposed management is a flexible approach that minimizes unnecessary embryo transfer cancellations in the majority (88.7%) of high risk for OHSS patients. PMID- 22938054 TI - Heterozygosity-behaviour correlations in nine-spined stickleback (Pungitius pungitius) populations: contrasting effects at random and functional loci. AB - The study of heterozygosity-fitness correlations (HFCs) has a long history in the fields of ecology and evolutionary biology but remains controversial. Recently, it has been shown that the genetic distance of markers from functional loci can be an important factor to be considered in addition to marker numbers and variability. In this study, we investigated the correlation between individual heterozygosity and behaviour (aggression, boldness and feeding activity) in nine spined stickleback (Pungitius pungitius) individuals originating from four populations in two contrasting environments. Offspring of full-sib families raised in a common garden setting were assessed for behaviour and genotyped using 84 microsatellite markers that were either located within or near behaviourally or physiologically important genes (termed 'functional') or were randomly selected. No associations were detected with any behavioural trait in any population or over all populations when genetic variability was measured using all 84 markers combined. However, when the markers were separated into three functional categories (behavioural, physiological and random), several significant associations were observed both with functional markers and random markers in one of the four populations assessed. Interestingly, contrasting correlations with behaviour were observed when using physiological gene (negative) and random (positive) markers. Upon dividing the physiological gene markers into further subcategories based on their specific physiological functions, a strong relationship between the heterozygosity of markers linked to osmoregulation-related genes, and behaviour was revealed in the brackish water population. Our results indicate that both local (physiological) and general (neutral) effects are important in shaping behaviour and that heterozygosity behaviour correlations are population dependent. PMID- 22938055 TI - Is inflammation a mitochondrial dysfunction-dependent event in fibromyalgia? AB - Fibromyalgia (FM) is a complex disorder that affects up to 5% of the general population worldwide. Both mitochondrial dysfunction and inflammation have been implicated in the pathophysiology of FM. We have investigated the possible relationship between mitochondrial dysfunction, oxidative stress, and inflammation in FM. We studied 30 women diagnosed with FM and 20 healthy women. Blood mononuclear cells (BMCs) from FM patients showed reduced level of coenzyme Q10 (CoQ10) and mtDNA contents and high level of mitochondrial reactive oxygen species (ROS) and serum tumor necrosis factor (TNF)-alpha and transcript levels. A significant negative correlation between CoQ10 and TNF-alpha levels (r=-0.588; p<0.01), and a positive correlation between ROS and TNF-alpha levels (r=0.791; p<0.001) were observed accompanied by a significant correlation of visual analogical scale with serum TNF-alpha and transcript levels (r=0.4507; p<0.05 and r=0.7089; p<0.001, respectively). TNF-alpha release was observed in an in vitro (BMCs) and in vivo (mice) CoQ10 deficiency model. Oral CoQ10 supplementation restored biochemical parameters and induced a significant improvement in clinical symptoms (p<0.001). These results lead to the hypothesis that inflammation could be a mitochondrial dysfunction-dependent event implicated in the pathophysiology of FM in several patients indicating at mitochondria as a possible new therapeutic target. PMID- 22938056 TI - Vandetanib: a guide to its use in advanced medullary thyroid cancer. AB - Vandetanib (CaprelsaTM) provides an acceptable treatment option in patients with advanced medullary thyroid cancer for whom, historically, there have been no effective therapies. Vandetanib, an orally active, multitargeted tyrosine kinase inhibitor, improves progression-free survival and tumor response in patients with unresectable, locally advanced or metastatic medullary thyroid cancer. It has an acceptable tolerability profile in this patient population, although it does have the potential to prolong the corrected QT interval. PMID- 22938058 TI - The influence of hydrogenation and oxygen vacancies on molybdenum oxides work function and gap states for application in organic optoelectronics. AB - Molybdenum oxide is used as a low-resistance anode interfacial layer in applications such as organic light emitting diodes and organic photovoltaics. However, little is known about the correlation between its stoichiometry and electronic properties, such as work function and occupied gap states. In addition, despite the fact that the knowledge of the exact oxide stoichiometry is of paramount importance, few studies have appeared in the literature discussing how this stoichiometry can be controlled to permit the desirable modification of the oxide's electronic structure. This work aims to investigate the beneficial role of hydrogenation (the incorporation of hydrogen within the oxide lattice) versus oxygen vacancy formation in tuning the electronic structure of molybdenum oxides while maintaining their high work function. A large improvement in the operational characteristics of both polymer light emitting devices and bulk heterojunction solar cells incorporating hydrogenated Mo oxides as hole injection/extraction layers was achieved as a result of favorable energy level alignment at the metal oxide/organic interface and enhanced charge transport through the formation of a large density of gap states near the Fermi level. PMID- 22938057 TI - Do highly divergent loci reside in genomic regions affecting reproductive isolation? A test using next-generation sequence data in Timema stick insects. AB - BACKGROUND: Genetic divergence during speciation with gene flow is heterogeneous across the genome, with some regions exhibiting stronger differentiation than others. Exceptionally differentiated regions are often assumed to experience reduced introgression, i.e., reduced flow of alleles from one population into another because such regions are affected by divergent selection or cause reproductive isolation. In contrast, the remainder of the genome can be homogenized by high introgression. Although many studies have documented variation across the genome in genetic differentiation, there are few tests of this hypothesis that explicitly quantify introgression. Here, we provide such a test using 38,304 SNPs in populations of Timema cristinae stick insects. We quantify whether loci that are highly divergent between geographically separated ('allopatric') populations exhibit unusual patterns of introgression in admixed populations. To the extent this is true, highly divergent loci between allopatric populations contribute to reproductive isolation in admixed populations. RESULTS: As predicted, we find a substantial association between locus-specific divergence between allopatric populations and locus-specific introgression in admixed populations. However, many loci depart from this relationship, sometimes strongly so. We also report evidence for selection against foreign alleles due to local adaptation. CONCLUSIONS: Loci that are strongly differentiated between allopatric populations sometimes contribute to reproductive isolation in admixed populations. However, geographic variation in selection and local adaptation, in aspects of genetic architecture (such as organization of genes, recombination rate variation, number and effect size of variants contributing to adaptation, etc.), and in stochastic evolutionary processes such as drift can cause strong differentiation of loci that do not always contribute to reproductive isolation. The results have implications for the theory of 'genomic islands of speciation'. PMID- 22938059 TI - Costing children's speech, language and communication interventions. AB - BACKGROUND: There are few economic evaluations of speech and language interventions. Such work requires underpinning by an accurate estimate of the costs of the intervention. This study seeks to address some of the complexities of this task by applying existing approaches of cost estimation to interventions described in published effectiveness studies. AIMS: The study has two aims: to identify a method of estimating unit costs based on the principle of long-run marginal opportunity costs; and to illustrate the challenges in estimating unit costs for speech and language interventions. METHOD & PROCEDURES: Descriptions of interventions were extracted from eight papers and combined with information on the unit cost of speech and language therapists to identify information requirements for a full-cost estimation of an intervention. OUTCOMES & RESULTS: Four challenges were found relating to the level of detail about the therapists, the participants, the scope of activities and parents. Different assumptions made about any of these elements will have a marked effect on the cost of the intervention. CONCLUSIONS & IMPLICATIONS: Nationally applicable unit cost data for speech and language therapists can be used as a reference point, but sufficient descriptive data about delivery and receipt of the intervention are key to accuracy. PMID- 22938060 TI - Using principles of learning to inform language therapy design for children with specific language impairment. AB - BACKGROUND: Language treatment for children with specific language impairment (SLI) often takes months to achieve moderate results. Interventions often do not incorporate the principles that are known to affect learning in unimpaired learners. AIMS: To outline some key findings about learning in typical populations and to suggest a model of how they might be applied to language treatment design as a catalyst for further research and discussion. METHODS & PROCEDURES: Three main principles of implicit learning are reviewed: variability, complexity and sleep-dependent consolidation. After explaining these principles, evidence is provided as to how they influence learning tasks in unimpaired learners. Information is reviewed on principles of learning as they apply to impaired populations, current treatment designs are also reviewed that conform to the principles, and ways in which principles of learning might be incorporated into language treatment design are demonstrated. MAIN CONTRIBUTION: This paper provides an outline for how theoretical knowledge might be applied to clinical practice in an effort to promote discussion. CONCLUSIONS & IMPLICATIONS: Although the authors look forward to more specific details on how the principles of learning relate to impaired populations, there is ample evidence to suggest that these principles should be considered during treatment design. PMID- 22938061 TI - Sentence repetition in children with specific language impairment: an investigation of underlying mechanisms. AB - BACKGROUND: Sentence repetition (SR) is a reliable clinical marker of specific language impairment (SLI). However, little is known about cognitive processes underpinning SR, or areas of breakdown in children with SLI. AIMS: The study investigated which cognitive mechanisms were most closely involved in SR performance: syntactic knowledge, phonological short-term memory (STM) and working memory (WM). METHODS & PROCEDURES: Twenty-three children with SLI (mean age = 6;7), 18 age-matched (mean age = 6;5) and 21 language-matched children (mean age = 4;8) repeated 180 sentences of varying length and complexity. Total words omitted, added or substituted were counted. Assessments of syntactic knowledge using a structural priming task, and assessments of WM, and phonological STM, were conducted. Twenty sentences were presented in a delayed repetition condition to investigate the role of phonological STM. OUTCOMES & RESULTS: The children with SLI made more SR errors than controls and found delayed repetition especially difficult. Their SR errors were qualitatively similar to errors on other production tasks. In the SLI group, all assessments were good predictors, though the priming task was the strongest. In the control groups WM tasks were the best predictors, but the phonological STM task was a poor predictor. CONCLUSIONS & IMPLICATIONS: The data support a multifaceted view of SR with a role for syntactic knowledge, WM and STM. 'Redintegration', whereby long-term memory representations are used to maintain information in short-term memory, is likely to be a key process. Specific errors in the SLI group are likely to reflect difficulties with underlying syntactic representations. Children with SLI may be more dependent on phonological STM than typically developing children. PMID- 22938062 TI - 'You needed to rehab ... families as well': family members' own goals for aphasia rehabilitation. AB - BACKGROUND: Aphasia affects family members in addition to the individuals with the communication disorder. In order to develop appropriate services for the relatives of people with aphasia post-stroke, their rehabilitation goals need to be identified. AIM: The aim of the current investigation was to identify the rehabilitation goals that family members of individuals with aphasia have for themselves. METHODS & PROCEDURES: Forty-eight family members of adults with aphasia post-stroke participated in in-depth semi-structured interviews to identify the rehabilitation goals they had for themselves. All the interviews were transcribed verbatim and analysed using qualitative content analysis. OUTCOMES & RESULTS: Analysis revealed seven categories of goals that the family members had for themselves: to be included in rehabilitation, to be provided with hope and positivity, to be able to communicate and maintain their relationship with the person with aphasia, to be given information, to be given support, to look after their own well-being, and to be able to cope with new responsibilities. A few participants reported that, at certain times during the rehabilitation process, they did not have any goals for themselves. CONCLUSIONS & IMPLICATIONS: This study highlights that family members of individuals with aphasia have a number of aphasia-related rehabilitation goals for themselves. In order to provide a family-centred approach to rehabilitation, health professionals, including speech-language pathologists, need systematically to identify and address family members' goals in light of the categories revealed in this investigation. PMID- 22938063 TI - Towards a definition: what does 'health promotion' mean to speech and language therapists? AB - BACKGROUND: As UK healthcare moves towards the ideals of prevention and enablement, health promotion is more commonly cited as an area of practice. In comparison with its allied health profession peers, physiotherapy and occupational therapy, the speech and language therapy profession has little evidence to demonstrate that it has explored what its members understand health promotion to mean or how they describe their current and future practice in relation to it. AIMS: To explore how speech and language therapists define health promotion and how they describe their current and future practice in relation to it. METHODS & PROCEDURES: Individual, semi-structured interviews were conducted with 15 community-based speech and language therapists. Interviews were transcribed verbatim and analysed using inductive coding. OUTCOMES & RESULTS: Participants viewed health promotion as a complex entity representing the processes of education and enablement in relation to responsibility for speech, language and communication skills. Participants viewed health promotion as a means of maximizing the scarce resource they represented. The vast majority of activities described as being illustrative of health promotion in a speech and language therapy context were examples of educational interventions, e.g. training, information provision. Participants believed that the speech and language therapist's role will continue to develop in relation to health promotion and that this will have implications for future workforce preparation. CONCLUSIONS & IMPLICATIONS: Participants viewed health promotion as both an educational, enabling process and as a strategy that maximizes the potential of speech and language therapy resources. Further research is indicated to develop professional consensus regarding the meaning of health promotion and to support a cohesive approach to workforce development in this area. PMID- 22938065 TI - Narrative abilities, memory and attention in children with a specific language impairment. AB - BACKGROUND: While narrative tasks have proven to be valid measures for detecting language disorders, measuring communicative skills and predicting future academic performance, research into the comparability of different narrative tasks has shown that outcomes are dependent on the type of task used. Although many of the studies detecting task differences touch upon the fact that tasks place differential demands on cognitive abilities like auditory attention and memory, few studies have related specific narrative tasks to these cognitive abilities. Examining this relation is especially warranted for children with specific language impairment (SLI), who are characterized by language problems, but often have problems in other cognitive domains as well. METHODS & PROCEDURES: In the current research, a comparison was made between a story retelling task (The Bus Story) and a story generation task (The Frog Story) in a group of children with SLI (n= 34) and a typically developing group (n= 38) from the same age range. In addition to the two narrative tasks, sustained auditory attention (TEA-Ch) and verbal working memory (WISC digit span and the Dutch version of the CVLT-C word list recall) were measured. Correlations were computed between the narrative, the memory and the attention scores. OUTCOMES & RESULTS: A group comparison showed that the children with SLI scored significantly worse than the typically developing children on several narrative measures as well as on sustained auditory attention and verbal working memory. A within-subjects comparison of the scores on the two narrative tasks showed a contrast between the tasks on several narrative measures. Furthermore, correlational analyses showed that, on the level of plot structure, the story generation task correlated with sustained auditory attention, while the story retelling task correlated with word list recall. Mean length of utterance (MLU) on the other hand correlated with digit span but not with sustained auditory attention. CONCLUSIONS: While children with SLI have problems with narratives in general, their performance is also dependent on the specific elicitation task used for research or diagnostics. Various narrative tasks generate different scores and are differentially correlated to cognitive skills like attention and memory, making the selection of a given task crucial in the clinical setting. PMID- 22938064 TI - Measuring word complexity in speech screening: single-word sampling to identify phonological delay/disorder in preschool children. AB - BACKGROUND: Children's speech sound development is assessed by comparing speech production with the typical development of speech sounds based on a child's age and developmental profile. One widely used method of sampling is to elicit a single-word sample along with connected speech. Words produced spontaneously rather than imitated may give a more accurate indication of a child's speech development. A published word complexity measure can be used to score later developing speech sounds and more complex word patterns. There is a need for a screening word list that is quick to administer and reliably differentiates children with typically developing speech from children with patterns of delayed/disordered speech. AIMS: To identify a short word list based on word complexity that could be spontaneously named by most typically developing children aged 3;00-5;05 years. METHODS & PROCEDURES: One hundred and five children aged between 3;00 and 5;05 years from three local authority nursery schools took part in the study. Items from a published speech assessment were modified and extended to include a range of phonemic targets in different word positions in 78 monosyllabic and polysyllabic words. The 78 words were ranked both by phonemic/phonetic complexity as measured by word complexity and by ease of spontaneous production. OUTCOME & RESULTS: The ten most complex words (hereafter Triage 10) were named spontaneously by more than 90% of the children. There was no significant difference between the complexity measures for five identified age groups when the data were examined in 6-month groups. A qualitative analysis revealed eight children with profiles of phonological delay or disorder. When these children were considered separately, there was a statistically significant difference (p < 0.005) between the mean word complexity measure of the group compared with the mean for the remaining children in all other age groups. The Triage 10 words reliably differentiated children with typically developing speech from those with delayed or disordered speech patterns. CONCLUSIONS & IMPLICATIONS: The Triage 10 words can be used as a screening tool for triage and general assessment and have the potential to monitor progress during intervention. Further testing is being undertaken to establish reliability with children referred to speech and language therapy services. PMID- 22938066 TI - Comparison between perceptual assessments of nasality and nasalance scores. AB - BACKGROUND: There are different reports of the usefulness of the NasometerTM as a complement to listening, often as correlation calculations between listening and nasalance measurements. Differences between findings have been attributed to listener experience and types of speech stimuli. AIMS: To compare nasalance scores from the Nasometer with perceptual assessments, for the same and different Swedish speech stimuli, using three groups of listeners with differing levels of experience in judging speech nasality. METHODS & PROCEDURES: To compare nasalance scores and blinded listener ratings of randomized recordings using three groups of listeners and two groups of speakers. Speakers were either classified as having hypernasal speech or speech with typical speech resonance. Listeners were speech-language pathologists (SLPs) working predominantly with resonance disorders, other SLPs and untrained listeners. OUTCOMES & RESULTS: Correlations (r(s)) between hypernasality ratings and nasalance scores for each listener group and speech stimuli were calculated. For both groups of SLPs all correlations between perceptual ratings and nasalance scores were significant at p= 0.01. The correlations between the nasalance scores and ratings by listeners in the SLP groups were higher than those for the untrained listener group regardless of stimulus type. Post-hoc Mann-Whitney U-tests showed that the only difference that was significant was expert SLP group versus untrained listener group. Secondly, correlations between perceptual ratings and oral stimulus nasalance scores were higher when the perceptual ratings were based on spontaneous speech rather than on the oral stimulus. However, a Wilcoxon signed rank test showed that the difference was not significant. A third finding was that correlations between oral stimulus nasalance scores and perceptual scores were higher than those between mixed stimulus nasalance scores and perceptual scores. A Wilcoxon signed rank test showed that the difference was significant. CONCLUSIONS & IMPLICATIONS: The Nasometer might be useful for the SLP with limited experience in assessing resonance disorders in differentiating between hyper- and hyponasality. With listener reliability for ratings of hypernasality still being an issue, the use of a nasalance score as a complement to the perceptual evaluation will also aid the expert SLP. It will give an alternative way of quantifying speech resonance and might help in especially hard to judge cases. PMID- 22938067 TI - Enablers and challenges of post-16 education and employment outcomes: the perspectives of young adults with a history of SLI. AB - BACKGROUND: Research studies have begun to investigate the post-16 outcomes for young adults with a specific language impairment (SLI). As yet only tentative conclusions can be drawn with respect to academic and employment outcomes and the factors that are associated with more positive outcomes. Evidence for these findings has relied predominantly on associations between various language, academic and psychosocial assessments. Little attention has been paid to the perspective of the young person. AIMS: To investigate from the perspective of a group of young people with a history of SLI the factors they believed have enabled and presented a challenge to their post-16 education and employment outcomes and experiences. METHODS & PROCEDURES: Nineteen (four female, 15 male) young people aged from 19 to 23 years (average age 21 years), who had all attended the same residential special school for pupils with SLI, were interviewed face to face to explore their views as to what had enabled and limited their transition experiences to date. The data were analysed using thematic analysis. OUTCOMES & RESULTS: The majority of the young people saw themselves as key agents of change and very active participants in steering their own transition since leaving school. They acknowledged the important role played by their parents and families and how factors such as SLI had affected their transition experiences. CONCLUSIONS & IMPLICATIONS: The study supports evidence from research with different groups of young people with special educational needs (SEN) and disabilities of the importance of school and post-16 curriculums which develop agency on behalf of the young person. PMID- 22938069 TI - Assessing lexicon: validation and developmental data of the Picture Naming Game (PiNG), a new picture naming task for toddlers. AB - BACKGROUND: Understanding lexical abilities in infants and toddlers is important, yet no single tool can be used. AIMS: To perform a validation of a new tool (known as the Picture Naming Game, or 'PiNG') for assessing lexical comprehension and production in toddlers and to obtain developmental trends for Italian children. METHODS & PROCEDURES: PiNG consists of four subtests: Noun Comprehension (NC), Noun Production (NP), Predicate Comprehension (PC) and Predicate Production (PP), each containing 20 lexical targets. It was administered to 388 children with typical development aged 19-37 months. The short form of the Italian version of the MacArthur-Bates Communicative Development Inventories (MB-CDI), previously completed by parents of participants, was used for the validation of PiNG. OUTCOMES & RESULTS: For the validation study, reliability, internal consistency and concurrent validity were analysed. The reliability was optimal for NC, NP and PP, and satisfactory for PC. Split-half analysis showed a fair internal consistency for all of the subtests. Concurrent validity was verified through the correlation with MB-CDI using Pearson's correlation coefficient, which was significant even after having controlled for age. To describe the developmental trends, data are provided for 1 month age intervals. The comprehension subtests showed a rapid increase at younger ages, with children reaching a plateau slightly earlier for the NC (at 30 months versus 33 months for the PC). The increase in the production subtests was gradual; PP appeared to be the most difficult subtest, administrable starting at the age of 24 months. When we analysed, as potential confounders for developmental trends, gender, parents' educational level, and the way in which the subtests were administered, no differences were found, except for a better performance for girls in the NP subtest. CONCLUSIONS & IMPLICATIONS: Overall, the results suggest that PiNG is suitable for children in the age range considered to evaluate language abilities. It can be used together with other tools with clinical and theoretical objectives also to describe lexical abilities in atypical populations, such as children with cognitive and/or language impairment, as well as with late-talking children. Finally, the four subtests can be administered separately or combined, which provides flexibility in clinical use, in that the individual child's linguistic and/or cognitive characteristics and level can be taken into consideration. PMID- 22938068 TI - Lingual kinematics during rapid syllable repetition in Parkinson's disease. AB - BACKGROUND: Rapid syllable repetition tasks are commonly used in the assessment of motor speech disorders. However, little is known about the articulatory kinematics during rapid syllable repetition in individuals with Parkinson's disease (PD). AIMS: To investigate and compare lingual kinematics during rapid syllable repetition in dysarthric speakers with PD (DPD), non-dysarthric speakers with PD (NDPD) and a group of healthy controls. METHODS & PROCEDURES: Electromagnetic articulography was used to record tongue-tip and tongue-back movement in five DPD and five NDPD participants during rapid repetition of /ta/and /ka/syllables, and matched with six healthy controls. OUTCOMES & RESULTS: Results revealed significant between-group differences for most of the kinematic parameters measured but comparable rapid syllable repetition rates. Post-hoc analyses indicated that the DPD participants, when compared with the NDPD participants, had similar range but prolonged duration of lingual movement. The DPD and NDPD participants had primarily increased range and prolonged duration of lingual movement accompanied by increased speed parameters, when compared with healthy controls. CONCLUSIONS & IMPLICATIONS: The findings of the present study contradict theories that suggest that the clinical features of hypokinetic dysarthria, including articulatory imprecision, are the outcome of restrictions in the range of movement of the muscles of the articulators. The observed prolonged duration of lingual movement in PD may plausibly be due to the observed increased range of lingual movement rather than slowness of lingual movement. PMID- 22938070 TI - Autonomic and emotional responses of graduate student clinicians in speech language pathology to stuttered speech. AB - BACKGROUND: Fluent speakers and people who stutter manifest alterations in autonomic and emotional responses as they view stuttered relative to fluent speech samples. These reactions are indicative of an aroused autonomic state and are hypothesized to be triggered by the abrupt breakdown in fluency exemplified in stuttered speech. Furthermore, these reactions are assumed to be the basis for the stereotypes held by different communicative partners towards people who stutter. AIMS: To examine the autonomic and emotional reactions of graduate student clinicians in speech-language pathology as they viewed fluent and severe stuttered speech samples. METHODS & PROCEDURES: Twenty-one female graduate student clinicians in speech-language pathology participated in this study. Each participant viewed four 30-s video samples (two fluent and two stuttered speech samples) while their autonomic responses (skin conductance response (SCR) and heart rate (HR)) were concurrently captured. Furthermore, emotional responses to stuttered and fluent speech samples were captured using the self-assessment manikin (SAM) and a rating scale with nine bipolar adjectives reflecting one's feelings. OUTCOMES & RESULTS: An increase in SCR and deceleration in HR was observed as graduate clinicians viewed stuttered speech samples versus fluent speech samples and the differences were statistically significant. In addition, results from the self-rating scales showed that participants had negative feelings (e.g., emotionally aroused, unpleasant, embarrassed, uncomfortable, etc.) while viewing stuttered speech. CONCLUSIONS & IMPLICATIONS: Findings suggest that graduate student clinicians in speech-language pathology demonstrated altered autonomic and emotional responses similar to those manifested by fluent and stuttered speakers as they viewed stuttered speech samples. Collectively, these findings support the contention that the inherent nature of stuttered speech triggers a visceral reaction in a listener, irrespective of their background and knowledge about the disorder. PMID- 22938071 TI - Social-communicative effects of the Picture Exchange Communication System (PECS) in autism spectrum disorders. AB - BACKGROUND: The Picture Exchange Communication System (PECS) is a common treatment choice for non-verbal children with autism. However, little empirical evidence is available on the usefulness of PECS in treating social-communication impairments in autism. AIMS: To test the effects of PECS on social-communicative skills in children with autism, concurrently taking into account standardized psychometric data, standardized functional assessment of adaptive behaviour, and information on social-communicative variables coded in an unstructured setting. METHODS & PROCEDURES: Eighteen preschool children (mean age = 38.78 months) were assigned to two intervention approaches, i.e. PECS and Conventional Language Therapy (CLT). Both PECS (Phases I-IV) and CLT were delivered three times per week, in 30-min sessions, for 6 months. Outcome measures were the following: Autism Diagnostic Observation Schedule (ADOS) domain scores for Communication and Reciprocal Social Interaction; Language and Personal-Social subscales of the Griffiths' Mental Developmental Scales (GMDS); Communication and Social Abilities domains of the Vineland Adaptive Behavior Scales (VABS); and several social communicative variables coded in an unstructured setting. OUTCOMES & RESULTS: Results demonstrated that the two groups did not differ at Time 1 (pre-treatment assessment), whereas at Time 2 (post-test) the PECS group showed a significant improvement with respect to the CLT group on the VABS social domain score and on almost all the social-communicative abilities coded in the unstructured setting (i.e. joint attention, request, initiation, cooperative play, but not eye contact). CONCLUSIONS & IMPLICATIONS: These findings showed that PECS intervention (Phases I-IV) can improve social-communicative skills in children with autism. This improvement is especially evident in standardized measures of adaptive behaviour and measures derived from the observation of children in an unstructured setting. PMID- 22938072 TI - Diagnosis of active tuberculosis using MPB64, a specific antigen of Mycobacterium bovis. AB - Because the incidence of tuberculosis (TB) is still high in developing countries, an inexpensive and rapid diagnostic test for this infection is needed. To develop a screening test for TB, MPB64 antigen was produced by recombinant technology and purified with a polyhistidine tag. Next, serum and urine samples from patients with TB and uninfected individuals were examined by the dot-blot assay method using this purified antigen. Serum samples from patients with TB reacted more strongly with MPB64 antigen than did those from uninfected individuals. In addition, serum samples from TB patients with active infection reacted more strongly with the antigen than did samples from patients with inactive TB. When urine samples were assessed using this assay, similar results were obtained. Correlations between the data obtained from serum and urine samples were analyzed for all subjects, including uninfected individuals, and a strong positive correlation between the results of serum and urine tests (n = 36, r = 0.672) was found. The sensitivity and specificity of this assay for serum samples was 85.7 % and 85.0 %, and for urine samples 75.0 % and 85.0 %, respectively. These results suggest that dot-blot assay with MPB64 antigen could be a useful screening test for active TB. Because urine samples can be obtained more easily than serum samples and because urine is less contagious, urine testing should probably be employed for screening purposes. PMID- 22938073 TI - The inner ear of Diacodexis, the oldest artiodactyl mammal. AB - We provide the first detailed description of the inner ear of the oldest artiodactyl, Diacodexis, based on a three-dimensional reconstruction extracted from computed tomography imagery of a skull of Diacodexis ilicis of earliest Wasatchian age (ca. 55 Ma). This description provides new anatomical data for the earliest artiodactyls, and reveals that the bony labyrinth of Diacodexis differs greatly from that of modern artiodactyls described so far. The bony labyrinth of Diacodexis presents a weakly coiled cochlea (720 degrees ), a secondary common crus, a dorsal extension of the anterior semicircular canal more pronounced than that of the posterior one, and a small angle between the basal turn of the bony cochlear canal and the lateral semicircular canal. This suite of characters also occurs in basal eutherian mammals. Diacodexis strongly resembles small living tragulid ruminants in its overall body shape and hindlimb proportions. Comparison of the bony labyrinth of Diacodexis to that of the tragulid Moschiola meminna (Indian mouse deer) reveals great morphological difference in cochlear shape and semicircular canal disposition. The shape of the cochlea suggests that Diacodexis was a high-frequency hearing specialist, with a high low-frequency hearing limit (543 Hz at 60 dB). By comparison, the estimated low-frequency limit of Moschiola meminna is much lower (186.0 Hz at 60 dB). We also assess the locomotor agility of Diacodexis based on measurements of the semicircular canals. Locomotor agility estimates for Diacodexis range between 3.62 and 3.93, and suggest a degree of agility compatible with a nimble, fast running to jumping animal. These results are congruent with the postcranial functional analysis for this extinct taxon. PMID- 22938074 TI - Epileptic seizures in patients following allogeneic hematopoietic stem cell transplantation: a retrospective analysis of incidence, risk factors, and survival rates. AB - The incidence of epileptic seizures among allogeneic hematopoietic stem cell transplant (allo-HSCT) patients has been poorly described. No report has systematically studied epilepsy's possible causes, risk factors, and effect on prognosis among allo-HSCT patients. We retrospectively examined data from 1461 patients who underwent allo-HSCT within the past 6.5 yr at the Institute of Hematology and People's Hospital, Peking University. The cumulative incidence of all epileptic seizure complications was 7.1%. Of the 79 transplant patients who had epileptic seizures, 3 (3.8%) experienced a seizure during the conditioning stage, 52 (65.8%) between day 0 and day 100, 20 (25.3%) from day 100 to the first year, and 4 (5.1%) after the first year. Multivariate regression analysis identified the age of the recipient as (<= 18 yr) (p < 0.001), donor type (p = 0.004), graft versus host disease (aGVHD) (p = 0.018), and hyponatremia (p = 0.003) as independent risk factors for epileptic seizures among allo-HSCT patients. The median survival time of patients with epileptic seizures was 246 d after transplantation (ranging between 18 and 2170 d). Survival after one yr and 6.5 yr was significantly reduced in patients who developed epileptic seizure complications compared with those who did not (57.2% vs. 75.7% at one yr, p = 0.015, and 31.1% vs. 71.4% at five yr, p < 0.001). Of the 79 patients who experienced epileptic seizure complications, 53.2% died (n = 42). The survival rate of these patients was relatively low, and cerebrovascular disorders or central nervous system infection-related epileptic seizures usually resulted in a high mortality and poor prognosis. A patient transplantation age which is younger than 18 yr, related mismatched transplants, aGVHD, and hyponatremia are risk factors for epileptic seizures in allo-HSCT recipients. Epileptic seizures among allo-HSCT patients are associated with a poor prognosis. PMID- 22938076 TI - High-flow bypass and tandem microsurgical-endovascular occlusion of recurrent proximal middle cerebral artery aneurysms in a pediatric patient. AB - The authors report the case of a 7-year-old boy with headaches, in whom CT angiography showed multiple intracranial aneurysms from the terminus region of the right internal carotid artery through the proximal right middle cerebral artery (MCA). Initially, the patient underwent clip reconstruction of the M(1) segment. Multiple microsurgical and endovascular treatments were required because the largest of these aneurysms recurred several times over the next 1.5 years. The first recurrence was treated with stent coiling and the second by microsurgical occlusion of the MCA combined with the use of a radial artery graft in a common carotid artery-to-MCA bypass. The aneurysm again recurred and was treated by proximal coil occlusion 15 months after the first treatment session. At a 7.5-year follow-up examination, the aneurysms remained occluded. This case highlights the benefit of combined endovascular and microsurgical techniques in the treatment of a complex and unusual case of proximal MCA aneurysmal disease. The patient, now 15 years old, is neurologically intact and able to participate in all activities. PMID- 22938075 TI - Diabetes exacerbates amyloid and neurovascular pathology in aging-accelerated mice. AB - Mounting evidence supports a link between diabetes, cognitive dysfunction, and aging. However, the physiological mechanisms by which diabetes impacts brain function and cognition are not fully understood. To determine how diabetes contributes to cognitive dysfunction and age-associated pathology, we used streptozotocin to induce type 1 diabetes (T1D) in senescence-accelerated prone 8 (SAMP8) and senescence-resistant 1 (SAMR1) mice. Contextual fear conditioning demonstrated that T1D resulted in the development of cognitive deficits in SAMR1 mice similar to those seen in age-matched, nondiabetic SAMP8 mice. No further cognitive deficits were observed when the SAMP8 mice were made diabetic. T1D dramatically increased Abeta and glial fibrillary acidic protein immunoreactivity in the hippocampus of SAMP8 mice and to a lesser extent in age-matched SAMR1 mice. Further analysis revealed aggregated Abeta within astrocyte processes surrounding vessels. Western blot analyses from T1D SAMP8 mice showed elevated amyloid precursor protein processing and protein glycation along with increased inflammation. T1D elevated tau phosphorylation in the SAMR1 mice but did not further increase it in the SAMP8 mice where it was already significantly higher. These data suggest that aberrant glucose metabolism potentiates the aging phenotype in old mice and contributes to early stage central nervous system pathology in younger animals. PMID- 22938077 TI - Reduced ventricular shunt rate in very preterm infants with severe intraventricular hemorrhage: an institutional experience. AB - OBJECT: Although survival for extremely low gestational age newborns (ELGANs) has improved in the past 3 decades, these infants remain prone to complications of prematurity, including intraventricular hemorrhage (IVH). The authors reviewed the outcomes for an entire cohort of ELGANs who suffered severe IVH at their institution during the past 12 years to gain a better understanding of the natural history of IVH and frequency of ventriculoperitoneal (VP) shunt placement in this population. METHODS: Data from the neonatal ICU (NICU) database, neurosurgery operative log, and medical records were used to identify and follow up all ELGANs who suffered a severe IVH between 1997 and 2008. Trends between Period 1 (1997-2001) and Period 2 (2004-2008) were analyzed using the Pearson chi square test. RESULTS: Between 1997 and 2008, 1335 ELGANs were admitted to the NICU at the authors' institution within 3 days of birth, and 111 (8.3%) of these infants suffered a severe IVH. Survival to 2 years, incidence of severe IVH, neonatal risk factors (gestational age, birth weight, and incidence of necrotizing enterocolitis), ventriculomegaly on cranial ultrasonography, and use of serial lumbar punctures for symptomatic hydrocephalus were all stable. Infants from period 2 had a significantly lower incidence of bronchopulmonary dysplasia and sepsis than infants from Period 1 (both p < 0.001). All ELGANs with severe IVH and ventriculomegaly underwent long-term follow-up to identify shunt status at late follow-up. Twenty-two ELGANs (20%) with severe IVH required a temporary ventriculosubgaleal (VSG) shunt. Three infants with VSG shunts showed spontaneous hydrocephalus resolution, and 2 infants died of unrelated causes during the neonatal admission. The temporary VSG shunt complication rate was 20% (12% infection and 8% malfunction). Sixteen percent of all ELGANs (18 of 111) with severe IVH eventually required permanent ventricular shunt insertion. Six (35%) of 17 infants with a permanent VP shunt required at least 1 permanent shunt revision during the 1st year. The proportion of ELGANs with severe IVH who required a temporary VSG (35%) or permanent VP shunt (30%) during Period 1 decreased by more than 60% in Period 2 (10% [p = 0.005] and 8.3% [p = 0.009], respectively). CONCLUSIONS: The authors report for the first time a marked reduction over the past 12 years in the proportion of ELGANs with severe IVH who required surgical intervention for hydrocephalus. Using the NICU database, the authors were able to identify and follow all ELGANs with severe IVH and ventriculomegaly. They speculate that the reduction in ventricular shunt rate results from improved neonatal medical care, including reduced infection, improved bronchopulmonary dysplasia, and postnatal steroid avoidance, which may aid innate repair mechanisms. Multicenter prospective trials and detailed analyses of NICU parameters of neonatal well-being are needed to understand how perinatal factors influence the propensity to require ventricular shunting. PMID- 22938078 TI - Infiltrative brainstem and cerebellar neurocytoma. AB - Neurocytomas are typically intraventricular in location, and extraventricular neurocytomas are uncommon. The authors report the unique case of a 15-year-old girl who was found to have a low-grade neurocytoma infiltrating the brainstem and cerebellum and spreading along the CSF pathways to the lateral and third ventricles. The patient underwent endoscopic third ventriculostomy to treat associated hydrocephalus, and biopsy specimens from intraventricular tumor nodules were obtained. Because of the low-grade pathology, the fact that the lesion was not amenable to resection, and the extensive radiation field required for radiation therapy, she has been treated conservatively with close follow-up. Over the course of almost 4 years since diagnosis, no additional treatment has been required. Neurocytoma with widespread infiltration of the brainstem and cerebellum has not been previously reported. PMID- 22938079 TI - Neurosurgical complications of left ventricular assist devices in children. AB - OBJECT: Left ventricular assist devices (LVADs) are continuous or pulsatile flow devices that could potentially be life-saving measures for patients with end stage heart failure. These devices have clear advantages over extracorporeal membrane oxygenation (ECMO) and are often used in adults. They are only recently being commonly used in the pediatric age group. As the use of LVADs becomes more mainstream in children, it is important to determine the complication profile associated with these devices. Furthermore, with the increasing application of LVADs in children, pediatric neurosurgeons are seeing a correlative increase in associated neurological complications. In this study, the authors reviewed the incidence of neurological complications due to LVAD use in the pediatric age group and the role of neurosurgery in treatment. METHODS: The authors examined data regarding patients with LVADs from the Texas Children's Hospital Heart Center database (July 01, 2007, to June 30, 2011) and recorded neurological complications requiring neurosurgical consultation. They identified 2 children who underwent craniotomies during LVAD treatment. RESULTS: Intracranial hemorrhage occurred in 3 (6.5%) of the 46 patients treated with an LVAD at the authors' institution. Of these patients, 2 were treated with craniotomies for life-threatening intracranial hemorrhages. The 3 patients in the neurosurgical cohort presented with cerebral infarction, decreased level of consciousness, and/or seizure. At the last follow-up (286, 503, and 550 days), 1 patient (case 2) had no decline in neurological status, underwent a successful heart transplant, and was discharged home; 1 patient (case 1) died of refractory cardiac failure; and 1 patient (case 3) was on an LVAD for destination therapy (that is, the LVAD is not a bridge to transplantation but rather the final treatment). This patient was discharged from the hospital, but he died of overwhelming fungemia at 286 days while on VAD support. CONCLUSIONS: Intracranial hemorrhage is a serious and feared complication of LVAD treatment. While the surgical risk is substantial due to systemic anticoagulation and significant medical comorbidities, neurosurgical evacuation of hemorrhage plays an important life-saving role that can yield successful and acceptable outcomes. PMID- 22938080 TI - Gamma knife surgery for pediatric arteriovenous malformations: a 25-year retrospective study. AB - OBJECT: The authors present their 25-year experience in treating pediatric arteriovenous malformations (AVMs) to allow comparisons with other historic studies and data in adults. METHODS: Data were collected from a prospectively maintained departmental database selected for age and supplemented by case note review and telephone interviews as appropriate. RESULTS: Three hundred sixty three patients, ages 1-16 years (mean +/- SD, 12 +/- 3.2 years), underwent 410 treatments; 4 had planned 2-stage treatments and 43 were retreated subsequent to an initial partial response. Fifty-eight percent received general anesthesia for the procedure. Sixteen percent had previously undergone embolization. The most common presenting symptoms were as follows: hemorrhage (80.2%), epilepsy (8.3%; overall seizure prevalence 19.9%), and migrainous headaches (6.3%). Only 0.28% of the AVMs were incidental findings. The mean lesion volume was 3.75 +/- 5.3 cm3 (range 0.01-32.8 cm3), with a median Spetzler-Martin grade of III (range I-V). The mean peripheral (therapeutic) dose was 22.7 +/- 2.3 Gy (range 15-25 Gy), corresponding to a mean maximum dose of 43.6 +/- 6 Gy (range 25-51.4 Gy). The obliteration rate was 71.3% in patients who received one treatment and 62.5% for retreated patients, with a mean obliteration time of 32.4 and 79.6 months, respectively. The overall obliteration rate was 82.7%. No follow-up data are as yet available for the 4 patients who underwent the staged treatments. Only 4 patients received peripheral doses below 20 Gy, and the AVM was obliterated in 3 of these patients. The other patients received 20, 22.5, or 25 Gy and had obliteration rates of 82.6%, 77.7%, and 86.3%, respectively. The bleeding rate postradiosurgery was 2.2%, and the cumulative complication rate was 3.6%, with radionecrosis being the most common complication (1.1%). CONCLUSIONS: Surprisingly, there was no correlation (p = 0.43) between outcome and radiosurgical dose when that dose was between 20 and 25 Gy, thus suggesting that the lower of these 2 doses may be effective. Radiosurgery for pediatric AVM is safe and effective. PMID- 22938082 TI - Clinical features and treatment of World Health Organization grade II and III meningiomas in childhood: report of 23 cases. AB - OBJECT: High-grade meningiomas in childhood are rare, and their clinical features are unknown. The objective of this study was to determine the clinical characteristics and prognosis of childhood high-grade meningiomas. METHODS: Twenty-three patients with childhood high-grade meningiomas were treated at the Huashan Hospital. Clinical data were collected, tumor samples were reexamined, and prognoses were attained through follow-up visits and telephone interviews. Survival probability was calculated using the Kaplan-Meier method. A 2-sided probability level of 0.05 was chosen for statistical significance. RESULTS: The series included 18 males and 5 females (mean age 12.1 years). The most common symptoms were headache and vomiting (43%). Three patients had accompanying neurofibromatosis type II (NF2). The high-grade meningioma cases with NF2 had larger tumor diameters than those without NF2 (p = 0.010). The skull base was the most common tumor site (39%). Complete resections were achieved in 11 patients after their initial operations. Adjuvant radiation therapy was performed in 9 cases. Follow-up evaluations were performed for 20 patients (mean follow-up 70 months). Ten patients experienced recurrences, 2 patients had lung metastases, and 7 patients died of the recurrence. The extent of surgery was significantly related to progression-free survival (PFS; p = 0.038). A negative progesterone receptor combined with strongly positive Bcl-2 immunoreactivity was significantly related to PFS (p = 0.001) and overall survival (p = 0.002). The MIB-1 labeling index was significantly related to overall survival (p = 0.018), whereas postoperative radiation therapy was not significantly related to PFS (p = 0.087) and overall survival (p = 0.40). CONCLUSIONS: Childhood high-grade meningioma is a rare tumor type. Childhood high-grade meningioma has a male predominance and the basilar region is the most common tumor location. Patients with these tumors have high recurrence and mortality rates. The extent of resection is an important prognosis factor. A negative progesterone receptor combined with a strongly positive Bcl-2 immunoreaction might predict cancer recurrence. The MIB-1 labeling index correlates with the prognosis, and an MIB-1 labeling index > 3% increases the risk of recurrence in childhood high-grade meningioma. More cases should be collected, and longer follow-up periods should be obtained, to evaluate the effects of postoperative radiation therapy in childhood high-grade meningioma. PMID- 22938081 TI - Treatment of choroid plexus tumors: a 20-year single institutional experience. AB - OBJECT: Choroid plexus tumors (CPTs) are rare intracranial neoplasms that constitute approximately 2%-5% of all pediatric brain tumors. Most of these tumors present with severe hydrocephalus. The optimal perioperative management and oncological care remain a matter of debate. The authors present the epidemiological and clinical features of CPTs from a 20-year single-institutional experience. METHODS: A total of 39 consecutive patients with pathologically proven CPTs (31 choroid plexus papillomas [CPPs] and 8 choroid plexus carcinomas [CPCs]) were included in this series. Patient demographics, clinical presentation, comorbidities, indications for surgery, radiological studies, tumor location, and all operative variables were reviewed for each case. Multivariate regression analysis was performed to identify independent predictors of tumor recurrence and survival. RESULTS: The overall mean age (+/- SD) was 13.13 +/- 19.59 years (15.27 +/- 21.10 years in the CPP group and 3.66 +/- 3.59 years in the CPC group). Hydrocephalus was noted at presentation in 34% of patients. The most common presenting symptoms were headache (32%) and nausea/vomiting (26%). Gross-total resection (GTR) was achieved in 86% of CPPs and in 71% of CPCs (p = 0.57). There was 100% survival in patients with CPPs observed at the 5- and 10 year follow-up and 71% survival in patients with CPCs at the 5-year follow-up. In a multivariate regression analysis, a diagnosis of papilloma, preoperative vision changes, or hydrocephalus; right ventricle tumor location; and GTR were all independently associated with a decreased likelihood of tumor recurrence at last follow-up. CONCLUSIONS: The authors' study suggests that patients with CPCs are more likely to experience local recurrence and metastasis; hence, GTR with chemotherapy and radiotherapy, particularly for CPCs, is pivotal in preventing recurrence and prolonging survival. While GTR was important for local control following resection of CPPs, it had a minimal effect on prolonging survival in this patient cohort. PMID- 22938083 TI - Effectiveness of a novel and scalable clinical decision support intervention to improve venous thromboembolism prophylaxis: a quasi-experimental study. AB - BACKGROUND: Venous thromboembolism (VTE) causes morbidity and mortality in hospitalized patients, and regulators and payors are encouraging the use of systems to prevent them. Here, we examine the effect of a computerized clinical decision support (CDS) intervention implemented across a multi-hospital academic health system on VTE prophylaxis and events. METHODS: The study included 223,062 inpatients admitted between April 2007 and May 2010, and used administrative and clinical data. The intervention was integrated into a commercial electronic health record (EHR) in an admission orderset used for all admissions. Three time periods were examined: baseline (period 1), and the time after implementation of the first CDS intervention (period 2) and a second iteration (period 3). Providers were prompted to accept or decline prophylaxis based on patient risk. Time series analyses examined the impact of the intervention on VTE prophylaxis during time periods two and three compared to baseline, and a simple pre-post design examined impact on VTE events and bleeds secondary to anticoagulation. VTE prophylaxis and events were also examined in a prespecified surgical subset of our population meeting the public reporting criteria defined by the Agency for Healthcare Research and Quality (AHRQ) Patient Safety Indicator (PSI). RESULTS: Unadjusted analyses suggested that "recommended", "any", and "pharmacologic" prophylaxis increased from baseline to the last study period (27.1% to 51.9%, 56.7% to 78.1%, and 42.0% to 54.4% respectively; p < 0.01 for all comparisons). Results were significant across all hospitals and the health system overall. Interrupted time series analyses suggested that our intervention increased the use of "recommended" and "any" prophylaxis by 7.9% and 9.6% respectively from baseline to time period 2 (p < 0.01 for both comparisons); and 6.6% and 9.6% respectively from baseline to the combined time periods 2 and 3 (p < 0.01 for both comparisons). There were no significant changes in "pharmacologic" prophylaxis in the adjusted model. The overall percent of patients with VTE increased from baseline to the last study period (2.0% to 2.2%; p = 0.03), but an analysis excluding patients with VTE "present on admission" (POA) demonstrated no difference in events (1.3% to 1.3%; p = 0.80). Overall bleeds did not significantly change. An analysis examining VTE prophylaxis and events in a surgical subset of patients defined by the AHRQ PSI demonstrated increased "recommended", "any", and "pharmacologic" prophylaxis from baseline to the last study period (32.3% to 60.0%, 62.8% to 85.7%, and 47.9% to 63.3% respectively; p < 0.01 for all comparisons) as well as reduced VTE events (2.2% to 1.7%; p < 0.01). CONCLUSIONS: The CDS intervention was associated with an increase in "recommended" and "any" VTE prophylaxis across the multi-hospital academic health system. The intervention was also associated with increased VTE rates in the overall study population, but a subanalysis using only admissions with appropriate POA documentation suggested no change in VTE rates, and a prespecified analysis of a surgical subset of our sample as defined by the AHRQ PSI for public reporting purposes suggested reduced VTE. This intervention was created in a commonly used commercial EHR and is scalable across institutions with similar systems. PMID- 22938084 TI - The effect of load on torques in point-to-point arm movements: a 3D model. AB - A dynamic, 3-dimensional model was developed to simulate slightly restricted (pronation-supination was not allowed) point-to-point movements of the upper limb under different external loads, which were modeled using 3 objects of distinct masses held in the hand. The model considered structural and biomechanical properties of the arm and measured coordinates of joint positions. The model predicted muscle torques generated by muscles and needed to produce the measured rotations in the shoulder and elbow joints. The effect of different object masses on torque profiles, magnitudes, and directions were studied. Correlation analysis has shown that torque profiles in the shoulder and elbow joints are load invariant. The shape of the torque magnitude-time curve is load invariant but it is scaled with the mass of the load. Objects with larger masses are associated with a lower deflection of the elbow torque with respect to the sagittal plane. Torque direction-time curve is load invariant scaled with the mass of the load. The authors propose that the load invariance of the torque magnitude-time curve and torque direction-time curve holds for object transporting arm movements not restricted to a plane. PMID- 22938085 TI - Synchronous lung and gastric cancers successfully treated with carboplatin and pemetrexed: a case report. AB - INTRODUCTION: Lung and gastric cancers are the first and second leading causes of death from cancer worldwide, and are especially prevalent in Eastern Asia. Relatively few reports are available in relation to the treatment and outcome of synchronous lung and gastric cancers, although there are increasing numbers of patients with these cancers. Efforts to develop more effective drugs for the treatment of synchronous cancers, without serious adverse effects, have been intensifying. Pemetrexed, a multi-targeted antifolate enzyme inhibitor, was approved by the United States Food and Drug Administration as a first-line chemotherapy for advanced non-squamous non-small cell lung cancer in 2007. Although clinical activity against several tumor types of adenocarcinoma, including gastric cancer, has been demonstrated, the efficacy of pemetrexed for gastric cancer remains to be fully evaluated. CASE PRESENTATION: We report a case involving a 62-year-old Japanese woman with synchronous locally-advanced poorly differentiated lung adenocarcinoma and poorly-differentiated gastric adenocarcinoma, containing signet-ring cells distinguished by immunohistochemical profiles. She had been treated with carboplatin and pemetrexed as a first-line chemotherapy for lung cancer, and had achieved partial responses for both lung and gastric cancers. These responses led to a favorable 12-month progression-free survival after the initiation of chemotherapy, and the patient is still alive more than 33 months after diagnosis. CONCLUSIONS: This case suggests a new chemotherapeutic regimen for patients with synchronous multiple primary cancers that have an adenocarcinoma background. PMID- 22938086 TI - Editor in Chief changes for Implementation Science. AB - Implementation Science, like all journals, needs to continue to develop. There will always be changes we need to make as next steps in improving the Journal for readers and improving how it runs. However, we now have our first change in Editors in Chief. We are fortunate to have been able to recruit two experienced academics who are also experienced editors--Professor Michel Wensing and Dr Anne Sales. I hope you will join me in welcoming them and give them, and continue to give Implementation Science, your support. PMID- 22938087 TI - Highly reproducible near-field optical imaging with sub-20-nm resolution based on template-stripped gold pyramids. AB - With a template-stripping fabrication technique, we demonstrate the mass fabrication of high-quality, uniform, ultrasharp (10 nm) metallic probes suitable for single-molecule fluorescence imaging, tip-enhanced Raman spectroscopy (TERS), and other near-field imaging techniques. We achieve reproducible single-molecule imaging with sub-20-nm spatial resolution and an enhancement in the detected fluorescence signal of up to 200. Similar results are obtained for TERS imaging of carbon nanotubes. We show that the large apex angle (70.5 degrees ) of our pyramidal tip is well suited to scatter the near-field optical signal into the far-field, leading to larger emission enhancement and hence to a larger quantum yield. Each gold or silver pyramidal probe is used on-demand, one at a time, and the unused tips can be stored for extended times without degradation or contamination. The high yield (>95%), reproducibility, durability, and massively parallel fabrication (1.5 million identical probes over a wafer) of the probes hold promise for reliable optical sensing and detection and for cementing near field optical imaging and spectroscopy as a routine characterization technique. PMID- 22938088 TI - Association of smoking status, cumulative smoking, duration of smoking cessation, age of starting smoking, and depression in Korean adults. AB - BACKGROUND: Many previous studies did not sufficiently control for several confounding factors that may affect the association between smoking and depression, such as socioeconomic status. We investigated the association between depression and smoking status, smoking exposure, duration of smoking cessation, and age of starting smoking while controlling for socioeconomic factors. METHODS: This study was based on a community health survey performed in Jeollanam-do, South Korea, between September and November 2009. In total, 20,084 subjects (9,118 males and 10,966 females) were included in the analysis. Information on smoking characteristics, such as smoking status, pack-years of smoking, and age of starting smoking, was collected using a standardized questionnaire. Depression was defined using the Korean CES-D score. RESULTS: The odds ratios (ORs) of depression were 1.35 (0.92-1.98) for former smokers and 1.77 (1.27-2.48) for current-smokers among males, and 2.67 (1.38-5.16) for former smokers and 3.72 (2.11-6.54) for current-smokers among females, after adjusting for other confounding factors. Compared to light smoking, heavy smoking was significantly associated with depression in males [OR = 3.97, 95% confidence interval (CI) = 1.42-11.14], but not in females (OR = 1.24, 95% CI = 0.73-2.09). No significant associations between depression and age of starting smoking and duration of smoking cessation were observed among former smokers. CONCLUSIONS: Our data demonstrate that smoking is strongly associated with depression, particularly among females. These findings suggest that depression prevention may need to be combined with smoking prevention and that different strategies may be needed for males and females. PMID- 22938089 TI - Student perception about working in rural Nepal after graduation: a study among first- and second-year medical students. AB - BACKGROUND: The Federal Democratic Republic of Nepal is a developing country in South Asia with a population of 29.8 million. In September 2011, there were 18 medical schools with 14 being in the private sector. KIST Medical College is a private school in Lalitpur district. The present study was conducted to obtain information on student perceptions about working in rural Nepal after graduation. METHODS: The study was conducted among first- and second-year undergraduate medical students using a semi-structured questionnaire developed by the authors using inputs from the literature and their experiences of teaching medical students. Year of study, gender, method of financing of medical education, place of family residence and occupation of parents were noted. Participant responses were analysed, grouped together and the number of respondents stating a particular response was noted. RESULTS: Of the 200 students, 185 (92.5%) participated with 95 being from the first year and 90 from the second. Most students were self-financing and from urban areas. Regarding the question of working in rural Nepal after graduation, 134 (72.4%) said they will work after their undergraduate course. Students preferred to work in the government or nongovernmental sector. Student felt doctors are reluctant to serve in rural Nepal due to inadequate facilities, low salary, less security, problems with their professional development, less equipment in health centres, decreased contact with family and difficulties in communicating with an illiterate, rural population. About 43% of respondents felt medical education does not adequately prepare them for rural service. Repeated rural exposure, postings in rural hospitals and health centres, and training students to diagnose and treat illness with less technology were suggested. The median monthly salary expected was 60 000 Nepalese rupees (US$ 820) and was significantly higher among first-year students. CONCLUSIONS: The majority of respondents were in favour of working in rural Nepal after graduation. They wanted facilities in rural areas and health centres to be improved. Changes in the education system were suggested. Providing relatively better facilities for rural doctors compared with urban doctors and reorienting medical education for producing doctors for rural Nepal can be considered. Further studies are required in other private medical schools. PMID- 22938090 TI - Concentration gradient induced morphology evolution of silica nanostructure growth on photoresist-derived carbon micropatterns. AB - The evolution of silica nanostructure morphology induced by local Si vapor source concentration gradient has been investigated by a smart design of experiments. Silica nanostructure or their assemblies with different morphologies are obtained on photoresist-derived three-dimensional carbon microelectrode array. At a temperature of 1,000 degrees C, rope-, feather-, and octopus-like nanowire assemblies can be obtained along with the Si vapor source concentration gradient flow. While at 950 degrees C, stringlike assemblies, bamboo-like nanostructures with large joints, and hollow structures with smaller sizes can be obtained along with the Si vapor source concentration gradient flow. Both vapor liquid-solid and vapor-quasiliquid-solid growth mechanisms have been applied to explain the diverse morphologies involving branching, connecting, and batch growth behaviors. The present approach offers a potential method for precise design and controlled synthesis of nanostructures with different features. PMID- 22938091 TI - Epigenetic alterations in preneoplastic and neoplastic lesions of the cervix. AB - Cervical cancer (CC) is one of the most malignant tumors and the second or third most common type of cancer in women worldwide. The association between human papillomavirus (HPV) and CC is widely known and accepted (99.7% of cases). At present, the pathogenesis mechanisms of CC are not entirely clear. It has been shown that inactivation of tumor suppressor genes and activation of oncogenes play a significant role in carcinogenesis, caused by the genetic and epigenetic alterations. In the past, it was generally thought that genetic mutation was a key event of tumor pathogenesis, especially somatic mutation of tumor suppressor genes. With deeper understanding of tumors in recent years, increasing evidence has shown that epigenetic silencing of those genes, as a result of aberrant hypermethylation of CpG islands in promoters and histone modification, is essential to carcinogenesis and metastasis. The term epigenetics refers to heritable changes in gene expression caused by regulation mechanisms, other than changes in DNA sequence. Specific epigenetic processes include DNA methylation, chromotin remodeling, histone modification, and microRNA regulations. These alterations, in combination or individually, make it possible to establish the methylation profiles, histone modification maps, and expression profiles characteristic of this pathology, which become useful tools for screening, early detection, or prognostic markers in cervical cancer. This paper reviews recent epigenetics research progress in the CC study, and tries to depict the relationships between CC and DNA methylation, histone modification, as well as microRNA regulations. PMID- 22938092 TI - Redox dysregulation in the pathophysiology of schizophrenia and bipolar disorder: insights from animal models. AB - SIGNIFICANCE: Schizophrenia (SZ) and bipolar disorder (BD) are classified as two distinct diseases. However, accumulating evidence shows that both disorders share genetic, pathological, and epidemiological characteristics. Based on genetic and functional findings, redox dysregulation due to an imbalance between pro-oxidants and antioxidant defense mechanisms has been proposed as a risk factor contributing to their pathophysiology. RECENT ADVANCES: Altered antioxidant systems and signs of increased oxidative stress are observed in peripheral tissues and brains of SZ and BD patients, including abnormal prefrontal levels of glutathione (GSH), the major cellular redox regulator and antioxidant. Here we review experimental data from rodent models demonstrating that permanent as well as transient GSH deficit results in behavioral, morphological, electrophysiological, and neurochemical alterations analogous to pathologies observed in patients. Mice with GSH deficit display increased stress reactivity, altered social behavior, impaired prepulse inhibition, and exaggerated locomotor responses to psychostimulant injection. These behavioral changes are accompanied by N-methyl-D-aspartate receptor hypofunction, elevated glutamate levels, impairment of parvalbumin GABA interneurons, abnormal neuronal synchronization, altered dopamine neurotransmission, and deficient myelination. CRITICAL ISSUES: Treatment with the GSH precursor and antioxidant N-acetylcysteine normalizes some of those deficits in mice, but also improves SZ and BD symptoms when given as adjunct to antipsychotic medication. FUTURE DIRECTIONS: These data demonstrate the usefulness of GSH-deficient rodent models to identify the mechanisms by which a redox imbalance could contribute to the development of SZ and BD pathophysiologies, and to develop novel therapeutic approaches based on antioxidant and redox regulator compounds. PMID- 22938093 TI - Structures and mechanisms of antitumor agents: xestoquinones uncouple cellular respiration and disrupt HIF signaling in human breast tumor cells. AB - The organic extract of a marine sponge, Petrosia alfiani, selectively inhibited iron chelator-induced hypoxia-inducible factor-1 (HIF-1) activation in a human breast tumor T47D cell-based reporter assay. Bioassay-guided fractionation yielded seven xestoquinones (1-7) including three new compounds: 14 hydroxymethylxestoquinone (1), 15-hydroxymethylxestoquinone (2), and 14,15 dihydroxestoquinone (3). Compounds 1-7 were evaluated for their effects on HIF-1 signaling, mitochondrial respiration, and tumor cell proliferation/viability. The known metabolites adociaquinones A (5) and B (6), which possess a 3,4-dihydro-2H 1,4-thiazine-1,1-dioxide moiety, potently and selectively inhibited iron chelator induced HIF-1 activation in T47D cells, each with an IC(50) value of 0.2 MUM. Mechanistic studies revealed that adociaquinones promote oxygen consumption without affecting mitochondrial membrane potential. Compound 1 both enhances respiration and decreases mitochondrial membrane potential, suggesting that it acts as a protonophore that uncouples mitochondrial respiration. PMID- 22938094 TI - Silicone finger prosthesis. A clinical report. AB - The loss of all or part of a finger following traumatic amputation may have a negative impact on physical and psychological well being. An esthetic prosthesis can offer psychological, functional, and rehabilitative advantages. The success of a prosthetic restoration primarily depends on its retention. This clinical report describes an alternative method of retention by scoring the master cast of a partially amputated finger, thus enhancing the vacuum effect for the retention of the prosthesis. The methodology of treatment is also explained. Silicone material was used to provide function and esthetics. PMID- 22938095 TI - Peripheral blood immunophenotypic analysis as a diagnostic tool for large granular lymphocyte leukemia. PMID- 22938096 TI - An unusual origin of the double left testicular artery in a male cadaver: a case report. AB - INTRODUCTION: Variations in the number and course of the testicular arteries, often coexisting with variations of the other branches arising from the abdominal aorta, are still reported to be of interest to urology surgeons. CASE PRESENTATION: During a routine dissection course, an unusual origin of the double left testicular artery was observed in the cadaver of a 68-year-old Caucasian man who donated his body to the Institute of Anatomy. CONCLUSIONS: A deeper understanding of the variations of the testicular arteries is necessary for all physicians whose practice is related to the testicles and their vascular stalk. PMID- 22938098 TI - Electron acceptors based on functionalizable cyclopenta[hi]aceanthrylenes and dicyclopenta[de,mn]tetracenes. AB - We report the synthesis and selective functionalization of two externally fused cyclopenta-fused polycyclic aromatic hydrocarbons (CP-PAHs) and demonstrate their electron accepting behavior. 2,7-Bis(trimethylsilyl)cyclopenta[hi]aceanthrylene (1) and 2,8-bis(trimethylsilyl)dicyclopenta[de,mn]tetracene (4) were prepared in a one-pot, palladium-catalyzed cross-coupling of (trimethylsilyl)acetylene and either 9,10-dibromoanthracene or 5,11-dibromotetracene, respectively. The trimethylsilyl groups were selectively converted into bromides via substitution with N-bromosuccinimide to create universal partners (2 and 6) for metal catalyzed cross-coupling reactions. To demonstrate the utility of the halogenated CP-PAHs, we successfully employed a Sonogashira cross-coupling between the CP PAHs and a phenylacetylene derivative. The resulting compounds (3 and 7) were found to be highly conjugated between the CP-PAH core and the substituents, as demonstrated by large bathochromic shifts in the absorption spectra as well as density functional theory calculations. Ethynylated CP-PAHs 3 and 7 were found to possess low optical bandgaps (1.52 and 1.51 eV, respectively) and displayed two reversible reductions. We further demonstrated the fullerene-like electron accepting behavior of 3 through solution-phase fluorescence quenching of the prototypical electron donor, poly(3-hexylthiophene). PMID- 22938099 TI - Effect of several germination treatments on phosphatases activities and degradation of phytate in faba bean (Vicia faba L.) and azuki bean (Vigna angularis L.). AB - Two assays were conducted to investigate the changes of faba bean (Vicia faba L.) and azuki bean (Vigna angularis L.) phosphatases (phytase [Phy] and acid phosphatase [AcPh]) and the degradation of its substrates (inositol phosphate esters) during seed germination. The 1st assay was to establish the optimal germination conditions of faba bean and azuki bean to improve the endogenous phosphatases and increase the hydrolysis of phytate and, in the second assay, to determine the different lower phosphate esters of myo-inositol produced during the germination process. In the 1st assay, seeds were soaked for 12 and 24 h and germinated for 3 and 5 d with and without the addition of gibberellic acid (GA(3) ). In the second assay, seeds were soaked for 12 h and germinated for 1, 3, and 5 d with GA(3) . Phy (up to 3625 and 1340 U/kg) and AcPh (up to 9456 and 2740 U/g) activities, and inositol hexaphosphate (IP6) (8.23 and 7.46 mg/g), inositol pentaphosphate (IP5) (0.55 and 0.82 mg/g), and inositol tetraphosphate (IP4) (0.26 and 0.01 mg/g) were detected in ungerminated faba bean and azuki bean, respectively. The germination process caused a significant increase of Phy and AcPh activities in faba bean (up to 147% and 210%) and azuki bean (up to 211% and 596%) and a reduction in the phytate phosphorus content (up to 81% and 63%, respectively). Phytate phosphorus content was affected only by soaking time in the case of faba bean. Finally, during the course of germination, IP6 and IP5 were rapidly degraded in faba bean (88% and 39%) and azuki bean (55% and 56%), and IP4 was only a short-living intermediate, which was increased during hydrolysis and degraded to inositol triphosphate. In this manner we could obtain a low-phytate, endogenous phosphatase-rich ingredient for enhancing human nutrition. PMID- 22938097 TI - Potential role of glucagon-like peptide-1 (GLP-1) in neuroprotection. AB - The current understanding of neurodegenerative processes in sporadic diseases such as Alzheimer's disease (AD), Parkinson's disease (PD) or multiple sclerosis is very limited. Several risk factors have been identified that may shed light on the underlying mechanisms that initiate the neurodegeneration. Type 2 diabetes mellitus has been identified as a risk factor for AD and PD. In AD patients, desensitization of insulin receptors in the brain has been shown, even in non diabetic patients. Insulin acts as a growth factor in the brain and supports neuronal repair, dendritic sprouting and synaptogenesis, and protection from oxidative stress. Importantly, several drugs have been developed to treat type 2 diabetes that re-sensitize insulin receptors and may be of use to prevent neurodegenerative processes. Glucagon-like peptide-1 (GLP-1) is a hormone that facilitates insulin release under high blood sugar conditions. Interestingly, GLP 1 also has very similar growth factor-like properties to insulin, and has been shown to reduce a range of degenerative processes. In pre-clinical studies, GLP-1 and longer-lasting protease-resistant analogues cross the blood-brain barrier, protect memory formation (AD) or motor activity (PD), protect synapses and synaptic functions, enhance neurogenesis, reduce apoptosis, protect neurons from oxidative stress, and reduce plaque formation and the chronic inflammation response in the brains of mouse models of AD, PD, amyotrophic lateral sclerosis, stroke and other degenerative diseases. GLP-1 signalling does not affect blood sugar levels in non-diabetic people and therapies that affect GLP-1 signalling have a good safety profile as shown by the chronic application of drugs currently on the market (liraglutide, Victoza((r)); NovoNordisk, Copenhagen, Denmark, and exendin-4, Byetta((r)); Amylin, San Diego, CA, USA). Based on the extensive evidence, several clinical trials are currently underway, testing liraglutide and exendin-4 in AD and PD patients. Therefore, GLP-1 analogues show great promise as a novel treatment for AD or other neurodegenerative conditions. PMID- 22938100 TI - Immunotoxicity induced by acute subtoxic doses of paraquat herbicide: implication of shifting cytokine gene expression toward T-helper (T(H))-17 phenotype. AB - Paraquat (PQ) is a free radical-inducing agent commonly used as an herbicide. This study assesses the acute immunotoxicity of PQ in BALB/c mice and examines its effect on cytokine gene expression profile. It was found that single subtoxic oral doses of 2, 4, and 20 mg/kg significantly inhibited the in vitro mitogen induced proliferation in both T and B cells. Also, such acute doses have resulted in significant reduction of the IgM plaque-forming cells counts. The impact of PQ on the cytokine gene expression of in vitro PHA-activated splenocytes was assessed at 2.0 and 0.006 MUg/mL. The concentrations used in vitro represent the lowest in vivo dose given in this study and FAO-WHO set PQ acceptable daily intake (ADI) dose, respectively. Interestingly, the RT2-PCR array for common cytokines' expression demonstrated that PQ had markedly elevated the mRNA expression of several proinflammatory cytokines at both concentrations. More importantly, at concentrations equivalent to ADI, PQ had caused a marked up regulation of IL-17 cytokine family including IL-17B, C, E, and F. Also, PQ has up-regulated mRNA expression of the T(H)-17-promoting cytokines IL-9 and -21. Together, these results show that PQ at higher concentrations can deplete immune functions, but at lower concentrations, it has potential to alter immune responses toward the proinflammatory profiles as that of T(H)-17. Such a T cell helper profile has been implicated in the development and the pathophysiology of several autoimmune and allergic diseases. Thus, considering that maximum residue levels (MRLs) of PQ set by FAO and WHO for certain food and animal feed crops range between 0.005 and 10.0 mg/kg, our findings stress the importance of applying strict regulation on the use of PQ as an herbicide. PMID- 22938101 TI - Critical role of Toll-like receptor 2 in Bacteroides fragilis-mediated immune responses in murine peritoneal mesothelial cells. AB - In this study, the role of Toll-like receptor 2 (TLR2) in immune responses of murine peritoneal mesothelial cells against Bacteroides fragilis was investigated. Enzyme linked immunosorbent assay was used to measure cytokines and chemokines. Activation of nuclear factor kappaB (NF-kappaB-alpha) and mitogen activated protein kinases (MAP kinases) was investigated by western blot analysis. B. fragilis induced production of interleukin-6, chemokine (C-X-C motif) ligand 1 (CXCL1) and chemokine (C-C motif) ligand 2 (CCL2) in wild type peritoneal mesothelial cells; this was impaired in TLR2-deficient cells. In addition, in response to B. fragilis, phosphorylation of inhibitory NF-kappaB alpha and c-Jun N-terminal kinase mitogen-activated protein kinase (MAPK) was induced in wild type mesothelial cells, but not in TLR2-deficient cells,. Inhibitor assay revealed that NF-kappaB and MAPKs are essential for B. fragilis induced production of CXCL1 and CCL2 in mesothelial cells. These findings suggest that TLR2 mediates immune responses in peritoneal mesothelial cells in response to B. fragilis. PMID- 22938102 TI - Public opinion of organ donation: a survey in Iran. AB - INTRODUCTION: The objective of this study was to assess the views of Tehran citizens in regard to donating their organs in case of brain death. METHODS: In this cross-sectional study, conducted between February 2009 and November 2010, two interviewers contacted 1379 people through random digit dialing for phone interviews. Phone calls were made between 6 and 9 pmon a workday, and those reaching companies or organizations were excluded. The interviewee was selected randomly from among the household members, and those 18 yr and older were included in the study. RESULTS: Of the 1379 people eligible for entering the study, 706 consented to have the interview (response rate = 51%). Among the respondents, 84.6% were willing to donate. Of these, 94.6% were willing to complete a donor card as well, but only 10.7% of them already had one. CONCLUSION: There should be simple processes for the public to declare their decision about organ donation in case of brain death. People should be encouraged to communicate their wishes with others so that family members can decide about their organ donation more easily. PMID- 22938105 TI - Bringing stillbirth out of the shadows for all women having a baby in Australia. PMID- 22938106 TI - Early medical abortion--available and safe. PMID- 22938107 TI - Reproductive technologies: the alchemy of life. PMID- 22938110 TI - "Click first, care second" photography. PMID- 22938111 TI - Do available predictions of future medical workforce requirements provide a sensible basis for planning? Yes. PMID- 22938112 TI - Do available predictions of future medical workforce requirements provide a sensible basis for planning? No. PMID- 22938113 TI - New money for chronic diseases: can clinicians and entrepreneurs deliver outcomes eluding governments? PMID- 22938114 TI - Tobacco plain packaging. PMID- 22938115 TI - Is swaddling damaging our babies' hips? PMID- 22938116 TI - Legal clarification of "loss of chance of a better outcome" in Australia. PMID- 22938117 TI - Hormone treatment of gender identity disorder in a cohort of children and adolescents. Comment. PMID- 22938118 TI - Hormone treatment of gender identity disorder in a cohort of children and adolescents. Comment. PMID- 22938120 TI - Listening to what Indigenous people in remote communities say about alcohol restrictions and cannabis use: "Good thing that the alcohol's gone, but the gunja has kept going". PMID- 22938121 TI - The value of a support group for doctors with substance use disorders. PMID- 22938122 TI - Support for parents following stillbirth. PMID- 22938123 TI - The Jarisch-Herxheimer reaction in a patient with leptospirosis: a foreseeable problem in managing spirochaete infections. PMID- 22938125 TI - Ethnicity and the risk of late-pregnancy stillbirth. AB - OBJECTIVE: To determine if maternal country of birth is associated with the risk of antepartum stillbirth in late pregnancy. DESIGN, SETTING AND PARTICIPANTS: Retrospective cross-sectional study of all singleton births at 37-42 weeks' gestation, excluding those with congenital abnormalities and intrapartum stillbirths, between 1 June 2001 and 31 May 2011 at Southern Health, a large metropolitan maternity service in Melbourne, Australia. MAIN OUTCOME MEASURE: Rate of late-pregnancy antepartum stillbirth, analysed by maternal country of birth. RESULTS: Among 44 326 births, there was a significant difference in the stillbirth rate by maternal country of birth (P < 0.001). The rate of stillbirth per 1000 births was 1.48 among Australian-born women, 3.55 among South Asian-born women and 1.06 among South-East-East Asian-born women. Women born in South Asia were 2.4 (95% CI, 1.4-4.0) times more likely to have a late-pregnancy stillbirth than women born in Australia (P < 0.001). There was no significant difference between women born in Australia and women born in South-East-East Asia (P = 0.34). Adjusting for potential confounding factors, South Asian maternal birth remained an independent risk factor for stillbirth (adjusted odds ratio, 2.5; 95% CI, 1.3-5.1; P = 0.009). CONCLUSION: Women born in South Asia have an increased risk of antepartum stillbirth in late pregnancy, compared with other women. This observation may have implications for the delivery of pregnancy care in Australia. PMID- 22938126 TI - Early medical abortion using low-dose mifepristone followed by buccal misoprostol: a large Australian observational study. AB - OBJECTIVE: To describe the use of mifepristone in combination with buccal misoprostol in women undergoing an early medical abortion (EMA) in Australia. DESIGN, SETTING AND PARTICIPANTS: Retrospective, observational study of 13,345 EMAs (gestational age <= 63 days) conducted at 15 Marie Stopes International Australia clinics between 1 September 2009 and 31 August 2011. INTERVENTION: Oral mifepristone 200 mg, administered at the clinic, followed 24-48 hours later by buccal misoprostol 800 ug, self-administered at home. MAIN OUTCOME MEASURE: Failure rate (proportion of women with an incomplete abortion requiring surgical aspiration or a continuing pregnancy). RESULTS: Pregnancy termination follow-up information was available for 83.4% (11 155/13 376) of EMAs. From the patient demographic database, the EMA failure rate was 3.5% (465/13 345). Of these, most (382; 2.9% of total) were incomplete abortions requiring surgical aspiration, and 83 (0.6% of total) were continuing pregnancies. Haemorrhage (16; 0.1%) and known or suspected infection (25; 0.2%) were infrequent. One woman, who did not seek follow-up despite signs of infection, died from sepsis (< 0.01%). In 6755 EMAs with clinic follow-up from April 2010 to August 2011, 6381 women participated in a survey. Most reported medium or heavy bleeding and moderate or severe pain/cramps; most also reported that bleeding, pain/cramps and their overall experience were as expected or better than expected. CONCLUSIONS: Mifepristone, with buccal misoprostol self-administered at home, for EMA up to 63 days of gestation had a low failure rate, was well accepted, and provided an effective treatment option with a favourable safety profile for women seeking an abortion in Australia. PMID- 22938127 TI - Online chlamydia testing: an innovative approach that appeals to young people. AB - OBJECTIVE: To evaluate data from an online chlamydia testing program (OLC) developed to increase young people's access to testing for chlamydia, the most commonly notified disease in Australia and Western Australia, with a high proportion of notifications among young people (< 30 years). DESIGN AND SETTING: The OLC was launched in February 2010, and our study covers the period February 2010 to June 2011. Without needing to first visit a doctor, OLC participants receive risk self-assessment, education, testing, and, if necessary, referral for treatment, and can complete an online satisfaction survey. MAIN OUTCOME MEASURES: Number and proportion of downloaded pathology forms that resulted in a test; demographic characteristics of participants; prevalence of chlamydia; completeness and timeliness of follow-up of positive test results; and participant satisfaction. RESULTS: More than half (56%) of the 675 OLC pathology form downloads resulted in a test, and chlamydia was detected in 18% (66/377). Of those tested, over half were men (55%), and 71% were aged < 30 years. All participants with a positive test result received appropriate clinical management, with 50% being treated within 7 days of specimen collection. Of the 17% (55/332) who completed an online satisfaction survey, almost all said they would recommend the service to a friend. CONCLUSION: Internet-based screening for chlamydia is an effective means of increasing access to testing for young people at risk of sexually transmitted infections and is a valuable addition to opportunistic, clinic-based strategies. PMID- 22938128 TI - Australian national birthweight percentiles by sex and gestational age, 1998 2007. AB - OBJECTIVE: To present updated national birthweight percentiles by gestational age for male and female singleton infants born in Australia. DESIGN AND SETTING: Cross-sectional population-based study of 2.53 million singleton live births in Australia between 1998 and 2007. MAIN OUTCOME MEASURES: Birthweight percentiles by gestational age and sex. RESULTS: Between 1998 and 2007, women in Australia gave birth to 2 539 237 live singleton infants. Of these, 2 537 627 had a gestational age between 20 and 44 weeks, and sex and birthweight data were available. Birthweight percentiles are presented by sex and gestational age for a total of 2 528 641 births, after excluding 8986 infants with outlying birthweights. Since the publication of the previous Australian birthweight percentiles in 1999, median birthweight for term babies has increased between 0 and 25 g for boys and between 5 g and 45 g for girls. CONCLUSIONS: There has been only a small increase in birthweight percentiles for babies of both sexes and most gestational ages since 1991-1994. These national percentiles provide a current Australian reference for clinicians and researchers assessing weight at birth. PMID- 22938129 TI - A no-fault compensation system for medical injury is long overdue. AB - The 2011 report of the Productivity Commission (PC) recommended the establishment of a no-fault national injury insurance scheme limited to "catastrophic" injury, including medical injury. The report is welcome, but represents a missed opportunity to establish simultaneously a much-needed no-fault scheme for all medical injuries. The existing indemnity scheme based on negligence remains a slow, costly, inefficient, ill targeted and stress-creating system. A fault-based negligence scheme cannot deter non-intentional errors and does little to identify or prevent systems failures. In addition, it discourages reporting, and thus is antithetical to the modern focus on universal patient safety. A no-fault scheme has the potential to be fairer, quicker and no more costly, and to contribute to patient safety. No-fault schemes have been in place in at least six developed countries for many years. This extensive experience in comparable countries should be examined to assist Australia to design an effective, comprehensive system. Before implementing the recommendations of the PC, the federal government should ask the Commission to study and promptly report on an ancillary no-fault scheme that covers all medical injury. PMID- 22938130 TI - How best do we compensate for accidental medical injuries? PMID- 22938131 TI - University of Melbourne Medical School: reflections of a graduate. PMID- 22938134 TI - A genome-wide identification and analysis of the basic helix-loop-helix transcription factors in the ponerine ant, Harpegnathos saltator. AB - BACKGROUND: The basic helix-loop-helix (bHLH) transcription factors and their homologs form a superfamily that plays essential roles in transcriptional networks of multiple developmental processes. bHLH family members have been identified in over 20 organisms, including fruit fly, zebrafish, human and mouse. RESULT: In this study, we conducted a genome-wide survey for bHLH sequences, and identified 57 bHLH sequences encoded in complete genome sequence of the ponerine ant, Harpegnathos saltator. Phylogenetic analysis of the bHLH domain sequences classified these genes into 38 bHLH families with 23, 14, 10, 1, 8 and 1 members in group A, B, C, D, E and F, respectively. The number of PabHLHs (ponerine ant bHLHs) with introns is higher than many other insect species, and they are found to have introns with average lengths only inferior to those of pea aphid. In addition, two H. saltator bHLHs named PaCrp1 and PaSide locate on two separate contigs in the genome. CONCLUSIONS: A putative full set of PabHLH genes is comparable with other insect species and genes encoding Oligo, MyoRb and Figalpha were not found in genomes of all insect species of which bHLH family members have been identified. Moreover, in-family phylogenetic analyses indicate that the PabHLH genes are more closely related with Apis mellifera than others. The present study will serve as a solid foundation for further investigations into the structure and function of bHLH proteins in the regulation of H. saltator development. PMID- 22938136 TI - Validation of reference genes for quantitative expression analysis by real-time rt-PCR in four lepidopteran insects. AB - Quantitative real-time polymerase chain reaction (qPCR) is an efficient and widely used technique to monitor gene expression. Housekeeping genes (HKGs) are often empirically selected as the reference genes for data normalization. However, the suitability of HKGs used as the reference genes has been seldom validated. Here, six HKGs were chosen (actin A3, actin A1, GAPDH, G3PDH, E2F, rp49) in four lepidopteran insects Bombyx mori L. (Lepidoptera: Bombycidae), Plutella xylostella L. (Plutellidae), Chilo suppressalis Walker (Crambidae), and Spodoptera exigua Hubner (Noctuidae) to study their expression stability. The algorithms of geNorm, NormFinder, stability index, and DeltaCt analysis were used to evaluate these HKGs. Across different developmental stages, actin A1 was the most stable in P. xylostella and C. suppressalis, but it was the least stable in B. mori and S. exigua. Rp49 and GAPDH were the most stable in B. mori and S. exigua, respectively. In different tissues, GAPDH, E2F, and Rp49 were the most stable in B. mori, S. exigua, and C. suppressalis, respectively. The relative abundances of Siwi genes estimated by 2(-DeltaDeltaCt) method were tested with different HKGs as the reference gene, proving the importance of internal controls in qPCR data analysis. The results not only presented a list of suitable reference genes in four lepidopteran insects, but also proved that the expression stabilities of HKGs were different among evolutionarily close species. There was no single universal reference gene that could be used in all situations. It is indispensable to validate the expression of HKGs before using them as the internal control in qPCR. PMID- 22938135 TI - Identifying factors likely to influence compliance with diagnostic imaging guideline recommendations for spine disorders among chiropractors in North America: a focus group study using the Theoretical Domains Framework. AB - BACKGROUND: The Theoretical Domains Framework (TDF) was developed to investigate determinants of specific clinical behaviors and inform the design of interventions to change professional behavior. This framework was used to explore the beliefs of chiropractors in an American Provider Network and two Canadian provinces about their adherence to evidence-based recommendations for spine radiography for uncomplicated back pain. The primary objective of the study was to identify chiropractors' beliefs about managing uncomplicated back pain without x-rays and to explore barriers and facilitators to implementing evidence-based recommendations on lumbar spine x-rays. A secondary objective was to compare chiropractors in the United States and Canada on their beliefs regarding the use of spine x-rays. METHODS: Six focus groups exploring beliefs about managing back pain without x-rays were conducted with a purposive sample. The interview guide was based upon the TDF. Focus groups were digitally recorded, transcribed verbatim, and analyzed by two independent assessors using thematic content analysis based on the TDF. RESULTS: Five domains were identified as likely relevant. Key beliefs within these domains included the following: conflicting comments about the potential consequences of not ordering x-rays (risk of missing a pathology, avoiding adverse treatment effects, risks of litigation, determining the treatment plan, and using x-ray-driven techniques contrasted with perceived benefits of minimizing patient radiation exposure and reducing costs; beliefs about consequences); beliefs regarding professional autonomy, professional credibility, lack of standardization, and agreement with guidelines widely varied ( social/professional role & identity); the influence of formal training, colleagues, and patients also appeared to be important factors ( social influences); conflicting comments regarding levels of confidence and comfort in managing patients without x-rays ( belief about capabilities); and guideline awareness and agreements ( knowledge). CONCLUSIONS: Chiropractors' use of diagnostic imaging appears to be influenced by a number of factors. Five key domains may be important considering the presence of conflicting beliefs, evidence of strong beliefs likely to impact the behavior of interest, and high frequency of beliefs. The results will inform the development of a theory-based survey to help identify potential targets for behavioral-change strategies. PMID- 22938137 TI - Regulation of lifespan by the mitochondrial electron transport chain: reactive oxygen species-dependent and reactive oxygen species-independent mechanisms. AB - SIGNIFICANCE: Aging is a consequence of the accumulation of cellular damage that impairs the capacity of an aging organism to adapt to stress. The Mitochondrial Free Radical Theory of Aging (MFRTA) has been one of the most influential ideas over the past 50 years. The MFRTA is supported by the accumulation of oxidative damage during aging along with comparative studies demonstrating that long-lived species or individuals produce fewer mitochondrial reactive oxygen species and have lower levels of oxidative damage. RECENT ADVANCES: Recently, however, species that combine high oxidative damage with a longer lifespan (i.e., naked mole rats) have been described. Moreover, most of the interventions based on antioxidant supplementation do not increase longevity, as would be predicted by the MFRTA. Studies to date provide a clear understanding that mitochondrial function regulates the rate of aging, but the underlying mechanisms remain unclear. CRITICAL ISSUES: Here, we review the reactive oxygen species (ROS) dependent and ROS-independent mechanisms by which mitochondria can affect longevity. We discuss the role of different ROS (superoxide, hydrogen peroxide, and hydroxyl radical), both as oxidants as well as signaling molecules. We also describe how mitochondria can regulate longevity by ROS-independent mechanisms. We discuss alterations in mitochondrial DNA, accumulation of cellular waste as a consequence of glyco- and lipoxidative damage, and the regulation of DNA maintenance enzymes as mechanisms that can determine longevity without involving ROS. FUTURE DIRECTIONS: We also show how the regulation of longevity is a complex process whereby ROS-dependent and ROS-independent mechanisms interact to determine the maximum lifespan of species and individuals. PMID- 22938138 TI - The experience of community health workers training in Iran: a qualitative study. AB - BACKGROUND: The role of Community Health Workers (CHWs) in improving access to basic healthcare services, and mobilising community actions on health is broadly recognised. The Primary Health Care (PHC) approach, identified in the Alma Ata conference in 1978, stressed the role of CHWs in addressing community health needs. Training of CHWs is one of the key aspects that generally seeks to develop new knowledge and skills related to specific tasks and to increase CHWs' capacity to communicate with and serve local people. This study aimed to analyse the CHW training process in Iran and how different components of training have impacted on CHW performance and satisfaction. METHODS: Data were collected from both primary and secondary sources. Training policies were reviewed using available policy documents, training materials and other relevant documents at national and provincial levels. Documentary analysis was supplemented by individual interviews with ninety-one Iranian CHWs from 18 provinces representing a broad range of age, work experience and educational levels, both male and female. RESULTS: Recognition of the CHW program and their training in the national health planning and financing facilitates the implementation and sustainability of the program. The existence of specialised training centres managed by district health network provides an appropriate training environment that delivers comprehensive training and increases CHWs' knowledge, skills and motivation to serve local communities. Changes in training content over time reflect an increasing number of programs integrated into PHC, complicating the work expected of CHWs. In-service training courses need to address better local needs. CONCLUSION: Although CHW programs vary by country and context, the CHW training program in Iran offers transferable lessons for countries intending to improve training as one of the key elements in their CHW program. PMID- 22938139 TI - Lack of impact of human immunodeficiency virus infection on the outcome of lymphoma patients transferred to the intensive care unit. AB - The impact of human immunodeficiency virus (HIV) infection on the outcome of patients with acquired immunodeficiency syndrome (AIDS)-related lymphoma with life-threatening complications requiring intensive care unit (ICU) admission is not well known. The objective of this study was to compare the outcome of patients with lymphoma transferred to the ICU according to HIV infection status. The clinical characteristics, reason for ICU admission, and outcome of 48 consecutive critically ill patients with lymphoma admitted to the ICU from January 2000 to March 2010 was retrospectively analyzed, focusing on their HIV serology status. Thirty-six patients were HIV-negative and 12 patients HIV positive. Burkitt lymphoma was more frequent in HIV-infected patients, whereas diffuse large B-cell lymphoma was more frequent in HIV-negative patients. The main acute life-threatening diseases precipitating ICU transfer were similar in both groups. Severe neutropenia was more frequent in HIV-positive than in HIV negative patients. With a median follow-up of 53 months after ICU admission, the overall survival probabilities were 15% (95% confidence interval [CI]: 3-27%) and 17% (95% CI: 0-38%) for HIV-negative and HIV-positive patients, respectively. The 2-year survival probabilities were 34% (95% CI: 10-58%) and 40% (95% CI: 0-43%) for HIV-negative and HIV-positive patients discharged from the ICU, respectively. In this study, HIV infection did not have a negative impact on the outcome of patients with lymphoma admitted to the ICU. PMID- 22938140 TI - Does a consumer training work? a follow-up survey of the PartecipaSalute training programs. AB - BACKGROUND: When properly trained through training programs on epidemiology, clinical research and healthcare policy, members of patients'/consumers' organizations could be helpful for a patient-oriented healthcare system. Since 2006 the not for profit project PartecipaSalute has organized periodic editions of a training program for representatives of citizens'/patients' organizations. After five editions of this training program, a survey of the long-term satisfaction and the impact on activities has been carried out. METHODS: A 17 questions follow-up questionnaire has been developed. The sample comprised 99 people who had taken part in at least one program edition. RESULTS: The overall response rate was 89% (89 responders/99 participants). About 98% of participants expressed general satisfaction with the training program and with the knowledge gained. Medical and informative topics were rated better than technical ones for their usefulness (96% versus 86%). The results of the survey showed a strong impact of the training course on single participants, while a weak outcome on the activities of the organizations was reported. CONCLUSIONS: The training program was positively rated, and improvements in personal knowledge were reported. Less impact was reported on organizations' activities. Participants showed a remarkable willingness to get more involved in healthcare decisions, and to boost their knowledge of health and research issues. The results show the importance of follow-up to understand the real value of training program and to better organize future programs. PMID- 22938143 TI - Late primary cytomegalovirus infection presenting with acute inflammatory demyelinating polyneuropathy in a heart transplant recipient: a case report and review of the literature. AB - Cytomegalovirus (CMV) infection is well recognized as a cause of morbidity and mortality in heart transplant recipients. Primary CMV infection can occur early post transplant in at-risk recipients with donor-derived infection, or any time after transplantation in community-acquired infection. We describe a unique case of primary CMV infection occurring 14 years after cardiac transplantation. In addition to end-organ CMV disease, this patient developed a post-infectious neurologic phenomenon, acute inflammatory demyelinating polyneuropathy. This entity has rarely been reported in the solid organ transplant population. PMID- 22938144 TI - Exposure to acute electromagnetic radiation of mobile phone exposure range alters transiently skin homeostasis of a model of pigmented reconstructed epidermis. AB - Exposure to electromagnetic radiations (EMR) produced by mobile phone concerns half the world's population and raises the problem of their impact on human health. In this study, we looked at the effects of mobile phone exposure (GSM basic, 900 MHz, SAR 2 mW g(-1) , 6 h) on a model of pigmented skin. We have analysed the expression and localization of various markers of keratinocyte and melanocyte differentiation 2, 6, 18 and 24 h after EMR exposure of reconstructed epidermis containing either only keratinocytes or a combination of keratinocytes and melanocytes grown on dead de-epidermized dermis, using histology, immunohistochemistry and Western blot. No changes were found in epidermal architecture, localization of epidermal markers, presence of apoptotic cells and the induction of p53 in both types of epidermis (with or without melanocytes) after exposure to EMR. In pigmented reconstructs, no change in the location and dendricity of melanocytes and in melanin transfer to neighbouring keratinocytes was detected after EMR exposure. Loricrin, cytokeratin 14 were significantly decreased at 6 h. The level of all markers increased at 24 h as compared to 6 h post-EMR exposure, associated with a significant decrease of the 20S proteasome activity. Our data indicate that exposure to 900 MHz frequency induces a transient alteration of epidermal homoeostasis, which may alter the protective capacity of the skin against external factors. Presence or absence of melanocytes did not modify the behaviour of reconstructs after EMR exposure. PMID- 22938142 TI - Toll-like receptor 4 signaling promotes epithelial-mesenchymal transition in human hepatocellular carcinoma induced by lipopolysaccharide. AB - BACKGROUND: The endotoxin level in the portal and peripheral veins of hepatocellular carcinoma (HCC) patients is higher and lipopolysaccharide (LPS), a cell wall constituent of gram-negative bacteria, has been reported to inhibit tumor growth. However, in this study, we found that LPS-induced toll-like receptor 4 (TLR4) signaling was involved in tumor invasion and survival, and the molecular mechanism was investigated, METHODS: Four HCC cell lines and a splenic vein metastasis of the nude mouse model were used to study the invasion ability of LPS-induced HCC cells and the epithelia-mesenchymal transition (EMT) in vitro and in vivo. A total of 106 clinical samples from HCC patients were used to evaluate TLR4 expression and analyze its association with clinicopathological characteristics RESULTS: The in vitro and in vivo experiments demonstrated that LPS could significantly enhance the invasive potential and induce EMT in HCC cells with TLR4 dependent. Further studies showed that LPS could directly activate nuclear factor kappa B (NF-kappaB) signaling through TLR4 in HCC cells. Interestingly, blocking NF-kappaB signaling significantly inhibited transcription factor Snail expression and thereby inhibited EMT occurrence. High expression of TLR4 in HCC tissues was strongly associated with both poor cancer-free survival and overall survival in patients. CONCLUSIONS: Our results indicate that TLR4 signaling is required for LPS-induced EMT, tumor cell invasion and metastasis, which provide molecular insights for LPS-related pathogenesis and a basis for developing new strategies against metastasis in HCC. PMID- 22938145 TI - Knoop hardness and effectiveness of dual-cured luting systems and flowable resin to bond leucite-reinforced ceramic to enamel. AB - PURPOSE: The aim of this study was to evaluate the Knoop microhardness and microshear bond strength (MSBS) of dual-cured luting systems and flowable resin bonded to leucite-reinforced ceramics and enamel. MATERIALS AND METHODS: Eighty bovine incisors were randomly divided into four groups per test (microhardness and microshear; n = 10) according to the bonding procedure: Excite DSC/Variolink, Clearfil SE Bond/Panavia F, Adper Scotchbond Multi-Purpose Plus/RelyX ARC, and Adper Single Bond 2/Filtek Z350 Flow. For the KHN measurement, the cement was applied on the enamel surface and light-cured through a ceramic disk (5 mm diameter * 1.2 mm thick). Five indentations were performed in each specimen and measured at HMV-2. For the microshear test, two cylinders of a leucite-reinforced ceramic (1 mm diameter * 2 mm height) were bonded to the enamel substrate in accordance with the bonding procedures previously established. One cylinder was tested 24 hours after cementation, and the other was subjected to thermocycling (2000 cycles) and then submitted to an MSBS test. The data from the hardness and bond strength tests were subjected to one- and two-way repeated-measures analysis of variance (ANOVA), respectively, and to Tukey's test (alpha= 0.05). RESULTS: Scotchbond/RelyX ARC presented higher values of bond strength, while Single Bond/Z350 Flow showed lower values. The thermocycling promoted a reduction in the bond strength values for all groups. Panavia F presented higher values of KHN, and the flowable resin presented the lowest. RelyX ARC and Variolink presented intermediate values on hardness evaluation. CONCLUSIONS: For ceramic cementation, dual-cured resin luting systems promoted more reliable bonding and microhardness values than the flowable resin. PMID- 22938141 TI - Current and emerging systemic treatment strategies for psoriasis. AB - Psoriasis is a common chronic inflammatory disease of the skin that has a significant impact on quality of life. A small number of systemic therapies are well established in psoriasis management. These have immunosuppressive and/or anti-proliferative effects on the skin and immune system. As understanding of the pathogenesis of psoriasis has advanced over the last 2 decades, there has been clearer appreciation of the genetic, cellular and immunological components of disease expression, which has provided new insight into potential therapeutic targets, including the development of biological therapies. Biologics offer a unique opportunity to block or inhibit specific key components of psoriasis pathogenesis. The introduction of tumour necrosis factor (TNF).alpha and interleukin (IL)-12/-23 inhibitors has resulted in remarkable clinical responses in patients with severe psoriasis and has led to the development of a range of other cytokine modulators currently undergoing investigation. More recently, research in keratinocyte biology and immune cell function, particularly intracellular signalling, has afforded additional opportunities to develop a range of small-molecule oral preparations that may prove effective in disease control. This paper reviews current and emerging systemic treatments in the management of psoriasis. PMID- 22938146 TI - Endoscopic hemostasis with endoscopic mucosal resection and multiple synchronous early gastric cancers: a case report. AB - INTRODUCTION: Endoscopic hemostasis for severe upper gastrointestinal bleeding due to tumors, such as gastrointestinal stromal tumors and malignant lymphoma, is temporarily effective. However, permanent hemostasis is difficult in many cases because of diffuse bleeding. CASE PRESENTATION: A 60-year-old Japanese woman was admitted to our hospital with hematemesis. Endoscopy revealed multiple gastric polyps and fresh blood in her stomach. One of the gastric polyps, which was associated with oozing bleeding, was found near the anterior wall of the lower gastric body. We initially applied hemostatic forceps and argon plasma coagulation over the tumor surface, but the bleeding persisted. After endoscopic mucosal resection, exposed vessels were seen at the base of the mucosal resection site with oozing bleeding. Coagulation of the bleeding vessels using hemostatic forceps allowed successful completion of the hemostatic procedure. Our patient also had eight synchronous gastric cancer lesions. Histological examination of the resected specimens showed various types of cancer. CONCLUSION: This is a case report of gastric cancer associated with eight gastric cancer lesions, confirmed by histology, in which hemostasis was achieved through endoscopy. PMID- 22938147 TI - The effects of extraction of pulpally involved primary teeth on weight, height and BMI in underweight Filipino children. A cluster randomized clinical trial. AB - BACKGROUND: Severe dental caries and the treatment thereof are reported to affect growth and well-being of young children. The objective of this study was to assess the effects of extraction of severely decayed pulpally involved primary teeth on weight and height in underweight preschool Filipino children. METHODS: Underweight preschool Filipino children with severe dental decay had their pulpally involved primary teeth extracted during a stepped wedge cluster randomized clinical trial. Day care centers were randomly divided into two groups; children from Group A day care centers received treatment as soon as practical, whereas children from Group B day care centers were treated four months after Group A. Clinical oral examinations using WHO criteria and the pufa index were carried out. Anthropometric measurements were done on both groups immediately before treatment of Group A and at follow-up four months later. Height and weight z-scores were calculated using 2006 and 2007 WHO Growth Standards. Multilevel analysis was used to assess the effect of dental extractions on changes in anthropometric measurements after dental treatment. RESULTS: Data on 164 children (85 in Group A and 79 in Group B), mean age 59.9 months, were analyzed. Both groups gained weight and height during the trial period. Children in Group A significantly increased their BMI (p < 0.001), and their weight-for-age (p < 0.01) and BMI-for-age z-scores (p < 0.001) after dental treatment, whereas untreated children in Group B did not. Children in Group A had significantly more weight gain (p < 0.01) compared to untreated children in Group B. However, children in Group A had an inverse change in height gain (p < 0.001). Adjustment for the time interval between the two visits had little effect on the results. CONCLUSIONS: The extraction of severely decayed primary teeth resulted in significant weight gain in underweight Filipino children. Untreated dental decay should be considered an important co-factor affecting child growth and should be considered when planning for interventions to improve child growth. TRIAL REGISTRATION: ISRCTN90779069 http://www.controlled trials.com/isrctn/isrctn_loa. PMID- 22938148 TI - Rate of cardiac arrhythmias and silent brain lesions in experienced marathon runners: rationale, design and baseline data of the Berlin Beat of Running study. AB - BACKGROUND: Regular exercise is beneficial for cardiovascular health but a recent meta-analysis indicated a relationship between extensive endurance sport and a higher risk of atrial fibrillation, an independent risk factor for stroke. However, data on the frequency of cardiac arrhythmias or (clinically silent) brain lesions during and after marathon running are missing. METHODS/DESIGN: In the prospective observational "Berlin Beat of Running" study experienced endurance athletes underwent clinical examination (CE), 3 Tesla brain magnetic resonance imaging (MRI), carotid ultrasound imaging (CUI) and serial blood sampling (BS) within 2-3 days prior (CE, MRI, CUI, BS), directly after (CE, BS) and within 2 days after (CE, MRI, BS) the 38th BMW BERLIN-MARATHON 2011. All participants wore a portable electrocardiogram (ECG)-recorder throughout the 4 to 5 days baseline study period. Participants with pathological MRI findings after the marathon, troponin elevations or detected cardiac arrhythmias will be asked to undergo cardiac MRI to rule out structural abnormalities. A follow-up is scheduled after one year. RESULTS: Here we report the baseline data of the enrolled 110 athletes aged 36-61 years. Their mean age was 48.8 +/- 6.0 years, 24.5% were female, 8.2% had hypertension and 2.7% had hyperlipidaemia. Participants have attended a mean of 7.5 +/- 6.6 marathon races within the last 5 years and a mean of 16 +/- 36 marathon races in total. Their weekly running distance prior to the 38th BMW BERLIN-MARATHON was 65 +/- 17 km. Finally, 108 (98.2%) Berlin Beat-Study participants successfully completed the 38th BMW BERLIN MARATHON 2011. DISCUSSION: Findings from the "Berlin Beats of Running" study will help to balance the benefits and risks of extensive endurance sport. ECG recording during the marathon might contribute to identify athletes at risk for cardiovascular events. MRI results will give new insights into the link between physical stress and brain damage. TRIAL REGISTRATION: clinicaltrials.gov NCT01428778. PMID- 22938149 TI - Effect of polymerization on antioxidant and xanthine oxidase inhibitory potential of sea buckthorn (H. rhamnoides) proanthocyanidins. AB - Inhibitory potential of sea buckthorn (Hippophae rhamnoides L) seed proanthocyanidins against oxidative stress and xanthine oxidase activity was evaluated. Composition of antioxidant proanthocyanidins was profiled by analyzing the cleavage products obtained by the acid catalyzed hydrolysis in the presence of phloroglucinol. Catechin, epicatechin, gallocatechin, and epigallocatechin were found as the extension and terminal subunits of proanthocyanidins with an average degree of polymerization (ADP) of 14.7. Seed proanthocyanidins showed considerably high antioxidant and xanthine oxidase inhibitory potentials. Antioxidant and xanthine oxidase inhibitory capacity evaluation of proanthocyanidin fractions with varying ADP showed that proanthocyanidins with lower molecular size were more effective as superoxide anion (ADP <= 4.2) and hydroxyl radical (ADP <= 5.9) scavengers and xanthine oxidase (ADP <= 3.1) inhibitors. ADP of the studied proanthocyanidin fractions did not show significant influence on their DPPH and ABTS radical scavenging and ferric reduction capacities. PMID- 22938150 TI - Introducing the Forensic Research/Reference on Genetics knowledge base, FROG-kb. AB - BACKGROUND: Online tools and databases based on multi-allelic short tandem repeat polymorphisms (STRPs) are actively used in forensic teaching, research, and investigations. The Fst value of each CODIS marker tends to be low across the populations of the world and most populations typically have all the common STRP alleles present diminishing the ability of these systems to discriminate ethnicity. Recently, considerable research is being conducted on single nucleotide polymorphisms (SNPs) to be considered for human identification and description. However, online tools and databases that can be used for forensic research and investigation are limited. METHODS: The back end DBMS (Database Management System) for FROG-kb is Oracle version 10. The front end is implemented with specific code using technologies such as Java, Java Servlet, JSP, JQuery, and GoogleCharts. RESULTS: We present an open access web application, FROG-kb (Forensic Research/Reference on Genetics-knowledge base, http://frog.med.yale.edu), that is useful for teaching and research relevant to forensics and can serve as a tool facilitating forensic practice. The underlying data for FROG-kb are provided by the already extensively used and referenced ALlele FREquency Database, ALFRED (http://alfred.med.yale.edu). In addition to displaying data in an organized manner, computational tools that use the underlying allele frequencies with user-provided data are implemented in FROG-kb. These tools are organized by the different published SNP/marker panels available. This web tool currently has implemented general functions possible for two types of SNP panels, individual identification and ancestry inference, and a prediction function specific to a phenotype informative panel for eye color. CONCLUSION: The current online version of FROG-kb already provides new and useful functionality. We expect FROG-kb to grow and expand in capabilities and welcome input from the forensic community in identifying datasets and functionalities that will be most helpful and useful. Thus, the structure and functionality of FROG-kb will be revised in an ongoing process of improvement. This paper describes the state as of early June 2012. PMID- 22938151 TI - Cytotoxic lignans from fruits of Cleistanthus indochinensis: synthesis of cleistantoxin derivatives. AB - Two new aryl-tetralin lignans, 1 and 2, were isolated from the fruits of Cleistanthus indochinensis by bioassay-guided purification. Their structures were determined by spectroscopic analysis including MS and 2D NMR. The absolute configurations of 1 and 2 were established from examination of their CD spectra. Compound 1 was cytotoxic against KB cells with an IC(50) value of 0.022 MUM, while compound 2 had weaker cytotoxicity, with an IC(50) value of 1.4 MUM. When tested against other cancer cell lines (MCF-7, MCF-7R, and HT29), 1 showed an IC(50) of 0.014 against MCF-7R cells and an IC(50) of 0.036 MUM against MCF-7 cells. A series of amide derivatives of a new lactone, homoderivatives of 1, were prepared. Of these derivatives, only compound 3 had weak cytotoxicity against KB cells. PMID- 22938152 TI - Homophobia in physical education and sport: the role of physical/sporting identity and attributes, authoritarian aggression, and social dominance orientation. AB - We examined levels of, and reasons for, anti-gay and anti-lesbian prejudice (homophobia) in pre-service physical education (PE) and non-physical education (non-PE) university students. Participants (N = 409; 66% female; N = 199 pre service physical educators) completed questionnaires assessing anti-gay and lesbian prejudice, authoritarianism, social dominance orientation (SDO), physical/athletic identity and self-concept, and physical attributes. ANCOVAs revealed that PE students had higher levels of anti-gay (p = .004) and lesbian prejudice than non-PE students (p = .008), respectively. Males reported greater anti-gay prejudice (p < .001), but not anti-lesbian prejudice, than females. Authoritarian aggression was positively associated with greater anti-gay (beta = .49) and lesbian prejudice (beta = .37) among male participants. Among females, higher authoritarian aggression and SDO was associated with greater anti-gay (beta = .34 and beta = .25, respectively) and lesbian (beta = .26 and beta = .16, respectively) prejudice. The physical identity-related constructs of athletic self-concept (beta = .-15) and perceived upper body strength (beta = .39) were associated with anti-gay attitudes among male participants. Physical attractiveness (beta = -.29) and upper body strength (beta = .29) were also associated with male participants' anti-lesbian prejudice. Regression analyses showed that the differences between PE and non-PE students in anti-gay and lesbian prejudice were largely mediated by authoritarianism and SDO. The present study is the first to examine the relationship between investment in physical/sporting identity and attributes and anti-gay and lesbian prejudice in PE/sport participants. In the present sample, anti-gay and lesbian prejudice was greater in pre-service PE students than non-PE students, but these differences appear to be explained by differences in conservative ideological traits. Additionally, physical identity and athletic attributes based around masculine ideals also appear to contribute to this prejudice in males. PMID- 22938153 TI - Stochastic errors vs. modeling errors in distance based phylogenetic reconstructions. AB - BACKGROUND: Distance-based phylogenetic reconstruction methods use evolutionary distances between species in order to reconstruct the phylogenetic tree spanning them. There are many different methods for estimating distances from sequence data. These methods assume different substitution models and have different statistical properties. Since the true substitution model is typically unknown, it is important to consider the effect of model misspecification on the performance of a distance estimation method. RESULTS: This paper continues the line of research which attempts to adjust to each given set of input sequences a distance function which maximizes the expected topological accuracy of the reconstructed tree. We focus here on the effect of systematic error caused by assuming an inadequate model, but consider also the stochastic error caused by using short sequences. We introduce a theoretical framework for analyzing both sources of error based on the notion of deviation from additivity, which quantifies the contribution of model misspecification to the estimation error. We demonstrate this framework by studying the behavior of the Jukes-Cantor distance function when applied to data generated according to Kimura's two-parameter model with a transition-transversion bias. We provide both a theoretical derivation for this case, and a detailed simulation study on quartet trees. CONCLUSIONS: We demonstrate both analytically and experimentally that by deliberately assuming an oversimplified evolutionary model, it is possible to increase the topological accuracy of reconstruction. Our theoretical framework provides new insights into the mechanisms that enables statistically inconsistent reconstruction methods to outperform consistent methods. PMID- 22938154 TI - Short-term response of soil spiders to cover-crop removal in an organic olive orchard in a Mediterranean setting. AB - This study shows that disturbance caused by cover-crop removal (CCR) in an organic olive orchard affects ground-spider populations. The effect of CCR on various organic olive-orchard plots was assessed by monitoring the abundance and diversity of ground-dwelling spiders. Covered plots in the organic olive orchard were compared with uncovered plots where the covers had been removed mechanically. CCR positively affected the most abundant spider species Zodarion styliferum (Simon) (Araneae: Zodariidae) as well as other species of running spiders belonging to the families Gnaphosidae and Lycosidae. Over time, the two types of plots did not significantly differ in diversity or dominance. Similarly, no differences were detected between the study plots in terms of the distribution of individuals when a cluster-similarity analysis was performed. This lack of difference in diversity might be due to the spatial scale used in the study or climatology. Because of their general effects, CCR profoundly changed the abundance of spiders in the olive orchard, but with no clear impact on spider diversity. PMID- 22938155 TI - Identification and characterization of a kunzeaol synthase from Thapsia garganica: implications for the biosynthesis of the pharmaceutical thapsigargin. AB - Thapsigargin is a major terpenoid constituent of Thapsia garganica root. Owing to its potent antagonistic effect on the sarcoplasmic/endoplasmic reticulum Ca2+ ATPase, thapsigargin has been widely used to study Ca2+ signalling and is also a potential drug for prostate cancer. Despite its importance, thapsigargin biosynthesis in T. garganica remains unknown. In order to decipher thapsigargin biosynthesis, deep transcript sequencing (454 and Illumina) of the T. garganica root was performed, and two terpene synthases (TgTPS1/2) were identified. Functional characterization of their encoded enzymes in a metabolically engineered yeast revealed that TgTPS1 synthesized delta-cadinene, whereas TgTPS2 produced ten distinct terpenoids. However, cultivation of the TgTPS2-expressing yeast in pH-maintained conditions (pH 6-7) yielded one major oxygenated sesquiterpenoid, suggesting that formation of multiple terpenoids was caused by acidity. The major terpene product from TgTPS2 was identified as 6beta hydroxygermacra-1(10),4-diene (kunzeaol) by mass-fragmentation pattern, retention index, the nature of its acid-induced degradation and NMR. Also, recombinant TgTPS2 efficiently catalysed the synthesis of kunzeaol in vitro from farnesyl diphosphate with a Km of 2.6 MUM and a kcat of 0.03 s-1. The present paper is the first report of a kunzeaol synthase, and a mechanism for the transformation of kunzeaol into the thapsigargin backbone is proposed. PMID- 22938156 TI - Protein tyrosine phosphatases in health and disease. AB - Protein tyrosine phosphatases (PTPs) represent a super-family of enzymes that play essential roles in normal development and physiology. In this review, we will discuss the PTPs that have a causative role in hereditary diseases in humans. In addition, recent progress in the development and analysis of animal models expressing mutant PTPs will be presented. The impact of PTP signaling on health and disease will be exemplified for the fields of bone development, synaptogenesis and central nervous system diseases. Collectively, research on PTPs since the late 1980's yielded the cogent view that development of PTP directed therapeutic tools is essential to further combat human disease. PMID- 22938157 TI - Systematized epidermal nevus with epidermolytic hyperkeratosis improving with topical calcipotriol/betametasone dipropionate combination ointment. AB - We present the case of a 5-year-old boy who presented with systematized epidermal nevus with evidence of epidermolytic hyperkeratosis on skin biopsy. He was otherwise well, with normal growth and development and no evidence of other organ system involvement. He had experienced only mild improvement with potent topical corticosteroids. He reported more-marked improvement after 2 months of topical calcipotriol/betamethasone dipropionate combination ointment once a day to the lesions. Extensive epidermal nevi can lead to severe cosmetic disfigurement. We recommend a trial of topical calcipotriol/betamethasone dipropionate ointment for patients with extensive epidermal nevus not amenable to surgical treatment. PMID- 22938158 TI - Polyphyletic origin of the genus Physarum (Physarales, Myxomycetes) revealed by nuclear rDNA mini-chromosome analysis and group I intron synapomorphy. AB - BACKGROUND: Physarales represents the largest taxonomic order among the plasmodial slime molds (myxomycetes). Physarales is of particular interest since the two best-studied myxomycete species, Physarum polycephalum and Didymium iridis, belong to this order and are currently subjected to whole genome and transcriptome analyses. Here we report molecular phylogeny based on ribosomal DNA (rDNA) sequences that includes 57 Physarales isolates. RESULTS: The Physarales nuclear rDNA sequences were found to be loaded with 222 autocatalytic group I introns, which may complicate correct alignments and subsequent phylogenetic tree constructions. Phylogenetic analysis of rDNA sequences depleted of introns confirmed monophyly of the Physarales families Didymiaceae and Physaraceae. Whereas good correlation was noted between phylogeny and taxonomy among the Didymiaceae isolates, significant deviations were seen in Physaraceae. The largest genus, Physarum, was found to be polyphyletic consisting of at least three well supported clades. A synapomorphy, located at the highly conserved G binding site of L2449 group I intron ribozymes further supported the Physarum clades. CONCLUSIONS: Our results provide molecular relationship of Physarales genera, species, and isolates. This information is important in further interpretations of comparative genomics nd transcriptomics. In addition, the result supports a polyphyletic origin of the genus Physarum and calls for a reevaluation of current taxonomy. PMID- 22938159 TI - Early findings of prospective anti-HLA donor specific antibodies monitoring study in pancreas transplantation: Indiana University Health Experience. AB - The significance of donor-specific antibodies (DSA) is not well known in the setting of pancreas transplantation. Since December 2009, we prospectively followed pancreas transplant patients with single-antigen-luminex-bead testing at one, two, three, six, and then every six months for the first two yr. Thirty-five of the 92 patients that underwent pancreas transplantation (13 pancreas-alone [PTA], 20 with a kidney [SPK], and two after a kidney [PAK]) agreed to participate in study. Median age at transplant was 45 yr and follow-up was 23 months. Majority were Caucasian (n = 33) and male (n = 18). Rabbit anti-thymocyte globulin induction was used. Median HLA-mismatch was 4.2 +/- 1.1. Eight patients (7SPK, 1PAK) developed post-transplant DSA at median follow-up of 76 d (26-119), 1 SPK had pre-formed DSA. Seven patients had both class I and class II DSA, one with class I and one with class II only. Mean peak class I DSA-MFI was 3529 (+/ 1456); class II DSA-MFI was 5734 (+/-3204) whereas cumulative DSA MFI (CI + CII) was 9264 (+/-4233). No difference was observed in the patient and donor demographics among patients with and without DSA. One patient in non-DSA group developed acute cellular rejection of pancreas. From our data it appears that post-transplant DSA in pancreas allograft recipients may not impact the early pancreatic allograft outcomes. The utility of prospective DSA monitoring in pancreatic transplant patients needs further evaluation and long-term follow-up. PMID- 22938160 TI - Mapping global health research investments, time for new thinking--a Babel Fish for research data. AB - Today we have an incomplete picture of how much the world is spending on health and disease-related research and development (R&D). As such it is difficult to align, or even begin to coordinate, health R&D investments with international public health priorities. Current efforts to track and map global health research investments are complex, resource-intensive, and caveat-laden. An ideal situation would be for all research funding to be classified using a set of common standards and definitions. However, the adoption of such a standard by everyone is not a realistic, pragmatic or even necessary goal. It is time for new thinking informed by the innovations in automated online translation - e.g. Yahoo's Babel Fish. We propose a feasibility study to develop a system that can translate and map the diverse research classification systems into a common standard, allowing the targeting of scarce research investments to where they are needed most. PMID- 22938161 TI - The general public's willingness to pay for tax increases to support unrestricted access to an Alzheimer's disease medication. AB - BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative disorder highlighted by progressive declines in cognitive and functional abilities. OBJECTIVE: Our objective was to assess the general public's maximum willingness to pay ((M)WTP) for an increase in annual personal income taxes to fund unrestricted access to AD medications. METHODS: We randomly recruited 500 Canadians nationally and used computer-assisted telephone interviewing to administer a questionnaire. The questionnaire contained four 'efficacy' scenarios describing an AD medication as capable of symptomatically treating cognitive decline or modifying disease progression. The scenarios also described the medication as having no adverse effects or a 30% chance of adverse effects. We randomized participants to order of scenarios and willingness-to-pay bid values; (M)WTP for each scenario was the highest accepted bid for that scenario. We conducted linear regression and bootstrap sensitivity analyses to investigate potential determinants of (M)WTP. RESULTS: Mean (M)WTP was highest for the 'disease modification/no adverse effects' scenario ($Can130.26) and lowest for the 'symptomatic treatment/30% chance of adverse effects' scenario ($Can99.16). Bootstrap analyses indicated none of our potential determinants (e.g. age, sex) were associated with participants' (M)WTP. CONCLUSIONS: The general public is willing to pay higher income taxes to fund unrestricted access to AD (especially disease-modifying) medications. Consequently, the public should favour placing new AD medications on public drug plans. As far as we are aware, no other study has elicited the general public's willingness to pay for AD medications. PMID- 22938162 TI - Photoinduced phase transfer of luminescent quantum dots to polar and aqueous media. AB - We report a new strategy for the photomediated phase transfer of luminescent quantum dots, QDs, and potentially other inorganic nanocrystals, from hydrophobic to polar and hydrophilic media. In particular, we demonstrate that UV-irradiation (lambda < 400 nm) promotes the in situ ligand exchange on hydrophobic CdSe QDs with lipoic acid (LA)-based ligands and their facile QD transfer to polar solvents and to buffer media. This convenient method obviates the need to use highly reactive agents for chemical reduction of the dithiolane groups on the ligands. It maintains the optical and spectroscopic properties of the QDs, while providing high photoluminescence yield and robust colloidal stability in various biologically relevant conditions. Furthermore, development of this technique significantly simplifies the preparation and purification of QDs with sensitive functionalities. Application of these QDs to imaging the brain of live mice provides detailed information about the brain vasculature over the period of a few hours. This straightforward approach offers exciting possibilities for expanded functional compatibilities and reaction orthogonality on the surface of inorganic nanocrystals. PMID- 22938163 TI - Neuronal c-Abl activation leads to induction of cell cycle and interferon signaling pathways. AB - BACKGROUND: Expression of active c-Abl in adult mouse forebrain neurons in the AblPP/tTA mice resulted in severe neurodegeneration, particularly in the CA1 region of the hippocampus. Neuronal loss was preceded and accompanied by substantial microgliosis and astrocytosis. In contrast, expression of constitutively active Arg (Abl-related gene) in mouse forebrain neurons (ArgPP/tTA mice) caused no detectable neuronal loss or gliosis, although protein expression and kinase activity were at similar levels to those in the AblPP/tTA mice. METHODS: To begin to elucidate the mechanism of c-Abl-induced neuronal loss and gliosis, gene expression analysis of AblPP/tTA mouse forebrain prior to development of overt pathology was performed. Selected results from gene expression studies were validated with quantitative reverse transcription PCR , immunoblotting and bromodeoxyuridine (BrdU) labeling, and by immunocytochemistry. RESULTS: Two of the top pathways upregulated in AblPP/tTA mice with c-Abl expression for 2 weeks were cell cycle and interferon signaling. However, only the expression of interferon signaling pathway genes remained elevated at 4 weeks of c-Abl induction. BrdU incorporation studies confirm that, while the cell cycle pathway is upregulated in AblPP/tTA mice at 2 weeks of c-Abl induction, the anatomical localization of the pathway is not consistent with previous pathology seen in the AblPP/tTA mice. Increased expression and activation of STAT1, a known component of interferon signaling and interferon-induced neuronal excitotoxicity, is an early consequence of c-Abl activation in AblPP/tTA mice and occurs in the CA1 region of the hippocampus, the same region that goes on to develop severe neurodegenerative pathology and neuroinflammation. Interestingly, no upregulation of gene expression of interferons themselves was detected. CONCLUSIONS: Our data suggest that the interferon signaling pathway may play a role in the pathologic processes caused by c-Abl expression in neurons, and that the AblPP/tTA mouse may be an excellent model for studying sterile inflammation and the effects of interferon signaling in the brain. PMID- 22938165 TI - Evidence-based options for treatment-resistant adult bipolar disorder patients. AB - OBJECTIVES: Many patients diagnosed with bipolar disorder (BD) respond incompletely or unsatisfactorily to available treatments. Given the potentially devastating nature of this prevalent disorder, there is a pressing need to improve clinical care of such patients. METHODS: We performed a literature review of the research findings related to treatment-resistant BD reported through February 2012. RESULTS: Therapeutic trials for treatment-resistant bipolar mania are uncommon, and provide few promising leads other than the use of clozapine. Far more pressing challenges are the depressive-dysthymic-dysphoric-mixed phases of BD and long-term prophylaxis. Therapeutic trials for treatment-resistant bipolar depression have assessed anticonvulsants, modern antipsychotics, glutamate [N-methyl-D-aspartate (NMDA)] antagonists, dopamine agonists, calcium channel blockers, and thyroid hormones, as well as behavioral therapy, sleep deprivation, light therapy, electroconvulsive therapy (ECT), transcranial magnetic stimulation, and deep brain stimulation-all of which are promising but limited in effectiveness. Several innovative pharmacological treatments (an anticholinesterase, a glutamine antagonist, a calcium-channel blocker, triiodothyronine, olanzapine and topiramate), ECT, and cognitive-behavior therapy have some support for long-term treatment of resistant BD patients, but most of trials of these treatments have been methodologically limited. CONCLUSIONS: Most studies identified were small, involved supplementation of typically complex ongoing treatments, varied in controls, randomization, and blinding, usually involved brief follow-up, and lacked replication. Clearer criteria for defining and predicting treatment resistance in BD are needed, as well as improved trial design with better controls, assessment of specific clinical subgroups, and longer follow-up. PMID- 22938166 TI - Volumetric reductions in the subgenual anterior cingulate cortex in adolescents with bipolar I disorder. AB - OBJECTIVES: A range of prefrontal and subcortical volumetric abnormalities have been found in adults and adolescents with bipolar disorder. It is unclear, however, if these deficits are present early in the onset of mania or are a consequence of multiple mood episodes or prolonged exposure to medication. The goal of this study was to examine whether youth with bipolar I disorder who recently experienced their first episode of mania are characterized by brain volumetric abnormalities. METHODS: Anatomical images from magnetic resonance imaging of 26 13- to 18-year-old adolescents with bipolar I disorder and 24 age comparable healthy controls with no personal or family history of psychopathology were analyzed using whole-brain voxel-based morphometry (VBM). RESULTS: Compared with healthy controls, adolescents with bipolar I disorder had significantly less gray matter volume in the left subgenual cingulate cortex [p<0.05, family-wise error (FWE)-corrected]. CONCLUSIONS: Adolescents with a recent single episode of mania have smaller subgenual cingulate cortex volume than do their healthy counterparts, suggesting that this anomaly occurs early in the onset of, or may predate the disorder. Longitudinal studies are needed to examine the impact of this volumetric reduction on the course and outcome of this disorder. PMID- 22938168 TI - Mental disorders in offspring of parents with bipolar and major depressive disorders. AB - OBJECTIVES: There is limited information on the specificity of associations between parental bipolar disorder (BPD) and major depressive disorder (MDD) and the risk of psychopathology in offspring. The chief aim of the present study was to investigate the association between mood disorder subtypes in the two parents and mental disorders in the offspring. METHODS: A total of 376 offspring (aged 6.0-17.9 years; mean=11.5years) of 72 patients with BPD (139 offspring), 56 patients with MDD (110 offspring), and 66 controls (127 offspring) participated in a family study conducted in two university hospital centers in Switzerland. Probands, offspring, and biological co-parents were interviewed by psychologists blind to proband diagnoses, using a semi-structured diagnostic interview. RESULTS: Rates of mood and anxiety disorders were elevated among offspring of BPD probands (34.5% any mood; 42.5% any anxiety) and MDD probands (25.5% any mood; 44.6% any anxiety) as compared to those of controls (12.6% any mood; 22.8% any anxiety). Moreover, recurrent MDD was more frequent among offspring of BPD probands (7.9%) than those of controls (1.6%). Parental concordance for bipolar spectrum disorders was associated with a further elevation in the rates of mood disorders in offspring (64.3% both parents versus 27.2% one parent). CONCLUSIONS: These findings provide unique information on the broad manifestations of parental mood disorders in their offspring. The earlier onset and increased risk of recurrent MDD in the offspring of parents with BPD compared to those of controls suggests that the episodicity characterizing BPD may emerge in childhood and adolescence. PMID- 22938167 TI - Nicotine intake and smoking topography in smokers with bipolar disorder. AB - OBJECTIVES: Cigarette smoking behavior in bipolar disorder (BPD), including the effects of mood-stabilizing medications, has not been well characterized. METHODS: We compared serum nicotine, nicotine metabolite levels, and smoking topography in 75 smokers with BPD to 86 control smokers (CON). For some comparisons, an additional control group of 75 smokers with schizophrenia (SCZ) were included. RESULTS: There were no differences between the BPD and CON groups in baseline smoking characteristics or serum nicotine or cotinine levels. Fifty one smokers with BPD (68.9%) were taking one of the following mood stabilizers: valproic acid, lamotrigine, carbamazepine, oxcarbazepine, lithium, or topiramate. The 3-hydroxycotinine-to-cotinine ratio, a marker of cytochrome P450 2A6 (CYP2A6) metabolic activity, was significantly higher in BPD versus CON and versus SCZ (0.68 versus 0.49 versus 0.54; p =0.002). The difference between groups, however, was no longer significant when the analysis was repeated with those taking hepatic enzyme-inducing drugs (carbamazepine, oxcarbazepine, and topiramate) included as a covariate. The time between puffs, or interpuff interval (IPI), was shorter in BPD versus CON by an average of 3.0sec (p<0.05), although this was no longer significant when we removed smokers from the analysis of those taking hepatic enzyme inducers. CONCLUSIONS: Smokers with BPD are not different from CON on most measures of nicotine intake and smoking topography. We found an increased rate of nicotine metabolism in smokers taking mood stabilizers that are hepatic enzyme inducers, including carbamazepine, oxcarbazepine, and topiramate. Smokers with rapid nicotine metabolism might be expected to smoke more intensely to compensate for the more rapid disappearance of nicotine from the blood and brain, and may have more difficulty in quitting smoking, although this requires further study. PMID- 22938164 TI - How Nox2-containing NADPH oxidase affects cortical circuits in the NMDA receptor antagonist model of schizophrenia. AB - SIGNIFICANCE: Schizophrenia is a complex neuropsychiatric disorder affecting around 1% of the population worldwide. Its mode of inheritance suggests a multigenic neurodevelopmental disorder with symptoms appearing during late adolescence/early adulthood, with its onset strongly influenced by environmental stimuli. Many neurotransmitter systems, including dopamine, glutamate, and gamma aminobutyric acid, show alterations in affected individuals, and the behavioral and physiological characteristics of the disease can be mimicked by drugs that produce blockade of N-methyl-d-aspartate glutamate receptors (NMDARs). RECENT ADVANCES: Mounting evidence suggests that drugs that block NMDARs specifically impair the inhibitory capacity of parvalbumin-expressing (PV+) fast-spiking neurons in adult and developing rodents, and alterations in these inhibitory neurons is one of the most consistent findings in the schizophrenic postmortem brain. Disruption of the inhibitory capacity of PV+ inhibitory neurons will alter the functional balance between excitation and inhibition in prefrontal cortical circuits producing impairment of working memory processes such as those observed in schizophrenia. CRITICAL ISSUES: Mechanistically, the effect of NMDAR antagonists can be attributed to the activation of the Nox2-dependent reduced form of nicotinamide adenine dinucleotide phosphate oxidase pathway in cortical neurons, which is consistent with the emerging role of oxidative stress in the pathogenesis of mental disorders, specifically schizophrenia. Here we review the mechanisms by which NMDAR antagonists produce lasting impairment of the cortical PV+ neuronal system and the roles played by Nox2-dependent oxidative stress mechanisms. FUTURE DIRECTIONS: The discovery of the pathways by which oxidative stress leads to unbalanced excitation and inhibition in cortical neural circuits opens a new perspective toward understanding the biological underpinnings of schizophrenia. PMID- 22938169 TI - Sleep apnea risk and clinical correlates in patients with bipolar disorder. AB - OBJECTIVE: Despite the high prevalence of risk factors for obstructive sleep apnea (OSA) among individuals with bipolar disorder, the presence of sleep disordered breathing has not been systematically assessed in this population. In this study, we sought to determine the level of risk for OSA in a population of remitted individuals with a diagnosis of bipolar I disorder. METHODS: A total of 72 individuals with a diagnosis of bipolar I disorder, all of whom were overweight by the World Health Organization criteria, completed the Berlin Questionnaire, a self-assessment tool to establish risk for OSA. RESULTS: Over half of this study population (54.1%) was found to be in the high-risk category for OSA. Participants at high risk for OSA scored significantly higher on measures of both depression and mania, even when sleep items were not counted in the total scores. CONCLUSIONS: Sleep apnea may be prevalent in patients with bipolar I disorder. Considering the substantial overlap of symptoms between OSA and depression and the potentially harmful effects of sleep disruption in patients with mood disorders, a systematic screening to assess prevalence and associated features of OSA in patients with bipolar disorder is warranted. PMID- 22938170 TI - The prevalence of common mental disorders among hospital physicians and their association with self-reported work ability: a cross-sectional study. AB - BACKGROUND: We studied the prevalence of common mental disorders among Dutch hospital physicians and investigated whether the presence of a mental disorder was associated with insufficient self-reported work ability. METHODS: A questionnaire was sent to all (n = 958) hospital physicians of one academic medical center, using validated scales to assess burnout, work-related fatigue, stress, posttraumatic stress disorder (PTSD), anxiety and depression. Furthermore, respondents were asked to rate their current work ability against the work ability in their own best period (adapted version of the first WAI item). The prevalence of each common mental disorder was calculated. In addition, odds ratios of reporting insufficient work ability for subjects with high complaint scores compared to physicians with low complaint scores were calculated for each mental disorder. RESULTS: The response rate was 51%, and 423 questionnaires were eligible for analysis. The mental disorder prevalence rates were as follows: work-related fatigue 42%, depression 29%, anxiety 24%, posttraumatic stress complaints 15%, stress complaints 15% and burnout 6%. The mean score for self-reported work ability was 8.1 (range 0-10), and 4% of respondents rated their own work ability as insufficient. Physicians with high mental health complaints were 3.5- for fatigue, 5.6- for PTSD, 7.1- for anxiety, 9.5- for burnout, 10.8- for depression and 13.6-fold for stress more likely to report their work ability as insufficient. CONCLUSIONS: The prevalence of common mental disorders among hospital physicians varied from 6% for burnout to 42% for work-related fatigue. Those physicians with high complaints had significantly 4- to 14 times increased odds of reporting their own work ability as insufficient. This work suggests that to ensure future workers health and patients safety occupational health services should plan appropriate intervention strategies. PMID- 22938171 TI - Pure choriocarcinoma of the testis presenting with jaundice: a case report and review of the literature. AB - INTRODUCTION: Testicular cancer is the most common malignancy in men 15- to 35 years-old. The North American standard classification divides testicular cancers into germ cell tumors and non-germ cell tumors. The lymphatic spread of germ cell tumors usually involves the retroperitoneal lymph nodes. However, this spread to the retroperitoneum rarely involves the hepatic hilum. We describe an unusual case of metastatic choriocarcinoma of the testis that was clinically mimicked by a cholestatic jaundice. This is an unusual presentation of testicular cancer and, to the best of our knowledge, the first report of this kind in the literature. CASE PRESENTATION: A 28-year-old Moroccan man presented with a four-week history of progressive obstructive jaundice, and weight loss to our emergency department. Abdominal ultrasound showed a dilatation of the biliary ducts due to pathologically enlarged lymph nodes of the hepatic hilum. A complete clinical and radiologic assessment to discover the primary tumor was negative except for pulmonary metastasis. In the laboratory findings at admission there were signs of cholestasis with an abnormal increase in the rate of testicular tumor markers (serum beta-human chorionic gonadotropin level was 11,000IU/ml), which subsequently led to the suspicion of a testicular tumor. Further evaluation included testicular palpation and ultrasound which revealed a testicular nodule. The patient underwent an inguinal orchidectomy of the right testis and histopathological examination confirmed a pure choriocarcinoma. The prognosis was poor due to lymph node involvement at the hepatic hilum. He died one month later, despite general chemotherapy. CONCLUSIONS: The clinical presentation of the disease and the rarity of this entity are two remarkable characteristics described in this case report which are rarely reported in literature. PMID- 22938172 TI - Temporal dynamics of circulating persistent organic pollutants in a fasting seabird under different environmental conditions. AB - Temporal dynamics of persistent organic pollutants (POPs) were examined in fasting common eider (Somateria mollissima) females in one subarctic (68 degrees N; over 5 years) and one high arctic colony (78 degrees N; 3 years). Blood concentrations of polychlorinated biphenyl (PCB)-153; 1-dichloro-2,2-bis (p chlorophenyl) ethylene (p,p'-DDE), and hexachlorobenzene (HCB) were measured twice each season in eider females (total n = 162) during incubation (at day 5 and day 20). The mean wet weight concentrations of PCB-153 were ~3-5 times higher in the subarctic colony, whereas p,p'-DDE and HCB concentrations tended to be higher in high arctic than in subarctic eiders late in the incubation period. All POPs increased during incubation fast, but the relative increase in mean concentration varied more among years in high arctic than in subarctic eiders. In the high arctic, both lipid-metabolism and the increase in circulating POP concentrations were highest in the year when the mean ambient temperature was lowest. Moreover, females with low body condition and high lipid metabolism (body mass loss) had stronger increase in circulating concentrations of p,p'-DDE and HCB; the effect size being within the same order of magnitude in the two colonies. Hence, since eiders at high latitudes metabolized relatively more lipids, they experienced higher exposure of p,p'-DDE and HCB over the incubation period than birds inhabiting the more benign subarctic region. PMID- 22938173 TI - Engineering mechanosensitive multivalent receptor-ligand interactions: why the nanolinker regions of bacterial adhesins matter. AB - Inspired by bacterial adhesins, we present a promising strategy of how to engineer peptides to probe various mechanical strains of extracellular matrix fibers. Functional sequence alignment of bacterial adhesins reveals that the bacterial linkers connecting the multivalent binding motifs recognizing fibronectin show considerable heterogeneity in length. Their length regulates the tunable affinities for fibronectin fibrils when stretched into different mechanical strain states. This platform has potential applications in probing extracellular matrix fiber strains in tissues. PMID- 22938174 TI - Implementing a "quality by design" approach to assure the safety and integrity of botanical dietary supplements. AB - Natural products have provided a basis for health care and medicine to humankind since the beginning of civilization. According to the World Health Organization (WHO), approximately 80% of the world population still relies on herbal medicines for health-related benefits. In the United States, over 42% of the population claimed to have used botanical dietary supplements to either augment their current diet or to "treat" or "prevent" a particular health-related issue. This has led to the development of a burgeoning industry in the U.S. ($4.8 billion per year in 2008) to supply dietary supplements to the consumer. However, many commercial botanical products are poorly defined scientifically, and the consumer must take it on faith that the supplement they are ingesting is an accurate representation of what is listed on the label, and that it contains the purportedly "active" constituents they seek. Many dietary supplement manufacturers, academic research groups, and governmental organizations are progressively attempting to construct a better scientific understanding of natural products, herbals, and botanical dietary supplements that have co-evolved with Western-style pharmaceutical medicines. However, a deficiency of knowledge is still evident, and this issue needs to be addressed in order to achieve a significant level of safety, efficacy, and quality for commercial natural products. The authors contend that a "quality by design" approach for botanical dietary supplements should be implemented in order to ensure the safety and integrity of these products. Initiating this approach with the authentication of the starting plant material is an essential first step, and in this review several techniques that can aid in this endeavor are outlined. PMID- 22938175 TI - Sequencing and analysis of the gastrula transcriptome of the brittle star Ophiocoma wendtii. AB - BACKGROUND: The gastrula stage represents the point in development at which the three primary germ layers diverge. At this point the gene regulatory networks that specify the germ layers are established and the genes that define the differentiated states of the tissues have begun to be activated. These networks have been well-characterized in sea urchins, but not in other echinoderms. Embryos of the brittle star Ophiocoma wendtii share a number of developmental features with sea urchin embryos, including the ingression of mesenchyme cells that give rise to an embryonic skeleton. Notable differences are that no micromeres are formed during cleavage divisions and no pigment cells are formed during development to the pluteus larval stage. More subtle changes in timing of developmental events also occur. To explore the molecular basis for the similarities and differences between these two echinoderms, we have sequenced and characterized the gastrula transcriptome of O. wendtii. METHODS: Development of Ophiocoma wendtii embryos was characterized and RNA was isolated from the gastrula stage. A transcriptome data base was generated from this RNA and was analyzed using a variety of methods to identify transcripts expressed and to compare those transcripts to those expressed at the gastrula stage in other organisms. RESULTS: Using existing databases, we identified brittle star transcripts that correspond to 3,385 genes, including 1,863 genes shared with the sea urchin Strongylocentrotus purpuratus gastrula transcriptome. We characterized the functional classes of genes present in the transcriptome and compared them to those found in this sea urchin. We then examined those members of the germ-layer specific gene regulatory networks (GRNs) of S. purpuratus that are expressed in the O. wendtii gastrula. Our results indicate that there is a shared 'genetic toolkit' central to the echinoderm gastrula, a key stage in embryonic development, though there are also differences that reflect changes in developmental processes. CONCLUSIONS: The brittle star expresses genes representing all functional classes at the gastrula stage. Brittle stars and sea urchins have comparable numbers of each class of genes and share many of the genes expressed at gastrulation. Examination of the brittle star genes in which sea urchin orthologs are utilized in germ layer specification reveals a relatively higher level of conservation of key regulatory components compared to the overall transcriptome. We also identify genes that were either lost or whose temporal expression has diverged from that of sea urchins. PMID- 22938176 TI - Effect of statin therapy on the progression of coronary atherosclerosis. AB - BACKGROUND: An increasing number of authors employing intravascular ultrasound (IVUS) and virtual histology (VH-IVUS) have investigated the effect of statin use on plaque volume (PV) and plaque composition. However, inconsistent results have been reported. Therefore, we conducted a meta-analysis to determine the appropriate regimen of statins to effectively stabilize vulnerable coronary plaques. METHODS: Online electronic databases were carefully searched for all relevant studies. We compared mean values of PV and plaque composition between baseline and follow-up in patients receiving statin therapy. We pooled treatment effects and calculated mean differences (MD) with the 95% confidence interval (CI) using a random-effects model. By stratified analyses, we explored the influence of clinical presentation, dose and duration of statin treatment, and low-density lipoprotein-cholesterol (LDL-C) levels on the effects of statins. RESULTS: Seventeen studies involving 2,171 patients were analyzed. Statin therapy significantly decreased PV (-5.3 mm(3); 95% CI: -3.3 mm(3) to -7.2 mm(3) P < 0.001), without heterogeneity. When considering the dose and duration of statins used, only subgroups employing a high dose and long duration demonstrated a significant reduction in PV (p < 0.001). A significant decrease in PV was noted if achieved LDL-C levels were <100 mg/dL (p < 0.001). Statin treatment could induce a twofold decrease in PV in patients with acute coronary syndrome (ACS) compared with that observed in patients with stable angina pectoris (SAP). A regressive trend was seen for necrotic core volume (MD: -2.1 mm(3); 95% CI: -4.7 mm(3) to 0.5 mm(3), P = 0.11). However, statin use did not induce a significant change for fibrotic, fibro-fatty, or dense calcium compositions. CONCLUSIONS: Our meta-analysis demonstrated that statin therapy (especially that involving a high dose and long duration and achieving <100 mg/dL LDL-C levels) can significantly decrease PV in patients with SAP or ACS. These data suggested that statins can be used to reduce the atheroma burden for secondary prevention by appropriately selecting the statin regimen. No significant change in plaque composition was seen after statin therapy. PMID- 22938177 TI - Determination of trimethylamine in spinach, cabbage, and lettuce at alkaline pH by headspace solid-phase microextraction. AB - Trimethylamine (TMA) found in some leafy vegetables, such as spinach, cabbage, and lettuce, at alkaline pH was identified and quantified using headspace solid phase microextraction and gas chromatography-mass spectrometry (HS-SPME and GC MS). HS-SPME conditions were optimized at an adsorption temperature of 50 degrees C, equilibration time of 5 min, and adsorption time of 5 min with 65 MUm of polydimethylsiloxane/divinylbenzene fiber. The TMA that was formed from spinach, cabbage, and lettuce was assayed at pH 7 to 11 for 0 to 4 h at 50 degrees C using HS-SPME. The results showed that the amount of TMA formed was dependent on pH. The amount of TMA formed increased dramatically at a pH greater than 9. TMA was not formed at a pH lower than 7. Spinach produced a higher amount of TMA than cabbage or lettuce. TMA was formed at alkaline pH from choline, betaine, and carnitine, which are TMA precursors. To confirm the SPME results, TMA was quantitated using the AOAC official method. Data obtained from chemical analysis were in good agreement with the SPME data. The formation mechanism of TMA is thought to be the Hofmann elimination reaction, which generates amine compounds at alkaline pH. PRACTICAL APPLICATION: Fishy off-flavor in foods is associated with trimethylamine (TMA), which is frequently found in fish and seafood. In this study, TMA was identified for the first time in some leafy vegetables, such as spinach, cabbage, and lettuce, at alkaline pH. The presence of TMA in leafy vegetables under certain circumstances such as high pH and temperature may affect the sensory properties of foods containing these vegetables. PMID- 22938178 TI - Bowel perforation secondary to illegally induced abortion: a tertiary hospital experience in Tanzania. AB - BACKGROUND: Bowel perforation though rarely reported is a serious complication of induced abortion, which is often performed illegally by persons without any medical training in developing countries. A sudden increase in the number of patients in our centre in recent years prompted the authors to analyze this problem. The study was conducted to describe our own experiences in the surgical management of these patients. METHODS: This was a retrospective study involving patients who were jointly managed by the surgical and gynecological teams at Bugando Medical Centre (BMC) for bowel perforation secondary to illegally induced abortion from January 2002 to December 2011. The statistical analysis was performed using SPSS version 17.0. RESULTS: A total of 68 patients (representing 4.2% of cases) were enrolled in the study. Their ages ranged from 14 to 45 years with a median age of 21 years. Majority of patients were, secondary school students/leavers (70.6%), unmarried (88.2%), nulliparous (80.9%), unemployed (82.4%) and most of them were dependent member of the family. Previous history of contraceptive use was reported in only 14.7% of cases. The majority of patients (79.4%) had procured the abortion in the 2nd trimester. Dilatation and curettage (82.4%) was the most common reported method used in procuring abortion. The interval from termination of pregnancy to presentation in hospital ranged from 1 to 14 days (median 6 days ). The ileum (51.5%) and sigmoid colon (22.1%) was the most common portions of the bowel affected. Resection and anastomosis with uterine repair was the most common (86.8%) surgical procedure performed. Complication and mortality rates were 47.1% and 10.3% respectively. According to multivariate logistic regression analysis, gestational age at termination of pregnancy, delayed presentation, delayed surgical treatment and presence of complications were significantly associated with mortality (P<0.001). The overall median length of hospital stay (LOS) was 18 days (1day to 128 days ). Patients who developed complications stayed longer in the hospital, and this was statistically significant (P=0.012). CONCLUSION: Bowel perforation following illegally induced abortion is still rampant in our environment and constitutes significantly to high maternal morbidity and mortality. Early recognition of the diagnosis, aggressive resuscitation and early institution of surgical management is of paramount importance if morbidity and mortality associated with bowel perforation are to be avoided. PMID- 22938180 TI - Estimated time limit: a brief review of a perceptually based scale. AB - The ability to predict performance is of great interest for athletes and coaches. It is helpful for the selection of athletes to a team, the prescription of individualized training and the determination of the optimal pacing strategy. However, it is often difficult to judge the time to exhaustion without maximal exercise testing, which is often difficult to schedule during a competitive season. Consequently, the purpose of this review is to present a recent tool based on subjective prediction of time to exhaustion than can be achieved without requiring a maximal effort. This tool is the estimated time limit (ETL) scale. This review summarizes all experimentations that have studied the ETL scale. These studies suggest that the ETL scale may be used to predict time to exhaustion. PMID- 22938179 TI - Reconstructing differentially co-expressed gene modules and regulatory networks of soybean cells. AB - BACKGROUND: Current experimental evidence indicates that functionally related genes show coordinated expression in order to perform their cellular functions. In this way, the cell transcriptional machinery can respond optimally to internal or external stimuli. This provides a research opportunity to identify and study co-expressed gene modules whose transcription is controlled by shared gene regulatory networks. RESULTS: We developed and integrated a set of computational methods of differential gene expression analysis, gene clustering, gene network inference, gene function prediction, and DNA motif identification to automatically identify differentially co-expressed gene modules, reconstruct their regulatory networks, and validate their correctness. We tested the methods using microarray data derived from soybean cells grown under various stress conditions. Our methods were able to identify 42 coherent gene modules within which average gene expression correlation coefficients are greater than 0.8 and reconstruct their putative regulatory networks. A total of 32 modules and their regulatory networks were further validated by the coherence of predicted gene functions and the consistency of putative transcription factor binding motifs. Approximately half of the 32 modules were partially supported by the literature, which demonstrates that the bioinformatic methods used can help elucidate the molecular responses of soybean cells upon various environmental stresses. CONCLUSIONS: The bioinformatics methods and genome-wide data sources for gene expression, clustering, regulation, and function analysis were integrated seamlessly into one modular protocol to systematically analyze and infer modules and networks from only differential expression genes in soybean cells grown under stress conditions. Our approach appears to effectively reduce the complexity of the problem, and is sufficiently robust and accurate to generate a rather complete and detailed view of putative soybean gene transcription logic potentially underlying the responses to the various environmental challenges. The same automated method can also be applied to reconstruct differentially co expressed gene modules and their regulatory networks from gene expression data of any other transcriptome. PMID- 22938181 TI - An infant with human parechovirus type 3 infection with a distinctive rash on the extremities. AB - Human parechovirus type 3 (HPeV3) is known to cause sepsis-like syndrome and meningoencephalitis in neonates and young infants. We herein report a neonatal case of sepsis-like syndrome due to HPeV3 infection, diagnosed using polymerase chain reaction (PCR), with a distinctive erythematous rash present mainly on the soles and palms that helped in the diagnosis of the disease. Combining the unique characteristics of rash and confirmation by PCR at the early stage of the disease led to the diagnosis of HPeV3, distinguishing it from sepsis and other critical disease conditions, and allowing for appropriate, rapid management. PMID- 22938182 TI - Measuring infertility in populations: constructing a standard definition for use with demographic and reproductive health surveys. AB - BACKGROUND: Infertility is a significant disability, yet there are no reliable estimates of its global prevalence. Studies on infertility prevalence define the condition inconsistently, rendering the comparison of studies or quantitative summaries of the literature difficult. This study analyzed key components of infertility to develop a definition that can be consistently applied to globally available household survey data. METHODS: We proposed a standard definition of infertility and used it to generate prevalence estimates using 53 Demographic and Health Surveys (DHS). The analysis was restricted to the subset of DHS that contained detailed fertility information collected through the reproductive health calendar. We performed sensitivity analyses for key components of the definition and used these to inform our recommendations for each element of the definition. RESULTS: Exposure type (couple status, contraceptive use, and intent), exposure time, and outcomes were key elements of the definition that we proposed. Our definition produced estimates that ranged from 0.6% to 3.4% for primary infertility and 8.7% to 32.6% for secondary infertility. Our sensitivity analyses showed that using an exposure measure of five years is less likely to misclassify fertile unions as infertile. Additionally, using a current, rather than continuous, measure of contraceptive use over five years resulted in a median relative error in secondary infertility of 20.7% (interquartile range of relative error [IQR]: 12.6%-26.9%), while not incorporating intent produced a corresponding error in secondary infertility of 58.2% (IQR: 44.3%-67.9%). CONCLUSIONS: In order to estimate the global burden of infertility, prevalence estimates using a consistent definition need to be generated. Our analysis provided a recommended definition that could be applied to widely available global household data. We also summarized potential biases that should be considered when making estimates of infertility prevalence using household survey data. PMID- 22938184 TI - Beneficial pharmacological effects of levosimendan on antioxidant status of acute inflammation induced in paw of rat: involvement in inflammatory mediators. AB - Levosimendan (LEVO) is a new calcium sensitizer with positive inotropic and vasodilating properties that represents a new pharmacological class of inotropic drugs that stimulate elevated cardiac output. The purpose of this study was to examine anti-inflammatory effect and antioxidant activity of LEVO in a carrageenan (CAR)-induced inflammatory paw oedema rat model. The CAR-induced rat groups received LEVO 1, 2 and 3 mg/kg by intraperitonally and indomethacin (IND) 25 mg/kg by oral gavage. LEVO inhibited CAR-induced paw oedema and suppressed the production of TNF-alpha, IL-1 and IL-6 at doses of 2 and 3 mg/kg. In contrast to CAR-injected paws, 2 and 3 mg/kg doses of LEVO and IND increased superoxide dismutase (SOD) activity and also both doses of LEVO, and IND decreased the 8 isoprostaglandin F2alpha (8-ISO) level. A 2 mg/kg dose of LEVO produced 39%, 46%, 61% and 64.7% anti-inflammatory effects (p < 0.0001) for the 1st, 2nd, 3rd and 4th hours, respectively. Other results of our current study have shown that SOD and glutathione for CAR-injected groups were lower, and 8-ISO level was higher than those for the healthy rat group. LEVO may be provided as a pharmacological agent in the prevention or treatment of diseases in which acute or chronic inflammation occurs based on a pathogenic factor. PMID- 22938183 TI - Insecticidal effect of labramin, a lectin-like protein isolated from seeds of the beach apricot tree, Labramia bojeri, on the Mediterranean flour moth, Ephestia kuehniella. AB - The objective of this work was to study the insecticidal effect of labramin, a protein that shows lectin-like properties. Labramin was isolated from seeds of the Beach Apricot tree, Labramia bojeri A. DC ex Dubard (Ericales: Sapotaceae), and assessed against the development of the Mediterranean flour moth Ephestia kuehniella Zeller (Lepidoptera: Pyralidae), an important pest of stored products such as corn, wheat, rice, and flour. Results showed that labramin caused 90% larval mortality when incorporated in an artificial diet at a level of 1% (w/w). The presence of 0.25% labramin in the diet affected the larval and pupal developmental periods and the percentage of emerging adults. Treatments resulted in elevated levels of trypsin activity in midgut and fecal materials, indicating that labramin may have affected enzyme-regulatory mechanisms by perturbing peritrophic membranes in the midgut of is. kuehniella larvae. The results of dietary experiments with E. kuehniella larvae showed a reduced efficiency for the conversion of ingested and digested food, and an increase in approximate digestibility and metabolic cost. These findings suggest that labramin may hold promise as a control agent to engineer crop plants for insect resistance. PMID- 22938185 TI - Individualized, discrete event, simulations provide insight into inter- and intra subject variability of extended-release, drug products. AB - OBJECTIVE: Develop and validate particular, concrete, and abstract yet plausible in silico mechanistic explanations for large intra- and interindividual variability observed for eleven bioequivalence study participants. Do so in the face of considerable uncertainty about mechanisms. METHODS: We constructed an object-oriented, discrete event model called subject (we use small caps to distinguish computational objects from their biological counterparts). It maps abstractly to a dissolution test system and study subject to whom product was administered orally. A subject comprises four interconnected grid spaces and event mechanisms that map to different physiological features and processes. Drugs move within and between spaces. We followed an established, Iterative Refinement Protocol. Individualized mechanisms were made sufficiently complicated to achieve prespecified Similarity Criteria, but no more so. Within subjects, the dissolution space is linked to both a product-subject Interaction Space and the GI tract. The GI tract and Interaction Space connect to plasma, from which drug is eliminated. RESULTS: We discovered parameterizations that enabled the eleven subject simulation results to achieve the most stringent Similarity Criteria. Simulated profiles closely resembled those with normal, odd, and double peaks. We observed important subject-by-formulation interactions within subjects. CONCLUSION: We hypothesize that there were interactions within bioequivalence study participants corresponding to the subject-by-formulation interactions within subjects. Further progress requires methods to transition currently abstract subject mechanisms iteratively and parsimoniously to be more physiologically realistic. As that objective is achieved, the approach presented is expected to become beneficial to drug development (e.g., controlled release) and to a reduction in the number of subjects needed per study plus faster regulatory review. PMID- 22938186 TI - Endoplasmic Reticulum stress induces hepatic stellate cell apoptosis and contributes to fibrosis resolution. AB - BACKGROUND: Survival of hepatic stellate cells (HSCs) is a hallmark of liver fibrosis, while the induction of HSC apoptosis may induce recovery. Activated HSC are resistant to many pro-apoptotic stimuli. To this issue, the role of Endoplasmic Reticulum (ER) stress in promoting apoptosis of HSCs and consequently fibrosis resolution is still debated. AIM: To evaluate the potential ER stress mediated apoptosis of HSCs and fibrosis resolution METHODS: HSCs were incubated with the ER stress agonists, tunicamycin or thapsigargin. In vivo, HSC were isolated from normal, bile duct-ligated (BDL) and bile duct-diverted (BDD) rats. RESULTS: In activated HSC, the specific inhibitor of ER stress-induced apoptosis, calpastatin, is significantly increased vs. quiescent HSCs. Calpain is conversely reduced in activated HSCs. This pattern of protein expression provides HSCs resistance to the ER stress signals of apoptosis (apoptosis-resistant phenotype). However, both tunicamycin and thapsigargin are able to induce apoptosis in HSCs in vitro, completely reversing the calpain/calpastatin pattern expression. Furthermore, in vivo, the fibrosis resolution observed in rat livers subjected to bile duct ligation (BDL) and subsequent bile duct diversion (BDD), leads to fibrosis resolution through a mechanism of HSCs apoptosis, potentially associated with ER stress: in fact, BDD rat liver shows an increased number of apoptotic HSCs associated with reduced calapstatin and increased calpain protein expression, leading to an apoptosis-sensible phenotype. CONCLUSIONS: ER stress sensitizes HSC to apoptosis both in vitro and in vivo. Thus, ER stress represents a key target to trigger cell death in activated HSC and promotes fibrosis resolution. PMID- 22938188 TI - Umbilical cord graft-versus-leukemia effect induces remission without the price of graft-versus-host disease: the possible role of NK cells. PMID- 22938187 TI - Rhodium-phosphoramidite catalyzed alkene hydroacylation: mechanism and octaketide natural product synthesis. AB - We describe a method that allows salicylaldehyde derivatives to be coupled with a wide range of unactivated alkenes at catalyst loadings as low as 2 mol %. A chiral phosphoramidite ligand and the precise stoichiometry of heterogeneous base are key for high catalytic activity and linear regioselectivity. This protocol was applied in the atom- and step-economical synthesis of eight biologically active octaketide natural products, including anticancer drug candidate cytosporone B. Mechanistic studies provide insight on parameters affecting decarbonylation, a side reaction that limits the turnover number for catalytic hydroacylation. Deuterium labeling studies show that branched hydride insertion is fully reversible, whereas linear hydride insertion is largely irreversible and turnover-limiting. We propose that ligand (R(a),R,R)-SIPHOS-PE effectively suppresses decarbonylation, and helps favor a turnover-limiting insertion, by lowering the barrier for reductive elimination in the linear-selective pathway. Together, these factors enable high reactivity and regioselectivity. PMID- 22938189 TI - Maintenance of implant hybrid prostheses: clinical and laboratory procedures. AB - Fixed implant hybrid prostheses have been used for the last 40+ years in the treatment of edentulous patients. These prostheses have provided long-term masticatory function for thousands of patients. The original treatment protocol included fabrication of cast metal frameworks that fit accurately on the restorative platforms or abutments and/or endosseous implants. Frameworks were designed to splint implants together; they also provided retention and support for the functional and esthetic portions of the fixed hybrid prostheses. Initially, edentulous patients were treated with maxillary complete dentures and mandibular fixed, hybrid prostheses. Denture teeth were used in both prostheses. Over the span of many years, occlusal surfaces of the denture teeth in the mandibular prostheses exhibited signs of occlusal abrasion and wear, sometimes completely abrading the teeth and denture bases, resulting in framework exposures. Ultimately, this resulted in decreased chewing efficiency and loss of vertical facial height. Patients would then return to clinicians and ask for retreatment. In certain instances, the underlying frameworks would have to be remade. This involved replicating the original series of appointments and significant additional expense to patients and clinicians alike. The protocol presented in this article avoids having to remake the most expensive portion of fixed implant prostheses--the frameworks. The protocol identifies the clinical and laboratory procedures involved in using existing frameworks and replacing preexisting denture bases and denture teeth, with minimal inconvenience to patients. PMID- 22938190 TI - Evaluating life-history strategies of reef corals from species traits. AB - Classifying the biological traits of organisms can test conceptual frameworks of life-history strategies and allow for predictions of how different species may respond to environmental disturbances. We apply a trait-based classification approach to a complex and threatened group of species, scleractinian corals. Using hierarchical clustering and random forests analyses, we identify up to four life-history strategies that appear globally consistent across 143 species of reef corals: competitive, weedy, stress-tolerant and generalist taxa, which are primarily separated by colony morphology, growth rate and reproductive mode. Documented shifts towards stress-tolerant, generalist and weedy species in coral reef communities are consistent with the expected responses of these life-history strategies. Our quantitative trait-based approach to classifying life-history strategies is objective, applicable to any taxa and a powerful tool that can be used to evaluate theories of community ecology and predict the impact of environmental and anthropogenic stressors on species assemblages. PMID- 22938191 TI - Systemic dissemination of chronic necrotizing pulmonary aspergillosis in an elderly woman without comorbidity: a case report. AB - INTRODUCTION: Chronic necrotizing pulmonary aspergillosis usually occurs in mildly immune-compromised hosts or those with underlying pulmonary disease. The radiographic pattern of chronic necrotizing pulmonary aspergillosis is typically a progressive upper lobe cavitary infiltrate with pleural thickening. We report here an atypical case of chronic necrotizing pulmonary aspergillosis mimicking lung cancer, which developed into a disseminated fatal disease in an older woman with no comorbidity. CASE PRESENTATION: An 80-year-old Japanese woman was referred to our hospital for a chest roentgenogram abnormality. Repeated fiber optic bronchoscopy could not confirm any definite diagnosis, and she refused further examinations. Considering the roentgenogram findings and her age, she was followed-up as a suspected case of lung cancer without any treatment. Then, 10 months later, she complained of visual disturbance and was admitted to our department of ophthalmology. She was diagnosed as having endophthalmitis. After treatment with corticosteroids for 20 days, she developed acute encephalitis and died four weeks later. Autopsy revealed dissemination of Aspergillus hyphae throughout her body, including her brain. CONCLUSIONS: In older patients, even if they do not have any comorbidity, chronic necrotizing pulmonary aspergillosis should be added to the differential diagnosis of solitary pulmonary lesions in a chest roentgenogram. PMID- 22938192 TI - Fe5C2 nanoparticles: a facile bromide-induced synthesis and as an active phase for Fischer-Tropsch synthesis. AB - Iron carbide nanoparticles have long been considered to have great potential in new energy conversion, nanomagnets, and nanomedicines. However, the conventional relatively harsh synthetic conditions of iron carbide hindered its wide applications. In this article, we present a facile wet-chemical route for the synthesis of Hagg iron carbide (Fe(5)C(2)) nanoparticles, in which bromide was found to be the key inducing agent for the conversion of Fe(CO)(5) to Fe(5)C(2) in the synthetic process. Furthermore, the as-synthesized Fe(5)C(2) nanoparticles were applied in the Fischer-Tropsch synthesis (FTS) and exhibited intrinsic catalytic activity in FTS, demonstrating that Fe(5)C(2) is an active phase for FTS. Compared with a conventional reduced-hematite catalyst, the Fe(5)C(2) nanoparticles showed enhanced catalytic performance in terms of CO conversion and product selectivity. PMID- 22938193 TI - Psychometric properties of the Patient Assessment Of Chronic Illness Care measure: acceptability, reliability and validity in United Kingdom patients with long-term conditions. AB - BACKGROUND: The Patient Assessment of Chronic Illness Care (PACIC) is a US measure of chronic illness quality of care, based on the influential Chronic Care Model (CCM). It measures a number of aspects of care, including patient activation; delivery system design and decision support; goal setting and tailoring; problem-solving and contextual counselling; follow-up and coordination. Although there is developing evidence of the utility of the scale, there is little evidence about its performance in the United Kingdom (UK). We present preliminary data on the psychometric performance of the PACIC in a large sample of UK patients with long-term conditions. METHOD: We collected PACIC, demographic, clinical and quality of care data from patients with long-term conditions across 38 general practices, as part of a wider longitudinal study. We assess rates of missing data, present descriptive and distributional data, assess internal consistency, and test validity through confirmatory factor analysis, and through associations between PACIC scores, patient characteristics and related measures. RESULTS: There was evidence that rates of missing data were high on PACIC (9.6% - 15.9%), and higher than on other scales used in the same survey. Most PACIC sub-scales showed reasonable levels of internal consistency (alpha = 0.68 - 0.94), responses did not demonstrate high skewness levels, and floor effects were more frequent (up to 30.4% on the follow up and co-ordination subscale) than ceiling effects (generally <5%). PACIC demonstrated preliminary evidence of validity in terms of measures of long-term condition care. Confirmatory factor analysis suggested that the five factor PACIC structure proposed by the scale developers did not fit the data: reporting separate factor scores may not always be appropriate. CONCLUSION: The importance of improving care for long-term conditions means that the development and validation of measures is a priority. The PACIC scale has demonstrated potential utility in this regard, but further assessment is required to assess low levels of completion of the scale, and to explore the performance of the scale in predicting outcomes and assessing the effects of interventions. PMID- 22938195 TI - Physical characteristics of experienced and junior open-wheel car drivers. AB - Despite the popularity of open-wheel car racing, scientific literature about the physical characteristics of competitive race car drivers is scarce. The purpose of this study was to compare selected fitness parameters of experienced and junior open-wheel race car drivers. The experienced drivers consisted of five Formula One, two GP2 and two Formula 3 drivers, and the nine junior drivers drove in the Formula Master, Koenig, BMW and Renault series. The following fitness parameters were tested: multiple reactions, multiple anticipation, postural stability, isometric upper body strength, isometric leg extension strength, isometric grip strength, cyclic foot speed and jump height. The group differences were calculated using the Mann-Whitney U-test. Because of the multiple testing strategy used, the statistical significance was Bonferroni corrected and set at P < 0.004. Significant differences between the experienced and junior drivers were found only for the jump height parameter (P = 0.002). The experienced drivers tended to perform better in leg strength (P = 0.009), cyclic foot speed (P = 0.024) and grip strength (P = 0.058). None of the other variables differed between the groups. The results suggested that the experienced drivers were significantly more powerful than the junior drivers: they tended to be quicker and stronger (18% to 25%) but without statistical significance. The experienced drivers demonstrated excellent strength and power compared with other high performance athletes. PMID- 22938196 TI - A fond farewell and grateful tribute to Christine A. Tanner, PhD, RN, FAAN. PMID- 22938197 TI - Rescuing the student presentation with Pecha Kucha. PMID- 22938198 TI - High structure sensitivity of vapor-phase furfural decarbonylation/hydrogenation reaction network as a function of size and shape of Pt nanoparticles. AB - Vapor-phase transformations of furfural in H(2) over a series of Pt nanoparticles (NPs) with various particle sizes (1.5-7.1 nm size range) and shapes (rounded, cubes, octahedra) encapsulated in poly(vinylpyrrolidone) (PVP) and dispersed on MCF-17 mesoporous silica were investigated at ambient pressure in the 443-513 K temperature range. Furan and furfuryl alcohol (FFA) were two primary products as a result of furfural decarbonylation and hydrogenation reactions, respectively. Under conditions of the study both reactions exhibited structure sensitivity evidenced by changes in product selectivities, turnover rates (TORs), and apparent activation energies (E(A)'s) with Pt particle size and shape. For instance, upon an increase in Pt particle size from 1.5 to 7.1 nm, the selectivity toward FFA increases from 1% to 66%, the TOR of FFA production increases from 1 * 10(-3) s(-1) to 7.6 * 10(-2) s(-1), and E(A) decreases from 104 kJ mol(-1) to 15 kJ mol(-1) (9.3 kPa furfural, 93 kPa H(2), 473 K). Conversely, under the same experimental conditions the decarbonylation reaction path is enhanced over smaller nanoparticles. The smallest NPs (1.5 nm) produced the highest selectivity (96%) and highest TOR values (8.8 * 10(-2) s(-1)) toward furan formation. The E(A) values for decarbonylation (~62 kJ mol(-1)) was Pt particle size independent. Furan was further converted to propylene via a decarbonylation reaction, but also to dihydrofuran, tetrahydrofuran, and n butanol in secondary reactions. Furfuryl alcohol was converted to mostly to 2 methylfuran. PMID- 22938194 TI - Navigating the fungal polyketide chemical space: from genes to molecules. AB - The iterative type I polyketide synthases (IPKSs) are central to the biosynthesis of an enormously diverse array of natural products in fungi. These natural products, known as polyketides, exhibit a wide range of biological activities and include clinically important drugs as well as undesirable toxins. The PKSs synthesize these structurally diverse polyketides via a series of decarboxylative condensations of malonyl-CoA extender units and beta-keto modifications in a highly programmed manner. Significant progress has been made over the past few years in understanding the biosynthetic mechanism and programming of fungal PKSs. The continuously expanding fungal genome sequence data have sparked genome directed discoveries of new fungal PKSs and associated products. The increasing number of fungal PKSs that have been linked to their products along with in-depth biochemical and structural characterizations of these large enzymes have remarkably improved our knowledge on the molecular basis for polyketide structural diversity in fungi. This Perspective highlights the recent advances and examines how the newly expanded paradigm has contributed to our ability to link fungal PKS genes to chemical structures and vice versa. The knowledge will help us navigate through the logarithmically expanding seas of genomic information for polyketide compound discovery and provided opportunities to reprogram these megasynthases to generate new chemical entities. PMID- 22938200 TI - The relationship between ventricular dilatation, neuropathological and neurobehavioural changes in hydrocephalic rats. AB - BACKGROUND: The motor and cognitive deficits observed in hydrocephalus are thought to be due to axonal damage within the periventricular white matter. This study was carried out to investigate the relationship between ventricular size, cellular changes in brain, and neurobehavioural deficits in rats with experimental hydrocephalus. METHODS: Hydrocephalus was induced in three-week old rats by intracisternal injection of kaolin. Behavioural and motor function were tested four weeks after hydrocephalus induction and correlated to ventricular enlargement which was classified into mild, moderate or severe. Gross brain morphology, routine histology and immunohistochemistry for oligodendrocytes (CNPase), microglia (Iba-1) and astrocytes (GFAP) were performed to assess the cellular changes. RESULTS: Decreases in open field activity and forelimb grip strength in hydrocephalus correlated with the degree of ventriculomegaly. Learning in Morris water maze was significantly impaired in hydrocephalic rats. Gradual stretching of the ependymal layer, thinning of the corpus callosum, extracellular oedema and reduced cortical thickness were observed as the degree of ventriculomegaly increased. A gradual loss of oligodendrocytes in the corpus callosum and cerebral cortex was most marked in the severely-hydrocephalic brains, whereas the widespread astrogliosis especially in the subependymal layer was most marked in the brains with mild hydrocephalus. Retraction of microglial processes and increase in Iba-1 immunoreactivity in the white matter was associated ventriculomegaly. CONCLUSIONS: In hydrocephalic rats, oligodendrocyte loss, microglia activation, astrogliosis in cortical areas and thinning of the corpus callosum were associated with ventriculomegaly. The degree of ventriculomegaly correlated with motor and cognitive deficits. PMID- 22938201 TI - Rescue of nonsense mutations by amlexanox in human cells. AB - BACKGROUND: Nonsense mutations are at the origin of many cancers and inherited genetic diseases. The consequence of nonsense mutations is often the absence of mutant gene expression due to the activation of an mRNA surveillance mechanism called nonsense-mediated mRNA decay (NMD). Strategies to rescue the expression of nonsense-containing mRNAs have been developed such as NMD inhibition or nonsense mutation readthrough. METHODS: Using a dedicated screening system, we sought molecules capable to block NMD. Additionally, 3 cell lines derived from patient cells and harboring a nonsense mutation were used to study the effect of the selected molecule on the level of nonsense-containing mRNAs and the synthesis of proteins from these mutant mRNAs. RESULTS: We demonstrate here that amlexanox, a drug used for decades, not only induces an increase in nonsense-containing mRNAs amount in treated cells, but also leads to the synthesis of the full-length protein in an efficient manner. We also demonstrated that these full length proteins are functional. CONCLUSIONS: As a result of this dual activity, amlexanox may be useful as a therapeutic approach for diseases caused by nonsense mutations. PMID- 22938199 TI - Reductive stress linked to small HSPs, G6PD, and Nrf2 pathways in heart disease. AB - SIGNIFICANCE: Aerobic organisms must exist between the dueling biological metabolic processes for energy and respiration and the obligatory generation of reactive oxygen species (ROS) whose deleterious consequences can reduce survival. Wide fluctuations in harmful ROS generation are circumvented by endogenous countermeasures (i.e., enzymatic and nonenzymatic antioxidants systems) whose capacity decline with aging and are enhanced by disease states. RECENT ADVANCES: Substantial efforts on the cellular and molecular underpinnings of oxidative stress has been complemented recently by the discovery that reductive stress similarly predisposes to inheritable cardiomyopathy, firmly establishing that the biological extremes of the redox spectrum play essential roles in disease pathogenesis. CRITICAL ISSUES: Because antioxidants by nutritional or pharmacological supplement to prevent or mitigate disease states have been largely disappointing, we hypothesize that lack of efficacy of antioxidants might be related to adverse outcomes in responders at the reductive end of the redox spectrum. As emerging concepts, such as reductive, as opposed, oxidative stress are further explored, there is an urgent and critical gap for biochemical phenotyping to guide the targeted clinical applications of therapeutic interventions. FUTURE DIRECTIONS: New approaches are vitally needed for characterizing redox states with the long-term goal to noninvasively assess distinct clinical states (e.g., presymptomatic, end-stage) with the diagnostic accuracy to guide personalized medicine. PMID- 22938203 TI - Lepidopterans as potential agents for the biological control of the invasive plant, Miconia calvescens. AB - This work investigated eight species of Lepidoptera associated with Miconia calvescens DC. (Myrtales: Melastomataceae) in Brazil, including six defoliators, Salbia lotanalis Druce (Lepidoptera: Pyralidae), Druentia inscita Schaus (Mimallonidae), Antiblemma leucocyma Hampson (Noctuidae), three Limacodidae species, a fruit borer Carposina cardinata Meyrick (Carposinidae), and a damager of flowers Pleuroprucha rudimentaria Guenee (Geometridae). Based on host specificity and the damage caused to plants, S. lotanalis and D. inscita are the most promising species for biological control of M. calvescens. Furthermore, if C. cardinata and P. rudimentaria have host specificity in future tests, these caterpillars could also be considered as appropriate biocontrol agents. PMID- 22938202 TI - Defining the boundaries of species specificity for the Saccharomyces cerevisiae glycosylphosphatidylinositol transamidase using a quantitative in vivo assay. AB - In eukaryotes, GPI (glycosylphosphatidylinositol) lipid anchoring of proteins is an abundant post-translational modification. The attachment of the GPI anchor is mediated by GPI-T (GPI transamidase), a multimeric, membrane-bound enzyme located in the ER (endoplasmic reticulum). Upon modification, GPI-anchored proteins enter the secretory pathway and ultimately become tethered to the cell surface by association with the plasma membrane and, in yeast, by covalent attachment to the outer glucan layer. This work demonstrates a novel in vivo assay for GPI-T. Saccharomyces cerevisiae INV (invertase), a soluble secreted protein, was converted into a substrate for GPI-T by appending the C-terminal 21 amino acid GPI-T signal sequence from the S. cerevisiae Yapsin 2 [Mkc7p (Y21)] on to the C terminus of INV. Using a colorimetric assay and biochemical partitioning, extracellular presentation of GPI-anchored INV was shown. Two human GPI-T signal sequences were also tested and each showed diminished extracellular INV activity, consistent with lower levels of GPI anchoring and species specificity. Human/fungal chimaeric signal sequences identified a small region of five amino acids that was predominantly responsible for this species specificity. PMID- 22938204 TI - Recovery of hydroxytyrosol rich extract from two-phase Chemlali olive pomace by chemical treatment. AB - A very simple method is proposed to produce hydroxytyrosol, a commercially unavailable compound with well-known biological properties which justify a potential commercial application. The 2-phase Chemlali olive pomace is selected as substrate for chemical treatment. Different conditions of chemical treatment, including concentration of acid and alkaline solutions, time and temperature, were assayed. A high amount of hydroxytyrosol (1360 mg/kg of fresh 2-phase olive pomace) was obtained using water bath after treatment at 80 degrees C for 90 min with 1 M of H(3) PO(4) . However, treatment of 2-phase Chemlali olive pomace using autoclave apparatus could produce a large amount of hydroxytyrosol (1993.60 and 1515.88 mg/kg of fresh alperujo, 1 M acid and basic catalyst, respectively). By taking into consideration practical and economic aspects, acid-catalyzed treatment was more effective using autoclave conditions, whereas the alkali catalyzed conditions were not very suitable. This study could provide useful information for industry to produce the potentially bioactive compound. PRACTICAL APPLICATION: The 2-phase Chemlali olive pomace is selected as substrate for chemical treatment. Treatment of "alperujo" using water bath or autoclave apparatus was carried out. A high amount of hydroxytyrosol was obtained using autoclave apparatus. PMID- 22938205 TI - Comparison of response rates and cost-effectiveness for a community-based survey: postal, internet and telephone modes with generic or personalised recruitment approaches. AB - BACKGROUND: Epidemiological research often requires collection of data from a representative sample of the community or recruitment of specific groups through broad community approaches. The population coverage of traditional survey methods such as mail-outs to residential addresses, and telephone contact via public directories or random-digit-dialing is declining and survey response rates are falling. There is a need to explore new sampling frames and consider multiple response modes including those offered by changes in telecommunications and internet technology. METHODS: We evaluated response rates and cost-effectiveness for three modes of survey administration (postal invitation/postal survey, postal invitation/internet survey and postal invitation/telephone survey) and two styles of contact approach (personalised and generic) in a community survey of greywater use. Potential respondents were contacted only once, with no follow up of non responders. RESULTS: The telephone survey produced the highest adjusted response rate (30.2%), followed by the personalised postal survey (10.5%), generic postal survey (7.5%) and then the internet survey (4.7% for the personalised approach and 2.2% for the generic approach). There were some differences in household characteristics and greywater use rates between respondents to different survey modes, and between respondents to personalised and generic approaches. These may be attributable to the differing levels of motivations needed for a response, and varying levels of interest in the survey topic among greywater users and non users. The generic postal survey had the lowest costs per valid survey received (Australian $22.93), followed by the personalised postal survey ($24.75). CONCLUSIONS: Our findings suggest that postal surveys currently remain the most economic option for population-based studies, with similar costs for personalised and generic approaches. Internet surveys may be effective for specialised groups where email lists are available for initial contact, but barriers other than household internet access still exist for community-based surveys. Given the increasing recruitment challenges facing community-based studies, there is an imperative to gather contemporary comparative data on different survey modes and recruitment approaches in order to determine their strengths, limitations and costs. Researchers also need to document and report on the potential biases in the target and respondent populations and how this may affect the data collected. PMID- 22938207 TI - Fabrication of a fractured mandibular bar-retained implant overdenture without implant-level impression making: a clinical report. AB - The most frequent mechanical complications of bar-retained implant overdentures (IODs) are fracture of the dentures, loosening of the bar screws, and the need to reactivate the retentive clips. When a bar-retained IOD with an acrylic resin base fractures, the existing bar attachment should be removed to fabricate a new overdenture. So far, no method has been previously described for remaking a fractured mandibular bar-retained IOD without removing the existing bar attachment. This article describes fabrication of a fractured mandibular bar retained IOD with distally placed ball attachments using attachment transfer analogs. The described technique allows the patient to use the existing overdenture temporarily until the new overdenture is delivered. PMID- 22938206 TI - Exploration of the core metabolism of symbiotic bacteria. AB - BACKGROUND: A large number of genome-scale metabolic networks is now available for many organisms, mostly bacteria. Previous works on minimal gene sets, when analysing host-dependent bacteria, found small common sets of metabolic genes. When such analyses are restricted to bacteria with similar lifestyles, larger portions of metabolism are expected to be shared and their composition is worth investigating. Here we report a comparative analysis of the small molecule metabolism of symbiotic bacteria, exploring common and variable portions as well as the contribution of different lifestyle groups to the reduction of a common set of metabolic capabilities. RESULTS: We found no reaction shared by all the bacteria analysed. Disregarding those with the smallest genomes, we still do not find a reaction core, however we did find a core of biochemical capabilities. While obligate intracellular symbionts have no core of reactions within their group, extracellular and cell-associated symbionts do have a small core composed of disconnected fragments. In agreement with previous findings in Escherichia coli, their cores are enriched in biosynthetic processes whereas the variable metabolisms have similar ratios of biosynthetic and degradation reactions. Conversely, the variable metabolism of obligate intracellular symbionts is enriched in anabolism. CONCLUSION: Even when removing the symbionts with the most reduced genomes, there is no core of reactions common to the analysed symbiotic bacteria. The main reason is the very high specialisation of obligate intracellular symbionts, however, host-dependence alone is not an explanation for such absence. The composition of the metabolism of cell-associated and extracellular bacteria shows that while they have similar needs in terms of the building blocks of their cells, they have to adapt to very distinct environments. On the other hand, in obligate intracellular bacteria, catabolism has largely disappeared, whereas synthetic routes appear to have been selected for depending on the nature of the symbiosis. As more genomes are added, we expect, based on our simulations, that the core of cell-associated and extracellular bacteria continues to diminish, converging to approximately 60 reactions. PMID- 22938208 TI - Hair-thread tourniquet syndrome: a hidden hazard. AB - Hair-thread tourniquet syndrome (HTTS) is a rare disorder characterized by the encircling of an appendage by a hair or thread. We report an 8-month-old boy with toe HTTS. Early recognition is required to avoid the serious consequences of its delayed diagnosis. PMID- 22938210 TI - Perspective: Supercooled liquids and glasses. AB - Supercooled liquids and glasses are important for current and developing technologies. Here we provide perspective on recent progress in this field. The interpretation of supercooled liquid and glass properties in terms of the potential energy landscape is discussed. We explore the connections between amorphous structure, high frequency motions, molecular motion, structural relaxation, stability against crystallization, and material properties. Recent developments that may lead to new materials or new applications of existing materials are described. PMID- 22938211 TI - Communication: Thermal rectification in liquids by manipulating the solid-liquid interface. AB - Thermal rectification, the origin of which lies in modifying the thermal resistance in a nonlinear manner, could significantly improve the thermal management of a wide range of nano-devices (both electronic and thermoelectric), thereby improving their efficiencies. Since rectification requires a material to be inhomogeneous, it has been typically associated with solids. However, the structure of solids is relatively difficult to manipulate, which makes the tuning of thermal rectification devices challenging. Since liquids are more amenable to tuning, this could open up new applications for thermal rectification. We use molecular dynamics simulations to demonstrate thermal rectification using liquid water. This is accomplished by creating an inhomogeneous water phase, either by changing the morphology of the surface in contact with the liquid or by imposing an arbitrary external force, which in practice could be through an electric or magnetic field. Our system consists of a bulk fluid that is confined in a reservoir that is bounded by two walls, one hot and the other cold. The interfacial (Kapitza) thermal resistance at the solid-fluid interface and the density gradient of the bulk fluid both influence the magnitude of the thermal rectification. However, we find that the role of the interfacial resistance is more prominent than the application of an external force on the bulk fluid. PMID- 22938209 TI - Vectorial secretion of CTGF as a cell-type specific response to LPA and TGF-beta in human tubular epithelial cells. AB - BACKGROUND: Increased expression of the pro-fibrotic protein connective tissue growth factor (CTGF) has been detected in injured kidneys and elevated urinary levels of CTGF are discussed as prognostic marker of chronic kidney disease. There is evidence that epithelial cells lining the renal tubular system contribute to uptake and secretion of CTGF. However, the role of different types of tubular epithelial cells in these processes so far has not been addressed in primary cultures of human cells. RESULTS: Tubular epithelial cells of proximal and distal origin were isolated from human kidneys and cultured as polarized cells in insert wells. The pro-fibrotic stimuli lysophosphatidic acid (LPA) and transforming growth factor beta (TGF-beta) were used to induce CTGF secretion.LPA activated CTGF secretion in proximal tubular cells when applied from either the apical or the basolateral side as shown by immunocytochemistry. CTGF was secreted exclusively to the apical side. Signaling pathways activated by LPA included MAP kinase and Rho kinase signaling. TGF-beta applied from either side also stimulated CTGF secretion primarily to the apical side with little basolateral release.Interestingly, TGF-beta activation induced different signaling pathways depending on the side of TGF-beta application. Smad signaling was almost exclusively activated from the basolateral side most prominently in cells of distal origin. Only part of these cells also synthesized CTGF indicating that Smad activation alone was not sufficient for CTGF induction. MAP kinases were involved in apical TGF-beta-mediated activation of CTGF synthesis in proximal cells and a subset of epithelial cells of distal origin. This subpopulation of distal tubular cells was also able to internalize recombinant apical CTGF, in addition to proximal cells which were the main cells to take up exogenous CTGF. CONCLUSIONS: Analysis of polarized human primary renal epithelial cells in a transwell system shows that vectorial secretion of the pro-fibrotic protein CTGF depends on the cell type, the stimulus and the signaling pathway activated. In all conditions, CTGF was secreted mainly to the apical side upon TGF-beta and LPA treatment and therefore, likely contributes to increased urinary CTGF levels in vivo. Moreover, CTGF secreted basolaterally may be active as paracrine pro fibrotic mediator. PMID- 22938213 TI - Exact dynamic properties of molecular motors. AB - Molecular motors play important roles within a biological cell, performing functions such as intracellular transport and gene transcription. Recent experimental work suggests that there are many plausible biochemical mechanisms that molecules such as myosin-V could use to achieve motion. To account for the abundance of possible discrete-stochastic frameworks that can arise when modeling molecular motor walks, a generalized and straightforward graphical method for calculating their dynamic properties is presented. It allows the calculation of the velocity, dispersion, and randomness ratio for any proposed system through analysis of its structure. This article extends work of King and Altman ["A schematic method of deriving the rate laws of enzyme-catalyzed reactions," J. Phys. Chem. 60, 1375-1378 (1956)] on networks of enzymatic reactions by calculating additional dynamic properties for spatially hopping systems. Results for n-state systems are presented: single chain, parallel pathway, divided pathway, and divided pathway with a chain. A novel technique for combining multiple system architectures coupled at a reference state is also demonstrated. Four-state examples illustrate the effectiveness and simplicity of these methods. PMID- 22938212 TI - Variational approach for nonpolar solvation analysis. AB - Solvation analysis is one of the most important tasks in chemical and biological modeling. Implicit solvent models are some of the most popular approaches. However, commonly used implicit solvent models rely on unphysical definitions of solvent-solute boundaries. Based on differential geometry, the present work defines the solvent-solute boundary via the variation of the nonpolar solvation free energy. The solvation free energy functional of the system is constructed based on a continuum description of the solvent and the discrete description of the solute, which are dynamically coupled by the solvent-solute boundaries via van der Waals interactions. The first variation of the energy functional gives rise to the governing Laplace-Beltrami equation. The present model predictions of the nonpolar solvation energies are in an excellent agreement with experimental data, which supports the validity of the proposed nonpolar solvation model. PMID- 22938214 TI - Towards a minimal stochastic model for a large class of diffusion-reactions on biological membranes. AB - Diffusion of biological molecules on 2D biological membranes can play an important role in the behavior of stochastic biochemical reaction systems. Yet, we still lack a fundamental understanding of circumstances where explicit accounting of the diffusion and spatial coordinates of molecules is necessary. In this work, we illustrate how time-dependent, non-exponential reaction probabilities naturally arise when explicitly accounting for the diffusion of molecules. We use the analytical expression of these probabilities to derive a novel algorithm which, while ignoring the exact position of the molecules, can still accurately capture diffusion effects. We investigate the regions of validity of the algorithm and show that for most parameter regimes, it constitutes an accurate framework for studying these systems. We also document scenarios where large spatial fluctuation effects mandate explicit consideration of all the molecules and their positions. Taken together, our results derive a fundamental understanding of the role of diffusion and spatial fluctuations in these systems. Simultaneously, they provide a general computational methodology for analyzing a broad class of biological networks whose behavior is influenced by diffusion on membranes. PMID- 22938215 TI - Particle-swarm structure prediction on clusters. AB - We have developed an efficient method for cluster structure prediction based on the generalization of particle swarm optimization (PSO). A local version of PSO algorithm was implemented to utilize a fine exploration of potential energy surface for a given non-periodic system. We have specifically devised a technique of so-called bond characterization matrix (BCM) to allow the proper measure on the structural similarity. The BCM technique was then employed to eliminate similar structures and define the desirable local search spaces. We find that the introduction of point group symmetries into generation of cluster structures enables structural diversity and apparently avoids the generation of liquid-like (or disordered) clusters for large systems, thus considerably improving the structural search efficiency. We have incorporated Metropolis criterion into our method to further enhance the structural evolution towards low-energy regimes of potential energy surfaces. Our method has been extensively benchmarked on Lennard Jones clusters with different sizes up to 150 atoms and applied into prediction of new structures of medium-sized Li(n) (n = 20, 40, 58) clusters. High search efficiency was achieved, demonstrating the reliability of the current methodology and its promise as a major method on cluster structure prediction. PMID- 22938216 TI - Avoided crossings, conical intersections, and low-lying excited states with a single reference method: the restricted active space spin-flip configuration interaction approach. AB - The restricted active space spin-flip CI (RASCI-SF) performance is tested in the electronic structure computation of the ground and the lowest electronically excited states in the presence of near-degeneracies. The feasibility of the method is demonstrated by analyzing the avoided crossing between the ionic and neutral singlet states of LiF along the molecular dissociation. The two potential energy surfaces (PESs) are explored by means of the energies of computed adiabatic and approximated diabatic states, dipole moments, and natural orbital electronic occupancies of both states. The RASCI-SF methodology is also used to study the ground and first excited singlet surface crossing involved in the double bond isomerization of ethylene, as a model case. The two-dimensional PESs of the ground (S(0)) and excited (S(1)) states are calculated for the complete configuration space of torsion and pyramidalization molecular distortions. The parameters that define the state energetics in the vicinity of the S(0)/S(1) conical intersection region are compared to complete active space self-consistent field (CASSCF) results. These examples show that it is possible to describe strongly correlated electronic states using a single reference methodology without the need to expand the wavefunction to high levels of collective excitations. Finally, RASCI is also examined in the electronic structure characterization of the ground and 2(1)A(g)(-), 1(1)B(u)(+), 1(1)B(u)(-), and 1(3)B(u)(-) states of all-trans polyenes with two to seven double bonds and beyond. Transition energies are compared to configuration interaction singles, time-dependent density functional theory (TDDFT), CASSCF, and its second-order perturbation correction calculations, and to experimental data. The capability of RASCI-SF to describe the nature and properties of each electronic state is discussed in detail. This example is also used to expose the properties of different truncations of the RASCI wavefunction and to show the possibility to use an excitation operator with any number of alpha-to-beta electronic promotions. PMID- 22938217 TI - Single-molecule stochastic times in a reversible bimolecular reaction. AB - In this work, we consider the reversible reaction between reactants of species A and B to form the product C. We consider this reaction as a prototype of many pseudobiomolecular reactions in biology, such as for instance molecular motors. We derive the exact probability density for the stochastic waiting time that a molecule of species A needs until the reaction with a molecule of species B takes place. We perform this computation taking fully into account the stochastic fluctuations in the number of molecules of species B. We show that at low numbers of participating molecules, the exact probability density differs from the exponential density derived by assuming the law of mass action. Finally, we discuss the condition of detailed balance in the exact stochastic and in the approximate treatment. PMID- 22938218 TI - NMR shielding tensors for density fitted local second-order Moller-Plesset perturbation theory using gauge including atomic orbitals. AB - An efficient method for the calculation of nuclear magnetic resonance (NMR) shielding tensors is presented, which treats electron correlation at the level of second-order Moller-Plesset perturbation theory. It uses spatially localized functions to span occupied and virtual molecular orbital spaces, respectively, which are expanded in a basis of gauge including atomic orbitals (GIAOs or London atomic orbitals). Doubly excited determinants are restricted to local subsets of the virtual space and pair energies with an interorbital distance beyond a certain threshold are omitted. Furthermore, density fitting is employed to factorize the electron repulsion integrals. Ordinary Gaussians are employed as fitting functions. It is shown that the errors in the resulting NMR shielding constant, introduced (i) by the local approximation and (ii) by density fitting, are very small or even negligible. The capabilities of the new program are demonstrated by calculations on some extended molecular systems, such as the cyclobutane pyrimidine dimer photolesion with adjacent nucleobases in the native intrahelical DNA double strand (ATTA sequence). Systems of that size were not accessible to correlated ab initio calculations of NMR spectra before. The presented method thus opens the door to new and interesting applications in this area. PMID- 22938219 TI - Analytic calculation of second-order electric response properties with the normalized elimination of the small component (NESC) method. AB - Analytic second derivatives of the relativistic energy for the calculation of electric response properties are derived utilizing the normalized elimination of the small component (NESC) method. Explicit formulas are given for electric static dipole polarizabilities and infrared intensities by starting at the NESC representation of electric dipole moments. The analytic derivatives are implemented in an existing NESC program and applied to calculate dipole moments, polarizabilities, and the infrared spectra of gold- and mercury-containing molecules as well as some actinide molecules. Comparison with experiment reveals the accuracy of NESC second order electric response properties. PMID- 22938220 TI - Electronic currents and Born-Oppenheimer molecular dynamics. AB - Born-Oppenheimer variable separation is the mainstay of studies of chemical reactivity and dynamics. A long-standing problem of this ansatz is the absence of electronic currents in a system undergoing dynamics. I analyze the physical origin of the "missing" electronic currents in Born-Oppenheimer wavefunctions. By examining the problem within the multi-state Born-Huang ansatz, I demonstrate that electronic currents arise from the first-order non-adiabatic coupling to electronically excited states. I derive two expressions for the electronic currents induced by nuclear motion. The sum-over-the-states formula, identical to the result of "complete adiabatic" treatment of Nafie [J. Chem. Phys. 79, 4950 (1983)] leads to a transparent and intuitive physical picture of the induced currents, but is unsuitable for practical implementation in all but the simplest systems. The equivalent expression in terms of the electronic energy derivatives is straightforward to implement numerically. I present first applications of this approach to small systems of potential chemical interest. PMID- 22938221 TI - Population and coherence dynamics in light harvesting complex II (LH2). AB - The electronic excitation population and coherence dynamics in the chromophores of the photosynthetic light harvesting complex 2 (LH2) B850 ring from purple bacteria (Rhodopseudomonas acidophila) have been studied theoretically at both physiological and cryogenic temperatures. Similar to the well-studied Fenna Matthews-Olson (FMO) protein, oscillations of the excitation population and coherence in the site basis are observed in LH2 by using a scaled hierarchical equation of motion approach. However, this oscillation time (300 fs) is much shorter compared to the FMO protein (650 fs) at cryogenic temperature. Both environment and high temperature are found to enhance the propagation speed of the exciton wave packet yet they shorten the coherence time and suppress the oscillation amplitude of coherence and the population. Our calculations show that a long-lived coherence between chromophore electronic excited states can exist in such a noisy biological environment. PMID- 22938222 TI - Validation of the reaction thermodynamics associated with NaSc(BH4)4 from first principles calculations: detecting metastable paths and identifying the minimum free energy path. AB - A critical drawback with first-principles thermodynamic calculations is the absence of the vibrational and entropic contributions to the prediction of reaction mechanisms, which could conclusively show that the predicted reaction mechanism might be not the most stable reaction path. This study focused on providing an answer to this problem by examining possible metastable paths for five reactant mixtures whose reaction mechanisms were previously predicted using first-principles thermodynamic calculations. The aim of this study was to find a minimum free energy path among all the possible paths of each reactant mixture. This effort provided the clear conclusion that the original reaction paths predicted from first-principles thermodynamic calculations were the most stable reaction paths at an appropriate H(2) pressure range for all cases. An additional examination associated with density functional theory uncertainty suggests how the ambiguity of reaction mechanisms predicted based on thermodynamic calculations should be understood and dealt with. PMID- 22938223 TI - Vibronic coupling in asymmetric bichromophores: theory and application to diphenylmethane. AB - The theory for modeling vibronic interactions in bichromophores was introduced in sixties by Witkowski and Moffitt [J. Chem. Phys. 33, 872 (1960)] and extended by Fulton and Gouterman [J. Chem. Phys. 35, 1059 (1961)]. The present work describes extension of this vibronic model to describe bichromophores with broken vibrational symmetry such as partly deuterated molecules. Additionally, the model is extended to include inter-chromophore vibrational modes. The model can treat multiple vibrational modes by employing Lanczos diagonalization procedure of sparse matrices. The developed vibronic model is applied to simulation of vibronic spectra of flexible bichromophore diphenylmethane and compared to high resolution experimental spectra [J. A. Stearns, N. R. Pillsbury, K. O. Douglass, C. W. Muller, T. S. Zwier, and D. F. Plusquellic, J. Chem. Phys. 129, 224305 (2008)]. PMID- 22938224 TI - Dynamics of a Holstein polaron with off-diagonal coupling. AB - Dynamics of a one-dimensional Holstein polaron with off-diagonal exciton-phonon coupling is studied by employing the Dirac-Frenkel time-dependent variational principle. The trial state used is the Davydov D(2) Ansatz with two sets of variational parameters, one for each constituting particle in the linearly coupled exciton-phonon system. Validity of the approach is carefully checked by quantifying how faithfully the trial state follows the Schrodinger equation. A close examination of variational outputs reveals fine details of polaron dynamics and intricacies of dynamic exciton-phonon correlations. In the absence of diagonal coupling, the change in the polaron effective mass hinges on the sign of the transfer integral due to the antisymmetric nature of the off-diagonal coupling. The role of the off-diagonal coupling switches from being an agent of transport at moderate coupling strengths to that of localization at large coupling strengths. Increasing the phonon bandwidth leads to a reduced polaron effective mass at the zone center and an overall lowering of the polaron band. PMID- 22938225 TI - Relating normal vibrational modes to local vibrational modes with the help of an adiabatic connection scheme. AB - Information on the electronic structure of a molecule and its chemical bonds is encoded in the molecular normal vibrational modes. However, normal vibrational modes result from a coupling of local vibrational modes, which means that only the latter can provide detailed insight into bonding and other structural features. In this work, it is proven that the adiabatic internal coordinate vibrational modes of Konkoli and Cremer [Int. J. Quantum Chem. 67, 29 (1998)] represent a unique set of local modes that is directly related to the normal vibrational modes. The missing link between these two sets of modes are the compliance constants of Decius, which turn out to be the reciprocals of the local mode force constants of Konkoli and Cremer. Using the compliance constants matrix, the local mode frequencies of any molecule can be converted into its normal mode frequencies with the help of an adiabatic connection scheme that defines the coupling of the local modes in terms of coupling frequencies and reveals how avoided crossings between the local modes lead to changes in the character of the normal modes. PMID- 22938226 TI - Multibody local approximation: application to conformational entropy calculations on biomolecules. AB - Multibody type expansions like mutual information expansions are widely used for computing or analyzing properties of large composite systems. The power of such expansions stems from their generality. Their weaknesses, however, are the large computational cost of including high order terms due to the combinatorial explosion and the fact that truncation errors do not decrease strictly with the expansion order. Herein, we take advantage of the redundancy of multibody expansions in order to derive an efficient reformulation that captures implicitly all-order correlation effects within a given cutoff, avoiding the combinatory explosion. This approach, which is cutoff dependent rather than order dependent, keeps the generality of the original expansions and simultaneously mitigates their limitations provided that a reasonable cutoff can be used. An application of particular interest can be the computation of the conformational entropy of flexible peptide molecules from molecular dynamics trajectories. By combining the multibody local estimations of conformational entropy with average values of the rigid-rotor and harmonic-oscillator entropic contributions, we obtain by far a tighter upper bound of the absolute entropy than the one obtained by the broadly used quasi-harmonic method. PMID- 22938227 TI - Overtone vibrational spectroscopy in H2-H2O complexes: a combined high level theoretical ab initio, dynamical and experimental study. AB - First results are reported on overtone (v(OH) = 2 <- 0) spectroscopy of weakly bound H(2)-H(2)O complexes in a slit supersonic jet, based on a novel combination of (i) vibrationally mediated predissociation of H(2)-H(2)O, followed by (ii) UV photodissociation of the resulting H(2)O, and (iii) UV laser induced fluorescence on the nascent OH radical. In addition, intermolecular dynamical calculations are performed in full 5D on the recent ab initio intermolecular potential of Valiron et al. [J. Chem. Phys. 129, 134306 (2008)] in order to further elucidate the identity of the infrared transitions detected. Excellent agreement is achieved between experimental and theoretical spectral predictions for the most strongly bound van der Waals complex consisting of ortho (I = 1) H(2) and ortho (I = 1) H(2)O (oH(2)-oH(2)O). Specifically, two distinct bands are seen in the oH(2) oH(2)O spectrum, corresponding to internal rotor states in the upper vibrational manifold of Sigma and Pi rotational character. However, none of the three other possible nuclear spin modifications (pH(2)-oH(2)O, pH(2)-pH(2)O, or oH(2)-pH(2)O) are observed above current signal to noise level, which for the pH(2) complexes is argued to arise from displacement by oH(2) in the expansion mixture to preferentially form the more strongly bound species. Direct measurement of oH(2) oH(2)O vibrational predissociation in the time domain reveals lifetimes of 15(2) ns and <5(2) ns for the Sigma and Pi states, respectively. Theoretical calculations permit the results to be interpreted in terms of near resonant energy levels and intermolecular alignment of the H(2) and H(2)O wavefunctions, providing insight into predissociation dynamical pathways from these metastable levels. PMID- 22938228 TI - Effects of classical nonlinear resonances in grazing diatom-surface collisions. AB - Energy transfer between vibrational, rotational, and translational degrees of freedom of a molecule during a collision process is enhanced when the classical frequencies associated with the initial state are in the proximity of nonlinear resonance conditions. We present an analysis of the classical resonant effects in the collisions of light diatoms with periodic surfaces, and discuss the initial conditions in which these effects can be observed. In particular, we find that for grazing incidence and resonant initial values of the classical frequencies, corresponding to specific vibro-rotational molecular states and translational energies, an efficient energy transfer between the intramolecular vibro rotational degrees of freedom and the translational degree of freedom along a symmetry direction on the surface can be found. This efficient energy transfer manifests itself in the emergence of specific peaks in the molecular diffraction patterns. The predictions of the resonance analysis are contrasted with the results of classical trajectory calculations obtained in a diatom-rigid surface collision model. PMID- 22938229 TI - The J = 2 ortho levels of the v = 0 to 6 np singlet Rydberg series of molecular hydrogen revisited. AB - The energies of the J = 2 ortho levels of the v = 0 to 6 Rydberg np singlet series of molecular hydrogen with absolute intensities of the R(1) and P(3) absorption lines were measured by a high-resolution synchrotron radiation experiment and calculated through a full ab initio multi-channel quantum defect approach. PMID- 22938230 TI - A generalised 17-state vibronic-coupling Hamiltonian model for ethylene. AB - In a previous work [B. Lasorne, M. A. Robb, H.-D. Meyer, and F. Gatti, "The electronic excited states of ethylene with large-amplitude deformations: A dynamical symmetry group investigation," Chem. Phys. 377, 30-45 (2010); and ibid. 382, 132 (2011) (Erratum)], we investigated the electronic structure of ethylene (ethene, C(2)H(4)) in terms of 17 dominant configurations selected at the multiconfiguration self-consistent field level of theory. These were shown to be sufficient to recover most of the static electron correlation among the first valence and Rydberg states at all geometries. We also devised a strategy to build a 17-quasidiabatic-state matrix representation of the electronic Hamiltonian for curvilinear coordinates using dynamical symmetry. Here, we present fitted surfaces in the form of a generalised vibronic-coupling Hamiltonian model for two nuclear coordinates, CC bond stretching and torsion. Dynamic electron correlation is included into the electronic structure to improve the energetics of the Rydberg states at the multireference configuration interaction level of theory. The chemical interpretation of the adiabatic states of interest does not change qualitatively, which validates our choice of underlying quasidiabatic states in the model. The absorption spectrum is calculated with quantum dynamics and partially assigned. This first two-dimensional model shows a surprisingly good agreement with the experimental spectrum. PMID- 22938231 TI - Intermolecular vibrations of fluorobenzene-Ar up to 130 cm(-1) in the ground electronic state. AB - Sixteen intermolecular vibrational levels of the S(0) state of the fluorobenzene Ar van der Waals complex have been observed using dispersed fluorescence. The levels range up to ~130 cm(-1) in vibrational energy. The vibrational energies have been modelled using a complete set of harmonic and quartic anharmonic constants and a cubic anharmonic coupling between the stretch and long axis bend overtone that becomes near ubiquitous at higher energies. The constants predict the observed band positions with a root mean square deviation of 0.04 cm(-1). The set of vibrational levels predicted by the constants, which includes unobserved bands, has been compared with the predictions of ab initio calculations, which include all vibrational levels up to 70-75 cm(-1). There are small differences in energy, particularly above 60 cm(-1), however, the main differences are in the assignments and are largely due to the limitations of assigning the ab initio wavefunctions to a simple stretch, bend, or combination when the states are mixed by the cubic anharmonic coupling. The availability of these experimental data presents an opportunity to extend ab initio calculations to higher vibrational energies to provide an assessment of the accuracy of the calculated potential surface away from the minimum. The intermolecular modes of the fluorobenzene Ar(2) trimer complex have also been investigated by dispersed fluorescence. The dominant structure is a pair of bands with a ~35 cm(-1) displacement from the origin band. Based on the set of vibrational modes calculated from the fluorobenzene-Ar frequencies, they are assigned to a Fermi resonance between the symmetric stretch and symmetric short axis bend overtone. The analysis of this resonance provides a measurement of the coupling strength between the stretch and short axis bend overtone in the dimer, an interaction that is not directly observed. The coupling matrix elements determined for the fluorobenzene-Ar stretch-long axis bend overtone and stretch-short axis bend overtone couplings are remarkably similar (3.8 cm(-1) cf. 3.2 cm(-1)). Several weak features seen in the fluorobenzene-Ar(2) spectrum have also been assigned. PMID- 22938232 TI - Synchrotron far infrared spectroscopy of the ground, nu5, and nu15 states of thiirane. AB - The high-resolution (0.001 cm(-1)) spectrum of thiirane has been recorded at the far-infrared beamline at the Australian synchrotron between 760-400 cm(-1) and 170-10 cm(-1). Ro-vibrational transitions of the highly Coriolis coupled nu(5) (628.1 cm(-1)) and nu(15) (669.7 cm(-1)) fundamentals, as well as pure rotational far-IR transitions have been assigned, and rotational, centrifugal distortion, and Coriolis interaction parameters determined. nu(15) gains the vast majority of its intensity from an interesting Coriolis intensity stealing mechanism, which is also outlined. PMID- 22938233 TI - Ionization and Coulomb explosion of small group 10 transition metal oxide clusters in strong light fields. AB - The ionization properties of small group 10 metal oxide clusters are explored using ultrafast pulses centered at 624 nm. Maximum atomic charge states resulting from Coulomb explosion were observed to be Ni(3+), Pd(3+), Pt(5+), and O(2+) species with similar ionization potentials ~30-35 eV. Ion signal as a function of laser intensity of each charge state of Ni, Pd, Pt, and O resulting from Coulomb explosion was mapped and compared to that predicted from semi-classical tunneling theory using sequential ionization potentials to quantify observed enhancements in ionization. The saturation intensity (I(sat)) of each charge state is measured and compared to previous studies on group 5 transition metal oxides. The atomic charge states of nickel showed a large enhancement in ionization compared to palladium and platinum, reflective of the differing bonding properties of each metal with oxygen. Results indicate that nickel oxide clusters undergo a greater extent of ionization enhancement as a result of multiple ionization mechanisms. The ionization enhancement behavior of each metal oxide species is explored herein. PMID- 22938234 TI - The electronic spectrum of CUONg4 (Ng = Ne, Ar, Kr, Xe): new insights in the interaction of the CUO molecule with noble gas matrices. AB - The electronic spectrum of the CUO molecule was investigated with the IHFSCC-SD (intermediate Hamiltonian Fock-space coupled cluster with singles and doubles) method and with TD-DFT (time-dependent density functional theory) employing the PBE and PBE0 exchange-correlation functionals. The importance of both spin-orbit coupling and correlation effects on the low-lying excited-states of this molecule are analyzed and discussed. Noble gas matrix effects on the energy ordering and vibrational frequencies of the lowest electronic states of the CUO molecule were investigated with density functional theory (DFT) and TD-DFT in a supermolecular as well as a frozen density embedding (FDE) subsystem approach. This data is used to test the suitability of the FDE approach to model the influence of different matrices on the vertical electronic transitions of this molecule. The most suitable potential was chosen to perform relativistic wave function theory in density functional theory calculations to study the vertical electronic spectra of the CUO and CUONg(4) with the IHFSCC-SD method. PMID- 22938235 TI - Dynamic polarizabilities of Zn and Cd and dispersion coefficients involving group 12 atoms. AB - The refractive index data for Zn and Cd measured by Goebel and Hohm are analyzed with a three-term Maxwell-Sellmeier expression which incorporates the experimental oscillator strengths of the first two dipole transitions. These expressions are extended to imaginary frequencies for the determination of the upper and lower bounds of the dynamic polarizabilities alpha(iomega), from which the van der Waals coefficients of two-body interactions and the non-additive three-body interactions are generated. The determined C(6) values for Zn(2) (359+/-8 a.u.) and Cd(2) (686+/-10 a.u.) are much larger than those originally estimated by Goebel and Hohm. This is because their one-term approximation of alpha(omega), which fits the measurements very well in the normal frequency range, greatly underestimates alpha(iomega) when the frequency is extended into the imaginary domain. On the other hand, the present results of heteronuclear interactions verify once again that Tang's one-term approximation of alpha(iomega) leads to accurate combining rules. The two- and three-body interaction coefficients between group 12 atoms (Zn, Cd, Hg) and the alkali, alkaline-earth, rare-gas atoms, and some molecules are estimated with these combining rules. PMID- 22938236 TI - Infrared absorption of trans-1-chloromethylallyl and trans-1-methylallyl radicals produced in photochemical reactions of trans-1,3-butadiene and Cl2 in solid para hydrogen. AB - The reactions of chlorine and hydrogen atoms with trans-1,3-butadiene in solid para-hydrogen (p-H(2)) were investigated with infrared (IR) absorption spectra. When a p-H(2) matrix containing Cl(2) and trans-1,3-butadiene was irradiated with ultraviolet light at 365 nm, intense lines at 650.3, 809.0, 962.2, 1240.6 cm(-1), and several weaker ones due to the trans-1-chloromethylallyl radical, ?(CH(2)CHCH)CH(2)Cl, appeared. Observed wavenumbers and relative intensities agree with the anharmonic vibrational wavenumbers and IR intensities predicted with the B3PW91/6-311++g(2d, 2p) method. That the Cl atom adds primarily to the terminal carbon atom of trans-1,3-butadiene is in agreement with the path of minimum energy predicted theoretically, but in contrast to the reaction of Cl + propene in solid p-H(2) [J. Amicangelo and Y.-P. Lee, J. Phys. Chem. Lett. 1, 2956 (2010)] in which the addition of Cl to the central C atom is favored, likely through steric effects in a p-H(2) matrix. A second set of lines, intense at 781.6, 957.9, 1433.6, 2968.8, 3023.5, 3107.3 cm(-1), were observed when the UV irradiated Cl(2)/trans-1,3-butadiene/p-H(2) matrix was further irradiated with IR light from a SiC source. These lines are assigned to the trans-1-methylallyl radical, ?(CH(2)CHCH)CH(3), produced from reaction of 1,3-butadiene with a H atom resulted from the reaction of Cl atoms with solid p-H(2) exposed to IR radiation. PMID- 22938237 TI - Quantification of hyperconjugative effect on the proton donor X-H bond length changes in the red- and blueshifted hydrogen-bonded complexes. AB - A whole dataset containing 55 hydrogen bonds were studied at the MP2/aug-cc-pVTZ level of theory. The changes of geometries and stretching vibrational frequencies show that there are 31 redshifted and 24 blueshifted hydrogen-bonded complexes. Natural bond orbital analysis was carried out at the B3LYP/aug-cc-pVTZ level of theory to obtain the electron densities in the bonding and antibonding orbitals of the proton donor X-H bond, which are closely associated with its bond length. Based on their relationship, a generally applicable method considering both the electron densities in the bonding and antibonding orbitals of the proton donor X H bond has been developed to quantitatively describe the hyperconjugative effect on the X-H bond length changes in these hydrogen-bonded complexes. PMID- 22938238 TI - Mass-analyzed threshold ionization and structural isomers of M3O4 (M = Sc, Y, and La). AB - M(3)O(4) (M = Sc, Y, and La) were produced in a pulsed laser-vaporization molecular beam source and studied by mass-analyzed threshold ionization (MATI) spectroscopy and electronic structure calculations. Adiabatic ionization energies (AIEs) of the neutral clusters and vibrational frequencies of the cations were measured accurately for the first time from the MATI spectra. Five possible structural isomers of M(3)O(4) were considered in the calculations and spectral analysis. A cage-like structure in C(3v) point group was identified as the most stable one. The structure is formed by fusing three M(2)O(2) fragments together, each sharing two O-M bonds with others. The ground electronic state of the neutral clusters is (2)A(1) with the unpaired electron being largely a metal based s character. Ionization of the (2)A(1) state yields a (1)A(1) ion state in a similar geometry to the neutral cluster. The AIEs of the clusters are 4.4556 (6), 4.0586(6), and 3.4750(6) eV for M = Sc, Y, and La, respectively. The observed vibrational modes of the cations include metal-oxygen stretching, metal triangle breathing, and oxygen-metal-oxygen rocking in the frequency range of 200 800 cm(-1). PMID- 22938239 TI - Photoelectron spectroscopic study of the E ? e Jahn-Teller effect in the presence of a tunable spin-orbit interaction. III. Two-state excitonic model accounting for observed trends in the X 2E ground state of CH3X+ (X=F, Cl, Br, I) and CH3Y (Y=O, S). AB - Open-shell molecules in doubly degenerate (2)E electronic states are subject to the E ? e Jahn-Teller effect and spin-orbit interactions. The rotational structure of the ground vibrational level of the X(+) (2)E ground state of CH(3)F(+) has been observed by high-resolution photoelectron spectroscopy. In contrast to what is observed in other members of the isoelectronic families CH(3)X(+) (X=Cl, Br, I) and CH(3)Y (Y=O, S), the spin-orbit interaction does not lead to a splitting of the ground state of CH(3)F(+). Observed trends in the spectra of the X (2)E ground states of these molecules are summarized. Whereas certain trends, such as the reduction of the observable effects of the Jahn Teller interactions and the increase of the spin-orbit splitting with increasing nuclear charge of X and Y are easily understood, other trends are more difficult to explain, such as the much reduced spin-orbit splitting in CH(3)F(+) compared to CH(3)O. A simple two-state excitonic model is used to account for the trends observed within the series of the methyl-halide radical cations and also the similarities and differences between CH(3)F(+) and the isoelectronic CH(3)O radical. Within this model, the electron hole in the (2)E ground states of CH(3)X(+) and CH(3)Y is described in terms of contributions from the halogenic (or chalcogenic) p(x, y) orbitals and the pyramidal-methylic (e) orbitals. This model enables a global, semi-quantitative description of the combined effects of the Jahn-Teller and spin-orbit interactions in these molecules and also a simple interpretation of the spin-orbit-coupling reduction factor zeta(e). PMID- 22938240 TI - Cooperative and substitution effects in enhancing strengths of halogen bonds in FCl...CNX complexes. AB - In this paper, the cooperative effect of halogen bond with hydrogen bond has been used to make a halogen bond in FCl-CNH dimer vary from a chlorine-shared one to an ion-pair one. The halogen bond is strengthened in FCl-CNH-CNH trimer and its maximal interaction energy equals to -76 kJ/mol when the number of CNH in FCl-CNH (CNH)(n) polymer approaches infinity. Once the free H atom in FCl-CNH-CNH trimer is replaced with alkali metals, the halogen bond becomes strong enough to be an ion-pair one in FCl-CNH-CNLi and FCl-CNH-CNNa trimers. An introduction of a Lewis acid in FCl-CNH dimer has a more prominent effect on the type of halogen bond. A prominent cooperative effect is found for the halogen bond and hydrogen bond in the trimers. FH-FCl-CNH-CNH and FH-FCl-CNH-CNLi tetramers have also been studied and the interaction energy of halogen bonding in FH-FCl-CNH-CNLi tetramer is about 12 times as much as that in the FCl-CNH dimer. The atoms in molecules and natural bond orbital analyses have been carried out for these complexes to understand the nature of halogen bond and the origin of the cooperativity. PMID- 22938241 TI - Understanding of nonlinear optical properties of CS2 from a microscopic viewpoint. AB - This study is to improve understanding of nonlinear optics through investigating the microstructures of carbon disulfide (CS(2)) liquid, an important nonlinear optical material. First principles methods are employed in this work to investigate the structure, vibrational spectra, and the 2nd hyperpolarizabilites of CS(2) clusters up to tetramers. Three types of molecular arrangements of clusters with different sizes are identified. The cluster conformations are prone to inter-converting under external disturbance due to the weak interactions among molecules. The correlation between the nonlinear optical properties and the conformation of CS(2) clusters are studied in detail in this work. PMID- 22938242 TI - Charge transfer excited state energies by perturbative delta self consistent field method. AB - We use our recently outlined perturbative approach to compute the lowest charge transfer excitation energies for a set of tetracynoehylene (TCNE)-hydrocarbon complexes, C(2)H(4)-C(2)F(4), NH(3)-F(2), pentacene-C(60), and tetraphenyl porphyrin-C(60) complexes. Results show that the method can provide a reliable description of charge transfer excitation energies, which are comparable to that obtained by time-dependent density functional theory using specially optimized range-corrected functionals. As the calculation cost of excited state is comparable to the ground state and the calculation of each excited state is independent of others, the method can be easily used to describe the charge transfer excited states of large donor-acceptor complexes containing 200 or more atoms. PMID- 22938243 TI - Charge transfer excitations in cofacial fullerene-porphyrin complexes. AB - Porphyrin and fullerene donor-acceptor complexes have been extensively studied for their photo-induced charge transfer characteristics. We present the electronic structure of ground states and a few charge transfer excited states of four cofacial porphyrin-fullerene molecular constructs studied using density functional theory at the all-electron level using large polarized basis sets. The donors are base and Zn-tetraphenyl porphyrins and the acceptor molecules are C(60) and C(70). The complexes reported here are non-bonded with a face-to-face distance between the porphyrin and the fullerene of 2.7 to 3.0 A. The energies of the low lying excited states including charge transfer states calculated using our recent excited state method are in good agreement with available experimental values. We find that replacing C(60) by C(70) in a given dyad may increase the lowest charge transfer excitation energy by about 0.27 eV. Variation of donor in these complexes has marginal effect on the lowest charge transfer excitation energy. The interfacial dipole moments and lowest charge transfer states are studied as a function of face-to-face distance. PMID- 22938244 TI - Microscopic models of mode-coupling theory: the F12 scenario. AB - We provide extended evidence that mode-coupling theory (MCT) of supercooled liquids for the F(12) schematic model admits a microscopic realization based on facilitated spin models with tunable facilitation. Depending on the facilitation strength, one observes two distinct dynamical glass transition lines--continuous and discontinuous--merging at a dynamical tricritical-like point with critical decay exponents consistently related by MCT predictions. The mechanisms of dynamical arrest can be naturally interpreted in geometrical terms: the discontinuous and continuous transitions correspond to bootstrap and standard percolation processes, in which the incipient spanning cluster of frozen spins forms either a compact or a fractal structure, respectively. Our cooperative dynamical facilitation picture of glassy behavior is complementary to the one based on disordered systems and can account for higher-order singularity scenarios in the absence of a finite temperature thermodynamic glass transition. We briefly comment on the relevance of our results to finite spatial dimensions and to the F(13) schematic model. PMID- 22938245 TI - Dielectric spectroscopy and ultrasonic study of propylene carbonate under ultra high pressures. AB - We present the high pressure dielectric spectroscopy (up to 4.2 GPa) and ultrasonic study (up to 1.7 GPa) of liquid and glassy propylene carbonate (PC). Both of the methods provide complementary pictures of the glass transition in PC under pressure. No other relaxation processes except alpha-relaxation have been found in the studied pressure interval. The propylene carbonate liquid is a glassformer where simple relaxation and the absence of beta-relaxation are registered in the record-breaking ranges of pressures and densities. The equation of state of liquid PC was extended up to 1 GPa from ultrasonic measurements of bulk modulus and is in good accordance with the previous equations developed from volumetric data. We measured the bulk and shear moduli and Poisson's ratio of glassy PC up to 1.7 GPa. Many relaxation and elastic properties of PC can be qualitatively described by the soft-sphere or Lennard-Jones model. However, for the quantitative description of entire set of the experimental data, these models are insufficient. Moreover, the Poisson coefficient value for glassy PC indicates a significant contribution of non-central forces to the intermolecular potential. The well-known correlation between Poisson's ratio and fragility index (obtained from dielectric relaxation) is confirmed for PC at ambient pressure, but it is violated with pressure increase. This indicates that different features of the potential energy landscape are responsible for the evolution of dielectric response and elasticity with pressure increase. PMID- 22938246 TI - Systematic coarse-graining of potential energy landscapes and dynamics in liquids. AB - Recent efforts have shown that the dynamic properties of a wide class of liquids can be mapped onto semi-universal scaling laws and constitutive relations that are motivated by thermodynamic analyses of much simpler models. In particular, it has been found that many systems exhibit dynamics whose behavior in state space closely follows that of soft-sphere particles interacting through an inverse power repulsion. In the present work, we show that a recently developed coarse graining theory provides a natural way to understand how arbitrary liquids can be mapped onto effective soft-sphere models and hence how one might potentially be able to extract underlying dynamical scaling laws. The theory is based on the relative entropy, an information metric that quantifies how well a soft-sphere approximation to a liquid's multidimensional potential energy landscape performs. We show that optimization of the relative entropy not only enables one to extract effective soft-sphere potentials that suggest an inherent scaling of thermodynamic and dynamic properties in temperature-density space, but that also has rather interesting connections to excess entropy based theories of liquid dynamics. We apply the approach to a binary mixture of Lennard-Jones particles, and show that it gives effective soft-sphere scaling laws that well-describe the behavior of the diffusion constants. Our results suggest that the relative entropy formalism may be useful for "perturbative" type theories of dynamics, offering a general strategy for systematically connecting complex energy landscapes to simpler reference ones with better understood dynamic behavior. PMID- 22938247 TI - Diffusion enhancement in core-softened fluid confined in nanotubes. AB - We study the effect of confinement in the dynamical behavior of a core-softened fluid. The fluid is modeled as a two length scales potential. This potential in the bulk reproduces the anomalous behavior observed in the density and in the diffusion of liquid water. A series of NpT molecular dynamics simulations for this two length scales fluid confined in a nanotube were performed. We obtain that the diffusion coefficient increases with the increase of the nanotube radius for wide channels as expected for normal fluids. However, for narrow channels, the confinement shows an enhancement in the diffusion coefficient when the nanotube radius decreases. This behavior, observed for water, is explained in the framework of the two length scales potential. PMID- 22938248 TI - First principles molecular dynamics study of filled ice hydrogen hydrate. AB - We investigated structural changes, phase diagram, and vibrational properties of hydrogen hydrate in filled-ice phase C(2) by using first principles molecular dynamics simulation. It was found that the experimentally reported "cubic" structure is unstable at low temperature and/or high pressure: The "cubic" structure reflects the symmetry at high (room) temperature where the hydrogen bond network is disordered and the hydrogen molecules are orientationally disordered due to thermal rotation. In this sense, the "cubic" symmetry would definitely be lowered at low temperature where the hydrogen bond network and the hydrogen molecules are expected to be ordered. At room temperature and below 30 GPa, it is the thermal effects that play an essential role in stabilizing the structure in "cubic" symmetry. Above 60 GPa, the hydrogen bonds in the framework would be symmetrized and the hydrogen bond order-disorder transition would disappear. These results also suggest the phase behavior of other filled-ice hydrates. In the case of rare gas hydrate, there would be no guest molecules' rotation-nonrotation transition since the guest molecules keep their spherical symmetry at any temperature. On the contrary methane hydrate MH-III would show complex transitions due to the lower symmetry of the guest molecule. These results would encourage further experimental studies, especially nuclear magnetic resonance spectroscopy and neutron scattering, on the phases of filled-ice hydrates at high pressures and/or low temperatures. PMID- 22938249 TI - Density maximum and polarizable models of water. AB - To estimate accurately the density of water over a wide range of temperatures with a density maximum at 4 degrees C is one of the most stringent tests of molecular models. The shape of the curve influences the ability to describe critical properties and to predict the freezing temperature. While it was demonstrated that with a proper parameter fit nonpolarizable models can approximate this behavior accurately, it is much more difficult to do this for polarizable models. We provide a short overview of rho-T diagrams for existing models, then we give an explanation of this difficulty. We present a version of the BK model [A. Baranyai and P. T. Kiss, J. Chem. Phys. 133, 144109 (2010); and ibid. 135, 234110 (2011)] which is capable to predict the density of water over a wide range of temperature. The BK model uses the charge-on-spring method with three Gaussian charges. Since the experimental dipole moment and the geometry is fixed, and the quadrupole moment is approximated by a least mean square procedure, parameters of the repulsion and dispersive attraction forces remained as free tools to match experimental properties. Relying on a simplified but plausible justification, the new version of the model uses repulsion and attraction as functions of the induced dipole moment of the molecule. The repulsive force increases, while the attractive force decreases with the size of the molecular dipole moment. At the same time dipole moment dependent dispersion forces are taking part in the polarization of the molecule. This scheme iterates well and, in addition to a reasonable density-temperature function, creates dipole distributions with accurate estimation of the dielectric constant of the liquid. PMID- 22938250 TI - Effect of soot microstructure on its ozonization reactivity. AB - Large uncertainty among the measured uptake coefficients of O(3) on soot highlights the importance of the sources and chemical structures of soot samples in this reaction. Soot samples with different microstructures were prepared by combusting n-hexane under controlled conditions. Their reactivities to O(3) were further investigated using in situ Raman spectroscopy. The fuel/oxygen ratio in the combustion experiments not only affected the diameter of the primary particles, but also influenced the micro-chemical structure of soot. Average diameters of soot particles decreased with the decreasing fuel/oxygen ratio. Compared to the "fuel-rich" flame soot, the "fuel-lean" flame soot showed lower structural uniformity with higher disordered carbon content at the graphene layer edges (D1 band) and the surface graphene layers (D2 band) and the amorphous carbon content (D3 band). This disordered carbon was identified as the reactive component for the ozonization of both the "fuel-rich" and "fuel-lean" flame soot samples. The kinetics study demonstrated that the disordered carbon at the surface graphene layers was more active than that at the graphene layer edges in one sample, and the reactivity of these two microstructures types to O(3) in the "fuel-rich" flame soot was higher than that in the "fuel-lean" flame soot. PMID- 22938252 TI - Concentration studies of collision-induced fundamental absorption of hydrogen dissolved in liquid neon. AB - We report further and more detailed results of our recent investigation [W. A. Herrebout, B. J. van der Veken, and A. P. Kouzov, Phys. Rev. Lett. 101, 093001 (2008)] on the collision-induced fundamental absorption by hydrogen dissolved in liquid neon (T ~ 25 K). The band shapes were studied in a wide range of concentrations (0.003-0.05 mole fractions) as well as for different ortho/para ratios and at much higher level of accuracy and resolution than before. Due to almost unhindered rotation of the hydrogen molecule and low temperature, an unprecedently rich frequency-domain picture produced by different terms of the interaction-induced polarization was observed. While some of them are conspicuous via fast intracell motion of a light guest (H(2)), others--induced by the electrostatic field of the guest--give rise to lines whose shapes are imprinted by fluctuations of the nearest surrounding. Strong motional narrowing observed on the guest-guest induced lines shows up in their Lorentzian shapes which are signatures of microscopic-scale diffusion. Near-Lorentzian peaks were also detected at the tops of the diffuse lines induced by isolated guests. Their formation may be associated with a long-living defect (vacancy) emerging in the vicinity of the polarization inductor. Altogether, our results give the first unambiguous spectroscopic evidence on the diffusional evolution of isolated binary interactions that emerge in dense chaotic media. PMID- 22938251 TI - Theory for cross effect dynamic nuclear polarization under magic-angle spinning in solid state nuclear magnetic resonance: the importance of level crossings. AB - We present theoretical calculations of dynamic nuclear polarization (DNP) due to the cross effect in nuclear magnetic resonance under magic-angle spinning (MAS). Using a three-spin model (two electrons and one nucleus), cross effect DNP with MAS for electron spins with a large g-anisotropy can be seen as a series of spin transitions at avoided crossings of the energy levels, with varying degrees of adiabaticity. If the electron spin-lattice relaxation time T(1e) is large relative to the MAS rotation period, the cross effect can happen as two separate events: (i) partial saturation of one electron spin by the applied microwaves as one electron spin resonance (ESR) frequency crosses the microwave frequency and (ii) flip of all three spins, when the difference of the two ESR frequencies crosses the nuclear frequency, which transfers polarization to the nuclear spin if the two electron spins have different polarizations. In addition, adiabatic level crossings at which the two ESR frequencies become equal serve to maintain non-uniform saturation across the ESR line. We present analytical results based on the Landau-Zener theory of adiabatic transitions, as well as numerical quantum mechanical calculations for the evolution of the time-dependent three-spin system. These calculations provide insight into the dependence of cross effect DNP on various experimental parameters, including MAS frequency, microwave field strength, spin relaxation rates, hyperfine and electron-electron dipole coupling strengths, and the nature of the biradical dopants. PMID- 22938253 TI - Vapor-liquid phase coexistence and transport properties of two-dimensional oligomers. AB - Grand-canonical transition-matrix Monte Carlo and histogram reweighting techniques are used herein to study the vapor-liquid coexistence properties of two-dimensional (2D) flexible oligomers with varying chain lengths (m = 1-8). The phase diagrams of the various 2D oligomers follow the correspondence state (CS) principle, akin to the behavior observed for bulk oligomers. The 2D critical density is not influenced by the oligomer chain length, which contrasts with the observation for the bulk oligomers. Line tension, calculated using Binder's formalism, in the reduced plot is found to be independent of chain length in contrast to the 3D behavior. The dynamical properties of 2D fluids are evaluated using molecular dynamics simulations, and the velocity and pressure autocorrelation functions are investigated using Green-Kubo (GK) relations to yield the diffusion and viscosity. The viscosity determined from 2D non equilibrium molecular dynamics simulation is compared with the viscosity estimated from the GK relations. The GK relations prove to be reliable and efficient for the calculation of 2D transport properties. Normal diffusive regions are identified in dense oligomeric fluid systems. The influence of molecular size on the diffusivity and viscosity is found to be diminished at specific CS points for the 2D oligomers considered herein. In contrast, the viscosity and diffusion of the 3D bulk fluid, at a reduced temperature and density, are strongly dependent on the molecular size at the same CS points. Furthermore, the viscosity increases and the diffusion decreases multifold in the 2D system relative to those in the 3D system, at the CS points. PMID- 22938254 TI - A molecular dynamics study to determine the solid-liquid interfacial tension using test area simulation method (TASM). AB - Molecular dynamics (MD) studies on heat transfer from a heated nanoparticle into the surrounding fluid have indicated that the fluid next to a spherical nanoparticle can get heated well above its boiling point without observing a phase change, while a contradicting behavior was observed for a flat surface fluid interface. Another interesting observation is that the critical heat flux was found to increase with increase in the wetting characteristics of solid. Thus, the interfacial tension or free energy of solid-liquid interface could play a pivotal role in the mechanism of heat transfer. A recent study by Gloor et al. [J. Chem. Phys. 123, 134703 (2005)] has proposed test area simulation method (TASM) for the determination of interfacial tension. The present study involves the determination and the comparison of solid-liquid interfacial tension for planar and spherical interfaces using MD based on TASM and analyze the results. A higher interfacial tension value is observed for spherical nanoparticle fluid interface compared to flat surface fluid interface. The results also indicate that the solid-liquid interfacial tension is a size and temperature dependent property. The results from this study are also expected to give better insights into the possible reasons for the observed differences in the thermal transport for spherical nanoparticle-liquid interface compared to planar-liquid interface. PMID- 22938255 TI - Effects of strain, d-band filling, and oxidation state on the surface electronic structure and reactivity of 3d perovskite surfaces. AB - Trends in the dissociative oxygen adsorption energy and oxygen vacancy formation energy on cubic LaBO(3) and SrBO(3) perovskite (001) surfaces (where B = Sc, Ti, V, Cr, Mn, Fe, Co, Ni, and Cu) and their dependence on strain, d-band filling, and oxidation state were examined using density functional theory in the generalized gradient approximation. The effects of strain were found to be small compared to the effects of d-band filling and oxidations state. Electronic structure descriptors such as the d-band center of the B-atom were identified for trends in the dissociative oxygen adsorption energy and for the oxygen vacancy formation energy. A chemical correlation between these two reaction energies was also identified showing the trends in these reaction energies are not independent of each other. PMID- 22938256 TI - Properties of patchy colloidal particles close to a surface: a Monte Carlo and density functional study. AB - We investigate the behavior of a patchy particle model close to a hard-wall via Monte Carlo simulation and density functional theory (DFT). Two DFT approaches, based on the homogeneous and inhomogeneous versions of Wertheim's first order perturbation theory for the association free energy are used. We evaluate, by simulation and theory, the equilibrium bulk phase diagram of the fluid and analyze the surface properties for two isochores, one of which is close to the liquid side of the gas-liquid coexistence curve. We find that the density profile near the wall crosses over from a typical high-temperature adsorption profile to a low-temperature desorption one, for the isochore close to coexistence. We relate this behavior to the properties of the bulk network liquid and find that the theoretical descriptions are reasonably accurate in this regime. At very low temperatures, however, an almost fully bonded network is formed, and the simulations reveal a second adsorption regime which is not captured by DFT. We trace this failure to the neglect of orientational correlations of the particles, which are found to exhibit surface induced orientational order in this regime. PMID- 22938257 TI - Molecular layers of ZnPc and FePc on Au(111) surface: charge transfer and chemical interaction. AB - We have studied zinc phthalocyanine (ZnPc) and iron phthalocyanine (FePc) thick films and monolayers on Au(111) using photoelectron spectroscopy and x-ray absorption spectroscopy. Both molecules are adsorbed flat on the surface at monolayer. ZnPc keeps this orientation in all investigated coverages, whereas FePc molecules stand up in the thick film. The stronger inter-molecular interaction of FePc molecules leads to change of orientation, as well as higher conductivity in FePc layer in comparison with ZnPc, which is reflected in thickness-dependent differences in core-level shifts. Work function changes indicate that both molecules donate charge to Au; through the pi-system. However, the Fe3d derived lowest unoccupied molecular orbital receives charge from the substrate when forming an interface state at the Fermi level. Thus, the central atom plays an important role in mediating the charge, but the charge transfer as a whole is a balance between the two different charge transfer channels; pi system and the central atom. PMID- 22938258 TI - Vapor-liquid interfacial properties of rigid-linear Lennard-Jones chains. AB - We have obtained the interfacial properties of short rigid-linear chains formed from tangentially bonded Lennard-Jones monomeric units from direct simulation of the vapour-liquid interface. The full long-range tails of the potential are accounted for by means of an improved version of the inhomogeneous long-range corrections of Janecek [J. Phys. Chem. B 110, 6264-6269 (2006)] proposed recently by MacDowell and Blas [J. Chem. Phys. 131, 074705 (2009)] valid for spherical as well as for rigid and flexible molecular systems. Three different model systems comprising of 3, 4, and 5 monomers per molecule are considered. The simulations are performed in the canonical ensemble, and the vapor-liquid interfacial tension is evaluated using the test-area method. In addition to the surface tension, we also obtain density profiles, coexistence densities, critical temperature and density, and interfacial thickness as functions of temperature, paying particular attention to the effect of the chain length and rigidity on these properties. According to our results, the main effect of increasing the chain length (at fixed temperature) is to sharpen the vapor-liquid interface and to increase the width of the biphasic coexistence region. As a result, the interfacial thickness decreases and the surface tension increases as the molecular chains get longer. The surface tension has been scaled by critical properties and represented as a function of the difference between coexistence densities relative to the critical density. PMID- 22938259 TI - Self-organization of amphiphilic macromolecules with local helix structure in concentrated solutions. AB - Concentrated solutions of amphiphilic macromolecules with local helical structure were studied by means of molecular dynamic simulations. It is shown that in poor solvent the macromolecules are assembled into wire-like aggregates having complex core-shell structure. The core consists of a hydrophobic backbone of the chains which intertwine around each other. It is protected by the shell of hydrophilic side groups. In racemic mixture of right-hand and left-hand helix macromolecules the wire-like complex is a chain of braid bundles of macromolecules with the same chirality stacking at their ends. The average number of macromolecules in the wire cross-section is close to that of separate bundles observed in dilute solutions of such macromolecules. The effects described here could serve as a simple model of self-organization in solutions of macromolecules with local helical structure. PMID- 22938260 TI - Component dynamics in polyvinylpyrrolidone concentrated aqueous solutions. AB - (2)H-nuclear magnetic resonance (NMR) and neutron scattering (NS) on isotopically labelled samples have been combined to investigate the structure and dynamics of polyvinylpyrrolidone (PVP) aqueous solutions (4 water molecules/monomeric unit). Neutron diffraction evidences the nanosegregation of polymer main-chains and water molecules leading to the presence of water clusters. NMR reveals the same characteristic times and spectral shape as those of the slower process observed by broadband dielectric spectroscopy in this system [S. Cerveny et al., J. Chem. Phys. 128, 044901 (2008)]. The temperature dependence of such relaxation time crosses over from a cooperative-like behavior at high temperatures to an Arrhenius behavior at lower temperatures. Below the crossover, NMR features the spectral shape as due to a symmetric distribution of relaxation times and the underlying motions as isotropic. NS results on the structural relaxation of both components-isolated via H/D labeling-show (i) anomalously stretched and non Gaussian functional forms of the intermediate scattering functions and (ii) a strong dynamic asymmetry between the components that increases with decreasing temperature. Strong heterogeneities associated to the nanosegregated structure and the dynamic asymmetry are invoked to explain the observed anomalies. On the other hand, at short times the atomic displacements are strongly coupled for PVP and water, presumably due to H-bond formation and densification of the sample upon hydration. PMID- 22938261 TI - Tuning effective interactions close to the critical point in colloidal suspensions. AB - We report a numerical investigation of two colloids immersed in a critical solvent, with the aim of quantifying the effective colloid-colloid interaction potential. By turning on an attraction between the colloid and the solvent particles we follow the evolution from the case in which the solvent density close to the colloids changes from values smaller than the bulk to values larger than the bulk. We thus effectively implement the so-called (+, +) and (-, -) boundary conditions defined in field theoretical approaches focused on the description of critical Casimir forces. We find that the effective potential at large distances decays exponentially, with a characteristic decay length compatible with the bulk critical correlation length, in full agreement with theoretical predictions. We also investigate the case of (+, -) boundary condition, where the effective potential becomes repulsive. Our study provides a guidance for a design of the interaction potential which can be exploited to control the stability of colloidal systems. PMID- 22938262 TI - Molecular mass dependence of point-to-set correlation length scale in polymers. AB - We use a recently proposed metric, termed the point-to-set correlation functions, to probe the molecular weight dependence of the relevant static length scales in glass-forming oligomeric chain liquids of 4, 5, 8, and 10 repeat units. In agreement with the results for simple, monatomic fluids, we find that static length scales of the oligomers increase monotonically when the temperature is lowered towards the glass transition temperature of the fluid. More interestingly, the static length scale increases with increasing chain length. Within the bounds of error in our simulations, the static length scale appears to scale as the radius of gyration of the oligomer, but with a prefactor, which is much larger than unity and which grows with the temperature. The preceding behavior contrasts with the length scales extracted from the radial distribution function of the oligomer system, which is practically independent of the chain length. PMID- 22938263 TI - Phase behavior of colloids and proteins in aqueous suspensions: theory and computer simulations. AB - The fluid phase behavior of colloidal suspensions with short-range attractive interactions is studied by means of Monte Carlo computer simulations and two theoretical approximations, namely, the discrete perturbation theory and the so called self-consistent Ornstein-Zernike approximation. The suspensions are modeled as hard-core attractive Yukawa (HCAY) and Asakura-Oosawa (AO) fluids. A detailed comparison of the liquid-vapor phase diagrams obtained through different routes is presented. We confirm Noro-Frenkel's extended law of scaling according to which the properties of a short-ranged fluid at a given temperature and density are independent of the detailed form of the interaction, but just depend on the value of the second virial coefficient. By mapping the HCAY and AO fluids onto an equivalent square-well fluid of appropriate range at the critical point we show that the critical temperature as a function of the effective range is independent of the interaction potential, i.e., all curves fall in a master curve. Our findings are corroborated with recent experimental data for lysozyme proteins. PMID- 22938264 TI - Broadside mobility of a disk in a viscous fluid near a plane wall with no-slip boundary condition. AB - The broadside motion of a disk in a viscous fluid towards a planar wall with no slip boundary condition is studied on the basis of the steady-state Stokes equations. It is shown that flow velocity and pressure of the fluid can be found conveniently from a superposition of elementary complex stream functions. The two amplitude functions characterizing the superposition are found from the numerical solution of a pair of integral equations for the axial and radial velocity components at the disk. The numerical procedure converges fast, provided the distance to the plane is not much smaller than the radius of the disk. For small distance the flow is well approximated by lubrication theory. PMID- 22938265 TI - Influence of non-universal effects on dynamical scaling in driven polymer translocation. AB - We study the dynamics of driven polymer translocation using both molecular dynamics (MD) simulations and a theoretical model based on the non-equilibrium tension propagation on the cis side subchain. We present theoretical and numerical evidence that the non-universal behavior observed in experiments and simulations are due to finite chain length effects that persist well beyond the relevant experimental and simulation regimes. In particular, we consider the influence of the pore-polymer interactions and show that they give a major contribution to the non-universal effects. In addition, we present comparisons between the theory and MD simulations for several quantities, showing extremely good agreement in the relevant parameter regimes. Finally, we discuss the potential limitations of the present theories. PMID- 22938266 TI - Robustness of atomistic Go models in predicting native-like folding intermediates. AB - Go models are exceedingly popular tools in computer simulations of protein folding. These models are native-centric, i.e., they are directly constructed from the protein's native structure. Therefore, it is important to understand up to which extent the atomistic details of the native structure dictate the folding behavior exhibited by Go models. Here we address this challenge by performing exhaustive discrete molecular dynamics simulations of a Go potential combined with a full atomistic protein representation. In particular, we investigate the robustness of this particular type of Go models in predicting the existence of intermediate states in protein folding. We focus on the N47G mutational form of the Spc-SH3 folding domain (x-ray structure) and compare its folding pathway with that of alternative native structures produced in silico. Our methodological strategy comprises equilibrium folding simulations, structural clustering, and principal component analysis. PMID- 22938267 TI - Invited article: polarization "down under": the polarized time-of-flight neutron reflectometer PLATYPUS. AB - This review presents the implementation and full characterization of the polarization equipment of the time-of-flight neutron reflectometer PLATYPUS at the Australian Nuclear Science and Technology Organisation (ANSTO). The functionality and efficiency of individual components are evaluated and found to maintain a high neutron beam polarization with a maximum of 99.3% through polarizing Fe/Si supermirrors. Neutron spin-flippers with efficiencies of 99.7% give full control over the incident and scattered neutron spin direction over the whole wavelength spectrum available in the instrument. The first scientific experiments illustrate data correction mechanisms for finite polarizations and reveal an extraordinarily high reproducibility for measuring magnetic thin film samples. The setup is now fully commissioned and available for users through the neutron beam proposal system of the Bragg Institute at ANSTO. PMID- 22938268 TI - Simultaneous surface plasmon resonance and x-ray absorption spectroscopy. AB - We present an experimental setup for the simultaneous measurement of surface plasmon resonance (SPR) and x-ray absorption spectroscopy (XAS) on metallic thin films at a synchrotron beamline. The system allows measuring in situ and in real time the effect of x-ray irradiation on the SPR curves to explore the interaction of x-rays with matter. It is also possible to record XAS spectra while exciting SPR in order to study changes in the films induced by the excitation of surface plasmons. Combined experiments recording simultaneously SPR and XAS curves while scanning different parameters can be also carried out. The relative variations in the SPR and XAS spectra that can be detected with this setup range from 10(-3) to 10(-5), depending on the particular experiment. PMID- 22938269 TI - Modulated heterodyne light scattering set-up for measuring long relaxation time at small and wide angle. AB - We present a simple, compact, and versatile experimental setup working in the heterodyne detection mode with modulation of the reference beam. The system is implemented with a collection optics based on a unimodal optical fiber coupler. This choice allows the heterodyne to be used in a wide range of scattering angles, even for very small ones, without losing the optical beating. The apparatus can be successfully used to study translational diffusive dynamics of dispersed particles at scattering angles smaller than 5 degrees and it is suitable for exploring slow relaxation processes in sub-Hertz frequency domain, for example, in glass-forming systems. It is also possible to measure the electrophoretic mobility by applying an electric field into a charged particles solution. PMID- 22938270 TI - Development of multi-channel Doppler spectroscopic measurement system using 8 * 8 multianode photomultiplier tube assembly. AB - Using an 8 * 8 channel photomultiplier tube assembly and a single Czerny-Turner monochromator, we have developed a novel Doppler spectroscopic system which can measure the time evolutions of spectral distribution of plasma emission from eight different lines of sight simultaneously. An optical lens system is employed to couple the output of the monochromator with the detector assembly, resulting in small cross-talks less than 5% in spatial distribution together with large magnification of up to 50 in wavelength direction. The suggested system yields cost-effective polychromatic measurements of eight spatial channels with uniform optical and electrical characteristics. PMID- 22938271 TI - Preparation of an exponentially rising optical pulse for efficient excitation of single atoms in free space. AB - We report on a simple method to prepare optical pulses with exponentially rising envelope on the time scale of a few ns. The scheme is based on the exponential transfer function of a fast transistor, which generates an exponentially rising envelope that is transferred first on a radio frequency carrier, and then on a coherent cw laser beam with an electro-optical phase modulator. The temporally shaped sideband is then extracted with an optical resonator and can be used to efficiently excite a single (87)Rb atom. PMID- 22938272 TI - A new double imaging velocity focusing coincidence experiment: i2PEPICO. AB - The vacuum ultraviolet (VUV) beamline of the Swiss Light Source has been upgraded after two years of operation. A new, turntable-type monochromator was constructed at the Paul Scherrer Institut, which allows for fast yaw-alignment as well as quick grating change and exchange. In addition to the original imaging photoelectron photoion coincidence endstation (iPEPICO), a second, complementary double imaging setup (i(2)PEPICO) has been built. Volatile samples can be introduced at room temperature or in a molecular beam, a pyrolysis source allows for radical production, and non-volatile solids can be evaporated in a heated cell. Monochromatic VUV radiation ionizes the sample and both photoelectrons and photoions are velocity map imaged onto two fast position sensitive detectors and detected in delayed coincidence. High intensity synchrotron radiation leads to ionization rates above 10(5) s(-1). New data acquisition and processing approaches are discussed for recording coincidence processes at high rates. The setup is capable of resolving pulsed molecular beam profiles and the synchrotron time structure temporally. The latter is shown by photoelectron autocorrelation, which displays both the 1.04 MHz ring clock frequency as well as resolving the micro-pulses with a separation of 2 ns. Kinetic energy release analysis on the dissociative photoionization of CF(4) indicates a dissociation mechanism change in the Franck-Condon allowed energy range of the first ion state. PMID- 22938273 TI - Perpendicular-flow, single-wafer atomic layer deposition reactor chamber design for use with in situ diagnostics. AB - A description is given of the design and performance of a diagnostic-accessible, perpendicular-flow, single-wafer deposition reactor for use with 50 mm wafers. The reactor chamber design is based on a simple flow tube, with diagnostic access achieved by replacing sections of the reactor chamber wall with recessed diagnostic ports. Reactor chamber performance is evaluated for the purpose of performing optical measurements during atomic layer deposition (ALD). Computational fluid dynamics simulations predict that the when used with windows the diagnostic port design produces minimal perturbations to the gas flow under typical deposition conditions, as compared to a design without diagnostic ports. Temperature measurements of the inside surface of a window installed in a diagnostic port suggest that for reactor chamber operation at 110 degrees C, under typical deposition conditions, the inside surface window temperature is approximately equal to or greater than the surrounding reactor chamber temperature, thereby minimizing possible species condensation on the window surface. As a consequence of using recessed diagnostic ports, an increase in the amplitude of optical intensity fluctuations was generally observed when performing measurements at elevated chamber temperatures. These intensity fluctuations could be readily reduced by enclosing the optical path to the exterior side of the windows. The performance of two straight-forward methods to reduce these intensity fluctuations is presented. The results outlined above demonstrate that this reactor design can be operated with short gas residence times and with all reactor surfaces at elevated temperatures, making it useful for simulating a wide range of gas flow conditions with relevance to microelectronics-related ALD processes. PMID- 22938274 TI - Micro optical power meter for direct in situ measurement of light transmitted from microscopic systems and focused on micro-samples. AB - This paper reports a micro optical power meter which is able to perform effective and precise measurement on the optical power at the focus of different microscopic systems. The power meter can be easily placed on the stages of different microscopes and even partly immersed into solution to directly measure the optical power transmitted from the microscope objective and focused on the sample suspended in solution. The testing experiments demonstrated that the power meter has the characteristics of high precision, excellent linearity, high sensitivity, good stability, and high responding speed. It can accurately measure power levels from 0.1 to 50 mW in visible wavelength in various conditions and environments, which may encounter in practical applications. The optical power measurements using the power meter performed in some biological cell culturing solutions and in air for the same laser light reveal the first time that the powers measured in solutions were about 5%-8% greater than that measured in air at the same position. This not only suggests the necessity of performing direct measurement in situ in solution to obtain the real optical power projected on the suspended samples, but also indicates that such a micro optical power meter can meet almost all the requirements of optical power measurement in different fields from biomedicine to material sciences. PMID- 22938275 TI - Absolute calibration method for nanosecond-resolved, time-streaked, fiber optic light collection, spectroscopy systems. AB - This paper describes a convenient and accurate method to calibrate fast (<1 ns resolution) streaked, fiber optic light collection, spectroscopy systems. Such systems are inherently difficult to calibrate due to the lack of sufficiently intense, calibrated light sources. Such a system is used to collect spectral data on plasmas generated in electron beam diodes fielded on the RITS-6 accelerator (8 12MV, 140-200kA) at Sandia National Laboratories. On RITS, plasma light is collected through a small diameter (200 MUm) optical fiber and recorded on a fast streak camera at the output of a 1 meter Czerny-Turner monochromator. For this paper, a 300 W xenon short arc lamp (Oriel Model 6258) was used as the calibration source. Since the radiance of the xenon arc varies from cathode to anode, just the area around the tip of the cathode ("hotspot") was imaged onto the fiber, to produce the highest intensity output. To compensate for chromatic aberrations, the signal was optimized at each wavelength measured. Output power was measured using 10 nm bandpass interference filters and a calibrated photodetector. These measurements give power at discrete wavelengths across the spectrum, and when linearly interpolated, provide a calibration curve for the lamp. The shape of the spectrum is determined by the collective response of the optics, monochromator, and streak tube across the spectral region of interest. The ratio of the spectral curve to the measured bandpass filter curve at each wavelength produces a correction factor (Q) curve. This curve is then applied to the experimental data and the resultant spectra are given in absolute intensity units (photons/sec/cm(2)/steradian/nm). Error analysis shows this method to be accurate to within +/- 20%, which represents a high level of accuracy for this type of measurement. PMID- 22938276 TI - Advanced experimental applications for x-ray transmission gratings spectroscopy using a novel grating fabrication method. AB - A novel fabrication method for soft x-ray transmission grating and other optical elements is presented. The method uses focused-ion-beam technology to fabricate high-quality free standing grating bars on transmission electron microscopy grids. High quality transmission gratings are obtained with superb accuracy and versatility. Using these gratings and back-illuminated CCD camera, absolutely calibrated x-ray spectra can be acquired for soft x-ray source diagnostics in the 100-3000 eV spectral range. Double grating combinations of identical or different parameters are easily fabricated, allowing advanced one-shot application of transmission grating spectroscopy. These applications include spectroscopy with different spectral resolutions, bandwidths, dynamic ranges, and may serve for identification of high-order contribution, and spectral calibrations of various x ray optical elements. PMID- 22938277 TI - High-speed acousto-optic shutter with no optical frequency shift. AB - Acousto-optic modulators are widely used for rapid switching and shuttering of laser beams. In many applications, the concomitant frequency shift is undesirable and must be compensated for elsewhere in the system. Here we present a simple method of achieving rapid laser power switching without an accompanying laser frequency shift. The demonstrated acousto-optic shutter achieves a switching time of around 25 ns, an extinction ratio of 46 dB, and efficiency comparable to a conventional double-pass acousto-optical modulator configuration. PMID- 22938278 TI - Fully integrated InGaAs/InP single-photon detector module with gigahertz sine wave gating. AB - InGaAs/InP single-photon avalanche diodes (SPADs) working in the regime of GHz clock rates are crucial components for the high-speed quantum key distribution (QKD). We have developed for the first time a compact, stable, and user-friendly tabletop InGaAs/InP single-photon detector system operating at a 1.25 GHz gate rate that fully integrates functions for controlling and optimizing SPAD performance. We characterize the key parameters of the detector system and test the long-term stability of the system for continuous operation of 75 h. The detector system can substantially enhance QKD performance and our present work paves the way for practical high-speed QKD applications. PMID- 22938279 TI - Quick-scanning x-ray absorption spectroscopy system with a servo-motor-driven channel-cut monochromator with a temporal resolution of 10 ms. AB - We have developed a quick-scanning x-ray absorption fine structure (QXAFS) system and installed it at the recently constructed synchrotron radiation beamline BL33XU at the SPring-8. Rapid acquisition of high-quality QXAFS data was realized by combining a servo-motor-driven Si channel-cut monochromator with a tapered undulator. Two tandemly aligned monochromators with channel-cut Si(111) and Si(220) crystals covered energy ranges of 4.0-28.2 keV and 6.6-46.0 keV, respectively. The system allows the users to adjust instantly the energy ranges of scans, the starting angles of oscillations, and the frequencies. The channel cut crystals are cooled with liquid nitrogen to enable them to withstand the high heat load from the undulator radiation. Deformation of the reflecting planes is reduced by clamping each crystal with two cooling blocks. Performance tests at the Cu K-edge demonstrated sufficiently high data quality for x-ray absorption near-edge structure and extended x-ray absorption fine-structure analyses with temporal resolutions of up to 10 and 25 ms, respectively. PMID- 22938280 TI - Nuclear magnetic resonance apparatus for pulsed high magnetic fields. AB - A nuclear magnetic resonance apparatus for experiments in pulsed high magnetic fields is described. The magnetic field pulses created together with various magnet coils determine the requirements such an apparatus has to fulfill to be operated successfully in pulsed fields. Independent of the chosen coil it is desirable to operate the entire experiment at the highest possible bandwidth such that a correspondingly large temporal fraction of the magnetic field pulse can be used to probe a given sample. Our apparatus offers a bandwidth of up to 20 MHz and has been tested successfully at the Hochfeld-Magnetlabor Dresden, even in a very fast dual coil magnet that has produced a peak field of 94.2 T. Using a medium-sized single coil with a significantly slower dependence, it is possible to perform advanced multi-pulse nuclear magnetic resonance experiments. As an example we discuss a Carr-Purcell spin echo sequence at a field of 62 T. PMID- 22938281 TI - High-temperature high-pressure all-metal pulsed source of van der Waals dimers: towards the Einstein-Podolsky-Rosen experiment. AB - An all-metal pulsed source of van der Waals (vdW) dimers was constructed; it operates at temperatures up to 1000 K and carrier gas stagnation pressures up to 10 bars. Performance of the source was demonstrated in the production and spectroscopy of both CdAr and Cd(2) molecules in a supersonic beam expansion. Simulation of the recorded laser induced fluorescence (LIF) excitation spectra using the B(3)1(5(3)P(1)) <- X(1)0(+)(5(1)S(0)) and b(3)0(u)(+)(5(3)P(1))< X(1)0(g)(+)(5(1)S(0)) transitions in CdAr and Cd(2), respectively, showed that these molecules were produced with a rotational temperature in the range from 3 K to 19 K. The source was incorporated into an experimental set-up dedicated to the realization of Bohm's spin-1/2 particle version of the Einstein-Podolsky-Rosen experiment for ((111)Cd)(2) molecules. PMID- 22938282 TI - Cryogenic linear Paul trap for cold highly charged ion experiments. AB - Storage and cooling of highly charged ions require ultra-high vacuum levels obtainable by means of cryogenic methods. We have developed a linear Paul trap operating at 4 K capable of very long ion storage times of about 30 h. A conservative upper bound of the H(2) partial pressure of about 10(-15) mbar (at 4 K) is obtained from this. External ion injection is possible and optimized optical access for lasers is provided, while exposure to black body radiation is minimized. First results of its operation with atomic and molecular ions are presented. An all-solid state laser system at 313 nm has been set up to provide cold Be(+) ions for sympathetic cooling of highly charged ions. PMID- 22938283 TI - Development and use of a two-dimensional interferometer to measure mass flow from a multi-shell Z-pinch gas puff. AB - For gas puff Z-pinches, the K-shell x-ray yield is maximized with the use of a multi-shell nozzle. Optimization of the yield, verification of hydrodynamic models of the nozzle flows, and plausible MHD code modeling of the implosions require data on the radial and axial (R,Z) distribution of mass in the nozzle's flow field. Interferometry is a well-established technique for acquiring such data. We describe the development and use of a two-dimensional interferometer with emphasis on the required data reduction methods. We also show that the instrument can derive the flow from each individual nozzle in a multi-shell system. PMID- 22938284 TI - High sensitivity microchannel plate detectors for space extreme ultraviolet missions. AB - Microchannel plate (MCP) detectors have been widely used as two-dimensional photon counting devices on numerous space EUV (extreme ultraviolet) missions. Although there are other choices for EUV photon detectors, the characteristic features of MCP detectors such as their light weight, low dark current, and high spatial resolution make them more desirable for space applications than any other detector. In addition, it is known that the photocathode can be tailored to increase the quantum detection efficiency (QDE) especially for longer UV wavelengths (100-150 nm). There are many types of photocathode materials available, typically alkali halides. In this study, we report on the EUV (50-150 nm) QDE evaluations for MCPs that were coated with Au, MgF(2), CsI, and KBr. We confirmed that CsI and KBr show 2-100 times higher QDEs than the bare photocathode MCPs, while Au and MgF(2) show reduced QDEs. In addition, the optimal geometrical parameters for the CsI deposition were also studied experimentally. The best CsI thickness was found to be 150 nm, and it should be deposited on the inner wall of the channels only where the EUV photons initially impinge. We will also discuss the techniques and procedures for reducing the degradation of the photocathode while it is being prepared on the ground before being deployed in space, as adopted by JAXA's EXCEED mission which will be launched in 2013. PMID- 22938285 TI - An assessment of comparative methods for approaching electrode polarization in dielectric permittivity measurements. AB - We examine the validity of three common methods for analysis and correction of the electrode polarization (EP) effect in dielectric spectroscopy measurements of conductive liquid samples. The methods considered are (i) algorithmic treatment by modeling the EP behavior at constant phase angle, (ii) varying the size of the electrode gap, and (iii) polypyrrole (PPyPss) layered electrodes. The latter is a relatively recent innovation suggested to be an efficient solution. We demonstrate that PPyPss coated electrodes do not diminish the effect of EP, and even add relaxation processes of its own. Our conclusion is that these polymer coated electrodes are not suitable for the correction of electrode polarization. PMID- 22938286 TI - Partial-transfer absorption imaging: a versatile technique for optimal imaging of ultracold gases. AB - Partial-transfer absorption imaging is a tool that enables optimal imaging of atomic clouds for a wide range of optical depths. In contrast to standard absorption imaging, the technique can be minimally destructive and can be used to obtain multiple successive images of the same sample. The technique involves transferring a small fraction of the sample from an initial internal atomic state to an auxiliary state and subsequently imaging that fraction absorptively on a cycling transition. The atoms remaining in the initial state are essentially unaffected. We demonstrate the technique, discuss its applicability, and compare its performance as a minimally destructive technique to that of phase-contrast imaging. PMID- 22938287 TI - Ethanol (C2H5OH) spray of sub-micron droplets for laser driven negative ion source. AB - Liquid ethanol (C(2)H(5)OH) was used to generate a spray of sub-micron droplets. Sprays with different nozzle geometries have been tested and characterised using Mie scattering to find scaling properties and to generate droplets with different diameters within the spray. Nozzles having throat diameters of 470 MUm and 560 MUm showed generation of ethanol spray with droplet diameters of (180 +/- 10) nm and (140 +/- 10) nm, respectively. These investigations were motivated by the observation of copious negative ions from these target systems, e.g., negative oxygen and carbon ions measured from water and ethanol sprays irradiated with ultra-intense (5 * 10(19) W/cm(2)), ultra short (40 fs) laser pulses. It is shown that the droplet diameter and the average atomic density of the spray have a significant effect on the numbers and energies of accelerated ions, both positive and negative. These targets open new possibilities for the creation of efficient and compact sources of different negative ion species. PMID- 22938288 TI - Compact steady-state and high-flux Falcon ion source for tests of plasma-facing materials. AB - This paper describes the design and operation of the Falcon ion source. It is based on conventional design of anode layer thrusters. This ion source is a versatile, compact, affordable, and highly functional in the research field of the fusion materials. The reversed magnetic field configuration of the source allows precise focusing of the ion beam into small spot of ~3 mm and also provides the limited capabilities for impurity mass-separation. As the result, the source generates steady-state ion beam, which irradiates surface with high heat (0.3 - 21 MW m(-2)) and particle fluxes (4 * 10(21) - 3 * 10(23) m(-2)s( 1)), which approaches the upper limit for the flux range expected in ITER. PMID- 22938289 TI - Microtron MT 25 as a source of neutrons. AB - The objective was to describe Microtron MT25 as a source of neutrons generated by bremsstrahlung induced photonuclear reactions in U and Pb targets. Bremsstrahlung photons were produced by electrons accelerated at energy 21.6 MeV. Spectral fluence of the generated neutrons was calculated with MCNPX code and then experimentally determined at two positions by means of a Bonner spheres spectrometer in which the detector of thermal neutrons was replaced by activation Mn tablets or track detectors CR-39 with a (10)B radiator. The measured neutron spectral fluence and the calculated anisotropy served for the estimation of neutron yield from the targets and for the determination of ambient dose equivalent rate at the place of measurement. Microtron MT25 is intended as one of the sources for testing neutron sensitive devices which will be sent into the space. PMID- 22938290 TI - Measurements of parallel electron velocity distributions using whistler wave absorption. AB - We describe a diagnostic to measure the parallel electron velocity distribution in a magnetized plasma that is overdense (omega(pe) > omega(ce)). This technique utilizes resonant absorption of whistler waves by electrons with velocities parallel to a background magnetic field. The whistler waves were launched and received by a pair of dipole antennas immersed in a cylindrical discharge plasma at two positions along an axial background magnetic field. The whistler wave frequency was swept from somewhat below and up to the electron cyclotron frequency omega(ce). As the frequency was swept, the wave was resonantly absorbed by the part of the electron phase space density which was Doppler shifted into resonance according to the relation omega - k([parallel])v([parallel]) = omega(ce). The measured absorption is directly related to the reduced parallel electron distribution function integrated along the wave trajectory. The background theory and initial results from this diagnostic are presented here. Though this diagnostic is best suited to detect tail populations of the parallel electron distribution function, these first results show that this diagnostic is also rather successful in measuring the bulk plasma density and temperature both during the plasma discharge and into the afterglow. PMID- 22938291 TI - Development of a low-energy and high-current pulsed neutral beam injector with a washer-gun plasma source for high-beta plasma experiments. AB - We have developed a novel and economical neutral-beam injection system by employing a washer-gun plasma source. It provides a low-cost and maintenance-free ion beam, thus eliminating the need for the filaments and water-cooling systems employed conventionally. In our primary experiments, the washer gun produced a source plasma with an electron temperature of approximately 5 eV and an electron density of 5 * 10(17) m(-3), i.e., conditions suitable for ion-beam extraction. The dependence of the extracted beam current on the acceleration voltage is consistent with space-charge current limitation, because the observed current density is almost proportional to the 3/2 power of the acceleration voltage below approximately 8 kV. By optimizing plasma formation, we successfully achieved beam extraction of up to 40 A at 15 kV and a pulse length in excess of 0.25 ms. Its low-voltage and high-current pulsed-beam properties enable us to apply this high power neutral beam injection into a high-beta compact torus plasma characterized by a low magnetic field. PMID- 22938292 TI - Development of a diagnostic technique based on Cherenkov effect for measurements of fast electrons in fusion devices. AB - A diagnostic technique based on the Cherenkov effect is proposed for detection and characterization of fast (super-thermal and runaway) electrons in fusion devices. The detectors of Cherenkov radiation have been specially designed for measurements in the ISTTOK tokamak. Properties of several materials have been studied to determine the most appropriate one to be used as a radiator of Cherenkov emission in the detector. This technique has enabled the detection of energetic electrons (70 keV and higher) and the determination of their spatial and temporal variations in the ISTTOK discharges. Measurement of hard x-ray emission has also been carried out in experiments for validation of the measuring capabilities of the Cherenkov-type detector and a high correlation was found between the data of both diagnostics. A reasonable agreement was found between experimental data and the results of numerical modeling of the runaway electron generation in ISTTOK. PMID- 22938293 TI - Layout and results from the initial operation of the high-resolution x-ray imaging crystal spectrometer on the Large Helical Device. AB - First results of ion and electron temperature profile measurements from the x-ray imaging crystal spectrometer (XICS) diagnostic on the Large Helical Device (LHD) are presented. This diagnostic system has been operational since the beginning of the 2011 LHD experimental campaign and is the first application of the XICS diagnostic technique to helical plasma geometry. The XICS diagnostic provides measurements of ion and electron temperature profiles in LHD with a spatial resolution of 2 cm and a maximum time resolution of 5 ms (typically 20 ms). Ion temperature profiles from the XICS diagnostic are possible under conditions where charge exchange recombination spectroscopy (CXRS) is not possible (high density) or is perturbative to the plasma (low density or radio frequency heated plasmas). Measurements are made by using a spherically bent crystal to provide a spectrally resolved 1D image of the plasma from line integrated emission of helium-like Ar(16 +). The final hardware design and configuration are detailed along with the calibration procedures. Line-integrated ion and electron temperature measurements are presented, and the measurement accuracy is discussed. Finally central temperature measurements from the XICS system are compared to measurements from the Thomson scattering and CXRS systems, showing excellent agreement. PMID- 22938294 TI - A collinear self-emission and laser-backlighting imaging diagnostic. AB - In this work we demonstrate a design for obtaining laser backlighting (e.g., interferometry) and time-resolved extreme ultraviolet self-emission images along the same line-of-sight. This is achieved by modifying a single optical component in the laser collection optics with apertures and pinhole arrangements suitable for single or multiple frame imaging onto a gated detector, such as a microchannel plate. Test results for exploding wire experiments show that machining of the optic does not affect the overall quality of the recovered laser images, and that, even with a multiple frame system, the area sacrificed to achieve collinear imaging is relatively small. The diagnostics can therefore allow direct correlation of laser and self-emission images and their derived quantities, such as electron density in the case of interferometry. Simple methods of image correlation are also demonstrated. PMID- 22938295 TI - Radiofrequency antenna for suppression of parasitic discharges in a helicon plasma thruster experiment. AB - A radiofrequency (rf) antenna for helicon plasma thruster experiments is developed and tested using a permanent magnets helicon plasma source immersed in a vacuum chamber. A magnetic nozzle is provided by permanent magnets arrays and an argon plasma is produced by a 13.56 MHz radiofrequency helicon-wave or inductively-coupled discharge. A parasitic discharge outside the source tube is successfully suppressed by covering the rf antenna with a ceramic ring and a grounded shield; a decrease in the ion saturation current of a Langmuir probe located outside the source tube is observed and the ion saturation current on axis increases simultaneously, compared with the case of a standard uncovered rf antenna. It is also demonstrated that the covered antenna can yield stable operation of the source. PMID- 22938296 TI - Separation of ion components produced by plasma-assisted catalytic ionization. AB - Positive and negative hydrogen ions are produced by plasma-assisted catalytic ionization using a porous nickel plate, where the irradiation current density and energy of positive ions produced by discharge to the porous plate are controlled. The ion energy distributions are analyzed from the properties of current densities of positive and negative ions extracted from the porous surface. Positive ions passing through fine pores of the porous plate and positive and negative ions produced on the porous surface are observed. It is clarified that the produced fluxes of positive and negative ions and the flux balance between them are controlled by the irradiation current density and energy, respectively. PMID- 22938297 TI - Differential phase contrast x-ray microimaging with scanning-imaging x-ray microscope optics. AB - A novel x-ray microimaging system that consists of a scanning microscope optics with a one-dimensional focusing (line-focusing) device and an imaging microscope optics with a one-dimensional objective is developed. These two optical systems are set normal to each other regarding the optical axis. A two-dimensional image is obtained with one-dimensional translation scan of the line probe. During scans, positional data in the normal to the scanning direction are obtained simultaneously with the imaging microscope optics. Differential phase contrast (DPC) image and absorption contrast (AC) image can be arbitrarily obtained by image processing after data acquisition. Preliminary experiment has been carried out by using a couple of one-dimensional Fresnel zone plate as the linear focusing device and the one-dimensional objective. Two-dimensional DPC and AC images of test sample have been successfully obtained with 8 keV x-rays. PMID- 22938298 TI - A near-field scanning microwave microscope for characterization of inhomogeneous photovoltaics. AB - We present a near-field scanning microwave microscope (NSMM) that has been configured for imaging photovoltaic samples. Our system incorporates a Pt-Ir tip inserted into an open-ended coaxial cable to form a weakly coupled resonator, allowing the microwave reflection S(11) signal to be measured across a sample over a frequency range of 1 GHz - 5 GHz. A phase-tuning circuit increased impedance-measurement sensitivity by allowing for tuning of the S(11) minimum down to -78 dBm. A bias-T and preamplifier enabled simultaneous, non-contact measurement of the DC tip-sample current, and a tuning fork feedback system provided simultaneous topographic data. Light-free tuning fork feedback provided characterization of photovoltaic samples both in the dark and under illumination at 405 nm. NSMM measurements were obtained on an inhomogeneous, third-generation Cu(In,Ga)Se(2) (CIGS) sample. The S(11) and DC current features were found to spatially broaden around grain boundaries with the sample under illumination. The broadening is attributed to optically generated charge that becomes trapped and changes the local depletion of the grain boundaries, thereby modifying the local capacitance. Imaging provided by the NSMM offers a new RF methodology to resolve and characterize nanoscale electrical features in photovoltaic materials and devices. PMID- 22938299 TI - Confocal micro-x-ray fluorescence spectrometer for light element analysis. AB - An existing micro-x-ray fluorescence (micro-XRF) spectrometer designed for light element analysis (6 <= Z <= 14) has been extended to confocal geometry: a second polycapillary x-ray optic has been introduced in front of the energy dispersive x ray detector. New piezo positioners for optimum alignment of both optics have been installed inside the vacuum chamber. The spectrometer offers now the possibility of true 3D elemental analysis in the micrometer regime. Depth resolution varies between 100 MUm at 1 keV fluorescence energy (Na-Kalpha) and 30 MUm for 17.5 keV (Mo). To further extend analytical capabilities a second x-ray tube with a Rh anode has been acquired to supplement to existing Mo anode tube. Lower limits of detection have been determined to be in the ppm region for confocal geometry. The spectrometer has been characterized and tested using different samples. Furthermore, results have been compared with SR micro-XRF to show the capabilities and limitations of this spectrometer. PMID- 22938300 TI - Method of electrochemical etching of tungsten tips with controllable profiles. AB - We demonstrate a new and simple process to fabricate tungsten tips with good control of the tip profile. In this process, we use a commercial function generator without any electronic cutoff circuit or complex mechanical setup. The tip length can be varied from 160 MUm to 10 mm, corresponding to an aspect ratio of 1.6-100. The radius of curvature of the tip apex can be controlled to a size <10 nm. Surface roughness and the taper angle can be controlled independently. Through control of the etching parameters, the tip length, the radius of curvature, surface roughness, and the taper angle can be controlled to suit different requirements of various applications. The possible etching mechanisms are also discussed. PMID- 22938301 TI - A compact instrument for adjusting laser beams to be accurately coincident and coaxial and its use in biomedical imaging using wave-mixed laser sources. AB - Biomedical imaging applications that involve nonlinear optical processes such as sum-frequency generation (SFG) and four-wave mixing require that the pulses are synchronized in time and the beams are coaxial to better than 400 MUrad. For this reason, folding mirrors are normally used to extend the beam path over a few meters so that detectors can be put into the beams to check their overlap at the start of a long path and also at the end of it. We have made a portable instrument with a footprint of only 22 cm * 11 cm * 16 cm that uses a short focal length lens and a telephoto combination for viewing the near-field and far-field simultaneously. Our instrument is simple to build and use, and we show its application in coherent anti-Stokes Raman scattering microscopy and SFG-based two photon fluorescence microscopy. PMID- 22938302 TI - Dark field photoelectron emission microscopy of micron scale few layer graphene. AB - We demonstrate dark field imaging in photoelectron emission microscopy (PEEM) of heterogeneous few layer graphene (FLG) furnace grown on SiC(000-1). Energy filtered, threshold PEEM is used to locate distinct zones of FLG graphene. In each region, selected by a field aperture, the k-space information is imaged using appropriate transfer optics. By selecting the photoelectron intensity at a given wave vector and using the inverse transfer optics, dark field PEEM gives a spatial distribution of the angular photoelectron emission. In the results presented here, the wave vector coordinates of the Dirac cones characteristic of commensurate rotations of FLG on SiC(000-1) are selected providing a map of the commensurate rotations across the surface. This special type of contrast is therefore a method to map the spatial distribution of the local band structure and offers a new laboratory tool for the characterisation of technically relevant, microscopically structured matter. PMID- 22938303 TI - Magneto-optical system for high speed real time imaging. AB - A new magneto-optical system has been developed to expand the range of high speed real time magneto-optical imaging. A special source for the external magnetic field has also been designed, using a pump solenoid to rapidly excite the field coil. Together with careful modifications of the cryostat, to reduce eddy currents, ramping rates reaching 3000 T/s have been achieved. Using a powerful laser as the light source, a custom designed optical assembly, and a high speed digital camera, real time imaging rates up to 30 000 frames per seconds have been demonstrated. PMID- 22938304 TI - Resonant control of an atomic force microscope micro-cantilever for active Q control. AB - Active Q control may be used to modify the effective quality (Q) factor of an atomic force microscope (AFM) micro-cantilever when operating in tapping mode. The control system uses velocity feedback to obtain an effective cantilever Q factor to achieve optimal scan speed and image resolution for the imaging environment and sample type. Time delay of the cantilever displacement signal is the most common method of cantilever velocity estimation. Spill-over effects from unmodeled dynamics may degrade the closed loop system performance, possibly resulting in system instability, when time delay velocity estimation is used. A resonant controller is proposed in this work as an alternate method of velocity estimation. This new controller has guaranteed closed loop stability, is easy to tune, and may be fitted into existing commercial AFMs with minimal modification. Images of a calibration grating are obtained using this controller to demonstrate its effectiveness. PMID- 22938305 TI - Instrumentation for dual-probe scanning near-field optical microscopy. AB - To investigate local carrier motions, we developed a dual-probe scanning near field optical microscope (SNOM) with two fiber probes where one is for photoexcitation and the other is for light collection. This instrumentation is based on two important techniques: the design of probe structures and distance control between the sample surface and the two probes. A finite-difference time domain method numerically analyzed and optimized the design for high efficiency photoexcitation and light collection, while a dual band modulation realized distance control. Real time detection of the oscillations of the probe tips using different frequencies independently controls the distance between the probe tip and the sample surface as well as the distance between the two probes. Thus, the collection probe can be scanned around an illumination probe without destroying the probe tips. To demonstrate our SNOM, we performed photoluminescence spectroscopy under the dual-probe configuration and observed carrier motions in an InGaN quantum well. PMID- 22938306 TI - Improving the signal-to-noise ratio of high-speed contact mode atomic force microscopy. AB - During high-speed contact mode atomic force microscopy, higher eigenmode flexural oscillations of the cantilever have been identified as the main source of noise in the resultant topography images. We show that by selectively filtering out the frequencies corresponding to these oscillations in the time domain prior to transforming the data into the spatial domain, significant improvements in image quality can be achieved. PMID- 22938307 TI - Three-axis correction of distortion due to positional drift in scanning probe microscopy. AB - Two common sources of distortion in scanning probe microscopy are piezo creep and thermal drift, the latter caused by slow thermal expansions of materials in the sample and microscope due to small changes in temperature over the course of a scan. We present a technique for correcting distortion due to thermal drift along all three spatial axes, along with simultaneous correction of z-axis piezo creep. Our method works by comparing each scanned topographical image to a second, partial scan, taken immediately afterwards, on which the fast and slow scan axes have been reversed. We model the positional distortion as a low-order polynomial function in three dimensions, searching for the set of correctional coefficients that minimizes the root-mean-square difference between the two scans. We demonstrate in a variety of real-world and simulated tests that this technique can routinely reduce distortion from these effects by over 90%, often to a precision of better than a single pixel. PMID- 22938308 TI - Appearance potential spectroscopy with a photon counting detector and multiple scattering spectral interpretation. AB - We describe a soft x-ray appearance potential spectroscopy apparatus, which uses a windowless hyperpure Ge detector operated in the photon counting mode. Direct comparisons of recorded spectra with the self-convolution of x-ray absorption spectra and with ab initio simulations in the multiple scattering framework are reported and discussed. PMID- 22938309 TI - Practical system for the direct measurement of magneto-caloric effect by micro thermocouples. AB - A system for direct measurements of the magneto-caloric effect (MCE) exploits a rapid transport of a sample into or from magnetic field in permanent Halbach-type (1 T) or superconducting (4.7 T) magnets. Time dependence of induced changes of the sample temperature, DeltaT(t), is detected directly by the differential Cu Constantan-Cu micro-thermocouples with time steps of 300 ms. A sample placed inside an evacuated simple LN(2) cryostat is either totally isolated (adiabatic conditions) or partly connected with the copper sample holder (non-adiabatic conditions). The last arrangement (a model of the Brayton cycle) is used to simulate an application of MCE in refrigeration techniques. The relations describing DeltaT(t) that allow an analysis of MCE of the studied materials are based on the general cooling law. The effect of the first-order magnetic transition on MCE of selected sample is also demonstrated by non-standard DeltaT(t) curves measured in the last mentioned experimental arrangements. PMID- 22938310 TI - Metallic Coulomb blockade thermometry down to 10 mK and below. AB - We present an improved nuclear refrigerator reaching 0.3 mK, aimed at microkelvin nanoelectronic experiments, and use it to investigate metallic Coulomb blockade thermometers (CBTs) with various resistances R. The high-R devices cool to slightly lower T, consistent with better isolation from the noise environment, and exhibit electron-phonon cooling [proportional] T(5) and a residual heat-leak of 40 aW. In contrast, the low-R CBTs display cooling with a clearly weaker T dependence, deviating from the electron-phonon mechanism. The CBTs agree excellently with the refrigerator temperature above 20 mK and reach a minimum-T of 7.5 +/- 0.2 mK. PMID- 22938311 TI - A compact high vacuum heating chamber for in-situ x-ray scattering studies. AB - A very compact multi purpose high vacuum heating chamber for x-ray scattering techniques was developed. The compact design allows the chamber to be installed on high precision diffractometers which usually cannot support heavy and/or large equipment. The chamber is covered by a Be dome allowing full access to the hemisphere above the sample which is required for in-plane grazing incident x-ray diffraction and out-off plane wide angle x-ray diffraction. PMID- 22938312 TI - The Oxford-Diamond In Situ Cell for studying chemical reactions using time resolved X-ray diffraction. AB - A versatile, infrared-heated, chemical reaction cell has been assembled and commissioned for the in situ study of a range of chemical syntheses using time resolved energy-dispersive X-ray diffraction (EDXRD) on Beamline I12 at the Diamond Light Source. Specialized reactor configurations have been constructed to enable in situ EDXRD investigation of samples under non-ambient conditions. Chemical reactions can be studied using a range of sample vessels such as alumina crucibles, steel hydrothermal autoclaves, and glassy carbon tubes, at temperatures up to 1200 degrees C. PMID- 22938313 TI - An RF-powered micro-reactor for the detection of astrobiological target molecules on planetary bodies. AB - We describe a sample-processing micro-reactor that utilizes 60 GHz RF radiation with approximately 730 mW of output power. The instrument design and performance characterization are described and then illustrated with modeling and experimental studies. The micro-reactor's efficiency on affecting hydrolysis of chemical bonds similar to those within large complex molecules was demonstrated: a disaccharide-sucrose-was hydrolyzed completely under micro-reactor conditions. The products of the micro-reactor-facilitated hydrolysis were analyzed using mass spectroscopy and proton nuclear magnetic resonance analytical techniques. PMID- 22938315 TI - Characterization of a scintillating mini-detector for time-of-flight positron emission tomography with depth-of-interaction. AB - By exploiting a suitable treatment of the scintillator surfaces, along with silicon photomultiplier photodetectors and specific algorithms for raw data analysis, we achieved a remarkable tradeoff between energy, time, and depth-of interaction (DOI) resolution, thus supporting the feasibility of a prostate time of-flight positron emission tomography probe, magnetic resonance imaging compatible, with the required features and performance. In numbers this means a detector element of 1.5 mm * 1.5 mm * 10 mm, promising to achieve at the same time energy resolution around 11.5%, coincidence resolving time around 300 ps corresponding to a space resolution <5 cm along the line of response, and DOI resolution even below 1 mm. We stress that such a time resolution allows to increase significantly the noise equivalent counting rate, and consequently improve the image quality and the lesion detection capability. PMID- 22938314 TI - An instrument for fast acquisition of fluorescence decay curves at picosecond resolution designed for "double kinetics" experiments: application to fluorescence resonance excitation energy transfer study of protein folding. AB - The information obtained by studying fluorescence decay of labeled biopolymers is a major resource for understanding the dynamics of their conformations and interactions. The lifetime of the excited states of probes attached to macromolecules is in the nanosecond time regime, and hence, a series of snapshot decay curves of such probes might - in principle - yield details of fast changes of ensembles of labeled molecules down to sub-microsecond time resolution. Hence, a major current challenge is the development of instruments for the low noise detection of fluorescence decay curves within the shortest possible time intervals. Here, we report the development of an instrument, picosecond double kinetics apparatus, that enables recording of multiple fluorescence decay curves with picosecond excitation pulses over wide spectral range during microsecond data collection for each curve. The design is based on recording and averaging multiphoton pulses of fluorescence decay using a fast 13 GHz oscilloscope during microsecond time intervals at selected time points over the course of a chemical reaction or conformational transition. We tested this instrument in a double kinetics experiment using reference probes (N-acetyl-tryptophanamide). Very low stochastic noise level was attained, and reliable multi-parameter analysis such as derivation of distance distributions from time resolved FRET (fluorescence resonance excitation energy transfer) measurements was achieved. The advantage of the pulse recording and averaging approach used here relative to double kinetics methods based on the established time correlated single photon counting method, is that in the pulse recording approach, averaging of substantially fewer kinetic experiments is sufficient for obtaining the data. This results in a major reduction in the consumption of labeled samples, which in many cases, enables the performance of important experiments that were not previously feasible. PMID- 22938316 TI - A soft and transparent handleable protein model. AB - The field of structural biology currently relies on computer-generated graphical representations of three-dimensional (3D) structures to conceptualize biomolecules. As the size and complexity of the molecular structure increases, model generation and peer discussions become more difficult. It is even more problematic when discussing protein-protein interactions wherein large surface area contact is considered. This report demonstrates the viability of a new handleable protein molecular model with a soft and transparent silicone body similar to the molecule's surface. A full-color printed main chain structure embedded in the silicone body enables users to simultaneously feel the molecular surface, view through the main chain structure, and manually simulate molecular docking. The interactive, hands-on experience deepens the user's intuitive understanding of the complicated 3D protein structure and elucidates ligand binding and protein-protein interactions. This model would be an effective discussion tool for the classroom or laboratory that stimulates inspired learning in this study field. PMID- 22938317 TI - Core-flood experiment for transport of reactive fluids in rocks. AB - Investigation of the transport of reactive fluids in porous rocks is an intriguing but challenging task and relevant in several areas of science and engineering such as geology, hydrogeology, and petroleum engineering. We designed and constructed an experimental setup to investigate physical and chemical processes caused by the flow of reactive and volatile fluids such as supercritical CO(2) and/or H(2)S in geological formations. Potential applications are geological sequestration of CO(2) in the frame of carbon capture and storage and acid-gas injection for sulfur disposal and/or enhanced oil recovery. The present paper outlines the design criteria and the realization of reactive transport experiments on the laboratory scale. We focus on the spatial and time evolution of rock and fluid composition as a result of chemical rock fluid interaction and the coupling of chemistry and fluid flow in porous rocks. PMID- 22938318 TI - Filamentary streamer discharges in argon at atmospheric pressure excited by surface plasmon polaritons. AB - This paper describes a microwave plasma jet in an argon atmosphere capable of generating filamentary streamer discharges within the entire quartz tube excited by surface waves of surface plasmon polaritons (SPPs) located in the tube. Several discharge streamers are immediately produced at the end of the copper wire when incident power reaches 20 W. From simulations, the wavelength of the surface wave was found to be approximately 5.7 cm. Although the developing streamers induce E-field enhancements favoring discharging, more streamer bifurcations requiring additional energy to maintain discharging diminish the resonant enhanced E-field. The underlying mechanism of the proposed plasma jet is resonant excitation of SPPs and its interaction with plasmas. PMID- 22938319 TI - Novel synchronization technique for two parallel connected sparkgap switches. AB - In this article a novel way of synchronizing two parallel connected sparkgap switches with accuracies of 1-5 ns for high frequency pulsed power applications is described. The circuit design of a synchronized sparkgap switch circuit is discussed. The circuit uses a combination of one master sparkgap and a set of inductor and capacitors to synchronize two sparkgaps and can be controlled via an IGBT switch. Critical issues for circuit design are presented together with analytical calculations and simulations. Experimental verification of the novel topology is carried out in a prototype experimental setup. Results showing nanosecond level of accuracy in synchronization are reported in this paper along with simulations and analysis. PMID- 22938320 TI - A modularized pulse forming line using glass-ceramic slabs. AB - In our lab, a kind of glass-ceramic slab has been chosen to study the issues of applying solid-state dielectrics to pulse forming lines (PFLs). Limited by the manufacture of the glass-ceramic bulk with large sizes, a single ceramic slab is hard to store sufficient power for the PFL. Therefore, a modularized PFL design concept is proposed in this paper. We regard a single ceramic slab as a module to form each single Blumlein PFL. We connect ceramic slabs in series to enlarge pulse width, and stack the ceramic Blumlein PFLs in parallel to increase the output voltage amplitude. Testing results of a single Blumlein PFL indicate that one ceramic slab contributes about 11 ns to the total pulse width which has a linear relation to the number of the ceramic slabs. We have developed a prototype facility of the 2-stage stacked Blumlein PFL with a length of 2 ceramic slabs. The PFL is dc charged up to 5 kV, and the output voltage pulse of 10 kV, 22 ns is measured across an 8 Omega load. Simulation and experiment results in good agreement demonstrate that the modularized design is reasonable. PMID- 22938321 TI - Wide-band current preamplifier for conductance measurements with large input capacitance. AB - A wide-band current preamplifier based on a composite operational amplifier is proposed. It has been shown that the bandwidth of the preamplifier can be significantly increased by enhancing the effective open-loop gain. The described 10(7) V/A current gain preamplifier had the bandwidth of about 100 kHz with the 1 nF input shunt capacitance. The measured preamplifier current noise was 46 fA/?Hz at 1 kHz, close to the design noise minimum. The voltage noise was found to be about 2.9 nV/?Hz at 1 kHz, which is in a good agreement with the value expected for the particular operational amplifier used in the input stage. By analysing the total produced noise we found that the optimal frequency range suitable for the fast lock-in measurements is from 1 kHz to 2 kHz. To obtain the same signal to-noise ratio, the reported preamplifier requires ~10% of the integration time needed in measurements made with a conventional preamplifier. PMID- 22938322 TI - Compact radio-frequency resonator for cryogenic ion traps. AB - We report on the investigation and implementation of a lumped-component, radio frequency resonator used in a cryogenic vacuum environment to drive an ion trap. The resonator was required to achieve the voltages necessary to trap (~100 V), while dissipating very little power. Ultimately, for an input voltage of 1.35 V, a voltage gain of 100 was measured at 5.7 K, using a design which dissipated only 18 mW. The resonator operated at a frequency of 7.64 MHz and had a Q of 700. Single (40)Ca(+) ions were confined in a trap driven by this device, providing proof of successful resonator operation at low temperature. PMID- 22938323 TI - Safe and consistent method of spot-welding platinum thermocouple wires and foils for high temperature measurements. AB - A low-voltage (mV) electronically triggered spot welding system for fabricating fine thermocouples and thin sheets used in high-temperature characterization of materials' properties is suggested. The system is based on the capacitance discharge method with a timed trigger for obtaining reliable and consistent welds. In contrast to existing techniques based on employing high voltage DC supplies for charging the capacitor or supplies with positive and negative rails, this method uses a simple, standard dual power supply available at most of the physical laboratories or can be acquired at a low cost. In addition, an efficient and simple method of fabricating non-sticking electrodes that do not contaminate the weld area is suggested and implemented. PMID- 22938324 TI - High resolution resistive thermometry for micro/nanoscale measurements. AB - High resolution thermometry plays an important role in several micro/nanoscale studies. Here, we present a detailed analysis of the resolution of resistance thermometry schemes that employ an electrical sensing current to monitor the temperature-dependent resistance. Specifically, we theoretically and experimentally analyze four different schemes where modulated or unmodulated temperatures in microdevices are measured using modulated or unmodulated sensing currents. Our analysis and experiments suggest that measurement of unmodulated temperatures using a modulated sensing current improves the resolution in comparison to a scenario where an unmodulated sensing current is used. However, depending on the exact measurement conditions, such improvements might be modest as the overall resolution may be limited by random low frequency environmental temperature fluctuations. More importantly, we find that high-resolution thermometry can be achieved in the measurement of modulated temperatures. Specifically, we show that by using appropriate instrumentation and a 10 kOmega platinum resistance thermometer it is possible to measure modulated temperatures (0.5-20 Hz) with a resolution of about 20-100 MUK. The advances described here will enable a dramatic improvement in the heat-current resolution of resistive thermometry based microdevices that are used for probing nanoscale phonon and photon transport. PMID- 22938325 TI - Adaptive feed-forward hysteresis compensation for piezoelectric actuators. AB - Piezoelectric actuators are often employed for high-resolution positioning tasks. Hysteresis and creep nonlinearities inherent in such actuators deteriorate positioning accuracy. An online adaptive nonlinear hysteresis compensation scheme for the case of symmetric hysteretic responses and certain periodic reference trajectories is presented. The method has low complexity and is well suited for real-time implementation. Experimental results are presented in order to verify the method, and it is seen that the error due to hysteresis is reduced by more than 90% compared to when assuming a linear response. PMID- 22938326 TI - Liquid nitrogen in fluid dynamics: visualization and velocimetry using frozen particles. AB - High-Reynolds-number flows are common both in nature and industrial applications, but are difficult to attain in laboratory settings using standard test fluids such as air and water. To extend the Reynolds number range, water and air have been replaced at times by low-viscosity fluids such as pressurized air, sulfur hexafluoride, and cryogenic nitrogen gas, as well as liquid and gaseous helium. With a few exceptions, liquid nitrogen has been neglected despite the fact that it has a kinematic viscosity of about a fifth of that of water at room temperature. We explore the use of liquid nitrogen here. In particular, we study the use of frozen particles for flow visualization and velocimetry in liquid nitrogen. We create particles in situ by injecting a gaseous mixture of room temperature nitrogen and an additional seeding gas into the flow. We present a systematic study of potential seeding gases to determine which create particles with the best fidelity and optical properties. The technique has proven capable of producing sub-micrometer sized tracers that allow particle tracking and particle image velocimetry. We review possible high-Reynolds-number experiments using this technique, and discuss the merits and challenges of using liquid nitrogen as a test fluid. PMID- 22938327 TI - Development of a compact and long range XYtheta(z) nano-positioning stage. AB - In this study, we describe the development of a novel, compact, and long range in plane XYtheta(z) nano-positioning stage with piezoelectric actuator and flexure mechanism. The stage is composed of an X-directional motion part and a Y, theta(z)-directional motion part, which are linked serially. The stage consists of a bridge-type amplifying mechanism for the amplification of deformation of the piezoelectric actuator, a double compound guide mechanism for performing only desired motion, and a circular hinge mechanism that permits rotational motion in the Y and theta(z)-stages. To set the design variables of the stage, optimal design is carried out. To verify the results of the optimal design process and the performance of the stage, the FEM simulation and experiment are carried out. The proposed XYtheta(z) nano-positioning stage has a translational motion range of 700 MUm and a rotational motion range of 0.3 degrees ; it has a closed-loop resolution of 5 nm, 5 nm, and 0.025 arcsec in the X-, Y-, and theta(z) directional motions, respectively. The proposed stage is a novelty in that it has a compact size of 200 * 200 * 30 mm(3), and decoupled kinematic design. PMID- 22938329 TI - Vertical impedance measurements on concrete bridge decks for assessing susceptibility of reinforcing steel to corrosion. AB - Corrosion is a pressing problem for aging concrete infrastructure, especially bridge decks. Because of its sensitivity to factors that affect corrosion of reinforcing steel in concrete, resistivity is an important structural health indicator for reinforced concrete structures. In this research, an instrument was developed to measure vertical impedance on concrete bridge decks. Measurements of vertical impedance on slabs prepared in the laboratory, on slabs removed from decommissioned bridge decks, and on an in-service bridge deck in the field demonstrate the utility of the new apparatus. PMID- 22938328 TI - Cavity ring-down spectroscopy with an automated control feedback system for investigating nitrate radical surface chemistry reactions. AB - Nitrate radical (NO(3)(?)) surface chemistry of indoor environments has not been well studied due to the difficulty in generating and maintaining NO(3)(?) at low concentrations for long term exposures. This article presents the Surface Chemistry Reactant Air Delivery and Experiment System (SCRADES), a novel feedback controlled system developed to deliver nitrate radicals at specified concentrations (50-500 ppt, +/-30 ppt) and flow rates (500-2000 ml min(-1)) to a variety of indoor surfaces to initiate reaction chemistry for periods of up to 72 h. The system uses a cavity ring-down spectrometer (CRDS), with a detection limit of 1.7 ppt, to measure the concentration of NO(3)(?) supplied to a 24 l experiment chamber. Nitrate radicals are introduced via thermal decomposition of N(2)O(5) and diluted with clean dry air until the desired concentration is achieved. Additionally, this article addresses details concerning NO(3)(?) loss through the system, consistency of the NO(3)(?) concentration delivered, and stability of the CRDS cavity over long exposure durations (72 h). PMID- 22938330 TI - A new instrument for dynamic helical squeeze flow which superposes oscillatory shear and oscillatory squeeze flow. AB - Simple shear flow has been widely used as a model flow system to investigate the rheological properties of complex fluids. Although it is useful and easy to apply, the shear flow is too simple compared with the complicated flows encountered in real processes. For this reason, it is necessary to study the rheological properties of viscoelastic fluids subjected to more complicated flow field. In this paper, we report a new instrument in which dynamic helical squeeze flow is generated. It superimposes the oscillatory squeeze flow on the oscillatory shear flow, and was designed to get more information on the microstructural change of complex fluids in the flow field which is more complex than conventional simple shear but is still well-defined. This instrument has advantages: the shear and normal stresses can be obtained simultaneously under the coupled flow field; the present design can be used to investigate the structural anisotropy in the direction of both rotational and vertical motion. This study provides a new design and methodology to investigate the rheological responses of complex fluids under dynamic helical squeeze flow. PMID- 22938331 TI - Design and development of a novel nuclear magnetic resonance detection for the gas phase ions by magnetic resonance acceleration technique. AB - Nuclear magnetic resonance (NMR) technique is a well-established powerful tool to study the physical and chemical properties of a wide range of materials. However, presently, NMR applications are essentially limited to materials in the condensed phase. Although magnetic resonance was originally demonstrated in gas phase molecular beam experiments, no application to gas phase molecular ions has yet been demonstrated. Here, we present a novel principle of NMR detection for gas phase ions based on a "magnetic resonance acceleration" technique and describe the design and construction of an apparatus which we are developing. We also present an experimental technique and some results on the formation and manipulation of cold ion packets in a strong magnetic field, which are the key innovations to detect NMR signal using the present method. We expect this novel method to lead new realm for the study of mass-selected gas-phase ions with interesting applications in both fundamental and applied sciences. PMID- 22938332 TI - Isochoric heating of foamed metal using pulsed power discharge as a making technique of warm dense matter. AB - To generate well-defined warm dense state for evaluating electrical conductivity by using pulsed-power discharge, we have proposed an isochoric heating of foamed metal. Isochoric heating can be achieved by surrounding the foamed metal with a rigid-walled sapphire capillary. We evaluate the temperature and electrical conductivity of the foam/plasma based on the line-pair method of the foam/plasma emission and on the voltage-current waveforms. The electrical conductivity observed agrees with previous experiments and predictions. Thus, the proposed technique yields the electrical conductivity of warm dense matter with a well defined temperature. PMID- 22938333 TI - Novel Euler-LaCoste linkage as a very low frequency vertical vibration isolator. AB - LaCoste linkage vibration isolators have shown excellent performance for ultra low frequency vertical vibration isolation. However, such isolators depend on the use of conventional pre-stressed coil springs, which suffer from creep. Here, we show that compressional Euler springs can be configured to create a stable tension unit for use in a LaCoste structure. In a proof of concept experiment, we demonstrate a vertical resonance frequency of 0.15 Hz in an Euler-LaCoste configuration with 200 mm height. The system enables the use of very low creep maraging steel as spring elements to eliminate the creep while minimising spring mass and reducing the effect of parasitic resonances. Larger scale systems with optimized Euler spring boundary conditions should achieve performance suitable for applications on third generation gravitational wave detectors such as the proposed Einstein telescope. PMID- 22938334 TI - High pressure sample cell for total internal reflection fluorescence spectroscopy at pressures up to 2500 bar. AB - Total internal reflection fluorescence (TIRF) spectroscopy is a surface sensitive technique that is widely used to characterize the structure and dynamics of molecules at planar liquid-solid interfaces. In particular, biomolecular systems, such as protein adsorbates and lipid membranes can easily be studied by TIRF spectroscopy. Applying pressure to molecular systems offers access to all kinds of volume changes occurring during assembly of molecules, phase transitions, and chemical reactions. So far, most of these volume changes have been characterized in bulk solution, only. Here, we describe the design and performance of a high pressure sample cell that allows for TIRF spectroscopy under high pressures up to 2500 bar (2.5 * 10(8) Pa), in order to expand the understanding of volume effects from the bulk phase to liquid-solid interfaces. The new sample cell is based on a cylindrical body made of Nimonic 90 alloy and incorporates a pressure transmitting sample cuvette. This cuvette is composed of a fused silica prism and a flexible rubber gasket. It contains the sample solution and ensures a complete separation of the sample from the liquid pressure medium. The sample solution is in contact with the inner wall of the prism forming the interface under study, where fluorescent molecules are immobilized. In this way, the new high pressure TIRF sample cell is very useful for studying any biomolecular layer that can be deposited at a planar water-silica interface. As examples, high pressure TIRF data of adsorbed lysozyme and two phospholipid membranes are presented. PMID- 22938335 TI - Design and implementation of a versatile and variable-frequency piezoelectric coefficient measurement system. AB - We present a simple but versatile piezoelectric coefficient measurement system, which can measure the longitudinal and transverse piezoelectric coefficients in the pressing and bending modes, respectively, at different applied forces and a wide range of frequencies. The functionality of this measurement system has been demonstrated on three samples, including a PbZr(0.52)Ti(0.48)O(3) (PZT) piezoelectric ceramic bulk, a ZnO thin film, and a laminated piezoelectric film sensor. The static longitudinal piezoelectric coefficients of the PZT bulk and the ZnO film are estimated to be around 210 and 8.1 pC/N, respectively. The static transverse piezoelectric coefficients of the ZnO film and the piezoelectric film sensor are determined to be, respectively, -0.284 and -0.031 C/m(2). PMID- 22938336 TI - High-resolution thermal expansion measurements under helium-gas pressure. AB - We report on the realization of a capacitive dilatometer, designed for high resolution measurements of length changes of a material for temperatures 1.4 K <= T <= 300 K and hydrostatic pressure P <= 250 MPa. Helium ((4)He) is used as a pressure-transmitting medium, ensuring hydrostatic-pressure conditions. Special emphasis has been given to guarantee, to a good approximation, constant-pressure conditions during temperature sweeps. The performance of the dilatometer is demonstrated by measurements of the coefficient of thermal expansion at pressures P ~/= 0.1 MPa (ambient pressure) and 104 MPa on a single crystal of azurite, Cu(3)(CO(3))(2)(OH)(2), a quasi-one-dimensional spin S = 1/2 Heisenberg antiferromagnet. The results indicate a strong effect of pressure on the magnetic interactions in this system. PMID- 22938337 TI - The resonant radio-frequency magnetic probe tuned by coaxial cable. AB - In this paper, the resonant rf magnetic probe is upgraded by replacing the rotary capacitor in the old version with the series-connected coaxial cable. The numerical calculation and the measurement with the prototype probe show that the rf magnetic probe can achieve resonance at a middle length of the series connected coaxial cable. The good electrical symmetry of the new rf magnetic probe is ensured by both the identity of series-connected coaxial cables and the new structure of the primary winding. Practical measurements conduced on an rf inductively coupled plasma source demonstrate that performances of the new rf magnetic probe are good. PMID- 22938338 TI - New-generation of cryogenic sapphire microwave oscillators for space, metrology, and scientific applications. AB - This article reports on the characterization of cryogenic sapphire oscillators (CSOs), and on the first test of a CSO in a real field installation, where ultimate frequency stability and continuous operation are critical issues, with no survey. Thanks to low-vibration liquid-He cryocooler design, Internet monitoring, and a significant effort of engineering, these oscillators could bridge the gap from an experiment to a fully reliable machine. The cryocooler needs scheduled maintenance every 2 years, which is usual for these devices. The direct comparison of two CSOs demonstrates a frequency stability of 5 * 10(-16) for 30 s <= tau <= 300 s integration time, and 4.5 * 10(-15) at 1 day (1 * 10( 14) typical). Two prototypes are fully operational, codenamed ELISA and ULISS. ELISA has been permanently installed the new deep space antenna station of the European Space Agency in Malargue, Argentina, in May 2012. ULISS is a transportable version of ELISA, modified to fit in a small van (8.5 m(2) footprint). Installation requires a few hours manpower and 1 day of operation to attain full stability. ULISS, intended for off-site experiments and as a technology demonstrator, and has successfully completed two long-distance travels. PMID- 22938339 TI - Ultra-precise tracking control of piezoelectric actuators via a fuzzy hysteresis model. AB - In this paper, a novel Takagi-Sugeno (T-S) fuzzy system based model is proposed for hysteresis in piezoelectric actuators. The antecedent and consequent structures of the fuzzy hysteresis model (FHM) can be, respectively, identified on-line through uniform partition approach and recursive least squares (RLS) algorithm. With respect to controller design, the inverse of FHM is used to develop a feedforward controller to cancel out the hysteresis effect. Then a hybrid controller is designed for high-performance tracking. It combines the feedforward controller with a proportional integral differential (PID) controller favourable for stabilization and disturbance compensation. To achieve nanometer scale tracking precision, the enhanced adaptive hybrid controller is further developed. It uses real-time input and output data to update FHM, thus changing the feedforward controller to suit the on-site hysteresis character of the piezoelectric actuator. Finally, as to 3 cases of 50 Hz sinusoidal, multiple frequency sinusoidal and 50 Hz triangular trajectories tracking, experimental results demonstrate the efficiency of the proposed controllers. Especially, being only 0.35% of the maximum desired displacement, the maximum error of 50 Hz sinusoidal tracking is greatly reduced to 5.8 nm, which clearly shows the ultra precise nanometer-scale tracking performance of the developed adaptive hybrid controller. PMID- 22938340 TI - Bioparticles assembled using low frequency vibration immune to evacuation drifts. AB - The use of low frequency vibration on suspensions of glass beads in a droplet has been shown to develop a strong degree of patterning (to a ring) due to the manner with which the surface waves are modified. Functionalized glass beads that serve as bioparticles permit for sensitive readings when concentrated at specific locations. However, a time controlled exposure with analytes is desirable. The replacement of the liquid medium with analyte through extraction is needed to conserve time. Nevertheless, we show here that extraction with a porous media, which is simple and useable in the field, will strongly displace the patterned beads. The liquid removal was found to be dependent on two mechanisms that affect the shape of the droplet, one of contact hysteresis due to the outer edge pinning, and the other of liquid being drawn into the porous media. From this, we developed and demonstrated a modified well structure that prevented micro-bead displacement during evacuation. An added strong advantage with this approach lies with its ability to require only analytes to be dispensed at the location of aggregated particles, which minimizes analyte usage. This was analytically established here. PMID- 22938341 TI - A polyvalent harmonic coil testing method for small-aperture magnets. AB - A method to characterize permanent and fast-pulsed iron-dominated magnets with small apertures is presented. The harmonic coil measurement technique is enhanced specifically for small-aperture magnets by (1) in situ calibration, for facing search-coil production inaccuracy, (2) rotating the magnet around its axis, for correcting systematic effects, and (3) measuring magnetic fluxes by stationary coils at different angular positions for measuring fast pulsed magnets. This method allows a quadrupole magnet for particle accelerators to be characterized completely, by assessing multipole field components, magnetic axis position, and field direction. In this paper, initially the metrological problems arising from testing small-aperture magnets are highlighted. Then, the basic ideas of the proposed method and the architecture of the corresponding measurement system are illustrated. Finally, experimental validation results are shown for small aperture permanent and fast-ramped quadrupole magnets for the new linear accelerator Linac4 at CERN (European Organization for Nuclear Research). PMID- 22938342 TI - A study of beam position diagnostics using beam-excited dipole modes in third harmonic superconducting accelerating cavities at a free-electron laser. AB - We investigate the feasibility of beam position diagnostics using higher order mode (HOM) signals excited by an electron beam in the third harmonic 3.9 GHz superconducting accelerating cavities at FLASH. After careful theoretical and experimental assessment of the HOM spectrum, three modal choices have been narrowed down to fulfill different diagnostics requirements. These are localized dipole beam-pipe modes, trapped cavity modes from the fifth dipole band, and propagating modes from the first two dipole bands. These modes are treated with various data analysis techniques: modal identification, direct linear regression (DLR), and singular value decomposition (SVD). Promising options for beam diagnostics are found from all three modal choices. This constitutes the first prediction, subsequently confirmed by experiments, of trapped HOMs in third harmonic cavities, and also the first direct comparison of DLR and SVD in the analysis of HOM-based beam diagnostics. PMID- 22938343 TI - Note: a method for estimating the resolution of nanopositioning systems. AB - This Note describes a new technique for estimating the resolution of nanopositioning systems. By recording the voltage applied to an actuator and performing a filtering operation, the position noise and resolution can be estimated. This technique is simple to apply in practice and does not require any additional sensors or specialized equipment. PMID- 22938344 TI - Note: a resonant fiber-optic piezoelectric scanner achieves a raster pattern by combining two distinct resonances. AB - The resonant fiber-optic piezoelectric scanner (RFPS) benefits imaging systems with compactness and flexibility, but previously its scanning manner was limited to non-raster patterns that suffer various deficiencies (e.g., nonuniform in terms of spatial coverage and sampling time). Here, we propose a method for the RFPS to achieve a raster pattern by producing different order resonances in the two orthogonal directions. Resonant frequencies of the RFPS are deduced by the Euler-Bernoulli beam theory, and investigated by finite element method. We experimentally fabricated a prototype RFPS, measured its properties to investigate the feasibility for raster scanning, and finally demonstrated the imaging ability. PMID- 22938345 TI - Note: spatial resolution of Fuji BAS-TR and BAS-SR imaging plates. AB - The spatial resolution of two types of imaging plates, Fuji BAS-TR and Fuji BAS SR, has been measured using a knife-edge x-ray source of 8-keV Cu K(alpha) radiation. The values for the spatial resolution, defined as the distance between 10% and 90% levels of the edge spread function, are 94 MUm and 109 MUm, respectively. The resolution values are important for quantitative analysis of x ray and particle imaging and spectroscopic diagnostics. PMID- 22938346 TI - Note: series and parallel tunable resonators based on a nematic liquid crystal cell as variable capacitance. AB - In this work, tunable series and parallel resonators based on a nematic liquid crystal cell as variable capacitance are proposed and characterized. Tunable resonance frequencies in the range of kHz have been obtained for the combination of the inductance and the liquid crystal cell (capacitance) used in the proposed circuits. Tuning range in frequency obtained is around an octave. PMID- 22938347 TI - Note: cryogenic microstripline-on-Kapton microwave interconnects. AB - Simple broadband microwave interconnects are needed for increasing the size of focal plane heterodyne radiometer arrays. We have measured loss and crosstalk for arrays of microstrip transmission lines in flex circuit technology at 297 and 77 K, finding good performance to at least 20 GHz. The dielectric constant of Kapton substrates changes very little from 297 to 77 K, and the electrical loss drops. The small cross-sectional area of metal in a printed circuit structure yields overall thermal conductivities similar to stainless steel coaxial cable. Operationally, the main performance tradeoffs are between crosstalk and thermal conductivity. We tested a patterned ground plane to reduce heat flux. PMID- 22938348 TI - Note: measurement of extreme-short current pulse duration of runaway electron beam in atmospheric pressure air. AB - This note reports the time-amplitude characteristic of the supershort avalanche electron beam with up to 20 ps time resolution. For the first time it is shown that the electron beam downstream of small-diameter diaphragms in atmospheric pressure air has a complex structure which depends on the interelectrode gap width and cathode design. With a spherical cathode and collimator the minimum duration at half maximum of the supershort avalanche electron beam current pulse was shown to be ~25 ps. The minimum duration at half maximum of one peak in the pulses with two peaks can reach ~25 ps too. PMID- 22938349 TI - Note: refractive index sensing of turbid media by differentiation of the reflectance profile: does error-correction work? AB - A widely used method for determining refractive index postulates that the derivative of the angular profile for light reflected from the sample is maximum at the critical angle for total internal reflection (TIR). It is well-known that in turbid media this "differentiation method" yields errors in refractive index. Unexplained anomalies in previous error-calculations are eliminated if one uses a recent model of TIR which departs from traditional Fresnel theory. However we find that, in practical situations, the refractive index obtained by differentiation even after error-correction is significantly different from the best estimate for the refractive index obtained by curve-fitting the reflectance data. Thus the differentiation method lacks scientific validity in turbid media. PMID- 22938350 TI - Note: rotaphone, a new self-calibrated six-degree-of-freedom seismic sensor. AB - We have developed and tested (calibration, linearity, and cross-axis errors) a new six-degree-of-freedom mechanical seismic sensor for collocated measurements of three translational and three rotational ground motion velocity components. The device consists of standard geophones arranged in parallel pairs to detect spatial gradients. The instrument operates in a high-frequency range (above the natural frequency of the geophones, 4.5 Hz). Its theoretical sensitivity limit in this range is 10(-9) m/s in ground velocity and 10(-9) rad/s in rotation rate. Small size and weight, and easy installation and maintenance make the instrument useful for local-earthquake recording and seismic prospecting. PMID- 22938351 TI - Note: a microfluidic chip setup for capillarity-assisted particle assembly. AB - We developed a microfluidic chip setup for capillarity-assisted particle assembly (CAPA). A capillary bridge is formed between the aperture of a silicon chip and the assembly template. The bridge is fed with particle suspension through a microfluidic channel on the chip top side. With this setup, we can control the particle assembly location and tune the suspension composition during particle assembly. In this note, we describe the chip setup, the CAPA process using the microfluidic chip, and results of complex particle assemblies, such as composite particle arrays and particle gradients, that could not be obtained using a conventional CAPA setup. PMID- 22938354 TI - Investigation of hydrodynamic focusing in a microfluidic coulter counter device. AB - The Coulter technique enables rapid analysis of particles or cells suspended in a fluid stream. In this technique, the cells are suspended in an electrically conductive solution, which is hydrodynamically focused by nonconducting sheath flows. The cells produce a characteristic voltage signal when they interrupt an electrical path. The population and size of the cells can be obtained through analyzing the voltage signal. In a microfluidic Coulter counter device, the hydrodynamic focusing technique is used to position the conducting sample stream and the cells and also to separate close cells to generate distinct signals for each cell and avoid signal jam. The performance of hydrodynamic focusing depends on the relative flow ratio between the sample stream and sheath stream. We use a numerical approach to study the hydrodynamic focusing in a microfluidic Coulter counter device. In this approach, the flow field is described by solving the incompressible Navier-Stokes equations. The sample stream concentration is modeled by an advection-diffusion equation. The motion of the cells is governed by the Newton-Euler equations of motion. Particle motion through the flow field is handled using an overlapping grid technique. A numerical model for studying a microfluidic Coulter counter has been validated. Using the model, the impact of relative flow rate on the performance of hydrodynamic focusing was studied. Our numerical results show that the position of the sample stream can be controlled by adjusting the relative flow rate. Our simulations also show that particles can be focused into the stream and initially close particles can be separated by the hydrodynamic focusing. From our study, we conclude that hydrodynamic focusing provides an effective way to control the position of the sample stream and cells and it also can be used to separate cells to avoid signal jam. PMID- 22938356 TI - Experimental validation of finite element models of intact and implanted composite hemipelvises using digital image correlation. AB - A detailed understanding of the changes in load transfer due to implantation is necessary to identify potential failure mechanisms of orthopedic implants. Computational finite element (FE) models provide full field data on intact and implanted bone structures, but their validity must be assessed for clinical relevance. The aim of this study was to test the validity of FE predicted strain distributions for the intact and implanted pelvis using the digital image correlation (DIC) strain measurement technique. FE models of an in vitro hemipelvis test setup were produced, both intact and implanted with an acetabular cup. Strain predictions were compared to DIC and strain rosette measurements. Regression analysis indicated a strong linear relationship between the measured and predicted strains, with a high correlation coefficient (R = 0.956 intact, 0.938 implanted) and a low standard error of the estimate (SE = 69.53 MUepsilon, 75.09 MUepsilon). Moreover, close agreement between the strain rosette and DIC measurements improved confidence in the validity of the DIC technique. The FE model therefore was supported as a valid predictor of the measured strain distribution in the intact and implanted composite pelvis models, confirming its suitability for further computational investigations. PMID- 22938355 TI - A quantitative comparison of mechanical blood damage parameters in rotary ventricular assist devices: shear stress, exposure time and hemolysis index. AB - Ventricular assist devices (VADs) have already helped many patients with heart failure but have the potential to assist more patients if current problems with blood damage (hemolysis, platelet activation, thrombosis and emboli, and destruction of the von Willebrand factor (vWf)) can be eliminated. A step towards this goal is better understanding of the relationships between shear stress, exposure time, and blood damage and, from there, the development of numerical models for the different types of blood damage to enable the design of improved VADs. In this study, computational fluid dynamics (CFD) was used to calculate the hemodynamics in three clinical VADs and two investigational VADs and the shear stress, residence time, and hemolysis were investigated. A new scalar transport model for hemolysis was developed. The results were compared with in vitro measurements of the pressure head in each VAD and the hemolysis index in two VADs. A comparative analysis of the blood damage related fluid dynamic parameters and hemolysis index was performed among the VADs. Compared to the centrifugal VADs, the axial VADs had: higher mean scalar shear stress (sss); a wider range of sss, with larger maxima and larger percentage volumes at both low and high sss; and longer residence times at very high sss. The hemolysis predictions were in agreement with the experiments and showed that the axial VADs had a higher hemolysis index. The increased hemolysis in axial VADs compared to centrifugal VADs is a direct result of their higher shear stresses and longer residence times. Since platelet activation and destruction of the vWf also require high shear stresses, the flow conditions inside axial VADs are likely to result in more of these types of blood damage compared with centrifugal VADs. PMID- 22938357 TI - New mathematical model to estimate tissue blood perfusion, thermal contact resistance and core temperature. AB - Analytical solutions were developed based on the Green's function method to describe heat transfer in tissue including the effects of blood perfusion. These one-dimensional transient solutions were used with a simple parameter estimation technique and experimental measurements of temperature and heat flux at the surface of simulated tissue. It was demonstrated how such surface measurements can be used during step changes in the surface thermal conditions to estimate the value of three important parameters: blood perfusion (w(b)), thermal contact resistance (R"), and core temperature of the tissue (T(core)). The new models were tested against finite-difference solutions of thermal events on the surface to show the validity of the analytical solution. Simulated data was used to demonstrate the response of the model in predicting optimal parameters from noisy temperature and heat flux measurements. Finally, the analytical model and simple parameter estimation routine were used with actual experimental data from perfusion in phantom tissue. The model was shown to provide a very good match with the data curves. This demonstrated the first time that all three of these important parameters (w(b), R", and T(core)) have simultaneously been estimated from a single set of thermal measurements at the surface of tissue. PMID- 22938358 TI - Numerical simulation of bubble transport in a bifurcating microchannel: a preliminary study. AB - In this paper, we present the computational fluid dynamics (CFD) simulations of bubble transport in a first generation bifurcating microchannel. In the present study, the human arteriole is modeled as a two-dimensional (2D) rectangular bifurcating microchannel. The microchannel is filled with blood and a single perfluorocarbon (PFC) bubble is introduced in the parent channel. The simulations are carried out to identify the lodging and dislodging pressures for two nondimensional bubble sizes, L(d) (ratio of the dimensional bubble length to the parent tube diameter), that is for L(d) = 1 and L(d) = 2. Subsequently, the bubble transport and splitting behavior due to the presence of symmetry and asymmetry in the daughter channels of the microchannel is studied for these bubble sizes. The splitting behavior of the bubble under the effect of gravity is also assessed and reported here. For the symmetric bifurcation model, the splitting ratio (SR) (ratio of bubble volume in bottom daughter channel to bubble volume in top daughter channel), of the bubble was found to be 1. For the asymmetric model, the splitting ratio was found to be less than 1. The loss in the bubble volume in the asymmetric model was attributed to surface tension effects and the resistance offered by the flow, which led to the bubble sticking and sliding along the walls of the channel. With the increase in roll angle, Phi (angle which the plane makes with the horizontal to study the effects of gravity), there was a decline in the splitting ratio. PMID- 22938359 TI - A model of strain-dependent glomerular basement membrane maintenance and its potential ramifications in health and disease. AB - A model is developed and analyzed for type IV collagen turnover in the kidney glomerular basement membrane (GBM), which is the primary structural element in the glomerular capillary wall. The model incorporates strain dependence in both deposition and removal of the GBM, leading to an equilibrium tissue strain at which deposition and removal are balanced. The GBM thickening decreases tissue strain per unit of transcapillary pressure drop according to the law of Laplace, but increases the transcapillary pressure drop required to maintain glomerular filtration. The model results are in agreement with the observed GBM alterations in Alport syndrome and thin basement membrane disease, and the model-predicted linear relation between the inverse capillary radius and inverse capillary thickness at equilibrium is consistent with published data on different mammals. In addition, the model predicts a minimum achievable strain in the GBM based on the geometry, properties, and mechanical environment; that is, an infinitely thick GBM would still experience a finite strain. Although the model assumptions would be invalid for an extremely thick GBM, the minimum achievable strain could be significant in diseases, such as Alport syndrome, characterized by focal GBM thickening. Finally, an examination of reasonable values for the model parameters suggests that the oncotic pressure drop-the osmotic pressure difference between the plasma and the filtrate due to large molecules-plays an important role in setting the GBM strain and, thus, leakage of protein into the urine may be protective against some GBM damage. PMID- 22938360 TI - The acute effect of bipolar radiofrequency energy thermal chondroplasty on intrinsic biomechanical properties and thickness of chondromalacic human articular cartilage. AB - Radio frequency energy (RFE) thermal chondroplasty has been a widely-utilized method of cartilage debridement in the past. Little is known regarding its effect on tissue mechanics. This study investigated the acute biomechanical effects of bipolar RFE treatment on human chondromalacic cartilage. Articular cartilage specimens were extracted (n = 50) from femoral condyle samples of patients undergoing total knee arthroplasty. Chondromalacia was graded with the Outerbridge classification system. Tissue thicknesses were measured using a needle punch test. Specimens underwent pretreatment load-relaxation testing using a spherical indenter. Bipolar RFE treatment was applied for 45 s and the indentation protocol was repeated. Structural properties were derived from the force-time data. Mechanical properties were derived using a fibril-reinforced biphasic cartilage model. Statistics were performed using repeated measures ANOVA. Cartilage thickness decreased after RFE treatment from a mean of 2.61 mm to 2.20 mm in Grade II, II-III, and III specimens (P < 0.001 each). Peak force increased after RFE treatment from a mean of 3.91 N to 4.91 N in Grade II and III specimens (P = 0.002 and P = 0.003, respectively). Equilibrium force increased after RFE treatment from a mean of 0.236 N to 0.457 N (P < 0.001 each grade). Time constant decreased after RFE treatment from a mean of 0.392 to 0.234 (P < 0.001 for each grade). Matrix modulus increased in all specimens following RFE treatment from a mean 259.12 kPa to 523.36 kPa (P < 0.001 each grade). Collagen fibril modulus decreased in Grade II and II-III specimens from 60.50 MPa to 42.04 MPa (P < 0.001 and P = 0.005, respectively). Tissue permeability decreased in Grade II and III specimens from 2.04 *10(-15) m(4)/Ns to 0.91 *10(-15) m(4)/Ns (P < 0.001 and P = 0.009, respectively). RFE treatment decreased thickness, time constant, fibril modulus, permeability, but increased peak force, equilibrium force, and matrix modulus. While resistance to shear and tension could be compromised due to removal of the superficial layer and decreased fibril modulus, RFE treatment increases matrix modulus and decreases tissue permeability which may restore the load- bearing capacity of the cartilage. PMID- 22938361 TI - On the infusion of a therapeutic agent into a solid tumor modeled as a poroelastic medium. AB - The direct infusion of an agent into a solid tumor, modeled as a spherical poroelastic material with anisotropic dependence of the tumor hydraulic conductivity upon the tissue deformation, is treated both by solving the coupled fluid/elastic equations, and by expressing the solution as an asymptotic expansion in terms of a small parameter, ratio between the driving pressure force in the fluid system, and the elastic properties of the solid. Results at order one match almost perfectly the solutions of the full system over a large range of infusion pressures. Comparison with experimental results is acceptable after the hydraulic conductivity of the medium is properly calibrated. Given the uncertain estimates of some model constants, the order zero solution of the expansion, for which fluid and porous matrix are decoupled, yields acceptable values and trends for all the physical fields of interest, rendering the coupled analysis (in the limit of small displacements) of little use. When the deformation of the tissue becomes large nonlinear elasticity theory must be resorted to. PMID- 22938362 TI - Comparison of strain-gage and fiber-optic goniometry for measuring knee kinematics during activities of daily living and exercise. AB - There is increasing interest in wearable sensor technology as a tool for rehabilitation applications in community or home environments. Recent studies have focused on evaluating inertial based sensing (accelerometers, gyroscopes, etc.) that provide only indirect measures of joint motion. Measurement of joint kinematics using flexible goniometry is more direct, and still popular in laboratory environments, but has received little attention as a potential tool for wearable systems. The aim of this study was to compare two goniometric devices: a traditional strain-gauge flexible goniometer, and a fiberoptic flexible goniometer, for measuring dynamic knee flexion/extension angles during activity of daily living: chair rise, and gait; and exercise: deep knee bends, against joint angles computed from a "gold standard" Vicon motion tracking system. Six young adults were recruited to perform the above activities in the lab while wearing a goniometer on each knee, and reflective markers for motion tracking. Kinematic data were collected simultaneously from the goniometers (one on each leg) and the motion tracking system (both legs). The results indicate that both goniometers were within 2-5 degrees of the Vicon angles for gait and chair rise. For some deep knee bend trials, disagreement with Vicon angles exceeded ten degrees for both devices. We conclude that both goniometers can record ADL knee movement faithfully and accurately, but should be carefully considered when high (>120 deg) knee flexion angles are required. PMID- 22938363 TI - An augmented Lagrangian method for sliding contact of soft tissue. AB - Despite the importance of sliding contact in diarthrodial joints, only a limited number of studies have addressed this type of problem, with the result that the mechanical behavior of articular cartilage in daily life remains poorly understood. In this paper, a finite element formulation is developed for the sliding contact of biphasic soft tissues. The augmented Lagrangian method is used to enforce the continuity of contact traction and fluid pressure across the contact interface. The resulting method is implemented in the commercial software COMSOL Multiphysics. The accuracy of the new implementation is verified using an example problem of sliding contact between a rigid, impermeable indenter and a cartilage layer for which analytical solutions have been obtained. The new implementation's capability to handle a complex loading regime is verified by modeling plowing tests of the temporomandibular joint (TMJ) disc. PMID- 22938364 TI - Three-dimensional static modeling of the lumbar spine. AB - This paper presents three-dimensional static modeling of the human lumbar spine to be used in the formation of anatomically-correct movement patterns for a fully cable-actuated robotic lumbar spine which can mimic in vivo human lumbar spine movements to provide better hands-on training for medical students. The mathematical model incorporates five lumbar vertebrae between the first lumbar vertebra and the sacrum, with dimensions of an average adult human spine. The vertebrae are connected to each other by elastic elements, torsional springs and a spherical joint located at the inferoposterior corner in the mid-sagittal plane of the vertebral body. Elastic elements represent the ligaments that surround the facet joints and the torsional springs represent the collective effect of intervertebral disc which plays a major role in balancing torsional load during upper body motion and the remaining ligaments that support the spinal column. The elastic elements and torsional springs are considered to be nonlinear. The nonlinear stiffness constants for six motion types were solved using a multiobjective optimization technique. The quantitative comparison between the angles of rotations predicted by the proposed model and in the experimental data confirmed that the model yields angles of rotation close to the experimental data. The main contribution is that the new model can be used for all motions while the experimental data was only obtained at discrete measurement points. PMID- 22938366 TI - Annual special JBME issue "Biomechanical engineering-year in review". PMID- 22938365 TI - Comparison of the in vitro hemodynamic performance of new flow diverters for bypass of brain aneurysms. AB - One possible treatment for cerebral aneurysms is a porous tubular structure, similar to a stent, called a flow diverter. A flow diverter can be placed across the neck of a cerebral aneurysm to induce the cessation of flow and initiate the formation of an intra-aneurysmal thrombus. This excludes the aneurysm from the parent artery and returns the flow of blood to normal. Previous flow diverting devices have been analyzed to determine optimal characteristics, such as braiding angle and wire diameter. From this information, a new optimized device was designed to achieve equivalent hemodynamic performance to the previous best device, but with better longitudinal flexibility to preserve physiological arterial configuration. The new device was tested in vitro in an elastomeric replica of the rabbit elastase induced aneurysm model and is now in the process of being tested in vivo. Particle image velocimetry was utilized to determine the velocity field in the plane of symmetry of the model under pulsatile flow conditions. Device hemodynamic performance indices such as the hydrodynamic circulation were evaluated from the velocity fields. Comparison of these indices with the previous best device and a control shows that the significant design changes of the device did not change its hemodynamic attributes (p > 0.05). PMID- 22938367 TI - Journal of biomechanical engineering update. PMID- 22938368 TI - The effect of low-magnitude, high-frequency vibration stimuli on the bone healing of rat incisor extraction socket. AB - Effects of small vibration stimuli on bone formation have been reported. In the present study, we used morphological and morphometric procedures to elucidate whether low-magnitude, high-frequency (LMHF) vibration stimuli could enhance the bone healing of rat incisor extraction sockets. After extraction of incisors from six-week-old rats, animals were assigned into a control group and two experimental groups to receive 50 Hz stimuli at either 0.05 mm or 0.2 mm peak-to peak for an hour/day. LMHF vibration stimuli were generated by placing the mandibles of the animals onto a vibration generator. All groups were subdivided into two, according to the study periods (1 and 3 weeks). After the study period, undecalcified ground sections were taken and morphological and morphometric analyses performed. At both 1 and 3 weeks, newly formed bone was observed mainly in the upper wall of the extraction socket in all groups. Morphometric analyses revealed that the trabecular thickness in both experimental groups at 1 week was significantly greater than that in the control. LMHF vibration stimuli had a positive effect on bone at the early stage of bone healing, particularly in trabecular thickness, at the incisor extraction socket. PMID- 22938369 TI - Porohyperviscoelastic model simultaneously predicts parenchymal fluid pressure and reaction force in perfused liver. AB - Porohyperviscoelastic (PHVE) modeling gives a simplified continuum approximation of pore fluid behavior within the parenchyma of liver tissue. This modeling approach is particularly applicable to tissue engineering of artificial livers, where the inherent complexity of the engineered scaffolds prevents the use of computational fluid dynamics. The objectives of this study were to simultaneously predict the experimental parenchymal fluid pressure (PFP) and compression response in a PHVE liver model. The model PFP matched the experimental measurements (318 Pa) to within 1.5%. Linear regression of both phases of compression, ramp, and hold, demonstrated a strong correlation between the model and the experimental reaction force (p<0.5). The ability of this PVE model to accurately predict both fluid and solid behavior is important due to the highly vascularized nature of liver tissue and the mechanosensitivity of liver cells to solid matrix and fluid flow properties. PMID- 22938370 TI - Exploring high frequency temporal fluctuations in the terminal aneurysm of the basilar bifurcation. AB - Cerebral aneurysms are a common cause of death and disability. Of all the cardiovascular diseases, aneurysms are perhaps the most strongly linked with the local fluid mechanic environment. Aside from early in vivo clinical work that hinted at the possibility of high-frequency intra-aneurysmal velocity oscillations, flow in cerebral aneurysms is most often assumed to be laminar. This work investigates, through the use of numerical simulations, the potential for disturbed flow to exist in the terminal aneurysm of the basilar bifurcation. The nature of the disturbed flow is explored using a series of four idealized basilar tip models, and the results supported by four patient specific terminal basilar tip aneurysms. All four idealized models demonstrated instability in the inflow jet through high frequency fluctuations in the velocity and the pressure at approximately 120 Hz. The instability arises through a breakdown of the inflow jet, which begins to oscillate upon entering the aneurysm. The wall shear stress undergoes similar high-frequency oscillations in both magnitude and direction. The neck and dome regions of the aneurysm present 180 deg changes in the direction of the wall shear stress, due to the formation of small recirculation zones near the shear layer of the jet (at the frequency of the inflow jet oscillation) and the oscillation of the impingement zone on the dome of the aneurysm, respectively. Similar results were observed in the patient-specific models, which showed high frequency fluctuations at approximately 112 Hz in two of the four models and oscillations in the magnitude and direction of the wall shear stress. These results demonstrate that there is potential for disturbed laminar unsteady flow in the terminal aneurysm of the basilar bifurcation. The instabilities appear similar to the first instability mode of a free round jet. PMID- 22938371 TI - Evaluation of a voxelized model based on DCE-MRI for tracer transport in tumor. AB - Recent advances in the treatment of cancer involving therapeutic agents have shown promising results. However, treatment efficacy can be limited due to inadequate and uneven uptake in solid tumors, thereby making the prediction of drug transport important for developing effective therapeutic strategies. In this study, a patient-specific computational porous media model (voxelized model) was developed for predicting the interstitial flow field and distribution of a systemically delivered magnetic resonance (MR) visible tracer in a tumor. The benefits of a voxel approach include less labor and less computational time (approximately an order of magnitude reduction compared to the traditional computational fluid dynamics (CFD) approach developed earlier by our group). The model results were compared with that obtained from a previous approach based on unstructured meshes along with MR-measured tracer concentration data within tumors, using statistical analysis and qualitative representations. The statistical analysis indicated the similarity between the structured and unstructured models' results with a low root mean square error (RMS) and a high correlation coefficient. The voxelized model captured features of the flow field and tracer distribution such as high interstitial fluid pressure inside the tumor and the heterogeneous distribution of the tracer. Predictions of tracer distribution by the voxelized approach also resulted in low RMS error when compared with MR-measured data over a 1 h time course. The similarity in the voxelized model results with experiment and the nonvoxelized model predictions were maintained across three different tumors. Overall, the voxelized model serves as a reliable and swift alternative to approaches using unstructured meshes in predicting extracellular transport within tumors. PMID- 22938372 TI - Multiscale model predicts tissue-level failure from collagen fiber-level damage. AB - Excessive tissue-level forces communicated to the microstructure and extracellular matrix of soft tissues can lead to damage and failure through poorly understood physical processes that are multiscale in nature. In this work, we propose a multiscale mechanical model for the failure of collagenous soft tissues that incorporates spatial heterogeneity in the microstructure and links the failure of discrete collagen fibers to the material response of the tissue. The model, which is based on experimental failure data derived from different collagen gel geometries, was able to predict the mechanical response and failure of type I collagen gels, and it demonstrated that a fiber-based rule (at the micrometer scale) for discrete failure can strongly shape the macroscale failure response of the gel (at the millimeter scale). The model may be a useful tool in predicting the macroscale failure conditions for soft tissues and engineered tissue analogs. In addition, the multiscale model provides a framework for the study of failure in complex fiber-based mechanical systems in general. PMID- 22938373 TI - Characterization of thigh and shank segment angular velocity during jump landing tasks commonly used to evaluate risk for ACL injury. AB - The dynamic movements associated with anterior cruciate ligament (ACL) injury during jump landing suggest that limb segment angular velocity can provide important information for understanding the conditions that lead to an injury. Angular velocity measures could provide a quick and simple method of assessing injury risk without the constraints of a laboratory. The objective of this study was to assess the inter-subject variations and the sensitivity of the thigh and shank segment angular velocity in order to determine if these measures could be used to characterize jump landing mechanisms. Additionally, this study tested the correlation between angular velocity and the knee abduction moment. Thirty-six healthy participants (18 male) performed drop jumps with bilateral and unilateral landing. Thigh and shank angular velocities were measured by a wearable inertial based system, and external knee moments were measured using a marker-based system. Discrete parameters were extracted from the data and compared between systems. For both jumping tasks, the angular velocity curves were well defined movement patterns with high inter-subject similarity in the sagittal plane and moderate to good similarity in the coronal and transverse planes. The angular velocity parameters were also able to detect differences between the two jumping tasks that were consistent across subjects. Furthermore, the coronal angular velocities were significantly correlated with the knee abduction moment (R of 0.28-0.51), which is a strong indicator of ACL injury risk. This study suggested that the thigh and shank angular velocities, which describe the angular dynamics of the movement, should be considered in future studies about ACL injury mechanisms. PMID- 22938375 TI - An approach to determine pressure profile generated by compression bandage using quasi-linear viscoelastic model. AB - Understanding the stress relaxation behavior of the compression bandage could be very useful in determining the behavior of the interface pressure exerted by the bandage on a limb during the course of the compression treatment. There has been no comprehensive study in the literature to investigate the pressure profile (interface pressure with time) generated by a compression bandage when applied at different levels of strain. The present study attempts to describe the pressure profile, with the use of a quasi-linear viscoelastic model, generated by a compression bandage during compression therapy. The quasi-linear viscoelastic (QLV) theory proposed by Fung (Fung, 1972, "Stress Strain History Relations of Soft Tissues in Simple Elongation," Biomechanics: Its Foundations and Objectives, Y. C. Fung, N. Perrone, and M. Anliker, eds., Prentice-Hall, Englewood Cliffs, NJ, pp. 181-207). was used to model the nonlinear time- and history-dependent relaxation behavior of the bandage using the ramp strain approach. The regression analysis was done to find the correlation between the pressure profile and the relaxation behavior of the bandage. The parameters of the QLV model, describing the relaxation behavior of the bandage, were used to determine the pressure profile generated by the bandage at different levels of strain. The relaxation behaviors of the bandage at different levels of strain were well described by the QLV model parameters. A high correlation coefficient (nearly 0.98) shows a good correlation of the pressure profile with the stress relaxation behavior of the bandage.The prediction of the pressure profile using the QLV model parameters were in agreement with the experimental data. The pressure profile generated by a compression bandage could be predicted using the QLV model describing the nonlinear relaxation behavior of the bandage. This new application of the QLV theory helps in evaluating the bandage performance during compression therapy as scientific wound care management. PMID- 22938376 TI - A preliminary biomechanical study of cyclic preconditioning effects on canine cadaveric whole femurs. AB - Biomechanical preconditioning of biological specimens by cyclic loading is routinely done presumably to stabilize properties prior to the main phase of a study. However, no prior studies have actually measured these effects for whole bone of any kind. The aim of this study, therefore, was to quantify these effects for whole bones. Fourteen matched pairs of fresh-frozen intact cadaveric canine femurs were sinusoidally loaded in 4-point bending from 50 N to 300 N at 1 Hz for 25 cycles. All femurs were tested in both anteroposterior (AP) and mediolateral (ML) bending planes. Bending stiffness (i.e., slope of the force-vs-displacement curve) and linearity R(2) (i.e., coefficient of determination) of each loading cycle were measured and compared statistically to determine the effect of limb side, cycle number, and bending plane. Stiffnesses rose from 809.7 to 867.7 N/mm (AP, left), 847.3 to 915.6 N/mm (AP, right), 829.2 to 892.5 N/mm (AP, combined), 538.7 to 580.4 N/mm (ML, left), 568.9 to 613.8 N/mm (ML, right), and 553.8 to 597.1 N/mm (ML, combined). Linearity R(2) rose from 0.96 to 0.99 (AP, left), 0.97 to 0.99 (AP, right), 0.96 to 0.99 (AP, combined), 0.95 to 0.98 (ML, left), 0.94 to 0.98 (ML, right), and 0.95 to 0.98 (ML, combined). Stiffness and linearity R(2) versus cycle number were well-described by exponential curves whose values leveled off, respectively, starting at 12 and 5 cycles. For stiffness, there were no statistical differences for left versus right femurs (p = 0.166), but there were effects due to cycle number (p < 0.0001) and AP versus ML bending plane (p < 0.0001). Similarly, for linearity, no statistical differences were noted due to limb side (p = 0.533), but there were effects due to cycle number (p < 0.0001) and AP versus ML bending plane (p = 0.006). A minimum of 12 preconditioning cycles was needed to fully stabilize both the stiffness and linearity of the canine femurs. This is the first study to measure the effects of mechanical preconditioning on whole bones, having some practical implications on research practices. PMID- 22938374 TI - Ultrasonic measurement of scleral cross-sectional strains during elevations of intraocular pressure: method validation and initial results in posterior porcine sclera. AB - BACKGROUND: Scleral biomechanical properties may be important in the pathogenesis and progression of glaucoma. The goal of this study is to develop and validate an ultrasound method for measuring cross-sectional distributive strains in the sclera during elevations of intraocular pressure (IOP). METHOD OF APPROACH: Porcine globes (n = 5) were tested within 24 hs postmortem. The posterior scleral shells were dissected and mounted onto a custom-built pressurization chamber. A high-frequency (55-MHz) ultrasound system (Vevo660, VisualSonics Inc., Toronto) was employed to acquire the radio frequency data during scans of the posterior pole along both circumferential and meridian directions. The IOP was gradually increased from 5 to 45 mmHg. The displacement fields were obtained from correlation-based ultrasound speckle tracking. A least-square strain estimator was used to calculate the strains in both axial and lateral directions. Experimental validation was performed by comparing tissue displacements calculated from ultrasound speckle tracking with those induced by an actuator. Theoretical analysis and simulation experiments were performed to optimize the ultrasound speckle tracking method and evaluate the accuracy and signal-to-noise ratio (SNR) in strain estimation. RESULTS: Porcine sclera exhibited significantly larger axial strains (e.g., -5.1 +/- 1.5% at 45 mmHg, meridian direction) than lateral strains (e.g., 2.2 +/- 0.7% at 45 mmHg, meridian direction) during IOP elevations (P's < 0.01). The strain magnitudes increased nonlinearly with pressure increase. The strain maps displayed heterogeneity through the thickness. The lateral strains were significantly smaller in the circumferential direction than the meridian direction at 45 mmHg (P < 0.05). Experimental validation showed that the ultrasound speckle tracking method was capable of tracking displacements at the accuracy of sub-micron to micron. Theoretical analysis predicted the dependence of the strain estimation SNR on the strain level, as well as signal processing parameters such as kernel size. Simulation results showed that ultrasound speckle tracking had a high accuracy for estimating strains of 1-5% and a high SNR for strains of 0.5-5%. CONCLUSIONS: A new experimental method based on ultrasound speckle tracking has been developed for obtaining cross sectional strain maps of the posterior sclera. This method provides a useful tool to examine distributive strains through the thickness of the sclera during elevations of IOP. PMID- 22938377 TI - Can scapular and humeral head position predict shoulder pain in adolescent swimmers and non-swimmers? AB - The aims of this study were to determine whether scapular and humeral head position can predict the development of shoulder pain in swimmers, whether those predictors were applicable to non-swimmers and the annual rate of shoulder pain in adolescent swimmers and non-swimmers. Forty-six adolescent swimmers and 43 adolescent non-swimmers were examined prospectively with a questionnaire and anthropometric measures. The questionnaire examined demographic and training variables. Anthropometric measures examined the distances between the T7 spinous process and the inferior scapula (Inferior Kibler) and T3 spinous process and the medial spine of the scapula (Superior Kibler), humeral head position in relation to the acromion using palpation, BMI and chest width. Shoulder pain was re assessed 12 months later by questionnaire. Shoulder pain in swimmers was best predicted by a larger BMI (OR = 1.48, P = 0.049), a smaller Inferior Kibler distance in abduction (e.g. OR = 0.90, P = 0.009) and a smaller horizontal distance between the anterior humeral head and the anterior acromion (OR = 0.76, P = 0.035). These variables were not significantly predictive of shoulder pain in non-swimmers. Annual prevalence of shoulder pain was 23.9% in swimmers and 30.8% in non-swimmers (chi(2) = 0.50, P = 0.478). PMID- 22938378 TI - Assessing the effect of introducing a new method into family planning programs in India, Peru, and Rwanda. AB - BACKGROUND: Introducing a new method into family planning programs requires careful attention to ensure it meets an actual need and has a positive effect on program goals. The Standard Days Method(r) is a fertility awareness-based method of family planning that is being introduced into family planning programs in countries around the world. It is different from other methods offered by programs, and may bring new couples into family planning, and increase contraceptive prevalence. The study assesses the effect on contraceptive use and prevalence of Introducing Standard Days Method into existing family planning services in whole regions of India, Peru, and Rwanda. METHODS: In collaboration with the Ministry of Health, health providers were given a contraceptive update on all methods, then trained in counseling on Standard Days Method. Efforts were made to promote demand in the context of informed choice. Routine monthly service statistics in control and intervention areas were used to assess the effect of Standard Days Method introduction at the clinic level; baseline and endline household-based surveys were undertaken to obtain results at the community level (n > 3400 women at endline). RESULTS: Demand for the method is evident in countries with different levels of contraceptive prevalence. The method attracts couples new to family planning, and introducing it into services may increase overall contraceptive prevalence. CONCLUSIONS: Introducing Standard Days Method into existing family planning has the potential of benefiting men and women in diverse settings and populations. This study illustrates the critical role of evidence in scaling up a health innovation. PMID- 22938379 TI - Role of support-nanoalloy interactions in the atomic-scale structural and chemical ordering for tuning catalytic sites. AB - The understanding of the atomic-scale structural and chemical ordering in supported nanosized alloy particles is fundamental for achieving active catalysts by design. This report shows how such knowledge can be obtained by a combination of techniques including X-ray photoelectron spectroscopy and synchrotron radiation based X-ray fine structure absorption spectroscopy and high-energy X ray diffraction coupled to atomic pair distribution function analysis, and how the support-nanoalloy interaction influences the catalytic activity of ternary nanoalloy (platinum-nickel-cobalt) particles on three different supports: carbon, silica, and titania. The reaction of carbon monoxide with oxygen is employed as a probe to the catalytic activity. The thermochemical processing of this ternary composition, in combination with the different support materials, is demonstrated to be capable of fine-tuning the catalytic activity and stability. The support nanoalloy interaction is shown to influence structural and chemical ordering in the nanoparticles, leading to support-tunable active sites on the nanoalloys for oxygen activation in the catalytic oxidation of carbon monoxide. A nickel/cobalt tuned catalytic site on the surface of nanoalloy is revealed for oxygen activation, which differs from the traditional oxygen-activation sites known for oxide-supported noble metal catalysts. The discovery of such support-nanoalloy interaction-enabled oxygen-activation sites introduces a very promising strategy for designing active catalysts in heterogeneous catalysis. PMID- 22938380 TI - Non-cryopreserved storage is feasible for autologous stem cell transplantation in multiple myeloma previously treated with melphalan. PMID- 22938381 TI - HLA class II polymorphisms and recurrent spontaneous abortion in a Southern Brazilian cohort. AB - A high proportion of human recurrent spontaneous abortions (RSA) remain unexplained. The possible association between RSA and different genetic polymorphisms within the human leucocyte antigen system (HLA system, the human major histocompatibility complex) has been investigated with conflicting results since many decades. Here, we describe a case-control study with 136 Southern Brazilian women of predominantly European ancestry (75 control and 61 cases with unexplained RSA). We investigated the relationship between unexplained RSA and alleles and genotypes from two classical loci of the HLA: HLA-DRB1 and HLA-DQB1, as well as three loci related to cytokine production and their serum levels: TNFA (-308G>A), IL10 (-1082G>A, -819T>C, -592A>C) and IFNG (+874A>T). Genotyping was performed by an allele-specific PCR method. While all results concerning cytokine related genes turned out to be negative, we found the genotype HLA-DQB1*02:02, 03:01 to be significantly decreased and the allele HLA-DRB1*11:04 to be significantly increased among patients. PMID- 22938382 TI - Targeted next-generation sequencing identifies a homozygous nonsense mutation in ABHD12, the gene underlying PHARC, in a family clinically diagnosed with Usher syndrome type 3. AB - BACKGROUND: Usher syndrome (USH) is an autosomal recessive genetically heterogeneous disorder with congenital sensorineural hearing impairment and retinitis pigmentosa (RP). We have identified a consanguineous Lebanese family with two affected members displaying progressive hearing loss, RP and cataracts, therefore clinically diagnosed as USH type 3 (USH3). Our study was aimed at the identification of the causative mutation in this USH3-like family. METHODS: Candidate loci were identified using genomewide SNP-array-based homozygosity mapping followed by targeted enrichment and next-generation sequencing. RESULTS: Using a capture array targeting the three identified homozygosity-by-descent regions on chromosomes 1q43-q44, 20p13-p12.2 and 20p11.23-q12, we identified a homozygous nonsense mutation, p.Arg65X, in ABHD12 segregating with the phenotype. CONCLUSION: Mutations of ABHD12, an enzyme hydrolyzing an endocannabinoid lipid transmitter, cause PHARC (polyneuropathy, hearing loss, ataxia, retinitis pigmentosa, and early-onset cataract). After the identification of the ABHD12 mutation in this family, one patient underwent neurological examination which revealed ataxia, but no polyneuropathy. ABHD12 is not known to be related to the USH protein interactome. The phenotype of our patient represents a variant of PHARC, an entity that should be taken into account as differential diagnosis for USH3. Our study demonstrates the potential of comprehensive genetic analysis for improving the clinical diagnosis. PMID- 22938383 TI - Interactions among shrub cover and the soil microclimate may determine future Arctic carbon budgets. AB - Arctic and Boreal terrestrial ecosystems are important components of the climate system because they contain vast amounts of soil carbon (C). Evidence suggests that deciduous shrubs are increasing in abundance, but the implications for ecosystem C budgets remain uncertain. Using midsummer CO(2) flux data from 21 sites spanning 16 degrees of latitude in the Arctic and Boreal biomes, we show that air temperature explains c. one-half of the variation in ecosystem respiration (ER) and that ER drives the pattern in net ecosystem CO(2) exchange across ecosystems. Woody sites were slightly stronger C sinks compared with herbaceous communities. However, woody sites with warm soils (> 10 degrees C) were net sources of CO(2) , whereas woody sites with cold soils (< 10 degrees C) were strong sinks. Our results indicate that transition to a shrub-dominated Arctic will increase the rate of C cycling, and may lead to net C loss if soil temperatures rise. PMID- 22938384 TI - The importance of job characteristics in determining medical care-seeking in the Dutch working population, a longitudinal survey study. AB - BACKGROUND: The working population is ageing, which will increase the number of workers with chronic health complaints, and, as a consequence, the number of workers seeking health care. It is very important to understand factors that influence medical care-seeking in order to control the costs. I will investigate which work characteristics independently attribute to later care-seeking in order to find possibilities to prevent unnecessary or inefficient care-seeking. METHODS: Data were collected in a longitudinal two-wave study (n = 2305 workers). The outcome measures were visits (yes/no and frequency) to a general practitioner (GP), a physical therapist, a medical specialist and/or a mental health professional. Multivariate regression analyses were carried out separately for men and women for workers with health complaints. RESULTS: In the Dutch working population, personal, health, and work characteristics, but not sickness absence, were associated with later care-seeking. Work characteristics independently attributed to medical care-seeking but only for men and only for the frequency of visits to the GP. Women experience more health complaints and seek health care more often than men. For women, experiencing a work handicap (health complaints that impede work performance) was the only work characteristic associated with more care-seeking (GP). For men, work characteristics that led to less care seeking were social support by colleagues (GP frequency), high levels of decision latitude (GP frequency) and high levels of social support by the supervisor (medical specialist). Other work characteristics led to more care-seeking: high levels of engagement (GP), full time work (GP frequency) and experiencing a work handicap (physical therapist). CONCLUSIONS: We can conclude that personal and health characteristics are most important when explaining medical care-seeking in the Dutch working population. Work characteristics independently attributed to medical care-seeking but only for men and only for the frequency of visits to the GP. The association between work characteristics and later medical care-seeking differed between health care providers and between men and women. If we aim at reducing health care costs for workers by preventing unnecessary or inefficient care, it is important to reduce the number of workers that report that health complaints impede their work performance. The supervisor could provide more social support, closely monitor workload in combination with work pressure and decision latitude, and when possible help to adjust working conditions. Health care providers could reduce medical costs by taking the work relatedness of health complaints into account and act accordingly, by decreasing the time to referral and waiting lists, and by providing appropriate care and avoiding unnecessary or harmful care. PMID- 22938385 TI - Chemical components and antioxidant activity of the peels of commercial apple shaped pear (fruit of Pyrus pyrifolia cv. pingguoli). AB - The apple-shaped pear, the fruit of the Pyrus pyrifolia cv. pingguoli (Rosaceae) tree, is one of the most popular fruits in the northern part of China. The current study is the 1st report of its bioactive components. We identified 10 metabolites from the peels (exocarp) of apple-shaped pear and assessed their toxicity. We then compared the anti-oxidant activity, amount of total phenolic compounds, and total condensed tannin content of the peels and flesh (mesocarp) of apple-shaped pear. The 6 major components in the peels and flesh of this fruit were quantified with Ultra Performance Liquid Chromatography-Electrospray Ionization Mass Spectrometry. Results revealed that the peels possessed stronger anti-oxidant activity and contained larger amounts of phenolic compounds than the flesh. These results provide insights into the potential health benefits of this fruit and support the use of the fruit peels and products containing peels or peel components. PRACTICAL APPLICATION: The present research provided evidences that the pulp and peel waste from the juice industry of apple-shaped pear may be a source of useful compounds. PMID- 22938386 TI - Preparation and Diels-Alder/cross coupling reactions of new 2-boron-substituted 1,3-dienes. AB - Several new 2-boron substituted dienes have been prepared and characterized. Their reactivity in Diels-Alder reactions has been examined and the boron substituted cycloadducts of those cycloaddition reactions have been used in cross coupling reactions. One-pot tandem Diels-Alder/cross coupling reactions of 2 boron substituted dienes are then also reported along with some experimental evidence that these one-pot reactions are proceeding through a Pd(II)-catalyzed Diels-Alder/cross coupling reaction pathway. PMID- 22938387 TI - Ordered two-dimensional superstructures of colloidal octapod-shaped nanocrystals on flat substrates. AB - We studied crystal structures in a monolayer consisting of anisotropic branched colloidal (nano)octapods. Experimentally, octapods were observed to form a monolayer on a substrate with a square-lattice crystal structure by drop-casting and fast evaporation of solvent. The experimental results were analyzed by Monte Carlo simulations using a hard octapod model consisting of four interpenetrating spherocylinders. We confirmed by means of free-energy calculations that crystal structures with a (binary-lattice) square morphology are indeed thermodynamically stable at high densities. The effect of the pod length-to-diameter ratio on the crystal structures was also considered and we used this to constructed the phase diagram for these hard octapods. In addition to the (binary-lattice) square crystal phase, a rhombic crystal and a hexagonal plastic-crystal (rotator) phase were obtained. Our phase diagram may prove instrumental in guiding future experimental studies. PMID- 22938388 TI - One-pot bioethanol production from cellulose by co-culture of Acremonium cellulolyticus and Saccharomyces cerevisiae. AB - BACKGROUND: While the ethanol production from biomass by consolidated bioprocess (CBP) is considered to be the most ideal process, simultaneous saccharification and fermentation (SSF) is the most appropriate strategy in practice. In this study, one-pot bioethanol production, including cellulase production, saccharification of cellulose, and ethanol production, was investigated for the conversion of biomass to biofuel by co-culture of two different microorganisms such as a hyper cellulase producer, Acremonium cellulolyticus C-1 and an ethanol producer Saccharomyces cerevisiae. Furthermore, the operational conditions of the one-pot process were evaluated for maximizing ethanol concentration from cellulose in a single reactor. RESULTS: Ethanol production from cellulose was carried out in one-pot bioethanol production process. A. cellulolyticus C-1 and S. cerevisiae were co-cultured in a single reactor. Cellulase producing-medium supplemented with 2.5 g/l of yeast extract was used for productions of both cellulase and ethanol. Cellulase production was achieved by A. cellulolyticus C-1 using Solka-Floc (SF) as a cellulase-inducing substrate. Subsequently, ethanol was produced with addition of both 10%(v/v) of S. cerevisiae inoculum and SF at the culture time of 60 h. Dissolved oxygen levels were adjusted at higher than 20% during cellulase producing phase and at lower than 10% during ethanol producing phase. Cellulase activity remained 8-12 FPU/ml throughout the one-pot process. When 50-300 g SF/l was used in 500 ml Erlenmeyer flask scale, the ethanol concentration and yield based on initial SF were as 8.7-46.3 g/l and 0.15 0.18 (g ethanol/g SF), respectively. In 3-l fermentor with 50-300 g SF/l, the ethanol concentration and yield were 9.5-35.1 g/l with their yields of 0.12-0.19 (g/g) respectively, demonstrating that the one-pot bioethanol production is a reproducible process in a scale-up bioconversion of cellulose to ethanol. CONCLUSION: A. cellulolyticus cells produce cellulase using SF. Subsequently, the produced cellulase saccharifies the SF, and then liberated reducing sugars are converted to ethanol by S. cerevisiae. These reactions were carried out in the one-pot process with two different microorganisms in a single reactor, which does require neither an addition of extraneous cellulase nor any pretreatment of cellulose. Collectively, the one-pot bioethanol production process with two different microorganisms could be an alternative strategy for a practical bioethanol production using biomass. PMID- 22938390 TI - Tongue anatomy and physiology, the scientific basis for a novel targeted neurostimulation system designed for the treatment of obstructive sleep apnea. AB - INTRODUCTION: Obstructive sleep apnea (OSA) is a chronic condition that affects millions adults. The effective standard treatment is positive airway pressure (PAP). However, approximately half of the patients that are prescribed PAP are unable or unwilling to comply with this therapy. Untreated OSA ultimately leads to very serious comorbidities. An alternative therapy for this patient population, therefore, is desirable. Hypoglossal nerve (HGN) stimulation is under investigation by multiple groups as a possible alternative therapy for OSA. OBJECTIVE: To understand the underlying mechanisms of actions related to HGN stimulation, and the implication of this knowledge for specifying and designing a neurostimulation system for the treatment of OSA. RESULTS: Loss of lingual and pharyngeal tone within a narrow airway is the primary mechanism for OSA. Posterior and anterior tongues are different in their anatomy and physiology. Muscle fibers in the posterior tongue are predominantly fatigue resistant that are responsible for the long sustained tonic activities required for maintaining the tongue's position and preventing its mass from falling into the retroglossal airway. The human tongue is a muscular hydrostat and hence would benefit from a sophisticated HGN stimulation system that is capable of achieving a concerted spatio-temporal interplay of multiple lingual muscles, including retrusors. CONCLUSION: Targeted neurostimulation of the proximal HGN presents as a viable system approach that is far more versatile and physiologic and quite different than prior systems. PMID- 22938389 TI - Macrophages and angiogenesis: a role for Wnt signaling. AB - Macrophages regulate many developmental and pathological processes in both embryonic and adult tissues, and recent studies have shown a significant role in angiogenesis. Similarly, Wnt signaling is fundamental to tissue morphogenesis and also has a role in vascular development. In this review, we summarize recent advances in the field of macrophage-regulated angiogenesis, with a focus on the role of macrophage-derived Wnt ligands. We review data that provide both direct and indirect evidence for macrophage-derived Wnt regulation of physiologic and pathologic angiogenesis. Finally, we propose that Wnt signaling plays a central role in differentiation of tumor associated and wound infiltrating macrophages to a proangiogenic phenotype. PMID- 22938391 TI - Association of cognition with temporal discounting in community based older persons. AB - BACKGROUND: The objective of this study was to test the hypothesis that cognitive function is negatively associated with temporal discounting in old age. METHODS: Participants were 388 community-dwelling older persons without dementia from the Rush Memory and Aging Project, an ongoing longitudinal epidemiologic study of aging in the Chicago metropolitan area. Temporal discounting was measured using standard questions in which participants were asked to choose between an immediate, smaller payment and a delayed, larger one. Cognition was measured using a detailed battery including 19 tests. The association between cognition and temporal discounting was examined via mixed models adjusted for age, sex, education, income, and the number of chronic medical conditions. RESULTS: Descriptive data revealed a consistent pattern whereby older persons with lower cognitive function were more likely to discount greater but delayed rewards compared to those with higher cognitive function. Further, in a mixed effect model adjusted for age, sex, education, income, and chronic medical conditions, global cognitive function was negatively associated with temporal discounting (estimate = -0.45, SE = 0.18, p = 0.015), such that a person with lower cognition exhibited greater discounting. Finally, in subsequent models examining domain specific associations, perceptual speed and visuospatial abilities were associated with temporal discounting, but episodic memory, semantic memory and working memory were not. CONCLUSION: Among older persons without dementia, a lower level of cognitive function is associated with greater temporal discounting. These findings have implications regarding the ability of older persons to make decisions that involve delayed rewards but maximize well-being. PMID- 22938392 TI - Evaluation of the immune responses induced by four targeted DNA vaccines encoding the juvenile liver fluke antigen, cathepsin B in a mouse model. AB - BACKGROUND: Liver fluke can infect cattle and sheep, and is also emerging as a human pathogen in developing countries. Cathepsin B (Cat B2) is a major cysteine protease secreted by the juvenile flukes. To enhance the immune responses of Cat B2, the cDNA sequence was fused with four different DNA vaccine vectors. The induced cellular and antibody responses were compared in vaccinated mice. METHODS: The following recombinant DNA vaccine constructs were constructed: empty vector VR1012 as negative control, cytoplasmic construct pVR1012 Cat B2, secretory construct pVR1020 Cat B2, chemokine-fused construct pMCP3 Cat B2 and lymph node targeting construct pCTLA-4 Cat B2. Plasmids were constructed using standard procedures, and positive constructs screened and selected using restriction digestion analysis followed by sequence analysis. The constructs were then tested in Cos-7 cells for in vitro expression, which was analysed using immunoblotting. Subsequently, female BALB/c mice were immunised with DNA constructs as vaccines. Elicited antibody responses were measured using ELISA. The ratio between IgG1 and IgG2a antibody responses was estimated among different vaccine groups. IgG antibody avidity assay was performed and the relative avidity index was calculated. The induced cytokine production from splenocytes of vaccinated animals was estimated using ELISPOT. RESULTS: DNA vaccine constructs carrying Cat B2 were expressed in Cos-7 cell lines and encoded protein was recognised using western blotting using rat anti- cathepsin B antibody. DNA vaccines elicited high Cat B2- specific IgG, IgG1, IgE and also modest IgG2a antibody responses. Cat B2 specific IL-4 T cell responses were also observed in Cat B2 vaccinated mice. The comparison of immunogenic potential in each of these constructs was demonstrated as enhanced antibody responses on the lymph-node targeting vector pCTLA-4 Cat B2, the high antibody avidity of chemo-attractant pMCP3 Cat B2 and stronger T cellular responses of non-secretory DNA vaccine pVR1012 Cat B2 in vaccinated animals. CONCLUSION: This study showed that the targeting DNA vaccine strategies enhanced specific immune responses to juvenile fluke Cat B2. The results of our current study have demonstrated that a gene based vaccine as an immunotherapeutic approach to combat Fasciola infection may be feasible. PMID- 22938393 TI - Measurement of the time required for a termite to pass through tunnels with different curvatures. AB - The subterranean termite, Reticulitermes speratus kyushuensis (Isoptera: Rhinotermitidae), excavate complex tunnel networks below the ground for foraging. The tunnels are either curved or meandering. In our previous study, results showed that termites passed smooth-rounded corners faster than they did around sharp corners. Smooth-rounded corners can be mathematically quantified by the curvature, representing the amount by which a geometric object deviates from a straight line. The present study explored how the time spent inside a tunnel changes in accordance with the degree of tunnel curvature. To do so, artificial tunnels with different curvatures were constructed in acryl substrates. Tunnels were 5 cm in length with widths of W - 2, 3, or 4 mm, and the distance between the two ends of the tunnel was D = 2, 3, 4, or 5 cm. A higher value of D signified a lower curvature. The time (tau) taken by a termite to pass through the tunnel was measured. In the case of W = 2 mm, the values of tau were statistically equal for D = 2, 3, or 4 cm, while tau for D = 5 cm was significantly lesser. In the case of W = 3, tau was statistically more for D = 2 and 3 cm than it was for D = 4 and 5 cm. For W = 4, tau was statistically equal for D = 2 and 3 cm, while tau for D = 4 cm was relatively shorter. Interestingly, the value of tau when D = 5 cm was statistically the same as D = 3 or 4 cm. These resulted from two types of termite behavior: biased walking and zigzag walking. PMID- 22938395 TI - Varicella-zoster virus as a possible cause of pityriasis lichenoides et varioliformis acuta. AB - The etiologic agents for pityriasis lichenoides et varioliformis acuta (PLEVA) are largely unknown, although it has been suggested that foreign antigens such as infectious agents are the pathogenic mechanism. We present a case suggesting a possible relationship between varicella-zoster virus and PLEVA. PMID- 22938394 TI - Examining and mitigating acellular hemoglobin vasoactivity. AB - SIGNIFICANCE: There has been a striking advancement in our understanding of red cell substitutes over the past decade. Although regulatory oversight has influenced many aspects of product development in this period, those who have approached the demonstration of efficacy of red cell substitutes have failed to understand their implication at the level of the microcirculation, where blood interacts closely with tissue. RECENT ADVANCES: The understanding of the adverse effects of acellular hemoglobin (Hb)-based oxygen carriers (HBOCs) has fortunately expanded from Hb-induced renal toxicity to a more complete list of biochemical mechanism. In addition, various unexpected adverse reactions were seen in early clinical studies. The effects of the presence of acellular Hb in plasma are relatively unique because of the convergence of mechanical and biochemical natures. CRITICAL ISSUES: Controlling the variables using genetic engineering and chemical modification to change specific characteristics of the Hb molecule may allow for solving the complex multivariate problems of acellular Hb vasoactivity. HBOCs may never be rendered free of negative effects; however, quantifying the nature and extent of microvascular complications establishes a platform for designing new ameliorative therapies. FUTURE DIRECTIONS: It is time to leave behind the study of vasoactivity and toxicity based on bench-top measurements of biochemical changes and those based solely on systemic parameters in vivo, and move to a more holistic analysis of the mechanisms creating the problems, complemented with meaningful studies of efficacy. PMID- 22938396 TI - De novo sequence assembly and characterisation of a partial transcriptome for an evolutionarily distinct reptile, the tuatara (Sphenodon punctatus). AB - BACKGROUND: The tuatara (Sphenodon punctatus) is a species of extraordinary zoological interest, being the only surviving member of an entire order of reptiles which diverged early in amniote evolution. In addition to their unique phylogenetic placement, many aspects of tuatara biology, including temperature dependent sex determination, cold adaptation and extreme longevity have the potential to inform studies of genome evolution and development. Despite increasing interest in the tuatara genome, genomic resources for the species are still very limited. We aimed to address this by assembling a transcriptome for tuatara from an early-stage embryo, which will provide a resource for genome annotation, molecular marker development and studies of development and adaptation in tuatara. RESULTS: We obtained 30 million paired-end 50 bp reads from an Illumina Genome Analyzer and assembled them with Velvet and Oases using a range of kmers. After removing redundancy and filtering out low quality transcripts, our transcriptome dataset contained 32911 transcripts, with an N50 of 675 and a mean length of 451 bp. Almost 50% (15965) of these transcripts could be annotated by comparison with the NCBI non-redundant (NR) protein database or the chicken, green anole and zebrafish UniGene sets. A scan of candidate genes and repetitive elements revealed genes involved in immune function, sex differentiation and temperature-sensitivity, as well as over 200 microsatellite markers. CONCLUSIONS: This dataset represents a major increase in genomic resources for the tuatara, increasing the number of annotated gene sequences from just 60 to almost 16,000. This will facilitate future research in sex determination, genome evolution, local adaptation and population genetics of tuatara, as well as inform studies on amniote evolution. PMID- 22938397 TI - Effects of the beta-agonist, isoprenaline, on the down-regulation, functional responsiveness and trafficking of beta2-adrenergic receptors with N-terminal polymorphisms. AB - The beta2-AR (beta2-adrenergic receptor) is an important target for respiratory and CVD (cardiovascular disease) medications. Clinical studies suggest that N terminal polymorphisms of beta2-AR may act as disease modifiers. We hypothesized that polymorphisms at amino acids 16 and 27 result in differential trafficking and down-regulation of beta2-AR variants following beta-agonist exposure. The functional consequences of the four possible combinations of these polymorphisms in the human beta2-AR (designated beta2-AR-RE, beta2-AR-GE, beta2-AR-RQ and beta2 AR-GQ) were studied using site-directed mutagenesis and recombinant expression in HEK-293 cells (human embryonic kidney cells). Ligand-binding assays demonstrated that after 24 h exposure to 1 MUM isoprenaline, isoforms with Arg16 (beta2-AR-RE and beta2-AR-RQ) underwent increased down-regulation compared with isoforms with Gly16 (beta2-AR-GE and beta2-AR-GQ). Consistent with these differences in down regulation between isoforms, prolonged isoprenaline treatment resulted in diminished cAMP response to subsequent isoprenaline challenge in beta2-AR-RE relative to beta2-AR-GE. Confocal microscopy revealed that the receptor isoforms had similar co-localization with the early endosomal marker EEA1 following isoprenaline treatment, suggesting that they had similar patterns of internalization. None of the isoforms exhibited significant co-localization with the recycling endosome marker Rab11 in response to isoprenaline treatment. Furthermore, we found that prolonged isoprenaline treatment led to a higher degree of co-localization of beta2-AR-RE with the lysosomal marker LAMP1 (lysosome-associated membrane protein 1) compared with that of beta2-AR-GE. Taken together, these results indicate that a mechanism responsible for differential responses of these receptor isoforms to the beta-agonist involves differences in the efficiency with which agonist-activated receptors are trafficked to the lysosomes for degradation, or differences in degradation in the lysosomes. PMID- 22938398 TI - Chronic renal outcome after living donor liver transplantation. AB - Chronic kidney disease (CKD) is one of the common complications after deceased donor liver transplantation. Although the worldwide pressing shortage in deceased donors has directed attention to living donor liver transplantation (LDLT), LDLT cohort data focusing on chronic renal dysfunction is limited. A total of 280 adult LDLT recipients (median 49 yr, 156 men) at the University of Tokyo hospital between 1996 and 2006 were reviewed. A total of 224 pre-transplant liver failure patients (80.0%) showed an estimated glomerular filtration rate (eGFR) of more than 60 mL/min/1.73 m(2). However, during follow-up at a mean of 1222 d after transplantation, eGFR declined to 60 mL/min/1.73 m(2) and 30 mL/min/1.73 m(2) in 150 (53.2%) and 21 (7.5%), respectively, and four patients (1.4%) required maintenance renal replacement therapy. Multivariate Cox proportional hazard model regression analysis revealed that recipient age (HR, 3.42 per 10-yr increment; p < 0.001) and pre-transplant eGFR (HR, 0.85 per 10-mL/min/1.73 m(2) increment; p = 0.04) were associated independently with a post-transplant decrease in eGFR to less than 30 mL/min/1.73 m(2). We conclude that higher age and lower pre transplant eGFR of an LDLT recipient indicate a high likelihood of subsequent development of advanced CKD. Preventive or therapeutic intervention should be optimized for these high-risk patients. PMID- 22938399 TI - Outcome of febrile neutropenic patients on granulocyte colony stimulating factor in a tertiary care hospital. AB - INTRODUCTION: Febrile neutropenia is a relatively frequent event in cancer patients treated with chemotherapy and improvement in absolute neutrophil count (ANC) has been linked directly to improved outcome. Evaluation of granulocyte colony stimulating factors (GCSFs) for treatment has shown reduced incidences of episodes of prolonged neutropenia and protracted hospitalization. To determine absolute neutrophil counts with GCSF in febrile neutropenic cancer patients admitted to a tertiary care centre and to co-relate the improvement in ANC with mortality and hospital discharge. METHODS: A prospective cross sectional study was carried at an oncology ward at Aga Khan University hospital from January 2010 to June 2011. All adult patients who were admitted and treated with GCSF for chemotherapy induced febrile neutropenia were included. Multivariable regression was conducted to identify the factors related with poor outcomes. RESULTS: A total of 131 patients with febrile neutropenia were identified with mean age of 43.2 (18-85) years, 79 (60%) being <= 50. Seventy-five (57%) had solid tumors and 56 (43%) hematological malignancies, including lymphoma. Fifty seven (43.5%) had an ANC less 100 cells/mm(3), 34 (26%) one between 100-300 cells/mm(3) and 40 (31%) an ANC greater than 300 cells/mm(3). Thirty (23%) patients showed ANC recovery in 1-3 days, and 74(56%) within 4-7 days. Thirteen (10%) patients showed no recovery. The overall mortality was 18 (13.7%) patients. The mean time for ANC recovery seen in hematological malignancies was 6.34 days whereas for solid tumors it was 4.88 days. Patients with ANC <100 cells/mm(3) were more likely to die than patients with ANC >300 cells/mm(3) by a factor of 4.3. Similarly patients >50 years of age were 2.7 times more likely to die than younger patients. CONCLUSION: Our study demonstrated that use of GCSF, in addition to intravenous antibiotics, in treatment of patients with chemotherapy induced febrile neutropenia accelerates neutrophil recovery, and shortens antibiotic therapy and hospitalization. We propose to risk classify the patients at the time of admission to evaluate the cost effectiveness of this approach in a resource constrained setup. PMID- 22938400 TI - Methyl isocyanate and carcinogenesis: bridgeable gaps in scientific knowledge. AB - Methyl isocyanate may have a role in cancer etiology, although the link is unclear. There is evidence in the literature that it can induce cancer in animals but the carcinogenic potency is weak. Pheochromocytoma of adrenal medulla and acinar cell tumors of pancreas have been observed in methyl isocyanate exposed animals. Conversely, emerging data from population-based epidemiological studies are contradictory since there is no evidence of such cancers in methyl isocyanate exposed humans. Recently, we reported a high prevalence of breast and lung cancers in such a population in Bhopal. In vitro findings appearing in the latest scientific literature suggest that genomic instability is caused by methyl isocyanate analogs in lung, colon, kidney, ovary epithelial cells, and that hepatocytes may undergo oncogenic transformation, have obvious implications. The conflicting information prompted us to present this update over the last three decades on methyl isocyanate-induced cancers after an extensive literature search using PubMed. While the pertinent literature remains limited, with a scarcity of strong laboratory analyses and field-epidemiological investigations, our succinct review of animal and human epidemiological data including in vitro evidences, should hopefully provide more insight to researchers, toxicologists, and public health professionals concerned with validation of the carcinogenicity of methyl isocyanate in humans. PMID- 22938401 TI - Metastasis-associated factors facilitating the progression of colorectal cancer. AB - Tumor metastasis remains the principal cause of treatment failure and poor prognosis in patients with colorectal cancer. It is a multistage process which includes proteolysis, motility and migration of cells, proliferation in a new site, and neoangiogenesis. A crucial step in the process of intra- and extra vasation is the activation of proteolytic enzymes capable of degrading the extracellular matrix (ECM). In this stage, urokinase plasminogen activator receptor (uPAR) and matrix metalloproteinases (MMPs) are necessary. Micrometastases need the presence of growth factor and vascular growth factor so that they can form macrometastasis. In addition, cell adhesion molecules (CAMs) and guanine nucleotide exchange factors (GEFs) play important roles in the progression of colorectal cancer and metastatic migration. Further elucidation of the mechanisms of how these molecules contribute will aid in the identification of diagnostic and prognostic markers as well as therapeutic targets for patients with colorectal metastasis. PMID- 22938402 TI - RNA interference as a plausible anticancer therapeutic tool. AB - RNA interference has created a breakthrough in gene silencing technology and there is now much debate on the successful usage of RNAi based methods in treating a number of debilitating diseases. Cancer is often regarded as a result of mutations in genomic DNA resulting in faulty gene expression. The occurrence of cancer can also be influenced by epigenetic irregularities in the chromatin structure which leads to alterations and mutations in DNA resulting in cancer cell formation. A number of therapeutic approaches have been put forth to treat cancer. Anti cancer therapy often involves chemotherapy targeting all the cells in common, whereby both cancer cells as well as normal cells get affected. Hence RNAi technology has potential to be a better therapeutic agent as it is possible to deactivate molecular targets like specific mutant genes. This review highlights the successful use of RNAi inducers against different types of cancer, thereby paving the way for specific therapeutic medicines. PMID- 22938403 TI - Impact of home education on levels of perceived social support for caregivers of cancer patients. AB - BACKGROUND: The healthcare needs of cancer patients are complex and persons involved in their caregiving process are faced with many issues that need to be addressed. The entire family and particularly the person taking on responsibility for patient care develop expectations from healthcare professionals, especially nurses. OBJECTIVE: The study was conducted to evaluate the impact of a home education program provided to caregivers of cancer patients on the level of their perceived social support and problems in caregiving. INTERVENTIONS/ METHODS: The caregivers of thirty seven cancer patients of 2,400 registered people in a family center were given an educational program in this descriptive and cross-sectional study twice a week for a month during the period of March 2011 - April 2011. RESULTS: Of all caregivers, 56.8% were between the ages 36-40, 94.5% were female, 91.9% had received no education on caregiving, 81.0% stated that they mostly felt physically and mentally inadequate in their caregiving. Perceived Social Support from the family indicated a significant difference at 8.05 +/- 4.38 before and 11.7 +/- 4.97 after the education. A comparison of the mean scores of caregivers on emotional issues before and after the education revealed the following: spiritual distress scores were 2.54 +/- 0.69 before and 2.44 +/- 0.43 after the education; hopelessness scores, 2.24 +/- 0.59 before and 2.23 +/- 0.38 after the education; ineffective individual coping was 3.89 +/- 1.42 before and 2.45 +/- 0.59 after the education; competing needs in decision-making were 3.54 +/- 0.69 before and 2.10 +/- 1.24 after the education; depressive feeling were 3.01+/-1.53 before and 2.02 +/- 0.99 after the education (p<0.05). CONCLUSIONS: Positive effects of home education on levels of perceived social support and caregiving problems of caregivers of cancer patients were observed. Home educational programs for caregivers of cancer patients are important for both better understanding of the requirements of their patients and themselves. PMID- 22938404 TI - Residential radon and lung cancer risk: an updated meta- analysis of case-control studies. AB - BACKGROUND: Numbers of epidemiological studies assessing residential radon exposure and risk of lung cancer have yielded inconsistent results. METHODS: We therefore performed a meta-analysis of relevant published case- control studies searched in the PubMed database through July 2011 to examine the association. The combined odds ratio (OR) were calculated using fixed- or random-effects models. Subgroup and dose-response analyses were also performed. RESULTS: We identified 22 case-control studies of residential radon and lung cancer risk involving 13,380 cases and 21,102 controls. The combined OR of lung cancer for the highest with the lowest exposure was 1.29 (95% CI 1.10-1.51). Dose-response analysis showed that every 100 Bq/m3 increment in residential radon exposure was associated with a significant 7% increase in lung cancer risk. Subgroup analysis displayed a more pronounced association in the studies conducted in Europe. Studies restricted to female or non-smokers demonstrated weakened associations between exposure and lung cancer. CONCLUSIONS: This meta- analysis provides new evidence supporting the conclusion that residential exposure to radon can significantly increase the risk of lung cancer in a dose-response manner. PMID- 22938405 TI - Bleomycin, etoposide and cisplatinum (BEP) chemotherapy for metastatic germ cell tumours: treatment outcomes at UKM medical centre, Malaysia. AB - INTRODUCTION: Although bleomycin/etoposide/cisplatinum (BEP) chemotherapy is established as the standard treatment for germ cell tumours, it requires significant experience in administration and toxicity management to maintain optimal dose intensity. A retrospective review of 30 patients was conducted at UKMMC to study treatment outcomes. METHODS AND MATERIALS: Patients with GCTs and treated with at least two cycles of BEP chemotherapy between January 2003 and Oct 2009 were eligible for this study. Patients received 4-6 cycles of bleomycin 30,000IU IV D1, D8 and D15 and either etoposide 100mg/m2 IV D1- D5 and cisplatin 20mg/m2 IV D1- D5 (5 day BEP regimen) or etoposide 165 mg/m2 D1- D3 and cisplatin 50mg/m2 D1-3 (3 day BEP regimen) every three weeks per cycle. All patients received prophylactic granulocyte colony-stimulating factor (GCSF) from days 6 to 10 of each cycle. The overall response rates, 2 year progression-free survival and overall survival of the whole cohort were assessed. RESULTS: Thirty patients fulfilled the inclusion criteria. Non-seminomatous GCTs comprised 93.3% of cases and gonadal and mediastinal primary sites were the most common. Sixty percent were classified as IGCCCG poor risk disease. Median follow-up was 26.6 months. The overall response rate (CR+PR) was 70%. The two year PFS and OS were 70% and 66%. There was a significant difference in terms of the overall response rate (85% vs 40%, p = 0.03) and in PFS (94.7% vs 50%, p = 0.003) between gonadal and extragonadal primary sites. CONCLUSION: It is possible to achieve outcomes similar to those in international clinical trials with close monitoring and good supportive care of patients undergoing BEP chemotherapy. There is a strong argument for patients with IGCCCG poor prognosis disease to be treated in specialist tertiary centres to optimize treatment outcomes. PMID- 22938406 TI - Threshold primary tumour sizes for nodal and distant metastases in papillary and follicular thyroid cancers. AB - BACKGROUND: In papillary and follicular thyroid cancers (PTC, FTC), nodal and distant metastasis are generally considered important determinants of recurrence and survival, respectively. However, there is no consensus about the threshold primary tumour size (PTS) for these determinants. The aim of this study was to assess size relationships for developing nodal, pulmonary, bone and overall distant metastases. METHODS: This prospective study covered 139 (93 females and 46 males) consecutive biopsy proven patients with PTC (114/139, mean age 41.0 +/- 15.7 years, M: F, 35%:65%) and FTC (25/139, mean age 39.2 +/- 14.3 years, M: F: 24%:76%). RESULTS: Average primary tumor size was 23.4 +/- 11.1 mm and 26.5 +/- 13.1 mm for PTC and FTC respectively (p value=0.223). Nodal metastasis was found more common in PTC than FTC (49% vs 28%, p value <0.05), whereas overall distant metastasis was approximately the same (13% and 24%, p value =0.277); however, bone metastasis was significantly higher in FTC than PTC (24% vs 5%, p value <0.05). Cumulative risk for nodal and distant metastases for FTC and PTC starts at PTS <20 mm and may indicate an unusual aggressive tumor behavior in the studied population. Highest cumulative risk for nodal and pulmonary metastases in PTC and for bone metastasis in FTC was found to be >= 50 mm PTS. CONCLUSION: We conclude that a PTS of <20 mm may indicate an unusual aggressive tumor behavior with highest cumulative risk for nodal and pulmonary metastases in PTC and for bone metastasis in FTC with a cutoff of >= 50 mm. PMID- 22938407 TI - Urothelial tumors of the urinary bladder in Manipur: a histopathological perspective. AB - OBJECTIVE: To study the histomorphological pattern of urothelial tumors of the urinary bladder in Manipur and to evaluate whether any correlation exists between tumor grade and muscle invasion. METHODS: A 10 year retrospective study of all consecutive cases diagnosed in the Department of Pathology RIMS - Imphal, between 1st January 2001 to 31st December 2010. RESULTS: The study included 26 cases of transitional cell tumors of urinary bladder. The male to female ratio was 1.5: 1 and the ages ranged from 38 years to 73 years (medians of 60 and 64 years, respectively). Of the total, 14 (53.9%) cases were low grade, 9 (34.6%) were high grade, 2 (7.7%) were papillomas and 1 (3.9%) was a papillary urothelial neoplasm of low malignant potential (PUNLMP). Pathological staging showed that 14 (53.9%) of the cases were stage PTa, four (15.4%) PT1, and eight (30.9%) PT2. Some 18.2% of low grade tumors and 75% of high grade tumors were invasive to the detrusor muscle layer. CONCLUSION: Bladder cancer is an uncommon disease, transitional tumors being the only histological type observed. It was more common in males than females, with peak incidence in seventh decade. Most of the tumors were non- invasive (PTa) and invasion to the detrusor muscle layer was seen in more than half of the high grade tumors. There is a definite correlation between advancing tumor grade and muscle invasion. PMID- 22938408 TI - Sodium intake, salt taste and gastric cancer risk according to Helicobacter pylori infection, smoking, histological type and tumor site in China. AB - AIM: The risk factors mostly strongly associated with gastric cancer are gastric bacteria Helicobacter pylori and diet. Using a case-control study among residents in Jinan, we examined the association between the salt taste and gastric cancer according to H. pylori infection, smoking and histological type as well as tumor site. METHODS: This population-based case-control study included 207 cases and 410 controls. Data on potential risk factors of gastric cancer were obtained by interview of cases and controls with a questionnaire, salt taste preference was measured for all subjects, and IgG antibodies to H. pylori were applied to assess infection. Risk measures were determined using unconditional logistic regression. RESULTS: The proportions of salt taste at intervals of 1.8-7.2 g/L and >= 7.2 g/L were significantly higher in cases than controls, with ORs of 1.56 (1.23-3.64) and 2.03 (2.12- 4.11), respectively, subjects with high salt intake having an elevated risk for gastric cancer when infected with H. pylori. Significant modification by smoking and tumor site was observed across the different measures of salt intake, the highest salt taste showed higher cancer risk in ever smokers or with non-cardia cancers. CONCLUSION: Our study supports the view that high intake of sodium is an important dietary risk factor for gastric cancer, with a synergistic effect found between salt and H.pylori and smoking, dependent on the tumor site. PMID- 22938409 TI - siRNA-mediated silencing of Notch-1 enhances docetaxel induced mitotic arrest and apoptosis in prostate cancer cells. AB - PURPOSE: Notch is an important signaling pathway that regulates cell fate, stem cell maintenance and the initiation of differentiation in many tissues. It has been reported that activation of Notch-1 contributes to tumorigenesis. However, whether Notch signaling might have a role in chemoresistance of prostate cancer is unclear. This study aimed to investigate the effects of Notch-1 silencing on the sensitivity of prostate cancer cells to docetaxel treatment. METHODS: siRNA against Notch-1 was transfected into PC-3 prostate cancer cells. Proliferation, apoptosis and cell cycle distribution were examined in the presence or absence of docetaxel by MTT and flow cytometry. Expression of p21(waf1/cip1) and Akt as well as activation of Akt in PC-3 cells were detected by Western blot and Real-time PCR. RESULTS: Silencing of Notch-1 promoted docetaxel induced cell growth inhibition, apoptosis and cell cycle arrest in PC-3 cells. In addition, these effects were associated with increased p21(waf1/cip1) expression and decreased Akt expression and activation in PC-3 cells. CONCLUSION: Notch-1 promotes chemoresistance of prostate cancer and could be a potential therapeutic target. PMID- 22938410 TI - MTHFR C667T polymorphism association with lung cancer risk in Henan province: a case-control study. AB - The current study was performed to assess any association between the methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism and risk of lung cancer in Henan province. This case-control study involved94 patients with newly histological confirmed lung cancer and 78 healthy controls. Genotyping was achieved with peripheral blood lymphocytes DNA and association of the polymorphism with risk of lung cancer was estimated by unconditional logistic regression analysis. The frequencies of the MTHFR 667TT genotype were 37.2% in cases compared with 23.1% in controls (chi2 = 4.008, P = 0.045). Individuals with the 667CC/CT genotype displayed a significantly reduced risk of lung cancer compared with those with the TT genotypes [adjusted odds ratio (OR), 0.506; 95% confidence interval (95% CI), 0.258 - 0.991]. The C667T polymorphism might have a significant effect on the occurrence of lung cancer in Henan province. PMID- 22938411 TI - Trends in nasopharyngeal carcinoma mortality in China, 1973-2005. AB - Nasopharyngeal carcinoma (NPC) is a disease with distinct ethnic and geographic distribution. The incidence of NPC in Chinese residing in Asia has declined over the last few decades, but NPC mortality trends in the entire Chinese population over time have not been systematically evaluated. In this study, we examined NPC mortality at the national level in China between 1973-2005. Mortality rates were derived from the databases of national retrospective surveys on cancer mortality conducted in the periods of 1973-1975, 1990-1992, and 2004-2005, respectively. NPC was classified according to the International classification of diseases. Age adjusted mortality rates were calculated by direct standardization according to the world standard population. Trends in rates were evaluated by age, gender, geographic areas, and socioeconomic status. From 1973 to 2005, there was a general trend of decrease in NPC mortality in China, with higher rates in the south on a downward trend in the north. The age-standardized NPC mortality rates were 2.60 per 100,000 in 1973-1975, 1.94 per 100,000 in 1990-1992, and 1.30 per 100,000 in 2004-2005, respectively. The trend was similar in both men and women, in both urban and rural areas, but the declining rates in females were more remarkable than in males. The mortality rates were higher for the age groups above 50 years than those less than 50 years of age, both showing downward trend over 30-year period. In summary, the overall NPC mortality has consistently decreased in China over the past three decades, particularly in women and in old adults. PMID- 22938412 TI - Galectin-9 acts as a prognostic factor with antimetastatic potential in hepatocellular carcinoma. AB - Considerable research has been conducted concerning galectin-9 and carcinomas, but little information is available about any relation with the hepatocellular carcinoma. In this study, we employed a small interfering RNA (siRNA) targeting galectin-9 to down-regulate the expression in HepG2 cells. As a result, after galectin-9 expression was reduced, cell aggregation was suppressed, while other behaviour such as the proliferation, adhesion and invasion to ECM, cell endothelial adhesion and transendothelial invasion of the cells were markedly enhanced. When tumors of 200 patients with hepatocellular carcinoma were tested for galectin-9 expression by immunohistochemistry, binding levels demonstrated intimate correlations with the histopathologic grade, lymph node metastasis, vascular invasion and intrahepatic metastasis (P<0.05). Moreover, survival analysis indicated that patients with galectin-9 expression had much longer survival time than those with negative lesions, and the Log-rank test indicated that this difference was statistical significant (P<0.0001). The Cox proportional hazards model suggested that negative galectin-9 expression in hepatocellular carcinoma represented a significant risk factor for patient survival. We propose that galectin-9 might be a new prognostic factor with antimetastatic potential in patients with hepatocellular carcinoma. PMID- 22938413 TI - Gallbladder carcinoma: analysis of prognostic factors in 132 cases. AB - OBJECTIVE: To evaluate the prognostic factors of gallbladder carcinoma. METHODS: Presentation, operative data, complications, and survival outcome were examined for 132 gallbladder carcinoma patients who underwent gallbladder surgery in our unit during 2002-2007, and follow-up results were obtained from every patient for univariate and multivariate survival analysis. RESULTS: The univariate analysis showed that gallbladder lesion history, tumor cell differentiation, Nevin staging, preoperative lymph node metastasis and the surgical approach significantly correlated with the prognosis of the patients (p <0.05). The results of the multivariate analysis (Cox regression) showed that gallbladder lesion history, Nevin staging and the surgical approach were independent predicators with relative risks of 6.9, 4.4, 2.8, respectively (p=0.002, 0.003, 0.008). CONCLUSION: Gallbladder lesion history, Nevin staging and the surgical approach are independent prognostic factors for gallbladder carcinoma, a rapidly fatal disease. Therefore, early diagnosis, anti-infective therapy and radical surgery are greatly needed to improve the prognosis of gallbladder carcinoma. PMID- 22938414 TI - Assessment and clinical significance of haematuria in Malaysian patients - relevance to early cancer diagnosis. AB - AIM: To study the causes and significance of both microscopic and macroscopic haematuria in adult patients and assess possible relevance to early detection of urological cancers. METHODS: 417 patients presenting with haematuria were assessed in our Urology Unit. Following confirmation of haematuria, these patients were subjected to imaging techniques and flexible cystoscopy. Parameters analysed included clinical characteristics, imaging results, flexible cystoscopy findings, time delay to diagnoses and eventual treatment and final diagnoses of all cases. RESULTS: 390 haematuria cases were analysed from 417 consecutive patients with haematuria. After 27 cases were excluded as they had previous history, 245 microscopic and 145 macroscopic. Age range was 17 to 95 years old with predominance of 152 females to 239 males. The racial distribution included 180 Chinese, 100 Indians,95 Malays and 15 other races. The final diagnoses were benign prostatic hyperplasia (22.6%), no cause found (22.3%), other causes (18.7%), urolithiasis (11.5%), urinary tract infection UTI (10.8%), non specific cystitis (10.3%), bladder tumours (2.8%) and other genitourinary tumours (1%). 11 new cases (2.8%) of bladder cancers were diagnosed, with a mean age of 59 years. Only 3 of 245 (1.2%) patients with microscopic haematuria had newly diagnosed bladder tumour compared with 8 of 145 (5.5%) patients with frank haematuria (p=0.016). Mean time taken from onset of symptoms to diagnosis of bladder cancer was 53.3 days with definitive treatment (TURBT) in 20.1 days from diagnosis. CONCLUSION: - This study has highlighted the common causes of haematuria in our local setting. We recommend that full and appropriate investigations be carried out on patients with frank haematuria especially those above 50 years old in order to provide earlier detection and prompt management of bladder diseases especially tumours. PMID- 22938415 TI - Association of genetic polymorphisms at 1q22 but not 10q23 with gastric cancer in a southern Chinese population. AB - OBJECTIVE: Data from a recent genome-wide association studiesy of gastric cancer (GC) and oesophageal squamous cell carcinoma in Chinese living in the Taihang Mountains of north-central China suggest that 1q22 and 10q23 are susceptibility associated regions for GC. However, this has not been confirmed in southern Chinese populations. The aim of this study was to investigate whether these polymorphisms at 1q22 and 10q23 are associated with the risk of GC in a southern Chinese population. METHODS: We selected seven top significant associated single nucleotide polymorphisms (SNPs) at 1q22 and 10q23 and conducted a population based case- control study in a southern Chinese population. Genotypes were determined using MassARRAYTM system (Sequenome, San Diego, CA). RESULTS: Two SNPs at 1q22, rs4072037 and rs4460629, were significantly associated with a reduced risk of GC, best fitting the dominant genetic model. Logistic regression models adjusted for age and sex showed that rs4072037 AG and GG (OR=0.64, P=0.017, compared with AA) and rs4460629 CT and TT (OR=0.54, P=0.0016, compared with TT) significantly reduced the risk of GC. However, no significant results for the five SNPs at 10q23 were obtained in this study. CONCLUSION: These outcomes indicate that 1q22 is associated with GC susceptibility in this southern Chinese population, while an association for the locus at 10q23 was not confirmed. PMID- 22938416 TI - Gene silencing of beta-catenin by RNAi inhibits proliferation of human esophageal cancer cells by inducing G0/G1 cell cycle arrest. AB - OBJECTIVES: The aim of the present study was to explore mechanisms underlying the effects of down-regulating beta-catenin expression on esophageal carcinoma (EC) cells. METHODS: Cell cycle distribution and apoptosis were determined using flow cytometry and annexin V apoptosis assay, respectively. Transmission electron microscopy (TEM) was used to examine changes in ultrastructure, while expression of cyclin D1 protein and mRNA was detected by western blot and real-time PCR. Proliferating cell nuclear antigen (PCNA) and extracellular signal-regulated kinase (ERK) 1/2 were evaluated by Western blot analysis. PCNA labeling index (LI) was determined by immunocytochemistry. RESULTS: Compared with pGen-3-con transfected and Eca-109 cells, the percentage of G0/G1-phase pGen-3-CTNNB1 transfected cells was obviously increased (P<0.05), with no significant difference among the three groups with regard to apoptosis (P>0.05). pGen-3 CTNNB1 transfected cells exhibited obvious decrease in cyclin D1 mRNA and protein expression (P<0.05) and the ultrastructure of Eca-109 cells underwent a significant change after being transfected with pGen-3-CTNNB1, suggesting that down-regulating beta-catenin expression can promote the differentiation and maturation. The expression of PCNA and the ERKI/2 phosphorylation state were also down-regulated in pGen-3-CTNNB1 transfected cells (P<0.05). At the same time, the PCNA labeling index was decreased accordingly (P<0.05). CONCLUSION: Inhibition of EC Eca-109 cellproliferation by down-regulating beta-catenin expression could improve cell ultrastructure by mediating blockade in G0/G1 through inhibiting cyclin D1, PCNA and the MAPK pathway (p-ERK1/2). PMID- 22938417 TI - Chemopreventive potential of Annona muricata L leaves on chemically-induced skin papillomagenesis in mice. AB - Annona muricata L (Annonaceae), commonly known as soursop has a long, rich history in herbal medicine with a lengthy recorded indigenous use. It had also been found to be a promising new anti-tumor agent in numerous in vitro studies. The present investigation concerns chemopreventive effects in a two-stage model of skin papillomagenesis. Chemopreventive effects of an ethanolic extract of A. muricata leaves (AMLE) was evaluated in 6-7 week old ICR mice given a single topical application of 7,12-dimethylbenza(alpha)anthracene (DMBA 100 MUg/100 MUl acetone) and promotion by repeated application of croton oil (1% in acetone/ twice a week) for 10 weeks. Morphological tumor incidence, burden and volume were measured, with histological evaluation of skin tissue. Topical application of AMLE at 30, 100 and 300 mg/kg significantly reduced DMBA/croton oil induced mice skin papillomagenesis in (i) peri-initiation protocol (AMLE from 7 days prior to 7 days after DMBA), (ii) promotion protocol (AMLE 30 minutes after croton oil), or (iii) both peri-initiation and promotion protocol (AMLE 7 days prior to 7 day after DMBA and AMLE 30 minutes after croton oil throughout the experimental period), in a dose dependent manner (p<0.05) as compared to carcinogen-treated control. Furthermore, the average latent period was significantly increased in the AMLE-treated group. Interestingly, At 100 and 300 mg/ kg, AMLE completely inhibited the tumor development in all stages. Histopathological study revealed that tumor growth from the AMLE-treated groups showed only slight hyperplasia and absence of keratin pearls and rete ridges. The results, thus suggest that the A.muricata leaves extract was able to suppress tumor initiation as well as tumor promotion even at lower dosage. PMID- 22938418 TI - Predictive value of XRCC1 and XRCC3 gene polymorphisms for risk of ovarian cancer death after chemotherapy. AB - OBJECTIVE: To investigate any association between XRCC1 and XRCC3 polymorphisms and outcome of platinum-based chemotherapy in ovarian cancer patients. METHODS: With a prospective study design was cases were consecutively collected from January 2005 to January 2007. All 310 included patients were followed-up until the end of January 2010. Genotyping of XRCC1 and XRCC3 polymorphisms was conducted by TaqMan Gene Expression assays. RESULTS: A total of 191 patients died during follow-up. Our study showed a lower survival rate in XRCC1 399 Arg/Arg genotype than Gln/ Gln, with a significant increased risk of death (HR=1.69, 95%CI=1.07-2.78). Similarly, those carrying XRCC3 Thr/ Thr genotype had a increased risk as compare to the Met/Met genotype, with a HR (95% CI) of 1.90 (1.12-3.41). There was no significant association between XRCC1 Arg194Trp and XRCC1Arg280His gene polymorphisms and ovarian cancer death. CONCLUSION: Our study demonstrates that polymorphisms in DNA repair genes have roles in the susceptibility and survival of ovarian cancer patients. PMID- 22938419 TI - Correlates of smoking, quit attempts and attitudes towards total smoking bans at university: findings from eleven faculties in Egypt. AB - OBJECTIVES: Smoking among university students represents a formidable and global public health challenge. We assessed the associations between socio-demographic, health and wellbeing variables as independent variables, with daily smoking, attempts to quit smoking, and agreement with smoking ban as dependent variables. METHODS: A sample of 3258 undergraduate students from eleven faculties at Assiut University, Assiut, Egypt, completed a general health questionnaire. RESULTS: Overall daily or occasional smoking in last three months prior to the survey was about 9% (8% occasional and 1% daily smokers), and smoking was generally more prevalent among males (male=17%, female=0.6%, P < 0.001). After adjustment for confounders, not having normal BMI and having a mother who completed at least bachelor's degree education was positively associated with daily smoking, and conversely, no history of illicit drug use was a protective factor. About 76% of smokers had attempted to quit smoking within the last 12 months prior to the survey. Although a large proportion of students agreed/ strongly agreed with the banning of smoking at university altogether (87%), such agreement was less likely among smokers. CONCLUSION: There is need for implementation of non-smoking policies on university premises, as well as regular up-to-date information on, and the periodic/yearly monitoring of tobacco use by university students employing standardised data collection instruments and reference periods. In addition, it would be valuable to develop campus-based educational/ awareness campaigns designed to counteract tobacco advertisement directed towards young people in Middle East countries. Otherwise, the danger could be that the current relatively low smoking prevalence among university students may escalate in the future. PMID- 22938420 TI - Evaluation of depression in newly diagnosed breast cancer cases in Hatay province of Turkey in 2011. AB - Breast cancer is the most frequently diagnosed cancer and the leading cause of cancer death in females in Turkey. The main problems experienced by women with breast cancer are physical losses, emotional distress and degradation in family, work and social roles. The purpose of this cross-sectional retrospective study was to investigate the socio-demographical characteristics and depressive symptoms of 125 newly diagnosed cases with breast cancer reported to cancer control department of Hatay provincial health directorate in 2011. To evaluate the depressive symptoms the Beck Depression Inventory (BDI) was used. All 125 cases who participated in the study were female. The mean age was 49.2 +/- 11.9. The mean BDI score of the cases was 17.5 +/- 10.6. The number of cases whose BDI scores were 17 and above was 65 (52.0%), and the number of cases whose BDI scores were under 17 was 60 (48.0%). The most striking finding in our study was that only 4 of the cases were receiving psychological help and support. The rate of depression was found high in our study and psychological support is a must for patients with a life threatening disease such as cancer. PMID- 22938421 TI - Chemopreventive efficacy of Moringa oleifera pods against 7, 12 dimethylbenz[a]anthracene induced hepatic carcinogenesis in mice. AB - Oxidative stress is a common mechanism contributing to initiation and progression of hepatic damage in a variety of liver disorders. Hence there is a great demand for the development of agents with potent antioxidant effect. The aim of the present investigation is to evaluate the efficacy of Moringa oleifera as a hepatoprotective and an antioxidant against 7, 12-dimethylbenz[a]anthracene induced hepatocellular damage. Single oral administration of DMBA (15 mg/kg) to mice resulted in significantly (p<0.001) depleted levels of xenobiotic enzymes like, cytochrome P450 and b5. DMBA induced oxidative stress was confirmed by decreased levels of reduced glutathione (GSH) and glutathione-S-transferase (GST) in the liver tissue. The status of hepatic aspartate transaminase (AST), alanine transaminase (ALT), and alkaline phosphatase (ALP) which is indicative of hepatocellular damage were also found to be decreased in DMBA administered mice. Pretreatment with the Moringa oleifera (200 and 400 mg/kg) orally for 14 days significantly reversed the DMBA induced alterations in the liver tissue and offered almost complete protection. The results from the present study indicate that Moringa oleifera exhibits good hepatoprotective and antioxidant potential against DMBA induced hepatocellular damage in mice that might be due to decreased free radical generation. PMID- 22938422 TI - Superoxide dismutase isoenzyme activities in plasma and tissues of Iraqi patients with breast cancer. AB - Breast cancer is the first of the most common ten cancers in Iraq. Its etiology is mulifactorial, oxidative stress and lipid peroxidation being suggested to play important roles in carcinogenesis. The purpose of this study was to investigate the oxidant-antioxidant status in breast cancer patients, by measuring SOD isoenzyme activities (total SOD, CuZn-SOD, Mn-SOD and EC-SOD) in plasma and breast tumors, and by estimating thiobarbituric reactive substance (TBRS) in tissue homogenates. General increase in total SOD activity was observed in plasma and tissue samples of breast tumors, greater in the malignant when compared to benign group (p<0.05). Mn- SOD showed a significant decrease in tissue malignant samples (p<0.05), and insignificant decrease in plasma malignant samples compared with control and benign samples. Plasma EC-SOD activity in both patient benign and malignant breast tumors demonstrated 3.5% and 22.8% increase, respectively. However, there was a decrease in tissue EC-SOD activity in malignant breast tumors when compared with benign. A similar tendency was noted for TBRS.We suggested that elevated total SOD might reflect a response to oxidative stress, and then may predict a state of excess reactive oxygen species in the carcinogenesis process. If there is proteolytic removal of the heparin binding domain, EC-SOD will lose its affinity for the extracellular matrix and diffuse out of the tissue. This will result in a decreased EC-SOD activity, thus leading to an increase in the steady-state concentration of O2- in this domain, and increase in EC-SOD activity in extracellular fluid. This might explain the result recorded here concerning the decrease in tissue EC-SOD activity and increase in plasma of breast cancer patients. PMID- 22938423 TI - Systematic review on Epstein-Barr virus (EBV) DNA in diagnosis of nasopharyngeal carcinoma in Asian populations. AB - OBJECTIVE: To conduct a meta-analysis to investigate the value of EBV DNA in diagnosis of nasopharyngeal cancer (NPC) in Asian populations, and provide important evidence for screening. METHODS: Prospective or respective case-control or cohort studies regarding the detection role of EBV DNA for NPC were included in our study. We conducted a comprehensive literature search in PubMed, EMBASE, and the Chinese Biomedical Database (CBM database between January 1980 and March 2012. RESULTS: A total of 18 studies with 1492 NPC cases and 2641 health controls were included. Almost of the included studies were conducted in China, and only one other conducted in Thailand. The overall results demonstrated that the pooled sensitivity, specificity, positive likelihood (+ LR) and negative likelihood ( LR) were 0.73 (0.71-0.75), 0.89 (0.88-0.90), 8.84 (5.65-13.84) and 0.19(0.11 0.32), respectively. The overall EBV DNA detection showed the largest area of 0.932 under the summary receiver operator curve (SROC). The accuracy of detection by plasma for NPC (0.86) was higher than in serum (0.81), with largest areas under the SROC of 0.97 and 0.91, respectively. CONCLUSION: Our results demonstrated the EBV DNA detection in plasma or serum has high sensitivity and specificity in diagnosis of NPC, especially in Chinese populations with a high risk of cancer. PMID- 22938424 TI - Predictive role of ERCC1 and XPD genetic polymorphisms in survival of Chinese non small cell lung cancer patients receiving chemotherapy. AB - AIM: There is increasing evidence that ERCC1 and XPD have roles in response to chemotherapy among patients with NSCLC, but the results are conflicting. Therefore, we conducted the present prospective study in a Chinese population. METHODS: A total of 632 primary NSCLC patients were included, followed-up from May 2006 to May 2011. Polymorphisms were detected by real time PCR with TaqMan probse, using genomic DNA extracted from peripheral blood samples. The Cox regression model was used to analyze the hazard ratios (HR) for ERCC1 and XPD. RESULTS: The median time of follow-up was 31.6 months. Our results showed the ERCC1 118 T/T(HR=1.65, 95% CI=1.17-2.43) and XPD 751 Gln/ Gln genotypes (HR=1.52, 95%CI=1.04-2.08) were associated with an increased risk of death from NSCLC. Moreover, the ERCC118 T allele and XPD 751 Gln allele genotypes had a more higher risk of death from NSCLC among both ex-smokers and current smokers. CONCLUSION: In summary, ERCC1 and XPD gene polymorphisms might provide better prognostic predictive information for NSCLC patients in Chinese populations, with smoking possibly interacting with the genotypes. PMID- 22938425 TI - Knowledge of cervical cancer and HPV vaccine post- vaccination among mothers and daughters in Vietnam. AB - BACKGROUND: Limited human papillomavirus (HPV) related knowledge might be a barrier to future vaccine acceptance. From 2008-2010, PATH conducted an HPV vaccination demonstration project in partnership with the government immunization program in Vietnam, which included awareness campaigns prior to vaccination. OBJECTIVE: To assess and compare knowledge and attitudes about cervical cancer and HPV vaccines between mothers and daughters, and whether knowledge was associated with vaccination status. METHODS: We analyzed HPV-related knowledge and attitude data from mother-daughter paired responses to a cross-sectional household survey. After parents completed the survey, daughters were asked the same questions. We calculated the frequency of responses for each question and devised a scaled composite measure for knowledge. RESULTS: Participants believed they had received enough information about cervical cancer and HPV vaccines and it was sufficient to make a decision about vaccination. Fifty percent of the participants knew HPV causes cervical cancer and 80% knew the HPV vaccine prevented cervical cancer. Mothers had more knowledge about cervical cancer and HPV infection (p<0.01), compared to daughters, who had more vaccine specific knowledge (p<0.01). However, the total mean knowledge score was similar for the groups. Girls not fully vaccinated had a lower mean knowledge score than fully vaccinated girls (p<0.001). CONCLUSIONS: Our results suggest that the purpose of the HPV vaccine was clearly messaged; however, some misconceptions about cervical cancer and HPV still exist. Limited knowledge about the magnitude of cervical cancer, HPV as a cause of cervical cancer, and HPV vaccines may have contributed to incomplete vaccination. PMID- 22938426 TI - Case-control study of single nucleotide polymorphisms of PSCA and MUC1 genes with gastric cancer in a Chinese. AB - AIMS: A case-control study of 300 gastric cancer patients and 300 controls was conducted to investigate whether the polymorphisms rs2294008 in PSCA and rs2070803 in MUC1 might be associated with risk of gastric cancer in a Chinese population. METHODS: Single nucleotide polymorphisms (SNPs) were genotyped using the Sequenom MassARRAY platform. RESULTS: The data showed that the rs2294008 TT genotype increased gastric cancer risk to an adjusted odds ratio (OR) of 2.26 (95%CI 1.25-4.07), TC to 1.72 (95%CI 1.23-2.42) and TC/TT to 1.81 (95% CI 1.31 2.50), while the rs2070803 GA genotype was associated with a decrease in risk to an adjusted OR of 0.42 (95% CI 0.28-0.62) and rs2070803 GA / AA to 0.46 (95% CI 0.32-0.67). Further stratification analysis revealed that rs2294008 in PSCA consistently increased risk of both intestinal and diffuse-type gastric cancers. The effect of rs2070803 in MUC1 was noteworthily also consistent with both subtypes. CONCLUSIONS: Our study suggested rs2294008 in the PSCA gene to be associated with increased risk of gastric cancer and rs2070803 in MUC1 to play a protective role in a Chinese population. PMID- 22938427 TI - The MTHFR C677T polymorphism and prostate cancer risk: new findings from a meta analysis of 7306 cases and 8062 controls. AB - Methylenetetrahydrofolate reductase (MTHFR) is an essential enzyme involved in folate metabolism; a single nucleotide polymorphism (SNP) C677T has been reported to be linked with altered incidences of several diseases. We here conducted a meta-analysis of 15 published epidemiological studies with a total of 7306 cases and 8062 controls to evaluate its association with prostate cancer risk with overall and subgroup analyses. No statistical relationship was found overall with any genetic model (TT vs. CC: OR = 0.80, 95%CI = [0.62, 1.04], P = 0.094; CT vs. CC: OR = 0.97, 95%CI = [0.84; 1.12], P = 0.667; Dominant: OR = 0.94, 95%CI = [0.82; 1.07], P = 0.343; Recessive: OR = 0.81, 95%CI = [0.64; 1.04], P = 0.104), but after the exclusion of several studies, we could observe the homozygote TT to confer less susceptibility to prostate cancer in carriers; moreover, different effects of the polymorphism on prostate cancer risk was detected from subgroup analysis stratified by participants' residential region: significant reduced prostate cancer risk was found to be associated with the polymorphism from Asian studies (TT vs. CC: OR = 0.47, 95%CI = [0.33; 0.67], P< 0.001; CT vs. CC: OR = 0.73, 95%CI = [0.60; 0.90], P = 0.002; Dominant: OR = 0.67, 95%CI = [0.56; 0.82], P< 0.001; Recessive: OR = 0.55, 95%CI = [0.40; 0.76], P< 0.001) while studies from Europe indicated a slight increased risk under dominant model with marginal significance (OR = 1.14, 95%CI = [0.99; 1.30], P = 0.064). Moreover, the protective effect of the polymorphism against prostate cancer was also shown by studies performed in yellow Asians (TT vs. CC: OR = 0.48, 95%CI = [0.31; 0.75], P = 0.001; CT vs. CC: OR = 0.68, 95%CI = [0.51; 0.90], P = 0.006; Dominant: OR = 0.63, 95%CI = [0.48; 0.82], P < 0.001; Recessive: OR = 0.57, 95%CI = [0.39; 0.84], P = 0.004). We propose that these phenomena should be viewed with the consideration of folate metabolism profile and different gene background as well as living habits of different populations, and more relevant studies should be conducted to confirm our hypothesis and provide a comprehensive and clear picture concerning this topic. PMID- 22938428 TI - 3R variant of thymidylate synthase 5'-untranslated enhanced region contributes to colorectal cancer risk: a meta-analysis. AB - BACKGROUND: Studies investigating the association of 2R/3R polymorphism in the thymidylate synthase 5'-untranslated enhanced region (TSER) and colorectal cancer (CRC) risk have reported conflicting results. Thus, a meta-analysis was performed to summarize the data on the potential association. METHODS: Pubmed, Embase and CBM databases were searched for all available studies. Links between the TSER 2R/3R polymorphism and CRC risk were estimated by odds ratios (ORs) with 95% confidence intervals (CIs). RESULTS: Seven case-control studies with a total of 2723 cases and 4030 controls were included in this meta-analysis. The results showed that the 3R variant of TSER 2R/3R polymorphism contributes to CRC risk in two comparison models (OR 3R vs. 2R =1.10, 95%CI 1.02-1.18, P = 0.015; OR Homozygote comparison model = 1.22 1.04-1.43, 95%CI 1.04- 1.43, P = 0.012). Subgroup analyses by ethnicity further demonstrated a contribution in Caucasians with three comparison models (OR 3R vs. 2R = 1.10, 95%CI 1.02-1.19, P = 0.015; OR Homozygote comparison model = 1.21, 95%CI 1.03-1.41, P = 0.019; OR Recessive comparison model = 1.18, 95%CI 1.05-1.33, P = 0.008). However, the association in the Asian population was still uncertain due to the limited data (all P values were more than 0.05). CONCLUSIONS: Our meta-analysis suggests that the 3R variant of Thymidylate synthase 5'-untranslated enhanced region 2R/3R polymorphism contributes to gastric cancer risk in the Caucasian population, while any association in Asian populations needs further study. PMID- 22938429 TI - Insights into the tobacco cessation scenario among dental graduates: an Indian perspective. AB - INTRODUCTION: To curb the ever growing menace of tobacco and its ill effects, it is essential to prevent its usage. Dental professionals' contributions can be invaluable in this venture. OBJECTIVES: To assess Indian dental graduates' knowledge, attitude and practices towards tobacco cessation; perceived effectiveness in pursuing tobacco cessation activities; perception of factors that interfere in tobacco cessation as barriers; and willingness to participate in tobacco cessation. Further, to determine associations among the aforementioned variables. METHODOLOGY: All house surgeons in Manipal College of Dental Sciences, Manipal University, Mangalore were included in the study. A structured, pre tested and self-administered questionnaire was employed to assess participants' knowledge, attitude, behavior, perceived effectiveness, perceived barriers and willingness to participate in tobacco cessation. Information regarding respondents' age, gender and residence was collected. RESULTS: A total of 100 out of 103 respondents participated in the study. Mean knowledge, attitude, behavior, perceived effectiveness, perceived barrier scores were 17.6 +/- 2.53 (73.2%), 72.1 +/- 6.59 (90.2%), 28.3 +/- 5.12 (67.4%), 13.3 +/- 5.36 (53.16%) and 35.0 +/- 3.79 (89.8%) respectively. Overall, 97% respondents were willing to participate in tobacco cessation activities. Correlation analysis revealed that knowledge was associated with attitude (r=0.36, p=0.00) and perceived barriers (r=0.34, p=0.00) and behavior was associated with perceived barriers (r=0.22, p=0.03). CONCLUSIONS: Respondents reported high knowledge and attitude scores, along with high perceived barriers scores and willingness to participate in tobacco cessation activities. Present study highlights the need for a more meaningful involvement of dental professionals in tobacco cessation and has policy implications for curriculum changes regarding the same. PMID- 22938430 TI - Whole genome analysis of human papillomavirus genotype 11 from cervix, larynx and lung. AB - The prevalence of human papillomavirus genotypes differs in various target organs. HPV16 is the most prevalent genotype in the cervix while genotypes 6 and 11 are highly prevalent in skin and aero-digestive tract infections. In this study HPV11 positive specimens were selected from cervix, larynx and lung biopsy tissue to analyze the whole genome by PCR and direct sequencing. Five HPV11 whole genomes were characterized, consisting of two cervical specimens, two laryngeal specimens and one lung specimen. The results showed high homology of HPV11 in these organs. Phylogenetic analysis showed that all HPV11 derived from various organs belonged to the same lineage. Molecular characterization and functional studies can further our understanding of virulence, expression or transmission. Additional studies on functional protein expression at different organ sites will also contribute to our knowledge of HPV infection in various organs. PMID- 22938431 TI - Fumonisin B1 contamination of cereals and risk of esophageal cancer in a high risk area in northeastern Iran. AB - INTRODUCTION: Fumonisin B1 (FB1) is a toxic and carcinogenic mycotoxin produced in cereals due to fungal infection. This study was conducted to determine FB1 contamination of rice and corn samples and its relationship with the rate of esophageal cancer (EC) in a high risk area in northeastern Iran. METHODS: In total, 66 rice and 66 corn samples were collected from 22 geographical subdivisions of Golestan province of Iran. The levels of FB1 were measured for each subdivision by thin layer and high pressure liquid chromatographies. The mean level of FB1 and the proportions of FB1 contaminated samples were compared between low and high EC-risk areas of the province. RESULTS: The mean of FB1 levels in corn and rice samples were 223.6 and 21.6 MUg/g, respectively. FB1 contamination was found in 50% and 40.9% of corn and rice samples, respectively. FB1 level was significantly higher in rice samples obtained from high EC-risk area (43.8 MUg/g) than those obtained from low risk area (8.93 MUg/g) (p value=0.01). The proportion of FB1 contaminated rice samples was also significantly greater in high (75%) than low (21.4%) EC-risk areas (p value=0.02). CONCLUSION: We found high levels of FB1 contamination in corn and rice samples from Golestan province of Iran, with a significant positive relationship between FB1 contamination in rice and the risk of EC. Therefore, fumonisin contamination in commonly used staple foods, especially rice, may be considered as a potential risk factor for EC in this high risk region. PMID- 22938432 TI - Distinct involvement of 9p21-24 and 13q14.1-14.3 chromosomal regions in raw betel nut induced esophageal cancers in the state of Meghalaya, India. AB - BACKGROUND: Raw betel nut (RBN) chewing is an important contributing factor for esophageal squamous cell carcinoma (ESCC), although associated genomic changes remain unclear. One difficulty in assessing the effects of exclusively RBN induced genetic alterations has been that earlier studies were performed with samples of patients commonly using tobacco and alcohol, in addition to betel quid. Both CDKN2A (at 9p21) and Rb1 gene (at 13q14.2) are regarded as tumor suppressors involved in the development of ESCC. Therefore, the present study aimed to verify the RBN's ability to induce ESCC and assess the involvement of CDKN2A and Rb1 genes. METHODS: A panel of dinucelotide polymorphic markers were chosen for loss of heterozygosity studies in 93 samples of which 34 were collected from patients with only RBN-chewing habit. Promoter hypermethylation was also investigated. RESULTS: Loss in microsatellite markers D9S1748 and D9S1749, located close to exon 1beta of CDKN2A/ARF gene at 9p21, was noted in 40% ESCC samples with the habit of RBN-chewing alone. Involvement of a novel site in the 9p23 region was also observed. Promoter hypermethylation of CDKN2A gene in the samples with the habit of only RBN-chewing alone was significantly higher (p=0.01) than Rb1 gene, also from the samples having the habit of use both RBN and tobacco (p=0.047). CONCLUSIONS: The data indicate that the disruption of 9p21 where CDKN2A gene resides, is the most frequent critical genetic event in RBN associated carcinogenesis. The involvement of 9p23 as well as 13q14.2 could be required in later stages in RBN-mediated carcinogenesis. PMID- 22938433 TI - The GSTT1 null genotype contributes to increased risk of prostate cancer in Asians: a meta-analysis. AB - BACKGROUND: Many studies have investigated the association between glutathione S transferase T 1 (GSTT1) null genotype and risk of prostate cancer, but the impact of GSTT1 null genotype in Asians is still unclear owing to inconsistencies across results. Thie present meta-analysis aimed to quantify the strength of the association between GSTT1 null genotype and risk of prostate cancer. METHODS: We searched the PubMed, Embase and Wangfang databases for studies of associations between the GSTT1 null genotype and risk of prostate cancer in Asians and estimated summary odds ratio (OR) with their 95% confidence interval (95% CI). RESULTS: A total of 11 case-control studies with 3,118 subjects were included in this meta-analysis, which showed the GSTT1 null genotype to be significantly associated with increased risk of prostate cancer in Asians (random-effects OR = 1.49, 95% CI 1.15-1.92, P = 0.002), also after adjustment for heterogeneity (fixed-effects OR = 1.45, 95% CI 1.23-1.70, P< 0.001). No evidence of publication bias was observed. CONCLUSIONS: This meta-analysis of available data suggested the GSTT1 null genotype does contribute to increased risk of prostate cancer in Asians. PMID- 22938434 TI - Prediction of time to recurrence and influencing factors for gastric cancer in Iran. AB - BACKGROUND: The patterns of gastric cancer recurrence vary across societies. We designed the current study in an attempt to evaluate and reveal the outbreak of the recurrence patterns of gastric cancer and also prediction of time to recurrence and its effected factors in Iran. MATERIALS AND METHODS: This research was performed from March 2003 to February 2007. Demographic characteristics, clinical and pathological diagnosis and classification including pathologic stage, tumor grade, tumor site and tumor size in of patients with GC recurrent were collected from patients' data files. To evaluate of factors affected on the relapse of the GC patients, gender, age at diagnosis, treatment type and Hgb were included in the research. Data were analyzed using Kaplan-Meier and logistic regression models. RESULTS: After treatment, 82 patients suffered recurrence, 42, 33 and 17 by the ends of first, second and third years. The mean ( SD) and median ( IQR) time to recurrence in patients with GC were 25.5 (20.6-30.1) and 21.5 (15.6-27.1) months, respectively. The results of multivariate analysis logistic regression showed that only pathologic stage, tumor grade and tumor site significantly affected the recurrence. CONCLUSIONS: We found that pathologic stage, tumor grade and tumor site significantly affect on the recurrence of GC which has a high positive prognostic value and might be functional for better follow-up and selecting the patients at risk. We also showed time to recurrence to be an important factor for follow-up of patients. PMID- 22938435 TI - Human papillomavirus screening in north Indian women. AB - OBJECTIVES: Human papillomavirus (HPV) is the major etiological agent of cervical cancer, a leading cause of morbidity and mortality in women worldwide. Screening strategies for reducing the burden of HPV-mediated carcinogenesis are emerging as an effective means for cervical cancer control and prevention in developing countries. Our study, therefore, aimed to identify HPV infection status in North Indian women during random population screening. METHODOLOGY: Cervical/vaginal exfoliated cells and/or Pap smear specimens were collected from 890 women of North Indian ethnicity residing in Lucknow and adjoining areas, during random population screening from June 2009-March 2012. HPV viral loads in clinical specimens were determined by the Hybrid Capture (hc)-2 HPV DNA assay, and subsequently, positive/negative/borderline HPV status was calculated. RESULTS: The HPV incidence in the present study was 11.7%. 751 out of a total of 890 women (84.4%) participating in our HPV screening program were HPV negative (HPV -), 104 (11.7%) tested positive (HPV +) while 35 (3.9%) showed borderline (HPV *) infection status. Furthermore, in the HPV + subjects (N=104), 18 (17.3%) showed strong positivity. We observed that HPV positivity tends to increase with age in North Indian women; the higher the viral load with increasing age, higher is the susceptibility to HPV-mediated cervical cancer. CONCLUSIONS: HPV viral load/genotyping may help in identifying women at risk of developing cervical cancer. However, cost- effective HPV screening protocols with a wider population coverage are warranted so as to reduce the burden of cervical cancer in women worldwide in the vaccine-era. PMID- 22938436 TI - RNA expression of cytochrome P450 in Mexican women with breast cancer. AB - Involvement of cytochrome P450 genes (CYPs) in breast cancer (BCa) may differ between populations, with expression patterns affected by tumorigenesis. This may have an important role in the metabolism of anticancer drugs and in the progression of cancer. The aim of this study was to determine the mRNA expression patterns of four cytochrome P450 genes (CYP2W1, 3A5, 4F11 and 8A1) in Mexican women with breast cancer. Real- time PCR analyses were conducted on 32 sets of human breast tumors and adjacent non-tumor tissues, as well as 20 normal breast tissues. Expression levels were tested for association with clinical and pathological data of patients. We found higher gene expression of CYP2W1, CYP3A5, CYP4F11 in BCa than in adjacent tissues and only low in normal mammary glands in our Mexican population while CYP8A1 was only expressed in BCa and adjacent tissues. We found that Ki67 protein expression was associated with clinicopathological features as well as with CYP2W1, CYP4F11 and CYP8A1 but not with CYP3A5. The results indicated that breast cancer tissues may be better able to metabolize carcinogens and other xenobiotics to active species than normal or adjacent non-tumor tissues. PMID- 22938437 TI - Comparison of validity of food group intake by food frequency questionnaire between pre- and post- adjustment estimates derived from 2-day 24-hour recalls in combination with the probability of consumption. AB - Validation of a food frequency questionnaire (FFQ) utilising a short-term measurement method is challenging when the reference method does not accurately reflect the usual food intake. In addition, food group intake that is not consumed on daily basis is more critical when episodically consumed foods are related and compared. To overcome these challenges, several statistical approaches have been developed to determine usual food intake distributions. The Multiple Source Method (MSM) can calculate the usual food intake by combining the frequency questions of an FFQ with the short-term food intake amount data. In this study, we applied the MSM to estimate the usual food group intake and evaluate the validity of an FFQ with a group of 333 Korean children (aged 3-6 y) who completed two 24-hour recalls (24HR) and one FFQ in 2010. After adjusting the data using the MSM procedure, the true rate of non-consumption for all food groups was less than 1% except for the beans group. The median Spearman correlation coefficients against FFQ of the mean of 2-d 24HRs data and the MSM adjusted data were 0.20 (range: 0.11 to 0.40) and 0.35 (range: 0.14 to 0.60), respectively. The weighted kappa values against FFQ ranged from 0.08 to 0.25 for the mean of 2-d 24HRs data and from 0.10 to 0.41 for the MSM-adjusted data. For most food groups, the MSM-adjusted data showed relatively stronger correlations against FFQ than raw 2-d 24HRs data, from 0.03 (beverages) to 0.34 (mushrooms). The results of this study indicated that the application of the MSM, which was a better estimate of the usual intake, could be worth considering in FFQ validation studies among Korean children. PMID- 22938438 TI - Assessment of nicotine dependence among smokers in a selected rural population in Kerala, India. AB - OBJECTIVES: An attempt was made to understand the nicotine dependence of smokers selected for an ongoing smoking cessation intervention programme in rural Kerala, India. METHODS: Data were collected from resident males in the age group of 18 to 60 years from 4 randomly allocated community development blocks of rural Thiruvananthapuram district (2 intervention and 2 control groups). Trained accredited social health activist workers were utilised to collect data from all groups through face to face interview. Nicotine dependence among participants was assessed by means of the six-item Fagerstrom Test for Nicotine Dependence (FTND) translated into the local language. The internal consistency of FTND was computed using Cronbach's alpha coefficient. Criterion validity (concurrent) was assessed by correlations of nicotine dependence scores with age at initiation of smoking and cumulative smoking volume in pack-years. RESULTS: Among the 928 smokers identified, 474 subjects were in the intervention area (mean age =44.6 years, SD =9.66 years) and 454 in the control area (mean age= 44.5 years, SD =10.30 years). The overall FTND score among current daily smokers was 5.04 (SD: 5.05). FTND scores in the control and intervention areas were 4.75 (SD: 2.57) and 4.92 (SD: 2.51) respectively. The FTND scores increased with age and decreased with higher literacy and socioeconomic status. The average FTND score was high among smokers using both bidi and cigarettes (mean 6.10, SD 2.17). Internal consistency analysis yielded a Cronbach's alpha coefficient of 0.70 in a subsample of 150 subjects, a moderate result. The association of the scale was strongest, with the number of pack-years smoked (rho = 0.677, p < 0.001). CONCLUSION: A moderate level of nicotine dependence was observed among smokers in the current study. Tobacco cessation strategies could be made more cost effective and productive if a baseline assessment of nicotine dependence is completed before any intervention. PMID- 22938439 TI - Continuous transarterial infusion chemotherapy with gemcitabine and 5 Fluorouracil for advanced pancreatic carcinoma. AB - PURPOSE: Pancreatic carcinoma is one of the most malignant tumors of the alimentary system, with relatively high incidence rates. The purpose of this study was to assess the efficacy and safety of two regimens for advanced pancreatic carcinoma: continuous transarterial infusion versus systemic venous chemotherapy with gemcitabine and 5-fluorouracil. METHODS: Of the 48 patients with advanced pancreatic carcinoma receiving chemotherapy with gemcitabine and 5 fluorouracil, 24 received the selective transarterial infusion, and 24 the systemic chemotherapy. For the continuous transarterial infusion group (experimental group), all patients received gemcitabine 1000 mg/m2,given by 30 minute transarterial infusion, on day 1 of a 4-week cycle for 2 cycles, and a dose of 600 mg/ m2 5-fluorouracil was infused on days 1~5 of a 4-week cycle for 2 cycles. For the systemic venous group (control group), gemcitabine and 5 fluorouracil were infused through a peripheral vein, a dose of 1000 mg/m2 gemcitabine being administrated over 30 min on days 1 and 8 of a 4-week cycle for 2 cycles, and a dose of 600 mg/m2 5-fluorouracil was infused on days 1~5 of a 4 week cycle for 2 cycles. The effectiveness and safety were evaluated after 2 cycles according to WHO criteria. RESULTS: The objective effective rate in transarterial group was 33.3% versus 25% in the systemic group, the difference not being significant (P=0.626). Clinical benefit rates(CBR) in the transarterial and systemic groups were 83.3% and 58.3%, respectively (P=0.014). The means and medians for survival time in transarterial group were higher than those of the systemic group (P<0.005). at the same time, the adverse effects did not significantly differ between the two groups (P>0.05). CONCLUSION: Continuous transarterial infusion chemotherapy with gemcitabine and 5-fluorouracil could improve clinical benefit rate and survival time of patients with advanced pancreatic carcinoma, compared with systemic venous chemotherapy. Since adverse effects were limited in the transarterial group, the regimen of continuous transarterial infusion chemotherapy can be used more extensively in clinical practice. A CT and MRI conventional sequence can be used for efficacy evaluation after chemotherapy in pancreatic carcinoma. PMID- 22938440 TI - Familial breast cancer registry program in patients referred to the cancer institute of Iran. AB - INTRODUCTION: Annually a considerable number of people die because of breast cancer, a common disease among women also in Iran. Identifying risk factors and susceptible people can lead to prevention or at least early diagnosis. Among susceptibility risks, 5-10% of patients have a family history predisposing factor which can influence the risk of incidence among the family. Having a registry program can be a more practical way to screen high risk families for preventive planning. METHOD: Based on inclusion criteria, a questionnaire was prepared and after a pilot study on a small number of patients, actual data were collected on 400 patients and processed in SPSS 16.0. RESULTS: Totally, 28.2%of the patients were younger than 40 years old and 36.8% had the included criteria for familial breast cancer (FBC). 102 patient's samples could be compared for receptor presentation. Similar to other studies, the number of triple negative breast cancers increased as the age decreased. CONCLUSION: The high percentage of patients with FBC among 400 cases in this study demonstrates that in order to design an infrastructural diagnostic protocol and screening of patients with FBC, a precise survey related to frequency and founder mutations of FBC is needed nationwide. PMID- 22938441 TI - Relationship between PTEN and Livin expression and malignancy of renal cell carcinomas. AB - OBJECTIVES: This study focused on PTEN and Livin expression and associations with malignancy in human renal clear cell carcinomas (RCCC). METHODS: PTEN and Livin expression was assessed in 100 RCCC tissue samples, 50 paracarcinoma cases, and 20 normal renal tissue samples using the immunohistochemical Streptavidin proxidase (SP) method. The relationships between binding and corresponding biological characteristics, such as histological grade, lymph node metastases, and clinical stages were analyzed. RESULTS: Positive PTEN expression in RCCC was significantly lower than in renal tissue adjacent to carcinoma tissue and normal renal tissue (P<0.01). Livin expression in the renal tissue adjacent to the carcinoma and normal renal tissues exhibited only low levels, whereas overall Livin expression in RCCC was statistically significant (P<0.01). In RCCC, PTEN expression rate gradually decreased with an increase in clinical stage, whereas that of Livin increased to statistically significant levels (P<0.01), PTEN and Livin levels being negatively correlated (r=-0.395, P<0.01). CONCLUSIONS: PTEN and Livin are important in RCCC development. The two factors combined are expected to provide indices for estimating RCCC malignancy and progression levels, as well as references for RCCC diagnosis and treatment. PMID- 22938442 TI - Passive smoking and cervical cancer risk: a meta-analysis based on 3,230 cases and 2,982 controls. AB - OBJECTIVE: Passive smoking has been considered as a risk factor of many cancers. To examine whether it might also pose a risk for cervical cancer, we performed a meta-analysis based on published case-control studies. METHODS: We searched the PubMed database and references of included studies up to February 10th, 2012 for relevant studies. After two authors independently assessed the methodological quality and extracted data, a meta-analysis was conducted using CMA v2 software. Publication bias was evaluated by funnel plot, using Egger's and Begg's tests. RESULTS: Finally 11 eligible studies yielded, involving 3,230 cases and 2,982 controls. The results showed that women who never smoke but exposed to smoking experience a 73% increase in risk of cervical cancer compared with non-exposed women (OR = 1.73, 95% CI = 1.35 - 2.21, p<0.001). Subgroup and sensitivity analyses indicated this result to be robust. Moderate publication bias was detected by visualing funnel plot, Egger's and Begg's tests. CONCLUSION: Based on currently available evidence, the findings of this meta-analysis suggests that passive smoking significantly and independently increases the risk of cervical cancer. PMID- 22938443 TI - Four years incidence rate of colorectal cancer in Iran: a survey of national cancer registry data - implications for screening. AB - INTRODUCTION: Design and implementation of screening programs in each country must be based on epidemiological data. Despite the relatively high incidence of CRC, there is no nationwide comprehensive program for screening in Iran. This study was designed to investigate national CRC data and help to determine guidelines for screening. METHODS: Incidence data used in this study were obtained from Iranian annual of National Cancer Registration report. Age standardized rates (ASR)were calculated using world standard population and were categorized by age, sex, anatomic subsite and morphology of tumor. Data were analyzed using SPSS.V.13 and Open Source Epidemiologic Statistics for Public Health software (OpenEpi v.2.3.1). RESULTS: A quarter of cases were less than 50 years of age. The majority of tumors were detected in the colon. The overall ASR in the four years period was 38.0 per 100000 and was higher for men compared women (P<0.05). Incidence rate of colorectal cancer increased with age. CONCLUSION: Results of present study indicated that incidence of colorectal cancer is relatively high in Iran. Incidence of CRC in people under 50 years and in rectum were reported higher than other countries that related etiologic factors should be investigate in further studies. According to the increasing of ASR after age 50 years, it seems that onset of screening at age 50 would be appropriate. PMID- 22938444 TI - Expression of proteasome activator REGgamma in human laryngeal carcinoma and associations with tumor suppressor proteins. AB - The functional significance of the proteasome activator REGgamma in the regulation of cell proliferation and apoptosis has been recognized. However, pathological contributions to tumor development remain to be elucidated. Both oncogenic proteins and tumor suppressors are targeted by REGgamma for proteasomal degradation. It has been proposed that the role of the REGgamma in the pathogenesis of cancer is cell- and context-specific. In this study, we aimed to explore the potential involvement of REGgamma in laryngeal carcinomas, comparing protein expression in tumor and adjacent tissues by immunohistochemical staining and Western blot analysis. We also characterized the correlation between the expression of REGgamma and the previously identified substrates p53 and p21. We showed that REGgamma was abnormally highly expressed in cancer tissues. Statistical analysis revealed that there was a positive relationship between the level of REGgamma and the expression of p53 and p21. Our study suggests that REgamma overexpression can facilitate the growth of laryngeal cancer cells. PMID- 22938445 TI - Predictive potential of glutathione S-transferase polymorphisms for prognosis of osteosarcoma patients on chemotherapy. AB - OBJECTIVE: To evaluate the predictive value of glutathione S-transferase (GST) gene polymorphisms for the prognosis of osteosarcoma patients receiving chemotherapy. METHODS: A total of 159 patients were included in our study between January 2005 and December 2007., with follow-up until January 2012. Genotyping was based upon the duplex polymerase-chain-reaction with the PCR-CTPP method. RESULTS: At the time of diagnosis, 15.4% of the patients presented with metastasis, while 22.3% developed metastasis during follow-up. At the time of final analysis on January 2012, the median follow-up was 45.5 months. Patients with null GSTM1 and GSTT1 had a higher event free survival rate than non-null genotype, but no significant association was found between the two genotypes and prognosis of osteosarcoma. Individuals with GSTP1 Val/Val genotype tended to live shorter than with the IIe/IIe genotype, and we found a significantly higher risk of death from osteosarcoma (adjusted HR=2.35, 95% CI=1.13-4.85). CONCLUSION: The GSTP1 gene polymorphism may have an important role in the prognosis of osteosarcoma patients with chemotherapy. Further analyses with larger samples and more genes encoding metabolizing and DNA repair enzymes are warranted. PMID- 22938446 TI - Set, a putative oncogene, as a biomarker for prenatal exposure to bisphenol A. AB - BACKGROUND: Bisphenol A (BPA), an endocrine disrupting chemical, has been suspected to pose carcinogenic risks. However, likely mechanisms are obscure and there are difficulties to estimating its real significance for cancer development. METHODS: We therefore studied BPA-induced proteomic alterations in immune organs of ICR mice offspring that were prenatally exposed to BPA (15 and 300 mg/L of drinking water). We performed 2D-gel analyses of samples, considering differences in spleen, exposure levels, sex, and ages. RESULTS: From proteomic analyses, we found various proteins were up- or down-regulated by BPA. Among them, SET, a putative oncogene and inhibitor of phosphatase 2A, was significantly down- regulated in a BPA dose-dependent manner. We also confirmed down-regulation of SET in western blot and real time PCR analyses. From gene network analysis, SET is predicted to communicate with other genes including CYP17, which is involved in biosynthesis and metabolism of sex-hormones. CONCLUSIONS: This study provided evidence that SET can be applied as a new biomarker for prenatal BPA exposure and suggests a potential new mechanism of action in that BPA may disrupt CYP17 via SET. PMID- 22938447 TI - Socio-demographic correlates of participation in mammography: a survey among women aged between 35- 69 in Tehran, Iran. AB - BACKGROUND: The rates of breast cancer have increased over the past two decades, and this raises concern about physical, psychological and social well-being of women with breast cancer. Further, few women really want to do breast cancer screening. We here investigated the socio-demographic correlates of mammography participation among 400 asymptomatic Iranian women aged between 35 and 69. METHODS: A cross-sectional survey was conducted at the four outpatient clinics of general hospitals in Tehran during the period from July through October, 2009. Bi variate analyses and multi-variate binary logistic regression were employed to find the socio- demographic predictors of mammography utilization among participants. RESULTS: The rate of mammography participation was 21.5% and relatively high because of access to general hospital services. More women who had undergone mammography were graduates from university or college, had full time or part-time employment, were insured whether public or private, reported a positive family history of breast cancer, and were in the middle income level (P <0.01).The largest number of participating women was in the age range of 41 to 50 years. The results of multivariate logistic regression further showed that education (95%CI: 0.131-0.622), monthly income (95%CI: 0.038-0.945), and family history of breast cancer (95%CI: 1.97-9.28) were significantly associated (all P <0.05)with mammography participation. CONCLUSIONS: The most important issue for a successful screening program is participation. Using a random sample, this study found that the potential predictor variables of mammography participation included a higher education level, a middle income level, and a positive family history of breast cancer for Iranian women after adjusting for all other demographic variables in the model. PMID- 22938448 TI - Comparing endoscopy and upper gastrointestinal X-ray for gastric cancer screening in South Korea: a cost-utility analysis. AB - BACKGROUND: There are limited data evaluating the cost-effectiveness of gastric cancer screening using endoscopy or upper gastrointestinal x-ray in the general population. OBJECTIVE: To evaluate the cost- effectiveness of population-based screening for gastric cancer in South Korea by decision analysis. METHODS: A time dependent Markov model for gastric cancer was constructed for healthy adults 30 years of age and older, and a deterministic sensitivity analysis was performed. Cost-utility analysis with multiple strategies was conducted to compare the costs and effects of 13 different screening alternatives with respect to the following eligibility criteria: age at the beginning of screening, screening interval, and screening method. The main outcome measurement was the incremental cost effectiveness ratio. RESULTS: The results revealed that annual endoscopic screening from ages 50-80 was the most cost-effective for the male population. In the females, biennial endoscopy screening from ages 50-80 was calculated as the most cost-effective strategy among the 12 screening alternatives. The most cost effective screening strategy may be adjustable according to the screening costs and the distribution of cancer stage at screening. The limitation was that effectiveness data were obtained from published sources. CONCLUSIONS: Using the threshold of $19,162 per quality-adjusted life year on the basis of the Korean gross domestic product (2008), as suggested by the World Health Organization, endoscopic gastric cancer screening starting at the age of 50 years was highly cost-effective in the Korean population. The national recommendation for gastric cancer screening should consider the starting age of screening, the screening interval, and the screening modality. PMID- 22938449 TI - Cytotoxicity, apoptosis induction and anti-metastatic potential of Oroxylum indicum in human breast cancer cells. AB - Despite clinical advances in anticancer therapy, there is still a need for novel anticancer metabolites, with higher efficacy and lesser side effects. Oroxylum indicum (L.) Vent. is a small tree of the Bignoniaceae family which is well known for its food and medicinal properties. In present study, the chemopreventive properties of O. indicum hot and cold non-polar extracts (petroleum ether and chloroform) were investigated with MDA- MB-231 (cancer cells) and WRL-68 (non tumor cells) by XTT assay. All the extracts, and particularly the petroleum ether hot extract (PHO), exhibited significantly (P<0.05) higher cytotoxicity in MDA-MB 231 when compared to WRL-68 cells. PHO was then tested for apoptosis induction in estrogen receptor (ER)-negative (MDA-MB-231) and ER-positive (MCF-7) breast cancer cells by cellular DNA fragmentation ELISA, where it proved more efficient in the MDA-MB-231 cells. Further, when PHO was tested for anti-metastatic potential in a cell migration inhibition assay, it exhibited beneficial effects. Thus non-polar extracts of O. indicum (especially PHO) can effectively target ER negative breast cancer cells to induce apoptosis, without harming normal cells by cancer-specific cytotoxicity. Hence, it could be considered as an extract with candidate precursors to possibly harness or alleviate ER-negative breast cancer progression even in advanced stages of malignancy. PMID- 22938450 TI - Clinical significance of basal-like breast cancer in Chinese women in Heilongjiang province. AB - BACKGROUND: Our objective was to clarify the clinical and biological characteristics of basal-like breast cancer (BLBC) and non-basal-like breast cancer (TN3BKE) in Heilongjiang. METHODS: We examined, by immunohistochemistry, expression of biological markers cytokeratin (CK) 5/6 and epidermal growth factor receptor (EGFR) and B cell specific moloney murine leukemia virus integration site 1( Bmi-1) in triple-negative breast cancer (TNBC). We studied the correlation between BLBC and several factors related to tumor progression, along with its prognostic value. RESULTS: In the 229 cases of operable TNBC, BLBC was detected in 178 (77.7%) and TN3BKE- in 51 (22.2%). There was no significant difference in clinicopathological factors between them, However, BLBC was significantly associated with Bmi-1 expression (P=0.000) and shorter disease-free survival (DFS) (P = 0.045) and overall survival (OS) (P=0.041). CONCLUSIONS: Compared with the non-basal group, patients with BLBC have a high expression of Bmi-1 and a poor prognosis. PMID- 22938451 TI - beta-Elemene induces apoptosis in human renal-cell carcinoma 786-0 cells through inhibition of MAPK/ERK and PI3K/Akt/ mTOR signalling pathways. AB - BACKGROUND: Renal-cell carcinoma (RCC) is resistant to almost all chemotherapeutics and radiation therapy. beta-Elemene, a promising anticancer drug extracted from a traditional Chinese medicine, has been shown to be effective against various tumors. In the present study, anti-tumor effects on RCC cells and the involved mechanisms were investigated. METHODS: Human RCC 786-0 cells were treated with different concentrations of beta-elemene, and cell viability and apoptosis were measured by 3-(4, 5-dimethylthiazol-2-yl)-2, 5 diphenyl tetrazolium bromide (MTT) assay and flow cytometry, respectively. Protein expression was assayed by western blotting. Autophagy was evaluated by transmission electron microscopy. RESULTS: beta-Elemene inhibited the viability of 786-0 cells in a dose- and time-dependent manner. The anti-tumor effect was associated with induction of apoptosis. Further study showed that beta-elemene inhibited the MAPK/ERK as well as PI3K/Akt/mTOR signalling pathways. Moreover, robust autophagy was observed in cells treated with beta-elemene. Combined treatment of beta-elemene with autophagy inhibitors 3-methyladenine or chlorochine significantly enhanced the anti-tumor effects. CONCLUSIONS: Our data provide first evidence that beta-elemene can inhibit the proliferation of RCC 786 0 cells by inducing apoptosis as well as protective autophagy. The anti-tumor effect was associated with the inhibition of MAPK/ERK and PI3K/Akt/mTOR signalling pathway. Inhibition of autophagy might be a useful way to enhance the anti-tumor effect of beta -elemene on 786-0 cells. PMID- 22938452 TI - Diagnostic and clinical significance of KIT(CD117) expression in thymic epithelial tumors in China. AB - AIMS: To study KIT (CD117) expression in thymic epithelial tumors in China, and investigate diagnostic and clinical significance. MATERIAL AND METHODS: Thymic epithelial tumors (TETs) from 102 patients (3 type A, 29 type AB, 5 type B1, 22 type B2, 29 typeB3 and 16 thymic carcinomas) were examined. Immunohistochemical staining with an antic-kit monoclonal antibody was performed on a tissue microarray. Relationships between KIT positive expression and the TET clinical characteristics (WHO histologic classification and Masaoka stage system) were analysed. RESULTS: The KIT positive expression rate was significantly higher in thymic carcinoma (60%, 9/16) than in thymoma (8%, 7/86), a strong correlation being found with the WHO classification, but not the Masaoka tumor stage. The overall survival for patients with KIT positive lesions was significantly worse. CONCLUSIONS: KIT is a good molecule marker to differentially diagnose thymic carcinoma from thymoma, while also serving as a predictor of prognosis for TETs. Further research into KIT mutations in Chinese TETs should be conducted to assess the efficacy of targeted therapy. PMID- 22938453 TI - Preferences of Malaysian cancer patients in communication of bad news. AB - BACKGROUND: Breaking bad news to cancer patients is a delicate and challenging task for most doctors. Better understanding of patients' preferences in breaking bad news can guide doctors in performing this task. OBJECTIVES: This study aimed to describe the preferences of Malaysian cancer patients regarding the communication of bad news. METHODOLOGY: This was a cross-sectional study conducted in the Oncology clinic of a tertiary teaching hospital. Two hundred adult cancer patients were recruited via purposive quota sampling. They were required to complete the Malay language version of the Measure of Patients' Preferences (MPP-BM) with minimal researcher assistance. Their responses were analysed using descriptive statistics. Association between demographic characteristics and domain scores were tested using non-parametric statistical tests. RESULTS: Nine items were rated by the patients as essential: "Doctor is honest about the severity of my condition", "Doctor describing my treatment options in detail", "Doctor telling me best treatment options", Doctor letting me know all of the different treatment options", "Doctor being up to date on research on my type of cancer", "Doctor telling me news directly", "Being given detailed info about results of medical tests", "Being told in person", and "Having doctor offer hope about my condition". All these items had median scores of 5/5 (IQR:4-5). The median scores for the three domains were: "Content and Facilitation" 74/85, "Emotional Support" 23/30 and "Structural and Informational Support" 31/40. Ethnicity was found to be significantly associated with scores for "Content and Facilitation" and "Emotional Support". Educational status was significantly associated with scores for "Structural and Informational Support". CONCLUSION: Malaysian cancer patients appreciate the ability of the doctor to provide adequate information using good communication skills during the process of breaking bad news. Provision of emotional support, structural support and informational support were also highly appreciated. PMID- 22938454 TI - Induction of apoptosis by methanolic extract of Rubia cordifolia Linn in HEp-2 cell line is mediated by reactive oxygen species. AB - Rubia cordifolia Linn, which belongs to the Rubiaceae family, is a well-known herb used in Ayurvedic medicine. In the present study, we investigated the influence of a methanolic extract (RC) on the induction of apoptosis in HEp-2 (human laryngeal carcinoma) cell line, as evidenced by cytotoxicity, morphological changes and modification in the levels of pro-oxidants. Inhibition of cell proliferation and lactate dehydrogenase (LDH) release increased in a time and dose-dependent manner. Further, reduced glutathione (GSH), glutathione transferase (GST) and protein levels decreased and lipid peroxidation increased significantly on RC treatment in a dose dependent manner when compared to controls. Based on the results we determined the optimal dose as 30 mg/ ml and the apoptotic effect of RC extract (30 mg/ml) on HEp-2 cells was confirmed by fluorescent microscopy and transmission electron microscopy (TEM) based on morphological and ultrastructural changes. RC extract suppressed the proliferation of HEp-2 oral cancer cells inducing apoptotic cell death in vitro. These results point to potential of RC extract as an agent for the treatment of laryngeal squamous cell carcinoma. PMID- 22938455 TI - Risk assessment of breast cancer in Guangdong, China: a community-based survey. AB - OBJECTIVES: Compared with Western countries, the incidence rates for breast cancer in China are still low. However, breast cancer appears to be hitting Chinese women at a much younger age, with a peak between 40 and 50 years. Furthermore, breast tumors of Asian women have molecular and genetic characteristics that are different from those of Caucasian women. METHODS: A community-based study was designed to evaluate the relationship between lifestyles and breast cancer risk in Chinese women residing in Guangzhou. 16,314 subjects completed the questionnaire. Potential confounding factors included sociodemographic characteristics. RESULTS: 33 individuals reported a history of breast cancer, yielding a prevalence rate of 202.3/100000. Associations between subjects'demographic and breast cancer risk factors were assessed. Breast cancer is associated with family history of breast cancer, X-rays received, benign breast disease and hyperlipoidemia or hypercholesteremia with elevated odds ratios. CONCLUSIONS: Family history of breast cancer, X-ray received benign breast disease and hyperlipoidemia or hypercholesteremia were significantly associated with risk of breast cancer and may have potential for breast cancer risk assessment. PMID- 22938456 TI - Antitumoral effects of Melissa officinalis on breast cancer in vitro and in vivo. AB - BACKGROUND: There is a long standing interest in the identification of medicinal plants and derived natural products for developing cancer therapeutics. Here we investigated the antiproliferative properties of Melissa officinalis (MO) from Turkey on breast cancer. METHODS: MO extracts were studied for cytotoxicity against breast cancer cell lines (MCF-7, MDA-MB-468 and MDA-MB-231). In vitro apoptosis studies were performed by annexin V staining and flow cytometry analyses. Immunohistochemistry for Ki-67 and caspase 7 in the tumoral tissue sections of DMBA-induced mammary tumors in rats was also performed, along with TUNEL assays to detect apoptotic cells. In vivo anticancer activity testing was carried out with reference to inhibition of growth of DMBA induced mammary tumors in rats. RESULTS: MO showed cytotoxicity against three cancer cell lines, inducing increase in Annexin-positive cells. Expression of caspase-7 protein and TUNEL positive cells were much higher in rats treated by MO, compared with the untreated control group, while expression of Ki-67 was decreased. Furthermore, in vivo studies showed that mean tumor volume inhibition ratio in MO treated group was 40% compared with the untreated rats. CONCLUSION: These results indicated that MO extrcts have antitumoral potential against breast cancer. PMID- 22938457 TI - Second-line irinotecan after cisplatin, fluoropyrimidin and docetaxel for chemotherapy of metastatic gastric cancer. AB - AIM: Tumors of upper gastrointestinal tract are among the cancers that have a quite lethal course. Cytotoxic chemotherapy is the most efficient therapeutic modality for metastatic gastric cancer. In patients who do not respond to first line treatment, the response rate to second-line therapies is generally low and the toxicity rates high. This study concerned the efficacy and the side effect profile of second-line therapy with irinotecan in the patients who were being followed-up with the diagnosis of metastatic gastric cancer in Izmir, Turkey. MATERIALS AND METHODS: We retrospectively evaluated the efficacy and toxicity in 31 patients with metastatic gastric adenocarcinoma who presented to the polyclinic of Medical Oncology of Izmir Ataturk Education and Research Hospital between May 2008 and July 2011. All received chemotherapy regimens containing cisplatin, fluoropyrimidine (5-FU) and docetaxel as the first-line therapy for late stage disease. Irinotecan as a single agent was given at a dose of 210 mg/m(2) on each 21 days. Irinotecan (180 mg/m(2) on day 1), 5-FU (500 mg/m(2) on days 1-2) and leucovorin (LV; 60 mg/m(2) on days 1-2) as a combined regimen were given over a 14 day period. RESULTS: Median age was 54 (range, 31-70). Irinotecan was given as a combined regimen for median 6 cycles (range, 3-12) and as a single agent for median 3 cycles (range, 1-10). Metastases were detected in one site in six patients (19%), in two different sites in 17 patients (55%) and in three or more sites in eight patients (26%). Four patients (12.9%) showed partial response and six patients (19.3%) showed stable disease. Progression- free survival (PFS) was found to be 3.26 months (95% CI, 2.3-4.2). Median overall survival (OS) was found to be 8.76 months (95% CI, 4.5-12.9). The most commonly seen grade 3/4 side effect was neutropenia but the the therapy was generally well-tolerated. CONCLUSIONS: In this study, it was demonstrated that second-line therapy with irinotecan given following the first-line therapy with cisplatin, fluoropyrimidine (5-FU) and docetaxel was efficient and safe. Further studies are needed for confirmation. PMID- 22938458 TI - Antioxidant properties of Rajgira (Amaranthus paniculatus) leaves and potential synergy in chemoprevention. AB - In recent years there has been a substantial increase in the use of functional foods for disease control. Fruits and vegetables produce phytochemicals such as flavonoids and antioxidants which can lower oxidative stress and reduce the risk of chronic ailments like cancer. The aim of the present study was to investigate the antioxidant capacity and the possible protective effects of Amaranthus paniculatus leaves on the antioxidant defense system in Ehrlich's ascites carcinoma (EAC) -treated mice. Oral administration of the leaf extract at different doses caused a significant decrease in tumor volume, viable cell count and tumor weight and elevated the life span of EAC bearing mice. It also showed an improved antioxidant potential as evidenced by a significant increase in the cellular antioxidant defense system such as catalase, superoxide dismutase and reduced glutathione and also significantly reduced the levels of TBARS. The levels of RBC, hemoglobin and lymphocyte count were altered in EAC bearing mice and were reverted back to near normal levels after the treatment with the leaf extracts. Their adequate content of total phenolics and flavonoids, DPPH scavenging activity which further suggests that the extracts exert a significant protection against oxidative stress conditions. PMID- 22938459 TI - A study on community perceptions of common cancers, determinants of community behaviour and program implementation in New Delhi, India. AB - Assessment of perceptions of the community, the determinants and development of their behavior regarding common malignancies, helps in establishing evidence based activities for prevention and early diagnosis of cancer. However information on this important aspect is lacking in our country. Qualitative methods were here used to obtain information through in depth interviews and Focus Group Discussions (FGDs) with all categories of identified stakeholders. Most were unaware of the activities of the cancer control program. Even the providers were not fully conversant. All respondents mentioned lack of diagnostic and treatment facilities in government, primary and secondary level facilities. Perceptions of different categories of stakeholders regarding why many community members did not attend screening camps and other services reflect the determinants of community behavior, acting independently as well as in combination. The cancer control program was thought to be restricted only to some private facilities and overcrowded government tertiary care facilities where the visits were time consuming. Almost all the facilities were considered curative oriented. Issues of supervision, monitoring and feedback were inadequately addressed by providers who were inadequately trained in many program activities. The program lacked effective planning, coordination and appropriate implementation at the grass roots level in Delhi. Social mobilization was grossly inadequate, as most of the community members were unaware of the existence of the program. Misconceptions about the risk factors, signs and symptoms, diagnosis, and treatment were common amongst community members as well as many of the providers. Thus the national cancer control program in our country needs further community participation and social mobilization. Accessibility, availability, acceptability and affordability of various preventive, curative and rehabilitative activities, as well as intersectoral coordination, training, supervision and monitoring of program activities, all need to be addressed to ensure the success of this important public health program. PMID- 22938460 TI - DNA repair gene ERCC1 and XPD polymorphisms predict glioma susceptibility and prognosis. AB - AIMS: We conducted a case-control study in a Chinese population to clarify the association between polymorphisms in ERCC1 and XPD and susceptibility and survival of glioma. METHODS: A total of 393 cases and 410 controls were selected from March 2007 to December 2011. Genotyping of ERCC1 and XPD was conducted by TaqMan assays using the ABI Prism 7911HT Sequence Detection System. All analyses were performed using the STATA statistical package. RESULTS: Polymorphisms in ERCC1 118C/T, ERCC1 8092C/A and XPD Asp312Asn showed no statistically significant difference between glioma cases and controls. However, individuals with the XPD 751Gln/Gln genotype had an increased risk of developing glioma compared with those with the Lys/Lys genotype (adjusted OR=1.64, 95% CI: 1.06-2.89). The ERCC1 118T/T genotype was associated with significantly higher median survival than the ERCC1 C/C genotype (HR=0.67, 95%CI=0.35-0.96). In addition, individuals with XPD 751Gln/Gln had a lower median survival time than XPD Lys/Lys carriers (HR=0.54, 95%CI=0.37- 0.93). CONCLUSION: In conclusion, we observed that the XPD 751Gln/Gln genotype is associated with glioma susceptibility, and ERCC1 118 T/T and XPD 751Gln/Gln genotypes confer a significantly better prognosis. PMID- 22938461 TI - Anti-HER-2 anti-CD3 bi-specific antibodies inhibit growth of HCT-116 colorectal carcinoma cells in vitro and in vivo. AB - OBJECTIVE: This study is conducted to evaluate the effects of anti-HER-2 anti-CD3 bi-specific antibodies(BsAb) on HER-2/neuover-expressing human colorectal carcinoma cells. METHODS: Growth was assessed by MTT assays after exposure of HCT 116 cells to Herceptin, anti-CD3 and BsAb antibodies. Immunocytochemistry was applied to test the HER-2 level of HCT-116. In a nude mouse model, HER-2 CD3 BsAb was combined with effector cells (peripheral blood lymph cells from normal human being) for observations on in Vivo growth of tumors. RESULTS: Compared with the control group, using effector cells combined with anti-CD3 McAb, Herceptin or HER2 CD3 BsAb, tumor cell growth in vitro and in vivo was significantly inhibited (P<0.05), most remarkably in the HER2 CD3 BsAb case. The growth of xenografts with HER2 CD3 BsAb combined with effector cells was also significantly inhibited when compared with the anti-CD3 McAb or Herceptin groups (P<0.05). CONCLUSION: HER-2/neu might be a useful target for immunotherapy in colorectal carcinoma, anti-HER2 anti-CD3 BsAb exerting clear anti-tumor effects. PMID- 22938462 TI - Integrin-linked kinase functions as a tumor promoter in bladder transitional cell carcinoma. AB - The aim of this study was to elucidate the role of the integrin-linked kinase (ILK) gene in development of human bladder transitional cell carcinoma (BTCC). Expression of ILK protein and ILK mRNA in 56 cases of human BTCC tissue and in 30 cases of adjacent normal bladder tissue was detected by immunohistochemistry S-P and reverse transcription polymerase chain reaction (RT-PCR), respectively. Four specific miRNA RNAi vectors targeting human ILK were synthesized and transfected into BIU-87 cells by liposome to obtain stable expression cell strains. The influence of ILK on proliferation of BTCC was detected by MTT, FCM on athymic mouse tumorigenesis. The positive rate of ILK protein in BTCC tissue (53.6%) was much higher than adjacent normal bladder tissue (10.0%) (p<0.05). Similarly, expression of ILK mRNA in BTCC tissue (0.540 +/- 0.083) was significantly higher than in adjacent normal bladder tissue (0.492 +/- 0.070) (p<0.05). MTT showed that the proliferation ability of miRNA-ILK transfected group was clearly decreased (p<0.05), the cell cycle being arrested in G0/G1-S, an tumorigenesis in vivo was also significantly reduced (p<0.05). ILK gene transcription and protein expression may be involved in the development of BTCC, so that ILK might be the new marker for early diagnosis and the new target for gene treatment. PMID- 22938463 TI - Toll-like receptor 5 agonist inhibition of growth of A549 lung cancer cells in vivo in a Myd88 dependent manner. AB - The purpose of this study was to examine the effect of a Toll-like receptor 5 (TLR5) agonist, CBLB502, on the growth and radiosensitivity of A549 lung cancer cells in vivo. Expression of myeloid differentiation factor 88 (MyD88) or TLR5 was stably knocked down in human lung cancer cells (A549) using lentivirus expressing short hairpin RNA targeting human MyD88 or TLR5. Lack of MyD88 or TLR5 expression enhanced tumor growth in mouse xenografts of A549 lung cancer cells. CBLB502 inhibited the growth of A549 lung cancer cells, not A549-MyD88-KD cells in vivo in the murine xenograft model. Our results showed that the inhibition of A549 by CBLB502 in vivo was realized through regulating the expression of neutrophil recruiting cytokines and neutrophil infiltration. Finally, we found that activation of TLR5 signaling did not affect the radiosensitivity of tumors in vivo. PMID- 22938464 TI - Establishment and characterization of MTDH knockdown by artificial MicroRNA interference - functions as a potential tumor suppressor in breast cancer. AB - BACKGROUND: Considerable evidence suggests that metadherin (MTDH) is a potentially crucial mediator of tumor malignancy and an important therapeutic target for simultaneously enhancing chemotherapy efficacy and reducing metastasis risk. Inhibition of MTDH expression by RNA interference has been shown in several previous research, but silencing MTDH expression by microRNA (miRNA) interference in breast cancer has not been established. In the present study, we investigated the role of MTDH-miRNA in down-regulation of proliferation, motility and migration of breast carcinoma cells. METHODS: Expression vectors of recombinant plasmids expressing artificial MTDH miRNA were constructed and transfected to knockdown MTDH expression in MDA-MB-231 breast cancer cells. Expression of MTDH mRNA and protein was detected by RT-PCR and Western blot, respectively. MTT assays were conducted to determine proliferation, and wound healing assays and transwell migration experiments for cell motility and migration. RESULTS: Transfection of recombinant a plasmid of pcDNA-MTDH-miR-4 significantly suppressed the MTDH mRNA and protein levels more than 69% in MDA-MB-231 breast cancer cells. This knockdown significantly inhibited proliferation, motility and migration as compared with controls. CONCLUSIONS: MTDH-miRNA may play an important role in down- regulating proliferation, motility and migration in breast cancer cells, and should be considered as a potential small molecule inhibitor therapeutic targeting strategy for the future. PMID- 22938465 TI - An experimental model for induction of lung cancer in rats by Chlamydia pneumoniae. AB - OBJECTIVE: To assess induction effects of Chlamydia pneumoniae (Cpn) on lung cancer in rats. METHODS: A lung cancer animal model was developed through repeated intratracheal injection of Cpn (TW-183) into the lungs of rats, with or without exposure to benzo(a)pyrene (Bp). Cpn antibodies (Cpn-IgA, -IgG, and -IgM) in serum were measured by microimmunofluorescence. Cpn-DNA or Cpn-Ag of rat lung cancer was detected through polymerase chain reaction or enzyme-linked immunosorbent assay. RESULTS: The prevalence of Cpn infection was 72.9% (35/48) in the Cpn group and 76.7% (33/43) in the Cpn plus benzo(a)pyrene (Bp) group, with incidences of lung carcinomas in the two groups of 14.6% (7/48) and 44.2% (19/43), respectively (P-values 0.001 and <0.001 compared with normal controls). CONCLUSIONS: A rat model of lung carcinoma induced by Cpn infection was successfully established in the laboratory for future studies on the treatment, prevention, and mechanisms of the disease. PMID- 22938466 TI - New model of in-situ xenograft lymphangiogenesis by a human colonic adenocarcinoma cell line in nude mice. AB - OBJECTIVE: To explore a new model of in-situ xenograft lymphangiogenesis of human colonic adenocarcinomas in nude mice. METHOD: On the basis of establishing subcutaneous xenograft lymphangiogenesis model of human colonic adenocarcinoms, in-situ xenografts were established through the in situ growth of the HT-29 human colonic adenocarcinoma cell line in nude mice. The numbers of lymphangiogenic microvessels, the expression of lymphatic endothelial cell markers lymphatic vessel endothelial hyaloronic acid receptor-1 (LYVE-1), D2-40 and the lymphatic endothelial growth factors vascular endothelial growth factor-C (VEGF-C), -D (VEGF-D) and receptor-3 (VEGFR-3) were compared by immunohistochemical staining, Western bolt and quantitative RT-PCR in xenograft in-situ models. RESULTS: Some microlymphatics with thin walls, large and irregular or collapsed cavities and increased LMVD, with strong positive of LYVE-1, D2-40 in immunohistochemistry, were observed, identical with the morphological characteristics of lymphatic vessels and capillaries. Expression of LYVE-1 and D2-40 proteins and mRNAs were significantly higher in xenografts in-situ than in the negative control group (both P<0.01). Moreover, the expression of VEGF-C, VEGF-D and VEGFR-3 proteins and mRNAs were significantly higher in xenografts in-situ (both P<0.01), in conformity with the signal regulation of the VEGF-C,-D/VEGFR-3 axis of tumor lymphangiogenesis. CONCLUSIONS: In-situ xenografts of a human colonic adenocarcinoma cell line demonstrate tumor lymphangiogenesis. This novel in-situ animal model should be useful for further studying mechanisms of lymph node metastasis, drug intervention and anti-metastasis therapy in colorectal cancer. PMID- 22938467 TI - Screening colonoscopy participation in Turkish colorectal cancer patients and their first degree relatives. AB - BACKGROUND: This study aimed to research the awareness of screening colonoscopy (SC) among patients with colorectal cancer (CRC) and their relatives. METHODOLOGY: A questionnaire form including information and behavior about colonoscopic screening for CRCs of patients and their first-degree relatives (FDRs) was prepared. RESULTS: A total of 406 CRC patients were enrolled into the study, with 1534 FDRs (siblings n: 1381 and parents n: 153) . Positive family history for CRC was found in 12% of the study population. Previous SC was performed in 11% of patients with CRC. Mean age of the patients whose FDRs underwent SC was lower than the patients whose FDRs did not (52 vs 57 years; p<0,001). The frequency of SC in FDRs was 64% in patients diagnosed CRC under 35 years of age. Persons having a positive family history of CRC had SC more often (51 vs 22%, p<0,001). FDRs of patients having a higher educational level and income had SC more frequently. CONCLUSIONS: When screening for CRC is planned, elderly subjects, those with family history for CRC, and those with low educational and lower income should be given especial attention in order that they be convinced to undergo screening for CRC. PMID- 22938468 TI - Deregulation of MTDH gene expression in gastric cancer. AB - AIM: Gastric cancer is the third most frequent cause of cancer mortality worldwide. In Iran, it is one of the leading causes at the national level. Localized at chromosome 8q22, the human MTDH gene has been reported to be over expressed in a spectrum of malignancies. However, since there is a lack of data concerning with expression in gastric cancer at the transcriptional level, in this study we evaluated MTDH expression in Iranian cases. METHODS: Totally, thirty paired gastric samples were examined by quantitative real-time RT-PCR. RESULTS: Although the mRNA expression was significantly elevated in 46.6% of the examined tumor tissues; its expression was low in others (36.6%). Moreover, there was only a marginal statistical difference between the MTDH gene expression of all tumor specimens compared to their paired non-tumor ones and no statistically significant association with the grades and types of the tumors. CONCLUSION: Taken together, our results demonstrated that expression of MTDH at the transcriptional level may be increased in gastric cancer tissue samples but with considerable heterogeneity. Due to this, it may have the potential to be used as a target for diagnostic/therapeutic purposes only in a subset of patients. PMID- 22938470 TI - Association between MDM2 promoter SNP309 T/G polymorphism and liver cancer risk - a meta-analysis. AB - BACKGROUND: Many studies have investigated the association between the MDM2 promoter SNP309 T/G polymorphism and liver cancer risk, but inconsistencies make drawwing definitive conclusions difficult. METHODS: We therefore searched main databases for articles relating MDM2 SNP309 T/G polymorphism to risk of liver cancer in humans and estimated summary odds ratio (OR) with 95% confidence intervals (95% CI) to assess the possible association in a meta-analysis. RESULTS: The main analysis revealed no significant heterogeneity, and the pooled ORs of fixed-effects were all significant (for G versus T, OR = 1.59, 95% CI 1.42 1.78; for GG versus TT, OR = 2.45, 95% CI 1.93-3.12; for GT versus TT, OR = 1.70, 95% CI 1.38-2.09; for GG versus GT, OR = 1.49, 95% CI 1.24-1.79; for GG and GT versus TT, OR = 1.95, 95% CI 1.61-2.38; for GG versus TT and GT, OR = 1.73, 95% CI 1.46-2.07). Subgroup analyses by ethnicity and sensitivity analyses both showed associations to remain significant. CONCLUSION: The present meta-analysis of available data showed a significant association between the MDM2 SNP309 T/G polymorphism and liver cancer risk, the MDM2 SNP309 G allele contributing to increased risk in both Asians and Caucasians in a graded, dose-dependent fashion. PMID- 22938469 TI - Induction of apoptosis in glioma cells and upregulation of Fas expression using the human interferon-beta gene. AB - We investigated whether IFN-beta inhibits the growth of human malignant glioma and induces glioma cell apoptosis using the human IFN-beta gene transfected into glioma cells. A eukaryonic expression vector (pSV2IFNbeta) for IFN-beta was transfected into the glioma cell line SHG44 using liposome transfection. Stable transfection and IFN-beta expression were confirmed using an enzyme-linked immunosorbent assay (ELISA). Cell apoptosis was also assessed by Hoechst staining and electron microscopy. In vivo experiments were used to establish a SHG44 glioma model in nude mice. Liposomes containing the human IFN-beta gene were injected into the SHG44 glioma of nude mice to observe glioma growth and calculate tumor size. Fas expression was evaluated using immunohistochemistry. The IFN-beta gene was successfully transfected and expressed in the SHG44 glioma cells in vitro. A significant difference in the number of apoptotic cells was observed between transfected and non- transfected cells. Glioma growth in nude mice was inhibited in vivo, with significant induction of apoptosis. Fas expression was also elevated. The IFN-beta gene induces apoptosis in glioma cells, possibly through upregulation of Fas. The IFN-beta gene modulation in the Fas pathway and apoptosis in glioma cells may be important for the treatment of gliomas. PMID- 22938471 TI - Efficient killing effect of osteosarcoma cells by cinobufacini and cisplatin in combination. AB - PURPOSE: To study the killing effects on osteosarcoma cells of cinobufacini and cisplatin in combination and the related mechanisms so as to explore the chemotherapeutic method with integrated traditional Chinese and Western medicines. METHODS: Cinobufacini and cisplatin were applied to OS732 cells singly or jointly and survival rates were measured by MTT assay. Changes in cellular shape were observed with inverted phase contrast and fluorescence microscopy and apoptosis rates were analyzed with flow cytometry (FCM). Immunocytochemistry were used to examine the Fas expression of OS732 cells. RESULTS: The combination of cinobufacini and cisplatin had the effect of up-regulating Fas expression and inducing apoptosis. The survival rate of combined application of 100 MUg/ml cinobufacini and 1 MUg/ml cisplatin on OS-732 cells was significantly lower than with either of the agents alone (p<0.01). Changes in cellular shape and apoptotic rates also indicated the apoptosis-inducing effects of combined application were much enhanced. CONCLUSION: The combination of cinobufacini and cisplatin demonstrated strong killing effects on OS-732 cells which might be related to up regulation of Fas expression. PMID- 22938472 TI - Quantitative assessment of the effects of MMP-2 polymorphisms on lung carcinoma risk. AB - BACKGROUND: Previous studies assessing associations between matrix metalloproteinase 2 (MMP-2) polymorphisms and lung cancer risk reported conflicting results. A meta-analysis was therefore performed to derive a more precise estimation. METHOD: Case-control studies assessing associations between MMP-2 C735T and C1306T polymorphisms and lung cancer risk were included. Pooled odds ratios (ORs) with 95% confidence intervals (CIs) were estimated. RESULTS: 7 studies with a total of 3,189 lung cancer cases and 3,013 controls were finally included into this meta-analysis. Overall, the MMP-2 C735T polymorphism was associated with lung cancer risk under the homozygote model (CC versus TT: OR =1.44, 95% CI = 1.03-2.02, I2 = 0%), while the MMP- 2 C1306T polymorphism also associated demonstrated links with all four models (all P values less than 0.05). Subgroup analyses by race suggested obvious associations between MMP-2 C735T and C1306T polymorphisms and lung cancer risk in Asians but not in Caucasians. There was no evidence for publication bias. CONCLUSION: Currently available evidence supports teh conclusion that MMP-2 C735T and C1306T polymorphisms influence susceptibility to lung cancer in Asians. PMID- 22938473 TI - Pancreatic cancer in Universiti Sains Malaysia Hospital: a retrospective review of years 2001-2008. AB - Pancreatic cancer is usually detected late and has a high mortality rate. Since little is known about this cancer in Malaysia, a review of all cases admitted to Universiti Sains Malaysia Hospital was conducted to identify the epidemiological distribution and assess survival. A list of pancreatic cancer patients in 2001 2008 was obtained from the Hospital Record Department. Only cases confirmed by radio-imaging or histo-pathology examination were included. We excluded those with incomplete medical records. Kaplan-Meier and Cox proportional hazard approaches were used for data analysis. Only 56 cases were included with a mean (SD) age of 49.6 (16.0) years, with 60.7% males and 82.1% of Malay ethnicity. Previous history included cholelithiasis in 23.2%, diabetes mellitus in 16.1%, previous laparotomy in 10.7%, chronic pancreatitis in 7.1%, alcohol drinking in 5.4% and positive family history in 3.6%. The common presenting history included 67.9% loss of appetite, 66.1% loss of weight, 58.9% jaundice and 46.4% abdominal pain. Tumour staging was: 21.5% stage l, 17.8% stage ll, 3.6% stage lll and 57.1% stage lV. The median (95% CI) survival time was 3.4 (0.5, 6.3) months and significant prognostic factors were duration of symptoms (HR 0.97; 95% CI: 0.95, 0.99; p value 0.013), ascites (HR 2.64; 95% CI: 1.28, 5.44; p value 0.008) and Whipple surgery (HR 4.20; 95% CI: 2.27, 7.76; p value <0.001). The history of presenting complaints was short and the majority presented at late stages of the disease, thus the median survival time was very poor. PMID- 22938474 TI - Validation of a palliative prognostic index to predict life expectancy for terminally ill cancer patients in a hospice consultation setting in Taiwan. AB - BACKGROUND: The aim of our study was to assess the practical utility of the palliative prognostic index (PPI) as a prognostic tool used by nurse specialists in a hospice consultation setting in Taiwan. METHODS: In total, 623 terminal cancer patients under hospice consultation care from one medical center in northern Taiwan were enrolled between January 1 and June 30, 2011. PPI was assessed by a nurse specialist at first hospice consultation and patients categorized into groups by prognosis (good, intermediate, poor). Patient survival was analyzed retrospectively to determine significance of between-group differences. RESULTS: By PPI sum score, 37.2% of patients were in the good prognosis group, 18% in the intermediate prognosis group and 44.8% in the poor prognosis group. The death rates were 56%, 81.2% and 89.6% and median survivals were 76, 18 and 7 days, respectively. The hazard ratio was 0.19 (95% confidence interval [CI] 0.10-0.24, p<0.001) for the poor versus good prognosis group and 0.54 (95% CI 0.43-0.69, p<0.001) for the poor versus intermediate prognosis group. The sensitivity and specificity for the poor prognosis group was 66% and 71%; the positive predictive value and negative predictive value were 81% and 52%, respectively, to predict patient death within 21 days (area under the curve of the receiver operating characteristic was 0.68). CONCLUSIONS: Assessment by PPI can accurately predict survival of terminal cancer patients receiving hospice consultation care. PPI is a simple tool and can be administered by nurse members of hospice consultation teams. PMID- 22938475 TI - Association of the PSCA rs2294008 C>T polymorphism with gastric cancer risk: evidence from a meta-analysis. AB - BACKGROUND: Multiple studies have reported associations between the PSCA rs2294008 C>T polymorphism and GC, but susceptibility has proven inconsistent. Therefore, we estimates the relationship between the rs2294008 C>T polymorphism and GC by meta-analysis. METHODS: PubMed, Embase and Web of Science databases were searched and nine independent case-control studies were included in this meta- analysis. Crude ORs with 95% CIs were extracted according to the Mantal Haenszel method and pooled to assess the strength of the association. RESULTS: We observed that the PSCA rs2294008 C>T polymorphism was significantly correlated with GC risk when all studies were pooled into the meta-analysis. Further subgroup analysis showed the polymorphism to be linked with diffuse and noncardia GC in the allele contrast model, homozygote codominant model, dominant model, and recessive model. However, no connection was apparent for intestinal and cardia GC. In the stratified analysis by ethnicity, significant associations were observed in Asians for the recessive model. Interestingly, the relationship was particularly significant in the Chinese population. CONCLUSIONS: Our findings suggest that the PSCA rs2294008 C>T polymorphism is a risk factor for GC, especially in diffuse and noncardia GC and in Chinese. PMID- 22938476 TI - Expression and clinical significance of STAT3, P-STAT3, and VEGF-C in small cell lung cancer. AB - OBJECTIVE: To determine STAT3, P-STAT3, and VEGF-C expression levels in small cell lung cancers (SCLCs), and discuss their role and clinical significance in SCLC development. METHOD: Immunohistochemical methods were applied to 128 cases of SCLC and 40 cases of adjacent normal tissue. RESULTS: The expression levels of STAT3, P-STAT3, and VEGF-C were higher in SCLC than in normal tissue (P<0.05). Pairwise comparisons showed positive correlations with lymph node metastasis, clinical stage, and tumor size (P<0.05). The expression levels were also related with the overall survival rates. CONCLUSION: STAT3 and VEGF-C play important roles in the development of SCLC, and might be expected to become new targets for SCLC treatment. PMID- 22938477 TI - Risk factors for premenopausal breast cancer: a case-control study in Uruguay. AB - In order to thoroughly analyze risk factors of breast cancer (BC) in premenopausal Uruguayan women, a case-control study was carried out at the Pereira Rossell Women's Hospital, Montevideo, where 253 incident BC cases and 497 frequency-matched healthy controls were interviewed on menstrual and reproductive story, were administered a short food frequency questionnaire and undertook a series of body measurements necessary to calculate body composition and somatotype. Odds ratio (OR) coefficients were taken as estimates of relative risk derived from unconditional logistic regression. Among the classical risk factors, only the family history of BC in first degree relatives was significantly associated with risk of premenopausal BC (OR=2.20, 95% CI 1.33-3.62). Interestingly, this risk factor was found to be stronger in women of ages >40 (OR=4.05, 95% CI 2.10-7.81), late menarche (OR= 2.39, 95% CI 1.18-4.85), early age for their first delivery (OR=3.02, 95% CI 1.26-7.22), short time between menarche and first delivery (OR=3.22, 95% CI 1.29-8.07), and with high parity (OR=4.10, 95% CI 1.79-9.36), although heterogeneity was detected only for age and parity. High consumption of red meat was positively associated with the disease risk (OR=2.20, 95% CI 1.35-3.60), in the same way as fried foods (OR=1.79, 95% CI 1.12-2.84). Conversely, a high intake of plant foods displayed a protective effect (OR=0.41, 95% CI 0.26-0.65). Except for hypertension (OR=1.55, 95% CI 1.03 2.35), none of the analyzed components of metabolic syndrome were associated to BC risk. Particular increases of risk for premenopausal BC were found for family history in first degree relatives in certain subsets derived from the menstrual reproductive history. Preventive strategies could broaden their scope if new studies confirm the present results, in view of the limited prevention measures that premenopausal BC currently has. PMID- 22938478 TI - Utility of serum and urine uPAR levels for diagnosis of breast cancer. AB - Malignant tumors have a capacity to degrade the extracellular matrix by controlled proteolysis. One system involved in these processes is the urokinase type plasminogen activator (uPA) system. uPAR levels are elevated in tumors from several types of cancer. Our study was planned to investigate serum and urine levels of uPAR in breast cancer patients (n=180) and healthy controls (n=60) by ELISA. Serum (p<0.001) and urine (p<0.001) uPAR values in the patients were both significantly elevated. High serum and urine levels of uPAR can be used as diagnostic tools in lymph node positive patients. PMID- 22938479 TI - HER2/neu expression in head and neck squamous cell carcinoma patients is not significantly elevated. AB - BACKGROUND: HER2/neu, a member of EGFR family, is over expressed in some tumors .The purpose of this study was to determine the salivary level and tissue expression of HER2/neu in patients with head and neck squamous cell carcinoma (HNSCC) and any correlation with clinicopathologic parameters. METHODS: An enzyme linked immunosorbent assay (ELISA) was used to evaluate the salivary level and immunohistochemistry (IHC) to assess tissue expression of HER2/neu in 28 patients with HNSCC and 25 healthy controls. RESULTS: The salivary levels of HER2/neu in HNSCC patients was not significantly higher than in the healthy controls (p>0.005). There was no apparent correlation in salivary HER2/neu level with clinicopathological features such as age, sex, grade, tumor size and nodal status. All HNSCC specimens were positive (membranous or/and cytoplasmic) for HER2/ neu, except one sample. Only one HNSCC specimen was stained in cytoplasm purely. All control specimens were membranous and cytoplasmic positive for HER2/neu. There was a significant difference between cytoplasmic staining in case and control groups (p-value<0.05). CONCLUSION: In our cases, no overexpression of HER2/neu was observed. Thus, our findings suggested that the use of Her-2 as a salivary marker of HNSCC cannot be recommended. PMID- 22938480 TI - Mda-9/syntenin promotes human brain glioma migration through focal adhesion kinase (FAK)-JNK and FAK-AKT signaling. AB - Invasion is usually recognized as the main reason for the high recurrence and death rates of glioma and restricts the efficacy of surgery and other therapies. Therefore, we aimed to investigate the mechanism involved in promotion effects of mda-9/syntenin on human glioma cell migration. The wound healing method was used to test the migration ability of human glioma cells CHG-5 and CHG-hS, stably overexpressing mda-9/syntenin. Western blotting was performed to determine the expression and phosphorylation of focal adhesion kinase (FAK) and JNK in CHG-5 and CHG-hS cells. The migration ability of CHG-hS cells was significantly higher than that of CHG-5 cells in fibronectin (FN)-coated culture plates. Phosphorylation of FAK on tyrosine 397, 576, and 925 sites was increased with time elapsed in CHG-hS cells. However, phosphorylated FAK on the tyrosine 861 site was not changed. Phosphorylated Src, JNK and Akt levels in CHG-hS cells were also significantly upregulated. Phosphorylation of JNK and Akt were abolished by the specific inhibitors SP600125 and LY294002, respectively. and the migration ability of CHG-hS cells was decreased, indicating that the JNK and PI3K/Akt pathways play important roles in regulating mda-9/syntenin-induced human brain glioma migration. Our results indicate Mda- 9/syntenin overexpression could activate FAK-JNK and FAK-Akt signaling and then enhance the migration capacity of human brain glioma cells. PMID- 22938481 TI - Matrix metalloproteinase-9 as a prognostic factor in gastric cancer: a meta analysis. AB - BACKGROUND: Matrix metalloproteinase-9 (MMP-9) is associated with disruption of basement membranes of blood vessels and promotion of metastasis through the lymphatics. However, its prognostic value for survival in patients with gastric cancer remains controversial. METHOD: We therefore conducted a meta-analysis of the published literature in order to clarify the impact of MMP-9. Clinical studies were selected for further analysis if they provided an independent assessment of MMP-9 in gastric cancer and reported analysis of survival data according to MMP-9 expression. RESULTS: A total of 11 studies, covering 1700 patients, were included for meta- analysis. A summary hazard ratio (HR) of all studies and sub-group hazard ratios were calculated. The combined HR suggested that a positive MMP-9 expression had an impact on overall survival: 1.25 (95% confidence interval 1.11-1.40) in all eligible studies; 1.13 (1.06-1.20) in 8 studies detecting MMP-9 by immunohistochemistry; 1.36 (1.12-1.65) in 7 studies from Asia. Only one study for DFS showed a significant impact on disease free survival (HR 1.73, 95%CI 1.27-2.34). CONCLUSIONS: Our findings suggested that MMP 9 protein expression might be a factor for a poor prognosis in patients with gastric cancer. However, the association was rather weak, so that more prospective studies should further explore the prognostic impact of MMP-9 mRNA and correlations between MMP-9 and clinicopathological characteristics. PMID- 22938482 TI - Weekly topotecan for recurrent small cell lung cancer - a retrospective Anatolian Medical Oncology Group study. AB - AIM: To evaluate efficacy and tolerability of topotecan treatment for recurrent small cell lung carcinoma. PATIENTS AND METHODS: A total of 62 patients were evaluated retrospectively. Statistical analysis was performed using GraphPad Instat (version 3.05). RESULTS: Fifty five patients (89%) were male and 7 (11%) were female. Median age was 56.7 +/- 9.3 (34-75). Forty eight of patients (80%) were extensive stage (ES) at the time of diagnosis. Fifty of the patients (80.6 Medical Oncology Clinic) were given median 5.36 cycles of cisplatin-etoposide (2 8 cycles). Time to recurrence was 15.6 +/- 6.13 weeks in patients with limited stage (LS) and 6.3 +/- 3.82 weeks in extensive stage (ES) (p<0.0001). Overall survival was 14.0 +/- 6.08 months in ES and 17.9 +/- 6.88 months in LS. The difference between two groups was statistically meaningful (p=0.0447). The overall survival of the patients was 14.8 +/- 6.43 months (4.5-40 months). In terms of survival, there was no difference between males and females (p=0.1171). In 17 (27%) patients who were refractory to topotecan or in whom progression occurred other chemotherapies were used. CONCLUSION: Small cell lung cancer is chemosensitive, but recurrences occur in short time. Other chemotherapy regimens are used in progression. Topotecan is one of them. Patients who were young and in whom recurrences occur late had given better response to topotecan. Because of the retrospective nature of the study, we couldn't reach the records exactly and consequently, rate and duration of response couldn't be calculated. In recurrent SCLC topotecan is one of the treatment choices. But both hematological and non hematological side effects should be taken into consideration. PMID- 22938483 TI - Influencing women's actions on cervical cancer screening and treatment in Karawang District, Indonesia. AB - INTRODUCTION: The impact of cervical cancer prevention programs depends on persuading women to go for screening and, if needed, treatment. As part of an evaluation of a pilot project in Indonesia, qualitative research was conducted to explore the factors that influence women's decisions regarding screening and treatment and to generate practical recommendations to increase service coverage and reduce loss to follow up. METHODS: Research was conducted at 7 of the 17 public health centers in Karawang District that implemented the pilot project. Interviews and focus group discussions were held with 20 women, 20 husbands, 10 doctors, 18 midwives, 3 district health officials, and 16 advocacy team members. RESULTS: Free services and mobile outreach events encouraged women to go for screening, along with promotional efforts by community health workers, advocacy teams, and the mass media. Knowledge and perceptions were the most important barriers to screening: women were not aware of cervical cancer risks, did not know the disease was treatable, and were fatalistic. Factors facilitating treatment were social support from husbands, relatives, and friends and the encouragement and role modeling of health workers. Barriers to prompt treatment included limited access to services and the requirement for husband's consent for cryotherapy. CONCLUSION: As cervical cancer prevention services are scaled up throughout Indonesia, the findings suggest three strategies to expand screening coverage and ensure prompt treatment: strengthening community mobilization and advocacy activities, modifying the service delivery model to encourage a single visit approach to screening and treatment, and working to gain men's support. PMID- 22938484 TI - Interest in health promotion among Korean American Seventh-day Adventists attending a religious retreat. AB - BACKGROUND: Little is known about interest in faith-based health promotion programs among Asian American populations. Among the Christian denominations, the Seventh-day Adventist (SDA) church is known to place a strong doctrinal emphasis on health. OBJECTIVES: To understand appropriate ways to develop and implement health promotion programs and to conduct research among Korean American SDAs. METHODS: We collaborated with the North American Division of Korean SDA Churches which sponsors annual week-long religious retreats for their church members. We developed and administered a 10-page questionnaire at their 2009 retreat in order to assess socio-demographic and church characteristics, religiosity, perceived relationship between health and religion, and interest and preferences for church based health promotion programs. RESULTS: Overall, 223 participants completed our survey (123 in Korean and 100 in English). The sample consisted of regular churchgoers who were involved in a variety of helping activities, and many holding leadership positions in their home churches. The vast majority was interested in receiving health information at church (80%) in the form of seminars, cooking classes and workshops (50-60%). Fewer respondents were interested in support groups (27%). Some interests and preferences differed between English and Korean language groups. CONCLUSION: Korean American SDA church retreat participants from a large geographic area are very interested in receiving health information and promoting health at their churches and can potentially serve as "agents of influence" in their respective communities. PMID- 22938485 TI - Information sources for Serbian women on cervical carcinoma risk factors. AB - BACKGROUND: The epidemiological situation regarding cervical carcinoma in Serbia is rather unfavorable and one of contributing factors is the insufficient interest of women concerning the risk factors responsible for occurrence of this disease. The aim of this study was to determine the sources of relevant information for women METHODS: An anonymous questionnaire was used for questioning of patients, students and women undergoing systematic examinations. There were 600 women in total in 2006, 2009 and 2010, and the data were statistically processed by the chi 2 test with Yates correction and the Fisher test. RESULTS: When observed for certain groups of tested women, and summed up for all three periods, there was a statistically significant difference for the answer "without any knowledge" (p=0.0001). When observed for certain years and summed up for all three tested groups, there was a statistically significant difference in answers regarding the source of information, the "doctor" (p=0.0011), "media" (p=0.0349) and "encyclopedia-internet" (p=0.0136). CONCLUSION: The media are a dominant source of information for women on risk factors for cervical cancer. The significance of the Internet increased during the three observed periods, while the students considered themselves least informed of all concerning risk factors. PMID- 22938486 TI - Biological response modifiers influence structure function relationship of hematopoietic stem and stromal cells in a mouse model of leukemia. AB - Biological response modifiers (BRMs) can alter interactions between the immune system and cancer cells to boost, direct, or restore the body's ability to fight disease. Mice with ethylnitrosourea- (ENU) induced leukemia were here used to monitor the therapeutic efficacy of lipopolysaccaride (LPS), Bacillus Calmette Guerin (BCG) and sheep erythrocytes (SRBC). Flow cytometry based CD34+ positivity analysis, clonogenicity, proliferation and ultrastructure studies using scanning electron microscopy (SEM) of stem cells in ENU induced animals with and without BRMs treatment were performed. BRMs improved the stem-stromal relationship structurally and functionally and might have potential for use as an adjunct in human stem cell therapy. PMID- 22938487 TI - Therapeutic profile of T11TS vs. T11TS+MiADMSA: a hunt for a more effective therapeutic regimen for arsenic exposure. AB - Arsenic exposure is a serious health hazard worldwide. We have previously established that it may result in immune suppression by upregulating Th2 cytokines while downregulating Th1 cytokines and causing lymphocytic death. Treatment modalities for arsenic poisoning have mainly been restricted to the use of chelating agents in the past. Only recently have combination therapies using a chelating agent in conjunction with other compounds such as anti-oxidants, micronutrients and various plant products, been introduced. In the present study, we used T11TS, a novel immune potentiating glycopeptide alone and in combination with the sulfhydryl-containing chelator, mono-iso-amyl-dimarcaptosuccinic acid (MiADMSA) as a therapeutic regimen to combat arsenic toxicity in a mouse model. Results indicated that Th1 cytokines such as TNF-alpha, IFNgamma, IL12 and the Th2 cytokines such as IL4, IL6, IL10 which were respectively downregulated and upregulated following arsenic induction were more efficiently restored to their near normal levels by T11TS alone in comparison with the combined regimen. Similar results were obtained with the apoptotic proteins studied, FasL, BAX, BCL2 and the caspases 3, 8 and 9, where again T11TS proved more potent than in combination with MiADMSA in preventing lymphocyte death. The results thus indicate that T11TS alone is more efficient in immune re-establishment after arsenic exposureas compared to combination therapy with T11TS+MiADMSA. PMID- 22938488 TI - The GSTP1 Ile105Val polymorphism is not associated with susceptibility to colorectal cancer. AB - The glutathione S transferase (GST) family is a major part of cellular defense mechanisms against endogenous and exogenous substances, many of which have carcinogenic potential. Alteration in the expression level or structure of the glutathione-S-transferase (GST) enzymes may lead to inadequate detoxification of potential carcinogens and consequently contribute to cancer development. A member of the glutathione-S-transferase (GST) family, GSTP1, is an attractive candidate for involvement in susceptibility to carcinogen-associated colorectal cancer. An A>G transition in exon 5 resulting in an Ile105Val amino acid substitution has been identified which alters catalytic efficiency. The present study investigated the possible impact of Ile105Val GSTP1 polymorphism on susceptibility to colorectal cancer. in Jordan We examined 90 tissue samples previously diagnosed with colorectal carcinoma, and 56 non-cancerous colon tissues. DNA was extracted from paraffin embedded tissues and the status of the GSTP1 polymorphism was determined using a polymerase chain reaction restriction fragment length polymorphism (RFLP) method. No statistically significant differences were found between colorectal cancer cases and controls for the GSTP1 Ile/Ile, Ile/Val and Val/Val genotypes. The glutathione S-transferase polymorphism was not associated with risk in colorectal cancer cases in Jordan stratified by age, sex, site, grade or tumor stage. In conclusion, the GSTP1 Ile105Val polymorphism is unlikely to affect the risk of colorectal cancer. PMID- 22938489 TI - Measuring socioeconomic disparities in cancer incidence in Tehran, 2008. AB - BACKGROUND: Health disparities exist among and within countries, while developing and low income countries suffer more. The aim of this study was to quantify cancer disparities with regard to socioeconomic position (SEP) in 22 districts of Tehran, Iran. METHOD: According to the national cancer registry, 7599 new cancer cases were recorded within 22 districts of Tehran in 2008. Based on combined data from census and a population-based health equity study (Urban HEART), socioeconomic position (SEP) was calculated for each district. Index of disparity, absolute and relative concentration indices (ACI and RCI) were used for measuring disparities in cancer incidence. RESULTS: The overall cancer age standardised rate (ASR) was 117.2 per 100,000 individuals (120.4 for men and 113.5 for women). Maximum ASR in both genders was seen in districts 6, 3, 1 and 2. Breast, colorectal, stomach, skin and prostate were the most common cancers. Districts with higher SEP had higher ASR (r=0.9, p<0.001). Positive ACI and RCI indicated that cancer cases accumulated in districts with high SEP. Female disparity was greater than for men in all measures. Breast, colorectal, prostate and bladder ASR ascended across SEP groups. Negative ACI and RCI in cervical and skin cancers in women indicate their aggregation in lower SEP groups. Breast cancer had the highest absolute disparities measure. CONCLUSION: This report provides an appropriate guide and new evidence on disparities across geographical, demographic and particular SEP groups. Higher ASR in specific districts warrants further research to investigate the background predisposing factors. PMID- 22938490 TI - Evaluation of chromosomal alteration in electrical workers occupationally exposed to low frequency of electro magnetic field (EMFs) in Coimbatore population, India. AB - Extremely low frequency electro magnetic fields (EMFs) have been classified as possibly carcinogenic to humans by the International Agency for Research on Cancer. An increased number of chromosomal alterations in peripheral lymphocytes are correlated with elevated incidence of cancer. The aim of the present study was to assess occupationally induced chromosomal damage in EMF workers exposed to low levels of radiation. We used conventional metaphase chromosome aberration (CA) analysis and the micronucleus (MN) assay as biological indicators of non ionizing radiation exposure. In the present study totally 70 subjects were selected including 50 exposed and 20 controls. Informed written consent was obtained from all participants and the study was performed in accordance with the Declaration of Helsinki and the approval of the local ethical committee. A higher degree of CA and MN was observed in exposed subjects compared to controls, the frequency of CA being significantly enhanced with long years of exposure (P<0.05). Moreover increase in CA and MN with age was noted in both exposed subjects and controls, but was significantly greater in the former. The results of this study demonstrated that a significant induction of cytogenetic damage in peripheral lymphocytes of workers occupationally exposed to EMFs in electric transformer and distribution stations. In conclusion, our findings suggest that EMFs possess genotoxic capability, as measured by CA and MN assays; CA analysis appeared more sensitive than other cytogenetic end-points. It can be concluded that chronic occupational exposure to EMFs may lead to an increased risk of genetic damage among electrical workers. PMID- 22938491 TI - Effects of monoclonal antibodies against human stathmin combined with paclitaxel on proliferation of the QG-56 human lung carcinoma cell line. AB - OBJECTIVE: To explore whether monoclonal antibodies against stathmin and the chemotherapuetic agent paclitaxel have synergenic effects in inhibiting growth and inducing apoptosis in human QG-56 cells. METHODS: QG-56 cells were treated with monoclonal antibodies against stathmin or paclitaxel alone or in combination, with untreated cells used as controls. After 24, 48, 72 and 96 hours the cell growth condition was observed under an inverted microscope and inhibition was studied by MTT assay; apoptosis was analyzed by flow cytometry. RESULTS: The populations decreased and cell shape and size changed after the various treatments. Monoclonal antibodies against stathmin and paclitaxel used alone or incombination inhibited the proliferation of QG-56 cells, especially in combination with synergism (P<0.05). Combined treatment also resulted in a significantly higher apoptosis rate than in the other groups (P<0.05). CONCLUSIONS: Monoclonal antibodies against stathmin and paclitaxel used alone or in combination can inhibit proliferation of QG-56 cells and induce apoptosis when applied together, The observed synergistic effects may have important implications for clinical application. PMID- 22938492 TI - High expression of stem cell marker ALDH1 is associated with reduced BRCA1 in invasive breast carcinomas. AB - BACKGROUND: Cancer stem cells (CSC) have been described in a variety of malignancies, including breast carcinomas. Among several markers, aldehyde dehydrogenase 1 (ALDH1) has been identified as reliable for breast cancer stem cells. Knockdown of BRCA1 in primary breast epithelial cells leads to an increase in cells expressing ALDH1. METHODS: We examined 127 breast carcinomas for expression of ALDH1, using immunohistochemistry and correlated with clinicopathological parameters as well as the BRAC1 status. RESULTS: Comparing the results for both ALDH1 and BRCA1 expression showed a significant inverse association between the two, indicating that reduced BRCA1 was more often seen in breast cancer cells expressing ALDH1 (p-value = 0.044). A total of 24/110 (22%) of tumours displayed the ALDH1 + / BRCA1 -/low phenotype, which showed a trend for a relation with a high grade (p-value= 0.056). Cytoplasmic expression of ALDH1 was not correlated with tumour characteristics. CONCLUSION: Taken together, our findings suggest that increased ALDH1 is inversely correlated with decreased BRCA1 in a series of unselected breast carcinomas. Therefore, ALDH1 positive (cancer stem) cells with reduced BRCA1 phenotype may indicate a subset of patients for whom specific targeting of the CSC marker ALDH1 and more aggressive adjuvant treatment is appropriate. PMID- 22938493 TI - Phorbol ester TPA modulates chemoresistance in the drug sensitive breast cancer cell line MCF-7 by inducing expression of drug efflux transporter ABCG2. AB - Recent studies have indicated a link between levels of cyclooxygenase-2 (COX-2) and development of the multidrug resistance (MDR) phenotype. The ATP-binding cassette sub-family G member 2 (ABCG2) is a major MDR-related transporter protein that is frequently overexpressed in cancer patients. In this study, we aimed to evaluate any positive correlation between COX-2 and ABCG2 gene expression using the COX-2 inducer 12-O-tetradecanoylphorbol-13-acetate (TPA) in human breast cancer cell lines. ABCG2 mRNA and protein expression was studied using real-time RT-PCR and flow cytometry, respectively. A significant increase of COX-2 mRNA expression (up to 11-fold by 4 h) was induced by TPA in MDA-MB-231 cells, this induction effect being lower in MCF-7 cells. TPA caused a considerable increase up to 9-fold in ABCG2 mRNA expression in parental MCF-7 cells, while it caused a small enhancement in ABCG2 expression up to 67 % by 4 h followed by a time dependent decrease in ABCG2 mRNA expression in MDA-MB-231 cells. TPA treatment resulted in a slight increase of ABCG2 protein expression in MCF-7 cells, while a time-dependent decrease in ABCG2 protein expression was occurred in MDA-MB-231 cells. In conclusion, based on the observed effects of TPA in MDA-Mb-231 cells, it is proposed that TPA up-regulates ABCG2 expression in the drug sensitive MCF-7 breast cancer cell line through COX-2 unrelated pathways. PMID- 22938494 TI - Clinicopathological characteristics of hepatocellular carcinoma in Turkey. AB - BACKGROUND: Hepatocellular carcinoma (HCC), the main malignant tumor of the liver, is very common and highly lethal. The aim of this study was to determine its clinicopathologic characteristics and risk factors in Turkey. MATERIALS AND METHODS: In this study, patients who were diagnosed as suffering from HCC in the period between August 2004 and December 2011 were evaluated retrospectively. RESULTS: A total of 98 patients were included, with a median age 61 (range: 16 to 82). Seventy nine (80.6%) were male 59 (60.2%) were infected with hepatitis B virus (HBV) and 15 (15.3%) with HCV, another 15 (15.3%) being alcohol abusers. Seventy two (73.5%) were at advanced stage and 54 (55.1%) had elevated serum alpha-fetoprotein (AFP). Surgery, chemoembolization, systemic chemotherapy and application of the tyrosine kinase inhibitor sorafenib were the major treatment options. CONCLUSIONS: According to our findings HCC is mostly diagnosed in advanced stage and age, being five times more common in males than females. Main risk factors of HCC are HBV infection, HCV infection and alcohol abuse. Elevation in AFP may facilitate early diagnosis of HCC in high risk groups. PMID- 22938495 TI - Socio demographic and reproductive risk factors for cervical cancer - a large prospective cohort study from rural India. AB - BACKGROUND: India shows some of the highest rates of cervical cancer worldwide, and more than 70% of the population is living in rural villages. Prospective cohort studies to determine the risk factors for cervical cancer are very rare from low and medium resource countries. The aim of this study was to quantify the effect of risk factors related to cervical cancer in a rural setting in South India. MATERIAL AND METHODS: Sociodemographic and reproductive potential risk factors for cervical cancer were studied using the data from a cohort of 30,958 women who constituted the unscreened control group in a randomised screening trial in Dindigul district, Tamilnadu, India. The analysis was accomplished with the Cox proportional hazard regression model. RESULTS: Women of increasing age (HR=2.4; 95% CI: 1.6, 3.8 in 50-59 vs 30-39), having many pregnancies (HR=7.1; 1.0, 52 in 4+ vs 0) and no education (HR=0.6; 0.2, 0.7 in high vs none) were found to be at significantly increased risk of cervical cancer. CONCLUSION: This cohort study gives very strong evidence to say that education is the fundamental factor among the sociodemographic and reproductive determinants of cervical cancer in low resource settings. Public awareness through education and improvements in living standards can play an important role in reducing the high incidence of cervical cancer in India. These findings further stress the importance of formulating public health policies aimed at increasing awareness and implementation of cervical cancer screening programmes. PMID- 22938496 TI - Gynecological malignancies: epidemiological characteristics of the patients in a tertiary care hospital in India. AB - BACKGROUND: This cross-sectional observational study was undertaken to identify the epidemiological characteristics of patients with gynecological malignancies in India, in relation to gynecological cancer risk. METHODS: In the gynecology out-patient clinic of a tertiary care hospital in Kolkata, India, the patients with suggestive symptoms of gynecological malignancies were screened. One hundred thirteen patients with histopathologically confirmed gynecological malignancies were interviewed. RESULTS: More than two-thirds of the cases (69.0%) occurred in the age range of 35-64 years and the same proportion of patients was from rural areas. Almost all the patients were "ever-married" (96.5%). More than half (54.9%) were illiterate/just literate. Nearly two-thirds (64.6%) were parity 3 or higher. Among the 18 patients with history of multiple sexual partners of the husband, 94.4% (17) were suffering from cervical malignancy, along with all the 3 patients with history of STD syndromes (sexually transmitted diseases) of their husbands. No one had given a history of condom use by her husband. Most of the patients (91.1%) used old / reused cloth pieces during menstruation. CONCLUSIONS: There is a need to increase awareness among women and the broader community about different epidemiological factors that may be responsible for increased risk of gynecological malignancies. PMID- 22938497 TI - Experimental strategies for induction of gastric adenocarcinomas under long-term proton pump inhibitor administration and Helicobacter pylori infection. PMID- 22938498 TI - TNF polymorphisms and cancer. PMID- 22938499 TI - Subcellular localization of tissue factor and human coronary artery smooth muscle cell migration. AB - BACKGROUND: Tissue factor (TF) is the most relevant physiological trigger of thrombosis. Additionally TF is a transmembrane receptor with cell signaling functions. OBJECTIVES: The aim of this study was to investigate TF subcellular localization, function and signaling in human coronary artery smooth muscle cell migration. METHODS: Coronary arteries and primary cultures of vascular smooth muscle cells (HVSMC) were obtained from human explanted hearts. Wound repair and Boyden chamber assays were used to measure migration in vitro. TF-pro-coagulant activity (TF-PCA) was measured in extracted cellular membranes. Analysis of TF distribution was performed by confocal microscopy. A nucleofector device was used for TF and protease activated receptor 2 (PAR2) silencing. mRNA levels were analyzed by RT-PCR. RESULTS: In migrating HVSMC TF translocates to the leading edge of the cells showing an intense patch-like staining in the lamellipodia. In the migrating front TF colocalizes with filamin (FLN) in the polarized lipid rafts. TF-PCA was increased in migrating cells. Silencing of the TF gene inhibits RSK-induced FLN-Ser-2152 phosphorylation, down-regulates CDC42, RhoA, and Rac1 protein expression and significantly inhibits cell migration. Silencing PAR2 also inhibits cell migration; however, silencing both TF and PAR2 induces a significantly higher effect on migration. Smooth muscle cells expressing TF have been identified in non-lipid-rich human coronary artery atherosclerotic plaques. CONCLUSIONS: TF translocates to the cell front in association with cytoskeleton proteins and regulates HVSMC migration by mechanisms dependent and independent of factor (F)VIIa/PAR2. These results extend the functional role of TF to smooth muscle cell trafficking in vessel wall remodeling. PMID- 22938500 TI - Incidence of transcortical tibial fractures with self-tapping and non-self tapping screws in a canine TPLO model. AB - OBJECTIVE: To compare the incidence of radiographically apparent transcortical diaphyseal tibial fractures between self-tapping screws (STS) and non-self tapping screws (NSTS) in a canine tibial plateau leveling osteotomy (TPLO) model. STUDY DESIGN: Case series. ANIMALS: Dogs (n = 106) that had TPLO. METHODS: NSTS (n = 107), STS titanium (n = 104), or STS stainless steel (n = 105) screws were used for TPLO. Effect of STS and NSTS were compared by reviewing postoperative craniocaudal and lateral radiographic projections taken immediately after TPLO. Three screws distal to the tibial osteotomy served as the in vivo model for canine cortical bone. A transcortical fracture was defined as the presence of a saucer-shaped radiolucent defect on the periosteal surface of the trans-cortex surrounding the screw and the presence of radiopaque material (bone) separate from the transcortical periosteal surface. The effect of screw type and STS material (stainless steel or titanium) on the incidence of transcortical fractures was evaluated. RESULTS: STS had a significantly higher (P = .006) incidence of transcortical fractures (18.0%) compared with NSTS (0.8%). The effect of STS material on the incidence of transcortical fractures was not significant (P = .485). No cis-cortical factures were identified. CONCLUSIONS: We suspect the increased incidence of transcortical fractures with STS is because of the shorter cutting flutes as compared with those of a tap used with a NSTS. PMID- 22938501 TI - A diversity-oriented approach to spirocyclic and fused hydantoins via olefin metathesis. AB - An efficient and general method is reported to prepare a diverse series of 5,5 spirocyclic and 1,5-, 4,5-, and 3,4-fused bicyclic imidazolidinone derivatives based on selective alkylation and ring closing metathesis (RCM) by exploiting the four possible points of diversity in the hydantoin ring. Hydantoins containing trienes and tetraenes undergo selective RCM and cross metathesis to afford functionalized spirohydantoins. A tandem metathesis sequence involving ring closing-ring opening-ring closing and cross metathesis (RC-RO-RC-CM) occurred with a hydantoin triene to give a bicyclic hydantoin dimer in high yield. The fused bicylic dimer could participate in cross metathesis to produce a functionalized fused hydantoin derivative. The methodology establishes novel routes to unnatural amino acids, proline homologues, and cyclic vicinal diamines. PMID- 22938502 TI - Myeloid cells in tumor inflammation. AB - Bone marrow derived myeloid cells progressively accumulate in tumors, where they establish an inflammatory microenvironment that is favorable for tumor growth and spread. These cells are comprised primarily of monocytic and granulocytic myeloid derived suppressor cells (MDSCs) or tumor-associated macrophages (TAMs), which are generally associated with a poor clinical outcome. MDSCs and TAMs promote tumor progression by stimulating immunosuppression, neovascularization, metastasis and resistance to anti-cancer therapy. Strategies to target the tumor promoting functions of myeloid cells could provide substantial therapeutic benefit to cancer patients. PMID- 22938503 TI - Comorbidity Cohort (2C) study: cardiovascular disease severity and comorbid osteoarthritis in primary care. AB - BACKGROUND: Two of the commonest chronic diseases experienced by older people in the general population are cardiovascular diseases and osteoarthritis. These conditions also commonly co-occur, which is only partly explained by age. Yet, there have been few studies investigating specific a priori hypotheses in testing the comorbid interaction between two chronic diseases and related health and healthcare outcomes. It is also unknown whether the stage or severity of the chronic disease influences the comorbidity impact. The overall plan is to investigate the interaction between cardiovascular severity groups (hypertension, ischaemic heart disease and heart failure) and osteoarthritis comorbidity, and their longitudinal impact on health and healthcare outcomes relative to either condition alone. METHODS: From ten general practices participating in a research network, adults aged 40 years and over were sampled to construct eight exclusive cohort groups (n = 9,676). Baseline groups were defined on the basis of computer clinical diagnostic data in a 3-year time-period (between 2006 and 2009) as: (i) without cardiovascular disease or osteoarthritis (reference group), (ii) index cardiovascular disease groups (hypertension, ischaemic heart disease and heart failure) without osteoarthritis, (iii) index osteoarthritis group without cardiovascular disease, and (vi) index cardiovascular disease groups comorbid with osteoarthritis. There were three main phases to longitudinal follow-up. The first (survey population) was to invite cohorts to complete a baseline postal health questionnaire, with 10 monthly brief interval health questionnaires, and a final 12-month follow-up questionnaire. The second phase (linkage population) was to link the collected survey data to patient clinical records with consent for the 3-year time-period before baseline, during the 12-month survey period and the 12 months after final questionnaire (total 5 years). The third phase (denominator population) was to construct an anonymised clinical data archive for the study five year period for the total baseline cohorts, linking clinical information such as diagnosis, prescriptions and referrals. DISCUSSION: The outcomes of the study will result in the determination of the specific interaction between cardiovascular severity and osteoarthritis comorbidity on the change and progression of physical health status in individuals and on the linked and associated clinical-decision making process in primary care. PMID- 22938504 TI - Understanding health systems, health economies and globalization: the need for social science perspectives. AB - The complex relationship between globalization and health calls for research from many disciplinary and methodological perspectives. This editorial gives an overview of the content trajectory of the interdisciplinary journal 'Globalization and Health' over the first six years of production, 2005 to 2010. The findings show that bio-medical and population health perspectives have been dominant but that social science perspectives have become more evident in recent years. The types of paper published have also changed, with a growing proportion of empirical studies. A special issue on 'Health systems, health economies and globalization: social science perspectives' is introduced, a collection of contributions written from the vantage points of economics, political science, psychology, sociology, business studies, social policy and research policy. The papers concern a range of issues pertaining to the globalization of healthcare markets and governance and regulation issues. They highlight the important contribution that can be made by the social sciences to this field, and also the practical and methodological challenges implicit in the study of globalization and health. PMID- 22938505 TI - Characterization of telomeric repeats in metaphase chromosomes and interphase nuclei of Syrian Hamster Fibroblasts. AB - BACKGROUND: Rodents have been reported to contain large arrays of interstitial telomeric sequences (TTAGGG)n (ITS) located in pericentromeric heterochromatin. The relative sizes of telomeric sequences at the ends of chromosomes (TS) and ITS in Syrian hamster (Mesocricetus auratus) cells have not been evaluated yet, as well as their structural organization in interphase nuclei. RESULTS: FISH signal distribution analysis was performed on DAPI-banded metaphase chromosomes of Syrian hamster fibroblasts, and relative lengths of telomere signals were estimated. Besides well-distinguished FISH signals from ITS located on chromosomes ##2, 4, 14, 20 and X that we reported earlier, low-intensity FISH signals were visualized with different frequency of detection on all other metacentric chromosomes excluding chromosome #21. The analysis of 3D-distribution of TS in interphase nuclei demonstrated that some TS foci formed clearly distinguished associations (2-3 foci in a cluster) in the nuclei of cells subjected to FISH or transfected with the plasmid expressing telomeric protein TRF1 fused with GFP. In G0 and G1/early S-phase, the average total number of GFP TRF1 foci per nucleus was less than that of PNA FISH foci in the corresponding cell cycle phases suggesting that TRF1 overexpression might contribute to the fusion of neighboring telomeres. The mean total number of GFP-TRF1 and FISH foci per nucleus was increased during the transition from G0 to G1/early S-phase that might be the consequence of duplication of some TS. CONCLUSIONS: The relative lengths of TS in Syrian hamster cells were found to be moderately variable. All but one metacentric chromosomes contain ITS in pericentromeric heterochromatin indicating that significant rearrangements of ancestral genome occurred in evolution. Visualization of GFP-TRF1 fibrils that formed bridges between distinct telomeric foci allowed suggesting that telomere associations observed in interphase cells are reversible. The data obtained in the study provide the further insight in the structure and dynamics of telomeric sequences in somatic mammalian cells. PMID- 22938507 TI - The effectiveness of antibrowning dip treatments to reduce after-cooking darkening in potatoes. AB - After-cooking darkening (ACD) is an inherent and undesirable trait that develops in cooked potatoes. The objective of this study was to evaluate the effectiveness of sodium acid sulfate (SAS) dip treatments compared to other antigraying treatments and a control to reduce ACD in boiled, Katahdin potatoes. Dip treatments were applied for 3 min prior to boiling and included: 3% SAS, 3% citric acid (CA), 3% sodium acid pyrophosphate (SAPP), along with a distilled water control. SAS- and CA-treated potatoes had slightly, but significantly (P <= 0.05) higher b* and chroma values, which indicates a more intense yellow potato color, with less graying, compared to the control. SAS- and CA-treated potatoes also had significantly (P<= 0.001) lower pH values for inner and outer potato surfaces than the control. No significant (P > 0.05) differences were detected for total phenolic or mineral contents among treatments. CA and SAPP samples had slightly, but significantly (P<= 0.05) higher moisture contents than the control. Sensory test results showed no significant differences for color, aftertaste, or overall acceptability. However, CA-treated samples were rated significantly (P<= 0.05) lower for flavor than all other treatments and panelists commented on sour notes. CA- and SAS-treated potatoes were scored slightly, but significantly lower for texture than other treatments due to a waxy outer layer. However, SAS was the most acidic dip treatment, but did not significantly affect flavor. Overall, results suggest that SAS was similarly accepted by consumers in comparison to CA and SAPP, which is the industry standard to reduce ACD. PRACTICAL APPLICATION: After-cooking darkening (ACD) is an undesirable potato trait that occurs after potatoes have been processed. Sodium acid pyrophosphate (SAPP) has been used as the industry standard to reduce ACD. Sodium acid sulfate (SAS) treatments prior to boiling appeared to be comparable to SAPP and citric acid in effectiveness to reduce ACD. SAS did not negatively affect the flavor of boiled potato samples according to sensory results. The SAS treatment may be more beneficial for potatoes intended for potato salad products. PMID- 22938506 TI - Targeted massive parallel sequencing: the effective detection of novel causative mutations associated with hearing loss in small families. AB - BACKGROUND: Hereditary hearing loss is one of the most common heterogeneous disorders, and genetic variants that can cause hearing loss have been identified in over sixty genes. Most of these hearing loss genes have been detected using classical genetic methods, typically starting with linkage analysis in large families with hereditary hearing loss. However, these classical strategies are not well suited for mutation analysis in smaller families who have insufficient genetic information. METHODS: Eighty known hearing loss genes were selected and simultaneously sequenced by targeted next-generation sequencing (NGS) in 8 Korean families with autosomal dominant non-syndromic sensorineural hearing loss. RESULTS: Five mutations in known hearing loss genes, including 1 nonsense and 4 missense mutations, were identified in 5 different genes (ACTG1, MYO1F, DIAPH1, POU4F3 and EYA4), and the genotypes for these mutations were consistent with the autosomal dominant inheritance pattern of hearing loss in each family. No mutational hot-spots were revealed in these Korean families. CONCLUSION: Targeted NGS allowed for the detection of pathogenic mutations in affected individuals who were not candidates for classical genetic studies. This report is the first documenting the effective use of an NGS technique to detect pathogenic mutations that underlie hearing loss in an East Asian population. Using this NGS technique to establish a database of common mutations in Korean patients with hearing loss and further data accumulation will contribute to the early diagnosis and fundamental therapies for hereditary hearing loss. PMID- 22938508 TI - Targeting wild-type Erythrocyte receptors for Plasmodium falciparum and vivax Merozoites by Zinc Finger Nucleases In- silico: Towards a Genetic Vaccine against Malaria. AB - BACKGROUND: Malaria causes immense human morbidity and mortality globally. The plasmodium species vivax and falciparum cause over 75 % clinical malaria cases. Until now, gene-based strategies against malaria have only been applied to plasmodium species and their mosquito-vector. Merozoites of these two respective plasmodium species target and invade red blood cells (RBCs) by using the duffy antigen receptor for chemokines (DARC), and Sialic Acid (SLC4A1) residues of the O-linked glycans of Glycophorin A. RBCs of naturally selected duffy-negative blacks are resistant to P.vivax tropism. We hypothesized that artificial aberration of the host-pathway by target mutagenesis of either RBC -receptors, may abolish or reduce susceptibility of the host to malaria. As a first step towards the experimental actualization of these concepts, we aimed to identify zinc finger arrays (ZFAs) for constructing ZFNs that target genes of either wild type host-RBC- receptors. METHODS: In-Silico Gene & Genome Informatics RESULTS: Using the genomic contextual nucleotide-sequences of homo-sapiens darc and glycophorin-a, and the ZFN-consortia software- CoDA-ZiFiT-ZFA and CoDA-ZiFiT-ZFN: we identified 163 and over 1,000 single zinc finger arrays (sZFAs) that bind sequences within the genes for the two respective RBC-receptors. Second, 2 and 18 paired zinc finger arrays (pZFAs) that are precursors for zinc finger nucleases (ZFNs) capable of cleaving the genes for darc and glycophorin-a were respectively assembled. Third, a mega-BLAST evaluation of the genome-wide cleavage specificity of this set of ZFNs was done, revealing alternate homologous nucleotide targets in the human genome other than darc or glycophorin A. CONCLUSIONS: ZFNs engineered with these ZFA-precursors--with further optimization to enhance their specificity to only darc and glycophorin-a, could be used in constructing an experimental gene-based-malaria vaccine. Alternatively, meganucleases and transcription activator-like (TAL) nucleases that target conserved stretches of darc and glycophorin-a DNA may serve the purpose of abrogating invasion of RBCs by falciparam and vivax plasmodia species. PMID- 22938509 TI - Explosive force production during isometric squats correlates with athletic performance in rugby union players. AB - This study investigated the association between explosive force production during isometric squats and athletic performance (sprint time and countermovement jump height). Sprint time (5 and 20 m) and jump height were recorded in 18 male elite standard varsity rugby union players. Participants also completed a series of maximal- and explosive-isometric squats to measure maximal force and explosive force at 50-ms intervals up to 250 ms from force onset. Sprint performance was related to early phase (<=100 ms) explosive force normalised to maximal force (5 m, r = -0.63, P = 0.005; and 20 m, r = -0.54, P = 0.020), but jump height was related to later phase (>100 ms) absolute explosive force (0.51 < r < 0.61; 0.006 < P < 0.035). When participants were separated for 5-m sprint time (< or >= 1s), the faster group had greater normalised explosive force in the first 150 ms of explosive-isometric squats (33-67%; 0.001 < P < 0.017). The results suggest that explosive force production during isometric squats was associated with athletic performance. Specifically, sprint performance was most strongly related to the proportion of maximal force achieved in the initial phase of explosive-isometric squats, whilst jump height was most strongly related to absolute force in the later phase of the explosive-isometric squats. PMID- 22938511 TI - Red cell and platelet-derived microparticles are increased in G6PD-deficient subjects. AB - In response to oxidative stress and during apoptosis, cells often shed microparticles (MPs), submicron elements carrying phosphatidylserine and protein antigens. Glucose-6-phosphate dehydrogenase (G6PD)-deficient cells are extremely sensitive to oxidative damage that may lead to the formation of MPs. To determine whether G6PD deficiency alters membrane phospholipid asymmetry and increases MPs production, we determined the concentrations and cellular origins of MPs in G6PD deficient individuals using flow cytometry. G6PD-deficient individuals showed an increase in circulating MPs concentrations as compared with G6PD-normal individuals [1051/MUL (865-2532/MUL) vs. 258/MUL (235-575/MUL), P < 0.01]. MPs concentrations were significantly increased with the severity of G6PD deficiency. Median MPs concentrations from individuals with severe G6PD deficiency, and individuals with moderate G6PD deficiency were 2567/MUL (1216-2532/MUL) and 984/MUL (685-2107/MUL), respectively (P < 0.01). Importantly, G6PD enzymatic activity was significantly correlated with MPs concentrations with r(2) = 0.731. MPs found in G6PD deficiency individuals were largely derived from red blood cells (RBCs) (45%) and platelets (30%). Additionally, Atomic Force Microscopy was used to study the morphology and measures the diameter of MPs found in G6PD deficient individuals. The mean (SD) width and height of RMPs were 0. 41 (0.18) and 2.04 (0.14) MUm, respectively. Together, these results indicate that MP concentration is significantly correlated with G6PD enzymatic activity and is increased in G6PD-deficient as compared with G6PD-normal individuals. Our data also provide an evidence for an alteration in cell membrane associated with a decreased in G6PD activity. However, the significance of MPs in G6PD deficiency needs further clarification. PMID- 22938510 TI - Mitochondrial plasticity in obesity and diabetes mellitus. AB - SIGNIFICANCE: Insulin resistance and its related diseases, obesity and type 2 diabetes mellitus (T2DM), have been linked to changes in aerobic metabolism, pointing to a possible role of mitochondria in the development of insulin resistance. RECENT ADVANCES: Refined methodology of ex vivo high-resolution respirometry and in vivo magnetic resonance spectroscopy now allows describing several features of mitochondria in humans. In addition to measuring mitochondrial function at baseline and after exercise-induced submaximal energy depletion, the response of mitochondria to endocrine and metabolic challenges, termed mitochondrial plasticity, can be assessed using hyperinsulinemic clamp tests. While insulin resistant states do not uniformly relate to baseline and post-exercise mitochondrial function, mitochondrial plasticity is typically impaired in insulin resistant relatives of T2DM, in overt T2DM and even in type 1 diabetes mellitus (T1DM). CRITICAL ISSUES: The variability of baseline mitochondrial function in the main target tissue of insulin action, skeletal muscle and liver, may be attributed to inherited and acquired changes in either mitochondrial quantity or quality. In addition to certain gene polymorphisms and aging, circulating glucose and lipid concentrations correlate with both mitochondrial function and plasticity. FUTURE DIRECTIONS: Despite the associations between features of mitochondrial function and insulin sensitivity, the question of a causal relationship between compromised mitochondrial plasticity and insulin resistance in the development of obesity and T2DM remains to be resolved. PMID- 22938513 TI - Comparison of transurethral enucleation with bipolar and transurethral resection in saline for managing benign prostatic hyperplasia. AB - Study Type--Therapy (case series) Level of Evidence 4. What's known on the subject? and What does the study add? Transurethral enucleation with bipolar (TUEB) has been widely adopted as an alternative to standard TURP, although the surgical technique, efficacy and safety of TUEB have not been described so far. The present study provides illustrations of the TUEB technique, as well as peri operative, 6-month and 12-month follow-up results of TUEB from a retrospective review of a single-institution experience comparing the efficacy and safety of TUEB and transurethral resection in saline for managing BPH. OBJECTIVE: * To illustrate the transurethral enucleation with bipolar (TUEB) technique and compare the efficacy and safety of TUEB and transurethral resection in saline (TURis) for managing benign prostatic hyperplasia (BPH). PATIENTS AND METHODS: * A retrospective review of a single-institution experience of 110 consecutive TUEB or TURis between 2008 and 2011 at our hospital was performed aiming to compare the efficacy and safety of TUEB and TURis for managing BPH (55 patients in each group). * Peri-operative data included operating time, resected tissue weight, changes in haemoglobin, duration of catheterization, hospital stay and early complications. * Postoperative outcomes included 6- and 12-month postoperative International Prostate Symptom Score (IPSS), and Quality of Life (QoL) score, uroflowmetry findings, change in serum prostate-specific antigen level and all late complications in the two groups. RESULTS: * Both groups were well matched for age, preoperative prostate volume, IPSS, QoL and uroflowmetry findings. * The change in haemoglobin at postoperative day 1 in the TUEB group was significantly less than in the TURis group (1.08 vs 1.60 g/dL; P < 0.001). * Catheterization time and hospital stay were significantly shorter in the TUEB group than in the TURis group and the mean retrieved tissue weight in the TUEB group was larger than that in the TURis group (41.3 vs 31.7 g; P = 0.007). * Patients in the two arms had comparable improvements in postoperative IPSS, QoL, maximum flow rate and postvoid residual urine volume. * The rates of complications were equally low with each procedure. CONCLUSION: * TUEB is superior to TURis, with less bleeding, as well as decreased catheter time and hospital stay, although showing equivalent efficacy at 12 months of follow-up. PMID- 22938512 TI - Introgression of Brown Norway CYP4A genes on to the Dahl salt-sensitive background restores vascular function in SS-5(BN) consomic rats. AB - The present study tested the hypothesis that the Dahl SS (salt-sensitive) rat has vascular dysfunction due, in part, to the up-regulation of the CYP4A/20-HETE (cytochrome P450 omega-hydroxylase 4A)/20-hydroxyeicosatetraenoic acid) system. To assess the role of vascular 20-HETE, SS rats were compared with SS-5(BN) consomic rats, carrying CYP4A alleles on chromosome 5 from the normotensive BN (Brown Norway) introgressed on to the SS genetic background. Cerebral arteries from SS-5(BN) rats had less CYP4A protein than arteries from SS rats fed either NS (normal-salt, 0.4% NaCl) or HS (high-salt, 4.0% NaCl) diet. ACh (acetylcholine)-induced dilation of MCAs (middle cerebral arteries) from SS and SS-5(BN) rats was present in SS-5(BN) rats fed on either an NS or HS diet, but absent in SS rats. In SS rats fed on either diet, ACh-induced dilation was restored by acute treatment with the CYP4A inhibitor DDMS (N-methyl-sulfonyl 12,12-dibromododec-11-enamide) or the 20-HETE antagonist 20-HEDE [20 hydroxyeicosa-6(Z),15(Z)-dienoic acid]. The restored response to ACh in DDMS treated SS rats was inhibited by L-NAME (N(G)nitro-L-arginine methyl ester) and unaffected by indomethacin or MS-PPOH [N-methylsulfonyl-6-(2 propargyloxyphenyl)hexanamide]. Vascular relaxation responses to the NO donor C(5)FeN(6)Na(2)O were intact in both SS and SS-5(BN) rats and unaffected by the acute addition of DDMS, indicating that the vascular dysfunction of the SS rat is due to a reduced bioavailability of NO instead of failure of the VSMCs (vascular smooth muscle cells) to respond to the vasodilator. Superoxide levels in cerebral arteries of SS-5(BN) rats [evaluated semi-quantitatively by DHE (dihydroethidium) fluorescence] were lower than those in the arteries of SS rats. These findings indicate that SS rats have an up-regulation of the CYP4A/20-HETE pathway resulting in elevated ROS (reactive oxygen species) and reduced NO bioavailability causing vascular dysfunction. PMID- 22938514 TI - Ocular toxocariasis. AB - Ocular toxocariasis is an uncommon worldwide parasitic infection that affects mostly children and is found in both rural and metropolitan areas. In many parts of the world, parasitic infections of the eye are a major cause of blindness. The diagnosis of toxocariasis is essentially clinical, based on the lesion morphology and supportive laboratory data such as serum enzyme-linked immunosorbent assay (ELISA) titers and ELISA Toxocara titers on aqueous humor; other diagnostic methods are imaging studies including optical coherence tomography, fluorescein angiography, computed tomography, and ocular ultrasound. Treatment is directed at complications arising from intraocular inflammation and vitreous membrane traction. Early vitrectomy may be of value both diagnostically and therapeutically. PMID- 22938515 TI - An evidence-based review of vascular endothelial growth factor inhibition in pediatric retinal diseases: part 2. Coats' disease, best disease, and uveitis with childhood neovascularization. AB - Vascular endothelial growth factor (VEGF) is an important factor in the pathogenesis of multiple retinal neovascular disorders. This report focuses on the quality and depth of new evidence for the use of VEGF inhibitors in selected pediatric ocular diseases, including Coats' disease, Best disease, and childhood uveitis. Because much of the literature comprises case reports and retrospective case series, the level of evidence supporting its use as a primary treatment option, or even as adjuvant therapy, is low. The standard of care is treatment of the underlying disorder to prevent neovascularization (retinal or subretinal), vitreous hemorrhage, or subsequent retinal detachment. However, these complications may not present until late in the disease course. It may then be useful to treat with these agents. Prospective studies are warranted to further elucidate the role of anti-VEGF therapy in these diseases. PMID- 22938516 TI - An evidence-based meta-analysis of vascular endothelial growth factor inhibition in pediatric retinal diseases: part 1. Retinopathy of prematurity. AB - Recently there has been interest in the novel, off-label use of anti-vascular endothelial growth factor (anti-VEGF) agents for various stages of retinopathy of prematurity (ROP). The authors report on the quality and depth of new evidence published from 2009 to 2011 concerning the treatment of retinopathy of prematurity (ROP) with bevacizumab (Avastin; Genentech Inc., South San Francisco, CA) as either primary or adjunctive treatment for ROP. There is significant variability in the evidence, quality, and design of the studies available in the literature. There has been a trend in the scientific literature of the past 2 years toward larger, multi-center, randomized studies investigating the role of bevacizumab in the treatment of ROP. More recent evidence suggests that monotherapy with intravitreal bevacizumab may be a viable first-line treatment for select cases of zone I ROP and possibly for posterior zone II disease. Adjunctive treatment with bevacizumab may enhance outcomes in patients treated with laser photocoagulation or pars plana vitrectomy. However, there are significant concerns regarding its long-term safety profile. Further prospective studies are warranted to more fully determine the role of anti-VEGF therapy in this disease. PMID- 22938517 TI - A comparison of different autorefractors with retinoscopy in children. AB - PURPOSE: To compare the results of different refractive error measurement devices including table-mounted and hand-held autorefractors and videoretinoscopy with cycloplegic retinoscopy (CR) in children to evaluate the usability and reliability of these devices in measuring refractive errors. METHODS: Two hundred eyes of 100 children underwent autorefraction using table-mounted autorefractor with and without cycloplegia and videoretinoscopy after cycloplegia. All results were compared statistically. RESULTS: The mean spheric values (SV) and spherical equivalent values (SEV) of the non-cycloplegic table-mounted autorefractor were found to be significantly lower and those of the cycloplegic table-mounted autorefractor were found to be significantly higher than CR results. There was no statistically significant difference in terms of mean SV and SEV between the hand held autorefractor and CR. Although the mean SV using videoretinoscopy were 0.15 diopters lower than CR, this difference was not significant. Comparing CR with the other refraction methods, all devices correlated with each other. Sensitivity in diagnosing myopia was low for all methods but sensitivity in diagnosing hyperopia and astigmatism was high for table-mounted and hand-held autorefractors. The other reliability parameters were found to be similar for all devices. CONCLUSIONS: Both videoretinoscopy and hand-held autorefractor can be used in both screening and examination for children as an alternative to CR and table-mounted autorefractor. PMID- 22938518 TI - Testicular and color variation in the kissing bug, Rhodnius brethesi, in Amazonas, Brazil. AB - Because of the morphological and morphometric variation of testicular follicles in different genera of the subfamily Triatominae, it was of interest to associate those parameters with the different medial pronotal band patterns (wide and narrow) found in Rhodnius brethesi (Matta) (Hemiptera: Reduviidae). This is a wild species often associated with Leopoldina piassaba Wallace (Arecales: Arecaceae) palm, with a geographical distribution restricted to the Amazon region. The specimens used were from the state of Amazonas, and were kept under conditions of 29 +/- 1 degrees C, 80 +/- 5% RH, 12:12 L:D photoperiod, and were fed weekly on blood from Swiss mice. Three-day-old fasting males were separated in accordance with the patterns of the medial pronotal band, dissected, and the testicles removed. After removal of the testicular membrane, the follicles were spread, drawn by camera lucida, and measured. The results showed that the testis of R. brethesi consists of seven follicles, divided into two groups by length; two long and five short. In specimens with a wide medial pronotal band, the long follicles were 5.4 mm in length, but in specimens with a narrow medial band, the long follicles were 5.64 mm in length. The difference was significant. The short follicles were not different in length, suggesting the presence of a possible complex "brethesi" in the Amazon region. PMID- 22938519 TI - Straightforward synthesis of dihydrobenzo[a]fluorenes through Au(I)-catalyzed formal [3 + 3] cycloadditions. AB - Dihydrobenzo[a]fluorene derivatives have been prepared by a formal intramolecular [3 + 3] cycloaddition of o-alkynylstyrenes bearing a secondary alkyl group at the beta-position of the styrene moiety. The process, catalyzed by a cationic gold(I) complex, involves a 1,2-hydride migration as the key step. 6,11-Dihydro-5H benzo[a]fluorenes could be obtained from the initially generated 6,6a-dihydro-5H benzo[a]fluorenes by subsequent heating of the reaction mixture under gold(I) or Bronsted acid catalysis or directly by conducting the reactions at high temperature. PMID- 22938520 TI - Biological invasion. PMID- 22938521 TI - Seed wasp invasions promoted by unregulated seed trade affect vegetal and animal biodiversity. AB - Cone and seed insects are considered the most important predators of tree seeds during the pre-dispersal phase of development. Among them, exotic seed chalcids in the genus Megastigmus invaded Europe as a result of the rapidly-increasing and mostly unregulated seed trade for afforestation and ornamental plantations. Unlike their economic impact in seed orchards, until recently, little attention was paid to the ecological impact of these insects. In the present study, selected case studies of alien Megastigmus spp. were considered to assess their specific impact on the potential of natural regeneration of native woody plants and on the native entomofauna competing for seed resource. We re-analyzed data from former studies that did not focus on these ecological interactions and, here, present previously unpublished results. Seeds of Douglas-fir, true cedars, true firs and wild roses were sampled all over Europe, and the relative importance of the native and invasive chalcid species was assessed as well as their specific impact on seed yield. In most cases, the recent arrival of alien chalcids resulted in a significant decrease in the regeneration potential of the host trees. In the absence of competitors, alien chalcids occupied the entire seed niche in Douglas-fir, but their impact tended to decrease after the arrival of invasive seed bugs. In firs, alien chalcids tended to displace the native chalcids, but not in wild roses and cedars, where their damage was increasing. Different biological traits that might explain invasive success of alien chalcids are discussed. However, no general invasive patterns seem to exist. PMID- 22938522 TI - Alien mammals in Europe: updated numbers and trends, and assessment of the effects on biodiversity. AB - This study provides an updated picture of mammal invasions in Europe, based on detailed analysis of information on introductions occurring from the Neolithic to recent times. The assessment considered all information on species introductions, known extinctions and successful eradication campaigns, to reconstruct a trend of alien mammals' establishment in the region. Through a comparative analysis of the data on introduction, with the information on the impact of alien mammals on native and threatened species of Europe, the present study also provides an objective assessment of the overall impact of mammal introductions on European biodiversity, including information on impact mechanisms. The results of this assessment confirm the constant increase of mammal invasions in Europe, with no indication of a reduction of the rate of introduction. The study also confirms the severe impact of alien mammals, which directly threaten a significant number of native species, including many highly threatened species. The results could help to prioritize species for response, as required by international conventions and obligations. PMID- 22938523 TI - Ecological correlates of invasion impact for Burmese pythons in Florida. AB - An invasive population of Burmese pythons (Python molurus bivittatus) is established across several thousand square kilometers of southern Florida and appears to have caused precipitous population declines among several species of native mammals. Why has this giant snake had such great success as an invasive species when many established reptiles have failed to spread? We scored the Burmese python for each of 15 literature-based attributes relative to predefined comparison groups from a diverse range of taxa and provide a review of the natural history and ecology of Burmese pythons relevant to each attribute. We focused on attributes linked to spread and magnitude of impacts rather than establishment success. Our results suggest that attributes related to body size and generalism appeared to be particularly applicable to the Burmese python's success in Florida. The attributes with the highest scores were: high reproductive potential, low vulnerability to predation, large adult body size, large offspring size and high dietary breadth. However, attributes of ectotherms in general and pythons in particular (including predatory mode, energetic efficiency and social interactions) might have also contributed to invasion success. Although establishment risk assessments are an important initial step in prevention of new establishments, evaluating species in terms of their potential for spreading widely and negatively impacting ecosystems might become part of the means by which resource managers prioritize control efforts in environments with large numbers of introduced species. PMID- 22938524 TI - Environmental temperatures, physiology and behavior limit the range expansion of invasive Burmese pythons in southeastern USA. AB - A well-established population of Burmese pythons resides in the Everglades of southern Florida. Prompted in part by a report that identified much of southern USA as suitable habitat for expansion or establishment of the Burmese python, we examined the plausibility of this snake to survive winters at sites north of the Everglades. We integrated daily low and high temperatures recorded from October to February from 2005-2011 at Homestead, Orlando and Gainesville, Florida; and Aiken, South Carolina, with minimum temperatures projected for python digestion (16 degrees C), activity (5 degrees C) and survival (0 degrees C). Mean low and high temperatures decreased northward from Homestead to Aiken and the number of days of freezing temperatures increased northward. Digestion was impaired or inhibited for 2 months in the Everglades and up to at least 5 months in Aiken, and activity was increasingly limited northward during these months. Reports of overwinter survivorship document that a single bout of low and freezing temperatures results in python death. The capacity for Burmese pythons to successfully overwinter in more temperate regions of the USA is seemingly prohibited because they lack the behaviors to seek refuge from, and the physiology to tolerate, cold temperatures. As tropical Southeast Asia is the source of the Everglades Burmese pythons, we predict it is unlikely that they will be able to successfully expand to or colonize more temperate areas of Florida and adjoining states due to their lack of behavioral and physiological traits to seek refuge from cold temperatures. PMID- 22938525 TI - Population structure and range expansion: the case of the invasive gastropod Cyclope neritea in northwest Iberian Peninsula. AB - Biotic invasions have a reputation for unpredictable behavior. Here, we report how slight changes in human activity responsible for the introduction and range expansion of a non-native mollusk have led to detectable differences in the genetics of the invasion. Cyclope neritea is a non-predatory gastropod introduced to 2 areas of the European Atlantic: the northwest Iberian Peninsula (NWIP) and the French Atlantic coast (FAC). Shellfish seabed farming is intense in both areas but focuses on different commercial species. Using mitochondrial gene sequences, the lower genetic diversity recorded along the NWIP suggests a more homogeneous range of source populations than in the FAC. Unlike FAC, genetic diversity and haplotype composition in the NWIP correlate with the date of first occurrence of C. neritea at each site rather than with geographical location. Although this pattern evokes the genetic signature expected under a serial founder colonization model from a single initial enclave, a comparison with samples from potential source populations suggests that the NWIP probably experienced several independent reintroductions. The jump dispersal pattern of C. neritea in the NWIP, together with the observation that populations established in the same year are genetically undifferentiated, point to human transport as the most plausible explanation for the current range expansion. Despite evidence for human-mediated dispersal, C. neritea managed to develop a seemingly non random genetic pattern in the NWIP. It is suggested that caution must be exerted when interpreting genetic patterns in invaders. PMID- 22938526 TI - Truth and consequences: the bioinvasion of the Mediterranean Sea. AB - Over 660 alien marine multicellular species have been recorded in the Mediterranean Sea, with many establishing viable populations and subsequently dispersing from their points of entry. A brief overview is presented of the current state of knowledge of bioinvasions in the Mediterranean Sea, with particular attention paid to gelatinous invasive species. A database of alien species records was used to characterize their identity, pattern of expansion and native region, and to discuss the relative importance of different taxa and vectors in the various regions of the sea. The temporal and spatial spread of 4 alien scyphozoans and 2 alien ctenophores is outlined. Although thermophilic species constitute the majority of Mediterranean aliens, Erythrean aliens are predominant in the east, with shipping and mariculture being mainly responsible for introductions in the northwest. The propagule pressure driving the Erythrean invasion is powerful in the establishment and spread of alien species in the eastern Mediterranean. The implications of the enlargement of the Suez Canal, reflecting patterns in global trade and economy, are briefly discussed. Finally, as alien species inventories play a pivotal role in informing regional policy and management decisions and identifying resource priorities, the scientific community is called upon to pay particular attention to their accuracy and veracity. PMID- 22938527 TI - Effects of temperature change on mussel, Mytilus. AB - An increasing body of research has demonstrated the often idiosyncratic responses of organisms to climate-related factors, such as increases in air, sea and land surface temperatures, especially when coupled with non-climatic stressors. This argues that sweeping generalizations about the likely impacts of climate change on organisms and ecosystems are likely less valuable than process-based explorations that focus on key species and ecosystems. Mussels in the genus Mytilus have been studied for centuries, and much is known of their physiology and ecology. Like other intertidal organisms, these animals may serve as early indicators of climate change impacts. As structuring species, their survival has cascading impacts on many other species, making them ecologically important, in addition to their economic value as a food source. Here, we briefly review the categories of information available on the effects of temperature change on mussels within this genus. Although a considerable body of information exists about the genus in general, knowledge gaps still exist, specifically in our ability to predict how specific populations are likely to respond to the effects of multiple stressors, both climate and non-climate related, and how these changes are likely to result in ecosystem-level responses. Whereas this genus provides an excellent model for exploring the effects of climate change on natural and human-managed ecosystems, much work remains if we are to make predictions of likely impacts of environmental change on scales that are relevant to climate adaptation. PMID- 22938528 TI - Prevalence of vitamin D insufficiency and low bone mineral density in elderly Thai nursing home residents. AB - BACKGROUND: Numerous emerging data from research on osteoporosis among Asians found differences from Caucasians. Therefore, the aim of this study was to determine the prevalence of vitamin D insufficiency and osteoporosis in elderly participants from two nursing homes in Thailand, a country located near the equator. METHODS: The subjects of this cross-sectional study comprised 93 elderly Thai women who were living in institutional long-term nursing homes for the aged. Demographic data, daily food and calcium intake, physical activity, and sunlight exposure were measured. Lumbar spine and femoral neck bone mineral density (BMD) and biochemical levels including serum 25 hydroxyvitamin D [25(OH)D] and bone turnover markers were assessed. Vitamin D insufficiency was defined as 25(OH)D level < 70 nmol/l. RESULTS: The mean age of subjects was 75.2 +/- 6.0 (SD) years. Dietary calcium intake was low (322 +/- 158 mg/day) The mean 25(OH)D level was 64.3 +/- 14.9 nmol/L and the prevalence of vitamin D insufficiency was 38.7% (95% CI: 28.8%, 49.4%). There was no correlation between serum 25(OH)D concentrations and age (r = -.11, p = 0.3). The mean BMD of lumbar spine and femoral neck were 0.92 +/- 0.19 and 0.65 +/- 0.10 g/cm2, respectively. Nearly a half of the subjects had osteopenia (44.1%, 95% CI: 33.8%, 54.8%) and osteoporosis (47.3%, 95% CI: 36.9%, 57.9%). Circulating C-terminal telopeptide of type I collagen (CTx) level correlated significantly with both lumbar spine (r = -0.26, p = 0.01) and femoral neck BMD (r = -0.25, p = 0.02). CONCLUSIONS: More than one-third of Thai elderly women residing in nursing homes had vitamin D insufficiency. Almost all nursing home residents had osteoporosis and/or osteopenia. PMID- 22938529 TI - Influence of light, temperature and salinity on dissolved organic carbon exudation rates in Zostera marina L. AB - BACKGROUND: Marine angiosperms, seagrasses, are sentinel species of marine ecosystem health and function. Seagrass carbon budgets provide insight on the minimum requirements needed to maintain this valuable resource. Carbon budgets are a balance between C fixation, growth, storage and loss rates, most of which are well characterized. However, relatively few measurements of dissolved organic carbon (DOC) leaf exudation or rhizodeposition rates exist for most seagrass species. Here I evaluate how eelgrass (Zostera marina L.) DOC exudation is affected by a single factor manipulation (light, temperature or salinity). Eelgrass plants were hydroponically exposed to treatments in experimental chambers (separate leaf and rhizome/root compartments) with artificial seawater medium. Regression analysis of changes in the DOC concentration through time was used to calculate DOC exudation rates. RESULTS: Exudation rates were similar across all treatments in all experiments. For all experiments, pooled leaf DOC exudation ranged between 0.032 and 0.069 mg C gdw-1 h-1, while rhizodeposition ranged between 0.024 and 0.045 mg C gdw-1 h-1. These rates are consistent with previously published values and provide first-order estimates for mechanistic models. CONCLUSIONS: Zostera marina carbon losses from either leaf exudation or rhizodeposition account for a small proportion of gross primary production (1.2 4.6%) and appear to be insensitive to short-term (e.g., hours to days) environmental variations in chamber experiments. Based on these preliminary experiments, I suggest that Z. marina DOC exudation may be a passive process and not an active transport process. PMID- 22938530 TI - Acquired epidermodysplasia verruciformis in a child with atopic dermatitis. AB - A 4-year-old girl with an established diagnosis of atopic dermatitis, previously severe and treated with cyclosporine, developed widespread papules that demonstrated changes consistent with epidermodysplasia verruciformis on biopsy. Human papilloma virus (HPV) typing was performed and was consistent with epidermodysplasia verruciformis-type HPV (type 5). These lesions rapidly resolved with a 2-week course of imiquimod. Rapid resolution and no family history of epidermodysplasia verruciformis make this most consistent with acquired epidermodysplasia verruciformis. This case is the first reported case of acquired epidermodysplasia verruciformis in a child without the human immunodeficiency virus and may be linked to cyclosporine use, which also has never been previously reported. PMID- 22938531 TI - Validation of a computer case definition for sudden cardiac death in opioid users. AB - BACKGROUND: To facilitate the use of automated databases for studies of sudden cardiac death, we previously developed a computerized case definition that had a positive predictive value between 86% and 88%. However, the definition has not been specifically validated for prescription opioid users, for whom out-of hospital overdose deaths may be difficult to distinguish from sudden cardiac death. FINDINGS: We assembled a cohort of persons 30-74 years of age prescribed propoxyphene or hydrocodone who had no life-threatening non-cardiovascular illness, diagnosed drug abuse, residence in a nursing home in the past year, or hospital stay within the past 30 days. Medical records were sought for a sample of 140 cohort deaths within 30 days of a prescription fill meeting the computer case definition. Of the 140 sampled deaths, 81 were adjudicated; 73 (90%) were sudden cardiac deaths. Two deaths had possible opioid overdose; after removing these two the positive predictive value was 88%. CONCLUSIONS: These findings are consistent with our previous validation studies and suggest the computer case definition of sudden cardiac death is a useful tool for pharmacoepidemiologic studies of opioid analgesics. PMID- 22938536 TI - Sickle cell disease severity scoring: a yet unsolved problem. PMID- 22938533 TI - Adipocytokine levels mark endothelial function in normotensive individuals. AB - BACKGROUND: Endothelial dysfunction is an independent risk factor for cardiovascular events. Inflammatory mediators released by the adipose tissue can lead to local insulin resistance and endothelial dysfunction. This study addressed the relationship of adipocytokines with endothelial function and blood pressure. METHODS: In 92 newly diagnosed, drug-naive essential hypertensive patients (HT, mean age 49 yrs) without organ damage and 66 normotensive subjects (NT, mean age 47 yrs), by an automated system, we measured endothelium-dependent and -independent vasodilation as brachial artery flow-mediated dilation before and after administration of glyceryl-trinitrate. Retinol binding protein-4 (RBP4) and resistin levels were determined by ELISA and RIA, respectively. Oxidative stress was evaluated by measuring serum malondyaldehyde (MDA). RESULTS: Flow mediated dilation was significantly (p = 0.03) lower in HT (5.3 +/- 2.6%) than NT (6.1 +/- 3.1%), while response to glyceryl-trinitrate (7.5 +/- 3.7% vs 7.9 +/- 3.4%) was similar. RBP4 (60.6 +/- 25.1 vs 61.3 +/- 25.9 MUg/ml), resistin (18.8 +/- 5.3 vs 19.9 +/- 6.1 ng/ml) and MDA levels (2.39 +/- 1.26 vs 2.08 +/- 1.17 nmol/ml) were not different in HT and NT.RBP4 (r = -0.25; p = 0.04) and resistin levels (r = -0.29; p = 0.03) were related to flow-mediated dilation in NT, but not in HT (r = -0.03 and r = -0.10, respectively). In NT, multivariate analysis including RBP4 and confounders showed that only BMI or waist circumference remained related to flow- mediated dilation. In the multivariate model including resistin and confounders, BMI, age and resistin were significantly related to flow-mediated dilation, while only age significant correlated with this parameter when BMI was replaced by waist circumference. CONCLUSIONS: Adipocytokine levels may be independent predictors of endothelial dysfunction in the peripheral circulation of healthy subjects, providing a pathophysiological link between inflammation from adipose tissue and early vascular alterations. PMID- 22938532 TI - Sequencing and analysis of a South Asian-Indian personal genome. AB - BACKGROUND: With over 1.3 billion people, India is estimated to contain three times more genetic diversity than does Europe. Next-generation sequencing technologies have facilitated the understanding of diversity by enabling whole genome sequencing at greater speed and lower cost. While genomes from people of European and Asian descent have been sequenced, only recently has a single male genome from the Indian subcontinent been published at sufficient depth and coverage. In this study we have sequenced and analyzed the genome of a South Asian Indian female (SAIF) from the Indian state of Kerala. RESULTS: We identified over 3.4 million SNPs in this genome including over 89,873 private variations. Comparison of the SAIF genome with several published personal genomes revealed that this individual shared ~50% of the SNPs with each of these genomes. Analysis of the SAIF mitochondrial genome showed that it was closely related to the U1 haplogroup which has been previously observed in Kerala. We assessed the SAIF genome for SNPs with health and disease consequences and found that the individual was at a higher risk for multiple sclerosis and a few other diseases. In analyzing SNPs that modulate drug response, we found a variation that predicts a favorable response to metformin, a drug used to treat diabetes. SNPs predictive of adverse reaction to warfarin indicated that the SAIF individual is not at risk for bleeding if treated with typical doses of warfarin. In addition, we report the presence of several additional SNPs of medical relevance. CONCLUSIONS: This is the first study to report the complete whole genome sequence of a female from the state of Kerala in India. The availability of this complete genome and variants will further aid studies aimed at understanding genetic diversity, identifying clinically relevant changes and assessing disease burden in the Indian population. PMID- 22938537 TI - Interactive effects of preindustrial, current and future atmospheric CO2 concentrations and temperature on soil fungi associated with two Eucalyptus species. AB - Soil microbial processes have a central role in global fluxes of the key biogenic greenhouse gases and are likely to respond rapidly to climate change. Whether climate change effects on microbial processes lead to a positive or negative feedback for terrestrial ecosystem resilience is unclear. In this study, we investigated the interactive effects of [CO(2)] and temperature on soil fungi associated with faster-growing Eucalyptus saligna and slower-growing Eucalyptus sideroxylon, and fungi that colonised hyphal in-growth bags. Plants were grown in native soil under controlled soil moisture conditions, while subjecting the above ground compartment to defined atmospheric conditions differing in CO(2) concentrations (290, 400, 650 MUL L(-1)) and temperature (26 and 30 degrees C). Terminal restriction fragment length polymorphism and sequencing methods were used to examine effects on the structure of the soil fungal communities. There was no significant effect of host plant or [CO(2)]/temperature treatment on fungal species richness (alpha diversity); however, there was a significant effect on soil fungal community composition (beta diversity) which was strongly influenced by eucalypt species. Interestingly, beta diversity of soil fungi associated with both eucalypt species was significantly influenced by the elevated [CO(2) ]/high temperature treatment, suggesting that the combination of future predicted levels of atmospheric [CO(2)] and projected increases in global temperature will significantly alter soil fungal community composition in eucalypt forest ecosystems, independent of eucalypt species composition. These changes may arise through direct effects of changes in [CO(2)] and temperature on soil fungi or through indirect effects, which is likely the case in this study given the plant-dependent nature of our observations. This study highlights the role of plant species in moderating below-ground responses to future predicted changes to [CO(2)] and temperature and the importance of considering integrated plant-soil system responses. PMID- 22938538 TI - Influence of gallate and pyrogallol moieties on the intestinal absorption of (-) epicatechin and (-)-epicatechin gallate. AB - The cellular accumulation of individual catechins was measured as an index of intestinal absorption to clarify the interactions among catechins. The cellular accumulation of (-)-epicatechin (EC) increased in the presence of other catechins. The ability of gallate catechin such as (-)-epigallocatechin gallate (EGCG) and (-)-epicatechin gallate (ECG) to increase the cellular accumulation of EC was greater than that of nongallate catechins. Gallic acid octyl ester (GAO) also increased the cellular accumulation of EC by 426% as compared with that in untreated cells. Conversely, the cellular accumulation of ECG was not influenced by other catechins, but it increased by 54% in the presence of GAO. Experiments using GAO derivatives indicated that the gallate moiety required the presence of a catechol group and a neighboring carbonyl group, whereas the pyrogallol moiety, without a neighboring carbonyl group, required 3 hydroxyl groups to increase the cellular accumulation of EC. Furthermore, gallate esters required long carbon chains to increase the same. The experiment using EGCG, GAO, or their derivatives indicated that the ability of gallate or pyrogallol moiety to increase the cellular accumulation of EC was restricted by their hydrophobicity. These results suggest that the co-administration of foods containing functional materials such as gallate or pyrogallol moieties, increases the intestinal absorption of catechin. PRACTICAL APPLICATION: The cellular accumulation of (-)-epicatechin increased by the gallate or pyrogallol moiety in catechin structure. The interaction among catechins appeared to affect intestinal absorption of catechin. The bioavailability of catechin may be improved by co-administration of functional foods. PMID- 22938539 TI - Positional adaptability in the design of mutation-resistant nonnucleoside HIV-1 reverse transcriptase inhibitors: a supramolecular perspective. AB - Drug resistance is a key cause of failed treatment of HIV infection. The efficacy of nonnucleoside reverse transcriptase-inhibiting (NNRTI) drugs is impaired by the rapid emergence of drug-resistant mutations. The literature supports the idea that purposefully designed flexible NNRTIs at an active site may help overcome drug resistance. It is proposed here that the usual "lock and key" model, with respect to NNRTI drug design, be expanded to consider creating "master keys" that would automatically adjust conformations to fit all of the "locks" mutations may make. The present work introduces the novel perspective of designing and creating supramolecular assemblies as potential NNRTIs (instead of the relatively more rigid single-molecule inhibitors). Specifically, flexible self-assembling quinhydrone supramolecular dimers formed from quinonoid monomers (designed to be highly flexible NNRTIs themselves) will be offered as a working example of this new perspective in NNRTI drug design. Quinonoid compounds have demonstrated binding interactions at various sites of the HIV-1 RT enzyme, including the elusive ribonuclease H area. Quinhydrone self-organized dimers have at some point in their molecular architecture a noncovalently interacting donor-acceptor ring pair complex. This complex is at the heart of the increased torsional, rotational, and translational motion this species will experience at a particular active site. Flexible supramolecular assemblies, together with their flexible monomer components, may offer a critical advantage in retaining potency against a wide range of drug-resistant HIV-1 RTs. This new supramolecular perspective may also have broader implications in the general field of antimicrobial drug design. PMID- 22938540 TI - Bladder outlet obstruction number: a good indicator of infravesical obstruction in patients with benign prostatic enlargement? AB - The objective of our study was to evaluate bladder outlet obstruction number (BOON) in order to predict infravesical obstruction in patients with benign prostatic enlargement (BPE). Two hundred patients with proven BPE from daily urological practice at the Urology Department of the Sarajevo University Clinical Centre were covered by a prospective study in period 2009-2011. All patients completed International Prostatic Symptom Score, their mean voided volume urine was determined from frequency-volume chart and their prostate volume was determined by transabdominal ultrasound. Subsequently, the patients had free uroflowmetry and they underwent complete urodynamic studies. BOON was calculated using the formula: prostate volume (cc)-3 x Qmax (ml/s)-0.2 x mean voided volume (ml). A satisfactory area under the curve (AUC) was obtained for the prediction of obstruction according to bladder outlet obstruction index, Schaefer obstruction class nomogram and group specific urethral resistance factor , with AUC of 0.83 (p<0.001). Following the comparison of different cut-off values of BOON according to the obstruction, the BOON >-20 has been found to be the most accurate obstruction indicator (sensitivity 76.5% and specificity 68.2%), with posttest probability of 77%. The BOON may be used in daily urological practice as a valid, non-invasive indicator of infravesical obstruction in patients with BPE, with a possibility of correct classification of obstruction in approximately 75% of the cases. Transabdominal ultrasound has shown to be applicable to the BOON formula in determining prostate volume. PMID- 22938541 TI - The comparison of thermal tissue injuries caused by ultrasonic scalpel and electrocautery use in rabbit tongue tissue. AB - The aim of this study compares to the increase in tissue temperature and the thermal histological effects of ultrasonic scalpel, bipolar and unipolar electrosurgery incisions in the tongue tissue of rabbits. This study evaluates the histopathological changes related to thermal change and the maximum temperature values in the peripheral tissue brought about by the incisions carried out by the three methods in a comparative way. To assess thermal tissue damage induced by the three instruments, maximum tissue temperatures were measured during the surgical procedure and tongue tissue samples were examined histopathologically following the surgery. The mean maximum temperature values of the groups were 93.93+/-2.76 Co for the unipolar electrocautery group, whereas 85.07+/-5.95 Co for the bipolar electrocautery group, and 108.23+/-7.64 Co for the ultrasonic scalpel group. There was a statistically significant relationship between the increase in maximum temperature values and the separation among tissue layers, edema, congestion, necrosis, hemorrhage, destruction in blood vessel walls and fibrin accumulation, and between the existence of fibrin thrombus and tissue damage depth (p<0.05). It was concluded that the bipolar electrocautery use gives way to less temperature increase in the tissues and less thermal tissue damage in comparison to the other methods. PMID- 22938542 TI - Hypoxia induces voltage-gated K+ (Kv) channel expression in pulmonary arterial smooth muscle cells through hypoxia-inducible factor-1 (HIF-1). AB - Hypoxia-inducible factor-1 (HIF-1) regulates the expression of hypoxia-inducible genes by binding erythropoietin (EPO) enhancer fragments. Of these genes, HIF-1 upregulates voltage-gated K+1.2 channels (Kv1.2) in rat PC12 cells. Whether HIF-1 regulates hypoxia-induced Kv channel expression in cultured pulmonary artery smooth muscle cells (PASMCs), however, has not been determined. In this study, we investigated the effects of hypoxia on the expression of Kv1.2 Kv1.5, Kv2.1, and Kv9.3 channels in PASMCs and examined the direct role of HIF-1 by transfecting either wild type or mutant EPO enhancer fragments. Our results showed that 18 h exposure to hypoxia significantly increased the expression of Kv1.2, Kv1.5, Kv2.1, and Kv9.3; and this hypoxia-induced upregulation was completely inhibited after transfection with the wild type but not mutant EPO enhancer fragment. These results indicate that HIF-1 regulates hypoxia-stimulated induction of Kv1.2 Kv1.5, Kv2.1, and Kv9.3 channels in cultured PASMCs. PMID- 22938543 TI - Brain natriuretic peptide release in acute myocardial infarction. AB - Brain natriuretic peptide (BNP) is released from ventricular myocites due to their stretching and volume overload. In heart failure there is BNP release. Aim of this study was to observe BNP release in acute myocardial infarction (AMI). We measured BNP in 75 patients with AMI. Control group (n=61) was similar by age and gender to AMI group. We found statistically significant elevation of BNP compared to controls (462.875 pg/ml vs 35.356 pg/ml, p< 0.001). Patients with severe systolic dysfunction had the highest BNP levels, while patients with the preserved systolic function had the lowest BNP levels (Group with EF< 30% BNP= 1129.036 pg/ml vs Group with EF31-40 % BNP= 690.177 pg/ml vs Group with EF 41-50% BNP= 274.396 pg/ml vs Group with EF> 51% BNP= 189.566 pg/ml, p< 0.001). We found statistically significant light positive correlation between BNP and left ventricle end-diastolic diameter (LVDd) (r= 0.246, p<0.05). and real positive correlation between BNP and peak troponin levels (r= 0.441, p < 0.05). BNP levels were higher in anteroseptal allocation of AMI compared to inferior allocation (835.80 pg/ml vs 243.03 pg/ml, p< 0.001) and in patients who were treated with heparin compared to fibrinolitic therapy (507.885 pg/ml vs 354.73 pg/ml, p< 0.05). BNP is elevated in AMI and is a quantitative biochemical marker related to the extent of infarction and the left ventricle systolic dysfunction. Besides echocardiographic calculation, elevation of BNP could be used for quick and easy determination of the left ventricle systolic dysfunction. PMID- 22938544 TI - Analysis of miRNA expression under stress in Arabidopsis thaliana. AB - MicroRNAs (miRNAs) are a class of small, 21-24 nucleotides long, non-coding RNAs involved in the post-transcriptional regulation of gene expression. Using the array analysis on Arabidopsis thaliana infected with the Oil-seed Rape Mosaic Virus (ORMV), we have found 28 up-regulated miRNAs. From them, six were selected for further validation by Northern blot analysis: miRNA172a, miRNA161, miRNA167a&b, miRNA168a&b, miRNA171a, and miRNA159. In addition, 29 miRNAs were detected in plants exposed to drought stress, 13 of those detected miRNAs were up regulated and 16 down-regulated miRNAs. Out of 29 differentially expressed miRNAs during the abiotic stress, six miRNAs (167a&b, 168a&b, 173, 171b&c, 399d and 447c) were chosen for Northern blot and RT-PCR analysis to confirm the array results. Interestingly, four out of these six miRNAs, 171b&c, 168a&b, 399d, and 447c, showed very high abundance of pri-miRNAs and pre-miRNAs. Furthermore, mature forms of miRNAs171b&c, 399d, and 447c, were not detectable in the rosette leaves, indicating that miRNA processing is tissue specific. In conclusion, using the array analysis we show that 28 miRNAs are involved in the plant response to viral infection and 29 miRNAs are involved in the regulation of drought stress. We also demonstrate that at least some miRNAs involved in the stress response in Arabidopsis thaliana are regulated at the maturation level. One such example is miRNA 171b&c. This miRNA is transcribed in all tissues, evidenced by its detected pri and pre-miRNA forms; however, its mature form is constitutively or transiently expressed depending on the tissue type. PMID- 22938545 TI - The effects of Crataegus aronia var. dentata Browicz extract on biochemical indices and apoptosis in partially hepatectomized liver in rats. AB - Crataegus species have been widely used in herbal medicine, especially for the hearth diseases. In the present study, the effect of Crataegus aronia var. dentata Browicz extract on partially hepatectomized rats was investigated with biochemical and TUNEL apoptosis assays. The extracts of the plant at the concentrations of 0.5 and 1 ml/100 g body weight/day were administered orally to the two experimental groups including partially hepatectomized rats for 42 days. At the end of the experimental period, animals were sacrificed, blood was collected for the assessment of serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST) and gamma-glutamyltransferase (GGT), and the liver tissue was used for TUNEL assay. In biochemical assay, it was found a significant decrease in the levels of serum ALT and AST in the experimental groups. On the other hand, the plant extract did not cause any significant changes in the level of GGT in these groups. In apoptosis assay, TUNEL positive hepatocytes could not be detected in both experimental groups. The present findings can suggest that Crataegus aronia var. dentata Browicz extract can decrease the levels of serum ALT and AST and play a role in apoptosis of hepatocytes in the liver of partially hepatectomized rats. However, further studies are required to confirm the effects of the plant extract on hepatoprotection and apoptosis in the regenerating liver after partial hepatectomy in animal models. PMID- 22938546 TI - Persistent submacular fluid diagnosed with optical coherence tomography after successful scleral buckle surgery for macula-off retinal detachment. AB - Crataegus species have been widely used in herbal medicine, especially for the hearth diseases. In the present study, the effect of Crataegus aronia var. dentata Browicz extract on partially hepatectomized rats was investigated with biochemical and TUNEL apoptosis assays. The extracts of the plant at the concentrations of 0.5 and 1 ml/100 g body weight/day were administered orally to the two experimental groups including partially hepatectomized rats for 42 days. At the end of the experimental period, animals were sacrificed, blood was collected for the assessment of serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST) and gamma-glutamyltransferase (GGT), and the liver tissue was used for TUNEL assay. In biochemical assay, it was found a significant decrease in the levels of serum ALT and AST in the experimental groups. On the other hand, the plant extract did not cause any significant changes in the level of GGT in these groups. In apoptosis assay, TUNEL positive hepatocytes could not be detected in both experimental groups. The present findings can suggest that Crataegus aronia var. dentata Browicz extract can decrease the levels of serum ALT and AST and play a role in apoptosis of hepatocytes in the liver of partially hepatectomized rats. However, further studies are required to confirm the effects of the plant extract on hepatoprotection and apoptosis in the regenerating liver after partial hepatectomy in animal models. PMID- 22938547 TI - Mitochondrial DNA 4977 bp deletion is a common phenomenon in hair and increases with age. AB - Mitochondrial DNA (mtDNA) is believed to be particularly susceptible to oxidative damage during aging, resulting in mtDNA point mutations, duplications, and deletions. Although mtDNA deletions have been reported in various human tissues, e.g., the brain, heart, and skeletal muscle, little is known about the occurrence in hair. Therefore, we screened for the presence of mtDNA 13162 bp, 10422 bp, 7663 bp, 7436 bp, 4989 bp, and 4977 bp deletions in 90 hair samples from subjects aged 5 days to 91 years by using polymerase chain reaction (PCR) and investigated the deletion load by TaqMan probe-based real-time PCR. We detected the mtDNA 4977 bp deletion in hair samples, but none of the other deletions that were screened for. The proportion of mtDNA 4977 deletion carriers was 98.3% (89/90) and the deletion loads increased from 0 to 1.436 +/- 0.2086% of the total mtDNA with an exponential increase with age (r = 0.677, p < 0.05). These results suggest that mtDNA 4977 bp deletion is a common phenomenon in hair and increases with age. These findings expand our understanding of the tissue-specific distribution of mtDNA deletions. PMID- 22938548 TI - Gait disorder rehabilitation using vision and non-vision based sensors: a systematic review. AB - Even though the amount of rehabilitation guidelines has never been greater, uncertainty continues to arise regarding the efficiency and effectiveness of the rehabilitation of gait disorders. This question has been hindered by the lack of information on accurate measurements of gait disorders. Thus, this article reviews the rehabilitation systems for gait disorder using vision and non-vision sensor technologies, as well as the combination of these. All papers published in the English language between 1990 and June, 2012 that had the phrases "gait disorder", "rehabilitation", "vision sensor", or "non vision sensor" in the title, abstract, or keywords were identified from the SpringerLink, ELSEVIER, PubMed, and IEEE databases. Some synonyms of these phrases and the logical words "and", "or", and "not" were also used in the article searching procedure. Out of the 91 published articles found, this review identified 84 articles that described the rehabilitation of gait disorders using different types of sensor technologies. This literature set presented strong evidence for the development of rehabilitation systems using a markerless vision-based sensor technology. We therefore believe that the information contained in this review paper will assist the progress of the development of rehabilitation systems for human gait disorders. PMID- 22938549 TI - Interdigitating dendritic cell sarcoma of the liver and lung: a case report with morphohological and immunohistochemical features of tumor. AB - Interdigitating dendritic cell sarcoma is extremely rare neoplasm that mainly occurs in the lymph nodes. Only 45 cases have been reported in the literature to date. We report a case of this sarcoma arising from the liver and lung, a previosly unreported site for this neoplasm. An 19-year-old girl deteriorated rapidly after artificial abortion and died 4 weeks later. Autopsy showed markedly enlarged liver and lung with numerous nodules up to 0.5 centimeters in diameter. Microscopically, nodules was composed of large pleomorphic cells that were immunohistochemically positive for proteins S-100 and vimentin, some of them expressed positivity to fascin and CD 68, with a rich small CD3 positive T lymphocytic infiltrateite around them. Based of these findings, the present case was diagnosed as interdigitating dendritic cell sarcoma, a neoplasm that remains a diagnostic and clinical challenge, because it can mimic a wide variety of other malignant tumors and tumor-like lesions. PMID- 22938550 TI - Surgical management of Charcot spinal arthropathy: a single-center retrospective series highlighting the evolution of management. AB - OBJECT: Charcot spinal arthropathy (CSA) is an uncommon disorder that occurs in the setting of conditions with decreased protective sensation of the vertebral column, resulting in vertebral joint degeneration, pain, and deformity. Historically, CSA treatment has been fraught with high failure rates. Over time, the authors' institution has trended toward a CSA treatment paradigm of intralesional debridement, circumferential fusion, and four-rod lumbopelvic fixation. As such, the overall objectives of this study were to define the specific clinical characteristics of this rare condition and to determine whether the authors' treatment paradigm has decreased the incidence of revision due to hardware failure/presumed pseudarthrosis or the development of a new CSA over the course of the study and in comparison with historical controls. METHODS: The authors performed a retrospective review of the clinical and radiographic records for all patients with CSA treated by the Spine Service at the University of Washington between 1997 and 2009. RESULTS: Twenty-three patients with CSA were identified. The mean age at presentation was 43.1 years, and the mean latency between spinal cord injury and CSA diagnosis was 19.6 years. The mean follow-up was 33.1 months. Pain and progressive deformity were the major presenting symptoms. Concomitant infection was identified in 17% of patients. Patients with CSA were noted to have long initial fusion constructs spanning an average of 8.4 vertebral levels. Charcot spinal arthropathy did not occur above the level of neurological injury. The vast majority of CSA cases occurred caudally along the spinal axis, with 65% occurring within 1 level of the caudal end of the index fusion construct and 35% occurring even farther distally. Revision due to hardware failure or the development of a new CSA level occurred in 35% of patients. Rates of treatment failure requiring revision significantly decreased over the course of the study, with revision occurring in 6 (66%) of 9 patients who underwent surgery before 2002, in comparison with only 2 (14%) of 14 treated between 2002 and 2009. During a mean follow-up period of 34 months, no treatment revision occurred in the subgroup of 9 patients who underwent four-rod lumbopelvic fixation. CONCLUSIONS: This study represents the largest reported modern surgical series of CSA patients. While revision rates were initially high and comparable to previous reports, the authors' multimodal treatment paradigm, which includes the use of bone morphogenetic protein and four-rod lumbopelvic fixation, dramatically reduced the incidence of treatment failure requiring revision over the course of the study period and represents a significant improvement in the treatment of CSA. PMID- 22938551 TI - Outcomes after surgery for spinal metastatic leiomyosarcoma. AB - OBJECT: Leiomyosarcoma is a smooth-muscle sarcoma that rarely metastasizes to the spine. Its clinical course is variable, although patients with metastatic leiomyosarcoma can experience prolonged survival as compared with patients with more aggressive metastatic tumors. The authors report their single-institution experience in the surgical treatment of patients with leiomyosarcoma metastatic to the spine. METHODS: A retrospective review of the electronic medical records was performed to obtain details on clinical management and outcomes for patients who had undergone surgical intervention for metastatic leiomyosarcoma of the spine. The few articles available in the current literature on this topic were also analyzed. RESULTS: Eight patients with metastatic leiomyosarcoma of the spine underwent surgical management between 2005 and 2011. Six patients (75%) had improvement in their Nurick grade. Patients who had presented with pain as a primary symptom experienced significant relief. Five patients (63%) had lesion recurrence, and 4 underwent repeat surgery at a mean of 10.2 months after their initial surgery. The mean duration of survival was 11.7 months (range 3.3-23.0 months). CONCLUSIONS: Leiomyosarcoma rarely metastasizes to the spine. However, surgical intervention can relieve pain and improve neurological function. Given the potential for prolonged survival, aggressive management should be considered in well-selected patients. PMID- 22938552 TI - Long-term results after posterior fossa decompression in syringomyelia with adult Chiari Type I malformation. AB - OBJECT: There is little information about the long-term effectiveness and complications following decompressive surgery for syringomyelia related to Chiari malformation Type I (CM-I). METHODS: Examining long-term clinical and radiological follow-up, the authors studied a mixed retrospective and prospective single-institution cohort of 109 consecutive surgically treated adult patients with syringomyelia and CM-I. All patients underwent a standardized surgical protocol: decompression of the craniocervical junction, arachnoid exploration, and shrinkage of the cerebellar tonsils. Factors predicting outcome were investigated. RESULTS: The retrospective arm consisted of 41 cases treated between 1990 and 1994, and the prospective arm comprised 68 patients treated between 1994 and 2001. The mean overall age was 45.9 years, and 58.8% of the population was female. The median follow-up period was 12.7 years. The most frequent initial symptoms were pain and sensory and gait disturbances. There was no perioperative death or neurological deterioration. The comprehensive perioperative complication rate was approximately 11%, with 3 cases (2.7%) of CSF leakage. Regression analysis showed that the best combination of clinical and radiological outcome predictors was age and duration of symptoms. Clinical follow up confirmed surgical result stability with clinical improvement of greater than 90% of the spinal and cranial manifestations over a long-term period. Two patients had radiological recurrences of syringomyelia without clinical signs 85 and 124 months after surgery. CONCLUSIONS: Certain clinical predictors of poor clinical and radiological prognosis were identified-namely, age at time of surgery and symptom duration. The results of the study provide additional long term data that support the effectiveness and safety of relieving CSF block at the craniocervical junction in CM-I-related syringomyelia. PMID- 22938553 TI - Union rates and prognostic variables of osteoporotic vertebral fractures treated with a rigid external support. AB - OBJECT: External supports serve as a traditional treatment option for osteoporotic vertebral fractures (OVFs). However, the role of external supports in the treatment of OVF remains inconclusive. The purpose of this study was to determine the role of a rigid external support in the healing of OVFs by prospectively evaluating union (fracture settling) rates and prognostic variables for patients suffering from an incident OVF. METHODS: Fifty-five patients with acute back pain were enrolled in this study after being diagnosed with an OVF based on MRI findings. Patients were treated using a plastic thoracolumbosacral orthosis (TLSO) and underwent follow-up at 2, 3, and 6 months. Vertebrae were referred to as "settled" when there was no dynamic mobility on sitting lateral and supine lateral radiographs. At the time of the 3- and 6-month follow-up visits, the patients were divided into 2 groups, the "settled group" and the "unsettled group." Patients in these groups were compared with regard to clinical and radiographic features. RESULTS: Of the 55 patients enrolled, 53 patients were followed up for 6 months. There were 14 men and 39 women with an average age of 75.3 years. Fracture settling of the affected vertebra was defined in 54.7% of the patients at 2 months, in 79.2% at 3 months, and in 88.7% at 6 months. All 5 components of the Japanese Orthopaedic Association Back Pain Evaluation Questionnaire improved significantly both at 3 months and 6 months. Patients in the unsettled group exhibited a statistically greater likelihood of having fractures at the thoracolumbar junction, Type A3 fractures, and fractures with a diffuse low-intensity area on T2-weighted MRI studies at 3 months. In contrast, at 6 months, the only statistically significant difference between the groups was patient age. CONCLUSIONS: The biomechanical disadvantages of OVFs (location, type, and size) adversely influencing the fracture healing were overcome by the treatment using a TLSO within 6 months. The authors' findings show that a TLSO plays a biomechanical role in the healing of OVFs. PMID- 22938554 TI - Lordosis restoration after anterior longitudinal ligament release and placement of lateral hyperlordotic interbody cages during the minimally invasive lateral transpsoas approach: a radiographic study in cadavers. AB - OBJECT: In the surgical treatment of spinal deformities, the importance of restoring lumbar lordosis is well recognized. Smith-Petersen osteotomies (SPOs) yield approximately 10 degrees of lordosis per level, whereas pedicle subtraction osteotomies result in as much as 30 degrees increased lumbar lordosis. Recently, selective release of the anterior longitudinal ligament (ALL) and placement of lordotic interbody grafts using the minimally invasive lateral retroperitoneal transpsoas approach (XLIF) has been performed as an attempt to increase lumbar lordosis while avoiding the morbidity of osteotomy. The objective of the present study was to measure the effect of the selective release of the ALL and varying degrees of lordotic implants placed using the XLIF approach on segmental lumbar lordosis in cadaveric specimens between L-1 and L-5. METHODS: Nine adult fresh-frozen cadaveric specimens were placed in the lateral decubitus position. Lateral radiographs were obtained at baseline and after 4 interventions at each level as follows: 1) placement of a standard 10 degrees lordotic cage, 2) ALL release and placement of a 10 degrees lordotic cage, 3) ALL release and placement of a 20 degrees lordotic cage, and 4) ALL release and placement of a 30 degrees lordotic cage. All four cages were implanted sequentially at each interbody level between L-1 and L-5. Before and after each intervention, segmental lumbar lordosis was measured in all specimens at each interbody level between L-1 and L-5 using the Cobb method on lateral radiography. RESULTS: The mean baseline segmental lordotic angles at L1-2, L2-3, L3-4, and L4-5 were -3.8 degrees , 3.8 degrees , 7.8 degrees , and 22.6 degrees , respectively. The mean lumbar lordosis was 29.4 degrees . Compared with baseline, the mean postimplantation increase in segmental lordosis in all levels combined was 0.9 degrees in Intervention 1 (10 degrees cage without ALL release); 4.1 degrees in Intervention 2 (ALL release with 10 degrees cage); 9.5 degrees in Intervention 3 (ALL release with 20 degrees cage); and 11.6 degrees in Intervention 4 (ALL release with 30 degrees cage). Foraminal height in the same sequence of conditions increased by 6.3%, 4.6%, 8.8% and 10.4%, respectively, while central disc height increased by 16.1%, 22.3%, 52.0% and 66.7%, respectively. Following ALL release and placement of lordotic cages at all 4 lumbar levels, the average global lumbar lordosis increase from preoperative lordosis was 3.2 degrees using 10 degrees cages, 12.0 degrees using 20 degrees cages, and 20.3 degrees using 30 degrees cages. Global lumbar lordosis with the cages at 4 levels exhibited a negative correlation with preoperative global lordosis (10 degrees , R = -0.756; 20 degrees , -0.730; and 30 degrees , R = 0.437). CONCLUSIONS: Combined ALL release and placement of increasingly lordotic lateral interbody cages leads to progressive gains in segmental lordosis in the lumbar spine. Mean global lumbar lordosis similarly increased with increasingly lordotic cages, although the effect with a single cage could not be evaluated. Greater global lordosis was achieved with smaller preoperative lordosis. The mean maximum increase in segmental lordosis of 11.6 degrees followed ALL release and placement of the 30 degrees cage. PMID- 22938555 TI - Hyperglycosylation prolongs the circulation of coagulation factor IX. PMID- 22938556 TI - The life cycle and immature stages of Kallima albofasciata, the endemic Oakleaf, in the Andaman Islands (Indian Ocean, Bay of Bengal). AB - Kallima albofasciata Moore 1877 (Lepidoptera: Nymphalidae), a species of Oakleaf butterfly reported for the first time from the Andaman Islands in 1874, was recognized as an insular endemic in 1877. Studies so far indicate that it is restricted to the contiguous islands of South and Middle Andamans. On these islands it apparently has a very localized distribution, giving rise to fears that it may be vulnerable and could face the threat of extinction with increasing developmental pressures on its habitat. Though it was reported to be extinct in 1993, its presence has since been documented and is currently protected by law in India. Nevertheless, nothing is known about the immature stages, its larval food plants or life history, and very little is known about its habitat and periods of occurrence on the islands. Here, details of all these aspects of this little known butterfly of the Andaman Islands are presented. This should prove useful in the formulation of a conservation strategy for this iconic Oriental butterfly. PMID- 22938558 TI - Computational modeling of the regulatory network organizing the wound response in Arabidopsis thaliana. AB - Plants are frequently wounded by mechanical impact or by insects, and their ability to adequately respond to wounding is essential for their survival and reproductive success. The wound response is mediated by a signal transduction and regulatory network. Molecular studies in Arabidopsis have identified the COI1 gene as a central component of this network. Current models of these networks qualitatively describe the wound response, but they are not directly assessed using quantitative gene expression data. We built a model comprising the key components of the Arabidopsis wound response using the transsys framework. For comparison, we constructed a null model that is devoid of any regulatory interactions, and various alternative models by rewiring the wound response model. All models were parametrized by computational optimization to generate synthetic gene expression profiles that approximate the empirical data set. We scored the fit of the synthetic to the empirical data with various distance measures, and used the median distance after optimization to directly and quantitatively assess the wound response model and its alternatives. Discrimination of candidate models depends substantially on the measure of gene expression profile distance. Using the null model to assess quality of the distance measures for discrimination, we identify correlation of log-ratio profiles as the most suitable distance. Our wound response model fits the empirical data significantly better than the alternative models. Gradual perturbation of the wound response model results in a corresponding gradual decline in fit. The optimization approach provides insights into biologically relevant features, such as robustness. It is a step toward enabling integrative studies of multiple cross-talking pathways, and thus may help to develop our understanding how the genome informs the mapping of environmental signals to phenotypic traits. PMID- 22938559 TI - Evolution and analysis of genetic networks for stable cellular growth and regeneration. AB - A computational model is presented that simulates stable growth of cellular structures that are in some cases capable of regeneration. In the model, cellular growth is governed by a gene regulatory network. By evolving the parameters and structure of the genetic network using a modified evolution strategy, a dynamically stable state can be achieved in the developmental process, where cell proliferation and cell apoptosis reach an equilibrium. The results of evolution with different setups in fitness evaluation during the development are compared with respect to their regeneration capability as well as their gene regulatory network structure. Network motifs responsible for stable growth and regeneration that emerged from the evolution are also analyzed. We expect that our findings can help to gain a better understanding of the process of growth and regeneration inspired by biological systems, in order to solve complex engineering problems, such as the design of self-healing materials. PMID- 22938560 TI - Wains: a pattern-seeking artificial life species. AB - We describe the initial phase of a research project to develop an artificial life framework designed to extract knowledge from large data sets with minimal preparation or ramp-up time. In this phase, we evolved an artificial life population with a new brain architecture. The agents have sufficient intelligence to discover patterns in data and to make survival decisions based on those patterns. The species uses diploid reproduction, Hebbian learning, and Kohonen self-organizing maps, in combination with novel techniques such as using pattern rich data as the environment and framing the data analysis as a survival problem for artificial life. The first generation of agents mastered the pattern discovery task well enough to thrive. Evolution further adapted the agents to their environment by making them a little more pessimistic, and also by making their brains more efficient. PMID- 22938561 TI - Evolving Boolean networks with structural dynamism. AB - This short article presents an abstract, tunable model of genomic structural change within the cell life cycle and explores its use with simulated evolution. A well-known Boolean model of genetic regulatory networks is extended to include changes in node connectivity based upon the current cell state to begin to capture some of the effects of transposable elements. The evolvability of such networks is explored using a version of the NK model of fitness landscapes with both synchronous and asynchronous updating. Structural dynamism is found to be selected for in nonstationary environments with both update schemes and subsequently shown capable of providing a mechanism for evolutionary innovation when such reorganizations are inherited. This is also found to be the case in stationary environments with asynchronous updating. PMID- 22938557 TI - A systematic review of reliability and objective criterion-related validity of physical activity questionnaires. AB - Physical inactivity is one of the four leading risk factors for global mortality. Accurate measurement of physical activity (PA) and in particular by physical activity questionnaires (PAQs) remains a challenge. The aim of this paper is to provide an updated systematic review of the reliability and validity characteristics of existing and more recently developed PAQs and to quantitatively compare the performance between existing and newly developed PAQs.A literature search of electronic databases was performed for studies assessing reliability and validity data of PAQs using an objective criterion measurement of PA between January 1997 and December 2011. Articles meeting the inclusion criteria were screened and data were extracted to provide a systematic overview of measurement properties. Due to differences in reported outcomes and criterion methods a quantitative meta-analysis was not possible.In total, 31 studies testing 34 newly developed PAQs, and 65 studies examining 96 existing PAQs were included. Very few PAQs showed good results on both reliability and validity. Median reliability correlation coefficients were 0.62-0.71 for existing, and 0.74-0.76 for new PAQs. Median validity coefficients ranged from 0.30-0.39 for existing, and from 0.25-0.41 for new PAQs.Although the majority of PAQs appear to have acceptable reliability, the validity is moderate at best. Newly developed PAQs do not appear to perform substantially better than existing PAQs in terms of reliability and validity. Future PAQ studies should include measures of absolute validity and the error structure of the instrument. PMID- 22938562 TI - Corpus-based intention recognition in cooperation dilemmas. AB - Intention recognition is ubiquitous in most social interactions among humans and other primates. Despite this, the role of intention recognition in the emergence of cooperative actions remains elusive. Resorting to the tools of evolutionary game theory, herein we describe a computational model showing how intention recognition coevolves with cooperation in populations of self-regarding individuals. By equipping some individuals with the capacity of assessing the intentions of others in the course of a prototypical dilemma of cooperation-the repeated prisoner's dilemma-we show how intention recognition is favored by natural selection, opening a window of opportunity for cooperation to thrive. We introduce a new strategy (IR) that is able to assign an intention to the actions of opponents, on the basis of an acquired corpus consisting of possible plans achieving that intention, as well as to then make decisions on the basis of such recognized intentions. The success of IR is grounded on the free exploitation of unconditional cooperators while remaining robust against unconditional defectors. In addition, we show how intention recognizers do indeed prevail against the best known successful strategies of iterated dilemmas of cooperation, even in the presence of errors and reduction of fitness associated with a small cognitive cost for performing intention recognition. PMID- 22938563 TI - An enhanced hypercube-based encoding for evolving the placement, density, and connectivity of neurons. AB - Intelligence in nature is the product of living brains, which are themselves the product of natural evolution. Although researchers in the field of neuroevolution (NE) attempt to recapitulate this process, artificial neural networks (ANNs) so far evolved through NE algorithms do not match the distinctive capabilities of biological brains. The recently introduced hypercube-based neuroevolution of augmenting topologies (HyperNEAT) approach narrowed this gap by demonstrating that the pattern of weights across the connectivity of an ANN can be generated as a function of its geometry, thereby allowing large ANNs to be evolved for high dimensional problems. Yet the positions and number of the neurons connected through this approach must be decided a priori by the user and, unlike in living brains, cannot change during evolution. Evolvable-substrate HyperNEAT (ES HyperNEAT), introduced in this article, addresses this limitation by automatically deducing the node geometry from implicit information in the pattern of weights encoded by HyperNEAT, thereby avoiding the need to evolve explicit placement. This approach not only can evolve the location of every neuron in the network, but also can represent regions of varying density, which means resolution can increase holistically over evolution. ES-HyperNEAT is demonstrated through multi-task, maze navigation, and modular retina domains, revealing that the ANNs generated by this new approach assume natural properties such as neural topography and geometric regularity. Also importantly, ES-HyperNEAT's compact indirect encoding can be seeded to begin with a bias toward a desired class of ANN topographies, which facilitates the evolutionary search. The main conclusion is that ES-HyperNEAT significantly expands the scope of neural structures that evolution can discover. PMID- 22938564 TI - Abundance, species composition of microzooplankton from the coastal waters of Port Blair, South Andaman Island. AB - BACKGROUND: Microzooplankton consisting of protists and metazoa <200 MUm. It displays unique feeding mechanisms and behaviours that allow them to graze cells up to five times their own volume. They can grow at rates which equal or exceed prey growth and can serve as a viable food source for metazoans. Moreover, they are individually inconspicuous, their recognition as significant consumers of oceanic primary production. The microzooplankton can be the dominant consumers of phytoplankton production in both oligo- and eutrophic regions of the ocean and are capable of consuming >100% of primary production. RESULTS: The microzooplankton of the South Andaman Sea were investigated during September 2011 to January 2012. A total of 44 species belong to 19 genera were recorded in this study. Tintinnids made larger contribution to the total abundance (34%) followed in order by dinoflagellates (24%), ciliates (20%) and copepod nauplii (18%). Foraminifera were numerically less (4%). Tintinnids were represented by 20 species belong to 13 genera, Heterotrophic dinoflagellates were represented by 17 species belong to 3 genera and Ciliates comprised 5 species belong to 3 genera. Eutintinus tineus, Tintinnopsis cylindrical, T. incertum, Protoperidinium divergens, Lomaniella oviformes, Strombidium minimum were the most prevalent microzooplankton. Standing stock of tintinnids ranged from 30-80 cells.L-1 and showed a reverse distribution with the distribution of chlorophyll a relatively higher species diversity and equitability was found in polluted harbour areas. CONCLUSIONS: The change of environmental variability affects the species composition and abundance of microzooplankton varied spatially and temporarily. The observations clearly demonstrated that the harbor area differed considerably from other area in terms of species present and phytoplankton biomass. Further, the phytoplankton abundance is showed to be strongly influenced by tintinnid with respect to the relationship of prey-predator. Consequently, further investigation on microzooplankton grazing would shed light on food web dynamics. PMID- 22938565 TI - Use of a United States-based laboratory as a hematopathology reference center for a developing country: logistics and results. AB - INTRODUCTION: With proper logistical support and sponsorship, a laboratory in an industrialized nation might be able to act as a reference laboratory for clinicians based in a developing country. METHODS: We built on previous experience in the clinical laboratory to see whether a specialized histopathology service (hematopathology) could be provided to a developing country without the expertise or experience to do it in country. RESULTS: Over an 13-year period, 582 cases from 579 individuals were analyzed. Principal pathologic findings included acute leukemia in 84 cases (14%), dyspoiesis in one or more of the hematopoietic lineages in 65 cases (11%, including three cases with high-grade myelodysplasia), 23 cases (4%) with findings suspicious for a chronic myeloproliferative disorder, 35 cases (6%) with findings suspicious for a lymphoproliferative disorder, and infectious organisms (presumably Leishmania in most instances) in 9 (1%) of cases. Specimens from 45 cases (8%) were unsatisfactory owing to extreme hemodilution and/or specimen degeneration. CONCLUSION: With proper support, a medical laboratory in an industrialized nation may serve as a reference facility for a developing nation. The use of existing infrastructure may be remarkably effective to achieve optimal turnaround time. Although the lack of ancillary studies and follow-up biopsies limit the ability to achieve a definitive diagnosis in many cases, this must be viewed in the context of the limited ability to diagnose or manage hematopoietic neoplasia in developing nations. PMID- 22938567 TI - Synthesis of fluorenone derivatives through Pd-catalyzed dehydrogenative cyclization. AB - Palladium-catalyzed dual C-H functionalization of benzophenones to form fluorenones by oxidative dehydrogenative cyclization is reported. This method provides a concise and effective route toward the synthesis of fluorenone derivatives, which shows outstanding functional group compatibility. PMID- 22938566 TI - Size and location of defects at the coupling interface affect lithotripter performance. AB - Study Type--Therapy (case series) Level of Evidence 4. What's known on the subject? and What does the study add? In shock wave lithotripsy air pockets tend to get caught between the therapy head of the lithotripter and the skin of the patient. Defects at the coupling interface hinder the transmission of shock wave energy into the body, reducing the effectiveness of treatment. This in vitro study shows that ineffective coupling not only blocks the transmission of acoustic pulses but also alters the properties of shock waves involved in the mechanisms of stone breakage, with the effect dependent on the size and location of defects at the coupling interface. OBJECTIVE: * To determine how the size and location of coupling defects caught between the therapy head of a lithotripter and the skin of a surrogate patient (i.e. the acoustic window of a test chamber) affect the features of shock waves responsible for stone breakage. MATERIALS AND METHODS: * Model defects were placed in the coupling gel between the therapy head of a Dornier Compact-S electromagnetic lithotripter (Dornier MedTech, Kennesaw, GA, USA) and the Mylar (biaxially oriented polyethylene terephthalate) (DuPont Teijin Films, Chester, VA, USA) window of a water-filled coupling test system. * A fibre-optic probe hydrophone was used to measure acoustic pressures and map the lateral dimensions of the focal zone of the lithotripter. * The effect of coupling conditions on stone breakage was assessed using gypsum model stones. RESULTS: * Stone breakage decreased in proportion to the area of the coupling defect; a centrally located defect blocking only 18% of the transmission area reduced stone breakage by an average of almost 30%. * The effect on stone breakage was greater for defects located on-axis and decreased as the defect was moved laterally; an 18% defect located near the periphery of the coupling window (2.0 cm off-axis) reduced stone breakage by only ~15% compared to when coupling was completely unobstructed. * Defects centred within the coupling window acted to narrow the focal width of the lithotripter; an 8.2% defect reduced the focal width ~30% compared to no obstruction (4.4 mm vs 6.5 mm). * Coupling defects located slightly off centre disrupted the symmetry of the acoustic field; an 18% defect positioned 1.0 cm off-axis shifted the focus of maximum positive pressure ~1.0 mm laterally. * Defects on and off-axis imposed a significant reduction in the energy density of shock waves across the focal zone. CONCLUSIONS: * In addition to blocking the transmission of shock-wave energy, coupling defects also disrupt the properties of shock waves that play a role in stone breakage, including the focal width of the lithotripter and the symmetry of the acoustic field * The effect is dependent on the size and location of defects, with defects near the centre of the coupling window having the greatest effect. * These data emphasize the importance of eliminating air pockets from the coupling interface, particularly defects located near the centre of the coupling window. PMID- 22938568 TI - Mapping vulnerability to climate change and its repercussions on human health in Pakistan. AB - BACKGROUND: Pakistan is highly vulnerable to climate change due to its geographic location, high dependence on agriculture and water resources, low adaptive capacity of its people, and weak system of emergency preparedness. This paper is the first ever attempt to rank the agro-ecological zones in Pakistan according to their vulnerability to climate change and to identify the potential health repercussions of each manifestation of climate change in the context of Pakistan. METHODS: A climate change vulnerability index is constructed as an un-weighted average of three sub-indices measuring (a) the ecological exposure of each region to climate change, (b) sensitivity of the population to climate change and (c) the adaptive capacity of the population inhabiting a particular region. The regions are ranked according to the value of this index and its components. Since health is one of the most important dimensions of human wellbeing, this paper also identifies the potential health repercussions of each manifestations of climate change and links it with the key manifestations of climate change in the context of Pakistan. RESULTS: The results indicate that Balochistan is the most vulnerable region with high sensitivity and low adaptive capacity followed by low intensity Punjab (mostly consisting of South Punjab) and Cotton/Wheat Sindh. The health risks that each of these regions face depend upon the type of threat that they face from climate change. Greater incidence of flooding, which may occur due to climate variability, poses the risk of diarrhoea and gastroenteritis; skin and eye Infections; acute respiratory infections; and malaria. Exposure to drought poses the potential health risks in the form of food insecurity and malnutrition; anaemia; night blindness; and scurvy. Increases in temperature pose health risks of heat stroke; malaria; dengue; respiratory diseases; and cardiovascular diseases. CONCLUSION: The study concludes that geographical zones that are more exposed to climate change in ecological and geographic terms- such as Balochistan, Low-Intensity Punjab, and Cotton-Wheat Sindh -also happen to be the most deprived regions in Pakistan in terms of socio-economic indicators, suggesting that the government needs to direct its efforts to the socio-economic uplift of these lagging regions to reduce their vulnerability to the adverse effects of climate change. PMID- 22938569 TI - Multi-walled carbon nanotubes translocate into the pleural cavity and induce visceral mesothelial proliferation in rats. AB - Multi-walled carbon nanotubes have a fibrous structure similar to asbestos and induce mesothelioma when injected into the peritoneal cavity. In the present study, we investigated whether carbon nanotubes administered into the lung through the trachea induce mesothelial lesions. Male F344 rats were treated with 0.5 mL of 500 MUg/mL suspensions of multi-walled carbon nanotubes or crocidolite five times over a 9-day period by intrapulmonary spraying. Pleural cavity lavage fluid, lung and chest wall were then collected. Multi-walled carbon nanotubes and crocidolite were found mainly in alveolar macrophages and mediastinal lymph nodes. Importantly, the fibers were also found in the cell pellets of the pleural cavity lavage, mostly in macrophages. Both multi-walled carbon nanotube and crocidolite treatment induced hyperplastic proliferative lesions of the visceral mesothelium, with their proliferating cell nuclear antigen indices approximately 10-fold that of the vehicle control. The hyperplastic lesions were associated with inflammatory cell infiltration and inflammation-induced fibrotic lesions of the pleural tissues. The fibers were not found in the mesothelial proliferative lesions themselves. In the pleural cavity, abundant inflammatory cell infiltration, mainly composed of macrophages, was observed. Conditioned cell culture media of macrophages treated with multi-walled carbon nanotubes and crocidolite and the supernatants of pleural cavity lavage fluid from the dosed rats increased mesothelial cell proliferation in vitro, suggesting that mesothelial proliferative lesions were induced by inflammatory events in the lung and pleural cavity and likely mediated by macrophages. In conclusion, intrapulmonary administration of multi-walled carbon nanotubes, like asbestos, induced mesothelial proliferation potentially associated with mesothelioma development. PMID- 22938570 TI - Combined metabolic engineering of precursor and co-factor supply to increase alpha-santalene production by Saccharomyces cerevisiae. AB - BACKGROUND: Sesquiterpenes are a class of natural products with a diverse range of attractive industrial proprieties. Due to economic difficulties of sesquiterpene production via extraction from plants or chemical synthesis there is interest in developing alternative and cost efficient bioprocesses. The hydrocarbon alpha-santalene is a precursor of sesquiterpenes with relevant commercial applications. Here, we construct an efficient Saccharomyces cerevisiae cell factory for alpha-santalene production. RESULTS: A multistep metabolic engineering strategy targeted to increase precursor and cofactor supply was employed to manipulate the yeast metabolic network in order to redirect carbon toward the desired product. To do so, genetic modifications were introduced acting to optimize the farnesyl diphosphate branch point, modulate the mevalonate pathway, modify the ammonium assimilation pathway and enhance the activity of a transcriptional activator. The approach employed resulted in an overall alpha santalene yield of a 0.0052 Cmmol (Cmmol glucose)(-1) corresponding to a 4-fold improvement over the reference strain. This strategy, combined with a specifically developed continuous fermentation process, led to a final alpha santalene productivity of 0.036 Cmmol (g biomass)(-1) h(-1). CONCLUSIONS: The results reported in this work illustrate how the combination of a metabolic engineering strategy with fermentation technology optimization can be used to obtain significant amounts of the high-value sesquiterpene alpha-santalene. This represents a starting point toward the construction of a yeast "sesquiterpene factory" and for the development of an economically viable bio-based process that has the potential to replace the current production methods. PMID- 22938572 TI - Cutaneous and mucosal blistering secondary to "huffing". AB - Hydrocarbons are a diverse group of organic compounds found in many households. Volatile substance abuse most often occurs in teenagers and younger adults. Recognition of the cutaneous side effects of hydrocarbon exposure by physicians is important because teens may not always admit to their abuse. PMID- 22938571 TI - Neuromuscular effects of G93A-SOD1 expression in zebrafish. AB - BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a fatal disorder involving the degeneration and loss of motor neurons. The mechanisms of motor neuron loss in ALS are unknown and there are no effective treatments. Defects in the distal axon and at the neuromuscular junction are early events in the disease course, and zebrafish provide a promising in vivo system to examine cellular mechanisms and treatments for these events in ALS pathogenesis. RESULTS: We demonstrate that transient genetic manipulation of zebrafish to express G93A-SOD1, a mutation associated with familial ALS, results in early defects in motor neuron outgrowth and axonal branching. This is consistent with previous reports on motor neuron axonal defects associated with familial ALS genes following knockdown or mutant protein overexpression. We also demonstrate that upregulation of growth factor signaling is capable of rescuing these early defects, validating the potential of the model for therapeutic discovery. We generated stable transgenic zebrafish lines expressing G93A-SOD1 to further characterize the consequences of G93A-SOD1 expression on neuromuscular pathology and disease progression. Behavioral monitoring reveals evidence of motor dysfunction and decreased activity in transgenic ALS zebrafish. Examination of neuromuscular and neuronal pathology throughout the disease course reveals a loss of neuromuscular junctions and alterations in motor neuron innervations patterns with disease progression. Finally, motor neuron cell loss is evident later in the disease. CONCLUSIONS: This sequence of events reflects the stepwise mechanisms of degeneration in ALS, and provides a novel model for mechanistic discovery and therapeutic development for neuromuscular degeneration in ALS. PMID- 22938573 TI - Implants of 6 mm vs. 11 mm lengths in the posterior maxilla and mandible: a 1 year multicenter randomized controlled trial. AB - BACKGROUND AND AIM: In cases with limited bone height, short implants could be a good alternative to augmentation procedures. The aim of this randomized controlled trial was to compare the clinical performance of implants of 6 mm or 11 mm in length in the posterior region. MATERIALS AND METHODS: In this multicenter trial (six study sites), 95 subjects were included. Subjects were randomly allocated to receiving implants with lengths of either 6 or 11 mm both with a diameter of 4 mm (OsseoSpeed(TM) 4.0 S; Astra Tech AB; Molndal, Sweden). In all cases, there had to be sufficient bone height to allow placement of an implant of at least 11 mm in length. Two or three implants were placed per subject using one-stage surgery with a 42-48 days' healing period before loading. They were restored with a screw-retained splinted fixed prosthesis. Clinical and radiographic examinations were performed preoperatively, postsurgery, at loading, and 6 and 12 months after prosthesis placement. RESULTS: A total of 208 implants were inserted in 49 subjects receiving 6-mm implants (test) and in 46 subjects receiving 11 mm implants (control). Two 6-mm implants failed before loading and one 6 and 11 mm implants failed before 1-year evaluation. From loading to the 12 months' follow-up, a mean marginal bone gain of 0.06 mm in the 6 mm group and 0.02 mm in the 11 mm group was found (P = 0.478). Soft tissue behavior was equal in both groups (Bleeding and plaque [P = 1.0] probing depth [P = 0.91]). CONCLUSION: One-year data indicate that treatment with the 6 mm implants is as reliable as treatment with the 11 mm implants. This provides a good treatment option in situations with limited bone height in the premolar and molar regions. Whether or not short implants provide a predictable treatment alternative to bone augmentation procedures remains to be investigated in the future randomized controlled clinical trials. PMID- 22938575 TI - Fate and distribution of fipronil on companion animals and in their indoor residences following spot-on flea treatments. AB - Use of fipronil {5-amino-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-4 trifluoromethyl)sulfinyl]-1H-pyrazole-3-carbonitrile CAS 120068-37-3} topical pet products on dogs and cats introduces low level residues into residences. Distribution and fate studies of fipronil on pets and in residences were performed to evaluate potential determinants of human exposure. Fipronil, desulfinyl fipronil, fipronil sulfone and fipronil sulfide were measured on hair clippings and brushed hair. The derivatives usually represented <10% of fipronil applied. Cotton gloves worn over impervious nitrile gloves, cotton cloths placed indoors in locations frequented by pets, and cotton socks worn by residents as direct dosimeters collected fipronil and its derivatives listed above in low amounts during 4-week study periods. Subsequent acid hydrolysis urine biomonitoring did not reveal significant excretion of biomarkers at ppb levels. The human exposure potential of fipronil is low relative to levels of health concern. PMID- 22938574 TI - Appraising the performance of genotyping tools in the prediction of coreceptor tropism in HIV-1 subtype C viruses. AB - BACKGROUND: In human immunodeficiency virus type 1 (HIV-1) infection, transmitted viruses generally use the CCR5 chemokine receptor as a coreceptor for host cell entry. In more than 50% of subtype B infections, a switch in coreceptor tropism from CCR5- to CXCR4-use occurs during disease progression. Phenotypic or genotypic approaches can be used to test for the presence of CXCR4-using viral variants in an individual's viral population that would result in resistance to treatment with CCR5-antagonists. While genotyping approaches for coreceptor tropism prediction in subtype B are well established and verified, they are less so for subtype C. METHODS: Here, using a dataset comprising V3 loop sequences from 349 CCR5-using and 56 CXCR4-using HIV-1 subtype C viruses we perform a comparative analysis of the predictive ability of 11 genotypic algorithms in their prediction of coreceptor tropism in subtype C. We calculate the sensitivity and specificity of each of the approaches as well as determining their overall accuracy. By separating the CXCR4-using viruses into CXCR4-exclusive (25 sequences) and dual-tropic (31 sequences) we evaluate the effect of the possible conflicting signal from dual-tropic viruses on the ability of a of the approaches to correctly predict coreceptor phenotype. RESULTS: We determined that geno2pheno with a false positive rate of 5% is the best approach for predicting CXCR4-usage in subtype C sequences with an accuracy of 94% (89% sensitivity and 99% specificity). Contrary to what has been reported for subtype B, the optimal approaches for prediction of CXCR4-usage in sequence from viruses that use CXCR4 exclusively, also perform best at predicting CXCR4-use in dual-tropic viral variants. CONCLUSIONS: The accuracy of genotyping approaches at correctly predicting the coreceptor usage of V3 sequences from subtype C viruses is very high. We suggest that genotyping approaches can be used to test for coreceptor tropism in HIV-1 group M subtype C with a high degree of confidence that they will identify CXCR4-usage in both CXCR4-exclusive and dual tropic variants. PMID- 22938576 TI - Assays of polychlorinated biphenyl congeners and co-contaminated heavy metals in the transgenic Arabidopsis plants carrying the recombinant guinea pig aryl hydrocarbon receptor-mediated beta-glucuronidase reporter gene expression system. AB - The transgenic Arabidopsis plant XgD2V11-6 carrying the recombinant guinea pig (g) aryl hydrocarbon receptor (AhR)-mediated beta-glucuronidase (GUS) reporter gene expression system was examined for assay of polychlorinated biphenyl (PCB) congeners and co-contaminated heavy metals. When the transgenic Arabidopsis plants were treated with PCB126 (toxic equivalency factor; TEF: 0.1) and PCB169 (TEF: 0.03), the GUS activity of the whole plants was increased significantly. After treatment with PCB80 (TEF: 0), the GUS activity was nearly the same level as that treated with 0.1% dimethylsulfoxide (DMSO) as a vehicle control. After exposure to a 1:1 mixture of PCB126 and PCB169, the GUS activity was increased additively. However, after exposure to a mixture of PCB126 and PCB80, the GUS activity was lower than that of the treatment with PCB126 alone. Thus, PCB80 seemed to be an antagonist towards AhR. When the transgenic plants were treated with each of the heavy metals Fe, Cu, Zn, Cd and Pb together with PCB126, Cd and Pb increased the PCB126-induced GUS activity. On the other hand, Fe, Cu and Zn did not affect the PCB126-induced GUS activity. In the presence of the biosurfactant mannosylerythritol lipid-B (MEL-B) and the carrier protein bovine serum albumin (BSA), the PCB126-induced GUS activity was increased, but the Cd assisted PCB126-induced GUS activity was not affected. Thus, MEL-B and BSA seemed to increase uptake and transport of PCB126, respectively. PMID- 22938577 TI - Evaluation of Saccharomyces cerevisiae strains as probiotic agent with aflatoxin B1 adsorption ability for use in poultry feedstuffs. AB - In this study the aflatoxin B1 (AFB1) removal capacity, the tolerance to salivary and gastrointestinal conditions, autoaggregation and coaggregation with pathogenic bacteria of Saccharomyces cerevisiae strains isolated from broiler feces, were evaluated. Only four of twelve isolated strains were identified as Saccharomyces cerevisiae using molecular techniques. The results obtained in AFB1 binding studies indicated that the amount of AFB1 removed was both strain and mycotoxin-concentration dependent. Therefore, a theoretical model was applied in order to select the most efficient strain to remove AFB1 in a wide range of mycotoxin concentration. The results indicated that S. cerevisiae 08 and S. cerevisiae 01 strains were the most efficient microorganisms in the mycotoxin removal. Viability on simulated salivary and gastrointestinal conditions was investigated and S. cerevisiae 08 strain showed the best results, achieving 98% of total survival whereas S. cerevisiae 01 reached only 75%. Autoaggregation and coaggregation assays showed S. cerevisiae 08 as the most appropriate strain, mainly because it was the unique strain able to coaggregate with the four bacterial pathogens assayed. Consequently, S. cerevisiae 08 is the best candidate for future in vivo studies useful to prevent aflatoxicosis. Further quantitative in vitro and in vivo studies are required to evaluate the real impact of yeast binding activity on the bioavailability of AFB1 in poultry. However, this study could be useful in selecting efficient strains in terms of AFB1 binding and provide an important contribution to research into microorganisms with potential probiotic effects on the host. PMID- 22938578 TI - Evaluation of pressurized liquid extraction for determination of organophosphorus and pyrethroid pesticides in soybean. AB - The purpose of this study was to develop an analytical method for the determination of organophosphorus and pyrethroid pesticides in soybean by pressurized liquid extraction (PLE). Two organic solvents, acetone and acetonitrile, were evaluated as extraction solvents. In both cases, the amount of extract was enhanced with increasing extraction temperature. The extracts obtained using acetonitrile were measured by gas chromatography/mass spectrometry after a cleanup process based on the analytical method for the Japanese Positive List System for Agricultural Chemicals Remaining in Foods. The effect of extraction temperature (range: 40- 130 degrees C) on extraction efficiency was evaluated by a recovery study using 21 organophosphorus pesticides and 10 pyrethroid pesticides as target analytes and acetonitrile as the solvent. The results indicated that at 130 degrees C, some organophosphorus pesticides might be degraded, whereas extraction temperatures between 70 degrees C and 100 degrees C were optimal. Next, a prepared sample containing fenitrothion and permethrin was analyzed. Although the sample was not soaked in water prior to analysis, PLE provided analytical results comparable to those obtained by solvent extraction with homogenization. Therefore, PLE is considered a simple and alternative technique for the extraction of organophosphorus and pyrethroid pesticides in soybean. PMID- 22938579 TI - Influence of sugar cane vinasse on the sorption and degradation of herbicides in soil under controlled conditions. AB - This study reports the influence of sugar cane vinasse on the persistence, sorption and leaching potential of diuron (3-(3,4-dichlorophenyl)-1,1 dimethylurea), hexazinone (3-cyclohexyl-6-(dimethylamino)-1-methyl-1,3,5-triazine 2,4-dione) and tebuthiuron (1-(5-tert-butyl-1,3,4-thiadiazol-2-yl)-1,3 dimethylurea) in both a clay and sandy soil from a tropical area of Brazil. The experiments were conducted out under controlled laboratory conditions. The addition of sugarcane vinasse to soil influenced the persistence and sorption of the herbicides in both the studied clay and sandy soils, with a considerable decrease in the diuron DT50 values in clay soil. The Ground Water Ubiquity Score (GUS) Index classifies the herbicides as leachers in both soils and treatments, with the exception of diuron, which is classified as a non-leacher in clay soil vinasse and as a transient herbicide in sandy soil. These results suggest that special attention should be given to areas such as those where the sandy soil was collected in this study, which is a recharge area of the Guarani Aquifer and is likely to experience groundwater contamination due to the high leaching potential of the applied pesticides. PMID- 22938580 TI - Quantification of ionophores in aged poultry litter using liquid chromatography tandem mass spectrometry. AB - Veterinary anticoccidials, biochemically known as ionophores, are widely used in poultry feed at therapeutic levels to treat Coccidiosis and at sub-therapeutic levels for growth- promotion. Commonly used ionophores in the US poultry industry are monensin, salinomycin, lasalocid and narasin. There is an increasing concern regarding the persistence of these anticoccidials in the environment. However, little attention has been directed to methods development for quantitatively measuring ionophores in complex environmental matrices such as poultry litters that are land applied. Here, we describe a rapid and sensitive liquid chromatography tandem mass spectrometry (LC-MS/MS)-based method developed for simultaneous quantification of monensin, lasalocid, salinomycin, and narasin in aged poultry litter samples. Results show significant level of monensin (97.8 +/- 3.2 MUg kg-1), lasalocid (19.2 +/- 6.6 MUg kg-1), salinomycin (70 +/- 2.7 MUg kg 1) and narasin (57.3 +/- 2.6 MUg kg-1) in poultry litter stored for over three years at < 5 degrees C. Our findings indicate that even after several years of unmanaged storage of poultry litter, ionophores may continue to persist in this matrix, raising the possibility of prolonged release into the environment. PMID- 22938581 TI - Impact of vegetated filter strips on sorbed herbicide concentrations and sorption equilibrium in agricultural plots. AB - The objective was to investigate the impact of vegetated filter strips on exported atrazine and deethylatrazine concentrations [dissolved and sorbed to eroded sediments (>1.5 MUm)], the deethylatrazine to atrazine ratio in water and sediments, the ratio of sorbed to dissolved herbicides in runoff and subsurface infiltration as well as field equilibrium state under natural climate during two seasons. We hypothesize that sorption equilibrium was not achieved in 2004 because of the short delay (<24 h) between herbicide application and the first rain event. In 2005, observations suggest that possible changing sorption equilibrium conditions were reached (20 days after atrazine application), especially for eroded sediments submitted to changing environmental conditions in subsurface. If confirmed by other experiments, this will raise the question of the representativeness of laboratory-determined soil sorption coefficients to predict the fate of pesticides. PMID- 22938585 TI - High-resolution melting analysis as a sensitive prescreening diagnostic tool to detect KRAS , BRAF , PIK3CA , and AKT1 mutations in formalin-fixed, paraffin embedded tissues. AB - CONTEXT: As the availability of targeted therapies for several tumor types increases, the need for rapid and sensitive mutation screening is growing. KRAS mutations constitutively activate the RAS/RAF/mitogen-activated protein kinase (MAPK) pathway and therefore play an important role in anti-epidermal growth factor receptor therapy for patients with colorectal cancers. Mutationally activated PIK3CA and AKT1 genes are promising therapeutic targets in breast cancer. In 60% to 70% of malignant melanomas, a mutation in BRAF can be found. Thus, the blocking of the oncogenic signaling induced by this mutation is now used as treatment approach. OBJECTIVE: To establish high-resolution melting assays for routinely used predictive analyses of KRAS , AKT1 , PIK3CA , and BRAF mutations. DESIGN: High-resolution melting assays were developed by using specifically designed primers and genomic DNA isolated either from cell lines or formalin-fixed paraffin-embedded tissues, oligonucleotides, or plasmids. Melting curve analyses were performed on the LightCyler platform and mutation analyses were additionally confirmed by Sanger sequencing. RESULTS: We developed high resolution melting assays by using genomic DNA containing the desired mutation, which enabled us to detect percentages of mutated DNA (3.1% to 12.5%) mixed in a wild-type background. Assays were evaluated by hybridization probes and/or Sanger sequencing to exclude pseudogene amplification. The high-resolution melting assays were validated with genomic DNA from different tumor entities. The concordance between Sanger sequencing and high-resolution melting was 99% for KRAS exon 2 and PIK3CA exon 20 and 100% for the remaining assays. CONCLUSIONS: High-resolution melting provides a valid and powerful tool for detecting genomic mutations efficiently. PMID- 22938586 TI - Centromere 17 copy number alteration: negative prognostic factor in invasive breast cancer? AB - CONTEXT: Chromosome 17 polysomy has been identified in 5% to 50% of invasive breast cancers; even though a relationship with human epidermal growth factor receptor 2 (HER2/ neu ) status has been reported, other studies have shown that coincident centromere 17 (Cep17) amplification may be the cause of an overestimation of chromosome 17 polysomy in fluorescence in situ hybridization (FISH) testing. OBJECTIVE: To evaluate polysomy/amplification of Cep17 in invasive breast cancer with relation to proliferative activity (Ki-67), estrogen receptor, progesterone receptor, and HER2/ neu status, in an attempt to identify a subgroup of patients with a worse prognosis. DESIGN: A total of 647 cases of invasive ductal breast cancer were collected and subjected to FISH analysis for HER2/neu gene and centromere 17 alteration, HercepTest for HER2/ neu protein expression, and routine immunohistochemistry for Ki-67 and hormone receptor status. RESULTS: Copy number gain of Cep17 was observed in 27.3% of cases. Within this group, HER2/neu gene amplification was detected in 14.1% of cases, whereas HER2/ neu expression was scored 3+ in 20.1% of cases; about half of the HER2/ neu overexpressing cases (9.8%) did not show amplification by FISH. Moreover, 69% of polysomic cases showed high Ki-67 index. CONCLUSIONS: (1) Centromere 17-altered cases are frequently HER2/ neu overexpressing but not amplified, resulting in HercepTest/FISH disagreement; (2) HER2/neu amplification is seen at a higher incidence in cases without Cep17 copy number alterations, which are therefore not necessarily due to chromosome 17 disorder; (3) proliferation index is significantly higher in aneusomic tumors. These data suggest that the presence of Cep17 alterations could identify a subset of breast cancers with more aggressive biological and clinical behavior, which may show nonresponsiveness to conventional therapy independently of HER2/neu amplification status. PMID- 22938587 TI - Small-intestine pneumocystis jiroveci pseudotumor as an acquired immunodeficiency syndrome-presenting illness: report of a case and review of the literature. AB - A Pneumocystis jiroveci infection-associated mass clinically mimicking a malignancy (ie, pseudotumor) is rare and usually occurs in the lung in association with Pneumocystis pneumonia. Pneumocystis jiroveci pseudotumors of the small intestine are extremely rare and represent an unusual form of disseminated P jiroveci infection. We present a case of small-intestine P jiroveci pseudotumor as an acquired immunodeficiency syndrome-presenting illness in a patient with coinfection with cytomegalovirus, no pulmonary symptoms, and no known risk factors for human immunodeficiency virus infection. This case reinforces the potential importance of cytomegalovirus coinfection in the disseminated form of Pneumocystis infection and illustrates the importance of an expanded differential diagnosis when confronted with a clinically atypical mass lesion. PMID- 22938590 TI - Transcriptomic and metabolomic profiling of chicken adipose tissue in response to insulin neutralization and fasting. AB - BACKGROUND: Domestic broiler chickens rapidly accumulate adipose tissue due to intensive genetic selection for rapid growth and are naturally hyperglycemic and insulin resistant, making them an attractive addition to the suite of rodent models used for studies of obesity and type 2 diabetes in humans. Furthermore, chicken adipose tissue is considered as poorly sensitive to insulin and lipolysis is under glucagon control. Excessive fat accumulation is also an economic and environmental concern for the broiler industry due to the loss of feed efficiency and excessive nitrogen wasting, as well as a negative trait for consumers who are increasingly conscious of dietary fat intake. Understanding the control of avian adipose tissue metabolism would both enhance the utility of chicken as a model organism for human obesity and insulin resistance and highlight new approaches to reduce fat deposition in commercial chickens. RESULTS: We combined transcriptomics and metabolomics to characterize the response of chicken adipose tissue to two energy manipulations, fasting and insulin deprivation in the fed state. Sixteen to 17 day-old commercial broiler chickens (ISA915) were fed ad libitum, fasted for five hours, or fed but deprived of insulin by injections of anti-insulin serum. Pair-wise contrasts of expression data identified a total of 2016 genes that were differentially expressed after correction for multiple testing, with the vast majority of differences due to fasting (1780 genes). Gene Ontology and KEGG pathway analyses indicated that a short term fast impacted expression of genes in a broad selection of pathways related to metabolism, signaling and adipogenesis. The effects of insulin neutralization largely overlapped with the response to fasting, but with more modest effects on adipose tissue metabolism. Tissue metabolomics indicated unique effects of insulin on amino acid metabolism. CONCLUSIONS: Collectively, these data provide a foundation for further study into the molecular basis for adipose expansion in commercial poultry and identify potential pathways through which fat accretion may be attenuated in the future through genetic selection or management practices. They also highlight chicken as a useful model organism in which to study the dynamic relationship between food intake, metabolism, and adipose tissue biology. PMID- 22938591 TI - Bacterial diversity from the source to the tap: a comparative study based on 16S rRNA gene-DGGE and culture-dependent methods. AB - This study aimed to assess the influence of water treatment and distribution on the bacterial communities with particular emphasis on tap water. Samples from the water treatment plant, the bulk supply distribution system and household taps, supplied by the same drinking water treatment plant, were analyzed using culture dependent and culture-independent methods. Water treatment imposed alterations in the composition of the bacterial community, although this effect was more evident in the cultivable bacteria rather than among the total community assessed by 16S rRNA gene-denaturing gradient gel electrophoresis (DGGE) profiling. Water disinfection, mainly chlorination, promoted a reduction on bacterial diversity and cultivability, with a shift in the pattern of cultivable bacteria from predominantly Gram-negative to predominately Gram-positive and acid-fast. Downstream of the chlorination stages, tap water, in comparison with raw water, presented higher diversity indices and cultivability percentages. From the source to the tap, members of the Alpha-, Beta- and Gammaproteobacteria were the predominant lineages identified using 16S rRNA gene-DGGE analysis. Although with a lower coverage, the DGGE-based lineage identifications were in agreement with those found using 454-pyrosequencing analysis. Despite the effectiveness of water treatment to eliminate or inactivate most of the bacteria, Proteobacteria such as Acinetobacter, Bosea and Sphingomonadaceae may successfully colonize tap water. PMID- 22938592 TI - Selective oxidation of 8,8'-hydroxylated binaphthols to bis-spironaphthalenones or binaphtho-para- and binaphtho-ortho-quinones. AB - The selective oxidation of a series of functionalized 8,8'-hydroxylated binaphthols to binaphtho-para- and binaphtho-ortho-quinones has been realized using either a Co-salen catalyst or ortho-iodoxybenzoic acid. A unique spirocyclic bis-spironaphthalenone was also obtained in good yield via a phenyliodonium diacetate promoted oxidative dearomatization. PMID- 22938593 TI - Quality of life and socio-professional reintegration after mild traumatic brain injury. AB - BACKGROUND: Controversy exists about the influence of intracranial injuries in mild traumatic brain injury (mTBI) on quality of life (QoL). Some patients do not fully recover from mTBI and experience neurocognitive impairment and reduction in quality of life. We evaluated the influence of structural brain damage on QoL and employment status (ES) after mTBI. METHODS: In a partially prospective design we evaluated QoL using Short-Form-36 (SF36) and current ES three years after trauma in 36 patients with mTBI in a matched pair design with two groups of 18 patients each with and without structural brain damage. RESULTS: Both groups showed a reduction in physical (Physical Functioning, Role Physical, Bodily Pain and General Health) and emotional parameters (Vitality, Social Functioning, Role Emotional and Mental Health) without significant difference between both groups (p = 0.305, p = 0.406, p = 0.624, p = 0.720, p = 0.934, p = 0.282, p = 0.811 and p = 0.270 respectively). ES was independent of structural brain damage and an influential factor for QoL. CONCLUSION: MTBI specific QoL assessment including focus on ES is necessary to identify patients at risk for impaired recovery. Structural brain injury as seen on CT scan is not useful as a prognostic tool to predict QoL or ES after mTBI. PMID- 22938594 TI - Acute neurorehabilitation versus treatment as usual. AB - Several clinical and government reviews have recommended specialised rehabilitation services for those recovering from neurological insult or neurosurgical intervention. Despite this, provision of 'rapid access'/acute neurorehabilitation units is extremely limited in the UK. In some areas, millions of people have no access to such facilities. Numerous articles have indicated that delayed access to neurorehabilitation in the acute recovery stage may worsen clinical outcomes and increase length of stay for patients. However, there has been a lack of studies directly comparing clinical outcomes between matched samples of patients in acute neurorehabilitation units versus patients receiving treatment-as-usual. In a study believed to be the first of its kind, this paper: (A) Describes the rationale and evidence base for acute neurorehabilitation. (B) Provides a comparison of clinical outcome scores Functional Independence Measure/Functional Assessment Measure (FIM-FAM) and also length of stay times for both of the aforementioned groups. The results show that all outcome areas except the 'communication' domain saw clinically and statistically significant improvements in the acute neurorehabilitation group. Length of stay was significantly reduced in the acute neurorehabilitation group. The case for reviewing the provision of acute neurorehabilitation units is now even more urgent and difficult to ignore. PMID- 22938595 TI - Medically treated prolactin-secreting pituitary adenomas: when should we operate? AB - BACKGROUND: The incidence of medical failure for prolactin (PRL)-secreting pituitary tumours is not well known. Object. The purpose of this study is to report clinical, radiographic and laboratory findings of PRL-secreting tumours that predict failed medical management. METHODS: An analysis of 92 consecutive patients was performed that met the inclusion criteria. Decision for surgery was made based on failure of dopamine agonists to either control clinical symptoms and normalise hormonal level or diminish mass effect on follow-up evaluation. RESULTS: Of the 92 patients treated, 14 patients (15%) required trans-nasal, trans-sphenoidal pituitary surgery (TSS). One patient underwent surgery for repair of a skull defect and 13 patients (14%) required surgery after failed medical management. Higher initial PRL was statistically significant regarding the need for surgical intervention, but a persistently abnormal level after initiation of treatment was a more significant predictor (Fisher exact test, p = 0.005 vs. p < 0.001). Size was also a statistically significant factor (p = 0.014); macroadenomas had a relative risk of 9.27 (95% CI: 1.15-74.86) for needing surgery compared to microadenomas. In addition, macroadenomas with cavernous sinus (CS) extension and pre-operative visual field deficit demonstrated a strong tendency for surgical intervention. CONCLUSION: Medical management remains the most effective treatment option for prolactinomas. A partial hormonal response to medical management seems to be the most significant predictive factor but adenomas > 20 mm, visual field deficit and invasion of the CS may help predict the need for surgery. We suggest a minimum trial period (at least 8 weeks) of medical treatment prior to the consideration of surgery. PMID- 22938596 TI - Hematopoietic stem cell transplantation induces immunologic tolerance in renal transplant patients via modulation of inflammatory and repair processes. AB - BACKGROUND: Inducing donor-specific tolerance in renal transplant patients could potentially prevent allograft rejection and calcineurin inhibitor nephrotoxicity. Combined kidney and hematopoietic stem cell transplant from an HLA-matched donor is an exploratory and promising therapy to induce immune tolerance. Investigation of molecular mechanisms involved in the disease is needed to understand the potential process of cell therapy and develop strategies to prevent this immunologic rejection. METHODS: We enrolled nine patients in a clinical study in which cryopreserved donor hematopoietic stem cells were infused on days 2, 4, and 6 after kidney transplantation. One month post-transplant, 4 plasma samples were collected from combined transplants (C + Tx), and 8 plasma samples from patients with kidney transplantation alone (Tx). High abundance proteins in plasma were depleted and the two-dimensional liquid chromatography-tandem mass spectrometry coupled with iTRAQ labeling was utilized to identify the protein profiling between the two groups. Clusters of up- and down-regulated protein profiles were submitted to MetaCore for the construction of transcriptional factors and regulation networks. RESULTS AND DISCUSSION: Among the 179 identified proteins, 65 proteins were found in C + Tx with at least a 2-fold change as compared with Tx. A subset of proteins related to the complement and coagulation cascade, including complement C3a,complement C5a, precrusors to fibrinogen alpha and beta chains,was significantly downregulated in C + Tx. Meanwhile, Apolipoprotein A1(ApoA1), ApoC1, ApoA2, ApoE, and ApoB were significantly lower in Tx compared to C + Tx. Gene ontology analysis showed that the dominant processes of differentially expressed proteins were associated with the inflammatory response and positive regulation of plasma lipoprotein particle remodeling. CONCLUSIONS: Thus, our study provides new insight into the molecular events in the hematopoietic stem cell-induced immunologic tolerance. PMID- 22938597 TI - Towards fair health policies for migrants and ethnic minorities: the case-study of ETHEALTH in Belgium. AB - BACKGROUND: In Europe, progress in the development of health policies that address the needs of migrants and ethnic minorities has been slow. This is partly due to the absence of a strategic commitment by the health authorities. The Ministry of Public Health commissioned the ETHEALTH (EThnicity &HEALTH) group to formulate relevant recommendations to the public authorities with a view to reducing health inequalities among ethnic minorities. This paper describes the political process and the outcomes of the ETHEALTH expert group. RESULTS: After ten meetings, the ETHEALTH group came up with 46 recommendations, which were presented at a national press conference in December 2011. Target groups concerned by these recommendations covered both irregular migrants and migrants entitled to the national insurance coverage. Recommendations were supported by the need of combining universal approaches to health care with more specific approaches. The scope of the recommendations concerned health care as well as prevention, health promotion and access to health care. When analysing the content of the recommendations, some ETHEALTH recommendations were not fully measurable, and time-related; they were, however, quite specific and realistic within the Belgian context. The weak political commitment of an executive agency was identified as a major obstacle to the implementation of the recommendations. CONCLUSIONS: The ETHEALTH group was an example of scientific advice on a global health issue. It also demonstrated the feasibility of coming up with a comprehensive strategy to decrease ethnic health inequalities, even in a political context where migration issues are sensitive. Two final lessons may be highlighted at the end of the first phase of the ETHEALTH project: firstly, the combination of scientific knowledge and practical expertise makes recommendations SMART; and, secondly, the low level of commitment on the part of policymakers might jeopardise the effective implementation of the recommendations. PMID- 22938598 TI - Neutrophil volume, conductivity and scatter parameters with effective modeling of molecular activity statistical program gives better results in neonatal sepsis. AB - INTRODUCTION: Neonatal sepsis remains an important clinical syndrome despite advances in neonatology. Current hematology analyzers can determine cell volume (V), conductivity for internal composition of cell (C) and light scatter for cytoplasmic granularity and nuclear structure (S), and standard deviations which are effective in the diagnosis of sepsis. Statistical models can be used to strengthen the diagnosis. Effective modeling of molecular activity (EMMA) uses combinatorial algorithm of the selection parameters for regression equation based on modified stepwise procedure. It allows obtaining different regression models with different combinations of parameters. METHODS: We investigated these parameters in screening of neonatal sepsis. We used LH780 hematological analyzer (Beckman Coulter, Fullerton, CA, USA). We combined these parameters with interleukin-6 (IL-6) and C-reactive protein (CRP) and developed models by EMMA. RESULTS: A total of 304 newborns, 76 proven sepsis, 130 clinical sepsis and 98 controls, were enrolled in the study. Mean neutrophil volume (MNV) and volume distribution width (VDW) were higher in both proven and clinical sepsis groups. We developed three models using MNV, VDW, IL-6, and CRP. These models gave more sensitivity and specificity than the usage of each marker alone. CONCLUSIONS: We suggest to use the combination of MNV and VDW with markers such as CRP and IL-6, and use diagnostic models created by EMMA. PMID- 22938599 TI - De novo generation of a phosphate starvation-regulated promoter in Candida glabrata. AB - What steps are required for a promoter to acquire regulation by an environmental condition? We address this question by examining a promoter in Candida glabrata that is regulated by phosphate starvation and the transcription factor Pho4. The gene PMU2 encodes a secreted acid phosphatase that resulted from gene duplication events not present in other Ascomycetes, and only this gene of the three paralogs has acquired Pho4 regulation. We observe that the PMU2 promoter from C. glabrata is not functional in Saccharomyces cerevisiae, which is surprising because it is regulated by Pho4, and Pho4 is regulated in a similar manner in both species - through phosphorylation and localization. Additionally, we determine that phosphate starvation-regulated promoters in C. glabrata do not require the coactivator Pho2, which is essential to the phosphate starvation response in S. cerevisiae. We define a region of the PMU2 promoter that is important for Pho4 regulation, and this promoter region does not contain the canonical CACGTX sequence that ScPho4 utilizes for phosphate starvation-dependent transcription. However, CgPho4 utilizes CACGTX in the CgPHO84 promoter, as mutation of this sequence decreases transcription. We conclude that the acquisition of PMU2 has expanded the binding specificity of CgPho4 relative to ScPho4. PMID- 22938601 TI - Multiplex optical sensing with surface-enhanced Raman scattering: a critical review. AB - Multiplex analysis permits the detection of several analytical targets at the same time. This approach may permit to draw a rapid and accurate diagnostic about the health of an individual or an environment. Among the analytical techniques with potential for multiplexing surface-enhanced Raman scattering (SERS) offer unique advantages such as ultrasensitive detection down low the deconvolution times, a unique signature containing all the vibrational information of the target molecules, and the possibility of performing the experiments even in very demanding environments such as natural or biological fluids. Here we review the late advances in multiplex SERS including the direct methods, those aided by the surface functionalization of the plasmonic nanoparticles and the use of SERS encoded particles. PMID- 22938602 TI - Speciation of the bio-available iodine and bromine forms in edible seaweed by high performance liquid chromatography hyphenated with inductively coupled plasma mass spectrometry. AB - A bioavailability study based on an in vitro dialyzability approach has been applied to assess the bio-available fractions of iodine and bromine species from edible seaweed. Iodide, iodate, 3-iodo-tyrosine (MIT), 3,5-diiodo-tyrosine (DIT), bromide and bromate were separated by anion exchange chromatography under a gradient elution mode (175 mM ammonium nitrate plus 15% (v/v) methanol, pH 3.8, as a mobile phase, and flow rates within the 0.5-1.5 mL min(-1) range). Inductively coupled plasma-mass spectrometry (ICP-MS) was used as a selective detector for iodine ((127)I) and bromine ((79)Br). Low dialyzability ratios (within the 2.0-18% range) were found for iodine species; whereas, moderate dialyzability percentages (from 9.0 to 40%) were obtained for bromine species. Iodide and bromide were the major species found in the dialyzates from seaweed, although MIT and bromate were also found in the dialyzates from most of the seaweed samples analysed. However, DIT was only found in dialyzates from Wakame, Kombu, and NIES 09 (Sargasso) certified reference material; whereas, iodate was not found in any dialyzate. Iodine dialyzability was found to be dependent on the protein content (negative correlation), and on the carbohydrate and dietary fibre levels (positive correlation). However, bromine dialyzability was only dependent on the protein amount in seaweed (negative correlation). PMID- 22938600 TI - Intracellularly grown gold nanoislands as SERS substrates for monitoring chromate, sulfate and nitrate localization sites in remediating bacteria biofilms by Raman chemical imaging. AB - Understanding the chemical composition of biofilm matrices is vital in different fields of biology such as surgery, dental medicine, synthetic grafts and bioremediation. The knowledge of biofilm development, composition, active reduction sites and remediation efficacy will help in the development of effective solutions and evaluation of remediating approaches prior to implementation. Surface-enhanced Raman spectroscopy (SERS) based imaging is an invaluable tool to obtain an understanding of the remediating efficacy of microorganisms and its role in the formation of organic and inorganic compounds in biofilms. We demonstrate for the first time, the presence of chromate, sulfate, nitrate and reduced trivalent chromium in soil biofilms. In addition, we demonstrate that SERS imaging was able to validate two observations made by previous studies on chromate/sulfate and chromate/nitrate interactions in Shewanella oneidensis MR-1 biofilms. Additionally, we show a detailed Raman mapping based evidence of the existence of chromate-sulfate competition for cellular entry. Subsequently, we use Raman mapping to study the effect of nitrate on chromate reduction. The findings presented in this paper are among the first to report - detection of multiple metallic ions in bacterial biofilms using intracellular SERS substrates. Such a detailed characterization of biofilms using gold nanoislands based SERS mapping substrate can be extended to study cellular localization of other metallic ions and chemical species of biological and toxicological significance and their effect on reduction reactions in bacterial biofilms. PMID- 22938603 TI - An electrochemical ascorbic acid sensor based on palladium nanoparticles supported on graphene oxide. AB - In this study, an electrochemical ascorbic acid (AA) sensor was constructed based on a glassy carbon electrode modified with palladium nanoparticles supported on graphene oxide (PdNPs-GO). PdNPs with a mean diameter of 2.6 nm were homogeneously deposited on GO sheets by the redox reaction between PdCl(4)(2-) and GO. Cyclic voltammetry and amperometric methods were used to evaluate the electrocatalytic activity towards the oxidation of AA in neutral media. Compared to a bare GC or a Pd electrode, the anodic peak potential of AA (0.006 V) at PdNPs-GO modified electrode was shifted negatively, and the large anodic peak potential separation (0.172 V) of AA and dopamine (DA), which could contribute to the synergistic effect of GO and PdNPs, was investigated. A further amperometric experiment proved that the proposed sensor was capable of sensitive and selective sensing of AA even in the presence of DA and uric acid. The modified electrode exhibited a rapid response to AA within 5s and the amperometric signal showed a good linear correlation to AA concentration in a broad range from 20 MUM to 2.28 mM with a correlation coefficient of R=0.9991. Moreover, the proposed sensor was applied to the determination of AA in vitamin C tablet samples. The satisfactory results obtained indicated that the proposed sensor was promising for the development of novel electrochemical sensing for AA determination. PMID- 22938604 TI - Development of a simultaneous extraction and cleanup method for pyrethroid pesticides from indoor house dust samples. AB - An efficient and reliable analytical method was developed for the sensitive and selective quantification of pyrethroid pesticides (PYRs) in house dust samples. The method is based on selective pressurized liquid extraction (SPLE) of the dust bound PYRs into dichloromethane (DCM) with analysis by gas chromatography/mass spectrometry. Various adsorbents and combinations of extraction solvents and temperatures were evaluated to achieve a high-throughput sample preparation that eliminates the post-extraction cleanup step. The final method used sulfuric acid impregnated silica (acid silica) and neutral silica together in the extraction cell with the dust sample to provide both extraction and cleanup simultaneously. The optimal ratio of dust/acid silica/silica was 1:0.8:8. The extraction was performed at 2000 psi, at 100 degrees C with DCM for 5 min in three cycles. Method precision and accuracy were evaluated by the analysis of triplicate aliquots of the dust samples and the samples fortified with the target PYRs. The accuracy measured as the recoveries of the PYRs in the fortified samples ranged from 85% to 120%. The precision measured as the relative standard deviation of replicate samples was within +/-25%. The SPLE method was applied to 20 house dust samples collected from households that participated in two field studies regarding exposures to pesticides and other pollutants. Similar concentrations of target PYRs were obtained for the SPLE and a stepwise extraction/cleanup procedure. The SPLE procedure reduces organic solvent consumption and increases the sample throughput when compared with a traditional stepwise extraction and cleanup procedure. This study demonstrates that the SPLE procedure can be applied to complex dust matrices for analysis of PYRs for large scale exposure or environmental monitoring studies. PMID- 22938605 TI - Electromembrane extraction of zwitterionic compounds as acid or base: comparison of extraction behavior at acidic and basic pHs. AB - This study has performed on electromembrane extraction (EME) of some zwitterionic compounds based on their acidic and basic properties. High performance liquid chromatography (HPLC) equipped with UV detection was used for determination of model compounds. Cetirizine (CTZ) and mesalazine (MS) were chosen as model compounds, and each of them was extracted from acidic (as a cation) and basic (as an anion) sample solutions, separately. 1-Octanol and 2-nitrophenyl octylether (NPOE) were used as the common supported liquid membrane (SLM) solvents. EME parameters, such as extraction time, extraction voltage and pH of donor and acceptor solutions were studied in details for cationic and anionic forms of each model compound and obtained results for two ionic forms (cationic and anionic) of each compound were compared together. Results showed that zwitterionic compounds could be extracted in both cationic and anionic forms. Moreover, it was found that the extraction of anionic form of each model compound could be done in low voltages when 1-octanol was used as the SLM solvent. Results showed that charge type was not highly effective on the extraction efficiency of model compounds whereas the position of charge within the molecule was the key parameter. In optimized conditions, enrichment factors (EF) of 27-60 that corresponded to recoveries ranging from 39 to 86% were achieved. PMID- 22938606 TI - Identification and quantification of odorous compounds from adhesives used in food packaging materials by headspace solid phase extraction and headspace solid phase microextraction coupled to gas chromatography-olfactometry-mass spectrometry. AB - Adhesives are often responsible for off-flavors in food in contact with packaging. The aim of this investigation was to identify by GC-O-MS the odorous compounds in five different types of adhesive (hotmelt, vinyl acetate ethylene, starch, polyvinyl acetate and acrylic) used in food packaging. In order to obtain a substantial number of compounds, they were extracted by two complementary extraction methods: HS-SPE and HS-SPME. Fifteen minutes extraction time using PDMS fiber for hotmelt adhesive and DVD/CAR/PDMS fiber for the other adhesives were the best conditions for defining a representative solvent-free adhesive extract using a rapid and simple D-GC-O technique. Thirty-three compounds were identified by GC-O-MS. These include butyric acid, acetic acid, methyl butyrate, 1-butanol and nonanal, which were present in most of the adhesives under study producing cheesy, rancid, sour, medicinal and green aromas, respectively. The concentrations were determined, the most abundant compound being acetic acid with concentrations from 22.9 to 8930 MUg g(-1) of adhesive. PMID- 22938608 TI - Analytical pyrolysis vs. classical wet chemical analysis to assess the decay of archaeological waterlogged wood. AB - The macromolecular complexity of wood limits the possibility of obtaining complete chemical information on its alteration in archaeological objects. This paper compares the results obtained in the characterisation of the components of archaeological wood by a classical wet chemical method and by an instrumental method based on pyrolysis in presence of hexamethyldisilazane coupled with gas chromatography/mass spectrometry, Py(HMDS)-GC/MS. We compare the results obtained with the two methods quantitatively. This enables us to evaluate the efficiency of Py(HMDS)-GC/MS in assessing the chemical composition and the state of conservation of degraded wood. The material analysed consisted of reference sound wood and waterlogged wood from the Zolte historical site, located on a small island on Lake Zaranskie in Poland. The samples are from the remains of settlements dating to a period between the 9th and the 12th centuries AD. The results obtained by Py(HMDS)-GC/MS analysis are consistent in the determination of the level of degradation of archaeological wood with the results obtained using traditional techniques. The pyrolysis method is faster, reproducible, and reveals not only the amount but also the quality of the wood constituents, needing a much smaller sample. PMID- 22938607 TI - Detoxification of organophosphate residues using phosphotriesterase and their evaluation using flow based biosensor. AB - Among known pesticide groups, organophosphates (OPs) have grasped attention due to their hazardous nature and their applications as pesticides and chemical weapons. This work presents the development of cost-effective column based biosensor for detoxification of OPs in water and milk. Enzyme phosphotriesterase (PTE) was immobilized on an activated Sepharose 4B via covalent coupling using an Omnifit glass column. Three different OPs, ethyl paraoxon (EPOx), malaoxon (MAO) and chlorpyriphos-oxon (CPO) were spiked in water and milk to test the detoxification of OPs. Mixtures of these pesticides were also tested to check the cumulative detoxification in the real samples. The efficiency of detoxification was evaluated using a highly sensitive acetylcholinesterase (AChE) B394 biosensor based flow system. The column conditions were optimized for the detoxification studied. The method was shown to be promising when we tested real milk samples spiked with OPs. Detoxification obtained in milk was up to 86% whereas in water, 100% detoxification was obtained. PMID- 22938609 TI - Fluorescence enhancement of CdTe/CdS quantum dots by coupling of glyphosate and its application for sensitive detection of copper ion. AB - A novel fluorescent probe for Cu(2+) determination based on the fluorescence quenching of glyphosate (Glyp)-functionalized quantum dots (QDs) was firstly reported. Glyp had been used to modify the surface of QDs to form Glyp functionalized QDs following the capping of thioglycolic acid on the core-shell CdTe/CdS QDs. Under the optimal conditions, the response was linearly proportional to the concentration of Cu(2+) between 2.4*10(-2)MUg mL(-1) and 28MUg mL(-1), with a detection limit of 1.3*10(-3)MUg mL(-1) (3delta). The Glyp functionalized QDs fluorescent probe offers good sensitivity and selectivity for detecting Cu(2+). The fluorescent probe was successfully used for the determination of Cu(2+) in environmental samples. The mechanism of reaction was also discussed. PMID- 22938610 TI - Revision of iron(III)-citrate speciation in aqueous solution. Voltammetric and spectrophotometric studies. AB - A detailed study of iron (III)-citrate speciation in aqueous solution (theta=25 degrees C, I(c)=0.7 mol L(-1)) was carried out by voltammetric and UV-vis spectrophotometric measurements and the obtained data were used for reconciled characterization of iron (III)-citrate complexes. Four different redox processes were registered in the voltammograms: at 0.1 V (pH=5.5) which corresponded to the reduction of iron(III)-monocitrate species (Fe:cit=1:1), at about -0.1 V (pH=5.5) that was related to the reduction of FeL(2)(5-), FeL(2)H(4-) and FeL(2)H(2)(3-) complexes, at -0.28 V (pH=5.5) which corresponded to the reduction of polynuclear iron(III)-citrate complex(es), and at -0.4V (pH=7.5) which was probably a consequence of Fe(cit)(2)(OH)(x) species reduction. Reversible redox process at 0.1 V allowed for the determination of iron(III)-citrate species and their stability constants by analyzing E(p) vs. pH and E(p) vs. [L(4-)] dependence. The UV-vis spectra recorded at varied pH revealed four different spectrally active species: FeLH (logbeta=25.69), FeL(2)H(2)(3-) (log beta=48.06), FeL(2)H(4-) (log beta=44.60), and FeL(2)(5-) (log beta=38.85). The stability constants obtained by spectrophotometry were in agreement with those determined electrochemically. The UV-vis spectra recorded at various citrate concentrations (pH=2.0) supported the results of spectrophotometric-potentiometric titration. PMID- 22938611 TI - Analytical procedure for the determination of Ethyl Lauroyl Arginate (LAE) to assess the kinetics and specific migration from a new antimicrobial active food packaging. AB - Ethyl Lauroyl Arginate (LAE) is a cationic tensoactive compound, soluble in water, with a wide activity spectrum against moulds and bacteria. LAE has been incorporated as antimicrobial agent into packaging materials for food contact and these materials require to comply with the specific migration criteria. In this paper, one analytical procedure has been developed and optimized for the analysis of LAE in food simulants after the migrations tests. It consists of the formation of an ionic pair between LAE and the inorganic complex Co(SCN)(4)(2-) in aqueous solution, followed by a liquid-liquid extraction in a suitable organic solvent and further UV-Vis absorbance measurement. In order to evaluate possible interferences, the ionic pair has been also analyzed by high performance liquid chromatography with UV-Vis detection. Both procedures provided similar analytical characteristics, with linear ranges from 1.10 to 25.00 mg kg(-1), linearity higher than 0.9886, limits of detection and quantification of 0.33 and 1.10 mg kg(-1), respectively, accuracy better than 1% as relative error and precision better than 3.6% expressed as RSD. Optimization of analytical techniques, thermal and chemical stability of LAE, as well as migration kinetics of LAE from experimental active packaging are reported and discussed. PMID- 22938612 TI - Colloidal gold nanoparticle probe-based immunochromatographic assay for the rapid detection of chromium ions in water and serum samples. AB - An immunochromatographic assay (ICA) using gold nanoparticles coated with monoclonal antibody (McAb) for the detection of chromium ions (Cr) in water and serum samples was developed, optimized and validated. Gold nanoparticles coated with affinity-purified monoclonal antibodies against isothiocyanobenzyl-EDTA (iEDTA)-chelated Cr(3+) were used as the detecting reagent in this completive immunoassay-based one-step test strip. The ICA was investigated to measure chromium speciation (Cr(3+) and Cr(6+) ions) in water samples. Chromium standard samples of 0-80 ng mL(-1) in water were determined by the test strips. The results showed that the visual lowest detection limit (LDL) of the test strip was 50.0 ng mL(-1). A portable colorimetric lateral flow reader was used for the quantification of Cr. The results indicated that the linear range of the ICA with colorimetric detection was 5-80 ng mL(-1). The ICA was also validated for the detection of chromium ions in serum samples. The test trips showed high stability in that they could be stored at 37 degrees C for at least 12 weeks without significant loss of activity. The test strip also showed good selectivity for Cr detection with negligible interference from other heavy metals. Because of its low cost and short testing time (within 5 min), the test strip is especially suitable for on-site large-scale screening of Cr-polluted water samples, biomonitoring of Cr exposure, and many other field applications. PMID- 22938613 TI - A novel sensing platform using aptamer and RNA polymerase-based amplification for detection of cancer cells. AB - Cancer is one of the most serious and lethal diseases around the world. Its early detection has become a challenging goal. To address this challenge, we developed a novel sensing platform using aptamer and RNA polymerase-based amplification for the detection of cancer cells. The assay uses the aptamer as a capture probe to recognize and bind the tumor marker on the surface of the cancer cells, forming an aptamer-based sandwich structure for collection of the cells in the microplate wells, and uses SYBR Green II dye as a tracer to produce strong fluorescence signal. The tumor marker interacts first with the recognition probes which were composed of the aptamer and single-stranded T7 RNA polymerase promoter. Then, the recognition probe hybridized with template probes to form a double-stranded T7 RNA polymerase promoter. This dsDNA region is extensively transcribed by T7 RNA polymerase to produce large amounts of RNAs, which are easily monitored using the SYBR Green II dye and a standard fluorometer, resulting in the amplification of the fluorescence signal. Using MCF-7 breast cancer cell as the model cell, the present sensing platform showed a linear range from 5.0*10(2) to 5.0*10(6) cells mL(-1) with a detection limit of 5.0*10(2) cells mL(-1). This work suggested a strategy to use RNA signal amplification combining aptamer recognition to develop a highly sensitive and selective method for cancer cells detection. PMID- 22938614 TI - A novel nonenzymatic sensor based on LaNi0.6Co0.4O3 modified electrode for hydrogen peroxide and glucose. AB - In this paper, LaNi(0.6)Co(0.4)O(3) (LNC) nanoparticles were synthesized by the sol-gel method, and the structure and morphology of LNC nanoparticles were characterized by X-ray diffraction spectrum, scanning electron microscopy and transmitting electron microscopy. And then, LNC was used to modify carbon paste electrode (CPE) without any adhesive to fabricate hydrogen peroxide and glucose sensor, and the results demonstrated that LNC exhibited strong electrocatalytical activity by cyclic voltammetry and amperometry. In H(2)O(2) determination, linear response was obtained in the concentration range of 10 nM-100 MUM with a detection limit of 1.0 nM. In glucose determination, there was the linear region of 0.05-200 MUM with a detection limit of 8.0 nM. Compared with other reports, the proposed sensor also displayed high sensitivity toward H(2)O(2) (1812.84 MUA mM(-1)cm(-2)) and glucose (643.0 MUA mM(-1)cm(-2)). Moreover, this prepared sensor was applied to detect glucose in blood serum and hydrogen peroxide in toothpaste samples with satisfied results, indicating its possibility in practical application. PMID- 22938615 TI - Tracking growth hormone abuse in sport: performance of marker proteins in a controlled setting. AB - Human growth hormone (hGH) abuse in sport is a challenge at present. The current strategy used, known as direct method, is based on the quantification of hGH variants in serum. An alternative strategy, known as indirect method, focuses on serum markers such as insulin-like growth factor I (IGF-I) and procollagen type III N-terminal propeptide (P-III-NP). The indirect method allows a longer window of detection (WOO) of hGH abuse. To evaluate the performance of the indirect method, in parallel to the direct method, a clinical trial with recombinant hGH (rhGH) was conducted on healthy male subjects during 7 days (0.026 mg(-1) kg(-1) person(-1) day(-1)). The data were fit to the discriminant formula proposed in the previously published GH-2000 project. The low sensitivity of the scores, judged from the high number of false negative outcomes, imposed a new discriminant analysis, standarised using local population subjects demographically similar to the ones of the study. The sensitivity of the method significantly increased, highlighting the importance of the standardisation. The indirect method allowed extended window of opportunity (WOO), although two false positive evaluations were observed derived from elevated basal IGF-I and P-III-NP concentrations stressing the need for an independent confirmation method. When direct and indirect methods were combined the best selectivity and sensitivity were achieved. PMID- 22938616 TI - Catalytic gold nanoparticles for fluorescent detection of mercury(II) and lead(II) ions. AB - In this study, we developed a fluorescence assay for the highly sensitive and selective detection of Hg(2+) and Pb(2+) ions using a gold nanoparticle (Au NP) based probe. The Hg-Au and Pb-Au alloys that formed on the Au NP surfaces allowed the Au NPs to exhibit peroxidase-mimicking catalytic activity in the H(2)O(2) mediated oxidation of Amplex UltraRed (AUR). The fluorescence of the AUR oxidation product increased upon increasing the concentration of either Hg(2+) or Pb(2+) ions. By controlling the pH values of 5mM tris-acetate buffers at 7.0 and 9.0, this H(2)O(2)-AUR-Au NP probe detected Hg(2+) and Pb(2+) ions, respectively, both with limits of detection (signal-to-noise ratio: 3) of 4.0 nM. The fluorescence intensity of the AUR oxidation product was proportional to the concentrations of Hg(2+) and Pb(2+) ions over ranges 0.05-1 MUM (R(2)=0.993) and 0.05-5 MUM (R(2)=0.996), respectively. The H(2)O(2)-AUR-Au NP probe was highly selective for Hg(2+) (>100-fold) and Pb(2+) (>300-fold) ions in the presence of other tested metal ions. We validated the practicality of this simple, selective, and sensitive H(2)O(2)-AUR-Au NP probe through determination of the concentrations of Hg(2+) and Pb(2+) ions in a lake water sample and of Pb(2+) ions in a blood sample. To the best of our knowledge, this system is the first example of Au NPs being used as enzyme-mimics for the fluorescence detection of Hg(2+) and Pb(2+) ions. PMID- 22938617 TI - Ultrasensitive photoelectrochemical sensing of nicotinamide adenine dinucleotide based on graphene-TiO2 nanohybrids under visible irradiation. AB - In this paper, the photoelectrochemical behavior of graphene-TiO(2) (G-TiO(2)) nanohybrids was investigated in the visible region and a new photoelectrochemical sensor for sensitive determination of nicotinamide adenine dinucleotide (NADH) was proposed. Under visible light, the G-TiO(2) nanohybrids possessed enhanced photocurrent, which was nearly 5 times than that of pure TiO(2) nanocrystals (NCs). Based on the enhanced photocurrent of G-TiO(2) nanohybrids toward NADH, a new photoelectrochemical methodology for ultrasensitive determination of NADH was developed. The proposed sensor showed linearly enhanced photocurrent by increasing the NADH concentration from 1.0*10(-8) to 2.0*10(-3) M with a low detection limit of 3.0*10(-9) M. Furthermore, this sensor exhibited good selectivity and stability towards NADH determination. This strategy opens up a new avenue for the application of graphene-based hybrids in the field of photoelectrochemical sensing and monitoring. PMID- 22938618 TI - Highly sensitive luminol electrochemiluminescence immunosensor based on ZnO nanoparticles and glucose oxidase decorated graphene for cancer biomarker detection. AB - In this work, we reported a sandwiched luminol electrochemiluminescence (ECL) immunosensor using ZnO nanoparticles (ZnONPs) and glucose oxidase (GOD) decorated graphene as labels and in situ generated hydrogen peroxide as coreactant. In order to construct the base of the immunosensor, a hybrid architecture of Au nanoparticles and graphene by reduction of HAuCl(4) and graphene oxide (GO) with ascorbic acid was prepared. The resulted hybrid architecture modified electrode provided an excellent platform for immobilization of antibody with good bioactivity and stability. Then, ZnONPs and GOD functionalized graphene labeled secondary antibody was designed for fabricating a novel sandwiched ECL immunosensor. Enhanced sensitivity was obtained by in situ generating hydrogen peroxide with glucose oxidase and the catalysis of ZnONPs to the ECL reaction of luminol-H(2)O(2) system. The as-prepared ECL immunosensor exhibited excellent analytical property for the detection of carcinoembryonic antigen (CEA) in the range from 10 pg mL(-1) to 80 ng mL(-1) and with a detection limit of 3.3 pg mL( 1) (SN(-1)=3). The amplification strategy performed good promise for clinical application of screening of cancer biomarkers. PMID- 22938619 TI - Fluorescence assay of catecholamines based on the inhibition of peroxidase-like activity of magnetite nanoparticles. AB - We report a fluorescence approach for the highly selective and sensitive detection of catecholamines using magnetite nanoparticles (Fe(3)O(4) NPs) in the presence of Amplex UltraRed (AUR) and H(2)O(2). Fe(3)O(4) NPs catalyze H(2)O(2) mediated oxidation of AUR. The resulting product fluoresces (excitation/emission maxima, ca. 568/587nm) more strongly, relative to AUR. When catecholamines bind to Fe(3)O(4), the complexes that are formed induce decreased activity of Fe(3)O(4) NPs, mediated through the coordination between Fe(3+) on the NP surface and the catechol moiety of catecholamines. As a result, Fe(3)O(4) NPs-catalyzed H(2)O(2)-mediated oxidation of AUR is inhibited by catecholamines. The limits of detection for dopamine (DA), L-DOPA, norepinephrine, and epinephrine were 3 nM, 3 nM, 3 nM, and 6 nM, respectively. The Fe(3)O(4) NPs-H(2)O(2)-AUR probe exhibited high selectivity (>1000-fold) toward catecholamines over other tested biomolecules that commonly exist in urine. Four catecholamines had similar sensitivity because the inhibition of the Fe(3)O(4) NPs activity relies on the presence of the catechol moiety. This approach also allowed the determination of tyrosinase activity because tyrosinase catalyzes the conversion of l-tyrosine to L-DOPA. We validated the practicality of the use of the Fe(3)O(4) NPs-H(2)O(2) AUR probe for the determination of the concentrations of DA in urine samples. PMID- 22938620 TI - Determination of nitrocellulose by capillary electrophoresis with laser-induced fluorescence detection. AB - The industrial application of nitrocellulose depends on its nitrogen content. When nitrocellulose presents high nitrogen content is used in the manufacture of explosives whereas nitrocellulose with low nitrogen content is used to make a wide range of daily and non-explosive products (e.g. cigarettes, paints, lacquers). This fact makes really important to develop a method for the determination and discrimination of nitrocellulose samples. This work reports, for the first time, the qualitative determination of nitrocellulose previously derivatized with 8-aminopyrene-1,3,6-trisulfonic acid (APTS) by capillary electrophoresis (CE-LIF) with laser-induced fluorescence detection (CE-LIF). APTS labeled nitrocellulose was determined in lowly and highly nitrated nitrocellulose samples present in collodions and smokeless gunpowders, respectively, after their pulverization in liquid nitrogen. The method described enables the visual discrimination of different nitrocelluloses on the basis of the different electrophoretic profiles obtained, and provides a useful tool to determine nitrocellulose. Additionally, the use of field-amplified sample injection (FASI) enabled enhanced sample detection, which made it possible to determine nitrocellulose contained in ~15 MUg of gunpowder. PMID- 22938621 TI - Congenital smooth muscle hamartoma on the face treated using vascular laser. AB - A congenital smooth muscle hamartoma is a rare, benign proliferation of smooth muscle bundles in the dermis that is usually diagnosed in the neonatal period or infancy. Surgical excision is the first-line therapeutic option, but in certain areas such as the face, surgery may be too aggressive, and different treatments should be considered. We present the case of a congenital smooth muscle hamartoma on the face treated using pulsed dye laser with good response. PMID- 22938622 TI - Editorial comment: Comparison of transurethral enucleation with bipolar and transurethral resection in saline for managing benign prostatic hyperplasia. PMID- 22938623 TI - Experimental in situ transformation of Pb smelter fly ash in acidic soils. AB - Soils in the vicinity of nonferrous metal smelters are often highly polluted by inorganic contaminants released from particulate emissions. We used a technique with double polyamide experimental bags (1-MUm mesh) to study the in situ transformation of fly ash (FA) from a secondary Pb smelter in acidic soil profiles. Between 62 and 66% of the FA dissolved after one year's exposure in the soils, leading to complete dissolution of primary caracolite (Na(3)Pb(2)(SO(4))(3)Cl) and KPb(2)Cl(5), with formation of secondary anglesite (PbSO(4)), minor PbSO(3), and trace carbonates. Release of Pb was pH-dependent, whereas not for Cd and Zn. Significant amounts of metals (mainly Cd and Zn) partitioned into labile soil fractions. The field data agreed with laboratory pH static leaching tests performed on FA, which was washed before the experiment to remove soluble salts. This indicates that appropriate laboratory leaching can accurately predict FA behavior in real-life scenarios (e.g., exposure in soil). PMID- 22938624 TI - Why are psychiatric imaging methods clinically unreliable? Conclusions and practical guidelines for authors, editors and reviewers. AB - No reliable anatomical or functional alterations have been confirmed in psychiatric neuroimaging; however it can become reliable with translational impact on clinical practice when considering crucial methodological issues. We provide guidelines to authors, editors and reviewers in the implementation/evaluation of neuroimaging studies to bend neuroimaging to be more than basic neuroscience. PMID- 22938625 TI - Surveillance considerations for malaria elimination. AB - Constant malaria monitoring and surveillance systems have been highlighted as critical for malaria elimination. The absence of robust monitoring and surveillance systems able to respond to outbreaks in a timely manner undeniably contributed to the failure of the last global attempt to eradicate malaria. Today, technological advances could allow for rapid detection of focal outbreaks and improved deployment of diagnostic and treatment supplies to areas needing support. However, optimizing diffusion activities (e.g., distributing vector controls and medicines, as well as deploying behaviour change campaigns) requires networks of diverse scholars to monitor, learn, and evaluate data and multiple organizations to coordinate their intervention activities. Surveillance systems that can gather, store and process information, from communities to national levels, in a centralized, widely accessible system will allow tailoring of surveillance and intervention efforts. Different systems and, thus reactions, will be effective in different endemic, geographical or socio-cultural contexts. Investing in carefully designed monitoring technologies, built for a multiple acter, dynamic system, will help to improve malaria elimination efforts by improving the coordination, timing, coverage, and deployment of malaria technologies. PMID- 22938626 TI - Emulate, envision, engage, and expand. PMID- 22938627 TI - Effects of interventions on depression in heart failure: a systematic review. AB - OBJECTIVE: We sought to conduct a systematic review to evaluate the effects of interventions on depression in adults with heart failure (HF). METHODS: Published, peer-reviewed, English-language, prospective interventional studies were identified in a search of Medline, CINAHL, PsychINFO, and the Cochrane Libraries of Systematic Reviews and Clinical Trials from 1996 through August 2011 and relevant bibliographies. Eligible studies included patients with New York Heart Association functional class II and III HF with experimental or quasiexperimental designs and preintervention and postintervention measures of depression. Ineligible studies were nonpharmacologic with a sample size <50, and drug studies without a comparison group. RESULTS: Twenty-three experimental and quasiexperimental studies that enrolled a total of 3564 persons with HF contributed evidence about 6 types of interventions: selective serotonin reuptake inhibitors (SSRIs), an erythropoiesis-stimulating agent, exercise, disease management programs, complementary and alternative medicine (CAM), and a multimodal intervention of cognitive behavioral therapy and exercise. Studies with SSRIs examined effects of sertraline, paroxetine, and citalopram. The CAM interventions included tai chi, progressive muscle relaxation therapy, and mindfulness-based stress reduction. CONCLUSIONS: Evidence is strong that pharmacology and CAM may improve depression. Moderate evidence supports the use of exercise. A strong body of evidence indicates that disease management programs do not improve depression. This review does not support the development of guidelines for treatment of depression in persons with HF because evidence is insufficient and, at times, contradictory. PMID- 22938631 TI - Evaluation of corneal thickness, anterior chamber depth, and iridocorneal angle following scleral buckling surgery with AS-OCT. AB - BACKGROUND AND OBJECTIVE: To evaluate the changes in central corneal thickness (CCT), anterior chamber depth (ACD), and iridocorneal angle (ICA) with anterior segment optical coherence tomography (AS-OCT) following scleral buckling surgery. PATIENTS AND METHODS: Thirty-one eyes with rhegmatogenous retinal detachment that underwent scleral buckling were included in this prospective study. Changes in CCT, ACD, and ICA were measured with AS-OCT. RESULTS: There was a significant increase in the CCT at 1 day and 1 week postoperatively. CCT became slightly thinner than the preoperative values at 1 month postoperatively. The ACD was relatively shallow at all visits after the surgery. The decrease in the ICA 0 degrees and 180 degrees values was statistically significant at 1 day, 1 week, and 1 month postoperatively. CONCLUSION: Changes in the CCT and ICA after scleral buckling were mild and almost returned to their preoperative levels within 6 months. However, ACD shallowing persisted even after 6 months. PMID- 22938630 TI - The roles played by highly truncated splice variants of G protein-coupled receptors. AB - Alternative splicing of G protein-coupled receptor (GPCR) genes greatly increases the total number of receptor isoforms which may be expressed in a cell dependent and time-dependent manner. This increased diversity of cell signaling options caused by the generation of splice variants is further enhanced by receptor dimerization. When alternative splicing generates highly truncated GPCRs with less than seven transmembrane (TM) domains, the predominant effect in vitro is that of a dominant-negative mutation associated with the retention of the wild type receptor in the endoplasmic reticulum (ER). For constitutively active (agonist-independent) GPCRs, their attenuated expression on the cell surface, and consequent decreased basal activity due to the dominant-negative effect of truncated splice variants, has pathological consequences. Truncated splice variants may conversely offer protection from disease when expression of co receptors for binding of infectious agents to cells is attenuated due to ER retention of the wild-type co-receptor. In this review, we will see that GPCRs retained in the ER can still be functionally active but also that highly truncated GPCRs may also be functionally active. Although rare, some truncated splice variants still bind ligand and activate cell signaling responses. More importantly, by forming heterodimers with full-length GPCRs, some truncated splice variants also provide opportunities to generate receptor complexes with unique pharmacological properties. So, instead of assuming that highly truncated GPCRs are associated with faulty transcription processes, it is time to reassess their potential benefit to the host organism. PMID- 22938632 TI - Assessment of vitreous incarceration in sclerotomies with OCT, ultrasound biomicroscopy, and direct visualization. AB - BACKGROUND AND OBJECTIVE: To compare anterior-segment optical coherence tomography (AS-OCT), ultrasound biomicroscopy (UBM), and direct visualization for detecting vitreous incarceration in sutureless sclerotomies. MATERIALS AND METHODS: Prospective, randomized, and observer-masked experimental study in which 23-gauge vitrectomy was performed in pig eyes. Postoperative incisional vitreous incarceration was evaluated by AS-OCT, UBM, and direct visualization. RESULTS: One hundred eighteen pig eyes were included. Vitreous entrapment was found in 7.9% (28 of 354), 59.6% (211 of 354), and 95.5% (338 of 354) of the sclerotomies analyzed by AS-OCT, UBM, and direct visualization, respectively. Direct visualization was the most sensible method for identifying incisional vitreous when compared with UBM and AS-OCT (P < .0001). In turn, UBM was superior to AS OCT for observing vitreous incarceration (P < .0001). CONCLUSION: Direct visualization is the most effective method for detecting vitreous entrapment. Regarding the imaging techniques, UBM was superior to AS-OCT for identifying vitreous incarceration. PMID- 22938637 TI - Chronic ankle instability. AB - Chronic instability of the ankle and anterolateral impingement syndrome are abnormalities that present as a result of inversion and forced plantar-flexion traumas of the foot, despite strict conservative management in the ER and in rehabilitation. A conservative approach is always the first choice of treatment, including anti-inflammatory medications, rehabilitation and proprioception, infiltration with steroids in impingement cases, and use of orthotics, whose true effectiveness is the subject of multiple studies and much debate. Good to excellent results can be obtained surgically with a minimally invasive approach, such as the arthroscopic technique presented herein. Such an approach is useful in managing a combination of conditions such as anterolateral impingement, synovitis, and osteochondral lesions of the talus. The method is easily reproducible, its learning curve is rapid, and it has the advantage of not preventing the use other arthroscopic methods, or open anatomic or nonanatomic methods (tendon transfers), in the case of failure. No nerve lesion was recorded, probably owing to the use of the security zone, and neither was there any arthrofibrosis, possibly related to the use of nonsteroidal anti-inflammatory medications in the immediate postsurgical period coupled with aggressive rehabilitation from the fourth week. The success of the technique is due to multidisciplinary team work leading to the ultimate achievement of patient satisfaction. This technique is not indicated for patients with a high sports demand or for sport professionals, until further biomechanical studies on its use and success are completed. PMID- 22938636 TI - Association between insertion/deletion polymorphism in angiotensin-converting enzyme gene and acute lung injury/acute respiratory distress syndrome: a meta analysis. AB - BACKGROUND: A previous meta-analysis reported a positive association between an insertion/deletion (I/D) polymorphism in the angiotensin-converting enzyme gene (ACE) and the risk of acute lung injury (ALI)/acute respiratory distress syndrome (ARDS). Here, we updated this meta-analysis and additionally assessed the association of this polymorphism with ALI/ARDS mortality. METHODS: We searched electronic databases through October 2011 for the terms "angiotensin-converting enzyme gene", "acute lung injury", and "acute respiratory distress syndrome," and reviewed all studies that reported the relationship of the I/D polymorphism in ACE with ALI/ARDS in humans. Seven studies met the inclusion criteria, comprising 532 ALI/ARDS patients, 3032 healthy controls, and 1432 patients without ALI/ARDS. We used three genetic models: the allele, dominant, and recessive models. RESULTS: The ACE I/D polymorphism was not associated with susceptibility to ALI/ARDS for any genetic model. However, the ACE I/D polymorphism was associated with the mortality risk of ALI/ARDS in Asian subjects ( P(allele) < 0.0001, P(dominant) = 0.001, P(recessive) = 0.002). This finding remained significant after correction for multiple comparisons. CONCLUSIONS: There is a possible association between the ACE I/D polymorphism genotype and the mortality risk of ALI/ARDS in Asians. PMID- 22938638 TI - Tendoscopy in stage I posterior tibial tendon dysfunction. AB - Stage I PTTD was defined by Johnson and Strom as tenosynovitis or tendinitis whereby tendon length remains normal, there is no hindfoot deformity, and diagnosis is basically clinical, characterized by swelling and tenderness posterior to the medial malleolus. The PTT has a hypovascular zone 40 mm proximal to the insertion of the tendon and 14 mm in length. Pain often is localized to this portion of the tendon. Tendon power might be normal, and the patient can perform single heel rise, sometimes with slight discomfort. This condition is often misdiagnosed as ankle sprain, which delays correct diagnosis and early treatment that may improve symptoms, stop the disease process, and prevent the development of adult acquired flatfoot deformity. Ultrasonography is a valuable adjunctive diagnostic tool for stage I PTTD, but the authors always indicate MRI for accurate diagnosis in such patients. Patients with stage I PTTD are first treated nonoperatively with nonsteroidal anti-inflammatory drugs for 5 days, cryotherapy, local ultrasound, and a PTTD airlift brace (Aircast) for 3 to 6 months. If symptoms persist, surgical debridement and synovectomy has been suggested. PTT tendoscopic synovectomy is a minimally invasive and effective surgical procedure to treat patients with stage I PTTD. It has the advantages of less wound pain, and fewer scar and wound problems. If tendon tear is observed during tendoscopy, it must be repaired with nonabsorbable sutures using a 3- or 4 cm incision. PMID- 22938639 TI - Subtle Lisfranc joint ligament lesions: surgical neoligamentplasty technique. AB - The results achieved with this technique after a mean follow-up of 8 years (85% excellent and good results) allow neoligamentplasty to be considered as a viable alternative to the classic procedures in the treatment of subtle intercuneiform and tarsometatarsal joint lesions. PMID- 22938640 TI - Pull-out technique for plantar plate repair of the metatarsophalangeal joint. AB - Plantar plate rupture is a common cause of forefoot pain, multiplanar malalignment, subluxation, or dislocation of the metatarsophalangeal joint (MTPJ). The treatments that have been described for MTPJ instability of lesser toes include amputation, lengthening and/or tendon transfer, periarticular soft tissue release (capsule, collateral ligaments, and plantar plate), colateral ligament reconstruction, metatarsal shortening osteotomy, and suture of plantar plate lesion. This article outlines the anatomy, pathogenesis, and diagnosis of plantar plate rupture, and describes a new technique that combines joint decompression by Weil osteotomy with a plantar plate repair using a pull-out technique. PMID- 22938641 TI - Peroneus longus transfer for drop foot in Hansen disease. AB - Leprosy or Hansen's disease is a chronic infectious disease caused by the Mycobacterium leprae. Nerve injury is a central feature of the pathogenesis of leprosy that results in autonomic, sensory and motor neuropathy. One of the most common secondary disabilities caused by Hansen's disease is the drop foot and it is found in 2% to 5% of newly-diagnosed leprosy patients. Unlike the clinical picture of traumatic injury of the common peroneal nerve where both of its branches (the deep peroneal nerve and the superficial peroneal nerve) are involved, in leprosy there is the possibility of isolated involvement of the deep peroneal nerve branch, sparing the superficial peroneal branch. The article discusses the advantages of using the peroneus longus tendon transfer to the dorsum of the foot instead of the posterior tibial tendon for the correction of dropfoot in selected cases where the peroneals tendons are intact. PMID- 22938643 TI - Use of poly(ether ether ketone) cages in foot and ankle surgery. AB - PEEK cages are an effective alternative when structural bone graft is needed for different fusions around the foot and ankle. Bone fusion rates are high when PEEK cages are filled with autologous bone. No difference in consolidation time in patients was noticed between the cages fixed with staples and those fixed with cannulated screws. Nerve damage, residual pain at the donor site, and cosmetic problems are avoided with the use of PEEK cages. There is no risk of transmission of hepatitis B, hepatitis C, and HIV when using PEEK cages. PMID- 22938642 TI - Calcaneonavicular ligament: anatomy, diagnosis, and treatment. AB - The calcaneonavicular ligament lesion may be single or related to posterior tibial tendon involvement; the clinical and image-based diagnosis is difficult, without pathognomonic signs. The diagnosis is made during surgery and the calcaneonavicular ligament should always be explored whenever the posterior tibial tendon is involved. PMID- 22938644 TI - Joint-preserving procedure for moderate hallux rigidus. AB - Hallux rigidus is a complex disorder, and numerous surgical procedures have been described for its management. Although the optimal technique has yet to be defined, it is important to individualize the degree of arthritis as well as other clinical features (metatarsal index, pain characteristics, and so forth) of each patient to achieve optimal results. The authors firmly believe that for patients with only dorsal pain, a cheilectomy is the ideal choice because good and reliable results can be achieved. When pain is also present around the joint or is combined, which is the most common scenario, their main choice now is to perform a decompressive osteotomy. The biomechanics of the joint are more adequately restored, soft tissues are relaxed, and remodeling of the contracted tissues is allowed. More investigation has still to be performed to elucidate the origin of this abnormality. PMID- 22938645 TI - Lesser toes proximal interphalangeal joint fusion in rigid claw toes. AB - Treatment of rigid claw toe is still subject to discussion and evolution. Arthrodesis or arthroplasty of the PIPJ is apparently the most reliable procedure. K wire seems be the most reliable way to solve this clinical issue, but different implants specifically created to treat PIPJ deformities are being developed, and still have to be tested clinically. The use of screws to fix the PIPJ is a valid alternative, although some problems remain to be solved, specifically pain in relation to the tip of the screw. Longer follow-up studies are needed to increase our knowledge of the treatment of this specific deformity. PMID- 22938646 TI - Osteotomy considerations in hallux valgus treatment: improving the correction power. AB - Efforts are currently being made to improve results in hallux valgus treatment. Different studies to design procedures that are more stable and efficient to correct deformities are underway, and new techniques will be presented in the following years. Better fixation devices will offer reliability in corrections, and hopefully will allow faster rehabilitation with fewer restrictions. Understanding the concept of correction power is important when deciding which technique to use. The origin of hallux valgus is not known, but evidence exists to assume that a correct skeletal and soft tissue balance is important to prevent recurrence and obtain good function. We think that a correct metatarsophalangeal reduction, in which the final position of the hallux is defined mainly by the skeletal alignment and not soft tissues, will dictate the final result. Pushing the metatarsal bone over the sesamoids and not moving the sesamoids under the metatarsal head is a new concept and it may allow better results for our patients. It is hoped that understanding of biomechanics will continue to evolve, and radiological measurements and corrections will produce better functional results for patients. PMID- 22938635 TI - Redox regulation of T-cell function: from molecular mechanisms to significance in human health and disease. AB - Reactive oxygen species (ROS) are thought to have effects on T-cell function and proliferation. Low concentrations of ROS in T cells are a prerequisite for cell survival, and increased ROS accumulation can lead to apoptosis/necrosis. The cellular redox state of a T cell can also affect T-cell receptor signaling, skewing the immune response. Various T-cell subsets have different redox statuses, and this differential ROS susceptibility could modulate the outcome of an immune response in various disease states. Recent advances in T-cell redox signaling reveal that ROS modulate signaling cascades such as the mitogen activated protein kinase, phosphoinositide 3-kinase (PI3K)/AKT, and JAK/STAT pathways. Also, tumor microenvironments, chronic T-cell stimulation leading to replicative senescence, gender, and age affect T-cell susceptibility to ROS, thereby contributing to diverse immune outcomes. Antioxidants such as glutathione, thioredoxin, superoxide dismutase, and catalase balance cellular oxidative stress. T-cell redox states are also regulated by expression of various vitamins and dietary compounds. Changes in T-cell redox regulation may affect the pathogenesis of various human diseases. Many strategies to control oxidative stress have been employed for various diseases, including the use of active antioxidants from dietary products and pharmacologic or genetic engineering of antioxidant genes in T cells. Here, we discuss the existence of a complex web of molecules/factors that exogenously or endogenously affect oxidants, and we relate these molecules to potential therapeutics. PMID- 22938647 TI - Foot & ankle innovations in Latin America. Preface. PMID- 22938649 TI - Cyclizative atmospheric CO2 fixation by unsaturated amines with t-BuOI leading to cyclic carbamates. AB - A cyclizative atmospheric CO(2) fixation by unsaturated amines such as allyl and propargyl amines under mild reaction conditions, efficiently leading to cyclic carbamates bearing a iodomethyl group, have been developed utilizing tert-butyl hypoiodite (t-BuOI). PMID- 22938648 TI - Temporal dynamics in the free-living bacterial community composition in the coastal North Sea. AB - The coastal North Sea is characterized by strong seasonal dynamics in abiotic and biotic variables. Hence, pronounced temporal changes in the bacterioplankton community composition can be expected. Catalyzed reporter deposition fluorescence in situ hybridization analysis showed a seasonal succession, with Alphaproteobacteria dominating before the spring phytoplankton bloom, Bacteroidetes increasing during the bloom (up to 60% of the prokaryotic community) and being replaced by Gammaproteobacteria during the postbloom period (on average 30% of prokaryotic cells). Daily changes in similarity of the bacterioplankton community assessed by Terminal Restriction Fragment Length Polymorphism averaged 0.08 day(-1) (Whittaker similarity index) for the free living bacterial community, resulting in a decreasing similarity between samples with increasing time up to approximately 150 days. After about 150 days, the community composition became increasingly similar to the initial composition. Changes in the bacterial community showed periods of fairly stable composition, interrupted by periods of rapid changes. Taken together, our results support the notion of a recurring bacterioplankton community in the coastal North Sea and indicate a tight coupling between the resources, the bacterial community metabolism, physiological structure and community composition throughout the seasonal cycle in the coastal North Sea. PMID- 22938650 TI - Pathological gambling: relationship to obesity, self-reported chronic medical conditions, poor lifestyle choices, and impaired quality of life. AB - BACKGROUND: Pathological gambling (PG) is an important public health problem that is prevalent, costly to society, and associated with substance misuse, depression, domestic violence, crime, and suicide. Despite these challenges, little is known about the physical health and medical correlates of PG. The goal of this project was to assess self-reported chronic medical conditions, medication usage, lifestyle choices, health care utilization, quality of life variables, and body mass index (BMI) in persons with and without PG. METHODS: Subjects with PG and community controls were systematically assessed for their medical health, lifestyle choices, medication usage, and health care utilization. We administered the Medical Outcome Study Short-Form 36 Health Survey to assess perceived health and quality of life. BMI was calculated for all subjects. Obesity was defined as having a BMI>=30kg/m(2). RESULTS: We compared 95 subjects with DSM-IV PG (South Oaks Gambling Screen [SOGS] score>=5) and 91 control subjects without PG (SOGS<=2) selected through random digit dialing from the general community. PG subjects and controls were similar in age and gender. Persons with PG had more medical and mental health conditions than controls, and were more likely to avoid regular exercise, smoke>=1 pack/day, drink>=5 servings of caffeine daily, and watch television>=20hours/week. They had more emergency department visits for physical and mental health conditions, were more likely to have been psychiatrically hospitalized in the past year, and were more likely to take psychotropic medication. They were less likely to have had regular dental visits and were more likely to put off medical care due to financial problems. Severity of gambling was positively correlated with number of medical conditions. Persons with PG had poorer self-reported health perceptions on all but one SF-36 subscale. Importantly, persons with PG had a higher BMI than controls and were more likely to be obese. CONCLUSIONS: PG is associated with obesity, chronic medical conditions, poor lifestyle choices, worse quality of life, and the use of costly forms of medical care. Pathological gamblers are less likely to receive regular dental care and are more likely to be unable to pay for medical care. The implications of the findings are discussed. PMID- 22938651 TI - Superior diagnostic performance of perfusion-cardiovascular magnetic resonance versus SPECT to detect coronary artery disease: The secondary endpoints of the multicenter multivendor MR-IMPACT II (Magnetic Resonance Imaging for Myocardial Perfusion Assessment in Coronary Artery Disease Trial). AB - BACKGROUND: Perfusion-cardiovascular magnetic resonance (CMR) is generally accepted as an alternative to SPECT to assess myocardial ischemia non-invasively. However its performance vs gated-SPECT and in sub-populations is not fully established. The goal was to compare in a multicenter setting the diagnostic performance of perfusion-CMR and gated-SPECT for the detection of CAD in various populations using conventional x-ray coronary angiography (CXA) as the standard of reference. METHODS: In 33 centers (in US and Europe) 533 patients, eligible for CXA or SPECT, were enrolled in this multivendor trial. SPECT and CXA were performed within 4 weeks before or after CMR in all patients. Prevalence of CAD in the sample was 49% and 515 patients received MR contrast medium. Drop-out rates for CMR and SPECT were 5.6% and 3.7%, respectively (ns). The study was powered for the primary endpoint of non-inferiority of CMR vs SPECT for both, sensitivity and specificity for the detection of CAD (using a single-threshold reading), the results for the primary endpoint were reported elsewhere. In this article secondary endpoints are presented, i.e. the diagnostic performance of CMR versus SPECT in subpopulations such as multi-vessel disease (MVD), in men, in women, and in patients without prior myocardial infarction (MI). For diagnostic performance assessment the area under the receiver-operator-characteristics-curve (AUC) was calculated. Readers were blinded versus clinical data, CXA, and imaging results. RESULTS: The diagnostic performance (= area under ROC = AUC) of CMR was superior to SPECT (p = 0.0004, n = 425) and to gated-SPECT (p = 0.018, n = 253). CMR performed better than SPECT in MVD (p = 0.003 vs all SPECT, p = 0.04 vs gated SPECT), in men (p = 0.004, n = 313) and in women (p = 0.03, n = 112) as well as in the non-infarct patients (p = 0.005, n = 186 in 1-3 vessel disease and p = 0.015, n = 140 in MVD). CONCLUSION: In this large multicenter, multivendor study the diagnostic performance of perfusion-CMR to detect CAD was superior to perfusion SPECT in the entire population and in sub-groups. Perfusion-CMR can be recommended as an alternative for SPECT imaging. TRIAL REGISTRATION: ClinicalTrials.gov, Identifier: NCT00977093. PMID- 22938653 TI - Recent status of total mercury and methyl mercury in the coastal waters of the northern Gulf of Mexico using oysters and sediments from NOAA's mussel watch program. AB - The current status of mercury concentrations in the Gulf of Mexico (GOM) were assessed using the Mussel Watch Program (MWP) contaminant monitoring data, which is based on the analysis of oyster tissue and sediment samples. In both matrices, tHg and MeHg concentrations varied broadly. Significant concentration differences (p<0.05) between the sub-regions of the eastern, central and western Gulf were observed with maximum concentrations (hotspots) found at specific sites all across the Gulf. Compared to the Food and Drug Administration's action level in seafood, maximum mercury values were low. Based on the long-term MWP data, tHg in tissues show fairly static temporal trends along the central and western Gulf coast, while strong decreasing trends were observed in the eastern Gulf. However, the presence of mercury hotspots indicates that mercury is still a concern in the GOM. The results complement existing information to further the understanding of mercury distributions in the GOM. PMID- 22938652 TI - Vital mitochondrial functions show profound changes during yeast culture ageing. AB - During a 10-day culture ageing, cells of the wild-type Saccharomyces cerevisiae strain JC 482 retain their viability, while mitochondrial function and morphology change. Cell routine and uncoupled respiration rates increase to a maximum on day 4 and then decline to near zero. The decline, which occurs also in mitochondria isolated from cells of different age, is not due to increasing proportion of petites. Rhodamine 123 fluorescence intensity reporting on mitochondrial membrane potential appears to drop slightly for 4 days and then more sharply at the time when respiration rate also decreases. The MitoTracker Green fluorescent signal related to the mitochondrial content per cell also decreases. The branched tubular mitochondrial network of 1-day-old cells dissolves into short fragments; during the first 4 days, this fragmentation is associated with increasing function of mitochondria, while later on, it accompanies functional decline, which is also indicated by the decreasing ratio of Rhodamine 123 fluorescence to MitoTracker Green fluorescence. As shown by cell counting, microscopy and flow cytometry, the cell size distribution in the population broadens, and the population thus becomes more heterogeneous. The changes in respiration rate, mitochondrial membrane potential, mass and structure point to changes in the mitochondrial status during ageing. PMID- 22938654 TI - Predictors of cancer-specific mortality after disease recurrence following radical cystectomy. AB - Study Type - Therapy (case series) Level of Evidence 4 What's known on the subject? and What does the study add? Outcomes after disease recurrence in patients with urothelial carcinoma of the bladder treated with radical cystectomy are variable, but the majority of patients die from the disease within 2 years after disease recurrence. Knowledge about prognostic factors that may influence survival after disease recurrence is limited. We found that outcomes after disease recurrence in patients with urothelial carcinoma of the bladder are significantly affected by common clinicopathological factors. In addition, a shorter time from surgery to disease recurrence is significantly associated with poor outcomes. These factors should be considered when scheduling salvage chemotherapy protocols/clinical trials. OBJECTIVE: To describe the natural history following disease recurrence after radical cystectomy (RC) and to identify prognostic factors that influence cancer-specific survival with special focus on time from RC to disease recurrence. METHODS: We identified 1545 patients from 16 international institutions who experienced disease recurrence after RC and bilateral lymphadenectomy. None of the patients received preoperative chemotherapy; 549 patients received adjuvant chemotherapy. A multivariable Cox regression model addressed time to cancer-specific mortality after disease recurrence. RESULTS: The median cancer-specific survival time after disease recurrence was 6.9 months (95% CI 6.3-7.4). Overall, 1254 of 1545 patients died from urothelial carcinoma of the bladder and 47 patients died from other causes. The actuarial cancer-specific survival estimate at 12 months after disease recurrence was 32%. On multivariable analysis, non-organ-confined tumour stages (hazard ratio [HR] 1.38, P= 0.002), lymph node metastasis (HR 1.25, P < 0.001), positive soft tissue surgical margin (HR 1.32, P= 0.002), female gender (HR 1.21, P= 0.003), advanced age (HR 1.16, P < 0.001) and a shorter interval from surgery to disease recurrence (P < 0.001) were significantly associated with cancer specific mortality. The adjusted risk of death from cancer within 1 year after disease recurrence for patients who recurred 6, 12 and 24 months after surgery was 70%, 64% and 60%, respectively. CONCLUSIONS: Over two-thirds of patients who experience disease recurrence of urothelial carcinoma of the bladder after RC die within 12 months. Common clinicopathological factors are strongly associated with cancer-specific mortality. A shorter time from surgery to disease recurrence is significantly associated with poor outcomes. Accurate risk stratification could help in patient counselling and decision-making regarding salvage treatment. PMID- 22938655 TI - Destabilized eYFP variants for dynamic gene expression studies in Corynebacterium glutamicum. AB - Fluorescent reporter proteins are widely used for the non-invasive monitoring of gene expression patterns, but dynamic measurements are hampered by the extremely high stability of GFP and homologue proteins. In this study, we used SsrA mediated peptide tagging for the construction of unstable variants of the GFP derivative eYFP (enhanced yellow fluorescent protein) and applied those for transient gene expression analysis in the industrial platform organism Corynebacterium glutamicum. PMID- 22938656 TI - Synthesis of CaO-based sorbents for CO(2) capture by a spray-drying technique. AB - Highly effective and durable CO(2) sorbents were synthesized with different calcium and support precursors using a spray-drying technique. It was found that spray-drying could be a useful technique for producing sorbents with enhanced cyclic performance, especially when d-gluconic acids of calcium and magnesium were used. Seven sorbents were synthesized with five calcium precursors and three inert solid precursors, and the sorbent made from calcium d-gluconte monohydrate and magnesium d-gluconate hydrate with 75 wt % CaO content achieved a high CO(2) sorption capacity of 0.46 g of CO(2)/g of calcined sorbent at the 44th cycle of carbonation and calcination. PMID- 22938657 TI - [Persistent inflammation-immunosuppression catabolism syndrome: a new explanation on inflammatory, immune- and metabolic situation of the blocked patients in ICU]. PMID- 22938658 TI - [Objective evaluation of the clinical significance of biomarkers in sepsis]. PMID- 22938659 TI - [Effects of postoperative restrictive fluid management on recovery of gastrointestinal function after elective colonic resection]. AB - OBJECTIVE: To investigate the effect of postoperative restrictive fluid management by ensuring adequate tissue perfusion on the recovery of gastrointestinal function after elective colonic resection. METHODS: Thirty patients suffered with elective colonic resection, after 6 hours of anesthesia recovery, were randomly divided into restrictive fluid management group (restrictive group, n=15) and traditional fluid management group (control group, n=15). From the surgery day to the 4th postoperative day, patients in restrictive group and control group received the total fluids of 25-35 ml*kg(-1)*d(-1) or 40 50 ml*kg(-1)*d(-1) respectively. Fluid balance, tissue perfusion, gastrointestinal function recovery time and the imbalance of fluid and electrolyte were recorded. RESULTS: The total fluid input and net fluid balance in restrictive group were significantly fewer than those in control group (total fluid input: 1782.56+/-258.38 ml/d vs. 2707.50+/-294.64 ml/d, net fluid balance: 316.67+/-202.86 ml/d vs. 623.33+/-244.38 ml/d, both P<0.05), and central venous pressure (CVP) was significantly lower than that in control group (4.03+/-1.81 mm Hg vs. 6.47+/-3.09 mm Hg, P<0.05). There were no differences in heart rate (HR) and mean arterial pressure (MAP) between two groups (HR: 85.03+/-13.49 bpm vs. 81.44+/-12.49 bpm, MAP: 80.65+/-11.39 mm Hg vs. 82.38+/-8.28 mm Hg, both P>0.05). The lactate clearance rate of the first postoperative 24 hours in restrictive group was higher than that in control group [35 (17, 53)% vs. 17 (-6, 33)%, P<0.05]. The times of bowel sounds recovery, the first flatus and stool passed in restrictive group were shorter than those in control group (bowel sounds: 37.43+/ 24.97 hours vs. 46.36+/-19.34 hours, flatus: 53.63+/-12.78 hours vs. 75.43+/ 20.07 hours, stool: 78.73+/-46.48 hours vs. 93.40+/-41.08 hours, all P<0.05). Vomiting was reduced in the restrictive group compared with control group (2 vs. 7, P<0.05). There were no differences in the occurrences of electrolyte imbalance (5 vs. 3), fluid insufficient (2 vs. 0) and fluid overload (0 vs. 1) between the two groups. CONCLUSION: The postoperative restrictive fluid management by ensuring tissue perfusion can shorten the gastrointestinal function recovery time after elective colonic resection, and may not increase the incidence of water and electrolyte disorders. PMID- 22938660 TI - [Clinical comparison study of Chinese adult serum cystatin C based estimated glomerular filtration rate equations]. AB - OBJECTIVE: To probe the clinical value of estimated glomerular filtration rate (GFR) formulas for adults Chinese based on the serum cystatin C(SCys C, SCysCAC). METHODS: GFRs for 96 cases of patient in hospital suffering from the kidney diseases without dialysis from January to December in 2011 were measured using clearance rate of (99m) Tc-diethylene triamine pentaacetic acid ((99m) Tc- DTPA, Tc-GFR) by prospective control study method. Based on the renal function, 96 patients were sorted into renal function insufficient group (RFI, n=54) and renal function normal group (RFN, n=42). The SCys C, serum creatinine (SCr) and blood urea nitrogen (BUN) were measured at the same day for calculating GFRs simultaneously by nine formulas such as SCysCAC, Arnal-Dade, Grubb, Filler, Grubb, Hojs, Larsson, Macisaac, Rule etc. The comparison were performed for the estimated GFRs (eGFRs) of renal insufficiency patients and those with normal renal function and the correlation analysis were done between the calculations and Tc-GFR respectively. RESULTS: eGFRs calculated by SCysCAC, Arnal-Dade, Larsson and Rule formulae always were close to those of Tc-GFR and that were 37.96+/-32.65 ml*min(-1)*1.73 m(-2), 33.69+/-25.24 ml*min(-1)*1.73 m(-2), 34.16+/ 33.65 ml*min(-1)*1.73 m(-2), 33.02+/-30.88 ml*min(-1)*1.73 m(-2) vs. 36.21+/ 31.16 ml*min(-1)*1.73 m(-2) in RFI group, 112.99+/-39.26 ml*min(-1)*1.73 m(-2), 101.86+/-72.29 ml*min(-1)*1.73 m(-2), 102.69+/-71.78 ml*min(-1)*1.73 m(-2), 99.12+/-69.54 ml*min(-1)*1.73 m(-2) vs. 110.54+/-48.98 ml*min(-1)*1.73 m(-2) in RFN group (all P>0.05). The absolute value difference between eGFR by SCysCAC, Larsson and Arnal-Dade formulae and Tc-GFR in RFN or RFI group showed no significant change and the absolute value of the value difference between SCysCAC eGFR and Tc-GFR was the least among the three absolute values and showed that eGFRs from the three formulas could all reflect the GFR accurately and the SCysCAC formula was the best. The correlation analysis showed the eGFRs from every formula could all to some extent reflect the glomerular function or GFR accurately. CONCLUSION: The SCysCAC formula was a quickly and accurate method for estimating GFR and may apply clinically. PMID- 22938661 TI - [Value of creatinine clearance rate estimated based on serum cystatin C in patients with acute kidney injury]. AB - OBJECTIVE: To investigate diagnostic value of creatinine clearance rate (CCr) based on serum cystatin C (SCys C) in acute kidney injury (AKI), and whether it could predict the need for renal replacement therapy (RRT). METHODS: The patients enrolled with the length of intensive care unit (ICU) stay over 3 days were collected from August 2010 to May 2011. According to the diagnosis of AKI during the ICU stay, patients were divided into the AKI group (n=21) and non-AKI group (n=30). After patients were admitted, the level of SCys C and creatinine (SCr) were measured so as to count CCr based on SCys C (SCys C-CCr) or on SCr (SCr-CCr) respectively, meanwhile urine volume and acute physiology and chronic health evaluation II (APACHE II) score were monitored. The value of CCr counted by SCys C and SCr on predict AKI and the correlations between RRT were compared. RESULTS: SCr-CCr and SCys C-CCr in AKI group both were significantly lower than non-AKI group all the way through on admission, and 2 days and 1 day before AKI diagnosed and the day AKI diagnosed. The level of SCys C-CCr on 2 days prior to AKI diagnosed was significantly lower than the day admitted (70.6+/-8.4 ml*min( 1)*1.73 m(-2) vs. 114.8+/-15.8 ml*min(-1)*1.73 m(-2), P<0.01), whereas the level of SCr-CCr were not significantly changed (76.4+/-19.3 ml*min(-1)*1.73 m(-2) vs. 78.7+/-22.1 ml*min(-1)*1.73 m(-2), P>0.05). Receptor operative curve (ROC) analysis indicated that SCys C-CCr could predict AKI earlier than SCr-CCr, as the area under curve (AUC) of SCys C-CCr and SCr-CCr on 2 days prior to AKI diagnosed were 0.859 and 0.664, respectively, and the sensitivity were 90.5% and 47.6%, the specificity were 76.2% and 81.0%. In AKI group 6 patients were treated with RRT, the AKI patients receiving RRT had significantly higher APACHE II score on admission (29.6+/-4.5 vs. 17.0+/-5.6, P<0.05) and less urine volume within 24 hours (740+/-465 ml vs. 1780+/-1230 ml, P<0.05) than patients not received RRT, however, SCys C-CCr has no significant difference between the sub-group (50.4+/ 11.2 ml*min(-1)*1.73 m(-2) vs. 53.0+/-8.4 ml*min(-1)*1.73 m(-2), P>0.05). SCys C CCr did not predict the need of RRT on the day to diagnose AKI (AUC=0.65). CONCLUSIONS: The sensitivity of SCys C-CCr were high, but its specificity not. The SCys C-CCr may be helpful for excluding diagnose of AKI in high risk patients. However, it could not predict the need for renal replacement therapy on the day AKI diagnosed. PMID- 22938662 TI - [Prospective observational study exploring the relationship between the levels and variability of blood glucose and the prognosis of critical patients]. AB - OBJECTIVE: To explore the relationship between the levels and variability of blood glucose and the prognosis of critical patients. METHODS: A prospective study was conducted. Blood glucose monitoring and prognosis observation were performed for the adult nondiabetic patients admitted in intensive care unit (ICU) from June 2011 to January 2012. Blood glucose monitoring terminal was 72 hours after admitting in ICU, prognosis was observed for 28 days after the end of turning into ICU. Acute physiology and chronic health evaluation II(APACHE II) scores when transferred into ICU and blood glucose variability [standard deviation (SD) of blood glucose, mean absolute blood glucose fluctuation amplitude (MAGE) and glycemic instability index (GLI)] were calculated. Patients were divided into death group and survival group according to the outcome, and the APACHE II score, mean blood glucose and blood glucose variability were compared between the two groups. Patients were divided into different groups based on the blood glucose, and the APACHE II score, blood glucose variability and 28-day mortality were compared among groups. RESULTS: Total 85 cases were enrolled. Compared with survivor group (n=58), in death group (n=27), APACHE II score (28.9+/-6.6 vs. 23.8+/-5.9), mean blood glucose (11.9+/-2.9 mmol/L vs. 9.4+/-1.8 mmol/L), SD of blood glucose (3.7+/-1.6 mmol/L vs. 2.4+/-1.0 mmol/L), MAGE (0.86+/-0.46 mmol/L vs. 0.54+/-0.25 mmol/L) and GLI (255.9+/-232.7 vs. 111.7+/-110.9) were increased (all P<0.05). SD of blood glucose (4.3+/-1.4 mmol/L), MAGE (1.1+/-0.4 mmol/L), GLI (345.3+/-210.3) and 28-day mortality (63.6%) in blood glucose >11.1 mmol/L group (n=22) were higher than those in <=11.1 mmol/L group (n=63, 2.3+/-0.9 mmol/L, 0.5+/-0.2 mmol/L, 91.9+/-91.2, 20.6%, respectively, all P<0.05) and 7.8-11.1 mmol/L group (n=52, 2.3+/-0.9 mmol/L, 0.5+/-0.2 mmol/L, 85.2+/-66.4, 25.0%, respectively, all P<0.05). There were no significant differences between 7.8-11.1 mmol/L group and <7.8 mmol/L group (n=11) in SD of blood glucose (2.0+/-0.9 mmol/L), MAGE (0.5+/-0.3 mmol/L), GLI (123.8+/-166.7) and 28-day mortality (0, all P>0.05). CONCLUSION: Blood glucose variability is associated with critical patient's 28-day mortality, and may predict mortality as good as APACHE II score. PMID- 22938663 TI - [Changes in plasma adiponectin concentrations in sepsis and its correlation with the severity of the disease]. AB - OBJECTIVE: To explore the regularity of changes in total adiponectin (APN) and high molecular bodyweight adiponectin (HAP) in sepsis, and its correlation with infection and its role on predicting prognosis. METHODS: A prospective study was conducted. Eighty patients with sepsis in intensive care unit (ICU) of Shengjing Hospital of China Medicine University from June to November in 2011 were enrolled in this study. The plasma APN (both total APN and HAP), procalcitonin (PCT), and endotoxin were determined with enzyme linked immunosorbent assay (ELISA) at 2 hours, 2 days, and 6 days after ICU admission. The acute physiology and chronic health evaluation II (APACHE II), sequential organ failure assessment (SOFA), and simplified acute physiology score II (SAPS II) scores were recorded, and insulin resistance index was calculated. Twenty healthy volunteers and 21 patients with systemic inflammation response syndrome (SIRS) were enrolled as controls and SIRS group. RESULTS: Plasma total APN and HAP in sepsis patients at 2 hours after ICU admission were significantly decreased compared with control group and SIRS group [total APN: 2.87 (2.28, 3.89) mg/L vs. 6.48+/-1.53 mg/L, 3.72 (2.67, 4.59) mg/L; HAP: 2.64 (2.07, 3.75) mg/L vs. 5.12+/-1.98 mg/L, 3.33 (2.23, 4.24) mg/L, P<0.05 or P<0.01]. A negative correlation was found between total APN and HAP in plasma and PCT (total APN r=-0.559, HAP r=-0.530, both P<0.01), but no correlation with endotoxin. Those correlations remained significantly in partial correlation analysis controlled by insulin resistance status. There were significances in APN among sepsis, severe sepsis and septic shock groups, and negative correlations were found between APN and APACHE II, SOFA, and SAPS II scores (total APN r value, -0.868, -0.766, -0.725; HAP r value, -0.859, -0.715, -0.692, all P<0.01). Total APN and HAP in plasma of survivors with sepsis (n=41) was gradually increased following the recovery of the disease (total APN chi(2)=34.520, HAP chi(2)=27.802, both P<0.01) and the level in non-survivors (n=7) was decreased (total APN chi(2)=3.938, HAP chi(2)=3.938, both P>0.05). The significantly negative correlations were found between total APN and HAP at 2 hours after ICU admission and ICU duration (total APN r=-0.275, P=0.014; HAP r=-0.299, P=0.007) and ventilation time (total APN r=-0.393, HAP r=-0.519, both P<0.01). CONCLUSIONS: Plasma total APN and HAP was decreased in septic patients, and negatively correlated with PCT. Plasma total APN and HAP played a role in diagnosis of infection and predicting the outcomes, and correlated with severity of sepsis. PMID- 22938664 TI - [Management of blood glucose during enteral nutrition in critical patients]. AB - OBJECTIVE: To investigate an effective and safe protocol for enteral nutrition (EN) patients permitting successfully transmit insulin administration from venous pump-in to subcutaneous injection. METHODS: A prospective randomized control study was conducted. Critical patients admitted to intensive care unit (ICU) of Beijing Tongren Hospital from September 2008 to February 2009 were randomly divided into two groups when the energy provided by EN up to half of the total energy requirement. Experiment group (n=44): the protocol was applied for insulin glargine and regular insulin injection; control group (n=43): protocol was applied for subcutaneous regular insulin injection. Target glucose range was 4.4 7.8 mmol/L (80-140 mg/dl). If blood glucose >=11.1 mmol/L was maintained twicely, the approach of insulin administration would convert from subcutaneous injection to venous pump-in using the computerized glucose control protocol. If the infusion rate of insulin was less than 3 U/h and lasted more than 6 hours, blood glucose <=7.8 mmol/L, insulin administration was switched to subcutaneous injection again. The general information and all glucose regulation data were recorded for analysis. RESULTS: The two groups did not differ at baseline for the general information, mean blood glucose and the glucose variation. A total of 1689 blood glucose records were analyzed. The mean blood glucose in experiment group, and was significantly lower than that in control group(7.58+/-1.17 mmol/L vs. 9.40+/-1.74 mmol/L, P<0.05). The rate of glucose values within target range in experiment group was significantly higher than that in control group [49.72% (534/1074) vs. 35.61% (219/615), P<0.01]. The glucose standard deviation (SD) in experiment group was significantly lower than that in control group (1.89+/-0.52 mmol/L vs. 2.17+/-0.94 mmol/L, P<0.05). The number of measurements needed per patient per day was significantly reduced in experiment group compared with control group (7.51+/-1.31 vs. 8.15+/-0.97, P<0.05). The ratio of patients converted to venous pump-in was significantly decreased in experiment group compared with control group (9.09% vs. 44.19%, P<0.01). Hypoglycemia (<=3.3 mmol/L) did not different between experiment group and control group [0.74% (8/1074) vs. 0.49% (3/615), P=0.75]. CONCLUSIONS: Compared with the conventional subcutaneous insulin injection protocol, this protocol with insulin glargine combined regular insulin subcutaneous injection can control the glucose level effectively during EN in critical patients. The glucose variation and the numbers of measurements were significantly reduced by this protocol. It is helpful for the insulin transmission from venous pump-in to subcutaneous injection. PMID- 22938665 TI - [The effects of rosiglitazone combined ceftazidime on peroxisome proliferator activated receptor gamma activity and interleukin in septic rats]. AB - OBJECTIVE: To observe the effects of rosiglitazone (RSG) and ceftazidime (CAZ) on peroxisome proliferator activated receptor gamma (PPARgamma) activity in nucleated cells and interleukin (IL-4, IL-6) levels in plasma in septic rats. METHODS: According to randomized digital table, 180 male Sprague-Dawley (SD) rats were assigned to control group, sham operation group, sepsis group, CAZ group, RSG group and combined CAZ and RSG group. Sepsis model was established by cecal ligation and puncture (CLP). Drugs were administered by intraperitoneal injection at 3-hour post-operation, once every 12-hour. The PPARgamma activity in nucleated cells and IL-4, IL-6 levels in plasma were detected by enzyme linked immunosorbent assay (ELISA) at 12, 24 and 48 hours post-operation. RESULTS: There was no difference in PPARgamma activity and levels of IL-4 and IL-6 at each time point post-operation between control group and sham operation group. Compared with control group and sham operation group, PPARgamma activity [absorbance (A) value] in nucleated cells in sepsis group, where downward trend was seen as time went on, significantly reduced (0.263+/-0.017 vs. 0.292+/-0.005, 0.294+/-0.007, both P<0.05). PPARgamma activity was significantly higher in CAZ group, RSG group and CAZ + RSG group than in sepsis group (0.282+/-0.008, 0.336+/-0.020, 0.347+/ 0.007 vs. 0.263+/-0.017, all P<0.05), CAZ + RSG group>RSG group >CAZ group (both P<0.05). Plasma IL-6 and IL-4 levels were higher in sepsis group than in control group and sham operation group (IL-6: 436.77+/-62.28 ng/L vs. 45.11+/-10.42 ng/L, 42.28+/-7.54 ng/L; IL-4: 89.24+/-25.06 ng/L vs. 41.34+/-7.08 ng/L, 41.49+/-7.27 ng/L, all P<0.05) and reached peak at 24 hours and 48 hours post-operation, respectively. Compared with sepsis group, IL-6 and IL-4 levels in CAZ group, RSG group and CAZ + RSG group were significantly decreased (IL-6: 273.48+/-12.13 ng/L, 317.64+/-14.10 ng/L, 253.94+/-13.57 ng/L vs. 436.77+/-62.28 ng/L; IL-4: 59.12+/-7.03 ng/L, 68.37+/-8.28 ng/L, 53.81+/-8.34 ng/L vs. 89.24+/-25.06 ng/L, all P<0.05), CAZ + RSG group < CAZ group < RSG group (all P<0.05). CONCLUSION: In septic rats, PPARgamma activity in nucleated cells was decreased. On the basis of effective antibiotic treatment, RSG might play a role in improving PPARgamma activity in nucleated cells and reducing the levels of inflammation mediators and anti-inflammatory in plasma. PMID- 22938666 TI - [The clinical trial of low dose heparin infusion for the treatment of thrombocytopenia in heat stroke patients]. PMID- 22938667 TI - [Study of the relationship between air temperature and stroke in Changzhi area]. PMID- 22938668 TI - [The analysis of death causes in 201 patients admitted to intensive care unit]. PMID- 22938669 TI - [Heat stroke induced intestinal mucosal mechanical barrier dysfunction]. PMID- 22938670 TI - [Biomarkers for the early diagnosis of acute kidney injury]. PMID- 22938671 TI - [Gastric residual volume and the application of gastrointestinal prokinetic agents in critical patients]. PMID- 22938672 TI - Molecular encapsulation in pyrogallolarene hexamers under nonequilibrium conditions. AB - Pyrogallol[4]arene is a macrocycle with a concave surface and 12 peripheral hydroxyl groups that mediate its self-assembly to form hexamers of octahedral symmetry in the solid state, in solution, and in the gas phase. These hexamers enclose approximately 1300 A(3) of space, which is filled with small molecules. In this study, we show that solvent-free conditions for guest entrapment in these hexamers, using molten guest molecules as solvent and allowing the capsules to assemble during cooling, results in exceptionally kinetically stable encapsulation complexes that are not formed in the presence of solvent and are not thermodynamically stable. The capsules' kinetic stabilities are strongly dependent on the size and shape of both guest and solvent molecules, with larger or nonplanar molecules with rigid geometries providing enhanced stability. The greatest observed barrier to guest exchange, DeltaG(?) = 32 +/- 0.7 kcal mol(-1) for encapsulated CCl(4) -> encapsulated pyrene, is, to the best of our knowledge, indicative of the most powerful kinetic trap ever observed for a synthetic, hydrogen-bonded encapsulation complex. Detailed NMR studies of the structures of the assemblies and the kinetics and mechanisms for guest exchange reveal that subtle differences in guest and solvent structure can impart profound effects on the behavior of the systems. Kinetic and thermodynamic stability, capsule symmetry and structure, guest tumbling rates, susceptibility to disruption by polar solvents, and even the mechanism for equilibration-the presence or absence of supramolecular intermediates-are all greatly influenced. The strongest observed kinetic traps provide encapsulation complexes that are not at equilibrium but are nonetheless indefinitely persistent at ambient temperatures, a property that invites future applications of supramolecular chemistry in open systems where equilibrium is not possible. PMID- 22938673 TI - [Progression of diabetic retinopathy after cataract surgery by phacoemulsification]. AB - PURPOSE: To study the effect of cataract surgery by phacoemulsification and intraocular lens implantation on the progression of diabetic retinopathy (DR) using the nonoperated fellow eye as a control, by a retrospective comparative study. PATIENTS AND METHODS: We studied 46 diabetic patients who underwent monocular cataract surgery by phacoemulsification with implantation of an intraocular lens within the capsular bag, with the nonoperated fellow eye used as a control. In all cases, the fellow eye exhibited only a very mild cataract, allowing for visualization of the fundus. Preoperative and 1, 3, 6 and 12 months postoperative ophthalmic examination and fundus photographs, supplemented if necessary by retinal fluorescein angiography, were performed to assess DR using the Alfediam classification. Patients were followed for at least 1 year. RESULTS: Among the 46 patients, preoperative DR was absent in 40 patients, and six patients had bilateral, symmetric non-proliferate diabetic retinopathy (NPDR): mild in four patients, moderate in one patient and moderately severe in another patient. Thirty-five eyes (76%) had postoperative best corrected visual acuity of 8/10 or better. Progression of DR occurred at about 23.9% (11/46) in the operated eyes and 19.6% (9/46) in the nonoperated eyes. As compared by the MacNemar test, there was no significant difference between operated and nonoperated eyes (P=0.68). CONCLUSION: This study demonstrates that cataract surgery by phacoemulsification does not represent an apparent risk factor for progression of DR. PMID- 22938675 TI - Assessment of professionalism: a consolidation of current thinking. AB - CONTEXT: Professionalism has become a hot topic in medical education. Professionalism needs to be assessed if it is to be viewed as both positive and relevant. OBJECTIVES: The assessment of professionalism is an evolving field. This review aims to consolidate current thinking. IMPLICATIONS: Assessment of professionalism has progressed from an initial focus on the development and attainment of professional identity, through identifying areas of deficiency, to the attainment of a set of identifiable positive attributes and behaviours. It is now beginning to recognise the challenge of assessing a multi-dimensional construct, looking beyond the measurement of behaviour to embrace a diversity of approaches. CONCLUSIONS: Professionalism should be assessed longitudinally. It requires combinations of different approaches, assessing professionalism at individual, interpersonal and societal/institutional levels. Increasing the depth and the quality of reliability and validity of existing programmes in various contexts may be more appropriate than concentrating on developing new instruments. Increasing the number of tests and the number of relevant contexts will increase the reliability of the result. Similarly increasing the number of observers increases reliability. Feedback, encouraging reflection, can promote change in behaviour and identity formation. PMID- 22938674 TI - Advocates, interest groups and Australian news coverage of alcohol advertising restrictions: content and framing analysis. AB - BACKGROUND: Legislating restrictions on alcohol advertising is a cost-effective measure to reduce consumption of alcohol. Yet Australia relies upon industry self regulation through voluntary codes of practice regarding the content, timing and placement of alcohol advertising. Ending industry self-regulation was recommended by the National Preventative Health Taskforce; a suggestion contested by the drinks industry. Debates about emerging alcohol-control policies regularly play out in the news media, with various groups seeking to influence the discussion. This paper examines news coverage of recommendations to restrict alcohol advertising to see how supporters and opponents frame the debate, with a view to providing some suggestions for policy advocates to advance the discussion. METHODS: We used content and framing analyses to examine 329 Australian newspaper items mentioning alcohol advertising restrictions over 24 months. All items were coded for mentions of specific types of advertising and types of advertising restrictions, the presence of news frames that opposed or endorsed advertising restrictions, statements made within each frame and the news-actors who appeared. RESULTS: Restrictions were the main focus in only 36% of 329 items. Alcohol advertising was conceived of as television (47%) and sport-related (56%). Restrictions were mentioned in non-specific terms (45%), or specified as restrictions on timing and placement (49%), or content (22%). Public health professionals (47%) appeared more frequently than drinks industry representatives (18%). Five supportive news frames suggested the policy is a sensible public health response, essential to protect children, needed to combat the drinks industry, required to stop pervasive branding, or as only an issue in sport. Four unsupportive frames positioned restrictions as unnecessary for a responsible industry, an attack on legitimate commercial activities, ineffective and 'nannyist', or inessential to government policy. Support varied among news actors, with public health professionals (94%) more supportive than the public (68%), community-based organisations (76%), the government (72%), and the sports (16%), drinks (3%), or advertising (4%) industries. CONCLUSION: Restrictions on alcohol advertising currently have low newsworthiness as a standalone issue. Future advocacy might better define the exact nature of required restrictions, anticipate vocal opposition and address forms of advertising beyond televised sport if exposure to advertising, especially among children, is to be reduced. PMID- 22938676 TI - Acquisition of clinical competence: Added value of clerkship real-life contextual experience. AB - BACKGROUND: Medical students' limited access to patients induces a shift of learning activities from clinical wards to classrooms. AIM: Identify clinical competencies specifically acquired during real-life contextual clerkship added to case-based tutorials, by a prospective, controlled study. METHODS: Students entering our eight-week internal medicine (IM) clerkship attended paper case based tutorials about 10 common presenting complaints and were assigned to an IM specialty ward. For each tutorial case, two groups of students were created: those assigned to a ward, the specialty of which was unrelated to the case (case unrelated ward, CUW) and those assigned to a ward, the specialty of which was related to the case (case-related ward, CRW). RESULTS: Forty-one students (30 CUW and 11 CRW) volunteered for the study. Both groups had similar previous experiences and pre-clerkship exam scores. The CRW students collected more relevant clinical information from the patient (69% vs. 55% of expected items, p=0.001) and elaborated charts of better quality (47% vs. 39% of expected items, p=0.05). Clinical-knowledge mean score was similar (70%) in both groups (p=0.92). CONCLUSIONS: While paper-case tutorials did provide students with clinical knowledge, real contextual experience brought additional, specific competencies. This supports the preservation of clinical exposure with supervision and feedback. PMID- 22938677 TI - Comparative effectiveness of instructional design features in simulation-based education: systematic review and meta-analysis. AB - BACKGROUND: Although technology-enhanced simulation is increasingly used in health professions education, features of effective simulation-based instructional design remain uncertain. AIMS: Evaluate the effectiveness of instructional design features through a systematic review of studies comparing different simulation-based interventions. METHODS: We systematically searched MEDLINE, EMBASE, CINAHL, ERIC, PsycINFO, Scopus, key journals, and previous review bibliographies through May 2011. We included original research studies that compared one simulation intervention with another and involved health professions learners. Working in duplicate, we evaluated study quality and abstracted information on learners, outcomes, and instructional design features. We pooled results using random effects meta-analysis. RESULTS: From a pool of 10,903 articles we identified 289 eligible studies enrolling 18,971 trainees, including 208 randomized trials. Inconsistency was usually large (I2 > 50%). For skills outcomes, pooled effect sizes (positive numbers favoring the instructional design feature) were 0.68 for range of difficulty (20 studies; p < 0.001), 0.68 for repetitive practice (7 studies; p = 0.06), 0.66 for distributed practice (6 studies; p = 0.03), 0.65 for interactivity (89 studies; p < 0.001), 0.62 for multiple learning strategies (70 studies; p < 0.001), 0.52 for individualized learning (59 studies; p < 0.001), 0.45 for mastery learning (3 studies; p = 0.57), 0.44 for feedback (80 studies; p < 0.001), 0.34 for longer time (23 studies; p = 0.005), 0.20 for clinical variation (16 studies; p = 0.24), and 0.22 for group training (8 studies; p = 0.09). CONCLUSIONS: These results confirm quantitatively the effectiveness of several instructional design features in simulation-based education. PMID- 22938678 TI - Educator appraisal--occurrence and experience of hospital consultants in north west England. AB - BACKGROUND: It is recommended all hospital consultants with educational responsibilities undergo appraisal of their educational role by their employer: a key component of revalidation. To support this process locally, the North Western Deanery developed guidance on educational appraisal. We wished to establish the frequency and perceived value of educator appraisal. METHODS: A web-based questionnaire of 605 hospital consultants with educational responsibilities in north-western England was conducted to collect data. RESULTS: Only 17.7% had been appraised for their educational responsibilities in the previous 36 months despite 92.7% undergoing appraisal of clinical work. Educational leads were statistically more likely to have had educational appraisal than educational supervisors (ES), similarly ES were more likely to have had appraisal than clinical supervisors (CS). Clinical specialty does not appear to be a major determining factor. The majority found the supporting documentation helpful in guiding data collection and subsequent recording of evidence. All respondents felt appraisals were conducted in a supportive manner with 76.6% stating appraisal had reassured them they were fulfilling their educational roles and helped 78.5% to identify an education personal development plan. CONCLUSIONS: The incidence of educator appraisal remains low but the experience is considered valuable and contributes effectively to educators' professional development. PMID- 22938679 TI - Optimal learning in a virtual patient simulation of cranial nerve palsies: the interaction between social learning context and student aptitude. AB - BACKGROUND: Simulation in medical education provides students with opportunities to practice interviews, examinations, and diagnosis formulation related to complex conditions without risks to patients. AIM: To examine differences between individual and team participation on learning outcomes and student perspectives through use of virtual patients (VPs) for teaching cranial nerve (CN) evaluation. METHODS: Fifty-seven medical students were randomly assigned to complete simulation exercises either as individuals or as members of three-person teams. Students interviewed, examined, and diagnosed VPs with possible CN damage in the neurological exam rehearsal virtual environment (NERVE). Knowledge of CN abnormalities was assessed pre- and post-simulation. Student perspectives of system usability were evaluated post-simulation. RESULTS: An aptitude-treatment interaction (ATI) effect was detected; at pre-test scores <= 50%, students in teams scored higher (83%) at post-test than did students as individuals (62%, p = 0.02). Post-simulation, students in teams reported greater confidence in their ability to diagnose CN abnormalities than did students as individuals (p = 0.02; mean rating = 4.0/5.0 and 3.4/5.0, respectively). CONCLUSION: The ATI effect allows us to begin defining best practices for the integration of VP simulators into the medical curriculum. We are persuaded to implement future NERVE exercises with small teams of medical students. PMID- 22938680 TI - How experienced tutors facilitate tutorial dynamics in PBL groups. AB - BACKGROUND: Problem-based learning (PBL) tutorial are conducted in small groups, and successful learning in such groups requires good group facilitating skills. There is a lack of research on actual skills employed by tutors in facilitating the group dynamics. AIM: To explore the process of PBL tutorial small groups, focusing on the tutors' actual behavior in facilitating group dynamics. METHODS: Eight experienced tutors from various departments in medical colleges participated in this research. Forty tutorial group sessions were videotaped. Among the 636 tutorial intervention episodes, 142 of them were associated with facilitating group dynamics. Tutors interventions as well as their recalls were transcribed verbatim. Qualitative research methods were utilized to analyze the data. RESULTS: There were 10 tutorial group dynamic situations and 48 tutorial skills. Analysis of the tutors' intentions employing these skills in the 10 situations showed that tutors were trying to achieve the following aims: (1) iteration of PBL principles, (2) delegation of responsibility to the students, (3) creation of a good discussion forum, and (4) the generation of a good learning atmosphere. CONCLUSION: Results from this study provide PBL tutors with a practical frame of reference on group dynamic facilitating skills and stimulate further research on this topic. PMID- 22938681 TI - Development of ACLEEM questionnaire, an instrument measuring residents' educational environment in postgraduate ambulatory setting. AB - BACKGROUND: Students' perceptions of their educational environment (EE) have been studied in undergraduate and postgraduate curricula. Postgraduate EE has been measured in hospital settings. However, there are no instruments available to measure the EE in postgraduate ambulatory settings. AIM: The aim of this study was to develop the "ambulatory care learning education environment measure" (ACLEEM). METHODS: A mixed methodology was used including three stages: (1) Grounded theory (focus groups); (2) Delphi technique to identify consensus; and (3) Pilot study. RESULTS: Three quota samples of approximately 60 stakeholders were formed, one as focus groups and two as Delphi panels. Eight focus groups were carried out including 58 residents (Latin-American Spanish speakers). The results were analysed and 173 items were offered to a National Delphi panel (61 residents and teachers). They reduced in two rounds the number of important items to 54. The 54-item questionnaire was then piloted with 63 residents and refined to the final version of the ACLEEM with 50 items and three domains. CONCLUSIONS: The 50-item inventory is a valid instrument to measure the EE in postgraduate ambulatory setting in Chile. Large-scale administration of the ACLEEM questionnaire to evaluate its construct validity and reliability are the next steps to test the psychometric properties of the instrument. PMID- 22938682 TI - Empathy in Iranian medical students: measurement model of the Jefferson scale of empathy. AB - BACKGROUND: Empathy is an important factor in patient-physician relationship that has beneficial effects in medical practice. Jefferson scale of empathy (JSE) has been specifically designed to assess empathy in health professionals (HP-version) and related students (S-version). Few validation studies have been performed on S version of the scale. AIMS: To examine empathy in a large sample of Iranian medical students, and also to study factor structure and psychometric properties of the Persian translation of the S-version of the JSE. METHOD: 1187 medical students (759 female) from 16 universities around the country participated in the study during 2009. Independent sample t-test, multivariate analysis of variance, and confirmatory factor analysis (CFA) were performed to analyze the data. RESULTS: Female students outscored male students in empathy. The trend for empathy had a negative relationship with years of education. JSE showed an acceptable internal consistency and test re-test reliability. CFA upheld the original three-factor structure--Perspective taking, compassionate care, and standing in the patient's shoes--consisting 20 items. CONCLUSION: The decrease in empathy during medical education is consistent with previous studies. The Persian version of JSE is a valid and reliable measure to tap empathy in a Persian speaking medical student. PMID- 22938683 TI - Anatomy teaching assistants: facilitating teaching skills for medical students through apprenticeship and mentoring. AB - BACKGROUND: Significant increase in the literature regarding "residents as teachers" highlights the importance of providing opportunities and implementing guidelines for continuing medical education and professional growth. While most medical students are enthusiastic about their future role as resident-educators, both students and residents feel uncomfortable teaching their peers due to the lack of necessary skills. However, whilst limited and perhaps only available to select individuals, opportunities for developing good teaching practice do exist and may be identified in courses that offer basic sciences. The Department of Anatomy, College of Medicine, Mayo Clinic offers a teaching assistant (TA) elective experience to third- and fourth-year medical students through integrated apprenticeship and mentoring during the human structure didactic block. AIM: This article, aims to describe a curriculum for a TA elective within the framework of a basic science course through mentoring and apprenticeship. RESULTS: Opportunities for medical students to become TAs, process of TAs' recruitment, mentoring and facilitation of teaching and education research skills, a method for providing feedback and debriefing are described. CONCLUSION: Developing teaching practice based on apprenticeship and mentoring lends to more accountability to both TA's and course faculty by incorporating universal competencies to facilitate the TA experience. PMID- 22938684 TI - Becoming a practitioner: workplace learning during the junior doctor's first year. AB - BACKGROUND: Newly qualified doctors (interns) report that they learn a great deal in the first year of practice, but exactly what is learnt is not well understood. AIMS: To document the reflections and perceptions of first year junior doctors in order to reveal and chronicle their informal and often tacit learning in the workplace within a practice methodology framework. METHODS: New Zealand interns, from three sites, participated in group interviews modelled on a conversation and joint enquiry style. RESULTS: We found that learning in the first year after graduation falls into three broad themes: (1) concrete tasks, (2) project management and (3) identity formation. Identity formation appeared the most challenging and included getting used to being seen by others as a doctor. CONCLUSION: All themes have implications for curriculum development and clinical supervision in both undergraduate programmes and during internship. The third theme (identify formation) is the most complex. We draw on a model from management literature, to describe intern education as a process of becoming: as an unfolding and as a transformation of the self over time. We argue that reconfiguring internship as a period of identity formation, and as a self determined, active process of 'becoming a doctor' provides a wider perspective than enculturation or socialisation theories to understand this significant transition. PMID- 22938685 TI - Evaluation of an e-PBL model to promote individual reasoning. AB - AIM: Medical educators should promote the development of student clinical reasoning toward independence in clinical settings. The objective of this study was to evaluate an online problem-based learning (e-PBL) model designed to promote student individual reasoning in supplement to traditional PBL. METHODS: Twelve e-PBL modules were added to the fully problem-based curriculum for Year 2 at Sungkyunkwan University School of Medicine (SKKUSOM). In this e-PBL, students worked on the problems individually in an online setting, followed by face-to face discussions in a colloquium. The cases were presented using interactive multimedia to enhance the authenticity of the case and stimulate student interest in learning. A formative evaluation study was conducted to determine student satisfaction with e-PBL and its effectiveness as perceived by the students using both quantitative and qualitative methods. A cohort of Year 2 students at SKKUSOM (n = 38) took part in this study. RESULTS: Students perceived e-PBL significantly more positively after they had taken a module in terms of its ability to foster problem-solving skills and its ability to allow them to learn in ways suited to individual learning styles. Additionally, student survey and interview revealed that a vast majority of students were satisfied with the overall learning process in e-PBL and perceived it positively in fostering knowledge acquisition and clinical reasoning. Moreover, students found the cases realistic and engaging. CONCLUSIONS: The results show the potential of e-PBL to enhance traditional PBL by promoting the development of individual reasoning in a flexible online learning environment and offering cases in an interactive multimedia format, which warrants further investigation into its impact on student learning outcomes. PMID- 22938686 TI - Nursing and medical students' perceptions of educational environment and their association with hostility dimensions. PMID- 22938687 TI - Two-dimensional structure of the MAAS-Global rating list for consultation skills of doctors. AB - BACKGROUND: The MAAS-Global (MG) is widely used to assess doctor-patient communication skills. Reliability and validity have been investigated, but little is known about its dimensionality. Assuming physicians tend to adopt certain styles or preferences in their communication with patients, a multi-dimensional structure of the MG can be hypothesized. AIM: This study investigates the dimensional structure of the MG and explores the validity of this structure by studying the relationship between potential MG sub-scales and general practice speciality trainees' personal characteristics. METHODS: Communication skills of 68 first-year trainees in a two-station objective structured clinical examination were assessed. Exploratory factor analysis was conducted on the resulting MG item scores. With t-tests and correlational analysis, the relationship between MG scores and trainees' personal characteristics was examined. RESULTS: Two well interpretable factors were found, representing patient-oriented and task-oriented communication skills. Being born in the Netherlands and empathy were positively associated with overall communication skills. Prior communication skills training was exclusively related to task-oriented communication skills. Empathy was associated with patient-oriented, but not with task-oriented communication skills. CONCLUSION: The two-dimensional structure of the MG may be valuable in gaining a better understanding of factors influencing the acquisition of communication skills. This may be used to optimize teaching methods in communication skills training. PMID- 22938688 TI - How well do medical students rate and communicate clinical empathy? AB - BACKGROUND: This article presents findings from a prospective, longitudinal cohort educational study investigating empathy communication in clinical consultations. It reports on changes in students' self-report empathy during medical undergraduate training, investigates how well peers can assess student competence in motivational interviewing/brief interventions (MI/BI) skills and explores the relationship between students' self-report empathy and peer- or tutor-assessments of competence. METHODS: 72 medical students completed the Jefferson Scale of Physician Empathy at three time points: at the beginning of their fifth year medical training (Time 1), after a specific MI/BI training session during their fifth year medical training (Time 2) and 1 year later during a revision session in year 6. Competence in BI/MI consultation was assessed using the validated tool Behaviour Change Counselling Index. RESULTS: A significant decline in medical students' empathy scores was observed from year 5 to year 6, consistent with international findings. Peer assessments and tutor ratings of competence in MI/BI skills performance were moderately correlated, but peer assessments were negatively correlated with medical students' self-rated empathy. Senior medical students who self-rated as more empathic received lower competence evaluations of MI/BI skills from their peers. Interventions to further investigate teaching and learning of empathy are discussed. PMID- 22938689 TI - A vertical study programme for medical students: peer-assisted learning in practice. AB - BACKGROUND: Monash University employs a vertically-integrated curriculum with cumulative knowledge testing throughout the course. To facilitate cross-year level revision, a vertical study programme (VESPA) was established using the principles of peer-assisted learning (PAL). AIM: To implement and evaluate VESPA in relation to defined objectives. METHODS: Following from a successful pilot, a working group organised five 2 h VESPA sessions over the course of 2009. Each was case-based and study materials were provided. Participants were allocated to a group of 10-15 students of all year levels, and pre-interns acted as facilitators. Sessions were evaluated using a 10-question survey. RESULTS: A total of 647 evaluation surveys were completed overall and participant numbers ranged from 79 to 182 per session. Of these, 624 (96%) agreed the case materials were easy to follow and 562 (87%) believed they allowed students from all year levels to contribute; 552 (85%) felt VESPA helped them understand curriculum content. There were no significant differences between sessions. CONCLUSIONS: VESPA represents an innovative application of PAL that has been well received by students. Potential benefits to participants include academic revision, the development of mentoring relationships and enhanced teaching and facilitation skills. This model of a structured revision programme would suit other settings with vertically-integrated curricula and assessment. PMID- 22938690 TI - Impact of mannose-binding lectin deficiency on radiocontrast-induced renal dysfunction: a post-hoc analysis of a multicenter randomized controlled trial. AB - BACKGROUND: Local renal ischemia is regarded as an important factor in the development of contrast-induced nephropathy (CIN). Mannose-binding lectin (MBL) is involved in the tissue damage during experimental ischemia/reperfusion injury of the kidneys. The aim of the present study was to investigate the association of MBL deficiency with radiocontrast-induced renal dysfunction in a large prospective cohort. METHODS: 246 patients with advanced non-dialysis-dependent renal dysfunction who underwent radiographic contrast procedures were included in the study. Baseline serum MBL levels were analyzed according to the occurrence of a creatinine-based (increase of >= 0.5 mg/dL or >= 25% within 48 hours) or cystatin C-based (increase of >= 10% within 24 hours) CIN. RESULTS: The incidence of creatinine-based and cystatin C-based CIN was 6.5% and 24%, respectively. MBL levels were not associated with the occurrence of creatinine-based CIN. However, patients that experienced a cystatin C increase of >= 10% showed significantly higher MBL levels than patients with a rise of <10% (median 2885 (IQR 1193-4471) vs. 1997 (IQR 439-3504)ng/mL, p = 0.01). In logistic regression analysis MBL deficiency (MBL levels <= 500 ng/ml) was identified as an inverse predictor of a cystatin C increase >= 10% (OR 0.34, 95% CI 0.15-0.8, p = 0.01). CONCLUSION: MBL deficiency was associated with a reduced radiocontrast-induced renal dysfunction as reflected by the course of cystatin C. Our findings support a possible role of MBL in the pathogenesis of CIN. PMID- 22938692 TI - Forensic grading of myocarditis: an experimental contribution to the distinction between lethal myocarditis and incidental myocarditis. AB - Myocarditis can be either the cause of the death of a person or just an incidental finding during the autopsy and the following histological examinations. To establish whether a single myocarditis is a lethal or just an incidental pathology a very careful grading is always mandatory. The aim of the present work is thus to test the hypothesis about the reliability of an evidence based distinction between the lethal myocarditis and the incidental myocarditis. The present work compares clinical and histological features from two different groups of myocarditis. Group A is composed of patients having myocarditis at the time of death, who certainly died from other reasons (i.e.: death by head gunshot with no survival time). Group B is composed of patients who died having a myocarditis as the only pathological evidence at the autopsy and the following histological and toxicological examinations and then who died because of the myocarditis. The lethal myocarditis and the incidental myocarditis differ statistically about last days' anamnesis, acute findings in the macroscopic analysis of the heart, neutrophilic infiltration, myocite necrosis, multiple sites interstitial oedema and perivascular cuffs. Such variables can be summarized in a scoring system able to quantitatively separate the lethal myocarditis from the incidental myocarditis. Such a reliable scoring system develops far behind the isolated grading of the myocite necrosis, even though the myocite necrosis should always be considered as a pivot variable for distinguishing lethal myocarditis from incidental myocarditis. The proposed scoring system is very easy to use and it is also appreciably money-sparing with its foundations in the simple combination of clinical anamnesis, autopsy and basic histology. Its routinary application could implement the objectivity in the forensic grading of myocarditis. PMID- 22938693 TI - Hyperspectral imaging for the age estimation of blood stains at the crime scene. AB - The age estimation of blood stains can provide important information on the temporal aspects of a crime. As previously shown, visible spectroscopy of blood stains can successfully be used for their age estimation. In the present study we evaluated the feasibility to use hyperspectral imaging for this purpose. Visible reflectance spectra of blood stains were recorded using a pushbroom hyperspectral imaging system. From these spectra, the relative amounts of oxyhemoglobin, methemoglobin and hemichrome within the blood stains were derived. By comparison of the hemoglobin derivative fractions with a reference dataset, the age of blood stains up to 200 days old was estimated. The absolute error of the age estimation task increased with age, with a median relative error of 13.4% of the actual age. To test the practical applicability of this method, a simulated crime scene was analyzed, in which blood stains of several ages were deposited. Hyperspectral imaging combined with the proposed analysis provided insight in the absolute age of the blood stains. Additionally, the blood stains were clustered based on their hemoglobin derivative fractions, without the use of a reference dataset. Results demonstrated that the order of formation of blood stains can be determined, even under unknown environmental circumstances, when no proficient reference dataset is available. These findings are an important step toward the practical implementation of blood stain age estimation in forensic casework. PMID- 22938691 TI - Increased mitochondrial activity in BMP7-treated brown adipocytes, due to increased CPT1- and CD36-mediated fatty acid uptake. AB - AIMS: Brown adipose tissue dissipates chemical energy in the form of heat and regulates triglyceride and glucose metabolism in the body. Factors that regulate fatty acid uptake and oxidation in brown adipocytes have not yet been fully elucidated. Bone morphogenetic protein 7 (BMP7) is a growth factor capable of inducing brown fat mitochondrial biogenesis during differentiation from adipocyte progenitors. Administration of BMP7 to mice also results in increased energy expenditure. To determine if BMP7 is able to affect the mitochondrial activity of mature brown adipocytes, independent of the differentiation process, we delivered BMP7 to mature brown adipocytes and measured mitochondrial activity. RESULTS: We found that BMP7 increased mitochondrial activity, including fatty acid oxidation and citrate synthase activity, without increasing the mitochondrial number. This was accompanied by an increase in fatty acid uptake and increased protein expression of CPT1 and CD36, which import fatty acids into the mitochondria and the cell, respectively. Importantly, inhibition of either CPT1 or CD36 resulted in a blunting of the mitochondrial activity of BMP7-treated cells. INNOVATION: These findings uncover a novel pathway regulating mitochondrial activities in mature brown adipocytes by BMP7-mediated fatty acid uptake and oxidation. CONCLUSION: In conclusion, BMP7 increases mitochondrial activity in mature brown adipocytes via increased fatty acid uptake and oxidation, a process that requires the fatty acid transporters CPT1 and CD36. PMID- 22938694 TI - Effects of feeding on luminal pH and morphology of the gastroesophageal junction of snakes. AB - At the gastroesophageal junction, most vertebrates possess a functional lower esophageal sphincter (LES) which may serve to regulate the passage of liquids and food into the stomach and prevent the reflux of gastric contents into the esophagus. Snakes seemingly lack an LES and consume meals large enough to extend anteriorly from the stomach into the esophagus thereby providing the opportunity for the reflux of gastric juices. To explore whether snakes experience or can prevent gastric reflux, we examined post-feeding changes of luminal pH of the distal esophagus and stomach, the fine scale luminal pH profile at the gastroesophageal junction, and the morphology of the gastroesophageal junction for the Burmese python (Python molurus), the African brown house snake (Lamprophis fuliginosus), and the diamondback water snake (Nerodia rhombifer). For each species fasted, there was no distension of the gastroesophageal junction and only modest changes in luminal pH from the distal esophagus into the stomach. Feeding resulted in marked distension and changes in tissue morphology of the gastroesophageal junction. Simultaneously, there was a significant decrease in luminal pH of the distal esophagus for pythons and house snakes, and for all three species a steep gradient in luminal pH decreasing across a 3-cm span from the distal edge of the esophagus into the proximal edge of the stomach. The moderate acidification of the distal most portion of the esophagus for pythons and house snakes suggests that there is some anterior movement of gastric juices across the gastroesophageal junction. Given that this modest reflux of gastric fluid is localized to the most distal region of the esophagus, snakes are apparently able to prevent and protect against acid reflux in the absence of a functional LES. PMID- 22938695 TI - The fitness consequences of the autotomous blue tail in lizards: an empirical test of predator response using clay models. AB - Numerous vertebrates employ one or more autotomous body parts as an anti predation mechanism. Many lizards possess an autotomous tail that is brightly colored blue, which has been suggested to either serve as a decoy mechanism to divert predator attention to the autotomous body part, as an interspecific signal, or as an aposematic signal to predators that it is distasteful or dangerous. While theoretical studies suggest that a conspicuous autotomous body part that increases the probability of escape while not increasing the rate of detection will be favorable over a completely cryptic form, there is little empirical evidence supporting the adaptive benefit of an autotomous blue tail. We used in situ clay models of a scincid lizard to test the fitness consequences of blue coloration. Lizard models with a dark base color and blue decoy coloration experienced no measurable difference in avian predation relative to an all-dark model, which suggests that blue coloration neither serves as an aposematic signal nor increases the conspicuousness of the lizard model. Despite statistically similar attack rates, avian attacks on models with blue coloration were indeed focused on body sections that were colored blue. Our results suggest that the blue tail in lizards serves as an effective decoy, and that avian predation has possibly played a role in the evolution of the blue tail. PMID- 22938696 TI - Loss of EphA4 impairs short-term spatial recognition memory performance and locomotor habituation. AB - EphA4 receptor (EphA4) tyrosine kinase is an important regulator of central nervous system development and synaptic plasticity in the mature brain, but its relevance to the control of normal behavior remains largely unexplored. This study is the first attempt to obtain a behavioral profile of constitutive homozygous and heterozygous EphA4 knockout mice. A deficit in locomotor habituation in the open field, impairment in spatial recognition in the Y-maze and reduced probability of spatial spontaneous alternation in the T-maze were identified in homozygous EphA4(-/-) mice, while heterozygo us EphA4(+/-) mice appeared normal on these tests in comparison with wild-type (WT) controls. The multiple phenotypes observed in EphA4(-/-) mice might stem from an underlying deficit in habituation learning, reflecting an elementary form of nonassociative learning that is in contrast to Pavlovian associative learning, which appeared unaffected by EphA4 disruption. A deficit in motor coordination on the accelerating rotarod was also demonstrated only in EphA4(-/-) mice--a finding in keeping with the presence of abnormal gait in EphA4(-/-) mice--although they were able to improve performance over training. There was no evidence for substantial changes in major neurochemical markers in various brain regions rich in EphA4 as shown by post-mortem analysis. This excludes the possibility of major neurochemical compensation in the brain of EphA4(-/-) mice. In summary, we have demonstrated for the first time the behavioral significance of EphA4 disruption, supporting further investigation of EphA4 as a possible target for behavioral interventions where habituation deficits are prominent. PMID- 22938697 TI - Vascular corticobasal syndrome caused by unilateral internal carotid artery occlusion. AB - A 65-year-old man developed progressive worsening of right-sided limb-kinetic apraxia and extrapyramidal dysfunction. His left internal carotid artery was found to be occluded, and there was general atrophy and severely decreased cerebral blood flow in the left hemisphere. He had experienced an acute infarction in the left watershed area before superficial temporal artery to middle cerebral artery bypass surgery. After surgery, the cerebral blood flow in the left hemisphere was remarkably improved. Unilateral internal carotid artery occlusion may result in clinical manifestations similar to corticobasal degeneration. PMID- 22938698 TI - Cumulative Risk Assessment (CRA): transforming the way we assess health risks. AB - Human health risk assessments continue to evolve and now focus on the need for cumulative risk assessment (CRA). CRA involves assessing the combined risk from coexposure to multiple chemical and nonchemical stressors for varying health effects. CRAs are broader in scope than traditional chemical risk assessments because they allow for a more comprehensive evaluation of the interaction between different stressors and their combined impact on human health. Future directions of CRA include greater emphasis on local-level community-based assessments; integrating environmental, occupational, community, and individual risk factors; and identifying and implementing common frameworks and risk metrics for incorporating multiple stressors. PMID- 22938700 TI - Computed tomographic colonography in diagnosis of asymptomatic pneumatosis cystoides intestinalis. PMID- 22938701 TI - Comment to: Changes of faecal microflora in patients with Crohn's disease treated with an elemental diet and total parenteral nutrition. PMID- 22938702 TI - The Chicago classification for achalasia in a French multicentric cohort. AB - BACKGROUND: Achalasia is divided into 3 subtypes using the Chicago classification for high-resolution manometry. Aim of this study was to apply this classification to a multicentric French cohort of achalasia and to compare clinical and manometric characteristics between the 3 subtypes. METHODS: Oesophageal symptoms were collected in a retrospective study of patients diagnosed with achalasia on high-resolution manometry. Manometry data were analyzed with oesophago-gastric junction resting and relaxation pressures, and upper oesophageal sphincter resting pressure. Achalasia was classified according to the Chicago classification. RESULTS: From 2007 to August 2011, achalasia was diagnosed in 169 patients, 14% classified as type I, 70% as type II and 16% as type III. Type III patients were older than types I and II (62 years vs. 52, p = 0.03). Ninety five percent of patients complained of dysphagia, 16% of chest pain (no difference between the 3 subtypes); 50% of type I patients presented regurgitations compared to 33% of type II and 22% of type III (p = 0.10). Oesophago-gastric junction and upper oesophageal sphincter pressures did not differ between the 3 groups. CONCLUSION: Type II was the more prevalent subtype of achalasia in this French multicentre cohort. The older age of patients with type III achalasia suggests a different pathophysiology. PMID- 22938703 TI - Lamellar macular hole formation in a patient with diabetic CME treated by intravitreal bevacizumab injections. AB - A 49-year-old woman with a diagnosis of diabetic cystoid macular edema in both eyes presented with the appearance of a macular hole in the left eye 1 month after intravitreal bevacizumab injection. Optical coherence tomography demonstrated a lamellar macular hole in the left eye. Although vitreomacular traction and epiretinal membrane are the possible underlying causes for the development of lamellar macular hole formation in eyes with cystoid macular edema, in this case previous optical coherence tomography scans revealed the complete separation of the posterior hyaloid membrane and the absence of an epiretinal membrane. The exact mechanism involved in the progression of cystoid macular edema to lamellar macular hole and the contribution of the intravitreal bevacizumab injections to this transformation remain unclear. PMID- 22938704 TI - Retinal metastasis simulating cytomegalovirus retinitis. AB - A 62-year-old man with lung cancer presented with a 2-week history of decreased vision and clinical features of cytomegalovirus retinitis. The patient was empirically treated for viral retinitis, but microbiological testing of the vitreous fluid was negative. Based on the suspicion for retinal metastasis, the patient underwent pars plana vitrectomy with retinal biopsy. Surgical techniques included the use of a chandelier illumination to enable bimanual manipulation of the retinal tissue, creation a focal retinal detachment with a 41-gauge subretinal cannula, diathermy demarcation of the biopsy site, localized retinectomy with vertical scissors, endolaser, and long-acting gas tamponade. Histopathologic examination revealed sheets of tumor cells with pleomorphic nuclei and positive staining for cytokeratins consistent with metastatic adenocarcinoma. The patient subsequently underwent external beam radiation and was alive 10 months after presentation. This surgical technique may be valuable in select patients with retinal metastasis for diagnostic, therapeutic, and counseling purposes. PMID- 22938699 TI - Thousands of microsatellite loci from the venomous coralsnake Micrurus fulvius and variability of select loci across populations and related species. AB - Studies of population genetics increasingly use next-generation DNA sequencing to identify microsatellite loci in nonmodel organisms. There are, however, relatively few studies that validate the feasibility of transitioning from marker development to experimental application across populations and species. North American coralsnakes of the Micrurus fulvius species complex occur in the United States and Mexico, and little is known about their population structure and phylogenetic relationships. This absence of information and population genetics markers is particularly concerning because they are highly venomous and have important implications on human health. To alleviate this problem in coralsnakes, we investigated the feasibility of using 454 shotgun sequences for microsatellite marker development. First, a genomic shotgun library from a single individual was sequenced (approximately 7.74 megabases; 26,831 reads) to identify potentially amplifiable microsatellite loci (PALs). We then hierarchically sampled 76 individuals from throughout the geographic distribution of the species complex and examined whether PALs were amplifiable and polymorphic. Approximately half of the loci tested were readily amplifiable from all individuals, and 80% of the loci tested for variation were variable and thus informative as population genetic markers. To evaluate the repetitive landscape characteristics across multiple snakes, we also compared microsatellite content between the coralsnake and two other previously sampled snakes, the venomous copperhead (Agkistrodon contortrix) and Burmese python (Python molurus). PMID- 22938705 TI - Prevalence and risk factors of childbirth-related post-traumatic stress symptoms. AB - BACKGROUND: There is evidence that traumatic birth experiences are associated with psychological impairments. This study aimed to estimate the prevalence of childbirth-related post-traumatic stress symptoms and its obstetric and perinatal risk factors among a sample of Iranian women. METHODS: This was a cross-sectional study carried out in Bushehr, Iran during a 3-months period from July to September 2009. Data were collected from all women attending eleven healthcare centers for postnatal care 6 to 8 weeks after childbirth. Those who had a traumatic delivery were identified and entered into the study. In order to assess childbirth-related post-traumatic stress, the Post-traumatic Symptom Scale Interview (PSS-I) was administered. Data on demographic, obstetric and perinatal characteristics also were collected. Multivariate logistic regression was performed to examine the association between childbirth-related post-traumatic stress and demographic and obstetric and perinatal variables. RESULTS: In all, 400 women were initially evaluated. Of these, 218 women (54.5%) had a traumatic delivery and overall, 80 women (20%) were found to be suffering from post-partum post-traumatic stress disorder (PTSD). Multiple logistic regression analysis revealed that post-partum PTSD was associated with educational level, gestational age at delivery, number of prenatal care visits, pregnancy complications, pregnancy intervals, labor duration, and mode of delivery. CONCLUSIONS: The findings indicated that the prevalence of traumatic birth experiences and post partum PTSD were relatively high among Iranian women. The findings also indicated that obstetric and perinatal variables were independently the most significant contributing factors to women's post-partum PTSD. It seems that a better perinatal care and supportive childbirth might help to reduce the burden of post partum PTSD among this population. PMID- 22938706 TI - Tiotropium in asthma poorly controlled with standard combination therapy. AB - BACKGROUND: Some patients with asthma have frequent exacerbations and persistent airflow obstruction despite treatment with inhaled glucocorticoids and long acting beta-agonists (LABAs). METHODS: In two replicate, randomized, controlled trials involving 912 patients with asthma who were receiving inhaled glucocorticoids and LABAs, we compared the effect on lung function and exacerbations of adding tiotropium (a total dose of 5 MUg) or placebo, both delivered by a soft-mist inhaler once daily for 48 weeks. All the patients were symptomatic, had a post-bronchodilator forced expiratory volume in 1 second (FEV(1)) of 80% or less of the predicted value, and had a history of at least one severe exacerbation in the previous year. RESULTS: The patients had a mean baseline FEV(1) of 62% of the predicted value; the mean age was 53 years. At 24 weeks, the mean (+/-SE) change in the peak FEV(1) from baseline was greater with tiotropium than with placebo in the two trials: a difference of 86+/-34 ml in trial 1 (P=0.01) and 154+/-32 ml in trial 2 (P<0.001). The predose (trough) FEV(1) also improved in trials 1 and 2 with tiotropium, as compared with placebo: a difference of 88+/-31 ml (P=0.01) and 111+/-30 ml (P<0.001), respectively. The addition of tiotropium increased the time to the first severe exacerbation (282 days vs. 226 days), with an overall reduction of 21% in the risk of a severe exacerbation (hazard ratio, 0.79; P=0.03). No deaths occurred; adverse events were similar in the two groups. CONCLUSIONS: In patients with poorly controlled asthma despite the use of inhaled glucocorticoids and LABAs, the addition of tiotropium significantly increased the time to the first severe exacerbation and provided modest sustained bronchodilation. (Funded by Boehringer Ingelheim and Pfizer; ClinicalTrials.gov numbers, NCT00772538 and NCT00776984.). PMID- 22938707 TI - Tiotropium for asthma--promise and caution. PMID- 22938708 TI - Methods for evaluating the impact of vertical programs on health systems: protocol for a study on the impact of the global polio eradication initiative on strengthening routine immunization and primary health care. AB - BACKGROUND: The impact of vertical programs on health systems is a much-debated topic, and more evidence on this complex relationship is needed. This article describes a research protocol developed to assess the relationship between the Global Polio Eradication Initiative, routine immunization, and primary health care in multiple settings. METHODS/DESIGN: This protocol was designed as a combination of quantitative and qualitative research methods, making use of comparative ethnographies. The study evaluates the impact of the Global Polio Eradication Initiative on routine immunization and primary health care by: (a) combining quantitative and qualitative work into one coherent study design; (b) using purposively selected qualitative case studies to systematically evaluate the impact of key contextual variables; and (c) making extensive use of the method of participant observation to create comparative ethnographies of the impact of a single vertical program administered in varied contexts. DISCUSSION: The study design has four major benefits: (1) the careful selection of a range of qualitative case studies allowed for systematic comparison; (2) the use of participant observation yielded important insights on how policy is put into practice; (3) results from our quantitative analysis could be explained by results from qualitative work; and (4) this research protocol can inform the creation of actionable recommendations. Here, recommendations for how to overcome potential challenges in carrying out such research are presented. This study illustrates the utility of mixed-methods research designs in which qualitative data are not just used to embellish quantitative results, but are an integral component of the analysis. PMID- 22938709 TI - An animal model of endocardial fibroelastosis. AB - BACKGROUND: Hypoplastic left heart syndrome (HLHS) is one of the most common severe congenital cardiac anomalies, characterized by a marked hypoplasia of left sided structures of the heart, which is commonly accompanied by a thick layer of fibroelastic tissue, termed endocardial fibroelastosis (EFE). Because human EFE develops only in fetal or neonatal hearts, and often in association with reduced blood flow, we sought to mimic these conditions by subjecting neonatal and 2-wk old rat hearts to variations of the heterotopically transplanted heart model with either no intracavitary or normal flow and compare endocardium with human EFE tissue. MATERIALS AND METHODS: Hearts obtained from neonatal and 2-wk-old rats were heterotopically transplanted in young adult Lewis rats in a working (loaded) or nonworking (unloaded) mode. After 2-wk survival, hearts were explanted for histologic analysis by staining for collagen, elastin, and cellular elements. These sections were compared with human EFE tissue from HLHS. RESULTS: EFE, consisting of collagen and elastin with scarce cellular and vascular components, developed only in neonatal unloaded transplanted hearts and displayed the same histopathologic findings as EFE from patients with HLHS. Loaded hearts and 2-wk old hearts did not show these alterations. CONCLUSIONS: This animal model for EFE will serve as a tool to study the mechanisms of EFE formation, such as fluid forces, in HLHS in a systematic manner. A better understanding of the underlying cause of the EFE formation in HLHS will help to develop novel treatment strategies to better preserve growth of the hypoplastic left ventricle. PMID- 22938710 TI - Parent attachment, school commitment, and problem behavior trajectories of diverse adolescents. AB - The purpose of this study was to examine the growth trajectories from early to late adolescence of teacher ratings of students' behavior problems from 9th through 11th grade and student self-reports of alcohol use in a sample of predominately minority adolescents (n = 179, 90% African-American and/or Hispanic, 43% boys, 57% girls) in a large, urban school district. The study investigated whether parent attachment, school commitment, gender, race/ethnicity, and educational placement influenced these outcomes. Multi-level growth modeling was the primary statistical procedure used. Results indicated that increased parent attachment was associated with reduced levels of alcohol use and school commitment was not associated with growth trajectories of problem behavior in the multilevel models, although gender, race/ethnicity and special education placement were significant predictors. Our findings suggest that teachers perceive greater levels of behavior problems for minority students and youth in special education. Student self reports also indicate adolescent frequency of alcohol use increases over time. PMID- 22938711 TI - Freeze-induced formation of bromine/chlorine interhalogen species from aqueous halide ion solutions. AB - Both gaseous bromine and bromine chloride have been monitored in polar environments and implicated in the destruction of tropospheric ozone. The formation mechanisms operating for these halogen compounds have been suggested previously. However, few laboratory studies have been performed using environmentally relevant concentrations of bromide and chloride ions in polar ice mimics. In aqueous solutions held at room temperature, previous studies have shown that the major product is the Cl(2)Br- trihalide ion when solutions of bromate, hydrochloric acid, and bromide ions are left to equilibrate. In contrast, the results of the cryochemical experiments presented here suggest that the dibromochloride ion (BrBrCl-) is the major product when solutions of bromate, sulfuric acid, bromide, and chloride ions are frozen. Such a species would preferentially release bromine to the gas phase. Hence, similar halide starting materials form structurally different trihalide ions when frozen, which are capable of releasing differing active halogens, BrCl and Br(2), to the gas-phase. This is a potentially important finding because Br(2) is photolyzed more readily and to longer wavelengths than BrCl and therefore the efficiency in forming products that can lead to ozone destruction in the atmosphere would be increased. Evidence is provided for the mechanism to occur by means of both the freeze concentration effect and the incorporation of ions into the growing ice phase. PMID- 22938712 TI - Biosynthetic pathway to neuromelanin and its aging process. AB - Using model compounds of the melanic component of neuromelanin (NM) prepared by tyrosinase oxidation at various ratios of dopamine (DA) and cysteine (Cys) under physiological conditions, we examined a biosynthetic pathway to NM and its aging process by following the time course of oxidation to NM and the subsequent structural modification of NM under various heating conditions. Chemical degradation methods were applied to the synthetic NM. 4-Amino-3 hydroxyphenylethylamine (4-AHPEA) and thiazole-2,4,5-tricarboxylic acid (TTCA) were used as markers of benzothiazine and benzothiazole units, respectively. By following the time course of the biosynthetic pathway of synthetic NM, we found that neurotoxic molecules are trapped in NM. An aging simulation of synthetic NM showed that benzothiazine units in NM are gradually converted to benzothiazole during the aging process. Thus, natural NM was found to be similar to aged (heated) NM prepared from a 2:1 molar ratio of DA and Cys. PMID- 22938714 TI - The pulmonary artery in COPD--does size matter? PMID- 22938713 TI - Role of aldo-keto reductases and other doxorubicin pharmacokinetic genes in doxorubicin resistance, DNA binding, and subcellular localization. AB - BACKGROUND: Since proteins involved in chemotherapy drug pharmacokinetics and pharmacodynamics have a strong impact on the uptake, metabolism, and efflux of such drugs, they likely play critical roles in resistance to chemotherapy drugs in cancer patients. METHODS: To investigate this hypothesis, we conducted a whole genome microarray study to identify difference in the expression of genes between isogenic doxorubicin-sensitive and doxorubicin-resistant MCF-7 breast tumour cells. We then assessed the degree of over-representation of doxorubicin pharmacokinetic and pharmacodynamic genes in the dataset of doxorubicin resistance genes. RESULTS: Of 27,958 Entrez genes on the array, 7.4 per cent or 2,063 genes were differentially expressed by >= 2-fold between wildtype and doxorubicin-resistant cells. The false discovery rate was set at 0.01 and the minimum p value for significance for any gene within the "hit list" was 0.01. Seventeen and 43 per cent of doxorubicin pharmacokinetic genes were over represented in the hit list, depending upon whether the gene name was identical or within the same gene family, respectively. The most over-represented genes were within the 1C and 1B families of aldo-keto reductases (AKRs), which convert doxorubicin to doxorubicinol. Other genes convert doxorubicin to other metabolites or affect the influx, efflux, or cytotoxicity of the drug. In further support of the role of AKRs in doxorubicin resistance, we observed that, in comparison to doxorubicin, doxorubincol exhibited dramatically reduced cytotoxicity, reduced DNA-binding activity, and strong localization to extra nuclear lysosomes. Pharmacologic inhibition of the above AKRs in doxorubicin resistant cells increased cellular doxorubicin levels, restored doxorubicin cytotoxicity and re-established doxorubicin localization to the nucleus. The properties of doxorubicinol were unaffected. CONCLUSIONS: These findings demonstrate the utility of using curated pharmacokinetic and pharmacodynamic knowledge bases to identify highly relevant genes associated with doxorubicin resistance. The induction of one or more of these genes was found to be correlated with changes in the drug's properties, while inhibiting one specific class of these genes (the AKRs) increased cellular doxorubicin content and restored drug DNA binding, cytotoxicity, and subcellular localization. PMID- 22938717 TI - Effectiveness of a peer-led HIV prevention intervention in secondary schools in Rwanda: results from a non-randomized controlled trial. AB - BACKGROUND: While the HIV epidemic is levelling off in sub-Saharan Africa, it remains at an unacceptably high level. Young people aged 15-24 years remain particularly vulnerable, resulting in a regional HIV prevalence of 1.4% in young men and 3.3% in young women. This study assesses the effectiveness of a peer-led HIV prevention intervention in secondary schools in Rwanda on young people's sexual behavior, HIV knowledge and attitudes. METHODS: In a non-randomized longitudinal controlled trial, fourteen schools were selected in two neighboring districts in Rwanda Bugesera (intervention) and Rwamagana (control). Students (n = 1950) in eight intervention and six control schools participated in three surveys (baseline, six and twelve months in the intervention). Analysis was done using linear and logistic regression using generalized estimation equations adjusted for propensity score. RESULTS: The overall retention rate was 72%. Time trends in sexual risk behavior (being sexually active, sex in last six months, condom use at last sex) were not significantly different in students from intervention and control schools, nor was the intervention associated with increased knowledge, perceived severity or perceived susceptibility. It did significantly reduce reported stigma. CONCLUSIONS: Analyzing this and other interventions, we identified several reasons for the observed limited effectiveness of peer education: 1) intervention activities (spreading information) are not tuned to objectives (changing behavior); 2) young people prefer receiving HIV information from other sources than peers; 3) outcome indicators are not adequate and the context of the relationship in which sex occurs and the context in which sex occurs is ignored. Effectiveness of peer education may increase through integration in holistic interventions and redefining peer educators' role as focal points for sensitization and referral to experts and services. Finally, we argue that a narrow focus on sexual risks will never significantly turn the tide. PMID- 22938719 TI - Micropollutant biotransformation kinetics associate with WWTP process parameters and microbial community characteristics. AB - The objective of this work was to identify relevant wastewater treatment plant (WWTP) parameters and underlying microbial processes that influence the biotransformation of a diverse set of micropollutants. To do this, we determined biotransformation rate constants for ten organic micropollutants in batch reactors seeded with activated sludge from ten diverse WWTPs. The estimated biotransformation rate constants for each compound ranged between one and four orders of magnitude among the ten WWTPs. The biotransformation rate constants were tested for statistical associations with various WWTP process parameters, amoA transcript abundance, and acetylene-inhibited monooxygenase activity. We determined that (i) ammonia removal associates with oxidative micropollutant biotransformation reaction rates; (ii) archaeal but not bacterial amoA transcripts associate with both ammonia removal and oxidative micropollutant biotransformation reaction rates; and (iii) the activity of acetylene-inhibited monooxygenases (including ammonia monooxygenase) associates with ammonia removal and the biotransformation rate of isoproturon, but does not associate with all oxidative micropollutant biotransformations. In combination, these results lead to the conclusion that ammonia removal and amoA transcript abundance can potentially be predictors of oxidative micropollutant biotransformation reactions, but that the biochemical mechanism is not necessarily linked to ammonia monooxygenase activity. PMID- 22938718 TI - Functional replacement of two highly conserved tetraloops in the bacterial ribosome. AB - Ribosomes are RNA-protein complexes responsible for protein synthesis. A dominant structural motif in the rRNAs is an RNA helix capped with a four-nucleotide loop, called a tetraloop. The sequence of the tetraloop is invariant at some positions in the rRNAs but is highly variable at other positions. The biological reason for the conservation of the tetraloop sequence at specific positions in the rRNAs is not clear. In the 16S rRNA, the GAAA tetraloop in helix 8 and the UACG tetraloop in helix 14 are highly conserved and located near the binding site for EF-Tu and EF-G. To investigate whether the structural stability of the tetraloop or the precise sequence of the tetraloop is important for function, we separately changed the GAAA tetraloop in helix 8 to a UACG tetraloop and the UACG tetraloop in helix 14 to a GAAA tetraloop. The effects of the tetraloop replacements on protein synthesis were analyzed in vivo and in vitro. Replacement of the tetraloops in helices 8 and 14 did not significantly affect the growth rate of the Escherichia coli (Delta7rrn) strain. However, the mutant ribosomes showed a slightly reduced rate of protein synthesis in vitro. In addition, we observed a 2 fold increase in the error rate of translation with the mutant ribosomes, which is consistent with an earlier report. Our results suggest that the tetraloops in helices 8 and 14 are highly conserved mainly for their structural stability and the precise sequences of these tetraloops are not critical for protein synthesis. PMID- 22938720 TI - Factors associated to temporal artery biopsy result in suspects of giant cell arteritis: a retrospective, multicenter, case-control study. AB - PURPOSE: To evaluate the positivity rate of temporal artery biopsies (TAB) performed in suspects of giant cell arteritis (GCA) and to study the epidemiological and clinical factors associated to the biopsy result. METHODS: A retrospective, multicenter, case-control study was performed, including three hundred and thirty-five patients who underwent TAB for a suspicion of GCA from 2001 to 2010. Clinical, epidemiological and pathology data were recovered from the patients' clinical records. Histologic diagnosis of GCA was made when active inflammation or giant cells were found in the arterial wall. RESULTS: Eighty-one biopsies (24.2%) were considered positive for GCA. Clinical factors independently associated to TAB result in a logistic regression analysis were temporal cutaneous hyperalgesia (OR = 10.8; p < 0.001), jaw claudication (OR = 4.6; p = 0.001), recent-onset headache (OR = 4.4; p = 0.001), decreased temporal pulse (OR = 2.8; p = 0.02), pain and stiffness in neck and shoulders (OR = 2.3; p = 0.05), unintentional weight loss (OR = 1.33; p = 0.003) and age (OR = 1.085; p = 0.004). Other factors such as length of the surgical specimen (OR = 1.079; p = 0.028) and erythrocyte sedimentation rate (OR = 1.042; p < 0.001) were also statistically significant. The model was accurate (C-index = 0.921), reliable (pHosmer-Lemeshow = 0.733) and consistent in the bootstrap sensitivity analysis. No significant association was detected between TAB result and number of days of previous systemic corticosteroid treatment (p = 0.146). However, an association was observed between TAB result and the total accumulated dose of previous systemic corticotherapy (p = 0.043). CONCLUSIONS: Exhaustive anamnesis and clinical examination remain of paramount importance in the diagnosis of GCA. To improve the yield of TAB, it should be performed specially in older patients with GCA compatible clinic. TAB could be avoided in patients with an isolated elevation of acute phase reactants, without GCA-compatible clinic. PMID- 22938721 TI - Simultaneous copy number gains of NUPR1 and ERBB2 predicting poor prognosis in early-stage breast cancer. AB - BACKGROUND: The full extent of chromosomal alterations and their biological implications in early breast carcinogenesis has not been well examined. In this study, we aimed to identify chromosomal alterations associated with poor prognosis in early-stage breast cancers (EBC). METHODS: A total of 145 EBCs (stage I and II) were examined in this study. We analyzed copy number alterations in a discovery set of 48 EBCs using oligoarray-comparative genomic hybridization. In addition, the recurrently altered regions (RARs) associated with poor prognosis were validated using an independent set of 97 EBCs. RESULTS: A total of 23 RARs were defined in the discovery set. Six were commonly detected in both stage I and II groups (> 50%), suggesting their connection with early breast tumorigenesis. There were gains on 1q21.2-q21.3, 8q24.13, 8q24.13-21, 8q24.3, and 8q24.3 and a loss on 8p23.1-p22. Among the 23 RARs, copy number gains on 16p11.2 (NUPR1) and 17q12 (ERBB2) showed a significant association with poor survival (P = 0.0186 and P = 0.0186, respectively). The patients simultaneously positive for both gains had a significantly worse prognosis (P = 0.0001). In the independent replication, the patients who were double-positive for NUPR1-ERBB2 gains also had a significantly poorer prognosis on multivariate analysis (HR = 7.31, 95% CI 2.65 20.15, P = 0.0001). CONCLUSIONS: The simultaneous gain of NUPR1 and ERBB2 can be a significant predictor of poor prognosis in EBC. Our study will help to elucidate the molecular mechanisms underlying early-stage breast cancer tumorigenesis. This study also highlights the potential for using combinations of copy number alterations as prognosis predictors for EBC. PMID- 22938715 TI - Pulmonary arterial enlargement and acute exacerbations of COPD. AB - BACKGROUND: Exacerbations of chronic obstructive pulmonary disease (COPD) are associated with accelerated loss of lung function and death. Identification of patients at risk for these events, particularly those requiring hospitalization, is of major importance. Severe pulmonary hypertension is an important complication of advanced COPD and predicts acute exacerbations, though pulmonary vascular abnormalities also occur early in the course of the disease. We hypothesized that a computed tomographic (CT) metric of pulmonary vascular disease (pulmonary artery enlargement, as determined by a ratio of the diameter of the pulmonary artery to the diameter of the aorta [PA:A ratio] of >1) would be associated with severe COPD exacerbations. METHODS: We conducted a multicenter, observational trial that enrolled current and former smokers with COPD. We determined the association between a PA:A ratio of more than 1 and a history at enrollment of severe exacerbations requiring hospitalization and then examined the usefulness of the ratio as a predictor of these events in a longitudinal follow-up of this cohort, as well as in an external validation cohort. We used logistic-regression and zero-inflated negative binomial regression analyses and adjusted for known risk factors for exacerbation. RESULTS: Multivariate logistic regression analysis showed a significant association between a PA:A ratio of more than 1 and a history of severe exacerbations at the time of enrollment in the trial (odds ratio, 4.78; 95% confidence interval [CI], 3.43 to 6.65; P<0.001). A PA:A ratio of more than 1 was also independently associated with an increased risk of future severe exacerbations in both the trial cohort (odds ratio, 3.44; 95% CI, 2.78 to 4.25; P<0.001) and the external validation cohort (odds ratio, 2.80; 95% CI, 2.11 to 3.71; P<0.001). In both cohorts, among all the variables analyzed, a PA:A ratio of more than 1 had the strongest association with severe exacerbations. CONCLUSIONS: Pulmonary artery enlargement (a PA:A ratio of >1), as detected by CT, was associated with severe exacerbations of COPD. (Funded by the National Heart, Lung, and Blood Institute; ClinicalTrials.gov numbers, NCT00608764 and NCT00292552.). PMID- 22938722 TI - German health interview and examination survey for adults (DEGS) - design, objectives and implementation of the first data collection wave. AB - BACKGROUND: The German Health Interview and Examination Survey for Adults (DEGS) is part of the recently established national health monitoring conducted by the Robert Koch Institute. DEGS combines a nationally representative periodic health survey and a longitudinal study based on follow-up of survey participants. Funding is provided by the German Ministry of Health and supplemented for specific research topics from other sources. METHODS/DESIGN: The first DEGS wave of data collection (DEGS1) extended from November 2008 to December 2011. Overall, 8152 men and women participated. Of these, 3959 persons already participated in the German National Health Interview and Examination Survey 1998 (GNHIES98) at which time they were 18-79 years of age. Another 4193 persons 18-79 years of age were recruited for DEGS1 in 2008-2011 based on two-stage stratified random sampling from local population registries. Health data and context variables were collected using standardized computer assisted personal interviews, self administered questionnaires, and standardized measurements and tests. In order to keep survey results representative for the population aged 18-79 years, results will be weighted by survey-specific weighting factors considering sampling and drop-out probabilities as well as deviations between the design-weighted net sample and German population statistics 2010. DISCUSSION: DEGS aims to establish a nationally representative data base on health of adults in Germany. This health data platform will be used for continuous health reporting and health care research. The results will help to support health policy planning and evaluation. Repeated cross-sectional surveys will permit analyses of time trends in morbidity, functional capacity levels, disability, and health risks and resources. Follow-up of study participants will provide the opportunity to study trajectories of health and disability. A special focus lies on chronic diseases including asthma, allergies, cardiovascular conditions, diabetes mellitus, and musculoskeletal diseases. Other core topics include vaccine-preventable diseases and immunization status, nutritional deficiencies, health in older age, and the association between health-related behavior and mental health. PMID- 22938723 TI - Oxygenation of monoenoic fatty acids by CYP175A1, an orphan cytochrome P450 from Thermus thermophilus HB27. AB - The catalytic activity of CYP175A1 toward monooxygenation of saturated and monounsaturated fatty acids of various chain lengths (C16-C24) has been investigated to assess the enzymatic properties of this orphan thermostable cytochrome P450 enzyme. The results showed that the enzyme could catalyze the reaction of monounsaturated fatty acids but not of saturated fatty acids. The product analyses using ESI-MS and GC-MS revealed an important regioselectivity in the CYP175A1 catalyzed monooxygenation of the monoenoic fatty acids depending on the ethylenic double bond (C?C) configuration. When the double bond was in cis configuration, an epoxy fatty acid was found to be the major product and two allyl-hydroxy fatty acids were found to be the minor products. But when the double bond was in trans-configuration the product distribution was reversed. The oxygenation efficiency was found to be the highest for palmitoleic acid (chain length C16), but there was no direct correlation of the activity with the chain length or the position of unsaturation of the fatty acid. Molecular docking calculations showed that the "U"-type conformations of the monoenoic fatty acids are particularly responsible for their binding in the enzyme pocket, and that is also consistent with the observed regioselectivity in the oxygenation reaction. The present results provide evidence that CYP175A1 can catalyze the regioselective oxygenation reaction of several monoenoic fatty acids though it cannot catalyze the oxygenation of the corresponding saturated analogues. These studies may provide critical information on the nature of the enzyme pocket and of the possible natural substrate of this orphan enzyme. PMID- 22938716 TI - Effect of inhaled glucocorticoids in childhood on adult height. AB - BACKGROUND: The use of inhaled glucocorticoids for persistent asthma causes a temporary reduction in growth velocity in prepubertal children. The resulting decrease in attained height 1 to 4 years after the initiation of inhaled glucocorticoids is thought not to decrease attained adult height. METHODS: We measured adult height in 943 of 1041 participants (90.6%) in the Childhood Asthma Management Program; adult height was determined at a mean (+/-SD) age of 24.9+/ 2.7 years. Starting at the age of 5 to 13 years, the participants had been randomly assigned to receive 400 MUg of budesonide, 16 mg of nedocromil, or placebo daily for 4 to 6 years. We calculated differences in adult height for each active treatment group, as compared with placebo, using multiple linear regression with adjustment for demographic characteristics, asthma features, and height at trial entry. RESULTS: Mean adult height was 1.2 cm lower (95% confidence interval [CI], -1.9 to -0.5) in the budesonide group than in the placebo group (P=0.001) and was 0.2 cm lower (95% CI, -0.9 to 0.5) in the nedocromil group than in the placebo group (P=0.61). A larger daily dose of inhaled glucocorticoid in the first 2 years was associated with a lower adult height (-0.1 cm for each microgram per kilogram of body weight) (P=0.007). The reduction in adult height in the budesonide group as compared with the placebo group was similar to that seen after 2 years of treatment (-1.3 cm; 95% CI, -1.7 to -0.9). During the first 2 years, decreased growth velocity in the budesonide group occurred primarily in prepubertal participants. CONCLUSIONS: The initial decrease in attained height associated with the use of inhaled glucocorticoids in prepubertal children persisted as a reduction in adult height, although the decrease was not progressive or cumulative. (Funded by the National Heart, Lung, and Blood Institute and the National Center for Research Resources; CAMP ClinicalTrials.gov number, NCT00000575.). PMID- 22938724 TI - Variation in corneal hysteresis and central corneal thickness among black, hispanic and white subjects. AB - PURPOSE: To determine whether differences in corneal hysteresis (CH) and central corneal thickness (CCT) between black, Hispanic and white subjects exist independently of one another. METHODS: Retrospective, cross-sectional data were reviewed for 807 eyes of 410 patients consecutively evaluated for glaucoma. Included patients had open angles, at least one reliable 24-2 perimetric examination and no evidence of nonglaucomatous vision loss. Patients underwent CH measurement with the ocular response analyzer followed by CCT measurement and full ocular examination. Patients were asked to self-classify their race or ethnicity. Statistical analyses were performed to identify characteristics that varied between black, Hispanic and white subjects and to explain this variation. RESULTS: Of the 270 patients (511 eyes) included, 84 were black, 96 Hispanic and 90 white. There were no significant differences in diagnosis, sex, age, intraocular pressure or glaucoma severity between races/ethnicities (p >= 0.16). Blacks were found to have lower CCT (529.3 MUm) and CH (8.7 mmHg) compared to Hispanics (544.7 MUm, p = 0.008; 9.4 mmHg, p = 0.007) and whites (549.9 MUm, p < 0.001; 9.8 mmHg, p < 0.001). On multivariable analysis, inter-racial/ethnic differences in CCT were not found to exist independent of CH (p >= 0.10), whereas the significant intergroup variation in CH remained after adjustment for CCT and other covariates (p <= 0.005). CONCLUSIONS: Variation in CCT between races/ethnicities does not exist independent of CH. However, significant intergroup variation in CH is present independent of CCT. This finding suggests that CH may be a preferable measurement to evaluate intergroup differences in corneal properties and their relationship to open-angle glaucoma. PMID- 22938725 TI - A unique discrete tetranuclear Cu'-Cu(N-N)2Cu-Cu' copper(II) complex, built from a MU3-1,2,4-triazolato-MU-carboxylato ligand, as an effective DNA cleavage agent. AB - The title compound, characterized by means of an X-ray structure analysis, represents an easy example of a noncatena "1 + 2 + 1" tetranuclear copper(II) MU(3)-triazolate compound. [Cu(4)(atc)(2)(dien)(4)(ClO(4))(2)](ClO(4))(2).2H(2)O (1), where H(2)atc = 5-amino-l,2,4-triazole-3-carboxylic acid and dien = diethylenetriamine = 1,4,7-triazaheptane, contains two copper atoms linked by a double diazinic bridge, each of which is further connected to a third and fourth copper atom (Cu') through the triply bridging triazolato ring and the bidentate carboxylato group of the atc(2-) ligands. The copper-copper distances within the tetranuclear unit are Cu-Cu = 4.059 A, Cu-Cu' = 5.686 and 6.370 A, and Cu'-Cu' = 11.373 A. The compound self-assembles into a tridimensional hydrogen-bonded network to generate a MOF. 1 exhibits antiferromagnetic behavior with g = 2.10(1), J = -34.1(2) cm(-1) and j = -5.50(3) cm(-1), where J is the coupling constant of the central Cu-Cu pair and j the coupling constant of the two Cu-Cu' (Cu(central)-Cu(pheripheral)) pairs, as defined by H = -JS(2)S(2a) - j (S(1)S(2) + S(2a)S(1a)). Complex 1 has been tested as nuclease mimic. It shows good binding propensity to calf thymus DNA, with a binding constant value of 6.20 * 10(6) M( 1) (K(app)) and DeltaT(m) = 18.3 degrees C. Moreover, the compound displays efficient oxidative cleavage of pUC18 DNA, even at low concentration, in the presence of a mild reducing agent (ascorbate), with a rate constant for the conversion of supercoiled to nicked DNA (k(obs)) of ~0.126 min(-1). The good reactivity of 1 toward DNA is explained from the electrostatic interactions of the cationic species produced in solution. PMID- 22938726 TI - Hypoxia targeted bifunctional suicide gene expression enhances radiotherapy in vitro and in vivo. AB - PURPOSE: To investigate whether hypoxia targeted bifunctional suicide gene expression-cytosine deaminase (CD) and uracil phosphoribosyltransferase (UPRT) with 5-FC treatments can enhance radiotherapy. MATERIALS AND METHODS: Stable transfectants of R3327-AT cells were established which express a triple-fusion gene: CD, UPRT and monomoric DsRed (mDsRed) controlled by a hypoxia inducible promoter. Hypoxia-induced expression/function of CDUPRTmDsRed was verified by western blot, flow cytometry, fluorescent microscopy, and cytotoxicity assay of 5 FU and 5-FC. Tumor-bearing mice were treated with 5-FC and local radiation. Tumor volume was monitored and compared with those treated with 5-FC or radiation alone. In addition, the CDUPRTmDsRed distribution in hypoxic regions of tumor sections was visualized with fluorescent microscopy. RESULTS: Hypoxic induction of CDUPRTmDsRed protein correlated with increased sensitivity to 5-FC and 5-FU. Significant radiosensitization effects were detected after 5-FC treatments under hypoxic conditions. In the tumor xenografts, the distribution of CDUPRTmDsRed expression visualized with fluorescence microscopy was co-localized with the hypoxia marker pimonidazole positive staining cells. Furthermore, administration of 5-FC to mice in combination with local irradiation resulted in significant tumor regression, as in comparison with 5-FC or radiation treatments alone. CONCLUSIONS: Our data suggest that the hypoxia-inducible CDUPRT/5-FC gene therapy strategy has the ability to specifically target hypoxic cancer cells and significantly improve the tumor control in combination with radiotherapy. PMID- 22938727 TI - The battle against nasopharyngeal cancer. AB - This is a review of the evolving efforts to understand and combat nasopharyngeal carcinoma (NPC), a most peculiar cancer with a distinctly skewed geographic and ethnic distribution. Multifactorial etiology with dynamic interplay of genetic predisposition, Epstein-Barr virus (EBV) infection and environmental carcinogens is suggested. With changing lifestyle in Hong Kong, the age-standardized incidence rate has decreased by more than 50% during the past 30 years. The advent of megavoltage radiotherapy has transformed this once lethal cancer into one that is readily curable. Advances in technology and addition of chemotherapy have led to gratifying improvements. Overall survival exceeding 75% at 5 years could now be achieved; series using advanced technique with intensity-modulation consistently achieved excellent locoregional control. Studies are on-going to develop more potent systemic therapy for distant control. Serious late toxicities remain a serious concern demanding further improvement in radiotherapy technique and optimization of dose fractionation. Translational researches are increasingly important for the ideal goals of prevention, early detection and more accurate prognostication/prediction to work toward personalized medicine. The battle against NPC is one of the most fascinating successes in oncology, it is highly hopeful that with international collaborations and concerted efforts, we can totally conquer this cancer. PMID- 22938728 TI - Comparison of triple-lumen central venous catheters impregnated with silver nanoparticles (AgTive(r)) vs conventional catheters in intensive care unit patients. AB - BACKGROUND: Silver-impregnated central venous catheters (CVCs) have been proposed as a means for preventing CVC colonization and related bloodstream infections (CRBSIs). AIM: To evaluate the efficacy of CVCs impregnated with silver nanoparticles in a large group of critically ill patients. METHODS: A prospective, randomized clinical trial was conducted in five intensive care units (ICUs). Three hundred and thirty-eight adult patients requiring CVCs between April 2006 and November 2008 were randomized to receive AgTive silver nanoparticle-impregnated (SC) or conventional (CC) CVCs. Primary endpoints were CVC colonization (growth of >=15 colony-forming units from the catheter tip) and incident CRBSIs (meeting the definitions of the Centers for Disease Control and Prevention). Infection-free time (days from initial CVC insertion to initial blood culture positivity) and ICU mortality rates were measured as secondary endpoints. FINDINGS: The SC group (N = 135) and CC group (N = 137) were similar in terms of clinical and laboratory parameters at baseline, reasons for ICU admission, complications during CVC insertion, and total time with CVC (mean +/- standard deviation; SC 13 +/- 24 vs CC 15 +/- 37 days). No significant intergroup differences were found in CVC colonization rates (SC 32.6% vs CC 30%; P = 0.7), CRBSI incidence rates (3.36 infections per 1000 catheter-days in both groups), infection-free times (SC 13 +/- 34 vs CC 12 +/- 12 days; P = 0.85) or ICU mortality (SC 46% vs CC 43%; P = 0.7). CONCLUSION: In critically ill patients, use of AgTive((r)) silver-nanoparticle-impregnated CVCs had no significant effect on CVC colonization, CRBSI incidence or ICU mortality. These CVCs cannot be recommended as an adjunctive tool for control of CRBSIs. PMID- 22938729 TI - Combined effects of hepatitis B virus infection and elevated alanine aminotransferase levels on dyslipidemia. AB - OBJECTIVE: Although elevated alanine aminotransferase (ALT) levels are associated with lipid profiles, most studies do not consider the role of hepatitis B virus (HBV) infection. This study investigated the combined effects of HBV infection and elevated ALT levels on the lipid profiles of Taiwanese adults. MATERIALS/METHODS: A total of 7695 subjects were enrolled after an annual health examination. Dyslipidemia was defined as serum total cholesterol>=200 mg/dL, serum triglyceride>=150 mg/dL, high-density lipoprotein cholesterol<40 mg/dL in men or <50 mg/dL in women, or low-density lipoprotein cholesterol>=130 mg/dL. Multiple logistic regression analysis was performed to assess the associations between dyslipidemia, HBV infection, and elevated ALT levels. RESULTS: Hepatitis B surface antigen positivity (HBV[+]) and elevated ALT levels (ALT[+], >=50 U/L) were observed in 13.5% and 12.2% of the subjects, respectively. Multiple logistic analysis revealed that the HBV(+) group had a significantly lower odds ratios (ORs) for hypercholesterolemia (OR, 0.8), hypertriglyceridemia (OR, 0.7), and high low-density lipoprotein cholesterol levels (OR, 0.8); whereas, the subjects with elevated ALT levels had significantly higher ORs for all of the dyslipidemia criteria. The interaction between HBV(+) and ALT(+) had a significantly lower OR for hypertriglyceridemia (OR, 0.7). The subjects with HBV infections had a significantly lower OR for hypertriglyceridemia regardless of the ALT levels. CONCLUSIONS: HBV infection and elevated ALT levels have opposite effects on dyslipidemia, whereas their combined effects result in a significantly lower OR for hypertriglyceridemia. PMID- 22938730 TI - Identification of amino acids important for binding of Clostridium perfringens epsilon toxin to host cells and to HAVCR1. AB - Clostridium perfringens epsilon toxin belongs to the aerolysin-like family of pore-forming toxins and is one of the most potent bacterial toxins known. The epsilon toxin causes fatal enterotoxemia in sheep, goats, and possibly humans. Evidence indicates that the toxin binds to protein receptors including hepatitis A virus cellular receptor 1 (HAVCR1), but the region of the toxin responsible for cell binding has not been identified. In the present study, we identify amino acids within the epsilon toxin important for this cell interaction. Site-specific mutagenesis was used to investigate the role of a surface-accessible cluster of aromatic amino acids, and purified mutant proteins were tested in a series of cell-culture assays to assess cytotoxic activity and cell binding. When added to cells, four mutant proteins (Etx-Y29E, Etx-Y30E, Etx-Y36E and Etx-Y196E) were severely impaired in their ability to not only kill host cells, but also in their ability to permeabilize the plasma membrane. Circular dichroism spectroscopy and thermal stability studies revealed that the wild-type and mutant proteins were similarly folded. Additional experiments revealed that these mutant proteins were defective in binding to host cells and to HAVCR1. These data indicate that an amino acid motif including Y29, Y30, Y36, and Y196 is important for the ability of epsilon toxin to interact with cells and HAVCR1. PMID- 22938731 TI - Subjective cold hyper-responsiveness grade reflects age- and duration-related increase of nonspecific nasal hyperreactivity. AB - OBJECTIVE: We evaluated the effect of patients' age and duration of allergic rhinitis on nonspecific nasal hyper-reactivity (NHR) using cold dry air (CDA) provocation. METHODS: In 156 patients of various ages with allergic rhinitis and different symptom duration, we evaluated the change of symptoms, the subjective cold hyper-responsiveness (SCH) grade, the change of acoustic parameters such as total nasal volume (TNV) and minimal cross-sectional area (MCA), and the amount of rhinorrhea before and after CDA provocation. RESULTS: Patients in different age or duration groups did not show significant differences in the change of each nasal symptom. SCH grade 2 or 3 was more frequently observed in patients older than 30 years (p=0.018). There was a significant correlation between the age of the patients and the SCH grade (R=0.184, p=0.022). Patients with >10 years of duration reported higher SCH grade (p=0.022). There was a significant correlation between the duration of disease and SCH grade (R=0.284, p<0.001). However, there were no significant differences in the change of TNV and MCA, and the amount of rhinorrhea after CDA provocation between different age and duration groups. CONCLUSION: SCH grade reflects the age- and duration-related increase of NHR. Further studies to elucidate the pathophysiologic mechanisms are needed in the future. PMID- 22938732 TI - Association of MTHFR 677T variant allele with risk of intracerebral haemorrhage: a meta-analysis. AB - BACKGROUND: Previous studies concerning the association between methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism and risk of intracerebral haemorrhage (ICH) reported conflicting results. A meta-analysis of published studies was performed to allow a more reliable estimate of this association. METHODS: Relevant studies concerning the association between MTHFR C677T polymorphism and risk of ICH were included into this meta-analysis. Odds ratios (OR) and 95% confidence intervals (CI) were determined for this gene disease association using fixed or random effect models. RESULTS: Finally, 16 studies with a total of 1828 cases and 4067 controls were included. Meta-analyses of a total of 16 studies showed that there was an obvious association of MTHFR 677T allele with risk of ICH under all four comparison models (OR(T vs. C)=1.38, 95% CI 1.17-1.62, P<0.001; OR(TT vs. CC)=1.90 95% CI 1.42-2.55, P<0.001; OR(TT vs. TC/CC)=1.38 95% CI 1.20-1.59, P<0.001; OR(TT/TC vs. CC)=1.41 95% CI 1.12 1.78, P=0.003). Besides, both subgroup analyses and sensitivity analysis further identified the association above. CONCLUSION: The MTHFR 677T allele is associated with risk of ICH, and individuals with TT genotype have an obviously higher risk of ICH than those with the CC genotype. PMID- 22938733 TI - Lack of association between two key SNPs on chromosome 12p13 and ischemic stroke in Chinese Uyghur population. AB - Recent genome-wide association studies (GWAS) have identified two key SNPs (rs11833579 and rs12425791) on chromosome 12p13 that were significantly associated with stroke in Caucasians. However, the validity of the association has remained controversial. We performed genetic association analyses in a very unique population which has 60% European ancestry and 40% East Asian ancestry. No significant association between these two SNPs and ischemic stroke was detected in this Chinese Uyghur population. PMID- 22938734 TI - Vascular risk factors in Alzheimer's disease - preliminary report. AB - BACKGROUND: The vascular risk factors are associated with an increased risk for vascular cognitive decline (VCD), but also with Alzheimer disease (AD). OBJECTIVE: To investigate vascular risk factors in relation to AD and VCD, with a non-invasive neurosonological methods in a clinical settings. RESULTS: A total of 296 patients with AD and 237 patients with VCD were included in the study. Hypertension, hyperlipidemia, diabetes mellitus, stroke, and white matter changes (p<0.001) were significantly more prevalent in VCD, although they were also present in AD patients. No statistically significant differences were obtained between groups regarding coronary disease, atrial fibrillation, average degree of carotid artery stenosis and carotid intima-media thickness (cITM). However, the patients with AD had carotid artery stenosis ">50%" (p=0.007) and present plaques (p<0.001) more frequently compared to vascular group. The significant associations between robust cognitive measure and vascular factors, diabetes mellitus, carotid stenosis, cITM, and type of plaques were identified only in VCD, but not in AD group. CONCLUSIONS: The vascular risk factors were more prevalent in VCD group, although they were also present in AD. With few treatment options available in AD, it may be important not to neglect the vascular risk factors. PMID- 22938739 TI - Trends in myocardial infarction mortality in Spain and the United States: a downhill or uphill race in the twenty-first century? PMID- 22938741 TI - Synthesis and study of optical properties of transition metals doped ZnS nanoparticles. AB - ZnS and transition metal (Mn, Co, Ni, Cu, Ag and Cd) doped ZnS were synthesized using chemical precipitation method in an air atmosphere. The structural and optical properties were studied using various techniques. The X-ray diffraction (XRD) analysis show that the particles are in cubic structure. The mean size of the nanoparticles calculated through Scherrer equation is in the range of 4-6.1 nm. Elemental dispersive (EDX) analysis of doped samples reveals the presence of doping ions. The scanning electron microscopic (SEM) and transmission electron microscopic (TEM) studies show that the synthesized particles are in spherical shape. Optical characterization of both undoped and doped samples was carried out by ultraviolet-visible (UV-Vis) and photoluminescence (PL) spectroscopy. The absorption spectra of all the samples are blue shifted from the bulk ZnS. An optimum doping level of the transition metals for enhanced PL properties are found through optical study. PMID- 22938740 TI - Population-based estimates of transbronchial lung biopsy utilization and complications. AB - BACKGROUND: Little is known about trends in the utilization or complication rates of transbronchial lung biopsy, particularly in community hospitals. METHODS: We used the Healthcare Cost and Utilization Project Florida State Inpatient and State Ambulatory Surgical Databases to assess trends in transbronchial lung biopsy utilization in adults from 2000 to 2009. We subsequently calculated population based estimates of complications associated with transbronchial lung biopsy (iatrogenic pneumothorax and procedure-related hemorrhage) and identified characteristics associated with complications. RESULTS: From 2000 to 2009, the age-adjusted rate of transbronchial biopsies per 100,000 adults in Florida decreased by 25% from 74 to 55 (p < 0.0001), despite stability in the overall utilization of bronchoscopy. Analysis of 82,059 procedures revealed that complications associated with transbronchial biopsy were uncommon and stable over the study period, with 0.97% (95% CI 0.94-1.01%) of procedures complicated by pneumothorax, 0.55% (95% CI 0.52-0.58%) by pneumothorax requiring chest tube placement, and 0.58% (95% CI 0.55-0.61%) by procedure-related hemorrhage. Patients with COPD (OR 1.51, 95% CI 1.31-1.75) and women (OR 1.32, 95% CI 1.15 1.52) were at increased risk for pneumothorax, while renal failure (OR 2.85, 95% CI 2.10-3.87), cirrhosis (OR 2.31, 95% CI 1.18-4.52), older age (OR 1.17, 95% CI 1.09-1.25) and female sex (OR 1.40, 95% CI 1.17-1.68) were associated with higher risk of procedure-related hemorrhage. CONCLUSIONS: Utilization of transbronchial lung biopsy is decreasing relative to the overall use of bronchoscopy. Nevertheless, it remains a safe procedure with low risk of complications. PMID- 22938742 TI - Fractals and the mind. PMID- 22938744 TI - Climate change and willful ignorance. PMID- 22938745 TI - Evidence and potential mechanisms for mindfulness practices and energy psychology for obesity and binge-eating disorder. AB - Obesity is a growing epidemic. Chronic stress produces endocrine and immune factors that are contributors to obesity's etiology. These biochemicals also can affect appetite and eating behaviors that can lead to binge-eating disorder. The inadequacies of standard care and the problem of patient noncompliance have inspired a search for alternative treatments. Proposals in the literature have called for combination therapies involving behavioral or new biological therapies. This manuscript suggests that mind-body interventions would be ideal for such combinations. Two mind-body modalities, energy psychology and mindfulness meditation, are reviewed for their potential in treating weight loss, stress, and behavior modification related to binge-eating disorder. Whereas mindfulness meditation and practices show more compelling evidence, energy psychology, in the infancy stages of elucidation, exhibits initially promising outcomes but requires further evidence-based trials. PMID- 22938747 TI - Holism at the National Intrepid Center of Excellence (NICoE). AB - Traumatic brain injury and posttraumatic stress disorder are the signature injuries of the Iraq and Afghanistan wars. Holistic medicine (comprising multispecialty care integration, patient/family-centered care, wellness interventions, and the construction of architectural "healing environments") has much to offer these patients. In this work we describe the architecture and holistic medicine programming of the National Intrepid Center of Excellence (NICoE), a new clinical research center for traumatic brain injury and posttraumatic stress disorder in the Military Health System. Architecture and clinical process are united in a "design/care continuum" for optimal healing. A groundbreaking institution, the NICoE foreshadows many trends in national healthcare for the 21st century. PMID- 22938746 TI - Retrolective studies on the survival of cancer patients treated with mistletoe extracts: a meta-analysis. AB - BACKGROUND: Studies reveal that patients with cancer are actively seeking supportive treatments and may use distinct coping strategies that might be helpful to extend survival time. In this respect, retrolective studies have been applied to examine the therapeutic potential of adjuvant mistletoe treatment. MATERIAL AND METHODS: The databases PubMed, EMBASE, AMED, and CAMbase were used to identify retrolective studies in mistletoe treatment. In addition to a review, we also performed a meta-analysis with respect to cancer patients' survival time by a random effects model. Overall estimates of treatment effects were displayed with a forest plot. RESULTS: A total of 17 articles met the inclusion criteria. From these, 10 duplicates and 3 descriptive literature and popular articles had to be removed, leaving 4 retrolective studies on mistletoe preparations and patients' survival conducted between 1985 and 2002, with a total of 3.324 patients (2.454 per protocol) recruited in 17 to 35 German and Swiss hospitals, wards, and private practices. Meta-analysis revealed a moderate overall effect of hazard ratios 0.59 (95% confidence interval 0.50-0.70) in favor of mistletoe treatment. DISCUSSION: Although we found a positive treatment effect, there are several methodological limitations with respect to the retrolective study design. PMID- 22938748 TI - Ritual and ceremony in intraoperative magnetic resonance imaging-assisted brain surgery. AB - Previous photographic research into traditional and shamanic healing practices in Peru and Bolivia and a review of the literature suggested that all medical practices have cultural determined nonmedical activities as integral parts of the healing encounter. These include costume, ritual, ceremony, environment factors that were looked for in a western clinical encounter for this paper. A patient was followed through pre-op preparation and iMRI assisted brain surgery. All activities were photographed extensively and evaluated in a broader healing context. A number of activities were visually and metaphorically comparable with those seen in other practices. These are discussed as rituals of intention on the part of the caregivers to focus their skills on healing and also to mindfully engage the patient in the healing process. Artistic observation and analysis may be an effective way to identify these non quantifiable elements of the healing encounter and suggest directions for further research into the emotional components of the healing process. PMID- 22938749 TI - Altars and icons: the surgical suite as a sacred ritual. PMID- 22938750 TI - A case study of chiropractic management of pregnancy-related heartburn with postulated fetal epigenome implications. AB - OBJECTIVE: This case study reports on chiropractic care for pregnancy-related heartburn. The purpose of this article is to relate the benefit of chiropractic treatment for one individual, to contrast chiropractic management with the biomedical standard of care for pregnancy-related heartburn, and to point to potential epigenetic implications of the standard of care. CLINICAL FEATURES: A 32-year-old woman who was 24 weeks pregnant presented with persistent heartburn that she was treating with ranitidine (Zantac(r)) and calcium carbonate (Tums(r)) daily at the initiation of chiropractic care. INTERVENTION AND OUTCOME: Findings of the initial examination were thoracic intersegmental dysfunction and pain upon palpation of the diaphragm, with hypertonicity noted. Therapy localization was positive for reflexes associated with the esophagus and lower esophageal sphincter, suggesting spasms. Emotional components also were identified in association with the symptoms by the use of a mind-body therapy called NeuroEmotional Technique. The patient was treated by adjusting the thoracic spine, manually releasing the diaphragm spasms, and releasing the esophageal spasm with an activator (a small hand-held instrument that creates a percussive force). The patient was symptom-free and did not use medication after the fifth treatment. She was followed throughout the remainder of her pregnancy and was asymptomatic and required no further treatment. CONCLUSIONS: A larger study should investigate the effectiveness of chiropractic care for the treatment of pregnancy-related heartburn. PMID- 22938752 TI - A student initiative for reducing stress in medical students: Stress-Less-Fest. PMID- 22938753 TI - Stenoses of the salivary ducts-sialendoscopy based diagnosis and treatment. AB - Our aim was to analyse the nature of a sialendoscopy-based classification and present its use in the treatment of stenoses of Wharton's and Stensen's ducts. The classification of stenoses of Wharton's duct has not been published before. We did 133 sialendoscopies in 114 patients who presented with possible obstruction of the ducts to the tertiary centre for ENT at the University Department in Poznan. Twenty-seven patients had their parotid ducts treated, and 24 their submandibular ducts. Suspicion of stenotic changes of the ductal system was suggested during ultrasound examination. They were examined with semirigid endoscopes that enabled direct visualisation of the stenotic areas. A total of 69 stenoses were diagnosed in 51 patients. Stenoses were divided into three groups according to their site. Patients with stenosis of the salivary ducts were treated by dilatation of the stenotic area, intraductal steroid injections, and insertion of a stent for 14-21 days. Forty of the 51 reported considerable improvement, and 7 partial improvement. Four patients had no improvement. Sialendoscopy is a safe way to treat obstruction of the salivary glands. Short and medium term follow up show that it is extremely successful. PMID- 22938754 TI - Comparison of EyeCam and anterior segment optical coherence tomography in detecting angle closure. AB - PURPOSE: To compare the diagnostic performance of EyeCam (Clarity Medical Systems, Pleasanton, CA, USA) and anterior segment optical coherence tomography (ASOCT, Visante; Carl Zeiss Meditec, Dublin, CA, USA) in detecting angle closure, using gonioscopy as the reference standard. METHODS: Ninety-eight phakic patients, recruited from a glaucoma clinic, underwent gonioscopy by a single examiner, and EyeCam and ASOCT imaging by another examiner. Another observer, masked to gonioscopy findings, graded EyeCam and ASOCT images. For both gonioscopy and EyeCam, a closed angle in a particular quadrant was defined if the posterior trabecular meshwork was not visible. For ASOCT, angle closure was defined by any contact between the iris and angle anterior to the scleral spur. An eye was diagnosed as having angle closure if >=2 quadrants were closed. Agreement and area under the receiver operating characteristic curves (AUC) were evaluated. RESULTS: The majority of subjects were Chinese (69/98, 70.4%) with a mean age of 60.6 years. Angle closure was diagnosed in 39/98 (39.8%) eyes with gonioscopy, 40/98 (40.8%) with EyeCam and 56/97 (57.7%) with ASOCT. The agreement (kappa statistic) for angle closure diagnosis for gonioscopy versus EyeCam was 0.89; gonioscopy versus ASOCT and EyeCam versus ASOCT were both 0.56. The AUC for detecting eyes with gonioscopic angle closure with EyeCam was 0.978 (95% CI: 0.93 1.0) and 0.847 (95% CI: 0.76-0.92, p < 0.01) for ASOCT. CONCLUSION: The diagnostic performance of EyeCam was better than ASOCT in detecting angle closure when gonioscopic grading was used as the reference standard. The agreement between the two imaging modalities was moderate. PMID- 22938755 TI - Menthol cigarette pricing at military and community retail outlets in the United States. AB - BACKGROUND: Cigarette prices at military exchanges historically have been discounted. DoD Instruction 1330.9 has mandated that prices be within 5% of the price offered in the local community since 2001. Because minorities are highly represented in the military, we determined whether menthol cigarette prices, the leading choice of African Americans, were compliant with the instruction. METHODS: We collected, via telephone, menthol cigarette price data from 48 randomly selected US military installation exchanges and matched local area Walmarts. We collected prices after taxes to determine the cost to consumer. Newport was selected as the index brand for menthol cigarettes because it is the leading and second leading brand smoked by African Americans and by Hispanics, respectively and has the second overall highest market share in the US. RESULTS: Smokers purchasing menthols at exchanges would realize average savings of 22.78%. There were no significant differences in savings based on military service (F = 1.850, p = 0.152) or US Census Division (F = 1.226, p = 0.311: data not shown). In addition, not a single exchange price was compliant with the DoD instruction. CONCLUSIONS: Newport menthol cigarettes at military exchanges cost substantially less than the nearest Walmart, with an average savings of 23%. Our findings demonstrate that menthol cigarettes are substantially discounted on military installations, in a manner similar to other cigarette prices, and that DoD Instruction 1330.09 is not enforced. PMID- 22938756 TI - Unexpected high levels of multidrug-resistant tuberculosis present new challenges for tuberculosis control. PMID- 22938758 TI - [Unintentional drowning by immersion. Epidemiological profile of victims attended in 21 Spanish emergency departments]. AB - OBJECTIVES: To determine the frequency of accidental drowning seen in paediatric emergency departments, to define the epidemiological profile of the victims, and to analyse the circumstances related to prognosis and survival. PATIENTS AND METHODS: A multicentre, prospective and descriptive study was conducted on victims of accidental drowning seen in 21 paediatric emergency departments between June and September 2009 and 2010. We collected personal, environmental, safety, security data, as well as the need for cardiopulmonary resuscitation (CPR), hospitalisation rate, sequelae and mortality. RESULTS: Out of 234,566 emergency department cases, 53 were due to accidental drowning (frequency: 2.2/10,000 consultations during the summer period, 64.2% males). The median age was 3.5 years (p25-75: 2.6-8.4), with 34 had less than 6 years. Thirty-two children were hospitalised. Most drowning occurred in the afternoon (40), in freshwater (49), in private pools (33) and unprotected (33). The victims, mostly healthy children (40), did not know how to swim (38) and were not wearing flotation systems (37/38). There was lack of supervision in 42 cases. Acidosis (20) and hypoxaemia (18) were the most frequent findings. Five children died, 4 were healthy, none knew how to swim or had a float device, and none were supervised. Thirty six children required CPR, mostly applied by family (15). In the children who died, CPR was started after 3 min. Two survivors had hemiparesis. CONCLUSIONS: Accidental drowning was a rare cause of consultation in paediatric emergency departments. In children less than 6 years, who did not know how to swim, did not use flotation devices in unprotected private pools, and were not properly supervised, there is an increased of suffering from accidental drowning and its associated morbidity. An immersion time> 10 min, starting CPR > 3 min, acidosis, hyponatraemia, and hypothermia on arrival at the emergency department increases mortality. Training family members in cardiopulmonary resuscitation can be useful. PMID- 22938759 TI - Pressure-induced transition from an antiferromagnet to a ferrimagnet for Mn(II)(TCNE)[C4(CN)8]1/2 (TCNE = tetracyanoethylene). AB - Mn(II)(TCNE)[C(4)(CN)(8)](1/2) (TCNE = tetracyanoethylene) exhibits a reversible pressure-induced piezomagnetic transition from a low magnetization antiferromagnetic state to a high magnetization ferrimagnetic state above 0.50 +/ 0.15 kbar. In the ferrimagnetic state, the critical temperature, T(c), increases with increasing hydrostatic pressure and is ~97 K at 12.6 kbar, the magnetization increases by 3 orders of magnitude (1000-fold), and the material becomes a hard magnet with a significant remnant magnetization. PMID- 22938760 TI - Maintenance treatment with long-acting injectable risperidone in first-episode schizophrenia: a randomized effectiveness study. AB - BACKGROUND: Because long-acting injectable (LAI) antipsychotics are largely reserved for persistently ill patients, little is known about the use of LAIs early in the course of illness for first-episode outpatients. METHOD: A prospective, open-label, randomized controlled trial was conducted in which outpatients with first-episode DSM-IV schizophreniform disorder, schizophrenia, or schizoaffective disorder were enrolled from December 2004 to March 2007. Participants were randomly assigned at a 2:1 ratio to a recommendation of changing to LAI risperidone microspheres (RLAI) (n = 26) or continuing oral antipsychotic treatment (n = 11) for up to 104 weeks. Primary outcomes were time until initial nonadherence (medication gap of >= 14 days) and medication attitudes as assessed with the Rating of Medication Influences scale. Patients randomly assigned to an RLAI recommendation could decline the recommendation, so analysis defined treatment groups by intent-to-treat and as-actually-treated. RESULTS: Eighty-one percent of patients (30/37) stopped medication within 104 weeks. There was a trend toward an initial adherence benefit favoring RLAI acceptors at 12 weeks (P = .058), but no significant difference between RLAI and oral antipsychotic treatment in time to initial nonadherence during the overall study (P = .188). Medication attitudes did not differ between groups. CONCLUSIONS: Acceptance of RLAI was associated with an initial adherence benefit that was not sustained over time. Early introduction of LAI therapy did not adversely affect adherence attitudes. The small size of the study and low power limit interpretation, but the few patients who remained adherent into a second year were all receiving RLAI. Nonadherence was almost universal in our first episode cohort, but nonadherence was more easily detected among first-episode patients treated with LAI therapy than it was with oral antipsychotics. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00220714. PMID- 22938757 TI - Prevalence of and risk factors for resistance to second-line drugs in people with multidrug-resistant tuberculosis in eight countries: a prospective cohort study. AB - BACKGROUND: The prevalence of extensively drug-resistant (XDR) tuberculosis is increasing due to the expanded use of second-line drugs in people with multidrug resistant (MDR) disease. We prospectively assessed resistance to second-line antituberculosis drugs in eight countries. METHODS: From Jan 1, 2005, to Dec 31, 2008, we enrolled consecutive adults with locally confirmed pulmonary MDR tuberculosis at the start of second-line treatment in Estonia, Latvia, Peru, Philippines, Russia, South Africa, South Korea, and Thailand. Drug-susceptibility testing for study purposes was done centrally at the Centers for Disease Control and Prevention for 11 first-line and second-line drugs. We compared the results with clinical and epidemiological data to identify risk factors for resistance to second-line drugs and XDR tuberculosis. FINDINGS: Among 1278 patients, 43.7% showed resistance to at least one second-line drug, 20.0% to at least one second line injectable drug, and 12.9% to at least one fluoroquinolone. 6.7% of patients had XDR tuberculosis (range across study sites 0.8-15.2%). Previous treatment with second-line drugs was consistently the strongest risk factor for resistance to these drugs, which increased the risk of XDR tuberculosis by more than four times. Fluoroquinolone resistance and XDR tuberculosis were more frequent in women than in men. Unemployment, alcohol abuse, and smoking were associated with resistance to second-line injectable drugs across countries. Other risk factors differed between drugs and countries. INTERPRETATION: Previous treatment with second-line drugs is a strong, consistent risk factor for resistance to these drugs, including XDR tuberculosis. Representative drug-susceptibility results could guide in-country policies for laboratory capacity and diagnostic strategies. FUNDING: US Agency for International Development, Centers for Disease Control and Prevention, National Institutes of Health/National Institute of Allergy and Infectious Diseases, and Korean Ministry of Health and Welfare. PMID- 22938761 TI - Visual perception of fatigued lifting actions. AB - Fatigue-related changes in lifting kinematics may expose workers to undue injury risks. Early detection of accumulating fatigue offers the prospect of intervention strategies to mitigate such fatigue-related risks. In a first step towards this objective, this study investigated whether fatigue detection was accessible to visual perception and, if so, what was the key visual information required for successful fatigue discrimination. Eighteen participants were tasked with identifying fatigued lifts when viewing 24 trials presented using both video and point-light representations. Each trial comprised a pair of lifting actions containing a fresh and a fatigued lift from the same individual presented in counter-balanced sequence. Confidence intervals demonstrated that the frequency of correct responses for both sexes exceeded chance expectations (50%) for both video (68%+/-12%) and point-light representations (67%+/-10%), demonstrating that fatigued lifting kinematics are open to visual perception. There were no significant differences between sexes or viewing condition, the latter result indicating kinematic dynamics as providing sufficient information for successful fatigue discrimination. Moreover, results from single viewer investigation reported fatigue detection (75%) from point-light information describing only the kinematics of the box lifted. These preliminary findings may have important workplace applications if fatigue discrimination rates can be improved upon through future research. PMID- 22938762 TI - The role of the ERK1/2 pathway as an alternative to the aging-diminished cyclic AMP pathway in calcitonin-mediated chondrogenesis in human nucleus pulposus. AB - Human disc degeneration initiated by aging in the central nucleus pulposus (hNP) is an irreversible process and the recovery has become seriously emerging. In this study, the related mechanisms of calcitonin on the regeneration of hNP and the effects of calcitonin on the age-related alterations were examined. The harvested hNP population was designated as YhNP (from young donor, age <50) and OhNP (from old donor, age >50). Primary OhNP cells showed more hypertrophic phenotypes than YhNP. However, calcitonin (10(-8)-10(-6) M) was able to induce the same chondrogenesis in both YhNP and OhNP by elevating chondrogenic specific mRNA and protein expressions. Their cell viabilities were increased with calcitonin treatment. No significant differences of calcitonin receptor (CTR) were expressed between YhNP and OhNP cells. Interestingly, in calcitonin-induced pathways for chondrogenesis, highly increased cyclic AMP (cAMP) was detected in YhNP but was strongly diminished by aging in OhNP after calcitonin treatment. However, to maintain the chondrogenesis, calcitonin-induced an alterative phosphorylated ERK1/2 (p-ERK) in both cells. After inhibiting ERK1/2 by PD98059, calcitonin-induced chondrogenesis in OhNP was almost restrained while YhNP cells were not affected. Our results demonstrated that the regeneration of calcitonin on hNP was maintained with aging which was satisfied by an alternative signaling pathway. Therefore, calcitonin shows great potential for clinical therapy for disc regeneration without aging considerations. PMID- 22938763 TI - Selective functionalization of nanofiber scaffolds to regulate salivary gland epithelial cell proliferation and polarity. AB - Epithelial cell types typically lose apicobasal polarity when cultured on 2D substrates, but apicobasal polarity is required for directional secretion by secretory cells, such as salivary gland acinar cells. We cultured salivary gland epithelial cells on poly(lactic-co-glycolic acid) (PLGA) nanofiber scaffolds that mimic the basement membrane, a specialized extracellular matrix, and examined cell proliferation and apicobasal polarization. Although cells proliferated on nanofibers, chitosan-coated nanofiber scaffolds stimulated proliferation of salivary gland epithelial cells. Although apicobasal cell polarity was promoted by the nanofiber scaffolds relative to flat surfaces, as determined by the apical localization of ZO-1, it was antagonized by the presence of chitosan. Neither salivary gland acinar nor ductal cells fully polarized on the nanofiber scaffolds, as determined by the homogenous membrane distribution of the mature tight junction marker, occludin. However, nanofiber scaffolds chemically functionalized with the basement membrane protein, laminin-111, promoted more mature tight junctions, as determined by apical localization of occludin, but did not affect cell proliferation. To emulate the multifunctional capabilities of the basement membrane, bifunctional PLGA nanofibers were generated. Both acinar and ductal cell lines responded to signals provided by bifunctional scaffolds coupled to chitosan and laminin-111, demonstrating the applicability of such scaffolds for epithelial cell types. PMID- 22938764 TI - The effect of the encapsulation of bacteria in redox phospholipid polymer hydrogels on electron transfer efficiency in living cell-based devices. AB - Development of living cell-based devices holds great promise in many biomedical and industrial applications. To increase our understanding of the process, we investigated the biological and electrochemical properties of a redox phospholipid polymer hydrogel containing an electron-generating bacteria (Shewanella oneidensis MR-1). A water-soluble and amphiphilic phospholipid polymer, poly(2-methacryloyloxyethyl phosphorylcholine-co-n-butyl methacrylate-co p-vinylphenylboronic acid-co-vinylferrocene) (PMBVF), was our choice for incorporation into a hydrogel matrix that promotes encapsulation of bacteria and acts as an electron transfer mediator. This hydrogel formed spontaneously and encapsulated Shewanella in three-dimensional structures. Visual analysis showed that the encapsulated Shewanella maintained viability and metabolic activity even after long-term storage. Cyclic voltammetry measurement indicated that the PMBVF/poly(vinyl alcohol) (PMBVF/PVA) hydrogel had stable and high electron transfer efficiency. Amperometric measurement showed that the hydrogel could maintain the electron transfer efficiency even when Shewanella was encapsulated. Thus, the PMBVF/PVA hydrogel not only provides a mild environment for long-term bacterial survival but also maintains electron transfer efficiency from the bacteria to the electrode. We conclude that hydrogel/bacteria hybrid biomaterials, such as PMBVF/PVA/Shewanella, may find application in the fabrication of living cell-based devices. PMID- 22938766 TI - The use of polymeric platinum(IV) prodrugs to deliver multinuclear platinum(II) drugs with reduced systemic toxicity and enhanced antitumor efficacy. AB - Two dinuclear platinum(IV) prodrugs were prepared from cisplatin and oxaliplatin, and tethered to amphiphilic biodegradable block copolymers. The polymeric dinuclear platinum(IV) prodrugs were allowed to self-assemble into nanomicelles, which showed reduced systemic toxicity, relatively long blood circulation, and enhanced antitumor efficacy. In this way, the bottleneck of present multinuclear platinum drugs, especially their severe systemic toxicity, might be overcome. PMID- 22938767 TI - Endometriosis: enigmatic in the pathogenesis and controversial in its therapy. PMID- 22938768 TI - Pharmacologic therapies in endometriosis: a systematic review. AB - To assess the literature on preclinical and clinical efficacy and safety data of pharmacologic groups proposed in the treatment of endometriosis, we performed a systematic review of publications from March 2002 to January 2012 via PubMed search. Additional relevant articles were identified from citations within these publications. A high number of medications were tested in preclinical models of endometriosis due to their theoretic capacity of disrupting important pathophysiologic pathways of the disease, such as inflammatory response, angiogenesis and cell survival, proliferation, migration, adhesion, and invasion. Tumor necrosis factor alpha-blockers, nuclear factor kappaB inhibitors, antiangiogenic agents, statins, antioxidants, immunomodulators, flavonoids, histone deacetylase inhibitors, matrix metalloproteinase inhibitors, metformin, novel modulators of sex steroids expression, and apoptotic agents were all effective in in vitro/animal models. Most of these agents have not been tried in the clinical setting, mainly because of the high risk of adverse effects. However, some of them can be used in humans. Dopamine agonists and valproic acid have already been tested in pilot studies with good results. Etanercept, metformin, and statins are used in humans for other indications, and endostatin is now being tested in phase 2 oncologic trials. These drugs may constitute alternatives to conventional therapy with estrogen inhibitors and anti inflammatory agents. PMID- 22938769 TI - Deep endometriosis: definition, diagnosis, and treatment. AB - Deep endometriosis, defined as adenomyosis externa, mostly presents as a single nodule, larger than 1 cm in diameter, in the vesicouterine fold or close to the lower 20 cm of the bowel. When diagnosed, most nodules are no longer progressive. In >95% of cases, deep endometriosis is associated with very severe pain (in >95%) and is probably a cofactor in infertility. Its prevalence is estimated to be 1% -2%. Deep endometriosis is suspected clinically and can be confirmed by ultrasonography or magnetic resonance imaging. Contrast enema is useful to evaluate the degree of sigmoid occlusion. Surgery requires expertise to identify smaller nodules in the bowel wall, and difficulty increases with the size of the nodules. Excision is feasible in over 90% of cases often requiring suture of the bowel muscularis or full-thickness defects. Segmental bowel resections are rarely needed except for sigmoid nodules. Deep endometriosis often involves the ureter causing hydronephrosis in some 5% of cases. The latter is associated with 18% ureteral lesions. Deep endometriosis surgery is associated with late complications such as late bowel and ureteral perforations, and recto-vaginal and uretero-vaginal fistulas. Although rare, these complications require expertise in follow-up and laparoscopic management. Pain relief after surgery is excellent and some 50% of women will conceive spontaneously, despite often severe adhesions after surgery. Recurrence of deep endometriosis is rare. In conclusion, defined as adenomyosis externa, deep endometriosis is a rarely a progressive and recurrent disease. The treatment of choice is surgical excision, while bowel resection should be avoided, except for the sigmoid. PMID- 22938765 TI - A review of combined experimental and computational procedures for assessing biopolymer structure-process-property relationships. AB - Tailored biomaterials with tunable functional properties are desirable for many applications ranging from drug delivery to regenerative medicine. To improve the predictability of biopolymer materials functionality, multiple design parameters need to be considered, along with appropriate models. In this article we review the state of the art of synthesis and processing related to the design of biopolymers, with an emphasis on the integration of bottom-up computational modeling in the design process. We consider three prominent examples of well studied biopolymer materials - elastin, silk, and collagen - and assess their hierarchical structure, intriguing functional properties and categorize existing approaches to study these materials. We find that an integrated design approach in which both experiments and computational modeling are used has rarely been applied for these materials due to difficulties in relating insights gained on different length- and time-scales. In this context, multiscale engineering offers a powerful means to accelerate the biomaterials design process for the development of tailored materials that suit the needs posed by the various applications. The combined use of experimental and computational tools has a very broad applicability not only in the field of biopolymers, but can be exploited to tailor the properties of other polymers and composite materials in general. PMID- 22938770 TI - Oocyte vitrification: a watershed in ART. PMID- 22938771 TI - Evidence-based reproductive risk epidemiology: the importance of multidisciplinary and multiprofessional methodologic collaboration. PMID- 22938772 TI - The genuine empty follicle syndrome: is the king naked? PMID- 22938774 TI - Heterosis for meat quality and fatty acid profiles in crosses among Bos indicus and Bos taurus finished on pasture or grain. AB - Physicochemical properties and fatty acid profiles of meat from Bos indicus, Bos taurus and crossbred B. taurus*B. indicus bullocks (n=216), finished on pasture or grain, were used to estimate the effects of heterosis. Meat quality and fatty acid profiles generally benefited with crossbreeding, but the advantages from heterosis differed among finishing systems. The Warner-Bratzler shear-force in fresh and aged meat was reduced due to heterosis in pasture-finishing, but the effect was minor under grain-finishing. With pasture-finishing, heterosis caused an increase of 5% in CLA concentration, but few other changes in fatty acid profiles. In grain-finishing, heterosis caused a reduction in intramuscular fat and cholesterol, increased amounts of PUFA, n-6 fatty acids and PUFA/SFA ratio, and a decline in atherogenic index. The Delta(9) desaturase estimated activity in crossbreds showed a behavior close to B. indicus, suggesting the existence of few loci and a dominance genetic effect on enzymes involved in fatty acid synthesis and metabolism. PMID- 22938775 TI - Effectiveness and safety of saquinavir/ritonavir in HIV-infected pregnant women: INEMA cohort. AB - OBJECTIVE: The authors had for aim to describe the effectiveness and the safety of a saquinavir/ritonavir (SQV/r) regimen, 1000/100mg twice daily, in HIV infected pregnant patients. PATIENTS AND METHOD: We made a prospective and observational study of HIV positive female patients beginning or going on SQV/r antiretroviral treatment (ART) during pregnancy. RESULTS: Sixty-two patients were enrolled from July 2007 to June 2009 in 10 infectious diseases units in France. Thirty-six women (group 1) were ART naive on inclusion, 20 (group 2) had been previously treated and then switched to SQV/r, six (group 3) were treated with SQV/r before pregnancy. 58 patients delivered while on SQV/r regimen after a median pregnancy duration of 39 WA. Eighty percent had a viral load below 50 copies/mL and 93% below 400 copies/mL: respectively 77% and 93.5% in group 1, 83% and 89% in group 2, 83% and 100% in group 3. The median SQV minimum concentrations (C(min)) measured at the third trimester and at delivery were adequate, respectively 0.91 mg/L and 0.86 mg/L. Most women (52%) had a vaginal delivery; 12 (21%) had an elective caesarean section, for obstetrics factors in eight cases. None of the newborns were HIV-infected at 6 months of age (n = 59, one death at day 3). Only one severe adverse event occurred due to saquinavir (maternal grade 3 hepatotoxicity). CONCLUSION: SQV/r 1000/100mg twice daily seems to be effective and safe in HIV-infected pregnant women with adequate saquinavir C(min). PMID- 22938776 TI - Inspiratory muscle training for diaphragm dysfunction after cardiac surgery. AB - OBJECTIVE: Diaphragm dysfunction is a complication of cardiac surgery with partial or absent spontaneous recovery in most cases. Surgical diaphragm plication represents the only option when symptoms persist. Because training improves functional nerve recovery after a nerve lesion, we hypothesized that early diaphragm muscle training may be beneficial. METHODS: A prospective, randomized at 2:1 ratio, controlled trial of diaphragm training using an adjustable pressure device (Threshold; Philips Respironics Inc, Murrysville, Pa) versus no training (sham device) was performed in patients with diaphragm paralysis after major cardiac surgery. This 1-year study recruited consecutive adult patients with sniff fluoroscopy-defined diaphragm paralysis after coronary bypass, valve replacement, or both. The outcome measures were diaphragm function recovery assessed by sniff fluoroscopy, maximum inspiratory and expiratory pressures, and lung function tests. RESULTS: A total of 69 patients were randomized. At 12 months, 52 patients completed the study assessments, 36 in the treatment group and 16 in the control group. Inspiratory muscle training produced a significant improvement of diaphragm mobility after 12 months (P < .001). Most patients in the training group (77.78%) experienced a partial improvement (41.67%) or achieved a complete improvement (36.11%) versus no improvement (87.5%) or partial recovery (12.5%) among controls. CONCLUSIONS: Inspiratory muscle training may improve inspiratory muscle strength and increases paralyzed diaphragm mobility. PMID- 22938777 TI - Differences in reported esophageal cancer resection outcomes between national clinical and administrative databases. AB - BACKGROUND: The Society of Thoracic Surgeons (STS) General Thoracic Surgery Database (GTSD) is the largest clinical thoracic surgical database in the United States. The purpose of the present study was to determine whether the GTSD esophagectomy outcomes are representative of nationwide outcomes by comparing them with other national clinical and administrative databases. METHODS: From 2002 to 2008, esophageal cancer resection outcomes from the GTSD were compared with those from the National Surgery Quality Improvement Program (NSQIP) and Nationwide Inpatient Sample (NIS). The observed differences in patient characteristics and postoperative events were also analyzed. RESULTS: Annual esophageal resection volumes have increased over time. However, as of 2008, the GTSD and NSQIP only capture a small proportion of resections performed nationally (36% and 11%, respectively). The median patient age and female gender were similar in all 3 databases. Mortality was significantly lower within the GTSD (3.2%) and NSQIP (2.6%) compared with the NIS (6.1%, P < .001). The median length of stay was lower in the GTSD (10 days) than in either the NSQIP (12 days) and NIS (12 days, P < .001). CONCLUSIONS: The STS GTSD reports outstanding mortality results and hospital length of stay for esophageal cancer resection. However, the surgical outcomes from the STS GTSD are not representative of the national results from programs not participating in the database. These results establish a reference for future esophagectomy comparisons and highlight the importance of increased participation and use of the STS GTSD. PMID- 22938778 TI - Discussion. PMID- 22938779 TI - Utility of concomitant tricuspid valve procedures for patients undergoing implantation of a continuous-flow left ventricular device. AB - OBJECTIVE: Patients referred for implantable continuous-flow left ventricular assist devices (cfLVAD) frequently have preoperative right heart failure and tricuspid regurgitation (TR). The objective of this report is to examine early clinical benefits of concomitant tricuspid surgery for these patients. METHODS: Sixty-one of 200 consecutive cfLVAD patients at our institution displayed preimplant right heart dysfunction and significant TR. Thirty-three underwent cfLVAD plus a tricuspid valve procedure (TVP), and 28 had cfLVAD alone. Preimplant characteristics and clinical outcomes were retrospectively studied. As previously described, post-LVAD right ventricular failure was defined as need for right ventricular assist device (RVAD) support or greater than 14 days of intravenous inotropic support. RESULTS: Preimplant characteristics were similar between the 2 groups. Cardiopulmonary bypass time was increased for the group that received concomitant TVPs. The most common TVP consisted of an undersizing ring annuloplasty. The cfLVAD-alone group had greater TR after implant relative to the cfLVAD+TVP group. The cfLVAD-alone group experienced greater postprocedure right ventricular failure relative to cfLVAD+TVP (46.4% vs 18.2%; P < .05). Furthermore, prolonged hospitalization was increased for the cfLVAD-alone group versus the cfLVAD+TVP. Survival was similar between the 2 groups. CONCLUSIONS: Concomitant TVP appears to reduce postprocedure right ventricular failure for patients with significant TR undergoing cfLVAD implantation. PMID- 22938780 TI - Face-to-face single patch: a new technique to repair the commissures of the mitral valve. PMID- 22938781 TI - Four-flap compound repair of thoracic hernia after sternum osteomyelitis and omentum flap. PMID- 22938785 TI - Early phase drug discovery: cheminformatics and computational techniques in identifying lead series. AB - Early drug discovery processes rely on hit finding procedures followed by extensive experimental confirmation in order to select high priority hit series which then undergo further scrutiny in hit-to-lead studies. The experimental cost and the risk associated with poor selection of lead series can be greatly reduced by the use of many different computational and cheminformatic techniques to sort and prioritize compounds. We describe the steps in typical hit identification and hit-to-lead programs and then describe how cheminformatic analysis assists this process. In particular, scaffold analysis, clustering and property calculations assist in the design of high-throughput screening libraries, the early analysis of hits and then organizing compounds into series for their progression from hits to leads. Additionally, these computational tools can be used in virtual screening to design hit-finding libraries and as procedures to help with early SAR exploration. PMID- 22938782 TI - Cell adhesion in Drosophila: versatility of cadherin and integrin complexes during development. AB - We highlight recent progress in understanding cadherin and integrin function in the model organism Drosophila. New functions for these adhesion receptors continue to be discovered in this system, emphasising the importance of cell adhesion within the developing organism and showing that the requirement for cell adhesion changes between cell types. New ways to control adhesion have been discovered, including controlling the expression and recruitment of adhesion components, their posttranslational modification, recycling and turnover. Importantly, even ubiquitous adhesion components can function differently in distinct cellular contexts. PMID- 22938786 TI - Discovery of 3H-imidazo[4,5-c]quinolin-4(5H)-ones as potent and selective dipeptidyl peptidase IV (DPP-4) inhibitors. AB - In recent years, dipeptidyl peptidase IV inhibitors have been noted as valuable agents for treatment of type 2 diabetes. Herein, we report the discovery of a novel potent DPP-4 inhibitor with 3H-imidazo[4,5-c]quinolin-4(5H)-one as skeleton. After efficient optimization of the lead compound 2a at the 7- and 8 positions using a docking study, we found 28 as a novel DPP-4 inhibitor with excellent selectivity against various DPP-4 homologues. Compound 28 showed strong DPP-4 inhibitory activity compared to marketed DPP-4 inhibitors. We also found that a carboxyl group at the 7-position could interact with the residue of Lys554 to form a salt bridge. Additionally, introduction of a carboxyl group to 7 position led to both activity enhancement and reduced risk for hERG channel inhibition and induced phospholipidosis. In our synthesis of compounds with 7 carboxyl group, we achieved efficient regioselective synthesis using bulky ester in the intramolecular palladium coupling reaction. PMID- 22938787 TI - Blood transfusion associated with shoulder arthroplasty. AB - BACKGROUND: Studies have reported high rates of transfusion in shoulder arthroplasty. This study was conducted to evaluate the rate of transfusion at our institution, to confirm reported risk factors for transfusion, and to look for changes over time.We hypothesized that transfusion rates associated with shoulder arthroplasty at our institution are lower than those recently reported and that the incidence of transfusion is higher in individuals with low preoperative hemoglobin, with revision arthroplasty, and in older individuals. MATERIALS AND METHODS: A retrospective review of 366 shoulder arthroplasties (323 patients) was performed. This included total shoulder arthroplasties, hemiarthroplasties, revision arthroplasties, and reverse total shoulder arthroplasties. Logistic regression analysis evaluated the association of clinical variables with transfusion. Early (1996-2005) and late (2006-2009) groups were compared to evaluate changes in demographics and transfusion rates over time. RESULTS: The overall transfusion rate was 7.4% (27 of 339). Predictors of transfusion were higher intraoperative blood loss, low preoperative hemoglobin level, and humeral cement fixation. Procedure type was not predictive of transfusion. There was no difference in transfusion rates between the early and late groups, but the late group had an increased use of general anesthesia combined with a regional block, increased intraoperative blood loss, and increased use of sequential compression devices for venous thromboembolism prophylaxis. CONCLUSIONS: Lower preoperative hemoglobin, higher intraoperative blood loss, and humeral cement fixation were predictors of transfusion, but not female sex, increasing age, type of procedure, or comorbidities. PMID- 22938788 TI - Osteoporosis and shoulder osteoarthritis: incidence, risk factors, and surgical implications. AB - BACKGROUND: Patients with osteoarthritis undergoing shoulder arthroplasty may suffer from osteoporosis. The purpose of this study was to determine whether computed tomography (CT)-derived Hounsfield unit (HU) measurements correlate with bone mineral density (BMD) and whether these data could predict implant size and fixation choice. MATERIALS AND METHODS: The study analyzed preoperative dual energy x-ray absorptiometry and shoulder CT scans for 230 patients who underwent total shoulder arthroplasty. Hip BMD and T scores and HU attenuation in the humerus were correlated. HU cutoff values were developed to aid in differentiating patients whose BMD values were within normal reference ranges from patients with osteopenia or osteoporosis. Risk factors associated with low BMD were correlated, and the effect of BMD on humeral stem size, and fixation method was investigated. RESULTS: Significant correlations between HU and hip BMD and T score were identified (P < .001). HU value ranges were identified that may alert the surgeon of metabolic bone disease. Significant correlation (P < 0.05) was found between low BMD and certain osteoporosis risk factors. Age at time of surgery was a predictor of cemented stem fixation (P = .024). Patients with a lower BMD were statistically more likely to receive a larger-diameter humeral stem (P = .016). CONCLUSIONS: Orthopedic surgeons may be able to use data obtained from shoulder CT scans to predict the need for larger stem size or cement fixation during shoulder arthroplasty. In combination with the risk factor profile, these data may be useful in predicting the need for an osteoporosis workup and treatment. LEVEL OF EVIDENCE: Level III, Study of Nonconsecutive Patients, Diagnostic Study. PMID- 22938790 TI - Resection arthroplasty for failed shoulder arthroplasty. AB - BACKGROUND: As shoulder arthroplasty becomes more common, the number of failed arthroplasties requiring revision is expected to increase. When revision arthroplasty is not feasible, resection arthroplasty has been used in an attempt to restore function and relieve pain. Although outcomes data for resection arthroplasty exist, studies comparing the outcomes after the removal of different primary shoulder arthroplasties have been limited. MATERIALS AND METHODS: This was a retrospective multicenter review of 26 patients who underwent resection arthroplasty for failure of a primary arthroplasty at a mean follow-up of 41.8 months (range, 12-130 months). Resection arthroplasty was performed for 6 failed total shoulder arthroplasties (TSAs), 7 failed hemiarthroplasties, and 13 failed reverse TSAs. RESULTS: Patients who underwent resection arthroplasty demonstrated significant improvement in visual analog scale pain score (6 +/- 4 preoperatively to 3 +/- 2 postoperatively). Mean active forward flexion and mean active external rotation decreased, but this difference was not significant. Subgroup analysis revealed that postoperative mean active forward flexion was significantly greater in patients undergoing resection arthroplasty after failed TSA than after reverse TSA (P = .01). CONCLUSIONS: Resection arthroplasty is effective in relieving pain, but patients have poor postoperative function. Patients with resection arthroplasty for failed reverse shoulder arthroplasty have worse function than those with failed hemiarthroplasty or TSA. Surgeons should be aware of this when assessing postoperative function. There is no difference in functional outcome between hemiarthroplasty and TSA. PMID- 22938789 TI - Validity of noncontrast magnetic resonance imaging in diagnosing superior labrum anterior-posterior tears. AB - BACKGROUND: The biceps labral complex has received much interest in recent years as a source of shoulder pain. Magnetic resonance imaging (MRI) is the imaging modality of choice for those patients with a suspected superior labrum anterior posterior (SLAP) tear. The goal of this study was to look at the accuracy of MRI without arthrography to correctly identify SLAP tears. METHODS: The study had a prospective, case-based, case-control design. Participants were consecutive patients seen at an orthopaedic outpatient clinic who received an MRI scan as part of their diagnostic cycle. All patients were aged at least 18 years, with various shoulder dysfunctions (impingement, rotator cuff tear, and so on) that were evaluated during a routine clinical evaluation. Arthroscopic surgery was performed as the reference standard for a SLAP lesion. RESULTS: Seventy-seven patients were evaluated during arthroscopic surgery. The pretest probability of a SLAP lesion-only diagnosis was 18.2%, and for a SLAP lesion with or without a concomitant diagnosis, the pretest probability was 66.2%. In both cases, use of MRI led to post-test probability values that were worse when a positive finding was identified on the MRI scan. DISCUSSION: The results of this study suggest that SLAP tears are often incorrectly diagnosed based on MRI evaluation, with MRI providing a high level of sensitivity and low level of specificity. On the basis of the results of this study, conventional MRI is not a suitable test to accurately evaluate the biceps labral complex for the presence of a SLAP tear. PMID- 22938791 TI - Short fasting and refeeding in red porgy (Pagrus pagrus, Linnaeus 1758): response of some haematological, biochemical and non specific immune parameters. AB - A short fasting-refeeding experience was applied to specimens of red porgy, Pagrus pagrus (Teleostei, Sparidae) to assess its effects on some physiological parameters. Haematological (haematocrit), biochemical (serum cortisol and glucose) and immunological (lysozyme, haemolytic and haemagglutinating activities) parameters were measured. For this study, two fish groups were considered: one was fasted for 14 days and then refed to satiation during further 7 and 15 days (indicated as fasted/refed group), the other was fed throughout the study and was taken as a control group. Significantly lower values were recorded for the condition index, the hepato-somatic index and viscero-somatic index in the fasted/refed group compared to the fed one. Fasting did not affect significantly the examined parameters, except for cortisol; refeeding for 7 days induced a significant increase in the haemoagglutinating titre and the spontaneous haemolytic activity, but when refeeding was extended to 14 days haemagglutinating and haemolytic values remained lower than those measured in fed fish. PMID- 22938793 TI - Age-dependent structural and radiological changes in the larynx. AB - AIM: To define radiological physiological changes in the larynx by establishing an age-related scale. MATERIALS AND METHODS: The present retrospective study used radiological records of patients that had undergone lateral cervical imaging. Three hundred patients were included. Thyroid cartilage was divided into anatomical regions. The hyoid bone was evaluated as the body and greater horns. Cases were compared by grouping by age and gender. RESULTS: Thyroid tissue and cricoid cartilage only became visible after the second decade. Ossification in the thyroid cartilage began in the posterior inferior horn and progressed to the superior horn and central lamina. It also began in the posterior part of the cricoid cartilage and moved forward with age. In the first decade, the body and greater horn parts of the hyoid bone could be seen more distinctly, and after the third decade the hyoid bone appeared as a single bone. The hyoid bone was the only structure ossified in the laryngeal region below the age of 20 and formed an image on direct imaging. CONCLUSIONS: Age-related changes to the laryngeal tissues are evident on radiographs. Clinicians should bear this in mind when evaluating neck radiographs. PMID- 22938792 TI - Baseline comorbidities in patients with rheumatoid arthritis who have been prescribed biological therapy: a case control study. AB - AIM: To determine whether rheumatoid arthritis (RA) patients who have been prescribed biological agents exhibit a different comorbidity burden than RA patients who take disease-modifying antirheumatic drugs (DMARDs) alone, and to understand the association between comorbidity and other variables, as well as the association between comorbidity and multimorbidity. METHODS: This observational case-control study included 114 RA patients treated with biological agents and a control group comprising 163 sex- and age-matched RA patients treated with DMARDs only. Current and previous data regarding the patients' disease activity, comorbidities, and treatments were collected. The data were analysed using bivariate and multivariate regression models. RESULTS: The patients who were prescribed biological agents exhibited poorer disease control, received more DMARDs and steroids, and underwent more total joint arthroplasties compared with the patients in the control group. However, the risk factors for cardiovascular disease and the comorbidity frequency were similar between cases and controls. The most prevalent comorbidities were hypertension, obesity, and respiratory, thyroid, and upper gastrointestinal disorders. The incidence of cardiovascular disease was low, and only 29% of the patients exhibited multimorbidities. A bivariate association of age, late diagnosis, joint replacements and a high score on the health assessment questionnaire score (HAQ) with comorbidity was observed. There were also correlations between the Charlson index and age, joint reconstructive surgery, disease activity (DAS28), and HAQ score. However, when binary logarithmic regression models were applied, only patient age remained significantly associated with comorbidity and multimorbidity [hazard ratio, 1.08; 95% confidence interval, 1.05-1.12; p<0.0005]. CONCLUSION: RA patients taking biological drugs have a comorbidity burden equivalent to those treated with DMARDs alone. Age is the main predictive factor of comorbidity in these patients. PMID- 22938794 TI - Effects of personality trait emotionality on acoustic startle response and prepulse inhibition including N100 and P200 event-related potential. AB - OBJECTIVES: To examine the association of personality trait-emotionality (behavioural inhibition system, BIS; behavioural activation system, BAS; anxiety and fear) and measures of auditory startle response (ASR) and prepulse inhibition (PPI) in a non-clinical sample. METHODS: Forty-seven women were tested for ASR and prepulse inhibition of the eyeblink component of the startle reflex as measured by electromyographic (EMG) responses of the left orbicularis oculi muscle and N100 and P200 components of the event-related potential (ERP) using sLORETA (standardized low resolution brain electromagnetic tomography). Startling stimuli (115 dB, 40 ms) were presented alone (pulse-alone) or were preceded by discrete (20 ms) prepulse stimuli (85 dB) at three prepulse-to-pulse intervals (30, 60 and 120 ms) over a steady background noise (70 dB). Measures of trait emotionality were assessed using a comprehensive battery of theoretically motivated personality scales. RESULTS: Consistent with previous reports, PPI (defined as percentage reduction in the amplitude of the ASR) increased as the prepulse-to-pulse interval increased. PPI measures were insensitive to individual differences in personality traits, while measures of ASR to pulse-alone stimuli disclosed significant effects. Higher BAS was associated with reduced N100 and P200 amplitudes to the pulse-alone stimulus, and with reduced current density for the N100 in the parietal lobe (BA40 and BA31). This effect indicated a smaller sensitivity or a higher avoidance level of these individuals for negative-startle stimuli. Higher trait anxiety was associated with larger ASR, suggesting an enhanced sensitivity to intense stimuli and a hasty style of reaction in anxious individuals. Lower self-report fear was associated with larger P200 amplitude, and enhanced current density in the medial and superior frontal gyrus (BA6). This effect indicates that prefrontal cortex may play an important role in inhibiting fear responses. CONCLUSIONS: Our findings are in good accordance with existing brain imaging studies and underline that ERP source localization is a useful alternative for identifying startle-relevant cortical regions. SIGNIFICANCE: The present observations extend previous startle findings observed in clinical samples to normal personality individuals. These results imply that hypotheses derived from clinical data may hold important implications for understanding human emotion and motivation, especially in relation to fear and anxiety. PMID- 22938795 TI - Oscillatory changes in cognitive networks activated during a three-stimulus visual paradigm: an intracerebral study. AB - OBJECTIVE: The aim of this work was to study the oscillatory changes during target and distractor stimuli processing. We focused mainly on responses after distractor stimuli in the prefrontal cortex and their possible relation to our previous results from the basal ganglia. METHODS: Five epilepsy surgery candidates with implanted depth electrodes performed a three-stimulus paradigm. The frequent stimulus (70%; without required response) was a small blue circle, the target stimulus (15%; with motor response) was a larger blue circle, and the distractor stimulus (15%; without required response) was a checkerboard. The SEEG signals from 404 electrode contacts were analysed using event-related de/synchronization (ERD/S) methodology. RESULTS: The main response to the target stimuli was ERD in the alpha and low beta bands, predominantly in the motor control areas, parietal cortex and hippocampus. The distractor stimuli were generally accompanied by an early theta frequency band power increase most markedly in the prefrontal cortex. CONCLUSIONS: Different ERD/S patterns underline attentional shifting to rare target ("go") and distractor ("no-go") stimuli. SIGNIFICANCE: As an increase in lower frequency band power is considered to be a correlate of active inhibition, the prefrontal structures seem to be essential for inhibition of non-required movements. PMID- 22938796 TI - Making physiological birth possible: birth at a free-standing birth centre in Berlin. AB - BACKGROUND: the practical training in midwifery education in Germany takes place predominantly in hospital delivery wards, where high rates of intervention and caesarean section prevail. When midwives practice birth assistance at free standing birth centres, they have to make adjustments to what they learned in the clinic to support women without the interventions common to hospital birth. OBJECTIVES: the primary aim of this study was to investigate and describe the approach of midwives practicing birth assistance at a free-standing birth centre. METHODOLOGY: a qualitative approach to data collection and analysis with grounded theory was used which included semi-structured expert interviews and participant observation. Five midwives were interviewed and nine births observed in the research period. The setting was a free-standing birth centre in a large German city with approximately 115 births per year. FINDINGS: the midwives all had to re learn birth assistance when commencing work outside of the hospital. However, having been trained predominantly in hospital maternity wards, they have retained many aspects characteristic of their training. The midwives use technology, although minimal, and medical discourse in combination with 1:1, woman-centred care. The birthing woman and midwife share authority at birth. The fetus is treated as an ally of the mother, suited for birth and cooperative. Through use of objective and subjective criteria, the midwives have their own approach to making physiological birth possible. KEY CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: to prepare midwives to support low-intervention birth, it is necessary to include training in birth assistance with women who birth physiologically, without interventions common to hospital birth. The results of this study would also suggest that the rate of interventions in hospital could be reduced if midwives gain more experience with women birthing without the above-mentioned interventions. PMID- 22938797 TI - Organisational strategies and midwives' readiness to provide care for out of hospital births: an analysis from the birthplace organisational case studies. AB - OBJECTIVE: the objective of the Birthplace in England Case Studies was to explore the organisational and professional issues that may impact on the quality and safety of labour and birth care in different birth settings: Home, Freestanding Midwifery Unit, Alongside Midwifery Unit or Obstetric Unit. This analysis examines the factors affecting the readiness of community midwives to provide women with choice of out of hospital birth, using the findings from the Birthplace in England Case Studies. DESIGN: organisational ethnographic case studies, including interviews with professionals, key stakeholders, women and partners, observations of service processes and document review. SETTING: a maximum variation sample of four maternity services in terms of configuration, region and population characteristics. All were selected from the Birthplace cohort study sample as services scoring 'best' or 'better' performing in the Health Care Commission survey of maternity services (HCC 2008). PARTICIPANTS: professionals and stakeholders (n=86), women (64), partners (6), plus 50 observations and 200 service documents. FINDINGS: each service experienced challenges in providing an integrated service to support choice of place of birth. Deployment of community midwives was a particular concern. Community midwives and managers expressed lack of confidence in availability to cover home birth care in particular, with the exception of caseload midwifery and a 'hub and spoke' model of care. Community midwives and women's interviews indicated that many lacked home birth experience and confidence. Those in midwifery units expressed higher levels of support and confidence. KEY CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: maternity services need to consider and develop models for provision of a more integrated model of staffing across hospital and community boundaries. PMID- 22938798 TI - Dystrophin/alpha1-syntrophin scaffold regulated PLC/PKC-dependent store-operated calcium entry in myotubes. AB - In skeletal muscles from patient suffering of Duchenne Muscular Dystrophy and from mdx mice, the absence of the cytoskeleton protein dystrophin has been shown to be essential for maintaining a normal calcium influx. We showed that a TRPC store-dependent cation influx is increased by loss of dystrophin or a scaffolding protein alpha1-syntrophin, however the mechanisms of this calcium mishandling are incompletely understood. First of all, we confirmed that TRPC1 but also STIM1 and Orai1 are supporting the store-operated cation entry which is enhanced in dystrophin-deficient myotubes. Next, we demonstrated that inhibition of PLC or PKC in dystrophin-deficient myotubes restores elevated cation entry to normal levels similarly to enforced minidystrophin expression. In addition, silencing alpha1-syntrophin also increased cation influx in a PLC/PKC dependent pathway. We also showed that alpha1-syntrophin and PLCbeta are part of a same protein complex reinforcing the idea of their inter-relation in calcium influx regulation. This elevated cation entry was decreased to normal levels by chelating intracellular free calcium with BAPTA-AM. Double treatments with BAPTA-AM and PLC or PKC inhibitors suggested that the elevation of cation influx by PLC/PKC pathway is dependent on cytosolic calcium. All these results demonstrate an involvement in dystrophin-deficient myotubes of a specific calcium/PKC/PLC pathway in elevation of store-operated cation influx supported by the STIM1/Orai1/TRPC1 proteins, which is normally regulated by the alpha1-syntrophin/dystrophin scaffold. PMID- 22938799 TI - Quantification of saponins in Dioscorea panthaica Prain et Burk rhizomes with monolithic column using rapid resolution liquid chromatography coupled with a triple quadruple electrospray tandem mass spectrometry. AB - The identification and quantification of saponins in crude extracts are challenging because of their similar structures and weak ultraviolet absorption. In this study, a rapid resolution liquid chromatography coupled with triple quadruple electrospray tandem mass spectrometric method was established to identify and quantify steroid saponins in the rhizomes of Dioscorea panthaica Prain et Burk, a traditional Chinese medicine. Six steroid saponins were simultaneously determined and quantified within 9min. All analytes were subjected to a RP-18e (50mm*2mm) monolithic column using a gradient elution program with a final detection using electrospray ionization tandem mass spectrometry in the negative ionization mode. The rapid resolution liquid chromatography/tandem mass spectrometry method achieved a limit of detection ranging from 0.52 to 20.40ngmL( 1) and a limit of quantification ranging from 1.20 to 75.20ngmL(-1) for the six studied steroidal saponins. The intra-day and inter-day precision (RSD) were less than 5.34%, and the recovery (RSD) was 1.50-3.51%. The highly sensitive and rapid method is suitable for the quantification of steroidal saponins in D. panthaica rhizomes. PMID- 22938800 TI - Rapid quantification of tryptophan and tyrosine in chemically defined cell culture media using fluorescence spectroscopy. AB - The rapid and inexpensive analysis of the complex cell culture media used in industrial mammalian cell culture is required for quality and variance monitoring. Excitation-emission matrix (EEM) spectroscopy combined with multi-way chemometrics is a robust methodology applicable for the analysis of raw materials, media, and bioprocess broths. We have shown that the methodology can identify compositional changes and predict the efficacy of media in terms of downstream titer [1]. Here we describe how to extend the measurement methodology for the quantification of tryptophan (Trp), tyrosine (Tyr) in complex chemically defined media. The sample type is an enriched basal RDF medium in which five significant fluorophores were identified: Trp, Tyr, pyridoxine, folic acid, and riboflavin. The relatively high chromophore concentrations and compositional complexity lead to very significant matrix effects which were assessed using PARAllel FACtor analysis2 (PARAFAC2). Taking these effects into account, N-way partial least squares (NPLS) combined with a modified standard addition method was used to build calibration models capable of quantifying Trp and Tyr with errors of ~4.5 and 5.5% respectively. This demonstrates the feasibility of using the EEM method for the rapid, quantitative analysis of Trp and Tyr in complex cell culture media with minimal sample handling as an alternative to chromatographic based methods. PMID- 22938801 TI - Structural and spectroscopic features of lutein/butanoyl-beta-cyclodextrin nanoassemblies. AB - Lutein, the primary carotenoid present in the central area of the retina of eye appears to be associated with the protection against age-related macular degeneration (the leading cause of blindness in older adults). Its lipophilicity and consequently its scarce water solubility (1.3*10(-9)M) represent a drawback for bioavailability. To circumvent these unfavorable characteristics, in this work lutein (Lut) have been encapsulated in amphiphilic cyclodextrin (ACyD) by following the well-established strategy of entrapping a lipophilic drug in CyD carriers. Primary face butyrate modified beta-cyclodextrins (C(4:7)) form in water nanoaggregates with a average size of 250nm and a zeta-potential of about 6mV. They are able to entrap lutein at 1:6 Lut/ACyD molar ratio by yielding nanoassemblies of vesicular aspect (320nm and -8mV) such as observed by static, dynamic and electrophoretic light-scattering. UV-vis measurements revealed that electronic properties of lutein were maintained when interact with ACyD nanoaggregates. The monitoring of the entapped carotenoid leaking from ACyD nanostructures was investigated suggesting the potential of Lut/ACyD nanoassemblies in drug delivery. PMID- 22938802 TI - Complications following distal biceps repair. AB - PURPOSE: Distal biceps rupture is a relatively uncommon injury. Surgical repair is performed in patients who seek increased flexion and supination strength over that which results from nonoperative treatment. The purpose of this study was to evaluate complications associated with surgical repair of the distal biceps tendon in a large series of patients. METHODS: We retrospectively reviewed 198 consecutive patients with distal biceps ruptures treated with surgical repair, and evaluated time from injury to repair, surgical technique, and complications. RESULTS: A total of 72 patients (36%) developed complications; 6 patients underwent additional surgery. Minor complications included lateral antebrachial cutaneous nerve paresthesia (26%), radial sensory nerve paresthesia (6%), and superficial infection (2%). Major complications included posterior interosseous nerve injury (4%), symptomatic heterotropic ossification (3%), and re-rupture (2%). CONCLUSIONS: Minor complications were common after distal biceps tendon repair; however, most were sensory nerve injuries that resolved with time. Major complications were infrequent, and few patients required revision surgery. Complications were more common after distal biceps tendon repair performed more than 28 days after rupture. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV. PMID- 22938803 TI - Interphalangeal joint salvage arthrodesis using the lister tubercle as bone graft. AB - Treating failed interphalangeal joint arthroplasty is challenging. After an implant or surgical device has been removed, minimal cortical bone remains, and cancellous bone is largely absent from the medullary canals. Several surgical techniques exist for athrodesis of these joints, which render the operated digit unnaturally straight and shortened. Using the Lister tubercle as a graft provides the unique benefits of maintaining the natural length of the joint while also lending a natural curvature to the finger. PMID- 22938804 TI - Correction of contracture and recurrence rates of Dupuytren contracture following invasive treatment: the importance of clear definitions. AB - PURPOSE: To call attention to the wide variety of definitions for recurrence that have been employed in studies of different invasive procedures for the treatment of Dupuytren contracture and how this important limitation has contributed to the wide range of reported results. METHODS: This study reviewed definitions and rates of contracture correction and recurrence in patients undergoing invasive treatment of Dupuytren contracture. A literature search was carried out in January 2011 using the terms "Dupuytren" AND ("fasciectomy" OR "fasciotomy" OR "dermofasciectomy" OR "aponeurotomy" OR "aponeurectomy") and limited to studies in English. RESULTS: The search returned 218 studies, of which 21 had definitions, quantitative results for contracture correction and recurrence, and a sample size of at least 20 patients. Definitions for correction of contracture and recurrence varied greatly among articles and were almost always qualitative. Percentages of patients who achieved correction of contracture (ie, responder rate) when evaluated at various times after completion of surgery ranged from 15% to 96% for fasciectomy/aponeurectomy. Responder rates were not reported for fasciotomy/aponeurotomy. Recurrence rates ranged from 12% to 73% for patients treated with fasciectomy/aponeurectomy and from 33% to 100% for fasciotomy/aponeurotomy. Review of these reports underscored the difficulty involved in comparing correction of contracture and recurrence rates for different surgical interventions because of differences in definition and duration of follow-up. CONCLUSIONS: Clearly defined objective definitions for correction of contracture and for recurrence are needed for more meaningful comparisons of results achieved with different surgical interventions. CLINICAL RELEVANCE: Recurrence after surgical intervention for Dupuytren contracture is common. This study, which evaluated reported rates of recurrence following surgical treatment of Dupuytren contracture, provides clinicians with practical information regarding expected long-term outcomes of surgical treatment choices. TYPE OF STUDY/LEVEL OF EVIDENCE: Economic and decision analysis III. PMID- 22938805 TI - The effect of osteoporosis on outcomes of operatively treated distal radius fractures. AB - PURPOSE: We hypothesized that postmenopausal osteoporotic women with distal radius fractures treated with open reduction internal fixation had worse functional outcomes than women without osteoporosis sustaining similar injuries. METHODS: We retrospectively reviewed prospectively collected data for 64 postmenopausal women treated with open reduction internal fixation for distal radius fractures between 2006 and 2010 with known bone mineral density measured by dual-energy x-ray absorptiometry at the time of injury (osteopenia, n = 44; osteoporosis, n = 20). Data collected included age, mechanism of injury, fracture severity, and associated comorbidities. Outcomes included range of motion, Disabilities of the Arm, Shoulder, and Hand (DASH) scores, and radiographic parameters of fracture reduction. We calculated patients' Charlson Comorbidity Index and tabulated complications. The primary outcome was DASH score at 12 months after injury. We applied multiple linear regression to determine whether bone mineral density status was predictive of functional outcomes 12 months after injury. We used logistic regression analysis to identify factors independently associated with poor outcomes and applied likelihood estimation to determine predictors of a high DASH score at 12 months. RESULTS: At 1 year postoperatively, women with osteoporosis had average DASH scores 15 points higher than those with osteopenia. Both osteoporosis and the Charlson Comorbidity Index were strong positive independent predictors of higher DASH scores (ie, poorer functional outcomes). There were no significant differences in range of motion or radiographic data between groups. Patients with osteoporosis had a higher rate of major complications. CONCLUSIONS: Osteoporosis had a negative impact on functional outcomes for women with distal radius fractures treated with open reduction internal fixation. Surgeons should identify high-risk patients, ensure close monitoring, and initiate appropriate preventative measures in this patient population. TYPE OF STUDY/LEVEL OF EVIDENCE: Prognostic II. PMID- 22938806 TI - Use of an iliac crest growth plate for the development of a neo-articulation for congenital transverse deficiencies at the wrist. AB - PURPOSE: Terminal congenital transverse deficiencies of the wrist and hand are rare malformations. They are usually treated with prosthetic devices. We describe here a surgical technique to create a neo-articulation that could provide mobility distal to the forearm and help children with terminal transverse deficiencies use orthotic devices. METHODS: This procedure involved an autologous, nonvascularized graft from the immature iliac crest. The graft was placed with its cartilaginous side facing the radial and ulnar articular surfaces. We studied the clinical, radiological, and functional outcomes of this technique in 2 pediatric cases 5 and 14 years after this procedure. RESULTS: The x-rays showed a mobile graft distally in the forearm. Magnetic resonance imaging showed a space between the graft and the radius and an intermediate signal on either side of the space highly suggestive of articular cartilage. These various elements were organized into a neo-articulation between the forearm and the graft. The functional ability at follow-up was greater compared with the absence of a graft. CONCLUSIONS: The results of basic research work on cartilage and chondrocytes may help explain the presence of persistent cartilaginous tissue on the articulated part of the graft. The good functional outcome provided by our surgical procedure may translate into reduced need for prosthesis acceptance. Our surgical procedure does not restore limb length, but does add a new functional ability. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV. PMID- 22938807 TI - Quality of life considerations in upper limb transplantation: review and future directions. AB - PURPOSE: As reconstructive transplantation emerges as an increasingly viable option for upper limb amputees, a better understanding of quality of life (QOL) outcomes is needed to evaluate the benefits and risks of the procedure from the patient perspective. METHODS: To address this need, we searched PubMed (1998 2011) to characterize QOL outcomes among upper limb transplant recipients. We identified 27 articles reporting on QOL outcomes in hand transplantation. Common instruments to assess domains of QOL in hand transplantation include the Disabilities of the Arm, Shoulder, and Hand questionnaire, the Medical Outcomes Study Short Form-36, and the International Registry on Hand and Composite Tissue Transplantation's Hand Transplantation Score System. RESULTS: Preliminary reports using standardized measures indicate that most hand transplant recipients described improved QOL. Several studies also qualitatively reported that recipients expressed satisfaction with cosmetic, sensory, functional, and social outcomes after transplantation. However, our review suggests that the measurement of QOL in hand transplantation is limited, although it is largely driven by QOL considerations. CONCLUSIONS: This review highlights the need for improved measurement of QOL in hand transplantation. The preliminary QOL findings across published hand transplantation articles will aid in improving the future assessment of QOL in hand transplantation. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic III. PMID- 22938809 TI - My occupational health nursing adventure. PMID- 22938808 TI - Reproducibility of retinal vessel oxygen saturation measurements in healthy young subjects. AB - PURPOSE: An adequate oxygenation and perfusion is essential for the function of the inner retina. Recently, several techniques for the measurement of retinal oxygen saturation became available. We set out to evaluate reproducibility of the measurements using a modified Retinal Vessel Analyzer. METHODS: A total of 20 healthy female and male subjects aged between 18 and 35 years (22.9 +/- 3.9; mean +/- SD) were included. The measurement of retinal oxygen saturation with the retinal oximeter employed in this study is based on optical reflectometry using the different absorption characteristics of oxygenated and deoxygenated haemoglobin. The intraclass correlation coefficients and the coefficients of variation (CV) for test-retest, short-term as well as day-to-day measurements were calculated. RESULTS: The intraclass correlation coefficients were between 0.91 and 0.94 for retinal branch arteries and between 0.84 and 0.88 for retinal branch veins. In retinal arteries, we calculated a test-retest CV of 3.24 +/- 3.18% for oxygen saturation measurements. In retinal veins, data were slightly less reproducible with a CV of 4.92 +/- 3.57%. Short-term reproducibility of both measurement cycles on each study day was in the same range (CV in retinal arteries: 2.91 +/- 2.42% and CV in retinal veins: 4.76 +/- 3.14%). The day-to-day coefficient of variation was slightly higher (CV in retinal arteries: 3.97 +/- 2.87% and CV in retinal veins: 6.18 +/- 3.36%). CONCLUSION: The reproducibility of haemoglobin oxygen saturation measurements using the retinal oximeter is acceptable. Further studies on the validity of the obtained results are, however, required. PMID- 22938810 TI - Osteoarthritis, osteoporosis, and exercise. AB - With the aging of the work force, occupational health nurses must prepare for encounters with clients who are challenged by osteoarthritis or osteoporosis. Clients should be encouraged to exercise safely to promote functioning at home and work. This article reviews recent literature on the benefits of exercise for workers with osteoarthritis, osteoporosis, or both. PMID- 22938811 TI - Cut-laceration injuries and related career groups in New Jersey career, vocational, and technical education courses and programs. AB - Investigations of young workers, including limited surveys in supervised school settings, suggested their elevated injury risk. This study identified factors contributing to cuts-lacerations among adolescents in New Jersey secondary school career, technical, and vocational education programs. Of 1,772 injuries reported between December 1, 1998, and September 1, 2010, 777 (44%) were cuts-lacerations; analyses focused on 224 reports (n = 182 post-exclusions) submitted after fall 2005 in three career groups-Food, Hospitality & Tourism (FH&T) (n = 71), Manufacturing & Construction (M&C) (n = 84), and Automotive & Transportation (A&T) (n = 27). Most students were "struck by" tools or hard surfaces (n = 93, 51%); 63 cuts were from knives in FH&T. In M&C, most cuts-lacerations were caused by hand-held tools (n = 18) and being "struck against/by" or "caught between hard surfaces" (n = 19). Males reported more cuts-lacerations (n = 145), most commonly among 11th graders (n = 54) and ages 16 to 17 years (n = 79). Fingers (n = 117) were most often injured, usually by cutting tools (n = 83). Training, supervision, and appropriate equipment, and further assessments of "struck by" and "pinch point" hazards, are needed. PMID- 22938813 TI - Hazardous drugs in health care settings--recognition and control. AB - NIOSH has updated its latest list of antineoplastic and other hazardous drugs in health care settings. PMID- 22938814 TI - Aerobic in situ stabilization of Landfill Konstanz Dorfweiher: leachate quality after 1 year of operation. AB - Modern landfill understanding points out controlled operation of landfills. Emissions from landfills are caused mainly by anaerobic biodegradation processes which continue for very long time periods after landfill closure. In situ landfill stabilization aims controlled reduction of emissions towards reduced expenditures as well as aftercare measures. Since April 2010, a new in situ stabilization technique is being applied at a pilot scale landfill (BAIV) within Landfill Konstanz Dorfweiher. This new method utilizes intermittent aeration and leachate recirculation for waste stabilization. In this study, influence of this technique on leachate quality is investigated. Among many other parameters, leachate analyses were conducted for COD, BOD(5), NH(4)-N, NO(2)-N, NO(3)-N, TKN and chloride besides continuously on site recorded pH, electrical conductivity and oxidation-reduction potential (ORP). Results from leachate quality analyses showed that biological activity in the landfill was accelerated resulting in initial higher leachate strength and reduced emission potential of landfill. During full scale in situ aeration, ambient conditions differ from optimized laboratory scale conditions which mainly concern temperature increase and deficient aeration of some landfill parts (Ritzkowski and Stegmann, 2005). Thus, as a field application results of this study have major importance on further process optimization and application. PMID- 22938815 TI - WITHDRAWN: A case-study of critical success factors for construction and demolition waste management: the pearl river delta region of china. AB - This article has been withdrawn at the request of the author(s) and/or editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy. PMID- 22938816 TI - Real-time in vivo assessment of levator ani muscle deformation in women. AB - OBJECTIVE: To study the deformation of the levator ani muscle in vivo with the use of real-time ultrasound imaging of the pelvic floor. STUDY DESIGN: Thirty-two women with symptoms of pelvic floor dysfunction underwent real-time in vivo assessment of the strain of the pelvic floor during Valsalva effort. All participants underwent clinical examination, urodynamics and 3D/4D translabial ultrasound scan of the pelvic floor. The deformation curves of the levator ani muscle were plotted and the difference in compliance according to the grade of urogenital prolapse was measured. One-way ANOVA and Spearman's correlation were used to test for significance of the relationship between variables (significance level P<0.05). Test-retest analysis of the ultrasound measurements of the levator hiatal dimensions was also conducted using intra-class correlation coefficient (ICC). RESULTS: The deformation curve of the levator hiatus showed a non-linear relationship with gradually increased Valsalva force, which was quite pronounced in the pubourethralis subdivision of the levator ani muscle complex. Women with significant pelvic organ prolapse demonstrated a less compliant levator ani muscle close to its origin from the pubic bone than women with non-significant prolapse (median maximum strain 26% vs 32%, respectively, P=0.03). CONCLUSIONS: Real-time in vivo assessment of levator ani muscle deformation in women is feasible and yields significant information. PMID- 22938817 TI - 17beta-Oestradiol activates proteolysis and increases invasion through phosphatidylinositol 3-kinase pathway in human cervical cancer cells. AB - OBJECTIVE: Despite evidence that oestrogen may play an important role in the carcinogenesis of cervical cancer, its action and mechanism in cervical cancer invasion are not well defined. STUDY DESIGN: The invasion induced by 17beta oestradiol (E2) was measured by invasion assay. Real-time polymerase chain reaction (PCR), Western blot, enzyme-linked immunosorbent assay (ELISA) and gelatin zymography were used to study the role of E2 on metastasis-related proteases. The signal pathway was also investigated. RESULTS: E2 was found to significantly enhance the invasion of cervical cell lines including HeLa, CaSki and SiHa cells, but not C33A cells. Moreover, E2 10(-8)M increased the expression and activation of matrix metalloproteinases (MMP-2 and MMP-9) in HeLa and CaSki cells, as shown by real-time PCR, Western blot, ELISA and gelatin zymography. The expression of tissue inhibitor of metalloproteinases (TIMP-1 and TIMP-2) was decreased significantly by E2. Pretreatment with GM6001 10 MUM (total MMP inhibitor) or SB-3CT 20 MUM (specific gelatinase inhibitor) blocked the pro invasive effect of E2. E2 was found to induce invasion via the phosphatidylinositol 3-kinase (PI3K) signalling pathway. CONCLUSION: E2 may contribute to cervical cancer metastasis through activation of proteolysis and increased invasion via the PI3K pathway. PMID- 22938818 TI - Toxoplasma gondii immunoglobulin G antibodies and nonfatal suicidal self-directed violence. AB - OBJECTIVE: The primary aim was to relate Toxoplasma gondii seropositivity and serointensity to scores on the self-rated Suicide Assessment Scale (SUAS-S). Another aim was to reevaluate the previously reported positive association between T gondii serointensity and a history of nonfatal suicidal self-directed violence. METHOD: This cross-sectional, observational study compared T gondii serointensity and seropositivity in plasma from 54 adult suicide attempters (inpatients at Lund University Hospital, Lund, Sweden) and 30 adult control subjects (randomly selected from the municipal population register in Lund, Sweden) recruited between 2006 and 2010. The potential of patients and controls for self-directed violence was evaluated with the SUAS-S. Psychiatric diagnoses were made according to DSM-IV criteria. Plasma samples were tested for immunoglobulin G antibodies to T gondii, cytomegalovirus, and herpes simplex virus type 1. Data were analyzed using multivariable logistic regression to investigate the association between T gondii serointensity or seropositivity and a history of nonfatal suicidal self-directed violence; multivariable linear regression was used to explore the relationship between T gondii serointensity or seropositivity and the SUAS-S. Both regression models included sex, age, and body mass index as covariates. RESULTS: Seropositivity of T gondii (adjusted odds ratio [OR] = 7.12; 95% CI, 1.66-30.6; P = .008) and serointensity of T gondii (adjusted OR = 2.01; 95% CI, 1.09-3.71; P = .03) were positively associated with a history of nonfatal suicidal self-directed violence. Seropositivity of T gondii was associated with higher SUAS-S scores, a relationship significant for the whole sample (P = .026), but not for suicide attempters only. No significant associations with other pathogens were identified. CONCLUSIONS: These results are consistent with previous reports on the association between T gondii infection and nonfatal suicidal self-directed violence. Confirming these results in future large longitudinal studies and including suicide as an outcome may lead to novel individualized approaches in suicide prevention. PMID- 22938819 TI - Epilepsy, poverty and early under-nutrition in rural Ethiopia. AB - PURPOSE: The incidence of epilepsy in Ethiopia is high compared with industrialised countries, but in most cases the cause of epilepsy is unknown. Childhood malnutrition remains widespread. We performed a case-control study to determine whether epilepsy is associated with poverty and markers of early under nutrition. METHODS: Patients with epilepsy (n=112), aged 18-45years, were recruited from epilepsy clinics in and around two towns in Ethiopia. Controls with a similar age and gender distribution (n=149) were recruited from patients and relatives attending general outpatient clinics. We administered a questionnaire to define the medical and social history of cases and controls, and then performed a series of anthropometric measurements. Unconditional logistic regression was used to estimate multivariate adjusted odds ratios. Multiple linear regression was used to estimate adjusted case-control differences for continuously distributed outcomes. RESULTS: Epilepsy was associated with illiteracy/low levels of education, odds ratio=3.0 (95% confidence interval: 1.7 5.6), subsistence farming, odds ratio=2.6 (1.2-5.6) and markers of poverty including poorer access to sanitation (p=0.009), greater overcrowding (p=0.008) and fewer possessions (p<0.001). Epilepsy was also associated with the father's death during childhood, odds ratio=2.2 (1.0-4.6). Body mass index was similar in cases and controls, but patients with epilepsy were shorter and lighter with reduced sitting height (p<0.001), bitrochanteric diameter (p=0.029) and hip size (p=0.003). Patients with epilepsy also had lower mid-upper arm circumference (p=0.011) and lean body mass (p=0.037). CONCLUSION: Epilepsy in Ethiopia is strongly associated with poor education and markers of poverty. Patients with epilepsy also had evidence of stunting and disproportionate skeletal growth, raising the possibility of a link between early under-nutrition and epilepsy. PMID- 22938820 TI - The hormone therapy, Premarin, impairs hippocampus-dependent spatial learning and memory and reduces activation of new granule neurons in response to memory in female rats. AB - Estrogens have been implicated as possible therapeutic agents for improving cognition in postmenopausal women and have been linked to neurodegenerative disorders such as Alzheimer's disease. However, the utility of Premarin (Wyeth Pharmaceuticals, Markham, ON, Canada), a conjugated equine estrogen and the most commonly prescribed hormone therapy, has recently been questioned. The purpose of this study was to investigate the effects of Premarin at 2 different doses (10 or 20 MUg) on hippocampus-dependent spatial learning and memory, hippocampal neurogenesis, and new neuronal activation using a rodent model of surgical menopause. Rats were treated daily with subcutaneous injections of Premarin and trained on the spatial working/reference memory version of the radial arm maze. Premarin impaired spatial reference and working learning and memory, increased hippocampal neurogenesis, but either decreased or increased activation of new neurons in response to memory retrieval as indexed by the expression of the immediate early gene product zif268, depending on the maturity of cells examined. This activation of new neurons was related to impaired performance in Premarin treated but not control-treated female rats. These results indicate that Premarin may be impairing hippocampus-dependent learning and memory by negatively altering the neurogenic environment in the dentate gyrus thus disrupting normal activity of new neurons. PMID- 22938821 TI - Meaning in life, insight and self-stigma among people with severe mental illness. AB - Recapturing meaning in life has been described as an essential element in the process of recovery from severe mental illness (SMI), but limited quantitative research still restricts our understanding of this phenomenon. The purpose of the current study was to explore the meaning in life among people with SMI and variables that may influence it such as internalized stigma and insight into the mental illness. We expected a significant negative correlation between internalized stigma and meaning in life, and that internalized stigma would moderate the relationship between insight and meaning in life. To explore these assumptions, 60 persons with SMI completed questionnaires that assessed their meaning in life, insight into their mental illness and internalized stigma, after which the data were analyzed using correlation and cluster analysis. Both hypotheses were confirmed. The mechanism behind the relationship between self stigma and meaning in life and the theoretical and clinical implications of the moderation model are discussed. PMID- 22938822 TI - Doxorubicin conjugated NaYF(4):Yb(3+)/Tm(3+) nanoparticles for therapy and sensing of drug delivery by luminescence resonance energy transfer. AB - In this study, we report an anticancer drug delivery system based on doxorubicin (DOX)-conjugated NaYF(4):Yb(3+)/Tm(3+) nanoparticles. The as-synthesized nanoparticles consist of uniform spherical nanoparticles with an average diameter of 25 nm. The drug delivery system demonstrates the ability to release DOX by cleavage of the hydrazone bond in mildly acidic environments. The spectra overlap between emission of donor NaYF(4):Yb(3+)/Tm(3+) nanoparticles at 452 nm ((1)D(2) >(3)F(4)) and 477 nm ((1)G(4)->(3)H(6)) and the broad absorbance of acceptor DOX centered at around 480 nm enables energy transfer to occur between the nanoparticles and DOX. The quenching and recovery of the up-conversion luminescence of NaYF(4):Yb(3+)/Tm(3+) by DOX due to luminescence resonance energy transfer (LRET) mechanism are applied as optical probe to confirm the DOX conjunction and monitor the release of DOX. The DOX-conjugated NaYF(4):Yb(3+)/Tm(3+) nanoparticles exhibit an obvious cytotoxic effect on SKOV3 ovarian cancer cells via MTT assay. Meanwhile, the endocytosis process of DOX conjugated NaYF(4):Yb(3+)/Tm(3+) nanoparticles by SKVO3 cells was demonstrated through confocal laser scanning microscopy (CLSM), flow cytometry and ICP-OES. Such drug delivery system, which combines pH-triggered drug-release and up converting nanoparticles-based LRET property, has excellent potential applications in cancer therapy and smart imaging. PMID- 22938823 TI - Highly accumulative production of L(+)-lactate from glucose by crystallization fermentation with immobilized Rhizopus oryzae. AB - In order to produce microbiologically large amount of l(+)-lactic acid (LA) from glucose, batch and fed-batch (intermittent addition of sterilized glucose powder aseptically) cultures of Rhizopus oryzae NBRC 5384 (identical to NRRL 395 and ATCC 9363) whose mycelia were immobilized in situ within sponge-like cubic particles (3.5 mm edge long) were carried out at 37 degrees C in a three baffled shake flask. Appropriately calculated amount of fine powdery calcium carbonate (CaCO(3)) was added initially or intermittently to control pH of the culture liquids. High accumulations of LA (145 g/L and 231 g/L, in reality 176 g/L and 280 g/L as anhydrous calcium lactate) were achieved by a batch (glucose concentration = 150 g/L) and a fed-batch cultures (the initial glucose concentration = 150 g/L and the intermittent addition of glucose equivalent to 100 g/L). In these cultures the yields and productivities of LA were, 95.0%, 1.42 g/L.h and 92.5%, 1.83 g/L.h, respectively. Existence of considerable amounts of calcium lactate (Ca(LA)(2)) as crystals in the culture broth was experimentally proved by two evidences: (i) heating up (70 degrees C) followed by quick low centrifugal force to remove remaining CaCO(3) solids from culture broth and then cooling down (37 degrees C) followed by incubation of the culture supernatant at 37 degrees C to observe recrystallization of Ca(LA)(2), and (ii) the measurement of solubility of Ca(LA)(2) in the culture media. It was conceptually discussed to be able to avoid the product inhibition by means of crystallization fermentation for the high accumulation of LA by R. oryzae. PMID- 22938824 TI - Biological function of a novel chrysovirus, CnV1-BS122, in the Korean Cryphonectria nitschkei BS122 strain. AB - Curing Cryphonectria nitschkei BS122 of a novel chrysovirus CnV1-BS122 infection was achieved by plating small hyphal fragments from an old plate and protoplasting followed by regeneration. Uneven distribution of mycoviruses within colonies was suggested. Comparing the CnV1-BS122-cured and -infected isogenic strains revealed that CnV1-BS122 infection resulted in reduced mycelial growth. PMID- 22938825 TI - Modelling lead bioaccessibility in urban topsoils based on data from Glasgow, London, Northampton and Swansea, UK. AB - Predictive linear regression (LR) modelling between bioaccessible Pb and a range of total elemental compositions and soil properties was executed for the Glasgow, London, Northampton and Swansea urban areas in order to assess the potential for developing a national urban bioaccessible Pb dataset for the UK. LR indicates that total Pb is the only highly significant independent variable for estimating the bioaccessibility of Pb. Bootstrap resampling shows that the relationship between total Pb and bioaccessible Pb is broadly the same in the four urban areas. The median bioaccessible fraction ranges from 38% in Northampton to 68% in London and Swansea. Results of this study can be used as part of a lines of evidence approach to localised risk assessment but should not be used to replace bioaccessibility testing at individual sites where local conditions may vary considerably from the broad overview presented in this study. PMID- 22938826 TI - EEG alpha power modulation of fMRI resting-state connectivity. AB - In the past decade, the fast and transient coupling and uncoupling of functionally related brain regions into networks has received much attention in cognitive neuroscience. Empirical tools to study network coupling include functional magnetic resonance imaging (fMRI)-based functional and/or effective connectivity, and electroencephalography (EEG)/magnetoencephalography-based measures of neuronal synchronization. Here we use simultaneously recorded EEG and fMRI to assess whether fMRI-based connectivity and frequency-specific EEG power are related. Using data collected during resting state, we studied whether posterior EEG alpha power fluctuations are correlated with connectivity within the visual network and between the visual cortex and the rest of the brain. The results show that when alpha power increases, BOLD connectivity between the primary visual cortex and occipital brain regions decreases and that the negative relation of the visual cortex with the anterior/medial thalamus decreases and the ventral-medial prefrontal cortex is reduced in strength. These effects were specific for the alpha band, and not observed in other frequency bands. The decreased connectivity within the visual system may indicate an enhanced functional inhibition during a higher alpha activity. This higher inhibition level also attenuates long-range intrinsic functional antagonism between the visual cortex and the other thalamic and cortical regions. Together, these results illustrate that power fluctuations in posterior alpha oscillations result in local and long-range neural connectivity changes. PMID- 22938827 TI - Thoracic aortobifemoral bypass in treatment of juxtarenal Leriche syndrome (midterm results). AB - BACKGROUND: The standard surgical treatment of infrarenal aortoiliac obstructive disease is abdominal aortobifemoral bypass (AABFB). However, alternative surgical procedures may be considered in cases of juxtarenal Leriche syndrome and previous aortofemoral graft obstruction. We present midterm results of 20 consecutive patients who underwent thoracic aortobifemoral bypass (TABFB) either as primary or secondary procedure. METHOD: Between 1999 and 2010, 20 patients who were diagnosed to have juxtarenal Leriche syndrome (n = 17) and failure of previous AABFB graft (n = 3) were enrolled. The patients were classified according to the Rutherford classification. Mean follow-up period was 60.9 +/- 38.3 months. Mean preoperative ankle-brachial index on the left lower extremity was 0.18 and on the right lower extremity was 0.20. RESULTS: Seventeen patients with the diagnosis of juxtarenal Lercihe syndrome were primarily and three patients were secondarily (for treatment of failed previous AABFB graft) treated using TABFB procedure. The mean ankle-brachial index at last follow-up was 0.75 on the left lower extremity and 0.76 on the right. One-year patency rate was 100%, and 5-year patency rate was 94%. CONCLUSION: TABFB precludes the risk of renal artery embolization in cases of juxtarenal obstruction, without adding any risk of morbidity and mortality. Its long-term patency is similar or even superior to conventional surgical bypass techniques. We propose its use as an initial treatment in juxtarenal Leriche syndrome as well as a remedial procedure in cases with previous AABFB graft occlusion. PMID- 22938828 TI - Microbiological investigation and clinical significance of Corynebacterium spp. in respiratory specimens. AB - The purpose of this retrospective study was to evaluate the pathogenic role of Corynebacterium species in lower respiratory tract infections as well as their routine laboratory investigation. From April 2007 to August 2009, 27 clinical isolates were significantly recovered from respiratory specimens of 27 different patients clinically suspected of having lower respiratory tract infections. The average age of patients was 65 years, while 22 (81%) patients presented at least 1 predisposing condition. Of the 27 patients, 15 (56%) were classified as infected according to Centers for Disease Control and Prevention/National Healthcare Safety Network criteria, with 93% of infections being hospital acquired. All isolates were accurately identified to the species level using molecular methods (i.e., 17 Corynebacterium pseudodiphtheriticum, 7 Corynebacterium striatum, and 3 Corynebacterium accolens), whereas phenotypic methods remained frequently unreliable for identifying C. striatum and C. accolens strains. All tested isolates were susceptible to amoxicillin, imipenem, vancomycin, linezolid, and tigecycline, whereas most of them were resistant to erythromycin. PMID- 22938830 TI - Management of AML: who do we really cure? AB - Most clinicians caring for patients with AML do not use the word "cure" casually, since for many patients diagnosed with AML, a state of cure or even of long term survival remains elusive. Analysis of prognostic factors may aid in defining the chance for cure in various AML subtypes, and improvements are required at all stages of AML treatment if cure is to be realized in a higher proportion of patients. In order to improve outcome, requirements will include targeting the mutation responsible for the leukemia emergence, suppressing the stem or progenitor cell which acquires the mutation, and the capability to deliver therapy to patients who themselves have adverse co-morbidities. PMID- 22938829 TI - Neighborhood characteristics and the initiation of marijuana use and binge drinking. AB - BACKGROUND: This study examines whether residential neighborhood characteristics influence the initiation of marijuana use and binge drinking, and if these neighborhood factors heighten or dampen peer influences on substance use. METHODS: Predictors of marijuana (N=6516) and binge drinking (N=6630) initiation over a 1-year period were identified using data from the National Longitudinal Study of Adolescent Health. Participants were of ages 12-19 years at baseline. The main predictor variables were neighborhood characteristics, using both objective (proportion of households below the poverty line and female-headed, unemployment rate, residential stability) and subjective (perceived cohesion and safety) measures. Binge drinking was defined as 5 or more drinks in a row. RESULTS: Initiation occurred for 12.9% of adolescents in the case of marijuana and 16.4% for binge drinking. Marijuana initiation was more likely among adolescents who lived in neighborhoods with a higher unemployment rate, and binge drinking initiation was more likely among those who perceived greater safety in their neighborhood, after adjusting for other neighborhood characteristics, demographics, friend characteristics, and behavioral and family risk factors. There was no evidence that neighborhood context moderates the associations of peer factors on initiation. CONCLUSIONS: Select neighborhood characteristics appear relevant to the initiation of marijuana use and binge drinking, although the mechanisms appear to be distinct for each substance. If these results are found to be robust, future research should aim to better understand how neighborhood context influences the initiation of adolescent substance use in order to inform prevention efforts. PMID- 22938831 TI - Retreatment with purine analogs in patients with chronic lymphocytic leukemia. AB - We evaluated the efficacy and toxicity of retreatment with purine analogs (PA) in 62 patients with relapsed chronic lymphocytic leukemia. Median OS and PFS after retreatment were 60 and 26 months, respectively. By multivariate analysis, minimal residual disease status, ZAP-70 expression and age had independent predictive power in terms of OS. Toxicity was mainly neutropenia (21%) and infections (39%). Second malignancies were observed in 10 (16%) patients. Our results outline that retreatment with PA is remarkably effective in patients with relapsed CLL, but with a significant toxicity. PMID- 22938832 TI - Proposed criteria for response assessment in patients treated in clinical trials for myeloproliferative neoplasms in blast phase (MPN-BP): formal recommendations from the post-myeloproliferative neoplasm acute myeloid leukemia consortium. AB - Leukemic transformation (LT) of a myeloproliferative neoplasm (MPN) is associated with a dismal prognosis and no medical therapies have shown a survival improvement in patients with MPN in blast phase (MPN-BP). Effective therapies for the treatment of MPN-BP are a serious unmet need. Consensus response criteria do not exist for the treatment of patients with MPN-BP and this is necessary for the uniformed reporting of treatment response in clinical trials. We have identified relevant MPN and MPN-BP features in order to define treatment response categories that reflect hematological, clinical, pathological, cytogenetic and molecular changes after therapeutic intervention. We plan to validate these proposed response criteria within multi-centered clinical trials. PMID- 22938834 TI - Yeasts from Colombian Kumis as source of peptides with Angiotensin I converting enzyme (ACE) inhibitory activity in milk. AB - This study investigated the possibility of using yeast strains in fermented milks to obtain products with high Angiotensin I-converting enzyme (ACE) inhibitory activity and low bitter taste. Ninety-three yeast strains isolated from Colombian Kumis in different geographic regions were molecularly identified, and their milk fermentation performances were determined. Molecular identification evidenced that Galactomyces geotrichum, Pichia kudriavzevii, Clavispora lusitaniae and Candida tropicalis, were the dominant species. Eighteen out of 93 strains produced fermented milk with ACE-inhibitory (ACEI) activity values ranging from 8.69 to 88.19%. Digestion of fermented milk samples by pepsin and pancreatin demonstrated an increase in ACEI activity, with C. lusitaniae KL4A as the best producer of ACEI peptides. Moreover, sensory analysis of the products containing the major ACE-inhibitory activity pointed out that P. kudriavzevii KL84A and Kluyveromyces marxianus KL26A could be selected as potential adjunct starter cultures in Kumis, since they made a considerable contribution to the ACE inhibitory activity and produced fermented milk without bitter taste. In this study we observed that Colombian Kumis can be an excellent vehicle for the isolation of yeasts with a potential to enhance bioactive peptides produced during milk fermentation. PMID- 22938833 TI - A multinational, multidisciplinary consensus for the diagnosis and management of spinal cord compression among patients with mucopolysaccharidosis VI. AB - Cervical cord compression is a sequela of mucopolysaccharidosis VI, a rare lysosomal storage disorder, and has devastating consequences. An international panel of orthopedic surgeons, neurosurgeons, anesthesiologists, neuroradiologists, metabolic pediatricians, and geneticists pooled their clinical expertise to codify recommendations for diagnosing, monitoring, and managing cervical cord compression; for surgical intervention criteria; and for best airway management practices during imaging or anesthesia. The recommendations offer ideal best practices but also attempt to recognize the worldwide spectrum of resource availability. Functional assessments and clinical neurological examinations remain the cornerstone for identification of early signs of myelopathy, but magnetic resonance imaging is the gold standard for identification of cervical cord compression. Difficult airways of MPS VI patients complicate the anesthetic and, thus, the surgical management of cervical cord compression. All patients with MPS VI require expert airway management during any surgical procedure. Neurophysiological monitoring of the MPS VI patient during complex spine or head and neck surgery is considered standard practice but should also be considered for other procedures performed with the patient under general anesthesia, depending on the length and type of the procedure. Surgical interventions may include cervical decompression, stabilization, or both. Specific techniques vary widely among surgeons. The onset, presentation, and rate of progression of cervical cord compression vary among patients with MPS VI. The availability of medical resources, the expertise and experience of members of the treatment team, and the standard treatment practices vary among centers of expertise. Referral to specialized, experienced MPS treatment centers should be considered for high-risk patients and those requiring complex procedures. Therefore, the key to optimal patient care is to implement best practices through meaningful communication among treatment team members at each center and among MPS VI specialists worldwide. PMID- 22938835 TI - Lysozyme resistance of the ropy strain Pediococcus parvulus IOEB 8801 is correlated with beta-glucan accumulation around the cell. AB - Lactic acid bacteria (LAB) are often exploited to carry out malolactic fermentation in wine. However, a few specific LAB strains and, more precisely, some Pediococcus parvulus strains synthesize a beta-glucan, which can be deleterious to wine quality as it confers a ropy texture to the wine that can no longer be commercialized. Although molecular methods exist to detect these unwanted microorganisms, ropy Pediococcus still remain difficult to remove from wine, because of their natural resistance to traditional wine stabilizing treatments. In this work, we show that ropy P. parvulus are resistant to lysozyme. We clearly demonstrate that this resistance may be ascribed to the presence of the beta-glucan that forms around the cell a protective barrier against anti-bacteria agents. Moreover, this resistance increases during bacterial growth. We show that using lysozyme with beta-glucanase can strongly improve the treatment against ropy strains, in model media as well as red and white wine based media. This work not only brings potential solutions to the wine industry, but also opens interesting perspectives for studying beta-glucan producing bacteria which are widespread in the food industry. PMID- 22938836 TI - Assessment of human exposure to 3rd generation cephalosporin resistant E. coli (CREC) through consumption of broiler meat in Belgium. AB - Acquired resistance of Escherichia coli to 3rd generation cephalosporin antimicrobials is a relevant issue in intensive broiler farming. In Belgium, about 35% of the E. coli strains isolated from live broilers are resistant to 3rd generation cephalosporins while over 60% of the broilers are found to be carrier of these 3rd generation cephalosporin resistant E. coli (CREC) after selective isolation. A model aimed at estimating the exposure of the consumer to CREC by consumption of broiler meat was elaborated. This model consists of different modules that simulate the farm to fork chain starting from primary production, over slaughter, processing and distribution to storage, preparation and consumption of broiler meat. Input data were obtained from the Belgian Food Safety agencies' annual monitoring plan and results from dedicated research programs or surveys. The outcome of the model using the available baseline data estimates that the probability of exposure to 1000 colony forming units (cfu) of CREC or more during consumption of a meal containing chicken meat is ca. 1.5%, the majority of exposure being caused by cross contamination in the kitchen. The proportion of CREC (within the total number of E. coli) at primary production and the overall contamination of broiler carcasses or broiler parts with E. coli are dominant factors in the consumer exposure to CREC. The risk of this exposure for human health cannot be estimated at this stage given a lack of understanding of the factors influencing the transfer of cephalosporin antimicrobial resistance genes from these E. coli to the human intestinal bacteria and data on the further consequences of the presence of CREC on human health. PMID- 22938837 TI - Smiles for Life: an oral health education resource. PMID- 22938838 TI - Occult nighttime hypertension in daytime normotensive older patients with obstructive sleep apnea. AB - OBJECTIVES: To assess nighttime blood pressure (BP), the dipping phenomenon and the relationships between nighttime BP, and polysomnography parameters in older patients with obstructive sleep apnea (OSA) who have been identified by their primary care physician as being normotensive during the daytime. DESIGN: Cross sectional study. SETTING: University hospital-based geriatric sleep center. PARTICIPANTS: Daytime normotensive, community-dwelling older adults, consecutively referred by their primary care physicians for suspicion of OSA. MEASUREMENTS: Overnight polysomnography and 24-hour ambulatory blood pressure measurement (ABPM). Daytime hypertension defined as systolic BP >=135 mm Hg and/or diastolic BP >=85 mm Hg. Nighttime hypertension defined as systolic BP >=120 mm Hg and/or diastolic BP >=70 mm Hg. Dipper pattern characterized by nighttime fall of mean BP >=10%. RESULTS: Forty-five participants (30 OSA; 15 non OSA) completed the study (76.9 +/- 6.2 years old). ABPM indicated clinically significant nighttime systolic (132.5 +/- 16.0) and diastolic (72.6 +/- 9.4) hypertension in patients with OSA previously classified as daytime normotensives and found only a mild degree of nighttime systolic hypertension (123.7 +/- 16.1) in patients without OSA (P = .105). A significant nondipping phenomenon was found in patients with OSA (-0.5 +/- 7.4 vs 5.4 +/- 6.4; P = .016). Nighttime mean BP (r = 0.301; P = .049) and dipping status (r = -0.478; P = .001) were correlated with apnea-hypopnea index. A significant correlation was found between systolic BP (r = 0.321; P = .035), diastolic BP (r = 0.373; P = .013), mean BP (r = 0.359; P = .018), and hypoxia (sleep time spend with SaO2 <90%). CONCLUSION: Daytime normotensive older adults with OSA are at high risk for having occult nighttime hypertension. Thus, 24-hour ABPM may be appropriate for older patients with OSA whose clinical blood pressure does not display any daytime elevation. PMID- 22938839 TI - Study of antibody/antigen binding kinetics by total internal reflection ellipsometry. AB - Total internal reflection ellipsometry (TIRE) has been applied for the investigation of (i) kinetics of biosensing layer formation, which was based on the immobilization of fragmented and intact antibodies, and (ii) kinetics of antigen interaction with the immobilized antibodies. It has been demonstrated that ellipsometric parameter Delta(t) showed much higher sensitivity at the initial phase of Au-protein and protein-protein interaction, while the parameter Psi(t) was more sensitive when the steady-state conditions were established. A new method, which taking into consideration this feature and nonlinear change of Delta(t) and Psi(t) parameters during various stages of biological layer formation process, was used for the calculation of antibody and antigen adsorption/interaction kinetics. The obtained results were analyzed using a model, which took into account partial reversibility during the formation of both antibody and antigen based monolayers. It was shown that the immobilization rate of antibody during the preparation of the sensing layer was similar for the formation of both intact and fragmented antibody based layers; however, the residence time was 25 times longer for intact antibody based layer formation in comparison to that of fragmented antibody based layer formation. On the contrary, residence time of antigen interaction with immobilized antibodies was about 8 times longer for the sensor based on fragmented antibodies. Moreover, it has been determined that the structural differences of immobilized antibodies (fragmented or intact) significantly influence antibody-antigen interaction rate, the major difference being in the residence time of antigen interaction with both types of immobilized antibodies. PMID- 22938840 TI - Multiwalled carbon nanotubes-ceramic electrode modified with substrate-selective imprinted polymer for ultra-trace detection of bovine serum albumin. AB - This study describes the synthesis of a new class of substrate-selective molecularly imprinted polymer. This involved tetraethylene glycol 3-morpholin propionate acrylate (functional monomer) and bovine serum albumin (template) for polymerization in aqueous condition, using "surface grafting-from" approach directly on a vinyl exposed multiwalled carbon nanotubes-ceramic electrode. The analyte recapture at pH 6.8 in aqueous environment simultaneously involved hydrophobically driven hydrogen bonds and ionic interactions between negatively charged bovine serum albumin and positively charged imprinted nanofilm. The selectively encapsulated bovine serum albumin first gets reduced at -0.9V and then oxidized within the cavity, without getting stripped off, to respond a differential pulse voltammetry signal. The limit of detection [0.42ng mL(-1) (3sigma, RSD<=1.02%)] obtained was free from any cross-reactivity and matrix complications in aqueous, pharmaceutical, serum, and liquid milk samples. The proposed sensor can be used as a practical sensor for ultra-trace analysis of bovine serum albumin in clinical settings. PMID- 22938841 TI - Signal amplified strategy based on target-induced strand release coupling cleavage of nicking endonuclease for the ultrasensitive detection of ochratoxin A. AB - In this work, a new signal amplified strategy based on target-induced strand release coupling cleavage of nicking endonuclease for the ultrasensitive detection of ochratoxin A (OTA) is reported. OTA aptamer (DNA1) and OTA aptamer complementary (DNA2) were immobilized onto a magnetic bead (MB). In the presence of OTA, DNA2 was dissociated and released from the MB. The released DNA2 then hybridized with DNA3, which was linked at the 5' terminus of the amplification template and can extend along the template in the presence of Phi 29 DNA polymerase. The formed double-stranded DNA was cleaved by nicking endonuclease Nb.BbvCI and produced a short single-stranded DNA. The cleaved DNA strand generated a new site by Phi 29 DNA polymerase and the process of extension and cleavage was cyclical. Thus, a amount of the short single-stranded DNA were produced. Using DNA and ABEI labeled carboxylic silica nanoparticles chemiluminescence (CL) probe, the short single-stranded DNA could be sensitively detected. The CL intensity (DeltaI) versus the concentration of OTA was linear in the range from 1.0*10(-12) to 5.0*10(-8)g mL(-1). The detection limit was 3.0*10( 13)g mL(-1), and the RSD was 3.4% at 1.0*10(-10)g mL(-1) (n=7). The developed method has been applied to detect OTA in naturally contaminated wheat samples. Due to its simplicity, sensitivity and no need of specific recognition of aptamer for cleavage, this CL bioassay offers a promising approach for the detection of OTA and other biomolecules. PMID- 22938842 TI - Antidepressive treatment with monoamine oxidase inhibitors and the occurrence of intraoperative hemodynamic events: a retrospective observational cohort study. AB - OBJECTIVE: To investigate the occurrence of intraoperative hemodynamic events when antidepressive treatment with monoamine oxidase inhibitors (MAOIs) was continued during anesthesia. METHOD: A retrospective observational cohort study was conducted among patients who were admitted for elective surgery requiring anesthesia in 8 Dutch hospitals (2004-2010). The index group included current users of irreversible (tranylcypromine) and reversible (moclobemide) MAOIs. The reference group included a sample of nonusers matched to the index group on hospital, type and period of surgery, and type of anesthesia (ratio 1:3). The outcome of interest was the occurrence of the following intraoperative hemodynamic events: hypotension or hypertension and tachycardia or bradycardia. RESULTS: Approximately 280,000 surgical procedures were performed in the participating hospitals in the total observational period of 33 years. The index group included 26 and 25 users of tranylcypromine and moclobemide, respectively. The reference groups included 149 nonusers. Intraoperative hypotension occurred less frequently in users of tranylcypromine (46%) than in nonusers (73%) (P = .01). The occurrence of hypertension, bradycardia, and tachycardia during anesthesia was not different between users of tranylcypromine (27%, 50%, and 12%, respectively) and those in the reference group (35%, 61%, and 26%, respectively). The occurrence of hypotension, hypertension, bradycardia, and tachycardia was not different between users of moclobemide and the reference group. CONCLUSIONS: Severe adverse hemodynamic events, such as hypertension and tachycardia, did not occur more frequently in users of both the irreversible MAOI tranylcypromine and the reversible MAO-A inhibitor moclobemide compared to nonusers. These findings suggest that there is no longer much justification to discontinue these MAOIs before surgery, with the considerable risk of compromising patients' psychiatric status. PMID- 22938843 TI - On the structural modification of 2-nitroimidazole-(99m)Tc(CO)(3) complex, a hypoxia marker, for improving in vivo pharmacokinetics. AB - INTRODUCTION: A 2-nitroimidazole-(99m)Tc(CO)(3) complex reported earlier showed promise with respect to its uptake and retention in hypoxic tumor. However, significant uptake and slow clearance from liver imposed severe limitations towards advocating its possible practical utility. In an attempt to improving its liver clearance, an ether linkage, which is known to help in liver clearance, was introduced in the molecule. METHODS: The 2-nitroimidazole iminodiacetic acid (IDA) derivative containing an ether linkage was synthesized in a five step procedure from 2-nitroimidazole. This derivative was radiolabeled using [(99m)Tc(CO)(3)(H(2)O)(3)](+) precursor complex. The corresponding Re(CO)(3) analogue was also synthesized in the macroscopic level for structural characterization. The (99m)Tc(CO)(3) complex was evaluated in an animal model bearing fibrosarcoma tumor. RESULTS: The in vivo evaluation of the complex indicated that, as envisaged, introduction of the ether linkage has improved clearance from the liver. The complex also showed higher retention in tumor compared to the 2-nitroimidazole-IDA-(99m)Tc(CO)(3) complex reported earlier. Though the tumor to muscle ratio improved with time, the tumor to blood ratio did not show any significant improvement. Despite improved liver clearance, there was significant liver activity present even at 3h p.i. attributable to gradual accumulation of activity cleared from muscle and blood. CONCLUSIONS: Though the introduction of ether linkage improved liver clearance of the modified 2 nitroimidazole complex, it was found that a single ether linkage was not sufficient to achieve the desirable level of clearance. Probably, a linker with multiple ether groups, such as a di- or tri-ethylene glycol spacer, may be a possible solution to this issue. PMID- 22938844 TI - Amygdala subregions differentially respond and rapidly adapt to threatening voices. AB - Emotional states can influence the human voice during speech utterances. Here, we tested the sensitivity and signal adaptation of functional activity located in amygdala subregions to threatening voices during high-resolution functional magnetic resonance imaging. Bilateral superficial (SF) complex and the right laterobasal (LB) complex of the amygdala were generally sensitive to emotional cues from speech prosody. Activity was stronger, however, when listeners directly focused on the emotional prosody of the voice instead of attending to a nonemotional feature. Explicit attention to prosody especially elicited activity in the right LB complex. Furthermore, the right SF specifically showed an effect of sensitization indicated by a significant signal increase in response to emotional voices which were preceded by neutral events. The bilateral SF showed signal habituation to repeated emotional voices indicated by a significant signal decrease for an emotional event preceded by another emotional event. The right SF and LB finally showed an effect of desensitization after the processing of emotional voices indicated by a signal decrease for neutral events that followed emotional events. Thus, different amygdala subregions are sensitive to threatening emotional voices, and their activity depends on the attentional focus as well as on the proximal temporal context of other neutral and emotional events. PMID- 22938845 TI - Pseudocortical and dissociate discriminative sensory dysfunction in a thalamic stroke. AB - In thalamic lesions a pseudocortical syndrome has been occasionally described but the effect of the lesion on the cortical network of tactile recognition has never been studied. We report a patient who developed tactile agnosia in the left hand after right thalamic stroke, configuring a pseudocortical sensory syndrome. The discriminative sensory dysfunction was dissociate because only tactile agnosia and mild pseudoathetosis were present. A functional magnetic resonance imaging (fMRI) study showed that tactile recognition with the unaffected hand recruited a bilateral fronto-parietal network. During recognition with the left hand the activation was restricted and lateralized to the ipsilateral hemisphere. In this patient with pseudocortical discriminative sensory dysfunction the lack of activation of the whole cortical network, implicated in tactile recognition, demonstrates that pseudocortical is functionally equivalent to cortical tactile agnosia. PMID- 22938846 TI - Rationale of mesenchymal stem cell therapy in kidney injury. AB - Numerous preclinical and clinical studies suggest that mesenchymal stem cells, also known as multipotent mesenchymal stromal cells (MSCs), may improve pathologic conditions involving different organs. These beneficial effects initially were ascribed to the differentiation of MSCs into organ parenchymal cells. However, at least in the kidney, this is a very rare event and the kidney protective effects of MSCs have been attributed mainly to paracrine mechanisms. MSCs release a number of trophic, anti-inflammatory, and immune-modulatory factors that may limit kidney injury and favor recovery. In this article, we provide an overview of the biologic activities of MSCs that may be relevant for the treatment of kidney injury in the context of a case vignette concerning a patient at high immunologic risk who underwent a second kidney transplantation followed by the development of ischemia-reperfusion injury and acute allograft rejection. We discuss the possible beneficial effect of MSC treatment in the light of preclinical and clinical data supporting the regenerative and immunomodulatory potential of MSCs. PMID- 22938847 TI - GFR estimation using the Cockcroft-Gault, MDRD study, and CKD-EPI equations in the elderly. PMID- 22938848 TI - Renal amyloidosis associated with a novel sequence variant of gelsolin. AB - We present a case of a 75-year-old woman who presented with progressive kidney failure. Kidney biopsy performed to determine the cause of kidney failure showed amyloidosis of undetermined type. Laser microdissection of the Congo Red-positive glomeruli followed by mass spectrometry studies showed a large number of spectra matching apolipoprotein E, serum amyloid P component, and gelsolin, consistent with a diagnosis of gelsolin-associated renal amyloidosis. Sequencing of the gelsolin gene revealed a previously undescribed sequence variant, a guanine to adenine substitution at nucleotide 580 of the coding sequence, corresponding to a predicted glycine to arginine mutation at amino acid 194. Gelsolin amyloidosis typically involves the nerves and skin, with only rare reported involvement of the kidney. An atypical finding on electron microscopy was that of a swirling pattern of the amyloid fibrils. The novel gelsolin variant may be responsible for the unusual clinical and pathologic presentation. The report also highlights the usefulness of laser microdissection and mass spectrometry in the typing of difficult cases of amyloidosis. PMID- 22938852 TI - US school/academic institution disaster and pandemic preparedness and seasonal influenza vaccination among school nurses. AB - BACKGROUND: School pandemic preparedness is essential, but has not been evaluated. METHODS: An online survey was sent to school nurses (from state school nurse associations and/or state departments of education) between May and July 2011. Overall school pandemic preparedness scores were calculated by assigning 1 point for each item in the school's pandemic plan; the maximum score was 11. Linear regression was used to describe factors associated with higher school pandemic preparedness scores. Nurse influenza vaccine uptake was assessed as well. RESULTS: A total of 1,997 nurses from 26 states completed the survey. Almost three-quarters (73.7%; n = 1,472) reported receiving the seasonal influenza vaccine during the 2010-11 season. Very few (2.2%; n = 43) reported that their school/district had a mandatory influenza vaccination policy. Pandemic preparedness scores ranged from 0 to 10 points, with an average score of 4.3. Determinants of school pandemic preparedness were as follows: planning to be a point of dispensing during a future pandemic (P < .001), having experienced multiple student or employee hospitalizations and/or deaths related to H1N1 during the pandemic (P = .01 or <.05, respectively), having a lead nurse complete the survey (P < .001), and having the school nurse study participant be a member of the school disaster planning committee (P < .001). CONCLUSIONS: US schools must continue to address gaps in pandemic planning. PMID- 22938849 TI - A physiologic-based approach to the evaluation of a patient with hyperphosphatemia. AB - Phosphate is required for skeletal mineralization, cellular energy regulation, synthesis of cell membranes and nucleic acids, and a variety of cell signaling pathways. Extracellular serum phosphate concentration is determined by the balance of gastrointestinal phosphate absorption, skeletal turnover, distribution in intracellular compartments, and renal phosphate excretion. An integrated system of hormones, receptors, and phosphate transporters regulates phosphate homeostasis, and a variety of hereditary and acquired perturbations in these regulators can result in hyperphosphatemia. Although kidney failure is the most common cause of hyperphosphatemia encountered by nephrologists, hyperphosphatemia that presents in patients with early stages of chronic kidney disease or normal kidney function should prompt a detailed evaluation that can be diagnostically challenging. In this teaching case, we describe a case of hyperphosphatemia out of proportion to the degree of decrease in glomerular filtration rate. We present a practical parathyroid hormone-based diagnostic approach that illustrates the current understanding of phosphate regulation in clinically meaningful terms for the practicing nephrologist. Finally, we illustrate how measurement of fibroblast growth factor 23 could be integrated in the future when the test becomes more widely available. PMID- 22938853 TI - Journal Club: a venue to advance evidence-based infection prevention practice. AB - Journal Clubs are a well-recognized strategy used by clinicians to critique and keep up to date with relevant literature. This article provides an example of an assessment of an article appearing in this issue of the American Journal of Infection Control titled, "US School/Academic Institution Disaster and Pandemic Preparedness and Seasonal Influenza Vaccination Among School Nurses." PMID- 22938854 TI - An unexpected benefit from enhanced 2009 H1N1 influenza surveillance. AB - Nosocomial outbreaks of influenza are reportable in New York State, but reporting compliance is unknown. We describe a surveillance system, instituted during the 2009 H1N1 outbreak, that coincidently allowed for the identification of influenza outbreaks in long-term care facilities. PMID- 22938856 TI - Knowledge-attitude-practice toward swine flu. PMID- 22938857 TI - Education as part of a multifaceted hand hygiene improvement program. PMID- 22938858 TI - Multidisciplinary hand hygiene factors in hospitals. PMID- 22938860 TI - Role of tachykinins and neurokinin receptor subtypes in the regulation of motility of the forestomach and abomasum in conscious sheep. AB - The present study was planned to evaluate role of tachykinins (TKs) and neurokinin (NK) receptors in the regulation of gastric motility in sheep. We examined the effects of intravenous (i.v.) injection of neurokinin A (NKA) and substance P (SP) on motility of the rumen, omasum, and abomasum in conscious sheep and the effects of NK receptor blockade on the effect of TKs using NK-1 receptor antagonist L-732,138 and NK-2 receptor antagonist SR48968. Moreover, the effect of NK receptor blockade on omasal cyclic contractions was examined. Intravenous injection of NKA and SP induced tonic contraction of rumen, omasum, and abomasum, and the contractile effect of NKA was more potent than that of SP in all the gastric regions. Although the effect of SP was not inhibited by L 732,138, the effect of NKA was significantly inhibited by SR48968. However, single infusion of SR48968 and L-732,138 did not alter cyclic electromyographic activity and basal intraluminal pressure in the omasum. These results imply that NKA and NK-2 receptors play a primary role in non-cholinergic regulation of ovine gastric motility, though NK-2 and NK-1 receptors seem unlikely to be involved in the physiological regulation of omasal cyclic contractions. PMID- 22938859 TI - Neuropeptide Y (NPY) in the extended amygdala is recruited during the transition to alcohol dependence. AB - Neuropeptide Y (NPY) is abundant in the extended amygdala, a conceptual macrostructure in the basal forebrain important for regulation of negative affective states. NPY has been attributed a central role in anxiety-like behavior, fear, nociception, and reward in rodents. Deletion of the NPY gene in mice produces a high-anxiety high-alcohol-drinking phenotype. NPY infused into the brains of rats selectively bred to consume high quantities of alcohol suppresses alcohol drinking by those animals, an effect that is mediated by central amygdala (CeA). Likewise, alcohol-preferring rats exhibit basal NPY deficits in CeA. NPY infused into the brains of alcohol-dependent rats blocks excessive alcohol drinking by those animals, an effect that also has been localized to the CeA. NPY in CeA may rescue dependence-induced increases in anxiety and alcohol drinking via inhibition of downstream effector regions that receive GABAergic inputs from CeA. It is hypothesized here that NPY modulates anxiety-like behavior via Y2R regulation of NPY release, whereas NPY modulation of alcohol-drinking behavior in alcohol-dependent animals occurs via Y2R regulation of GABA release. PMID- 22938861 TI - Sleep duration and its correlates in middle-aged and elderly Chinese women: the Shanghai Women's Health Study. AB - BACKGROUND: Abnormal sleep duration, either long or short, is associated with disease risk and mortality. Little information is available on sleep duration and its correlates among Chinese women. METHODS: Using information collected from 68,832 women who participated in the Shanghai Women's Health Study (SWHS), we evaluated sleep duration and its correlations with sociodemographic and lifestyle factors, health status, and anthropometric measurements and their indexes using polynomial logistic regression. RESULTS: The mean age of the study population was 59.6 years (SD=9.0; range: 44.6-79.9 years) at time of sleep duration assessment. Approximately 80% of women reported sleeping 6-8 h/day, 11.5% slept 5h or less, and 8.7% slept 9h or more. As expected, age was the strongest predictor for sleep duration and was negatively correlated with sleep duration. In general, sleep duration was positively associated with energy intake, intakes of total meat and fruits, body mass index (BMI), waist-hip ratio (WHR), and waist circumference (WC) after adjustment for age and other factors. Both short and long sleep duration were negatively associated with education level, family income, and leisure-time physical activity and positively associated with number of live births, history of night shift work, and certain chronic diseases, compared to sleep duration around 7 h/day (6.5-7.4h/day). Short sleep duration was related to tea consumption and passive smoking. Long sleep duration was related to menopausal status and marital status. CONCLUSIONS: In this large, population based study, we found that sleep duration among middle-aged and elderly Chinese women was associated with several sociodemographic and lifestyle factors and with disease status. The main limitation of the study is the cross-sectional design that does not allow us to draw any causal inference. However, this study provides information for future investigation into the nature of these associations so that recommendations can be developed to reduce sleep problems in middle-aged and elderly Chinese women. It also provides important information on potential confounders for investigation of sleep duration on health outcomes in this population. PMID- 22938863 TI - Stress analysis during jaw movement based on vivo computed tomography images from patients with temporomandibular disorders. AB - The purpose of this study is to develop three-dimensional (3D) finite element models of temporomandibular joints (TMJs) and to investigate stress distributions. To determine the causes of temporomandibular disorders (TMDs), the magnitude and location of the maximum stresses under physiological loading must be considered. Stress analysis TMD models were reconstructed from computed tomography (CT) data. Several studies have investigated finite element TMJ models, but few have used a bilateral mandible model that includes jaw closing and maximum opening. In this study, the authors defined an asymmetry index for the different stress values on each side joint; this index has not yet been investigated. According to clinical observation, one joint affects the other side joint during mastication. Three symptom-free volunteers and three symptomatic patients were selected as the control group (CG) and TMD group (TG), respectively. For the TG, data analysis indicated that the condyle was asymmetrical during jaw closing, while both the condyle and disc were slightly asymmetrical during jaw opening. The maximum stresses did not significantly differ between the CG and TG for either closing or opening of the jaw. The results of this study have a potential clinical benefit in terms of proving superior biomechanical behaviour. PMID- 22938862 TI - Personality disorder features and insomnia status amongst hypnotic-dependent adults. AB - OBJECTIVE: To determine the prevalence of personality disorders and their relation to insomnia parameters among persons with chronic insomnia with hypnotic dependence. METHODS: Eighty-four adults with chronic insomnia with hypnotic dependence completed the SCID-II personality questionnaire, two-weeks of sleep diaries, polysomnography, and measures of insomnia severity, impact, fatigue severity, depression, anxiety, and quality of life. Frequencies, between-subjects t-tests and hierarchical regression models were conducted. RESULTS: Cluster C personality disorders were most prevalent (50%). Obsessive-Compulsive personality disorder (OCPD) was most common (n=39). These individuals compared to participants with no personality disorders did not differ in objective and subjective sleep parameters. Yet, they had poorer insomnia-related daytime functioning. OCPD and Avoidant personality disorders features were associated with poorer daytime functioning. OCPD features were related to greater fatigue severity, and overestimation of time awake was trending. Schizotypal and Schizoid features were positively associated with insomnia severity. Dependent personality disorder features were related to underestimating time awake. CONCLUSIONS: Cluster C personality disorders were highly prevalent in patients with chronic insomnia with hypnotic dependence. Features of Cluster C and A personality disorders were variously associated with poorer insomnia-related daytime functioning, fatigue, and estimation of nightly wake-time. Future interventions may need to address these personality features. PMID- 22938864 TI - Msh2-Msh3 interferes with Okazaki fragment processing to promote trinucleotide repeat expansions. AB - Trinucleotide repeat (TNR) expansions are the underlying cause of more than 40 neurodegenerative and neuromuscular diseases, including myotonic dystrophy and Huntington's disease. Although genetic evidence points to errors in DNA replication and/or repair as the cause of these diseases, clear molecular mechanisms have not been described. Here, we focused on the role of the mismatch repair complex Msh2-Msh3 in promoting TNR expansions. We demonstrate that Msh2 Msh3 promotes CTG and CAG repeat expansions in vivo in Saccharomyces cerevisiae. Furthermore, we provide biochemical evidence that Msh2-Msh3 directly interferes with normal Okazaki fragment processing by flap endonuclease1 (Rad27) and DNA ligase I (Cdc9) in the presence of TNR sequences, thereby producing small, incremental expansion events. We believe that this is the first mechanistic evidence showing the interplay of replication and repair proteins in the expansion of sequences during lagging-strand DNA replication. PMID- 22938865 TI - Protein biophysics explains why highly abundant proteins evolve slowly. AB - The consistent observation across all kingdoms of life that highly abundant proteins evolve slowly demonstrates that cellular abundance is a key determinant of protein evolutionary rate. However, other empirical findings, such as the broad distribution of evolutionary rates, suggest that additional variables determine the rate of protein evolution. Here, we report that under the global selection against the cytotoxic effects of misfolded proteins, folding stability (DeltaG), simultaneous with abundance, is a causal variable of evolutionary rate. Using both theoretical analysis and multiscale simulations, we demonstrate that the anticorrelation between the premutation DeltaG and the arising mutational effect (DeltaDeltaG), purely biophysical in origin, is a necessary requirement for abundance-evolutionary rate covariation. Additionally, we predict and demonstrate in bacteria that the strength of abundance-evolutionary rate correlation depends on the divergence time separating reference genomes. Altogether, these results highlight the intrinsic role of protein biophysics in the emerging universal patterns of molecular evolution. PMID- 22938866 TI - The GPS motif is a molecular switch for bimodal activities of adhesion class G protein-coupled receptors. AB - Adhesion class G protein-coupled receptors (aGPCR) form the second largest group of seven-transmembrane-spanning (7TM) receptors whose molecular layout and function differ from canonical 7TM receptors. Despite their essential roles in immunity, tumorigenesis, and development, the mechanisms of aGPCR activation and signal transduction have remained obscure to date. Here, we use a transgenic assay to define the protein domains required in vivo for the activity of the prototypical aGPCR LAT-1/Latrophilin in Caenorhabditis elegans. We show that the GPCR proteolytic site (GPS) motif, the molecular hallmark feature of the entire aGPCR class, is essential for LAT-1 signaling serving in two different activity modes of the receptor. Surprisingly, neither mode requires cleavage but presence of the GPS, which relays interactions with at least two different partners. Our work thus uncovers the versatile nature of aGPCR activity in molecular detail and places the GPS motif in a central position for diverse protein-protein interactions. PMID- 22938868 TI - Contemporary management of postchemotherapy testis cancer. AB - CONTEXT: Some controversy still exists regarding the management of testis cancer following chemotherapy for disseminated disease. OBJECTIVE: To review the available literature concerning the management of postchemotherapy testis cancer. EVIDENCE ACQUISITION: A Medline search was conducted to identify original and review articles, as well as guidelines addressing the management of testis cancer following first-line chemotherapy. Keywords included germ cell tumor, testis cancer, retroperitoneal lymph node dissection, and chemotherapy. The most relevant articles were critically reviewed with the consensus of all the collaborative authors, who have expertise in the management of germ cell tumors (GCTs). EVIDENCE SYNTHESIS: Approximately one-third of patients who undergo chemotherapy for metastatic GCTs have residual retroperitoneal disease. All patients with residual masses >=1cm after chemotherapy for nonseminomatous GCTs should undergo postchemotherapy retroperitoneal lymph node dissection (PC-RPLND) because of the risk of mature teratoma in 40-45% of cases and of viable GCT in 10 15% of cases. Patients who obtain a complete serologic remission and radiographic residual <1 cm after chemotherapy have a 6-9% risk of relapse. Patients with a completely resected teratoma in only the PC-RPLND specimen have a >90% chance of cure, while patients with viable GCTs should be considered for additional therapy, depending on the percentage of viable tumor. In patients with disseminated seminoma, postchemotherapy masses <3cm may be safely observed, while patients with masses >3 cm should be evaluated with positron emission tomography (PET)/computed tomography 2 mo after completion of chemotherapy, with very selective administration of PC-RPLND. Late relapse occurring >2 yr after chemotherapy is rare, and surgery remains the mainstay of therapy in cases of resectable masses independent of tumor markers. There is still controversy on whether high-dose chemotherapy confers a survival benefit compared with conventional-dose chemotherapy in the salvage setting. Surgery should always be considered for resectable masses following salvage therapies or in chemoresistant disease to maximize chance of cure. CONCLUSIONS: Patients with advanced GCTs can achieve long-term disease-free survival when chemotherapy is combined with expert and judicious resection of residual disease. PC-RPLND is recommended for residual masses >1cm identified on postchemotherapy imaging in nonseminomatous GCT and possibly for PET-positive residual disease >=3cm in treated seminomas. PMID- 22938867 TI - Autoreceptor control of peptide/neurotransmitter corelease from PDF neurons determines allocation of circadian activity in drosophila. AB - Drosophila melanogaster flies concentrate behavioral activity around dawn and dusk. This organization of daily activity is controlled by central circadian clock neurons, including the lateral-ventral pacemaker neurons (LN(v)s) that secrete the neuropeptide PDF (pigment dispersing factor). Previous studies have demonstrated the requirement for PDF signaling to PDF receptor (PDFR)-expressing dorsal clock neurons in organizing circadian activity. Although LN(v)s also express functional PDFR, the role of these autoreceptors has remained enigmatic. Here, we show that (1) PDFR activation in LN(v)s shifts the balance of circadian activity from evening to morning, similar to behavioral responses to summer-like environmental conditions, and (2) this shift is mediated by stimulation of the Galpha,s-cAMP pathway and a consequent change in PDF/neurotransmitter corelease from the LN(v)s. These results suggest another mechanism for environmental control of the allocation of circadian activity and provide new general insight into the role of neuropeptide autoreceptors in behavioral control circuits. PMID- 22938869 TI - ICUD-EAU International Consultation on Bladder Cancer 2012: Urothelial carcinoma of the prostate. AB - CONTEXT: The Second International Consultation on Bladder Cancer recommendations on urothelial carcinoma (UC) of the prostate were presented at the 2011 European Association of Urology Congress in Vienna, Austria, on March 18, 2011. OBJECTIVE: Our aim is to summarize the Second International Consultation on Bladder Cancer recommendations on UC of the prostate to help clinicians assess the current evidence-based management. EVIDENCE ACQUISITION: The committee performed a thorough review of new data and updated previous recommendations. Levels of evidence and grades of recommendation were assigned based on a systematic review of the literature that included a search of online databases and review articles. EVIDENCE SYNTHESIS: Once a non-muscle-invasive high-grade tumor or carcinoma in situ (CIS) of the bladder has been diagnosed, careful follow-up of the prostatic urethra is necessary. Noninvasive UC including CIS of the prostate should be treated with intravesical bacillus Calmette-Guerin (BCG) following endoscopic resection. A transurethral resection of the prostate may improve contact of BCG with the prostatic urethra, and it appears that response rates to BCG are increased (level of evidence: 3). Transurethral biopsy of the prostatic urethra is effective in identifying prostatic involvement but may not accurately reveal the extent of involvement, particularly with stromal invasion. Stromal invasion by UC of the prostate carries a poor prognosis. Radical cystoprostatectomy is the treatment of choice for locoregional control in patients with prostatic stromal invasion. CONCLUSIONS: These recommendations contain updated information on the diagnosis and treatment of UC of the prostate. However, prospective trials are needed to further elucidate the best management of these patients. PMID- 22938870 TI - Unsuccessful prior attempts to terminate pregnancy among women seeking first trimester abortion at registered facilities in Bihar and Jharkhand, India. AB - Many abortion seekers in India attempt to induce abortion on their own, by accessing oral medication/preparations from a chemist without a prescription or from an unauthorized provider, and present at registered facilities if these attempts fail. However, little is known about those whose efforts fail or the ways in which programmes and policies may address the needs of such women. This paper explores the experiences of women whose efforts failed, including their socio-demographic profile, the preparations they used, and the extent to which they experienced serious complications, delayed seeking care from an authorized provider, or delayed abortion until the second trimester of pregnancy. Data come from a larger study assessing the feasibility of the provision of medical abortion by non-physicians; a total of 3394 women who sought medical abortion from selected clinical settings in Bihar and Jharkhand between 2008 and 2010 constitute the sample. Prior to visiting the clinic, nearly a third of these women (31%) had made at least one unsuccessful attempt to terminate the unwanted pregnancy by using a range of oral medications/preparations available over-the counter in medical shops. Logistic regression analysis suggests that educated women (OR 1.6-1.7), those from urban areas (OR 6.2) and those from Bihar (OR 1.6) were significantly more likely than women with no education, rural women and those from Jharkhand to have used such medication. Also notable is that the average gestational age of women who had made a previous attempt to terminate their pregnancy was almost identical to that of women who had not done so when they presented at the registered facility. These findings may inform policies and programmes that seek to identify and reduce the potential risks associated with unauthorized abortion-seeking practices, and highlight the need to fully inform women, chemists and providers about oral medications, what works and what does not, and how effective medication must be taken. PMID- 22938871 TI - How the doc should (not) talk: when breaking bad news with negations influences patients' immediate responses and medical adherence intentions. AB - OBJECTIVE: We investigate the role of specific formulations in a doctor's bad news delivery. We focus on the effects of negations and message framing on patients' immediate responses to the message and the doctor, and long-term consequences including quality of life and medical adherence intentions. METHODS: Two lab experiments with 2 (language use: negations vs. affirmations)*2 (framing: positive vs. negative) between-subjects designs. After reading a transcription (experiment 1) or seeing a film clip (experiment 2), participants rated their evaluation of the message and the doctor, expected quality of life, and medical adherence intentions. RESULTS: Positively framed bad news with negations score more negative on these dependent variables than positively framed affirmations (both experiments). For negatively framed negations, these results are reversed (experiment 2). Furthermore, the evaluations of the message (experiment 1) and the doctor (both experiments) mediate the interaction of framing and language use on medical adherence intentions. CONCLUSIONS: Small linguistic variations (i.e., negations vs. affirmations) in breaking bad news can have a significant impact on the health message, doctor evaluation and medical adherence intentions. PRACTICE IMPLICATIONS: Doctors should refrain from using negations to break positively framed news, and employ negations when breaking negatively framed news. PMID- 22938873 TI - Age change in the adult human scapula. AB - This paper illustrates how the generalized age changes of the scapula reported by Graves (1921, 1922, 1939) are not universally applicable across sex or ancestral groups, and should therefore be reexamined. Previous work on the human scapula has shown this bone to be a dynamic skeletal element, which changes morphologically and metrically with advancing age. The research presented in this paper demonstrates how age related changes of the scapula vary according to sex and ancestral group and elucidates the unique pattern of change observed in scapulae of four different sex/ancestry groups. Twenty-three measurements were collected from a total of 804 individuals (169 Black females, 194 Black males, 139 White females, and 302 White males) ranging in age from 19 to 93 years from the Hamann-Todd Osteological Collection, a 19th-20th century American population. The results of this study suggest Graves's dual processes of ossification and atrophy are oversimplified and not universally applicable to all sex and/or ancestry groups. Only one age related change, an increase in border thickness, is shared between all four groups included in this study. However, no two sex/ancestry groups have thickness increases identical in either degree, or location. Therefore, as this study demonstrates, it is inappropriate to assume that, without careful examination of the population by sex and group specific categories, any single pattern of scapula morphology change is applicable to all individuals as they age. PMID- 22938872 TI - Bronchiolitis outbreak caused by respiratory syncytial virus in southwest Bangladesh, 2010. AB - BACKGROUND: During July 2010, newspapers reported a respiratory disease outbreak in southwestern Bangladesh resulting in the admission of children to a secondary care hospital. We investigated this outbreak to determine the etiology and explore possible risk factors. METHODS: The hospital's physician diagnosed children aged <2 years with cough, tachypnea or dyspnea, and expiratory wheeze as having acute bronchiolitis. We reviewed the hospital records and listed case patients admitted between 26 June and 26 July 2010. We surveyed the case patients and collected nasal and throat swabs to test for respiratory viruses. RESULTS: We identified 101 admitted acute bronchiolitis case patients. Fifty-nine (58%) of these were admitted between 16 and 20 July. Among the 29 case patients surveyed, the median age was 4 months and 65% were males. We identified respiratory syncytial virus (RSV) in 91% (21/23) of the samples, 43% of which had a dual viral infection. Most case patients (90%) were treated with broad-spectrum antibiotics. There were no reported deaths. CONCLUSIONS: The sudden increase in admitted acute bronchiolitis case patients, their median age, and identification of RSV in the majority of samples suggest an outbreak of RSV bronchiolitis. Research to identify strategies to prevent respiratory infections including RSV in low-income settings should be prioritized. Factors that perpetuate antibiotic use in managing this viral syndrome should also be explored. PMID- 22938874 TI - The role of the neuromuscular medicine and physiatry specialists in the multidisciplinary management of neuromuscular disease. AB - The neuromuscular medicine and physiatry specialists are key health care providers who work cooperatively with a multidisciplinary team to provide coordinated care for individuals with neuromuscular diseases (NMDs). The director or coordinator of the team must be aware of the potential issues specific to NMDs and be able to access the interventions that are the foundations for proper care in NMD. Ultimate goals include maximizing health and functional capacities, performing medical monitoring and surveillance to inhibit and prevent complications, and promoting access and full integration into the community to optimize quality of life. PMID- 22938876 TI - Electrodiagnosis in neuromuscular disease. AB - Electromyography (EMG) is an important diagnostic tool for the assessment of individuals with various neuromuscular diseases. It should be an extension of a thorough history and physical examination. Some prototypical characteristics and findings of EMG and nerve conduction studies are discussed; however, a more thorough discussion can be found in the textbooks and resources sited in the article. With an increase in molecular genetic diagnostics, EMG continues to play an important role in the diagnosis and management of patients with neuromuscular diseases and also provides a cost-effective diagnostic workup before ordering a battery of costly genetic tests. PMID- 22938877 TI - A practical approach to molecular diagnostic testing in neuromuscular diseases. AB - Molecular diagnosis is an important aspect in the care of patients with neuromuscular disorders. Because of the rapidly evolving nature of the field, the approach to obtaining a molecular diagnosis may be challenging. This article provides a general approach to molecular diagnostic testing while reviewing the principles of genetics and genetic disorders and the indications and limitations of testing methods in common hereditary neuromuscular disorders. PMID- 22938875 TI - Clinical approach to the diagnostic evaluation of hereditary and acquired neuromuscular diseases. AB - For diagnostic evaluation of a neuromuscular disease, the clinician must be able to obtain a relevant patient and family history and perform focused general, musculoskeletal, neurologic, and functional physical examinations to direct further diagnostic evaluations. Laboratory studies for hereditary neuromuscular diseases include the relevant molecular genetic studies. The electromyogram and nerve-conduction studies remain an extension of the physical examination, and help to guide further diagnostic studies such as molecular genetics and muscle and nerve biopsies. All diagnostic information needs are to be interpreted within the context of relevant historical information, family history, physical examination, laboratory data, electrophysiology, pathology, and molecular genetics. PMID- 22938878 TI - Muscle biopsy evaluation in neuromuscular disorders. AB - This article reviews the indications for a muscle biopsy, and then gives a step by-step description of the processes of muscle selection through to interpreting the biopsy report. The article aims to aid the clinician in preparing for a muscle biopsy procedure to avoid common pitfalls and obtain optimal results from this minimally invasive procedure. The basic anatomic structure of normal muscle is reviewed to provide a foundation for understanding common patterns of pathologic change observed in muscle disease and common and disease-specific histopathologic findings are presented, focusing on a select group of neuromuscular diseases. PMID- 22938879 TI - Physical therapy evaluation and management in neuromuscular diseases. AB - Neuromuscular disorders (NMDs) are a group of myopathic or neuropathic diseases that directly or indirectly affect the functioning of muscle. Physical therapists (PTs) have extensive specialized training in musculoskeletal evaluation and assessment that gives them the tools to meet the significant needs of this population. This article reviews the role of PTs in treating the NMD population with a discussion of available evaluation techniques and interventions and with an effort to differentiate between treatments known to apply to this population and conventional practice of PTs. The status of currently available outcome measures used for research and their applicability to clinics are presented. PMID- 22938880 TI - Exercise in neuromuscular diseases. AB - This article reviews the current knowledge regarding the benefits and contraindications of exercise on individuals with neuromuscular diseases (NMDs). Specific exercise prescriptions for individuals with NMDs do not exist because the evidence base is limited. Understanding the effect of exercise on individuals with NMDs requires the implementation of a series of multicenter, randomized controlled trials that are sufficiently powered and use reliable and valid outcome measures to assess the effect of exercise interventions-a major effort for each NMD. In addition to traditional measures of exercise efficacy, outcome variables should include measures of functional status and health-related quality of life. PMID- 22938882 TI - Augmentative and alternative communication for people with progressive neuromuscular disease. AB - Individuals with progressive neuromuscular disease often experience complex communication needs and consequently find that interaction using their natural speech may not sufficiently meet their daily needs. Increasingly, assistive technology advances provide accommodations for and/or access to communication. Assistive technology related to communication is referred to as augmentative and alternative communication (AAC). The nature of communication challenges in progressive neuromuscular diseases can be as varied as the AAC options currently available. AAC systems continue to be designed and implemented to provide targeted assistance based on an individual's changing needs. PMID- 22938881 TI - Prevention and management of limb contractures in neuromuscular diseases. AB - Limb contractures are a common impairment in neuromuscular diseases. They contribute to increased disability from decreased motor performance, mobility limitations, reduced functional range of motion, loss of function for activities of daily living, and increased pain. The pathogenesis of contractures is multifactorial. Myopathic conditions are associated with more severe limb contractures compared with neuropathic disorders. Although the evidence supporting the efficacy of multiple interventions to improve range of motion in neuromuscular diseases in a sustained manner is lacking, there are generally accepted principles with regard to splinting, bracing, stretching, and surgery that help minimize the impact or disability from contractures. PMID- 22938883 TI - Robotics, assistive technology, and occupational therapy management to improve upper limb function in pediatric neuromuscular diseases. AB - This article presents an overview of occupational therapy assessments and treatment options for individuals with neuromuscular disabilities, with a particular focus on children with neuromuscular disorders. The discussion includes descriptions of standard treatments, commercial adaptive equipment, and homemade adaptive solutions. The state of the art in therapeutic and assistive robots and orthoses for the upper and lower extremity is also provided. PMID- 22938884 TI - Disease burden in neuromuscular disease: the role of chronic pain. AB - This article reviews the evidence showing that chronic pain is a significant problem for patients with neuromuscular disease (NMD). Future directions are discussed, including the need for studies addressing the degree to which chronic pain contributes to disease burden and how psychosocial factors influence the experience of pain and its impact. Better measurement tools for chronic pain, quality of life, and burden of disease are needed and could be used via NMD registries to address the knowledge gap in this area. PMID- 22938885 TI - Specialty care and therapeutics. Foreword. PMID- 22938886 TI - Neuromuscular disease management and rehabilitation, part I: diagnostic and therapy issues. PMID- 22938887 TI - William M. Fowler, Jr., MD. Dedication. PMID- 22938888 TI - [Meningococcemia during eculizumab treatment]. PMID- 22938889 TI - Pregnancy and bipolar disorder: a systematic review. AB - OBJECTIVE: The postpartum period is generally considered a time of heightened vulnerability to bipolar disorder; however, there is controversy about the effect of pregnancy on the course of bipolar disorder. This article reviews the literature on the relationship between pregnancy and bipolar disorder and suggests areas for future research. DATA SOURCES AND STUDY SELECTION: Three electronic databases, MEDLINE (1966-2010), PsycINFO (1840-2010), and EMBASE, were searched on April 30, 2010, using the following keywords: pregnancy, bipolar disorder, manic depressive disorder, suicide, hospitalization, pharmacotherapy, and psychotherapy. The reference lists of articles identified were also searched. All relevant papers published in English were included. RESULTS: A total of 70 articles were identified and included in the review. Evidence from studies using nonclinical samples, some retrospective studies, and studies on psychiatric hospitalization rates is suggestive of a positive effect of pregnancy on bipolar disorder; however, recent studies conducted at tertiary care facilities have reported high rates of recurrence following discontinuation of mood stabilizers. CONCLUSIONS: Understanding the relationship between pregnancy and bipolar disorder has implications for perinatal treatment and etiologic understanding of the disorder. Research is urgently needed to estimate the prevalence of bipolar disorder during pregnancy, using both clinical and nonclinical samples. PMID- 22938890 TI - In-shoe center of pressure: indirect force plate vs. direct insole measurement. AB - BACKGROUND: In-shoe center of pressure (COP) measurement is essential in biomechanics. COP can be measured directly utilizing pressure-sensitive insoles, or calculated indirectly via force plate-generated data. While the latter does not require the use of additional measurement hardware (shoe insoles), its precision at calculating in-shoe COP has not been determined. Our purpose was to ascertain the precision of force plate in-shoe COP calculations and enhance their accuracy through a mathematical algorithm. METHODS: Twelve male students participated in the study. In-shoe COP was measured synchronously via the Pedar-X insole system and AMTI force plates, comparing the measurements of both systems. A mathematical algorithm was created to improve agreement between the systems and comparisons were recalculated. RESULTS: The two methods showed different measurements of in-shoe COP. The medio-lateral (ML) and anterior-posterior (AP) Pearson correlation coefficients between systems were 0.44 +/- 0.35 and 0.99 +/- 0.01, and the ML and AP RMS errors were 6.3 +/- 3.0 mm and 43.0 +/- 12.5 mm, respectively. Using a mathematical algorithm, the differences between the measurements of each system could be reduced significantly (all P<0.001). CONCLUSIONS: Without adjustment, force plates give an approximate location of the COP. Using an adjustment model greatly improves the accuracy of the COP trajectory during stance. PMID- 22938891 TI - Memory and inventio: from inventory to invention--Presidential Address to the 2012 Society of University Surgeons, Las Vegas, Nevada. PMID- 22938892 TI - Society of University Surgeons mentorship: fostering personal relationships. PMID- 22938893 TI - Elderly patients may benefit from tight glucose control. AB - BACKGROUND: While minimizing hyperglycemia in critically injured patients improves outcomes, it is debatable whether postinjury glucose control should aim for conventional glucose control levels (<=180 mg/dL) or tight glucose control levels (81-108 mg/dL). We queried our 17-year prospective database of patients at risk for postinjury multiple organ failure to examine the association between glucose levels and adverse outcomes. METHODS: Acutely injured patients admitted to a Level I trauma center intensive care unit from 1992 to 2008 who were more than 15 years of age, had Injury Severity Scores >15, and who survived >48 hours were eligible for the study. Multiple logistic regression was used to determine the independent association of glucose control with adverse outcomes (death, ventilator-free days, intensive care unit-free days, and major infections), adjusted for Injury Severity Score, age, and red blood cell transfusion in the first 12 hours. RESULTS: Overall, 2,231 patients were eligible, of whom 153 (6.9%) died. The mean age was 37.8 +/- 0.4 years, and the median Injury Severity Score was 27 (interquartile range, 21-35). The majority (77%) of these patients maintained mean glucose within conventional glucose control levels and only 10% achieved mean glucose levels within tight glucose control levels. Nonsurvivors required greater doses of insulin to control glucose levels and had greater mean insulin to glucose ratios (t test; P = .025). After adjusting for confounders, mean glucose remained significantly associated with the studied adverse outcomes. Age significantly modified all these associations with older patients seeming to benefit more from tight glucose control levels than their younger counterparts. CONCLUSION: Age is an effect modifier of the association between glucose levels and adverse outcomes. Future studies including larger samples of elderly trauma patients are needed to determine the ideal levels for glucose control in this growing population. PMID- 22938894 TI - Does selective beta-1 blockade provide bone marrow protection after trauma/hemorrhagic shock? AB - BACKGROUND: Previously, nonselective beta-blockade (BB) with propranolol demonstrated protection of the bone marrow (BM) after trauma and hemorrhagic shock (HS). Because selective beta-1 blockers are used commonly for their cardiac protection, the aim of this study was to more clearly define the role of specific beta adrenergic receptors in BM protection after trauma and HS. METHODS: Male Sprague-Dawley rats underwent unilateral lung contusion (LC) followed by HS for 45 minutes. After resuscitation, animals were injected with a selective beta blocker, atenolol (B1B), butoxamine (B2B), or SR59230A (B3B). Animals were killed at 3 hours or 7 days. Heart rate and blood pressure were measured throughout the study period. BM cellularity, growth of hematopoietic progenitor cells (HPCs) in BM, and hemoglobin levels (Hb) were assessed. RESULTS: Treatment with a B2B or B3B after LCHS restored both BM cellularity and BM HPC colony growth at 3 hours and 7 days. In contrast, treatment with a B1B had no effect on BM cellularity or HPC growth but did decrease heart effectively rate throughout the study. Treatment with a B3B after LCHS increased Hb as compared with LCHS alone. CONCLUSION: After trauma and HS, protection of BM for 7 days was seen with use of either a selective beta-2 or beta-3 blocker. Use of a selective beta-1 blocker was ineffective in protecting the BM despite a physiologic decrease in heart rate. Therefore, the protection of BM is via the beta-2 and beta-3 receptors and it is not via a direct cardiovascular effect. PMID- 22938895 TI - Blood transfusion and cancer surgery outcomes: a continued reason for concern. AB - BACKGROUND: The adverse effects of blood transfusion after cancer surgery have been recently challenged in older anemic persons or those with substantial intraoperative blood loss. We hypothesized that intraoperative blood transfusions continue to adversely impact short-term cancer surgery outcomes regardless of age or preoperative hematocrit levels. METHODS: Using the 2005 to 2008 American College of Surgeons National Surgical Quality Improvement Program, we identified 38,926 patients who underwent cancer surgery. Pre-, intra-, and postoperative factors were compared by units of blood transfusion a patient received. Stratified multivariable analyses, by age and hematocrit level, were performed to assess the impact of blood transfusion on operative outcomes, adjusting for covariates. RESULTS: Fourteen percent of patients received an intraoperative blood transfusion. Of those, >60% received only 1 to 2 units of blood. Receipt of intraoperative blood transfusion was associated with higher rates of 30-day operative mortality, major complications, total number of complications, and prolonged length of stay across age groups and in persons with low to normal hematocrit levels. CONCLUSION: The present study shows that intraoperative blood transfusion adversely impacts short-term operative cancer surgery outcomes across all age groups and in those with low to normal hematocrit levels. These findings provide insightful implications on the patterns of blood transfusion during cancer surgery that deserve further investigation. PMID- 22938896 TI - Obesity and readmission in elderly surgical patients. AB - BACKGROUND: Reducing readmissions has become a focus in efforts by Medicare to improve health care quality and reduce costs. This study aimed to determine whether causes for readmission differed between obese and nonobese patients, possibly allowing for targeted interventions. METHODS: A matched case control study of Medicare patients admitted between 2002 and 2006 who were readmitted after hip or knee surgery, colectomy, or thoracotomy was performed. Patients were matched exactly for procedure, while also balancing on hospital, age, and sex. Conditional logistic regression was used to study the odds of readmission for very obese cases (body mass index >35 kg/m2) versus normal weight patients (body mass index of 20-30 kg/m2) after also controlling for race, transfer-in and emergency status, and comorbidities. RESULTS: Among 15,914 patient admissions, we identified 1,380 readmitted patients and 2,760 controls. The risk of readmission was increased for obese compared to nonobese patients both before and after controlling for comorbidities (before: odds ratio, 1.35; P = .003; after: odds ratio, 1.25; P = .04). Reasons for readmission varied by procedure but were not different by body mass index category. CONCLUSION: Obese patients have an increased risk of readmission, yet the reasons for readmission in obese patients appear to be similar to those for nonobese patients, suggesting that improved postdischarge management for the obese cannot focus on a few specific causes of readmission but must instead provide a broad range of interventions. PMID- 22938899 TI - Indications for sentinel lymph node biopsy in multifocal and multicentric breast cancer. AB - BACKGROUND: Multifocal and multicentric breast cancers have been regarded as relative contraindications for sentinel lymph node (SLN) biopsy, because initial validation studies noted an association with greater false-negative rates. The purpose of this study is to perform a meta-analysis of the literature evaluating the feasibility and accuracy of SLN biopsy in multifocal and multicentric breast cancer. METHODS: A PubMed search retrieved original articles published between 2000 and 2010 in which the authors evaluated the accuracy of SLN biopsy in multifocal and multicentric breast cancer. Sixteen original articles were included in our meta-analysis. RESULTS: Nine-hundred thirty-two patients with multifocal and multicentric breast cancer underwent SLN biopsy followed by axillary lymph node dissection. The overall accuracy rate and false-negative rate are 96% and 7.7%, respectively. Of the 37 false-negative biopsies, 7 patients had an additional relative contraindication for SLN biopsy. If we exclude these patients with additional known relative contraindication to SLN biopsy, the accuracy and false-negative rates are 96.7% and 6.3%, respectively. CONCLUSION: When a multifocal or multicentric breast cancer has an additional relative contraindication to performing SLN biopsy, such as neoadjuvant chemotherapy or T > 5 cm, the false-negative rate increases. PMID- 22938898 TI - Surgical complications in 275 HIV-infected liver and/or kidney transplantation recipients. AB - BACKGROUND: In this report, we examine the surgical safety and complications (SC) among 125 liver (L) and 150 kidney (K) HIV+ transplantation (TX) recipients in a prospective nonrandomized U.S. multicenter trial. METHODS: Subjects were required to have CD4+ T-cell counts >200/100 cells/mm3 (K/L) and undetectable plasma HIV-1 RNA (Viral Load [VL]) (K) or expected posttransplantation suppression (L). Impact of SCs (N >= 7) was evaluated by use of the proportional hazards models. Baseline morbidity predictors for SCs (N >= 7) were assessed in univariate proportional hazards models. RESULTS: At median 2.7 (interquartile range 1.9-4.1) and 2.3 (1.0 3.7) years after TX, 3-month and 1-year graft survival were [K] 96% (95% CI 91% 98%) and 91% (95% CI 85%-94%) and [L] 91% (95% CI 85%-95%) and 77% (95% CI 69% 84%), respectively. A total of 14 K and 28 L graft losses occurred in the first year; 6 K and 11 L were in the first 3 months. A total of 26 (17%) K and 43 (34%) L experienced 29 and 62 SCs, respectively. In the liver multivariate model, re exploration was marginally associated (hazard ratio [HR] 2.8; 95% CI 1.0-8.4; P = .06) with increased risk of graft loss, whereas a greater MELD score before transplantation (HR 1.07 per point increase; 95% CI: 1.01-1.14; P = .02), and detectable viral load before TX (HR 3.6; 95% CI 0.9-14.6; P = .07) was associated with an increased risk of wound infections/dehiscence. CONCLUSION: The rates and outcomes of surgical complications are similar to what has been observed in the non-HIV setting in carefully selected HIV-infected liver and kidney TX recipients. PMID- 22938897 TI - Cost-effectiveness analysis of cholecystectomy during Roux-en-Y gastric bypass for morbid obesity. AB - BACKGROUND: Controversy exists regarding the use of concurrent cholecystectomy during Roux-en-Y gastric bypass performed for morbid obesity. METHODS: A decision model was developed to evaluate the cost-effectiveness of current strategies: routine concurrent cholecystectomy, Roux-en-Y gastric bypass alone with or without postoperative ursodiol therapy, and selective cholecystectomy based on preoperative findings on ultrasonography. Probabilities were obtained from a comprehensive literature review. Costs and hospital days were obtained from the Healthcare Cost and Utilization Project Nationwide Inpatient Sample. One-way sensitivity analyses were performed. RESULTS: The least expensive strategy was to perform RYGB alone without preoperative ultrasonography, with an average cost (over RYGB costs) of $537 per patient. RYGB with concurrent cholecystectomy had a cost of $631. Selective cholecystectomy based on preoperative ultrasonography was dominated by the other 2 strategies. Our model was most sensitive to the probability of developing gallbladder-related symptoms after RYGB alone. When the incidence of gallbladder-related symptoms was <4.6%, the dominant strategy was to perform a RYGB alone without preoperative ultrasonography. For values >6.9%, performing concurrent cholecystectomy at the time of the RYGB was superior to other strategies. When ursodiol was used, the least expensive strategy was to perform a concurrent cholecystectomy during RYGB. CONCLUSION: The main factor determining the most cost-effective strategy is the incidence of gallbladder related symptoms after RYGB. The use of ursodiol was associated with an increase in cost that does not justify its use after RYGB. Finally, selective cholecystectomy based on preoperative ultrasonography was dominated by the other strategies in the scenarios evaluated. PMID- 22938900 TI - The effect of depression on stage at diagnosis, treatment, and survival in pancreatic adenocarcinoma. AB - BACKGROUND: Depression has been associated with delayed presentation, inadequate treatment, and poor survival in patients with cancer. METHODS: Using Surveillance, Epidemiology and End Results and Medicare linked data (1992-2005), we identified patients with pancreatic adenocarcinoma (N = 23,745). International classification of diseases, 9th edition, clinical modification codes were used to evaluate depression during the 3 to 27 months before the diagnosis of cancer. The effect of depression on receipt of therapy and survival was evaluated in univariate and multivariate models. RESULTS: Of patients with pancreatic cancer in our study, 7.9% had a diagnosis of depression (N = 1,868). Depression was associated with increased age, female sex, white race, single or widowed status, and advanced stage disease (P < .0001). In an adjusted model, patients with locoregional disease and depression had 37% lower odds of undergoing surgical resection (odds ratio, 0.63; 95% confidence interval, 0.52-0.76). In patients with locoregional disease, depression was associated with lower 2-year survival (hazard ratio, 1.20; 95% confidence interval, 1.09-1.32). After adjusting for surgical resection, this association was attenuated (hazard ratio, 1.14; 95% confidence interval, 1.04-1.26). In patients who underwent surgical resection, depression was a significant predictor of survival (hazard ratio, 1.34; 95% confidence interval, 1.04-1.73). Patients with distant disease and depression had 21% lower odds of receiving chemotherapy (odds ratio, 0.79; 95% confidence interval, 0.70-0.90). After adjusting for chemotherapy for distant disease, depression was no longer a significant predictor of survival (hazard ratio, 1.03; 95% confidence interval, 0.97-1.09). CONCLUSION: The decreased survival associated with depression appears to be mediated by a lower likelihood of appropriate treatment in depressed patients. Accurate recognition and treatment of pancreatic cancer patients with depression may improve treatment rates and survival. PMID- 22938902 TI - Cost-effectiveness analysis of repeat fine-needle aspiration for thyroid biopsies read as atypia of undetermined significance. AB - BACKGROUND: The 2007 National Cancer Institute (NCI) conference on Thyroid Fine Needle Aspiration (FNA) introduced the category atypia of undetermined significance (AUS) or follicular lesion of undetermined significance (FLUS). Repeat FNA in 3 to 6 months was recommended for low-risk patients. Compliance with these recommendations has been suboptimal. We hypothesized that repeat FNA would be more effective than diagnostic lobectomy, with decreased costs and improved rates of cancer detection. METHODS: Cost-effectiveness analysis was performed in which we compared diagnostic lobectomy with repeat FNA. A Markov model was developed. Outcomes and probabilities were identified from literature review. Third-party payer costs were estimated in 2010 US dollars. Outcomes were weighted by use of the quality-of-life utility factors, yielding quality-adjusted life years (QALYs). Monte Carlo simulation and sensitivity analysis were used to examine the uncertainty of probability, cost, and utility estimates. RESULTS: The diagnostic lobectomy strategy cost $8,057 and produced 23.99 QALYs. Repeat FNA cost $2,462 and produced 24.05 QALYs. Repeat FNA was dominant until the cost of FNA increased to $6,091. Dominance of the repeat FNA strategy was not sensitive to the cost of operation or the complication rate. CONCLUSION: The NCI recommendations for repeat FNA regarding follow-up of AUS/FLUS results are cost effective. Improving compliance with these guidelines should lead to less overall costs, greater quality of life, and fewer unnecessary operations. PMID- 22938901 TI - Vodka and wine consumption in a swine model of metabolic syndrome alters insulin signaling pathways in the liver and skeletal muscle. AB - BACKGROUND: The purpose of this study was to examine the effects of alcohol in the context of metabolic syndrome on insulin signaling pathways in the liver and skeletal muscle. METHODS: Twenty-six Yorkshire swine were fed a hypercaloric, high-fat diet for 4 weeks then split into 3 groups: hypercholesterolemic diet alone (HCC, n = 9), hypercholesterolemic diet with vodka (HCVOD, n = 9), and hypercholesterolemic diet with wine (HCW, n = 8) for 7 weeks. Animals underwent intravenous dextrose challenge before euthanasia and tissue collection. RESULTS: HCC, HCVOD, and HCW groups had similar blood fasting glucose levels, liver function test, and body mass index. Thirty and 60 minutes after dextrose infusion, HCVOD and HCW groups had significantly increased blood glucose levels compared with the HCC group. The HCW group had significantly increased levels of insulin compared with the HCC group. Immunoblotting in skeletal muscle demonstrated that alcohol up-regulates p-IRS1, IRS2, AKT, AMPKalpha, PPARalpha, Fox01, and GLUT4. In the liver, HCW had up-regulation of AKT, AMPKalpha, and GLUT4 compared with HCC. Skeletal muscle immunohistochemistry demonstrated increased sarcolemmal expression of GLUT4 in both alcohol groups compared with HCC. CONCLUSION: Moderate alcohol consumption in a swine model of metabolic syndrome worsens glucose metabolism by altering activation of the insulin signaling pathway in the liver and skeletal muscle. PMID- 22938903 TI - Human mesenchymal stem cell and epithelial hepatic carcinoma cell lines in admixture: concurrent stimulation of cancer-associated fibroblasts and epithelial to-mesenchymal transition markers. AB - BACKGROUND: The microenvironments of neoplasms influence both mesenchymal stem cell differentiation into cancer-associated fibroblasts (CAF) and tumor cell line differentiation to mesenchymal phenotypes via epithelial-to-mesenchymal transition (EMT). Using direct cell-cell contact approximating the microenvironment of a neoplasm, we investigated the role of this interaction in human mesenchymal stem cells (hMSCs) and epithelial hepatic carcinoma SK-Hep1 cells by evaluating CAF differentiation and EMT. METHODS: hMSCs and SK-Hep1 cells were homogenously cultured for 12 hours with media only, OPN-R3 aptamer blockade of OPN, or RGD peptide blockade of integrin receptor, negative control mutant OPN R3 aptamer, and RGE peptide blockade. mRNA was isolated from each subpopulation, and real-time-polymerase chain reaction was performed for CAF markers and EMT transcription factors and structural proteins. RESULTS: SK-Hep1 cells in admixture with hMSCs showed increased EMT marker vimentin expression that was ablated with OPN-R3 aptamer or RGD blockade. SK-Hep1 cells when cultured with hMSC admixture increased Snail and Slug expression that was hindered with OPN-R3 aptamer. hMSCs acquired CAF markers tenascin-c and SDF-1 in admixture that was ablated with either OPN-R3 aptamer or RGD blockade. All SK-Hep1 and hMSC negative control subpopulations were statistically equivalent to media-only groups. Fluorescence photography exhibited the critical cell-cell interfaces and acquired EMT traits of SK-Hep1. CONCLUSION: We conclude that direct interaction of cell lines closely replicates the native neoplasm microenvironment. Our experiments reveal soluble OPN or integrin receptor blockade independently prevents progression to metastatic phenotype by acquisition of CAF and EMT markers. PMID- 22938905 TI - Advanced age is an independent predictor for increased morbidity and mortality after emergent surgery for diverticulitis. AB - BACKGROUND: The objectives of our study were to determine the association between age and postoperative outcomes after emergency surgery for diverticulitis and to identify risk factors for postoperative mortality among elderly patients. METHODS: All patients from the American College of Surgeons National Surgical Quality Improvement Program 2005-2009 Participant User Files undergoing emergent surgery for diverticulitis were included. Multivariate logistic regression was used to determine the association between age and postoperative morbidity and mortality after adjustment for perioperative variables. A separate regression model was used to determine risk factors for postoperative mortality among elderly patients, with specific postoperative complications being included as potential predictors. RESULTS: We included 2,264 patients for analysis, of whom 1,267 (56%) were <65 years old (nonelderly), 648 (28.6%) were 65-79 years old (elderly), and 349 (15.4%) were >=80 years old (super-elderly). Advanced age was a significant predictor of 30-day postoperative mortality, and to a lesser extent postoperative morbidity. Among those patients >=65 years old, super-elderly age classification remained a significant predictor of mortality after adjustment for the presence or absence of postoperative complications. Mortality among elderly and super-elderly patients was greatest in the setting of specific complications, such as septic shock, prolonged postoperative mechanical ventilation, and acute renal failure. CONCLUSION: Advanced age is an independent risk factor for death after emergency surgery for diverticulitis, with mortality being greatest among elderly patients who experience certain postoperative complications. Prevention of these complications should form the cornerstone of initiatives designed to lower the mortality associated with emergency surgery in elderly patients. PMID- 22938904 TI - Creating a "pro-survival" phenotype through epigenetic modulation. AB - BACKGROUND: We demonstrated recently that treatment with suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor, improved survival in a rodent model of lipopolysaccharide (LPS)-induced endotoxic shock. The precise mechanisms, however, have not been well-defined. The aim of this study was to investigate the impact of SAHA treatment on gene expression profiles at an early stage of shock. METHODS: Male C57BL/6J mice were treated with or without SAHA (50 mg/kg, IP), followed by a lethal dose of LPS (20 mg/kg, IP) and a second dose of SAHA. Lungs of the animals (LPS and SAHA+LPS groups; n = 3 per group) were harvested 3 hours post-LPS insult. Sham mice (no LPS and no SAHA) served as controls. RNA was isolated from the tissues and gene expression was analyzed using Affymatrix microarray (23,000 genes). A lower confidence bound of fold change was determined for comparison of LPS versus SAHA + LPS, and genes with a lower confidence bound of >2 were considered to be differentially expressed. Reverse transcriptase polymerase chain reaction, Western blotting, and tissue staining were performed to verify the key changes. Network graphs were used to determine gene interaction and biologic relevance. RESULTS: The expression of many genes known to be involved in septic pathophysiology changed after the LPS insult. Interestingly, a number of genes not implicated previously in the septic response were also altered. SAHA treatment attenuated expression of several key genes involved in inflammation. It also decreased neutrophil infiltration in lungs and histologic evidence of acute lung injury. Further analysis confirmed genes engaged in the cellular and humoral arms of the innate immune system were specifically inhibited by SAHA. Gene network analysis identified numerous molecules for the potential development of targeted therapies. CONCLUSION: Administration of SAHA in a rodent model of LPS shock rapidly modulates gene transcription, with an attenuation of inflammatory mediators derived from both arms (cellular and humoral) of the innate immune system. This may be a novel mechanism responsible for the survival advantage seen with SAHA treatment. PMID- 22938906 TI - A prehospital shock index for trauma correlates with measures of hospital resource use and mortality. AB - BACKGROUND: The assessment and treatment of trauma patients begins in the prehospital environment. Studies have validated the shock index as a correlate for mortality and the identification of shock in trauma patients. We investigated the use of the first shock index obtained in the prehospital environment and the first shock index obtained upon arrival in the trauma center as correlates for other outcomes to evaluate its usefulness as a triage tool. METHODS: This is a retrospective review of data from a level I trauma center. Prehospital and trauma center shock indices for 16,269 patients were evaluated as correlates for duration of hospital stay, duration of stay in the intensive care unit, the number of ventilator days, blood product use, and destination of transfer from the trauma center. RESULTS: Pearson correlation coefficients revealed that the relationship of prehospital and trauma center shock indices were correlates for duration of hospital stay, duration of stay in the intensive care unit, the number of ventilator days, and blood product use. A chi-square analysis found that shock indices >=0.9 indicate a higher likelihood of disposition to the intensive care unit, operating room, or death. CONCLUSION: A prehospital shock index for trauma correlates with measures of hospital resource use and mortality. A prospective study is needed to determine the use of this measure as a triage tool. PMID- 22938907 TI - Developing a comprehensive, proficiency-based training program for robotic surgery. AB - INTRODUCTION: Robotically assisted surgery has become very popular for numerous surgical disciplines, yet training practices remain variable with little to no validation. The purpose of this study was to develop a comprehensive, proficiency based robotic training program. METHODS: A skill deconstruction list was generated by observation of robotic operations and interviews with experts. Available resources were used, and other components were developed as needed to develop a comprehensive, proficiency-based curriculum to teach all deconstructed skills. Preliminary construct and content validity and curriculum feasibility were evaluated. RESULTS: The skill deconstruction list contained 23 items. Curricular components included an online tutorial, a half-day interactive session, and 9 inanimate exercises with objective metrics. Novice (546 +/- 26) and expert (923 +/- 60) inanimate composite scores were different (P < .001), supporting construct validity, and substantial pre-test to post-test improvement was noted after successful training completion. All 23 deconstructed skills were rated as highly relevant (4.9 +/- 0.5; 5-point scale), and no skills were absent from the curriculum, supporting content validity. CONCLUSION: These data suggest that this proficiency-based training curriculum comprehensively addresses the skills necessary to perform robotic operations with early construct and content validity and feasibility demonstrated. Further validation is encouraged. PMID- 22938908 TI - Can simulation improve the traditional method of root cause analysis: a preliminary investigation. AB - INTRODUCTION: The Joint Commission on Accreditation of Healthcare Organizations recommendations for conducting root cause analysis (RCA) include identifying "root causes" and "common-cause variation" rather than "proximate causes" and "special-cause variation" to create interventions. Simulation for health care RCA is a novel technique but has not been compared with traditional RCA methods. METHODS: All of the RCAs of adverse events conducted at Tulane Hospital between September 2010 and September 2011 were reviewed. A case of missed postprocedural, preoperative hemorrhage resulting in death was chosen. Hospital records were analyzed to identify the presumed root causes. A simulation of the event was developed and conducted. Six test subjects (preoperative and postanesthesia care unit nurses) participated in the simulation. Root causes identified by simulation analysis were compared with those identified by traditional RCA. RESULTS: In 2 of 6 simulations, the adverse event was duplicated. The root cause identified by standard RCA technique was inattention to signs of bleeding in the patient/ lack of appropriate monitoring of the patient by nursing staff ("special-cause variation"). Simulation-based RCA revealed that the root cause was not only inadequate monitoring, but also the lack of physical presence of physicians in the care environment ("common-cause variation"). Simulation-based RCA identified root causes more amenable to intervention. DISCUSSION: This study demonstrates that simulation-based RCA can identify additional root causes amenable to making health care interventions when compared with traditional RCA. PMID- 22938909 TI - [An oral chronic pain syndrome]. PMID- 22938910 TI - Effect of a single-piece and a three-piece acrylic sharp-edged IOL on posterior capsule opacification. AB - BACKGROUND: To compare the intensity of posterior capsule opacification (PCO) between two intraocular lenses (IOLs) of the same optic material, but with different haptic design (1-piece vs. 3-piece). METHODS: This prospective intraindividual controlled cohort study comprised eighty eyes of 40 patients with bilateral age-related cataract. Each patient received a Polylens Y10 (Polytech, Germany) 1-piece IOL in 1 eye and a Polylens Y30 (Polytech, Germany) 3-piece IOL in the contralateral eye. The IOL type in the first operated eye was randomly assigned before patient recruitment. Digital slitlamp photographs were taken 1 year postoperatively using a standardized photographic technique for regeneratory PCO. The amount of PCO was assessed subjectively at the slitlamp and objectively using automated image-analysis software. RESULTS: The Polylens Y10 (1-piece) group showed significantly higher regeneratory and fibrotic PCO scores 1 year after surgery in subjective slitlamp evaluation, however not with objective evaluation using automated image-analysis software. Subjective PCO assessment resulted in a mean PCO score (scale = 0-10) of 1.6 in the Polylens Y10 group and 0.6 in the Polylens Y30 group at 1 year (p < 0.05). The mean automated image analysis software PCO score was 1.5 in the Polylens Y10 group and 0.9 in the Polylens Y30 group (p = 0.6). CONCLUSION: Both investigated IOLs showed good clinical performance regarding PCO, BCVA and IOL-centration. The Polylens Y10 IOL showed slightly more regeneratory PCO than the 3-piece acrylic IOL 1 year after surgery. PMID- 22938911 TI - Serotonin and ionizing radiation synergistically affect proliferation and adhesion molecule expression of malignant melanoma cells. AB - BACKGROUND: Mast cells are key effectors of the immune system and are involved in a variety of physiological and pathophysiological processes. Dermal mast cells have been demonstrated to degranulate as a consequence of ionizing radiation exposure. Mast cells accumulate at the periphery of skin tumours including malignant melanoma. Melanoma cells thus represent a potential target for the action of mediators released from irradiated mast cells. OBJECTIVE: In this study, we evaluated the effects of serotonin and ionizing radiation on the proliferation and the adhesion molecule expression of malignant melanoma cells. METHODS: Human mast cells (HMC-1) were examined for serotonin release after irradiation using an enzyme-linked immunosorbent assay (ELISA). Protein expression of serotonin receptors and adhesion molecules on human melanoma cells (IPC-298) was investigated by flow cytometry. Cell attachment to fibronectin was determined by an adhesion assay. Proliferation and cell cycle kinetics were analysed by proliferation assay and 5-bromodeoxyuridine (BrdU)/DNA dual parameter flow cytometry, respectively. RESULTS: Ionizing radiation exposure resulted in serotonin release by HMC-1 cells. Expression of serotonin receptors was detected on IPC-298 cells. Serotonin enhanced the radiation-induced reduction in melanoma cell proliferation. Serotonin and ionizing radiation synergistically increased the expression of adhesion molecules on melanoma cells and improved cell adhesion to fibronectin. The up-regulation of cellular adhesion molecule expression was attenuated by inhibitors to phosphatidylinositol 3-kinase, mitogen-activated protein (MAP) ERK kinase and protein kinase C. CONCLUSIONS: Our data suggest that serotonin released from irradiated dermal mast cells modulates the radiation response of human melanoma cells. We postulate that radiation-induced mast cell degranulation and mediator release have a great impact on malignant melanoma cell development. PMID- 22938912 TI - Deliberative dialogues as a mechanism for knowledge translation and exchange in health systems decision-making. AB - Models that describe the key features and intended effects of specific knowledge translation and exchange (KTE) interventions are much less prominent than models that provide a more general understanding of KTE. Our aim was to develop a model in order to describe the key features and intended effects of deliberative dialogues used as a KTE strategy and to understand how deliberative dialogues can support evidence-informed policymaking. By using critical interpretive synthesis, we identified 17 papers representing four fields of enquiry and integrated our findings into a model. The key features described in the model are: 1) an appropriate (i.e., conducive to the particular dialogue) meeting environment; 2) an appropriate mix of participants; and, 3) an appropriate use of research evidence. These features combine to create three types of intended effects: 1) short-term individual-level; 3) medium-term community/organizational-level; and, 3) long-term system-level. The concept of capacity building helps to explain the relationship between features and effects. The model is a useful contribution to the KTE field because it is a practical tool that could be used to guide the development and evaluation of deliberative dialogues in order to understand more about achieving particular outcomes in relation to specific issues or contexts. PMID- 22938913 TI - Development of road safety performance indicators for trauma management in Europe. AB - Trauma management (TM) covers two types of medical treatment: the initial one provided by Emergency Medical Services (EMS) and a further one provided by permanent medical facilities. There is a consensus in the professional literature that to reduce the severity and the number of road crash victims, the TM system should provide rapid and adequate initial care of injury, combined with sufficient further treatment at a hospital or trauma centre. Recognizing the important role of TM for reducing road crash injury outcome, it was decided, within the EU funded SafetyNet project, to develop road safety performance indicators (SPIs) which would characterize the level of TM systems' performance in European countries and enable country comparisons. The concept of TM SPIs was developed based on a literature study of performance indicators in TM, a survey of available practices in Europe and data availability examinations. A set of TM SPIs was introduced including 14 indicators which characterize five issues such as: availability of EMS stations; availability and composition of EMS medical staff; availability and composition of EMS transportation units; characteristics of the EMS response time, and availability of trauma beds in permanent medical facilities. Basic information on the TM systems was collected in close cooperation with the national expert group. A dataset with TM SPIs for 21 countries was created. It was demonstrated that the countries can be compared using selected TM SPIs. Moreover, a more general comparison of the TM systems' performance in the countries is possible, using multiple ranking and statistical weighting techniques. By both methods, final estimates were received enabling the recognition of groups of countries with similar levels of the TM system's performance. The results of various trials were consistent as to the recognition of countries with high or low level of the TM systems' performance, where in grouping countries with intermediate levels of the TM system's performance some differences were observed. The SafetyNet project's practice demonstrated that data collection for estimating TM SPIs is not an easy task but is realizable for the majority of countries. The TM SPIs' message is currently limited to the availability of trauma care services. Further development of the TM SPIs should focus on characteristics of actual treatment supplied, based on combined police and medical road crash related databases. PMID- 22938914 TI - Brief versus extended counseling along with buprenorphine/naloxone for HIV infected opioid dependent patients. AB - Untreated opioid dependence adversely affects HIV outcomes. Integrating buprenorphine/naloxone into HIV treatment settings is feasible; however, the optimal level of counseling has not been established. We conducted a 12-week randomized clinical trial of physician management (PM) versus PM plus enhanced medical management (EMM) in 47 subjects. At 12 weeks, there were no differences between the two groups in percentage of opioid negative urines (63.6% PM vs. 69.0% PM+EMM, p=.5), maximum duration of continuous abstinence (4.9 weeks PM vs. 5.2 weeks PM+EMM, p=.8) or retention (80% PM vs. 59% PM+EMM, p=.1). The percentage of subjects with detectable HIV viral loads decreased from 58% at baseline to 40% at 12 weeks across both groups (p=.02 for time) with no between group differences (p=.84 and p=.27 for the interaction). Providing more extensive counseling beyond PM is feasible in an HIV clinic, but we are unable to detect an improvement in outcomes associated with these services. PMID- 22938916 TI - Chaotic dynamics of a three species prey-predator competition model with bionomic harvesting due to delayed environmental noise as external driving force. AB - We consider a biological economic model based on prey-predator interactions to study the dynamical behaviour of a fishery resource system consisting of one prey and two predators surviving on the same prey. The mathematical model is a set of first order non-linear differential equations in three variables with the population densities of one prey and the two predators. All the possible equilibrium points of the model are identified, where the local and global stabilities are investigated. Biological and bionomical equilibriums of the system are also derived. We have analysed the population intensities of fluctuations i.e., variances around the positive equilibrium due to noise with incorporation of a constant delay leading to chaos, and lastly have investigated the stability and chaotic phenomena with a computer simulation. PMID- 22938915 TI - Linkage into specialist hepatitis C treatment services of injecting drug users attending a needle syringe program-based primary healthcare centre. AB - Injecting drug users (IDUs), the key risk population for hepatitis C virus (HCV) infection, constitute just a small proportion of HCV treatment clients. This study describes an HCV treatment assessment model developed by an inner-city IDU targeted primary healthcare (PHC) facility and, using a retrospective clinical audit, documents predictors of successful referrals to a tertiary liver clinic. Between July 2006-December 2010, 479 clients attended the PHC, of whom 353 (74%) were screened for HCV antibody. Sixty percent (212/353) tested positive, of whom 93% (197/212) were screened for HCV-RNA with 73% (143/197) positive. Referrals to a tertiary liver clinic were provided to 96 clients, of whom 68 (71%) attended. Eleven clients commenced antiviral therapy (AVT), with seven achieving sustained virological responses by December 2010. Clients who had not recently injected drugs and those with elevated ALT levels were more likely to attend the referrals, while those not prescribed psychiatric medications were more likely to commence AVT. The relatively high uptake of referrals, the number of individuals commencing AVT and final treatment outcomes are reasonably encouraging, highlighting the potential of targeted PHC services to facilitate reductions in liver disease burden among IDUs. PMID- 22938917 TI - The New Microbiology: a conference at the Institut de France. AB - In May 2012, three European Academies held a conference on the present and future of microbiology. The conference, entitled "The New Microbiology", was a joint effort of the French Academie des sciences, of the German National Academy of Sciences Leopoldina and of the British Royal Society. The organizers - Pascale Cossart and Philippe Sansonetti from the "Academie des sciences", David Holden and Richard Moxon from the "Royal Society", and Jorg Hacker and Jurgen Hesseman from the "Leopoldina Nationale Akademie der Wissenschaften" - wanted to highlight the current renaissance in the field of microbiology mostly due to the advent of technological developments and allowing for single-cell analysis, rapid and inexpensive genome-wide comparisons, sophisticated microscopy and quantitative large-scale studies of RNA regulation and proteomics. The conference took place in the historical Palais de l'Institut de France in Paris with the strong support of Jean-Francois Bach, Secretaire Perpetuel of the Academie des sciences. PMID- 22938918 TI - Collagen type I together with fibronectin provide a better support for endothelialization. AB - Endothelialization of vascular implants is limited by the inability of cells to retain adhesion when exposed to flow. Extracellular matrix proteins, including fibronectin and collagen, enhance cell adherence on materials. This study investigated the behaviour of Human Umbilical Vein Endothelial Cells (HUVEC) on extracellular matrix coated polystyrene. Collagen and fibronectin were coated as single and double layers to analyse differences in cell proliferation, morphology, and cell-protein interactions. Significantly higher endothelial cell proliferation and migration rates were observed on the collagen and collagen+fibronectin coating compared to the uncoated or fibronectin-coated sample. Immmunofluorescent microscopy showed evidence of extracellular matrix remodelling in the double, collagen+fibronectin coating. These results strongly suggest that a double coating of collagen+fibronectin provides a better support structure for endothelial cell growth and contributes to improve the ability of vascular implants to become and remain endothelialized. PMID- 22938919 TI - Ontogenesis of agonistic vocalizations in the cichlid fish Metriaclima zebra. AB - While acoustic communication has been described in adults of various fish species, our knowledge about the ontogeny of fish sound production is limited. In adults, sound signals are known to be involved during aggressive interactions. However, aggressive behaviour may appear early in the life of fishes due to the possible competition for food and space. If acoustic signals are used to send information to competitors, sounds are likely to play a role during interactions between juvenile fish as well. The apparition and evolution of sound production were monitored in a group of juveniles of the cichlid fish Metriaclima zebra from hatching to 4 months of age. In addition, the link between vocalizations and agonistic behaviour was studied during dyadic interactions at three different ages. Sounds production appeared to be present early in the development of this fish and increased along with the number of aggressive behaviours. Recorded sounds consisted, in juveniles, in isolated pulses showing a decrease in frequency and duration as the fish grew. In adults, sounds became bursts of pulses but the transition from isolated to repetitive pulses was not observed. These results are compared to the existing literature on sound production ontogeny in fishes. PMID- 22938920 TI - Discrimination through silk recognition: the case of the two-spotted spider mite Tetranychus urticae. AB - Choosing a suitable habitat is a main step in the settlement process, particularly for species having weak movement abilities. Reliable cues are thus needed for habitat selection. In silk-spinning arthropods, silk can be used as a social cue to select an appropriate location. Silk can also provide information on the presence of related or non-related individuals. In this article, we compare the settlement behaviour of two strains of the two-spotted spider mite, Tetranychus urticae, in response to the presence of silk woven by an individual of its own or another strain. We then examined how individuals behaved when confronted with both types of silk (own/another strain) simultaneously. Both strains were sensitive to related silk. Settlement decision for both strains did not differ according to the origin of the silk. Mites used the silk as a communication cue for habitat selection and strain discrimination. Our results provide experimental evidence for the use of multiple social cues in the settlement decision by weaving mites. PMID- 22938921 TI - [Phytoplankton distribution in the upwelling areas of the Moroccan Atlantic coast localized between 32 degrees 30'N and 24 degrees N]. AB - Marine phytoplankton was studied in January and July 2002 along of four transects: 32 degrees 30'N, 29 degrees N, 24 degrees 30'N and 24 degrees N. A total of 142 taxa were recorded in this area. The maximal specific richness, both in summer and in winter, was registered around Dakhla (24 degrees N). The global spatiotemporal variability of species richness and specific diversity showed that the most structured and species-rich populations are situated in the coastal areas. The vertical variation of the two parameters showed homogeneity between depth levels. The maximal phytoplanktonic densities are recorded in the southern transects due to the permanent upwelling activity in the southern Atlantic coast. The bathymetric distribution of densities was more heterogeneous during summer, characterized by a high intensity of upwelling. The species Thalassionema nitzschioides, Asterionellopsis glacialis, Melosira, Chaetoceros and Leptocylindrus minimus are indicators of upwelling. PMID- 22938922 TI - Humiculous scorpions: on the genera Ananteris Thorell, 1891 and Microananteris Lourenco, 2004 (Scorpiones: Buthidae), with the description of a new species from French Guiana. AB - A new species of humicolous buthid scorpion is described on the basis of a single male specimen collected in a rainforest in French Guiana. The collection was performed by extraction with the use of Winkler methods. New considerations about the ecology and biogeography of micro-scorpions of the 'Ananteris group' (sensu subfamily Ananterinae Pocock, 1900), are proposed in relation to their possible evolution from endogeous to epygean environments. PMID- 22938924 TI - A few unpleasant facts about atherosclerotic arterial disease in the United States and the world. PMID- 22938923 TI - Molecular phylogenetic redefinition of Herpetomonas (Kinetoplastea, Trypanosomatidae), a genus of insect parasites associated with flies. AB - In order to review the taxonomy of the genus Herpetomonas through phylogenetic and morphological analyses we barcoded 527 insect trypanosomatids by sequencing the V7V8 region of the small subunit ribosomal RNA (SSU rRNA) gene. Fifty two flagellates, 90% of them from Diptera, revealed to be related to known species of Herpetomonas. Sequences of entire glycosomal glyceraldehyde phosphate dehydrogenase (gGAPDH) and SSU rRNA genes were employed for phylogenetic inferences including representatives of all genera of Trypanosomatidae. In the resulting phylogenetic trees, the selected flagellates clustered into a monophyletic assemblage that we are considering as the redefined genus Herpetomonas. Internal transcribed spacer 1 (ITS1) rDNA sequences and putative secondary structures of this region were compared for evaluation of inter- and intraspecific variability. The flagellates were classified in six already known species and five new species. In addition, two Leptomonas spp. were moved to Herpetomonas, now comprising 13 valid species, while four species were excluded from the genus. Light and electron microscopy revealed the extreme polymorphism of Herpetomonas, hindering genus and species identification by morphological characteristics. Our findings also showed that some species of Herpetomonas are generalist parasites of flies and appear to be as cosmopolitan as their hosts. PMID- 22938925 TI - Emphasizing statin safety in the hospitalized patient: a review. AB - This review examines the safe use of statin therapy in the hospitalized patient. Available data support initiation of statin therapy during hospitalization in patients with acute coronary syndromes or established cardiovascular disease and in high-risk patients with diabetes mellitus and chronic kidney disease (except for those on maintenance hemodialysis). Because of the increased risk of cardiovascular disease, statins are given to solid-organ transplant survivors and those treated with protease inhibitors for human immunodeficiency virus. However, in the multidrug, acute illness hospital environment, safety considerations become paramount. We review the essentials of statin metabolism and drug-drug interactions to provide the hospital physician with information to minimize potentially serious adverse statin effects. PMID- 22938926 TI - Changing patterns of anemia management in US hemodialysis patients. AB - BACKGROUND: Erythropoiesis-stimulating agents and adjuvant intravenous iron have been the primary treatment for anemia in chronic kidney disease. Recent clinical and policy-related events have challenged this traditional paradigm, particularly in regard to erythropoiesis-stimulating agents. Less is known about the impact of these events on intravenous iron use. METHODS: United States Renal Data System data (2002-2008) on Medicare hemodialysis patients were examined. For each patient, monthly intravenous iron dose, erythropoiesis-stimulating agent dose, and hemoglobin values were determined. Data were summarized by calendar quarter and plotted for the entire sample and by demographic, clinical, and facility level subgroups. Marginal means for these variables also were computed to account for changes in patient characteristics over time. RESULTS: Quarterly iron use increased from 64% in 2002 to 76% in 2008. Mean quarterly iron dose increased from 500 mg in 2002 to 650 mg in 2008. Mean monthly erythropoiesis-stimulating agent dose (per quarter) increased from 2002 to 2006 and then declined. Mean hemoglobin values followed a pattern similar to erythropoiesis-stimulating agent dose. The same patterns in iron, erythropoiesis-stimulating agent dose, and hemoglobin were generally observed across demographic, clinical, facility, and geographic subgroups, with some important differences between subgroups, specifically race and dialysis vintage. CONCLUSIONS: Anemia management patterns have changed markedly between 2002 and 2008, with a steady increase in intravenous iron use even after declines in erythropoiesis-stimulating agent dose and hemoglobin. The clinical impacts of these changes need further evaluation. PMID- 22938927 TI - Telephone follow-up as a primary care intervention for postdischarge outcomes improvement: a systematic review. AB - OBJECTIVE: Postdischarge telephone follow-up plays an integral part in transitional care efforts in many regions. We systematically reviewed the literature to evaluate the evidence regarding the impact of primary care-based telephone follow-up on postdischarge emergency department visits and hospital readmissions. METHODS: We performed an electronic database search for relevant telephone follow-up studies originating in adult primary care settings. RESULTS: Only 3 studies (N=1765) met entry criteria for this review. None of the studies demonstrated evidence of reduced admissions or emergency department visits from primary care-based telephone follow-ups. All 3 studies reported improved primary care office contact as a result of telephone follow-up intervention. CONCLUSIONS: Despite the growing use of primary care-based telephone follow-up in the postdischarge period, there are no high-quality studies demonstrating its benefit. However, its positive impact on patient engagement holds potentially meaningful implications. In light of recent national health care legislation, the primary care field is ripe for high-quality studies to evaluate the effectiveness of telephone follow-up for patients in the postdischarge period. Particular areas of research focus are discussed. PMID- 22938928 TI - Interventions to increase osteoporosis treatment in patients with 'incidentally' detected vertebral fractures. AB - BACKGROUND: Most vertebral compression fractures are not recognized or treated. We conducted a controlled trial in older patients with vertebral fractures incidentally reported on chest radiographs, comparing usual care with osteoporosis interventions directed at physicians (opinion-leader-endorsed evidence summaries and reminders) or physicians+patients (adding activation with leaflets and telephone counseling). METHODS: Patients aged >60 years who were discharged home from emergency departments and who had vertebral fractures reported but were not treated for osteoporosis were allocated to usual care (control) or physician intervention using alternate-week time series. After 3 months, untreated controls were re-allocated to physician+patient intervention. Allocation was concealed, outcomes ascertainment blinded, and analyses intent-to treat. Primary outcome was starting osteoporosis treatment within 3 months. RESULTS: There were 1315 consecutive patients screened, and 240 allocated to control (n=123) or physician intervention (n=117). Groups were similar at baseline (average age 74 years, 45% female, 58% previous fractures). Compared with controls, physician interventions significantly (all P <.001) increased osteoporosis treatment (20 [17%] vs 2 [2%]), bone mineral density testing (51 [44%] vs 5 [4%]), and bone mineral density testing or treatment (57 [49%] vs 7 [6%]). Three months after controls were re-allocated to physician+patient interventions, 22% had started treatment and 65% had bone mineral density testing or treatment (P <.001 vs controls). Physician+patient interventions increased bone mineral density testing or treatment an additional 16% compared with physician interventions (P=.01). CONCLUSIONS: An opinion-leader-based intervention targeting physicians substantially improved rates of bone mineral density testing and osteoporosis treatment in patients with incidental vertebral fractures, compared with usual care. Even better osteoporosis management was achieved by adding patient activation to physician interventions [NCT00388908]. PMID- 22938929 TI - Publication trends among internal medicine residents and graduates. PMID- 22938930 TI - Pseudo-septal myocardial infarction due to electrocardiographic lead misplacement. PMID- 22938932 TI - Getting started: the benefit of formulary decision support. PMID- 22938933 TI - Negative P wave in V1 is the key to identifying high placement of V1-V2 electrodes in nonpathological subjects. PMID- 22938934 TI - Imaging of thyrotoxicosis. AB - The diagnostic algorithm for patients with Graves' disease frequently involves the use of thyroid autoantibody testing and radioisotope scanning (full text available online: http://education.amjmed.com/pp1/248). However, ultrasound has myriad uses in the evaluation of patients with hyperthyroidism. The purpose of this paper is to review the medical literature outlining the important role that ultrasonography (US) can play in the diagnosis and management of patients with hyperthyroidism. We will make a case for the use of ultrasonography in the initial evaluation of all patients with thyrotoxicosis. This review will delineate the advantages of ultrasonography compared to nuclear medicine imaging in determining the etiology of the hyperthyroidism. The role of sonography in predicting remission and relapse of Graves' disease will also be examined. Finally, this paper will detail the importance of ultrasonography in the workup of hyperthyroidism during pregnancy. We will also outline its utility for predicting fetal thyroid dysfunction in maternal Graves' disease without the need for cordocentesis and its attendant complications. PMID- 22938935 TI - Autoimmune thyrotoxicosis: diagnostic challenges. AB - Autoimmune thyrotoxicosis or Graves' disease (GD) is the most common cause of hyperthyroidism in the United States (full text available online: http://education.amjmed.com/pp1/249). GD occurs more often in women (ratio 5:1) and has a population prevalence of 1-2%. A genetic determinant to the susceptibility to GD is suspected because of familial clustering of the disease, a high sibling recurrence risk, and the familial occurrence of thyroid autoantibodies. GD is a systemic autoimmune thyroid disorder characterized by the infiltration of immune effector cells and thyroid-antigen-specific T cells into the thyroid and thyroid stimulating hormone receptor (TSHR) expressing tissues, i.e. orbit, skin, with the production of autoantibodies to well-defined thyroidal antigens. Stimulatory autoantibodies in GD activate the TSHR leading to thyroid hyperplasia and unregulated thyroid hormone production and secretion. Diagnosis of GD is straightforward in a patient with a diffusely enlarged, heterogeneous, hypervascular (increased Doppler flow on neck ultrasound) thyroid gland, associated orbitopathy, biochemically confirmed thyrotoxicosis, positive TSHR autoantibodies, and often a family history of autoimmune disorders. PMID- 22938936 TI - Laboratory testing in hyperthyroidism. AB - The clinical diagnosis of hypo- or hyperthyroidism is difficult (full text available online: http://education.amjmed.com/pp1/272). Clinical symptoms and signs are often non-specific, and there is incomplete correlation between structural and functional thyroid gland changes. Laboratory testing is therefore indispensible in establishing the diagnosis of thyrotoxicosis. Similar considerations apply to treatment monitoring. Laboratory testing also plays a crucial role in establishing the most likely cause for a patient's hyperthyroidism. Finally, during pregnancy, when isotopic scanning is relatively contraindicated and ultrasound is more difficult to interpret, laboratory testing becomes even more important. PMID- 22938938 TI - Experimental infection of laboratory mice with two Bartonella tribocorum strains from wild Mus species: a homologous host-bacteria model system at the genus level. AB - To date no experimental infection studies have been conducted in laboratory mice using Mus spp. bartonella strains. Therefore we designed a study to evaluate the in vivo infection characteristics of 2 Bartonella tribocorum strains from wild Mus spp. in laboratory mice with the aim of developing a mouse model that reproduces characteristics of naturally acquired bartonella infections in rodents. Groups of outbred CD1 female mice were subcutaneously inoculated with low doses of 2 mouse bartonella strains (10, 100, and 1000 bacteria/mouse). Blood was collected weekly for 27 weeks to evaluate bacteraemia kinetics in infected mice. Mouse urine collected during weeks 3-6 post-inoculation was also tested for viable bacteria to determine whether urine might serve as a source of bacterial transmission. Mice were susceptible to infection with both strains. Bacteraemias in mice lasted up to 25 weeks, sometimes with abacteraemic intervals, and achieved levels up to 107 cfu/ml of blood. Temporal lags in bacteraemia onset of up to 19 weeks in length were noted at different inoculum doses. No viable bacteria were detected in mouse urine. Bacteraemic mice displayed characteristics of infection similar to those observed in natural rodent hosts during longitudinal field studies. This mouse model of persistent bacteraemia should be suitable for a variety of experimental uses. PMID- 22938939 TI - A meta-analytic review of polyunsaturated fatty acid compositions in dementia. AB - OBJECTIVE: To determine whether the levels of docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA), arachidonic acid (AA), total n-3 polyunsaturated fatty acids (PUFAs), and total n-6 PUFAs were changed in patients with dementia or predementia syndrome. DATA SOURCES: PubMed was searched for studies from first date available to July 2011 using the following search terms: (dementia OR cognitive impairment OR mild cognitive impairment) AND (omega-3 OR omega-6 OR polyunsaturated fatty acid OR docosahexaenoic acid OR DHA OR eicosapentaenoic acid OR EPA). The search was limited to literature in English and to human studies. The references of relevant articles and review articles were searched for citations not indexed in PubMed. STUDY SELECTION: Studies were included if they measured levels of EPA, DHA, AA, total n-3 PUFAs, or total n-6 PUFAs from peripheral blood tissues in subjects with cognitive deficits (dementia or predementia syndrome) and elderly controls and were published in peer-reviewed journals. The search yielded 10 articles including 2,280 subjects. DATA EXTRACTION: The study design, sample size, PUFA levels for both patients and control subjects, sampling tissue, diagnoses and diagnostic criteria for cognitive deficits, and distribution of mean age and gender of included subjects were extracted for each study. RESULTS: In a random-effects model, we found that the levels of EPA (effect size [ES] = -0.47, P < .0001), DHA (ES = -0.33, P = .017), and total n-3 PUFAs (ES = -0.46, P = .001) were decreased in patients with dementia. However, the levels of EPA (ES = -0.44, P = .002), but not DHA or other PUFAs, were significantly lower in patients with predementia syndrome. CONCLUSIONS: Our results support the important role of n-3 PUFAs in the pathophysiology of dementia. In addition, the analyses of predementia studies indicate that EPA might be not only a disease-state marker but also a risk factor for cognitive impairment. PMID- 22938940 TI - ER stress in diffuse large B cell lymphoma: GRP94 is a possible biomarker in germinal center versus activated B-cell type. AB - The process of B-cell development is characterized by the activation of the unfolded protein response. Under certain circumstances, the unfolded protein response can be manipulated in a cell death-inducing way. Therefore, tackling the unfolded protein response might be an attractive strategy in the treatment of diffuse large B-cell lymphomas. Our research showed more basal unfolded protein response activity and differences in the inducibility of ER stress in activated B cell versus germinal center cell lines. Moreover, the diffuse large B cell lymphoma patient data revealed that the glucose-regulated protein 94 is new potential discriminator for diffuse large B cell lymphoma. PMID- 22938941 TI - Pentamidine sensitizes chronic myelogenous leukemia K562 cells to TRAIL-induced apoptosis. AB - Pentamidine (PMD) is an anti-protozoa drug with potential anticancer activity. Here we show that PMD at clinically achievable plasma drug concentrations slightly inhibited the growth of human leukemia cell lines. PMD close to its therapeutic doses sensitized TRAIL-resistant K562 cells to the cytokine and potentiated TRAIL-induced apoptosis through activation of caspase-8 and -3. When we investigated the underlying mechanism, we observed that treatment with PMD increased DR5 expression at both mRNA and protein levels and down-regulated anti apoptotic XIAP and Mcl-1 protein levels. This study provides a rationale for a more in-depth exploration into the combined treatment with PMD and TRAIL as a valuable strategy for leukemia therapy. PMID- 22938942 TI - The adverse prognosis for acute myeloid leukemia patients with superior autologous stem cell mobilization. PMID- 22938945 TI - Cluster-tic syndrome as the first clinical manifestation of a dural carotid cavernous fistula. PMID- 22938944 TI - Angiographic restenosis and its clinical impact after infrapopliteal angioplasty. AB - OBJECTIVE: To assess 3- and 12-month angiographic restenosis rates and their clinical impact after infrapopliteal angioplasty. DESIGN: Prospective multicenter study. MATERIALS AND METHODS: We analyzed 68 critical ischemic limbs (tissue loss: 58 limbs) from 63 consecutive patients due to isolated infrapopliteal lesions who underwent angioplasty alone. Primary endpoint was 3-month angiographic restenosis rate; secondary endpoints were 12-month angiographic restenosis rate, and 3- and 12-month rates of mortality, major amputation and reintervention. Three- and 12-month frequency of ambulatory status and of freedom from ischemic symptoms, and time to wound healing in the ischemic wound group, were compared between restenotic and non-restenotic groups. Angiographic restenosis predictors were assessed by multivariable analysis. RESULTS: 95% of cases had 3-month angiography; restenosis rate was 73%: 40% restenosis and 33% re occlusion. Twelve-month follow-up angiography was conducted for the patients without 3-month angiographic restenosis, and restenosis rate at 12 months was 82%. Non-administration of cilostazol and statin, and chronic total occlusion were 3-month angiographic restenosis predictors. Three- and 12-month mortality was 5% and 12%, respectively. Despite no patients having undergone amputation, 15% had persistent ischemic symptoms, and 48% of limbs underwent reintervention within 12 months. During the same study period, ambulatory status and limbs with complete healing were more frequently observed in the non-restenosis group than in the restenosis group. In the tissue loss group, time to wound healing in the restenosis group was longer than in the non-restenosis group (127 days vs. 66 days, p = 0.02). CONCLUSION: The extremely high angiographic restenosis rate after infrapopliteal angioplasty may adversely impact clinical status improvement. PMID- 22938943 TI - Maternal and preterm fetal sheep responses to dexmedetomidine. AB - BACKGROUND: The alpha(2) adrenergic receptor agonist dexmedetomidine has some unique pharmacologic properties that could benefit pregnant patients (and their fetuses) when they require sedation, analgesia, and/or anesthesia during pregnancy. The purpose of the present study was to delineate maternal and fetal responses to an intravenous infusion of dexmedetomidine. METHODS: This study was conducted on surgically-recovered preterm sheep instrumented for physiologic recording and blood sampling. Maternal and fetal cardiovascular and blood gas parameters and fetal cerebral oxygenation levels were recorded before, during, and after 3h of dexmedetomidine infusion to the ewe at a rate of 1 MUg/kg/h. RESULTS: Drug infusion produced overt sedation but no apparent respiratory depression as evidenced by stable maternal arterial blood gases; fetal blood gases were also stable. The one blood parameter to change was serum glucose, By the end of the 3-h infusion, glucose increased from 49+/-10 to 104+/-33mg/dL in the ewe and from 22+/-3 to 48+/-16mg/dL in the fetus; it declined post-drug exposure but remained elevated compared to the starting levels (maternal, 63+/ 12mg/dL, P=0.0497; and fetal, 24+/-4mg/dL, P=0.012). With respect to cardiovascular status, dexmedetomidine produced a decrease in maternal blood pressure and heart rate with fluctuations in uterine blood flow but had no discernable effect on fetal heart rate or mean arterial pressure. Likewise, maternal drug infusion had no effect on fetal cerebral oxygenation, as measured by in utero near-infrared spectroscopy. CONCLUSIONS: Using a clinically-relevant dosing regimen, intravenous infusion of dexmedetomidine produced significant maternal sedation without altering fetal physiologic status. Results from this initial acute assessment support the conduct of further studies to determine if dexmedetomidine has clinical utility for sedation and pain control during pregnancy. PMID- 22938947 TI - Esophageal rupture in a 25-year-old man. PMID- 22938948 TI - Spice it up. PMID- 22938950 TI - Airlift northwest. PMID- 22938951 TI - Life flight network. PMID- 22938952 TI - Northwest MedStar. PMID- 22938953 TI - San Juan Island air ambulance. PMID- 22938954 TI - Non-urgent commercial air travel after acute myocardial infarction: a review of the literature and commentary on the recommendations. PMID- 22938955 TI - Air medical repatriation: compassionate and palliative care consideration during transport. AB - As the world's population ages, the number of elderly and very elderly international travelers continues to increases. Many of these travelers are afflicted with multiple, often severe, medical conditions; in fact, a significant portion of these elderly travelers are considered end stage with respect to their disease state. While traveling, they are exposed to travel hazards and deterioration of their already compromised health. Once acute illness or injury occurs, medically appropriate, compassionate repatriation of these elderly patients is associated with a range of complex challenges. In this series, we present 4 cases that demonstrate these challenges. PMID- 22938956 TI - Lithium battery fires: implications for air medical transport. AB - Lithium-ion batteries provide more power and longer life to electronic medical devices, with the benefits of reduced size and weight. It is no wonder medical device manufacturers are designing these batteries into their products. Lithium batteries are found in cell phones, electronic tablets, computers, and portable medical devices such as ventilators, intravenous pumps, pacemakers, incubators, and ventricular assist devices. Yet, if improperly handled, lithium batteries can pose a serious fire threat to air medical transport personnel. Specifically, this article discusses how lithium-ion batteries work, the fire danger associated with them, preventive measures to reduce the likelihood of a lithium battery fire, and emergency procedures that should be performed in that event. PMID- 22938959 TI - Humeral shaft fractures: retrospective results of non-operative and operative treatment of 186 patients. AB - BACKGROUND: Humeral shaft fractures account for 1-3% of all fractures and 20% of the fractures involving the humerus. The aim of the current study was to compare the outcome after operative and non-operative treatment of humeral shaft fractures, by comparing the time to radiological union and the rates of delayed union and complications. METHODS: All patients aged 16 years or over treated for a humeral shaft fracture during a 5-year period were included in this retrospective analysis; periprosthetic and pathological fractures were excluded. Radiographs and medical charts were retrieved and reviewed in order to collect data on fracture classification, time to radiographic consolidation and the occurrence of adverse events. RESULTS: A total of 186 patients were included; 91 were treated non-operatively and 95 were treated operatively. Mean age was 58.7 +/- 1.5 years and 57.0% were female. In 83.3% of the patients, only the humerus was affected. A fall from standing height was the most common cause of the fracture (72.0%). Consolidation time varied from a median of 11-28 weeks. The rate of radial nerve palsy in both groups was similar: 8.8% versus 9.5%. In 5.3% of the operatively treated patients, the palsy resulted from the operation. Likewise, delayed union rates were similar in both groups: 18.7% following non operative treatment versus 18.9% following surgery. CONCLUSION: The data indicated that consolidation time and complication rates were similar after operative and non-operative treatment. A prospective randomised clinical trial comparing non-operative with operative treatment is needed in order to examine other aspects of outcome, meaning shoulder and elbow function, postoperative infection rates, trauma-related quality of life and patient satisfaction. PMID- 22938960 TI - Impact of remobilized contaminants in Mytilus edulis during dredging operations in a harbour area: bioaccumulation and biomarker responses. AB - Dredging operations in harbours are recurrent to maintain accessibility and navigational depths. One of the main environmental risks of these operations is the remobilization of contaminants trapped in the sediments, rendering them more bioavailable to the biota. However, regulatory policies regarding the contamination risk of dredging chiefly apply to the disposal of dredged materials rather than the direct impact of the procedure itself. In order to assess the ecotoxicological risk of harbour dredging operations in a polluted estuary (the Tagus, W Portugal), the present study compared bioaccumulation and biomarker responses in field-deployed mussels before and after the beginning of operations, complemented by sediment characterization and risk analysis based on standardized sediment quality guidelines. The results revealed a very significant increase in genotoxicity and oxidative stress from the beginning of dredging onwards, which was accompanied by increased bioaccumulation of toxicants, especially polycyclic aromatic hydrocarbons (PAHs) and polychlorinated biphenyls (PCBs). Overall, the results indicate the importance of surveying the direct impacts of these procedures on local contamination, especially considering these sediments had been previously classified as "trace contaminated", according to normative guidelines, and therefore safe for disposal. This study shows the importance of obtaining both chemical and biological data in standard monitoring procedures and that the remobilization of contaminants by dredging operations may be grossly underestimated, which calls for caution when assessing the impact of these activities even in low to moderately polluted areas. PMID- 22938961 TI - Molecular basis of acquired epileptogenesis. PMID- 22938962 TI - Cellular bases of focal and generalized epilepsies. PMID- 22938964 TI - Animal models. AB - Epilepsy accounts for a significant portion of the dis-ease burden worldwide. Research in this field is fundamental and mandatory. Animal models have played, and still play, a substantial role in understanding the patho-physiology and treatment of human epilepsies. A large number and variety of approaches are available, and they have been applied to many animals. In this chapter the in vitro and in vivo animal models are discussed,with major emphasis on the in vivo studies. Models have used phylogenetically different animals - from worms to monkeys. Our attention has been dedicated mainly to rodents.In clinical practice, developmental aspects of epilepsy often differ from those in adults. Animal models have often helped to clarify these differences. In this chapter, developmental aspects have been emphasized.Electrical stimulation and chemical induced models of seizures have been described first, as they represent the oldest and most common models. Among these models, kindling raised great interest, especially for the study of the epileptogenesis. Acquired focal models mimic seizures and occasionally epilepsies secondary to abnormal cortical development, hypoxia, trauma, and hemorrhage.Better knowledge of epileptic syndromes will help to create new animal models. To date, absence epilepsy is one of the most common and (often) benign forms of epilepsy. There are several models, including acute pharmacological models (PTZ, penicillin, THIP, GBL) and chronic models (GAERS, WAG/Rij). Although atypical absence seizures are less benign, thus needing more investigation, only two models are so far available (AY 9944,MAM-AY). Infantile spasms are an early childhood encephalopathy that is usually associated with a poor out-come. The investigation of this syndrome in animal models is recent and fascinating. Different approaches have been used including genetic (Down syndrome,ARX mutation) and acquired (multiple hit, TTX, CRH,betamethasone-NMDA) models.An entire section has been dedicated to genetic models, from the older models obtained with spontaneous mutations (GEPRs) to the new engineered knockout, knocking, and transgenic models. Some of these models have been created based on recently recognized patho-genesis such as benign familial neonatal epilepsy, early infantile encephalopathy with suppression bursts, severe myoclonic epilepsy of infancy, the tuberous sclerosis model, and the progressive myoclonic epilepsy. The contribution of animal models to epilepsy re-search is unquestionable. The development of further strategies is necessary to find novel strategies to cure epileptic patients, and optimistically to allow scientists first and clinicians subsequently to prevent epilepsy and its consequences. PMID- 22938963 TI - Epilepsy as a dynamic disease of neuronal networks. PMID- 22938965 TI - Classification of epilepsies and seizures: historical perspective and future directions. PMID- 22938966 TI - The epidemiology of the epilepsies. PMID- 22938967 TI - Maturation of the human brain and epilepsy. AB - All features of childhood epilepsy are intimately related to brain development. The clinical EEG features of seizures are closely related to developmental changes in cell growth, synapse formation, and myelination. The immature brain is highly excitable due to the depolarizing effects of GABA, overexpression of glutamatergic receptors, and lack of efficient inhibitory control. Seizures have an age-specific effect on brain development.Whereas early life seizures rarely result in cell loss, they can induce changes in synapse organization and receptor physiology. PMID- 22938968 TI - Genetics of idiopathic epilepsies. PMID- 22938969 TI - The genetics of focal epilepsies. PMID- 22938970 TI - Inflammation and epilepsy. PMID- 22938971 TI - Age-related epileptic encephalopathies. PMID- 22938972 TI - Epileptic syndromes with focal seizures of childhood and adolescence. PMID- 22938973 TI - Idiopathic generalized epilepsies. PMID- 22938974 TI - Temporal lobe epilepsy. AB - In the last two decades our understanding of MTLE and its pathophysiology has grown remarkably. Perhaps the most important recognition is that it is not a single entity with a uniform pathology. Rather, it is associated with significant variations in pathology that, in turn, are likely associated with different causes, functional anatomies, physiologies, and outcomes to treatment (medi-cal and surgical). There are numerous changes in the expression of channels and receptors that contribute to the development of epilepsy and, perhaps, drug resistance. This progress in our understanding has also been aided immeasurably by the development of animal models with many parallels to the human condition.These models have allowed us to look at changes in anatomy and physiology and to dissect the circuits in ways that have not been possible in humans. The animal models have also allowed us to create hypotheses about the pathophysiology of the disorder that we have started to exam-ine with the new imaging tools. At present, it is best to summarize our understanding of MTLE by saying there are multiple changes in multiple sites that contribute to the development of the chronic condition. For this reason alone, we should consider MTLE to be a systems disorder. PMID- 22938975 TI - Extratemporal epilepsies. PMID- 22938976 TI - Reflex epilepsies. PMID- 22938977 TI - Psychogenic nonepileptic seizures. AB - Treatment for PNES must be individualized. A combination of approaches is probably the most beneficial for improvement. Treatment should not simply emphasize removing maladaptive PNES behaviour, but should also focus on learning new coping skills and removing secondary gains. If PNES persist, therapy should be re-evaluated. PMID- 22938978 TI - Syncope. PMID- 22938979 TI - Sleep and epilepsy. PMID- 22938980 TI - Electroencephalography and video-electroencephalography. PMID- 22938981 TI - Magnetoencephalography. PMID- 22938982 TI - Structural brain imaging. PMID- 22938983 TI - Functional magnetic resonance imaging: focus localization. PMID- 22938984 TI - Functional magnetic resonance imaging: functional mapping. PMID- 22938985 TI - Magnetic resonance spectroscopy in epilepsy. PMID- 22938986 TI - Epilepsy diagnosis: positron emission tomography. PMID- 22938987 TI - Peri-ictal single-photon emission computed tomography: principles and applications in epilepsy evaluation. PMID- 22938988 TI - Clinical neuropsychology in epilepsy: theoretical and practical issues. PMID- 22938989 TI - Neuropsychiatric complications of epilepsy. PMID- 22938992 TI - Protective role of humoral immune responses during an outbreak of hepatitis E in Egypt. AB - Although the seroprevalence of hepatitis E virus (HEV) is approximately 80% in adult Egyptians living in rural areas, symptomatic HEV-caused acute viral hepatitis (AVH) is sporadic and relatively uncommon. To investigate the dichotomy between HEV infection and clinical AVH, HEV-specific immune responses in patients with symptomatic and asymptomatic HEV infection during a waterborne outbreak in Egypt were examined. Of 235 acute hepatitis patients in Assiut hospitals screened for HEV infection, 42 (17.9%) were acute hepatitis patients confirmed as HEV caused AVH; 37 (88%) of the 42 patients were residents of rural areas, and 14 (33%) were from one village (Kom El-Mansoura). Another 200 contacts of AVH cases in this village were screened for HEV and 14 (7.0%), all of whom were family members of AVH cases, were asymptomatic HEV IgM-positive. HEV infections in this village peaked during the summer. Asymptomatic HEV seroconverters had significantly higher levels of epitope-specific neutralising (p=0.006) and high avidity (p=0.04) anti-HEV antibodies than the corresponding AVH cases. In conclusion, naturally acquired humoral immune responses appear to protect HEV exposed subjects from AVH during an HEV outbreak in Egypt. PMID- 22938993 TI - Divergent selection for ester-linked diferulates in maize pith stalk tissues. Effects on cell wall composition and degradability. AB - Cross-linking of grass cell wall components through diferulates (DFAs) has a marked impact on cell wall properties. However, results of genetic selection for DFA concentration have not been reported for any grass species. We report here the results of direct selection for ester-linked DFA concentration in maize stalk pith tissues and the associated changes in cell wall composition and biodegradability. After two cycles of divergent selection, maize populations selected for higher total DFA (DFAT) content (CHs) had 16% higher DFAT concentrations than populations selected for lower DFAT content (CLs). These significant DFA concentration gains suggest that DFA deposition in maize pith parenchyma cell walls is a highly heritable trait that is genetically regulated and can be modified trough conventional breeding. Maize populations selected for higher DFAT had 13% less glucose and 10% lower total cell wall concentration than CLs, suggesting that increased cross-linking of feruloylated arabinoxylans results in repacking of the matrix and possibly in thinner and firmer cell walls. Divergent selection affected esterified DFAT and monomeric ferulate ether cross link concentrations differently, supporting the hypothesis that the biosynthesis of these cell wall components are separately regulated. As expected, a more higher DFA ester cross-coupled arabinoxylan network had an effect on rumen cell wall degradability (CLs showed 12% higher 24-h total polysaccharide degradability than CHs). Interestingly, 8-8-coupled DFAs, previously associated with cell wall strength, were the best predictors of pith cell wall degradability (negative impact). Thus, further research on the involvement of these specific DFA regioisomers in limiting cell wall biodegradability is encouraged. PMID- 22938994 TI - Terpenoids from Russula lepida and R. amarissima (Basidiomycota, Russulaceae). AB - Four aristolane sesquiterpenes were isolated from the fruiting bodies of Russula lepida and R. amarissima, namely (1R,2S)-1,2-dihydroxyaristolone (6), (2S,11S) 2,12-dihydroxy-aristolone (7), (1R,2S,11S)-1,2,12-trihydroxyaristolone (8), (1S,2S,11S)-1,2,12-trihydroxy-aristolone (9). In addition, a seco-cucurbitane triterpene, i.e. 3,4-secocucurbita-4,24E-diene-3-hydroxy-26-carboxylic acid (14) was isolated from both species. The configuration at C-2 of the already known rulepidol (2-hydroxyaristolone, 5) was corrected as S instead of R. Several more aristolane and nardosinane sesquiterpenes, as well as cucurbitane triterpenes, already reported both from European and Chinese samples of R. lepida, were also isolated. Compound 14 showed moderate cell growth inhibitory activity. PMID- 22938995 TI - Antiviral chlorinated daphnane diterpenoid orthoesters from the bark and wood of Trigonostemon cherrieri. AB - The chemical study of the bark and the wood of Trigonostemon cherrieri, a rare endemic plant of New Caledonia, led to the isolation of a series of highly oxygenated daphnane diterpenoid orthoesters (DDO) bearing an uncommon chlorinated moiety: trigocherrins A-F and trigocherriolides A-D. Herein, we describe the isolation and structure elucidation of the DDO (trigocherrins B-F and trigocherriolides A-D). We also report the antiviral activity of trigocherrins A, B and F (1, 2 and 6) and trigocherriolides A, B and C (7-9) against various emerging pathogens: chikungunya virus (CHIKV), Sindbis virus (SINV), Semliki forest virus (SFV) and dengue virus (DENV). PMID- 22938996 TI - Localized cutaneous argyria: a report of 2 cases. PMID- 22938997 TI - Preoperative 15-MHz ultrasound assessment of tumor thickness in malignant melanoma. AB - BACKGROUND: Tumor thickness is of great importance in the management of cutaneous malignant melanoma (MM): this variable not only affects prognosis but is also a key factor in planning surgical margins and selecting candidates for sentinel node biopsy. Breslow depth is the standard histologic measure of thickness, but technological advances have provided imaging techniques such as cutaneous ultrasound that can potentially assess tumor thickness and enable prompt initiation of definitive treatment. OBJECTIVES: a) To evaluate the utility of ultrasound assessment of tumor thickness in MM, and b) to analyze histologic variables that affect ultrasound assessments of thickness. MATERIALS AND METHODS: Retrospective study of a consecutive series of 79 primary cutaneous MMs in which tumor thickness had been assessed by 15-MHz ultrasound before surgery. We gathered data from histology reports, studying Breslow depth and the presence of ulceration, regression, inflammatory infiltrate, and associated nevi. Correlation coefficients were calculated to evaluate the strength of association between Breslow depth and thickness assessed by ultrasound. We also calculated the sensitivity, specificity, and positive and negative predictive values of ultrasound measurement in the diagnosis of MMs more than 1mm thick. Associations between histologic variables and the overestimation of thickness by ultrasound were also analyzed. RESULTS: The 79 primary MMs studied had a mean (SD) Breslow depth of 0.8 (1.4) mm. There was moderate correlation and agreement between Breslow depth and the ultrasound assessment of thickness (Pearson correlation coefficient, 0.678; intraclass correlation coefficient, 0.78). The tendency of ultrasound to overestimate thickness was nonsignificantly related to the presence of a moderate to intense infiltrate and associated nevi (P>.05). The sensitivity of ultrasound for the diagnosis of MM over 1mm thick was 82%; specificity was 80%, and positive and negative predictive values were 54% and 94%, respectively. CONCLUSIONS: Ultrasound imaging quite correctly identifies thin MMs and can be useful for planning adequate surgical margins; however, there are limitations on its usefulness in the diagnosis of thick MMs. Additional studies are required to confirm whether certain histologic characteristics, such as the presence of a moderate to intense inflammatory infiltrate or associated nevi can lead to overestimation of thickness by ultrasound, limiting the clinical utility of this imaging technique in MM management. PMID- 22938998 TI - Rapid and efficient sonochemical formation of gold nanoparticles under ambient conditions using functional alkoxysilane. AB - Gold nanoparticles (NPs) are rapidly and efficiently formed under ambient conditions with a novel and highly-efficient sonochemical promoter. Despite of the presence of free oxygen, 3-glycidoxypropyltrimethoxysilane (GPTMS) showed remarkable efficiency in promoting the reduction rate of Au (III) than that of conventional promoters (primary alcohols). This is likely attributed to the formation of a variety of radical scavengers, which are alcoholic products from sonochemical hydrolysis of the epoxide group and methoxysilane moieties of GPTMS under weakly acidic conditions. Interestingly, the promotion is quenched by amine or thiol-functionalized alkoxysilane, thereby producing marginal amounts of gold NPs. Furthermore, products of hydrolyzed GPTMS were confirmed to attach on the surface of gold NPs by attenuated total reflectance-Fourier transform infrared spectroscopy. However, according to transmission electron microscopy images, gold NPs that were produced in the presence of GPTMS tend to fuse with each other as condensation of silanols occurs, forming worm- or nugget-like gold nanostructures. The use of long chain surfactants (i.e. polyethylene glycol terminated with hydroxyl or carboxyl) inhibited the fusion, leading to mono dispersed gold NPs. Additionally, the fact that this approach requires neither an ultrasound source with high frequency nor anaerobic conditions provides a huge advantage. These findings could potentially open an avenue for rapid and large scale green-synthesis of gold NPs in future work. PMID- 22938999 TI - Extraction of lipids from microalgae by ultrasound application: prospection of the optimal extraction method. AB - Microalgae have the ability to grow rapidly, synthesize and accumulate large amounts (approximately 20-50% of dry weight) of lipids. A successful and economically viable algae based oil industry will depend on the selection of appropriate microalgal strains and the selection of the most suitable lipid extraction method. In this paper, five extraction methods were evaluated regarding the extraction of lipids from Chlorella vulgaris: Bligh and Dyer, Chen, Folch, Hara and Radin, and Soxhlet. Furthermore, the addition of silica powder was studied to evaluate the introduction of more shear stress to the system as to increase the disruption of cell walls. Among the studied methods, the Bligh and Dyer method assisted by ultrasound resulted in the highest extraction of oil from C. vulgaris (52.5% w/w). Addition of powder silica did not improve the extraction of oil. PMID- 22939000 TI - The use of Weissler method for scale-up a Kraft pulp oxidation by TEMPO-mediated system from a batch mode to a continuous flow-through sonoreactor. AB - The efficiency of cellulose oxidation mediated by the 4-acetamido-TEMPO radical under ultrasonic cavitation was investigated using two ultrasonic systems: a batch lab scale ultrasonic bath with a glass reactor and a semi-continuous flow through sonoreactor. The main objective was to explore the possibility of scaling up the production of oxidized cellulose under ultrasound, from a lab scale process to a pilot plant process, which served as a precursor for producing nanofibrils cellulose. It was found that under acoustic cavitation, the efficiency of TEMPO-mediation oxidation of native cellulose was significantly improved, particularly in the flow-through sonoreactor. In comparison with the glass reactor, the flow-through sonoreactor reduce the applied energy by 88% while increasing 7.8 times the production rate of radicals. These results enable a possibility of producing oxidized fibers for industrial applications. PMID- 22939001 TI - Ultrasound promoted one-pot synthesis of 2-amino-4,8-dihydropyrano[3,2-b]pyran-3 carbonitrile scaffolds in aqueous media: a complementary 'green chemistry' tool to organic synthesis. AB - A green and simple approach to assembling of 2-amino-4,8-dihydropyrano[3,2 b]pyran-3-carbonitrile scaffolds via three-component reaction of kojic acid, malononitrile, and aromatic aldehydes in aqueous media under ultrasound irradiation is described. The combinatorial synthesis was achieved for this methodology with applying ultrasound irradiation while making use of water as green solvent. In comparison to conventional methods, experimental simplicity, good functional group tolerance, excellent yields, short routine, and selectivity without the need for a transition metal or base catalyst are prominent features of this green procedure. PMID- 22939002 TI - Subcellular impact of sonoporation on plant cells: issues to be addressed in ultrasound-mediated gene transfer. AB - Sonoporation (membrane perforation via ultrasonic cavitation) is known to be realizable in plant cells on a reversible basis. However, cell viability may concomitantly be affected over the process, and limited knowledge is now available on how such cytotoxic impact comes about. This work has investigated how sonoporation may affect plant cells at a subcellular level and in turn activate programmed cell death (PCD). Tobacco BY-2 cells were used as the plant model, and sonoporation was applied through a microbubble-mediated approach with 100:1 cell-to-bubble ratio, free-field peak rarefaction pressure of either 0.4 or 0.9 MPa, and 1 MHz ultrasound frequency (administered in pulsed standing-wave mode at 10% duty cycle, 1 kHz pulse repetition frequency, and 1 min duration). Fluoroscopy results showed that sonoporated tobacco cells may undergo plasma membrane depolarization and reactive oxygen species elevation (two cellular disruption events closely connected to PCD). It was also found that the mitochondria of sonoporated tobacco cells may lose their outer membrane potential over time (observed using confocal microscopy) and consequently release stores of cytochrome-c proteins (determined by Western Blotting) into the cytoplasm to activate PCD. These findings provide insight into the underlying mechanisms responsible for sonoporation-induced cytotoxicity in plant cells. They should be taken into account when using this membrane perforation approach for gene transfection applications in plant biotechnology. PMID- 22939003 TI - Ultrasound artificially nucleated bubbles and their sonochemical radical production. AB - We describe the ejection of bubbles from air-filled pits micromachined on a silicon surface when exposed to ultrasound at a frequency of approximately 200 kHz. As the pressure amplitude is increased the bubbles ejected from the micropits tend to be larger and they interact in complex ways. With more than one pit, there is a threshold pressure beyond which the bubbles follow a trajectory parallel to the substrate surface and converge at the center point of the pit array. We have determined the size distribution of bubbles ejected from one, two and three pits, for three different pressure amplitudes and correlated them with sonochemical OH. radical production. Experimental evidence of shock wave emission from the bubble clusters, deformed bubble shapes and jetting events that might lead to surface erosion are presented. We describe numerical simulations of sonochemical conversion using the empirical bubble size distributions, and compare the calculated values with experimental results. PMID- 22939004 TI - Dances with black widow spiders: dysregulation of glutamate signalling enters centre stage in ADHD. AB - Attention-deficit/hyperactivity disorder (ADHD) is a common neurodevelopmental disorder with impairments across the lifespan. The persistence of ADHD is associated with considerable liability to neuropsychiatric co-morbidity such as depression, anxiety and substance use disorder. The substantial heritability of ADHD is well documented and recent genome-wide analyses for risk genes revealed synaptic adhesion molecules (e.g. latrophilin-3, LPHN3; fibronectin leucine-rich repeat transmembrane protein-3, FLRT3), glutamate receptors (e.g. metabotropic glutamate receptor-5, GRM5) and mediators of intracellular signalling pathways (e.g. nitric oxide synthase-1, NOS1). These genes encode principal components of the molecular machinery that connects pre- and postsynaptic neurons, facilitates glutamatergic transmission, controls synaptic plasticity and empowers intersecting neural circuits to process and refine information. Thus, identification of genetic variation affecting molecules essential for the formation, specification and function of excitatory synapses is refocusing research efforts on ADHD pathogenesis to include the long-neglected glutamate system. PMID- 22939005 TI - Evaluation of common variants in 16 genes involved in the regulation of neurotransmitter release in ADHD. AB - Attention-deficit hyperactivity disorder (ADHD) is a neurobehavioral disorder characterized by inappropriate difficulties to sustain attention, control impulses and modulate activity level. Although ADHD is one of the most prevalent childhood psychiatric disorders, it also persists into adulthood in around 30-50% of the cases. Based on the effect of psychostimulants used in the pharmacological treatment of ADHD, dysfunctions in neuroplasticity mechanisms and synapses have been postulated to be involved in the pathophysiology of ADHD. With this background, we evaluated, both in childhood and adulthood ADHD, the role of several genes involved in the control of neurotransmitter release through synaptic vesicle docking, fusion and recycling processes by means of a population based association study. We analyzed single nucleotide polymorphisms across 16 genes in a clinical sample of 950 ADHD patients (506 adults and 444 children) and 905 controls. Single and multiple-marker analyses identified several significant associations after correcting for multiple testing with a false discovery rate (FDR) of 15%: (i) the SYT2 gene was strongly associated with both adulthood and childhood ADHD (p=0.001, OR=1.49 (1.18-1.89) and p=0.007, OR=1.37 (1.09-1.72), respectively) and (ii) STX1A was found associated with ADHD only in adults (p=0.0041; OR=1.28 (1.08-1.51)). These data provide preliminary evidence for the involvement of genes that participate in the control of neurotransmitter release in the genetic predisposition to ADHD through a gene-system association study. Further follow-up studies in larger cohorts and deep-sequencing of the associated genomic regions are required to identify sequence variants directly involved in ADHD. PMID- 22939006 TI - The effect of 6-week treatment with escitalopram on CCK-4 challenge: a placebo controlled study in CCK-4-sensitive healthy volunteers. AB - Cholecystokinin-tetrapeptide (CCK-4)-induced panic attacks are reportedly attenuated by effective treatment with antipanic antidepressants in patients with panic disorder, but in healthy volunteers such effects are not well studied. The aim of this study was to assess the effect of 6-week treatment with an SSRI escitalopram on CCK-4-induced symptoms in healthy volunteers, who previously responded with a panic attack to CCK-4 challenge. A total of 18 healthy subjects (10 males and eight females, mean age 22.5 +/- 5.8) received a 6-week treatment with escitalopram (10 mg/day) and placebo followed by CCK-4 challenge (50 MUg) in a double-blind crossover design. The panic rate was 67% after treatment with escitalopram and 56% after treatment with placebo (p = 0.7). Thus, the results showed a significant reduction in CCK-4-induced panic rates without significant differences between escitalopram and placebo conditions. There were no significant effects of either treatment on any other variable of anxiety or cardiovascular indices. Secondary analysis showed no effect of gender or 5-HTTLPR polymorphism on response to CCK-4 challenge. This study demonstrated that in contrast to the findings in patients with panic disorder, in CCK-4-sensitive healthy volunteers the treatment with an antipanic SSRI did not cause a reduction of CCK-4-induced panic attacks beyond the effect of placebo. The mechanisms behind this discrepancy and the reasons of the decrease in sensitivity to CCK-4 challenge on repeated administration remain to be clarified in future studies. PMID- 22939007 TI - Korea National Survey for Environmental Pollutants in the human body 2008: 1 hydroxypyrene, 2-naphthol, and cotinine in urine of the Korean population. AB - The Korea National Survey for Environmental Pollutants in the human body conducts representative Korean population studies, which were first initiated in 2005 in Korea. This study was conducted from 2008 to 2009 to determine the exposure levels of polycyclic aromatic hydrocarbons and nicotine in the Korean general population. The study population consisted of 4702 adult subjects from 196 sampling locations including coastal, rural, and urban areas. The urinary levels of 1-hydroxypyrene, 2-naphthol, and cotinine were measured for exposure of polycyclic aromatic hydrocarbons and nicotine. The geometric means of the urinary 1-hydroxypyrene, 2-naphthol and cotinine concentrations in the Korean general population were 0.15 MUg/L (95% confidence interval (CI): 0.13-0.17), 3.84 MUg/L (95% CI: 3.57-4.11) and 47.42 MUg/L (95% CI: 40.52-54.32) respectively. When these values were compared with reference ranges for the United States and Germany, the levels of 1-hydroxypyrene, 2-naphthol, and cotinine were very similar for Korea and Germany, however, these levels were slightly lower in the United States. This study is the first nationwide survey of exposure to polycyclic aromatic hydrocarbons and nicotine in Korea and provides a background reference range for exposure to polycyclic aromatic hydrocarbons and nicotine in the Korean general population. PMID- 22939008 TI - Genetic and non-genetic parameters related to embryo production in superovulated Large White (LW) gilts. AB - The aim of this study was to identify genetic and non genetic factors which might affect results of embryo production of Large White (LW) cyclic gilts from data collected in one herd during 6 years. Donors (n=1060) were synchronized with a progestogen treatment and luteolysis was induced 13-15 days later by 2 injections of cloprostenol. To stimulate follicular development 800IU eCG was then injected 24h later, followed by 500IU hCG 48h later. Donors were inseminated twice; depending on the onset of oestrus, the interval between hCG treatment and first insemination (hCGAI1) was either 24 or 41 h. Embryos were collected at 5-6 days after the 1st AI by flushing uterine horns. Traits of interest were the number of corpora lutea (CL), the number of flushed embryos (FE), the number of transferable embryos (TE) and the number of unfertilized embryos (UE). The average number of TE was 18.8 +/- 9.0. The main sources of variation for CL, FE and TE were the season (P<=0.002) and hCGAI1 (P<=0.001) effects. For the interval of 24h of hCGIA1 the number of TE was increased by 4 compared with the TE obtained for the 41 h interval of hCGIA1. Maternal and paternal genetic effects were estimated using restricted maximum likelihood methodology applied to the univariate animal model, whereas genetic covariance components were estimated in bivariate models. Estimates of maternal heritability were 0.45 for CL, 0.32 for FE, 0.29 for TE and 0.05 for UE whereas for the paternal effect, heritabilities were very low (<0.06). Genetic correlation between CL, FE and TE variables were very high (>0.89) for the maternal effect. A breeding scheme based on CL selection in response to superovulation could thus improve the number of transferable embryos. PMID- 22939009 TI - Pressure pain threshold and oral health-related quality of life implications of patients with alloplastic temporomandibular joint replacement--a prospective study. AB - PURPOSE: Alloplastic total temporomandibular joint replacement (TJR) for end stage disease, congenital disorders, and after ablative surgery has been shown improve function and to decrease pain. The purpose of this study was to evaluate the pain pressure threshold (PPT) and oral health-related quality of life (OHRQoL) in patients undergoing alloplastic TJR. MATERIALS AND METHODS: Subjects requiring TJR from May 2007 through February 2011 were enrolled in the study. The PPT and OHRQoL were measured preoperatively and 2, 6, and 12 months postoperatively. The primary predictor variable was postoperative time (preoperatively and 2, 6, and 12 months postoperatively). The primary outcome variables were the PPT and OHRQoL. RESULTS: Seventeen subjects requiring TJR were enrolled in and completed the required 12-month follow-up. There was no difference in the PPT at any time point. There was a significant improvement in the OHRQoL domain of psychological discomfort (P = .04) at 12 months. Facial pain intensity, temporomandibular joint pain, mandibular function, and diet were also significantly improved at 12 months (P = .001). CONCLUSION: Alloplastic TJR appears to decrease pain, improve function and diet, and decrease psychological discomfort. PMID- 22939010 TI - An extremely unusual case of Garre's osteomyelitis of the mandibular condyle after surgical removal of third molars. PMID- 22939011 TI - Microsurgical free flap reconstructions of head and neck region in 406 cases: a 13-year experience. AB - PURPOSE: The reconstruction of extended soft tissue and bony defects in the maxillofacial region with microsurgical flaps is considered to be the therapy of first choice. The aim of this retrospective study was to detect different influencing factors concerning flap survival. MATERIALS AND METHODS: We examined the data of 406 patient cases (121 female and 285 male cases; mean age, 57 years) undergoing reconstruction with a microsurgical flap in our facility between 1998 and 2010. In these cases 326 soft tissue flaps (radial forearm flap, scapula flap, latissimus dorsi flap, anterolateral thigh flap, lateral arm flap, and jejunum flap) and 80 bony flaps (fibula flap and deep circumflex iliac artery flap) were examined. Evaluated parameters were, among others, the timing of reconstruction, defect localization, and recipient vessels used (external vs internal jugular system), as well as anticoagulative management. We statistically analyzed data by means of a chi(2) test, taking account of the odds ratio with P < .05, which was deemed significant. RESULTS: The overall flap survival rate was approximately 92%, without any gender- or age-specific differences. Primary reconstructions proceeded distinctly more successfully than secondary reconstructions (P < .01). Likewise, the defect localization exerted a significant effect on the survival rate (P = .01), with a more caudal localization affecting flap survival positively. Finally, neither the anticoagulation regimen nor the choice of recipient vein system exercised an influence on the survival rate. CONCLUSIONS: Microsurgical tissue transfer is a convenient and reliable method in maxillofacial surgery, provided that one is aware of the determining factors for success. PMID- 22939012 TI - A mechanism to explain the behaviour of spread films of meibomian lipids. PMID- 22939013 TI - Elderly and very elderly advanced ovarian cancer patients: does the age influence the surgical management? AB - BACKGROUND: To examine the surgical treatment and clinical outcome of elderly and very elderly advanced epithelial ovarian cancer patients. METHODS: We retrospectively analyzed FIGO stage IIIC-IV ovarian cancer patients, divided in elderly (Group A, >65 and <75 years) and very elderly patients (Group B, >= 75 years) treated by primary debulking surgery (PDS) or by interval debulking surgery (IDS) at the Catholic University at Rome and Campobasso, Italy. RESULTS: 164 patients were included: 123 (Group A) and 41 (Group B). Complete cytoreduction was achieved in 60 patients (60.6%) in Group A and in 20 patients (62.5%) in Group B (p = 0.75). In the remaining cases, optimal cytoreduction was performed (39 cases (39.4%) in Group A and 12 (37.5%) in Group B; p = 0.75). In Group A complete/optimal debulking was achieved in 53 patients (53.5%) at PDS and in 46 patients (46.5%) at IDS (p = 0.55). In the Group B a higher rate of patients was debulked at IDS with respect to PDS (10 (31.3%) vs. 22 patients (68.7%); p = 0.02). In Group A patients debulked at PDS showed better DFS (p = 0.007) and OS (p = 0.003) with respect to patients submitted to successful IDS, whereas in group B we did not observed any survival difference according to time of cytoreduction. CONCLUSIONS: Our data suggest that elderly and very elderly patients may tolerate radical and ultra-radical surgery. These patients should be managed in a gynecologic oncology unit, with prudent but complete approach. PMID- 22939014 TI - Introducing new vaccines into the South African national immunisation programme - a case study. PMID- 22939015 TI - Rotavirus vaccination within the South African Expanded Programme on Immunisation. AB - Diarrhoeal diseases are ranked the third major cause of childhood mortality in South African children less than 5 years, where the majority of deaths are among black children. Acute severe dehydrating rotavirus diarrhoea remains an important contributor towards childhood mortality and morbidity and has been well documented in South Africa. As the preventive strategy to control rotavirus diarrhoea, South Africa became the first country in the WHO African Region to adopt the rotavirus vaccine in the national childhood immunisation programme in August 2009. The rotavirus vaccine in use, Rotarix, GSK Biologicals, is given at 6 and 14 weeks of age, along with other vaccines as part of Expanded Programme on Immunisation (EPI). Studies which facilitated the introduction of rotavirus vaccine in South Africa included the burden of rotavirus disease and strain surveillance, economic burden of rotavirus infection and clinical trials to assess the safety and efficacy of vaccine candidates. This paper reviews the epidemiology of rotavirus in South Africa, outlines some of the steps followed to introduce rotavirus vaccine in the EPI, and highlights the early positive impact of vaccination in reducing the rotavirus burden of disease based on the post marketing surveillance studies at Dr George Mukhari hospital, a sentinel site at University of Limpopo teaching hospital in Pretoria, South Africa, which has conducted rotavirus surveillance for >20 years. PMID- 22939016 TI - Introduction of pneumococcal conjugate vaccine into the public immunization program in South Africa: translating research into policy. AB - In April 2009, South Africa was the first African country to introduce pneumococcal polysaccharide-protein conjugate vaccine (PCV) into its public immunization program. This review summarizes studies on pneumococcal epidemiology and PCV undertaken in South Africa, which contributed to the process of advocating for the inclusion of PCV into the public immunization program. Surveillance prior to the introduction of 7-valent PCV (PCV-7) indicated that 70% (418/593) of invasive pneumococcal disease (IPD) in infants, the age-group at highest risk of IPD, was attributable to PCV-7 serotypes. Furthermore, 65% of all IPD in children under-5 years was associated with underlying HIV infection. Initial immunogenicity studies reported that PCV vaccination of antiretroviral naive HIV-infected children was associated with lower geometric mean antibody concentrations and proportion with a serotype-specific antibody concentration above the putative threshold (>=0.35 MUg/ml) of protection for IPD for some of the serotypes. The functionality of antibody induced by PCV in HIV-infected infants was inferior to that of HIV-uninfected infants. Vaccine efficacy of 9 valent PCV in a trial from South Africa reported an 83% reduction of vaccine serotype IPD in HIV-uninfected children in the first two years of life, with protection persisting thereafter. However, vaccine efficacy against vaccine serotype IPD declined from 65% at 2.3 years of age to 39% by six years of age in antiretroviral-naive HIV-infected children. Based on the observation that a two dose primary series of PCV during infancy resulted in similar immunogenicity compared to a three-dose schedule, as well as similar impact on nasopharyngeal colonization and effectiveness against IPD in HIV-uninfected children, the South African immunization program adopted a two-dose primary series with a booster dose at 9 months of age. This schedule was largely premised on containing the cost of vaccine introduction, whilst including a booster dose of PCV to assist in prolonging the duration of protection in HIV-infected children. PMID- 22939017 TI - Introducing human papillomavirus vaccines into the health system in South Africa. AB - South Africa has a high incidence of cervical cancer, with an age-standardised rate of approximately 27 per 100,000. In 2000, South Africa launched a national screening programme for cervical cancer prevention, offering three Papanicolaou smears per lifetime starting after the age of 30 with 10-year intervals. However, in the public sector, this national screening programme has not been implemented widely. Vaccination would offer the best primary prevention. Currently there are two HPV vaccines registered in South Africa: the bivalent vaccine Cervarix, containing VLP antigens for oncogenic HPV types 16 and 18; and the quadrivalent vaccine Gardasil, containing VLP antigens for HPV types 16 and 18, as well as non oncogenic HPV types 6 and 11, which are the most common types causing genital warts. The vaccines are recommended for prophylactic use, and should ideally be given before exposure to HPV, which is before sexual debut, to girls aged 11-12 years. Possible routes for delivering the HPV vaccine could be either the routine EPI programme at the age of 12 years when dT is being administered, or through the school system, e.g. to girls attending grade 5 or 6. PMID- 22939018 TI - New vaccine introduction in the East and Southern African sub-region of the WHO African region in the context of GIVS and MDGs. AB - Immunization programmes have over the years proven to be effective and useful in infectious disease control. However, based on current trends that show that many developing countries will not reach the Millennium Development Goals (MDG) targets, there is an urgent need to accelerate efforts to control the most common conditions still responsible for the largest morbidity and mortality in children under 5 years of age, like diarrhoea and pneumonia, for which safe and effective vaccines are now available. Through World Health Organization (WHO) and United Nations Children's Fund (UNICEF) strategies and initiatives like the Global Immunization Vision and Strategy (GIVS), Accelerated Disease Control and Reach Every District (RED), major positive achievements like the increasing number of children reached with Diphtheria-Tetanus-Pertussis (DTP) vaccines, significant measles mortality reduction, and the almost complete eradication of polio, have been realised. Many children in developing countries have access to life saving vaccines through the Global Alliance for Vaccines and Immunization (GAVI) support. Supplementary immunization activities against measles and polio continue to offer opportunities to deliver measles and polio vaccines, and other life saving interventions. The Global Immunization Vision and Strategy 2006-2015 (GIVS framework) can effectively be used to guide countries in addressing some of the remaining challenges to reach the unreached and increase coverage of traditional vaccines, immunize more people against more diseases, support decision making to introduce new vaccines, as well as recognize the opportunity to invest in community health through cost-effective immunization programmes. Introduction of new vaccines should be strengthened and used as vehicles for health systems strengthening as well as for delivery of comprehensive primary health interventions to impact positively on the spiralling disease burden and reduce overall child mortality. A number of countries have adopted and operationalized GIVS through comprehensive multi-year plans for immunization (cMYP). This paper reviews progress with respect to introduction of some of the new vaccines in the East and Southern sub-region of WHO African region in the context of GIVS and MDGs as well as the challenges thereof. PMID- 22939019 TI - Introduction of inactivated polio vaccine (IPV) into the routine immunization schedule of South Africa. AB - South Africa is currently the only country on the African continent using inactivated polio vaccine (IPV) for routine immunization in a sequential schedule in combination with oral polio vaccine (OPV). IPV is a component of an injectable pentavalent vaccine introduced nationwide in April 2009 and administered according to EPI schedule at 6, 10 and 14 weeks with a booster dose at 18 months. OPV is administered at birth and together with the first IPV dose at 6 weeks, which stimulates gut immune system producing a memory IgA response (OPV), followed by IPV to minimize the risk of vaccine associated paralytic polio (VAPP). OPV is also given to all children under 5 years of age as part of regular mass immunizations campaigns. The decision to incorporate IPV into the routine schedule was not based on cost-effectiveness, which it is not. Other factors were taken into account: Firstly, the sequence benefits from the initial mucosal contact with live(vaccine) virus which promotes the IgA response from subsequent IPV, as well as herd immunity from OPV, together with the safety of IPV. Secondly, given the widespread and increasing use of IPV in the developed world, public acceptance of vaccination in general is enhanced in South Africa which is classified as an upper middle income developing country. Thirdly, to address equity concerns because of the growing use of IPV in the private sector. Fourthly, the advent of combination vaccines facilitated the incorporation of IPV into the EPI schedule. PMID- 22939020 TI - Combination vaccines in the South African setting. AB - The number of vaccines available and included as part of the national immunization schedules, has increased significantly over the past few decades. This impacts on patient/parent compliance and creates a challenge for health care providers for implementation of schedules necessitating training and infrastructure improvements. Use of combination rather than component vaccines offers advantages for compliance by single dose administration of various antigens, reducing stock costing as well as reducing cost of additional health care visits. Combination vaccines are often significantly more expensive than individual constituent vaccines. Concerns regarding an increased incidence of adverse events with use of combination vaccines have not been confirmed and rates may seem high as the adverse events seem to mimic the sum total of adverse event rates for each individual antigen used but may in fact be lower. Manufacturers typically advise against interchanging use of vaccine products. Despite this, health authorities advocate use of an alternative vaccine where the original vaccine in not available, to ensure continuity of vaccination. A notable exception is the acellular pertussis vaccine. Partly, because no serological correlates of immunity exist, but also a general lack of convincing follow up studies has prompted the recommendation for manufacturer fidelity for at least the first 3 vaccine doses. According to the South African Medicines Formulary, a variety of vaccines are available in South Africa. Although a large number are available in the private sector, the only true combination vaccine included in the current state EPI, modified in 2009, is the DTaP-IPV/Hib vaccine (Diphtheria, Tetanus, acellular Pertussis, inactivated Poliomyelitis virus and Haemophilus influenzae type b). There are many reasons justifying the use of combination vaccines rather that the individual constituent formulations. Implementation of use in the South African setting at this point is still limited, but may offer an exciting avenue of expanding the antigen repertoire without impacting on side effects, efficacy or complexity of scheduling. PMID- 22939021 TI - An update after 16 years of hepatitis B vaccination in South Africa. AB - Hepatitis B (HB) virus (HBV) infection is highly endemic with at least 65 million chronic HB surface antigen (HBsAg) carriers in Africa, 25% of whom are expected to die from liver disease. Before the introduction of the HB vaccine, the prevalence of chronic carriage of HBV in black South Africans was 9.6%, with 76% having been previously exposed to HBV. The major transmission route in South Africa is unexplained horizontal transmission between toddlers, with most transmission occurring before the age of 5 years. During adolescence and early adulthood, sexual transmission becomes the dominant route, while healthcare workers (HCWs) are also at risk for parenteral/percutaneous transmission during occupational exposures. In 1995 the South African Department of Health (SADoH) incorporated the HB vaccine, administered as a monovalent, into the Expanded Programme on Immunisation (EPI) at 6, 10, and 14 weeks of age, and studies conducted thereafter have found it to be safe and highly effective. Catch-up vaccination for adolescents was not introduced and there is no schools-based vaccination programme. The SADoH recommends HB vaccination of HCWs, but this is not mandatory and there is no national policy, thus HB vaccination uptake in HCWs is sub-optimal. Since 1995, studies on children have found that the prevalence of chronic HBsAg carriage has decreased, as has the incidence of paediatric hepatocellular carcinoma and HBV-related membranous nephropathy. The SADoH should focus their efforts on attaining a high infant HB vaccine coverage, prepare for introducing a HB birth dose, and consider using a hexavalent vaccine (DTaP-IPV Hib-HepB). The department may also want to consider including targeted HB vaccination for 12 year-olds, if their Road to Health Cards show they were not vaccinated as infants. A national policy is needed for HCWs to ensure that they are fully vaccinated and protected against HBV infection. PMID- 22939022 TI - Haemophilus influenzae type b conjugate vaccines - a South African perspective. AB - Introduction of Hib vaccine is known to positively impact on reduction of both morbidity and mortality in children less than 5 years of age. Incorporation of this vaccine into a National EPI, however, does come at a significant cost, which is especially important in non-GAVI funded countries. Compounded reduction in response in certain patient populations and possible indication of booster doses further impacts on cost-benefit analyses. Despite these issues, South Africa has supplied Hib vaccine as part of the National EPI in the form of a combination vaccine, Pentaxim, which combines Hib with Diphtheria, Tetanus, acellular Pertussis (DTP) and Poliomyelitis since 2009. Prior to this, another combination vaccine was utilized containing Hib and DTP. This has subsequently lead to a significant reduction in invasive Hib disease post-introduction, therefore largely justifying utilization. PMID- 22939023 TI - When, and how, should we introduce a combination measles-mumps-rubella (MMR) vaccine into the national childhood expanded immunization programme in South Africa? AB - This article briefly reviews the history and epidemiology of measles, mumps and rubella disease and the case for introducing combination measles-mumps-rubella (MMR) vaccine into the national childhood immunization schedule in South Africa. Despite adopting the World Health Organization's Measles Elimination strategy in 1996 and achieving a significant decrease the incidence of measles, added effort is needed in South and southern Africa to reach the goal to eliminate endogenous spread measles. Mumps is still common disease of childhood and while there are few sequelae, even the rare complications are important in large populations. Congenital rubella syndrome is seldom reported, but it is estimated that of the million or so children born every year in South Africa over 600 infants are affected to some degree by rubella infection. The naturally acquired immunity to rubella in women of childbearing age in South Africa has been estimated at over 90%, so that introducing a rubella containing vaccine in childhood may paradoxically increase the proportion of girls reaching puberty still susceptible to rubella. The elimination of endogenous measles and rubella is being achieved in many countries in South America, and despite the recent measles epidemic, must still be seriously considered for South and southern Africa. Current constraints and potential steps needed to reach the goal in South Africa are discussed. PMID- 22939024 TI - Immunising the HIV-infected child: a view from sub-Saharan Africa. AB - The HIV-infected children are prone to multitude of infections. In sub-Saharan Africa, HIV/AIDS is certainly an important acquired immunodeficiency and is more likely to negatively impact on immunisation programmes than other forms of immunodeficiencies. Although HIV infection is generally not a contra-indication for immunisation, high background HIV prevalence in the region may result in lower rates of vaccine immunogenicity, efficacy and population immunity. Nevertheless, vaccination is still better than natural infection; the risk of vaccination far outweighs the risk of infection with the pathogen. The primary focus of this review is to discuss the lessons learned in vaccinating HIV infected children particularly with key live-attenuated vaccines in Africa such as Bacille Calmette-Guerin (BCG), measles, oral polio vaccine (OPV), yellow fever and rotavirus. Immunisation against influenza virus, a common cause of respiratory illness, is also discussed as multiple guidelines recommend influenza vaccination for number of groups at high risk such as patients infected with HIV. PMID- 22939025 TI - Meeting the need for advocacy, social mobilisation and communication in the introduction of three new vaccines in South Africa - successes and challenges. AB - Advocacy, social mobilisation and communication are key components of the successful introduction of new vaccines into childhood immunisation schedules. The development of many new vaccines and the innovation of finance mechanisms, means more efficacious vaccines are becoming available to children in developing countries. At the same time, communication technology is developing at a rapid rate, and with the dramatic decrease in vaccine-preventable diseases over the past few decades, the public have become increasingly exposed to confusing and conflicting information about the need for vaccination. The science of vaccines has become more complex, making effective, clear and consistent communication for healthcare workers and caregivers critical to the uptake of and adherence to life saving vaccination. The introduction of two new vaccines, the 7-valent pneumococcal conjugate vaccine and the rotavirus vaccine together with the new pentavalent vaccine, which includes inactivated polio vaccine and replaced the former combination vaccine with four antigens, into the South African Expanded Programme on Immunisation over a short period of time, has been met with a number of challenges, some of which led to a lowering of confidence in the Department of Health to deliver on its promises. Had consistent advocacy, social mobilisation and communication efforts not been in place, efforts to make an impact on the burden of disease may not have been as successful. This paper focuses on the lessons learned about effective advocacy with decision makers, social mobilisation, communication with parents and caregivers, and training healthcare workers regarding the introduction of the new vaccines. PMID- 22939026 TI - Addressing public questioning and concerns about vaccination in South Africa: a guide for healthcare workers. AB - Vaccination is one of the most cost-effective and successful public health interventions in the history of mankind. Anecdotal evidence, the media, and South African-based anti-vaccination websites and blogs point to the existence of anti vaccination lobbies in South Africa, although the part played by these lobbies in sub-optimal vaccination coverage is unknown at present. This article discusses some of the claims made by South African anti-vaccination groups, including some drawn from anti-vaccination lobbyists based in highly resourced countries. While research is underway to better understand the scope and influence of anti-vaccine groups, it is important to build capacity among healthcare workers within the Expanded Programme on Immunisation of South Africa to enable them to deal empathically and effectively with parents and caregivers who have been exposed to anti-vaccination messages and who question the need to vaccinate their children. Claims that vaccines cause adverse effects need to be supported by valid and reliable scientific evidence. However, evidence alone that vaccines are safe and effective does not always result in parents being convinced to vaccinate their children. In addition to providing important evidence of vaccine safety, this paper discusses the important role of communication - especially dialogue - in building public trust in vaccination with the ultimate goal of increasing vaccination coverage and preventing future outbreaks of vaccine-preventable diseases. PMID- 22939027 TI - Financing vaccinations - the South African experience. AB - South Africa provides a useful country case study for financing vaccinations. It has been an early adopter of new vaccinations and has financed these almost exclusively from domestic resources, largely through general taxation. National vaccination policy is determined by the Department of Health, based on advice from a national advisory group on immunisation. Standard health economic criteria of effectiveness, cost-effectiveness, affordability and burden of disease are used to assess whether new vaccinations should be introduced. Global guidelines and the advice of local and international experts are also helpful in making the determination to introduce new vaccines. In terms of recent decisions to introduce new vaccines against pneumococcal disease and rotavirus diarrhoea in children, the evidence has proved unequivocal. Universal rollout has been implemented even though this has led to a fivefold increase in national spending on vaccines. The total cost to government remains below 1-1.5% of public expenditures for health, which is viewed by the South African authorities as affordable and necessary given the number of lives saved and morbidity averted. To manage the rapid increase in domestic spending, efforts have been made to scale up coverage over several years, give greater attention to negotiating price reductions and, in some cases, obtain initial donations or frontloaded deliveries to facilitate earlier universal rollout. There has been strong support from a wide range of stakeholders for the early introduction of new generation vaccines. PMID- 22939028 TI - The decision making process on new vaccines introduction in South Africa. AB - South Africa has a functional decision making process for the introduction of new vaccines; with an established National Immunisation Technical Advisory Group (NITAG), referred to as National Advisory Group on Immunisation (NAGI). South Africa has played a leadership role in the African continent with introduction of new vaccines, which dates back to 1995 with the introduction of hepatitis B, followed by the Haemophilus influenzae type b in 1999 and recently the national roll out of the pneumococcal conjugate and rotavirus vaccines in 2009. NAGI has the responsibility to deliberate on key policy issues as part of the process for decision making on the introduction of new vaccines. In developing recommendations NAGI considers: disease burden, cost effectiveness, and the impact on the Expanded Programme on Immunisation (EPI). Although guidance and recommendations from WHO are considered, the decision to introduce a new vaccine in South Africa is based on local data. NAGI recommendations are presented to the National Department of Health (NDOH). The NDOH pursues the matter further through the involvement of provinces. When an agreement has been reached to accept the NAGI recommendations, the NDOH seeks funding from the Ministry of Finance (MOF). Once funds are available, the new vaccines are implemented by the immunisation programme. Although there is an established functional system for decision making in South Africa, some areas need to be addressed. A system should be developed to allow the NDOH, NAGI and the MOF to engage in the deliberations on financial and economic impact of new vaccines. It is further recommended that a committee be established that will assess the programmatic issues to weigh the potential benefits of a new vaccine. Furthermore, political commitment should support the immunisation programme and strengthen it so that it can make an impact in the achievement of the Millennium Development Goal no. 4 of reducing child mortality. PMID- 22939029 TI - Compensatory cognitive training for psychosis: effects in a randomized controlled trial. AB - OBJECTIVE: Treatments for the cognitive impairments of schizophrenia are urgently needed. We developed and tested a 12-week, group-based, manualized, compensatory cognitive training intervention targeting prospective memory, attention, learning/memory, and executive functioning. The intervention focused on compensatory strategies, such as calendar use, self-talk, note taking, and a 6 step problem-solving method, and did not require computers. METHOD: In a randomized controlled trial, 69 outpatients with DSM-IV primary psychotic disorders were assigned to receive standard pharmacotherapy alone or compensatory cognitive training + standard pharmacotherapy for 12 weeks. Assessments of neuropsychological performance and functional capacity (primary outcomes) and psychiatric symptom severity, quality of life, social skills performance, cognitive insight, and self-reported everyday functioning (secondary outcomes) were administered at baseline, posttreatment, and 3-month follow-up. Data were collected between September 2003 and August 2009. RESULTS: Hierarchical linear modeling analyses demonstrated significant compensatory cognitive training associated effects on attention at follow-up (P = .049), verbal memory at posttreatment and follow-up (P values <= .039), and functional capacity (University of California, San Diego Performance-based Skills Assessment) at follow-up (P = .004). The compensatory cognitive training group also differentially improved in negative symptom severity at posttreatment and follow up (P values <= .025) and subjective quality of life at follow-up (P = .002). CONCLUSIONS: Compensatory cognitive training, a low-tech, brief intervention, has the potential to improve not only cognitive performance but also functional skills, negative symptoms, and self-rated quality of life in people with psychosis. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01521026. PMID- 22939030 TI - Mitigation of adverse effects of chlorpyrifos by 24-epibrassinolide and analysis of stress markers in a rice variety Pusa Basmati-1. AB - The present paper first time reports the role of 24-epibrassinolide (EBL) in mitigating the adverse effects of Chlorpyrifos (CPF), a broad spectrum organophosphate insecticide by regulating the antioxidant defence system in an elite indica rice variety Pusa Basmati-1. It investigates the effect of CPF (0.02%, 0.04% and 0.06%) and EBL (10(-11), 10(-9) and 10(-7)M) treatments alone and in combination on rice seedlings. Various growth parameters, protein, proline and malondialdehyde (MDA) content and activities of antioxidant enzymes of seedlings were analysed. CPF showed an adverse effect on growth and protein content of seedlings whereas it leads to an enhancement in the level of MDA and proline content. The activities of antioxidant enzymes such as superoxide dismutase (SOD), ascorbate peroxidase (APX), catalase (CAT), guaiacol peroxidase (GPX) and monodehydroascorbate reductase (MDHAR) increased after treatment with CPF. Application of different concentrations of EBL along with CPF resulted in an overall improvement in the growth, level of protein and proline content and in the activity of various antioxidant enzymes whereas a decline in the levels of MDA content was observed. The work also investigated the changes at the transcript level of some key antioxidant enzymes like Cu/Zn-SOD, Fe-SOD, Mn-SOD, APX, CAT and GR. The expression of most of the genes was enhanced in response to CPF treatment. Application of EBL in conjunction with CPF resulted in a distinct enhancement in the transcript accumulation of Fe-SOD and CAT showing their important role in EBL mediated amelioration of CPF induced stress. PMID- 22939031 TI - Sense, memory, and decision-making in the somatosensory cortical network. AB - The brain constructs representations of objects and concepts based in sensory information combined with experience. This mental process, that we call perception, is the result of a chain of events consisting of phenomena such as detection, memory, discrimination, categorization and decision-making. Although the phenomenon of perception is not necessarily dependent on a given sensory modality (e.g. visual perception, auditory, tactile), single sensory models are indispensable for studying the neural mechanisms that generate it. The somatosensory system is a suitable model for studying the manner in which presentation of a single physical variable (e.g. vibration) triggers a perceptual process. Here, we discuss some recent studies in the somatosensory system that in our view, constitute a breakthrough to understanding decision making. PMID- 22939032 TI - Resilin-like protein in the clamp sclerites of the gill monogenean Diplozoon paradoxum Nordmann, 1832. AB - Resilin is a soft and elastic protein, which is found in many exoskeletal structures of arthropods. Proteins with similar chemical properties have been described for other invertebrates including monogenean fish parasites. However, for the latter taxon no clear microscopic evidence for a resilin-like protein has been shown so far. Here, we present the results of detailed microscopic analyses of the clamp sclerites (attachment devices) of the monogenean Diplozoon paradoxum. Toluidine blue, which is known to stain resilin, selectively stained the material in the clamp sclerites. In addition, when exposed to UV light, this material exhibited an intense blue autofluorescence. The emission spectrum of this autofluorescence has its maximum at 424 nm and is nearly identical to emission spectra of blue autofluorescences observed in 2 well-studied structures containing high proportions of resilin in the exoskeleton of the locust Schistocerca gregaria. The results strongly indicate that the sclerite material of D. paradoxum contains a resilin-like protein. The presence of such a protein likely enhances the attachment efficiency of the clamp sclerites and increases their lifetime. PMID- 22939033 TI - Thioredoxin and glutathione systems in Plasmodium falciparum. AB - Despite a 50% decrease in malaria infections between 2000 and 2010, malaria is still one of the three leading infectious diseases with an estimated 216 million cases worldwide in 2010. More than 90% of all malaria infections were caused by Plasmodium falciparum, a unicellular eukaryotic parasite that faces oxidative stress challenges while developing in Anopheles mosquitoes and humans. Reactive oxygen and nitrogen species threatening the parasite are either endogenously produced by heme derived from hemoglobin degradation or they are from exogenous sources such as the host immune defense. In order to maintain the intracellular redox balance, P. falciparum employs a complex thioredoxin and glutathione system based on the thioredoxin reductase/thioredoxin and glutathione reductase/glutathione couples. P. falciparum thioredoxin reductase reduces thioredoxin and a range of low molecular weight compounds, while glutathione reductase is highly specific for its substrate glutathione disulfide. Since Plasmodium spp. lack catalase and a classical glutathione peroxidase, their redox balance depends on a complex set of five peroxiredoxins differentially located in the cytosol, apicoplast, mitochondria, and nucleus with partially overlapping substrate preferences. Moreover, P. falciparum employs a set of members belonging to the thioredoxin superfamily such as three thioredoxins, two thioredoxin-like proteins, a dithiol and three monocysteine glutaredoxins, and a redox-active plasmoredoxin with largely redundant functions. This review aims at summarizing our current knowledge on the functional redox networks of the malaria parasite P. falciparum. PMID- 22939034 TI - Efficacy and tolerability of linagliptin added to a sulfonylurea regimen in patients with inadequately controlled type 2 diabetes mellitus: an 18-week, multicenter, randomized, double-blind, placebo-controlled trial. AB - BACKGROUND: Some patients with type 2 diabetes mellitus (T2DM) receiving monotherapy with a sulfonylurea (SU) are unable to meet recommended glycemic targets over the long term and require additional pharmacologic agents to maintain glycemic control. This study was designed to assess the utility of adjunctive therapy with the dipeptidyl peptidase (DPP)-4 inhibitor linagliptin in patients with T2DM inadequately controlled with SU monotherapy. OBJECTIVE: To assess the efficacy and tolerability of linagliptin as add-on therapy in patients with inadequately controlled T2DM despite background therapy with an SU. METHODS: In this Phase III, multicenter, randomized, double-blind, placebo-controlled trial, patients with inadequately controlled T2DM on SU monotherapy were randomly assigned to receive treatment with linagliptin 5 mg once daily (n = 161) or placebo (n = 84) for 18 weeks. The primary end point was the mean change in hemoglobin (Hb) A(1c) from baseline to week 18, evaluated using ANCOVA. Tolerability was assessed using laboratory analysis, spontaneous reporting, and physical examination and interview. RESULTS: Mean baseline characteristics were similar in the linagliptin and placebo groups. Linagliptin treatment was associated with a placebo-corrected mean (95% CI) change in HbA(1c) from baseline (8.6%) to 18 weeks of -0.47% (-0.70 to -0.24; P < 0.0001). Patients in the linagliptin group were more likely compared with placebo to achieve the HbA(1c) target level of <7.0% after 18 weeks of treatment (15.2% vs 3.7%, respectively; odds ratio [OR] = 6.5; 95% CI, 1.7-24.8; P = 0.007). Similarly, patients in the linagliptin group were more likely to achieve an HbA(1c) reduction of >=0.5% compared with those in the placebo group (57.6% vs 22.0%; OR = 5.1, 95% CI 2.7 9.6; P < 0.0001). The overall frequency of adverse events was similar between the linagliptin and placebo groups (42.2% vs 42.9%). The incidences of hypoglycemic events were not significantly different between the 2 groups (5.6% vs 4.8%), and none of the hypoglycemic episodes were assessed as severe by the investigator. The difference in the changes in mean body weight was not significant (+0.43 vs 0.01 kg; P = 0.12). CONCLUSIONS: The addition of linagliptin to SU therapy for 18 weeks in these patients with T2DM was associated with statistically significant and clinically meaningful reductions in HbA(1c) compared with placebo. The overall tolerability of linagliptin was similar to that of placebo, with a low risk for hypoglycemia and no significant weight gain. These findings support the use of linagliptin as adjunctive therapy in patients with T2DM inadequately controlled on SU monotherapy. ClinicalTrials.gov identifier: NCT00819091. PMID- 22939036 TI - The Seattle Heart Failure Model predicts survival in patients with cardiac resynchronization therapy: a validation study. AB - BACKGROUND: The Seattle Heart Failure Model (SHFM) predicts mortality in patients with heart failure, but no study has investigated model performance in subjects with cardiac resynchronization therapy (CRT). METHODS AND RESULTS: Prospectively collected registry data of 427 patients with CRT were used for the evaluation of the discrimination and calibration performance of the SHFM. The primary end point was all-cause mortality. Calibration profile was assessed with the use of Hosmer Lemeshow tests, and discrimination was assessed by calculating areas under receiver operating characteristic curves (AUCs) derived from the model. Mean (SD) age of the study population was 61.2 (11.1) years (72.6% male). During a median follow-up of 24.7 months, 16.9% (72/427) of the patients reached the primary end point, with observed outcomes of 34/303, 54/234, and 72/97 at years 1, 2, and 5, respectively. No evidence of insufficient fit was found in any calibration tests. AUC estimates in all subjects were 0.7377 (95% CI 0.6575-0.8179) at year 1, 0.7936 (95% CI 0.7317-0.8556) at year 2, and 0.7572 (95% CI 0.6455-0.8689) at year 5. CONCLUSIONS: SHFM offers an accurate prediction of survival in patients with CRT, with good observed calibration and AUC estimates indicating discrimination performance similar to those found by earlier validation studies. PMID- 22939035 TI - Implantable cardiac defibrillators and sudden death in recent onset nonischemic cardiomyopathy: results from IMAC2. AB - BACKGROUND: Given the potential for recovery in recent onset nonischemic cardiomyopathy (ROCM), the timing and need for implantable cardioverter defibrillator (ICDs) remains controversial. We examined the utilization of ICDs and the impact on survival for subjects with ROCM. METHODS AND RESULTS: An National Heart, Lung, and Blood Institute sponsored registry enrolled 373 subjects with ROCM, all with a left ventricular ejection fraction (LVEF) <=0.40 and <=6 months of symptoms. The mean age was 45 +/- 14 years, 38% were female, 21% black, 75% New York Heart Association II/III, and the mean LVEF was 0.24 +/- 0.08. Survival was comparable for subjects with an ICD within 1 month of entry (n = 43, 1/2/3 year % survival = 97/97/92) and those with no ICD at 1 month (n = 330, % survival = 98/97/95, P = .30) and between those with and without an ICD at 6 months (ICD, n = 73, 1/2/3 year % survival = 98/98/95; no ICD, n = 300, % survival = 98/96/95, P = .95). There were only 6 sudden cardiac deaths (SCD) noted (% survival free from SCD = 99/98/97) and these occurred in 1.9% of subjects without ICD and 0.9% of those with a device (P = .50). CONCLUSIONS: In a multicenter cohort of ROCM the risk of SCD was low at 1% per year. Early ICD placement did not impact survival and can be deferred while assessing potential for myocardial recovery. PMID- 22939037 TI - Cardiac transplantation can be safely performed with low donor-to-recipient body weight ratios. AB - BACKGROUND: United Network for Organ Sharing adult heart transplant criteria recommend against using same-sex donors with a donor-recipient body weight ratio <0.7. The same criteria recommend against a female donor to male recipient body weight ratio <0.9. We attempted to determine if transplantation with low donor recipient body weight ratios can be safely performed. METHODS AND RESULTS: Transplants with same-sex donor-recipient body weight ratio <0.7 and female donor male recipient body weight ratio <0.9 were compared with age- and sex-matched control subjects with ideally matched donor weights. Of the 123 patients undergoing transplantation, 23 met low donor-recipient body weight ratio criteria. This cohort was compared with 22 ideally weight-matched patients. There was no difference in survival at 1, 5, and 10 years (P = .68). Freedom from rejection (52.2 vs 50.0%; P = 1.0), creatinine clearance change (-1.3 vs 5.7 mL/min; P = .88), duration of inotropic support (191.5 vs 208.8 h; P = .65), and duration of mechanical ventilation (156.3 vs 84.5 h; P = .52) were similar. Intensive care (290.5 vs 368.6 h; P = .71) and hospital length of stay (35.4 vs 36.7 d; P = .94) were not different. CONCLUSIONS: Accepted donor-recipient weight match criteria may be extended to increase the donor pool. PMID- 22939038 TI - Changes in uric acid levels and allopurinol use in chronic heart failure: association with improved survival. AB - OBJECTIVE: Uric acid (UA) levels are frequently increased in patients with heart failure (HF), and may be an indicator of a poor prognosis and an innovative target for treatment. We evaluated the effect of UA and allopurinol use on clinical outcome in patients with HF. METHODS AND RESULTS: We evaluated patients with a diagnosis of HF at a Health Maintenance Organization (n = 6204). Patients were followed for cardiac-related hospitalizations and death. Mean UA levels were 6.5 +/- 1.9 mg/dL. Median follow-up was 498 days. We divided patients into quartiles of serum UA; 22.6% (n = 1,568) were in the highest UA level quartile (>7.7 mg/dL). Cox regression analysis after adjustment for significant predictors including age, sex, ischemic heart disease, hypertension, atrial fibrillation, body mass index, hemoglobin, sodium, estimated glomerular filtration rate, urea levels, standard HF drug therapies, and allopurinol demonstrated that high UA levels (>7.7 mg/dL) were a predictor of increased mortality (hazard ratio [HR] 1.37, 95% confidence interval [CI] 1.17-1.60; P < .0001) and increased cardiac hospitalizations (HR 1.10, 95% CI 1.01-1.22; P < .05). An increase in UA levels during follow-up was also an independent predictor of mortality (HR 1.46, 95% CI 1.25-1.71; P < .00001) and cardiac hospitalizations (HR 1.15, 95% CI 1.06-1.23; P < .00001). Treatment with allopurinol was independently associated with improved survival (HR 0.79, 95% CI 0.64-0.98; P < .05). Echocardiographic data demonstrated a significant correlation between UA levels and E/A ratio, a marker of diastolic dysfunction. CONCLUSIONS: Increased UA levels and an increase in UA during follow-up were independent predictors of increased morbidity and mortality. Treatment with allopurinol was associated with improved survival. PMID- 22939039 TI - Hemodynamic determinants of the abnormal cardiopulmonary exercise response in heart failure with preserved left ventricular ejection fraction. AB - BACKGROUND: The cardiopulmonary exercise testing (CPET) response in heart failure with preserved left ventricular ejection fraction (HFPEF) is incompletely understood. We aimed to describe the CPET response in HFPEF and to assess its invasive hemodynamic determinants. METHODS AND RESULTS: Ten patients with HFPEF and 8 asymptomatic controls underwent resting and exercise right heart catheterization and maximal symptom-limited CPET. The slope of the minute ventilation/carbon dioxide production relationship (VE/VCO(2) slope; 34.3 +/- 5.4 vs. 28.4 +/- 3.4; P = .02) was steeper, peak oxygen consumption (peak VO(2); 15.1 +/- 4.9 vs. 26.6 +/- 12.5 mL*kg(-1)*min(-1); P = .02) was lower, and heart rate recovery 1 minute after exercise termination (HRR-1; 10 +/- 5 vs. 27 +/- 10 beats/min; P < .001) was slower in HFPEF compared to controls. A steeper VE/VCO(2) slope (r = 0.67, P = .002), lower peak VO(2) (r = -0.48, P = .04), and slower HRR-1 (r = -0.58, P = .02) were significantly related to a higher ratio of the change in pulmonary capillary wedge pressure per change in work rate as a measure of the left ventricular pressure volume relationship. CONCLUSIONS: In HFPEF patients, fundamental alterations in the CPET profile occur and these may, in part, result from the rapid rise in left ventricular filling pressures which accompanies exercise in these patients. PMID- 22939040 TI - Fatigue, inflammation, and projected mortality in heart failure. AB - BACKGROUND: Fatigue is a prominent and poorly understood symptom of heart failure with reduced ejection fraction (HFrEF). The purpose of this study was to determine whether fatigue correlated with immune biomarkers and prognosis. METHODS/RESULTS: In patients with HFrEF (N = 59) and healthy controls (N = 25), we prospectively measured fatigue (Profile of Mood States), depressive symptoms (Patient Health Questionnaire-8), sleep quality (Pittsburgh Sleep Quality Index), and immune biomarkers (plasma C-reactive protein [CRP], tumor necrosis factor alpha [TNFalpha], and interleukins [IL-6 and IL-10]). Seattle Heart Failure Model (SHFM) mortality risk scores were determined. Patients with HFrEF had significantly greater fatigue and depressive symptoms and poorer sleep quality compared to control subjects. When controlling for depressive symptoms, however, fatigue did not differ significantly between patients with HFrEF and controls. Patients with HFrEF had significantly lower levels of IL-10 compared to controls. Cytokines did not correlate significantly with fatigue, but fatigue was significantly associated with higher SHFM scores. CONCLUSIONS: Depressive symptoms were an important covariate of fatigue in patients with HFrEF. Our study findings were the first to show a positive association between fatigue and the SHFM score, indicating that fatigue was associated with poorer prognosis. PMID- 22939041 TI - Angiotensin receptor type 1 single nucleotide polymorphism 1166A/C is associated with malignant arrhythmias and altered circulating miR-155 levels in patients with chronic heart failure. AB - BACKGROUND: Sudden cardiac death (SCD) from ventricular tachyarrhythmias accounts for approximately 450,000 annual deaths in the United States; many of these cases involve patients with chronic heart failure (HF). Prediction of which HF patients are most susceptible to SCD is difficult, and it is uncertain whether gene polymorphisms associated with HF outcomes are also linked to arrhythmic risk. METHODS: We evaluated 485 patients with chronic HF to see whether the angiotensin receptor type 1 (AT1R) 1166A/C or angiotensin-converting enzyme insertion/deletion (ACE I/D) polymorphisms were associated with a higher rate of ventricular arrhythmias requiring implantable cardioverter defibrillator (ICD) therapies over a 5-year period. We assessed the correlation between polymorphisms and antitachycardia pacing (ATP) and/or ICD shocks. RESULTS: Patients with AT1R 1166CC genotype had an increased rate of all events: ATP plus ICD shocks (P = .02). There was no association between ACE I/D genotype and ICD therapies. Furthermore, circulating levels of microRNA-155 (miR-155), a microRNA known to posttranscriptionally regulate AT1R expression, were significantly decreased in the CC compared with the AC and AA genotypes and were associated with ICD events. CONCLUSION: Our study suggests that the AT1R-1166CC genotype is associated with increased ICD therapies in patients with chronic HF, and the level of circulating miR-155 may be a potential marker for arrhythmic risk. Although these findings are novel, they will need replication and validation in larger cohorts of chronic HF patients. PMID- 22939043 TI - Aerobic exercise training delays cardiac dysfunction and improves autonomic control of circulation in diabetic rats undergoing myocardial infarction. AB - BACKGROUND: Exercise training (ET) has been used as a nonpharmacological strategy for treatment of diabetes and myocardial infarction (MI) separately. We evaluated the effects ET on functional and molecular left ventricular (LV) parameters as well as on autonomic function and mortality in diabetics after MI. METHODS AND RESULTS: Male Wistar rats were divided into control (C), sedentary-diabetic infarcted (SDI), and trained-diabetic infarcted (TDI) groups. MI was induced after 15 days of streptozotocin-diabetes induction. Seven days after MI, the trained group underwent ET protocol (90 days, 50-70% maximal oxygen consumption VO(2)max). LV function was evaluated noninvasively and invasively; baroreflex sensitivity, pulse interval variability, cardiac output, tissue blood flows, VEGF mRNA and protein, HIF1-alpha mRNA, and Ca(2+) handling proteins were measured. MI area was reduced in TDI (21 +/- 4%) compared with SDI (38 +/- 4%). ET induced improvement in cardiac function, hemodynamics, and tissue blood flows. These changes were probable consequences of a better expression of Ca(2+) handling proteins, increased VEGF mRNA and protein expression as well as improvement in autonomic function, that resulted in reduction of mortality in TDI (33%) compared with SDI (68%) animals. CONCLUSIONS: ET reduced cardiac and peripheral dysfunction and preserved autonomic control in diabetic infarcted rats. Consequently, these changes resulted in improved VO(2)max and survival after MI. PMID- 22939042 TI - Abnormalities of calcium handling proteins in skeletal muscle mirror those of the heart in humans with heart failure: a shared mechanism? AB - BACKGROUND: In the failing human heart, abnormalities of Ca(2+) cycling have been described, but there is scant knowledge about Ca(2+) handling in the skeletal muscle of humans with heart failure (HF). We tested the hypothesis that in humans with HF, Ca(2+) cycling proteins in skeletal muscle are abnormal. METHODS AND RESULTS: Ten advanced HF patients (50.4 +/- 3.7 years), and 9 age-matched controls underwent vastus lateralis biopsy. Western blot analysis showed that sarco(endo)plasmic reticulum Ca(2+)-ATPase (SERCA)2a, which is responsible for Ca(2+) sequestration into the sarcoplasmic reticulum(SR), was lower in HF versus controls (4.8 +/- 0.5 vs 7.5 +/- 0.8 AU, P = .01). Although phospholamban (PLN), which inhibits SERCA2a, was not different in HF versus controls, phosphorylation (SER16 site) of PLN, which relieves this inhibition, was reduced (0.8 +/- 0.1 vs 3.9 +/- 0.9 AU, P = .004). Dihydropyridine receptors were reduced in HF, (2.1 +/- 0.4 vs 3.6 +/- 0.5 AU, P = .04). We tested the hypothesis that these abnormalities of Ca(2+) handling protein content and regulation were due to increased oxidative stress, but oxygen radical scavenger proteins were not elevated in the skeletal muscle of HF patients. CONCLUSION: In chronic HF, marked abnormalities of Ca(2+) handling proteins are present in skeletal muscle, which mirror those in failing heart tissue. This suggests a common mechanism, such as chronic augmentation of sympathetic activity and autophosphorylation of Ca(2+) calmodulin-dependent-protein kinase II. PMID- 22939044 TI - Transthoracic echocardiography of the HeartWare left ventricular assist device. AB - BACKGROUND: The unique findings on transthoracic echocardiography of the HeartWare left ventricular assist device (LVAD) have not been previously described. METHODS AND RESULTS: HeartWare LVADs were implanted in 19 patients from May 2009 through December 2010; 152 comprehensive transthoracic echocardiograms (TTEs) performed postoperatively on these patients were retrospectively analyzed for device component visualization, inlet cannula/outflow conduit flow velocities, and imaging artifacts. The inlet cannula was adequately visualized in 66% of studies, incompletely visualized in 14%, and not visualized in 20%. Spectral Doppler interrogation of inlet cannula flow velocity was always uninterpretable due to artifact. Standard parasternal long axis and apical views always included the inlet cannula in the imaging sector, resulting in a prominent "waterfall" color Doppler artifact obscuring the mitral valve. Inclusion of the inlet cannula in the imaging sector also precluded spectral Doppler interrogation of the mitral valve owing to artifact. The outflow conduit was partially visualized and interrogated by spectral Doppler in 68% of studies, and the average measured peak flow velocity was 1.4 m/s (range 1.0-1.9 m/s). CONCLUSIONS: The HeartWare LVAD inlet cannula and outflow conduit are both readily visualized by TTE in a majority of patients. However, significant color and spectral Doppler artifacts occur when the inlet cannula is visualized in the imaging sector, necessitating routine off-axis Doppler interrogation of the mitral valve. PMID- 22939046 TI - Transnational health care: from a global terminology towards transnational health region development. AB - Within European cross-border health care, recent studies have identified several types of international patients. Within the Anglo-Saxon setting, the specific terminology of medical tourism is used. The analytical purpose of the paper is to resolve this semantic difference by suggesting an alternative terminology, 'transnational health care' that is understood as a 'context-controlled and coordinated network of health services'. For demand-driven trans-border access seekers and cross-border access searchers, there is a need to opt for regional health-policy strategies. For supply-driven sending context actors and receiving context actors, there would be organizational benefits to these strategies. Applying the terminology of trans-border access seekers, cross-border access searchers, sending context and receiving context actors results in a transnational patient mobility typology of twelve types of international patients, based on the criteria of geographical distance, cultural distance and searching efforts, public/private/no cover and private/public provision of health services. Finally, the normative purpose of the paper is to encourage the use of this terminology to promote a policy route for transnational health regions. It is suggested that the development of transnational health regions, each with their own medical and supportive service characteristics, could enhance governmental context-controlled decision power in applying sustainable health destination management. PMID- 22939045 TI - Prioritizing genetic variants for causality on the basis of preferential linkage disequilibrium. AB - To date, the widely used genome-wide association studies (GWASs) of the human genome have reported thousands of variants that are significantly associated with various human traits. However, in the vast majority of these cases, the causal variants responsible for the observed associations remain unknown. In order to facilitate the identification of causal variants, we designed a simple computational method called the "preferential linkage disequilibrium (LD)" approach, which follows the variants discovered by GWASs to pinpoint the causal variants, even if they are rare compared with the discovery variants. The approach is based on the hypothesis that the GWAS-discovered variant is better at tagging the causal variants than are most other variants evaluated in the original GWAS. Applying the preferential LD approach to the GWAS signals of five human traits for which the causal variants are already known, we successfully placed the known causal variants among the top ten candidates in the majority of these cases. Application of this method to additional GWASs, including those of hepatitis C virus treatment response, plasma levels of clotting factors, and late onset Alzheimer disease, has led to the identification of a number of promising candidate causal variants. This method represents a useful tool for delineating causal variants by bringing together GWAS signals and the rapidly accumulating variant data from next-generation sequencing. PMID- 22939047 TI - Challenges to orphan drugs access in Eastern Europe: the case of Bulgaria. AB - This article explores how an Eastern European country could deal with orphan drugs access, combining EU policies with its own national settings. The cross sectional observational study takes the total number of orphan drugs (61) available on EU level by March 2011, and then consecutively filters it through the requirements and criteria of relevant Bulgarian legislation on registration, pricing and reimbursement of medicinal products, obtaining the final number of accessible orphan drugs (16) in Bulgaria. The study further evaluates the average time period from market authorisation to positive reimbursement decision by Bulgarian health authorities (43+/-29.1 months). Access to orphan drugs should be provided on a reasonable and justified basis. Having in mind the limited availability of resources, it is not a question whether to prioritise rarity, but to create legitimate mechanisms for properly assessing orphan drugs' value and optimally using this value, according to the society's needs and views. The analysis identifies four important challenges to orphan drugs' access in Eastern Europe: (1) elaboration of new orphan drugs pricing approaches, (2) further interaction of cost-effectiveness analysis with medical criteria, (3) active introduction of epidemiological registries for rare diseases, and (4) research of societal preferences and raising public awareness. PMID- 22939048 TI - Impact of a team and leaders-directed strategy to improve nurses' adherence to hand hygiene guidelines: a cluster randomised trial. AB - BACKGROUND: Improving hand hygiene compliance is still a major challenge for most hospitals. Innovative approaches are needed. OBJECTIVE: We tested whether an innovative, theory based, team and leaders-directed strategy would be more effective in increasing hand hygiene compliance rates in nurses than a literature based state-of-the-art strategy. DESIGN AND SETTING: A cluster randomised controlled trial called HELPING HANDS was conducted in 67 nursing wards of three hospitals in the Netherlands. PARTICIPANTS: All affiliated nurses of the nursing wards. Wards were randomly assigned to either the team and leaders-directed strategy (30 wards) or the state-of-the-art strategy (37 wards). METHODS: The control arm received a state-of-the-art strategy including education, reminders, feedback and targeting adequate products and facilities. The experimental group received all elements of the state-of-the-art strategy supplemented with interventions based on social influence and leadership, comprising specific team and leaders-directed activities. Strategies were delivered during a period of six months. We monitored nurses' HH compliance during routine patient care before and directly after strategy delivery, as well as six months later. Secondary outcomes were compliance with each type of hand hygiene opportunity, the presence of jewellery and whether the nurses wore long-sleeved clothes. The effects were evaluated on an intention-to-treat basis by comparing the post-strategy hand hygiene compliance rates with the baseline rates. Multilevel analysis was applied to compensate for the clustered nature of the data using mixed linear modelling techniques. RESULTS: During the study, we observed 10,785 opportunities for appropriate hand hygiene in 2733 nurses. The compliance in the state-of-the-art group increased from 23% to 42% in the short term and to 46% in the long run. The hand hygiene compliance in the team and leaders-directed group improved from 20% to 53% in the short term and remained 53% in the long run. The difference between both strategies showed an Odds Ratio of 1.64 (95% CI 1.33-2.02) in favour of the team and leaders-directed strategy. CONCLUSIONS: Our results support the added value of social influence and enhanced leadership in hand hygiene improvement strategies. The methodology of the latter also seems promising for improving team performance with other patient safety issues. TRIAL REGISTRATION: ClinicalTrials.gov [NCT00548015]. PMID- 22939049 TI - Body mass index estimates using a categorical body weight variable: a cross sectional secondary data analysis. AB - BACKGROUND: Self-reported weight data have been considered questionable because of under- or over-reporting trends and stigma, especially among females. OBJECTIVES: This study aimed to evaluate the quality of self-reported categorical weight information used to determine body mass index (BMI) groups among females. DESIGN: Cross-sectional secondary data analysis. SETTINGS: This study used two datasets: a nurse survey of the Nurses Worklife and Health Study (NWHS) in the 2 US states, and the 2003-2004 National Health and Nutrition Examination Survey (NHANES). PARTICIPANTS: This analysis included 2203 female nurses in the NWHS and 606 female participants in the NHANES, all of whom aged 22-83 years and were currently employed with at least a college education. METHODS: BMI groups created using self-reported categorical weight data were compared to those derived from continuous weight responses and to the gold standard: scale measured weight data. RESULTS: When using the median values of each weight category, similar distributions of BMI groups were found to those obtained from continuous self reported responses and direct scaled measures of weight. The groupings derived from the BMI median estimates demonstrated good agreement with those obtained from the directly scaled BMI data and good criterion/construct validity. CONCLUSIONS: BMI-based weight groups derived from self-reported categorical weight responses demonstrated good psychometric properties when the median value was used to calculate the BMI, and may promote more complete responding, especially among women. PMID- 22939050 TI - Metabolic and degenerative disorders. PMID- 22939051 TI - Neurocutaneous syndromes. PMID- 22939052 TI - Cortical malformations. PMID- 22939053 TI - Epilepsy-associated brain tumors. PMID- 22939054 TI - Seizures after stroke. PMID- 22939055 TI - Posttraumatic epilepsy. PMID- 22939056 TI - Infection and inflammation. PMID- 22939057 TI - Hippocampal sclerosis. PMID- 22939058 TI - Natural course of epilepsies. PMID- 22939059 TI - Mechanisms of action of antiseizure drugs. PMID- 22939060 TI - Principles of drug treatment in adults. PMID- 22939061 TI - Principles of drug treatment in children. PMID- 22939062 TI - Antiepileptic drugs: advantages and disadvantages. PMID- 22939063 TI - Pharmacoresistance. PMID- 22939065 TI - Ketogenic diet. PMID- 22939064 TI - Gender issues. PMID- 22939066 TI - Status epilepticus in children. PMID- 22939067 TI - Status epilepticus in adults. PMID- 22939068 TI - Who is a surgical candidate? PMID- 22939069 TI - Preoperative evaluation in children for epilepsy surgery. PMID- 22939070 TI - Presurgical evaluation in adults: noninvasive. PMID- 22939071 TI - Invasive evaluation. PMID- 22939072 TI - Epilepsy neurosurgery in children. PMID- 22939073 TI - Surgery in adults: temporal resections. PMID- 22939074 TI - Lateral extratemporal resections in adults. AB - The presurgical evaluation in cases of extratemporal epilepsy is much less stereotypic than it is for mesial temporal lobe epilepsy. The finding of even a tiny structural lesion may be relevant but needs verification that it matches the seizure onset zone. Often invasive analysis is necessary to produce such evidence and to assess the relationship to adjacent eloquent cortex. Invasive analysis exposes the patient to an additional surgical procedure and to the morbidity associated with it. Therapeutic resections may comprise lesionectomy, topectomy, or lobectomy. Epileptogenic cortex that coincides with indispensable eloquent cortex can be treated with multiple subpial transections. A large variety of lesions may be epileptogenic, ranging from posttraumatic gliosis, over dysplasias and vascular malformations, to low-grade tumors. Intraoperative monitoring of adjacent brain functions under anesthesia or awake surgery may be used. Unless a circumscribed lesionectomy is possible, results in extratemporal epilepsy tend to be less favorable than in mesial temporal lobe epilepsy. PMID- 22939075 TI - Surgical management of medial extratemporal epilepsy. PMID- 22939076 TI - Epilepsy treatment in developing countries: drug treatment. PMID- 22939077 TI - Epilepsy surgery in developing countries. PMID- 22939078 TI - Neurostimulation for epilepsy. PMID- 22939079 TI - Innovative treatments for epilepsy: radiosurgery and local delivery. PMID- 22939080 TI - Social aspects of epilepsy and rehabilitation. PMID- 22939081 TI - Economic aspects of epilepsy. PMID- 22939084 TI - Genetic anomalies consistent with gonadal mosaicism encountered in a sexual assault-homicide. PMID- 22939085 TI - Atrial reverse remodeling: restitution of early tachycardia-induced alterations of atrial ion currents after termination of rapid atrial pacing in rabbits. AB - BACKGROUND AND PURPOSE: Studies report on the reversal of electrophysiological parameters altered by atrial tachycardia after cessation of the latter. However, there is no data concerning reversal of tachycardia-induced alterations of ion currents. Reverse remodeling of atrial ion currents (I(Ca,L), I(to), I(sus)) was studied in our rabbit model of tachycardia-induced electrical remodeling. METHODS: Three groups each with four animals were built. Rapid atrial pacing (600/min) for 5 days was applied in all groups. Thereafter, different time intervals (5, 10, 20 days) were awaited before the patch clamp experiments. RESULTS: Similar to I(to) remodeling in our model, within 20 days after cessation of atrial tachycardia, time course of I(to) reverse remodeling was also U-shaped. In contrast, there was no significant recovery of I(Ca,L) which was initially reduced by rapid atrial pacing. CONCLUSION: Relevance of a missing recovery of I(Ca,L) is likely as this current is closely linked with intracellular calcium handling. PMID- 22939086 TI - Dexamethasone-induced skeletal muscle atrophy was associated with upregulation of myostatin promoter activity. AB - Some recent studies showed that the glucocorticoid-induced muscle atrophy was associated with myostatin, a negative regulator of skeletal muscle. In this study, two experiments were performed to investigate the relationship between the glucocorticoid-induced ultrastructural changes in skeletal muscle and the myostatin gene expression, and to examine in vivo whether the glucocorticoid induced upregulation of myostatin gene expression is associated with the myostatin promoter activity. In the first experiment, the Kun-Ming mice with similar body weights were treated with high-dose dexamethasone. The results showed that high-dose dexamethasone caused myofibrillar disorganization or degradation and mitochondrial swelling or vacuolization, which were accompanied with the upregulation of myostatin expression. In the second experiment, the mice were treated with the wild-type or GRE (glucocorticoid response elements)-mutant myostatin promoter vector and high-dose dexamethasone alone or together with RU486. The results showed that the mutation of GRE motif resulted in the obvious decrease of the myostatin promoter activity, the high-dose dexamethasone promoted significantly the activity of the wild-type myostatin promoter but did not affect the activity of the GRE-mutant myostatin promoter, and RU486 inhibited the effect of dexamethasone on the wild-type myostatin promoter activity. Taken together, these results suggested that the dexamethasone-induced changes in ultrastructure of skeletal muscle were associated with the upregulation of myostatin gene expression and the upregulation was partly attributed to the binding of glucocorticoid receptor to GRE motifs along myostatin promoter. PMID- 22939087 TI - Incidence and genetic aspects of patellar luxation in Pomeranian dogs in Thailand. AB - There is a high incidence of patellar luxation (PL) in Pomeranian dogs from Thailand. DNA samples were collected from 59 dogs originating from 15 families. PL was present in 75% of the dogs with a male:female ratio of 1:1.95. Polymorphic microsatellites situated close to the COL6A1, COL6A3, COL9A1, COL9A2, and COL9A3 genes were analyzed for linkage to the phenotype. Sibling-pair analysis revealed that none of the collagen markers analyzed had a high non-parametric linkage score with the highest score, 1.56, for COL9A2 (P=0.07). The low LOD scores for these collagen genes indicated a non-involvement in the pathogenesis of PL in Pomeranians. An association study with a low density single nucleotide polymorphism (SNP) set indicated the possible involvement of a region on chromosome 7. The association of this region remained indicative when larger groups of 43 cases and 40 controls were compared (Chi square test P=0.01). PMID- 22939088 TI - Upregulation of articular synovial membrane MU-opioid-like receptors in an acute equine synovitis model. AB - Intra-articular injection of opioids provides analgesia in painful equine joints and MU-opioid receptors (MORs) have been demonstrated in equine synovial membranes. The aim of this study was to determine whether acute inflammatory conditions will lead to up-regulation of MOR in equine synovial membranes and whether anti-inflammatory treatment can prevent any such upregulation. In a two period, blinded, placebo-controlled randomised cross-over design, lipopolysaccharide (LPS, 1.0 ng) was injected into the left or right middle carpal joint of seven healthy ponies. Arthroscopy and synovial membrane biopsy was performed under general anaesthesia at baseline, 48 h (T48) and 672 h (T672) after LPS injection, with ponies assigned to receive either phenylbutazone (PBZ 2.2mg/kg PO BID) or placebo from 2h post-LPS. Ponies were scored for pain and lameness. Repeated synovial fluid samples were obtained and the degree of synovitis scored both macroscopically and microscopically. The density and staining pattern of MOR-like protein in synovial membrane biopsies over the course of the synovitis with or without PBZ treatment was evaluated using immunohistochemical techniques. LPS injection consistently induced a severe transient synovitis. Pain and lameness were significantly attenuated by treatment with PBZ. Up-regulation of MOR-like protein in the inflamed equine synovial membrane could be demonstrated in the placebo treated animals, but not in the PBZ treated animals overall, although there were no significant differences at any individual time-point between the two groups. It was concluded that acute inflammation will up-regulate MOR, while anti-inflammatory treatment will attenuate this response. PMID- 22939090 TI - Effect of low Fe3+ doping on characteristics, sonocatalytic activity and reusability of TiO2 nanotubes catalysts for removal of Rhodamine B from water. AB - Fe-doped titanium dioxide (TiO(2)) nanotubes were prepared using sol-gel followed by hydrothermal methods and characterized using various methods. The sonocatalytic activity was evaluated based on oxidation of Rhodamine B under ultrasonic irradiation. Iron ions (Fe(3+)) might incorporate into the lattice and intercalated in the interlayer spaces of TiO(2) nanotubes. The catalysts showed narrower band gap energies, higher specific surface areas, more active surface oxygen vacancies and significantly improved sonocatalytic activity. The optimum Fe doping at Fe:Ti=0.005 showed the highest sonocatalytic activity and exceeded that of un-doped TiO(2) nanotubes by a factor of 2.3 times. It was believed that Fe(3+) doping induced the formation of new states close to the valence band and conduction bands and accelerated the separation of charge carriers. Leached Fe(3+) could catalyze Fenton-like reaction and led to an increase in the hydroxyl radical (OH) generation. Fe-doped TiO(2) nanotubes could retain high degradation efficiency even after being reused for 4 cycles with minimal loss of Fe from the surface of the catalyst. PMID- 22939089 TI - Clinical and mental health correlates and risk factors for intimate partner violence among HIV-positive women in an inner-city HIV clinic. AB - BACKGROUND: Intimate partner violence (IPV) is a serious health concern for women in the United States, and HIV-positive women experience more frequent and severe abuse compared with HIV-negative women. The goals of this study were to determine the prevalence of IPV among HIV-infected women receiving care in an urban clinic and to determine the HIV clinical and mental health correlates of IPV among HIV positive women. METHODS: We conducted a cross-sectional survey among 196 women visiting an inner-city HIV clinic. Women were eligible if they were 18 years of age or older, English speaking, and received both HIV primary and gynecologic care at the clinic. The survey queried demographics, drug and alcohol history, depressive symptoms, and IPV, using the Partner Violence Scale. Antiretroviral therapy (ART), CD4 cell count, HIV-1 RNA level, and appointment adherence were abstracted from clinical records. FINDINGS: Overall, 26.5% of women reported experiencing IPV in the past year. There were no differences in sociodemographics, substance use, ART prescription, CD4 count, or HIV-1 RNA level between women who experienced IPV and those who had not. Women with mild and severe depressive symptoms were significantly more likely to report IPV compared with those without, with adjusted odds ratios of 3.4 and 5.5, respectively. Women who missed gynecologic appointments were 1.9 times more likely to report experiencing IPV. CONCLUSIONS: IPV is prevalent among women presenting for HIV care, and depressive symptoms or missed gynecologic appointments should prompt further screening for IPV. PMID- 22939091 TI - Enhanced reductive dechlorination of tetrachloroethene during reduction of cobalamin (III) by nano-mackinawite. AB - We demonstrated adsorption and reduction of cobalamin(III) (Co(III)) on nano mackinawite (nFeS) surface and their impact on reductive dechlorination of tetrachloroethene (PCE). The adsorption of Co(III) on the nFeS surface followed Langmuir isotherm and the reduction of Co(III) provided different reactive surface chemical species on nFeS surface. Content of Fe(2+)S on nFeS surface decreased (45.9-14.5%) as Fe(2+)S was oxidized to Fe(3+)S and Fe(3+)O coupled with the surface reduction of Co(III) to cobalamin(II) (Co(II)). S(2-) and S(n)(2 ) contents on the nFeS surface also decreased by 48.5% and 82.3%, respectively during the formation of sulfidecobalamin(II) (=S(2-)Co(II)) by the reactive surface sulfur. PCE was fully degraded in nFeSCo(III) suspension at pH 8.3 in 120 h. The dechlorination kinetic rate constant of PCE in the nFeSCo(III) suspension (k(FeSCo(III))=0.188+/-0.003 h(-1)) was 145 times greater than that in nFeS suspension, showing a potential role of =S(2-)Co(II) as an electron transfer mediator to shuttle electrons for the enhanced reductive dechlorination. PCE was transformed to acetylene and 1,3-butadiene as major products via reductive beta elimination and isomerization reactions, respectively. The experimental findings can provide basic knowledge to identify a reaction mechanism for the enhanced reductive dechlorination of chlorinated organic by biogeochemical reactions possibly observed in natural reducing environments. PMID- 22939092 TI - Influence of inoculation of arsenic-resistant Staphylococcus arlettae on growth and arsenic uptake in Brassica juncea (L.) Czern. Var. R-46. AB - An arsenic hypertolerant bacterium was isolated from arsenic contaminated site of West Bengal, India. The bacteria was identified as Staphylococcus arlettae strain NBRIEAG-6, based on 16S rDNA analysis. S. arlettae was able to remove arsenic from liquid media and possesses arsC gene, gene responsible for arsenate reductase activity. The biochemical profiling of the isolated strain showed that it had the capacity of producing indole acetic acid (IAA), siderophores and 1 aminocyclopropane-1-carboxylic acid (ACC) deaminase. Furthermore, an experiment was conducted to test the effect of S. arlettae inoculation on concurrent plant growth promotion and arsenic uptake in Indian mustard plant [Brassica juncea (L.) Czern. Var. R-46] when grown in arsenic spiked (5, 10 and 15 mg kg(-1)) soil. The microbial inoculation significantly (p<0.05) increased biomass, protein, chlorophyll and carotenoids contents in test plant. Moreover, as compared to the non-inoculated control, the As concentration in shoot and root of inoculated plants were increased from 3.73 to 34.16% and 87.35 to 99.93%, respectively. The experimental results show that the plant growth promoting bacteria NBRIEAG-6 has the ability to help B. juncea to accumulate As maximally in plant root, and therefore it can be accounted as a new bacteria for As phytostabilization. PMID- 22939093 TI - An alternative to killing? Treatment of reservoir hosts to control a vector and pathogen in a susceptible species. AB - Parasite-mediated apparent competition occurs when one species affects another through the action of a shared parasite. One way of controlling the parasite in the more susceptible host is to manage the reservoir host. Culling can cause issues in terms of ethics and biodiversity impacts, therefore we ask: can treating, as compared to culling, a wildlife host protect a target species from the shared parasite? We used Susceptible Infected Recovered (SIR) models parameterized for the tick-borne louping ill virus (LIV) system. Deer are the key hosts of the vector (Ixodes ricinus) that transmits LIV to red grouse Lagopus lagopus scoticus, causing high mortality. The model was run under scenarios of varying acaricide efficacy and deer densities. The model predicted that treating deer can increase grouse density through controlling ticks and LIV, if acaricide efficacies are high and deer densities low. Comparing deer treated with 70% acaricide efficacy with a 70% cull rate suggested that treatment may be more effective than culling if initial deer densities are high. Our results will help inform tick control policies, optimize the targeting of control methods and identify conditions where host management is most likely to succeed. Our approach is applicable to other host-vector-pathogen systems. PMID- 22939094 TI - Using animated computer-generated text and graphics to depict the risks and benefits of medical treatment. AB - OBJECTIVE: Conventional print materials for presenting risks and benefits of treatment are often difficult to understand. This study was undertaken to evaluate and compare subjects' understanding and perceptions of risks and benefits presented using animated computerized text and graphics. METHODS: Adult subjects were randomized to receive identical risk/benefit information regarding taking statins that was presented on an iPad (Apple Corp, Cupertino, Calif) in 1 of 4 different animated formats: text/numbers, pie chart, bar graph, and pictograph. Subjects completed a questionnaire regarding their preferences and perceptions of the message delivery together with their understanding of the information. Health literacy, numeracy, and need for cognition were measured using validated instruments. RESULTS: There were no differences in subject understanding based on the different formats. However, significantly more subjects preferred graphs (82.5%) compared with text (17.5%, P<.001). Specifically, subjects preferred pictographs (32.0%) and bar graphs (31.0%) over pie charts (19.5%) and text (17.5%). Subjects whose preference for message delivery matched their randomly assigned format (preference match) had significantly greater understanding and satisfaction compared with those assigned to something other than their preference. CONCLUSIONS: Results showed that computer-animated depictions of risks and benefits offer an effective means to describe medical risk/benefit statistics. That understanding and satisfaction were significantly better when the format matched the individual's preference for message delivery is important and reinforces the value of "tailoring" information to the individual's needs and preferences. PMID- 22939095 TI - Medicine and the humanities: joining two cultures. PMID- 22939096 TI - Bandemia with normal white blood cell counts associated with infection. AB - OBJECTIVE: Measuring immature white blood cell forms ("bands") has been considered clinically unnecessary. We performed this study to determine whether elevated band counts, with normal total white blood cells on admission, were associated with infection or in-hospital death. METHODS: We performed a retrospective cohort study including all patients admitted to the Christiana Care Health System 2-hospital, 1100-bed community-based academic health system in 2009 with normal white blood cells (3800-10,800 per mm(3)) on admission who had manual differentials performed. We defined our band groups as normal (<=10% bands and other immature cells), moderate (11%-19%), or high (>=20%). Via chart review, we ascertained vital signs and culture results for all patients with elevated bands and 407 randomly sampled patients with normal bands. Cultures likely to be contaminants were excluded. We used multivariable logistic regression to determine whether bandemia was predictive of significant positive cultures or death. RESULTS: Of 2342 patients, 167 (7.1%) had high bands and 205 (8.6%) had moderate bands. The mean white blood cell count was 7.5 cells/mm(3), with no difference among groups. Bandemia was associated with increased odds of having any significant positive culture (adjusted odds ratio [OR], 2.0, 95% confidence interval [CI], 1.3-3.1 for moderate bands; adjusted OR, 2.8, 95% CI, 1.7-4.3 for high bands) and having positive blood cultures (adjusted OR, 3.8, 95% CI, 2.0-7.2 for moderate bands; adjusted OR, 6.2, 95% CI, 3.2-11.8 for high bands). Patients with moderate or high bands also had increased odds of in-hospital death (adjusted OR, 3.2, 95% CI, 1.7-6.1; adjusted OR, 4.7, 95% CI, 2.4-9.0, respectively). CONCLUSIONS: Even with normal total white blood cells, patients with moderate and high bandemia on admission had significantly increased odds of having positive cultures, including blood cultures, and of in-hospital mortality. PMID- 22939097 TI - Characteristics, symptoms, and outcome of severe dysnatremias present on hospital admission. AB - OBJECTIVE: Dysnatremias are common in critically ill patients and associated with adverse outcomes, but their incidence, nature, and treatment rarely have been studied systematically in the population presenting to the emergency department. We conducted a study in patients presenting to the emergency department of the University of Bern. METHODS: In this retrospective case series at a university hospital in Switzerland, 77,847 patients admitted to the emergency department between April 1, 2008, and March 31, 2011, were included. Serum sodium was measured in 43,911 of these patients. Severe hyponatremia was defined as less than 121 mmol/L, and severe hypernatremia was defined as less than 149 mmol/L. RESULTS: Hypernatremia (sodium>145 mmol/L) was present in 2% of patients, and hyponatremia (sodium<135 mmol/L) was present in 10% of patients. A total of 74 patients had severe hypernatremia, and 168 patients had severe hyponatremia. Some 38% of patients with severe hypernatremia and 64% of patients with hyponatremia had neurologic symptoms. The occurrence of symptoms was related to the absolute elevation of serum sodium. Somnolence and disorientation were the leading symptoms in hypernatremic patients, and nausea, falls, and weakness were the leading symptoms in hyponatremic patients. The rate of correction did not differ between symptomatic and asymptomatic patients. Patients with symptomatic hypernatremia showed a further increase in serum sodium concentration during the first 24 hours after admission. Corrective measures were not taken in 18% of hypernatremic patients and 4% of hyponatremic patients. CONCLUSIONS: Dysnatremias are common in the emergency department. Hyponatremia and hypernatremia have different symptoms. Contrary to recommendations, serum sodium is not corrected more rapidly in symptomatic patients. PMID- 22939098 TI - [General anaesthesia and obstetric bleeding in caesarean section. One year's experience in a university hospital]. AB - INTRODUCTION: Obstetric haemorrhage is an important worldwide cause of morbidity and mortality. General anaesthesia for caesarean section is rarely used. Our goal is to analyse the incidence, causes and risk factors associated with general anaesthesia for caesarean section, and the prevalence of obstetric haemorrhage (HO), its risk factors and predictors of post-caesarean HO together with the use of blood in our hospital population. METHODS: A retrospective study was conducted on all caesarean section discharge reports from PACU in 2008. RESULTS: General anaesthesia was required in 12.4% of the patients. Epidural catheter failure as a cause of general anaesthesia was infrequent (2.8%) and within the recommended standards. CONCLUSIONS: The most frequent indications for caesarean section under general anaesthesia included mainly life-threatening emergencies, and the most important risk factors for general anaesthesia, including coagulation disorders, bleeding in the third trimester, foetal distress and severe pre-eclampsia. General anaesthesia is a risk factor for transfusion, as is abruptio placentae, placenta previa and pre-eclampsia. PMID- 22939099 TI - Ultrasound description of Pecs II (modified Pecs I): a novel approach to breast surgery. AB - OBJECTIVE: The Pecs block (pectoral nerves block) is an easy and reliable superficial block inspired by the infraclavicular block approach and the transversus abdominis plane blocks. Once the pectoralis muscles are located under the clavicle the space between the two muscles is dissected to reach the lateral pectoral and the medial pectoral nerves. The main indications are breast expanders and subpectoral prosthesis where the distension of these muscles is extremely painful. MATERIAL AND METHODS: A second version of the Pecs block is described, called "modified Pecs block" or Pecs block type II. This novel approach aims to block at least the pectoral nerves, the intercostobrachial, intercostals III-IV-V-VI and the long thoracic nerve. These nerves need to be blocked to provide complete analgesia during breast surgery, and it is an alternative or a rescue block if paravertebral blocks and thoracic epidurals failed. This block has been used in our unit in the past year for the Pecs I indications described, and in addition for, tumorectomies, wide excisions, and axillary clearances. RESULTS AND CONCLUSIONS: The ultrasound sequence to perform this block is shown, together with simple X-ray dye images and gadolinium MRI images to understand the spread and pathways that can explain the benefit of this novel approach. PMID- 22939100 TI - Management of favorable-risk patients with metastatic renal cell carcinoma: when to start and when to stop targeted therapy. AB - Targeted therapy has changed the treatment of metastatic renal cell carcinoma (mRCC). However, it is unclear if patients need to start systemic therapy immediately or if treatment can be deferred. Identification of the appropriate time to discontinue therapy is also uncertain. We reviewed treatment guidelines and trials evaluating targeted agents for mRCC to assess the evidence regarding commencing and discontinuing therapy for mRCC. Guidelines recommend that patients with mRCC receive targeted agents; however, they do not address when therapy should start. Risk factors based on Memorial Sloan-Kettering Cancer Center (MSKCC) or Heng criteria can be used to stratify patients. MSKCC prognostic factors include Karnofsky performance status (< 80%), high lactate dehydrogenase levels, low hemoglobin levels, high serum calcium levels, and time from diagnosis to start of therapy < 1 year. In patients with poor and intermediate risk (>= 3 and 1-2 factors, respectively) and/or with high tumor burden, targeted therapy should commence as soon as possible. In patients with MSKCC good-risk disease and few disease symptoms, active surveillance may be appropriate. Regular monitoring is required so that treatment can be initiated upon evidence of active disease. Second-line therapy is usually commenced after disease progression; however, because of the limitations of radiologic assessment of response to targeted therapies, other factors may need to be considered to guide decisions regarding stopping or switching therapy. These include scenarios such as a mixed response to therapy. For selected patients at favorable risk, active surveillance may be feasible; however, strict monitoring is required. PMID- 22939101 TI - Investigation of the chemopreventive potential of neem leaf subfractions in the hamster buccal pouch model and phytochemical characterization. AB - Chemoprevention by medicinal plants has evolved as a practical strategy to control the incidence of cancer. Azadirachta indica (neem) containing various bioactive components is a promising candidate for chemoprevention. The present study was undertaken to evaluate the chemopreventive efficacy of the bioactive subfractions ethyl acetate chloroform insoluble fraction (ECIF) and the methanol ethyl acetate insoluble fraction (MEIF) following activity-guided fractionation of neem leaf extract. Analysis of the mechanism of chemoprevention revealed multitargeted mode of action that involved modulation of xenobiotic-metabolizing enzymes, inhibition of cell proliferation, induction of mitochondrial apoptosis, and abrogation of NF-kappaB signaling. HP-TLC, GC-MS and LC-MS analyses indicated the presence of several polar phytochemical entities in the neem leaf subfractions that might be responsible for their potent chemopreventive efficacy. PMID- 22939103 TI - Daytime REM sleep in Parkinson's disease. AB - BACKGROUND: Previous studies have demonstrated both clinical and neurochemical similarities between Parkinson's disease (PD) and narcolepsy. The intrusion of REM sleep into the daytime remains a cardinal feature of narcolepsy, but the importance of these intrusions in PD remains unclear. In this study we examined REM sleep during daytime Maintenance of Wakefulness Testing (MWT) in PD patients. METHODS: Patients spent 2 consecutive nights and days in the sleep laboratory. During the daytime, we employed a modified MWT procedure in which each daytime nap opportunity (4 per day) was extended to 40 min, regardless of whether the patient was able to sleep or how much the patient slept. We examined each nap opportunity for the presence of REM sleep and time to fall asleep. RESULTS: Eleven of 63 PD patients studied showed 2 or more REM episodes and 10 showed 1 REM episode on their daytime MWTs. Nocturnal sleep characteristics and sleep disorders were unrelated to the presence of daytime REM sleep, however, patients with daytime REM were significantly sleepier during the daytime than those patients without REM. Demographic and clinical variables, including Unified Parkinson's Disease Rating Scale motor scores and levodopa dose equivalents, were unrelated to the presence of REM sleep. CONCLUSIONS: A sizeable proportion of PD patients demonstrated REM sleep and daytime sleep tendency during daytime nap testing. These data confirm similarities in REM intrusions between narcolepsy and PD, perhaps suggesting parallel neurodegenerative conditions of hypocretin deficiency. PMID- 22939104 TI - Kyphoplasty versus vertebroplasty in osteoporotic thoracolumbar spine fractures. Short-term retrospective review of a multicentre cohort of 127 consecutive patients. AB - BACKGROUND: Osteoporotic spine fractures induce a heavy burden in terms of both general health and healthcare costs. The objective of this multicentre study by the French Society for Spine Surgery (SFCR) was to compare outcomes after vertebroplasty and kyphoplasty in the treatment of osteoporotic thoracolumbar vertebral fractures. HYPOTHESIS: We hypothesised that differences existed between vertebroplasty and kyphoplasty, notably regarding operative time and reduction efficacy, from which criteria for patient selection might be inferred. MATERIAL AND METHODS: We conducted a retrospective multicentre review of 127 patients with Magerl Type A low-energy fractures after a fall from standing height between 2007 and 2010; 85 were managed with vertebroplasty and 42 with kyphoplasty. Age was not a selection criterion. We recorded pain intensity, time to management, operative time, kyphosis angle, wedge angle, cement leakage rate, and degree of cement filling. RESULTS: Operative time was 43 minutes with kyphoplasty and 24 minutes with vertebroplasty (P=0.0002). Both techniques relieved pain, with no significant difference. Kyphoplasty significantly improved the wedge angle, by +6 degrees , versus +2 degrees with vertebroplasty (P=0.002). With kyphoplasty, the volume injected was larger and cement distribution was less favourable. Leakage rates were similar. DISCUSSION: Despite the heterogeneity of our study, our data confirm the effectiveness of kyphoplasty in alleviating pain and decreasing deformities due to osteoporotic vertebral fractures. Vertebroplasty is a faster and less costly procedure that remains useful; no detectable clinical complications occur with vertebroplasty, which ensures better anchoring of the cement in the cancellous bone. PMID- 22939105 TI - Is patient self-assessment of flexion after TKR able to identify risk of manipulation under anaesthesia? AB - BACKGROUND: Patient self-assessment of postoperative knee flexion following knee replacement was introduced at our institution. This protocol had a dual objective: improve follow-up and act as an early indicator to identify patients at risk of requiring a manipulation under anaesthesia. The aim of our study was to audit the use of this patient self-assessment tool and evaluate whether these outcomes were being achieved. MATERIALS AND METHODS: A prospective audit of patients admitted for total knee replacements under the care of one orthopaedic consultant between April and October 2009. Participants were asked to measure and record daily maximum knee flexion whilst sitting, from discharge through to six week follow-up. Patients were advised to contact the arthroplasty team if flexion reduced by 10 degrees or more for three consecutive days. Patient's documented knee flexion was compared to that measured on discharge and at six weeks postoperatively by clinicians. RESULTS: Seventy-nine participants (82 knees) were included with 61 participants (64 knees) returning data for analysis (78% compliance rate). Comparison of patient and clinician measurements showed a mean difference of +2 degrees with limits of agreements from -12 degrees to +15 degrees . At a mean follow-up of six weeks maximum flexion (measured by clinician) was 99 degrees (95%CI 97 degrees , 102 degrees ) and 92% had a 90 degrees flexion or greater. During the audit period, six patients met the criteria to contact the arthroplasty team, however none of them followed this instruction. DISCUSSION: Patient self-assessment of knee flexion at home with a simple goniometer was accurate enough to be useful and 92% of patients reached 90 degrees maximum flexion at six weeks. However this self-assessment method was not successful as an early indicator to identify patients at risk of requiring a manipulation under anaesthesia. Future studies into alternative identifiers are required. LEVEL OF EVIDENCE: Level III. Investigating a diagnostic test. PMID- 22939106 TI - Surgical treatment of hindfoot inflammatory diseases: 107 arthrodesis. AB - INTRODUCTION: In rheumatoid diseases, hindfoot arthrodesis abolishes pain and corrects deformity. The choice between selective and double arthrodesis depends on whether the hindfoot malalignment is fixed or not. Indications for surgery are well codified. The various types of arthrodesis have never been assessed together on a large series. We here report a series that is substantial in numbers and in follow-up. MATERIALS AND METHODS: A continuous single-center retrospective study included patients with native hindfoot inflammatory disease treated by arthrodesis between 1996 and 2009. RESULTS: Around 80% of patients were followed up, for a mean 7 years. Fifty-four isolated talonavicular arthrodeses, 14 talocalcaneal arthrodeses and 39 double arthrodeses were performed. 96% of patients had rheumatoid arthritis and 4% spondylarthritis. 62% were completely pain-free at follow-up. The satisfaction rate was 91% and mean AOFAS score 70%. 6% of patients showed symptomatic non-union, mainly associated with talonavicular arthrodesis. In 22% of double arthrodeses and 11% of talonavicular arthrodeses, ankle status required surgical revision. In double arthrodesis, there was no correlation between hindfoot deviation and secondary deterioration in ankle status. Talocalcaneal arthrodesis was associated with radiologic hindfoot varus, both preoperatively and at follow-up. DISCUSSION: Non-union was the main complication in talonavicular arthrodesis. The rate of secondary ankle surgery was significantly elevated in double arthrodesis. These findings support Suckel's cadaver studies, which, in 2007, reported early deterioration in ankle status in double arthrodesis, due to mechanical overloading. Talocalcaneal arthrodesis proved reliable and simple, free of major complications and with a 100% satisfaction rate. CONCLUSION: Double arthrodesis showed the greatest benefit in terms of restoring foot architecture, but was associated with a higher rate of deterioration in ankle status. Preventive double arthrodesis is not recommended in case of isolated arthritis with reducible hindfoot malalignment. PMID- 22939107 TI - Axial rotation of the first metatarsal head in a normal population and hallux valgus patients. AB - HYPOTHESIS: Does metatarsal pronation exist and, if so, what is its impact? INTRODUCTION: Hallux valgus is a deformity associating angulation and a rotational component. The present study sought to investigate the nature and origin of the coronal plane displacement. MATERIALS AND METHODS: A prospective single-center radiological and anatomic study was conducted on 100 feet operated on for hallux valgus. Baseline X-ray determined the preoperative position of the 1st metatarsal head in the coronal plane. The range of motion (ROM) of the cuneometatarsal joint in pronation-supination was measured peroperatively. An anatomic study investigated possible diaphyseal torsion. RESULTS: Mean radiologic pronation in hallux valgus was 12.7 degrees (range, 0 degrees -40 degrees ). Cuneometatarsal rotational ROM was determined by adding peroperative ROM in pronation (mean, 9.3 degrees ; range, 0 degrees -30 degrees ) and in supination (mean, 8.7 degrees ; range, 0 degrees -20 degrees ). Intermetatarsal divergence showed no correlation with radiologic pronation or ROM in pronation. Radiologic pronation showed no correlation with peroperative ROM in pronation. Pronation of the metatarsal head was never observed without associated sesamoid pronation; the latter, however, was in some cases observed without the former. Twenty randomly selected metatarsal cadaver specimens from the anatomy laboratory of the University of Nice (France) showed diaphyseal torsion in 80% of cases, with the metatarsal head in neutral position or in supination with respect to the base. DISCUSSION: In hallux valgus, 1st ray pronation appears to be systematic, in contrast to the typical supination found in the general population. Metatarsal rotation is always associated with sesamoid rotation, whereas the converse is not the case: displacement of the sesamoids appears to displace the metatarsal head via the metatarsosesamoid ligaments. This "drive-belt" effect, however, varies in its mechanical properties and the transmission is imperfect and likely subject to progressive ligament stretching, so that head rotation does not exactly follow and may even become independent of the sesamoid displacement. Radiologic and clinical rotation thus do not match any longer. The anatomic study showed that, while diaphyseal torsion cannot be ruled out, the metatarsal pronation mainly derives from cuneometatarsal joint rotational instability, the evolution of which does not parallel lateral instability, no correlation being found between degree of varus and rotational instability. CONCLUSION: The present study found metatarsal pronation to be associated with hallux valgus, making a preoperative AP view useful; the underlying mechanism was generally cuneometatarsal instability. Although difficult to specify exactly without correlation between radiological and clinical data, any such pronation raises the question of whether replacing the metatarsal head on its sesamoid supports is sufficient to achieve stability in all planes, or whether on the contrary derotation should be associated to metatarsal valgization osteotomy to restore horizontal support. LEVEL OF EVIDENCE: Level IV. PMID- 22939108 TI - Methylprednisolone use is associated with endothelial cell activation following cardiac surgery. AB - BACKGROUND: The objective of this study was to investigate the effect of the perioperative use of methylprednisolone in medium doses on markers of endothelial cell activation in patients with coronary artery disease undergoing cardiopulmonary bypass. METHODS: In this prospective, double-blinded, placebo controlled, randomised study, 44 patients, undergoing a coronary artery bypass graft surgery received either methylprednisolone 20 mg/kg or a placebo intraoperatively after anaesthesia induction. The primary endpoint was endothelin 1, and secondary endpoints were E-selectin, interleukin (IL)-6 and IL-10, PaO(2)/FiO(2) coefficient, and microalbuminuria. RESULTS: Endothelin-1 was higher in the study group postoperatively at 10 min (p=0.0008), 2 h (p=0.02), 4 h (p=0.005), and 24 h (p=0.004). IL-6 was lower in the study group postoperatively at 2 h (p=0.03), 4 h (p=0.04), and 24 h (p<0.0001). IL-10 was higher in the study group postoperatively at 10 min (p<0.0001), 2 h (p=0.009), and 4 h (p=0.001). PaO(2)/FiO(2) was lower in the study group at 24 h after surgery (p=0.03). Microalbuminuria was similar in both groups. CONCLUSION: Despite an obvious anti inflammatory effect, methylprednisolone causes endothelial cell activation in patients undergoing cardiopulmonary bypass. PMID- 22939109 TI - The role of the preoperative screening of sleep apnoea by Berlin Questionnaire and Epworth Sleepiness Scale for postoperative atrial fibrillation. AB - BACKGROUND: Undiagnosed obstructive sleep apnoea (OSA) is a risk factor for postoperative atrial fibrillation (POAF) as well as for heart disease in general. This necessitates screening during preoperative assessment to facilitate the implementation of strategies to minimise the postoperative risk. Overnight polysomnography is the "gold standard" for the diagnosis of OSA but may be impractical during preoperative assessment, and so questionnaires may be useful for screening OSA. The Berlin Questionnaire (BQ) and Epworth Sleepiness Scale (ESS) are two of the widely prescreening tools for persons who may suffer from sleep disorders. Thus, screening for and treating OSA as part of the routine preoperative evaluation of cardiac surgical patients may be a useful strategy for preventing POAF. OBJECTIVE: We investigated whether there is an association between POAF and sleep disorders evaluated by the BQ and ESS in this settings. METHODS: In 73 consecutive patients undergoing CABG with cardiopulmonary bypass, preoperative clinical characteristics and operational data were examined. During the clinical evaluation, all patients answered the ESS and BQ voluntarily upon admission. Patients were continuously monitored for the occurrence of sustained postoperative AF while hospitalised. RESULTS: There were 33 patients with POAF and 40 patients without POAF as age- and gender-matched controls. The prevalence of high score in ESS was higher in POAF group compared to control group (52% vs 27%; p: 0.030). There was a higher prevalence of high risk for OSA in BQ in the POAF group (58% vs 34%; p: 0.044). CONCLUSION: Preoperative questionnaire-based diagnosis of OSA by the simple BQ and ESS may be useful in predicting POAF, and can be easily incorporated into routine screening of surgical patients undergoing CABG operation. PMID- 22939110 TI - Screening for determinants of self-care in patients with chronic heart failure. AB - Heart failure self-care is vital to achieving clinical stability and improved health outcomes. Yet despite the attention it has been given, in both research and clinical practice, effective self-care remains elusive. It is recognised that there are many patient factors that impact on attaining effective self-care skills. Systematic research is warranted to resolve the knowledge gap of how patients process information and develop the necessary self-care skills. In addition, sound screening tools are needed to assess factors that hinder the development of effective heart failure self-care skills. In this manner, education and support strategies can be applied on an individualised needs basis to enhance health outcomes. PMID- 22939111 TI - Still questioning the association between egg consumption and the risk of cardiovascular diseases. PMID- 22939112 TI - "Everything was spiraling out of control": experiences of anxiety in people with chronic obstructive pulmonary disease. AB - OBJECTIVE: This study sought to elicit and describe the first-hand experiences of anxiety in community patients with stable chronic obstructive pulmonary disease (COPD). Anxiety is common among patients with COPD. Clinical anxiety affects up to two thirds of patients, leading to reduced quality of life and physical functioning. There has been little research exploring the experiences of anxiety in patients with COPD, particularly in individuals with stable respiratory symptoms. METHODS: We interviewed 14 community patients with stable COPD and self reported symptoms of anxiety. Data were analyzed using thematic network analysis to develop basic, organizing, and global themes. RESULTS: Patients reported intense thoughts of fear, hopelessness, and confusion that were associated with the anxiety and panic attacks. Self-management was important, particularly self talk coping strategies. CONCLUSIONS: Unmanaged anxiety seems to be particularly distressing for patients with COPD. Self-management strategies can be highly effective in preventing and managing anxiety. PMID- 22939113 TI - Association of macrophage migration inhibitory factor gene polymorphisms with Behcet's disease in a Han Chinese population. AB - OBJECTIVE: To examine whether polymorphisms of the macrophage migration inhibitory factor (MIF) gene are associated with Behcet's disease (BD) in a Han Chinese population. DESIGN: Case-control study. PARTICIPANTS: A total of 600 patients with BD and 600 age-, sex-, and ethnically matched healthy controls were enrolled. METHODS: Two single nucleotide polymorphisms (SNPs), rs755622 and rs2096525, were genotyped using a polymerase chain reaction (PCR) restriction fragment length polymorphism assay. Allele and genotype frequencies were compared between patients and controls using the chi-square test. The expression of MIF was examined by real-time PCR. MAIN OUTCOME MEASURES: Association of SNPs in MIF with BD. RESULTS: Significantly decreased frequencies of the rs755622 genotype GG and G allele were found in patients with BD compared with controls. The frequencies of the genotype TT and T allele of the SNP rs2096525 were significantly lower in patients with BD compared with controls. Stratification analysis showed that the frequencies of rs755622 genotype GG in the oral aphthae, genital ulceration, or hypopyon subgroups were significantly decreased compared with controls (all P(c) < 0.05). A significantly lower frequency of the G allele of rs755622 was observed in the oral aphthae, genital ulceration, hypopyon, and arthritis subgroups compared with controls (P(c) < 0.05). The frequencies of the rs2096525 genotype TT and T alleles were also decreased in the oral aphthae, genital ulceration, hypopyon, and skin lesion subgroups compared with the controls (P(c) < 0.01). The results also showed that the expression of MIF mRNA in individuals carrying the CC genotype of rs755622 was 1.78- and 1.92-fold higher than in those carrying the GC or GG genotype. CONCLUSIONS: This study identified a strong association of the 2 SNPs, rs755622 and rs2096525, in the MIF gene with BD and suggests that the involvement of MIF in BD may be through regulation of its mRNA expression. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article. PMID- 22939116 TI - Magnetic and ultrasonic investigations on magnetite nanofluids. AB - Magnetite nanofluids of various concentrations have been prepared through co precipitation method. The structural and magnetic properties of the magnetic nanofluids have been analyzed which respectively revealed their face centered cubic crystal structure and super paramagnetic behavior. Ultrasonic investigations have been made for the nanofluids at different temperatures and magnetic fields. Open- and close-packed water structure is considered to explain the temperature effects. The inter particle interactions of surface modified nanomagnetite particle and the cluster formation are realized through the variations in ultrasonic parameters. PMID- 22939115 TI - Bcl-2 associated anthanogen-1 (Bag-1) expression and prognostic value in pancreatic head and periampullary cancer. AB - The expression of anti-apoptosis gene Bcl-2 associated anthanogen-1 (Bag-1), has been associated with outcome in several cancer types, however its prognostic role in pancreatic cancer is unknown. Aim was therefore to evaluate expression of Bag 1 in two anatomically closely related however prognostically different tumours, pancreatic head- and periampullary cancer and correlate expression with outcome. Bag-1 protein expression was studied by immunohistochemistry on original paraffin embedded tissue from 217 patients with microscopic radical resection (R0) of adenocarcinoma of the pancreatic head or periampullary region. Expression was assessed for associations with recurrence free- (RFS), cancer specific- (CSS), overall survival (OS) and conventional prognostic factors. Nuclear Bag-1 was present in 80% of tumours. In 40% Bag-1 resided in the cytosol, which was almost exclusively associated with nuclear expression. Nuclear Bag-1 protein was identified as an independent factor predicting a favourable outcome following radical resection of pancreatic head cancer. Eighteen percent of patients with nuclear Bag-1 were recurrence free and alive 5 years following surgery compared to none of the patients lacking expression. In periampullary cancer Bag-1 was not associated with outcome. In conclusion, Bag-1 was present in the majority of both pancreatic head- and periampullary cancers. However it was only identified as a discriminator of outcome in pancreatic head cancer. PMID- 22939114 TI - Optical coherence tomography grading reproducibility during the Comparison of Age related Macular Degeneration Treatments Trials. AB - OBJECTIVE: To report reading center reproducibility during grading of Stratus optical coherence tomography (OCT) (Carl Zeiss Meditec, Dublin, CA) images obtained during the Comparison of Age-Related Macular Degeneration Treatments Trials (CATT). DESIGN: Prospective, clinical trial. PARTICIPANTS: Independent reading teams reevaluated 270 OCT scans randomly sampled from the first 2 years of CATT enrollment. To assess temporal drift, a cohort of 23 scans submitted during the initial portion of the CATT study was longitudinally followed with serial reproducibility analysis. INTERVENTION: The CATT readers performed standardized grading of OCT images. A reader team, composed of 2 independent readers and a senior reader, evaluated each scan. Grading included the CATT OCT end points of total thickness at the foveal center point and intraretinal fluid (IRF), subretinal fluid (SRF), and subretinal pigment epithelium (RPE) fluid. Independent reading teams masked to the results of initial grading reevaluated scans to determine the reproducibility of qualitative grading and measurements. MAIN OUTCOME MEASURES: Categorical grading agreement was reported using percent agreement and kappa statistic, and measurement agreement was reported using intraclass correlations and paired differences. RESULTS: Reading center teams reproducibly graded IRF (percent agreement = 73%, kappa = 0.48; 95% confidence interval [CI], 0.38-0.58), SRF (percent agreement = 90%; kappa = 0.80; 95% CI, 0.73-0.87), and sub-RPE fluid (percent agreement 88%; kappa = 0.75; 95% CI, 0.67 0.83). For independent reading center team measurements of total thickness at the foveal center point, the intraclass correlation was 0.99 (95% CI, 0.99-0.99), and the mean paired difference between reading center teams was 4 MUm (95% limits of agreement, -55 to 47 MUm). There was no qualitative or quantitative grading drift. CONCLUSIONS: The standardized protocols used to evaluate OCT scans from the CATT study were reproducible. The methods used are suitable to monitor OCT imaging data from a large, neovascular age-related macular degeneration, interventional, multicenter study. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article. PMID- 22939117 TI - Engineering surface adhered poly(vinyl alcohol) physical hydrogels as enzymatic microreactors. AB - In this work, we characterize physical hydrogels based on poly(vinyl alcohol), PVA, as intelligent biointerfaces for surface-mediated drug delivery. Specifically, we assemble microstructured (MUS) surface adhered hydrogels via noncryogenic gelation of PVA, namely polymer coagulation using sodium sulfate (Na(2)SO(4)). We present systematic investigation of concentrations of Na(2)SO(4) as a tool of control over assembly of MUS PVA hydrogels and quantify polymer losses and retention within the hydrogels. For polymer quantification, we use custom-made PVA with single terminal thiol group in a form of mixed disulfide with Ellman's reagent which provides for a facile UV-vis assay of polymer content in coagulation baths, subsequent washes in physiological buffer, and within the hydrogel phase. Polymer coagulation using varied concentrations of sodium sulfate afforded biointerfaces with controlled elasticity for potential uses in investigating mechano-sensitive effects of mammalian cell culture. For surface mediated drug delivery, we propose a novel concept termed Substrate Mediated Enzyme Prodrug Therapy (SMEPT) and characterize MUS PVA hydrogels as reservoirs for enzymatic cargo. Assembled functional interfaces are used as matrices for cell culture and delivery of anticancer drug achieved through administration of a benign prodrug, its conversion into an active therapeutic within the hydrogel phase, and subsequent internalization by adhered hepatic cells. Taken together, the presented data contribute significantly to the development of novel matrices for surface-mediated drug delivery and other biomedical applications. PMID- 22939118 TI - Depressive symptoms and suicidal thoughts among former users of finasteride with persistent sexual side effects. AB - OBJECTIVE: Finasteride, a commonly prescribed medication for male pattern hair loss, has recently been associated with persistent sexual side effects. In addition, depression has recently been added to the product labeling of Propecia (finasteride 1 mg). Finasteride reduces the levels of several neuroactive steroids linked to sexual function and depression. This study assesses depressive symptoms and suicidal thoughts in former users of finasteride who developed persistent sexual side effects despite the discontinuation of finasteride. METHOD: In 2010-2011, former users of finasteride (n = 61) with persistent sexual side effects for >= 3 months were administered standardized interviews that gathered demographic information, medical and psychiatric histories, and information on medication use, sexual function, and alcohol consumption. All former users were otherwise healthy men with no baseline sexual dysfunction, chronic medical conditions, current or past psychiatric conditions, or use of oral prescription medications before or during finasteride use. A control group of men (n = 29), recruited from the community, had male pattern hair loss but had never used finasteride and denied any history of psychiatric conditions or use of psychiatric medications. The primary outcomes were the prevalence of depressive symptoms and the prevalence of suicidal thoughts as determined by the Beck depression inventory II (BDI-II); all subjects self-administered this questionnaire at the time of the interview or up to 10 months later. RESULTS: Rates of depressive symptoms (BDI-II score >= 14) were significantly higher in the former finasteride users (75%; 46/61) as compared to the controls (10%; 3/29) (P < .0001). Moderate or severe depressive symptoms (BDI-II score >= 20) were present in 64% (39/61) of the finasteride group and 0% of the controls. Suicidal thoughts were present in 44% (27/61) of the former finasteride users and in 3% (1/29) of the controls (P < .0001). CONCLUSIONS: Clinicians and potential users of finasteride should be aware of the potential risk of depressive symptoms and suicidal thoughts. The preliminary findings of this study warrant further research with controlled studies. PMID- 22939119 TI - Structure and organization of an avian haemosporidian assemblage in a Neotropical savanna in Brazil. AB - Studies on avian haemosporidia are on the rise, but we still lack a basic understanding of how ecological and evolutionary factors mold the distributions of haemosporidia among species in the same bird community. We studied the structure and organization of a local avian haemosporidian assemblage (genera Plasmodium and Haemoproteus) in the Cerrado biome of Central Brazil for 5 years. We obtained 790 blood samples from 54 bird species of which 166 (21%) were infected with haemosporidians based on molecular diagnostics. Partial sequences of the parasite cytochrome b gene revealed 18 differentiated avian haemosporidian lineages. We also analysed the relationship of life-history traits (i.e., nesting height, migration status, nest type, sociality, body mass, and embryo development period) of the 14 most abundant bird species with the prevalence of avian haemosporidia. It was found that host species that bred socially presented a higher prevalence of Haemoproteus (Parahaemoproteus) than bird species that bred in pairs. Thus, aspects of host behaviour could be responsible for differential exposure to vectors. The assemblage of avian haemosporidia studied here also confirms a pattern that is emerging in recent studies using molecular markers to identify avian haemosporidians, namely that many lineages are host generalists. PMID- 22939120 TI - Influence of buffer composition on the distribution of inkjet printed protein molecules and the resulting spot morphology. AB - Producing high quality protein microarrays on inexpensive substrates like polystyrene is a big challenge in the field of diagnostics. Using a non-contact inkjet printer we have produced microarrays on polystyrene slides for two different biotinylated biomolecules, bovine serum albumin (BSA-biotin) and immunoglobulin-G (IgG-biotin), and studied the influence of buffer (composition and pH) on the spot morphology and signal intensity. Atomic force microscopy revealed the morphological pattern of the (biomolecule) spots printed from phosphate buffer (pH 7.4), phosphate buffered saline (pH 7.4) and carbonate buffer (pH 9.6). The spots showed an irregular crust-like appearance when printed in phosphate buffered saline (pH 7.4), mainly due to the high NaCl content, whereas spots of biomolecules printed in carbonate buffer (pH 9.6) showed a smooth morphology. In addition, the rinsing of these dried spots led to the loss of a considerable fraction of the biomolecules, leaving behind a small fraction that is compatible with the (mono)layer. It was confirmed by confocal laser microscopy that the quality of the spots with respect to the uniformity and distribution of the biomolecules therein was superior when printed in carbonate buffer (pH 9.6) as compared to other buffer systems. Particularly, spotting in PBS yielded spots having a very irregular distribution and morphology. PMID- 22939121 TI - Label-free electrochemical aptasensor for sensitive thrombin detection using layer-by-layer self-assembled multilayers with toluidine blue-graphene composites and gold nanoparticles. AB - In the present study, toluidine blue-graphene (Tb-Gra) nanocomposites were prepared to design a Lable-free electrochemical aptasensor for highly sensitive detection of thrombin based on layer-by-layer (LBL) technology. The nanocomposites with excellent redox electrochemical activities were first immobilized on the gold nanoparticles (nano-Au) modified glassy carbon electrodes (GCE). Then, the LBL structure was performed by electrostatic adsorption between the positively charged Tb-Gra and negatively charged nano-Au, which formed {Tb Gra/nano-Au}(n) multilayer films for electroactive species enrichment and biomolecule immobilization. Subsequently, the thiolated thrombin binding aptamer (TBA) was assembled on the nano-Au surface through Au-S bond. In the presence of target thrombin (TB), the TBA on the multilayer could catch the thrombin onto the electrode surface, which resulted in a barrier for electro-transfer, leading to the decrease of the electrochemical signal of Tb-Gra nanocomposites. Under the optimal conditions, a wide detection range from 0.001 nM to 80 nM and a low detection limit of 0.33 pM (defined as S/N=3) for thrombin were obtained. In addition, the sensor exhibited excellent selectivity against other proteins. PMID- 22939122 TI - An insight into the adsorption and electrochemical processes occurring during the analysis of copper and lead in wines, using an electrochemical quartz crystal nanobalance. AB - Copper and lead in wine were quantified by anodic stripping voltammetry (ASV), performed onto the gold electrode of a piezoelectric quartz crystal. Both current or mass changes could be used as analytical signals, without a statistical difference in the results (alpha=0.05). However, the plot of mass vs. potential provided an in depth understanding of the electrochemical processes and allowed studying adsorption phenomena. Copper interaction with fructose is an example of a process which was not possible to ignore by observing the mass change on the gold electrode of the piezoelectric quartz crystal. PMID- 22939123 TI - Quantitative assessment of the contribution of high resolution mass spectrometric analysis to the reliability of compound confirmation. AB - Applications of high resolution mass spectrometry (HRMS) in food safety and residue analysis have increased remarkably over the last few years. The high resolution detection of ions reportedly enhances the assay selectivity but quantitative assessment of HRMS contribution to the assay selectivity has not yet been undertaken. We devised a method to assess the impact of instrument resolution on the probability that a spectral assignment to a given compound was made in error. The method allows for evaluating the quality of a spectral assignment based on resolution and the number of fragmentation stages. It thus provides a firm basis for comparing analytical methods performed on very different mass spectrometric instrumental platforms as well as in the context of the current regulatory framework. PMID- 22939124 TI - Calibration of potentiometric sensor arrays with a reduced number of standards. AB - In this paper a novel calibration procedure for the parameter determination of ion-selective electrodes used in an array is described. Commonly used procedures require a large number of standards to determine the parameters based on the Nicolsky-Eisenman model. The elaborated procedure reduces the number of standards to a minimum by using a standard containing a mixture of ions instead of a couple of pure standards. This paper presents a complete calibration procedure, which consists of designing the composition of the standards, parameter determination and verification of the calibration results. Comparison of the results obtained by the procedure presented with results obtained by the Two-Point Calibration and Separate Solution methods proves that the accuracies of both procedures are comparable. The outlined procedure can be applied in multicomponent analysers. PMID- 22939125 TI - Head space voltammetry: a novel voltammetric method for volatile organics and a case study for phenol. AB - Present paper describes the results of a novel method which combines the Head space (HS) preconcentration of the analyte on the electrode prior to the voltammetric analysis. Thereafter, the method was called HS-Voltammetry. The performance of the method was tested upon using an electroactive and volatile molecule, phenol molecule, which gives an oxidation peak at conventional electrodes. In this study, a glassy carbon electrode was modified with polypyrrole by electropolymerization and then, the electrode was placed over the solution in a sealed vial heated gently on a hotplate with a stirrer for phenol determination. By controlling the thickness of the polymeric coating and optimizing preconcentration parameters such as vial pH and temperature, stirring rate and exposure time, a very consistent (5.2% at 5.0*10(-7) M) fraction of the analyte can be extracted during a predetermined time. The oxidation peak current at 0.8 V depended linearly on the phenol concentration over a wide range (3 orders of magnitude). The detection limit was estimated as 7.0*10(-8) M at 60 degrees C (S/N=3) which is well below the limit set by the European Community for phenols in wastewaters (ca. 5*10(-6) M). The effect of other phenolic compounds was also examined and it was shown that head space preconcentration eliminated the interference of non-volatile phenolic acids studied. For volatile phenolic compounds, the selectivity can be maintained in cases when isolated peaks are obtained for each component. The proposed method has been applied successfully for the determination of phenol in artificial wastewater and recovery percentage was calculated as 93%. PMID- 22939126 TI - Green determination of the presence of volatile organic compounds in vehicle repair shops through passive sampling. AB - A simple, fast and green direct analytical methodology has been developed to evaluate the concentration level of volatile organic compounds (VOCs) in indoor areas of vehicle repair shops using membrane devices as passive samplers. VOCs retained in the samplers were directly determined without any sample pre treatment and avoiding the use of solvents by head space (HS) coupled to gas chromatography-mass spectrometry (GC-MS) in only 20 min. Benzene, toluene, tetrachloroethene, m,p-xylene and o-xylene were found at concentration levels from 0.1 to 11.2 mg m(-3). PMID- 22939127 TI - Analysis of renal stones by capillary isotachophoresis. AB - An analytical method for the determination of the composition of renal stones by capillary isotachophoresis with conductometric detection was developed. Using different leading/terminating electrolyte systems, the qualitative and quantitative analysis of organic compounds (urate, xanthate, oxalate) and inorganic ions (phosphate, Ca(2+), Mg(2+), Na(+), NH(4)(+)) species commonly present in mixed renal stones in three separate steps can be carried out with limits of detection about 10 MUmol/L. The developed method was validated by the analysis of real samples and can be used for urinary calculi classification. In addition, it was verified that this method can also be employed for the determination of the above mentioned analytes in some other samples (bones, teeth) concerning apatite biominerals (fluoro-, carbonate-, chloro-apatite). PMID- 22939128 TI - Improved chromatographic response function in HILIC analysis: application to mixture of antidepressants. AB - This paper presents exploration of chromatographic behavior in HILIC system by experimental design and improved chromatographic response function denoted as N(CRF)*. As a model mixture six antidepressants were chosen: selegiline, mianserine, sertraline, moclobemide, fluoxetine and maprotiline. Due to complexity of retention mechanisms in HILIC system, detailed examination of experimental space assessing the influence of important factors (acetonitrile content in the mobile phase, buffer concentration and pH of the mobile phase) and their interactions was done by applying 3(3) experimental design. N(CRF)* is developed and designed to be the only output of the system which simultaneously measures the separation of all the examined substances, the chromatographic run duration and the quality of the obtained peaks shape. It allowed objective estimation of overall chromatogram quality and excluded the arbitrary judgment in ambiguous situations. The applied function highlighted the influence of investigated factors on entire mixture and enabled identification of experimental regions where the chromatographic behavior was satisfactory. Applied experimental design strategy combined with N(CRF)* proved to be valuable assistance in HILIC separation of complex mixtures. PMID- 22939129 TI - Determination of organophosphorus pesticides using dispersive liquid-liquid microextraction combined with reversed electrode polarity stacking mode-micellar electrokinetic chromatography. AB - A rapid and sensitive method using two preconcentration techniques, dispersive liquid-liquid microextraction (DLLME) followed by reversed electrode polarity stacking mode (REPSM) was developed for the analysis of five organophosphorus pesticides (OPPs) by micellar electrokinetic chromatography (MEKC). Parameters that affect the efficiency of the extraction in DLLME and preconcentration by REPSM, such as the kind and volume of the extraction and disperser solvents, salt addition, sample matrix and injection time were investigated and optimized. Under the optimum conditions, the enrichment factors were obtained in the range from 477 to 635. The linearity of the method for parathion, azinphos and fenitrithion was in the range of 20-1000 ng mL(-1), and for malathion and diazinon in the range of 50-1000 ng mL(-1), with correlation coefficients (r(2)) ranging from 0.9931 to 0.9992. The limits of detecton (LODs) at a signal-to-noice ratio of 3 ranged from 3 to 15 ng mL(-1). The relative recoveries of five OPPs from water samples at spiking levels of 20 and 200 ng mL(-1) for parathion, azinphos and fenitrithion, and 50 and 500 ng mL(-1) for malathion and diazinon, were 69.5 103%. The proposed method provided high enrichment factors, good precision and accuracy with a short analysis time. PMID- 22939130 TI - Optical detection/collection of toxic Cd(II) ions using cubic Ia3d aluminosilica mesocage sensors. AB - Optical sensors for selective removal and detection of extremely toxic ions such as cadmium (Cd(II)) in aquatic samples were successfully fabricated via simple strategy. Aluminosilica-based network platforms are used as selective mesopore shape and size carriers in order to fabricate optical sensors through the direct functionalization of alpha, beta, gamma, and delta-tetrakis(1-methylpyridinium-4 yl)porphine rho-toluenesulfonate (TMPyP) moieties without any prior surface modification using silane or thiol agents. In turn, the key advantage of a heretical three-dimensional (3D) cubic Ia3d mesocage is the facile access of target ions such as ion transports and the high affinity responses of TMPyP receptor-Cd(II) analyte binding events, which result in the easy generation and transduction of optical signals even at the trace level of the Cd(II) ion. The optical sensor design-based aluminosilica cages enable the sensitive detection and selective removal of Cd(II) ions even at ultra-trace concentrations of 10( 10)mol/dm(3) with rapid response time (in minutes). This rational strategy is crucial to the development of optical mesocollectors (i.e., probe surface-mounted naked-eye ion-sensor strips) with highly selective Cd(II) ion removal from aqueous water. These new classes of optical mesocollectors exhibit long-term stability and reusability of deleterious Cd(II) ions, which makes them efficient for various analytical applications. PMID- 22939131 TI - Detection of trace levels of lead in aqueous liquids using extractive electrospray ionization tandem mass spectrometry. AB - A sensitive approach, based on semi-quantitative measurement of the characteristic fragments in multi-stage extractive electrospray ionization mass spectrometry (EESI-MS(n)), was developed for fast detection of trace levels of lead in aqueous liquids including mineral water, lake water, tap water, energy drinks, soft drinks, beer, orange juice, and tea. A disodium ethylene-diamine tetraacetic acid (EDTA) aqueous solution was electrosprayed to produce negatively charged primary ions which then intersected the neutral sample plume to generate anions of EDTA-Pb(II) complexes. The charged EDTA-Pb(II) complexes were characterized with multistage collision induced dissociation (CID) experiments. The limit of detection (LOD) using EESI-MS(3) was estimated to be at the level of 10(-13)g/mL for directly detecting lead in many of these samples. The linear dynamic range was higher than 2 orders of magnitude. A single sample analysis could be completed within 2 min with reasonable semi-quantitative performance, e.g., relative standard deviations (RSDs) for deionized water were 4.6-7.6% during 5 experimental runs (each of them had 10 repeated measurements). Coca-cola and Huiyuan orange juice, representative beverage samples with complex matrices, generated recovery rates of 91.5% and 129%, respectively. Our experimental data demonstrated that EESI-MS is a useful tool for the fast detection of lead in various solutions, and EESI-MS showed promises for fast screening of lead contaminated aqueous liquid samples. PMID- 22939132 TI - Preparation of a novel dual-function strong cation exchange/hydrophobic interaction chromatography stationary phase for protein separation. AB - We have explored a novel dual-function stationary phase which combines both strong cation exchange (SCX) and hydrophobic interaction chromatography (HIC) characteristics. The novel dual-function stationary phase is based on porous and spherical silica gel functionalized with ligand containing sulfonic and benzyl groups capable of electrostatic and hydrophobic interaction functionalities, which displays HIC character in a high salt concentration, and IEC character in a low salt concentration in mobile phase employed. As a result, it can be employed to separate proteins with SCX and HIC modes, respectively. The resolution and selectivity of the dual-function stationary phase were evaluated under both HIC and SCX modes with standard proteins and can be comparable to that of conventional IEC and HIC columns. More than 96% of mass and bioactivity recoveries of proteins can be achieved in both HIC and SCX modes, respectively. The results indicated that the novel dual-function column could replace two individual SCX and HIC columns for protein separation. Mixed retention mechanism of proteins on this dual-function column based on stoichiometric displacement theory (SDT) in LC was investigated to find the optimal balance of the magnitude of electrostatic and hydrophobic interactions between protein and the ligand on the silica surface in order to obtain high resolution and selectivity for protein separation. In addition, the effects of the hydrophobicity of the ligand of the dual-function packings and pH of the mobile phase used on protein separation were also investigated in detail. The results show that the ligand with suitable hydrophobicity to match the electrostatic interaction is very important to prepare the dual-function stationary phase, and a better resolution and selectivity can be obtained at pH 6.5 in SCX mode. Therefore, the dual-function column can replace two individual SCX and HIC columns for protein separation and be used to set up two-dimensional liquid chromatography with a single column (2DLC-1C), which can also be employed to separate three kinds of active proteins completely, such as lysozyme, ovotransferrin and ovalbumin from egg white. The result is very important not only to the development of new 2DLC technology with a single column for proteomics, but also to recombinant protein drug production for saving column expense and simplifying the process in biotechnology. PMID- 22939133 TI - Analysis of free fatty acids in Notopterygium forbesii Boiss by a novel HPLC method with fluorescence detection. AB - A new labeling reagent for fatty acids, 1-(9H-carbazol-9-yl) propan-2-yl methanesulfonate (CPMS), has been synthesized and successfully applied to the HPLC determination of fatty acids in traditional Chinese herb Notopterygium forbesii Boiss. The reaction of CPMS with fatty acids could proceed easily and quickly in the presence of K(2)CO(3) catalyst within 30 min. The derivatives exhibit excellent fluorescence property with excitation and emission wavelengths of 293 nm and 360 nm respectively. The 34 derivatives of fatty acids were separated on a BDS C8 reversed-phase column with gradient elution. Good linear correlations were observed for all fatty acids with correlation coefficients of >0.996. The detection limits at a signal-to-noise ratio of 3 were in the range 0.032-0.312 MUg g(-1). Free fatty acids in the roots, stem, leaves and petioles of N. forbesii Boiss from different places were analyzed by the developed method. This is the first time that the fatty acids composition of N. forbesii Boiss has been reported. This method also shows powerful potential for the trace analysis of fatty acids or other carboxylic acids from complex samples. PMID- 22939134 TI - A sensitive and efficient method for simultaneous trace detection and identification of triterpene acids and its application to pharmacokinetic study. AB - A sensitive and efficient method for simultaneous trace detection of seven triterpene acids was developed and validated for analysis of rat plasma samples. The required micro-sampling of only 20 MUL blood reduced the difficulty in blood collection and the injury to animal. The whole pretreatment procedure was more conveniently finished within 26 min through the application of the semi-automated derivatization extraction method to biological samples. Seven analytes were rapidly separated within 30 min on reversed-phase Akasil-C18 column and quantified by fluorescence detector. Online ion trap MS with atmospheric pressure chemical ionization (APCI) source was used for further identification. The novel application of artificial neural network (ANN) combined with genetic algorithm (GA) to optimization of derivatization was performed and compared with the classical response surface methodology (RSM). Optimal derivatization condition was validated by multi-criteria and nonparametric tests and used successfully to achieve the rather high sensitivity (limit of detection: 0.67-1.08 ng/mL). The limit of reactant concentration (LORC) special for derivatization was studied and the lower values (2.53-4.03 ng/mL) ensured the trace detection. Results of validation demonstrated the advantages for pharmacokinetic study, such as higher sensitivity, better accuracy, easier pretreatment and shorter run-time. Pharmacokinetic study of triterpene acids after oral administration of Salvia miltiorrhiza extract to mice was conducted for the first time. The present method provided more sensitive and efficient alternative for the medical detection of bioactive constituents from herbal extract in the biological liquid. PMID- 22939135 TI - Electrochemical nanoporous alumina membrane-based label-free DNA biosensor for the detection of Legionella sp. AB - An electrochemical nanoporous alumina membrane-based label free DNA biosensor is developed using 5'-aminated DNA probes immobilized into the nanochannels of alumina. Alumina nanoporous membrane-like structure is carved over platinum wire electrode of 76 MUm diameter dimension by electrochemical anodization. The hybridization of complementary target DNA with probe DNA molecules attached inside the nanochannels influences the pore size and ionic conductivity. Electrochemical biosensing signal is derived from only redox species Fe(CN)(6)(4 ) across single wire Pt electrode. The biosensors sensing mechanism relies on the monitoring of electrode's Faradaic current response toward redox species, Fe(CN)(6)(4-), which is sensitive toward the hybridization of complementary target with probe DNA immobilized into the alumina nanochannels. The biosensor demonstrates wide linear range over 7 orders of magnitude with ultrasensitive detection limit 3.1*10(-13) M for the quantification of ss 21 mer DNA sequence and selectively differentiates the complementary sequence from target sequences with single base mismatch (MM1) and triple bases mismatch (MM3) of different strain of Legionella sp. Its applicability is also challenged against real time Legionella pneumophila genomic DNA sample derived from the asymmetric PCR method. PMID- 22939136 TI - Photometric determination of phosphorus in mineralized biodiesel using a micro flow-batch analyzer with solenoid micro-pumps. AB - A method for the determination of phosphorus in mineralized biodiesel using a micro-flow-batch analyzer (MUFBA) with solenoid micro-pumps was proposed. The samples were mineralized using an ashing procedure at 550 degrees C followed by dissolution of the residue. The determination of phosphorus was performed by employing the well-known molybdenum blue method. The measures of the absorbance were performed at 850 nm using an InfraRed LED integrated into the MUFBA. Comparing with the reference method, no statistically significant differences were observed when applying the paired t-test at a 95% confidence level. Recovery study shows results between 97.9% and 105.8%. The proposed microsystem using solenoid micro-pumps presented satisfactory robustness and high sampling rate (190 h(-1)), with satisfactory reproducibility (relative standard deviation <4.5%, n=3), low reagents consumption (32 MUL per analysis) and cost to build the device. Moreover, MUFBA presents limit of detection (0.014 mg Kg(-1)), precision and accuracy compatible with the biodiesel regulations that establish a maximum concentration of 10 mg Kg(-1) (Brazil, USA, EU), suggesting that it is a good alternative for the determination of phosphorus in biodiesel. PMID- 22939137 TI - Systematic comparisons of various spectrophotometric and colorimetric methods to measure concentrations of protein, peptide and amino acid: detectable limits, linear dynamic ranges, interferences, practicality and unit costs. AB - There is limited and inconclusive information regarding detectable limits and linear dynamic ranges of various quantitative protein assays. We thus performed systematic comparisons of seven commonly used methods, including direct spectrophotometric quantitation at lambda205 and lambda280 nm (A205 and A280, respectively), bicinchoninic acid (BCA), Biuret, Bradford, Lowry and Ninhydrin methods. Purified BSA, porcine kidney extract, tryptic digested peptides derived from purified BSA, and glycine, were used as representative purified protein, complex protein mixture, peptide and amino acid, respectively. Bradford method was the most sensitive assay (LOD=0.006 mg/ml) and had the widest range of detectability (LOD-UOD=0.006-100mg/ml) for purified protein and complex protein mixture. For peptide, A205, A280, Lowry and Ninhydrin methods had a comparable LOD (0.006 mg/ml), but Ninhydrin method had the widest detectability range (LOD UOD=0.006-100mg/ml). For amino acid, A205 and Ninhydrin methods had a comparable LOD (0.006 mg/ml), but A205 had a wider detectability range (LOD-UOD=0.006-6.250 mg/ml). Biuret method offered the widest linear dynamic range for purified protein and complex protein mixture (0.391-100mg/ml), A280 offered the widest linear dynamic range for peptide (0.024-6.250 mg/ml), and Ninhydrin method offered the widest linear dynamic range for amino acid (0.024-0.195 mg/ml). Both Laemmli's and 2-D lysis buffers had dramatic interfering effects on all assays. Concerning the practicality and unit costs, A205 and A280 were the most favorable. Among the colorimetric methods, Bradford method consumed the least amount of samples and shortest analytical time with the lowest unit cost. These are the most extensive comparative data of commonly used quantitative protein assays that will be useful for selecting the most suitable method for each study. PMID- 22939138 TI - Biosensor based on atemoya peroxidase immobilised on modified nanoclay for glyphosate biomonitoring. AB - A biosensor based on atemoya peroxidase immobilised on modified nanoclay was developed for the determination of glyphosate by the enzyme inhibition method. The inhibitor effect of the biocide results in a decrease in the current response of the hydroquinone that was used as a phenolic substrate to obtain the base signal. The biosensor was constructed using graphite powder, multiwalled carbon nanotubes, peroxidase immobilised on nanoclay and mineral oil. Square-wave voltammetry was utilised for the optimisation and application of the biosensor, and several parameters were investigated to determine the optimum experimental conditions. The best performance was obtained using a 0.1 mol L(-1) phosphate buffer solution (pH 7.0), 1.9*10(-4) mol L(-1) hydrogen peroxide, a frequency of 30 Hz, a pulse amplitude of 50 mV and a scan increment of 4 mV. The glyphosate concentration response was linear between 0.10 and 4.55 mg L(-1) with a detection limit of 30 MUg L(-1). The average recovery of glyphosate from spiked water samples ranged from 94.9 to 108.9%. The biosensor remained stable for a period of eight weeks. PMID- 22939139 TI - CdS/TiO2-fluorescein isothiocyanate nanoparticles as fluorescence resonance energy transfer probe for the determination of trace alkaline phosphatase based on affinity adsorption assay. AB - The CdS/TiO(2)-fluorescein isothiocyanate (FITC) luminescent nanoparticles (CdS/TiO(2)-FITC) with the particle size of 20 nm have been synthesized by sol gel method. CdS/TiO(2)-FITC could emit the fluorescence of both FITC and CdS/TiO(2). The fluorescence resonance energy transfer (FRET) occurred between the donor CdS/TiO(2) and the acceptor FITC in the CdS/TiO(2)-FITC. Taking advantages of the excellent characteristics of FRET, a new CdS/TiO(2)-FITC FRET labeling reagent and a CdS/TiO(2)-FITC-wheat germ agglutinin (CdS/TiO(2)-FITC WGA) fluorescent probe have been developed. The FRET occurring between the donor CdS/TiO(2) and the acceptor FITC in the labelled product CdS/TiO(2)-FITC-WGA-AP, formed in the affinity adsorption reaction between the WGA in this CdS/TiO(2) FITC-WGA fluorescent probe and alkaline phosphatase (AP), sharply enhanced the fluorescence signal of FITC and quench the fluorescence signal of CdS/TiO(2). Moreover, the DeltaF (the change of the fluorescence signal) of FITC and CdS/TiO(2) were proportional to the content of AP, respectively. Thus, a new method that CdS/TiO(2)-fluorescein isothiocyanate nanoparticles for the determination of trace AP based on FRET-affinity adsorption assay has been established. The limit of quantification (LOQ) of the method was 1.3*10(-17) g AP mL(-1) for CdS/TiO(2) and 1.1*10(-17) g AP mL(-1) for FITC, respectively. This sensitive, rapid, high selective and precise method has been applied to the determination of AP in human serum and the prediction of human disease with the results agreed well with enzyme-linked immunosorbent assay (ELISA) in Zhangzhou Municipal Hospital of Fujian Province. Simultaneously, the reaction mechanism for the determination of AP was also discussed. PMID- 22939140 TI - In-situ metathesis reaction combined with ultrasound-assisted ionic liquid dispersive liquid-liquid microextraction method for the determination of phenylurea pesticides in water samples. AB - A novel microextraction technique, named in-situ metathesis reaction, combined with ultrasound-assisted ionic liquid dispersive liquid-liquid microextraction was developed for the determination of five phenylurea pesticides (i.e., diuron, diflubenzuron, teflubenzuron, flufenoxuron, and chlorfluazuron) in environmental water samples. In the developed method, 360 MUL LiNTf(2) aqueous solution (0.162 g/mL) was added to the sample solution containing a small amount of [C(6)MIM]Cl (0.034 g) to form a water-immiscible ionic liquid, [C(6)MIM]NTf(2), as extraction solution. The mixed solutions were placed in an ultrasonic water bath at 150 W for 4min and centrifuged at 3500 rpm for 10 min to achieve phase separation. After centrifugation, fine droplets of the extractant phase settled to the bottom of the centrifuge tube and were directly injected into the high-performance liquid chromatography system for analysis. The quantity of [C(6)MIM]Cl, the molar ratio of [C(6)MIM]Cl and LiNTf(2), ionic strength, ultrasound time, and centrifugation time, were optimized using a Plackett-Burman design. Significant factors obtained were optimized by employing a central composite design. The optimized technique provides good repeatability (RSD 2.4 to 3.5%), linearity (0.5 MUg/L to 500 MUg/L), low LODs (0.06 MUg/L to 0.08 MUg/L) and great enrichment factor (244 to 268). The developed method can be applied in routine analysis for the determining of phenylurea pesticides in environmental samples. PMID- 22939141 TI - Flow electrochemical analyses of zinc by stripping voltammetry on graphite felt electrode. AB - A flow sensor for trace analysis of zinc, using graphite felt as working electrode is reported here. A flow cell, well-adapted to 3-D porous electrodes and capable to do both the preconcentration step at a cathodic potential and the stripping of the zinc was successfully developed. It was demonstrated that this cell allows to obtain better electrochemical signals for Zn(2+) compared to a standard three-electrodes cell and that the percolation during accumulation increases the kinetics of electrodeposition. The influence on Zn(2+) signal of the deposition potential, the time of deposition and the flow rate was studied. The resulting sensor shows a linear response towards Zn(2+) with a linear range of 10(-6)-10(-4)M and a limit of detection of 5*10(-7) M for an analysis time of 5 min. The interferences study showed that the Cr(3+), Pb(2+), Cd(2+) ions have a small effect on the Zn electrochemical signal, whereas Fe(3+), Cu(2+), Co(2+) and Ni(2+) ions strongly influence it. The electrode was tested on real samples (tap water spiked with Zn(2+), food supplement) with a good recovery by applying the standard addition method. PMID- 22939142 TI - Inter-laboratory exercise on antibiotic drugs analysis in aqueous samples. AB - An inter-laboratory exercise was organized under the PHARMAS EU project, by the Advanced School of Public Health (EHESP), in order to evaluate the performances of analytical methods for the measurement of antibiotics in waters (surface and tap). This is the first time such an exercise on antibiotics has been organized in Europe, using different kinds of analytical methods and devices. In this exercise thirteen laboratories from five countries (Canada, France, Italy, the Netherlands and Portugal) participated, and a total number of 78 samples were distributed. During the exercise, 2 testing samples (3 bottles of each) prepared from tap water and river water, respectively, spiked with antibiotics, were sent to participants and analyzed over a period of one month. A final number of 77 (98.7%) testing samples were considered. Depending on substances studied by each participant, 305 values in duplicate were collected, with the results for each sample being expressed as the target concentration. A statistical study was initiated using 611 results. The mean value, standard deviation, coefficient of variation, standard uncertainty of the mean, median, the minimum and maximum values of each series as well as the 95% confidence interval were obtained from each participant laboratory. In this exercise, 36 results (6% of accounted values) were outliers according to the distribution over the median (box plot). The outlier results were excluded. In order to establish the stability of testing samples in the course of the exercise, differences between variances obtained for every type of sample at different intervals were evaluated. The results showed no representative variations and it can be considered that all samples were stable during the exercise. The goals of this inter-laboratory study were to assess results variability when analysis is conducted by different laboratories, to evaluate the influence of different matrix samples, and to determine the rate at which participating laboratories successfully completed the tests initiated. PMID- 22939143 TI - Determination of alcohol sulfates in wastewater treatment plant influents and effluents by gas chromatography-mass spectrometry. AB - In the present paper, we developed an accurate method for the analysis of alcohol sulfates (AS) in wastewater samples from wastewater treatment plant (WWTP) influents and effluents. Although many methodologies have been published in the literature concerning the study of anionic surfactants in environmental samples, at present, the number of analytical methodologies that focus in the determination of AS by gas chromatography in the different environmental compartments is limited. The reason for this is that gas chromatography-mass spectrometry (GC-MS) technique requires a previous hydrolysis reaction followed by derivatization reactions. In the present work, we proposed a new procedure in which the hydrolysis and derivatization reactions take place in one single step and AS are directly converted to trimethylsilyl derivatives. The main factors affecting solid-phase extraction (SPE), hydrolysis/derivatization and GC-MS procedures were accurately optimised. Quantification of the target compounds was performed by using GC-MS in selected ion monitoring (SIM) mode. The limits of detection (LOD) obtained ranged from 0.2 to 0.3 MUg L(-1), and limits of quantification (LOQ) from 0.5 to 1.0 MUg L(-1), while inter- and intra-day variability was under 5%. A recovery assay was also carried out. Recovery rates for homologues in spiked samples ranged from 96 to 103%. The proposed method was successfully applied for the determination of anionic surfactants in wastewater samples from one WWTP located in Granada (Spain). Concentration levels for the homologues up to 39.4 MUg L(-1) in influent and up to 8.1 MUg L(-1) in effluent wastewater samples. PMID- 22939144 TI - Non-destructive crystal size determination in geological samples of archaeological use by means of infrared spectroscopy. AB - The determination of crystal size of chert samples can provide suitable information about the raw material used for the manufacture of archeological items. X-ray diffraction (XRD) has been widely used for this purpose in several scientific areas. However, the historical value of archeological pieces makes this procedure sometimes unfeasible and thus, non-invasive new analytical approaches are required. In this sense, a new method was developed relating the crystal size obtained by means of XRD and infrared spectroscopy (IR) using partial least squares regression. The IR spectra collected from a large amount of different geological chert samples of archeological use were pre-processed following different treatments (i.e., derivatization or sample-wise normalization) to obtain the best regression model. The full cross-validation was satisfactorily validated using real samples and the experimental root mean standard error of precision value was 165 A whereas the average precision of the estimated size value was 3%. The features of infrared bands were also evaluated in order to know the background of the prediction ability. In the studied case, the variance in the model was associated to the differences in the characteristic stretching and bending infrared bands of SiO(2). Based on this fact, it would be feasible to estimate the crystal size if it is built beforehand a chemometric model relating the size measured by standard methods and the IR spectra. PMID- 22939145 TI - Use of X-ray diffraction technique and chemometrics to aid soil sampling strategies in traceability studies. AB - Aim of this work is to assess the potentialities of the X-ray powder diffraction technique as fingerprinting technique, i.e. as a preliminary tool to assess soil samples variability, in terms of geochemical features, in the context of food geographical traceability. A correct approach to sampling procedure is always a critical issue in scientific investigation. In particular, in food geographical traceability studies, where the cause-effect relations between the soil of origin and the final foodstuff is sought, a representative sampling of the territory under investigation is certainly an imperative. This research concerns a pilot study to investigate the field homogeneity with respect to both field extension and sampling depth, taking also into account the seasonal variability. Four Lambrusco production sites of the Modena district were considered. The X-Ray diffraction spectra, collected on the powder of each soil sample, were treated as fingerprint profiles to be deciphered by multivariate and multi-way data analysis, namely PCA and PARAFAC. The differentiation pattern observed in soil samples, as obtained by this fast and non-destructive analytical approach, well matches with the results obtained by characterization with other costly analytical techniques, such as ICP/MS, GFAAS, FAAS, etc. Thus, the proposed approach furnishes a rational basis to reduce the number of soil samples to be collected for further analytical characterization, i.e. metals content, isotopic ratio of radiogenic element, etc., while maintaining an exhaustive description of the investigated production areas. PMID- 22939146 TI - Effects of grinding and shaking on Cd, Pb and Zn distribution in anthropogenically impacted soils. AB - The effects of grinding size and shaking process on the results of Cd (cadmium), Pb (lead) and Zn (zinc) distribution measurements three agricultural and three kitchen garden soils highly contaminated by past atmospheric fallout of two lead and zinc smelters in northern France were studied. The physico-chemical parameters and pseudo-total concentration of metals within these soils were determined. The fractionation of metals was performed in triplicate, using the procedure recommended by the Standards, Measurements and Testing program (SM&T), on each air-dried soil sample, ground to pass through 2-mm, 0.315-mm and 0.250-mm sieves and using a reciprocating or rotary shaker. The samples were analysed by flame or electrothermal absorption atomic spectrometry using a self-reversal background system. For both shaking processes, the grinding size had no effect on the fractionation of metals in contaminated agricultural soils. In contrast, using a reciprocating shaker, the fractionation of metals in the kitchen garden samples sieved at <2mm was so different that in the samples prepared to pass through the 0.315-mm and 0.250-mm sieves. Therefore changes (use of a 50 mL graduated polypropylene centrifuge tube, evaporation of the solution to a fixed volume in step 3 and the use of an automatic shaking heating bath) were made to the initial procedure and a rotary shaker was used to improve the suspension of the soil samples during extraction. For all grinding sizes, the fractionation of the three metals contained in the contaminated kitchen garden soil samples was successfully achieved. Nevertheless, some discrepancies from samples sieved at <2mm were obtained. On the other hand, it is worth noting that the effect of the type of shaker on the distribution of metal depended on the soil and the grinding size. From an analytical point of view, precision and trueness were improved after optimisation of the procedure for all sequential extraction procedure steps. The best results were obtained for samples sieved at <0.250 mm. Similar trends were obtained using the CRM BCR((r))-701 certified material. All the results showed that optimisation of the sequential extraction procedure could be adopted for the Cd-, Pb- and Zn-partitioning in contaminated kitchen garden soils with high-level anthropogenic sources. PMID- 22939147 TI - Dispersive liquid-liquid microextraction combined with microvolume spectrophotometry to turn green the 5530 APHA standard method for determining phenols in water and wastewater. AB - In this work, a new method based on the combination of dispersive liquid-liquid microextraction (DLLME) with microvolume spectrophotometry has been developed as a greener and miniaturized alternative to the 5530 APHA standard method for determining phenols in water and wastewater. The method relies on the oxidative coupling of phenols with 4-aminoantipyrine (4-AAP). In order to preconcentrate the dye formed, the classical liquid-liquid extraction used in the 5530 APHA method (involving 500 mL of sample and 50 mL of trichloromethane) has been replaced by DLLME (with 5 mL of sample, 50 MUL of trichloromethane and 200 MUL of acetonitrile). After optimization, the method yielded limits of detection and quantification (0.8 and 2.5 MUg L(-1), respectively) that were comparable with those obtained by the 5530 APHA standard method. Repeatability, expressed as relative standard deviation, was 5.2% (N=6), and the enrichment factor (EF) was 700. The proposed method was applied to the determination of phenols in different water samples and a wastewater with recoveries in the range 90-99%. The greenness profile was established in accordance with the suggestions made by the NEMI (National Environmental Methods Index). The absence of PBT (persistent bioaccumulative and toxic chemicals) and corrosive reagents and a drastic reduction of generated wastes can be emphasized. PMID- 22939148 TI - Use of solid phase extraction for the sequential injection determination of alkaline phosphatase activity in dynamic water systems. AB - In this work, a solid phase extraction sequential injection methodology for the determination of alkaline phosphatase activity in dynamic water systems was developed. The determination of the enzymatic activity was based on the spectrophotometric detection of a coloured product, p-nitrophenol, at 405 nm. The p-nitrophenol is the product of the catalytic decomposition of p-nitrophenyl phosphate, a non-coloured substrate. Considering the low levels expected in natural waters and exploiting the fact of alkaline phosphatase being a metalloprotein, the enzyme was pre-concentrated in-line using a NTA Superflow resin charged with Zn(2+) ions. The developed sequential injection method enabled a quantification range of 0.044-0.441 unit mL(-1) of enzyme activity with a detection limit of 0.0082 unit mL(-1) enzyme activity (1.9 MUmol L(-1) of pNP) and a determination rate of 17 h(-1). Recovery tests confirmed the accuracy of the developed sequential injection method and it was effectively applied to different natural waters and to plant root extracts. PMID- 22939149 TI - Accurate quantification of the mercapturic acids of acrylonitrile and its genotoxic metabolite cyanoethylene-epoxide in human urine by isotope-dilution LC ESI/MS/MS. AB - Acrylonitrile is a highly important industrial chemical with a high production volume worldwide, especially in the plastics industry. It is classified as a possible human carcinogen by the International Agency for Research on Cancer (IARC group 2B). During metabolism of acrylonitrile, the genotoxic metabolite cyanoethylene-epoxide is formed. The urinary mercapturic acids of acrylonitrile, namely N-acetyl-S-(2-cyanoethyl)-L-cysteine (CEMA) and cyanoethylene-epoxide, namely N-acetyl-S-(1-cyano-2-hydroxyethyl)-L-cysteine (CHEMA) are specific biomarkers for the determination of individual internal exposure to acrylonitrile and its highly reactive metabolite. We have developed and validated a sensitive method for the accurate determination of CEMA and CHEMA in human urine with a multidimensional LC/MS/MS-method using deuterium-labelled analogues for both analytes as internal standards. Analytes were stripped from urinary matrix by online extraction on a restricted access material, transferred to the analytical column and determined by tandem mass spectrometry. The limit of quantification (LOQ) for CEMA and CHEMA was 1 MUg/L urine and allowed to quantify the background exposure of the (smoking) general population. Precision within and between series for CHEMA ranged from 2.6 to 8.0% at four concentrations ranging from 8.3 to 86 MUg/L urine, mean accuracy was between 94 and 100%. For CEMA, precision within and between series ranged from 2.4 to 14.5% at four concentrations ranging from 15.1 to 196 MUg/L urine, mean accuracy was between 91 and 104%. We applied the method to spot urine samples of 83 subjects of the general population with no known occupational exposure to acrylonitrile. Median levels (range) for CEMA and CHEMA in urine samples of non-smokers (n=47) were 1.9 MUg/L (<1-16.4 MUg/L) and<1 MUg/L (<1-3 MUg/L), while in urine samples of smokers (n=36), median levels were 184 MUg/L (2-907 MUg/L) and 29.3 MUg/L (<1-147 MUg/L), respectively. Smokers showed a significantly higher excretion of both acrylonitrile metabolites (p<0.001). Due to its automation and high sensitivity, our method is well suited for application in experimental studies on acrylonitrile metabolism or occupational studies. PMID- 22939150 TI - Operator care and eco-concerned development of a fast, facile and economical assay for basic nitrogenous drugs based on simplified ion-pair mini-scale extraction using safer solvent combined with drop-based spectrophotometry. AB - A fast, facile, and economical assay for basic nitrogenous drugs has been developed based on the mini-scale extraction of the drug-dye ion pair complex combined with the use of safe-for-analyst and eco-friendlier organic extractant and drop-based micro-spectrophotometry. Instead of using large volume devices, the extraction was simply carried out in typical 1.5 mL microcentrifuge tubes along with the use of micropipettes for accurate transfer of liquids, vortex mixer for efficient partitioning of solutes and benchtop centrifuge for rapid phase separation. In the last step, back-extraction was performed by using the microvolume of acidic solution in order to concentrate the colored species into a confined aqueous microdrop and to keep the analyst away from unwanted contact and inhalation of organic solvents during the quantitation step which was achieved by using cuvetteless UV-vis micro-spectrophotometry without any prior dilutions. Using chlorpheniramine maleate as a representative analyte and n-butyl acetate as a less toxic and non-ozone depleting extractant, the miniaturized method was less laborious and much faster. It was accurate, precise and insensitive to the interferences from common excipients. Notably, it gave the assay results of drug in tablets and oral solution comparable to the large-scale pharmacopeial method while the consumption of organic solvents and the release of wastes were lowered by 200-400 folds. PMID- 22939151 TI - Determination of L-tryptophan based on graphene oxide-magnetite-molecularly imprinted polymers and chemiluminescence. AB - A new method for determination of L-tryptophan (L-try) using the flow injection chemiluminescence (FI-CL) system of KMnO(4)-SnCl(2)-CHOH based on a graphene oxide-magnetite-molecularly imprinted polymer (GM-MIP) is described. The L-try GM MIP was synthesized using graphene oxide (G) which improved the adsorption capacity as carrier, and magnetite nanoparticles which made the polymers easier to use in the sensor. The adsorption performance and properties were characterized. The GM-MIP was used in CL analysis to increase the selectivity and the possible mechanism was also discussed. The CL sensor responded linearly to the concentration of L-try over the range from 2.10*10(-7) to 7.09*10(-4) M with a detection limit of 2.11*10(-8) M (3sigma). The relative standard deviation (RSD) for the determination of 3.0*10(-5) M L-try was 2.40% (n=11). On the basis of speediness and sensitivity, the sensor is reusable and shows a great improvement in selectivity and adsorption capacity over other sensors. The sensor has been used for the determination of L-try in drug samples. PMID- 22939152 TI - The chemical generation of NO for the determination of nitrite by high-resolution continuum source molecular absorption spectrometry. AB - In the present work, we propose a method for the determination of nitrite based on the chemical generation of nitric oxide (NO) and its detection by high resolution continuum source molecular absorption spectrometry. NO is generated by the reduction of nitrite in acidic media with ascorbic acid as the reducing agent and then transferred into a quartz cell by a stream of argon carrier gas. The conditions under which the NO is generated are as follows: 0.4 mol L(-1) hydrochloric acid, 1.5%(w/v) ascorbic acid, an argon gas pressure of 0.03 MPa and an injection time of the reducing agent of 4s. All measurements of molecular absorption were performed using the NO line at 215.360 nm, and the signal was measured by peak height. Under these conditions, the method described has limits of detection and quantification of 0.045 and 0.150 MUg mL(-1) of nitrite, respectively. The calibration curve is linear for nitrite concentrations in the range 0.15-15 MUg mL(-1). The precision, estimated as the relative standard deviation (RSD), was 3.5% and 4.4% for solutions with nitrite concentrations of 0.5 and 5.0 MUg mL(-1), respectively. This method was applied to the analysis of different water samples (well water, drinking water and river water) collected in Cachoeira City, Bahia State, Brazil. The results were in agreement with those obtained by a spectrophotometric method using the Griess reaction. Addition/recovery tests were also performed to check the validity of the proposed method. Recoveries of 93-106% were achieved. PMID- 22939153 TI - Energy dispersive X-ray fluorescence and scattering assessment of soil quality via partial least squares and artificial neural networks analytical modeling approaches. AB - Soil quality assessment (SQA) calls for rapid, simple and affordable but accurate analysis of soil quality indicators (SQIs). Routine methods of soil analysis are tedious and expensive. Energy dispersive X-ray fluorescence and scattering (EDXRFS) spectrometry in conjunction with chemometrics is a potentially powerful method for rapid SQA. In this study, a 25 m Ci (109)Cd isotope source XRF spectrometer was used to realize EDXRFS spectrometry of soils. Glycerol (a simulate of "organic" soil solution) and kaolin (a model clay soil) doped with soil micro (Fe, Cu, Zn) and macro (NO(3)(-), SO(4)(2-), H(2)PO(4)(-)) nutrients were used to train multivariate chemometric calibration models for direct (non invasive) analysis of SQIs based on partial least squares (PLS) and artificial neural networks (ANN). The techniques were compared for each SQI with respect to speed, robustness, correction ability for matrix effects, and resolution of spectral overlap. The method was then applied to perform direct rapid analysis of SQIs in field soils. A one-way ANOVA test showed no statistical difference at 95% confidence interval between PLS and ANN results compared to reference soil nutrients. PLS was more accurate analyzing C, N, Na, P and Zn (R(2)>0.9) and low SEP of (0.05%, 0.01%, 0.01%, and 1.98 MUg g(-1)respectively), while ANN was better suited for analysis of Mg, Cu and Fe (R(2)>0.9 and SEP of 0.08%, 4.02 MUg g(-1), and 0.88 MUg g(-1) respectively). PMID- 22939154 TI - On-line measurement of propofol using membrane inlet ion mobility spectrometer. AB - The concentration of propofol in patient's exhaled air is an indicator of the anesthetic depth. In the present study, a membrane inlet ion mobility spectrometer (MI-IMS) was built for the on-line measurement of propofol. Compared with the direct sample introduction, the membrane inlet could eliminate the interference of moisture and improve the selectivity of propofol. Effects of membrane temperature and carrier gas flow rate on the sensitivity and response time have been investigated experimentally and theoretically. Under the optimized experimental conditions of membrane temperature 100 degrees C and carrier gas flow rate 200 mL min(-1), the calculated limit of detection (LOD) for propofol was 1 ppbv, and the calibration curve was linear in the range of 10-83 ppbv with a correlation coefficient (R(2)) of 0.993. Finally, the propofol concentration in an anaesthetized mouse exhaled air was monitored continuously to demonstrate the capability of MI-IMS in the on-line measurement of propofol in real samples. PMID- 22939155 TI - Automated flow system for sildenafil enrichment using surfactant coated solid phase with fluorescence detection. AB - In this work, Amberlite XAD-1180 resin is used for on-line surfactant-mediated pre-concentration of sildenafil as a prior step for its fluorescent detection. In order to activate the column for sildenafil pre-concentration, the cationic surfactant (hexadecyltrimethylammoniunm bromide, HTAB) is adsorbed onto the resin. In these conditions, sildenafil is retained by HTAB-resin and then it is eluted with ethanol and analyzed by spectrofluorimetry. Drug-surfactant association produces a considerable fluorescence enhancement, increasing considerably the sensitivity of detection. Therefore, sildenafil can be pre concentrated and quantitatively determined, with a detection limit of 0.2 ng mL( 1). The proposed method was successfully applied to the analysis of bulk drug, human urine, tablets, and local herbal medicine. Validation processes were performed by recovering studies and statistical analysis with satisfactory results. PMID- 22939156 TI - A rapid cIEF-ESI-MS/MS method for host cell protein analysis of a recombinant human monoclonal antibody. AB - A rapid and reproducible system that couples capillary isoelectric focusing to a high-resolution mass spectrometer was developed for on-line analysis and identification of protein digests. Magnetic microsphere-based immobilized trypsin was used for protein digestion to reduce the digestion time to 10 min, with a total analysis time of 4h. A three-protein-mixture (myoglobin, BSA, cytochrome c) with a molarity ratio of 1:10:50 was successfully digested and identified. This system was also used to analyze host cell protein impurities in a recombinant humanized monoclonal antibody product in which the sample was product-depleted using affinity capture on protein A/protein L columns prior to analysis. A database search identified 37 host cell proteins with peptide and protein identity probability greater than 0.9. PMID- 22939157 TI - Magnetic solid-phase extraction of five pyrethroids from environmental water samples followed by ultrafast liquid chromatography analysis. AB - In this study, the polystyrene-coated magnetic nanoparticles (MNPs/PSt) were successfully prepared and characterized by Fourier transform infrared spectroscopy, transmission electron microscopy and vibrating sample magnetometry. The as-prepared MNPs/PSt were used as the adsorbent in magnetic solid phase extraction of five pyrethroids, including lambda-cyhalothrin, deltamethrin, esfenvalerate, permethrin, bifenthrin, in environmental water samples. The five pyrethroids were determined by ultra fast liquid chromatography-ultraviolet spectrometry. The influencing factors, including amount of MNPs/Pst, extraction time, pH value, type and volume of desorption solvent and desorption time, were examined and optimized. The extraction recoveries obtained with merely 50mg of MNPs/Pst were very satisfactory. The whole extraction process could be completed within 0.5h. The MNPs/PSt can be reused after an easy washing process. Thus, a simple, green, economical, time saving and effective method for pyrethroids analysis in environmental water samples was established. A high enrichment factor of 500 was achieved and the limits of detection for lambda-cyhalothrin, deltamethrin, esfenvalerate, permethrin, bifenthrin were 0.015+/-0.001 ng mL(-1), 0.012+/-0.001 ng mL(-1), 0.026+/-0.001 ng mL(-1), 0.020+/-0.001 ng mL(-1), 0.013+/-0.001 ng mL(-1), respectively. Recoveries obtained by analyzing spiked water samples at three concentration levels (0.100+/-0.001 ng mL(-1), 1.000+/ 0.001 ng mL(-1), 10.000+/-0.001 ng mL(-1)) were between 78.97+/-8.38% and 96.05+/ 8.38%. The standard curves for the five pyrethroids showed good linearity with the correlation coefficients in the range of 0.9994-0.9999. The intra-day and inter-day precision were satisfactory with the RSDs in the range of 2.05-5.52% and 2.73-8.38%, respectively. PMID- 22939158 TI - Electrochemical preparation of poly(p-phenylenediamine-co-aniline) composite coating on a stainless steel wire for the headspace solid-phase microextraction and gas chromatographic determination of some derivatives of benzene. AB - A poly(p-phenylenediamine-co-aniline) composite coating was prepared on a stainless steel wire through electrochemical method. The coating was characterized by scanning electron microscopy, Fourier transform infrared spectrophotometry and thermogravimetry. It showed thin slice shape and netlike microstructure, and thus it had large surface area and large extraction capacity. When the resulting fiber was used for the headspace solid-phase microextraction of some derivatives of benzene (i.e. chlorobenzene, 1,3-dimethylbenzene, 1,2 dimethylbenzene, 2-chlorotoluene, 1,3,5-trimethylbenzene, 1,2,4 trimethylbenzene), followed by gas chromatographic (GC) analysis, it presented better performance than the polyaniline coated stainless steel wire. Under the optimized conditions, the GC peak areas were linear to their concentration in the ranges of about 0.5-500 MUg L(-1), with correlation coefficients of 0.9911 0.9989; the detection limits were 0.2-0.88 MUg L(-1)(S/N=3). The run-to-run RSD was smaller than 5.5% (n=5), and the fiber-to-fiber RSD was 3.5%-12.7% (n=3). The fiber was quite stable and durable; after it was used for about 140 times, its extraction efficiency kept almost unchanged. The developed method was successfully applied to the determination of the derivatives of benzene in waste water, and the recoveries were 86.9%-107.7%. PMID- 22939159 TI - Microwave-assisted digestion of organic samples: how simple can it become? AB - Advancements in sample preparation for performing trace analysis of inorganic analytes are coming from the dissemination of microwave-assisted procedures, but there is still room for improvements by looking for simple and easily applied procedures. Recently it was proposed a new approach called single reaction chamber with capability for digestions at high pressures and temperatures using simple vials and racks. This was a limitation of former cavity microwave ovens with closed vessels. It was demonstrated here that the use of single reaction chamber approach allows the implementation of efficient digestions using diluted solutions of nitric acid and also allows addressing a critical need of sample preparation for inorganic analysis by running mixed batches of samples. The feasibility of this procedure was demonstrated for organic samples and accuracy was proved by using certified reference materials of apple leaves, bovine liver and whole milk powder. Digestions performed of whole milk powder and bovine liver using 2.0 mol L(-1) nitric acid solution plus concentrated hydrogen peroxide at 240 degrees C led to residual carbon contents of 0.825 and 1.50% and residual acidities of 1.04 and 0.618 mol L(-1), respectively. These parameters are fully compatible with further measurements using ICP OES or ICP-MS. Al, Cu, Fe, Mn, Mo, Rb, Se, Sr, and Zn were accurately determined by ICP OES or ICP-MS depending on their concentrations in digests. PMID- 22939160 TI - Novel hybrid organic-inorganic monolithic column containing mesoporous nanoparticles for capillary electrochromatography. AB - The rod-shaped SBA-15-C(18) mesoporous nanoparticles were incorporated into hybrid organic-inorganic monolithic column with aminopropyl moiety to develop novel stationary phases with mixing mechanism of reverse phase and ion exchange. Experimental conditions including dispersion pattern, nanoparticles percentage were optimized for simple and stable column preparation. The monolithic columns were evaluated with mixture of organic acids in capillary electrochromatography (CEC) mode and the column efficiency reaches 280, 000 plates/m. The results indicate that the column containing nanoparticles enhances both selectivity and column efficiency due to high specific surface area of nanoparticles and mixing separation mechanism. PMID- 22939162 TI - [Membranes in pre-implantation surgery]. AB - The use of membranes in pre-implantation surgery is part of the guided bone regeneration (GBR) concept, one of the usual bone augmentation techniques. Membranes for GBR procedures have two main uses: a mechanical function to maintain bone regeneration space and a physical function as cellular barrier. The goal is to promote colonization of the regeneration space located under the membrane, by osteogenic cells from the residual bone walls. GBR was the subject of numerous publications and protocols since its first use in the 1980s. These protocols are mainly supported by team experience and the level of evidence is poor. Few indications are truly validated. The goal of our study was to review the recent literature on membrane use for pre-implantations surgery, and, in the absence of any consensus, to provide some arguments for their rational use. PMID- 22939163 TI - Need to develop new nonsteroidal anti-inflammatory drug formulations. AB - BACKGROUND: In the management of pain, primary care physicians are often the first to diagnose and treat acute or chronic painful conditions. This places them in an important intersection to manage pain, in which safe and effective therapeutic options are paramount for their patients. For decades, NSAIDs have been routinely prescribed for relief of mild to moderate acute and chronic pain. Yet, safety and tolerability concerns associated with the use of this class of drugs continue to be an issue for patients and clinicians. OBJECTIVE: The objective of this review was to discuss the unmet medical needs of patients in the management of pain and inflammation, review the dose-dependent safety data associated with use of NSAIDs, and discuss the need to develop new NSAID formulations to improve safety and tolerability while maintaining efficacy. METHODS: We performed literature searches of the PubMed and Cochrane Library databases through December 2012 for articles in English that reported dose dependent safety and tolerability data associated with use of NSAIDs. RESULTS: The risk of serious, dose-dependent adverse events involving the gastrointestinal tract, cardiovascular system, and kidneys is associated with use of NSAIDs. On the basis of these findings, the US Food and Drug Administration has requested that the package insert for all NSAIDs be revised to include a boxed warning highlighting the potential increased risk of cardiovascular events and the risk of serious, and potentially life-threatening, gastrointestinal tract bleeding. While using lower dosages of a particular NSAID may be associated with lower rates of adverse events, maintaining the clinical efficacy of standard NSAID dosages remains a challenge. CONCLUSIONS: There is a need to develop new and effective NSAID formulations to minimize the safety and tolerability concerns associated with currently available NSAIDs, yet maintain efficacy in management of inflammation and pain. PMID- 22939164 TI - Statins and new-onset diabetes: a retrospective longitudinal cohort study. AB - BACKGROUND: Statins have been linked to new-onset diabetes (NOD); however, the effect of statins on the development of NOD in patients with hypertension and dyslipidemia has not been well studied. OBJECTIVE: The goal of this study was to investigate the association between statins and NOD. METHODS: This was a retrospective cohort study performed by using data from claim forms provided to the central regional branch of the Bureau of National Health Insurance in Taiwan from July 2006 to December 2009. Prescriptions for statins before the index date were retrieved from a prescription database. We estimated the hazards ratios (HRs) of NOD associated with statin use. Nondiabetic subjects served as the reference group. RESULTS: A total of 1360 (8.5%) NOD cases were identified among 16,027 patients with hypertension and dyslipidemia during the study period. The risk of NOD after adjusting for sex and age was higher among users of pravastatin (HR, 1.34 [95% CI, 1.15-1.55]) and atorvastatin (HR, 1.29 [95% CI, 1.16-1.44]) than among nonusers. Patients who took fluvastatin (HR, 0.45 [95% CI, 0.34 0.60]), lovastatin (HR, 0.71 [95% CI, 0.61-0.84]), and rosuvastatin (HR, 0.54 [95% CI, 0.39-0.77]) were at lower risk of developing NOD than nonusers. Simvastatin was not associated with risk of NOD. Furthermore, the risk of NOD after adjusting for concomitant medication usage and mean dose of statins was neutral among users of atorvastatin. Pravastatin, fluvastatin, lovastatin, simvastatin, and rosuvastatin produced similar results as adjusting for sex and age. CONCLUSIONS: These outpatients with hypertension and dyslipidemia who took fluvastatin, lovastatin, and rosuvastatin were at lower risk of NOD, whereas patients who took pravastatin were at greater risk. Simvastatin and atorvastatin seemed to have a neutral effect. Our study also demonstrated that atorvastatin has a dose-response effect on NOD risk. Because this was a descriptive study, temporality and subsequent causality of all statins and NOD could not be shown. Further study and independent confirmation of the causality between statin use and NOD in larger clinical trials are warranted. PMID- 22939165 TI - Mapping different intra-hemispheric parietal-motor networks using twin Coil TMS. AB - BACKGROUND: Accumulating evidence suggests anatomical and functional differences in connectivity between the anterior and posterior parts of the inferior-parietal lobule (IPL) and the frontal motor areas. OBJECTIVE/HYPOTHESIS: This study investigates whether different intra-hemispheric parietal-motor interactions can be observed along the anterior-posterior axis of the IPL in the resting human brain. METHODS: We use a twin coil transcranial magnetic stimulation technique to test intra-hemispheric interactions between three points adjacent to the intra parietal sulcus (anterior, central, posterior) and the ipsilateral primary motor cortex (M1) at rest in both hemispheres. RESULTS: We found that stimulation of the anterior IPL resulted in an inhibition of the ipsilateral M1 in both hemispheres. Stimulation of the central and posterior IPL resulted in a facilitatory effect on ipsilateral M1 in the left but not for the right hemisphere. Additionally we show that there is considerable inter-subject variability concerning the optimal parietal facilitatory and inhibitory position. CONCLUSIONS: The IPL has distinct inhibitory and facilitatory connections to the ipsilateral M1. Whereas inhibitory connections are observed in both hemispheres, facilitatory connections are asymmetric. These parietal-motor networks may represent the basis for the functional differences between these regions in reaching and grasping tasks and mirror the functional asymmetry observed in the motor system. From a practical point of view, we note that the inter-subject variability means that future TMS studies of the parietal area might consider a hot-spot localization similar to the procedures commonly used for M1. PMID- 22939166 TI - IUGA/ICS terminology and classification of complications of prosthesis and graft insertion--rereading will revalidate. PMID- 22939167 TI - Subarachnoid haemorrhage induces an inflammatory response followed by a delayed persisting increase in asymmetric dimethylarginine. AB - OBJECTIVE: Subarachnoid haemorrhage (SAH) is associated with an inflammatory systemic response and cardiovascular complications. Asymmetric dimethyl arginine (ADMA), an endogenous inhibitor of nitric oxide synthase, mediates vasoconstriction and might contribute to cerebral vasoconstriction and cardiovascular complications after SAH. ADMA is also involved in inflammation and induces endothelial dysfunction. The aim of this study was to evaluate whether and how CRP (marker for systemic inflammation) and ADMA increased in patients during the acute phase (first week) after SAH. The ADMA level was also assessed in the patients in a non-acute phase (three months), and in healthy controls. METHODS: A prospective study of 20 patients with aneurysmal SAH. ADMA and CRP were followed daily during the first week after SAH and a follow up sample for ADMA was obtained 3 months later. A single blood sample for ADMA was collected from age- and sex-matched healthy controls (n = 40, two for each case). RESULTS: CRP increased significantly from day 2; 16 (Confidence interval (CI) 10-23) mg/L to day 4; 84 (CI 47-120) mg/L, (p < 0.01). ADMA increased significantly from day 2; 0.22 (CI 0.17-0.27) MUmol/L, to day 7; 0.37 (CI 0.21-0.54) MUmol/L, p < 0.01. ADMA remained elevated at a 3-month follow-up: 0.36 (CI 0.31-0.42) MUmol/L. ADMA in the first sample from the patients (day 1-3); 0.25 (CI 0.19-0.30) MUmol/L, was not different from ADMA in matched healthy controls; 0.25 (CI 0.20-0.31), p > 0.05. CONCLUSION: After SAH, CRP and ADMA in serum increased significantly during the first week and ADMA remained elevated 3 months later. PMID- 22939168 TI - Biomarkers in clinical laboratory sciences: reinventing the wheel? PMID- 22939169 TI - Reduction of non-specific binding in immunoassays requiring long incubations. AB - Despite the studies so far about the non-specific binding of antibody molecule to the plastic of solid phase in enzyme-linked immunoassays, background binding in microwell Elisa continues to be a troublesome problem.Non-specific immunoglobulin from an undiluted serum sample can adhere to the surface of a 'blocked' plate to result in a maximal signal in an antigen capture assay for specific antibody to render analysis virtually impossible in undiluted serum when using labelled anti species antibodies. Yet it is desirable in many circumstances that the maximum sensitivity achievable by the simple expedient of using a concentrated sample (undiluted serum) be exploited, for example in the analysis of antibodies to HIV in the interest of earlier diagnosis. To circumvent this problem we have developed an alternative strategy in which a biotinylated capture reagent is preincubated with the serum sample for the necessary time after which the biotinylated ligand/antibody complex is itself rapidly captured in streptavidin coated wells at 4 degrees C, with subsequent detection with labelled anti-species immunoglobulin. This manoeuvre enables the capture ligand to be incubated with undiluted serum sample for long time periods resulting in improved specificity of detection. By this means we describe a general method to improve the specificity of serum antibody immunoassays which will be expected to produce the benefit of more rapid diagnosis by signalling antibody production earlier in the abnormal state. Furthermore, our new method could be used to reduce non-specific binding in other immunological assays such as antibody arrays to which much attention has recently been paid. PMID- 22939170 TI - TEMPS-A and long-term lithium response: positive correlation with hyperthymic temperament. AB - BACKGROUND: Lithium is still regarded as a cornerstone for the long-term treatment of bipolar disorder. The best response to lithium is associated with clinical features of episodic clinical course, complete remission, bipolar family history and low psychiatric comorbidity. However, a specific personality profile for the best lithium response was not estimated so far. Such a possibility occurred with an advent of temperament scale for bipolar disorder and of an ability to quantitatively assess lithium prophylactic response. METHODS: The study was performed on 71 patients with bipolar mood disorder (21 males, 50 females), aged 31-82 (59+/-12) years, which have been treated with lithium carbonate for at least 5 years (5-37 years, mean 15 years). In all patients, the assessment of five temperaments of TEMPS-A scale (depressive, cyclothymic, hyperthymic, irritable and anxious) was done, and correlated with the quality of lithium prophylaxis according to Alda scale. RESULTS: The mean scores for five temperaments of TEMPS-A were not significantly different in male and female patients. The response to lithium correlated significantly positively with hyperthymic temperament score (r=0.31, p=0.009), and negatively with anxiety (r= 0.27, p=0.022), cyclothymic (r=-0.26, p=0.032), and depressive (r=-0.23, p=0.052) temperaments scores. LIMITATIONS: Relatively small number of patients. CONCLUSIONS: The main finding of the study is an association of lithium response with hyperthymic temperament. This positive correlation as well as other negative correlations between lithium response and TEMPS-A temperaments are discussed in view of clinical and genetic findings in bipolar patients. PMID- 22939171 TI - Lipidated promiscuous peptides vaccine for tuberculosis-endemic regions. AB - Despite nine decades of Bacillus Calmette--Guerin (BCG) vaccination, tuberculosis continues to be a major global health challenge. Clinical trials worldwide have proved the inadequacy of the BCG vaccine in preventing the manifestation of pulmonary tuberculosis in adults. Ironically, the efficacy of BCG is poorest in tuberculosis endemic areas. Factors such as nontuberculous or environmental mycobacteria and helminth infestation have been suggested to limit the efficacy of BCG. Hence, in high TB-burden countries, radically novel strategies of vaccination are urgently required. Here we showcase the properties of lipidated promiscuous peptide vaccines that target and activate cells of the innate and adaptive immune systems by employing a Toll-like receptor-2 agonist, S-[2,3 bis(palmitoyloxy)propyl]cysteine (Pam2Cys). Such a strategy elicits robust protection and enduring memory responses by type 1 T helper cells (Th1). Consequently, lipidated peptides may yield a better vaccine than BCG. PMID- 22939172 TI - CCAAT-box binding transcription factors in plants: Y so many? AB - Transcription factors belonging to the CCAAT-box binding factor family (also known as the Nuclear Factor Y) are present in all higher eukaryotes. Studies in plants have revealed that each subunit of this heterotrimeric transcription factor is encoded by a gene belonging to a multigene family allowing a considerable modularity. In this review, we focus on recent findings concerning the expression patterns and potential functions of different members of these NF Y protein families using a phylogenetic approach. During the course of evolution plant CCAAT-box binding factors seem to have diversified into at least two main groups. The first group has more general expression patterns and/or functions whereas the second group has acquired more specific expression patterns and/or functions and could play key roles in specific pathways. PMID- 22939174 TI - Clinical neuropathology practice guide 5-2012: updated guideline for the diagnosis of antineuronal antibodies. AB - In recent years there is an increasing description of novel anti-neuronal antibodies that are associated with paraneoplastic and non-paraneoplastic neurological syndromes. These antibodies are useful in clinical practice to confirm the immunmediated origin of the neurological disorder and are helpful in tumor search. Currently, antineuronal antibodies can be classified according to the location of the recognized antigen into two groups, 1.) intraneuronal antigens and 2.) antigens located in the cell membrane. Different techniques are established for detecting these antibodies: tissue-based assay (TBA), cell-based assay (CBA), immunoblot, immunoprecipitation assay (IP), and ELISA. TBA detect most of the antibodies, however, different pretreatment methods of rat brain are necessary to visualize either Group 1 or 2 antibodies. Higher specificity is provided by immunoblots, applicable for Group 1 antibodies, and CBA, suitable for Group 2 antibodies. IP and ELISA may be useful for the detection of specific antibodies or to solve particular issues such as antibody titers. Diagnosis of paraneoplastic and non-paraneoplastic neurological syndromes has important implications on treatment and follow-up of patients. Selection and proper combination of test systems and appropriate knowledge of the clinical information will provide a maximum of sensitivity and specificity in identifying the associated antibody. PMID- 22939175 TI - Fractal analysis of microvascular networks in malignant brain tumors. AB - Brain tumors are characterized by a microvascular network which differs from normal brain vascularity. Different tumors show individual angiogenic patterns. Microvascular heterogeneity can also be observed within a neoplastic histotype. It has been shown that quantification of neoplastic microvascular patterns could be used in combination with the histological grade for tumor characterization and to refine clinical prognoses, even if no objective parameters have yet been validated. To overcome the limits of the Euclidean approach, we employ fractal geometry to analyze the geometric complexity underlying the microangioarchitectural networks in brain tumors. We have developed a computer aided fractal-based analysis for the quantification of the microvascular patterns in histological specimens and ultra-high-field (7-Tesla) magnetic resonance images. We demonstrate that the fractal parameters are valid estimators of microvascular geometrical complexity. Furthermore, our analysis allows us to demonstrate the high geometrical variability underlying the angioarchitecture of glioblastoma multiforme and to differentiate low-grade from malignant tumors in histological specimens and radiological images. Based on the results of this study, we speculate the existence of a gradient in the geometrical complexity of microvascular networks from those in the normal brain to those in malignant brain tumors. Here, we summarize a new methodology for the application of fractal analysis to the study of the microangioarchitecture of brain tumors; we further suggest this approach as a tool for quantifying and categorizing different neoplastic microvascular patterns and as a potential morphometric biomarker for use in clinical practice. PMID- 22939176 TI - Primary human glioblastomas - prognostic value of clinical and histopathological parameters. AB - BACKGROUND: Glioblastoma (GBM) is the most common primary malignant human brain tumor with a poor prognosis. The diagnosis of GBM is based on histological features, however, few studies have evaluated their prognostic relevance in light of the latest WHO classification of 2007. AIM: In this study we have evaluated the prognostic value of several clinical and histological characteristics encountered in human GBMs according to the WHO 2007 criteria. MATERIAL AND METHODS: 199 patients with primary GBM consecutively operated and histologically reviewed according to the 2007 WHO scheme, were included. Several clinical and histological features were recorded and related to survival. RESULTS: Mean age of the GBM patients at diagnosis was 62 years (range 21 - 84). Male/female ratio was 1.3/1, and the median survival was 8.0 months (95% CI: 7.1 - 9.0 months). In a multivariate COX analysis age, WHO performance score, subcortical localization, extent of surgery, radiation treatment, chemotherapy, and the presence of large necrosis had individual effect on overall survival (p < 0.05). In addition, females, tumors with angiocentric growth, with pseudopalisades, or without lymphocyte infiltration were related to shorter survival in univariate analyses (p < 0.05). CONCLUSION: Our findings confirm the strong prognostic value of age, treatment, performance score, and localization for glioblastoma patients. Amongst the histopathological features only large necrosis was an independent prognostic factor. PMID- 22939177 TI - Central nervous system pathology in an infant with short-chain acyl-CoA dehydrogenase deficiency (SCADD): evidence for abnormal neuronal migration as part of its phenotypic spectrum. PMID- 22939178 TI - De novo gliosarcoma occurring in the posterior fossa of a 11-year-old girl. PMID- 22939179 TI - Tendon motion and strain patterns evaluated with two-dimensional ultrasound elastography. AB - The purpose of this study was to evaluate the use of 2D ultrasound elastography to assess tendon tissue motion and strain under axial loading conditions. Four porcine flexor tendons were cyclically loaded to 4% peak strain using a servo hydraulic test system. An ultrasound transducer was positioned to image a longitudinal cross-section of the tendon during loading. Ultrasound radiofrequency (RF) data were collected at 63 frames per second simultaneously with applied force and crosshead displacement. A grid of nodes was manually positioned on an ultrasound image of the unloaded tendon. Small kernels (2*1 mm) centered at each node were then cross-correlated with search regions centered at corresponding nodal locations in the subsequent frame. Frame-to-frame nodal displacements were defined as the values that maximized the normalized cross correlations. This process was repeated across all frames in the loading cycle, providing a measurement of the 2D trajectories of tissue motion throughout the loading cycle. The high resolution displacement measures along the RF beam direction were spatially differentiated to estimate the transverse (relative to tendon fibers) tissue strains. The nodal displacements obtained using this method were very repeatable, with average along-fiber trajectories that were highly correlated (average r=0.99) with the prescribed crosshead displacements. The elastography transverse strains were also repeatable and were consistent with average transverse strains estimated via changes in tendon width. The apparent Poisson's ratios (0.82-1.64) exceeded the incompressibility limit, but are comparable to values found for tendon in prior experimental and computational studies. The results demonstrate that 2D ultrasound elastography is a promising approach for noninvasively assessing localized tissue motion and strain patterns. PMID- 22939180 TI - Acute transfusion practice during trauma resuscitation: who, when, where and why? AB - BACKGROUND: Early transfusion (ET=within 24h) has been shown to be required in approximately 5% of trauma patients. Critical care transfusion guidelines control transfusion triggers by evidence based cut-offs. Empirical guidelines influence decision making for ET in trauma. AIM: to describe the patterns, indications and timing of ET at level 1 trauma centre. METHODS: A 12-month prospective study was performed on all trauma admissions requiring ET. Demographics, mechanism, injury severity (ISS) were collected. Timing, location, volume, the clinician initiating first unit of transfusion, reason for transfusion was recorded, with corresponding blood gas results and physiological parameters. Mortality, ICU admission, length of stay, need for emergent surgery were outcomes. RESULTS: From 965 trauma admissions 91 (9%) required ET (76% male, median age: 38 (10-88, IQR: 22-59), blunt mechanism: 87%, ISS: 25 (4-66, IQR: 16-34). 43% (39/91) had massive transfusion protocol (MTP) activation. ET was initiated in ED (52%), OR (38%) or ICU (10%). MTP transfusions were started at a median of 0.5h (0.5-4, IQR: 0.5 1.5), whilst non-MTP transfusions were initiated at a median 3h (0.5-23, IQR: 2 9). The first unit of ET was initiated by trauma surgeon (35%), anaesthetist (30%), ED (19%), ICU (13%) and general surgeon (3%). Transfusions triggers at the first unit of transfusion were 'expected or ongoing bleeding' 29%, dropping haemoglobin 26%, haemorrhagic shock 24%, hypotension 10%, tachycardia 8%. Median systolic blood pressure was 90 (45-125, IQR: 80-100), heart rate was 100 (53-163, IQR: 80-120), haemoglobin was 96 (50-166, IQR: 85-114)g/l and base excess was 4.2(-22.1 to 2.7, IQR: -7.2 to 2.4)mmol/l at the time of transfusion. Emergency surgery was required in 86% (78/91). ICU admission rate was 69% (63/91). Mortality was 14%. Low volume transfusion (1-2 units) was more likely to lead to overtransfusion (Hb>110 g/l). CONCLUSION: The prospective evaluation of acutely transfused trauma patients showed a distinct pattern of transfusion triggers as the patient passes from ED to the OT and arrives to the ICU. The conventional transfusion trigger (haemoglobin level) is not appropriate in ET as early transfusion triggers are based on vital signs, blood gas results, injury patterns and anticipated major bleeding. PMID- 22939181 TI - Shape-shifting gametocytes: how and why does P. falciparum go banana-shaped? AB - Plasmodium falciparum is named for the crescent or falciform shape it adopts when preparing to undergo transfer to a mosquito vector. By contrast, gametocytes of the other (less virulent) human malaria parasites retain a more rounded shape. We describe the machinery that elongates falciparum gametocytes and discuss its relation with the machinery that elongates the invasive zoites. We address the question - why do falciparum malaria gametocytes go banana-shaped? The answer may lie in the finding that gametocyte maturation is associated with an increase in cellular deformability. The shape-shifting ability of gametocytes may facilitate the sequestration of early-stage gametocytes, while enabling late-stage gametocytes to circulate in the blood stream without being removed by the mechanical filtering mechanisms in the host spleen. PMID- 22939182 TI - The phosphoproteome of the adenovirus type 2 virion. AB - We have used a proteomics approach to identify sites of phosphorylation in the structural proteins of the Adenovirus type 2 particle. This protein modification might play an important role during infection. Peptides from highly purified virus were enriched for phosphorylations and analyzed by liquid chromatography high-resolving mass spectrometry. Phosphorylations were identified in 11 structural peptides and 29 non-redundant phosphorylation sites were unambiguously assigned to specific amino acid. An unexpected result was the finding of phosphotyrosine in two of the viral polypeptides. The most highly phosphorylated protein was pIIIa with 12 identified phosphorylation sites. An identified preference for proline or leucine residue flanking the phosphorylation sites downstream suggests that cellular kinases are involved in many of the phosphorylations. Structural modeling showed that one site in the hexon is located on the outer side of the virus and could be of importance for the virus when attaching and entering cells. PMID- 22939183 TI - Journal clubs: a two-site case study of nurses' continuing professional development. AB - OBJECTIVE: The purpose of this study was to explore the experience of intensive care unit nurses in two nursing journal clubs. BACKGROUND: Few nurses feel comfortable using evidence to guide their practice. Communities of nurses are beginning to be understood as essential for the production and transfer of knowledge. Journal clubs are a meeting among colleagues to discuss professional literature. However, there is little nursing journal club research. SETTINGS AND PARTICIPANTS: Over six months, 70 healthcare professionals (including 64 nurses) participated in monthly journal club meetings in two ICUs of one Ontario hospital. METHODS: A qualitative two-site case study methodology with six data collection methods was employed including individual interviews, focus groups, surveys, document analysis, and field notes. FINDINGS: Journal clubs provided nurses with incentive and confidence to read research articles, created a community of practice, provided a structure to reflect-on-practice, and led to reported changes in clinical practice. However, any gains in competence of nurses with research critical appraisal skills were probably modest. CONCLUSION: Journal clubs can foster modest knowledge translation and evidence-based practice at a grass roots level. However, journal clubs may have a greater impact when implemented alongside other knowledge translation strategies such as working with graduate prepared nurses. PMID- 22939184 TI - Identification of 1-butyl-3-(1-(4-methyl)naphtoyl)indole detected for the first time in "herbal high" products on the Italian market. AB - The results of the analysis of some herbal products and powders adulterated with alkylindoles recovered on the Italian market between 2010 and 2011 are reported. Besides the well-known alkyindoles JWH-018 and JWH-073, other derivatives such as JWH-250 and AM-694 have been detected and for the first time in Italy 1-butyl-3 (1-(4-methyl)naphthoyl)indole (compound 1), the 4-methylnaphthoyl analogue of JWH 073. This compound as well as the other alkylindoles has been synthesized and characterized by (1)H NMR, (13)C NMR, DSC, GC/MS, and elemental analysis. The quantitative analyses of the samples have been carried out by means of the GC/FID method developed in our laboratory for the analysis of herbal high products containing naphthoylindoles; the quantity of the cannabimimetic substances ranged from 6 mg/g to 47 mg/g. PMID- 22939186 TI - Journal of the American Medical Directors Association: the state of the journal. PMID- 22939187 TI - Effect of support materials on supported platinum catalyst prepared using a supercritical fluid deposition technique and their catalytic performance for hydrogen-rich gas production from lignocellulosic biomass. AB - A number of supported Pt catalysts have been prepared by supercritical carbon dioxide deposition technique using various supports. The reduction of Pt precursor to metal performed by heat treatment under nitrogen flow. The prepared catalysts were evaluated for gasification of wheat straw biomass hydrolysates and glucose solution for hydrogen-rich gas production. The activities of the catalysts were highly affected by distribution, amount and particle sizes of platinum on the support. In general carbon-based supported Pt catalysts exhibited better catalytic activity compared to other supports to be used. Compared to biomass hydrolysate feed, gasification of glucose always resulted in higher volume of gas mixture, however, hydrogen selectivity was decreased in all catalyst except multi-walled carbon nanotube. The deposition of Pt particles inner side of that support makes the large organic substrates inaccessible to reach and react with those metal particles. PMID- 22939188 TI - Reduction of Cr(VI) by Escherichia coli BL21 in the presence of redox mediators. AB - Anthraquinone-2,7-disulfonate (2,7-AQDS), anthraquinone-1-sulfonate (alpha-AQS), anthraquinone-2-sulfonate (AQS), anthraquinone-2,6-disulfonate (AQDS) and anthraquinone-1,5-disulfonate (1,5-AQDS) were selected as redox mediators for Cr(VI) reduction by Escherichia coli BL21. In the presence of 0.8mmoll(-1) AQS, the Cr(VI) reduction efficiency was 98.5% in 7.5h, whereas it was only 21-34% in the absence of a mediator or in the presence of alpha-AQS, 1,5-AQDS, AQDS, 2,7 AQDS. A linear correlation, k=0.768C(AQS)+1.5531 (R(2)=0.9935), was found for the reaction constant, k (mg Cr(VI) g(-1) dry cell weight h(-1)) and the AQS concentration (C(AQS)). The Arrhenius equation described the Cr(VI) reduction in the tested temperature range, and the pre-exponential factor A was 13.249mg Cr(VI) g(-1) dry cell weight h(-1),and the activation energy Ea was 28.01kJmol( 1). Glucose was the best carbon sources, and the optimum pH was 6.0. The Cr(VI) reduction rate obtained with AQS is a significant improvement over low conventional anaerobic reduction rates. PMID- 22939189 TI - Ethanol production by repeated-batch simultaneous saccharification and fermentation (SSF) of alkali-treated rice straw using immobilized Saccharomyces cerevisiae cells. AB - Repeated-batch simultaneous saccharification and fermentation (SSF) of alkali treated rice straw using immobilized yeast was developed to produce ethanol. Saccharomyces cerevisiae cells were immobilized by entrapping in photocrosslinkable resin beads, and we evaluated the possibility of its reuse and ethanol production ability. In batch SSF of 20% (w/w) rice straw, the ethanol yields based on the glucan content of the immobilized cells were slightly low (76.9% of the theoretical yield) compared to free cells (85.2% of the theoretical yield). In repeated-batch SSF of 20% (w/w) rice straw, stable ethanol production of approx. 38gL(-1) and an ethanol yield of 84.7% were obtained. The immobilizing carrier could be reused without disintegration or any negative effect on ethanol production ability. PMID- 22939190 TI - Modulation of HIV reservoirs by host HLA: bridging the gap between vaccine and cure. AB - Latent HIV reservoirs are the greatest challenge facing an HIV cure. Here, we review recent evidence supporting an important role for the host immune response, in particular HLA class I-restricted CD8+ T lymphocytes, in modulating HIV reservoirs during natural infection. These observations indicate that factors governing immune-mediated control of HIV may also contribute to the clearance of viral reservoirs. As such, critical gaps in our understanding of HIV immunology hinder efforts to develop both an effective HIV vaccine as well as novel therapies that may lead to a cure. The importance of elucidating correlates of protective cellular immunity should be recognized during research to develop and test potential HIV elimination strategies. PMID- 22939191 TI - The case of Robert Herrlinger: a unique postwar controversy on the ethics of the anatomical use of bodies of the executed during National Socialism. AB - Historical evidence shows that German anatomists used bodies of executed victims of the National Socialist (NS) regime for anatomical purposes. However, there has been little direct information on these anatomists' thoughts and motivations, and a public discussion of their activities and ethics only started in the late 1980s. The present study documents a unique postwar controversy surrounding the promotion of the anatomist and medical historian Robert Herrlinger at the university of Wurzburg in the late 1950s. This intramural debate had originally been mentioned by Goetz Aly in 1987. Herrlinger's files record his career as a representative of the discipline of medical history at the university of Wurzburg from 1951 to 1960. He never worked there as an active anatomist. When the university senate applied for his appointment as full professor in 1957, the internist Ernst Wollheim, the pediatrician Joseph Stroder, and the psychiatrist Heinrich Scheller strongly opposed this move in a dissenting opinion based on Herrlinger's anatomical work on bodies of executed NS-victims. They claimed that he lacked the moral prerequisites required in a teacher of medical ethics. A highly controversial debate followed and was remarkable for addressing most of the questions of the ethical and political attitudes and responsibilities of anatomists in NS-Germany that are still being discussed today and are relevant for modern anatomy. It was also significant that Wollheim, Stroder and Scheller objected to Herrlinger in his role as a medical historian, not as an anatomist. The senate finally rejected the dissenting opinion and Herrlinger was promoted. PMID- 22939192 TI - Postpartum paraparesis from spinal neurofibroma. AB - BACKGROUND CONTEXT: One hallmark of neurofibromatosis Type 1 (NF1) is the presence of multiple neurofibromas, which are hormonally responsive and may undergo rapid growth during periods of hormonal surge. Although spinal neurofibromas occur in up to 40% of patients with NF1, they rarely cause neurologic sequelae, especially in the young. PURPOSE: To document a unique case of acute postpartum paraparesis in a young woman because of an extradural neurofibroma compressing the conus medullaris and discuss the possible hormonal influences related to rapid growth of this otherwise "benign" nerve sheath tumor. This case demonstrates the importance of closely monitoring patients with known NF1 for neurologic symptoms, especially during pregnancy and the postpartum period. We also seek to describe the management of this patient, which resulted in an excellent outcome. STUDY DESIGN: Case report and literature review. METHODS: Detailed history was obtained from the patient and her family members. All medical records, imaging studies, histopathological findings, and pertinent literature were reviewed. RESULTS: After evaluating a 26-year-old postpartum woman with NF1 for paraparesis, magnetic resonance imaging of the lumbar spine revealed a large heterogeneously enhancing mass at the conus medullaris. She subsequently underwent resection of the mass via laminectomy. Postoperatively, the patient exhibited marked improvement in weakness and was able to ambulate with assistance 2 days later. Histopathological examination of the mass revealed a neurofibroma with strong expression of estrogen and progesterone receptors. CONCLUSIONS: This patient had a spinal neurofibroma, which likely grew in size within the peripartum period, causing a neurologic emergency. The rapid growth of the neurofibroma may have been the result of hormonal influence of estrogen or progesterone or both. To the best of our knowledge, rapid paraparesis caused by a spinal neurofibroma has never been reported in a peripartum setting. Laminectomy with complete tumor resection is the preferred treatment for spinal neurofibromas causing acute neurologic symptoms. PMID- 22939193 TI - First molecular identification of Entamoeba moshkovskii in Malaysia. AB - Entamoeba moshkovskii and Entamoeba dispar are microscopically indistinguishable from the pathogenic species Entamoeba histolytica. Although sporadic cases of human infection with E. moshkovskii have been reported, the amoeba is still considered primarily as a free-living amoeba. A cross-sectional study was carried out among Orang Asli communities in 3 different states of Peninsular Malaysia. Fecal samples were examined by formalin-ether sedimentation and trichrome staining techniques and then single-round PCR assay was used to detect E. moshkovskii. Out of 500 fecal samples examined microscopically, 93 (18.6%) samples were positive for E. histolytica/E. dispar/E. moshkovskii complex cysts and/or trophozoites. PCR products were detected in 106 fecal samples. E. moshkovskii isolates were detected in 13 (12.3%) fecal samples. Of the 13 E. moshkovskii-positive samples, 5 were of single isolation of E. moshkovskii, 6 were also positive for E. dispar, and only 2 samples were positive for E. dispar and E. histolytica. Moreover, 3 E. moshkovskii-positive samples were collected from symptomatic individuals while the remaining 10 samples were from asymptomatic subjects. This is the first report on the identification of E. moshkovskii in Malaysia. Further studies are needed to confirm the pathogenicity of E. moshkovskii infection and determine the epidemiology among Orang Asli communities in Malaysia. PMID- 22939194 TI - Additive-free fabrication of spherical hollow palladium/copper alloyed nanostructures for fuel cell application. AB - Herein, through tuning the surface energy difference of the major crystal planes by alloying, hollow palladium/copper alloyed nanostructures are successfully prepared through a one-pot template-free strategy. Compared with the solid PdCu alloyed nanoparticles, the hollow PdCu alloyed nanostructures exhibit the increased accessible electrochemical active surface area and the enhanced electrocatalytic activity for formic acid oxidation. It is concluded that the as prepared hollow PdCu alloyed nanostructures would be a potential candidate as an anode electrocatalyst in direct formic acid fuel cell. More importantly, the strategy developed in this study might be expanded to fabricate other metal alloyed hollow nanostructures. PMID- 22939195 TI - Fulminant cerebral infarction of anterior and posterior cerebral circulation after ascending type of facial necrotizing fasciitis. AB - Necrotizing fasciitis is a soft tissue infection that is characterized by extensive necrosis of the subcutaneous fat, neurovascular structures, and fascia. Cerebral infarction after facial necrotizing fasciitis has been rarely reported. A 61-year-old woman with diabetes was admitted with painful swelling of her right cheek. One day later, she was stuporous and quadriplegic. A computed tomographic scan of her face revealed right facial infection in the periorbital soft tissue, parotid, buccal muscle, and maxillary sinusitis. A computed tomographic scan of the brain revealed cerebral infarction in the right hemisphere, left frontal area, and both cerebellum. Four days later, she died from cerebral edema and septic shock. Involvement of the cerebral vasculature, such as the carotid or vertebral artery by necrotizing fasciitis, can cause cerebral infarction. Facial necrotizing fasciitis should be treated early with surgical treatment and the appropriate antibiotic therapy. PMID- 22939196 TI - Selection of carotid artery stenting or endarterectomy based on magnetic resonance plaque imaging reduced periprocedural adverse events. AB - BACKGROUND: The aim of this study was to elucidate the impact of treatment selection, either carotid stenting or endarterectomy, based on preoperative magnetic resonance (MR) plaque imaging on periprocedural events. METHODS: A total of 205 consecutive patients with high-grade carotid artery stenosis scheduled for elective revascularization with stenting or endarterectomy were retrospectively analyzed. In period 1, 95 patients were treated regardless of preoperative plaque imaging. In period 2, 110 patients received time of flight MR angiography, and endarterectomy was selected when a high-intensity signal in the plaque was observed on MR angiography because it indicated an unstable plaque. Periprocedural clinical results and outcome at 30 days were analyzed. RESULTS: In period 1, 5 patients (5.3%) were treated with endarterectomy and the other 90 patients (94.7%) were treated with stenting. In period 2, 35 patients (31.8%) were treated with endarterectomy and the other 75 patients (68.2%) were treated with stenting. Periprocedural adverse events, including any stroke, myocardial infarction, or death, were significantly more frequent in period 1 than in period 2 (9.5% v 1.8%; P = .034). Ischemic stroke was significantly reduced from period 1 to period 2 (7.4% v 0.9%; P = .043). Multivariate logistic regression analysis revealed "treatment selection by plaque imaging" was the only factor identified as an independent predictor of periprocedural events (P = .043). CONCLUSIONS: Treatment selection based on preoperative plaque imaging appears useful for reducing periprocedural events of carotid artery revascularizations. PMID- 22939197 TI - Hybrid operating room for the treatment of complex neurovascular and brachiocephalic lesions. AB - BACKGROUND: We examine the impact of the installation of integrated hybrid operating rooms (ORs) that allow both surgical and endovascular procedures and are designed for less invasive and 1-stage treatment of complex neurovascular lesions. METHODS: We retrospectively analyzed our experience in the treatment of complex neurovascular lesions in a hybrid OR. RESULTS: Three patients with distal middle cerebral artery (MCA) aneurysms underwent a proximal clip occlusion or endovascular trapping with a superficial temporal artery-MCA bypass after correct localization of the recipient branch distal to the aneurysm using superselective intra-arterial infusion of indocyanine green under an operating microscope. Two patients with innominate artery stenosis were treated with retrograde stenting from the common carotid artery (CCA) with distal protection of the internal carotid artery (ICA) alone, and with antegrade stenting with dual protection of the ipsilateral ICA and the vertebral artery. Two patients with tandem stenosis of the proximal CCA and carotid bifurcation underwent 1-stage retrograde stenting combined with a carotid endarterectomy. A patient with the innominate artery and the proximal CCA stenosis underwent staged percutaneous antegrade angioplasty of the innominate artery followed by retrograde stenting of both lesions. A patient with tandem stenosis of the subclavian and innominate arteries underwent 1-stage retrograde stenting. In 2 patients with carotid stenosis that was difficult to access via the endovascular route, carotid stenting was performed by direct puncture of the proximal CCA. No patients suffered from new postoperative neurologic deficits. CONCLUSIONS: The integration of a high-end hybrid OR enables combined endovascular and surgical procedures for complex neurovascular and brachiocephalic lesions in a 1-stage treatment. PMID- 22939198 TI - Presentation and outcomes of "wake-up strokes" in a large randomized stroke trial: analysis of data from the International Stroke Trial. AB - BACKGROUND: Recent studies comparing the outcomes of wake-up stroke (WUS) and stroke while awake (SWA) patients reveal better outcomes among SWA patients, attributable in part to their higher rates of thrombolysis. Patients with WUS are largely excluded from therapy. Earlier analyses, conducted before the approval of alteplase for acute stroke, show the true divergence of natural histories between these 2 groups. METHODS: We analyzed 17,398 patients with ischemic stroke from the International Stroke Trial and compared both presentations and outcomes between the WUS and SWA groups. Severity was assessed by level of consciousness, Oxfordshire Community Stroke Project (OCSP) stroke classification, number of neurologic deficits, and predicted probability of dependency or death. Outcomes were assessed at day 14 and at 6 months. Outcome assessments were controlled for potential confounders. RESULTS: WUS represented 29.6% of all ischemic strokes. More severe OSCP stroke type (total anterior circulation syndrome) was less common in WUS. Although more patients with WUS were alert at presentation with a lower predicted probability of dependency, the 14-day mortality rates and rates of poor outcome at 6 months were similar between the 2 groups. CONCLUSIONS: WUS patients comprise one quarter to one third of ischemic stroke patients. Despite their more benign presentations, they deteriorate to outcome rates similar to SWA. Although they are typically excluded from time-dependent acute interventions, patients with WUS may benefit from acute intervention to prevent this worsening natural history. PMID- 22939199 TI - Diagnosis of moyamoya disease on magnetic resonance imaging: are flow voids in the basal ganglia an essential criterion for definitive diagnosis? AB - Flow voids in the basal ganglia cannot always be recognized on magnetic resonance imaging, even in patients with typical moyamoya disease. In this report, flow voids in the basal ganglia and cisternal flow voids of the sylvian valley were evaluated in patients with moyamoya disease, and their diagnostic value was verified. A total of 41 consecutive patients with moyamoya disease were included in this analysis. The number of flow voids in the basal ganglia and the sylvian valley were counted on each side by 3 observers. Then the numbers of flow voids were compared between the patients with moyamoya disease and controls. The patients with moyamoya disease had a significantly higher mean number of flow voids in the basal ganglia and the sylvian valley (P < .0001); however, the number of flow voids in the basal ganglia was 0 or 1 in 69 sides (28.0%) in patients with moyamoya disease. Comparative analysis using the area under the receiver operating curve indicated that the evaluation of flow voids in the sylvian valley was significantly superior method to that in the basal ganglia (P < .0001). The cutoff value for the number of cisternal flow voids in the sylvian valley for the diagnosis of moyamoya disease was 6. Based on these findings, we recommend a definitive diagnosis of moyamoya disease should include assessment for abnormal vessels around the terminal portions of the internal carotid arteries. PMID- 22939200 TI - Effects of sex difference on clinical features of acute ischemic stroke in Japan. AB - BACKGROUND: Sex differences in stroke characteristics and outcomes have been inconsistent. The goal of this study was to determine the influence of sex on underlying patient characteristics, stroke subtypes and conditions, and outcomes after ischemic stroke from a nationwide registration study. METHODS: A total of 33,953 patients with acute ischemic stroke, including 13,323 women, were registered in a multicenter, hospital-based registration study based on a computerized database from 162 Japanese institutes (the Japan Standard Stroke Registry Study) between January 2000 and November 2007. RESULTS: Women were significantly older than men at stroke onset (75.0 +/- 11.7 v 69.3 +/- 11.4 years; P < .0001). After age adjustment, women more frequently had cardioembolic events (odds ratio [OR] 1.090; 95% confidence interval [95% CI] 1.036-1.146; P = .0009) and other strokes (OR 1.177; 95% CI 1.079-1.284; P = .0003) and were more hypertensive (OR 1.056; 95% CI 1.006-1.108; P = .0267) and more dyslipidemic (OR 1.301; 95% CI 1.234-1.373; P < .0001) than men. After multivariate adjustment, onset-to-arrival time was longer (beta = 0.0554; P = .026), the initial National Institutes of Health Stroke Scale score was higher (beta = 0.1565; P < .001), and the duration of hospitalization was longer (beta = 0.035; P = .010) in women than in men. At hospital discharge, women less commonly had a modified Rankin Scale (mRS) score of 0 to 1 (OR 0.802; 95% CI 0.741-0.868; P < .0001) and more commonly had a mRS score of 4 to 6 (OR 1.410; 95% CI 1.293-1.537; P < .0001) than men. CONCLUSIONS: Women developed more severe strokes than men in Japan. After multivariate adjustment for initial severity and other characteristics, acute care hospital stays were longer and stroke outcomes at discharge were worse in women than in men. PMID- 22939201 TI - Alcohol is a risk factor not for thalamic but for putaminal hemorrhage: the Akita Stroke Registry. AB - BACKGROUND: Although the risk factors of cerebral hemorrhage were established long ago, there is little agreement as to the risk factors for the site of cerebral hemorrhage. METHODS: We obtained mass health screening data collected between 1990 and 2000 regarding 151,796 subjects from the Akita Prefectural Federation of Agricultural Cooperative for Health and Welfare. A first-ever cerebral hemorrhage occurring <3 years after the screening examination was defined as an event. Stroke events were determined from the Akita stroke registry between 1990 and 2003. Clinical risk factors for stroke, such as age, blood pressure, severe obesity (body mass index >30 kg/m(2)), low serum total cholesterol, hepatic disorder, renal disorder, and drinking habits were then assessed. RESULTS: Cerebral hemorrhage developed in 344 cases in the study population. The distribution of subtypes (putaminal hemorrhage [PH], thalamic hemorrhage [TH], and subcortical hemorrhage [SH]) were 122 cases (35.5%), 110 cases (32.0%), and 44 cases (12.8%), respectively. We evaluated the risk factors by multiple logistic regression analysis among these 3 groups. Age was a significant risk factor among these 3 groups, but blood pressure was not a risk factor in SH. Low serum cholesterol and drinking habits were significant risk factors only in PH. Hepatic disorder was a strong risk factor in PH and a weak risk factor in TH. Interestingly, a drinking habit was a significant risk factor only in PH. CONCLUSIONS: Drinking habits had been a risk factor for cerebral hemorrhage, but it was a risk factor not for PH and not for TH or SH. PMID- 22939202 TI - Eradication therapy for Pseudomonas aeruginosa colonization episodes in cystic fibrosis patients not chronically colonized by P. aeruginosa. AB - Pseudomonas aeruginosa (Pa) is one of the most common and clinically important pathogens in patients with cystic fibrosis (CF). Chronic Pa colonization in CF patients is associated with increased morbidity and mortality. Pa strains causing early infection are usually antibiotic sensitive and have low bacterial density in the airways. As a result, the treatment strategy has shifted from suppressive therapy in patients chronically colonized by Pa to attempts at early eradication therapy as soon as Pa is detected. In the literature, different treatment regimens have been studied. However, the optimal treatment regimen and duration of treatment are not yet determined. In this article, an overview on the natural history of early Pa colonization and the history of eradication treatment is given. Moreover, the results of the different eradication treatment trials and directions for future research are discussed. PMID- 22939203 TI - Design and evaluation of various methods for the construction of kinetic performance limit plots for supercritical fluid chromatography. AB - Supercritical fluid chromatography (SFC) is attributed many advantages over high performance liquid chromatography (HPLC). Next to the fact that SFC is greener than HPLC, which is especially important for preparative separations, SFC is claimed to be able to deliver faster separations at higher efficiencies (N) than HPLC. This is due to the higher diffusitivity of analytes in supercritical fluids compared to liquids (higher optimum mobile phase velocity) and to the lower viscosity of the mobile phases in SFC compared to HPLC, which results in smaller pressure drops allowing the use of longer columns and/or columns packed with smaller particles at higher velocities. In order to quantify this claimed kinetic performance advantage, it is essential to construct unbiased kinetic plots to make the comparison between HPLC and SFC. The high compressibility of the mobile phase in SFC however makes this problematic. A variable column length (L) kinetic plot method is therefore developed in this work. Because the pressure history in the column is kept constant for every data point in this method, this way of working definitely delivers exact values for the kinetic performance limits in SFC. It is shown that the traditional way of measuring the performance as a function of flow rate (fixed back pressure and column length) cannot deliver the same correct results as this variable L method. However, the isopycnic way of working on a fixed column length has also been proven to be a good alternative for the expensive and time consuming variable L method. Finally, isopycnic kinetic plots are used to compare SFC and HPLC performance in a quantitative way. PMID- 22939204 TI - Performance characteristics of new superficially porous particles. AB - Superficially porous particles (also called Fused-Core, core shell or porous shell particles) show distinct advantages over comparable totally porous particles for separating small molecules. Columns of Fused-Core particles exhibit very high efficiency because of superior eddy dispersion properties (smaller van Deemter A term). The efficiency for columns of 2.7 MUm Fused-Core particles actually rivals that for sub-2 MUm totally porous particles with only about one half the back pressure. These Fused-Core particles show special advantages with larger molecules for fast separations at high mobile phase velocities because of superior mass transfer (kinetic) properties (smaller van Deemter C term). This report describes the effect of different particle size and porous shell thicknesses on chromatographic performance for Fused-Core particles. Particle characteristics can significantly affect factors of separation importance. For example, the reduced plate height of packed columns is affected by particle diameter. Interestingly, larger Fused-Core particles show smaller reduced plate heights than smaller Fused-Core particles. Also, porous shell thickness has a strong effect on solute retention as well as separation efficiency, and particle surface area has a direct influence on sample loading characteristics. Fused-Core particles with a wide range of physical characteristics have been developed that allows the preparation of stable, efficient packed columns. PMID- 22939205 TI - Chiral separation of amino acids derivatised with fluorescein isothiocyanate by single isomer derivatives 3-monodeoxy-3-monoamino-beta- and gamma-cyclodextrins: the effect of the cavity size. AB - Thirteen enantiomeric pairs of alpha-amino acids derivatised with fluorescein isothiocyanate (FITC-AAs) were separated in capillary electrophoresis (CE) using as chiral selectors the single isomer derivatives (SIDs) 3-monodeoxy-3-monoamino beta- and gamma-cyclodextrins. The chiral separation data obtained by these strictly homologous compounds, show different behaviours, allowing to hypothesise a possible structure of the obtained selector-analyte complexes, as well as highlighting the crucial role of the cavity size and the significant effects on the resolution obtained by small differences in the structural characteristics of these analytes. PMID- 22939206 TI - Optimization of matrix solid-phase dispersion for liquid chromatography tandem mass spectrometry analysis of 12 pharmaceuticals in sediments. AB - The matrix solid-phase dispersion (MSPD) technique accompanied with LC-MS/MS detection for the purpose of determination of 12 pharmaceuticals (sulfaguanidine, sulfadiazine, sulfamethazine, sulfamethoxazole, trimethoprim, roxithromycin, praziquantel, febantel, enrofloxacin, ciprofloxacin, norfloxacin and procaine) applied to sediment samples has been described in this paper. Different parameters, such as the type of solid phase, the elution solvent and its volume have been investigated. The analytes were successfully extracted by C18 as an MSPD sorbent with 5 mL of acetonitrile:5% of oxalic acid=6:4 (v/v) as an elution solvent. The proposed method provides a linear response over the concentration range of 0.0005-100 MUg/g, depending on pharmaceuticals with correlation coefficients above 0.9928 in all cases except for trimethoprim (0.9889). Also, the method has revealed low limits of detection (0.125-500 ng/g), good precision (intra and inter-day), a relative standard deviation below 15% and recoveries above 80%, except for roxithromycin, febantel and enrofloxacin. The method has been successfully applied to analysis of different sediment samples. PMID- 22939207 TI - Determination of hydroxylated stilbenes in wine by dispersive liquid-liquid microextraction followed by gas chromatography mass spectrometry. AB - Dispersive liquid-liquid microextraction (DLLME) has been proposed, for first time, to determine the concentrations of three hydroxylated stilbenes (trans isomers of pterostilbene, resveratrol and piceatannol) in wine samples. DLLME was preceded by an acetylation step and followed by gas chromatography mass spectrometry (GC-MS) to achieve limits of quantification (LOQs) comprised between 0.6 and 5 ngmL(-1), linear responses up to 5000 ngmL(-1), excellent accuracy (overall recoveries ranged from 90 to 102% for samples spiked at different levels from 50 to 1000 ngmL(-1)) and standard deviations below 12%. Sample intake and organic solvents consumption remained at 1 and 0.6 mL, respectively, with a total sample preparation (derivatization and concentration) time around 15 min. The trans-isomers of piceatannol and resveratrol were measured in wine samples at concentrations up to 0.5 and 2.6 MUgmL(-1), respectively. In addition to their cis-forms, the dihydrogenated analogues of both antioxidants were detected in red wines. To the best of our knowledge, this is the first report describing the presence of dihydropiceatannol in wine. On the other hand, pterostilbene remained below the detection limits of the method in all the processed samples. In addition to the relative low levels of this stilbene existing in grapes, its lipophilic character appears to limit the transfer from grapes skins to wine. PMID- 22939208 TI - Lipophilicity screening of novel drug-like compounds and comparison to clog P. AB - We determined the distribution coefficients of solutes between a polymer film phase (polyvinyl chloride (PVC) with 67% (w/w) dioctyl sebacate (DOS)) and an aqueous phase in a 96-well format. The parallel measurement approach is efficient and uses very little material. Polymer-water distribution coefficients (D(pw)) at different pH values yield the pKa and polymer-water partition coefficient values (P(pw)) of the solutes. log P(pw) of a prominent drug-like compound, 2H-1,2,6 thiadiazine, 3-methyl-5-phenyl-,1,1-dioxide, is in good agreement with clog P, while the pK(a) value is substantially different from calculated values. This method has been also successfully applied to a library of novel drug-like compounds. log D(pw) values (at pH 4.0, 7.0, 10.0) of 24 novel drug-like compounds have been determined with good reproducibility with the 96-well plate approach. Differences between experimental values and a variety of available calculated values are significant. This emphasizes the need for laboratory separations-based measurements of log D. PMID- 22939209 TI - Efficiency gain limits of the parallel segmented inlet and outlet flow concept in analytical liquid chromatography columns suffering from radial transcolumn packing density gradients. AB - The maximal gain in efficiency that can be expected from the use of the segmented column end fittings that were recently introduced to alleviate the effect of transcolumn packing density gradients has been quantified and generalized using numerical computations of the band broadening process. It was found that, for an unretained compound in a column with a parabolic packing density gradient, the use of a segmented inlet or a segmented outlet allows to eliminate about 60-100% of the plate height contribution (H(tc)) originating from a parabolic transcolumn velocity gradient in a d(c)=4.6 mm column. In a d(c)=2.1 mm column, these percentages change from 10 to 100%. Using a combined segmented in- and outlet, H(tc) can be reduced by about 90-100% (d(c)=4.6 mm column) or 20-100% (d(c)=2.1 mm column). The strong variation of these gain percentages is due to fact that they depend very strongly on the column length and the flow rate. Dimensionless graphs have been established that allow to directly quantify the effect for each specific case. It was also found that, in agreement with one's physical intuition, trans-column velocity profiles that are more flat in the central region benefit more from the concept than sharp, parabolic-like profiles. The gain margins furthermore tend to become smaller with increasing retention and increasing diffusion coefficient. PMID- 22939210 TI - A cluster of meningococcal disease caused by rifampicin-resistant C meningococci in France, April 2012. AB - In April 2012, a cluster of two cases of meningococcal disease caused by rifampicin-resistant C meningococci was reported in the Champagne-Ardenne region, France. The two cases occurred in a student population living in the same town but studying at different schools. Bacteriological and epidemiological investigations of cases have shown that the isolates of both cases were non differentiable. PMID- 22939211 TI - Using an outbreak to study the sensitivity of the surveillance of enterohaemorrhagic Escherichia coli and other enteropathic Escherichia coli in Bavaria, Germany, January to October 2011. AB - Following an outbreak of enterohaemorrhagic Escherichia coli (EHEC) in Germany 2011, we observed increases in EHEC and non-EHEC E. coli cases in Bavaria. We compared the demographic, clinical and laboratory features of the cases reported during the outbreak period, but not related to the outbreak, to the cases reported before and after. The number of EHEC and non-EHEC E. coli cases notified per week during the outbreak was fivefold and twofold higher respectively, compared to previous years. EHEC cases notified during the outbreak were more often reported with bloody diarrhoea, and less often with unspecified diarrhoea, compared to the other periods. They were more often hospitalised during the outbreak and the following period compared to the period before. Their median age (26.5 years, range: 0-90) was higher compared to before (14.5 years, range: 0-94) and after (5 years, range: 0-81). The median age of non-EHEC E. coli cases notified during the outbreak period (18 years, range 0-88) was also higher than before and after (2 years, p<0.001). The surveillance system likely underestimates the incidence of both EHEC and non-EHEC E. coli cases, especially among adults, and overestimates the proportion of severe EHEC cases. Testing all stool samples from patients with diarrhoea for enteropathic E. coli should be considered. PMID- 22939212 TI - Prevalence and determinants associated with healthcare-associated infections in long-term care facilities (HALT) in the Netherlands, May to June 2010. AB - HAIs (healthcare-associated infections) are likely to become an increasing public health problem. Therefore, a point-prevalence study called HALT (Healthcare associated infections in long-term-care facilities) was set up by the European Centre for Disease Prevention and Control to determine the prevalence, antibiotic use and determinants associated with HAIs. In the Netherlands, 10 nursing homes (in total 1,429 elderly residents) participated in the study between May and June 2010. Risk and protective factors were determined by calculating relative risks (RRs) and performing multilevel Poisson regression. An overall infection prevalence of 2.8% was found and 3.5% of the residents used antibiotics. Residents' characteristics such as the presence of pressure wounds (RR: 2.58; 95% CI:1.04-6.39) and other wounds (RR: 5.70; 95% CI: 2.99-10.86) were risk factors for an HAI, whereas being male (RR: 0.43; 95% CI: 0.21-0.91) was protective. Nursing home characteristics, such as the percentage of shared rooms ( >= 2%) (RR: 0.49; 95% CI: 0.39-0.62) and percentage of incontinent residents (>= 3%) (RR: 0.72; 95% CI: 0.61-0.85) were protective determinants in a multivariate analysis. Special attention is therefore needed for female residents and residents with pressure and other wounds for the prevention of HAIs in Dutch nursing homes. PMID- 22939214 TI - Subfoveal choroidal thickness change following segmental scleral buckling for rhegmatogenous retinal detachment. AB - PURPOSE: To report the morphologic changes of the subfoveal choroidal thickness using spectral-domain optical coherence tomography following segmental scleral buckling. DESIGN: Retrospective, observational case series. METHODS: The study included 21 eyes of 20 patients who underwent segmental scleral buckling for the treatment of rhegmatogenous retinal detachment. All patients underwent the measurements of the subfoveal choroidal thickness preoperatively and 1 week, 1 month, and 3 months after the surgery. The changes in choroidal thickness, 4 mm from the fovea, before and 1 week after surgery were analyzed in the buckled and unbuckled side. RESULTS: The preoperative mean subfoveal choroidal thickness of operated eyes was 239.2 +/- 91.0 MUm. The postoperative mean subfoveal choroidal thicknesses of operated eyes at 1 week, 1 month, and 3 months were 267.6 +/- 96.8 MUm, 250.6 +/- 95.8 MUm, and 239.4 +/- 95.6 MUm, respectively. There were significant differences between preoperative subfoveal choroidal thickness and 1 week-postoperative and 1-month-postoperative subfoveal choroidal thicknesses (P < .01, P = .03, ANOVA), and there was no significant difference between subfoveal choroidal thicknesses preoperatively and 3 months postoperatively (P > .99, ANOVA). The changes in choroidal thickness of the buckled and unbuckled side preoperatively and 1 week postoperatively were not significantly different (n = 8, P = .589, 2-way ANOVA). CONCLUSION: The subfoveal choroidal thickness may change temporarily following segmental scleral buckling surgery. This may be the result of reversible subclinical microcirculatory dysfunction of the choroid. PMID- 22939216 TI - Interstitial fluid contains higher in vitro IGF bioactivity than serum: a study utilizing the suction blister technique. AB - CONTEXT: Circulating insulin-like growth factors (IGFs) are bound in complexes which affect their tissue-accessibility. Interstitial fluid is in close proximity to target cells, but the IGF-system is not well-described herein. OBJECTIVE: To perform a thorough comparison of the IGF-system in suction blister fluid (SBF) vs. in serum, with emphasis on bioactive IGF levels. DESIGN: Eight hour study including samples collected in the fasting state (20 h) and after a meal. SETTING: Clinical research facility. PARTICIPANTS: Six healthy males (age 37.0+/ 8.8 years, BMI 22.5+/-1.4 kg/m(2)) (mean+/-SD). MAIN OUTCOME MEASURE: Serum and SBF concentrations of bioactive IGF (determined in vitro by specific IGF-I receptor (IGF-IR) phosphorylation assay), immunoreactive IGF and IGF binding protein (IGFBP) levels, Western ligand blotting (WLB) of IGFBPs and IGFBP-3 Western immunoblotting (WiB). RESULTS: The ability of SBF to phosphorylate the IGF-IR in vitro was 41+/-27% higher than that of serum (P=0.007 by repeated measures ANOVA). By contrast, immunoreactive IGF and IGFBP-concentrations were approximately 50% lower in SBF than in serum (all P<=0.002). A marked difference in the composition of IGFBPs between serum and SBF was observed, including 3-fold elevated amounts of IGFBP-3 fragments in SBF (P<0.001). For both IGF-I, IGF-II and IGFBP-2, the effect of food intake differed between serum and SBF (all P<=0.03). CONCLUSION: Despite lower concentrations, the in vitro IGF bioactivity was higher in SBF than in serum. This may relate to an increased enzymatic IGFBP degradation and an altered IGFBP-composition in SBF, making more IGF-I and -II accessible to the IGF-IR. The impact of food intake on the IGF system differs between serum and interstitial fluid. PMID- 22939215 TI - Genomic determinants of normal tissue toxicity after radiotherapy for head and neck malignancy: a systematic review. AB - Interindividual variations in radiotoxicity responses exist despite uniform treatment protocols. It is speculated that normal genetic variants, particularly single nucleotide polymorphisms (SNPs) may influence normal head and neck (HN) tissue radiotoxicity. This first-ever systematic review was undertaken to evaluate the association of SNPs with normal HN tissues radiotoxicity. Multiple databases (1950-February 2012) were reviewed using a combination of related keywords and MeSH terms. All published HN radiotoxicity studies with sufficient relevant data for extraction were included. The outcomes evaluated were acute and late radiotoxicity endpoints. Methodological quality assessment based on the STrengthening the REporting of Genetic Association (STREGA) statement was performed. Seven articles from 692 articles searched fulfilled the eligibility criteria. Recruited sample sizes were small (range, 32-140). There were 5/7 case control studies. All studies used multimodality treatment with heterogeneous radiation parameters. Candidate gene approach was used in all studies. Fourteen SNPs from 9 genes were evaluated from the following pathways: DNA damage response, radiation fibrogenesis and oxidative/xenobiotic metabolism. Acute radiotoxicity events were associated with SNPs of DNA repair genes (OR, 3.01 4.08). SNPs of TGFbeta1 were associated with osteoradionecrosis (OR, 4.2) and subcutaneous fibrosis. Genetic association studies in HN radiotoxicity currently provide hypothesis-generating findings that require validation in larger studies. Future studies must incorporate critical methodological issues and technological improvements, including using a genome-wide approach. Headway is possible through case-pooling of existing clinical trial data which could create a larger sample size of well-characterized treatment and endpoints. Also, on-going HN cancer clinical trials should consider extending their toxicity evaluation to include genetic association studies. PMID- 22939217 TI - Growth hormone potentiates thyroid hormone effects on post-exercise phosphocreatine recovery in skeletal muscle. AB - OBJECTIVE: The aim of the study was to determine the respective impact of thyroxine and growth hormone on in vivo skeletal mitochondrial function assessed via post exercise phosphocreatine recovery. DESIGN: The hind leg muscles of 32 hypophysectomized rats were investigated using (31)P nuclear magnetic resonance spectroscopy at rest and during the recovery period following a non tetanic stimulation of the sciatic nerve. Each rat was supplemented with hydrocortisone and was randomly assigned to one of the 4 groups: the group Hx was maintained in hypopituitarism., the group HxT was treated with 1 MUg/100g/day of thyroxine (T4), the group HxG with 0.2 IU/kg/day of recombinant human GH (rGH) and the group HxGT by both thyroxine and rGH. Inorganic phosphate (Pi), phosphocreatine (PCr) and ATP were directly measured on the spectra, permitting the calculation of the phosphorylation potential (PP). RESULTS: At rest, the rats treated with rGH or T4 exhibited higher PCr levels than rats Hx. The recovery rates of PCr and PP were higher in rats treated with T4 than in T4-deprivated rats, suggesting improved mitochondrial function. The rats treated by both T4 and rGH showed higher PCr and PP recovery than those maintained in hypopituitarism or treated with T4 or rGH alone. CONCLUSIONS: The study demonstrates that in contrast to T4, GH given alone in hypophysectomized rats does not improve in vivo mitochondrial oxidative metabolism. Growth hormone potentiates T4 effects on oxidative metabolism. PMID- 22939218 TI - A cross-sectional study of the relationships between illness insight, internalized stigma, and suicide risk in individuals with schizophrenia. AB - BACKGROUND: Suicide is the major cause of premature death among individuals with schizophrenia. Ironically, one factor that heightens suicide risk is insight into mental illness. Little is known, however, about how insight contributes to suicidality. Recent evidence suggests that negative outcomes related to insight might depend on whether or not the individual accepts the stigmatizing beliefs about the mental illness. OBJECTIVE: The present study examined the interactive effects of insight and internalized stigma on suicide risk in individuals with schizophrenia. We hypothesized that insight into mental illness and internalized stigma would increase suicide risk and that internalized stigma would moderate the effect of insight on suicide risk. DESIGN AND PARTICIPANTS: A cross-sectional design was used in this study. A convenience sample of 200 individuals with schizophrenia was recruited from an outpatient clinic in the Eastern catchment area in Alexandria, Egypt. METHODS: Eligible study participants were individuals with an illness duration not exceeding ten years, currently in outpatient treatment and follow-up, and post-acute or in a stable phase of their disorder. Individuals provided signed consent to participate and were interviewed to assess suicide risk, insight, internalized stigma of mental illness and depression. RESULTS: Slightly more than 38% of the study participants were classified as having a severe suicide risk. As predicted, suicide risk was positively associated with insight (r=.55, p<.001), internalized stigma (r=.79, p<.001), and depression (r=.78, p<.001). However, the influence of insight was not significant after controlling for covariates in the regression model (beta=-.02, ns). Internalized stigma and depression independently predicted suicide risk, explaining 74% of variance in suicide risk, F(change) (6, 191)=11.54, p<.001. Greater insight was significantly linked to increased levels of internalized stigma (r=.59, p<.001) and depression (r=.61, p<.001). Internalized stigma did not moderate the influence of insight on suicide risk. CONCLUSION: The present study draws attention to the robust influence of internalized stigma in increasing suicide risk and suggests clinical approaches for managing internalized stigma and suicide risk among individuals with schizophrenia. PMID- 22939219 TI - Ceramic modifications of porous titanium: effects on macrophage activation. AB - Porous titanium is one of the most widely used implant materials because of its mechanical properties, however, it is also characterised by low bioactivity. To improve the above parameter we prepared three modifications of the porous (30 wt%) titanium (Ti) surface by covering it with bioactive hydroxyapatite (HA), bioglass (BG) and calcium silicate (CS). Subsequently we tested the impact of the modifications on macrophages directing the inflammatory response that might compromise the implant bioactivity. In the study we investigated the in vitro effects of the materials on murine cell line RAW 264.7 macrophage adherence, morphology and activation (production/release of metalloproteinase MMP-9 and pro- and anti-inflammatory cytokines). CS Ti decreased the macrophage adherence and up regulated the release of several pro-inflammatory mediators, including TNF-alpha, IL-6, IL-12. Also HA Ti reduced the cell adherence but other parameters were generally not increased, except of TNF-alpha. In contrast, BG Ti improved macrophage adherence and either decreased production of multiple mediators (MMP 9, TNF-alpha, IFN-gamma, MCP-1) or did not change it in comparison to the porous titanium. We can conclude that analyzing the effects on the inflammatory response initiated by macrophages in vitro, calcium silicate did not improve the biological properties of the porous titanium. The improved bioactivity of titanium was, however, achieved by the application of the hydroxyapatite and bioglass layers. The present in vitro results suggest that these materials, HA Ti and especially BG Ti, may be suitable for in vivo application and thus justify their further investigation. PMID- 22939220 TI - Assessment of sources of human pathogens and fecal contamination in a Florida freshwater lake. AB - We investigated the potential for a variety of environmental reservoirs to harbor or contribute fecal indicator bacteria (FIB), DNA markers of human fecal contamination, and human pathogens to a freshwater lake. We hypothesized that submerged aquatic vegetation (SAV), sediments, and stormwater act as reservoirs and/or provide inputs of FIB and human pathogens to this inland water. Analysis included microbial source tracking (MST) markers of sewage contamination (Enterococcus faecium esp gene, human-associated Bacteroides HF183, and human polyomaviruses), pathogens (Salmonella, Cryptosporidium, Giardia, and enteric viruses), and FIB (fecal coliforms, Escherichia coli, and enterococci). Bayesian analysis was used to assess relationships among microbial and physicochemical variables. FIB in the water were correlated with concentrations in SAV and sediment. Furthermore, the correlation of antecedent rainfall and major rain events with FIB concentrations and detection of human markers and pathogens points toward multiple reservoirs for microbial contaminants in this system. Although pathogens and human-source markers were detected in 55% and 21% of samples, respectively, markers rarely coincided with pathogen detection. Bayesian analysis revealed that low concentrations (<45 CFU * 100 ml(-1)) of fecal coliforms were associated with 93% probability that pathogens would not be detected; furthermore the Bayes net model showed associations between elevated temperature and rainfall with fecal coliform and enterococci concentrations, but not E. coli. These data indicate that many under-studied matrices (e.g. SAV, sediment, stormwater) are important reservoirs for FIB and potentially human pathogens and demonstrate the usefulness of Bayes net analysis for water quality assessment. PMID- 22939221 TI - A solar-driven UV/Chlorine advanced oxidation process. AB - An overlap of the absorption spectrum of the hypochlorite ion (OCl(-)) and the ultraviolet (UV) end of the solar emission spectrum implies that solar photons can probably initiate the UV/chlorine advanced oxidation process (AOP). The application of this solar process to water and wastewater treatment has been investigated in this study. At the bench-scale, the OCl(-) photolysis quantum yield at 303 nm (representative of the lower end of the solar UV region) and at concentrations from 0 to 4.23 mM was 0.87 +/- 0.01. Also the hydroxyl radical yield factor (for an OCl(-) concentration of 1.13 mM) was 0.70 +/- 0.02. Application of this process, at the bench-scale and under actual sunlight, led to methylene blue (MB) photobleaching and cyclohexanoic acid (CHA) photodegradation. For MB photobleaching, the OCl(-) concentration was the key factor causing an increase in the pseudo first-order rate constants. The MB photobleaching quantum yield was affected by the MB concentration, but not much by the OCl(-) concentration. For CHA photodegradation, an optimal OCl(-) concentration of 1.55 mM was obtained for a 0.23 mM CHA concentration, and a scavenger effect was observed when higher OCl(-) concentrations were applied. Quantum yields of 0.09 +/- 0.01 and 0.89 +/- 0.06 were found for CHA photodegradation and OCl(-) photolysis, respectively. In addition, based on the Air Mass 1.5 reference solar spectrum and experimental quantum yields, a theoretical calculation method was developed to estimate the initial rate for photoreactions under sunlight. The theoretical initial rates agreed well with the experimental rates for both MB photobleaching and CHA photodegradation. PMID- 22939222 TI - A novel structure of scalable air-cathode without Nafion and Pt by rolling activated carbon and PTFE as catalyst layer in microbial fuel cells. AB - Single chambered air-cathode microbial fuel cells (MFCs) are promising to be scaled up as sustainable wastewater treatment systems. However, the current air cathode made by brushing noble metal catalyst and Nafion binder onto carbon matrix becomes one of the biggest bottlenecks for the further development of MFCs due to its high cost, huge labor-consuming and less accuracy. A novel structure of air-cathode was constructed here by rolling activated carbon (AC) and polytetrafluoroethylene (PTFE) as catalyst layer to enhance the reproducibility and improve the performance by an optimized three-phase interface (TPI). Air cathodes with AC/PTFE ratios of 3, 5, 6, 8 and 11 in the catalyst layer were prepared, and the physical and electrochemical techniques were employed to investigate their surface microstructure and electrochemical characteristics. Uniform cross-linked ropiness networks were observed from the catalyst layer of all the cathodes and increased as the AC/PTFE ratio decreased, while the exchange currents were positively related to this ratio. Maximum power densities (MPDs) decreased as follows: AC/PTFE = 6 (802 mW m(-2) at 3.4 A m(-2)), 5 (704 mW m(-2) at 2.2 mA m(-2)), 8 (647 mW m(-2) at 2.2 A m(-2)), 3 (597 mW m(-2) at 2.1 A m( 2)) and 11 (584 mW m(-2) at 2.0 mA m(-2)), which was due to the changes of both the capacitance characteristics and conductivities according to the electrochemical impedance spectrum (EIS) analysis. This study demonstrated that inexpensive, highly reproducible, high performance and scalable air-cathode can be produced by rolling method without using noble metal and expensive binder. PMID- 22939223 TI - 2012 EHRA/HRS expert consensus statement on cardiac resynchronization therapy in heart failure: implant and follow-up recommendations and management. PMID- 22939225 TI - Do cancer cells have distinct adhesions in 3D collagen matrices and in vivo? AB - During metastasis, cancer cells breach the basement membrane and migrate through the stroma mostly composed of a network of collagen I fibers. Cell migration on 2D is initiated by protrusion of the cell membrane followed by formation of adhesions that link the actin cytoskeleton to the extracellular matrix (ECM). Cells then move forwards by exerting traction forces on the adhesions at its front and by disassembling adhesions at the rear. In 2D, only the ventral surface of a migrating cell is in contact with the ECM, where cell-matrix adhesions are assembled. In 3D matrices, even though the whole surface of a migrating cell is available for interacting with the ECM, it is unclear whether discrete adhesion structures actually exist. Using high-resolution confocal microscopy we imaged the endogenous adhesome proteins in three different cancer cell types embedded in non-pepsinized collagen type I, polymerized at a slow rate, to allow the formation of a network that resembles the organization of EMC observed in vivo. Vinculin aggregates were detected in the cellular protrusions, frequently colocalizing with collagen fibers, implying they correspond to adhesion structures in 3D. As the distance from the substrate bottom increases, adhesion aggregates become smaller and almost undetectable in some cell lines. Using intravital imaging we show here, for the first time, the existence of adhesome proteins aggregates in vivo. These aggregates share similarities with the ones found in 3D collagen matrices. It still remains to be determined if adhesions assembled in 3D and in vivo share functional similarities to the well-described adhesions in 2D. This will provide a major step forward in understanding cell migration in more physiological environments. PMID- 22939226 TI - Site-specific cellular functions of MT1-MMP. AB - The response to environmental cues such as inflammatory stimuli requires coordinated cellular functions. Certain proteins have functions on both sides of the plasma membrane to allow coordination between the extracellular and intracellular milieus. The membrane-anchored matrix metalloproteinase MT1-MMP is well positioned to sense and modify the extracellular environment by processing matrix components, transmembrane proteins and soluble factors. Recent findings show, however, that MT1-MMP also plays unexpected intracellular roles in macrophages through its location at the plasma membrane, the Golgi or the nucleus, impacting cell motility, metabolism and gene transcription. MT1-MMP is thus an example of the evolutionary diversification of protein function, allowing optimal coordination between extracellular stimuli and cellular responses. It remains to be determined whether these new MT1-MMP functions are specific to macrophages, professional phagocytes involved in inflammation, or are present in other inflammation-responsive cells. In this review, we will summarize these site specific MT1-MMP functions in macrophages and comment on the possible conservation of these functions in endothelial cells. PMID- 22939228 TI - Association of polymorphisms in microRNA-binding sites and colorectal cancer in an Iranian population. AB - MicroRNAs (miRNAs) are agents of post-transcriptional gene expression, and they can affect many functions of an individual cell or tissue from extracellular matrix production to inflammatory processes and tumor development. We aimed to determine the possible role of miRNA-binding site polymorphisms located in five cancer-related genes: IL-16, CDKN2A (p16), RAF1, PTGER4, and ITGB4 in colorectal cancer (CRC) risk modification in an Iranian population. This study was performed on 643 individuals (249 CRC cases and 394 healthy controls). We selected five cancer-related genes (IL-16, CDKN2A (p16), RAF1, PTGER4, and ITGB4) and investigated the genotypes of the 3' untranslated region miRNA-binding site polymorphisms in these genes in our study population. The restriction fragment length polymorphism results were confirmed by a direct sequencing method. We found a statistically significant difference between the rs1131445 polymorphism of the IL-16 gene and CRC. The frequencies of the genotypes TT, CT, and CC in controls were 51%, 40.4%, and 8.6%, respectively, and in cases were 41.4%, 44.1%, and 14.5%, respectively, which shows a significant association between the CC genotype of the rs1131445 polymorphism and CRC (P = 0.004). The frequency of the C allele in the CRC group was higher than in the controls, and the C allele of the rs1131445 polymorphism was found to be in association with CRC (P = 0.009). These associations remained significant after Bonferroni's correction for multiple testing. We found that the AA genotype of the rs743554 polymorphism in the ITGB4 gene and the T allele of the rs1051208 polymorphism of the RAF1 gene were associated with the risk of CRC in females; however, after Bonferroni's correction we found that they were non-significant. Finally, we can conclude that a significant relationship exists between the miRNA-binding site polymorphism of the IL-16 gene and CRC risk in the Iranian population. PMID- 22939227 TI - Li-Fraumeni syndrome: report of a clinical research workshop and creation of a research consortium. AB - Li-Fraumeni syndrome (LFS) is a rare dominantly inherited cancer predisposition syndrome that was first described in 1969. In most families, it is caused by germline mutations in the TP53 gene and is characterized by early onset of multiple specific cancers and very high lifetime cumulative cancer risk. Despite significant progress in understanding the molecular biology of TP53, the optimal clinical management of this syndrome is poorly defined. We convened a workshop on November 2, 2010, at the National Institutes of Health in Bethesda, Maryland, bringing together clinicians and scientists, as well as individuals from families with LFS, to review the state of the science, address clinical management issues, stimulate collaborative research, and engage the LFS family community. This workshop also led to the creation of the Li-Fraumeni Exploration (LiFE) Research Consortium. PMID- 22939229 TI - Immunoglobulin heavy chain (IGH@) translocations negatively impact treatment-free survival for chronic lymphocytic leukemia patients who have an isolated deletion 13q abnormality. AB - Immunoglobulin heavy chain translocations (t(IGH@)) are suggested to portend a poor prognosis in chronic lymphocytic leukemia (CLL). To determine the clinical significance of a t(IGH@) on CLL-specific cytogenetic abnormalities, we analyzed the outcomes of 142 CLL patients referred for fluorescence in situ hybridization (FISH) analysis with our standard FISH panel, which includes testing for a t(IGH@). Whereas patients with unfavorable (deletion 17p, deletion 11q) and intermediate (trisomy 12, normal FISH) cytogenetics with concomitant t(IGH@) had similar median treatment-free survival (TFS) as those without a t(IGH@), patients with deletion 13q (del13q) and a t(IGH@) had significantly worse TFS than those without a t(IGH@): median TFS 4.7 versus 8.0 years, P = 0.03 (hazard ratio 4.21, 95% confidence interval 1.06-16.69 y, P = 0.04 in multivariate analysis after adjusting for age, sex, Rai stage, and white blood cell count). The presence of a t(IGH@) further stratified patients with del13q into two prognostic entities, whereby outcomes of those with coexistent del13q and a t(IGH@) were similar to outcomes of those with high risk cytogenetics. Knowledge of the t(IGH@) status in CLL is therefore of clinical importance, as del13q patients with concomitant t(IGH@) may not retain the previously expected favorable outcome. PMID- 22939230 TI - Exploring the relationships between tobacco smoking and schizophrenia in first degree relatives. AB - Up to 90% of individuals with schizophrenia suffer from nicotine dependence. Both schizophrenia and nicotine consumption have strong genetic components, which may overlap. The relationship between schizophrenia and nicotine dependence remains unclear, due in part to confounding factors. Studies of the relationship between nicotine consumption and milder schizophrenia-related phenotypes, such as schizotypy, in first-degree relatives of individuals with schizophrenia could help to better understand the relationship between smoking and schizophrenia while avoiding such confounders. We assessed the proportion of smokers, their level of nicotine dependence and their level of schizotypy in a sample of 98 first-degree relatives of schizophrenic subjects and 110 healthy controls. Partial correlation analysis was used to assess the relationship between schizotypal dimensions and smoking dependence. The prevalence of smoking and nicotine dependence levels were higher in the relatives than in the healthy control group. We found no relationship between nicotine dependence and the magnitude of schizotypal features in either group. Our results support the hypothesis that the relationship between schizophrenia and smoking is largely mediated by common familial factors, which may be genetic. PMID- 22939231 TI - The lack of association between catechol-O-methyl-transferase Val108/158Met polymorphism and smoking in schizophrenia and alcohol dependence. PMID- 22939232 TI - Review: Structure-function and biological properties of the atypical chemokine receptor D6. AB - The atypical chemokine receptor D6 was initially called "silent" on the basis of lack of conventional signaling events that lead to directional cell migration. It has emerged that D6 is able to bind and drive to degradative compartments most inflammatory CC chemokines and that is able to convey G-protein independent signaling events to optimize its scavenging activity. We here summarize the knowledge available today on D6 structural and signaling properties and its essential role for the control of inflammatory cells traffic and proper development of the adaptive immune response. PMID- 22939233 TI - Benzimidazoles as benzamide replacements within cyclohexane-based CC chemokine receptor 2 (CCR2) antagonists. AB - We describe the design, synthesis, and evaluation of benzimidazoles as benzamide replacements within a series of trisubstituted cyclohexane CCR2 antagonists. 7 Trifluoromethylbenzimidazoles displayed potent binding and functional antagonism of CCR2 while being selective over CCR3. These benzimidazoles were also incorporated into lactam-containing antagonists, thus completely eliminating the customary bis-amide. PMID- 22939234 TI - Potent and orally efficacious benzothiazole amides as TRPV1 antagonists. AB - Benzothiazole amides were identified as TRPV1 antagonists from high throughput screening using recombinant human TRPV1 receptor and structure-activity relationships were explored to pinpoint key pharmacophore interactions. By increasing aqueous solubility, through the attachment of polar groups to the benzothiazole core, and enhancing metabolic stability, by blocking metabolic sites, the drug-like properties and pharmokinetic profiles of benzothiazole compounds were sufficiently optimized such that their therapeutic potential could be verified in rat pharmacological models of pain. PMID- 22939235 TI - Exploring converse molecular mechanisms of anti-HIV-1 antibodies using a synthetic CXCR4 mimic. AB - Different molecular mechanisms of the two broadly neutralizing anti-HIV-1 antibodies b12 and VRC01, as evidenced by their converse effects on the interaction of HIV-1 envelope glycoprotein gp120 with cellular coreceptors, were demonstrated using a synthetic CXCR4 mimetic peptide (CX4-M1) as coreceptor surrogate. While the interaction of gp120 with CX4-M1 was distinctly enhanced by VRC01, b12 was shown to have the contrary effect, and also to inhibit the VRC01 induced enhancement of gp120 binding to the CXCR4 mimetic peptide. PMID- 22939236 TI - Practices of French family physicians concerning varicella vaccination for teenagers. AB - OBJECTIVES: The authors assessed the knowledge and practices of French family physicians concerning the application of the new 2007 varicella vaccination guidelines for non-immune teenagers, 12 to 18 years of age. They also estimated the vaccination coverage in this population. METHOD: A questionnaire link was sent by to 1008 family physicians of the French Inserm Sentinel network. Each family physician had to include the last teenager aged 12 to 18 years seen in consultation, with no or uncertain history of clinical varicella. RESULTS: One hundred and forty-one family physicians agreed to participate and included one patient (participation rate=14%) between 4th November 2010 and 4th January 2011. One hundred and thirty-three questionnaires out of 141 (94%) were analyzed. Three patients were vaccinated and 127 were not, giving a weak vaccination coverage in the investigated population at 2%. Eighty-nine family physicians (70%) did not know about the recommendation, and 90 (71%) declared that they had no intention to vaccinate their patient against varicella. CONCLUSION: Guidelines on varicella vaccination of non-immune teenagers are poorly followed and accepted by family physicians. Vaccination coverage is very low, and efforts should be made to improve application of recommendations. PMID- 22939237 TI - Construct validity of a new rating scale for self-reported impairments in persons with late effects of polio. AB - OBJECTIVE: To evaluate the construct validity of a new rating scale for self reported impairments in persons with late effects of polio. DESIGN: Psychometric analysis of data on self-perceived impairments in persons with prior polio. PARTICIPANTS: Two hundred seventy-three persons with prior polio (119 men and 154 women; mean age, 63.5 years). METHOD: Rasch analysis of a 13-item rating scale with 5 response categories, in which the participants rated how much they have been bothered by various post-polio-related impairments during the past 2 weeks. RESULTS: The initial analysis showed disordered categories, misfit with some of the items, multidimensionality, and local dependency. After adjustment of the categories, which resulted in a 4-category rating scale, fit to the model was achieved, but the scale still showed signs of multidimensionality. Analyses of local dependency revealed correlations among some of the items, which resulted in a 5 testlet solution, which gave fit to the model and unidimensionality. CONCLUSION: After adjustment of the categories and local dependency, this new rating scale, Self-Reported Impairments in Persons With Late Effects of Polio, can be considered as unidimensional. The good psychometric properties implies that the Self-Reported Impairments in Persons With Late Effects of Polio scale could be a useful rating scale that would increase our understanding of the impairments that persons with late effects of polio can experience. With further refinements, this scale may assist in the planning and evaluation of appropriate rehabilitation interventions. PMID- 22939238 TI - Changes in biomechanical properties of glenohumeral joint capsules with adhesive capsulitis by repeated capsule-preserving hydraulic distensions with saline solution and corticosteroid. AB - OBJECTIVE: To investigate whether capsule-preserving hydraulic distension with saline solution and corticosteroid for adhesive capsulitis induces biomechanical alterations in glenohumeral joint capsules along with clinical improvements. DESIGN: A case series. SETTING: University outpatient clinic of physical medicine and rehabilitation. PARTICIPANTS: Eighteen patients with unilateral adhesive capsulitis. INTERVENTION AND MAIN OUTCOME MEASUREMENTS: Three hydraulic distensions with saline solution and corticosteroid were performed with 1-month intervals. To avoid rupturing capsules, all distensions were monitored by using real-time pressure-volume curves. Stiffness, maximal volume capacity, and pressure at the maximal volume capacity of the capsule were measured at each intervention. Clinical parameters, such as pain and range of motion, were recorded before, 3 days after, and 1 month after each distension. RESULTS: Stiffness decreased (47.6 +/- 27.1 mm Hg/mL to 31.7 +/- 18.4 mm Hg/mL to 24.2 +/- 14.0 mm Hg/mL, mean SD) and maximal volume capacity increased (18.8 +/- 7.3 mL to 20.5 +/- 7.5 mL to 24.2 +/- 7.0 mL, mean SD) significantly (P = .001 for both) at each repeated hydraulic distension. Pressure at the maximal volume capacity tended to decrease, but the decrements were not statistically significant (P = .662). The clinical parameters were significantly improved throughout and 1 month after the 3 repeat procedures (P < .05 for all). CONCLUSION: Capsule-preserving hydraulic distension changed the biomechanical properties of the glenohumeral joint capsule, lessening the stiffness and enlarging the volume capacity. These alterations were accompanied by improved range of motion and relief of pain. Repeated capsule-preserving hydraulic distension with saline solution and corticosteroid would be useful to treat adhesive capsulitis and to evaluate the treatment results. PMID- 22939239 TI - Patient-, treatment-, and facility-level structural characteristics associated with the receipt of preoperative lower extremity amputation rehabilitation. AB - OBJECTIVES: To determine patient, treatment, or facility characteristics that influence decisions to initiate a rehabilitation assessment before transtibial or transfemoral amputation within the Veterans Affairs (VA) health care system. DESIGN: Retrospective database study. SETTING: VA medical centers. PARTICIPANTS: A total of 4226 veterans with lower extremity amputations discharged from a VA medical center between October 1, 2002, and September 30, 2004. OUTCOME: Evidence of a preoperative rehabilitation assessment after the index surgical stay admission but before the surgical date. RESULTS: Evidence was found that 343 of 4226 veterans (8.12%) with lower extremity amputations received preoperative rehabilitation assessments. Veterans receiving preoperative rehabilitation were more likely to be older, admitted from home, or transferred from another hospital. Patients who underwent surgical amputation at smaller-sized hospitals or in the South Central or Mountain Pacific regions were more likely to receive preoperative rehabilitation compared with patients in mid-sized hospitals or in the Northeast, Southeast, or Midwest regions. Patients with evidence of paralysis, patients treated in facilities with programs accredited by the Commission on Accreditation of Rehabilitation Facilities (P < .01), and patients in the second data wave were less likely to receive preoperative rehabilitation. After accounting for patient-, treatment-, and facility-level structural characteristics, we found that older patients were more likely to receive preoperative rehabilitation services (odds ratio [OR] 1.01, 95% confidence interval [CI] 1.01-1.02). Patients with a contributing amputation etiology of a previous amputation complication were more likely to receive preoperative consultation rehabilitation services (OR 1.50, 95% CI 1.02-2.19) compared with patients who did not have this etiology. Compared with patients treated in the Southeast region of the United States, those treated in the South Central region (OR 2.52, 95% CI 1.82-3.48) or Mountain Pacific region (OR 1.62, 95% CI 1.11 2.37) were more likely to receive preoperative consultation rehabilitation services. Patients with evidence of paralysis were less likely to receive preoperative rehabilitative services compared with patients who did not have this condition (OR 0.29, 95% CI 0.09-0.93), and patients treated in mid-sized hospitals also were less likely to receive preoperative rehabilitative services compared with patients treated in smaller-sized facilities (OR 0.38, 95% CI 0.27 0.53). Veterans in the second data year were less likely to receive services compared with patients in the first year (OR 0.74, 95% CI 0.58-0.94). CONCLUSIONS: Rehabilitation assessment before lower extremity amputation surgery is a rare occurrence in the VA health care system. Practice patterns appear to be driven by location and not by patient characteristics. PMID- 22939240 TI - Effects of infertility on gender differences in marital relationship and quality of life: a case-control study of Turkish couples. AB - OBJECTIVES: Although there are many studies trying to evaluate the effect of infertility on marital relations (MR) and quality of life (QoL) in developed counties, there have been no studies in Turkey. As in many societies around the world, lack of pregnancy and the resulting childlessness are often highly stigmatized, leading to profound social suffering for infertile couples in Turkey. STUDY DESIGN: This study was planned as a case-control study in order to investigate the effects of infertility on MR and QoL. It was conducted among 58 primary infertile and 51 fertile couples. The Dyadic Adjustment Scale (DAS) and the World Health Organization QoL Scale (WHOQOL-BREF) were applied at the infertility department of the Istanbul University's faculty of medicine. The t test, Mann-Whitney U, ANOVA and Pearson's correlation coefficient were used. RESULTS: The socio-demographic properties were similar for both groups. The QoL average score was higher for the infertile group. There were no gender differences in QoL for infertile couples. The total DAS score was higher than the cut-off score for both groups (114.44 +/- 18.53 for infertile, 110.29 +/- 18.28 for fertile couples; p>0.05). Infertile women's DAS and QoL scores were higher than the fertile women's (p<0.05). Other than in the social domain, all QoL scores were higher for infertile men than fertile men (p<0.05). There was a positive correlation between the DAS and QoL scores. CONCLUSIONS: It was determined that infertility did not have a negative impact on MR and QoL measurements. There were no gender differences. PMID- 22939241 TI - Therapeutic management of uterine fibroid tumors: updated French guidelines. AB - The medical management of symptomatic non-submucosal uterine fibroid tumors (leiomyomas or myomas) is based on the treatment of abnormal uterine bleeding by any of the following: progestogens, a levonorgestrel-releasing intrauterine device, tranexamic acid, nonsteroidal anti-inflammatory drugs, or GnRH analogs. Selective progesterone receptor modulators are currently being evaluated and have recently been approved for fibroid treatment. Neither combined estrogen progestogen contraception nor hormone treatment of the menopause is contraindicated in women with fibroids. When pregnancy is desired, whether or not infertility is being treated by assisted reproductive technology, hysteroscopic resection in one or two separate procedures of submucosal fibroids less than 4 cm in length is recommended, regardless of whether they are symptomatic. Interstitial, also known as intramural, fibroids have a negative effect on fertility but treating them does not improve fertility. Myomectomy is therefore indicated only for symptomatic fibroids; depending on their size and number, and may be performed by laparoscopy or laparotomy. Physicians must explain to women the potential consequences of myomas and myomectomy on future pregnancy. For perimenopausal women who have been informed of the alternatives and the risks, hysterectomy is the most effective treatment for symptomatic fibroids and is associated with a high rate of patient satisfaction. When possible, the vaginal or laparoscopic routes should be preferred to laparotomy for hysterectomies for fibroids considered typical on imaging. Because uterine artery embolization is an effective treatment with low long-term morbidity, it is an option for symptomatic fibroids in women who do not want to become pregnant, and a validated alternative to myomectomy and hysterectomy that must be offered to patients. Myolysis is under assessment, and research on its use is recommended. Isolated laparoscopic ligation of the uterine arteries is a potential alternative to uterine artery embolization; it also complements myomectomy by reducing intraoperative bleeding. It is possible to use second-generation techniques of endometrial ablation to treat submucosal fibroids in women whose families are complete. Subtotal hysterectomy is a possible alternative to total hysterectomy for fibroid treatment, given that by laparotomy the former has a lower complication rate than the latter, while by laparoscopy, these rates are the same. In each case, the patient is informed about the benefit and risk associated with each therapeutic option. PMID- 22939242 TI - Evaluation of the pooling of swabs for real-time PCR detection of low titre shedding of low pathogenicity avian influenza in turkeys. AB - The purpose of this study was to determine whether pooling avian influenza (AI) positive swabs with negative swabs has a detrimental effect on the sensitivity of AI real-time reverse transcription-polymerase chain reactions (rRT-PCRs). Cloacal and buccal swabs were sampled daily from 12 turkeys infected with A/goose/England/07(H2N2). For half the turkeys, each swab was mixed with four swabs from known AI-negative turkeys, and for the other half the swabs were tested individually. Bayesian modelling was used to (i) determine whether pooling the positive swabs compromised the cycle threshold (C(t)) value obtained from the rRT-PCRs, and (ii) estimate the likelihood of detection of an H2N2 infected turkey flock via rRT-PCR for pooled and individually tested swabs (cloacal and buccal) vs. the number of days post-infection of the flock. Results indicated that there was no significant effect of compromising AI rRT-PCR sensitivity by pooling a weak positive swab with negative swabs on the Ct values which were obtained. Pooled sampling was able to widen the detection window compared to individual sampling, for the same number of rRT-PCR tests. This indicates that pooled sampling would be an effective method of reducing the number of tests to be performed to determine flock status during an AI outbreak and for surveillance. PMID- 22939243 TI - Photoluminescence (PL) quenching and enhanced photocatalytic activity of Au decorated ZnO nanorods fabricated through microwave-assisted chemical synthesis. AB - ZnO nanorods decorated with gold nanoparticles of ~20 nm average size were fabricated by microwave-assisted chemical synthesis. For the surface-attached growth of metal nanoparticles, the ZnO nanostructures were first functionalized by sodium citrate and then the metal ions were reduced under microwave heating. While the incorporation of gold nanoparticles at the surface seen to quench both the band edge and visible emissions of the ZnO nanostructures, it enhances the degradation rate of Rhodamine 6G up to 3 folds under UV emission. The mechanisms of citrate functionalization, growth of Au nanoparticles on the surface of the oxide nanostructures, luminescence emission quenching, and enhanced photocatalytic activity of the composite nanostructures have been discussed. PMID- 22939244 TI - MicroRNA expression profiling of esophageal cancer before and after induction chemoradiotherapy. AB - BACKGROUND: The prognosis for esophageal cancer is poor but may be improved by neoadjuvant therapy. A complete pathologic response (pCR) is associated with improved survival. We conducted a study to profile the expression of microRNAs (miRNAs) in esophageal cancer before and after induction therapy. Our aims were to identify those miRNAs that are differentially regulated after induction therapy and attempt to describe a miRNA pattern that could predict pCR. METHODS: Total RNA was extracted from pretreatment and posttreatment specimens from 25 patients who underwent trimodal therapy using concurrent irinotecan/cisplatin and radiotherapy followed by surgical treatment. miRNAs were labeled and hybridized to the Illumina miRNA BeadChip microarray (Illumina, Inc, San Diego, CA). Expression data was quantified using BeadStudio software (Illumina), using a cutoff for significant gene differences of p less than 0.05 with a 2-fold difference in expression. Survival analysis was performed using SPSS, version 18 (SPSS, Inc, Chicago, IL). RESULTS: Using pretreatment biopsy specimens, 71 miRNAs were significantly different between pCR and non-pCR groups. Of these, 5 miRNAs were greater than 2-fold differentially regulated, including miR-296, recently shown to be of prognostic significance in esophageal carcinoma. After induction therapy, 568 miRNAs were found to be significantly upregulated or downregulated, 111 of which had a 2-fold difference. Patients with high levels of miR-135b or miR-145 in the posttreatment biopsy specimens had significantly shorter median disease-free survival (DFS) than did those with low levels (11.5 versus 5.1 months; p=0.04; 11.5 versus 2.8 months; p=0.03). CONCLUSIONS: miRNA expression profiling of pretreatment biopsy specimens revealed 5 miRNAs differentially expressed in patients with pCR compared with patients without pCR. We have also identified 111 miRNAs significantly upregulated or downregulated after induction therapy, some of which may be predictive of outcome. Further study of these miRNAs may elucidate a novel understanding of mechanisms of resistance to chemotherapy or radiotherapy. PMID- 22939245 TI - Supercharged pedicled jejunal interposition for esophageal replacement: a 10-year experience. AB - BACKGROUND: Esophageal continuity after esophagectomy can be established without a viable stomach conduit by using the colon or jejunum. The current study evaluated the technical outcomes of the long-segment supercharged jejunal (SPJ) interposition. METHODS: A database was developed to capture patient characteristics, operative technique, and outcomes for patients with an SPJ interposition at 2 institutions from 2000 to 2010. A multivariable analysis was performed to determine predictors of leak and graft loss. A selective prospective manometric analysis was performed to describe peristalsis of the SPJ. RESULTS: Of the 60 patients undergoing SPJ reconstruction, 44 (73%) were men, and the median age was 57 years (range, 28 to 76 years). The operation in 23 patients (38%) was performed to reverse esophageal discontinuity, and 57 (95%) patients underwent reconstruction for cancer. Early complications included 18 instances (30%) of pneumonia, 19 anastomotic leaks (32%), and 5 instances of graft loss with diversion (8%). Three patients (5%) died in the hospital or within 30 days. After jejunal reconstruction, 50 patients (83%) were able to return to a regular diet. The 90-day mortality rate was 10% (n=6). Characteristic postoperative manometric findings included segmental peristalsis, as is typical for in situ jejunum. Median survival was 28 months and the 5-year survival rate was 30%. CONCLUSIONS: An SPJ conduit can reestablish or maintain gastrointestinal continuity in high risk patients when the stomach is unavailable. This is our preferred conduit for reconstruction of the esophagus over the colon. PMID- 22939246 TI - Hemodynamic index for risk stratification after neonatal total anomalous pulmonary venous drainage repair. AB - BACKGROUND: Repair of total anomalous pulmonary venous drainage (TAPVD) in neonates remains a challenge. It is associated with a high mortality. We aimed at determining a method for risk stratification of this group of patients. METHODS: From 1994 to 2008, 54 patients underwent simple TAPVD operations during the first month of life. Mean pulmonary arterial pressure (PAP), mean systemic arterial pressure (MAP), systolic blood pressure, diastolic blood pressure, central venous pressure, and left atrial pressure were recorded in 44 of the 54 patients for the first 36 hours postoperatively. The remaining 10 patients were excluded because data from invasive pressure monitoring were not available. RESULTS: There were overall 8 deaths (18.2%, 8/44), including 4 (9%, 4/44) early deaths, and 5 reoperations (11.4%, 5/44). The mean PAP was 23.1 +/- 6.4 mm Hg, the mean MAP was 50.3 +/- 5 mm Hg, and the PAP-to MAP-ratio (PAP/MAP) was 0.80 +/- 0.36. By multivariable logistic analysis, the risk factors for mortality were a higher PAP/MAP (p = 0.037) and lower operative weight (p = 0.02). All deaths had either a PAP/MAP of greater than 0.80 or an operative weight of less than 2.5 kg. Hemodynamic index (PAP/MAP divided by operative weight) was predictive of mortality (p = 0.007). Furthermore, the hemodynamic index (p = 0.003) predicted prolonged length of stay in the intensive care unit by regression analysis. CONCLUSIONS: The hemodynamic index (PAP/MAP/weight) >=0.25 in the first 36 hours after TAPVD repair in neonates is predictive of mortality. A higher index predicted longer stay in the intensive care unit. This hemodynamic index may be a useful adjunct for risk stratification in neonates undergoing TAPVD repair. PMID- 22939247 TI - Composite aortic root replacement for complex prosthetic valve endocarditis: initial clinical results and long-term follow-up of high-risk patients. AB - BACKGROUND: Little information is available regarding the clinical and long-term results of patients with complex prosthetic valve endocarditis (PVE) involving the aortic root who undergo root replacement based on the Cabrol or Bentall procedures. METHODS: Between January 2007 and December 2011, 148 patients underwent cardiac operations for PVE. The analysis included 31 patients with complex PVE and concomitant destruction of the aortic root. Of these, 13 patients were treated by the Cabrol procedure and 18 patients by the Bentall procedure. The mean EuroSCORE for mortality was 50.7%+/-3.8%. Mean follow-up was 3.8+/-0.4 years (range, <=8.0 years), with a total of 97 patient-years. RESULTS: The observed 30-day mortality was 12.9% and 5-year survival was 75.3%. The most common cause of death was septic multiple organ failure (42.9%). Independent predictors of mortality in multivariate analyses were terminal renal failure (odds ratio [OR], 4.8; p<0.01), type 2 diabetes mellitus (OR, 4.6; p<0.01), postoperative renal failure (OR, 4.0; p<0.01), and staphylococcal infection (OR, 2.1; p=0.01). The prevalence of freedom from reinfection was 100.0% and that from valve-related events was 93.5%. CONCLUSIONS: Complex PVE is associated with quite high mortality and morbidity. Composite aortic root replacement provided good clinical and long-term outcomes as well as a low prevalence of reinfection and valve-related events. These results seem not to be inferior to those reported for noncomplex PVE. If the Bentall "button" technique was not feasible, the Cabrol procedure also provided excellent results. PMID- 22939248 TI - Impact of acute kidney injury on one-year survival after surgery for aortic dissection. AB - BACKGROUND: Surgical treatment is an option for both type A aortic dissection and complicated type B aortic dissection. Acute kidney injury (AKI) influences the disease course after surgery. Our hypothesis was that AKI should be an important prognostic factor for aortic dissection after surgical treatment. METHODS: Between July 2005 and October 2010, 268 patients (mean age 53 +/- 14 years; range, 16 to 88) underwent open surgery for aortic dissection. We reviewed the clinical presentations, surgical variables, and postoperative outcomes to identify the risk factors of death. The 256 patients were divided into groups, with and without AKI, within 24 hours after operation according to the RIFLE (acronym for risk, injury, failure, loss, end stage) criteria. RESULTS: The in hospital mortality rate was 17.9%, the 1-year mortality rate was 18.7%, and the major adverse cardiac events rate within 1 year was 29.9%. In multivariate analysis, patients more than 70 years of age (hazard ratio [HR] 2.390, p = 0.029), cardiogenic shock (HR 2.895, p = 0.005), preoperative ventilator use (HR 4.137, p = 0.018), operation at midnight (HR 2.295, p = 0.028), longer bypass time (HR 1.007, p < 0.001), and AKI (HR 2.552, p = 0.041) were clinical predictors of mortality. Kaplan-Meier analysis showed that the survival rate was strongly correlated with the severity of AKI by the RIFLE criteria. The independent predictors of AKI included hypertension (odds ratio 2.340, p = 0.027), sepsis (odds ratio 2.594, p = 0.043), and lower limb malperfusion (odds ratio 4.558, p = 0.022). CONCLUSIONS: Our study provides outcomes of postoperative aortic dissection. We found that AKI was a predictor of 1-year mortality by using the RIFLE criteria. Factors associated with increased 1-year mortality and AKI should be taken into consideration for surgery and postoperative care. PMID- 22939249 TI - Dynamic behavior of plastids related to environmental response. AB - In contrast to the sessile life style of plants, organelles within plant cells exhibit dynamic behavior. Plastid movements largely depend on actin cytoskeleton and are thought to be closely linked to adaptive responses to environmental changes. Advances in live-cell imaging technology combined with molecular genetics have demonstrated the underlying mechanism and the causal relationship between plastid motility and physiological significance in environmental response. Here, recent studies on the regulatory mechanisms of two types of chloroplast movement are reviewed. Studies on regulatory mechanisms of plastid behaviors related to environmental adaptation both in short-term (acute responses) and in long-term (developmental) processes would provide new insight into diversity in role(s) of plastids in a particular cell that do not only involve photosynthesis. PMID- 22939250 TI - Epigenetic variation: origin and transgenerational inheritance. AB - Recent studies have revealed that epigenetic variation in plant populations exceeds genetic diversity and that it is influenced by the environment. Nevertheless, epigenetic differences are not entirely independent of shared ancestry. Epigenetic modifications have gained increasing attention, because one can now study their patterns across the entire genome and in many different individuals. Not only do epigenetic phenomena modulate the activity of the genome in response to environmental stimuli, but they also constitute a potential source of natural variation. Understanding the emergence and heritability of epigenetic variants is critical for understanding how they might become subject to natural selection and thus affect genetic diversity. Here we review progress in characterizing natural epigenetic variants in model and nonmodel plant species and how this work is helping to delineate the role of epigenetic changes in evolution. PMID- 22939251 TI - Insights from paleogenomic and population studies into the consequences of dosage sensitive gene expression in plants. AB - Classical studies of plant phenotypes of individuals with whole or partial genome dosage changes led to the concept of genomic balance. Subsequent studies of gene expression in ploidy and aneuploidy series showed a greater number of modulations in aneuploid plants than with whole genome changes leading to the idea that gene expression processes were modulated by stoichiometric changes of interacting regulatory factors. Recent studies of genomic sequences and copy number variants in populations reveal different fates of duplicate genes depending on whole genome or segmental duplication. Following polyploidy formation, members of macromolecular complexes persist in the evolutionary lineage longer than random genes and a complementary pattern is found for segmental duplications in that there is an underrepresentation of members of macromolecular complexes. These and other studies described suggest there are negative fitness consequences when an imbalance occurs for members of macromolecular complexes including regulatory functions. PMID- 22939253 TI - Effect of grafting architecture on the surfactant-like behavior of clay poly(NiPAAm) nanohybrids. AB - A new class of clay-polymer nanohybrids was synthesized by grafting poly(N isopropylacrylamide) (PNiPAAm) on the edge of nanoscale silicate platelets (NSPs) through covalently bonded linkers to form various architectures. The inherent ionic character of NSPs and the organic moieties of isopropyl amide in PNiPAAms impart surface active properties to the nanohybrids. Surface tension and particle size measurements were used to determine the critical micelle concentrations (CMCs) of the nanohybrids. It was found that PNiPAAm brushes grafted onto NSPs with the single-headed linkers are loosely packed and can expand easily in water causing inter-hybrid interactions. In contrast, PNiPAAm brushes grafted onto NSPs with the double-headed linkers may alternatively exhibit intra-hybrid interactions and the hybrids tend to exist in a dispersed state. Consequently, the latter has a higher CMC than the former. In addition, the CMC can be tailored by adjusting the grafting density of the linkers on the NSP surfaces. The densely grafted nanohybrids exhibit close inter-hybrid contact resulting in a lower CMC than that for the sparsely grafted nanohybrids. Molecular simulations were also performed to study the effects of the polymer-grafted architecture and the density of the linkers on the micellar behavior of NSP-PNiPAAm hybrids. The simulation results were found to be in good agreement with the experimental observations. Thus, it is possible to control the surface active properties and aggregation of the clay-PNiPAAm hybrids by manipulating the organic grafting architectures of the silicate platelets. PMID- 22939252 TI - Controllable synthesis and catalysis application of hierarchical PS/Au core-shell nanocomposites. AB - Polystyrene (PS)/gold (Au) core-shell nanocomposites with tunable size, high stability, and excellent catalytic activity have been synthesized by a facile method that combines the ionic self-assembly with the in situ reduction. The composition and stoichiometry, as well as its morphology and optical properties of these nanocomposites have been examined and verified by various characterization techniques. The size and the coverage of gold nanoparticles (NPs) can be simply tailored by changing the amount of 3 aminopropyltrimethoxysilane (APTES), the functionalization time, the protonation time, and the amount of chloroauric acid (HAuCl(4)). The continuous red shifts of the localized surface plasmon resonance absorption of the Au NPs on the PS spheres are observed. Importantly, the obtained Au NPs with controllable and uniform size on the surfaces of amino-functionalized PS spheres exhibit excellent size-dependent catalytic properties for the reduction of 4-nitrophenol (4-NP) by NaBH(4). PMID- 22939254 TI - Removal of heavy metal ions from aqueous solution using Fe3O4-SiO2-poly(1,2 diaminobenzene) core-shell sub-micron particles. AB - In this work, Fe(3)O(4)-SiO(2)-poly(1,2-diaminobenzene) sub-micron particles (FSPs) with high saturated magnetization of ~60-70 emu/g were developed and utilized for the removal of As(III), Cu(II), and Cr(III) ions from aqueous solution. The isothermal results fitted well with the Freundlich model and the kinetic results fitted well with the two-site pseudo-second-order model, which indicated that multilayer adsorption of As(III), Cu(II), and Cr(III) ions on FSPs occurred at two sites with different energy of adsorption. The maximum adsorption capacities followed the order of As(III) (84+/-5 mg/g, pH=6.0)>Cr(III) (77+/-3 mg/g, pH=5.3)>Cu(II) (65+/-3 mg/g, pH=6.0). And the chelating interaction was considered as the main adsorption mechanism. The as-prepared materials were chemically stable with low leaching of Fe (<=1.7 wt.%) and poly(1,2 diaminobenzene) (<=4.9 wt.%) in tap water, sea water, and acidic/basic solutions. These metal-loaded FSPs could be easily recovered from aqueous solutions using a permanent magnet within 20s. They could also be easily regenerated with acid. The present work indicates that the FSPs are promising for removal of heavy metal ions in field application. PMID- 22939255 TI - Synthesis and properties of titanomagnetite (Fe(3-x)Ti(x)O4) nanoparticles: a tunable solid-state Fe(II/III) redox system. AB - Titanomagnetite (Fe(3-x)Ti(x)O(4)) nanoparticles were synthesized by room temperature aqueous precipitation, in which Ti(IV) replaces Fe(III) and is charge compensated by conversion of Fe(III) to Fe(II) in the unit cell. A comprehensive suite of tools was used to probe composition, structure, and magnetic properties down to site-occupancy level, emphasizing distribution and accessibility of Fe(II) as a function of x. Synthesis of nanoparticles in the range 0<=x<=0.6 was attempted; Ti, total Fe and Fe(II) content were verified by chemical analysis. TEM indicated homogeneous spherical 9-12 nm particles. MU-XRD and Mossbauer spectroscopy on anoxic aqueous suspensions verified the inverse spinel structure and Ti(IV) incorporation in the unit cell up to x<=0.38, based on Fe(II)/Fe(III) ratio deduced from the unit cell edge and Mossbauer spectra. Nanoparticles with a higher value of x possessed a minor amorphous secondary Fe(II)/Ti(IV) phase. XANES/EXAFS indicated Ti(IV) incorporation in the octahedral sublattice (B-site) and proportional increases in Fe(II)/Fe(III) ratio. XA/XMCD indicated that increases arise from increasing B-site Fe(II), and that these charge-balancing equivalents segregate to those B-sites near particle surfaces. Dissolution studies showed that this segregation persists after release of Fe(II) into solution, in amounts systematically proportional to x and thus the Fe(II)/Fe(III) ratio. A mechanistic reaction model was developed entailing mobile B-site Fe(II) supplying a highly interactive surface phase that undergoes interfacial electron transfer with oxidants in solution, sustained by outward Fe(II) migration from particle interiors and concurrent inward migration of charge-balancing cationic vacancies in a ratio of 3:1. PMID- 22939256 TI - Interactions of phenothiazine drugs with bile salts: micellization and binding studies. AB - An evaluation of the interactions of phenothiazine tranquilizer drugs (promazine hydrochloride; PMZ and promethazine hydrochloride; PMT) with bile salts viz., sodium cholate (NaC) and sodium deoxycholate (NaDC) in aqueous medium, investigated through different physicochemical measurements is presented in this work. The mixed micellization behavior and surface properties of the phenothiazine-bile salt systems have been analyzed by conductivity and surface tension measurements. Application of different theoretical approaches to all the phenothiazine-bile salt mixtures shows a non-ideal behavior. Further, the spectroscopic techniques such as UV-visible and steady state fluorescence have been employed to study the binding of phenothiazines with bile salts. The stoichiometric ratios, binding constants (K), and free energy change (DeltaG) for the phenothiazine-bile salt complexes were estimated from the Benesi-Hildebrand (B-H) double reciprocal plots obtained by using the changes in spectral intensities of phenothiazines on addition of bile salts. The results are discussed in the light of use of bile salts as promising drug delivery agents for phenothiazines and hence improve their bioavailabilty. PMID- 22939257 TI - Temperature and pH dual-responsive coatings of oligoperoxide-graft-poly(N isopropylacrylamide): wettability, morphology, and protein adsorption. AB - Poly(N-isopropylacrylamide) (PNIPAM) coatings attached to glass with novel approach involving polymerization from oligoperoxide grafted to surface with (3 aminopropyl)triethoxysilane exhibit not only temperature- but also pH-dependence of wettability and protein adsorption. Wettability and composition of coatings, fabricated with different polymerization times, were determined using contact angle measurements and Time Of Flight-Secondary Ion Mass Spectrometry (TOF-SIMS), respectively. Thermal response of wettability, measured between 20 and 40 degrees C, was prominent at pH 9 and 7 and diminished or absent at pH 5 and 3. This indicates a transition between hydrated loose coils and hydrophobic collapsed chains that is blocked at low pH. Higher surface roughness and dramatically increased adsorption of model protein (lentil lectin labeled with fluorescein isothiocyanate) were observed with AFM and fluorescence microscopy to occur in hydrophobic phases (at pH 3, for pH varied at constant temperature of 22 degrees C and at ~33 degrees C, for temperature varied at constant pH 9). Protein adsorption response to pH was confirmed by TOF-SIMS and Principal Component Analysis. PMID- 22939258 TI - Effects of emulsifier hydrophile-lipophile balance and emulsifier concentration on the distributions of gallic acid, propyl gallate, and alpha-tocopherol in corn oil emulsions. AB - We evaluated the effects of the hydrophile-lipophile balance (HLB) and emulsifier concentration on the distribution of the antioxidants gallic acid (GA), propyl gallate (PG), and alpha-tocopherol (TOC) between the aqueous, interfacial, and oil regions of food-grade emulsions composed of stripped corn oil, acidic water, and a mixture of the non-ionic surfactants Tween 20, 40, 80, and Span 20. The distribution of the antioxidants (AOs) is described by two partition constants, that between the oil-interfacial region, P(O)(I), and that between the aqueous and interfacial region, P(W)(I), of the emulsions. The partition constants were determined from the kinetic analyses of the variation in the observed rate constant, k(obs), for the reaction between the AOs and the hydrophobic 4 hexadecylbenzenediazonium ions, 16-ArN(2)(+), with the emulsifier volume fraction. The effects of emulsifier HLB on the second-order rate constants in the interfacial region k(I) were also evaluated for each antioxidant. Results show that an increase in emulsifier concentration promotes the incorporation of AOs to the interfacial region of the emulsions, so that at surfactant volume fractions of 0.04, more than 90% of GA and PG and more than 50% of TOC are located in that region. A decrease in the HLB favors the incorporation of PG and TOC to the interfacial region of the emulsions but has a negligible effect on the fraction of GA in that region. The %AOs in the interfacial region of the emulsions does not correlate with the polarity of the antioxidant, so that GA and PG are predominantly located in the aqueous-interfacial regions of the emulsion rather that in the oil droplet interior; meanwhile, TOC is mostly located in the oil interfacial regions. Results should aid to understand how antioxidants are distributed in food-grade emulsions and their relative efficiency in inhibiting lipid oxidation. PMID- 22939259 TI - Optical properties of thin films of zinc oxide quantum dots and polydimethylsiloxane: UV-blocking and the effect of cross-linking. AB - Thin films of polydimethylsiloxane (PDMS) and ZnO quantum dots (QDs) were built up as multilayers by spin-coating. The films are characterized by a UV-blocking ability that increases with increasing number of bilayers. Photoluminescence (PL) emission spectra of the thin films occur at 522 nm, which is the PL wavelength of the ZnO QDs dispersion, but with a lower intensity and a quantum yield (QY) less than 1% that of the dispersion. Cross-linking has introduced new features to the absorption spectra in that the absorption peak was absent. These changes were attributed to the morphological and structural changes revealed by transmission electron microscopy (TEM) and Fourier transform infrared spectroscopy (FTIR), respectively. TEM showed that the ZnO particle size in the film increased from 7 (+/-2.7) nm to 16 (+/-7.8) upon cross-linking. The FTIR spectra suggest that ZnO QDs are involved in the cross-linking of PDMS and that the surface of the ZnO QDs has been chemically modified. PMID- 22939260 TI - Chromatographic analysis, anti-proliferative and radical scavenging activity of Pinus wallichina essential oil growing in high altitude areas of Kashmir, India. AB - PURPOSE: To evaluate the in vitro anti-proliferative and radical scavenging properties of the essential oil and its fractions and to determine the chemo-type of P. wallichiana essential oil. METHOD: Pinus wallichiana oil was extracted by hydro-distillation and fractionated by silica gel column chromatography method. The oil and its fractions were analyzed by Gas chromatography, Gas chromatography mass spectrometry and (13)C NMR. Different concentrations of oil 12.5, 25, 50 and 100MUg/ml and single concentration 50MUg/ml of its fractions B(1), B(2), A(2), G(2), Uk(13) and I(2) were evaluated for its anti-proliferative activity by in vitro {3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide} assay against human monocyte, lung carcinoma, liver adenocarcinoma, prostate and ovarian carcinoma, while as the radical scavenging activity was evaluated by different in vitro DPPH assays. RESULTS: The analyses indicated the presence of 17 constituents with beta-pinene (46.8%) and alpha-pinene (25.2%) as major constituents. The oil and its fractions showed significant anti-proliferative activity. The radical scavenging activity also showed good results. CONCLUSION: The oil could be used as a drug to control the diseases like cancer, cirrhosis and arteriosclerosis, caused by reactive oxygen species. PMID- 22939261 TI - Asiaticoside enhances normal human skin cell migration, attachment and growth in vitro wound healing model. AB - Wound healing proceeds through a complex collaborative process involving many types of cells. Keratinocytes and fibroblasts of epidermal and dermal layers of the skin play prominent roles in this process. Asiaticoside, an active component of Centella asiatica, is known for beneficial effects on keloid and hypertrophic scar. However, the effects of this compound on normal human skin cells are not well known. Using in vitro systems, we observed the effects of asiaticoside on normal human skin cell behaviors related to healing. In a wound closure seeding model, asiaticoside increased migration rates of skin cells. By observing the numbers of cells attached and the area occupied by the cells, we concluded that asiaticoside also enhanced the initial skin cell adhesion. In cell proliferation assays, asiaticoside induced an increase in the number of normal human dermal fibroblasts. In conclusion, asiaticoside promotes skin cell behaviors involved in wound healing; and as a bioactive component of an artificial skin, may have therapeutic value. PMID- 22939262 TI - Wood elastic characterization from a single sample by resonant ultrasound spectroscopy. AB - The goal of this paper is to propose an experimental method allowing the identification of the complete elastic tensor of anisotropic biological materials such as wood using only one sample. To do so, two complementary methods are used. First, the wood eigen-directions are defined from a sample of spherical shape that is then cut into a cube in a way to perform resonant ultrasound spectroscopy (RUS). The method is successfully applied on a reference beech sample with known orthotropic directions. A comparison of the identified elastic constants with those from the literature and some inferred from ultrasonic transmission measurements is given. PMID- 22939263 TI - Re: cigarette smoking influences the clinical and occupational outcome of patients with tibial shaft fractures [Injury 2011;42(December (12)):1435-42]. PMID- 22939264 TI - [Impact factor and other quality indicators in Anales de Pediatria]. PMID- 22939265 TI - Presence and sources of anthropogenic perfluoroalkyl acids in high-consumption tap-water based beverages. AB - This study investigates the presence and sources of perfluorinated alkyl acids (PFAAs) in tap water and corresponding tap-water based beverages such as coffee and cola collected in the city of Amsterdam, The Netherlands. Exposure pathways studies have shown that low concentrations of PFAA in tap water already may pose a high contribution to daily human exposure. Tap water samples (n=4) had higher concentrations of PFAAs than the corresponding post-mixed cola (n=4). The lower PFAA levels in the cola were attributed to the pre-treatment of tap water in the mixing machines and dilution with cola syrup. In coffee samples from a coffee machine perfluorooctanoic acid (PFOA) at 4 ng L(-1) was the dominating analyte (n=12). The concentrations of PFHpA, PFOA and non branched PFOS were found to be significantly higher in manually (self) brewed coffee than in the corresponding tap water (n=4). The contribution from short-chain PFAA analogs could not be quantified due to low recoveries. Leaching experiments at different temperatures were performed with fluoropolymers-containing tubes to investigate the potential of leaching from tubes used in beverage preparation (n=16). Fluoropolymer tubes showed leaching of PFAAs at high (80 degrees C) temperature but its relevance for contamination of beverages in practice is small. The specific contribution from perfluoropolymer tubing inside the beverage preparation machines could not be assessed since no information was available from the manufacturers. The present study shows that although different beverage preparation processes possibly affect the concentrations of PFAAs encountered in the final consumed product, the water used for preparation remains the most important source of PFAAs. This in turn has implications for areas where drinking water is contaminated. Tap-water based beverages will possibly be an additional source of human exposure to PFAAs and need to be considered in exposure modeling. PMID- 22939266 TI - Whole-organism concentration ratios for plutonium in wildlife from past US nuclear research data. AB - Whole-organism concentration ratios (CRwo-media) for plutonium (Pu) in wildlife were calculated using data from the broad range of organism types and environmental settings of the US nuclear research program. Original sources included site-specific reports and scientific journal articles typically from 1960s to 80s research. Most of the calculated CRwo-media values are new to existing data sets, and, for some wildlife categories, serve to fill gaps or add to sparse data including those for terrestrial reptile; freshwater bird, crustacean and zooplankton; and marine crustacean and zooplankton. Ratios of Pu concentration in the whole-organism to that in specific tissues and organs are provided here for a range of freshwater and marine fish. The CRwo-media values in fish living in liquid discharge ponds were two orders of magnitude higher than those for similar species living in lakes receiving Pu from atmospheric fallout, suggesting the physico-chemical form of the source Pu can dominate over other factors related to transfer, such as organism size and feeding behavior. Small rodent data indicated one to two order of magnitude increases when carcass, pelt, and gastrointestinal tract were included together in the whole-organism calculation compared to that for carcass alone. Only 4% of Pu resided in the carcass of small rodents compared to 75% in the gastrointestinal tract and 21% in the pelt. PMID- 22939267 TI - Validation of determination of plasma metabolites derived from thyme bioactive compounds by improved liquid chromatography coupled to tandem mass spectrometry. AB - In the present study, a selective and sensitive method, based on microelution solid-phase extraction (MUSPE) plate and ultra-performance liquid chromatography coupled to tandem mass spectrometry (UPLC-MS/MS) was validated and applied to determine the plasma metabolites of the bioactive compounds of thyme. For validation process, standards of the more representative components of the phenolic and monoterpene fractions of thyme were spiked in plasma samples and then the quality parameters of the method were studied. Extraction recoveries (%R) of the studied compounds were higher than 75%, and the matrix effect (%ME) was lower than 18%. The LODs ranged from 1 to 65 MUg/L, except for the thymol sulfate metabolite, which was 240 MUg/L. This method was then applied for the analysis of rat plasma obtained at different times, from 0 to 6h, after an acute intake of thyme extract (5 g/kg body weight). Different thyme metabolites were identified and were mainly derived from rosmarinic acid (coumaric acid sulfate, caffeic acid sulfate, ferulic acid sulfate, hydroxyphenylpropionic acid sulfate, dihydroxyphenylpropionic acid sulfate and hydroxybenzoic acid) and thymol (thymol sulfate and thymol glucuronide). The most abundant thyme metabolites generated were hydroxyphenylpropionic acid sulfate and thymol sulfate, their respective concentrations in plasma being 446 and 8464 MUM 1h after the intake of the thyme extract. PMID- 22939268 TI - Ultrahigh pressure extraction of lignan compounds from Dysosma versipellis and purification by high-speed counter-current chromatography. AB - Ultrahigh pressure extraction (UPE) was employed to extract podophyllotoxin and 4'-demethylpodophyllotoxin from Dysosma versipellis. The effects of extraction parameters including extraction solvents, pressure, time and solid/liquid ratio were investigated using a High Hydrostatic Pressure Processor. The optimal condition for UPE of the target compounds was 80% methanol, 200 MPa of pressure, 1 min of extraction time and 1:12 (g/mL) of solid/liquid ratio. Podophyllotoxin and 4'-demethylpodophyllotoxin in the crude extract were purified by high-speed counter-current chromatography (HSCCC) with a two-phase solvent system composed of petroleum ether-ethyl acetate-methanol-water (10:10:8:12, v/v), and the fractions were analyzed by HPLC, ESI-MS and (1)H NMR. As a result, 73.7 mg podophyllotoxin and 16.5mg 4'-demethylpodophyllotoxin with purities over 96% were obtained from 260 mg crude sample in one-step separation. PMID- 22939269 TI - Concentration and selective fractionation of an antihypertensive peptide from an alfalfa white proteins hydrolysate by mixed ion-exchange centrifugal partition chromatography. AB - This article reports a promising use of the mixed ion-exchange centrifugal partition chromatography (MIXCPC) technique in the field of downstream processes. A complex alfalfa white protein concentrate hydrolysate (AWPC hydrolysate) showing anti-hypertensive properties was successfully fractionated by MIXCPC to yield a L-valyl-L-tryptophan (VW) enriched fraction in one run. This dipeptide shows an interesting anti-angiotensin converting enzyme (anti-ACE) activity. An analytical method based on RP-LC/MS-MS was developed to quantify the target VW peptide in both the starting material and the enriched fractions. The best results for the MIXCPC fractionation were obtained by the combined use of the quaternary biphasic solvent system, methyl-tert-butylether/acetonitrile/n butanol/water (2:1:2:5, v/v) in the descending mode, of the lipophilic di(2 ethylhexyl)phosphoric acid (DEHPA) cation-exchanger with an exchanger (DEHPA)/peptides ratio of 15, and of two displacers: calcium chloride and hydrochloric acid. The complexity of the starting material involved the selectivity optimization by splitting the stationary phase into two sections that differed by their triethylamine concentration. From 1g of AWPC hydrolysate containing 0.26% of VW, 30.7 mg of a VW enriched fraction were recovered with a purity of 10.9%, corresponding to a purification factor of 41 and a recovery of 97%. PMID- 22939270 TI - Liquid chromatographic mass spectrometric (LC/MS/MS) determination of plasma hydroxocobalamin and cyanocobalamin concentrations after hydroxocobalamin antidote treatment for cyanide poisoning. AB - Cyanide poisoning occurs in individuals after fire smoke inhalation and after oral ingestion of cyanide. Hydroxocobalamin (HOCbl), a hydroxylated form of vitamin B(12), is often used as an antidote to treat cyanide toxicity. It has a high affinity for cyanide and rapidly removes cyanide from tissue by forming cyanocobalamin (CNCbl). Little information is available on the pharmacokinetics of HOCbl and CNCbl largely because of the lack of analytical methods for analyzing HOCbl and CNCbl. In this study, we developed a new liquid chromatographic mass spectrometric (LC/MS/MS) method for the quantitative analysis of plasma HOCbl and CNCbl in the porcine (Sus scrofa) model. The method uses on-column extraction, reversed phase gradient chromatography, and multiple reaction monitoring (MRM) for quantitation. MRM transitions monitored were 664.7 >147.3 and 664.7->359.2 for HOCbl and 678.8->147.3, 678.8->359.1 678.8->457.1 for CNCbl. The limit of detection (LOD) and the lower limit of quantitation (LLOQ) were 1.0 and 1.0 MUmole/L, respectively, for plasma HOCbl and 0.1 and 0.5 MUmole/L for plasma CNCbl. The within-day and between-day CVs were 4.3 and 6.4% for plasma HOCbl at 500.0 MUmole/L and 5.5 and 5.7% for CNCbl at 100.0 MUmole/L (n=6). The plasma HOCbl and CNCbl calibrations curves were linear from 100.0 to 2000.0 and 50.0 to 500.0 MUmole/L, respectively. Based on 6 separate calibration curves the average linear regression coefficient (R(2)) for both HOCbl and CNCbl was 0.992. The LC/M/MS method was found to be accurate and precise and has been validated by determining the plasma HOCbl and CNCbl concentrations in 11 pigs that were treated with HOCbl for cyanide poisoning. PMID- 22939271 TI - Barnyard grass stress up regulates the biosynthesis of phenolic compounds in allelopathic rice. AB - Allelopathic rice cultivar PI312777 (PI) and non-allelopathic rice cultivar Lemont (Le) were mixed with barnyard grass (Echinochloa crus-galli L., BYG) at various ratios (rice:weed ratios of 4:1, 2:1, and 1:1) in hydroponic cultures. The expression of four genes, i.e. phenylalanine ammonia-lyase (PAL), cinnamate-4 hydroxylase (C4H), ferulic acid 5-hydroxylase (F5H), and caffeic acid O methyltransferases (COMT), which are involved in the biosynthesis of the phenolic compounds in rice, were evaluated by a quantitative real-time polymerase chain reaction (qRT-PCR). The contents of phenolic compounds in leaves, roots, and culture solutions of the two rice cultivars were determined using high performance liquid chromatography (HPLC). The results showed that all of the four genes were up-regulated in leaves and roots of the allelopathic rice PI at all rice:weed ratios. However, three of the four genes, C4H, F5H, and COMT, were down regulated in the leaves and roots of the non-allelopathic rice Le. The degree to which PAL was up-regulated in leaves and roots was much higher in PI than in Le. The contents of phenolic compounds in PI leaves, roots, and culture solutions were higher than that in Le leaves, roots, and culture solutions. The higher expression of the genes involved in the phenylpropanoid metabolism and the higher contents of phenolic compounds in PI are consistent with the higher inhibitory rates of PI on BYG. These results indicate that the PAL gene in PI is more sensitive to BYG stress than in Le, and barnyard grass up regulates the biosynthesis of phenolic compound in allelopathic rice. PMID- 22939272 TI - Psychoendocrine validation of a short measure for assessment of perceived stress management skills in different non-clinical populations. AB - BACKGROUND: We investigated the psychometric properties of a short questionnaire for combined assessment of different perceived stress management skills in the general population and tested whether scores relate to physiological stress reactivity. METHODS: For psychometric evaluation, we determined the factor structure of the questionnaire and investigated its measurement invariance in the participant groups and over time in three different independent samples representing the general population (total N=332). Reliability was tested by estimating test-retest reliability, internal consistency, and item reliabilities. We examined convergent and criterion validity using selected criterion variables. For endocrine validation, 35 healthy non-smoking and medication-free men in a laboratory study and 35 male and female employees in a workplace study underwent an acute standardized psychosocial stress task. We assessed stress management skills and measured salivary cortisol before and several times up to 60 min (workplace study) and 120 min (laboratory study) after stress. Potential confounders were controlled. RESULTS: The factor structure of the questionnaire consists of five scales reflecting acceptably distinct stress management skills such as cognitive strategies, use of social support, relaxation strategies, anger regulation, and perception of bodily tension. This factor structure was stable across participant groups and over time. Internal consistencies, item reliabilities, and test-retest reliabilities met established statistical requirements. Convergent and criterion validity were also established. In both endocrine validation studies, higher stress management skills were independently associated with lower cortisol stress reactivity (p's<.029). CONCLUSIONS: Our findings suggest that the questionnaire has good psychometric properties and that it relates to subjective psychological and objective physiological stress indicators. Therefore, the instrument seems a suitable measure for differential assessment of stress management skills in the general population. PMID- 22939273 TI - Expression of sheep interleukin 23 (IL23A, alpha subunit p19) in two distinct gastrointestinal diseases. AB - This paper reports the sequence of sheep interleukin 23A (p19), and shows that it shares 98% identity with bovine IL23A, 85% with human and 76% with mouse IL23A. It also reports the existence of two allelic variants that differ largely within the region encoding the amino terminal polypeptide signal sequence. An optimized RT-qPCR assay was used to quantify IL23A transcripts in sheep infected with two common gastrointestinal pathogens, the intracellular bacterium Mycobacterium avium subspecies paratuberculosis and the parasitic nematode Teladorsagia circumcincta. No differential expression of IL23A was detected in the mesenteric lymph node of sheep with the different pathogenic forms of paratuberculosis, however significantly high levels of IL23A were detected in the ileal mucosa of the paucibacillary form in comparison with the asymptomatic or multibacillary forms. Similarly, significantly high levels were present in the gastric lymph node draining T. circumcincta-infected abomasum in susceptible sheep. High levels of IL23A seem to be associated with lymphocytic infiltration and inflammation in both diseases but not with the macrophage infiltrate of multibacillary paratuberculosis. PMID- 22939274 TI - Identification of invariant natural killer T cells in porcine peripheral blood. AB - The pig is a relevant preclinical model for numerous pathologies used to validate therapeutic strategies for translation to human. Although invariant natural killer T (iNKT) lymphocytes are a component of innate immunity implicated in many pathological processes, little is known on their characterization in swine. By addressing this issue using mouse alpha-galactosylceramide-loaded CD1d tetramers (alpha-GC-CD1dTT), which are commonly used to track iNKT cells, we were able to unequivocally identify CD3(+)alpha-GC-CD1dTT(+) cells in porcine peripheral blood, hereafter referred to as swine iNKT cells. These lymphocytes are enriched in CD4(-)CD8(+) and CD4(-)CD8(-) cells, harbor an activated-memory phenotype (SLA DR(+)CD45RA(-)), express the intracellular promyelocytic-leukemia-zinc-finger (PLZF) transcription factor and are significantly enriched in IFN-gamma-producing cells after in vitro activation in comparison with conventional T cells. Importantly, in presence of IL-2 and IL-15, the iNKT cell ligand alpha-GC induces selective expansion of CD3(+)alpha-GC-CD1dTT(+) cells, confirming the reactivity of swine iNKT cells against alpha-GC. When associated with alpha-GC, IL-33, an alarmin of IL-1 family recently described to target iNKT cells, leads to a greater expansion of CD3(+)alpha-GC-CD1dTT(+) cells than IL-2 and IL-15. Altogether, our results provide the first phenotypic and functional description of swine iNKT cells allowing to further study the critical role of iNKT cells in porcine models of organ injury. PMID- 22939275 TI - Becker muscular dystrophy with widespread muscle hypertrophy and a non-sense mutation of exon 2. AB - Becker muscular dystrophy features progressive proximal weakness, wasting and often focal hypertrophy. We present a patient with pain and cramps from adolescence. Widespread muscle hypertrophy, preserved muscle strength and a 10-20 fold raised CPK were noted. Muscle biopsy was dystrophic, and Western blot showed a 95% reduction of dystrophin levels. Genetic analyses revealed a non-sense mutation in exon 2 of the dystrophin gene. This mutation is predicted to result in a Duchenne phenotype, but resulted in a mild Becker muscular dystrophy with widespread muscle hypertrophy. We suggest that this unusual phenotype is caused by translation re-initiation downstream from the mutation site. PMID- 22939276 TI - A randomized prospective multicenter trial of a novel vascular sealant. AB - BACKGROUND: Increasing use of anticoagulant medications, particularly antiplatelet therapies, can increase the difficulty in obtaining adequate suture line hemostasis. Multiple vascular sealants have been used as adjuncts to surgical procedures, but none of them have been universally successful. The aim of this study was to evaluate the safety and effectiveness of a new prophylactic vascular sealant in arterial surgery. METHODS: A randomized prospective multi institutional trial was undertaken comparing ArterX Vascular Sealant (AVS) with Gelfoam Plus during open arterial reconstruction. RESULTS: Three hundred thirty one anastomotic sites in 217 patients were randomized. One hundred one of 167 (60.5%) anastomotic sites in the AVS group achieved immediate hemostasis compared with 65 of 164 (39.6%) in the control group (P = 0.001). In anastomoses with polytetrafluoroethylene grafts, 105 of 167 (62.5%) in the AVS group achieved immediate hemostasis compared with 56 of 164 (34.0%) in the control group (P < 0.001). No significant differences were noted in morbidity or mortality. Operative time was significantly less in the AVS group compared with the control group (3.2 vs. 3.8 hours, P < 0.01). CONCLUSION: Use of AVS results in superior hemostatic effectiveness compared with Gelfoam Plus, with no difference in safety. Although no cost analysis was performed, cost savings likely resulted from significantly decreased operative time. PMID- 22939277 TI - Memory modulation by weak synchronous deep brain stimulation: a pilot study. AB - Zero-lag phase synchronization of EEG activity has been reported to be a central mechanism accompanying long-term memory formation. In this pilot study, we examined the effects of synchronous low-amplitude stimulation of the rhinal cortex and the hippocampus in eleven temporal lobe epilepsy patients. The impact of in-phase stimulation (zero lag) on long-term memory encoding of words was contrasted with anti-phase (180 degrees phase lag) and sham stimulation. We hypothesized more correctly remembered words for the in-phase compared to the sham condition and fewer correctly remembered words for the anti-phase vs. the sham condition. Indeed, we observed a trend for a linear condition effect for correctly remembered words, which is in accordance to our prediction (in-phase > sham > anti-phase). This finding suggests that even weak synchronous deep brain stimulation of rhinal cortex and hippocampus may modulate memory performance, while clear evidence for an enhancement of memory by this kind of deep brain simulation is still lacking. PMID- 22939278 TI - Light flashes in cancer patients treated with heavy ions. AB - Light flashes (phosphenes) are reported by most of the astronauts during spaceflight and patients treated with radiotherapy for brain tumors. They are induced by cosmic ray traversals, but the target area is unknown. With a correlation analysis of the visual sensation and the position of the beam in patients treated with energetic carbon ions for skull base tumors, we demonstrate here that light flashes are elicited only when the energetic particles hit the retina. PMID- 22939279 TI - Gastric bypass--a combined restrictive and malabsorbtive procedure or a malabsorbtive procedure alone? PMID- 22939280 TI - Quality of life in body dysmorphic disorder. AB - Body dysmorphic disorder (BDD) has a significant impact on the patients' quality of life (QOL). This is an initial literature review of QOL in patients with BDD, examining the extent of QOL impairments, the impact of psychiatric comorbidity on QOL, and the effect of treatment on QOL in BDD. Studies were identified through PubMed, MEDLINE, and PsycINFO searches from 1960-2011 using the keywords: "quality of life," "body dysmorphic disorder," "dysmorphophobia," and "body image." Studies included in this review were selected using specific criteria by two authors reaching consensus. Most BDD research studies have used symptom severity measures mainly to study BDD and its treatments. BBD with or without comorbidities is significantly associated with poor QOL and functioning. Studies show that treatment of BDD, either by psychopharmacological treatments such as selective serotonin reuptake inhibitors (SSRIs) or cognitive behavior therapy, might have positive effects on QOL, although these results need to be replicated in larger studies. In conclusion, QOL could add significant value to the assessment of BDD if used as one of the primary measures in research and clinical work in BDD, by providing more information and clearer understanding on the impact of the illness on satisfaction with activities of daily life and overall sense of wellbeing before and after treatment. PMID- 22939281 TI - Predictive value of negative cone margin status for risk of residual disease among women with cervical adenocarcinoma in situ. AB - OBJECTIVE: To determine the value of negative cone margins in predicting residual disease in women with adenocarcinoma in situ (ACIS). METHODS: Data were retrospectively analyzed from 60 women with ACIS who underwent conization at Chiang Mai University Hospital between March, 1998, and December, 2010. Negative margin status was defined as absence of neoplastic epithelium at all margins, coupled with presence of normal cervical epithelium. The association between the incidence of residual lesions and cone margin status was analyzed via chi(2) or Fisher exact test. RESULTS: When adjusted for age and completeness of visualization of the cervical squamocolumnar junction during colposcopy, women who underwent loop electrosurgical excision procedure were 4 times more likely to have positive cone margins than those who underwent cold-knife conization (95% CI, 1.13-16.43). Residual disease was not found among 26 women who had negative cone margins, but was observed in 17 (65.4%) of 26 women with positive cone margins (P<0.001). CONCLUSION: Women with ACIS who had negative cone margins were found to have a notably low risk of residual disease. Adherence to the standard method of cone sampling and criteria for negative margin status might contribute to a high predictive value of negative cone margins. PMID- 22939282 TI - Anharmonic vibrational studies of L-aspartic acid using HF and DFT calculations. AB - The experimental and theoretical studies on the structure, molecular properties and vibrational spectra of L-aspartic acid are presented. The molecular structure, harmonic and anharmonic vibrational frequencies, molecular properties, MEP mapping, NBO analysis and electronic spectra of L-aspartic acid have been reported. Computed geometrical parameters and anharmonic frequencies of fundamental, combination and overtone transitions were found in satisfactory agreement with the experimental data. The UV-Vis spectrum of present molecule has been recorded and the electronic properties such as HOMO and LUMO energies and few low lying excited states were carried out by using time dependent density functional theory (TD-DFT) approach. Natural Bond Orbital (NBO) analysis has been performed for analyzing charge delocalization throughout the molecule. Molecular electrostatic potential map has also been used for quantitative measure of the chemical activities of various sites of the molecule. PMID- 22939283 TI - Molecular and crystal structures, vibrational studies and quantum chemical calculations of 3 and 5-nitroderivatives of 2-amino-4-methylpyridine. AB - The crystal structures of 2-amino-4-methyl-3-nitropyridine (I), 2-amino-4-methyl 3,5-dinitropyridine (II) and 2-amino-4-methyl-5-nitropyridine (III) have been determined. The compounds crystallize in the monoclinic P2(1)/n, triclinic P-1 and monoclinic C2/c space groups, respectively. These structures are stabilized by a combination of N-H...N and N-H...O hydrogen bonds and exhibit layered arrangement with a dimeric N-H...N motif in which the molecular units are related by inversion centre. The molecular structures of the studied compounds have been determined using the DFT B3LYP/6-311G(2d,2p) approach and compared to those derived from X-ray studies. The IR and Raman wavenumbers have been calculated from the optimized geometry of monomers and dimers formed in the unit cell and compared to the experimental values obtained from the spectra. PMID- 22939284 TI - Synthesis and spectral characterization of trinuclear, oxo-centered, carboxylate bridged, mixed-valence iron complexes with Schiff bases. AB - Some novel trinuclear, oxo-centered, carboxylate-bridged, mixed-valence iron complexes of the general formula [Fe(3)O(OOCR)(3)(SB)(3)L(3)] (where R=C(13)H(27), C(15)H(31) or C(17)H(35,) HSB=Schiff bases and L=Ethanol) have been synthesized by the stepwise substitutions of acetate ions from MU(3)-oxo hexa(acetato)tri(aqua)iron(II)diiron(III), first with straight chain carboxylic acids and then with Schiff bases. The complexes were characterized by elemental analyses, molecular weight determinations and spectral (electronic, infrared, FAB mass, Mossbauer and powder XRD) studies. Molar conductance measurements indicated the complexes to be non-electrolytes in nitrobenzene. Bridging nature of carboxylate and Schiff base anions in the complexes was established by their infrared spectra. Mossbauer spectroscopic studies indicated two quadrupole-split doublets due to Fe(II) and Fe(III) ions at 80, 200 and 295K, confirming the complexes are mixed-valence species. This was also supported by the observed electronic spectra of the complexes. Magnetic susceptibility measurements displayed octahedral geometry around iron in mixed-valence state and a net antiferromagnetic exchange coupling via MU-oxo atom. Trinuclear nature of the complexes was confirmed by their molecular weight determination and FAB mass spectra. A plausible structure for these complexes has been established on the basis of spectral and magnetic moment data. PMID- 22939286 TI - Replicative intermediates of porcine circovirus in animal tissue cultured cells or in bacteria undergoing copy-release replication. AB - Porcine circovirus (PCV) has been assumed to replicate its genome via the rolling circle replication (RCR) mechanism because it encodes a Rep protein that contains several amino acid motifs commonly found in other RCR biological systems. Two proteins, Rep and Rep', are essential for PCV DNA replication in mammalian cells. In this work, replicative intermediates of PCV-infected porcine kidney (PK15) cells or copy-release of PCV genomes from a head-to-tail tandem construct (without Rep') in Escherichia coli were examined. In PK15 cells, replicative intermediates consistent with complementary-strand replication which converts single-stranded circular genome to double-stranded supercoiled DNA and RCR which generates single-stranded plus strand progeny genome were observed. To a lesser extent, intermediates suggestive of recombination-dependent replication were also detected. In Escherichia coli, copy release of the single-stranded circular PCV genome with conversion to a supercoiled molecule by complementary-strand synthesis was observed. However, replicative intermediates indicative of RCR were not detected. PMID- 22939285 TI - West Nile virus growth is independent of autophagy activation. AB - West Nile virus (WNV) is an arthropod-borne virus with a worldwide distribution that causes neurologic disease and death. Autophagy is a cellular homeostatic mechanism involved in antiviral responses but can be subverted to support viral growth as well. We show that autophagy is induced by WNV infection in cell culture and in primary neuron cultures. Following WNV infection, lysosomes co localize with autophagosomes resulting in LC3B-II turnover and autolysosomal acidification. However, activation or inhibition of autophagy has no significant effect on WNV growth but pharmacologic inhibition of PI3 kinases associated with autophagy reduce WNV growth. Basal levels of p62/sequestosome1(SQSTM1) do not significantly change following WNV-induced autophagy activation, but p62 is turned over or degraded by autophagy activation implying that p62 expression is increased following WNV-infection. These data show that WNV-induces autophagy but viral growth is independent of autophagy activation suggesting that WNV-specific interactions with autophagy have diverged from other flaviviruses. PMID- 22939287 TI - Predictive models of safety based on audit findings: Part 1: Model development and reliability. AB - This consecutive study was aimed at the quantitative validation of safety audit tools as predictors of safety performance, as we were unable to find prior studies that tested audit validity against safety outcomes. An aviation maintenance domain was chosen for this work as both audits and safety outcomes are currently prescribed and regulated. In Part 1, we developed a Human Factors/Ergonomics classification framework based on HFACS model (Shappell and Wiegmann, 2001a,b), for the human errors detected by audits, because merely counting audit findings did not predict future safety. The framework was tested for measurement reliability using four participants, two of whom classified errors on 1238 audit reports. Kappa values leveled out after about 200 audits at between 0.5 and 0.8 for different tiers of errors categories. This showed sufficient reliability to proceed with prediction validity testing in Part 2. PMID- 22939289 TI - The effects of ligamentous injury in the human lower cervical spine. AB - Damage is often sustained by the anterior longitudinal ligament (ALL) and ligamentum flavum (LF) in the cervical spine subsequent to whiplash or other cervical trauma. These ligaments afford substantial cervical stability when healthy, but the ability of the ALL and LF to stabilize the spine when injured is not as conclusively studied. In order to address this issue, the current study excised ALL and LF tissues from cadaveric spines and experimentally simulated whiplash-type damage to the isolated ligaments. Stiffnesses and toe region lengths were measured for both the uninjured and damaged states. These ligamentous mechanical properties were then inputted into a previously-validated finite element (FE) model of the cervical spine and the kinematic effects of various clinically relevant combinations of ligamentous injury were predicted. The data indicated three and five-fold increases in toe region length for the LF and ALL injury variants, respectively. These toe length distensions resulted in FE predictions of supra-physiologic ranges of motion, and these motions were comparable to spines with no ligamentous support. Finally, a set of cadaveric cervical spine ligament-sectioning experiments confirmed the FE predictions and supported the finding that partial injury to the relevant ligaments produces equivalent cervical kinematic signatures to spines that have completely compromised ALL and LF tissues. PMID- 22939290 TI - Validation of a novel method for quantifying and comparing regional ACL elongations during uniaxial tensile loading. AB - Given the complex three-dimensional (3D) knee joint loading associated with anterior cruciate ligament (ACL) injuries, accurate site- and bundle-specific strain measurements are critical. The purpose of this study was to quantify tensile load-induced migrations of radio-opaque markers injected directly into the ACL, as a first step in validating a roentgen stereophotogrammetric analysis based method for measuring ligament strain. Small markers were inserted into the femur and tibia, as well as injected into the antero-medial bundle of the ACL of eight (42-56 yrs) femur-ACL-tibia complexes (FATCs). The FATCs were then loaded under tension along the ligament's longitudinal axis by a material testing machine from 10 N to 50 N, 100 N, 125 N, and 150 N, each over 10 load-unload cycles. Complexes were imaged before the loading protocol, between each loading sequence, and after the protocol via biplane radiography. Marker migrations within the ACL tissue were quantified as the difference in their 3D positions between the pre- and each post-loading condition. Negligible migration was evident, with the lowest average root mean square values observed along the longitudinal axis of the ACL, ranging from 0.128 to 0.219 mm. Further, neither marker location nor load magnitude significantly affected migration values. This innovative method, therefore, presents as a plausible means to measure global and regional ACL strains, as small as 0.75% strain. In particular, it may provide important new insights in ACL strain behaviors during complex 3D knee load states associated with ligament injury. PMID- 22939288 TI - Altered lipid concentrations of liver, heart and plasma but not brain in HIV-1 transgenic rats. AB - Disturbed lipid metabolism has been reported in antiretroviral-naive HIV-1 infected patients suggesting a direct effect of the virus on lipid metabolism. To test that the HIV-1 virus alone could alter lipid concentrations, we measured these concentrations in an HIV-1 transgenic (Tg) rat model of human HIV-1 infection, which demonstrates peripheral and central pathology by 7-9 months of age. Concentrations were measured in high-energy microwaved heart, brain and liver from 7-9 month-old HIV-1 Tg and wildtype rats, and in plasma from non microwaved rats. Plasma triglycerides and liver cholesteryl ester and total cholesterol concentrations were significantly higher in HIV-1 Tg rats than controls. Heart and plasma fatty acid concentrations reflected concentration differences in liver, which showed higher n-3 and n-6 polyunsaturated fatty acid (PUFA) concentrations in multiple lipid compartments. Fatty acid concentrations were increased or decreased in heart and liver phospholipid subfractions. Brain fatty acid concentrations differed significantly between the groups for minor fatty acids such as linoleic acid and n-3 docosapentaenoic acid. The profound changes in heart, plasma and liver lipid concentrations suggest a direct effect of chronic exposure to the HIV-1 virus on peripheral lipid (including PUFA) metabolism. PMID- 22939291 TI - The mechanical and morphological properties of 6 year-old cranial bone. AB - Traumatic Brain Injury (TBI) is a leading cause of mortality and morbidity for children in the United States. The unavailability of pediatric cadavers makes it difficult to study and characterize the mechanical behavior of the pediatric skull. Computer based finite element modeling could provide valuable insights, but the utility of these models depends upon the accuracy of cranial material property inputs. In this study, 47 samples from one six year-old human cranium were tested to failure via four point bending to study the effects of strain rate and the structure of skull bone on modulus of elasticity and failure properties for both cranial bone and suture. The results show that strain rate does not have a statistically meaningful effect on the mechanical properties of the six year old skull over the range of strain rates studied (average low rate of 0.045 s( 1), average medium rate of 0.44 s(-1), and an average high rate of 2.2 s(-1)), but that these properties do depend on the growth patterns and morphology of the skull. The thickness of the bone was found to vary with structure. The bending stiffness (per unit width) for tri-layer bone (12.32+/-5.18 Nm(2)/m) was significantly higher than that of cortical bone and sutures (5.58+/-1.46 Nm(2)/m and 3.70+/-1.88 Nm(2)/m respectively). The modulus of elasticity was 9.87+/-1.24 GPa for cranial cortical bone and 1.10+/-0.53 GPa for sutures. The effective elastic modulus of tri-layer bone was 3.69+/-0.92 GPa. Accurate models of the pediatric skull should account for the differences amongst these three distinct tissues in the six year-old skull. PMID- 22939292 TI - A unified deformable (UD) segment model for quantifying total power of anatomical and prosthetic below-knee structures during stance in gait. AB - Anatomically-relevant (AR) biomechanical models are traditionally used to quantify joint powers and segmental energies of lower extremity structures during gait. While AR models contain a series of rigid body segments linked together via mechanical joints, prosthetic below-knee structures are often deformable objects without a definable ankle joint. Consequently, the application of AR models for the study of prosthetic limbs has been problematic. The purpose of this study was to develop and validate a unified deformable (UD) segment model for quantifying the total power of below-knee structures. Estimates of total below-knee power derived via the UD segment model were compared to those derived via an AR model during stance in gait of eleven healthy subjects. The UD segment model achieved similar results to the AR model. Differences in peak power, total positive work, and total negative work were 1.91+/-0.31%, 3.97+/-0.49%, and 1.39+/-0.33%, relative to the AR model estimates. The main advantage of the UD segment model is that it does not require the definition of an ankle joint or foot structures. Therefore, this technique may be valuable for facilitating direct comparisons between anatomical and disparate prosthetic below-knee structures in future studies. PMID- 22939293 TI - Water as origin of hysteresis in zinc tin oxide thin-film transistors. AB - The hysteresis behavior of transparent zinc tin oxide (ZTO) thin film transistors (TFTs) is identified to be a result of short-term bias stress induced by the measurement. The related density of shallow defect states can be adjusted by the amount of water in the ambient. Time-resolved studies of the TFTs under varied ambient demonstrate that hysteresis can be immediately switched on and off by the adsorption and desorption of water, respectively. These findings are expected to be of general importance also for other oxide-based TFTs. PMID- 22939294 TI - Ultrasound-enhanced monoclonal antibody production. AB - With the rapidly growing demand for monoclonal antibody (mAb)-based products, new technologies are urgently needed to increase mAb production while reducing manufacturing costs. To solve this problem, we report our research findings of using low-intensity pulsed ultrasound (LIPUS) to enhance mAb production. LIPUS with frequency of 1.5 MHz and pulse repetition frequency of 1 kHz, as well as duty cycle of 20%, was used to stimulate hybridoma cells to enhance the production of mAb, anti-CD4 (hybridoma GK1.5). The enzyme-linked immunosorbent assay results show a 60.42 +/- 7.63% increase of mAb expression in hybridoma cells. The evidence of structural changes of the cellular outer membrane in both transmission electron microscopy and scanning electron microscopy images and the more than 20% lactate dehydrogenase release indicates that the increased mAb production is related to the increased cell permeability induced by LIPUS. This value-added ultrasound technology provides a potential cost-effective solution for pharmaceutical companies to manufacture mAb-based drugs. The technology, in turn, can reduce the drug manufacturing costs and decrease health care spending. PMID- 22939295 TI - Overview of progress in clinical toxicology testing. AB - Clinical toxicology is the branch of the subject focused primarily on the diagnosis, treatment, prevention, and management of human poisoning. Its practice is most typically carried out in hospital and clinic settings where it is supported by a variety of clinical laboratory services, the historical development of which is the subject of this article. PMID- 22939296 TI - The prescription drug abuse epidemic. AB - In the United States, the nonmedical use of prescription drugs is the second most common illicit drug use, behind only marijuana. This article discusses the abuse issues with three of the most widely abused prescription drugs: opioids, central nervous system (CNS) depressants (eg, benzodiazepines), and stimulants (eg, amphetamine-dextroamphetamine and methylphenideate) in the United States. Efforts to deal with the problem are described as well. PMID- 22939297 TI - Urine drug testing for pain management. AB - An epidemic of prescription drug abuse in the United States has increased the burden on clinical toxicology testing laboratories. Urine drug testing provides objective evidence for compliance and aberrant drug behavior in patients on chronic (non-cancer) pain management. This article describes the testing menu, drug testing assays including tandem mass spectrometry and their limitations, interpretation of opiate results and clinical considerations. PMID- 22939298 TI - Alcohol biomarkers. AB - Excessive alcohol consumption poses a wide variety of significant immediate and long-term health risks. Ethanol biomarkers have clinical utility for detection, diagnosis, and treatment of alcohol use disorders as well as for screening for fetal alcohol exposure. Indirect biomarkers are those that reflect the toxic effects of ethanol on organs, tissues, or body biochemistry, whereas direct biomarkers are products of ethanol metabolism. Liver enzymes, carbohydrate deficient transferrin and mean corpuscular volume are discussed as examples of indirect markers of alcohol use. Commentary on the direct ethanol markers includes the following: acetaldehyde adducts, ethyl glucuronide, ethyl sulfate, phosphatidylethanol and fatty acids ethyl esters. PMID- 22939299 TI - Drug abuse: newly-emerging drugs and trends. AB - Drug abusers have access to new, more potent compounds that evade existing laws by virtue of their novel chemical structures. These drugs are available for purchase at stores and over the internet. The drugs are not illegal because they are so new that laws have not yet been passed to ban them. These drugs are leading to emergency department visits for cardiovascular, neurologic, and psychiatric complications. Standard drug screens are not designed to detect these new substances. The internet provides access to drugs for substance abusers but also provides physicians speed of access to the habits of substance abusers. PMID- 22939300 TI - Bath salts. AB - "Bath salts" has attracted young adults primarily due to its stimulatory and hallucinogenic effects akin to amphetamines and cocaine. Although other designer amines have been incorporated to newer generation "bath salts", synthetic cathinones remain to be their major component. This article discusses our current understanding of the chemistry and metabolism of synthetic cathinones. It also presents a comprehensive review of the most recent laboratory analyses done on this class of compounds in drug products and biological samples. PMID- 22939301 TI - The utility of immunoassays for urine drug testing. AB - Substance abuse is a significant problem in the United States, with cocaine, marijuana, alcohol and heroin as the most commonly abused drugs. This article focuses on urine drug testing to evaluate potential drug abuse or overdose in the emergent care setting using qualitative immunoassays. Discussion is included regarding the principles of how to validate qualitative immunoassays; how to decide on appropriate specimen type, test menu and cutoff; the limitations of immunoassays; how to communicate test results to clinicians; and use of urine drug testing at point of care. PMID- 22939302 TI - Drug testing in the neonate. AB - Drug testing in newborns comes with analytical, therapeutic, and legal issues, and interpretation of results may be left to physicians, nurses, or social services workers. The unique analytical and legal caveats pose a variety of challenges and therapeutic issues. Positive drug screening results can allow for proper medical management of withdrawal symptoms for certain drug classes. Legal implications and involvement of social services for assessment of child safety surround positive urine or meconium drug samples. Because laboratory results can potentially remove newborns from their biological parents, the caveats and limitations of drug testing in this population are of utmost importance. PMID- 22939303 TI - Toxicology testing in alternative specimen matrices. AB - Most toxicology testing involves serum, blood, or urine. Sampling from a site of action such as nerve endings or receptors on cells is not usually available, so often blood is used. Plasma and serum are logical sources to monitor without the interference of red cells. Other types of specimens may be tested and may even be required. Most of such testing has become possible as a result of newer instrumentation. Many of these alternative specimens have very low concentrations of the drugs, drug metabolites, or other toxins. Liquid chromatography-tandem mass spectrometry has allowed testing of these alternative specimens. PMID- 22939304 TI - Principles and procedures in forensic toxicology. AB - The principles and procedures employed in a modern forensic toxicology lab are detailed in this review. Aspects of Behavioral and Postmortem toxicology, including certification of analysts and accreditation of labs, chain of custody requirements, typical testing services provided, rationale for specimen selection, and principles of quality assurance are discussed. Interpretation of toxicology results in postmortem specimens requires the toxicologist and pathologist to be cognizant of drug-drug interactions, drug polymorphisms and pharmacogenomics, the gross signs of toxic pathology, postmortem redistribution, confirmation of systemic toxicity in suspected overdoses, the possibility of developed tolerance, and the effects of decomposition on drug concentration. PMID- 22939305 TI - Pharmacogenomics and the future of toxicology testing. AB - Pharmacogenomics is a useful tool in clinical toxicology for characterizing many gene polymorphisms associated with different pharmacokinetics or pharmacodynamics of exogenously administered drugs. These genetic variants may determine ranges of variation in such fundamental aspects as drug-metabolizing enzymes, drug transporters, drug receptors, or targets of drug action. Toxicologically significant drugs for which the FDA has required the manufacturer to identify relevant pharmacogenomics markers on the label include carisoprodol, citalopram, codeine, and risperidone. For personalized medicine, combining pharmacogenomics testing with therapeutic drug monitoring may allow the identification of individuals who need lower or higher doses, or even a different drug. PMID- 22939306 TI - Regulatory issues in accreditation of toxicology laboratories. AB - Clinical toxicology laboratories and forensic toxicology laboratories operate in a highly regulated environment. This article outlines major US legal/regulatory issues and requirements relevant to accreditation of toxicology laboratories (state and local regulations are not covered in any depth). The most fundamental regulatory distinction involves the purposes for which the laboratory operates: clinical versus nonclinical. The applicable regulations and the requirements and options for operations depend most basically on this consideration, with clinical toxicology laboratories being directly subject to federal law including mandated options for accreditation and forensic toxicology laboratories being subject to degrees of voluntary or state government-required accreditation. PMID- 22939307 TI - Toxicology testing. PMID- 22939308 TI - The influence of empirical contact networks on modelling diseases in cattle. AB - We present two stochastic models of the passage of an SEIR (susceptible-latent infected-resistant) disease through herds of cattle. One model is based on a contact network constructed via continuously recorded interaction data from two herds of cattle, the other, a matching network constructed using the principles of mass-action mixing. The recorded contact data were produced by attaching proximity data loggers to two separate herds of cattle during two separate recording periods. The network constructed using the principles of mass-action mixing uses the same number of contacts as the recorded network but distributes them randomly amongst the animals. The recorded networks had a greater number of repeated contacts, lower closeness and clustering scores and greater average path length than the mass-action networks. A lower proportion of simulations of the recorded network produce any disease spread when compared to those simulations of the mass-action network and, of those that did, fewer infected animals were predicted. For all parameter values tested, within the sensitivity analysis, similar differences were found between the recorded and mass-action network models. PMID- 22939309 TI - Towards measles elimination in Italy: monitoring herd immunity by Bayesian mixture modelling of serological data. AB - The analysis of post-vaccination serological data poses nontrivial issues to the epidemiologists and policy makers who want to assess the effects of immunisation programmes. This is especially true for infections on the path to elimination as is the case for measles. We address these problems by using Bayesian Normal mixture models fitted to antibody counts data. This methodology allows us to estimate the seroprevalence of measles by age and, in contrast to conventional methods based on fixed cut-off points, to also distinguish between groups of individuals with different degrees of immunisation. We applied our methodology to two serological samples collected in Tuscany (Italy) in 2003 and in 2005-2006 respectively, i.e., before and after a large vaccination campaign targeted to school-age children. Besides showing the impact of the campaign, we were able to accurately identify a large pocket of susceptible individuals aged about 13-14 in 2005-2006, and a larger group of weakly immune individuals aged about 20 in 2005 2006. These cohorts therefore represent possible targets for further interventions towards measles elimination. PMID- 22939310 TI - Estimating influenza latency and infectious period durations using viral excretion data. AB - Influenza infection natural history is often described as a progression through four successive stages: Susceptible-Exposed/Latent-Infectious-Removed (SEIR). The duration of each stage determines the average generation time, the time between infection of a case and infection of his/her infector. Recently, several authors have justified somewhat arbitrary choices in stage durations by how close the resulting generation time distribution was to viral excretion over time after infection. Taking this reasoning one step further, we propose that the viral excretion profile over time can be used directly to estimate the required parameters in an SEIR model. In our approach, the latency and infectious period distributions are estimated by minimizing the Kullback-Leibler divergence between the model-based generation time probability density function and the normalized average viral excretion profile. Following this approach, we estimated that the latency and infectious period last respectively 1.6 and 1.0 days on average using excretion profiles from experimental infections. Interestingly, we find that only 5% of cases are infectious for more than 2.9 days. We also discuss the consequences of these estimates for the evaluation of the efficacy of control measures such as isolation or treatment. We estimate that, under a best-case scenario where symptoms appear at the end of the latency period, index cases must be isolated or treated at most within 16h after symptoms onset to avoid 50% of secondary cases. This study provides the first estimates of latency and infectious period for influenza based directly on viral excretion data. It provides additional evidence that isolation or treatment of cases would be effective only if adopted shortly after symptoms onset, and shows that four days of isolation may be enough to avoid most transmissions. PMID- 22939311 TI - The impact of personal experiences with infection and vaccination on behaviour incidence dynamics of seasonal influenza. AB - Personal experiences with past infection events, or perceived vaccine failures and complications, are known to drive vaccine uptake. We coupled a model of individual vaccinating decisions, influenced by these drivers, with a contact network model of influenza transmission dynamics. The impact of non-influenzal influenza-like illness (niILI) on decision-making was also incorporated: it was possible for individuals to mistake niILI for true influenza. Our objectives were to (1) evaluate the impact of personal experiences on vaccine coverage; (2) understand the impact of niILI on behaviour-incidence dynamics; (3) determine which factors influence vaccine coverage stability; and (4) determine whether vaccination strategies can become correlated on the network in the absence of social influence. We found that certain aspects of personal experience can significantly impact behaviour-incidence dynamics. For instance, longer term memory for past events had a strong stabilising effect on vaccine coverage dynamics, although it could either increase or decrease average vaccine coverage depending on whether memory of past infections or past vaccine failures dominated. When vaccine immunity wanes slowly, vaccine coverage is low and stable, and infection incidence is also very low, unless the effects of niILI are ignored. Strategy correlations can occur in the absence of imitation, on account of the neighbour-neighbour transmission of infection and history-dependent decision making. Finally, niILI weakens the behaviour-incidence coupling and therefore tends to stabilise dynamics, as well as breaking up strategy correlations. Behavioural feedbacks, and the quality of self-diagnosis of niILI, may need to be considered in future programs adopting "universal" flu vaccines conferring long-term immunity. Public health interventions that focus on reminding individuals about their previous influenza infections, as well as communicating facts about vaccine efficacy and the difference between influenza and niILI, may be an effective way to increase vaccine coverage and prevent unexpected drops in coverage. PMID- 22939312 TI - Ecological and inhost factors promoting distinct parasite life-history strategies in Lyme borreliosis. AB - Understanding the ecology and evolution of tick-borne parasites is the foundation for preventing and managing tick-borne diseases. Tick-borne diseases such as Lyme borreliosis, are an emerging health threat in America, Europe, and Asia. Certain strains of Borrelia burgdorferi (the etiological agent of Lyme borreliosis) sampled in nature appear to be rapidly cleared by murine hosts. These strains, unlike their inhost-persistent counterparts, are unlikely to manifest severe disease. Their emergence and abundance in North America is unclear. Understanding why strains adopt a persistent or rapid-clearing phenotype is a crucial question in Lyme biology. Using dynamic, data-driven infectivity profiles in a competitive, two-strain mathematical model, we show that these phenotypes are differentially favored under distinct ecological conditions (i.e. vector phenology). We argue these two phenotypes represent distinct parasite life history strategies, impacting regional Lyme disease severity across North America. PMID- 22939313 TI - Within-farm transmission dynamics of foot and mouth disease as revealed by the 2001 epidemic in Great Britain. AB - This paper uses statistical and mathematical models to examine the potential impact of within-farm transmission dynamics on the spread of the 2001 foot and mouth disease (FMD) outbreak in Great Britain. We partly parameterize a simple within farm transmission model using data from experimental studies of FMD pathogenesis, embed this model within an existing between-farm transmission model, and then estimate unknown parameters (such as the species-specific within farm reproduction number) from the 2001 epidemic case data using Markov Chain Monte-Carlo (MCMC) methods. If the probability of detecting an infected premises depends on farm size and species mix then the within-farm species specific basic reproduction ratios for baseline models are estimated to be 21 (16, 25) and 14 (10, 19) for cattle and sheep, respectively. Alternatively, if detection is independent of farm size, then the corresponding estimates are 49 (41, 61) and 10 (1.4, 21). Both model variants predict that the average fraction of total farm infectiousness accumulated prior to detection of infection on an IP is about 30 50% in cattle or mixed farms. The corresponding estimate for sheep farms depended more on the detection model, being 65-80% if detection was linked to the farms' characteristics, but only 25% if not. We highlighted evidence which reinforces the role of within-farm dynamics in contributing to the long tail of the 2001 epidemic. PMID- 22939315 TI - Bilateral sudden sensorineural hearing loss as an initial presentation of myelodysplastic syndrome. AB - This study reports an unusual case in which myelodysplastic syndrome presented bilateral sudden sensorineural hearing loss as the first symptom of the disease. The aural symptoms and signs such as tinnitus, dizziness, and hearing impairment of a hematologic disease are common. However, sudden hearing loss as the first manifestation of a hematologic disease is extremely rare. A 76-year-old woman presented with bilateral sudden hearing loss. The patient was found to have myelodysplastic syndrome during a workup for her hearing loss. Unfortunately, the patient's hearing loss did not improve after the medical treatment. PMID- 22939316 TI - Prognostic value of immunophenotyping and gene mutations in elderly patients with acute myeloid leukemia with normal karyotype. AB - Elderly patients with acute myeloid leukemia generally have a poor prognosis and a highly heterogeneous clinical outcome. Prognostic indicators are required for and aid in patient stratification. However, the prognostic value of genetic mutations and immunophenotypic features in elderly normal karyotype acute myeloid leukemia, the largest cytogenetic risk group, remains unclear. We investigated the genetic mutations NPM1, FLT3-ITD, and FLT3-TKD and expression of the membrane antigens CD7, CD15, CD34, and CD56 in 144 elderly patients with de novo normal karyotype acute myeloid leukemia to retrospectively analyze the prognostic and clinical relevance of these parameters. CD7, CD15, CD34, and CD56 were expressed in 24%, 47%, 52%, and 15% of patients, respectively. NPM1 and FLT3-ITD mutations were detected in 51% and 17% of patients, respectively. Complete remission was obtained in 94 patients (65%), and the median overall survival was 16.5 months. Univariate analysis detected 5 markers with prognostic relevance: high leukocyte count, FLT3-ITD mutations, NPM1 mutations, CD34 expression, and CD56 expression in acute myeloid leukemia blasts. In multivariate analysis, patients with NPM1 predicted a higher complete remission (CR) rate (P = .016), longer event-free survival (P = .008), and longer overall survival (P = .049). FLT3-ITD mutations predicted a shorter event-free survival (P = .002) and shorter overall survival (P < .001). CD56 remained an independent predictor for lower CR rate (P = .021) and shorter event-free survival (P = .002). Our data highlight the prognostic importance of both genetic and immunophenotypic characteristics in this population of elderly patients with newly diagnosed normal karyotype acute myeloid leukemia. By combining genetic and immunophenotypic markers, we can divide patients into distinct prognostic groups with important implications for prognostic stratification and risk-adapted therapy. PMID- 22939314 TI - A degradable, bioactive, gelatinized alginate hydrogel to improve stem cell/growth factor delivery and facilitate healing after myocardial infarction. AB - Despite remarkable effectiveness of reperfusion and drug therapies to reduce morbidity and mortality following myocardial infarction (MI), many patients have debilitating symptoms and impaired left ventricular (LV) function highlighting the need for improved post-MI therapies. A promising concept currently under investigation is intramyocardial injection of high-water content, polymeric biomaterial gels (e.g., hydrogels) to modulate myocardial scar formation and LV adverse remodeling. We propose a degradable, bioactive hydrogel that forms a unique microstructure of continuous, parallel capillary-like channels (Capgel). We hypothesize that the innovative architecture and composition of Capgel can serve as a platform for endogenous cell recruitment and drug/cell delivery, therefore facilitating myocardial repair after MI. PMID- 22939317 TI - Characteristics, management of the neck, and oncological outcomes of malignant minor salivary gland tumours in the oral and sinonasal regions. AB - The aim of this study was to evaluate the characteristics of malignant tumours of the minor salivary glands in the oral and sinonasal regions, to make sure that the neck was managed correctly, and to identify oncological outcomes, retrospectively, at a single hospital. A total of 60 patients were reviewed. Forty-nine patients had intraoral lesions and 11 had sinonasal lesions. Of the 60 patients, 28 had stage I to II malignant tumours, and 32 had stage III to IV tumours. Treatment was almost exclusively surgical. One of the 16 patients whose nodes were clinically clear had an elective neck dissection. Adjuvant radiotherapy was given if indicated. The mean follow-up period was 52 months (range 13-190). Sinonasal lesions were all advanced T-stage at diagnosis, had more invaded resection margins, and a higher local recurrence rate than intraoral lesions. There was no regional recurrence in those patients whose nodes were clinically invaded and who had therapeutic neck dissection, or in the patient whose nodes were clinically clear and who had an elective neck dissection. Occult metastases developed exclusively in adenoid cystic carcinomas (ACC), the rate of which was 4/16. Regional recurrence developed in 4 patients who had never had elective treatment to the neck 2 of whom mixed pattern ACC and 2 who had low grade mucoepidermoid carcinomas (MEC). The overall survival was 90% at 2 years, 77% at 5 years, and 74% at 10 years. Sinonasal minor salivary gland tumours require careful follow-up because resection margins are more likely to be invaded by tumour, and they have a higher local recurrence rate than intraoral lesions. Elective neck dissection is needed, particularly for MEC and also to prevent regional recurrence in ACC. PMID- 22939318 TI - Patterns of weight change and progression to overweight and obesity differ in men and women: implications for research and interventions. AB - OBJECTIVE: To evaluate long-term patterns of weight change and progression to overweight and obesity during adulthood. DESIGN: Prospective study. Changes in mean BMI, waist circumference (WC) and weight were assessed over a mean 26-year follow-up (1971-1975 to 1998-2001). Mean BMI (95% CI) and mean WC (95% CI) of men and women in BMI and age groups were computed. Mean weight change in BMI and age categories was compared using analysis of covariance. SETTING: Framingham Heart Study Offspring/Spouse Nutrition Study. SUBJECTS: Men and women (n 2394) aged 20 63 years. RESULTS: During follow-up, increases in BMI (men: 2?2 kg/m2; women: 3?7 kg/m2) and WC (men: 5?7 cm; women: 15?1 cm) were larger in women than men. BMI gains were greatest in younger adults (20-39 years) and smallest in obese older adults (50-69 years). The prevalence of obesity doubled in men (to 33?2%) and tripled in women (to 26?6 %). Among normal-weight individuals, abdominal obesity developed in women only. The prevalence of abdominal obesity increased 1?8-fold in men (to 53?0%) and 2?4-fold in women (to 71?2 %). Weight gain was greatest in the youngest adults (20-29 years), particularly women. Gains continued into the fifth decade among men and then declined in the sixth decade; in women gains continued into the sixth decade. CONCLUSIONS: Patterns of weight change and progression to obesity during adulthood differ in men and women. Preventive intervention strategies for overweight and obesity need to consider age- and sex specific patterns of changes in anthropometric measures. PMID- 22939319 TI - Sinus lift access in partial maxillectomies. AB - Maxillectomies often result in anatomical defects that need to be reconstructed. In partial maxillectomies, the most significant defect is the formation of an oronasal or oral-antral fistula. This creates discomfort and needs to be addressed secondarily with local or regional flaps. Here, we describe a technique adopted in 8 patients in which limited maxillectomies are carried out in a way that preserves the nasal and sinus mucosa, preventing the formation of fistulas and allowing the use of flaps that would normally carry a high risk of fistula formation. Contemporary bone reconstruction with grafts was used in 2 patients. Sparing the sinus and nasal mucosa during maxillectomies is an easy, safe procedure that can prevent a number of complications and can be recommended in selected cases. PMID- 22939320 TI - Accuracy of a plastic facial cast fabricated with a custom tray in comparison with cone beam computed tomography. AB - OBJECTIVE: The aim of this study was to test the accuracy of a plaster cast fabricated with a facial custom tray. STUDY DESIGN: Sixteen patients with unilateral cleft lip and palate were enrolled in this study. Cone beam computed tomography (CBCT) scanning and facial plaster cast were obtained before surgery. Three-dimensional (3D) coordinates of 6 selected landmarks were recorded directly in CBCT by Mimics and indirectly on the plaster cast by using an electronic caliper and parallel milling machine. The accuracy of the plaster cast was compared with that of CBCT by using the t test and Lin's concordance correlation coefficient. P values less than 0.05 were considered statistically significant. RESULTS: Horizontal and vertical measurements were larger and sagittal measurements were smaller in plaster cast measurements, but none of these differences was statistically significant (P values ranged from 0.063 to 0.774). Lin's agreement test also showed that the plaster cast had high agreement with CBCT measurements (concordance correlation coefficients ranged from 0.6319 to 0.9599). CONCLUSIONS: Plaster cast fabricated with a custom tray is an accurate method in facial 3D analysis. PMID- 22939321 TI - Autogenous teeth used for bone grafting: a comparison with traditional grafting materials. AB - OBJECTIVES: This study evaluated the surface structures and physicochemical characteristics of a novel autogenous tooth bone graft material currently in clinical use. STUDY DESIGN: The material's surface structure was compared with a variety of other bone graft materials via scanning electron microscope (SEM). The crystalline structure of the autogenous tooth bone graft material from the crown (AutoBT crown) and root (AutoBT root), xenograft (BioOss), alloplastic material (MBCP), allograft (ICB), and autogenous mandibular cortical bone were compared using x-ray diffraction (XRD) analysis. The solubility of each material was measured with the Ca/P dissolution test. RESULTS: The results of the SEM analysis showed that the pattern associated with AutoBT was similar to that from autogenous cortical bones. In the XRD analysis, AutoBT root and allograft showed a low crystalline structure similar to that of autogenous cortical bones. In the CaP dissolution test, the amount of calcium and phosphorus dissolution in AutoBT was significant from the beginning, while displaying a pattern similar to that of autogenous cortical bones. CONCLUSIONS: In conclusion, autogenous tooth bone graft materials can be considered to have physicochemical characteristics similar to those of autogenous bones. PMID- 22939322 TI - Survival of patients with pathologic T0N+ oral and oropharyngeal cancer after neoadjuvant therapy and surgery: the minority report. AB - OBJECTIVES: Treatment outcome of patients with oral and oropharyngeal squamous cell carcinoma (OOSCC) achieving complete pathologic response at the primary site (ypT0) but incomplete response in loco-regional lymph nodes after preoperative chemoradiation (ypN+) is poorly described in the literature. This study's objective was to assess the survival of patients with OOSCC with ypT0N+ disease. STUDY DESIGN: 176 patients with primary locally advanced OOSCC undergoing preoperative chemoradiotherapy were stratified according to the pathologic TNM classification into 6 groups: ypT0N0M0 (46%), ypT0N+M0 (10%), ypTNM I (24%), ypTNM II (4%), ypTNM III (6%), and ypTNM IV (10%). RESULTS: Three-year overall survival (OS) and recurrence-free survival (RFS) rates for the ypT0N+M0 group were both 61.8% and were similar to those of the ypTNM I group (OS 62.4%; RFS rate of 59.2%). CONCLUSIONS: Survival analyses showed that patients with OOSCC with ypT0N+ disease have a similar prognosis to those with pathologic TNM stage I. PMID- 22939323 TI - Multiple oral squamous cell carcinomas associated with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy. AB - Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is a rare autosomal recessive disorder characterized by chronic mucocutaneous candidiasis, hypoparathyroidism, and adrenal insufficiency. Chronic oral candidiasis is frequently the first manifestation of the condition. There is an increased incidence of oral squamous cell carcinomas at an early age in this population, and it is possible that chronic oral candidal infection has a role in oral carcinogenesis in patients with APECED. We present a case of multiple oral squamous cell carcinomas in a 35-year-old woman with chronic mucocutaneous candidiasis as a component of APECED. Our patient has had 3 confirmed oral squamous cell carcinomas to date, which have been managed with laser resection and ablation. She remains on systemic antifungal therapy and is under regular surveillance in a multidisciplinary head and neck clinic. PMID- 22939324 TI - Composition of the blood supply in the sublingual and submandibular spaces and its relationship to the lateral lingual foramen of the mandible. AB - OBJECTIVE: The purpose of this research was to contribute to minimizing arterial disruption during mandibular surgical procedures by clarifying the course of the arteries supplying the sublingual and submental regions. STUDY DESIGN: Heads of 75 human cadavers were dissected to identify the arterial supply of the sublingual and submental regions. Computed tomography scans were performed to visualize the lateral lingual foramina of the mandibles. RESULTS: The facial artery was found to contribute to the composition of almost half of the sublingual arteries studied. Furthermore, it was demonstrated that the arterial supply to an incisor tooth is often from the submental artery. CONCLUSIONS: Our data provide important information for coping with bleeding or hematoma occurring during surgical procedures in the mandibular region. PMID- 22939325 TI - Tacrolimus on Kimura's disease: a case report. AB - OBJECTIVE: We report preliminary results of an ongoing study that assesses the efficacy of tacrolimus on Kimura's disease (KD). STUDY DESIGN: A patient with refractory KD after surgery and treatment with prednisone was treated with tacrolimus. Tacrolimus (FK-506) was administered at an initial dosage of 1 mg every 12 hours, and FK-506 concentration in the blood was monitored monthly. FK 506 blood concentration was controlled within 5 to 15 MUg/L. After 6 months, the dosage of tacrolimus was reduced to 0.5 mg daily for another 2 months and then treatment was stopped. RESULTS: Swelling of the bilateral salivary glands disappeared within the first week. No serious side effects were noted and the disease has not recurred in the 2 years of follow-up. CONCLUSIONS: Tacrolimus may be an effective treatment for patients with KD, but more research is needed to determine its long-term efficacy and safety as well as its mechanism of action. PMID- 22939326 TI - Clinical analysis of 194 cases of head and neck hamartoma. AB - OBJECTIVE: The aim of this study was to analyze the clinical management of hamartomas in the head and neck region (HNH). STUDY DESIGN: From January 1996 to December 2011, a retrospective analysis of 194 patients with HNH was performed. The preoperative examinations, surgical treatment, and prognosis were recorded and analyzed. RESULTS: Of the 194 patients, 107 were male and 87 female. Their ages ranged from 1 month to 82 years with a mean of 33 years. The most common locations were the oral mucosa (68.6%) and head and neck skin (27.3%). The course of disease ranged from 1 to 264 months with a mean of 66 months. Routine laboratory examinations were within normal limits. All patients underwent surgical removal of the lesions and prognosis was good. CONCLUSIONS: The clinical characteristics of HNH are not specific, and the clinical manifestation is always the same for benign tumors. The first choice of treatment is surgical excision, which results in a good prognosis. PMID- 22939327 TI - Idiopathic bone cavities of the mandible: an update on recurrence rates and case report. AB - Idiopathic bone cavities (IBCs) are usually an incidental finding, often found in long bones but also in the craniofacial skeleton. Typically solitary, IBCs can present at multiple sites. Surgical exploration alone has proved effective, although recurrence does occur, particularly in cases with multiple lesions. The average time necessary to observe either recurrence or complete healing has been reported to be more than 3 years. Previously reported low recurrence rates for IBCs in the craniofacial skeleton may have been artificially low because of insufficient long-term follow-up. Providers should be prepared for long-term follow-up and care of these patients. The case of the patient presented here supports the need for long-term follow-up. PMID- 22939328 TI - Case report of spontaneous hemorrhage in a sublingual arteriovenous malformation causing an emergent airway obstruction. AB - The literature is devoid of articles on spontaneous orofacial hemorrhage with hematoma formation without an underlying condition. Rupture of an arteriovenous malformation (AVM) is possibly the rarest form of spontaneous hemorrhage and life threatening hematoma formation. This pathology is widely known because of its occurrence in the central nervous system, but it can appear in any location. AVM is not generally thought to be an inherited disorder, except in the context of a specific hereditary syndrome. AVMs can be seen using computerized tomographic angiography, but distraction angiography is the gold standard for diagnosis and treatment decision making. Surgery is the mainstay of treatment; however, endovascular embolization has become an important adjunct to surgical intervention. With shrinkage of the lesion or definitive treatment with coils, particles, or glue. Other important considerations in the choice of treatment are the patient's age, lesion size and location, and prior history of hemorrhage. PMID- 22939329 TI - A contact-free volumetric measurement of facial volume after third molar osteotomy: proof of concept. AB - OBJECTIVE: The present study tested the reliability of an optical scanning device for the objective assessment of postoperative facial swelling. STUDY DESIGN: Twenty control subjects bearing a defined volume of water (10-30 mL) in an intraorally carried balloon were tested to assess the measurement accuracy of the device. As a proof of concept, facial volumes of 59 surgical cases were recorded before osteotomy and 1 and 7 days after intervention with the use of a structured light scanner. RESULTS: The median difference between the applied and the measured volumes was 0.67 mL for the control test with the artificial swelling simulated using water balloons. For subjects having third molar osteotomy, extraoral volume increased to 5.29 cm(3) 1 day after surgery (95% CI 5.22-8.52) and decreased to 0.00 mL (95% CI 0.85-2.55) after 7 days. CONCLUSIONS: Contact free visible-light 3-dimensional scanning is reliable for the objective assessment of postoperative facial swelling. PMID- 22939330 TI - The effect of radiofrequency ablation on microbiology of the tonsils. AB - OBJECTIVE: To investigate the effect of tonsil size reduction using temperature controlled radiofrequency on the number of pathogenic bacteria in the tonsil tissue. MATERIALS AND METHODS: This study was performed on 25 patients who had undergone tonsillectomy under general anesthesia at our clinic. Immediately after the cold knife tonsillectomy both tonsils were removed, one was included in the control and the other one was included in the study group. In vitro radiofrequency was applied to the tonsil in the study group at eight distinct points, each lasting 15s. Biopsy materials were taken under sterile conditions from the center of each tonsil for further culturing. RESULTS: The difference in bacterial number was investigated between the two groups. The bacterial number following radiofrequency administration was found to be significantly very lower compared to the control group (p<0.01). Radiofrequency administration significantly reduced growth of all types of bacteria. CONCLUSION: The radiofrequency tonsil ablation technique, which is used safely and effectively in the management of obstructive tonsil hypertrophy, currently has no indication for the treatment of patients with chronic and recurrent tonsillitis. However, when the right conditions are provided, the radiofrequency tonsil ablation technique may be applied to patients with chronic and recurrent tonsillitis and further studies investigating the differences in the frequency of patients' tonsillitis episodes should be undertaken. PMID- 22939331 TI - Exploring the conformational space of amorphous cellulose using NMR chemical shifts. AB - (13)C-labeled amorphous cellulose and (13)C NMR chemical shifts by 2D (13)C-(13)C correlation spectroscopy were obtained in the regenerated solid-state from ionic liquids. On the basis of the assigned chemical shifts, combined with information from molecular dynamics and quantum chemistry computer simulations a twisted structure for amorphous cellulose is proposed exposing more hydrophilic surface than that of extended crystalline cellulose. PMID- 22939332 TI - Production of resistant starch from taro (Colocasia esculenta L. Schott) corm and determination of its effects on health by in vitro methods. AB - The aim of the study was the production of resistant starch from taro (Colocasia esculenta L. Schott) corm and determination of its effects on health by in vitro methods. Starch was isolated from taro corms with 98% purity, and 10.4+/-0.5% amylose content. By application of heating, autoclaving, enzymatic debranching, retrogradation, and drying processes to taro starch for two times, resistant starch (RS) content was increased 16 fold (35.1+/-1.9%, dry basis). The expected glycemic index (eGI) of taro starch and taro resistant starch was determined as 60.6+/-0.5 and 51.9+/-0.9, respectively and the decrease in the glycemic index of taro resistant starch was found as statistically significant (P<0.05). The in vitro binding of bile acids by taro starch and taro resistant starch relative to cholesterol decreasing drug cholestyramine were 5.2+/-0.2% and 7.6+/-1.7%, respectively. PMID- 22939333 TI - The polysaccharides from Ganoderma lucidum: Are they always inhibitors on human hepatocarcinoma cells? AB - The antitumor activity of intracellular polysaccharides from submerged fermentation of Ganoderma lucidum was investigated focusing on the inhibition on human liver cancer cells. The polysaccharides inhibited human hepatocarcinoma cell HepG2 during earlier phase with lower dosage but obviously became less functional in later phase regardless of the dosage applied. However, apoptosis of the drugged HepG2 cells appeared in later incubation phase with high dosage, and the apoptosis could be enhanced by supplemental dose of the intracellular polysaccharides. Nevertheless, the intracellular polysaccharides inhibited other human hepatocarcinoma cells such as BEL-7402 and Huh-7 but luckily stimulated human normal liver cell L02 only in a positive dose- and time-dependent manner; so did the sulfated extracellular polysaccharides when it inhibited HepG2 and L02 cells. However, the toxicity of sulfated extracellular polysaccharides to L02 cells can be eliminated by the intracellular polysaccharides. PMID- 22939334 TI - Natural polymer-based magnetic hydrogels: Potential vectors for remote-controlled drug release. AB - The preparation and characterization of natural polymer-based hydrogels that contain 50-nm diameter magnetite (i.e., FeO:Fe(2)O(3)) nanoparticles are described herein. Fourier-transform infrared spectroscopy (FTIR) analysis confirmed the efficiency of the polysaccharide-modifying process. Thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), and compressive moduli demostrate that the presence of magnetite improves thermal and mechanical resistance. Transient diffusion of water in magnetic hydrogels was analyzed via boundary layer mass transfer across an expaning interface, and the degree of swelling of these polysaccharide hydrogels decreases in the presence of magnetite, with no variation in the binary diffusion mechanism. The absence of hysteresis loops and coercivity observed via magnetometry suggests that magnetic hydrogels are useful for remote-controlled drug release, as demonstrated by magnetic-field-induced release of curcumin. Experiments reveal that magnetic hydrogels with greater magnetic susceptibility have the potential to release larger concentrations of drugs from the hydrogel network. PMID- 22939335 TI - Enzymatic fingerprinting of arabinoxylan and beta-glucan in triticale, barley and tritordeum grains. AB - Enzymatic fingerprinting of arabinoxylan (AX) and beta-glucan using endo-xylanase and lichenase, respectively, helps determine the structural heterogeneity between different cereals and within genotypes of the same cereal. This study characterised the structural features of AX and beta-glucan in whole grains of eight triticale cultivars grown at two locations, 20 barley cultivars/lines with wide variation in composition and morphology and five tritordeum breeding lines. Principal component analysis (PCA) resulted in clear clustering of these cereals. In general, barley and tritordeum had a higher relative proportion of highly branched arabinoxylan oligosaccharides (AXOS) than triticale. Subsequent analysis of triticale revealed two clusters based on growing region along principal component (PC) 1, while PC2 explained the genetic variability and was based on mono-substitution and di-substitution in AX fragments. PCA of beta-glucan features separated the three cereals based on beta-glucan content. The molar ratio of trisaccharide to tetrasaccharide was 2.5-3.4 in triticale, 2.3-3.3 in barley and 2.8-3.4 in tritordeum. Barley showed a strong positive correlation (r=0.86) between beta-glucan content and relative proportion of trisaccharide. The results show that structural features of AX and beta-glucan vary between and within triticale, barley and tritordeum grains which might be important determinants of end-use quality of grains. PMID- 22939337 TI - Preparation and evaluation of warfarin-beta-cyclodextrin loaded chitosan nanoparticles for transdermal delivery. AB - The main objective of the present work was to prepare warfarin-beta-cyclodextrin (WAF-beta-CD) loaded chitosan (CS) nanoparticles for transdermal delivery. CS is a hydrophilic carrier therefore, to overcome the hydrophobic nature of WAF and allow its incorporation into CS nanoparticles, WAF was first complexed with beta cyclodextrin (beta-CD). CS nanoparticles were prepared by ionotropic pre-gelation using tripolyphosphate (TPP). Morphology, size and structure characterization of nanoparticles were carried out using SEM, TEM and FTIR, respectively. Nanoparticles prepared with 3:1 CS:TPP weight ratio and 2mg/ml final CS concentration were found optimum. They possessed spherical particles (35+/-12nm diameter) with narrow size distribution (PDI=0.364) and 94% entrapment efficiency. The in vitro release as well as the ex vivo permeation profiles of WAF-beta-CD from the selected nanoparticle formulation were studied at different time intervals up to 8h. In vitro release of WAF-beta-CD from CS nanoparticles followed a Higuchi release profile whereas its ex vivo permeation (at pH 7.4) followed a zero order permeation profile. Results suggested that the developed WAF-beta-CD loaded CS carrier could offer a controlled and constant delivery of WAF transdermally. PMID- 22939338 TI - In vitro antiviral activity of sulfated Auricularia auricula polysaccharides. AB - Total Auricularia auricula polysaccharide (AAP(t)) was prepared by extracting and removing the proteins. Column chromatography was used to further graded it into AAP(1) and AAP(2). Three AAPs were modified by chlorosulfonic acid-pyridine method to obtain three sulfated AAPs (sAAPs), sAAP(t), sAAP(1) and sAAP(2), respectively. Three sAAPs and Newcastle disease virus (NDV) were added into cultivation system of chicken embryo fibroblast (CEF) in three manners, pre-, post- and simultaneous-adding polysaccharide with NDV respectively, taking three non-modified AAPs as control. Their anti-viral activities were compared by MTT method. The results showed that sAAPs and AAPs at a certain concentration could significantly inhibit the cellular infectivity of NDV in three manners. The effects of sAAPs were better than that of AAPs. It indicated that sulfated modification could enhance the antiviral activity of AAP. sAAP(1) and sAAP(t) possessed stronger activity and would be as the component of a new-type antiviral drug. PMID- 22939339 TI - Synthesis of organosoluble chitosan derivatives with polyphenolic side chains. AB - A one-pot synthesis was used to produce chitosan derivatives with polyphenolic side chains via a regioselective phenolic coupling reaction. Under Mannich reaction conditions, treatment of chitosan with formaldehyde and methyl 2,4 dihydroxybenzoate gave N-(2,6-dihydroxy-3-methoxycarbonylphenyl)methylated chitosan in good yield (87%). Formation of a CC bond occurred regioselectively at the C(3) position of methyl 2,4-dihydroxybenzoate. Chitosan derivatives having various phenolic compounds as a side chain were easily synthesized in a similar manner. The chitosan derivatives showed good biodegradability and improved their solubility in methanol (9.8mg mL(-1)) and 2-methoxyethanol (> 10mg mL(-1)). The UV protection provided by the derivatives with phenolic benzophenone side chain was evaluated using UV spectra of polyethylene terephthalate and poly(vinyl butyral-co-vinyl alcohol-co-vinyl acetate) films coated with the derivatives and the derivatives absorbed effectively in the UV-A region (<60%). Self-aggregation of the chitosan derivatives with the phenolic side chain was observed by using a fluorescent probe in aqueous solution. PMID- 22939340 TI - Synthesis of chitosan networks: Swelling, drug release, and magnetically assisted BSA separation using Fe3O4 nanoparticles. AB - Chitosan (CS) nanohydrogel networks were prepared by reaction with glyceroldiglycidylether (GDE) and poly(dimethylsiloxane) (PDMS), as crosslinking agents in an emulsion system. The nanogel content increased with increasing the amount of crosslinkers and reached to a maximum of 90% with GDE. The nanogels structure was characterized by FT-IR, AFM, DSC, and TGA. The average size for CS GDE and CS-PDMS particles were 59nm and 180nm, respectively. The swelling behavior of nanohydrogels was observed to be dependent on pH, temperature, degree of crosslinking, and on the chemical structure of crosslinker. The equilibrium water content of CS-GDE nanohydrogels reached to a maximum of 600% at neutral pH, and decreased at high and low pH and low temperature. These nanohydrogels were tested for sodium diclofenac (SDF) loading and releasing efficiency. The covalent conjugation of bovine serum albumin (BSA) and magnetic Fe(3)O(4) nanoparticles on the hydrogels were found to hold a potential application in magnetically assisted bioseparation. PMID- 22939341 TI - Regioselective fluorescent labeling of N,N,N-trimethyl chitosan via oxime formation. AB - Fluorescent labeling of chitosan and its derivatives is widely used for in vitro visualization and is accomplished by random introduction of the fluorophore to the polymer backbone, conceivably altering the bioactivity of the polymer. Here, we report for the first time the regioselective conjugation of a fluorophore to the reducing end of a fully N,N,N-trimethylated chitosan (TMC) by oxime formation. End-labeled conjugation of 5-(2 ((aminooxyacetyl)amino)ethylamino)naphthalene-1-sulfonic acid (EDANS-O-NH(2)) fluorophore to TMC to form TMC-oxime-EDANS (f-TMC) was confirmed by (1)H NMR and fluorescence spectroscopy. Average molecular weight calculations of f-TMC with (1)H NMR and fluorescence spectroscopy gave similar results or ~7.7kDa. f-TMC in human bronchial epithelial cells was both cell membrane bound as well as intracellularly localized. This demonstrates the proof-of-concept for selective oxime formation at the reducing end of a chitosan derivative, which can be used for tracking chitosan in gene and drug delivery purposes and gives rise to further modifications with other functional groups. PMID- 22939342 TI - Chitosan coated alginate beads for the survival of microencapsulated Lactobacillus plantarum in pomegranate juice. AB - This work studied the effect of multi-layer coating of alginate beads on the survival of encapsulated Lactobacillus plantarum in simulated gastric solution and during storage in pomegranate juice at 4 degrees C. Uncoated, single and double chitosan coated beads were examined. The survival of the cells in simulated gastric solution (pH 1.5) was improved in the case of the chitosan coated beads by 0.5-2 logs compared to the uncoated beads. The cell concentration in pomegranate juice after six weeks of storage was higher than 5.5logCFU/mL for single and double coated beads, whereas for free cells and uncoated beads the cells died after 4 weeks of storage. In simulated gastric solution, the size of the beads decreased and their hardness increased with time; however, the opposite trend was observed for pomegranate juice, indicating that there is no correlation between cell survival and the hardness of the beads. PMID- 22939343 TI - Triamcinolone solubilization by (2-hydroxypropyl)-beta-cyclodextrin: A spectroscopic and computational approach. AB - The molecular foundations of the use of (2-hydroxypropyl)-beta-cyclodextrin (HPbetaCD) as solubility promoter of triamcinolone acetonide (TrA), a corticosteroid with very low aqueous solubility, was investigated by a multidisciplinary spectroscopic and computational approach. Aqueous solutions of TrA and HPbetaCD were investigated by UV and NMR spectroscopies. The association constant was determined by phase solubility diagrams and by the Foster-Fyfe method whereas the nature of the drug/cyclodextrin aggregates was probed by using the NMR DOSY technique. ROE measurements in solution led to stereochemical information regarding the nature of inclusion processes. TrA/HPbetaCD powders were prepared and investigated by Raman spectroscopy supported by computational methods. A molecular interaction of the hydroxyacyl chain with cyclodextrin, not identified in solution, was detected. Raman imaging experiments confirmed the attainment of a molecularly homogeneous system when the TrA/HPbetaCD molar ratio was 1:7 whereas TrA crystallized for mixtures richer in TrA (1:3.5) forming domains with size in the range of 10-15MUm. We demonstrate that the combined use of several spectroscopical techniques with specific responsivities allows a detailed depiction of drug/cyclodextrin interaction useful in the development of novel pharmaceutical formulation. PMID- 22939344 TI - Sequence analysis of the sulfated rhamno-oligosaccharides derived from a sulfated rhamnan. AB - Three sulfated rhamno-oligosaccharides, designated O1, O2 and O3, were obtained by mild acid hydrolysis of the sulfated rhamnan and purified by gel-permeation chromatography. On the basis of one- and two-dimensional nuclear magnetic resonance (1D, 2D NMR) spectroscopic analyses, the oligosaccharide O1 was characterized to be alpha-L-Rhap-(2SO4)-(1->3)-alpha-L-Rhap. The fragmentation pattern of the homogeneous disaccharide in the product ion spectra was recognized by negative-ion electrospray tandem mass spectrometry with collision-induced dissociation (ES-CID MS/MS). With the principles established, the sequences of the oligosaccharides O2 and O3 were deduced to be alpha-L-Rhap-(2SO4)-(1->3) alpha-L-Rhap-(1->3)-alpha-L-Rhap, and alpha-L-Rhap-(2SO4)-(1->3)-alpha-L-Rhap-(1 >3)-alpha-L-Rhap-(1->3)-alpha-L-Rhap (2SO(4)), respectively. The investigation demonstrated that the sulfated rhamnan-derived oligosaccharides were novel sulfated oligosaccharides different from those of other polysaccharides-degraded from algae, and it could be possible to determine the sequence of the sulfated rhamno-oligosaccharides directly from the glycosidic cleavage fragmentation in the product ion spectra. PMID- 22939345 TI - Fermented and enzymatic production of chitin/chitosan oligosaccharides by extracellular chitinases from Bacillus cereus TKU027. AB - Two chitinases, Chi I and Chi II, were purified from the culture supernatant of Bacillus cereus TKU027 with shrimp head powder (SHP) as the sole carbon/nitrogen source. The molecular masses of Chi I and Chi II determined using SDS-PAGE were approximately 65kDa and 63kDa, respectively. Chi I toward various surfactants showed high stability, such as SDS, Tween 20, Tween 40 and Triton X-100, and these surfactants were stimulator of Chi I chitinase activity. Concomitant with the production of Chi I and Chi II, chitin oligosaccharides were also observed in the culture supernatant, including chitobiose, chitotriose, chitotetrose and chitopentose at concentrations of 0.44mg/mL, 0.08mg/mL, 0.09mg/mL and 0.43mg/mL, respectively. Chitosan with 60% deacetylation was degraded by TKU027 crude enzyme to prepare chitooligosaccharides. MALDI-TOF MS analysis of the enzymatic hydrolyzates indicated that the products were mainly chitooligosaccharides with degree of polymerization (DP) in the 4-9 range. PMID- 22939346 TI - Adsorption of methylene blue dye from aqueous solution by sugar extracted spent rice biomass. AB - This study was aimed at using sugar extracted spent rice biomass (SRB) as a potential adsorbent to remove methylene blue (MB) dye from aqueous solution. The SRB was used without any modification. A three factor full factorial experimental design (2(3)) was employed to investigate the effect of factors (adsorbent dose, dye concentration, temperature) and their interaction on the adsorption capacity and color removal. Two levels for each factor were used; adsorbent dose (0.25 0.5g/100mL), dye concentration (25-50mg/L), and temperature (25-45 degrees C). Initial dye concentration and adsorbent dosage were found as significant factors for the adsorption of MB dye. Langmuir isotherm (R(2)>0.998) best explained the equilibrium of MB adsorption on SRB with monolayer adsorption capacity of 8.13mg/g. The pseudo-second order model (R(2)>0.999) was best fitted to explain the adsorption kinetics. Thermodynamic investigation revealed that the adsorption process was spontaneous, endothermic, and was feasible to treat dyeing wastewater. PMID- 22939348 TI - Rheological properties of aqueous solution containing xanthan gum and cationic cellulose JR400. AB - Rheological properties of aqueous solution containing xanthan gum (XG) and cationic cellulose JR400 were investigated at different composition ratio, shear rate, pH and electrolyte concentrations. It was found that the mixing of XG and JR400 can induce a viscosity-increasing effect for the mixed solution. As the concentration fraction (f(JR)) of JR400 in the mixed solution increases from 0 to 0.40 with the total polymer concentration (c(t)) of 1%, the solution transforms from an elastic fluid into a viscoelastic one, while as f(JR) decreases from 1 to 0.78, the solution transforms from a viscous fluid into a viscoelastic one. At pH 5-10, both the viscosity and elasticity of XG/JR400 mixture (f(JR)=0.15) are independent of pH and the viscosity-increasing effect is obvious. Outside this pH range, the viscosity, elasticity and viscosity-increasing effect of the mixture decrease. The increase of added NaCl concentration and shear rate can induce the decrease of viscosity, elasticity and viscosity-increasing effect of the XG/JR400 mixture. PMID- 22939347 TI - The PEI-introduced CS shell/PMMA core nanoparticle for silencing the expression of E6/E7 oncogenes in human cervical cells. AB - In this study, we examined the potential of cationic nanoparticle - polyethyleneimine-introduced chitosan shell/poly (methyl methacrylate) core nanoparticles (CS-PEI) for siRNA delivery. Initially, DNA delivery was performed to validate the capability of CS-PEI for gene delivery in the human cervical cancer cell line, SiHa. siRNA delivery were subsequently carried out to evaluate the silencing effect on targeted E6 and E7 oncogenes. Physicochemical properties including size, zeta potential and morphology of CS-PEI/DNA and CS-PEI/siRNA complexes, were analyzed. The surface charges and sizes of the complexes were observed at different N/P ratios. The hydrodynamic sizes of the CS-PEI/DNA and CS PEI/siRNA were approximately 300-400 and 400-500nm, respectively. Complexes were positively charged depending on the amount of added CS-PEI. AFM images revealed the mono-dispersed and spherical shapes of the complexes. Gel retardation assay confirmed that CS-PEI nanoparticles completely formed complexes with DNA and siRNA at a N/P ratio of 1.6. For DNA transfection, CS-PEI provided the highest transfection result. Localization of siRNA delivered through CS-PEI was confirmed by differential interference contrast (DIC) confocal imaging. The silencing effect of siRNA specific to HPV 16 E6/E7 oncogene was examined at 18 and 24h post transfection. The results demonstrated the capacity of CS-PEI to suppress the expression of HVP oncogenes. PMID- 22939349 TI - The potential of pectin as a stabilizer for liposomal drug delivery systems. AB - The aim of the present study was to investigate the potential of different types of pectin as stabilizers for liposomal drug delivery systems. Positively charged liposomes were coated with commercially available and purified low-methoxylated (LM), high-methoxylated (HM) and amidated (AM) pectins. The samples were stored for up to 12 weeks at 4 degrees C, at room temperature and at 35 degrees C. The change in liposomal size and size distribution, zeta potential, pH, leakage of encapsulated carboxyfluorescein (CF), and lipid degradation were studied. All the types of pectin were found to protect the liposomes against aggregation during storage. The pectin coat did not affect the permeability of the liposome membrane. HM and LM pectin seemed to be the most promising types of pectin due to minimal changes in the zeta potentials during storage for these samples and no detectable lipid degradation. It is concluded that pectin may be used for stabilizing liposomal drug delivery systems. PMID- 22939350 TI - Copper inclusion in cellulose using sodium D-gluconate complexes. AB - Copper containing cellulose material is of growing interest, e.g. offering alternative in the field of antimicrobials. Solutions of copper d-gluconate complexes (Cu(2+)-DGL) were used to introduce copper ions into a swollen cellulosic matrix. A ligand exchange mechanism forms the chemical basis of the sorption process. Copper sorption in cellulose was studied in the range between pH 6 and 13. An estimate for the complex stabilities of the Cu-cellulose system could be derived from the calculated species distribution of the different Cu(2+) DGL complexes present. Spectrophotometry and cyclic voltammetry of Cu(2+)-DGL complex solution were used to confirm the presence of different species participating in the ligand exchange reaction. The pH dependent uptake of Cu(2+) ions in the cellulose matrix can be explained on the basis of the relative stabilities of Cu(2+)-DGL complex vs. Cu(2+)-cellulose complexes. In comparison to pH 10, higher copper content was observed at pH 6 and 13. Copper content was limited by carboxyl content of cellulosic materials, thus in analogy to the structure of Cu(2+)-DGL complexes participation of the carboxyl group as complex forming site is proposed. At high Cu(2+)-concentration and longer time of immersion in the copper complex solutions formation of solid deposits was observed on the surface of the treated fibres. PMID- 22939351 TI - Preparation, characterization and cytocompatibility of polyurethane/cellulose based liquid crystal composite membranes. AB - Two types of polyurethane/liquid crystal (PU/LC) composite membranes with different LC contents, namely polyurethane/octyl hydroxypropyl cellulose ester (PU/OPC) and polyurethane/propyl hydroxypropyl cellulose ester (PU/PPC), were prepared and studied. The effects of surface properties on cell compatibility of the membranes were elucidated. PPC tended to assemble to independent phases in the composite membranes, while OPC formed uniformly distributed LC domains. As the introduction of LC, phase separation occurred, and the crystallization of PU was disrupted. The surface of PU/LC composite membranes showed fingerprint texture and two-phase morphology. Hydrophilicity of the two types of composite membranes exhibited a reversal tendency with the increase of LC contents. Cells seeded on the composite membranes presented favorable growth when the content of LC was over 30%, especially on PU/OPC complex. The surface morphology, phase separation between LC and PU as well as the type of LC showed significant effects on the cell behaviors. PMID- 22939352 TI - Preparation and characterization of antimicrobial wound dressings based on silver, gellan, PVA and borax. AB - Silver-loaded dressings are designed to provide the same antimicrobial activity of topical silver, with the advantages of a sustained silver release and a reduced number of dressing changes. Moreover, such type of dressing must provide a moist environment, avoiding fiber shedding, dehydration and adherence to the wound site. Here we describe the preparation of a novel silver-loaded dressing based on a Gellan/Hyaff((r)) (Ge-H) non woven, treated with a polyvinyl alcohol (PVA)/borax system capable to enhance the entrapment of silver in the dressing and to modulate its release. The new hydrophilic non woven dressings show enhanced water uptake capability and slow dehydration rates. A sustained silver release is also achieved. The antibacterial activity was confirmed on Staphylococcus aureus and Pseudomonas aeruginosa. PMID- 22939353 TI - Self-assembly of amylose-grafted carboxymethyl cellulose. AB - In this study, we performed the self-assembly of the amylose-grafted carboxymethyl cellulose sodium salt (NaCMC) for the formation of nanofiber films under aqueous conditions. The introduction of amylose graft chains was conducted by the chemoenzymatic approach including phosphorylase-catalyzed enzymatic polymerization. The product had the rigid NaCMC main chain, which further assembled leading to nanofibers by the formation of double helix between the long amylose graft chains in the intermolecular NaCMC chains of the products. The lengths of the fibers were depended on degrees of polymerization of amylose chains. The nanofiber films were constructed by drying the alkaline solutions of the amylose-grafted NaCMC. The lengths of the nanofibers strongly affected their arrangements in the films. The nanofibers were merged further by washing out alkali to produce the robust nanofiber films. PMID- 22939354 TI - Single step synthesis and characterization of thermoresponsive hyaluronan hydrogels. AB - An efficient and scale-up ready single-step synthesis for the conjugation of thermoresponsive polymers to hyaluronic acid (HA) was established. Jeffamines((r)) (JFM) and poly(N-isopropylacrylamide) (PNIPAM) were grafted to HA via direct amidation mediated by 1,1'-carbonyldiimidazole activation. The temperature-induced gelation of the semi-synthetic co-polymers was characterized by rheology as a function of the temperature and by differential scanning calorimetry (DSC). A HA-JFM conjugate with sol-gel transition in a physiologically relevant temperature range was identified. The grafting of PNIPAM resulted in the drastic change of the main rheological properties of native HA, revealing the hydrophobic non-covalent nature of the interactions between the thermoresponsive brushes in the gel state. Owing to the reversibility of these interactions and the sharpness of the transition, the HA-PNIPAM conjugates are suitable candidates for the incorporation of drugs, cells or ceramic materials for different biomedical applications. PMID- 22939355 TI - Kinetics and mechanism of thermal degradation of pentose- and hexose-based carbohydrate polymers. AB - This work aims at study of thermal degradation kinetics and mechanism of pentose- and hexose-based carbohydrate polymers isolated from Plantago ovata (PO), Salvia aegyptiaca (SA) and Ocimum basilicum (OB). The analysis was performed by isoconversional method. The materials exhibited mainly two-stage degradation. The weight loss at ambient-115 degrees C characterized by low activation energy corresponds to loss of moisture. The kinetic triplets consisting of E, A and g(alpha) model of the materials were determined. The major degradation stage represents a loss of high boiling volatile components. This stage is exothermic in nature. Above 340 degrees C complete degradation takes place leaving a residue of 10-15%. The master plots of g(alpha) function clearly differentiated the degradation mechanism of hexose-based OB and SA polymers and pentose-based PO polymer. The pentose-based carbohydrate polymer showed D(4) type and the hexose based polymers showed A(4) type degradation mechanism. PMID- 22939357 TI - A serious impasse: gallstone ileus. PMID- 22939356 TI - Haploinsufficiency of E-selectin ligand-1 is associated with reduced atherosclerotic plaque macrophage content while complete deficiency leads to early embryonic lethality in mice. AB - E-selectin-1 (ESL-1), also known as golgi complex-localized glycoprotein-1 (GLG1), homocysteine-rich fibroblast growth factor receptor (CGR-1), and latent transforming growth factor-beta complex protein 1 (LTCP-1), is a multifunctional protein with widespread tissue distribution. To determine the functional consequences of ESL-1 deficiency, mice were generated carrying an ESL-1 gene trap. After backcrossing to C57BL6/J for 6 generations, mice heterozygous for the gene trap (ESL-1(+/-)) were intercrossed to produce ESL-1(-/-) mice, however ESL 1(-/-) mice were not viable, even at embryonic day E10.5. To determine the effect of heterozygous ESL-1 deficiency on atherosclerosis, apolipoprotein E deficient (ApoE(-/-)), ESL-1(+/-) mice were generated and fed western diet. Compared to ApoE(-/-), ESL-1(+)(/)(+) mice, atherosclerotic lesions from ApoE(-/-), ESL-1(+/ ) contained more collagen and fewer macrophages, suggesting increased plaque stability. In conclusion, heterozygous deficiency of ESL-1 is associated with features of increased atherosclerotic plaque stability while complete deficiency of ESL-1 leads to embryonic lethality. PMID- 22939358 TI - Antihypertensive efficacy of hydrochlorothiazide vs chlorthalidone combined with azilsartan medoxomil. AB - BACKGROUND: Chlorthalidone has proven efficacy to reduce cardiovascular morbidity and mortality, yet it is infrequently used in practice. This study provides a direct comparison of chlorthalidone with hydrochlorothiazide, each combined with the angiotensin receptor blocker azilsartan medoxomil, on blood pressure reduction and control rates. METHODS: This is a randomized, double-blind, titrate to-target blood pressure trial comparing the single-pill combination of azilsartan medoxomil and chlorthalidone versus co-administration of azilsartan medoxomil and hydrochlorothiazide in participants with stage 2 primary hypertension. After 2 weeks of treatment with azilsartan medoxomil 40 mg alone, all participants also received 12.5 mg of diuretic for 4 weeks (up to week 6) and were titrated to 25 mg for another 4 weeks (up to week 10) if they failed to achieve target blood pressure. The primary end point was change in clinic systolic blood pressure. Target blood pressure was defined as clinic blood pressure <140/90 mm Hg for participants without diabetes or chronic kidney disease or <130/80 mm Hg for participants with diabetes or chronic kidney disease. RESULTS: The mean age of the 609 participants was 56.4 years, and the mean baseline clinic blood pressure was 164.6/95.4 mm Hg. The primary end point analysis at week 6 demonstrated a greater reduction of clinic systolic blood pressure for the chlorthalidone (-35.1 mm Hg) versus hydrochlorothiazide combination (-29.5 mm Hg) (mean difference, -5.6 mm Hg; 95% confidence interval, 8.3 to -2.9; P <.001). The mean difference in 24-hour ambulatory systolic blood pressure at week 6 was -5.8 mm Hg (95% confidence interval, -8.4 to -3.2; P <.001), favoring the azilsartan medoxomil/chlorthalidone group. The percentage of participants achieving target clinic blood pressure at week 6 was greater for the chlorthalidone versus hydrochlorothiazide combination (64.1% vs 45.9%, P <.001). Drug discontinuations due to adverse events were not statistically significantly different between groups (9.3% vs 7.3%, P = .38), and hypokalemia was uncommon in both groups. CONCLUSIONS: Chlorthalidone combined with azilsartan medoxomil provides better blood pressure reduction and a higher likelihood of achieving blood pressure control than hydrochlorothiazide combined with azilsartan medoxomil. This benefit occurred without a difference in safety measurements. PMID- 22939359 TI - Incidence of thrombocytopenia among patients receiving heparin venous thromboembolism prophylaxis. AB - BACKGROUND: Heparin is commonly used for venous thromboembolism prophylaxis; however, the incidence of acquired thrombocytopenia in this setting has not been well described. METHODS: The Complications After Thrombocytopenia Caused by Heparin (CATCH) Registry was designed to evaluate the risk of thrombocytopenia among patients receiving heparin in diverse clinical settings. We examined the incidence, management, and outcomes of thrombocytopenia (platelet count decrease >=50% or to nadir <150*10(9)/L) among patients with normal admission platelet counts (>=150*10(9)/L) who received >=72 hours of heparin venous thromboembolism prophylaxis. RESULTS: Among 1017 patients receiving heparin venous thromboembolism prophylaxis, 190 (19%) developed thrombocytopenia. Factors significantly associated with the development of thrombocytopenia include higher admission platelet count, ventilator use, prolonged heparin exposure, unfractionated heparin use, lower admission blood pressure, and cardiac surgery. For thrombocytopenic patients, only 5% received serologic testing for heparin induced thrombocytopenia, and a hematology consult was obtained in 3%, but none were switched to a direct thrombin inhibitor. Acquired thrombocytopenia was not associated with increased in-hospital risk of mortality or thromboembolic events (adjusted odds ratio 1.06; 95% confidence interval, 0.57-1.95); however, it was associated with increased Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO) moderate or severe bleeding risk (adjusted odds ratio 4.49; 95% confidence interval, 2.24-9.02). CONCLUSION: Thrombocytopenia occurs frequently in patients on heparin venous thromboembolism prophylaxis, yet its diagnosis has minimal impact on downstream management. The development of thrombocytopenia is associated with increased bleeding risk. PMID- 22939360 TI - Rate or rhythm control for atrial fibrillation: update and controversies. AB - Atrial fibrillation is associated with increased mortality and considerable morbidity, including stroke, heart failure, and diminished quality of life. Despite these adverse outcomes, rhythm control has not demonstrated benefit in clinical trials. Antiarrhythmic medications, including recently developed agents, have limited efficacy in achieving durable sinus rhythm and substantial toxicity. A rate-control strategy is therefore more attractive for minimally symptomatic patients, but younger and more symptomatic patients may benefit from restoration of sinus rhythm. Catheter ablation is more effective than medications in preventing arrhythmia recurrence, avoids adverse effects associated with antiarrhythmic drugs, and should be considered early in symptomatic patients when success is likely. However, more definitive data are needed from randomized trials assessing long-term outcomes after ablation, including stroke risk and mortality. Clinical decision tools help select the appropriate management for individual patients. Lenient rate management is easy to achieve and seems reasonably safe for certain patients, although the optimum rate varies with individual comorbidities. Because safer and more effective pharmacologic and interventional therapies are now available, an individualized approach to atrial fibrillation management is essential. PMID- 22939361 TI - Abdominal migraine, another cause of abdominal pain in adults. AB - BACKGROUND: Abdominal migraine is a diagnostically challenging childhood disorder, characterized by recurrent episodes of abdominal pain, which has not been clearly demonstrated to occur in adults. METHODS: We used 2 sets of consensus criteria for the diagnosis of abdominal migraine in children to evaluate adults suspected of having this condition in both our own patient population and in the medical literature. Two patients in our clinic and 11 patients from the medical literature composed our initial study cohort and were analyzed using the International Classification of Headache Disorders, 2(nd) Edition and American College of Gastroenterology Rome III Diagnostic Criteria for abdominal migraine in children. RESULTS: Ten of these patients met inclusion criteria for definite or probable abdominal migraine and comprised our final study cohort. The 10 patients from this adult cohort shared common demographic and clinical characteristics with children suffering from abdominal migraine, including a familial history of migraine in 90%. CONCLUSIONS: Our findings demonstrate that abdominal migraine occurs and should be considered in the differential diagnosis of recurrent abdominal pain in adults, especially if there is a family history of migraine headaches. PMID- 22939362 TI - Scores to predict major bleeding risk during oral anticoagulation therapy: a prospective validation study. AB - BACKGROUND: Clinical scores may help physicians to better assess the individual risk/benefit of oral anticoagulant therapy. We aimed to externally validate and compare the prognostic performance of 7 clinical prediction scores for major bleeding events during oral anticoagulation therapy. METHODS: We followed 515 adult patients taking oral anticoagulants to measure the first major bleeding event over a 12-month follow-up period. The performance of each score to predict the risk of major bleeding and the physician's subjective assessment of bleeding risk were compared with the C statistic. RESULTS: The cumulative incidence of a first major bleeding event during follow-up was 6.8% (35/515). According to the 7 scoring systems, the proportions of major bleeding ranged from 3.0% to 5.7% for low-risk, 6.7% to 9.9% for intermediate-risk, and 7.4% to 15.4% for high-risk patients. The overall predictive accuracy of the scores was poor, with the C statistic ranging from 0.54 to 0.61 and not significantly different from each other (P=.84). Only the Anticoagulation and Risk Factors in Atrial Fibrillation score performed slightly better than would be expected by chance (C statistic, 0.61; 95% confidence interval, 0.52-0.70). The performance of the scores was not statistically better than physicians' subjective risk assessments (C statistic, 0.55; P=.94). CONCLUSION: The performance of 7 clinical scoring systems in predicting major bleeding events in patients receiving oral anticoagulation therapy was poor and not better than physicians' subjective assessments. PMID- 22939363 TI - WHO-5, a tool focusing on psychological needs in patients with diabetes: the French contribution to the DAWN study. AB - AIM: In 2001, the international Diabetes Attitudes, Wishes and Needs (DAWN) programme was launched to evaluate the psychosocial impact of diabetes. In France, DAWN experts carried out an observational study to further understand the impact of diabetes on the psychological well-being of people with diabetes, using the French version of the WHO-5 questionnaire. METHODS: The WHO-5, a unidimensional five-item questionnaire that measures positive psychological well being, was completed by 2213 patients (1670 with diabetes). A total sum score was calculated, ranging on a scale from 0 to 25. A score less than 13 indicated impaired well-being and a score less than 8 reflected likely depression. RESULTS: The mean total well-being score for the whole study population was 14.1+/-5.5, and 14.3+/-5.5 for patients with diabetes and 13.5+/-5.4 for patients with other chronic diseases. The average score for patients with diabetes only (15.1+/-5.2) was higher than those for the other subgroups (P=0.005), whereas the average scores for those using insulin (14.8+/-5.2) and women with diabetes (13.2+/-5.6) were significantly lower compared with the whole diabetic group (15.6+/-5.1 [P=0.03] and 15+/-5.2 [P<0.001], respectively). CONCLUSION: The WHO-5 questionnaire showed satisfactory psychometric properties in a large sample of French diabetic patients. The scale is unidimensional and highlighted differences in well-being, which was lower in diabetic women, in patients with other chronic diseases and in those treated with insulin. PMID- 22939364 TI - Lymphadenopathy and splenomegaly in an HIV-infected man. PMID- 22939365 TI - Computed-aided diagnosis (CAD) in the detection of breast cancer. AB - Computer-aided detection (CAD) systems have been developed for interpretation to improve mammographic detection of breast cancer at screening by reducing the number of false-negative interpretation that can be caused by subtle findings, radiologist distraction and complex architecture. They use a digitized mammographic image that can be obtained from both screen-film mammography and full field digital mammography. Its performance in breast cancer detection is dependent on the performance of the CAD itself, the population to which it is applied and the radiologists who use it. There is a clear benefit to the use of CAD in less experienced radiologist and in detecting breast carcinomas presenting as microcalcifications. This review gives a detailed description CAD systems used in mammography and their performance in assistance of reading in screening mammography and as an alternative to double reading. Other CAD systems developed for MRI and ultrasound are also presented and discussed. PMID- 22939366 TI - Assessment of memory/attention impairment in children with primary nocturnal enuresis: a voxel-based morphometry study. AB - AIM: Assessment of memory/attention impairment and related exploration of the gray matter differential MR density variations between children with and without primary nocturnal enuresis (PNE) using voxel-based morphometry (VBM) methodology is the aim of the present study. METHODS: A total of 75 right-handed PNE children (M/F=39:36, average age 10.4+/-1.3 years) and 72 age-matched, right-handed, healthy controls (M/F=40:32, 10.0 +/- 1.2 years) were recruited for the study. First, intelligence tests were performed using the China-Wechsler Intelligence Scale for Children (C-WISC) in both PNE and control children. The full intelligence quotient (FIQ), verbal IQ (VIQ), performance IQ (PIQ), and memory/caution (M/C) factor were measured. Voxel-based morphometry (VBM) was performed using high resolution 3 Tesla T1-weighted MR images, processed using VBM5 in the PNE and control children. Student's t-test or Mann-Whitney U test were performed to analyze the difference in the gray matter density (GMD) between the PNE and control children. RESULTS: The FIQ, VIQ, and PIQ in the PNE group were within the normal range and did not significantly differ from the control group, though the M/C factor was statistically lower in the PNE group. Compared with normal controls, PNE children exhibited lower GMD in the right dorsolateral prefrontal cortex (DLPFC) and the left cerebellum (P<0.001). CONCLUSION: Impairment in memory/attention was detected in PNE children, and the structural abnormalities of the right DLPFC and left cerebellum are likely to be implicated in these deficits. PMID- 22939367 TI - Altered functional connectivity of the dorsolateral prefrontal cortex in first episode patients with major depressive disorder. AB - BACKGROUND: The aim of this study was to investigate resting-state functional connectivity alteration of the right dorsolateral prefrontal cortex (DLPFC) in patients with first-episode major depressive disorder (MDD). METHODS: Twenty-two first-episode MDD patients and thirty age-, gender- and education-matched healthy control subjects were enrolled. Rest state functional magnetic resonance images and structure magnetic resonance images were scanned. The functional connectivity analysis was done based on the result of voxel-based morphometry (VBM). And the right DLPFC was chosen as the seed region of interests (ROI), as its gray matter density (GMD) decreased in the MDD patients compared with controls and its GMD values were negative correlation with the Hamilton Depression Rating Scale (HDRS) scores. RESULTS: Compared to healthy controls, the MDD patients showed increased functional connectivity with right the DLPFC in the left dorsal anterior cingulate cortex (ACC), left parahippocampal gyrus (PHG), thalamus and precentral gyrus. In contrast, there were decreased functional connectivity between the right DLPFC and right parietal lobe. CONCLUSIONS: By applying the VBM results to the functional connectivity analysis, the study suggested that abnormality of GMD in right DLPFC might be related to the functional connectivity alteration in the pathophysiology of MDD, which might be useful in further characterizing structure function relations in this disorder. PMID- 22939368 TI - The road to purified hematopoietic stem cell transplants is paved with antibodies. AB - Hematopoietic progenitor cell replacement therapy remains a surprisingly unrefined process. In general, unmanipulated bone marrow or mobilized peripheral blood (MPB) grafts which carry potentially harmful passenger cells are administered after treating recipients with high-dose chemotherapy and/or radiotherapy to eradicate malignant disease, eliminate immunologic barriers to allogeneic cell engraftment, and to 'make space' for rare donor stem cells within the stem cell niche. The sequalae of such treatments are substantial, including direct organ toxicity and nonspecific inflammation that contribute to the development of graft-versus-host disease (GVHD) and poor immune reconstitution. Passenger tumor cells that contaminate autologous hematopoietic grafts may contribute to relapse post-transplant. Use of antibodies to rid grafts of unwanted cell populations, and to eliminate or minimize the need for nonspecifically cytotoxic therapies used to condition transplant recipients, will dramatically improve the safety profile of allogeneic and gene-modified autologous hematopoietic stem cell therapies. PMID- 22939369 TI - Cellular uptake and processing of enamel matrix derivative by human periodontal ligament fibroblasts. AB - OBJECTIVE: Enamel matrix derivative (EMD), is an extract of porcine developing enamel matrix. Its commercialised form Emdogain, is claimed to stimulate periodontal regeneration by recapitulating original developmental processes, although the mechanism remains unclear. Our objective was to investigate interactions between EMD and human periodontal ligament (HPDL) fibroblasts in vitro. DESIGN: HPDL fibroblasts were cultured in the presence of fluorescently labelled EMD and cellular EMD uptake was monitored using confocal laser scanning microscopy and immunohistochemistry. Internalised EMD proteins were characterised using SDS-PAGE. RESULTS: EMD was internalised by HPDL fibroblasts leading to the appearance of multiple, vesicle-like structure in the cytoplasm. The internalised protein was composed mainly of the major 20kDa amelogenin component of EMD which was subsequently processed with time to generate a cumulative 5kDa component. CONCLUSIONS: Cellular uptake and subsequent intracellular processing of EMD components by dental mesenchymal cells may play a role in EMD bioactivity and in part explain the turnover of Emdogain when placed clinically. PMID- 22939370 TI - The antimicrobial activity of alpha-bisabolol and tea tree oil against Solobacterium moorei, a Gram-positive bacterium associated with halitosis. AB - OBJECTIVE: To investigate the antimicrobial effect of alpha-bisabolol and tea tree oil alone and in combination against the halitosis-associated Gram-positive bacillus Solobacterium moorei. DESIGN: The inhibitory activity of alpha-bisabolol and tea tree oil against the reference strain S. moorei CCUG39336 and four clinical S. moorei isolates was investigated by a direct exposure test. Additionally, the ability of alpha-bisabolol to increase the sensitivity of S. moorei was tested by pretreating the bacteria with sublethal concentrations prior to the administration of tea tree oil. RESULTS: A dose-dependent killing was observed for the antimicrobial agents in a direct exposure test with the reference strain S. moorei CCUG39336. Concentrations of >=0.5% tea tree oil caused decreases in viability of >5 log colony forming units/ml even after short incubation periods, while bacterial viability was less affected by alpha bisabolol. The combination of 0.1% alpha-bisabolol plus 0.05% tea tree oil showed a synergistic effect on S. moorei strain CCUG39336 and on two of the four clinical S. moorei isolates tested. However, incubation of S. moorei with a sublethal concentration of 0.1% alpha-bisabolol for three days prior to the administration of 0.05% tea tree oil did not enhance the antibacterial effect of tea tree oil. CONCLUSION: Halitosis-associated bacterium S. moorei is susceptible to the antimicrobial agents tea tree oil and alpha-bisabolol, suggesting that these compounds might be beneficial in oral healthcare products. PMID- 22939371 TI - Assessing the oral microbiota of healthy and alcohol-treated rats using whole genome DNA probes from human bacteria. AB - OBJECTIVE: This study aimed to evaluate the capacity of whole-genome DNA probes prepared from human oral bacteria to cross-react with bacteria from the oral cavity of rats, and to assess the influence of alcohol ingestion on the animals' oral biofilm. DESIGN: Twenty four mature Wistar rats were equally divided in two groups. One group (control) was fed balanced diet of rat pellets and water. The alcohol-treated group (AT) received the same diet and 20% ethanol solution. Upon euthanasia after 30 days, bacterial samples from the oral biofilm covering the animals' teeth were collected using microbrushes. Bacteria identification and quantification were performed using the DNA checkerboard hybridization method with 33 probes prepared from human oral bacteria. Signals corresponding to bacterial genome counts and percentages were compared using a Mann-Whitney U test with a significance level <0.05. RESULTS: Cross-reaction for all targeted species, except Streptococcus mutans and Streptococcus mitis-like species, occurred in the control group. Escherichia coli, Pseudomonas aeruginosa, Porphyromonas endodontalis, and Veillonella parvula-like species only produced detectable signals in the AT group. Significantly more signals were detected in the control group compared to the AT group (p=0.001). The percentage of E. coli like species was highest in both groups. CONCLUSIONS: Whole-genome DNA probes prepared from human oral bacteria can cross-react with rats' oral bacterial species. Alcohol consumption is associated with lower levels and diversity of bacterial species in the oral cavity of rats. PMID- 22939372 TI - Dental wear in dolphins (Cetacea: Delphinidae) from southern Brazil. AB - (1) Dental wear is a common phenomenon in mammals. Its occurrence is influenced by tooth anatomy, animal physiology, biomechanics and behaviour. So far, investigations of dental wear in cetaceans have been scanty and superficial. We compare the frequencies of occurrence, location and intensity of dental wear in some species of dolphins from southern Brazil, South Atlantic Ocean. (2) Teeth of ten species were evaluated using a stereoscopic microscope to identify wear facets, which were classified according to location, anatomical position and wear intensity. (3) Frequencies of dental wear were high for all species with exception of Delphinus capensis, with less than 50% of teeth worn. Simultaneous wear facets in the apex and lateral of teeth were more common than facets restricted to the apex or lateral faces. Wear on the dental crown was more common, but some species showed less frequent wear down to the cingulum or root level. Superficial wear seems to be the general trend for dolphins, but Stenella coeruleoalba and Pseudorca crassidens showed a higher frequency of severe wear. Only for Tursiops truncatus the frequencies of wear were significantly different between males and females. When considering the ontogeny of dental wear, only for T. truncatus and Stenella frontalis indexes of dental wear were correlated with body length. (4) Whether dental wear has implications or not in fitness and feeding behaviour, severely worn teeth may expose the pulp cavity and increase the susceptibility to local infections. PMID- 22939373 TI - Facilitatory effect of AC-iontophoresis of lidocaine hydrochloride on the permeability of human enamel and dentine in extracted teeth. AB - OBJECTIVES: The objectives of the present study were to quantitatively evaluate chemical permeability through human enamel/dentine using conductometry and to clarify if alternating current (AC) iontophoresis facilitates such permeability. MATERIALS AND METHODS: Electrical impedance of different concentrations of lidocaine hydrochloride was measured using a bipolar platinum impedance probe. A quadratic curve closely fitted to the response functions between conductance and lidocaine hydrochloride. For analysis of the passage of lidocaine hydrochloride through human enamel/dentine, eight premolars that were extracted for orthodontic treatment were sectioned at the cemento-enamel junction. The tooth crowns were held between two chambers with a double O-ring. The enamel-side chamber was filled with lidocaine hydrochloride, and the pulp-side chamber was filled with extrapure water. Two platinum plate electrodes were set at the end of each chamber to pass alternating current. A simulated interstitial pulp pressure was applied to the pulp-side chamber. The change in the concentration of lidocaine hydrochloride in the pulp-side chamber was measured every 2min using a platinum recording probe positioned at the centre of the pulp-side chamber. Passive entry without iontophoresis was used as a control. RESULTS: The level of lidocaine hydrochloride that passed through enamel/dentine against the dentinal fluid flow increased with time. Electrical conductance (G, mho) correlated closely to the concentration (x, mmol/L) of lidocaine hydrochloride (G=2.16x(2)+0.0289x+0.000376, r(2)=0.999). CONCLUSIONS: Lidocaine hydrochloride can pass through enamel/dentine. Conductometry showed that the level of lidocaine hydrochloride that passed through enamel/dentine was increased by AC iontophoresis. PMID- 22939374 TI - Assessment of masticatory performance, bite force, orthodontic treatment need and orofacial dysfunction in children and adolescents. AB - OBJECTIVES: Few studies have evaluated the relationship between morphological and functional characteristics of the masticatory apparatus in young subjects. Thus, the aim of this study was to evaluate masticatory performance (MP), maximal bite force (BF), orthodontic treatment need and orofacial dysfunction in children and adolescents. DESIGN: The sample consisted of 316 subjects of both genders, with an age range 6-16years divided into 4 groups: early mixed, intermediate mixed, late mixed and permanent dentition. MP was evaluated by the individual's ability to comminute a chewable test material in order to determine median particle size (X(50)) and distribution of particles in different sieves ("b"). BF was determined using a digital gnatodynamometer with fork strength of 10mm. Orofacial function and orthodontic treatment need were screened using the Nordic Orofacial Test-Screening (NOT-S) protocol and Index of Orthodontic Treatment Need (IOTN), respectively. The results were submitted to descriptive statistics, normality test, analysis of variance and stepwise multiple linear regression to test relationship between MP and studied independent variables. RESULTS: Variance of X(50) and b between groups was statistically significant. But evaluation of variables that significantly contributed to MP variation showed that age, body mass index (BMI), BF and the presence of sleep bruxism were negatively related to X(50) and the NOT-S clinical exam scores showed a positive relationship with X(50). CONCLUSION: In the studied sample, age, BMI, BF and the presence of sleep bruxism were related to better MP; but the increase in NOT-S scores was significantly related to poorer MP. PMID- 22939375 TI - Peptidoglycan of Actinomyces naeslundii induces inflammatory cytokine production and stimulates osteoclastogenesis in alveolar bone resorption. AB - OBJECTIVE: Actinomyces naeslundii, plays an important role in forming dental biofilms and causes gingival inflammation. Although peptidoglycan, the major cell wall component of Gram-positive bacteria, has been demonstrated to induce inflammatory cytokines, little is known about the association of peptidoglycan with alveolar bone resorption. This study investigated the involvement of peptidoglycan from A. naeslundii in osteoclast formation and bone resorption. DESIGN: Osteoclast formation and function induced by peptidoglycan of A. naeslundii T14V were examined using the co-culture system of MCTC3/PA6 cells and BALB/c mouse bone marrow cells. Osteoclast formation was evaluated to count TRAP positive multi-nuclei cells as osteoclasts. The function of osteoclasts was assessed by measuring the areas of pits absorbed. Inflammatory cytokine genes expressions, such as interleukin (IL)-1beta, IL-6, and tumor necrosis factor (TNF)-alpha, were examined by RT-PCR analysis using murine peritoneal macrophages. Experimental periodontitis was performed in Sprague-Dawley rats orally infected with A. naeslundii. RESULTS: TRAP-positive multi-nuclei cells and the areas of pits induced by peptidoglycan were significantly greater than controls (p<0.01). Gene expression levels of IL-1beta, IL-6, and TNF-alpha induced by A. naeslundii PGN were stronger than controls. In experimental periodontitis, bone loss of A. naeslundii-infected rats was comparable to that of rats induced by Porphyromonas gingivalis, which has been reported to be a periodontal pathogenic agent, being significantly greater than that of the sham group (p<0.01). CONCLUSIONS: These results suggest that peptidoglycan of A. naeslundii is an important virulence factor in the development of periodontitis. PMID- 22939376 TI - Difference equation model for isothermal gas chromatography expresses retention behavior of homologues of n-alkanes excluding the influence of holdup time. AB - A difference equation (DE) model is developed using the methylene retention increment (Deltatz) of n-alkanes to avoid the influence of gas holdup time (tM). The effects of the equation orders (1st-5th) on the accuracy of a curve fitting show that a linear equation (LE) is less satisfactory and it is not necessary to use a complicated cubic or higher order equation. The relationship between the logarithm of Deltatz and the carbon number (z) of the n-alkanes under isothermal conditions closely follows the quadratic equation for C3-C30n-alkanes at column temperatures of 24-260 degrees C. The first and second order forward differences of the expression (Deltalog Deltatz and Delta2log Deltatz, respectively) are linear and constant, respectively, which validates the DE model. This DE model lays a necessary foundation for further developing a retention model to accurately describe the relationship between the adjusted retention time and z of n-alkanes. PMID- 22939377 TI - Wide-range screening of banned veterinary drugs in urine by ultra high liquid chromatography coupled to high-resolution mass spectrometry. AB - In this work, an ultra high performance liquid chromatography-high resolution mass spectrometry (UHPLC-HRMS) methodology is proposed for the multi-class multi residue screening of banned and unauthorized veterinary drugs in bovine urine, using an Orbitrap ExactiveTM analyzer working at a resolving power of 50,000 FWHM in full scan, both in positive and negative mode. The method currently covers 87 analytes belonging to different families such as steroid hormones, beta-agonists, resorcylic acid lactones (RAL), stilbens, tranquillizers, nitroimidazoles, corticosteroids, NSAIDs, amphenicoles, thyreostatics and other substances such as dapsone. A database including the elemental composition, the polarity of acquisition, retention time and expected adducts was built for the targeted analysis, and a high mass accuracy (<5 ppm) was set as one of the identification criteria. After comparing different sample preparation procedures, QuEChERS was selected as the most appropriate methodology. An efficient separation of analytes was achieved using ultra high performance liquid chromatography with a column packed with sub-2 MUm particles. The performance of the method has been evaluated in accordance with the EU guidelines for the validation of screening methods for the analysis of veterinary drugs residues. The screening target concentrations were established between 0.2 MUg/l and 20 MUg/l, demonstrating the usefulness of UHPLC-HRMS as an ideal tool for compliance monitoring in regulatory laboratories. PMID- 22939378 TI - Analytical strategy to reveal the in vivo process of multi-component herbal medicine: a pharmacokinetic study of licorice using liquid chromatography coupled with triple quadrupole mass spectrometry. AB - Although various techniques have been employed to analyze drug metabolites, the metabolism of multi-component herbal medicine has seldom been fully addressed. In contrast to chemical drugs, a number of compounds in herbal medicine could get into circulation and then be metabolized. Moreover, these compounds may have metabolic interactions which make their pharmacokinetics (PK) even more complicated. The present work aims to elucidate the multi-component pharmacokinetics of a herbal medicine, and to demonstrate how PK behaviors were altered by co-existing constituents. Licorice (Glycyrrhiza uralensis Fisch.), a most commonly used herbal medicine, was chosen as a model. A strategy was proposed to compare the PK profiles of licorice extract with those of nine single compounds. These compounds were major bioactive constituents of licorice, and represented various structural types (flavanone, chalcone, isoflavone, saponin, and coumarin). We established a segmented selected reaction monitoring LC/MS/MS method to simultaneously monitor 63 licorice metabolites in rat plasma, and obtained the PK profiles of 55 metabolites. The results indicated that interactions among licorice compounds altered their PK behaviors in 4 aspects: improvement in bioavailability for aglycones (133- and 109-fold increase for liquiritigenin and isoliquiritigenin, respectively), prolongation in system circulation for glycosides (0.3h delay in T(max) for liquiritin apioside and isoliquiritin apioside), decrease of potential toxicity for saponins such as glycyrrhizic acid, and shift in plasma distribution for phase II metabolites. This is the first attempt to systematically reveal the in vivo process of licorice. Moreover, the study indicates noticeable interactions to alter pharmacokinetics among licorice compounds, which may be characteristic for herbal medicines. PMID- 22939379 TI - Selective pressurised liquid extraction of halogenated pesticides and polychlorinated biphenyls from pine needles. AB - Pine needles are an ideal matrix for the long-term monitoring of semi-volatile organic compounds in the atmosphere because they are naturally occurring and distributed worldwide. However, typical extraction methods result in the co elution of matrix-interfering compounds and thus require time-consuming clean-up steps. A selective pressurised liquid extraction method (S-PLE) for extracting current-use pesticides, historic-use pesticides and polychlorinated biphenyls (PCBs) from pine needles that does not require additional clean-up steps was developed and validated. The selective extraction was achieved by packing the extraction vessel with a fat retainer, Florisil, down-stream of the pine needle matrix. A fat to fat-retainer ratio of 0.0057 (corresponding to 35 g of Florisil per 10 g of pine needle sample) was selected to minimise the co-elution of matrix interfering compounds. Three 5-min extractions were performed using 25:75 (v/v) dichloromethane:n-hexane and a solvent flush of 150%. The mean recovery of spiked current-use pesticides, historic-use pesticides and PCBs using this method was 71%, 72%, and 84%, respectively. The method was validated by comparing target analyte concentrations measured in a pine needle sample using the optimised S-PLE method to those obtained using a conventional PLE method with external clean-up. The method detection limits and reproducibility were similar for the two methods; however, sample preparation time was 67% shorter when using the S-PLE method. PMID- 22939380 TI - Ultra high performance liquid chromatography-electrospray ionization-tandem mass spectrometry screening method for direct analysis of designer drugs, "spice" and stimulants in oral fluid. AB - An ultra high performance liquid chromatography-electrospray ionization-tandem mass spectrometry (UHPLC-ESI-MS/MS) screening method for the direct analysis in oral fluid (OF) of 24 drugs, including new synthetic cannabinoids and so-called "smart" designer drugs, in a single chromatographic run was set up. Benzylpiperazine, methylone, 5,6-methylenedioxy-2-aminoindane (MDAI), fenproporex, 4-fluoroamphetamine (4-FA), 4-methyl-N-ethylcathinone (4-MEC), 4 methylamphetamine (4-MA), methylbenzodioxolylbutanamine (MBDB), mephedrone, methylthioamphetamine (MTA), methylenedioxypyrovalerone (MDPV), mefenorex, nabilone, furfenorex, clobenzorex, JWH-200, AM 694, JWH-250, JWH-073, JWH-018, JWH-019, JWH-122, HU 210 and CP 47497 were determined in a chromatographic run of 9 min only with no sample pre-treatment, after addition of ISs and dilution in mobile phase A. This method is designed to be applied to 250 MUL of OF sample, anyway is suitable to be used on smaller volumes (till 100 MUL). LODs vary from 1ng/mL to 20 ng/mL. No interfering peaks were observed due to similar analytes, common therapeutic drugs or endogenous compounds. Matrix effect, although present especially for mephedrone, is acceptable, allowing the detection of the compounds at the LODs described. The developed method was applied on 400 real OF samples from on-site tests performed by police officers. PMID- 22939381 TI - Modelling the decline of pH in muscles of lamb carcases. AB - Assuming an exponential decay model (EDM) for pH decline as a function of temperature, ideal shortening (i.e. neither hot nor cold shortening) for an individual carcase occurs if and only if that carcase's model parameters fall within a specific sub-region of three dimensional space. This paper demonstrates that simply fitting EDMs to a sample of carcases and using the proportion of sampled carcases with estimated parameters within the specific sub-region can lead to seriously biassed estimates for the proportion of carcases ideally shortened. This is particularly so if the EDMs are fitted separately to each sampled carcase but also remains the case, to a lesser extent, if the models are fitted jointly using random effects modelling. A preferred estimate is based on the probability that an independently selected carcase has model parameters within the specific region, based on the distribution of the EMD parameters. The distribution of EMD parameters is obtained via the fitted random effects exponential decay model. PMID- 22939382 TI - Highly ordered mesoporous TiO2-Fe2O3 mixed oxide synthesized by sol-gel pathway: an efficient and reusable heterogeneous catalyst for dehalogenation reaction. AB - Highly ordered two-dimensional (2D) hexagonal TiO(2)-Fe(2)O(3) mixed-oxide material MFT-1, which is composed of very tiny nanoparticles, is synthesized using sodium dodecylsulfate (SDS) as a structure-directing agent. Interestingly, synthesis of an ordered mesophase was not possible using SDS as a template for mesoporous pure Fe(2)O(3) or TiO(2) phases. This mesoporous iron-titanium mixed oxide material has been characterized by powder X-ray diffraction (XRD), field emission scanning electron microscopy (FESEM), high-resolution transmission electron microscopy (HRTEM), N(2) sorption, ultraviolet-visible light diffuse reflectance spectroscopy (UV-vis DRS) studies. N(2) sorption analysis revealed high surface areas (126-385 m(2) g(-1)) and narrow pore size distributions (3.1 3.4 nm) for different samples. UV-vis DRS spectra and wide-angle powder XRD patterns indicate that the material is composed of alpha-Fe(2)O(3) and anatase TiO(2) phases. This TiO(2)-Fe(2)O(3) mixed-oxide material can act as a very efficient and reusable catalyst in the dehalogenation of aromatic chloride-, bromide-, and iodide-tolerating -F, -CN, -CH(3), -OCH(3) and -NO(2) functional groups in the aromatic ring using 2-propanol as the dispersion medium. PMID- 22939383 TI - Infant feeding intentions among first time pregnant women in urban Melbourne, Australia. AB - OBJECTIVE: to identify first time pregnant women's infant feeding intentions for the first 2 years of life. DESIGN: a qualitative phenomenological approach was used, with semi-structured interviews as the primary method of data collection. SETTING: two of Eastern Health's antenatal clinics in the outer east region of Melbourne, Australia. PARTICIPANTS: seven first time pregnant women from an Eastern Health antenatal clinic. MAIN OUTCOME MEASURE: women's infant feeding intention for the first 2 years of life. MAIN FINDINGS: all the participants intend to breast feed their infant for around 6 months. Women rely heavily on information about infant feeding options from friends, books and the internet, as the information provided by health professionals was found to be inadequate, acquired late in the pregnancy and difficult to access. KEY CONCLUSIONS: the information women receive from midwives at antenatal appointments and parenting classes about infant feeding options is inadequate, as women are not satisfied with the timing, amount and usefulness of the information they receive. IMPLICATIONS FOR PRACTICE: in order to see an increase in the rate of breast feeding it is imperative to create supportive environments for women to breast feed, and for midwives and health professionals to provide information and continued support for women in both the pre- and postnatal period. PMID- 22939384 TI - The promise and challenges of randomized controlled trials for surgical interventions. PMID- 22939385 TI - A trial postmortem: challenges in conducting a randomized, double-blind, phase 2 study in men with castration-resistant prostate cancer. PMID- 22939386 TI - Pelvic lymph node dissection in prostate cancer: the mystery is taking shape. PMID- 22939387 TI - Potentiation of inflammatory CXCL8 signalling sustains cell survival in PTEN deficient prostate carcinoma. AB - BACKGROUND: Inflammation and genetic instability are enabling characteristics of prostate carcinoma (PCa). Inactivation of the tumour suppressor gene phosphatase and tensin homolog (PTEN) is prevalent in early PCa. The relationship of PTEN deficiency to inflammatory signalling remains to be characterised. OBJECTIVE: To determine how loss of PTEN functionality modulates expression and efficacy of clinically relevant, proinflammatory chemokines in PCa. DESIGN, SETTING, AND PARTICIPANTS: Experiments were performed in established cell-based PCa models, supported by pathologic analysis of chemokine expression in prostate tissue harvested from PTEN heterozygous (Pten(+/-)) mice harbouring inactivation of one PTEN allele. INTERVENTIONS: Small interfering RNA (siRNA)- or small hairpin RNA (shRNA)-directed strategies were used to repress PTEN expression and resultant interleukin-8 (CXCL8) signalling, determined under normal and hypoxic culture conditions. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Changes in chemokine expression in PCa cells and tissue were analysed by real-time polymerase chain reaction (PCR), immunoblotting, enzyme-linked immunosorbent assay (ELISA), and immunohistochemistry; effects of chemokine signalling on cell function were assessed by cell cycle analysis, apoptosis, and survival assays. RESULTS AND LIMITATIONS: Transient (siRNA) or prolonged (shRNA) PTEN repression increased expression of CXCL8 and its receptors, chemokine (C-X-C motif) receptor (CXCR) 1 and CXCR2, in PCa cells. Hypoxia-induced increases in CXCL8, CXCR1, and CXCR2 expression were greater in magnitude and duration in PTEN-depleted cells. Autocrine CXCL8 signalling was more efficacious in PTEN-depleted cells, inducing hypoxia-inducible factor-1 (HIF-1) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappaB) transcription and regulating genes involved in survival and angiogenesis. Increased expression of the orthologous chemokine KC was observed in regions displaying atypical cytologic features in Pten(+/-) murine prostate tissue relative to normal epithelium in wild-type PTEN (Pten(WT)) glands. Attenuation of CXCL8 signalling decreased viability of PCa cells harbouring partial or complete PTEN loss through promotion of G1 cell cycle arrest and apoptosis. The current absence of clinical validation is a limitation of the study. CONCLUSIONS: PTEN loss induces a selective upregulation of CXCL8 signalling that sustains the growth and survival of PTEN-deficient prostate epithelium. PMID- 22939388 TI - Major depression in the era of economic crisis: a replication of a cross sectional study across Greece. AB - BACKGROUND: The study endeavoured to gauge the impact of the current economic crisis on the mental health of the Greek population. Particularly, it explored changes in the prevalence rates of major depression between 2008 and 2011, and its link to financial hardship. Furthermore, the study also identified potential predictors of major depression in 2011. METHODS: Two nationwide cross-sectional teleophone surveys were conducted in 2008 and 2011 following the same methodology. A random and representative sample of 2.197 and 2.256 people, respectively, participated in the studies. Major depression was assessed with the Structural Clinical Interview, whereas financial strain with the Index of Personal Economic Distress (IPED), an original scale with good psychometric properties. RESULTS: In 2011, one-month prevalence rate of major depression was found to be 8.2%, as compared to the corresponding rate in 2008, which was 3.3%. Significant increases in prevalence rates were observed for the majority of the population subgroups. A significant association was recorded between major depression and economic hardship. Young people, married persons, individuals with financial distress and people who use medication displayed increased odds of suffering from major depression in 2011. LIMITATIONS: Participants' responses concerning financial difficulties were not confirmed from collateral accounts. Moreover, the direction of causality between financial hardship and major depression is unclear. CONCLUSIONS: The impact of the economic crisis on the mental health of the population is pervasive. Services and clinicians should focus on the primary prevention of major depression as well as on its timely recognition and treatment. PMID- 22939389 TI - Emotion regulation is the essential skill for improving depressive symptoms. AB - BACKGROUND: For decades, research has shown that various skills (e.g., social skills) are associated with depressive symptoms. In recent years, much work has focused on skills for regulating emotion. Unfortunately, nearly all of these studies have investigated isolated skills. By contrast, the aim of the present study was the combined assessment of multiple skills in order to simultaneously analyze their relevance for depressive symptomatology. The authors wanted to identify skill domains that are essential for improving depressive symptoms. METHODS: The sample consisted of N=124 inpatients assessed at admission and discharge. Seven different skills were measured using a structured multidimensional interview. In addition, the severity of depressive symptoms was assessed. RESULTS: Correlations between the improvements in skills and depressive symptoms reached significance for every skill domain ranging from r=.21 to r=.54. A multiple hierarchical regression analysis was conducted with pre-treatment scores of skills. Compared to other domains, only emotion regulation significantly predicted the improvement of depressive symptomatology. Moreover, emotion regulation at pre-treatment turned out to be a moderator of the association between improvements in skills and the reduction of depressive symptoms. LIMITATIONS: Because this study primarily focused on skills, no conclusions can be drawn regarding the relevance of these skills in relation to other predictors of therapy outcome. CONCLUSIONS: Even when various skills are tested simultaneously, emotion regulation appears to be the essential skill influencing depressive symptom improvement. Therefore, a targeted enhancement of this skill may help to optimize the outcome regarding the treatment of depressive symptomatology. PMID- 22939391 TI - Intakes and sources of isoflavones, lignans, enterolignans, coumestrol and soya containing foods in the Norfolk arm of the European Prospective Investigation into Cancer and Nutrition (EPIC-Norfolk), from 7 d food diaries, using a newly updated database. AB - OBJECTIVE: A diet rich in phyto-oestrogens has been suggested to protect against a variety of common diseases but UK intake data on phyto-oestrogens or their food sources are sparse. The present study estimates the average intakes of isoflavones, lignans, enterolignans and coumestrol from 7 d food diaries and provides data on total isoflavone, lignan and phyto-oestrogen consumption by food group. DESIGN: Development of a food composition database for twelve phyto oestrogens and analysis of soya food and phyto-oestrogen consumption in a populationbased study. SETTING: Men and women, aged 40-79 years, from the general population participating in the Norfolk arm of the European Prospective Investigation into Cancer and Nutrition (EPIC-Norfolk) between 1993 and 1997, with nutrient and food data from 7 d food diaries. SUBJECTS: A subset of 20 437 participants. RESULTS: The median daily phyto-oestrogen intake for all men was 1199 mg (interquartile range 934-1537mg; mean 1504mg, SD 1502mg) and 888mg for all women (interquartile range 710-1135 mg; mean 1205 mg, SD 1701mg). In soya consumers, median daily intakes were higher: 2861 mg in men (interquartile range 1304-7269mg; mean 5051mg, SD 5031mg) and 3142 mg in women (interquartile range 1089-7327mg; mean 5396 mg, SD 6092 mg). In both men and women, bread made the greatest contribution to phyto-oestrogen intake - 40?8% and 35?6%, respectively. In soya consumers, vegetable dishes and soya/goat's/sheep's milks were the main contributors - 45?7% and 21?3% in men and 38?4% and 33?7% in women, respectively. CONCLUSIONS: The ability to estimate phyto-oestrogen intake in Western populations more accurately will aid investigations into their suggested effects on health. PMID- 22939390 TI - Depression symptoms and stressful life events among college students in Puerto Rico. AB - BACKGROUND: The transition from adolescence to adulthood is associated with stressful adaptation experiences that may increase symptoms of depression. We explored the prevalence and sex differences of depressive symptoms and suicidal ideation in freshmen Latino college students in Puerto Rico, and identified stressful life events that could contribute to symptoms of depression. METHODS: Two thousand one hundred sixty-three freshmen college students from the University of Puerto Rico (UPR) public education system were assessed for depression symptoms using the Beck Depression Inventory (BDI) and stressful life events using open questions. RESULTS: Nine percent of the sample reported depression symptoms at a moderate or severe level (BDI>20). Chi square analyses revealed a significantly higher prevalence for three of the stressful life events in females than males: relocation (10.2% females vs. 7.3% males; X(2) (1)=4.13, p=.042), break-up of a significant relationship (25.3% females vs. 17.8% males; X(2) (1)=13.76, p<.001), and illness (11.2% females vs. 7.3% males; X(2) (1)=7.23, p=.007). The model that best explained the variance of BDI scores among females was the presence of suicide risk, relationship break-up, illness, and relocation for college, whereas for males a similar model without the relationship break-up variable resulted in a better fit. CONCLUSIONS: Freshmen college students present a broad range of depression symptoms and certain stressful life events are associated with an increased prevalence of depression symptoms. Early detection of depression and tailored prevention programs should be developed to improve both mental health and academic performance among the college population. PMID- 22939392 TI - Quantitative structure-activity relationships (QSARs) for the transformation of organic micropollutants during oxidative water treatment. AB - Various oxidants such as chlorine, chlorine dioxide, ferrate(VI), ozone, and hydroxyl radicals can be applied for eliminating organic micropollutant by oxidative transformation during water treatment in systems such as drinking water, wastewater, and water reuse. Over the last decades, many second-order rate constants (k) have been determined for the reaction of these oxidants with model compounds and micropollutants. Good correlations (quantitative structure-activity relationships or QSARs) are often found between the k-values for an oxidation reaction of closely related compounds (i.e. having a common organic functional group) and substituent descriptor variables such as Hammett or Taft sigma constants. In this study, we developed QSARs for the oxidation of organic and some inorganic compounds and organic micropollutants transformation during oxidative water treatment. A number of 18 QSARs were developed based on overall 412 k-values for the reaction of chlorine, chlorine dioxide, ferrate, and ozone with organic compounds containing electron-rich moieties such as phenols, anilines, olefins, and amines. On average, 303 out of 412 (74%) k-values were predicted by these QSARs within a factor of 1/3-3 compared to the measured values. For HO(.) reactions, some principles and estimation methods of k-values (e.g. the Group Contribution Method) are discussed. The developed QSARs and the Group Contribution Method could be used to predict the k-values for various emerging organic micropollutants. As a demonstration, 39 out of 45 (87%) predicted k-values were found within a factor 1/3-3 compared to the measured values for the selected emerging micropollutants. Finally, it is discussed how the uncertainty in the predicted k-values using the QSARs affects the accuracy of prediction for micropollutant elimination during oxidative water treatment. PMID- 22939393 TI - Groundwater quality protection at biosolids land application sites. AB - Using the United States (US) Environmental Protection Agency's (EPA) Multimedia, Multi-pathway, Multi-receptor Exposure and Risk Assessment (3MRA) technology, a computer-based biosolids groundwater risk characterization screening tool (RCST) was developed. The RCST, which generates a non-carcinogenic human health risk estimate (i.e., hazard quotient or HQ value), has the ability to conduct screening-level risk-based characterization of potential human risks associated with pollutants released from biosolids land application sites. The HQ is a human health indicator that is equal to the ratio of the pollutant dose (mass of pollutant per unit body weight per time) to the specific pollutant reference dose (R(f)d) which, in turn, is a human health benchmark defined by the EPA as a scientific estimate of the daily exposure level. A HQ value equal to or greater than one (1) suggests that the resulting conditions pose an unacceptable risk to human health. The focus of the current study was to evaluate whether the present regulatory limits established for biosolids pollutants (e.g., heavy metals) were sufficiently protective of human health associated with potential groundwater consumption using a new EPA risk assessment tool. Application of the RCST to two biosolids land application sites located near Columbus, Georgia predicted that, when the depth to groundwater was maintained at a distance of at least 2 m, regulated pollutant concentrations as large as ten (10) times the current regulatory limit (i.e., Title 40 of the US Code of Federal Regulations Part 503 - Ceiling Concentration Limit) could be safely land applied at rates as high as ninety (90) Megagrams per hectare (Mg ha(-1)) with no apparent non-carcinogenic human health effects associated with groundwater consumption. At these pollutant concentrations, the HQ ranged from 1.79 * 10(-9) for cadmium to 3.03 * 10(-3) for selenium. Only under unrealistically high biosolids application rates were the public health risks associated with groundwater impairment characterized as significant (HQ >= 1.0). For example, when the biosolids application rate was increased to 450 Megagrams per hectare (Mg ha(-1)) and the pollutant concentrations were increased to ten times the 40 CFR Part 503 Ceiling Concentration Limit, a HQ value of 2.23 was estimated (selenium). Similarly, when the biosolids application rate was increased to 900 Mg ha(-1) and the pollutant concentrations were increased to ten times the regulatory limit, the HQ ranged varied from 1.4 (for zinc) to 324.0 (for selenium). PMID- 22939394 TI - Driver-injury severity in single-vehicle crashes in California: A mixed logit analysis of heterogeneity due to age and gender. AB - This research develops a mixed logit model of driver-injury severity in single vehicle crashes in California. The research especially considers the heterogeneous effects of age and gender. Older drivers (65+ years old) were found to have a random parameter with about half the population having a higher probability of a fatal injury given a crash than the comparison group of 25-64 year olds with all other factors than age kept constant. The other half of the 65+ population had a lower probability of fatal injury. Heterogeneity was also noted in vehicle age, but related to the gender of the driver, with males linked to, on average, a higher probability of fatal injury in a newer vehicle compared with females, all other factors kept constant. These effects lend support to the use of mixed logit models in injury severity research and show age and gender based population heterogeneity. Several other factors were found to significantly increase the probability of fatal injury for drivers in single-vehicle crashes, most notably: male driver, drunk driving, unsafe speed, older driver (65+) driving an older vehicle, and darkness without streetlights. PMID- 22939395 TI - The motorcyclist impact against a light vehicle: epidemiological, accidentological and biomechanic analysis. AB - This paper summarizes the results obtained within the framework of the French PROMOTO Project (PROtection of the MOTOrcyclist). The aim of this project was to analyze the impact between a motorcycle and a light vehicle from an epidemiological, accidentological and biomechanical point of view. The results have made it possible to outline the most frequent accident configurations such as the "turn on the left" and the most common injuries sustained by motorized two wheelers (head and trunk). The biomechanic analysis has enabled a better understanding of the kinematics involved in an impact between a motorized two wheeler and a light vehicle in various accident configurations (chronology and speed impact). While it is well known that motorcyclists frequently receive life threatening injuries to the head, spine and torso, this paper has been able to observe specific injury mechanisms such as pelvis impacts against the vehicle fuel tank and hyper-extension of the neck due to head impact on passenger cars. PMID- 22939396 TI - KIT mutation detection in Tunisian patients with newly diagnosed myelogenous leukemia: prevalence and prognostic significance. AB - The KIT gene encodes a class III tyrosine kinase receptor in which specific somatic mutations have been found to be associated with many diseases. In this work, we investigated the prevalence of KIT mutations in patients with chronic and acute myelogenous leukemia (CML and AML) and their prognostic significance. A total of 157 subjects were included in the present study (84 patients with CML, 33 with AML, and 40 healthy controls). Patients were analyzed at the first diagnosis, and the KIT mutations were screened by polymerase chain reaction (PCR) and direct sequencing technologies. The results demonstrated the presence of a G/A transition at codon 796, which is associated with the R796K protein variation. This mutation was detected at 21.42% in the CML subgroup and was absent in both AML patients and healthy controls; however, no correlation was found between this mutation and clinical parameters such as the molecular response to Gleevec. In conclusion, we retain that the KIT gene is highly mutated in the CML subgroup, but its role as a prognostic factor needs to be further elucidated. PMID- 22939397 TI - IPP5, a novel inhibitor of protein phosphatase 1, suppresses tumor growth and progression of cervical carcinoma cells by inducing G2/M arrest. AB - Protein phosphatase 1 (PP1) is a major serine/threonine phosphatase that controls gene expression and cell cycle progression. Here, we report the characterization of a novel human bone marrow stromal cell (BMSC)-derived protein called protein phosphatase 1 inhibitor 5 (IPP5), which was obtained by large-scale random sequencing of a human BMSC cDNA library. The human IPP5 cDNA encodes a protein of 116 amino acid residues, which shares high homology with human protein phosphatase 1 inhibitor-1 (PPI-1). The effect of IPP5 on tumor growth and the underlying molecular mechanisms were investigated by overexpression of IPP5 in HeLa cells, a human cervical carcinoma cell line. Our results demonstrated that overexpression of the active mutant IPP5 inhibited the growth of HeLa cells both in vitro and in vivo. Biochemical analysis demonstrated that active mutant IPP5 mediated G2/M arrest of HeLa cells involved regulation of cyclin A1, cyclin B1, CDK1, p21, and p53, as well as increased inhibition of ERK activation. Furthermore, overexpression of the active mutant IPP5 leads to the formation of dikaryons following the failure of cytokinesis. Therefore, IPP5 might be a potential growth inhibitor for human tumor cells, especially for cervical carcinoma cells, and it could contribute to the development of new therapeutic strategies for human cervical cancer treatment. PMID- 22939398 TI - Pediatric acute lymphoblastic leukemia with a t(8;14)(q11.2;q32): B-cell disease with a high proportion of Down syndrome: a Children's Oncology Group study. AB - The rare translocation t(8;14)(q11.2;q32) has been described in patients with B cell acute lymphoblastic leukemia (ALL), particularly patients with Down syndrome (DS). We describe patients with the t(8;14)(q11.2;q32) who were identified by the Children's Oncology Group (COG) ALL cytogenetics database, expanding our previous report of 10 patients with this translocation. Twenty-two such patients were treated with COG protocols. All patients had B-cell ALL, and seven (31.8%) had DS. None of the children with DS had an event; thus, these patients had a superior estimated 5-year event-free survival (EFS) compared to non-DS patients (100% vs. 50.1 +/- 17.7%; P = 0.04). Only one patient (4.5%) had a concomitant Philadelphia chromosome t(9;22)(q34;q11.2). The cytogenetics data of two additional patients, who were not eligible for COG protocols, are also included in this report. In conclusion, ALL patients with the recurring translocation t(8;14)(q11.2;q32) have the B-cell phenotype and a high percentage have DS. Children with DS and the t(8;14)(q11.2;q34) have improved EFS using standard COG therapy compared to non-DS patients. We did not find an increased number of patients with a concomitant Philadelphia chromosome in this population. PMID- 22939399 TI - MLPA is a powerful tool for detecting lymphoblastic transformation in chronic myeloid leukemia and revealing the clonal origin of relapse in pediatric acute lymphoblastic leukemia. AB - Copy number alterations (CNAs) at 58 different loci have been investigated in 95 bone marrow or peripheral blood samples from patients with chronic myeloid leukemia (CML) or pediatric acute lymphoblastic leukemia (pALL) using multiplex ligation-dependent probe amplification (MLPA). In all but one case, the CNA profile correctly distinguished patients with CML who were in chronic phase from those in lymphoblast crisis. Within the chronic phase group, we could not separate patients resistant to imatinib therapy from those who were good responders. In our investigation of patients with pALL, a panel of MLPA probes broader than ever before was applied. Paired diagnostic and relapse samples from patients with pALL demonstrated clonally related or independent dominant clones, suggesting the presence of a pre-leukemic cell group. Identification of the origin of cell populations dominating at relapse will have a great effect on future treatment strategies. In summary, we have demonstrated the versatility of MLPA by using this cost-effective technique for two new applications. PMID- 22939400 TI - The MDM2 SNP309 G allele is not preferentially amplified in bone and soft tissue tumors. AB - The transcriptional enhancer region in intron 1 of the proto-oncogene MDM2 contains a polymorphic site (SNP309) that may harbor a G or a T nucleotide. Previous studies have shown that the G allele confers a higher affinity for the Sp1 transcription factor, resulting in an increased transcriptional activity of MDM2. A constitutional G allele has also been associated with earlier onset of various cancer types, and studies of sarcomas have shown an enrichment of the G allele in tumors with MDM2 amplification, notably atypical lipomatous tumor (also known as well-differentiated liposarcoma). In the present study, we analyzed the SNP309 genotype in blood samples and tumor tissue from 57 patients with bone or soft tissue tumors showing amplification of MDM2. We did not observe any constitutional enrichment of the G allele. More importantly, there was no preferential amplification of the G allele in tumor tissue from TG heterozygotes. The expression levels of MDM2 messenger RNA were not higher in tumors with amplification of the G allele than in tumors with amplification of the T allele. Thus, we could not find any evidence for a selective advantage of the SNP309 G allele in bone and soft tissue tumors with MDM2 amplification. PMID- 22939401 TI - Resequencing analysis of the candidate tyrosine kinase and RAS pathway gene families in multiple myeloma. AB - Multiple myeloma (MM) is an incurable, B-cell malignancy characterized by the clonal proliferation and accumulation of malignant plasma cells in bone marrow. Despite recent advances in the understanding of genomic aberrations, a comprehensive catalogue of clinically actionable mutations in MM is just beginning to emerge. The tyrosine kinase (TK) and RAS oncogenes, which encode important regulators of various signaling pathways, are among the most frequently altered gene families in cancer. To clarify the role of TK and RAS genes in the pathogenesis of MM, we performed a systematic, targeted screening of mutations on prioritized RAS and TK genes, in CD138-sorted bone marrow specimens from 42 untreated patients. We identified a total of 24 mutations in the KRAS, PIK3CA, INSR, LTK, and MERTK genes. In particular, seven novel mutations in addition to known KRAS mutations were observed. Prediction analysis tools PolyPhen and Sorting Intolerant from Tolerant (SIFT) were used to assess the functional significance of these novel mutations. Our analysis predicted that these mutations may have a deleterious effect, resulting in the functional alteration of proteins involved in the pathogenesis of myeloma. While further investigation is needed to determine the functional consequences of these proteins, mutational testing of the RAS and TK genes in larger myeloma cohorts might also be useful to establish the recurrent nature of these mutations. PMID- 22939402 TI - Nexplanon, a radiopaque etonogestrel implant in combination with a next generation applicator: 3-year results of a noncomparative multicenter trial. AB - OBJECTIVE: To investigate the efficacy, safety, removal characteristics, and x ray visibility of Nexplanon, a radiopaque etonogestrel contraceptive implant combined with a next-generation applicator. STUDY DESIGN: A 3-year, nocomparative, multicenter study in women aged 18-40 years at 23 clinical sites. RESULTS: Of 301 women who had an implant inserted, none became pregnant while the implant was in situ. Serious adverse events were reported in 16 of 301 (5.3%) women; none were judged as drug related. Fibrosis around the implant was the most common removal complication (4.4%). The implant was visible on X-ray and palpable before removal with a mean removal time of 2 minutes. CONCLUSION: Nexplanon showed high contraceptive efficacy, palpability before removal, short removal times, and few removal complications. Nexplanon provides clinicians with a long term hormonal contraceptive method with a safety and efficacy profile comparable to Implanon, radiopacity, and a new applicator. PMID- 22939404 TI - An association between the inferior humeral head osteophyte and teres minor fatty infiltration: evidence for axillary nerve entrapment in glenohumeral osteoarthritis. AB - BACKGROUND: Glenohumeral osteoarthritis often results in inferior humeral osteophytes. Anatomic studies suggest that the axillary neurovascular bundle is in close proximity to the glenohumeral capsule. We therefore hypothesize that an inferior humeral osteophyte of sufficient magnitude could encroach on the axillary nerve and result in measurable fatty infiltration of the teres minor muscle. MATERIALS AND METHODS: Preoperative magnetic resonance imaging studies of 91 consecutive arthritic shoulders were retrospectively reviewed. Two cohorts were established based on the presence of a humeral osteophyte. The distances from the axillary neurovascular bundle to various osseous structures were measured using calibrated software. Objective quantitative measurements of the degree of fatty infiltration of the teres minor muscles were obtained with image analysis software. Results were compared between cohorts. RESULTS: The distance between the inferior humerus and axillary neurovascular bundle was inversely correlated to the size of the inferior humeral osteophyte (rho = -0.631, P < .001). Fatty infiltration of the teres minor was greater when an inferior osteophyte was present (11.9%) than when an osteophyte was not present (4.4%) (P = .004). A statistically significant correlation between the size of the humeral head spur and quantity of fat in the teres minor muscle belly (rho = 0.297, P = .005) was identified. CONCLUSION: These data are consistent with our hypothesis that the axillary nerve may be entrapped by the inferior humeral osteophyte often presenting with glenohumeral osteoarthritis. Entrapment may affect axillary nerve function and lead to changes in the teres minor muscle. Axillary neuropathy from an inferior humeral osteophyte may represent a contributing and treatable cause of pain in patients with glenohumeral osteoarthritis. PMID- 22939405 TI - Limited physical therapy utilization protocol does not affect impairment and disability in Workers' Compensation patients after rotator cuff repair: a short term follow-up study. AB - BACKGROUND: Treatment of rotator cuff tears in injured workers is associated with poorer outcomes and abnormally high utilization of clinical services. This study evaluates the effect on impairment and disability rates after the implementation of an accelerated independent rehabilitation protocol on injured workers undergoing mini-open rotator cuff repair. MATERIALS AND METHODS: Seventy-one primary rotator cuff repairs in injured workers were reviewed at least 1 year after claim closure. Outcomes based on permanent partial disability and impairment were compared among 28 patients using traditional outpatient physical therapy (group A) and 43 patients using an accelerated protocol-driven independent exercise program (group B). The number of physical therapy visits attended, disability, and impairment rates were compared between the 2 groups. RESULTS: Group B used a median of 16 physical therapy visits, which were 9 fewer visits per patient than group A (P < .001). This constituted a 36% reduction in the median number of physical therapy visits without negatively affecting disability and impairment rates. The difference between the 2 groups in time to release to work or time to claim closure was not significant. CONCLUSIONS: The implementation of an accelerated, independent, exercise protocol reduced physical therapy utilization to levels below national best-practices benchmarks without negatively affecting impairment or disability rates in Workers' Compensation patients undergoing mini-open rotator cuff repair. LEVEL OF EVIDENCE: Level IV, Retrospective Case Series, Prognostic Study. PMID- 22939406 TI - Experimental pain inhibits infraspinatus activation during isometric external rotation. AB - BACKGROUND: The effect of pain on muscle activation is poorly understood. This study examined the effects of acute experimental pain on rotator cuff muscle force and voluntary activation (VA). We hypothesized that acute subacromial pain would cause inhibition of infraspinatus VA with a corresponding decrease in external rotation force. MATERIALS AND METHODS: Seventeen healthy adults with no known shoulder pathology were tested. Isolated external rotation force was tested on a dynamometer. Participants performed 2 baseline maximum voluntary isometric contractions of external rotation, during which maximal electrical stimulation was used to assess VA. To elicit pain, 1.5 mL 5% hypertonic saline was injected into the subacromial space, and testing of maximum voluntary isometric contractions force and VA was repeated 3 times at 5-minute intervals. RESULTS: Mean +/- standard deviation initial pain from the injection was 6.6 +/- 1.3 points of 10 possible and produced a 32.8% decline in force and a 22.7% decline in VA (P < .05). Pain diminished over a 10-minute period. As pain resolved, force and VA improved (P < .0125). There was a strong relationship between force and VA (r(2) = 0.78, P < .05) and a moderate relationship between pain and VA (r(2) = 0.31, P < .05). CONCLUSIONS: Experimental subacromial pain elicits a decline in force and VA of the infraspinatus. Although this study only examines acute experimental pain, it supports the concept that pain affects rotator cuff muscle recruitment and function, which may contribute to abnormal shoulder mechanics in patients with rotator cuff pathology. PMID- 22939403 TI - Hsp65-producing Lactococcus lactis prevents experimental autoimmune encephalomyelitis in mice by inducing CD4+LAP+ regulatory T cells. AB - Heat shock proteins (Hsps) participate in the cellular response to stress and they are hiperexpressed in inflammatory conditions. They are also known to play a major role in immune modulation, controlling, for instance, autoimmune responses. In this study, we showed that oral administration of a recombinant Lactococcus lactis strain that produces and releases LPS-free Hsp65 prevented the development of experimental autoimmune encephalomyelitis (EAE) in C57BL/6 mice. This was confirmed by the reduced inflammatory cell infiltrate and absence of injury signs in the spinal cord. The effect was associated with reduced IL-17 and increased IL 10 production in mesenteric lymph node and spleen cell cultures. Hsp65-producing L. lactis-fed mice had a remarkable increase in the number of natural and inducible CD4+Foxp3+ regulatory T (Treg) cells and CD4+LAP+ (Latency-associated peptide) Tregs - which express the membrane-bound TGF-beta - in spleen, inguinal and mesenteric lymph nodes as well as in spinal cord. Moreover, many Tregs co expressed Foxp3 and LAP. In vivo depletion of LAP+ cells abrogated the effect of Hsp65-producing L. lactis in EAE prevention and worsened disease in medium-fed mice. Thus, Hsp65-L.lactis seems to boost this critical regulatory circuit involved in controlling EAE development in mice. PMID- 22939407 TI - Factors affecting the stability of reverse shoulder arthroplasty: a biomechanical study. AB - BACKGROUND: Despite the success of reverse shoulder arthroplasty (RSA) in treating patients with painful pseudoparalytic shoulders, instability is a common complication and currently the factors affecting stability are not well understood. The objective of this study was to investigate a number of factors as well as the interactions between factors to determine how they affect the stability of the prosthesis. These factors included: active arm posture (abduction and abduction plane angles), loading direction, glenosphere diameter and eccentricity, and humeral socket constraint. METHODS: Force required to dislocate the joint, determined using a biomechanical shoulder simulator, was used as a measure of stability. A factorial design experiment was implemented to examine the factors and interactions. RESULTS: Actively increasing the abduction angle by 15 degrees leads to a 30% increase in stability and use of an inferior offset rather than a centered glenosphere improved stability by 17%. Use of a more constrained humeral socket also increased stability; but the effect was dependent on loading direction, with a 88% improvement for superior loading, 66% for posterior, 36% for anterior, and no change for inferior loading. Abduction plane angle and glenosphere diameter had no effect on stability. CONCLUSION: Increased glenohumeral abduction and the use of an inferior-offset glenosphere were found to increase the stability of RSA. Additionally, use of a more constrained humeral socket increased stability for anterior, posterior, and superior loading. These identified factor effects have the potential to decrease the risk of dislocation following RSA. PMID- 22939408 TI - The influence of wrist posture on the time and frequency EMG signal measures of forearm muscles. AB - This study investigates how altering wrist posture influences the relationship between the time and frequency measures of the electromyography (EMG) signal of extensor digitorum communis (EDC) and flexor carpi ulnaris (FCU). Thirteen participants exerted handgrip force related to maximum voluntary contraction (MVC) in four tests: 20%MVC and 50%MVC in neutral wrist posture and 20%MVC in full wrist flexion and extension. EMG measurements from EDC and FCU were used to calculate normalized values of amplitude (nRMS) and mean and median frequency of the power spectrum (nMPF, nMF). During muscle shortening (wrist flexion for FCU and wrist extension for EDC) nRMS was approximately twofold higher than in neutral posture for FCU and fourfold for EDC. All measures obtained at 20%MVC in neutral posture were significantly different from 20%MVC in wrist flexion for FCU and 20%MVC in wrist extension for EDC (p<0.05). Differences between 50%MVC and 20%MVC at neutral posture (nRMS) were significant for both muscles, although in nMPF and nMF for EDC only. Muscle shortening changed the pattern of statistical significance when the time and frequency domain measures were compared, whereas muscle lengthening did not. It can be concluded that muscle shortening caused by altering wrist posture influences the relationship between the time and frequency measures in both muscles. This suggests that in studies using EMG in different wrist postures, changes in the relationship between the time and the frequency measures should be considered. PMID- 22939409 TI - Gait variability and regularity of people with transtibial amputations. AB - Gait temporal-spatial variability and step regularity as measured by trunk accelerometry, measures relevant to fall risk and mobility, have not been well studied in individuals with lower-limb amputations. The study objective was to explore the differences in gait variability and regularity between individuals with unilateral transtibial amputations due to vascular (VAS) or nonvascular (NVAS) reasons and fall history over the past year. Of the 34 individuals with trans-tibial amputations who participated, 72% of the 18 individuals with VAS and 50% of the 16 individuals with NVAS had experienced at least one fall in the past year. The incidence of falls was not significantly different between groups. Variability measures included the coefficient of variation (CV) in swing time and step length obtained from an electronic walkway. Regularity measures included anteroposterior, medial-lateral and vertical step regularity obtained from trunk accelerations. When controlling for velocity, balance confidence and time since amputation, there were no significant differences in gait variability or regularity measures between individuals with VAS and NVAS. In comparing fallers to nonfallers, no significant differences were found in gait variability or regularity measures when controlling for velocity and balance confidence. Vertical step regularity (p=0.026) was found to be the only significant parameter related to fall history, while it only had poor to fair discriminatory ability related to fall history. There is some indication that individuals who have experienced a fall may walk with decreased regularity and this should be explored in future studies. PMID- 22939410 TI - The effects of cam femoroacetabular impingement corrective surgery on lower extremity gait biomechanics. AB - Surgery to correct cam femoroacetabular impingement (FAI) is increasingly popular. Nevertheless, no known study has analyzed both the three-dimensional lower-extremity joint kinematics and kinetics to quantify FAI surgical outcomes. The purpose of this study was to determine the effects of FAI surgery on the affected lower-extremity joint mechanics during gait by comparing the three dimensional hip, knee, ankle and pelvic angular displacements, as well as the hip, knee and ankle moments and powers of preoperative and postoperative FAI groups, and a healthy control group. Ten patients with unilateral symptomatic cam FAI, who underwent corrective surgery using an open or combined technique, participated in the biomechanical analysis of level walking preoperatively and postoperatively. Thirteen healthy control subjects provided normative data. Results showed that gait biomechanics of FAI patients did not return to normal after surgery. Postoperatively, patients had reduced hip frontal and sagittal plane ROM, smaller peak hip abduction and internal rotation moments, and decreased peak hip power generation compared to the control group. Despite reductions in hip pain, hip impairments and trends detected preoperatively, perhaps due to modified gait patterns, persisted postoperatively. Additional discrepancies in lower-extremity joint mechanics were observed postoperatively, which are believed to have resulted from partial muscle impairment caused by the surgical approaches. Further research is required to confirm the reasons for which lower-extremity gait mechanics of FAI patients do not return to normal following surgery. Clarifying these causes could help improve surgical techniques and rehabilitation programs for the treatment of FAI, and thus improve surgical outcomes. PMID- 22939411 TI - Effect of turning angle on falls caused by induced slips during turning. AB - The present study examined whether turning increases the risk of falling because of an induced slip. Fifteen healthy adult male participants were instructed to walk in a straight line and turn 30 degrees , 45 degrees , and 60 degrees to the right with the left and right feet on a stainless steel floor covered with 70 wt% glycerol solution. The frequency of trials in which falls occurred was examined. The maximum distance (D(max)), magnitude of relative velocity (v(r_max)) between the whole body center of mass (COM) and COM of the foot (sliding foot) segment, and the parallel and perpendicular components of the relative distance/velocity (D(parallel_max), D(perpendicular_max)/v(r_parallel_max), and v(r_perpendicular_max)) during the slipping period were calculated using kinematic data collected from a three-dimensional motion capture system. Mean frequency of fall trials increased significantly as turning angle increased (p<0.001). Depending on the turning angle and pivoting foot, the difference between the frequency of fall trials for 60 degrees turning (55.6%) with the right foot and that for straight walking (13.3%) was 42.3%. Distance and relative velocity between the whole body COM and COM of sliding foot segment (corresponding approximately to center of pressure) perpendicular to the progressing direction increased with turning angle. Bivariate regression analysis demonstrated that D(perpendicular_max) value (R(2)=0.834; p<0.01) and v(r_perpendicular_max)value (R(2)=0.594; p<0.05) were significantly correlated with the frequency of falls. PMID- 22939412 TI - Transformation between different local coordinate systems of the scapula. AB - The existence of multiple local coordinate systems (LCSs) for the scapula makes it difficult to compare the kinematics of the scapula across various studies and reports. This study aimed to build transformation matrices between different LCSs for the scapula and to provide the coordinates of previously measured muscles and ligaments around the scapula with respect to the International Society of Biomechanics (ISB) recommended LCS. The bony landmarks necessary for building various local coordinate systems were digitized on 13 CT scanned scapulae. The LCSs were built based on the digitized bony landmarks and then used for calculating the transformation equations. The approximate coordinates of 28 muscles and ligaments of the scapula were expressed with respect to the ISB recommended LCS using the derived transformation equations. The results of this study may be used for the comparison of scapula kinematics data with respect to various LCSs and for building a scapula biomechanical model with respect to ISB recommended LCS. PMID- 22939413 TI - Monitoring the effects of floods on submerged macrophytes in a large river. AB - The lower Ebro River (Catalonia, Spain) has recently undergone a regime shift from a phytoplankton to a macrophyte-dominated system. Macrophytes started to spread at the end of the 1990s and since 2002 artificial floods (flushing flows) of short duration (1-2 days) are released from the Riba-roja dam once or twice a year in order to reduce macrophyte density. The aim of this study was to analyse the spatiotemporal trends of the submerged macrophytes in two stretches of the lower Ebro River using high-resolution hydroacoustic methods, in order to elucidate the effects of artificial floods and natural floods on its distribution and abundance. Results showed that the mean cover in the two studied stretches (Mora and Ginestar) was not reduced after a flushing flow (from 36.59% to 55.85% in Mora, and from 21.18% to 21.05% in Ginestar), but it was greatly reduced after the natural flood (down to 9.79% in Mora and 2.04% in Ginestar); surprisingly the cover increased in Mora after the artificial flood. In order to increase the efficiency of floods in controlling macrophyte spreading, the magnitude and frequency of them should largely increase, as well as the suspended sediment load, approaching as much as possible to the original flood pattern before dam construction. Hydroacoustic methods combined with geostatistics and interpolation in GIS can accurately monitor spatiotemporal trends of submerged macrophytes in large rivers. This is the first article to apply this monitoring system to submerged macrophytes in rivers. PMID- 22939414 TI - Characterization of "Candidatus Nebulobacter yamunensis" from the cytoplasm of Euplotes aediculatus (Ciliophora, Spirotrichea) and emended description of the family Francisellaceae. AB - Our knowledge of ciliate endosymbionts occurrence and diversity greatly expanded in the last decades, due to the development of characterization methods for uncultivable bacteria. Symbionts related to human pathogens such as rickettsiae and francisellae have been detected inside the cytoplasm of different ciliate species. In the present work, we have characterized a novel Francisella-related bacterium inside the rich prokaryotic community harbored by a population of Euplotes aediculatus (Ciliophora, Spirotrichea). Following the "Full-Cycle rRNA Approach" we obtained the almost full-length 16S rRNA gene sequence of this bacterium, and developed probes for diagnostic fluorescence in situ hybridizations. Attempts to culture the endosymbiont outside of its host failed. We classified this novel organism in a new taxon for which we propose the name "Candidatus Nebulobacter yamunensis". In order to investigate its evolutionary relationships, we have also performed phylogenetic analyses on the class Gammaproteobacteria and the order Thiotrichales, which include the monogeneric family Francisellaceae. We found highly supported evidences for the establishment of a new monophyletic taxon including Francisella species, other organisms currently incertae sedis, and "Candidatus Nebulobacter yamunensis". These organisms form a clade sharing a signature sequence not present in other Thiotrichales bacteria. Moreover, most of them have developed an intracellular life cycle inside eukaryotic organisms. We emended the original description of family Francisellaceae in order to encompass all members of the described clade. PMID- 22939416 TI - Mathematical modeling in economics: comment on "Thermostatted kinetic equations as models for complex systems in physics and life sciences" by Carlo Bianca. PMID- 22939417 TI - The carbapenem-resistant Enterobacteriaceae score: a bedside score to rule out infection with carbapenem-resistant Enterobacteriaceae among hospitalized patients. AB - Patients infected with carbapenem-resistant Enterobacteriaceae often experience delays in initiation of appropriate antimicrobial therapy and increased mortality. A score was developed to differentiate bloodstream infections caused by carbapenem-resistant Enterobacteriaceae (16 patients) versus extended-spectrum beta-lactamase-producing Enterobacteriaceae (166 patients). A score of >= 32 demonstrated high area under the curve of 0.80 (95% confidence interval: 0.68 0.92) and a negative predictive value of 97%. PMID- 22939418 TI - Improved detection of toxigenic Clostridium difficile using the Cepheid Xpert C difficile assay and impact on C difficile infection rates in a tertiary hospital: a double-edged sword. AB - Recent recommendations suggest implementation of a 2-step diagnostic algorithm for the laboratory detection of toxigenic Clostridium difficile. We found that the rate of toxigenic C difficile detection in our laboratory doubled after the introduction of an algorithm that incorporated polymerase chain reaction testing. This led to an abrupt 70% increase in the overall rate of C difficile infection in our institution. PMID- 22939419 TI - Words of wisdom. Re: Long-term results of small intestinal submucosa graft in bulbar urethral reconstruction. PMID- 22939420 TI - Words of wisdom. Re: Pilot study of the vesicocutaneous continent catheterizable stoma (mitrofanoff) in adults--high complication rates. PMID- 22939421 TI - Words of wisdom. Re: A randomized trial of urodynamic testing before stress incontinence surgery. PMID- 22939422 TI - Words of wisdom. Re: Prospective assessment of prostate cancer aggressiveness using 3-T diffusion-weighted magnetic resonance imaging-guided biopsies versus a systematic 10-core transrectal ultrasound prostate biopsy cohort. PMID- 22939423 TI - Words of wisdom. Re: Video technique for human robot-assisted microsurgical vasovasostomy. PMID- 22939424 TI - Words of wisdom. Re: Therapeutic targeting of SPINK1-positive prostate cancer. PMID- 22939425 TI - Development of diffuse double layers in column-wicking experiments: implications for pH-dependent contact angles on quartz. AB - The pH dependence of contact angles in quartz powder beds was studied by column wicking. The rate of capillary penetration was found to be highest at the isoelectric point of quartz which, by applying the classical Washburn equation, results in a minimum contact angle at the isoelectric point. Direct contact angle measurements however show that the contact angle is at a maximum at the point of zero charge (see e.g. [1-6]). By measuring the permeability of powder columns with aqueous solutions of varying pH, it is shown that the permeability reaches a maximum at the isoelectric point. This suggests that the rate of capillary penetration is influenced by the permeability of the powder columns towards respective aqueous solutions. The difference in permeability can be explained by the notion of an electroosmotic counter-pressure which was already recognized by Klinkenberg. An approach is presented that involves the calculation of capillary constants from permeability measurements of the corresponding aqueous solutions. An equation is derived that takes direct account for the electroosmotic counter pressure. Application of this equation combined with capillary constants calculated from permeabilities of the corresponding aqueous solutions results in the expected contact angle-pH relationship. PMID- 22939426 TI - Competitive adsorption of phenol and 3-chlorophenol on purified MWCNTs. AB - A commercial multiwall carbon nanotube and its carboxylated derivate (CNTC and COOHC, respectively) was used after purification to study the competitive adsorption of phenol (P) and m-chlorophenol (CP) from 0.1 M aqueous NaCl solutions without external pH control. The adsorption takes place practically exclusively on the external surface of the nanotubes. The uptake of P is suppressed in comparison to its single solute behaviour on both nanotubes, independently of the initial pollutant concentration. The uptake of CP however is more sensitive to the concentration and the surface chemistry of the nanotube. The measured co-adsorption isotherms were compared to the isotherms calculated from the competitive Langmuir model (CLM). Preferential adsorption of CP was observed in about 95% of the relative concentration range. The total adsorption may exceed the corresponding single component sorption capacity. PMID- 22939427 TI - Superposition-additive approach in the description of thermodynamic parameters of formation and clusterization of substituted alkanes at the air/water interface. AB - The superposition-additive approach developed previously was shown to be applicable for the calculations of the thermodynamic parameters of formation and atomization of conjugate systems, their dipole polarizability, molecular diamagnetic susceptibility, pi-electronic ring currents, etc. In the present work, the applicability of this approach for the calculation of the thermodynamic parameters of formation and clusterization at the water/air interface of alkanes, fatty alcohols, thioalcohols, amines, nitriles, fatty acids (C(n)H(2n+1)X, X is the functional group) and cis-unsaturated carboxylic acids (C(n)H(2n-1)COOH) is studied. Using the proposed approach the thermodynamic quantities determined agree well with the available data, either calculated using the semiempirical (PM3) quantum chemical method, or obtained in experiments. In particular, for enthalpy and Gibbs' energy of the formation of substituted alkane monomers from the elementary substances, and their absolute entropy, the standard deviations of the values calculated according to the superposition-additive scheme with the mutual superimposition domain C(n-2)H(2n-4) (n is the number of carbon atoms in the alkyl chain) from the results of PM3 calculations for alkanes, alcohols, thioalcohols, amines, fatty acids, nitriles and cis-unsaturated carboxylic acids are respectively: 0.05, 0.004, 2.87, 0.02, 0.01, 0.77, and 0.01 kJ/mol for enthalpy; 2.32, 5.26, 4.49, 0.53, 1.22, 1.02, 5.30 J/(molK) for absolute entropy; 0.69, 1.56, 3.82, 0.15, 0.37, 0.69, 1.58 kJ/mol for Gibbs' energy, whereas the deviations from the experimental data are: 0.52, 5.75, 1.40, 1.00, 4.86 kJ/mol; 0.52, 0.63, 1.40, 6.11, 2.21 J/(molK); 2.52, 5.76, 1.58, 1.78, 4.86 kJ/mol, respectively (for nitriles and cis-unsaturated carboxylic acids experimental data are not available). The proposed approach provides also quite accurate estimates of enthalpy, entropy and Gibbs' energy of boiling and melting, critical temperatures and standard heat capacities for several classes of substituted alkanes. For the calculation of thermodynamic functions of clusterization of dimers, trimers and tetramers of fatty alcohols, thioalcohols, amines, carboxylic acids and cis-unsaturated carboxylic acids two superposition-additive schemes are proposed which ensure the correct superimposition of the molecular graphs, including intermolecular hydrogen-hydrogen interactions in the clusters. The calculations involve the thermodynamic parameters of clusterization obtained earlier by the PM3 method. It is shown that the proposed approach reproduces quite accurately the values calculated earlier and is applicable for the prediction of the thermodynamic parameters of the formation of surfactant monolayers. PMID- 22939428 TI - Influence of blood pressure profile on frailty phenotype in community-dwelling elders in Brazil - FIBRA study. AB - Frailty is a clinical condition associated with pathological aging and biological vulnerability. In the spectrum of events related to frailty, aging of the cardiocirculatory system and abnormalities in arterial blood pressure (BP) partly explain the changes in tissue perfusion and, potentially, the decrease in physiological reserves. This study investigated the relationship between BP levels, systemic arterial hypertension (SAH) and the frailty phenotype by analyzing frailty criteria in a cross-sectional model into the FIBRA network, a populational sample of community-dwelling elders in Southeastern Brazil. Study participants with >=65 years were selected by probabilistic sampling of residents in the urban area of the municipality of Campinas (n=900). Considering frailty as a whole and the difference between genders, there was a greater proportion of frail or pre-frail individuals among women than men. Analysis of individual frailty criteria showed that weight loss and fatigue were more common among women (18.3% vs. 12.5%, p=0.034 and 22.5% vs. 11.9%, p<0.001, respectively). Comparison of individuals with or without SAH failed to reveal any differences related to frailty criteria. Nevertheless, averages of diastolic blood pressure (DBP) and mean arterial blood pressure values were lower among elderly individuals with reduced grip strength, physical activity and the frailty classification as a whole (OR 0.986, IC 0.975-0.997) (for every 1 mmHg reduction in MBP values, the likelihood of being frail increased 1.4%). Our findings corroborate the relationship between BP values and frailty in the elderly and contribute to an understanding of the pathophysiological mechanisms of the syndrome. PMID- 22939429 TI - The impact of cardiopulmonary bypass on factor XIII levels in children. PMID- 22939430 TI - Long-term treatment of venous thromboembolism with tinzaparin compared to vitamin K antagonists: a meta-analysis of 5 randomized trials in non-cancer and cancer patients. AB - PURPOSE: Due to its specific pharmacokinetic profile, tinzaparin, a low-molecular weight heparin (LMWH), appears not to be associated with anti-factor Xa accumulation. Our meta-analysis aimed at determining whether long-term curative doses of tinzaparin is a valuable alternative to vitamin K antagonists (VKA) for the treatment of symptomatic venous thromboembolism (VTE), especially in patients with cancer who are at higher risk of recurrence and bleeding. MATERIALS AND METHODS: A systematic literature search identified randomized studies on long term tinzaparin compared to VKA in patients with VTE. Outcome measures were VTE recurrence, major bleeding, deaths and net clinical benefit combining the three endpoints during the treatment period and at one year. Pooled relative risk was estimated using the logarithm of the relative risk (RR) method based on a fixed effect model in the overall population and cancer population. RESULTS: Five randomized controlled studies were eligible. No difference between groups in VTE recurrence was found in the overall population (RR=0.85 [0.55; 1.31]). In cancer patients, a non-significant 38% VTE risk reduction in favor of tinzaparin was observed on treatment (RR=0.62 [0.30; 1.31]). The difference was significant at the end of follow-up at one year (RR=0.40 [0.19; 0.82], p<0.01). The incidence of major bleeding in the tinzaparin group was not significantly different from the VKA group in the overall population and cancer patients. CONCLUSIONS: Tinzaparin appears as a valuable option for long-term treatment of patients in whom VKA are contraindicated or difficult to monitor. Tinzaparin may have a more favorable benefit-risk ratio than VKA in patients with cancer and VTE. PMID- 22939431 TI - Complementary effects of nanosilver and superhydrophobic coatings on the prevention of marine bacterial adhesion. AB - A superhydrophobic coating composed of silver nanoparticles enclosed in multilayered polyelectrolyte films was deposited onto copper with the aim of preventing bacterial adhesion. Observations from scanning electron microscopy (SEM) and atomic force microscopy (AFM) showed that the amplified exponential growth of the multilayers could induce distinguishable, hierarchical micro- and nanostructures simultaneously. This growth caused the surface roughness to amplify in a lotus-leaf-like manner. UV/visible spectroscopy, X-ray photoelectron spectroscopy (XPS), and transmission electron microscopy (TEM) confirmed the formation of well-dispersed Ag(0) nanoparticles (with sizes from 4-6 nm) in the films. SEM and fluorescence microscope images of the exposed surfaces revealed that the pattern of adhesion and the density of bacterial cells differed depending on the surface energy and the number of Ag(+) ions released during the various immersion time periods. The complementary effects of nanosilver and superhydrophobic coatings can help to effectively reduce bacterial adhesion and the formation of biofilms. PMID- 22939432 TI - Eating and feeding behaviors of obese women: origins and outcomes. PMID- 22939433 TI - Our role in achieving food security for all. PMID- 22939434 TI - The MyPlate message chronicle: one year and counting! PMID- 22939435 TI - Gluten in cosmetics: is there a reason for concern? PMID- 22939436 TI - The many modes of mentoring: new spins on the classic relationship. PMID- 22939437 TI - Gluten-free diet: imprudent dietary advice for the general population? PMID- 22939438 TI - Self-determined, autonomous regulation of eating behavior is related to lower body mass index in a nationwide survey of middle-aged women. AB - BACKGROUND: The associations among people's level of autonomy in regulating their eating behaviors, food patterns, and degree of obesity have not been investigated in a general adult population. OBJECTIVES: Our objectives were to cross sectionally examine, in a nationally representative sample of adult New Zealand women, the associations between different styles of eating behavior regulation and body mass index (BMI), with specific food and eating habits as hypothesized mediators. DESIGN: During May 2009, a sample of 2,500 New Zealand women aged 40 to 50 years was randomly selected from the nationwide electoral rolls. A 66% (n=1,601) participation rate was achieved. Potential participants were mailed a self-administered questionnaire containing the Regulation of Eating Behavior scale, questions on specific food and eating habits (frequency of binge eating, speed of eating, usual daily servings of fruits and vegetables, usual frequency of intake of several high-fat and/or high-sugar foods), and height and weight. STATISTICAL ANALYSES: Univariate linear regression models were used to examine the associations among demographic, health and behavioral variables, and BMI. Multivariate linear regression models were developed to investigate the relationships between autonomous and controlled forms of eating behavior regulation and BMI, with specific food and eating habits as mediators. RESULTS: After adjusting for potential confounders as well as specific food and eating habits that were potential mediators, BMI was statistically significantly lower by 2% (95% CI -2.7% to -1.4%; P<0.001) for every 10-unit increase in autonomous regulation, and statistically significantly higher by 1.4% (95% CI 0.4% to 2.3%; P=0.005) for every 10-unit increase in controlled regulation. The relationships between autonomous regulation and BMI as well as controlled regulation and BMI were only partially mediated by the specific food and eating habits measured. CONCLUSIONS: Although the direction of causality requires confirmation, the results provide support for the applicability of Self-Determination Theory, and suggest that developing more autonomous motivation for eating behavior is likely to facilitate healthier food habits and lower BMI in middle-aged women. PMID- 22939439 TI - Short- and long-term eating habit modification predicts weight change in overweight, postmenopausal women: results from the WOMAN study. AB - BACKGROUND: Standard behavioral obesity treatment produces poor long-term results. Focusing on healthy eating behaviors rather than energy intake may be an alternative strategy. In addition, important behaviors might differ for short- vs long-term weight control. OBJECTIVE: Our aim was to describe and compare associations between changes in eating behaviors and weight after 6 and 48 months. DESIGN: We performed secondary analysis of data collected during a randomized weight-loss intervention trial with 48-month follow-up. PARTICIPANTS: We studied 481 overweight and obese postmenopausal women enrolled in the Women on the Move through Activity and Nutrition (WOMAN) Study. MAIN OUTCOME MEASURES: We measured changes in weight from baseline to 6 and 48 months. STATISTICAL ANALYSES PERFORMED: Linear regression models were used to examine the associations between 6- and 48-month changes in eating habits assessed by the Conner Diet Habit Survey and changes in weight. Analyses were conducted in the combined study population and stratified by randomization group. RESULTS: At 6 months in the combined population, weight loss was independently associated with decreased desserts (P<0.001), restaurant eating (P=0.042), sugar-sweetened beverages (P=0.009), and fried foods (P<0.001), and increased fish consumption (P=0.003). Results were similar in intervention participants; only reduced desserts and fried foods associated with weight loss in controls. At 48 months in the combined population, weight loss was again associated with decreased desserts (P=0.003) and sugar sweetened beverages (P=0.011), but also decreased meats/cheeses (P=0.024) and increased fruits/vegetables (P<0.001). Decreased meats/cheeses predicted weight loss in intervention participants; desserts, sugar-sweetened beverages, and fruits/vegetables were independently associated in controls. CONCLUSIONS: Changes in eating behaviors were associated with weight change, although important behaviors differed for short- and long-term weight change and by randomization group. Future studies should determine whether interventions targeting these behaviors could improve long-term obesity treatment outcomes. PMID- 22939440 TI - Pregravid body mass index is associated with early introduction of complementary foods. AB - OBJECTIVE: To determine whether women who entered pregnancy overweight or obese were less likely to follow American Academy of Pediatrics guidelines for introducing complementary foods to infants after 4 months of age. In addition, we explored whether psychological factors accounted for any of the effect of pregravid body mass index on age of complementary food introduction. DESIGN: A prospective cohort study from 2001 to 2005 that recruited pregnant women between 15 to 20 gestational weeks with follow-up through 12 months postpartum from University of North Carolina hospitals (n=550). STATISTICAL ANALYSIS: Multinomial models were used to estimate relative risk ratios. The outcome was age of complementary food introduction, categorized as younger than 4 months of age, 4 to 6 months, and 6 months or later (referent). Maternal body mass index was categorized as underweight (<18.5), normal weight (18.5 to 24.9), and overweight/obese (>=25). A series of regression analyses tested mediation by psychological factors measured during pregnancy (depressive symptoms, stress, and anxiety). RESULTS: More than a third of the study population (35.7% of 550) entered pregnancy overweight/obese. The majority of participants (75.3%) introduced foods to their infants between 4 and 6 months of age. Compared with normal-weight women, those who were overweight/obese before pregnancy were more likely (relative risk ratios=2.22 [95% CI 1.23 to 4.01]) to introduce complementary foods before the infant was 4 months old, adjusting for race, education, and poverty status. Depressive symptoms, stress, and anxiety did not account for any of the effect of pregravid overweight/obesity on early food introduction. CONCLUSIONS: The results suggest that overweight and obese women are more likely to introduce complementary foods early and that psychological factors during pregnancy do not influence this relationship. Future studies need to explore why overweight/obese women are less likely to meet the American Academy of Pediatrics recommendations for the introduction of complementary food. PMID- 22939442 TI - Inter-rater reliability of ohio school-based overweight and obesity surveillance data. AB - Measurement of height and weight in large studies may force the use of multiple measurers. The purpose of this study was to evaluate the reliability of height, weight, and body mass index (BMI) measures collected by multiple measurers in a large, statewide BMI surveillance program. A random subsample of schools (n=30) was selected from schools that participated in the 2009 to 2010 Ohio third-grade Oral Health/BMI surveillance program. Children (n=1,189) were measured by multiple volunteer health professional measurers and again by a trained researcher, who was standard across all schools. Mean differences for height, weight, and BMI percentiles were calculated for BMI category classifications. Agreement was estimated by the reliability coefficient, McNemar's test, and Kappa statistic. Sensitivity, specificity, and positive and negative predictive values were estimated using the trained researcher measures as the reference. Overall mean differences (95% confidence interval) were 0.45 (0.41-0.48) cm for height, 0.07 (-0.01-0.15) kg for weight, and 1.37 (1.20-1.53) for BMI. The correlation coefficient for all three measures was over 0.9 (P<0.01), indicating a strong positive association between measures. BMI category classifications showed substantial reliability (Kappa range: 0.94-0.96). Percentage agreement ranged from 98% to 99% for all BMI categories, as did sensitivities and specificities. Positive predictive values for all BMI categories were approximately 97%, and close to 100% for negative predictive values. Reliability for height, weight, BMI percentile, and BMI classification was very high, supporting the use of multiple trained measurers in a statewide BMI surveillance program. Similar methods can be applied to other public health and clinical settings to improve anthropometric measurement reliability. PMID- 22939441 TI - Food insecurity is associated with obesity among US adults in 12 states. AB - A redesigned food insecurity question that measured food stress was included in the 2009 Behavioral Risk Factor Surveillance System in the Social Context optional module. The objective of our study was to examine the association between food stress and obesity using this question as a surrogate for food insecurity. Our analytic sample included 66,553 adults from 12 states. Food insecurity was determined by response (always/usually/sometimes) to the question, "How often in the past 12 months would you say you were worried or stressed about having enough money to buy nutritious meals?" T tests were used to compare prevalence differences between groups, and logistic regression was used to examine the association between food insecurity and obesity. Among the 12 states, the prevalence of obesity was 27.1% overall, 25.2% among food secure adults, and 35.1% among food insecure adults. Food insecure adults had 32% increased odds of being obese compared to food secure adults. Compared with food secure adults, food insecure adults had significantly higher prevalence of obesity in the following population subgroups: adults ages >=30 years, women, non-Hispanic whites, non-Hispanic blacks, adults with some college education or a college degree, a household income of <$25,000 or $50,000 to $74,999, and adults with none or two children in their households. One in three food insecure adults were obese. Food insecurity was associated with obesity in the overall population and most population subgroups. These findings are consistent with previous research and highlight the importance of increasing access to affordable healthy foods for all adults. PMID- 22939443 TI - Agreement between different methods and predictive equations for resting energy expenditure in overweight and obese Brazilian men. AB - Predictive equations and methods tend to overestimate or underestimate resting energy expenditure (REE) compared with indirect calorimetry (IC). This cross sectional study aimed to evaluate the agreement between methods and equations for REE estimation of overweight and obese Brazilian men. Data from 48 healthy volunteers, ages 20 to 43 years and with body mass index ranging from 26.4 to 35.2, were collected between October 2008 and October 2009. REE was measured by IC, using Deltatrac (IC1) and KORR-MetaCheck (IC2) devices. It was estimated by bioelectrical impedance analysis (BIA) using tetrapolar (BIA1) and bipolar (BIA2) devices, and by the equations of Mifflin, World Health Organization/Food and Agriculture Organization/United Nations University, Fleisch, Horie-Waitzberg and Gonzalez, and Ireton-Jones. The association and agreement among the methods and equations were assessed by the interclass correlation coefficient, Bland-Altman analysis, and by the percentage of the difference between values obtained from the standard method and alternative methods and equations. Most methods showed high agreement with IC1. The highest agreements were found for Mifflin (-2.14%), Fleisch (-3.05%), Horie-Waitzberg and Gonzalez (4.41%), and BIA2 (5.25%). Similar results were shown by the Bland-Altman analyses. BIA2, followed by BIA1, Ireton Jones, Mifflin, and Fleisch, showed the highest association with IC1. Thus, the Mifflin, Fleisch, Horie-Waitzberg and Gonzalez equations, and BIA2, were the most accurate methods for REE estimation in this study. However, because those equations have shown considerable variability, they should be used cautiously. In addition, the IC2 was not found to be an accurate method for REE estimation in overweight and obese men included in this study. PMID- 22939444 TI - Position of the Academy of Nutrition and Dietetics: the impact of fluoride on health. AB - It is the position of the Academy of Nutrition and Dietetics to support optimal systemic and topical fluoride as an important public health measure to promote oral health and overall health throughout life. Fluoride is an important element in the mineralization of bone and teeth. The proper use of topical and systemic fluoride has resulted in major reductions in dental caries and its associated disability. Dental caries remains the most prevalent chronic disease in children and affects all age groups of the population. The Centers for Disease Control and Prevention has named fluoridation of water as one of the 10 most important public health measures of the 21st century. Currently, >72% of the US population that is served by community water systems benefits from water fluoridation. However, only 27 states provide fluoridated water to more than three quarters of the state's residents on public water systems. Fluoride also plays a role in bone health. However, at this time, use of high doses of fluoride for osteoporosis prevention is considered experimental only. Dietetics practitioners should routinely monitor and promote the use of fluorides for all age groups. PMID- 22939445 TI - Academy of Nutrition and Dietetics: standards of practice and standards of professional performance for registered dietitians (competent, proficient, and expert) in intellectual and developmental disabilities. PMID- 22939446 TI - Is There Research to Support the Statement that Healthy Diets Cost More? PMID- 22939447 TI - [Sex differences in the relationship between vigorous vs. moderate intensity exercise and risk markers of overweight and obesity in healthy adults]. AB - INTRODUCTION: Several studies have extensively documented the benefits of moderate intensity physical training for reducing the risk of cardiovascular death in the management of overweight and obesity. However, the benefits of vigorous intensity training are small. OBJECTIVE: To examine sex differences in the relationship between vigorous vs. moderate intensity exercise and risk markers for overweight and obesity in healthy adults. METHODS: A cross-sectional, descriptive study in 304 healthy subjects (n=218 men, n=86 women). The short version of the International Physical Activity Questionnaire (IPAQ) was used to stratify exercise intensity into two categories, moderate and vigorous. Body mass index (BMI) and percent body fat (%BF) were calculated, and waist circumference (WC) was measured as risk markers of overweight and obesity. RESULTS: No significant differences were found in risk markers of overweight and obesity in the male group depending on exercise intensityh. As compared to women training at moderate intensity, those making vigorous exercise had lower BMI (25.7+/-3.0 kg/m(2) vs.22.5+/-1.7 kg/m(2)), WC (79.2+/-6.8 cm vs. 76.0+/-3.1 cm), and BF (33.5+/-2.6% vs. 28.1+/-5.3%) levels (P<0.05 for all). CONCLUSIONS: Vigorous intensity training is associated with lower values of markers of overweight and obesity in women, but not in men. PMID- 22939448 TI - Effect of epivascular cardiac autonomic nerve stimulation on cardiac function. AB - BACKGROUND: The cardiac plexus contains sympathetic and parasympathetic cardiac nerves. Our goal was to assess the hemodynamic and functional effects of stimulating the cardiac autonomic nervous system (CANS) at the epivascular surfaces of the cardiac plexus. Although CANS therapy to modulate cardiovascular function has drawn widespread interest, research has focused only on stimulating parasympathetic or sympathetic nerves, not both at once. METHODS: Using general anesthesia and an open-chest surgical procedure, 12 dogs received epivascular stimulation of the cardiac plexus. A bipolar electrode was placed between the right pulmonary artery (PA) and the ascending aorta, with the stimulation frequency/pulse width held constant (20 Hz/4 ms) and the voltage varied (10-50 V). Left ventricular (LV) pressure-volume loops and hemodynamic data were recorded with and without stimulation. RESULTS: In all dogs, aortic and LV systolic pressures, maximum rate of change of LV pressure, and LV stroke work increased (p<0.0001), as did cardiac output (2.9+/-1.0-0.4+/-1.0 L/min; p=0.001), end-systolic elastance (1.2+/-0.4-1.5+/-0.5 mm Hg/mL; p=0.0001), preload recruitable stroke work (30.1+/-11.0-39.3+/-7.8 mm Hg; p=0.003), and LV ejection fraction (p=0.012). Systemic vascular resistance increased slightly (p=0.04), and pulmonary vascular resistance decreased (p=0.01). Mean heart rate and pulmonary arterial, central venous, and left atrial pressures remained unchanged (p>0.1). CONCLUSIONS: In contrast to inotropic drugs, epivascular CANS stimulation induced a significant and selective increase in LV contractility with no increase in heart rate. PMID- 22939449 TI - Contemporary outcomes in infants with congenital heart disease and bochdalek diaphragmatic hernia. AB - BACKGROUND: Fifteen percent of infants with congenital diaphragmatic hernia (CDH) are born with a coexisting cardiac anomaly. The purpose of this study was to evaluate contemporary outcomes in this patient population and to identify potential risk factors for in-hospital mortality. METHODS: Data from all CDH neonates with congenital heart disease managed at a single pediatric tertiary care referral center between 1997 and 2011 were retrospectively analyzed. RESULTS: Forty (18%) of 216 CDH patients had a cardiac anomaly. This group was associated with a significant decrease in overall survival when compared with patients without cardiac anomaly (55% versus 81%; p = 0.001). There was no association between type of cardiac anomaly and mortality based on risk stratification according to the Risk Adjustment for Congenital Heart Surgery and The Society of Thoracic Surgeons-European Association for Cardiothoracic Surgery scoring systems (p = 0.86 and p = 0.87, respectively). Birth weight was similarly no different between survivors and nonsurvivors (2.8 +/- 0.6 kg versus 2.8 +/- 0.9 kg, respectively; p = 0.98). There was a trend toward increased extracorporeal membrane oxygenation use among nonsurvivors (p = 0.13). Infants with hemodynamic stability enabling subsequent cardiac repair were associated with lower mortality (p = 0.04). Survivors had a wide spectrum of long-term morbidity, but most had some evidence of neurodevelopmental impairment. CONCLUSIONS: This large single-institution series suggests that the overall prognosis of infants with concomitant CDH and congenital heart disease can be quite variable, regardless of the type of heart anomaly. Hemodynamic instability and need for extracorporeal membrane oxygenation correlate with higher mortality. Although some long-term survivors have excellent outcomes, most suffer from chronic, long-term morbidities. PMID- 22939450 TI - Progression rate and early surgical experience in the new aggressive aneurysms osteoarthritis syndrome. AB - BACKGROUND: Aneurysms-osteoarthritis syndrome (AOS), caused by SMAD3 mutations, is a recently described autosomal dominant condition characterized by aneurysms throughout the arterial tree in combination with osteoarthritis. The objective of the present study was to evaluate progression rate of aortic dilation and surgical outcome in AOS patients. METHODS: All AOS patients are regularly monitored according to our clinical AOS protocol. Patients with at least two follow-up visits or who underwent aortic root surgery during follow-up were included in this cohort study. Clinical and surgical data were obtained from chart abstraction. RESULTS: We included 22 patients (aged 38 +/- 15 years; 41% male) with the molecular diagnosis of AOS. Follow-up duration was 3.3 years (interquartile range, 1.6 to 5.1). In the 17 patients who were managed conservatively, aortic root diameter increased from 37.5 +/- 5.1 mm at baseline to 40.3 +/- 6.2 mm at follow-up (p = 0.008). Progression rate of aortic dilation was highest at the level of the sinus of Valsalva (2.5 +/- 5.8 mm per year) and significantly correlated with the initial diameter (r = 0.603, p = 0.017). Ten patients successfully underwent valve-sparing aortic root replacement, 5 after previous watchful waiting. Mean preoperative aortic diameter was 46.6 +/- 4.0 mm. The operations were not complicated by fragility of tissue. After a postoperative period of 2.8 years (interquartile range, 0.7 to 5.4), no mortality or reoperations had occurred, and all patients remained asymptomatic. CONCLUSIONS: Aneurysm growth in AOS patients can be fast and unpredictable, warranting extensive and frequent cardiovascular monitoring. Valve-sparing aortic root replacement is a safe and effective procedure for the management of aortic root aneurysms in AOS patients. PMID- 22939451 TI - Preoperative anemia does not increase the risks of early surgical revascularization after myocardial infarction. AB - BACKGROUND: Recent clinical studies suggest preoperative anemia may increase mortality and morbidity after cardiac surgery. Anemic patients are potentially even more vulnerable in the setting of a recent myocardial infarction (MI). The objective of this study was to investigate the impact of preoperative anemia on short-term outcomes after coronary bypass surgery in patients with a recent MI. METHODS: We conducted a retrospective cohort study of 655 patients who underwent an isolated coronary bypass procedure within 21 days of MI, 432 of whom were anemic preoperatively, defined as a hemoglobin less than 13 g/dL for men and less than 12 g/dL for women. The primary outcomes were in-hospital mortality and major adverse events (MAE), which included MI, stroke, and renal failure requiring dialysis. RESULTS: Before risk adjustment, in-hospital mortality and the incidence of MAE were significantly higher in patients with anemia versus no anemia (mortality, 5.1% versus 1.4%, p = 0.02; MAE, 8.6% versus 3.1%, p = 0.009). After risk adjustment, the association between preoperative anemia and mortality or MAE became insignificant (mortality odds ratio 2.34, 95% confidence interval: 0.56 to 9.87, p = 0.25; MAE odds ratio 1.13, 95% confidence interval: 0.46 to 2.79, p = 0.78). Preoperative hemoglobin, treated as a continuous variable, yielded similar results. CONCLUSIONS: Preoperative anemia does not directly increase risks of surgical revascularization performed within 21 days of MI. PMID- 22939453 TI - Are there cost benefits to fentanyl for breakthrough pain? PMID- 22939454 TI - Long-term "real-life" usefulness of the Victoria Bowel Performance Scale. PMID- 22939455 TI - Preemptive use of palliative sedation and amyotrophic lateral sclerosis. PMID- 22939457 TI - Preliminary study of a web-based tool for enhancing the informed consent process in schizophrenia research. AB - Printed research consent forms serve to legally document what has been disclosed, but are usually suboptimal as a means of actually communicating that information to potential participants. We conducted a preliminary study of web-based multimedia consent. Participants included 19 patients with schizophrenia and 16 normal comparison (NC) subjects randomly assigned to a routine or web-media consent. Although comprehension among NCs was excellent regardless of consent condition, the web-based consent was associated with better comprehension and satisfaction among patients with schizophrenia. Findings suggest that web-aided multimedia consent is feasible and potentially more effective than printed consent forms in schizophrenia research. PMID- 22939456 TI - The effects of stimulus timing features on P300 speller performance. AB - OBJECTIVE: Despite numerous examinations of factors affecting P300 speller performance, the impact of stimulus presentation parameters remains incompletely understood. This study examines the effects of four distinct stimulus presentation parameters (stimulus-off time [ISI(*)], interstimulus interval [ISI], flash duration, and flash-duration:ISI ratio) on the accuracy and efficiency of the P300 speller performance. METHODS: EEG data from a 32-electrode set were recorded from six subjects using a row-column paradigm of the speller task and analyzed offline. RESULTS: P300 speller accuracy is affected by the number of trial repetitions (F(14,354) = 69.002, p < 0.0001), as expected. In addition, longer ISI and ISI(*) times resulted in higher accuracy and characters per minute [CPM] rates. Subsets of the entire group (i.e. good vs. poor performers) were compared to show consistency of performance trends despite great variance among subjects. Moreover, the same significant effects were observed whether using the entire 32-electrode dataset or the reduced 8-channel set described by Sharbrough et al. (1991). CONCLUSIONS: Despite variability in user performance, both ISI(*) and ISI can affect P300 speller performance. SIGNIFICANCE: P300 system optimization must consider critical stimulus timing features including ISI(*) and ISI. Further characterization of the impact of these timing features in online experiments is warranted and the differential effect on accuracy and CPM should be more comprehensively explored. PMID- 22939458 TI - Medical care costs of newly diagnosed children with structural-metabolic epilepsy: a one year prevalence-based approached. AB - PURPOSE: Aims of this study were to estimate the first-year medical care costs of newly diagnosed children with structural-metabolic epilepsy and to determine the cost-driving factors in the selected population. METHOD: This was a prevalence based retrospective chart review that included patients who attended a pediatric neurology clinic in a tertiary referral center in Malaysia. The total first-year medical care costs were estimated from the provider (i.e., hospital) perspective, using a bottom-up, microcosting analysis. Medical chart/billing data (i.e., case reports) obtained from the hospital (i.e., provider) were collected to determine the resources used. Prices or cost data were standardized for the year 2010 (One Malaysian Ringgit MYR is equivalent to 0.26 Euro or 0.32 USD). RESULTS: The most expensive item in the costs list was antiepileptic drugs, whereas ultrasound examination represented the cheapest item. Hospitalization and the use of non antiepileptic drugs were the second and third most costly items, respectively. The cost of therapeutic drug monitoring comprised only a small proportion of the total annual expenditure. None of the demographic variables (i.e., gender, race, and age) significantly impacted the first-year medical care costs. Similarly, child development, seizure type, therapy type (i.e., polytherapy versus monotherapy), and therapeutic drug monitoring utilization were also not associated with the cost of management. The first-year medical care costs positively correlated with seizure frequency (r(s)=0.294, p=0.001). However, the only variable that significantly predict the first-year medical care costs was the type of antiepileptic drugs (R(2)=0.292, F=7.772, p<0.001). CONCLUSION: This investigation was the first cost analysis study of epilepsy in Malaysia. The total first-year medical care costs for 120 patients with structural-metabolic epilepsy were MYR 202,816 (i.e., MYR 1690.13 per patient per year). The study findings highlight the importance of optimizing seizure control in reducing the cost of management. PMID- 22939459 TI - Head space solid phase microextraction based on nano-structured lead dioxide: application to the speciation of volatile organoselenium in environmental and biological samples. AB - A novel and efficient speciation method based on the nano-structured lead dioxide as stationary phase of head space solid phase microextraction combined with gas chromatography mass spectrometry (GC-MS) was developed for the determination of volatile organoselenium compounds (dimethylselenide (DMSe) and dimethyldiselenide (DMDSe)) in different biological and environmental samples. PbO(2) particles with a diameter in the range of 50-70 nm have been grown on platinum wire via elechtrochemical deposition. The effect of different variables on the extraction efficiency was studied simultaneously using an experimental design. The variables of interest in the HS-SPME were condition of coating preparation, desorption time, stirring rate, desorption temperature, ionic strength, time and temperature of extraction. A Plackett-Burman design was performed for screening in order to determine the significant variables affecting the extraction efficiency. Then, the significant factors were optimized by a Box-Behnken design (BBD) and the response surface equations were derived. The detection limit and relative standard deviation (RSD) (n=5, c=50 MUgL(-1)) for DMSe were 16 ngL(-1) and 4.3%, respectively. They were also obtained for DMDSe as 11ngL(-1) and 4.6%, respectively. The developed technique was found to be applicable to spiked environmental and biological samples. PMID- 22939460 TI - Correlation between ultra-high performance liquid chromatography-tandem mass spectrometry and reversed-phase thin-layer chromatography hydrophobicity data for evaluation of angiotensin-converting enzyme inhibitors absorption. AB - In this research seven ACE inhibitors (enalapril, quinapril, fosinopril, lisinopril, cilazapril, ramipril, benazepril) were studied to evaluate the correlation between their absorption and ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS) and reversed-phase thin-layer chromatography (RP-TLC) hydrophobicity data (phi(0) or C(0) parameters, respectively). Their absorption values were in the range of 25-60%, while calculated KOWWIN logP values were from -0.94 to 6.61. Additionally, perindopril (absorption 70%, KOWWIN logP 2.59) and moexipril (absorption 22%, KOWWIN logP 3.36) were introduced for the theoretical considerations due to their high/low absorption values which were on the opposite sites in comparison with the majority of ACE inhibitors (25-60%). In the theoretical considerations it was shown that the solubility data (logS) must be considered, as independent variable, simultaneously with KOWWIN logP to obtain reliable correlation (r(2)=0.7208) between absorption and ACE inhibitors lipophilicity. As the main topic of this study, the relationships between literature available and absorption data predicted by multiple linear regression (MLR) using logS values besides chromatographically obtained hydrophobicity parameters C(0) (r(2)=0.6424) or phi(0) (r(2)=0.6762) were studied proving that these parameters could be used in ACE inhibitors absorption evaluation. The UHPLC-MS method provides the direct application of experimentally obtained phi(0) values that is the advantage of this method. For better MLR correlation of ACE inhibitors absorption with C(0) parameters (RP-TLC) and logS, mathematical conversion of C(0) parameters to logC(0) values was necessary based on requisite for probability value of regression analysis (P<0.05). The accordance and differences between hydrophobicity parameters obtained by UHPLC-MS and RP-TLC were defined. PMID- 22939461 TI - Inadequate feeding of infant and young children in India: lack of nutritional information or food affordability? AB - OBJECTIVE: Despite a rapidly growing economy and rising income levels in India, improvements in child malnutrition have lagged. Data from the most recent National Family Health Survey reveal that the infant and young child feeding (IYCF) practices recommended by the WHO and the Indian Government, including the timely introduction of solid food, are not being followed by a majority of mothers in India. It is puzzling that even among rich households children are not being fed adequately. The present study analyses the socioeconomic factors that contribute to this phenomenon, including the role of nutritional information. DESIGN: IYCF practices from the latest National Family Health Survey (2005-2006) were analysed. Multivariate logistic regression analyses were performed to establish the determinants of poor feeding practices. The indicators recommended by the WHO were used to assess the IYCF practices. SETTING: India. SUBJECTS: Children (n 9241) aged 6-18 months. RESULTS: Wealth was shown to have only a small effect on feeding practices. For children aged 6-8 months, the mother's wealth status was not found to be a significant determinant of sound feeding practices. Strikingly, nutritional advice on infant feeding practices provided by health professionals (including anganwadi workers) was strongly correlated with improved practices across all age groups. Exposure to the media was also found to be a significant determinant. CONCLUSIONS: Providing appropriate information may be a crucial determinant of sound feeding practices. Efforts to eradicate malnutrition should include the broader goals of improving knowledge related to childhood nutrition and IYCF practices. PMID- 22939463 TI - [Eosinophilic esophagitis]. PMID- 22939464 TI - [Gastroesophageal reflux disease: diagnostic tests]. PMID- 22939466 TI - [Barrett's esophagus]. PMID- 22939465 TI - [Medical and non-medical treatment of gastroesophageal reflux disease]. PMID- 22939462 TI - alpha Power, alpha asymmetry and anterior cingulate cortex activity in depressed males and females. AB - Left fronto-cortical hypoactivity, thought to reflect reduced activity in approach-related systems, and right parietal hypoactivity, associated with emotional under-arousal, have been noted in major depressive disorder (MDD). Altered theta activity in the anterior cingulate cortex (ACC) has also been associated with the disorder. We assessed resting frontal and parietal alpha asymmetry and power in non-medicated MDD (N = 53; 29 females) and control (N = 43; 23 females) individuals. Theta activity was examined using standardized low resolution electromagnetic tomography (sLORETA) in the ACC [BA24ab and BA32 comprising the rostral ACC and BA25/subgenual (sg) ACC]. The MDD group, and particularly depressed males, displayed increased overall frontal and parietal alpha power and left midfrontal hypoactivity (alpha(2)-indexed). They also exhibited increased sgACC theta(2) activity. MDD females had increased right parietal activity, suggesting increased emotive arousal. Thus, unmedicated depressed adults were characterized by lower activity in regions implicated in approach/positive affective tendencies as well as diffuse cortical hypoarousal, though sex specific modulations emerged. Altered theta in the sgACC may reflect emotion regulation abnormalities in MDD. PMID- 22939467 TI - [Helicobacter pylori infection]. PMID- 22939468 TI - [Non-steroidal anti-inflammatory drugs: prevention and treatment of complications]. PMID- 22939469 TI - [Obesity: pathogenesis and nonsurgical treatment]. PMID- 22939470 TI - [Obesity: surgical treatment and new therapeutic modalities]. PMID- 22939471 TI - [The intestinal microbiota in health and disease]. PMID- 22939472 TI - [Prebiotics, probiotics and symbiotics]. PMID- 22939473 TI - [Nutrigenomics, proteomics, and metabolomics in the prevention and treatment of gastrointestinal diseases]. PMID- 22939474 TI - [Celiac disease]. PMID- 22939475 TI - [Diarrhea and deficient absorption]. PMID- 22939476 TI - [Inflammatory bowel disease: what's new in diagnosis?]. PMID- 22939477 TI - [Treatment of inflammatory bowel disease]. PMID- 22939478 TI - [Motor and functional disorders of the esophagus]. PMID- 22939479 TI - [Dyspepsia]. PMID- 22939480 TI - [Gastroparesis]. PMID- 22939481 TI - [Irritable bowel syndrome (IBS) in the 2012 DDW]. PMID- 22939482 TI - [Constipation and anorectal disorders]. PMID- 22939483 TI - [Early cancer: new diagnostic and endoscopic resection techniques]. PMID- 22939484 TI - [Diagnosis and management of gastrointestinal hemorrhage]. PMID- 22939485 TI - [Therapeutic endoscopic ultrasound]. PMID- 22939486 TI - [Treatment of biliary obstruction in pancreatic cancer]. PMID- 22939487 TI - [New technologies in endoscopy]. PMID- 22939488 TI - [Update in abdominal radiology]. PMID- 22939489 TI - [The best of the Digestive Disease Week (DDW)]. PMID- 22939490 TI - [The Best of the United European Gastroenterology Week (UEGW) 2011]. PMID- 22939491 TI - [The best of the Congress of the American Association for the Study of Liver Diseases]. PMID- 22939492 TI - [The best of the meeting of the American College of Surgeons]. PMID- 22939493 TI - [Fatty liver, alcoholic steatohepatitis, and non-alcoholic steatohepatitis]. PMID- 22939494 TI - [New therapies in chronic hepatitis]. PMID- 22939495 TI - [Hepatic fibrosis]. PMID- 22939496 TI - [Cirrhosis complications]. PMID- 22939497 TI - [Liver transplantation]. PMID- 22939498 TI - [Acute pancreatitis]. PMID- 22939499 TI - [Recent advances in esophagogastric carcinoma patient management]. PMID- 22939500 TI - [Premalignant lesion screening, surveillance and colorectal cancer]. PMID- 22939501 TI - [Hepatobiliary tumors]. PMID- 22939502 TI - [Pancreatic tumors: an update]. PMID- 22939503 TI - Young patient with acute ischemic stroke due to papillary carcinoma of the thyroid. AB - Hypercoagulability is a condition predisposing to arterial or venous thrombosis and is associated frequently with malignancy. We present a rare acute ischemic stroke in a young patient that was the presenting feature for a newly diagnosed papillary carcinoma of the thyroid. Extensive vascular and hematological work-up was normal except for a large patent foramen ovale (PFO). This finding, along with the association of most vascular events with hypercoagulability being of venous origin, makes the mechanism of paradoxical embolism through the large PFO the probable cause of stroke in our patient. PMID- 22939504 TI - Internal carotid artery to superior ophthalmic vein fistula: a case report. PMID- 22939505 TI - Simultaneous quantification of Amaryllidaceae alkaloids from Zephyranthes grandiflora by UPLC-DAD/ESI-MS/MS. AB - A rapid, simple and sensitive ultra performance liquid chromatography-diode array detection method (UPLC-DAD) was developed and validated for quantification of four biologically important Amaryllidaceae alkaloids viz. lycoramine, hamayne, haemanthamine and tortuosine in Zephyranthes grandiflora. The method employed BEH C(18) column (2.1mm*100mm, 1.7MUm particle size) with linear gradient elution of acetonitrile and water (0.05% formic acid) in a flow rate of 0.3mL/min and at lambda(max) 280nm. Standard calibration curve for the analytes were linear (r(2)>=0.9999), precise (intra-day RSDs<1.33% and inter-day RSDs<2.67%) and accurate (97.8-105.3%). The developed method was applied to the quality assessment of samples collected during different seasons and showed significant variation with an optimum amounts of these alkaloids in rainy season. The method was also applied for identification of Amaryllidaceae alkaloids in the plant and overall, seventeen Amaryllidaceae alkaloids of different structural types lycorine, haemanthamine, galanthamine, narciclasine were characterised. This study provides a qualitative and quantitative method for analysis of Amaryllidaceae alkaloids. PMID- 22939506 TI - Aging magnifies the effects of dopamine transporter and D2 receptor genes on backward serial memory. AB - Aging compromises dopamine transporter (DAT) and receptor mechanisms in the frontostriatal circuitry. In a sample of 1288 younger and older adults, we investigated (i) whether individual differences in genotypes of the DAT gene (i.e., SLC6A3, the DAT variable number of tandem repeat 9/9, 9/10, and 10/10) and in the D2 receptor (DRD2) gene (i.e., the C957T [rs6277] CC and any T) interactively contribute to phenotype variations in episodic memory performance; and (ii) whether these genetic effects are magnified in older adults, because of considerable declines in the dopamine functions. Our results showed that carrying genotypes associated with higher levels of striatal synaptic dopamine (DAT 9/9) and higher density of extrastriatal D2 receptors (C957T CC) were associated with better backward serial recall, an episodic memory task with high encoding and retrieval demands. Critically, the gene-gene interaction effect was reliably stronger in older than in younger adults. In line with the resource modulation hypothesis, our findings suggest that aging-related decline in brain phenotypes (e.g., dopamine functions) could alter the relations between genotypes and behavioral phenotypes (e.g., episodic memory). PMID- 22939508 TI - A fluorescence switch sensor for 6-mercaptopurine detection based on gold nanoparticles stabilized by biomacromolecule. AB - It is of great significance to develop a simple and powerful assay of 6 mercaptopurine (6-MP) because of its serious side effect and variable activity with the plasma concentration. In this contribution, a fluorescence switch sensor for trace amount detection of 6-MP was successfully developed based on the fluorescent gold nanoparticles stabilized by macromolecules. With the turn-off and on of the fluorescence signal at 640 nm of the analytical system, the selectivity of the present assay was largely improved. Trace amount of 6-MP could be detected in the linear range 1.0*10(-7) M-1.2*10(-4) M with a detection limit 1.98*10(-8) M. Under a UV lamp, the color change with the variation of the 6-MP concentration could be seen clearly by naked eyes. The sensitivity and selectivity are several-fold greater than other methods. And also it proved to be able to detect trace amount of 6-MP in real samples. The present assay largely improved the application of spectral methods in quantitative analysis of 6-MP. PMID- 22939507 TI - Immunosensor with fluid control mechanism for salivary cortisol analysis. AB - The purpose of this research is to demonstrate a new design for a cortisol immunosensor for the noninvasive and quantitative analysis of salivary cortisol. We propose a cortisol immunosensor with a fluid control mechanism which has both a vertical flow and a lateral flow. The detected current resulting from a competitive reaction between the sample cortisol and a glucose oxidase (GOD) labeled cortisol conjugate was found to be inversely related to the concentration of cortisol in the sample solution. A calibration curve using the relative detected current showed a R(2)=0.98 and CV=14% for a range of standard cortisol solutions corresponding to the concentrations of native salivary cortisol (0.1-10 ng/ml). The measurement could be accomplished within 35 min and the cortisol immunosensor could be reused. These results show promise for realizing an on-site and easy-to-use biosensor for cortisol. Used for evaluation of human salivary cortisol levels, the cortisol immunosensor measurement corresponded closely with commercially available ELISA method (R(2)=0.92). Our results indicate the promise of the new cortisol immunosensor for noninvasive, point of care measurement of human salivary cortisol levels. PMID- 22939509 TI - Single-pipetting microfluidic assay device for rapid detection of Salmonella from poultry package. AB - A direct, sensitive, near-real-time, handheld optical immunoassay device was developed to detect Salmonella typhimurium in the naturally occurring liquid from fresh poultry packages (hereafter "chicken matrix"), with just single pipetting of sample (i.e., no filtration, culturing and/or isolation, thus reducing the assay time and the error associated with them). Carboxylated, polystyrene microparticles were covalently conjugated with anti-Salmonella, and the immunoagglutination due to the presence of Salmonella was detected by reading the Mie scatter signals from the microfluidic channels using a handheld device. The presence of chicken matrix did not affect the light scatter signal, since the optical parameters (particle size d, wavelength of incident light lambda and scatter angle theta) were optimized to minimize the effect of sample matrix (animal tissues and blood proteins, etc.). The sample was loaded into a microfluidic chip that was split into two channels, one pre-loaded with vacuum dried, antibody-conjugated particles and the other with vacuum-dried, bovine serum albumin-conjugated particles. This eliminated the need for a separate negative control, effectively minimizing chip-to-chip and sample-to-sample variations. Particles and the sample were diffused in-channel through chemical agitation by Tween 80, also vacuum-dried within the microchannels. Sequential mixing of the sample to the reagents under a strict laminar flow condition synergistically improved the reproducibility and linearity of the assay. In addition, dried particles were shown to successfully detect lower Salmonella concentrations for up to 8 weeks. The handheld device contains simplified circuitry eliminating unnecessary adjustment stages, providing a stable signal, thus maximizing sensitivity. Total assay time was 10 min, and the detection limit 10 CFU mL(-1) was observed in all matrices, demonstrating the suitability of this device for field assays. PMID- 22939510 TI - Development of a rapid low cost fluorescent biosensor for the detection of food contaminants. AB - A prototype fluorescent based biosensor has been developed for the antibody based detection of food related contaminants. Its performance was characterised and showed a typical antibody binding signal of 200-2000 mV, a short term noise of 9.1 mV, and baseline slope of -0.016 mV/s over 4h. Bulk signal detection repeatability (n=23) and reproducibility (n=3) were less than 2.4%CV. The biosensor detection unit was evaluated using two food related model systems proving its ability to monitor both binding using commercial products and inhibition through the development of an assay. This assay development potential was evaluated by observing the biosensor's performance whilst appraising several labelled antibody and glass slide configurations. The molecular interaction between biotin and an anti-biotin antibody was shown to be inhibited by 41% due to the presence of biotin in a sample. A food toxin (domoic acid) calibration curve was produced, with %CVs ranging from 2.7 to 7.8%, and a midpoint of approximately 17 ng/ml with further optimisation possible. The ultimate aim of this study was to demonstrate the working principles of this innovative biosensor as a potential portable tool with the opportunity of interchangeable assays. The biosensor design is applicable for the requirements of routine food contaminant analysis, with respect to performance, functionality and cost. PMID- 22939511 TI - Improved microbial fuel cell performance by encapsulating microbial cells with a nickel-coated sponge. AB - Development of novel anodic materials that could facilitate microbial biofilm formation, substrate transfer, and electron transfer is vital to enhance the performance of microbial fuel cells (MFCs). In this work, nickel-coated sponge, as a novel and inexpensive material with an open three-dimensional macro-porous structure, was employed as an anode to encapsulate microbial cells. Compared with planar carbon paper, the nickel-coated sponge did not only offer a high surface area to facilitate microbial cells attachment and colonization but also supported sufficient substrate transfer and electron transfer due to multiplexed and highly conductive pathways. As expected, the resulting nickel-coated sponge biofilm demonstrated excellent electrochemical activity and power output stability during electricity generation processes. A higher maximum power density of 996 mW m(-2) and a longer, more stable electricity generation period were achieved with the nickel-coated sponge biofilm than previously reported results. Notably, chemical oxygen demand (COD) removal reached 90.3% in the anode chamber, suggesting that the nickel-coated sponge is a highly promising anodic material and an efficient immobilization method for the fabrication of MFCs. PMID- 22939512 TI - Measuring biomass specific ammonium, nitrite and phosphate uptake rates in aerobic granular sludge. AB - Aerobic granular sludge (AGS) technology offers the possibility to remove organic carbon, nitrogen and phosphorus in a single reactor system. The granular structure is stratified in such a way that both aerobic and anaerobic/anoxic layers are present. Since most of the biological processes in AGS systems occur simultaneously, the measurement and estimation of the capacity of specific conversions is complicated compared to suspended biomass. The determination of the activities of different functional groups in aerobic granular sludge allows for identification of the potential metabolic capacity of the sludge and aids to analyze bioreactor performance. It allows for comparison of different sludges and enables improved understanding of the interaction and competition between different metabolic groups of microorganisms. The most appropriate experimental conditions and methods to determine specific ammonium, nitrite and phosphate uptake rates under normal operation of AGS reactors were evaluated and described in this study. Extra biomass characterization experiments determining the maximum uptake rate of these compounds on optimized conditions were performed as well to see how much spare capacity was available. The methodologies proposed may serve as an experimental frame of reference for investigating the metabolic capacities of microbial functional groups in biofilm processes. PMID- 22939513 TI - Large-scale utilization of water hyacinth for nutrient removal in Lake Dianchi in China: the effects on the water quality, macrozoobenthos and zooplankton. AB - An ecological engineering project using water hyacinth for nutrient removal was performed in Baishan Bay of a large shallow eutrophic lake, Lake Dianchi in China. In the present study, a systematic survey of water quality, macrozoobenthos and zooplankton inside (IWH), around (AWH) and far away (FWH) water hyacinth mats was conducted in Baishan Bay from August to October 2010. The results showed that the water quality significantly improved at AWH area. Concentrations of nitrogen and phosphorus were lower and transparency was higher at AWH area than those in IWH and FWH areas. Total densities, dominant species densities, and biodiversity indexes of macrozoobenthos and cladocerans as well as copepods did not differ (P>0.05) among each other in all three areas. It was significantly (P<0.05) different for those of rotifers at IWH area compared to those in AWH and FWH areas. The results might suggest a tremendous potential for the utilization of water hyacinth in the eutrophic lake like Lake Dianchi for nutrients removal. PMID- 22939514 TI - Polybrominated diphenyl ether metabolism in field collected fish from the Gila River, Arizona, USA--levels, possible sources, and patterns. AB - Polybrominated diphenyl ethers (PBDEs) were determined in fish collected from the Gila River, Arizona, a tributary of the Colorado River in the lower part of the Colorado River Basin. Fish samples were collected at sites on the Gila River downstream from Hayden, Phoenix, and Arlington, Arizona in late summer 2003. The Gila River is ephemeral upstream of the Phoenix urban area due to dams and irrigation projects and has limited perennial flow downstream of Phoenix due to wastewater and irrigation return flows. Fifty PBDE congeners were analyzed by high resolution gas chromatography/high resolution mass spectrometry using labeled surrogate standards in composite samples of male and female common carp (Cyrpinus carpio), largemouth bass (Micropterus salmoides) and channel catfish (Ictalurus punctatus). The predominant PBDE congeners detected and quantified were 47, 100, 153, 49, 28, and 17. Concentrations of total PBDEs in these fish ranged from 1.4 to 12700 ng g(-1) wet weight, which are some of the highest concentrations reported in fish from the United States. Differences in metabolism of several PBDE congeners by carp is clear at the Phoenix site; congeners with at least one ring of 2,4,5-substitution are preferentially metabolized as are congeners with 2,3,4-substitution. PMID- 22939515 TI - Triclosan reduces the levels of global DNA methylation in HepG2 cells. AB - Triclosan (TCS), an antibacterial agent, is widely used in a variety of personal care and industrial products. TCS is associated with the development of liver tumors in rodents and has become a concern to environmental and human health. This study is aimed at investigating whether TCS could modulate the levels of global DNA methylation (GDM) in human hepatocytes. We found that treatment with different doses (1.25-10 MUM) of TCS did not affect HepG2 cell viability, but significantly reduced the levels of GDM in HepG2 cells, and inhibited DNMT1 activity. Furthermore, treatment with TCS significantly inhibited the methylated DNA-binding domain 2 (MBD2), MBD3, and MeCP2 mRNA transcription. In addition, treatment with TCS promoted the accumulation of 8-hydroxy-2-deoxyguanosine (8 OHdG) in a dose-dependent manner, which was abrogated by treatment with an antioxidant, N-acetylcysteine (NAC). Collectively, our data indicated that TCS reduced the levels of GDM and down-regulated the MBD2, MBD3, and MeCP2 gene expression by increasing 8-OHdG levels and inhibiting the DNMT1 activity in HepG2 cells. PMID- 22939516 TI - Time-lapsed imaging of implant fixation failure in human femoral heads. AB - The failure mechanisms of bone-implant constructs are still incompletely understood, because the role of the peri-implant bone in implant stability is unclear. We hypothesized that implant fixation failure is preceded by substantial peri-implant bone failure. A new device was developed that combines mechanical testing of large bone-implant constructs with high-resolution peripheral quantitative computed tomography, following the principles of image-guided failure assessment (IGFA). In this study, we investigated the push-in failure behavior of dynamic hip screws (DHS) implanted in human cadaveric femoral heads. For the first time the fixation failure of a clinically used implant in human trabecular bone could be experimentally visualized at the microstructural level. The ultimate force was highly correlated with the peri-implant bone volume fraction (R(2)=0.85). We demonstrated that primary fixation failure of DHS implants was accompanied by trabecular bone failure in the immediate peri-implant bone region only. Such experimental data are crucial to enhance the understanding on the quality of the bone-implant interface and of the trabecular bone in the process of implant fixation failure. We believe that this newly developed device will be beneficial for the development of new implant designs, especially for use in osteoporotic bone. PMID- 22939517 TI - An SEMG computer interface using three myoelectric sites for proportional two dimensional cursor motion control and clicking for individuals with spinal cord injuries. AB - We developed an alternative computer interface using surface electromyography (sEMG) for individuals with spinal cord injuries (SCI) to access a computer. We designed this interface to make a cursor move on a two-dimensional screen and to click using only three muscles for each subject. In addition, a user can voluntarily control cursor movement speed by modulating muscle contraction levels. Three SCI patients and 10 healthy subjects volunteered to evaluate the performance of this interface using Fitts' law test in a two-dimensional testing setup. The throughputs (TP) of our interface were 0.1962+/-0.0562 b/s for the SCI patients and 0.4356+/-0.0706 b/s for the healthy subjects. This interface could help SCI patients handle a wider range of activities such as browsing the Internet and communicating with others. PMID- 22939519 TI - Reply to 'Methicillin-resistant Staphylococcus aureus'. PMID- 22939518 TI - Effect of dual blockade of the renin-angiotensin system on the progression of type 2 diabetic nephropathy: a randomized trial. AB - BACKGROUND: Blockade of the renin-angiotensin system with angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers has been shown to lessen the rate of decrease in glomerular filtration rate in patients with diabetic nephropathy. STUDY DESIGN: A multicenter open-label randomized controlled trial to compare the efficacy of combining the angiotensin-converting enzyme inhibitor lisinopril and the angiotensin II receptor blocker irbesartan with that of each drug in monotherapy (at both high and equipotent doses) in slowing the progression of type 2 diabetic nephropathy. SETTING & POPULATION: 133 patients with type 2 diabetic nephropathy (age, 66 +/- 8 years; 76% men) from 17 centers in Spain. INTERVENTION: Patients were randomly assigned (1:1:2) to lisinopril (n = 35), irbesartan (n = 28), or the combination of both (n = 70). OUTCOMES: The primary composite outcome was a >50% increase in baseline serum creatinine level, end-stage renal disease, or death. RESULTS: Baseline values for mean estimated glomerular filtration rate and blood pressure were 49 +/- 21 mL/min/1.73 m(2) and 153 +/- 19/81 +/- 11 mm Hg. Mean geometric baseline proteinuria was protein excretion of 1.32 (95% CI, 1.10-1.62) g/g creatinine. After a median follow-up of 32 months, 21 (30%) patients in the combination group, 10 (29%) in the lisinopril group, and 8 (29%) in the irbesartan group reached the primary outcome. HRs were 0.96 (95% CI, 0.44-2.05; P = 0.9) and 0.90 (95% CI, 0.39-2.02; P = 0.8) for the combination versus the lisinopril and irbesartan groups, respectively. There were no significant differences in proteinuria reduction or blood pressure control between groups. The number of adverse events, including hyperkalemia, was similar in all 3 groups. LIMITATIONS: The study was not double blind. The sample size studied was small. CONCLUSIONS: We were unable to show a benefit of the combination of lisinopril and irbesartan compared to either agent alone at optimal high doses on the risk of progression of type 2 diabetic nephropathy. PMID- 22939520 TI - Child loss and psychosis onset: evidence for traumatic experience as an etiological factor in psychosis. AB - Previous research suggests that trauma may contribute to psychosis onset. In this study, we examine the effect of parental loss of a child on the onset of psychotic experience using data from the National Comorbidity Survey Replication, hypothesizing that child loss will precede the onset of psychosis and will be associated with a later age of onset. We likewise tested this association for six other psychiatric conditions to demonstrate specificity for psychosis. Individuals with a psychotic disorder who had lost a child had a significantly later age of onset, particularly in males, even when controlling for demographic variables and co-occurring substance abuse and psychiatric disorders. Psychosis onset frequently occurred within a year of child loss. No associations were found between child loss and onset of other psychiatric conditions, supporting specificity of the effect on psychosis. The presented findings implicate child loss as an etiological factor in the onset of psychosis, providing converging evidence with previous studies demonstrating associations between more widely studied trauma exposures (abuse, neglect, and assault) and psychosis. PMID- 22939521 TI - Self-attacking and self-reassurance in persecutory delusions: a comparison of healthy, depressed and paranoid individuals. AB - Previous research has found that reduced self-reassurance and heightened verbal 'self-attacking' of a sadistic and persecutory nature are both associated with greater subclinical paranoia. Whether these processes are also linked to clinical paranoia remains unclear. To investigate this further, we asked 15 people with persecutory delusions, 15 people with depression and 19 non-psychiatric controls to complete several self-report questionnaires assessing their forms and functions of self-attacking. We found that people with persecutory delusions engaged in more self-attacking of a hateful nature and less self-reassurance than non-psychiatric controls, but not people with depression. Participants with persecutory delusions were also less likely than both healthy and depressed participants to report criticising themselves for self-corrective reasons. Hateful self-attacking, reduced self-reassurance and reduced self-corrective self criticism may be involved in the development or maintenance of persecutory delusions. Limitations, clinical implications and directions for future research are discussed. PMID- 22939523 TI - Susceptibility of canine and feline bacterial pathogens to pradofloxacin and comparison with other fluoroquinolones approved for companion animals. AB - In this study, 908 bacterial pathogens from defined infections of dogs and cats were tested for their susceptibility to the novel fluoroquinolone pradofloxacin, which was approved in 2011 for use in cats and dogs. Most of the bacteria tested (Staphylococcus aureus, Staphylococcus pseudintermedius, Escherichia coli, beta haemolytic streptococci, Pasteurella multocida and Bordetella bronchiseptica) exhibited low pradofloxacin MIC(90) values of <= 0.25 MUg/ml. Solely Proteus spp. and Pseudomonas aeruginosa had higher MIC(90) values of >= 4 MUg/ml. Only six (3.4%) of 177 S. pseudintermedius and 12 (5.3%) of 227 E. coli isolates showed pradofloxacin MICs of >= 2 MUg/ml. Analysis of the quinolone resistance determining regions of the target genes identified double mutations in GyrA that resulted in amino acid exchanges S83L+D87N or S83L+D87Y and single or double mutations in ParC that resulted in amino acid exchanges S80I or S80I+E84G in all 12 E. coli isolates. The six S. pseudintermedius isolates exhibited amino acid exchanges S84L or E88K in GyrA and S80I in GrlA. Comparative analysis of the MICs of pradofloxacin and the MICs determined for enrofloxacin and its main metabolite ciprofloxacin, but also marbofloxacin, orbifloxacin, difloxacin and ibafloxacin was conducted for the target pathogens S. pseudintermedius, E. coli and P. multocida. This comparison confirmed that pradofloxacin MICs were significantly lower than those of the other tested fluoroquinolones. PMID- 22939525 TI - Waterproof active paper via laser surface micropatterning of magnetic nanoparticles. AB - Paper is one of the oldest and most abundant materials known to man. Recently, there has been a considerable interest in creating paper devices by combining paper with other functional materials. In this letter, we demonstrate a simple fabrication technique to create water-resistant ferro-patterns on wax paper using CO(2) laser ablation. A resolution of about 100 MUm is achieved which is mostly limited by the cellulose fiber size (~50 MUm) in the wax paper and can be improved by using a smaller cellulose matrix. Laser ablation results in modification of surface morphology and chemistry, leading to a change in surface energy. We also present a 2D model for ferrofluid deposition relating the size of the pattern to the amount of ferroparticles deposited on the surface. Finally, a paper gripper is presented to demonstrate advantages of our technique, which allows microscale patterning and machining in a single step. PMID- 22939524 TI - Disfluency patterns and phonological skills near stuttering onset. AB - There is a substantial amount of literature reporting the incidence of phonological difficulties to be higher for children who stutter when compared to normally fluent children, suggesting a link between stuttering and phonology. In view of this, the purpose of the investigation was to determine whether, among children who stutter, there are relationships between phonological skills and the initial characteristics of stuttering. That is, close to the onset of stuttering, there are differences in specific stuttering patterns between children who exhibit minimal and moderate phonological deviations in terms of frequency of stuttering and length of stuttering events? Twenty-nine preschool children near the onset of stuttering, ranging in age from 29 to 49 months, with a mean of 39.17 months, were divided into two groups based on the level of phonological ability: minimal phonological deviations and moderate phonological deviations. The children's level of stuttering-like disfluencies was examined. Results revealed no statistically significant differences in the stuttering characteristics of the two groups near onset, calling into the question the nature of the stuttering-phonology link. PMID- 22939526 TI - Exposure-response relationships in work-related musculoskeletal disorders in elbows and hands - A synthesis of group-level data on exposure and response obtained using uniform methods of data collection. AB - There is a serious lack of quantitative data regarding exposure-response relationships between occupational risk factors and musculoskeletal elbow and hand disorders. This paper explores such relationships in group-level data from our earlier cross-sectional studies. Prevalence of complaints (Nordic Questionnaire) and diagnoses (physical examination) were recorded in 19 groups of female workers (1891 individuals), and 8 groups of male workers (761 individuals), with highly similar work tasks within each group. Linear regression was performed on the group means of wrist postures and angular velocity (obtained by electrogoniometers), as well as muscular load (obtained using electromyography), recorded in representative sub-samples, and psychosocial exposure (Job Content Questionnaire). To tackle within-group variations in physical exposure, sensitivity analyses were performed by bootstrapping simulations, rendering confidence intervals. The sex-adjusted slope of the regression line (beta) for wrist angular velocity vs. complaints during the past 7 days was 0.6%/( degrees /s), (95% CI 0.3-0.9), and for carpal tunnel syndrome (CTS) 0.2%/( degrees /s), (0.1-0.3). For palmar flexion, p50, beta over the past 7 days was 0.8%/ degrees (0.4-1.2); for CTS 0.3%/ degrees (0.1-0.5); beta for muscular activity p90: 0.9%/%MVE (0.3-1.6), and 0.3%/%MVE (-0.03-0.6) respectively and finally beta for muscular rest: -1.2%/%time (-2.4-0.03) and 0.5%/%time (-0.9 to -0.01). Relationships were also demonstrated for low job control, job strain and isostrain. Women exhibited a higher prevalence of complaints than men. In conclusion, we have established quantitative exposure response relationships between physical work load and elbow/hand disorders. Wrist angular velocity was the most consistent risk factor. PMID- 22939527 TI - Poly(ethylene oxide)-poly(styrene oxide)-poly(ethylene oxide) copolymers: micellization, drug solubilization, and gelling features. AB - Two new poly(ethylene oxide)-poly(styrene oxide) triblock copolymers (PEO-PSO PEO) with optimized block lengths selected on the basis of previous studies were synthesized with the aim of achieving a maximal solubilization ability and a suitable sustained release, while keeping very low material expense and excellent aqueous copolymer solubility. The self-assembling and gelling properties of these copolymers were characterized by means of light scattering, fluorescence spectroscopy, transmission electron microscopy, and rheometry. Both copolymers formed spherical micelles (12-14 nm) at very low concentrations. At larger concentration (>25 wt%), copolymer solutions showed a rich phase behavior, with the appearance of two types of rheologically active (more viscous) fluids and of physical gels depending on solution temperature and concentration. The copolymer behaved notably different despite their relatively similar block lengths. The ability of the polymeric micellar solutions to solubilize the antifungal drug griseofulvin was evaluated and compared to that reported for other structurally related block copolymers. Drug solubilization values up to 55 mg g(-1) were achieved, which are greater than those obtained by previously analyzed poly(ethylene oxide)-poly(styrene oxide), poly(ethylene oxide)-poly(butylene oxide), and poly(ethylene oxide)-poly(propylene oxide) block copolymers. The results indicate that the selected SO/EO ratio and copolymer block lengths were optimal for simultaneously achieving low critical micelle concentrations (cmc) values and large drug encapsulation ability. The amount of drug released from the polymeric micelles was larger at pH 7.4 than at acidic conditions, although still sustained over 1 day. PMID- 22939528 TI - Investigation of the reversibility of the unimer-to-aggregate transition in block copolymers by surface tension-measurements. AB - Two DNA-block copolymers, poly(caprolactone)-DNA and poly(methyl metacrylate) DNA, were synthesized by conjugation of a short single strand of DNA (12 or 22mer) to a single reactive group at one end of the synthetic polymer. These polymers self-assemble in water, without the need of any cosolvent, forming micelle-like aggregates that were imaged by TEM. The solution behavior of the bioconjugated polymers was investigated by surface tension measurements. In the direction of dilution, the surface tension was measured using a down-scaled Wilhelmy plate method. To proceed in the reverse direction (concentration), we measured the surface tension of a sessile drop during its evaporation. This latter method was firstly validated using ionic and non-ionic surfactants, including polymeric surfactants. It was then applied to investigate the unimer to micelles transition of the DNA-block copolymers. In all cases, a reversible transition was observed demonstrating the existence of a critical micellar concentration, close to 0.01 mmol L(-1) for all the conjugates. The CMC was only slightly influenced by the length of the hydrophilic DNA block. PMID- 22939529 TI - Treatment strategies according to clinical features in a naturalistic cohort study of bipolar patients: a principal component analysis of lifetime pharmacological and biophysic treatment options. AB - BACKGROUND: The treatment of patients with bipolar disorder (BD) is complex and psychiatrists often have to change treatment strategies. However, available data do not provide information about the most frequent patterns of treatment strategies prescribed in clinical practice and clinical/socio-demographic factors of drugs prescription. OBJECTIVE: The aims of this study were: (1) to identify specific patterns of life-time treatment strategies in a representative sample of bipolar patients; (2) to assess consistency with guidelines recommendations; and (3) to investigate clinical/socio-demographic of patients. METHODS: Six-hundred and four BD I and II out-patients were enrolled in a naturalistic cohort study at the Barcelona Bipolar Disorders Program, in a cross-sectional analysis. A principal component analysis was applied to group psychotropic drugs into fewer underlying clusters which represent patterns of treatment strategies more frequently adopted in the life-time naturalistic treatment of BD. RESULTS: Three main factors corresponding to three main prescription patterns were identified, which explained about 60% of cases, namely, Factor 1 (21.1% of common variance), defined the "antimanic stabilisation package" including treatments with antimanic mechanism of action in predominantly manic-psychotic BD I patients; Factor 2 (20.4%), "antidepressive stabilisation package" that grouped predominantly depressed patients, and Factor 3 (16.4%) defined the "anti-bipolar II package", including antidepressant monotherapy in BD II patients with depressive predominant polarity, melancholic features and higher rates of suicide behaviours. CONCLUSIONS: This study identified three patterns of lifetime treatment strategies in three specific and different groups of naturalistically treated bipolar patients. PMID- 22939532 TI - Plexin-B1: a potential diagnostic biomarker for glioma and a future target for glioma immunotherapy. AB - Gliomas are the most common tumors in the central nervous system. Plexin-B1 is abundantly expressed in the nervous system as an axonal guidance molecule during neuronal development. However, the correlation between its expression and the clinical characteristics of gliomas, and its therapeutic significance, remain largely unexplored. In this study, we detected the expression of Plexin-B1 in clinical glioma tissue samples. Plexin-B1 was highly expressed in the cytoplasm and on the membrane of glioma tissues, while only trace levels of Plexin-B1 were present in normal brain tissue. The expression level of Plexin-B1 in glioma tissue was associated with the pathological grade of the glioma. In addition, we used flow cytometry to analyze the expression of Plexin-B1 in glioma cell lines and its ligand, semaphorin 4D (Sema4D), in natural killer (NK) cell lines. Cytotoxicity assays showed cytolysis of the U251 glioma cell line by the NK cell line, NK92, and this was markedly downregulated when the neutralizing antibody to Plexin-B1 was added. This study demonstrates that Plexin-B1 could be used as a diagnostic biomarker, and also suggests that it may be involved in the cytotoxicity of NK cells to glioma cells. Plexin-B1 could be a useful future target for glioma immunotherapy. PMID- 22939530 TI - Assessing health-related quality of life in patients with restless legs syndrome in Korea: comparison with other chronic medical diseases. AB - BACKGROUND: There have been few quality of life (QoL) studies of patients with restless legs syndrome (RLS) in Asian countries. We studied the QoL of patients with RLS and compared it to normal controls and patients with hypertension, type 2 diabetes, or osteoarthritis in Korea. METHODS: A total of 215 RLS patients (141 female; mean age 51.7 +/- 13.5) were enrolled. All patients completed the questionnaires, including all the Korean versions of SF-36, RLS QoL, the International RLS Severity scale (IRLS), the Pittsburgh Sleep Quality Index (PSQI), and the Beck Depression Inventory-2 (BDI-2). These results were compared with the scores from normal controls (N=214) and from patients with hypertension (196), uncomplicated type 2 diabetes (185), or osteoarthritis of the knee (177). RESULTS: The SF-36 QoL in patients with RLS was lower than that of the normal controls, and even lower than patients with hypertension or diabetes, but higher than those with osteoarthritis. The SF-36 Qol of RLS patients showed a significantly negative correlation with the severity of RLS symptoms(r=-0.430, p<0.001) and the severity of depression (r=-0.565, p<0.001), but was not significantly related to gender, age, or age-of-symptom onset (early or late onset). Step-wise multiple regression identified three factors related to SF-36 QoL: depression (46.5% of RLS had responses on BDI-2 indicating depression) (beta=-.899, p<0.001), RLS symptom severity (K-IRLS) (beta=-.718, p<0.001), and gender (female) (beta=-6.128, p=0.007). CONCLUSIONS: These findings show that RLS has a considerable impact on the QoL of Koreans, which is comparable with studies of western countries. The QoL impairment relates to the degree of depression with RLS for Koreans. PMID- 22939533 TI - Alzheimer's disease and euthanasia. AB - Employing the tenets of philosophical materialism, this paper discusses the ethical debate surrounding assisted suicide for persons suffering end-stage Alzheimer's. It first presents a classification of the dissociative situations between "human individual" and "human person". It then moves on to discuss challenges to diagnosed persons and their caregivers in relation to the cardinal virtues of Spinozistic ethics--strength of character (fortitudo), firmness (animositas) and generosity (generositas). Finally, a number of ideas attached to the debate--"right of choice", "death with dignity", "quality of life" and "compassion in dying"--are discussed in order to clarify their foundations. PMID- 22939534 TI - Unexpecting age. AB - This essay argues that how we view our own old age is highly influenced by socially pervasive, though never explicit, expectations regarding old age as a generic category. I idenfiy four key expectations - the right to an old age; the idea that being old means being endowed with certain (positive or negative) characteristics; the fragmented relationship between the phases of life; and the assumption of the asocial nature of the aging process--and explore the sometimes contradictory ways in which these impact upon our own journeys through the life course. PMID- 22939535 TI - Grief in the initial adjustment process to the continuing care retirement community. AB - This paper examined the transition to continuing care retirement communities (CCRCs) within the framework of anticipatory and disenfranchised grief. Qualitative interviews with 29 residents and 19 adult children were conducted. Three major thematic categories emerged from the data. The first theme reflected ambivalence, dialectics or uncertainty about the CCRC as manifested by the various names assigned to it by respondents. The second theme reflected the acknowledgement of present and anticipatory losses and grief in response to the move. The final theme reflected respondents' disenfranchisement of their grief and loss and their view of the transition in a positive light. In their early adjustment period, residents and adult children are ambivalent about the transition, but often refrain from acknowledging their losses openly because of the image of the CCRC as a status symbol. Open acknowledgement of losses associated with the transition might be beneficial. PMID- 22939536 TI - The living arrangements of older immigrants from the former Soviet Union: a comparison of Israel and the United States. AB - With the unprecedented emigration from the former Soviet Union (FSU) during the 1990s as context, this study described the living arrangements of older FSU immigrants living in Israel and the US. Living arrangement choices represented an important strategy for coping with the migration process. Census data from Israel and the US were employed to examine the relationships among living arrangements (independent households, multigenerational households, and extended households) and personal characteristics, including duration of residence, Jewish identity, education, and home ownership. Results showed that the less time older immigrants lived in the host country, the more likely they lived in a multigenerational or extended household. The residency length and household relationship was stronger in Israel than in the US. Also, older FSU immigrants who owned their own home and who lived in a metropolitan area were more likely to live in a complex household than in an independent household. We discussed how the economic and social environments in each country contributed to the variability in living arrangement options among these older immigrants. PMID- 22939537 TI - Being part of an enacted togetherness: narratives of elderly people with depression. AB - In this article, we explored how five elderly persons with depression engaged in everyday activities with others, over time, and how this was related to their experience of meaning. Repeated interviews and participant observations generated data that was analysed using a narrative approach. Analysis identified togetherness as an acted relation, "enacted togetherness", emphasising how the act of doing everyday activities with someone created togetherness and belonging, and being part of an enacted togetherness seemed to be a way for the participants to negotiate and construct meaning. Opportunities for doing things together with someone were closely associated to the place where the participants lived. Furthermore, engagement in activities together with others created hope and expectations of future acting. Findings from this research can extend our understanding of how participating in everyday activities is experienced as a social process including change over time, presenting the perspective of elderly people themselves. In light of these findings, we highlight the need to consider how opportunities to become part of an enacted togetherness can be created. Also, we aspire to contribute to the debate on how to understand the complexity related to social aspects of ageing and add to the emerging understanding of everyday activities as transactional, incorporating people and the environment in a dynamic process that goes beyond the individual. PMID- 22939538 TI - Stakeholder perspectives on transitions of nursing home residents to hospital emergency departments and back in two Canadian provinces. AB - Major gaps exist in our understanding of transitions in care for older persons living in nursing homes. The purpose of the study was to identify key elements, from multiple stakeholder perspectives, that influence the success of transitions experienced by nursing home residents when they required transfer to a hospital emergency department. This interpretive descriptive study was conducted in two cities in the Canadian provinces of British Columbia and Alberta. Data were collected from 71 participants via focus groups and individual interviews with nursing home residents, family members, and professional healthcare providers working in nursing homes, emergency departments, and emergency medical services. Transcripts were analyzed using constant comparison. The elements contributing to the success of transitions reflected a patient- and family-centered approach to care. Transitions were influenced by the complex interplay of multiple elements that included: knowing the resident; critical geriatric knowledge and skilled assessment; positive relationships; effective communication; and timeliness. When one or more of the elements was absent or compromised, the success of the transition was also compromised. There was consistency about the importance of all the identified elements across all stakeholder groups whether they are residents, family members, or health professionals in nursing homes, emergency departments or emergency medical services. Aspects of many of these elements are modifiable and suggest viable targets for interventions aimed at improving the success of transitions for this vulnerable population. PMID- 22939539 TI - Mothers, daughters and midlife (self)-discoveries: gender and aging in the Amanda Cross' Kate Fansler series. AB - In the same way that many aspects of gender cannot be understood aside from their relationship to race, class, culture, nationality and/or sexuality, the interactions between gender and aging constitute an interesting field for academic research, without which we cannot gain full insight into the complex and multi-faceted nature of gender studies. Although the American writer and Columbia professor Carolyn Gold Heilbrun (1926-2003) is more widely known for her best selling mystery novels, published under the pseudonym of Amanda Cross, she also authored remarkable pieces of non-fiction in which she asserted her long-standing commitment to feminism, while she also challenged established notions on women and aging and advocated for a reassessment of those negative views. To my mind, the Kate Fansler novels became an instrument to reach a massive audience of female readers who might not have read her non-fiction, but who were perhaps finding it difficult to reach fulfillment as women under patriarchy, especially upon reaching middle age. Taking her essays in feminism and literary criticism as a basis and her later fiction as substantiation to my argument, this paper will try to reveal the ways in which Heilbrun's seemingly more superficial and much more commercial mystery novels as Amanda Cross were used a catalyst that informed her feminist principles while vindicating the need to rethink about issues concerning literary representations of mature women and cultural stereotypes about motherhood. PMID- 22939540 TI - Negotiating a moral identity in the context of later life care. AB - Strategies to maintain independence for older people have received considerable attention as a social policy solution to the financial and social impact of the ageing population. Critical scholars in gerontology have also highlighted the negative consequences of promoting independence in this way. Understandings of independence have profound implications for caring relationships as people age. To investigate the ways that older people talk about caring we interviewed 48 people aged 55-70 years. A discourse analysis of these data showed that a dominant discourse of 'independence' was drawn upon to value self-sufficiency and construct dependence on others as burdensome. This construction of care provides a comfortable position for those who can afford to purchase professional care; however, those without resources are unable to accept unpaid help without also accepting a position of dependency. An alternative discourse of 'being there' constructs having others to provide personal care as a virtue and obligations to provide such care as based on family duty and affection. This discourse emphasises connections between people and a moral obligation to care which also creates difficulties for those with fewer material resources. The position for a dependent older subject in these two discourses may seem incompatible but can be reconciled by reframing independence as autonomy. Autonomy for those requiring care alongside a wider recognition of caring as the responsibility of all members of the community rather than with individual family members would support a flexible approach to later life care arrangements. PMID- 22939541 TI - A photovoice study of older adults' conceptualizations of risk. AB - Risk is a multifaceted and complex concept that mediates quality of life through the balance between risk taking and risk avoidance. Society expects older adults to identify and manage their personal risks yet little is known about the meaning of risk in their daily lives and how they balance the tensions between taking and avoiding risks. Therefore the purpose of this study was to explore how older adults construe risk. A qualitative exploratory study that incorporated photovoice methodology was used. Seventeen older adults, over a weeklong period, took pictures and kept a log of the places, spaces, events, activities, or situations that best represented risk. Subsequently, they participated in a follow-up individual interview. Older adults viewed risk both positively and negatively, judging the saliency of a risk according to criteria that related both to the risk itself and to personal characteristics. Although risk was avoided in specific situations, risk taking was participants' primary approach to risk, which assumed three forms: adaptive, opportunistic, and/or unjustifiable. Contrary to societal views, older adults view risk as constructive and personally relevant, and as something to be taken and need to be supported in risk taking rather than risk avoidance. PMID- 22939542 TI - Multiple social contexts in qualitative bereavement research. AB - Little research focuses on the ways that bereaved family members react to and make meaning of their experience of the death of an elderly father and husband. In a qualitative, ethnographic study of 34 bereaved families we examined how family members respond to two inter-related social contexts: 1. social-cultural values and attitudes such as attitudes toward grieving for old persons, and 2. the inter-personal dyadic relationship between interviewer and interviewee. An underlying theme of uncertainty pervades the study participants' views of what is normal and expected in their own process of bereavement. Implications for future bereavement research are suggested. PMID- 22939543 TI - The role of sports in making sense of the process of growing old. AB - Drawing on interviews with 22 athletically active old men and women, the study explores whether and how the practice of sports can affect old adults' processes of sense-making about old age and the process of growing old in ways that challenge dominant constructions about old age. Thereto, the study will explore the possible impact of gender in this process. The results show that men and women who continue to practice competitive sports into old age make sense of the process of growing old by focusing primarily on their physical abilities, at least in the context of sports. This focus on capability age allows them partly, although not completely, to challenge the usual thinking about old age and the process of growing old. PMID- 22939544 TI - Elder care as "frustrating" and "boring": understanding the persistence of negative attitudes toward older patients among physicians-in-training. AB - OBJECTIVES: This study explores the attitudes of physicians-in-training toward older patients. Specifically, we examine why, despite increasing exposure to geriatrics in medical school curricula, medical students and residents continue to have negative attitudes toward caring for older patients. METHODS: This study used ethnography, a technique used by anthropologists that includes participant observation, semi-structured interviews, and facilitated group discussions. Research was conducted at two tertiary-care academic hospitals in urban Northern California, and focused on eliciting the opinions, beliefs, and practices of physicians-in-training toward geriatrics. RESULTS: We found that the majority of physicians-in-training in this study expressed a mix of positive and negative views about caring for older patients. We argue that physicians-in-trainings' attitudes toward older patients are shaped by a number of heterogeneous and frequently conflicting factors, including both the formal and so-called "hidden" curricula in medical education, institutional demands on physicians to encourage speed and efficiency of care, and portrayals of the process of aging as simultaneously as a "problem" of inevitable biological decay and an opportunity for medical intervention. DISCUSSION: Efforts to educate medical students and residents about appropriate geriatric care tend to reproduce the paradoxes and uncertainties surrounding aging in biomedicine. These ambiguities contribute to the tendency of physicians-in-training to develop moralizing attitudes about older patients and other patient groups labeled "frustrating" or "boring". PMID- 22939545 TI - "And mostly they have a need for sleeping pills": physicians' views on treatment of sleep disorders with drugs in nursing homes. AB - The percentage of nursing home residents treated with hypnotic medications is high, as many authors report, despite the fact that such medications are almost always associated with undesirable effects for old people. This article takes a closer look at nursing home physicians' views of prescriptions when treating sleep disorders of nursing home residents. How do physicians characterize the treatment strategy for residents suffering from sleep disorders? How do they balance the benefits and risks of the hypnotic medication? Under what circumstances do they accept negative consequences? To answer these questions, N=20 physicians (aged 36 to 68 years) in 16 nursing homes in a German city were interviewed. The physicians were either employed by nursing homes or worked on a contract basis. Comparative categorization of the data produced a typology across cases. Three interpretative patterns concerning the use of drugs for treating sleep disorders were identified--"by request," "ambivalence," and "reflected prescription." Differences between them were determined by the significance of residents' wishes, neglect of risks, particularly that of addiction, and the attempt to balance benefits and disadvantages. The study showed deficits in professional management of sleep disorders in nursing homes. PMID- 22939546 TI - Family members' strategies when their elderly relatives consider relocation to a residential home--adapting, representing and avoiding. AB - The aim of this article is to reveal how family members act, react and reason when their elderly relative considers relocation to a residential home. Since family members are usually involved in the logistics of their elderly relative's relocation, yet simultaneously expected not to influence the decision, the focus is on how family members experience participation in the relocation process in a Swedish context. 17 family members are included in 27 open, semi-structured interviews and follow-up contacts. Prominent features in the findings are firstly the family members' ambition to tone down their personal opinions, even though in their minds their personal preferences are clear, and secondly, the family members' ambivalence about continuity and change in their everyday lives. Family members are found to apply the adapting, the representing, or the avoiding strategy, indirectly also influencing their interaction with the care manager. Siblings applied the adapting strategy, spouses the representing strategy, while family members in the younger generation at times switched between the strategies. PMID- 22939547 TI - Narratives of aging in intimate partner violence: the double lens of violence and old age. AB - PURPOSE: With the increase in life expectancy, couples living in intimate partner violence are aging together. The aim of this article is to explore the constructions of aging in intimate partner violence as narratives of couplehood or narratives of old age. DESIGN AND METHODS: Thirty individual in-depth interviews with 15 older Israeli couples were tape-recorded, transcribed verbatim and analyzed using a narrative approach. RESULTS: Three main domains emerged from the data: health issue narratives, loneliness narratives and relationships with adult offspring narratives. Each of the narratives that emerged from the data analysis consists of a narrative of old age constructing IPV and a narrative of IPV constructing old age. IMPLICATIONS: Conflictual couplehood dynamics, such as intimate partner violence in old age, is not one-dimensional, but is diverse and complex and this should be taken into consideration. PMID- 22939548 TI - "You feel like people are looking at you and laughing": older adults' perceptions of aquatic physical activity. AB - Older adults' participation in Physical Activity (PA) in the United Kingdom remains low. Moreover, although the subjective and narrative elements of aging are increasingly studied, promotion of healthy behaviours such as aquatic PA still frequently reduces older adults to passive recipients who rely on health professionals for their wellbeing. Using a figurational perspective, the relationship between participants' perceptions of the aging body and participation in aquatic activity was investigated. Interviews were completed with 22 adults aged over 50 years (7 men, 15 women). Participants highlighted a number of perceptual barriers that were contoured by wider social representations of older adults. Perceptions focussed upon the perceived limitations of the aging body. The need for regular participation in PA was recognised. However the potential for angst when wearing a bathing costume in the presence of 'others' was expressed, particularly amongst those considering themselves overweight. Participants objectified their bodies and compared them with those of other participants. The difficulties of managing physical (e.g. injury and illness) and environmental risk were described. At the same time, participants experienced the development of new webs of interdependence. These webs were both enabling and constraining. Some participants felt empowered. However, the exclusivity of many aquatic activity sessions re-emphasised the status of older adults as outsiders in the wider figuration of physical activity. PMID- 22939549 TI - "It's your badge of inclusion": the Red Hat Society as a gendered subculture of aging. AB - Although studies document the health-enhancing effects of social engagement, they reveal little about the underlying mechanisms operating within specific organizational contexts. Limited attention is given to the role of inequality- particularly age and gender--in shaping either the organizations to which we belong or their consequences for our well-being. We address this issue by examining the Red Hat Society, a social organization for middle-aged and older women. Interviews with members (n=52) illustrate how age and gender inequality interact to shape the organization, which can be viewed as a gendered subculture of aging. Drawing on this framework, we discuss four processes through which participation generates benefits for older women involved in age- and gender segregated organizations: enhancing social networks, countering invisibility, creating positive frames for aging experiences, and promoting youthful identities. PMID- 22939550 TI - Prospective evaluation of laparoscopic assisted cystectomy and ileal conduit in advanced multiple sclerosis. AB - OBJECTIVE: To assess the morbidity, mortality, and impact on quality of life and renal function after laparoscopic cystectomy and ileal conduit in patients with multiple sclerosis with lower urinary tract symptom refractory to conservative management. MATERIALS AND METHODS: A prospective study was conducted between February 2004 and December 2010 on 44 consecutive patients with multiple sclerosis who underwent laparoscopic cystectomy and ileal conduit for lower urinary tract symptom. Median Expanded Disability Status Scale score was 8 (6.5 8.5). Mean duration of multiple sclerosis was 19.3 +/- 7.9 years. The quality of life was determined using the validated Qualiveen questionnaire preoperatively and at minimum 6 months after the surgery. RESULTS: No conversion to open surgery was required. Postoperative morbidity rate was 18.2%; minor (Clavien <= 2) and major (Clavien >= 3) complications occurred in 13.6% and 6.8%, respectively. Mean follow-up was 44.5 +/- 20.6 months. Complications noted were asymptomatic ureteroileal stenosis (n = 6) and pyelonephritis (n = 3). Neurological status and Expanded Disability Status Scale score remained stable throughout. Renal function remained unchanged. Limitations, constraints, and specific urinary impact index subscores of the Qualiveen were significantly improved at 6 months time. CONCLUSION: Laparoscopic cystectomy and ileal conduit for lower urinary tract symptom in advanced multiple sclerosis is a safe procedure with low complications. Neurological status and renal function remain stable and quality of life improves and continues to remain improved during long-term follow-up, suggesting this to be an attractive option in patients with advanced multiple sclerosis with lower urinary tract symptom refractory to conservative treatment. PMID- 22939551 TI - Jejunal interposition reconstruction with a stomach preserving esophagectomy improves postoperative weight loss and reflux symptoms for esophageal cancer patients. AB - BACKGROUND: Conventional reconstruction after an esophagectomy uses a gastric tube, which commonly causes several postoperative complaints such as gastric acid reflux in long-term survival cases. Intestinal interposition between the remnant esophagus and the stomach is an option to reduce complaints, and in this study, the advantages of jejunal interposition reconstruction with a stomach preserving esophagectomy (SPE) were assessed. MATERIALS AND METHODS: Eleven cases of jejunal interposition with an SPE and 16 cases with gastric tube reconstruction as a control were subject to a comparison of operation time, amount of bleeding, postoperative quality of life, and endoscopic findings. RESULTS: The SPE group had a longer operation time (SPE: 560 +/- 121 min, control 414 +/- 83 min, P = 0.038), whereas there was no significant difference in blood loss. Postoperative weight loss was significantly recovered in the SPE group (SPE versus control = 94.0 +/- 5.4% versus 87.5 +/- 4.7% at 3 mo, P = 0.017; 97.2 +/- 7.5% versus 85.0 +/- 5.2% at 6 mo, P = 0.010), and there was a significant decrease in the occurrence of reflux symptoms such as heartburn, odynophagia, and cough when jejunal interposition with an SPE was done. Furthermore, reflux esophagitis and Barrett's epithelium were found in six out of 12 cases (50%) of the control group by postoperative endoscopy, while no cases in the SPE group had either condition (P < 0.01). CONCLUSIONS: This reconstruction method is a promising option to improve postoperative quality of life, mainly due to the long-term elimination of reflux esophagitis, which assists in the recovery of postoperative weight loss. PMID- 22939552 TI - Dexmedetomidine inhibits the secretion of high mobility group box 1 from lipopolysaccharide-activated macrophages in vitro. AB - BACKGROUND: High mobility group box 1 (HMGB1) is a critical proinflammatory factor that is closely related to mortality in sepsis patients. Dexmedetomidine has been proven to reduce the mortality rate from endotoxin shock and attenuate endotoxin-induced acute lung injury. These effects result from reduced secretion of many proinflammatory mediators, although it is not clear whether dexmedetomidine affects the secretion of HMGB1. In this study, we explored the effect of dexmedetomidine on the expression and secretion of HMGB1 from lipopolysaccharide (LPS)-activated macrophages. METHODS: We incubated RAW264.7 cells with LPS in the presence or absence of various concentrations of dexmedetomidine. We used an enzyme-linked immunosorbent assay to detect the secretion levels of HMGB1 in the culture supernatant. We employed real-time polymerase chain reaction to assess the expression of HMGB1 mRNA, and used a nuclear/cytoplasm extraction kit to extract the nuclear and cytoplasmic proteins. We employed Western blotting to observe changes in the translocation of HMGB1 from the nucleus to the cytoplasm. In addition, we used a nuclear factor (NF) kappaB p50/p65 transcription factor assay kit to analyze NF-kappaB activity in the nuclear extract. RESULTS: Dexmedetomidine inhibited the translocation of HMGB1 from the nucleus to the cytoplasm and its extracellular secretion in LPS activated macrophages while suppressing the expression of HMGB1 mRNA. Dexmedetomidine inhibited the translocation of NF-kappaB from the cytoplasm to the nucleus in LPS-activated macrophages in a dose-dependent manner. Moreover, these effects were significantly reversed by the alpha2-adrenergic receptor antagonist yohimbine. CONCLUSIONS: Our study demonstrates that dexmedetomidine inhibits the translocation of HMGB1 from the nucleus to the cytoplasm and the expression of HMGB1 mRNA at clinically relevant dosages. The mechanism responsible for these effects may be through the NF-kappaB signaling pathway and the alpha2-adrenergic receptors. PMID- 22939553 TI - Hypertension and marginal ulceration after gastric bypass. PMID- 22939554 TI - Splenic conservation: variation between pediatric and adult trauma centers. AB - OBJECTIVES: Nonoperative management of hemodynamically stable children and adolescents with splenic injury regardless of grade has become standard; however, numerous studies have shown a wide variation in management. We compared the treatment and outcomes of adolescent splenic injuries in our region, which includes a pediatric level I trauma center (PTC) and an adult level I trauma center (ATC). METHODS: A retrospective review of the trauma registry was performed on patients 14 to 17 y old with blunt splenic injury admitted to either the local PTC or ATC from January 1999 through December 2010. Demographics, interventions, and hospital course were recorded and compared using Fisher exact, Student t-test, and multivariate analysis. RESULTS: Eighty-six adolescent patients presenting to the PTC and 65 patients presenting to the ATC met the criteria over the 12-y period. Although the ATC received more significantly injured and slightly older patients, logistic multivariate analysis demonstrated that the location of presentation was the only independent factor associated with splenectomy (P = 0.0015). A higher injury severity score was associated with a longer length of stay (LOS), but the nonoperative approach was not associated with a longer LOS (P = 0.96). CONCLUSIONS: Our study demonstrates that the location of presentation was independently associated with splenectomy while controlling for a higher injury severity score at the ATC. With the higher percentage of nonoperative management, treatment at the PTC was not associated with an increased LOS (total or intensive care unit). PMID- 22939555 TI - The relationship between C-reactive protein and atherosclerosis differs on the basis of body mass index: the Dallas Heart Study. AB - OBJECTIVES: This study sought to evaluate whether the relationship between C reactive protein (CRP) and atherosclerosis is modified by body mass index (BMI). BACKGROUND: CRP levels are affected by obesity, and it is unknown whether the associations between CRP and cardiovascular (CV) disease differ between obese and nonobese individuals. METHODS: We measured CRP and multiple atherosclerosis phenotypes, including coronary artery calcification (CAC) (n = 2,685), aortic wall thickness (AWT) (n = 2,238), and aortic plaque burden (APB) (n = 2,224), in subjects ages 30 to 65 years from the Dallas Heart Study. The associations of CRP with CAC, AWT, and APB were compared across categories of BMI (normal, 18.5 to <25 kg/m(2); overweight, 25 to <30 kg/m(2); obese, >=30 kg/m(2)) in sex stratified analyses. RESULTS: The overall prevalence of obesity was 38% in men and 53% in women. Increasing CRP levels (<1 mg/l, 1 to 3 mg/l, >3 mg/l) were associated with increased CAC prevalence in normal and overweight men and in normal weight women (p < 0.01), but not in obese subjects of either sex. Likewise, the correlations between CRP and AWT and APB diminished with increasing BMI and were nonsignificant in obese individuals (p < 0.05 in nonobese, p > 0.1 in obese). Interaction tests between CRP and obesity were significant for all atherosclerosis measures in men and for AWT and ABP in women (p interaction <0.05 each). In both sexes, the c-statistics of CRP for all 3 atherosclerosis measures were greater for normal weight than obese individuals. CONCLUSIONS: In a large, population-based study, the association between CRP and multiple measures of atherosclerosis is diminished in obese individuals. The role of CRP for predicting CV outcomes in obese subjects requires further evaluation. PMID- 22939556 TI - Renal artery calcification and mortality among clinically asymptomatic adults. AB - OBJECTIVES: The goal of this study was to assess the associations between renal artery calcification (RAC) and mortality in a healthy outpatient cohort with no known cardiovascular disease (CVD). BACKGROUND: Studies in individuals with known diabetes and kidney disease have suggested that RAC confers additional mortality risk independent of coronary artery calcification, but this hypothesis has not been explored in healthier populations. METHODS: RAC was assessed by using computed tomography scan in healthy outpatients with no known CVD. Cox proportional hazards models were used to examine the association of RAC with mortality. RESULTS: The mean age of participants was 57 years; 42.6% were women. RAC was present in 622 (14%) of 4,450 participants. Over a median follow-up of 8.2 years, there were 178 deaths. After adjustment for age, sex, diabetes, smoking, cholesterol, and family history of CVD, the presence of RAC conferred a >60% increased hazard for all-cause mortality (hazard ratio [HR]: 1.63 [95% confidence interval (CI): 1.17 to 2.29]). Adjustment for calcification in other vascular beds attenuated this association (HR: 1.40 [95% CI: 0.99 to 1.97]). Adjustment for hypertension, a potential mediator of the association, did not substantially change the results (HR: 1.44 [95% CI: 1.02 to 2.03]). Adding RAC to a model including Framingham risk and coronary artery calcification improved the predictive ability of the model, from 0.73 to 0.77 (p = 0.0002); the net reclassification index was 14.4% for the addition of RAC. Results for cardiovascular mortality were not significant and were limited by the small number of cardiovascular deaths. CONCLUSIONS: RAC was associated with an increased risk of subsequent all-cause mortality in healthy outpatient individuals, independent of traditional cardiac risk factors. The risk was modestly attenuated by adjustment for vascular calcification in other vascular beds, suggesting partial confounding by systemic calcified atherosclerosis. The effect did not seem to be mediated by hypertension. PMID- 22939557 TI - Regional treatment effects in studies of cardiorenal drugs: a summary of recent clinical trials. PMID- 22939558 TI - Surgical approaches to mitral regurgitation. AB - Surgical approaches to correct mitral regurgitation (MR) have evolved over 50 years and form much of the basis for percutaneous approaches to the mitral valve. Surgical mitral repairs have been more durable with use of annuloplasty, but recurrent regurgitation not resulting in reoperation can occur. The mitral leaflets may be resected or augmented, with recent trends to preserve leaflet coaptation surfaces if possible. Mitral chords tend to be replaced or transferred instead of being shortened. Mitral replacement still has a role when more durable and reliable than repair. Surgical incisions have varied from full sternotomy down to percutaneous access only, with less invasiveness usually requiring a trade-off versus effectiveness or ease of application. Less invasive options in treating MR may encourage higher-risk patients to seek anatomic therapy, whether surgical or percutaneous. Rapidly evolving technology will continue to be a dominant driver of surgical approaches to MR, with increasing overlap and interaction with percutaneous approaches. PMID- 22939559 TI - Duration of myocardial early systolic lengthening predicts the presence of significant coronary artery disease. AB - OBJECTIVES: This study sought to investigate whether the duration of left ventricular (LV) early systolic lengthening could accurately identify patients with significant coronary artery disease (CAD). BACKGROUND: Ischemic myocardium with reduced active force will lengthen when LV pressure rises during early systole before onset of systolic shortening. METHODS: We included 88 patients with suspected CAD referred to elective diagnostic coronary angiography. Two of these patients were excluded from the study due to evidence of previous myocardial infarction on contrast-enhanced magnetic resonance imaging. Speckle tracking echocardiography was performed before coronary angiography and at follow up scheduled 1 year after revascularization, and global longitudinal strain and duration of average LV early systolic lengthening were recorded. RESULTS: Forty three of 86 patients had significant CAD. The duration of early systolic lengthening was significantly prolonged in patients with significant CAD compared with patients without significant coronary artery stenoses (76 +/- 37 ms vs. 38 +/- 23 ms, p < 0.001). Correspondingly, global systolic strain was significantly lower in patients with CAD (-17.7 +/- 3.0% vs. -19.5 +/- 2.6%, p = 0.003). Prolonged duration of early systolic lengthening showed the best accuracy in detecting CAD, with an area under the receiver-operating characteristic curve of 0.83. The area under the curve for global strain was 0.68. At 1-year follow-up, the duration of early systolic lengthening was significantly reduced (64 +/- 37 ms vs. 76 +/- 37 ms, p = 0.041) in the patients treated with revascularization. CONCLUSIONS: Duration of myocardial early systolic lengthening was prolonged in patients with significant CAD; this might be a useful parameter to identify patients who might benefit from reperfusion therapy. PMID- 22939560 TI - Effects of bariatric surgery on cardiac ectopic fat: lesser decrease in epicardial fat compared to visceral fat loss and no change in myocardial triglyceride content. AB - OBJECTIVES: This study investigated the effect of bariatric surgery (BS)-induced weight loss on cardiac ectopic fat using 3T magnetic resonance imaging in morbid obesity. BACKGROUND: Heart disease is one of the leading causes of mortality and morbidity in obese patients. Deposition of cardiac ectopic fat has been related to increased heart risk. Whether sustained weight loss can modulate epicardial fat or myocardial fat is unknown. METHODS: Twenty-three morbidly obese patients underwent 1H-magnetic resonance spectroscopy to determine myocardial triglyceride content (MTGC), magnetic resonance imaging to assess epicardial fat volume (EFV), cardiac function, and computed tomography visceral abdominal fat (VAF) measurements at baseline and 6 months after BS. RESULTS: The BS reduced body mass index significantly, from 43.1+/-4.5 kg/m2 to 32.3+/-4.0 kg/m2, subcutaneous fat from 649+/-162 cm2 to 442+/-127 cm2, VAF from 190+/-83 cm2 to 107+/-44 cm2, and EFV from 137+/-37 ml to 98+/-25 ml (all p<0.0001). There was no significant change in MTGC: 1.03+/-0.2% versus 1.1+/-0.2% (p=0.85). A significant reduction in left ventricular mass (118+/-24 g vs. 101+/-18 g) and cardiac output (7.1+/ 1.6 l/min vs. 5.4+/-1.0 l/min) was observed and was statistically associated with weight loss (p<0.05). The loss in EFV was limited (-27+/-11%) compared to VAF diminution (-40+/-19%). The EFV variation was not correlated with percentage of body mass index or VAF loss (p=0.007). The ratio of %EFV to %VAF loss decreased with sleep apnea syndrome (1.34+/-0.3 vs. 0.52+/-0.08, p<0.05). CONCLUSIONS: Six month BS modulates differently cardiac ectopic fat deposition, with a significant decrease in epicardial fat and no change in myocardial fat. Epicardial fat volume loss was limited in patients with sleep apnea. (Impact of Bariatric Surgery on Epicardial Adipose Tissue and on Myocardial Function; NCT01284816). PMID- 22939562 TI - Galectin-3 in cardiovascular disease: a possible window into early myocardial fibrosis. PMID- 22939561 TI - Galectin-3, a marker of cardiac fibrosis, predicts incident heart failure in the community. AB - OBJECTIVES: The aim of this study was to examine the relation of galectin-3 (Gal 3), a marker of cardiac fibrosis, with incident heart failure (HF) in the community. BACKGROUND: Gal-3 is an emerging prognostic biomarker in HF, and experimental studies suggest that Gal-3 is an important mediator of cardiac fibrosis. Whether elevated Gal-3 concentrations precede the development of HF is unknown. METHODS: Gal-3 concentrations were measured in 3,353 participants in the Framingham Offspring Cohort (mean age 59 years; 53% women). The relation of Gal-3 to incident HF was assessed using proportional hazards regression. RESULTS: Gal-3 was associated with increased left ventricular mass in age-adjusted and sex adjusted analyses (p = 0.001); this association was attenuated in multivariate analyses (p = 0.06). A total of 166 participants developed incident HF and 468 died during a mean follow-up period of 11.2 years. Gal-3 was associated with risk for incident HF (hazard ratio [HR]: 1.28 per 1 SD increase in log Gal-3; 95% confidence interval [CI]: 1.14 to 1.43; p < 0.0001) and remained significant after adjustment for clinical variables and B-type natriuretic peptide (HR: 1.23; 95% CI: 1.04 to 1.47; p = 0.02). Gal-3 was also associated with risk for all cause mortality (multivariable-adjusted HR: 1.15; 95% CI: 1.04 to 1.28; p = 0.01). The addition of Gal-3 to clinical factors resulted in negligible changes to the C-statistic and minor improvements in net reclassification improvement. CONCLUSIONS: Higher concentration of Gal-3, a marker of cardiac fibrosis, is associated with increased risk for incident HF and mortality. Future studies evaluating the role of Gal-3 in cardiac remodeling may provide further insights into the role of Gal-3 in the pathophysiology of HF. PMID- 22939563 TI - [Incidence of whooping cough in the city of Barcelona between 1999 and 2011]. AB - INTRODUCTION: The aim of the study was to describe the long-term incidence of whooping cough in a large city. METHODS: Descriptive study of the cases reported in the notifiable disease registry between 1999 and 2011 in Barcelona. RESULTS: An increase in incidence was observed, especially in children and in the year 2011. Children younger than one year still were most affected, with a specific rate of 426.87/100,000 in 2011. CONCLUSION: A new approach in adolescent and adult vaccination is needed to provide more protection to younger children, as well as research to assess a possible shift in the bacteria itself. PMID- 22939564 TI - WITHDRAWN: Executive summary. Consensus document of National AIDS Plan Secretariat/AIDS Expert Group on healthcare assistance for HIV infected women. AB - This article has been withdrawn at the request of the author(s) and/or editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy. PMID- 22939565 TI - [Assessment of the impact of the new health legislation on illegal immigrants in Spain: the case of human immunodeficiency virus infection]. AB - The immigrant population in Spain, whether legal or not, has been entitled to healthcare under the same conditions as the Spanish population since the year 2000. The entry into vigour of the Royal Decree-Law 12/2012 of 20 April has significantly restricted this right, so that unauthorized or non-resident foreigners may now only receive emergency care, if they are under 18 or pregnant women. Out of an estimated 459,909 illegal immigrants in our country, 2,700 to 4,600 are probably infected with HIV; 1,800 to 3,220 know that they are infected, and 80% of the latter could receive antiretroviral treatment. The Royal Decree Law is likely to cause many undesirable consequences in this population infected with HIV: increasing mortality, promoting the emergence of opportunistic diseases, increasing hospital admissions, increasing infections in the population (by HIV and other pathogens), or contributing to mother to child transmission of HIV. The expected increase in morbidity and mortality will be a greater cost in patient care, a cost which will be significantly higher in the more immunosuppressed patients. Therefore, the enforcement of the Royal Decree-Law will be much less cost-effective in the short term than was expected, and will negatively affect our country's public health, especially for those patients infected with HIV who will not be covered, thus increasing healthcare medium to long term costs, and moving away from the international health goals that were established. PMID- 22939567 TI - Initial antiretroviral therapy: the dilemmas ahead. PMID- 22939566 TI - [In vitro activity of 18 antimicrobial agents against clinical isolates of Acinetobacter spp.: multicenter national study GEIH-REIPI-Ab 2010]. AB - OBJECTIVES: To determine the prevalence of resistance to antimicrobials in Acinetobacter baumannii (A. baumannii) from Spain and to compare it with those obtained in the first national study (GEIH-Ab project 2000). METHODS: A total of 446 isolates of A. baumannii obtained from 43 Spanish hospitals during February March 2010 were studied. Identification of A. baumannii was confirmed by ARDRA and MALDI-TOF. Susceptibility to 18 antimicrobial agents was determined by microdilution (Clinical and Laboratory Standards Institute, CLSI). The CLSI break points were used, except for doripenem, rifampin, sulbactam (Societe Francaise de Microbiologie [SFM] break-points) and tigecycline (European Committee on Antimicrobial Susceptibility Testing [EUCAST] break-points for Enterobacteriaceae). RESULTS: The percentage of resistant isolates (intermediate susceptible plus resistant) was: > 94% (ceftazidime, piperacillin and ciprofloxacin), 82-86% (carbapenems, tetracycline), 60-70% (tobramycin, sulbactam, gentamicin, doxycycline), 49% (amikacin), 30% (minocycline, rifampin), 24% (tigecycline), and 3% (colistin). These isolates were, in comparison with those of the first study, more resistant (P < .01) to ceftazidime (99% vs 83%), carbapenems (82-86% vs 43-48%), sulbactam (65% vs 53%) and colistin (3% vs 0%), but more susceptible to aminoglycosides (particularly gentamicin: 70% vs 96% of resistant isolates), tetracycline (83% vs 91%) and rifampicin (30% vs 51%). CONCLUSION: There is a high prevalence of A. baumannii resistant to antimicrobials, particularly to carbapenems. The resistance to carbapenems, ceftazidime and sulbactam was significantly higher than that observed for isolates from the GEIH-Ab project 2000. The resistance to aminoglycosides, tetracycline and rifampin, however, was significantly decreased. PMID- 22939568 TI - Value normalization in decision making: theory and evidence. AB - A sizable body of evidence has shown that the brain computes several types of value-related signals to guide decision making, such as stimulus values, outcome values, and prediction errors. A critical question for understanding decision making mechanisms is whether these value signals are computed using an absolute or a normalized code. Under an absolute code, the neural response used to represent the value of a given stimulus does not depend on what other values might have been encountered. By contrast, under a normalized code, the neural response associated with a given value depends on its relative position in the distribution of values. This review provides a simple framework for thinking about value normalization, and uses it to evaluate the existing experimental evidence. PMID- 22939569 TI - Conscious motor intention emerges in the inferior parietal lobule. AB - Willed actions are characterized by the subjective experience of 'conscious intention'. During the last decade the neural bases of this experience have been widely investigated. Previous findings have suggested that conscious intention emerges in the mesial precentral area (MPA) including the supplementary and pre supplementary motor area. However, this assumption was later challenged by evidence indicating a key contribution of the inferior parietal lobule (IPL) in this process. In this review we show that this second hypothesis is the most plausible. We provide behavioral, clinical and electrophysiological evidence that IPL, rather than MPA, mediates the early subjective experience of 'wanting to move'. We argue that MPA generates a feeling of 'motor urge', near movement onset, when the inhibitory control exerted on the low-level motor areas is released. We propose that goal directed actions trigger two forms of motor intention: the first, 'wanting to move' intention is under the control of the inferior parietal regions and specifies a general goal to be reached before movement planning; the second, the 'urge to move' intention, is controlled by mesial precentral areas and signals the time when the planned movement is about to start. The time locked activation of these two forms of intention is at the basis of movement control. PMID- 22939571 TI - A universal preference for equality in health? Reasons to reconsider properties of applied social welfare functions. AB - The literature on how to combine efficiency and equity considerations in the social valuation of health allocations has borrowed extensively from applied welfare economics, including the literature on inequality measurement. By so doing, it has adopted normative assumptions that have been applied for evaluating the allocation of welfare (or income) rather than the allocation of health, including the assumption of a monotonically declining social marginal value of welfare/income/health. At the same time, empirical studies that have elicited social preferences for allocation of health have reported results that are seemingly incompatible with this assumption. There are two ways of addressing this inconsistency; we may censor the stated preferences by arguing that they cannot be supported by normative arguments, or we may reject or modify the analytical framework in order to accommodate the stated preferences. We argue that the stated preferences can be supported by normative reasoning and therefore conclude that one should be cautious in applying the standard welfare economic framework to the allocation of health. PMID- 22939570 TI - The belly rules the nose: feeding state-dependent modulation of peripheral chemosensory responses. AB - Feeding history and the presence of food dramatically alter chemosensory behaviors. Recent results indicate that internal nutritional state can gate peripheral gustatory and olfactory sensory responses to affect behavior. Focusing primarily on recent work in C. elegans and Drosophila, I describe the neuromodulatory mechanisms that translate feeding state information into changes in chemosensory neuron response properties and behavioral output. PMID- 22939572 TI - Identification, characterization and suppression of side-products formed during the synthesis of high dose 68Ga-DOTA-TATE. AB - In the course of the establishment of (68)Ga-DOTA-TATE production for clinical use a shoulder comprising presumably several impurities was observed in the chromatogram of the analytical radio-HPLC. LC-MS/MS results support the hypothesis that some of these radioimpurities are radiolytic oxidation by products of (68)Ga-DOTA-TATE. A new HPLC method was developed for quality control of (68)Ga-DOTA-TATE. Significant improvement on the radiochemical purity of (68)Ga-DOTA-TATE was achieved by the addition of ascorbic acid or ethanol to the reaction mixture. PMID- 22939573 TI - Consumption of arsenic and other elements from vegetables and drinking water from an arsenic-contaminated area of Bangladesh. AB - The study assesses the daily consumption by adults of arsenic (As) and other elements in drinking water and home-grown vegetables in a severely As contaminated area of Bangladesh. Most of the examined elements in drinking water were below the World Health Organization (WHO) guideline values except As. The median concentrations of As, cadmium (Cd), chromium (Cr), cobalt (Co), copper (Cu), lead (Pb), Mn, nickel (Ni), and zinc (Zn) in vegetables were 90 MUg kg(-1), 111 MUg kg(-1), 0.80 mg kg(-1), 168 MUg kg(-1), 13 mg kg(-1), 2.1 mg kg(-1), 65 mg kg(-1), 1.7 mg kg(-1), and 50 mg kg(-1), respectively. Daily intakes of As, Cd, Cr, Co, Cu, Pb, manganese (Mn), Ni, and Zn from vegetables and drinking water for adults were 839 MUg, 2.9 MUg, 20.8 MUg, 5.5 MUg, 0.35 mg, 56.4 MUg, 2.0mg, 49.1 MUg, and 1.3mg, respectively. The health risks from consuming vegetables were estimated by comparing these figures with the WHO/FAO provisional tolerable weekly or daily intake (PTWI or PTDI). Vegetables alone contribute 0.05 MUg of As and 0.008 mg of Cu per kg of body weight (bw) daily; 0.42 MUg of Cd, 8.77 mg of Pb, and 0.03 mg of Zn per kg bw weekly. Other food sources and particularly dietary staple rice need to be evaluated to determine the exact health risks from such foods. PMID- 22939574 TI - Kikuchi-Fujimoto lymphadenitis: role of parvovirus B-19, Epstein-Barr virus, human herpesvirus 6, and human herpesvirus 8. AB - Kikuchi-Fujimoto lymphadenitis is a self-limited disorder that typically presents in young females as painless cervical lymphadenopathy with fever, anemia, and leukopenia. The clinical manifestations and pathologic findings suggest a viral etiology, yet specific etiologic agents remain unknown. Although there are studies reporting positive associations between Kikuchi-Fujimoto lymphadenitis and parvovirus B19 and herpesviruses, other studies have failed to find an association with these viruses. To our knowledge, this current study is the largest study of Kikuchi-Fujimoto lymphadenitis in Western patients that used polymerase chain reaction testing for 4 different common viral pathogens often implicated as etiologic agents in Kikuchi-Fujimoto lymphadenitis. Archival material from 3 institutions was included, following confirmation of the diagnosis of Kikuchi-Fujimoto lymphadenitis by 2 independent pathologists. Polymerase chain reaction from the paraffin-embedded tissue sections for parvovirus B19, Epstein-Barr virus, human herpesvirus 6, and human herpesvirus 8 was performed. Eighteen cases of Kikuchi-Fujimoto lymphadenitis were analyzed, 12 of which (60%) were cervical lymph nodes. All the cases showed typical geographic necrosis with abundant apoptotic debris, although the degree of necrosis was variable. Polymerase chain reaction revealed a high prevalence of parvovirus B19 in the controls (44%); there were fewer positive cases seen in the Kikuchi Fujimoto lymphadenitis cases (11%), but this did not reach statistical significance (P = .25).There were no significant differences between cases and controls in the prevalence of Epstein-Barr virus, human herpesvirus 6, and human herpesvirus 8 (P = .50 for all 3). Polymerase chain reaction failed to reveal a positive association between Kikuchi-Fujimoto lymphadenitis and 4 common suspected viral agents. These findings do not support a role for Epstein-Barr virus, human herpesvirus 6, human herpesvirus 8, or parvovirus B19 in the pathogenesis of Kikuchi-Fujimoto lymphadenitis. PMID- 22939575 TI - Juxtaglomerular cell tumor: a morphological, immunohistochemical and genetic study of six cases. AB - Juxtaglomerular cell tumors (JGCTs) are rare tumors characterized by renin synthesis, hyperaldosteronism and hypertension. A curious immunohistochemical overlap between JGCT and gastrointestinal stromal tumor (GIST) including the expression of vimentin, CD34, CD117, alpha-smooth muscle actin was previously reported, prompting us to further investigate JGCT and its phenotypic and molecular genetic characteristics. Virtual karyotyping showed gain of chromosomes 3, 4, 10, 13, 17 and 18 in one JGCT, and fluorescence in situ hybridization (FISH) study confirmed this multiple gain pattern. Additionally, loss of chromosome 9 was observed in four of six cases analyzed with FISH. A whole genome expression analysis revealed 415 up-regulated (including renin, and CD117) and 325 down-regulated genes between the 2 cases. The study confirmed earlier reports on the gain of chromosomes 4 and 10, and provided further evidence of up regulation of the genes located on these 2 chromosomes. For the first time our study indicated the importance of the loss of chromosome 9 and loss of expression of several tumor suppressor genes located on this chromosome as possible pathogenetic events important in development of JGCT. PMID- 22939576 TI - Expression of E-cadherin in angiomyolipoma. AB - Angiomyolipoma is the most common member of perivascular epithelioid cell tumors that characteristically express myogenic and melanocytic markers. E-cadherin is a calcium-dependent cell-cell adhesion molecule that is repressed in epithelial to mesenchymal transition occurring in carcinomas. E-cadherin has not, thus far, been systematically studied in angiomyolipoma. We analyzed a series of 42 angiomyolipomas with E-cadherin and discussed its clinicopathologic significance. Forty-two cases of angiomyolipomas (35 renal, 5 hepatic, and 2 retroperitoneal) were examined histologically. E-cadherin was investigated immunohistochemically and compared with other significant markers found in angiomyolipoma in all cases. The percentages of tumors staining positively were E-cadherin (98%), smooth muscle actin (98%), actin (93%), HMB-45 (93%), Melan-A (90%), S-100 (38%), and CD117 (60%). The intensity of E-cadherin staining was moderate to strong in 30 cases (71%). E-cadherin stained both the cytoplasm and cell membrane of tumor cells, but membrane staining was stronger in the epithelioid tumor cells than in the spindle-shaped tumor cells. E-cadherin may serve as an additional diagnostic marker for angiomyolipoma. Angiomyolipoma should be included in the differential diagnosis of E-cadherin-positive tumors. Stronger membrane immunoreactivity for E cadherin in epithelioid tumor cells is possibly related to constitution of their epithelioid architecture, but the pathogenetic significance of E-cadherin in angiomyolipoma remains to be further studied. PMID- 22939577 TI - Digital image analysis as a tool to assess the effects of imatinib on trabecular bone in patients with chronic myelogenous leukemia. AB - Skeletal integrity is sustained by osteoblast-osteoclast interactions, controlled by several signaling pathways that include tyrosine kinases. Imatinib is a tyrosine kinase inhibitor with an extended therapeutic range based on its ability to differentially bind to receptor and nonreceptor tyrosine kinases. In this study, we used digital image analysis to assess changes in trabecular bone surface area within bone marrow biopsy specimens of 34 patients with chronic phase chronic myelogenous leukemia treated with single-agent imatinib. These patients were 25 men and 9 women with a median age of 59 years. We selected representative areas of paired bone marrow biopsy specimens obtained at baseline and within the subsequent 48 months. Computer-assisted analysis was performed to calculate trabecular bone area (TBA) within the sample by using the equation TBA% = sum of trabecular area/total biopsy specimen area. Percentage changes were defined as DeltaTBA% and were arbitrarily subdivided into marked (>50%), moderate (10%-50%), and mild (<10%). During the study interval, TBA% increased in 24 patients (71%) and decreased in 10 patients (29%). Overall, there was a significant increase in TBA% (P = .02). No correlation was found between changes in trabecular bone area and either clinical or cytogenetic response (P = .25). The results show that imatinib therapy can alter trabecular bone in bone marrow biopsy specimens of chronic myelogenous leukemia patients, most often resulting in an increase in TBA%. PMID- 22939578 TI - Immunohistochemistry of colorectal carcinoma: current practice and evolving applications. AB - The relatively high incidence of adenocarcinoma of the colon and rectum (colorectal carcinoma) in the general population makes its pathologic diagnosis one of the more frequent exercises in anatomical pathology. Although typically mundane in the primary setting, the correct identification of metastatic colorectal carcinoma or exclusion of metastatic disease from carcinoma arising in other anatomical foci can be problematic. The advent of targeted therapies and refinement of more traditional cytotoxic chemotherapeutic regimens mandates not only a more confident appraisal of site of origin but also assessment of those tumor-specific features that may alter therapeutic decisions. Despite the exponential increase in our understanding of the molecular pathogenesis of colorectal carcinoma, immunohistochemistry remains the foundation for resolution of these problematic cases and the number of antibodies available to the practicing pathologist continues to expand at a steady rate. In some cases, immunohistochemistry may also provide valuable prognostic information, either independently or as a surrogate marker for a specific route of carcinogenesis such as microsatellite instability. This review will focus on the use of new and more established immunohistochemistry markers in the diagnosis of colorectal carcinoma, with an emphasis on aberrant staining patterns of the various colorectal carcinoma subtypes as well as the utility of these markers in specific differential diagnostic settings. PMID- 22939579 TI - Capecitabine-induced chest pain relieved by diltiazem. AB - Five patients with primary colorectal adenocarcinoma or anal squamous cell carcinoma were started on a 2-weeks-on, 1-week-off capecitabine dosing regimen in addition to other chemotherapeutic agents and/or radiation. Within the first few doses, patients experienced chest pain and/or dyspnea at rest or with exertion. Acute electrocardiographic findings suggestive of ischemia were found in some cases at initial presentation, and 1 patient had troponin elevation consistent with an acute ST-segment elevation myocardial infarction. Subsequent ischemia evaluations were not suggestive of clinically significant coronary artery disease. All patients experienced immediate and sustained relief from chest pain after discontinuation of capecitabine and were able to successfully tolerate retreatment using a novel management strategy based on secondary prophylaxis with diltiazem. In conclusion, guidelines for the evaluation of and therapy for capecitabine-induced chest pain are proposed. PMID- 22939580 TI - Longevity of implantable electrophysiology devices explanted from patients having autopsy in hospitals. AB - The cost of cardiac implantable electrophysiologic devices (CIEDs) remains prohibitively high for many patients in low- and middle-income countries. Recent efforts have focused on obtaining CIEDs for donation and reuse in low- and middle income countries from funeral homes and after device upgrades. Most patients in the United States die in health care facilities, yet few data exist on the acceptability for reuse of devices from hospital morgues. Three hundred thirty four autopsies were performed at the University of Pennsylvania morgue from February 2009 to July 2011, during which CIEDs were routinely removed and collected. Devices were interrogated to ascertain remaining longevity. When a longevity estimate was not provided by the device, the manufacturer was contacted to obtain an estimate. Date of death was obtained from the electronic medical record. Twenty-seven patients (8% of autopsies performed) had CIEDs, of which 17 (63%) were pacemakers and 10 (37%) were implantable cardioverter-defibrillators. Two of the defibrillators were part of cardiac resynchronization therapy systems. CIEDs were interrogated 1.7 +/- 0.7 years after death. The mean time between implantation and death was 2.5 +/- 2.3 years, but 13 (48%) devices were implanted within 1 year of death. Nine devices (33%) had <1 year of battery life remaining, 10 devices (37%) had an estimated longevity of 1 to 4 years, and 8 devices (30%) had longevity estimates of >=4 years. In conclusion, a significant percentage of patients who underwent autopsy had CIEDs implanted <1 year before death. Hospital morgues may serve as a source for devices in reuse programs, provided patients or their next of kin authorize donation. PMID- 22939582 TI - Smaragdyrins: emeralds of expanded porphyrin family. AB - Porphyrins are tetrapyrrolic 18 pi electron conjugated macrocycles with wide applications that range from materials to medicine. Expanded porphyrins, synthetic analogues of porphyrins that contain more than 18 pi electrons in the conjugated pathway, have an increased number of pyrroles or other heterocyles or multiple meso-carbon bridges. The expanded porphyrins have attracted tremendous attention because of unique features such as anion binding or transport that are not present in porphyrins. Expanded porphyrins exhibit wide applications that include their use in the coordination of large metal ions, as contrasting agents in magnetic resonance imaging (MRI), as sensitizers for photodynamic therapy (PDT) and as materials for nonlinear optical (NLO) studies. Pentaphyrin 1, sapphyrin 2, and smaragdyrin 3 are expanded porphyrins that include five pyrroles or heterocyclic rings. They differ from each other in the number of bridging carbons and direct bonds that connect the five heterocyclic rings. Sapphyrins were the first stable expanded porphyrins reported in the literature and remain one of the most extensively studied macrocycles. The strategies used to synthesize sapphyrins are well established, and these macrocycles are versatile anion binding agents. They possess rich porphyrin-like coordination chemistry and have been used in diverse applications. This Account reviews developments in smaragdyrin chemistry. Although smaragdyrins were discovered at the same time as sapphyrins, the chemistry of smaragdyrins remained underdeveloped because of synthetic difficulties and their comparative instability. Earlier efforts resulted in the isolation of stable beta-substituted smaragdyrins and meso-aryl isosmaragdyrins. Recently, researchers have synthesized stable meso-aryl smaragdyrins by [3 + 2] oxidative coupling reactions. These results have stimulated renewed research interest in the exploration of these compounds for anion and cation binding, energy transfer, fluorescent sensors, and their NLO properties. Recently reported results on smaragdyrin macrocycles have set the stage for further synthetic studies to produce stable meso-aryl smaragdyrins with different inner cores to study their properties and potential for various applications. PMID- 22939581 TI - Comparison of frequency of periprocedural myocardial infarction in patients with and without diabetes mellitus to those with previously unknown but elevated glycated hemoglobin levels (from the TWENTE Trial). AB - In patients without a history of diabetes mellitus, increased levels of glycated hemoglobin (HbA1c) are associated with higher cardiovascular risk. The relation between undetected diabetes and clinical outcome after percutaneous coronary intervention is unknown. To investigate whether these patients may have an increased risk of periprocedural myocardial infarction (PMI), the most frequent adverse event after percutaneous coronary intervention, we assessed patients of the TWENTE trial (a randomized, controlled, second-generation drug-eluting stent trial) in whom HbA1c data were available. Patients were classified as known diabetics or patients without a history of diabetes who were subdivided into undetected diabetics (HbA1c >=6.5%) and nondiabetics (HbA1c <6.5%). Systematic measurement of cardiac biomarkers and electrocardiographic assessment were performed. One-year clinical outcome was also compared. Of 626 patients, 44 (7%) were undetected diabetics, 181 (29%) were known diabetics, and 401 (64%) were nondiabetics. In undetected diabetics the PMI rate was higher than in nondiabetics (13.6% vs 3.7%, p = 0.01) and known diabetics (13.6% vs 6.1%, p = 0.11). Multivariate analysis adjusting for covariates confirmed a significantly higher PMI risk in undetected diabetics compared to nondiabetics (odds ratio 6.13, 95% confidence interval 2.07 to 18.13, p = 0.001) and known diabetics (odds ratio 3.73, 95% confidence interval 1.17 to 11.89, p = 0.03). After 1 year, target vessel MI rate was significantly higher in undetected diabetics (p = 0.02) than in nondiabetics, which was related mainly to differences in PMI. Target vessel failure was numerically larger in unknown diabetics than in nondiabetics, but this difference did not reach statistical significance (13.6% vs 8.0%, p = 0.25). In conclusion, undetected diabetics were shown to have an increased risk of PMI. PMID- 22939583 TI - Lymph node dissection in endometrial cancer treatment--to do or not to do, that remains the question. PMID- 22939585 TI - CXCL12 improves immune responses to neurotropic virus propagation in the CNS by attracting antibody secreting cells. AB - A previous study showed that increases in chemokine expression and recruitment of antibody secreting cells (ASCs) in the CNS after intracerebral immunization contributed to the suppression of a neurotropic virus. In this study, intracerebral chemokine injection was used to investigate the usefulness of chemokines for controlling neurotropic viruses. Both CXCL12 and a cocktail chemokine (a mixture of CXCL9, 10, 12 and 13) attracted antigen-specific ASCs more strongly than CXCL9, 10 and 13 in an in vitro chemotaxis assay and in vivo intracerebral chemokine injection experiments. Mice pre-treated intracerebrally with CXCL12 and the cocktail chemokine showed an increased survival rate after intracerebral infection with rabies virus. These results suggest that intracerebral CXCL12 injection induces the migration of ASCs and suppresses the neuropathogenicity of rabies virus in the CNS. PMID- 22939586 TI - Subtalar arthroscopy with calcaneal skeletal traction in a hanging position. AB - Several arthroscopic approaches to the subtalar joint have been developed in the supine, lateral, or prone position. However, it is difficult to use the posteromedial portal with the patient in the supine or lateral position and the anterolateral portal with the patient prone. Furthermore, obtaining joint distraction in the lateral or prone position is difficult. We present a technique that enables the combination of 2 posterior portals and lateral portals to the subtalar joint with calcaneal skeletal traction in a hanging position for better visualization and instrumentation of the joint. PMID- 22939587 TI - Last man standing--survival analysis. AB - Most studies that involve following patient outcomes for long periods of time are subject to loss of patients to follow-up. To account for such loss while gleaning the maximal amount of information from the data available requires special techniques. PMID- 22939588 TI - Association of circulating adiponectin with testosterone in women during the menopausal transition. AB - OBJECTIVE: We examined (1) the change in circulating adiponectin in women during the menopausal transition and (2) the associations of adiponectin levels with estrogen, androgen and sex hormone-binding globulin (SHBG) in women during the menopausal transition. METHODS: We conducted a cross-sectional study in 235 healthy women and divided them into 7 stages by menstrual regularity and follicle stimulating hormone (FSH) level. Serum levels of adiponectin, estradiol, total testosterone, dehydroepiandrosterone-sulfate (DHEA-S) and SHBG were measured. Levels of free and bioavailable testosterone were calculated by using total testosterone, albumin and SHBG. RESULTS: Serum adiponectin levels showed a U curve, levels being low in early and late menopausal transition and gradually becoming higher after menopause. Adiponectin levels were negatively correlated with levels of free testosterone, bioavailable testosterone and DHEA-S and were positively correlated with SHBG in postmenopausal women for whom more than 1 year had passed since menopause. Adiponectin level was not correlated with estradiol level. CONCLUSION: Circulating adiponectin level shows a U-curve during the menopausal transition and adiponectin level is associated with levels of free and bioavailable testosterone and DHEA-S in postmenopause. PMID- 22939589 TI - Cell-mediated non-allergic rhinitis in children. AB - OBJECTIVE: Non-allergic rhinitis is a heterogeneous disease whose etiology is largely unknown. Nasal cytology only allows us to recognize different non allergic rhinitis forms on the basis of the prevalent inflammatory cell infiltrate: non-allergic rhinitis with eosinophils, with neutrophils, with mast cells and with both eosinophils and mast-cells. The aim of this study is to define the incidence, clinical features and comorbidity of the different types of cell-mediated non-allergic rhinitis in a pediatric age group. METHODS: One hundred and fourteen non-allergic children with chronic nasal obstruction and associated symptoms (rhinorrhea, sneezing and nasal itchiness) were retrospectively selected. All patients had been submitted to a clinical history, pediatric evaluation, anterior rhinoscopy and fiberendoscopy, rhinomanometry and nasal cytology. RESULTS: Non-allergic rhinitis with neutrophils was present in 46 (40.4%) children, non-allergic rhinitis with eosinophils in 53 (46.5%), non allergic rhinitis with mast-cells in 12 (10.5%) and non-allergic rhinitis with both eosinophils and mast-cells in 3 (2.6%). Nasal obstruction was prevalent in non-allergic rhinitis with eosinophils and in non-allergic rhinitis with mast cells patients (P<0.001) whereas rhinorrea and sneezing only in the form with eosinophils (P<0.0001). Nasal itching on the other hand was prevalent in the form with mast-cells (P<0.0003). Non-allergic rhinitis with eosinophils group showed a higher probability of asthma (P<0.02) and respiratory sleep disorders (P<0.04). CONCLUSIONS: In the pediatric age group the most frequent forms of non-allergic rhinitis are those with eosinophils or with neutrophils. A diagnosis of non allergic rhinitis with eosinophils in children presumes more severe symptoms and a higher incidence of pulmonary disease and roncopathy. PMID- 22939590 TI - Rearrangement in 22q11 implicated in Iranian patients with mental retardation. AB - Chromosome 22, particularly 22q11.2 region, is predisposed to rearrangements due to misalignments of low-copy repeats (LCRs). DiGeorge/velo-cardio-facial syndrome is a common disorder resulting from microdeletion within the same band. Although both deletion and duplication in this region are expected to occur in equal proportions as reciprocal events caused by LCR-mediated rearrangements, very few microduplications have been identified. The phenotype of these patients with microduplications is extremely diverse, ranging from normal to behavioral abnormalities to multiple defects, only some of which are reminiscent of the 22q11.2 deletion syndrome. The aim of this study was to investigate 22q11.2 microdeletion and microduplication among Iranian patients with mental retardation. For this purpose, 46 mental retarded patients who were tested negative for fragile X syndrome were involved in this study. The samples were assessed for 22q11.2 microduplication and microdeletions by Semi-Quantitative Multiplex Polymerase chain reaction (SQMPCR). MLPA was carried out to confirm the findings and to rule out other abnormalities in subtelomeric region. We found three patients with microdeletion and one with microduplication and one with 10p deletion syndrome. These findings proved evidence that microdeletion and microduplication of 22q11.2 can be a reason of mental retardation in Iranian population with unknown causes. PMID- 22939591 TI - Auditory neuropathy in a low-risk population: a review of the literature. AB - OBJECTIVE: Collect all available published evidence on the prevalence of auditory neuropathy in the well baby population and calculate the contribution of this to the false negative rate of oto-acoustic emission based newborn hearing screening programs. METHOD: PubMed and EMBASE were searched for relevant articles published between 1996 and 2010. Medical Subject Headings terms included 'Auditory disease', 'Prevalence' and 'Child' and their relevant synonyms. Included were original studies, which focused on well babies and reported the prevalence of auditory neuropathy. RESULTS: Of 519 citations 4 articles met the inclusion criteria. The population based prevalence of auditory neuropathy in children in population hearing screening was found to vary between 0.006% (SD 0.006) and 0.03% (SD 0.02). The false negative rate, caused by missed children with auditory neuropathy, is between 4 and 17%. CONCLUSION: The available information on the prevalence of auditory neuropathy in the well baby population is poor. However, if oto-acoustic emission screening is used in the first stage of a neonatal hearing screening program, children with auditory neuropathy are missed. The cost effectiveness of population-based screening using auditory brainstem response should be studied. PMID- 22939592 TI - Cortical auditory evoked potential (P1): a potential objective indicator for auditory rehabilitation outcome. AB - OBJECTIVE: Cortical auditory evoked potentials are a non-invasive tool that can provide objective information on maturation of the auditory pathways. This work was designed to study the role of cortical auditory evoked potential (P1) in assessment of the benefits of amplification and aural rehabilitation in hearing impaired children. DESIGN: The study consisted of 31 children classified into 2 groups. Study group included 18 hearing impaired children ranging in age 4-14 years old and classified into two subgroups according to adequacy of aural rehabilitation. A control group consisted of 13 normal hearing children ranging in age from 5 to 13 years. All children were subjected to history taking, basic audiological evaluation, intelligence quotient and language assessment. Cortical auditory evoked potential (P1) was measured using synthesized speech syllable /da/ as a recording stimulus that was presented binaurally via a loudspeaker. RESULTS: P1 was recorded in all children with significantly prolonged latencies in hearing impaired children with inadequate rehabilitation. P1 latency was correlated to hearing loss duration in hearing impaired children with inadequate aural rehabilitation. Auditory experience was correlated with P1 latency in hearing impaired children with adequate aural rehabilitation. CONCLUSION: Cortical auditory evoked potential (P1) might provide a clinical tool to monitor aural rehabilitation outcome and to guide intervention choices. PMID- 22939593 TI - Butanol production from renewable biomass by clostridia. AB - Global energy crisis and limited supply of petroleum fuels have rekindled the worldwide focus towards development of a sustainable technology for alternative fuel production. Utilization of abundant renewable biomass offers an excellent opportunity for the development of an economical biofuel production process at a scale sufficiently large to have an impact on sustainability and security objectives. Additionally, several environmental benefits have also been linked with the utilization of renewable biomass. Butanol is considered to be superior to ethanol due to its higher energy content and less hygroscopy. This has led to an increased research interest in butanol production from renewable biomass in recent years. In this paper, we review the various aspects of utilizing renewable biomass for clostridial butanol production. Focus is given on various alternative substrates that have been used for butanol production and on fermentation strategies recently reported to improve butanol production. PMID- 22939594 TI - Microwave-assisted hydrothermal hydrolysis of cellobiose and effects of additions of halide salts. AB - Microwave irradiation was compared with induction heating for hydrothermal hydrolysis of cellobiose. Microwave heating improved glucose selectivity and resulted in a pH of the hydrolyzates that was ?0.57 units lower than those from conventional heating, which suggests that fewer side-reactions occurred. Halide salts of alkali and alkali earth metals improved microwave-assisted hydrothermal saccharification of cellobiose at lower reaction severity by around 0.3 of logR(0). NaCl addition of ?10mM reduced the required microwave output to 58.6 66.2% as compared to conventional microwave-hydrothermal hydrolysis without halide salts. Kinetic analyses revealed that the addition of salt increased the hydrolysis rate by increasing the frequency factor of the reaction. The results showed that microwave irradiation in the presence of microwave-absorbing salts is effective for hydrothermal hydrolysis of carbohydrates. PMID- 22939595 TI - Algal biomass dehydration. AB - Biofuels are viewed as promising alternatives to conventional fossil fuels because they have the potential to eliminate major environmental problems created by fossil fuels. Among the still developing biofuel technologies, biodiesel production from algae offers a greater prospect for large-scale practical use, as algae are capable of producing much more yield than other biofuels. While research on algae-based biofuel is still in its developing stage, extensive work on laboratory- and pilot-scale algae harvesting systems with promising prospects has been reported. This paper presented a discussion of the literature review on recent advances in algae separation, harvesting and drying for biofuel production. The review and discussion focus on destabilization of algae, algae harvesting technologies and algae drying processes. Challenges and prospects of algae harvesting are also outlined. PMID- 22939596 TI - Overexpression and characterization of a novel (S)-specific extended short-chain dehydrogenase/reductase from Candida parapsilosis. AB - The gene encoding a putative protein from Candida parapsilosis CDC317 (CPE) was cloned and overexpressed in Escherichia coli. The protein was amenable to overexpression in E. coli and constituted 35% of the total cell protein content. The optimal activity was determined at pH 5.5 and 40 degrees C with the substrate 4-chloro-3-oxobutanoate ethyl ester (COBE). The optical purity of the product was over 99% enantiomeric excess for the (S)-isomer, and the molar conversion yield of the product was 91.1%. The apparent k(m) value for COBE was 0.19+/-0.01mM, which is an order of magnitude lower than that of other enzymes in the literature. PMID- 22939597 TI - New candidate for biofuel feedstock beyond terrestrial biomass for thermo chemical process (pyrolysis/gasification) enhanced by carbon dioxide (CO2). AB - The enhanced thermo-chemical process (i.e., pyrolysis/gasification) of various macroalgae using carbon dioxide (CO(2)) as a reaction medium was mainly investigated. The enhanced thermo-chemical process was achieved by expediting the thermal cracking of volatile chemical species derived from the thermal degradation of the macroalgae. This process enables the modification of the end products from the thermo-chemical process and significant reduction of the amount of condensable hydrocarbons (i.e., tar, ~50%), thereby directly increasing the efficiency of the gasification process. PMID- 22939598 TI - Two-stage in situ gas stripping for enhanced butanol fermentation and energy saving product recovery. AB - Two-stage gas stripping for butanol recovery from acetone-butanol-ethanol (ABE) fermentation with Clostridium acetobutylicum JB200 in a fibrous bed bioreactor was studied. Compared to fermentation without in situ gas stripping, more ABE (10.0 g/L acetone, 19.2 g/L butanol, 1.7 g/L ethanol vs. 7.9 g/L acetone, 16.2 g/L butanol, 1.4 g/L ethanol) were produced, with a higher butanol yield (0.25 g/g vs. 0.20 g/g) and productivity (0.40 g/L.h vs. 0.30 g/L.h) due to reduced butanol inhibition. The first-stage gas stripping produced a condensate containing 175.6 g/L butanol (227.0 g/L ABE), which after phase separation formed an organic phase containing 612.3g/L butanol (660.7 g/L ABE) and an aqueous phase containing 101.3 g/L butanol (153.2 g/L ABE). After second-stage gas stripping, a highly concentrated product containing 420.3 g/L butanol (532.3 g/L ABE) was obtained. The process is thus effective in producing high-titer butanol that can be purified with much less energy. PMID- 22939599 TI - Direct lipid extraction from wet Chlamydomonas reinhardtii biomass using osmotic shock. AB - High-cost downstream process is a major bottleneck for producing microalgal biodiesel at reasonable price. Conventional lipid extraction process necessitates biomass drying process, which requires substantial amount of energy. In this regard, lipid extraction from wet biomass must be an attractive solution. However, it is almost impossible to recover lipid directly from wet microalgae with current technology. In this study, we conceived osmotic shock treatment as a novel method to extract lipid efficiently. Osmotic shock treatment was applied directly to wet Chlamydomonas reinhardtii biomass with water content >99%, along with both polar and non-polar organic solvents. Our results demonstrated that osmotic shock could increase lipid recovery approximately 2 times. We also investigated whether the presence of cell wall or different cell stages could have any impact on lipid recovery. Cell wall-less mutant stains and senescent cell phase could display significantly increased lipid recovery. Taken together, our results suggested that osmotic shock is a promising technique for wet lipid extraction from microalgal biomass and successfully determined that specific manipulation of biomass in certain cell phase could enhance lipid recovery further. PMID- 22939600 TI - Simultaneous degradation of phenol and n-hexadecane by Acinetobacter strains. AB - Three phenol- and alkanes-degrading bacterial strains were isolated from a freshwater sample. Upon the 16S rRNA gene analysis, phenotype and physiological features, the three strains were designated as Acinetobacter sp. with both phenol hydroxylase gene (phe) and alkane monooxygenase gene (alkM) detected. They could simultaneously degrade phenol and n-hexadecane for growth, but prefer phenol than n-hexadecane. Between phenol (400mgl(-1)) and n-hexadecane (400mgl(-1)), n hexadecane enhanced phenol degradation in mineral salt medium (MSM), while phenol affects negatively the n-hexadecane degradation. However, combination of phenol (400mgl(-1)) and n-hexadecane (400mgl(-1)) in MSM led to higher growth of the strains than the phenol and n-hexadecane separately. The transcription levels of phe and alkM genes supported the physiological properties of the strains. PMID- 22939601 TI - Reed canary grass as a feedstock for 2nd generation bioethanol production. AB - The enzymatic hydrolysis and fermentation of reed canary grass, harvested in the spring or autumn, and barley straw were studied. Steam pretreated materials were efficiently hydrolysed by commercial enzymes with a dosage of 10-20FPU/g d.m. Reed canary grass harvested in the spring was hydrolysed more efficiently than the autumn-harvested reed canary grass. Additional beta-glucosidase improved the release of glucose and xylose during the hydrolysis reaction. The hydrolysis rate and level of reed canary grass with a commercial Trichoderma reesei cellulase could be improved by supplementation of purified enzymes. The addition of CBH II improved the hydrolysis level by 10% in 48hours' hydrolysis. Efficient mixing was shown to be important for hydrolysis already at 10% dry matter consistency. The highest ethanol concentration (20g/l) and yield (82%) was obtained with reed canary grass at 10% d.m. consistency. PMID- 22939602 TI - Enhanced bioethanol production from pretreated corn stover via multi-positive effect of casein micelles. AB - Casein polypeptides containing substructures of alphas1-casein, beta-casein, k casein, alphas2-casein were used as a lignin-blocker at above critical micelles concentration to improve the bioethanol production of dilute acid, lime, alkali, extrusion and AFEX pretreated corn stover (CS). Application of 0.5 g/g glucan of casein was found to effectively increase the glucose yield of CS pretreated with dilute acid, lime, alkali, extrusion and AFEX by 31.9%, 17.0%, 22.7%, 29.5%, and 17.4%, respectively with no positive impact on Avicel. Consequently 96 h simultaneous saccharification and fermentation (SSF) of these hydrolysates reduced the fermentation period by up to 48 h and increased the theoretical yield of ethanol by 8.48-33.7% compared to control. Application of casein during saccharification reduced the enzyme utilization by 33.0%. Recycling of hydrolysate from casein-treated CS for a 2nd round hydrolysis resulted in average glucose yield of 36.4% compared to 29.0% control. PMID- 22939603 TI - Enhancement of enzymatic digestibility of Eucalyptus grandis pretreated by NaOH catalyzed steam explosion. AB - NaOH catalyzed steam explosion was applied to improve the enzymatic digestibility of Eucalyptus grandis. The impregnation of wood chip with NaOH solutions before steam explosion was carried out to investigate the effects of alkaline catalysis on solid recovery, enzymatic digestibility, and glucose recovery. The lignin removal was significantly affected by NaOH as a catalyst and the glucose recovery increased with increased severity index. The use of NaOH showed higher enzymatic digestibility than the use of water at most severity indexes due to the delignification of biomass and the increase of accessibility to cellulose of enzyme. The maximum glucose recovery was 65.55% having 4.4361 of severity index with 7wt.% of NaOH catalyzed steam explosion at 210 degrees C during 9min. NaOH catalyzed steam explosion was effective to enhance the enzymatic digestibility due to the removal of lignin. PMID- 22939604 TI - Improvement of bacterial hydrogen production by ATP in mixed organic compounds extracted from Rhodobacter sphaeroides aerobically cultured under dark conditions. AB - The aim of this study was to increase the hydrogen production of recombinant Escherichia coli harboring HupSL hydrogenase by supplementing physiologically activating compounds extracted from Rhodobacter sphaeroides cultured under anaerobic dark condition after treating them with dimethyl sulfoxide, and the 0.5% extracts contained 4*10(-8)M ATP, which was 100-fold higher than that in the extracts from E. coli. In addition, it was found that the hydrogen production from recombinant E. coli harboring HupSL hydrogenase isolated from R. sphaeroides was doubled under anaerobic conditions when it was supplemented by the extracts from R. sphaeroides cultured aerobically in dark conditions, and this also showed consistent pattern with the increased level of HupSL hydrogenase expression. Therefore, we conclude that the mixed organic compounds extracted from R. sphaeroides have an ATP which enhances the hydrogen production by increasing the amount of HupSL hydrogenase. PMID- 22939605 TI - On the association between glioma, wireless phones, heredity and ionising radiation. AB - We performed two case-control studies on brain tumours diagnosed during 1 January 1997 to 30 June 2000 and 1 July 2000 to 31 December 2003, respectively. Living cases and controls aged 20-80 years were included. An additional study was performed on deceased cases with a malignant brain tumour using deceased controls. Pooled results for glioma yielded for ipsilateral use of mobile phone odds ratio (OR)=2.9, 95% confidence interval (CI)=1.8-4.7 in the >10 years latency group. The corresponding result for cordless phone was OR=3.8, 95% CI=1.8 8.1. OR increased statistically significant for cumulative use of wireless phones per 100h and per year of latency. For high-grade glioma ipsilateral use of mobile phone gave OR=3.9, 95% CI=2.3-6.6 and cordless phone OR=5.5, 95% CI=2.3-13 in the >10 years latency group. Heredity for brain tumour gave OR=3.4, 95% CI=2.1-5.5 for glioma. There was no interaction with use of wireless phones. X-ray investigation of the head gave overall OR=1.3, 95% CI=1.1-1.7 for glioma without interaction with use of wireless phones or heredity. In conclusion use of mobile and cordless phone increased the risk for glioma with highest OR for ipsilateral use, latency >10 years and third tertile of cumulative use in hours. In total, the risk was highest in the age group <20 years for first use of a wireless phone. PMID- 22939606 TI - Micelles catalyzed chemo- and regio-selective one pot and one step synthesis of 2,3,5,6-tetrakis(alkyl and arylsulfanyl)-1,4-benzoquinones and 2,5 diaminosubstituted-1,4-benzoquinones "In-Water" and their biological evaluation as antibacterial and antifungal agents. AB - Chemo- and regio-selective one pot and one step synthesis of novel 2,3,5,6 tetrakis (substituted thio)cyclohexa-2,5-diene-1,4-diones (4d-14), 2,5-dichloro 3,6-diaminocyclohexa-2,5-diene-1,4-diones and 2,5-diaminocyclohexa-2,5-diene-1,4 diones (16) by economical green methodology approach using LD (Laundry detergent) as a catalyst "In-Water" by nucleophilic addition and substitution reactions of 1,4-benzoquinone and chloranil with sulfur and nitrogen nucleophiles in high yields has been demonstrated. The antifungal profile of 4 and 16 indicates that compounds 4d and 16f had better antifungal activity compared to clinically prevalent antifungal drugs Fluconazole, 5-Fluorocytosine and Clotrimazole against Sporothrix schenckii and Trichophyton mentagraphytes. 16f had also been found to possess better antibacterial activity compared to Ampicillin in vitro against Escherichia coli, Staphylococcus aureus and Klebsiella pneumoniae. Compound 16f did not exhibit any toxicity towards mammalian cells L929. PMID- 22939607 TI - Diagnosis of ST-elevation myocardial infarction in the presence of left bundle branch block with the ST-elevation to S-wave ratio in a modified Sgarbossa rule. AB - STUDY OBJECTIVE: Sgarbossa's rule, proposed for the diagnosis of acute myocardial infarction in the presence of left bundle branch block, has had suboptimal diagnostic utility. We hypothesize that a revised rule, in which the third Sgarbossa component (excessively discordant ST-segment elevation as defined by >=5 mm of ST-segment elevation in the setting of a negative QRS) is replaced by one defined proportionally by ST-segment elevation to S-wave depth (ST/S ratio), will have better diagnostic utility for ST-segment elevation myocardial infarction (STEMI) equivalent, using documented coronary occlusion on angiography as reference standard. METHODS: We collected admission ECGs for all patients with an acutely occluded coronary artery and left bundle branch block at 3 institutions. The ECGs of emergency department patients with chest pain or dyspnea and left bundle branch block, but without coronary occlusion, were used as controls. The R or S wave, whichever was most prominent, and ST segments, relative to the PR segment, were measured to the nearest 0.5 mm. The ST/S ratio was calculated for each lead that has both discordant ST deviation of greater than or equal to 1 mm and an R or S wave of opposite polarity; others were set to 0. The cut point for the most negative ST/S ratio with at least 90% specificity was determined. The revised rule is unweighted, requiring just 1 of 3 criteria. Diagnostic utilities of the original and revised Sgarbossa rules were computed and compared. McNemar's test was used to compare sensitivities and specificities. RESULTS: The study and control groups included 33 and 129 ECGs, respectively. The cut point selected for relative discordant ST-segment elevation was -0.25. Excessive absolute discordant ST-segment elevation of 5 mm was present in at least one lead in 30% of ECGs in patients with confirmed coronary occlusion versus 9% of the control group, whereas excessive relative discordant ST-segment elevation less than -0.25 was present in 79% vs. 9% [corrected].Sensitivity of the revised rule in which ST-segment elevation with an ST/S ratio less than or equal to -0.25 replaces ST-segment elevation greater than or equal to 5 mm was significantly greater than either the weighted (P<.001) or unweighted (P=.008) Sgarbossa rule: 91% (95% confidence interval [CI] 76% to 98%) versus 52% (95% CI 34% to 69%) versus 67% (95% CI 48% to 82%). Specificity of the revised rule was lower than that of the weighted rule (P=.002) and similar to that of the unweighted rule (P=1.0): 90% (95% CI 83% to 95%) versus 98% (95% CI 93% to 100%) versus 90% (95% CI 83% to 95%). Positive and negative likelihood ratios for the revised rule were 9.0 (95% CI 8.0 to 10) and 0.1 (95% CI 0.03 to 0.3). The revised rule was significantly more accurate than both the weighted (16% difference; 95% CI 5% to 27%) and unweighted (12% difference; 95% CI 2% to 22%) Sgarbossa rules. CONCLUSION: Replacement of the absolute ST-elevation measurement of greater than or equal to 5 mm in the third component of the Sgarbossa rule with an ST/S ratio less than -0.25 greatly improves diagnostic utility of the rule for STEMI. An unweighted rule using this criterion resulted in excellent prediction for acute coronary occlusion. PMID- 22939608 TI - Estimating the weight of children in Kenya: do the Broselow tape and age-based formulas measure up? AB - STUDY OBJECTIVE: Validated methods for weight estimation of children are readily available in developed countries; however, their utility in developing countries with higher rates of malnutrition and infectious disease is unknown. The goal of this study is to determine the validity of a height-based estimate, the Broselow tape, compared with age-based estimations among pediatric patients in Western Kenya. METHODS: A prospective cross-sectional study of all sick children presenting to the emergency department of a government referral hospital in Eldoret, Kenya, was performed. Measured weight was compared with predicted weights according to the Broselow tape and commonly used advanced pediatric life support (APLS) and Nelson's age-based formulas. A Bland-Altman analysis was used to determine agreement between each method and actual weight. The method for weight prediction was determined a priori to be equivalent to the actual weight if the 95% confidence interval for the mean percentage difference between the predicted and actual weight was less than 10%. RESULTS: Nine hundred sixty-seven children were included in analysis. The overall mean percentage difference for the actual weight and Broselow predicted weight was -2.2%, whereas APLS and Nelson's predictions were -5.2% and -10.4%, respectively. The overall agreement between Broselow color zone and actual weight was 65.5%, with overestimate typically occurring by only 1 color zone. CONCLUSION: The Broselow tape and APLS formula predict the weights of children in western Kenya. According to its better performance, ease of use, and provision of drug dosing and equipment size, the Broselow tape is superior to age-based formulas for estimation of weight in Kenyan children. PMID- 22939610 TI - Water allocation assessment in low flow river under data scarce conditions: a study of hydrological simulation in Mediterranean basin. AB - River Francoli is a small river in Catalonia (northeastern Spain) with an average annual low flow (~2 m(3)/s). The purpose of the River Francoli watershed assessments is to support and inform region-wide planning efforts from the perspective of water protection, climate change and water allocation. In this study, a hydrological model of the Francoli River watershed was developed for use as a tool for watershed planning, water resource assessment, and ultimately, water allocation purposes using hydrological data from 2002 to 2006 inclusive. The modeling package selected for this application is DHI's MIKE BASIN. This model is a strategic scale water resource management simulation model, which includes modeling of both land surface and subsurface hydrological processes. Topographic, land use, hydrological, rainfall, and meteorological data were used to develop the model segmentation and input. Due to the unavailability of required catchment runoff data, the NAM rainfall-runoff model was used to calculate runoff of all the sub-watersheds. The results reveal a potential pressure on the availability of groundwater and surface water in the lower part of River Francoli as was expected by the IPCC for Mediterranean river basins. The study also revealed that due to the complex hydrological regime existing in the study area and data scarcity, a comprehensive physically based method was required to better represent the interaction between groundwater and surface water. The combined ArcGIS/MIKE BASIN models appear as a useful tool to assess the hydrological cycle and to better understand water allocation to different sectors in the Francoli River watershed. PMID- 22939609 TI - Levels of PCDDs, PCDFs, and dioxin-like PCBs in human milk among Hong Kong mothers. AB - Dioxins are a family of persistent organic pollutants (POPs) listed under the Stockholm Convention, and include PCDDs, PCDFs, and dioxin-like PCBs. These toxic chemicals are carcinogenic, widely dispersed, and have long half-lives. They have contaminated the food web and, being fat-soluble, accumulate in adipose tissues and milk in the human body. To assess human exposure, we collected breast milk samples from 137 first-time mothers recruited from around Hong Kong. Samples were analysed by HRGC-HRMS in four pools, according to the subject's age and length of residency. Exposure was related to age, duration of stay, and possibly diet. Generally, older mothers, and mothers with a longer stay in Hong Kong, had higher levels of dioxins in their milk. This pattern was clearest for the PCBs, although deviations were observed for some of the PCDD/Fs. Mean concentrations, measured per gram of lipid weight in terms of WHO toxic equivalents (WHO-TEQs), were 7.48 pg/g for PCDD/Fs and 3.79 pg/g for PCBs, giving a total of 11.27 pg/g for PCDD/Fs and PCBs combined. Compared to an earlier Hong Kong study we conducted in 2002, the mean WHO-TEQ values in our latest findings were about 9% lower overall for PCDD/Fs and 19% lower for PCBs, with the mean total WHO-TEQ for PCDD/Fs and PCBs being around 13% lower in this study. This indicates a general declining trend in the levels of POPs in Hong Kong. However, our levels were still high when compared to those in some other Asian-Pacific countries. More stringent policies on reducing and eliminating POPs should help to lower these. Continued surveillance for POPs in human milk, as well as in common foodstuffs, will provide us with important information on human exposures that will be necessary for tracking our progress, and making future health risk assessments. PMID- 22939611 TI - The use of wooden sticks to assess stream ecosystem functioning: comparison with leaf breakdown rates. AB - Breakdown of organic matter is a key process in streams and rivers, and thus, it has potential to assess functional impairment of river ecosystems. Because the litter-bag method commonly used to measure leaf breakdown is time consuming and expensive, several authors proposed to measure breakdown of wooden sticks instead. Nevertheless, currently there is little information on the performance of wooden sticks versus that of leaves. We compared the breakdown of tongue depressors made of untreated poplar wood, to that of six common leaf species in two large streams in the Basque Country (northern Spain), one polluted and the other unpolluted. Breakdown rates ranged from 0.0011 to 0.0120 day(-1), and were significantly lower in the polluted stream. Wooden sticks performed very similarly to leaves, but were less affected by flood-induced physical abrasion. The ranking of the materials according to their breakdown rate was consistent, irrespective of the stream. The experiments with leaves were 10 times more costly for breakdown rate, 4 times if we include the rest of the variables measured. Therefore wooden sticks offer a promising tool to assess river ecosystem functioning, although more research is necessary to define the thresholds for ecosystem functional impairment. PMID- 22939612 TI - Reconstruction of fetal brain MRI with intensity matching and complete outlier removal. AB - We propose a method for the reconstruction of volumetric fetal MRI from 2D slices, comprising super-resolution reconstruction of the volume interleaved with slice-to-volume registration to correct for the motion. The method incorporates novel intensity matching of acquired 2D slices and robust statistics which completely excludes identified misregistered or corrupted voxels and slices. The reconstruction method is applied to motion-corrupted data simulated from MRI of a preterm neonate, as well as 10 clinically acquired thick-slice fetal MRI scans and three scan-sequence optimized thin-slice fetal datasets. The proposed method produced high quality reconstruction results from all the datasets to which it was applied. Quantitative analysis performed on simulated and clinical data shows that both intensity matching and robust statistics result in statistically significant improvement of super-resolution reconstruction. The proposed novel EM based robust statistics also improves the reconstruction when compared to previously proposed Huber robust statistics. The best results are obtained when thin-slice data and the correct approximation of the point spread function is used. This paper addresses the need for a comprehensive reconstruction algorithm of 3D fetal MRI, so far lacking in the scientific literature. PMID- 22939613 TI - Imaging diagnosis of congenital brain anomalies and injuries. AB - Fetal brain is rapidly developing and changing its appearance week by week during pregnancy. The brain is the most important organ but it is quite hard to observe detailed structure of this organ by conventional transabdominal sonography. Transvaginal high-resolution ultrasound and three-dimensional (3D) ultrasound has been a great diagnostic tool for evaluation of three-dimensional structure of fetal central nervous system (CNS). This method has contributed to the prenatal assessment of congenital CNS anomalies, intracranial vascular anomalies and acquired brain damage in utero. It is possible to observe the whole brain structure by magnetic resonance imaging in the post half of pregnancy but transvaginal high-resolution 3D ultrasound is certainly powerful modality as well for understanding brain anatomy. Longitudinally and carefully evaluation of neurological short- or long-term prognosis should be required according to precise prenatal diagnosis, for proper counseling and management based on precise evidence. PMID- 22939614 TI - Singles engage the RNA interference pathway. AB - Single-stranded RNAs interact with components of the RNA interference pathway to reduce the expression of target mRNAs. Now, Lima et al. and Yu et al. show that, with extensive chemical modifications, small single-stranded RNAs can robustly induce gene silencing with efficacy similar to their double-stranded counterparts. PMID- 22939615 TI - Holding on through DNA replication: histone modification or modifier? AB - Histone methylation is widely believed to contribute to epigenetic inheritance by persevering through DNA replication and subsequently templating methylation of daughter chromosome regions. However, a report in this issue (Petruk et al.) suggests that chromatin association of the methytransferase complexes themselves persists through replication and re-establishes histone methylation. PMID- 22939616 TI - LIS1 clamps dynein to the microtubule. AB - Cytoplasmic dynein is a motor essential for numerous mechanical processes in eukaryotic cells. How its activity is regulated is largely unknown. By using a combination of approaches including single-molecule biophysics and electron microscopy, Huang et al. in this issue uncover the regulatory mechanism by which LIS1 controls the activity of cytoplasmic dynein. PMID- 22939617 TI - A cornucopia of candidates for deafness. AB - Many genes involved in deafness are yet to be discovered. Here, Senthilan et al. focus on the Drosophila Johnston's organ to uncover a wide variety of genes, including several unexpected candidates as well as those already known to underlie deafness in mice and humans. PMID- 22939618 TI - Single-stranded siRNAs activate RNAi in animals. AB - The therapeutic utility of siRNAs is limited by the requirement for complex formulations to deliver them to tissues. If potent single-stranded RNAs could be identified, they would provide a simpler path to pharmacological agents. Here, we describe single-stranded siRNAs (ss-siRNAs) that silence gene expression in animals absent lipid formulation. Effective ss-siRNAs were identified by iterative design by determining structure-activity relationships correlating chemically modified single strands and Argonaute 2 (AGO2) activities, potency in cells, nuclease stability, and pharmacokinetics. We find that the passenger strand is not necessary for potent gene silencing. The guide-strand activity requires AGO2, demonstrating action through the RNAi pathway. ss-siRNA action requires a 5' phosphate to achieve activity in vivo, and we developed a metabolically stable 5'-(E)-vinylphosphonate (5'-VP) with conformation and sterioelectronic properties similar to the natural phosphate. Identification of potent ss-siRNAs offers an additional option for RNAi therapeutics and an alternate perspective on RNAi mechanism. PMID- 22939619 TI - Single-stranded RNAs use RNAi to potently and allele-selectively inhibit mutant huntingtin expression. AB - Mutant huntingtin (HTT) protein causes Huntington disease (HD), an incurable neurological disorder. Silencing mutant HTT using nucleic acids would eliminate the root cause of HD. Developing nucleic acid drugs is challenging, and an ideal clinical approach to gene silencing would combine the simplicity of single stranded antisense oligonucleotides with the efficiency of RNAi. Here, we describe RNAi by single-stranded siRNAs (ss-siRNAs). ss-siRNAs are potent (>100 fold more than unmodified RNA) and allele-selective (>30-fold) inhibitors of mutant HTT expression in cells derived from HD patients. Strategic placement of mismatched bases mimics micro-RNA recognition and optimizes discrimination between mutant and wild-type alleles. ss-siRNAs require Argonaute protein and function through the RNAi pathway. Intraventricular infusion of ss-siRNA produced selective silencing of the mutant HTT allele throughout the brain in a mouse HD model. These data demonstrate that chemically modified ss-siRNAs function through the RNAi pathway and provide allele-selective compounds for clinical development. PMID- 22939620 TI - Glucosylated hydroxymethyluracil, DNA base J, prevents transcriptional readthrough in Leishmania. AB - Some Ts in nuclear DNA of trypanosomes and Leishmania are hydroxylated and glucosylated to yield base J (beta-D-glucosyl-hydroxymethyluracil). In Leishmania, about 99% of J is located in telomeric repeats. We show here that most of the remaining J is located at chromosome-internal RNA polymerase II termination sites. This internal J and telomeric J can be reduced by a knockout of J-binding protein 2 (JBP2), an enzyme involved in the first step of J biosynthesis. J levels are further reduced by growing Leishmania JBP2 knockout cells in BrdU-containing medium, resulting in cell death. The loss of internal J in JBP2 knockout cells is accompanied by massive readthrough at RNA polymerase II termination sites. The readthrough varies between transcription units but may extend over 100 kb. We conclude that J is required for proper transcription termination and infer that the absence of internal J kills Leishmania by massive readthrough of transcriptional stops. PMID- 22939621 TI - Step-wise methylation of histone H3K9 positions heterochromatin at the nuclear periphery. AB - The factors that sequester transcriptionally repressed heterochromatin at the nuclear periphery are currently unknown. In a genome-wide RNAi screen, we found that depletion of S-adenosylmethionine (SAM) synthetase reduces histone methylation globally and causes derepression and release of heterochromatin from the nuclear periphery in Caenorhabditis elegans embryos. Analysis of histone methyltransferases (HMTs) showed that elimination of two HMTs, MET-2 and SET-25, mimics the loss of SAM synthetase, abrogating the perinuclear attachment of heterochromatic transgenes and of native chromosomal arms rich in histone H3 lysine 9 methylation. The two HMTs target H3K9 in a consecutive fashion: MET-2, a SETDB1 homolog, mediates mono- and dimethylation, and SET-25, a previously uncharacterized HMT, deposits H3K9me3. SET-25 colocalizes with its own product in perinuclear foci, in a manner dependent on H3K9me3, but not on its catalytic domain. This colocalization suggests an autonomous, self-reinforcing mechanism for the establishment and propagation of repeat-rich heterochromatin. PMID- 22939622 TI - Prdm3 and Prdm16 are H3K9me1 methyltransferases required for mammalian heterochromatin integrity. AB - Heterochromatin serves important functions, protecting genome integrity and stabilizing gene expression programs. Although the Suv39h methyltransferases (KMTs) are known to ensure pericentric H3K9me3 methylation, the mechanisms that initiate and maintain mammalian heterochromatin organization remain elusive. We developed a biochemical assay and used in vivo analyses in mouse embryonic fibroblasts to identify Prdm3 and Prdm16 as redundant H3K9me1-specific KMTs that direct cytoplasmic H3K9me1 methylation. The H3K9me1 is converted in the nucleus to H3K9me3 by the Suv39h enzymes to reinforce heterochromatin. Simultaneous depletion of Prdm3 and Prdm16 abrogates H3K9me1 methylation, prevents Suv39h dependent H3K9me3 trimethylation, and derepresses major satellite transcription. Most strikingly, DNA-FISH and electron microscopy reveal that combined impairment of Prdm3 and Prdm16 results in disintegration of heterochromatic foci and disruption of the nuclear lamina. Our data identify Prdm3 and Prdm16 as H3K9me1 methyltransferases and expose a functional framework in which anchoring to the nuclear periphery helps maintain the integrity of mammalian heterochromatin. PMID- 22939623 TI - Lis1 acts as a "clutch" between the ATPase and microtubule-binding domains of the dynein motor. AB - The lissencephaly protein Lis1 has been reported to regulate the mechanical behavior of cytoplasmic dynein, the primary minus-end-directed microtubule motor. However, the regulatory mechanism remains poorly understood. Here, we address this issue using purified proteins from Saccharomyces cerevisiae and a combination of techniques, including single-molecule imaging and single-particle electron microscopy. We show that rather than binding to the main ATPase site within dynein's AAA+ ring or its microtubule-binding stalk directly, Lis1 engages the interface between these elements. Lis1 causes individual dynein motors to remain attached to microtubules for extended periods, even during cycles of ATP hydrolysis that would canonically induce detachment. Thus, Lis1 operates like a "clutch" that prevents dynein's ATPase domain from transmitting a detachment signal to its track-binding domain. We discuss how these findings provide a conserved mechanism for dynein functions in living cells that require prolonged microtubule attachments. PMID- 22939625 TI - Self-organized shuttling: generating sharp dorsoventral polarity in the early Drosophila embryo. AB - Morphogen gradients pattern tissues and organs during development. When morphogen production is spatially restricted, diffusion and degradation are sufficient to generate sharp concentration gradients. It is less clear how sharp gradients can arise within the source of a broadly expressed morphogen. A recent solution relies on localized production of an inhibitor outside the domain of morphogen production, which effectively redistributes (shuttles) and concentrates the morphogen within its expression domain. Here, we study how a sharp gradient is established without a localized inhibitor, focusing on early dorsoventral patterning of the Drosophila embryo, where an active ligand and its inhibitor are concomitantly generated in a broad ventral domain. Using theory and experiments, we show that a sharp Toll activation gradient is produced through "self-organized shuttling," which dynamically relocalizes inhibitor production to lateral regions, followed by inhibitor-dependent ventral shuttling of the activating ligand Spatzle. Shuttling may represent a general paradigm for patterning early embryos. PMID- 22939624 TI - Quantitative analysis of HSP90-client interactions reveals principles of substrate recognition. AB - HSP90 is a molecular chaperone that associates with numerous substrate proteins called clients. It plays many important roles in human biology and medicine, but determinants of client recognition by HSP90 have remained frustratingly elusive. We systematically and quantitatively surveyed most human kinases, transcription factors, and E3 ligases for interaction with HSP90 and its cochaperone CDC37. Unexpectedly, many more kinases than transcription factors bound HSP90. CDC37 interacted with kinases, but not with transcription factors or E3 ligases. HSP90::kinase interactions varied continuously over a 100-fold range and provided a platform to study client protein recognition. In wild-type clients, HSP90 did not bind particular sequence motifs, but rather associated with intrinsically unstable kinases. Stabilization of the kinase in either its active or inactive conformation with diverse small molecules decreased HSP90 association. Our results establish HSP90 client recognition as a combinatorial process: CDC37 provides recognition of the kinase family, whereas thermodynamic parameters determine client binding within the family. PMID- 22939626 TI - Structurally distinct bacterial TBC-like GAPs link Arf GTPase to Rab1 inactivation to counteract host defenses. AB - Rab GTPases are frequent targets of vacuole-living bacterial pathogens for appropriate trafficking of the vacuole. Here we discover that bacterial effectors including VirA from nonvacuole Shigella flexneri and EspG from extracellular Enteropathogenic Escherichia coli (EPEC) harbor TBC-like dual-finger motifs and exhibits potent RabGAP activities. Specific inactivation of Rab1 by VirA/EspG disrupts ER-to-Golgi trafficking. S. flexneri intracellular persistence requires VirA TBC-like GAP activity that mediates bacterial escape from autophagy-mediated host defense. Rab1 inactivation by EspG severely blocks host secretory pathway, resulting in inhibited interleukin-8 secretion from infected cells. Crystal structures of VirA/EspG-Rab1-GDP-aluminum fluoride complexes highlight TBC-like catalytic role for the arginine and glutamine finger residues and reveal a 3D architecture distinct from that of the TBC domain. Structure of Arf6-EspG-Rab1 ternary complex illustrates a pathogenic signaling complex that rewires host Arf signaling to Rab1 inactivation. Structural distinctions of VirA/EspG further predict a possible extensive presence of TBC-like RabGAP effectors in counteracting various host defenses. PMID- 22939627 TI - Drosophila auditory organ genes and genetic hearing defects. AB - The Drosophila auditory organ shares equivalent transduction mechanisms with vertebrate hair cells, and both are specified by atonal family genes. Using a whole-organ knockout strategy based on atonal, we have identified 274 Drosophila auditory organ genes. Only four of these genes had previously been associated with fly hearing, yet one in five of the genes that we identified has a human cognate that is implicated in hearing disorders. Mutant analysis of 42 genes shows that more than half of them contribute to auditory organ function, with phenotypes including hearing loss, auditory hypersusceptibility, and ringing ears. We not only discover ion channels and motors important for hearing, but also show that auditory stimulus processing involves chemoreceptor proteins as well as phototransducer components. Our findings demonstrate mechanosensory roles for ionotropic receptors and visual rhodopsins and indicate that different sensory modalities utilize common signaling cascades. PMID- 22939630 TI - SnapShot: the nuclear envelope II. PMID- 22939628 TI - Role of leaky neuronal ryanodine receptors in stress-induced cognitive dysfunction. AB - The type 2 ryanodine receptor/calcium release channel (RyR2), required for excitation-contraction coupling in the heart, is abundant in the brain. Chronic stress induces catecholamine biosynthesis and release, stimulating beta adrenergic receptors and activating cAMP signaling pathways in neurons. In a murine chronic restraint stress model, neuronal RyR2 were phosphorylated by protein kinase A (PKA), oxidized, and nitrosylated, resulting in depletion of the stabilizing subunit calstabin2 (FKBP12.6) from the channel complex and intracellular calcium leak. Stress-induced cognitive dysfunction, including deficits in learning and memory, and reduced long-term potentiation (LTP) at the hippocampal CA3-CA1 connection were rescued by oral administration of S107, a compound developed in our laboratory that stabilizes RyR2-calstabin2 interaction, or by genetic ablation of the RyR2 PKA phosphorylation site at serine 2808. Thus, neuronal RyR2 remodeling contributes to stress-induced cognitive dysfunction. Leaky RyR2 could be a therapeutic target for treatment of stress-induced cognitive dysfunction. PMID- 22939629 TI - A census of human soluble protein complexes. AB - Cellular processes often depend on stable physical associations between proteins. Despite recent progress, knowledge of the composition of human protein complexes remains limited. To close this gap, we applied an integrative global proteomic profiling approach, based on chromatographic separation of cultured human cell extracts into more than one thousand biochemical fractions that were subsequently analyzed by quantitative tandem mass spectrometry, to systematically identify a network of 13,993 high-confidence physical interactions among 3,006 stably associated soluble human proteins. Most of the 622 putative protein complexes we report are linked to core biological processes and encompass both candidate disease genes and unannotated proteins to inform on mechanism. Strikingly, whereas larger multiprotein assemblies tend to be more extensively annotated and evolutionarily conserved, human protein complexes with five or fewer subunits are far more likely to be functionally unannotated or restricted to vertebrates, suggesting more recent functional innovations. PMID- 22939631 TI - High sensitivity measurement of amino acid isotope enrichment using liquid chromatography-mass spectrometry. AB - Measurement of the incorporation or conversion of infused stable isotope enriched metabolites in vivo such as amino acids plays a key role in metabolic research. Specific routes are frequently probed in knockout mouse models limiting the available amount of sample. Although less precise as compared to combustion isotope ratio mass spectrometry (C-IRMS), gas chromatography-mass spectrometry (GC-MS) or liquid chromatography-mass spectrometry (LC-MS) techniques are therefore often the method of choice to measure isotopic enrichment of target metabolites. However, under conditions of metabolic depletion, the precision of these systems becomes limiting. In this paper, studies were performed to enhance the sensitivity and precision of isotope enrichment measurements using LC-MS. Ion statistics and resolution were identified as critical factors for this application when using a linear trap mass spectrometer. The combination with an automated pre-column derivatization and a carefully selected solvent mix allowed us to measure isotopic enrichments down to 0.005% at plasma concentrations as low as 5 MUmol/l, an improvement by a factor of 100 compared to alternative methods. The resulting method now allowed measurement of the in vivo conversion of the amino acid arginine into citrulline as a marker for the production of nitric oxide in an in vivo murine endotoxemia model with depleted plasma levels of arginine and citrulline. PMID- 22939632 TI - Protein pre-fractionation with a mixed-bed ion exchange column in 3D LC-MS/MS proteome analysis. AB - The fractionation of complex samples at the protein level prior to shotgun proteomics analysis is an efficient means to more comprehensive analysis of samples. A mixed-bed ion-exchange (IEX) column, packed with both weak anion exchange (WAX) and weak cation exchange (WCX) materials, was used for the first dimensional separation of complex samples at the protein level using volatile solvents. The peptides from digestion of each fraction were then identified by 2D SCX-RP-LC-MS/MS. We applied this 3D strategy to mouse mammary tumor 4T1 cell lysate and identified a total of 3084 proteins in a typical experiment. The moderate separation performance of the mixed-bed IEX column facilitated the in depth identification of the proteins in the complex sample. There were some acceptable inter-fraction overlaps. Nearly half (45.8%) of the proteins were only identified in single fractions, while 82.3% were identified in no more than 3 fractions. The identified proteins covered a broad range of pI, size and grand average hydrophobicity (GRAVY) values. Detailed analysis of proteins identified in each fraction elucidated the separation characteristics of mixed-bed IEX. Retention on mixed-bed IEX was associated, but not restricted to the extreme pI values (pI<5, pI>10) and to the percentage of charged residues of both signs. In conclusion, we have exploited the mixed-bed IEX column to establish an efficient and comprehensive identification method for complex samples. PMID- 22939633 TI - Using ERDS to infer copy-number variants in high-coverage genomes. AB - Although there are many methods available for inferring copy-number variants (CNVs) from next-generation sequence data, there remains a need for a system that is computationally efficient but that retains good sensitivity and specificity across all types of CNVs. Here, we introduce a new method, estimation by read depth with single-nucleotide variants (ERDS), and use various approaches to compare its performance to other methods. We found that for common CNVs and high coverage genomes, ERDS performs as well as the best method currently available (Genome STRiP), whereas for rare CNVs and high-coverage genomes, ERDS performs better than any available method. Importantly, ERDS accommodates both unique and highly amplified regions of the genome and does so without requiring separate alignments for calling CNVs and other variants. These comparisons show that for genomes sequenced at high coverage, ERDS provides a computationally convenient method that calls CNVs as well as or better than any currently available method. PMID- 22939634 TI - Contribution of global rare copy-number variants to the risk of sporadic congenital heart disease. AB - Previous studies have shown that copy-number variants (CNVs) contribute to the risk of complex developmental phenotypes. However, the contribution of global CNV burden to the risk of sporadic congenital heart disease (CHD) remains incompletely defined. We generated genome-wide CNV data by using Illumina 660W Quad SNP arrays in 2,256 individuals with CHD, 283 trio CHD-affected families, and 1,538 controls. We found association of rare genic deletions with CHD risk (odds ratio [OR] = 1.8, p = 0.0008). Rare deletions in study participants with CHD had higher gene content (p = 0.001) with higher haploinsufficiency scores (p = 0.03) than they did in controls, and they were enriched with Wnt-signaling genes (p = 1 * 10(-5)). Recurrent 15q11.2 deletions were associated with CHD risk (OR = 8.2, p = 0.02). Rare de novo CNVs were observed in ~5% of CHD trios; 10 out of 11 occurred on the paternally transmitted chromosome (p = 0.01). Some of the rare de novo CNVs spanned genes known to be involved in heart development (e.g., HAND2 and GJA5). Rare genic deletions contribute ~4% of the population attributable risk of sporadic CHD. Second to previously described CNVs at 1q21.1, deletions at 15q11.2 and those implicating Wnt signaling are the most significant contributors to the risk of sporadic CHD. Rare de novo CNVs identified in CHD trios exhibit paternal origin bias. PMID- 22939635 TI - Genome-wide association and population genetic analysis of C-reactive protein in African American and Hispanic American women. AB - C-reactive protein (CRP) is a systemic inflammation marker that predicts future cardiovascular risk. CRP levels are higher in African Americans and Hispanic Americans than in European Americans, but the genetic determinants of CRP in these admixed United States minority populations are largely unknown. We performed genome-wide association studies (GWASs) of 8,280 African American (AA) and 3,548 Hispanic American (HA) postmenopausal women from the Women's Health Initiative SNP Health Association Resource. We discovered and validated a CRP associated variant of triggering receptors expressed by myeloid cells 2 (TREM2) in chromosomal region 6p21 (p = 10(-10)). The TREM2 variant associated with higher CRP is common in Africa but rare in other ancestral populations. In AA women, the CRP region in 1q23 contained a strong admixture association signal (p = 10(-17)), which appears to be related to several independent CRP-associated alleles; the strongest of these is present only in African ancestral populations and is associated with higher CRP. Of the other genomic loci previously associated with CRP through GWASs of European populations, most loci (LEPR, IL1RN, IL6R, GCKR, NLRP3, HNF1A, HNF4A, and APOC1) showed consistent patterns of association with CRP in AA and HA women. In summary, we have identified a common TREM2 variant associated with CRP in United States minority populations. The genetic architecture underlying the CRP phenotype in AA women is complex and involves genetic variants shared across populations, as well as variants specific to populations of African descent. PMID- 22939636 TI - RTTN mutations link primary cilia function to organization of the human cerebral cortex. AB - Polymicrogyria is a malformation of the developing cerebral cortex caused by abnormal organization and characterized by many small gyri and fusion of the outer molecular layer. We have identified autosomal-recessive mutations in RTTN, encoding Rotatin, in individuals with bilateral diffuse polymicrogyria from two separate families. Rotatin determines early embryonic axial rotation, as well as anteroposterior and dorsoventral patterning in the mouse. Human Rotatin has recently been identified as a centrosome-associated protein. The Drosophila melanogaster homolog of Rotatin, Ana3, is needed for structural integrity of centrioles and basal bodies and maintenance of sensory neurons. We show that Rotatin colocalizes with the basal bodies at the primary cilium. Cultured fibroblasts from affected individuals have structural abnormalities of the cilia and exhibit downregulation of BMP4, WNT5A, and WNT2B, which are key regulators of cortical patterning and are expressed at the cortical hem, the cortex-organizing center that gives rise to Cajal-Retzius (CR) neurons. Interestingly, we have shown that in mouse embryos, Rotatin colocalizes with CR neurons at the subpial marginal zone. Knockdown experiments in human fibroblasts and neural stem cells confirm a role for RTTN in cilia structure and function. RTTN mutations therefore link aberrant ciliary function to abnormal development and organization of the cortex in human individuals. PMID- 22939637 TI - A prospective multicenter registry of patients with chronic gastroesophageal reflux disease receiving transoral incisionless fundoplication. AB - BACKGROUND: This study was undertaken to validate previously reported safety and symptomatic outcomes of transoral incisionless fundoplication (TIF), evaluate the relative benefit of TIF within different gastroesophageal reflux disease (GERD) subgroups, and to determine predictors of success in community settings. STUDY DESIGN: Between January 2010 and February 2011, 100 consecutive patients who underwent TIF procedures at 10 centers were enrolled in this prospective, open label, multicenter, single-arm study. Symptom improvement and objective outcomes of TIF were analyzed at 6-month follow-up. RESULTS: One hundred TIF procedures were performed. No complications were reported. Median GERD symptom duration was 9 years (range 1 to 35 years) and median duration of proton pump inhibitor (PPI) use was 7 years (1 to 20 years). Maximal medical therapy resulted in incomplete symptom control for 92% of patients; GERD Health-Related Quality of Life (GERD HRQL) total score was normalized in 73%. Median heartburn and regurgitation scores improved significantly, from 18 (range 0 to 30) and 15 (range 0 to 30) on PPIs before TIF to 3 (range 0 to 25) and 0 (range 0 to 25), respectively; p < 0.001. Median Reflux Symptom Index scores were reduced after TIF from 24 (range 14 to 41) to 7 (range 0 to 44); p < 0.001. Eighty percent of patients were completely off PPIs after TIF vs 92% of patients on PPIs before TIF. Preoperative factors associated with clinical outcomes were less severe heartburn (total GERD HRQL <= 30, p = 0.02) and the presence of esophagitis (p < 0.02). CONCLUSIONS: Transoral incisionless fundoplication is safe and effective in multiple community based settings in the treatment of medically refractory GERD, as demonstrated by an absence of complications, excellent symptom relief, and complete cessation of PPIs at 6-month follow-up. PMID- 22939639 TI - Myelin basic protein autoantibodies, white matter disease and stroke outcome. AB - Antibodies to brain antigens are present in stroke survivors. In this study, we assessed autoantibody responses to white matter antigens, their correlation to white matter disease and stroke outcome. Antibody titers (immunoglobulin G [igG]) to myelin basic protein (MBP), proteolipid protein (PLP) and tetanus toxoid (TT) were available at one or more time points for 112 subjects with ischemic stroke. In comparison to the control subjects (N=40), there was a global decrease in IgG titers to TT early after stroke. Patients with white matter disease on magnetic resonance imaging had elevated titers of antibodies to both MBP and PLP at 30days after stroke, and anti-MBP antibodies were associated with worse outcome. The potential pathologic consequences of antibodies to white matter, especially MBP, is deserving of further investigation. PMID- 22939641 TI - Selective use of hand and forearm muscles during bone screw insertion: a natural torque meter. AB - PURPOSE: To compare the maximum torque produced by different muscle groups and its influence on mini-implant insertion torque and fracture prevention. MATERIALS AND METHODS: Eighty-seven professionals were evaluated for the maximum torque produced on a screwdriver by a combined action between the thumb and index finger (maximum digital torque [MDT]) and by the forearm supination movement (maximum brachial torque [MBT]). Ninety mini-implants distributed among 9 different diameters were fractured to determine the fracture torque (FT). The fracture resistance index (FRI) was obtained from: FRI_MDT = FT/MDT and FRI_MBT = FT/MBT. Analysis of variance and t tests were used to compare the groups. RESULTS: The MDT was smaller than the MBT, and the 2 measurements were smaller in female subjects. The FT increased for each 0.1-mm increment in diameter. The FRI_MDT was greater than FRI_MBT for all diameters. An FRI_MDT greater than 1 was found when the diameter was greater than or equal to 1.5 mm. An FRI_MBT greater than 1 occurred with diameters equal to or greater than 1.7 mm for female subjects and 1.8 mm for male subjects. CONCLUSIONS: The digital torque was 42% smaller than the brachial torque, and it was mechanically safer and biologically more compatible, allowing the prevention of the fracture of mini-implants with a diameter 1.5 mm or thicker owing to an insertion torque limitation at 15 N-cm. PMID- 22939640 TI - A retrospective study of using removable occlusal splint in the treatment of condylar fracture in children. AB - BACKGROUND: Although the concept of conservative treatment for paediatric condylar fracture is well understood, there is still a lack of a recognized method for treating child patients with a condylar fracture. The purpose of this study was to investigate the effect of the removable occlusal splint in treating condylar fractures in children and adolescents. MATERIALS AND METHODS: Forty children and adolescents with condylar fracture, aged 3-16, were included in this study. A removable occlusal splint with varying thickness was fabricated according to the age, developmental stage of the mandible, and degree of condylar dislocation. This was worn for 1-3 months, accompanied by functional exercises. Follow-up was carried out by clinical observation and panoramic X-ray. RESULTS: Clinically satisfactory results with good occlusion were obtained in all the patients, along with unimpaired function and normal growth and development of the mandible. The panoramic image showed remodelling and reconstruction of the fractured condyles. CONCLUSIONS: Our results confirm that conservative treatment has a satisfactory clinical outcome in treating condylar fracture in children. The removable occlusal splint is a promising approach for treating condylar fracture in children and adolescents. PMID- 22939642 TI - Comparison of 2 hyaluronic acid drugs for the treatment of temporomandibular joint osteoarthritis. AB - PURPOSE: To compare the effectiveness of 2 treatment protocols providing 5 weekly temporomandibular joint (TMJ) arthrocenteses immediately followed by injections of 2 different molecular weight hyaluronic acid (HA) drugs to manage symptoms in patients with inflammatory-degenerative TMJ disease. MATERIALS AND METHODS: Patients with a Research Diagnostic Criteria for Temporomandibular Disorders diagnosis of osteoarthritis were randomly assigned to 1 of 2 study groups receiving either low- or medium-molecular weight HA after arthrocentesis. The level of maximum pain at chewing was the primary outcome variable, and maximum pain at rest, subjective chewing efficiency, functional limitation, treatment tolerability, perceived treatment effectiveness, and jaw range-of-motion function in millimeters were the secondary outcomes. All variables were assessed and compared between groups at baseline, at the end of treatment, and 3 months later. RESULTS: Forty subjects entered the study. At the end of the follow-up period, all the outcome variables improved in both groups of patients. A between-group comparison of changes over time showed that differences were not significant for any of the outcome variables, that is, pain at chewing (F = 0.056, P = .815), pain at rest (F = 0.383, P = .541), chewing efficiency (F = 0.050, P = .825), functional limitation (F = 0.268, P = .609), and mouth opening (F = 0.003, P = .954). In addition, no between-group differences were shown for perceived treatment effectiveness and treatment tolerability. CONCLUSIONS: Similar positive effectiveness was shown for 2 treatment protocols for TMJ osteoarthritis (ie, 5 session single-needle arthrocentesis plus low- or medium-molecular weight HA). PMID- 22939643 TI - The effect of preoperative recombinant erythropoietin on postoperative hematocrit level after orthognathic surgery. AB - PURPOSE: To compare the postoperative red cell mass as indicated by the hematocrit value of orthognathic surgery patients given iron supplementation and a single preoperative dose of erythropoietin alpha (EPO) and patients who did not receive either EPO or iron supplementation. PATIENTS AND METHODS: Subjects who had a Le Fort I osteotomy (LFI) or a combination of LFI and bilateral sagittal split osteotomy between 2005 and 2008 and were aged at least 13 years were included. Subjects were excluded if they had a history of maxillofacial trauma, a craniofacial syndrome, or a major systemic medical condition. Subjects either had EPO administered with iron supplements before surgery (surgeon A protocol) or received neither (surgeon B protocol). Venous blood samples were taken, in accordance with clinic protocol, before surgery (before administration of EPO) and on postoperative day 1. Multiple linear regression with backward selection was used to analyze the change in hematocrit value. Explanatory variables included group, preoperative hematocrit level, age, gender, length of surgery, blood loss, and crystalloid (fluid replacement) volume. RESULTS: The study included 178 eligible patients: 86 (48%) had a combination of LFI and bilateral sagittal split osteotomy and 92 (52%) had an isolated LFI. Of the patients, 114 (64%) had EPO/iron supplements administered before surgery whereas 64 did not. The mean change in hematocrit level as an indicator of the change in red cell mass was statistically significantly different (P = .01) for the subjects who received preoperative administration of EPO with iron supplementation compared with those who did not receive EPO plus iron. The administration of EPO plus iron was protective: the decrease in hematocrit level after surgery was smaller for subjects in the EPO group even after we controlled for age, gender, preoperative hematocrit level, length of surgery, blood loss, and crystalloid (fluid replacement) volume. CONCLUSIONS: A single preoperative dose of erythropoietin with iron supplementation resulted in a smaller decrease, on average, in postoperative red cell mass as indicated by hematocrit value in patients with complicated orthognathic surgery procedures. PMID- 22939645 TI - Recommending organized screening programs for adults in Greece: a Delphi consensus study. AB - OBJECTIVE: In the absence of organized screening programs in Greece, the aim of this study is to propose a set of programs, which exhibit potential to improve health system's performance. METHODS: A literature review was conducted to identify those programs fulfilling certain screening evaluation criteria. Using Delphi method programs identified were evaluated by a multi-professional expert panel who were asked to provide their consent and recommendations for the implementation, target-group, rescreening interval, primary screening method and social insurance reimbursement level. Kuder-Richardson 20 and Cronbach's alpha were used for assessing internal consistency and number of rounds. RESULTS: The majority of experts supported the introduction of organized screening programs for breast cancer, cervical cancer, colorectal cancer, abdominal aortic aneurysm and vascular risk assessment. Major disagreements arose on the target-group of the colorectal cancer and abdominal aortic aneurysm program concerning age limits. Experts argued that only those fulfilling programs' eligibility criteria or those referred should be reimbursed by social insurance. CONCLUSION: Recommended screening programs provide for the first time a comprehensive and consensus based proposal for the secondary prevention policy of the country. They are expected to contribute to the reduction of the disease burden from important health problems and to the optimum allocation of resources invested in health. PMID- 22939646 TI - Clinical guidelines in the European Union: mapping the regulatory basis, development, quality control, implementation and evaluation across member states. AB - INTRODUCTION: Clinical guidelines are advocated to improve the quality of care, especially for chronic diseases. However, the regulatory basis of clinical guidelines, their development, quality control, implementation and use as well as evaluation within countries across the European Union is not systematically known. METHODS: Using information collected from key informants in each country by means of a structured questionnaire, this mapping exercise illustrates the varied status of guideline production in European Union countries. RESULTS: Most European Union countries have an established national, regional or local clinical guideline programme, and a substantial proportion have developed guidelines on the prevention and management of chronic diseases. Several countries have mechanisms in place to ensure the quality of scientific evidence used for the development of guidelines is high and that the process is consistent and transparent. Others are only now taking an interest in guideline development and are taking the first steps towards establishing ways of implementing them. The majority of countries have no legal basis for the development of guidelines and those that have well established systems mostly implement them on a voluntary basis. The process of guideline development varies in its degrees of decentralisation across countries with many different types of organisations taking on this responsibility. There is general acceptance of the value of the instrument developed by the AGREE collaboration for evaluating the methodological robustness of guidelines. However, the extent to which guidelines are implemented in Europe is unknown, as there is no systematic data collection and, in most countries, no structure to enable it. There are few examples of formal evaluations of the development, quality, implementation and use of guidelines. CONCLUSIONS: Our findings call for renewed efforts to respond to the severe lack of standardized guideline terminology and accessibility as well as rigorous studies to evaluate the relationship between different ways to develop guidelines and their methodological quality, between their quality and the actual implementation and usage, and finally between implementation and health outcomes. PMID- 22939644 TI - Major histocompatibility complex class I proteins in brain development and plasticity. AB - Proper development of the central nervous system (CNS) requires the establishment of appropriate connections between neurons. Recent work suggests that this process is controlled by a balance between synaptogenic molecules and proteins that negatively regulate synapse formation and plasticity. Surprisingly, many of these newly identified synapse-limiting molecules are classic 'immune' proteins. In particular, major histocompatibility complex class I (MHCI) molecules regulate neurite outgrowth, the establishment and function of cortical connections, activity-dependent refinement in the visual system, and long-term and homeostatic plasticity. This review summarizes our current understanding of MHCI expression and function in the CNS, as well as the potential mechanisms used by MHCI to regulate brain development and plasticity. PMID- 22939647 TI - [Epidemiological surveillance and prenatal diagnosis of congenital anomalies in the Parisian population, 1981-2007]. AB - OBJECTIVES: To assess overall and malformation-specific trends in the prevalence and prenatal diagnosis of congenital anomalies in the Parisian population. METHODS: The Paris Registry of Congenital Malformations is population-based and since 1981 has registered all cases with structural birth defects or chromosomal anomalies in the Parisian population. The total and livebirth prevalence and the proportion of cases with prenatal diagnosis were calculated for all anomalies and 20 malformations selected based on their higher frequency and their impact on health outcomes. RESULTS: The overall prevalence was 3.30% (95% CI 3.27-3.33), and the livebirth prevalence 2.42% (95% CI 2.39-2.45). The proportion of cases diagnosed prenatally increased from 16.5% (95% CI 14.1-19.1) in 1983 to 70.7% (95% CI 68.3-73.1) in 2007. Terminations of pregnancy for fetal anomaly (TOPFA) increased from 8.8% (95% CI 7.0-10.8) in 1983 to 35.6% (95% CI 33.1-38.1) in 2007. These results varied substantially for the 20 congenital anomalies studied. CONCLUSION: We found an increase in the overall prevalence of all anomalies, especially for chromosomal abnormalities. The observed increase is at least to a large extent due to trends in delayed childbearing and an increase in both pre- and postnatal diagnosis of congenital anomalies in our population. PMID- 22939648 TI - [Kawasaki disease: what's new in 2012?]. PMID- 22939649 TI - [Neonatal cellulitis caused by group B Streptococcus]. AB - Dermohypodermitis (cellulitis) in newborn infants and in infants aged up to 3 months is uncommon and often not typical. Because group B Streptococcus is known to induce rapid life-threatening complications, early diagnosis leading to emergency treatment is of utmost importance. We report on the case of a 14-day old girl, initially admitted for viral bronchiolitis with suspected bacterial pulmonary infection, in the absence of any cutaneous injury. The disease actually was cellulitis of the face, caused by group B Streptococcus. The baby presented with a severe septic clinical condition. Early treatment with antibiotics (intravenous amoxicillin for 10 days) allowed a favorable course, with rapid control of the sepsis and regression of the submandibular tumefaction. PMID- 22939650 TI - Who prescribes buprenorphine for rural patients? The impact of specialty, location and practice type in Washington State. AB - We determined the specialty, geographic location, practice type and treatment capacity of waivered clinicians in Washington State. We utilized the April 2011 Drug Enforcement Agency roster of all waivered buprenorphine prescribers and cross-referenced the data with information from the American Medical Association and online resources. Waivered physicians, as compared to Washington State physicians overall, are more likely to be primary care providers, be older, less likely to be younger than 35 years, and more likely to be female. Isolated rural areas have the lowest provider to population ratios. Ten counties lack either a buprenorphine provider or a methadone clinic. In rural areas, waivered physicians work predominately in federally-subsidized safety-net settings, which underscores the need for continued governmental support of primary care and mental health in these settings. PMID- 22939653 TI - Airborne particulate matter-associated endotoxin and proinflammatory responses. PMID- 22939654 TI - [Denial of pregnancy and neonaticide: psychopathological and clinical features]. AB - Pregnancy denial and neonaticide have recently received media coverage following a series of French cases of neonatal killing. Although it has been known for a long time that some women deny their pregnancy and may kill their newborns, there is still no consensus on the etiopathogenic factors involved in the denial of pregnancy occurrence. Even though neonaticide is often committed by young, poor, unmarried women with little or no prenatal care, it appears that denial of pregnancy is a heterogeneous condition associated with different psychological features. Societies are ambivalent with regard to mothers who killed their children and tend to lay the entire blame on them. Furthermore, there is a widespread lack of understanding among the public on these affairs, when birth control techniques and methods are widely available. The purpose of this article is to describe the different types of pregnancy denial and neonaticide and to review the still debated etiopathogenic hypotheses. The absence of the physical changes of pregnancy at the time of the denial such as cessation of menstruation, abdominal swelling or perception of foetal movements is also discussed. PMID- 22939655 TI - [Palindromic rheumatism]. AB - Palindromic rheumatism is characterized by episodes of arthritis or para arthritis leaving no residual or radiographic changes. Several diseases should be ruled out in the differential diagnosis. Evolution to rheumatoid arthritis is common, especially in patient with positive rheumatoid factor and anticitrullinated peptides. In seronegative patients, palindromic rheumatism could be part of the spectrum of autoinflammatory diseases because of a high frequency of MEFV mutations. Treatment remains discussed. The use of antimalarials could delay the development of rheumatoid arthritis or another connective tissue disease. PMID- 22939657 TI - Crisis management turns Taiwan's plasticizer nightmare into progressive policy. PMID- 22939658 TI - Molecular imaging in the management of cervical cancer. AB - Positron emission tomography (PET), magnetic resonance imaging (MRI), and integrated 18-fluorodeoxyglucose ((18)F-FDG) PET/computed tomography are valuable techniques for assessing prognosis, treatment response after the completion of concurrent chemoradiation, suspicious or documented recurrence, unexplained post therapy elevations in tumor markers, and the response to salvage treatment when managing cervical cancer. However, PET plays a limited role in the primary staging of MRI-defined node-negative patients. Currently, (18)F-FDG is still the only tracer approved for routine use, but several novel targeting PET compounds, high-Tesla MRI machines, diffusion-weighted imaging without contrast, and dynamic nuclear polarized-enhanced (13)C-MR spectroscopic imaging may hold promising applications. PMID- 22939651 TI - Atopic dermatitis results in intrinsic barrier and immune abnormalities: implications for contact dermatitis. AB - Atopic dermatitis (AD), as well as irritant contact dermatitis (ICD) and allergic contact dermatitis (ACD), are common skin diseases. These diseases are characterized by skin inflammation mediated by activated innate immunity or acquired immune mechanisms. Although AD, ICD, and ACD can be encountered in pure forms by allergists and dermatologists, patients with AD often present with increased frequency of ICD and ACD. Although a disturbed barrier alone could potentiate immune reactivity in patients with AD through increased antigen penetration, additional immune mechanisms might explain the increased susceptibility of atopic patients to ICD and ACD. This review discusses cellular pathways associated with increased skin inflammation in all 3 conditions and presents mechanisms that might contribute to the increased rate of ICD and ACD in patients with AD. PMID- 22939659 TI - Risk factors of severe novel influenza A (H1N1) infections in hospitalized children. AB - BACKGROUND/PURPOSE: Data on hospitalized novel influenza A (H1N1) infected children are limited and urgently in demand. We conducted a clinical study to identify clinical features and risk factors associated with severe novel H1N1 infections of children in Taiwan. METHODS: From July 24, 2009 to December 4, 2009, data from 61 hospitalized children infected with 2009 novel H1N1 were collected. Demographics, underlying medical conditions, clinical data, receipt of antiviral therapy, need for intensive care and outcome were analyzed to identify clinical features and risk factors of severe infections. RESULTS: Of the 61 inpatients, the male to female ratio was 41 to 20 and the most common age group was between 6 and 12 years (36%). Almost all (98%) patients had fever, 53 (87%) patients received oseltamivir treatment and 51% of them received oseltamivir within 48 hours. Fourteen (23%) needed intensive care and 3 died. Obesity (a Body Mass Index >= 25 kg/m(2) in children >= 2 years of age, or a body weight >= the 95(th) percentile in children <2 years of age), dyspnea, C-reactive protein (CRP) > 3 mg/dL, pleural effusion, and delayed antiviral therapy were significantly associated with the need for intensive care and/or death. CONCLUSION: Obesity, dyspnea, CRP > 3 mg/dL, pleural effusion, and delayed antiviral therapy are significantly associated with severe novel H1N1 infections in children. PMID- 22939660 TI - Rapid-test sensitivity for novel swine-origin pandemic influenza A. AB - BACKGROUND/PURPOSE: Rapid diagnosis of influenza was important in the global pandemic influenza A/H1N1 outbreak. The QuickVue Influenza A+B test is one of the most common tests for rapid diagnosis of influenza. We evaluated the sensitivity and specificity of the test in children. METHODS: We collected data from 970 patients with influenza-like illness who received rapid influenza antigen tests using the QuickVue Influenza A+B test as well as viral isolation. We compared the results with that of viral isolation and reverse-transcriptase polymerase chain reaction (RT-PCR) assays. RESULTS: Based on viral culture, the QuickVue Influenza A+B test had an overall sensitivity of 0.82 (419/513) and specificity of 0.99 (70/71), with a positive predictive value (PPV) of 0.74 (419/563) and a negative predictive value (NPV) of 0.77 (313/407). The sensitivity of QuickVue was significantly higher in specimens with high viral loads. If the viral loads were less than 10(6), the sensitivity of QuickVue was 0.62, while the sensitivity of QuickVue was 0.88 if the viral loads were higher than 10(6) (p<0.001). Logistic regression analysis showed that higher viral loads correlated with positive QuickVue results (p<0.001). On the first day of fever, the sensitivity of QuickVue was only 0.67; on the second day, the sensitivity was 0.86; on the third day, the sensitivity was 0.98, and on the fourth day, the sensitivity was 0.90. The sensitivity is significantly higher on days 2-3 in comparison with the first day of fever (p<0.05). We calculated the correlation of viral load and fever days, and the result showed higher mean viral load on the second and third days of fever. Age did not affect the sensitivity. CONCLUSION: In children, the sensitivity of QuickVue Influenza A+B test was 0.82. In addition, the sensitivity was significantly elevated in the higher viral load group and on the third day of fever. PMID- 22939661 TI - Seroprevalence of hepatitis virus infection in men who have sex with men aged 18 40 years in Taiwan. AB - BACKGROUND/PURPOSE: Men who have sex with men (MSM) are at increased risk for hepatitis A virus (HAV), hepatitis B virus (HBV), and hepatitis C virus (HCV) infections than the general population. Comparisons of the seroprevalence rates of these hepatitis viruses between HIV-positive and HIV-negative MSM are rarely performed in Taiwan. METHODS: Between January 2009 and June 2010, data on the serologies for HAV, HBV, and HCV were collected from two groups of patients: HIV negative MSM, aged 18-40 years, who sought voluntary counseling and testing (VCT) for HIV infection, and HIV-positive MSM of the same age group who sought HIV care at the National Taiwan University Hospital. Both groups of patients were also tested for syphilis. RESULTS: During the 18-month study period, 690 HIV-negative MSM and 438 HIV-positive MSM were enrolled and tested for anti-HAV antibody, HBV surface antigen (HBsAg), hepatitis B core antibody (anti-HBc antibody), and anti HCV antibody. HIV-positive MSM were older than HIV-negative MSM (30.5 +/- 5.4 vs. 25.8 +/- 4.7 years, p < 0.01). For HIV-positive MSM, the mean CD4 lymphocyte count was 477.6 +/- 230.0 cells/MUL and 46% of them had undetectable plasma HIV RNA load (< 40 copies/mL by reverse transcription-polymerase chain reaction assay). The overall seroprevalence rates of HAV, HBsAg, and HCV in HIV-positive MSM were 15.1%, 16.4%, and 5.5%, respectively, while in HIV-negative MSM, they were 7.4%, 6.2%, and 0.4%, respectively. In the multivariate analysis, age was significantly associated with seropositivity for HAV (OR [per one age group increase]: 1.96; 95% CI: 1.6-2.5), HBsAg (OR: 2.02; 95% CI: 1.6-2.6), anti-HBc (OR: 2.68; 95% CI: 2.3-3.2), anti-HCV (OR: 1.67; 95% CI: 1.0-2.7), and anti-HBs (OR: 1.25; 95% CI: 1.0-1.5). HIV infection was associated with seropositivity for HBsAg (OR: 1.73; 95% CI: 1.1-2.7), anti-HBc (OR: 2.44; 95% CI: 1.8-3.3), HCV (OR: 8.91; 95% CI: 2.5-31.4), and syphilis (OR: 11.21; 95% CI: 6.7-18.9). CONCLUSION: HIV-positive MSM have a higher seroprevalence rate of HBV and HCV infection than HIV-negative MSM in Taiwan. Vaccination and safe-sex counseling should be provided to prevent the transmission of hepatitis viruses among MSM who may be engaged in high-risk behaviors. PMID- 22939662 TI - Safety and efficacy of adefovir therapy for lamivudine-resistant hepatitis B virus infection in renal transplant recipients. AB - BACKGROUND/PURPOSE: The emergence of lamivudine (LAM)-resistant mutants after prolonged LAM therapy may reduce its therapeutic effects against hepatitis B virus (HBV). Adefovir dipivoxil (ADV) is an effective treatment of LAM-resistant HBV infections. However, only limited data are available regarding the safety and efficacy of ADV for treating HBsAg-positive renal transplant recipients. METHODS: Fourteen HBsAg-positive patients who underwent renal transplantation and developed the YMDD mutation after prolonged LAM therapy were retrospectively analyzed. Five patients were administered ADV monotherapy, while nine patients received ADV plus LAM combination therapy. Data on age, gender, duration of previous LAM treatment, pre-LAM HBV DNA and liver enzyme levels, duration of LAM treatment prior to the emergence of mutations, duration of ADV rescue therapy, and the clinical outcomes of treatment (i.e., normalization of alanine transaminase (ALT) and undetectable HBV DNA levels) were analyzed. RESULTS: The mean age of the patients was 46.8 +/- 11.5 years. Males were predominantly studied. The mean follow-up duration of rescue therapy was 38.2 +/- 18.3 months. At the beginning of rescue therapy, the mean serum ALT level was 142.2 +/- 99.8 IU/mL, while the median serum level of HBV DNA was 7.85 log(10) copies/mL. Patients who received combination therapy tended to demonstrate undetectable serum HBV DNA levels, but no significant differences in terms of clinical outcomes were observed between patients who received ADV monotherapy and patients who received combination therapy. After 12 months of treatment, 13 patients (92.8%) developed normalized ALT levels. Five (35.7%) and six (42.8%) patients achieved undetectable serum HBV DNA levels after 12 months and 24 months of treatment, respectively. No virological breakthroughs were observed. Twenty-nine percent of the patients developed moderate to severe renal insufficiency. CONCLUSION: Although no statistical difference was noted, ADV plus LAM combination therapy tended to demonstrate a higher therapeutic efficacy than ADV monotherapy for treating LAM-resistant HBV infection in renal transplant recipients. Renal function should be closely monitored in order to ameliorate nephrotoxicity. PMID- 22939663 TI - Impact of vaccination with seven-valent pneumococcal conjugate vaccine on virologic and immunologic outcomes among HIV-infected adult patients in the era of highly active antiretroviral therapy. AB - BACKGROUND/PURPOSE: Pneumococcal polysaccharide vaccination may be associated with adverse outcomes in HIV-infected individuals who did not receive highly active antiretroviral therapy (HAART). Our aim was to evaluate the impact of vaccination with seven-valent pneumococcal conjugate vaccine (PCV) on the short term clinical, virologic, and immunologic outcomes among HIV-infected adult patients in the HAART era. METHODS: A total of 429 HIV-infected adult patients were enrolled from October 2008 to March 2010: 213 received two doses of seven valent PCV given at a 4-week interval and 216 received one dose. All patients were given 1-week diary to record any discomfort after vaccination. Data of serial CD4 and plasma HIV RNA load measurements were recorded. RESULTS: Of the 429 patients with a mean CD4 count of 305 cells/MUL, 289 (67.4%) were receiving HAART and 175 (40.8%) had plasma HIV RNA load <40 copies/mL at vaccination. Of the 396 patients (92.3%) who returned the diary, injection site soreness (24.0%) and pain (10.4%) were the most commonly reported adverse effects. After 3-4 months of vaccination, CD4 count increased by 40 cells/MUL in 278 patients (68.2%) who continued HAART, compared with a decrease of 38 cells/MUL in 131 patients (31.8%) who were not on HAART (p < 0.001), while the respective change in plasma HIV RNA load was 0.8 versus 0.2 log(10) copies/mL (p = 0.09). One patient died, two developed opportunistic infections, and one developed pneumococcal pneumonia following vaccination. CONCLUSION: Vaccination with seven valent PCV among HIV-infected patients is generally safe, which has no detrimental effect on CD4 count and plasma HIV RNA load in patients receiving HAART. (ClinicalTrials.gov number, NCT00885628). PMID- 22939664 TI - Carbon monoxide: an old poison with a new way of poisoning. AB - We present two events of carbon monoxide (CO) poisoning, which spread out through ventilation pipes to kill or injure neighbors. This is a previously undocumented poisoning process. In the first event, three people died and eight others suffered CO poisoning from a gas-powered water heater in an apartment building. Similar to the first event, three people expired and three others were injured by CO poisoning in the second event. We subsequently determined the cause of these tragedies were due to obstructions at the openings of ventilation pipes. CO is one of the most common causes of poisoning worldwide and these cases often result in tragedy. Early recognition of CO poisoning resulting from obstructed ventilation pipes will facilitate proper management and prevent possible lethal disasters. Additionally, all clinicians and other paramedical personnel ought to raise the suspicion of chemical-related casualties when encountering clusters of patients from a single locale. PMID- 22939665 TI - Lack of resistance-associated mutations in UL54 and UL97 genes of circulating cytomegalovirus strains isolated in a medical center in Taiwan. AB - Human cytomegalovirus (HCMV) is a large DNA virus and a member of the betaherpesvirus family. HCMV infection is extremely common in human populations and can cause severe diseases in immunocompromised hosts. Ganciclovir is the most widely used antiviral drug for cytomegalovirus infection and works by blocking the amplification of HCMV. HCMV strains resistant to ganciclovir have been detected in recent decades and mainly result from mutations in UL97 (protein kinase) and UL54 (DNA polymerase) genes. In order to understand the prevalence of resistance of HCMV in Taiwan, we studied 40 clinical isolates to detect the mutations of UL97 and UL54 that might be related to resistance. The results showed that no mutation known to cause ganciclovir resistance was detected in any strain, but some polymorphisms (N685S, A688V, A885T, N898D in UL54; D605E in UL97) were frequently observed. Our results suggest that resistant HCMV strains are not prevalent in Taiwan. PMID- 22939666 TI - Single laparoscopic hepatectomy for a 11-cm hepatocellular carcinoma. PMID- 22939667 TI - What is it to grow old? PMID- 22939668 TI - Management of early neonatal infections: a work in progress. PMID- 22939669 TI - Genomic medicine steps closer to the clinic. PMID- 22939670 TI - Thalidomide and its sequelae. PMID- 22939671 TI - Women Deliver: closing the gap for reproductive and maternal health-call for papers. PMID- 22939673 TI - Herawati Sudoyo: champion of basic science in Indonesia. PMID- 22939674 TI - Pazopanib for metastatic soft-tissue sarcoma. PMID- 22939676 TI - Cash transfer scheme for reducing HIV and herpes simplex type 2. PMID- 22939678 TI - Cash transfer scheme for reducing HIV and herpes simplex type 2. PMID- 22939680 TI - Red reflex examination for retinoblastoma. PMID- 22939681 TI - Syrian public health and doctors. PMID- 22939682 TI - Reflections on the causes of forced abortion in China. PMID- 22939683 TI - One world, one health: beyond the Millennium Development Goals. PMID- 22939684 TI - The International Diabetes Federation: losing its credibility by partnering with Nestle? PMID- 22939685 TI - Mental health in the USA: no easy answers. PMID- 22939686 TI - Hip to the heart. PMID- 22939687 TI - Lipid lowering drugs and the risk of recurrent venous thromboembolism. AB - INTRODUCTION: Several studies have suggested that statins may lower the risk of venous thromboembolism (VTE), whereas fibrates may increase this risk. However, no studies have evaluated whether lipid-lowering drugs (LLD) use was associated with the risk of VTE recurrence. MATERIALS AND METHODS: In a prospective cohort study, we followed-up all patients who had been treated for a first unprovoked VTE event in our centre. The association between LLD exposure and risk of recurrence of VTE after discontinuation of anticoagulation was analyzed with Cox proportional hazards model with adjustment for age, sex, body mass index, site of thrombosis, antiplatelets use, and duration of anticoagulation before inclusion in the study. RESULTS: 432 patients (median age 65.5 years interquartile range 45.0-75.0, 174 men) were followed up for a median of 29.5 months after discontinuation of anticoagulation. Sixty patients (13.9%) had recurrent VTE. During follow-up, 48 patients (11.1%) received statins, 36 patients (8.3%) received fibrates. In multivariate analysis, the risk of recurrent VTE associated with statin exposure was 1.02 (95% confidence interval 0.36-2.91) and 2.15 (95% confidence interval 1.01-4.61) for fibrate exposure. CONCLUSION: Our results suggest an association between fibrate intake and an increased risk of recurrent VTE, whereas statin intake was not associated with recurrent VTE. Larger studies are needed to validate these results. PMID- 22939688 TI - Visualization of blood supply to the 'vascularized nerve' with anterolateral thigh flap using indocyanine green fluorescence angiography. PMID- 22939689 TI - WITHDRAWN: An evolutionary framework for culture and creativity: Selectionism versus communal exchange. AB - This article has been withdrawn at the request of the Editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy. PMID- 22939690 TI - Perinatal HIV testing and diagnosis in Illinois after implementation of the Perinatal Rapid Testing Initiative. AB - OBJECTIVE: The objective of the study was to assess whether implementation of a statewide initiative was associated with changes in perinatal human immunodeficiency virus (HIV) testing practices. STUDY DESIGN: This was an observational cohort study of all 1,141,799 women who delivered in Illinois birthing hospitals over a 7 year period after the introduction of the Perinatal Rapid Testing Implementation in Illinois (PRTII) initiative. Changes in the frequencies of HIV status documentation, rapid test utilization, and newborns discharged with unknown HIV status were assessed. RESULTS: The comparison of annual data from 2005 to 2011 demonstrated a 63% decrease in women with undocumented HIV status (11.7% vs 4.3%, P < .001), a 98% decrease in women with unknown status who did not receive rapid testing (29.6% vs 0.5%, P < .001), and a greater than 99% decrease in newborns with undocumented status at discharge (2.74% vs 0.01%, P < .001). CONCLUSION: This statewide initiative resulted in a significant and sustained increase in the frequency of maternal-baby pairs who were discharged from the hospital with documented HIV status. PMID- 22939691 TI - Cesarean section and development of the immune system in the offspring. AB - This review examines the relation between the mode of delivery and development of the immune system in the offspring. Recent epidemiological studies provide evidence that elective cesarean section (CS) is associated with aberrant short term immune responses in the newborn infant, and a greater risk of developing immune diseases such as asthma, allergies, type 1 diabetes, and celiac disease. However, it is still unknown whether CS causes a long-term effect on the immune system of the offspring that contributes to compromised immune health. With the dramatic increase in the rate of CS today, a greater emphasis should be placed on the discussion among both professionals and childbearing women on potential consequences of CS on the health of the offspring. PMID- 22939693 TI - Craniosynostosis. AB - Craniosynostosis is a complex condition, characterized by the premature fusion of one of more of the cranial sutures. They can be seen individually or as part of multisystem syndromes. This review uses computed tomography (CT) with three dimensional reconstructions to help describe some of the types and classifications of craniosynostosis, as well as describing some of the associations and the management of craniosynostosis. PMID- 22939692 TI - Near-infrared fluorescence sentinel lymph node mapping of the oral cavity in head and neck cancer patients. AB - OBJECTIVES: Elective neck dissection is frequently performed during surgery in head and neck cancer patients. The sentinel lymph node (SLN) procedure can prevent the morbidity of a neck dissection and improve lymph node staging by fine pathology. Near-infrared (NIR) fluorescence imaging is a promising technique to identify the sentinel lymph node (SLN) intraoperatively. This feasibility study explored the use of indocyanine green adsorbed to human serum albumin (ICG:HSA) for SLN mapping in head and neck cancer patients. MATERIALS AND METHODS: A total of 10 consecutive patients with oral cavity or oropharyngeal cancer and a clinical N0 neck were included. After exposure of the neck, 1.6 mL of ICG:HSA (500 MUM) was injected at four quadrants around the tumor. During the neck dissection, levels I-IV were measured for fluorescence using the Mini-FLARE imaging system. RESULTS: In all 10 patients, NIR fluorescence imaging enabled visualization of one or more SLNs. A total of 17 SLNs were identified. The mean contrast between the fluorescent signal of the lymph nodes and of the surrounding tissue was 8.7+/-6.4. In 3 patients, of which 1 was false-negative, lymph node metastases were found. After administration of ICG:HSA, the average number of fluorescent lymph nodes significantly increased over time (P<0.001). CONCLUSION: This study demonstrated feasibility to detect draining lymph nodes in head and neck cancer patients using NIR fluorescence imaging. However, the fluorescent tracer quickly migrated beyond the SLN to higher tier nodes. PMID- 22939694 TI - The emerging role of cardiovascular MRI for suspected cardioembolic stroke. AB - Stroke is a leading cause of morbidity and long-term disability worldwide and is often the result of embolic material from the heart or proximal aorta. These are referred to as cardioembolic sources of stroke. The investigation of patients with suspected cardioembolic stroke has traditionally been the mainstay of echocardiography. Cardiac magnetic resonance imaging (MRI) is a powerful imaging technique that has rapidly evolved over the last decade and is playing an ever increasing role in clinical cardiovascular imaging. This review of the literature aims to furnish the reader with an understanding of the role of cardiac MRI across the spectrum of causes of cardioembolic sources of stroke by providing the reader with an overview of the indications, technical considerations, a proposed imaging algorithm, and capabilities of this technology with selected illustrated examples of disease entities. PMID- 22939695 TI - Oxazolo[3,2-a]pyridine. A new structural scaffold for the reversal of multi-drug resistance in Leishmania. AB - Compounds belonging to three different classes of fused heterocyclic systems, structurally related to Calcium-channel blockers of the 1,4-dihydropyridine family, were evaluated in their ability to overcome leishmanial resistance to common drugs in a MDR Leishmania tropica strain. Compounds with the skeletal basis of oxazolo[3,2-a]pyridine displayed significant reversion of resistance to daunomycin and miltefosine, with reversion indexes up to 6.7-fold and 8.7-fold, respectively. Most interestingly, the enantiopure compound 20S attained to revert the resistance to both drugs and fairly more significantly than its enantiomer 20R. PMID- 22939696 TI - Phenethyl nicotinamides, a novel class of Na(V)1.7 channel blockers: structure and activity relationship. AB - The Na(V)1.7 ion channel is an attractive target for development of potential analgesic drugs based on strong genetic links between mutations in the gene coding for the channel protein and inheritable pain conditions. The (S)-N-chroman 3-ylcarboxamide series, exemplified by 1, was used as a starting point for development of new channel blockers, resulting in the phenethyl nicotinamide series. The structure and activity relationship for this series was established and the metabolic issues of early analogues were addressed by appropriate substitutions. Compound 33 displayed acceptable overall in vitro properties and in vivo rat PK profile. PMID- 22939697 TI - Synthesis, radiolabeling and initial in vivo evaluation of [(11)C]KSM-01 for imaging PPAR-alpha receptors. AB - Peroxisome proliferator-activated receptor alpha (PPAR-alpha) is a ligand activated nuclear receptor transcription factor that regulates the fatty acid beta-oxidation. An in vitro assay identified the p-methoxy phenyl ureido thiobutyric acid derivative KSM-01 (IC(50)=0.28+/-0.09nM) having a higher affinity to activate PPAR-alpha than the PPAR-alpha agonist GW7647 (IC(50)=0.46+/ 0.19nM). In this study, we report the synthesis and initial in vivo evaluation of [(11)C]KSM-01. The radiosynthesis was carried out by first alkylating the corresponding p-phenol precursor with [(11)C]MeI in DMF using NaOH, followed by deprotection of the t-butyl ester group by TFA, yielding [(11)C]KSM-01. SUV analysis of dynamic micro PET/CT imaging data showed that [(11)C]KSM-01 accumulation was ~2.0-fold greater in cardiac-specific PPAR-alpha overexpressing transgenic mice compared to wild-type littermates. The post-PET biodistribution studies were consistent with these results and demonstrated 2.5-fold greater radiotracer uptake in the heart of transgenic mice compared to the wild-type littermates. These results demonstrate the potential utility of PPAR-alpha agonists as PET radiopharmaceuticals. PMID- 22939698 TI - Three new 12-carbamoylated streptothricins from Streptomyces sp. I08A 1776. AB - Two new streptothricins (1 and 2) and a new streptothricin acid derivative (3), all with the carbamoyl group substituted at C-12 of the gulosamine moiety, together with the known N(beta)-acetylstreptothricin D acid (4), have been isolated from the culture broth of Streptomyces sp. I08A 1776. The structures of the new compounds were determined by MS, CD, and 1D and 2D NMR spectroscopic data analysis. The isolated compounds were evaluated for antibacterial and antifungal activities. Streptothricin E (6) showed potent activity against the clinically isolated extensively drug-resistant Mycobacterium tuberculosis with MIC values of 0.25-0.5MUg/mL. PMID- 22939699 TI - [Cellularity and extracellularity: the multi-fibrillar system: from cytoskeleton to connective tissue]. AB - This brief text aims at illustrating the interactions between connective tissue fibers and cell cytoskeleton fibers. These two networks are connected by molecular bridges at the level of the cell membrane of the cells of the connective and vascular tissues, allowing functional adjustments across the two domains, but also the transduction of forces and tensions into a biochemical alphabet. The signaling between the cell kern and its environment, but equally the other way round, from the environment to the core of the cell, depends on it. PMID- 22939702 TI - Rubeosis iridis as a sign of underlying carotid stenosis. AB - Severe carotid stenosis may be associated with uncommon clinical symptoms. We report a case of ocular ischemic syndrome and subsequent rubeosis iridis due to a high-grade carotid stenosis. The patient recovered visual acuity and his normal iris coloring after carotid endarterectomy. Rubeosis iridis may be the only clinical sign associated with severe carotid stenosis, making it mandatory to rule out the presence of carotid narrowing when it is detected. Establishing an early diagnosis is essential to improve quality of life, prognosis, and patients' outcome. PMID- 22939701 TI - International nursing students and what impacts their clinical learning: literature review. AB - This paper reviews the sparse literature about international nursing students' clinical learning experiences, and also draws on the literature about international higher education students' learning experiences across disciplines as well as nursing students' experiences when undertaking international clinical placements. The paper aims to identify factors that may impact international nursing students' clinical learning with a view to initiating further research into these students' attributes and how to work with these to enhance the students' clinical learning. Issues commonly cited as affecting international students are socialisation, communication, culture, relationships, and unmet expectations and aspirations. International student attributes tend to be included by implication rather than as part of the literature's focus. The review concludes that recognition and valuing of international nursing students' attributes in academic and clinical contexts are needed to facilitate effective strategies to support their clinical practice in new environments. PMID- 22939703 TI - Imaging soft matters in water with torsional mode atomic force microscopy. AB - We have developed a high-sensitivity atomic force microscopy (AFM) mode operated in aqueous environment based on the torsional resonance of the cantilever. It is found that the torsional mode can achieve a good spatial resolution even with a relatively large tip. We have used this mode to image different soft materials in water, including DNA molecules and purple membrane. High-resolution images of purple membrane can be obtained at a relatively low ion concentration under a long-range electrostatic force. Thus the torsional mode allows investigators to probe surface structures and their properties under a wide range of solution conditions. PMID- 22939700 TI - Genetic insights on sleep schedules: this time, it's PERsonal. AB - The study of circadian rhythms is emerging as a fruitful opportunity for understanding cellular mechanisms that govern human physiology and behavior, fueled by evidence directly linking sleep disorders to genetic mutations affecting circadian molecular pathways. Familial advanced sleep-phase disorder (FASPD) is the first recognized Mendelian circadian rhythm trait, and affected individuals exhibit exceptionally early sleep-wake onset due to altered post translational regulation of period homolog 2 (PER2). Behavioral and cellular circadian rhythms are analogously affected because the circadian period length of behavior is reduced in the absence of environmental time cues, and cycle duration of the molecular clock is likewise shortened. In light of these findings, we review the PER2 dynamics in the context of circadian regulation to reveal the mechanism of sleep-schedule modulation. Understanding PER2 regulation and functionality may shed new light on how our genetic composition can influence our sleep-wake behaviors. PMID- 22939704 TI - Microwave TM(010) cavities as versatile 4D electron optical elements. AB - The realization of high quality ultrashort pulsed beams requires ultrafast time dependent electron optics. We present derivations of closed expressions both for the longitudinal and transverse focusing powers of resonant microwave TM010 cavities. The derived expressions are validated by particle tracking simulations using realistic cavity fields. For small field amplitudes, in which case the "weak lens" approximation holds, the focusing powers obtained from simulations are in good agreement with the derived expressions. Furthermore, the required phase and temperature stability for synchronization of electron bunches generated by femtosecond photoemission are discussed. PMID- 22939705 TI - [The right ventricle in heart surgery]. PMID- 22939706 TI - When and where plant cells divide: a perspective from computational modeling. AB - Computational modeling of growing plant tissues raises two basic questions about plant cell division: when does a cell decide to divide and where is the new wall placed? Although biologists and modelers commonly assume that a cell divides after it reaches a threshold size, two recent experiments show that models with variable division sizes better replicate the tissue. Similarly, comparing model predictions with living plant cells reveals that the choice of division plane is variable, although the shortest path dividing a cell in half (i.e. the minimal surface area) is the most probable division plane. PMID- 22939707 TI - Does phase angle correlate with hyperhomocysteinemia? A study of patients with classical homocystinuria. AB - The role of the phase angle in hyperhomocysteinemia has yet to be assessed. Classical homocystinuria is a rare genetic disease characterized by severe hyperhomocysteinemia, as well as increased levels of methionine and reduced levels of cysteine. The objective of this study was to investigate the potential relationship between phase angle and homocysteine, cysteine, and methionine levels in patients with classical homocystinuria. Eight patients were included in the study. Phase angle was measured with a tetrapolar bioimpedance analyzer. Serum homocysteine, cysteine, and methionine levels were measured by HPLC. Only three patients had adequate metabolic control of their disease. Median phase angle was 5.9 degrees (range = 5.4 degrees -8.5 degrees ). There was a significant correlation between phase angle and levels of homocysteine (r = 0.807, p = 0.015), methionine (r = -0.711, p = 0.048), and cysteine (r = 0.836, p = 0.010). Was also positively correlated with BMI and arm muscle circumference (p < 0.05). Two patients had phase angles below the 5th percentile, and only one above the 50th percentile. Our findings suggest that cellular integrity is affected in patients with high homocysteine levels, thus indicating that phase angle could be a valuable indicator of prognosis and classical homocystinuria. It also suggests a role for this indicator in other forms of hyperhomocysteinemia and other inborn errors of metabolism. PMID- 22939708 TI - [100 years of x-ray interference]. PMID- 22939709 TI - Assessing the impact of scaling-up bednet coverage through agricultural loan programmes: evidence from a cluster randomised controlled trial in Katete, Zambia. AB - To investigate the effectiveness of scaling-up existing bednet distribution campaigns, a randomised controlled trial with 516 farming households in Katete District, a rural area with highly endemic malaria in Zambia's Eastern Province, was evaluated. In the trial, selected farmers were assigned to bednet programmes that allowed them to obtain additional bednets for free or at subsidised prices through agricultural loan programmes. On average, 2.4 nets were distributed in the free distribution group and 0.9 in the net loan group. The marginal health impact of additional nets appears large, reducing the odds of self-reported all cause morbidity by 40-42% and the odds of self-reported confirmed malaria by 53 60%. PMID- 22939710 TI - Helminth transmission in simple pit latrines. AB - Simple pit latrines often represent the cheapest form of sanitation for poor communities. However, simple latrines lack a concrete slab and are therefore classified as an unimproved form of sanitation. This study collected soil samples in simple pit latrines and analysed them for the presence of helminth eggs; 71% of all collected samples were positive for eggs. The absence of a roof from the latrine was the only factor associated with lower egg concentrations. The findings support the classification of simple pit latrines as an unimproved form of sanitation. PMID- 22939711 TI - Role of enterocytes in dyslipidemia of insulin-resistant states. AB - The increase in cardiovascular morbidity and mortality associated to insulin resistance (IR) states (obesity, metabolic syndrome, type 2 diabetes) represents a major public health problem. In IR, dyslipidemia typically include hypertriglyceridemia, low high density lipoprotein cholesterol, increased small and dense low density lipoprotein particles, and post-prandial hyperlipidemia, which play a direct or indirect role in the mechanisms of atherosclerosis. Dyslipidemia is mainly due to accumulation of circulating triglyceride-rich lipoproteins from the liver and bowel. The bowel has traditionally been seen as a passive organ, but current evidence confirms that it is an active organ subject to regulation by free fatty acids, insulin, incretins, and inflammation. Two new concepts have emerged: intestinal IR and overproduction of chylomicrons in hyperinsulinemic/IR states. A better understanding of intestinal IR may make the enterocyte a therapeutic target. PMID- 22939712 TI - Lorcaserin approval in the United States: paving the way? PMID- 22939714 TI - The safety of adjuvants in influenza vaccines during pregnancy: what do we know and why do we need them? PMID- 22939713 TI - Systems genetics of metabolism: the use of the BXD murine reference panel for multiscalar integration of traits. AB - Metabolic homeostasis is achieved by complex molecular and cellular networks that differ significantly among individuals and are difficult to model with genetically engineered lines of mice optimized to study single gene function. Here, we systematically acquired metabolic phenotypes by using the EUMODIC EMPReSS protocols across a large panel of isogenic but diverse strains of mice (BXD type) to study the genetic control of metabolism. We generated and analyzed 140 classical phenotypes and deposited these in an open-access web service for systems genetics (www.genenetwork.org). Heritability, influence of sex, and genetic modifiers of traits were examined singly and jointly by using quantitative-trait locus (QTL) and expression QTL-mapping methods. Traits and networks were linked to loci encompassing both known variants and novel candidate genes, including alkaline phosphatase (ALPL), here linked to hypophosphatasia. The assembled and curated phenotypes provide key resources and exemplars that can be used to dissect complex metabolic traits and disorders. PMID- 22939715 TI - Quality patient care in labor and delivery: a call to action. PMID- 22939717 TI - Safety of MF59-adjuvanted A/H1N1 influenza vaccine in pregnancy: a comparative cohort study. AB - OBJECTIVE: The 2009-2010 A/H1N1 pandemic provided a unique setting to study the safety of MF59-adjuvanted vaccination in pregnancy. STUDY DESIGN: This was an observational cohort study of the safety of an MF59-adjuvanted A/H1N1 vaccine (Focetria) conducted among 4508 pregnant women (2295 vaccinated vs 2213 unvaccinated), with 3 month follow-up of neonates. RESULTS: No maternal deaths or abortions occurred among the vaccinated women. No differences between the vaccinated and unvaccinated cohorts were observed for gestational diabetes, preeclampsia, stillbirth, low birthweight, neonatal deaths, or congenital malformations. The risk of premature birth was significantly decreased among the vaccinated women (adjusted proportional hazard, 0.69; 95% confidence interval, 0.51-0.92). No differences were observed in rates of congenital malformations after vaccination in the first (2.1%), second (2.7%), or third (2.1%) trimesters. CONCLUSION: There was no evidence of a safety risk for MF59-adjuvanted A/H1N1 vaccination in pregnant women; protection was observed against premature birth. PMID- 22939718 TI - Strenuous exercise during pregnancy: is there a limit? AB - OBJECTIVE: The purpose of this study was to evaluate fetal responses to strenuous exercise in physically active and inactive women. STUDY DESIGN: Forty-five healthy women (15 who were nonexercisers, 15 who were regularly active, 15 who were highly active) underwent a peak treadmill test at 28 weeks' gestation to 32 weeks 6 days' gestation. Fetal well-being (umbilical artery Doppler indices, fetal heart tracing/rate, biophysical profile [BPP]) was evaluated before and after exercise. Uterine artery Doppler scans were also obtained. RESULTS: Umbilical and uterine artery Doppler indices were similar among activity groups and did not change with exercise (P > .05). BPP and fetal heart tracings were reassuring in all groups. However, subgroup analyses showed transient fetal heart rate decelerations after exercise and elevated umbilical and uterine artery Doppler indices in 5 highly active women. After this, BPP and fetal heart tracings were reassuring. CONCLUSION: Overall fetal well-being is reassuring after short-duration, strenuous exercise in both active and inactive pregnant women. A subset of highly active women experienced transient fetal heart rate decelerations and Doppler changes immediately after exercise. Athletes may push beyond a threshold intensity at which fetal well-being may be compromised. However, potential impact on neonatal outcomes is unknown. PMID- 22939719 TI - Oxytocin and catechol-O-methyltransferase receptor genotype predict the length of the first stage of labor. AB - OBJECTIVE: We aimed to identify genetic factors that influence the rate of the first stage of labor. STUDY DESIGN: We prospectively enrolled 233 laboring nulliparous parturients. Demographic, clinical, and genetic data were collected. We evaluated the influence of population and individual variability using a nonlinear mixed effects model. RESULTS: Parturients who were homozygous for "G" at oxytocin receptor gene rs53576 transitioned to active labor later and thus had slower labor. Catechol-O-methyltransferase rs4633 genotype TT was associated with slower latent phase labor. Labor induction with prostaglandin was associated with faster labor, and request for meperidine was associated with slower labor. Birthweight was related inversely to the rate of the active phase. CONCLUSION: There are demographic, clinical, and genetic factors that influence an individual's rate of labor progress. This information could be used in automated form to improve the prediction of the length of the first stage of labor. PMID- 22939720 TI - Trends in planned early birth: a population-based study. AB - OBJECTIVE: The purpose of this study was to describe trends and outcomes of planned births. STUDY DESIGN: Data from linked birth and hospital records for 779,521 singleton births at >=33 weeks' gestation from 2001-2009 were used to determine trends in planned births (prelabor cesarean section and labor inductions). Adverse outcomes were composite indicators of maternal and neonatal morbidity/death. RESULTS: From 2001-2009, there were increases in labor inductions and prelabor cesarean deliveries at <40 weeks' gestation, but no decrease in the stillbirth rate (trend P = .34). By 2009, 14.9% of live births at >=33 weeks' gestation were prelabor cesarean deliveries before the due date; 11.4% were inductions. As planned births increased, maternal risks shifted, which included a decline in inductions with maternal hypertension from 31.9-23.9%. Earlier birth was contemporaneous with increases (trend P < .001) in neonatal and maternal morbidity rates from 3.0-3.2% and 1.1-1.5%, respectively. CONCLUSION: Planned birth before the due date is increasing without a contemporaneous reduction of stillbirths. PMID- 22939721 TI - Abnormal vascular architecture at the placental-maternal interface in placenta increta. AB - OBJECTIVE: The objective of the study was to characterize the vascular architecture at the placental-maternal interface in pregnancies complicated by placenta increta and normal pregnancies. STUDY DESIGN: Vessel numbers and cross section area density and spatial and area distributions in 13 placenta-increta placental beds were compared with 9 normal placental beds using computer-assisted image analysis of whole-slide CD31 immunolabeled sections. RESULTS: The total areas occupied by vessels in normal and placenta-increta placental beds were comparable, but vessels were significantly sparser and larger in the latter. Moreover, placenta-increta-vessel distributions (area and distance from the placental-myometrial junction) were more heterogeneous. CONCLUSION: Size and spatial organization of the placenta-increta vascular architecture at the placental-maternal interface differed from normal and might partially explain the severe hemorrhage observed during placenta-increta deliveries. PMID- 22939722 TI - Impact of chorionicity on risk and timing of intrauterine fetal demise in twin pregnancies. AB - OBJECTIVE: We sought to estimate the association between chorionicity and intrauterine fetal demise (IUFD) of one or both fetuses in twin pregnancies. STUDY DESIGN: In a retrospective cohort of twins undergoing anatomic survey, risk of IUFD in monochorionic and dichorionic twins was compared. The primary outcome was IUFD of one or both fetuses; secondary outcomes included nonanomalous fetal deaths. RESULTS: Of 2161 twin pregnancies meeting inclusion criteria, 86 had at least 1 IUFD and 32 experienced a double fetal loss. Monochorionic pregnancies had an increased risk of a single demise (adjusted odds ratio, 1.69; 95% confidence interval, 1.04-2.75) and a double demise (adjusted odds ratio, 2.11; 95% confidence interval, 1.02-4.37). Of all double demises, 70% occurred <24 weeks. CONCLUSION: Monochorionic twins carry an increased risk of fetal death compared to dichorionic twins. Double demise occurs primarily <24 weeks, regardless of chorionicity. PMID- 22939724 TI - Laparoscopic versus open radical hysterectomy for elderly patients with early stage cervical cancer. AB - OBJECTIVE: We sought to compare surgical and survival outcomes of laparoscopic radical hysterectomy (LRH) vs open radical hysterectomy (ORH) in elderly patients with early-stage cervical cancer. STUDY DESIGN: A retrospective analysis was performed on elderly patients (>=65 years) who underwent either LRH (n = 99) or ORH (n = 159) due to stage IA2-IIA2 cervical cancer. RESULTS: One patient (1%) in LRH group required conversion to laparotomy. Operating time (P = .035), estimated blood loss (P = .002), recovery of bowel movement (P < .001), and postoperative hospital stay (P < .001) were significantly shorter or lower in LRH group. Postoperative complications were significantly less frequent in LRH group (P = .026). After the median follow-up time of 45 months, the 5-year disease-free survival (95% vs 93%, P = .350) and overall survival (96% vs 95%, P = .361) did not differ between LRH and ORH groups. CONCLUSION: Elderly patients tolerated well both LRH and ORH. LRH was associated with better surgical outcomes compared to ORH without increasing intraoperative complications or decreasing survival. PMID- 22939723 TI - Brain damage in preterm newborns and maternal medication: the ELGAN Study. AB - OBJECTIVE: We sought to evaluate the association between maternal medication use during pregnancy and cerebral white matter damage and cerebral palsy (CP) among very preterm infants. STUDY DESIGN: This analysis of data from the Extremely Low Gestational Age Newborns (ELGAN) Study included 877 infants born <28 weeks' gestation. Mothers were interviewed, charts were reviewed, placentas were cultured and assessed histologically, and children were evaluated at 24 months corrected age. A diagnostic algorithm classified neurologic findings as quadriparetic CP, diparetic CP, hemiparetic CP, or no CP. RESULTS: After adjustment for the potential confounding of disorders for which medications might have been indicated, the risk of quadriparetic CP remained elevated among the infants of mothers who consumed aspirin (odds ratio [OR], 3.0; 95% confidence interval [CI], 1.3-6.9) and nonsteroidal antiinflammatory drugs (NSAIDs) (OR, 2.4; 95% CI, 1.04-5.8). The risk of diparetic CP was also associated with maternal consumption of an NSAID, but only if the consumption was not approved by a physician (OR, 3.5; 95% CI 1.1-11.0). CONCLUSION: The possibility that aspirin and NSAID use in pregnancy could lead to perinatal brain damage cannot be excluded. PMID- 22939725 TI - A nomogram for predicting lymph node metastasis of presumed stage I and II endometrial cancer. AB - OBJECTIVE: Our objective was to develop a nomogram based on pathological hysterectomy characteristics to provide a more individualized and accurate estimation of lymph node metastasis in endometrial cancer. STUDY DESIGN: Data from the Surveillance, Epidemiology, and End Results database for 18,294 patients who underwent hysterectomy and lymphadenectomy were analyzed. A multivariate logistic regression analysis of selected prognostic features was performed, and a nomogram to predict lymph node metastasis was constructed. A cohort of 434 patients was used for the external validation. RESULTS: The nomogram showed good discrimination with an area under the receiver operating characteristic curve of 0.80 (95% confidence interval, 0.79-0.81) in the training set and 0.79 (95% confidence interval, 0.78-0.80) in the validation set. The nomogram was well calibrated. CONCLUSION: We developed a nomogram based on 5 clinical and pathological characteristics to predict lymph node metastasis with a high concordance probability. PMID- 22939727 TI - Trial of labor versus repeat cesarean: are patients making an informed decision? AB - OBJECTIVE: Most women eligible for a trial of labor after a cesarean (TOLAC) undergo an elective repeat cesarean section (ERCS). We hypothesized that this is largely because of poor patient education. STUDY DESIGN: This was a prospective study of women who presented to our hospital from November 2010 through July 2011 who were candidates for TOLAC. Women filled out a questionnaire prior to their scheduled ERCS or upon admission for TOLAC. A chi(2) and a Student t test were used, as appropriate. RESULTS: The study included 155 women, 87 for TOLAC and 68 for ERCS. Women in both groups demonstrated a lack of knowledge on the risks and benefits of TOLAC and ERCS. When patients perceived their providers as having a preference for ERCS, very few chose TOLAC, whereas the majority chose TOLAC if this was their provider's preference. CONCLUSION: Candidates for TOLAC appear to know little about the risks and benefits associated with their mode of delivery, and provider preference affects this choice. PMID- 22939728 TI - Association and prediction of neonatal acidemia. AB - OBJECTIVE: The objective of this study was to estimate the predictive ability of electronic fetal monitoring (EFM) patterns immediately prior to delivery for acidemia at term birth. STUDY DESIGN: This was a 4-year retrospective cohort study of 5388 consecutive singleton, nonanomalous gestations of 37 weeks or longer. The primary exposure was the EFM pattern in the 30 minutes preceding delivery. EFM patterns were prospectively interpreted using Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) nomenclature as well as non-NICHD measurements of decelerations. The primary outcome was umbilical cord arterial pH of 7.10 or less. RESULTS: Four NICHD defined EFM features within the 30 minutes prior to birth demonstrated the greatest association with acidemia: repetitive prolonged decelerations (area under the curve [AUC] 0.81), baseline tachycardia (AUC 0.80), repetitive variable decelerations (AUC 0.79), and repetitive late decelerations (0.78) after adjusting for nulliparity, fever, prolonged first stage, and obesity. A non-NICHD measure, total deceleration area, demonstrated superior predictive ability for acidemia (AUC 0.83, P = .04). CONCLUSION: A non-NICHD measure of deceleration frequency and severity in the second stage performed superior to 4 NICHD EFM features for predicting fetal acidemia. PMID- 22939726 TI - Growth and insulin dynamics in two generations of female offspring of mothers receiving a single course of synthetic glucocorticoids. AB - OBJECTIVE: Synthetic glucocorticoid administration to women threatening preterm delivery increases neonatal survival. However, mounting evidence shows that fetal exposure to glucocorticoid levels higher than appropriate for current maturation adversely programs offspring development. We examined fetal synthetic glucocorticoid multigenerational metabolic effects on F1 and F2 female offspring. STUDY DESIGN: At 0.7 gestation, pregnant F0 ewes received 4 injections of dexamethasone (2 mg, approximately 60 ug.kg(-1) day(-1) 12 hours apart) or saline (control). F1 female offspring were bred to produce F2 female offspring. Postpubertal pancreatic beta-cell function was tested in F1 and F2 by intravenous glucose tolerance test. RESULTS: F1 and F2 ewe lambs showed reduced birthweight and morphometrics, and similar increased fasting glucose and decreased intravenous glucose tolerance test beta-cell response. CONCLUSION: This is the first demonstration of multigenerational programming of later life beta-cell response by clinically relevant doses of synthetic glucocorticoid indicating the need for study of long-term effects of fetal exposure to synthetic glucocorticoid. PMID- 22939729 TI - Can statins reduce the inflammatory response associated with preterm birth in an animal model? AB - OBJECTIVE: The objective of the study was to determine the effect of statins on lipopolysaccharide (LPS)-induced inflammatory response in a mouse model of preterm birth (PTB). STUDY DESIGN: Day 15 CD1 mice were randomly allocated to intraperitoneal LPS injection (100 MUg) or control. Mice in the LPS group were pretreated, 16 and 2 hours prior, with pravastatin (10 MUg/g), simvastatin (10 MUg/g), or vehicle control. Animals were sacrificed 6 hours after LPS. Cytokine messenger ribonucleic acid (mRNA) expression in the uterus and cervix, and concentrations in the maternal serum and amniotic fluid (AF) were determined. RESULTS: Pravastatin reduced interleukin (IL)-1beta and IL-6 mRNA expression in the uterus and cervix, respectively, and serum IL-1beta and granulocyte macrophage colony-stimulating factor (GM-CSF) concentrations. Simvastatin reduced IL-1beta and IL-6 mRNA expressions in the uterus, IL-6 and tumor necrosis factor alpha (TNF-alpha) in the cervix, and IL-1beta, IL-2, IL-12p70, IL-13, TNF-alpha, GM-CSF, and interferon-gamma concentrations in the serum and IL-6 in AF. CONCLUSION: Statins reduce the LPS-induced inflammatory responses in a mouse model of PTB. PMID- 22939730 TI - Antenatal lamivudine to reduce perinatal hepatitis B transmission: a cost effectiveness analysis. AB - OBJECTIVES: This study aimed to determine whether administration of lamivudine to pregnant women with chronic hepatitis B in the third trimester is a cost effective strategy in preventing perinatal transmission. STUDY DESIGN: We developed a decision analysis model to compare the cost-effectiveness of 2 management strategies for chronic hepatitis B in pregnancy: (1) expectant management or (2) lamivudine administration in the third trimester. We assumed that lamivudine reduced perinatal transmission by 62%. RESULTS: Our Markov model demonstrated that lamivudine administration is the dominant strategy. For every 1000 infected pregnant women treated with lamivudine, $337,000 is saved and 314 quality-adjusted life-years are gained. For every 1000 pregnancies with maternal hepatitis B, lamivudine prevents 21 cases of hepatocellular carcinoma and 5 liver transplants in the offspring. The model remained robust in sensitivity analysis. CONCLUSION: Antenatal lamivudine administration to pregnant patients with hepatitis B is cost-effective, and frequently cost-saving, under a wide range of circumstances. PMID- 22939731 TI - Comparison of 12-hour urine protein and protein:creatinine ratio with 24-hour urine protein for the diagnosis of preeclampsia. AB - OBJECTIVE: The purpose of this study was to evaluate the performance of the 12 hour urine protein >165 mg and protein:creatinine ratio >0.15 for the prediction of 24-hour urine protein of >=300 mg in patients with suspected preeclampsia. STUDY DESIGN: We performed a prospective observational study of 90 women who had been admitted with suspected preeclampsia. Protein:creatinine ratio and 12- and 24-hour urine specimens were collected for each patient. Test characteristics for the identification of 24-hour urine protein >=300 mg were calculated. RESULTS: A 12-hour urine protein >165 mg and protein:creatinine ratio of >0.15 correlated significantly with 24-hour urine protein >=300 mg (r = 0.99; P < .001; and r = 0.54; P < .001, respectively). A 12-hour urine protein >165 mg performed better than protein:creatinine ratio as a predictor of a 24-hour urine protein >=300 mg (sensitivity, 96% and 89%; specificity, 100% and 49%; positive predictive value, 100% and 32%; negative predictive value, 98% and 91%, respectively). CONCLUSION: The high correlation of a 12-hour urine protein >165 mg with a 24-hour urine protein >=300 mg (with the benefit of a shorter evaluation time) and the high negative predictive value of protein:creatinine ratio suggest that the use of both these tests have a role in the evaluation and treatment of women with suspected preeclampsia. PMID- 22939732 TI - Discussion: 'vitamin D deficiency in pregnancy and gestational diabetes,' by Burris et al. AB - In the roundtable that follows, clinicians discuss a study published in this issue of the Journal in light of its methodology, relevance to practice, and implications for future research. Article discussed: Burris HH, Rifas-Shiman SL, Kleinman K, et al. Vitamin D deficiency in pregnancy and gestational diabetes. Am J Obstet Gynecol 2012;207:182.e1-8. PMID- 22939733 TI - A face inversion effect without a face. AB - Numerous studies have attributed the face inversion effect (FIE) to configural processing of internal facial features in upright but not inverted faces. Recent findings suggest that face mechanisms can be activated by faceless stimuli presented in the context of a body. Here we asked whether faceless stimuli with or without body context may induce an inversion effect as large as the FIE. In Study 1 participants performed a sequential matching task for upright and inverted faces, faceless heads with full, minimal or no body context, headless bodies and bodies viewed from the back. Results show inversion effects as large as the FIE for faceless heads with full or minimal body context, but not for faceless heads without body context, headless bodies or bodies viewed from the back. These findings remarkably show that in contrast to the well-established configural explanation for the FIE, the FIE does not necessarily depend on the processing of internal facial features, but can be also triggered for faceless stimuli presented in body context. In Study 2 participants rated the extent to which they detected a face in stimuli presented with or without faces briefly followed by a mask. We found that faceless stimuli that generated a large inversion effect were rated higher for the existence of a face than faceless stimuli that generated small or no inversion effects. These findings further suggest that the FIE can be generated by a contextually induced face percept at the face detection stage rather than the face identification stage. PMID- 22939734 TI - Perceptual, categorical, and affective processing of ambiguous smiling facial expressions. AB - Why is a face with a smile but non-happy eyes likely to be interpreted as happy? We used blended expressions in which a smiling mouth was incongruent with the eyes (e.g., angry eyes), as well as genuine expressions with congruent eyes and mouth (e.g., both happy or angry). Tasks involved detection of a smiling mouth (perceptual), categorization of the expression (semantic), and valence evaluation (affective). The face stimulus display duration and stimulus onset asynchrony (SOA) were varied to assess the time course of each process. Results indicated that (a) a smiling mouth was visually more salient than the eyes both in truly happy and blended expressions; (b) a smile led viewers to categorize blended expressions as happy similarly for upright and inverted faces; (c) truly happy, but not blended, expressions primed the affective evaluation of probe scenes 550 ms following face onset; (d) both truly happy and blended expressions primed the detection of a smile in a probe scene by 170 ms post-stimulus; and (e) smile detection and expression categorization had similar processing thresholds and preceded affective evaluation. We conclude that the saliency of single physical features such as the mouth shape makes the smile quickly accessible to the visual system, which initially speeds up expression categorization regardless of congruence with the eyes. Only when the eye expression is later configurally integrated with the mouth, will affective discrimination begin. The present research provides support for serial models of facial expression processing. PMID- 22939735 TI - Picasso in the mind's eye of the beholder: three-dimensional filling-in of ambiguous line drawings. AB - Cartoon-style line drawings contain very condensed information, after all most of the page stays blank. Yet, they constrain the contents of immediate visual awareness to an extraordinary extent. This is true even for drawings that are - though nominally "representational" - not even in central projection. Moreover, the strokes used in a drawing may stand for a bewildering variety of entities in the world. We studied Picasso drawings from the 1940s in which the artist famously combined multiple viewpoints. We find that the pictorial reliefs obtained from various observers agree to a large extent, and that the differences are of a very specific nature, typically involving variations in the mutual spatial attitudes of rigid body parts in figure studies. Although the purely planar layout of the drawings accounts for much of visual awareness, observers also use the sparse depth cues provided by the artist to evoke volumetric impressions. Observers also freely insert "template knowledge" about the structure of familiar generic objects. PMID- 22939736 TI - Induction and repair of DNA double-strand breaks using constant-field gel electrophoresis and apoptosis as predictive markers for sensitivity of cancer cells to cisplatin. AB - This study was designed to evaluate some parameters that may play a role in the prediction of cancer cells sensitivity to cisplatin (CIS). Sensitivity, induction and repair of DNA double-strand breaks (DSB), cell cycle regulation and induction of apoptosis were measured in four cancer cell lines with different sensitivities to CIS. Using a sulphorhodamine-B assay, the cervical carcinoma cells (HeLa) were found to be the most sensitive to CIS followed by breast carcinoma cells (MCF-7) and liver carcinoma cells (HepG2). Colon carcinoma HCT116 cells were the most resistant. As measured by constant-field gel electrophoresis (CFGE), DSB induction, but not residual DSB exhibited a significant correlation with the sensitivity of cells to CIS. Flow cytometric DNA ploidy analysis revealed that 67% of HeLa cells and 10% of MCF-7 cells shift to sub-G1 phase after incubation with CIS. Additionally, CIS induced the arrest of MCF-7 cells in S-phase and the arrest of HepG2 and HCT116 cells in both S phase and G2/M phase. Determination of the Fas-L level and Caspase-9 activity indicated that CIS-induced apoptosis results from the mitochondrial (intrinsic) pathway. These results, if confirmed using clinical samples, indicate that the induction of DNA DSB as measured by CFGE and the induction of apoptosis should be considered, along with other predictive markers, in future clinical trials to develop predictive assays for platinum -based therapy. PMID- 22939737 TI - A pose-independent method for 3D face landmark formalization. AB - Recently, 3D landmark extraction has been widely researched and experimented in medical field, for both corrective and aesthetic purposes. Automation of these procedures on three-dimensional face renderings is something desirable for the specialists who work in this field. In this work we propose a new method for accurate landmark localization on facial scans. The method relies on geometrical descriptors, such as curvatures and Shape Index, for computing candidate and initial points, and on a statistical model based on Procrustes Analysis and Principal Component Analysis, which is fitted to candidate points, for extracting the final landmarks. The elaborated method is independent on face pose. PMID- 22939738 TI - The Spanish Lung Transplant Registry: first report of results (2006-2010). AB - The Spanish Lung Transplant Registry (SLTR) began its activities in 2006 with the participation of all the lung transplantation (LT) groups with active programs in Spain. This report presents for the first time an overall description and results of the patients who received lung transplants in Spain from 2006 to 2010. LT activity has grown progressively, and in this time period 951 adults and 31 children underwent lung transplantation. The mean age of the recipients was 48.2, while the mean age among the lung donors was 41.7. In adult LT, the most frequent cause for lung transplantation was emphysema/COPD, followed by idiopathic pulmonary fibrosis, both representing more than 60% the total number of indications. The probability for survival after adult LT to one and three years was 72% and 60%, respectively, although in patients who survived until the third month post-transplantation, these survival rates reached 89.7% and 75.2%. The factors that most clearly influenced patient survival were the age of the recipient and the diagnosis that indicated the transplantation. Among the pediatric transplantations, cystic fibrosis was the main cause for transplantation (68%), with a one-year survival of 80% and a three-year survival of 70%. In adult as well as pediatric transplantations, the most frequent cause of death was infection. These data confirm the consolidated situation of LT in Spain as a therapeutic option for advanced chronic respiratory disease, both in children as well as in adults. PMID- 22939739 TI - [Tuberculosis and immigration: a remaining challenge for public health]. PMID- 22939740 TI - Management of patients in a dedicated burns intensive care unit (BICU) in a developing country. AB - BACKGROUND: In Pakistan the practice of managing extensive burns in dedicated intensive care units is not well established. This audit aims to define the characteristics of the victims of major burns and factors that increase mortality and outcome of the protocol-based management in a dedicated burns intensive care unit (BICU). PATIENTS AND METHODS: This prospective audit included all patients admitted to the BICU of Suleiman Dawood Burns Unit in Karachi from 1st September 2002 to 31st August 2011. Demographic information, type and place of burn, total body surface area burn (TBSA), type of organ support provided, length of ICU stay, any associated medical diseases, and out outcome were documented. RESULTS: A total of 1597 patients were admitted to the BICU in 9 years. Median age of the patients was 22 (IQR =32-7). 32% victims were children <14 years and only 7% were >50 years old. Male to female ratio was 1.4:1. Fire was the leading cause of burns in adults (64%) and scald burns were most common in (64%) in children. 72.4% of the accidents happened at home, where kitchen was the commonest location (597 cases). Mean TBSA burnt was 32.5% (SD +/- 22.95%, 95%CI: 31.36-33.61). 27% patients needed ventilatory support, 4% were dialyzed and split skin graftings were performed in 20% patients. Average length of ICU stay was 10.42 days. Epilepsy, psychiatric illness and drug addiction were not common associations with burns. Overall mortality was 41.30% but it decreased over the years from 75% to 27%. CONCLUSIONS: Groups of people most vulnerable to sustain burn are young females getting burnt in the kitchen, young males getting burnt at work, and small children falling in pots of hot water stored for drinking or bathing. TBSA >40%, age >50 years, fire burn and female gender were associated with a higher risk of death. Carefully planned, protocol based management of burn patients by burn teams of dedicated healthcare professionals, even with limited resources reduced mortality. RECOMMENDATIONS: Burn hazard awareness, prevention and educational programmes targeted at the vulnerable population, i.e. women and young children at home and men at their work place is the single most cost effective way of reducing the incidence of burns in developing countries. PMID- 22939741 TI - Pre-procedural flow-mediated dilation associated to arterial spasm during transulnar coronary angiography and interventions. PMID- 22939742 TI - Lessons from C. elegans: signaling pathways for longevity. AB - Recent research using model organisms such as the nematode Caenorhabditis elegans has highlighted a crucial role for several conserved signaling pathways in longevity determination. Here, we review three major endocrine- and nutrient sensing signaling pathways with influence on lifespan, the insulin/insulin-like growth factor (IGF), target of rapamycin (TOR), and germline signaling pathways. Although these pathways engage distinct sets of transcription factors, the three pathways appear to modulate aging in C. elegans through partially overlapping effector mechanisms, including lipid metabolism and autophagy. This review highlights the latest advances in our understanding of how the insulin/IGF-1, TOR, and germline signaling pathways utilize different transcription factors to modulate aging in C. elegans with special emphasis on the role of lipid metabolism and autophagy. PMID- 22939744 TI - Meta-analysis of trials comparing laparoscopic transperitoneal and retroperitoneal adrenalectomy. AB - BACKGROUND: Laparoscopic adrenalectomies are being performed increasingly, either with transperitoneal or retroperitoneal approaches. Studies comparing the 2 approaches have not shown the superiority of either technique, but these studies are limited by small sample sizes and single-institution designs. To overcome these limitations, we performed a meta-analysis of studies comparing lateral transperitoneal adrenalectomy and retroperitoneal adrenalectomy. METHODS: A systematic review of studies comparing lateral transperitoneal adrenalectomy and retroperitoneal adrenalectomy was conducted. Study endpoints included perioperative outcomes and measures of postoperative recovery. Meta-analysis was performed using a random effects model, pooling variables evaluated by more than 3 studies. RESULTS: Twenty-one studies comparing a total of 1,205 lateral transperitoneal adrenalectomies and 688 retroperitoneal adrenalectomies were suitable for meta-analysis. Patients in the 2 groups were similar in term of age, sex, body mass index, lesion size and location, and rates of malignancy. There were no statistically significant differences between lateral transperitoneal adrenalectomy and retroperitoneal adrenalectomy in terms of operative time, blood loss, hospital stay, time to oral intake, overall and major morbidity, and mortality. CONCLUSION: Both lateral transperitoneal adrenalectomy and retroperitoneal adrenalectomy are associated with very low rates of perioperative complications. According to our meta-analysis, clinical outcomes after either technique are similar. For most adrenal lesions requiring operation, minimally invasive adrenalectomy can be performed safely and effectively with either transperitoneal or the retroperitoneal approach. Additional studies may be needed to analyze if any difference in long-term results exist. PMID- 22939743 TI - Metabolic master regulators: sharing information among multiple systems. AB - Obesity and diabetes are caused by defects in metabolically sensitive tissues. Attention has been paid to insulin resistance as the key relevant pathosis, with a detailed focus on signal transduction pathways in metabolic tissues. Evidence exists to support an important role for each tissue in metabolic homeostasis and a potential causative role in both diabetes and obesity. The redox metabolome, that coordinates tissue responses and reflects shared control and regulation, is our focus. Consideration is given to the possibility that pathosis results from contributions of all relevant tissues, by virtue of a circulating communication system. Validation of this model would support simultaneous regulation of all collaborating metabolic organs through changes in the circulation, regardless of whether change was initiated exogenously or by a single organ. PMID- 22939745 TI - Prospective determination of percutaneous endoscopic gastrostomy complication rates in children: still a safe procedure. AB - BACKGROUND: Percutaneous endoscopic gastrostomy (PEG) placement in children has come under scrutiny with reports of improved safety profiles using laparoscopic assisted techniques. However, these reports are generally limited by their retrospective nature and the inclusion of historically determined PEG complication rates in children. Complication rates associated with PEG placement in children have not been prospectively studied, and a true modern understanding of the safety profile of PEG when performed in children is unknown. We prospectively followed children undergoing PEG to establish a clear and current understanding of the complication rates associated with this procedure. METHODS: Consecutive PEG procedures performed between December 2009 and August 2010 at a single, tertiary-care pediatric hospital were enrolled for study. Patients were followed prospectively for 90 days with data regarding complications acquired via standardized interviews at 7, 30, and 90 days postoperatively. RESULTS: We enrolled 103 patients for study. Median age and weight at time of operation was 8 months (range, 2 weeks-21 years) and 6.9 kg (range, 2-42). Patients underwent primary placement of either a PEG button (n = 70) or PEG tube (n = 33). There were no intraoperative complications, with a 100% procedure completion rate. Six deaths occurred during this follow-up time period (mean of 37 days postoperatively) and were attributed to causes other than PEG placement. Four patients were lost to follow-up. One PEG tube was electively discontinued before the end of the follow-up period without complication. Of the remaining 92 patients with complete data, 13 complications were observed in 10 patients. Total complication rate was 14%. CONCLUSION: Rates of PEG complications observed in this prospective study are low and are generally minor. Observed rates of PEG specific complications are lower than historic reports. The safety profile of PEG when performed in today's pediatric population remains comparable in safety to techniques such as laparoscopic-assisted gastrostomy. PMID- 22939746 TI - Implementation of a small bowel obstruction guideline improves hospital efficiency. AB - BACKGROUND: We performed an internal review of triage decisions and outcomes for all patients admitted for small bowel obstruction (SBO). Concern for potential delays in operation led to formalization of an institution-wide SBO management guideline. We hypothesized that use of the guideline would improve initial triage and patient outcomes. METHODS: Members of the departments of surgery, medicine, and emergency medicine created a SBO service triage and initial management guideline that was instituted in 2011 after education and a multidisciplinary Grand Rounds on the subject. Administrative data from fiscal year 2010 (FY2010) was compared with the first 6 months of 2011. Time to computed tomography scan, the OR, general surgery (GS) consultation, and hospital duration of stay were collected and compared for those admitted to a medicine service before (Med2010) and after (Med2011) the guideline and those admitted to a general surgery service before (GS2010) and after (GS2011) the guideline. Groups were compared with Student t test and chi2 analysis. RESULTS: There were 490 SBO admissions in FY2010 and 240 in the first 6 months of 2011. After implementation of the guidelines, the percent of SBO patients admitted to GS2011 increased from 55 to 66% (P < .01). The percent of patients admitted to a medicine service requiring operation for SBO did not change from 14 to 7% for Med2011, but there was a shorter time to GS consultation (P < .001). Time from admission to operation decreased from 0.9 to 0.4 days (P < .05) with a mean decrease in hospital duration of stay of 2 days (8 +/- 6 compared with 6 +/- 4 days, P < .001) for those admitted during GS2011. CONCLUSION: Implementation of a hospital-wide SBO guideline that addressed initial management and triage shortened time to operative intervention and hospital duration of stay for patients requiring operative therapy for SBO. PMID- 22939747 TI - The storage lesion of packed red blood cells affects coagulation. AB - BACKGROUND: The storage lesion of packed red blood cells (PRBCs) consists of biochemical changes associated with increased inflammatory mediators and decreased oxygen-carrying capacity. The effect of storage on the coagulation system is less well studied. The purpose of this study is to determine how PRBC storage time affects the activated coagulation time (ACT), using an in vitro model. METHODS: Type-matched PRBCs and fresh-frozen plasma were mixed, warmed to 37 degrees C, and recalcified. The microsample ACT was repeatedly determined by 2 methods (ACT+ and ACT-LR) at 1 week, 3 weeks, and 5 weeks after date of donation. Hematocrit, pH, and ionized calcium were measured to assess how the model compared to physiologic circumstances. Statistical analysis was performed using the Student 2-tailed t-test with unequal variance. RESULTS: Hematocrit, pH, and ionized calcium were successfully maintained within narrow ranges. The model was notably acidotic, consistent with circumstances of shock and massive transfusion. There was no significant difference in the ACT+ between week 1 and week 3 (P = .183), but there was a significant difference between week 3 and week 5 (P = .029) and between week 1 and week 5 (P = .007). The ACT-LR showed a significant difference between week 1 and week 3 (P = .001), but not between week 3 and week 5 (P = .286). There was again a strong difference between week 1 and week 5 results (P = .011). CONCLUSION: In an isolated in vitro model, the storage lesion of PRBCs is associated with decreased coagulation. This may have relevance for transfusion practices in coagulation-sensitive circumstances such as trauma. PMID- 22939748 TI - Dysphagia postfundoplication: more commonly hiatal outflow resistance than poor esophageal body motility. AB - BACKGROUND: Historically, risk assessment for postfundoplication dysphagia has been focused on esophageal body motility, which has proven to be an unreliable prediction tool. Our aim was to determine factors responsible for persistent postoperative dysphagia. METHODS: Fourteen postfundoplication patients with primary dysphagia were selected for focused study. Twenty-five asymptomatic post Nissen patients and 17 unoperated subjects served as controls. Pre- and postoperative clinical and high-resolution manometry parameters were compared. RESULTS: Thirteen of the 14 symptomatic patients (92.9%) had normal postoperative esophageal body function, determined manometrically. In contrast, 13 of 14 (92.9%) had evidence of esophageal outflow obstruction, 9 of 14 (64.3%) manometrically, and 4 of 14 (28.6%) on endoscopy/esophagram. Median gastroesophageal junction integrated relaxation pressure was significantly greater (16.2 mm Hg) in symptomatic than in asymptomatic post-Nissen patients (11.1 mm Hg, P = .05) or unoperated subjects (10.6 mm Hg, P = .02). Sixty-four percent (9/14) of symptomatic patients had an increased mean relaxation pressure. Dysphagia was present in 9 of 14 (64.3%) preoperatively, and elevated postoperative relaxation pressure was independently associated with dysphagia. CONCLUSION: These data suggest that postoperative alterations in hiatal functional anatomy are the primary factors responsible for post-Nissen dysphagia. Impaired relaxation of the neo-high pressure zone, recognizable as an abnormal relaxation pressure, best discriminates patients with dysphagia from those without symptoms postfundoplication. PMID- 22939749 TI - Factors affecting primary fascial closure of the open abdomen in the nontrauma patient. AB - INTRODUCTION: Septic wound complications are known to limit the ability of surgeons to perform primary fascial closure after damage control laparotomy (DCL) in patients with trauma. Factors preventing primary fascial closure after DCL in nontrauma patients, however, are unknown. We aim to identify these risk factors. METHODS: Institutional research board approval was obtained to review the medical records of nontrauma patients undergoing DCL between December 2006 and June 2010. Patients who died before an attempt at fascial closure were excluded. Univariate analysis was performed comparing patients with primary fascial closure to partial fascial or planned ventral hernia. Data are presented as median or percentage as appropriate. Statistical significance was considered at P < .05. RESULTS: One hundred eighty-one patients were identified (53% male), of whom 8 died before an attempt at fascial closure, leaving 173 patients within the study cohort. Primary fascial closure was achieved in 111 patients (64%), with the remaining patients receiving either partial fascial or planned ventral hernia closure. The cumulative rate of primary fascial closure plateaued by day 12 at 62%. Patients who achieved primary fascial closure had a greater incidence of pre-existent coronary artery disease (32% vs 16%) and arrhythmia (27% vs 11%). There was a superior base deficit on admission (-7 vs -9) in the primary closure cohort. There was equivalent mortality (21% vs 25%) and intensive care unit stay (9 days vs 14 days); however, the overall hospital stay (22 vs 42 days) and ventilator days (4 vs 6) in the primary fascial closure group were shortened. Success of primary fascial closure was associated with lower incidence of septic complications (39% vs 59%), enterocutaneous fistulae (4% vs 11%), and intra abdominal abscess (14% vs 33%), as well as fewer days of open abdomen management (2 vs 6), and number of serial abdominal explorations (2 vs 4) and a lower fluid balance over the first 10 days. CONCLUSION: The development of septic complications such as intra-abdominal abscess and enterocutaneous fistulae were associated with inability to primarily close the fascia after DCL. In addition, longer duration of open abdomen management, greater number of serial abdominal explorations, and worse base deficits were negatively associated with primary fascial closure. PMID- 22939752 TI - Effect of fine wire electrode insertion on gait patterns in children with hemiplegic cerebral palsy. AB - BACKGROUND: Fine wire electromyography (EMG) is commonly used for surgical decision making in equinovarus foot deformity. However, this invasive technique may have the unwanted effect of altering the gait of children with cerebral palsy (CP). The purpose of this study was to determine if fine wire insertion into the posterior tibialis muscle affects temporal-spatial parameters and hindfoot kinematics during gait in children with equinovarus secondary to hemiplegic CP. METHODS: 12 children with hemiplegic CP who presented with an equinovarus foot (mean age 12.5 yrs, four right-sided, eight left-sided) were recruited. Temporal spatial parameters and 3-D segmental foot and ankle kinematic gait data were collected utilizing standard gait analysis and the Milwaukee Foot Model (MFM). Three representative trials with and without fine wire electrode insertion were compared to determine the effect of electrode placement in the posterior tibialis on temporal spatial-parameters and hindfoot sagittal, coronal and transverse plane kinematic peaks, timing of kinematic peaks, and excursions. RESULTS: No significant differences in any temporal-spatial or kinematic parameters were observed between "with wire" and "without wire" conditions. Strong correlations were observed among the gait parameters, with the exception of cadence, for the two conditions. DISCUSSION: Fine wire insertion into the posterior tibialis had no measurable effect on the gait of individuals with equinovarus secondary to hemiplegic CP. This suggests that the simultaneous collection of segmental foot and ankle kinematics and fine wire EMG data of the posterior tibialis is acceptable for surgical decision making in this patient population. PMID- 22939751 TI - High-frequency stimulation of the substantia nigra induces serotonin-dependent depression-like behavior in animal models. PMID- 22939750 TI - Radiographic assessment of splenic injury without contrast: is contrast truly needed? AB - INTRODUCTION: Computed tomography (CT) has become an essential tool in the assessment of the stable trauma patient. Intravenous (i.v.) contrast is commonly relied upon to provide superior image quality, particularly for solid-organ injury. However, a substantial proportion of injured patients have contraindications to i.v. contrast. Little information exists concerning the repercussions of CT imaging without i.v. contrast, specifically for splenic injury. METHODS: We performed a retrospective analysis using data from our trauma registry and chart review as part of a quality improvement project at our institution. All patients with splenic injury, during a 3-year period (2008 2010), where a CT of the abdomen without i.v. contrast (DRY) early during their admission were selected. All splenic injuries had to have been verified with abdominal CT imaging with i.v. contrast (CONTRAST) or via intraoperative findings. DRY images were independently read by a single, blinded, radiologist and assessed for parenchymal injury or "suspicious" splenic injury findings and compared with CONTRAST imaging results or intraoperative findings. RESULTS: During the time period of the study, 319 patients had documented splenic injury with 44 (14%) patients undergoing DRY imaging, which was also verified by CONTRAST imaging or operative findings. Splenic parenchymal injury was only visualized in 38% of patients DRY patients. "Suspicious" splenic injury radiographic findings were common. When these less-specific findings for splenic injury were incorporated in the radiographic assessment, DRY imaging had more than 93% sensitivity for detecting splenic injury. CONCLUSION: DRY imaging is increasingly being performed after injury and has a low sensitivity in detecting splenic parenchymal injury. However, less-specific radiographic findings suspicious for splenic injury in combination provide high sensitivity for the detection of splenic injury. These results suggest CONTRAST imaging is preferred to detect splenic injury; however, in those patients who have contraindications to i.v. contrast, DRY imagining may be able to select those who require close monitoring or intervention. PMID- 22939753 TI - Do thigh circumference and mass changes alter knee biomechanics during walking? AB - Obese adults walk with different biomechanics compared to healthy weight adults. Previous studies have focused on knee biomechanics because they are associated with development and progression of osteoarthritis. Changes in thigh mass and circumference that occur as body weight increases may influence gait. The purpose of this study was to determine if increases in thigh mass and circumference alter gait biomechanics. For 20 healthy weight young adults (10 male and 10 female) knee kinematic, kinetic and gait temporospatial variables were collected using a three-dimensional motion capture system and a force platform during over ground walking. Data were collected during control, increased thigh mass, increased thigh circumference, and both increased mass and circumference conditions. Increases in thigh segment parameters reflected changes expected with a 10 point increase in body mass index. Step width was wider during the added circumference and combination conditions compared to the control condition. Increases in thigh circumference associated with obesity increase step width. This suggests the greater step width observed in obese adults compared to healthy weight adults is a result of the physical constraints introduced by their wider thigh segments. Peak knee flexion angle, peak knee extension moment, peak knee adduction angle, and peak knee abduction moment were similar in all conditions. Thus, acute changes in thigh segment parameters did not result in knee biomechanics suggestive of an increased risk of knee osteoarthritis. PMID- 22939754 TI - Posterior tibial tendon dysfunction and flatfoot: analysis with simulated walking. AB - Many biomechanical studies investigated pathology of flatfoot and effects of operations on flatfoot. The majority of cadaveric studies are limited to the quasistatic response to static joint loads. This study examined the unconstrained joint motion of the foot and ankle during stance phase utilizing a dynamic foot ankle simulator in simulated stage 2 posterior tibial tendon dysfunction (PTTD). Muscle forces were applied on the extrinsic tendons of the foot using six servo pneumatic cylinders to simulate their action. Vertical and fore-aft shear forces were applied and tibial advancement was performed with the servomotors. Three dimensional movements of multiple bones of the foot were monitored with a magnetic tracking system. Twenty-two fresh-frozen lower extremities were studied in the intact condition, then following sectioning peritalar constraints to create a flatfoot and unloading the posterior tibial muscle force. Kinematics in the intact condition were consistent with gait analysis data for normals. There were altered kinematics in the flatfoot condition, particularly in coronal and transverse planes. Calcaneal eversion relative to the tibia averaged 11.1+/-2.8 degrees compared to 5.8+/-2.3 degrees in the normal condition. Calcaneal-tibial external rotation was significantly increased in flatfeet from mean of 2.3+/-1.7 degrees to 8.1+/-4.0 degrees . There were also significant changes in metatarsal tibial eversion and external rotation in the flatfoot condition. The simulated PTTD with flatfoot was consistent with previous data obtained in patients with PTTD. The use of a flatfoot model will enable more detailed study on the flatfoot condition and/or effect of surgical treatment. PMID- 22939755 TI - Thymic stromal lymphopoietin and allergic disease. AB - The importance of the epithelium in initiating and controlling immune responses is becoming more appreciated. For example, allergen contact first occurs at mucosal sites exposed to the external environment, such as the skin, airways, and gastrointestinal tract. This exposure leads to the production of a variety of cytokines and chemokines that are involved in driving allergic inflammatory responses. One such product is thymic stromal lymphopoietin (TSLP). Recent studies in both human subjects and murine models have implicated TSLP in the development and progression of allergic diseases. This review will highlight recent advances in the understanding of the role of TSLP in these inflammatory diseases. Importantly, these insights into TSLP's multifaceted role could potentially allow for novel therapeutic manipulations of these disorders. PMID- 22939757 TI - Which factors in raw cow's milk contribute to protection against allergies? AB - Several epidemiologic studies have shown that growing up in a farming environment is associated with a decreased risk of allergies. A factor that correlates strongly with this effect is the early ingestion of unheated cow's milk. Although, to date, no controlled studies on raw milk consumption have been performed to formally demonstrate this effect, several factors in bovine milk have been described that might explain how raw cow's milk consumption can decrease the risk of allergies. In addition, increasing knowledge on the immunologically active factors in breast milk have also contributed to our understanding of the effects of bovine milk in infants because many of the factors in bovine milk are expected to have functional effects in human subjects as well. Here we review these factors and their mechanisms of action and compare their presence in bovine milk and breast milk. A better understanding of these factors, as well as how to retain them, might ultimately lead to the development of mildly processed milk and infant nutrition products that could become a part of preventive strategies to reduce the incidence of allergic disease. PMID- 22939756 TI - A specific sphingosine kinase 1 inhibitor attenuates airway hyperresponsiveness and inflammation in a mast cell-dependent murine model of allergic asthma. AB - BACKGROUND: Sphingosine-1-phosphate (S1P), which is produced by 2 sphingosine kinase (SphK) isoenzymes, SphK1 and SphK2, has been implicated in IgE-mediated mast cell responses. However, studies of allergic inflammation in isotype specific SphK knockout mice have not clarified their contribution, and the role that S1P plays in vivo in a mast cell- and IgE-dependent murine model of allergic asthma has not yet been examined. OBJECTIVE: We used an isoenzyme-specific SphK1 inhibitor, SK1-I, to investigate the contributions of S1P and SphK1 to mast cell dependent airway hyperresponsiveness (AHR) and airway inflammation in mice. METHODS: Allergic airway inflammation and AHR were examined in a mast cell dependent murine model of ovalbumin (OVA)-induced asthma. C57BL/6 mice received intranasal delivery of SK1-I before sensitization and challenge with OVA or only before challenge. RESULTS: SK1-I inhibited antigen-dependent activation of human and murine mast cells and suppressed activation of nuclear factor kappaB (NF kappaB), a master transcription factor that regulates the expression of proinflammatory cytokines. SK1-I treatment of mice sensitized to OVA in the absence of adjuvant, in which mast cell-dependent allergic inflammation develops, significantly reduced OVA-induced AHR to methacholine; decreased numbers of eosinophils and levels of the cytokines IL-4, IL-5, IL-6, IL-13, IFN-gamma, and TNF-alpha and the chemokines eotaxin and CCL2 in bronchoalveolar lavage fluid; and decreased pulmonary inflammation, as well as activation of NF-kappaB in the lungs. CONCLUSION: S1P and SphK1 play important roles in mast cell-dependent, OVA induced allergic inflammation and AHR, in part by regulating the NF-kappaB pathway. PMID- 22939758 TI - High-dose sublingual immunotherapy with single-dose aqueous grass pollen extract in children is effective and safe: a double-blind, placebo-controlled study. AB - BACKGROUND: Sublingual allergen-specific immunotherapy is a viable alternative to subcutaneous immunotherapy particularly attractive for use in children. OBJECTIVE: This study investigated efficacy and safety of high-dose sublingual immunotherapy (SLIT) in children allergic to grass pollen in a randomized, double blind, placebo-controlled trial. METHODS: After a baseline seasonal observation, 207 children aged 4 to 12 years with grass pollen-allergic rhinitis/rhinoconjunctivitis with/without bronchial asthma (Global Initiative for Asthma I/II) received either high-dose grass pollen SLIT or placebo daily for 1 pre-/co-seasonal period. The primary end point was the change of the area under the curve of the symptom-medication score (SMS) from the baseline season to the first season after start of treatment. Secondary outcomes were well days, responders, immunologic changes, and safety. RESULTS: Mean changes in the area under the curve of the SMS from the baseline to the first grass pollen season after the start of treatment were -212.5 for the active group and -97.8 for the placebo group (P = .0040). Rhinoconjunctivitis SMS (P = .0020) and separated symptom and medication scores were also statistically different between the 2 groups (P = .0121 and P = .0226, respectively). The number of well days and the percentage of responders were greater in the active group. Changes in allergen specific IgE and IgG levels indicated a significant immunologic effect. The treatment was well tolerated, and no serious treatment-related events were reported. CONCLUSIONS: This study confirmed that this SLIT preparation significantly reduced symptoms and medication use in children with grass pollen allergic rhinoconjunctivitis. The preparation showed significant effects on allergen-specific antibodies, was well tolerated, and appeared to be a valid therapeutic option in children allergic to grass pollen. This trial was registered at www.clinicaltrials.gov as NCT00841256. PMID- 22939759 TI - Peach allergy in China: a dominant role for mugwort pollen lipid transfer protein as a primary sensitizer. PMID- 22939760 TI - WITHDRAWN: Risk Factors and Interventions for Ventilator-Associated Pneumonia in Pediatric Patients. AB - The Publisher regrets that this article is an accidental duplication of an article that has already been published, doi:10.1016/j.pedn.2012.03.027. The duplicate article has therefore been withdrawn. PMID- 22939762 TI - You eat with your eyes first. AB - While the senses of taste, smell, and vision are distinct, visual stimuli have been shown to alter the perception of taste, smell, and flavor. Color may be the most obvious visual cue, but expectations through learned associations are set by other visual cues as well, including gloss, evenness, and shape. These expectations exert cognitive top-down influences that can and sometimes do alter assessments of taste and flavor. PMID- 22939763 TI - The effect of temperament and responsiveness towards humans on the behavior, physiology and milk production of multi-parous dairy cows in a familiar and novel milking environment. AB - The objectives of this study were to investigate whether; 1) temperament or 2) behavioral responsiveness to humans, can affect the behavior, physiology and productivity of dairy cows being milked in a familiar and novel milking environment. Temperament of multi-parous cows was defined based on exit time from a restraint device, as High Responders (HR; n=10), Medium Responders (MR; n=10) or Low Responders (LR; n=10). The behavioral response of cows to humans was assessed using four tests: restraint, exit speed, avoidance distance test and a voluntary approach test. Cows were milked according to their established routines in a rotary (familiar) milking parlor and behavioral, physiological and production data were collected over five consecutive days, including heart rate, cortisol and oxytocin concentrations and milk yield. The following week, cows were milked in a novel environment (herringbone parlor within the same farm facility) over five consecutive days, and the data and sample collection program was repeated. Cows were then given an exogenous adrenocorticotropic hormone (ACTH) challenge to measure adrenal responsiveness. Exit time was negatively correlated with the behavioral responses of cows to restraint and human avoidance distance (HAD) in the paddock and arena. The behavioral response of cows to the milking process was greater in MR than LR and HR cows in the familiar and novel milking environments. Milk yields were greater in LR than HR cows in the novel but not the familiar milking parlor. Oxytocin concentrations increased during milking in the novel environment, regardless of cow temperament. In the familiar and novel environments, heart rates were higher in HR than LR cows before and during milking and rMSSD was lower in HR cows during milking in a novel environment. There was no difference in cortisol concentrations between LR and HR cows in response to an ACTH challenge, but HR cows had higher baseline cortisol levels than LR cows. The number of leg lifts cows performed when restrained in the crush was associated with several physiological and milk production measures. These results indicate that cows with different temperaments vary in their basal physiology as well as their behavioral and physiological responses to milking and stress associated with being milked in a novel environment. PMID- 22939761 TI - Hairy tale of signaling in hair follicle development and cycling. AB - Hair follicles (HFs) is an appendage from the vertebrate skin epithelium, and is critical for environmental sensing, animal appearance, and body heat maintenance. HFs arise from the embryonic ectoderm and regenerate cyclically during adult life. Distinct morphological and functional stages from development through homeostasis have been extensively studied for the past decades to dissect the critical molecular mechanisms. Accumulating work suggests that different signaling cascades, such as Wnt, Bmp, Shh, and Notch, together with specific combinations of transcription factors are at work at different stages. Here we provide a comprehensive review of mouse genetics studies, which include lineage tracing along with knockout and over-expression of core genes from key signaling pathways, to paint an updated view of the molecular regulatory network that govern each stage of hair follicle development and adult cycling. PMID- 22939764 TI - Neurocognitive effects of multivitamin supplementation on the steady state visually evoked potential (SSVEP) measure of brain activity in elderly women. AB - OBJECTIVE: Growing evidence suggests that dietary supplementation with selected micronutrients and nutraceuticals may have the potential to improve cognition in older adults. Fewer studies have investigated the effects of these substances on brain activity. METHODS: This study was a randomised, double-blind, placebo controlled trial, conducted to explore the effects of 16 weeks supplementation with a combined multivitamin, mineral and herbal formula on the steady state visually evoked potential (SSVEP) measure of brain electrical activity. Participants were elderly women aged between 64 and 79 years, with subjective memory complaints. Baseline and post-treatment SSVEP data was obtained for 22 participants in the multivitamin group and 19 in the placebo group. A spatial working memory delayed response task (DRT) was performed during the recording of the SSVEP. RESULTS: The results revealed that when compared to placebo, multivitamin supplementation delayed SSVEP latency during retrieval, interpreted as an increase in inhibitory neural processes. Behavioural performance on the DRT was not improved by the multivitamin, however improved performance accuracy was associated with increased midline central SSVEP latency. There were no multivitamin-related effects on SSVEP amplitude. CONCLUSION: These findings indicate that in the elderly, multivitamin supplementation may enhance neural efficiency during memory retrieval. PMID- 22939766 TI - Can weight-related health risk be more accurately assessed by BMI, or by gender specific calculations of Percentage Body Fatness? AB - The problem of obesity over the last 10 years has consistently been referred to as a 'global epidemic'. The Body Mass Index (BMI) is the currently accepted measure for classifying weight-related risk, but is a crude measure that has not changed in 150 years. It is recognised as having significant limitations, largely due to its lack of distinction between fat and muscle tissue. As the health risks of obesity are linked to the fat content of the body, a more accurate method of classifying would be Percentage Body Fatness (PBF). Although skinfold thickness analysis is recognised as a valid and accurate estimate of PBF in field studies, this method is not routinely used in clinical practice. Using data collected from young adults in the United Kingdom, we compared classifications (underweight, normal weight, overweight and obese) using BMI, with classifications using estimated PBF (from skinfold thickness analysis). We identified disparity between these two methods in approximately 1/3 of participants. BMI correctly classified 66.5% of females and 62.7% of males, with different gender profiles of incorrect classification. Regression analysis was conducted using estimated PBF (by skinfold thickness analysis) as the dependent variable, with explanatory variables of age, height, weight, systolic blood pressure, frequency of vigorous exercise and grip strength. The resulting gender-specific formulae derived from this regression analysis provides a regression R(2) of around 65%, and improved correct classifications to 74% for females and 76% for males. This represents an average improvement of roughly ten percentage points over BMI (male: 7.2% points; female: 13.4% points). We hypothesise that the presented formulae provide gender specific calculations of PBF, which result in a more accurate indicator of weight related health risk, compared with BMI in this population. This provides a new approach to an increasingly important clinical issue. These formulae use data that can be easily, quickly and cost-effectively measured in a practice setting. If shown to be repeatable with larger and more diverse populations, the PBF formulae could provide an alternative to the BMI as the major indicator of body composition related health risk. This would ensure resources are targeted more appropriately and efficiently. PMID- 22939765 TI - Nicotine induces a conditioned place preference in male Japanese quail (Coturnix japonica). AB - Visual stimuli may play an important role in the development and maintenance of addiction in humans. Research with a visually-oriented animal model such as Japanese quail (Coturnix japonica) may provide insight into how visual cues contribute to the addiction process. The aim of the current study was to investigate the rewarding properties of nicotine in male Japanese quail using a biased conditioned place preference (CPP) procedure. Adult male quail (N=30) were allowed to freely explore the entire CPP apparatus during a place preference pre test and time spent in each chamber was measured. During nicotine conditioning sessions, quail were administered nicotine (0.5, 1.0, or 2.0mg/kg) or saline and were then confined to their initially least preferred chamber. On alternating days, all quail received saline and were confined to their initially preferred chamber. Locomotor activity was assessed in both chambers. The conditioning chambers had yellow or green walls to enhance the visual salience of each context. Following 8 conditioning sessions (4 nicotine; 4 saline), quail were allowed to explore the entire apparatus during a CPP post-test and time spent in each chamber was measured. The results indicated that quail treated with 0.5 and 1.0mg/kg nicotine significantly increased the amount of time they spent in the nicotine-paired chamber compared to saline controls, suggesting that nicotine produced a CPP. Furthermore, quail treated with 0.5mg/kg nicotine showed a significant increase in locomotor activity with repeated treatments. The current findings suggest that nicotine may have a rewarding effect in quail and may tentatively suggest that the neuropharmacological mechanisms that mediate CPP for nicotine are conserved in birds. PMID- 22939767 TI - Etiopathogenic perspectives on chronic psycho traumatic and chronic psychotic symptoms: the hypothesis of a hyperdopaminergic endophenotype of PTSD. AB - Post traumatic stress disorder (PTSD) is a complex and heterogeneous disorder, which specific symptoms are re-experiencing, increased arousal and avoidance of stimuli associated with the trauma. PTSD has much comorbidity like depression, substance abuse, somatic complaints, repeated dissociative phenomena and transitory or chronic psychotic reactions. PTSD can manifest itself in different clinical forms: some patients present higher symptoms in one domain as compared to another, probably because of abnormalities in different neurobiological systems. Hyposerotonergic and hypernoradrenergic PTSD endophenotypes have been previously identified and the purpose of this paper is to focus on the hypothesis of a hyperdopaminergic endophenotype. The current review discusses several entities: PTSD with psychotic features with or without depression, the comorbide use of psychoactive substances that increase psychotic symptoms and traumatic brain injuries as agents of psycho traumatic and psychotic features. For all of these nosographic entities, the dopaminergic neuromodulation may play a central role. The hypothesis of a hyperdopaminergic endophenotype of PTSD opens up new research and therapeutic perspectives. Although antipsychotics are frequently used for people with PTSD further studies are needed to develop a consensus on the guidelines for treating the psychotic forms of PTSD. PMID- 22939768 TI - A novel treatment for vestibular disorder with FGLM-NH2 plus SSSR. AB - Topical FGLM-NH(2) (Phenylalanine-Glycine-Leucine-Methionine-Amide) plus SSSR (Serine-Serine-Serine-Arginine) facilitates recovery from vestibular disorders induced by (+/-)-alpha-amino-3-hydroxy-5-methyl-isoxazole-4-propionic acid (AMPA) in guinea pigs and might offer a treatment strategy for patients with peripheral vestibular disorders. The tetrapeptide FGLM-NH(2) derived from substance P (SP) can be used to treat corneal disorders when combined with SSSR, which is a tetrapeptide derived from insulin-like growth factor-1 (IGF-1). We examined the influence of FGLM-NH(2) plus SSSR when locally applied to the unilateral inner ear of guinea pigs with vestibular disorder induced by AMPA. A total of 18 Hartley white guinea pigs were assigned to groups receiving either FGLM-NH(2) plus SSSR, artificial perilymph, or no treatment at all. A hole was drilled adjacent to the round window, with AMPA then infused into the hole in order to induce the vestibular disorder. Thereafter, FGLM-NH(2) plus SSSR or artificial perilymph was delivered via an osmotic pump that was inserted into the hole. Sinusoidal rotation tests were used for observing spontaneous nystagmus and for measurements of the vestibulo-ocular reflexes (VOR). Two animals from each group were immunohistochemically examined at 24h after the treatment. Spontaneous nystagmus decreased immediately after FGLM-NH(2) plus SSSR infusion. The recovery of the VOR gains was statistically faster than that seen in the control group at 3 and 7 days after treatment. Immunohistochemical examination revealed that many synaptic ribbons, which are markers of the synapse, were stained in the FGLM NH(2) plus SSSR group compared with the untreated group. Topical application of FGLM-NH(2) plus SSSR accelerates functional recovery from AMPA-induced vestibular disorders by facilitating synaptic regeneration in guinea pigs. PMID- 22939769 TI - The TAT peptide endows PACAP with an enhanced ability to traverse bio-barriers. AB - Pituitary adenylate cyclase-activating polypeptide (PACAP) is a potential therapeutic neuropeptide. The 11-amino acid human immunodeficiency virus TAT protein transduction domain is able to deliver protein cargoes across the cell membrane and the blood-brain barrier. A novel fusion protein PACAP-TAT, containing TAT at the C-terminus of PACAP was therefore produced and studied for the ability to cross blood barriers. The gene encoding PACAP-TAT was cloned into the expression vector pKYB, and the target peptide PACAP-TAT was purified using the Intein Mediated Purification with an Affinity Chitin-binding Tag (IMPACT) system. The results of cell assays showed that PACAP-TAT stimulated the cell viability of PAC1-CHO cells with the same potency as PACAP, which indicated that the fusion of TAT did not affect the ability of PACAP-TAT to activate the PACAP specific receptor PAC1. The transfer efficiencies of PACAP-TAT and PACAP across the blood-brain barrier (BBB), blood-air barrier (BAB) and blood-testis barrier (BTB) were assayed using peptides labeled with fluorescein isothiocyanate (FITC). The results showed that PACAP-TAT traversed blood barriers with an efficiency approximately 2.5-fold greater than PACAP. Fluorescence microscopic examination showed that PACAP-TAT traversed the BBB significantly more efficiently than PACAP. Furthermore, intraperitoneal (i.p.) injection of PACAP-TAT induced a stronger inhibitory effect on food intake than PACAP (p<0.01, PACAP-TAT vs. PACAP), which indicated that TAT helped to increase the localization of PACAP-TAT in the brain. Preparation of PACAP-TAT with the enhanced ability to cross biological barriers will improve its route of administration and expand its scope of application. PMID- 22939770 TI - Perceptual learning and the development of expertise: a discussion paper. PMID- 22939771 TI - Graduates from dual qualification courses, registered nurse and health visitor: a career history study. AB - BACKGROUND: Educationalists and managers internationally are challenged to find ways of preparing, recruiting early in their careers, and retaining nurses into public health roles in primary care. Public health nursing qualifications are post-initial nurse registration in the United Kingdom as in some other countries. In the mid twentieth century there were a number of innovative programmes of dual qualification: registered nurse and health visitor (the United Kingdom term for public health nurse). OBJECTIVE: To investigate the career histories of graduates from courses integrating both nursing and health visitor qualifications. DESIGN: An observational, survey study. SETTING: The United Kingdom. PARTICIPANTS: A purposive sample of graduates from integrated registered nurse and health visitor programmes, 1959-1995, from one University. METHODS: Self completed, anonymous, survey sent to graduates, with contact details known to the University and through snowballing techniques, in 2011. FINDINGS: Forty five women (56%), graduates in all four decades, returned the survey. A significant majority (82%) had taken up health visitor posts on completing the course. Over their careers, 42% of all jobs held were as health visitors. Only four never worked in a post that required a health visiting qualification. Most had undertaken paid work throughout their careers that focused on aspects of public health, often linked to child, maternal and/or family wellbeing. Many held teaching/lecturing and management posts at some point in their career. Those holding management posts were more likely to report leaving them as a result of organisational re structuring or redundancy than those in non-management posts. CONCLUSIONS: Courses that prepare students to be both nurses and health visitors result in a majority of graduates who take up posts as health visitors on qualification and subsequently. Nurse education planners may find this evidence of value in determining ways of providing a future workforce for public health nursing. PMID- 22939772 TI - Computer-navigated revision total knee arthroplasty for failed unicompartmental knee arthroplasty. AB - The most frequent technical difficulty encountered at unicompartmental knee arthroplasty (UKA) revision to total knee arthroplasty (TKA) is filling in all bone defects. These bone defects can render difficult components positioning, mechanical axis restitution, and ligament balance assessment, which are the three most important parameters for successful TKA. We describe a computer-assisted technique which makes it possible to control these three parameters before removal of the implants that have caused the bone defects. Our study is based on a series of 20 cases, with a minimum follow-up of 2 years. The anatomical and clinical results were very satisfying and comparable to results of primary TKA. We recommend this computer-navigated technique, which is as simple as a primary TKA procedure. PMID- 22939773 TI - Hypolipidemic applications of microcrystalline cellulose composite synthesized from different agricultural residues. AB - Microcrystalline cellulose was prepared from bean hull, rice straw and rice hull. The use of rice hull and rice straw pulp in different proportions as a source of silica to prepare silicified microcrystalline cellulose was investigated. Preparations of microcrystalline cellulose-potato starch composites with different potato starch concentrations were performed. All samples were characterized through various techniques. Physical and mechanical properties of the prepared tablets were tested. The biological activities of one composite was tested in a hyperlipidemic rat model and compared to orlistat to assess its antilipidemic potential. This composite exhibited remarkable antilipidemic effect with decreased insulin sensitivity. PMID- 22939774 TI - Idiopathic brood disease syndrome and queen events as precursors of colony mortality in migratory beekeeping operations in the eastern United States. AB - Using standard epidemiological methods, this study set out to quantify the risk associated with exposure to easily diagnosed factors on colony mortality and morbidity in three migratory beekeeping operations. Fifty-six percent of all colonies monitored during the 10-month period died. The relative risk (RR) that a colony would die over the short term (~50 days) was appreciably increased in colonies diagnosed with Idiopathic Brood Disease Syndrome (IBDS), a condition where brood of different ages appear molten on the bottom of cells (RR=3.2), or with a "queen event" (e.g., evidence of queen replacement or failure; RR=3.1). We also found that several risk factors-including the incidence of a poor brood pattern, chalkbood (CB), deformed wing virus (DWV), sacbrood virus (SBV), and exceeding the threshold of 5 Varroa mites per 100 bees-were differentially expressed in different beekeeping operations. Further, we found that a diagnosis of several factors were significantly more or less likely to be associated with a simultaneous diagnosis of another risk factor. These finding support the growing consensus that the causes of colony mortality are multiple and interrelated. PMID- 22939775 TI - An investigation of the movement patterns and biosecurity practices on Thoroughbred and Standardbred stud farms in New Zealand. AB - Utilising a face-to-face interview of stud managers, a survey was conducted to investigate the movement patterns around, and biosecurity practices on, Thoroughbred and Standardbred stud farms. Eligible stud farms (n=60) were identified from the 2009 Thoroughbred stallion register and 2009 Standardbred stallion register, and stud managers were asked to participate in the interview. In total, 27 stud managers agreed to participate in the study, and participating stud farms included 38% of Thoroughbred and 60% of Standardbred mares bred in 2009. All stud managers reported the movement of horses to and from their stud farm. The median number of movement events per year was 127 (interquartile range 83-300). The frequency of movement events from a stud farm was not associated with the breed of horse managed on the stud farm, however Thoroughbred horses travelled further than Standardbred horses during these movement events (P<0.001). The movement patterns of horses around stud farms showed a strong seasonality associated with the commercial breeding season of each breed. While 26 (96%) of stud managers reported having procedures in place for checking newly arriving horses, only 6 (22%) stud managers reported isolating horses on arrival as a standard protocol. The main reason for isolating horses on properties, where isolation was not a standard procedure, was in response to strangles outbreaks on other stud farms (n=10). Only 2 (7%) stud managers reported implementing visitor protocols, and these protocols only applied to visiting veterinarians, but not to farriers. These findings have important implications for the control of both endemic and exotic infectious disease outbreaks within the New Zealand breeding population as the high frequency of movement around stud farms, the high number of visitors to stud farms and the lack of effective biosecurity practices or visitor protocols will be critical factors in the spread of equine influenza during an outbreak. PMID- 22939776 TI - Histochemical analysis of glycoproteins in the secretory cells in the epidermis of the head skin of Indian Major Carp, Labeo rohita. AB - A series of histochemical procedures were employed to localise and characterise glycoprotein (GP) classes produced by the epithelial cells, the type A and the type B mucous goblet cells (MGCs) and the club cells in the epidermis of Labeo rohita. The epithelial cells secreted GPs with oxidizable vicinal diols and GPs with sialic acid residues without O-acyl substitution in low concentrations. The type A MGCs and the type B MGCs, in contrast, produced these GPs in high concentrations. Further, these MGCs produced GPs with O-sulphate esters as well. GPs with O-sulphate esters were produced in high concentration by the type A MGCs and in low concentration by the type B MGCs. The club cells produced GPs with oxidizable vicinal diols in trace amounts. Production of more than one type of GPs suggested a basis for functional discrimination in their role in the mucous secretions at the skin surface. This is considered an adaptation to environment inhabited by the fish and is discussed in relation to their role in lubrication, protection and inhibition of the invasion and proliferation of pathogenic micro organisms. PMID- 22939777 TI - In vivo and in vitro Leishmania amazonensis infection induces autophagy in macrophages. AB - Autophagy is the primary mechanism of degradation of cellular proteins and at least two functions can be attributed to this biological phenomenon: increased nutrient supply via recycling of the products of autophagy under nutrient starvation; and antimicrobial response involved in the innate immune system. Many microorganisms induce host cell autophagy and it has been proposed as a pathway by which parasites compete with the host cell for limited resources. In this report we provide evidence that the intracellular parasite Leishmania amazonensis induces autophagy in macrophages. Using western blotting, the LC3II protein, a marker of autophagosomes, was detected in cell cultures with a high infection index. Macrophages infected with L. amazonensis were examined by transmission electronic microscopy, which revealed enlarged myelin-like structures typical late autophagosome and autolysosome. Other evidence indicating autophagy was Lysotracker red dye uptake by the macrophages. Autophagy also occurs in the leishmaniasis skin lesions of BALB/c mice, detected by immunohistochemistry with anti-LC3II antibody. In this study, autophagy inhibitor 3-methyladenine (3MA) reduced the infection index, while autophagy inductors, such as rapamycin or starvation, did not alter the infection index in cultivated macrophages, suggesting that one aspect of the role of autophagy could be the provision of nutritive support to the parasite. PMID- 22939778 TI - Fiducial-free CyberKnife radiosurgery for residual metastatic spinal tumor after decompression and instrumentation. AB - Stereotactic spinal radiotherapy is a promising technology for use in the multidisciplinary management of benign and malignant spinal tumors. We present two patients with residual metastatic spinal tumors and their treatment with CyberKnife (Accuray, Sunnyvale, CA, USA) after decompression and instrumentation, one of which was successful and the other not. A 73-year-old male patient was admitted with bilateral extremity weakness (Grade IV) and voiding difficulty that had developed 2 days previously. CyberKnife treatment for the residual tumor after surgery with decompression and instrumentation was attempted, but could not be performed due to imaging interference caused by the instrumentation. A second patient, a 49-year-old male, was admitted with right extremity weakness and voiding difficulty that had developed 5 months previously. In this patient, we were able to perform CyberKnife treatment on the residual tumor after decompression and instrumentation. Based on these two patients, we believe that fiducial-free CyberKnife treatment is not suitable for treatment of residual metastatic spinal tumors at the upper thoracic levels, after decompression with instrumentation. This is due to the difficulties in matching digitally reconstructed radiographs with live radiographic images, as a result of the larger inclination and smaller vertebral body surface at the upper thoracic level. PMID- 22939779 TI - Abnormalities of neuromuscular transmission in patients with Miller-Fisher syndrome. AB - The mechanism of motor weakness in patients with Miller-Fisher syndrome (MFS) remains to be fully elucidated. We performed stimulated single fibre electromyography (sSFEMG) in a clinically weak frontalis muscle in a patient with MFS. Stimulate single fiber EMG revealed increased jitter in over 50% of the apparent single fibre action potentials from the frontalis muscle in addition to increased mean jitter. The findings in the present study suggest dysfunction of neuromuscular transmission in patients with MFS. PMID- 22939780 TI - The neurophysiological basis of the integration of written and heard syllables in dyslexic adults. AB - OBJECTIVE: Letter-speech sound integration in fluent readers takes place automatically and is dependent on temporal synchrony between letters and sounds. In developmental dyslexia, however, letter-speech sound associations are hard to learn, compromising accurate and fluent reading. We studied the effect of printed text on processing speech sounds in dyslexic and fluent adult readers. METHODS: Visual stimuli were presented with sequences of spoken syllables including vowel or consonant changes, or changes in syllable intensity, frequency, or vowel duration. As visual material, written syllables or their scrambled images were used. The auditory stimuli were presented either synchronously with the visual stimuli or time delayed. The mismatch negativity (MMN), an index of automatic neural change detection, was recorded. RESULTS: MMN amplitudes were larger to syllable changes in combination with written syllables than with scrambled images in fluent readers. However, dyslexic readers showed no difference between syllables vs. scrambled image condition. Furthermore, MMNs to consonant and frequency changes peaked later in dyslexic than fluent readers. CONCLUSIONS: Our results suggest deficient and sluggish audiovisual integration in dyslexic individuals, which is not dependent on the phonological relevance of the deviant type. SIGNIFICANCE: Unlike previous studies, our study included several different types of syllable changes presented with concurrent print, enabling us to determine in more detail the nature of the audiovisual deficit in dyslexia. PMID- 22939781 TI - Short communication: survival, growth to weaning, and subsequent fertility of live-born dairy heifers after a difficult birth. AB - The experience of a difficult birth (dystocia) is traumatic and has adverse effects on the newborn in various species. Despite affecting up to 1 in 3 births in dairy cattle, studies on calves have been mostly limited to the first day of life. The objective of this study was to investigate the effects of dystocia on the survival to calving, growth to weaning, and subsequent fertility as nulliparous animals. Historical data from live-born Holstein heifer calves born from cows with various birth difficulty scores (no assistance; moderate; high difficulty) were obtained from 2 herds (Edinburgh herd: n=1,237; Crichton Royal Farm herd: n=721). Each herd was analyzed separately for birth weights, weaning weights, growth rate to weaning, number of services to conception, and age at first calving using REML and generalized linear mixed model analyses. Survival analysis (Cox proportional hazards model) was used in the Edinburgh herd to analyze the subsequent survival of live-born heifers, whereas descriptive data are presented for the Crichton Royal Farm herd. A higher mortality risk to weaning and to first service was observed in the live-born heifers that experienced moderate difficulty at birth compared with heifers born naturally. Surviving dystocial heifers had similar growth-to-weaning and fertility performance as heifers born naturally in both herds. It could be that the performance of dystocial heifers that survived to weaning was not affected or that it was compensated for by farm management. This study highlights long-term effects of the early experience of a difficult birth and thereby stresses the importance of preventing dystocia not just from the point of view of the adult cow, but also from the perspective of the calf. This would also improve farm efficiency and calf welfare. PMID- 22939782 TI - Pregnancy per artificial insemination after presynchronizing estrous cycles with the Presynch-10 protocol or prostaglandin F2alpha injection followed by gonadotropin-releasing hormone before Ovsynch-56 in 4 dairy herds of lactating dairy cows. AB - The objective was to determine the effect of 2 presynchronization treatments on first-service pregnancy per artificial insemination (P/AI) in 4 dairy herds during warm and cool seasons of the year. Cows with ear tags ending with even digits at calving were enrolled in Presynch-10 (Presynch-10): two 25-mg injections of PGF2alpha (i.e., PG-1 and PG-2) 14 d apart. Cows with ear tags ending with odd digits were enrolled in PG-3-G: one 25-mg injection of PG (Pre PG) 3 d before injection of 100MUg of GnRH (Pre-GnRH), with the Pre-PG injection administered at the same time as PG-2 in the Presynch-10 treatment. Ten days after PG-2 or Pre-PG, all cows were enrolled in a timed AI protocol (Ovsynch-56; injection of GnRH 7 d before GnRH-1 and 56 h after GnRH-2 PG with AI 16 to 18 h after GnRH-2). Median days in milk (DIM) at scheduled timed AI were 75 d, which did not differ among herds. Cows detected in estrus before the scheduled timed AI were inseminated early (early bred, EB). Pregnancy was diagnosed at d 32 to 38 and at d 60 to 66 after timed AI by transrectal ultrasonography or transrectal palpation. Data were analyzed with herd as a random effect and with fixed effects of treatment (EB, Presynch-10, or PG-3-G), parity (primiparous vs. multiparous), season [hot (June through September) vs. cool-cold (October through May)], DIM, estrus at timed AI (0 vs. 1), and all 2-way interactions with treatment. The P/AI at d 32 to 38 for EB (n=472), Presynch-10 (n=1,247), and PG-3-G (n=1,286) were 31.4, 35.0, and 41.2%, respectively; P/AI at d 60 to 66 was 29.8, 32.2, and 37.3%, respectively. Season significantly influenced P/AI at d 32 to 38 and d 60 to 66, but a treatment by season interaction was not detected. The P/AI for PG-3 G and Presynch-10 treatments did not differ during cool-cold weather (d 32 to 38: 46.8 vs. 44.3%; d 60 to 66: 41.6 vs. 41.1%, respectively), but PG-3-G and Presynch-10 produced more P/AI than EB at d 32 to 38. During the summer, P/AI in PG-3-G was greater than in Presynch-10 (d 32 to 38: 35.9 vs. 26.7% and d 60 to 66: 33.2 vs. 24.4%, respectively), and P/AI in EB cows did not differ from that of Presynch-10 cows. Although pregnancy loss did not differ for EB, Presynch-10, and PG-3-G treatments (4.0, 6.7, and 9.3%, respectively), pregnancy loss from d 32 to 38 and d 60 to 66 was 2-fold greater in thinner cows (<2.5 vs. >=2.5; 9.0 vs. 4.4%). We concluded that presynchronizing estrous cycles with PG-3-G produced more P/AI than inseminating cows at estrus during cooler weather and was superior to Presynch-10 during the summer. PMID- 22939783 TI - Relationship between daily rumination time and estrus of dairy cows. AB - The aim of the study was to investigate whether rumination time (RT) was related to estrus in dairy cattle. On 4 farms, cows were equipped with a microphone-based sensor system that allowed continuous recording (in blocks of 2 h) of RT. The analyzed data set consisted of 265 verified estrus cycles of 224 animals with artificial insemination leading to conception. The day of estrus (d 0) was defined as the day when estrus was identified either by measurement of physical activity or by visual observation. In estrous cows, RT was significantly reduced. With a duration of 355 min/d, the minimum RT was found on the day of estrus compared with the base level of 429 min/d during the reference period (the mean of 3 d before and 3 d after estrus). The average decrease in RT was 17% (74 min), ranging between -71 and +16% among animals. Herd and parity affected the RT decrease during estrus. Among the 4 analyzed herds, the RT decrease of cows in estrus ranged between 14% (60 min/d) and 24% (94 min/d). The decrease in RT was more pronounced in primiparous than in mature cows. In conclusion, RT is reduced on the day of estrus on average. The RT decrease during estrus was characterized by high variation among cows. PMID- 22939784 TI - Exopolysaccharides modify functional properties of whey protein concentrate. AB - The objective of this research was to produce whey protein concentrate (WPC) with modified functionality using exopolysaccharide- (EPS) producing cultures. Two different EPS-producing cultures, Lactococcus lactis ssp. cremoris JFR and Streptococcus thermophilus, producing EPS1 and EPS2 respectively, were used in this study. One EPS-nonproducing commercial cheese culture (DVS 850; Chr. Hansen, Milwaukee, WI) was used as the control. Reconstituted sweet whey powder was used in this study to eliminate variations from fresh whey. Cultures grown overnight in reconstituted WPC (10% wt/vol) were added, directly or after overnight cooling (cooled EPS), at 2% (wt/vol) to 6% (wt/wt) solution of reconstituted whey. Whey was then high-temperature, short-time pasteurized at 75 degrees C for 35s and ultrafiltered to a volume reduction factor of 5. Ultrafiltered whey (retentate) was spray dried at inlet and outlet air temperatures of 200 and 90 degrees C, respectively, to obtain WPC. In general, the solubility of WPC was higher at pH 7 than at pH 3. Whey protein concentrate containing EPS2 exhibited higher protein solubility than did WPC containing no EPS. Also, the presence of EPS in WPC decreased protein denaturation. The emulsifying ability of WPC containing EPS was higher than that in control. Addition of EPS to WPC significantly enhanced its gelling ability. Foam overrun and hydrophobicity of WPC were not affected by addition of EPS. In conclusion, data obtained from this study show that EPS modify WPC functionality. The extent of modification depends on the type of EPS. Cooling of culture containing EPS before its addition to whey further reduced WPC protein denaturation and increased its solubility at pH 7 and gel hardness. PMID- 22939785 TI - The effects of social contact and milk allowance on responses to handling, play, and social behavior in young dairy calves. AB - The aim of this study was to investigate the effects of social contact and milk allowance on social behavior, play behavior, and responses to handling in dairy calves. Forty test calves and 16 companion calves were allocated to 1 of 5 treatments from birth to 4 wk of age: (1) housed singly and fed 5 L of milk/d; (2) housed singly and fed 9 L of milk/d; (3) housed in pairs and fed 5 L of milk/d; (4) housed in pairs and fed 9 L of milk/d; or (5) kept with the dam and fed 9 L of milk/d. From 4 to 6 wk of age, all calves were offered 5 L of milk/d to promote intake of solid feed before weaning. At 6 wk of age, all calves were weaned, and at 7 wk of age, they were grouped (7 calves/group: 1 test calf from each treatment and 2 companion calves). The response to restraint during blood sampling was recorded weekly; singly housed calves struggled more during restraint than did calves kept with the dam, and pair-housed calves struggled at an intermediate level. Play behavior was recorded for 20 min/wk after the provision of fresh straw; calves housed singly and fed a low milk allowance spent less time playing than did calves in all other treatments. Three days after grouping, calves were subjected to a feed competition test; calves receiving the high milk allowance and housed in pairs spent more time feeding than did those receiving the high milk allowance and housed singly, with all other treatments showing intermediate responses. These results indicate that social contact decreased responses to restraint and increased play and competitive success. The high milk allowance increased play but reduced competitive success after grouping. Lower responses to restraint indicated less responsiveness to stress. Play is considered an indicator of positive welfare, and competitive success helps calves succeed in a group environment. PMID- 22939786 TI - Environmental contamination with Mycobacterium avium subspecies paratuberculosis within and around a dairy barn under experimental conditions. AB - To establish environmental contamination in and around a dairy barn, cows shedding Mycobacterium avium ssp. paratuberculosis (MAP) were housed in a freestall barn. Fecal samples were collected 15 times at 3-wk intervals, and samples of all animals were cultured by using the Trek Diagnostic Systems culture system (Cleveland, OH) to quantify levels of MAP shedding. In parallel, air and floor dust samples were collected inside and outside the experimental farm and analyzed by IS900 real-time PCR for the presence of MAP DNA. Inside the barn, MAP was detected with equal frequency in samples directly contaminated with feces compared with air dust samples above animal level and in dust samples of the corridor. Dust samples collected within the barn were positive more frequently than outside samples, with exception of the outside sample from the farmer's doormat. The risk of MAP exposure was distributed evenly within the dairy barn. Additionally, footwear should be considered as a high-risk fomite for dispersion of dust-related MAP outside the barn. Prevention of MAP exposure in youngstock may require housing of youngstock in separate barns as an additional management measure. PMID- 22939787 TI - Short communication: genotype imputation within and across Nordic cattle breeds. AB - This study investigated the accuracies of imputation from 50K genotypes to high density genotypes for animals from the Danish, Swedish, or Finnish Red dairy cattle populations, using either a national, combined Red, or combined Red and Holstein reference population. Combining the Red populations increased the imputation accuracy for all 3 populations compared with using single-nationality references. Including Holstein animals in the reference further increased the imputation accuracy for Danish Red. PMID- 22939788 TI - Metabolic characteristics of proteins and biomolecular spectroscopic profiles in different batches of feedstock (wheat) and their co-products (wheat distillers dried grains with solubles) from the same bioethanol processing plant. AB - The objectives of this study were (1) to reveal the metabolic characteristics of proteins in different batches of feedstock (wheat) for bioethanol production and their co-products (wheat distillers dried grains with solubles, wDDGS) from the same bioethanol processing plant, and (2) to characterize biomolecular spectral profile associated with nutrient digestion in the rumen and intestine of dairy cattle. The metabolic characteristics of proteins were determined using the DVE/OEB system (where DVE=total truly absorbed protein supply, and OEB=degraded balance of protein) based on chemical profiles and rumen and intestinal digestion data from dairy cattle. The biomolecular spectral characteristics were investigated by using the molecular spectroscopy technique attenuated total reflectance-Fourier transform infrared spectroscopy (ATR-FT/IR). Multivariate molecular spectral analyses-agglomerative hierarchical cluster analysis (AHCA), and principal component analysis (PCA)-were conducted to identify the spectral differences in biomolecular inherent structure among the wheat and wDDGS batches. The results showed that (1) the metabolic characteristics of proteins in the wheat and wDDGS from the same bioethanol processing plant were significantly affected by batch, with total truly absorbed protein supply (DVE value) ranging from 101 to 116 g/kg of dry matter (DM) in wheat and from 153 to 182 g/kg of DM in wDDGS; (2) the degraded balance of protein (OEB value) in the wDDGS (but not the wheat) from the same bioethanol processing plant was significantly affected by batch, with the OEB value ranging from -19 to -26 g/kg of DM in the wheat and from 145 to 181 g/kg of DM in the wDDGS; and (3) the biomolecular spectral analyses with AHCA and PCA revealed biomolecular spectral profiles and differences among the wheat and wDDGS samples. PMID- 22939789 TI - Combined effect of heat treatment and ionic strength on the functionality of whey proteins. AB - A 5% (wt/vol) whey protein isolate (WPI) dispersion (pH 6.5) with different concentrations of NaCl was submitted to dynamic heat treatment. Protein dispersions were characterized as to their rheological properties, particle sizes, morphology, denaturation temperatures, and protein surface hydrophobicity. At low ionic strength (<200 mmol/kg), gel elastic modulus increased and strongest gel stiffness was achieved. High salt concentrations lead to a weaker gel, whereas no gels at all were formed without salt. The gelation temperature was also influenced by ionic strength and an increase in denaturation temperature and thermal stability was also observed by using differential scanning calorimetry. Additionally, heat-induced changes in secondary structures upon salt augmentation were followed by Fourier transform infrared spectroscopy. Secondary structural elements estimations obtained from amide I assignments were correlated with those from amide III assignments. Upon salt increase, no differences in secondary structure were observed without heating, whereas upon heating and without salt increase, the Fourier transform infrared spectroscopy data revealed an increase in intermolecular beta-sheets at the cost of beta-turns and random coils, with no change in alpha-helical structures. However, NaCl addition along with dynamic heat treatment of WPI dispersion showed a stabilizing effect on the secondary structural elements of both amide I and amide III bands. Whey protein isolate dispersions in water were also characterized by transmission electron microscopy by a spherical shape with 2 populations (6 and 70 nm). Salt increase alone resulted in the formation of denser aggregates, whereas a transition from spherical/compact protein aggregates to linear ones was observed due to combined salt/heat effect. The important size of these edifices was confirmed by microscopy and light-scattering techniques. Moreover, protein surface hydrophobicity related to the number of hydrophobic sites available decreased significantly. Finally, experimental results demonstrated the strong interaction between ionic strength and dynamic thermal treatment on protein functional properties and their careful adjustment could enable the food industry to effectively use WPI as a gelling agent. PMID- 22939790 TI - Effects of natural and simulated rainfall on indicators of ensilability and nutritive value for wilting alfalfa forages sampled before preservation as silage. AB - The frustrations of forage producers attempting to conserve high-quality alfalfa (Medicago sativa L.) silage during periods of unstable or inclement weather are widely known. Our objectives for this series of studies were to (1) assess indicators of ensilability, such as pH, buffering capacity, water-soluble carbohydrates (WSC), and starch for wilting alfalfa forages receiving no rainfall or damaged by simulated or natural rainfall events; (2) use these data as inputs to calculate the threshold moisture concentration that would prohibit a clostridially dominated fermentation; and (3) further evaluate the effects of rain damage or no rain damage on measures of forage nutritive value. Rainfall events were applied to wilting forages by both simulated and natural methods over multiple studies distributed across 4 independent forage harvests. Generally, simulated rainfall was applied to alfalfa under controlled conditions in which forages were relatively wet at the time of application, and subsequently were dried to final moisture endpoints under near ideal conditions within a constant temperature/humidity environmental chamber, thereby limiting postwetting wilting time to <=21 h. As a result, indicators of ensilability, as well as measures of nutritive value, changed only marginally as a result of treatment. Consistently, reductions in concentrations of WSC and starch occurred, but changes in WSC were relatively modest, and postwetting concentrations of WSC may have been buoyed by hydrolysis of starch. When forages were subjected to natural rainfall events followed by prolonged exposure under field conditions, indicators of ensilability were much less desirable. In one study in which alfalfa received 49.3mm of natural rainfall over a prolonged (8-d) field-exposure period, fresh pH increased from 6.48 to 7.43 within all forages exposed to these extended, moist wilting conditions. Furthermore, sharp reductions were observed in buffering capacity (410 vs. 337 meq/kg of DM), WSC (6.13 vs. 2.90%), starch (2.28 vs. 0.45%), and clostridially dominated fermentation (62.7 vs. 59.4%). Based on these experiments, the potential for good fermentation is affected only minimally by single rainfall events applied to relatively wet forages, provided these events are followed by rapid dehydration; however, attaining acceptable silage fermentations with forages subjected to prolonged exposure under poor drying conditions is likely to be far more problematic. PMID- 22939791 TI - Short communication: performance of a blocking antibody ELISA bulk-tank milk test for detection of dairy sheep flocks exposed to border disease virus. AB - The aim of this study was to investigate the test characteristics of a blocking antibody ELISA applied to bulk-tank milk (BTM) samples for the detection of dairy sheep flocks positive for antibodies to border disease virus. In 161 flocks recruited in 2009 and 2010, the antibody inhibition percentage (AIP) in BTM was compared with the prevalence estimate of antibody-positive ewes obtained from an age-representative sample of 45 milking ewes. A strong negative exponential relationship (R(2)=0.89) was found between AIP in BTM and seroprevalence level. Using receiver operating characteristic analysis, the best AIP decision threshold in BTM to discriminate between low (<10%) and high (>=10%) antibody-positive flocks was 65%. Diagnostic performance estimates based on observed seroprevalence levels and Monte Carlo simulations showed that this threshold value was associated with high sensitivity and specificity (91.9+/-5.5% and 95.9+/-1.6%, respectively), whereas the 80% decision threshold recommended in dairy cows yielded lower specificity (83.6+/-2.0%). Results obtained from the same flocks during 2 subsequent milking campaigns showed that the 65% AIP cut-off value was associated with fewer false-positive results and is preferred. Testing of BTM samples could be a powerful tool in inferring border disease virus seroprevalence in a flock and in Pestivirus control schemes in dairy sheep flocks. PMID- 22939792 TI - An alkalinizing oral rehydration solution containing lecithin-coated citrus fiber is superior to a nonalkalinizing solution in treating 360 calves with naturally acquired diarrhea. AB - The aim of this field study was to compare the efficacy and cost of 2 commercially available oral rehydration therapy (ORT) solutions in treating dairy calves with naturally acquired diarrhea. A total of 1,349 newborn Holstein Friesian calves were prospectively enrolled in the study. Calves were housed in individual hutches and fed a mixture of pasteurized hospital milk and an all-milk protein milk replacer twice per day. Calves were monitored twice each day from d 2 of life until 30 d of age for the presence or absence of diarrhea, and were assigned a fecal score and a hydration score at each examination. Calves that developed mild to severe diarrhea that did not need intravenous fluids and did not have clinical evidence of concurrent disease (n = 360) were assigned randomly to receive 1 of 2 commercial ORT solutions: a hypertonic alkalinizing ORT containing lecithin-coated citrus fibers (Diaque, group D, n = 180; Boehringer Ingelheim, Ingelheim, Germany), and an isotonic nonalkalinizing ORT (RE-SORB, group R, n = 180; Pfizer Animal Health, New York, NY) for 2 to 8d; the duration of treatment depended on whether diarrhea was still present. No significant differences were observed in mortality rates or treatment failure rates between the 2 treatment groups. Fecal consistency returned to normal more quickly in group D calves than in group R calves; consequently, group D calves were treated for 1d less than were group R calves. The increase in body weight after 4d of treatment was larger in group D than in group R. The average daily gain from birth to weaning in calves that did not develop concurrent disease (such as pneumonia) during the study period tended to be higher in group D calves (0.53+/ 0.11 kg/d) than in group R calves (0.51+/-0.09 kg/d). The smaller number of treatments at a lower cost per treatment produced a cost advantage of $4.82 per treated calf in group D calves compared with group R calves. Our findings support the concept that milk should continue to be fed to diarrheic calves that are being administered an ORT solution in order to maintain growth. PMID- 22939793 TI - Identification of the critical amino acid residues of immunoglobulin E and immunoglobulin G epitopes in beta-lactoglobulin by alanine scanning analysis. AB - beta-Lactoglobulin represents one of the major allergens causing cow milk allergy. Few studies have clearly evaluated immunological relationships between IgE- and IgG-binding epitopes of beta-lactoglobulin. For characterization of immunological epitopes, peptides of 15 amino acids (AA) in length were synthesized. Immunoglobulin E- and IgG-binding epitopes were immunolabeled with individual sera from cow milk-allergic patients. Alanine scanning of immunodominant epitopes was used to identify the critical AA of IgE- and IgG binding epitopes. The results showed that 4 IgE-binding epitopes were identified. Our initial data revealed IgE-binding epitopes at AA 17 to 31, AA 72 to 86, AA 92 to 106, and AA 152 to 166. Threonine 20, Met23, and Asp27 are the critical AA of IgE-binding epitopes. Two IgG epitopes were identified, which were located at AA 22 to 36 and AA 127 to 141. The critical AA of IgG-binding epitopes were Leu26 and Val31. Results obtained from this study will provide necessary information to alter the cDNA to encode a protein capable of activating milk-specific T cells, but with reduced IgE- or IgG-binding capacity. PMID- 22939794 TI - Effect of different treatments on the ability of alpha-lactalbumin to form nanoparticles. AB - Nanoparticles of bovine alpha-lactalbumin (alpha-LA) prepared by desolvation and glutaraldehyde crosslinking are promising carriers for bioactive compounds in foods. The objective of this work was to study the effect of changes in hydrophobic interactions by using different desolvating agents (acetone, ethanol, or isopropanol) and the use of a heat or high-pressure treatment step before the desolvation process on the size, structure, and properties of alpha-LA nanoparticles. In all cases, a high average particle yield of 99.63% was obtained. Smaller sizes (152.3 nm) can be obtained with the use of acetone as the desolvating agent and without any pretreatment. This is the first time that alpha LA nanoparticles in the size range of 100 to 200 nm have been obtained. These nanoparticles, with an isoelectric point of 3.61, are very stable at pH values >4.8, based on their zeta-potential, although their antioxidant activity is weak. The use of the desolvating agent with the smallest polarity index (isopropanol) produced the largest particles (293.4 to 324.9 nm) in all cases. These results support the idea that controlling hydrophobic interactions is a means to control the size of alpha-LA nanoparticles. No effect of pretreatment on nanoparticle size could be detected. All types of nanoparticles were easily degraded by the proteolytic enzymes assayed. PMID- 22939795 TI - Short communication: lying behavior of lactating dairy cows is influenced by lameness especially around feeding time. AB - Lameness is considered one of the most common welfare and productive problems in dairy cattle. The objective of this study was to evaluate differences in lying behavior between moderately lame and nonlame lactating cows under commercial conditions. Data were collected from 10 free-stall commercial herds, which were feeding on exactly the same ration once daily. All lactating cows were scored for lameness according to a 1 to 5 locomotion scoring system. Only cows with a lameness score between 1 and 4 were considered in the study. In each herd, between 10 and 15 lame cows (scored as 3 or 4) were chosen, and for each lame cow, a nonlame cow (scored as 1) within the same parity and similar days in milk was also selected. Pendant data loggers were then placed on the right hind leg of each cow for 10 d to record lying behavior at 1-min intervals. In addition, the time of feed delivery was recorded in each herd on a daily basis. Total daily lying time, daily number of lying bouts, lying bout duration, laterality (side of recumbence), and lying behavior around feed delivery time were evaluated using a mixed-effects model that accounted for the fixed effects of lameness, days in milk, parity, and the interaction between parity and lameness, plus the random effects of herd. Total daily lying time (721+/-24.2 min/d) tended to increase with days in milk, but it was not affected by lameness or parity. Likewise, no differences were found in the number of lying bouts (9.6+/-0.49/d) or laterality (47+/-2.6% of time lying on the right side). However, the mean bout duration was longer in lame (89.3+/-3.89 min) compared with nonlame (80.7+/-3.90 min) cows. It is interesting that lame cows stood up 13 min later than nonlame cows relative to the time when the ration was delivered. In addition, lame cows lay down 19 min earlier than nonlame ones after the feed was delivered, which implies that nonlame cows spent more time standing, and probably eating, than did lame cows. It was concluded that lame cows have longer lying bouts than nonlame animals, and that lying behavior around feed delivery time may be an effective proxy to identify moderately lame cows. PMID- 22939796 TI - Infection dynamics of digital dermatitis in first-lactation Holstein cows in an infected herd. AB - Digital dermatitis (DD) refers to painful lesions primarily affecting the skin in the interdigital region of dairy cattle. The purpose of this study was to evaluate the dynamics of DD in 39 cows, observed at approximately 3-d intervals, for the first 6 mo of lactation. Specifically, the study aimed at evaluating different levels of DD susceptibility in cows, identifying the bacterial colonization of the interdigital skin, and exploring the relationship between clinical DD diagnosis and laboratory findings. Three different susceptibility categories were identified for DD: 1=consistently healthy cow; 2=intermittently infected cow; and 3=consistently infected cow. Susceptibility categories were associated with age at calving. The average age at calving was 775 d (SD +/ 43.4), with the youngest heifer calving at age 669 d and the oldest heifer at 858 d. Advancing age at calving was associated with greater odds of being intermittently or consistently infected. This corresponded with an odds ratio of 2.02 over a period of 30 d. During the study period, 161 DD lesions were identified in 28 of the 39 cows (72%). Of those 28 cows, 13 cows were consistently infected. The remaining 11 of the 39 cows (28%) showed slight thickening of the skin with no pain (5 cows) and no signs of skin changes (6 cows). Histopathology and fluorescence in situ hybridization were possible to perform on 132 biopsy samples. A clinical diagnosis of DD was confirmed in 70% of the lesions by histopathology, and colonization of Treponema spp. Dichelobacter nodosus was found in 35 samples (29%). PMID- 22939797 TI - Evaluation of antimicrobial edible coatings from a whey protein isolate base to improve the shelf life of cheese. AB - The objective of this work was to evaluate the effectiveness of antimicrobial edible coatings to wrap cheeses, throughout 60 d of storage, as an alternative to commercial nonedible coatings. Coatings were prepared using whey protein isolate, glycerol, guar gum, sunflower oil, and Tween 20 as a base matrix, together with several combinations of antimicrobial compounds-natamycin and lactic acid, natamycin and chitooligosaccharides (COS), and natamycin, lactic acid, and COS. Application of coating on cheese decreased water loss (~10%, wt/wt), hardness, and color change; however, salt and fat contents were not significantly affected. Moreover, the antimicrobial edible coatings did not permit growth of pathogenic or contaminant microorganisms, while allowing regular growth of lactic acid bacteria throughout storage. Commercial nonedible coatings inhibited only yeasts and molds. The antimicrobial edible coating containing natamycin and lactic acid was the best in sensory terms. Because these antimicrobial coatings are manufactured from food-grade materials, they can be consumed as an integral part of cheese, which represents a competitive advantage over nonedible coatings. PMID- 22939798 TI - Genetic and nongenetic variation in plasma and milk beta-hydroxybutyrate and milk acetone concentrations of early-lactation dairy cows. AB - This study assessed genetic variation, heritability estimates, and genetic correlations for concentrations of plasma beta-hydroxybutyrate (BHBA), milk BHBA, and milk acetone in early lactation to investigate differences between cows in susceptibility to hyperketonemia and possibilities to use test-day milk ketone bodies for genetic improvement. Blood and test-day milk samples were collected on randomly selected dairy farms in the Netherlands from cows of various parities between 5 and 60 d in milk. Plasma samples were analyzed for BHBA (reference test for hyperketonemia) and test-day milk samples were analyzed for BHBA and acetone using Fourier-transform infrared spectroscopy. The final data set consisted of plasma BHBA concentrations of 1,615 cows from 122 herds. Milk BHBA and milk acetone concentrations were determined for 1,565 cows. Genetic variation, heritability, and proportion of phenotypic variation attributable to the herd were estimated using an animal model with fixed effects for parity and season, a covariate for days in milk, and random effects for herd, animal, and error. Genetic correlations for plasma BHBA, milk BHBA, and milk acetone were estimated using bivariate analyses. The heritability estimate for plasma BHBA concentrations in early lactation was 0.17, whereas heritability estimates for milk BHBA and milk acetone were 0.16 and 0.10, respectively. This indicates that selective breeding may contribute to a lower incidence of hyperketonemia in early lactation. For the 3 traits, the proportion of variance attributable to herd was larger than the additive genetic variance, underlining the importance of on-farm feeding and management in the etiology of hyperketonemia in fresh cows. Prevention strategies for hyperketonemia can, therefore, include both feeding and management strategies at dairy farms (short-term) and genetic improvement through breeding programs (long-term). Genetic correlations between concentrations of plasma BHBA and milk BHBA (0.52) or milk acetone (0.52) were moderate. As milk ketone bodies can be routinely analyzed at test days, this may provide a practical alternative for breeding programs aimed at reducing hyperketonemia in early lactation. PMID- 22939799 TI - Effect of xylitol on the functional properties of low-fat process cheese. AB - Process cheese (PC) is a dairy food prepared by blending natural cheese, salt, emulsifying salts, and other dairy and nondairy ingredients, and heating with continuous agitation to produce a homogeneous product. Fat is a critical component of PC and plays an important role in its functional characteristics. The health concerns associated with fat consumption have led to an increase in the demand for low-fat dairy products. Reducing the fat content of PC results in poor functional properties such as increased hardness and reduced melt characteristics. The objective of the current study was to evaluate the effect of xylitol on the functional properties of low-fat PC. Three different low-fat PC formulations were prepared with 0% (control), 2%, and 4% xylitol. All 3 PC formulations were formulated to contain 5% fat, and each treatment was manufactured in triplicate. Rheological characteristics including elastic modulus, viscous modulus, and temperature at Tandelta = 1 (melt temperature) were determined using dynamic stress rheometry (DSR). The DSR was carried out at a frequency of 1.5 Hz and stress levels of 400 Pa, using a temperature sweep from 20 to 90 degrees C. The hardness of the samples was determined by using texture profile analysis (TPA). Compositional analysis indicated that all treatments had similar fat, protein, and moisture contents. Elastic and viscous moduli results obtained with DSR showed a significant difference between 0% xylitol (control) and xylitol-containing treatments in the temperature range of 30 to 80 degrees C. The melt temperature was not significantly different between the 3 treatments. However, TPA demonstrated that the addition of xylitol significantly decreased the hardness of low-fat PC. Based on TPA and DSR data obtained in this study, we determined that xylitol addition improved the functional properties of low-fat PC. PMID- 22939800 TI - Antiplatelet treatment in primary and secondary stroke prevention in women. AB - Stroke is a leading cause of death worldwide and the first cause of disability in the Western world. Over the last 20 years, antiplatelet agents have reduced overall stroke rates in primary and secondary prevention in men. However, this has not been the case for women. In this narrative review, the most widely used antiplatelet therapies for primary and secondary prevention in stroke, excluding cardioembolic stroke, will be outlined. First, the largest randomised controlled trials will be analysed as well as the enrolment percentages of women. Second, analyses on sex-interaction effects in each study will be examined. Moreover, the Authors will discuss the need to develop targeted antiplatelet therapies specifically for women. Based on current results, the most randomised clinical trials and meta-analyses on antiplatelet agents in cerebrovascular disease have not performed sub-analyses on sex-related differences and this is mainly because women were underrepresented. Despite this, antiplatelet agents are considered to be equally effective for both sexes in primary and secondary stroke prevention. Finally, aspirin is the most widely studied antiplatelet in women and has been shown to provide greater benefit for women as primary prevention of ischemic stroke without a significant increased risk in haemorrhage. PMID- 22939801 TI - Obstructive sleep apnea syndrome. AB - Obstructive sleep apnea (OSA) syndrome is a common but often unrecognized disorder caused by pharyngeal collapse during sleep and characterized by frequent awakenings, disrupted sleep and consequent excessive daytime sleepiness. With the increasing epidemic of obesity, the most important risk factor for OSA, prevalence of the disease will increase over the coming years thus representing an important public-health problem. In fact, it is now recognized that there is an association between OSA and hypertension, metabolic syndrome, diabetes, heart failure, coronary artery disease, arrhythmias, stroke, pulmonary hypertension, neurocognitive and mood disorders. Diagnosis is based on the combined evaluation of clinical manifestations and objective sleep study findings. Cardinal symptoms include snoring, sleepiness and significant reports of sleep apnea episodes. Polysomnography represents the gold standard to confirm the clinical suspicion of OSA syndrome, to assess its severity and to guide therapeutic choices. Behavioral, medical and surgical options are available for the treatment. Continuous positive airway pressure (CPAP) represents the treatment of choice in most patients. CPAP has been demonstrated to be effective in reducing symptoms, cardiovascular morbidity and mortality and neurocognitive sequelae, but it is often poorly tolerated. The results of clinical studies do not support surgery and pharmacological therapy as first-line treatment, but these approaches might be useful in selected patients. A better understanding of mechanisms underlying the disease could improve therapeutic strategies and reduce the social impact of OSA syndrome. PMID- 22939802 TI - The association of Raynaud's syndrome with cisplatin-based chemotherapy - a meta analysis. AB - BACKGROUND: Vasospastic disorders of the digital circulation such as the Raynaud's syndrome (RS) are known side-effects of treatment of cisplatin-based chemotherapy. The prevalence of RS in patients during treatment with cisplatin based chemotherapy is not well-defined. OBJECTIVE: The objective of this paper was to assess the prevalence of RS in patients receiving cisplatin-based chemotherapy - a meta-analysis of published data was performed. MATERIAL AND METHODS: The PubMed database of the National Library of Medicine and ISI Web of Knowledge was used for studies dealing with RS and patients receiving cisplatin based chemotherapy. The studies provided sufficient data to estimate the prevalence of RS in patients receiving cisplatin-based chemotherapy. A forest plot was determined by the revealed prevalences. Statistical analysis was based on methods for a random effects meta-analysis and a finite mixture model for proportions. Publication bias was investigated with the linear regression test (Egger's method). A meta-regression was conducted by the year of publication and latitude. RESULTS: 24 eligible studies, contributing data on 2749 subjects, were included in this meta-analysis. For RS in patients receiving cisplatin-based chemotherapy a pooled prevalence of 24% and 95% CI (0.175, 0.313) was obtained. A mixture model analysis found four latent classes. Statistically, publication bias was not present (p-value 0.74). The meta-regression indicated that the odds ratio increased when the latitude increased, too (p-value 0.011). CONCLUSION: Despite some heterogeneity there is a possible indication of an association between RS and patients receiving cisplatin-based chemotherapy. PMID- 22939803 TI - Prognostic value of serum cystatin C and N-terminal pro b-type natriuretic peptide in patients with acute heart failure. AB - BACKGROUND: Cystatin C (CysC) is a good prognostic marker in heart failure. However, there is not much information of CysC combined with other biomarkers in acute heart failure (AHF). AIM: To assess prognostic value of CysC and N-terminal pro-brain natriuretic peptide (NT-proBNP) in patients hospitalized for AHF with no apparent deterioration of renal function. DESIGN: Prospective, multicenter, observational study. METHODS: CysC and NTpro-BNP were measured in patients consecutively admitted with a diagnosis of AHF. Patients with, NTpro-BNP concentration above 900 pg/mL and serum creatinine below 1.3mg/dL, were included for statistical analysis. End-point of the study was all-cause mortality during a 12-month follow-up. RESULTS: 526 patients with AHF and NTpro-BNP concentration above 900 pg/mL were included in the study. From this group, 367 patients (69.8%) had serum creatinine below 1.3mg/dL. Receiver operating characteristic (ROC) curves were used to determine the best cut-off value for CysC. Patients with a concentration of CsyC above 1.25mg/dL had a 37.8% mortality rate, vs. 13.6% for those below cut-off (p<0.001). After Cox proportional hazard model, age, CysC, low total cholesterol and HF with preserved ejection fraction remained significantly associated with all-cause mortality during one-year follow-up. CONCLUSIONS: In AHF and normal or slightly impaired renal function, performance of CysC may be superior to NT-proBNP. Hence, CysC may be the preferred biomarker in the assessment of patients with AHF and slightly impaired renal function. PMID- 22939804 TI - Red blood cell distribution width and its relation to cardiac function and biomarkers in a prospective hospital cohort referred for echocardiography. AB - BACKGROUND: Red blood cell distribution width (RDW), a measure of anisocytosis, is a prognostic biomarker for heart failure (HF). However it is still unclear how RDW is associated with heart function and established cardiac biomarkers. METHODS AND RESULTS: In a prospective hospital cohort of 296 patients referred for echocardiography because of suspected HF, blood sampling and clinical examination were performed within 24h after echocardiography. The patients were divided into four HF groups, including one group where the HF diagnosis was uncertain (gray zone). In the patients the mean age was 70 +/- 11 years, 44% with systolic HF (SHF), 18% with heart failure with normal ejection fraction (HFNEF), 17% with gray zone and 21% without HF (non-HF). RDW was higher among patients with SHF and HFNEF, compared with gray zone and non-HF patients. The distribution of different variables over the RDW quartiles showed an inverse correlation between RDW levels and LVEF and a positive correlation between RDW and NT-proBNP levels. Further analysis with stepwise multiple linear regression demonstrated that NT-proBNP levels, but not LVEF, were independently correlated with RDW. CONCLUSION: In patients referred for echocardiography because of suspected HF, RDW levels were higher in patients with SHF and HFNEF. Moreover, NT-proBNP levels were independently linked with elevated RDW. PMID- 22939805 TI - The effects of electrode misplacement on clinicians' interpretation of the standard 12-lead electrocardiogram. AB - INTRODUCTION: This study investigates how a particular incorrect electrode configuration affects the 12-lead Electrocardiogram (ECG). METHODS: A correct and an incorrect 12-lead ECG were extracted from a 192-lead BSPM. This was done for 232 BSPMs yielding 464 12-lead ECGs. The particular incorrect ECG involved displacing electrodes V1 and V2 in the second intercostal space whilst also offsetting the remaining electrodes. These ECGs were examined in two stages: (a) analysis of the effects of electrode misplacement on signal morphology and (b) analysis of how often the incorrect electrode configuration changed the diagnosis of two clinicians in a random sample of 75 patients. RESULTS: According to the Root Mean Square Error (RMSE) of the difference between PQRST intervals in the correct and incorrect ECGs, lead V2 is the most affected lead (mean: 185 MUV +/- 82 MUV), followed by lead V4 (mean: 114 MUV +/- 59 MUV) and lead V1 (mean: 100 MUV +/- 47 MUV). It was found that if the incorrect electrode configuration is applied, there is a 17% to a 24% chance the diagnostic interpretation will be different. Quantified using Similarity Coefficient (SC) leads V1 and V2 were found to be more alike when misplaced in the second intercostal space. The average SC between these leads when correctly placed was 0.08 (+/- 0.65), however when incorrectly placed, the average SC was 0.43 (+/- 0.3). CONCLUSION: There is a reasonable chance this particular incorrect electrode configuration will change the diagnosis of the 12-lead ECG. This highlights the importance of developing algorithms to detect electrode misplacement along with better education regarding ECG acquisition. PMID- 22939806 TI - Plasma metalloproteinase-9 and restrictive filling pattern as major predictors of outcome in patients with ischemic cardiomyopathy. AB - OBJECTIVE: Assessment of plasma matrix metalloproteinase-9 (MMP-9) and Doppler markers of increased left ventricular (LV) filling pressure may be added to risk stratify patients with ischemic cardiomyopathy (IC). Therefore, we aimed at investigating the value of plasma MMP-9 and restrictive filling pattern (RFP) in IC patients. METHODS: Eighty-eight consecutive patients hospitalized for heart failure (LV ejection fraction <= 40%) due to IC were enrolled. A complete M-mode and two-dimensional echo-Doppler examination were performed. Patients were defined as having RFP if they had a mitral E wave deceleration time<150 ms. Plasma MMP-9 and N-terminal protype-B natriuretic peptide levels were assessed at the time of the index echocardiogram. The end point was all-cause mortality or hospitalization for worsening HF. Follow-up period was 25 +/- 17 months. RESULTS: Median value of MMP-9 was 714 ng/ml. On univariate analysis, a number of measurements predicted the composite end point: NYHA class>2, RFP, MMP-9>60.5 ng/ml, LV ejection fraction<27%, anemia, pulmonary pressure >= 35 mm Hg, N terminal protype-B natriuretic peptide>1742 pg/ml, and glomerular filtration rate<60 ml/min/1.73 m(2). Independent variables of outcome were anemia (HR=1.9, p=0.031), and the combination of plasma MMP-9 and RFP (HR=3.2, p=0.004). On Kaplan-Meier survival curves, patients with elevated MMP-9 levels and RFP had the lowest event-free survival rate (log-rank: 29.0, p<0.0001). The net reclassification improvement showed a significant increase in the prediction model when elevated MMP-9 and RFP were added to the base model that included clinical, biochemical and echocardiographic parameters (p<0.0001). CONCLUSION: MMP-9 levels and RFP have an incremental predictive value to risk classify IC patients. PMID- 22939807 TI - Pacing of the interventricular septum versus the right ventricular apex: a prospective, randomized study. AB - BACKGROUND: Left ventricular (LV) function may be impaired by right ventricular (RV) apical pacing. The interventricular septum is an alternative pacing site, but randomized data are limited. Our aim was to compare ejection fraction (EF) resulting from pacing the interventricular septum versus the RV apex. METHODS: RV lead implantation was randomized to the apex or the mid-septum. LVEF and RVEF were determined at baseline and after 1 and 4 years by radionuclide angiography. RESULTS: We enrolled 59 patients, of whom 28 were randomized to the apical group and 31 to the septal group, with follow-up available in 47 patients at 1 year and 33 patients at 4 years. LVEF in the apical and in the septal groups was 55 +/- 8% vs. 46 +/- 15% (p=0.021) at 1 year and 53 +/- 12% vs. 47 +/- 15% (p=0.20) at 4 years. Echocardiography confirmed a mid-septal lead position in only 54% of patients in the septal group, with an anterior position in the remaining patients. In the septal group, LVEF decreased significantly in patients with an anterior RV lead (-10.0 +/- 7.7%, p=0.003 at 1 year and -8.0 +/- 9.5%, p=0.035 at 4 years), but not in patients who had a mid-septal lead. Left intraventricular dyssynchrony was significantly increased in case of an anterior RV lead. RVEF was not significantly impaired by RV pacing, regardless of RV lead position. CONCLUSIONS: Pacing at the RV septum confers no advantage in terms of ventricular function compared to the apex. Furthermore, inadvertent placement of the RV lead in an anterior position instead of the mid-septum results in reduced LV function. PMID- 22939808 TI - Haptoglobin genotype and cardiovascular outcomes in diabetes mellitus - natural history of the disease and the effect of vitamin E treatment. Meta-analysis of the medical literature. AB - BACKGROUND: Diabetes mellitus carries a high risk for vascular events. Diabetics with different haptoglobin (Hp) types may carry different risk profiles, and may respond differently to vitamin E treatment. We aim to summarize the evidence about cardiovascular risk in diabetic patients, according to their Hp type, and the effect of vitamin E treatment on these sub-groups. METHODS: We searched MEDLINE and on-going trials' databases until February 2011; gray literature; reference lists of identified articles; and experts. Two investigators screened and selected studies that prospectively followed cardiovascular outcomes in diabetic patients with different Hp types (natural history analysis), and randomized controlled trials reporting the effect of vitamin E on cardiovascular outcomes in diabetics, in which Hp typing was performed (interventional analysis). RESULTS: Five and three studies, comprising 1829 and 2110 patients, were eligible for the natural history and the interventional analyses, respectively. The percentage of diabetic patients experiencing non-fatal MI, stroke, or cardiovascular death was significantly higher in the Hp 2-2 population (odds ratio (OR) 2.03 (95% confidence interval (CI) 1.46 to 2.81)). In patients with Hp 2-2 genotype, the OR for a combined endpoint was 0.66 in favor of the vitamin E treated group (95% CI 0.48 to 0.9). This effect was not shown in other Hp types. CONCLUSION: Hp type 2-2 carries a high risk of cardiovascular events in diabetic patients. A pharmacogenomic approach towards treatment of diabetic patients with vitamin E may be warranted. PMID- 22939809 TI - The prevalence of renal artery stenosis among patients with diabetes mellitus. AB - BACKGROUND: Patients with diabetes mellitus (DM) have a high prevalence of atherosclerotic vascular lesions. It is therefore reasonable to assume that also the rate of renal artery stenosis (RAS) is higher. The presence of a RAS can have implications for the treatment of patients with diabetes mellitus and hypertension and renal impairment. Therefore it is important to be informed about the chance that a RAS is present among such patients. METHODS: We prospectively studied the prevalence of atherosclerotic renal artery stenosis (RAS) among patients with diabetes mellitus. Patients were included if they were diagnosed with DM and hypertension with or without impairment of renal function. If causes of renal disease other than DM or hypertension were more probable on the basis of biochemical data, then such patients were excluded. A magnetic resonance angiography (MRA) of the renal arteries was made in 54 included successive patients. RESULTS: PATIENT CHARACTERISTICS: mean age 59 +/- 8.5 years (range 35 to 80). Eight patients had DM 1 and 46 DM 2. Mean BMI was 31.4 +/- 5.6 kg/m(2). A RAS was present in 18 of the 54 (33%) patients, 3 patients had bilateral stenoses. Factors related to the presence of RAS were diastolic blood pressure, glomerular filtration rate and dyslipidaemia. CONCLUSION: In this group of diabetic patients with hypertension and or renal impairment the prevalence of RAS was 33%. PMID- 22939810 TI - Resistant hypertension in visceral obesity. AB - BACKGROUND: Visceral obesity increases the risk of arterial hypertension (78% of cases of hypertension in men and 65% of cases in women). The aim of the study is to assess the role of visceral obesity in causing resistant hypertension (RH). METHODS: The survey was performed on 5065 hypertensive patients with visceral obesity. BP control was analyzed on the basis of office and home BP measurements. Patients reporting non-compliance were excluded from the study. RESULTS: The percentage of RH after excluding undertreated patients (receiving less than 3 drugs or on at least 3-drug regimen without diuretic and without reaching target BP goal) was 13.9%. RH was more frequent only in obese with BMI >= 35 and <40 kg/m(2) (16.2%) and in morbidly obese individuals (26.5%). Patients with BMI >= 35 and <40 kg/m(2) and with morbid obesity were receiving three-drug therapy more frequently than patients with visceral obesity and BMI<30 kg/m(2). A multiple regression analysis revealed that obesity was associated with RH independent from longer than 5-year period of antihypertensive therapy, diabetes, smoking cigarettes, cardiovascular disease and heart failure. The analysis of home BP measurement revealed that in 11.1% of patients RH was in fact "white coat" hypertension. CONCLUSIONS: Undertreatment, underuse of diuretics in multidrug regimens, and the "white-coat" effect are the most common reasons for over diagnosing resistant hypertension in patients with visceral obesity. Obesity is an independent risk factor for the occurrence of RH. PMID- 22939811 TI - Reduced heme oxygenase-1 expression in steatotic livers infected with hepatitis C virus. AB - Hepatic nonalcoholic fatty liver disease (NAFLD) is known to exacerbate liver injury due to chronic hepatitis C infection. Heme oxygenase-1 (HO-1) is an important protective antioxidative defense enzyme that is known to be induced in response to NAFLD and other liver injuries. The aim of this study was to evaluate HO-1 expression in HCV infected human livers with concomitant NAFLD. METHODS: We compared levels of HO-1 in NAFLD liver biopsies from patients with or without chronic HCV infection using immunohistochemistry, immunoblots and real time RT PCR. We also evaluated frozen sections of liver with dihydroethidium (DHE) or dichlorofluorescein (DCF) fluorescence staining to evaluate O(2)(-) and peroxide production respectively. RESULTS: HO-1 expression was only increased in NAFLD livers without HCV infection, while HCV infected livers showed reduced HO-1 levels, regardless whether NAFLD was present. In uninfected livers with NAFLD, HO 1 expression was primarily localized in hepatocytes containing fat and areas of injury around the central vein. However, both NAFLD with and without concomitant HCV infection showed high levels of O(2)(-) or peroxide production compared to normal human liver control samples. CONCLUSIONS: These findings support the hypothesis that NAFLD is an important process for hepatocyte oxidative stress and injury in liver diseases. They also suggest that HCV can repress HO-1 induction in vivo even when other inducers of HO-1 are present. PMID- 22939812 TI - Mean platelet volume and beta-thromboglobulin levels in familial Mediterranean fever: effect of colchicine use? AB - BACKGROUND: Many studies have shown that subclinical inflammation persisted during remission period of Familial Mediterranean Fever (FMF) patients but long term effects of subclinical inflammation in these patients aren't clearly known. Besides, a few of the recent studies revealed that risk of atherosclerosis had increased in FMF patients. beta-Thromboglobulin (beta-TG) is considered as a sensitive marker of platelet activation. In this study Mean Platelet Volume (MPV) and beta-TG levels were evaluated in FMF patients. METHODS: Following the Local Ethics Committee's consent, 25 FMF patients were included in the study. Twenty eight age and sex matched healthy volunteers were recruited as a control group. Lipid profile, inflammatory parameters, hemogram, beta-TG, MPV were assessed. Statistical analysis was performed with SPSS for Windows 16.00. RESULTS: Group I consisted of 25 FMF cases (16 females, 9 males; mean age: 35.72 +/- 12.34 years), Group II consisted of 28 cases (22 females, 6 males; mean age 31.78 +/- 10.31 years). There was no statistically significant difference between the groups in terms of age and gender distribution, smoking status, total cholesterol, triglyceride, LDL and MPV (p>0.05). HDL levels were found to be statistically lower in Group I (p:0.04). Median beta-TG levels was significantly higher in Group II than Group I (129.50 (range:372.00) ng/mL versus 104.00 (range:212.80) ng/mL respectively; p:0.03). CONCLUSION: In this study MPV and beta-TG were evaluated for FMF cases and healthy controls, beta-TG levels were found significantly lower among patients; we hypothesized that this difference may have resulted from the effect of colchicine use on platelet functions. PMID- 22939813 TI - Antibodies against the N-terminal domain of annexin A2 in antiphospholipid syndrome. AB - Annexin A2 (ANXA2, an endothelial cell receptor for plasminogen and tissue plasminogen activator) has been identified as a new autoantigen in antiphospholipid syndrome (APS). The aim of the present study was to evaluate the presence of antibodies against the N-terminal domain of annexin A2 (ANXA2) in primary APS (PAPS). By using a synthetic peptide corresponding to the 31N terminal amino acids of ANXA2 (ANXA2(N31)) as an antigen, we performed an enzyme linked immunosorbent assay (ELISA) to measure anti-ANXA2(N31) IgG and IgM antibodies in the serum of PAPS patients (n=19), systemic lupus erythematosus (SLE) patients (n=50) and healthy blood donors (n=106). We did not find any statistically differences between the three groups in terms of IgG and IgM anti ANXA2(N31) titres. Elevated IgG anti-ANXA2(N31) titres were not observed in the serum of PAPS or SLE patients who had previously tested positive for anti-ANXA2 antibodies. Thus, the ANXA2 N-terminal domain does not appear to be the target antigen for anti-ANXA2 antibodies in APS. PMID- 22939814 TI - Hypovitaminosis D: don't forget dementia. PMID- 22939816 TI - WITHDRAWN: Molecular Characteristics of Bone Marrow Mesenchymal Stem Cells: An Appealing Source for Regenerative Medicine. AB - The Publisher regrets that this article is an accidental duplication of an article that has already been published, http://dx.doi.org/10.1016/j.hlc.2012.04.021. The duplicate article has therefore been withdrawn. PMID- 22939815 TI - Recent advances in bone tissue engineering scaffolds. AB - Bone disorders are of significant concern due to increase in the median age of our population. Traditionally, bone grafts have been used to restore damaged bone. Synthetic biomaterials are now being used as bone graft substitutes. These biomaterials were initially selected for structural restoration based on their biomechanical properties. Later scaffolds were engineered to be bioactive or bioresorbable to enhance tissue growth. Now scaffolds are designed to induce bone formation and vascularization. These scaffolds are often porous, made of biodegradable materials that harbor different growth factors, drugs, genes, or stem cells. In this review, we highlight recent advances in bone scaffolds and discuss aspects that still need to be improved. PMID- 22939817 TI - Ethnicity and the risk of development of Crohn's disease of the ileal pouch. AB - BACKGROUND: A system-wide, multi-ethnicity study on Crohn's disease (CD) of the pouch, including Indian American (IA) patients has not been conducted. AIM: To compare the frequency of subsequent development of CD of the pouch for African American (AA), Hispanic-American (HA), IA and Caucasian patients with ulcerative (UC) undergoing ileal-pouch anal anastomosis (IPAA). METHODS: In this historical cohort study from our Pouch Registry, patients with restorative proctocolectomy and IPAA for IBD with identifiable, self-declared racial background (i.e. AA, HA, IA or Caucasian) were included. Univariable and multivariable analyses were performed to identify risk factors for CD of the pouch. RESULTS: The study included 235 patients: AA (N=26), HA (N=37), IA (N=22) and randomly selected Caucasian (N=150) controls. Greater number of HA and Caucasians had a history of smoking than IA (27.3% and 27.0% vs. 0; p=0.007). Caucasians and HA were also more likely to have a family history of IBD than IA or AA (25% vs. 27% vs. 5% vs. 4%; p=0.016.) IA less frequently had extensive colitis before colectomy than Caucasians (71.4% vs. 94.0%; p=0.004) and more frequently required anti-TNF biologics than HA (22.7% vs. 0; p=0.016). On multivariable logistic regression analysis, AA (odds ratio [OR]=10.1, 95% confidence interval [CI]: 1.03, 1365.8, p=0.004) and Caucasians (OR=11.1, 95% CI: 1.4, 1427.2, p=0.015) had a higher risk of developing CD of the pouch than IA. However, the event-free survival was not significantly different between the groups on Cox regression analysis, presumably due to the sample size. CONCLUSION: Racial background may be associated with different risk for the development of CD of the pouch for patients with IBD undergoing IPAA. PMID- 22939818 TI - Cognitive disconnective syndrome by single strategic strokes in vascular dementia. AB - Strategic regions correspond to associative, limbic and paralimbic structures and related circuits, that underpin cognitive/behavioral functions. Strokes in these eloquent sites produce pictures of vascular dementia with syndromic features due to specific site lesion and/or interruption of their interconnections. This study aims at analysing subcortical strategic strokes that express similar cognitive/behavioral elements, by sharing common pathways. Patients (n=6) who attended in specialized ambulatory, were submitted to neuropsychological and neuroimaging assessments through MRI (GE Signa Horizon 1.5T) and brain SPECT (Millennium MG, ECD [TC-99m]). Stroke locations and respective main symptoms were: 1. anteromedian thalamus [L]: anterograde and retrograde amnesia (ARA), expression aphasia (EA), executive dysfunction (ED), apathy, and depression; 2. anterior thalamus [R]: ARA, inattention, apathy, and aggressiveness; 3. dorsomedian thalamus [L]: inattention, ED, anosognosia, and aggressiveness; 4. central paramedian thalamus [R]: EA, visual perception deficits (VPD), ED, infantility, and personality disorder; 5. caudate nucleus (ventral-head) [L]: VPD, ED, delirium, visual hallucinations, and personality disorder; and 6. anterior capsule [L]: VPD, ED, apathy, and depression. Vascular strategic syndromes connote the predominantly impaired cognitive/behavioral symptom of each site. Temporal and frontal disconnection symptoms were produced by disrupted MTT/hippocampal and IML/amygdala circuits expressing amnesic syndrome associated with heterogeneous dysexecutive syndrome, in all the cases, by disrupting frontal basal ganglia-thalamus-cortical net, in three different levels of their pathway. PMID- 22939821 TI - Elastic constants of Ultrasonic Additive Manufactured Al 3003-H18. AB - Ultrasonic Additive Manufacturing (UAM), also known as Ultrasonic Consolidation (UC), is a layered manufacturing process in which thin metal foils are ultrasonically bonded to a previously bonded foil substrate to create a net part. Optimization of process variables (amplitude, normal load and velocity) is done to minimize voids along the bonded interfaces. This work pertains to the evaluation of bonds in UAM builds through ultrasonic testing of a build's elastic constants. Results from ultrasonic testing on UAM parts indicate orthotropic material symmetry and a reduction of up to 48% in elastic constant values compared to a control sample. The reduction in elastic constant values is attributed to interfacial voids. In addition, the elastic constants in the plane of the Al foils have nearly the same value, while the constants normal to the foil direction have much different values. In contrast, measurements from builds made with Very High Power Ultrasonic Additive Manufacturing (VHP UAM) show a drastic improvement in elastic properties, approaching values similar to that of bulk aluminum. PMID- 22939820 TI - The kynurenine pathway in neurodegenerative diseases: mechanistic and therapeutic considerations. AB - The kynurenine pathway (KP), the primary route of tryptophan degradation in mammalian cells, consists of many metabolites including kynurenic acid (KYNA), quinolinic acid (QUIN), 3-hydroxykynurenine (3-HK) and picolinic acid (PIC). The former two are neuroactive, while the latter two are molecules with pro-oxidants and antioxidants properties. These agents are considered to be involved in aging and numerous neurodegenerative diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD) and amyotrophic lateral sclerosis (ALS). Several studies have demonstrated that altered kynurenine metabolism plays an important role in the pathogenesis of this group of diseases. The important metabolites and key enzymes show significant importance in those disorders. Both analogs of the neuroprotective metabolites and small molecule enzyme inhibitors preventing the formation of neurotoxic compounds may have potential therapeutic significance. In this review we discuss the mechanistic and therapeutic considerations of KP in aging and the main neurodegenerative diseases and review the updated knowledge in this therapeutic field. PMID- 22939822 TI - The effectiveness of pedicled groin flaps in the treatment of hand defects: results of 49 patients. AB - PURPOSE: Despite the growing number of free and local flaps used for repairing defects of the hand, groin flaps are also still widely used. The aims of this study were to evaluate the outcome of a large series of patients whose defects were covered by pedicled groin flaps, and to find out whether it is still indicated in replacing damaged soft tissue of the hand in the era of microsurgery. METHODS: From 1982 to 2009, we treated 85 patients with soft tissue defects on the hand and distal forearm with pedicled groin flaps in our department and recorded them in a prospective database. We interviewed and examined 49 patients in this cohort. RESULTS: The mean age of the 85 patients was 33 years, the male/female ratio was 4:1, the mean hospital stay was 29 +/- 13 days, and the mean follow-up was 9 years. The duration to flap division was 24 +/ 5 days. Altogether, we performed a mean of 4.6 operations per patient, including thinning of the flap, deepening of the interdigital fold, and stump and flap revisions. One flap loss occurred. Of the 49 patients, results were mostly classified as good, and 82% of patients would undergo the procedure again. The mean Disabilities of the Arm, Shoulder, and Hand score value was 23 +/- 17. The Vancouver Scar Scale showed nearly normal height and vascularity of the groin flap (0.2 +/- 0.4 and 0.3 +/- 0.6, respectively), pigmentation was slightly abnormal (0.8 +/- 0.6), and pliability was evaluated between "supple" and "yielding" (1.5 +/- 1.2). CONCLUSIONS: Results achieved with the groin flaps were positive. Most patients were satisfied with the results, and the operation was easily performed when McGregor's recommendations were followed. Nevertheless, considering the high number of secondary operations, the long hospital stay, and immobilization of the arm, groin flaps should be used only when free flaps or regional pedicle flaps are either not feasible or not indicated. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic III. PMID- 22939823 TI - Anatomy of the thumb metacarpophalangeal ulnar and radial collateral ligaments. AB - PURPOSE: To describe the origin and insertion of the ulnar (UCL) and radial collateral ligaments (RCL) of the thumb metacarpophalangeal (MCP) joint. METHODS: We dissected 18 UCLs and 18 RCLs from fresh-frozen human cadaveric thumbs. We removed all soft tissue overlying the MCP joint, isolating the proper collateral ligaments. We detached the collateral ligaments from the bone while marking their origin and insertion points and measured these attachment sites in relation to bony landmarks by digital photo analysis. RESULTS: The center of the UCL origin at the metacarpal was 4.2 mm from the dorsal surface and 5.3 mm from the articular surface. The dorsal aspect of the metacarpal origin site was 2.1 mm from the dorsal edge of the metacarpal. The center of the phalangeal insertion was 2.8 mm from the volar surface and 3.4 mm from the articular surface. The volar aspect of the phalangeal insertion site was 0.7 mm from the volar edge of the phalanx. The center of the RCL origin at the metacarpal was 3.5 mm from the dorsal surface and 3.3 mm from the articular surface. The dorsal aspect of the metacarpal origin site was 1.5 mm from the dorsal edge of the metacarpal. The center of the phalangeal insertion was 2.8 mm from the volar surface and 2.6 mm from the articular surface. The volar aspect of the phalangeal insertion site was 0.5 mm from the volar edge of the phalanx. CONCLUSIONS: Our study accurately defined the origin and insertion sites of the UCL and RCL of the thumb MCP joint. CLINICAL RELEVANCE: An accurate definition of the anatomical origin and insertion points of the thumb MCP UCL and RCL may allow for more successful surgical repair and reconstruction. PMID- 22939824 TI - Transfer of nerve branch to the brachialis to reconstruct elbow extension in incomplete tetraplegia: case report. AB - We undertook a brachialis to triceps nerve transfer to restore elbow extension in a 53-year-old man 5 months after he sustained a spine injury that resulted in a central cord syndrome. Within 3 months of surgery, the patient had recovered active elbow extension and had M3 level strength, which increased to M4 and 5 kg of strength by 12 months postoperatively. Despite transferring an antagonist nerve for triceps reinnervation, the patient had no problems controlling active elbow flexion-extension. Harvesting the brachialis nerve caused no permanent decrease in elbow flexion strength. PMID- 22939825 TI - Complex syndactyly: aesthetic and objective outcomes. AB - PURPOSE: Outcome data after the treatment of complex syndactyly are lacking. The purpose of this investigation was to critically analyze and report our results after surgical reconstruction of complex syndactyly. METHODS: We included 13 patients and 21 hands (25 webspaces) in this retrospective call-back investigation. There were 17 middle/ring finger and 8 ring/little finger complex syndactylies, each with a defined, isolated osseous bridge between the distal phalanges. We excluded complicated and syndrome-associated syndactylies. Patients returned for clinical examination and subjective assessment at an average of 9 years (range, 2-27 y) after the most recent surgery. Of 21 hands, 6 had undergone a revision surgery. RESULTS: The Vancouver Scar Scale scores averaged 3 (range, 0 6), web creep averaged 1.5 (range, 0-3), and total active motion averaged 148 degrees for the affected fingers. In the middle/ring finger syndactylies, the middle finger was most commonly supinated (average, 13 degrees ) and ulnarly deviated (average, 9 degrees ), and the ring finger was either supinated or pronated and radially deviated (average, 13 degrees ). In the ring/little finger syndactylies, the ring finger was most commonly supinated (average, 8 degrees ) without deviation, and the little finger was most commonly pronated (average, 8 degrees ) and radially deviated (average, 24 degrees ). There was a notable nail wall deformity in most fingers. Surgeon visual analog scale scores (range, 0-10, where lower scores are better) averaged 2.8 (range, 0.8-5.0). Patient visual analog scale scores were 0.4 (range, 0-3) for pain, 1.9 (range, 0-10) for appearance, and 1.1 (range, 0-3) for function. CONCLUSIONS: Complex syndactyly reconstruction is challenging, and common postsurgical findings include rotational and angular deformity and nail deformity. When deformity was present, the fingers typically rotated away from and deviated toward the site of the previous complex syndactyly. We describe how we have altered our approach based on these findings. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV. PMID- 22939826 TI - Corrective osteotomy for combined intra- and extra-articular distal radius malunion. AB - PURPOSE: This study evaluated the functional outcome of corrective osteotomy for combined intra- and extra-articular malunions of the distal radius using multiple outcome scores. METHODS: We evaluated 18 skeletally mature patients at an average of 78 months after corrective osteotomy for a combined intra- and extra-articular malunion of the distal part of the radius. The indication for osteotomy in all patients was the combination of an extra-articular deformity (>= 15 degrees volar or >= 10 degrees dorsal angulation or >= 3 mm radial shortening) and intra articular incongruity of 2 mm or greater (maximum stepoff or gap), as measured on lateral and posteroanterior radiographs. The average interval from the injury to the osteotomy was 9 months. The average maximum stepoff or gap of the articular surface before surgery was 4 mm. RESULTS: All 18 patients healed uneventfully and the final articular incongruity was reduced to 2 mm or less. Final range of motion and grip strength significantly improved, averaging 89% and 84% of the uninjured side and 185% and 241% of the preoperative measures, respectively. The rate of excellent or good results was 72% according to the validated rating system Mayo Modified Wrist Score, and 89% according to the unvalidated system of Gartland and Werley. The mean Disabilities of the Arm, Shoulder, and Hand score was 11, which corresponds to mild perceived disability. Of the 18 cases, 11 normalized upper limb function. Five patients had complications; all were successfully treated. According to the rating system of Knirk and Jupiter, 4 had grade 1 and 1 had grade 2 osteoarthritis of the radiocarpal joint on radiographs. Two of those patients reported occasional mild pain. Radiographic osteoarthritis did not correlate with strength, motion, and wrist scores. CONCLUSIONS: Outcomes of corrective osteotomy for combined intra- and extra-articular malunions were comparable to those of osteotomy for isolated intra- and extra-articular malunions. A successful corrective osteotomy for the treatment of complex intra- and extra-articular distal radius malunions can improve wrist function. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV. PMID- 22939827 TI - Symptomatic neural loop causing hemidigital anesthesia: case report. AB - Digital neural loops were identified over a century ago and are common findings in cadaveric studies of palmar and digital anatomy. Symptomatic digital neural loops are rare. We report a case of hemidigital anesthesia resulting from a proper digital nerve neural loop penetrated by its common digital artery in the palm. After neurolysis of the median nerve and the common and proper digital nerves to the third webspace, we transected the common digital artery, transposed it out of the neural loop, and repaired it. The patient's sensory symptoms fully resolved over 6 weeks. The differential diagnosis, diagnostic workup, and surgical treatment are reviewed. PMID- 22939828 TI - Missed childhood-onset carpal tunnel syndrome diagnosed as chronic pain: case report. AB - We report the case of a 15-year-old girl with a red, swollen, and painful right hand. She first developed symptoms when she was 7 years old. Numerous physicians evaluated her at various institutions but were able to classify her only with chronic pain syndrome. She continued with regular occupational therapy and had to use special aids to compensate throughout school. After 8 years of treatment with no improvement, she presented to our office, where we diagnosed carpal tunnel syndrome. Intraoperative findings revealed a large proximal muscle belly of the index lumbrical, a thickened transverse carpal ligament, and marked compression of the median nerve. Two weeks after the surgery, her symptoms cleared; at 5 months, she remained symptom free. PMID- 22939829 TI - A national survey of program director opinions of core competencies and structure of hand surgery fellowship training. AB - PURPOSE: We assessed hand surgery program directors' opinions of essential components of hand surgery training and potential changes in the structure of hand surgery programs. METHODS: We recruited all 74 program directors of Accreditation Council of Graduate Medical Education-accredited hand surgery fellowship programs to participate. We designed a web-based survey to assess program directors' support for changes in the structure of training programs and to assess opinions of components that are essential for graduates to be proficient. Respondents were asked to rate 9 general areas of practice, 97 knowledge topics, and 172 procedures. Each component was considered essential if 50% or more of respondents thought that graduates must be fully knowledgeable of the topic and be able to perform the procedure at the end of training. RESULTS: The response rate was 84% (n = 62). A minority of program directors (n = 15; 24%) supported creation of additional pathways for hand surgery training, and nearly three-quarters (n = 46; 74%) preferred a fellowship model to an integrated residency model. Most program directors (n = 40; 65%) thought that a 1-year fellowship was sufficient to train a competent hand surgeon. Wrist, distal radius/ulna, forearm, and peripheral nerve conditions were rated as essential areas of practice. Of the detailed components, 76 of 97 knowledge topics and 98 of 172 procedures were rated as essential. Only 48% respondents (n = 30) rated microsurgery as it relates to free tissue transfer as essential. However, small and large vessel laceration repairs were rated as essential by 92% (n = 57) and 77% (n = 48) of respondents, respectively. CONCLUSIONS: This study found resistance to prolonging the length of fellowship training and introduction of an integrated residency pathway. To train all hand surgeons in essential components of hand surgery, programs must individually evaluate exposure provided and find innovative ways to augment training when necessary. CLINICAL RELEVANCE: Studies of curriculum content in hand surgery affect the future scope of hand surgery practice and highlight areas in need of reform and enhancement. PMID- 22939830 TI - Sonographic appearance of the flexor tendon, volar plate, and A1 pulley with respect to the severity of trigger finger. AB - PURPOSE: To evaluate trigger digits with sonography to determine morphological changes in the A1 pulley, flexor tendon, and volar plate in relation to the severity of triggering. METHODS: We evaluated 67 trigger digits and graded them into 1 of 4 groups. We compared the groups according to severity and to contralateral fingers, which served as controls. RESULTS: The thickness of the flexor tendons under the A1 pulley was proportional to the severity of triggering. The anteroposterior thickness of the flexor tendon increased significantly among the grades exhibiting triggering regardless of the affected digit. However, in digits other than the thumb, tendon thickness increased even in the absence of active triggering. Thickening tended to be greater with finger flexion. The A1 pulley exhibited the greatest thickness and the volar plate exhibited significant thickening in the group that exhibited continuous triggering that was easily reduced with active extension (grade III). CONCLUSIONS: The flexor tendon thickened significantly before patients experienced triggering except in the thumb. In the thumb, the flexor tendon and A1 pulley thickened significantly only after patients exhibited triggering. Thickening of the volar plate appears to have an important role in continuous triggering. Although most clinicians can easily determine the severity of a trigger digit by clinical examination, ultrasound might be helpful for objectively understanding the severity and response to treatment, by examining the thickness of the flexor tendon and A1 pulley. In particular, sonographic measurement of the A1 pulley might be useful in judging the progression of trigger finger severity. In cases where a Doppler signal is detected inside the A1 pulley, more conservative therapies might be worth considering before surgery. TYPE OF STUDY/LEVEL OF EVIDENCE: Diagnostic IotaIotaIota. PMID- 22939831 TI - Schwannoma of the hand in an infant: case report. AB - Schwannomas (neurilemmomas) are the most common benign tumors of peripheral nerves and originate from the myelinating cells of the nerve sheath. We present a case of congenital schwannoma of the hand. PMID- 22939832 TI - Aquatic eggs are fertilised by multiple males not engaged in amplexus in a stream breeding frog. AB - In anuran amphibians, multiple males amplexing a single female to fertilise her eggs has been found for less than 25 species, whereas matings without amplexus are known for less than five species. Here we provide a new example of simultaneous polyandry with multiple males not engaged in amplexus, in Feirana taihangnicus, a stream-dwelling, explosive breeder endemic to central China. Laboratory experiments showed that when one female was kept with one male in a vessel with elevated, flat stones, the female stood on her head with her swollen cloaca against the undersurface of the stone substrate to lay eggs (clutch size ranged from 371 to 533, n=7 females). Then, 10-102 min after oviposition began, the male stood on his head and released sperm over the eggs distributed as a single layer on the stone surfaces. It took about 3h for the female to finish oviposition and for the male to finish fertilisation. On average, 96% of eggs were fertilised. In natural oviposition habitats, stream sections with slow flowing, we observed that 1 up to 15 males (8.7+/-6.6, n=6 cases), none in amplexus, participated in fertilising the eggs deposited by a single female. Evolutionary implications of this unusual reproductive strategy remain to be explored. PMID- 22939834 TI - Combining support vector machine with genetic algorithm to classify ultrasound breast tumor images. AB - To promote the classification accuracy and decrease the time of extracting features and finding (near) optimal classification model of an ultrasound breast tumor image computer-aided diagnosis system, we propose an approach which simultaneously combines feature selection and parameter setting in this study. In our approach ultrasound breast tumors were segmented automatically by a level set method. The auto-covariance texture features and morphologic features were first extracted following the use of a genetic algorithm to detect significant features and determine the near-optimal parameters for the support vector machine (SVM) to identify the tumor as benign or malignant. The proposed CAD system can differentiate benign from malignant breast tumors with high accuracy and short feature extraction time. According to the experimental results, the accuracy of the proposed CAD system for classifying breast tumors is 95.24% and the computing time of the proposed system for calculating features of all breast tumor images is only 8% of that of a system without feature selection. Furthermore, the time of finding (near) optimal classification model is significantly than that of grid search. It is therefore clinically useful in reducing the number of biopsies of benign lesions and offers a second reading to assist inexperienced physicians in avoiding misdiagnosis. PMID- 22939833 TI - Age at menarche and cardiovascular disease mortality in Singaporean Chinese women: the Singapore Chinese Health Study. AB - PURPOSE: To examine whether age at menarche was inversely associated with cardiovascular disease (CVD) mortality in Singaporean Chinese women. METHODS: We followed prospectively 34,022 Chinese women aged 45 to 74 at enrollment (1993 1998), with complete data on study variables, through 2009 for primary cause of death from CVD, including coronary heart disease (CHD) and cerebrovascular disease (CERE). Hazard ratios (HRs) for CVD mortality were computed across menarcheal age categories and adjusted for potential confounders and body mass index. RESULTS: Over 460,374 person-years of follow-up, 1852 women died from CVD, 998 from CHD and 557 from CERE. There was a significant interaction between age at menarche and smoking (P < .05). In nonsmokers, age at menarche was inversely associated with risk for CVD and CHD mortality. HRs (and 95% confidence interval) for CVD mortality across menarcheal age categories (<= 12, 13-14, 15-16, >= 17) were 1.06 (0.87-1.29), 1 (referent), 0.89 (0.79-1.00), and 0.80 (0.69-0.93), respectively (P(trend) < .001); HRs for CHD mortality were 1.06 (0.80-1.34), 1 (referent), 0.76 (0.65-0.90), and 0.72 (0.58-0.88), respectively (P(trend) < .001). Among nonsmokers, there was no association between age at menarche and CERE mortality. Among smokers, menarcheal age was not associated with CVD, CHD or CERE mortality. CONCLUSIONS: Menarcheal age was inversely associated with risk of CVD mortality in nonsmoking Chinese women. PMID- 22939835 TI - Absence of inactivating mutations and deletions in the DMRT1 and FGF9 genes in a large cohort of 46,XY patients with gonadal dysgenesis. AB - Despite advances in our understanding of the mechanisms involved in sex determination and differentiation, the specific roles of many genes in these processes are not completely understood in humans. Both DMRT1 and FGF9 are among this group of genes. Dmrt1 controls germ cell differentiation, proliferation, migration and pluripotency and Sertoli cell proliferation and differentiation. Fgf9 has been considered a critical factor in early testicular development and germ cell survival in mice. We screened for the presence of DMRT1 and FGF9 mutations in 33 patients with 46,XY gonadal dysgenesis. No deletions in either DMRT1 or FGF9 were identified using the MLPA technique. Eight allelic variants of DMRT1 were identified, and in silico analysis suggested that the novel c.968 15insTTCTCTCT variant and the c.774G>C (rs146975077) variant could have potentially deleterious effects on the DMRT1 protein. Nine previously described FGF9 allelic variants and six different alleles of the 3' UTR microsatellite were identified. However, none of these DMRT1 or FGF9 variants was associated with increased 46,XY gonadal dysgenesis. In conclusion, our study suggests that neither DMRT1 nor FGF9 abnormalities are frequently involved in dysgenetic male gonad development in patients with non-syndromic 46,XY disorder of sex development. PMID- 22939836 TI - Restless legs syndrome symptomatology, attitudes and beliefs among treated and untreated individuals. AB - BACKGROUND: Restless legs syndrome (RLS) is an under-diagnosed and under-treated disorder in the community. Little is known regarding the factors associated with treatment seeking for RLS. Based on Andersen's behavioral model for health service utilization, we compared predisposing factors, enabling or impeding factors and need for care factors among participants without RLS (NRs), participants with untreated RLS (URs) and participants with treated RLS (TRs). METHODS: The study sample consisted of 105 participants (NRs: n=41; URs: n=29; TRs: n=35) who were evaluated face-to-face based on the Hopkins Telephone Diagnostic Interview. We compared the groups with respect to sociodemographic variables, insurance status, attitudes and beliefs toward RLS and RLS treatment, symptom severity, impact on quality of life and subjective description of RLS symptoms. RESULTS: URs were older (72.6 years versus 61.1 years) and had a higher proportion of African Americans (44.8% versus 8.6%) (p<0.01 for both). Compared to NRs and URs, TRs endorsed a stronger belief that RLS is a serious medical condition and causes marked psychosocial impairment (p<0.01 for both). TRs reported greater RLS symptom severity than URs (p<0.01), but the impact of RLS on quality on life was similar in both groups. TRs were more likely to use specific descriptors to describe symptoms of RLS than URs. CONCLUSIONS: Based on Andersen's model, predisposing and need for care factors including Caucasian race, greater concern about the impact of RLS on daily activity and more frequent endorsement of RLS symptom descriptors were associated with receiving treatment for RLS. Further study is needed to identify barriers to treatment in individuals with undiagnosed and untreated RLS in the community. PMID- 22939837 TI - Lifestyle, self-reported morbidities, and poor sleep quality among Brazilian workers. AB - OBJECTIVE: To examine perceived poor sleep quality and its association with unhealthy lifestyle and self-reported morbidities among Brazilian workers. METHODS: This study was part of a national survey involving 47,477 workers who received a questionnaire about lifestyle. Chi-square tests and logistic regression (OR=Odds Ratio) were conducted. RESULTS: Poor sleep quality was reported by 21% of workers and was more prevalent among women (p<0.01). After being adjusted for socio-demographic indicators, negative perception of health, well-being, stress, self-reported morbidities, physical inactivity during leisure time (OR: 1.18) in both genders, and inadequate fruit and vegetable intake (OR(men): 1.15; OR(women): 1.17), as well as excessive alcohol consumption (OR: 1.15) in men remained associated with poor sleep quality. With respect to morbidities, only diabetes in women (OR: 1.46) and hypertension in men (OR: 1.18) were associated with poor sleep quality. CONCLUSIONS: Our findings indicate that certain unhealthy behaviors and self-reported morbidities were associated with poor sleep quality. Efficient initiatives should be implemented to promote a healthier lifestyle among workers, which could reduce or control glucose levels and blood pressure in addition to improving perceived sleep quality. PMID- 22939838 TI - Evidence for tryptophan being a signal molecule that inhibits conidial anastomosis tube fusion during colony initiation in Neurospora crassa. AB - Mycelial interconnectedness achieved by hyphal fusion has been hypothesized to facilitate the distribution and sharing of nutrients between different parts of a mycelium, especially when nutrients are heterogeneously distributed in the environment. However, the link between environmental nutrient availability and hyphal fusion is little understood. Here, we report that amino acids and extracellular pH regulate conidial anastomosis tube (CAT) fusion during colony initiation in Neurospora crassa. Quantitative analyses revealed that low extracellular pH and certain amino acids, particularly tryptophan, inhibit CAT fusion. Conidial germination was also inhibited by tryptophan but this inhibition was mitigated by the presence of other amino acids. This provides evidence for tryptophan having a role as a signal molecule that regulates CAT fusion. Tryptophan acts intracellularly because two amino acid permease mutants (Deltamtr and Deltaaap-20) exhibited resistance against tryptophan-mediated inhibition of CAT fusion. Tryptophan and low pH did not significantly affect vegetative hyphal fusion in mature colonies, indicating that the latter is regulated in a different manner to CAT fusion. PMID- 22939839 TI - A mass-spectroscopic method for measuring des-Leu albumin--a novel marker for chronic pancreatitis. AB - OBJECTIVES: Chronic pancreatitis is a progressive inflammatory disease leading to pancreatic insufficiency. The diagnosis of chronic pancreatitis is challenging, especially in early disease and the current tests have low sensitivity, may be invasive or have limited availability. We previously identified a truncated form of albumin lacking the C-terminal leucine, des-Leu albumin, which was present at high concentration in pancreatitis. We have developed a liquid-chromatography tandem-mass spectrometry (LC-MS/MS) method for measuring this peptide and make some preliminary observations on patient samples. METHODS: Serum samples from patients with established pancreatitis and controls were obtained. Diluted serum samples or prepared standards were digested with trypsin. Aliquots of the digest were separated on a reversed-phase column using water:acetonitrile:formic acid mobile-phase with tandem-mass spectrometry detection. Percentage composition of des-Leu albumin was determined from a response curve. RESULTS: The C-terminal peptide, LVAASQAALG- of des-Leu albumin was identified by m/z 901->725, wild type albumin by m/z 1014->825. Additional fragments were monitored as internal reference for digestion and sample integrity. Inter-assay imprecision was estimated at 10%. The percentage composition of des-Leu albumin segregated with the diagnosis of established pancreatitis with median levels of des-Leu albumin of 68% in patients compared to 5% in controls. CONCLUSIONS: Des-Leu albumin is a promising novel biomarker for chronic pancreatitis. It allowed clear discrimination of patients with pancreatitis from controls and its long half-life may facilitate monitoring of disease activity. The method described could readily be undertaken in modern clinical chemistry laboratories and will form the basis for further study. PMID- 22939841 TI - Large plasmids of Escherichia coli and Salmonella encode highly diverse arrays of accessory genes on common replicon families. AB - Plasmids are important in evolution and adaptation of host bacteria, yet we lack a comprehensive picture of their own natural variation. We used replicon typing and RFLP analysis to assess diversity and distribution of plasmids in the ECOR, SARA, SARB and SARC reference collections of Escherichia coli and Salmonella. Plasmids, especially large (>=30 kb) plasmids, are abundant in these collections. Host species and genotype clearly impact plasmid prevalence; plasmids are more abundant in ECOR than SAR, but, within ECOR, subgroup B2 strains have the fewest large plasmids. The majority of large plasmids have unique RFLP patterns, suggesting high variation, even within dominant replicon families IncF and IncI1. We found only four conserved plasmid types within ECOR, none of which are widely distributed. Within SAR, conserved plasmid types are primarily serovar-specific, including a pSLT-like plasmid in 13 Typhimurium strains. Conservation of pSLT contrasts with variability of other plasmids, suggesting evolution of serovar specific virulence plasmids is distinct from that of most enterobacterial plasmids. We sequenced a conserved serovar Heidelberg plasmid but did not detect virulence or antibiotic resistance genes. Our data illustrate the high degree of natural variation in large plasmids of E. coli and Salmonella, even among plasmids sharing backbone genes. PMID- 22939840 TI - Selective translation during stress in Escherichia coli. AB - The bacterial stress response, a strategy to cope with environmental changes, is generally known to operate on the transcriptional level. Here, we discuss a novel paradigm for stress adaptation at the post-transcriptional level, based on the recent discovery of a stress-induced modified form of the translation machinery in Escherichia coli that is generated by MazF, the toxin component of the toxin antitoxin (TA) module mazEF. Under stress, the induced endoribonuclease MazF removes the 3'-terminal 43 nucleotides of the 16S rRNA of ribosomes and, concomitantly, the 5'-untranslated regions (UTRs) of specific transcripts. This elegant mechanism enables selective translation due to the complementary effect of MazF on ribosomes and mRNAs, and also represents the first example of functional ribosome heterogeneity based on rRNA alteration. PMID- 22939842 TI - Regulation of CYP3A4 and CYP3A5 expression and modulation of "intracrine" metabolism of androgens in prostate cells by liganded vitamin D receptor. AB - We investigated the capacity for vitamin D receptor (VDR) to modulate the expression of CYP3A4 and other genes that may facilitate the oxidative inactivation of androgens such as testosterone and androstanediol within prostate cells. We report that exposure to the active hormonal form of vitamin D markedly increased gene expression of CYP3A4 and CYP3A5 and ultimately achieved levels of intracellular CYP3A enzyme activity within LNCaP prostate cancer cells that were comparable to that observed for Caco2 cells, an established model of CYP3A induction, and resulted in the increased turnover of testosterone to its inactive 6beta-OH metabolite. We demonstrate that VDR directs CYP3A4 and CYP3A5 expression through binding to distinct regulatory motifs located within the 5' promoter regions of both genes. The current data highlight the potential application of VDR-based treatment regimes as a means to limit the bioavailability of growth promoting androgens within the tumor microenvironment. PMID- 22939843 TI - beta-Arrestin1-mediated recruitment of c-Src underlies the proliferative action of glucagon-like peptide-1 in pancreatic beta INS832/13 cells. AB - Glucagon-like peptide-1 (GLP-1), a glucoincretin hormone secreted by intestinal L cells, is a potent growth factor for the pancreatic beta-cell. The development of GLP-1 mimetics and enhancers as a novel class of anti-diabetes medications underpins the importance of elucidating the molecular basis of GLP-1 signaling. In the present study, we sought to test the hypothesis that beta-arrestin mediated recruitment of c-Src underlies the proliferative action of GLP-1 in beta cells. Our results show that GLP-1 increased c-Src phosphorylation in INS832/13 cells, an effect inhibited by siRNA-mediated beta-arrestin1 knockdown. Pharmacological inhibition of c-Src and overexpression of a dominant-negative c Src mutant protein curtailed GLP-1-induced beta-cell proliferation. Co immunoprecipitation experiments showed a physical association between c-Src and both beta-arrestin1 and GLP-1R upon GLP-1 treatment. Moreover, expression of beta arrestin1 mutants that lack the ability to bind c-Src blunted GLP-1-induced proliferation. Conversely, expression of a beta-arrestin1 mutant that fails to target G protein-coupled receptors to clathrin-coated pits for sequestration/degradation maximally increased beta-cell proliferation. We propose that the formation of a signaling complex comprising the agonist-stimulated GLP 1R, beta-arrestin1 and c-Src is required for the action of GLP-1 on beta-cell mass. PMID- 22939844 TI - Reduced insulin secretion correlates with decreased expression of exocytotic genes in pancreatic islets from patients with type 2 diabetes. AB - Reduced insulin release has been linked to defect exocytosis in beta-cells. However, whether expression of genes suggested to be involved in the exocytotic process (exocytotic genes) is altered in pancreatic islets from patients with type 2 diabetes (T2D), and correlate to insulin secretion, needs to be further investigated. Analysing expression levels of 23 exocytotic genes using microarray revealed reduced expression of five genes in human T2D islets (chi(2)=13.25; p<0.001). Gene expression of STX1A, SYT4, SYT7, SYT11, SYT13, SNAP25 and STXBP1 correlated negatively to in vivo measurements of HbA1c levels and positively to glucose stimulated insulin secretion (GSIS) in vitro in human islets. STX1A, SYT4 and SYT11 protein levels correspondingly decreased in human T2D islets. Moreover, silencing of SYT4 and SYT13 reduced GSIS in INS1-832/13 cells. Our data support that reduced expression of exocytotic genes contributes to impaired insulin secretion, and suggest decreased expression of these genes as part of T2D pathogenesis. PMID- 22939845 TI - Effects of anabolic androgenic steroids on chylomicron metabolism. AB - OBJECTIVE: To evaluate the effects of anabolic androgenic steroids (AAS) on chylomicron metabolism. METHODS: An artificial lipid emulsion labeled with radioactive cholesteryl ester (CE) and triglycerides (TG) mimicking chylomicrons was intravenously injected into individuals who regularly weight trained and made regular use of AAS (WT+AAS group), normolipidemic sedentary individuals (SDT group) and individuals who also regularly weight trained but did not use AAS (WT group). Fractional clearance rates (FCR) were determined by compartmental analysis for emulsion plasma decay curves. RESULTS: FCR-CE for the WT+AAS group was reduced (0.0073 +/- 0.0079 min(-1), 0.0155 +/- 0.0100 min(-1), 0.0149 +/- 0.0160 min(-1), respectively; p<0.05), FCR-TG was similar for both the WT and SDT groups. HDL-C plasma concentrations were lower in the WT+AAS group when compared to the WT and SDT groups (22 +/- 13; 41 +/- 7; 38 +/- 13 mg/dL, respectively; p<0.001). Hepatic triglyceride lipase activity was greater in the WT+AAS group when compared to the WT and SDT groups (7243 +/- 1822; 3898 +/- 1232; 2058 +/- 749, respectively; p<0.001). However, no difference was observed for lipoprotein lipase activity. CONCLUSIONS: Data strongly suggest that AAS may reduce the removal from the plasma of chylomicron remnants, which are known atherogenic factors. PMID- 22939846 TI - Independent control of force and timing symmetry in dynamic standing balance: implications for rehabilitation of hemiparetic stroke patients. AB - The extent to which force and timing are independently controlled has aroused research interest. The present study aims to examine the relationship between force and timing symmetrical performances during repetitive body weight shifting. Eight hemiparetic stroke patients and eight age- and gender-matched controls were required to repetitively shift weight from one leg to the other while standing with each foot on a separate force plate. Instructions emphasised symmetry of weight transfer in each direction. No knowledge of result feedback was given. The ratio of the vertical ground reaction forces between the legs (force symmetry) was contrasted with the ratio of the intervals between leftward and rightward movements (timing symmetry). The patients showed more asymmetric and variable performances than the controls. Timing symmetry was more variable than force symmetry. In both groups, force and timing symmetry were uncorrelated. Autocovariance estimates revealed persistent alternation of large and small ground reaction forces, whereas a tendency for alternation between short and long intervals rapidly damped to zero. In conclusion, both healthy and stroke participants exhibit independent control of the force and timing symmetry under the task of natural weight shifting. This may explain the weakness of current balance retraining paradigms based on visual biofeedback, in which an emphasis on force symmetry fails to help timing performance in dynamic tasks. PMID- 22939847 TI - Technical proficiency among table tennis players with and without intellectual disabilities. AB - A relatively small body of research addresses the effect of intellectual impairment on proficiency in sport. The aim in the present study was to determine whether the technical proficiency of table tennis players (TTP) with and without intellectual disability (ID), matched for years of training experience, are different. The sample consisted of 71 elite TTP with ID (41 males, age=27+/-8 years, IQ=61+/-9; and 30 females, age=28+/-8 years, IQ=57+/-10; M+/-SD) and a comparison group of 17 players (12 males; age=24+/-12 years; and 5 females, age=20+/-9 years) without ID. All were assessed using a test-battery that included 10 sets of five basic and five advanced technical skills. Statistical analysis (ANOVA) revealed no gender differences in proficiency. The total score on technical proficiency for ID players (63.7%+/-12.5) ranged between 53% (advanced strokes) and 76% (basic strokes). Table tennis players without ID scored significantly better: 87.6%+/-6.2 (range: 80-94%). The significance of these differences in technical proficiency held even when delimiting the comparison to the top 8 players (age=25.9+/-7.0, IQ=61.8+/-9.8) with ID and counter-parts without ID who competed at regional levels in their country. The top eight players scored 73.1%+/-7.4 (range: 65-81.6%). These results suggest that impaired cognitive functioning may have a direct bearing on technical proficiency in sport. PMID- 22939848 TI - Observational training in visual half-fields and the coding of movement sequences. AB - An experiment was conducted to determine if gating information to different hemispheres during observational training facilitates the development of a movement representation. Participants were randomly assigned to one of three observation groups that differed in terms of the type of visual half-field presentation during observation (right visual half-field (RVF), left visual half field (LVF), or in central position (CE)), and a control group (CG). On Day 1, visual stimuli indicating the pattern of movement to be produced were projected on the respective hemisphere. The task participants observed was a 1300 ms spatial-temporal pattern of elbow flexions and extensions. On Day 2, participants physically performed the task in an inter-manual transfer paradigm with a retention test, and two contralateral transfer tests; a mirror transfer test which required the same pattern of muscle activation and limb joint angles and a non-mirror transfer test which reinstated the visual-spatial pattern of the sequence. The results demonstrated that participants of the CE, RVF and the LVF groups showed superior retention and transfer performance compared to participants of the CG. Participants of the CE- and LVF-groups demonstrated an advantage when the visual-spatial coordinates were reinstated compared to the motor coordinates, while participants of the RVF-group did not promote specific transfer patterns. These results will be discussed in the context of hemisphere specialization. PMID- 22939849 TI - Action-contingent vibrotactile flow facilitates the detection of ground level obstacles with a partly virtual sensory substitution device. AB - This research considers a sensory substitution device that allows the exploration of the environment through normal walking, leaning and standing. The device includes an array of 24 coin motors placed vertically on the torso, with the intensity of vibration of each motor being a function of the distance to the first-encountered object. Thresholds were determined for the detection of ground level obstacles (raised target platforms). On average, blindfolded participants were able to detect platforms with heights of 9 to 17 cm, but the thresholds differed for different experimental conditions. Experiment 1 showed that the detection threshold is lower for use with exploratory movements than for use without exploratory movements. Experiments 2 and 3 compared dynamic groups, who made exploratory movements and received vibrotactile flow contingent on their movements, with yoked groups, who received the same vibrotactile flow as the dynamic groups independently of their own movements. The detection thresholds were lower for the dynamic groups than for the yoked groups, meaning that the contingency of vibrotactile flow on exploratory movements is important beyond a higher-order vibrotactile flow by itself. PMID- 22939850 TI - Kicking performance in relation to balance ability over the support leg. AB - Balance control is presumed to be a fundamental constraint on the organization of skilled movement. The current experiment explored whether single-leg balance ability predicted kicking performance on the other leg. Thirty-eight participants ranging widely in skill kicked a soccer ball with the right and left legs for maximum accuracy and velocity and performed single-leg balance on a force plate for 30 s with the right and left legs. Significant correlations between single leg balance and kicking accuracy, but not velocity, were found. Left leg balance was more highly correlated than right leg balance with right (dominant) leg kicking accuracy. However, the same pattern of relations was not seen between single-leg balance and left (non-dominant) leg kicking accuracy. These findings provide preliminary support for the importance of balance ability in kicking performance. The importance of balance in the production of athletic skills is discussed and additional experimental paradigms are suggested that might further our knowledge in this area. PMID- 22939851 TI - Fate of estrogenic hormones in wastewater and sludge treatment: A review of properties and analytical detection techniques in sludge matrix. AB - Estrogenic hormones (estrone (E1), 17beta-estradiol (E2), estriol (E3), 17alpha ethinylestradiol (EE2)) are the major contributor to the total estrogenicity in waterways. Presence of these compounds in biosolids is also causing concern in terms of their use as soil amendment. In comparison with wastewater treatment, removal of estrogenic compounds in sewage sludge has received less attention. This paper presents a literature review regarding the source and occurrence of these pollutants in our environment. The removal pathways of estrogenic compounds in engineered systems, such as full-scale wastewater treatment plants (WWTPs), are also discussed. Review of the fate studies revealed that activated sludge system with nutrient removal shows very high (>90%) removal of estrogenic hormones in most of the cases. Although, aerobic digestion showed better attenuation of estrogenic compounds, anaerobic digestion increased the overall estrogenicity of biosolids. Finally, this paper highlights the challenges involved in analytical determination of these compounds in sewage sludge matrix. PMID- 22939853 TI - Recurrent empyema secondary to persistent spinal compression of the left main bronchus. PMID- 22939852 TI - A randomized comparison of the Saphenous Vein Versus Right Internal Thoracic Artery as a Y-Composite Graft (SAVE RITA) trial: early results. AB - OBJECTIVE: The Saphenous Vein Versus Right Internal Thoracic Artery as a Y Composite Graft trial was designed to evaluate the saphenous vein compared with the right internal thoracic artery as a Y-composite graft anastomosed to the side of the left internal thoracic artery. In this early analysis, we compared early angiographic patency rates and clinical outcomes. METHODS: From September 2008 to October 2011, 224 patients with multivessel coronary artery disease were randomized prospectively to undergo off-pump revascularization using the saphenous vein group (n = 112) or the right internal thoracic artery group (n = 112) as Y-composite grafts. Early postoperative (1.4 +/- 1.1 days) angiographic patency and clinical outcomes were compared. RESULTS: There was 1 operative death in the right internal thoracic artery group. No statistically significant differences in postoperative morbidities, including atrial fibrillation and acute renal failure, were observed between the groups. The number of distal anastomoses using the side-arm Y-composite graft (saphenous vein vs right internal thoracic artery) were 2.3 +/- 0.8 and 1.9 +/- 0.7 in the saphenous vein and right internal thoracic artery groups, respectively (P < .001). A third conduit was used in 44 patients (saphenous vein group vs right internal thoracic artery group, 4/109 vs 40/110; P < .001) to extend the side-arm Y-composite graft for complete revascularization. Early angiography demonstrated an overall patency rate of 99.4% (771 of 776 distal anastomoses). Patency rates of the side-arm Y-composite graft (saphenous vein vs right internal thoracic artery) were 98.8% (245 of 248) and 99.5% (207 of 208) in the saphenous vein and right internal thoracic artery groups, respectively (P = .629). CONCLUSIONS: A third conduit was needed to extend the right internal thoracic artery composite graft and reach the target vessels in 36.4% (40/110) of the patients. The saphenous vein composite graft was comparable with the right internal thoracic artery composite graft in terms of early angiographic patency and clinical outcomes. PMID- 22939854 TI - Prevention of the second stage of epithelial loss is a potential novel treatment for bronchiolitis obliterans. AB - OBJECTIVES: Loss of epithelial cells is one of the key factors that lead to airway fibrosis. Loss of epithelial cells may decrease the barrier to host cell infiltration into the lumen, allowing deposition of extracellular matrix, with subsequent obliteration of the airway. The objective of this study was to determine whether injection of epithelial cells/progenitor cells from the recipient into the lumen of the donor trachea could prevent bronchiolitis obliterans (BO) in a mouse heterotopic tracheal transplantation (HTT) model. METHODS: A major histocompatibility complex class I and class II mismatch of mouse HTT model of BO was used. Epithelial cells from recipient mice were isolated and reinjected into the lumen of the allografts on day 3 after transplantation. Rag-1 knock-out and isografts were also performed as controls. The grafts were analyzed by immunohistochemistry and densitometric analysis. RESULTS: The results demonstrated that tracheal epithelium was lost by day 3, regenerated between 3 to 7 days, and was lost again in all allografts, but not in the isografts or in Rag-1 knock-out groups by day 12. The reconstituted epithelium was donor originated on day 7 based on green fluorescent protein staining. Furthermore, with the injection of recipient cells into the tracheal lumen, loss of the epithelium was not observed and the luminal obliteration was significantly less in the allografts. CONCLUSIONS: Injection of recipient epithelial cells prevents the second phase of epithelial loss and significantly decreases BO development in an HTT model. Clinically, the use of injected recipient epithelial cells could be a novel treatment for BO. PMID- 22939856 TI - Open antegrade aortic stent implantation after surgical treatment in type A aortic dissection. PMID- 22939857 TI - Discussion. PMID- 22939855 TI - Superior cavopulmonary anastomosis timing and outcomes in infants with single ventricle. AB - OBJECTIVES: We sought to identify factors associated with the timing and surgical outcomes of the superior cavopulmonary anastomosis. METHODS: The Pediatric Heart Network's Infant Single Ventricle trial database identified participants who underwent superior cavopulmonary anastomosis. Factors potentially associated with age at superior cavopulmonary anastomosis, length of stay and death by 14 months of age were evaluated. Factors included subject demographics, cardiac anatomy, measures from neonatal hospitalization and pre-superior cavopulmonary anastomosis visit, adverse events, echocardiographic variables, intraoperative variables, superior cavopulmonary anastomosis type, and number of concurrent cardiac surgical procedures. Age at superior cavopulmonary anastomosis was analyzed using Cox proportional hazards regression. Natural log length of stay was analyzed by multiple linear regression. RESULTS: Superior cavopulmonary anastomosis was performed in 193 subjects at 5.2 months of age (interquartile range, 4.2, 6.2) and weight of 5.9 kg (interquartile range, 5.3, 6.6). The median length of stay was 7 days (interquartile range, 6, 10). There were 3 deaths and 1 transplant during the superior cavopulmonary anastomosis hospitalization, and 3 deaths and 3 transplants between discharge and 14 months of age. Age at superior cavopulmonary anastomosis was associated with center and interstage adverse events. A longer length of stay was associated with younger age and greater case complexity. Superior cavopulmonary anastomosis type, valve regurgitation, ventricular ejection fraction, and ventricular end-diastolic pressure were not independently associated with age at superior cavopulmonary anastomosis or the length of stay. CONCLUSIONS: Greater case complexity and more frequent interstage adverse events are associated with an earlier age at superior cavopulmonary anastomosis. Significant variation in age at superior cavopulmonary anastomosis among centers, independent of subject factors, highlights a lack of consensus regarding the optimal timing. Factors associated with length of stay could offer insights for improving presuperior cavopulmonary anastomosis care and surgical outcome. PMID- 22939858 TI - Discussion. PMID- 22939859 TI - Isolated tricuspid valve surgery in patients with previous cardiac surgery. AB - OBJECTIVES: Few studies have been published in literature on outcomes of isolated tricuspid valve (TV) surgery when performed as a reoperation. Hence, we analyzed our early and midterm results of TV surgery in this unique group of patients. METHODS: We performed a retrospective analysis of 82 consecutive patients who underwent isolated TV surgery as a reoperation at our institution between 1997 and 2010. Symptomatic TV regurgitation (84.2%), acute endocarditis (14.6%), and valve thrombosis after TV repair (1.2%) were the indications for surgery. A minimally invasive access through a right anterolateral thoracotomy was the preferred approach in 60% of the patients. Previous cardiac operations included mitral, aortic, and TV surgery in 60%, 29%, and 27% and coronary bypass surgery in 18%, usually performed as combined procedures. Elective surgery was performed in 67.1% of the patients. Mean patient age was 64.1 +/- 11.9 years, 28% being male with an average logistic EuroSCORE of 16.4% +/- 14.3%. Follow-up was 96% complete, with a mean duration of 2.6 +/- 2.4 years. RESULTS: Overall thirty-day mortality was 14.6%; for patients without and with endocarditis, it was 12.9% and 25%. Thirty-day mortality for patients undergoing elective surgery was 4.0%. Overall 2-year survival was 63.0% +/- 5.5%. The 2-year freedom from TV-related reoperation was 93.5% +/- 3.3%. CONCLUSIONS: Postoperative results of isolated TV surgery as a reoperation are acceptable when performed electively but dismal in patients undergoing nonelective surgery. Thus, redo TV surgery, when indicated, should be performed sooner rather than later. Minimally invasive surgery through a right lateral minithoracotomy is a safe approach for patients with elective surgery. PMID- 22939860 TI - Discussion. PMID- 22939861 TI - Omental reinforcement of the thoracic esophagogastric anastomosis: an analysis of leak and reintervention rates in patients undergoing planned and salvage esophagectomy. AB - OBJECTIVE: An uncontained thoracic anastomotic leak may cause severe morbidity or mortality. Thoracic transposition of an omental flap along with the gastric conduit may decrease leak incidence, severity, or need for reoperations after esophagectomy. METHODS: We identified 607 patients who underwent esophagectomy with thoracic anastomosis between January 2001 and August 2011. All patients were studied for leak postoperatively. Four leak grades were defined, ranging from radiographic leak to conduit loss. Univariate and multivariate analyses were performed to identify variables associated with anastomotic leak. RESULTS: Omental reinforcement was used in 215 of 607 patients (35%). Anastomotic leak occurred in 51 of 607 patients (8.4%). Patients with omentum had a significantly lower (odds ratio [OR], 0.4; P = .014) anastomotic leak rate (4.7%) compared with patients without omentum (10.5%). Salvage resections were performed in 69 patients and 23 (32%) received omentum; the leak rate with omentum was 4.6% compared with 15% without (OR, 0.27; P = .24). Patients undergoing planned esophagectomy with omentum had a significantly lower leak rate than patients without omentum (4.7% vs 9.8%) (OR, 0.43; P = .04). Reoperations to rescue an anastomotic leak (Grade 3) was less common with omentum (OR, 0.26; P = .024). Multivariate analysis identified omental reinforcement (OR, 0.45; P = .034) and surgeon (OR, 3.4; P = .001) as variables predictive of an anastomotic leak. CONCLUSIONS: Omental reinforcement of thoracic esophagogastric anastomoses decreases overall leak rate and need for reoperation. We recommend pedicled omental transposition to reinforce all thoracic anastomoses. Endoscopic evaluation of significant anastomotic leaks is still warranted. PMID- 22939862 TI - Surgical technical performance scores are predictors of late mortality and unplanned reinterventions in infants after cardiac surgery. AB - OBJECTIVE: We have previously shown that surgical Technical Performance Scores (TPS) are important predictors of early postoperative morbidity across a wide spectrum of procedures and that intraoperative recognition and intervention of residual defects resulted in improved outcomes. We hypothesized that these scores would also be important predictors of midterm outcomes. METHODS: Neonates and infants aged younger 6 months were prospectively followed from the index surgery for a minimum of 1 year. The TPS were calculated using previously published criteria, including intraoperative course, predischarge echocardiograms or catheterizations, and clinical data, and graded as optimal, adequate, or inadequate. Case complexity was determined by the Risk Adjustment for Congenital Heart Surgery-1 category. The primary outcome was mortality, and the secondary outcome was the need for unplanned reinterventions. Outcomes were analyzed using nonparametric methods and a logistic regression model. RESULTS: A total of 166 patients were included in our study, with 7 early deaths. The remaining 159 patients (Risk Adjustment for Congenital Heart Surgery-1 category 4-6, 76 [48%]; neonates, 78 [49%]) were followed for a minimum of 1 year after surgery. There were 14 late deaths or late transplantations and 55 late reinterventions. On univariate analysis, the TPS were associated with mortality (P < .001) and reintervention (P = .04). On logistic regression analysis, inadequate TPS was associated with late mortality (P < .001; odds ratio, 7.2; 95% confidence interval, 2.2-23.6), and Risk Adjustment for Congenital Heart Surgery-1 category (P = .004; odds ratio, 3.7; 1.5-8.8) at index surgery was associated with need for late unplanned reintervention. CONCLUSIONS: Technical performance affects midterm survival after infant heart surgery. Inadequate TPS can be used to prospectively identify patients at ongoing risk of demise and the need for reintervention. An aggressive approach to diagnosing and treating residual lesions at the initial operation is warranted. PMID- 22939863 TI - The role of hepatic metastases and pulmonary tumor burden in predicting survival after complete pulmonary resection for colorectal cancer. AB - OBJECTIVE: Our objective was to investigate the role of clinicopathologic factors as predictors of outcome after complete pulmonary resection for metastatic colorectal cancer. METHODS: Consecutive patients undergoing radical pulmonary resection for colorectal cancer at our institution were included in the study. Clinicopathologic variables including sex, age, site and stage of the primary tumor, disease-free interval, prior hepatic resection, timing of pulmonary metastases, preoperative chemotherapy, type of pulmonary resection, number, size, and location of pulmonary metastases, and thoracic lymph node involvement were retrospectively collected and investigated for prognostic significance. Survival curves were generated by the Kaplan-Meier technique and difference between factors were evaluated by the log-rank test. RESULTS: A total of 127 patients undergoing pulmonary resection between 1997 and 2009 were included in the study. The median follow-up was 67.1 months. The median overall survival from the time of pulmonary resection was 48.9 months. The 5-year overall survival was 45.4%. Among all investigated prognostic variables, the number of pulmonary metastases (1 vs >1) was the most important factor affecting the outcome after pulmonary resection (5-year overall survival 55.4% vs 32.2%; hazard rate, 1.92; P = .006). CONCLUSIONS: In this study, the presence of a single pulmonary metastasis was a favorable predictor of survival after complete pulmonary resection for metastatic colorectal cancer. All the other prognostic variables did not seem to affect survival and should not contraindicate such surgery in clinical practice. However, the study sample size does not allow us to draw any definitive conclusion, and further investigation of the role of these prognostic factors in larger series is warranted. PMID- 22939864 TI - One-stage bilateral total hip arthroplasty: functional outcomes and complications in 112 patients. AB - BACKGROUND: Advantages of one-stage bilateral total hip arthroplasty (THA) include a single hospital stay, a shorter rehabilitation time, and decreased management costs per patient. However, concern about a possible increase in the perioperative complication rate has limited the use of this strategy. Here, our objectives were to evaluate morbidity and mortality, as well as functional outcomes, in patients managed with one-stage bilateral THA. HYPOTHESIS: The complication rate after one-stage bilateral THA is not significantly different from that after unilateral THA. MATERIALS AND METHODS: Four French surgical centres participated in a retrospective observational study of patients managed with one-stage bilateral THA. The 112 included patients (55 women) had a mean age of 59 years (range, 22-84) and a mean follow-up of 30 months (6-103). RESULTS: Mean hospital stay length was 10.8 days (6-27), mean operative time was 162 minutes (95-270), and mean haemoglobin levels were 14.3g/dL preoperatively and 10.1g/dL postoperatively. No perioperative deaths were recorded. Deep vein thrombosis occurred in eight (7.1%) patients and pulmonary embolism in six (5.4%). The Merle d'Aubigne score improved from 9.25 +/- 2.9 (3-16) preoperatively to 17.5 +/- 1 (14-18) at last follow-up. All but three patients (109/112, 97%) said they would choose the same operation again and 102/112 (91%) said they would recommend it to a family member. DISCUSSION: The results of this multicentre retrospective study indicate that one-stage bilateral THA is a valid alternative to two-stage bilateral THA in ASA 1 and 2 patients with a preoperative haemoglobin level of about 14 g/L. The major complication rate was 7.1%, which was slightly higher than after unilateral THA, and the main complications were deep vein thrombosis and pulmonary embolism. PMID- 22939865 TI - Neuro-orthopaedic evaluation of children and adolescents: a simplified algorithm. AB - Orthopaedic surgeons are often the first physicians to evaluate paediatric patients in the event of delayed walking, gait abnormalities, or parental concern about motor abilities. Therefore, orthopaedic surgeons must be thoroughly familiar with the normal neurodevelopmental stages. Neurological disorders are often first recognised during an orthopaedic evaluation. Minimal neurological abnormalities should be taken as warning signs that require additional investigations. Consequently, the evaluation must follow a strict protocol, even in children referred for apparently trivial functional disorders. We have developed an original physical examination protocol in which the largest possible number of signs is sought in each body position to ensure that the examination is both systematic and rapid. About ten minutes are required when all findings are normal. This protocol is extremely helpful for identifying the cause of the problem that motivated the evaluation or for reassuring the child and family. The main causes of paediatric orthopaedic disorders are cerebral palsy, spinal dysraphism, myopathies, peripheral neuropathies, motor neuron diseases, and intraspinal tumours. In some instances, no definitive diagnosis can be established clinically. In this situation, appropriate orthopaedic treatment can be initiated, although considerable caution is in order when establishing the indications. The cause may be detected only much later, when the clinical manifestations become more prominent. PMID- 22939866 TI - Decision making for mothers with cancer: maintaining the mother-child bond. AB - PURPOSE: The objective of this study was to explore the process of decision making in mothers with cancer when they are mothering young children. The purpose of this article is to describe the core category that emerged from the study as well as the conditions precipitating decision making and the consequences of decision making for mothers with cancer. METHODS AND SAMPLE: A qualitative methodology based on the tenets of constructivist grounded theory was used to conduct ten interviews with eight mothers with cancer. KEY RESULTS: Data analysis revealed the core category, the conditions of the decision situation as well as the consequences of decision making. The core category was the meaning that mothers made of decisions, specifically that each decision was made to maintain the mother-child bond. The conditions of the mothers' lives influenced the meaning mothers assigned to decisions. The consequences of decision making were displayed by these mothers through coping strategies to facilitate maintaining the mother-child bond in times of distress. CONCLUSIONS: The conditions of the mothers' lives created a context in which mothers made meaning of decisions. Mothers aimed to maintain their bonds with their children in the decision making process and used various coping strategies as a consequence to distress from decisional situations. The results have implications for future decision making research in cancer care. PMID- 22939867 TI - Intra-articular lentivirus-mediated insertion of the fat-1 gene ameliorates osteoarthritis. AB - Osteoarthritis (OA) is a gradually progressive degenerative disease characterized by gradual inflammatory loss of articular cartilage caused by increased proteolytic catabolism, mediated by interleukin-1 (IL-1), tumor necrosis factor alpha (TNF-alpha), matrix metalloproteinase (MMPs), aggrecanases and other proteinases, and reduced anabolism of cartilage components, contributed by interleukin-4 (IL-4), interleukin-10 (IL-10), insulin-like growth factor 1 (IGF 1), transforming growth factor beta (TGF-beta), and bone morphogenetic proteins (BMPs). Substantial studies showed n-3 polyunsaturated fatty acids (n-3 PUFAs) exhibit a powerful anti-inflammatory effects in and ex vivo through reducing the production of IL-1 and TNF-alpha and increasing the expression of IL-4, IL-10, TGF-beta and IGF-1 in OA. Meanwhile, more convincing results are observed in the fat-1 transgenic mice, which are exogenously inserted in a fat-1 gene from Caenorhabditis elegans, which can endogenously convert n-6 polyunsaturated fatty acids (n-6 PUFAs) to n-3 PUFAs. Taken together, it has long been realized that dietary supplementation with fish oils that are plentiful of n-3 PUFAs can bring benefits in the treatment of osteoarthritis. Previously two phase I human studies based on in vitro transfer of the cDNA via lentivirus to arthritic joints have confirmed its feasibility and safety in human subjects. Consequently, we hypothesis that directly infect the chondrocytes and synoviocytes with lentivirus carrying the fat-1 gene could be a well therapeutic strategy for OA in humans. PMID- 22939868 TI - A beta-defensin 1-like antimicrobial peptide from the tree shrew, Tupaia belangeri. AB - A novel beta-defensin 1-like antimicrobial peptide (beta-defensin 1TB) containing 36 amino acid residues was purified and characterized from the serum of the tree shrew, Tupaia belangeri. Its amino acid sequence was determined as DHYLCVKNEGICLYSSCPSYTKIEGTCYGGKAKCCK, by Edman degradation, mass spectrometry analysis, and cDNA cloning. Evolution analysis indicated that beta-defensin 1TB showed maximal similarity to the beta-defensin 1 identified from cotton-top tamarin, Saguinus oedipus. beta-defensin 1TB exerted potential antimicrobial activities against wide spectrum of microorganisms including Gram-negative and positive bacteria and fungi. It showed little hemolitic activity to human or rabbit red cells. To the best of our knowledge, this is the first report of antimicrobial peptide from Tupaiidae. PMID- 22939869 TI - Identification, basic characterization and evolutionary analysis of differentially spliced mRNA isoforms of human YAP1 gene. AB - The YAP1 gene encodes a potent new oncogene and stem cell factor. However, in some cancers, the YAP1 gene plays a role of tumor suppressor. At present, the gene and its products are intensely studied and its cDNAs are used as transgenes in cellular and animal models. Here, we report 4 new potential mRNA splicing isoforms of the YAP1 gene, bringing the total number of isoforms to 8. We detected all 8 YAP1 isoforms in a panel of human tissues and evaluated the expression of the longest isoform of YAP1 (YAP1-2delta) using Real Time PCR. All YAP1 isoforms are barely detectable in human leukocytes compared to fair levels of expression found in other human tissues. We analyzed the structure of the genomic region that gave rise to alternatively spliced YAP1 transcripts in different metazoans. We found that YAP1 isoforms, which utilize exon 6 emerged in evolution with the appearance of amniotes. Interestingly, 6 YAP1 isoforms, which contain the exon 5 extension, exon 6 or both would have their leucine zipper region disrupted in the predicted protein product, compared to the intact leucine zipper found in two YAP1 (alpha) isoforms. This observation has direct functional ramifications for YAP1 signaling. We also propose a normalized nomenclature for the mRNA splice variants of the YAP1 gene, which should aid in the characterization of signaling differences among the potential protein products of the YAP1 gene. PMID- 22939870 TI - The CXCL12 G801A polymorphism and cancer risk: evidence from 17 case-control studies. AB - CXCL12 has been implicated in human carcinogenesis, but the association between the most-studied G801A polymorphism (rs1801157) and the risk of various cancers was reported with inconclusive results. The aim of this study was to assess the association between the CXCL12 G801A polymorphism and cancer risk. A meta analysis of 17 studies with 3048 cancer patients and 4522 controls was conducted to evaluate the strength of the association using odds ratio (OR) with its 95% confidence interval (CI). The overall results showed that the variant genotypes were associated with a significantly increased risk of all cancer types (OR=1.38, 95%CI=1.18-1.61 for GA versus GG, and OR=1.36, 95%CI=1.17-1.59 for GA/AA versus GG). In the stratified analyses, there was a significantly increased risk for the studies of breast cancer (OR=1.64, 95% CI=1.16-2.33 for AA versus GG, OR=1.42, 95%CI=1.18-1.71 for GA versus GG, and OR=1.44, 95%CI=1.21-1.72 for GA/AA versus GG) and lung cancer (OR=2.86, 95% CI=1.75-4.69 for AA versus GG, OR=1.62, 95% CI=1.20-2.18 for GA vs. GG, OR=1.80, 95% CI=1.36-2.39 for GA/AA versus GG, and OR=2.24, 95%CI=1.41-3.57 for AA versus GA/GG), which remained for the studies of Asian populations and hospital-based control sources. Although some modest bias could not be eliminated, this meta-analysis indicates that the CXCL12 G801A polymorphism is a low-penetrance risk factor for cancer development. PMID- 22939871 TI - Characterization and expressional analysis of Dleu7 during Xenopus tropicalis embryogenesis. AB - We characterized the genomic structure and developmental expression of the Dleu7 (deleted in lymphocytic leukemia, 7) gene in Xenopus tropicalis and the evolution of the gene across species. Within the protein-coding sequence (CDS) region, X. tropicalis Dleu7 consists of two exons and one intron. However, bioinformatic analysis indicates that this 211-amino-acid protein contains no obvious functional domains or known motifs. Reverse-transcription polymerase chain reaction and whole-mount in situ hybridization results revealed that, in addition to its expression in the blood island region, some regions of the central nervous system, and subdomains of the neural tube, X. tropicalis Dleu7 is zygotically expressed primarily in mesoderm tissues such as notochord and muscles during early embryogenesis. Expression in notochord is consistent with results from genome-wide association studies suggesting that DLEU7 is related to human adult height. Expression in the blood island region, where blood cell precursors (including B cells) are generated, implies a potential conserved role for Dleu7 in B-cell development between amphibians and mammals. Expression of Dleu7 in some regions of the central nervous system and subdomains of the neural tube also suggests other functions in development. Phylogenetic analysis indicated that Dleu7 is a vertebrate-specific gene and undergoes strong selective pressure in lower vertebrates but is functionally constrained in higher mammals. When subcellular localization was examined by overexpression of enhanced green fluorescent protein fusion protein, Dleu7 showed centrosome localization with main distribution in cytoplasm. Treating gastrula embryos with SU5402, a small molecular inhibitor of the fibroblast growth factor (FGF) receptor, confirmed that Dleu7 expression in mesoderm is regulated by FGF signaling. Our data provide important clues for pathogenesis and physiology during development from the perspective of evolutionary conservation. PMID- 22939872 TI - In vivo detection of microscopic anisotropy using quadruple pulsed-field gradient (qPFG) diffusion MRI on a clinical scanner. AB - We report our design and implementation of a quadruple pulsed-field gradient (qPFG) diffusion MRI pulse sequence on a whole-body clinical scanner and demonstrate its ability to non-invasively detect restriction-induced microscopic anisotropy in human brain tissue. The microstructural information measured using qPFG diffusion MRI in white matter complements that provided by diffusion tensor imaging (DTI) and exclusively characterizes diffusion of water trapped in microscopic compartments with unique measures of average cell geometry. We describe the effect of white matter fiber orientation on the expected MR signal and highlight the importance of incorporating such information in the axon diameter measurement using a suitable mathematical framework. Integration of qPFG diffusion-weighted images (DWI) with fiber orientations measured using high resolution DTI allows the estimation of average axon diameters in the corpus callosum of healthy human volunteers. Maps of inter-hemispheric average axon diameters reveal an anterior-posterior variation in good topographical agreement with anatomical measurements reported in previous post-mortem studies. With further technical refinements and additional clinical validation, qPFG diffusion MRI could provide a quantitative whole-brain histological assessment of white and gray matter, enabling a wide range of neuroimaging applications for improved diagnosis of neurodegenerative pathologies, monitoring neurodevelopmental processes, and mapping brain connectivity. PMID- 22939873 TI - Iterative approach of dual regression with a sparse prior enhances the performance of independent component analysis for group functional magnetic resonance imaging (fMRI) data. AB - This study proposes an iterative dual-regression (DR) approach with sparse prior regularization to better estimate an individual's neuronal activation using the results of an independent component analysis (ICA) method applied to a temporally concatenated group of functional magnetic resonance imaging (fMRI) data (i.e., Tc GICA method). An ordinary DR approach estimates the spatial patterns (SPs) of neuronal activation and corresponding time courses (TCs) specific to each individual's fMRI data with two steps involving least-squares (LS) solutions. Our proposed approach employs iterative LS solutions to refine both the individual SPs and TCs with an additional a priori assumption of sparseness in the SPs (i.e., minimally overlapping SPs) based on L(1)-norm minimization. To quantitatively evaluate the performance of this approach, semi-artificial fMRI data were created from resting-state fMRI data with the following considerations: (1) an artificially designed spatial layout of neuronal activation patterns with varying overlap sizes across subjects and (2) a BOLD time series (TS) with variable parameters such as onset time, duration, and maximum BOLD levels. To systematically control the spatial layout variability of neuronal activation patterns across the "subjects" (n=12), the degree of spatial overlap across all subjects was varied from a minimum of 1 voxel (i.e., 0.5-voxel cubic radius) to a maximum of 81 voxels (i.e., 2.5-voxel radius) across the task-related SPs with a size of 100 voxels for both the block-based and event-related task paradigms. In addition, several levels of maximum percentage BOLD intensity (i.e., 0.5, 1.0, 2.0, and 3.0%) were used for each degree of spatial overlap size. From the results, the estimated individual SPs of neuronal activation obtained from the proposed iterative DR approach with a sparse prior showed an enhanced true positive rate and reduced false positive rate compared to the ordinary DR approach. The estimated TCs of the task-related SPs from our proposed approach showed greater temporal correlation coefficients with a reference hemodynamic response function than those of the ordinary DR approach. Moreover, the efficacy of the proposed DR approach was also successfully demonstrated by the results of real fMRI data acquired from left-/right-hand clenching tasks in both block-based and event-related task paradigms. PMID- 22939874 TI - Filtering induces correlation in fMRI resting state data. AB - Correlation-based functional MRI connectivity methods typically impose a temporal sample independence assumption on the data. However, the conventional use of temporal filtering to address the high noise content of fMRI data may introduce sample dependence. Violation of the independence assumption has ramifications for the distribution of sample correlation which, if unaccounted for, may invalidate connectivity results. To enable the use of temporal filtering for noise suppression while maintaining the integrity of connectivity results, we derive the distribution of sample correlation between filtered timeseries as a function of the filter frequency response. Corrected distributions are also derived for statistical inference tests of sample correlation between filtered timeseries, including Fisher's z-transformation and the Student's t-test. Crucially, the proposed corrections are valid for any unknown true correlation and arbitrary filter specifications. Empirical simulations demonstrate the potential for temporal filtering to artificially induce connectivity by introducing sample dependence, and verify the utility of the proposed corrections in mitigating this effect. The importance of our corrections is exemplified in a resting state fMRI connectivity analysis: seed-voxel correlation maps generated from filtered data using uncorrected test variates yield an unfeasible number of connections to the left primary motor cortex, suggesting artificially induced connectivity, while maps acquired from filtered data using corrected test variates exhibit bilateral connectivity in the primary motor cortex, in conformance with expected results as seen in the literature. PMID- 22939875 TI - Three dimensional evaluation of facial asymmetry after mandibular reconstruction: validation of a new method using stereophotogrammetry. AB - The scientific literature is sparse on reports that evaluate facial asymmetry after mandibular reconstructive surgery objectively. The aim of this study is to introduce and validate a new method, using three dimensional (3D) stereophotogrammetry, that quantifies soft-tissue facial asymmetry in patients who have undergone mandibular reconstruction. To validate the new method, two observers applied the method on 3D photographs of five patients and five controls. An inter-observer difference of 0.04 mm (-0.08 to 0.17) was found with a measurement error of 0.13 mm. 15 3D photographs of the mandibular reconstructed patients were compared with 24 3D photographs of healthy controls. A significant difference (1.19 mm) in asymmetry was found between patients and controls. It is concluded that this new measuring method is a valid, fast and clinically applicable technique to quantify soft-tissue facial asymmetry. It is concluded that facial symmetry in patients is not restored to the level of the control group with the mandibular reconstruction method applied. PMID- 22939876 TI - Oral function after maxillectomy and reconstruction with an obturator. AB - Maxillectomy defects can be reconstructed by a prosthetic obturator or (free) flap transfer, but there is no consensus about the optimal method. This study evaluated 32 maxillectomy patients with prosthetic obturation regarding function (mastication, subjective oral and swallowing complaints and maximal mouth opening). Outcomes were related to the extent of the resection (Brown maxillectomy classification), dentition and history of adjuvant radiotherapy. Maxillectomy defects ranged from 2-1 to 4B on the Brown classification, and most had a defect graded as 2-A or 2-B. Mean mixing ability test after 10 chewing strokes was 24.2 and after 20 chewing strokes 19.7, which compares to edentulous healthy individuals. None of the outcomes was influenced by Brown classification. Radiotherapy negatively influenced mean maximal mouth opening (29.1mm versus 40.9 mm, p=0.017) and subjective outcomes. Edentate obturated patients had worse outcomes than dentate patients, measured by mixing ability test and questionnaire. In conclusion, mastication after obturator reconstruction of a maxillectomy defect is comparable to mastication with full dentures. Size of the maxillectomy defect did not significantly influence functional outcome, but adjuvant radiotherapy resulted in worse mouth opening and self-reported oral and swallowing problems. Residual dentition had a positive influence on mastication and subjective outcomes. PMID- 22939877 TI - Quality of life among alcohol-dependent patients: how satisfactory are the available instruments? A systematic review. AB - AIM: The purpose of this systematic review was to compare quality-of-life instruments used as outcome measures in randomized clinical trials for alcohol dependence treatment. METHODS: Randomized controlled clinical trials, indexed in the EMBASE, PubMed and PsycINFO databases since 1981, which aimed at improving the quality of life in alcohol-dependent patients and used as instrument to measure the quality of life, as specifically designated by the authors, were included. RESULTS: Of the 331 articles screened, 18 studies were included in the review. Eight different quality-of-life instruments were used as outcome measures. Twenty-seven life domains were explored. Between-scale heterogeneity was high. The scale most frequently used was the medical outcomes study 36-item short-form health survey (SF-36). Only 1 clinical trial demonstrated a significant difference between intervention groups at all endpoints, using the quality of life enjoyment and satisfaction questionnaire (Q-LES-Q). CONCLUSION: Because many different instruments were used, it is difficult to compare quality of-life improvement between trials. The most frequently used instrument was a generic health status measure that may not be well suited as a quality-of-life measure for subjects with alcohol dependence. The construction and validation of a specific patient-reported outcome based on alcohol-dependent patients' concerns would effectively contribute to the assessment of treatment efficacy. PMID- 22939878 TI - The natural history of efforts to stop smoking: a prospective cohort study. AB - BACKGROUND: In a prior study, we found changing tobacco use was more complex than previously thought, with users often transitioning between intending to quit and not intending to quit, and among typical use, abstinence, and reduction, on multiple occasions. The current study attempted to replicate those results. METHODS: A convenience sample of 40 tobacco smokers who intended to quit within the next 3 months called in nightly for 28 days to an interactive voice response system to report cigs/day and daily intentions to smoke or not for the next day. We provided no treatment. RESULTS: Within the month of the study, 32% of smokers had multiple episodes of intentions to not smoke, and 64% transitioned among smoking as usual, abstinence, and reduction status on multiple occasions. When participants reported that they intended not to smoke the next day, 56% of the time they did not make a quit attempt the next day. Just under half (44%) of quit attempts occurred on days with no intentions to quit the night before. Most quit attempts (69%) lasted less than a day. Reduction in cigs/day was as common as abstinence. CONCLUSIONS: Our prospective results replicated retrospective findings that most attempts to stop smoking result in a complex pattern of changes in smoking. These results suggest treatments should accommodate (a) multiple quit attempts over a short period, (b) reduction episodes, (c) unplanned quit attempts, and (d) immediate relapse. PMID- 22939879 TI - RBM25/LUC7L3 function in cardiac sodium channel splicing regulation of human heart failure. AB - Alternative splicing is a posttranscriptional mechanism that can substantially change the pattern of gene expression. Up to 95% of human genes have multiexon alternative spliced forms, suggesting that alternative splicing is one of the most significant components of the functional complexity of the human genome. Nevertheless, alternative splicing regulation has received comparatively little attention in the study of cardiac diseases. When investigating SCN5A splicing abnormalities in heart failure (HF), we found that 47 of 181 known splicing regulators were upregulated in HF compared to controls, which indicates that splicing regulation may play a key role in HF. Our results show that angiotensin II and hypoxia, signals common to HF, result in increased LUC7L3 and RBM25 splicing regulators, increased binding of RBM25 to SCN5A mRNA, increased SCN5A splice variant abundances, decreased full-length SCN5A mRNA and protein, and decreased Na(+) current. These observations may shed light on a mechanism whereby cardiac function and arrhythmic risk are associated and allow for refined predictions of which patients may be at highest arrhythmic risk or suffer from Na(+) channel blocking anti-arrhythmic drug complications. PMID- 22939880 TI - Comprehensive treatment of malignant mesothelioma patients after the failure of systemic chemotherapy. AB - Malignant mesothelioma (MM) is an aggressive neoplasm usually arising from the mesothelial surfaces of the pleural or peritoneal cavity. Currently, no standard therapy is available. The most commonly used therapy is cytoreductive surgery combined with systematic chemotherapy, but the median overall survival (OS) is less than 12 months; moreover, treatments are lacking for patients in whom chemotherapy has failed and/or who cannot withstand surgery. We investigated multiple minimally invasive therapies (cryosurgery, photodynamic therapy and intracavity chemotherapy) for the treatment of MM patients in whom systemic chemotherapy had failed. Twenty-seven patients were divided into comprehensive (combination of the three therapies) and palliative (intracavity chemotherapy only) treatment groups. The OS of patients who received comprehensive treatment was significantly longer than that of those who received palliative treatment (median OS: 64 vs. 9 months, P<0.001). This interesting result was not associated with treatment timing, but was closely associated with repeated treatments. PMID- 22939881 TI - In vivo assessment of murine elastase-induced abdominal aortic aneurysm with high resolution magnetic resonance imaging. AB - OBJECTIVES: There are, to date, no published non-invasive or longitudinal studies performed in mice to measure aortic diameter and wall thickness in an elastase induced abdominal aortic aneurysm. This MRI study at 11.75 T aimed at evaluating the reliability of longitudinal in vivo aortic diameter and wall thickness measurements in this particular model. METHODS: Adult male C57BL/6 mice underwent transient elastase or heat-inactivated elastase perfusion (controls). Aortic dilatation was measured before, during and immediately after elastase perfusion, and again 14 days after, with a calibrated ocular grid. MRI was performed just before initial surgery and at day 14 before harvest using an 11.75 T MR microscopy imager. RESULTS: Aortic diameter was significantly greater in elastase perfused mice compared to controls as measured by optic grid (1.150 +/- 0.153 mm vs 0.939 +/- 0.07 mm, P = 0.038) and according to MRI measurement of the outer diameter on spin echo images (1.203 +/- 0.105 mm vs 1070 +/- 0.048 mm, P = 0.0067). Aortic wall thickness was found to be significantly increased in elastase-perfused mice at day 14. CONCLUSIONS: This study demonstrates in the mouse elastase-induced aneurysm model that characterization of aneurysm development by its inner and outer vessel diameter and vessel wall thickness can be carried out longitudinally using high resolution MRI without significant mortality. PMID- 22939882 TI - Estimating historic exposures at the European Gaseous Diffusion plants. AB - This paper describes the methods and results of an occupational exposure assessment covering 30 years of operation of the EURODIF establishment (1978 2008). The exposure assessment includes radiological, physical and chemical hazards, and takes into account of organizational changes at the establishment. Furthermore, it includes efforts to better quantify the levels of exposures using available industrial hygiene and health physics data. In total, 227 workers participated in the assessment of 26 different occupational exposures in 102 general workstations through 1978-2008. Only 7% of exposure levels were rectified by experts for internal consistency reasons. Noise, heat, trichloroethylene and soluble uranium compounds were the most prevalent exposures at the plant although their levels tended to decrease across time. Assessments of occupational exposure to noise based on JEM exposure levels were fairly well correlated with noise measurement data (Spearman's correlation coefficient, rho=0.43) while JEM-based assessments of uranium exposure were not well correlated with uranium atmospheric measurements. This study demonstrates the importance of non-radiological exposure in the nuclear fuel industry and highlights the difficulties in managing the risks arising from these exposures. Occupational exposures remain difficult to quantify due to the scarcity of reliable monitoring data and the absence of binding occupational exposure limits for some of considered hazards. PMID- 22939883 TI - SIRT1 in metabolic syndrome: where to target matters. AB - Sirtuin 1 (SIRT1), the mammalian ortholog of yeast Sir2p, is a highly conserved NAD(+)-dependent protein deacetylase that has emerged as a key cardiometabolic regulator. During the past decade, Sir2p has been the focus of intense investigations and discussion because it regulates longevity in yeast, worms and flies. Although the extrapolation of data obtained from yeast Sir2p to mammalian SIRT1 cannot be automatic, animal studies provide convincing evidence that SIRT1 is a potent protector against aging-associated pathologies, in particular metabolic disorders and cardiovascular diseases. Indeed, many exciting connections exist between the protein deacetylation function of SIRT1 and its role in fundamental biological responses to various nutritional and environmental signals. As a result, pharmaceutical and nutriceutical interventions targeting SIRT1 are promising strategies to combat aging-associated diseases. The present review summarizes the recent progress in SIRT1 research with a particular focus on the specificities of this protein in individual tissues as they relate to cardiometabolic control. PMID- 22939884 TI - Basic mechanisms of migraine and its acute treatment. AB - Migraine is a neurovascular disorder characterized by recurrent unilateral headaches accompanied by nausea, vomiting, photophobia and phonophobia. Current theories suggest that the initiation of a migraine attack involves a primary event in the central nervous system (CNS), probably involving a combination of genetic changes in ion channels and environmental changes, which renders the individual more sensitive to environmental factors; this may, in turn, result in a wave of cortical spreading depression (CSD) when the attack is initiated. Genetically, migraine is a complex familial disorder in which the severity and the susceptibility of individuals are most likely governed by several genes that vary between families. Early PET studies have suggested the involvement of a migraine active region in the brainstem. Migraine headache is associated with trigeminal nerve activation and calcitonin gene-related peptide (CGRP) release from the trigeminovascular system. Administration of triptans (5-HT(1B/1D) receptor agonists) causes the headache to subside and the levels of CGRP to normalize. Moreover, administration of CGRP receptor antagonists aborts the headache. Recent immunohistochemical and pharmacological results suggest that the trigeminal system has receptors for CGRP; further, 5-HT(1B/1D) receptors, which inhibit the action of CGRP in pain transmission when activated, have been demonstrated. This offers an explanation for the treatment response. The present review provides an updated analysis of the basic mechanisms involved in the pathophysiology of migraine and the various pharmacological approaches (including 5-HT(1B/1D) receptor agonists, CGRP receptor antagonists and glutamate receptor antagonists) that have shown efficacy for the acute treatment of this disorder. PMID- 22939885 TI - Differences in transcriptional effects of 1alpha,25 dihydroxyvitamin D3 on fibroblasts associated to breast carcinomas and from paired normal breast tissues. AB - The effects of 1alpha,25 dihydroxyvitamin D3 (1,25D) on breast carcinoma associated fibroblasts (CAFs) are still unknown. This study aimed to identify genes whose expression was altered after 1,25D treatment in CAFs and matched adjacent normal mammary associated fibroblasts (NAFs). CAFs and NAFs (from 5 patients) were cultured with or without (control) 1,25D 100 nM. Both CAF and NAF expressed vitamin D receptor (VDR) and 1,25D induction of the genomic pathway was detected through up-regulation of the target gene CYP24A1. Microarray analysis showed that despite presenting 50% of overlapping genes, CAFs and NAFs exhibited distinct transcriptional profiles after 1,25D treatment (FDR<0.05). Functional analysis revealed that in CAFs, genes associated with proliferation (NRG1, WNT5A, PDGFC) were down regulated and those involved in immune modulation (NFKBIA, TREM 1) were up regulated, consistent with anti tumor activities of 1,25D in breast cancer. In NAFs, a distinct subset of genes was induced by 1,25D, involved in anti apoptosis, detoxification, antibacterial defense system and protection against oxidative stress, which may limit carcinogenesis. Co-expression network and interactome analysis of genes commonly regulated by 1,25D in NAFs and CAFs revealed differences in their co-expression values, suggesting that 1,25D effects in NAFs are distinct from those triggered in CAFs. PMID- 22939887 TI - Efficacy and mechanism of action of Proellex, an antiprogestin in aromatase overexpressing and Letrozole resistant T47D breast cancer cells. AB - Aromatase inhibitors (AI) are considered as a first line therapy for ER+PR+ breast cancers. However, many patients acquire resistance to AI. In this study, we determined the response of antiprogestin CDB-4124 (Proellex) on the aromatase overexpressing and Letrozole resistant cell lines and also studies its mechanism of action in inhibition of breast cancer cell proliferation. For these studies we generated aromatase overexpressing T47D (T47Darom) and respective control (T47Dcon) breast cancer cell lines by stable transfection with plasmid containing CYP19A1 gene, or empty vector respectively. Letrozole resistant cell line (T47DaromLR) was generated by incubating T47Darom for 75 weeks in the presence of 10 MUM Letrozole. Cell proliferation was determined by MTT or crystal violet assays. Gene expressions were quantified by QRT-PCR whereas proteins were identified by western blot analyses, flow cytometry and immunofluorescence staining. Aromatase activity was determined by estradiol ELISA. The effects of Proellex on the anchorage independent growth were measured by soft agar colony formation. Statistical differences between the various groups were determined by Student's 't' test or ANOVA followed by Bonferroni's post hoc test. Results showed that T47Darom and T47DaromLR cell lines had significantly higher aromatase expression (mRNA; 80-90 fold and protein) and as a result exhibited increased aromatization of testosterone to estradiol as compared to T47Dcon. Both these cell lines showed enhanced growth in the presence of Testosterone (50-60%). In T47DaromLR cells increased PR-B and EGFR expression as compared to T47Dcon cells was observed. Proellex and other known aromatase inhibitors (Letrozole, Anastrozole, and Exemestane) inhibited testosterone induced cell proliferation and anchorage independent growth of T47Darom cells. Cell growth inhibition was significantly greater when cells were treated with Proellex alone or in combination with other AIs as compared to AIs alone. Proellex inhibited mRNA and protein levels of PR-B, reduced PRB/p300 complex formation in the nuclei and significantly reduced EGFR expression in T47Darom cells. Our results in the present study indicate that antiproliferative effect of Proellex is probably due to PR-B/EGFR modulation in ER+PR+, aromatase expressing cells. Overall these results suggest that antiprogestin, Proellex can be developed as a possible treatment strategy for aromatase overexpressing ER+/PR+ breast cancer patients as well as for aromatase inhibitor resistant breast cancer patients. PMID- 22939886 TI - Equivalent anticancer activities of dietary vitamin D and calcitriol in an animal model of breast cancer: importance of mammary CYP27B1 for treatment and prevention. AB - Calcitriol [1,25(OH)2D3], the hormonally active form of vitamin D exerts anti proliferative, pro-apoptotic, anti-inflammatory effects and other anticancer actions in breast cancer (BCa) cell cultures and animal models of BCa. Our research is focused on investigating the potential beneficial effects of dietary vitamin D3 compared to calcitriol and the underlying mechanisms in BCa treatment and chemoprevention. We recently found that dietary vitamin D3 exhibits significant tumor inhibitory effects in xenograft models of BCa that are equivalent to those elicited by the administration of the active hormone calcitriol. At the easily achievable dose tested in our studies, dietary vitamin D3 exhibited substantial tumor inhibitory activity and, unlike calcitriol, did not cause hypercalcemia demonstrating its relative safety. We found elevations in circulating calcitriol as well as increased CYP27B1 expression in the tumor and the intestine in tumor-bearing mice ingesting a vitamin D3-supplemented diet. We hypothesize that the elevation in circulating 25(OH)D induced by dietary vitamin D3 supplements stimulates local synthesis of calcitriol in the mammary tumor microenvironment and the ensuing paracrine/autocrine actions play a major role in the anticancer activity of dietary vitamin D3. Our findings suggest that the endocrine activity of calcitriol derived from tumor and other extra-renal sources such as the intestine, probably also plays a role in mediating the anticancer effects of dietary vitamin D3. Thus it appears that multiple sites of 1alpha hydroxylation contribute to the anticancer effects of dietary vitamin D3. Our data strongly suggest that dietary vitamin D will be useful in the chemoprevention and treatment of BCa since it is a safe, economical and easily available nutritional agent that is equivalent to calcitriol in exerting anticancer effects, at least in mouse models. Furthermore, adequate vitamin D nutrition and avoidance of vitamin D deficiency appear to be important in reducing BCa risk. These findings warrant clinical trials in BCa patients and in women at high risk for BCa to evaluate the benefits of dietary vitamin D3 supplementation. This article is part of a Special Issue entitled 'Vitamin D Workshop'. PMID- 22939888 TI - Phenotype modulation of airway smooth muscle in asthma. AB - The biological responses of airway smooth muscle (ASM) are diverse, in part due to ASM phenotype plasticity. ASM phenotype plasticity refers to the ability of ASM cells to change the degree of a variety of functions, including contractility, proliferation, migration and secretion of inflammatory mediators. This plasticity occurs due to intrinsic or acquired abnormalities in ASM cells, and these abnormalities or predisposition of the ASM cell may alter the ASM response and in some cases recapitulate disease hallmarks of asthma. These phenotypic changes are ultimately determined by multiple stimuli and occur due to alterations in the intricate balance or reversible state that maintains ASM cells in either a contractile or synthetic state, through processes termed maturation or modulation, respectively. To elucidate the role of ASM phenotype in disease states, numerous in vitro studies have suggested a phenotypic switch in ASM primary cell cultures as an explanation for the plethora of responses mediated by ASM cells. Moreover, there is overwhelming evidence suggesting that the immunomodulatory response of ASM is due to the acquisition of a synthetic phenotype; however, whether this degree of plasticity is present in vivo as opposed to cell culture-based models remains speculative. Nonetheless, this review will give an overall scope of ASM phenotypic markers, triggers of ASM phenotype modulation and novel therapeutic approaches to control ASM phenotype plasticity. PMID- 22939889 TI - Status of clomiphene citrate and metformin for infertility in PCOS. AB - Though widely used, there is uncertainty about the effectiveness and adverse effects of metformin and clomiphene citrate (CC) for infertility in polycystic ovary syndrome (PCOS). A systematic review (SR) of the best available evidence suggests that both CC and metformin are better than placebo for increasing ovulation and pregnancy rates, but CC is more effective than metformin for ovulation, pregnancy and live-birth rates, in PCOS patients with body mass index (BMI) >30. A combination of CC and metformin is superior to either metformin alone or CC alone, depending on the BMI and CC sensitivity of the patient. This SR provides key messages to guide clinicians and consumers on the use of these interventions in different subgroups of women with PCOS. PMID- 22939890 TI - Prevalence and risk factors for auditory neuropathy spectrum disorder in a screened newborn population at risk for hearing loss. AB - OBJECTIVE: To determine the prevalence of Auditory Neuropathy Spectrum Disorder (ANSD) among infants with sensorineural hearing loss (SNHL) and discuss the risk factors. METHODS: The study group was comprised of children diagnosed with ANSD. Criteria for inclusion in the study group were as follows: permanent sensorineural hearing loss (SNHL); normal transient evoked or distortion product OAEs; absent or elevated middle-ear muscle reflexes (MEMR); severely abnormal or absent ABR waveform. All newborns were screened via a two-stage protocol, involving OAEs and ABR for the repeatedly referred cases and all neonates with one or more risk factors. RESULTS: From 2002 to 2011, 9419 infants whose hearing ability was uncertain or who had risk factors for hearing loss were investigated. From this population, 352 were diagnosed with SNHL. Of these 352 children, 18 (5.1%) were diagnosed with ANSD. In the ANSD group, prematurity and low birth weight (<1500 g) were observed in 5 cases; ototoxical medication in 8 cases; mechanical ventilation in excess of 5 days in 5 cases. Hyperbilirubinemia was observed in 7 cases, but severe hyperbilirubinemia requiring an exchange transfusion was not observed; 4 patients had no risk factors, 6 patients had only one risk factor, and the 8 remaining had two or more risk factors. CONCLUSION: Auditory Neuropathy Spectrum Disorder is not an extremely rare hearing disorder. Screening for hearing loss via OAEs, MEMR and ABR examinations concurrently are essential for the accurate diagnosis of ANSD. PMID- 22939891 TI - Palate abnormalities in Chilean patients with chromosome 22q11 microdeletion syndrome. AB - OBJECTIVE: Chromosome 22q11 microdeletion syndrome (del22q11) is the most frequent microdeletion syndrome in humans, with an estimated incidence of 1/4000. It is recognized as a common identifiable cause of cleft palate. We characterized palatal abnormalities in a large cohort of Chilean patients with del22q11. METHODS: Patients with the deletion were evaluated by geneticists and speech pathologists, including nasopharyngoscopy when indicated. Comparisons between groups with and without palatal abnormalities were performed using Fisher's exact test and Mann-Whitney U test. RESULTS: Two hundred and one patients were included in the study. Palate abnormalities were present in 154 patients (76.6%). The most frequent finding was submucous cleft palate (both classic and occult forms) seen in 80 patients (39.8% of the total group). Overt cleft palate or cleft lip/palate was seen in 30 patients (14.9%). Patients without palate abnormalities had significantly greater frequency of congenital heart disease and higher mortality. CONCLUSIONS: Our data show a high frequency of palate abnormalities without significant association with congenital heart disease. The most common types of palate defects seen in this series are usually not evident on physical examination and thus require a high index of suspicion and active evaluation through nasopharyngoscopy. PMID- 22939892 TI - Feasibility of a remote monitoring system for home-based non-invasive positive pressure ventilation of children and infants. AB - OBJECTIVE: We examined the safety, efficacy, and caregiver satisfaction of a remote monitoring system for home-based non-invasive positive pressure ventilation of children and infants with upper airway obstruction. METHODS: Fourteen pediatric patients (age 50 days to 12 years) treated in our ENT unit from March 2009 to July 2011 and requiring home-based non-invasive positive pressure ventilation were enrolled in this feasibility study; one patient underwent CPAP and the other 13 patients underwent Bi-PAP. User satisfaction with the monitoring system was assessed by questionnaires given at regular intervals to parents and attending physicians. Compliance was determined by the number of days that parents uploaded data to the central server. In addition, the feasibility of the system was analyzed by comparing costs and time expenditures with traditional clinic visits. RESULTS: The patients' parents (primary caregivers) uploaded data via the system on 93.3% of trial days, indicating good compliance. No system or device failures occurred. Both parents and physicians considered the system convenient and ease to use according to >80% of the returned questionnaires, indicating high user satisfaction. The mean distance between the patients' homes and the hospital was 113 +/- 71 km, and parents required 371 +/- 182 min to reach the hospital for a follow-up visit. In contrast, it took only 5.7 +/- 3.1 min per day to transmit data (P<0.05 compared to hospital travel time). As of August 2011, average cost per patient was 632 Chinese yuan (Y), which was Y924 (59.4%) lower than the cost of clinic visits (Y1556). CONCLUSIONS: The remote monitoring system was safe, reliable, easy to use, cost effective, and widely acceptable to both parents and physicians. This system may allow for safe and effective home-based non-invasive positive pressure ventilation for children with upper airway obstructions in developing countries with limited health care budgets or for patients from remote regions. PMID- 22939893 TI - Ultrasound-guided injection of botulinum toxin A into the submandibular gland in children and young adults with sialorrhoea. AB - Hypersalivation is a common and distressing complaint in children with neuromuscular disorders such as cerebral palsy. Complications associated with severe drooling include daily changes of clothing, perioral dermatitis, dental problems, dehydration, and aspiration pneumonia, which potentially have a detrimental effect on the quality of life of the patient and carer. In this paper we update our previous work to show the potential benefits of ultrasound-guided injection of botulinum toxin A (BTX-A) into the submandibular gland and report on new patients and follow-up data on the existing group. PMID- 22939894 TI - Healing patterns of critical size bony defects in rats after grafting with bone substitutes soaked in recombinant human bone morphogenetic protein-2: histological and histometric evaluation. AB - The aim of the study was to evaluate the effect of different bone substitutes soaked in recombinant human bone morphogenetic protein-2 (rhBMP-2) on the healing of critical size defects in calvarial bone. Defects were created in 24 Sprague Dawley rats. The rhBMP-2 was diluted to obtain a final concentration of 0.2mg/ml. Rats were divided into four groups and treated as follows: in the first group the defect was filled with anorganic bovine bone mineral (ABBM) and rhBMP-2, the second group was treated with freeze-dried bone allograft (FDBA) and rhBMP-2, and the third group was treated with autogenous bone (AUTO). In the control group the defects were left untreated. Animals were killed after 8weeks and calcified histological sections prepared. Histometric measurements showed that mean (SD) bone formation was 4.00 (1.69)mm(2) in the ABBM group, 2.56 (1.06)mm(2) in the FDBA group, and 2.30 (0.34)mm(2) in the AUTO group. The difference between the ABBM group and the other 3 groups was significant (p<0.0001) with a mean bone formation of 0.82 (0.25)mm(2) in the control group. There was no significant difference between the FDBA and the AUTO groups (p=0.96). Within the limits of this study we concluded that the addition of rhBMP-2 to bone substitutes was efficacious in regenerating bone in critical size bone defects in calveria in rats. PMID- 22939895 TI - Perpendicularity misjudgments caused by contextual stimulus elements. AB - It has been demonstrated in previous studies that the illusions of extent of the Brentano type can be explained by the perceptual positional shifts of the stimulus terminators in direction of the centers-of-masses (centroids) of adjacent contextual flanks [Bulatov, A. et al. (2011). Contextual flanks' tilting and magnitude of illusion of extent. Vision Research, 51(1), 58-64]. In the present study, the applicability of the centroid approach to explain the right angle misjudgments was tested psychophysically using stimuli composed of three small disks (dots) forming an imaginary rectangular triangle. Stimuli comprised the Muller-Lyer wings or line segments (bars) as the contextual distracters rotated around the vertices of the triangle, and changes in the magnitude of the illusion of perpendicularity were measured in a set of experiments. A good resemblance between the experimental data and theoretical predictions obtained strongly supports the suggestion regarding the common "centroid" origin of the illusions of extent of the Brentano type and misperception of the perpendicularity investigated. PMID- 22939896 TI - Synergetic effect of alkaline earth metal oxides and iron oxides on the degradation of hexachlorobenzene and its degradation pathway. AB - The degradation of hexachlorobenzene (HCB) was carried out over physical mixtures of a series of alkaline earth metal oxides (MO: M=Mg, Ca, Sr, Ba) and iron oxides with different crystal types (Fe(x)O(y):Fe(2)O(3) or Fe(3)O(4)) at 300 degrees C. These physical mixtures all showed a synergetic effect toward the degradation of HCB. A range of degradation products were identified by various methods, including tri- to penta-chlorobenzenes by gas chromatography/mass spectrometry (GC-MS), tri- to penta-chlorophenols, tetrachlorocatechol (TCC) and tetrachlorohydroquinone (TCHQ) by GC-MS after derivatization, and formic and acetic acids by ion chromatography. Two degradation pathways, hydrodechlorination and oxidative degradation, appear to occur competitively. However, more sequential chlorinated benzene and phenol congeners were formed over mixed MO/Fe(3)O(4) than over mixed MO/Fe(2)O(3) under the same conditions. The oxidative reaction dominated over mixed MO/Fe(2)O(3) and was promoted as the major reaction by the synergetic effect, while both the oxidative and hydrodechlorination reactions were important over mixed MO/Fe(3)O(4), and both pathways are remarkably promoted by the synergetic effect. The enhanced hydrodechlorination may be attributed to free electrons generated by the transformation of Fe(3)O(4) into Fe(2)O(3), and hydrogen provided by water adsorbed on the MO. PMID- 22939897 TI - Practical method for PCB degradation using Pd/C-H2-Mg system. AB - Polychlorinated biphenyls (PCBs) were mainly used as lubricants and coolants in electrical equipment. However, their chemical stabilities as well as hydrophobic properties caused persistent environmental pollution and damage to human health based on their bioaccumulative property. PCBs are currently targeted for worldwide elimination and should be disposed by 2028 based on the Stockholm Convention on Persistent Organic Pollutants. The conventional PCB degradation methods require high-heat, high-pressure or/and strongly basic conditions. The development of a safer and more practical method, therefore, is desired. We have reported a catalytic degradation method of PCBs based on a palladium on carbon (Pd/C)-catalyzed dechlorination in the presence of Et(3)N under ambient hydrogen pressure and temperature. In this study, we demonstrate a more practical system using magnesium metal instead of Et(3)N for the dechlorination of a variety of aromatic chlorides. The method was applicable for the complete degradation of a variety of PCB mixtures, such as Aroclor 1242, 1248, 1254 and PCBs removed from a capacitor to produce only biphenyl and magnesium chloride as the maritime component, both of which are less toxic and easily separable. Moreover, the Pd/C could be recovered and reused at least five times without any loss of catalytic activity. The present Pd/C-Mg-H(2) system is a simple, safe, inexpensive, and environmentally-benign degradation method of PCBs. PMID- 22939898 TI - Comparative study of the destruction of polychlorinated dibenzo-p-dioxins and dibenzofurans during Fenton and electrochemical oxidation of landfill leachates. AB - Two advanced oxidation processes (AOPs) that provide a broad-spectrum contaminant destruction option were applied to the treatment of the leachates, namely electrochemical and Fenton oxidation. Despite the similar efficiency in the oxidation of major organic contaminants, approximately 90% reduction of chemical oxygen demand after 180 min, our results showed a different behaviour of both AOPs in the oxidation of polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs). A concentration reduction of 73% for 1,2,3,4,6,7,8-HpCDD and of 71% for OCDD was reached after 180 min of electrochemical oxidation and the total toxic equivalent of the sample was reduced in 58%. However, Fenton oxidation followed a different trend and for similar operation times, it was detected an increase in the concentration of several PCDD/Fs congeners, specially stressed for the major congeners 1,2,3,4,6,7,8-HpCDD, OCDD and OCDF, and in the total toxicity of the sample between 12.5% and 128%. Comparison of the results and the rationale behind their difference are finally discussed. PMID- 22939899 TI - Cell transplantation approaches to retinal ganglion cell neuroprotection in glaucoma. AB - Glaucoma is a complex neurodegenerative disease that involves interactions among multiple signaling pathways, ultimately leading to progressive retinal ganglion cell (RGC) death. The development of neuroprotective approaches to glaucoma therapy could preserve vision by modulating these pathologic pathways or by acting directly on RGCs to attenuate cell death and maintain function. Intraocular cell transplantation is being evaluated as one approach to achieve sustained RGC neuroprotection. Unlike traditional pharmacological approaches, transplanted cells might be capable of simultaneously targeting multiple pro survival pathways via local delivery of secreted factors and/or via modulation of the intraocular microenvironment. Elucidating the mechanisms by which different cell types attenuate RGC death in models of glaucoma may uncover additional novel mechanisms of neuroprotection. In this review, we will discuss the rationale for transplantation-based approaches to neuroprotection for glaucoma and explore the various mechanisms of action proposed to account for RGC neuroprotection achieved by two distinct cell classes that have been studied most extensively for this purpose: glial cells and mesenchymal stem cells. PMID- 22939900 TI - Cholesterol and the development of clear-cell renal carcinoma. AB - The majority of kidney cancers are clear-cell carcinomas (ccRCC), characterized by the accumulation of cholesterol, cholesterol esters, other neutral lipids and glycogen. Rather than being a passive bystander, the clear-cell phenotype is suggested to be a biomarker of deregulated cholesterol and lipid biosynthesis, which plays an important role in development of the disease. One clue to this relationship has come from the elucidation of the hereditary kidney cancer gene, TRC8, which functions partly to degrade key regulators of endogenous cholesterol and lipid biosynthesis. In addition, deregulation of the mevalonate pathway has been shown to play a key role in cellular transformation and invasion. These findings are supported by considerable epidemiologic data linking obesity and the deregulation of lipid biosynthesis to ccRCC. PMID- 22939901 TI - Development of a hyperparasitoid wasp in different stages of its primary parasitoid and secondary herbivore hosts. AB - Parasitoid wasps are model organisms for exploring constraints on life history and development strategies in arthropods. Koinobiont parasitoids attack hosts that may vary considerably in size at parasitation. Thus far, studies exploring koinobiont development in hosts of different size have been exclusively done with primary parasitoids attacking insect herbivores. However, the larvae of primary koinobiont parasitoids may in turn be attacked by koinobiont hyperparasitoids. We examined development of the gregarious hyperparasitoid Baryscapus galactopus in different stages of its primary parasitoid host, Cotesia glomerata, itself developing in different stages of caterpillars of the cabbage butterfly, Pieris brassicae. This is the first study exploring hyperparasitoid development in different stages of a primary and secondary host. Second instar (L2) larvae of P. brassicae were parasitized by C. glomerata, and separate cohorts of L3 to L5 P. brassicae containing different stages of C. glomerata were then presented to B. galactopus females. B. galactopus was able to parasitize tiny larvae of C. glomerata in L3 caterpillars of P. brassicae, but hyperparasitism efficiency increased in later instars of both C. glomerata and P. brassicae. Development time of B. galactopus was extended in younger C. glomerata/P. brassicae hosts, whereas adult mass was largest when C. glomerata was attacked in L3 through early L5 P. brassicae. Our results show that B. galactopus adjusts its development rate in accordance with the size of both its primary and secondary hosts, in order to ensure survival. Adaptive responses to phylogenetic constraints on the development of primary hyperparasitoids are discussed. PMID- 22939902 TI - Bayesian inference of force dynamics during morphogenesis. AB - During morphogenesis, cells push and pull each other to trigger precise deformations of a tissue to shape the body. Therefore, to understand the development of animal forms, it is essential to analyze how mechanical forces coordinate behaviors of individual cells that underlie tissue deformations. However, the lack of a direct and non-invasive force-measurement method has hampered our ability to identify the underlying physical principles required to regulate morphogenesis. In this study, by employing Bayesian statistics, we develop a novel inverse problem framework to estimate the pressure of each cell and the tension of each contact surface from the observed geometry of the cells. We confirmed that the true and estimated values of forces fit well in artificially generated data sets. Moreover, estimates of forces in Drosophila epithelial tissues are consistent with other readouts of forces obtained by indirect or invasive methods such as laser-induced destruction of cortical actin cables. Using the method, we clarify the developmental changes in the patterns of tensile force in the Drosophila dorsal thorax. In summary, the batch and noninvasive nature of the described force-estimation method will enable us to analyze the mechanical control of morphogenesis at an unprecedented quantitative level. PMID- 22939903 TI - Disentangling dispersal, vicariance and adaptive radiation patterns: a case study using armyworms in the pest genus Spodoptera (Lepidoptera: Noctuidae). AB - Thanks to the recent development of integrative approaches that combine dated phylogenies with models of biogeographic evolution, it is becoming more feasible to assess the roles of dispersal and vicariance in creating complex patterns of geographical distribution. However, the historical biogeography of taxa with good dispersal abilities, like birds or flying insects, still remains largely unknown because of the lack of complete phylogenies accompanied by robust estimates of divergence times. In this study, we investigate the evolution and historical biogeography of the globally distributed pest genus Spodoptera (Lepidoptera: Noctuidae) using complete taxon sampling and an extensive set of analyses. Through the analysis of a combined morphological and molecular dataset, we provide the first robust phylogenetic framework for this widespread and economically important group of moths. Historical biogeography approaches indicate that dispersal events have been the driving force in the biogeographic history of the group. One of the most interesting findings of this study is the probable occurrence of two symmetric long-distance dispersal events between the Afrotropical and the Neotropical region, which appear to have occurred in the late Miocene. Even more remarkably, our dated phylogenies reveal that the diversification of the clade that includes specialist grass feeders has followed closely the expansion of grasslands in the Miocene, similar to the adaptive radiation of specialist grazing mammals during the same period. PMID- 22939904 TI - In vitro-expanded CD4(+)CD25(high)Foxp3(+) regulatory T cells controls corneal allograft rejection. AB - AIMS: Natural CD4(+)CD25(+) regulatory cells (nTregs) have been implicated in maintaining peripheral immune tolerance. This study aims to test whether immunotherapy using in vitro-expanded Treg (iTregs) could suppress allograft rejection in corneal transplantation model. METHODS: Natural CD4(+)CD25(+) T cells were freshly purified from naive mice and expanded in vitro by culturing with anti-CD3/CD28-coated Dynabeads, interleukin (IL)-2 and transforming growth factor (TGF-beta1). Suppression ability of iTregs was assayed by co-culturing with CD4(+)CD25(-) T cells (Teff) in vitro and by targeting corneal allograft rejection in vivo. Tracking of iTreg after adoptive transfer in vivo were examined by CFSE labeling. RESULTS: Natural Treg cells were expanded by culturing with anti-CD3/CD28-coated Dynabeads in the presence of IL-2 and TGF-beta1. Compared with nTregs, iTregs had similar expression of CD62L, and PD- L1, lower expression of CD69, higher levels of PD-1, CD25, and Foxp3. iTreg cells exerted stronger suppression function than natural Treg cells when cocultured with CD4(+)CD25(-) T cells in vitro and prevented fully MHC-mismatched corneal allograft rejection. Survival of iTreg cells could suppress alloimmune reaction and most prone to migrate to graft draining LNs and spleens. Moreover, maintaining CD25 expression on iTregs was indicative for preservation of allosuppression. CONCLUSION: Therapeutic use of in vitro-expanded CD4(+)CD25(+) T cells may be a effective and safe tool for controlling allograft rejection and may help induce allograft tolerance. PMID- 22939905 TI - KIR2DS2 and KIR2DS4 promoter hypomethylation patterns in patients undergoing hematopoietic cell transplantation (HCT). AB - The killer cell Ig-like receptor (KIR)-MHC class I pathway is an integral part of natural killer cell immunity, and its role in host protection from both cancer and infection is important. In addition, we have shown elevated KIR2DS2 and 2DS4 expression in PBMCs of patients undergoing hematopoietic cell transplantation (HCT) [1]. Since all inhibitory KIR promoters are known to be heavily methylated, the question asked here is how and when KIR2DS2 and 2DS4 promoters had changed their methylation profile in association with HCT. Genomic DNA, extracted from 20 KIR2DS2/4+ donor and recipient cells, was treated with sodium bisulfate that will modify the unmethylated cytosine into uracil. Sequencing chromatographs were examined for C/T double peak indicative of base conversion. A CpG island in KIR2DS2 promoter spans from -160 to +26 with six cytosine sites. In contrast, the KIR2DS4 promoter CpG island contains three cytosine sites. The noted increase of unmethylated sites was associated with increased KIR expression as measured by mRNA-cDNA Q-PCR. In addition, the frequency of unmethylated sites in the CpG island was increased after HCT. The mechanism through which hypomethylation occurs after HCT is not known but it suggests a linkage to NK clonal expansion during the process of NK education in response to transplant therapy or viral infection. PMID- 22939906 TI - Human papillomavirus, lichen sclerosus and penile cancer: a study in Belgium. AB - PURPOSE: The prevalence of penile cancer varies between 1.5 (industrialized countries) and 4.5 per 100,000 men (non-industrialized countries). Predominant histological subtype is squamous cell carcinoma (SCC). Human papillomavirus (HPV) is found in 40-46% of cases: penile cancer is considered to behave as vulvar cancer. Non HPV related risk factors are lack of circumcision, phimosis, chronic inflammation, and smoking. The role of lichen sclerosus (LS) is unclear. Clinical diagnosis is difficult and treatment often mutilating. Preventive measures can be taken since the risk factors are known: the use of the prophylactic HPV vaccines may contribute. We measured the prevalence of HPV and LS in penile cancer in Belgium. MATERIALS AND METHODS: We found 76 samples of penile lesions in the archives of the departments of Histology of four university hospitals in Belgium. Real-time PCR of type-specific HPV DNA was performed targeting 18 HPV types. PRINCIPAL RESULTS: Patients with penile intraepithelial neoplasia (PeIN) were 56.1 years of age: patients with invasive penile cancer (IPC) 68.5 (p=0.009). Fifty-five samples (55/76) were adequate for HPV targeting. Overall HPV DNA was 70.9%: 89.5% in samples of PeIN (n=19) and 61.1% in samples of IPC (n=36). Invasive penile cancer samples were less likely to be HPV infected (p=0.028). HPV 16 was most prevalent: 48.3%: 20% PeIN, and 28.3% IPC. HPV DNA of the types, included in the prophylactic vaccines, was found in 33% of PeIN and 31.7% of IPC samples. Thrice, low risk HPV (lrHPV) types 6 (1 IPC) and 11 (1 PeIN, 1 IPC) were solely present. There was no difference in the presence of LS between HPV positive and HPV negative samples (p=0.944). CONCLUSIONS: Prevalence of HPV DNA in penile lesions in Belgium is high. However, the prophylactic vaccines may contribute to primary prevention of only a subset of cases. The role of LS remains unclear. PMID- 22939908 TI - Perceptions matter: beliefs about influenza vaccine and vaccination behavior among elderly white, black and Hispanic Americans. AB - BACKGROUND: Knowledge and beliefs about influenza vaccine that differ across racial or ethnic groups may promote racial or ethnic disparities in vaccination. OBJECTIVE: To identify associations between vaccination behavior and personal beliefs about influenza vaccine by race or ethnicity and education levels among the U.S. elderly population. METHODS: Data from a national telephone survey conducted in 2004 were used for this study. Responses for 3875 adults >= 65 years of age were analyzed using logistic regression methods. RESULTS: Racial and ethnic differences in beliefs were observed. For example, whites were more likely to believe influenza vaccine is very effective in preventing influenza compared to blacks and Hispanics (whites, 60%; blacks, 47%, and Hispanics, 51%, p<0.01). Among adults who believed the vaccine is very effective, self-reported vaccination was substantially higher across all racial/ethnic groups (whites, 93%; blacks, 76%; Hispanics, 78%) compared to adults who believed the vaccine was only somewhat effective (whites 67%; blacks 61%, Hispanics 61%). Also, vaccination coverage differed by education level and personal beliefs of whites, blacks, and Hispanics. CONCLUSIONS: Knowledge and beliefs about influenza vaccine may be important determinants of influenza vaccination among racial/ethnic groups. Strategies to increase coverage should highlight the burden of influenza disease in racial and ethnic populations, the benefits and safety of vaccinations and personal vulnerability to influenza disease if not vaccinated. For greater effectiveness, factors associated with the education levels of some communities may need to be considered when developing or implementing new strategies that target specific racial or ethnic groups. PMID- 22939907 TI - Rapid reduction in invasive pneumococcal disease after introduction of PCV7 into the National Immunization Plan in Israel. AB - BACKGROUND: The 7-valent conjugated vaccine (PCV7) was introduced into the Israeli National Immunization Program (NIP) in July 2009 (2, 4, 12 months schedule; 2 dose catch-up in second year of life). Nationwide active prospective surveillance on invasive pneumococcal disease (IPD) has been conducted in children since 1989. In the current study, IPD epidemiology in children <5 years during the 20 years before and 18 months after PCV7 NIP initiation, is reported. METHODS: All 27 centers performing blood/cerebrospinal fluid (CSF) cultures in children reported monthly IPD cases. Capture-recapture approach was used for completeness. RESULTS: During 1989-2010, 6022 IPD cases were reported in children <5 years; PCV7 serotypes (7VST) caused ~50% of all episodes. In 2009 and 2010, 7VST IPD incidences <5 years of age (per 100,000) were 15.9 and 5.4, respectively (a 43% and 81% decrease, respectively) compared to 2003-2007 (mean incidence 27.8). Serotype 6A dynamics resembled those of 7VST. The respective overall IPD incidence decreases were 23% and 42%. The incidence dynamics of serotypes 1, 3, 5, 7F and 19A IPD were characterized by considerable fluctuations over the study period without any upwards or downwards trend in any of the age groups. The overall incidence of serotypes not included in the 13-valent pneumococcal conjugate vaccine (PCV13) did not vary significantly during the study period. By the end of 2010, 72% of the remaining IPD was caused by pneumococcal serotypes included in PCV13. CONCLUSIONS: An active prospective long-term surveillance, showed a rapid and sharp decline in IPD in children <5 years following initiation of NIP with PCV7. No serotype replacement has been observed so far. The transition from PCV7 to PCV13 initiated in October 2010 may lead to a further substantial decrease in IPD. Follow-up is needed to better determine the long term PCV effects. PMID- 22939909 TI - Efficacy of marker vaccine candidate CP7_E2alf in piglets with maternally derived C-strain antibodies. AB - Marker vaccines offer the possibility to differentiate classical swine fever (CSF) infected from CSF vaccinated animals based on serology and their implementation will ensure free trade with pigs. Therefore, new generations of promising marker vaccines have been developed, among them the chimeric vaccine CP7_E2alf. However, in populations previously vaccinated with live attenuated vaccines like the C-strain, passive immunity through maternal antibodies can interfere with efficacy of CP7_E2alf vaccination. Therefore, the efficacy of CP7_E2alf was examined in piglets from sows vaccinated once intramuscularly with C-strain vaccine 4 weeks before farrowing. Thus, these piglets were vaccinated intramuscularly with CP7_E2alf at the age of 5 or 8 weeks. Subsequently, the piglets and their mock-vaccinated littermate controls were challenged 2 weeks post vaccination with highly virulent Classical swine fever virus (CSFV) strain "Koslov". CP7_E2alf provided clinical protection upon challenge as no severe clinical signs or mortality was observed in the vaccinated piglets. Post mortem examination revealed pathological changes associated to CSFV only in the mock vaccinated piglets. No infectious CSFV could be isolated from the tonsils of the vaccinated piglets. Two weeks after vaccination at the time of challenge, the vaccinated piglets only, had an increase in the ELISA antibody titer. Interestingly, the maternally derived immunity in the mock-vaccinated control piglets seems to neutralize the challenge virus. Thus, the previously observed 100% mortality in naive (negative for antibodies to CSFV) piglets infected with CSFV Koslov was reduced in the control piglets of this study to 30% for challenge at the age of 7 weeks and 50% at the age of 10 weeks, respectively. In conclusion, CP7_E2alf proved to be effective in preventing mortality, severe clinical signs and pathological lesions in 5 or 8 weeks old piglets positive for maternal antibodies derived from sows vaccinated intramuscularly 4 weeks before farrowing with one dose of C-strain vaccine. PMID- 22939910 TI - In vitro evaluation of human hybrid cell lines generated by fusion of B lymphoblastoid cells and ex vivo tumour cells as candidate vaccines for haematological malignancies. AB - Fusions of dendritic cells (DCs) and tumour cells have been shown to induce protective immunity to tumour challenge in animal models, and to represent a promising approach to cancer immunotherapy. The broader clinical application of this approach, however, is potentially constrained by the lack of replicative capacity and limited standardisation of fusion cell preparations. We show here that fusion of ex vivo tumour cells isolated from patients with a range of haematological malignancies with the human B-lymphoblastoid cell line (LCL), HMy2, followed by chemical selection of the hybridomas, generated stable, self replicating human hybrid cell lines that grew continuously in tissue culture, and survived freeze/thawing cycles. The hybrid cell lines expressed HLA class I and class II molecules, and the major T-cell costimulatory molecules, CD80 and CD86. All but two of 14 hybrid cell lines generated expressed tumour-associated antigens that were not expressed by HMy2 cells, and were therefore derived from the parent tumour cells. The hybrid cell lines stimulated allogeneic T-cell proliferative responses and interferon-gamma release in vitro to a considerably greater degree than their respective parent tumour cells. The enhanced T-cell stimulation was inhibited by CTLA4-Ig fusion protein, and by blocking antibodies to MHC class I and class II molecules. Finally, all of five LCL/tumour hybrid cell lines tested induced tumour antigen-specific cytotoxic T-cell responses in vitro in PBL from healthy, HLA-A2+ individuals, as detected by HLA-A2-peptide pentamer staining and cellular cytotoxicity. These data show that stable hybrid cell lines, with enhanced immunostimulatory properties and potential for therapeutic vaccination, can be generated by in vitro fusion and chemical selection of B-LCL and ex vivo haematological tumour cells. PMID- 22939911 TI - Investigation on the artificial exchange signals induced by the RIDER effect in CODEX experiments. AB - The CODEX (center-band only detection of exchange) NMR experiment is widely used for the detection of slow motions in organic solids, especially polymers. However, the RIDER (relaxation-induced dipolar exchange with recoupling) effect may result in artificial exchange signals in the CODEX pure exchange spectrum, which greatly limits the application of CODEX method. Herein, we investigate the distance range that the RIDER effect can reach by performing CODEX experiments on two typical organic solids, hexadecyltrimethylammonium bromide (CTAB) and semi crystalline polyamide-6 (PA6) where there are no slow molecular motions at room temperature. Our experimental results demonstrate that generally two-bond distance is far enough to ignore the RIDER effect resulted from the dipolar interactions between (13)C and the fast relaxing heteronucleus (14)N. From the built-up curve of RIDER signals as a function of recoupling time and mixing time, it is clearly revealed that the RIDER effect can greatly affect the signal from (13)C directly bonded with (14)N. However, this RIDER effect accounts less than 3% of the reference intensity for signals from (13)C not directly bonded with (14)N if typical recoupling (~0.5 ms) and mixing times (~0.5 s) are used for the investigation of slow motions. When longer recoupling and mixing time are used, there are small RIDER signals even for the (13)C far away from the (14)N. These signals, to a large degree, result from the spin diffusion effect and/or the special microscopic molecule arrangement. However, they are so small compared to the reference signal (~5%) that they can be ignored. Finally, according to the simulation results, it is worth noting that the RIDER signal is still generally negligible compared to the signals due to slow motions if the chemical shift anisotropy reorientation during the mixing time is not too small(larger than 20 degrees ) under the condition of 4t(r) recoupling time at the magic-angle spinning speed of 6.5 kHz. PMID- 22939912 TI - Review of Shiga-toxin-producing Escherichia coli (STEC) and their significance in dairy production. AB - The involvement of the pathogenic Shiga-toxin-producing Escherichia coli (STEC; also called verocytotoxic-producing E. coli or VTEC) in sporadic cases and disease outbreaks is presently increasing. Infrequent cases are due to ingestion of milk and dairy products. As ruminants are healthy carriers of STEC and most dairy products may provide these bacteria with favourable conditions for their growth, milk and dairy products are a potential source of STEC. But not all STEC serotypes are pathogens; only relatively small numbers in the entire family of STEC are pathogenic. This review focuses on the recent advances in understanding of STEC and their significance in milk and dairy products. It is intended to gather the information that is needed to understand how these bacteria are described, detected and characterised, how they contaminate milk and grow in dairy products, and how the dairy industry can prevent them from affecting the consumer. PMID- 22939913 TI - Association between Rho-kinase (ROCK2) gene polymorphisms and Behcet's disease. AB - Behcet's disease (BD) is a multi-systemic vasculitis. The aim of this study was to investigate the association between Rho-kinase (ROCK2) gene polymorphisms and patients with BD in a Turkish population. A total of 194 BD patients and 276 healthy controls with similar age and sex were included to this study. Polymorphisms were analyzed in genomic DNA using a BioMark 96.96 dynamic array system. mRNA from blood samples was extracted, and real-time polymerase chain reaction was performed for ROCK2 gene expression. There were marked changes in both genotype (TT, 41.8%; TA, 30.3%) and allele (T, 57%; A, 43%) frequencies for the rs35768389 (Asp601Val) polymorphism in patients compared with controls (TT, 64.6%; TA, 9.4%, P < 0.0001; T, 69.3%; A, 30.7%, P = 0.0004). Although CC genotype (52.0%) of rs1515219 polymorphism were more frequent, CT genotype (27.7%) were less frequent among the patients than controls (CC, 31.7%, CT, 44.6%, P = 0.0001). There was an increase in C allele (65.8% vs 54.0%) and decrease in T allele frequencies (34.2% vs 46.0%, P = 0.001) in patients. However, no associations were found with rs726843, rs2290156, rs965665, rs10178332, rs2230774, rs6755196, rs10929732, and rs34945852 polymorphisms. There was an increase in peripheral blood mRNA ROCK2 expressions in patients. This is the first study to examine the involvement of ROCK2 gene variation in the risk of incident BD. The results strongly suggest that ROCK2 gene polymorphisms may modify individual susceptibility to BD in the Turkish population. PMID- 22939914 TI - Four types of inorganic nanoparticles stimulate the inflammatory reaction in brain microglia and damage neurons in vitro. AB - Once nanoparticles enter the central nervous system (CNS), they immediately encounter a complex environment of resident microglial immune cell and neurons. In the present study, NPs of 20-60nm in diameter (SiO(2)-NPs, TiO(2)-NPs, HAP-NPs and Fe(3)O(4)-NPs) were evaluated for their ability to induce microglia-mediated neurodegeneration. The microglia were directly exposed to NPs. The results showed that both TiO(2)-NPs and HAP-NPs induced significant iNOS expression, resulting in NO release from the microglia. The expression levels of MCP-1 and MIP-1alpha were also upregulated. These activation effects were accompanied by the activation of the transcription factor NF-kappaB. In addition, the secretion levels of TNF-alpha, IL-1beta and IL-6 were variably increased by all four NPs. Subsequently, the cell-free supernatants from microglia monocultures were harvested and tested for their ability to stimulate PC12 cells. The results demonstrated that microglia-derived soluble factors induced by TiO(2)-NPs suppressed Th gene expression, and those by TiO(2)-NPs and HAP-NPs caused cytotoxicity in PC12 cells. Taken together, these results suggest that the NPs induced microglial activation and subsequently caused the release of proinflammatory factors that contributed to the dysfunction and cytotoxicity in PC12 cells. PMID- 22939915 TI - Dioscin, a natural steroid saponin, shows remarkable protective effect against acetaminophen-induced liver damage in vitro and in vivo. AB - The aim of the study was to investigate the protective effect of dioscin against APAP-induced hepatotoxicity. In the in vitro tests, HepG2 cells were given APAP pretreatment with or without dioscin. In the in vivo experiments, mice were orally administrated dioscin for five days and then given APAP. Some biochemical and morphology parameters were assayed and the possible mechanism was investigated. Dioscin improved AST release, mitochondrial dysfunction, apoptosis and necrosis of HepG2 cells induced by APAP. Following administration of dioscin, APAP-induced hepatotoxicity in mice was significantly attenuated. Furthermore, the liver cell apoptosis and necrosis, and hepatic mitochondrial edema were also prevented. Fifteen differentially expressed proteins were found by using proteomics, and six of them, Suox, Krt18, Rgn, Prdx1, MDH and PNP were validated. These proteins may be involved in the hepatoprotective effect of dioscin and might cooperate with the levels of Ca(2+) in mitochondria, decreased expression of ATP2A2, and decreased mitochondrial cardiolipin. In addition, dioscin inhibited APAP-induced activation and expression of CYP2E1, up-regulated the expression of Bcl-2 and Bid, and inhibited the expression of Bax, Bak and p53. Dioscin showed a remarkable protective effect against APAP-induced hepatotoxicity by adjusting mitochondrial function. These results indicated that dioscin has the capability on the treatment of liver injury. PMID- 22939916 TI - The disruption of mitochondrial metabolism and ion homeostasis in chicken hearts exposed to manganese. AB - Exposure to high levels of manganese (Mn) can result in cardiotoxicity in animals. However, little is known about the effect of excess Mn on poultry hearts. The aim of this study was to investigate the effect of dietary Mn on chicken cardiac injuries and the possible mechanisms of this process. In the present study, 400 fifty-day-old Hy-line brown cocks were randomly divided into four groups, and were fed either a commercial diet (containing 100mg/kg Mn) or a Mn-supplemented diet containing 600mg/kg, 900mg/kg, or 1800mg/kg Mn for 30, 60 or 90 days, respectively. Next, we examined several biomarkers of cardiac injury, including biochemical blood serum analyses, electrocardiogram assays, histological analyses, ultra-structural assays and apoptosis assays. To investigate the possible mechanisms of Mn-induced cardiotoxicity, we examined the effect of MnCl(2) on mitochondrial function and metal ion homeostasis. We found that subchronic MnCl(2) exposure induced damage in chicken hearts. Further investigations indicated that possible mechanisms for Mn-induced chicken cardiac injury included the disruption of mitochondrial metabolism and the alteration of ion homeostasis. PMID- 22939918 TI - Non-tuberculous mycobacteria and their surface lipids efficiently induced IL-17 production in human T cells. AB - Interleukin-17 (IL-17) is produced by a subset of CD4(+) T helper (Th) lymphocytes known as Th17 cells. In humans, IL-1beta, enhanced by IL-6 and IL-23 is crucial for differentiation of these cells. IL-17 evokes inflammation and is involved in host defence against microorganisms, although little is known about its role in diseases caused by non-tuberculous mycobacteria. The genus Mycobacterium contains both obligate and opportunistic pathogens as well as saprophytes, and the mycobacterial cell envelope is unique in its abundance of lipids. Here we investigated IL-17 and IL-23 production in human PBMC in response to intact UV-inactivated mycobacteria and mycobacterial surface lipids from two opportunistic (Mycobacterium avium and Mycobacterium abscessus) and one generally non-pathogenic (Mycobacterium gordonae) species. Representative Gram-positive (Enterococcus faecalis, Streptococcus mitis) and Gram-negative (Escherichia coli) bacteria were included as controls. Intact mycobacteria induced production of large amounts of IL-17, while IL-17 responses to control bacteria were negligible. Purified CD4(+) T cells, but not CD4-depleted cell fractions, produced this IL-17. Isolated mycobacterial surface lipids induced IL-17, but not IL-23 production. The ability of the non-tuberculous mycobacteria to induce IL-17 production in CD4(+) T cells was the same regardless of the pathogenic potential of the particular mycobacterial species. PMID- 22939919 TI - Blindsight in children with congenital and acquired cerebral lesions. AB - It has been shown that unconscious visual function can survive lesions to optical radiations and/or primary visual cortex (V1), a phenomenon termed "blindsight". Studies on animal models (cat and monkey) show that the age when the lesion occurs determines the extent of residual visual capacities. Much less is known about the functional and underlying neuronal repercussions of early cortical damage in humans. We measured sensitivity to several visual tasks in four children with congenital unilateral brain lesions that severely affected optic radiations, and in another group of three children with similar lesions, acquired in childhood. In two of the congenital patients, we measured blood oxygenation level dependent (BOLD) activity in response to stimulation of each visual field quadrants. Results show clear evidence of residual unconscious processing of position, orientation and motion of visual stimuli displayed in the scotoma of congenitally lesioned children, but not in the children with acquired lesions. The calcarine cortical BOLD responses were abnormally elicited by stimulation of the ipsilateral visual field and in the scotoma region, demonstrating a profound neuronal reorganization. In conclusion, our data suggest that congenital lesions can trigger massive reorganization of the visual system to alleviate functional effects of early brain insults. PMID- 22939920 TI - A correlation-matrix-based hierarchical clustering method for functional connectivity analysis. AB - In this study, a correlation matrix based hierarchical clustering (CMBHC) method is introduced to extract multiple correlation patterns from resting-state functional magnetic resonance imaging (fMRI) data. It was applied to spontaneous fMRI signals acquired from anesthetized rats, and the results were then compared with those obtained using independent component analysis (ICA), one of the most popular multivariate analysis method for analyzing spontaneous fMRI signals. It was demonstrated that the CMBHC has a higher sensitivity than the ICA, particularly on a single run data, for identifying correlation structures with relatively weak connections, for instance, the thalamocortical connections. Compared to the seed-based correlation analysis, the CMBHC does not require a priori information and thus can avoid potential biases caused by seed selection, and multiple patterns can be extracted at one time. In contrast to other multivariate methods, the CMBHC is based on spatiotemporal correlations of fMRI signals and its analysis outcomes are easy to interpret as the strength of functional connectivity. Moreover, its sensitivity of detecting patterns remains relatively high even for a single dataset. In conclusion, the CMBHC method could be a useful tool for investigating resting-state brain connectivity and function. PMID- 22939921 TI - Recording from defined populations of retinal ganglion cells using a high-density CMOS-integrated microelectrode array with real-time switchable electrode selection. AB - In order to understand how retinal circuits encode visual scenes, the neural activity of defined populations of retinal ganglion cells (RGCs) has to be investigated. Here we report on a method for stimulating, detecting, and subsequently targeting defined populations of RGCs. The possibility to select a distinct population of RGCs for extracellular recording enables the design of experiments that can increase our understanding of how these neurons extract precise spatio-temporal features from the visual scene, and how the brain interprets retinal signals. We used light stimulation to elicit a response from physiologically distinct types of RGCs and then utilized the dynamic configurability capabilities of a microelectronics-based high-density microelectrode array (MEA) to record their synchronous action potentials. The layout characteristics of the MEA made it possible to stimulate and record from multiple, highly overlapping RGCs simultaneously without light-induced artifacts. The high-density of electrodes and the high signal-to-noise ratio of the MEA circuitry allowed for recording of the activity of each RGC on 14+/-7 electrodes. The spatial features of the electrical activity of each RGC greatly facilitated spike sorting. We were thus able to localize, identify and record from defined RGCs within a region of mouse retina. In addition, we stimulated and recorded from genetically modified RGCs to demonstrate the applicability of optogenetic methods, which introduces an additional feature to target a defined cell type. The developed methodologies can likewise be applied to other neuronal preparations including brain slices or cultured neurons. PMID- 22939923 TI - Incorporation of an aggrecan mimic prevents proteolytic degradation of anisotropic cartilage analogs. AB - Biomimetic scaffolds that promote regeneration and resist proteolysis are required as a tissue engineering solution to repair or replace a broad range of diseased tissues. Native corrosive environments, such as the richly enzymatic milieu of diseased articular cartilage, degrade the local extracellular matrix structure, so an implantable replacement must both replicate the healthy structure and demonstrate substantial proteolytic immunity, yet promote regeneration, if long-term functional success is to be achieved. Here, we combine magnetically aligned collagen with peptidoglycans, biosynthetic molecules that mimic proteoglycan activity but lack core proteins susceptible to proteases, to develop cartilage scaffold analogs with tailored functionality. With the incorporation of the aggrecan mimic, we demonstrate an ability to enhance bulk mechanical properties and prevent cytokine-induced degradation. Furthermore, fiber alignment in collagen scaffolds enhanced the gene expression of aggrecan, indicating cell responsiveness to anisotropy that also better replicates the natural environment of cartilage. Finally, the expression of type II collagen is enhanced with both alignment and incorporation of the aggrecan mimic, showing synergism between fiber alignment and incorporation of the aggrecan mimic. The work presented here identified a mechanistic synergy of matrix molecules and organization to prevent proteolysis while simultaneously upregulating protein expression. PMID- 22939922 TI - Detection of bursts and pauses in spike trains. AB - Midbrain dopaminergic neurons in vivo exhibit a wide range of firing patterns. They normally fire constantly at a low rate, and speed up, firing a phasic burst when reward exceeds prediction, or pause when an expected reward does not occur. Therefore, the detection of bursts and pauses from spike train data is a critical problem when studying the role of phasic dopamine (DA) in reward related learning, and other DA dependent behaviors. However, few statistical methods have been developed that can identify bursts and pauses simultaneously. We propose a new statistical method, the Robust Gaussian Surprise (RGS) method, which performs an exhaustive search of bursts and pauses in spike trains simultaneously. We found that the RGS method is adaptable to various patterns of spike trains recorded in vivo, and is not influenced by baseline firing rate, making it applicable to all in vivo spike trains where baseline firing rates vary over time. We compare the performance of the RGS method to other methods of detecting bursts, such as the Poisson Surprise (PS), Rank Surprise (RS), and Template methods. Analysis of data using the RGS method reveals potential mechanisms underlying how bursts and pauses are controlled in DA neurons. PMID- 22939924 TI - Micropatterning-retinoic acid co-control of neuronal cell morphology and neurite outgrowth. AB - Creating physical-biochemical superposed microenvironments optimal for stimulating neurite outgrowth would be beneficial for neuronal regenerative medicine. We investigated potential co-regulatory effects of cell micropatterning and retinoic acid (RA) soluble factor on neuronal cell morphology and neurite outgrowth. Human neuroblastoma (SH-SY5Y) cell patterning sensitivity could be enhanced by poly-L-lysine-g-polyethylene glycol cell-repellent back-filling, enabling cell confinement in lanes as narrow as 5 MUm. Cells patterned on narrow (5 and 10 MUm) lanes showed preferred nucleus orientation following the patterning direction. These cells also showed high nucleus aspect ratio but constrained nucleus spreading. On the other hand, cells on wide (20 MUm and above) lanes showed random nucleus orientation and cell and nucleus sizes similar to those on unpatterned controls. All these changes were generally maintained with or without RA. Confining cells on narrow (5 and 10 MUm) lanes, even without RA, significantly enhanced neurite extension relative to unpatterned control, which was further stimulated by RA. Interestingly, cell patterning on 5 and 10 MUm lanes without RA produced longer neurites relative to the RA treatment alone case. Our data on the potential interplay between microscale physical cell confinement and RA-soluble stimulation may provide a new, integrative insight on how to trigger neurite/axon formation for neuronal regenerative medicine. PMID- 22939925 TI - Water-soluble antioxidant derivative poly(triethylene glycol methyl acrylate-co alpha-tocopheryl acrylate) as a potential prodrug to enable localized neuroprotection. AB - Implantable microelectrode arrays (MEA) hold enormous hope for individuals with sensory or motor deficits. However, long-term function of MEA remains a critical hurdle. The objective of this study was to synthesize an antioxidant prodrug that can be delivered to the neural tissue around the implant and present a pharmacological depot to combat the injurious oxidative stress around the MEA. In this report, monomers of triethylene glycol methyl acrylate and alpha-tocopheryl acrylate, a synthetic derivative of the antioxidant alpha-tocopherol (vitamin E, Ve), were copolymerized to obtain poly(triethylene glycol methyl acrylate-co alpha-tocopheryl acrylate) (PVT) with different compositions. In contrast to the poor water solubility of Ve, solubility of the PVT prodrug in water can reach as high as 3.1 mg ml(-1) (equivalent to 500 MUM Ve) by tuning the copolymer composition. To demonstrate the applicability of the prodrug for MEA implants, PVT was successfully deposited on silicon substrates with poly(acrylic acid) (PAA) or tannic acid (TA) using the layer-by-layer technique mediated by hydrogen bonding. Ellipsometry and quartz crystal microbalance data showed that the multilayers of PAA/PVT were destructible at physiological pH. In contrast, multilayers of TA/PVT were stable. The PVT prodrug was non-cytotoxic toward A172 human astrocytes. Furthermore, PVT was able to protect astrocytes against oxidative stress exerted by H(2)O(2) in vitro. Using a free radical scavenging assay, the protection mechanism was attributed to the hydrolysis of the labile ester linkage and release of the active Ve. PMID- 22939926 TI - A comparative study of young and mature bovine cortical bone. AB - The mechanical properties and microstructure of young and mature bovine femur bone were investigated by optical microscopy and compression testing in the longitudinal and transverse directions for untreated, deproteinized and demineralized cases. Optical microscopy revealed that mature bone has a more established and less porous microstructure compared to young bone. Mature bone was found to be stronger in both directions for the untreated and deproteinized cases. Mature untreated bone was also found to be stiffer and less tough compared to young bone in both directions. These results are related to the increase in mineralization of mature bone and significant microstructural differences. Young bone was found to be stronger in both directions for the demineralized case, which is attributed to alterations in the collagen network with age. PMID- 22939927 TI - Randomized double-blind controlled trial of bovine lactoferrin for prevention of diarrhea in children. AB - OBJECTIVE: To determine the effect of bovine lactoferrin (bLF) on prevention of diarrhea in children. STUDY DESIGN: We conducted a community-based randomized double-blind placebo controlled trial comparing supplementation with bLF vs placebo. Previously weaned children were enrolled at 12-18 months and followed for 6 months with daily home visits for data collection and supplement administration. Anthropometric measures were done monthly. RESULTS: Five hundred fifty-five children were randomized: 277 to bLF and 278 to placebo; 65 dropped out; 147 894 doses were administered (92% compliance). Overall there were 91 446 child-days of observation and 1235 diarrhea episodes lasting 6219 days. The main pathogens isolated during diarrheal episodes were norovirus (35.0%), enteropathogenic E coli (11.4%), Campylobacter (10.6%), enteroaggregative E coli (8.4%), enterotoxigenic E coli (6.9%), and Shigella (6.6%). The diarrhea incidence was not different between groups: 5.4 vs 5.2 episodes/child/year for bLF and placebo, respectively (P = .375). However, the diarrhea longitudinal prevalence was lower in the bLF group vs placebo (6.6% vs 7.0%, P = .017), as well as the median duration of episodes (4.8 vs 5.3 days, P = .046), proportion of episodes with moderate or severe dehydration (1.0% vs 2.6%, P = .045), and liquid stools load (95.0 vs 98.6) liquid stools/child/year, P < .001). There were no adverse events related to the intervention. CONCLUSIONS: Although there was no decrease in diarrhea incidence, longitudinal prevalence and severity were decreased with LF. PMID- 22939928 TI - Age-dependent changes in the size of adenotonsillar tissue in childhood: implications for sleep-disordered breathing. AB - OBJECTIVE: To analyze age-associated changes in linear and cross-sectional area (CSA) measurements of adenoid, tonsils, and pharyngeal lumen. STUDY DESIGN: Measurements were completed in head magnetic resonance imaging examinations performed for diagnostic purposes. Linear and nonlinear regression models were applied to describe the effect of age on the size of soft tissues and upper airway. RESULTS: Magnetic resonance imaging data were analyzed in 149 children without snoring (aged 0-15.9 years) and in 33 children with snoring (aged 1.6-15 years). In the children without snoring, adenoid size increased during the first 7-8 years of life and then decreased gradually [% (adenoid oblique width/mental spine-clivus length) = 11.38 + 1.52 (age) - 0.11 (age)(2), R(2) = 0.22, P < .01; adenoid CSA = 90.75 + 41.93 (age) - 2.47 (age)(2); R(2) = 0.50; P < .01]. Nasopharyngeal airway CSA increased slowly up to age 8 years and rapidly thereafter. Similar patterns were noted for the tonsils and oropharyngeal airway. In contrast, in children with snoring, adenoid and tonsils were large irrespective of age, and nasopharyngeal airway size increased slowly with age. CONCLUSIONS: In children without snoring, growing adenotonsillar tissue narrows the upper airway lumen to variable degrees only during the first 8 years of life. In contrast, in children with snoring, appreciable pharyngeal lymphoid tissue enlargement is present during the preschool years and persists beyond the eighth birthday. PMID- 22939931 TI - Potential health risks to adults and children in the UK from exposure to dietary lead in gamebirds shot with lead ammunition. AB - We estimate potential risks to human health in the UK from dietary exposure to lead from wild gamebirds killed by shooting. The main source of exposure to lead in Europe is now dietary. We used data on lead concentrations in UK gamebirds, from which gunshot had been removed following cooking to simulate human exposure to lead. We used UK food consumption and lead concentration data to evaluate the number of gamebird meals consumed weekly that would be expected, based upon published studies, to result in changes, over and above those resulting from exposure to lead in the base diet, in intelligence quotient (IQ), Systolic Blood Pressure and chronic kidney disease (CKD) considered in a recent opinion of the European Food Safety Authority (EFSA) to be significant at a population level and also in SAT test scores and in rates of spontaneous abortion. We found the consumption of <1 meal of game a week may be associated with a one point reduction in IQ in children and 1.2-6.5 gamebird meals per week may be associated with the other effects. These results should help to inform the development of appropriate responses to the risks from ingesting lead from ammunition in game in the UK and European Union (EU). PMID- 22939930 TI - Conditional Aurora A deficiency differentially affects early mouse embryo patterning. AB - Aurora A is a mitotic kinase essential for cell proliferation. In mice, ablation of Aurora A results in mitotic arrest and pre-implantation lethality, preventing studies at later stages of development. Here we report the effects of Aurora A ablation on embryo patterning at early post-implantation stages. Inactivation of Aurora A in the epiblast or visceral endoderm layers of the conceptus leads to apoptosis and inhibition of embryo growth, causing lethality and resorption at approximately E9.5. The effects on embryo patterning, however, depend on the tissue affected by the mutation. Embryos with an epiblast ablation of Aurora A properly establish the anteroposterior axis but fail to progress through gastrulation. In contrast, mutation of Aurora A in the visceral endoderm, leads to posteriorization of the conceptus or failure to elongate the anteroposterior axis. Injection of ES cells into Aurora A epiblast knockout blastocysts reconstitutes embryonic development to E9.5, indicating that the extra-embryonic tissues in these mutant embryos can sustain development to organogenesis stages. Our results reveal new ways to induce apoptosis and to ablate cells in a tissue specific manner in vivo. Moreover, they show that epiblast-ablated embryos can be used to test the potency of stem cells. PMID- 22939932 TI - The influence of fining agents on the removal of some pesticides from white wine of Vitis vinifera L. cv. Emir. AB - The influences of fining agents (activated carbon, casein, kieselsol-gelatine, bentonite and polyvinylpolypyrrolidone) and their doses (low, middle, high) on the removal of six pesticides used in viticulture (vinclozolin, penconazole, alpha-endosulfan, imazalil, nuarimol and tetradifon) from white wine were investigated. The pesticides were added into white wine obtained from the Emir grape, and then the wine was clarified with the use of fining agents at low, middle and high doses. After the fining, extraction of pesticides from the wine was made by liquid-liquid extraction. Quantification and identification were performed by the multiresidual method using GC-MS and GC-ECD techniques. The effect of the fining agents on these pesticides ranged from little to large. Of the fining agents, activated carbon showed the largest effect on the removal of pesticides. The pesticide removal efficiencies of the fining agents were in the following order: activated carbon, casein, bentonite and kieselsol-gelatine. Polyvinylpolypyrrolidone (PVPP) had the least effect on the removal of pesticides. A linear relation was not found between fining agent doses and the amount of removed pesticides. alpha-Endosulfan, penconazole, imazalil and tetradifon were removed by the fining agents at the highest levels. Vinclozolin and nuarimol were the pesticides least affected, except activated carbon and casein. PMID- 22939929 TI - Association of impaired linear growth and worse neurodevelopmental outcome in infants with single ventricle physiology: a report from the pediatric heart network infant single ventricle trial. AB - OBJECTIVES: To describe neurodevelopmental outcomes in infants with single ventricle (SV) physiology and determine factors associated with worse outcomes. STUDY DESIGN: Neurodevelopmental outcomes for infants with SV enrolled in a multicenter drug trial were assessed at 14 months of age using the Bayley Scales of Infant Development-II. Multivariable regression analysis was used to identify factors associated with worse outcomes. RESULTS: Neurodevelopmental testing was performed at 14 +/- 1 months in 170/185 subjects in the trial. Hypoplastic left heart syndrome was present in 59% and 75% had undergone the Norwood operation. Mean Psychomotor Developmental Index (PDI) and mental developmental index (MDI) were 80 +/- 18 and 96 +/- 14, respectively, (normal 100 +/- 15, P < .001 for each). Group-based trajectory analysis provided a 2-group model ("high" and "low") for height z-score trajectory and brain type natriuretic peptide (BNP) trajectory. The predicted PDI scores were 15 points higher in the "high" height z score trajectory compared with the "low" cluster (P < .001). A higher number of serious adverse events during the trial was associated with lower PDI scores (P = .02). The predicted MDI scores were 13-17 points lower in "low height trajectory high BNP trajectory" group compared with the other 3 groups (P < .001). MDI scores were also lower in subjects who required extracorporeal membrane oxygenation during the neonatal hospitalization (P = .01) or supplemental oxygen at discharge (P = .01). CONCLUSIONS: Neurodevelopmental outcome at 14 months of age is impaired in infants with SV physiology. Low height trajectory and high BNP trajectory were associated with worse neurodevelopmental outcomes. Efforts to improve nutritional status alone may not improve neurodevelopmental outcomes. PMID- 22939933 TI - Mechanisms of natural brassinosteroid-induced apoptosis of prostate cancer cells. AB - Brassinosteroids (BRs) are a group of polyhydroxylated sterol derivatives with important regulatory roles in various plant physiological processes. The aim of this study was to examine the mechanism of the antiproliferative activity of natural BRs 28-homocastasterone (28-homoCS) and 24-epibrassinolide (24-epiBL) in hormone-sensitive and -insensitive (LNCaP and DU-145, respectively) human prostate cancer cell lines. The effects of BRs on prostate cancer cells were surveyed using flow cytometry, Western blotting, TUNEL, DNA ladder assays and immunofluorescence analyses. The studied BRs inhibited cell growth and induced G(1) blocks in LNCaP cells accompanied by reductions in cyclin D(1), CDK4/6 and pRb expression. Following BR treatment of DU-145 cells, increases in proportions of cells in the G(2)/M phase of cell cycle were observed, accompanied by down regulation of cyclins A and B(1). Changes in AR localization patterns in LNCaP cells treated with BRs were shown by immunofluorescence analysis. Furthermore, apoptotic detection methods demonstrated induction of apoptosis mediated by BRs in both cell lines, although changes in the expression of apoptosis-related proteins were modulated differently by 28-homoCS and 24-piBL in each cell line. The studied BRs seem to exert potent growth inhibitory and pro-apoptotic effects and could be therefore highly valuable new candidates for prostate anticancer drugs. PMID- 22939934 TI - Correlation of total polyphenolic content with antioxidant and antibacterial activity of 24 extracts from Greek domestic Lamiaceae species. AB - Lamiaceae family species are considered important because of their use in folk medicine, culinary and flavouring throughout the world. Their interesting bioactivities are attributed mainly to essential oils, polyphenols and terpenes. However, there are only few studies about polyphenolic extracts from Lamiaceae plants. Thus, 24 polyphenolic extracts from three Lamiaceae genera, Salvia, Mentha and Sideritis, collected in Greece were examined for antioxidant and antibacterial activity in correlation with their polyphenolic content. The results showed that the tested polyphenolic extracts had strong free radical scavenging activity against DPPH. and ABTS(+) radicals and protected from hydroxyl and peroxyl radical-induced DNA damage. Moreover, five extracts inhibited Staphylococcus aureus growth. Furthermore, the results showed that the total polyphenolic content is not correlated with the above activities, although this relation was different within each plant genus. This is the first study regarding the antioxidant and antibacterial activity of Salvia pomifera ssp. calycina, S. pomifera ssp. pomifera, Mentha microphylla and Sideritis raeseri ssp. attica species, and one of the few concerning protection from DNA damage and antibacterial activity of polyphenolic extracts from the rest of the tested species. PMID- 22939935 TI - Occurrence of aflatoxin M(1) in some samples of UHT, raw & pasteurized milk from Indian states of Karnataka and Tamilnadu. AB - Aflatoxin M(1) (AFM(1)) is a toxic metabolite found in the milk of lactating animals which have consumed feedstuffs contaminated with aflatoxin B(1). Ultra high temperature treated (UHT) milk is a product which is becoming popular in developing countries like India as there is a lack of proper cold storage or refrigeration facilities. In this study, 45 samples of UHT milk of popular brands prevalent in the market were analyzed for the presence of AFM(1) by reversed phase HPLC using fluorescent detector after cleanup of sample with immunoaffinity columns. All samples of plain UHT milk were positive for AFM(1) and 38% of these contained levels more than 0.5 MUg/kg, the maximum permitted limit prescribed by the Codex Alimentarius Commission and by the mandatory regulations of the country, the FSSAI Regulations, 2011. In 62.5% of flavored UHT milk, AFM(1) was below detectable levels (0.02 MUgL(-1)). However, 12.5% of these samples also contained levels exceeding the maximum permitted limits. AFM(1) was present in 61.6% of the 52 raw milk samples analyzed from the two states of Karnataka and Tamilnadu with a range of 0.1-3.8 MUgL(-1). 17.3% of these samples also exceeded the regulatory limits of the country. PMID- 22939936 TI - Analysis of dioxins, furans and DL-PCBs in food and feed samples from Lithuania and estimation of human intake. AB - The methods, validated for determination of dibenzo-p-dioxins, dibenzofurans and dioxin like-polychlorinated biphenyls were applied for investigation of food and feed matrixes. Validation criteria on repeatability and reproducibility conditions comply with the requirements of European Commission. Validated methods were successfully applied for determination of PCDD/F and DL-PCB in fish, meat and feed using HRGC-HRMS. Statistical data was evaluated. One focal point of this work was to determine a fit for dioxins, furans and DL-PCBs of fatty fish for human consumption from the Baltic Sea ICES 26. Daily intake was found to be in the range of 2-4 TEQ pg/kg body weight and it is in the range of recommended TDI of 1-4 TEQ pg/kg body weight. The range of Baltic cod liver was 2-4 pg TEQ kgbw( 1)d(-1) WHO-TEQ((1998)) PCDD/F, PCB and its consumption was forbidden in Lithuania in 2011. Baltic fish represents 97.9% of human daily intake. Other matrixes like meat, eggs and feed did not exceed the maximum limit set by EU during the period of 2005-2011. PMID- 22939937 TI - Proinflammatory activation of macrophages by bisphenol A-glycidyl-methacrylate involved NFkappaB activation via PI3K/Akt pathway. AB - AIM: Bisphenol A-glycidyl-methacrylate (BisGMA), a dental composite resin and dentin bonding agent, might prompt inflammatory effects to adjacent tissues. Macrophages are a major cellular component of the inflammatory sites. Little is known about the mechanisms of BisGMA on macrophages activation. The aim of this study was to evaluate BisGMA on proinflammatory mediators generation of murine macrophage RAW264.7 cells. METHODS: IL-1beta and IL-6 were analyzed by enzyme linked immunosorbent assay. Nitric oxide, extracellular superoxide anion, and intracellular reaction oxygen species were measured by Griess assay, ferricytochrome c, and 2',7'-dichlorofluorescein assay, respectively. Expression of iNOS, p-p65, IkappaB, and p-Akt was analyzed by Western blotting. RESULTS: BisGMA augmented the generation of IL-1beta, IL-6, nitric oxide and the expression of iNOS in a time- and dose-dependent manner (p<0.05). BisGMA enhanced the generation of intracellular and extracellular ROS in a dose-dependent manner (p<0.05). The levels of p65 phosphorylation, IkappaB degradation, and Akt phosphorylation were found to be increased in a time- and dose-dependent manner (p<0.05). CONCLUSIONS: These results indicate that BisGMA could induce nitric oxide, ROS, and inflammatory cytokines in macrophages. In addition, BisGMA may active macrophage via NF-kappaB activation, IkappaB degradation, and p-Akt activation. PMID- 22939938 TI - The methanolic fraction of Centratherum anthelminticum seed downregulates pro inflammatory cytokines, oxidative stress, and hyperglycemia in STZ-nicotinamide induced type 2 diabetic rats. AB - This study aimed to ascertain the potential of Centratherum anthelminticum seeds methanolic fraction (CAMFs) for the management of type 2 diabetes and its associated complications. CAMFs was initially tested on beta-TC6 cells for H(2)O(2)-induced nuclear factor-kappaB (NF-kappaB) translocation effects. The result displayed that CAMFs significantly inhibited NF-kappaB translocation from cytoplasm into the nucleus, dose-dependently. Furthermore, a 12-week sub-chronic CAMFs study was carried out on streptozotocin (STZ)-nicotinamide-induced type 2 diabetic rat model to evaluate glycemia, essential biochemical parameters, lipid levels, oxidative stress markers, and pro-inflammatory cytokines level. Our study result showed that CAMFs reduced hyperglycemia by increasing serum insulin, C peptide, total protein, and albumin levels, significantly. Whereas, elevated blood glucose, glycated hemoglobin, lipids and enzyme activities were restored to near normal. CAMFs confirmed antioxidant potential by elevating glutathione (GSH) and reducing malondialdehyde (MDA) levels in diabetic rats. Interestingly, CAMFs down-regulated elevated tumor necrosis factor alpha (TNF-alpha), interleukin (IL) 1beta and IL-6 in the tissues and serum of the diabetic rats. We conclude that CAMFs exerted apparent antidiabetic effects and demonstrated as a valuable candidate nutraceutical for insulin-resistant type 2 diabetes and its associated complications such as dyslipidemia, oxidative stress, and inflammation. PMID- 22939939 TI - Curcumin ameloriates heat stress via inhibition of oxidative stress and modulation of Nrf2/HO-1 pathway in quail. AB - Curcumin, a natural polyphenol in the spice turmeric, exhibits antioxidant and antiinflammatory properties. This study was conducted to elucidate the action mode of curcumin alleviation of oxidative stress in heat-stressed quail. A total of 180 birds (10 d old) were assigned randomly to be reared at either 22 degrees C (Thermoneutral) or 34 degrees C (Heat stress) for 8 h/d (0900-1700) until the age of 42 d. Birds in both environments were randomly fed 1 of 3 diets: basal diet and basal diet added with 0, 200 or 400 mg of curcumin per kg of diet. Each of the 2*3 factorially arranged experimental groups was replicated in 10 cages, each containing three birds. In response to increasing supplemental curcumin level, there were linear increases in cumulative feed intake, final body weight, and weight gain, and nuclear factor erythroid 2-related factor two level and heme oxygenase one level; linear decreases in feed efficiency, serum, muscle and liver malondialdehyde level, respectively and inflammatory transcription factor, nuclear factor-kappaB and heat shock proteins 70 level (P<0.0001 for all). The results indicated that curcumin alleviates oxidative stress through modulating the hepatic nuclear transcription factors and heat shock proteins 70 in heat stressed quails. PMID- 22939940 TI - Applicability of in vitro tests for skin irritation and corrosion to regulatory classification schemes: substantiating test strategies with data from routine studies. AB - Skin corrosion or irritation refers to the production of irreversible or reversible damage to the skin following the application of a test substance, respectively. Traditionally, hazard assessments are conducted using the in vivo Draize skin test, but recently in vitro tests using reconstructed human epidermis (RhE) models have gained regulatory acceptance. In this study, skin corrosion (SCT) and irritation tests (SIT) using a RhE model were implemented to reduce the number of in vivo tests required by regulatory bodies. One hundred and thirty four materials were tested from a wide range of substance classes included 46 agrochemical formulations. Results were assessed according to UN GHS, EU-CLP, ANVISA and US EPA classification schemes. There was high correlation between the two in vitro tests. Assessment of the SCT sensitivity was not possible due to the limited number of corrosives in the data set; SCT specificity and accuracy were 89% for all classification systems. Accuracy (63-76%) and sensitivity (53-67%) were low in the SIT. Specificity and concordance for agrochemical formulations alone in both the SCT and SIT were comparable to the values for the complete data set (SCT: 91% vs. 89% specificity, 91% vs. 89% accuracy and SIT: 64-88% vs. 70 85% specificity, 56-75% vs. 63-76% accuracy). PMID- 22939941 TI - Analysis of drought-tolerant sugar beet (Beta vulgaris L.) mutants induced with gamma radiation using SDS-PAGE and ISSR markers. AB - Drought is one of the major environmental stresses which greatly affect the plant growth and productivity. In the present study, various doses (0-75Gy) of gamma rays were applied to investigate the effect of radiation on shoot tip explants. It was observed that the regeneration rates and plant fresh weights decreased significantly with an increase in radiation dose. The optimal irradiation doses for mutation induction were determined at 15 and 20Gy. Afterwards, the induction of somatic mutation in sugar beet (Beta vulgaris L.) was investigated by irradiation of shoot tips with 15 and 20Gy gamma rays. Irradiated shoot tips were sub-cultured and M(1)V(1)-M(1)V(3) generations were obtained. Mutants tolerant to drought stress were selected on MS medium, supplemented with 10 and 20gl(-1) PEG6000. Of the M(1)V(3) plantlets, drought-tolerant mutants were selected. Leaf soluble proteins obtained from the control and drought-tolerant mutants were analyzed by SDS-PAGE. A total of 22 protein bands were determined and 2 of them were observed to be drought-tolerant mutants except the control. Polymorphism was also detected among the control and drought-tolerant mutants by DNA fingerprinting using ISSR markers. A total of 106 PCR fragments were amplified with 19 ISSR primers and 91 of them were polymorphic. The dendrograms were separated into two main clusters. First cluster included M8 mutant plant, which was applied 20Gy gamma radiation and regenerated on selective culture media containing 10gl(-1) PEG6000 concentration, and the second cluster was further divided into five sub-clusters. PMID- 22939942 TI - Facilitation and habituation of the startle reflex over the tonically active biceps brachii muscle contralateral to electrical stimuli. AB - The aim of the present investigation was to explore the impact of muscle contraction on startle reflex responses after electrical stimuli (single or trains of 3) and to study startle reflex habituation. The electromyogram was recorded over the tonically active biceps brachii muscle in 19 healthy subjects contralateral to electrical stimuli (9-12mA) that were delivered at 1.0 and 0.4Hz over the superficial radial nerve. The muscle contraction level was varied by loading weight on the subject's bent arm (0.0, 1.0 or 1.5kg). Furthermore, short term reflex habituation was investigated using 30 blocks of 5 subsequent stimuli. Startle response amplitudes gained significantly (p<0.05) after (i) train stimuli as compared with single stimuli, during (ii) high versus low levels of muscle contraction, and at (iii) 0.4Hz versus 1.0Hz stimuli. Startle reflex amplitudes decreased significantly by the influence of preceding stimuli (p<0.05). This study provides evidence that the startle reflex can be significantly influenced by weight load, i.e. by volitional influences. Startle reflex investigation over a contracted limb muscle results in a high probability of startle release and thereby improved detection of SR habituation following preceding stimuli. PMID- 22939944 TI - High-density multielectrode array with independently maneuverable electrodes and silicone oil fluid isolation system for chronic recording from macaque monkey. AB - Chronic multielectrode recording has become a widely used technique in the past twenty years, and there are multiple standardized methods. As for recording with high-density array, the most common method in macaque monkeys is to use a subdural array with fixed electrodes. In this study, we utilized the electrode array with independently maneuverable electrodes arranged in high-density, which was originally designed for use on small animals, and redesigned it for use on macaque monkeys while maintaining the virtues of maneuverability and high density. We successfully recorded single and multiunit activities from up to 49 channels in the V1 and inferior temporal (IT) cortex of macaque monkeys. The main change in the surgical procedure was to remove a 5 mm diameter area of dura mater. The main changes in the design were (1) to have a constricted layer of heavy silicone oil at the interface with the animal to isolate the electrical circuit from the cerebrospinal fluid, and (2) to have a fluid draining system that can shunt any potential postsurgical subcranial exudate to the extracranial space. PMID- 22939943 TI - Osteocyte control of osteoclastogenesis. AB - Multiple lines of evidence support the idea that osteocytes act as mechanosensors in bone and that they control bone formation, in part, by expressing the Wnt antagonist sclerostin. However, the role of osteocytes in the control of bone resorption has been less clear. Recent studies have demonstrated that osteocytes are the major source of the cytokine RANKL involved in osteoclast formation in cancellous bone. The goal of this review is to discuss these and other studies that reveal mechanisms whereby osteocytes control osteoclast formation and thus bone resorption. PMID- 22939945 TI - Peripheral brain-derived neurotrophic factor changes along treatment with extended release quetiapine during acute mood episodes: an open-label trial in drug-free patients with bipolar disorder. AB - Molecules that are involved in neuronal intercommunication and adaptability of neural networks, such as brain-derived neurotrophic factor (BDNF), are targets of pathophysiological investigation in bipolar disorder (BD). Quetiapine is an attested treatment in this disorder, used in acute mood episodes. The aim of this study was to report prospective changes in serum BDNF levels in drug-free patients in acute mood episodes of BD who received treatment with extended release quetiapine along a 16 week follow-up. Assessments were performed at baseline and weeks 2, 4, 8 and 16 with the Young Mania Rating Scale, the Hamilton Depression Rating Scale and the Clinical Global Impression severity scale. In these visits, serum BDNF levels were measured. Mixed effect models were used to investigate longitudinal changes. Twenty-five patients were included for this analysis, seventeen in a current depressive episode and eight in a manic/mixed episode. A significant improvement from baseline to endpoint was displayed. In the mixed model, significant main effects for episode and time appeared, and a time versus episode interaction showing increasing BDNF levels with time in those with a depressive episode, but a decrease in BDNF levels with time in those with a manic/mixed episode. BDNF may be a biomarker with differential response according to the polarity of mood episodes. PMID- 22939946 TI - Health outcomes of older patients colonized by multi-drug resistant bacteria (MDRB): a one-year follow-up study. AB - The objective of this study was to examine whether asymptomatic colonization with MDRB would affect outcomes in older patients one year after hospitalization in a geriatric ward. Patient samples were analyzed to identify specific MDRBs, including methicillin-resistant Staphylococcus aureus (MRSA), extended-spectrum beta-lactamase-producing Enterobaceriaceae (ESBLE), and vancomycin-resistant enterococci (VRE). Among 337 patients screened at hospital admission, 62 (18%) carried one or more MDRB isolates (MRSA: n=23; ESBLE: n=39; VRE: n=2). At 12 months after admission, 320 patients were interviewed by telephone (17 patients lost to follow up) to assess all-cause mortality, nursing home admissions, functional decline, and hospital readmissions. All-cause mortality rates were similar in MDRB carriers (34%; n=61) and non-carriers (30%; n=259) (P=0.512). Nursing home admission, functional decline, and hospital readmission did not differ between the two groups. In this population, predictors of mortality were: male gender (P=0.002), cognitive disorders at admission (P=0.028), low pre albumin level at admission (P=0.048), a high level of co-morbidities (P=0.002), and a history of an acute condition in the three months prior to initial hospital admission (P=0.024). In conclusion, in this cohort of older patients, asymptomatic MDRB colonization was not significantly associated with adverse health outcomes at a one-year follow-up after hospitalization. The potential limitations of the study were the small sample size, relatively high mortality rate, and lack of MDRB reassessment during the follow-up. PMID- 22939947 TI - Malnutrition is associated with an increased risk of falls and impaired activity in elderly patients in Dutch residential long-term care (LTC): a cross-sectional study. AB - PURPOSE OF THE STUDY: Falls are frequent in LTC, with considerable health consequences. This study explores the relationship between malnutrition, activity, and falls in Dutch LTC residents and the influence of nutritional intervention on this relationship. DESIGN AND METHODS: A secondary data analysis of a cross-sectional, multi-center point prevalence and incidence measurement. SETTING: 81 LTC settings in The Netherlands. PARTICIPANTS: 6.701 LTC residents aged 65 and older; mean age 84; 70% female. Prevalence measurements of nutritional status and activity, and a 30 days incidence measurement of falls. RESULTS: Of all participating residents, 9.8% sustained at least one fall, and 22.8% was malnourished. Malnourished residents were more often a faller (odd ratio (OR) 1.78; p<0.01) and inactive (OR 1.7, p<0.01) than non-malnourished residents. Multivariate analysis confirmed the relation between malnutrition and fallers, without interference of activity. In the malnourished group with nutritional intervention, the percentage of fallers was lower than in the malnourished group without nutritional intervention (OR 0.738; p=0.056). IMPLICATIONS: Malnutrition is associated with an increased risk of being a faller and with impaired activity in Dutch LTC residents. Malnourished residents who receive nutritional intervention have a lower risk of being a faller. PMID- 22939948 TI - Pre- and post-Chernobyl accident levels of 129I and 137Cs in the Southern Baltic Sea by brown seaweed Fucus vesiculosus. AB - (129)I is a very long-lived radionuclide (T(1/2) = 15.7 * 10(6) years) that is present in the environment both because of natural and anthropogenic sources. In this work (129)I concentration and (129)I/(127)I ratio have been determined in seaweed Fucus vesiculosus collected in the Southern Baltic Sea during 1982 and 1986 (post-Chernobyl accident). The resulting data were evaluated in terms of (129)I concentrations, (129)I/(127)I and (129)I/(137)Cs ratios. (129)I concentrations were found to be in the order of (0.82-5.89) * 10(9) atoms g(-1) in 1982 and (1.33-38.83) * 10(9) atoms g(-1) in 1986. The (129)I/(127)I ratios ranged from (22.7-87.8) * 10(-10) for seaweed collected in 1982 and from (26.1 305.5) * 10(-10) for seaweed collected in 1986. Also a linear relationship was established for (127)I concentrations in seawater and salinity in this area, enabling the estimation of concentration factors for (127)I in F. vesiculosus. The high levels of (129)I and (129)I/(127)I in the Kattegat and their gradually decreasing trend to the Baltic Sea indicates that the most important contribution to the (129)I inventory in the Baltic Sea area comes from Sellafield and La Hague reprocessing plants. With respect to Chernobyl accident, (129)I concentrations in samples collected in 1986 were not much higher than those expected in less contaminated samples from 1982. This supports the view that the contribution of the Chernobyl accident to (129)I in the Baltic region was not significant. PMID- 22939949 TI - Adsorption and desorption of uranium (VI) in aerated zone soil. AB - In this paper, the adsorption and desorption behavior of uranium (VI) in aerated zone soil (from Southwest China) was systematically investigated using a static experimental method in order to provide useful information for safety assessment of the disposal of (ultra-)low uraniferous radioactive waste, as well as a potential remediation method for uranium-contaminated soils. The adsorption behavior of uranium (VI) was firstly studied by batch experiments as functions of contact time, pH, liquid/solid ratio, temperature, colloids, minerals and coexistent ions. The results indicated that the adsorption of uranium (VI) by natural soil was efficient at an initial concentration of 10 mg/L uranium (VI) nitrate solution with 100 mg natural soil at room temperature when pH is about 7.0. The adsorption was strongly influenced by the solution pH, contact time, initial concentration and colloids. The adsorption equilibrium for uranium (VI) in soil was obtained within 24 h and the process could be described by the Langmuir adsorption equation. For uranium (VI) desorption, EDTA, citric acid and HNO(3) were evaluated under different conditions of temperature, concentration and proportion of liquid to solid. The adsorbed uranium (VI) on natural soil could be easily extracted by all these agents, especially by HNO(3), implying that the uranium-contaminated soils can be remedied by these reagents. PMID- 22939950 TI - Effect of arbuscular mycorrhizal (AM) fungi on 137Cs uptake by plants grown on different soils. AB - The potential use of mycorrhiza as a bioremediation agent for soils contaminated by radiocesium was evaluated in a greenhouse experiment. The uptake of (137)Cs by cucumber, perennial ryegrass, and sunflower after inoculation with a commercial arbuscular mycorrhizal (AM) product in soils contaminated with (137)Cs was investigated, with non-mycorrhizal quinoa included as a "reference" plant. The effect of cucumber and ryegrass inoculation with AM fungi on (137)Cs uptake was inconsistent. The effect of AM fungi was most pronounced in sunflower: both plant biomass and (137)Cs uptake increased on loamy sand and loamy soils. The total (137)Cs activity accumulated within AM host sunflower on loamy sand and loamy soils was 2.4 and 3.2-fold higher than in non-inoculated plants. Although the enhanced uptake of (137)Cs by quinoa plants on loamy soil inoculated by the AM fungi was observed, the infection of the fungi to the plants was not confirmed. PMID- 22939951 TI - Sentinel lymph node metastasis is not predictive of poor outcome in patients with problematic spitzoid melanocytic tumors. AB - The diagnosis and clinical management of spitzoid melanocytic tumors with atypical features remain problematic and controversial. In the past decade, sentinel lymph node mapping has been advocated as a diagnostic test in this setting to discriminate melanoma from benign tumors. Recent studies, however, consistently show that despite the presence of lymph node metastases these patients almost always fare well. We investigated the outcome of patients with atypical Spitz tumors and spitzoid melanoma who received sentinel lymph node mapping to clarify current recommendations in managing patients with these diagnostically challenging tumors. A search of the electronic files of the Massachusetts General Hospital Pathology Service identified 41 patients treated with sentinel lymph node biopsy for atypical Spitz tumor or spitzoid melanoma from 1998 to 2008. These patients included 23 patients with atypical Spitz tumors and 17 patients with spitzoid melanoma. Sentinel lymph nodes were positive in 26% of patients with atypical Spitz tumors (6/23) and 35% with spitzoid melanomas (6/17). One patient with spitzoid melanoma developed in-transit metastasis; 0 of 40 patients developed metastases beyond the regional lymph node basin with a mean follow-up of 57 months. Sentinel lymph node biopsy may not be a reliable prognostic discriminatory test in patients with atypical Spitz tumors. Patients with spitzoid melanomas and positive sentinel lymph nodes have a more indolent course than those with bona fide conventional melanoma and positive sentinel nodes. PMID- 22939952 TI - The expression of the high-mobility group A2 protein in colorectal cancer and surrounding fibroblasts is linked to tumor invasiveness. AB - Tumor staging of colorectal cancer is typically based on conventional TNM and Dukes classifications. However, additional information could be useful, and there is a significant interest in identifying molecular markers that are related to genetic or epigenetic processes. Using immunohistochemistry, we analyzed the expression of the high-mobility group A2 (previously high-mobility group 1-C [HMGI-C]) protein in 103 colorectal cancer cases to determine its use as a biomarker in colorectal cancer to integrate morphological staging. We found a progressive increase of the high-mobility group A2 protein expression in colorectal cancer tumor samples from cases in which all of the tumor cells were negative up to cases in which all of the tumor cells stained positive. Increased high-mobility group A2 expression is strongly associated with an increase in tumor invasiveness, which was measured through both budding and vascular invasion (P < .0001). Kaplan-Meier estimates showed a decrease in overall survival when vascular invasion is present (P = .023). Moreover, a fraction of the analyzed samples showed high-mobility group A2-positive stromal fibroblasts. Although high mobility group A2-positive tumors were associated with cell invasiveness, high mobility group A2-positive stromal fibroblasts were correlated with less invasive tumors. High-mobility group A2 protein expression could be used as a prognostic marker to provide prospective information on patient outcome, complementing the data obtained using conventional pathologic staging systems. PMID- 22939953 TI - Identification of novel predictive markers for the prognosis of pancreatic ductal adenocarcinoma. AB - Pancreatic cancer is a disease with poor prognosis and high mortality. To identify novel molecular markers that could predict the prognosis of pancreatic ductal adenocarcinoma, a total of 114 pancreatic ductal adenocarcinomas and 99 peritumoral tissues were collected. Protein levels of cleaved caspase-3, cyclin D1, epidermal growth factor receptor and Her-2 (human epidermal growth factor receptor 2) were measured by immunohistochemistry. Molecular abnormalities of cyclin D1/q11, Her-2/q17, and epidermal growth factor receptor/p7 were detected using fluorescence in situ hybridization. Results demonstrated that the protein levels of cleaved caspase-3, epidermal growth factor receptor, Her-2, and cyclin D1 were significantly higher in pancreatic ductal adenocarcinoma than that in peritumoral tissues (P = .000). Significantly more amplifications of epidermal growth factor receptor, Her-2, and cyclin D1 were observed in pancreatic ductal adenocarcinoma patients than in peritumoral tissues. In addition, 51.8% of pancreatic ductal adenocarcinoma tumors showed polysomy 7, 50% showed polysomy 11, and 40.4% showed polysomy 17. However, no polysomy was observed in peritumoral tissues. Her-2 amplification and polysomy 17 significantly correlated with poor prognosis of pancreatic ductal adenocarcinoma (P = .008 and P = .005, respectively). Interestingly, only cleaved caspase-3 protein level significantly correlated with poor survival in pancreatic ductal adenocarcinoma patients (P = .000). We also observed significant correlations of cleaved caspase-3 level with epidermal growth factor receptor, Her-2, and cyclin D1 protein levels and the molecular abnormalities of Her-2 and cyclin D1. Conclusively, cleaved caspase-3 level is an ideal biomarker to predict prognosis in pancreatic ductal adenocarcinoma patients and might be a better target for pancreatic ductal adenocarcinoma treatment than epidermal growth factor receptor/Her-2 and cyclin D1. PMID- 22939954 TI - Galectin 1 expression is associated with tumor invasion and metastasis in stage IB to IIA cervical cancer. AB - Galectin 1 is a 14-kd laminin-binding lectin involved in important biologic mechanisms of tumors, including neoplastic transformation, cell survival, angiogenesis, cell proliferation, and metastasis. In this study, we investigated the role of galectin 1 in cell survival and metastasis in cervical cancer. The expression of galectin 1 was determined in 73 formalin-fixed, paraffin-embedded cervical cancer tissues using an immunohistochemical method and compared with clinicopathologic risk factors for recurrence after surgery. To evaluate the role of galectin 1 in cell proliferation and invasion, we performed proliferation and invasion assays with galectin 1 small interfering RNA (siRNA) using cervical cancer cell lines, including HeLa and SiHa cells. Immunohistochemical analysis revealed that galectin 1 expression was found in most peritumoral stroma samples (72/73; 98.6%). Galectin 1 expression was significantly correlated with the depth of invasion in the cervix (P=.015) and lymph node metastasis (P=.045) on univariate analysis. When progression-free survival of all of the patients studied was analyzed based upon galectin 1 expression, galectin 1 expression was not correlated with progression-free survival (P=.32). Down-regulation of galectin 1 using small interfering RNA resulted in the inhibition of cell growth and proliferation of HeLa and SiHa cells. Moreover, the ability of cells to invade was significantly reduced by galectin 1 small interfering RNA. Our results revealed that high galectin 1 expression in peritumoral stroma was significantly correlated with depth of invasion in cervical lesions and lymph node metastasis of cervical cancer and that galectin 1 may be functionally involved in cell proliferation and invasion. PMID- 22939955 TI - COL4A3 expression correlates with pathogenesis, pathologic behaviors, and prognosis of gastric carcinomas. AB - COL4A3 protein belongs to type IV collagen family and is closely linked to kidney diseases and cancer. To clarify the roles of COL4A3 in gastric carcinogenesis and subsequent progression, its expression was examined by immunohistochemistry on tissue microarrays containing gastric carcinomas, adjacent intestinal metaplasia, pure intestinal metaplasia, and gastritis. Gastric carcinoma tissue and cell lines were studied for COL4A3 expression by Western blotting and reverse transcription-polymerase chain reaction. We found that COL4A3 was differentially expressed in GES-1, AGS, BGC-823, GT-3 TKB, HGC-27, KATO-III, MGC-803, MKN28, MKN45, SCH, SGC-7901, and STKM-2 at both messenger RNA and protein levels. Carcinomas showed statistically lower COL4A3 expression than matched nonneoplastic mucosa (P < .05). Expression was strong in intestinal metaplasia in comparison with gastritis and carcinoma (P < .05). There was greater COL4A3 expression in carcinoma than gastritis (P < .05). Expression of COL4A3 protein was positively correlated with tumor size, lymphatic invasion, venous invasion, and TNM stage (P < .05). There was more COL4A3 expression in diffuse than in intestinal-type carcinomas regardless of invasion into the muscularis propria (P < .05). Histologically, all signet ring cell (n = 43) and mucinous (n = 12) carcinomas showed COL4A3 expression. Kaplan-Meier analysis indicated that COL4A3 expression was negatively associated with a favorable prognosis of overall, advanced, and intestinal-type gastric carcinomas (P < .05). Aberrant COL4A3 expression might play an important role in the pathogenesis and subsequent progression of gastric carcinoma. COL4A3 overexpression might be used as a marker of gastric intestinal metaplasia and mucinous and signet ring cell carcinoma. PMID- 22939956 TI - Prognostic factors in T1 bladder urothelial carcinoma: the value of recording millimetric depth of invasion, diameter of invasive carcinoma, and muscularis mucosa invasion. AB - pT1 bladder urothelial carcinomas represent a heterogeneous group of tumors with different biologic behaviors, and identifying the subset of tumors that carries a high risk of disease recurrence and progression is therefore important. We evaluated the prognostic significance of substaging 86 cases of pT1 bladder urothelial carcinoma based on different pathologic parameters. The mean tumor depth was 1.1 mm, and the mean diameter of the invasive focus was 2.2 mm. The mean number of tissue fragments with invasion was 4.4. Lymphovascular invasion and concomitant carcinoma in situ were present in 13% and 45% of cases, respectively. Although 56% of patients recurred, 18% experienced disease progression. Multivariate analysis showed a significant association between muscularis mucosa invasion (P = .007), depth of invasion (P = .0001), diameter of invasive focus (P = .014), and progression. Furthermore, depth of invasion more than 3 mm was significantly associated with progression of disease, achieving a sensitivity of 31%, specificity of 99%, and predictive value of 79%. In comparison, the cutoff values for the diameter of invasive carcinoma that correlated best with outcome was 6 mm for progression. Lastly, combining both variables showed a strong prognostic accuracy where it predicted 94% of recurrences. Importantly, all cases with depth of invasion more than 3 mm and diameter more than 6 mm progressed. Lymphovascular invasion or concomitant carcinoma in situ did not correlate with outcome. From the current data, we do recommend reporting muscularis mucosa invasion whenever possible. Alternatively, tumor depth and tumor diameter should be included in the final pathology report in individual cases in which muscularis mucosa invasion cannot be assessed. PMID- 22939957 TI - Noninvasive micropapillary urothelial carcinoma: a clinicopathologic study of 18 cases. AB - Noninvasive micropapillary urothelial carcinoma consists of slender tufts of urothelial carcinoma lacking fibrovascular cores analogous to ovarian papillary serous tumors of borderline malignancy. Eighteen noninvasive micropapillary urothelial carcinoma cases were identified from the Pathology Department of The Johns Hopkins Hospital (2000-2011). Patients lacked history of invasive urothelial carcinoma. Two patterns of noninvasive micropapillary urothelial carcinoma were identified: (1) as a variant of noninvasive high-grade papillary urothelial carcinoma (high-grade papillary urothelial carcinoma/micropapillary urothelial carcinoma) (n = 13 cases) and (2) as a variant of urothelial carcinoma in situ (carcinoma in situ/micropapillary urothelial carcinoma) (n = 5 cases with 2 of these patients also having high-grade papillary urothelial carcinoma/micropapillary urothelial carcinoma). Of 18 patients, 16 (88%) were male with a mean age of 71.8 years (range, 54-87 years). Of the 12 patients initially treated with surveillance, Bacillus-Calmette Guerin, or intravesical chemotherapy, 4 did not recur and were without evidence of disease at 6, 21, 24, and 39 months. Four patients experienced recurrences with 3 of them without evidence of disease at 36, 52, and 72 months and with the fourth whose last follow-up was at 84 months when recurrence occurred. One patient is alive at 11 months with disease, and 1 died of other causes at 1 month. Two patients progressed to pT2 and pT3 disease at 5 and 21 months, respectively. It is critical to differentiate and clearly specify in pathology reports whether micropapillary urothelial carcinoma is invasive or noninvasive because invasive micropapillary urothelial carcinoma is an aggressive disease with a high degree of understaging, whereas some cases of noninvasive micropapillary urothelial carcinoma are not necessarily associated with an adverse outcome. PMID- 22939958 TI - Clinicopathologic analysis of loss of AT-rich interactive domain 1A expression in endometrial cancer. AB - Loss of the AT-rich interactive domain 1A (a putative tumor suppressor) protein BAF250a has recently been described as a frequent event in endometrial carcinoma. In this study, we determined the significance of the loss of AT-rich interactive domain 1A immunoreactivity for several clinicopathologic features of uterine endometrioid carcinoma. AT-rich interactive domain 1A expression was assessed by immunohistochemistry using 111 paraffin-embedded tissue specimens and clinical data collected by a retrospective medical record review. The correlations between loss of AT-rich interactive domain 1A protein and clinicopathologic and prognostic features were examined. In addition, the expression of PTEN, p53, Her2, and MLH1 was assessed by immunohistochemistry and compared with AT-rich interactive domain 1A expression. AT-rich interactive domain 1A immunoreactivity was undetectable in 27 (24%) of 111 analyzed endometrioid endometrial carcinomas. There was no significant difference between negative and positive cases of AT rich interactive domain 1A in terms of any clinicopathologic features examined (International Federation of Gynecology and Obstetrics stage, grade, depth of myometrial invasion, lymph node metastasis, lymphovascular space invasion, body mass index, postmenopausal status, patient age at diagnosis, and estrogen and progesterone receptor status). The comparison between the expression of AT-rich interactive domain 1A and the expression of PTEN, p53, Her2, and MLH1 also revealed no significant association. There was no significant correlation between AT-rich interactive domain 1A expression and progression-free/overall survival of patients. This study provides the first examination of the clinicopathologic relationship between AT-rich interactive domain 1A protein expression and endometrial carcinoma. No significant differences between positive and negative cases of AT-rich interactive domain 1A were observed with respect to any clinicopathologic features or patient survival. PMID- 22939959 TI - Ki-67 expression in axillary lymph node metastases in breast cancer is prognostically significant. AB - Several studies have documented the prognostic significance of cell proliferation in breast cancer and its positive relationship with tumor grade, size, mitotic activity, hormonal and Her-2 status, and tumor progression. The Ki-67 antigen provides an accurate measure of the growth fraction of a tumor. Ki-67 expression in 103 primary breast carcinomas and their corresponding axillary lymph node metastases was correlated with age, tumor grade, size, estrogen receptor (ER), progesterone receptor (PgR), p53, epidermal growth factor receptor (EGFR), Bcl-2, Her-2 status, and patients' overall survival. Median Ki-67 expression in primary and metastatic tumors was 20% and 15%, respectively. Although there was no difference in overall survival (P = .65, log-rank test) between primary tumors with less than or at least 10% Ki-67 expression, there was significantly better overall survival when Ki-67 expression in lymph nodes was less than 10% (P = .040). For patients whose primary tumors exhibited Ki-67 expression less than 10%, most of their metastatic lesions had a similar low Ki-67; these patients had a favorable outcome. A small subgroup was noted to have a nodal Ki-67 of 10% or more and worse survival (P = .047). For patients whose primary tumors had a Ki-67 of 10% or more, most of their metastatic lesions had similar high Ki-67 values; however, a group of 12 patients had lymph node Ki-67 less than 10% and had a better overall survival (P = .092). Our results showed that measurement of Ki-67 in lymph node is superior to its evaluation in primary tumors. Identification of subgroups of patients in whom Ki-67 expression in lymph nodes differs from expression in primary tumor may assist in the selection of therapeutic options. PMID- 22939960 TI - Diagnostic contribution of left ventricular endomyocardial biopsy in patients with clinical phenotype of hypertrophic cardiomyopathy. AB - Hypertrophic cardiomyopathy phenotype is shared by heterogeneous entities. The purpose of the study was to evaluate the diagnostic role of left ventricular endomyocardial biopsy. One hundred fifty-one consecutive patients with unexplained left ventricular hypertrophy and normal/elevated QRS voltages or left bundle-branch block underwent left ventricular endomyocardial biopsy because of associated left ventricular dysfunction (37%), presence of sporadic form of left ventricular hypertrophy (32%), or patient desire for a definite diagnosis (31%). Biopsy samples were processed for histology and electron microscopy. Blood samples were collected for histologically oriented gene analysis of major sarcomeric (MYH7, MYBPC3, TNNT2, TPM1) and lysosomal (LAMP2, PRKAG2, alpha galactosidase A) proteins. Histology showed changes consistent/compatible with hypertrophic cardiomyopathy in 124 patients: myocardial storage disease in 18 due to Fabry disease in 12 and glycogen-storage disease in 6 and myocardial infiltrative disease in 9 because of amyloidosis in 7 and sarcoidosis in 2. Gene analysis was positive in 67% of patients with hypertrophic cardiomyopathy (MYH7 mutation in 36, MYBP in 29, TNNT2 in 14, and TPM1 in 5) and in 83% of patients with lysosomal storage disease (alpha-galactosidase A mutation in 12, PRKAG2 in 2, and LAMP2 in 1). In patients with hypertrophic cardiomyopathy phenotype, left ventricular endomyocardial biopsy is safe and may recognize infiltrative/storage diseases in up to 18% of evolving and sporadic cases. PMID- 22939961 TI - Gene expression microarray-based assay to determine tumor site of origin in a series of metastatic tumors to the ovary and peritoneal carcinomatosis of suspected gynecologic origin. AB - The origin of the primary tumor is sometimes difficult to determine in peritoneal and ovarian metastases. A series of 25 metastatic tumors to the ovary and 7 cases of peritoneal carcinomatosis of suspected gynecologic origin were collected. Total RNA was extracted from frozen tumor tissue and studied by the Tissue of Origin-Frozen test, a microarray-based gene expression test from Pathwork Diagnostics (Redwood City, CA). Independently, formalin-fixed, paraffin-embedded tumor tissue was subjected to pathologic analysis. Immunohistochemical stains included keratins 7 and 20, estrogen and progesterone receptors, CDX2, villin, CEA, WT-1, TTF-1, mammoglobin, GCDF-15, and CD31. Clinical data were considered as gold standard, and after clinicopathologic evaluation, the tissue of origin was found in 29 cases. The Tissue of Origin-Frozen test correctly identified the ovary as site of origin in 7 of 7 peritoneal carcinomatosis cases, whereas immunohistochemical stains only allowed appropriate recognition in 5. In addition, the Tissue of Origin-Frozen test identified correctly the site of origin in 18 of the 22 metastatic tumors to the ovary with known origin. In the remaining 4 tumors, the correct origin was the second option in 2 cases and was not determined in the other 2. Immunohistochemistry correctly identified the site of origin in 17 of these 22 ovarian metastases. A combination of Tissue of Origin Frozen and immunohistochemistry correctly identified the site of origin in 19 of 22 ovarian metastases of known origin. Although conventional pathologic examination and immunohistochemistry are commonly used for assessing the tumor site of origin, Tissue of Origin testing can be useful in difficult cases. PMID- 22939962 TI - Enhancing the strategic management of practice learning through the introduction of the role of Learning Environment Manager. AB - This paper describes a process evaluation project designed to enhance the strategic management of practice learning within a large Hospital in the North of England. The aim of the project was to introduce the role of the Learning Environment Manager with dedicated responsibility for practice learning of undergraduate student nurses within the Hospital's 49 practice-settings. Whilst aspects of this role were already evident in several of these settings, the project sought to locate and standardise responsibilities related to the organisation and management of learning and teaching in practice explicitly within the existing staffing structure of each practice-setting. Focus group interviews were used to explore significant aspects of the project with key stakeholder groups comprising Learning Environment Managers, the Hospital Clinical Educator, Hospital Department Managers, Ward Managers, Mentors, University Link Lecturers and undergraduate Student Nurses. Interview data were analysed using thematic content analysis. The findings of the project suggest that the Learning Environment Manager role affords providers of practice learning with a robust approach to establish organisation-wide benchmarks that standardise the strategic management of practice learning in collaboration with partner Universities. The role incorporated many operational activities previously undertaken by the Hospital Clinical Educator, thus enabling the Hospital Clinical Educator to make a more strategic contribution to the on-going quality monitoring and enhancement of practice learning across the Hospital. The Learning Environment Manager role was found to provide mentors with high levels of support which in turn helped to promote consistent, positive and holistic practice learning experiences for undergraduate student nurses across the Hospital. Importantly, the role offers a potent catalyst for nurses in practice to regain responsibility for practice learning and re-establish the value of practice teaching. PMID- 22939963 TI - Influence on SPF of the quantity of sunscreen product applied. AB - It is now a clearly established fact that ultraviolet radiation is involved in the induction of skin cancer such as carcinoma and melanoma. The most efficient means of protection is by using clothes. For uncovered areas, it is essential to apply a sun product. For some time, various authors have been wondering about the inefficiency or indeed the dangerousness of sun products. Cases of sunburn are still just as frequent in children. We have chosen to study the influence of the quantity of sun product applied on the skin on the level of efficiency obtained. Twenty commercially-available products with SPFs varying between 10 and 50+ and belonging to all levels of protection, that is to say "low", "medium" and "high", were tested in vitro at 5 different doses (5.0, 7.5, 10.0, 12.5 and 15.0 mg for a surface area of 25 cm(2)). We were able to demonstrate that there was a polynomial relationship between the SPF and the quantity of product on the skin's surface. It can be seen that when the dose is halved, the SPF is divided by a variable factor according to the product, from 1.5 to 3.8. PMID- 22939964 TI - Preparation and evaluation of antifungal efficacy of griseofulvin loaded deformable membrane vesicles in optimized guinea pig model of Microsporum canis- dermatophytosis. AB - The present study is aimed at the encapsulation of griseofulvin in the deformable membrane vesicles (DMVs) for dermal delivery. Presently, griseofulvin is available only in conventional oral dosage forms that suffer from the issues of poor and highly variable bioavailability, numerous systemic side effects and long duration of treatment. Multi-lamellar drug-loaded DMVs of griseofulvin (Indian Patent Application 208/DEL/2009) were prepared by thin-film hydration method and were optimized for type and concentration of edge activator (EA). The optimized formulation was evaluated for vesicular shape, size, drug entrapment efficiency, drug content, pH, stability, spreadability, ex vivo skin permeation, dermatokinetics, skin sensitivity, in vitro antifungal assay and in vivo antifungal activity against Microsporum canis using guinea pig model for dermatophytosis. The optimized DMVs illustrated remarkably higher drug permeation and skin retention when compared with liposomes. A complete clinical and mycological cure was observed in animals treated with topical griseofulvin formulation in 10 days. The formulation was observed to be non-sensitizing, histopathologically safe, and stable at 5+/-3 degrees C, 25+/-2 degrees C and 40+/-2 degrees C for a period of six months. The results indicated that the topical formulation of DMVs of griseofulvin could be utilized as an alternative to reduce the encumbrance of conventional oral formulations. PMID- 22939965 TI - The delineation of the morphology of charged liposomal vectors via a fractal analysis in aqueous and biological media: physicochemical and self-assembly studies. AB - The present study deals with the physicochemical characterization of DPPC:DPPG (9:1 molar ratio) and DPPC:DODAP (9:1 molar ratio) liposomes, and the determination of their fractal dimension in HPLC-grade water, PBS and in FBS. Light scattering techniques were used in order to extract information on the structure, morphology, size and surface charge of liposomes in an ageing study and their structural response to changes in concentration and temperature. Fluorescence spectroscopy showed that the microviscosity of cationic liposomes changed by an increase of temperature. The fractal dimension, d(f), was found equal to 1.8 for reconstituted DPPC:DPPG (9:1) and DPPC:DODAP (9:1) liposomes in aqueous media. Aggregation of reconstituted DPPC:DPPG (9:1) and DPPC:DODAP (9:1) liposomes in FBS was observed. Their fractal dimensions were 1.46 and 2.45, respectively. The first order aggregation kinetics of DPPC:DODAP (9:1) liposomes in the presence of serum proteins was determined; the aggregates of cationic liposomes with serum components remained stable during 20 days with fractal dimension 2.5. The responsiveness of cationic liposomes to changes in temperature in the three dispersion media has revealed the self-assembly and the morphological complexity of cationic vectors. Finally, we suggest that these studies could be used for developing effective advanced drug delivery nano systems (aDDnSs) based on their fractal characteristics which effectively draw their morphological profile. PMID- 22939966 TI - Characterisation of high dose aerosols from dry powder inhalers. AB - Developments in high dose dry powder aerosol delivery will increasingly challenge the applicability of currently used aerosol characterisation techniques. With cascade impaction analysis bounce effects can negatively influence stage collection efficiency, especially with increasing impactor loads. In this study the suitability of the multi stage liquid impinger (MSLI) and the Next Generation Impactor (NGI) for the characterisation of dry powder aerosols containing up to 50mg of drug is evaluated. The occurrence of bounce effects is quantitatively assessed by comparison with data obtained from laser diffraction analysis. The liquid based impaction surfaces of the MSLI largely prevent bounce effects, but the low number of cut-off values associated with this impactor hinders accurate data interpretation. With the NGI, a standard high viscosity plate coating insufficiently reduces bounce effects, causing the fraction <1 MUm to be higher than what can maximally be expected based on the primary particle size distribution (PSD) obtained from RODOS dispersion. With this type of impactor, the use of solvent soaked filters as impaction surface is necessary to eliminate bounce effects. PMID- 22939967 TI - GC-MS profiling of the phytochemical constituents of the oleoresin from Copaifera langsdorffii Desf. and a preliminary in vivo evaluation of its antipsoriatic effect. AB - Copaiba is the oleoresin (OR) obtained from Copaifera (Fabaceae), a neotropical tree which grows in Amazon regions. The balsam, constituted by an essential oil and a resinous fraction is used as folkloristic remedy in the treatment of several inflammatory diseases and for its antioxidant and antibacterial properties. Aim of this work was (a) to carry out a characterization by GC-MS of the volatile and nonvolatile constituents of Copaifera langsdorffii Desf. oleoresin (OR); (b) to investigate the mechanism of its anti-inflammatory activity; (c) to evaluate its antipsoriatic effect after oral intake/topical application. The volatile fraction (yield: 22.51%, w/w) shows: alpha-bergamotene (48.38%), alpha-himachalene (11.17%), beta-selinene (5.00%) and beta caryophyllene (5.47%). The OR residue (77.49%, w/w), after derivatization, showed as main constituents the following compounds: copalic, abietic, daniellic, lambertinic, labd-7-en-15-oic, pimaric, isopimaric acids and kaur16-en18-oic acid. Preincubation of LPS-stimulated human THP-1 monocytes with increasing concentrations of the OR purified fraction (OR-PF), containing diterpene acids, diterpenes and sesquiterpenes, reduced the release of pro-inflammatory cytokines (IL-1beta, IL-6, TNFalpha) in a dose-range of 0.1-10 MUM. In addition, in cell culture system of human THP-1 monocytes, 1 MUM OR-PF counteracts LPS-driven NF kappaB nuclear translocation. In a preliminary clinical trial three patients affected by chronic psoriasis, treated with oral intake or topical application of the OR, exhibited a significant improvement of the typical signs of this disease, i.e. erythema, skin thickness, and scaliness. In conclusion, the results of this work, beside an extensive analytical characterization of the OR chemical composition, provide strong evidences that its anti-inflammatory activity is related to the inhibition of the NF-kappaB nuclear translocation, and consequently of proinflammatory cytokines secretion. PMID- 22939968 TI - Exploring the fate of liposomes in the intestine by dynamic in vitro lipolysis. AB - Liposomes are generally well tolerated drug delivery systems with a potential use for the oral route. However, little is known about the fate of liposomes during exposure to the conditions in the gastro-intestinal tract (GIT). To gain a better understanding of liposome stability in the intestine, a dynamic in vitro lipolysis model, which so far has only been used for the in vitro characterisation of other lipid-based drug delivery systems, was applied to different liposomal formulations. Liposome size and phospholipid (PL) digestion were determined as two markers for liposome stability. In addition, the effect of PL degradation on the ability to maintain liposomally incorporated danazol in solution during lipolysis was evaluated in order to address the feasibility of liposomes designed for oral administration. Rate and extend of hydrolysis of PLs mediated by pancreatic enzymes was determined by titration and HPLC. Size of liposomes was determined by dynamic light scattering during incubation in lipolysis medium (LM) and during lipolysis. SPC-based (soy phosphatidylcholine) liposomes were stable in LM, whereas for EPC-3-based (hydrated egg phosphatidylcholine) formulations the formation of aggregates of around 1 MUm in diameter was observed over time. After 60 min lipolysis more than 80% of PLs of the SPC-liposomes were digested, but dependent on the liposome concentration only a slight change in size and size distribution could be observed. Although EPC-3 formulations did form aggregates during lipolysis, the lipids exhibited a higher stability compared to SPC and only 30% of the PLs were digested. No direct correlation between liposome integrity assessed by vesicle size and PL digestion was observed. Danazol content in the liposomes was around 5% (mol/mol danazol/total lipid) and hardly any precipitation was detected during the lipolysis assay, despite pronounced lipolytic degradation and change in vesicle size. In conclusion, the tested dynamic in vitro lipolysis model is suitable for the assessment of liposome stability in the intestine. Furthermore, liposomes might be a useful alternative to other lipid based delivery systems for the oral delivery of poorly soluble drugs. PMID- 22939969 TI - Prestorage gamma irradiation induces oxidative injury to red cells. AB - BACKGROUND: Gamma irradiation of blood results in the formation free radicals, which interact with lipids and proteins in the membranes of red blood cells. We have investigated oxidative injury to gamma-irradiated red cells by measuring markers of oxidative injury and its correlation with red cell membrane damage. METHODS: Thirty red cell blood units were irradiated at 25 Gy using Gamma Irradiator (Nordion, Canada) and stored at 4 degrees C for 28 days. Markers of oxidative injury such as MDA levels, methemoglobin formation and osmotic fragility and markers of membrane damage including supernatant Hb, supernatant K(+), and LDH were studied. RESULTS: There was a progressive and statistically significant increase in markers of oxidative injury such as MDA (3.76 v/s 5.01), and methemoglobin formation (1.87 v/s 3.58) in irradiated red cells compared to control non-irradiated cells. Exposure to gamma irradiation caused significant increase in markers of hemolysis such as supernatant Hb (0.087 v/s 0.363), K(+) (35.1 v/s 51.2) and LDH (366.9 v/s 587.4) over the storage period of 28 days. CONCLUSION: Gamma irradiation increases lipid peroxidation and oxidative injury to the red cells. PMID- 22939970 TI - HbA1c: a prognostic biomarker in the surgical and critically ill patient population. PMID- 22939971 TI - The great masquerader: atypical neuroleptic malignant syndrome after cardiac surgery. PMID- 22939973 TI - [6]-Gingerol induces caspase 3 dependent apoptosis and autophagy in cancer cells: drug-DNA interaction and expression of certain signal genes in HeLa cells. AB - [6]-Gingerol, a pharmacologically important bioactive component of ginger, has been reported to have anti-hyperglycemic, anti-cancer and anti-oxidative properties, but mechanisms through which these are achieved are largely unclear. The present study focuses on apoptosis and autophagy, two key events of anti cancer activity, in HeLa cells treated with [6]-gingerol. The treated cells showed several morphological changes, including externalization of phosphatidyl serine, degradation of DNA and increase in TUNEL positivity. Furthermore, there was depolarization of mitochondrial membrane potential, providing evidence of mitochondria mediated apoptosis. The expression of caspase 3 and PARP was increased in cells exposed to [6]-gingerol. Circular dichroism study for testing drug-DNA interaction with both calf thymus and nuclear DNA as target revealed that the drug had potential to bind with the nuclear DNA and induce conformational changes of DNA. The over-expression of NFkbeta, AKT and Bcl2 genes in cancer cells was down-regulated by [6]-gingerol treatment. On the other hand the expression levels of TNFalpha, Bax and cytochrome c were enhanced in [6] gingerol treated cells. Thus, overall results suggest that [6]-gingerol has potential to bind with DNA and induce cell death by autophagy and caspase 3 mediated apoptosis. PMID- 22939972 TI - Depletion of cellular glutathione modulates LIF-induced JAK1-STAT3 signaling in cardiac myocytes. AB - Previously we reported that the sesquiterpene lactone parthenolide induces oxidative stress in cardiac myocytes, which blocks Janus kinase (JAK) activation by the interleukin 6 (IL-6)-type cytokines. One implication suggested by this finding is that IL-6 signaling is dependent upon cellular anti-oxidant defenses or redox status. Therefore, the present study was undertaken to directly test the hypothesis that JAK1 signaling by the IL-6-type cytokines in cardiac myocytes is impaired by glutathione (GSH) depletion, since this tripeptide is one of the major anti-oxidant molecules and redox-buffers in cells. Cardiac myocytes were pretreated for 6h with l-buthionine-sulfoximine (BSO) to inhibit GSH synthesis. After 24h, cells were dosed with the IL-6-like cytokine, leukemia inhibitory factor (LIF). BSO treatment decreased GSH levels and dose-dependently attenuated activation of JAK1, Signal Transducer and Activator of Transcription 3 (STAT3), and extracellular signal regulated kinases 1 and 2 (ERK1/2). Addition of glutathione monoethyl ester, which is cleaved intracellularly to GSH, prevented attenuation of LIF-induced JAK1 and STAT3 activation, as did the reductant N acetyl-cysteine. Unexpectedly, LIF-induced STAT1 activation was unaffected by GSH depletion. Evidence was found that STAT3 is more resistant than STAT1 to intermolecular disulfide bond formation under oxidizing conditions and more likely to retain the monomeric form, suggesting that conformational differences explain the differential effect of GSH depletion on STAT1 and STAT3. Overall, our findings indicate that activation of both JAK1 and STAT3 is redox-sensitive and the character of IL-6 type cytokine signaling in cardiac myocytes is sensitive to changes in the cellular redox status. In cardiac myocytes, activation of STAT1 may be favored over STAT3 under oxidizing conditions due to GSH depletion and/or augmented reactive oxygen species production, such as in ischemia-reperfusion and heart failure. PMID- 22939974 TI - Protective effects of magnesium supplementation on metabolic energy derangements in lipopolysaccharide-induced cardiotoxicity in mice. AB - Metabolic derangements and bioenergetic failure are major contributors to sepsis induced multiple organ dysfunctions. Due to the well known role of magnesium (Mg) as a cofactor in many enzymatic reactions that involve energy creation and utilization, the present investigation was directed to estimate the cardioprotective effect of Mg supplementation in lipopolysaccharide (LPS)-induced metabolic energy changes in mice. Oral doses of Mg aspartate (20 or 40 mg/kg) were administered once daily for 7 day. Mice were then subjected to a single intraperitoneal injection of LPS (2 mg/kg). Plasma was separated 3 h after LPS injection for determination of creatine kinase-MB activity. Animals were then sacrificed and the hearts were separated for estimation of tissue thiobarbituric acid reactive substances, reduced glutathione, lactate, pyruvate, adenine nucleotides, creatine phosphate and cardiac Na(+),K(+)-ATPase activity. Finally, electron microscopic examination was performed to visualize the protective effects of Mg pretreatment on mitochondrial ultrastructure. In general, the higher dose of Mg was more effective than the lower dose in ameliorating creatine kinase-MB elevation and the state of oxidative stress, lactate accumulation, pyruvate reduction as well as preserving creatine phosphate, adenine nucleotides and Na(+),K(+)-ATPase activity. Moreover, the higher dose of Mg provided a significant cardioprotection against the mitochondrial ultrastructural changes. Mg therapy can afford a significant protection against metabolic energy derangements and mitochondrial ultrastructural changes induced by LPS cardiotoxicity in mice. PMID- 22939975 TI - A pioneer in medicine and surgery: Charles Sedillot (1804-1883). AB - Professor Charles Sedillot (1804-1883) is one of the pioneers of modern medicine, surgery, anaesthesiology, histopathology and infectiology. Unfortunately, he remains unknown outside of the circles of French military medicine historians. He was the first surgeon in the world to offer techniques such as coxofemoral dislocation and internal urethrotomy, thus becoming a pioneer in endoscopic surgery. By introducing general anaesthesia in France, he revolutionised patient care. In addition, he laid the foundation for the modern, algorithmic treatment of tumours by adopting the principles of clinical histopathology. Long before the description put forth by Semmelweiss (1818-1865), he foresaw and understood the existence and action of microorganisms, which he termed microbes, in the development of postoperative infections. For his work, he was honoured by his peers in France but remained unknown beyond the borders of his homeland. Here, we present a succinct report of the considerable accomplishments of the life and work of this outstanding physician and surgeon. PMID- 22939976 TI - Duodenal gastrointestinal stromal tumors: review on clinical and surgical aspects. AB - INTRODUCTION: Gastrointestinal stromal tumors (GISTs) arising in the duodenum represent a rare entity and can be very demanding to manage. The diagnosis can be difficult (as these tumors can be misdiagnosed as pancreatic head tumors), and to treat owing to the complex anatomy of the duodenum and of the pancreatic head. Complete resection may require extensive procedures such as pancreaticodudodenectomy. METHODS AND RESULTS: An extensive literature review regarding clinico-pathological features, diagnostic investigations and surgical options in the management of duodenal GISTs has been performed. CONCLUSIONS: Duodenal GISTs have uncertain malignant potential, and they may be asymptomatic, or present with abdominal pain or bleeding. A preoperative diagnosis can be difficult to obtain. Endoscopic ultrasound and fine needle aspiration cytology (FNAC) may be helpful. Surgical R0 resection remains the only curative approach. However, owing to the complex anatomy of the duodenum, limited resection is not always feasible. In these cases, extensive procedures such as pancreaticoduodenectomy or pancreas-preserving duodenectomy are the treatment of choice. PMID- 22939977 TI - Development of a simple and rapid protocol for the production of customized intertypic recombinant polioviruses. AB - The three attenuated strains Sabin are used as oral vaccine to immunize against poliomyelitis in many countries. Low vaccine coverage can allow these strains to circulate among non-immunized people, accumulating genetic modifications through nucleotide substitutions and recombination with non-polio enteroviruses. These modifications can induce a loss of attenuation, so promoting the emergence of pathogenic vaccine-derived polioviruses responsible for poliomyelitis outbreaks. In vitro-engineered chimeric viruses containing both Sabin and non-polio sequences constitute a powerful tool for understanding the constraints that drive and limit the recombination events between the Sabin strains and other enteroviruses and to understand the consequences on the viral phenotypic properties of substitutions of large genomic regions due to recombination events. A method was optimized that allowed the rapid production of customized Sabin derived viruses. By using sequences from Sabin 2 and 3 polioviruses and from non polio field enteroviruses, several recombinant genomes were engineered by using fusion PCR. The corresponding viruses were recovered after cell transfection. This method was found able to generate rapidly a wide range of unnatural viruses with multiple breakpoints that can be chosen precisely. Furthermore, this method is also suitable to engineer nucleotide deletions, insertions and/or substitutions within a given genome, so increasing the number of unnatural viruses that can be studied. PMID- 22939978 TI - Simultaneous detection of the seven main tomato-infecting RNA viruses by two multiplex reverse transcription polymerase chain reactions. AB - Cucumber mosaic virus, Tomato spotted wilt virus, Tomato mosaic virus, Tomato chlorosis virus, Pepino mosaic virus, Torrado tomato virus and Tomato infectious chlorosis virus cause serious damage and significant economic losses in tomato crops worldwide. The early detection of these pathogens is essential for preventing the viruses from spreading and improving their control. In this study, a procedure based on two multiplex RT-PCRs was developed for the sensitive and reliable detection of these seven viruses. Serial dilutions of positive controls were analysed by this methodology, and the results were compared with those obtained by ELISA and singleplex versions of RT-PCR. The multiplex and singleplex RT-PCR assays were able to detect specific targets at the same dilution and were 100 times more sensitive than ELISA. The multiplex versions were able to detect composite samples containing different concentrations of specific targets at ratios from 1:1 to 1:1000. In addition, 45 symptomatic tomato samples collected in different tomato-growing areas of Sicily (Italy) were analysed by multiplex RT PCR, singleplex RT-PCR and commercially available ELISA tests. Similar results were obtained using the RT-PCR techniques, with a higher sensitivity than ELISA, revealing a common occurrence of mixed infections and confirming the presence of these seven virus species in Italy. PMID- 22939979 TI - Comparison of relaxation training with a cognitive-behavioural intervention for indicated prevention of depression in university students: a randomized controlled trial. AB - Although cognitive-behavioural programmes for preventing depression have produced promising findings, their administration requires extensive training. Relaxation techniques are more straightforward psychological strategies, but they have not been investigated in the prevention of depression. This trial aimed to compare the results of relaxation training (RT) with that of a cognitive-behavioural programme (CBT) for prevention of depression in university students with elevated depressive symptoms. The 133 participants (mean age 23.3 years, 82% women) were randomly assigned to CBT or RT. Both programmes were administered to groups of 5 or 6 participants in eight weekly 90-min sessions. Participants were evaluated by independent raters before, immediately after, and 3 and 6 months after taking part in the programmes. By itself, intervention type had no significant effect on either depression or anxiety scores. The scores were lower at the follow-up time points with respect to pre-intervention scores. Effect size was greatest between pre- and immediately post-intervention scores for CBT, d = 1.32, 95% CI [1.00, 1.64], and between pre- and 6-month post-intervention scores for RT, d = 0.75, 95% CI [0.47, 1.03]. Anxiety symptoms were significantly improved by both interventions at 3-month follow-up, and by CBT at 6-month follow-up also. In the medium term (3-6 months), relaxation training produced similar reductions in depressive and anxiety symptoms as a more complex cognitive-behavioural programme. PMID- 22939980 TI - Increasing MuSK activity delays denervation and improves motor function in ALS mice. AB - Amyotrophic lateral sclerosis (ALS) is a devastating disease that progresses from detachment of motor nerve terminals to complete muscle paralysis and lethal respiratory failure within 5 years of diagnosis. Genetic studies have linked mutations in several genes to ALS, and mice bearing mutations in SOD1 recapitulate hallmark features of the disease. We investigated whether disease symptoms can be ameliorated by co-opting the retrograde signaling pathway that promotes attachment of nerve terminals to muscle. We crossed SOD1G93A mice with transgenic mice that express MuSK, a receptor tyrosine kinase that is required for retrograde signaling, and we used histological and behavioral assays to assess motor innervation and behavior. A 3-fold increase in MuSK expression delayed the onset and reduced the extent of muscle denervation, improving motor function for more than a month without altering survival. These findings suggest that increasing MuSK activity by pharmacological means has the potential to improve motor function in ALS. PMID- 22939981 TI - CEL-Seq: single-cell RNA-Seq by multiplexed linear amplification. AB - High-throughput sequencing has allowed for unprecedented detail in gene expression analyses, yet its efficient application to single cells is challenged by the small starting amounts of RNA. We have developed CEL-Seq, a method for overcoming this limitation by barcoding and pooling samples before linearly amplifying mRNA with the use of one round of in vitro transcription. We show that CEL-Seq gives more reproducible, linear, and sensitive results than a PCR-based amplification method. We demonstrate the power of this method by studying early C. elegans embryonic development at single-cell resolution. Differential distribution of transcripts between sister cells is seen as early as the two-cell stage embryo, and zygotic expression in the somatic cell lineages is enriched for transcription factors. The robust transcriptome quantifications enabled by CEL Seq will be useful for transcriptomic analyses of complex tissues containing populations of diverse cell types. PMID- 22939982 TI - TNF-induced target cell killing by CTL activated through cross-presentation. AB - Viruses can escape cytotoxic T cell (CTL) immunity by avoiding presentation of viral components via endogenous MHC class I antigen presentation in infected cells. Cross-priming of viral antigens circumvents such immune escape by allowing noninfected dendritic cells to activate virus-specific CTLs, but they remain ineffective against infected cells in which immune escape is functional. Here, we show that cross-presentation of antigen released from adenovirus-infected hepatocytes by liver sinusoidal endothelial cells stimulated cross-primed effector CTLs to release tumor necrosis factor (TNF), which killed virus-infected hepatocytes through caspase activation. TNF receptor signaling specifically eliminated infected hepatocytes that showed impaired anti-apoptotic defense. Thus, CTL immune surveillance against infection relies on two similarly important but distinct effector functions that are both MHC restricted, requiring either direct antigen recognition on target cells and canonical CTL effector function or cross-presentation and a noncanonical effector function mediated by TNF. PMID- 22939984 TI - Flow cytometry and cell sorting: the next generation. PMID- 22939983 TI - Repression of transcription by WT1-BASP1 requires the myristoylation of BASP1 and the PIP2-dependent recruitment of histone deacetylase. AB - The Wilms' tumor 1 protein WT1 is a transcriptional regulator that is involved in cell growth and differentiation. The transcriptional corepressor BASP1 interacts with WT1 and converts WT1 from a transcriptional activator to a repressor. Here, we demonstrate that the N-terminal myristoylation of BASP1 is required in order to elicit transcriptional repression at WT1 target genes. We show that myristoylated BASP1 binds to nuclear PIP2, which leads to the recruitment of PIP2 to the promoter regions of WT1-dependent target genes. BASP1's myristoylation and association with PIP2 are required for the interaction of BASP1 with HDAC1, which mediates the recruitment of HDAC1 to the promoter and elicits transcriptional repression. Our findings uncover a role for myristoylation in transcription, as well as a critical function for PIP2 in gene-specific transcriptional repression through the recruitment of histone deacetylase. PMID- 22939985 TI - Attenuation of virulence of Lawsonia intracellularis after in vitro passages and its effects on the experimental reproduction of porcine proliferative enteropathy. AB - Non-pathogenic Lawsonia intracellularis variants have been obtained through multiple passages in cell culture but there is no information regarding the number of passages necessary to attenuate a pathogenic isolate. The present study evaluated the susceptibility of pigs to L. intracellularis after 10, 20 and 40 passages in vitro. Three groups (six animals/group) were inoculated with pure culture of L. intracellularis on passage 10, 20 or 40 and one group with placebo. The animals were monitored for clinical signs, fecal shedding and serological IgG response during 28 days post-inoculation. Gross and histologic lesions and the level of infection based on the amount of L. intracellularis-specific antigen in the intestinal mucosa identified by immunohistochemistry were evaluated in two animals from each group on days 14, 21 and 28. Animals inoculated with passages 10 and 20 demonstrated proliferative lesions typical of porcine proliferative enteropathy associated with the presence of Lawsonia-specific antigen in the intestinal mucosa. Passage 40-inoculated pigs did not show proliferative lesions or presence of Lawsonia antigen at any time point throughout the study. Similar patterns of the fecal shedding were observed in passage 10 and 20-infected pigs but those infected with passage 40 shed for a short period. Serological IgG responses in passage 10 and 20-inoculated pigs were detected from day 14 post infection but not at all in passage 40-inoculated animals. These results demonstrate attenuation of the virulence properties of L. intracellularis between 20 and 40 cell passages in vitro. This information will be valuable for design of future experimental models and for studying the mechanisms involved in the attenuation of L. intracellularis virulence. PMID- 22939986 TI - Identification and characterization of the arginine deiminase system of Streptococcus canis. AB - Although Streptococcus (S.) canis is known to cause severe infections in dogs and cats and harbors a clear zoonotic potential, knowledge about physiology and pathogenesis is mostly elusive. The arginine deiminase system (ADS) has been described in certain streptococcal species and its role in the establishment of infection has been suggested. In this study we focused on the identification and characterization of the ADS in S. canis. Using genome sequencing and subsequent in silico analysis we identified the ADS of S. canis as a gene cluster composed of seven genes. RT-PCR analysis revealed that the ADS of S. canis is transcribed in four transcriptional units, comprising three monocistronical mRNAs and one operon structure. As a secondary metabolic pathway, the ADS of S. canis is strictly regulated by carbon catabolite repression (CCR) and arginine as demonstrated on transcriptional, translational, and enzymatical level, respectively. Furthermore, growth kinetics with a chemically defined medium clearly showed that arginine, the substrate of the ADS, is essential for the biological fitness of S. canis. Using Immuno-electron microscopy analysis, we observed a surface-exposed localization of the ADS enzymes arginine deiminase (ArcA), ornithine carbamoyltransferase (ArcB), and carbamate kinase (ArcC), respectively, which might suggest the contribution of the ADS to the development of streptococcal infections. PMID- 22939987 TI - Non-typhoidal Salmonella encephalopathy involving lipopolysaccharide in cattle. AB - This study assessed the involvement of lipopolysaccharide (LPS) in the non typhoidal Salmonella encephalopathy (NTSE) caused by a unique isolate of Salmonella enterica serovar Saint-paul (SstpNPG). NTSE was prevented by genetic (deletion of murE) or pharmacologic (polymyxin) disruption of LPS on SstpNPG although the disruption of LPS did not deter brain penetration of the strain. This is the first study to demonstrate that LPS is involved in the manifestations of NTSE. PMID- 22939988 TI - A dietary colorant crocin mitigates arthritis and associated secondary complications by modulating cartilage deteriorating enzymes, inflammatory mediators and antioxidant status. AB - Articular cartilage degeneration and inflammation are the hallmark of progressive arthritis and is the leading cause of disability in 10-15% of middle aged individuals across the world. Cartilage and synovium are mainly degraded by either enzymatic or non-enzymatic ways. Matrix metalloproteinases (MMPs), hyaluronidases (HAases) and aggrecanases are the enzymatic mediators and inflammatory cytokines and reactive oxygen species being non-enzymatic mediators. In addition, MMPs and HAases generated end-products act as inflammation inducers via CD44 and TLR-4 receptors involved NF-kappaB pathway. Although several drugs have been used to treat arthritis, numerous reports describe the side effects of these drugs that may turn fatal. On this account several medicinal plants and their isolated molecules have been involved in modern medicine strategies to fight against arthritis. In view of this, the present study investigated the antiarthritic potentiality of Crocin, a dietary colorant carotenoid isolated from stigma of Crocus sativus. Crocin effectively neutralized the augmented serum levels of enzymatic (MMP-13, MMP-3 and MMP-9 and HAases) and non-enzymatic (TNF alpha, IL-1beta, NF-kappaB, IL-6, COX-2, PGE(2) and ROS) inflammatory mediators. Further, Crocin re-established the arthritis altered antioxidant status of the system (GSH, SOD, CAT and GST). It also protected the bone resorption by inhibiting the elevated levels of bone joint exoglycosidases, cathepsin-D and tartrate resistant acid phosphatases. Taken together, Crocin revitalized the arthritis induced cartilage and bone deterioration along with inflammation and oxidative damage that could be accredited to its antioxidant nature. Thus, Crocin could be an effective antiarthritic agent which can equally nullify the arthritis associated secondary complication. PMID- 22939989 TI - FoxC1-dependent regulation of vascular endothelial growth factor signaling in corneal avascularity. AB - Angiogenesis is a crucial process whereby new blood vessels are formed from pre existing vessels, and it occurs under both normal and pathophysiological conditions. The process is precisely regulated through the balance between proangiogenic and anti-angiogenic mechanisms, and many of these mechanisms have been well-characterized through extensive research. However, little is known about how angiogenesis is regulated at the transcriptional level. We have recently shown that deletion of the Forkhead box (Fox) transcription factor Foxc1 in cells of neural crest (NC) lineage leads to aberrant vessel growth in the normally avascular corneas of mice, and that the effect is cell type-specific because the corneas of mice lacking Foxc1 expression in vascular endothelial cells remained avascular. The NC-specific Foxc1 deletion was also associated with elevated levels of both proangiogenic factors, such as the matrix metalloproteases (MMPs) MMP-3, MMP-9, and MMP-19 and the angiogenic inhibitor soluble vascular endothelial growth factor receptor 1 (sVEGFR-1). Thus, FoxC1 appears to control angiogenesis by regulating two distinct and opposing mechanisms; if so, vascular development could be determined, at least in part, by a competitive balance between proangiogenic and anti-angiogenic FoxC1-regulated pathways. In this review, we describe the mechanisms by which FoxC1 regulates vessel growth and discuss how these observations could contribute to a more complete understanding of the role of FoxC1 in pathological angiogenesis. PMID- 22939990 TI - PGC-1 proteins and heart failure. AB - The transcriptional coactivators PGC-1alpha and PGC-1beta are master regulators of oxidative phosphorylation and fatty acid oxidation gene expression. Pressure overload hypertrophy and heart failure are associated with repressed PGC-1alpha and PGC-1beta gene expression. Maintaining expression of PGC-1alpha and -beta preserves contractile function in response to a pathological increase in workload. Here, we discuss the regulation of PGC-1 proteins under conditions of pressure overload hypertrophy and heart failure. PMID- 22939991 TI - Acute nicotine differentially impacts anticipatory valence- and magnitude-related striatal activity. AB - BACKGROUND: Dopaminergic activity plays a role in mediating the rewarding aspects of abused drugs, including nicotine. Nicotine modulates the reinforcing properties of other motivational stimuli, yet the mechanisms of this interaction are poorly understood. This study aimed to ascertain the impact of nicotine exposure on neuronal activity associated with reinforcing outcomes in dependent smokers. METHODS: Smokers (n = 28) and control subjects (n = 28) underwent functional imaging during performance of a monetary incentive delay task. Using a randomized, counterbalanced design, smokers completed scanning after placement of a nicotine or placebo patch; nonsmokers were scanned twice without nicotine manipulation. In regions along dopaminergic pathway trajectories, we considered event-related activity for valence (reward/gain vs. punishment/loss), magnitude (small, medium, large), and outcome (successful vs. unsuccessful). RESULTS: Both nicotine and placebo patch conditions were associated with reduced activity in regions supporting anticipatory valence, including ventral striatum. In contrast, relative to controls, acute nicotine increased activity in dorsal striatum for anticipated magnitude. Across conditions, anticipatory valence-related activity in the striatum was negatively associated with plasma nicotine concentration, whereas the number of cigarettes daily correlated negatively with loss anticipation activity in the medial prefrontal cortex only during abstinence. CONCLUSIONS: These data suggest a partial dissociation in the state- and trait specific effects of smoking and nicotine exposure on magnitude- and valence dependent anticipatory activity within discrete reward processing brain regions. Such variability may help explain, in part, nicotine's impact on the reinforcing properties of nondrug stimuli and speak to the continued motivation to smoke and cessation difficulty. PMID- 22939992 TI - Predictors of marijuana relapse in the human laboratory: robust impact of tobacco cigarette smoking status. AB - BACKGROUND: Few marijuana smokers in treatment achieve sustained abstinence, yet factors contributing to high relapse rates are unknown. METHODS: Study 1: data from five inpatient laboratory studies assessing marijuana intoxication, withdrawal, and relapse were combined to assess factors predicting the likelihood and severity of relapse. Daily, nontreatment-seeking marijuana smokers (n = 51; 10 +/- 5 marijuana cigarettes/day) were enrolled. Study 2: to isolate the effects of cigarette smoking, marijuana intoxication, withdrawal, and relapse were assessed in daily marijuana and cigarette smokers (n = 15) under two within subject, counter-balanced conditions: while smoking tobacco cigarettes as usual (SAU), and after at least 5 days without cigarettes (Quit). RESULTS: Study 1: 49% of participants relapsed the first day active marijuana became available. Tobacco cigarette smokers (75%), who were not abstaining from cigarettes, were far more likely to relapse than non-cigarette smokers (odds ratio: 19, p < .01). Individuals experiencing more positive subjective effects (i.e., feeling "high") after marijuana administration and those with more negative affect and sleep disruption during marijuana withdrawal were more likely to have severe relapse episodes (p < .05). Study 2: most participants (>87%) relapsed to marijuana whether in the SAU or Quit phase. Tobacco cigarette smoking did not significantly influence relapse, nor did it affect marijuana intoxication or most symptoms of withdrawal relative to tobacco cessation. CONCLUSIONS: Daily marijuana smokers who also smoke cigarettes have high rates of marijuana relapse, and cigarette smoking versus recent abstinence does not directly influence this association. These data indicate that current cigarette smoking is a clinically important marker for increased risk of marijuana relapse. PMID- 22939993 TI - Susceptibility to intracerebral hemorrhage-induced brain injury segregates with low aerobic capacity in rats. AB - Although low exercise capacity is a risk factor for stroke, the exact mechanisms that underlie this connection are not known. As a model system for exploring the association between aerobic capacity and disease risks we applied two-way artificial selection over numerous generations in rats to produce low capacity runners (LCR) and high capacity runners (HCR). Here we compared intracerebral hemorrhage (ICH)-induced brain injury in both genders of these rat lines. HCR and LCR rats had 100MUl blood injected into the right caudate and were killed at days 1, 3, 7 and 28 for brain water content determination, immunohistochemistry, histology, Western blot, and behavioral tests. Compared to male HCRs, male LCRs had more severe ICH-induced brain injury including worse brain edema, necroptosis, brain atrophy, and neurological deficits, but not increased numbers of Fluoro-Jade C positive cells or elevated cleaved caspase-3 levels. This was associated with greater microglial activation, and heme oxygenase-1 and protease activated receptor (PAR)-1 upregulation. In females, edema was also greater in LCRs than in HCRs, although it was less severe in females than in males for both LCRs and HCRs. Thus, ICH-induced brain injury was more severe in LCRs, a model of low exercise capacity, than in HCRs. Increased activation of microglia and PAR-1 may participate mechanistically in increased ICH-susceptibility. Females were protected against ICH-induced brain edema formation in both HCRs and LCRs. PMID- 22939995 TI - IL-6 promotes ICAM-1 expression and cell motility in human osteosarcoma. AB - Osteosarcoma is characterized by a high malignant and metastatic potential. Interleukin-6 (IL-6) is a multifunctional cytokine that is associated with the disease status and outcomes of cancers. However, the effect of IL-6 on migration activity in human osteosarcoma cells is mostly unknown. Here we found that IL-6 increased the migration and expression of intercellular adhesion molecule-1 (ICAM 1) in human osteosarcoma cells. Transfection of cells with ICAM-1 siRNA reduced IL-6-mediated cell migration. We also found that expression of IL-6 was significantly greater in human osteosarcoma tissues than in normal bone. The integrin-linked kinase (ILK)/Akt/AP-1 pathway was activated after IL-6 treatment, and IL-6-induced expression of ICAM-1 and migration activity was inhibited by the specific inhibitor and siRNA of ILK, Akt, and AP-1 cascades. In addition, over expression of IL-6 shRNA inhibited the migratory ability and ICAM-1 expression in osteosarcoma cells. Taken together, these results indicate that IL-6 and IL-6 receptor interaction occurs through ILK and Akt, which in turn activates AP-1, resulting in the activations of ICAM-1 and contributing the migration of human osteosarcoma cells. PMID- 22939994 TI - Pregnane xenobiotic receptor in cancer pathogenesis and therapeutic response. AB - Pregnane xenobiotic receptor (PXR) is an orphan nuclear receptor that regulates the metabolism of endobiotics and xenobiotics. PXR is promiscuous and unique in that it is activated by a diverse group of xenochemicals, including therapeutic anticancer drugs and naturally-occurring endocrine disruptors. PXR has been predominantly studied to understand its regulatory role in xenobiotic clearance in liver and intestine via induction of drug metabolizing enzymes and drug transporters. PXR, however, is widely expressed and has functional implications in other normal and malignant tissues, including breast, prostate, ovary, endometrium and bone. The differential expression of PXR and its target genes in cancer tissues has been suggested to determine the prognosis of chemotherapeutic outcome. In addition, the emerging evidence points to the implications of PXR in regulating apoptotic and antiapoptotic as well as growth factor signaling that promote tumor proliferation and metastasis. In this review, we highlight the recent progress made in understanding the role of PXR in cancer, discuss the future directions to further understand the mechanistic role of PXR in cancer, and conclude with the need to identify novel selective PXR modulators. PMID- 22939997 TI - SPARC and DNA methylation: possible diagnostic and therapeutic implications in gastrointestinal cancers. AB - DNA methylation is a major contributor to epigenetic alterations and as such is a potential biomarker and therapeutic target in gastrointestinal malignancies. DNA methylation is commonly observed in several Gastrointestinal (GI) malignancies including pancreatic and colorectal cancer. Methylation results in decreased expression of tumor suppressor genes. Secreted protein acidic and rich in cysteine (SPARC) is a tumor suppressor gene that can be functionally inactivated through methylation. SPARC is commonly dysregulated in GI malignancies. Inhibition of DNA methylation can reverse the silencing of SPARC. In the present review, we will discuss recent advances in our understanding of the features of DNA methylation that pertain to SPARC, focusing on their functional and clinical relevance in GI carcinogenesis. PMID- 22939996 TI - A perspective on the role of estrogen in hormone-induced prostate carcinogenesis. AB - Androgens are thought to cause prostate cancer, but the precise mechanisms by which they do so are unclear. Data, mostly from animal studies, suggest that for androgens to cause prostate cancer they must be aromatized to estrogen and act in concert with these estrogen metabolites. Androgen-receptor mediated activity of androgens and estrogen receptor-mediated effects of estrogen metabolites are likely to be necessary, but estrogen genotoxicity appears to be a probable critical factor as well. Only when all these mechanisms are active, may prostate carcinogenesis result. Convincing proof-of-concept studies are needed to definitively test this concept which, if proven, may lead to clinically feasible chemoprevention approaches interfering with these mechanisms. PMID- 22939998 TI - Allopregnanolone regulates neurogenesis and depressive/anxiety-like behaviour in a social isolation rodent model of chronic stress. AB - Chronic stress has been implicated as a causal factor in depression and anxiety, and is associated with neuroendocrine dysfunction and impaired hippocampal neurogenesis. The neurosteroid allopregnanolone (3alpha,5alpha-THP; ALLO) has been shown to be reduced in depressed patients. ALLO is "stress responsive" and plays a major role in regulating hypothalamic-pituitary-adrenal (HPA) axis function. We propose that reduced ALLO levels following chronic stress leads to HPA hyperactivity due to diminished ALLO regulation. This will result in increased glucocorticoid levels and reduced BDNF expression, leading to impaired hippocampal neurogenesis and the precipitation of depression/anxiety. To investigate this, chronic stress was induced using the social isolation model and depressive/anxiety-like behaviour assessed using the novelty-suppressed feeding test and forced-swim test. The social isolation model was associated with a significant reduction in endogenous ALLO levels and a depressive/anxiety-like behavioural profile. When exogenous ALLO was administered from the onset of isolation it prevented the development of depressive/anxiety-like behaviours and impairment of hippocampal neurogenesis. When treatment was initiated following six weeks of social isolation, behavioural profile was restored and deficits in BDNF and neurogenesis were not observed. Supporting our hypothesis we observed that socially isolated animals exhibited reduced HPA responsiveness, which was either prevented or normalised with ALLO treatment. Combined, these results indicate that administration of exogenous ALLO either during or following a period of chronic stress can prevent or normalise HPA dysfunction and impairment of hippocampal neurogenesis respectively, precluding the establishment of depressive/anxiety-like behaviours. ALLO may therefore provide a novel therapeutic target for the treatment of depression/anxiety. PMID- 22939999 TI - Maternal deprivation effects on brain plasticity and recognition memory in adolescent male and female rats. AB - Data from both human and animal studies suggest that exposure to stressful life events at neonatal stages may increase the risk of psychopathology at adulthood. In particular, early maternal deprivation, 24 h at postnatal day (pnd) 9, has been associated with persistent neurobehavioural changes similar to those present in developmental psychopathologies such as depression and schizophrenic-related disorders. Most neuropsychiatric disorders first appear during adolescence, however, the effects of MD on adolescent animals' brain and behaviour have been scarcely explored. In the present study, we aimed to investigate the emotional and cognitive consequences of MD in adolescent male and female rats, as well as possible underlying neurobiological mechanisms within frontal cortex and hippocampus. Animals were exposed to a battery of behavioural tasks, from pnd 35 to 42, to evaluate cognitive [spontaneous alternation task (SAT) and novel object test (NOT)] and anxiety-related responses [elevated plus maze (EPM)] during adolescence. Changes in neuronal and glial cells, alterations in synaptic plasticity as well as modifications in cannabinoid receptor expression were investigated in a parallel group of control and adolescent (pnd 40) male and female animals. Notably, MD induced a significant impairment in recognition memory exclusively among females. A generalized decrease in NeuN expression was found in MD animals, together with an increase in hippocampal glial fibrillar acidic protein (GFAP) expression exclusively among MD adolescent males. In addition, MD induced in the frontal cortex and hippocampus of male and female adolescent rats a significant reduction in brain derived neurotrophic factor (BDNF) and postsynaptic density (PSD95) levels, together with a decrease in synaptophysin in frontal cortex and neural cell adhesion molecule (NCAM) in hippocampus. MD induced, in animals of both sexes, a significant reduction in CB1R expression, but an increase in CB2R that was statistically significant only for the frontal cortex. Taken together, these results indicate that adolescent females are more vulnerable than males to the cognitive deficits derived from MD despite the changes in neural cells, cannabinoid receptors, as well as the reduction in neural plasticity seem to be similar in both sexes. Further investigation is needed to understand the neurobiological mechanisms underlying the sexual dimorphisms associated to the MD effects, and thus, for a better understanding of the specific sex-dependent vulnerabilities to early life stress. This article is part of the Special Issue entitled 'Neurodevelopmental Disorders'. PMID- 22940001 TI - Rett syndrome treatment in mouse models: searching for effective targets and strategies. AB - Rett syndrome (RTT) is a pervasive developmental disorder, primarily affecting girls with a prevalence of 1 in every 10,000 births; it represents the second most common cause of intellectual disability in females. Mutations in the gene encoding methyl-CpG-binding protein 2 (MECP2) have been identified as clear etiological factors in more than 90% of classical RTT cases. Whereas the mechanisms leading to the severe, progressive and specific neurological dysfunctions when this gene is mutated still remain to be elucidated, a series of different mouse models have been generated, bearing different Mecp2 mutation. Neurobehavioural analysis in these mouse lines have been carried out and phenotyping analysis can be now utilised to preclinically evaluate the effects of potential RTT treatments. This review summarizes the different results achieved in this research field taking into account different key targets identified to ameliorate RTT phenotype in mouse models, including those not directly downstream of MeCP2 and those limited to the early phases of postnatal development. This article is part of the Special Issue entitled 'Neurodevelopmental Disorders'. PMID- 22940000 TI - Adenosine and autism: a spectrum of opportunities. AB - In rodents, insufficient adenosine produces behavioral and physiological symptoms consistent with several comorbidities of autism. In rodents and humans, stimuli postulated to increase adenosine can ameliorate these comorbidities. Because adenosine is a broad homeostatic regulator of cell function and nervous system activity, increasing adenosine's influence might be a new therapeutic target for autism with multiple beneficial effects. This article is part of the Special Issue entitled 'Neurodevelopmental Disorders'. PMID- 22940002 TI - Toxicity of depleted uranium on isolated rat kidney mitochondria. AB - BACKGROUND: Kidney is known as the most sensitive target organ for depleted uranium (DU) toxicity in comparison to other organs. Although the oxidative stress and mitochondrial damage induced by DU has been well investigated, the precise mechanism of DU-induced nephrotoxicity has not been thoroughly recognized yet. METHODS: Kidney mitochondria were obtained using differential centrifugation from Wistar rats and mitochondrial toxicity endpoints were then determined in both in vivo and in vitro uranyl acetate (UA) exposure cases. RESULTS: Single injection of UA (0, 0.5, 1 and 2mg/kg, i.p.) caused a significant increase in blood urea nitrogen and creatinine levels. Isolated mitochondria from the UA treated rat kidney showed a marked elevation in oxidative stress accompanied by mitochondrial membrane potential (MMP) collapse as compared to control group. Incubation of isolated kidney mitochondria with UA (50, 100 and 200MUM) manifested that UA can disrupt the electron transfer chain at complex II and III that leads to induction of reactive oxygen species (ROS) formation, lipid peroxidation, and glutathione oxidation. Disturbances in oxidative phosphorylation were also demonstrated through decreased ATP concentration and ATP/ADP ratio in UA-treated mitochondria. In addition, UA induced a significant damage in mitochondrial outer membrane. Moreover, MMP collapse, mitochondrial swelling and cytochrome c release were observed following the UA treatment in isolated mitochondria. GENERAL SIGNIFICANCE: Both our in vivo and in vitro results showed that UA-induced nephrotoxicity is linked to the impairment of electron transfer chain especially at complex II and III which leads to subsequent oxidative stress. PMID- 22940003 TI - Crystal structure of a conformation-dependent rabbit IgG Fab specific for amyloid prefibrillar oligomers. AB - BACKGROUND: Although rabbit antibodies are widely used in research, no structures of rabbit antigen-binding fragments (Fab) have been reported. M204 is a rabbit monoclonal antibody that recognizes a generic epitope that is common to prefibrillar amyloid oligomers formed from many different amyloidogenic sequences. Amyloid oligomers are widely suspected to be a primary causative agent of pathogenesis in several age-related neurodegenerative diseases, such as Alzheimer's disease. The detailed structure of these amyloid oligomers is not known nor is the mechanism for the recognition of the generic epitope by conformation-dependent monoclonal antibodies. METHOD: As a first approach to understanding the mechanism of conformation-dependent antibody recognition, we have crystallized the Fab of M204. RESULTS: We have determined the structure of the Fab of M204 at 1.54A resolution. The crystal structure reveals details of the M204 antigen combining site and features unique to rabbit Fabs such as an interdomain disulfide bond on its light chain. GENERAL SIGNIFICANCE: Based on the structural features of the antigen-combining site of the M204, we rule out a "steric zipper" formation, as found in numerous amyloid fibril structures, as a mechanism of antibody-antigen recognition. The details of the first rabbit immunoglobulin Fab structure might also be useful for exploiting the potential of rabbit monoclonal antibodies for the development of humanized rabbit antibodies as therapeutic agents. PMID- 22940004 TI - Detection of viral and bacterial respiratory pathogens in patients with cystic fibrosis. AB - The presence of viral respiratory infections is associated closely with exacerbations in patients with cystic fibrosis. Viral and bacterial multiplex PCRs were developed and applied to nasal swab samples from children with cystic fibrosis. This showed a large number of individuals with cystic fibrosis were infected with rhinoviruses, and more were infected with viral than bacterial pathogens. All individuals with parainfluenza 3 virus had clinical exacerbations of their cystic fibrosis, and although 3/4 of these children were co-infected with HRV. The findings do not suggest a significant association for any other virus or bacteria with exacerbation. There is clear evidence some viral infections are associated with cystic fibrosis that dual infection is more likely to produce symptoms, and mechanisms of viral-induced exacerbation should be elucidated. PMID- 22940005 TI - Value of platelet pharmacogenetics in common clinical practice of patients with ST-segment elevation myocardial infarction. AB - BACKGROUND: Antiplatelet drug resistance is a well-known problem, causing recurrent cardiovascular events. Multiple genetic polymorphisms have been related to antiplatelet resistance by several large trials, however data from common clinical practice is limited. We examined the influence of previously described polymorphisms, related to aspirin and clopidogrel resistance, on treatment outcome in a real life unselected population of patients presenting with ST segment elevation myocardial infarction (STEMI) treated with percutaneous coronary intervention. METHODS AND RESULTS: This cohort study consisted of 1327 patients with STEMI. Patients were treated according to a standardized guideline based protocol. Nine polymorphisms, COX1 (-842A>G), P2Y1 (893C>T), GPIa (807C>T), GPIIIa (PlA1/A2), CYP2C19 (*2, *3 and *17), ABCB1 (3435T>C) and PON1 (576A>G), were genotyped. During 1 year of follow up the primary endpoint, a composite of cardiac death or recurrent myocardial infarction, was reached in 86 patients. The COX1 and CYP2C19*2 polymorphisms were associated with the primary endpoint, HR 2.55 (95% CI 1.48-4.40), P=0.001 and HR 2.03 (1.34-3.09) P=0.001, respectively. The combined analysis demonstrated a 2.5-fold increased risk for individuals with >= 2 risk alleles, P=6.9 * 10(-9). The association of COX1 was driven by mortality related events whereas that of CYP2C19*2 was mainly attributed to myocardial infarction and stent thrombosis. CONCLUSION: In this unselected, real life population of STEMI patient on dual-antiplatelet therapy, the polymorphisms COX1 -842A>G and CYP2C19*2 were determinants of thrombotic complications during follow-up. We show that in a clinical setting, testing for these polymorphisms could be of value in the identification of STEMI patients at risk for recurrent cardiovascular events. PMID- 22940006 TI - Comprehensive analysis of methods used for the evaluation of compounds against Mycobacterium tuberculosis. AB - In drug development, there are typically a series of preclinical studies that must be completed with new compounds or regimens before use in humans. A sequence of in vitro assays followed by in vivo testing in validated animal models to assess the activity against Mycobacterium tuberculosis, pharmacology and toxicity is generally used for advancing compounds against tuberculosis in a preclinical stage. A plethora of different assay systems and conditions are used to study the effect of drug candidates on the growth of M. tuberculosis, making it difficult to compare data from one laboratory to another. The Bill and Melinda Gates Foundation recognized the scientific gap to delineate the spectrum of variables in experimental protocols, identify which of these are biologically significant, and converge towards a rationally derived standard set of optimized assays for evaluating compounds. The goals of this document are to recommend protocols and hence accelerate the process of TB drug discovery and testing. Data gathered from preclinical in vitro and in vivo assays during personal visits to laboratories and an electronic survey of methodologies sent to investigators is reported. Comments, opinions, experiences as well as final recommendations from those currently engaged in such preclinical studies for TB drug testing are being presented. Certain in vitro assays and mouse efficacy models were re-evaluated in the laboratory as head-to-head experiments and a summary is provided on the results obtained. It is our hope that this information will be a valuable resource for investigators in the field to move forward in an efficient way and that key variables of assays are included to ensure accuracy of results which can then be used for designing human clinical trials. This document then concludes with remaining questions and critical gaps that are in need of further validation and experimentation. PMID- 22940008 TI - Climate change impact assessment on Veneto and Friuli Plain groundwater. Part I: an integrated modeling approach for hazard scenario construction. AB - Climate change impacts on water resources, particularly groundwater, is a highly debated topic worldwide, triggering international attention and interest from both researchers and policy makers due to its relevant link with European water policy directives (e.g. 2000/60/EC and 2007/118/EC) and related environmental objectives. The understanding of long-term impacts of climate variability and change is therefore a key challenge in order to address effective protection measures and to implement sustainable management of water resources. This paper presents the modeling approach adopted within the Life+ project TRUST (Tool for Regional-scale assessment of groUndwater Storage improvement in adaptation to climaTe change) in order to provide climate change hazard scenarios for the shallow groundwater of high Veneto and Friuli Plain, Northern Italy. Given the aim to evaluate potential impacts on water quantity and quality (e.g. groundwater level variation, decrease of water availability for irrigation, variations of nitrate infiltration processes), the modeling approach integrated an ensemble of climate, hydrologic and hydrogeologic models running from the global to the regional scale. Global and regional climate models and downscaling techniques were used to make climate simulations for the reference period 1961-1990 and the projection period 2010-2100. The simulation of the recent climate was performed using observed radiative forcings, whereas the projections have been done prescribing the radiative forcings according to the IPCC A1B emission scenario. The climate simulations and the downscaling, then, provided the precipitation, temperatures and evapo-transpiration fields used for the impact analysis. Based on downscaled climate projections, 3 reference scenarios for the period 2071-2100 (i.e. the driest, the wettest and the mild year) were selected and used to run a regional geomorphoclimatic and hydrogeological model. The final output of the model ensemble produced information about the potential variations of the water balance components (e.g. river discharge, groundwater level and volume) due to climate change. Such projections were used to develop potential hazard scenarios for the case study area, to be further applied within climate change risk assessment studies for groundwater resources and associated ecosystems. This paper describes the models' chain and the methodological approach adopted in the TRUST project and analyzes the hazard scenarios produced in order to investigate climate change risks for the case study area. PMID- 22940009 TI - Differences in genomic architecture between two distinct geographical strains of the blood fluke Schistosoma japonicum reveal potential phenotype basis. AB - The Chinese (SjC) and Philippine (SjP) strains of the blood fluke Schistosoma japonicum have been shown to present clearly different phenotypes in fecundity, pathology, drug sensitivity and immunology. We used microarray based comparative genomic hybridisation (aCGH) to investigate structural differences in the genomes of the two strains and identified seven distinct regions of the S. japonicum genome that present differential aCGH representing either deletion or duplication regions in SjP. Within these regions, genes predicted to be associated with the recognised phenotypic differences were identified and that may provide new insights into the biology and evolution of the two strains, with implications for the epidemiology and control of schistosomiasis japonica in China and the Philippines. PMID- 22940010 TI - Impact of subclinical hypothyroidism on the development of non-alcoholic fatty liver disease: a prospective case-control study. PMID- 22940011 TI - Understanding recovery: changes in the relationships of the International Classification of Functioning (ICF) components over time. AB - The International Classification of Functioning, Disability and Health framework describes human functioning through body structure and function, activity and participation in the context of a person's social and physical environment. This work tested the temporal relationships of these components. Our hypotheses were: 1) there would be associations among physical impairment, activity limitations and participation restrictions within time; 2) prior status of a component would be associated with future status; 3) prior status of one component would influence status of a second component (e.g. prior activity limitations would be associated with current participation restrictions); and, 4) the magnitude of the within time relationships of the components would vary over time. Participants from Canada with primary hip or knee joint replacement (n = 931), an intervention with predictable improvement in pain and disability, completed standardized outcome measures pre-surgery and five times in the first year post-surgery. These included physical impairment (pain), activity limitations and participation restrictions. ICF component relationships were evaluated cross-sectionally and longitudinally using path analysis adjusting for age, sex, BMI, hip vs. knee, low back pain and mood. All component scores improved significantly over time. The path coefficients supported the hypotheses in that both within and across time, physical impairment was associated with activity limitation and activity limitation was associated with participation restriction; prior status and change in a component were associated with current status in another component; and, the magnitude of the path coefficients varied over time with stronger associations among components to three months post surgery than later in recovery with the exception of the association between impairment and participation restrictions which was of similar magnitude at all times. This work enhances understanding of the complexities of the ICF component relationships in evaluating disability over time. Further longitudinal studies including evaluation of contextual factors are required. PMID- 22940012 TI - Conceptualising the prevention of adverse obstetric outcomes among immigrants using the 'three delays' framework in a high-income context. AB - Women from high-mortality settings in sub-Saharan Africa can remain at risk for adverse maternal outcomes even after migrating to low-mortality settings. To conceptualise underlying socio-cultural factors, we assume a 'maternal migration effect' as pre-migration influences on pregnant women's post-migration care seeking and consistent utilisation of available care. We apply the 'three delays' framework, developed for low-income African contexts, to a high-income western scenario, and aim to identify delay-causing influences on the pathway to optimal facility treatment. We also compare factors influencing the expectations of women and maternal health providers during care encounters. In 2005-2006, we interviewed 54 immigrant African women and 62 maternal providers in greater London, United Kingdom. Participants were recruited by snowball and purposive sampling. We used a hermeneutic, naturalistic study design to create a qualitative proxy for medical anthropology. Data were triangulated to the framework and to the national health system maternity care guidelines. This maintained the original three phases of (1) care-seeking, (2) facility accessibility, and (3) receipt of optimal care, but modified the framework for a migration context. Delays to reciprocal care encounters in Phase 3 result from Phase 1 factors of 'broken trust, which can be mutually held between women and providers. An additional factor is women's 'negative responses to future care', which include rationalisations made during non-emergency situations about future late-booking, low-adherence or refusal of treatment. The greatest potential for delay was found during the care encounter, suggesting that perceived Phase 1 factors have stronger influence on Phase 3 than in the original framework. Phase 2 'language discordance' can lead to a 'reliance on interpreter service', which can cause delays in Phase 3, when 'reciprocal incongruent language ability' is worsened by suboptimal interpreter systems. 'Non-reciprocating care conceptualisations', 'limited system-level care guidelines', and 'low staff levels' can additionally delay timely care in Phase 3. PMID- 22940013 TI - Malaria and helminthic co-infection among HIV-positive pregnant women: prevalence and effects of antiretroviral therapy. AB - The impact of malaria on anemia and the interplay with helminths underline the importance of addressing the interactions between HIV/AIDS, malaria and intestinal helminth infections in pregnancy. The aim of this study was to determine the prevalence of malaria-helminth dual infections among HIV positive pregnant mothers after 12 months of ART. A cross sectional study was conducted on intestinal helminths and malaria dual infections among HIV-positive pregnant women attending antenatal health centers in Rwanda. Stool and malaria blood slide examinations were performed on 328 women residing in rural (n=166) and peri-urban locations (n=162). BMI, CD4 cell count, hemoglobin levels, type of ART and viral load of participants were assessed. Within the study group, 38% of individuals harbored helminths, 21% had malaria and 10% were infected with both. The most prevalent helminth species were Ascaris lumbricoides (20.7%), followed by Trichuris trichiura (9.2%), and Ancylostoma duodenale and Necator americanus (1.2%). Helminth infections were characterized by low hemoglobin and CD4 counts. Subjects treated with a d4T, 3TC, NVP regimen had a reduced risk of T. trichiura infection (OR, 0.27; 95% CIs, 0.10-0.76; p<0.05) and malaria-helminth dual infection (OR, 0.29; 95% CI, 0.11-0.75; p<0.05) compared to those receiving AZT, 3TC, NVP. This study shows a high prevalence of malaria and helminth infection among HIV-positive pregnant women in Rwanda. The differential effect of ARTs on the risk of helminth infection is of interest and should be examined prospectively in larger patient groups. PMID- 22940014 TI - Efficacy and safety of two closely spaced doses of praziquantel against Schistosoma haematobium and S. mansoni and re-infection patterns in school-aged children in Niger. AB - The aim of this study was to assess the efficacy and safety of two closely spaced doses of praziquantel (PZQ) against Schistosoma haematobium and S. mansoni infection in school-aged children, and to characterise re-infection patterns over a 12-month period. The study was carried out in five villages in western Niger: Falmado, Seberi and Libore (single S. haematobium infection foci), and Diambala and Namarigoungou (mixed S. haematobium-S. mansoni infection foci). Parasitological examinations consisted of triplicate urine filtrations and triplicate Kato-Katz thick smears at each visit. Two 40mg/kg oral doses of PZQ were administered 3 weeks apart. Adverse events were monitored within 4h after dosing by the survey team and 24h after treatment using a questionnaire. Our final study cohort comprised 877 children who were infected with either S. haematobium, or S. mansoni, or both species concurrently and received both doses of PZQ. Follow-up visits were conducted 6 weeks, 6 months and 12 months after the first dose of PZQ. At baseline, the geometric mean (GM) infection intensity of S. haematobium ranged from 3.6 (Diambala) to 30.3eggs/10ml of urine (Falmado). The GM infection intensity of S. mansoni ranged from 86.7 (Diambala) to 151.4eggs/g of stool (Namarigoungou). Adverse events were reported by 33.0% and 1.5% of the children after the first and second doses of PZQ, respectively. We found cure rates (CRs) in S. haematobium-infected children 3 weeks after the second dose of PZQ ranging between 49.2% (Falmado) and 98.4% (Namarigoungou) and moderate-to high egg reduction rates (ERRs) (71.4-100%). Regarding S. mansoni, only moderate CRs and ERRs were found (51.7-58.8% in Diambala, 55.2-60.2% in Namarigoungou). Twelve months post-treatment, prevalence rates approached pre-treatment levels, but infection intensities remained low. In conclusion, PZQ, given in two closely spaced doses, is efficacious against S. haematobium, but the low ERR observed against S. mansoni raises concern about mounting PZQ tolerance. PMID- 22940015 TI - Immunization with excreted/secreted proteins in AS/n mice activating cellular and humoral response against Toxoplasma gondii infection. AB - This study investigated how Toxoplasma gondii excretory-secretory antigens (ESA) stimulate the humoral and cellular response in infected hosts. We evaluated IFN gamma, IL-4 TNF-alpha, and IL-10 levels as well as humoral response of ESA immunized AS/n mice. T. gondii lysate antigen (TLA), a crude antigen, was used in all experiments to evaluate the immune response. Chronic infected and naive mice were used as control groups, since the immune response is well known. The challenge experiments showed the parasitemia levels, determined by real time PCR and survival index. The naive group had early mortality and higher parasitemia than the ESA-immunized mouse group. In addition the chronic infected group had no parasitemia and mortality. Both ESA-immunized and chronic infected mice produced a similar level of IFN-gamma and TNF-alpha. ESA, also, activated cells from immunized mice to produce IL-4 and IL-10 in lower levels compared to those cells collected from chronic mice but sufficient to modulate IFN-gamma and TNF-alpha synthesis, preventing an excessive immune response that could cause extensive inflammation and host tissue damage. After 6 weeks, ESA-immunized mice had low IgM and IgG2a levels and high IgG1 levels. Purified anti-ESA IgG were able to opsonize tachyzoites (RH strain), and mice that received these parasites had lower parasitemia, and mortality was delayed 48 h, compared with the same results from those receiving parasites opsonized with IgG purified from naive mice. The protective immune response in the chronic infection was efficient in protecting the host against infection caused by other T. gondii strain and ESA participate in stimulating the host humoral and cellular responses. The immunization assays showed that ESA can elicit high IgG1, IFN-gamma and TNF-alpha production and, a lower amount of IgM, IgG2, IL-10 and IL-4, suggesting a mixed Th1/Th2 profile. PMID- 22940016 TI - Functional roles of mannose-binding protein in the adhesion, cytotoxicity and phagocytosis of Acanthamoeba castellanii. AB - Acanthamoeba castellanii is a single-celled protozoan that is widely distributed in the environment and is a well-known of causing human keratitis, a vision threatening infection. In this study, an ethyl methane sulfonate (EMS) and a selection of saccharide were applied to A. castellanii by chemical mutagenesis. To understand the functional roles of a mannose-binding protein (MBP). A. castellanii were treated with methyl-alpha-D-mannopyranoside abbreviated Man, with and without the EMS pre-treatment, and their adhesion and cytotoxicity were analyzed, using a human brain microvascular endothelial cell (HBMEC) as the target cell. Both EMS and Man mutants exhibited significantly decreased levels of MBP expression and cytotoxicity to HBMEC, but showed similar levels of binding to HBMEC, as compared with the wild type. Of interest was that the exogenous mannose inhibited amoebae (i.e., Man mutant) binding to the HBMEC by <20%. Only the mutant Man exhibited a significant decrease in bacterial uptake, as compared to the wild type, 0.020 vs 0.032 (p<0.05) and proteolytic activity. The results showed that MBP should be clearly provided as the pathogenic target candidate, to further target-based therapy, but EMS mutation should not be associated with initial adhesion and phagocytosis of A. castellanii. PMID- 22940017 TI - Plasmodium vivax: reverse transcriptase real-time PCR for gametocyte detection and quantitation in clinical samples. AB - The proportion of Plasmodium vivax-infected subjects that carry mature gametocytes, and thus are potentially infectious, remains poorly characterized in endemic settings. Here, we describe a quantitative reverse transcriptase (RT) real-time PCR (qRT-PCR) that targets transcripts of the mature gametocyte specific pvs25 gene. We found mature gametocytes in 42 of 44 (95.4%) P. vivax infections diagnosed during an ongoing cohort study in northwestern Brazil. SYBR green qRT-PCR was more sensitive than a conventional RT-PCR that targets the same gene. Molecular detection of gametocytes failed, however, when dried bloodspots were used for RNA isolation and complementary DNA synthesis. Estimating the number of pvs25 gene transcripts allowed for examining the potential infectiousness of gametocyte carriers in a quantitative way. We found that most (61.9%) gametocyte carriers were either asymptomatic or had subpatent parasitemias and would have been missed by routine malaria control strategies. However, potentially undiagnosed gametocyte carriers usually had low-density infections and contributed a small fraction (up to 4%) to the overall gametocyte burden in the community. Further studies are required to determine the relative contribution to malaria transmission of long-lasting but low-density gametocytemias in asymptomatic carriers that are left undiagnosed and untreated. PMID- 22940019 TI - Affective taste responses in the presence of reward- and aversion-conditioned stimuli and their relationship to psychomotor sensitization and place conditioning. AB - Anecdotal experience and empirical evidence suggest animals approach or avoid conditioned stimuli based on the ability of those stimuli to elicit affective responses or interfere with affective assessments of ongoing stimuli. Thus, this study investigated the relationship between the ability of drug-conditioned environments to induce conditioned place preference or aversion and their ability to influence palatability responses to sucrose and quinine in those same environments. Mice were conditioned to methamphetamine (2mg/kg), morphine (10mg/kg) or naloxone (10mg/kg). Following testing for the expression of place conditioning, palatability responses to sucrose and quinine in the conditioned contexts were assessed. In general, virtually no effects of exposure to drug conditioned contexts on overall positive or aversive palatability responses were observed. However, in naloxone-conditioned mice, the strength of conditioned place aversion to the naloxone-paired context correlated with aversive taste reactivity responses to quinine in that context. In morphine-conditioned mice, positive reactions to sucrose in the morphine-paired context negatively correlated with positive reactions to sucrose in the vehicle-paired context. Interestingly, the rate of methamphetamine-induced behavioral sensitization during conditioning and positive taste responses to sucrose in the methamphetamine-paired context positively correlated. These studies suggest that conditioned stimuli interact with or modulate the affective experience of ongoing unconditioned stimuli such as tastants, and these may reflect behavioral processes that guide behavior optimally. PMID- 22940020 TI - Two cases of CD30+, anaplastic lymphoma kinase (ALK)-negative anaplastic large cell lymphoma with oral manifestations. AB - Anaplastic large cell lymphoma (ALCL), a subgroup of T-cell non-Hodgkin's lymphoma, is an uncommon tumor exhibiting CD30 positivity and a characteristic immunophenotypic profile. Histologically, ALCL is characterized by the proliferation of large, anaplastic lymphoid cells with eccentric horseshoe- or kidney-shaped nuclei and one or more prominent nucleoli. Rare cases have been cited in the literature of ALCL presenting primarily in the oral cavity. The purpose of this article was to present 2 instructive cases of CD30+, anaplastic lymphoma kinase-negative ALCL with oral and systemic involvement. PMID- 22940018 TI - A rodent "self-report" measure of methamphetamine craving? Rat ultrasonic vocalizations during methamphetamine self-administration, extinction, and reinstatement. AB - Rats emit ultrasonic vocalizations (USVs) in a variety of contexts, and it is increasingly clear that USVs reflect more complex information than mere positive and negative affect states. We sought to examine USVs in a common model of addiction and relapse, the self-administration/reinstatement paradigm, in order to gain insight into subjective states experienced by rats during various types of methamphetamine seeking. We measured three subtypes of "50kHz" USVs [flats, trills, and non-trill frequency modulated (FM) USVs], as well as long and short duration "22kHz" USVs, during self-administration and extinction training, and during reinstatement elicited by cues, a methamphetamine prime, cues+prime, or the pharmacological stressor yohimbine. During self-administration and extinction, rats emitted many flats and FMs, (and short duration "22kHz" USVs on day 1 of self-administration), but few trills. In contrast, methamphetamine priming injections potently enhanced FMs and trills, and trill production was correlated with the degree of methamphetamine+cue-elicited reinstatement. Cues alone yielded increases only in flat USVs during reinstatement, though a subset of rats displaying strong cue-induced reinstatement also emitted long duration, aversion-related "22kHz" USVs. Although yohimbine administration caused reinstatement, it did not induce "22kHz" USVs in methamphetamine-experienced or methamphetamine-naive rats (unlike footshock stress, which did induce long duration "22kHz" USVs). These findings demonstrate heterogeneity of rat USVs emitted during different types of methamphetamine seeking, and highlight their potential usefulness for gaining insight into the subjective states of rats in rodent models of drug addiction and relapse. PMID- 22940021 TI - An integrative approach for comparing microcirculation between normal and alveolar cleft gingiva in children scheduled for secondary bone grafting procedures. AB - OBJECTIVE: The aim of this study was to compare microcirculatory parameters in normal versus alveolar cleft gingiva in children selected for secondary bone grafting procedures. STUDY DESIGN: This study included 11 consecutive patients with complete unilateral alveolar clefts who required secondary bone grafting procedures. In a split-mouth design, noninvasive real-time simultaneous measurements among tissue oxygen saturation (StO2), hemoglobin level (rHb), and blood flow parameters were obtained from normal and alveolar cleft gingiva using spectrophotometry and laser Doppler flowmetry. Subsequent noninvasive capillary density measurements and tissue microangioarchitecture were assessed using sidestream dark-field imaging. RESULTS: There were no significant differences in StO2 and rHb between normal and alveolar cleft gingiva. Blood flow, blood flow velocity, and capillary density were significantly decreased in alveolar cleft gingiva (P < 0.05). CONCLUSIONS: Alveolar cleft reconstructions alter gingival microperfusion properties, and microvascular changes adapt to conserve peak oxygen saturation. PMID- 22940022 TI - Factors predictive of pterygoid process fractures after pterygomaxillary separation without using an osteotome in Le Fort I osteotomy. AB - OBJECTIVE: This study demonstrated pterygomaxillary disjunction patterns and elucidated factors related to unfavorable pterygomaxillary junction fractures in Le Fort I osteotomy without using an osteotome. STUDY DESIGN: Clinical and anatomical data obtained from computed tomography images (100 sides) were analyzed for their ability to predict patterns of pterygomaxillary disjunction. RESULTS: Separation of the pterygomaxillary junction was most frequently performed at the maxillary tuberosity (48.0%). Twenty-eight pterygoid plates were fractured. Male gender, increased age, thickness of the pterygomaxillary junction, and length of the maxillary tuberosity were significant risk factors for pterygoid process fractures. We also identified that a pterygomaxillary junction thickness less than 2.6 mm and a maxillary tuberosity length of more than 11.5 mm indicated a statistically significant risk of pterygoid process fractures. CONCLUSIONS: Prediction of frangible pterygoid plates by preoperative quantitative evaluation of morphometric values provides useful information for selecting safe procedures. PMID- 22940023 TI - Epidemiology of maxillofacial injury in children under 15 years of age in southern China. AB - OBJECTIVE: This retrospective study was conducted to report the epidemiology of maxillofacial injuries of children <15 years old in China. STUDY DESIGN: Data collected in this study included age, sex, etiology, date of injury, anatomic site of injury, and treatment modality. Regarding treatment, conservative technique and surgery were both used. The analyses involved were descriptive statistics and chi(2) test. RESULTS: There were 335 men and 135 women, with a gender ratio of 2.48:1. Bicycle accident was the leading cause of injury. The common sites of soft tissue injury included gingiva, chin, lip, cheek, palate/pharynx, and tongue/mouth floor. In addition, the mandible was most involved in facial skeleton injury. Conservative treatment was generally preferred for such pediatric patients. CONCLUSIONS: Boys were prone to be victims of maxillofacial trauma. Preventive measures should be applied both indoors and outdoors. Patients in the growing phase should be monitored periodically to detect and prevent early facial asymmetry or malocclusion. PMID- 22940025 TI - Role of neuronal calcium sensor-1 in the cardiovascular system. AB - Calcium (Ca(2+)) is an important intracellular messenger, regulating myocyte contraction via excitation-contraction (EC) coupling and gene transcription underlying hypertrophy in the heart. Although the mechanisms of EC coupling in the immature heart are believed to be different from those in the adult heart because of the structural immaturity of the sarcoplasmic reticulum in the young heart, the details of these mechanisms are not completely understood. Neuronal Ca(2+) sensor-1 (NCS-1) is an EF-hand Ca(2+)-binding protein that is highly expressed in young hearts; however, little is known about its cardiac functions. In this review, we summarize our recent findings indicating that NCS-1 acts as a novel regulator enhancing Ca(2+) signals in the heart and hence promoting contraction in the immature heart and hypertrophy in the adult heart. Possible signal transduction pathways are also discussed. PMID- 22940024 TI - Translational findings from cardiovascular stem cell research. AB - The possibility of using stem cells to regenerate damaged myocardium has been actively investigated since the late 1990s. Consistent with the traditional view that the heart is a "postmitotic" organ that possesses minimal capacity for self repair, much of the preclinical and clinical work has focused exclusively on introducing stem cells into the heart, with the hope of differentiation of these cells into functioning cardiomyocytes. This approach is ongoing and retains promise but to date has yielded inconsistent successes. More recently, it has become widely appreciated that the heart possesses endogenous repair mechanisms that, if adequately stimulated, might regenerate damaged cardiac tissue from in situ cardiac stem cells. Accordingly, much recent work has focused on engaging and enhancing endogenous cardiac repair mechanisms. This article reviews the literature on stem cell-based myocardial regeneration, placing emphasis on the mutually enriching interaction between basic and clinical research. PMID- 22940026 TI - Resistance to artemisinin-based combination therapy. PMID- 22940028 TI - Liv.52 up-regulates cellular antioxidants and increase glucose uptake to circumvent oleic acid induced hepatic steatosis in HepG2 cells. AB - HepG2 cells were rendered steatotic by supplementing 2.0mM oleic acid (OA) in the culture media for 24h. OA induced hepatic steatosis in HepG2 cells was marked by significant accumulation of lipid droplets as determined by Oil-Red-O (ORO) based colorimetric assay, increased triacylglycerol (TAG) and increased lipid peroxidation. It was also marked by increased inflammatory cytokines TNF-alpha and IL-8 with decreased enzymic and non-enzymic antioxidant molecules and decreased cell proliferation associated with insulin resistance and DNA fragmentation. Addition of Liv.52 hydro-alcoholic extract (LHAE) 50MUg/mL to the steatotic cells was effective in increasing the insulin mediated glucose uptake by 3.13 folds and increased cell proliferation by 3.81 folds with decreased TAG content (55%) and cytokines. The intracellular glutathione content was increased by 8.9 folds without substantial increase in GSSG content. LHAE decreased TNF alpha and IL-8 by 51% and 6.5% folds respectively, lipid peroxidation by 65% and inhibited DNA fragmentation by 69%. The superoxide dismutase, catalase and glutathione peroxidase activities were increased by 88%, 128% and 64% respectively. Albumin and urea content was increased while the alanine aminotransferase (ALAT) activity was significantly decreased by LHAE. Hence, LHAE effectively attenuate molecular perturbations associated with non-alcoholic fatty liver disease (NAFLD) indications in HepG2 cells. PMID- 22940027 TI - Artemisinin-resistant Plasmodium falciparum in Pursat province, western Cambodia: a parasite clearance rate study. AB - BACKGROUND: Artemisinin-resistant Plasmodium falciparum has been reported in Pailin, western Cambodia, detected as a slow parasite clearance rate in vivo. Emergence of this phenotype in western Thailand and possibly elsewhere threatens to compromise the effectiveness of all artemisinin-based combination therapies. Parasite genetics is associated with parasite clearance rate but does not account for all variation. We investigated contributions of both parasite genetics and host factors to the artemisinin-resistance phenotype in Pursat, western Cambodia. METHODS: Between June 19 and Nov 28, 2009, and June 26 and Dec 6, 2010, we enrolled patients aged 10 years or older with uncomplicated falciparum malaria, a density of asexual parasites of at least 10,000 per MUL of whole blood, no symptoms or signs of severe malaria, no other cause of febrile illness, and no chronic illness. We gave participants 4 mg/kg artesunate at 0, 24, and 48 h, 15 mg/kg mefloquine at 72 h, and 10 mg/kg mefloquine at 96 h. We assessed parasite density on thick blood films every 6 h until undetectable. The parasite clearance half-life was calculated from the parasite clearance curve. We genotyped parasites with 18 microsatellite markers and patients for haemoglobin E, alpha thalassaemia, and a mutation of G6PD, which encodes glucose-6-phosphate dehydrogenase. To account for the possible effects of acquired immunity on half life, we used three surrogates for increased likelihood of exposure to P falciparum: age, sex, and place of residence. This study is registered with ClinicalTrials.gov, number NCT00341003. FINDINGS: We assessed 3504 individuals from all six districts of Pursat province seeking treatment for malaria symptoms. We enrolled 168 patients with falciparum malaria who met inclusion criteria. The geometric mean half-life was 5.85 h (95% CI 5.54-6.18) in Pursat, similar to that reported in Pailin (p=0.109). We identified two genetically different parasite clone groups: parasite group 1 (PG1) and parasite group 2 (PG2). Non-significant increases in parasite clearance half-life were seen in patients with haemoglobin E (0.55 h; p=0.078), those of male sex (0.96 h; p=0.064), and in 2010 (0.68 h; p=0.068); PG1 was associated with a significant increase (0.79 h; p=0.033). The mean parasite heritability of half-life was 0.40 (SD 0.17). INTERPRETATION: Heritable artemisinin resistance is established in a second Cambodian province. To accurately identify parasites that are intrinsically susceptible or resistant to artemisinins, future studies should explore the effect of erythrocyte polymorphisms and specific immune responses on half-life variation. FUNDING: Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health. PMID- 22940029 TI - Pain evaluation after a non-nociceptive stimulus in preterm infants during the first 28days of life. AB - BACKGROUND: Protective mechanisms that modulate and lead to habituation to pain are immature in preterm newborn infants. AIMS: To evaluate if a routine non painful handling will be perceived as painful throughout the neonatal period in newborn infants with 28-32 weeks of gestational age. STUDY DESIGN: Prospective cohort study. SUBJECTS: 36 preterm infants without malformations evaluated for pain during a diaper change. OUTCOME MEASURES: Patients were studied at three times (5 min prior, during, and 3 min after the diaper change) during five moments (72 h, 7, 14, 21 and 28 days of life) by evaluation of heart rate, oxygen saturation and 3 validated pain assessment tools: the Neonatal Infant Pain Scale (NIPS), the Behavioral Indicators of Infant Pain (BIIP) and Premature Infant Pain Profile (PIPP). Results were analyzed by repeated measures ANOVA adjusted for gender, gestational age at birth, number of painful procedures and use of opioids. RESULTS: Patients had, at birth, mean gestational age of 30.2+/-1.4 weeks, birthweight of 1257+/-238g, with 50% males. Analysis of pain assessment tools did not show increase of pain presence or pain scores at the five sequential evaluation moments. The variation of oxygen saturation during the three study times was similar at the different post-natal ages, but heart rate variation increased significantly from 72 h until the 28th day of life. CONCLUSIONS: In preterm infants, the non-nociceptive handling does not trigger pain responses even after 28 days of neonatal care, which includes the experience of repetitive procedural pain. PMID- 22940030 TI - Loop ileostomies in colorectal cancer patients--morbidity and risk factors for nonreversal. AB - BACKGROUND: In colorectal cancer patients, loop ileostomies are used to protect an anastomosis, in salvage surgery after a complication, and as a palliative measure. The aim of this study was to identify complications to the ileostomy, time until reversal, and risk factors for nonclosure or a permanent stoma. MATERIAL AND METHODS: Consecutive patients who received a loop ileostomy with the diagnosis of colorectal cancer at index surgery in four hospitals in Region Vastra Gotaland, Sweden, from January 1, 2007 until February 28, 2010 were retrospectively studied. Demography, events during index surgery, complications related to the ileostomy and technique, and complications during closure were registered. RESULTS: A total of 262 patients received a loop ileostomy. Loop iliostomies were constructed during emergency surgery in 15% of patients. Forty three percent had complications related to the ileostomy; most common were high volume output and leakage of stomal output. Morbidity after closure was high, at 28%, and mortality was 1%. Eighty-six percent had their stoma closed, median time 178 (3-700) d. Risk factors for nonreversal were postoperative complications to index surgery and advanced cancer disease. Eleven percent received a secondary stoma, and at the end of the study 23% had a permanent stoma. CONCLUSIONS: The morbidity related to loop ileostomies and loop ileostomy closure is considerable. One in five patients will have a permanent stoma, and our conclusion is that for emergency patients with advanced disease another type of stoma should be chosen, if possible, to reduce the morbidity. PMID- 22940031 TI - Is acute appendicitis in the weather forecast? PMID- 22940032 TI - The conditioning effect of ex vivo normothermic perfusion in an experimental kidney model. AB - BACKGROUND: A short period of isolated normothermic perfusion (NP) can be used to improve the condition of the kidney after periods of warm and cold ischemic injury. However, the mechanisms underlying this beneficial effect have not been determined. MATERIALS AND METHODS: Porcine kidneys were retrieved after 10 min of warm ischemic injury and stored by either static cold storage (CS) for 24 h (control) or CS for 23 h followed by 1 h of NP at 38 degrees C with leukocyte depleted autologous blood (NP). After preservation, kidneys in both groups underwent 3 h of ex vivo reperfusion to assess the injury (n = 6). RESULTS: NP kidneys had significantly lower levels of intrarenal resistance (NP 2.28 +/- 1.1 versus control 3.86 +/- 1.2 mm Hg/mL/h; P = 0.040), maintained their acid base homeostasis (P = 0.080), and had higher levels of oxygen consumption (NP 42.6 +/- 19.5 versus control 20.8 +/- 5.7 mL/min/g; P = 0.026) and reduced tubular injury (P = 0.008) compared with kidneys in the control group during reperfusion. There were no significant differences in the levels of inflammatory cytokines (interleukin [IL]-1beta, IL-8, or tumor necrosis factor-alpha; P > 0.05) or in renal function (creatinine clearance NP 2.6 +/- 1.3 versus control 3.0 +/- 1.5 mL/min/100 g; P = 0.070). However, levels of IL-6 were significantly raised in the NP group after reperfusion (P = 0.016). Levels of heat shock protein 70 were upregulated after 1 h of NP and expression increased during reperfusion to a significantly higher level than in the control group (P = 0.045). CONCLUSION: Kidneys undergoing a short period of NP had improved metabolic function and less tubular injury compared with static cold-stored kidneys. The increased expression of heat shock protein 70 and IL-6 suggests that NP may upregulate mechanisms that condition the kidney. PMID- 22940033 TI - MicroRNA expression following activated protein C treatment during septic shock. AB - BACKGROUND: Sepsis induces systemic stress by augmenting inflammatory and procoagulant responses, resulting in microvascular dysfunction and end organ failure, events modulated by the protein C pathway. MicroRNAs (miRNAs) are small noncoding RNAs involved in post-transcriptional regulation of genes; yet, their role in sepsis is poorly defined. We hypothesized that activated protein C (aPC) selectively alters specific miRNA expression implicated in protection of hepatic function during septic shock. METHODS: Male Sprague-Dawley rats underwent sham or cecal ligation and puncture surgery; 24 h later, we randomized them to aPC (1 mg/kg) or vehicle (0.9% [w/v] saline) treatment via an indwelling venous catheter (12-h intervals for 24 h). We performed gene array and quantitative reverse transcriptase-polymerase chain reaction analysis on hepatic RNA to determine miRNA expression and determined predicted mRNA targets using a bioinformatics approach. We confirmed beneficial effects of aPC treatment in the cecal ligation and puncture model of sepsis by survival and blood chemistries, and histologically. RESULTS: Of 351 rat miRNAs examined, 17 were highly expressed during sepsis and restored to basal levels after aPC treatment. We confirmed expression of select miRNAs (miR-182, -199a-5p, -203, -211, -222, and -29b) using quantitative reverse transcriptase-polymerase chain reaction. In silico analysis identified nine miRNAs significantly regulating target genes of the focal adhesion pathway. CONCLUSIONS: These data suggest that aPC treatment coordinates beneficial cytoprotective effects during sepsis by modulating miRNA expression. Whereas translational effects remain to be fully elucidated in a clinical setting, we demonstrate here the potential experimental and computational benefits of using of microRNA analysis in sepsis. PMID- 22940034 TI - Femoral and carotid intima media thickness--two different measurements in two different arteries. PMID- 22940035 TI - Prevalence and clinical relevance of Th17 cells in patients with gastric cancer. AB - BACKGROUND: Th17 cells have recently been identified as a distinct T helper (Th) lineage in a cancer animal model and in human cancers. Their specific role in tumor immunity is unclear. We, therefore, sought to evaluate the role of Th17 cells in gastric cancer. METHODS: The prevalence of Th1, Th2, Treg, and Th17 cells in both peripheral blood mononuclear cells (PBMC) and gastric tissue was evaluated by multicolor flow cytometry. The concentration of interleukin (IL)-17 in sera was quantitated by enzyme-linked immunosorbent assay. RESULTS: We observed a clear difference in the prevalence of Th17 cells in PBMC (0.34 +/- 0.24%) versus gastric cancer tissues (19.4 +/- 12.1) (P = 0.0002). Subset specific phenotypic analysis of CD4+ T cells in both PBMC and gastric cancer tissue showed that Th1 and Treg cells predominate in PBMC, whereas Th17 cells are the most abundant CD4+ T cell subset in cancerous tissue. The concentrations of IL-17, a hallmark of Th17, in gastric cancer patients and normal controls were 0.6 +/- 0.67 and 0.16 +/- 0.19 pg/mL (P = 0.0032). Five-year survival rates of patients with high IL-17 and low IL-17 concentration were 47.1% and 83.9% (P = 0.0075). Multivariate analysis indicated that IL-17 concentration was an independent prognostic indicator, as well as lymph node metastasis. CONCLUSIONS: There was a significant skewing toward a Th17 phenotype in gastric cancer tissue. IL-17 seems to play an important role in the progression of gastric cancer. PMID- 22940036 TI - Cardiotrophin-1, an antiinflammatory cytokine; is there a therapeutic role in orthotopic liver transplantation? PMID- 22940037 TI - College student adoption of non-pharmaceutical interventions during the 2009 H1N1 influenza pandemic: a study of two Texas universities in Fall 2009. AB - OBJECTIVE: College students were at high risk for contracting the 2009 H1N1 virus. Many universities implemented campaigns to encourage use of non pharmaceutical interventions (NPIs) to reduce the spread of the virus. The purpose of this study was to determine factors related to student adoption of NPIs. METHODS: Online surveys were conducted at two universities prior to the availability of the H1N1 vaccine. In total, 909 students participated. RESULTS: More than 80% of students adopted at least one action to reduce the likelihood of contracting the flu. Perception of the public health threat was associated with use of each of the NPIs. Perceived susceptibility, previous seasonal flu vaccination, and symptom knowledge were associated with four of the five NPIs. CONCLUSION: Increasing college student understanding of the threat posed by a pandemic, as well as their susceptibility to that threat, could encourage the use of NPIs prior to availability of a vaccine. PMID- 22940038 TI - Physical activity patterns in Mozambique: urban/rural differences during epidemiological transition. AB - OBJECTIVE: To assess the socio-demographic determinants of physical activity, by intensity and domain, across urban and rural areas in Mozambican adults. METHOD: A national representative sample (n=3323) of subjects aged 25-64 years was evaluated in 2005 following the World Health Organization (WHO) Stepwise Approach to Chronic Disease Risk Factor Surveillance (STEPS), which includes the Global Physical Activity Questionnaire. We computed prevalences, and age- and education adjusted prevalence ratios (PR), with 95% confidence intervals (95%CI). RESULTS: Most of the Mozambicans reported a high physical activity level, according to the WHO criteria (urban women: 83.2%, 95%CI 77.4, 89.0; rural women: 93.2%, 95%CI 89.0, 97.3; urban men: 78.9%, 95%CI 74.7, 83.1; rural men: 91.6%, 95%CI 85.5, 97.6). The prevalences of <75 min/week of vigorous activities were higher in urban settings (women: PR=2.21; men: PR=2.28) and increased with education, regardless of place of residence (PR ranging between 1.75 and 5.72 for more vs. less educated subjects). Work activities were the most important contributor to the overall physical activity, followed by transport. CONCLUSION: Most of the Mozambicans reported to be physically active. Vigorous activities were less common in urban areas and among the more educated subjects, depicting an ongoing shift to more sedentary behaviours in this setting. PMID- 22940039 TI - In vitro cell migration and invasion assays. AB - Determining the migratory and invasive capacity of tumor and stromal cells and clarifying the underlying mechanisms is most relevant for novel strategies in cancer diagnosis, prognosis, drug development and treatment. Here we shortly summarize the different modes of cell travelling and review in vitro methods, which can be used to evaluate migration and invasion. We provide a concise summary of established migration/invasion assays described in the literature, list advantages, limitations and drawbacks, give a tabular overview for convenience and depict the basic principles of the assays graphically. In many cases particular research problems and specific cell types do not leave a choice for a broad variety of usable assays. However, for most standard applications using adherent cells, based on our experience we suggest to use exclusion zone assays to evaluate migration/invasion. We substantiate our choice by demonstrating that the advantages outbalance the drawbacks e.g. the simple setup, the easy readout, the kinetic analysis, the evaluation of cell morphology and the feasibility to perform the assay with standard laboratory equipment. Finally, innovative 3D migration and invasion models including heterotypic cell interactions are discussed. These methods recapitulate the in vivo situation most closely. Results obtained with these assays have already shed new light on cancer cell spreading and potentially will uncover unknown mechanisms. PMID- 22940040 TI - Toxicologically important trace elements and organic compounds investigated in size-fractionated urban particulate matter collected near the Prague highway. AB - Urban particulate matter was collected in the most exposed area of Prague, near a busy highway, in order to provide petrographic and chemical characterization useful for health impact assessment in that locality or other applications. Samples were collected from filters of the air conditioning system in two years, 2009 and 2010, and sieved into four grain-size fractions: 0.507-0.119 mm, 0.119 0.063 mm, <0.063 mm and sub-fraction <0.025 mm. Methods of destructive and non destructive analyses were used for the determination of total analyte (As, Cd, Cr, Mn, Ni, Pb, Zn) contents. Labile forms of some toxicologically important analytes were tested in 2 M HNO(3) extracted solutions. A composition of inorganic and carbonaceous particles of natural and anthropogenic origin and their morphology were studied by optical and electron microscopy. Organic solvent extracts of the samples were analyzed using gas chromatography to compare the organic compound distribution in fractions. Only slight differences between 2009 and 2010 years are visible. The relatively high extractable part of most investigated elements confirms mobility and potential availability to organisms. The changes can be recognized in the petrographic and organic composition in samples from both years, which were likely the result of various inputs of source materials. Specific organic marker compounds indicate contribution from fossil fuels, plant materials and bacteria. PMID- 22940041 TI - The role of microbial adaptation and biodegradable dissolved organic carbon on the attenuation of trace organic chemicals during groundwater recharge. AB - It is widely recognized that efficient biological attenuation of bulk organic matter and trace organic chemicals (TOrC) can occur in managed aquifer recharge (MAR) systems receiving reclaimed water. The heterotrophic microbial activity in these subsurface systems is a function of the availability of biodegradable dissolved organic carbon (BDOC) present in reclaimed water. This study examined the influence of environmental factors, such as BDOC-rich (>1.6 mg/L) and BDOC starving (<1mg/L) conditions and microbial adaptation, on the attenuation of TOrC, including clofibric acid, dichlorprop, gemfibrozil, ibuprofen, ketoprofen, mecoprop, and naproxen, within soil-columns mimicking groundwater recharge. Under conditions that were characterized by a lack of BDOC and a biocommunity that was not yet adapted to these conditions, attenuation of biodegradable TOrC was less than 15%. After a three-month adaptation period, biotransformation increased to more than 80% for the biodegradable TOrC. This suggests that adaptation likely initiates enzyme expressions that eventually results in TOrC transformations even under seemingly less favorable conditions (i.e., lack of biodegradable carbon). For both non-adapted (stressed) and adapted conditions in the presence of higher concentrations of BDOC and travel times of 7 days, the degree of biotransformation was variable across compounds but generally exceeded 25%. This suggests that BDOC above a minimum level (>1.6 mg/L) can provide favorable microbial conditions resulting in TOrC removal, even for non-adapted systems. However, it is noteworthy that adapted MAR systems that were fed with low BDOC levels performed similarly or better with respect to TOrC biotransformation than systems that received BDOC levels above 1.6 mg/L. These findings are important for field-scale applications. They suggest that MAR facilities that are microbiologically active and are fed with highly treated water with effluent concentrations of less than 1 mg/L (i.e., nanofiltration permeate) can still attenuate biodegradable TOrC. PMID- 22940042 TI - An accurate retrieval of leaf water content from mid to thermal infrared spectra using continuous wavelet analysis. AB - Leaf water content determines plant health, vitality, photosynthetic efficiency and is an important indicator of drought assessment. The retrieval of leaf water content from the visible to shortwave infrared spectra is well known. Here for the first time, we estimated leaf water content from the mid to thermal infrared (2.5-14.0 MUm) spectra, based on continuous wavelet analysis. The dataset comprised 394 spectra from nine plant species, with different water contents achieved through progressive drying. To identify the spectral feature most sensitive to the variations in leaf water content, first the Directional Hemispherical Reflectance (DHR) spectra were transformed into a wavelet power scalogram, and then linear relations were established between the wavelet power scalogram and leaf water content. The six individual wavelet features identified in the mid infrared yielded high correlations with leaf water content (R(2)=0.86 maximum, 0.83 minimum), as well as low RMSE (minimum 8.56%, maximum 9.27%). The combination of four wavelet features produced the most accurate model (R(2)=0.88, RMSE=8.00%). The models were consistent in terms of accuracy estimation for both calibration and validation datasets, indicating that leaf water content can be accurately retrieved from the mid to thermal infrared domain of the electromagnetic radiation. PMID- 22940043 TI - Selective serotonin re-uptake inhibitors (SSRIs) in the aquatic environment: an ecopharmacovigilance approach. AB - Selective serotonin re-uptake inhibitors (SSRIs) antidepressants are among the most prescribed pharmaceutical active substances throughout the world. The occurrence of these widely used compounds in different environmental compartments (wastewaters, surface, ground and drinking waters, and sediments), justify the growing concern about these emerging environmental pollutants. Viewing an ecopharmacovigilance approach, a comprehensive discussion of the state of the art regarding different contamination sources, fate, degradation and occurrence is presented. Information on the current distribution levels and fate in different environmental matrices continues to be sparse and measures are imperative to improve awareness and encourage precautionary actions to minimize SSRIs' environmental impact. PMID- 22940044 TI - Characteristics of DDTs in fish from Lake Taihu: an indicator of continual DDTs input in China. AB - Four typical freshwater fish species in Lake Taihu (TH), China, were collected and analyzed for the residue levels of DDT and its metabolites DDD and DDE (sum of o,p'- and p,p'-DDT, DDD, and DDE is designated as DDTs). The DDTs concentrations ranged from 3.24 to 37.1 ng/g, and p,p'-DDE was the dominant isomer, followed by p,p'-DDD and o,p'-DDT. Source identification indicated that DDTs in TH was mostly stemmed from the historical usage of technical DDT mixture, but a new source of DDT, i.e., dicofol-type DDT, also occurred. The results from the present work, together with previously published data, clearly indicate that dicofol-type DDT was widespread and was an important continual source of DDTs in China. PMID- 22940045 TI - Are pesticide residues associated to rice production affecting oyster production in Delta del Ebro, NE Spain? AB - Pesticide usage in Delta del Ebro (NE Spain) during the rice growing season has been associated with oyster episodes of mortality that occur early in summer. However, there are no studies that have directly evaluated pesticide levels and effects in oysters (Crassotrea gigas) cultured in Ebro's Bays. In this study pesticide levels in water, metal body burdens and up to 12 different biochemical markers were monitored in gills and digestive glands of oysters transplanted from May to June in 2008 and 2009. Biochemical responses evidenced clear differences in oysters from 2008 and 2009. Oysters transplanted in 2009 showed their antioxidant defenses unaffected from May to June and consequently increased levels of tissue damage measured as lipid peroxidation and DNA strand breaks and of mortality rates. Conversely oysters transplanted in 2008 increase their antioxidant defenses from May to June, had low levels of lipid peroxidation and DNA damage and low mortality rates. Some pesticides in water such as bentazone and propanil together with high temperatures and salinity levels were related with tissue damage in oyster transplanted in 2008 but the observed large differences between years indicate that abiotic factors alone could not explain the high mortalities observed in 2009. An analysis of recent reported studies pointed out in the direction that in addition to abiotic factors the use of oysters sensitive to diseases may explain the observed responses. PMID- 22940046 TI - CYP2E1 and oxidant stress in alcoholic and non-alcoholic fatty liver disease. AB - Alcoholic (ALD) and non-alcoholic fatty liver diseases (NAFLD) are clinical conditions leading to hepatocellular injury and inflammation resulting from alcohol consumption, high fat diet, obesity and diabetes, among others. Oxidant stress is a major contributing factor to the pathogenesis of ALD and NAFLD. Multiple studies have shown that generation of reactive oxygen species (ROS) is key for the progression of fatty liver to steatohepatitis. Cytochrome P450 2E1 (CYP2E1) plays a critical role in ROS generation and CYP2E1 is also induced by alcohol itself. This review summarizes the role of CYP2E1 in ALD and NAFLD. PMID- 22940047 TI - Synthesis, growth and vibrational spectroscopic study of a novel coumarinoylthiazole. AB - An efficient route was developed for the synthesis of novel 3-(2-morpholinyl-4 phenylthiazol-5-oyl)coumarin (MPTC). FT-IR spectrum of MPTC was recorded and analyzed. The crystal structure data are also described. The vibrational wavenumbers were computed theoretically using the Gaussian03 package of programs using HF/6-31G(d) and B3LYP/6-31G(d) levels of theory. The data obtained from vibrational wave number calculations are used to assign vibrational bands observed in the infrared spectra of MPTC. The first hyperpolarizability, infrared absorption band intensities and intensities of raman active bands are reported. The calculated first hyperpolarizability is comparable with the values reported for compounds of similar structure. The structural parameters of MPTC obtained from XRD studies are in agreement with the calculated values. The unit cell parameters of crystals of MPTC are: a=8.6017(10)A, b=9.9735(5)A, c=13.3870(13)A, alpha=111.123(6) degrees , beta=90.102(9) degrees , gamma=110.246(6) degrees , and Z=2,1.397 Mg/m(3). PMID- 22940048 TI - Synthesis, spectroscopic, thermal and antimicrobial studies of toluene-3,4 dithiolatoarsenic(III) derivatives with some oxygen and sulphur donor ligands. AB - Replacement reactions of toluene-3,4-dithiolatoarsenic(III) chloride with oxygen and sulphur donor ligands like benzoic acid, thiobenzoic acid, anhydrous sodium acetate, thioacetic acid, phenol, thiophenol, sodium salicylate and thio glycolic acid in 1:1 molar ratio as well as disodium oxalate in 2:1 molar ratio in refluxing anhydrous benzene yielded toluene-3,4-dithiolatoarsenic(III) mono oxo or thio carboxylic or phenolic derivatives of the general formula SC(6)H(3)(CH(3))SAsR {where R=OOCC(6)H(5), SOCC(6)H(5), OOCCH(3), SOCCH(3), OC(6)H(5), SC(6)H(5), OOCC(6)H(4)(OH), SCH(2)COOH} and SC(6)H(3)(CH(3))SAsOOC COOAsS(CH(3))C(6)H(3)S. These synthesized derivatives are yellow, yellow-brown solids/ liquids and are soluble in common organic solvents like benzene, chloroform, dichloromethane, dimethyl formamide, dimethyl sulphoxide etc. These derivatives have been characterized by melting point determination, molecular weight determination, elemental analysis (C, H, S and As), spectral {UV, IR, NMR ((1)H and (13)C), ESI-Mass, SEM and powder X-ray diffraction} and thermal (TGA, DTA and DSC) studies. Some of these compounds have been screened for their antimicrobial activities using the disc diffusion method. These derivatives have shown good activity as antibacterial and antifungal agents on some selected bacterial and fungal strains, which increased on increasing the concentration. Chloroamphenicol and terbinafin were used as standards for the comparison. PMID- 22940049 TI - Aloe barbadensis Miller mediated green synthesis of mono-disperse copper oxide nanoparticles: optical properties. AB - In this paper, we report on the synthesis of nanostructured copper oxide particles by both chemical and biological method. A facile and efficient synthesis of copper oxide nanoparticles was carried out with controlled surface properties via green chemistry approach. The CuO nanoparticles synthesized are monodisperse and versatile and were characterized with the help of UV-Vis, PL, FT IR, XRD, SEM, and TEM techniques. The particles are crystalline in nature and average sizes were between 15 and 30 nm. The morphology of the nanoparticles can be controlled by tuning the amount of Aloe vera extract. This new eco-friendly approach of synthesis is a novel, cheap, and convenient technique suitable for large scale commercial production and health related applications of CuO nanoparticles. PMID- 22940050 TI - Amplified spontaneous emission spectra from the superexciplex of coumarin 138. AB - In this report the dual amplified spontaneous emission (ASE) characteristics of coumarin 138 (C(138)) had been studied, under different solvent environments. The results obtained were compared with coumarin 461 (C(461)) and coumarin 450 (C(450)), which have closely related structure. The results showed that all these dyes could produce ASE from superexciplex - a new molecular species - formed only under high inversion densities, obtainable by pulsed laser excitation. We have strong indication that a superexciplex with TICT conformation is capable of producing strong ASE. PMID- 22940051 TI - Growth and characterization of Methyl 2-amino-5-bromobenzoate crystal for NLO applications. AB - Good quality single crystal of organic Methyl 2-amino-5-bromobenzoate (M2A5B) was grown using slow evaporation solution growth technique. The grown crystal was confirmed by single crystal X-ray diffraction. The functional groups and vibrational frequencies were identified using FT-IR and FT-Raman spectral analyses. The presence of hydrogen and carbon atoms in the grown sample was confirmed with proton and carbon NMR spectral studies. The optical energy band gap of the title compound is found to be 2.7 eV from the optical transmission spectra. The refractive indices n(x), n(y), and n(z) were found to be 1.569, 1.587 and 1.600, respectively using Brewster's angle method. The melting point of the material obtained with melting point apparatus is 74 degrees C. Thermal stability of the grown crystal was studied by thermogravimetric analysis (TGA) and differential thermal analysis (DTA). The mechanical behaviour of the grown crystal was analyzed with Vicker's microhardness tester. The particle size dependent second harmonic generation efficiency for M2A5B was evaluated by Kurtz Perry powder method using Nd:YAG laser, which established the existence of phase matching. PMID- 22940052 TI - Study on the conformation changes of Lysozyme induced by Hypocrellin A: the mechanism investigation. AB - The interactions between Lysozyme and Hypocrellin A are investigated in details using time-resolved fluorescence, fourier transform infrared spectroscopy (FTIR), circular dichroism spectroscopy (CD), three-dimensional fluorescence spectra, and thermal gravimetric analysis (TGA) techniques. The results of time-resolved fluorescence suggest that the quenching mechanism is static quenching. FTIR and CD spectroscopy provide evidences of the reducing of alpha-helix after interaction. Hypocrellin A could change the micro-environmental of Lysozyme according to hydrophobic interaction between the aromatic ring and the hydrophobic amino acid residues, and the altered polypeptide backbone structures induce the reduction of alpha-helical structures. Moreover, TGA study further demonstrates the structure changes of Lysozyme on the effect of Hypocrellin A. This study could provide some important information for the derivatives of HA in pharmacy, pharmacology and biochemistry. PMID- 22940053 TI - Physicochemical insights in non-covalent interaction of a newly designed triporphyrin with fullerenes C60 and C70 in solution. AB - The present paper reports the synthesis of free-base (H(2)-1) and zinc triporphyrins Zn-1, and their supramolecular complexes with C(60) and C(70) in toluene. While UV-Vis studies reveal ground state interaction between fullerenes and triporphyrins, steady state fluorescence measurements establish quenching of fluorescence of triporphyrins by fullerenes. Binding constants data evoke that Zn 1 may be employed as an efficient tweezers for C(70) in toluene. Time resolved emission studies establish relatively long-lived charge separated state for the C(70)/triporphyrin complexes. Molecular mechanics force field calculations in vacuo interpret the stability difference between C(60)/and C(70)/complexes of triporphyrin. PMID- 22940054 TI - Bacteremia in blood or marrow transplantation patients: clinical risk factors for infection and emerging antibiotic resistance. AB - Bacterial infections continue to be a leading cause of mortality and morbidity in patients who undergo blood and marrow transplantations (BMTs). The relative importance of different clinical features (donor type, graft cell source, and conditioning regimen) on the incidence and timing of posttransplantation bacterial infections is uncertain, but a detailed analysis could better guide prevention and therapy. We retrospectively analyzed the incidence and risk factors for early bacterial infections, as well as patterns of antibiotic resistance. We observed 613 bacteremic events among 349 of 834 patients who underwent BMT treated at the University of Minnesota from 2005 to 2010 (cumulative incidence 42%; 95% confidence interval [CI], 38-45). Donor type (allogeneic vs autologous) had the greatest impact on the incidence of bacteremia within 100 days posttransplantation. Among allogeneic transplantations, myeloablative (MA), compared to reduced-intensity conditioning (RIC) was associated with a significantly greater risk of bacteremia, as was the development of acute graft-versus-host disease (aGVHD). Additionally, patients who underwent BMT, compared to the contemporaneous hospital population, developed infections with more frequent resistance to antibiotics used in the treatment against commonly isolated bacterial organisms. These findings have important clinical implications regarding the use and selection of both prophylactic and empiric antibiotic regimens. PMID- 22940055 TI - Phase II trial of 131-Iodine tositumomab with high-dose chemotherapy and autologous stem cell transplantation for relapsed diffuse large B cell lymphoma. AB - The purpose of this study was to evaluate the standard outpatient dose of 131 Iodine tositumomab (75 cGy) combined with high-dose carmustine, etoposide, cytarabine, and melphalan (BEAM) followed by autologous stem cell rescue for the treatment of chemotherapy-sensitive relapsed or refractory, or high-risk first complete remission (CR) patients with diffuse large B cell non-Hodgkin's lymphoma (DLBCL). Forty patients with chemotherapy-sensitive persistent or relapsed or high/intermediate or high international prognostic index DLCBL were treated in a phase II trial combining 75 cGy 131-Iodine tositumomab with high-dose BEAM followed by autologous stem cell transplantation. The CR rate after transplantation was 78%, and the overall response rate was 80%. Short-term and long-term toxicities were similar to historical control patients treated with BEAM alone. With a median follow-up of 6 years (range, 3-10 years), the 5-year overall survival (OS) was 72% (95% confidence interval [CI], 55%-83%), and the 5 year progression-free survival (PFS) rate was 70% (95% CI, 53%-82%). The PFS and OS were encouraging in this group of chemotherapy-sensitive persistent, relapsed, or high-risk patients with DLBCL. A follow-up phase III trial with 131-Iodine tositumomab/BEAM vs rituximab/BEAM was planned based on this information. PMID- 22940056 TI - A randomized trial of one versus two doses of influenza vaccine after allogeneic transplantation. AB - Influenza infection after allogeneic hematopoietic cell transplantation (allo HCT) can result in severe complications. The effectiveness of the annual vaccine depends on age, immune competence, and the antigenic potential of the 3 strains included. We hypothesized that a second vaccine dose, the standard of care for vaccine-naive children, might improve post hematopoietic cell transplantation (HCT) immune responses. Patients >60 days post-HCT were randomized to receive either 1 (n = 33) or 2 (n = 32) influenza vaccine doses separated by 1 month. The primary endpoint was whether 2 vaccinations induced superior immunity; however, we found no difference. Secondary endpoints were to identify variables associated with responses. Both hemagglutination inhibition (HI; P < .005) and ELISpot responses (P = .03) were greater for patients vaccinated >= 1 year posttransplantation. Umbilical cord blood (UCB) recipients showed less IFN-gamma responses (P < .001). Interestingly, there was a positive correlation between the total number of CD19(+) cells before vaccination and seroconversion (P = .01) and an inverse correlation for IFN-gamma responses (P = .05). Variables not associated with vaccine responses included prevaccine CD4(+) cell counts (total, naive, or memory), steroid usage at vaccination, age, or conditioning intensity. Time from transplantation to vaccination and absolute CD19(+) cell counts were the strongest predictors of vaccine responses. Methods to improve influenza vaccine responses after allo-HCT are needed. PMID- 22940057 TI - Unmanipulated haploidentical bone marrow transplantation and posttransplantation cyclophosphamide for hematologic malignancies after myeloablative conditioning. AB - Fifty patients with high-risk hematologic malignancies, underwent an unmanipulated haploidentical bone marrow transplantation (BMT), followed by posttransplantation high-dose cyclophosphamide (PT-CY): the myeloablative (MA) conditioning consisted of thiotepa, busulfan, fludarabine (n = 35), or total body irradiation (TBI), fludarabine (n = 15). The median age was 42 years (range, 18 66 years); 23 patients were in remission, 27 had active disease, and 10 patients were receiving a second allograft. Graft-versus-host disease (GVHD) prophylaxis consisted in PT-CY on day +3 and +5, cyclosporine (from day 0), and mycophenolate (from day +1). Three patients died before engraftment, and 2 patients had autologous recovery: 45 patients (90%) had full-donor chimerism on day +30. The median day for neutrophil engraftment was day +18 (range, 13-30 days). The cumulative incidence of grade II-III acute GVHD (aGVHD) was 12%, and of moderate chronic GVHD (cGVHD) 10%. With a median follow-up for surviving patients of 333 days (range, 149-623 days), the cumulative incidence of transplantation-related mortality (TRM) was 18%, and the rate of relapse was 26%. The actuarial 22-month disease-free survival (DFS) rate was 68% for patients in remission and 37% for patients with active disease (P < .001). Causes of death were pneumonia (n = 3), hemorrhage (n = 3), sepsis (n = 3), and relapse (n = 7). In conclusion, an MA conditioning regimen followed by haploidentical BMT with PT-CY results in a low risk of aGVHD and cGVHD and encouraging rates of TRM and DFS. PMID- 22940058 TI - Fibrin clot properties in women heterozygous for factor V Leiden mutation: effects of oral contraceptives. AB - INTRODUCTION: Oral contraceptives (OC) in the presence of factor V Leiden mutation (FVL) markedly increase the risk of venous thromboembolism (VTE). Little is known about the OC and FVL-related alterations in fibrin clot properties. SUBJECTS AND METHODS: Plasma fibrin clot permeability (K(s)) and efficiency of lysis, reflected by clot lysis time (CLT) and the rate of D-dimer release from clots (D-D(rate)) induced by recombinant tissue plasminogen activator (tPA) were determined in 25 women with a family history of VTE who were heterozygous for FVL [FVL(+/-) - twice, on third-generation OC and after their discontinuation. Female non-carriers of FVL, matched for demographics, using OC and after their discontinuation served as controls (n=25). All participants had no personal history of VTE. RESULTS: OC discontinuation in FVL(+/-) women resulted in shortened CLT (-9%), and increased K(s) (+4%) and D-D(rate) (+1.4%; all p<0.01). Alterations in fibrin clot properties were associated with decreased prothrombin fragments 1+2 (F1+2) (-8%), plasminogen activator inhibitor-1 (PAI-1) antigen ( 11%), and thrombin activatable fibrinolysis inhibitor (TAFI) activity (-20%; all p<0.01). During OC use FVL(+/-) carriers compared with non-carriers had higher platelet count, activity of PAI-1, TAFI, and tPA, as well as prolonged CLT and higher D-D(max), along with lower D-D(rate) and K(s). Multiple regression analysis adjusted for fibrinogen and age, showed that PAI-1 antigen and TAFI activity independently predicted CLT in FVL(+/-) women on OC. CONCLUSION: FVL(+/ ) is associated with hypofibrinolysis in apparently healthy women and third generation OC administration unfavorably alters plasma clot characteristics in female FVL(+/-) carriers with a family history of thrombotic events. PMID- 22940059 TI - Activation of MAPKs in the anti-beta2GPI/beta2GPI-induced tissue factor expression through TLR4/IRAKs pathway in THP-1 cells. AB - Our previous study has demonstrated that the Toll-like receptor 4 (TLR4) signaling pathways contribute to the induction of tissue factor (TF) expression by anti-beta(2)-glycoprotein I/beta(2)-glycoprotein I (anti beta(2)GPI/beta(2)GPI) in human acute monocytic leukemia cell line THP-1. In this study, we focused on the identification of the downstream targets of the TLR4 pathways. When THP-1 cells were treated with anti-beta(2)GPI/beta(2)GPI complex, enhanced TF expression was observed, along with induced phosphorylation of p38, ERK1/2 and JNK1/2 MAPKs. When the activity of MAPKs was blocked by their corresponding inhibitors (SB203580: p38; U0126: ERK; SP600125: JNK), the expression of TF was reduced significantly. Furthermore, the anti beta(2)GPI/beta(2)GPI-induced phosphorylation of p38, ERK1/2 and JNK1/2 was inhibited significantly by TAK-242, a blocker of the signaling transduction mediated by the intracellular domain of TLR4; sc-204013, a specific inhibitor of IRAKs, was also able to partially inhibit the phosphorylation of the MAPKs. Our results demonstrated that MAPKs (p38, ERK1/2 and JNK1/2) were the crucial downstream targets of the anti-beta(2)GPI/beta(2)GPI-triggered TLR4 signaling pathways in THP-1 cells. This essential role of MAPKs may also promote better understanding of the pathogenesis of antiphospholipid syndrome (APS). PMID- 22940060 TI - Establishing safe and effective antithrombotic therapy use in children.....finally. PMID- 22940061 TI - Evaluating use of cattle winter feeding areas by elk and white-tailed deer: implications for managing bovine tuberculosis transmission risk from the ground up. AB - Transmission of bovine tuberculosis (Mycobacterium bovis) among wildlife and livestock has created important risks for conservation and agriculture. Management strategies aimed at controlling TB have typically been top-down, regionally focused, and government-led programs that were at best only partially successful. The purpose of this study was to quantify co-mingling of elk and white-tailed deer (WTD) with cattle at multiple spatial scales (i.e., the regional farm scale and winter cattle feeding area patch) in southwestern Manitoba, Canada, to assess the potential for bovine tuberculosis transmission and identify alternative management strategies. For each spatial scale we quantified use of cattle farms by elk and white-tailed deer. We mailed questionnaires to rural households and then conducted personal interviews with 86 cattle farmers to map the spatial distribution of their cattle winter feeding areas at a fine scale. We deployed Global Positioning System (GPS) collars on 48 wild elk and 16 wild white-tailed deer from 2003 to 2011. Elk were observed on farms by 66% of cattle producers, including 5% and 20% who observed direct and indirect contact, respectively, between elk and cattle. Cattle producers consistently (~100%) observed white-tailed deer on their farms, including 11% and 47% whom observed direct and indirect contact, respectively, between white-tailed deer and cattle. A higher probability of white-tailed deer-cattle contact at the regional scale occurs on farms that (1) left crop residues specifically for wildlife, (2) had larger cattle herds, (3) used round bale feeders, and (4) were farther away from protected areas. None of the GPS-collared elk locations overlapped with cattle winter feeding areas. In contrast, 21% of GPS-collared white-tailed deer locations overlapped with winter cattle winter feeding areas (22% of these were from male WTD and 78% were from female WTD). White-tailed deer selected cattle winter feeding areas with higher (1) forage crop, (2) grassland/rangeland, and (3) forest cover around the cattle feeding area. Farmers overall expressed strongly negative attitudes toward eradicating the elk population or fencing the park to eradicate TB, but were generally supportive of less invasive and farm-based approaches. Our results suggested that management efforts to prevent TB transmission at the wildlife-agriculture interface can be effectively implemented using a 'bottom-up' approach that focuses on practical, farm-based mitigation strategies. This approach can be implemented by individual farm operators, is relatively low cost, and is generally well supported by farmers relative to other more extreme and controversial measures like wildlife eradication. PMID- 22940062 TI - Assessing the effectiveness of strategies to implement clinical guidelines for the management of chronic diseases at primary care level in EU Member States: a systematic review. AB - PURPOSE AND SETTING: This review aimed to evaluate the effectiveness of strategies to implement clinical guidelines for chronic disease management in primary care in EU Member States. METHODS: We conducted a systematic review of interventional studies assessing the implementation of clinical guidelines. We searched five databases (EMBASE, MEDLINE, CENTRAL, Eppi-Centre and Clinicaltrials.gov) following a strict Cochrane methodology. We included studies focusing on the management of chronic diseases in adults in primary care. RESULTS: A total of 21 studies were found. The implementation strategy was fully effective in only four (19%), partially effective in eight (38%), and not effective in nine (43%). The probability that an intervention would be effective was only slightly higher with multifaceted strategies, compared to single interventions. However, effect size varied across studies; therefore it was not possible to determine the most successful strategy. Only eight studies evaluated the impact on patients' health and only two of those showed significant improvement, while in five there was an improvement in the process of care which did not translate into an improvement in health outcomes. Only four studies reported any data on the cost of the implementation but none undertook a cost effectiveness analysis. Only one study presented data on the barriers to the implementation of guidelines, noting a lack of awareness and agreement about clinical guidelines. CONCLUSION: Our results reveal that there are only a few rigorous studies which assess the effectiveness of a strategy to implement clinical guidelines in Europe. Moreover, the results are not consistent in showing which strategy is the most appropriate to facilitate their implementation. Therefore, further research is needed to develop more rigorous studies to evaluate health outcomes associated with the implementation of clinical guidelines; to assess the cost-effectiveness of implementing clinical guidelines; and to investigate the perspective of service users and health service staff. PMID- 22940063 TI - Impact of smoke-free hospital grounds policies: patient experiences and perceptions. AB - Implementation of a smoke-free hospital grounds policy changes the health care context for patients. This article examines patient's perspectives, providing insight into the shifting culture of smoking in hospitals and the impact of smoke free policy during hospitalization. This qualitative study used semi-structured interviews (N=82) to explore patient perspectives of tobacco use, policy compliance, and abstinence support in Canadian hospitals with smoke-free grounds policies. Results indicated general support for smoke-free policies, but also highlighted that the intended goals were not realized; patients reported the policy is routinely violated, second-hand smoke exposure remained common at hospital entrances and assessment and treatment of tobacco dependency was inadequate. Patients provided rationales for policy violation, which included significant concern for personal safety. Health authorities must lend careful consideration to the effects of policy on hospitalization. Study results highlight patient views on tobacco dependence, hospitalization, and treatment expectations, which when adequately addressed could support abstinence, promote healthy recovery and hospital policy compliance. PMID- 22940064 TI - Benefits of a single payment system: case study of Abu Dhabi health system reforms. AB - In 2005 leaders in the wealthy Emirate of Abu Dhabi inherited an health system from their predecessors that was well-intentioned in its historic design, but that did not live up to aspirations in any dimension. First, the Emirate defined a vision to deliver "world-class" quality care in response to citizen's needs. It has since introduced tiered mandatory health insurance for all inhabitants linked to a single standard payment system, which generates accurate data as an invaluable by-product. A newly created independent health system regulator monitors these data and licenses, audits, and inspects all health service professionals, facilities, and insurers accordingly. We analyse these health system reforms using the "Getting Health Reform Right" framework. Our analysis suggests that an integrated set of reforms addressing all reform levers is critical to achieving the outcomes observed. The reform programme has improved access, by giving all residents health cards. The approximate doubling of demand has been matched by flexible supply, with the private sector adding 5 new hospitals and 93 clinics to the health system infrastructure since 2006. The focus on reliable raw-data flows through the single standard payment system functions as a motor for improvement services, innovation, and investment, for instance by allowing payers to 'pay for quality', which may well be applicable in other contexts. PMID- 22940065 TI - Prebiotic-non-digestible oligosaccharides preference of probiotic bifidobacteria and antimicrobial activity against Clostridium difficile. AB - Bifidobacterium breve 46, Bifidobacterium lactis 8:8 and Bifidobacterium longum 6:18 and three reference strains B. breve CCUG 24611, B. lactis JCM 10602, and Bifidobacterium pseudocatenulatum JCM 1200 were examined for acid and bile tolerance, prebiotic utilization and antimicrobial activity against four Clostridium difficile (CD) strains including the hypervirulent strain, PCR ribotype NAP1/027. B. lactis 8:8 and B. lactis JCM 10602 exhibited a high tolerance in MRSC broth with pH 2.5 for 30 min. B. breve 46 and B. lactis 8:8 remained 100% viable in MRSC broth with 5% porcine bile after 4 h. All six strains showed a high prebiotic degrading ability (prebiotic score) with galactooligosaccharides (GOS), isomaltooligosaccharides (IMOS) and lactulose as carbon sources and moderate degradation of fructooligosaccharides (FOS). Xylooligosaccharides (XOS) was metabolized to a greater extent by B. lactis 8:8, B. lactis JCM 10602, B. pseudocatenulatum JCM 1200 and B. longum 6:18 (prebiotic score >50%). All strains exhibited extracellular antimicrobial activity (AMA) against four CD strains including the CD NAP1/027. AMA of B. breve 46, B. lactis 8:8 and B. lactis JCM 10602 strains was mainly ascribed to a combined action of organic acids and heat stable, protease sensitive antimicrobial peptides when cells were grown in MRSC broth with glucose and by acids when grown with five different prebiotic-non-digestible oligosaccharides (NDOs). None of C. difficile strains degraded five prebiotic-NDOs. Whole cells of B. breve 46 and B. lactis 8:8 and their supernatants inhibited the growth and toxin production of the CD NAP1/027 strain. PMID- 22940067 TI - Does iron inhibit calcification during atherosclerosis? AB - Oxidative stress has been implicated in the etiology of atherosclerosis and even held responsible for plaque calcification. Transition metals such as iron aggravate oxidative stress. To understand the relation between calcium and iron in atherosclerotic lesions, a sensitive technique is required that is quantitatively accurate and avoids isolation of plaques or staining/fixing tissue, because these processes introduce contaminants and redistribute elements within the tissue. In this study, the three ion-beam techniques of scanning transmission ion microscopy, Rutherford backscattering spectrometry, and particle induced X-ray emission have been combined in conjunction with a high-energy (MeV) proton microprobe to map the spatial distribution of the elements and quantify them simultaneously in atherosclerotic rabbit arteries. The results show that iron and calcium within the atherosclerotic lesions exhibit a highly significant spatial inverse correlation. It may be that iron accelerates the progression of atherosclerotic lesion development, but suppresses calcification. Alternatively, calcification could be a defense mechanism against atherosclerotic progression by excluding iron. PMID- 22940066 TI - Native rates of superoxide production from multiple sites in isolated mitochondria measured using endogenous reporters. AB - Individual sites of superoxide production in the mitochondrial respiratory chain have previously been defined and partially characterized using specific inhibitors, but the native contribution of each site to total superoxide production in the absence of inhibitors is unknown. We estimated rates of superoxide production (measured as H(2)O(2)) at various sites in rat muscle mitochondria using specific endogenous reporters. The rate of superoxide production by the complex I flavin (site I(F)) was calibrated to the reduction state of endogenous NAD(P)H. Similarly, the rate of superoxide production by the complex III site of quinol oxidation (site III(Qo)) was calibrated to the reduction state of endogenous cytochrome b(566). We then measured the endogenous reporters in mitochondria oxidizing NADH-generating substrates, without added respiratory inhibitors, with and without ATP synthesis. We used the calibrated reporters to calculate the rates of superoxide production from sites I(F) and III(Qo). The calculated rates of superoxide production accounted for much of the measured overall rates. During ATP synthesis, site I(F) was the dominant superoxide producer. Under nonphosphorylating conditions, overall rates were higher, and sites I(F) and III(Qo) and unidentified sites (perhaps the complex I site of quinone reduction, site I(Q)) all made substantial contributions to measured H(2)O(2) production. PMID- 22940068 TI - Effect of dexmedetomidine vs. acepromazine-methadone premedication on limb to lung circulation time in dogs. AB - The study compared limb-to-lung circulation times (CT) in dogs under general anaesthesia after premedication with dexmedetomidine (DEX) or acepromazine methadone (ACE-M). Healthy male and female dogs (n=20) were randomly assigned to receive acepromazine 0.04mg/kg and methadone 0.2mg/kg intramuscularly (IM), or DEX 0.01mg/kg IM. Anesthesia was induced with propofol and maintained with isoflurane at similar concentration in both groups. Mechanical ventilation was started immediately (20breaths/min; inspiratory to expiratory ratio 1:2) and tidal volume was adjusted to achieve an end-tidal CO2 concentration (PE'CO2) of between 3.9 and 5.3kPa. Ten minutes later arterial blood gas was analyzed and baseline data recorded for 3 minutes. A single dose of sodium bicarbonate 0,5mEq/kg was administered intravenously over 10 s starting with inspiration. Limb-to-lung CT was defined as the time interval between the start of bicarbonate injection and the recording of the highest PE'CO2. Following bicarbonate administration, PE'CO2 increased, and then rapidly decreased to baseline in both groups. CT was shorter in the ACE-M group (20+/-2.3 vs. 27+/-5.1s). Bodyweight was higher in the ACE-M group (30.6+/-3.9 vs. 23.3+/-6.8kg). Mean arterial blood pressure was higher in the DEX group (92+/-9 vs. 73+/-7mmHg) but premedication with DEX significantly prolonged CT compared to premedication with ACE-M. PMID- 22940069 TI - Commentary to "Secondary vaginoplasty for disorders of sex development: is there a right time? Challenges with compliance and follow-up at a multidisciplinary centre". PMID- 22940070 TI - Leukemic blasts with the paroxysmal nocturnal hemoglobinuria phenotype in children with acute lymphoblastic leukemia. AB - It has been proposed that genomic instability is essential to account for the multiplicity of mutations often seen in malignancies. Using the X-linked PIG-A gene as a sentinel gene for spontaneous inactivating somatic mutations, we previously showed that healthy individuals harbor granulocytes with the PIG-A mutant (paroxysmal nocturnal hemoglobinuria) phenotype at a median frequency (f) of ~12 * 10(-6). Herein, we used a similar approach to determine f in blast cells derived from 19 individuals with acute lymphoblastic leukemia (ALL) and in immortalized Epstein-Barr virus-transformed B-cell cultures (human B lymphoblastoid cell lines) from 19 healthy donors. The B-lymphoblastoid cell lines exhibited a unimodal distribution, with a median f value of 11 * 10(-6). In contrast, analysis of the f values for the ALL samples revealed at least two distinct populations: one population, representing approximately half of the samples (n = 10), had a median f value of 13 * 10(-6), and the remaining samples (n = 9) had a median f value of 566 * 10(-6). We conclude that in ALL, there are two distinct phenotypes with respect to hypermutability, which we hypothesize will correlate with the number of pathogenic mutations required to produce the leukemia. PMID- 22940071 TI - Type VII collagen deficiency causes defective tooth enamel formation due to poor differentiation of ameloblasts. AB - Recessive dystrophic epidermolysis bullosa (RDEB) is caused by mutations in the gene encoding type VII collagen (COL7), a major component of anchoring fibrils in the epidermal basement membrane zone. Patients with RDEB present a low oral hygiene index and prevalent tooth abnormalities with caries. We examined the tooth enamel structure of an RDEB patient by scanning electron microscopy. It showed irregular enamel prisms, indicating structural enamel defects. To elucidate the pathomechanisms of enamel defects due to COL7 deficiency, we investigated tooth formation in Col7a1(-/-) and COL7-rescued humanized mice that we have established. The enamel from Col7a1(-/-) mice had normal surface structure. The enamel calcification and chemical composition of Col7a1(-/-) mice were similar to those of the wild type. However, transverse sections of teeth from the Col7a1(-/-) mice showed irregular enamel prisms, which were also observed in the RDEB patient. Furthermore, the Col7a1(-/-) mice teeth had poorly differentiated ameloblasts, lacking normal enamel protein-secreting Tomes' processes, and showed reduced mRNA expression of amelogenin and other enamel related molecules. These enamel abnormalities were corrected in the COL7-rescued humanized mice expressing a human COL7A1 transgene. These findings suggest that COL7 regulates ameloblast differentiation and is essential for the formation of Tomes' processes. Collectively, COL7 deficiency is thought to disrupt epithelial mesenchymal interactions, leading to defective ameloblast differentiation and enamel malformation in RDEB patients. PMID- 22940072 TI - Combined inhibition of c-Abl and PDGF receptors for prevention and treatment of murine sclerodermatous chronic graft-versus-host disease. AB - Chronic graft-versus-host disease (cGvHD) is a common complication of allogeneic bone marrow transplantation, and has a major effect on the long-term prognosis. The molecular mechanisms underlying cGvHD have been only partially revealed, and molecular targeted therapies have not yet been established for clinical use. We examined the effects of the combined inhibition of the Abelson kinase (c-Abl) and platelet-derived growth factor receptors (PDGFR) in experimental sclerodermatous cGvHD. Treatment using imatinib or nilotinib abolished the aberrant activation of c-Abl and PDGFR and protected against experimental cGvHD. Preventive therapy using imatinib or nilotinib inhibited the development of sclerodermatous cGvHD. Clinical features such as weight loss, alopecia, and skin ulcers, and histologic features with dermal thickening and accumulation of collagen were significantly reduced in mice that received imatinib or nilotinib therapy, but not in mice that received prednisone therapy. Of note, imatinib and nilotinib were also effective for treatment of experimental cGvHD that had already been clinically manifested. In summary, the combined inhibition of c-Abl and PDGFR is effective for prevention and treatment of experimental sclerodermatous cGvHD. Considering the high morbidity associated with cGvHD, the lack of efficient molecular therapies for clinical use, and first positive signals from uncontrolled studies of imatinib, combined inhibition of c-Abl and PDGFR might be a promising future strategy for treatment of sclerodermatous cGvHD. PMID- 22940073 TI - Accelerated axonal loss following acute CNS demyelination in mice lacking protein tyrosine phosphatase receptor type Z. AB - Protein tyrosine phosphatase receptor type Z (Ptprz) is widely expressed in the mammalian central nervous system and has been suggested to regulate oligodendrocyte survival and differentiation. We investigated the role of Ptprz in oligodendrocyte remyelination after acute, toxin-induced demyelination in Ptprz null mice. We found neither obvious impairment in the recruitment of oligodendrocyte precursor cells, astrocytes, or reactive microglia/macrophage to lesions nor a failure for oligodendrocyte precursor cells to differentiate and remyelinate axons at the lesions. However, we observed an unexpected increase in the number of dystrophic axons by 3 days after demyelination, followed by prominent Wallerian degeneration by 21 days in the Ptprz-deficient mice. Moreover, quantitative gait analysis revealed a deficit of locomotor behavior in the mutant mice, suggesting increased vulnerability to axonal injury. We propose that Ptprz is necessary to maintain central nervous system axonal integrity in a demyelinating environment and may be an important target of axonal protection in inflammatory demyelinating diseases, such as multiple sclerosis and periventricular leukomalacia. PMID- 22940074 TI - Evolution of abnormal eye movements in Wernicke's encephalopathy: correlation with serial MRI findings. AB - A 33-year-old woman with Wernicke's encephalopathy (WE) due to poor oral intake after allogeneic stem cell transplantation for acute myeloid leukemia showed a sequential development of bilateral gaze-evoked nystagmus (GEN), rightward gaze palsy, and upbeat nystagmus. Initial MRIs obtained when she had GEN only showed a lesion involving the medullary tegmentum, and follow-up MRIs revealed additional lesions in the pontine and midbrain tegmentum along with development of rightward gaze palsy, and finally bilateral medial thalamus lesions in association with upbeat nystagmus. The evolution of abnormal ocular motor findings and serial MRI changes in our patient with WE provide imaging evidence on relative vulnerability of the neural structures, and on the progression of lesions and ocular motor findings in thiamine deficiency. PMID- 22940076 TI - Celiac disease and selected long-term health issues. AB - Celiac disease is a genetically-based and immunologically-mediated systemic disorder, affecting primarily the small intestine in adults. About 0.5-1% of most populations studied are affected, with up to 2% in Finland. In families, specifically first-degree relatives, up to 20% may have the disease. Despite increased awareness among physicians and the public, celiac disease is still markedly under-diagnosed at all ages, including the elderly. Although serological screening is now widely used, celiac disease remains a biopsy-defined disorder, and a critical element to the correct diagnosis is documentation of a response to a gluten-free diet (since it is a gluten-sensitive disease). Sometimes, after the diagnosis has been established with a treatment response, changes re-appear and seem resistant to a gluten-free diet. Usually, poor or limited diet compliance, possibly from an unrecognized gluten source is responsible. In others, another superimposed cause, such as an infectious agent, could be important. Finally, another associated disease causing similar clinical and biopsy features or, alternatively, a complicating disorder may develop, such as a lymphoma. Some with biopsy features suggestive of celiac disease may not respond to a gluten-free diet. These may not have celiac disease at all, but instead, a sprue-like intestinal disease, or so-called unclassified sprue. PMID- 22940075 TI - Safety and efficacy of tenofovir/IQP-0528 combination gels - a dual compartment microbicide for HIV-1 prevention. AB - Tenofovir (TFV) is a nucleotide reverse transcriptase inhibitor and IQP-0528 is a non-nucleoside reverse transcriptase inhibitor that also blocks virus entry. TFV and IQP-0528 alone have shown antiviral activity as microbicide gels. Because combination therapy will likely be more potent than mono-therapy, these drugs have been chosen to make a combination microbicide gel containing 2.5% TFV/1% IQP 0528. Safety and efficacy testing was done to evaluate five prototype combination gels. The gels retained TZM-bl cell and ectocervical and colorectal tissue viability. Further, the epithelium of the ectocervical and colorectal tissue remained intact after a 24h exposure. The ED(50) calculated from the formulations for IQP-0528 was ~32nM and for TFV was ~59nM and their inhibitory activity was not affected by semen. The ED(50) of TFV in the combination gels was ~100-fold lower than when calculated for the drug substance alone reflecting the activity of the more potent IQP-0528. When ectocervical and colorectal tissue were treated with the combination gels, HIV-1 p24 release was reduced by >=1log(10) and >=2log(10), respectively. Immunohistochemistry for the ectocervical tissues treated with combination gels showed no HIV-1 infected cells at study end. With the increased realization of receptive anal intercourse among heterosexual couples often in conjunction with vaginal intercourse, having a safe and effective microbicide for both mucosal sites is critical. The safety and efficacy profiles of the gels were similar for ectocervical and colorectal tissues suggesting these gels have the potential for dual compartment use. PMID- 22940077 TI - Noradrenergic activity regulated dexamethasone-induced increase of 5-HT3 receptor mediated glutamate release in the rat's prelimbic cortex. AB - Stress hormone, glutamatergic system, serotonergic system and the noradrenergic system are involved in depressive disorders. However, the relationship among these is still unclear. The present study examined the effect of dexamethasone (DEX) on the presynaptic glutamate release of synaptosomes from the rat's prelimbic cortex by using biochemical methods combined with pharmacological approaches. The results showed that dexamethasone increased the glutamate release of synaptosomes in a dose-dependent manner. The concentration-response relationship of this effect of DEX was inverse U-shaped with a maximum at 3 MUm. Further study showed that glucocorticoid receptor (GR) antagonist and GR siRNA had no effect on the DEX-induced glutamate release but 5-HT3 receptor antagonist could block the DEX-induced glutamate release which suggested that DEX produced the increased effect on the glutamate release not by GR, but through the activation of the 5-HT3 receptors which led to the influx of extrasynaptosomal Ca2+. Moreover, beta3 adrenergic receptor agonist could block the DEX-induced glutamate release. This result suggested that the effect of DEX on the glutamate release could be regulated by noradrenergic system. The mechanism study showed that beta(3) adrenergic receptors regulated the DEX-induced glutamate release via Gs protein-adenylate cyclase (AC)-protein kinase A (PKA) signal transduction pathway. PMID- 22940078 TI - Advanced glycated albumin impairs HDL anti-inflammatory activity and primes macrophages for inflammatory response that reduces reverse cholesterol transport. AB - OBJECTIVE: We investigated the effect of advanced glycated albumin (AGE-albumin) on macrophage sensitivity to inflammation elicited by S100B calgranulin and lipopolysaccharide (LPS) and the mechanism by which HDL modulates this response. We also measured the influence of the culture medium, isolated from macrophages treated with AGE-albumin, on reverse cholesterol transport (RCT). METHODS AND RESULTS: Macrophages were incubated with control (C) or AGE-albumin in the presence or absence of HDL, followed by incubations with S100B or LPS. Also, culture medium obtained from cells treated with C- or AGE-albumin, following S100B or LPS stimulation was utilized to treat naive macrophages in order to evaluate cholesterol efflux and the expression of HDL receptors. In comparison with C-albumin, AGE-albumin, promoted a greater secretion of cytokines after stimulation with S100B or LPS. A greater amount of cytokines was also produced by macrophages treated with AGE-albumin even in the presence of HDL. Cytokine enriched medium, drawn from incubations with AGE-albumin and S100B or LPS impaired the cholesterol efflux mediated by apoA-I (23% and 37%, respectively), HDL(2) (43% and 47%, respectively) and HDL(3) (20% and 8.5%, respectively) and reduced ABCA-1 protein level (16% and 26%, respectively). CONCLUSIONS: AGE albumin primes macrophages for an inflammatory response impairing the RCT. Moreover, AGE-albumin abrogates the anti-inflammatory role of HDL, which may aggravate the development of atherosclerosis in DM. PMID- 22940079 TI - Automatic integration of auditory and visual information is not simultaneous in Chinese. AB - ERP studies have revealed that for alphabetic languages letter/speech-sound integration develops with brain maturation and reading instruction over a relatively long period of time. Experienced adult readers associate letters and speech sounds automatically, as indexed by enhanced mismatch negativity (MMN) to simultaneously presented stimuli, but reveal attenuated MMN when the speech sound stimuli are presented with a delay. Chinese as a logographic language differs substantially from alphabetic languages and therefore integration processes might be characterized by unique timing mechanisms. In the present study, MMN was used to investigate the timing and automaticity of association between characters and lexical tones in adult native Chinese speakers. A character was presented simultaneously with a lexical tone, or with either a 100ms stimulus onset asynchrony (SOA) or a 200ms SOA in separate conditions. MMN was enhanced when the character and the lexical tone were presented with 100ms SOA, while no significant MMN enhancement was observed with simultaneous presentation or with 200ms SOA. These results suggest that the automatic association of characters and lexical tones in experienced Chinese adult readers requires more processing time than for alphabetic languages. These results highlight critical differences between fundamental reading processes across different writing systems. The neural differences between alphabetic and logographic languages for letter/character and speech-sound/tone integration need to be taken into consideration when considering past and future research on reading processes in these languages and especially for investigations of reading disorders, such as developmental dyslexia. PMID- 22940080 TI - Absence of SHATI/Nat8l reduces social interaction in mice. AB - We previously identified a novel molecule "Shati/Nat8l" from the nucleus accumbens of mice. However, the physiological roles of the SHATI protein are not clear. To investigate the effect of SHATI on the central nervous system and behavior, we studied knockout mice of this protein. We carried out various behavior tests using Shati-knockout mice. Shati-knockout mice did not differ from wild type mice in learning and memory. In the open field test, Shati-knockout mice did not differ from wild-type mice in time of stay in the outer, middle and center areas. On the other hand, Shati-knockout mice showed increases in rearing and grooming time in the open field test, and exploration time of novel objects. These results suggested that knockout of the Shati gene may increase exploration in specific circumstances. Interestingly, the Shati-knockout mice avoided social interaction with unfamiliar mice out of their home cage, although there was no difference in social interaction in their home cage compared with wild type mice. Lack of the Shati gene increased brain-derived neurotrophic factor (BDNF) mRNA in the prefrontal cortex and hippocampus, and decreased glial cell line-derived neurotrophic factor (GDNF) mRNA in the striatum and hippocampus, and lipopolysaccharides-induced TNF-alpha factor (LITAF) mRNA in the striatum. Since these factors play important roles in behavior, alteration of expression of these factors may be related to the induction of exploration and reduction of social interaction in Shati-knockout mice. PMID- 22940081 TI - CTF1-51, a truncated carboxyl-terminal fragment of amyloid precursor protein, suppresses the effects of Abeta42-lowering gamma-secretase modulators. AB - The pathogenesis of Alzheimer's disease (AD) is correlated with the toxicity of amyloid beta-peptide (Abeta), especially Abeta42. gamma-Secretase modulators (GSMs) are compounds that alter production of Abeta42 without interfering with the physiological function of gamma-secretase. Abeta42-lowering GSMs have been studied with the hope of using them as therapeutic or prophylactic drugs for AD. However, the mechanism of action of GSMs is not well defined. We examined the effect of Abeta42-lowering GSMs on model cells producing large amounts of Abeta42: CHO cells expressing CTF1-51, a precursor peptide of Abeta that is mainly cleaved into Abeta42. Our results indicate that the effect of GSM in the model was weak. Thus, we conclude that CTF1-51 cleavage mainly yields Abeta42 and suppresses the effects of some GSMs, a phenomenon that may be related to their mechanism of action. PMID- 22940082 TI - Selenium-enriched Candida utilis: Efficient preparation with l-methionine and antioxidant capacity in rats. AB - Selenium-enriched Candida utilis has attracted much attention due to its expanding application in food and feed additives. The objective of this study was to efficiently prepare selenium-enriched C. utilis and to investigate the effects of the prepared yeast on antioxidant capacity in rats. A batch culture of selenium-enriched C. utilis was first carried out, and the addition of sodium selenite (Na(2)SeO(3)) after all glucose had been consumed was found to favor higher intracellular glutathione and organic selenium content. Moreover, l methionine boosted yeast cell growth and glutathione biosynthesis, and prevented glutathione from leaking to the extracellular space that can be caused by Na(2)SeO(3). We therefore developed a two-stage culture strategy involving supplementation with l-methionine and Na(2)SeO(3) at separate culture phases to improve the performance of selenized C. utilis. Using this two-stage culture strategy, intracellular glutathione content reached 18.6 mg/g and 15.5mg/g, respectively, in batch and fed-batch systems, and organic selenium content reached 905.2 MUg/g and 984.7 MUg/g, respectively. The effects of selenium enriched C. utilis on the activities of antioxidant related enzymes in rats were investigated, and the prepared selenium-enriched C. utilis was shown to be an optimal dietary supplement for enhancing antioxidant capacity in rats. PMID- 22940083 TI - Increased whole blood manganese concentrations observed in children with iron deficiency anaemia. AB - A prospective observational study was carried out at Alder Hey Children's Hospital, Liverpool, England, UK on children aged 1-6 years attending the pathology department for routine blood tests (n=225). Whole blood manganese concentrations were measured plus the following markers of iron status; haemoglobin, MCV, MCH, RBC count, ferritin, transferrin saturation and soluble transferrin receptors. Multiple regression analysis was performed, with blood manganese as the dependent variable and factors of iron status, age and gender as independent variables. A strong relationship between blood manganese and iron deficiency was demonstrated (adjusted R(2)=34.3%, p<0.001) and the primary contributing factors to this relationship were haematological indices and soluble transferrin receptors. Subjects were categorised according to iron status using serum ferritin, transferrin saturation and haemoglobin indices. Children with iron deficiency anaemia had higher median blood manganese concentrations (16.4 MUg/L, range 11.7-42.4, n=20) than children with iron sufficiency (11 MUg/L, range 5.9-20.9, n=59, p<0.001). This suggests that children with iron deficiency anaemia may be at risk from manganese toxicity (whole blood manganese >20 MUg/L), and that this may lead to neurological problems. Treatment of iron deficiency in children is important both to improve iron status and to reduce the risk of manganese toxicity. PMID- 22940084 TI - Implicit gambling attitudes in problem gamblers: positive but not negative implicit associations. AB - BACKGROUND AND OBJECTIVES: Implicit attitudes (associations) are involved in the generation of substance use behaviors. However, little is known about the role of this automatic cognitive processing in deregulated behaviors without substance use, such as abnormal gambling. This study examined whether problem gamblers exhibit both positive and negative implicit attitudes toward gambling-related stimuli. METHODS: Twenty-five problem gamblers and 25 control participants performed two unipolar (pleasant; unpleasant) Single-Target Implicit Association Tasks (unipolar ST-IAT), in which gambling pictures were associated with either pleasant (or unpleasant for the negative unipolar ST-IAT) or neutral words. Explicit attitudes toward gambling were also recorded. RESULTS: We found in problem gamblers: (i) both positive implicit and explicit attitudes toward gambling; (ii) no negative implicit gambling association; (iii) that only positive explicit attitudes positively correlated with the gambling severity score. LIMITATIONS: (i) the use of only one type of reaction time task; (ii) the use of both words and pictures in a same IAT; (iii) problem gamblers have been compared to non-gamblers instead of being contrasted with healthy non-problem gamblers. CONCLUSIONS: Whereas our gamblers experienced deleterious effects related to gambling, implicit attitude toward gambling remained positive, thus hampering attempts to quit gambling. Possible clinical interventions targeting implicit cognition in problem gamblers were discussed. PMID- 22940085 TI - The double-stranded RNA-binding protein Staufen 2 regulates eye size. AB - Regulation of tissue size is a poorly understood process. Mammalian Staufen 2 (Stau2) is a double-stranded mRNA binding protein known to regulate dendrite formation in vitro as well as cell survival and migration in vivo. Three Stau2 isoforms have been identified in the brain of mammals. Here we show that all these Stau2 isoforms are also expressed in the developing eye of chicken embryos. Strikingly, ectopic expression of Stau2 was sufficient to increase eye size, suggesting a novel biological role of Stau2 in eye morphogenesis. Moreover, down regulation of Stau2 in vivo resulted in a small eye. Microphthalmia was not associated with either increased cell death or differentiation but with reduced cell proliferation. Rescue experiments showed that all three Stau2 isoforms present in the developing eye could prevent microphthalmia. Finally, we showed that Stau2 silencing decreased HES-1 and Sox-2 in the developing eye. These data highlight a new biological function for Stau2 and suggest that translation control of specific Stau2-associated transcripts may be a key regulator of tissue size. PMID- 22940086 TI - D. melanogaster, mitochondria and neurodegeneration: small model organism, big discoveries. AB - In developed countries, increased life expectancy is accompanied by an increased prevalence of age-related disorders like cancer and neurodegenerative diseases. Albeit the molecular mechanisms behind the clinically, pathologically and etiologically heterogeneous forms of neurodegeneration are often unclear, impairment of mitochondrial fusion-fission and dynamics emerged in recent years as a feature of neuronal dysfunction and death, pinpointing the need for animal models to investigate the relationship between mitochondrial shape and neurodegeneration. While research on mammalian models is slowed down by the complexity of the organisms and their genomes, the long latency of the symptoms and by the difficulty to generate and analyze large cohorts, the lower metazoan Drosophila melanogaster overcomes these problems, proving to be a suitable model to study neurodegenerative diseases and mitochondria-shaping proteins. Here we will summarize our current knowledge on the link between mitochondrial shape and models of neurodegeneration in the fruitfly. This article is part of a Special Issue entitled 'Mitochondrial function and dysfunction in neurodegeneration'. PMID- 22940087 TI - Prevalence and risk factors of diabetes in patients with Klinefelter syndrome: a longitudinal observational study. AB - OBJECTIVE: To evaluate the prevalence and risk factors of diabetes in patients with Klinefelter syndrome. DESIGN: Retrospective longitudinal study. SETTING: Medical college hospital. PATIENT(S): Klinefelter group (n = 39) and idiopathic hypogonadotropic hypogonadism (IHH) group (n = 40). INTERVENTION(S): Testosterone replacement therapy. MAIN OUTCOME MEASURE(S): The metabolic parameters, lipid profiles, and sex hormones were compared before and after T replacement therapy. The median duration of follow-up was 4 years in the Klinefelter group and 5.2 years in the IHH group. RESULT(S): The prevalence of diabetes was 20.5% (8 of 39) in the Klinefelter group and 5% in the IHH group. In the Klinefelter group, the incidence of diabetes was 12.5% in patients with 47,XXY karyotype and 57.1% in patients with other atypical karyotypes, such as 46XY/47XXY chimera. In the Klinefelter group, the average (+/- SD) age at diagnosis of diabetes was 27.1 +/- 4.5 years. Four subjects had diabetes before T therapy, and their blood glucose did not improve after T replacement. One patient had a history of acute pancreatitis. Two other subjects had very high triglyceride levels. During the follow-up, body weight increased more in Klinefelter patients than in IHH patients. CONCLUSION(S): The prevalence of diabetes is higher in Klinefelter patients than in IHH patients, possibly owing to abnormal karyotypes. Other risk factors, such as low T level, high body weight, acute pancreatitis, and high triglyceride levels, may also contribute to the development of diabetes. PMID- 22940088 TI - In vitro effects on intestinal bacterium of physalins from Physalis alkekengi var. Francheti. AB - Intestinal probiotic bacterium stimulative activity-guided fractionation of Physalis alkekengi var. Francheti calyces extract resulted in the isolation of four new physalins (1-4). Their structures were elucidated as 5alpha, 6beta dihydroxy-25, 27-dihydro-7-deoxyphysalin A (1), 5alpha, 6beta-dihydroxyphysalin R (2), 3beta-hydroxy-2-hydrophysalin A (3) and 5alpha-hydroxy-7-dehydro-25, 27 dihydro-7-deoxyneophysalin A (4) by UV, MS, 1D and 2D NMR spectroscopy. Growth curves of Lactobacillus delbrueckii and Escherichia coli for different total physalins extract (TPE) concentrations were tested in vitro. Middle concentrations (0.78mg/mL-1.56mg/mL) of TPE promoted the growth of L. delbrueckii, but all inhibited the growth of E. coli, in which the bacteriostatic activity increased while TPE concentration increases. Physalins showed stimulative effects on the growth of probiotic bacteria but inhibitory effects on the growth of pathogenic bacteria. PMID- 22940089 TI - Phenotypic expression of Bardet-Biedl syndrome in patients homozygous for the common M390R mutation in the BBS1 gene. AB - PURPOSE: To characterize the phenotype of Bardet-Biedl syndrome (BBS) patients homozygous for the BBS1 M390R mutation. METHODS: Three patients [PT1, F, 27 years old (yo) at last examination, 14-year follow-up (F/U) PT2, F, 15-yo PT3, M, 15 yo, both 1-year F/U] underwent eye exams, Goldmann visual fields (GVFs), dark- (DA) and light-adapted (LA) electroretinograms (ERGs), spectral domain optical coherence tomography (SD-OCT) and fundus autofluorescence (FAF). Vision and systemic history were also collected. RESULTS: All patients had night blindness, hyperopic astigmatism, ptosis or mild blepharospasm, foot polydactyly, 5th finger clinodactyly, history of headaches, and variable, diet-responsive obesity. Two had asthma, PT1 was developmentally delayed, PT2 had Asperger-like symptoms, and PT3 had normal cognition. At age 14, acuity was 20/100 in PT1, who had nystagmus since age 2, 20/40 in PT2 and 20/30 in PT3. By 27yo PT1 progressed to 20/320, by 15 yo PT2 was 20/60 and PT3 remained stable. PT1 had well preserved peripheral GVFs, with minimal progression over 10 years of F/U. PT2 and PT3 presented with ring scotomas and I4e<5 degrees . All patients had severe generalized visual sensitivity depression. ERGs were consistently recordable (also rod ERG in PT3 after 60 min DA), but progressed to non-recordable in PT1. Mixed DA ERGs exhibited electronegativity. In PT3, this was partly due to a bleaching effect during bright-flash DA averaging, partly to ON?OFF LA response compromise. PT2 and 3 had, on SD-OCTs, generalized macular thinning, normal retinal lamination, and widespread photoreceptor outer/inner segment attenuation except foveally, and multiple rings of abnormal FAF configuring a complex bull's eye-pattern. PT1 had macular atrophy. All patients also had peripapillary nerve fiber layer thickening. CONCLUSIONS: The observed phenotype matches very closely that reported in patients by Azari et al. (IOVS 2006) and in the Bbs1-M390R knock-in mouse model, and expands it to the characterization of important ERG response characteristics that provide insight in the pathogenesis of retinopathy in these patients. Our findings confirm the consistent pathogenicity of the BBS1 M390R mutation. PMID- 22940090 TI - Moderated mediation path analysis of Mexican traumatic brain injury patient social functioning, family functioning, and caregiver mental health. AB - OBJECTIVE: To examine the system of connections among traumatic brain injury (TBI) patient social functioning, family functioning, and caregiver depression and burden in Mexico. DESIGN: Cross-sectional survey. SETTING: A public medical facility. PARTICIPANTS: Mexican TBI patient-caregiver dyads (N=84) participated in this study. Most of the patients with TBI were men (81%), with an average age +/- SD of 38.83+/-13.44 years. The majority of caregivers (86%) were women, with an average age +/- SD of 51.74+/-11.29. INTERVENTION: Not applicable. MAIN OUTCOME MEASURES: Outcomes assessed included family functioning (Family Satisfaction Scale), patient social functioning (Medical Outcomes Study 36-Item Short-Form Health Survey), and caregiver mental health (Patient Health Questionnaire-9 and Zarit Burden Interview). RESULTS: A moderated mediation path model found that patient social functioning and family functioning predicted caregiver burden, and caregiver burden mediated the effect of family functioning on caregiver depression. Caregivers with strong family functioning tended to have low burden, no matter the level of patient social functioning. This path model provided an excellent fit and explained 47% of the variance in caregiver burden and 36% of the variance in caregiver depression. CONCLUSIONS: In Mexico, strong family functioning is an important buffer in the relationship between TBI patient social functioning deficits and caregiver mental health, especially because familism is a core value in Latino culture. Rehabilitation interventions designed to strengthen family functioning may improve caregiver mental health, thereby influencing the quality of informal care that caregivers are able to provide. PMID- 22940091 TI - Polymorphisms in the lectin pathway genes as a possible cause of early chronic Pseudomonas aeruginosa colonization in cystic fibrosis patients. AB - Genes of innate immunity may be involved in early onset of chronic Pa (Pseudomonas aeruginosa) colonization (cPaC) in cystic fibrosis (CF) patients. We studied 19 single nucleotide polymorphisms (SNPs) in 5 genes coding for proteins of the lectin complement pathway: MBL2 (Mannose binding lectin 2), MASP 1, 2, 3 (MBL-associated serine Protease) and FCN 1, 2 (Ficolin) gene in 96 CF patients. Association survival analysis using different genetic models was performed looking for an association between SNPs and age at onset of cPaC. CF patients who are MBL deficient are earlier chronic Pa colonized compared to MBL sufficient patients. Also patients with MBL2 genotype YO/YO, YO/XA, XA/XA, YA/YO and YA/XA are earlier chronic Pa colonized. CF patients heterozygous or homozygous for mutant alleles of two linked SNPs in the FCN1 gene (rs2989727 and rs1071583) are earlier colonized with Pa. Similarly, earlier onset of Pa colonization is seen in CF patients heterozygous for linked SNPs of FCN2 gene (rs7865453 and rs7851696) and MASP3 gene (rs7851696). Variants in MBL2, FCN1, FCN2 and MASP3 genes are significantly associated with earlier onset of chronic P. aeruginosa colonization. PMID- 22940092 TI - Use of simultaneous depth and MEG recording may provide complementary information regarding the epileptogenic region. AB - Simultaneous SEEG-MEG recording has the potential to define the epileptic spike source accurately. We present a case of a 55-year-old female with intractable left temporal lobe epilepsy in whom we evaluated the relationship between the amplitude recorded from SEEG electrodes, inserted in the lateral temporal region, and their distance from the MEG-modelled spike. We found a quadratic fall-off relationship between the amplitude and distance. This result supports the concept that the MEG dipoles reflect the "centre" of spike locations and may provide comprehensive information for SEEG which records spike activities directly but is inherently limited in spatial sampling. PMID- 22940093 TI - Electroporation enhances mitomycin C cytotoxicity on T24 bladder cancer cell line: a potential improvement of intravesical chemotherapy in bladder cancer. AB - Intravesical mitomycin instillation combined with electric pulses is being used experimentally for the treatment of T1 bladder tumors, in patients unfit for surgery. Electroporation may enhance the uptake of chemotherapeutics by permeabilization of cell membranes. We investigated if electroporation improves the cytotoxicity of mitomycin. In two cell lines, T24 (bladder cancer cell line) and DC3F (Chinese hamster fibroblast), exposure to different concentrations of mitomycin (0.01-2000MUM) was tested with and without electroporation (6 pulses of 1kV/cm, duration: 99MUs, frequency: 1Hz). Cell viability was assessed by colorimetric assay (MTT). For both cell lines, mitomycin's IC_50 was approximately 1000MUM in both pulsed and unpulsed cells. On T24 cells, electroporation and mitomycin caused (relative reduction) RR of survival of: 25%, 31% and 29%, by concentrations 0MUM, 500MUM and 1000MUM respectively. For DC3F cells, the RRs of survival were: 28%, 29%, and 33%, by concentrations 0MUM, 500MUM and 1000MUM respectively. In conclusion, electroporation and mitomycin together are about 30% more effective than mitomycin alone. The results help to elucidate the additive effect of mitomycin and electric pulses and support the use of this combination in the treatment of bladder cancer. PMID- 22940094 TI - Vitrification of oocytes, embryos and blastocysts. AB - In assisted reproductive technology, cryopreservation of human oocytes and embryos has been significantly improved by refined slow-cooling and the new vitrification method. The slow-cooling method requires a programmed cryo-machine, and usually takes several hours. It is, however, difficult to eliminate injuries resulting from ice formation completely. Vitrification has become a reliable strategy because it is simple, can lead to high survival rates and viability, and has better clinical outcome. Vitrification transforms cells into an amorphous glassy state inside and outside the vitrified cell with ultra-rapid cooling and warming steps by plunging the oocytes and embryos into liquid nitrogen, instead of ice-crystal formation. Over the past decade, several advances in vitrification technologies have improved clinical efficiency and outcome. In this chapter, we focus on vitrification technologies for cryopreservation in human assisted reproductive technology. PMID- 22940095 TI - Ras and Rap1 govern spatiotemporal dynamic of activated ERK in pituitary living cells. AB - The Ras/Raf/MEK/ERK is a conserved signalling pathway involved in the control of fundamental cellular processes. Despite extensive research, how this pathway can process a myriad of diverse extracellular inputs into substrate specificity to determine biological outcomes is not fully understood. It has been established that the ERK1/2 pathway is an integrative point in the control of the pituitary function exerted by various extracellular signals. In addition we previously established that the GTPases Ras and Rap1 play a key role in the regulation of ERK1/2-dependent prolactin transcription by EGF or the cAMP-dependent neuropeptide VIP. In this report, using the FRET-based biosensor of ERK activity (EKAR) in the pituitary GH4C1 cell line, we show that both EGF and VIP tightly control the spatiotemporal dynamic of activated ERK with different magnitude and duration. Importantly, we provide the first evidence of a differential control of cytoplasmic and nuclear pools of activated ERK by the GTPases Ras and Rap1. Ras is required for nuclear magnitude and duration of EGF-dependent ERK activation, whereas it is required for both VIP-activated cytoplasmic and nuclear ERK pools. Rap1 is exclusively involved in VIP-activated ERK nuclear pool. Moreover, consistent with the control of the nuclear pool of activated ERK by the GTPases, we observe the same differential role of Ras and Rap1 on ERK nuclear translocation triggered by EGF or VIP. Together these findings identify Ras and Rap1 as determinant partners in shaping nuclear and cytoplasmic ERK kinetics in response to EGF and VIP, which in turn should control pituitary secretion. PMID- 22940096 TI - RECQL4 in genomic instability and aging. AB - Helicases are ubiquitous proteins that unwind DNA and participate in DNA metabolism including replication, repair, transcription, and chromatin organization. The highly conserved RecQ helicase family proteins are important in these transactions and have been termed the guardians of the genome. Humans have five members of this family: WRN, BLM, RECQL4, RECQL1, and RECQL5. The first three of are associated with premature aging and cancer prone syndromes, but the latter two proteins have not yet been implicated in any human disease. Although WRN and BLM have been fairly well characterized, RECQL4 has only recently been intensively investigated. The sum of this work to date has shown that RECQL4 has helicase activity and localizes to telomeres and mitochondria. In addition, new protein partners are emerging, implicating RECQL4 in novel processes. Here, we describe these recent findings which place RECQL4 at the crossroads of genomic instability and aging processes. PMID- 22940097 TI - Inflammatory monocytes activate memory CD8(+) T and innate NK lymphocytes independent of cognate antigen during microbial pathogen invasion. AB - Memory CD8(+) T cells induced upon immunization exhibit improved functional features that contribute to protection of immunized hosts. Although both cognate antigen recognition and inflammation are important for memory CD8(+) T cell reactivation, the relative contribution of these factors and the cell types providing these signals in vivo are poorly defined. Here, we show that Ly6C(+)CCR2(+) inflammatory monocytes, a subset of monocytes, largely orchestrate memory CD8(+) T and NK lymphocytes activation by differentiating into interleukin 18 (IL-18)- and IL-15-producing cells in an inflammasome and type I interferon IRF3-dependent manner. Memory CD8(+) T cells became potent effector cells by sensing inflammation from monocytes independently of their cognate antigen. Like NK cells, they underwent rapid mobilization, upregulated intense and sustained effector functions during bacterial, viral, and parasitic infections, and contributed to innate responses and protection in vivo. Thus, inflammatory monocyte-derived IL-18 and IL-15 are critical to initiate memory CD8(+) T and NK lymphocytes differentiation into antimicrobial effector cells. PMID- 22940098 TI - Lymphotoxin-beta receptor signaling through NF-kappaB2-RelB pathway reprograms adipocyte precursors as lymph node stromal cells. AB - Lymph node development during embryogenesis involves lymphotoxin-beta receptor engagement and subsequent differentiation of a poorly defined population of mesenchymal cells into lymphoid tissue organizer cells. Here, we showed that embryonic mesenchymal cells with characteristics of adipocyte precursors present in the microenvironment of lymph nodes gave rise to lymph node organizer cells. Signaling through the lymphotoxin-beta receptor controlled the fate of adipocyte precursor cells by blocking adipogenesis and instead promoting lymphoid tissue stromal cell differentiation. This effect involved activation of the NF-kappaB2 RelB signaling pathway and inhibition of the expression of the key adipogenic factors Ppargamma and Cebpalpha. In vivo organogenesis assays show that embryonic and adult adipocyte precursor cells can migrate into newborn lymph nodes and differentiate into a variety of lymph node stromal cells. Thus, we propose that adipose tissues act as a source of lymphoid stroma for lymph nodes and other lymphoid structures associated with fat. PMID- 22940099 TI - Geographical distribution updating of Tunisian leishmaniasis foci: about the isoenzymatic analysis of 694 strains. AB - Over a period of ten years, a series of 694 Leishmania strains from Tunisian leishmaniasis foci were isolated and identified by isoenzymatic analysis. Strains were obtained from human cutaneous and visceral leishmaniasis in immunocompetent subjects, visceral leishmaniasis in imunocompromised individuals and from dogs with visceral leishmaniasis. Two classically dermotropic species, Leishmania (L.) major and Leishmania killicki were found. L. major with the single zymodeme MON 25 was the most isolated in cutaneous leishmaniasis foci of the Centre and South of Tunisia with a recent northern extension. L. killicki zymodeme MON-8 was sporadically found both in its classical microfocus of Tataouine in southeastern Tunisia as well as in some new foci in Southwestern, Central and Northern Tunisia. Leishmania infantum with its three zymodemes MON-1, MON-24 and MON-80 was isolated from both visceral and cutaneous human cases. The majority of L. infantum strains were found in the Northern part of the country; however, some strains were reported for the first time in the Southern part. L. infantum MON-1 was the only zymodeme isolated from canine leishmaniasis. PMID- 22940100 TI - Magnetic affinity enzyme-linked immunoassay based on recombinant 26 kDa glutathione-S-transferase for serological diagnosis of schistosomiasis japonica. AB - Schistosomiasis remains a serious worldwide public health problem. Improving the diagnostic assay for surveillance and monitoring will contribute to hastening the possible elimination of the disease in endemic regions. Therefore, this study aims to develop magnetic affinity enzyme-linked immunoassay (MEIA) for serological diagnosis of schistosomiasis based on recombinant 26kDa glutathione-S transferase of Schistosoma japonicum (rSj26GST). BALB/c mice infected with S. japonicum cercariae (40 per mouse) were used. After infecting for 6 weeks, the antibody was detected by MEIA. All of the infected mouse sera were effectively determined by MEIA. Compared with the enzyme-linked immunosorbent assay (ELISA), MEIA has a higher ratio of the mean positive value to the mean negative value (P/N) at the same dilution ratio (3.92 versus 2.66). MEIA was further applied for diagnosis of human schistosomiasis. Sera from 28 schistosomiasis-confirmed patients with low-intensity infection, 15 treated patients, and 20 non-endemic negative controls, were used to assess the assay. The results showed that MEIA and ELISA had similarity in positive detection rates. However, the higher P/N of MEIA was observed at the same dilution ratio. MEIA had high negative rate in detection of specific IgG in the treated patients. Moreover, there was no cross reaction with the sera of paragonimiasis patients. These results suggested that MEIA based on rSj26GST is a simple, rapid, convenient assay for the diagnosis of schistosomiasis. PMID- 22940101 TI - Adaptation of the neutral bacterial comet assay to assess antimicrobial-mediated DNA double-strand breaks in Escherichia coli. AB - This study aimed to determine the mechanism of action of a natural antibacterial clay mineral mixture, designated as CB, by investigating the induction of DNA double-strand breaks (DSBs) in Escherichia coli. To quantify DNA damage upon exposure to soluble antimicrobial compounds, we modified a bacterial neutral comet assay, which associates the general length of an electrophoresed chromosome, or comet, with the degree of DSB-associated DNA damage. To appropriately account for antimicrobial-mediated strand fragmentation, suitable control reactions consisting of exposures to water, ethanol, kanamycin, and bleomycin were developed and optimized for the assay. Bacterial exposure to the CB clay resulted in significantly longer comet lengths, compared to water and kanamycin exposures, suggesting that the induction of DNA DSBs contributes to the killing activity of this antibacterial clay mineral mixture. The comet assay protocol described herein provides a general technique for evaluating soluble antimicrobial-derived DNA damage and for comparing DNA fragmentation between experimental and control assays. PMID- 22940102 TI - Progress in understanding preferential detection of live cells using viability dyes in combination with DNA amplification. AB - The ideal scenario in most applications of microbial diagnostics is that only viable cells are detected. Bacteria were traditionally considered viable when they could be cultured, whereas today's viability concept tends to be alternatively based on the presence of some form of metabolic activity, a positive energy status, responsiveness, detection of RNA transcripts that tend to degrade rapidly after cell death, or of an intact membrane. The latter criterion, although conservative, was the focus of one of the most successful recent approaches to detect viable cells in combination with DNA amplification techniques. The technology is based on sample treatment with the photoactivatable, and cell membrane impermeant, nucleic acid intercalating dyes ethidium monoazide (EMA) or propidium monoazide (PMA) followed by light exposure prior to extraction of DNA and amplification. Light activation of DNA-bound dye molecules results in irreversible DNA modification and subsequent inhibition of its amplification. Sample pretreatment with viability dyes has so far been mainly used in combination with PCR (leading to the term viability PCR, v-PCR), and increasingly with isothermal amplification method. The principle is not limited to bacteria, but has also successfully been applied to fungi, protozoa and viruses. Despite the success of the method, some practical limitations have been identified, especially when applied to environmental samples. In part they can be minimized by choice of experimental parameters and conditions adequate for a particular sample. This review summarizes current knowledge and presents aspects which are important when designing experiments employing viability dyes. PMID- 22940103 TI - Explaining the enforcement gap in China: local government support and internal agency obstacles as predictors of enforcement actions in Guangzhou. AB - This study investigates how local government support for enforcement and internal agency obstacles explain the enforcement gap in Guangzhou, China. It was found that agency obstacles associated with insufficient resources and job ambiguity, in particular, affect enforcement officials' perceptions of enforcement difficulty. Somewhat more surprisingly, however, local government support was not found to be a significant predictor of these perceptions. In addition, this study identified four significant relationships associated with specific enforcement actions. First and second, perceptions of enforcement difficulty appear to lead to fewer inspections, but also have a weak positive effect on the frequency of fines levied. Third, poor coordination within the bureau was found to be associated with fewer violations being processed. Fourth, and contrary to expectations, local government support was found to suppress the frequency of inspections while having no significant effect on violations or fines. Overall, these findings suggest that increased local government support for the enforcement of environmental regulation in China may not necessarily lead to more rigorous enforcement, at least if enforcement rigor is measured in terms of inspections, citations and fines. PMID- 22940104 TI - Response of drought and fertilization in Erica andevalensis seed banks: significance for conservation management. AB - The present study attempts to investigate the size, composition and seedling dynamics of the seed bank of a metalliferous and vulnerable species, Erica andevalensis. Samples were taken during spring and autumn from two different sites. We also studied the effects of nutrient solution, irrigation from the river Tinto and irrigation deficit on seeding establishment and survival. Only E. andevalensis and Poaceae species emerged from the seed banks, although the former was dominant (98%). Germination and seedling establishment was totally inhibited by the waters of the river Tinto. Seed density was high in the soils of both seed banks irrigated with water and nutrient solution. We found no seasonal differences in the seed bank and number of germinated seeds and mortality rate and density were similar. From the standpoint of restoration management, the results indicate that the seed bank is a very important factor for successful species establishment. PMID- 22940105 TI - Biochemical and biophysical origins of cadherin selectivity and adhesion strength. AB - Classical cadherins are single-pass transmembrane proteins mediating adhesive interactions between animal cells. As such, they play key roles during morphogenetic movements, in cell sorting and in tissue integrity. Being positioned at the cell-cell interface, cadherins are most likely important players in mechanotransduction pathways. This review briefly outlines our current understanding of the biochemical and biophysical basis for various adhesive properties of cadherins and the ensuing intercellular adhesive strength and specificity. We summarize the attempts to explain cadherin specificity from their ultrastructural features and their adhesive behavior at the single molecule level. The role of cadherin clusters and cooperative binding is then reviewed. Lastly, we consider the attempts to understand the link between local stress and the adhesive properties of cadherin-mediated junctions. PMID- 22940106 TI - Deletion of a single helix from the transmembrane domain causes large changes in membrane insertion properties and secondary structure of the bacterial conjugation protein TrwB. AB - TrwB is an essential protein in the conjugative transfer of plasmid R388. The protein consists of a bulky cytosolic domain containing the catalytic site, and a small transmembrane domain (TMD). Our previous studies support the idea that the TMD plays an essential role in the activity, structure and stability of the protein. We have prepared a mutant, TrwBDeltaN50 that lacks one of the two alpha helices in the TMD. The mutant has been studied both in detergent suspension and reconstituted in lipid vesicles. Deletion of a single helix from the TMD is enough to increase markedly the affinity of TrwB for ATP. The deletion changes the secondary structure of the cytosolic domain, whose infrared spectroscopy (IR) spectra become similar to those of the mutant TrwBDeltaN70 lacking the whole TMD. Interestingly, when TrwBDeltaN50 is reconstituted into lipid membranes, the cytosolic domain orients itself towards the vesicle interior, opposite to what happens for wild-type TrwB. In addition, we analyze the secondary structure of the TMD and TMD-lacking mutant TrwBDeltaN70, and found that the sum IR spectrum of the two protein fragments is different from that of the native protein, indicating the irreversibility of changes caused in TrwB by deletion of the TMD. PMID- 22940107 TI - Sexual violence against women: the scope of the problem. AB - Rape and sexual violence occur in all societies, and cut across all social classes. Prevalence estimates of rape victimisation range between 6 and 59% of women having experienced sexual abuse from their husbands or boyfriends in their lifetime. Two population-based studies from South Africa have found that 28% and 37% of men, respectively, have perpetrated rape. Estimates of rape perpetration from high-income countries seem to be lower than those from low- and middle income countries; however, current data make it impossible to confirm this. Women and girls are much more likely to be the victims and men the perpetrators and, in most instances, the perpetrator is known to the victim. Children are particularly vulnerable to sexual abuse, with girls being at greater risk, especially while at school and at home. High rates of child sexual abuse are emerging from the research, with an increasing understanding of the effect of child sexual abuse on later perpetration and victimisation, highlighting the importance of primary prevention for sexual violence to address childhood exposures to violence. Much of our knowledge about sexual violence has historically been based on research undertaken in high-income countries. This, however, is changing with the emergence of good-quality studies from other settings, particularly in Africa, alongside an increasing number of multi-country studies looking at interpersonal and sexual violence. Most countries lack population data on perpetration of sexual violence, across all categories, including children, and a major gap exists in research on sexual violence among sub-groups and populations. Much of the existing research has limitations that affect cross-study comparability, owing to differences in definitions, research tools, methods and sampling used. Improved research is essential. Research priorities for understanding the magnitude of sexual violence prevalence include assessment of the prevalence and patterns of sexual violence victimisation and perpetration in a range of settings, across a range of acts of sexual violence, in men and women, in adults and children, using methodologies based on best practice in gender-based violence research and standard measures of different forms of sexual violence; research on the social context of sexual violence perpetration and victimisation by both men and women; and methodological research to measure sexual violence for particular population sub-groups or violence types, such as child perpetrators or young child victims, or sexual harassment at work and school. PMID- 22940108 TI - GABA-mediated induction of early neuronal markers expression in postnatal rat progenitor cells in culture. AB - Retinogenesis is a developmental process that involves the sequential formation of neurons and glia from retinal progenitors. Once retinogenesis is completed, Muller glial cells can be stimulated to differentiate into neuronal lineages and constitute a retina-intrinsic source of neural progenitors. The identification of the intrinsic and extrinsic factors that control proliferation and differentiation of Muller cells or retinal progenitors is needed in order to fully define their potential therapeutic use in regenerative approaches. Here we determined the response of retinal progenitors derived from Muller glia primary cell cultures to GABA-activated signal transduction cascades. Using Western blot analysis, immunocytochemistry and calcium imaging we found that GABA induces an increase of the number of progenitor cells that present spontaneous intracellular calcium transients as well as their frequency, which involve the participation of L-type voltage-gated calcium channels (VGCCs). This process correlates with the activation of transcription factor CREB through Ser33 phosphorylation and the induction of expression of the early neuronal markers NeuroD1 and betaIII tubulin. GABA-mediated CREB phosphorylation was rapid and sustained and the pharmacological blockade of CREB activity inhibited the effect of GABA on NeuroD1 expression. Furthermore, consistent with the role of CREB as a histone acetyltransferase recruiter, we demonstrate that GABA induces the modification of histone H4 acetylation pattern in these cells suggesting that epigenetic alterations participate in the differentiation process. Our results support the notion that postnatal retinal progenitors derived from Muller glia primary cell cultures respond to GABA through the same molecular pathway previously characterized in hippocampal progenitors and developing neurons. We speculate that the induction of GABA receptor signaling could represent a novel strategy to enhance neural versus glial specification from these cells through genetic and epigenetic mechanisms. PMID- 22940109 TI - Parasite-induced suppression of aggregation under predation risk in a freshwater amphipod: sociality of infected amphipods. AB - Recent findings suggest that grouping with conspecifics is part of the behavioural defences developed by amphipod crustaceans to face predation risk by fish. Amphipods commonly serve as intermediate hosts for trophically transmitted parasites. These parasites are known for their ability to alter intermediate host phenotype in a way that promotes predation by definitive hosts, where they reproduce. If aggregation in amphipods dilutes the risk to be preyed on by fish, then it may dilute the probability of transmission for the parasite using fish as definitive hosts. Using experimental infections, we tested whether infection with the fish acanthocephalan Pomphorhynchus laevis alters attraction to conspecifics in the amphipod intermediate host Gammarus pulex. We also measured G. pulex's activity and reaction to light to detect potential links between changes in aggregation and changes in other behaviours. The attraction to conspecifics in the presence of predator cue, a behaviour found in uninfected gammarids, was cancelled by the infection, while phototaxis was reversed and activity unchanged. We found no correlation between the three behaviours in infected amphipods, while activity and aggregation were negatively correlated in uninfected individuals after the detection of predation cue. The physiological causes and the adaptive value of aggregation suppression are discussed in the context of a multidimensional manipulation. PMID- 22940110 TI - S-nitrosoglutathione-induced toxicity in Drosophila melanogaster: Delayed pupation and induced mild oxidative/nitrosative stress in eclosed flies. AB - The toxicity of the nitric oxide donor S-nitrosoglutathione (GSNO) was tested on the Drosophila melanogaster model system. Fly larvae were raised on food supplemented with GSNO at concentrations of 1.0, 1.5 or 4.0mM. Food supplementation with GSNO caused a developmental delay in the flies. Biochemical analyses of oxidative stress markers and activities of antioxidant and associated enzymes were carried out on 2-day-old flies that emerged from control larvae and larvae fed on food supplemented with GSNO. Larval exposure to GSNO resulted in lower activities of aconitase in both sexes and also lower activities of catalase and isocitrate dehydrogenase in adult males relative to the control cohort. Larval treatment with GSNO resulted in higher carbonyl protein content and higher activities of glucose-6-phosphate dehydrogenase in males and higher activities of superoxide dismutase and glutathione-S-transferase in both sexes. Among the parameters tested, aconitase activity and developmental end points may be useful early indicators of toxicity caused by GSNO. PMID- 22940111 TI - Cryptogenic West syndrome and subsequent mesial temporal lobe epilepsy. AB - We report on a male patient who experienced a previously unreported sequence of cryptogenic West syndrome in infancy and subsequent mesial temporal lobe epilepsy. His complex partial seizures were consistently characterised by motionless staring with brief right eye blinking. Scalp electroencephalography (EEG) showed bilateral temporal spikes which were dominant on the right side. Magnetic resonance imaging (MRI) revealed no organic brain lesion. Invasive EEG recording captured seizures with right hippocampal onset. The patient became seizure-free following right temporal lobectomy at 27 years, 8 months of age. Pathological examination of the resected specimen revealed corpora amylacea and gliosis in the temporal cortex but no clear findings of hippocampal sclerosis. It is suggested that an epileptogenic lesion causing MRI-negative mesial temporal lobe epilepsy may give rise to apparent cryptogenic West syndrome in infancy. PMID- 22940112 TI - Structural considerations for chromatin state models with transcription as a functional readout. AB - Lacking from the rapidly evolving field of chromatin regulation is a discrete model of chromatin states. We propose that each state in such a model should meet two conditions: a structural component and a quantifiable effect on transcription. The practical benefits to the field of a model with greater than two states (including one with six states, as described herein) would be to improve interpretation of data from disparate organ systems, to reflect temporal and developmental dynamics and to integrate the, at present, conceptually and experimentally disparate analyses of individual genetic loci (in vitro or using single gene approaches) and genome-wide features (including ChlP-seq, chromosomal capture and mRNA expression via microarrays/sequencing). PMID- 22940113 TI - Colonization of the satellite cell niche by skeletal muscle progenitor cells depends on Notch signals. AB - Skeletal muscle growth and regeneration rely on myogenic progenitor and satellite cells, the stem cells of postnatal muscle. Elimination of Notch signals during mouse development results in premature differentiation of myogenic progenitors and formation of very small muscle groups. Here we show that this drastic effect is rescued by mutation of the muscle differentiation factor MyoD. However, rescued myogenic progenitors do not assume a satellite cell position and contribute poorly to myofiber growth. The disrupted homing is due to a deficit in basal lamina assembly around emerging satellite cells and to their impaired adhesion to myofibers. On a molecular level, emerging satellite cells deregulate the expression of basal lamina components and adhesion molecules like integrin alpha7, collagen XVIIIalpha1, Megf10, and Mcam. We conclude that Notch signals control homing of satellite cells, stimulating them to contribute to their own microenvironment and to adhere to myofibers. PMID- 22940115 TI - Effect of preen oil on plumage bacteria: an experimental test with the mallard. AB - Feathers are essential for avian thermoregulation, communication or flight and a reduction of plumage condition may alter these functions and reduce individual fitness. Recently, descriptive studies provided evidence that birds carry feather degrading bacteria on their plumage that have the ability to degrade feathers rapidly under laboratory conditions. If such bacteria reduce avian fitness, natural selection should favour the evolution of anti-bacterial defences to limit the effects of these detrimental microorganisms. Preening behaviour and associated preen gland secretions have been proposed as the main factor used by birds to limit feather-degrading bacterial growth and some recent in vitro studies provided evidence that uropygial oil inhibited the growth of some keratinolytic strains in passerines. However, preen oil antimicrobial properties remained to be experimentally tested in vivo. We conducted an experiment with mallards (Anas platyrhynchos) onto which we fixed a removable mechanism that blocked access to the uropygial gland in a first group of mallards, whilst birds in a second group had the same removable mechanism but access to their gland and a third group of birds had normal access to their gland. We found no significant effect of our treatment on total and feather-degrading bacterial loads. Three hypotheses may explain the discrepancy between our results and previous in vitro studies. First, in vitro studies may have over-estimated the bactericidal properties of the preen oil. Second, preen gland deprivation may have affected only a small portion of the feather-degrading bacterial community. Third, ducks and passerine oils might have different bactericidal properties. PMID- 22940114 TI - Regulation of endocytic clathrin dynamics by cargo ubiquitination. AB - VIDEO ABSTRACT: Some endocytic cargoes control clathrin-coated pit (CCP) maturation, but it is not known how such regulation is communicated. We found that MU-opioid neuropeptide receptors signal to their enclosing CCPs by ubiquitination. Nonubiquitinated receptors delay CCPs at an intermediate stage of maturation, after clathrin lattice assembly is complete but before membrane scission. Receptor ubiquitination relieves this inhibition, effectively triggering CCP scission and producing a receptor-containing endocytic vesicle. The ubiquitin modification that conveys this endocytosis-promoting signal is added to the receptor's first cytoplasmic loop, catalyzed by the Smurf2 ubiquitin ligase, and coordinated with activation-dependent receptor phosphorylation and clustering through Smurf2 recruitment by the endocytic adaptor beta-arrestin. Epsin1 detects the signal at the CCP and is required for ubiquitin-promoted scission. This cargo-to-coat communication system mediates a biochemical checkpoint that ensures appropriate receptor ubiquitination for later trafficking, and it controls specific receptor loading into CCPs by sensing when a sufficient quorum is reached. PMID- 22940116 TI - Noninvasive photoacoustic computed tomography of mouse brain metabolism in vivo. AB - We have demonstrated the feasibility of imaging mouse brain metabolism using photoacoustic computed tomography (PACT), a fast, noninvasive and functional imaging modality with optical contrast and acoustic resolution. Brain responses to forepaw stimulations were imaged transdermally and transcranially. 2-NBDG, which diffuses well across the blood-brain-barrier, provided exogenous contrast for photoacoustic imaging of glucose response. Concurrently, hemoglobin provided endogenous contrast for photoacoustic imaging of hemodynamic response. Glucose and hemodynamic responses were quantitatively decoupled by using two-wavelength measurements. We found that glucose uptake and blood perfusion around the somatosensory region of the contralateral hemisphere were both increased by stimulations, indicating elevated neuron activity. While the glucose response area was more homogenous and confined within the somatosensory region, the hemodynamic response area had a clear vascular pattern and spread wider than the somatosensory region. Our results demonstrate that 2-NBDG-enhanced PACT is a promising tool for noninvasive studies of brain metabolism. PMID- 22940118 TI - Second trimester amniotic fluid adiponectin level is affected by maternal tobacco exposure, insulin, and PAPP-A level. AB - OBJECTIVES: Adiponectin is an adipocyte-derived plasma protein with insulin sensitizing and antiatherosclerotic properties. The objectives of the present study were to determine the amniotic fluid (AF) concentration of adiponectin during the second trimester of pregnancy and to demonstrate its association with maternal and fetal variables and AF concentrations of insulin, leptin, and pregnancy-associated-plasma-protein A (PAPP-A). STUDY DESIGN: We performed a cross-sectional study of 222 pregnant women who underwent amniocentesis at 15-18 weeks for genetic reasons. No malformation or chromosomal disorder was found in the newborn after birth. AF adiponectin, leptin, PAPP-A, and insulin concentrations were measured using commercially available assays. All maternal, fetal, and biochemical variables were studied using univariate and multivariate linear regression analysis to determine their association with the AF concentration of adiponectin. RESULTS: Adiponectin concentration was negatively correlated with maternal smoking status (beta=-5.208; p<0.001) and positively correlated with levels of insulin (beta=0.621; p=0.002) and PAPP-A (beta=40.150; p<0.001). Non-significant correlations were found between adiponectin concentration and maternal age, maternal body mass index, gestational age at amniocentesis, fetal gender, and AF level of leptin. CONCLUSION: These findings suggest that the fetus and its membrane adipocytokines, in relationship with maternal and other fetal variables, play a dynamic role in the regulation of energy and oxidative stress homeostasis due to its insulin-sensitizing and antiatherosclerotic effects. The association of these molecules with maternal tobacco consumption during pregnancy could have perinatal implications. PMID- 22940117 TI - The different faces of one's self: an fMRI study into the recognition of current and past self-facial appearances. AB - Mirror self-recognition is often considered as an index of self-awareness. Neuroimaging studies have identified a neural circuit specialised for the recognition of one's own current facial appearance. However, faces change considerably over a lifespan, highlighting the necessity for representations of one's face to continually be updated. We used fMRI to investigate the different neural circuits involved in the recognition of the childhood and current, adult, faces of one's self. Participants viewed images of either their own face as it currently looks morphed with the face of a familiar other or their childhood face morphed with the childhood face of the familiar other. Activity in areas which have a generalised selectivity for faces, including the inferior occipital gyrus, the superior parietal lobule and the inferior temporal gyrus, varied with the amount of current self in an image. Activity in areas involved in memory encoding and retrieval, including the hippocampus and the posterior cingulate gyrus, and areas involved in creating a sense of body ownership, including the temporo parietal junction and the inferior parietal lobule, varied with the amount of childhood self in an image. We suggest that the recognition of one's own past or present face is underpinned by different cognitive processes in distinct neural circuits. Current self-recognition engages areas involved in perceptual face processing, whereas childhood self-recognition recruits networks involved in body ownership and memory processing. PMID- 22940119 TI - The effect of progesterone supplementation on pregnancy rates in controlled ovarian stimulation and intrauterine insemination cycles: a randomized prospective trial. AB - OBJECTIVE: To evaluate the effect of vaginal progesterone as luteal phase support on pregnancy rates in controlled ovarian stimulation and intrauterine insemination cycles in couples with unexplained or mild male factor infertility. STUDY DESIGN: 290 Patients who met the inclusion criteria were included in a prospective randomized controlled trial. All patients underwent controlled ovarian stimulation and intrauterine insemination: 148 patients were randomized to start with a supported cycle and 142 patients with an unsupported cycle. In supported cycles, patients received vaginal progesterone once daily from the day after insemination until 12 weeks of pregnancy or, in non-pregnant women, for 14 days. No progesterone was given during unsupported cycles. The main outcome measures were clinical pregnancy rates per cycle. RESULTS: In total, 148 cycles with luteal phase support and 142 cycles without luteal phase support were performed. The clinical pregnancy rates per cycle were higher for cycles with luteal phase support than for the unsupported cycles (24.3% vs. 14.1% respectively, p=0.027). CONCLUSION: The use of vaginal suppositories as luteal phase support significantly improved clinical pregnancy rates in controlled ovarian stimulation and intrauterine insemination in patients with unexplained or mild male factor infertility. PMID- 22940120 TI - The immunomodulatory effects of abortion-prone mice decidual and serum soluble factors on macrophages and splenocytes. AB - OBJECTIVES: To determine the immune status of the abortion mouse model at the feto-maternal interface and at the systemic level simultaneously. STUDY DESIGN: Mid-pregnancy serum and decidual cell supernatants (DS) were obtained from abortion and non-abortion mouse models. The effect of serum and DS on PHA or LPS induced lymphocyte proliferation was investigated by MTT reduction assay. Treated macrophages and LPS-stimulated macrophages were evaluated for viability and also for nitric oxide (NO) production by Griess reagent. RESULTS: Our results showed that DS from the abortion mouse model significantly decreased LPS-stimulated splenocyte proliferation, and increased proliferation in PHA-stimulated splenocytes, compared with that in the non-abortion mouse model. Proliferation assays for mid-pregnancy serum were the same on LPS- and PHA-stimulated splenocytes. NO production was decreased by non-abortion DS, similar to that observed for serum treatment in LPS-stimulated macrophages in abortion mice. CONCLUSIONS: These findings suggest that in the abortion mouse model, soluble factors within the decidua are more effective than serum soluble factors in altering immune responses that may be involved in the complex process of fetal rejection. PMID- 22940121 TI - Community DECISIONS: stakeholder focused watershed planning. AB - Successful watershed planning can be enhanced by stakeholder involvement in developing and implementing plans that reflect community goals and resource limitations. Community DECISIONS (Community Decision Support for Integrated, On the-ground Nutrient Reduction Strategies) is a structured decision process to help stakeholders evaluate strategies that reduce watershed nutrient imbalances. A nutrient accounting algorithm and nutrient treatment database provide information on nutrient loadings and costs of alternative strategies to reduce loadings. Stakeholders were asked to formulate goals for the North Fork Shenandoah River Watershed in Virginia and select among strategies to achieve those goals. The Vector Analytic Hierarchy Process was used to rank strategies. Stakeholders preferred a Maximum strategy that included point source upgrades, riparian buffers, no-till corn silage, wheat cover, and bioretention filters in developed areas. Participants generally agreed that the process helped improve communication among stakeholders, was helpful for watershed planning, and should be used for TMDL (Total Maximum Daily Load) planning. Participants suggested more attention be paid to ensuring that all relevant issues are addressed and all information needed to make decisions is available. Watershed planning should provide stakeholders with clear scientific information about physical and socioeconomic processes. However, planning processes must give stakeholders adequate time to consider issues that may not have been addressed by existing scientific models and datasets. PMID- 22940122 TI - DECA: a new model for assessing the foliar uptake of atmospheric lead by vegetation, using Lactuca sativa as an example. AB - In the context of peri-urban atmospheric pollution by industrial lead recycling emissions, metal can transfer to plant shoots. Home gardeners consuming their produce can therefore be exposed to metal pollution. The Human Health Risk Assessment Protocol (HHRAP) model from the United States Environmental Protection Agency (US EPA) classically used in risk assessment provides foliar metal uptake predictions for large farms but is not adapted to cultures in kitchen gardens. Thus, this study developed a new model, entitled "DECA", which includes individually measured parameters and the washing of vegetables before human consumption. Results given by DECA and HHRAP models were compared with experimental measurements of lettuce. The data calculated by the DECA model were highly correlated with the measured values; the HHRAP model overestimates foliar lead uptake. Moreover, strong influences of factor of washing and time-dependent variations of loss coefficient were highlighted. Finally, the DECA model provided important risk assessment data regarding consumption of vegetables from kitchen gardens. PMID- 22940123 TI - Coastal zone management with stochastic multi-criteria analysis. AB - The methodology for coastal management proposed in this study takes into account the physical processes of the coastal system and the stochastic nature of forcing agents. Simulation techniques are used to assess the uncertainty in the performance of a set of predefined management strategies based on different criteria representing the main concerns of interest groups. This statistical information as well as the distribution function that characterizes the uncertainty regarding the preferences of the decision makers is fed into a stochastic multi-criteria acceptability analysis that provides the probability of alternatives obtaining certain ranks and also calculates the preferences of a typical decision maker who supports an alternative. This methodology was applied as a management solution for Playa Granada in the Guadalfeo River Delta (Granada, Spain), where the construction of a dam in the river basin is causing severe erosion. The analysis of shoreline evolution took into account the coupled action of atmosphere, ocean, and land agents and their intrinsic stochastic character. This study considered five different management strategies. The criteria selected for the analysis were the economic benefits for three interest groups: (i) indirect beneficiaries of tourist activities; (ii) beach homeowners; and (iii) the administration. The strategies were ranked according to their effectiveness, and the relative importance given to each criterion was obtained. PMID- 22940124 TI - Food waste co-digestion with sewage sludge--realising its potential in the UK. AB - The application of anaerobic co-digestion of food waste with sewage sludge, although well established in many European countries, is still in its infancy in the UK. This process has many benefits to offer, with a successful application often associated with increased renewable energy potential, outweighing constraints associated with the variability of food waste and its handling requirements prior to co-digestion. With both regulations and water infrastructures designed and constructed on the basis of linear views and sectorial requirements and conditions and technologies from the past in many parts of the world, in the UK, sewage sludge and food waste digestion operations are also under very different regulatory and management regimes. With sustainability requiring that we do not address single issues in isolation, but through a systems approach that delivers integrated solutions, co-digestion of food waste with sewage sludge could become such a solution. If carefully applied, co-digestion can deliver beneficial synergies for the water industry and authorities responsible for food waste management. The collaboration of all relevant stakeholders and regulators to support changes to current regulatory frameworks to enable this, is proposed as the way forward, particularly as their complexity has been identified as the major hurdle to the implementation of co digestion in the UK. PMID- 22940125 TI - Bio-inspired dental multilayers: effects of layer architecture on the contact induced deformation. AB - The ceramic crown structures under occlusal contact are idealized as flat multilayered structures that are deformed under Hertzian contact loading. Those multilayers consist of a crown-like ceramic top layer, an adhesive layer and the dentin-like substrate. Bio-inspired design of the adhesive layer proposed functionally graded multilayers (FGM) that mimic the dentin-enamel junction in natural teeth. This paper examines the effects of FGM layer architecture on the contact-induced deformation of bio-inspired dental multilayers. Finite element modeling was used to explore the effects of thickness and architecture on the contact-induced stresses that are induced in bio-inspired dental multilayers. A layered nanocomposite structure was then fabricated by the sequential rolling of micro-scale nanocomposite materials with local moduli that increase from the side near the soft dentin-like polymer composite foundation to the side near the top ceramic layer. The loading rate dependence of the critical failure loads is shown to be well predicted by a slow crack growth model, which integrates the actual mechanical properties that are obtained from nanoindentation experiments. PMID- 22940126 TI - Overcoming drug resistance of MCF-7/ADR cells by altering intracellular distribution of doxorubicin via MVP knockdown with a novel siRNA polyamidoamine hyaluronic acid complex. AB - Drug resistance is one of the critical reasons leading to failure in chemotherapy. Enormous studies have been focused on increasing intracellular drug accumulation through inhibiting P-glycoprotein (Pgp). Meanwhile, we found that major vault protein (MVP) may be also involved in drug resistance of human breast cancer MCF-7/ADR cells by transporting doxorubicin (DOX) from the action target (i.e. nucleus) to cytoplasma. Herein polyamidoamine (PAMAM) dendrimers was functionalized by a polysaccharide hyaluronic acid (HA) to effectively deliver DOX as well as MVP targeted small-interfering RNA (MVP-siRNA) to down regulate MVP expression and improve DOX chemotherapy in MCF-7/ADR cells. In comparison with DOX solution (IC50=48.5 MUM), an enhanced cytotoxicity could be observed for DOX PAMAM-HA (IC50=11.3 MUM) as well as enhanced tumor target, higher intracellular accumulation, increased blood circulating time and less in vivo toxicity. Furthermore, codelivery of siRNA and DOX by PAMAM-HA exhibited satisfactory gene silencing effect as well as enhanced stability and efficient intracellular delivery of siRNA, which allowed DOX access to nucleus and induced subsequent much more cytotoxicity than siRNA absent case as a result of MVP knockdown. This observation highlights a promising application of novel nanocarrier PAMAM-HA, which could co-deliver anticancer drug and siRNA, in reversing drug resistance by altering intracellular drug distribution. PMID- 22940127 TI - Polyacetal-stilbene conjugates - The first examples of polymer therapeutics for the inhibition of HIF-1 in the treatment of solid tumours. AB - We report here the first examples of Polymer Therapeutics synthesised with the intention of inhibiting Hypoxia Inducible Factor-1 (HIF-1), a transcription factor heavily involved in numerous cell processes under a low oxygen environment. Four compounds were selected for use in these systems; Diethylstilbestrol (DES), Bisphenol A (BIS), Dienestrol (DIENES) and Hexestrol (HEX), which were chosen from a large family of similar molecules known as Stilbenes. These are non-steroidal molecules with structural similarities to oestrogen, and of which DES and BIS have previously been reported for HIF-1 inhibition. These molecules were incorporated into a poly(ethylene glycol) (PEG) based polyacetal system using a reaction of short PEG chains with di(ethylene glycol) divinyl ether units and an acid catalyst and without the need for biodegradable linkers. With an improved polyacetal synthesis strategy we obtained high yields of water soluble polymer conjugates with desirable drug loadings and tailored molecular weights (Mw 23,000-35,000g/mol) with relatively narrow polydispersities (pdi 1.3-1.5). These polymers were found to be hydrolytically cleaved under acid conditions (such as those found in endosomes, lysosomes or the extracellular fluid of some tumours) yielding the free drug. Additionally, they were found to be stable over prolonged periods of time at pH 7.4 mimicking blood plasma. Of the four polymers synthesised, the conjugates of DES and BIS displayed the best activity for HIF-1alpha inhibition in HeLa 9xHRE-Luc tumour cells. More importantly, these conjugates were found to exhibit little to no cell toxicity, contrary to the free drugs, and consequently, they significantly enhanced drug therapeutic index (TI 3.5 vs. 7.2 for free DES vs. DES-polyacetal 2a, and TI 1.1 vs. >20 for free BIS vs. BIS-polyacetal 1b). PMID- 22940128 TI - Rapid skin permeabilization by the simultaneous application of dual-frequency, high-intensity ultrasound. AB - Low-frequency ultrasound has been studied extensively due to its ability to enhance skin permeability. In spite of this effort, improvements in enhancing the efficacy of transdermal ultrasound treatments have been limited. Currently, when greater skin permeability is desired at a given frequency, one is limited to increasing the intensity or the duration of the ultrasound treatment, which carries the risk of thermal side effects. Therefore, the ability to increase skin permeability without increasing ultrasound intensity or treatment time would represent a significant and desirable outcome. Here, we hypothesize that the simultaneous application of two distinct ultrasound frequencies, in the range of 20 kHz to 3 MHz, can enhance the efficacy of ultrasound exposure. Aluminum foil pitting experiments showed a significant increase in cavitational activity when two frequencies were applied instead of just one low frequency. Additionally, in vitro tests with porcine skin indicated that the permeability and resulting formation of localized transport regions are greatly enhanced when two frequencies (low and high) are used simultaneously. These results were corroborated with glucose (180 Da) and inulin (5000 Da) transdermal flux experiments, which showed greater permeant delivery both into and through the dual-frequency pre-treated skin. PMID- 22940129 TI - miR-429 regulation of osmotic stress transcription factor 1 (OSTF1) in tilapia during osmotic stress. AB - The Nile tilapia represents an excellent model for osmoregulation study. Osmotic stress transcription factor 1 (OSTF1) identified in tilapia gill epithelium is a critical element of osmosensory signal transduction by means of transcriptional regulation. Thus, tight regulation of OSTF1 level is necessary for tilapia osmotic adaptation. microRNAs (miRNAs), have emerged as a crucial regulator of gene expression at post-transcriptional level. We reasoned that OSTF1 expression could be regulated by miRNAs. By bioinformatics analysis, we identified a putative miR-429 binding site in the OSTF1 mRNA. Interestingly, miR-429 is down regulated in tilapia upon osmotic stress, consistent with OSTF1 protein up regulation. miR-429 directly regulates OSTF1 expression by targeting its 3'-UTR, and inhibition of miR-429 substantially increases OSTF1 level in vivo. Moreover, miR-429 loss of function could influence the regulation of plasma osmolality and ion concentration responding to osmotic stress. Taken together, miR-429 is an endogenous regulator of OSTF1 expression, which participates in a regulatory circuit that allows rapid gene program transitions in response to osmotic stress. PMID- 22940130 TI - Melanoregulin is stably targeted to the melanosome membrane by palmitoylation. AB - In mammals, pigments are made by melanocytes within a specialized organelle, the melanosome. Mature, pigment-laden melanosomes are then transferred to keratinocytes to drive the visible pigmentation of the animal's hair and skin. The dilute suppressor (dsu) locus encodes an extragenic suppressor of the pigmentation defect exhibited by mice lacking myosin Va (i.e. dilute mice). We recently showed that melanoregulin, the product of the dsu locus, functions as a negative regulator of a shedding mechanism that drives the intercellular transfer of melanosomes from the melanocyte to the keratinocyte. Here we address melanoregulin's localization within the melanocyte, as well as the molecular basis for its localization. First, we confirm and extend recently published results using exogenous, GFP-tagged melanoregulin by showing that endogenous melanoregulin also targets extensively to melanosomes. Second, using site directed mutagenesis, metabolic labeling with H(3)-palmitate, and an inhibitor of palmitoylation in vivo, we show that the targeting of melanoregulin to the limiting membranes of melanosomes in melanocytes and lysosomes in CV1 cells depends critically on the palmitoylation of one or more of six closely-spaced cysteine residues located near melanoregulin's N-terminus. Finally, using Fluorescence Recovery after Photobleaching (FRAP), we show that melanoregulin-GFP exhibits little if any tendency to cycle in and out of the melanosome membrane. We conclude that multiple palmitoylation serves to stably anchor melanoregulin in the melanosome membrane. PMID- 22940131 TI - MicroRNA 16 modulates epithelial sodium channel in human alveolar epithelial cells. AB - Acute lung injury (ALI) is a devastating disease characterized by pulmonary edema. Removal of edema from the air spaces of lung is a critical function of the epithelial sodium channel (ENaC) in ALI. The molecular mechanisms behind resolution of pulmonary edema are incompletely understood. MicroRNA's (miRNA) are crucial gene regulators and are dysregulated in various diseases including ALI. Recent studies suggest that microRNA-16 (miR-16) targets serotonin transporter (SERT) involved in the serotonin (5-HT) transmitter system. Alterations in serotonin levels have been reported in various pulmonary diseases. However, the role of miR-16 on its target SERT, and ENaC, a key ion channel involved in the resolution of pulmonary edema, have not been studied. In the present study, the expression patterns of miR-16, SERT, ENaC and serotonin were investigated in mice exposed to room air and hyperoxia. The effects of miR-16 overexpression on ENaC, SERT, TGF-beta and Nedd4 in human alveolar epithelial cells were analyzed. miR-16 and ENaC were downregulated in mice exposed to hyperoxia. miR-16 downregulation in mouse lung was correlated with an increase in SERT expression and pulmonary edema. Overexpression of miR-16 in human alveolar epithelial cells (A549) suppressed SERT and increased ENaCbeta levels when compared to control-vector transfected cells. In addition, miR-16 over expression suppressed TGFbeta release, a critical inhibitor of ENaC. Interestingly Nedd4, a negative regulator of ENaC remained unaltered in miR-16 over expressed A549 cells when compared to controls. Taken together, our data suggests that miR-16 upregulates ENaC, a major sodium channel involved in resolution of pulmonary edema in ALI. PMID- 22940132 TI - Calcium regulates caveolin-1 expression at the transcriptional level. AB - Caveolin-1, an indispensable component of caveolae serving as a transformation suppressor protein, is highly expressed in poorly metastatic mouse osteosarcoma FBJ-S1 cells while highly metastatic FBJ-LL cells express low levels of caveolin 1. Calcium concentration is higher in FBJ-S1 cells than in FBJ-LL cells; therefore, we investigated the possibility that calcium signaling positively regulates caveolin-1 in mouse FBJ-S1 cells. When cells were treated with the calcium channel blocker nifedipine, cyclosporin A (a calcineurin inhibitor), or INCA-6 (a nuclear factor of activated T-cells [NFAT] inhibitor), caveolin-1 expression at the mRNA and protein levels decreased. RNA silencing of voltage dependent L-type calcium channel subunit alpha-1C resulted in suppression of caveolin-1 expression. This novel caveolin-1 regulation pathway was also identified in mouse NIH 3T3 cells and Lewis lung carcinoma cells. These results indicate that caveolin-1 is positively regulated at the transcriptional level through a novel calcium signaling pathway mediated by L-type calcium channel/Ca(2+)/calcineurin/NFAT. PMID- 22940133 TI - MiR-124 suppresses cell proliferation in hepatocellular carcinoma by targeting PIK3CA. AB - MicroRNAs (miRNAs) have crucial roles in the development and progression of human cancers, including hepatocellular carcinoma (HCC). Recent studies have shown that microRNA-124 (miR-124) was downregulated in HCC; however, the underlying mechanisms by which miR-124 suppresses tumorigenesis in HCC are largely unknown. In this study, we report that phosphoinositide 3-kinase catalytic subunit alpha (PIK3CA) is a novel target of miR-124 in HepG2 cells. Overexpression of miR-124 resulted in decreased expression of PIK3CA at both mRNA and protein levels. We found that miR-124 overexpression markedly suppressed cell proliferation by inducing G1-phase cell-cycle arrest in vitro. Consistent with the restoring miR 124 expression, PIK3CA knockdown suppressed cell proliferation, whereas overexpression of PIK3CA abolished the suppressive effect of miR-124. Mechanistic studies showed that miR-124-mediated reduction of PIK3CA resulted in suppression of PI3K/Akt pathway. The expressions of Akt and mTOR, key components of the PI3K/Akt pathway, were all downregulated. Moreover, we found overexpressed miR 124 effectively repressed tumor growth in xenograft animal experiments. Taken together, our results demonstrate that miR-124 functions as a growth-suppressive miRNA and plays an important role in inhibiting the tumorigenesis through targeting PIK3CA. PMID- 22940134 TI - alpha-Iso-cubebene, a natural compound isolated from Schisandra chinensis fruit, has therapeutic benefit against polymicrobial sepsis. AB - alpha-Iso-cubebene, a natural compound isolated from Schisandra chinensis fruit, strongly enhanced survival rate in cecal ligation and puncture (CLP) challenge induced sepsis. The mechanism involved the marked reduction of viable bacteria in the peritoneal fluid, by virtue of increased phagocytic activity and production of hydrogen peroxide. alpha-Iso-cubebene also significantly attenuated lung inflammation and widespread immune cell apoptosis in a mouse CLP sepsis model, and inhibited the production of proinflammatory cytokines including tumor necrosis factor-alpha, interleukin (IL)-1beta, and IL-6 in CLP mice and lipopolysaccharide-stimulated splenocytes. The results indicate that alpha-iso cubebene can reverse the progression of toxic shock by triggering multiple protective downstream signaling pathways to enhance microbial killing and maintain organ function and leukocyte survival. PMID- 22940135 TI - Development and comparison of neural network based soft sensors for online estimation of cement clinker quality. AB - The online estimation of process outputs mostly related to quality, as opposed to their belated measurement by means of hardware measuring devices and laboratory analysis, represents the most valuable feature of soft sensors. As of now there have been very few attempts for soft sensing of cement clinker quality which is mostly done by offline laboratory analysis resulting at times in low quality clinker. In the present work three different neural network based soft sensors have been developed for online estimation of cement clinker properties. Different input and output data for a rotary cement kiln were collected from a cement plant producing 10,000 tons of clinker per day. The raw data were pre-processed to remove the outliers and the resulting missing data were imputed. The processed data were then used to develop a back propagation neural network model, a radial basis network model and a regression network model to estimate the clinker quality online. A comparison of the estimation capabilities of the three models has been done by simulation of the developed models. It was observed that radial basis network model produced better estimation capabilities than the back propagation and regression network models. PMID- 22940136 TI - Quantum and impulse noise filtering from breast mammogram images. AB - Recent advances in the field of image processing have shown that level of noise highly affect the quality and accuracy of classification when working with mammographic images. In this paper, we have proposed a method that consists of two major modules: noise detection and noise filtering. For detection purpose, neural network is used which effectively detect the noise from highly corrupted images. Pixel values of the window and some other features are used as feature for the training of neural network. For noise removal, three filters are used. The weighted average value of these three filters is filled on noisy pixels. The proposed technique has been tested on salt & pepper and quantum noise present in mammogram images. Peak signal to noise ratio (PSNR) and structural similarity index measure (SSIM) are used for comparison of proposed technique with different existing techniques. Experiments shows that proposed technique produce better results as compare to existing methods. PMID- 22940137 TI - Electromagnetic fields instantaneously modulate nitric oxide signaling in challenged biological systems. AB - This study shows that a non-thermal pulse-modulated RF signal (PRF), configured to modulate calmodulin (CaM) activation via acceleration of Ca(2+) binding kinetics, produced an immediate nearly 3-fold increase in nitric oxide (NO) from dopaminergic MN9D cultures (P < 0.001). NO was measured electrochemically in real time using a NO selective membrane electrode, which showed the PRF effect occurred within the first seconds after lipopolysaccharide (LPS) challenge. Further support that the site of action of PRF involves CaM is provided in human fibroblast cultures challenged with low serum and exposed for 15 min to the identical PRF signal. In this case a CaM antagonist W-7 could be added to the culture 3 h prior to PRF exposure. Those results showed the PRF signal produced nearly a two-fold increase in NO, which could be blocked by W-7 (P < 0.001). To the authors' knowledge this is the first report of a real-time effect of non thermal electromagnetic fields (EMF) on NO release from challenged cells. The results provide mechanistic support for the many reported bioeffects of EMF in which NO plays a role. Thus, in a typical clinical application for acute post operative pain, or chronic pain from, e.g., osteoarthritis, EMF therapy could be employed to modulate the dynamics of NO via Ca/CaM-dependent constitutive nitric oxide synthase (cNOS) in the target tissue. This, in turn, would modulate the dynamics of the signaling pathways the body uses in response to the various phases of healing after physical or chemical insult or injury. PMID- 22940138 TI - Combination of injectable ethinyl estradiol and drospirenone drug-delivery systems and characterization of their in vitro release. AB - Our aim was to investigate the in vitro release and combination of ethinyl estradiol (EE) and drospirenone (DRSP) drug-delivery systems. DRSP poly(lactic-co glycolic acid) (PLGA) microparticles and organogels containing DRSP microcrystals were prepared and characterized with regard to properties influencing drug release. The morphology and release kinetics of DRSP PLGA microparticles indicated that DRSP is dispersed in the polymer. The in vitro release profiles correlated well with in vivo data. Although DRSP degradation is known to be acid catalyzed, DRSP was relatively stable in the PLGA matrix. Aqueous DRSP PLGA microparticle suspensions were combinable with EE PLGA microparticles and EE poly(butylcyanoacrylate) (PBCA) microcapsules without interacting. EE release from PLGA microparticles was faster than DRSP release; EE release is assumed to be primarily controlled by drug diffusion. Liquid-filled EE PBCA microcapsules were shown to be more robust than air-filled EE PBCA microcapsules; the bursting of microcapsules accelerating the drug delivery was therefore delayed. The drug release profile for DRSP organogels was fairly linear with the square root of time. The system was not combinable with EE PBCA microcapsules. In contrast, incorporation of EE PLGA microparticles in organogels resulted in prolonged EE release. The drug release of EE and DRSP was thus approximated. PMID- 22940139 TI - Characterisation and expression during sex differentiation of Sox19 from the sea bass Dicentrarchus labrax. AB - The Sox family of transcription factors are involved in a variety of developmental processes including sex determination and gonadal differentiation. Sox19 is a particularly interesting member of this family that has been found only in fish, though mammals have a very diverged orthologue that is designated Sox15 and assigned to a different Sox family subgroup. Here we describe the cloning and characterisation of sox19 from the European sea bass (Dicentrarchus labrax), an important aquaculture species in which sex ratios skewed in favour of males are frequently encountered. The sea bass sox19 gene contains a single intron, encodes a protein of 309 amino acids, has multiple transcription start sites and may produce a truncated splice variant. Sox19 mRNA is present in many adult tissues, with the highest expression in the brain and gonads. Interestingly, the gene is strongly upregulated in the differentiation of the ovary but not the testis, suggesting a role in ovarian differentiation. PMID- 22940140 TI - Community treatment adoption of contingency management: a conceptual profile of U.S. clinics based on innovativeness of executive staff. AB - BACKGROUND: Community adoption of contingency management (CM) varies considerably, and executive innovativeness may help explain variance due to its presumed influence on clinic decision-making. METHODS: Sixteen U.S. opioid treatment programs (OTPs) were visited, with ethnographic interviewing used in casual contacts with executives to inform their eventual classification by study investigators into one of Rogers' (2003) five adopter categories. Audio-recorded interviews were also conducted individually with the executive and three staff members (N = 64) wherein they reported reactions to clinic CM implementation during the prior year, from which study investigators later identified salient excerpts during interview transcript reviews. RESULTS: The executive sample was progressive, with 56% classified as innovators or early adopters. Implementation reports and corresponding staff reactions were generally consistent with what might be expected according to diffusion theory. Clinics led by innovators had durably implemented multiple CM applications, for which staff voiced support. Clinics led by early adopters reported CM exposure via research trial participation, with mixed reporting of sustained and discontinued applications and similarly mixed staff views. Clinics led by early majority adopters employed CM selectively for administrative purposes, with staff reticence about its expansion to therapeutic uses. Clinics led by late majority adopters had either deferred or discontinued CM adoption, with typically disenchanted staff views. Clinics led by a laggard executive evidenced no CM exposure and strongly dogmatic staff views against its use. CONCLUSION: Study findings are consistent with diffusion theory precepts, and illustrate pervasive influences of executive innovativeness on clinic practices and staff impressions of implementation experiences. PMID- 22940141 TI - 'Opioid drought', Canadian-style? Potential implications of the 'natural experiment' of delisting oxycontin in Canada. PMID- 22940142 TI - Association between harm reduction intervention uptake and recent hepatitis C infection among people who inject drugs attending sites that provide sterile injecting equipment in Scotland. AB - BACKGROUND: Prevalence of the hepatitis C virus (HCV) among people who inject drugs (PWID) in Scotland is high. The Scottish Government has invested significantly in harm reduction interventions with the goal of reducing HCV transmission among PWID. In evaluating the effectiveness of interventions, estimates of HCV incidence are essential. METHODS: During 2008-2009, PWID were recruited from services providing sterile injecting equipment across mainland Scotland, completed an interviewer-administered questionnaire and provided a dried blood spot for anonymous anti-HCV and HCV-RNA testing. Recent infections were defined as anti-HCV negative and HCV-RNA positive. Logistic regression was undertaken to examine associations between recent HCV infection and self-reported uptake of methadone maintenance therapy (MMT) and injection equipment. RESULTS: Fifty-four percent (1367/2555) of participants were anti-HCV positive. We detected 24 recent HCV infections, yielding incidence rate estimates ranging from 10.8 to 21.9 per 100 person-years. After adjustment for confounders, those with high needle/syringe coverage had reduced odds of recent infection (adjusted odds ratio [AOR] 0.32, 95% CI 0.10-1.00, p=0.050). In the Greater Glasgow & Clyde region only, we observed a reduced odds of recent infection among those currently receiving MMT, relative to those on MMT in the last six months but not currently (AOR 0.04, 95% CI 0.001-1.07, p=0.055). The effect of combined uptake of MMT and high needle/syringe coverage was only significant in unadjusted analyses (OR 0.34, 95% CI 0.12-0.97, p=0.043; AOR 0.48, 95% CI 0.16-1.48, p=0.203). CONCLUSION: We report the first large-scale, national application of a novel method designed to determine incidence of HCV among PWID using a cross-sectional design. Subsequent sweeps of this survey will increase statistical power and allow us to gauge the impact of preventive interventions. PMID- 22940143 TI - Tumor necrosis factor alpha -308G>A, -863C>A, -857C>T gene polymorphisms and tuberculosis susceptibility: a meta-analysis. AB - BACKGROUND/AIMS: A large number of studies have shown that polymorphisms in the tumor necrosis factor-alpha (TNF-alpha, TNFA) gene are implicated in susceptibility to tuberculosis (TB). However, the results are inconsistent. We performed this meta-analysis to estimate the association between polymorphisms in the TNFA gene and TB susceptibility. METHODS: Relevant studies published before March 2012 were identified by searching PubMed, ISI web of knowledge, EBSCO and CNKI. The strength of relationship between the TNFA gene and TB susceptibility was assessed using odds ratios (ORs). RESULTS: A total number of twenty-three case-control studies including 3630 cases and 4055 controls were identified referring to three previously chosen single-nucleotide polymorphisms (SNPs): 308G>A, -863C>A and -857C>T. No association was found between -308G>A, -863C>A and TB susceptibility: -308G>A (GG+GA vs. AA): OR 0.85, 95%CI: 0.55-1.30, P=0.44; -863C>A (CC+CA vs. AA): OR 0.93, 95%CI: 0.84-1.81, P=0.83. Increased risk of TB was associated with -857C>T in the dominant genetic model (CC+CT vs. TT: OR 2.13, 95%CI: 1.25-3.63, P=0.01), the heterozygote comparison (CT vs. TT: OR 2.69, 95%CI: 1.44-5.02, P=0.00) and the homozygote comparison (CC vs. TT: OR 2.08, 95%CI: 1.22-3.53, P=0.01) in Asian subjects. CONCLUSION: There is an increased association between TNFA -857C>T polymorphism and TB risk among Asian subjects. No association was found between -308G>A and -863C>A with TB risk. Due to several limitations in the present study, well-designed epidemiological studies with large sample size among different ethnicities should be performed in the future. PMID- 22940144 TI - The "right" decision. PMID- 22940145 TI - Falsely pessimistic prognosis by EEG in post-anoxic coma after cardiac arrest: the borderland of nonconvulsive status epilepticus. AB - BACKGROUND: Prognostication following anoxic coma relies on clinical assessment and is assisted by neurophysiology. A non-evolving EEG spike burst/isoelectric suppression pattern after the first 24 hours almost invariably indicates poor outcome, while an evolving pattern implies nonconvulsive status epilepticus (NCSE) that may "hide" surviving brain activity and is amenable to treatment. CASE STUDY: We present the case of a 53-year-old woman who had a witnessed out-of hospital ventricular fibrillation cardiac arrest, was resuscitated by paramedics, but remained comatose. An EEG, performed 36 hours post-insult, showed an unremitting, non-evolving, unresponsive 2-6 Hz high-voltage spike burst/isoelectric suppression pattern, which remained unchanged at 96 hours post insult, following therapeutic hypothermia. During this period, she was completely off sedation and taking triple antiepileptic treatment, without systemic confounding disorders. Although the initial pattern was indicative of poor neurological outcome, she eventually made meaningful functional recovery; the last EEG showed satisfactory background rhythms and stimulus-induced epileptiform discharges without seizures. CONCLUSION: In post-anoxic coma, non-evolving >2 Hz spike burst/isoelectric suppression pattern may still reflect NCSE and therefore should be considered in the diagnostic EEG criteria for NCSE. Such borderline patterns should not dissuade physicians from intensifying treatment until more confident prognostication can be made. PMID- 22940146 TI - Identification of phoslactomycin biosynthetic gene clusters from Streptomyces platensis SAM-0654 and characterization of PnR1 and PnR2 as positive transcriptional regulators. AB - Phoslactomycins (PLMs) are inhibitors of protein serine/threonine phosphatase 2A showing diverse and important antifungal, antibacterial and antitumor activity. PLMs are polyketide natural products and produced by several Streptomyces species. The PLMs biosynthetic gene clusters were identified from Streptomyces platensis SAM-0654 and localized in two separate genomic regions, consisting of 27 open reading frames that encode polyketide synthases (PKSs), enzymes for cyclohexanecarboxyl-CoA (CHC-CoA) and ethylmalonyl-CoA (Em-CoA) synthesis, enzymes for post-PKS modifications, proposed regulators, and putative resistance transporters. Bioinformatic analysis and inactivation experiment of regulatory genes suggest that PnR1 and PnR2 are two positive regulators of PLMs biosynthesis. Gene transcription analysis by reverse transcriptase PCR (RT-PCR) of the PLMs gene cluster demonstrated that PnR1 and PnR2 activate the transcription of the structural biosynthetic genes while PnR2 specially governs the transcription of pnR1 in a higher level. PMID- 22940147 TI - Association between Glu298Asp/677C-T single nucleotide polymorphism in the eNOS/MTHRF gene and blood stasis syndrome of ischemic stroke. AB - Blood stasis syndrome of ischemic stroke (BSS-IS) is a common clinical phenotype that may be affected by certain mutagenic environmental factors or chemotherapeutic drugs; however, the role of susceptibility genes remains unclear. Previous studies have shown that ischemic stroke (IS) was closely associated with the Glu298Asp polymorphism in the eNOS gene and the 677C-T (Ala >Val) polymorphism in methylenetetrahydrofolate reductase (MTHRF) gene. Therefore, these two single nucleotide polymorphisms (SNPs) were selected to detect their associations with BSS-IS in this study. A SNP chip was employed to screen the SNP variation between both groups, and the results were verified using denaturing high-performance liquid chromatography (DHPLC) and restriction fragment length polymorphism (RFLP). The results confirmed that the TT genotype of Glu298Asp in the eNOS gene may be one of the risk factors associated with BSS IS, while the genotype of 677C-T (Ala->Val) in the MTHRF gene may not be relevant to BSS-IS. PMID- 22940148 TI - Functional polymorphisms in the interleukin-12 gene contribute to cancer risk: evidence from a meta-analysis of 18 case-control studies. AB - BACKGROUND: Emerging evidence from preclinical and clinical studies has shown that interleukin-12 (IL-12) has some effectiveness against endogenously arising carcinogenesis. Several potentially functional polymorphisms of IL-12 gene have been implicated in cancer risk, but individually published studies showed inconclusive results. The aim of this study was to investigate the association between IL-12 polymorphisms and cancer risk. METHODS: The MEDLINE, EMBASE, Web of science and CBM databases were searched for all articles published up to June 10, 2012 that addressed IL-12 polymorphisms and cancer risk. Statistical analyses were performed using RevMan 5.1.6 and STATA 12.0 softwares. RESULTS: Eighteen studies were included with a total of 6463 cancer cases and 7412 healthy controls. We found that the 3'UTR A>C (rs3212227) polymorphism of IL-12B gene was associated with significantly increased overall risk of cancers using random effects model (C vs A: odds ratio [OR]=1.14, 95% confidence interval [CI]: 1.02 1.27; AC+CC vs AA: OR=1.20, 95%CI: 1.01-1.43). However, the 3'UTR G>A (rs568408), IVS2 T>A (rs582054) and 5'UTR T>G (rs2243115) polymorphisms of IL-12A gene did not appear to have an influence on cancer susceptibility. Further subgroup analyses showed that the 3'UTR A>C (rs3212227) polymorphism was associated with increased cancer risks in the subgroups of Asians, cervical and nasopharyngeal cancers. CONCLUSIONS: Results from the current meta-analysis indicates that the 3'UTR A>C (rs3212227) polymorphism of IL-12B gene might be a potential biomarker for cancer risk among Asians, especially for cervical and nasopharyngeal cancers. PMID- 22940149 TI - The use of a radial basis neural network and genetic algorithm for improving the efficiency of laccase-mediated dye decolourization. AB - A radial basis function neural network (RBF) and genetic algorithm (GA) were applied to improve the efficiency of the oxidative decolourization of the recalcitrant dye Reactive Black 5 (RB 5) by a technical laccase (Trametes spp.) and the natural mediator acetosyringone (ACS). The decolourization of RB 5 in aqueous solution was studied with a 3(4) factorial design including different levels of laccase (2, 100, 200 U L(-1)), acetosyringone (5, 50, 100 MUM), pH value (3, 4.5, 6) and incubation time (10, 20, 30 min). The generated RBF network was mathematically evaluated by several statistical indices and revealed better results than a classical quadratic response surface (RS) model. The experimental data showed that within 10 min of incubation time a complete decolourization (>90%) was achieved by using the highest amount of laccase (200 U L(-1)) and acetosyringone (100 MUM) at pH 6. By applying the RBF-GA methodology, the efficiency of the laccase-mediated decolourization was improved by minimising the required amount of laccase and acetosyringone by 25% and 21.7% respectively. Complete decolourization (>90%) was obtained within 10 min at the GA-optimised process conditions of laccase (150 U L(-1)) and acetosyringone (78.3 MUM) at pH 5.67. These results illustrate that the RBF-GA methodology could be a powerful technique during scale-up studies. PMID- 22940150 TI - Structure and properties of chitin/alginate blend membranes from NaOH/urea aqueous solution. AB - Chitin/alginate (CA) blend membranes were successfully prepared from 8 wt% NaOH/4 wt% urea aqueous solution by coagulating with 0.5M CaCl(2) aqueous solution containing 5 wt% HCl. Morphology, mechanical properties, thermal stability, and antimicrobial effects of the membranes were investigated by scanning electron microscopy, IR and UV spectroscopes, X-ray diffraction, tensile tests, thermogravimetric analysis, water swelling and antimicrobial tests. The CA blends were miscible when the content of alginate was range from 33 to 67 wt%. The crystallinity of the blend membranes decreased with an increase of alginate. Comparing with chitin membranes, the tensile strength and breaking elongation of the blend membranes were obviously improved in dry and wet states. The best values of the tensile strength and breaking elongation were 48 MPa and 27%, respectively. All the blend membranes still retained obvious antimicrobial effects toward S. aureus and E. coli. Therefore, they showed potential for biomedical application. PMID- 22940151 TI - Species boundaries and possible hybridization between the black mongoose (Galerella nigrata) and the slender mongoose (Galerella sanguinea). AB - Major climatic oscillations since the mid-Miocene climatic optimum are known to have played a key role in promoting speciation events. In this study we use molecular data to elucidate the evolutionary history of Galerella nigrata and link its divergence to known major climatic events. A total of 51 samples from G. nigrata and 17 from Galerella sanguinea were used to provide the first molecular evidence that G. nigrata may be a species in its own right. Both mitochondrial cytochrome b and the nuclear beta-fibrinogen intron seven sequences of G. nigrata form distinct monophyletic clades, separate from its sister species G. sanguinea. We estimate the divergence of these two species to have occurred 3.85-4.27 million years ago, coinciding with a period of the Plio-Pleistocene that was characterised by cooling global temperatures and strong aridity in southern Africa. However, evidence for potential hybridization between the two species was documented for ten individuals using phenotypic (pelage colouration) and/or molecular (nuclear and mtDNA sequences and microsatellite loci) data. There appeared to be a bias towards unidirectional hybridization with all potential hybrids showing mtDNA haplotypes from G. nigrata. We suggest that as the desert expanded across Namibia, G. sanguinea likely retreated with the savanna, leaving some mongooses stranded on the granite inselbergs of north-western Namibia. Subsequent adaptation of these mongooses to local conditions on granite inselbergs could have led to ecological speciation. Secondary contact zones would have been re-established with subsequent global warming events. It appears that the two species have not yet undergone complete reproductive isolation. PMID- 22940152 TI - Phylogeography of an Atlantic forest passerine reveals demographic stability through the last glacial maximum. AB - In this study we analyzed the phylogeographic pattern and historical demography of an endemic Atlantic forest (AF) bird, Basileuterus leucoblepharus, and test the influence of the last glacial maximum (LGM) on its population effective size using coalescent simulations. We address two main questions: (i) Does B. leucoblepharus present population genetic structure congruent with the patterns observed for other AF organisms? (ii) How did the LGM affect the effective population size of B. leucoblepharus? We sequenced 914 bp of the mitochondrial gene cytochrome b and 512 bp of the nuclear intron 5 of beta-fibrinogen of 62 individuals from 15 localities along the AF. Both molecular markers revealed no genetic structure in B. leucoblepharus. Neutrality tests based on both loci showed significant demographic expansion. The extended Bayesian skyline plot showed that the species seems to have experienced demographic expansion starting around 300,000 years ago, during the late Pleistocene. This date does not coincide with the LGM and the dynamics of population size showed stability during the LGM. To further test the effect of the LGM on this species, we simulated seven demographic scenarios to explore whether populations suffered specific bottlenecks. The scenarios most congruent with our data were population stability during the LGM with bottlenecks older than this period. This is the first example of an AF organism that does not show phylogeographic breaks caused by vicariant events associated to climate change and geotectonic activities in the Quaternary. Differential ecological, environmental tolerances and habitat requirements are possibly influencing the different evolutionary histories of these organisms. Our results show that the history of organism diversification in this megadiverse Neotropical forest is complex. PMID- 22940153 TI - Effects of the Qinghai-Tibetan Plateau uplift and environmental changes on phylogeographic structure of the Daurian Partridge (Perdix dauuricae) in China. AB - Data from eight microsatellite loci were used to assess the evolutionary demographic processes of Daurian Partridges from 285 individuals distributed among 23 populations throughout much of the species' distribution range in China. Phylogenetic analysis using microsatellite DNA data indicated that the species were geographically structured and were split into two distinctive phylogroups A and B, splitting partridges geographically from high plateaus vs. lowlands in northern China with high bootstrap support in phylogenetic trees. Each of cluster A and cluster B was comprised with two subgroups respectively. Cluster A was further subdivided into the Loess Plateau group and the Qinghai-Tibetan group. Two subgroups of cluster B corresponded to populations of Liupan Mountains and northern China, respectively. This subdivision was confirmed by Bayesian clustering and population assignment analyses of microsatellite genotypes which indicated strong isolation of these groups/populations. Our results suggested that the vicariance patterns of genetic structures of Daurian Partridge may have resulted from: (1) the uplift of the Qinghai-Tibetan Plateau and the Loess Plateau followed by the increased aridification and desertification in northern China in Middle Pleistocene, (2) the monsoon and the existence of Qinling Mountains and Liupan Mountains, and (3) the glacial cycles from the late of Middle Pleistocene to early of Late Pleistocene. In addition, BOTTLENECK analysis indicated that Daurian Partridge had been experienced recent evolutionary bottlenecks. PMID- 22940154 TI - Pathological and physiological effects of nicking on brown crab (Cancer pagurus) in the Irish crustacean fishery. AB - Nicking is used in fisheries to immobilize claws of brown crab (Cancer pagurus) in order to prevent cannibalism and fighting during storage. Nicking fractures the apodemes creating an open wound and damage to the internal claw tissues, which is the most valuable product of brown crab. In turn, this results in a reduction of quality of product and possibly compromises the host's defence mechanisms to other physiological challenges experienced throughout the post harvest process. This study assessed the effects of nicking on the physiology and pathology of brown crab from the Irish fishery over 7 days. Results showed significantly elevated levels of muscle necrosis (P=0.005), total pathologies (P=0.022) and encirculating granulocytes in nicked crab compared to non-nicked crab. Mean glucose (212.0 MUg/mL+/-108.4), lactate (36.52 MUg/mL+/-38.74) and RI (11.05n+/-1.78) levels were higher in nicked crab indicating increased stress levels. Overall, histology results showed a significantly higher (P=0.022) occurrence of pathologies, such as melanised nodules, in nicked animals. In addition to an observed reduction in the quality of claw muscle, nicked crab also showed significantly higher (P=0.005) levels of necrosis in claw muscle. From the results of this study it is recommended that alternative retention methods are used. PMID- 22940155 TI - Implicit attitudes towards children with autism versus normally developing children as predictors of professional burnout and psychopathology. AB - Tutors trained in applied behaviour analysis (n = 16) and mainstream school teachers (n = 16) were exposed to an Implicit Relational Assessment Procedure (IRAP) designed to assess implicit attitudes towards individuals with autism versus normally developing individuals. Participants also completed a range of explicit measures, including measures of professional burnout and psychopathology. All participants produced more negative biases towards children with autism compared to children who were normally developing. Increased negativity towards autism on the IRAP predicted similar attitudes on some of the explicit measures and also correlated with increased levels of self-reported psychopathology and professional burnout for the tutors working with children with autism. Results suggest that implicit measures of attitudes may provide a marker for professional burnout. PMID- 22940156 TI - How disabling are pediatric burns? Functional independence in Dutch pediatric patients with burns. AB - Although the attention for functional outcomes after burn injury has grown over the past decades, little is known about functional independence in performing activities of daily living in children after burn injury. Therefore, in this prospective cohort study functional independence was measured by burn care professionals with the WeeFIM((r)) instrument in 119 pediatric patients with burns (age: 6 months-16 years; 58.8% boys) in the Netherlands. In order to identify whether functional independence was affected, participants' total scores on the WeeFIM((r)) instrument were compared to American norm values. Of the participants assessed at 2 weeks post burn (n = 117), 3 months post burn (n = 68) and/or 6 months post burn (n = 38), 22, 9 and 9 participants showed affected performance, respectively. Improvements in WeeFIM((r)) total scores for the total study population between 2 weeks and 6 months post burn were significant (Wilcoxon T = 2.5; p<.001, effect size = -0.59). Individual improvements were found to be significant for 30.3% of the assessed participants between 2 weeks and 3 months post burn, and for 12.1% between 3 and 6 months post burn. This study is unique in providing data on functional independence for this large and special population. However, a proportion of participants were lost to follow-up and the use of the WeeFIM((r)) instrument in this specific population and setting has its limitations. To conclude, burn injury impacts functional independence in children, yet the vast majority of Dutch pediatric patients with burns returns to functional independence typical for age within 6 months post burn. PMID- 22940157 TI - Motor profile of children with attention deficit hyperactivity disorder, combined type. AB - OBJECTIVES: The aim of this study was to assess the motor profile of children with attention deficit hyperactivity disorder (ADHD), combined type. METHOD: The case group consisted of 34 treatment-naive, male patients, aged 7-11 years, who had been diagnosed with ADHD, combined type, without comorbidities (except oppositional defiant disorder). The control group was composed of 32 age- and gender-matched, typically developing children. The evaluation was made using the Motor Development Scale, which assessed global and fine motricity, balance, body scheme, and spatial and temporal organization. RESULTS: The results showed that the motor quotients in all areas studied were lower in the ADHD group than in the control group, although in most cases they represent normal values relative to the scale (53% were classified as having "normal medium" motor development, 29% "normal low", 9% "very low", 6% "normal high" and 3% as "lower"). Statistically significant differences between groups were observed in general motor age, general motor quotient, balance, spatial organization, and fine and global motricity. CONCLUSION: Difficulties in motor performance were observed in the children with ADHD, combined type. The identification of such deficits may assist in the design of therapeutic protocols for the treatment of children with this type of ADHD. PMID- 22940158 TI - Executive function in Williams and Down syndromes. AB - Williams (WS) and Down (DS) syndromes are characterised by roughly opposing ability profiles. Relative verbal strengths and visuospatial difficulties have been reported in those with WS, while expressive language difficulties have been observed in individuals with DS. Few investigations into the executive function (EF) skills of these groups have examined the effect of verbal/visuospatial task type on performance. Analogous verbal and visuospatial measures were administered to these populations within four EF domains: executive-loaded working memory (ELWM), inhibition, fluency and set-shifting. Performance in both groups was compared to that of typically developing (TD) children using regression techniques controlling for potentially influential cognitive/developmental factors. Individuals with WS showed the expected relative visuospatial difficulties, as indicated by poorer performance than TD individuals, on tests of ELWM and fluency. Individuals with DS displayed the expected relative verbal difficulty in the domain of set-shifting. In addition, each population showed pervasive deficits across modality in one domain; ELWM for individuals with DS, and inhibition for individuals with WS. Individuals with WS and DS showed EF difficulties in comparison to a TD group, but, their executive performance was affected by EF task type (verbal/visuospatial) and EF domain in different ways. While the findings indicated that EF in these populations is characterised by a range of specific strengths and weaknesses, it was also suggested that the relative verbal/visuospatial strengths associated with each population do not consistently manifest across EF domains. Lastly, syndrome specificity was indicated by the differences in groups' performance patterns. PMID- 22940159 TI - Psychological adjustment and levels of self esteem in children with visual-motor integration difficulties influences the results of a randomized intervention trial. AB - This study evaluates how much the effects of intervention programs are influenced by pre-existing psychological adjustment and self-esteem levels in kindergarten and first grade children with poor visual-motor integration skills, from low socioeconomic backgrounds. One hundred and sixteen mainstream kindergarten and first-grade children, from low socioeconomic backgrounds, scoring below the 25th percentile on a measure of visual-motor integration (VMI) were recruited and randomly divided into two parallel intervention groups. One intervention group received directive visual-motor intervention (DVMI), while the second intervention group received a non-directive supportive intervention (NDSI). Tests were administered to evaluate visual-motor integration skills outcome. Children with higher baseline measures of psychological adjustment and self-esteem responded better in NDSI while children with lower baseline performance on psychological adjustment and self-esteem responded better in DVMI. This study suggests that children from low socioeconomic backgrounds with low VMI performance scores will benefit more from intervention programs if clinicians choose the type of intervention according to baseline psychological adjustment and self-esteem measures. PMID- 22940160 TI - Inhibitory mechanisms in Down syndrome: is there a specific or general deficit? AB - The cognitive profile of individuals with Down syndrome (DS) is known to be characterized by an impaired executive functioning, but inhibition-related processes have not been extensively examined in this setting. The aim of the present study was to investigate whether individuals with DS have any specific or general deficit in inhibitory processes. Tasks measuring prepotent response inhibition (the animal Stroop test), proactive interference (proactive interference task and intrusion errors), and response to distracters (directed forgetting task) were administered together with a working memory test to 19 individuals with DS and 19 typically developing (TD) children matched for mental age. Confirming previous findings, our results showed that the DS group performed less well in a verbal working memory task than the TD children. Analyzing our findings for the three inhibitory tasks yielded a picture of the DS children having a generalized difficulty in suppressing information that is irrelevant, or no longer relevant, to the goals of the task. These results suggest that DS is related not to specific, but rather to generalized inhibitory difficulties. PMID- 22940161 TI - Measuring physical activity in children and youth living with intellectual disabilities: a systematic review. AB - Accurate assessment of physical activity is necessary in determining levels of physical activity in children living with intellectual disability (ID) and assessing effectiveness of intervention programmes. A systematic review of measures of physical activity in children with ID was undertaken using the PRISMA guidelines. MEDLINE-PubMed, Scopus, CINAHL Plus with Full Text and SPORT Discus (up to May 2012) databases were searched and articles were identified. The following inclusion criteria were used; articles in English which reported original research and measured physical activity levels in children with ID, and participants of school age (5-18 years). Searches were limited to articles from peer-reviewed journals and those available in full text. The search identified 5087 titles. Seventy-eight articles were retained for full review and 30 met the inclusion criteria. The review identified a clear deficiency in the number of validity and reliability studies of tools used to quantify physical activity in children with ID. Objective measurement of physical activity provided consistent results. Despite the differences in study design and methodological quality, there was agreement among studies that children with ID were significantly less active compared to children without disabilities. Refusal to wear instruments, movement limitations in children with ID, and positioning of devices were common issues. Future studies should focus on determining the validity and reliability of tools used to assess physical activity in children with ID. PMID- 22940162 TI - The profile of performance skills and emotional factors in the context of participation among young children with Developmental Coordination Disorder. AB - Participation is a person's involvement in daily activities in a variety of environments, roles and life situations. Children with Developmental Coordination Disorder (DCD) experience difficulties in gaining academic achievements or in their engagement in activity of daily living. Motor difficulties have a negative effect on the ability to participate, as well as on various affective components. Senses of coherence, effort and hope have not yet been assessed, within the context of participation, in children with DCD. The purpose of the present study is to look into the relations between participation and senses of coherence, effort and hope among children with DCD, in comparison to typically developed children. Fifty subjects aged 5-6 years participated in the study, 25 of whom are children diagnosed with DCD, the other 25 being typical children. The DCD diagnosis was established according to the DSM-IV criteria and the M-ABC test. All children completed the coherence questionnaire for children as well as the children's questionnaire on effort and hope. Parents completed the Children Participation Questionnaire (CPQ), and the Performance Skills Questionnaire (PSQ). Children with DCD had lower performance skills, lower sense of coherence, hope, and effort than their peers. They less enjoy their participation and their parents are less satisfied in comparison to control group. Significant correlations were found between sense of coherence and hope to participation. Process skills were found to be the main predictor for explaining child's participation. While treating children with DCD we have to consider also socio psychological aspects that may be weakened. PMID- 22940163 TI - Fostering hand washing before lunch by students attending a special needs young adult program. AB - A multiple baseline across groups design was used to investigate the effects of a treatment package on hand washing before lunch by five students with disabilities who attended a young adult educational program. To evaluate hand washing, a lotion called Glo Germ was applied to participants' hands. Glo Germ is visible under a black light, which allowed the quality of hand washing to be assessed by comparing the amount visible before and after hand washing using a 3-point scale. Following a baseline period in which hand washing was assessed, participants were exposed to a hand washing training procedure, which improved one participant's hand washing. Next, a lottery system was imposed in which the number of lottery tickets earned each day depended on the quality of hand washing, specifically, on the rating assigned (0, 1, or 2). This condition was associated with improved hand washing by the other four participants. Finally, a condition adding feedback to the lottery system resulted in further improvements in the quality of hand washing for all participants. Follow up data indicated modest maintenance of hand washing after lunch. These results suggest that treatment packages similar to that used in the present study merit further investigation and that Glo Germ is of value in ascertaining the quality of hand washing. PMID- 22940164 TI - Psychosocial work-related predictors and consequences of personal burnout among staff working with people with intellectual disabilities. AB - The purposes of this study were to investigate the potential predictors of personal burnout among staff working with people with intellectual disabilities and to investigate whether personal burnout is associated with health and work related outcomes. A cross-sectional survey was carried out in 2011 in 30 residential facilities in northern Germany (N = 409, response rate 45%). The German standard version of the Copenhagen Psychosocial Questionnaire was used. In a multiple logistic regression analysis, we identified factors which were predictive of personal burnout, such as work-privacy conflict (OR = 1.04, 95% CI 1.03, 1.05), emotional demands (OR = 1.03, 95% CI 1.01, 1.05), role conflicts (OR = 1.02, 95% CI 1.02, 1.03), job insecurity (OR = 1.03, 95% CI 1.01, 1.05) and feedback (OR = 0.98, 95% CI 0.97, 0.99). These factors explained 49% of the total variance. Higher levels of personal burnout were significantly correlated with higher rates of intention to leave the job and cognitive stress symptoms (p<.01). Low values of personal burnout were associated with greater job satisfaction, good general health, and higher satisfaction with life (p<.01). The present study indicates that improving the psychosocial work environment at the organizational level may reduce personal burnout and may also diminish unfavorable outcomes, such as intention to leave or job dissatisfaction. PMID- 22940165 TI - Subtypes in 22q11.2 deletion syndrome associated with behaviour and neurofacial morphology. AB - 22q11.2 deletion syndrome (22q11DS) has a complex phenotype with more than 180 characteristics, including cardiac anomalies, cleft palate, intellectual disabilities, a typical facial morphology, and mental health problems. However, the variable phenotype makes it difficult to predict clinical outcome, such as the high prevalence of psychosis among adults with 22q11DS (~25-30% vs. ~1% in the general population). The purpose of this study was to investigate whether subtypes exist among people with 22q11DS, with a similar phenotype and an increased risk of developing mental health problems. Physical, cognitive and behavioural data from 50 children and adolescents with 22q11DS were included in a k-means cluster analysis. Two distinct phenotypes were identified: Type-1 presented with a more severe phenotype including significantly impaired verbal memory, lower intellectual and academic ability, as well as statistically significant reduced total brain volume. In addition, we identified a trend effect for reduced temporal grey matter. Type-1 also presented with autism-spectrum traits, whereas Type-2 could be described as having more 22q11DS-typical face morphology, being predominately affected by executive function deficits, but otherwise being relatively high functioning with regard to cognition and behaviour. The confirmation of well-defined subtypes in 22q11DS can lead to better prognostic information enabling early identification of people with 22q11DS at high risk of psychiatric disorders. The identification of subtypes in a group of people with a relatively homogenous genetic deletion such as 22q11DS is also valuable to understand clinical outcomes. PMID- 22940166 TI - Effect of recreational noise exposure on hearing impairment among teenage students. AB - Several studies have focused on the potential impact of children's hearing loss on learning and development. Recently, numerous teenage students have been found to be fond of listening to music on personal devices and participating in recreational music activities. The objective of this study was to investigate teenage students' hearing impairment, their experience with recreational noise exposure, and their self-reported hearing. The participants were 1878 first-year students at a university in Taiwan. The result of the pure tone audiometry test showed that 11.9% of the participants had one or two ears with a hearing threshold over 25 dB. Over the past year, approximately 80.9% of the participants had taken part in at least one loud-noise recreational activity, and 90.9% of the participants were in the habit of using earphones. Among the participants, 190 students with a high level of recreational noise exposure were assigned to the exposure group, and 191 students with a low level of recreational noise exposure constituted the control group. The exposure group had more hearing problems than the control group, but no significant difference existed between the two groups in the pure tone audiometry test (p=0.857). It is suggested that the schools should reinforce hearing health education and proactively provide intervention measures, such as hearing tests, evaluation of noise exposure, and hearing protection. PMID- 22940167 TI - Reported numbers of patients with rare diseases based on ten-year longitudinal national disability registries in Taiwan. AB - This paper aims to describe a general demographic picture of patients with rare diseases in Taiwan and particularly focuses on the prevalence of rare diseases over time, age and gender distributions. We analyzed data mainly from the national disability registry from 2002 to 2011 in Taiwan, Republic of China. The results showed that the number of rare diseases increased from 93 to 193 between 2002 and 2011 and that the prevalence of rare diseases increased from 0.02 to 0.74 per 10,000 people in this time period. The gender ratio (male/female) was between 1.02 and 1.13 during this time period, with male cases representing a higher percentage than female cases in the rare disease population. The occurrence of rare diseases was significantly increased in children 3-5 years of age and elementary school children 6-14 years of age. The data also revealed that the occurrence of rare diseases in Taiwan was attributed primarily to pathogenic diseases and secondarily to genetic diseases. To obtain precise epidemiological data on rare diseases for future healthcare planning, this study highlights the importance of the cooperation of healthcare authorities with the social welfare department to strengthen the ability of the public healthcare system to regularly monitor and measure the occurrence of rare diseases in the community. PMID- 22940168 TI - Using iPods((r)) and iPads((r)) in teaching programs for individuals with developmental disabilities: a systematic review. AB - We conducted a systematic review of studies that involved iPods((r)), iPads((r)), and related devices (e.g., iPhones((r))) in teaching programs for individuals with developmental disabilities. The search yielded 15 studies covering five domains: (a) academic, (b) communication, (c) employment, (d) leisure, and (e) transitioning across school settings. The 15 studies reported outcomes for 47 participants, who ranged from 4 to 27 years of age and had a diagnosis of autism spectrum disorder (ASD) and/or intellectual disability. Most studies involved the use of iPods((r)) or iPads((r)) and aimed to either (a) deliver instructional prompts via the iPod Touch((r)) or iPad((r)), or (b) teach the person to operate an iPod Touch((r)) or iPad((r)) to access preferred stimuli. The latter also included operating an iPod Touch((r)) or an iPad((r)) as a speech-generating device (SGD) to request preferred stimuli. The results of these 15 studies were largely positive, suggesting that iPods((r)), iPod Touch((r)), iPads((r)), and related devices are viable technological aids for individuals with developmental disabilities. PMID- 22940169 TI - Physical activity in a total population of children and adolescents with cerebral palsy. AB - The aims of this study were to describe the participation in physical activity of children with cerebral palsy (CP) at school and during leisure time and to identify characteristics associated with physical activity. The frequency of receiving physiotherapeutic interventions were described as a variable of interest. A total population of 364 children with verified CP aged 7-17 years living in the Skane region in Sweden was studied using cross-sectional data from the CP follow-up programme (CPUP). Proportional odds ratios showed the most severe gross motor limitations Gross Motor Function Classification System Expanded and Revised (GMFCS-E&R) to be a characteristic for low participation in physical education at school (PE) and GMFCS-E&R level III to be a characteristic for low participation in regular physical leisure activity. The age group of 7-11 years and obesity were characteristics associated with high participation in PE, whereas thinness was associated with low participation in regular physical leisure time activities. The highest proportion of children receiving physiotherapeutic interventions was found in GMFCS-E&R level III, while mental retardation, especially if moderate or severe, proved to be an independent characteristic associated with low frequency of physiotherapeutic interventions. Gender and epilepsy did not influence the odds for participation in physical activities. Special considerations are needed when planning interventions for increased physical activity in children with CP, as the individual prerequisites differ, even among children with the same gross motor function level according to the GMFCS-E&R. PMID- 22940171 TI - Family beyond parents? An exploration of family configurations and psychological adjustment in young adults with intellectual disabilities. AB - This research explores the family configurations of young adults with intellectual disability. Based on a sample of 40 individuals interviewed two times in a year, we found as many as four types of family configurations, with distinct compositions, and different types of social capital. This diversity is not without consequences for individual psychological adjustment. The results are discussed in the light of the configurational approach to families. PMID- 22940170 TI - How does brain activation differ in children with unilateral cerebral palsy compared to typically developing children, during active and passive movements, and tactile stimulation? An fMRI study. AB - The aim of the functional magnetic resonance imaging (fMRI) study was to investigate brain activation associated with active and passive movements, and tactile stimulation in 17 children with right-sided unilateral cerebral palsy (CP), compared to 19 typically developing children (TD). The active movements consisted of repetitive opening and closing of the hand. For passive movements, an MRI-compatible robot moved the finger up and down. Tactile stimulation was provided by manually stroking the dorsal surface of the hand with a sponge cotton cloth. In both groups, contralateral primary sensorimotor cortex activation (SM1) was seen for all tasks, as well as additional contralateral primary somatosensory cortex (S1) activation for passive movements. Ipsilateral cerebellar activity was observed in TD children during all tasks, but only during active movements in CP children. Of interest was additional ipsilateral SM1 recruitment in CP during active movements as well as ipsilateral S1 activation during passive movements and tactile stimulation. Another interesting new finding was the contralateral cerebellum activation in both groups during different tasks, also in cerebellar areas not primarily linked to the sensorimotor network. Active movements elicited significantly more brain activation in CP compared to TD children. In both groups, active movements displayed significantly more brain activation compared to passive movements and tactile stimulation. PMID- 22940172 TI - How can the autonomic nervous system contribute to urinary continence following radical prostatectomy? A "boson-like" conundrum. PMID- 22940173 TI - Current status and future directions of robotic single-site surgery: a systematic review. AB - CONTEXT: Despite the increasing interest in laparoendoscopic single-site surgery (LESS) worldwide, the actual role of this novel approach in the field of minimally invasive urologic surgery remains to be determined. It has been postulated that robotic technology could be applied to LESS to overcome the current constraints. OBJECTIVE: To summarize and critically analyze the available evidence on the current status and future of robotic applications in single-site surgery. EVIDENCE ACQUISITION: A systematic literature review was performed in April 2011 using PubMed and the Thomson-Reuters Web of Science. In the free-text protocol, the following terms were applied: robotic single site surgery, robotic single port surgery, robotic single incision surgery, and robotic laparoendoscopic single site surgery. Review articles, editorials, commentaries, and letters to the editor were included only if deemed to contain relevant information. In addition, cited references from the selected articles and from review articles retrieved in the search were assessed for significant manuscripts not previously included. The authors selected 55 articles according to the search strategy based on Preferred Reporting Items for Systematic Reviews and Meta analysis criteria. EVIDENCE SYNTHESIS: The volume of available clinical outcomes of robotic LESS (R-LESS) has considerably grown since the pioneering description of the first successful clinical series of single-port robotic procedures. So far, a cumulative number of roughly 150 robotic urologic LESS cases have been reported by different institutions across the globe with a variety of techniques and port configurations. The feasibility of robot-assisted single-incision colorectal procedures, as well as of many gynecologic procedures, has also been demonstrated. A novel set of single-site instruments specifically dedicated to LESS is now commercially available for use with the da Vinci Si surgical system, and both experimental and clinical use have been reported. However, the current robotic systems were specifically designed for LESS. The ideal robotic platform should have a low external profile, the possibility of being deployed through a single access site, and the possibility of restoring intra-abdominal triangulation while maintaining the maximum degree of freedom for precise maneuvers and strength for reliable traction. Several purpose-built robotic prototypes for single-port surgery are being tested. CONCLUSIONS: Significant advances have been achieved in the field of R-LESS since the first reported clinical series in 2009. Given the several advantages offered by current the da Vinci system, it is likely that its adoption in this field will increase. The recent introduction of purpose-built instrumentation is likely to further foster the application of robotics to LESS. However, we are still far from the ideal robotic platform. Significant improvements are needed before this technique might reach widespread adoption beyond selected centers. Further advances in the field of robotic technology are expected to provide the optimal interface to facilitate LESS. PMID- 22940174 TI - Surgical management of kidney cancer in france: overview of the last decade. PMID- 22940175 TI - Proteomic and physiological responses of the halophyte Cakile maritima to moderate salinity at the germinative and vegetative stages. AB - Responses of the halophyte Cakile maritima to moderate salinity were addressed at germination and vegetative stages by bringing together proteomics and eco physiological approaches. 75 mM NaCl-salinity delayed significantly the germination process and decreased slightly the seed germination percentage compared to salt-free conditions. Monitoring the proteome profile between 0 h and 120 h after seed sowing revealed a delay in the degradation of seed storage proteins when germination took place under salinity, which may explain the slower germination rate observed. Of the sixty-seven proteins identified by mass spectrometry, several proteins involved in glycolysis, amino acid metabolism, photosynthesis, and protein folding showed significantly increased abundance during germination. This pattern was less pronounced under salinity. At the vegetative stage, 100mM NaCl-salinity stimulated significantly the plant growth, which was sustained by enhanced leaf expansion, water content, and photosynthetic activity. Comparative proteome analyses of leaf tissue revealed 44 proteins with different abundance changes, most of which being involved in energy metabolism. A specific set of proteins predominantly involved in photosynthesis and respiration showed significantly higher abundance in salt-treated plants. Altogether, combining proteomics with eco-physiological tools provides valuable information, which contributes to improve our understanding in the salt-response of this halophyte during its life cycle. PMID- 22940176 TI - Identification of Bacillus selenitireducens MLS10 maltose phosphorylase possessing synthetic ability for branched alpha-D-glucosyl trisaccharides. AB - We discovered an inverting maltose phosphorylase (Bsel2056) belonging to glycoside hydrolase family 65 from Bacillus selenitireducens MLS10, which possesses synthetic ability for alpha-D-glucosyl disaccharides and trisaccharides through the reverse phosphorolysis with beta-D-glucose 1-phosphate as the donor. Bsel2056 showed the flexibility for monosaccharide acceptors with alternative C2 substituent (2-amino-2-deoxy-D-glucose, 2-deoxy-D-arabino-hexose, 2-acetamido-2 deoxy-D-glucose, D-mannose), resulting in production of 1,4-alpha-D-glucosyl disaccharides with strict regioselectivity. In addition, Bsel2056 synthesized two maltose derivatives possessing additional D-glucosyl residue bound to C2 position of the D-glucose residue at the reducing end, 1,4-alpha-D-glucopyranosyl-[1,2 alpha-D-glucopyranosyl]-D-glucose and 1,4-alpha-D-glucopyranosyl-[1,2-beta-D glucopyranosyl]-D-glucose, from 1,2-alpha-D-glucopyranosyl-D-glucose (kojibiose) and 1,2-beta-D-glucopyranosyl-D-glucose (sophorose), respectively, as the acceptors. These results suggested that Bsel2056 possessed a binding space to accommodate the bulky C2 substituent of D-glucose. PMID- 22940177 TI - Synthesis of pentasaccharides corresponding to the glycoform II of the outer core region of the Pseudomonas aeruginosa lipopolysaccharide. AB - Cystic fibrosis (CF) is a congenital disease caused by a mutation in a gene responsible for the synthesis of a membrane protein called the cystic fibrosis transmembrane conductance regulator (CFTR). Resistance to Pseudomonas aeruginosa infection is closely related to the biological properties of CFTR; however, these properties have not been clearly linked to the known role of CFTR as a chloride and bicarbonate ion channel. Indeed, data indicate that CFTR is an epithelial cell receptor for P. aeruginosa, with CFTR binding to the oligosaccharide of the outer core region of the bacterial lipopolysaccharide (LPS), of which two distinct glycoforms have been identified. Binding leads to effective innate immunity to clear this pathogen in individuals with wild-type CFTR. To reveal the molecular basis of elimination of the bacterium through this interaction, the synthesis of pentasaccharides corresponding to both glycoforms of the outer core region of P. aeruginosa LPS was undertaken. Here we report the synthesis of the glycoform II. Like glycoform I, it was prepared as three pentasaccharides bearing naturally occurring N-alanyl and N-acetyl substituents in the galactosamine moiety as well as unnatural N-acetylalanine to reveal the role of the amino group in the alanyl substituent. Key features of the synthesis were two alpha glucosylations with glucosyl donors bearing alpha-stereodirecting acyl groups at O-6 and/or O-3 and high-yielding reduction of the azido group followed by N acylation and final O-debenzylation. PMID- 22940178 TI - cDNA cloning and bacterial expression of a PL-14 alginate lyase from a herbivorous marine snail Littorina brevicula. AB - Herbivorous marine snails like Littorina species are known to possess alginate lyases in their digestive tracts. The Littorina enzymes have been identified as endolytic polymannuronate (poly(M)) lyases (EC 4.2.2.3); however, it is still unclear which polysaccharide-lyase family (PL) the Littorina enzymes belong to, since no complete primary structure of Littorina enzymes has been determined. Thus, in the present study, we analyzed the primary structure of LbAly28, a 28kDa alginate lyase isozyme of Littorina brevicula, by the cDNA method. LbAly28 cDNAs were amplified by PCR followed by 5'- and 3'-RACE PCRs from the L. brevicula hepatopancreas cDNA. A cDNA covering entire coding region of LbAly28 consisted of 1129bp and encoded an amino-acid sequence of 291 residues. The deduced amino-acid sequence comprised an initiation methionine, a putative signal peptide of 14 residues, a propeptide-like region of 16 residues, and a mature LbAly28 domain of 260 residues. The mature LbAly28 domain showed 43-53% amino-acid identities with other molluscan PL-14 enzymes. The catalytically important residues in PL-14 enzymes, which were identified in the Chlorella virus glucuronate-specific lyase vAL-1 and Aplysia poly(M) lyase AkAly30, were also conserved in LbAly28. Site directed mutagenesis regarding these residues, that is, replacements of Lys94, Lys97, Thr121, Arg 123, Tyr135, and Tyr137 to Ala, decreased the activity of recombinant LbAly28 to various degrees. From these results we concluded that LbAly28 is a member of PL-14 alginate lyases. Besides the effects of above mutations, we noticed that the replacement of T121 by Ala changed the substrate preference of LbAly28. Namely, the activities toward sodium alginate and poly(MG) block substrate increased and became comparable with the activity toward poly(M) block substrate. This suggests that the region including T121 of LbAly28 closely relates to the recognition of poly(MG) region of alginate. PMID- 22940179 TI - Non-symmetric liquid crystal dimer containing a carbohydrate-based moiety. AB - The synthesis and characterisation of a novel non-symmetric liquid crystal dimer, 1-[3-O-(D-glucopyranos-3-yl)]-8-[(4-methoxyazobenzene-4'-oxy)]octane is reported. This exhibits glassy behaviour and a highly interdigitated smectic A phase in which the aromatic and alkyl structural fragments overlap. Variable temperature infrared spectroscopy reveals that the strength and extent of hydrogen bonding within the system does not show a marked change at either the glass transition or at the smectic A-isotropic transition. This observation indicates that the smectic A-isotropic transition is driven by changes in the van der Waals interactions between the molecules while hydrogen bonded aggregates persist into the isotropic phase. PMID- 22940180 TI - The potential for oligosaccharide production from the hemicellulose fraction of biomasses through pretreatment processes: xylooligosaccharides (XOS), arabinooligosaccharides (AOS), and mannooligosaccharides (MOS). AB - Hemicellulosic oligosaccharides are sugar molecules that contain xylose, mannose, and arabinose in variable concentrations ranging from 3 to 10 molecules. These medium and long chain sugars can be classified as non-digestible carbohydrates, thus playing an important role in gastrointestinal health as prebiotics. Their physiological benefits, primarily stimulation of the proliferation of lactic acid bacteria and bifidobacteria in the colon informs their significance as high value nutraceuticals in the food and pharmaceutical industry. In addition they are well known as useful components of important pharmaceutical products. There are two main ways of producing these sugars from biomass, which include enzymatic and non enzymatic pretreatments. Each of the two processes has advantages and disadvantages. Enzymatic processes are associated with high costs, higher concentration of monomeric sugars, and low oligosaccharide yields while thermo chemical processes are usually associated with undesirable byproducts such as furfural and lower oligosaccharide yields. In this paper we discuss the benefits and constraints for optimization of different methods for the production of oligosaccharides from biomass. PMID- 22940181 TI - Regioselective glucosylation of inositols catalyzed by Thermoanaerobacter sp. CGTase. AB - Monoglucosylated products of L-chiro-, D-chiro-, muco-, and allo-inositol were synthesized by regioselective alpha-D-glucosylation with cyclodextrin glucosyl transferase from Thermoanaerobacter sp. after hydrolysis of by products with Aspergillus niger glucoamylase. While the reactions carried out with D-chiro-, muco-, and allo-inositol resulted in the regioselective formation of monoglucosylated products, two products were obtained in the reaction with L chiro-inositol. Through the structural characterization of the glucosylated inositols here we demonstrated that the selectivity observed in the glucosylation of several inositols by Thermoanaerobacter sp. CGTase, is analogous to the specificity observed for the glucosylation of beta-D-glucopyranose and equivalent glucosides. PMID- 22940182 TI - Conformational analysis of an extracellular polysaccharide produced by Sphaerotilus natans. AB - Sphaerotilus natans is a filamentous sheath-forming bacterium, commonly found in bulking activated sludge. The bulky nature of this bacterium is caused by an extracellular polysaccharide (EPS). EPS is a linear acidic polysaccharide with the following chemical structure: [ -> 4)-alpha-D-Glcp-(1 -> 2)-beta-D-GlcpA-(1 > 2)-alpha-L-Rhap-(1 -> 3)-beta-L-Rhap-(1 -> ](n). (1)H-(1)H and (1)H-(13)C correlation nuclear magnetic resonance (NMR) experiments were performed to acquire nuclear Overhauser effect signals, which were used for conformational elucidation. Molecular mechanics calculations were performed on each disaccharide unit of the EPS building blocks. On the basis of the results of the calculations, the conformation of a pentasaccharide fragment was estimated. After confirmation of the coincidence between the NMR data and the predicted conformation of the pentasaccharide fragment, the conformation of a heptadecasaccharide fragment was estimated using the same procedure. The heptadecasaccharide was found to form a (12/1) helix and take locally folded chain, which is attributed to a triangular arrangement formed by a series of residues, alpha-D-Glcp-(1 -> 2)-beta-D-GlcpA-(1 -> 2)-alpha-L-Rhap. This arrangement is caused by the peculiar consecutive (1 -> 2) linkages and reinforced by a hydrogen bond between the alpha-glucosyl and alpha-rhamnosyl residues. Considering the steric hindrance due to this triangular arrangement, EPS molecules are not supposed to form double helix in an aqueous environment. We propose the name 'sphaeran' to refer to this unique chemical structure and properties of EPS. PMID- 22940183 TI - Effects of the anticonvulsant lacosamide compared to valproate and lamotrigine on cocaine-enhanced reward in rats. AB - Some drugs developed as anticonvulsants (notably, valproate and lamotrigine) have therapeutic effects in bipolar and related disorders. Lacosamide, a recently approved anticonvulsant, has unique effects on sodium channels that may play a role in producing the mood-stabilizing effects of anticonvulsant drugs. We tested whether lacosamide would have effects similar to or different from valproate and lamotrigine in a model of reward and elevated mood. The intracranial self stimulation (ICSS) test is sensitive to the function of brain reward systems. Changes in ICSS may model aspects of disorders characterized by abnormalities of reward and motivation. Cocaine elevates mood, and reduction of cocaine-induced facilitation of ICSS has been used to predict antimanic-like or mood stabilizing effects of drugs. We tested lacosamide, lamotrigine, and valproate in the rat ICSS test alone or in the presence of cocaine. A high dose of lacosamide (30 mg/kg) significantly elevated ICSS thresholds, indicating that it reduced the rewarding impact of medial forebrain bundle stimulation. Lower doses (3-10 mg/kg) did not alter ICSS, but blocked the cocaine-induced lowering of ICSS thresholds. The highest doses of valproate (300 mg/kg) and lamotrigine (30 mg/kg) also elevated ICSS thresholds, and only these high doses significantly lowered cocaine induced effects. Of the drugs tested, only lacosamide significantly attenuated the reward-facilitating effects of cocaine at doses that had no effects on ICSS response in the absence of cocaine. Abnormalities of mood and reward are common in psychiatric disorders, and these results suggest that lacosamide deserves further study in models of these disorders. PMID- 22940184 TI - Alantolactone suppresses inducible nitric oxide synthase and cyclooxygenase-2 expression by down-regulating NF-kappaB, MAPK and AP-1 via the MyD88 signaling pathway in LPS-activated RAW 264.7 cells. AB - Several sesquiterpene lactones are the active components of several medicinal plants and have been demonstrated to perform various pharmacological functions. In this study, we investigated the anti-inflammatory effects of alantolactone, a sesquiterpene lactone isolated from the root of Aucklandia lappa, in lipopolysaccharide (LPS)-stimulated RAW 264.7 cells and peritoneal macrophages. Alantolactone inhibited inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2) protein and mRNA transcription, as well as the downstream products, nitric oxide (NO), prostaglandin E(2) (PGE(2)) and tumor necrosis factor-alpha (TNF-alpha). Investigation of the effects on nuclear factor kappaB (NF-kappaB) signaling showed that alantolactone inhibits the phosphorylation of inhibitory kappaB (IkappaB)-alpha and IkappaB kinase (IKK) and the subsequent translocation of the p65 and p50 NF-kappaB subunits to the nucleus. Moreover, inhibition of mitogen-activated protein kinases (MAPKs), including c-Jun N-terminal kinase (JNK), extracellular signal-regulated kinase (ERK) and p38 MAPK, and activator protein-1 (AP-1) was also observed. A further study indicated that alantolactone attenuated the phosphorylation of Akt and inhibited the expression of MyD88 and Toll-interleukin 1 receptor domain-containing adaptor protein (TIRAP), an upstream signaling molecule required for IKK and MAPKs activation. Taken together, these results suggest that alantolactone exerts its anti-inflammatory effect in LPS-stimulated RAW 264.7 cells by suppressing NF-kappaB activation and MAPKs phophorylation via downregulation of the MyD88 signaling pathway. Thus, alantolactone may provide a useful therapeutic approach for inflammation associated diseases. PMID- 22940185 TI - Th1 immunity induction by ginsenoside Re involves in protection of mice against disseminated candidiasis due to Candida albicans. AB - Type-1 and -2 responses of T helper lymphocytes demonstrate essentially different and opposite effector functions. In the present study, we determined the immunoregulatory effect of ginsenoside Re against disseminated candidiasis due to Candida albicans. This fungus may be one of the most problematic fungi for humans. Results showed that Re had no growth-inhibitory effect on C. albicans. In contrast, mice groups given Re intraperitoneally before intravenous challenge with live C. albicans survived longer against disseminated candidiasis than Re untreated mice. All of the ten control mice died by day 15, whereas seven out of ten Re-treated mice survived during the entire duration of the 40 day-observation resulting in mean survival times (MST) of 32.7 +/- 13.4 (MST +/- S.E.) days. These survival values were almost the same as the values obtained from Rg1 treated mice used for a positive control. Through determining the kidneys' candidal colony forming unit, we found that the disease severity of Re-treated mice was far less than that of Re-untreated animals. This protection was transferable by the CD4+T cells (RECD4T) from Re-treated mice similar to (RGCD4T) CD4+T cells from Rg1-treated animals. A cytokine profile revealed the Th1- lineage development of dominant IFNg and IL-2 from RECD4T. However, the protection was abolished when mice were treated with anti-mouse IFNg. In addition, a hemolytic assay showed that Re at 1000 MUg/ml caused no hemolysis. All of these data indicate that Re has the immunoregulatory effect of CD4+T cell mediated immune response that is led from a Type 1-dominant immunity. PMID- 22940186 TI - Role of interplay between IL-4 and IFN-gamma in the in regulating M1 macrophage polarization induced by Nattectin. AB - Recently our group described that Nattectin, a C-type lectin of the venom of Thalassophryne nattereri shows a potent pro-inflammatory capacity. Here, we demonstrated that Nattectin is able to induce M1 macrophage marker iNOS, and up regulate the expression of MHC class II, CD80, CD86 and CD40 molecules. The increase in MHC class II and CD49a integrin expression with MMP-9 production and endocytic capacity depend on lectin function of Nattectin. Moreover, the polarization of peritoneal and bone marrow-derived macrophages induced by Nattectin to M1 profile is dependent on Th1 cytokines (IL-12 and IFN-gamma), and negatively regulated by Th2 cytokines (IL-4, IL-10 and IL-13). Also we reveal that IL-4 play a dual role in this polarization: a regular action of IL-4 was seen in the negative regulation of the CD40 expression, but an unexpected positive regulation was seen in the expression of CCR7 and MHC class II. Finally, our in vivo studies showed that the influx of neutrophils and small peritoneal macrophage--F4/80(low)MHCII(hi) induced by Nattectin is totally dependent on IL-4 and IFN-gamma cytokines. Furthermore, the induction of IL-6 release is negatively regulated by IL-4 and positively regulated by IL-12 and IFN-gamma. Together, the results allowed us to expand the knowledge about the regulation of macrophage activation, as well as confirmed the ability of Nattectin, a fish C-type lectin, as an important immunomodulatory agent. PMID- 22940188 TI - Correlation of the degree of conversion with the amount of elutable substances in nano-hybrid dental composites. AB - OBJECTIVES: This study's purpose was to measure and compare the degree of conversion (DC) and the amount of elutable substances from modern resin-based composites (RBCs) as function of polymerization time. One nano-hybrid RBC based on tricyclodecane-(TCD)-urethane (Venus((r)) Diamond) and two conventionally formulated RBCs (TetricEvo Ceram((r)), FiltekTM Supreme XTE) were considered. METHOD: DC (n=5) was investigated in real time for 5min by Fourier transform infrared spectroscopy (ATR-FTIR) in a filling depth of 2mm at varied irradiation times (5, 10, 20, 40s). After storing the specimens in ethanol/water for 7 d at 37 degrees C the eluates were analyzed by gas chromatography/mass spectrometry. Results were statistically analyzed using a multivariate analysis (alpha=0.05) an independent t-test (p<0.05) and a Pearson correlation analysis. RESULTS: In all groups increasing curing time resulted in a significant increase in DC. For TetricEvo Ceram((r)) a high significant inverse correlation was found between DC and the amount of eluted camphorquinone (CQ, Pearson correlation coefficient= 0.88), ethylene glycol dimethacrylate (EGDMA, -0.73), 4-N,N-dimethylaminobenzoic acid ethylester (DMABEE, -0.87), triethylene glycol dimethacrylate (TEGDMA, 0.68), Tinuvin P (-0.71) and bisphenol-A-polyetheylene glycol dimethacrylate (BisEMA, -0.84). Unexpectedly DC and the amount of eluted methyl acrylate (MAA) correlated directly (0.72). In the specimens of Venus((r)) Diamond a significant inverse correlation was found between DC and the amount of eluted CQ (-0.69) and TEGDMA (-0.50), whereas in the specimen of FiltekTM Supreme XTE DC correlated with CQ (-0.96), EGDMA (-0.70), DMABEE (-0.87), TEGDMA (-0.92) and MAA (-0.92). SIGNIFICANCE: This study demonstrated a strong inverse correlation between DC and elutable substances in RBCs. Both evaluation methods emphasis the importance of an adequate polymerization (20, 40s), since short curing-times (5, 10s) resulted in lower DC and higher amount of eluted substances with toxic potential. PMID- 22940187 TI - Fatty liver and anti-oxidant enzyme activities along with peroxisome proliferator activated receptors gamma and alpha expressions in the liver of Wilson's disease. AB - BACKGROUND: The mechanisms of liver damage and steatosis in Wilson's disease (WD) presenting accumulation of copper generating oxidants remain unclear. Recent studies have shown that peroxisome proliferator-activated receptors (PPARs), in particular PPARs alpha and gamma, regulate fat content of the liver together with the anti-oxidant and anti-inflammation systems. However, such PPARs have never been studied in WD. METHODS: We examined PPARs along with the liver damage and steatosis of WD using liver specimens from affected patients exhibiting mild liver damage (group I, n = 5), moderate or greater liver damage (group II, n = 10) and fulminant hepatic failure (group III, n = 5), and from asymptomatic carriers (group H, n = 4). RESULTS: PPAR alpha expression was increased over the control levels in groups H and I but was decreased in groups II and III in parallel with the progression of liver damage (group H = I>II>III). PPAR gamma expression was inversely increased (group Holfactory bulbs>skin>muscles>brain. At the end of the experiment, uranium was present in non-negligible quantities in sensory tissues. In parallel, fish exposed to uranium showed severe sensory tissue alterations at the level of the olfactory and lateral line systems. In both sensory systems, the gross morphology was altered and the sensory hair cells were significantly damaged very early after the initiation of exposure (from the 3rd day). At the end of the experiment, after 23 days of depuration, the lateral line system still displayed slight tissue alterations, but approximately 80% of the neuromasts in this system had regenerated. In contrast, the olfactory system took more time to recover, as more than half of the olfactory rosettes observed remained destroyed at the end of the experiment. This study showed, for the first time, that uranium is able to damage fish sensory tissues to such an extent that tissue regeneration is delayed. PMID- 22940225 TI - Basal and 3-methylcholanthrene-induced expression of cytochrome P450 1A, 1B and 1C genes in the Brazilian guppy, Poecilia vivipara. AB - In fish there are four cytochrome P450 (CYP1) subfamilies: CYP1A, CYP1B, CYP1C, and CYP1D. Here we cloned Poecilia vivipara CYP1A, with an inferred amino acid sequence 91% identical to CYP1A from the killifish Fundulus heteroclitus, another member of the Cypriniformes, and an important model in ecotoxicology. In addition, we examined the expression of CYP1A, CYP1B1, and CYP1C1 by qPCR in liver, gill, and intestine of adult P. vivipara injected with 3 methylcholanthrene (3-MC) or held in clean water (control group) for 24h. All three tissues examined showed basal expression of the three CYP1 genes. CYP1A was most strongly expressed in the liver, while CYP1B1, and CYP1C1 were most strongly expressed in the gill and intestine respectively. 3-MC induced CYP1A, CYP1B1, and CYP1C1 significantly (20-120-fold) in the three organs, consistent with the regulation of CYP1A, CYP1B1 and CYP1C1 via the aryl hydrocarbon receptor. Validation of CYP1 gene biomarkers in fish collected from a contaminated urban mangrove environment was confirmed with significant induction of CYP1A and CYP1C1 in gills (10-15-fold) and CYP1B1 in liver (23-fold), relative to fish from a control site. The responsiveness of these CYP1 genes indicates P. vivipara is suitable as a model for environmental toxicology studies and environmental assessment in Brazil. PMID- 22940226 TI - The effect of guggulipid and nimesulide on MPTP-induced mediators of neuroinflammation in rat astrocytoma cells, C6. AB - Oxidative stress plays an important role in the pathophysiology of Parkinson's disease (PD) but its mechanism is still not properly explored. Cyclooxygenase-2 (COX-2) inhibition has also been known a major neuroprotective strategy in the various 1-methyl-4-phenyl 1,2,3,6 tetrahydropyridine (MPTP) induced models of Parkinson's disease (PD) but its role in astrocytes is still not properly understood. The present study demonstrated that, guggulipid and nimesulide (preferentially selective COX-2 inhibitor) treatment of rat astrocytoma cells, C6 for 24 h significantly decreased MPTP (400 MUM) induced nitrative and oxidative stress and intracellular calcium ion (Ca(2+)) level. Guggulipid and nimesulide also deactivated MPTP-induced P-p38 MAPK (Phosphorylated p38 mitogen-activated protein kinase) and down regulated expressions of cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS) and CHOP (C/EBP, homologous protein 10). At transcriptional level of inflammatory cytokine genes, guggulipid and nimesulide down regulated MPTP-induced tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta) mRNA expressions with up regulations in interleukin-6 (IL-6) and interleukin-1alpha (IL-1alpha) mRNA expressions. In addition to this, guggulipid and nimesulide inhibited translocation of nuclear factor kappa-B (NF-kappaB) from cytosol to nucleus. In conclusion, our findings elucidated the potential antioxidant and anti-neuroinflammatory effect of guggulipid and nimesulide in rat astrocytoma cells C6, which may suggest the use of these drugs in the management of neuroinflammation associated pathophysiology of PD. PMID- 22940227 TI - EPR spin trapping evaluation of ROS production in human fibroblasts exposed to cerium oxide nanoparticles: evidence for NADPH oxidase and mitochondrial stimulation. AB - To better understand the antioxidant (enzyme mimetic, free radical scavenger) versus oxidant and cytotoxic properties of the industrially used cerium oxide nanoparticles (nano-CeO(2)), we investigated their effects on reactive oxygen species formation and changes in the antioxidant pool of human dermal and murine 3T3 fibroblasts at doses relevant to chronic inhalation or contact with skin. Electron paramagnetic resonance (EPR) spin trapping with the nitrone DEPMPO showed that pretreatment of the cells with the nanoparticles dose-dependently triggered the release in the culture medium of superoxide dismutase- and catalase inhibitable DEPMPO/hydroxyl radical adducts (DEPMPO-OH) and ascorbyl radical, a marker of ascorbate depletion. This DEPMPO-OH formation occurred 2 to 24 h following removal of the particles from the medium and paralleled with an increase of cell lipid peroxidation. These effects of internalized nano-CeO(2) on spin adduct formation were then investigated at the cellular level by using specific NADPH oxidase inhibitors, transfection techniques and a mitochondria targeted antioxidant. When micromolar doses of nano-CeO(2) were used, weak DEPMPO OH levels but no loss of cell viability were observed, suggesting that cell signaling mechanisms through protein synthesis and membrane NADPH oxidase activation occurred. Incubation of the cells with higher millimolar doses provoked a 25-60-fold higher DEPMPO-OH formation together with a decrease in cell viability, early apoptosis induction and antioxidant depletion. These cytotoxic effects could be due to activation of both the mitochondrial source and Nox2 and Nox4 dependent NADPH oxidase complex. Regarding possible mechanisms of nano CeO(2)-induced free radical formation in cells, in vitro EPR and spectrophotometric studies suggest that, contrary to Fe(2+) ions, the Ce(3+) redox state at the surface of the particles is probably not an efficient catalyst of hydroxyl radical formation by a Fenton-like reaction in vivo. PMID- 22940228 TI - Magnetic resonance in N staging of lung cancer. PMID- 22940229 TI - Ultrasound guided percutaneous microwave ablation of benign thyroid nodules: safety and imaging follow-up in 222 patients. AB - OBJECTIVE: Microwave ablation is a minimally invasive technique that has been used to treat benign and malignant tumors of liver, lung and kidney. Towards thyroid nodules, only a few cases are reported so far. The aim of the study was to investigate the effectiveness and safety of ultrasound-guided percutaneous microwave ablation in the treatment of benign thyroid nodules with a large sample. MATERIALS AND METHODS: A total of 477 benign thyroid nodules in 222 patients underwent microwave ablation in our department from July 2009 to March 2012. Microwave ablation was carried out using microwave antenna (16G) under local anesthesia. Nodule volume, thyroid function and clinical symptoms were evaluated before treatment and at 1, 3, more than 6 months. The study was ethics committee approved and written informed consents were obtained from all patients. RESULTS: All thyroid nodules significantly decreased in size after microwave ablation. A 6-month follow-up was achieved in 254 of 477 nodules, and the mean decrease in the volume of thyroid nodules was from 2.13 +/- 4.42 ml to 0.45 +/- 0.90 ml, with a mean percent decrease of 0.65 +/- 0.65. A volume-reduction ratio greater than 50% was observed in 82.3% (209/254) of index nodules, and 30.7% (78/254) of index nodules disappeared 6-month after the ablation. The treatment was well tolerated and no major complications were observed except pain and transient voice changes. CONCLUSIONS: Microwave ablation seems to be a safe and effective technique for the treatment of benign thyroid nodules. Further prospective randomized studies are needed to define the role of the procedure in the treatment of thyroid nodules. PMID- 22940230 TI - Prognostic factors related to clinical outcome following thrombectomy in ischemic stroke (RECOST study). 50 patients prospective study. AB - BACKGROUND AND AIMS: New thrombectomy devices allow successful and rapid recanalization in acute ischemic stroke. Nevertheless prognostics factors need to be systematically analyzed in the context of these new therapeutic strategies. The aim of this study was to analyze prognostic factors related to clinical outcome following Solitaire FR thrombectomy in ischemic stroke. METHODS: Fifty consecutive ischemic stroke patients with large vessel occlusion were included. Three treatment strategies were applied; rescue therapy, combined therapy, and standalone thrombectomy. DWI ASPECT score<5 was the main exclusion criterion after initial MRI (T2, T2, TOF, FLAIR, DWI). Sexes, age, time to recanalization were prospectively collected. Clinical outcome was assessed post treatment, day one and discharge by means of a NIHSS. Three months mRS evaluation was performed by an independent neurologist. The probability of good outcome at 3 months was assessed by forward stepwise logistic regression using baseline NIHSS score, Glasgow score at entrance, hyperglycemia, dyslipidemia, blood-brain barrier disruption on post-operative CT, embolic and hemorrhagic post procedural complication, ischemic brain lesion extension on 24h imaging, NIHSS at discharge, ASPECT score, and time to recanalization. All variables significantly associated with the outcome in the univariate analysis were entered in the model. The significance of adding or removing a variable from the logistic model was determined by the maximum likelihood ratio test. Odds-ratio (OR) and their 95% confidence intervals were calculated. RESULTS: At 3 months 54% of patients had a mRS 0-2, 70% in MCA, 44% in ICA, and 43% in BA with an overall mortality rate of 12%. Baseline NIHSS score (p=0.001), abnormal Glasgow score at entrance (p=0.053) hyperglycemia (p=0.023), dyslipidemia (p=0.031), blood-brain barrier disruption (p=0.022), embolic and hemorrhagic post procedural complication, ischemic brain lesion extension on 24h imaging (p=0.008), NIHSS at discharge (0.001) were all factors significantly associated with 3 month clinical outcome. ASPECT subgroup (5-7 and 8-10), and time to recanalization were not correlated to 3 months outcome. Baseline NIHSS score (OR, 1.228; 95% CI, 1.075-1.402; p=0.002), hyperglycemia (OR, 10.013; 95% CI, 1.068-93.915; p=0.04), emerged as independent predictors of outcome at 3 months. Overall embolic complication rate was 10%, and symptomatic intracranial hemorrhage was 2%. CONCLUSION: The MCA location was associated with the best clinical outcome. A DWI ASPECT cutoff score of 5 was reliable and safe. No correlation with time to recanalization was observed in this study. NIHSS and hyperglycemia at admission were the two factors independently associated with a bad outcome at 90 days. PMID- 22940231 TI - Reward processing and intertemporal decision making in adults and adolescents: the role of impulsivity and decision consistency. AB - Several studies report differences between adults and adolescents in reward processing and impulsivity. Consistently, adolescents are more impulsive in their decision making, as measured by intertemporal choice tasks. Since impulsivity affects an individual's perception and neural processing of rewards, it is unclear whether previously reported differences in brain activation between adults and adolescents are primarily due to maturation of the brain reward system or differences in impulsivity (i.e. discounting behaviour). To disentangle this, we analysed data from 235 adolescents and 29 adults who performed an intertemporal choice task in which monetary rewards were adapted to individual impulsivity. Using functional magnetic resonance imaging (fMRI), we measured brain activity and assessed impulsivity and consistency of choices at the behavioural level. Although adolescents discounted delayed rewards more steeply than adults, when controlling for impulsivity, neural processing of reward value did not differ between groups. However, more impulsive subjects showed a lower brain response to delayed rewards, independent of age. Concerning decision making, adolescents exhibited a lower consistency of choices and less brain activity in the parietal network than adults. We conclude that processing of the value of prospective delayed rewards is more sensitive to discounting behaviour than to chronological age. Lower consistency of intertemporal choices might indicate ongoing maturation of parietal brain areas in adolescents. PMID- 22940232 TI - An immortalised astrocyte cell line maintains the in vivo phenotype of a primary porcine in vitro blood-brain barrier model. AB - Whilst it is well documented that all components of the neurovascular unit contribute to the restrictive nature of the blood-brain barrier (BBB), astrocytes have been identified as the cellular component most likely to play an essential role in maintaining the barrier properties. The aim of this study was to examine the impact of the rat astrocyte cell line, CTX-TNA2, on the structural and functional characteristics of an in vitro BBB and determine the capacity of this astrocyte cell line to maintain the BBB phenotype. Co-culture of the CTX-TNA2 cells with primary porcine brain endothelial cells produced an in vitro BBB model which retains key features of the in vivo BBB. High transendothelial electrical resistances, comparable to those reported in vivo, were obtained. Ultrastructural analysis revealed distinct intercellular tight junction protein complexes and immunocytochemistry confirmed expression of the tight junction proteins ZO-1 and occludin. Western blotting and fluorescent tracer assays confirmed expression and functional activity of P-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2) efflux transporters. Studies employing Alexa-fluor 555-conjugated human transferrin revealed temperature-sensitive internalisation indicating the BBB model retains functional receptor-mediated transferrin uptake. The findings of this study indicate that a robust BBB model has been produced and this is the first report of the inductive capacity of the CTX-TNA2 cell line. Since this in vitro BBB model possesses many key characteristics of the BBB in vivo it has the potential to be a valuable tool for the study of biochemical and physiological processes associated with the BBB. PMID- 22940233 TI - Can we reduce the dosage of biologics in spondyloarthritis? AB - TNF blockers have revolutionized the management of spondyloarthritis (SpA). To date, four anti-TNFalpha agents (etanercept, infliximab, adalimumab, golimumab) have been approved for the management of ankylosing spondylitis (AS) and psoriatic arthritis (PsA). The first objective in the management of AS and PsA with TNF inhibitors is to reduce disease activity to clinical remission or low disease activity. After remission has been achieved, this state should be maintained as long as possible. However, the financial burden associated with the cost of anti-TNF agents as well as concerns about their long-term safety suggest reducing the dosage of the drug or discontinuing the therapy in the hopes of drug free remission. The aim of this review is to examine what has, till now, been published on this topic in axial SpA, which includes AS and non-radiographic axial SpA (nr-axSpA), peripheral SpA and PsA. Discontinuation of therapy in axial SpA is not possible in the majority of patients, while on the contrary, reducing the dosage often is. In some patients with peripheral SpA and PsA it is also possible to discontinue therapy and to achieve drug-free remission. PMID- 22940234 TI - The relationship between geometric patterns of hydrogen bonds and periodic dinucleotides in nucleosome structures. AB - Statistical analysis of hydrogen bonds between the DNA chain and histones in nucleosomes shows that there is a periodicity about 10 base pairs along the DNA sequence. This periodicity also exists in dinucleotides which are found to be highly correlated with these hydrogen bonds. By analyzing the components of these protein-DNA hydrogen bonds, we find that more than 86% of them are formed in periodic dinucleotides and one or more hydrogen bonds exist in the majority of periodic dinucleotides. We use the alpha shape model to study the geometric properties of hydrogen bonds in nucleosomes, and find that periodic dinucleotides have convex surface curvatures, which indicates that they have close contact with the histones. The results in this work show that hydrogen bonds in the periodic dinucleotides play a crucial role in the formation of a nucleosome. PMID- 22940235 TI - A phylogenetic comparative method for studying multivariate adaptation. AB - Phylogenetic comparative methods have been limited in the way they model adaptation. Although some progress has been made, there are still no methods that can fully account for coadaptation between traits. Based on Ornstein-Uhlenbeck (OU) models of adaptive evolution, we present a method, with R implementation, in which multiple traits evolve both in response to each other and, as in previous OU models, to fixed or randomly evolving predictor variables. We present the interpretation of the model parameters in terms of evolutionary and optimal regressions enabling the study of allometric and adaptive relationships between traits. To illustrate the method we reanalyze a data set of antler and body-size evolution in deer (Cervidae). PMID- 22940236 TI - Accumulation of neutral mutations in growing cell colonies with competition. AB - Neutral mutations play an important role in many biological processes including cancer initiation and progression, the generation of drug resistance in bacterial and viral diseases as well as cancers, and the development of organs in multicellular organisms. In this paper we study how neutral mutants are accumulated in nonlinearly growing colonies of cells subject to growth constraints such as crowding or lack of resources. We investigate different types of growth control which range from "division-controlled" to "death-controlled" growth (and various mixtures of both). In division-controlled growth, the burden of handling overcrowding lies with the process of cell-divisions, the divisions slow down as the carrying capacity is approached. In death-controlled growth, it is death rate that increases to slow down expansion. We show that division controlled growth minimizes the number of accumulated mutations, and death controlled growth corresponds to the maximum number of mutants. We check that these results hold in both deterministic and stochastic settings. We further develop a general (deterministic) theory of neutral mutations and achieve an analytical understanding of the mutant accumulation in colonies of a given size in the absence of back-mutations. The long-term dynamics of mutants in the presence of back-mutations is also addressed. In particular, with equal forward- and back-mutation rates, if division-controlled and a death-controlled types are competing for space and nutrients, cells obeying division-controlled growth will dominate the population. PMID- 22940237 TI - Restricted cooperative games on metabolic networks reveal functionally important reactions. AB - Understanding the emerging properties of complex biological systems is in the crux of systems biology studies. Computational methods for elucidating the role of each component in the synergetic interplay can be used to identify targets for genetic and metabolic engineering. In particular, we aim at determining the importance of reactions in a metabolic network with respect to a specific biological function. Therefore, we propose a novel game-theoretic framework which integrates restricted cooperative games with the outcome of flux balance analysis. We define productivity games on metabolic networks and present an analysis of their unrestricted and restricted variants based on the game theoretic solution concept of the Shapley value. Correspondingly, this concept provides a characterization of the robustness and functional centrality for each enzyme involved in a given metabolic network. Furthermore, the comparison of two different environments - feast and famine - demonstrates the dependence of the results on the imposed flux capacities. PMID- 22940238 TI - The interactions of phenanthroline compounds with DNAs: preferential binding to telomeric quadruplex over duplex. AB - Compounds that bind and stabilize selectively human telomeric quadruplex DNA structures are of significant interest due to their potential to inhibit telomerase and to halt tumor cell proliferation. In our previous study, we found that three novel phenanthroline derivatives could induce and stabilize significantly the formation of an antiparallel structure of human telomeric G quadruplex DNA (G(3)(T(2)AG(3))(3)), moreover, these compounds could bind selectively to G-quadruplex over duplex. In order to understand their binding nature, in this work we investigated the interactions of compounds 1-3 with human telomeric G-quadruplex and i-motif (C(3)(A(2)TC(3))(3)) DNAs together with calf thymus DNAs (ct DNA) by means of absorption, fluorescence and CD spectroscopies and competition dialysis assay. Results showed that all three compounds showed the highest affinity for G-quadruplex structure although with least affinity for ct DNA. Compounds 1-3 could also stabilize the structure of i-motif with an increase in melting temperature (DeltaT(m)) of 7.6, 7.2 and 10.1 degrees C, respectively, in the presence of 10 times excess of compounds. Their binding stoichiometric ratios were 2:1 and 1:1 for G-quadruplex and i-motif DNAs, respectively. The thermodynamic parameters results indicated that the binding of compound to either quadruplex or duplex DNAs was entropically driven and hydrophobic force played a major role in the reaction. PMID- 22940239 TI - Preparation of nano cellulose fibers and its application in kappa-carrageenan based film. AB - Bio-based nanocomposite films were successfully developed using nanofibrillated cellulose (NFC) as the reinforcing phase and kappa-carrageenan (KCRG) as the matrix. NFC was successfully synthesis from short stable cotton fibers by chemo mechanical process. The bionanocomposites were prepared by incorporating 0.1, 0.2, 0.3, 0.4, 0.5, and 1wt% of the NFC into a KCRG matrix using a solution casting method there characterization was done in terms of thermal properties (DSC), morphology (SEM), water vapor transmission rate (WVTR), oxygen transmission rate (OTR), X-ray diffractograms (XRD), and tensile properties. The main conclusion arising from the analysis of the result is that the bionanocomposites containing 0.4wt% of NFC exhibited the highest enhancement in tensile strength it is almost 44% improvement. WVTR and OTR results showed improvement of all nanocomposite film compare to control KCRG film. PMID- 22940240 TI - Maternal child feeding practices and eating behaviors of women with extreme obesity and those who have undergone bariatric surgery. AB - BACKGROUND: Bariatric surgery is the most effective treatment of extreme obesity. Few studies, however, have explored some of the lifestyle behaviors (i.e., grocery shopping and cooking methods) thought to contribute to postoperative weight maintenance. To date, the child feeding practices of women who have undergone bariatric surgery have not been explored. The study setting was a university in the United States. METHODS: A total of 41 women awaiting bariatric surgery were assessed preoperatively; an additional 23 women who had undergone bariatric surgery (6-24 mo previously) were also assessed. The participants had to be responsible for feeding a child (age range 2-16 yr) in their home. Self report measures assessed demographics, maternal child feeding practices, eating behaviors, and available household foods. Bivariate correlations were used to investigate the relationships among the measures. Independent sample t tests assessed group differences, and 1-way analysis of variance and concepts of linear progression and regression were used to determine whether the findings remained statistically significant after controlling for demographic variables. RESULTS: Women who had undergone surgery, compared with those awaiting surgery, reported more frequent modeling of healthy eating for their child (P = .009), significantly greater levels of cognitive restraint (P = .001), and lower levels of disinhibition (P = .019). Some between-group differences were found in grocery shopping frequency (P = .093) and in select foods available in the home (P = .101 to P = .151), which approached statistical significance. CONCLUSION: Mothers who had undergone bariatric surgery demonstrated healthy eating for their child and were engaged in healthier eating behaviors themselves compared with women awaiting surgery. Intervening with mothers who are undergoing bariatric surgery could present a unique opportunity for modifying the home food environment and promoting healthy eating among other family members, especially those children at risk of extreme obesity. PMID- 22940241 TI - Devil's Claw-a review of the ethnobotany, phytochemistry and biological activity of Harpagophytum procumbens. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Harpagophytum procumbens subps. procumbens (Burch.) DC. ex Meisn. (Pedaliaceae) is an important traditional medicine growing in the Kalahari region of southern Africa where it is consumed as a general health tonic and for treating diverse ailments including arthritis, pain, fever, ulcers and boils. AIM OF THE REVIEW: To provide a comprehensive overview of the ethnobotany, phytochemistry and biological activity of H. procumbens and possibly make recommendations for further research. MATERIALS AND METHODS: Peer-reviewed articles on H. procumbens were acquired on Scopus, ScienceDirect and SciFinder, there was no specific timeline set for the search. A focus group discussion was held with different communities in Botswana to further understand ethnobotanical uses of the plant. RESULTS: Harpogophytum procumbens is used for a wide variety of health conditions in the form of infusions, decoctions, tinctures, powders and extracts. In addition to the common local use for arthritis and pain, other ethnomedicinal uses include dyspepsia, fever, blood diseases, urinary tract infections, postpartum pain, sprains, sores, ulcers and boils. Scientific studies revealed that H. procumbens exhibits analgesic, anti-oxidant, anti-diabetic, anti epileptic, antimicrobial and antimalarial activities amongst others. Iridoid glycosides and phenylpropanoid glycosides have been the focus of phytochemical investigations as the biological activity has been ascribed to the iridoid glycosides (such as harpagoside and harpagide), which are common in nature and are known to possess anti-inflammatory activity. In addition, it has been shown that the hydrolysed products of harpagoside and harpagide have more pronounced anti-inflammatory activity when compared to the unhydrolysed compounds. Harpagophytum zeyheri is a close taxonomic ally of H. procumbens but H. procumbens is the favoured species of commerce, and contains higher levels of the pharmacologically active constituents. The two are used interchangeably and H. procumbens raw material is often intentionally adulterated with H. zeyheri and this may impact on the efficacy of inadequately controlled health products. The main exporter of this highly commercialised plant is Namibia. In 2009 alone, Harpagophytum exports were worth approximately ?1.06 million. The high demand for health products based on this plant has led to over-harvesting, raising concerns about sustainability. Although only the secondary tubers are utilised commercially, the whole plant is often destroyed during harvesting. CONCLUSIONS: Harpagophytum procumbens is used to treat a wide range of ailments. Some of the ethnobotanical claims have been confirmed through in vitro studies, however, when the constituents deemed to be the biologically active compounds were isolated the efficacy was lower than that of the whole extract. This necessitates the use of a different approach where all the metabolites are considered using a robust method such as spectroscopy; the phytochemical data can then be superimposed on the biological activity. Furthermore, there is a need to develop rapid and efficient quality control methods for both raw materials and products because the orthodox methods in current use are time-consuming and labour intensive. PMID- 22940242 TI - A survey of folk remedies for gastrointestinal tract diseases from Thailand's three southern border provinces. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Gastrointestinal tract diseases commonly occur in Thailand. However, surveying for finding out traditional drugs has never been done. AIM OF STUDY: To quantify and categorize the folk medicinal remedies that are used for healing the gastrointestinal tract by the traditional healers living in Thailand's three southern border provinces. MATERIALS AND METHODS: The Pattani, Yala and Narathiwat provinces were selected. Semi-structured interviews of nine healers were conducted to collect information that included the remedy names, herbal ingredients, plant parts used, preparation, properties and treatment methods. The data were then further analyzed. RESULT: The results revealed that 39 multi-species remedies and 36 single-species remedies were used to treat gastrointestinal disorders. A total of 103 plant species and 5 other materia medica were used as therapeutics. Most of the plants used were of the Zingiberaceae, Fabaceae and Euphorbiaceae families. Furthermore, it was found that although most of the healers used different remedies for a particular disease, some of the ingredients might have been similar. For example, Caesalpinia bonduc (L.) Roxb. was an ingredient used for parasitic disease remedies, and Senna alata (L.) Roxb. was used for constipation remedies. CONCLUSION: A review of the literature revealed 57 plant species and 2 other materia medica that have already been tested for their biological activities, whereas 46 plant species and 3 materia medica have never been tested. Consequently, research should be performed to confirm the pharmacological properties of folk remedies. PMID- 22940244 TI - Pupillary hippus in nonconvulsive status epilepticus. AB - We report the video recording of a patient who experienced pupillary hippus during an episode of nonconvulsive status epilepticus. [Published with video sequences]. PMID- 22940243 TI - Methanol extract of Osbeckia stellata suppresses lipopolysaccharide- and HCl/ethanol-induced inflammatory responses by inhibiting Src/Syk and IRAK1. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Osbeckia stellata Buch.-Ham. ex D.Don is traditionally prescribed to treat various inflammatory diseases. However, how this plant is able to modulate inflammatory responses is unknown. This study explored the anti-inflammatory effects of 99% methanol extracts of O. stellata (Os-ME). MATERIALS AND METHODS: The anti-inflammatory effect of Os-ME was evaluated by measuring the levels of nitric oxide (NO) and prostaglandin E(2) (PGE(2)) in lipopolysaccharide (LPS)-treated RAW264.7 macrophage cells and by determining gastric inflammatory lesions in mice induced by HCl/ethanol (EtOH). The molecular mechanisms of the inhibitions were elucidated by analyzing the activation of transcription factors, upstream signaling cascade, and the kinase activities of target enzymes. RESULTS: Os-ME dose-dependently diminished the release of NO and PGE(2), and suppressed the expression of inducible NO synthase and cyclooxygenase-2 in LPS-treated RAW264.7 cells. Os-ME clearly inhibited the translocation of c-Rel, a subunit of nuclear factor kappaB (NF-kappaB), and c Fos, a subunit of activator protein-1 (AP-1), and their regulatory upstream enzymes including Src, Syk, and IRAK1. Interestingly, orally administered Os-ME ameliorated acute inflammatory symptoms and suppressed the activation of Src, Syk, and IRAK1 induced by HCl/EtOH treatment in mouse stomach. CONCLUSION: Os-ME can be considered as an orally available anti-inflammatory herbal remedy with Src/Syk/NF-kappaB and IRAK1/AP-1 inhibitory properties. PMID- 22940245 TI - RPA assists HSF1 access to nucleosomal DNA by recruiting histone chaperone FACT. AB - Transcription factor access to regulatory elements is prevented by the nucleosome. Heat shock factor 1 (HSF1) is a winged helix transcription factor that plays roles in control and stressed conditions by gaining access to target elements, but mechanisms of HSF1 access are not well known in mammalian cells. Here, we show the physical interaction between the wing motif of human HSF1 and replication protein A (RPA), which is involved in DNA metabolism. Depletion of RPA1 abolishes HSF1 access to the promoter of HSP70 in unstressed condition and delays its rapid activation in response to heat shock. The HSF1-RPA complex leads to preloading of RNA polymerase II and opens the chromatin structure by recruiting a histone chaperone, FACT. Furthermore, this interaction is required for melanoma cell proliferation. These results provide a mechanism of constitutive HSF1 access to nucleosomal DNA, which is important for both basal and inducible gene expression. PMID- 22940246 TI - A high-throughput chromatin immunoprecipitation approach reveals principles of dynamic gene regulation in mammals. AB - Understanding the principles governing mammalian gene regulation has been hampered by the difficulty in measuring in vivo binding dynamics of large numbers of transcription factors (TF) to DNA. Here, we develop a high-throughput Chromatin ImmunoPrecipitation (HT-ChIP) method to systematically map protein-DNA interactions. HT-ChIP was applied to define the dynamics of DNA binding by 25 TFs and 4 chromatin marks at 4 time-points following pathogen stimulus of dendritic cells. Analyzing over 180,000 TF-DNA interactions we find that TFs vary substantially in their temporal binding landscapes. This data suggests a model for transcription regulation whereby TF networks are hierarchically organized into cell differentiation factors, factors that bind targets prior to stimulus to prime them for induction, and factors that regulate specific gene programs. Overlaying HT-ChIP data on gene-expression dynamics shows that many TF-DNA interactions are established prior to the stimuli, predominantly at immediate early genes, and identified specific TF ensembles that coordinately regulate gene induction. PMID- 22940247 TI - NERD, a plant-specific GW protein, defines an additional RNAi-dependent chromatin based pathway in Arabidopsis. AB - In Arabidopsis, transcriptional gene silencing (TGS) can be triggered by 24 nt small-interfering RNAs (siRNAs) through the RNA-directed DNA methylation (RdDM) pathway. By functional analysis of NERD, a GW repeat- and PHD finger-containing protein, we demonstrate that Arabidopsis harbors a second siRNA-dependent DNA methylation pathway targeting a subset of nonconserved genomic loci. The activity of the NERD-dependent pathway differs from RdDM by the fact that it relies both on silencing-related factors previously implicated only in posttranscriptional gene silencing (PTGS), including RNA-DEPENDENT RNA POLYMERASE1/6 and ARGONAUTE2, and most likely on 21 nt siRNAs. A central role for NERD in integrating RNA silencing and chromatin signals in transcriptional silencing is supported by data showing that it binds both to histone H3 and AGO2 proteins and contributes to siRNA accumulation at a NERD-targeted locus. Our results unravel the existence of a conserved chromatin-based RNA silencing pathway encompassing both PTGS and TGS components in plants. PMID- 22940248 TI - Processive steps in the reverse direction require uncoupling of the lead head lever arm of myosin VI. AB - Myosin VI is the only known reverse-direction myosin motor. It has an unprecedented means of amplifying movements within the motor involving rearrangements of the converter subdomain at the C terminus of the motor and an unusual lever arm projecting from the converter. While the average step size of a myosin VI dimer is 30-36 nm, the step size is highly variable, presenting a challenge to the lever arm mechanism by which all myosins are thought to move. Herein, we present structures of myosin VI that reveal regions of compliance that allow an uncoupling of the lead head when movement is modeled on actin. The location of the compliance restricts the possible actin binding sites and predicts the observed stepping behavior. The model reveals that myosin VI, unlike plus-end directed myosins, does not use a pure lever arm mechanism, but instead steps with a mechanism analogous to the kinesin neck-linker uncoupling model. PMID- 22940249 TI - Ago hook and RNA helicase motifs underpin dual roles for SDE3 in antiviral defense and silencing of nonconserved intergenic regions. AB - In Arabidopsis thaliana, the putative RNA-helicase SDE3 assists posttranscriptional-gene-silencing (PTGS) amplification by RNA-dependent-RNA polymerase-6 (RDR6). SDE3 homologs in Drosophila, worm and human contribute to silence viruses, transposons or recently duplicated genes but the underlying mechanisms remain largely unknown. Here, we demonstrate that SDE3 is present with the PTGS effectors AGO1 and AGO2 in higher-order protein complexes owing to a specialized GW-repeat-containing C-terminal domain. We uncover an essential contribution of the RNA-helicase activity and a facilitating role for AGO binding in SDE3 action, which occurs downstream of RDR6. We show that these biochemical properties underpin dual roles for SDE3 in antiviral defense and, unexpectedly, in transposon silencing via a hitherto unanticipated pathway that correlates with DNA methylation, suggesting a continuum of action between PTGS and chromatin level silencing. We identified endogenous SDE3 targets corresponding to nonconserved intergenic regions, transposons and recently evolved pseudogenes, unraveling striking functional convergences among plant and metazoan SDE3 pathways. PMID- 22940251 TI - Novel semi-interpenetrating hydrogel networks with enhanced mechanical properties and thermoresponsive engineered drug delivery, designed as bioactive endotracheal tube biomaterials. AB - Thermoresponsive polymeric platforms are used to optimise drug delivery in pharmaceutical systems and bioactive medical devices. However, the practical application of these systems is compromised by their poor mechanical properties. This study describes the design of thermoresponsive semi-interpenetrating polymer networks (s-IPNs) based on cross-linked p(NIPAA) or p(NIPAA-co-HEMA) hydrogels containing poly(epsilon-caprolactone) designed to address this issue. Using DSC, the lower critical solution temperature of the co-polymer and p(NIPAA) matrices were circa 34 degrees C and 32 degrees C, respectively. PCL was physically dispersed within the hydrogel matrices as confirmed using confocal scanning laser microscopy and DSC and resulted in marked changes in the mechanical properties (ultimate tensile strength, Young's modulus) without adversely compromising the elongation properties. P(NIPAA) networks containing dispersed PCL exhibited thermoresponsive swelling properties following immersion in buffer (pH 7), with the equilibrium-swelling ratio being greater at 20 degrees C than 37 degrees C and greatest for p(NIPAA)/PCL systems at 20 degrees C. The incorporation of PCL significantly lowered the equilibrium swelling ratio of the various networks but this was not deemed practically significant for s-IPNs based on p(NIPAA). Thermoresponsive release of metronidazole was observed from s-IPN composed of p(NIPAA)/PCL at 37 degrees C but not from p(NIPAA-co-HEMA)/PCL at this temperature. In all other platforms, drug release at 20 degrees C was significantly similar to that at 37 degrees C and was diffusion controlled. This study has uniquely described a strategy by which thermoresponsive drug release may be performed from polymeric platforms with highly elastic properties. It is proposed that these materials may be used clinically as bioactive endotracheal tubes, designed to offer enhanced resistance to ventilator associated pneumonia, a clinical condition associated with the use of endotracheal tubes where stimulus responsive drug release from biomaterials of significant mechanical properties would be advantageous. PMID- 22940250 TI - The APC/C subunit Mnd2/Apc15 promotes Cdc20 autoubiquitination and spindle assembly checkpoint inactivation. AB - The fidelity of chromosome segregation depends on the spindle assembly checkpoint (SAC). In the presence of unattached kinetochores, anaphase is delayed when three SAC components (Mad2, Mad3/BubR1, and Bub3) inhibit Cdc20, the activating subunit of the anaphase-promoting complex (APC/C). We analyzed the role of Cdc20 autoubiquitination in the SAC of budding yeast. Reconstitution with purified components revealed that a Mad3-Bub3 complex synergizes with Mad2 to lock Cdc20 on the APC/C and stimulate Cdc20 autoubiquitination, while inhibiting ubiquitination of substrates. SAC-dependent Cdc20 autoubiquitination required the Mnd2/Apc15 subunit of the APC/C. General inhibition of Cdc20 ubiquitination in vivo resulted in high Cdc20 levels and a failure to establish a SAC arrest, suggesting that SAC establishment depends on low Cdc20 levels. Specific inhibition of SAC-dependent ubiquitination, by deletion of Mnd2, allowed establishment of a SAC arrest but delayed release from the arrest, suggesting that Cdc20 ubiquitination is also required for SAC inactivation. PMID- 22940253 TI - Perspective from the founding editors. Preface. PMID- 22940252 TI - Ethnic differences in polyomavirus simian virus 40 seroprevalence among women in Houston, Texas. AB - OBJECTIVE: To examine the prevalence and distribution among racial/ethnic groups of polyomavirus SV40 antibodies in women in Houston, Texas. METHODS: Women in three different cohorts reflecting the evolving demographics of Houston were evaluated for frequency of SV40 antibodies using a plaque-reduction neutralization assay. RESULTS: Women in cohort A (enrolled 1972-1973) were 68% (145/212) African-American and 32% Caucasian; the overall frequency of SV40 neutralizing antibodies was 7%. Women in cohort B (enrolled 1975-1977) were Caucasian with an overall frequency of SV40 neutralizing antibodies of 18% (37/211). Women in cohort C (enrolled 1993-1995) were 50% (199/400) African American, 25% Caucasian, and 25% Hispanic; the overall frequency of SV40 neutralizing antibodies was 10%. Logistic regression analysis for cohort A showed no difference in SV40 neutralizing antibodies with respect to race/ethnicity, pregnancy status, number of previous pregnancies, or history of sexually transmitted diseases. For cohort C, race/ethnicity was identified as a significant factor associated with SV40 neutralizing antibodies, with Hispanics having a seroprevalence of 23% compared to 5-6% in the other two groups (p = 0.01). CONCLUSIONS: A significantly higher SV40 seroprevalence was found among Hispanics than other racial/ethnic groups in the city of Houston. Findings are compatible with a model that certain population groups potentially exposed to SV40-contaminated oral poliovaccines have maintained cycles of SV40 infections. PMID- 22940254 TI - A prospective study on the safety of herbal medicines, used alone or with conventional medicines. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Along with increase of herbal medicine use worldwide, the safety of traditional herbal medicines frequently becomes a medical issue. AIM OF THE STUDY: This study aimed to investigate the incidence of herbal medicine-induced adverse effects on liver functions. SUBJECTS AND METHODS: A prospective study was performed with 313 inpatients (87 male and 226 female) receiving herbal prescriptions during hospitalization. The patients were classified into two groups based on their treatments: one group received herbal medicines only (57 patients), and another received herbal and conventional medicines concurrently (256 patients). All patients were given liver and renal function tests at the start of hospitalization (baseline) and at approximately 2 week intervals thereafter, until discharge. RESULTS: Six of the 313 patients showed abnormal liver function without related clinical symptoms (1.9%, 95% CI 0.38-3.41); none of the patients in the herbal group had abnormal result in liver function tests (0% of 57 patients) while all six had received a combination of herbal and conventional medicines (2.3% of 256 patients, 95% CI 0.46-4.14). CONCLUSION: Our findings indicate that herbal drugs used alone are relatively safe, but the risk for adverse reactions may increase when herbal and conventional drugs are taken concurrently. PMID- 22940255 TI - IgA production in the large intestine is modulated by a different mechanism than in the small intestine: Bacteroides acidifaciens promotes IgA production in the large intestine by inducing germinal center formation and increasing the number of IgA+ B cells. AB - It has been demonstrated that intestinal commensal bacteria induce immunoglobulin (Ig) A production by promoting the development of gut-associated lymphoid tissues in the small intestine. However, the precise mechanism whereby these bacteria modulate IgA production in the large intestine, which harbors the majority of intestinal commensals, is poorly understood. In addition, it is not known which commensal bacteria induce IgA production in the small intestine and which induce production in the large intestine. To address these issues, we generated gnotobiotic mice mono-associated with different murine commensal bacteria by inoculating germ-free (GF) mice with Lactobacillus johnsonii or Bacteroides acidifaciens. In GF mice, IgA production was barely detectable in the small intestine and was not detected in the large intestine. Interestingly, total IgA secretion in the large intestinal mucosa of B. acidifaciens mono-associated (BA) mice was significantly greater than that of GF and L. johnsonii mono-associated (LJ) mice. However, there was no difference in total IgA production in the small intestine of GF, LJ and BA mice. In addition, in the large intestine of BA mice, the expression of IgA(+) cells and germinal center formation were more remarkable than in GF and LJ mice. Furthermore, B. acidifaciens-specific IgA was detected in the large intestine of BA mice. These results suggest that the production of IgA in the large intestine may be modulated by a different mechanism than that in the small intestine, and that B. acidifaciens is one of the predominant bacteria responsible for promoting IgA production in the large intestine. PMID- 22940256 TI - Altered redox state and apoptosis in the pathogenesis of systemic lupus erythematosus. AB - An altered redox status and increased lymphocyte apoptosis have been implicated in the development of systemic lupus erythematosus (SLE). In this study, we evaluated the relationship between glutathione (GSH) depletion, reactive oxygen species (ROS) and, the progression of apoptosis and their association with SLE severity. Significant low levels of intracellular glutathione, total thiol and altered redox state (GSH/GSSG) were found in SLE patients, in which lymphocyte apoptosis and activated caspase-3 expression in the lymphocytes were remarkably increased. The severity of disease was positively allied with the increased levels of lymphocyte apoptosis and caspase-3, but negatively with the decreased levels of total thiol, depleted intracellular glutathione and altered redox state (GSH/GSSG). The lymphocyte apoptosis and activated caspase-3 expression were negatively associated with intracellular levels of GSH and redox state and positively associated with the elevated levels of multiple oxidative stress markers; ROS and lipid peroxidation measured as malondialdehyde (MDA). These results suggest that GSH depletion and elevated oxidative stress trigger apoptosis and may be coupled with the severity of the disease. PMID- 22940257 TI - The classification of MDS: from FAB to WHO and beyond. AB - The purpose of any classification of hematologic neoplasms is to provide reliable criteria for their diagnosis and their classification into clinically relevant disease entities. In 1982, the French - American - British (FAB) group introduced such a classification for the myelodysplastic syndromes (MDS), a heterogenous group of diseases that prior to the FAB scheme was often referred to only as "preleukemia." Over the ensuing two decades, the FAB classification facilitated hundreds of morphologic, clinical, and genetic studies that helped to clarify the disease process and its management. The World Health Organization (WHO) classification of MDS is a consensus classification first introduced in 2001 and revised in 2008. It maintains much of the structure and philosophy of the FAB classification, but draws upon more recently acquired biologic and clinical information to refine the diagnostic criteria and improve its prognostic value. This paper outlines the evolution from the FAB to the WHO classification of MDS and gives a glimpse of what might lie beyond. PMID- 22940258 TI - Infectious diseases and risk of leukemia and non-Hodgkin's lymphoma: a case control study. AB - The aim of this investigation was to evaluate the association between common infectious diseases and the risk of hematological malignancies in an adult population. Data were drawn from a population based case-control study that included 165 cases (125 lymphoid and 40 myeloid neoplasms) and 233 controls. Occurrence of childhood diseases (measles, rubella, chickenpox, mumps, pertussis and scarlet fever) was slightly inversely associated with the risk of both malignancies, but statistical significance was not reached. The data of infections occurring after 14 years of age indicated an increasing risk of lymphoid malignancies (OR=2.9, p<0.05). PMID- 22940259 TI - Outcomes of adult patients with relapsed acute lymphoblastic leukemia following frontline treatment with a pediatric regimen. AB - We analyzed the outcome of 46 patients with acute lymphoblastic leukemia (ALL) who relapsed following treatment with a pediatric-based protocol; 34 received intensive re-induction chemotherapy, with a CR2 rate of 62%, median overall survival (OS) 7.8 months, median relapse-free survival 5.2 months and one year OS 19%. Allogeneic HSCT was performed in 8 patients in CR2/3, with a median OS 2.2 months. OS was superior in patients who relapsed after completion of chemotherapy, compared to those relapsing on treatment. The outcome of adult ALL relapsing after treatment was therefore poor, and novel salvage strategies are needed to improve outcomes. PMID- 22940260 TI - Climate warming may increase aphids' dropping probabilities in response to high temperatures. AB - Dropping off is considered an anti-predator behavior for aphids since previous studies have shown that it reduces the risk of predation. However, little attention is paid to dropping behavior triggered by other external stresses such as daytime high temperatures which are predicted to become more frequent in the context of climate warming. Here we defined a new parameter, drop-off temperature (DOT), to describe the critical temperature at which an aphid drops off its host plant when the ambient temperature increases gradually and slowly. Detailed studies were conducted to reveal effects of short-term acclimation (temperature, exposure time at high-temperature and starvation) on DOT of an aphid species, Sitobion avenae. Our objectives were to test if the aphids dropped off host plant to avoid high temperatures and how short-term acclimation affected the aphids' dropping behavior in response to heat stress. We suggest that dropping is a behavioral thermoregulation to avoid heat stress, since aphids started to move before they dropped off and the dropped aphids were still able to control their muscles prior to knockdown. The adults starved for 12 h had higher DOT values than those that were unstarved or starved for 6 h, and there was a trade-off between behavioral thermoregulation and energy acquisition. Higher temperatures and longer exposure times at high temperatures significantly lowered the aphids' DOT, suggested that the aphids avoid heat stress by dropping when exposed to high temperatures. Climate warming may therefore increase the aphids' dropping probabilities and consequently affect the aphids' individual development and population growth. PMID- 22940261 TI - Improvement of ginsenoside Rg1 on hematopoietic function in cyclophosphamide induced myelosuppression mice. AB - This study was aimed to investigate the effects of ginsenoside Rg1 (Rg1) on hematopoietic function of bone marrow in cyclophosphamide-induced bone marrow depression mice. Mice were given cyclophosphamide (150mg/kg, i.p. for three days) to produce bone marrow depression. Rg1 was then administrated at 7.5 and 15mg/kg by i.p. for seven days. Bone marrow cells number was counted, and the percentage of hematopoietic stem cells (Lin(-)Sca-1(+)c-kit(+)) was quantified by flow cytometry. The histology of femoral bone was examined by H&E staining. The expression of calcium-sensing receptor mRNA was determined by the real time RT PCR. Rg1 (7.5 and 15mg/kg) protected against cyclophosphamide-induced bone marrow depression, as evidenced by increased bone marrow cell numbers and improved femoral bone morphology. The percentage of Lin(-)Sca-1(+)c-kit(+) cells and lymphoid lineage CD3(+) cells were lower in cyclophosphamide group, but returned towards normal after Rg1 treatment in both bone marrow and peripheral blood cells. Expression of calcium-sensing receptor mRNA was increased in bone marrow cells on the 10th day after cyclophosphamide, but it was returned to normal level after Rg1 treatment. Rg1 alone did not produce these changes in normal mice. These results demonstrated that Rg1 improved hematopoietic function of bone marrow in cyclophosphamide-induced myelosuppression. PMID- 22940262 TI - Therapeutic role of telmisartan against acetaminophen hepatotoxicity in mice. AB - The therapeutic potential of telmisartan was investigated in mice exposed to acute hepatotoxicity induced by a single dose of acetaminophen (500 mg/kg, p.o.). Telmisartan treatment (two i.p. injections, 10mg/kg, each) was given at 1 and 12h following acetaminophen administration. Telmisartan significantly reduced the level of serum alanine aminotransferase, and suppressed lipid peroxidation, prevented the depletion of the antioxidant defenses (reduced glutathione level, and catalase and superoxide dismutase activities), and attenuated the elevation of nitric oxide resulted from acetaminophen administration. Also, telmisartan ameliorated the histopathological liver tissue damage induced by acetaminophen. Immunohistochemical analysis revealed that telmisartan significantly decreased the expression of inducible nitric oxide synthase, tumor necrosis factor-alpha, cyclooxygenase-2, nuclear factor-kappaB and caspase-3 in liver tissue of mice received acetaminophen overdose. In conclusion, telmisartan can be considered as a potential therapeutic option to protect against acute acetaminophen hepatotoxicity commonly encountered in clinical practice. PMID- 22940263 TI - Twelve-month bracket failure rate with amorphous calcium phosphate bonding system. AB - The aim of the study was to compare the survival rate of orthodontic brackets over a 12-month period using amorphous calcium phosphate (ACP) bonding system with a conventional adhesive (CA). In 30 patients with a mean age of 15 years 7 months, one operator bonded 138 brackets with a split-mouth design, using a resin based CA and ACP-containing adhesive. The survival rate of the brackets was estimated by Kaplan-Meier analysis. Bracket survival distributions with respect to bonding procedure, dental arch, type of tooth (incisor, canine, and premolar), and patients' gender were compared using the log-rank test. The bond failure interface was determined using the Adhesive Remnant Index (ARI). The bond failure rates of the CA and ACP-containing adhesive were 2.67 and 3.8 per cent, respectively. There was no significant difference between the failure rates of ACP and CA-bonded systems (P > 0.05). Survival rates did not show significant differences between the upper and lower dental arches (P > 0.05). Lower survival rates were found for canine and premolar teeth than incisors (P < 0.05). Bond failure rates were higher for males than females (P < 0.05). There was a significant difference for ARI scores between the adhesive materials (P = 0.028); more of the ACP-based adhesive was left on the tooth at debond. ACP-containing adhesive can be effectively used to bond orthodontic brackets and can serve as a practicable alternative to the conventional bonding adhesives. PMID- 22940264 TI - Retained epidural catheter tip. PMID- 22940265 TI - Placental abruption occurring soon after labor combined spinal-epidural analgesia. AB - We present a case of placental abruption necessitating emergency cesarean section in an otherwise uncomplicated patient soon after initiation of combined spinal epidural analgesia in labor. Administration of spinal opioids has the potential to cause fetal bradycardia due to uterine hypertonicity following rapid onset of analgesia. In this case, a previously bloody show before placement of combined spinal-epidural analgesia may have been evidence of a small abruption. We hypothesize that uterine hypertonicity following administration of spinal opioids may have hastened the development of an existing placental abruption. PMID- 22940266 TI - Blinatumomab: a historical perspective. AB - For decades, chemotherapy has been the backbone for the treatment of patients with B cell malignancies. Depending on the individual disease, monoclonal antibodies, irradiation and/or hematopoietic stem cell transplantation are added. However, the current standard of care--particularly for patients with relapsed disease--is often not sufficient to achieve durable remissions. A highly promising new drug candidate in late-stage clinical development for treatment of B cell malignancies is blinatumomab (MT103 or AMG 103). This bispecific antibody construct has dual specificity for CD19 and CD3 and belongs to the class of bispecific T cell engager (BiTE(r)) antibodies, which can potentially engage all cytotoxic T cells of a patient for redirected lysis of tumor cells. Here, we review how blinatumomab has so far been pre-clinically and clinically developed for the treatment of patients with non-Hodgkin's lymphoma and acute lymphoblastic leukemia. PMID- 22940267 TI - Validated method for the determination of misoprostol acid in whole blood by ultra performance liquid chromatography-tandem mass spectrometry. AB - Misoprostol is a pharmaceutical synthetic compound, analog of prostaglandin E1, frequently used as an abortifacient in not medically supervised or self-induced abortions, particularly in countries with restrictive abortion laws representing a serious public health problem. The aim of this study was to develop and validate a sensitive analytical method for the determination of misoprostol acid in whole blood samples. The samples were prepared by SPE and the chromatographic separation was performed by UPLC-MS/MS using ESI- and MRM mode with an Acquity UPLC((r)) BEH C18 (50mm*2.1mm i.d., 1.7MUm) column using a methanol-ammonium 0.1% solution gradient in a total run time of 7.0min. The method showed to be selective and linear in range 25-2000ng/L. The LOD and LOQ were 10ng/L and 25ng/L, respectively. The recovery ranged from 89 to 97%. No carryover and significant matrix effect were observed. The intra- and inter-assay precisions and the inter-assay accuracy results were 4.0% and 5.4%, 5.5% and 4.1%, and -1.4% and -2.8%, for the concentrations 50 and 500ng/L, respectively. The method developed allows the analysis of misoprostol acid in whole blood samples with adequate sensitivity to the concentration range obtained from therapeutic doses. The method was successfully used in a controlled misoprostol administration study and has been applied in our laboratory in the forensic toxicology field. PMID- 22940269 TI - B vitamins relieve neuropathic pain behaviors induced by infraorbital nerve constriction in rats. AB - AIMS: There is mounting evidence that use of B vitamins can help control neuropathic pain. This study investigated if treatment with B1, B6 and B12 vitamins, alone or in combination with carbamazepine, can ameliorate distinct nociceptive behaviors in a model of trigeminal neuropathic pain. MAIN METHODS: Male Wistar rats were submitted to infraorbital nerve constriction or sham surgery and received a 5-day treatment with one of the B vitamins, a single carbamazepine injection or the association of both treatments and were tested for facial thermal and mechanical hyperalgesia at different time intervals. KEY FINDINGS: Repeated treatment with B1 (thiamine), B6 (pyridoxine) and B12 (cyanocobalamin) vitamins (at 180, 180 and 18 mg/kg/day, respectively, for 5 days) prevented the development of heat hyperalgesia after infraorbital nerve injury, but only B12 and B6 treatments attenuated cold and mechanical hyperalgesia, respectively. A single injection of carbamazepine (30 mg/kg) significantly reduced thermal, but not mechanical, hyperalgesia after nerve injury. Combinations of lower doses of each B vitamin (B1 and B6 at 18 mg/kg/day and B12 at 1.8 mg/kg/day for 5 days) with carbamazepine (10mg/kg) markedly reduced heat hyperalgesia after infraorbital nerve injury. Treatment with B12 (1.8 mg/kg/day) combined with carbamazepine (10mg/kg) also synergized to attenuate cold hyperalgesia at some time points, but combination of B6 (18 mg/kg/day) with carbamazepine (30 mg/kg) failed to modify mechanical hyperalgesia. SIGNIFICANCE: We suggest that B vitamins might constitute a relevant adjuvant to control some aspects of the pain afflicting patients suffering from trigeminal neuropathic pain. PMID- 22940270 TI - Stability of trimeric DENV envelope protein at low and neutral pH: an insight from MD study. AB - Change in pH plays a crucial role in the stability and function of the dengue envelope (DENV) protein during conformational transition from dimeric (pre-fusion state) to trimeric form (post-fusion state). In the present study we have performed various molecular dynamics (MD) simulations of the trimeric DENV protein at different pH and ionic concentrations. We have used total binding energy to justify the stability of the complex using the MMPBSA method. We found a remarkable increase in the stability of the complex at neutral pH (pH~7) due to the increment of sodium ions. However, at very low pH (pH~4), the total energy of the complex becomes high enough to destabilize the complex. At a specific pH, almost at a range of 6, the stability of the complex is significantly better than the stability of the trimer at neutral pH, which connotes that the trimer is most stable at this pH (pH~6). PMID- 22940268 TI - Brain regional differences in CB1 receptor adaptation and regulation of transcription. AB - Cannabinoid CB1 receptors (CB1Rs) are expressed throughout the brain and mediate the central effects of cannabinoids, including Delta(9)-tetrahydrocannabinol (THC), the main psychoactive constituent of marijuana. Repeated THC administration produces tolerance to cannabinoid-mediated effects, although the magnitude of tolerance varies by effect. Consistent with this observation, CB1R desensitization and downregulation, as well as induction of immediate early genes (IEGs), vary by brain region. Zif268 and c-Fos are induced in the forebrain after acute THC administration. Phosphorylation of the cAMP response-element binding protein (CREB) is increased in a region-specific manner after THC administration. Results differ between acute versus repeated THC injection, and suggest that tolerance to IEG activation might develop in some regions. Repeated THC treatment produces CB1R desensitization and downregulation in the brain, although less adaption occurs in the striatum as compared to regions such as the hippocampus. Repeated THC treatment also induces expression of DeltaFosB, a very stable isoform of FosB, in the striatum. Transgenic expression of ?FosB in the striatum enhances the rewarding effects of several drugs, but its role in THC-mediated effects is not known. The inverse regional relationship between CB1R desensitization and ?FosB induction suggests that these adaptations might inhibit each other, although this possibility has not been investigated. The differential regional expression of individual IEGs by acute or repeated THC administration suggests that regulation of target genes and effects on CB1R signaling will contribute to the behavioral effects of THC. PMID- 22940271 TI - [Transrectal biopsy scheme can predict incorrect histological grading in prostate cancer]. AB - OBJECTIVE: To identify factors that might explain why a prostate with a Gleason score (GS) <7 in the biopsy specimen can turn out to have a GS >=7 in the surgical specimen. MATERIAL AND METHODS: We compared the GS of biopsy specimens with the GS of surgical specimens in 185 patients who underwent surgery for prostate cancer. We calculated the sensitivity, specificity, and predictive values for the GS of the biopsy specimens. We used Cohen's kappa to determine the degree of concordance between a GS of <7 and >=7 for the biopsy specimen and the surgical specimen. Age, a family history of prostate cancer, total prostate specific antigen (tPSA), digital rectal examination, prostate structure and volume, and the number of biopsy cores (biopsy scheme) were analyzed using multivariable logistic regression. RESULTS: Histological study of biopsy specimens yielded high sensitivity (98%) but low specificity (49%) for GS <=6 and low sensitivity (35, 26%) and high specificity (93, 99%) for GS=7 and GS >=7, respectively. Cohen's kappa for the GS from the biopsy and surgical specimens was 0.43 (95% CI=30-56%). The biopsy scheme was the only predictor of discordance in the GS between the two techniques. Among the other variables included in the model, only tPSA showed a slightly significant association. Taking a scheme with less than 7 cores as a reference, we found no difference with 8 to 9 cores but we did find a difference with 10 to 11 cores and with 12 or more cores, with a prevalence ratio of 0.138 (95% CI=0.030-0.513) and 0.277 (95% CI=0.091-0.806), respectively. CONCLUSION: The GS of the biopsy depends on the scheme. This factor must be taken into account when choosing a treatment option in patients with low tumor grade in biopsy specimens. PMID- 22940272 TI - Hexabromocyclododecane in terrestrial passerine birds from e-waste, urban and rural locations in the Pearl River Delta, South China: levels, biomagnification, diastereoisomer- and enantiomer-specific accumulation. AB - Diastereoisomers and enantiomers of hexabromocyclododecane (HBCD) were determined in muscle and stomach contents of three terrestrial passerine birds from e-waste, urban and rural locations in South China. The highest HBCD concentration was found at the urban site, followed by the e-waste site, suggesting that HBCD was linked to urbanization and industrialization, as well as e-waste recycling activities. Trophic magnification for alpha-HBCD was observed in the terrestrial food chain. Diastereisomeric pattern in birds showed the predominance of alpha isomer, with a minor contribution of gamma-isomer. The enantiomeric analysis revealed a preferential enrichment of (-)-alpha-HBCD and (+)-gamma-HBCD. The similarity in enantiomeric fractions of HBCD isomers between muscle and stomach contents of birds suggested that dietary uptake may be responsible for the observed nonracemic distribution of HBCD isomers in the studied birds although in vivo enantioselective biotic processes cannot be ruled out. PMID- 22940273 TI - Warm season chloride concentrations in stream habitats of freshwater mussel species at risk. AB - Warm season (May-October) chloride concentrations were assessed in stream habitats of freshwater mussel species at risk in southern Ontario, Canada. Significant increases in concentrations were observed at 96% of 24 long-term (1975-2009) monitoring sites. Concentrations were described as a function of road density indicating an anthropogenic source of chloride. Linear regression showed that 36% of the variation of concentrations was explained by road salt use by the provincial transportation ministry. Results suggest that long-term road salt use and retention is contributing to a gradual increase in baseline chloride concentrations in at risk mussel habitats. Exposure of sensitive mussel larvae (glochidia) to increasing chloride concentrations may affect recruitment to at risk mussel populations. PMID- 22940274 TI - Methylmercury in water, sediment, and invertebrates in created wetlands of Rouge Park, Toronto, Canada. AB - Thousands of hectares of wetlands are created annually because wetlands provide beneficial ecosystem services. Wetlands are also key sites for production of the bioaccumulative neurotoxin methylmercury (MeHg), but little is known about MeHg production in created systems. Here, we studied methylmercury in sediment, water, and invertebrates in created wetlands of various ages. Sediment MeHg reached 8 ng g(-1) in the newest wetland, which was significantly greater than in natural, control wetlands. This trend was mirrored in several invertebrate taxa, whose concentrations reached as high as 1.6 MUg g(-1) in the newest wetland, above levels thought to affect reproduction in birds. The MeHg concentrations in created wetland invertebrate taxa generally decreased with increasing wetland age, possibly due to a combination of deeper anoxia and less organic matter accumulation in younger wetlands. A short-term management intervention and/or improved engineering design may be necessary to reduce the mercury-associated risk in newly created wetlands. PMID- 22940275 TI - Integrated assessment on groundwater nitrate by unsaturated zone probing and aquifer sampling with environmental tracers. AB - By employing chemical and isotopic tracers ((15)N and (18)O in NO(3)(-)), we investigated the main processes controlling nitrate distribution in the unsaturated zone and aquifer. Soil water was extracted from two soil cores drilled in a typical agricultural cropping area of the North China Plain (NCP), where groundwater was also sampled. The results indicate that evaporation and denitrification are the two major causes of the distribution of nitrate in soil water extracts in the unsaturated zone. Evaporation from unsaturated zone is evidenced by a positive correlation between chloride and nitrate, and denitrification by a strong linear relationship between [Formula: see text] and ln(NO(3)(-)/Cl). The latter is estimated to account for up to 50% of the nitrate loss from soil drainage. In the saturated zone, nitrate is reduced at varying extents (100 mg/L and 10 mg/L at two sites, respectively), largely by dilution of the aquifer water. PMID- 22940276 TI - Impaired health-related quality of life in elderly women is associated with multimorbidity: results from the Korean National Health and Nutrition Examination Survey. AB - BACKGROUND: Multimorbidity is a common problem in elderly populations and is significantly associated with functional decline, disability, and mortality. However, the sex-specific characteristics of multimorbidity and its effect on patients' quality of life (QOL) have not been clearly established. METHODS: We analyzed the Korean National Health and Nutrition Examination Survey database. EuroQol 5D (a standardized health outcomes measurement instrument that includes 2 dimensions, the EuroQol 5 Dimension [EQ-5D] index score and the EuroQol visual analogue scale [EQ-VAS]) was used to evaluate QOL. Multimorbidity was evaluated using data on blood pressure measurements, blood chemistry examinations, and anthropometric assessments, as well as a survey that assessed health status. RESULTS: A total of 1419 patients aged >=65 years were included in the analysis (age = 72.40 [0.19] years; 39.3% men). Multimorbidity was significantly associated with being a woman; however, it was not associated with age. The EQ-5D index score and EQ-VAS score were significantly lower in patients with multimorbidity, especially among the elderly women. The inverse association between QOL and the number of chronic diseases was maintained without a floor effect. Hypertension was the most common disease; however, QOL was significantly associated with musculoskeletal disease, stroke, and depression, all of which were more common in female patients. There was no significant difference in QOL between men and women with similar levels of comorbidity. CONCLUSION: Both the amount and pattern of chronic diseases have been associated with QOL in elderly populations. Elderly women have low levels of QOL due to multimorbidity and a higher prevalence of chronic disease, which is related to impaired QOL. PMID- 22940278 TI - Neutrophil CD64 expression as a biomarker in the early diagnosis of bacterial infection: a meta-analysis. AB - BACKGROUND: Neutrophil CD64 expression is widely reported as an efficacious biomarker to differentiate infected patients from other non-infected patients. This meta-analysis was conducted to comprehensively and quantitatively summarize the accuracy of neutrophil CD64 in the early diagnosis of bacterial infection. METHODS: A systematic review of related studies was conducted, and the sensitivity, specificity, and other data about the accuracy of CD64 expression on neutrophils were pooled using random effects models with 95% confidence intervals (CI) as the effect measurements. Summary receiver operating characteristic (SROC) curves and the Q* value were also calculated in the meta-analysis. Heterogeneity was tested, as well as the publication bias. Potential sources of heterogeneity were explored by assessing whether or not certain covariates significantly influenced the summary diagnostic odds ratio (SDOR). RESULTS: A total of 26 studies including 3944 patients met the inclusion criteria for the final analysis. The summary estimate was 0.76 (95% CI 0.74-0.78) for sensitivity and 0.85 (95% CI 0.83-0.86) for specificity. The positive likelihood ratio (PLR), negative likelihood ratio (NLR), SDOR, and area under the SROC of neutrophil CD64 expression with Q* value were 6.67 (95% CI 4.67-9.53), 0.24 (95% CI 0.18-0.31), 34.29 (95% CI 19.59-60.01), and 0.92 (Q*=0.85), respectively. The pooled data from the included studies had high heterogeneity and the Egger test suggested a publication bias. CONCLUSIONS: On the basis of our meta-analysis, neutrophil CD64 expression could be a promising and meaningful biomarker for diagnosing bacterial infection. Nevertheless, more large prospective studies should be carried out before the neutrophil CD64 test is used widely in the clinical setting because of the various cut-off values. PMID- 22940277 TI - The Chlamydia trachomatis CT149 protein exhibits esterase activity in vitro and catalyzes cholesteryl ester hydrolysis when expressed in HeLa cells. AB - Chlamydia, like other intracellular bacteria, are auxotrophic for a variety of essential metabolites and obtain cholesterol and fatty acids from their eukaryotic host cell, however not many Chlamydia-specific enzymes have been identified that are involved in lipid metabolism. In silico analysis of one candidate Chlamydia trachomatis enzyme, annotated as a conserved putative hydrolase (CT149), identified two lipase/esterase GXSXG motifs, and a potential cholesterol recognition/interaction amino acid consensus (CRAC) sequence. His-tag purified recombinant CT149 exhibited ester hydrolysis activity in a nitrophenyl acetate-based cell-free assay system. When cholesteryl linoleate was used as substrate, ester hydrolysis occurred and production of cholesterol was detected by high performance liquid chromatography. Exogenous expression of transfected CT149 in HeLa cells resulted in a significant decrease of cytoplasmic cholesteryl esters within 48 h. These results demonstrate that CT149 has cholesterol esterase activity and is likely to contribute to the hydrolysis of eukaryotic cholesteryl esters during intracellular chlamydial growth. PMID- 22940279 TI - Drug treatment of multidrug-resistant osteoarticular tuberculosis: a systematic literature review. AB - OBJECTIVE: To review the literature in order to determine the best treatment options for multidrug-resistant tuberculosis (MDR-TB) of the skeletal system. METHODS: We searched the PubMed database for all case reports of osteoarticular MDR-TB that provided information on drug treatment and clinical outcome. RESULTS: We identified six cases with spinal MDR-TB and seven with extraspinal MDR-TB and reviewed their susceptibility tests, treatments administered, surgical treatments, and clinical outcomes. All patients had a successful clinical outcome (either cured or improved) except one who died due to septicemia. One patient with spinal MDR-TB and four patients with extraspinal MDR-TB had a successful outcome with medical treatment alone. Two patients who received treatment for a shorter time or with fewer drugs than recommended were cured with the addition of surgery. CONCLUSIONS: Osteoarticular MDR-TB is very infrequently reported in the literature. The few cases reviewed suggest that it is possible to achieve a good outcome with second-line anti-tuberculous drugs, and that surgery might be useful for cases in which an optimized medical treatment is not possible. PMID- 22940280 TI - Neonatal tetanus elimination in Pakistan: progress and challenges. AB - Pakistan is one of the 34 countries that have not achieved the neonatal tetanus (NT) global elimination target set by the World Health Organization (WHO). NT, caused by Clostridium tetani, is a highly fatal infection of the neonatal period. It is one of the most underreported diseases and remains a major but preventable cause of neonatal and infant mortality in many developing countries. In 1989, the World Health Assembly called for the elimination of NT by 1995, and since then considerable progress has been made using the following strategies: clean delivery practices, routine tetanus toxoid (TT) immunization of pregnant women, and immunization of all women of childbearing age with three doses of TT vaccine in high-risk areas during supplementary immunization campaigns. This review presents the activities, progress, and challenges in achieving NT elimination in Pakistan. A review of the literature found TT vaccination coverage in Pakistan ranged from 60% to 74% over the last decade. Low vaccination coverage, the main driver for NT in Pakistan, is due to many factors, including demand failure for TT vaccine resulting from inadequate knowledge of TT vaccine among reproductive age females and inadequate information about the benefits of TT provided by health care workers and the media. Other factors linked to low vaccination coverage include residing in rural areas, lack of formal education, poor knowledge about place and time to get vaccinated, and lack of awareness about the importance of vaccination. A disparity exists in TT vaccination coverage and antenatal care between urban and rural areas due to access and utilization of health care services. NT reporting is incomplete, as cases from the private sector and rural areas are underreported. To successfully eliminate NT, women of reproductive age must be made aware of the benefits of TT vaccine, not only to themselves, but also to their families. Effective communication strategies for TT vaccine delivery and health education focusing on increasing awareness of NT are strongly suggested. It is imperative that the private and government sectors work cooperatively to report NT cases and improve routine TT vaccination coverage. PMID- 22940281 TI - Randomised controlled monotherapy trials: which comparators to use? AB - As approximately 50% of patients with newly diagnosed epilepsy achieve seizure remission after initial monotherapy, the selection of the first-choice drug to be used as the gold standard in randomised clinical trials is critical. Several first and second generation drugs have been used in regulatory and pragmatic monotherapy trials with similar efficacy but differing pharmacokinetic, tolerability, and safety profiles. None of the available compounds has an ideal profile and second generation drugs do not appear to present unequivocal advantages in this regard. Compared to first generation drugs, some newer generation antiepileptic drugs may be preferred as they have similar efficacy but lower potential for idiosyncratic reactions and drug interactions. However, more recent antiepileptic drugs also have limitations, which include lack of superiority and, in some cases, unbearable adverse effects. In this light, there are no standard criteria as a reference for the selection of the best comparator for new monotherapy trials. However, according to the recommendations of evidence based guidelines, carbamazepine still represents the first-choice drug for patients with partial epilepsy. Ethosuximide may be an option for absence epilepsy. In contrast, for the treatment of patients with other generalised epilepsies, there is no clear indication of preferred drug, as valproate, which has been found to prevail over other compounds, should be withheld in women of childbearing age due to its teratogenic potential, and there is insufficient evidence to choose an alternative drug. PMID- 22940283 TI - Relation between dynamics, activity and thermal stability within the cholinesterase family. AB - Incoherent neutron scattering is one of the most powerful tools for studying dynamics in biological matter. Using the cold neutron backscattering spectrometer IN16 at the Institut Laue Langevin (ILL, Grenoble, France), temperature dependence of cholinesterases' dynamics (human butyrylcholinesterase from plasma: hBChE; recombinant human acetylcholinesterase: hAChE and recombinant mouse acetylcholinesterase: mAChE) was examined using elastic incoherent neutron scattering (EINS). The dynamics was characterized by the averaged atomic mean square displacement (MSD), associated with the sample flexibility at a given temperature. We found MSD values of hAChE above the dynamical transition temperature (around 200K) larger than for mAChE and hBChE, implying that hAChE is more flexible than the other ChEs. Activation energies for thermodynamical transition were extracted through the frequency window model (FWM) (Becker et al. 2004) [1] and turned out to increase from hBChE to mAChE and finally to hAChE, inversely to the MSDs relations. Between 280 and 316K, catalytic studies of these enzymes were carried out using thiocholine esters: at the same temperature, the hAChE activity was systematically higher than the mAChE or hBChE ones. Our results thus suggest a strong correlation between dynamics and activity within the ChE family. We also studied and compared the ChEs thermal inactivation kinetics. Here, no direct correlation with the dynamics was observed, thus suggesting that relations between enzyme dynamics and catalytic stability are more complex. Finally, the possible relation between flexibility and protein ability to grow in crystals is discussed. PMID- 22940282 TI - Nicotinic acetylcholine receptor mediates nicotine-induced actin cytoskeletal remodeling and extracellular matrix degradation by vascular smooth muscle cells. AB - Cigarette smoking is a significant risk factor for atherosclerosis, which involves the invasion of vascular smooth muscle cells (VSMCs) from the media to intima. A hallmark of many invasive cells is actin cytoskeletal remodeling in the form of podosomes, accompanied by extracellular matrix (ECM) degradation. A7r5 VSMCs form podosomes in response to PKC activation. In this study, we found that cigarette smoke extract, nicotine, and the cholinergic agonist, carbachol, were similarly effective in inducing the formation of podosome rosettes in A7r5 VSMCs. alpha-Bungarotoxin and atropine experiments confirmed the involvement of nicotinic acetylcholine receptors (nAChRs). Western blotting and immunofluorescence experiments revealed the aggregation of nAChRs at podosome rosettes. Cycloheximide experiments and media exchange experiments suggested that autocrine factor(s) and intracellular phenotypic modulation are putative mechanisms. In situ zymography experiments indicated that, in response to PKC activation, nicotine-treated cells degraded ECM near podosome rosettes, and possibly endocytose ECM fragments to intracellular compartments. Invasion assay of human aortic smooth muscle cells indicated that nicotine and PKC activation individually and synergistically enhanced cell invasion through ECM. Results from this study suggest that nicotine enhances the ability of VSMCs to degrade and invade ECM. nAChR activation, actin cytoskeletal remodeling and phenotypic modulation are possible mechanisms. PMID- 22940284 TI - Neural evidence for a multifaceted model of attachment security. AB - The sense of attachment security has been linked with a host of beneficial outcomes related to personal and relational well-being. Moreover, research has demonstrated that the sense of attachment security can be enhanced via cognitive priming techniques. Studies using such techniques have shown that security priming results with similar outcomes as dispositional attachment security. The way security priming leads to these effects, however, is yet to be unveiled. Using fMRI we took one step in that direction and examined the neural mechanisms underlying enhanced attachment security. Participants were exposed to explicit and implicit security- and insecurity-related words. Security priming led to co occurring activation in brain areas reflective of cognitive, affective, and behavioral processes (e.g., medial frontal cortex, parahippocampus, BA 6). There were activation differences based on attachment style. This research serves as an important step in mapping out the security process and supports a conceptualization of security as part of a behavioral system with multiple components. PMID- 22940285 TI - Defense peptides from barnyard grass (Echinochloa crusgalli L.) seeds. AB - A number of defense polypeptides from latent seeds of weed cereal barnyard grass (Echinochloa crusgalli L.) has been isolated and characterized using an acidic extraction and high performance liquid chromatography methods in combination with MALDI-TOF mass spectrometry and Edman sequencing. Members of three antimicrobial peptide families and two protease inhibitor families were found to be localized in barnyard grass seeds. Their biological activity concerning to Gram-Positive and Gram-Negative phytopathogenic bacteria, as well as oomycete Phytophthora infestans, has been investigated. Diversity of barnyard grass defense peptides is a significant factor that provides a resistance of E. crusgalli seeds to germination and latent phases. PMID- 22940286 TI - Long-term physical exercise induces changes in sirtuin 1 pathway and oxidative parameters in adult rat tissues. AB - The protein deacetylase, sirtuin 1, is suggested as a master regulator of exercise-induced beneficial effects. Sirtuin 1 modulates mitochondrial biogenesis, primarily via its ability to deacetylate and activate proliferator activated receptor-gamma coactivator-1alpha (PGC-1alpha), interacting with AMPK kinase. Redox cell status can also influence this regulatory axis and together they form an important convergence point in hormesis during the aging process. Here, we tested whether treadmill training (36weeks), as a paradigm of long-term moderate exercise, modifies the AMPK-sirtuin 1-PGC-1alpha axis and redox balance in rat gastrocnemius muscle, liver and heart. Physical activity induced increases in sirtuin 1 protein levels in all the aged rat tissues studied, as well as total PGC-1alpha levels. However, no changes in AMPK activation or significant differences in mitochondrial biogenesis (by measuring electron transport chain protein content) were found after exercise training. Parallel to these changes, we observed an improvement of oxidative stress defenses, mainly in muscle, with modification of the antioxidant enzyme machinery resulting in a reduction in lipid peroxidation and protein carbonylation. Thus, we demonstrate that moderate long-term exercise promotes tissue adaptations, increasing muscle, liver and heart sirtuin 1 protein content and activity and increasing PGC-1alpha protein expression. However, AMPK activation or mitochondrial biogenesis is not modified, but it cannot be discarded that its participation in the adaptive mechanism which prevents the development of the deleterious effects of age. PMID- 22940287 TI - Arsenic uptake in upland rice inoculated with a combination or single arbuscular mycorrhizal fungi. AB - A pot trial was conducted to investigate the role of arbuscular mycorrhizal fungi (AMF) on arsenic (As) uptake of upland rice (Oryza sativa L.) cultivar, Zhonghan 221; where the following 3 species of Glomus geosporum (Gg), G. mosseae (Gm) and G. versiforme (Gv) were applied as single or combined inoculations. In general, Gm significantly enhanced (p<0.05) total As concentration in Zhonghan 221 when compared to the non mycorrhizal (NM) treatment. The treatment inoculated with Gg + Gm increased total phosphorus (P) uptake and decreased total As uptake in the ingestible rice parts (husks and grains). In terms of AMF colonization rates, Gm had significantly higher (p<0.05) average values of 57.3% and 66.6% when grown in As0 and As40 soils, respectively, in comparison to that of Gg and Gv, and finally dropped to 3.63% when grown in As80 soil. There was a significant difference (p<0.05) between single AMF species (Gg or Gv) and AMF mixture treatments (Gg + Gv, Gg + Gm, Gv + Gm and Gg + Gv + Gm) in terms of total As concentrations in rice. No significant correlation between AMF colonization rates and As uptake in grains (r = 0.150, p > 0.01) and total P (r = 0.002, p > 0.01) were observed. PMID- 22940288 TI - Epigenetic regulation of the 1,25-dihydroxyvitamin D3 24-hydroxylase (CYP24A1) in colon cancer cells. AB - Calcitriol is the hormonally active form of vitamin D and has anti-proliferative and pro-apoptotic effects. Calcitriol and its precursor calcidiol (25(OH)D3) are degraded by the 1,25-dihydroxyvitamin D3 24-hydroxylase (CYP24A1). This enzyme is overexpressed in colorectal tumors, however, the mechanisms of this overexpression remain to be elucidated. CYP24A1 mRNA level differs among colorectal cancer cell lines and range from almost undetectable to high. Since DNA methylation and histone acetylation regulate CYP24A1 gene expression in prostate cancer cell lines, we investigated whether epigenetic mechanisms could explain the differences in basal expression of CYP24A1 in colon cancer cells. Methyltransferase inhibitor 5-aza-2'-deoxycytidine (DAC) treatment resulted in an over 50-fold induction of CYP24A1 mRNA expression in Coga1A and HT-29 cells but in no response in Caco2/AQ and Coga13 cells. This finding is supported by a strong increase in CYP24A1 activity after DAC treatment in Coga1A (35%). In addition, calcitriol and DAC had synergistic effects on CYP24A1 gene transcription. Interestingly, the CYP24A1 promoter was not methylated in Coga1A and HT-29 (<5%), while in Caco2/AQ it was 62% methylated. This suggests that DNA demethylation must activate genes upstream of CYP24A1 rather than act on the gene itself. However, transcriptional regulators of CYP24A1 such as vitamin D receptor (VDR), retinoid X receptor (RXR), specificity protein 1 (SP1), or mediator complex subunit 1 (MED1) were not upregulated. We conclude that in colon cancer cells, CYP24A1 gene expression is inducible by methyltransferase and some histone deacetylase inhibitors in a cell line-dependent manner. This effect does not correlate with the methylation state of the promoter and therefore must affect genes upstream of CYP24A1. This article is part of a Special Issue 'Vitamin D Workshop'. PMID- 22940289 TI - Glutathione homeostasis as an important and novel factor controlling blossom-end rot development in calcium-deficient tomato fruits. AB - Based on previous results in which oxidative metabolism was suggested as a possible inducer of blossom-end rot (BER), the main questions addressed here were whether calcium deficiency is the main factor that induces BER or whether this physiological disorder a general stress-related phenomenon? Tomato plants were grown under optimal or deficient calcium concentrations. Only the application of 0.1mM calcium resulted in BER induction, although only half of the fruits grown under this treatment had this disorder. Having fruits showing or not showing BER in the same plant and treatment provided us with a powerful tool that we used to investigate whether calcium deficiency operates alongside another mechanism in the induction of BER. Whether or not this other mechanism was the one controlling BER incidence was also investigated. We performed a complete study of the oxidative metabolism in the pericarp of healthy fruits and in the healthy portion of BER-affected fruits. Calcium deficiency led to an induction of NADPH oxidase, superoxide dismutase, dehydro- and monodehydroascorbate reductase, and to an inhibition of catalase, ascorbate peroxidase and glutathione reductase, with a concomitant accumulation of hydrogen peroxide and an increase in lipid peroxidation. While the ascorbate redox state was not affected by calcium deficiency, the glutathione redox state was markedly reduced. We conclude that calcium deficiency fundamentally affected the activity of the ascorbate glutathione enzymes, with special importance to the inhibition of GR, which lead to a reduction of the glutathione redox state. This could cause the breakdown of cellular homeostasis, the inhibition of other enzymes responsible for H(2)O(2) detoxification, and ultimately an increase of lipid peroxidation. Therefore, BER is defined here as the visual symptom of a massive lipid peroxidation event caused by the breakdown of cellular glutathione homeostasis. PMID- 22940290 TI - Separation of abscission zone cells in detached Azolla roots depends on apoplastic pH. AB - In studies on the mechanism of cell separation during abscission, little attention has been paid to the apoplastic environment. We found that the apoplastic pH surrounding abscission zone cells in detached roots of the water fern Azolla plays a major role in cell separation. Abscission zone cells of detached Azolla roots were separated rapidly in a buffer at neutral pH and slowly in a buffer at pH below 4.0. However, cell separation rarely occurred at pH 5.0 5.5. Light and electron microscopy revealed that cell separation was caused by a degradation of the middle lamella between abscission zone cells at both pH values, neutral and below 4.0. Low temperature and papain treatment inhibited cell separation. Enzyme(s) in the cell wall of the abscission zone cells might be involved in the degradation of the pectin of the middle lamella and the resultant, pH-dependent cell separation. By contrast, in Phaseolus leaf petioles, unlike Azolla roots, cell separation was slow and increased only at acidic pH. The rapid cell separation, as observed in Azolla roots at neutral pH, did not occur. Indirect immunofluorescence microscopy, using anti-pectin monoclonal antibodies, revealed that the cell wall pectins of the abscission zone cells of Azolla roots and Phaseolus leaf petioles looked similar and changed similarly during cell separation. Thus, the pH-related differences in cell separation mechanisms of Azolla and Phaseolus might not be due to differences in cell wall pectin, but to differences in cell wall-located enzymatic activities responsible for the degradation of pectic substances. A possible enzyme system is discussed. PMID- 22940291 TI - Long-term persistence of neutralising antibodies against bluetongue virus serotype 8 in naturally infected cattle. AB - Neutralising antibodies to bluetongue virus (BTV) in convalescent cattle have been described as persistent. Controlled laboratory studies, however, rarely last longer than a couple of weeks and long-term field data are lacking. This study followed twelve cattle that had been naturally infected with bluetongue virus serotype 8 (BTV-8) in Germany in 2006. Using ELISAs and a serum neutralisation test, we found a strong humoral immune response four to six years after the last exposure to BTV-8; based on data from long-term vaccine studies, it is highly likely that this coincides with immunity to reinfection with the same serotype. PMID- 22940292 TI - Clinicopathological differences between breast cancer in patients with primary metastatic disease and those without: a multicentre study. AB - OBJECTIVE: Approximately 6% of breast cancer (BC) patients present with primary metastatic disease (pmBC) at first diagnosis. The clinicopathological differences between tumours from patients who have metastatic disease and those who do not are unclear. METHODS: This study was an exploratory analysis of patients with pmBC treated in 8 German breast cancer centres between 1998 and 2010. Phenotypes were defined using the following immunohistochemical markers: oestrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (Her2). The control arm included the group of patients who had neither local recurrence nor distant metastases at a follow-up of at least 30 months after initial diagnosis. RESULTS: A total of 2214 patients were included. Of these, 1642 had non metastatic BC, and 572 had pmBC. Eighty-five patients (15%) with pmBC were diagnosed at stage T1. On multivariate analysis, factors associated with pmBC were as follows: positive lymph node status, grade 3, lobular histology and Luminal B phenotype (Her 2 positive). Of the sample, 197 patients (34%) with pmBC were diagnosed as stage T2, 90 patients (16%) were diagnosed as stage T3, and 200 patients (35%) were diagnosed as stage T4. Only positive lymph node status and grade 3 were reported as risk factors for distant metastases in patients with stage T3 and T4 cancer. CONCLUSION: There are differences in the clinicopathological features among breast cancer patients with primary metastases and those without. Receptor expression and histological type play a minor role in the risk for metastasis in patients with stage T3 and T4 disease when compared to patients with T1 pmBC tumours. On initial diagnosis, lobular histology and Luminal B positivity (Her 2 positive) in T1 pmBC were determined to be risk factors for primary metastatic disease. PMID- 22940293 TI - Alteration of brain volume in IL-6 overexpressing mice related to autism. AB - Abnormal neuroimmune responses have been reported to be associated with autism and could be appropriate targets for pharmacologic intervention. Our previous studies showed that neuroimmune factor, interleukin (IL)-6, was significantly elevated in the fontal cortex and cerebellum of autistic subjects. The IL-6 overexpressing mice displayed several autism-like features as well as an abnormal dendritic spine morphology and synaptic function. The purpose of this study was to examine the volumetric differences in the brain of IL-6 overexpressing mice and compare with corresponding control mice using magnetic resonance imaging. Here we show that IL-6 overexpressing mice display an increase in the total brain volume. In addition, the lateral ventricle is also enlarged in the IL-6 overexpressing mice. The brain structures surrounding the lateral ventricle were squeezed and deformed from the normal location. These results indicate that IL-6 elevation in the brain could mediate neuroanatomical abnormalities. Taking together with our previous findings, a mechanism by which IL-6 may be involved in the pathogenesis of autism is proposed. PMID- 22940294 TI - Molecular cloning and characterization of a novel beta-glucosidase with high hydrolyzing ability for soybean isoflavone glycosides and glucose-tolerance from soil metagenomic library. AB - A novel beta-glucosidase (Bgl1269) was identified from a metagenomic library of mangrove soil by activity-based functional screening. Sequence analysis revealed that Bgl1269 encodes a protein of 422 amino acids. After being overexpressed in Escherichia coli and purified, the enzymatic properties of Bgl1269 were investigated. The recombinant enzyme displayed a pH optimum of 6.0 and a temperature optimum of 40 degrees C, and the addition of most common metal ions (1 or 10mM) increased the enzymatic activity evidently. In addition, the enzyme showed high hydrolyzing ability for soybean isoflavone glycosides, and 0.8unit of enzyme could completely converted daidzin and genistin (0.5mg/mL) to daidzein and genistein at 40 degrees C for 0.5h. Interestingly, Bgl1269 also exhibited a very high glucose-tolerance, with the highest inhibition constant K(i) (4.28M) among beta-glucosidases reported so far. These properties make it a good candidate in the production of soybean isoflavone aglycones after further study. PMID- 22940295 TI - Effect of particle size and ammonium sulfate concentration on rice bran fermentation with the fungus Rhizopus oryzae. AB - The effects of rice bran particle size (0.18-0.39mm) and ammonium sulfate concentration in the nutrient solution (2-8g/L) on biomass production, protein and phenolic content generated by solid state fermentation with the fungus Rhizopus oryzae (CCT 1217) were studied. Particle size had a positive effect on biomass production and a negative effect (p?0.05) on protein and phenolic contents. Ammonium sulfate concentration had a positive effect (p?0.05) on biomass and phenolic content gain. Cultivation of fungus in rice bran with particle size of 0.18mm and in the presence of 8g/L ammonium sulfate, resulted in protein levels of 20g/100g dry wt and phenolics content of 4mg/g dry wt. These values were 53 and 65% higher than those achieved with unfermented rice bran. The results demonstrate that the fermentation process increased the value of compounds recovered for potential use in food formulations. PMID- 22940296 TI - Effect of surfactant-induced cell surface modifications on electron transport system and catechol 1,2-dioxygenase activities and phenanthrene biodegradation by Citrobacter sp. SA01. AB - In order to better understand how surfactants affect biodegradation of hydrophobic organic compounds (HOCs), Tween 80 and sodium dodecyl benzene sulfonate (SDBS), were selected to investigate effects on cell surface hydrophobicity (CSH), electron transport system (ETS) activities and phenanthrene biodegradation by Citrobacter sp. SA01. Tween 80 and SDBS increased CSH by 19.8 25.2%, ETS activities by 352.1-376.0MUmol/gmin, catechol 1,2-dioxygenase (C12) activities by 50.8-52.7U/L, and phenanthrene biodegradation by 8.9-17.2% separately in the presence of 50mg/L of surfactants as compared to in their absence. Lipopolysaccharide (LPS) release was 334.7MUg/mg in the presence of both surfactants whereas in their absence only 8.6-44.4MUg/mg of LPS was released. Thus, enhanced LPS release probably increased ETS and C12 activities as well as phenanthrene biodegradation by increasing CSH. The results demonstrate that surfactant-enhanced CSH provides a simple, yet effective strategy for field applications of surfactant-enhanced bioremediation of HOCs. PMID- 22940297 TI - Characterization of changes of lignin structure in the processes of cooking with solid alkali and different active oxygen. AB - The cooking with solid alkali and active oxygen has a high selectivity for delignification. In the present work, the O(2) and H(2)O(2) were separately combined with MgO used in cornstalk cooking for investigating their effects on delignification. After cooking, the lignins in raw material, pulp, and yellow liquor were all characterized by HSQC NMR. The results showed that the syringyl (S/S'/S") units and beta-O-4' (A/A'/A") structures had different reactivity in the cooking with MgO and H(2)O(2) due to their different structures on side chains. Whereas the syringyl (S/S'/S") units could be completely decomposed when the MgO and O(2) were used, and the beta-O-4' (A/A'/A") structures could be partly degraded. A novel structure G' unit with a carbonyl group was only generated in the cooking with MgO and O(2). In addition, the H unit, non-phenolic beta-beta' (B) and beta-5' (C) structures were all stable in both of the two cooking processes. PMID- 22940298 TI - Fractionation and characterization of dissolved extracellular and intracellular products derived from floccular sludge and aerobic granules. AB - Dissolved extracellular and intracellular polymeric substances (DEPS and DIPS) from floccular sludge and aerobic granules were extracted and fractionated based on compound hydrophobicity. Compared with floccular sludge, aerobic granules contained lower amounts of DEPS and DIPS. Fourier transforms infrared spectra suggested that large amounts of proteins and polysaccharides existed in colloidal form in the extracellular polymeric substances of aerobic granules. Fluorescence excitation-emission matrix spectra revealed that tightly bound DEPS (TB-DEPS) and DIPS were humified after sludge granulation. Meanwhile, the proportions of hydrophilic contents in the TB-DEPS and DIPS fractions decreased from 45.3% to 28.3% and from 40.1% to 18.9%, respectively. These data indicated that TB-DEPS and DIPS from aerobic granules were more hydrophobic than those from floccular sludge. The results of the hierarchical cluster analysis further confirmed that the characteristics of dissolved organic matters between floccular and granular sludge were distinctly different. PMID- 22940299 TI - Chemical characteristics of beddings for swine: effects of bedding depths and of addition of inoculums in a pilot-scale. AB - The effect of depths and of addition of inoculums on the chemical content of swine beddings was evaluated. For beddings 0.25m (25D) and 0.50m (50D) deep, three treatments were tested in two repeats with the same beddings: control (no inoculums); T1 (250g of Bacillus cereus var. toyoii at 8.4*10(7)CFU/g); and T2 (250g of a pool of Bacillus sp. at 8.4*10(7)CFU/g) (250g for 25D and 500g for 50D). For 25D, the C:N ratio was lower, but N, K and C contents were greater than for 50D (P<0.05). The inoculums did not benefit any chemical parameter (P>0.05). In the second repeat, beddings presented lower C:N ratio and greater N, P and K contents than in the first repeat (P<0.05). Thus, the compost produced after using 25D twice had greater fertilizer value than that of 50D. PMID- 22940300 TI - The cold adaptability of microorganisms with different carbon source in activated sludge treating synthetical wastewater. AB - The cold adaptability of microorganisms with different carbon source under 5 degrees C was studied in activated sludge for treating synthetical wastewater. Phospholipid fatty acid (PLFA) analysis indicated contents of unsaturated fatty acids in cell membrane at 5 degrees C were 13.66% and 24.96% higher for glucose and sodium acetate source than that at 25 degrees C. PLFA biomarkers showed more Gram-negative bacteria enriched than Gram-positive bacteria in low-temperature activated sludge. The Shannon-Wiener diversity analysis demonstrated glucose fed reactor in low temperature had lower PLFA diversity index (1.21-1.30) than that at 25 degrees C and sodium acetate source was reverse (1.08-0.69). The 16S rRNA analysis manifested certain microbes were considerably suitable for existence under cold environment, most of which belong to Gram-negative bacteria. PMID- 22940301 TI - Microwave assisted esterification of acidified oil from waste cooking oil by CERP/PES catalytic membrane for biodiesel production. AB - The traditional heating and microwave assisted method for biodiesel production using cation ion-exchange resin particles (CERP)/PES catalytic membrane were comparatively studied to achieve economic and effective method for utilization of free fatty acids (FFAs) from waste cooking oil (WCO). The optimal esterification conditions of the two methods were investigated and the experimental results showed that microwave irradiation exhibited a remarkable enhanced effect for esterification compared with that of traditional heating method. The FFAs conversion of microwave assisted esterification reached 97.4% under the optimal conditions of reaction temperature 60 degrees C, methanol/acidified oil mass ratio 2.0:1, catalytic membrane (annealed at 120 degrees C) loading 3g, microwave power 360W and reaction time 90min. The study results showed that it is a fast, easy and green way to produce biodiesel applying microwave irradiation. PMID- 22940302 TI - Performance of autotrophic nitrogen removal in the granular sludge bed reactor. AB - The autotrophic nitrogen removal process in the granular sludge bed reactor (GSB ANR process) is a new and promising biotechnology for nitrogen removal from wastewater, which requires single reactor, simple operation and inorganic carbon. The results showed that the GSB-ANR process could be successfully started up with nitrifying granular sludge as inoculum. The volumetric nitrogen loading rate and the volumetric nitrogen removal rate reached 5.44 and 2.57kgNm(-3)day(-1), respectively, which were significantly higher than the level reported for the autotrophic nitrogen removal processes in single reactor. The predominant functional microorganisms were from Planctomycetes and Nitrosomonas. The excellent performance of GSB-ANR process was ascribed to: (a) The high activities of aerobic ammonia-oxidizing bacteria (AOB) and anaerobic ammonium oxidation (ANAMMOX) bacteria; (b) the good settlability of the granular sludge; (c) the suitable DO concentration that satisfied the oxygen requirement of AOB and prevented ANAMMOX bacteria from oxygen inhibition. PMID- 22940303 TI - Biological treatment of steroidal drug industrial effluent and electricity generation in the microbial fuel cells. AB - The single chamber microbial fuel cells (MFCs) were used to treat steroidal drug production wastewater (SPW) and generate electricity simultaneously. The results indicated that the maximum COD removal efficiency reached 82%, total nitrogen and sulfate removal rate approached 62.47% and 26.46%, respectively. The maximum power density and the Coulombic efficiency reached to 22.3Wm(-3) and 30%, respectively. The scanning electron microscope showed that the dominant microbial populations were remarkably different in morphology on the surface of SPW and acetate-fed anodes. PCR-denaturing gradient gel electrophoresis profiles revealed that the microbial community structure fed with different concentrations of SPW presented a gradual succession and unique bacterial sequences were detected on the SPW and acetate-fed anodes. This research demonstrates that MFCs fed with SPW achieved a high efficiency of power density and simultaneous nutrient removal, and the dominant microorganisms on the anode were related to the types and the concentrations of substrates. PMID- 22940304 TI - Enhanced desorption of humin-bound phenanthrene by attached phenanthrene degrading bacteria. AB - The objective of the study was to test the hypothesis that the attachment of polycyclic aromatic hydrocarbons (PAHs)-degrading bacteria can promote desorption of PAHs from humin, thereby increasing their bioavailability. Biodegradation of humin-bound phenanthrene (PHE) - a model compound for PAHs - was investigated using two PHE-degrading bacteria, Sphingobium sp. PHE3 and Micrococcus sp. PHE9, respectively. Sorption data of PHE to humin fitted well into the modified Freundlich equation. Further, a new sorption band appeared at 1262cm(-1), demonstrating intermolecular interactions between PHE and humin. Interestingly, approximately 65.3% of humin-bound PHE was degraded by both strains, although only about 17.8% of PHE could be desorbed from humin by Tenax extraction. Furthermore, both strains grew well in mineral medium and also attached to humin surfaces for substrate uptake. It is proposed that the attached bacteria could possibly consume PHE on the humin via interactions between bacterial surfaces and humin, thereby overcoming the low PHE bioavailability and resulting in enhanced degradation. PMID- 22940305 TI - Torrefaction and low temperature carbonization of oil palm fiber and Eucalyptus in nitrogen and air atmospheres. AB - Torrefaction is a pretreatment method for upgrading biomass as solid fuels. To provide flexible operations for effectively upgrading biomass at lower costs, the aim of this study was to investigate the properties of oil palm fiber and eucalyptus pretreated in nitrogen and air atmospheres at temperatures of 250-350 degrees C for 1h. Based on energy and solid yield and introducing an energy-mass co-benefit index (EMCI), oil palm fiber pretreatment under nitrogen at 300 degrees C provided the solid fuel with higher energy density and less volume compared to other temperatures. Pretreatment of oil palm fiber in air resulted in the fuel with low solid and energy yields and is therefore not recommended. For eucalyptus, nitrogen and air can be employed to upgrade the biomass, and the suggested temperatures are 325 and 275 degrees C, respectively. PMID- 22940306 TI - Integrated fungal biomass and activated sludge treatment for textile wastewaters bioremediation. AB - A combined biological process was investigated for effective textile wastewater treatment. The process consisted of a first step performed by selected fungal biomasses, mainly devoted to the effluent decolourisation, and of a subsequent stage by means of activated sludge, in order to reduce the remaining COD and toxicity. In particular, the treatment with Trametes pubescens MUT 2400, selected over nine strains, achieved very good results in respect to all parameters. The final scale-up phase in a moving bed bioreactor with the supported biomass of the fungus allowed to verify the effectiveness of the treatment with high volumes. Despite promising results, further steps must be taken in order to optimize the use of these biomasses for a full exploitation of their oxidative potential in textile wastewater treatment. PMID- 22940307 TI - Catalyst-free fatty acid methyl ester production from wet activated sludge under subcritical water and methanol condition. AB - Wet activated sludge was converted directly into biodiesel using water as hydrolysis reagent to enhance the extraction of lipid in activated sludge, and as catalyst for the conversion of neutral lipids into biodiesel under subcritical conditions. At 175 degrees C, 3.5MPa, a methanol to sludge ratio of 30 (mL/g) and a sludge water content of 84wt.%, about 90% conversion to fatty acid methyl esters was achieved within 24h without the need for conventional catalysts such as KOH and H(2)SO(4). Since water is employed as a catalyst, its removal is not required; therefore, the processing costs for producing biodiesel from activated sludge are reduced. The method has the potential for applications to other feedstock with high water contents such as micro-algae. PMID- 22940308 TI - Production and characterization of acidophilic xylanolytic enzymes from Penicillium oxalicum GZ-2. AB - Multiple acidophilic xylanolytic enzymes were produced by Penicillium oxalicum GZ 2 during growth on wheat straw, rice straw, corn stover, and wheat bran. The expression of xylanase isoforms was dependent on substrate type and nitrogen source. The zymograms produced by the SDS-PAGE resolution of the crude enzymes indicated that wheat straw was the best inducer, resulting in the highest xylanase (115.2U/mL) and beta-xylosidase (89mU/mL) activities during submerged fermentation. The optimum temperature and pH for xylanase activity were 50 degrees C and 4.0, respectively; however, the crude xylanase enzymes exhibited remarkable stability over a broad pH range and showed more than 90% activity at 50 degrees C for 30min at pH 4.0-8.0. The results revealed that P. oxalicum GZ-2 is a promising acidophilic xylanase-producing microorganism that has great potential to be used in biofuels, animal feed, and food industry applications. PMID- 22940309 TI - Structural modeling and further improvement in pH stability and activity of a highly-active xylanase from an uncultured rumen fungus. AB - Rumen fungi are a rich source of enzymes degrading lignocelluloses. XynR8 is a glycosyl hydrolase family 11 xylanase previously cloned from unpurified rumen fungal cultures. Phylogenetic analysis suggested that xynR8 was obtained from a Neocallimastix species. Recombinant XynR8 expressed in Escherichia coli was highly active and stable between pH 3.0 and 11.0, and displayed a V(max) of 66,672MUmolmin(-1)mg(-1), a k(cat) of 38,975s(-1), and a K(m) of 11.20mg/mL towards soluble oat spelt xylan. Based on molecular modeling, residues N41 and N58, important in stabilizing two loops and the structure of XynR8, were mutated to D. Both mutant enzymes showed higher tolerance to pH 2.0. The V(max), k(cat) and K(m) of the N41D and N58D mutant enzymes were 79,645MUmolmin(-1)mg(-1), 46,493s(-1), 29.29mg/mL, and 96,689MUmolmin(-1)mg(-1), 56,503s(-1), and 21.24mg/mL, respectively. Thus, they are good candidates for application, including biofuel production. PMID- 22940310 TI - Production of soluble recombinant proteins in Escherichia coli: effects of process conditions and chaperone co-expression on cell growth and production of xylanase. AB - In this study, effects of temperature, inducer concentration, time of induction and co-expression of molecular chaperones (GroEL-GroES and DnaKJE), on cell growth and solubilization of model protein, xylanases, were investigated. The yield of soluble xylanases increased with decreasing cultivation temperature and inducer level. In addition, co-expression of DnaKJE chaperone resulted in increased soluble xylanases though the time of induction of chaperone and target protein had a bearing on this yield. A combination of chaperone co-expression and partial induction resulted in ~40% (in DnaKJE) and 33% (in GroEL-GroES) of total xylanase yield in soluble fraction. However, the conditions for maximum yield of soluble r-XynB and maximum % soluble expression of r-XynB were different. Higher expression of soluble xylanases in a scalable semi-synthetic medium showed potential of the process for soluble enzyme production. PMID- 22940312 TI - Bioaugmentation for treating transient or continuous p-nitrophenol shock loads in an aerobic sequencing batch reactor. AB - Bioaugmentation with an enriched microbial population was applied in an aerobic sequencing batch reactor (SBR) receiving transient or continuous shock loads of p nitrophenol (PNP). The effect of the amount of biomass added for bioaugmentation was assessed by using two different dosages (2% or 5% w/w of the total biomass in the seeded SBR). In both cases, total PNP removal was achieved during the transient PNP shock load occurring after bioaugmentation. However, after a long PNP starvation period the only experiment still showing total PNP removal during a second PNP shock load was the one where a dosage of 5% w/w was applied. The results suggested that the dosage is a key factor for the implementation of a successful bioaugmentation strategy. In addition, the performance of a bioaugmented SBR receiving a continuous PNP shock load was enhanced when compared to a non-bioaugmented SBR. PMID- 22940311 TI - Cell surface engineering of alpha-l-rhamnosidase for naringin hydrolysis. AB - An alpha-l-rhamnosidase gene (rhaL1) containing an open reading frame of 2046-bp encoding a 681-amino acid protein (RhaL1) was cloned from Alternaria sp. L1 for naringin hydrolysis on the cell surface of Saccharomyces cerevisiae EBY-100. RhaL1 anchored to the yeast cell surface showed maximum enzyme activity at pH 6.0 6.5 and 70 degrees C and was stable at pH 2.5-12.0 below 60 degrees C. When the yeast cells were employed to hydrolyze naringin in grapefruit juice, about 85% naringin was hydrolyzed at 60 degrees C in 10min. The yeast cells were harvested and recycled for the next batch. The hydrolysis rate of the naringin was maintained at over 80% for 10 batches. These results demonstrate the stability of the RhaL1-expressing yeast cells and effective in hydrolysis of naringin in juice. Thus, the system could have promise for industrial bitterness reduction. PMID- 22940313 TI - Production of polygalacturonases by Aspergillus oryzae in stirred tank and internal- and external-loop airlift reactors. AB - The production of endo- and exo-polygalacturonase (PG) by Aspergillus oryzae was assessed in stirred tank reactors (STRs), internal-loop airlift reactors (ILARs) and external-loop airlift reactors (ELARs). For STR production, we compared culture media formulated with either pectin (WBE) or partially hydrolyzed pectin. The highest enzyme activities were obtained in medium that contained 50% pectin in hydrolyzed form (WBE5). PG production in the three reactor types was compared for WBE5 and low salt WBE medium, with additional salts added at 48, 60 and 72h (WBES). The ELARs performed better than the ILARs in WBES medium where the exo-PG was the same concentration as for STRs and the endo-PG was 20% lower. These results indicate that PG production is higher under experimental conditions that result in higher cell growth with minimum pH values less than 3.0. PMID- 22940314 TI - Continuous microalgae recovery using electrolysis: effect of different electrode pairs and timing of polarity exchange. AB - Microalgae have great potential as a feedstock for biofuel production. Continuous operation is an important benefit of the continuous electrolytic microalgae (CEM) harvest system, but it is necessary to optimize cultivability and recovery efficiency in order to improve overall performance. Two pairs of best-candidate electrodes for polarity exchange (PE) were examined to improve these two key factors: (i) aluminum and dimensionally stable anode (Al-DSA), and (ii) Al platinum (Al-Pt). Al-DSA was better than Al-Pt because it led to less cell damage and was less expensive. Moreover, cell viability and recovery were improved by optimizing the timing of PE. A P1:P2 ratio of 1:1.5 at 5min and 1:1.2 at 10min yielded the best results, with greatly reduced electricity consumption and enhanced cell viability and recovery. The CEM harvest system appears to be a well suited option for the harvest of microalgae for biofuel production. PMID- 22940315 TI - A protease-resistant exo-polygalacturonase from Klebsiella sp. Y1 with good activity and stability over a wide pH range in the digestive tract. AB - Polygalacturonases are important feed and food additives. In the present study an exo-polygalacturonase gene (pgu B) was cloned from Klebsiella sp. Y1 CGMCC 4433 and expressed in Escherichia coli BL21 (DE3). pgu B encodes a 658-amino acid polypeptide belonging to Glycoside Hydrolase Family 28. The optimal pH and temperature of exo-PGU B activity were 6.0 and 40-50 degrees C, respectively. The enzyme exhibited >35% of maximum activity within the pH range of 2.0-12.0. Exo PGU B or an exo-PGU B/ endo-polygalacturonase mixture reduced the viscosity of polygalacturonic acid (1.0%, w/v) by 15.6 and 39.4%, respectively. Under simulated alimentary tract conditions, exo-PGU B was very stable (>25% activity from pH 1.5 to 6.8) and active, releasing 53.7 and 109.6MUg of galacturonic acid from 400 to 800MUg of polygalacturonic acid, respectively. These properties make exo-PGU B a potentially valuable additive for applications in feed and food. PMID- 22940316 TI - Surface area expansion of electrodes with grass-like nanostructures and gold nanoparticles to enhance electricity generation in microbial fuel cells. AB - Microbial fuel cells (MFCs) have applications possibilities for wastewater treatment, biotransformation, and biosensor, but the development of highly efficient electrode materials is critical for enhancing the power generation. Two types of electrodes modified with nanoparticles or grass-like nanostructure (termed nanograss) were used. A two-chamber MFC with plain silicium electrodes achieved a maximum power density of 0.002mW/m(2), while an electrode with nanograss of titanium and gold deposited on one side gave a maximum power density of 2.5mW/m(2). Deposition of titanium and gold on both sides of plain silicium showed a maximum power density of 86.0mW/m(2). Further expanding the surface area of carbon-paper electrodes with gold nanoparticles resulted in a maximum stable power density of 346.9mW/m(2) which is 2.9 times higher than that achieved with conventional carbon-paper. These results show that fabrication of electrodes with nanograss could be an efficient way to increase the power generation. PMID- 22940317 TI - Increased hydrogen production in co-culture of Chlamydomonas reinhardtii and Bradyrhizobium japonicum. AB - Co-cultivation of Bradyrhizobium japonicum with Chlamydomonas reinhardtii strain cc849 or the transgenic strain lba, which was hetero-expressed the gene of the soybean leghemoglobin apoprotein Lba in chloroplasts of the strain cc849, in Tris acetate-phosphate (TAP) or TAP-sulfur free media, improved H(2) yield. H(2) production was 14 times and growth was 26% higher when strain lba and B. japonicum were co-cultured, as compared with cultivation of the algal strain alone under the same conditions. The increase in respiration rate or fast O(2) consumption by about 8 times in the co-cultures was the major reason for the improvement. PMID- 22940318 TI - Optimized alkaline pretreatment of sludge before anaerobic digestion. AB - NaOH was used to disintegrate a mixture composed mainly of primary sludge with biofilm sludge before anaerobic digestion in batch experiments. NaOH pretreatment dissolved some organic substances, and the optimum dose was 0.1mol/L. After the alkali-treated sludge was fed into the digesters, the higher pH delayed the start of digestion and reduced the biogas production during the initial stage, although the system recovered after a lag phase when the dose was lower than 0.04mol/L. Acid conditioning was necessary, but the increased salinity also impacted on the digestion efficiency. For sludge pretreatment, the optimum NaOH dose was 0.1mol/L, and the initial pH of the batch digesters needs to be controlled at less than eight. Under optimized conditions, the organic degradation rate was 38.3% and the biogas yield was 0.65L/g volatile suspended solid (VSS), whereas these values for the control were 30.3% and 0.64L/g VSS, respectively. PMID- 22940319 TI - Effect of thermal pretreatments on hydrocarbon recovery from Botryococcus braunii. AB - Thermal pretreatment were tested to increase the recovery of hydrocarbons from Botryococcus braunii/water mixtures via extraction with hexane. The effectiveness of treatment temperature was dependent on the B. braunii strain and the lowest temperatures which recovered over 90% of hydrocarbons were 60, 85 and 75 degrees C for the Yamanaka, Showa and Kawaguchi-1 strains respectively. The holding times of thermal pretreatment had less of an influence on hydrocarbon recovery than treatment temperature and, depending on the strain, recoveries of between 74.9% and 94.9% were achieved after thermal pretreatments at 80-90 degrees C for only 2.5min. These results suggest thermal pretreatment could reduce the energy consumption of oil recovery process from wet B. braunii cells. PMID- 22940320 TI - Optimization of the hydrogen yield from single-stage photofermentation of glucose by Rhodobacter capsulatus JP91 using response surface methodology. AB - Hydrogen production from glucose via single-stage photofermentation was examined with the photosynthetic bacterium Rhodobacter capsulatus JP91 (hup-). Response surface methodology with Box-Behnken design was used to optimize the independent experimental variables of glucose concentration, glutamate concentration and light intensity, as well as examining their interactive effects for maximization of molar hydrogen yield. Under optimal condition with a light intensity of 175W/m(2), 35mM glucose, and 4.5mM glutamate, a maximum hydrogen yield of 5.5 (+/ 0.15)molH(2)/molglucose, and a maximum nitrogenase activity of 246 (+/ 3.5)nmolC(2)H(4)/ml/min were obtained. Densitometric analysis of nitrogenase Fe protein expression under different conditions showed significant variation in Fe protein expression with a maximum at the optimized central point. Even under optimum conditions for hydrogen production, a significant fraction of the Fe protein was found in the ADP-ribosylated state, suggesting that further improvement in yields might be possible. PMID- 22940321 TI - Molecular approach to evaluate biostimulation of 1,2-dibromoethane in contaminated groundwater. AB - This study investigated the effect of co-substrate amendments on EDB biodegradation under aerobic conditions. Microcosms were established using contaminated soil and groundwater samples and maintained under in situ conditions to determine EDB degradation rates, and the diversity and abundance of EDB degrading indigenous bacteria. After 100days of incubation, between 25% and 56% of the initial EDB was degraded in the microcosms, with added jet fuel providing highest degradation rates (2.97+/-0.49yr(-1)). In all microcosms, the quantity of dehalogenase genes did not change significantly, while the number of BTEX monooxygenase and phenol hydroxylase genes increased with jet fuel amendments. These results indicate that EDB was not degraded by prior dehalogenation, but rather by cometabolism with adapted indigenous microorganisms. This is also reflected in the history of the plume, which originated from an aviation gasoline pipeline leak. This study suggests that biostimulation of EDB is possible at aerobic groundwater sites. PMID- 22940322 TI - Purification, kinetic characterization and properties of a novel thermo-tolerant extracellular protease from Kluyveromyces marxianus IFO 0288 with potential biotechnological interest. AB - A novel extracellular hydrolase of ~45kDa molecular mass was purified from Kluyveromyces marxianus IFO 0288 cultures and characterized as serine protease. The K(m)-value of protease (designated protease-KM-IFO-0288-A), which was found active in media containing elevated [NaCl] but lacking EDTAK(2), decreased with increasing [Ca(2+)]. The protease maintained considerable activity at the range of 10-60 degrees C and pH 6.00-10.25, with optimum k(cat)/K(m)-value at 35.5 degrees C and pH 7.75. It was strongly affected by specific irreversible inhibitors of serine proteases while was unaffected by inhibitors of cysteine proteases. Significant rate constants, activation energies, and proton inventories were estimated from the profiles of Michaelis-Menten parameters, versus pH, temperature and deuterium atom fraction, in the hydrolysis of Suc-AAPF pNA showing that protease-KM-IFO-0288-A performs catalysis via a charge-relay system. The properties of protease-KM-IFO-0288-A suggest that K. marxianus represents a valuable source of extracellular protease of biotechnological interest which, given its GRAS status, could find several important applications. PMID- 22940323 TI - Efficiency of Blenke cascade system for continuous bio-ethanol fermentation. AB - A gas lift-system with inserts (so-called Blenke cascade system) for continuous bio-ethanol fermentation was constructed. Gas introduced at the bottom of the column created toroidal vortices in the fluid cells between inserts, enhancing mixing and improving residence time behavior without stirring equipment being necessary. The parameters mash type, start-up strategy, yeast-recycle model and yeast separation were studied concerning the efficiency of the ethanol production. The best results obtained were for a filtered mash, a double saccharification principle (DSP), a batch start-up strategy, an activation recycle model and a lamella settler connected in series with a small conventional gravitational settler for yeast cells separation. Using this system, the fermentation residence time was tau=4-5.5h, depending on substrate type. Eighty five percent of the yeast cells could be separated. High volumetric ethanol productivity (Q(p)=20.43g/Lh) and yield E(y)=98% were achieved. Continuous fermentation, yeast recycling and sedimentation were contamination-free processes. PMID- 22940324 TI - Sensitivity analysis of autotrophic N removal by a granule based bioreactor: Influence of mass transfer versus microbial kinetics. AB - A comprehensive and global sensitivity analysis was conducted under a range of operating conditions. The relative importance of mass transfer resistance versus kinetic parameters was studied and found to depend on the operating regime as follows: Operating under the optimal loading ratio of 1.90(gO(2)/m(3)/d)/(gN/m(3)/d), the system was influenced by mass transfer (10% impact on nitrogen removal) and performance was limited by AOB activity (75% impact on nitrogen removal), while operating above, AnAOB activity was limiting (68% impact on nitrogen removal). The negative effect of oxygen mass transfer had an impact of 15% on nitrogen removal. Summarizing such quantitative analyses led to formulation of an optimal operation window, which serves a valuable tool for diagnosis of performance problems and identification of optimal solutions in nitritation/anammox applications. PMID- 22940325 TI - Non-equilibrium zinc uptake onto compost particles from synthetic stormwater. AB - Zinc uptake onto different particle size compost was evaluated in batch and column studies using a synthetic stormwater to quantify sorption capacity and kinetics. The results showed that the pseudo equilibrium time for uptake increased from 2h to greater than 120h as the particle size of compost increased from 75MUm to 6.75mm. This was due to intra-particle diffusion becoming a rate limiting process as the particle size increased. Column effluent data with 1.18mm particles could be fitted by Freundlich isotherm while that from the 4.75mm particles and a mixed particle size columns showed rate limited sorption with tailing and could not be adequately fitted using an equilibrium based isotherm. The results have established rate-limited sorption in amended filtration media due to larger particles under these flow conditions. This needs to be accounted for in the design of these filtration media and during performance modelling. PMID- 22940326 TI - Esterification of bio-oil from mallee (Eucalyptus loxophleba ssp. gratiae) leaves with a solid acid catalyst: Conversion of the cyclic ether and terpenoids into hydrocarbons. AB - Bio-oil from pyrolysis of mallee (Eucalyptus loxophleba ssp. gratiae) leaves differs from that obtained with wood by its content of cyclic ethers, terpenoids and N-containing organic compounds. Upgrading of the leaf bio-oil in methanol with a solid acid catalyst was investigated and it was found that the N containing organics in the bio-oil lead to deactivation of the catalyst in the initial stage of exposure and have to be removed via employing high catalyst loading to allow the occurrence of other acid-catalysed reactions. Eucalyptol, the main cyclic ether in the bio-oil, could be converted into the aromatic hydrocarbon, p-cymene, through a series of intermediates including alpha terpineol, terpinolene, and alpha-terpinene. Various steps such as ring-opening, dehydration, isomerisation, and aromatization were involved in the conversion of eucalyptol. The terpenoids in bio-oil could also be converted into aromatic hydrocarbons that can serve as starting materials for the synthesis of fine chemicals, via the similar processes. PMID- 22940327 TI - Isolation and characterization of a lipopeptide bioemulsifier produced by Pseudomonas nitroreducens TSB.MJ10 isolated from a mangrove ecosystem. AB - Pseudomonas nitroreducens TSB.MJ10 exhibiting growth and bioemulsifier production with 0.5% sodium benzoate as the sole carbon source was isolated from a mangrove ecosystem in the vicinity of a petroleum pump. The bioemulsifier is a lipopeptide that is stable over a pH range of 5-11 and a temperature range of 20-90 degrees C and showed emulsifying activity in the presence of relatively high NaCl concentrations (up to 25%). The bioemulsifier formed stable emulsions with aliphatic (hexadecane, n-heptane, cyclohexane), aromatic (xylene, benzene, toluene) and petroleum (gasoline, diesel, kerosene, crude oil) compounds. It exhibited a maximum emulsification activity with weathered crude oil (97%) and was capable of transforming the rheological behavior of the pseudoplastic to a Newtonian fluid. The results reveal the potential of the bioemulsifier for use in bioremediation of hydrocarbons in marine environments and in enhanced oil recovery. PMID- 22940328 TI - The effect of pH control and 'hydraulic flush' on hydrolysis and Volatile Fatty Acids (VFA) production and profile in anaerobic leach bed reactors digesting a high solids content substrate. AB - The effect of hydraulic flush and pH control on hydrolysis, Volatile Fatty Acids (VFA) production and profile in anaerobic leach bed reactors was investigated for the first time. Six reactors were operated under different regimes for two consecutive batches of 28days each. Buffering at pH ~6.5 improved hydrolysis (Volatile Solid (VS) degradation) and VFA production by ~50%. Butyric and acetic acid were dominant when reactors were buffered, while only butyric acid was produced at low pH. Hydraulic flush enhanced VS degradation and VFA production by ~15% and ~32%, respectively. Most Probable Number (MPN) of cellulolytic microorganisms indicated a wash out when hydraulic flush was applied, but pH control helped to counteract this. The highest VS degradation (~89%), VFA yield (0.84kgCODkg(-1)VS(added)) and theoretical methane potential (0.37m(3)CH(4)kg( 1)VS(added)) were obtained when pH control and hydraulic flush were applied, and therefore, these conditions are recommended. PMID- 22940329 TI - Electrofiltration as a purification strategy for microbial poly-(3 hydroxybutyrate). AB - The biodegradable polyester poly-(3-hydroxybutyrate) (PHB), produced by Ralstonia eutropha in batch and fed-batch processes, was purified by electrofiltration. The protein film on PHB granules determines their high negative zeta potential, enabling the application of electrofiltration as an integrated technology in the downstream processing of PHB. In order to determine the optimal purification parameters, various pressure and electric field strength conditions were tested. Electrofiltration of PHB at 4bars and 4V/mm provided an up to four times higher concentration factor than conventional filtration. FT-Raman spectroscopy demonstrated that electrofiltration did not result in structural changes to the products. The study demonstrates the efficiency and practical advantages of electrofiltration as a promising downstream step in the PHB production technology. PMID- 22940330 TI - Lipid production by Chlorella vulgaris after a shift from nutrient-rich to nitrogen starvation conditions. AB - A two-stage process, composed of growth under nutrient-rich conditions followed by cultivation under nitrogen starvation and controlled conditions of phosphate, light intensity, aeration, and carbon sources was applied for lipid production by the green alga Chlorella vulgaris. Using conditions without addition of nitrogen, 2mg/L PO(4)-P, light intensity of 100MUmol/m(2)/s and 0.25vvm of air, about 43% of dry cell weight accumulated as lipids after 12h, which equates to a lipid productivity of 77.8mg/L/d. In a medium containing 5mg/L NO(3)-N and 2mg/L PO(4) P, and at a light intensity of 100MUmol/m(2)/s and 0.25vvm of 2% CO(2), about 53% of dry cell weight consisted of lipids after 24h, representing a lipid productivity of 77.1mg/L/d. The low amount of nutrients, moderate aeration and light intensity were helpful for increasing lipid productivity. PMID- 22940331 TI - A strategy for enrichment of the bioactive sphingoid base-1-phosphates produced by Hypericum perforatum L. in a balloon type airlift reactor. AB - An efficient enrichment method using immobilized metal affinity chromatography (IMAC) was developed for selective extraction of bioactive sphingoid base-1 phosphates (SB1Ps) from adventitious roots of Hypericum perforatum cultured in bioreactor. The phosphate-selective IMAC enrichment coupled with LC-MS/MS enabled sensitive analysis of low-abundance SB1Ps present in the root biomass, which would not be feasible otherwise due to severe interferences from complex biological matrices. The time-dependent growth rate and production of SB1Ps from adventitious roots were investigated. The level of phytosphingosine-1-phosphate, which was found to be the major SB1Ps, reached a maximum amount of 635.6pmolpergram of dry weight after 3weeks of culture and decreased between 3 and 5weeks of culture subsequently. On the other hand, sphingosine-1-phosphate and sphinganine-1-phosphate were present at levels of 18.91 and 73.15pmolpergram of dry weight, respectively, after a week of culture and their level decreased thereafter. PMID- 22940333 TI - Reactivity of syringyl and guaiacyl lignin units and delignification kinetics in the kraft pulping of Eucalyptus globulus wood using Py-GC-MS/FID. AB - Eucalyptus globulus sapwood and heartwood showed no differences in lignin content (23.0% vs. 23.7%) and composition: syringyl-lignin (17.9% vs. 18.0%) and guaiacyl lignin (4.8% vs. 5.2%). Delignification kinetics of S- and G-units in heartwood and sapwood was investigated by Py-GC-MS/FID at 130, 150 and 170 degrees C and modeled as double first-order reactions. Reactivity differences between S and G units were small during the main pulping phase and the higher reactivity of S over G units was better expressed in the later pulping stage. The residual lignin composition in pulps was different from wood or from samples in the initial delignification stages, with more G and H-units. S/G ratio ranged from 3 to 4.5 when pulp residual lignin was higher than 10%, decreasing rapidly to less than 1. The S/H was initially around 20 (until 15% residual lignin), decreasing to 4 when residual lignin was about 3%. PMID- 22940332 TI - Efficacy and reusability of alginate-immobilized live and heat-inactivated Trichoderma asperellum cells for Cu (II) removal from aqueous solution. AB - Cu(II) removal efficacies of alginate-immobilized Trichoderma asperellum using viable and non-viable forms were investigated with respect to time, pH, and initial Cu(II) concentrations. The reusability potential of the biomass was determined based on sorption/desorption tests. Cu(II) biosorption by immobilized heat-inactivated T. asperellum cells was the most efficient, with 134.22mg Cu(II) removed g(-1) adsorbent, compared to immobilized viable cells and plain alginate beads (control) with 105.96 and 94.04mg Cu(II) adsorbed g(-1) adsorbent, respectively. Immobilized non-viable cells achieved equilibrium more rapidly within 4h. For all biosorbents, optimum pH for Cu(II) removal was between pH 4 and 5. Reusability of all biosorbents were similar, with more than 90% Cu(II) desorbed with HCl. These alginate-immobilized cells can be applied to reduce clogging and post-separation process incurred from use of suspended biomass. PMID- 22940334 TI - Mathematical relationships between spore concentrations, delta-endotoxin levels, and entomotoxicity of Bacillus thuringiensis preparations produced in different fermentation media. AB - Mathematic relationships between spore concentrations, delta-endotoxin concentrations and entomotoxicity (Tx) of Bacillus thuringiensis var. kurstaki HD 1 (Btk HD-1) preparations produced in six different media were analysed. The relationship between delta-endotoxin and spore concentration and SpTx-spore (specific Tx per 1000 spore) and spore concentration produced in the different media (starch industry wastewater (SIW) with total solids (TS) concentration of 15g/L, SIW with TS of 30g/L, SIW supplemented with 0.2% (w/v) colloidal chitin, SIW supplemented with 1.25% (w/v) cornstarch and 0.2% (v/v) Tween 80, secondary sludge, and semi-synthetic medium) strictly followed the Power law. Tx and delta endotoxin concentration followed the exponential relation whereas a definite relation between Tx and spore concentration could not be established. Spore and delta-endotoxin produced at the early time (12h) during fermentation might be more toxic than those produced during latter period of fermentation irrespective of media used. Tx and delta-endotoxin concentration exhibited a semi-log linear relationship. Based on these findings, delta-endotoxin concentration can be determined rapidly to monitor the progress of the biopesticide production process. PMID- 22940335 TI - The structure, density and settlability of anammox granular sludge in high-rate reactors. AB - Microscopic observation and settling test were carried out to investigate the structure, density and settlability of anammox granules taken from a high-rate upflow anaerobic sludge blanket (UASB) reactor. The results showed that the anammox granules were irregular in shape and uneven on surface, and their structure included granule, subunit, microbial cell cluster and single cell. The gas pockets were often observed in the anammox granules, and they originated from the obstruction of gas tunnel by extracellular polymer substances (EPSs) and the inflation of produced dinitrogen gas. The volume of gas pockets became larger with the increasing diameter of anammox granules, which led to the decreasing density and the floatation of anammox granules. The diameter of anammox granules should be controlled at less than 2.20mm to avoid the granule floatation. A hypothesized mechanism for the granulation and floatation of anammox biomass was proposed. PMID- 22940336 TI - Comparison of Escherichia coli and anaerobic consortia derived from compost as anodic biocatalysts in a glycerol-oxidizing microbial fuel cell. AB - Using glycerol from biodiesel production as a fuel in a microbial fuel cell (MFC) will generate electricity and value-added by-products from what is currently considered waste. This research screened Escherichia coli W3110 (ATCC 27325) and a mixed culture enriched from compost (AR2) as anodic biocatalysts in a mediatorless glycerol-oxidizing MFC. In an H-type MFC, the mixed culture AR2 biocatalyst produced a maximum power density of 11.7mWm(-2) compared to 9.8mWm( 2) using E. coli W3110 as the anodic catalyst. In batch operation of the fuel cell, the mixed culture AR2 was able to anaerobically consume 29g/L of glycerol compared to only 3.3g/L using the E. coli strain. The mixed culture was also shown to concurrently produce 1,3-propanediol, a value-added product, and electricity from a pure glycerol feedstock in an MFC. PMID- 22940337 TI - FeCl3 and acetic acid co-catalyzed hydrolysis of corncob for improving furfural production and lignin removal from residue. AB - In order to increase furfural yield and lignin removal, both FeCl(3) and acetic acid were used to co-catalyze the hydrolysis of corncob. A series of experiments were carried out to investigate the effects of acetic acid, FeCl(3) concentrations and temperatures on furfural production and residue characteristics. The results showed that high FeCl(3) concentrations caused serious cellulose degradation while acetic acid was more effective for lignin removal. A maximum furfural yield of 67.89% (35.74% higher than that in conventional sulfuric acid-catalyzed process) was obtained at 180 degrees C in the presence of 20mM of FeCl(3) and 3% of acetic acid. Simultaneously, lignin removal reached 54.79%, and 74.29% of the cellulose was remained for further utilization. Acetic acid and FeCl(3) co-catalyzed hydrolysis was not only a high efficiency and environmental friendly technique, but also provided a possibility to utilize the furfural residue for ethanol production and other industries. PMID- 22940338 TI - Efficient production of biodiesel from waste grease: one-pot esterification and transesterification with tandem lipases. AB - A novel concept and efficient method for producing biodiesel (FAME) from grease (15-40wt% free fatty acid, FFA) were developed by using tandem lipases for one pot esterification of FFA and transesterification of triglyceride with methanol in a solvent-free system. Combining immobilized Candida antarctica lipase B (CALB) (Novozyme 435) favoring the esterification and immobilized Thermomyces lanuginosus lipase (TLL) (Lipozyme TLIM) preferring the transesterification at 2:8 (wt/wt) gave FAME in 80% yield, being better than that with Novozyme 435 or Lipozyme TLIM. Recombinant Escherichia coli (Calb/Tll) co-expressing CALB and TLL was engineered as a more efficient tandem-lipases system. Using wet or dry cells (4wt%) gave FAME in 87% or 95% yield, which is much better than that with E. coli cells expressing either CALB or TLL alone. Cells of E. coli (Calb/Tll) were recycled for five times and retained 75% productivity, thus being practical for producing biodiesel from grease. PMID- 22940339 TI - Measuring the concentration of carboxylic acid groups in torrefied spruce wood. AB - Torrefaction is moderate thermal treatment (~200-300 degrees C) to improve the energy density, handling and storage properties of biomass fuels. In biomass, carboxylic sites are partially responsible for its hygroscopic. These sites are degraded to varying extents during torrefaction. In this paper, we apply methylene blue sorption and potentiometric titration to measure the concentration of carboxylic acid groups in spruce wood torrefied for 30min at temperatures between 180 and 300 degrees C. The results from both methods were applicable and the values agreed well. A decrease in the equilibrium moisture content at different humidity was also measured for the torrefied wood samples, which is in good agreement with the decrease in carboxylic acid sites. Thus both methods offer a means of directly measuring the decomposition of carboxylic groups in biomass during torrefaction as a valuable parameter in evaluating the extent of torrefaction which provides new information to the chemical changes occurring during torrefaction. PMID- 22940340 TI - Chemometric formulation of bacterial consortium-AVS for improved decolorization of resonance-stabilized and heteropolyaromatic dyes. AB - A bacterial consortium-AVS, consisting of Pseudomonas desmolyticum NCIM 2112, Kocuria rosea MTCC 1532 and Micrococcus glutamicus NCIM 2168 was formulated chemometrically, using the mixture design matrix based on the design of experiments methodology. The formulated consortium-AVS decolorized acid blue 15 and methylene blue with a higher average decolorization rate, which is more rapid than that of the pure cultures. The UV-vis spectrophotometric, Fourier transform infra red spectrophotometric and high performance liquid chromatographic analysis confirm that the decolorization was due to biodegradation by oxido-reductive enzymes, produced by the consortium-AVS. The toxicological assessment of plant growth parameters and the chlorophyll pigment concentrations of Phaseolus mungo and Triticum aestivum seedlings revealed the reduced toxic nature of the biodegraded products. PMID- 22940341 TI - Comparative performance of UASB and anaerobic hybrid reactors for the treatment of complex phenolic wastewater. AB - The performance of an upflow anaerobic sludge blanket (UASB) reactor and an anaerobic hybrid reactor (AHR) was investigated for the treatment of simulated coal wastewater containing toxic phenolics at different hydraulic retention times (0.75-0.33d). Fast start-up and granulation of biomass could be achieved in an AHR (45d) than UASB (58d) reactor. Reduction of HRT from 1.5 to 0.33d resulted in a decline in phenolics removal efficiency from 99% to 77% in AHR and 95% to 68% in UASB reactor respectively. AHR could withstand 2.5 times the selected phenolics loading compared to UASB reactor that could not withstand even 1.2 times the selected phenolics loading. Residence time distribution (RTD) study revealed a plug flow regime in the AHR and completely mixed regime in UASB reactor respectively. Energy economics of the reactors revealed that 12,159MJd( 1) more energy can be generated using AHR than UASB reactor. PMID- 22940342 TI - Biochemical characterization of consortium compost of toxic weeds Parthenium hysterophorus and Eichhornia crassipe. AB - Parthenium hysterophorus and Eichhornia crassipes are two uncontrolled weeds with high concentration of N, P, K, Zn and Fe that makes them suitable for composting. Three types of compost viz. Parthenium and Eichhornia each alone as well as combined were prepared. Biochemical and enzymatic analysis of the compost in addition to seed germination was performed. Phenols, organic carbon, C/N and C/P ratios were found to decrease significantly while N, P, K, polyphenol oxidase increased significantly in combined compost. Furthermore, seed germination test of Vigna radiata and Triticum seeds, revealed a significant increase in root, shoot length and germination index in 60days old combined compost. It can be concluded that combined composting of Parthenium with Eichhornia not only reduces the allelopathic effect but also increases its nutrient quality and thus could be promising for organic farming and bioremediation. PMID- 22940343 TI - Development and validation of a minimal growth medium for recycling Chlorella vulgaris culture. AB - When microalgae culture medium is recycled, ions (e.g. Na(+), K(+), Ca(2+)) that were not assimilated by the microalgae accumulate in the medium. Therefore, a growth medium (HAMGM) was developed that included ions that were more easily assimilated by Chlorella vulgaris, such as ammonium one (NH(4)(+)). Recycling performance was studied by carrying out 8-week continuous cultivation of C. vulgaris with recycled HAMGM medium. No loss of biomass productivity was observed compared to culture in a conventional medium, and accumulation of ions over time was negligible. PMID- 22940344 TI - Effects of step-feed on granulation processes and nitrogen removal performances of partial nitrifying granules. AB - Two anoxic/oxic sequencing batch reactors (A/O SBRs) were operated to investigate the effects of step-feed on granulation processes and performances of partial nitrifying granules (PNG). R1 was operated in a traditional single-feed mode, while a two-step-feed strategy was used in R2. Results showed that R1 had a faster granulation process and better performance in maintaining partial nitrification compared with R2, indicating that the step-feed mode had a negative effect of on formation of PNG. However, after full granulation, PNG in both reactors had similar properties in terms of suspended solids (MLSS), sludge volume index (SVI) and granule size. Moreover, mature granules in R2 had a higher nitrite accumulation rate than that in R1. Step-feed strategy was also observed to enhance denitrification and TN removal, as well as ammonia oxidation. It can be concluded that step-feed was unfavorable for cultivating PNG, but it significantly improved the nitrogen removal performance of PNG. PMID- 22940345 TI - Concentration of lignocellulosic hydrolyzates by solar membrane distillation. AB - A small solar energy collector was run to heat lignocellulosic hydrolyzates through an exchanger, and the heated hydrolyzate was concentrated by vacuum membrane distillation (VMD). Under optimal conditions of velocity of 1.0m/s and 65 degrees C, glucose rejection was 99.5% and the flux was 8.46Lm(-2)h(-1). Fermentation of the concentrated hydrolyzate produced 2.64 times the amount of ethanol as fermentation using the original hydrolyzate. The results of this work indicated the possibility to decrease the thermal energy consumption of lignocellulosic ethanol through using VMD. PMID- 22940346 TI - Evaluating the potential use of myxomycetes as a source of lipids for biodiesel production. AB - The myxomycetes are a group of primitive phagotrophic eukaryotes characterized by a distinctive plasmodial stage that is well known for its rapid growth rate. In the present study, biomass and lipid production of several different species of myxomycetes were investigated. Physarum polycephalum was found to produce the highest amounts of both dry biomass (1.30g), and lipid (0.143g) per 20mL medium (equal to 65.0g biomass and 7.15g lipid per one liter of medium). Analysis of P. polycephalum lipids by thin layer chromatography (TLC) and fatty acid methyl esters (FAMES) by gas chromatography-mass spectrometry (GC-MS) techniques showed that the major lipid type is triglyceride (95.5%), followed by phospholipids (2.6%); diglyceride (0.92%) and monoglyceride (0.92%). Myxomycete lipids consist of three dominant fatty acids: oleic (20%), linoleic (33%), and palmitoleic (17%). These results suggest that P. polycephalum has considerable potential as a source of lipids for biodiesel production. PMID- 22940347 TI - Inhibition of xyloglucanase from an alkalothermophilic Thermomonospora sp. by a peptidic aspartic protease inhibitor from Penicillium sp. VM24. AB - A bifunctional inhibitor from Penicillium sp VM24 causing inactivation of xyloglucanase from Thermomonospora sp and an aspartic protease from Aspergillus saitoi was identified. Steady state kinetics studies of xyloglucanase and the inhibitor revealed an irreversible, non-competitive, two-step inhibition mechanism with IC(50) and K(i) values of 780 and 500nM respectively. The interaction of o-phthalaldehyde (OPTA)-labeled xyloglucanase with the inhibitor revealed that the inhibitor binds to the active site of the enzyme. Far- and near UV spectrophotometric analysis suggests that the conformational changes induced in xyloglucanase by the inhibitor may be due to irreversible denaturation of enzyme. The bifunctional inhibitor may have potential as a biocontrol agent for the protection of plants against phytopathogenic fungi. PMID- 22940348 TI - Efficient single-stage autotrophic nitrogen removal with dilute wastewater through oxygen supply control. AB - Autotrophic nitrogen removal via ammonia oxidizing (AOB) and anaerobic ammonium oxidizing (anammox) bacteria was evaluated for treatment of a dilute 50mg/L ammonia-containing solution in a single-stage nitrogen-removal filter at 25 degrees C. Important was an external oxygenation system that permitted close control and measurement of oxygen supply, a difficulty with the generally used diffused air systems. Hydraulic retention time (HRT) was reduced in steps from 15 to 1h. At 1h HRT, total nitrogen (TN) removals varied between 73% and 94%, the maximum being obtained with a benchmark oxygenation ratio of 0.75mol O(2)/mol ammonia fed. At higher ratios, nitrate was formed causing TN removal efficiency to decrease. With lower ratios, TN and ammonia removals decreased in proportion to the decrease in BOR. When operating at or below the BOR, nitrate formation equaled no more than 2% of the ammonia removed, a value much less than has previously been reported. PMID- 22940349 TI - Long-term evaluation of a 10-liter serpentine-type microbial fuel cell stack treating brewery wastewater. AB - A 10-liter serpentine-type microbial fuel cell (MFC) stack was constructed by extending 40 tubular air-cathode MFC units in a 3-D alignment pattern. When operated in series and fed with brewery wastewater, the stack produced an open circuit voltage of 23.0V and a maximum power density of 4.1W/m(3) (at 0.7A/m(3)). During long-term performance (180days), electrochemical tests were conducted to explore the reasons for deterioration in performance of the stack system. Cyclic voltammetric measurements suggested that the cathodes, not the anodes, were responsible for the decrease in performance over time. After the cathode surface was rinsed with water, the power density produced by the stack system fully recovered instantaneously, due to the decrease in cathode alkalization and increase in humidity of the cathode side. This study provided an optimal configuration of a MFC stack for MFC scale-up towards large-scale applications. PMID- 22940350 TI - Gas-liquid countercurrent integration process for continuous biodiesel production using a microporous solid base KF/CaO as catalyst. AB - A continuous-flow integration process was developed for biodiesel production using rapeseed oil as feedstock, based on the countercurrent contact reaction between gas and liquid, separation of glycerol on-line and cyclic utilization of methanol. Orthogonal experimental design and response surface methodology were adopted to optimize technological parameters. A second-order polynomial model for the biodiesel yield was established and validated experimentally. The high determination coefficient (R(2)=98.98%) and the low probability value (Pr<0.0001) proved that the model matched the experimental data, and had a high predictive ability. The optimal technological parameters were: 81.5 degrees C reaction temperature, 51.7cm fill height of catalyst KF/CaO and 105.98kPa system pressure. Under these conditions, the average yield of triplicate experiments was 93.7%, indicating the continuous-flow process has good potential in the manufacture of biodiesel. PMID- 22940351 TI - Biofiltration of ethyl acetate by Pseudomonas putida immobilized on walnut shell. AB - A biofilter packed with walnut shells was used to eliminate ethyl acetate from an air stream. The shells treated with NaOH were used as medium for immobilization of Pseudomonas putida PTCC 1694. At an empty bed residence time (EBRT) of 60s, a removal efficiency of 99% was achieved at inlet concentrations lower than 430ppm of ethyl acetate. The removal efficiency decreased below 80% with an increase in inlet concentration of ethyl acetate. When the EBRT was increased to 75 s, the removal efficiency remained above 80% even though the inlet loading rate was increased to 421g/m(3)h. Michaelis-Menten type and zero-order diffusion limited models were employed and the predicted data perfectly matched the experimental data. Thus P. putida immobilized on walnut shell has potential for the removal of ethyl acetate from air streams. PMID- 22940352 TI - Effect of hydrothermal pretreatment of sunflower oil cake on biomethane potential focusing on fibre composition. AB - The aim of this study was to elucidate the effect of hydrothermal pretreatment at 25, 100, 150 and 200 degrees C on fibre composition and the biomethane potential of sunflower oil cake (SuOC). An increase in pretreatment temperature from 25 to 200 degrees C caused a decrease in hemicellulose content in the solid pretreated fraction from 13 to 6% while the lignin content increased by 16%. Soluble compounds also increased with temperature. Digestion of solid fractions from pretreatments at 25, 100, 150 and 200 degrees C in batch assays at 35+/-1 degrees C resulted in methane yields of 114+/-9, 105+/-7, 82+/-7 and 53+/-8mL CH(4) g( 1)COD(added), respectively. The corresponding methane yields for the liquid fractions were 276+/-6, 310+/-4, 220+/-15 and 247+/-10mL CH(4) g(-1)COD(added), respectively. Therefore the overall methane yield was highest for SuOC pretreated at 100 degrees C; however, this value was only 6.5% higher than that achieved after pretreatment at 25 degrees C. PMID- 22940353 TI - Biomass-to-electricity: analysis and optimization of the complete pathway steam explosion--enzymatic hydrolysis--anaerobic digestion with ICE vs SOFC as biogas users. AB - The paper deals with the energy analysis and optimization of a complete biomass to-electricity energy pathway, starting from raw biomass towards the production of renewable electricity. The first step (biomass-to-biogas) is based on a real pilot plant located in Environment Park S.p.A. (Torino, Italy) with three main steps ((1) impregnation; (2) steam explosion; (3) enzymatic hydrolysis), completed by a two-step anaerobic fermentation. In the second step (biogas-to electricity), the paper considers two technologies: internal combustion engines and a stack of solid oxide fuel cells. First, the complete pathway has been modeled and validated through experimental data. After, the model has been used for an analysis and optimization of the complete thermo-chemical and biological process, with the objective function of maximization of the energy balance at minimum consumption. The comparison between ICE and SOFC shows the better performance of the integrated plants based on SOFC. PMID- 22940354 TI - Pyrolysis characteristics and kinetics of the alga Saccharina japonica. AB - Saccharina japonica can be converted to bio-oil, gas, and char through pyrolysis. In this study, the pyrolysis characteristics of S. japonica were investigated using a thermogravimetric analyzer. Most of the materials decomposed between 200 degrees C and 350 degrees C at heating rates of 10-20 degrees C/min. The apparent activation energy increased from 102.5kJmol(-1) to 269.7kJmol(-1) with increasing pyrolysis conversion. The kinetic parameters of S. japonica pyrolysis were determined using nonlinear least-squares regression of the experimental data assuming first-order kinetics. The kinetic rate constants indicated that the predominant reaction pathway was B (bio-oil) to C (gas; C(1)-C(4)), rather than A (S. japonica) to B (bio-oil) and/or to C (gas; C(1)-C(4)). The proposed lumped kinetics of S. japonica pyrolysis offers a guide for the scale-up of the process at the research and industrial level. PMID- 22940355 TI - Modeling wastewater biodecolorization with reactive blue 4 in fixed bed bioreactor by Trametes subectypus: biokinetic, biosorption and transport. AB - A biodecolorization model that considers the simultaneous mechanism of biosorption and biodegradation of a synthetic dye by immobilized white-rot fungus Trametes subectypus B32 in a fixed bed bioreactor was developed. The model parameters (biokinetic, biosorption and macroscopic transport) were determined by independent experiments. The biodecolorization model was used to determine the effect of variables such as immobilized biomass content, volumetric flow of wastewater, dye feeding concentration and initial dye concentration. By means of the model was possible to predict in the steady state, the limits of immobilized T. subectypus to biodecolorize polluted influent, being the model predictions similar in extent to previous reports. A dimensionless module of biosorption bioreaction (phi=q(max)v(z)/r(max)L) was proposed to be used like criterion whenever one of the two mechanisms controls the biodecolorization. The model could be used for the designing and scaling up of fixed bed bioreactors with immobilized white-rot fungi for the biodecolorization process. PMID- 22940356 TI - Online monitoring of volatile organic compound production and emission during sewage sludge composting. AB - The production and emission of volatile organic compounds (VOCs) were studied using an online monitoring method in a well-operated sludge composting plant. Results indicated that VOC production within the pile was different from emission at the pile surface. The total mass of VOC production was 1.09gCkgDM(-1), which was 2.3 times as high as the total mass of emission. The maximum production and emission masses occurred in the mesophilic phase of composting and were 444 and 202mgkgDM(-1)d(-1), respectively. VOC production and emission rates also varied rapidly at different times. The relationship of VOC production rates and time in an on/off aeration cycle at different periods could be expressed as a quadratic equation, while the emission rate could be expressed as a linear equation. PMID- 22940357 TI - Pseudomonas otitidis as a potential biocatalyst for polyhydroxyalkanoates (PHA) synthesis using synthetic wastewater and acidogenic effluents. AB - Polyhydroxyalkanoates (PHA) production using Pseudomonas otitidis, a newly isolated strain from PHA producing bioreactor was investigated using synthetic acids (SA) and acidogenic effluents (AE) from biohydrogen reactor at different organic loading rates (OLRs). P. otitidis showed ability to grow and accumulate PHA, with simultaneous waste remediation. AE showed less PHA production (54%, OLR3), than SA (58%, OLR2). PHA composition showed co-polymer, poly-3(hydroxy butyrate-co-hydroxy valerate), P3(HB-co-HV). Bioprocess evaluation and enzymatic activities showed good correlation with PHA production. Kinetic studies on the growth of bacteria using different models at varying OLR were substantiated with PHA production. High substrate removal was registered at OLR1 (SA, 87%; AE, 82%). AE could be used as an alternative for pure substrates keeping in view of their high cost. PMID- 22940358 TI - Influence of terminal electron acceptor availability to the anodic oxidation on the electrogenic activity of microbial fuel cell (MFC). AB - The electrogenic activity of microbial fuel cell (MFC) with the function of anode placement from the terminal electron acceptor (TEA) was evaluated. Shorter anode distances from TEA showed higher electrogenesis due to the feasibility of higher electron acceptance as well as their discharge towards TEA. Substrate degradation was also higher at shorter anode placements from TEA due to the optimum substrate availability to the anodic biofilm. Bio-electro kinetics showed significant variation in the catalytic currents and exchange current densities with the function of anode placement indicating its role in electron acceptance and their transfer to the cathode. Anode placement of 3cm showed higher electrogenesis (406.38mW/m(2)) and substrate degradation (63.12%) along with significantly reduced polarization (6.72Omega) and charge transfer resistances compared to other anodic placements. The spacing between electrodes is crucial in accepting electrons as well as their discharge towards TEA which ultimately governs the power generation efficacy. PMID- 22940359 TI - Biochemical methane potential of microalgae: influence of substrate to inoculum ratio, biomass concentration and pretreatment. AB - The anaerobic digestion of three microalgae mixtures was evaluated at different substrate to inoculum (S/I) ratios (0.5, 1 and 3), biomass concentrations (3, 10 and 20gTS/kg) and pretreatments (thermal hydrolysis, ultrasound and biological treatment). An S/I ratio of 0.5 and 10gTS/kg resulted in the highest final methane productivities regardless of the microalgae tested (ranging from 188 to 395mL CH(4)/gVS(added)). The biological pretreatment supported negligible enhancements on CH(4) productivity, while the highest increase (46-62%) was achieved for the thermal hydrolysis. The optimum temperature of this pretreatment depended on the microalgae species. The ultrasound pretreatment brought about increases in CH(4) productivity ranging from 6% to 24% at 10,000kJ/kgTS, without further increases at higher energy inputs. The results here obtained confirmed the lack of correlation between the solubilization degree and the methane enhancement potential and pointed out that anaerobic digestion of algae after thermal pretreatment is a promising technology for renewable energy production. PMID- 22940360 TI - Performance of intermittently aerated up-flow sludge bed reactor and sequencing batch reactor treating industrial estate wastewater: a comparative study. AB - In this study, an innovative aerobic/anoxic sludge bed bioreactor with two feeding regimes, continuous-fed (an up-flow sludge bed reactor (USBR)) and batch fed (sequencing batch reactor (SBR)), was evaluated for the treatment of an industrial estate wastewater with low BOD(5)/COD ratio. The process performance in the two regimes was compared. Two numerical independent variables (retention/react time and aeration time) were selected to analyze, model and optimize the process. Response surface methodology with central composite design (CCD) was used with five levels of hydraulic retention time (HRT)/react time (12 36h) and aeration time (40-60min/h). In order to analyze the process, ten dependent parameters as the process responses were studied. As a result, HRT/react time showed a decreasing impact on the responses measured in both hydraulic regimes, USBR and SBR. The USBR showed better performance than the SBR in removal of total COD, slowly biodegradable COD, total nitrogen and total Kjeldahl nitrogen. PMID- 22940361 TI - Enhanced methane production from pig manure anaerobic digestion using fish and biodiesel wastes as co-substrates. AB - Co-digestion of pig manure (PM(1)) with fish (FW(2)) and biodiesel waste (BW(3)) was evaluated and compared with sole PM digestion. Results indicated that co digestion of PM with FW and/or BW is possible as long as ammonium and volatile fatty acids remained under inhibitory levels by adjusting the operating conditions, such as feed composition, organic loading rate (OLR) and hydraulic retention time (HRT). PM and FW co-digestion (90:10 and 95:5, w/w(4)) was possible at OLR of 1-1.5g COD/Ld, resulting in biogas production rates of 0.4-0.6 L/Ld and COD removal efficiencies of 65-70%. Regarding BW, good results (biogas production of 0.9 L/Ld and COD elimination of 85%) were achieved with less than 5% feeding rate. Overall, operating at the same OLR, the biogas production and methane content in the co-digester was higher than in the only PM digester. PMID- 22940362 TI - Sewage sludge disintegration by combined treatment of alkaline+high pressure homogenization. AB - Alkaline pretreatment combined with high pressure homogenization (HPH) was applied to promote sewage sludge disintegration. For sewage sludge with a total solid content of 1.82%, sludge disintegration degree (DD(COD)) with combined treatment was higher than the sum of DD(COD) with single alkaline and single HPH treatment. NaOH dosage ?0.04mol/L, homogenization pressure ?60MPa and a single homogenization cycle were the suitable conditions for combined sludge treatment. The combined sludge treatment showed a maximum DD(COD) of 59.26%. By regression analysis, the combined sludge disintegration model was established as 11 DD(COD)=0.713C(0.334)P(0.234)N(0.119), showing that the effect of operating parameters on sludge disintegration followed the order: NaOH dosage>homogenization pressure>number of homogenization cycle. The energy efficiency with combined sludge treatment significantly increased compared with that with single HPH treatment, and the high energy efficiency was achieved at low homogenization pressure with a single homogenization cycle. PMID- 22940363 TI - Validation of a simple model accounting for light and temperature effect on microalgal growth. AB - A new model is set up to represent the effect of temperature and light on microalgae growth, and predict the productivity of outdoor microalgae based processes. This model includes three cardinal temperatures (T(min), T(opt), and T(max)) and three parameters associated to the light response (MU(max), I(opt) and alpha). These six parameters have a clear biological meaning which makes model calibration straightforward. An algorithm to estimate both the model parameters and their associated confidence regions is developed. Results show that this model can successfully represent experimental data sets from 15 species cultivated in different experimental conditions. The model predictions, when compared to realistic temperatures recorded in outdoor photobioreactors or raceways, point out a strong decrease of productivity due to over-warming for most commercial species. PMID- 22940364 TI - Cultivation of green alga Botryococcus braunii in raceway, circular ponds under outdoor conditions and its growth, hydrocarbon production. AB - The present study focused on cultivation, seasonal variation in growth, hydrocarbon production, fatty acids profiles of Botryococcus braunii (LB-572 and N-836) in raceway & circular ponds under outdoor conditions. After 18days of cultivation the biomass yield and hydrocarbon contents were increased in both raceway and circular ponds. The fat content was found to be around 24% (w/w) with palmitic and oleic acids as prominent fatty acids. Hydrocarbons of C(20)-C(30) carbon chain length were higher in raceway and circular ponds. Maximum biomass yield (2gL(-1)) and hydrocarbon content (28%) were observed in Nov-Dec. In case of B. braunii (N-836) after 25days of cultivation the biomass yield was 1gL(-1) and hydrocarbon content was 27%. Supplementation of 0.1% NaHCO(3) in the medium resulted in biomass yield of 1.5gL(-1) and hydrocarbon content of 30% compared to control. PMID- 22940365 TI - Early warning indicators for process failure due to organic overloading by rapeseed oil in one-stage continuously stirred tank reactor, sewage sludge and waste digesters. AB - Early warning indicators for process failures were investigated to develop a reliable method to increase the production efficiency of biogas plants. Organic overloads by the excessive addition of rapeseed oil were used to provoke the decrease in the gas production rate. Besides typical monitoring parameters, as pH, methane and hydrogen contents, biogas production rate and concentrations of fatty acids; carbon dioxide content, concentrations of calcium and phosphate were monitored. The concentration ratio of volatile fatty acids to calcium acted as an early warning indicator (EWI-VFA/Ca). The EWI-VFA/Ca always clearly and reliably indicated a process imbalance by exhibiting a 2- to 3-fold increase 3-7days before the process failure occurred. At this time, it was still possible to take countermeasures successfully. Furthermore, increases in phosphate concentration and in the concentration ratio of phosphate to calcium also indicated a process failure, in some cases, even earlier than the EWI-VFA/Ca. PMID- 22940366 TI - Early hydrophobic collapse of alpha1-antitrypsin facilitates formation of a metastable state: insights from oxidative labeling and mass spectrometry. AB - The biologically active conformation of alpha1-antitrypsin (alpha1AT) and other serine protease inhibitors represents a metastable state, characterized by an exposed reactive center loop (RCL) that acts as bait for the target enzyme. The protein can also adopt an inactive "latent" conformation that has the RCL inserted as a central strand in beta-sheet A. This latent form is thermodynamically more stable than the active conformation. Nonetheless, folding of alpha1AT consistently yields the active state. The reasons that the metastable form is kinetically preferred remain controversial. The current work demonstrates that a carefully orchestrated folding mechanism prevents RCL insertion into sheet A. Temporal changes in solvent accessibility during folding are monitored using pulsed oxidative labeling and mass spectrometry. The data obtained in this way complement recent hydrogen/deuterium exchange results. Those hydrogen/deuterium exchange measurements revealed that securing of the RCL by hydrogen bonding of the first beta-strand in sheet C is one factor that favors formation of the active conformation. The oxidative labeling data presented here reveal that this anchoring is preceded by the formation of hydrophobic contacts in a confined region of the protein. This partial collapse sequesters the RCL insertion site early on and is therefore instrumental in steering alpha1AT towards its active conformation. RCL anchoring by hydrogen bonding starts to contribute at a later stage. Together, these two factors ensure that formation of the active conformation is kinetically favored. This work demonstrates how the use of complementary labeling techniques can provide insights into the mechanisms of protracted folding reactions. PMID- 22940368 TI - Concordant chemical reaction networks and the Species-Reaction Graph. AB - In a recent paper it was shown that, for chemical reaction networks possessing a subtle structural property called concordance, dynamical behavior of a very circumscribed (and largely stable) kind is enforced, so long as the kinetics lies within the very broad and natural weakly monotonic class. In particular, multiple equilibria are precluded, as are degenerate positive equilibria. Moreover, under certain circumstances, also related to concordance, all real eigenvalues associated with a positive equilibrium are negative. Although concordance of a reaction network can be decided by readily available computational means, we show here that, when a nondegenerate network's Species-Reaction Graph satisfies certain mild conditions, concordance and its dynamical consequences are ensured. These conditions are weaker than earlier ones invoked to establish kinetic system injectivity, which, in turn, is just one ramification of network concordance. Because the Species-Reaction Graph resembles pathway depictions often drawn by biochemists, results here expand the possibility of inferring significant dynamical information directly from standard biochemical reaction diagrams. PMID- 22940367 TI - The structure of human GALNS reveals the molecular basis for mucopolysaccharidosis IV A. AB - Lysosomal enzymes catalyze the breakdown of macromolecules in the cell. In humans, loss of activity of a lysosomal enzyme leads to an inherited metabolic defect known as a lysosomal storage disorder. The human lysosomal enzyme galactosamine-6-sulfatase (GALNS, also known as N-acetylgalactosamine-6-sulfatase and GalN6S; E.C. 3.1.6.4) is deficient in patients with the lysosomal storage disease mucopolysaccharidosis IV A (also known as MPS IV A and Morquio A). Here, we report the three-dimensional structure of human GALNS, determined by X-ray crystallography at 2.2A resolution. The structure reveals a catalytic gem diol nucleophile derived from modification of a cysteine side chain. The active site of GALNS is a large, positively charged trench suitable for binding polyanionic substrates such as keratan sulfate and chondroitin-6-sulfate. Enzymatic assays on the insect-cell-expressed human GALNS indicate activity against synthetic substrates and inhibition by both substrate and product. Mapping 120 MPS IV A missense mutations onto the structure reveals that a majority of mutations affect the hydrophobic core of the structure, indicating that most MPS IV A cases result from misfolding of GALNS. Comparison of the structure of GALNS to paralogous sulfatases shows a wide variety of active-site geometries in the family but strict conservation of the catalytic machinery. Overall, the structure and the known mutations establish the molecular basis for MPS IV A and for the larger MPS family of diseases. PMID- 22940369 TI - Expression and regulation of activated leukocyte cell adhesion molecule in human retinal vascular endothelial cells. AB - Activated leukocyte cell adhesion molecule (ALCAM; CD166) is an immunoglobulin superfamily member that has been described in several non-ocular endothelial populations, but not in relation to endothelium within the eye. Studies in extraocular systems have implicated ALCAM in angiogenesis and leukocyte transendothelial migration, which are key processes in retinal vascular diseases. We investigated the expression of ALCAM in human retinal endothelium, and studied the regulation of expression by established angiogenic and inflammatory stimuli. Retinal endothelial expression of ALCAM was detected in primary retinal endothelial cultures isolated from human cadavers by RT-PCR (n = 4 donors) and Western blot (n = 4 donors), and in intact human retina by immunohistochemistry (n = 3 donors). In the 4 donors studied by RT-PCR, transcript encoding the truncated soluble isoform, sALCAM, was also detected. Quantitative real-time RT PCR demonstrated significant up-regulation of ALCAM and sALCAM in response to stimulation with master cytokine, tumor necrosis factor (TNF)-alpha. However, general inflammatory stimulus, lipopolysaccharide (LPS), and the prototype Th1, Th2 and Th17 cytokines, interferon (IFN)-gamma, interleukin (IL)-4 and IL-17A, respectively, did not impact ALCAM or sALCAM expression. In contrast, expression of ALCAM was significantly up-regulated by vascular endothelial growth factor (VEGF)(165). Up-regulation in the presence of VEGF and TNF-alpha, but not LPS, IFN-gamma, IL-4 and IL-17A, suggests a potential role for ALCAM in human retinal angiogenesis in some settings. PMID- 22940370 TI - Retinal arteriolar responses to acute severe elevation in systemic blood pressure in cats: role of endothelium-derived factors. AB - The purpose of this study was to investigate the roles of endothelium-derived factors in the retinal arteriolar responses to acute severe elevation in systemic blood pressure (BP) in cats. Acute elevation of mean arterial BP by 60% for 5 min was achieved by inflating a balloon-tipped catheter in the descending aorta. The retinal arteriolar diameter, flow velocity, wall shear rate (WSR) and blood flow (RBF) changes during BP elevation were assessed with laser Doppler velocimetry 2 h after intravitreal injections of nitric oxide (NO) synthase inhibitor l-NAME, cyclooxygenase inhibitor indomethacin, endothelin-1 receptor antagonists (BQ-123 for type A and BQ-788 for type B), or Rho kinase inhibitor fasudil. BP elevation caused a marked increase in retinal arteriolar flow velocity and WSR with slight vasoconstriction, resulting in an increase in RBF. The increases in velocity, WSR and RBF, but not diameter, were correlated with the increase in ocular perfusion pressure. With l-NAME or indomethacin, the increase in RBF upon BP elevation was significantly attenuated due to enhanced retinal arteriolar vasoconstriction. In contrast, BQ-123 and fasudil potentiated the increased RBF. BQ-788 had no effect on arteriolar diameter and hemodynamics. Our data suggest that acute elevation of BP by 60% leads to an increase in RBF due to the release of NO and prostanoids probably through a shear stress-induced vasodilation mechanism. The release of endothelin-1 and Rho kinase activation help to limit RBF augmentation by counteracting the vasodilation. It appears that the retinal endothelium, by releasing vasoactive substances, contributes to RBF regulation during acute severe elevation of systemic blood pressure. PMID- 22940371 TI - Effects of grapefruit and Seville orange juices on the pharmacokinetic properties of colchicine in healthy subjects. AB - BACKGROUND: The labeling for colchicine (indicated for acute gout flares or prophylaxis) includes strict advisories regarding drug-drug and drug-food interactions, including warnings against consuming grapefruit or grapefruit juice during treatment. Two of the furocoumarins in grapefruit juice and Seville orange juice can inhibit intestinal cytochrome P450 (CYP) isozyme 3A4 and P-glycoprotein (involved in colchicine metabolism and transport). Severe toxicities in patients consuming these juices while taking other drugs metabolized through these pathways have been reported. OBJECTIVE: Two Phase I studies assessed the effects of multiple daily consumptions of Seville orange juice or grapefruit juice on the pharmacokinetic properties of colchicine in healthy volunteers. METHODS: Healthy volunteers were enrolled in 2 open-label, Phase I studies. Undiluted juice (240 mL) was administered twice daily for 4 days. Pharmacokinetic data were obtained following a single 0.6-mg dose of colchicine before the administration of juice and again following a single 0.6-mg dose of colchicine on the final day of juice administration. In each study, blood samples for pharmacokinetics were collected before dosing with colchicine and at 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 24 hours postdose. All subjects were monitored for adverse events (AEs) throughout the confinement portion of the study and were queried at the outpatient visits. AEs were coded according to corresponding MedDRA-coded system organ classes. RESULTS: Forty-four subjects received either grapefruit juice (72.7% male; 90.9% white) or Seville orange juice (62.5% female; 100% white). Although it is considered to be a moderate concentration-dependent CYP3A4 inhibitor, grapefruit juice did not significantly affect the pharmacokinetic parameters of colchicine. When colchicine was administered with Seville orange juice, a moderate inhibitor, C(max) and AUC were decreased by ~24% and ~20%, respectively. Seville orange juice also caused, on average, a 1-hour delay in T(max). Colchicine in combination with grapefruit or Seville orange juice was well tolerated. There were no significant treatment-related AEs reported, and the most likely AEs were general gastrointestinal events. CONCLUSIONS: In contrast to label warnings based on the literature, grapefruit juice did not affect the pharmacokinetics of colchicine. Seville orange juice paradoxically reduced absorption of colchicine and increased T(max), but the clinical significance of this is unknown. Contrary to the expected effects of inhibiting the enzymes that metabolize colchicine, neither juice increased exposure to colchicine. However, the absence of a positive control in these studies dictates that caution should be used when applying these results clinically. ClinicalTrials.gov identifiers: NCT00960193 and NCT00984009. PMID- 22940372 TI - Living donor kidney transplantation among ethnic minorities in the Netherlands: a model for breaking the hurdles. AB - OBJECTIVE: Despite living donor kidney transplantation (LDKT) being the optimal treatment option for patients with end-stage renal disease, we observed a significant inequality in the number of LDKT performed between patients of Dutch versus non-Dutch descent. We conducted a focus group study to explore modifiable hurdles to LDKT. METHODS: Focus group discussions and in-depth interviews were conducted among 50 end-stage renal patients. Analyses were conducted according to 'grounded theory' using Atlas.ti. RESULTS: We found nearly all patients to be in favor of LDKT (96%). However, multiple factors played a role in considering LDKT. Four potentially modifiable hurdles were derived: (1) inadequate patient education, (2) impeding cognitions and emotions, (3) restrictive social influences, and (4) suboptimal communication. With regard to solutions, we found that our patients were open to home-based group education on renal replacement therapy options (88% in favor). CONCLUSION: The study highlights the need for sensitivity and awareness of the influence of cultural factors on decision-making when discussing living donation with culturally diverse populations. PRACTICE IMPLICATIONS: Since the majority of our patients were open to a tailored group education in their own homes, we see this as an opportunity to address factors that influence equality in access to LDKT. PMID- 22940373 TI - Measuring the degree of closeness to the cancer experience: development and initial validation of the CONNection to the Experience of Cancer Scale (CONNECS). AB - OBJECTIVE: To describe the development and psychometric testing of items measuring connection to the cancer experience through a close friend or relative. METHODS: Ten items assess four aspects of connection to cancer: emotional and cognitive involvement, kind and amount of shared experience, perceived similarity to the affected person, and negative change witnessed. Interviews were conducted with 2200 women close to someone with cancer. The sample was split into two samples for exploratory and confirmatory factor analysis. Sample 1 (n=1342) was used to examine the underlying structure of the items. Sample 2 (n=858) was used for CFA. Internal consistency and reliability analysis were also conducted. RESULTS: Three factors with moderate correlation were extracted: general closeness, resemblance, and cognitive processing. Results from the CFA analysis confirmed a good fit of the three-factor model (Bentler-Bonett NIF=0.973, Bentler Bonett NNFI=0.975, RMSEA=0.040 and CFI=0.984) and all path coefficients were statistically significant. CONCLUSION: Findings provide preliminary evidence for the reliability and construct validity of the CONNECS scale in measuring individuals' connection to the cancer experience through a close friend or relative. PRACTICE IMPLICATIONS: CONNECS may be a useful tool for examining the impact of the cancer experience on risk perceptions, cancer worry, and medical decision making. PMID- 22940374 TI - African American prostate cancer survivors' treatment decision-making and quality of life. AB - OBJECTIVE: To examine African-American prostate cancer (PCa) survivors' involvement in treatment decision-making (TDM), and examine the association between TDM and quality of life (QOL), using secondary data. METHODS: African American PCa survivors (181) were recruited from the North Carolina Central Cancer Registry. Participants completed a cross-sectional survey that asked about their chosen cancer treatment, TDM factors, and PCa-specific QOL (using the Expanded Prostate Cancer Index Composite--EPIC). Multivariate analysis of covariance was conducted to determine the association between TDM and QOL, controlling for confounders. RESULTS: Most men reported being active (44.2%) or collaborative (38.1%) in TDM, while 14.4% preferred a passive role. Adjusting for marital status, education and treatment, passive patients reported somewhat better QOL compared to active patients in the following QOL domains: urinary summary (p=0.04), urinary function (p=0.01), and urinary incontinence (p=0.03). CONCLUSION: Most African-American PCa survivors preferred to be, and were, actively or collaboratively involved in TDM. However, those who preferred a passive role reported better PCa-specific QOL for the urinary domain compared to others. PRACTICE IMPLICATIONS: It is important to assess patients' TDM preference. Patients' QOL may differ by their TDM role, such that active patients may be more bothered by treatment side effects than other patients. PMID- 22940375 TI - FOLFIRI regimen: an effective second-line chemotherapy after failure of etoposide platinum combination in patients with neuroendocrine carcinomas grade 3. AB - Patients with neuroendocrine carcinomas (NECs) grade 3 have a poor prognosis. Etoposide-platinum combination is the standard chemotherapy but the role of a second-line therapy remains unknown. Irinotecan alone or in combination has shown some efficacy in patients treated for small cell lung cancer which had pathological similarities with neuroendocine tumors. The aim of this study is to determine safety and efficacy of the FOLFIRI regimen in patients with NECs grade 3 after failure of etoposide-platinum combination. This study was retrospective, including patients with NECs grade 3 and treated with the FOLFIRI regimen after progression or toxicity of etoposide-platinum combination in first-line. Patients with Eastern Cooperative Oncology Group (ECOG) performance status >=3 and/or serum alkaline phosphatase >=5*upper limit of normal value (ULN) and/or bilirubin >=1.5*ULN were excluded. Among 39 patients who failed etoposide-platinum combination, 19 (49%; 12 women, median age 53 (29-78) years) received the FOLFIRI regimen with a median number of 6 (1-16) courses. Six patients (31%) had at least one episode of grades 3-4 toxicity (neutropenia, n=3; diarrhea, n=3) without toxic death. Six patients (31%) had objective response, 6 (31%) stable disease, and 7 (38%) tumor progression. Median progression-free survival under FOLFIRI was 4 months. Overall survival was 18 vs 6.8 months in noneligible patients. FOLFIRI regimen is a safe and potentially efficient chemotherapy given as second-line in patients with NECs grade 3 who remain in good condition and with correct liver tests after failure of etoposide-platinum combination. These results should be confirmed in a future prospective study. PMID- 22940376 TI - Methicillin-resistant Staphylococcus aureus. PMID- 22940377 TI - [After titanium, peek ?]. AB - The PEEK-Optima((r)), composite mixture of polyetheretherketon and inert materials, is used in orthopedics, spinal surgery and cranio-facial surgery. It could be used in dental implantology because of its biological and mechanical properties. The results of an experimental and finite element study made on basal implant prototypes, on basal implantology show that PEEK, contrary to titanium, has a compound structure that allows to optimize the distribution of masticatory forces around the implant. These results should be confirmed by a clinical study according to research regulation. PMID- 22940379 TI - A review of the effect of immunization programs on antimicrobial utilization. AB - The objective of this review is to summarize and evaluate the literature pertaining to antimicrobial utilization with respect to implementation of immunization programs or within clinical studies assessing vaccine effectiveness. A literature search was performed using the search terms vaccine; immunization; antimicrobial; antibiotic; influenza; pneumococcal; haemophilus; meningococcal in MEDLINE (1948-May 2012), EMBASE (1980-May 2012), International Pharmaceutical Abstracts (1970-May 2012), Google, and Google Scholar. Identified clinical or epidemiological studies were included if antimicrobial utilization was listed as a reported outcome. Seven articles (three randomized controlled trials and four epidemiological studies) were identified and included in the review. These studies reported outcomes associated with pneumococcal and influenza immunization programs. All studies reported decreased antibiotic use associated with initiation of immunization programs or increased uptake of available vaccines. Large-scale epidemiological studies confirm population-wide decreases observed from short-term randomized controlled trials. Antibiotic reductions ranged from 5 to 10% in randomized controlled trials to relative reductions of 64% in epidemiological studies. These findings suggest that immunization programs may reduce antibiotic utilization. As such, vaccination status queries and updates should become part of routine care for both hospitalized and non-hospitalized patients. Immunization programs should be considered as part of institution-wide antimicrobial stewardship programs. PMID- 22940378 TI - The impact of new vaccine introduction on immunization and health systems: a review of the published literature. AB - We conducted a systematic review of the published literature to examine the impact of new vaccine introduction on countries' immunization and broader health systems. Six publication databases were searched using 104 vaccine and health system-related search terms. The search yielded 15,795 unique articles dating from December 31, 1911 to September 29, 2010. Based on review of the title and abstract, 654 (4%) of these articles were found to be potentially relevant and were referred for full review. After full review, 130 articles were found to be relevant and included in the analysis. These articles represented vaccines introduced to protect against 10 different diseases (hepatitis A, hepatitis B, Haemophilus influenzae type b disease, human papilloma virus infection, influenza, Japanese encephalitis, meningococcal meningitis, Streptococcus pneumoniae disease, rotavirus diarrhea and typhoid), in various formulations and combinations. Most reviewed articles (97 [75%]) reported experiences in high income countries. New vaccine introduction was most efficient when the vaccine was introduced into an existing delivery platform and when introduced in combination with a vaccine already in the routine childhood immunization schedule (i.e., as a combination vaccine). New vaccine introduction did not impact coverage of vaccines already included in the routine childhood immunization schedule. The need for increased cold chain capacity was frequently reported. New vaccines facilitated the introduction and widespread use of auto-disable syringes into the immunization and the broader health systems. The importance of training and education for health care workers and social mobilization was frequently noted. There was evidence in high-income countries that new vaccine introduction was associated with reduced health-care costs. Future evaluations of new vaccine introductions should include the systematic and objective assessment of the impacts on a country's immunization system and broader health system, especially in lower-income countries. PMID- 22940380 TI - US Military contributions to the global response to pandemic chikungunya. AB - Chikungunya virus, transmitted by mosquitoes to man, causes an acute illness characterized by fever, rash and striking joint symptoms. US Military investigators developed, manufactured at The Salk Institute-Government Services Division (TSI-GSD), and tested the live, attenuated Chikungunya Vaccine TSI-GSD 218. The manufacturing facility stopped production in 1994. The Chikungunya Vaccine TSI-GSD-218 development effort was terminated in 1998, and materials were archived. In 2005, an alarming outbreak of chikungunya disease began in Africa and spread to islands in the Indian Ocean and throughout much of Asia. Abrupt epidemics with high attack rates and serious, even fatal, complications were reported, and travelers carried the virus to Europe and the Americas. In response to urgent requests, the US Military offered assistance by providing non-exclusive access to the previously stored vaccine production seed materials, bulk vaccine, regulatory documentation, and reports of previous clinical trials. Five companies requested technology transfers. This experience provides lessons about epidemiological unpredictability, preparedness, vaccine manufacturing, the potential global importance of vaccine seed materials and the advisability of a global strategic plan. Consideration should be given to banking of vaccine production seeds, cell substrates, and manufacturing instructions. In view of the manufacturability, attenuation, and immunogenicity of Chikungunya Vaccine TSI-GSD 218, authorities may wish to consider this product as a possible candidate itself, as a comparator vaccine to improve upon, as a seed for inactivated vaccine, or as a source of virus or antigen for neutralization assays or immunoassays. PMID- 22940381 TI - Vaccination with the recombinant chimeric antigen recNcMIC3-1-R induces a non protective Th2-type immune response in the pregnant mouse model for N. caninum infection. AB - The major route of transmission of Neospora caninum in cattle is transplacentally from an infected cow to its progeny. Therefore, a vaccine should be able to prevent both the horizontal transmission from contaminated food or water and the vertical transmission. We have previously shown that a chimeric vaccine composed of predicted immunogenic epitopes of NcMIC3, NcMIC1 and NcROP2 (recNcMIC3-1-R) significantly reduced the cerebral infection in BALB/c mice. In this study, mice were first vaccinated, then mated and pregnant mice were challenged with 2*10(6)N. caninum tachyzoites at day 7-9 of pregnancy. Partial protection was only observed in the mice vaccinated with a tachyzoite crude protein extract but no protection against vertical transmission or cerebral infection in the dams was observed in the group vaccinated with recNcMIC3-1-R. Serological and cytokine analysis showed an overall lower cytokine level in sera associated with a dominant IL-4 expression and high IgG1 titers. Thus, the Th2-type immune response observed in the pregnant mice was not protective against experimental neosporosis, in contrary to the mixed Th1-/Th2-type immune response observed in the non-pregnant mouse model. These results demonstrate that the immunomodulation that occurs during pregnancy was not favorable for the protection against N. caninum infection conferred by vaccination with recNcMIC3-1-R. PMID- 22940382 TI - Pre-existing virus-specific CD8(+) T-cells provide protection against pneumovirus induced disease in mice. AB - Pneumoviruses such as pneumonia virus of mice (PVM), bovine respiratory syncytial virus (bRSV) or human (h)RSV are closely related pneumoviruses that cause severe respiratory disease in their respective hosts. It is well-known that T-cell responses are essential in pneumovirus clearance, but pneumovirus-specific T-cell responses also are important mediators of severe immunopathology. In this study we determined whether memory- or pre-existing, transferred virus-specific CD8(+) T-cells provide protection against PVM-induced disease. We show that during infection with a sublethal dose of PVM, both natural killer (NK) cells and CD8(+) T-cells expand relatively late. Induction of CD8(+) T-cell memory against a single CD8(+) T-cell epitope, by dendritic cell (DC)-peptide immunization, leads to partial protection against PVM challenge and prevents Th2 differentiation of PVM-induced CD4 T-cells. In addition, adoptively transferred PVM-specific CD8(+) T-cells, covering the entire PVM-specific CD8(+) T-cell repertoire, provide partial protection from PVM-induced disease. From these data we infer that antigen-specific memory CD8(+) T-cells offer significant protection to PVM induced disease. Thus, CD8(+) T-cells, despite being a major cause of PVM associated pathology during primary infection, may offer promising targets of a protective pneumovirus vaccine. PMID- 22940383 TI - Adjustment of gut hormones release pattern following a fixed mealtime change in human. AB - BACKGROUND: Gut hormones secretion is related to habitual mealtimes. However, how fast gut hormones adjust to that change when people change their fixed mealtime remains unknown. METHODS: Seven healthy male volunteers were asked to eat a test breakfast at 0700 am for 2 weeks before the start of the study. Then, their fixed mealtime was intentionally changed from 0700 am to 0900 am for next 2 weeks. Blood samples were drawn every half hour from 0500 am until next 3h after breakfast for determining gut hormone levels every week. RESULTS: After a change in fixed mealtime, the release pattern of acylated ghrelin was first adjusted identically according to the change and then total ghrelin was made. The meal related fluctuations of acylated ghrelin were delayed by 120 min from week 1 after the change, while those of total ghrelin were delayed by 60 min at week 1, by 120 min at week 2. Two weeks was not enough time to adjust completely for PYY(3-36) to the change. CONCLUSION: Two weeks is enough time until the pattern release of ghrelin, but not PYY(3-36) , is adjusted fully after a fixed mealtime change in human. PMID- 22940384 TI - [Salute to Sandor Nagy]. PMID- 22940385 TI - [Experimental studies of microcirculatory changes in the bone]. AB - INTRODUCTION/AIMS: Our aim was to characterize the periosteal microvascular reaction induced by the destruction of endosteal vasculature by reaming, and to monitor the time sequence of the events. We have also compared the microcirculatory effects of different implant materials that are most frequently employed in human endoprosthetics. MATERIALS AND METHODS: The right tibia of male Wistar rats was reamed by microsurgical means and implanted with titanium, steel alloy or polyethylene nails. Intravital videomicroscopic examinations of the anteromedial and anterolateral surfaces of the tibial periosteum were performed to evaluate the changes in the overall vascular and capillary densities. Microscopic mechanical tests were used to assess the stability of the implants. In control groups, reaming without nailing was performed and the microvascular changes were examined 6 and 12 weeks after surgery. RESULTS: Reaming alone caused a significant increase in the vascular density of the anteromedial periosteum and a bilateral increase in capillary density. Vascular density at the anteromedial side was increased after all of the implant materials applied, while only polyethylene induced remarkable increases in the capillary and vascular densities at the anterolateral side. Furthermore, polyethylene did not bring about osseointegration. CONCLUSIONS: Enhanced periosteal angiogenesis could be demonstrated after 12 weeks following tibial reaming. The compensatory microvascular reactions evoked by destruction of endosteal microcirculation of long bones are not influenced by osseo-integrative implant materials, but materials of poor osseointegration properties induce considerable compensatory increases in the microvascular density of the periosteum. PMID- 22940386 TI - [Experimental studies on microcirculatory inflammatory reactions of the urinary bladder]. AB - BACKGROUND: The vascular endothelium is a primary target of ischemia/reperfusion (IR) injury of the urinary bladder. In case of interstitial cystitis (painful bladder syndrome) or in cyclophosphamide-induced hemorrhagic cystitis, the injury is initiated at the epithelial/urothelial surface and propagates towards the interstitium, causing secondary involvement of the microvasculature. Hence the aim of our study was to assess and compare the microcirculatory aspects of the non-infectious forms of cystitis with that of IR-caused reactions. MATERIALS AND METHODS: In male Sprague-Dawley rats, interstitial cystitis was induced by intravesical instillation of protamine sulphate (2 mg in 200 MUl saline for 30 min; n = 6). In another group, cyclophosphamide (75 mg/kg, ip) was administered 24 hr prior to the experiments (n = 5). In the third group, urinary bladder ischemia was induced by 60-min occlusion of the vessels supplying the bladder (n = 5). The microcirculatory inflammatory reactions were investigated by fluorescence intravital microscopy 60 min after reperfusion and 24 hr after protamine sulphate instillation or cyclophosphamide administration, respectively. In the control group, the bladder was instilled with saline (n = 5). RESULTS: Rolling of leukocytes increased ~3-fold in the postcapillary vessels in the protamine sulphate-treated group and the increase in this parameter was ~5 and ~6.5-fold in cyclophosphamide and IR groups, respectively. The increase in leukocyte adherence reached similar, approx. 7-fold increase in each of the challenged groups. The red blood cell velocity in the capillaries decreased in the protamine sulphate and IR groups, while the velocity increased moderately in the cyclophosphamide-treated group. CONCLUSIONS: Our results demonstrate that direct endothelial injury (caused by IR), as well as protamine sulphate and cyclophosphamide administrations induce inflammatory microcirculatory changes of the urinary bladder. These observations suggest a causative role for microcirculatory disturbances in the pathogenesis of interstitial cystitis and hemorrhagic cystitis as well. PMID- 22940387 TI - [Comparative study of novel therapeutic possibilities in animal experimental model of inflammatory bowel disease]. AB - INTRODUCTION: The consequence of inflammatory bowel diseases (IBD) is cytokine mediated severe local tissue damage. Our aim was to determine the extent of inflammatory response and to influence the morphologic changes during the subacute phase of trinitro-benzene sulfonic acid (TNBS)-induced experimental colitis by oral phosphatidylcholine (PC) and N-methyl-D-aspartate (NMDA) receptor antagonist kynurenic acid therapy. METHODS: Sprague-Dawley rats were randomized to control, untreated colitis (ic TNBS), colitis fed with 2% PC-containing diet (3 days pre-treatment +3 days treatment after TNBS induction), colitis with kynurenic acid treatment (on day 6, n = 7) groups. The colitis was characterized by tissue myeloperoxidase and plasma TNF-alpha levels, the extent of tissue damage, structural changes in microvasculature (FITC-dextran staining) and mucosal injury (acridine orange staining) were determined by in vivo confocal laser scanning endomicroscopy (Optiscan Five1, Australia) and conventional histology (hematoxyilin-eosin staining). RESULTS: Significant elevation in myeloperoxidase and TNF-alpha levels with remarkable damage in epithelial structure was detected in the colitis group. Both treatment regimens significantly decreased the level of inflammatory activation but only PC pretreatment could preserve the number of goblet cells and the epithelial structure. Treatment with kynurenic acid did not alter the morphology changes. CONCLUSION: Oral PC pretreatment is a promising possibility in the therapy of IBDs through decreasing inflammatory reaction and increasing the number of goblet cells. PMID- 22940388 TI - [Clinically relevant sepsis model in minipigs]. AB - OBJECTIVE: Our aim was to develop a large animal model of sepsis induced by fecal peritonitis, which reproduces the characteristic macrohemodynamic, microcirculatory and inflammatory changes seen in human sepsis. MATERIALS AND METHODS: Anesthetized minipigs were subjected to fecal peritonitis (n = 9; 0.5 g/kg i.p. autofeces) or sham-operation (i.p. saline, n = 6). Invasive hemodynamic monitoring was started with regular blood gas analyses between the 15-24 hr of the insult. Sublingual microcirculation was characterized by red blood cell velocity changes (with orthogonal polarization spectral imaging), and the extravascular lung water index (EVLWI) was measured. The plasma levels of big endothelin (big-ET) and high-mobility group box protein-1 (HMGB1) were determined from venous blood samples. RESULTS: The mean arterial pressure gradually decreased below 70 mmHg in septic animals, while the heart rate and cardiac output increased constantly. In spite of the hyperdynamic reaction, significant elevation of the EVLWI was observed, while the sublingual microcirculation deteriorated, as compared with the control group. The big-ET and HMGB1 plasma concentrations were significantly elevated between 6-24 hr of peritonitis. CONCLUSION: The in vivo data suggest that our fecal peritonitis-induced experimental sepsis model is of clinical relevance, and may play useful roles in the development of novel, sepsis-related therapies. PMID- 22940389 TI - [Characterization of the antiinflammatory properties of methane inhalation during ischaemia-reperfusion]. AB - INTRODUCTION: Gastrointestinal methane generation has been demonstrated in various conditions, but it is not known whether it has any impact on the mammalian physiology or pathophysiology. Our aim was to characterize the effects of exogenous methane on the process of inflammatory events induced by reoxygenation in a canine model of ischemia-reperfusion. MATERIALS AND METHODS: Sodium pentobarbital-anesthetized inbred beagle dogs (n = 18) were randomly assigned to sham-operated or ischemia-reperfusion (I/R) groups. I/R was induced by occluding the superior mesenteric artery for 1 h, and the subsequent reperfusion was monitored for 3 h. For 5 min before reperfusion, the animals were mechanically ventilated with normoxic artificial air with or without 2.5% methane. The macrohemodynamics and small intestinal pCO2 gap changes were recorded and tissue superoxide and nitrotyrosine levels and myeloperoxidase activity changes were determined in intestinal biopsy samples. Structural mucosal damage was measured via light microscopy and HE staining. RESULTS: Methane inhalation positively influenced the macrohemodynamic changes, significantly reduced the intestinal pCO2 gap changes and the magnitude of the tissue damage after reperfusion. Further, the intestinal myeloperoxidase activity, the superoxide and nitrotyrosine levels were reduced. CONCLUSIONS: These data demonstrate the anti-inflammatory profile of methane. The study provides evidence that exogenous methane modulates leukocyte activation and affects key events of I/R-induced oxidative and nitrosative stress. PMID- 22940390 TI - [In vitro development of laparoscopic skills]. AB - Minimally invasive surgery is a popular alternative to open surgical procedures. Laparoscopic surgeries require highly skilled surgeons with solid theoretical background and significant amount of practice. Pelvitrainers or simulators provide a good opportunity for practicing and developing laparoscopic skills. Laparoscopic training of medical students of the Semmelweis University is performed at the Institute of Experimental Surgery and Surgical Techniques on Apollo pelvitrainers. The trainer, the performed exercises and the time limits have to be validated by several measurements. Statistical evaluation of the results provides a possibility for the numerical evaluation of surgical skills as well as validating the usability of the pelvitrainer. In our study we tested the peg transfer exercise in pelvitrainers on four groups with different surgical background and level of expertise, complete novices (50 persons), medical students (326 persons), surgical residents (15), and experienced surgeons (4), respectively. A time limit of 240 s was defined for novices and 100 s for professionals. During the evaluation of the results the average time and the number of errors were calculated. The mean completion time of amateurs was 365.7 +/- 130 s (mean +/- standard deviation), with 2.57 errors. The performance of medical students was characterized by 159.3 +/- 61.1 s average time with 1.21 errors, the completion time of residents was 257.9 +/- 75.7 s with 1.13 error points, and 117.2 +/- 29.1 s for the surgeons. These data show significant differences between the group, except between the results of medical students and surgeons. We plan to extend this study with the inclusion of more, experienced surgeons. PMID- 22940391 TI - [Predictive factors of invasion with initial diagnosis of ductal carcinoma in situ based on core biopsy]. AB - INTRODUCTION: Previous studies suggest that sentinel lymph node biopsy (SLNB) should not be performed in case of pure ductal carcinoma in situ (DCIS) routinely. In order to avoid a second operation for invasive cancer detected postoperatively the chance of invasion need to be determined preoperatively. The purpose of our retrospective study was to evaluate the sensitivity of core biopsy and determine the predictive value of clinical and histological factors of invasion in cases when DCIS diagnosed preoperatively. MATERIAL AND METHODS: Between January 2006 and December 2011, 1311 patients were treated for breast cancer in our institute, of whom preoperative core biopsy showed DCIS in 50 cases. Wide excision or quadrantectomy was performed in 41 cases, re-excision was necessary in 6 cases for positive surgical margins and mastectomy was carried out in four patients for multicentricity. In further 9 cases extensive tumour size indicated mastectomy straight away. SLNB was carried out in 31 patients, axillary block dissection (ABD) in 8 patients, while ABD for positive sentinel nodes in another two cases. Pathology showed invasion in 17 (34,7 %) cases. RESULTS: Multivariate analysis showed that tumour grade, symptomatic disease, patients' age were significant predictors of invasion. Although preoperative tumour size also showed correlation with invasiveness, this was statistically not significant. CONCLUSION: Evaluation of a larger patient population might be helpful to identify women who should undergo tumour excision and SLNB as a single step operation due to increased risk of invasive disease despite the preoperative diagnosis of DCIS. PMID- 22940392 TI - [Postconditioning -- effective method against distant organ dysfunction?]. AB - INTRODUCTION: The ischemia-reperfusion injury of the small intestine is a condition of high mortality, which occurs following superior mesenteric artery (SMA) embolization or circulatory redistribution. The aim of the study was to evaluate the local and systemic effects of postconditioning in a rat model of small intestine ischemia-reperfusion. METHODS: Male Wistar rats underwent 60 min ischemia by the clamping of the SMA, followed by 6 hrs of reperfusion. The animals (n = 30) were randomized into three groups: sham-operated, control-, and postconditioned. Postconditioning was performed at the very onset of reperfusion by 6 alternating cycles of 10-10 seconds reperfusion/reocclusion, for a total of 2 min. At the end of the reperfusion blood and tissue (small intestine, lungs, kidney, liver) samples were taken for histological examination. The antioxidant status of small intestine was measured from intestinal homogenates. RESULTS: Histologic results revealed increased damage in control-group lungs, kidney, liver and small intestine in comparison with the postconditioned group. The injury was supported by significantly higher wet/dry weight ratio (p = 0.026), and serum levels of creatinine (p = 0.013), ASAT (p = 0.038), LDH (p = 0.028) and CK (p = 0.038) in the control group. The postconditioned group showed lower serum IL-6 levels (420 pg/ml vs. 188 pg/ml), as well as significantly higher mucosal antioxidant concentration. CONCLUSIONS: Postconditioning was able to decrease not only local, but the systemic damage intensity also, after a small intestinal ischemic-reperfusion episode. PMID- 22940393 TI - [Hybrid repair for a ruptured aortic arch and descending aortic aneurysm in a kidney-transplanted patient]. AB - CASE REPORT: We present a case of a 53 year old male renal transplanted patient, who presented with severe dyspnea. Chest X-ray and CT angiography showed a left sided haemothorax caused by an aortic arch aneurysm rupture. Acute operation was carried out, an ascendo-anonymo-carotid "Y" bypass was performed from sternotomy and a stent graft implantation through femoral artery. As a second step, the blood clot mass, which caused compression atelectasis of the left lung, was removed by a thoracic surgeon. At follow-up the patient was in good condition, the bypass graft functioned well, the stent graft stayed in good position, the aneurysm sack was reduced and the left lung expanded well. DISCUSSION: Traditional operation of aortic arch aneurysm carries high mortality and morbidity rate, because of use of extracorporeal perfusion and deep hypothermic circulatory arrest. Hybrid operation became an alternative treatment. After circulation of supra-aortic arteries secured by "debranching procedure", a stent graft implantation is done. Such interventions means less strain for patients, but strict follow up is required, because lack of long-term data. Hybrid reconstruction of the aortic arch aneurysm is rarely performed in acute cases, but means an alternative treatment for high risk patients with acceptable results. PMID- 22940396 TI - [Abstracts from the 61th Congress of the Hungarian Surgical Society, 13-15 September, 2012, Szeged, Hungary]. PMID- 22940399 TI - The missing link between faces and names: evidence from Alzheimer's disease patients. AB - Retrieval of proper names is a cause of concern and complaint among elderly adults and it is an early symptom of patients suffering from neurodegenerative diseases such as Alzheimer's disease (AD). While it is well established that AD patients have deficits of proper name retrieval, the nature of such impairment is not yet fully understood. Specifically, it is unknown whether this deficit is due to a degradation of the links between faces and proper names, or due to deficits in intentionally accessing and retrieving proper names from faces. Here, we aim to investigate the integrity of the links between famous faces and proper names in AD while minimizing the impact of the explicit retrieval. We compare the performances of AD patients and elderly controls in a face-name priming task. We assess the integrity of the link between faces and names at two different levels: identity level - the name and face belong to the same person; and semantic level the name and face belong to the same category (e.g., politicians). Our results reveal that AD patients compared with controls show intact semantic priming but reduced priming for person identity. This suggests that the deficits in intentionally retrieving proper names in AD are the result of a partial disruption of the network at the identity level, i.e., the links between known faces and proper names. PMID- 22940400 TI - Alterations in error-related brain activity and post-error behavior over time. AB - This study examines the relation between the error-related negativity (ERN) and post-error behavior over time in healthy young adults (N=61). Event-related brain potentials were collected during two sessions of an identical flanker task. Results indicated changes in ERN and post-error accuracy were related across task sessions, with more negative ERN associated with greater improvements in post error accuracy. This relationship was independent of any cross-sectional relationships between overall task performance, individual difference factors, including personality and self-efficacy, and indices of self-regulatory action monitoring. These results indicate that the relation between ERN and post-error accuracy remains intact and consistent regardless of variation in this set of individual difference factors previously associated with both of these indices of self-regulatory action monitoring, providing support for the strength, robustness, and persistence of this relationship in the process of adaptively controlling behavior to enhance task performance. PMID- 22940401 TI - Nanoencapsulation of polyphenols for protective effect against colon-rectal cancer. AB - The human population at large is exposed to many critical factors (e.g. bad food habits, chemical substances, and stress) leading to the development of serious diseases. Colon or colorectal cancer is one of the most prevalent types of cancer in many countries. Despite being a multi-factorial chronic disease, resulting from the interaction of multiple genetic and environmental factors, the critical factor is mostly a poor diet regimen. Therefore, an accumulation of constant mutations leads to a complex arrangement of events during tumor initiation, development and propagation. It is well known that many plants are rich in polyphenols with anti-oxidant, anti-atherogenic, anti-diabetic, anti-cancer, anti viral, and anti-inflammatory properties. These compounds are secondary metabolites with the ability to donate electrons to free radicals through different mechanisms. In recent years, a large number of studies have attributed a protective effect to polyphenols and foods containing these compounds (e.g. plants, vegetables, cereals, tea, coffee or chocolate). Polyphenolic compounds have been described to inhibit cancer development and propagation, being used as chemopreventive agents. Some polyphenols reported a preventive action against colon cancer, e.g. curcumin, gallic acid, ellagic acid, and epigallocatechin-3 gallate. The present article focuses on the properties of these molecules as chemopreventive agents and the recent advances on their formulation in nanoparticulate systems for targeted therapy and increased bioavailability. PMID- 22940402 TI - Deep vein thrombosis: current status and nanotechnology advances. AB - Deep vein thrombosis (DVT) affects up to 2 million people in the United States, and worldwide incidence is 70 to 113 cases per 100,000 per year. Mortality from DVT is often due to subsequent pulmonary embolism (PE). Precise diagnosis and treatment is thereby essential for the management of DVT. DVT is diagnosed by a thorough history and physical examination followed by laboratory and diagnostic tests. The choice of laboratory and diagnostic test is dependent on clinical pretest probability. Available laboratory and diagnostic techniques mainly involve D-dimer test, ultrasound, venography, and magnetic resonance imaging. The latter two diagnostic tools require high doses of contrast agents including either radioactive or toxic materials. The available treatment options include lifestyle modifications, mechanical compression, anticoagulant therapy, inferior vena cava filter, and thrombolysis/thrombolectomy. All of these medical and surgical treatments have serious side effects including improper clot clearance and increased risk of hemorrhage occurrence. Therefore, research in this field has recently focused on the development of non-invasive and accurate diagnostics, such as ultrasound enhanced techniques and molecular imaging methods, to assess thrombus location and its treatment course. The frontier of nanomedicine also shows high prospects in tackling DVT with efficient targeted drug delivery. This review describes the pathology of DVT along with successive medical problems such as PE and features a detailed listing of various diagnostic and therapeutic modalities that have been in use and are under development. PMID- 22940404 TI - Dermatoscopy of hair shaft disorders. AB - Until a few years ago the diagnosis of hair shaft disorders was based on light microscopy or scanning electron microscopy on plucked or cut samples of hair. Dermatoscopy is a new fast, noninvasive, and cost-efficient technique for easy in office diagnosis of all hair shaft abnormalities including conditions such as pili trianguli and canaliculi that are not recognizable by examining hair shafts under the light microscope. It can also be used to identify disease limited to the eyebrows or eyelashes. Dermatoscopy allows for fast examination of the entire scalp and is very helpful to identify the affected hair shafts when the disease is focal. PMID- 22940403 TI - Key technologies for the industrial production of fumaric acid by fermentation. AB - The growing concern about the safety of food and dairy additives and the increasing costs of petroleum-based chemicals have rekindled the interest in the fermentation processes for fumaric acid production. The key problems of the industrial production of microbial fumaric acid are reviewed in this paper. Various strategies, including strain improvement, morphology control, substrate choice, fermentation process and separation process, are summarized and compared, and their economical possibilities for industrial processes are discussed. The market prospects and technological strategies for value-added fumaric acid derivatives are also addressed. The future prospects of microbial fumaric acid production are proposed at the end of this article. PMID- 22940405 TI - Nonmalignant cutaneous findings associated with vemurafenib use in patients with metastatic melanoma. AB - Nonmalignant cutaneous findings associated with the use of vemurafenib have only recently been described in the literature. Patients receiving vemurafenib have exhibited cutaneous reactions including prominent follicular plugging, hand-foot skin reaction, exuberant seborrheic dermatitis-like hyperkeratosis of the face, keratosis pilaris, and diffuse spiny follicular hyperkeratosis. Many of these nonmalignant cutaneous findings are associated with abnormal follicular keratinization thought to be secondary to abnormal signaling of the mitogen activated protein kinase pathway that occurs with the use of BRAF inhibitors. Whether underlying Ras mutations affect this abnormal signaling as in malignant lesions is still unknown. Different therapeutic options exist for these patients that may result in significant improvement in some of these nonmalignant cutaneous findings. Conservative treatment should focus on topical therapies such as topical retinoids or topical steroids. However, systemic therapies such as concomitant oral retinoids or MEK inhibitors should be considered for more severe or refractory cutaneous findings. PMID- 22940406 TI - Cutaneous gnathostomiasis: report of 6 cases with emphasis on histopathological demonstration of the larva. AB - BACKGROUND: Cutaneous gnathostomiasis is an emerging food-borne parasitic zoonosis. Histopathological demonstration of the larva on random biopsy specimen of erythematous plaques is infrequent because of its migrating nature. OBJECTIVE: We sought to determine whether medical treatment with albendazole or ivermectin increases the diagnostic yield of skin biopsy specimen. METHODS: A retrospective chart review was conducted in a private dermatology practice in Lima, Peru. Cases with a clinical diagnosis of nodular migratory panniculitis and pathological diagnosis of eosinophilic panniculitis or gnathostomiasis were reviewed. Only cases with definitive diagnosis confirmed by histopathology or parasite isolation were included in the study. RESULTS: A definitive diagnosis of gnathostomiasis was rendered in 6 of 55 reviewed cases. Histopathological or gross identification of the nematode's larva was made obtaining a biopsy specimen of papules or pseudofuruncles that developed after oral antiparasitic treatment. LIMITATIONS: This is a retrospective case series study and no serologic testing was available. CONCLUSION: Biopsy of a papule or pseudofuruncle subsequent to oral treatment increases the likelihood of demonstrating the larva on skin biopsy specimen, which allows definitive diagnosis and may have therapeutic benefit. PMID- 22940407 TI - Targeting gut flora to prevent progression of hepatocellular carcinoma. AB - Increased translocation of intestinal bacteria is a hallmark of chronic liver disease and contributes to hepatic inflammation and fibrosis. Here we tested the hypothesis that the intestinal microbiota and Toll-like receptors (TLRs) promote hepatocellular carcinoma(HCC), a long-term consequence of chronic liver injury, inflammation,and fibrosis. Hepatocarcinogenesis in chronically injured livers depended on the intestinal microbiota and TLR4 activation in nonbone-marrow derived resident liver cells. TLR4 and the intestinal microbiota were not required for HCC initiation but for HCC promotion, mediating increased proliferation, expression of the hepatomitogen epiregulin, and prevention of apoptosis. Gut sterilization restricted to late stages of hepatocarcinogenesis reduced HCC, suggesting that the intestinal microbiota and TLR4 represent therapeutic targets for HCC prevention in advanced liver disease. PMID- 22940408 TI - Use of early-TIPS for high-risk variceal bleeding: results of a post-RCT surveillance study. AB - BACKGROUND & AIMS: In a recent randomized international clinical trial (RCT) in high-risk cirrhotic patients with acute variceal bleeding, the early use of transjugular intrahepatic portosystemic shunt (TIPS) was associated with marked and significant reductions in both treatment failure and mortality. The aim of this study was to confirm these results in clinical practice in the same centers of the RCT study. METHODS: We retrospectively reviewed patients admitted for acute variceal bleeding and high risk of treatment failure (Child C <14 or Child B plus active bleeding), treated with early-TIPS (n=45) or drugs+endoscopic therapy (ET) (n=30). RESULTS: Patients treated with early-TIPS had a much lower incidence of failure to control bleeding or rebleeding than patients receiving drug+ET (3 vs. 15; p <0.001). The 1-year actuarial probability of remaining free of this composite end point was 93% vs. 53% (p <0.001). The same was observed in mortality (1-year actuarial survival was 86% vs. 70% respectively; p=0.056). Actuarial curves of failure to control bleeding+rebleeding and of survival were well within the confidence intervals of those observed in the RCT. CONCLUSIONS: This study supports the early use of TIPS in patients with cirrhosis and a high risk variceal bleeding. PMID- 22940409 TI - X-ray spectra and quality parameters from Monte Carlo simulation and analytical filters. AB - BEAMnrc was used to derive the X-ray spectra, from which HVL and homogeneity coefficient were determined, for different kVp and filtration settings. Except for the peak at 61 keV, the spectra are in good agreement with the IPEM report 78 data for the case of filtered beams, whereas the unfiltered beams exhibit softer spectra. Although the current attenuation data deviates from the IPEM 78 data by ~+/-0.5%, this has negligible effects on the calculated HVL values. PMID- 22940410 TI - Gamma irradiation of cultural artifacts for disinfection using Monte Carlo simulations. AB - In this study, it has been investigated the disinfection of Korean cultural artifacts by gamma irradiation, simulating the absorbed dose distribution on the object with the Monte Carlo methodology. Fungal contamination was identified on two traditional Korean agricultural tools, Hongdukkae and Holtae, which had been stored in a museum. Nine primary species were identified from these items: Bjerkandera adusta, Dothideomycetes sp., Penicillium sp., Cladosporium tenuissimum, Aspergillus versicolor, Penicillium sp., Entrophospora sp., Aspergillus sydowii, and Corynascus sepedonium. However, these fungi were completely inactivated by gamma irradiation at an absorbed dose of 20kGy on the front side. Monte Carlo N Particle Transport Code was used to simulate the doses applied to these cultural artifacts, and the measured dose distributions were well predicted by the simulations. These results show that irradiation is effective for the disinfection of cultural artifacts and that dose distribution can be predicted with Monte Carlo simulations, allowing the optimization of the radiation treatment. PMID- 22940411 TI - Detection of low level gaseous releases and dose evaluation from continuous gamma dose measurements using a wavelet transformation technique. AB - Measurement of environmental dose in the vicinity of a nuclear power plant site (Tarapur, India) is carried out continuously for the years 2007-2010 and attempts have been made to quantify the additional contributions from nuclear power plants over natural background by segregating the background fluctuations from the events due to plume passage using a non-decimated wavelet approach. A conservative estimate obtained using wavelet based analysis has shown a maximum annual dose of 38 MUSv in a year at 1.6 km and 4.8 MUSv at 10 km from the installation. The detected events within a year are in good agreement with the month wise wind-rose profile indicating reliability of the algorithm for proper detection of an event from the continuous dose rate measurements. The results were validated with the dispersion model dose predictions using the source term from routine monitoring data and meteorological parameters. PMID- 22940413 TI - Feasibility for direct rapid energy dispersive X-ray fluorescence (EDXRF) and scattering analysis of complex matrix liquids by partial least squares. AB - The greatest challenge to material characterization by XRF technique is encountered in direct trace analysis of complex matrices. We exploited partial least squares (PLS) in conjunction with energy dispersive X-ray fluorescence and scattering (EDXRFS) spectrometry to rapidly (200 s) analyze lubricating oils. The PLS-EDXRFS method affords non-invasive quality assurance (QA) analysis of complex matrix liquids as it gave optimistic results for both heavy- and low-Z metal additives. Scatter peaks may further be used for QA characterization via the light elements. PMID- 22940412 TI - 18F half-life measurement using a high-purity germanium detector. AB - The half-life of (18)F has been measured using HPGe detectors with a (137)Cs reference source. The counting ratio of 511 keV gamma-rays from (18)F to 622 keV gamma-rays from (137)Cs was fitted for the half-life with a weighted least-square method. Uncertainties due to the systematic effects arising from the measurement of a high activity (18)F source were studied in detail. The half-life of (18)F was found to be (109.72+/-0.19) min. The result is in a good agreement with the recommended value of (109.728+/-0.019) min evaluated at the Laborotaire National Henri Becquerel (LNHB). PMID- 22940414 TI - Proton-induced cross sections relevant to production of 225Ac and 223Ra in natural thorium targets below 200 MeV. AB - Cross sections for (223,)(225)Ra, (225)Ac and (227)Th production by the proton bombardment of natural thorium targets were measured at proton energies below 200 MeV. Our measurements are in good agreement with previously published data and offer a complete excitation function for (223,)(225)Ra in the energy range above 90 MeV. Comparison of theoretical predictions with the experimental data shows reasonable-to-good agreement. Results indicate that accelerator-based production of (225)Ac and (223)Ra below 200 MeV is a viable production method. PMID- 22940415 TI - Measurement of the 225Ac half-life. AB - The (225)Ac half-life was determined by measuring the activity of (225)Ac sources as a function of time, using various detection techniques: alpha-particle counting with a planar silicon detector at a defined small solid angle and in a nearly-2pi geometry, 4pialpha+beta counting with a windowless CsI sandwich spectrometer and with a pressurised proportional counter, gamma-ray spectrometry with a HPGe detector and with a NaI(Tl) well detector. Depending on the technique, the decay was followed for 59-141 d, which is about 6-14 times the (225)Ac half-life. The six measurement results were in good mutual agreement and their mean value is T(1/2)((225)Ac)=9.920 (3)d. This half-life value is more precise and better documented than the currently recommended value of 10.0 d, based on two old measurements lacking uncertainty evaluations. PMID- 22940416 TI - Optimization of [11C]DASB-synthesis: vessel-based and flow-through microreactor methods. AB - The intention for the present study was to implement a microfluidic set-up for N (11)C-methylations in a flow-through microreactor device with [(11)C]DASB as model-compound and [(11)C]CH(3)I and [(11)C]CH(3)OTf, respectively, as (11)C methylation agents. Due to an observed "aging" effect of the (11)C-methylation agents' solution, this goal was not achieved. Nevertheless, based on these observations, the time consumption for the vessel-based routine production of [(11)C]DASB was reduced (34+/-1 min) and RCY was increased to 45.1+/-4.6% (EOB; 5.2+/-0.95 GBq EOS). PMID- 22940417 TI - Respiratory complications of Ehlers-Danlos syndrome type IV. AB - We describe a case of Ehlers-Danlos syndrome (EDS) type IV in a male in early half in his twenties, who experienced recurrent and eventually fatal pulmonary hemorrhage. EDS type IV is a rare disorder of type III collagen synthesis that is characterized by unusual facies, thin translucent skin with a venous vascular pattern, easy bruising, and hypermobility of the small joints. Autopsy findings showed hypermobility of the joints and distensibility of the skin. Microscopically, the abdominal skin showed substantially decreased dermal thickness. Moreover, the reticular dermis showed fine collagen bundles and large interstitial spaces compared with the skin from a normal control that showed large collagen bundles. Individual elastic fibers were also thicker than those observed in the skin of a normal control. The thoracic aorta showed thin adventitia and a relative increase in elastic fibers. The parenchyma of both the lungs showed markedly diffuse hemorrhage with hemosiderin-laden alveolar macrophages or old thrombi and organized thrombi in the small bronchi. Furthermore, both sections of the lung showed multiple fibrous nodules containing benign metaplastic bone. Vascular wall disruption and tearing of the vessel walls in the lung parenchyma were also observed. We concluded that EDS type IV led to the patient's death because of pulmonary hemorrhage. Because this syndrome resulted in the patient's death from arterial and bowel rupture, it is important to consider EDS as a potential cause of sudden death. PMID- 22940418 TI - Immobilization of flavin adenine dinucleotide (FAD) onto carbon cloth and its application as working electrode in an electroenzymatic bioreactor. AB - A high porosity carbon cloth with immobilized FAD was employed as working electrode in electrochemical NADH-regeneration procedure. Carbon cloth was oxidized with hot acids to create surface carboxyl group and then coupled by adenine amino group of FAD with carbodiimide in the presence of N hydroxysulfosuccinimide. The bioelectrocatalytic NADH-regeneration was coupled to the conversion of achiral substrate pyruvate into chiral product l-lactate by l lactate dehydrogenase (l-LDH) within the same reactor. The conversion was completed at 96h in bioreactor with FAD-modified carbon cloth, resulting in about 6mM of l-lactate from 10mM of pyruvate. While with bare carbon cloth, the yield at 120h was around 5mM. Immobilized FAD on the surface of carbon cloth electrode facilitated it to carry electrons from electrode to electron transfer enzymes; thereby NADH-regeneration was accelerated to drive the enzymatic reaction efficiently. PMID- 22940419 TI - Polymorphisms of the acid sensing histidine kinase gene arsS in Helicobacter pylori populations from anatomically distinct gastric sites. AB - Phase variation is frequently utilized by bacterial species to affect gene expression such that phenotypic variants are maintained within populations, ensuring survival as environmental or host conditions change. Unusual among Helicobacter pylori phase variable or contingency genes is arsS, encoding a sensory histidine kinase involved in the acid acclimation of the organism. The presence of a 3' homopolymeric cytosine tract of variable length in arsS among Helicobacter pylori strains allows for the expression of various functional ArsS isoforms, differing in carboxy-terminal protein domains. In this study, we analyzed this 3'arsS region via amplified fragment length polymorphism (AFLP) and sequencing analyses for H. pylori populations from 3 different gastric sites of 12 patients. Our data indicate the presence of multiple arsS alleles within each population of H. pylori derived from the gastric antrum, cardia, or corpus of these patients. We also show that H. pylori, derived from the same anatomical site and patient, are predicted to express multiple ArsS isoforms in each population investigated. Furthermore, we identify a polymorphic deletion within arsS that generates another alternate ArsS C-terminal end. These findings suggest that four C-terminal variations of ArsS adds to the complexity of the ArsRS acid adaptation mechanism as a whole and may influence the ability of H. pylori to persist in the gastric niche for decades. PMID- 22940420 TI - Angiogenin in middle-aged type 1 diabetes patients. AB - BACKGROUND: Angiogenin levels are increased in children and adolescent patients with type 1 diabetes, regardless of the extent of diabetic microangiopathy. However, little is known about the angiogenin concentrations in adults with type 1 diabetes. Thus we studied its level in middle aged subjects with the presence of diabetic nephro-, retino and neuropathy. METHODS: We investigated the data of 57 (age 39+/-6.6 years, 45.6% of males) patients with type 1 diabetes and 38 age matched control subjects without diabetes (age 37.1+/-5.9 years, 42.1% of males), including medical histories, evidences of microangiopathy and serum angiogenin concentrations. RESULTS: Serum angiogenin level was lower in patients with type 1 diabetes [384.2(190.4-999.8) ng/ml] compared to controls [460.4(230.6-708.2) ng/ml], p=0.04. In patients with overt diabetic nephropathy the angiogenin level was higher when compared to patients without nephropathy [568.2(269.6-999.8) vs 369.4(190.4-999.8) ng/ml, p=0.01]. There were no differences between angiogenin levels in subgroups of patients distinguished by the presence of other microvascular complications or other concomitant vascular risk factors despite cigarette smoking [smokers: 516.2(294.4-999.8) vs. non-smokers: 372.1(190.4 924.8) ng/ml, p=0.01]. CONCLUSIONS: Regardless of the presence of diabetic microangiopathy, angiogenin level in middle-aged type 1 diabetes patients is lower than in controls. The presence of overt nephropathy and smoking habit in middle-aged patients with type 1 diabetes are associated with higher angiogenin level. PMID- 22940421 TI - Systems of attitudes towards production in the pork industry. A cross-national study. AB - Existing research on public attitudes towards agricultural production systems is largely descriptive, abstracting from the processes through which members of the general public generate their evaluations of such systems. The present paper adopts a systems perspective on such evaluations, understanding them as embedded into a wider attitude system that consists of attitudes towards objects of different abstraction levels, ranging from personal value orientations over general socio-political attitudes to evaluations of specific characteristics of agricultural production systems. It is assumed that evaluative affect propagates through the system in such a way that the system becomes evaluatively consistent and operates as a schema for the generation of evaluative judgments. In the empirical part of the paper, the causal structure of an attitude system from which people derive their evaluations of pork production systems was modelled. The analysis was based on data from a cross-national survey involving 1931 participants from Belgium, Denmark, Germany and Poland. The survey questionnaire contained measures of personal value orientations and attitudes towards environment and nature, industrial food production, food and the environment, technological progress, animal welfare, local employment and local economy. In addition, the survey included a conjoint task by which participants' evaluations of the importance of production system attributes were measured. The data were analysed by means of causal search algorithms and structural equation models. The results suggest that evaluative judgments of the importance of pork production system attributes are generated in a schematic manner, driven by personal value orientations. The effect of personal value orientations was strong and largely unmediated by attitudes of an intermediate level of generality, suggesting that the dependent variables in the particular attitude system that was modelled here can be understood as value judgments in a literal sense. PMID- 22940422 TI - Carotid artery stenting performed with a flow-reversal technique: improved technical performance. AB - OBJECTIVE: To report our experience in carotid artery stenting (CAS) with GORE flow reversal system, focusing the assessment of its efficacy, security and practice procedure evolution. METHODS: Twelve patients treated for atherosclerotic carotid stenosis were prospectively evaluated. All patients were symptomatic. Carotid symptoms were embolic stroke in eight, watershed stroke in two and transient ischemic attack (TIA) in two patients. All patients underwent carotid ultrasound, brain magnetic resonance image and magnetic resonance angiography before CAS procedure. The procedure time and the flow reversal time were registered. Neurological outcome was evaluated before treatment, during the first 48 hours post-treatment and after 3 months. RESULTS: CAS was successful in all cases. Mean procedure time was 33.8 minutes. Mean flow reversal time was 7.3 minutes. Temporary bradycardia occurred with six patients without associated hemodynamic instability. NIHSS patients' scores ranged from 0 to 5 (average 1.1) on admission and remained unchanged during 48 hours after treatment. mRS patients' scores ranged from 0 to 3 (average 1.6) on admission and remained unchanged during the follow-up of 3 months. There were no complications concerning groin puncture, or general anesthesia, or myocardial infarct or death. CONCLUSION: In our present selected subjects, the CAS procedure using the GORE flow reversal system appeared to be safe and effective, with improved technical performance of the procedure. This was observed in particular with the flow reversal times achieved. Thus, studies comparing the GORE system and other protection devices are suggested to ascertain all of the benefits of flow reversal during CAS. PMID- 22940423 TI - HIV immune complexes prevent excitotoxicity by interaction with NMDA receptors. AB - PURPOSE: Human immunodeficiency virus-1 (HIV)-associated neurocognitive disorder (HAND) is a neurodegenerative disease for which there is no available neuroprotective therapy. Viral proteins, such as Tat, have been implicated as agents of neurotoxicity via multiple mechanisms, including effects by directly binding to the NMDA receptor. We evaluated the ability of the immune response against Tat to modulate neurotoxicity at glutamate receptors. METHODS: Neurotoxicity was measured in primary neuronal-glial cultures and in hippocampal slice cultures. We used immunoprecipitation experiments to demonstrate interaction between Tat, NMDA receptor, and anti-Tat antibody. Using known structures of Tat and NMDA receptors, we developed a model of their interactions. RESULTS: Antibodies to Tat attenuated Tat-mediated neurotoxicity. Interestingly, Tat immune complexes also blocked neurotoxicity caused by NMDA receptor agonists but not kainate/AMPA receptor agonists. Neither Tat nor antibody alone blocked the excitotoxic effect, nor did an unrelated antigen-antibody complex. The protective effect of the Tat immune complexes was also lost when Tat was modified by nitrosylation or by using a deletion mutant of Tat. CONCLUSIONS: The ability of viral immune complexes to interact with NMDA receptors and prevent excitotoxicity represents a novel host defense mechanism. Host immune responses may influence host susceptibility to various effects of viral proteins, modulating HIV complications, such as onset of HAND. These observations provide rationale for development of vaccine therapies targeting Tat for prevention of HAND. PMID- 22940424 TI - Reinforcing properties of Pramipexole in normal and parkinsonian rats. AB - Striatal D2 and D3 dopamine receptors are involved in mediating the reinforcing properties of natural rewards and drugs. In Parkinson's disease, while D2/3 dopamine agonists alleviate motor symptoms, behavioral addictions and withdrawal syndrome are reported in up to 15% of patients. The origin of such adverse effects is poorly understood but suggests that D2/3 agonists could possess reinforcing properties. We evaluated the reinforcing properties of the widely used D2/3 agonist, Pramipexole (PPX), in normal and parkinsonian rats. Intracerebroventricular injections of 6-OHDA induced a bilateral loss of tyrosine hydroxylase-positive cells in the substantia nigra (-51%) and ventral tegmental area (-31%). The animals were then allowed to self-administer intravenous PPX under fixed ratio and progressive ratio (PR) reinforcement schedules before being tested for extinction of PPX seeking. While parkinsonian were slower than sham rats in acquiring self-administration behavior, they later reached the same level of intake. The reinforcing value of PPX, as assessed during PR and extinction, was moderate in both groups. PPX heightened ?FosB expression in dorsal striatum of lesioned rats and similar PR results involved different striatal subregions between groups. Altogether, our results show that drug-naive rats self-administer PPX and that the dopaminergic lesion does not affect its reinforcing effects. While PPX reinforcing value was moderate in most rats, a subset of animals displayed a high number of responses and appeared to be particularly sensitive to this drug. These data suggest that PPX may not be responsible for the reported side-effects but rather call for further investigating the differential vulnerability among individuals. PMID- 22940425 TI - Fluorescent primuline derivatives inhibit hepatitis C virus NS3-catalyzed RNA unwinding, peptide hydrolysis and viral replicase formation. AB - The hepatitis C virus (HCV) multifunctional nonstructural protein 3 (NS3) is a protease that cleaves viral and host proteins and a helicase that separates DNA and RNA structures in reactions fueled by ATP hydrolysis. Li et al. (2012) recently synthesized a series of new NS3 helicase inhibitors from the benzothiazole dimer component of the fluorescent yellow dye primuline. This study further characterizes a subset of these primuline derivatives with respect to their specificity, mechanism of action, and effect on cells harboring HCV subgenomic replicons. All compounds inhibited DNA and RNA unwinding catalyzed by NS3 from different HCV genotypes, but only some inhibited the NS3 protease function, and few had any effect on HCV NS3 catalyzed ATP hydrolysis. A different subset contained potent inhibitors of RNA stimulated ATP hydrolysis catalyzed by the related NS3 protein from Dengue virus. In assays monitoring intrinsic protein fluorescence in the absence of nucleic acids, the compounds cooperatively bound NS3 with K(d)s that reflect their potency in assays. The fluorescent properties of the primuline derivatives both in vitro and in cells are also described. The primuline derivative that was the most active against subgenomic replicons in cells caused a 14-fold drop in HCV RNA levels (IC(50)=5+/-2MUM). In cells, the most effective primuline derivative did not inhibit the cellular activity of NS3 protease but disrupted HCV replicase structures. PMID- 22940427 TI - Repetition priming in the stop signal task: the electrophysiology of sequential effects of stopping. AB - Inhibition of a response affects the processing of subsequent stimuli. When a response has to be made to a stimulus to which a response was previously inhibited, response time increases. In this study, we investigated the neurophysiological underpinnings of this repetition priming phenomenon. We aimed at distinguishing between two possible mechanisms. Firstly, it could be that slowing after a successful inhibition trial originates at the response execution level and is due to the reactivation of the system responsible for motor inhibition interfering with execution of the go response. The second possibility is that interference occurs at the more abstract level of conflicting action goals or plans (i.e. "stop" and "go") that are activated prior to response execution. We analyzed activity over primary motor cortices and the parietal cortex in a stop signal task. Stimulus repetition led to a decrease in activity over primary motor cortices but irrespective of history of stopping. Stopping on the previous trial did affect the stimulus-locked parietal P300 only on repetition of the stimulus, mimicking the behavioral pattern. Furthermore, the P300 was lateralized and affected by both stimulus onset and response time, suggesting that the interference caused by inhibition priming is situated between stimulus perception and response execution. Taken together, these findings show that the prolonged response times to a stimulus that was previously successfully inhibited to, do not originate from reactivated suppression of motor output, but are caused by interference between a stop and a go goal in parietal cortex that hampers translation from stimulus to response. PMID- 22940426 TI - Subjective cognitive complaints and amyloid burden in cognitively normal older individuals. AB - Accumulating evidence suggests that subjective cognitive complaints (SCC) may indicate subtle cognitive decline characteristic of individuals with preclinical Alzheimer's disease (AD). In this study, we sought to build upon previous studies by associating SCC and amyloid-beta deposition using positron emission tomography with Pittsburgh Compound B (PiB-PET) in cognitively normal older individuals. One hundred thirty one subjects (mean age 73.5+/-6) were administered three subjective cognitive questionnaires and a brief neuropsychological battery. A relationship between a subjective memory complaints composite score and cortical PiB binding was found to be significant, even after controlling for depressive symptoms. By contrast, there were no significant relationships between objective cognitive measures of memory and executive functions and cortical PiB binding. Our study suggests that SCC may be an early indicator of AD pathology detectable prior to significant objective impairment. PMID- 22940429 TI - The plasma clearance of the Fusarium toxin deoxynivalenol (DON) is decreased in endotoxemic pigs. AB - The plasma elimination kinetics of the Fusarium toxin deoxynivalenol (DON) was investigated in male castrated pigs (40.4+/-3.7 kg) when infused intravenously either alone (100 MUg/kg/h, n=6) or together with lipopolysaccharides (LPS, 7.5 MUg/kg/h, n=6). The maximum DON concentration after one hour of infusion was significantly higher by 61% in the DON+LPS Group compared to pigs infused with DON alone. The area under the plasma DON concentration vs. time curve of the DON+LPS Group was approximately twice as high as that of the DON Group after 24h while the initial (0.63 vs. 0.6 h) and terminal half-lifes (2.97 vs. 2.30 h) remained uninfluenced. The apparent volume of distribution and the plasma clearance were significantly lower for the DON+LPS Group compared to the DON Group (2.14 vs. 1.45 L/kg and 11.9 vs. 5.87 mL/kg/min). Glucuronidated DON seemed to persist longer in the DON+LPS Group. In conclusion, clearance of DON was decreased during an LPS induced acute phase reaction in pigs. Whether the higher plasma DON concentrations in endotoxemic pigs are due to a hemodynamically associated longer persistence of the DON glucuronide or because of an altered glucuronidation activity needs to be examined further. PMID- 22940428 TI - Relationship between brainstem, cortical and behavioral measures relevant to pitch salience in humans. AB - Neural representation of pitch-relevant information at both the brainstem and cortical levels of processing is influenced by language or music experience. However, the functional roles of brainstem and cortical neural mechanisms in the hierarchical network for language processing, and how they drive and maintain experience-dependent reorganization are not known. In an effort to evaluate the possible interplay between these two levels of pitch processing, we introduce a novel electrophysiological approach to evaluate pitch-relevant neural activity at the brainstem and auditory cortex concurrently. Brainstem frequency-following responses and cortical pitch responses were recorded from participants in response to iterated rippled noise stimuli that varied in stimulus periodicity (pitch salience). A control condition using iterated rippled noise devoid of pitch was employed to ensure pitch specificity of the cortical pitch response. Neural data were compared with behavioral pitch discrimination thresholds. Results showed that magnitudes of neural responses increase systematically and that behavioral pitch discrimination improves with increasing stimulus periodicity, indicating more robust encoding for salient pitch. Absence of cortical pitch response in the control condition confirms that the cortical pitch response is specific to pitch. Behavioral pitch discrimination was better predicted by brainstem and cortical responses together as compared to each separately. The close correspondence between neural and behavioral data suggest that neural correlates of pitch salience that emerge in early, preattentive stages of processing in the brainstem may drive and maintain with high fidelity the early cortical representations of pitch. These neural representations together contain adequate information for the development of perceptual pitch salience. PMID- 22940430 TI - Antioxidant activity and protective effect of Turnera ulmifolia Linn. var. elegans against carbon tetrachloride-induced oxidative damage in rats. AB - The present study aimed to determine whether the leaves of Turnera ulmifolia Linn. var. elegans extract exert significant antioxidant activity. The antioxidant activity of its hydroethanolic extract (HEETU) was evaluated by assessing (a) its radical scavenging ability in vitro, and (b) its in vivo effect on lipid peroxidation and antioxidant enzyme activities. The in vitro antioxidant assay (DPPH) clearly supported HEETU free radical scavenging potential. Moreover, glutathione content and antioxidant enzyme activities (glutathione peroxidase, superoxide dismutase and catalase) were significantly enhanced in CCl(4)-treated rats due to oral HEETU-treatment (500 mg/kgb.w.) over 7 and 21 days. In addition, an improvement was observed in lipid peroxidation and serum biochemical parameters (aspartate aminotransferase and alanine aminotransferase), indicating a protective effect against CCl(4)-induced liver injuries, confirmed by histopathological studies. The HEETU effect was comparable to the standard drug Legalon(r) (50 mg/kgb.w.) under the same experimental condition. Quantitative analysis of the HPLC extract revealed the presence of flavonoids, wich mediate the effects of antioxidant and oxidative stress. In conclusion, extract components exhibit antioxidant and hepatoprotective activities in vitro and in vivo. PMID- 22940432 TI - Development of a modified vitrification strategy suitable for subsequent scale-up for hepatocyte preservation. AB - This work explores the design of a vitrification solution (VS) for scaled-up cryopreservation of hepatocytes, by adapting VS(basic) (40% (v/v) ethylene glycol 0.6M sucrose, i.e. 7.17 M ethylene glycol 0.6M sucrose), previously proven effective in vitrifying bioengineered constructs and stem cells. The initial section of the scale-up study involved the selection of non-penetrating additives to supplement VS(basic) and increase the solution's total solute concentration. This involved a systematic approach with a step-by-step elimination of non penetrating cryoprotectants, based on their effect on cells after long/short term exposures to high/low concentrations of the additives alone or in combinations, on the attachment ability of hepatocytes after exposure. At a second stage, hepatocyte suspension was vitrified and functions were assessed after continuous culture up to 5 days. Results indicated Ficoll as the least toxic additive. Within 60 min, the exposure of hepatocytes to a solution composed of 9% Ficoll+0.6M sucrose (10-3 M Ficoll+0.6 M sucrose) sustained attachment efficiency of 95%, similar to control. Furthermore, this additive did not cause any detriment to the attachment of these cells when supplementing the base vitrification solution VS(basic). The addition of 9% Ficoll, raised the total solute concentration to 74.06% (w/v) with a negligible 10-3 M increase in molarity of the solution. This suggests main factor in inducing detriment to cells was the molar contribution of the additive. Vitrification protocol for scale-up condition sustained hepatocyte suspension attachment efficiency and albumin production. We conclude that although established approach will permit scaling-up of vitrification of hepatocyte suspension, vitrification of hepatocytes which are attached prior to vitrification is more effective by comparison. PMID- 22940433 TI - Expression of the tetraspanin family members Tspan3, Tspan4, Tspan5 and Tspan7 during Xenopus laevis embryonic development. AB - Tetraspanins comprise a large family of integral membrane proteins involved in the regulation of cell adhesion, migration and fusion. In humans it consists of 33 members divided in four subfamilies. Here, we examined the spatial and temporal gene expression of four related tetraspanins during the embryonic development of Xenopus laevis by quantitative real-time PCR and in situ hybridization: Tspan3 (encoded by the gene Tm4sf8 gene) Tspan4 (encoded by the gene Tm4sf7), Tspan5 (encoded by the gene Tm4sf9) and Tspan7 (encoded by the gene Tm4sf2). These genes appeared first in the vertebrates during the evolution and are conserved across different species. In humans, they were associated with several diseases such as sclerosis, mental retardation and cancer; however their physiological role remained unclear. This work provides a comprehensive comparative analysis of the expression of these tetraspanins during the development of X. laevis. The more closely related tetraspanins Tspan3, Tspan4 and Tspan7 exhibited very similar spatial expression patterns, albeit differing in their temporal occurrence. The corresponding transcripts were found in the dorsal animal ectoderm at blastula stage. At early tailbud stages (stage 26) the genes were expressed in the migrating cranial neural crest located in the somites, developing eye, brain, and in otic vesicles. In contrast, Tspan5 appeared first at later stages of development and was detected prominently in the notochord. These data support close relatedness of Tspan3, Tspan4 and Tspan7. The expression of these tetraspanins in the cells with a high migratory potential, e.g. neural crest cells, suggests their role in the regulation of migration processes, characteristic for tetraspanin family members, during development. Similarity of the expression profiles might indicate at least partial functional redundancy, which is in concordance with earlier findings of tissue-limited or absent phenotypes in the knock-down studies of tetraspanins family members performed. PMID- 22940434 TI - Establishing a total allowable concentration of o-toluidine in drinking water incorporating early lifestage exposure and susceptibility. AB - o-Toluidine is a monocyclic aromatic amine present in the formulation of some materials that contact drinking water. NSF/ANSI 61 Annex A (2011) and US EPA (2005a) risk assessment guidelines were used to determine an acceptable drinking water level. Occupational exposure to o-toluidine is associated with an increased risk of bladder cancer but human disease rates could not be used to establish risk values due to inadequate exposure data and coexposures in the epidemiology cohorts. Chronic dietary exposure to o-toluidine hydrochloride was associated with benign and malignant tumors in both sexes of F344 rats and B6C3F1 mice. o Toluidine is genotoxic in vitro and in vivo. A 10(-5) cancer risk level was extrapolated from the human equivalent BMDL(10) of 13mg/kg-day for the combined incidence of papillomas and carcinomas of the bladder transitional epithelium in female rats. Considering varying susceptibility to tumor development at different life stages, the unit risk was modified to incorporate potency adjustments for early-life exposures. A framework for lifestage adjustment is presented that makes assumptions evident. For this assessment, the lifetime unit risk derived was ~2-fold greater than the unadjusted adult lifetime unit risk, and the resulting Total Allowable Concentration in drinking water is 20MUg/L. PMID- 22940431 TI - Effects of heat shock protein 72 (Hsp72) on evolution of astrocyte activation following stroke in the mouse. AB - Astrocyte activation is a hallmark of the response to brain ischemia consisting of changes in gene expression and morphology. Heat shock protein 72 (Hsp72) protects from cerebral ischemia, and although several protective mechanisms have been investigated, effects on astrocyte activation have not been studied. To identify potential mechanisms of protection, microarray analysis was used to assess gene expression in the ischemic hemispheres of wild-type (WT) and Hsp72 overexpressing (Hsp72Tg) mice 24 h after middle cerebral artery occlusion or sham surgery. After stroke both genotypes exhibited changes in genes related to apoptosis, inflammation, and stress, with more downregulated genes in Hsp72Tg and more inflammation-related genes increased in WT mice. Genes indicative of astrocyte activation were also upregulated in both genotypes. To measure the extent and time course of astrocyte activation after stroke, detailed histological and morphological analyses were performed in the cortical penumbra. We observed a marked and persistent increase in glial fibrillary acidic protein (GFAP) and a transient increase in vimentin. No change in overall astrocyte number was observed based on glutamine synthetase immunoreactivity. Hsp72Tg and WT mice were compared for density of astrocytes expressing activation markers and astrocytic morphology. In animals with comparable infarct size, overexpression of Hsp72 reduced the density of GFAP- and vimentin-expressing cells, and decreased astrocyte morphological complexity 72 h following stroke. However, by 30 days astrocyte activation was similar between genotypes. These data indicate that early modulation of astrocyte activation provides an additional novel mechanism associated with Hsp72 overexpression in the setting of ischemia. PMID- 22940435 TI - Reduced exposure evaluation of an Electrically Heated Cigarette Smoking System. Part 1: Non-clinical and clinical insights. AB - The following series of papers presents an extensive assessment of the Electrically Heated Cigarette Smoking System EHCSS series-K cigarette vs. conventional lit-end cigarettes (CC) as an example for an extended testing strategy for evaluation of reduced exposure. The EHCSS produces smoke through electrical heating of tobacco. The EHCSS series-K heater was designed for exclusive use with EHCSS cigarettes, and cannot be used to smoke (CC). Compared to the University of Kentucky Reference Research cigarette 2R4F and a series of commercial CC, mainstream cigarette smoke of both the non-menthol and menthol flavored EHCSS cigarettes showed a reduced delivery of a series of selected harmful and potentially harmful constituents (HPHC), mutagenic activity determined using the Salmonella typhimurium Reverse Mutation (Ames) assay, and cytotoxicity in the Neutral Red Uptake Assay. Clinical evaluations confirmed reduced exposure to HPHC and excretion of mutagenic material under controlled clinical conditions. Reductions in HPHC exposure were confirmed in a real-world ambulatory clinical study. Potential biomarkers of cardiovascular risk were also reduced under real-world ambulatory conditions. A modeling approach, 'nicotine bridging', was developed based on the determination of nicotine exposure in clinical evaluations which indicated that exposure to HPHC for which biomarkers of exposure do not exist would also be reduced. PMID- 22940436 TI - Reduced exposure evaluation of an Electrically Heated Cigarette Smoking System. Part 3: Eight-day randomized clinical trial in the UK. AB - A randomized, controlled, open-label, parallel-group, single-center study to determine biomarkers of exposure to nine selected harmful and potentially harmful constituents (HPHC) in cigarette smoke and urinary excretion of mutagenic material in 160 male and female subjects smoking Marlboro cigarettes (6 mg tar, 0.5mg nicotine, and 7.0mg CO) at baseline. Subjects were randomized to continue smoking Marlboro cigarettes, or switch to using an Electrically Heated Cigarette Smoking System (EHCSS) smoking one of two EHCSS series-K cigarettes, the EHCSS-K6 cigarette (5mg tar, 0.3mg nicotine, and 0.6 mg CO) or the EHCSS-K3 cigarette (3mg tar, 0.2mg nicotine, and 0.6 mg CO), or switch to smoking Philip Morris One cigarettes (1mg tar, 0.1mg nicotine, and 2.0mg CO), or to no-smoking. The mean decreases from baseline to Day 8 were statistically significant (p <= 0.05) for all determined HPHC including benzene and CO (the primary objectives), and urinary excretion of mutagenic material in the EHCSS-K6 (range -35.5 +/- 29.2% to -79.4 +/- 14.6% [mean +/- standard deviation]), EHCSS-K3 (range -41.2 +/- 26.6% to -83.1 +/- 9.2%), and PM1 (range -14.6 +/- 24.1% to -39.4 +/- 17.5%) groups. The largest reductions in exposure occurred in the no-smoking group (range -55.4 +/- 45.0% to -100.0 +/- 0.0%). PMID- 22940437 TI - Reduced exposure evaluation of an Electrically Heated Cigarette Smoking System. Part 5: 8-Day randomized clinical trial in Japan. AB - A randomized, controlled, open-label, parallel-group, single-center study to determine biomarkers of exposure to twelve selected harmful and potentially harmful constituents (HPHCs) in cigarette smoke and urinary excretion of mutagenic material in 128 male and female Japanese subjects smoking Marlboro cigarettes (6 mg tar, 0.5mg nicotine, and 7.0mg CO) at baseline. Subjects were randomized to continue smoking Marlboro cigarettes, or switch to the Electrically Heated Cigarette Smoking System (EHCSS) and smoke either the EHCSS-K6 (5mg tar, 0.3mg nicotine, and 0.6 mg CO) or the EHCSS-K3 (3mg tar, 0.2mg nicotine, and 0.6 mg CO) cigarette, or switch to smoking Lark One cigarettes (1mg tar, 0.1mg nicotine, and 2.0mg CO), or to no-smoking. The mean decreases from baseline to Day 8 were statistically significant (p <= 0.05) for all cigarette smoke HPHC including CO (the primary objective) and excretion of mutagenic material in the EHCSS-K6 (range: -14.6% to -75.6%) and EHCSS-K3 (range: -9.8% to -73.0%) groups. Statistically significant reductions (all p <= 0.05) in exposure to ten cigarette smoke HPHC (range: -5.9% to -34.6%), but not urinary mutagenicity, were observed in the Lark One group. The largest mean reductions in exposure to HPHC (all p <= 0.01 level) occurred in the no-smoking group (range: -13.7% to -97.6%). PMID- 22940438 TI - The RESTORE-2 trial: proof of safety and efficacy of "regenerative-cell enriched" fat-grafting? PMID- 22940439 TI - Chronic intermittent hypoxia exposure induces atherosclerosis in ApoE knockout mice: role of NF-kappaB p50. AB - Current animal models of chronic intermittent hypoxia (CIH)-induced atherosclerosis have limitations. Mechanisms of CIH-induced atherosclerosis are poorly understood. This study tested new mouse models of CIH-induced atherosclerosis and defined the role of NF-kappaB p50 in CIH-induced atherosclerosis. Mice deficient in apolipoprotein E (ApoE-KO) or in both ApoE and p50 genes (ApoE-p50-DKO) were exposed to sham or CIH. Atherosclerotic lesions on aortic preparations were analyzed. CIH exposure caused atherosclerosis in ApoE-KO mice fed a normal chow diet and with no preexisting atherosclerotic condition in an exposure time-dependent manner. CIH caused more pronounced atherosclerotic lesions in ApoE-p50-DKO mice on a normal chow diet without preexisting atherosclerosis. ApoE-KO and ApoE-p50-DKO mice exposed to CIH for 30 and 9 weeks, respectively, displayed similar areas of atherosclerotic lesions on cross sections of aortic root. P50 gene deletion in ApoE-p50-DKO mice significantly augmented CIH-induced serum levels of tumor necrosis factor-alpha and IL-6, aortic tumor necrosis factor-alpha, and inducible nitric oxide synthase expression and aortic infiltration of Mac3-positive macrophages. CIH caused a greater elevation in serum cholesterol level in ApoE-p50-DKO than in ApoE-KO mice. CIH down-regulated hepatic low-density lipoprotein receptor and HMG-CoA reductase expression in ApoE-p50-DKO but not in ApoE-KO mice. We found two new mouse models that are useful for studying mechanisms and pathways of CIH-induced atherosclerosis. We showed that NF-kappaB p50 protects against CIH-induced atherosclerosis by inhibiting vascular inflammation and hypercholesterolemia. PMID- 22940440 TI - Necrostatin-1 protects photoreceptors from cell death and improves functional outcome after experimental retinal detachment. AB - Necroptosis is a recently discovered programmed necrosis. Evidence demonstrated the importance of necroptosis in neuronal cell death. Necrostatin-1 is a specific inhibitor of necroptosis. In this study, we investigated the role of necrostatin 1 on photoreceptor survival and functional protection after experimental retinal detachment (RD) in rats. Necrostatin-1/inactive analogue of necrostatin-1 was introduced into the subretinal space at RD induction and 6 hours afterward, respectively. We found that necrostatin-1 attenuated retinal histopathological damage and reduced plasma membrane breakdown (a morphological hallmark of necroptosis) in outer retinal layers. Transmission electron microscopy showed that necrostatin-1 directly protected neurons by inhibiting necroptotic, not apoptotic, cell death. Treatment with necrostatin-1 inhibited the induction of receptor-interacting protein kinase phosphorylation after RD (a biomarker of necroptosis). Finally, electroretinographic recording proved that necrostatin-1 contributed to objective functional improvement after RD. These findings indicate that necrostatin-1 is a promising therapeutic agent that protects photoreceptors from necroptosis and improves functional outcome. PMID- 22940441 TI - Bordetella pertussis in a neonatal intensive care unit: identification of the mother as the likely source. AB - Bordetella pertussis, the cause of whooping cough, is highly contagious. A female, twin 1, born at 34 weeks of gestation and present on a neonatal intensive care unit for 19 days, became apnoeic and bradycardic. A pernasal swab, sent when pertussis was clinically suspected, grew B. pertussis. Twin 2 had similar symptoms. The mother admitted having a prolonged cough. Polymerase chain reaction of pernasal swabs was positive for both twins, and the mother had positive pertussis serology. An incident management committee was convened. Fifty neonates and 117 healthcare workers were identified as contacts and were offered information, azithromycin chemoprophylaxis and/or pertussis vaccination according to UK national guidelines. PMID- 22940442 TI - miRNA_Targets: a database for miRNA target predictions in coding and non-coding regions of mRNAs. AB - MicroRNAs (miRNAs) are small non-coding RNAs that play a role in post transcriptional regulation of gene expression in most eukaryotes. They help in fine-tuning gene expression by targeting messenger RNAs (mRNA). The interactions of miRNAs and mRNAs are sequence specific and computational tools have been developed to predict miRNA target sites on mRNAs, but miRNA research has been mainly focused on target sites within 3' untranslated regions (UTRs) of genes. There is a need for an easily accessible repository of genome wide full length mRNA - miRNA target predictions with versatile search capabilities and visualization tools. We have created a web accessible database of miRNA target predictions for human, mouse, cow, chicken, Zebra fish, fruit fly and Caenorhabditis elegans using two different target prediction algorithms, The database has target predictions for miRNA's on 5' UTRs, coding region and 3' UTRs of all mRNAs. This database can be freely accessed at http://mamsap.it.deakin.edu.au/mirna_targets/. PMID- 22940443 TI - Primary care: an important role in the future of veterinary education. PMID- 22940444 TI - Academic veterinary medicine and One Health education: it is more than clinical applications. PMID- 22940445 TI - The influence of contact conditions and micromotions on the fretting behavior of modular titanium alloy taper connections. AB - Modularity of femoral stems and neck components has become a more frequently used tool for an optimized restoration of the hip joint center and improvement of patient biomechanics. The additional taper interface increases the risk of mechanical failure due to fretting and crevice corrosion. Several failures of titanium alloy neck adapters have been documented in case-reports. An experimental fretting device was developed in this study to systematically investigate the effect of micromotion and contact pressure on fretting damage in contact situations similar to taper interfaces of modular hip prostheses under cyclic loading representative of in vivo load conditions. As a first application, the fretting behavior of Ti-6Al-4V titanium alloy components was investigated. Micromotions were varied between 10MUm and 50MUm, maximum contact pressures between 400 and 860N/mm(2). All modes of fretting damage were observed: Fretting wear was found for high micromotions in combination with low contact pressures. Fretting fatigue occurred with reduced movement or increased contact pressures. With small micromotions or high normal pressures, low fretting damage was observed. The developed device can be used to evaluate taper design (and especially contact geometry) as well as different materials prior to clinical use. PMID- 22940447 TI - Enhanced binding of trigonal DNA-carbohydrate conjugates to lectin. AB - Novel trigonal DNA-carbohydrate conjugates were prepared and evaluated to explore efficient carbohydrate-lectin interactions. Carbohydrate-modified oligonucleotides were enzymatically prepared, then hybridized to form 3-way junction DNAs. The thermal stabilities of the junctions were assessed by UV melting analysis and formation of constructs was confirmed by gel electrophoresis. Fluorescence titration assays revealed that the trigonal DNA carbohydrate conjugates exhibit high affinity to lectins depending on the distribution of carbohydrates presented in each arm. These results suggest that self-assembled 3-way DNA architectures could offer a useful platform for controlling the spatial distribution of carbohydrates on conjugates and achieving more efficient molecular recognition. PMID- 22940446 TI - Mesenchymal stem cells increase collagen infiltration and improve wound healing response to porous titanium percutaneous implants. AB - Epidermal downgrowth, commonly associated with long-term percutaneous implants, weakens the skin-implant seal and greatly increases the vulnerability of the site to infection. To improve the skin attachment and early tissue integration with porous metal percutaneous implants, we evaluated the effect of bone marrow derived mesenchymal stem cells (BMMSCs) to provide wound healing cues and vascularization to the dermal and epidermal tissues in establishing a barrier with the implant. Two porous metal percutaneous implants, one treated with BMMSCs and one untreated, were placed subdermally on the dorsum of Lewis rats. Implants were evaluated at 0, 3, 7, 28, and 56 days after implantation. Histological analyses evaluated cellular infiltrates, vascularization, quantity and quality of tissue ingrowth, epidermal downgrowth, and fibrous encapsulation. The amount of collagen infiltrating the porous coating was significantly greater for the BMMSC treated implants at 3 and 28 days post implantation compared to untreated implants. There was an early influx and resolution of cellular inflammatory infiltrates in the treated implants compared to the untreated, though not statistically significant. Vascularization increased over time in both treated and untreated implants, with no statistical significance. Epidermal downgrowth was minimally observed in all implants with or without the BMMSC treatment. Our results suggest that BMMSCs can influence an early and rapid resolution of acute and chronic inflammation in wound healing, and can stimulate early collagen deposition and granulation tissue associated with later stages of wound repair. These findings provide evidence that BMMSCs can stimulate a more rapid and improved barrier between the skin and porous metal percutaneous implant. PMID- 22940448 TI - Rhododendric acid A, a new ursane-type PTP1B inhibitor from the endangered plant Rhododendron brachycarpum G. Don. AB - In spite of the critical role of the natural products in drug discovery, surprising little attention has been placed on endangered and rare plant species that could play a pivotal role in pharmaceutical and fiber development. Protein tyrosine phosphatase-1B (PTP1B), which blocks insulin signaling, has been gaining interest to be a promising therapeutic target for the treatment of type 2 diabetes mellitus. Bioassay-guided fractionation on the leaves of Rhododendron brachycarpum G. Don (Ericaceae) yielded seven PTP1B inhibitory triterpenoids, including a new triterpene, rhododendric acid A (1). Their PTP1B inhibitory potency and their lipophilicity were investigated to provide a feasible scaffold that may overcome the innate limitation of the previously reported PTP1B inhibitors. PMID- 22940449 TI - Chitooligosaccharides induce apoptosis in human myeloid leukemia HL-60 cells. AB - In this study we propose a novel anticancer agent using hetero chitooligosaccharide (hetero-COS). To examine the possibility of the hetero-COS as a anticancer agent, we prepared nine kinds of hetero-COS with relatively higher molecular weights (90, 75 and 50-COS I, 5-10kDa), medium molecular weights (90, 75 and 50-COS II, 1-5kDa), and lower molecular weights (90, 75 and 50-III, below 1kDa), and their anticancer properties were investigated on HL-60 cells using flow cytometry and morphological analysis. The results obtained indicate that 90-COS III, which is relatively higher degree of deacetylation and lower molecular weights, showed the highest anticancer activity, and the data showed the anticancer property of the hetero-COSs depended on their degree of deacetylation values and molecular weight. PMID- 22940450 TI - 13,28-Epoxy triterpenoid saponins from Ardisia japonica selectively inhibit proliferation of liver cancer cells without affecting normal liver cells. AB - Twenty 13,28-epoxy and related triterpenoid saponins from Ardisia japonica were evaluated for their anti-proliferative activity on human liver cancer cells and normal liver cells. Eight saponins selectively inhibited the growth of liver cancer Bel-7402 and HepG-2 cells without affecting the survival of normal liver HL-7702 cells. The structure-activity relationship analyses indicated that the 13,28-epoxy, 16alpha-hydroxy, and C-30 methyl moieties in the sapogenin parts and the glycosyl moiety consisting from tetra- to hepta-saccharide units are important for this activity. Among the active saponins, ardisianoside B (2) and 3beta-O-beta-d-glucopyranosyl-(1->2)-[alpha-l-rhamnopyranosyl-(1->2)-beta-d glucopyranosyl-(1->4)]-alpha-l-arabinopyranosyl-13beta,28-epoxy-16alpha hydroxyoleanane (3) showed the most potent anti-proliferative activity against Bel-7402 cells in a dose- and time-dependent manner. The selective anti proliferative activity is attributed to the different cellular responses (CDKs and cyclins levels, cell cycle arrest and apoptosis) between tumor and normal liver cells. Exposure to 2 and 3 selectively led to cell cycle arrest and apoptosis in Bel-7402 cells together with the increased pro-apoptotic caspase-8 and the decreased anti-apoptotic Cdc25A levels. PMID- 22940451 TI - Alloantigen-stimulated induction and release of CD30 in patients with end-stage renal failure. AB - High serum levels of soluble CD30 (sCD30) are associated with poor renal allograft survival, and regulatory T cells (Tregs) influence allograft survival depending on CD30 signaling. However, how sCD30 modulates alloimmune responses remains poorly understood. We measured the level of Tregs and sCD30 in patients with end-stage renal failure (ESRF) and analyzed whether allo- or polyclonal stimulation of the patients' T cells results in the expression and release of CD30. ESRF patients showed increased serum sCD30 levels and lower percentages of circulating Tregs as compared to healthy controls (HC) (p<0.001 and 0.024). Polyclonal and allogeneic stimulation resulted in higher expression of CD30, and after polyclonal stimulation, ESRF patients showed higher percentages of CD30 expressing T cells than HC (p<0.001). Compared to autologous stimulation, allogeneic stimulation induced significantly higher expression of CD30 on T cells of ESRF patients only. After polyclonal as well as allogeneic stimulation, an increased sCD30 content was found in culture supernatants of both ESRF patients and HC (p<0.001). Together with decreased Tregs, high serum sCD30 and increased induction of CD30 on T cells after polyclonal stimulation may explain exacerbated alloimmune responses and poor allograft survival in ESRF patients in whom immunosuppression is not able to control the alloimmune response. PMID- 22940453 TI - Expression patterns of defense genes in resistance of the panicles exserted from the caulis and from the tillers to neck blast in rice. AB - The rice variety Xiushui227 is resistant to neck blast in the panicles exserted from the caulis but susceptible in the panicles from the tillers, however, the other variety Xiushui09 is susceptible to neck blast in the panicles from the caulis but resistant in the panicles from the tillers. These two varieties were used to analyze the expression patterns of defense genes in the panicles from the caulis and the first first-class tiller at the preliminary heading stage, after inoculating the necks in vitro with Magnaporthe oryzae, respectively. All defense genes (pathogenesis-related genes PR1a, Gns1 (1,3; 1,4-beta-glucanase), Cht-1 (chitinase), PR4, PR5, and PR10a, secondary metabolite pathway genes PAL (phenylalanine ammonia-lyase), CHS (chalcone synthase), and LOX (lipoxygenase), and oxidative stress-related protein genes POX22.3 (peroxidase), and PPO (polyphenol oxidase)) used in this experiment except Cht-1 and PR5 could participate in defending Xiushui227 against neck blast in the panicles from the caulis. All defense genes used in this study except Cht-1, PR10a, and PPO may play roles in defending Xiushui09 against neck blast in the panicles from the tillers. PMID- 22940452 TI - takeout-dependent longevity is associated with altered Juvenile Hormone signaling. AB - In order to understand the molecular mechanisms of longevity regulation, we recently performed a screen designed to enrich for genes common to several longevity interventions. Using this approach, we identified the Drosophila melanogaster gene takeout. takeout is upregulated in a variety of long-lived flies, and extends life span when overexpressed. Here, we investigate the mechanisms of takeout-dependent longevity. takeout overexpression specifically in the fat body is sufficient to increase fly longevity and is additive to the longevity effects of Dietary Restriction. takeout long-lived flies do not show phenotypes often associated with increased longevity, such as enhanced stress resistance or major metabolic abnormalities. However, males exhibit greatly diminished courtship behavior, leading to a reduction in fertility. Interestingly, takeout contains a binding domain for Juvenile Hormone, a fly hormone that plays a role in the regulation of developmental transitions. Importantly, the longevity and courtship phenotypes of takeout overexpressing flies are reversed by treatment with the Juvenile Hormone analog methoprene. These data suggest that takeout is a key player in the tradeoff-switch between fertility and longevity. takeout may control fertility via modulation of courtship behavior. This regulation may occur through Juvenile Hormone binding to takeout and a subsequent reduction in Juvenile Hormone signaling activity. PMID- 22940454 TI - Maternal depression, family functioning and children's longitudinal development. AB - Analysis of data from the Canadian National Longitudinal Survey of Children and Youth reveals that 6% of children are born to mothers who experienced symptoms of depression during their first 2 years of life. The prevalence rises steadily until children are 10 years of age when it reaches 9%, and thereafter remains relatively stable. Children of depressed mothers are at increased risk of having low receptive vocabulary and displaying inattention or physical aggression at ages 4 to 5 years, only partially attributable to family demographic factors, family functioning and parenting qualities. Maternal depression occurring when the child was 2 to 3 years of age, was a risk factor for anxiety in 10 and 11 year olds. Timing or duration of maternal depression had no effect on math achievement. The risk of poor child outcome was greatest for mothers who experienced depression continuously or when their child was 2 to 3 years or older. Nurses need to assess and intervene to reduce the impact of depression on mothers and their children's development, well beyond the postpartum period. PMID- 22940455 TI - Vagus nerve stimulation modulates visceral pain-related affective memory. AB - Within a biopsychosocial model of pain, pain is seen as a conscious experience modulated by mental, emotional and sensory mechanisms. Recently, using a rodent visceral pain assay that combines the colorectal distension (CRD) model with the conditioned place avoidance (CPA) paradigms, we measured a learned behavior that directly reflects the affective component of visceral pain, and showed that perigenual anterior cingulate cortex (pACC) activation is critical for memory processing involved in long-term visceral affective state and prediction of aversive stimuli by contextual cue. Electrical vagus nerve stimulation (VNS) has become an established therapy for treatment-resistant epilepsy. VNS has also been shown to enhance memory performance in rats and humans. High-intensity VNS (400 MUA) immediately following conditional training significantly increases the CRD induced CPA scores, and enhanced the pain affective memory retention. In contrast, VNS (400 MUA) had no effect on CPA induced by non-nociceptive aversive stimulus (U69,593). Low-intensity VNS (40 MUA) had no effect on CRD-induced CPA. Electrophysiological recording showed that VNS (400 MUA) had no effect on basal and CRD-induced ACC neuronal firing. Further, VNS did not alter CRD-induced visceral pain responses suggesting high intensity VNS facilitates visceral pain aversive memory independent of sensory discriminative aspects of visceral pain processing. The findings that vagus nerve stimulation facilities visceral pain related affective memory underscore the importance of memory in visceral pain perception, and support the theory that postprandial factors may act on vagal afferents to modulate ongoing nature of visceral pain-induced affective disorder observed in the clinic, such as irritable bowel syndrome. PMID- 22940456 TI - The role of the medial prefrontal cortex in the acquisition, retention, and reversal of a tactile visuospatial conditional discrimination task. AB - The medial prefrontal cortex (mPFC) is responsible for executive functions such as abstract rule coding, strategy switching, and behavioral flexibility; however, there is some debate regarding the extent to which mPFC is involved in reversal learning, especially in complex multisensory tasks such as conditional discrimination. Therefore, we investigated the effects of mPFC inactivation on the acquisition, retention, and reversal of a visuospatial conditional discrimination (CD) task. In experiment 1, muscimol was infused through bilateral cannulae on days 1, 2, and 3 to test the effects of mPFC inactivation on task acquisition and days 19, 20, and 21 to test the effects on retention of the task. For experiment 2, rats were trained on the CD task for 21 days with no infusions given, after which the reward contingency was reversed, with infusions given during the first six days of reversal. The results of experiment 1 showed that the muscimol and saline groups did not differ on acquisition or retention. However, experiment 2 showed that the muscimol group displayed significantly more performance errors than the control group during reversal. Compared to the control group, the muscimol group also showed a decreased tendency to use a side bias strategy during the intermediate stages of reversal. The failure of the muscimol group to exhibit a side bias suggests that the mPFC is necessary for sampling strategies necessary for the reversal of a visuospatial CD task. PMID- 22940457 TI - Antidepressant-like effects of Cortex Mori Radicis extract via bidirectional phosphorylation of glucocorticoid receptors in the hippocampus. AB - Excessive and prolonged secretion of adrenal glucocorticoids leads to a wide range of pathophysiological processes, including depression. Glucocorticoids, which act at glucocorticoid receptors (GR), are key regulators of the limbic hypothalamic-pituitary-adrenocortical (HPA) axis. In the present study, the antidepressant-like effects of the alcohol extract Cortex Mori Radicis (CMR) and its role in GR signalling were investigated. Male Wistar rats were administered CMR extract (50, 100, 200mg/kg, p.o.) daily for 5 days and then exposed to the forced swim test (FST). Behavioural analyses showed that CMR extract dose dependently decreased immobility time during forced swimming. CMR extract also decreased the limbic HPA axis response to the FST, as indicated by an attenuated corticosterone response and decreased c-fos immunoreactivity in the dentate gyrus. Reduced hippocampal GR expression following exposure to the FST was reversed by CMR treatment. Moreover, a prominent increase in GR phosphorylation at S232 and a decrease at S246 were noted following treatment with CMR. This resulted in a high pGR(S232)/(S246) ratio. CMR treatment also produced a downregulation of serine/threonine protein phosphatase 5 levels, producing a strong negative relationship with pGR(S232). Taken together, our findings suggest that the alcohol extract CMR promotes antidepressant-like effects through bidirectional phosphorylation of GR at S232 and S246. PMID- 22940458 TI - Domestic sewage sludge composting in a rotary drum reactor: optimizing the thermophilic stage. AB - The aim of this paper was to study the influence of four process variables (turning frequency, gas-phase oxygen level, type of bulking agent and sludge/bulking agent mixing ratio) on the performance of the sewage sludge composting process using a rotary drum pilot scale reactor, in order to optimize the thermophilic stage and reduce the processing time. Powdered sawdust, wood shavings, wood chips, prunings waste and straw were used as bulking agents and the thermophilic stage temperature profile was used as the main indicator for gauging if the composting process was developing correctly. Our results showed that a 12 h(-1) turning frequency and an oxygen concentration of 10% were the optimal conditions for the composting process to develop. The best results were obtained by mixing the sewage sludge with wood shavings in a 3:1 w/w ratio (on a wet basis), which adapted the initial moisture content and porosity to an optimal range and led to a maximum temperature of 70 degrees C being reached thus ensuring the complete removal of pathogens. Moisture, C:N ratio, pH, organic matter, heavy metals, pathogens and stability were all analysed for every mixture obtained at the end of the thermophilic stage. These parameters were compared with the limits established by the Spanish regulation on fertilizers (RD 824/2005) in order to assess if the compost obtained could be used on agricultural soils. The right combination of having optimal process variables combined with an appropriate reactor design allowed the thermophilic stage of the composting process to be speeded up, hence obtaining a compost product, after just two weeks of processing that (with the exception of the moisture content) complied with the Spanish legal requirements for fertilizers, without requiring a later maturation stage. PMID- 22940459 TI - Road project opportunity costs subject to a regional constraint on greenhouse gas emissions. AB - France has constrained the Aquitaine region to set up a climate plan to avoid an emission of 2883 ktCO(2)eq for the period 2007-2013. In parallel, the region has decided to carry out the construction of road infrastructures in order to avoid very high congestion costs. Those road projects will involve an increase in greenhouse gas (GHG) emissions during that period. In the present context of strong sustainability, all emissions (direct and indirect) generated by those projects should be offset. At the regional level, the offsetting of GHG emissions is usually carried out by implementing carbon sequestration projects or projects that reduce energy demand. This paper aims at determining the maximum budget for financing GHG emissions offsetting projects, with computation being based on the opportunity costs of projects, the minimum cost of economic activity reduction required to offset emissions from those projects. The maximum budget devoted to GHG emissions offsetting projects should not exceed ?(2001) 1920 M to ?(2001) 3592 M, according to low/high traffic growth assumptions. PMID- 22940460 TI - Assessment of the role of in situ generated (E)-2,4-diene-valproic acid in the toxicity of valproic acid and (E)-2-ene-valproic acid in sandwich-cultured rat hepatocytes. AB - Valproic acid (VPA) undergoes cytochrome P450-mediated desaturation to form 4-ene VPA, which subsequently yields (E)-2,4-diene-VPA by beta-oxidation. Another biotransformation pathway involves beta-oxidation of VPA to form (E)-2-ene-VPA, which also generates (E)-2,4-diene-VPA by cytochrome P450-mediated desaturation. Although the synthetic form of (E)-2,4-diene-VPA is more hepatotoxic than VPA as shown in various experimental models, there is no conclusive evidence to implicate the in situ generated (E)-2,4-diene-VPA in VPA hepatotoxicity. The present study investigated the effects of modulating the in situ formation of (E) 2,4-diene-VPA on markers of oxidative stress (formation of 2',7' dichlorofluorescein; DCF), steatosis (accumulation of BODIPY 558/568 C12), necrosis (release of lactate dehydrogenase; LDH), and on cellular total glutathione (GSH) levels in sandwich-cultured rat hepatocytes treated with VPA or (E)-2-ene-VPA. Treatment with either of these chemicals alone increased each of the toxicity endpoints. In VPA-treated hepatocytes, (E)-2,4-diene-VPA was detected only at trace levels, even after phenobarbital (PB) pretreatment and there was no effect on the toxicity of VPA. Furthermore, pretreatment with a cytochrome P450 enzyme inhibitor, 1-aminobenzotriazole (1-ABT), did not influence the extent of VPA toxicity in both PB-pretreated and vehicle-pretreated hepatocytes. However, in (E)-2-ene-VPA-treated hepatocytes, PB pretreatment greatly enhanced the levels of (E)-2,4-diene-VPA and this was accompanied by a further enhancement of the effects of (E)-2-ene-VPA on DCF formation, BODIPY accumulation, LDH release, and GSH depletion. Pretreatment with 1-ABT reduced the concentrations of (E)-2,4-diene-VPA and the extent of (E)-2-ene-VPA toxicity; however, this occurred in PB-pretreated hepatocytes, but not in control hepatocytes. In conclusion, in situ generated (E)-2,4-diene-VPA is not responsible for the hepatocyte toxicity of VPA, whereas it contributes to the toxicity of (E)-2-ene-VPA in PB-pretreated rat hepatocytes. PMID- 22940461 TI - Hybrid advantage in skin peptide immune defenses of water frogs (Pelophylax esculentus) at risk from emerging pathogens. AB - Heterogeneity in immune defense effectors can benefit hosts encountering a variety of parasites and pathogens. Antimicrobial peptides (AMPs) are a diverse set of immune defense effectors in many amphibians, and are secreted from dermal granular glands to protect the skin from infection. Over 50 different skin peptides have been reported from the European water frog hybridogenic complex (Pelophylax esculentus complex), consisting of the hybrid P. esculentus, and the parent species Pelophylax lessonae and Pelophylax ridibundus. In central Europe the hybrid is sympatric with only P. lessonae, while in other areas all three species can co-occur. Amphibian immune defenses are likely under selective pressure from emerging pathogens such as the chytrid fungus Batrachochytrium dendrobatidis (Bd). To assess if hybridization affects immune defenses against Bd, we compared skin peptides of the three species in terms of (i) quantity, (ii) activity against Bd, (iii) repertoire, and (iv) stability. Hybrids secreted AMPs at higher quantities and with greater fungicidal activity compared to cohabiting P. lessonae. Compared to P. ridibundus, AMPs from hybrids were of similar quantity but slightly greater antifungal activity. Mass spectrometric analyses (MALDI-TOF) revealed that of all three species P. esculentus has the greatest peptide diversity, a repertoire inclusive of peptides occurring in either one or the other parent species. Measurements of degradation dynamics indicate that peptides remain relatively stable on the skin of all species for over an hour after induction of skin gland secretions. Our data demonstrate that the hybrid has more effective peptide defenses against Bd and a richer peptide repertoire than either parent species. Hybrid advantage in environments hosting virulent pathogens may contribute to disassortative mating preferences, and we suggest that AMP diversity may be analogous to major histocompatibility complex (MHC) heterozygosity by benefiting hosts encountering multiple parasites. PMID- 22940462 TI - Associations between daily chronic pain intensity, daily anger expression, and trait anger expressiveness: an ecological momentary assessment study. AB - Links between elevated trait anger expressiveness (anger-out) and greater chronic pain intensity are well documented, but pain-related effects of expressive behaviors actually used to regulate anger when it is experienced have been little explored. This study used ecological momentary assessment methods to explore prospective associations between daily behavioral anger expression and daily chronic pain intensity. Forty-eight chronic low back pain (LBP) patients and 36 healthy controls completed electronic diary ratings of momentary pain and behavioral anger expression in response to random prompts 4 times daily for 7 days. Across groups, greater trait anger-out was associated with greater daily behavioral anger expression (P<0.001). LBP participants showed higher levels of daily anger expression than controls (P<0.001). Generalized estimating equation analyses in the LBP group revealed a lagged main effect of greater behavioral anger expression on increased chronic pain intensity in the subsequent assessment period (P<0.05). Examination of a trait*situation model for anger-out revealed prospective associations between elevated chronic pain intensity and later increases in behavioral anger expression that were restricted largely to individuals low in trait anger-out (P<0.001). Trait*situation interactions for trait anger suppression (anger-in) indicated similar influences of pain intensity on subsequent behavioral anger expression occurring among low anger-in persons (P<0.001). Overlap with trait and state negative affect did not account for study findings. This study for the first time documents lagged within-day influences of behavioral anger expression on subsequent chronic pain intensity. Trait anger regulation style may moderate associations between behavioral anger expression and chronic pain intensity. PMID- 22940463 TI - Predictors of chronic shoulder pain after 5 years in a working population. AB - The role of psychosocial and physical factors in the development of shoulder pain has now been clearly demonstrated. However, only a few studies have analyzed these associations over time. The main goal of this study was to evaluate the predictive value of work-related psychological and mechanical factors on chronic shoulder pain. A total of 12,714 subjects (65% men) born in 1938, 1943, 1948, and 1953 participating in a French prospective longitudinal epidemiological investigation in 1990 to 1995 Enquete Sante Travail Et Vieillissement (ESTEV) were included. Clinical examination was performed by 400 trained occupational physicians. Personal factors and work exposure were assessed by self-administered questionnaires. Statistical associations between chronic shoulder pain and personal and occupational factors were analyzed using logistic regression modeling. A total of 1706 subjects experienced chronic shoulder pain in 1990, and 2089 experienced chronic shoulder pain in 1995. The incidence of chronic shoulder pain in 1995 was 11% (n=1355). Forceful effort (odds ratio [OR]=1.24 95% CI [1.05 1.44], awkward posture (OR=1.34 95% CI [1.19-1.52]), decision latitude (OR=1.19 [1.04 to 1.35]), and psychological demand (OR=1.19 95% CI [1.06-1.32]) in 1990 were significantly associated with chronic shoulder pain in 1995, even after adjustment for personal factors and previous shoulder pain status. Awkward posture (OR=1.43 [1.25 to 1.63]), psychological demand (OR=1.24 [1.09 to 1.40]), and decision latitude (OR=1.21 [1.04 to 1.41] work-related factors in 1990 were associated with the development of chronic shoulder pain between 1990 and 1995. These results suggest that awkward posture, forceful effort, job demand, and decision control are predictors of chronic shoulder pain at work. Interventions designed to reduce the incidence of chronic shoulder pain must include both mechanical and psychological factors. PMID- 22940464 TI - Effects of gonadal hormones on the peripheral cannabinoid receptor 1 (CB1R) system under a myositis condition in rats. AB - In this study, we assessed the effects of peripherally administered cannabinoids in an orofacial myositis model, and the role of sex hormones in cannabinoid receptor (CBR) expression in trigeminal ganglia (TG). Peripherally administered arachidonylcyclopropylamide (ACPA), a specific CB1R agonist, significantly attenuated complete Freund's adjuvant (CFA)-induced mechanical hypersensitivity in the masseter muscle in male rats. The ACPA effect was blocked by a local administration of AM251, a specific CB1R antagonist, but not by AM630, a specific CB2R antagonist. In female rats, a 30-fold higher dose of ACPA was required to produce a moderate reduction in mechanical hypersensitivity. CFA injected in masseter muscle significantly upregulated CB1R mRNA expression in TG in male, but not in female, rats. There was a close correlation between the CB1R mRNA levels in TG and the antihyperalgesic effect of ACPA. Interleukin (IL)-1beta and IL-6, which are elevated in the muscle tissue following CFA treatment, induced a significant upregulation of CB1R mRNA expression in TG from male rats. The upregulation of CB1R was prevented in TG cultures from orchidectomized male rats, which was restored by the application of testosterone. The cytokines did not alter the CB1R mRNA level in TG from intact as well as ovariectomized female rats. Neither estradiol supplement nor estrogen receptor blockade had any effects on CB1R expression. These data indicate that testosterone, but not estradiol, is required for the regulation of CB1Rs in TG under inflammatory conditions, which provide explanations for the sex differences in the antihyperalgesic effects of peripherally administered cannabinoids. PMID- 22940465 TI - Fragrance chemicals lyral and lilial decrease viability of HaCat cells' by increasing free radical production and lowering intracellular ATP level: protection by antioxidants. AB - We investigate in this study the biochemical effects on cells in culture of two commonly used fragrance chemicals: lyral and lilial. Whereas both chemicals exerted a significant effect on primary keratinocyte(s), HaCat cells, no effect was obtained with any of HepG2, Hek293, Caco2, NIH3T3, and MCF7 cells. Lyral and lilial: (a) decreased the viability of HaCat cells with a 50% cell death at 100 and 60 nM respectively; (b) decreased significantly in a dose dependant manner the intracellular ATP level following 12-h of treatment; (c) inhibited complexes I and II of electron transport chain in liver sub-mitochondrial particles; and (d) increased reactive oxygen species generation that was reversed by N-acetyl cysteine and trolox and the natural antioxidant lipoic acid, without influencing the level of free and/or oxidized glutathione. Lipoic acid protected HaCat cells against the decrease in viability induced by either compound. Dehydrogenation of lyral and lilial produce alpha,beta-unsaturated aldehydes, that reacts with lipoic acid requiring proteins resulting in their inhibition. We propose lyral and lilial as toxic to mitochondria that have a direct effect on electron transport chain, increase ROS production, derange mitochondrial membrane potential, and decrease cellular ATP level, leading thus to cell death. PMID- 22940466 TI - Silver nanoparticles induce toxicity in A549 cells via ROS-dependent and ROS independent pathways. AB - Silver nanoparticles (AgNPs) are incorporated into a large number of consumer and medical products. Several experiments have demonstrated that AgNPs can be toxic to the vital organs of humans and especially to the lung. The present study evaluated the in vitro mechanisms of AgNP (<100 nm) toxicity in relationship to the generation of reactive oxygen species (ROS) in A549 cells. AgNPs caused ROS formation in the cells, a reduction in their cell viability and mitochondrial membrane potential (MMP), an increase in the proportion of cells in the sub-G1 (apoptosis) population, S phase arrest and down-regulation of the cell cycle associated proliferating cell nuclear antigen (PCNA) protein, in a concentration- and time-dependent manner. Pretreatment of the A549 cells with N-acetyl-cysteine (NAC), an antioxidant, decreased the effects of AgNPs on the reduced cell viability, change in the MMP and proportion of cells in the sub-G1population, but had no effect on the AgNP-mediated S phase arrest or down-regulation of PCNA. These observations allow us to propose that the in vitro toxic effects of AgNPs on A549 cells are mediated via both ROS-dependent (cytotoxicity) and ROS independent (cell cycle arrest) pathways. PMID- 22940467 TI - [Giant-cell arteritis and Takayasu arteritis: epidemiological, diagnostic and treatment aspects]. AB - Giant-cell arteritis (GCA) and Takayasu arteritis (TAK) are primary systemic granulomatous large-vessel vasculitides. Whether both entities represent distinct phenotypic expressions of a shared etiopathogenic process remains hypothetical. GCA more commonly affects subjects of northern European background while the clinical observation that TAK might be more common in populations of Asian or African ancestry needs to be confirmed by epidemiological studies. Distinct human leukocyte antigen class II associations were identified as genetic risk factors of GCA and TAK. The increasing incidence of GCA also suggests an environmental cause. Temporal artery biopsy is the main diagnostic test for GCA, although MRI and Doppler ultrasonography of the temporal or occipital arteries may also reveal vessel wall inflammation. MRI, CT and positron emission tomography with 18F fluodeoxyglucose have progressively replaced conventional invasive imaging modalities for study of large-vessel disease. The diagnostic accuracy of these 3 imaging modalities seems equivalent, but their value in the follow-up of GCA and TAK is less clear. According to studies based on modern imaging techniques, 70 80% of patients with newly diagnosed GCA show an involvement of the aorta and/or the major branches of the aorta. Glucocorticoids are the reference therapy for GCA. Adjunctive therapy, notably with methotrexate, appears to enhance disease control and reduce glucocorticoid exposure. IL-6 blockade has hope as a new treatment option for GCA. Principles of therapy for TAK are similar to those of GCA, except that TNFalpha blockers, particularly infliximab, seem to show good results in TAK and revascularization procedures are an important part of the TAK therapy. PMID- 22940468 TI - Electrical activity can impose time of day on the circadian transcriptome of pacemaker neurons. AB - BACKGROUND: Circadian (~24 hr) rhythms offer one of the best examples of how gene expression is tied to behavior. Circadian pacemaker neurons contain molecular clocks that control 24 hr rhythms in gene expression that in turn regulate electrical activity rhythms to control behavior. RESULTS: Here we demonstrate the inverse relationship: there are broad transcriptional changes in Drosophila clock neurons (LN(v)s) in response to altered electrical activity, including a large set of circadian genes. Hyperexciting LN(v)s creates a morning-like expression profile for many circadian genes while hyperpolarization leads to an evening-like transcriptional state. The electrical effects robustly persist in per(0) mutant LN(v)s but not in cyc(0) mutant LN(v)s, suggesting that neuronal activity interacts with the transcriptional activators of the core circadian clock. Bioinformatic and immunocytochemical analyses suggest that CREB family transcription factors link LN(v) electrical state to circadian gene expression. CONCLUSIONS: The electrical state of a clock neuron can impose time of day to its transcriptional program. We propose that this acts as an internal zeitgeber to add robustness and precision to circadian behavioral rhythms. PMID- 22940469 TI - A predictive computational model of the dynamic 3D interphase yeast nucleus. AB - BACKGROUND: Despite the absence of internal membranes, the nucleus of eukaryotic cells is spatially organized, with chromosomes and individual loci occupying dynamic, but nonrandom, spatial positions relative to nuclear landmarks and to each other. These positional preferences correlate with gene expression and DNA repair, recombination, and replication. Yet the principles that govern nuclear organization remain poorly understood and detailed predictive models are lacking. RESULTS: We present a computational model of dynamic chromosome configurations in the interphase yeast nucleus that is based on first principles and is able to statistically predict the positioning of any locus in nuclear space. Despite its simplicity, the model agrees with extensive previous and new measurements on locus positioning and with genome-wide DNA contact frequencies. Notably, our model recapitulates the position and morphology of the nucleolus, the observed variations in locus positions, and variations in contact frequencies within and across chromosomes, as well as subchromosomal contact features. The model is also able to correctly predict nuclear reorganization accompanying a reduction in ribosomal DNA transcription, and sites of chromosomal rearrangements tend to occur where the model predicted high contact frequencies. CONCLUSIONS: Our results suggest that large-scale yeast nuclear architecture can be largely understood as a consequence of generic properties of crowded polymers rather than of specific DNA-binding factors and that configurations of chromosomes and DNA contacts are dictated mainly by genomic location and chromosome lengths. Our model provides a quantitative framework to understand and predict large-scale spatial genome organization and its interplay with functional processes. PMID- 22940470 TI - DNA methylation dynamics during sexual reproduction in Arabidopsis thaliana. AB - DNA methylation maintains genome stability and regulates gene expression [1]. In mammals, DNA methylation is reprogrammed in the germline from one generation to the next [2]. In plants, it was considered that patterns of DNA methylation are stably maintained through sexual reproduction [3-6]. However, a recent report showed discrete variations of DNA methylation profiles from mother to daughter plants [7]. The mechanisms that explain these variations have remained unknown. Here, we report that maintenance DNA methyltransferases are barely expressed during Arabidopsis female gametogenesis. In contrast, after fertilization both maintenance and de novo DNA methyltransferases are expressed strongly in the embryo. Embryogenesis is marked by increased de novo DNA methylation, reaching levels that are further maintained in the adult plant. The accumulation of these epigenetic marks after fertilization silences a methylation-sensitive fluorescent reporter. De novo DNA methylation in the embryo provides a mechanism that could account for the gradual remethylation of experimentally demethylated genomes [8, 9]. In conclusion, we uncover that DNA methylation activity fluctuates during sexual reproduction. This cycle likely explains variations of genome-wide patterns of DNA methylation across generations in Arabidopsis [7, 10] and enables a limited degree of reprogramming of the epigenome. PMID- 22940471 TI - Neutrophil-delivered myeloperoxidase dampens the hydrogen peroxide burst after tissue wounding in zebrafish. AB - Prompt neutrophil arrival is critical for host defense immediately after injury [1-3]. Following wounding, a hydrogen peroxide (H(2)O(2)) burst generated in injured tissues is the earliest known leukocyte chemoattractant [4]. Generating this tissue-scale H(2)O(2) gradient uses dual oxidase [4] and neutrophils sense H(2)O(2) by a mechanism involving the LYN Src-family kinase [5], but the molecular mechanisms responsible for H(2)O(2) clearance are unknown [6]. Neutrophils carry abundant amounts of myeloperoxidase, an enzyme catalyzing an H(2)O(2)-consuming reaction [7, 8]. We hypothesized that this neutrophil delivered myeloperoxidase downregulates the high tissue H(2)O(2) concentrations that follow wounding. This was tested in zebrafish using simultaneous fluorophore based imaging of H(2)O(2) concentrations and leukocytes [4, 9-11] and a new neutrophil-replete but myeloperoxidase-deficient mutant (durif). Leukocyte depleted zebrafish had an abnormally sustained wound H(2)O(2) burst, indicating that leukocytes themselves were required for H(2)O(2) downregulation. Myeloperoxidase-deficient zebrafish also had abnormally sustained high wound H(2)O(2) concentrations despite similar numbers of arriving neutrophils. A local H(2)O(2)/myeloperoxidase interaction within wound-recruited neutrophils was demonstrated. These data demonstrate that leukocyte-delivered myeloperoxidase cell-autonomously downregulates tissue-generated wound H(2)O(2) gradients in vivo, defining a new requirement for myeloperoxidase during inflammation. Durif provides a new animal model of myeloperoxidase deficiency closely phenocopying the prevalent human disorder [7, 12, 13], offering unique possibilities for investigating its clinical consequences. PMID- 22940472 TI - Autonomous circuitry for substrate exploration in freely moving Drosophila larvae. AB - BACKGROUND: Many organisms, from bacteria to human hunter-gatherers, use specialized random walk strategies to explore their environment. Such behaviors are an efficient stratagem for sampling the environment and usually consist of an alternation between straight runs and turns that redirect these runs. Drosophila larvae execute an exploratory routine of this kind that consists of sequences of straight crawls, pauses, turns, and redirected crawls. Central pattern generating networks underlying rhythmic movements are distributed along the anteroposterior axis of the nervous system. The way in which the operation of these networks is incorporated into extended behavioral routines such as substrate exploration has not yet been explored. In particular, the part played by the brain in dictating the sequence of movements required is unknown. RESULTS: We report the use of a genetic method to block synaptic activity acutely in the brain and subesophageal ganglia (SOG) of larvae during active exploratory behavior. We show that the brain and SOG are not required for the normal performance of an exploratory routine. Alternation between crawls and turns is an intrinsic property of the abdominal and/or thoracic networks. The brain modifies this autonomous routine during goal-directed movements such as those of chemotaxis. Nonetheless, light avoidance behavior can be mediated in the absence of brain activity solely by the sensorimotor system of the abdomen and thorax. CONCLUSIONS: The sequence of movements for substrate exploration is an autonomous capacity of the thoracic and abdominal nervous system. The brain modulates this exploratory routine in response to environmental cues. PMID- 22940473 TI - Cognitive ability influences reproductive life history variation in the wild. AB - Cognition has been studied intensively for several decades, but the evolutionary processes that shape individual variation in cognitive traits remain elusive [1 3]. For instance, the strength of selection on a cognitive trait has never been estimated in a natural population, and the possibility that positive links with life history variation [1-5] are mitigated by costs [6] or confounded by ecological factors remains unexplored in the wild. We assessed novel problem solving performance in 468 wild great tits Parus major temporarily taken into captivity and subsequently followed up their reproductive performance in the wild. Problem-solver females produced larger clutches than nonsolvers. This benefit did not arise because solvers timed their breeding better, occupied better habitats, or compromised offspring quality or their own survival. Instead, foraging range size and day length were relatively small and short, respectively, for solvers, suggesting that they were more efficient at exploiting their environment. In contrast to the positive effect on clutch size, problem solvers deserted their nests more often, leading to little or no overall selection on problem-solving performance. Our results are consistent with the idea that variation in cognitive ability is shaped by contrasting effects on different life history traits directly linked to fitness [1, 3]. PMID- 22940474 TI - Liquid chromatography-tandem mass spectrometric assay for the ALK inhibitor crizotinib in mouse plasma. AB - A quantitative bioanalytical liquid chromatography-tandem mass spectrometric (LC MS/MS) assay for the ALK inhibitor crizotinib was developed and validated. Plasma samples were pre-treated using protein precipitation with acetonitrile containing crizotinib-(13)C(2)-(2)H(5) as internal standard. The extract was directly injected into the chromatographic system after dilution with water. This system consisted of a sub-2 MUm particle, trifunctional bonded octadecyl silica column with a gradient using 0.1% (v/v) of ammonium hydroxide in water and methanol. The eluate was transferred into the electrospray interface with positive ionization and the analyte was detected in the selected reaction monitoring mode of a triple quadrupole mass spectrometer. The assay was validated in a 10-10,000 ng/ml calibration range with r(2)=0.99980+/-0.00014 for double logarithmic linear regression (n=5). Within day precisions (n=6) were 3.4-4.8%, between day (3 days; n=18) precisions 3.6-4.9%. Accuracies were between 107% and 112% for the whole calibration range. The drug was sufficiently stable under all relevant analytical conditions. Oxidative metabolites of crizotinib were monitored semi quantitatively. Finally, the assay was successfully used to assess drug pharmacokinetics in mice. PMID- 22940475 TI - Neuropsychological correlates of the P300 in patients with Alzheimer's disease. AB - OBJECTIVES: The P300 is a useful psychophysiological index that reflects cognitive functions; however, the relationship between P300 indices and neuropsychological tests in Alzheimer's disease (AD) patients is unclear. METHODS: Thirty-one AD patients and 31 elderly normal control (NC) subjects were recruited. Age and education level were matched between the two groups. The relationship between the P300 and the Korean version of the Consortium to Establish a Registry for Alzheimer's disease (CERAD-K) assessment packet (including 11 neuropsychological tests) was examined in AD patients. RESULTS: Compared to the NC subjects, the AD patients exhibited significantly decreased P300 amplitudes; however, there was no significant difference between the two groups in terms of P300 latency. After a permutation-based correction for multiple tests, P300 amplitudes at the Cz and Pz electrodes were significantly correlated with performance on the word list recognition, constructional praxis, and word fluency neuropsychological tests in the AD patients. Additionally, P300 latencies at the Pz and C6 electrodes were also significantly correlated with performance on the Mini-Mental State Examination, CERAD-K version (MMSE-K), and Trail Making Test part A (TMT-A) neuropsychological tests in the AD patients. CONCLUSIONS: The results suggest that the P300 is responsive to the deterioration of language, memory, and executive functions observed in AD patients. Although there was no significant difference between the AD patients and NC subjects in the P300 latency, P300 latency has been shown to reflect impaired global cognition and attention deficits associated with AD. Our results suggest that P300 indices could be used as biological markers that indicate impaired neuropsychological functions in AD patients. PMID- 22940476 TI - Effects of ADORA2A gene variation and caffeine on prepulse inhibition: a multi level risk model of anxiety. AB - The complex pathogenesis of anxiety and panic disorder in particular has been suggested to be influenced by genetic factors such as the adenosine A2A receptor gene (ADORA2A) 1976T>C polymorphism (rs5751876) as well as neuropsychological factors such as early information processing deficits. In 114 healthy individuals (males=57, females=57) controlled for anxiety sensitivity (AS), a multi-level risk model of the development of anxiety was applied: Genetic (ADORA2A 1976T>C variant) and biochemical (300 mg of caffeine citrate vs. placebo) factors were hypothesized to influence early information processing as measured by the prepulse inhibition/facilitation paradigm (stimulus onset asynchronies (SOAs) of 60, 120, 240, 480 and 2000ms between prepulses and startle stimuli). A fourfold interaction of genotype, intervention, gender, and SOAs was discerned. Stratification by SOAs revealed that at 120 ms and 240 ms SOAs in the caffeine condition, PPI was impaired in female ADORA2A 1976TT risk genotype carriers as compared to male ADORA2A 1976TT homozygotes, while no significant effects were observed in the ADORA2A 1976CC/CT non-risk genotype or placebo group. Only in high anxiety sensitive probands, a significant intervention effect was discerned with impaired prepulse facilitation (PPF) due to caffeine. The present results point to an impaired ability to selectively process very early information and to gate irrelevant sensory information, respectively, in female ADORA2A 1976TT homozygotes in response to caffeine, providing further evidence for the adenosinergic system to be involved in the pathogenesis of anxiety. PMID- 22940477 TI - Parkinson's disease in patients and obligate carriers of Gaucher disease. AB - BACKGROUND: Gaucher disease is an autosomal recessive disorder caused by glucocerebrosidase gene mutations. Accumulating evidence from several Parkinson's disease cohorts of varying ethnicities suggests that glucocerebrosidase mutations even in the heterozygous state (carriers) may be a susceptibility factor for Parkinson's. Very few studies have analyzed the frequency of Parkinson's in carriers and individuals with Gaucher disease. OBJECTIVE: To determine frequency of Parkinson's in patients with Gaucher disease and obligate carriers of glucocerebrosidase mutations and compare it with a control group. METHODS: A questionnaire was completed by 100 Ashkenazi Jewish Gaucher patients followed at our center and 109 ethnicity-matched controls with no personal or family history of Gaucher disease. RESULTS: Frequency of Parkinson's was higher in Gaucher patients (8/100) than in controls (0/109; P = 0.0024). Frequency of Parkinson's in obligate carriers (11/200) was higher than controls (6/218), but the difference was not statistically significant (P = 0.215). Average age of onset of Parkinson's was earlier in Gaucher patients (57.2) than the general population and in obligate carriers (60) when compared with controls (76.8; P = 0.01). The L444P genotype was more frequent in Gaucher patients who reported a parent with Parkinson's (36.40%) than those who did not (4.50%). CONCLUSION: Our study suggests that the risk for developing Parkinson's may be higher in affected versus carriers of glucocerebrosidase mutations and suggests that L444P may pose a higher risk of developing Parkinson's than other mutations. It also confirms previous findings that the age of onset of Parkinson's associated with glucocerebrosidase mutations is earlier than in the general population. PMID- 22940478 TI - Hco-LGC-38 is novel nematode cys-loop GABA receptor subunit. AB - We have identified and characterized a novel cys-loop GABA receptor subunit (Hco LGC-38) from the parasitic nematode Haemonchus contortus. This subunit is present in parasitic and free-living nematodes and shares similarity to both the UNC-49 group of GABA receptor subunits from nematodes and the resistant to dieldrin (RDL) receptors of insects. Expression of the Hco-lgc-38 gene in Xenopus oocytes and subsequent electrophysiological analysis has revealed that the gene encodes a homomeric channel sensitive to GABA (EC(50) 19 MUM) and the GABA analogue muscimol. The sensitivity of the Hco-LGC-38 channel to GABA is similar to reported values for the Drosophila RDL receptor whereas its lower sensitivity to muscimol is similar to nematode GABA receptors. Hco-LGC-38 is also highly sensitive to the channel blocker picrotoxin and moderately sensitive to fipronil and dieldrin. Homology modeling of Hco-LGC-38 and subsequent docking of GABA and muscimol into the binding site has uncovered several types of potential interactions with binding-site residues and overall appears to share similarity with models of other invertebrate GABA receptors. PMID- 22940479 TI - A regional approach for mineral soil weathering estimation and critical load assessment in boreal Saskatchewan, Canada. AB - In boreal regions of the province of Saskatchewan, Canada, there is concern over emerging acid precursor emission sources associated with the oil sands industry. Base cation weathering rates (BC(w)) and steady-state critical loads of sulfur (CL(S)) were identified for upland forest soil plots (n=107) in 45 ecodistricts according to a new method for approximation of BC(w) in the region. This method was developed by regression of simple soil and site properties with BC(w) calculated through application of a soil chemical model (PROFILE). PROFILE was parameterized using detailed physicochemical data for a subset (n=35) of the sites. Sand content, soil moisture and latitude emerged as important predictive variables in this empirical regression approximation. Base cation weathering varied widely (0.1-8000 mmol(c) m(-3) yr(-1)) across the study sites, consistent with their contrasting soil properties. Several sites had lower rates than observed in other acid-sensitive regions of Canada owing to quartz dominated mineralogy and coarse-textured soils with very low surface area. Weathering was variable within ecodistricts, although rates were consistently low among ecodistricts located in the northwest of the province. Overall, half of the forest plots demonstrated CL(S) less than 45 mmol(c) m(-2) yr(-1). Historically, the acidification risk in this region has been considered low and monitoring has been limited. Given the very low CL(S) in many northern ecodistricts and the potential for increased acid deposition as oil sands activities expand, soil acidification in these regions warrants further study. PMID- 22940480 TI - Wastewater filtration and re-use: an alternative water source for London. AB - The rapid growth and climate of the Greater London region have contributed towards large deficits in water supply. Inexpensive, energy-efficient and sustainable water resource schemes are increasingly sought as a means to boost supply. Here, we propose a small-scale recycling scheme whereby tertiary-treated wastewater is pumped to the Cretaceous chalk of the London Basin. By taking advantage of the natural filtration properties of the underlying chalk, contaminants can be effectively attenuated over relatively short length scales to result in pure water. The problem is approached from four different scales. First, we define two localities in London where such a pumping scheme might operate; regions which combine a thick unsaturated zone and high chalk transmissivity, both essential to ensure maximum contaminant removal and minimum environmental impact. Secondly, the effects of pumping fluid into the Chalk at the two localities are quantified using a finite-difference groundwater flow model. We show that rivers impose a regular groundwater flow regime, whereas pre existing abstraction wells will lead to less predictable results. Thirdly, we consider the effect of fractures on channelling rapid fluid flow within the rock mass. By digitising a fracture map based upon outcrop measurements from chalk exposed on the Kent coast similar to that beneath London, we quantify transport patterns of wastewater after injection. Imbibition to the chalk matrix (and therefore filtration) will occur where fluid pressure gradients are highest, for instance around disconnected fracture tips. Finally we demonstrate the efficacy of chalk in contaminant removal by injecting an analogue 'effluent' through a chalk core. ICP-AES analysis on the recovered solution shows the contaminants (viz. a suite of heavy metals) are arrested or removed over relatively small time and length-scales. Numerical and analytical solutions fit the data poorly, shedding some light on the importance of hydrodynamic dispersion of aqueous contaminants within the chalk. PMID- 22940481 TI - Burnt sugarcane harvesting: particulate matter exposure and the effects on lung function, oxidative stress, and urinary 1-hydroxypyrene. AB - Non-mechanised sugarcane harvesting preceded by burning exposes workers and the people of neighbouring towns to high concentrations of pollutants. This study was aimed to evaluate the respiratory symptoms, lung function and oxidative stress markers in sugarcane workers and the residents of Mendonca, an agricultural town in Brazil, during the non-harvesting and harvesting periods and to assess the population and individual exposures to fine particulate matter (PM(2.5)). Sugarcane workers and healthy volunteers were evaluated with two respiratory symptom questionnaires, spirometry, urinary 1-hydroxypyrene levels, and the measurement of antioxidant enzymes and plasma malonaldehyde during the non harvesting and harvesting periods. The environmental assessment was determined from PM(2.5) concentration. PM(2.5) level increased from 8 MUg/m3 during the non harvesting period to 23.5 MUg/m3 in the town and 61 MUg/m3 on the plantations during the harvesting period. Wheezing, coughing, sneezing, and breathlessness increased significantly in both groups during the harvesting period, but more markedly in workers. A decrease in lung function and antioxidant enzyme activity was observed in both populations during harvesting; this decrease was greater among the sugarcane workers. The urinary 1-hydroxypyrene levels only increased in the sugarcane workers during the harvesting period. The malonaldehyde levels were elevated in both groups, with a higher increase observed in the workers. This research demonstrates the exposure of sugarcane workers and the inhabitants of a neighbouring town to high PM(2.5) concentrations during the sugarcane harvest period. This exposure was higher among the sugarcane workers, as illustrated by both higher PM(2.5) concentrations in the sugarcane fields and higher urinary 1 hydroxypyrene levels in the volunteers in this group. The higher incidence of respiratory symptoms, greater decrease in lung function and more marked elevation of oxidative stress markers among the sugarcane workers during the harvest confirms the greater effect magnitude in this population and a dose-dependent relationship between pollution and the observed effects. PMID- 22940482 TI - Occurrences of nitrosamines in chlorinated and chloraminated drinking water in three representative cities, China. AB - An investigation of the occurrence of nine nitrosamines in drinking water following different water treatment processes was conducted using samples from seven drinking water treatment plants in three cities and tap waters in one city in China. The total nitrosamine levels ranged from not detected (n.d.) to 43.45 ng/L. The species and concentrations of the nine nitrosamines varied with disinfection methods and source waters. N-nitrosodimethylamine (NDMA), which is the nitrosamines of greatest concern, was identified in raw water, disinfecting water, finished water and tap water samples, ranging from 0.8 to 21.6, 0.12 to 24.2, n.d. to 8.8, and n.d. to 13.3 ng/L, respectively. Chloramination alone produced the most significant amounts of NDMA, while ozonation followed by chloramination led to moderately reduced levels. Additionally, chlorination produced relatively less NDMA, while low pressure ultraviolet radiation followed by chlorination could also significantly reduce them. Total organic carbon is one of the most important factors influencing nitrosamines formation in disinfecting water. In contrast, the addition of chlorine following any other disinfection was found to increase the formation of the other eight species of nitrosamines. The three nitrosamines recommended for monitoring by the US EPA were detected in the tap water samples, but most were present at levels below those that pose a risk to human health. Nevertheless, the occurrence and concentration of nitrosamines regulated in the Drinking Water Contaminant Candidate List could cause some potential human effects and therefore warrant attention. PMID- 22940483 TI - Assessment of the contribution from wood burning to the PM10 aerosol in Flanders, Belgium. AB - From February 2010 to February 2011 PM10 aerosol samples were simultaneously taken every 4th day at 7 monitoring sites in Flanders, Belgium. Two of the sites (i.e., Borgerhout and Gent) were urban background sites; one (i.e., Mechelen) a suburban background site, and the other four (i.e., Hamme, Lier, Retie, and Houtem) rural background sites, whereby Hamme and Lier were expected to be particularly impacted by biomass burning. The samplings were done for 24h and 47 mm diameter Pallflex(r) TissuquartzTM 2500 QAT-UP filters were used. After sampling the PM10 mass concentration was determined by weighing; organic and elemental carbon (OC and EC) were measured by thermal-optical transmission analysis and the wood burning tracers levoglucosan, mannosan, and galactosan were determined by means of gas chromatography/mass spectrometry. The atmospheric concentrations of levoglucosan and the other two monosaccharide anhydrides showed a very clear seasonal variation at each site, with highest levels in winter, followed by autumn, spring, and summer. The levoglucosan levels for 5 of our 7 sites (i.e., Retie, Lier, Mechelen, Borgerhout, and Gent) were very highly correlated with each other (all between site correlation coefficients r>0.9, except for one value of 0.86) and the levels in the parallel samples of these 5 sites were similar, indicating that wood burning at these 5 sites was a regional phenomenon and that it was taking place in many individual houses on similar occasions (e.g., on cold days, weekends or holidays). The levoglucosan levels at Houtem and the correlation coefficients of the 5 sites with Houtem were lower, which is explained by the fact that the latter site is at less than 20 km from the North Sea so that the air there is often diluted by rather clean westerly maritime air. A peculiar behavior was seen for Hamme, with on many occasions very high levoglucosan levels, which was attributed to the fact that there is wood burning going on in several houses nearby this site. From our levoglucosan/mannosan ratios we derived the relative contributions of softwood and hardwood burning, thereby following the same approach as used by Schmidl et al. (Atmos Environ 2008;38:126-41). It was found that softwood burning accounted, on average, for about 70%, and there was little variation in this percentage with site or with season. The levoglucosan data were used to assess the contribution of wood burning to the OC and to the PM10 mass, again following the approach of Schmidl et al. (2008). The annual average contributions of wood burning OC to the PM10 OC were in the range of 20-25% for 6 of our 7 sites and 36% for Hamme; the averages for summer were 2.0-3.9% for the 6 sites and 14.5% for Hamme; the corresponding data for winter were 36-43% and 60%. As to the contribution from wood burning to the PM10 mass, the annual averages were in the range of 4.8-6.3% for 6 of our 7 sites and 13.3% at Hamme; the averages for summer were 0.51-1.14% for the 6 sites and 5.0% for Hamme; the corresponding data for winter were 8.6 11.3% and 22%. Our finding that wood burning is an important contributor to the OC and the PM10 mass, especially in winter, is in line with published data from various other sites in other European countries. PMID- 22940484 TI - The formation of reactive species having hydroxyl radical-like reactivity from UV photolysis of N-nitrosodimethylamine (NDMA): kinetics and mechanism. AB - This study focuses on the detailed mechanism by which N-nitrosodimethylamine (NDMA) is photolyzed to form oxidized products, i.e., NO(2)(-) and NO(3)(-), and reveals a key reactive species produced during the photolysis of NDMA. Under acidic conditions, NO(2)(-) formed from the photodecomposition of NDMA was more prevalent than NO(3)(-). In this result, key species for the formation of NO(2)( ) are presumably N(2)O(3) and N(2)O(4) as termination products as well as NO and O(2) as reactants. Conversely, under alkaline conditions, NO(3)(-) was more prevalent than NO(2)(-). For this result, a key species for NO(3)(-) formation is presumably peroxynitrite (ONOO(-)). A detailed mechanistic study was performed with a competition reaction (or kinetics) between NDMA and p nitrosodimethylaniline (PNDA) probe for hydroxyl radical (OH). It is fortuitous that the second-order rate constant for NDMA with an unknown reactive species (URS) was 5.13*10(8) M(-1) s(-1), which was similar to its published value for the reaction of NDMA+OH. Our study results showed that a key reactive species generated during NDMA photo-decomposition had hydroxyl radical-like reactivity and in particular, under alkaline conditions, it is most likely ONOO(-) as a source of nitrate ion. Therefore, for the first time, we experimentally report that an URS having OH-like reactivity can be formed during photochemical NDMA decomposition. This URS could contribute to the formations of NO(2)(-) and NO(3)( ). PMID- 22940486 TI - Prolonged postoperative venous thrombo-embolism prophylaxis is cost-effective in advanced ovarian cancer patients. AB - OBJECTIVE: The purpose of this study was to investigate the cost-effectiveness of prolonged prophylaxis with enoxaparin in high-risk surgical patients with ovarian cancer. In addition, we sought to quantify the impact of prolonged prophylaxis (PP) on the incidence of venous thromboembolism (VTE), its related complications, and overall patient survival. METHODS: A Markov decision analytic model was used to estimate the costs, resource allocation and outcomes associated with the prolonged use of enoxaparin, for a total of four weeks after surgery, in patients undergoing primary debulking surgery for stage IIIC ovarian cancer. We estimated incremental cost per quality-adjusted life-year (QALY) at one and five year intervals; the estimated reduction in VTE episodes, bleeding episodes, and survival at the five year interval for a simulated cohort of 10,000 women. RESULTS: The incremental cost effectiveness ratio (ICER) for prolonged prophylaxis (PP) was $5236/QALY and $-1462/QALY at one and five years respectively. For patients receiving PP, the model estimated a 12% reduction in the clinically evident VTE episodes and a higher five-year survival (31.61% vs. 29.96%; p<0.0001). Resource allocation analysis reveals that 95% of initial investment cost of prolonged enoxaparin is recovered within one year. CONCLUSIONS: In ovarian cancer patients undergoing open abdominal surgery, prolonged VTE prophylaxis not only improves patient outcomes, but is also a cost saving strategy when modeled over five years. A significant reduction in the episodes of VTE and a higher overall survival warrants consideration for the routine use of PP in this patient population. PMID- 22940485 TI - New views on the pathogenesis of high-grade pelvic serous carcinoma with suggestions for advancing future research. PMID- 22940487 TI - Histopathologic differences account for racial disparity in uterine cancer survival. AB - OBJECTIVE: The incidence for uterine cancers has been reported to be higher among white women, whereas mortality is higher among black women. Reasons for the higher mortality among black women are not completely understood. The aim of our study is to examine the relationship between race/ethnicity, histopathologic subtype, and survival in uterine cancer. METHODS: We abstracted socio demographic, treatment, and survival data for all women who were diagnosed with uterine cancer at Montefiore Medical Center from January 1999 through December 2009. Pathology records were reviewed. RESULTS: 984 patients were identified. Racial/ethnic distribution was 382 (39%) white, 308 (31%) black, 232 (24%) Hispanic, and 62 (6.3%) other races, mixed, or unknown. 592 (60%) patients had endometrioid histology. Blacks were much more likely than whites to have non endometrioid histologies (p<0.001), including papillary serous, carcinosarcoma, and leiomyosarcoma. Blacks and Hispanics were at least as likely as whites to receive either chemotherapy or radiation therapy. The hazard ratio for death for black versus white patients was 1.94 (p<0.001) when all histological subtypes were included. The hazard ratio for Hispanics for death was 1.2 (p=0.32) compared to whites. However, when patients were divided into endometrioid and non endometrioid histological subtypes, there was no significant difference in survival by race/ethnicity. CONCLUSION: Black patients with uterine cancer are much more likely to die and are much more likely to have non-endometrioid histologies than white patients. There are no differences in survival among white, black, or Hispanic women with uterine cancer, after control for histological subtype. PMID- 22940488 TI - Detection of PAX8 and p53 is beneficial in recognizing metastatic carcinomas in pelvic washings, especially in cases with suspicious cytology. AB - OBJECTIVE: The aim of this study is to evaluate the detection of paired box gene 8 (PAX8) and p53 with immunohistochemistry in pelvic washing cell block sections. METHODS: A total of 92 cases were used in this study, which were assigned to three groups according to the cytopathology files. The first group with positive cytology including endometrial and ovarian carcinomas comprised 32 cases. The second group with suspicious cytology for endometrial or ovarian carcinomas consisted of 29 cases. The third group with negative cytology (regarded as mesothelial cells) included 31 cases. The pelvic washing cell blocks underwent immunohistochemistry to detect PAX8 and p53 expression. RESULTS: Immunoreactivity for PAX8 was found in 75% (24/32) of the cases in the group with positive cytology, in 6.9% (2/29) of the cases with suspicious cytology, and in none of the 31 cases with negative cytology (sensitivity: 75%; specificity: 100%; p<0.05). p53 expression was detected in 37.5% (12/32) of the cases in the first group, in 3.4% (1/29) of the cases in the second group, and in none of the cases in the third group (sensitivity: 37.5%; specificity: 100%; p<0.05). Moreover, the combined expression of PAX8 and p53 showed the same result as the single expression of p53 in the three groups. CONCLUSION: The detection of PAX8 and p53 is beneficial in recognizing metastatic carcinomas in pelvic washings, especially in cases with suspicious cytology, which additionally supports the Mullerian origin of these carcinomas. PMID- 22940490 TI - Ultrastaging of para-aortic lymph nodes in stage IIIC1 endometrial cancer: a preliminary report. AB - OBJECTIVE: The aim of this study was to determine the rate of occult metastasis, including isolated tumor cells, in para-aortic lymph nodes of patients with stage IIIC1 endometrial cancer who underwent pelvic and para-aortic lymphadenectomy. METHODS: A series of 15 patients who had undergone combined pelvic and para aortic lymphadenectomy during the period from 2004 to 2010 and who were diagnosed as being positive for pelvic node metastasis but negative for para-aortic node metastasis were included in this study. Ultra-staging by multiple slicing, staining with hematoxylin/eosin and cytokeratin, and microscopic inspection was performed on a total of 242 para-aortic lymph nodes. RESULTS: Eleven (73.3%) of the 15 patients had occult para-aortic lymph node metastasis. Two patients (13.3%) had macrometastasis and nine patients (60.0%) had isolated tumor cells. Type 2 endometrial cancer tended to have a higher rate of occult metastasis than that of type 1 cancer (90% vs. 40%, P=0.07). The rate of occult para-aortic node metastasis was not related to the number of metastatic pelvic nodes. Five patients suffered recurrence in the lung or in the intraabdomen, but lymph node recurrence was not found in any case. CONCLUSION: Patients with stage IIIC1 endometrial cancer have a potentially high rate of occult para-aortic node metastasis. Local treatment of the para-aortic region should be considered in patients with stage IIIC1 endometrial cancer until effective adjuvant therapy is established. PMID- 22940489 TI - Impact of genetic testing on endometrial cancer risk-reducing practices in women at risk for Lynch syndrome. AB - OBJECTIVE: Due to the increased lifetime risk of endometrial cancer (EC), guidelines recommend that women with Lynch syndrome (LS) age >= 35 undergo annual EC surveillance or prophylactic hysterectomy (PH). The aim of this study was to examine the uptake of these risk-reducing strategies. METHODS: The study population included women meeting clinical criteria for genetic evaluation for LS. Data on cancer risk-reducing behaviors were collected from subjects enrolled in two distinct studies: (1) a multicenter cross-sectional study involving completion of a one-time questionnaire, or (2) a single-center longitudinal study in which subjects completed questionnaires before and after undergoing genetic testing. The main outcome was uptake of EC risk-reducing practices. RESULTS: In the cross-sectional cohort, 58/77 (75%) women at risk for LS-associated EC reported engaging in EC risk-reduction. Personal history of genetic testing was associated with uptake of EC surveillance or PH (OR 17.1; 95% CI 4.1-70.9). Prior to genetic testing for LS, 26/40 (65%) women in the longitudinal cohort reported engaging in EC risk-reduction. At one-year follow-up, 16/16 (100%) mismatch repair (MMR) gene mutation carriers were adherent to guidelines for EC risk reduction, 9 (56%) of whom had undergone PH. By three-year follow-up, 11/16 (69%) MMR mutation carriers had undergone PH. Among women with negative or uninformative genetic test results, none underwent PH after testing. CONCLUSIONS: Genetic testing for LS is strongly associated with uptake of EC risk-reducing practices. Women found to have LS in this study underwent prophylactic gynecologic surgery at rates comparable to those published for BRCA1/2 mutation carriers. PMID- 22940491 TI - A prospective assessment of the reliability of frozen section to direct intraoperative decision making in endometrial cancer. AB - OBJECTIVE: To determine the reliability of intraoperative frozen sections (IFSs) for surgical staging of endometrial cancer (EC). METHODS: Data were collected prospectively on 784 consecutive patients with EC who were undergoing a hysterectomy at our institution from January 1, 2004, to December 31, 2008. The need for surgical staging was decided through IFS using 4 variables: tumor size, histologic grade, histologic subtype, and depth of myometrial invasion (MI). The IFS results were compared with the permanent paraffin sections (PSs) to assess for discordances. RESULTS: In 30 of the 784 cases (4%), the PS pathology report was amended with discordant results. In addition, a definitive diagnosis of the 4 parameters was deferred to PS in 53 cases (7%), of which 30 (4%) were concordant and 23 (3%) were discordant. IFS-related deviations from the prescribed surgical algorithm occurred in 10 cases (1.3%; 95% confidence interval, 0.6%-2.3%). Of these 10 cases, 3 were amendments after PS review and 7 were IFS deferrals for definitive PS interpretation. CONCLUSIONS: Clinically significant discordance between IFS and PS occurred in only 1.3% of cases. Despite skepticism expressed in the medical literature, IFS provides highly reliable data to guide intraoperative treatment decisions at institutions with sufficient pathologic expertise. PMID- 22940492 TI - Identification of the optimal pathway to reach an accurate diagnosis in the absence of an early detection strategy for ovarian cancer. AB - OBJECTIVES: There is a lack of knowledge about the health care events experienced by individual patients that lead to a definitive diagnosis of ovarian cancer (OC). The goal of this study was to describe the various pathways and to identify an optimal path to accurate diagnosis. METHODS: Women who were referred to gynecologic oncology for a suspected OC were enrolled to this study. Medical records (MRs) from all health care providers were obtained from the time the patient recalled first suspecting a health issue through the time of diagnosis to build a decision tree model. A Monte Carlo simulation was conducted of 83,000 patients to identify the optimal pathway to reach diagnosis. RESULTS: In the Monte Carlo simulation, gynecologic oncologists and gynecologists accounted for the most efficient diagnosis in over 37.9% and 29.2% of suspected OC cases, respectively, in terms of the least amount of time to reach diagnosis. Gynecologic oncologists were further associated with the fewest health care visits needed to reach diagnosis in 37% of the simulation cases; however, 23% of trials were indifferent to any specific provider. CONCLUSIONS: The decision tree provides a more comprehensive view of the complexity in reaching an accurate diagnosis of OC. This analysis was able to identify the health care utilization patterns that underlie the events that occur to reach an accurate diagnosis in the setting of a suspected OC, and was able to identify the most efficient pathways that utilize the fewest health care resources in the least amount of time. PMID- 22940494 TI - Redox control of cytosolic Akt phosphorylation in PTEN null cells. AB - This article demonstrates a role for intracellular reactive oxygen species in the hyperphosphorylation of Akt in cells that have lost the expression of the tumor suppressor PTEN. Using mouse embryonic fibroblasts in which the expression of PTEN was knocked out, we show that a decrease in intracellular superoxide anion resulted in a rapid dephosphorylation of Akt at Thr308 followed by Ser473. Whereas dephosphorylation was detected in the cytosolic pool of Akt, phosphorylation of the membrane pool of the kinase remained unaffected. Dephosphorylation of cytosolic Akt was attributed to an increase in the interaction between Akt and the catalytic subunit of the protein phosphatase PP2A, which correlated with an increase in the amount of the oxidized versus the reduced form of the kinase. These results were corroborated in the PTEN knockout prostate cancer cell line LNCaP and in the melanoma cell line M14 stably transfected with a constitutively active form of Rac1. PMID- 22940495 TI - Hydrogen peroxide-induced poly(ADP-ribosyl)ation regulates osteogenic differentiation-associated cell death. AB - We set out to investigate the role of poly(ADP-ribosylation), the attachment of NAD(+)-derived (ADP-ribose)(n) polymers to proteins, in the regulation of osteogenic differentiation of SAOS-2 cells and mesenchymal stem cells. In osteogenic differentiation medium, SAOS-2 cells showed mineralization and expressed alkaline phosphatase and osteoblastic marker genes such as Runx2, osterix, BMP2, and osteopontin. The cells also released hydrogen peroxide, displayed poly(ADP-ribose) polymerase (PARP) activation, and showed commitment to cell death (apoptosis and necrosis). Scavenging reactive oxygen species by glutathione or decomposing hydrogen peroxide by the addition of catalase reduced differentiation, PARP activation, and cell death. We silenced the expression of the main PAR-synthesizing enzyme PARP-1 and the PAR-degrading enzyme poly(ADP ribose) glycohydrolase (PARG) in SAOS-2 osteosarcoma cells (shPARP-1 and shPARG, respectively). Both shPARP-1- and shPARG-silenced cells exhibited altered differentiation, with the most notable change being increased osteopontin expression but decreased alkaline phosphatase activity. PARP-1 silencing suppressed both apoptotic and necrotic cell death, but the PARP inhibitor PJ34 sensitized cells to cell death, indicating that the effects of PARP-1 silencing are not related to the activity of the enzyme. PARG silencing resulted in more apoptosis and, in the last days of differentiation, a shift from apoptosis toward necrosis. In conclusion our data prove that hydrogen peroxide-induced poly(ADP ribose) signaling regulates cell death and osteodifferentiation. PMID- 22940497 TI - Chronic fatigue and affective disorders in older adults: evidence from the 2007 British National Psychiatric Morbidity Survey. AB - BACKGROUND: Although chronic fatigue is common in old age, the association between chronic fatigue and common affective disorders is largely unknown. AIMS: To fill this research gap, the present study aims to determine the relationship between chronic fatigue and common psychiatric disorders among older adults aged 65 and older. METHOD: A national representative sample of 1793 England community dwelling respondents aged 65 and above was assessed in the 2007 Adult Psychiatric Morbidity Survey (APMS) using the Revised Clinical Interview Schedule to measure chronic fatigue and common psychiatric disorders. Demographic characteristics, medical conditions, and four health-related variables based on the Short Form 12 were also measured. RESULTS: The prevalence of chronic fatigue was 18.6%. Bivariate analyses revealed that chronic fatigue was more common among women and non-white ethnicities. In addition, chronic fatigue was significantly related to depression, mixed anxiety and depressive disorder, and generalized anxiety disorder after adjusting for demographic variables, medical conditions, and four other health-related variables. CONCLUSION: The prevalence rate of chronic fatigue in our sample is higher than a previous study. The psychiatric comorbidity of chronic fatigue supports the notion that chronic fatigue has a strong impact on quality of life in old age. PMID- 22940496 TI - Lipidomics of oxidized polyunsaturated fatty acids. AB - Lipid mediators are produced from the oxidation of polyunsaturated fatty acids through enzymatic and free radical-mediated reactions. When subject to oxygenation via cyclooxygenases, lipoxygenases, and cytochrome P450 monooxygenases, polyunsaturated fatty acids give rise to an array of metabolites including eicosanoids, docosanoids, and octadecanoids. These potent bioactive lipids are involved in many biochemical and signaling pathways, with inflammation being of particular importance. Moreover, because they are produced by more than one pathway and substrate, and are present in a variety of biological milieus, their analysis is not always possible with conventional assays. Liquid chromatography coupled to electrospray mass spectrometry offers a versatile and sensitive approach for the analysis of bioactive lipids, allowing specific and accurate quantitation of multiple species present in the same sample. Here we explain the principles of this approach to mediator lipidomics and present detailed protocols for the assay of enzymatically produced oxygenated metabolites of polyunsaturated fatty acids that can be tailored to answer biological questions or facilitate assessment of nutritional and pharmacological interventions. PMID- 22940493 TI - Prevalence and risk factors for cervical HPV infection and abnormalities in young adult women at enrolment in the multinational PATRICIA trial. AB - OBJECTIVE: We evaluated baseline data from the PApilloma TRIal against Cancer In young Adults (PATRICIA; NCT00122681) on the association between behavioral risk factors and HPV infection and cervical abnormalities. METHODS: Women completed behavioral questionnaires at baseline. Prevalence of HPV infection and cervical abnormalities (detected by cytological or histological procedures) and association with behavioral risk factors were analyzed by univariate and stepwise multivariable logistic regressions. RESULTS: 16782 women completed questionnaires. Among 16748 women with data for HPV infection, 4059 (24.2%) were infected with any HPV type. Among 16757 women with data for cytological abnormalities, 1626 (9.7%) had a cytological abnormality, of whom 1170 (72.0%) were infected with at least one oncogenic HPV type including HPV-16 (22.7%) and HPV-18 (9.3%). Multivariable analysis (adjusted for age and region, N=14404) showed a significant association between infection with any HPV type and not living with a partner, smoking, age <15 years at first sexual intercourse, higher number of sexual partners during the past 12 months, longer duration of hormonal contraception and history of sexually transmitted infection (STI). For cervical abnormalities, only history of STI (excluding Chlamydia trachomatis) remained significant in the multivariable analysis after adjusting for HPV infection. CONCLUSIONS: Women reporting 3+ sexual partners in the past 12 months had the highest risk of HPV infection at baseline. HPV infection was the main risk factor for cervical abnormalities, and history of STIs excluding Chlamydia trachomatis increased risk to a lesser extent. Although behavioral factors can influence risk, all sexually active women are susceptible to HPV infection. PMID- 22940498 TI - Incidence of late-life depression: a systematic review. AB - BACKGROUND: In the past years, many studies have examined the prevalence of late life depression. However, incidence studies, especially those including the oldest age groups, remained rare. The objective of this article is therefore to provide a systematic review on incidence of depressive disorders in latest life. METHODS: A systematic search of the literature published between 1985 and 2011 was conducted using MEDLINE, Web of Science, PsycInfo and Cochrane databases. Inclusion criteria were: incidence specified for persons aged>=70 years at baseline, population-based sample or primary care sample. Incidence rates or risks were extracted or calculated. RESULTS: We found 20 studies reporting incidence according to categorical (n=14) or dimensional diagnoses (n=6). The incidence of depressive disorders varied considerably. Major Depression (MD) was found to occur less often than Minor Depression (MinD), whereas clinically relevant depressive symptoms are at least as frequent as MinD. The incidence rate of MD was 0.2-14.1/100 person-years, and incidence of clinically relevant depressive symptoms was 6.8/100 person-years. Female incidence was mostly higher than male. Associations between age and incidence revealed to be rather inconsistent between studies. LIMITATIONS: Methodological diversity of the studies concerning diagnostics, data collection methods, incidence definitions and sampling make the results difficult to interprete. CONCLUSIONS: This review is the first to have focused on incidence studies on depression in latest life. The frequent occurrence of clinically relevant depressive symptoms will have to be considered in future health care planning. Physical health and psychosocial influences appear to be key variables in depression prevention. PMID- 22940499 TI - Identification of new scavengers for hydroxyl radicals and superoxide dismutase by utilising ultraviolet A photoreaction of 8-methoxypsoralen and a variety of mutants of Escherichia coli: implications on certain diseases of DNA repair deficiency. AB - 8-Methoxypsoralen+UVA (ultraviolet light of 320-400 nm) known as PUVA has been in use for a number of years for the treatment of psoriasis and vitiligo. The treatment possibly works on the basis of UVA photoactivated 8-methoxypsoralen binding to DNA forming both single strand and double strand type damage. We have used Escherichia coli as model system in studying PUVA induced DNA damage and repair. It has been known for some time that the photoactivated 8 methoxypsoralen, besides intercalating with DNA, generates at least two reactive oxygen species (ROS): hydroxyl radicals and superoxide anions, and also singlet oxygen. In this study it has been found that, in E. coli, malate dehydrogenase, succinate dehydrogenase and NADH:ubiquinone oxidoreductase can protect cells from PUVA killing presumably by scavenging these ROS. Possible mechanisms have been proposed for these enzymes as cell protectors. Studies also suggest the potential for the use of PUVA in the treatment of a large number of human diseases. This study also finds that, unlike 8-methoxypsoralen, trioxsalen (4,5',8 trimethylpsoralen, another derivative of psoralens) does not generate ROS by UVA photoactivation; and hence the mode of action of trioxsalen and PUVA overlaps only in the binding of these molecules to DNA in the presence of UVA. PMID- 22940500 TI - Effect of oxidative stress on plasma membrane fluidity of THP-1 induced macrophages. AB - Plasma membrane is one of the preferential targets of reactive oxygen species which cause lipid peroxidation. This process modifies membrane properties such as membrane fluidity, a very important physical feature known to modulate membrane protein localization and function. The aim of this study is to evaluate the effect of oxidative stress on plasma membrane fluidity regionalization of single living THP-1 macrophages. These cells were oxidized with H(2)O(2) at different concentrations, and plasma membrane fluidity was analyzed by two-photon microscopy in combination with the environment-sensitive probe Laurdan. Results show a significant H(2)O(2) concentration dependent increase in the frequency of rigid lipid regions, mainly attributable to lipid rafts, at the expense of the intermediate fluidity regions. A novel statistical analysis evaluated changes in size and number of lipid raft domains under oxidative stress conditions, as lipid rafts are platforms aiding cell signaling and are thought to have relevant roles in macrophage functions. It is shown that H(2)O(2) causes an increase in the number, but not the size, of raft domains. As macrophages are highly resistant to H(2)O(2), these new raft domains might be involved in cell survival pathways. PMID- 22940501 TI - The Fading Electricity Theory of Ageing: the missing biophysical principle? AB - Since a few years convincing data are accumulating showing that some of the premises of the master integrative theory of ageing, namely Harman's Reactive Oxygen Species or free radical theory, are less well founded than originally assumed. In addition, none of the about another dozen documented ageing mechanisms seems to hold the final answer as to the ultimate cause and evolutionary significance of ageing. This review raises the question whether, perhaps, something important has been overlooked, namely a biophysical principle, electrical in nature. The first cell on earth started to be alive when its system for generating its own electricity, carried by inorganic ions, became operational. Any cell dies at the very moment that this system irreversibly collapses. In between birth and death, the system is subject to wear and tear because any cell's overall repair system is not 100 percent waterproof; otherwise adaptation would not be an option. The Fading Electricity Theory of Ageing has all necessary properties for acting as a universal major integrative concept. The advent of novel methods will facilitate the study of bioelectrical phenomena with molecular biological methods in combination with optogenetics, thereby offering challenging possibilities for innovative research in evo-gero. PMID- 22940502 TI - Health impact and damage cost assessment of pesticides in Europe. AB - Health impacts from pesticide use are of continuous concern in the European population, requiring a constant evaluation of European pesticide policy. However, health impacts have never been quantified accounting for specific crops contributing differently to overall human exposure as well as accounting for individual substances showing distinct environmental behavior and toxicity. We quantify health impacts and related damage costs from exposure to 133 pesticides applied in 24 European countries in 2003 adding up to almost 50% of the total pesticide mass applied in that year. Only 13 substances applied to 3 crop classes (grapes/vines, fruit trees, vegetables) contribute to 90% of the overall health impacts of about 2000 disability-adjusted life years in Europe per year corresponding to annual damage costs of 78 million Euro. Considering uncertainties along the full impact pathway mainly attributable to non-cancer dose-response relationships and residues in treated crops, we obtain an average burden of lifetime lost per person of 2.6 hours (95% confidence interval between 22 seconds and 45.3 days) or costs per person over lifetime of 12 Euro (95% confidence interval between 0.03 Euro and 5142 Euro), respectively. 33 of the 133 assessed substances accounting for 20% of health impacts in 2003 are now banned from the European market according to current legislation. The main limitation in assessing human health impacts from pesticides is related to the lack of systematic application data for all used substances. Since health impacts can be substantially influenced by the choice of pesticides, the need for more information about substance application becomes evident. PMID- 22940503 TI - Construction and characterization of bifunctional TIM-3-EGFP fusion proteins. AB - T cell immunoglobulin mucin-3 (TIM-3) is the first surface molecule to be found that specifically identifies Th1 cells in both mice and humans, and it negatively regulates Th1 responses. TIM-3 protein is a type I membrane protein. Overexpression of membrane proteins is a major problem to overcome in studies of membrane protein structure and function. In this study, a fusion between the gene encoding human TIM-3 and EGFP was successfully constructed and expressed in Escherichia coli. To our knowledge, this is the first time that human TIM-3 has been overexpressed in E. coli. We showed that the TIM-3-EGFP fusion protein mediates the recognition and binding of apoptotic cells. Furthermore, we demonstrated that the interactions of TIM-3-EGFP with apoptotic cells were blocked by TIM-3-Ig fusion proteins. Taken together, these results suggest that the human TIM-3 protein may act as a receptor for apoptotic cells. PMID- 22940505 TI - The impact of the impact factor. PMID- 22940504 TI - Heterologous expression, purification and cofactor reconstitution of the reductive dehalogenase PceA from Dehalobacter restrictus. AB - Organohalide respiration is used by a limited set of anaerobic bacteria to derive energy from the reduction of halogenated organic compounds. The enzymes that catalyze the reductive dehalogenation reaction, the reductive dehalogenases, represent a novel and distinct class of cobalamin and Fe-S cluster dependent enzymes. Until now, biochemical studies on reductive dehalogenases have been hampered by the lack of a reliable protein source. Here we present an efficient and robust heterologous production system for the reductive dehalogenase PceA from Dehalobacter restrictus. Large quantities of Strep-tagged PceA fused to a cold-shock induced trigger factor could be obtained from Escherichia coli. The recombinant enzyme was conveniently purified in milligram quantities under anaerobic conditions by StrepTactin affinity chromatography, and the trigger factor could be removed through limited proteolysis. Characterization of the purified PceA by UV-Vis and electron paramagnetic resonance (EPR) spectroscopy reveal that the recombinant protein binds methylcobalamin in the base-on form after proteolytic cleavage of the trigger factor, and that 4Fe-4S clusters can be chemically reconstituted under anoxic conditions. This study demonstrates a novel PceA production platform that allows further study of this new enzyme class. PMID- 22940507 TI - Preparing research manuscripts for publication: a guide for authors. PMID- 22940508 TI - Management of diabetes and pancreatic cancer. PMID- 22940509 TI - Diabetes and cancer: impact on health-related quality of life. AB - PURPOSE/OBJECTIVES: To explore whether three factors (physical function, mental health, and social function) of health-related quality of life (HRQOL) are impacted differently in patients with cancer and diabetes when compared to those with cancer who do not have diabetes at the beginning of chemotherapy. DESIGN: Secondary analysis using baseline data from two randomized, controlled trials. SETTING: Two comprehensive cancer centers, one community cancer oncology program, and six hospital-affiliated community oncology centers. SAMPLE: 661 patients aged 21 years or older with a solid tumor cancer or lymphoma undergoing cancer treatment. METHODS: Baseline data from both randomized, controlled trials were used. The SF-36(r) was used to measure physical function, mental health, and social function. Analysis included descriptive statistics and a general linear model. MAIN RESEARCH VARIABLES: Presence or absence of diabetes and physical function, social function, and mental health. FINDINGS: Patients with cancer and diabetes had significantly lower levels of physical function (p < 0.001) when compared to those who had cancer without diabetes. The interaction of diabetes and age was found to be significantly predictive of mental health (p < 0.05). CONCLUSIONS: The presence of diabetes negatively impacts physical function and mental health in patients undergoing chemotherapy. IMPLICATIONS FOR NURSING: Nurses should be aware of diabetes' effect on HRQOL in patients with cancer. In addition, nurses may need to intervene earlier for patients with diabetes and cancer to maintain or improve their quality of life. PMID- 22940510 TI - Impact of malglycemia on clinical outcomes in hospitalized patients with cancer: a review of the literature. AB - PURPOSE/OBJECTIVES: To examine empirical research regarding the role of malglycemia (hyperglycemia, hypoglycemia, or glycemic variability) on clinical outcomes among hospitalized patients with cancer. DATA SOURCES: Research articles were obtained from the Ovid, PubMed, and CINAHL(r) databases. Key words used in the search included hyperglycemia or malglycemia and neoplasm combined with venous thromboembolism, infection, or mortality. DATA SYNTHESIS: Eleven research articles were examined reporting the impact of malglycemia on various outcomes, including infection, mortality or survival, length of hospital stay, and toxicity. CONCLUSIONS: Findings suggest that malglycemia may have a negative impact on outcomes for hospitalized patients with cancer. Increased rates of infection, mortality, length of stay, and toxicities, as well as decreased survival, were reported. IMPLICATIONS FOR NURSING: Oncology nurses play an important role in the identification of patients with malglycemia. Early assessment and intervention for those patients can improve outcomes and quality of life. PMID- 22940511 TI - Effects of exercise on fatigue, sleep, and performance: a randomized trial. AB - PURPOSE/OBJECTIVES: To compare usual care with a home-based individualized exercise program (HBIEP) in patients receiving intensive treatment for multiple myeloma (MM)and epoetin alfa therapy. DESIGN: Randomized trial with repeated measures of two groups (one experimental and one control) and an approximate 15 week experimental period. SETTING: Outpatient setting of the Myeloma Institute for Research and Therapy at the Rockfellow Cancer Center at the University of Arkansas for Medical Sciences. SAMPLE: 187 patients with newly diagnosed MM enrolled in a separate study evaluating effectiveness of the Total Therapy regimen, with or without thalidomide. METHODS: Measurements included the Profile of Mood States fatigue scale, Functional Assessment of Cancer Therapy-Fatigue, ActiGraph(r) recordings, 6-Minute Walk Test, and hemoglobin levels at baseline and before and after stem cell collection. Descriptive statistics were used to compare demographics and treatment effects, and repeated measures analysis of variance was used to determine effects of HBIEP. MAIN RESEARCH VARIABLES: Fatigue, nighttime sleep, performance (aerobic capacity) as dependent or outcome measures, and HBIEP combining strength building and aerobic exercise as the independent variable. FINDINGS: Both groups were equivalent for age, gender, race, receipt of thalidomide, hemoglobin levels, and type of treatment regimen for MM. No statistically significant differences existed among the experimental and control groups for fatigue, sleep, or performance (aerobic capacity). Statistically significant differences (p < 0.05) were found in each of the study outcomes for all patients as treatment progressed and patients experienced more fatigue and poorer nighttime sleep and performance (aerobic capacity). CONCLUSIONS: The effect of exercise seemed to be minimal on decreasing fatigue, improving sleep, and improving performance (aerobic capacity). IMPLICATIONS FOR NURSING: Exercise is safe and has physiologic benefits for patients undergoing MM treatment; exercise combined with epoetin alfa helped alleviate anemia. PMID- 22940512 TI - Recruitment and retention of older adolescent and young adult female survivors of childhood cancer in longitudinal research. AB - PURPOSE/OBJECTIVES: To describe the challenges encountered in the recruitment and retention of a sample of older adolescent and young adult female survivors of childhood cancer for a longitudinal study testing a targeted psychosocial intervention aimed at enhancing hope. DATA SOURCES: Published literature on constructing longitudinal intervention studies and strategies in the recruitment and retention of childhood cancer survivors in research was used to develop the protocol of this study. DATA SYNTHESIS: Using empirical literature to construct the study's design resulted in achieving certain goals for the design, but not in the recruitment and retention of study participants. Using online technology to deliver the intervention and collect data was efficient and effective. Traditional approaches to recruitment and retention of those survivors, however, were not effective. Use of more novel approaches to enroll study participants demonstrated only modest success. CONCLUSIONS: Additional research is needed on strategies to successfully recruit and retain older adolescents and young adult female survivors of childhood cancer in longitudinal intervention studies. IMPLICATIONS FOR NURSING: The improvement in the psychological well-being of female survivors of childhood cancer remains an important outcome in ongoing care. The need to continue to identify creative and effective ways to recruit and retain those survivors is warranted. PMID- 22940513 TI - The experience of a diagnosis of advanced lung cancer: sleep is not a priority when living my life. AB - PURPOSE/OBJECTIVES: To describe common practices and shared meanings of sleep wake disturbances in individuals with newly diagnosed non-small cell lung cancer (NSCLC) before treatment and evaluate their preexisting sleep disturbances. RESEARCH APPROACH: Open-ended interviews of patients newly diagnosed with lung cancer. SETTING: A Veterans Administration hospital and a comprehensive cancer center in the northeastern United States. PARTICIPANTS: 26 patients newly diagnosed with NSCLC who chose chemotherapy treatment. METHODOLOGIC APPROACH: Interpretive phenomenology based on Heideggarian hermeneutics. MAIN RESEARCH VARIABLES: Meaning of diagnosis on life experiences and sleep practices. FINDINGS: Participants described four related themes: (a) the diagnosis as devastating yet not surprising, (b) treatment as hope for more time, (c) keeping life normal, and (d) sleep patterns as long lived. CONCLUSIONS: Although participants did not complain about sleep difficulties, they described a history of sleep disturbances and poor sleep hygiene. Participants focused their trust on the treatment, giving them more time to follow their priorities and ignoring the effects of sleep deprivation on their quality of life. INTERPRETATION: Healthcare professionals may design interventions to encourage keeping life as normal as possible, focusing on improving sleep, which may ultimately prolong patients' lives. PMID- 22940514 TI - Helping patients and their family caregivers cope with cancer. AB - Family caregivers face multiple demands as they care for their loved ones with cancer, and these demands have increased dramatically in recent years. Patients with cancer now receive toxic treatments in outpatient settings and return home to the care of their family members. Some patients receive in-home infusions, which were unheard of a few years ago. Family caregivers provide tasks that were previously provided by nurses; however, caregivers lack the educational preparation that nurses receive. PMID- 22940517 TI - Changes and predictors of unmet supportive care needs in Taiwanese women with newly diagnosed breast cancer. AB - PURPOSE/OBJECTIVES: To investigate changes in unmet supportive care needs and factors affecting those needs in Taiwanese women with newly diagnosed breast cancer. DESIGN: Prospective longitudinal survey. SETTING: Two general surgery outpatient departments at a large medical center in northern Taiwan. SAMPLE: 124 women with newly diagnosed breast cancer. METHODS: Needs were assessed with the Supportive Care Needs Survey-Short Form at diagnosis (T1) and one month (T2), two months (T3), and three months (T4) after diagnosis. MAIN RESEARCH VARIABLES: Supportive care needs. FINDINGS: Women had moderate-to-high levels of unmet needs, with the highest being in the health system and information domain at each time point. Levels in the domains of psychological, health system and information, and sexuality needs were higher (p < 0.001) at T1 than at T2, T3, and T4. However, levels of unmet physical and daily living needs increased significantly over time (p < 0.001). Unmet supportive care needs were significantly predicted by younger age and higher levels of education, symptom distress, trait anxiety, state anxiety, and time since diagnosis. CONCLUSIONS: Supportive care needs changed significantly over time and were predicted by personal characteristics, as well as physical and emotional factors. IMPLICATIONS FOR NURSING: Oncology nurses should assess the needs of patients with breast cancer and provide them with individualized, culturally sensitive informational, social, and emotional support from breast cancer diagnosis through the first four months of treatment. PMID- 22940518 TI - Health-seeking behaviors and sexuality in rectal cancer survivors in Taiwan: associations with spirituality and resourcefulness. AB - PURPOSE/OBJECTIVES: To examine the relationships between two health-seeking behaviors (HSBs), spirituality and resourcefulness, as well as demographics, cancer-related factors, and sexuality indicators, within the context of Schlotfeldt's health-seeking model in rectal cancer survivors. DESIGN: Secondary analysis, correlational, and cross-sectional. SETTING: A teaching hospital in southern Taiwan. SAMPLE: 120 adults with rectal cancer. METHODS: Data were collected during face-to-face interviews using the Body-Mind-Spirit Well-Being Inventory-Spirituality scale; Resourcefulness Scale; Sexual Self-Schema Scale (male and female versions); Evaluating and Nurturing Relationship Issues, Communication, Happiness (ENRICH) Couple Scale-Communication; ENRICH Sexual Relationship Scale; International Index of Erectile Function; and the Female Sexual Function Index. Correlational analysis, one-way analyses of variance, and independent sample t tests were used to analyze data. MAIN RESEARCH VARIABLES: Spirituality, resourcefulness, HSBs, and sexuality. FINDINGS: Spirituality and resourcefulness were associated with sexual self-concept and sexual satisfaction in men and women. Spirituality was correlated with resourcefulness. Greater resourcefulness was found in women, as well as in men and women who had higher education and fewer comorbid conditions. Spirituality was not associated with gender, education, or number of comorbid conditions. Neither spirituality nor resourcefulness was associated with age, religion, stage of disease, time since surgery, type of cancer treatment, or sexual function. CONCLUSIONS: Resourcefulness and spirituality were associated with the sexuality indicators of satisfaction and self-concept, which may have an impact on the physical and psychological health of adults with rectal cancer. IMPLICATIONS FOR NURSING: The findings suggest a need to focus on strengthening HSBs through teaching resourcefulness and encouraging spirituality to enhance sexual self-concept and improve sexual satisfaction in this patient group. PMID- 22940519 TI - Oncology nurses' obstacles and supportive behaviors in end-of-life care: providing vital family care. AB - PURPOSE/OBJECTIVES: To determine the impact of obstacles and supportive behaviors in end-of-life (EOL) care as perceived by hospital-based oncology nurses. DESIGN: A 69-item mailed survey. SETTING: National random sample. SAMPLE: 1,005 nurse members of the Oncology Nursing Society who had provided EOL care for patients with cancer. METHODS: Three mailings yielded 380 usable responses from 912 eligible respondents, resulting in a 42% return rate. MAIN RESEARCH VARIABLES: Size and frequency of EOL care obstacles and supportive behaviors for patients with cancer in a hospital setting. FINDINGS: Results of this research demonstrate the need for more EOL education and help in forming teams of nurses, social and palliative care workers, and physicians to support high-quality care. Another finding was the need for other nurses at a facility to give the nurse caring for the dying patient more time to support the patient and family. CONCLUSIONS: Dealing with the family is vital in providing optimal EOL care to patients dying from cancer. By carefully listening to the experience, concerns, and recommendations of hospital-based oncology nurses, compassionate EOL care can be provided to these patients and their families. IMPLICATIONS FOR NURSING: Oncology nurses are dedicated to providing the best EOL care to their patients and patients' families. This study helped to identify research-based obstacles and supportive behaviors regarding the provision of high-quality EOL care. PMID- 22940520 TI - Predictors of a fall event in hospitalized patients with cancer. AB - PURPOSE/OBJECTIVES: To determine predictors of fall events in hospitalized patients with cancer and develop a scoring system to predict fall events. DESIGN: Retrospective medical record review. SETTING: A 1,200-bed tertiary care hospital in northeastern Ohio. SAMPLE: 145 patients with cancer who did not have a fall event were randomly selected from all oncology admissions from February 2006 January 2007 and compared to 143 hospitalized patients with cancer who had a fall event during the same period. METHODS: Multivariable logistic regression models predicting falls were fit. Risk score analysis was completed using bootstrap samples to evaluate discrimination between patients who did or did not fall and agreement between predicted and actual fall status. A nomogram of risk scores was created. MAIN RESEARCH VARIABLES: Fall episodes during hospitalization and patient characteristics that predict falls. FINDINGS: While patients were hospitalized for cancer care, their predictors of a fall episode were low pain level, abnormal gait, cancer type, presence of metastasis, antidepressant and antipsychotic medication use, and blood product use (all p < 0.02); risk model c statistic was 0.89. CONCLUSIONS: For hospitalized patients with cancer, predictors reflecting greater fall episode risk can be assessed easily by nursing staff and acted on when the risk is sufficiently high. IMPLICATIONS FOR NURSING: Understanding specific risk factors of falls in an adult oncology population may lead to interventions that reduce fall risk. PMID- 22940522 TI - Exploration of how women make treatment decisions after a breast cancer diagnosis. AB - PURPOSE/OBJECTIVES: To examine the information needs of women after receiving a diagnosis of breast cancer, investigate how decisions about treatment options are made, and assess personal responses to the decisions made. DESIGN: Mixed-methods approach using quantitative and qualitative data. SETTING: The University of Kansas Medical Center and Quinn Plastic Surgery Center, both in the midwestern United States. SAMPLE: 102 breast cancer survivors who had completed all forms of treatment for at least three months and less than five years. METHODS: Phase I participants completed five questionnaires about informational needs, confidence and satisfaction with the decision, decisional regret, and conflict. In phase II, 15 participants were purposively sampled from the 102 survivors to participate in a focus group session. Data analysis included frequencies and multiple regression for phase I and qualitative content analysis for phase II. MAIN RESEARCH VARIABLES: Informational needs, confidence and satisfaction with the decision, and decisional regret and conflict. FINDINGS: The variables (widowed, confidence and satisfaction with decision, and decisional conflict and regret) significantly (p = 0.01) accounted for 14% of the variance in informational needs. Two themes emerged from the study: (a) feelings, thoughts, and essential factors that impact treatment considerations, and (b) tips for enhancing treatment consideration options. CONCLUSIONS: The study's results show that women viewed informational needs as very important in making treatment decisions after being diagnosed with breast cancer. IMPLICATIONS FOR NURSING: The treatment team should provide the information, with consideration of the patient's personal preferences, that will assist women to make informed, confident, and satisfied decisions about treatment choices. PMID- 22940521 TI - Strength and balance training for adults with peripheral neuropathy and high risk of fall: current evidence and implications for future research. AB - PURPOSE/OBJECTIVES: To evaluate the evidence for strength- and balance-training programs in patients at high risk for falls, discuss how results of existing studies might guide clinical practice, and discuss directions for additional research. DATA SOURCES: A search of PubMed and CINAHL(r) databases was conducted in June 2011 using the terms strength, balance training, falls, elderly, and neuropathy. Only clinical trials conducted using specific strength- or balance training exercises that included community-dwelling adults and examined falls, fall risk, balance, and/or strength as outcome measures were included in this review. DATA SYNTHESIS: One matched case-control study and two randomized, controlled studies evaluating strength and balance training in patients with diabetes-related peripheral neuropathy were identified. Eleven studies evaluating strength and balance programs in community-dwelling adults at high risk for falls were identified. CONCLUSIONS: The findings from the reviewed studies provide substantial evidence to support the use of strength and balance training for older adults at risk for falls, and detail early evidence to support strength and balance training for individuals with peripheral neuropathy. IMPLICATIONS FOR NURSING: The evidence demonstrates that strength and balance training is safe and effective at reducing falls and improving lower extremity strength and balance in adults aged 50 years and older at high risk for falls, including patients with diabetic peripheral neuropathy. Future studies should evaluate the effects of strength and balance training in patients with cancer, particularly individuals with chemotherapy-induced peripheral neuropathy. PMID- 22940523 TI - Recruitment and retention strategies of African American and Latina American breast cancer survivors in a longitudinal psycho-oncology study. AB - PURPOSE/OBJECTIVES: To describe recruitment and retention strategies of a psychosocial intervention with African American and Latina American breast cancer survivors (BCSs). DESIGN: Prospective design with pre- and post-testing. SETTING: A mailed survey and assignment to telephone counseling or education booklet only. SAMPLE: 587 African American and Latina American BCSs were recruited. METHODS: The sample was drawn from the population-based California cancer and hospital registries, as well as community agencies. Mailed self-report health-related quality-of-life assessments were at baseline and 4-6 months follow-up. MAIN RESEARCH VARIABLES: Accrual outcomes; recruitment and retention strategies. FINDINGS: A total of 375 (64%) completed the baseline survey and 320 (55%) completed both baseline and follow-up assessments. The recruitment outcomes suggest that very special attention must be paid to the initial recruitment of Latina Americans to engage their interest and participation. For African Americans, particular attention must be devoted to their retention to address potential attrition. CONCLUSIONS: Findings suggest that the inclusion of lower income and ethnic minority cancer survivors in a longitudinal intervention study is doable. The results indicate that recruitment outcomes are influenced by participant and study characteristics. Successful enrollment requires investigations that attend to culturally and socioecologically informed recruitment and retention strategies, from staff selection, training, and supervision to overall study approach protocol, to address barriers to participation. IMPLICATIONS FOR NURSING: Nursing research and practice have championed survivorship care, including psychosocial care. This article outlines practical strategies to recruit and retain population-based samples, ethnic minorities, and underserved survivors. PMID- 22940524 TI - The lived experience of men diagnosed with prostate cancer. AB - PURPOSE/OBJECTIVES: To investigate the lived experience of prostate cancer from a patient perspective. RESEARCH APPROACH: Descriptive, qualitative. SETTING: Community setting. PARTICIPANTS: 10 men with prostate cancer aged 62-70 years. METHODOLOGIC APPROACH: A hermeneutic phenomenologic method using semistructured, open-ended questions addressing the lived experience. DATA SYNTHESIS: Phenomenology of praxis proposed by van Manen guided the data analysis and transformed personal experiences into disciplinary understanding. FINDINGS: The use of van Manen's method of inquiry and analysis has contributed to the findings of the study by providing a way to explore the meaning of the lived experiences in an attempt to understand living with prostate cancer. Several themes were identified: living in the unknown, yearning to understand and know, struggling with unreliability of body, bearing the diagnosis of cancer, shifting priorities in the gap, and feeling comfort in the presence of others. CONCLUSIONS: Oncology nurses can use van Manen's four fundamental existentials-lived space (spatiality), lived body (corporeality), lived time (temporality), and lived other (relationality)-to understand the lived experience of prostate cancer. Nurses have many opportunities to impact the lives of men diagnosed with prostate cancer, including diagnosis, management of physical integrity, management of psychosocial integrity, and providing education. INTERPRETATION: Nurses may encourage men to describe their diagnosis story and illness experience to better understand the meaning of the prostate cancer experience and to provide appropriate nursing care. PMID- 22940525 TI - NEPA, EPA and risk assessment: Has EPA lost its way? AB - The EPA risk assessment practice denies the inclusion of beneficial responses in the evaluation process. This practice represents a marked deviation from the original guidelines set forth within NEPA, which required the integrated goal of environmental protection as including both a reduction in risk as well as an enhancement of health benefit. It is time for regulatory agencies such as EPA to incorporate both harm and benefit within its risk assessment process. PMID- 22940526 TI - The human visual system uses a global closure mechanism. AB - Research asserting that the visual system instantiates a global closure heuristic in contour integration has been challenged by an argument that behaviorally detected closure enhancement could be accounted for by low-level local mechanisms driven by collinearity or "good continuation" interacting with proximity. The present study investigated this issue in three experiments. Exp. 1 compared the visibility of closed and open contours using circles and S-contours from low to moderately high angles of path curvature in a temporal alternative-forced choice task. Circles were more detectable than S-contours, an effect that increased with curvature. The closure enhancement observed can, however, be explained by the fact that circles contain more 'contiguity' than S-contours. Additional tests added discontinuities to otherwise closed paths to control for the effects of good continuation and closure independently. Exp. 2 compared the visibility of incomplete circles (C-contours) and S-contours derived from the full circles and S-contours in Exp. 1. Exp. 3a compared the visibility of arc pairs arranged in an enclosed position similar to "()" and a non-enclosed position similar to ")(". Results consistently showed enhanced visibility of contour configurations enclosing a region even after controlling for differences in contiguity and changes of curvature direction. A control test (Exp. 3b) demonstrated that the gap in the contours of Exp. 3a was too large to be bridged by local-level collinearity/proximity alone. The combination of good continuation and proximity alone does not explain the closure effects observed across these tests, as demonstrated through the application of a Bayesian model of collinearity and proximity (Geisler et al., 2001) to the stimuli in Exps. 3a and 3b. These results argue for the presence of a global closure-driven contour enhancing mechanism in human vision. PMID- 22940528 TI - Exposure to the steroid hormone 20-hydroxyecdysone modulates agonistic interactions in male Homarus americanus. AB - In this study we present evidence that 20-hydroxyecdysone (20E) affects agonistic behavior in male American lobsters and that male and female animals differ in their response to the hormone. Thirty-minute staged fights were conducted between large males exposed either to artificial seawater (ASW) or 20E and small, anosmic opponents. The nephropores of both combatants were blocked. Fights were videotaped and quantitatively analyzed for aggressive, defensive and avoidance behaviors using an ethogram in which behaviors are ranked according to aggressiveness. Unlike female lobsters, exposing male lobsters to 20E did not increase their aggressive behavior; however, there was a marginally significant trend toward an increase in defensive behaviors with a lower aggressive content than in their ASW-exposed counterparts. The opponents of 20E-exposed animals performed significantly more aggressive behaviors than their counterparts. In fights with 20E-exposed animals, the overall aggressive intensity of the fight was increased and the animals performed a greater number of avoidance behaviors. Unlike the effects of 20E on females, where exposure to 20E caused an increase in overall agonistic arousal, males only exhibited a change in frequency of their behaviors. These findings suggest that while 20E affects both males and females in agonistic encounters, the nature of the effect is different for the two sexes. PMID- 22940529 TI - Robust elemental mapping of nanostructures at ultrahigh resolution using event streamed spectrum imaging in an aberration-corrected analytical electron microscope. AB - We describe the application of X-ray energy dispersive spectroscopy (XEDS) event streamed spectral imaging (ESSI) in an aberration-corrected analytical electron microscope (AEM) as a reliable method for the acquisition of ultra-high spatial resolution elemental maps. With the ESSI approach, the XEDS spectral image is acquired over multiple frames at rates typically reserved for imaging experiments. This approach differs significantly from that typically employed in the AEM, where spectrum image data is acquired serially (a pixel at a time) using per-pixel dwell times that are orders of magnitude larger. The ESSI approach provides numerous advantages, most notably the ability to use the relatively strong transmitted electron image signals as a reference to spatially register the sparse XEDS data. State-of-the-art implementations of ESSI allow this registration to be performed "on-the-fly", such that drift correction is performed in real time. In addition, the electron dose imparted to the specimen is spread over time, meaning the instantaneous dose at a given point in the specimen is orders of magnitude lower than that imparted using serial spectral imaging. Thus, ESSI enables the high spatial resolution analysis of dose-rate sensitive specimens. The application of this technique to several nanoscale systems is discussed, along with the potential for its use in combination with improved detector designs. PMID- 22940530 TI - Effects of growth pressure on the structural and optical properties of multi quantum wells (MQWs) in blue LED. AB - The effects of growth pressure in metal-organic chemical vapor deposition (MOCVD) on the structural and optical properties of InGaN/GaN multiple-quantum-wells (MQWs) grown on c-plane sapphire substrate were investigated by scanning transmission electron microscopy (STEM), atom probe tomography (APT), Raman spectroscopy and electroluminescence (EL) spectroscopy. As the growth pressure decreased, the growth rate of the InGaN layer increased, leading to a decrease in the frequency of the GaN A1(LO) mode peak and broadening of its full width half maximum (FWHM). The intensity of the EL spectra peaked at a growth pressure of 250 Torr with a narrow FWHM at high forward current. These optical properties are explained by either a high degree of compositional fluctuation of indium in the MQW and/or the high crystallinity of the InGaN layer due to the low growth rate under high pressure. PMID- 22940527 TI - Social subordination impairs hypothalamic-pituitary-adrenal function in female rhesus monkeys. AB - Linear dominance hierarchies organize and maintain stability in female rhesus macaque (Macaca mulatta) social groups regardless of group size. As a consequence of their low social status, subordinate females suffer from an array of adverse outcomes including reproductive compromise, impaired immune function, and poor cardiovascular health. However, data that differentiate limbic-hypothalamic pituitary-adrenal axis (LHPA) parameters between dominant from subordinate female monkeys are inconsistent, bringing into question whether social subordination alters the LHPA axis in female macaques. One difficulty in examining LHPA function in macaques may be the confounding effects of cycling ovarian steroids that are known to modulate LHPA activity. The current study used ovariectomized dominant and subordinate female rhesus monkeys to examine the effect that social subordination has on LHPA function by measuring morning and diurnal serum cortisol levels, dexamethasone (Dex) suppression of cortisol, metabolic clearance of Dex, and ACTH stimulation of adrenal cortisol release and cortisol response following exposure to acute social isolation. Compared to dominant females, subordinate females showed diminished morning peak cortisol secretion, weakened glucocorticoid negative feedback, and decreased adrenal cortisol response to an ACTH challenge as well as a restrained cortisol response following social isolation. However, the metabolism of Dex did not account for differences in Dex suppression between dominant and subordinate females. These results indicate that the ability to mount and limit glucocorticoid release is significantly reduced by psychosocial stress in female rhesus macaques, suggesting a hyporesponsive LHPA phenotype which resembles that observed in several human psychopathologies. PMID- 22940531 TI - Characterization of surface metallic states in SrTiO3 by means of aberration corrected electron microscopy. AB - An unusual conducting surface state can be produced in SrTiO3 substrates by irradiation with Argon ions from a plasma source, at low energy and high doses. The effects of irradiation are analyzed here by atomic force microscopy (AFM) and aberration corrected scanning transmission electron microscopy (STEM) combined with electron energy loss spectroscopy (EELS). Depth sensitive studies demonstrate the existence of a heavily damaged surface layer and an oxygen vacancy rich layer immediately underneath, both induced during the irradiation process. We find a clear dependence of the Ti oxidation state with the depth, with a very intense Ti(3+) component near the surface. Oxygen vacancies act as n type doping by releasing electrons into the lattice and producing an insulator-to metal transition, which explains the unusual metallic behavior of these samples. PMID- 22940532 TI - Image simulation for atomic resolution secondary electron image. AB - It has been demonstrated recently that an atomic resolution secondary electron (SE) image can be achieved with a scanning transmission electron microscope (STEM) equipped with a probe-aberration corrector. Its high sensitivity to the surface structure provides a powerful tool to simultaneously study both surface and bulk structure in the STEM, in the combination with the annular dark field (ADF) image. To quantitatively explain the atomic resolution SE image and retrieve surface-structure information, an image simulation is required. Here, we develop a method to simultaneously calculate, for the first time, the atomic resolution SE and ADF-STEM images, based on the multislice method with a frozen phonon approximation. An object function for secondary electrons, derived from the inelastic scattering, is used to calculate the intensity distribution of the secondary electrons emitted from each slice. The simulations show that the SE image contrast is sensitive to the surface structure and the electron inelastic mean free path, but insensitive to specimen thickness when the thickness is more than 5 nm. The simulated SE images for SrTiO(3) crystal show good agreement with the experimental observations. PMID- 22940533 TI - Thermostatted kinetic equations as models for complex systems in physics and life sciences. AB - Statistical mechanics is a powerful method for understanding equilibrium thermodynamics. An equivalent theoretical framework for nonequilibrium systems has remained elusive. The thermodynamic forces driving the system away from equilibrium introduce energy that must be dissipated if nonequilibrium steady states are to be obtained. Historically, further terms were introduced, collectively called a thermostat, whose original application was to generate constant-temperature equilibrium ensembles. This review surveys kinetic models coupled with time-reversible deterministic thermostats for the modeling of large systems composed both by inert matter particles and living entities. The introduction of deterministic thermostats allows to model the onset of nonequilibrium stationary states that are typical of most real-world complex systems. The first part of the paper is focused on a general presentation of the main physical and mathematical definitions and tools: nonequilibrium phenomena, Gauss least constraint principle and Gaussian thermostats. The second part provides a review of a variety of thermostatted mathematical models in physics and life sciences, including Kac, Boltzmann, Jager-Segel and the thermostatted (continuous and discrete) kinetic for active particles models. Applications refer to semiconductor devices, nanosciences, biological phenomena, vehicular traffic, social and economics systems, crowds and swarms dynamics. PMID- 22940534 TI - Consciousness, crosstalk, and the mereological fallacy: an evolutionary perspective. AB - The cross-sectional decontextualization afflicting contemporary neuroscience - attributing to 'the brain' what is the province of the whole organism - is mirrored by an evolutionary decontextualization exceptionalizing consciousness. The living state is characterized by cognitive processes at all scales and levels of organization. Many can be associated with dual information sources that 'speak' a 'language' of behavior-in-context. Shifting global broadcasts analogous to consciousness, albeit far slower - wound healing, tumor control, immune function, gene expression, etc. - have emerged through repeated evolutionary exaptation of the crosstalk and noise inherent to all information transmission. These recruit 'unconscious' cognitive modules into tunable arrays as needed to meet threats and opportunities across multiple frames of reference. The development is straightforward, based on the powerful necessary conditions imposed by the asymptotic limit theorems of communication theory, in the same sense that the Central Limit Theorem constrains sums of stochastic variates. Recognition of information as a form of free energy instantiated by physical processes that consume free energy permits analogs to phase transition and nonequilibrium thermodynamic arguments, leading to 'dynamic regression models' useful for data analysis. PMID- 22940535 TI - Effects of N-acetyl-L-cysteine on bleomycin induced oxidative stress in malignant testicular germ cell tumors. AB - Testicular cancer is a very common cancer in males aged 15-44 years. Bleomycin is used in chemotherapy regimens in the treatment of patients having testicular germ cell tumor. Bleomycin generates oxygen radicals, induces oxidative cleavage of DNA strand and induces apoptosis in cancer cells. There is no study in the literature investigating effects of N-Acetyl-L-Cysteine (NAC) on bleomycin induced oxidative stress in testicular germ cell tumors. For this reason, we studied effects of NAC on oxidative stress produced in wild-type NTera-2 and p53 mutant NCCIT testis cancer cells incubated with bleomycin and compared the results with H(2)O(2) which directly produces oxidative stress. We determined protein carbonyl content, thiobarbituric acid reactive substances (TBARS), glutathione (GSH), 8-isoprostane, lipid hydroperoxide levels and total antioxidant capacity in both testicular cancer cells. Bleomycin and H(2)O(2) significantly increased 8-isoprostane, TBARS, protein carbonyl and lipid hydroperoxide levels in NTera-2 and NCCIT cells. Bleomycin and H(2)O(2) significantly decreased antioxidant capacity and GSH levels in both cell lines. Co-incubation with NAC significantly decreased lipid hydroperoxide, 8 isoprostane, protein carbonyl content and TBARS levels increased by bleomycin and H(2)O(2). NAC enhanced GSH levels and antioxidant capacity in the NTera-2 and NCCIT cells. It can be concluded that NAC diminishes oxidative stress in human testicular cancer cells induced by bleomycin and H(2)O(2). PMID- 22940536 TI - 11beta-Hydroxysteroid dehydrogenase type 1 contributes to the regulation of 7 oxysterol levels in the arterial wall through the inter-conversion of 7 ketocholesterol and 7beta-hydroxycholesterol. AB - The atherogenic 7-oxysterols, 7-ketocholesterol (7-KC) and 7beta hydroxycholesterol (7betaOHC), can directly impair arterial function. Inter conversion of 7-KC and 7betaOHC has recently been shown as a novel role for the glucocorticoid-metabolizing enzyme 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1). Since this enzyme is expressed in vascular smooth muscle cells, we addressed the hypothesis that inter-conversion of 7-KC and 7betaOHC by 11beta HSD1 may contribute to regulation of arterial function. Incubation (4-24 h) of aortic rings with either 7-KC (25 MUM) or 7betaOHC (20 MUM) had no effect on endothelium-dependent (acetylcholine) or -independent (sodium nitroprusside) relaxation. In contrast, exposure to 7-KC (but not to 7betaOHC) attenuated noradrenaline-induced contraction (E(max)) after 4 h (0.78 +/- 0.28 vs 0.40 +/- 0.08 mN/mm; p < 0.05) and 24 h (2.28 +/- 0.34 vs 1.56 +/- 0.48 mN/mm; p < 0.05). Both 7-oxysterols were detected by GCMS in the aortic wall of chow-fed C57Bl6/J mice, with concentrations of 7-KC (1.41 +/- 0.81 ng/mg) higher (p = 0.05) than 7betaOHC (0.16 +/- 0.06 ng/mg). In isolated mouse aortic rings 11beta-HSD1 was shown to act as an oxo-reductase, inter-converting 7-KC and 7betaOHC. This activity was lost in aorta from 11beta-HSD1(-/-) mice, which had low oxysterol levels. Renal homogenates from 11beta-HSD1(-/-) mice were used to confirm that the type 2 isozyme of 11beta-HSD does not inter-convert 7-KC and 7betaOHC. These results demonstrate that 7-KC has greater effects than 7betaOHC on vascular function, and that 11beta-HSD1 can inter-convert 7-KC and 7betaOHC in the arterial wall, contributing to the regulation of 7-oxysterol levels and potentially influencing vascular function. This mechanism may be important in the cardioprotective effects of 11beta-HSD1 inhibitors. PMID- 22940538 TI - Chemical and cellular antioxidant activity of two novel peptides designed based on glutathione structure. AB - Two novel peptides, ECH (Glu-Cys-His) and YECG (Tyr-Glu-Cys-Gly), were designed based on glutathione (Glu-Cys-Gly, GSH) and their antioxidant activities were studied. Various chemical methods based on single-electron-transfer (SET) and hydrogen-atom-transfer (HAT) were applied to evaluate the antioxidant activities of the peptides. For SET-based assay, tripeptide ECH displayed the highest DPPH radical scavenging activity (80.16%) and the strongest reducing power (A(700)=0.378). Besides, ECH also exhibited the best inhibition activity toward linoleic acid peroxidation with inhibition rate 98.25% at 7th day, which is a HAT based assay. However, for another two HAT-based assays, it was tetrapeptide YECG that showed extraordinary oxygen radical absorption capacity (ORAC value=2.42 MUM Trolox/MUM) and ABTS free radical scavenging ability (8.88 mM Trolox/mM). In vitro cultured PC12 cell model also suggested that YECG gave the best protection for PC12 cells to resist H(2)O(2)-treated necrosis. It was found that the discrepancy of antioxidant capacity between ECH and YECG was caused by the presence of antioxidant amino acids (His/Tyr) and their position in peptide chain. With His located at C-terminal position, ECH demonstrated good electrons donating capacity, while with Tyr at N-terminal position, YECG exhibited strong oxygen radical absorbance capacity. PMID- 22940539 TI - Prognostic importance of markers for inflammation, angiogenesis and apoptosis in high grade glial tumors during temozolomide and radiotherapy. AB - INTRODUCTION: Angiogenesis, inflammation and apoptosis have an important place in the carcinogenesis of high-grade gliomas (HGG). We evaluated the postoperative levels and the prognostic importance of tumor necrosis factor-alpha (TNFalpha), interleukin 6 (IL6), endoglin (CD105), vascular endothelial growth factor (VEGF), M65 and M30 as markers of inflammation, angiogenesis and apoptosis in patients with HGG. METHODS AND RESULTS: Postoperative pretreatment sera were collected from 44 newly diagnosed patients with HGG. The control group was also consisted of 44 healthy people. The median age of all patients with HGG was 59 (range: 30 80). Temozolomide concurrent with radiotherapy was given to 37 patients. Thereafter 24 patients received consolidation temozolomide monotherapy. Mean chemotherapy cycle was 4.2. Progression free survival and overall survival were 6 (95% CI; 5.16-6.83) and 16 months (95% CI; 13.07-18.93) respectively in patients treated with concurrent chemoradiotherapy and consolidation chemotherapy. Relative to the control cohort endoglin (p = 0.000) and TNFalpha (p = 0.000) levels were significantly lower; however VEGF (p = 0.030) levels were higher in the patient group. In contrast, there were no significant change in IL-6 levels and the plasma apoptotic markers M65 (p = 0.085) and M30 (p = 0.292). In separate log rank tests, these biological markers did not correlate with survival. DISCUSSION AND CONCLUSION: In HGG, a significant decrease in endoglin and TNFalpha levels was observed, while VEGF levels were significantly increased postoperatively. However, with the power from this patient population, no correlation with survival was observed. PMID- 22940537 TI - Epstein-Barr virus reactivation during pregnancy and postpartum: effects of race and racial discrimination. AB - OBJECTIVE: Adverse pregnancy outcomes, including preterm birth, are markedly higher among African-Americans versus Whites. Stress-induced immune dysregulation may contribute to these effects. Epstein-Barr virus (EBV) reactivation provides a robust model for examining cellular immune competence. This study examined associations of EBV virus capsid antigen immunoglobulin G (VCA IgG) with gestational stage, race, and racial discrimination in women during pregnancy and postpartum. METHODS: Fifty-six women (38 African-American, 18 White) were included. African-Americans and Whites did not differ in age, education, income, parity, or body mass index (ps >= .51). During the 1st, 2nd, and 3rd trimester and ~5 weeks postpartum, women completed measures of racial discrimination, perceived stress, anxiety, depressive symptoms and health behaviors. EBV VCA IgG antibody titers were measured via ELISA in serum collected at each visit. RESULTS: In the overall sample, EBV VCA IgG antibody titers were lower in the 3rd versus 1st trimester (p=.002). At every timepoint (1st, 2nd, 3rd trimester and postpartum), African-American women exhibited higher serum EBV VCA IgG antibody titers than Whites (ps<.001). This effect was most pronounced among African Americans reporting greater racial discrimination [p=.03 (1st), .04 (2nd), .12 (3rd), .06 (postpartum)]. Associations of race and racial discrimination with EBV VCA IgG antibody titers were not accounted for by other measures of stress or health behaviors. CONCLUSIONS: Compared to Whites, African-American women showed higher EBV VCA IgG antibody titers, indicative of impaired cellular immune competence, across pregnancy and postpartum. This effect was particularly pronounced among African-American women reporting greater racial discrimination, supporting a role for chronic stress in this association. In women overall, EBV antibody titers declined during late as compared to early pregnancy. This may be due to pregnancy-related changes in cell-mediated immune function, humoral immune function, and/or antibody transfer to the fetus in late gestation. As a possible marker of stress-induced immune dysregulation during pregnancy, the role of EBV reactivation in racial disparities in perinatal health warrants further attention. PMID- 22940540 TI - Glycyrrhizin regulates CD4+T cell response during liver fibrogenesis via JNK, ERK and PI3K/AKT pathway. AB - The aims of this study were to elucidate the immunomodulatory effects of glycyrrhizin (GL) on CD4(+)T cell responses during liver fibrogenesis. To obtain in vivo evidence about the effects of GL on CD4(+)T cells in livers and spleens of concanavalin A (ConA)-induced mouse model, mice were administrated with ConA together with or without GL for 8 weeks. Mice treated with GL dramatically prevented liver inflammation and fibrosis. Besides, GL inhibited the infiltration of T helper (Th) cell type 1, Th2, Th17 and regulatory T cells (Treg) in livers and spleens of mouse fibrosis models, and regulated the Th1/Th2 and Treg/Th17 balances respectively to a relative dominance of Th1 and Treg lineages in livers. Moreover, GL dramatically enhanced the antifibrotic cytokine interferon (IFN) gamma and interleukin (IL)-10. GL at a concentration of 10 or 100 MUg/mL was respectively incubated with ConA-stimulated splenic CD4(+)T cells in vitro, and JNK inhibitor (SP600125), ERK inhibitor (U0126), p38 inhibitor (SB203580) or PI3K/AKT inhibitor (LY29400225) was added during the incubation. Notably, GL not only inhibited ConA-induced proliferation of splenic CD4(+)T cells but also enhanced the mRNAs of IFN-gamma and IL-10 in these cells. Be similar to the effects of GL, SP600125, U0126 and LY29400225, however not SB203580, also inhibited ConA-induced CD4(+)T cell proliferation, indicating the involvement of JNK, ERK and PI3K/AKT in this process. Moreover, GL significantly inhibited ConA induced phosphorylation of JNK, ERK and PI3K/AKT in vitro. Collectively, GL might alleviate liver injury and fibrosis progression via regulation of CD4(+)T cell response in JNK, ERK and PI3K/AKT-dependent pathways. PMID- 22940541 TI - EMG activation of trunk and upper limb muscles following experimentally-induced overpronation and oversupination of the feet in quiet standing. AB - Kinematic studies have shown that experimentally-induced overpronation or oversupination of the subtalar joint may alter the position of the legs, hips and pelvis and consequently the trunk and upper limb. The purpose of the present study was to examine whether such foot deformity affects the activity of muscles that act on the trunk and upper limb. Twenty-eight healthy individuals (11 males and 17 females) 21.4+/-1.9 years of age without skeletal deformity, leg length discrepancy (LLD), overpronated or oversupinated feet or excessive lateral pelvic inclination volunteered for the study. Bilateral EMG recordings of the latissimus dorsi, pectoralis major and rectus abdominis were undertaken for 30-s with each subject in the relaxed standing position and at 5 degrees and 10 degrees bilateral or unilateral overpronation or oversupination of the foot on the dominant side using wooden wedge-shape blocks. The recorded EMG activity was normalised based on the EMG activity produced by the muscles under investigation during maximum isometric voluntary contraction. The findings of the present study revealed that neither bilateral nor unilateral overpronation/oversupination of the feet induced a significant alteration of the EMG activity of the latissimus dorsi, pectoralis major and rectus abdominis on either the dominant or non dominant side. These findings suggest that in the absence of other major structural deformity bilateral or unilateral foot overpronation or oversupination does not affect the EMG activity of muscles that act on the trunk and upper limb in quiet standing. PMID- 22940543 TI - Factors influencing dynamic prioritization during dual-task walking in healthy young adults. AB - Appropriate prioritization during dual-task walking is necessary to achieve task goals and maintain walking stability. We examined the effects of increased walking task difficulty on dual-task walking prioritization in healthy young adults. Walking under simple usual-base conditions was similar between equal focus and cognitive-focus instructions, but these differed from walking-focus instructions, consistent with cognitive task prioritization. In contrast, narrow base walking was similar between equal-focus and walking-focus instructions, but these differed from cognitive-focus instructions. This shift in prioritization with increasing walking task difficulty suggests that prioritization is dynamic and flexible. PMID- 22940542 TI - How does age affect leg muscle activity/coactivity during uphill and downhill walking? AB - Walking uphill and downhill can be challenging for community-dwelling old adults. We investigated the effects of age on leg muscle activity amplitudes and timing during level, uphill, and downhill walking. We hypothesized that old adults would exhibit smaller increases in ankle extensor muscle activities and greater increases in hip extensor muscle activities compared to young adults during uphill vs. level walking. We also hypothesized that, compared to level walking, antagonist leg muscle coactivation would be disproportionately greater in old vs. young adults during downhill walking. Ten old (72+/-5yrs) and ten young (25+/ 4yrs) subjects walked at 1.25m/s on a treadmill at seven grades (0 degrees , +/-3 degrees , +/-6 degrees , +/-9 degrees ). We quantified the stance phase electromyographic activities of the gluteus maximus (GMAX), biceps femoris (BF), rectus femoris (RF), vastus medialis (VM), medial gastrocnemius (MG), soleus (SOL), and tibialis anterior (TA). Old adults exhibited smaller increases in MG activity with steeper uphill grade than young adults (e.g., +136% vs. +174% at 9 degrees ). A disproportionate recruitment of hip muscles led to GMAX activity approaching the maximum isometric capacity of these active old adults at steep uphill grades (e.g., old vs. young, 73% MVC vs. 33% MVC at +9 degrees ). Neither uphill nor downhill walking affected the greater coactivation of antagonist muscles in old vs. young adults. We conclude that the disproportionate recruitment of hip muscles with advanced age may have critical implications for maintaining independent mobility in old adults, particularly at steeper uphill grades. PMID- 22940546 TI - Genetic analysis of the DLGAP1 gene as a candidate gene for schizophrenia. AB - Schizophrenia is a severe chronic mental disorder with high genetic components in its etiology. Several studies indicated that synaptic dysfunction is involved in the pathophysiology of schizophrenia. Postsynaptic synapse-associated protein 90/postsynaptic density 95-associated proteins (SAPAPs) constitute a part of the N-methyl-d-aspartate receptor-associated postsynaptic density proteins, and are involved in synapse formation. We hypothesized that genetic variants of the SAPAPs might be associated with schizophrenia. Thus, we systemically sequenced all the exons of the discs, large (Drosophila) homolog-associated protein 1 (DLGAP1) gene that encodes SAPAP1 in a sample of 121 schizophrenic patients and 120 controls from Taiwan. We totally identified six genetic variants, including five known SNPs (rs145691437, rs3786431, rs201567254, rs3745051 and rs11662259) and one rare missense mutation (c.1922A>G) in this sample. SNP- and haplotype based analyses showed no association of these SNPs with schizophrenia. The c.1922A>G mutation that changes the amino acid lysine to arginine at codon 641 was found in one out of 121 patients, but not in 275 control subjects, suggesting it might be a patient-specific mutation. Nevertheless, bioinformatic analysis showed this mutation does not affect the function of the DLGAP1 gene and appears to be a benign variant. Hence, its relationship with the pathogenesis remains to be investigated. PMID- 22940544 TI - New insights into the functional significance of the acidic region of the unique N-terminal extension of cardiac troponin I. AB - Previous structural studies indicated a special functional role for an acidic region composed of residues 1-10 in the unique N-terminal peptide of cardiac troponin I (cTnI). Employing LC-MS/MS, we determined the presence of phosphorylation sites at S5/S6 in cTnI from wild type mouse hearts as well as in hearts of mice chronically expressing active protein kinase C-epsilon (PKCepsilon) and exhibiting severe dilated cardiomyopathy (DCM). To determine the functional significance of these phosphorylations, we cloned and expressed wild type cTnI, (Wt), and cTnI variants expressing pseudo-phosphorylation cTnI-(S5D), cTnI(S6D), as well as cTnI(S5A) and cTnI(S6A). We exchanged native Tn of detergent-extracted (skinned) fiber bundles with Tn reconstituted with the variant cTnIs and measured tension and cross-bridge dynamics. Compared to controls, myofilaments controlled by cTnI with pseudo-phosphorylation (S6D) or Ala substitution (S6A) demonstrated a significant depression in maximum tension, ATPase rate, and ktr, but no change in half-maximally activating Ca(2+). In contrast, pseudo-phosphorylation at position 5 (S5D) had no effects, although S5A induced an increase in Ca(2+)-sensitivity with no change in maximum tension or ktr. We further tested the impact of acidic domain modifications on myofilament function in studies examining the effects of cTnI(A2V), a mutation linked to DCM. This mutation significantly altered the inhibitory activity of cTnI as well as cooperativity of activation of myofilament tension, but not when S23/S24 were pseudo-phosphorylated. Our data indicate a new functional and pathological role of amino acid modifications in the N-terminal acidic domain of cTnI that is modified by phosphorylations at cTnI(S23/S24). This article is part of a Special Issue entitled: Cardiomyocyte Biology: Cardiac Pathways of Differentiation, Metabolism and Contraction. PMID- 22940547 TI - Preliminary evidence for association between schizophrenia and polymorphisms in the regulatory Regions of the ADRA2A, DRD3 and SNAP-25 Genes. AB - The results of linkage and candidate gene association studies have led to a range of hypotheses about the pathogenesis of schizophrenia. We limited our study to polymorphisms in candidate genes involved in dopaminergic and noradrenergic systems, and in the 25KDa synaptosomal-associated protein (SNAP-25) gene that is related to neurotransmitter exocytosis. Eight single nucleotide polymorphisms (SNPs) in regulating or coding regions of genes for the alpha-2A adrenergic receptor (ADRA2A), dopamine receptors D1 and D3 (DRD1 and DRD3), dopamine beta hydroxylase (DBH) and SNAP-25 were genotyped in male patients with schizophrenia (n=192) and in healthy controls (n=213). These polymorphisms were previously associated with schizophrenia. The allelic association between schizophrenia and ADRA2A rs1800544 polymorphism, SNAP-25 rs1503112 polymorphism, and DRD3 rs6280 polymorphism was found in our study. However, only observations for rs1503112 survived correction for multiple testing. Association was also evaluated by considering the polymorphisms as interactions; in this case, a likelihood ratio test (LRT) revealed evidence for association with schizophrenia in four polymorphism combinations: two DRD3*SNAP-25 combinations (rs6280*rs3746544 and rs6280*rs3746544, P=0.02), one ADRA2A*SNAP25 combination (rs1800544*rs3746544) and one ADRA2A*DBH combination (rs1800544*rs2519152). Our results are in agreement with the previously proposed role of DNA polymorphisms involved in dopaminergic, noradrenergic and synaptic functions in the pathogenesis of schizophrenia. Further relevant studies including larger sample size and more markers are needed to confirm our results. PMID- 22940548 TI - Optimization of formulation and process parameters for the production of nanosuspension by wet media milling technique: effect of Vitamin E TPGS and nanocrystal particle size on oral absorption. AB - The purpose of this study was to develop nanosuspension formulations of a poorly soluble drug using a wet media milling technique. The milling process was optimized by studying the effects of critical process parameters on the size of nanoparticles using a factorial design approach. During the design of experiments (DOEs) study, different concentrations of Vitamin E TPGS in the suspensions were used to evaluate its influence on the stabilization of a nanosuspension. Once the final formulation was optimized, a pharmacokinetic study was performed in beagle dogs to investigate the effect of different ranges of particle size of nanocrystals on the plasma profile. A significant increase in AUC and C(max) was observed when the drug substance was converted into nanocrystals, likely due to the increase in dissolution rate. Results also revealed that the nanosuspension formulation (consists of nanocrystals with narrow size distribution, having a mean particle size<300 nm) produced less variability with regards to the individual plasma concentrations in the dogs when compared an alternate nanocrystal formulation (consists of nanocrystals with broad size distribution having a mean particle size<750 nm). This type of observation can be explained due to the Ostwald ripening phenomena between the nanocrystals when the particle size distribution was very broad (higher poly dispersity index). Surprisingly, the un-micronized suspension containing Vitamin E TPGS did not show any significant impact on pharmacokinetic parameters. PMID- 22940545 TI - Neuroestrogen, rapid action of estradiol, and GnRH neurons. AB - Estradiol plays a pivotal role in the control of GnRH neuronal function, hence female reproduction. A series of recent studies in our laboratory indicate that rapid excitatory actions of estradiol directly modify GnRH neuronal activity in primate GnRH neurons through GPR30 and STX-sensitive receptors. Similar rapid direct actions of estradiol through estrogen receptor beta are also described in mouse GnRH neurons. In this review, we propose two novel hypotheses as a possible physiological role of estradiol in primates. First, while ovarian estradiol initiates the preovulatory GnRH surge through interneurons expressing estrogen receptor alpha, rapid direct membrane-initiated action of estradiol may play a role in sustaining GnRH surge release for many hours. Second, locally produced neuroestrogens may contribute to pulsatile GnRH release. Either way, estradiol synthesized in interneurons in the hypothalamus may play a significant role in the control of the GnRH surge and/or pulsatility of GnRH release. PMID- 22940549 TI - GABAA receptor-mediated feedforward and feedback inhibition differentially modulate hippocampal spike timing-dependent plasticity. AB - Synaptic plasticity is believed to play an important role in hippocampal learning and memory. The precise and relative timing of pre- and postsynaptic activity has been shown to determine the sign and amplitude of hippocampal synaptic plasticity through spike timing-dependent plasticity (STDP). While most studies on STDP have mainly focused on excitatory synapses, neural networks are composed not only of excitatory synapses, but also of inhibitory synapses. Interneurons are known to make inhibitory synaptic connections with hippocampal CA1 pyramidal neurons through feedforward and feedback inhibitory networks. However, the roles of different inhibitory network structures on STDP remain unknown. Using a simplified hippocampal network model with a deterministic Ca(2+) dynamics dependent STDP model, we show that feedforward and feedback inhibitory networks differentially modulate STDP. Moreover, inhibitory synaptic weight and synaptic location influenced the STDP profile. Taken together, our results provide a computational role of inhibitory network in STDP and in memory processing of hippocampal circuits. PMID- 22940550 TI - Toll-like receptor 9 signaling has anti-inflammatory effects on the early phase of Helicobacter pylori-induced gastritis. AB - Helicobacter pylori (H. pylori)-induced immune responses in the gastric mucosa are skewed toward T helper (Th) 1 phenotype, which is characterized by predominant production of tumor necrosis factor (TNF)-alpha and interferon (IFN) gamma by helper T cells. Toll-like receptors (TLRs) play an essential role in mucosal defense against microbes through the recognition of bacterial molecules. Among the members of the TLR family, TLR9 recognizes bacterial unmethylated CpG DNA sites, and signal transduction of TLR9 induces production of a variety of cytokines, including type-I IFN (IFN-alpha/beta). We investigated the expression and role of TLR9 in H. pylori-induced gastritis in mice. Expression of TLR9 mRNA in the gastric tissue increased after infection with H. pylori. TLR9 was mainly expressed in the macrophages, dendritic cells, and CD3(+) cells in the gastric mucosa. Neutrophil infiltration and the expression levels of TNF-alpha and IFN gamma mRNA were higher in TLR9 knockout (KO) mice than in wild-type mice at 2 and 4 months after H. pylori inoculation. These differences in inflammatory parameters between H. pylori-infected wild-type and TLR9 KO mice disappeared 6 months after H. pylori inoculation. Expression of interleukin-4 mRNA, typical Th2 cytokine, in the gastric tissue did not differ between H. pylori-infected wild type and TLR9 KO mice. Expression level of IFN-alpha/beta mRNA in the TLR9 KO mice was lower than that in wild-type mice by 4 months after inoculation. Administration of IFN-alpha reduced H. pylori infection-induced increase in neutrophil infiltration and the expression levels of TNF-alpha and IFN-gamma mRNA in TLR9 KO mice. Our findings suggest that TLR9 signaling plays important roles in the suppression of H. pylori-induced gastritis in the early phase via downregulation of Th1-type cytokines modulated by IFN-alpha. PMID- 22940551 TI - Formation of a heterooctameric complex between aspartate alpha-decarboxylase and its cognate activating factor, PanZ, is CoA-dependent. AB - The existence of a fifth essential protein for pantothenate biosynthesis in some enteric bacteria has recently been reported by Stuecker et al. [10] and Nozaki et al. (in press) [9]. This protein, PanZ, catalyses the activation of the PanD zymogen to form ADC and is essential for prototrophic growth. In this paper, we characterise the interaction of PanZ with coenzyme A and a constitutively inactive mutant of PanD using a combination of isothermal titration calorimetry and mass spectrometry. These approaches reveal that the two proteins interact with nanomolar affinity in a CoA-dependent fashion to form a heterooctameric complex. PMID- 22940552 TI - MicroRNA-29a is up-regulated in beta-cells by glucose and decreases glucose stimulated insulin secretion. AB - Chronically elevated levels of glucose impair pancreatic beta-cell function while inducing beta-cell proliferation. MicroRNA-29a (miR-29a) levels are increased in several tissues in diabetic animals and mediate decreased insulin-stimulated glucose-transport of adipocytes. The aim was to investigate the impact of glucose on miR-29a levels in INS-1E beta-cells and in human islets of Langerhans and furthermore to evaluate the impact of miR-29a on beta-cell function and proliferation. Increased glucose levels up-regulated miR-29a in beta-cells and human and rat islets of Langerhans. Glucose-stimulated insulin-secretion (GSIS) of INS-1E beta-cells was decreased by forced expression of miR-29a, while depletion of endogenous miR-29a improved GSIS. Over-expression of miR-29a increased INS-1E proliferation. Thus, miR-29a up-regulation is involved in glucose-induced proliferation of beta-cells. Furthermore, as depletion of miR-29a improves beta-cell function, miR-29a is a mediator of glucose-induced beta-cell dysfunction. Glucose-induced up-regulation of miR-29a in beta-cells could be implicated in progression from impaired glucose tolerance to type 2 diabetes. PMID- 22940553 TI - Otorhinolaryngological manifestations in granulomatosis with polyangiitis (Wegener's). AB - Granulomatosis with polyangiitis (Wegener's, GPA) is an uncommon disease of unknown etiology classically involves the ELK triad of the ear, nose, throat (E), lungs (L) and kidneys (K) with necrotizing granulomatous inflammation and vasculitis. Most of the initial symptoms begin in the head and neck region with a wide spectrum of involvement of any site ranging from the nasal septum, paranasal sinuses, oral mucosa, larynx and even the external, middle and internal ear. Diagnosis may be delayed because the onset is heterogeneous and sometimes limited to one organ. The pathologic findings of a characteristic inflammatory reaction pattern, and the serum findings of elevated antineutrophil cytoplasmic antibodies can help to establish the diagnosis. The differentiation from other conditions that mimic GPA such as lymphoma and infections is of critical importance to initiate appropriate treatment. Treatment of the underlying disease is medical with the use of immunosuppressive agents and will not be reviewed here. This review focuses on the otorhinolaryngologic manifestation and complication of GPA as well as their surgical management and specifies the role of the otorhinolaryngologist as an integral member of the multidisciplinary care team for patients with GPA. PMID- 22940554 TI - Cocaine-induced midline destructive lesions - an autoimmune disease? AB - In Europe it is estimated that around 13million of adults (15-64years) have used cocaine at least once in their lifetime. The most frequently used route of administration for the drug is intranasal inhalation, or "snorting", and thus the adverse effects of cocaine on the nasal tract are very common. Habitual nasal insufflations of cocaine may cause mucosal lesions, and if cocaine use becomes chronic and compulsive, progressive damage of the mucosa and perichondrium leads to ischemic necrosis of septal cartilage and perforation of the nasal septum. Occasionally, cocaine-induced lesions cause extensive destruction of the osteocartilaginous structures of nose, sinuses and palate that can mimic other diseases such as tumors, infections, and immunological diseases. Thorough diagnostic workup, including endoscopic, radiologic, histopathologic and serologic testing is imperative to arrive at the proper diagnosis and to initiate appropriate local and systemic treatment. Positive antineutrophil cytoplasmic antibody (ANCA) test results may be found in an unexpectedly large proportion of patients with CIMDL. In several instances their lesions are clinically indistinguishable from granulomatosis with polyangiitis (Wegener's) limited to the upper respiratory tract. CIMDL seem to be the result of a necrotizing inflammatory tissue response triggered by cocaine abuse in a subset of patients predisposed to produce ANCA, particularly those reacting with HNE. The presence of these HNE-ANCA seems to promote or define the disease phenotype. CIMDL do not respond well to immunosuppressive therapy. Only the consistent removal of persistent stimuli of autoantibody production (cocaine, bacterial superinfections) can halt the disease process, prevent the progression of the lesions and promise success of surgical repair procedures. PMID- 22940555 TI - Aicardi-Goutieres syndrome, a rare neurological disease in children: a new autoimmune disorder? AB - Aicardi-Goutieres syndrome (AGS), described by J. Aicardi and F. Goutieres in 1984, is a rare neurological disease with onset in infancy. It is often misdiagnosed as a sequela of congenital infection or recognized later. Nowadays almost 200 cases are reported all over the world, most of them collected by the International Aicardi-Goutieres Syndrome Association (IAGSA), founded in Pavia (Italy) in 2000. AGS (MIM 225750) is a genetically-determined encephalopathy characterized by severe neurological dysfunction, acquired microcephaly associated with severe prognosis quoad valetudinem, and less frequently also quoad vitam. Some AGS children also develop some symptoms overlapping with systemic lupus erythematosus (SLE). Intracranial calcification, white matter involvement and brain atrophy revealed on MRI, lymphocytosis and elevated levels of interferon alpha (IFN-alpha) in the cerebrospinal fluid (CSF) are features of both AGS and congenital viral infection. No evidence of congenital infection at serological exams has ever been found. A genetic etiology was hypothesized since the first descriptions, because of the recurrence in families, and demonstrated some years ago. Nowadays five genes (AGS1-5), if mutated, can be responsible for 90% of the cases. The transmission is autosomal recessive but there are also rare "de novo" autosomal dominant cases. Even if pathogenesis is still almost unknown, it seems that responsible genes are involved in nucleic acid reparation mechanisms and consequently in a secondary activation of innate autoimmunity. The relative lack of precise information on pathogenesis and on the evolution of the disease over time has not yet allowed the creation of codified diagnostic and therapeutic models and programs. PMID- 22940556 TI - Effects of marine silages enriched with Lactobacillus sakei 5-4 on haemato immunological and growth response in Pacific red snapper (Lutjanus peru) exposed to Aeromonas veronii. AB - Combined effects of marine silages enriched with Lactobacillus sakei 5-4 were evaluated on growth performance, immune activity and disease resistance of Pacific red snapper (Lutjanus peru) against Aeromonas veronii infection. The experimental fish were divided into three groups which were fed with each one of the following diets: silage-probiotic-free diet (control, C group), Pacific creole-fish silage diet supplemented with live L. sakei (10(6) CFU g(-1)) (FSLact group) and Humboldt squid silage diet supplemented with live L. sakei (10(6) CFU g(-1)) (SSLact group) for 6 weeks. After 6 weeks, fish were immunocompromised with pathogenic A. veronii and spleen and liver samples were processed for histopathological studies. Generally, the results showed enhanced growth performance in fish fed the diet containing SSLact at 6 and 7 weeks compared with fish fed control diet. Addition of SSLact had an increase in plasmatic protein at week 6 and post-challenge. Hemoglobin concentration increased after challenge in fish fed with SSLact compared to control group. At week 6 and post-challenge the results indicated that, the fish groups which received diet supplemented with SSLact revealed significant increase in humoral immune parameters. Histologically, fish fed C diets showed marked fatty degeneration and great activation of melanomacrophage centers compare with SSLact and FSLact groups. These results support the idea that the marine silages with squid as protein source enriched or combined with L. sakei 5-4 increases the body weight and stimulates the physiological and humoral immune parameters in Pacific red snapper infected with A. veronii. PMID- 22940558 TI - Protective effects of taurine against alloxan-induced diabetic cataracts and refraction changes in New Zealand White rabbits. AB - The present study examined the protective effects of taurine on alloxan-induced diabetic cataracts and lens damage in male New Zealand White rabbits. The animals were randomly divided into three treatment groups: (1) normal control (vehicle administration); (2) diabetes (100 mg/kg alloxan administration); and (3) diabetes + taurine (1% [w/v] taurine dissolved in drinking water and alloxan administration). The results showed that alloxan-induced diabetes caused significant (p < 0.05) hyperglycemia, hyperopic refraction shifts, cataract formation and lens damage compared with the normal control group. In contrast, the administration of taurine for 24 weeks significantly ameliorated the alloxan induced elevated levels of blood glucose, level of hyperopic refraction error shifts in the eyes and progression of diabetic cataract formation in the lens in rabbits. Moreover, histopathology showed that the taurine supplement reduced the incidence of lens lesions induced by hyperglycemia. Overall, the studies demonstrate that taurine exhibits potent protective effects against alloxan induced diabetic cataracts and refraction changes in rabbits. PMID- 22940557 TI - Quantitative light-induced fluorescence (QLF): a tool for early occlusal dental caries detection and supporting decision making in vivo. AB - OBJECTIVES: This study reports the development and assessment of a novel method using quantitative light-induced fluorescence (QLF), to determine whether QLF parameters DeltaF and DeltaQ were appropriate for aiding diagnosis and clinical decision making of early occlusal mineral loss by comparing QLF analysis with actual restorative management. METHODS: Following ethical approval, 46 subjects attending a dental teaching hospital were enrolled. White light digital (WL) and QLF images/analyses of 46 unrestored posterior teeth with suspected occlusal caries were made after a clinical decision had already been taken to explore fissures operatively. WL and QLF imaging/analysis were repeated after initial cavity preparation. The type of restorative treatment was determined by the supervising clinician independent of any imaging performed. Actual restorative management carried out was recorded as fissure sealant/preventive resin restoration (F/P) or class I occlusal restoration (Rest.) thus reflecting the extent of intervention (=gold standard). All QLF images were analysed independently. RESULTS: The results showed statistically significant differences between the two treatment groups DeltaF (p=0.002) (mean 22.60 - F/P and 28.80 - Rest.) and DeltaQ (p=0.012) (mean 230.49 - F/P and 348.30 - Rest.). CONCLUSIONS: DeltaF and DeltaQ values may be useful in aiding clinical diagnosis and decision making in relation to the management of early mineral loss and restorative intervention of occlusal caries. CLINICAL SIGNIFICANCE: QLF has the potential to be a valuable tool for caries diagnosis in clinical practice. PMID- 22940559 TI - Constipation in palliative care: what do we use as definitions and outcome measures? AB - CONTEXT: Advances in the management of constipation in palliative care remain hindered by the lack of agreed-upon diagnostic criteria. OBJECTIVES: The objective of this work was to emphasize this issue by systematically examining the eligibility and primary outcome measures in studies of constipation in the hospice and palliative care population. METHODS: A palliative care-specific electronic literature search was undertaken using the validated domain filter "palliative care" and topic filter "constipation" in CareSearch (www.caresearch.com.au), which interrogates PubMed in real time (1965-2011). Studies were included if they were primary reports of the treatment of constipation in a palliative care setting. Articles could be prospective or retrospective; randomized controlled trials, cohort studies, or case series. RESULTS: Twenty articles on the palliative care population were included in which there were six different definitions of constipation. Only 12 of 20 articles used their cited definitions of constipation as the studies' primary outcome measures and four of four blinded, randomized, controlled trials. Articles that used the time between bowel actions or the use of laxatives as the definition of constipation were most likely to report outcomes based on these criteria. CONCLUSION: Constipation is a significant problem in palliative care; however, not having an agreed-upon definition limits research initiatives and the ability to apply these results clinically to people with constipation. Four domains are suggested as pivotal to the diagnosis: any life-long history of constipation (using the Rome Criteria), evaluation of physical changes that may cause or worsen constipation, the subjective sensation (such as feelings of incomplete defecation or bloating or fullness), and objective changes (such as frequency or consistency of stools). PMID- 22940560 TI - Enrollment and events of hospice patients with heart failure vs. cancer. AB - CONTEXT: Hospice care is traditionally used for patients with advanced cancer, but it is increasingly considered for patients with end-stage heart failure. OBJECTIVES: We compared enrollment patterns and clinical events of hospice patients with end-stage heart failure with those of patients with advanced cancer. METHODS: Using Medicare data linked with pharmacy and cancer registry data, we identified patients who were diagnosed with either heart failure or advanced cancer between 1997 and 2004, admitted to hospice at least once after their diagnosis, and died during the study period. We compared patterns of referral, use of acute services, and site of death of hospice patients with heart failure with those of patients with advanced cancer. Logistic regression models were constructed to determine the factors associated with late hospice enrollment as well as the use of and death in acute care. RESULTS: We identified 1580 heart failure patients and 3840 advanced cancer patients: mean ages were 86 and 80 years, 82% and 68% were women, and 97% and 94% were white, respectively. Compared with patients with advanced cancer, those with heart failure were more frequently referred to hospice from hospitals (35% vs. 24%) and nursing facilities (9% vs. 7%) (both P<0.01). Discharge from hospice before death was similar for patients with heart failure and patients with advanced cancer (10% vs. 9%, P=0.03). Among patients remaining in hospice, patients with heart failure were more likely to have been enrolled within three days of death (20% vs.11%, P<0.01). The prevalence of death in acute care settings was low in both groups after hospice enrollment (4% heart failure vs. 2% advanced cancer, P<0.01). Although the median interval between enrollment and death was shorter for heart failure patients (12 vs. 20 days, P<0.001), emergency department visits and hospitalizations after hospice enrollment were more frequent in patients with heart failure (13% vs. 10% and 9% vs. 6%, respectively, both P<0.01). CONCLUSION: Compared with patients with advanced cancer, referral to hospice is more often initiated during acute care encounters for patients with end-stage heart failure, who also more frequently return to acute care settings even after hospice enrollment. PMID- 22940561 TI - Management of moderate-to-severe dyspnea in hospitalized patients receiving palliative care. AB - CONTEXT: Benzodiazepines (BZDs) are commonly prescribed for relief of dyspnea in palliative care, yet few data describe their efficacy. OBJECTIVES: To describe the management of moderate-to-severe dyspnea in palliative care patients. METHODS: Chart review of inpatients with moderate or severe dyspnea on initial evaluation by a palliative care service. We recorded dyspnea scores at follow-up (24 hours later) and use of BZDs and opioids. RESULTS: The records of 115 patients were reviewed. The mean age of patients was 64 years and primary diagnoses included cancer (64%, n=73), heart failure (8%, n=9), and chronic obstructive pulmonary disease (5%, n=6). At initial assessment, 73% (n=84) of the patients had moderate and 27% (n=31) had severe dyspnea. At follow-up, 74% (n=85) of patients reported an improvement in their dyspnea, of which 42% (n=36) had received opioids alone, 37% (n=31) had BZDs concurrent with opioids, 2% (n=2) had BZDs alone, and 19% (n=16) had received neither opioids nor BZDs. Logistic regression analysis identified that patients who received BZDs and opioids had increased odds of improved dyspnea (odds ratio 5.5, 95% CI 1.4, 21.3) compared with those receiving no medications. CONCLUSION: Most patients reported improvement in dyspnea at 24 hours after palliative care service consultation. Consistent with existing evidence, most patients with dyspnea received opioids but only the combination of opioids and BZDs was independently associated with improvement in dyspnea. Further research on the role of BZDs alone and in combination with opioids may lead to better treatments for this distressing symptom. PMID- 22940563 TI - Modeling the longitudinal transitions of performance status in cancer outpatients: time to discuss palliative care. AB - CONTEXT: Understanding the longitudinal transitions of performance status among persons with cancer can assist providers in determining the appropriate time to initiate palliative care support. OBJECTIVES: To model longitudinal transitions of performance status in cancer outpatients, to determine the probabilities of improvement and deterioration in performance status over time, and to evaluate the factors associated with rates of transitions. METHODS: This population-based, retrospective, cohort study comprised adult outpatients diagnosed with any type of cancer and assessed for performance status throughout their observation period using the Palliative Performance Scale (PPS; scale 0-100; 0 indicates death). At every PPS assessment, patients were assigned to one of four states: stable state (PPS score 70-100), transitional state (PPS score 40-60), end-of-life state (PPS score 10-30), or dead. A Markov multistate model under the presence of interval censoring was used to examine the rate of state-to-state transitions. RESULTS: There were 11,374 patients representing nearly 71,000 assessments. Patients with lung cancer in the transitional state had a 27.7% chance of being dead at the end of one month vs. 17.5% in patients with breast cancer. The average time spent in the transitional state was 6.6 weeks for patients diagnosed with gastrointestinal cancer vs. 8.8 weeks for patients with breast cancer. The rate at which one moves from the transitional state to death was higher for patients with lung cancer than those with breast cancer. CONCLUSION: We estimated the probability and direction of change in performance status in cancer outpatients. Entry into the transitional state may serve as an indicator for referral for palliative care support. Mean end-of-life sojourn times are too short to allow meaningful integration of palliative care. PMID- 22940562 TI - Frequency and predictors of patient deviation from prescribed opioids and barriers to opioid pain management in patients with advanced cancer. AB - CONTEXT: Approximately 80% of patients with advanced cancer report pain and receive opioids. Information is limited about deviations from prescribed opioid doses and barriers to pain control, but poor opioid adherence has been reported in 49%-70% of patients. OBJECTIVES: To evaluate the frequency and severity of self-reported opioid deviation and barriers to opioid pain management in outpatients with advanced cancer. METHODS: We surveyed 198 patients and collected pain scores (0-10), prescribed opioid dose, confidential patient-reported opioid prescription dose and intake (as long as there was no severe opioid deviation), barriers to pain management (Barriers Questionnaire-II [BQ-II]) scores, and adherence scores. Opioid deviation was defined as <70% or >130% of the prescribed dose. RESULTS: Median patient age was 55 years; 91 (46%) were female. Median pain intensity and morphine equivalent daily dose were 4 (interquartile range=3-7) and 120mg (interquartile range=45-270mg), respectively. Prescribed and patient reported prescribed doses were highly correlated for regular (r=0.90, P<0.001) and regular plus breakthrough opioid intake (r=0.94, P<0.001). Nineteen (9.6%) patients deviated. Deviation was more frequent in males (P=0.039) and nonwhites (P=0.0270). Nonwhite patients had higher scores on the BQ-II than white patients (P=0.038). Low adherence scores were significantly associated with higher BQ-II scores (1.99+/-0.80) for lower motivation score vs. 1.61+/-0.77 for higher score, P=0.007; and 2.13+/-0.79 for lower knowledge score vs. 1.57+/-0.72 for higher score, P=0.001. CONCLUSION: Very few patients reported dose deviations, which were mostly toward lower dose. More research is necessary to better characterize the frequency and predictors of opioid deviation in this population. PMID- 22940564 TI - "All my tears were gone": suffering and cancer pain in Southwest American Indians. AB - CONTEXT: Although minority patients with cancer are more likely to be undermedicated for cancer pain than non-Hispanic whites, little is known about the experience of cancer pain in American Indians (AIs). OBJECTIVES: To describe the experience of cancer and cancer pain in a sample of southwestern AIs. METHODS: Ethnographic interviews were conducted with 13 patients and 11 health care providers, caregivers, and community members; two questionnaires were used to collect demographic and pain data. RESULTS: Barriers to pain control among AIs included difficulties describing pain, a belief that cancer pain is inevitable and untreatable, and an aversion to taking opioid pain medication. Prescriber inexperience also was cited as a barrier to pain management. AIs described a strong desire to protect their privacy regarding their illness, and many felt that expressing pain was a sign of weakness. The inability to participate in spiritual and cultural activities caused AIs distress, and some discontinued treatment or missed chemotherapy appointments to engage in these activities. CONCLUSION: Results revealed new knowledge about the cancer pain experience in AIs. The observation of the close relationship between treatment compliance and the patient's ability to participate in ceremonial and spiritual activities provides new insight into the problem of incomplete cancer treatment in this population. The finding that AI patients have a multidimensional conceptualization of pain will assist clinicians with obtaining more detailed and informative pain assessments. PMID- 22940565 TI - [Spanish Society of Hospital Paediatrics]. PMID- 22940566 TI - Sequence variation identified in the 18S rRNA gene of Theileria mutans and Theileria velifera from the African buffalo (Syncerus caffer). AB - The African buffalo (Syncerus caffer) is a natural reservoir host for both pathogenic and non-pathogenic Theileria species. These often occur naturally as mixed infections in buffalo. Although the benign and mildly pathogenic forms do not have any significant economic importance, their presence could complicate the interpretation of diagnostic test results aimed at the specific diagnosis of the pathogenic Theileria parva in cattle and buffalo in South Africa. The 18S rRNA gene has been used as the target in a quantitative real-time PCR (qPCR) assay for the detection of T. parva infections. However, the extent of sequence variation within this gene in the non-pathogenic Theileria spp. of the Africa buffalo is not well known. The aim of this study was, therefore, to characterise the full length 18S rRNA genes of Theileria mutans, Theileria sp. (strain MSD) and T. velifera and to determine the possible influence of any sequence variation on the specific detection of T. parva using the 18S rRNA qPCR. The reverse line blot (RLB) hybridization assay was used to select samples which either tested positive for several different Theileria spp., or which hybridised only with the Babesia/Theileria genus-specific probe and not with any of the Babesia or Theileria species-specific probes. The full-length 18S rRNA genes from 14 samples, originating from 13 buffalo and one bovine from different localities in South Africa, were amplified, cloned and the resulting recombinants sequenced. Variations in the 18S rRNA gene sequences were identified in T. mutans, Theileria sp. (strain MSD) and T. velifera, with the greatest diversity observed amongst the T. mutans variants. This variation possibly explained why the RLB hybridization assay failed to detect T. mutans and T. velifera in some of the analysed samples. PMID- 22940567 TI - Immunogenicity of virus-like particles containing modified goose parvovirus VP2 protein. AB - The major capsid protein VP2 of goose parvovirus (GPV) expressed using a baculovirus expression system (BES) assembles into virus-like particles (VLPs). To optimize VP2 gene expression in Sf9 cells, we converted wild-type VP2 (VP2) codons into codons that are more common in insect genes. This change greatly increased VP2 protein production in Sf9 cells. The protein generated from the codon-optimized VP2 (optVP2) was detected by immunoblotting and an indirect immunofluorescence assay (IFA). Transmission electron microscopy analysis revealed the formation of VLPs. These findings indicate that optVP2 yielded stable and high-quality VLPs. Immunogenicity assays revealed that the VLPs are highly immunogenic, elicit a high level of neutralizing antibodies and provide protection against lethal challenge. The antibody levels appeared to be directly related to the number of GP-Ag-positive hepatocytes. The variation trends for GP Ag-positive hepatocytes were similar in the vaccine groups. In comparison with the control group, the optVP2 VLPs groups exhibited obviously better responses. These data indicate that the VLPs retained immunoreactivity and had strong immunogenicity in susceptible geese. Thus, GPV optVP2 appears to be a good candidate for the vaccination of goslings. PMID- 22940568 TI - Inhibition on hepatitis B virus in vitro of lectin from Musca domestica pupa via the activation of NF-kappaB. AB - The present study reported that the secretions of HBsAg and HBeAg in HepG2.2.15 cells were significantly decreased under the treatment of lectin from Musca domestica pupa (MPL). Both the replication of hepatitis B virus (HBV) DNA and HBV cccDNA in cells, and the copies of extracellular HBV DNA were inhibited by MPL. The mRNA expressions of interleukin-2 (IL-2), gamma interferon (INF-gamma) and MxA were up-regulated by MPL treatments, but down-regulated when nuclear factor kappaB (NF-kappaB) signal pathway was blocked by pyrrolidine dithiocarbamate (PDTC). Subsequent investigation revealed that nuclear factor-kappaB inhibitory kappaB (IkappaB) in endochylema was inhibited and NF-kappaB was translocated into the nucleus. These findings indicate that MPL could inhibit HBV replication via the induction of the expression of IL-2, INF-gamma and MxA through the activation of NF-kappaB. PMID- 22940569 TI - Comprehensive diversity analysis of viroids infecting grapevine in China and Japan. AB - To date, several viroid species have been shown to infect grapevine, including Hop stunt viroid (HpSVd), Citrus exocortis viroid (CEVd), Australian grapevine viroid (AGVd), Grapevine yellow speckle viroid-1 (GYSVd-1), Grapevine yellow speckle viroid-2 (GYSVd-2) and a tentative new species, Grapevine yellow speckle viroid-3 (GYSVd-3). Here, we identified and analyzed the distribution, genetic diversity, and molecular properties of viroids infecting grapevine cultivated in China and Japan, including old grapevines. The analysis showed that all the five known viroids and a tentative species GYSVd-3 infecting grapevine exist in China, and three of them (HpSVd, GYSVd-1 and GYSVd-3) exist in Japan. The contrast in diversity of viroid species in old grapevines from China and Japan may reflect different history of viticulture between the two countries. In general, the species of viroids infecting grapevine in China, as well as those in Iran and Australia, were more diverse than in the other countries. The population structure of viroids infecting grapevine in China and Japan showed species dependency; i.e., HpSVd shared similar population structures in both countries, but GYSVd-1, GYSVd-2, and AGVd showed regional disparity even within the same country, although the role of sequence diversity in the biology of viroids infecting grapevine, such as the pathogenicity and evolution, still needs further study. PMID- 22940570 TI - The role of fibres and the hypodermis in Compositae melanin secretion. AB - Melanins are dark, insoluble pigments that are resistant to concentrated acids and bleaching by oxidising agents. Phytomelanin (or phytomelan) is present in the seed coat of some Asparagales and in the fruits of some Compositae. In Compositae fruits, melanin is deposited in the schizogenous spaces between the hypodermis and underlying fibrous layer. Phytomelanin in Compositae is poorly understood, and there are only speculations regarding the cells that produce the pigment and the cellular processes involved in the secretion and polymerisation of phytomelanin. This report describes the cellular processes involved in the secretion of phytomelanin in the pericarp of Praxelis diffusa, a species with a structure typical of the family. The ovaries and fruits at different stages were fixed and processed according to the standard methods of studies of light microscopy and transmission electron microscopy. Hypodermal cells have abundant rough endoplasmic reticulum and mitochondria, and the nuclei have chromatin that is less dense than other cells. These characteristics are typical of cells that synthesise protein/amino acids and suggest no carbohydrate secretion. The fibres, however, have a dense cytoplasm rich in the Golgi bodies that are associated with vesicles and smooth endoplasmic reticulum, common characteristics of carbohydrate secretory cells. Our results indicate that the hypodermal cells are not responsible for the secretion of phytomelanin, as previously described in the literature; in contrast, this function is assigned to the adjacent fibres, which have an organisation typical of cells that secrete carbohydrates. PMID- 22940571 TI - Morphological and ultrastructural characterization of Carposina sasakii larvae (Lepidoptera: Carposinidae) infected by Beauveria bassiana (Ascomycota: Hypocreales: Clavicipitaceae). AB - The aim of this study was to better understand the pathogenesis of the entomopathogenic fungus Beauveria bassiana (Balsamo) strain TST05 observed on the peach fruit moth (Carposina sasakii (Matsumura)), an important orchard pest. The morphological and ultrastructural characterization of the mature larvae of C. sasakii infected by B. bassiana was investigated by using light, scanning and transmission electron microscopy. The results of the study show that B. bassiana TST05 infected the host larvae mainly by penetrating the integument. The conidia of the fungus adhere easily to the area around the mouthparts and to the basal area around the acanthae on the thorax and abdomen. Observations of the host's defensive response to the fungal attack indicated that dark spots appeared on the cuticle and that melanization appeared in the hemocoel. After overcoming the host's defense system, the pathogen grew and reproduced primarily in the hemocoel. The infection spread sequentially to the internal tissues, e.g., fat body, muscle, Malpighian tubules, gut and even the silk gland. Ultimately, the larval internal organs and tissues were damaged very extensively. Finally, the fungus emerged through the cuticle of the dead insect and released conidiophores that could act as new pathogens to infect other larvae. PMID- 22940572 TI - A novel dense CO(2) supercritical fluid technology for the development of microparticulate delivery systems containing ketoprofen. AB - VarioSol(r) is an innovative, solvent-free technology able to produce microparticles exploiting near-critical CO(2) properties as spraying and cooling agent. The aim of the present work was to evaluate the feasibility to produce in a single processing step by VarioSol(r) technology, oral ketoprofen-loaded microparticles with gastro-protective properties. The obtained products were powders composed of regular in shape and small in diameter microparticles, characterized by high drug content (40%) and good flow properties. Microparticles were composed by anionic lipids scarcely soluble at acidic pH, blended with gastro-resistant polymers of the methacrylate type. In vitro drug release results indicated that the drug was rapidly delivered from the microparticulate systems in phosphate buffer at pH 6.8, while in acidic medium, the microparticles were able to retard the drug release process but without reaching complete gastro resistance. However, the results obtained in this study, although non optimal, are not far from the specifications required for gastro-resistant release products (i.e., no more than 10% drug released after 1h at pH 1.0) according to EMA guidelines and represent a good starting point for future formulation development. PMID- 22940574 TI - Metabolic activation by human arylacetamide deacetylase, CYP2E1, and CYP1A2 causes phenacetin-induced methemoglobinemia. AB - Phenacetin has been used as an analgesic antipyretic but has now been withdrawn from the market due to adverse effects such as methemoglobinemia and renal failure. It has been suggested that metabolic activation causes these adverse effects; yet, the precise mechanisms remain unknown. We previously demonstrated that human arylacetamide deacetylase (AADAC) was the principal enzyme catalyzing the hydrolysis of phenacetin. In this study, we assessed whether AADAC was involved in phenacetin-induced methemoglobinemia. A high methemoglobin (Met-Hb) level in the blood was detected 1 h after administration of phenacetin (250 mg/kg, p.o.) to male C57BL/6 mice. Pre-administration of tri-o-tolylphosphate, a general esterase inhibitor, was found to decrease the levels of Met-Hb and the plasma concentration of p-phenetidine, a hydrolyzed metabolite of phenacetin. An in vitro study using red blood cells revealed that incubation of phenacetin or p phenetidine with human liver microsomes (HLM) increased the formation of Met-Hb. To identify the enzymes involved in the formation of Met-Hb, we used recombinant enzymes and HLM treated with inhibitors in the measurement of the formation of Met-Hb. High levels of Met-Hb were observed following incubation of human AADAC with either cytochrome P450 (CYP) 1A2 or CYP2E1. Furthermore, the increased Met Hb formation by the incubation of HLM with phenacetin was significantly inhibited to 25.1 +/- 0.7% of control by eserine, a potent AADAC inhibitor. In conclusion, we found that the hydrolysis by AADAC and subsequent metabolism by CYP1A2 and CYP2E1 play predominant roles in phenacetin-induced methemoglobinemia. PMID- 22940576 TI - Host metabolism regulates growth and differentiation of Toxoplasma gondii. AB - A critical step in the pathogenesis of Toxoplasma gondii is conversion from the fast-replicating tachyzoite form experienced during acute infection to the slow replicating bradyzoite form that establishes long-lived tissue cysts during chronic infection. Bradyzoite cyst development exhibits a clear tissue tropism in vivo, yet conditions of the host cell environment that influence this tropism remain unclear. Using an in vitro assay of bradyzoite conversion, we have found that cell types differ dramatically in the ability to facilitate differentiation of tachyzoites into bradyzoites. Characterization of cell types that were either resistant or permissive for conversion revealed that resistant cell lines release low molecular weight metabolites that could support tachyzoite growth under metabolic stress conditions and thereby inhibit bradyzoite formation in permissive cells. Biochemical analysis revealed that the glycolytic metabolite lactate is an inhibitory component of supernatants from resistant cells. Furthermore, upregulation of glycolysis in permissive cells through the addition of glucose or by overexpression of the host kinase, Akt, was sufficient to convert cells from a permissive to a resistant phenotype. These results suggest that the metabolic state of the host cell may play a role in determining the predilection of the parasite to switch from the tachyzoite to bradyzoite form. PMID- 22940577 TI - Planning as inference. AB - Recent developments in decision-making research are bringing the topic of planning back to center stage in cognitive science. This renewed interest reopens an old, but still unanswered question: how exactly does planning happen? What are the underlying information processing operations and how are they implemented in the brain? Although a range of interesting possibilities exists, recent work has introduced a potentially transformative new idea, according to which planning is accomplished through probabilistic inference. PMID- 22940575 TI - Rhythm and blues: animal models of epilepsy and depression comorbidity. AB - Clinical evidence shows a strong, bidirectional comorbidity between depression and epilepsy that is associated with decreased quality of life and responsivity to pharmacotherapies. At present, the neurobiological underpinnings of this comorbidity remain hazy. To complicate matters, anticonvulsant drugs can cause mood disturbances, while antidepressant drugs can lower seizure threshold, making it difficult to treat patients suffering from both depression and epilepsy. Animal models have been created to untangle the mechanisms behind the relationship between these disorders and to serve as screening tools for new therapies targeted to treat both simultaneously. These animal models are based on chemical interventions (e.g. pentylenetetrazol, kainic acid, pilocarpine), electrical stimulations (e.g. kindling, electroshock), and genetic/selective breeding paradigms (e.g. genetically epilepsy-prone rats (GEPRs), genetic absence epilepsy rat from Strasbourg (GAERS), WAG/Rij rats, swim lo-active rats (SwLo)). Studies on these animal models point to some potential mechanisms that could explain epilepsy and depression comorbidity, such as various components of the dopaminergic, noradrenergic, serotonergic, and GABAergic systems, as well as key brain regions, like the amygdala and hippocampus. These models have also been used to screen possible therapies. The purpose of the present review is to highlight the importance of animal models in research on comorbid epilepsy and depression and to explore the contributions of these models to our understanding of the mechanisms and potential treatments for these disorders. PMID- 22940578 TI - The role of regulatory RNA in cognitive evolution. AB - The evolution of the human brain has resulted in the emergence of higher-order cognitive abilities, such as reasoning, planning and social awareness. Although there has been a concomitant increase in brain size and complexity, and component diversification, we argue that RNA regulation of epigenetic processes, RNA editing, and the controlled mobilization of transposable elements have provided the major substrates for cognitive advance. We also suggest that these expanded capacities and flexibilities have led to the collateral emergence of psychiatric fragilities and conditions. PMID- 22940579 TI - Clonal expansion and functional exhaustion of monoclonal marginal zone B cells in mixed cryoglobulinemia: the yin and yang of HCV-driven lymphoproliferation and autoimmunity. AB - Monoclonal marginal zone (MZ) B cells expressing a V(H)1-69-encoded idiotype accumulate in HCV-associated mixed cryoglobulinemia (MC). These cells recognize the E2 protein of HCV and their massive clonal expansion reflects the propensity of MZ B cells to proliferate robustly upon antigenic stimulation by microorganisms, a property that makes them prone to neoplastic transformation. V(H)1-69(+) B cells of MC patients are phenotypically heterogeneous and resemble either mature MZ B cells (IgM(+)CD27(+)CD21(high)) or the unusual CD21(low) B cells that accumulate in other immunological disorders such as common variable immunodeficiency (CVID) or HIV infection. The CD21(low) V(H)1-69(+) B cells of MC patients, like those of CVID and HIV patients, are anergic to BCR and TLR9 stimulation and display deregulation of several anergy-related genes; proliferative anergy is also observed in CD21(high) MZ-like V(H)1-69(+) B cells, that over-express the antiproliferative transcriptional repressor Stra13. Upon evolution to splenic marginal zone lymphoma, MZ-like V(H)1-69(+) B cells down regulate Stra13 and partially recover their capacity to proliferate in response to TLR9 ligation. Like yin and yang, robust clonal expansion and early proliferative anergy may be viewed as the opposite forces balancing the responses of human MZ B cells to chronic microbial stimuli. Disruption of this balance facilitates autoimmunity and lymphoproliferation. PMID- 22940580 TI - Identification and susceptibility testing of microorganism by direct inoculation from positive blood culture bottles by combining MALDI-TOF and Vitek-2 Compact is rapid and effective. AB - OBJECTIVES: The objective of this study was to evaluate the reliability and accuracy of the combined use of MALDI-TOF MS bacterial identification and the Vitek-2 Compact antimicrobial susceptibility testing (AST) directly from positive blood cultures. METHODS: Direct identification by MALDI-TOF MS and AST were performed in parallel to the standard methods in all positively flagged blood cultures bottles during the study period. RESULTS: Three hundred and twenty four monomicrobial positive blood cultures were included in the present study, with 257 Gram-negative and 67 Gram-positive isolates. MALDI-TOF MS identification directly from blood bottles reported the correct identification for Enterobacteriaceae in 97.7%, non-fermentative Gram-negative bacilli 75.0%, Staphylococcus aureus 75.8%, coagulase negative staphylococci 63.3% and enterococci 63.3%. A total 6156 isolate/antimicrobial agent combinations were tested. Enterobacteriaceae group and non-fermentative Gram-negative Bacilli showed an agreement of 96.67% and 92.30%, respectively, for the Gram-positive cocci the overall agreement found was 97.84%. CONCLUSIONS: We conclude that direct identification by MALDI-TOF and inoculation of Vitek-2 Compact AST with positive blood culture bottles yielded very good results and decreased time between initial inoculation of blood culture media and determination of the antibiotic susceptibility for Gram-negative rods and Gram-positive cocci causing bacteremia. PMID- 22940581 TI - The loops facing the active site of prolyl oligopeptidase are crucial components in substrate gating and specificity. AB - Prolyl oligopeptidase (POP) has emerged as a drug target for neurological diseases. A flexible loop structure comprising loop A (res. 189-209) and loop B (res. 577-608) at the domain interface is implicated in substrate entry to the active site. Here we determined kinetic and structural properties of POP with mutations in loop A, loop B, and in two additional flexible loops (the catalytic His loop, propeller Asp/Glu loop). POP lacking loop A proved to be an inefficient enzyme, as did POP with a mutation in loop B (T590C). Both variants displayed an altered substrate preference profile, with reduced ligand binding capacity. Conversely, the T202C mutation increased the flexibility of loop A, enhancing the catalytic efficiency beyond that of the native enzyme. The T590C mutation in loop B increased the preference for shorter peptides, indicating a role in substrate gating. Loop A and the His loop are disordered in the H680A mutant crystal structure, as seen in previous bacterial POP structures, implying coordinated structural dynamics of these loops. Unlike native POP, variants with a malfunctioning loop A were not inhibited by a 17-mer peptide that may bind non productively to an exosite involving loop A. Biophysical studies suggest a predominantly closed resting state for POP with higher flexibility at the physiological temperature. The flexible loop A, loop B and His loop system at the active site is the main regulator of substrate gating and specificity and represents a new inhibitor target. PMID- 22940582 TI - Identification of unknown protein function using metabolite cocktail screening. AB - Proteins of unknown function comprise a significant fraction of sequenced genomes. Defining the roles of these proteins is vital to understanding cellular processes. Here, we describe a method to determine a protein function based on the identification of its natural ligand(s) by the crystallographic screening of the binding of a metabolite library, followed by a focused search in the metabolic space. The method was applied to two protein families with unknown function, PF01256 and YjeF_N. The PF01256 proteins, represented by YxkO from Bacillus subtilis and the C-terminal domain of Tm0922 from Thermotoga maritima, were shown to catalyze ADP/ATP-dependent NAD(P)H-hydrate dehydratation, a previously described orphan activity. The YjeF_N proteins, represented by mouse apolipoprotein A-I binding protein and the N-terminal domain of Tm0922, were found to interact with an adenosine diphosphoribose-related substrate and likely serve as ADP-ribosyltransferases. Crystallographic screening of metabolites serves as an efficient tool in functional analyses of uncharacterized proteins. PMID- 22940583 TI - Structure of an asymmetric ternary protein complex provides insight for membrane interaction. AB - Plasma membrane repair involves the coordinated effort of proteins and the inner phospholipid surface to mend the rupture and return the cell back to homeostasis. Here, we present the three-dimensional structure of a multiprotein complex that includes S100A10, annexin A2, and AHNAK, which along with dysferlin, functions in muscle and cardiac tissue repair. The 3.5 A resolution X-ray structure shows that a single region from the AHNAK C terminus is recruited by an S100A10-annexin A2 heterotetramer, forming an asymmetric ternary complex. The AHNAK peptide adopts a coil conformation that arches across the heterotetramer contacting both annexin A2 and S100A10 protomers with tight affinity (~30 nM) and establishing a structural rationale whereby both S100A10 and annexin proteins are needed in AHNAK recruitment. The structure evokes a model whereby AHNAK is targeted to the membrane surface through sandwiching of the binding region between the S100A10/annexin A2 complex and the phospholipid membrane. PMID- 22940585 TI - Activation of tRNA maturation by downstream uracil residues in B. subtilis. AB - Ribonuclease (RNase) Z is involved in the maturation of the 3' ends of transfer RNAs (tRNAs) in all three kingdoms of life. To prevent futile cycles of CCA addition and removal, eukaryotic RNase Z discriminates against mature tRNAs bearing a CCA motif, with the first cytosine residue (C74) being the key antideterminant. Here, we show that, remarkably, the B. subtilis enzyme does not discriminate against cytosine in position 74, but rather is highly stimulated by uracil in this location. Consistent with this observation, the vast majority of B. subtilis tRNA precursor substrates of RNase Z naturally contain U74. Those tRNA precursors with a uracil further downstream are also substrates for RNase Z, but are matured in a two-step endo/exonuclease reaction. We solved the first crystal structure of B. subtilis RNase Z bound to a tRNA(Thr) precursor with U74 and show that the enzyme has a specific binding pocket for this nucleotide. PMID- 22940584 TI - The molecular basis for substrate specificity of the nuclear NIPP1:PP1 holoenzyme. AB - Regulation of protein phosphatase 1 (PP1) is controlled by a diverse array of regulatory proteins. However, how these proteins direct PP1 specificity is not well understood. More than one-third of the nuclear pool of PP1 forms a holoenzyme with the nuclear inhibitor of PP1, NIPP1, to regulate chromatin remodeling, among other essential biological functions. Here, we show that the PP1-binding domain of NIPP1 is an intrinsically disordered protein, which binds PP1 in an unexpected manner. NIPP1 forms an alpha helix that engages PP1 at a unique interaction site, using polar rather than hydrophobic contacts. Importantly, the structure also reveals a shared PP1 interaction site outside of the RVxF motif, the PhiPhi motif. Finally, we show that NIPP1:PP1 substrate selectivity is determined by altered electrostatics and enhanced substrate localization. Together, our results provide the molecular basis by which NIPP1 directs PP1 substrate specificity in the nucleus. PMID- 22940586 TI - Influence of sildenafil on the antidepressant activity of bupropion and venlafaxine in the forced swim test in mice. AB - Recent studies highlight the involvement of the nitrergic system in the mechanism of action of antidepressant drugs. Sildenafil, a selective PDE5 inhibitor, was shown to abolish the anti-immobility effects of bupropion, venlafaxine and s citalopram in mice. In this study we assessed the effects of sildenafil on the activity of bupropion and venlafaxine in the forced swim test in mice. Swim trials were conducted by placing mice in glass cylinders filled with water for 6min and the duration of the behavioral immobility during the last 4min of the test was evaluated. Locomotor activity was evaluated with photoresistor actimeters. Brain and serum concentrations of the studied antidepressants were determined by HPLC method. Sildenafil at a dose of 20mg/kg, but not 5 and 10mg/kg, significantly increased the anti-immobility action of bupropion (20mg/kg). The antidepressant activity of venlafaxine (2mg/kg) was potentiated by joint administration with sildenafil at doses of 10 and 20mg/kg. Since the combined treatments did not increase the locomotor activity, the antidepressant like effects were not related to non-specific behavioral activation. Data from pharmacokinetic studies revealed that sildenafil increased bupropion and venlafaxine levels in serum without affecting their concentrations in the brain. The present study demonstrates the enhancement of anti-immobility action of bupropion and venlafaxine by sildenafil co-administration. The observed changes might have been partly due to pharmacokinetic interactions. However, mechanisms underlying the effects of sildenafil on the antidepressant activity of bupropion and venlafaxine should be carefully evaluated in further studies. PMID- 22940587 TI - Piracetam, an AMPAkine drug, facilitates memory consolidation in the day-old chick. AB - Piracetam is an AMPAkine drug that may have a range of different mechanisms at the cellular level, and which has been shown to facilitate memory, amongst its other effects. This series of experiments demonstrated that a 10mg/kg dose of piracetam facilitated memory consolidation in the day-old chick when injected from immediately until 120min after weak training (i.e. using a 20% v/v concentration of methyl anthranilate) with the passive avoidance learning task. Administration of piracetam immediately after training led to memory facilitation which lasted for up to 24h following training. This dose of the AMPAkine was not shown to facilitate memory reconsolidation. These findings support the contention that application of the AMPAkine piracetam facilitates memory using a weak training task, and extend the range of actions previously noted with NMDA-related agents to those which also facilitate the AMPA receptor. PMID- 22940588 TI - Antidepressant-like effect of ursolic acid isolated from Rosmarinus officinalis L. in mice: evidence for the involvement of the dopaminergic system. AB - Ursolic acid, a constituent from Rosmarinus officinalis, is a triterpenoid compound which has been extensively known for its anticancer and antioxidant properties. In the present study, we investigated the antidepressant-like effect of ursolic acid isolated from this plant in two predictive tests of antidepressant property, the tail suspension test (TST) and the forced swimming test (FST) in mice. Furthermore, the involvement of dopaminergic system in its antidepressant-like effect was investigated in the TST. Ursolic acid reduced the immobility time in the TST (0.01 and 0.1mg/kg, p.o.) and in the FST (10mg/kg, p.o.), similar to fluoxetine (10mg/kg, p.o.), imipramine (1mg/kg, p.o.) and bupropion (10mg/kg, p.o.). The effect of ursolic acid (0.1mg/kg, p.o.) in the TST was prevented by the pretreatment of mice with SCH23390 (0.05mg/kg, s.c., a dopamine D(1) receptor antagonist) and sulpiride (50mg/kg, i.p., a dopamine D(2) receptor antagonist). The administration of a sub-effective dose of ursolic acid (0.001mg/kg, p.o.) in combination with sub-effective doses of SKF38393 (0.1mg/kg, s.c., a dopamine D(1) receptor agonist), apomorphine (0.5MUg/kg, i.p., a preferential dopamine D(2) receptor agonist) or bupropion (1mg/kg, i.p., a dual dopamine/noradrenaline reuptake inhibitor) reduced the immobility time in the TST as compared with either drug alone. Ursolic acid and dopaminergic agents alone or in combination did not cause significant alterations in the locomotor and exploratory activities. These results indicate that the antidepressant-like effect of ursolic acid in the TST is likely mediated by an interaction with the dopaminergic system, through the activation of dopamine D(1) and D(2) receptors. PMID- 22940590 TI - Physical exercise as a possible strategy for brain protection: evidence from mitochondrial-mediated mechanisms. AB - Aging and neurodegenerative conditions such as Alzheimer and Parkinson diseases are characterized by tissue and mitochondrial changes that compromise brain function. Alterations can include increased reactive oxygen species production and impaired antioxidant capacity with a consequent increase in oxidative damage, mitochondrial dysfunction that compromises brain ATP production, and ultimately increased apoptotic signaling and neuronal death. Among several non pharmacological strategies to prevent brain degeneration, physical exercise is a surprisingly effective strategy, which antagonizes brain tissue and mitochondrial dysfunction. The present review aims to discuss the role of physical exercise in the modulation of the mechanisms involved in neuroprotection including the activation of signaling pathways underlying brain protection. PMID- 22940589 TI - Quantitative magnetization transfer imaging of human brain at 7 T. AB - Quantitative magnetization transfer (qMT) imaging yields indices describing the interactions between free water protons and immobile macromolecular protons. These indices include the macromolecular to free pool size ratio (PSR), which has been shown to be correlated with myelin content in white matter. Because of the long scan times required for whole-brain imaging (~20-30 min), qMT studies of the human brain have not found widespread application. Herein, we investigated whether the increased signal-to-noise ratio available at 7.0 T could be used to reduce qMT scan times. More specifically, we developed a selective inversion recovery (SIR) qMT imaging protocol with a i) novel transmit radiofrequency (B(1)(+)) and static field (B(0)) insensitive inversion pulse, ii) turbo field echo readout, and iii) reduced TR. In vivo qMT data were obtained in the brains of healthy volunteers at 7.0 T using the resulting protocol (scan time~40 s/slice, resolution=2 * 2 * 3 mm(3)). Reliability was also assessed in repeated acquisitions. The results of this study demonstrate that SIR qMT imaging can be reliably performed within the radiofrequency power restrictions present at 7.0 T, even in the presence of large B(1)(+) and B(0) inhomogeneities. Consistent with qMT studies at lower field strengths, the observed PSR values were higher in white matter (mean+/-SD=17.6 +/- 1.3%) relative to gray matter (10.3 +/- 1.6%) at 7.0 T. In addition, regional variations in PSR were observed in white matter. Together, these results suggest that qMT measurements are feasible at 7.0 T and may eventually allow for the high-resolution assessment of changes in composition throughout the normal and diseased human brain in vivo. PMID- 22940592 TI - Epigenetic control of transposon transcription and mobility in Arabidopsis. AB - The mobility of genetic elements called transposable elements (TEs) was discovered half a century ago by Barbara McClintock. Although she had recognized them as chromosomal controlling elements, for much of the consequent time TEs were primarily considered as parasites of the host genome. However the recent explosion of discoveries in the fields of genomics and epigenetics have unambiguously shown the importance of TEs in genome function and evolution. Bursts of endogenous TEs have been reported in plants with epigenetic misregulation, revealing the molecular mechanisms underlying their control. We review here the different steps in TE invasion of the host genome involving epigenetic control and environmental stress responses. As TEs propagate in plant genomes and attract epigenetic marks, their neo-insertions can lead to the formation of new, heritable epigenetic variants (epialleles) of genes in their vicinity and impact on host gene regulatory networks. The epigenetic interplay between TE and genes thus plays a crucial role in the TE-host co-evolution. PMID- 22940591 TI - Motivations and objections to implement a spondyloarthritis integrated care pathway. A qualitative study with primary care physicians. AB - BACKGROUND AND OBJECTIVES: Previous to the development of a clinical pathway (CP) for early spondyloarthritis (SpA), a qualitative study was performed to know the attitude of primary care physicians (PCP) with respect to CP implementation. METHODS: 5 discussion groups (2 in Madrid, 2 in Barcelona and 1 in Sevilla) and 3 interviews in Bilbao, were performed. PCP with different profiles were included. Groups and interviews were carried out by experts on qualitative methodology. RESULTS: PCP know little about CP. Motivations of professionals to work on a SpA CP were: to improve patients care, availability of a specialist consultant, possibility of learning and doing research, remuneration, and professional recognition. Objections to CP implementation were: extra work, excessive bureaucracy, absence of a specialist consultant, computer difficulties, and no remuneration. SpA knowledge by PCP was defective. PCP associated the term "spondylitis" with osteoarthritis, low-back pain, ankylosing spondylitis and psoriatic arthritis. They only referred patients to the rheumatologist to confirm the diagnosis, when patients complained and when treatment was ineffective. CONCLUSIONS: For an optimal CP implementation, the following is deemed necessary: 1) a practical, simple program that eases the interaction with the rheumatologist without an increase on the PCP work load; 2) to provide continuous feedback by the specialist and 3) to provide knowledge on SpA to PCP. PMID- 22940593 TI - Determining DNA supercoiling enthalpy by isothermal titration calorimetry. AB - DNA supercoiling plays a critical role in certain essential DNA transactions, such as DNA replication, recombination, and transcription. For this reason, exploring energetics of DNA supercoiling is fundamentally important for understanding its biological functions. In this paper, using a unique property of DNA intercalators, such as ethidium bromide and daunorubicin, which bind to supercoiled, nicked, and relaxed DNA templates with different DNA-binding enthalpies, we determined DNA supercoiling enthalpy of plasmid pXXZ6, a 4.5 kb plasmid to be about 11.5 kcal/mol per linking number change. This determination allowed us to partition the DNA supercoiling free energy into enthalpic and entropic contributions where the unfavorable DNA supercoiling free energy exclusively originated from the large positive supercoiling enthalpy and was compensated by a large, favorable entropy term (TDeltaS). PMID- 22940595 TI - Feasibility of a laryngeal tube for airway management during cardiac arrest by first responders. AB - Airway management is of major importance in prehospital emergency care. Bag-valve mask (BVM) ventilation and endotracheal intubation (ETI) have been shown to be difficult, especially when caregivers are inexperienced. Alternative methods have been studied, and supraglottic devices have been shown to provide reasonable ease of placement and effective ventilation in manikin studies and anaesthetised patients. First responders (FR) are employed by many emergency medical services (EMS) to shorten initiation of emergency care, and they are trained to provide basic CPR including BVM and use of automated external defibrillators (AED) in case of out-of-hospital cardiac arrest (OCHA). The aim of this research was to study the feasibility of manikin-trained FRs using a laryngeal tube (LT) as a primary airway method during cardiac arrest. We trained 300 FRs to use a LT during OHCA. The FRs used a LT in 64 OHCA cases. The LT was correctly placed on the first attempt in 46/64 cases (71.9%) and on the second attempt in 13/64 cases (20.3%). Insertion was reported as being easy in 55/64 cases (85.9%). Median insertion time was 23.1s, with a range of 3-240s. We found that after manikin training, the FRs inserted the LT and performed adequate ventilation with a reasonable success rate and insertion time. PMID- 22940594 TI - Isolation, enzymatic characterization and antiedematogenic activity of the first reported rattlesnake hyaluronidase from Crotalus durissus terrificus venom. AB - A hyaluronidase (CdtHya1) from Crotalus durissus terrificus snake venom (CdtV) was isolated and showed to exhibit a high activity on hyaluronan cleavage. However, surveys on this enzyme are still limited. This study aimed at its isolation, functional/structural characterization and the evaluation of its effect on the spreading of crotoxin and phospholipase A(2) (PLA(2)). The enzyme was purified through cation exchange, gel filtration and hydrophobic chromatography. After that, it was submitted to a reverse-phase fast protein liquid chromatography (RP-FPLC) and Edman degradation sequencing, which showed the first N-terminal 44 amino acid residues whose sequence evidenced identity with other snake venom hyaluronidases. CdtHya1 is a monomeric glycoprotein of 64.5 kDa estimated by SDS-PAGE under reducing conditions. It exhibited maximum activity in the presence of 0.2 M NaCl, at 37 degrees C, pH 5.5 and a specificity to hyaluronan higher than that to chondroitin-4-sulphate, chondroitin 6-sulphate or dermatan. Divalent cations (Ca(2+) and Mg(2+)) and 1 M NaCl significantly reduced the enzyme activity. The specific activity of CdtHya1 was 5066 turbidity reducing units (TRU)/mg, against 145 TRU/mg for the soluble venom, representing a 34.9-fold purification. The pure enzyme increased the diffusion of crotoxin and PLA(2) through mice tissues. CdtHya1 (32 TRU/40 MUL) potentiated crotoxin action, as evidenced by mice death, and it decreased the oedema caused by subplantar injections of buffer, crotoxin or PLA(2), thus evidencing the relevance of hyaluronidase in the crotalic envenoming. This work yielded a highly active antiedematogenic hyaluronidase from CdtV, the first one isolated from rattlesnake venoms. PMID- 22940596 TI - The impact of early do not resuscitate (DNR) orders on patient care and outcomes following resuscitation from out of hospital cardiac arrest. AB - OBJECTIVES: Among patients successfully resuscitated from out-of-hospital cardiac arrest (OHCA) and admitted to California hospitals, we examined how the placement of a do not resuscitate (DNR) order in the first 24h after admission was associated with patient care, procedures and inhospital survival. We further analyzed hospital and patient demographic factors associated with early DNR placement among patients admitted following OHCA. METHODS: We identified post OHCA patients from a statewide California database of hospital admissions from 2002 to 2010. Documentation of patient and hospital demographics, hospital interventions, and patient outcome were analyzed by descriptive statistics and multiple regression models to calculate odds ratios and 95% confidence intervals. RESULTS: Of 5212 patients admitted to California hospitals after resuscitation from OHCA, 1692 (32.5%) had a DNR order placed in the first 24h after admission. These patients had decreased frequency of cardiac catheterization (1.1% vs. 4.3%), blood transfusion (7.6% vs. 11.2%), ICD placement (0.1% vs. 1.1%), and survival to discharge (5.2% vs. 21.6%, all p-values<0.0001). There was wide intrahospital variability and significant racial differences in the adjusted odds of early DNR orders (Asian, OR 0.67, 95% CI 0.48-0.95; Black, OR 0.49, 95% CI 0.35-0.69). CONCLUSIONS: Early DNR placement is associated with a decrease in potentially critical hospital interventions, procedures, and survival to discharge, and wide variability in practice patterns between hospitals. In the absence of prior patient wishes, DNR placement within 24h may be premature given the lack of early prognostic indicators after OHCA. PMID- 22940599 TI - Push hard and fast (but not too fast). PMID- 22940597 TI - Increased mortality with early therapeutic hypothermia after cardiac arrest - a case study in allocation bias. PMID- 22940600 TI - Ivabradine but not propranolol delays the time to onset of ischaemia-induced ventricular fibrillation by preserving myocardial metabolic energy status. AB - OBJECTIVE: Heart rate reduction (HRR) has shown a beneficial impact on the prevention of ventricular fibrillation, which could be explained by increased myocardial blood flow and preservation of mitochondrial structure. Here, we assessed the HRR impact on time to onset of ventricular fibrillation (TOVF) and myocardial metabolic energy status. METHODS AND RESULTS: An acute myocardial ischaemia was induced in pigs until ventricular fibrillation onset and TOVF was then measured. High-energy phosphates were measured in ventricular samples from the ischaemic region by nuclear magnetic resonance. Saline, ivabradine (IVA, a selective heart rate-lowering agent) and propranolol (PROPRA, a beta-blocker) were administered intravenously, 30 and 60 min respectively prior to ischaemia to ensure stable HRR. To study specifically the HRR impact, another set of animals received IVA and was submitted to rapid atrial pacing (200 bpm) to abolish HRR. IVA and PROPRA induced a similar HRR (IVA: 22-26%, PRORA: 20-21%, p<0.01 vs. control), which was associated with a significant increase in TOVF with IVA (2325s) compared to PROPRA (682s) and saline (401s). This effect was abolished by atrial pacing performed during ischaemia and throughout the entire experimental session. Only IVA partially prevented the decrease in phosphocreatine-to-ATP ratio (CrP/ATP) ratio and the ADP accumulation at the onset of ventricular fibrillation. Finally, CrP/ATP ratio levels were correlated with TOVF (r=0.74, p<0.001). CONCLUSION: Unlike PROPRA, IVA delayed the time to onset of ischaemia induced ventricular fibrillation by preserving myocardial energy status, supporting the pertinence of IVA in the management of patients with coronary artery disease. PMID- 22940601 TI - Potassium induced cardiac standstill during conventional cardiopulmonary resuscitation in a pig model of prolonged ventricular fibrillation cardiac arrest: a feasibility study. AB - AIM OF THE STUDY: Potassium-based cardioplegia has been the gold standard for cardioprotection during cardiac surgery. We sought to evaluate the feasibility and the effects of potassium-induced cardiac standstill during conventional cardiopulmonary resuscitation (CPR) in a pig model of prolonged ventricular fibrillation (VF). METHODS: VF was induced in 20 pigs, and circulatory arrest was maintained for 14 min. Animals were then resuscitated by standard CPR. Coincident with the start of CPR, 20 ml of saline (control group) or 0.9 mequiv.kg(-1) of potassium chloride diluted to 20 ml (potassium group) was administered into right atrium. RESULTS: Administration of potassium resulted in asystole lasting for 1.0 min (0.2) in the potassium group animals. VF reappeared in all but one animal, in which wide QRS complex bradycardia followed. Restoration of spontaneous circulation (ROSC) was attained in two animals (20%) in the control group and in seven animals (70%) in the potassium group (p=0.070). Resuscitated animals in the potassium group required fewer countershocks (3, 4 vs. 2 (1-2)), smaller doses of adrenaline (1.84, 1.84 vs. 0.94 (0.90-1.00)mg), and shorter duration of CPR (8, 10 vs. 4.0 (4.0-4.0)min) than did the control group. Potassium concentrations normalised rapidly after ROSC in both groups, and the potassium concentrations at 5 min (5.5, 6.6 vs. 6.8 (6.5-7.8)mequiv.l(-1)) and 4h (4.9, 5.4 vs. 5.9 (5.1 6.4)mequiv.l(-1)) after ROSC were similar in the both groups. CONCLUSION: In a pig model of untreated VF cardiac arrest for 14 min, resuscitation with potassium induced cardiac standstill during conventional CPR was found to be feasible. PMID- 22940602 TI - Matrix metalloproteinases (MMPs) are required for wound closure and healing during larval leg regeneration in the flour beetle, Tribolium castaneum. AB - Regenerative abilities are found ubiquitously among many metazoan taxa. To compare mechanisms underlying the initial stages of limb regeneration between insects and vertebrates, the roles of matrix metalloproteinases (MMPs) and fibroblast growth factor (FGF) signaling were investigated in the red flour beetle, Tribolium castaneum. RNA interference-mediated knockdown of MMP2 expression delayed wound healing and subsequent leg regeneration. Additionally, pairwise knockdown of MMP1/2 and MMP2/3, but not MMP1/3, resulted in inhibition of wound closure. Wound healing on the dorsal epidermis after injury was also delayed when MMPs were silenced. Our findings show that functionally redundant MMPs play key roles during limb regeneration and wound healing in Tribolium. This MMP-mediated wound healing is necessary for the subsequent formation of a blastema. In contrast, silencing of FGF receptor did not interfere with the initial stages of leg regeneration despite the alterations in tanning of the cuticle. Thus, insects and vertebrates appear to employ similar developmental processes for the initial stages of wound closure during limb regeneration, while the role of FGF in limb regeneration appears to be unique to vertebrates. PMID- 22940603 TI - Community destruction and traumatic stress in post-tsunami Indonesia. AB - How are individuals affected when the communities they live in change for the worse? This question is central to understanding neighborhood effects, but few study designs generate estimates that can be interpreted causally. We address issues of inference through a natural experiment, examining post-traumatic stress at multiple time points in a population differentially exposed to the 2004 Indian Ocean tsunami. The data, from the Study of the Tsunami Aftermath and Recovery, include interviews with over 16,000 Indonesian adults before and after the event. These data are combined with satellite imagery, direct observation, and informant interviews to examine the consequences of community destruction for post traumatic stress. Using multilevel linear mixed models, we show that community destruction worsens post-traumatic stress, net of rigorous controls for individual experiences of trauma and loss. Furthermore, the effect of community destruction persists over time and extends across a wide range of community types. PMID- 22940604 TI - Diabetes triggers a PARP1 mediated death pathway in the heart through participation of FoxO1. AB - Cardiomyocyte cell death is a major contributing factor for diabetic cardiomyopathy, and multiple mechanisms have been proposed for its development. We hypothesized that following diabetes, an increased nuclear presence of the Forkhead transcription factor, FoxO1, could turn on cardiac cell death through mediation of nitrosative stress. Streptozotocin (100 mg/kg) was used to induce irreversible hyperglycemia in Wistar rats, and heart tissues and blood samples extracted starting from 1 to 4 days. Diazoxide (100 mg/kg), which produced acute reversible hyperglycemia, were followed for up to 12 h. In both animal models of hyperglycemia, attenuation of survival signals was accompanied by increased nuclear FoxO1. This was accompanied by a simultaneous increase in iNOS expression and iNOS induced protein nitrosylation of GAPDH, increased GAPDH binding to Siah1 and facilitated nuclear translocation of the complex. Even though caspase-3 was cleaved during diabetes, its nitrosylation modification affected its ability to inactivate PARP. As a result, there was PARP activation followed by nuclear compartmentalization of AIF, and increased phosphatidyl serine externalization. Our data suggests a role for FoxO1 mediated iNOS induced S-nitrosylation of target proteins like GAPDH and caspase-3 in initiating cardiac cell death following hyperglycemia, and could explain the impact of glycemic control in preventing cardiovascular disease in patients with diabetes. PMID- 22940606 TI - Impairment of green-lipped mussel (Perna canaliculus) physiology by waterborne cadmium: relationship to tissue bioaccumulation and effect of exposure duration. AB - Laboratory studies were performed to assess the impact of acute and subchronic cadmium (Cd) exposure on the green-lipped mussel, Perna canaliculus. A 96 h median lethal concentration (LC(50)) value of 8160 MUg L(-1) was determined, characterising this species as relatively tolerant to Cd exposure. Acute (96 h; at 2000 and 4000 MUg Cd L(-1)) and subchronic (28 d; at 200 and 2000 MUg Cd L( 1)) waterborne exposures were then conducted to investigate the impact of Cd exposure on physiological responses (e.g. clearance (feeding) rate, absorption efficiency, oxygen uptake, ammonia production, oxygen to nitrogen ratio, scope for growth) and tissue Cd accumulation. Cd accumulation in digestive gland showed saturation with respect to increasing exposure concentration, while the gill tissue Cd accumulation followed a positive linear relationship with Cd exposure level. Clearance rates declined during both acute and subchronic exposures at levels of 2000 MUg Cd L(-1) or higher. Impairments of clearance rates were strongly correlated with tissue Cd accumulation. Coupled with their importance as a food source, and their wide coastal distribution, these data suggests that P. canaliculus may be a species useful as an indicator species for trace metal pollution in coastal environments. PMID- 22940605 TI - 5-HT(2B) antagonism arrests non-canonical TGF-beta1-induced valvular myofibroblast differentiation. AB - Transforming growth factor-beta1 (TGF-beta1) induces myofibroblast activation of quiescent aortic valve interstitial cells (AVICs), a differentiation process implicated in calcific aortic valve disease (CAVD). The ubiquity of TGF-beta1 signaling makes it difficult to target in a tissue specific manner; however, the serotonin 2B receptor (5-HT(2B)) is highly localized to cardiopulmonary tissues and agonism of this receptor displays pro-fibrotic effects in a TGF-beta1 dependent manner. Therefore, we hypothesized that antagonism of 5-HT(2B) opposes TGF-beta1-induced pathologic differentiation of AVICs and may offer a druggable target to prevent CAVD. To test this hypothesis, we assessed the interaction of 5 HT(2B) antagonism with canonical and non-canonical TGF-beta1 pathways to inhibit TGF-beta1-induced activation of isolated porcine AVICs in vitro. Here we show that AVIC activation and subsequent calcific nodule formation is completely mitigated by 5-HT(2B) antagonism. Interestingly, 5-HT(2B) antagonism does not inhibit canonical TGF-beta1 signaling as identified by Smad3 phosphorylation and activation of a partial plasminogen activator inhibitor-1 promoter (PAI-1, a transcriptional target of Smad3), but prevents non-canonical p38 MAPK phosphorylation. It was initially suspected that 5-HT(2B) antagonism prevents Src tyrosine kinase phosphorylation; however, we found that this is not the case and time-lapse microscopy indicates that 5-HT(2B) antagonism prevents non-canonical TGF-beta1 signaling by physically arresting Src tyrosine kinase. This study demonstrates the necessity of non-canonical TGF-beta1 signaling in leading to pathologic AVIC differentiation. Moreover, we believe that the results of this study suggest 5-HT(2B) antagonism as a novel therapeutic approach for CAVD that merits further investigation. PMID- 22940607 TI - Molecular and cellular effects induced by hexavalent chromium in Mediterranean mussels. AB - The present study evaluated the effects of Cr(VI) in digestive gland of the Mediterranean mussel (Mytilus galloprovincialis) exposed for 1 week to the metal at 1, 10, and 50 ng/L. Tissue accumulation of Cr and lysosomal biomarkers were measured. Moreover, a low-density DNA microarray was used to identify early molecular markers of metal exposure. A concentration-dependent increase in tissue Cr concentrations was observed in both digestive gland and remaining soft tissues. A reduction of lysosomal membrane stability was detected in digestive gland at 10 and 50 ng/L of Cr(VI), indicating a loss of cell functional integrity. The expression of mRNAs encoding 13 genes involved in metal resistance (mt10, mt20), molecular chaperoning (hsp70), immune response (mytlB, mytcA and lys), transcriptional (histones h1, h2-a and h4), and antioxidant/detoxification (cat, mrp2, mvp) processes were significantly altered already at the lowest Cr(VI) concentration, where the effects at the histological level were nonsignificant. Altogether, data point out that depending on the exposure concentration Cr(VI) may cause or not oxidative stress altering the efficiency of the antioxidant system in counteracting the effects of Cr as a redox-active metal. Moreover, changes of mRNA expression profiles induced by Cr(VI) concentrations as low as 1-50 ng/L were related to altered immunomodulation, DNA stability, and stress response pathways previously proven to be affected by the metal. The molecular targets presently identified may drive the development of new biomarkers for Cr exposure or help their interpretation. PMID- 22940609 TI - Robust classifying of prokaryotic genomes. AB - In this paper, we propose a method to classify prokaryotic genomes using the agglomerative information bottleneck method for unsupervised clustering. Although the method we present here is closely related to a group of methods based on detecting the presence or absence of genes, our method is different because it uses gene lengths as well. We show that this amended method is reliable. For robustness evaluation, we apply bootstrap and jackknife techniques to input data. As a result, we are able to propose an approach to determine the stability level of a cladogram. We demonstrate that the genome tree produced for a selected small group of genomes looks a lot like a phylogenetic tree of this group. PMID- 22940608 TI - Changes in fibroblast growth factor-2 and FGF receptors in the frog visual system during optic nerve regeneration. AB - We have previously shown that application of fibroblast growth factor-2 (FGF-2) to cut optic nerve axons enhances retinal ganglion cell (RGC) survival in the adult frog visual system. These actions are mediated via activation of its high affinity receptor FGFR1, enhanced BDNF and TrkB expression, increased CREB phosphorylation, and by promoting MAPK and PKA signaling pathways. The role of endogenous FGF-2 in this system is less well understood. In this study, we determine the distribution of FGF-2 and its receptors in normal animals and in animals at different times after optic nerve cut. Immunohistochemistry and Western blot analysis were conducted using specific antibodies against FGF-2 and its receptors in control retinas and optic tecta, and after one, three, and six weeks post nerve injury. FGF-2 was transiently increased in the retina while it was reduced in the optic tectum just one week after optic nerve transection. Axotomy induced a prolonged upregulation of FGFR1 and FGFR3 in both retina and tectum. FGFR4 levels decreased in the retina shortly after axotomy, whereas a significant increase was detected in the optic tectum. FGFR2 distribution was not affected by the optic nerve lesion. Changes in the presence of these proteins after axotomy suggest a potential role during regeneration. PMID- 22940610 TI - Electrophysiological and behavioral effects of group I metabotropic glutamate receptors on pallidal neurons in rats. AB - The globus pallidus plays a critical role in movement regulation. Morphological studies have shown that group I mGluRs including mGluR1 and mGluR5 are expressed in the globus pallidus. Up to now, little is known about the in vivo electrophysiological effects of group I mGluRs on the pallidal neurons. The present study investigated the electrophysiological effects of group I mGluRs on the firing rate of pallidal neurons in anesthetized rats. Single unit in vivo extracellular recordings showed that micropressure ejection of group I mGluRs agonist, 3,5-dihydroxyphenylglycine (DHPG), increased the spontaneous firing rate of pallidal neurons. DHPG-induced excitation could be blocked by mGluR1 antagonist, (S)-(+)-alpha-amino-4-carboxy-2-methylb-enzeneacetic acid (LY367385), but not mGluR5 antagonist, 2-methyl-6-(phenylethynyl)-pyridine (MPEP). LY367385 alone had no effect but MPEP alone increased the excitability of pallidal neurons. Unilateral microinjection of DHPG into the globus pallidus induced a contralateral dystonic posturing in the presence of systemic haloperidol administration and this effect could be blocked by LY367385 but not MPEP. The present in vivo electrophysiological and behavioral studies indicate that group I mGluRs could produce excitatory effect on pallidal neurons via mGluR1, and blockade of mGluR5 also has an excitatory effect on pallidal neurons. Our findings suggest that the effects of globus pallidus in movement regulation is partly mediated by group I mGluRs. PMID- 22940611 TI - Poly (4-styrenesulfonic acid-co-maleic acid) is an entry inhibitor against both HIV-1 and HSV infections - potential as a dual functional microbicide. AB - Genital herpes is one of the most prevalent sexually transmitted diseases (STD) caused by herpes simplex viruses type 1 and 2 (HSV-1 and -2). HSV is considered as a major risk factor in human immunodeficiency virus type-1 (HIV-1) infection and rapid progression to acquired immunodeficiency syndrome (AIDS). Here, we reported the finding of a polymer of styrenesulfonic acid and maleic acid (PSM) which exhibited antiviral activity with low cytotoxicity. PSM exhibited in vitro inhibitory activity against HIV-1 pseudovirus and HSV-1 and -2. In vivo efficacy of PSM against HSV-2 (G) was also investigated. We found that both 1% and 5% PSM gels protected mice from HSV-2 vaginal infection and disease progression significantly. Mechanistic analysis demonstrated that PSM was likely an entry inhibitor that disrupted viral attachment to the target cells. In particular, PSM disrupted gp120 binding to CD4 by interacting with the gp120 V3-loop and the CD4 binding site. The in vitro cytotoxicity studies showed that PSM did not stimulate NF-kappaB activation and up-regulation of proinflammatory cytokine IL-1beta and IL-8 in vaginal epithelial cells. In addition, PSM also showed low adverse effect on the growth of vaginal Lactobacillus strains. PSM is, therefore, a novel viral entry inhibitor and a potential microbicide candidate against both HIV-1 and HSV. PMID- 22940612 TI - FAM161A, associated with retinitis pigmentosa, is a component of the cilia-basal body complex and interacts with proteins involved in ciliopathies. AB - Retinitis pigmentosa (RP) is a retinal degenerative disease characterized by the progressive loss of photoreceptors. We have previously demonstrated that RP can be caused by recessive mutations in the human FAM161A gene, encoding a protein with unknown function that contains a conserved region shared only with a distant paralog, FAM161B. In this study, we show that FAM161A localizes at the base of the photoreceptor connecting cilium in human, mouse and rat. Furthermore, it is also present at the ciliary basal body in ciliated mammalian cells, both in native conditions and upon the expression of recombinant tagged proteins. Yeast two-hybrid analysis of binary interactions between FAM161A and an array of ciliary and ciliopathy-associated proteins reveals direct interaction with lebercilin, CEP290, OFD1 and SDCCAG8, all involved in hereditary retinal degeneration. These interactions are mediated by the C-terminal moiety of FAM161A, as demonstrated by pull-down experiments in cultured cell lines and in bovine retinal extracts. As other ciliary proteins, FAM161A can also interact with the microtubules and organize itself into microtubule-dependent intracellular networks. Moreover, small interfering RNA-mediated depletion of FAM161A transcripts in cultured cells causes the reduction in assembled primary cilia. Taken together, these data indicate that FAM161A-associated RP can be considered as a novel retinal ciliopathy and that its molecular pathogenesis may be related to other ciliopathies. PMID- 22940613 TI - Changes in alcohol drinking patterns and their consequences among Norwegian doctors from 2000 to 2010: a longitudinal study based on national samples. AB - AIMS: To describe changes in the patterns and consequences of alcohol use among Norwegian doctors from 2000 to 2010. METHODS: Longitudinal study based on data from nation-wide postal surveys in 2000 and 2010 among a representative sample of 682 doctors in Norway. The Alcohol Use Disorder Identification Test (AUDIT) was used to measure the changes in drinking patterns (frequency of drinking, frequency of heavy drinking and quantity of drinking), symptoms of alcohol dependence and adverse consequences of drinking. A score above 8 was defined as hazardous drinking. RESULTS: From 2000 to 2010, the proportion of doctors who used alcohol twice a week or more significantly increased from 31.4 (27.9-34.9) % to 48.7 (44.9-48.7) %, and the proportion of those who drank to intoxication weekly or more decreased significantly from 6.6 (4.7-8.6) % to 2.5 (1.3-1.7) %. The proportion who scored above 8 on the AUDIT decreased from 10.7 (8.4-13.0) % in 2000 to 8.2 (6.2-10.3) % in 2010. There was a significant increase in the partial AUDIT-score for drinking patterns (t = 2.4; P = 0.016), and a significant decrease in the partial AUDIT-score for adverse consequences of drinking (t = 3.6; P < 0.001). The partial AUDIT-score for symptoms of alcohol dependence did not change significantly (t = -1.6; P = 0.112). There were gender differences in drinking patterns. Females had less frequent alcohol consumption and fewer episodes of heavy and hazardous drinking in 2000 and 2010. CONCLUSION: The drinking pattern of Norwegian doctors has changed over the past decade towards more moderate alcohol consumption and less negative alcohol-related consequences. Changes in the attitude towards alcohol consumption may to a certain extent explain these findings. PMID- 22940614 TI - High prevalence of forgoing healthcare for economic reasons in Switzerland: a population-based study in a region with universal health insurance coverage. AB - OBJECTIVE: To investigate the determinants and the 4-year evolution of the forgoing of healthcare for economic reasons in Switzerland. METHOD: Population based survey (2007-2010) of a representative sample aged 35-74 years in the Canton of Geneva, Switzerland. Healthcare forgone, socioeconomic and insurance status, marital status, and presence of dependent children were assessed using standardized methods. RESULTS: A total of 2601 subjects were included in the analyses. Of the subjects, 13.8% (358/2601) reported having forgone healthcare for economic reasons, with the percentage varying from 3.7% in the group with a monthly income >= 13,000 CHF (1CHF ~ 1$) to 30.9% in the group with a monthly income <3000 CHF. In subjects with a monthly income <3000 CHF, the percentage who had forgone healthcare increased from 22.5% in 2007/8 to 34.7% in 2010 (P trend=0.2). Forgoing healthcare for economic reasons was associated with lower income, female gender, smoking status, lower job position, having dependent children, being divorced and single, paying a higher deductible, and receiving a premium subsidy. CONCLUSION: In a Swiss region with universal health insurance coverage, the reported prevalence of forgoing healthcare for economic reasons was high and greatly dependent on socioeconomic factors. Our data suggested an increasing trend among participants with the lowest income. PMID- 22940615 TI - Disparities in alcohol use: does race matter as much as place? AB - OBJECTIVES: National estimates of race differences in alcohol use suggest that whites are more likely to be current and binge users of alcohol. These findings fail to account for race differences in the social and environmental context where people live. This study aims to determine whether race disparities persist in alcohol use among individuals who share similar social and environmental conditions. METHODS: We compared race disparities between individuals living in a low-income racially integrated urban community without race differences in socioeconomic status (EHDIC-SWB) to individuals from the National Health Interview Survey (NHIS 2003) to determine if race disparities in alcohol use were attenuated in the integrated environment. RESULTS: In the NHIS 2003 sample, compared to whites, African Americans had lower odds of being a current drinker (OR=0.56, 95% CI=0.49-0.64) and binge drinker (OR=0.68, 95% CI=0.58-0.80) independent of covariates. However in the EHDIC-SWB sample, African Americans had similar odds of being a current drinker (OR=0.94, 95% CI=0.67-1.33) and binge drinker (OR=1.02, 95% CI=0.77-1.35) compared to whites. CONCLUSIONS: Among individuals who share similar social and environmental risk exposures, race group differences in alcohol use patterns are similar. PMID- 22940616 TI - Further study of translational research for preventive medicine. PMID- 22940617 TI - EUK-207 protects human intestinal microvascular endothelial cells (HIMEC) against irradiation-induced apoptosis through the Bcl2 pathway. AB - AIM: To elucidate the signaling mechanisms involved in the protective effect of EUK-207 against irradiation-induced cellular damage and apoptosis in human intestinal microvasculature endothelial cells (HIMEC). METHODS: HIMECs were irradiated and treated with EUK-207. Using hydroethidine and DCF-DA fluorescent probe the intracellular superoxide and reactive oxygen species (ROS) were determined. By real-time PCR and western blotting caspase-3, Bcl2 and Bax genes and proteins were analyzed. Proliferation was determined by [(3)H]-thymidine uptake. Immunofluorescence staining was used for translocation of p65 NFkappaB subunit. KEY FINDING: Irradiation increased ROS production, apoptosis, Bax, Caspase3 and NFkB activity in HIMEC and inhibited cell survival/growth/proliferation. EUK-207 restored the endothelial functions, markedly inhibited the ROS, up-regulated the Bcl2 and down-regulated Bax and prevented NFkappaB caspase 3 activity in HIMEC. SIGNIFICANCE: HIMEC provide a novel model to define the effect of irradiation induced endothelial dysfunction. Our findings suggest that EUK-207 effectively inhibits the damaging effect of irradiation. PMID- 22940618 TI - Nicotinic acetylcholine receptor stimulation impairs epidermal permeability barrier function and recovery and modulates cornified envelope proteins. AB - AIM: To characterize how nicotinic acetylcholine receptors (nAChRs) influence epidermal barrier function and recovery following prolonged stress or direct nAChR activation or antagonism. MAIN METHODS: Mice were subjected to psychological stress or treated topically with nAChR agonist or antagonist for 3 days. We assessed barrier permeability and recovery by measuring transepidermal water loss (TEWL) before and after barrier disruption. In parallel, we analyzed the production and localization of several epidermal cornified envelope proteins in mouse skin and in human EpiDermTM organotypic constructs stimulated with a nAChR agonist (nicotine) and/or a nAChR selective antagonist (alpha bungarotoxin). KEY FINDINGS: We determined that psychological stress in mice impairs barrier permeability function and recovery, an effect that is reversed by application of the alpha7 selective nAChR antagonist, alpha-bungarotoxin (Bung). In the absence of stress, both topical nicotine or Bung treatment alone impaired barrier permeability. We further observed that stress, topical nicotine, or topical Bung treatment in mice influenced the abundance and/or localization of filaggrin, loricrin, and involucrin. Similar alterations in these three major cornified envelope proteins were observed in human EpiDermTM cultures. SIGNIFICANCE: Perceived psychological stress and nicotine usage can both initiate or exacerbate several dermatoses by altering the cutaneous permeability barrier. Modulation of nAChRs by topical agonists or antagonists may be used to improve epidermal barrier function in skin diseases associated with defects in epidermal barrier permeability. PMID- 22940619 TI - Corticosterone suppresses the proliferation of BV2 microglia cells via glucocorticoid, but not mineralocorticoid receptor. AB - AIMS: Corticosterone (CORT), which is often referred to as the stress hormone, is a well-known regulator of peripheral immune responses and also shows anti inflammatory properties in the brain. Microglia play a key role in immune response and inflammation in the brain. However, it is still unclear how CORT affects microglia. In this study, we focused on the effects of CORT on the proliferation and survival of microglia using mouse microglia cell line BV2. MAIN METHODS: We used WST-8 and LDH (lactate dehydrogenase) assays to check the effects of CORT for the proliferation and survival in BV2 microglia cells. We also analyzed the expression pattern of proteins which related to CORT signal cascades using western blotting analysis. KEY FINDINGS: Under treatment with 0.1, 1 and 10MUM CORT for 24h, the BV2 proliferation rate decreased to 83, 77 and 70% of that in the control. Moreover, this inhibition was blocked by treatment with mifepristone, a glucocorticoid receptor (GR) antagonist, but not by spironolactone, a mineralocorticoid receptor (MR) antagonist. Moreover, an LDH assay showed that CORT was dose-dependently cytotoxic toward BV2 microglia cells and this cytotoxicity was partially abolished by treatment with mifepristone. In addition, treatment with CORT resulted in the translocation of GR, but not MR, from the cytosol to the nucleus. SIGNIFICANCE: Our findings suggested that CORT suppresses the proliferation of BV2 microglia cells accompanied with a cytotoxic effect that is induced by the formation of a CORT-GR complex. PMID- 22940621 TI - Oxygenation of the newborn: a molecular approach. AB - In this review oxygenation and hyperoxic injury of newborn infants are described through molecular and genetic levels. Protection and repair mechanisms that may be important for a new understanding of oxidative stress in the newborn are discussed. The research summarized in this article represents a basis for the reduced oxygen supplementation and oxidative load of newborn babies, especially since the turn of the century. The mechanisms discussed may also contribute to an understanding of why hyperoxic resuscitation of the newborn may damage DNA and affect its repair, thus increasing the risk that it may be carcinogenic. Today, term babies should be resuscitated with air rather than 100% oxygen and very and extremely low birth weight infants in need of stabilization or resuscitation at birth should be administered initially 21-30% oxygen and the level should be titrated according to the response, preferably measured by pulse oximetry. In the postnatal period the oxygen saturation should be targeted low <95%; however, saturations between 85 and 89% seem to increase mortality. The optimal oxygen saturation target for these infants postnatally is still unknown. PMID- 22940622 TI - Innovation in surfactant therapy I: surfactant lavage and surfactant administration by fluid bolus using minimally invasive techniques. AB - Innovation in the field of exogenous surfactant therapy continues more than two decades after the drug became commercially available. One such innovation, lung lavage using dilute surfactant, has been investigated in both laboratory and clinical settings as a treatment for meconium aspiration syndrome (MAS). Studies in animal models of MAS have affirmed that dilute surfactant lavage can remove meconium from the lung, with resultant improvement in lung function. In human infants both non-randomised studies and two randomised controlled trials have demonstrated a potential benefit of dilute surfactant lavage over standard care. The largest clinical trial, performed by our research group in infants with severe MAS, found that lung lavage using two 15-ml/kg aliquots of dilute surfactant did not reduce the duration of respiratory support, but did appear to reduce the composite outcome of death or need for extracorporeal membrane oxygenation. A further trial of lavage therapy is planned to more precisely define the effect on survival. Innovative approaches to surfactant therapy have also extended to the preterm infant, for whom the more widespread use of continuous positive airway pressure (CPAP) has meant delaying or avoiding administration of surfactant. In an effort to circumvent this problem, less invasive techniques of bolus surfactant therapy have been trialled, including instillation directly into the pharynx, via laryngeal mask and via brief tracheal catheterisation. In a recent clinical trial, instillation of surfactant into the trachea using a flexible feeding tube was found to reduce the need for subsequent intubation. We have developed an alternative method of brief tracheal catheterisation in which surfactant is delivered via a semi-rigid vascular catheter inserted through the vocal cords under direct vision. In studies to date, this technique has been relatively easy to perform, and resulted in rapid improvement in lung function and reduced need for subsequent ventilation and duration of oxygen therapy. We are now commencing large-scale clinical trials of this method in preterm infants on CPAP. PMID- 22940620 TI - Nrf2 promotes alveolar mitochondrial biogenesis and resolution of lung injury in Staphylococcus aureus pneumonia in mice. AB - Acute lung injury (ALI) initiates protective responses involving genes downstream of the Nrf2 (Nfe2l2) transcription factor, including heme oxygenase-1 (HO-1), which stimulates mitochondrial biogenesis and related anti-inflammatory processes. We examined mitochondrial biogenesis during Staphylococcus aureus pneumonia in mice and the effect of Nrf2 deficiency on lung mitochondrial biogenesis and resolution of lung inflammation. S. aureus pneumonia established by nasal insufflation of live bacteria was studied in mitochondrial reporter (mt COX8-GFP) mice, wild-type (WT) mice, and Nrf2-/- mice. Bronchoalveolar lavage, wet/dry ratios, real-time RT-PCR and Western analysis, immunohistochemistry, and fluorescence microscopy were performed on the lung at 0, 6, 24, and 48 h. The mice survived S. aureus inoculations at 5*108 CFU despite diffuse lung inflammation and edema, but the Nrf2-/- lung showed increased ALI. In mt-COX8-GFP mice, mitochondrial fluorescence was enhanced in bronchial and alveolar type II (AT2) epithelial cells. WT mice displayed rapid HO-1 upregulation and lower proinflammatory TNF-alpha, IL-1beta, and CCL2 and, especially in AT2 cells, higher anti-inflammatory IL-10 and suppressor of cytokine signaling-3 than Nrf2-/ mice. In the alveolar region, WT but not Nrf2-/- mice showed strongly induced nuclear respiratory factor-1, PGC-1alpha, mitochondrial transcription factor-A, SOD2, Bnip3, mtDNA copy number, and citrate synthase. These findings indicate that S. aureus pneumonia induces Nrf2-dependent mitochondrial biogenesis in the alveolar region, mainly in AT2 cells. Absence of Nrf2 suppresses the alveolar transcriptional network for mitochondrial biogenesis and anti-inflammation, which worsens ALI. The findings link redox activation of mitochondrial biogenesis to ALI resolution. PMID- 22940623 TI - Innovation in surfactant therapy II: surfactant administration by aerosolization. AB - Instilled bolus surfactant is the only approved surfactant treatment for neonatal respiratory distress syndrome. However, recent trends towards increased utilization of noninvasive respiratory support for preterm infants with surfactant deficiency have created a demand for a similarly noninvasive means of administering exogenous surfactant. Past approaches to surfactant nebulization met with varying success due to inefficient aerosol devices resulting in low intrapulmonary delivery doses of surfactant with variable clinical effectiveness. The recent development of vibrating membrane nebulizers, coupled with appropriate positioning of the interface device, indicates that efficient delivery of aerosolized surfactant is now a realistic goal in infants. Evidence of clinical effect despite low total administered dose in pilot studies, together with suggestions of enhanced homogeneity of pulmonary distribution indicate that this therapy may be applied in a cost-effective manner, with minimal patient handling and disruption. These studies need to be subjected to appropriately designed randomized controlled trials. Further work is also required to determine the optimum delivery route (mask, intranasal prong, nasopharyngeal or laryngeal), dosing amount and redosing interval. PMID- 22940626 TI - 27th International Workshop on Surfactant Replacement, Lisbon, June 1-2, 2012. PMID- 22940624 TI - Mechanisms of injury to the preterm lung and airway: implications for long-term pulmonary outcome. AB - Despite changes in the epidemiology of bronchopulmonary dysplasia (BPD), longer term morbidity, particularly in the form of airway dysfunction, remains a substantial problem in former preterm infants. The stage for this respiratory morbidity may begin as early as the transition from fetal to neonatal life. Newer therapeutic approaches for BPD should be directed toward minimizing this longer term respiratory morbidity. Neonatal animal models focused primarily on hyperoxic exposure may provide important insights into the pathogenesis of longer-term airway hyperreactivity in this population. PMID- 22940625 TI - Current technology in the diagnosis of developmentally related lung disorders. AB - Respiratory disorders that present in the newborn period may result from structural, functional, or acquired mechanisms that limit gas exchange between the airspace and vascular bed. Exciting new imaging, gene sequencing, mass spectrometry, and molecular and cell-based techniques are enhancing our understanding of mechanisms of disease; highlighting the complexity of interactions between genes, development, and environment in the manifestation of health and disease; and becoming part of the clinical armamentarium for the care of patients. Some of these technologies and their clinical potential are briefly reviewed in this paper. PMID- 22940627 TI - Dvl3 translocates IPMK to the cell membrane in response to Wnt. AB - Wnt3a binds Frizzled-1 and the LRP5/6 co-receptors, ultimately activating Lef/Tcf sensitive gene transcription in development. Inositol polyphosphate multikinase, IPMK, which possesses inositol phosphate kinase and lipid inositol kinase activities, is essential in Wnt3a regulation of its canonical pathway as well as physiologically in AMPK signaling. In the current report we show that translocation of IPMK to the cell membrane, where its substrates exist in high abundance, is obligate to its function in Wnt signaling. Translocation of IPMK to the cell membrane occurs within 5 min after Wnt3a stimulation. IPMK ducking onto Dishevelled-3 (Dvl3) requires a PDZ domain and the COOH-terminal prolyly-rich tail of Dvl3. Wnt3a-stimulates mobilization of Dvl3 to the cell membrane, translocating IPMK to the cell membrane also, to facilitate downstream signaling of Frizzled1. Deletion mutant of IPMK lacking the NH2-terminal variable region, IPMKDeltaN, fails to translocate to the cell membrane and to propagate canonical signaling. Targeting the IPMKDeltaN back to the cell membrane by addition of an isoprenylated CAAX box rescues its function in Wnt3a downstream signaling. PMID- 22940628 TI - The Gbeta3 splice variant associated with the C825T gene polymorphism is an unstable and functionally inactive protein. AB - A splice variant of Gbeta3, termed Gbeta3s, has been associated with the C825T polymorphism in the Gbeta3 gene and linked with many human disorders. However, the biochemical properties and functionality of Gbeta3s remain controversial. Here, using multidisciplinary approaches including co-immunoprecipitation analysis and bioluminescence resonance energy transfer (BRET) measurements, we showed that unlike Gbeta3, Gbeta3s failed to form complexes with either Ggamma or Galpha subunits. Moreover, using a mutant Ggamma2 deficient in lipid modification to purify Gbeta3s from Sf9 cells without the use of detergents, we further showed that the failure of Gbeta3s to form dimers with Ggamma was not due to the instability of the dimers in detergents, but rather, reflected the intrinsic properties of Gbeta3s. Additional studies indicated that Gbeta3s is unstable, and unable to localize properly to the plasma membrane and to activate diverse Gbetagamma effectors including PLCbeta2/3, PI3Kgamma, ERKs and the Rho guanine exchange factor (RhoGEF) PLEKHG2. Thus, these data suggest that the pathological effects of Gbeta3 C825T polymorphism may result from the downregulation of Gbeta3 function. However, we found that the chemokine SDF1alpha transmits signals primarily through Gbeta1 and Gbeta2, but not Gbeta3, to regulate chemotaxis of several human lymphocytic cell lines, indicating the effects of Gbeta3 C825T polymorphism are likely to be tissue and/or stimuli specific and its association with various disorders in different tissues should be interpreted with great caution. PMID- 22940629 TI - An essential role of MAG in mediating axon-myelin attachment in Charcot-Marie Tooth 1A disease. AB - Charcot-Marie-Tooth disease type 1A (CMT1A) is a hereditary demyelinating peripheral neuropathy caused by the duplication of the PMP22 gene. Demyelination precedes the occurrence of clinical symptoms that correlate with axonal degeneration. It was postulated that a disturbed axon-glia interface contributes to altered myelination consequently leading to axonal degeneration. In this study, we examined the expression of MAG and Necl4, two critical adhesion molecules that are present at the axon-glia interface, in sural nerve biopsies of CMT1A patients and in peripheral nerves of mice overexpressing human PMP22, an animal model for CMT1A. We show an increase in the expression of MAG and a strong decrease of Necl4 in biopsies of CMT1A patients as well as in CMT1A mice. Expression analysis revealed that MAG is strongly upregulated during peripheral nerve maturation, whereas Necl4 expression remains very low. Ablating MAG in CMT1A mice results in separation of axons from their myelin sheath. Our data show that MAG is important for axon-glia contact in a model for CMT1A, and suggest that its increased expression in CMT1A disease has a compensatory role in the pathology of the disease. Thus, we demonstrate that MAG together with other adhesion molecules such as Necl4 is important in sustaining axonal integrity. PMID- 22940631 TI - Insulin-induced recurrent hypoglycemia exacerbates diabetic brain mitochondrial dysfunction and oxidative imbalance. AB - Intensive insulin therapy can prevent or slow the progression of long-term diabetes complications but, at the same time, it increases the risk for episodes of severe hypoglycemia. In our study, we used a protocol intended to mimic the levels of blood glucose that occur in type 1 diabetic patients under an intensive insulin therapy. Streptozotocin (STZ)-induced diabetic rats were treated subcutaneously with twice-daily insulin injections for 2weeks to induce hypoglycemic episodes. Brain cortical and hippocampal mitochondria were isolated and mitochondrial bioenergetics (respiratory chain and phosphorylation system) and oxidative status parameters (malondialdehyde (MDA) levels, mitochondrial aconitase activity and enzymatic and non-enzymatic antioxidant defenses) were analyzed. The protein levels of synaptophysin, a marker of synaptic integrity, and caspase 9 activity were also evaluated in cortical and hippocampal homogenates. Brain cortical mitochondria isolated from hyper- and recurrent hypoglycemic animals presented higher levels of MDA and alpha-tocopherol together with an increased glutathione disulfide reductase activity, lower manganese superoxide dismutase (MnSOD) activity and glutathione-to-glutathione disulfide (GSH/GSSG) ratio. No significant alterations were found in cortical mitochondrial respiratory chain and oxidative phosphorylation system. Hippocampal mitochondria from both experimental groups presented an impaired oxidative phosphorylation system characterized by a decreased mitochondrial energization potential and ATP levels and higher repolarization lag phase. In addition, higher MDA levels and decreased GSH/GSSG, alpha-tocopherol levels, and aconitase, glutathione peroxidase and MnSOD activities were observed in both groups of animals. Hippocampal mitochondria from recurrent hypoglycemic animals also showed an impairment of the respiratory chain characterized by a lower state 3 of respiration, respiratory control ratio and ADP/O index, and a higher state 4 of respiration. Additionally, a non-statistically significant decrease in synaptophysin protein levels was observed in cortical homogenates from recurrent hypoglycemic rats as well as in hippocampal homogenates from hyperglycemic and recurrent hypoglycemic rats. An increase in caspase 9 activity was also observed in hippocampal homogenates from hyperglycemic and recurrent hypoglycemic animals. Our results show that mitochondrial dysfunction induced by long-term hyperglycemic effects is exacerbated by recurrent hypoglycemia, which may compromise the function and integrity of brain cells. PMID- 22940630 TI - Constitutive alpha- and beta-secretase cleavages of the amyloid precursor protein are partially coupled in neurons, but not in frequently used cell lines. AB - Proteolytic cleavage of the amyloid precursor protein (APP) by the two proteases alpha- and beta-secretases controls the generation of the amyloid beta peptide (Abeta), a key player in Alzheimer's disease pathogenesis. The alpha-secretase ADAM10 and the beta-secretase BACE1 have opposite effects on Abeta generation and are assumed to compete for APP as a substrate, such that their cleavages are inversely coupled. This concept was mainly demonstrated in studies using activation or overexpression of alpha- and beta-secretases. Here, we report that this inverse coupling is not seen to the same extent upon inhibition of the endogenous proteases. Genetic and pharmacological inhibition of ADAM10 and BACE1 revealed that the endogenous, constitutive alpha-secretase cleavage of APP is largely uncoupled from beta-secretase cleavage and Abeta generation in neuroglioma H4 cells and in neuronally differentiated SH-SY5Y cells. In contrast, inverse coupling was observed in primary cortical neurons. However, this coupling was not bidirectional. Inhibition of BACE1 increased ADAM10 cleavage of APP, but a reduction of ADAM10 activity did not increase the BACE1 cleavage of APP in the neurons. Our analysis shows that the inverse coupling of the endogenous alpha- and beta-secretase cleavages depends on the cellular model and suggests that a reduction of ADAM10 activity is unlikely to increase the AD risk through increased beta-secretase cleavage. PMID- 22940632 TI - Efficient expansion and dopaminergic differentiation of human fetal ventral midbrain neural stem cells by midbrain morphogens. AB - Human fetal midbrain tissue grafting has provided proof-of-concept for dopamine cell replacement therapy (CRT) in Parkinson's disease (PD). However, limited tissue availability has hindered the development and widespread use of this experimental therapy. Here we present a method for generating large numbers of midbrain dopaminergic (DA) neurons based on expanding and differentiating neural stem/progenitor cells present in the human ventral midbrain (hVM) tissue. Our results show that hVM neurospheres (hVMN) with low cell numbers, unlike their rodent counterparts, expand the total number of cells 3-fold, whilst retaining their capacity to differentiate into midbrain DA neurons. Moreover, Wnt5a promoted DA differentiation of expanded cells resulting in improved morphological maturation, midbrain DA marker expression, DA release and electrophysiological properties. This method results in cell preparations that, after expansion and differentiation, can contain 6-fold more midbrain DA neurons than the starting VM preparation. Thus, our results provide evidence that by improving expansion and differentiation of progenitors present in the hVM it is possible to greatly enrich cell preparations for DA neurons. This method could substantially reduce the amount of human fetal midbrain tissue necessary for CRT in patients with PD, which could have major implications for the widespread adoption of this approach. PMID- 22940633 TI - Attenuated TLR4/MAPK signaling in monocytes from patients with CRMO results in impaired IL-10 expression. AB - Chronic recurrent multifocal osteomyelitis (CRMO) is an autoinflammatory bone disorder of unknown origin. We previously demonstrated that monocytes from CRMO patients fail to express the immune-modulatory cytokine interleukin-10 (IL-10) in a chromatin dependent manner. Here, we demonstrate that attenuated extracellular signal regulated kinase (ERK)1 and 2 signaling in response to TLR4 activation results in failure to induce IL-10 expression in monocytes from CRMO patients. Attenuated ERK1/2 activation results in 1) reduced levels of Sp-1, a transcription factor that induces IL-10 expression in monocytes, and 2) impaired H3S10 phosphorylation of the IL10 promoter, an activating epigenetic mark. The pro-inflammatory cytokines tumor necrosis factor (TNF)alpha and IL-6 are not negatively affected, resulting in an imbalance towards pro-inflammatory cytokines. Thus, impaired ERK1/2 signaling with subsequently reduced Sp-1 expression and H3S10 phosphorylation of the IL10 promoter may centrally contribute to the pathophysiology of CRMO. PMID- 22940634 TI - A novel mutation in the interleukin-1 receptor antagonist associated with intrauterine disease onset. AB - Deficiency of the IL-1 receptor antagonist (DIRA) is a recently described rare autoinflammatory disease, caused by loss of function mutations in IL1RN leading to the unopposed activation of the IL-1 pathway. We describe a novel nonsense mutation in the IL1RN gene, associated with early intrauterine onset, death and multiorgan involvement in a prematurely born baby. The protein prediction model indicated that the novel Q119X mutation would result in a nonfunctional protein by impairing the ability of the IL-1Ra to bind and antagonize signaling through the IL-1R. Since the disorder may mimic severe bacterial infections and the treatment with anakinra is life saving, we intend to raise awareness of the syndrome and the possibility of a founder mutation that may lead to the diagnosis of additional cases in Turkey. The clinical suspicion of DIRA is critical to avoid improper management of the patients with antibiotics alone and death from multiorgan failure. PMID- 22940636 TI - Assessment of the molecular structure of the borate mineral boracite Mg3B7O13Cl using vibrational spectroscopy. AB - Boracite is a magnesium borate mineral with formula: Mg(3)B(7)O(13)Cl and occurs as blue green, colorless, gray, yellow to white crystals in the orthorhombic - pyramidal crystal system. An intense Raman band at 1009 cm(-1) was assigned to the BO stretching vibration of the B(7)O(13) units. Raman bands at 1121, 1136, 1143 cm(-1) are attributed to the in-plane bending vibrations of trigonal boron. Four sharp Raman bands observed at 415, 494, 621 and 671 cm(-1) are simply defined as trigonal and tetrahedral borate bending modes. The Raman spectrum clearly shows intense Raman bands at 3405 and 3494 cm(-1), thus indicating that some Cl anions have been replaced with OH units. The molecular structure of a natural boracite has been assessed by using vibrational spectroscopy. PMID- 22940635 TI - IL-2 controls trafficking receptor gene expression and Th2 response for skin and lung inflammation. AB - Both Il2(-/-) mice and Scurfy (Sf) mutant mice that are deficient in FoxP3, develop multi-organ inflammation but only the latter display severe skin and lung inflammation. In contrast, Sf.Il2(-/-) double mutant mice do not display skin inflammation and markedly reduced lung inflammation. In this review, we summarize our recent findings based on microarray, q-PCR and functional studies of 10 Sf double mutant mice. These studies revealed novel pro-inflammatory functions of IL 2 in regulating inflammation in an organ-specific manner. IL-2 exerts its "organ specific" pro-inflammatory function by regulating the migration and retention of CD4(+) T-cells (both Th1 and Th2) specifically to the skin and lung. In addition, IL-2 is also required for regulating the Th2 cytokine response during T-cell activation. Further studies on these IL-2-regulated genes will help in identifying novel targets for intervention in inflammatory diseases of skin and lung. PMID- 22940637 TI - Economic booms and risky sexual behavior: evidence from Zambian copper mining cities. AB - Existing studies suggest that individual and household level economic shocks affect the demand for and supply of risky sex. However, little evidence exists on the effects of an aggregate shock on equilibrium risky sexual behavior. This paper examines the effects of the early twenty-first century copper boom on risky sexual behavior in Zambian copper mining cities. The results suggest that the copper boom substantially reduced rates of transactional sex and multiple partnerships in copper mining cities. These effects were partly concentrated among young adults and copper boom induced in-migration to mining cities appears to have contributed to these reductions. PMID- 22940638 TI - Junior doctors' preferences for specialty choice. AB - A number of studies suggest that there is an over-supply of specialists and an under-supply of general practitioners in many developed countries. Previous econometric studies of specialty choice from the US suggest that although income plays a role, other non-pecuniary factors may be important. This paper presents a novel application of a choice experiment to identify the effects of expected future earnings and other attributes on specialty choice. We find the implied marginal wage estimated from our discrete choice model is close to the actual wages of senior specialists, but much higher than those of senior GPs. In a policy simulation we find that increasing GPs' earnings by $50,000, or increasing opportunities for procedural or academic work can increase the number of junior doctors choosing general practice by between 8 and 13 percentage points. The simulation implies an earnings elasticity of specialty choice of 0.95. PMID- 22940639 TI - Spermatozoa recruit prostasomes in response to capacitation induction. AB - Seminal plasma contains various types of extracellular vesicles, including 'prostasomes'. Prostasomes are small vesicles secreted by prostatic epithelial cells that can be recruited by and fuse with sperm cells in response of progesterone that is released by oocyte surrounding cumulus cells. This delivers Ca(2+) signaling tools that allow the sperm cell to gain hypermotility and undergo the acrosome reaction. Conditions for binding of prostasomes to sperm cells are however unclear. We found that classically used prostasome markers are in fact heterogeneously expressed on distinct populations of small and large vesicles in seminal plasma. To study interactions between prostasomes and spermatozoa we used the stallion as a model organism. A homogeneous population of ~60nm prostasomes was first separated from larger vesicles and labeled with biotin. Binding of biotinylated prostasomes to individual live spermatozoa was then monitored by flow cytometry. Contrary to assumptions in the literature, we found that such highly purified prostasomes bound to live sperm only after capacitation had been initiated, and specifically at pH >=7.5. Using fluorescence microscopy, we observed that prostasomes bound primarily to the head of live sperm. We propose that in vivo, prostasomes may bind to sperm cells in the uterus, to be carried in association with sperm cells into oviduct and to fuse with the sperm cell only during the final approach of the oocyte. This article is part of a Special Issue entitled: An Updated Secretome. PMID- 22940640 TI - The effect of fulvic acid on pre- and postaggregation state of Abeta(17-42): molecular dynamics simulation studies. AB - Alzheimer's disease (AD), a neurodegenerative disorder, is directly related to the aggregation of Abeta peptides. These peptides can self-assemble from monomers to higher oligomeric or fibrillar structures in a highly ordered and efficient manner. This self-assembly process is accompanied by a structural transition of the aggregated proteins from their normal fold into a predominantly beta-sheet secondary structure. 14ns molecular dynamics simulation revealed that fulvic acid interrupted the dimer formation of Abeta(17-42) peptide while in its absence Abeta(17-42) dimer formation occurred at ~12ns. Additionally, fulvic acid disrupted the preformed Abeta(17-42) trimer in a very short time interval (12ns). These results may provide an insight in the drug design against Abeta(17-42) peptide aggregation using fulvic acid as lead molecule against Abeta(17-42) mediated cytotoxicity and neurodegeneration. PMID- 22940641 TI - Efficiency at rest: magnetoencephalographic resting-state connectivity and individual differences in verbal working memory. AB - Inter-individual differences in cognitive performance are based on an efficient use of task-related brain resources. However, little is known yet on how these differences might be reflected on resting-state brain networks. Here we used Magnetoencephalography resting-state recordings to assess the relationship between a behavioral measurement of verbal working memory and functional connectivity as measured through Mutual Information. We studied theta (4-8 Hz), low alpha (8-10 Hz), high alpha (10-13 Hz), low beta (13-18 Hz) and high beta (18 30 Hz) frequency bands. A higher verbal working memory capacity was associated with a lower mutual information in the low alpha band, prominently among right anterior and left-lateral sensors. The results suggest that an efficient brain organization in the domain of verbal working memory might be related to a lower resting-state functional connectivity across large-scale brain networks possibly involving right prefrontal and left perisylvian areas. PMID- 22940642 TI - Links between adolescent sympathetic and parasympathetic nervous system functioning and interpersonal behavior over time. AB - Extensive research has investigated links between individual differences in youths' autonomic nervous system (ANS) functioning and psychological outcomes related to emotion regulation, yet little of this research has examined developmental change. The study tested whether individual differences in youths' tonic and stress-induced ANS functioning, assessed at age 14, and changes in ANS functioning from age 14 to 16 predicted corresponding changes in youths' behavioral warmth, as displayed during videotaped mother-child conflict interactions conducted at age 14 and 16. Increased behavioral warmth was predicted by increased baseline respiratory sinus arrhythmia (RSA), increased SCL stress reactivity, decreased RSA stress reactivity (i.e., greater vagal suppression), and decreased baseline SCL. There was also an interaction between RSA stress reactivity at age 14 and changes in maternal warmth from age 14 to 16, such that increased maternal warmth was only associated with increased adolescent warmth for adolescents with lower RSA stress reactivity at age 14. PMID- 22940643 TI - Heart rate variability is associated with emotion recognition: direct evidence for a relationship between the autonomic nervous system and social cognition. AB - It is well established that heart rate variability (HRV) plays an important role in social communication. Polyvagal theory suggests that HRV may provide a sensitive marker of one's ability to respond and recognize social cues. The aim of the present study was to directly test this hypothesis. Resting-state HRV was collected and performance on the Reading the Mind in the Eyes Test was assessed in 65 volunteers. HRV was positively associated with performance on this emotion recognition task confirming our hypothesis and these findings were retained after controlling for a variety of confounding variables known to influence HRV - sex, BMI, smoking habits, physical activity levels, depression, anxiety, and stress. Our data suggests that increased HRV may provide a novel marker of one's ability to recognize emotions in humans. Implications for understanding the biological basis of emotion recognition, and social impairment in humans are discussed. PMID- 22940644 TI - Genetics: The MAPT locus-a genetic paradigm in disease susceptibility. PMID- 22940645 TI - Dopamine transporter genotype predicts attentional asymmetry in healthy adults. AB - A number of recent studies suggest that DNA variation in the dopamine transporter gene (DAT1) influences spatial attention asymmetry in clinical populations such as ADHD, but confirmation in non-clinical samples is required. Since non-spatial factors such as attentional load have been shown to influence spatial biases in clinical conditions, here we sought to determine whether any association between DAT1 genotype and spatial bias might be moderated by non-spatial attentional load. Healthy adults were asked to react to sudden onset peripheral targets while demand on non-spatial attention was manipulated via a central task. Participants were genotyped for a DAT1 variable number of tandem repeat (VNTR) polymorphism. The 10-repeat allele of this variant is a replicated susceptibility allele for ADHD and has been shown to associate with spatial bias. As expected, an overall leftward asymmetry/pseudoneglect was observed when the data were averaged across the entire sample. When data were stratified by DAT1 genotype, individuals lacking homozygosity for the 10-repeat DAT1 allele (non-10/10) showed a pronounced leftward bias that was significantly different from zero. In line with past reports from children with ADHD, this leftward bias was attenuated in individuals who were homozygous for the DAT1 10-repeat allele (10/10), suggestive of relatively weaker right hemisphere dominance for spatial attention. This effect of DAT1 genotype on spatial bias was not modulated by non-spatial attention load. These data confirm in healthy adult participants both the existence and the direction of the relationship previously reported between DAT1 genotype and spatial bias in children with ADHD. These data add to a growing body of evidence showing that spatial attentional asymmetry is a stable quantitative trait, with individual differences in this trait significantly predicted by common DNA variation in the DAT1 gene. PMID- 22940646 TI - Silver nanoparticles induce premutagenic DNA oxidation that can be prevented by phytochemicals from Gentiana asclepiadea. AB - Among nanomaterials, silver nanoparticles (AgNPs) have the broadest and most commercial applications due to their antibacterial properties, highlighting the need for exploring their potential toxicity and underlying mechanisms of action. Our main aim was to investigate whether AgNPs exert toxicity by inducing oxidative damage to DNA in human kidney HEK 293 cells. In addition, we tested whether this damage could be counteracted by plant extracts containing phytochemicals such as swertiamarin, mangiferin and homoorientin with high antioxidant abilities. We show that AgNPs (20 nm) are taken up by cells and localised in vacuoles and cytoplasm. Exposure to 1, 25 or 100 ug/ml AgNPs leads to a significant dose-dependent increase in oxidised DNA base lesions (8-oxo-7,8 dihydroguanine or 8-oxoG) detected by the comet assay after incubation of nucleoids with 8-oxoG DNA glycosylase. Oxidised DNA base lesions and strand breaks caused by AgNPs were diminished by aqueous and methanolic extracts from both haulm and flower of Gentiana asclepiadea. PMID- 22940647 TI - Arginine-vasotocin expression and participation in reproduction and social behavior in males of the cichlid fish Cichlasoma dimerus. AB - In non-mammalian vertebrates, the nonapeptide arginine-vasotocin (AVT) is involved in the regulation of social behavior related to reproduction and aggression. The cichlid fish Cichlasoma dimerus is a monogamous species with complex social hierarchies. Males are found in one of two basic alternative phenotypes: Non-territorial and territorial males. In this work we characterize the vasotocinergic system in males of C. dimerus in relation to social status with particular emphasis on the various putative sites of action of AVT across the hypothalamic-pituitary-gonad (HPG) axis, and its effects on reproductive and social behavior. The location and distribution of vasotocinergic neurons in the brain was studied, highlighting a morphometric analysis of AVT producing neurons in males of different social status. The effect of AVT on pituitary gonadotropin secretion was analyzed by single pituitary culture while expression of AVT in peripheral organs was studied by RT-PCR using specific primers. Finally, the role of AVT on testicular androgen release was assessed by in vitro incubation of testis. Results showed a positive effect of AVT on gonadotropin secretion, where beta-LH showcased a triphasic response under increasing AVT concentration, while beta-FSH's response was dose-dependent and directly proportional. AVT showed a positive and concentration-dependent effect over testicular androgens synthesis and secretion in vitro. Vasotocin expression was observed in testicular somatic tissue located in the interstitial compartment. Thus, the AVT system in C. dimerus appears to be of high complexity, with multiple sites of action in the hypothalamus-pituitary-gonadal axis. PMID- 22940648 TI - A sensitive method based on fluorescence-detected circular dichroism for protein local structure analysis. AB - We report an improved fluorescence-detected circular dichroism (FDCD)-based analytical method that is useful for probing protein three-dimensional structures. The method uses a novel FDCD device with an ellipsoidal mirror that functions on a standard circular dichroism (CD) spectrometer and eliminates all artifacts. Our experiments demonstrated three important findings. First, the method is applicable to any proteins either by using intrinsic fluorescence derived from tryptophan residues or by introducing a fluorescent label onto nonfluorescent proteins. Second, by using intrinsic fluorescence, FDCD spectroscopy can detect a structural change in the tertiary structure of metmyoglobin due to stepwise denaturation on a change in pH. Such changes could not be detected by conventional CD spectroscopy. Third, based on the typical advantages of fluorescence-based analyses, FDCD measurements enable observation of only the target proteins in a solution even in the presence of other peptides. Using our ellipsoidal mirror FDCD device, we could observe structural changes of fluorescently labeled calmodulin on binding with Ca(2+) and/or interacting with binding peptides. Because FDCD appears to reflect the protein's local structure around the fluorophore, it may provide a useful means for "pinpoint analysis" of protein structures. PMID- 22940649 TI - Simultaneous quantification of tetrahydrobiopterin, dihydrobiopterin, and biopterin by liquid chromatography coupled electrospray tandem mass spectrometry. AB - A simple and rapid liquid chromatography-tandem mass spectrometry (LC-MS/MS) based method was developed for the quantification of tetrahydrobiopterin (BH4), dihydrobiopterin (BH2), and biopterin (B) in human umbilical vein endothelial cells (HUVECs). Freshly prepared cell samples were treated with a mixture consisting of 0.2M trichloroacetic acid (TCA) and a cocktail of various antioxidants in order to precipitate proteins and other cellular components and to stabilize red/ox conditions in the lysates. Chromatography of the cell lysates was performed on a Poroshell 120 SB-C18 column (2.7MUm, 150*2.1mm) using a stepwise gradient elution made from two mobile phases. Quantification was performed on a triple quadrupole mass spectrometer employing electrospray ionization with the operating conditions as multiple reaction monitoring (MRM) at positive ion mode. Total chromatographic run time was 23min. The method was validated for analysis in HUVECs, and the limits of quantification were 1nM for BH4 and BH2 and 2.5nM for B. Standard curves were linear in the concentration ranges of 1 to 100nM for BH4 and BH2 and 2.5 to 100nM for B. The current study reports a novel method for the simultaneous and direct quantification of BH4, BH2, and B in a single injection. PMID- 22940650 TI - Optical sequence probing with the homologous recombination protein RecA. AB - In this study, we used the homologous recombination protein RecA to locate a specific sequence on DNA. Single-stranded (ss) DNA (80-mer, 5'-biotinylated), complementary to the sequence of interest, was labeled with quantum dots (Qdots((r))) via biotin-avidin binding. The DNA was then mixed with RecA to form a fluorescent-labeled ssDNA-RecA complex. lambda DNA, which was used as the target DNA, was stretch-and-positioned onto microelectrodes by using the electrostatic method. When the ssDNA-RecA complex was fed to the suspended target DNA, clear fluorescence spots were observed on individual target DNA molecules. The histogram of the probe-binding position along the target DNA was measured, and the peak was found to correspond to the location complementary to the probe ssDNA. This result shows a potential use for recombination proteins in facilitating the optical detection of DNA sequences. PMID- 22940651 TI - CIP (cleaning-in-place) stability of AlGaN/GaN pH sensors. AB - The CIP stability of pH sensitive ion-sensitive field-effect transistors based on AlGaN/GaN heterostructures was investigated. For epitaxial AlGaN/GaN films with high structural quality, CIP tests did not degrade the sensor surface and pH sensitivities of 55-58 mV/pH were achieved. Several different passivation schemes based on SiO(x), SiN(x), AlN, and nanocrystalline diamond were compared with special attention given to compatibility to standard microelectronic device technologies as well as biocompatibility of the passivation films. The CIP stability was evaluated with a main focus on the morphological stability. All stacks containing a SiO2 or an AlN layer were etched by the NaOH solution in the CIP process. Reliable passivations withstanding the NaOH solution were provided by stacks of ICP-CVD grown and sputtered SiN(x) as well as diamond reinforced passivations. Drift levels about 0.001 pH/h and stable sensitivity over several CIP cycles were achieved for optimized sensor structures. PMID- 22940652 TI - [New concept of mitral valve repair for posterior leaflet prolapse]. AB - BACKGROUND: Conventional repair of posterior mitral valve prolapse involves quadrangular resection and sliding plasty. However, these 2 methods require annular plication and useful leaflet tissue is sacrificed. METHODS: Our concept is to make an ideally shaped posterior leaflet without annular plication. When the leaflet is not high, we select triangular resection( TRR). For a high leaflet, we developed hourglass resection (HGR). The hourglass shape consists of 2 triangles:the upper inverted triangle is resected and the lower triangle is resected and sutured to the annulus. From 2007 to 2012, 65 patients with mitral regurgitation (MR) with leaflet prolapse were repaired. 49 patients who had posterior leaflet prolapse were analized in this study. The mean age was 61.7+/ 11.5 years and 67.3% were men. RESULTS: All patients underwent successful repair. There were no hospital deaths, or no systolic anterior motion. In 1 patient, repair was repeated 1 month post-operatively. The mean follow-up period was 2.6+/ 1.5 (0.1 ~ 4.9) years. There were no late deaths. The most recent echocardiogram revealed no MR in 36, mild MR in 12, and moderate MR in 1 cases. CONCLUSION: The short-term results of our strategy for posterior leaflet repair are good. PMID- 22940653 TI - [Incidence of string-like adhesion between thoracic wall and bullae observed during video-assisted thoracic surgery( VATS) for spontaneous pneumothorax]. AB - It is not rare that string-like adhesion between lung apex and chest wall is observed during videoassisted thoracic surgery (VATS) for spontaneous pneumothorax. This adhesion may cause hemothorax which requires emergency operation, although the precise incidence of such cases is uncertain. We analyzed consecutive 120 spontaneous pneumothorax cases underwent VATS at Suzuka General Hospital from January 2005 to September 2008. Twenty-one out of 120 (17.5%) were such cases receiving partial resection of the lung including the adhesion after dividing it. Pathological study revealed the bullae close to the adhesion in all cases, suggesting that these adhesion caused after possible former pneumothorax. Thus, 21 cases might be recurrent pneumothorax. Even in clinically 1st onset pneumothorax, those cases may be good indication for VATS. PMID- 22940654 TI - [Mitral valve replacement in dextrocardia and situs inversus]. AB - Cardiac surgery for acquired valvular diseases in patients with dextrocardia is extremely rare. We report a surgical case of mitral valve replacement and tricuspid annuloplasty in a patient with dextrocardia and situs inversus. A 74 year-old man with dextrocardia and situs inversus, who had undergone patch closure of atrial septal defect 25 years before, was referred for surgical treatment of severe mitral and tricuspid valve regurgitation. Preoperative computed tomography( CT) showed dextrocardia, situs inversus, interruption of the inferior vena cava with an azygos vein continuation, and drainage of the hepatic vein into the right atrium. Under redo-median sternotomoy, cardiopulmonary bypass was established by cannulating the ascending aorta, the superior vena cava, the right femoral and the hepatic veins. The surgeon operated from the left side of the operating table, and had an excellent exposure to the mitral and tricuspid valves during the operation. Mitral valve replacement and tricuspid annuloplasty were performed successfully. The postoperative course was uneventful. PMID- 22940655 TI - [Pulmonary arteriovenous fistula with Rendu-Osler-Weber disease]. AB - A 36-year-old man was admitted to our hospital for examination of a nodular shadow in the left lung. Chest 3-dimensional computed tomography (3D-CT) revealed a pulmonary arteriovenous fistula (PAVF) of 21 mm in diameter composed of the feeding artery (A4) and the draining vein (V4) in the left S4. Abdominal enhanced CT revealed multiple hepatic arteriovenous fistula. Brain CT revealed a cavernous hemangioma in right occipital cerebrum. He had a family history, habitual epistaxis, and oral telangiectasia and was diagnosed as Rendu-Osler-Weber disease (hereditary hemorrhagic telangiectasia:HHT). According to his family history, PAVF was likely to be a risk factor of brain infarction and abscess, and the wedge resection of the lingual lobe was performed to remove PAVF. PMID- 22940656 TI - [Two-staged hybrid surgery for an extended thoracic aortic aneurysm with Komerell's diverticulum]. AB - We have successfully performed 2 staged hybrid operation for an extended thoracic aortic aneurysm with Komerell diverticulum, which lessened surgical stress of the patient with avoidance of postoperative complications. An 82-year-old man who had been under observation for thoracic aortic aneurysm was admitted to the hospital with continuous chest discomfort. The patient initially underwent graft replacement for an ascending and arch aneurysm by using the elephant trunk technique. Thirty-five days later, he underwent endovascular repair for the residual descending thoracic aneurysm. The postoperative course was uneventful, and postoperative computed tomography (CT) revealed no stent migration and just a little type II endoleak. This 2 staged hybrid approach might be less invasive than the conventional approach, and be a potential therapeutic option for high risk patients with an extended thoracic aortic aneurysm. PMID- 22940657 TI - [Arterial switch operation for transposition of the great arteries with situs inversus and mirror image dextrocardia]. AB - We report a successful arterial switch operation for complete transposition of great arteries with atrial and visceral situs inversus totalis and mirror image dextrocardia in a 12-day-old infant girl. The aorta was located left side-by-side to the pulmonary trunk with a single coronary artery (mirror image of 1RLCx). After French maneuver, the posterior circumference of the neo-aorta was reconstructed. Then the coronary button was transplanted into the neo-aorta with a trap door technique carefully avoiding any twist and over-stretch. The neo pulmonary trunk was reconstructed with an autologous pericardial patch and sutured to the longitudinal incision made into the left central pulmonary artery. The baby was discharged from hospital and has been doing well without any morbidity relating myocardial ischemia. PMID- 22940658 TI - [Right lower lobectomy with flap bronchoplasty for primary lung cancer]. AB - A 59-year-old man was referred to our hospital for further investigation of an abnormal chest shadow. A chest computed tomography( CT) revealed a tumor shadow originating in the superior segment( S6)of the right lower lobe. Bronchoscopy showed no visible tumor, but adenocarcinoma cells were detected in brush cytology samples. We diagnosed primary lung cancer, classified as cT2aN0M0, and planned a radical operation. Intraoperatively, since the tumor had invaded the outer wall of intermediate bronchus, we considered a flap bronchoplasty to preserve the middle lobe. The right lower lobectomy and partial resection of intermediate bronchus were made with preserving unaffected ventral wall of lower bronchus. The lower bronchus remnant was used as a flap to cover the defect in the intermediate bronchus. The postoperative course was uneventful, and bronchoscopic findings revealed good healing of the suture line and sufficient airway patency. PMID- 22940659 TI - [Traumatic aortic injury]. AB - Optimal timing of surgical repair for traumatic aortic injury (TAI) is still controversial. We have experienced 3 cases of TAI. The 1st one suffered from severe multisystem trauma in addition to TAI, so we performed graft replacement of the proximal descending aorta electively 31 days after the injury. The 2nd one had massive pleural effusion on admission and we performed urgent operation. They recovered uneventfully. The last one died of aortic re-rupture during anesthetic induction despite attempting emergent operation. In patients with serious multisystem trauma besides TAI, surgical repair can be delayed as long as there are no signs of on-going rupture and/or bleeding, however close observation, serial computed tomography( CT) check-ups and strict control of blood pressure are needed. PMID- 22940660 TI - [Cardiac failure caused by intrapericardial chronic expanding hematoma 18 years after CABG]. AB - Chronic expanding hematoma(CEH)was first recognized by Reid in 1980. It begins to expand chronically more than 1 month after surgery or trauma, which is considered the possible cause of bleeding. It resembles chronic subdural hematoma. Most of the reports on CEH are those in the thoracic cavity or muscles, and few are in the pericardial cavity after open heart surgery. Our case was a 64-year-old male, who had undergone coronary artery bypass grafting (CABG) 18 years before. He presented with symptoms of heart failure such as exertional dyspnea, general fatigue and appetite loss. Computed tomography( CT) scan showed severe compression of the left ventricle by a large mass, and he was diagnosed with intrapericardial CEH. Resection of the severely calcified epicardium as well as removal of the hematoma in the pericardial cavity was performed, and the symptoms of heart failure improved. No recurrence has been noted for 1 year since the operation. A long-term follow-up will be necessary. PMID- 22940661 TI - [Peripheral pulmonary artery aneurysm treated with embolization]. AB - Althogh peripheral pulmonary aneurysm is a rare entity, the majority of cases become fatal if left untreated, due to sudden rupture and exsanguination. This emphasizes the need for treatment whenever a diagnosis made. A 81-year-old woman was found to have a coin lesion in the left middle field. Enhanced computed tomography (CT) showed strong staining and pulmonary angiography revealed a saccular dilation of the left A3b branch of the pulmonary artery. Successful embolization of the branch of the pulmonary artery was performed. PMID- 22940662 TI - [Lung adenocarcinoma presented with reticular pattern in which both CA19-9 and carcinoembryonic antigen( CEA) were recognized as markers]. AB - A 79-year-old male whose chest X-ray revealed a localized reticular shadow in health check was once treated medically with a diagnosis of interstitial pneumonia. Regardless of the treatment, the shadow increased in its size. Positron emission tomography (PET)-computed tomography(CT) was suggestive of a primary lung cancer in clinical stage IIIA. CA19-9 and CEA were 3,568.5 U/ml and 178.2 ng/ml respectively, and a left lower lobectomy was performed. The postoperative course was uneventful. Both tumor markers declined shortly after the surgery. But they increased in 8 months after the surgery associated with tumor recurrence. In spite of chemotherapy, the patient was expired 15 months following the surgery. Immunohistochemical staining showed the tumor was a well differentiated adenocarcinoma with positive findings of both CEA and CA19-9. PMID- 22940663 TI - [Hyperbaric oxygen therapy for air embolism complicating computed tomography (CT) guided needle marking of the lung]. AB - Preoperative computed tomography( CT)-guided marking with a short hook wire for small sized lung tumors has become popular along with the spread of thoracoscopic surgery. Systemic arterial air embolism is a very rare but potentially fatal complication. The patient was a 79-year-old man who was found to have a mixed ground glass opacity shadow on chest CT. Almost immediately after marking, he lost consciousness and complete atrio-ventricular (AV) block was found on the electrocardiogram (ECG) monitor. Brain CT showed intravascular air bubbles in the right frontal lobe. Two hours later, his conscious level was recovered completely but remained left hemiplegia. Five hours later, he was transported to another hospital for hyperbaric oxygen therapy. After 3 episodes of the treatment, left hemiplegia recovered with slight sense disorder in the left little finger. When neurologic findings are remained after air embolism, hyperbaric oxygen therapy should be arranged immediately. PMID- 22940664 TI - [Mitral valve replacement after previous coronary artrey bypass grafting( CABG) with functioning left internal thoracic artery( LITA) grafts in an elderly patient; report of a case]. AB - An 85-year-old woman had a history of coronary artery bypass grafting (CABG) performed 7 years ago, and dyspnea on effort had been worsening recently. Since echocardiography showed severe mitral valve regurgitation( MR), mitral valve repair was suggested. Preoperative enhanced computed tomography (CT) showed the patent functioning left internal thoracic artery (LITA) graft. Mitral valve replacement (MVR) using a 25 mm CEP bioprosthesis was performed successfully via resternotomy without any intraoperative injury of the heart. Myocardial protection without clamping of functioning LITA was done by both antegrade and retrograde continuous coronary perfusion (RCCP) under mild hypothermia. The postoperative clinical course was uneventful without any hemodynamic compromise. She was discharged on postoperative day 21 without any cardiac events following early introduction of cardiac rehabilitation. From these results, mitral valve reoperation by RCCP under mild hypothermia without control of functioning internal thoracic artery( ITA) grafts could be a safe option in some cases. PMID- 22940665 TI - [Infected implantable cardioverter-defibrillator lead extraction under deep hypothermic circulatory arrest; report of a case]. AB - We performed infected implantable cardioverter-defibrillator lead extraction under deep hypothermic circulatory arrest in a 58-year-old man. Venogram during the implantation of the lead had revealed complete obstruction of the innominate vein. Preoperative trans-esophageal ecocardiogram revealed intracardiac vegetation with a diameter of 20*13 mm. Because of advanced adhesion and large vegetation, we performed lead extraction under cardiopulmonary bypass. The leads were adherent to the wall of the superior vena cava( SVC) and the innominate vein and could not be extracted. So we converted to deep hypothermic circulatory arrest. We performed venotomy in the SVC and the innominate vein to achieve complete visualization. The leads were extracted under direct vision. Postoperative course was uneventful without recurrence. Extraction of implantable devices is highly recommended when infection occurs. When adhesion of the lead is suspected, safe extraction can be performed by venotomy of the innominate vein under deep hypothermic circulatory arrest. PMID- 22940666 TI - [Esophageal fish bone migrating to the lung; report of a case]. AB - A 55-year-old female felt a transient chest pain soon after a fish meal. Sixteen days later she presented a local clinic with fever of 38 degrees C. After chest computed tomography( CT) and upper gastrointestinal endoscopy showed fish bone embedded in the wall of the middle portion of the esophagus, she referred to our hospital 22 days after the meal. Thirty days after the meal ,endoscopic removal of the fish bone was challenged bygastroentenologists in vain. Chest CT after the attempt showed migration of the fish bone to the lung adjacent to the right inferior pulmonary vein. The fish bone which stuck out from the lung after division of the pulmonary ligament was removed successfully under thoracoscopic surgery. The patient is well 26 months after the surgery. PMID- 22940667 TI - [Invasive thymoma with extensive growth in the superior vena cava;report of a case]. AB - An anterior mediastinal tumor was incidentally found in a 58-year-old asymptomatic woman on a medical checkup. Computed tomography (CT) demonstrated a large tumor plugging the almost entire lumen of the superior vena cava (SVC), and 3 nodules in the bilateral lungs. The tumor seemed most likely an advanced thymoma or thymic carcinoma extending into the SVC and presenting with lung metastases. The patient underwent a combined resection of the invasive tumor and the SVC under cardiopulmonary bypass (CPB), and lung wedge resection for the nodules. The bilateral brachiocephalic veins were reconstructed with the separate grafts. The invasive tumor and the lung nodules were histologically confirmed as thymoma. Resection and reconstruction of the SVC was successfully performed under CPB for extirpation of an invasive thymoma with extensive intracaval growth. Combination chemotherapy for the relapsing lung metastases finally achieved complete response 41 months after surgery. PMID- 22940668 TI - Biophysical characterization of the proton-coupled oligopeptide transporter YjdL. AB - Proton-coupled oligopeptide transporters (POTs) utilize the electrochemical proton gradient to facilitate uptake of di- or tripeptide molecules. YjdL is one of four POTs found in Escherichia coli. It has shown an extraordinary preference for di- rather than tripeptides, and is therefore significantly different from prototypical POTs such as the human hPepT1. Nonetheless YjdL contains several highly conserved POT residues, which include Glu388 that is located in the putative substrate binding cavity. Here we present biophysical characterization of WT-YjdL and Glu388Gln. Isothermal titration calorimetrical studies exhibit a K(d) of 14 MUM for binding of Ala-Lys to WT-YjdL. Expectedly, no binding could be detected for the tripeptide Ala-Ala-Lys. Surprisingly however, binding could not be detected for Ala-Gln, although earlier studies indicated inhibitory potencies of Ala-Gln to be comparable to Ala-Lys (IC(50) values of 0.6 compared to 0.3mM). Finally, Ala-Lys binding to Glu388Gln was also undetectable which may support a previously suggested role in interaction with the ligand peptide N-terminus. PMID- 22940669 TI - The effect of stroke on immune function. AB - Neurological disorders affect over one billion lives each year worldwide. With population aging, this number is on the rise, making neurological disorders a major public health concern. Within this category, stroke represents the second leading cause of death, ranking after heart disease, and is associated with long term physical disabilities and impaired quality of life. In this review, we will focus our attention on examining the tight crosstalk between brain and immune system and how disruption of this mutual interaction is at the basis of stroke pathophysiology. We will also explore the emerging literature in support of the use of immuno-modulatory molecules as potential therapeutic interventions in stroke. This article is part of a Special Issue entitled 'Neuroinflammation in neurodegeneration and neurodysfunction'. PMID- 22940670 TI - Informatics and operations--let's get integrated. AB - The widespread adoption of commercial electronic health records (EHRs) presents a significant challenge to the field of informatics. In their current form, EHRs function as a walled garden and prevent the integration of outside tools and services. This impedes the widespread adoption and diffusion of research interventions into the clinic. In most institutions, EHRs are supported by clinical operations staff who are largely separate from their informatics counterparts. This relationship needs to change. Research informatics and clinical operations need to work more closely on the implementation and configuration of EHRs to ensure that they are used to collect high-quality data for research and improvement at the point of care. At the same time, the informatics community needs to lobby commercial EHR vendors to open their systems and design new architectures that allow for the integration of external applications and services. PMID- 22940671 TI - Gas extrusion in natural products total synthesis. AB - The thermodynamic driving force from the release of a gaseous molecule drives a broad range of synthetic transformations. This review focuses on gas expulsion in key reactions within natural products total syntheses, selected from the past two decades. The highlighted examples survey transformations that generate sulfur dioxide, carbon dioxide, carbonyl sulfide, or nitrogen through polar, radical, pericyclic, photochemical, or organometallic mechanisms. Of particular interest are applications wherein the gas extrusion enables formation of a synthetically challenging motif, such as an unusually hindered or strained bond. PMID- 22940672 TI - Kinetics, products, and mechanisms of secondary organic aerosol formation. AB - Secondary organic aerosol (SOA) is formed in the atmosphere when volatile organic compounds (VOCs) emitted from anthropogenic and biogenic sources are oxidized by reactions with OH radicals, O(3), NO(3) radicals, or Cl atoms to form less volatile products that subsequently partition into aerosol particles. Once in particles, these organic compounds can undergo heterogenous/multiphase reactions to form more highly oxidized or oligomeric products. SOA comprises a large fraction of atmospheric aerosol mass and can have significant effects on atmospheric chemistry, visibility, human health, and climate. Previous articles have reviewed the kinetics, products, and mechanisms of atmospheric VOC reactions and the general chemistry and physics involved in SOA formation. In this article we present a detailed review of VOC and heterogeneous/multiphase chemistry as they apply to SOA formation, with a focus on the effects of VOC molecular structure on the kinetics of initial reactions with the major atmospheric oxidants, the subsequent reactions of alkyl, alkyl peroxy, and alkoxy radical intermediates, and the composition of the resulting products. Structural features of reactants and products discussed include compound carbon number; linear, branched, and cyclic configurations; the presence of C[double bond, length as m dash]C bonds and aromatic rings; and functional groups such as carbonyl, hydroxyl, ester, hydroxperoxy, carboxyl, peroxycarboxyl, nitrate, and peroxynitrate. The intention of this review is to provide atmospheric chemists with sufficient information to understand the dominant pathways by which the major classes of atmospheric VOCs react to form SOA products, and the further reactions of these products in particles. This will allow reasonable predictions to be made, based on molecular structure, about the kinetics, products, and mechanisms of VOC and heterogeneous/multiphase reactions, including the effects of important variables such as VOC, oxidant, and NO(x) concentrations as well as temperature, humidity, and particle acidity. Such knowledge should be useful for interpreting the results of laboratory and field studies and for developing atmospheric chemistry models. A number of recommendations for future research are also presented. PMID- 22940673 TI - Expression of concern. Stress associated with group living in a long-lived bird. PMID- 22940675 TI - Controlling synaptotagmin activity by electrostatic screening. AB - Exocytosis of neurosecretory vesicles is mediated by the SNARE (soluble N ethylmaleimide-sensitive factor attachment protein receptor) proteins syntaxin-1, synaptobrevin and SNAP-25, with synaptotagmin functioning as the major Ca(2+) sensor for triggering membrane fusion. Here we show that bovine chromaffin granules readily fuse with large unilamellar liposomes in a SNARE-dependent manner. Fusion is enhanced by Ca(2+), but only when the target liposomes contain phosphatidylinositol-4,5-bisphosphate and when polyphosphate anions, such as nucleotides or pyrophosphate, are present. Ca(2+)-dependent enhancement is mediated by endogenous synaptotagmin-1. Polyphosphates operate by an electrostatic mechanism that reverses an inactivating cis association of synaptotagmin-1 with its own membrane without affecting trans binding. Hence, the balancing of trans- and cis-membrane interactions of synaptotagmin-1 could be a crucial element in the pathway of Ca(2+)-dependent exocytosis. PMID- 22940678 TI - The development of scientific consultants: how the tobacco industry creates controversy on the carcinogenicity of tobacco-specific nitrosamines. AB - BACKGROUND: Tobacco-specific nitrosamines (TSNAs) are a group of carcinogens, which originate from nicotine and other tobacco alkaloids during fermentation and burning of tobacco. Between 1990 and 2010, the tobacco industry-funded extensive academic research on TSNAs in Germany. The objective was to gain better knowledge of how industry aims and strategies correlate with contents of publications by German toxicologists accepting tobacco industry funding by focusing on one prominent such toxicologist. METHODS AND FINDINGS: The authors analysed previously secret tobacco industry documents that were disclosed following a series of litigation cases in the USA and compared them with peer-reviewed published results of tobacco industry-funded toxicologists. The tobacco industry, in particular Philip Morris, developed sophisticated strategies to downplay TSNA's carcinogenic potential. Over 2 decades, German toxicologist Elmar Richter, faculty member of the renowned Ludwig-Maximilians-University, Munich, received substantial financial support from the tobacco industry. Numerous publications show that his research findings supported the aims of the tobacco industry. In his commissioned work, he suggested that TSNA burden can be explained by misclassification of smokers or assay background levels caused by TSNA-like molecules from food. Other publications cast doubt on the relevance of animal testing for TSNAs to humans claiming a detoxifying effect of nicotine on the metabolism of TSNAs or suggesting that adducts of TSNAs are unsuitable as biomarkers of exposure to tobacco smoke. CONCLUSIONS: Economic interests of the tobacco industry have strongly influenced the research activity of Richter and his group. The publications of his working group about carcinogenic effects of TSNAs published between 1992 and 2009 should therefore not be regarded as independent. Scientists and policy makers should consider the long-standing and intensive inter-relation between certain toxicologists and the tobacco industry when assessing the research results and consider ignoring them. PMID- 22940676 TI - Spatial elucidation of motion in proteins by ensemble-based structure calculation using exact NOEs. AB - Proteins are inherently dynamic systems whose motions cover large ranges in both magnitude and timescale. Because of the omnipresence of motion, it is likely that dynamics have important roles in the function of biomolecules. For detailed understanding of a protein's function, the three-dimensional structure and description of its dynamics are therefore required. Structure determination methods are well established, and NMR-relaxation phenomena provide insights into local molecular dynamics; moreover, recently several attempts have been made to detect concerted motion. Here, we present an ensemble-based structure determination protocol using ensemble-averaged distance restraints obtained from exact NOE rates. Application to the model protein GB3 establishes an ensemble of structures that reveals correlated motion across the beta-sheet, concerted motion between the backbone and side chains localized in the structure core, and a lack of concerted conformational exchange between the beta-sheet and the alpha-helix. PMID- 22940677 TI - Assessing secondhand smoke using biological markers. AB - Secondhand smoke exposure (SHSe) is a known cause of many adverse health effects in adults and children. Increasingly, SHSe assessment is an element of tobacco control research and implementation worldwide. In spite of decades of development of approaches to assess SHSe, there are still unresolved methodological issues; therefore, a multidisciplinary expert meeting was held to catalogue the approaches to assess SHSe and with the goal of providing a set of uniform methods for future use by investigators and thereby facilitate comparisons of findings across studies. The meeting, held at Johns Hopkins, in Baltimore, Maryland, USA, was supported by the Flight Attendant Medical Research Institute (FAMRI). A series of articles were developed to summarise what is known about self-reported, environmental and biological SHSe measurements. Non-smokers inhale toxicants in SHS, which are mainly products of combustion of organic materials and are not specific to tobacco smoke exposure. Biomarkers specific to SHSe are nicotine and its metabolites (e.g., cotinine), and metabolites of 4-(methylnitrosamino)-1-(3 pyridyl)-1-butanone (NNK). Cotinine is the preferred blood, saliva and urine biomarker for SHSe. Cotinine and nicotine can also be measured in hair and toenails. NNAL (4-[methylnitrosamino]-1-[3-pyridyl]-1-butanol), a metabolite of NNK, can be determined in the urine of SHS-exposed non-smokers. The selection of a particular biomarker of SHSe and the analytic biological medium depends on the scientific or public health question of interest, study design and setting, subjects, and funding. This manuscript summarises the scientific evidence on the use of biomarkers to measure SHSe, analytical methods, biological matrices and their interpretation. PMID- 22940679 TI - High ambulatory blood pressure values associated with non-alcoholic fatty liver in middle-aged adults. AB - OBJECTIVE: Nonalcoholic fatty liver and hypertension are associated with metabolic syndrome. Both conditions increase the risk for cardiovascular morbidity. The objective of this study was to analyze whether 24-h blood pressure (BP) levels and nondipping phenomenon associate with hepatic steatosis defined as liver brightness. METHODS: Twenty-four hour ambulatory BP measurement (ABPM) and liver brightness were investigated in a population-based cohort of 890 hypertensive (n = 433) and normotensive (n = 457) individuals aged 40-60 years. ABPM was recorded using the fully automatic SpaceLabs90207 oscillometric unit. RESULTS: Fatty liver was associated with male sex, increased alcohol consumption, high BMI, large waist (P < 0.001 for all) and increased prevalence of smoking (P < 0.03). Values of alanine aminotransferase (ALT), gamma-glutamyltransferase (GGT), triglycerides and high-sensitivity CRP (hsCRP) were higher and high density lipoprotein cholesterol lower (P < 0.001 for all) in individuals with fatty liver. After adjustments for BMI, sex and age, fatty liver was associated with 24-h (P < 0.005), daytime (P < 0.02) and night-time (P < 0.005) SBP measurements and DBP at daytime (P < 0.03). The association with nondipping showed only a trend (P = 0.057). CONCLUSION: Significantly higher ambulatory daytime and night-time SBP levels were seen in individuals with fatty liver. Nondipping does not seem to associate with liver fat. The coexistence of liver fat accumulation and high BP are likely to potentiate the risk for cardiovascular disease. PMID- 22940680 TI - Variant on chromosome 9p is associated with left ventricular mass: results from two cohorts of essential hypertensive individuals. AB - OBJECTIVES: It is well known that among hypertensive patients, an increased left ventricular mass (LVM) is a powerful predictor of cardiovascular morbidity and mortality. However, the mechanisms underlying LVM in hypertension are not completely understood, as the absolute value of blood pressure and other risk factors associated do not predict alone a definite LVM progression. Recently, the 9p21 chromosomal region has been consistently associated with coronary heart disease. METHODS AND RESULTS: We examined the association of 384 single nucleotide polymorphisms (SNPs) in the short arm of chromosome 9 with LVM in 821 hypertensive individuals from northern Italy. We identified a SNP (rs894379) in the intronic region of the centlein, centrosomal protein (CNTLN) gene on chromosome 9p22, whose minor allele G is associated with an increased LVM. We performed a follow-up validation analysis for the top SNP in 1038 hypertensive individuals from southern Italy. We then combined the results and found a nominal association for rs894379 (beta = 2.46, P = 0.0026). CONCLUSION: We describe a new variant associated with echocardiography LVM. This result, though it needs to be further investigated, may improve our understanding of the genetic determination of this prognostically relevant trait. PMID- 22940681 TI - Pediatric reference values of carotid-femoral pulse wave velocity determined with an oscillometric device. AB - BACKGROUND: A semi-automated devise for oscillometric measurement (Vicorder) of carotid-femoral pulse wave velocity (cfPWV) has been considered to be especially suited for multicenter studies in children and adolescents. METHODS: Within a healthy pediatric population (156 boys/158 girls; mean age 10.8 years, range 5.0 19.6 years), the transit time of the pulse wave was measured oscillometrically (Vicorder) between a carotid and femoral cuff. For calculation of cfPWV, the traveled path length was set to 80% of the direct distance between both sites of measurement. Reference tables were generated using the maximum-likelihood curve fitting technique and SD scores were calculated. Normalizing the same set of data with reference values specific for applanation tonometry yielded Z(at)values. Effects of sex, age, height, weight, BMI, blood pressure (BP), and heart rate on cfPWV as well as the correlation between sex-specific age-related and height related Z(osci) and Z(at)were investigated. RESULTS: Sex-specific reference values and curves for cfPWV as a function of age and height are presented. cfPWV correlated positively with age, height, weight, SBP, mean arterial BP, and sex (each P < 0.005). Multiple regression analysis identified age, sex, and mean arterial pressure as significant independent predictors of cfPWV explaining 42% of the overall variability. Strong linear relationships between Z(osci) and Z(at) were noted and per sex a set of age and height-related equation for conversion was derived: Z(at),age = -0.22 + 0.68 * Z(osci),age; r = 0.98 and Z(at),height = -0.33 + 0.66 * Z(osci),height; r = 0.99 in boys and Z(at),age = -0.61 + 0.81 * Z(osci),age; r = 0.98 and Z(at),height = -0.73 + 0.72 * Z(osci),height; r = 0.97 in girls (each P < 0.001). CONCLUSION: A strong linear association between height-related oscillometric and tonometric Z-scores was observed. Age related Z-scores are of limited value when comparing results across different populations and methods. PMID- 22940682 TI - Maternal cardiovascular changes from pre-pregnancy to very early pregnancy. AB - OBJECTIVE: Our aim was to assess changes in maternal cardiovascular haemodynamics, including central blood pressure (BP), wave reflections and aortic stiffness, from pre-pregnancy to very early pregnancy. METHODS: Fifty-six healthy nulliparous or women with previous uncomplicated pregnancy were studied prior to conception and in very early pregnancy. Assessments of brachial and central BPs, pulse wave reflection quantified by augmentation index (AIx), aortic stiffness using carotid femoral pulse wave velocity (aPWV) and cardiac output (CO) were performed. RESULTS: Pregnancy measurements were obtained at median gestational age of 6.3 weeks [interquartile range (IQR) 6-6.5 weeks] from the last menstrual period. Whilst heart rate (HR) increased from 67 +/- 10 to 71 +/- 10 bpm. (P = 0.001), brachial SBP, DBP and central SBP were all lower than the pre pregnancy values (109 +/- 10 to 104 +/- 7 mmHg, 72 +/- 8 to 65 +/- 6 mmHg and 99 +/- 10 to 92 +/- 7 mmHg, respectively; P < 0.001 for all). AIx adjusted for HR fell (19 +/- 10 to 13 +/- 9%; P = 0.001) as did peripheral vascular resistance (PVR; 1234 +/- 229 to 1128 +/- 280 dynes/s/cm; P = 0.003). aPWV adjusted for mean arterial pressure (MAP) was unchanged (5.3 +/- 0.6 to 5.1 +/- 0.6m/s; P = 0.2). CONCLUSION: Significant changes occur in brachial and central BP, AIx and PVR in successful, ongoing pregnancies, by about 6-7 weeks gestation; much earlier than has hitherto been assumed. Using late first trimester data as 'baseline' cannot be relied on to estimate the extent of cardiovascular changes in normal pregnancy. Future studies of cardiovascular changes in pregnancy should, therefore, have a pre-pregnancy starting point. PMID- 22940683 TI - [Radiological diagnostics of the small bowel]. AB - The barium meal with plain X-ray films of the small intestine has for decades been the undisputed gold standard in imaging of the small intestine. More recently, X-rays and fluoroscopy with an overall accuracy of 73% have been replaced by multislice computed tomography (MSCT) or modern magnetic resonance imaging (MRI). Ultrasound is suitable for the orienting investigation of the small intestine in the context of general abdominal sonography as well as for dedicated examinations with a sensitivity of 67-96% and a specificity up to 97%. The endoscopic examinations of the small bowel, such as video capsule endoscopy and double-balloon enteroscopy are expensive and time-consuming techniques, which provide valuable information in special indications. Other than with the stomach or colon, the diagnostics of primary small intestine tumors plays a relatively subordinate role due to the low incidence of 3-5% of all gastrointestinal (GI) neoplasms but with a high sensitivity of 84% and a specificity of up to 97% for computed tomography (CT) and MRI. Predominant questions are those concerning ileus or the diagnostics of passage disturbances after preceding operations, to depict bowel obstructions, adhesions or the involvement of the small bowel in peritoneal carcinomatosis. The sensitivity per lesion in the initial evaluation of Crohn's disease (CD) is 47-68% for capsule endoscopy, 43% for MRI and 21% for CT enterography. In cases of known CD, the sensitivity is 70% for capsule endoscopy and 79% for MRI. A further indication is the evaluation of acute or occult gastrointestinal bleeding. PMID- 22940685 TI - [Do not be deceived: altered magnetic resonance characteristics of gliadel implants after glioma resection]. PMID- 22940684 TI - [Clinical symptoms of hydrocephalus]. AB - CLINICAL ISSUE: A correct interpretation of radiological data in cases of suspected hydrocephalus is not possible when ignoring patient age and clinical symptoms. STANDARD TREATMENT: An in-depth knowledge of clinical findings is accordingly essential. INNOVATIONS: New pathophysiological findings and a detailed assignment of previously unrecognized or ignored clinical symptoms to various entities of the spectrum of hydrocephalus disorders allow a coherent diagnosis drawn from clinical and radiological data. For this purpose it is necessary to know the specific symptoms of hydrocephalus in relation to age. Especially in chronic hydrocephalus, this is of utmost importance to avoid misdiagnosis. DIAGNOSTIC WORK-UP: The radiological method of choice depends on the age and the specific issue to be addressed. ACHIEVEMENTS: The typical clinical symptoms of different hydrocephalus entities presented here must be considered as confirmed knowledge. PRACTICAL RECOMMENDATIONS: Only the synopsis of clinical and radiological findings currently allows correct interpretation of imaging. There is a threat of misdiagnosis if interpretation is restricted purely to radiological findings as the sole predictive value of modern imaging is still too limited despite all innovations. PMID- 22940686 TI - Factors that influence beverage choices at meal times. An application of the food choice kaleidoscope framework. AB - Beverages are consumed at almost every meal occasion, but knowledge about the factors that influence beverage choice is less than for food choice. The aim of this research was to characterize and quantify factors that influence beverage choices at meal times. Insights into what beverages are chosen by whom, when and where can be helpful for manufacturers, dieticians/health care providers, and health policy makers. A descriptive framework - the food choice kaleidoscope (Jaeger et al., 2011) - was applied to self-reported 24h food recall data from a sample of New Zealand consumers. Participants (n=164) described 8356 meal occasions in terms of foods and beverages consumed, and the contextual characteristics of the occasion. Beverage choice was explored with random parameter logit regressions to reveal influences linked to food items eaten, context factors and person factors. Thereby this study contributed to the food choice kaleidoscope research approach by expressing the degree of context dependency in the form of odds ratios and according significance levels. The exploration of co-occurrence of beverages with food items suggests that beverage meal item combinations can be meal specific. Furthermore, this study integrates psychographic variables into the 'person' mirror of the food choice kaleidoscope. A measure of habit in beverage choice was obtained from the inter-participant correlation. PMID- 22940687 TI - Toddlers' food preferences. The impact of novel food exposure, maternal preferences and food neophobia. AB - Food preferences have been identified as a key determinant of children's food acceptance and consumption. The aim of this study was to identify factors that influence children's liking for fruits, vegetables and non-core foods. Participants were Australian mothers (median age at delivery=31years, 18-46years) and their two-year-old children (M=24months, SD=1month; 52% female) allocated to the control group (N=245) of the NOURISH RCT. The effects of repeated exposure to new foods, maternal food preferences and child food neophobia on toddlers' liking of vegetables, fruits and non-core foods and the proportion never tried were examined via hierarchical regression models; adjusting for key maternal (age, BMI, education) and child covariates (birth weight Z-score, gender), duration of breastfeeding and age of introduction to solids. Maternal preferences corresponded with child preferences. Food neophobia among toddlers was associated with liking fewer vegetables and fruits, and trying fewer vegetables. Number of repeated exposures to new food was not significantly associated with food liking at this age. Results highlight the need to: (i) encourage parents to offer a wide range of foods, regardless of their own food preferences, and (ii) provide parents with guidance on managing food neophobia. PMID- 22940688 TI - Perception of oyster-based products by French consumers. The effect of processing and role of social representations. AB - The search for new markets in the seafood sector, associated with the question of the continuity of raw oyster consumption over generations can be an opportunity for processors to extend their ranges with oyster-based products. The twofold aim of this study was to evaluate the impact of processing and social representation on perception of oyster-based products by French consumers and to identify the best means of development in order to avoid possible failure in the market. Five products with different degrees of processing (cooked oysters in a half-shell, hot preparation for toast, potted oyster, oyster butter and oyster-based soup) were presented within focus groups and consumer tests, at home and in canteens with the staff of several companies in order to reach consumers with different ages and professional activities. The results showed that social representation had a strong impact and that behaviours were contrasted according to the initial profile of the consumer (traditional raw oyster consumers or non-consumers) and their age distribution (younger and older people). The degree of processing has to be adapted to each segment. It is suggested to develop early exposure to influence the food choices and preferences of the youngest consumers on a long term basis. PMID- 22940689 TI - Cargo carriers from the Golgi to the cell surface. AB - In this issue, Malhotra and colleagues use biochemical approaches to identify a new class of secretory cargo carriers (CARTS) that do not contain the larger cargoes, collagen or Vesicular stomatitis virus (VSV)-G glycoprotein. CARTS appear to be basolateral membrane-directed carriers that use myosin for their motility but not for their formation. PMID- 22940690 TI - The hSSB1 orthologue Obfc2b is essential for skeletogenesis but dispensable for the DNA damage response in vivo. AB - Human single-stranded DNA-binding protein 1 (hSSB1), encoded by OBFC2B, was recently characterized as an essential factor for the initiation of DNA damage checkpoints and the maintenance of genomic stability. Here, we report that loss of Obfc2b in mice results in perinatal lethality characterized by growth delay and skeletal abnormalities. These abnormalities are associated with accumulation of gammaH2ax, apoptosis and defective pre-cartilage condensation, which is essential for normal bone formation. However, deficiency of Obfc2b does not affect the initiation of DNA damage checkpoints, Atm activation, or the maintenance of genomic stability in B lymphocytes and primary fibroblasts. Loss of Obfc2b results in increased expression of its homologue Obfc2a (hSSB2). In contrast to Obfc2b deficiency, depletion of Obfc2a in fibroblasts results in impaired proliferation, accumulation of gammaH2ax and increased genomic instability. Thus, the hSSB1 orthologue Obfc2b has a unique function during embryogenesis limited to cell types that contribute to bone formation. While being dispensable in most other cell lineages, its absence leads to a compensatory increase in Obfc2a protein, a homologue required for the maintenance of genomic integrity. PMID- 22940693 TI - Effects of the putative antipsychotic alstonine on glutamate uptake in acute hippocampal slices. AB - A dysfunctional glutamatergic system is thought to be central to the negative symptoms and cognitive deficits recognized as determinant to the poor quality of life of people with schizophrenia. Modulating glutamate uptake has, thus, been suggested as a novel target for antipsychotics. Alstonine is an indole alkaloid sharing with atypical antipsychotics the profile in animal models relevant to schizophrenia, though divergent in its mechanism of action. The aim of this study was to evaluate the effects of alstonine on glutamate uptake. Additionally, the effects on glutathione content and extracellular S100B levels were assessed. Acute hippocampal slices were incubated with haloperidol (10MUM), clozapine (10 and 100MUM) or alstonine (1-100MUM), alone or in combination with apomorphine (100MUM), and 5-HT(2) receptor antagonists (0.01MUM altanserin and 0.1MUM SB 242084). A reduction in glutamate uptake was observed with alstonine and clozapine, but not haloperidol. Apomorphine abolished the effect of clozapine, whereas 5-HT(2A) and 5-HT(2C) antagonists abolished the effects of alstonine. Increased levels of glutathione were observed only with alstonine, also the only compound that failed to decrease the release of S100B. This study shows that alstonine decreases glutamate uptake, which may be beneficial to the glutamatergic deficit observed in schizophrenia. Noteworthily, the decrease in glutamate uptake is compatible with the reversal of MK-801-induced social interaction and working memory deficits. An additional potential benefit of alstonine as an antipsychotic is its ability to increase glutathione, a key cellular antioxidant reported to be decreased in the brain of patients with schizophrenia. Adding to the characterization of the novel mechanism of action of alstonine, the lack of effect of apomorphine in alstonine-induced changes in glutamate uptake reinforces that D(2) receptors are not primarily implicated. Though clearly mediated by 5-HT(2A) and 5-HT(2C) serotonin receptors, the precise mechanisms that result in the effects of alstonine on glutamate uptake warrant elucidation. PMID- 22940691 TI - Endoglin mediates fibronectin/alpha5beta1 integrin and TGF-beta pathway crosstalk in endothelial cells. AB - Both the transforming growth factor beta (TGF-beta) and integrin signalling pathways have well-established roles in angiogenesis. However, how these pathways integrate to regulate angiogenesis is unknown. Here, we show that the extracellular matrix component, fibronectin, and its cellular receptor, alpha5beta1 integrin, specifically increase TGF-beta1- and BMP-9-induced Smad1/5/8 phosphorylation via the TGF-beta superfamily receptors endoglin and activin-like kinase-1 (ALK1). Fibronectin and alpha5beta1 integrin increase Smad1/5/8 signalling by promoting endoglin/ALK1 cell surface complex formation. In a reciprocal manner, TGF-beta1 activates alpha5beta1 integrin and downstream signalling to focal adhesion kinase (FAK) in an endoglin-dependent manner. alpha5beta1 integrin and endoglin form a complex on the cell surface and co internalize, with their internalization regulating alpha5beta1 integrin activation and signalling. Functionally, endoglin-mediated fibronectin/alpha5beta1 integrin and TGF-beta pathway crosstalk alter the responses of endothelial cells to TGF-beta1, switching TGF-beta1 from a promoter to a suppressor of migration, inhibiting TGF-beta1-mediated apoptosis to promote capillary stability, and partially mediating developmental angiogenesis in vivo. These studies provide a novel mechanism for the regulation of TGF-beta superfamily signalling and endothelial function through crosstalk with integrin signalling pathways. PMID- 22940694 TI - Cholesterol as a key player in the balance of evoked and spontaneous glutamate release in rat brain cortical synaptosomes. AB - Membrane rafts are domains enriched in sphingolipids, glycolipids and cholesterol that are able to compartmentalize cellular processes. Noteworthy, many proteins have been assigned to membrane rafts including those related to the control of the synaptic vesicle release machinery, which is a important step for neurotransmission between synapses. In this work, we have investigated the role of cholesterol in key steps of glutamate release in isolated nerve terminals (synaptosomes) from rat brain cortices. Incubation of synaptosomes with methyl beta-cyclodextrin (MbetaCD) induced glutamate release in a dose-dependent fashion. HgammaCD, a cyclodextrin with low affinity for cholesterol, had no significant effect on spontaneous glutamate release. When we evaluated the effects of MbetaCD on glutamate release induced by depolarizing stimuli, we observed that MbetaCD treatment inhibited the KCl-evoked glutamate release. The glutamate release induced by MbetaCD was not altered by treatment with EGTA nor with EGTA-AM. The KCl-evoked glutamate release was no further inhibited when synaptosomes were incubated with MbetaCD in the absence of calcium. We therefore investigated whether the cholesterol removal by MbetaCD changes intrasynaptosomal sodium and calcium levels. Our results suggested that the cholesterol removal effect on spontaneous and evoked glutamate release might be upstream to sodium and calcium entry through voltage-activated channels. We therefore tested if MbetaCD would have a direct effect on synaptic vesicle exocytosis and we showed that cholesterol removal by MbetaCD induced spontaneous exocytosis and inhibited synaptic vesicle exocytosis evoked by depolarizing stimuli. Lastly, we investigated the effect of protein kinase inhibitors on the spontaneous exocytosis evoked by MbetaCD and we observed a statistically significant reduction of synaptic vesicles exocytosis. In conclusion, our work shows that cholesterol removal facilitates protein kinase activation that favors spontaneous synaptic vesicles and consequently glutamate release in isolated nerve terminals. PMID- 22940692 TI - Anchored phosphatases modulate glucose homeostasis. AB - Endocrine release of insulin principally controls glucose homeostasis. Nutrient induced exocytosis of insulin granules from pancreatic beta-cells involves ion channels and mobilization of Ca(2+) and cyclic AMP (cAMP) signalling pathways. Whole-animal physiology, islet studies and live-beta-cell imaging approaches reveal that ablation of the kinase/phosphatase anchoring protein AKAP150 impairs insulin secretion in mice. Loss of AKAP150 impacts L-type Ca(2+) currents, and attenuates cytoplasmic accumulation of Ca(2+) and cAMP in beta-cells. Yet surprisingly AKAP150 null animals display improved glucose handling and heightened insulin sensitivity in skeletal muscle. More refined analyses of AKAP150 knock-in mice unable to anchor protein kinase A or protein phosphatase 2B uncover an unexpected observation that tethering of phosphatases to a seven residue sequence of the anchoring protein is the predominant molecular event underlying these metabolic phenotypes. Thus anchored signalling events that facilitate insulin secretion and glucose homeostasis may be set by AKAP150 associated phosphatase activity. PMID- 22940695 TI - Effect of chronic l-DOPA treatment on 5-HT(1A) receptors in parkinsonian monkey brain. AB - After chronic use of l-3,4-dihydroxyphenylalanine (l-DOPA), most Parkinson's disease (PD) patients suffer from its side effects, especially motor complications called l-DOPA-induced dyskinesia (LID). 5-HT(1A) agonists were tested to treat LID but many were reported to worsen parkinsonism. In this study, we evaluated changes in concentration of serotonin and its metabolite 5 hydroxyindoleacetic acid (5-HIAA) and of 5-HT(1A) receptors in control monkeys, 1 methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) monkeys, dyskinetic MPTP monkeys treated chronically with l-DOPA, low dyskinetic MPTP monkeys treated with l-DOPA and drugs of various pharmacological activities: Ro 61-8048 (an inhibitor of kynurenine hydroxylase) or docosahexaenoic acid (DHA) and dyskinetic MPTP monkeys treated with l-DOPA+naltrexone (an opioid receptor antagonist). Striatal serotonin concentrations were reduced in MPTP monkeys compared to controls. Higher striatal 5-HIAA/serotonin concentration ratios in l-DOPA-treated monkeys compared to untreated monkeys suggest an intense activity of serotonin axon terminals but this value was similar in dyskinetic and nondyskinetic animals treated with or without adjunct treatment with l-DOPA. As measured by autoradiography with [(3)H]8-hydroxy-2-(di-n-propyl) aminotetralin (8-OH-DPAT), a decrease of 5-HT(1A) receptor specific binding was observed in the posterior/dorsal region of the anterior cingulate gyrus and posterior/ventral area of the superior frontal gyrus of MPTP monkeys compared to controls. An increase of 5-HT(1A) receptor specific binding was observed in the hippocampus of MPTP monkeys treated with l-DOPA regardless to their adjunct treatment. Cortical 5-HT(1A) receptor specific binding was increased in the l-DOPA-treated MPTP monkeys alone or with DHA or naltrexone and this increase was prevented in low dyskinetic MPTP monkeys treated with l-DOPA and Ro 61-8048. These results highlight the importance of 5-HT(1A) receptor alterations in treatment of PD with l-DOPA. PMID- 22940696 TI - Lentigines in previous psoriatic plaques in a patient treated with infliximab. PMID- 22940697 TI - Complete anal sphincter complex disruption from intercourse: A case report and literature review. AB - INTRODUCTION: Anal sphincter injuries are uncommon injuries outside of obstetric practice - but they may cause disastrous complications. PRESENTATION OF CASE: We present a case of complete anal sphincter disruption from anal intercourse in a 25 year old woman. Clinical management is presented and technical details of the repair are discussed. She had an uneventful post-operative course and good continence after 154 days of follow up. DISCUSSION: This is one of a handful of reported cases of anal sphincter disruption secondary to anal intercourse. The established risk factors in this case included receptive anal intercourse coupled with alcohol use. We review the pertinent surgical principles that should be observed when repairing these injuries, including anatomically correct repair and appropriate suture choice. There is little evidence to support simultaneous faecal diversion for primary repair of acute perineal lacerations. CONCLUSION: Acute post-coital sphincter injuries should be treated operatively on an emergent basis, without diversion because they are low energy injuries with minimal tissue loss and excellent blood supply. Although repair of each injury should be individualized, the majority of these injuries do not require concomitant protective colostomy creation. PMID- 22940698 TI - Leiomyoma of kidney: An Indian experience with literature review. AB - INTRODUCTION: Leiomyoma of kidney is an exceptional finding in the urinary tract. Though most of these tumors are detected on autopsy, still it remains a diagnostic challenge. PRESENTATION OF CASE: We report three adult cases of renal leiomyoma in our institute who presented with abdominal mass and haematuria in last 8 years. DISCUSSION: Leiomyoma has been reported in other organs but renal leiomyoma is rare tumour, though in autopsy series they are second in order of frequency among the renal mesenchymal neoplasms, and few cases have been described in the literature. Still no Indian experience is evaluated on this rare site of occurrence. CONCLUSION: Considering the difficulty of clinical diagnosis of this tumour, strong suspicion is indicated when a patient presents with voluminous, well circumscribed renal lesions. PMID- 22940699 TI - Squamous cell carcinoma in an esophageal diverticulum below the aortic arch. AB - INTRODUCTION: Esophageal diverticula frequently arise from pharyngoesophageal transition area, tracheal bifurcation and epiphrenic region. Carcinoma arising from esophageal diverticulum is rarely seen. We report a patient with a squamous cell carcinoma arising within an esophageal diverticulum below the aortic arch. PRESENTATION OF CASE: A 70-year-old man was diagnosed to have a squamous cell carcinoma of the vocal cord with enlarged lymph nodes in the neck, as well as a squamous cell carcinoma arising within an esophageal diverticulum below the aortic arch. There have been no reported cases of esophageal cancer arising from a diverticulum below the aortic arch. Preoperative radiotherapy for the esophageal cancer and pharyngeal cancer was given, followed by surgery. The excised specimen of the esophageal diverticulum and its external appearance revealed that it lacked muscle fibers, with a type 0-IIa lesion arising from the diverticulum. Microscopic examination showed three lymph nodes at the superior mediastinum were positive for malignancy. Bilateral pleural dissemination was detected 7 months after esophagectomy. DISCUSSION: Cancer arising from an esophageal diverticulum is mainly found at an advanced stage because of delayed diagnosis. The absence of muscularis propia may lead to early invasion. Thus, cancers within an esophageal diverticulum are considered to be at a more advanced stage than similar cancers arising elsewhere. CONCLUSION: For detecting of cancer arising from an esophageal diverticulum, a high index of awareness is important. Delay in diagnosis makes surgical management difficult. PMID- 22940700 TI - Reactive halogen chemistry in the troposphere. AB - Halogen chemistry is well known for ozone destruction in the stratosphere, however reactive halogens also play an important role in the chemistry of the troposphere. In the last two decades, an increasing number of reactive halogen species have been detected in a wide range of environmental conditions from the polar to the tropical troposphere. Growing observational evidence suggests a regional to global relevance of reactive halogens for the oxidising capacity of the troposphere. This critical review summarises our current understanding and uncertainties of the main halogen photochemistry processes, including the current knowledge of the atmospheric impact of halogen chemistry as well as open questions and future research needs. PMID- 22940701 TI - ADAM10 overexpression in human non-small cell lung cancer correlates with cell migration and invasion through the activation of the Notch1 signaling pathway. AB - A disintegrin and metalloproteinase 10 (ADAM10) was identified as a key protease in the ectodomain shedding of various substrates, such as Notch1 protein, ErbB2 and E-cadherin, which are important in the development of non-small cell lung cancer (NSCLC). The aim of this study was to investi-gate the role of ADAM10 in NSCLC metastasis.We characterized the expression of ADAM10 and Notch1 in human NSCLC tissues in vivo. Immunohistochemical analysis indicated that ADAM10 expression was significantly increased in the NSCLC tissues, particularly in the metastatic tissues. Futhermore, ADAM10 overexpression positively correlated with Notch1 expression in the NSCLC tissues. The in vitro downregulation of ADAM10 expression using ADAM10 short hairpin RNA (shRNA) reduced the migration and invasion of NSCLC cells. We present further evidence that ADAM10 promotes NSCLC cell migration and invasion via the activation of the Notch1 signaling pathway. Taken together, our results suggest that ADAM10 may serve as a potential target for the therapeutic intervention of NSCLC metastasis. The data provided in this study may aid in the further understanding of the function of ADAM10 in the progression of NSCLC and open new perspectives for the diagnosis and treatment of NSCLC. PMID- 22940702 TI - miR-203 inhibits the migration and invasion of esophageal squamous cell carcinoma by regulating LASP1. AB - The expression of microRNA-203 (miR-203) in esophageal squamous cell carcinoma (ESCC) tissues is remarkably lower than that in non-ESCC tissues. We investigated how miR-203 could influence the development of ESCC cells. Our analyses revealed that miR-203 inhibited the migration and invasion of ESCC cells. Genome-wide gene expression data and target site inhibition assays showed that miR-203 appears to directly regulate LIM and SH3 protein 1 (LASP1). The knockdown of LASP1 resulted in inhibition of the migration and invasion of ESCC cells. Our results suggest that miR-203 and its target LASP1, may be associated with the progression of ESCC. In clinical ESCC specimens, the expression levels of miR-203, which were lower compared to those in normal tissues, were inversely correlated with the mRNA expression levels of LASP1. Moreover, we found that there was a significant correlation between the expression levels of miR-203 and the relapse-free survival. The identification of a cancer network regulated by miR-203 could provide new insights into the potential mechanisms of the progression of ESCC. PMID- 22940703 TI - Sea urchin tooth mineralization: calcite present early in the aboral plumula. AB - In both vertebrate bone, containing carbonated hydroxyapatite as the mineral phase, and in invertebrate hard tissue comprised of calcium carbonate, a popular view is that the mineral phase develops from a long-lived amorphous precursor which later transforms into crystal form. Important questions linked to this popular view are: when and where is the crystallized material formed, and is amorphous solid added subsequently to the crystalline substrate? Sea urchin teeth, in which the earliest mineral forms within isolated compartments, in a time and position dependent manner, allow direct investigation of the timing of crystallization of the calcite primary plates. Living teeth of the sea urchin Lytechinus variegatus, in their native coelomic fluid, were examined by high energy synchrotron X-ray diffraction. The diffraction data show that calcite is present in the most aboral portions of the plumula, representing the very earliest stages of mineralization, and that this calcite has the same crystal orientation as in the more mature adoral portions of the same tooth. Raman spectroscopy of the aboral plumula confirms the initial primary plate mineral material is calcite and does not detect amorphous calcium carbonate; in the more mature adoral incisal flange, it does detect a broader calcite peak, consistent with two or more magnesium compositions. We hypothesize that some portion of each syncytial membrane in the plumula provides the information for nucleation of identically oriented calcite crystals that subsequently develop to form the complex geometry of the single crystal sea urchin tooth. PMID- 22940704 TI - Structure-activity relationship and antitumor activity of thio-benzodiazepines as p53-MDM2 protein-protein interaction inhibitors. AB - In order to discuss the structure-activity relationship (SAR) of the thio benzodiazepine compounds which showed excellent activity against p53-MDM2 protein protein interaction, we designed and synthesized twenty compounds with electrophilic and nucleophilic groups on the benzene ring. Among them, compounds 8i (K(i) = 91 nM) and 8n (K(i) = 89 nM) showed better binding activity than that of the reference drug Nutlin-3a (K(i) = 121 nM). In addition, in vitro antitumor activity against Saos-2, U-2 OS, A549 and NCI-H1299 cell-lines were assayed by the MTT method. Especially, compounds 8i and 8n possessed excellent biological activity and good selectivity comparable to Nutlin-3a, which were promising candidates for further evaluation. PMID- 22940705 TI - COX inhibitors Indomethacin and Sulindac derivatives as antiproliferative agents: synthesis, biological evaluation, and mechanism investigation. AB - Cyclooxygenase (COX) inhibitors Indomethacin and its structural analogs Sulindac exhibit cell growth inhibition and apoptosis inducing activities in various cancer cell lines via COX independent mechanisms. In this study, the molecular structures of Indomethacin and Sulindac were used as starting scaffolds to design novel analogs and their effects on the proliferation of human cancer cells were evaluated. Compared to Indomethacin and Sulindac inhibiting cancer cell proliferation with IC(50)s of more than 1 mM, the derivatives displayed significantly increased activities. Especially, one of the Indomethacin analogs inhibited the growth of a series of cancer cell lines with IC(50)s around 0.5 MUM 3 MUM. Mechanistic investigation revealed that the new analog was in fact a tubulin inhibitor, although the parental compound Indomethacin did not show any tubulin inhibitory activity. Tubulin polymerization assay indicated this compound inhibited tubulin assembly at high concentrations, but promoted this process at low concentrations which is a very unique mechanism. The binding mode of this compound in tubulin was predicted using the molecular docking simulation. PMID- 22940706 TI - Synthesis and biological evaluation of novel isoellipticine derivatives and salts. AB - Synthesis of novel 7-substituted isoellipticines and isoellipticinium salts is described, with optimisation of routes, representing a new class of anti-cancer agent. Initial assessment of biological activity using a topoisomerase II decatenation assay and NCI screening highlighted strong anti-cancer activity, further developed in a panel of isoellipticinium salts. Interestingly, low correlation between results of the topoisomerase II decatenation assay and NCI screen throughout the panel suggest that topo II is not the most important biological target with respect to anti-cancer activity in this new class of compounds. Results also suggest that solubility is not the limiting factor in activity of the isoellipticinium salts. Overall, 20 novel ellipticine analogues were prepared and full anti-cancer profiling was completed for 13 isoellipticine derivatives and salts. Two compounds display significant specificity towards CNS cancer cell lines and are lead compounds for future development. PMID- 22940707 TI - A new physical model based on cascading column experiments to reproduce the radial flow and transport of micro-iron particles. AB - In the field of aquifer restoration and civil engineering, fluids and suspensions are delivered in porous media via well injection. The flow field resulting around the well is three-dimensional. Since two and three-dimensional experiments which can be used to reproduce such flow fields are, although accurate, extremely elaborate and time consuming, the authors suggest to substitute them by a cascade of interdependent, one-dimensional (column) experiments. The new method is used to simulate the injection in aquifers of micro-iron particles dispersed in a shear thinning gel of guar gum and allows the prediction of iron particle distribution around the well and of injection pressure. The method respects the mass balance at the field scale and its predictions are in good agreement with those of a mathematical model proposed in the literature. The method is consistent with the Triad Approach, a way to improve remediation efficiency proposed by the U.S. Environmental Protection Agency. The representativeness of the proposed tests combined with their simplicity and relative inexpensiveness make this new method applicable and useful in the planning and design of real remediation. PMID- 22940708 TI - Bone marrow lesions are associated with altered trabecular morphometry. AB - OBJECTIVE: Bone marrow lesions (BMLs) are a common magnetic resonance (MR) feature in patients with osteoarthritis, however their pathological basis remains poorly understood and has not been evaluated in vivo. Our aim was to evaluate the trabecular structure associated with the presence and size of BMLs present in the same regions of interest (ROI) using quantitative MR-based trabecular morphometry. DESIGN: 158 participants in the Osteoarthritis Initiative (OAI) were imaged with a coronal 3D fast imaging with steady state precession (FISP) sequence for trabecular morphometry in the same session as the OAI 3 T MR knee evaluation. The proximal medial tibial subchondral bone in the central weight bearing ROI on these knee 3D FISP images were quantitatively evaluated for apparent bone volume fraction, trabecular number, spacing, and thickness. BMLs were also evaluated in the subchondral bone immediately adjacent to the articular cartilage. BML volume was also evaluated within the same trabecular morphometry ROI and semi-quantitatively classified as none, small, or large. Kruskal-Wallis test was used to determine if mean apparent bone volume fraction, trabecular number, spacing, or thickness differed by BML score. RESULTS: Compared to knees with ROIs containing no BMLs, knees with small or large BMLs had statistically higher apparent bone volume fraction (P < 0.01), trabecular number (P < 0.01), and thickness (P = 0.02), and lower trabecular spacing (P < 0.01). CONCLUSIONS: Compared to knees with ROIs containing no BMLs, knees with ROIs containing small or large BMLs had higher apparent bone volume fraction, trabecular number and thickness, but lower trabecular spacing. These findings may represent areas of locally increased bone remodeling or compression. PMID- 22940709 TI - Sleep quality and associated factors in ankylosing spondylitis: relationship with disease parameters, psychological status and quality of life. AB - The aim of this study is to investigate sleep quality in patients with ankylosing spondylitis (AS) and to evaluate the relationship of the disease parameters with sleep disturbance. Eighty AS patients (60 males and 20 females) fulfilling the modified New York criteria, and 52 age- and gender-matched controls (33 males and 19 females) were enrolled in the study. Sleep quality was assessed using the Pittsburgh Sleep Quality Index (PSQI). Pain was measured by visual analogue scale. The disease activity and functional status were assessed by the Bath AS disease Activity Index and the Bath AS Functional Index. The Bath AS Metrology Index was used to evaluate mobility restrictions, and the Bath AS Radiology Index was employed to evaluate the radiological damage. The psychological status and quality of life were assessed with the hospital anxiety-depression scale and AS quality of life scale. The patients with AS had significantly more unfavourable scores in the subjective sleep quality, habitual sleep efficiency domains (p < 0.001) and the total PSQI score (p < 0.05). Poor sleep quality (total PSQI score) was positively correlated with increased pain, poor quality of life, higher depressed mood, higher disease activity and mobility restrictions. Pain was also an independent contributor to poorer sleep quality (p = 0.002). The sleep quality is disturbed in patients with AS. The lower quality of sleep is greatly associated with the pain, disease activity, depression, quality of life and increased limitation of mobility. PMID- 22940710 TI - Ultrasonography in developmental dysplasia of the hip: what have we learned? AB - Developmental dysplasia of the hip (DDH) is an important but poorly defined entity, the natural history of which is incompletely understood. The term encompasses a disease spectrum ranging from a stable hip with a mildly dysplastic acetabulum to complete hip dislocation. Much controversy surrounds the diagnosis, imaging and management of this condition. We present a review of the history of US imaging of DDH from the radiologist's perspective, summarising the most widely recognised US methods described to date. We discuss controversies in the approach to US examination, with particular emphasis on current opinions. The existing scientific evidence for and variations in the practice of US screening for DDH, including recommendations from the United States Preventive Services Task Force and the ESPR DDH Taskforce Group respectively, are discussed. PMID- 22940712 TI - Stress fracture of the femoral neck in a child: a case report. AB - A 7-year-old boy developed complaints of pain in the left groin. These complaints started spontaneously. Initial plain radiographs of the pelvis indicated no abnormalities. As the symptoms persisted for 6 weeks, the young patient and his parents visited our institution. Clinical investigation showed a slight extension deficit of the left hip. New radiographs and MRI indicated a fracture line with sclerosis along the inferior border of the left femoral neck. In retrospect, this stress fracture of the femoral neck was also visible on the initial radiographs. Seven months after the onset of complaints in the left groin and prescribed partial weight bearing with crutches, callus formation with consolidation of the femoral neck was observed on radiographs. Eleven months after onset, the patient recovered fully without any residual symptoms. After 21 months, the young patient did not have any complaints or restrictions in physical activity. Because of its highly rare nature, stress fractures of the femoral neck in children are easy to miss initially. This was also applicable in our case. Extensive differential diagnosis of a child with pain in the groin furthermore adds to the difficulty in the diagnosis of a stress fracture of the femoral neck. This case report emphasizes the importance of the evaluation of radiographs and observation in children with hip complaints. Similarly, interdisciplinary consultation and cooperation between the general practitioner, orthopaedic surgeon, radiologist and paediatrician is essential in the diagnosis, evaluation and treatment of these young patients. PMID- 22940711 TI - Ultrasound-guided corticosteroid injection therapy for juvenile idiopathic arthritis: 12-year care experience. AB - BACKGROUND: Intra-articular corticosteroid injections are a safe and effective treatment for patients with juvenile idiopathic arthritis. The potential scope of care in ultrasound-guided corticosteroid therapy in children and a joint-based corticosteroid dose protocol designed to optimize interdisciplinary care are not found in the current literature. OBJECTIVE: The purpose of this study was to report the spectrum of care, technique and safety of ultrasound-guided corticosteroid injection therapy in patients with juvenile idiopathic arthritis and to propose an age-weight-joint-based corticosteroid dose protocol. MATERIALS AND METHODS: A retrospective analysis was performed of 198 patients (ages 21 months to 28 years) referred for treatment of juvenile idiopathic arthritis with corticosteroid therapy. Symptomatic joints and tendon sheaths were treated as prescribed by the referring rheumatologist. An age-weight-joint-based dose protocol was developed and utilized for corticosteroid dose prescription. RESULTS: A total of 1,444 corticosteroid injections (1,340 joints, 104 tendon sheaths) were performed under US guidance. Injection sites included small, medium and large appendicular skeletal joints (upper extremity 497, lower extremity 837) and six temporomandibular joints. For patients with recurrent symptoms, 414 repeat injections were performed, with an average time interval of 17.7 months (range, 0.5-101.5 months) between injections. Complications occurred in 2.6% of injections and included subcutaneous tissue atrophy, skin hypopigmentation, erythema and pruritis. CONCLUSION: US-guided corticosteroid injection therapy provides dynamic, precise and safe treatment of a broad spectrum of joints and tendon sheaths throughout the entire pediatric musculoskeletal system. An age weight-joint-based corticosteroid dose protocol is effective and integral to interdisciplinary care of patients with juvenile idiopathic arthritis. PMID- 22940713 TI - Effectiveness of adjuvanted influenza vaccination in elderly subjects in northern Italy. AB - Although vaccination against influenza is recommended for elderly and high-risk patients in many countries, efficacy in the elderly has been suboptimal. The MF59 adjuvanted trivalent inactivated vaccine (ATIV) was developed to increase the immune response of elderly subjects to influenza vaccination, but its effectiveness has not yet been well documented. This prospective, observational study evaluated the relative effectiveness of ATIV versus nonadjuvanted trivalent inactivated vaccine (TIV) in individuals at least 65 years of age in Lombardy, northern Italy. Hospitalizations for influenza or pneumonia (International Classification of Diseases, Ninth Revision, Clinical Modification, codes 480-487) during the 2006-2007, 2007-2008, and 2008-2009 influenza seasons were identified from administrative databases. Stratified and regression analyses, including the propensity score to adjust for confounding, as well as generalized estimating equations to account for repeated vaccination, were used. Overall, 107,661 records were evaluated, contributing 170,988 person-seasons of observation. Since ATIV is preferentially recommended for more frail individuals, subjects vaccinated with ATIV were older and had more functional impairment and comorbidities. In the primary analysis, risk of hospitalization for influenza or pneumonia was 25% lower for ATIV relative to TIV (relative risk = 0.75, 95% confidence interval: 0.57, 0.98). To the extent that there is residual bias, ATIV is likely to be even more protective than this result suggests. PMID- 22940714 TI - The novel resveratrol analogue HS-1793 induces apoptosis via the mitochondrial pathway in murine breast cancer cells. AB - Resveratrol (3,4',5 tri-hydroxystilbene), a natural plant polyphenol, has gained interest as a non-toxic chemopreventive agent capable of inducing tumor cell death in a variety of cancer types. Several studies were undertaken to obtain synthetic analogues of resveratrol with potent anticancer activity. The aim of the present study was to investigate the effect of HS-1793 as a new resveratrol analog on apoptosis via the mitochondrial pathway in murine breast cancer cells. A pharmacological dose (1.3-20 uM) of HS-1793 exerted a cytotoxic effect on murine breast cancer cells resulting in apoptosis. HS-1793-mediated cytotoxicity in FM3A cells by several apoptotic events including mitochondrial cytochrome c release, activation of caspase-3 and PARP occurred. In addition, HS-1793 induced collapse of ?Psim and enhanced AIF and Endo G release from mitochondria while undergoing apoptosis. These results demonstrate that the cytotoxicity by HS-1793 in FM3A cells can mainly be attributed to apoptosis via a mitochondrial pathway by caspase activation or contributions of AIF and Endo G. PMID- 22940716 TI - Association between fully automated MRI-based volumetry of different brain regions and neuropsychological test performance in patients with amnestic mild cognitive impairment and Alzheimer's disease. AB - Fully automated magnetic resonance imaging (MRI)-based volumetry may serve as biomarker for the diagnosis in patients with mild cognitive impairment (MCI) or dementia. We aimed at investigating the relation between fully automated MRI based volumetric measures and neuropsychological test performance in amnestic MCI and patients with mild dementia due to Alzheimer's disease (AD) in a cross sectional and longitudinal study. In order to assess a possible prognostic value of fully automated MRI-based volumetry for future cognitive performance, the rate of change of neuropsychological test performance over time was also tested for its correlation with fully automated MRI-based volumetry at baseline. In 50 subjects, 18 with amnestic MCI, 21 with mild AD, and 11 controls, neuropsychological testing and T1-weighted MRI were performed at baseline and at a mean follow-up interval of 2.1 +/- 0.5 years (n = 19). Fully automated MRI volumetry of the grey matter volume (GMV) was performed using a combined stereotactic normalisation and segmentation approach as provided by SPM8 and a set of pre-defined binary lobe masks. Left and right hippocampus masks were derived from probabilistic cytoarchitectonic maps. Volumes of the inner and outer liquor space were also determined automatically from the MRI. Pearson's test was used for the correlation analyses. Left hippocampal GMV was significantly correlated with performance in memory tasks, and left temporal GMV was related to performance in language tasks. Bilateral frontal, parietal and occipital GMVs were correlated to performance in neuropsychological tests comprising multiple domains. Rate of GMV change in the left hippocampus was correlated with decline of performance in the Boston Naming Test (BNT), Mini-Mental Status Examination, and trail making test B (TMT-B). The decrease of BNT and TMT-A performance over time correlated with the loss of grey matter in multiple brain regions. We conclude that fully automated MRI-based volumetry allows detection of regional grey matter volume loss that correlates with neuropsychological performance in patients with amnestic MCI or mild AD. Because of the high level of automation, MRI-based volumetry may easily be integrated into clinical routine to complement the current diagnostic procedure. PMID- 22940715 TI - Loss of neutral ceramidase increases inflammation in a mouse model of inflammatory bowel disease. AB - Sphingolipids are emerging as important mediators of immune and inflammatory responses. We have previously demonstrated that sphingosine-1-phosphate (S1P) and its synthetic enzyme sphingosine kinase-1 (SK1) play an important role in inflammatory bowel disease. S1P generation is dependent on SK phosphorylation of sphingosine. Generation of sphingosine results only from the breakdown of ceramide by ceramidases (CDase). In this study, we set out to determine the role of neutral CDase (nCDase) in S1P generation and inflammatory bowel disease. To this end, we established nCDase expression is increased in patients with ulcerative colitis. Using the dextran sulfate sodium (DSS)-induced colitis model, we determined nCDase activity increased in colon epithelium, but not submucosa, in wild-type (WT) mice. Following DSS, ceramide levels were elevated in colon epithelium from WT and nCDase(-/-) mice, while S1P levels were significantly elevated only in the epithelium of nCDase(-/-) mice. Similarly, cyclooxygenase-2 (Cox-2) levels were significantly elevated only in the epithelium of nCDase(-/-) mice. Neutral CDase(-/-) mice also exhibited higher endotoxin levels in circulation, as well as higher circulating levels of S1P. This increase in S1P in nCDase(-/-) mice was accompanied by a marked leukocytosis, most notably circulating neutrophils and lymphocytes. Taken together these data demonstrate that loss of nCDase results in an unexpected increase in S1P generation in inflammation, and suggests that nCDase may actually protect against inflammation. PMID- 22940717 TI - [The collections of the museum and archives of the German Society of Urology. Reflections on objects in the museum]. AB - Objects in a museum that were used by urologists are part of the history of urology. If we know how to look at them they can be sources for a better understanding of the history of urology. In a museum visitors are confronted with objects during exhibitions which are the stage on which one possible interpretation of the history of urology is displayed. Objects have become"carriers of symbols" between the past and present (Pomian). Collections from medical societies which are not connected with a university or another public institution cannot be legitimized on the basis of the argument of conserving historical heritage only. The museum itself with its many tasks and as a classical site of scientific communication should be seen as a topic of scientific interest. PMID- 22940718 TI - [Surgical treatment of male lower urinary tract symptoms (LUTS)]. AB - Surgical treatment of lower urinary tract symptoms (LUTS) due to benign prostatic obstruction (BPO) comprises a variety of treatment modalities. Transurethral resection of the prostate (TURP) is considered the gold standard. In the last decade various new techniques have emerged with encouraging functional results. However, long-term data are missing in order to evaluate the efficacy and safety. This review aims to describe new widely available techniques and to assess the underlying evidence. PMID- 22940723 TI - The impact of subjective birth experiences on post-traumatic stress symptoms: a longitudinal study. AB - The aim of this prospective study was to examine the etiology of post-traumatic stress symptoms following childbirth within a transactional framework of stress. Participants were women (N = 1,499) from the Akershus Birth Cohort. These women were followed from pregnancy to 8 weeks postpartum. We modeled predisposing factors (e.g., fear of childbirth) and precipitating factors (subjective and objective birth experiences) as predictors of post-traumatic stress symptoms. Post-traumatic stress symptoms were measured by means of the Impact of Event Scale, objective birth experiences by means of birth journals, and subjective birth experiences by means of three questions. A structural equation model showed that subjective birth experiences had the highest association with post-traumatic stress symptoms. Moreover, they mediated the effect of predisposing factors and objective birth experiences. The results suggest that women's subjective birth experiences are the most important factor in the development of post-traumatic stress symptoms following childbirth. PMID- 22940724 TI - Proteomic differential display identifies upregulated vinculin as a possible biomarker of pancreatic cancer. AB - Pancreatic cancer (PC) is characterized by rapid tumor spread, and very few patients with PC survive for more than 5 years. It is imperative to discover additional diagnostic biomarkers or specific therapeutic targets in order to improve the treatment of patients with PC. In search for useful biomarkers, we analyzed ten pairs of non-cancerous and cancer tissues from patients with PC by two-dimensional gel electrophoresis (2-DE). Nineteen protein spots showed differential expression on 2-DE gels between the cancer and non-cancerous tissues. Six upregulated protein spots were identified by liquid chromatography tandem mass spectrometry (LC-MS/MS) as calreticulin, glutathione synthetase, stathmin, vinculin, alpha-enolase and glyceraldehyde-3-phosphate dehydrogenase. Western blotting demonstrated that vinculin was predominantly expressed in the pancreatic cancer tissues compared with to non-cancerous tissues. Our findings indicate that vinculin may be a clinically useful biomarker of PC. PMID- 22940725 TI - Total synthesis of epothilones using functionalised allylstannanes for remote stereocontrol. AB - Two syntheses of the C(7)-C(16)-fragment 41 of epothilone D 2 were developed that were based on tin(IV) bromide mediated reactions of 5,6-difunctionalised hex-2 enylstannanes with aldehydes. In the first synthesis, (5S)-6-tert butyldimethylsilyloxy-5-hydroxy-2-methylhex-2-enyl(tributyl)stannane 20 was reacted with (E)-but-2-enal to give (2S,7R,4Z,8E)-1-tert-butyldimethylsilyloxy-5 methyldeca-4,8-diene-2,7-diol 26 containing ca. 20% of its (7S)-epimer. Following desilylation, the crystalline (2S,7R)-triol 32 was protected as its acetonide 33 and esterified to give the (4-methoxybenzyloxy)acetate 34. An Ireland-Claisen rearrangement of this ester gave methyl (2R,3S,10S,4E,7Z)-3,7-dimethyl-10,11 (dimethylmethylene)dioxy-2-(4-methoxybenzyloxy)undeca-4,7-dienoate 35 that was converted into (2S,9S,6Z)-2,6-dimethyl-9,10-(dimethylmethylene)dioxydec-6-en-1-ol 41 by regioselective alkene manipulation, ester reduction and cleavage of the resulting terminal diol 40 with a reductive work-up. The second synthesis involved the tin(IV) bromide mediated reaction between the stannane 20 and (3S)-4 (4-methoxybenzyloxy)-3-methylbutanal 44 that gave (2S,7S,9S,4Z)-1-tert butyldimethylsilyloxy-5,9-dimethyl-10-(4-methoxybenzyloxy)dec-4-ene-2,7-diol 45 containing ca. 20% of its (7R)-epimer. After desilylation and protection of the vicinal diol as its acetonide 46, a Barton-McCombie reductive removal of the remaining hydroxyl group gave the (2S,9S,6Z)-2,6-dimethyl-9,10 (dimethylmethylene)dioxydec-6-en-1-ol 41 after oxidative removal of the PMB ether. The first of these syntheses uses just one chiral starting material, but the second is shorter and more convergent. It was therefore modified by the use of (5S)-6-tert-butyldimethylsilyloxy-5-(2-trimethylsilylethoxy)methoxy-2 methylhex-2-enyl(tributyl)stannane 49 that reacted with (3S)-4-(4 methoxybenzyloxy)-3-methylbutanal 44 to give a 50:50 mixture of the C(4)-epimers of (2S,9S,6Z)-10-tert-butyldimethylsilyloxy-1-(4-methoxybenzyloxy)-2,6-dimethyl-9 (2-trimethylsilylethoxy)methoxydec-6-en-4-ol 50 with high fidelity for formation of the (Z)-alkene. Following the Barton-McCombie deoxygenation, the product 52 was taken through to (2S,9S,6Z,10E)-2,6,10-trimethyl-11-(2-methyl-1,3-thiazol-4 yl)-9-(2-trimethylsilylethoxy)methoxyundeca-6,10-dienal 59 that corresponded to the fully functionalised C(7)-C(17) fragment of epothilone D 2. A precedented stereoselective aldol condensation followed by O-protection, selective deprotection, oxidation and macrocyclisation then gave the macrolide 71 that was deprotected to complete a synthesis of epothilone D 2. Finally regio- and stereo selective epoxidation gave epothilone B 1. PMID- 22940727 TI - Atmospheric chemistry. PMID- 22940726 TI - A mouse diversity panel approach reveals the potential for clinical kidney injury due to DB289 not predicted by classical rodent models. AB - DB289 is the first oral drug shown in clinical trials to have efficacy in treating African trypanosomiasis (African sleeping sickness). Mild liver toxicity was noted but was not treatment limiting. However, development of DB289 was terminated when several treated subjects developed severe kidney injury, a liability not predicted from preclinical testing. We tested the hypothesis that the kidney safety liability of DB289 would be detected in a mouse diversity panel (MDP) comprised of 34 genetically diverse inbred mouse strains. MDP mice received 10 days of oral treatment with DB289 or vehicle and classical renal biomarkers blood urea nitrogen (BUN) and serum creatinine (sCr), as well as urine biomarkers of kidney injury were measured. While BUN and sCr remained within reference ranges, marked elevations were observed for kidney injury molecule-1 (KIM-1) in the urine of sensitive mouse strains. KIM-1 elevations were not always coincident with elevations in alanine aminotransferase (ALT), suggesting that renal injury was not linked to hepatic injury. Genome-wide association analyses of KIM-1 elevations indicated that genes participating in cholesterol and lipid biosynthesis and transport, oxidative stress, and cytokine release may play a role in DB289 renal injury. Taken together, the data resulting from this study highlight the utility of using an MDP to predict clinically relevant toxicities, to identify relevant toxicity biomarkers that may translate into the clinic, and to identify potential mechanisms underlying toxicities. In addition, the sensitive mouse strains identified in this study may be useful in screening next in-class compounds for renal injury. PMID- 22940728 TI - Gap-junction-mediated cell-to-cell communication. AB - Cells of multicellular organisms need to communicate with each other and have evolved various mechanisms for this purpose, the most direct and quickest of which is through channels that directly connect the cytoplasms of adjacent cells. Such intercellular channels span the two plasma membranes and the intercellular space and result from the docking of two hemichannels. These channels are densely packed into plasma-membrane spatial microdomains termed "gap junctions" and allow cells to exchange ions and small molecules directly. A hemichannel is a hexameric torus of junctional proteins around an aqueous pore. Vertebrates express two families of gap-junction proteins: the well-characterized connexins and the more recently discovered pannexins, the latter being related to invertebrate innexins ("invertebrate connexins"). Some gap-junctional hemichannels also appear to mediate cell-extracellular communication. Communicating junctions play crucial roles in the maintenance of homeostasis, morphogenesis, cell differentiation and growth control in metazoans. Gap-junctional channels are not passive conduits, as previously long regarded, but use "gating" mechanisms to open and close the central pore in response to biological stimuli (e.g. a change in the transjunctional voltage). Their permeability is finely tuned by complex mechanisms that have just begun to be identified. Given their ubiquity and diversity, gap junctions play crucial roles in a plethora of functions and their dysfunctions are involved in a wide range of diseases. However, the exact mechanisms involved remain poorly understood. PMID- 22940729 TI - Expression of the clock genes Per1 and Bmal1 during follicle development in the rat ovary. Effects of gonadotropin stimulation and hypophysectomy. AB - Daily oscillations of clock genes have recently been demonstrated in the ovaries of several species. Clock gene knockout or mutant mice demonstrate a variety of reproductive defects. Accumulating evidence suggests that these rhythms act to synchronise the expression of specific ovarian genes to hypothalamo-pituitary signals and that they are regulated by one or both of the gonadotropins. The aim of this study has been to examine the spatio-temporal expression of the clock genes Per1 and Bmal1 during gonadotropin-independent and gonadotropin-dependent follicle development in the rat ovary. We have examined the ovaries of prepubertal rats, of prepubertal rats stimulated with equine chorionic gonadotropin (eCG)/human chorionic gonadotropin (hCG) and of hypophysectomised adult animals. Using quantitative reverse transcription with the polymerase chain reaction, in situ hybridisation histochemistry and immunohistochemistry, we have demonstrated that the expression of the two clock genes is low and arrhythmic in ovarian cells during early gonadotropin-independent follicle development in prepubertal animals and in hypophysectomised animals. We have also demonstrated that the expression of the clock genes becomes rhythmic following eCG stimulation in the theca interna cells and the secondary interstitial cells and that, following additional hCG stimulation, the expression of the clock genes also becomes rhythmic in the granulosa cells of preovulatory follicles. These findings link the initiation of clock gene rhythms in the rat ovary to the luteinising hormone receptor and suggest a functional link to androgen and progesterone production. In hypophysectomised animals, rhythmic clock gene expression is also observed in the corpora lutea and in secondary interstitial cells demonstrating that, in these compartments, entrainment of clock gene rhythms is gonadotropin independent. PMID- 22940730 TI - Primary cutaneous aggressive epidermotropic CD8+ T-cell lymphoma: report of two cases with no evidence of systemic disease. PMID- 22940731 TI - IAEA survey of paediatric computed tomography practice in 40 countries in Asia, Europe, Latin America and Africa: procedures and protocols. AB - OBJECTIVE: To survey procedures and protocols in paediatric computed tomography (CT) in 40 less resourced countries. METHODS: Under a project of the International Atomic Energy Agency, 146 CT facilities in 40 countries of Africa, Asia, Europe and Latin America responded to an electronic survey of CT technology, exposure parameters, CT protocols and doses. RESULTS: Modern MDCT systems are available in 77 % of the facilities surveyed with dedicated paediatric CT protocols available in 94 %. However, protocols for some age groups were unavailable in around 50 % of the facilities surveyed. Indication-based protocols were used in 57 % of facilities. Estimates of radiation dose using CTDI or DLP from standard CT protocols demonstrated wide variation up to a factor of 100. CTDI(vol) values for the head and chest were between two and five times those for an adult at some sites. Sedation and use of shielding were frequently reported; immobilisation was not. Records of exposure factors were kept at 49 % of sites. CONCLUSION: There is significant potential for improvement in CT practice and protocol use for children in less resourced countries. Dose estimates for young children varied widely. This survey provides critical baseline data for ongoing quality improvement efforts by the IAEA. PMID- 22940733 TI - The ammonia transport, retention and futile cycling problem in cyanobacteria. AB - Ammonia is the preferred nitrogen source for many algae including the cyanobacterium Synechococcus elongatis (Synechococcus R-2; PCC 7942). Modelling ammonia uptake by cells is not straightforward because it exists in solution as NH(3) and NH (4) (+) . NH(3) is readily diffusible not only via the lipid bilayer but also through aquaporins and other more specific porins. On the other hand, NH (4) (+) requires cationic transporters to cross a membrane. Significant intracellular ammonia pools (~1-10 mol m(-3)) are essential for the synthesis of amino acids from ammonia. The most common model envisaged for how cells take up ammonia and use it as a nitrogen source is the "pump-leak model" where uptake occurs through a simple diffusion of NH(3) or through an energy-driven NH (4) (+) pump balancing a leak of NH(3) out of the cell. The flaw in such models is that cells maintain intracellular pools of ammonia much higher than predicted by such models. With caution, [(14)C]-methylamine can be used as an analogue tracer for ammonia and has been used to test various models of ammonia transport and metabolism. In this study, simple "proton trapping" accumulation by the diffusion of uncharged CH(3)NH(2) has been compared to systems where CH(3)NH (3) (+) is taken up through channels, driven by the membrane potential (DeltaU (i,o)) or the electrochemical potential for Na(+) (DeltaMUNa (i,o) (+) ). No model can be reconciled with experimental data unless the permeability of CH(3)NH(2) across the cell membrane is asymmetric: permeability into the cell is very high through gated porins, whereas permeability out of the cell is very low (~40 nm s(-1)) and independent of the extracellular pH. The best model is a Na (in) (+) /CH(3)NH (3) (+) (in) co-porter driven by DeltaMUNa (i,o) (+) balancing synthesis of methylglutamine and a slow leak governed by Ficks law, and so there is significant futile cycling of methylamine across the cell membrane to maintain intracellular methylamine pools high enough for fixation by glutamine synthetase. The modified pump-leak model with asymmetric permeability of the uncharged form is a viable model for understanding ammonia uptake and retention in plants, free living microbes and organisms in symbiotic relationships. PMID- 22940732 TI - Revised systematics of Holospora-like bacteria and characterization of "Candidatus Gortzia infectiva", a novel macronuclear symbiont of Paramecium jenningsi. AB - The genus Holospora (Rickettsiales) includes highly infectious nuclear symbionts of the ciliate Paramecium with unique morphology and life cycle. To date, nine species have been described, but a molecular characterization is lacking for most of them. In this study, we have characterized a novel Holospora-like bacterium (HLB) living in the macronuclei of a Paramecium jenningsi population. This bacterium was morphologically and ultrastructurally investigated in detail, and its life cycle and infection capabilities were described. We also obtained its 16S rRNA gene sequence and developed a specific probe for fluorescence in situ hybridization experiments. A new taxon, "Candidatus Gortzia infectiva", was established for this HLB according to its unique characteristics and the relatively low DNA sequence similarities shared with other bacteria. The phylogeny of the order Rickettsiales based on 16S rRNA gene sequences has been inferred, adding to the available data the sequence of the novel bacterium and those of two Holospora species (Holospora obtusa and Holospora undulata) characterized for the purpose. Our phylogenetic analysis provided molecular support for the monophyly of HLBs and showed a possible pattern of evolution for some of their features. We suggested to classify inside the family Holosporaceae only HLBs, excluding other more distantly related and phenotypically different Paramecium endosymbionts. PMID- 22940735 TI - AhR-mediated potency of sediments and soils in estuarine and coastal areas of the Yellow Sea region: a comparison between Korea and China. AB - Extracts of sediments (n = 45) and soils (n = 37) collected from the coast of the Yellow Sea, in Korea and China, were screened for their ability to induce dioxin like gene expression in vitro using the H4IIE-luc, transactivation bioassay. Significant dioxin-like potency was observed except for a few soils from Korea. Concentrations of TCDD-EQ (2,3,7,8-tetrachlorodibenzo-p-dioxin equivalents) in sediments were comparable between Korea and China, but concentrations of TCDD-EQ in soil were 2-fold greater from Korea. Mass balance analysis indicated that concentrations of TCDD-EQ were to some degree chemical- and/or matrix-dependent, but were much more site-specific. For example, the proportion of the TCDD-EQ that could be identified varied among locations, which suggests different sources. Unidentified AhR-active compounds represented a greater proportion of the TCDD-EQ in samples from Korea, which suggests that sources in Korea were more complex than those in China. Potential sources of TCDD-EQ were investigated by considering land-uses and local activities. PMID- 22940734 TI - Microbial diversity and PAH catabolic genes tracking spatial heterogeneity of PAH concentrations. AB - We analyzed the within-site spatial heterogeneity of microbial community diversity, polyaromatic hydrocarbon (PAH) catabolic genotypes, and physiochemical soil properties at a creosote contaminated site. Genetic diversity and community structure were evaluated from an analysis of denaturant gradient gel electrophoresis (DGGE) of polymerase chain reaction (PCR)-amplified sequences of 16S rRNA gene. The potential PAH degradation capability was determined from PCR amplification of a suit of aromatic dioxygenase genes. Microbial diversity, evenness, and PAH genotypes were patchily distributed, and hot and cold spots of their distribution coincided with hot and cold spots of the PAH distribution. The analyses revealed a positive covariation between microbial diversity, biomass, evenness, and PAH concentration, implying that the creosote contamination at this site promotes diversity and abundance. Three patchily distributed PAH-degrading genotypes, NAH, phnA, and pdo1, were identified, and their abundances were positively correlated with the PAH concentration and the fraction of soil organic carbon. The covariation of the PAH concentration with the number and spatial distribution of catabolic genotypes suggests that a field site capacity to degrade PAHs may vary with the extent of contamination. PMID- 22940737 TI - Fighting mycobacteria through ISGylation. PMID- 22940738 TI - TRIAD1 is negatively regulated by the MDM2 E3 ligase. AB - Two RING fingers and DRIL1 (TRIAD1) is a proapoptotic protein that promotes p53 activation in several cancer cell lines, including MCF7, U2OS and A549 cells. In this study, we demonstrated that TRIAD1 is a novel ubiquitination target for proteasome-dependent degradation by murine double minute 2 (MDM2). TRIAD1 was found to interact with and be ubiquitinated by MDM2. RNA interference against MDM2 increased endogenous TRIAD1 protein stability. The functional study results suggested that TRIAD1 degradation by MDM2 suppresses TRIAD1-mediated cell growth. These data suggested a novel negative regulatory mechanism of TRIAD1 via MDM2 E3 ligase ubiquitination. PMID- 22940736 TI - Apical acidity decreases inhibitory effect of omeprazole on Mg(2+) absorption and claudin-7 and -12 expression in Caco-2 monolayers. AB - Clinical studies reported hypomagnesaemia in long-term omeprazole usage that was probably due to intestinal Mg(2+) wasting. Our previous report demonstrated the inhibitory effect of omeprazole on passive Mg(2+) transport across Caco-2 monolayers. The present study aimed to identify the underlying mechanism of omeprazole suppression of passive Mg(2+) absorption. By using Caco-2 monolayers, we demonstrated a potent inhibitory effect of omeprazole on passive Mg(2+), but not Ca(2+), transport across Caco-2 monolayers. Omeprazole shifted the %maximum passive Mg(2+) transport-Mg(2+) concentration curves to the right, and increased the half maximal effective concentration of those dose-response curves, indicating a lower Mg(2+) affinity of the paracellular channel. By continually monitoring the apical pH, we showed that omeprazole suppressed apical acid accumulation. Neomycin and spermine had no effect on passive Mg(2+) transport of either control or omeprazole treated monolayers, indicating that omeprazole suppressed passive Mg(2+) transport in a calcium sensing receptor (CaSR) independent manner. The results of western blot analysis showed that omeprazole significantly suppressed claudin (Cldn)-7 and -12, but not Cldn-2, expression in Caco-2 cells. By using apical solution of pH 5.5, 6.0, 6.5, and 7.0, we found that apical acidity markedly increased passive Mg(2+) transport, Mg(2+) affinity of the paracellular channel, and Cldn-7 and -12 expression in Caco-2 monolayers. Apical acidity abolished the inhibitory effect of omeprazole on passive Mg(2+) transport and Cldn-7 and -12 expression. Our results provided the evidence for the regulation of intestinal passive Mg(2+) absorption by luminal acidity-induced increase in Cldn-7 and -12 expression. PMID- 22940739 TI - Chewing ability in an urban and rural population over 40 years in Shandong Province, China. AB - OBJECTIVES: This study aimed to assess chewing ability related to dental status. MATERIAL AND METHODS: One thousand four hundred sixty-two Chinese subjects over 40 years, dentate in both jaws, were categorized in a hierarchical functional classification system with and without tooth replacements. Chewing ability was analyzed using multivariable logistic regression including five dental conditions ( ">=10 teeth in each jaw"; "complete anterior regions"; "sufficient premolar regions" (>=3 posterior occluding pairs (POPs)); "sufficient molar regions" (bilaterally >=1 POP); and tooth replacement), adjusted for six background variables. Likelihood ratios for chewing problems were assessed at each level of the hierarchical classification system based on these dental conditions. RESULTS: Seventy-eight to 91 % of subjects reported no or minor chewing problems. The conditions ">=10 teeth in each jaw", and "complete anterior regions" were not associated, whereas "sufficient premolar regions" and "sufficient molar regions" were associated with chewing problems (Ors, 0.33-0.58). If classified hierarchically, the condition ">=10 teeth in each jaw" was relevant for chewing problems (likelihood ratios 3.3-3.7). "Sufficient premolar region" and "sufficient molar region" were relevant to reduce the likelihood ratios for having chewing problems (both approximately with a factor 2), both for soft and for hard foods. Subjects with artificial teeth added had similar chance for chewing problems compared to counterparts with natural teeth only. However, if comparing replaced teeth with natural teeth, subjects with tooth replacement showed higher chance for chewing problems. CONCLUSIONS: Chewing ability was strongly associated with dental conditions. CLINICAL RELEVANCE: The presence of at least 10 teeth in each jaw had highest impact on chewing ability. PMID- 22940740 TI - Acute and chronic toxicity of buprofezin on Daphnia magna and the recovery evaluation. AB - The toxic effects of buprofezin on Daphnia magna after both chronic and acute exposures were evaluated according to OECD guidelines. A 48-h acute exposure of buprofezin resulted in daphnid immobility at an EC(50) of 0.44 mg/L. In a 14 days chronic exposure of buprofezin (0, 0.025, 0.05, 0.10 and 0.15 mg/L), the development and reproduction of daphnids were all significantly affected and the body length was more sensitive than other observed parameters. However, the adverse effects of buprofezin on parental daphnids can be passed on to their offspring and cannot be recovered in a short time. PMID- 22940741 TI - 4-Liter split-dose polyethylene glycol is superior to other bowel preparations, based on systematic review and meta-analysis. AB - BACKGROUND & AIMS: Adequate bowel cleansing is an important determinant of the efficacy of screening colonoscopy. Polyethylene glycol (PEG)-based solutions are used commonly in bowel preparation, but their poor palatability and large volumes (4 L) influence compliance. Adjunct therapies, such as bisacodyl, split-dose regimens, and lower-volume regimens have been tested. We performed a meta analysis to determine whether a 4-L split dose of PEG is better than others for bowel cleansing before colonoscopy. METHODS: We searched MEDLINE, the Cochrane Central Register of Controlled Trials and Database, recent abstracts from major conference proceedings, references from selected reviews and randomized trials (http://clinicaltrials.gov), and Google Scholar, through September 2011, for high quality, randomized trials that compared 4-L split-dose PEG without adjunct therapy with other bowel preparation methods. Nine of 2477 trials considered were used in the analysis. We calculated pooled estimates of bowel preparation quality (primary outcome: excellent or good), preparation compliance, favorable overall experiences, willingness to repeat same preparation, and side effects. We calculated pooled estimates of odds ratios by fixed- and random-effects models. We also assessed heterogeneity among studies and publication bias. RESULTS: The overall pooled odds ratio for excellent or good bowel preparation quality for 4-L split-dose PEG was 3.46, compared with other methods (95% confidence interval, 2.45-4.89; P < .01). Although there was significant heterogeneity in results among studies, 7 of 9 reported a significant benefit from the 4-L split-dose PEG preparation. There were no significant differences between PEG and others in preparation compliance, favorable overall experience, willingness to repeat the same preparation, abdominal cramping, nausea, or sleep disturbance. There was no significant publication bias based on funnel plot. CONCLUSIONS: A meta-analysis showed that 4-L split-dose PEG is better than other bowel preparation methods for colonoscopy. Significant heterogeneity among studies might result from differences in patient demographics and protocols. A 4-L split dose of PEG should be considered the standard with which new bowel preparation methods are compared. PMID- 22940742 TI - Betaine inhibits in vitro and in vivo angiogenesis through suppression of the NF kappaB and Akt signaling pathways. AB - Angiogenesis is defined as the formation of new blood vessels form existing vessels surrounding a tumor. The process of angiogenesis is an important step for tumor growth and metastasis, as is inflammation. Thus, angiogenesis inhibitors that suppress inflammation have been studied as an anticancer treatment. Recently, many research groups have investigated the anti-angiogenic activity of natural compounds since some have been demonstrated to have anticancer properties. Among many natural compounds, we focused on betaine, which is known to suppress inflammation. Betaine, trimethylglycine (TMG), was first discovered in the juice of sugar beets and was later shown to be present in wheat, shellfish and spinach. In Southeast Asia, betaine is used in traditional oriental medicine for the treatment of hepatic disorders. Here, we report the anti-angiogenic action of betaine. Betaine inhibited in vitro angiogenic cascade, tube formation, migration and invasion of human umbilical vein endothelial cells (HUVECs). Betaine also inhibited in vivo angiogenesis in the mouse Matrigel plug assay. The mRNA expression levels of basic fibroblast growth factor (bFGF), matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-9 (MMP-9) in HUVECs were decreased by betaine treatment. In addition, betaine suppressed NF-kappaB and Akt activation. PMID- 22940743 TI - Auditory verbal hallucinations: imaging, analysis, and intervention. AB - In this article, we will link neuroimaging, data analysis, and intervention methods in an important psychiatric condition: auditory verbal hallucinations (AVH). The clinical and phenomenological background as well as neurophysiological findings will be covered and discussed with respect to noninvasive brain stimulation. Additionally, methods of noninvasive brain stimulation will be presented as ways to intervene with AVH. Finally, preliminary conclusions and possible future perspectives will be proposed. PMID- 22940744 TI - Multimodal functional and structural imaging investigations in psychosis research. AB - Substantial pathophysiological questions about the relationship of brain pathologies in psychosis can only be answered by multimodal neuroimaging approaches combining different imaging modalities such as structural MRI (sMRI), functional MRI (fMRI), diffusion tensor imaging (DTI), positron emission tomography (PET) and magnetic-resonance spectroscopy. In particular, the multimodal imaging approach has the potential to shed light on the neuronal mechanisms underlying the major brain structural and functional pathophysiological features of schizophrenia and high-risk states such as prefronto-temporal gray matter reduction, altered higher-order cognitive processing, or disturbed dopaminergic and glutamatergic neurotransmission. In recent years, valuable new findings have been revealed in these fields by multimodal imaging studies mostly reflecting a direct and aligned correlation of brain pathologies in psychosis. However, the amount of multimodal studies is still limited, and further efforts have to be made to consolidate previous findings and to extend the scope to other pathophysiological parameters contributing to the pathogenesis of psychosis. Here, investigating the genetic foundations of brain pathology relationships is a major challenge for future multimodal imaging applications in psychosis research. PMID- 22940746 TI - Pay it forward. PMID- 22940745 TI - The DGPPN research project on mental healthcare utilization in Germany: inpatient and outpatient treatment of persons with depression by different disciplines. AB - The analysis of the utilization of mental healthcare services using routine data provided by statutory health insurance companies and pension funds is a way to assess the frequency of service use, the distribution of the service use among various healthcare settings (inpatients vs. outpatients, rehabilitation according mainly to the German Social Code Book IX vs. curative treatment according to the German Social Code Book V [note that some elements of rehabilitation are financed according to Social Code Book V as well]) and medical disciplines (psychiatry and psychosomatic medicine vs. somatic disciplines and general medicine). In addition, these data can provide information on the social consequences of mental disorders, as assessed by the number of cases and the duration of sick leave or case numbers of early retirement due to mental disorders. In this study, healthcare utilization data from 10 million Germans were analysed. Within a 3 year observation period (2005-2007), about one-third (approx. 3.3 million) persons had a contact with a healthcare service due to a diagnosis of the ICD-10 groups F0-F5. Given the large number of persons with depression in Germany, the initial results of an analysis of mental healthcare utilization due to depression are presented here. Among the study group of 3.3 million Germans with mental healthcare utilization within the observation period, 1.4 million had at least one contact to healthcare system due to the diagnosis of depression. In most cases, depression was diagnosed without specification of severity. It was found that non-psychiatric disciplines like general practitioners were the most frequently used providers in outpatient mental health care, whereas inpatient treatment predominantly occurred in psychiatric departments. For those persons with depression for which a severity-indicating ICD-10 code was used, it was found that utilization of psychiatric and psychosomatic disciplines increased in both in- and outpatient treatment compared to use of general medical facilities with more severe depression. Specialists for psychosomatic medicine and psychological psychotherapists predominantly treated cases of mild and moderate depression, whereas severe cases were mostly cared for by psychiatrists or psychiatric departments. PMID- 22940747 TI - Allosteric agonists of the calcium receptor (CaR): fluorine and SF5 analogues of cinacalcet. AB - Three selectively fluorinated cinacalcet analogues are prepared and their activity as calcium-sensing receptor (CaR) agonists is assessed. Individual (2R,1'R)-2 and (2S,1'R)-3 fluorocinacalcet diastereoisomers were prepared using the MacMillan asymmetric fluorination reaction. Assays with the recombinant human CaR revealed that both diastereoisomers have a similar potency to each other although slightly lower (75-80%) than that of cinacalcet 1. The SF(5)-cinacalcet analogue 4 was prepared from meta-pentafluorosulfanyl benzyl alcohol and has ~75% agonist activity relative to cinacalcet 1 indicating that the SF(5) group can replace the CF(3) group and retain significant bioactivity. PMID- 22940748 TI - NIH Mouse Metabolic Phenotyping Centers: the power of centralized phenotyping. AB - The Mouse Metabolic Phenotyping Centers (MMPCs) were founded in 2001 by the National Institutes of Health (NIH) to advance biomedical research by providing the scientific community with standardized, high-quality phenotyping services for mouse models of diabetes, obesity, and their complications. The intent is to allow researchers to take optimum advantage of the many new mouse models produced in labs and in high-throughput public efforts. The six MMPCs are located at universities around the country and perform complex metabolic tests in intact mice and hormone and analyte assays in tissues on a fee-for-service basis. Testing is subsidized by the NIH in order to reduce the barriers for mouse researchers. Although data derived from these tests belong to the researcher submitting mice or tissues, these data are archived after publication in a public database run by the MMPC Coordinating and Bioinformatics Unit. It is hoped that data from experiments performed in many mouse models of metabolic diseases, using standard protocols, will be useful in understanding the nature of these complex disorders. The current areas of expertise include energy balance and body composition, insulin action and secretion, whole-body and tissue carbohydrate and lipid metabolism, cardiovascular and renal function, and metabolic pathway kinetics. In addition to providing services, the MMPC staff provides expertise and advice to researchers, and works to develop and refine test protocols to best meet the community's needs in light of current scientific developments. Test technology is disseminated by publications and through annual courses. PMID- 22940749 TI - The International Mouse Phenotyping Consortium: past and future perspectives on mouse phenotyping. AB - Determining the function of all mammalian genes remains a major challenge for the biomedical science community in the 21st century. The goal of the International Mouse Phenotyping Consortium (IMPC) over the next 10 years is to undertake broad based phenotyping of 20,000 mouse genes, providing an unprecedented insight into mammalian gene function. This short article explores the drivers for large-scale mouse phenotyping and provides an overview of the aims and processes involved in IMPC mouse production and phenotyping. PMID- 22940750 TI - Co-templating ionothermal synthesis and structure characterization of two new 2D layered aluminophosphates. AB - For the first time, the co-templating ionothermal methodology was used in the preparation of layered aluminophosphate materials. With the addition of either 1,2-ethylenediamine or 1,6-hexanediamine to the ionic liquid 1-ethyl-3-methyl imidazolium chloride, two new 2D layered aluminophosphates RUB-A1 [Al(3)P(4)O(16)][NH(3)CH(2)CH(2)NH(3)](0.5)[C(6)N(2)H(11)](2) and RUB-A2 [Al(3)P(4)O(16)][NH(3)(CH(2))(6)NH(3)][NH(3)(CH(2))(6)NH(2)](0.5)[C(6)N(2)H(11)]( .5)[H(2)O] have been synthesized ionothermally by co-templating. The structure of RUB-A1 has been determined from single-crystal X-ray diffraction data using direct methods, while the structure of RUB-A2 has been solved ab initio from powder X-ray diffraction data with limited resolution using direct-space methods. Both of these two compounds have a 2D layered structure consisting of macroanionic sheets of composition [Al(3)P(4)O(16)](3-) stacked in an AAAA sequence. The inorganic layers are built up from alternatively vertex-sharing [AlO(4)]- and [PO(3)(=O)]-tetrahedral units forming a 4.6.8 and a 4.6.12 network for RUB-A1 and RUB-A2, respectively. The layer topology of RUB-A1 is closely related to the previously known 4.6.8-layer topology but with a different sequence of phosphoryl group orientation. Combining the results of structure analysis with the NMR, chemical analysis and TG-DTA experiments, we show that both the ionic liquid cation and the protonated diamines are located in the interlayer space and together direct the formation of these two structures. PMID- 22940751 TI - Electrophysiological responses in mothers to their own and unfamiliar child's gaze information. AB - An attachment bond between a mother and her child is one of the most intimate human relationships. It is important for a mother to be sensitive to her child's gaze direction because exchanging gaze information plays a vital role in their relationship. Furthermore, recent studies have revealed differential neural activation patterns in mothers when presented the faces of their own children or the unfamiliar child of other people. Based on these findings, in the present study, we investigated whether mothers show differential neural responses to gaze information of their own child compared to that of an unfamiliar child. To this end, event-related-potentials elicited by the faces of one's own or an unfamiliar child with straight or averted gaze directions were measured using an oddball paradigm. The results showed that peak amplitudes of the N170 component were enlarged by viewing the straight gazes compared to the averted gazes of one's own child, but not of an unfamiliar child. When the gaze was directed straight, the P3 amplitude elicited by one's own child's face is smaller than that elicited by an unfamiliar child's face. P3s elicited in viewing one's own child's face with averted gaze and in viewing an unfamiliar child's face with straight gaze were positively correlated with state-anxiety. These results bolster the hypothesis that processing the gaze information of one's own child elicits differential neural activation compared to the gaze information of an other person's unfamiliar child at both perceptual and evaluative stages of face processing. PMID- 22940752 TI - Saliva DHEAS changes in patients suffering from psychopathological disorders arising from bullying at work. AB - BACKGROUND: Psychological disorders arising from bullying at work (BW) are common. The relationship between these disorders and putative markers is not well established. AIMS: To measure saliva dehydroepiandrosterone sulphate (DHEAS) and saliva cortisol as putative markers in individuals suffering from BW. METHODS: Forty one subjects suffering from BW were screened for mental distress at the institute of occupational health in Clermont-Ferrand, France. They were compared with 28 psychologically healthy controls (group C). The conditions causing BW were recorded. The hospital anxiety and depression (HAD) scale, the Beech questionnaire and the visual analogic scale (VAS) of stress were used to determine the psychological consequences of BW. Saliva samples were collected at awakening (7 am), 30 and 60 min after awakening, and then every 2 h until bed time (11 pm). RESULTS: The BW group had significantly higher scores on the HAD scale, higher stress on the VAS, and a higher score on the Beech questionnaire. They also had a significantly higher saliva concentration of DHEAS. There was no significant difference between groups in cortisol levels at any time, nor in area under the curve (AUC) and cortisol awakening response (CAR). There was a significant positive correlation between HAD and VAS scores and DHEAS levels, but not between cortisol levels or AUC or CAR. CONCLUSION: In contrast to saliva cortisol levels, saliva DHEAS levels are modified after psychological distress arising from BW. This discrepancy probably arises from the stability conferred by the very long half life of DHEAS of about 15 h. PMID- 22940753 TI - Association of polymorphisms in BDNF, MTHFR, and genes involved in the dopaminergic pathway with memory in a healthy Chinese population. AB - The contribution of genetic factors to the memory is widely acknowledged. Research suggests that these factors include genes involved in the dopaminergic pathway, as well as the genes for brain-derived neurotrophic factor (BDNF) and methylenetetrahydrofolate reductase (MTHFR). The activity of the products of these genes is affected by single nucleotide polymorphisms (SNPs) within the genes. This study investigates the association between memory and SNPs in genes involved in the dopaminergic pathway, as well as in the BDNF and MTHFR genes, in a sample of healthy individuals. The sample includes 134 Taiwanese undergraduate volunteers of similar cognitive ability. The Chinese versions of the Wechsler Memory Scale (WMS-III) and Wechsler Adult Intelligence Scale (WAIS-III) were employed. Our findings indicate that the BDNF Met66Val polymorphism and dopamine receptor D3 (DRD3) Ser9Gly polymorphism are associated significantly with long term auditory memory. Further analysis detects no significant associations in the other polymorphisms and indices. Future replicated studies with larger sample sizes, and studies that consider different ethnic groups, are encouraged. PMID- 22940754 TI - Endothelial cells undergo morphological, biomechanical, and dynamic changes in response to tumor necrosis factor-alpha. AB - The immune response triggers a complicated sequence of events, one of which is release of the cytokine tumor necrosis factor-alpha (TNF-alpha) from stromal cells, for example monocytes and macrophages. In this work we investigated the biophysical effects of TNF-alpha on endothelial cells (ECs), including changes in cell morphology, biomechanics, migration, and cytoskeletal dynamics. We found that TNF-alpha induces a wide distribution of cell area and aspect ratio, with these properties increasing on average during treatment. Interestingly, aspect ratio peaks after approximately 10 h of exposure to TNF-alpha, corresponding also to a peak in exerted traction forces. Meanwhile, ECs treated with TNF-alpha soften, and we associate this with significant increases in estimated cellular volume. In addition, our evaluation of migratory dynamics revealed an inverse correlation between cell aspect ratio and migration speed after TNF-alpha treatment, suggesting that cell shape may be an important functional regulator of EC migration during an inflammatory response. Finally, we addressed the basic mechanics of how the reorganization of F-actin filaments occurs during TNF-alpha treatment, and observed a dynamic shift of existing actin filaments. Together, our results suggest a functional link between EC morphology, biomechanics, migration, and cytoskeletal dynamics during an inflammatory response. PMID- 22940756 TI - Time for change in culture. PMID- 22940755 TI - Norms of decision making in the ICU: a case study of two academic medical centers at the extremes of end-of-life treatment intensity. AB - PURPOSE: To explore norms of decision making regarding life-sustaining treatments (LSTs) at two academic medical centers (AMCs) that contribute to their opposite extremes of end-of-life ICU use. METHODS: We conducted a 4-week mixed methods case study at each AMC in 2008-2009 involving direct observation of patient care during rounds in the main medical ICU, semi-structured interviews with staff, patients, and families, and collection of artifacts (e.g., patient lists, standardized forms). We compared patterns of decision making regarding initiation, continuation, and withdrawal of LST using tests of proportions and grounded theory analysis of field note and interview transcripts. RESULTS: We observed 80 patients [26 (32.5 %) >=65 years old] staffed by 4 attendings, and interviewed 23 staff and 3 patients/families at the low-intensity AMC (LI-AMC), and observed 73 patients [26 (35.6 %) >=65 years old] staffed by 4 attending physicians and interviewed 26 staff and 4 patients/families at the high-intensity AMC (HI-AMC). LST initiation among patients over 65 was similar, except feeding tubes (0 % LI-AMC versus 31 % HI-AMC, p = 0.002). The LI-AMC was more likely to use a time-limited trial of LST, followed by withdrawal (27 vs. 8 %, p = 0.01) and to have a known outcome of death (31 vs. 4 %, p < 0.001). We identified qualitative differences in goals of LST, the determination of "dying," concern about harms of commission versus omission, and physician self-efficacy for LST decision making. CONCLUSIONS: Time-limited trials of LST at the LI-AMC and open ended use of LST at the HI-AMC explain some of the AMCs' nationally profiled differences in end-of-life ICU use. PMID- 22940757 TI - Atypical clinical appearance of eosinophilic pustular folliculitis of seborrheic areas of the face. AB - Eosinophilic pustular folliculitis is a pruritic eruption that preferentially involves the face. It is characterized by well-demarcated erythema, extending peripherally with a central clearing and pigmentation, together with sterile pustules lining the periphery. We describe five cases of eosinophilic pustular folliculitis with pruritic papules and erythema on seborrheic areas of the face, which lacked the typical features of classic eosinophilic pustular folliculitis- pustules and peripheral extension--but showed eosinophilic infiltration of the hair follicles, histologically. The eruption quickly responded to oral indomethacin except for one case that responded to tranilast and one case that was associated with acquired immunodeficiency syndrome, with recurrences in defined areas of the face. Our findings in these cases suggest that eosinophilic pustular folliculitis may vary in clinical appearance. PMID- 22940758 TI - Granulocyte colony-stimulating factor potentiates differentiation induction by all-trans retinoic acid and arsenic trioxide and enhances arsenic uptake in the acute promyelocytic leukemia cell line HT93A. AB - The effects of arsenic trioxide (ATO), all-trans retinoic acid (ATRA) and granulocyte colony-stimulating factor (G-CSF), alone or in combination, were investigated by focusing on differentiation, growth inhibition and arsenic uptake in the acute promyelocytic leukemia (APL) cell line HT93A. ATO induced differentiation at low concentrations (0.125 uM) and apoptosis at high concentrations (1-2 uM). Furthermore, ATRA induced greater differentiation than ATO. No synergistic effect of ATRA and ATO was found on differentiation. G-CSF promoted differentiation-inducing activities of both ATO and ATRA. The combination of ATRA and G-CSF showed maximum differentiation and ATO addition was not beneficial. Addition of 1 uM ATRA and/or 50 ng/ml G-CSF to ATO did not affect apoptosis compared to ATO treatment alone. ATRA induced expression of aquaporin-9 (AQP9), a transmembrane transporter recognized as a major pathway of arsenic uptake, in a time- and dose-dependent manner. However, treatment with 1 uM ATRA decreased arsenic uptake by 43.7% compared to control subject. Although G-CSF addition did not enhance AQP9 expression in the cells, the reduced arsenic uptake was recovered to the same level as that in controls. ATRA decreased cell viability and addition of 50 ng/ml G-CSF to ATRA significantly increased the number of viable cells compared with that in ATRA alone treated cells. G-CSF not only promotes differentiation-inducing activities of both ATRA and ATO, but also makes APL cells vulnerable to increased arsenic uptake. These observations provide new insights into combination therapy using these three agents for the treatment of APL. PMID- 22940759 TI - Drosophila egg chamber elongation: insights into how tissues and organs are shaped. AB - As tissues and organs are formed, they acquire a specific shape that plays an integral role in their ability to function properly. A relatively simple system that has been used to examine how tissues and organs are shaped is the formation of an elongated Drosophila egg. While it has been known for some time that Drosophila egg elongation requires interactions between a polarized intracellular basal actin network and a polarized extracellular network of basal lamina proteins, how these interactions contribute to egg elongation remained unclear. Recent studies using live imaging have revealed two novel processes, global tissue rotation and oscillating basal actomyosin contractions, which have provided significant insight into how the two polarized protein networks cooperate to produce an elongated egg. This review summarizes the proteins involved in Drosophila egg elongation and how this recent work has contributed to our current understanding of how egg elongation is achieved. PMID- 22940760 TI - Tumor budding is a significant indicator of a poor prognosis in lung squamous cell carcinoma patients. AB - Lung cancer is a leading cause of cancer mortality worldwide and patients occasionally develop local recurrence or distant metastasis soon after curative resection. Reports of new therapeutic strategies for lung squamous cell carcinoma (SqCC) are extremely rare, while selective anticancer therapy has been reported for lung adenocarcinoma. The aim of this study was to identify clinicopathological prognostic factors for SqCC. We analyzed tumor budding and infiltrative patterns (INF) in 103 cases of surgically-resected SqCC. Tumor infiltrative patterns were classified into three groups (INFa, b and c) and INFc was infiltrative growth at the tumor invasive front. The cases with an INFc component [INFc(+)]were significantly associated with venous invasion (P=0.014) and the scirrhous stromal type (P<0.001). The overall survival rate of patients with INFc(+) was significantly lower than that of patients without the INFc component [INFc(-); P=0.003]. Tumor budding was defined as a single cancer cell or a small nest of up to four cancer cells within stromal tissue. The cases with tumor budding [Bud(+)] were significantly associated with lymph node metastasis (P=0.001), lymphatic invasion (P=0.002), INFc(+) (P<0.001) and the scirrhous stromal type (P=0.014). Patients with the Bud(+) type had a lower overall survival rate than patients with the Bud(-) type (P<0.001). Multivariate analysis demonstrated that tumor budding [hazard ratio (HR), 2.766; 95% confidence interval (CI), 1.497-5.109] and lymph node metastasis (HR, 1.937; 95% CI, 1.097 3.419) were independent predictors of mortality. In conclusion, tumor budding is a significant indicator of a high malignant potential and poor prognosis in SqCC of the lung. PMID- 22940761 TI - Physical activity is linked to ceruloplasmin in the striatum of intact but not MPTP-treated primates. AB - Ceruloplasmin is a protective ferroxidase. Although some studies suggest that plasma ceruloplasmin levels are raised by exercise, the impact of exercise on brain ceruloplasmin is unknown. We have examined whether striatal ceruloplasmin is raised with treadmill exercise and/or is correlated with spontaneous physical activity in rhesus monkeys. Parkinson's disease is characterized by a loss in ceruloplasmin and, similarly, Parkinson's models lead to a loss in antioxidant defenses. Exercise might protect against Parkinson's disease and is known to prevent antioxidant loss in experimental models. We have therefore examined whether treadmill exercise prevents ceruloplasmin loss in monkeys treated unilaterally with the dopaminergic neurotoxin MPTP (1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine). We found that exercise raised ceruloplasmin expression in the caudate and accumbens but not the putamen of intact monkeys. However, putamen ceruloplasmin was correlated with spontaneous activity in a home pen. MPTP alone did not cause unilateral loss of ceruloplasmin but blocked the impact of exercise on ceruloplasmin. Similarly, the correlation between putamen ceruloplasmin and activity was also lost with MPTP. MPTP elicited loss of tyrosine hydroxylase in the treated hemisphere; the remaining tyrosine hydroxylase was correlated with overall daily activity (spontaneous activity plus that induced by the treadmill). Thus, treadmill activity can raise ceruloplasmin but this impact and the link with spontaneous activity are both diminished in Parkinsonian primates. Furthermore, low overall physical activity predicts greater loss of dopaminergic phenotype in MPTP-treated primates. These data have implications for the maintenance of active lifestyles in both healthy and neurodegenerative conditions. PMID- 22940762 TI - Utility of head CT in the evaluation of vertigo/dizziness in the emergency department. AB - Acute dizziness (including vertigo) is a common reason to visit the emergency room, and imaging with head CT is often performed initially to exclude a central cause. In this study, consecutive patients presenting with dizziness and undergoing head CT were retrospectively reviewed to determine diagnostic yield. Four hundred forty-eight consecutive head CTs in a representative sample of dizzy emergency room (ER) patients, including patients with other neurological symptoms, were reviewed to identify an acute or subacute cause for acute dizziness along with the frequency and modalities used in follow-up imaging. The diagnostic yield for head CT ordered in the ER for acute dizziness is low (2.2 %; 1.6 % for emergent findings), but MRI changes the diagnosis up to 16 % of the time, acutely in 8 % of cases. Consistent with the American College of Radiology appropriateness criteria and the literature, this study suggests a low diagnostic yield for CT in the evaluation of acute dizziness but an important role for MRI in appropriately selected cases. PMID- 22940763 TI - Haplogrouping mitochondrial DNA sequences in Legal Medicine/Forensic Genetics. AB - Haplogrouping refers to the classification of (partial) mitochondrial DNA (mtDNA) sequences into haplogroups using the current knowledge of the worldwide mtDNA phylogeny. Haplogroup assignment of mtDNA control-region sequences assists in the focused comparison with closely related complete mtDNA sequences and thus serves two main goals in forensic genetics: first is the a posteriori quality analysis of sequencing results and second is the prediction of relevant coding-region sites for confirmation or further refinement of haplogroup status. The latter may be important in forensic casework where discrimination power needs to be as high as possible. However, most articles published in forensic genetics perform haplogrouping only in a rudimentary or incorrect way. The present study features PhyloTree as the key tool for assigning control-region sequences to haplogroups and elaborates on additional Web-based searches for finding near-matches with complete mtDNA genomes in the databases. In contrast, none of the automated haplogrouping tools available can yet compete with manual haplogrouping using PhyloTree plus additional Web-based searches, especially when confronted with artificial recombinants still present in forensic mtDNA datasets. We review and classify the various attempts at haplogrouping by using a multiplex approach or relying on automated haplogrouping. Furthermore, we re-examine a few articles in forensic journals providing mtDNA population data where appropriate haplogrouping following PhyloTree immediately highlights several kinds of sequence errors. PMID- 22940764 TI - Whole genome amplification of degraded and nondegraded DNA for forensic purposes. AB - Degraded DNA is often analyzed in forensic genetics laboratories. Reliable analysis of degraded DNA is of great importance, since its results impact the quality and reliability of expert testimonies. Recently, a number of whole genome amplification (WGA) methods have been proposed as preamplification tools. They work on the premise of being able to generate microgram quantities of DNA from as little as the quantity of DNA from a single cell. We chose, investigated, and compared seven WGA methods to evaluate their ability to "recover" degraded and nondegraded DNA: degenerate oligonucleotide-primed PCR, primer extension preamplification PCR, GenomePlexTM WGA commercial kit (Sigma), multiple displacement amplification, GenomiPhiTM Amplification kit (Amersham Biosciences), restriction and circularization-aided rolling circle amplification, and blunt-end ligation-mediated WGA. The efficiency and reliability of those methods were analyzed and compared using SGMPlus, YFiler, mtDNA, and Y-chromosome SNP typing. The best results for nondegraded DNA were obtained with GenomiPhi and PEP methods. In the case of degraded DNA (200 bp), the best results were obtained with GenomePlex which successfully amplified also severely degraded DNA (100 bp), thus enabling correct typing of mtDNA and Y-SNP loci. WGA may be very useful in analysis of low copy number DNA or degraded DNA in forensic genetics, especially after introduction of some improvements (sample pooling and replicate DNA typing). PMID- 22940765 TI - Comparative evaluation of alternative batteries of genetic markers to complement autosomal STRs in kinship investigations: autosomal indels vs. X-chromosome STRs. AB - Kinship investigations such as paternity are currently solved using sets of (commercially available) highly polymorphic autosomal short tandem repeats (STRs), which lead to powerful likelihood ratios (LR). Still, some difficult cases arise whenever the kinship is much more remote or if the alternative hypotheses are not correctly formulated due to the lack of information (for e.g. there is an unknown relationship between the alleged and the true fathers). In these situations, beyond the routinely used marker set, laboratories usually enlarge the number and/or the type of markers analysed. Among these, autosomal indels and X-chromosome STRs have gained popularity. The aim of this study was to compare the results obtained after complementing an initial set of autosomal STRs with indels or with X-chromosome-specific STRs in simulated paternity cases where the alleged father is a close relative of the real one. Results show that in paternity cases where a low number of incompatibilities are observed, the best strategy is to increase the number of autosomal STRs under analysis. Nevertheless, if these are not available, our study globally shows that in father daughter duos, a set of 12 X-STRs is more advantageous than 38 highly diverse autosomal biallelic markers. Additionally, the usefulness of X-STRs was also evaluated in cases where only a close relative of the alleged parent (father or mother) is available for testing. For those situations where these markers have the power to exclude, strong LR values are obtained. In the remaining cases, LRs are usually weak and sometimes the results are more likely under the wrong kinship hypothesis. PMID- 22940766 TI - Hyperglycemia-induced oxidative stress is independent of excess abdominal adiposity in normal-weight women with polycystic ovary syndrome. AB - STUDY QUESTION: What is the effect of glucose ingestion on leukocytic reactive oxygen species (ROS) generation in normal-weight women with polycystic ovary syndrome (PCOS) with and without excess abdominal adiposity (AA)? SUMMARY ANSWER: Normal-weight women with PCOS exhibit an increase in leukocytic ROS generation in response to glucose ingestion, and this increase is independent of excess AA. WHAT IS KNOWN ALREADY: Excess adipose tissue is a source of oxidative stress. Normal-weight women with PCOS exhibit oxidative stress and can have excess AA. STUDY DESIGN AND SIZE: This is a cross-sectional study involving 30 reproductive age women. PARTICIPANTS/MATERIALS, SETTING AND METHODS: Fourteen normal-weight women with PCOS (6 normal AA, 8 excess AA) and 16 body composition-matched controls (8 normal AA, 8 excess AA) underwent body composition assessment by dual energy absorptiometry and an oral glucose tolerance test (OGTT) at a university medical center. Insulin sensitivity was derived from the OGTT (IS(OGTT)). Blood was drawn while fasting and 2 h after glucose ingestion to measure leukocytic ROS generation and p47(phox) protein content and plasma thiobarbituric acid-reactive substances (TBARS) and C-reactive protein (CRP). MAIN RESULTS AND THE ROLE OF CHANCE: Compared with controls, both PCOS groups exhibited lower IS(OGTT) (43 54%) and greater percentage change (% change) in ROS generation (96-140%), p47(phox) protein (18-28%) and TBARS (17-48%). Compared with women with PCOS with excess AA, those with normal AA exhibited higher testosterone levels (29%) and lower CRP levels (70%). For the combined groups, IS(OGTT) was negatively correlated with the % change in ROS generation and p47(phox) protein. CRP was positively correlated with abdominal fat. The % change in p47(phox) protein was positively correlated with CRP and androgens. LIMITATIONS, REASONS FOR CAUTION: Although this study is adequately powered to assess differences in ROS generation between the women with PCOS and control participants, the modest sample size merits caution when interpreting the corroborative results of the additional measures of oxidative stress and inflammation. WIDER IMPLICATIONS OF THE FINDINGS: This study highlights the unique pro-oxidant contribution of circulating leukocytes in the development of insulin resistance and hyperandrogenism in PCOS. STUDY FUNDING/COMPETING INTEREST(S): Supported by NIH grant HD-048535 to F.G. The authors have nothing to disclose. PMID- 22940767 TI - Live birth rates following natural cycle IVF in women with poor ovarian response according to the Bologna criteria. AB - STUDY QUESTION: What is the effect of natural cycle IVF in women with poor ovarian response according to the new ESHRE definition for poor ovarian responders: the Bologna criteria? SUMMARY ANSWER: Although natural cycle IVF is a promising treatment option for normal responders, poor ovarian responders, as described by the Bologna criteria, have a very poor prognosis and do not appear to experience substantial benefits with natural cycle IVF. WHAT IS KNOWN ALREADY: Previous trials have shown that natural cycle IVF is an effective treatment for the general infertile population and might be an option for poor ovarian responders. However, none of the trials have examined the effect of natural cycle IVF in poor responders according to the Bologna criteria, the newly introduced definition by the ESHRE Working Group on Poor Ovarian Response Definition. In this trial, we examined the effect of natural cycle IVF in poor ovarian responders fulfilling the Bologna criteria. STUDY DESIGN, SIZE, DURATION: In this retrospective cohort trial, 164 consecutive patients, undergoing 469 natural cycle IVFs between 2008 and 2011 were included. Patients were stratified as poor and normal responders: 136 (390 cycles) were poor ovarian responders according to the Bologna criteria, whereas 28 women (79 treatment cycles) did not fulfil the criteria and were considered as normal responders. PARTICIPANTS/MATERIALS, SETTING, METHODS: All patients were monitored with hormonal analysis and ultrasound scan every second day, from Day 7 or 8 of the cycle onwards. When a follicle of >16 mm was observed, ovulation was triggered with 5000 IU of i.m. hCG and oocyte retrieval was performed 32 h later. MAIN RESULTS AND THE ROLE OF CHANCE: Live birth rates in poor responders according to the Bologna criteria were significantly lower compared with the control group of women; the live birth rate per cycle was 2.6 versus 8.9%, P = 0.006 and the live birth rate per treated patient was 7.4 versus 25%, P = 0.005. In poor responders according to the Bologna criteria, live birth rates were consistently low and did not differ among different age groups (<= 35 years, 36-39 years and >= 40 years), with a range from 6.8 to 7.9%. LIMITATIONS, REASONS FOR CAUTION: A limitation of our analysis is its retrospective design; however, taking into account that we included only consecutive patients treated with exactly the same protocol, the likelihood of selection bias might be considerably limited. In addition, the control group in our study refers to women of younger age and therefore the promising results among patients who did not fulfil the Bologna criteria apply only to women of younger age. WIDER IMPLICATIONS OF THE FINDINGS: Our trial suggests that although natural cycle IVF is a promising treatment option for younger normal responders, its potential is very limited to poor ovarian responders as described by the Bologna criteria, irrespective of patient's age. This highlights the very poor prognosis of these women and therefore the urgent need for future trials to examine the effect of ovarian stimulation protocols in women with poor ovarian response as described by the Bologna criteria. STUDY FUNDING/COMPETING INTEREST(S): No funding was used. There are no competing interests to declare. PMID- 22940769 TI - Intake of food groups and idiopathic asthenozoospermia: a case-control study. AB - STUDY QUESTION: Is there any association between the intake of different food groups and the risk of idiopathic asthenozoospermia? SUMMARY ANSWER: A high intake of processed meat and sweets was positively associated with a higher risk of asthenozoospermia, whereas a high intake of fruits, vegetables, poultry, skim milk and sea foods was associated with a lower risk. WHAT IS KNOWN ALREADY: A high intake of lipophilic foods like meat products or milk may be negatively associated with semen quality in humans, whereas some fruits or vegetables may maintain or improve semen quality. STUDY DESIGN, SIZE, DURATION: A case-control study including 72 asthenozoospermic men and 169 normozoospermic men all from infertile couples who underwent face-to-face private interviews, from January 2011 to December 2011. PARTICIPANTS/MATERIALS, SETTING, METHODS: Semen was assessed by volume, sperm concentration, motility and morphology. Usual dietary intakes were assessed using a semi-quantitative food frequency questionnaire. Odds ratios (ORs), 95% confidence intervals (CIs) and evaluation of trends were calculated using logistic regression. The first tertile served as the reference category for regression analyses. MAIN RESULTS AND THE ROLE OF CHANCE: After adjusting for potential confounders, the risk of asthenozoospermia was significantly higher in the highest tertiles of processed meat (OR: 2.03, 95% CI: 1.70-2.44) and sweets intake (OR: 2.05, 95% CI: 1.09-2.26). Conversely, being in the highest tertile of total fruits and vegetables, the intake of dark green vegetables, skim milk, poultry and sea food intake was associated with a lower risk of asthenozoospermia (P for trend = 0.04, 0.01, 0.02, 0.03 and 0.04, respectively). LIMITATIONS, REASONS FOR CAUTION: Recall bias, selection bias and measurement bias are inevitable in this kind of study and residual confounding due to omission or imprecise measurement of important covariates remains possible. WIDER IMPLICATIONS OF THE FINDINGS: Patients with asthenozoospermia should be advised to adhere to a diet rich in fruits, vegetables, poultry, skim milk and sea foods while low in processed meat and sweets. STUDY FUNDING/COMPETING INTEREST(S): This study was financially supported by the National Nutrition and Food Technology Research Institute, Faculty of Nutrition and Food Technology, Shahid Beheshti University of Medical Science, Tehran, Iran. No conflict of interests to declare. PMID- 22940768 TI - Paternal age at birth is associated with offspring leukocyte telomere length in the nurses' health study. AB - STUDY QUESTION: Is the association between paternal age at birth and offspring leukocyte telomere length (LTL) an artifact of early life socioeconomic status (SES)? SUMMARY ANSWER: Indicators of early life SES did not alter the relationship between paternal age at birth and offspring LTL among a population of white female nurses. WHAT IS KNOWN ALREADY: Telomere length is considered a highly heritable trait. Recent studies report a positive correlation between paternal age at birth and offspring LTL. Maternal age at birth has also been positively associated with offspring LTL, but may stem from the strong correlation with paternal age at birth. STUDY DESIGN, SIZE AND DURATION: The Nurses' Health Study (NHS) is an ongoing prospective cohort study of 121 700 female registered nurses who were enrolled in 1976. Great effort goes into maintaining a high degree of follow-up among our cohort participants (>95% of potential person-years). In 1989-1990, a subset of 32 826 women provided blood samples from which we selected participants for several nested case-control studies of telomere length and incident chronic disease. We used existing LTL data on a total of 4250 disease-free women who also reported maternal and paternal age at birth for this study. PARTICIPANTS/MATERIALS, SETTING AND METHODS: Nested case-control studies of stroke, myocardial infarction, cancers of the breast, endometrium, skin, pancreas and colon, as well as colon adenoma, were conducted within the blood sub-cohort. Each study used the following study design: for each case of a disease diagnosed after blood collection, a risk-set sampling scheme was used to select from one to three controls from the remaining participants in the blood sub-cohort who were free of that disease when the case was diagnosed. Controls were matched to cases by age at blood collection (+/- 1 year), date of blood collection (+/- 3 months), menopausal status, recent postmenopausal hormone use at blood collection (within 3 months, except for the myocardial infarction case-control study), as well as other factors carefully chosen for each individual study. The current analysis was limited to healthy controls. We also included existing LTL data from a small random sample of women participating in a cognitive sub-study. LTL was measured using the quantitative PCR-based method. Exposure and covariate information are extracted from biennial questionnaires completed by the participants. MAIN RESULTS AND THE ROLE OF CHANCE: We found a strong association between paternal age at birth and participant LTL (P = 1.6 * 10(-5)) that remained robust after controlling for indicators of early life SES. Maternal age at birth showed a weak inverse association with participant LTL after adjusting for age at blood collection and paternal age at birth (P = 0.01). We also noted a stronger association between paternal age at birth and participant LTL among premenopausal than among postmenopausal women (P(interaction) = 0.045). However, this observation may be due to chance as premenopausal women represented only 12.6% (N = 535) of the study population and LTL was not correlated with age at menopause, total or estrogen-only hormone therapy (HT) use suggesting that changes in in vivo estrogen exposure do not influence telomere length regulation. LIMITATIONS AND REASONS FOR CAUTION: The women in our study are not representative of the general US female population, with an underrepresentation of non-white and low social class groups. Although the interaction was not significant, we noted that the paternal age at birth association with offspring LTL appeared weaker among women whose parents did not own their home at the time of the participant's birth. As telomere dynamics may differ among individuals who are most socioeconomically deprived, SES indicators may have more of an influence on the relationship between paternal age at birth and offspring LTL in such populations. WIDER IMPLICATIONS OF THE FINDINGS: As of yet, our and prior studies have not identified childhood or adult characteristics that confound the paternal age at birth association with offspring LTL, supporting the hypothesis that offspring may inherit the longer telomeres found in sperm of older men. The biological implications of the paternal age effect are unknown. A recent theory proposed that the inheritance of longer telomere from older men may be an adaptive signal of reproductive lifespan, while another theory links telomere length attrition to female reproductive senescence. However, we are unaware of any data to substantiate a relationship between paternal age at birth and daughter's fertility. Generalizability of our study results to other white female populations is supported by prior reports of paternal age at birth and offspring telomere length. Furthermore, a confounding relationship between paternal or maternal age at birth and SES was not observed in a study of SES and telomere length. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by the National Institutes of Health (grants numbers: CA87969, CA49449, CA065725, CA132190, CA139586, HL088521, CA140790, CA133914, CA132175, ES01664 to M.D.); and by the American Health Association Foundation. We have no competing interests to declare. PMID- 22940770 TI - Common chromosomal imbalances and stemness-related protein expression markers in endometriotic lesions from different anatomical sites: the potential role of stem cells. AB - BACKGROUND: Endometriosis is a multifactorial gynecological disease characterized by the presence of functional endometrium-like tissue in ectopic sites. Several studies have focused on elucidating the immunological, endocrine, environmental and genetic factors involved in endometriosis. However, its pathogenesis is still unclear. METHODS: High-resolution comparative genomic hybridization was applied to screen for genomic imbalances in laser microdissected stromal and epithelial cells from 20 endometriotic lesions and three samples of eutopic endometrium derived from eight patients. The expression of seven stemness-related markers (CD9, CD13, CD24, CD34, CD133, CD117/c-Kit and Oct-4) in endometrial tissue samples was evaluated by immunohistochemistry. RESULTS: Samples of eutopic endometrium showed normal genomic profiles. In ectopic tissues, an average of 68 genomic imbalances was detected per sample. DNA losses were more frequently detected and involved mainly 3p, 5q, 7p, 9p, 11q, 16q, 18q and 19q. Many of the genomic imbalances detected were common to endometriotic stroma and epithelia and also among different endometriotic sites from the same patient. These findings suggested a clonal origin of the endometriotic cells and the putative involvement of stem cells. Positive immunostaining for CD9, CD34, c-Kit and Oct-4 markers was detected in isolated epithelial and/or stromal cells in eutopic and ectopic endometrium in the majority of cases. CONCLUSIONS: The presence of shared genomic alterations in stromal and epithelial cells from different anatomical sites of the same patient and the expression of stemness-related markers suggested that endometriosis arises as a clonal proliferation with the putative involvement of stem cells. PMID- 22940771 TI - Motile sperm organelle morphology evaluation-selected globozoospermic human sperm with an acrosomal bud exhibits novel patterns and higher levels of phospholipase C zeta. AB - STUDY QUESTION: Does motile sperm organelle morphology examination (MSOME) affect levels and localization patterns of the oocyte activation factor phospholipase C zeta (PLCzeta) in globozoospermic sperm with and without an acrosomal bud? SUMMARY ANSWER: MSOME identified round-headed globozoospermic sperm with increased levels of PLCzeta relative to sperm from the same sample that did not undergo MSOME, and identified novel patterns of PLCzeta localization in sperm exhibiting an acrosomal bud. WHAT IS KNOWN ALREADY: Absence or reduction in the level of PLCzeta in the sperm head, abnormal localization patterning, or defective functional ability as a result of PLCzeta gene mutation, have been linked to certain types of human male factor infertility in which oocyte activation is deficient. It has been determined that a subpopulation of sperm (1%) from a patient exhibiting 100% globozoospermia presented with an acrosome bud upon MSOME. A cycle of intracytoplasmic morphologically selected sperm injection, carried out with sperm exhibiting an acrosomal bud led to pregnancy and birth of a healthy baby boy, without the use of assisted oocyte activation (AOA). STUDY DESIGN, SIZE, DURATION: Immunofluorescent analysis of PLCzeta in globozoospermic sperm from three patients, before and after MSOME. PARTICIPANTS/MATERIALS, SETTING, METHODS: Quantitative immunofluorescence was used to investigate PLCzeta levels and localization patterns in individual sperm (n = 1 patient) identified by MSOME and isolated by micromanipulation, and presenting with and without the acrosomal bud. A secondary aim was to investigate levels and localization patterns of PLCzeta in sperm before and after MSOME from two other globozoospermic men. MAIN RESULTS AND THE ROLE OF CHANCE: Non globozoospermic control sperm exhibited characteristic localization patterns of PLCzeta immunofluorescence. Completely round-headed globozoospermic sperm from patients 1-3 were either devoid of PLCzeta immunofluorescence, or exhibited an abnormal, punctate, pattern of PLCzeta localization. PLCzeta immunofluorescence in sperm exhibiting an acrosomal bud was observed in the midpiece with varying fluorescent intensity and was detected in 28.5% of such sperm. The majority of sperm with an acrosomal bud (43.0%) exhibited punctate patterns of PLCzeta localization within the sperm head. A further 28.5% of sperm exhibited PLCzeta in both the head and the midpiece. Total levels of PLCzeta, and the proportions of sperm exhibiting PLCzeta immunoreactivity, showed significant variance (P <= 0.05) amongst control [45.8 arbitrary units (a.u.) and 95.7%, respectively], non MSOME-selected (25.9 a.u. and 46.1%, respectively) and MSOME-selected globozoospermic sperm (33.4 a.u. and 65.0%, respectively). Total levels of PLCzeta immunofluorescence, and proportions of sperm exhibiting PLCzeta immunoreactivity, in control sperm was significantly higher (P<= 0.05) compared with non-MSOME-selected sperm, but not significantly different from MSOME selected sperm. LIMITATIONS, REASONS FOR CAUTION: The low numbers of sperm analysed may not be ideal for conclusive statistical analysis. Evaluation of the effects of MSOME on morphologically normal sperm would confirm conclusions. WIDER IMPLICATIONS OF THE FINDINGS: The present findings provide hope for the future treatment of globozoospermia without the need for AOA, and provide further evidence for the clinical application of PLCzeta as a therapeutic and prognostic tool. STUDY FUNDING/COMPETING INTEREST(S): The research described herein was funded by the Nuffield Department of Obstetrics and Gynaecology, University of Oxford. The authors report no conflict of interest. PMID- 22940772 TI - Patterns of local recurrence after radical cystectomy in a contemporary series of patients with muscle-invasive bladder cancer. AB - PURPOSE: To describe the epidemiology, clinical features, and prognostic factors of local recurrence (LR) in a large case series of patients treated by radical cystectomy (RC) for bladder cancer. METHODS: A retrospective study was conducted on 903 patients treated in a single tertiary reference center. All cases of LR were identified. Descriptive analysis was performed on the clinical features, evolution, and overall mortality of these patients. Prognostic factors of LR were assessed using the Mann-Whitney test for continuous variables and the chi(2) test for categorical variables. RESULTS: Fifty-three patients were diagnosed with LR during follow-up (5.9 %). One patient had concomitant distant metastasis. Pain was the most frequent symptom leading to diagnosis. Mean time interval from RC to LR was 14.4 +/- 13 months (1-64) with 50 % of cases diagnosed in the first postoperative year. Overall median survival of patients diagnosed with LR was 9 months [95 % confidence interval (6-11)]. Advanced pathological stage (T3 or T4) and lymph-node invasion were associated with increased LR rate in univariate and multivariate analysis. Presence of squamous cell carcinoma (SCC) was associated with a poorer prognosis after LR compared to pure urothelial carcinoma (p = 0.04). None of the parameters tested was associated with time interval between RC and LR diagnosis. CONCLUSIONS: LR is not uncommon, favored by high pathological stage (T3/T4), and has a very bad prognosis, particularly when SCC is present. LR must be carefully tracked during follow-up after RC, and optimal management of these cases remains to be determined. PMID- 22940773 TI - Lower urinary tract symptoms in relation to region of birth in 95,393 men living in Australia: the 45 and Up Study. AB - PURPOSE: Lower urinary tract symptoms (LUTS) are very common among older men globally, but evidence regarding the relationship between LUTS and country of origin is limited. This study aimed to investigate the relationship between the prevalence of LUTS and region of birth in a large, ethnically diverse population of older men resident in New South Wales, Australia. METHODS: Data on LUTS, demographic and behavioural factors were collected by postal questionnaire from 2006 to 2009 and analysed for 95,393 men aged 45 and over from the 45 and Up Study, who had not had previous prostate surgery. Logistic regression was used to investigate the association between region of birth and moderate/severe LUTS, ascertained using a modified International Prostate Symptom Score, adjusting for age, income, education, alcohol consumption and smoking. RESULTS: Overall, 18,530 (19.4 %) men had moderate or severe LUTS. Compared to Australian-born men, prevalence of moderate/severe LUTS was significantly higher in men born in the Middle East & North Africa, Southeast Asia and North America regions (adjusted odds ratios (OR) = 1.43; 95 % CI = 1.23-1.66, OR = 1.25; 1.10-1.42, OR = 1.26; 1.05-1.52, respectively), whereas men from the UK & Ireland had significantly lower prevalence (OR = 0.85; 0.80-0.90). Patterns of association were generally similar for storage- and voiding-related types of LUTS. However, participants born in Sub-Saharan Africa showed a significantly elevated prevalence of moderate/severe voiding symptoms (1.22; 1.03-1.45) but not storage symptoms, compared to Australian-born respondents. CONCLUSION: The prevalence of LUTS and of specific subtypes of LUTS varies according to region of birth. PMID- 22940774 TI - Preliminary observations of MHC class I A region polymorphism in three populations of Chinese-origin rhesus macaques. AB - Rhesus macaques are an animal model for the study of a variety of human diseases. The Chinese rhesus macaques have been widely used in biomedical research in recent years. However, the polymorphism of major histocompatibility complex (MHC) class I A region among different local populations of Chinese rhesus macaques has never been investigated. In this study, we identified 46 Mamu-A alleles by cDNA cloning and sequencing on a cohort of 53 Chinese rhesus monkeys including Zhiming, Chuanxi, and Fujian populations, of which 5 were first reported in rhesus monkeys. The frequencies of alleles were identified for each population. The result suggests that the repertoire of allelic variants of MHC class I A region found in different populations of Chinese macaques is largely non overlapping. The frequencies of alleles and the popular allele are also different for different populations. PCR-SSP experiment further confirms the different frequencies of two alleles, Mamu-A*026:01 and Mamu-A*022:01, in additional 99 Zhiming monkeys and 191 Chuanxi monkeys. Our findings have important practical implications in that the origin of the individuals and the genetic polymorphism of the monkeys need to be considered at the level of local populations for Chinese rhesus monkeys in biomedical research. Further immunogenetic work is needed to investigate the MHC polymorphism among different populations of Chinese rhesus macaques and to reveal the functional implication of such polymorphism and disease outcome correlations. PMID- 22940775 TI - Enhanced proliferation of human hepatoma cells by PAR-2 agonists via the ERK/AP-1 pathway. AB - To investigate the expression and role of PAR-2 in the proliferation of the human hepatoma cell line HepG2, PAR-2 protein and mRNA expression were evaluated by immuno-histochemistry, immunofluorescence and RT-PCR analysis. The signaling pathways downstream of PAR-2 activation that lead to hepatoma cell proliferation were analyzed. The results showed that PAR-2 is expressed in human hepatoma cells and PAR-2 mRNA expression was found to be upregulated in cells treated with trypsin or SLIGKV-NH2 (P<0.001). The proliferation rate of HepG2 cells treated with trypsin or SLIGKV-NH2 was significantly increased (P<0.001). The percentage of S phase, G2/M phase and the proliferation index (PI) of HepG2 cells treated with trypsin or SLIGKV-NH2 were significantly elevated (P<0.001). The proliferative responses of HepG2 to trypsin and SLIGKV-NH2 were associated with the upregulation of c-fos and PCNA, which were significantly blocked by PD98059 pretreatment. In conclusion, our results indicate that PAR-2 enhances proliferation of human hepatoma cells possibly via the ERK/AP-1 pathway. PMID- 22940776 TI - Comparative photodynamic inactivation of antibiotic resistant bacteria by first and second generation cationic photosensitizers. AB - Photodynamic inactivation (PDI) is an efficient approach against a wide range of microorganisms and can be viewed as an alternative for the treatment of microbial infections. In this work we synthesized "first" and "second" generation photosensitizers (PSs), the tetra-cationic porphyrin and the new penta-cationic chlorin , respectively, and evaluated their efficiency against two antibiotic resistant bacterial strains, Staphylococcus aureus and Pseudomonas aeruginosa. The PS was obtained in very good yield by an easy synthesis method. The PDI studies were performed in parallel with 5,10,15,20-tetrakis(1-methylpyridinium-4 yl)porphyrin tetra-iodide (), a widely studied PS in PDI, and the obtained results were compared. Two different light ranges were used: white light (400-800 nm) and red light (530-800 nm) delivered at a fluence rate of 150 mW cm(-2). The results show that both strains, even though antibiotic resistant, were efficiently inactivated by the three PSs, chlorin being the most effective. For the Gram positive bacterium S. aureus a 7.0 log reduction was observed after 5-10 min of irradiation, at a concentration of 0.5 MUM, whereas for the Gram negative P. aeruginosa, similar photoinactivation occurred at a higher PS concentration (10 MUM) and after a longer irradiation period (30 min). The synthetic chlorin can be regarded as promising for the treatment of bacterial infections under red light, which penetrates deeper in living tissues. The results of this study open the possibility to prepare a new series of chlorin-type derivatives to efficiently photoinactivate Gram (+) and (-) antibiotic resistant bacteria. The efficient PDI with the chlorin indicates high potential for the use of a scaffold in the preparation of new generation PSs based on cationic chlorin derivatives. PMID- 22940778 TI - Nonlinear optical properties for a class of hexa-peri-hexabenzocoronene chromophores: a computational investigation. AB - The systematic investigation of the linear and nonlinear optical properties on such a class of hexa-peri-hexabenzocoronene (HBC) chromophores is of significance for rationally designing two-photon absorption (TPA) materials. The results indicate that increasing the strength of electron-donating or accepting terminal groups leads to bathochromic-shift of the absorption band and enhancement of the TPA cross section (delta(max)). For the molecules with fluorinated methylene and cyano substituents, replacement of a double bond by a triple bond in the conjugated linker produces the increase of delta(max), owing to the lower bond length alternation and better rigidity of phenylene-ethynylene. In contrast, for the molecules with nitro groups, the similar replacement results in a slight decrease of delta(max) because N-HBC-E-NO2 has excellent planarity architecture and effective electronic coupling. The TPA spectra are red-shifted and the delta(max) values are enhanced as the number of branches increases. Thus, a solvatochromism effect has a positive influence on the TPA response of the nitryl compounds due to larger polarization of the nitro moiety. We have shed light on the linear relationship between the first hyperpolarizability and delta(max). These HBC derivatives hold potential as high-performance nonlinear optical materials. PMID- 22940777 TI - The beneficial effects of a direct thrombin inhibitor, dabigatran etexilate, on the development and stability of atherosclerotic lesions in apolipoprotein E deficient mice : dabigatran etexilate and atherosclerosis. AB - PURPOSE: Dabigatran etexilate (DE) constitutes a novel, direct thrombin inhibitor. Regarding the association of thrombin with atherogenesis, we assessed the effects of DE on the development and stability of atherosclerotic lesions in apolipoprotein-E deficient (ApoE-/-) mice. MATERIALS-METHODS: Fifty male ApoE-/- mice were randomized to receive western-type diet either supplemented with DE 7.5 mg DE/g chow) (DE-group, n = 25) or matching placebo as control (CO-group, n = 25) for 12 weeks. After this period, all mice underwent carotid artery injury with ferric chloride and the time to thrombotic total occlusion (TTO) was measured. Then, mice were euthanatized and each aortic arch was analyzed for the mean plaque area, the content of macrophages, elastin, collagen, nuclear factor kappaB (NFkappaB), vascular cell adhesion molecule-1 (VCAM-1), matrix metalloproteinase-9 (MMP-9) and its inhibitor (TIMP-1). RESULTS: DE-group showed significantly longer TTO compared to CO-group (8.9 +/- 2.3 min vs 3.5 +/- 1.1 min, p < 0.001) and the mean plaque area was smaller in DE-group than CO-group (441.00 +/- 160.01 * 10(3) MUm(2) vs 132.12 +/- 32.17 * 10(3) MUm(2), p < 0.001). Atherosclerotic lesions derived from DE-treated mice showed increased collagen (p = 0.043) and elastin (p = 0.031) content, thicker fibrous caps (p < 0.001) and reduced number of internal elastic lamina ruptures per mm of arterial girth (p < 0.001) when compared to CO-group. Notably, DE treatment seemed to promote plaque stability possibly by reducing concentrations of NFkappaB, VCAM-1, macrophages and MMP-9 and increasing TIMP-1 within atherosclerotic lesions (p < 0.05). CONCLUSIONS: DE attenuates arterial thrombosis, reduces lesion size and may promote plaque stability in ApoE-/- mice. The plaque-stabilizing effects of chronic thrombin inhibition might be the result of the favorable modification of inflammatory mechanisms. PMID- 22940779 TI - The results of corrective osteotomy for valgus arthritic knees. AB - PURPOSE: To evaluate the results of corrective varus osteotomy in the treatment of arthritic knees with valgus deformity. METHODS: The data were retrieved from a literature review. Each relevant study was screened for demographic details, surgical techniques, follow-up periods, clinical outcomes, and complications. RESULTS: A total of 27 publications describing the results of varus osteotomies for valgus arthritic knees were reviewed. All were small case series studies, variable in their patient population, surgical techniques, rehabilitation protocols, follow-up periods, clinical assessments and were categorized as level IV of scientific evidence. CONCLUSION: The role of varus osteotomy remains poorly defined. The literature generally supports this procedure in active and cooperative patients to reduce pain and delay the need for knee replacement. New techniques hold promising results regarding shortening of rehabilitation time and low reoperation and complication rates. LEVEL OF EVIDENCE: IV. PMID- 22940780 TI - Repeatability of relative peripheral refraction in untreated and orthokeratology treated eyes. AB - PURPOSE: To determine the repeatability of relative peripheral refraction (RPR) measurements using an open-view automatic refractor in untreated and orthokeratology (ortho-k)-treated eyes of children. METHODS: Cycloplegic central (CR) and peripheral refraction (PR) across the central 60 degrees horizontal field at 10 degrees intervals were measured in children (6-9 years) using a Shin Nippon NVision K5001 autorefractor. In experiment 1, measurements were repeated at the same visit for 59 untreated (right) eyes, whereas in experiment 2, measurements were repeated at the same visit and another visit (1-2 weeks apart) for 24 ortho-k-treated (right) eyes to determine the intra- and intervisit repeatability, respectively. Measurements were transposed into M, J0, and J45 vectors, and RPR were calculated by subtracting central refraction from PR values. Intra- and intervisit differences and coefficients of repeatability (COR) of RPR were determined. RESULTS: The mean intravisit differences in RPR for all three vectors were <=0.05 D for untreated eyes, and both intra- and intervisit differences in RPR were <=0.32 D for ortho-k-treated eyes. No significant intra- and intervisit differences in RPR were found at any field angle in this study. COR of measurements were <+/-0.71 D in the untreated eyes, and <+/-1.25 D (intravisit) and <+/-3.00 D (intervisit) in ortho-k-treated eyes. The COR increased with field angles in all situations and were greater in ortho-k-treated than in untreated eyes. In ortho-k-treated eyes, intervisit COR of measurements beyond central 40 degrees field were larger than the intravisit COR. CONCLUSIONS: The mean intra- and intervisit differences of RPR measurements were small in both untreated and ortho-k-treated eyes. Variability of PR measurements increased with field angle and with ortho-k treatment. PMID- 22940782 TI - Accommodative response/stimulus by dynamic retinoscopy: near add guidelines. AB - PURPOSE: Monocular estimation method (MEM) dynamic retinoscopy and low neutral (LN) dynamic retinoscopy are common procedures for evaluating the need for near point plus adds for improved near-point performance in non-presbyopes. A combination of MEM and LN has been suggested to be a method of plotting accommodative response/accommodative stimulus functions and evaluating guidelines for prescribing from MEM. METHODS: Using a combined MEM-LN procedure, MEM was performed on 80 young adults at 40 cm, with distance correction and with plus adds in 0.25 D steps up to and including +2.00 D. Modified Thorington dissociated phorias were also performed with each of the plus adds. Subjects picked a preferred add, which subjectively made print easiest and most comfortable to read. RESULTS: The mean preferred add was +0.58 D over the distance prescription. The add derived from subtracting 0.25 D from the lag of accommodation with distance correction averaged 0.10 D more plus than the preferred add. The add at which dynamic retinoscopy showed a "with" motion of 0.25 D averaged 0.54 more plus than the preferred add. The add at which dynamic retinoscopy showed a "with" motion of 0.50 D averaged 0.16 more plus than the preferred add. CONCLUSIONS: Adds derived from subtracting 0.25 D from the lag with distance correction and from finding the add that yields 0.50 D of "with" motion compared favorably with the preferred adds on average, but the standard deviations of the differences were high. Those guidelines could be reasonable starting points for the prescription of near-point plus adds for non-presbyopes, but follow-up testing to confirm or adjust add power would be advisable in the clinical setting. PMID- 22940781 TI - Transepithelial cross-linking in keratoconus patients: confocal analysis. AB - PURPOSE: To analyze the modifications of the corneal layers after transepithelial (TE) corneal cross-linking (CXL). METHODS: Twenty eyes of 20 patients with progressive keratoconus were treated with TE-CXL (without epithelium debridement), and their corneas analyzed at different times, up to 18 months, by confocal microscopy using a Nidek Confoscan 4. RESULTS: The epithelial layer, after an initial disorganization due to the TE technique, returned to a normal state after 2 weeks. Keratocytes and nerve fibers in the stroma decreased in number (approximately 25%), to return to a normal density at about 6 months after the procedure. A demarcation dense line indicative of effective cross-linking could be observed after 6 months at a depth of around 60 MUm below the Bowman membrane. The endothelium remained unaffected at all examination times. CONCLUSIONS: The TE-CXL procedure appears to be safe and effective at least up to 18 months. The absence of epithelium debridement (necessary in the classical technique) makes the procedure more comfortable for the patient, and allows the treatment of thinner corneas (between 360 and 400 MUm) and problematic patients. PMID- 22940783 TI - Progressive addition lens measurement by point diffraction interferometry. AB - PURPOSE: Design a device for accurate measurements of local optical properties of progressive addition lenses (PALs). METHODS: A point diffraction interferometer has been adapted to measure local prescriptions of PALs. RESULTS: The most basic configuration of the interferometer for the measurement of PALs showed in this work presents high dynamic range and accuracy as well as the possibility of choosing the number and position of measurement points. Measurements are taken within a region of interest within a radius of about 0.4 to 1.5 mm. Different PAL designs are measured by the method proposed here and compared with results by a last generation commercial lens mapper. With the point diffraction interferometer we also compared several PAL designs in order to analyze their properties in the progression zone. CONCLUSIONS: The device is compact, robust, and fairly accurate, and the operational principle is very simple. By direct measurements it provides the local dioptric power, i.e., the second order wavefront properties, of the lens for selected regions of interest. The position and area can be chosen by the user. The only mobile part of the setup allows for the selection of the measurement points without any additional prismatic correction or movement of the PAL. PMID- 22940784 TI - Simulating images seen by patients with inhomogeneous sensitivity losses. AB - PURPOSE: We aim to simulate how colored images are perceived by subjects with local achromatic and chromatic contrast sensitivity losses in the visual field (VF). METHODS: The spatiochromatic corresponding pair algorithm, introduced in a previous article (J Opt Soc Am (A) 2004;21:176-186), has been implemented with a linear model of the visual system. Spatial information is processed separately by the chromatic and achromatic mechanisms by means of a multiscale model, with sensors selective to frequency, orientation, and spatial position, whose mechanism-dependent relative weights change with the spatial location of the image. These weights have been obtained from perimetric data from a patient with Leber's Hereditary Optic Neuropathy and an age-matched sample of normal subjects, using achromatic, red-green, and blue-yellow gratings of different spatial frequencies. Distortion contours for each mechanism have been derived from the images simulating the perception of these subjects at different locations in the VF. RESULTS: The images simulating the perception of normal subjects at different locations of the VF show a fast decrease in image quality with eccentricity. The same analysis carried out with the Leber's Hereditary Optic Neuropathy patient reveals worse overall image quality throughout the VF, plus a color vision defect resembling red-green dichromacy at fovea and trichromatic anomaly in the rest of the VF. CONCLUSIONS: In the present article, we show that implementing the algorithm with a spatial vision model that considers the changes in contrast sensitivity with spatial location of the stimulus may reveal the local effects that are suffered, in general, by pathological subjects, and that are ignored by simpler spatial vision models. PMID- 22940785 TI - Surgical control of limbic encephalitis associated with LGI1 antibodies. AB - Limbic encephalitis with LGI1 antibodies may cause drug-resistant temporal lobe epilepsy. We report a case of a young man with progressive drug-resistant focal epilepsy, hyperhidrosis, and memory impairment associated with a left mesial temporal lesion. Epilepsy surgery was performed with the provisional diagnosis of cortical dysplasia or tumour. A neuropathological study following amygdalohippocampectomy revealed limbic encephalitis and LGI1 antibodies were identified in the serum. Two and a half years after surgery, the patient remains seizure-free without medication, with normal memory and without hyperhidrosis. Although immunosuppression is the first-line therapy for autoimmune limbic encephalitis, this case suggests that, in selected cases, a lasting response can be achieved with surgery. PMID- 22940786 TI - Enhanced histamine production through the induction of histidine decarboxylase expression by phorbol ester in Jurkat cells. AB - Histamine (HA), a mediator of inflammation, type I allergic responses and neurotransmission, is synthesized from L-histidine, the reaction of which is catalyzed by histidine decarboxylase (HDC). HDC has been reported to be induced by various stimuli, not only in mast cells and basophils, but also in T lymphocytes and macrophages. Although its mRNA has been shown to be increased in Jurkat cells when treated with phorbol 12-myristate 13-acetate (TPA), little is known concerning the induced production of HA by HDC. The present study quantified the trace amounts of intracellular HA using ultra-high liquid chromatography in combination with the 6-aminoquinoline carbamate-derivatization technique. To test whether the cellular level of HA is elevated by the induction of HDC in Jurkat cells treated with TPA, the peak corresponding to authentic HA in the cell lysate was fractioned and its molecular weight determined by matrix assisted laser desorption/ionization quadrupole ion trap time-of-flight mass spectrometry. The results of this study show that the HA level is increased by the induction of HDC expression by TPA in Jurkat cells. Therefore, this method is useful in elucidating the physiological significance of HA production. PMID- 22940787 TI - Low intensity cognitive behavioural therapy for psychosis: a pilot study. AB - BACKGROUND AND OBJECTIVES: The dissemination and delivery of psychological therapies for people with psychosis has been limited by workforce and organisational factors. 'Low Intensity' (LI) delivery, whereby staff are trained to deliver brief, focused, manualised interventions, may be one way of improving access. In this study, we piloted a new LI intervention specifically for people with psychosis, aimed at helping people to reach a personal recovery goal, whilst targeting anxious avoidance or depression-related inactivity. Frontline mental health workers were trained to deliver the intervention. We report here on the impact of the intervention on therapeutic outcomes. METHODS: Twelve people with psychosis and either anxious avoidance or low mood, who wanted to work towards a personal goal, completed the intervention and a battery of assessments of mood, functioning and psychotic symptoms. RESULTS: Eleven out of the twelve participants achieved their personal goals. The results of a series of Friedman K related sample tests revealed significant improvements in depression, clinical distress, activity levels, negative symptoms and delusions across the three time points, and no change in hallucinations, or anxious avoidance. Staff and participant satisfaction was high. LIMITATIONS: The study is a small uncontrolled pilot study. Outcomes should therefore be interpreted with caution, pending replication. CONCLUSIONS: The new LI intervention shows preliminary evidence of effectiveness and is a feasible model of therapy delivery for people with psychosis. The results suggest that frontline mental health workers can be trained relatively easily to deliver the intervention. A larger, randomised controlled trial is warranted to determine the effectiveness of the intervention and training programme. PMID- 22940788 TI - Measuring automatic associations: validation of algorithms for the Implicit Association Test (IAT) in a laboratory setting. AB - BACKGROUND AND OBJECTIVES: In their paper, "Understanding and using the Implicit Association Test: I. An improved scoring algorithm", Greenwald, Nosek, and Banaji (2003) investigated different ways to calculate the IAT-effect. However, up to now, it remained unclear whether these findings - based on internet data - also generalize to laboratory settings. Therefore, the main goal of the present study was to cross-validate scoring algorithms for the IAT in a laboratory setting, specifically in the domain of psychopathology. METHODS: Four known IAT algorithms and seven alternative IAT algorithms were evaluated on several performance criteria in the large-scale laboratory sample of the Netherlands Study of Depression and Anxiety (N = 2981) in which two IATs were included to obtain measurements of automatic self-anxious and automatic self-depressed associations. RESULTS AND CONCLUSIONS: Results clearly demonstrated that the D(2SD)-measure and the D(600)-measure as well as an alternative algorithm based on the correct trials only (D(noEP)-measure) are suitable to be used in a laboratory setting for IATs with a fixed order of category combinations. It remains important to further replicate these findings, especially in studies that include outcome measures of more spontaneous kinds of behaviors. PMID- 22940789 TI - A novel gold nanoparticles-based assay for rapid detection of Melissococcus plutonius, the causative agent of European foulbrood. AB - European foulbrood (EFB) is a severe bacterial brood disease of honey bees (Apis mellifera) caused by Melissococcus plutonius. Diagnosis of EFB in the field is based on visual inspection of brood-combs and detection of diseased larvae. However, symptoms of EFB may be easily obscured by other diseases or abnormalities in the brood, making definitive diagnosis difficult. Hence, confirmatory laboratory assays, such as PCR and real-time PCR, are used to verify the presence of M plutonius in suspected colonies. While these methods are accurate and specific, they are time consuming and labour intensive. Herein, we report development of a label-free colorimetric nanodiagnostic method for direct detection of unamplified M plutonius DNA using unmodified gold nanoparticles. Under appropriate conditions, the DNA probes hybridised with their complementary target sequences in the sample DNA, which resulted in aggregation of the gold nanoparticles and a concomitant red to blue colour change, which was observed visually. The assay could detect as few as 25 copies of the M plutonius cell wall associated protease gene within 20 minutes. The assay results were in 100 per cent concordance with real-time PCR-positive and PCR-negative samples. Our study demonstrated that the gold nanoparticles-based assay is a specific and sensitive tool for rapid detection of M plutonius. PMID- 22940790 TI - Response of the Nrf2 protection system in human monocytic cells after ionising irradiation. AB - In response to reactive oxygen species (ROS) or electrophiles, the transcription factor nuclear factor-erythroid 2 (NF-E2)-related factor 2 (Nrf2) rapidly translocates into the nucleus and induces the expression of various antioxidant genes, such as heme oxygenase-1 (HO-1). Low linear energy transfer (LET) ionising radiations such as X-rays generate ROS, which cause biological damage. However, little is known about whether the Nrf2 system in human monocytic cells is activated by low LET ionising irradiation. Therefore, in this study, the response of the Nrf2 system to X-irradiation in human monocytic THP1 cells was investigated. Following exposure of THP1 cells to X-rays (1-5 Gy), intracellular ROS levels were measured using 2',7'-dichlorodihydrofluorescein diacetate, Nrf2 localisation was determined using immunofluorescence staining and HO-1 mRNA and protein expression were examined. Although ROS were generated by irradiation in a dose-dependent manner, they disappeared immediately after irradiation. Nrf2 translocation into the nucleus was observed 6 h after 5 Gy X-irradiation but was not detected following 1-2 Gy irradiation or in non-irradiated controls. HO-1 expression was significantly higher in 5 Gy-irradiated cells after 24 h than in non-irradiated controls. These results indicate that high-dose irradiation (5 Gy) activates Nrf2 and that the Nrf2 protection system may function from 24 h after irradiation in human monocytic cells. PMID- 22940791 TI - The influence of environmental factors on the deposition velocity of thoron progeny. AB - Passive measuring devices are comprehensively employed in thoron progeny surveys, while the deposition velocity of thoron progeny is the most critical parameter, which varies in different environments. In this study, to analyse the influence of environmental factors on thoron progeny deposition velocity, an improved model was proposed on the basis of Lai's aerosol deposition model and the Jacobi's model, and a series of measurements were carried out to verify the model. According to the calculations, deposition velocity decreases with increasing aerosol diameter and also aerosol concentration, while increases with increasing ventilation rate. In typical indoor environments, a typical value of 1.26 * 10( 5)m s(-1) is recommended, with a range between 7.6 * 10(-7) and 3.2 * 10(-4) m s( 1). PMID- 22940792 TI - Distribution of uranium and some selected trace metals in human scalp hair from Balkans. AB - The possible consequences of the use of depleted uranium (DU) used in Balkan conflicts in 1995 and 1999 for the people and the environment of this reason need attention. The heavy metal content in human hair may serve as a good indicator of dietary, environmental and occupational exposures to the metal compounds. The present work summarises the distribution of uranium and some selected trace metals such as Mn, Ni, Cu, Zn, Sr, Cd and Cs in the scalp hair of inhabitants from Balkans exposed to DU directly and indirectly, i.e. Han Pijesak, Bratoselce and Gornja Stubla areas. Except U and Cs, all other metals were compared with the worldwide reported values of occupationally unexposed persons. Uranium concentrations show a wide variation ranging from 0.9 +/- 0.05 to 449 +/- 12 ug kg(-1). Although hair samples were collected from Balkan conflict zones, uranium isotopic measurement ((235)U/(238)U) shows a natural origin rather than DU. PMID- 22940793 TI - Exposure of population from residential radon: a case study for district Hattian, Azad Kashmir, Sub-Himalayas, Pakistan. AB - Indoor air quality has acquired considerable importance in recent years. Tighter buildings with poorer ventilation systems have led towards higher levels of indoor air pollution. Radon is considered to be most significant perilous gas among the various air contaminants found in the residential environment. To determine the risk posed by residential radon exposure, a survey was carried out in the Hattian district of the state of Azad Jammu and Kashmir, Pakistan. In this context, 160 houses were carefully selected for the installation of CR-39-based National Radiological Protection Board-type detectors installation. After exposing the CR-39 detectors for a period of 90 d, they were etched in 6 M chemical solution of sodium hydroxide at a temperature of 80 degrees C for a period of 16 h. The detectors were read under an optical microscope and observed track densities were converted into the indoor radon concentration using a calibration factor of 2.7 tracks cm(-2) h(-1) per kBqm(-3). For the current study, observed radon concentrations ranged from 35 to 175 Bqm(-3), whereas the mean annual effective radon doses received by the inhabitants of the area ranged from 0.88 +/- 0.12 to 4.41 +/- 0.20 mSv with an average value of 2.62 +/- 0.12 mSv. These reported values are less than the limits (standards) recommended by the different world organisations. PMID- 22940794 TI - Mechanosensitive ion channels: an evolutionary and scientific tour de force in mechanobiology. PMID- 22940795 TI - Tilt and decentration of an intraocular lens implanted in the ciliary sulcus after capsular bag defect during cataract surgery. AB - PURPOSE: To determine the impact of ciliary sulcus implantation after capsular bag defect on tilt and decentration of foldable intraocular lenses (IOL) measured by a novel device. METHODS: This prospective noncomparative single-center investigation included patients (N = 10) older than age 60 who underwent cataract surgery with a posterior capsular bag defect and implantation of a threepiece hydrophilic aberration neutral IOL (OphthalmoPro AC 7013) in the ciliary sulcus. All eyes (N = 10) were examined using the OPD-Scan II (Nidek). Spherical aberration (Z4,0), vertical coma (Z3,-1), and horizontal coma (Z3,1) were calculated for a 5.0 mm pupil. Lens tilt and decentration was studied using a new Purkinjemeter. RESULTS: The mean horizontal optic tilt was 7.68 degrees +/- 5.16 (SD) and the mean vertical optic tilt was 3.01 degrees +/- 2.44 (SD). Horizontal decentration was 0.4 +/- 0.33 mm (SD) and vertical decentration was 0.31 +/- 0.21 mm (SD). Corneal aberrations were partially compensated by IOL- related aberrations. CONCLUSIONS: Both tilt and decentration of sulcus-fixated IOLs exceeded the tolerable amounts evaluated for aspheric IOLs in eye model experiments. However, these spheric IOLs showed mitigation rather than accentuation of corneal wavefront aberrations in the rare event of capsular bag defect during cataract surgery. PMID- 22940796 TI - A comparison between Goldmann applanation tonometry and dynamic contour tonometry after photorefractive keratectomy. AB - BACKGROUND: The intraocular pressure (IOP) could be measured by both Goldmann applanation tonometry (GAT) and dynamic contour tonometry (DCT). Although these two methods have been discussed widely after laser-assisted sub-epithelial keratectomy (LASIK), there is little data in the cases undergoing photorefractive keratectomy (PRK). We aimed to compare the changes of IOP measurements obtained by GAT and DCT after PRK for myopia/myopic astigmatism. METHODS: This prospective study enrolled 77 candidates (154 eyes) for PRK to correct myopia or myopic astigmatism and 30 matched patients (30 eyes) with myopia or myopic astigmatism who served as controls. Changes of the IOP measurements (DeltaIOP) obtained by GAT and DCT before and at 6 months after PRK in the operated eyes, and at baseline and 6 months later in the controls, were documented. Changes of the central corneal thickness (DeltaCCT) were determined in the same fashion. RESULTS: The mean IOP readings obtained by DCT were comparable before and at 6 months after procedure (18.34 +/- 3.03 mmHg and 17.87 +/- 2.61 mmHg respectively, p = 0.41); whereas the mean IOP reading obtained by GAT decreased significantly 6 months postoperatively (17.92 +/- 3.63 mmHg and 16.25 +/- 2.66 mmHg, p < 0.001). A significant correlation was present between the DeltaIOP obtained by GAT and DeltaCCT (r = 0.61, p < 0.001). Similar correlation was not significant between the DCT-obtained DeltaIOP and the DeltaCCT (r = 0.07, p = 0.44). The mean DeltaIOP obtained by GAT was significantly higher in the operated eyes than in the controls (-1.54 +/- 1.45 vs 0.07 +/- 0.44 mmHg, p = 0.02). The mean DCT obtained DeltaIOP was just marginally insignificant between the operated and nonoperated eyes (-0.63 +/- 0.59 vs 0.02 +/- 0.38 mmHg respectively; p = 0.09). CONCLUSIONS: The authors recommend DCT after PRK in the cases with myopia or myopic astigmatism. PMID- 22940797 TI - Visual acuity and factors influencing automobile driving status in 1,000 patients age 60 and older. AB - BACKGROUND: The objective of this prospective observational study was to evaluate the number of people driving in accordance with common legal standards, measured through far binocular visual acuity, and to identify variables associated with driving habits outside of legal standards. METHODS: Subjects aged 60 years and older were recruited at a tertiary referral center (University Hospital of Mont Godinne, Yvoir, Belgium). Ophthalmological examination was conducted in all subjects by an ophthalmologist. Visual acuity was measured with the modified Early Treatment Diabetic Retinopathy charts at a distance of 4 m on each eye for far binocular visual acuity, defined as equal or better than 20/40, according to the European legal driving requirements. Details on demographic, socioeconomic, and medical characteristics were obtained from all participants by questionnaires. Numerical variables were compared with the Wilcoxon rank sum test. Categorical and ordinal parameters were compared with the Chi-square test or the Cochran test respectively. RESULTS: One thousand subjects (447 women and 553 men) were enrolled in the study over a period of 7 months (mean age: 71.3 +/- 8.8 years), of whom 810 were current drivers. Among the 810 current drivers, 732 (90.4 %) had a far binocular visual acuity equal or better than 20/40 (mean 0.89), and 78 (9.6 %) did not (mean 0.36). Among the 190 non-drivers, 94 (49.5 %) never drove; 47 (24.7 %) had stopped driving because of their impaired vision; and 49 (25.8 %) had stopped driving for other reasons. A logistic regression was performed to identify the variables statistically associated with the practice of driving among licensed drivers without minimal visual requirements, which revealed that a non-recent ophthalmological examination (p < 0.001), the subject's non-perception of impaired vision (p = 0.001), and non-access to stores without a car (p < 0.001) were influencing factors. CONCLUSIONS: In our study, 81 % of subjects aged 60 years and older were still driving, of whom 10 % did not meet the European legal driving requirements set at equal or better than 20/40. The variables associated with driving status were the time of last examination, non-perception of a visual impairment, and limited access to stores without a car. PMID- 22940798 TI - The diagnosis of glaucoma in highly myopic individuals requires longitudinal data. PMID- 22940799 TI - Deletion of pyruvate decarboxylase by a new method for efficient markerless gene deletions in Gluconobacter oxydans. AB - Gluconobacter oxydans, a biotechnologically relevant species which incompletely oxidizes a large variety of carbohydrates, alcohols, and related compounds, contains a gene for pyruvate decarboxylase (PDC). This enzyme is found only in very few species of bacteria where it is normally involved in anaerobic ethanol formation via acetaldehyde. In order to clarify the role of PDC in the strictly oxidative metabolism of acetic acid bacteria, we developed a markerless in-frame deletion system for strain G. oxydans 621H which uses 5-fluorouracil together with a plasmid-encoded uracil phosphoribosyltransferase as counter selection method and used this technique to delete the PDC gene (GOX1081) of G. oxydans 621H. The PDC deletion mutant accumulated large amounts of pyruvate but almost no acetate during growth on D-mannitol, D-fructose or in the presence of L-lactate. This suggested that in G. oxydans acetate formation occurs by decarboxylation of pyruvate and subsequent oxidation of acetaldehyde to acetate. This observation and the efficiency of the markerless deletion system were confirmed by constructing deletion mutants of two acetaldehyde dehydrogenases (GOX1122 and GOX2018) and of the acetyl-CoA-synthetase (GOX0412). Acetate formation during growth of these mutants on mannitol did not differ significantly from the wild type strain. PMID- 22940800 TI - Heterologous production of cellobiose dehydrogenases from the basidiomycete Coprinopsis cinerea and the ascomycete Podospora anserina and their effect on saccharification of wheat straw. AB - Cellobiose dehydrogenases (CDHs) are extracellular glycosylated haemoflavoenzymes produced by many different wood-degrading and phytopathogenic fungi. Putative cellobiose dehydrogenase genes are recurrently discovered by genome sequencing projects in various phylogenetically distinct fungi. The genomes from the basidiomycete Coprinopsis cinerea and the ascomycete Podospora anserina were screened for candidate cdh genes, and one and three putative gene models were evidenced, respectively. Two putative cdh genes were selected and successfully expressed for the first time in Aspergillus niger. CDH activity was measured for both constructions (CDHcc and CDHpa), and both recombinant CDHs were purified to homogeneity and subsequently characterised. Kinetic constants were determined for several carbohydrates including beta-1,4-linked di- and oligosaccharides. Optimal temperature and pH were 60 degrees C and 5 for CDHcc and 65-70 degrees C and 6 for CDHpa. Both CDHs showed a broad range of pH stability between 4 and 8. The effect of both CDHs on saccharification of micronized wheat straw by an industrial Trichoderma reesei secretome was determined. The addition of each CDH systematically decreased the release of total reducing sugars, but to different extents and according to the CDH concentration. Analytical methods were carried out to quantify the release of glucose, xylose and gluconic acid. An increase of glucose and xylose was measured at a low CDHcc concentration. At moderated and high CDHcc and CDHpa concentrations, glucose was severely reduced with a concomitant increase of gluconic acid. In conclusion, these results give new insights into the physical and chemical parameters and diversity of basidiomycetous and ascomycetous CDHs. These findings also demonstrated that CDH drastically influenced the saccharification on a natural substrate, and thus, CDH origin, concentration and potential enzymatic partners should be carefully considered in future artificial secretomes for biofuel applications. PMID- 22940801 TI - Biodegradation of dioxin by a newly isolated Rhodococcus sp. with the involvement of self-transmissible plasmids. AB - A newly isolated Rhodococcus sp. strain p52 could aerobically utilize dibenzofuran as the sole source of carbon and energy, and completely remove dibenzofuran at 500 mg l(-1) within 48 h. The strain metabolizes dibenzofuran by initial angular dioxygenation to yield 2,2',3-trihydroxybiphenyl. Strain p52 could also remove 70 % of 100 mg l(-1) 2-chlorodibenzofuran within 96 h and could metabolize a variety of aromatic compounds, namely dibenzo-p-dioxin, 2,8 dichlorodibenzofuran, dibenzothiophene, biphenyl, naphthalene, fluorene, phenanthrene, anthracene, carbazole, indole, xanthene, phenoxathiin, xanthone, and 9-fluorenone. Two distinct gene clusters encoding angular dioxygenases (DbfA and DfdA) were amplified and sequenced. The dbfA and dfdA gene clusters are located on two circular plasmids, pDF01 and pDF02, respectively. Both plasmids are self-transmissible; that is, they can transfer to the Gram-positive bacterium Bacillus cereus by conjugation. PMID- 22940802 TI - Directed evolution of poly[(R)-3-hydroxybutyrate] depolymerase using cell surface display system: functional importance of asparagine at position 285. AB - Poly[(R)-3-hydroxybutyrate] (PHB) depolymerase from Ralstonia pickettii T1 (PhaZRpiT1) consists of three functional domains to effectively degrade solid PHB materials, and its catalytic domain catalyzes the ester bond cleavage of the substrate. We performed the directed evolution of PhaZRpiT1 targeted at the catalytic domain in combination with the cell surface display method to effectively screen for mutants with improved p-nitrophenyl butyrate (pNPC4) activity. Mutated PhaZRpiT1 genes generated by error-prone PCR were fused to the oprI gene to display them as fusion proteins on Escherichia coli cell surface. Some cells displaying the mutant enzymes showed a two- to fourfold increase in pNPC4 hydrolysis activity relative to cells displaying wild-type enzyme. These mutant genes were recombined by a staggered extension process and the recombined enzymes were displayed to result in a five- to eightfold higher pNPC4 hydrolysis activity than the wild type. To further evaluate the mutation effects, unfused and undisplayed enzymes were prepared and applied to the hydrolysis of p nitrophenyl esters having different chain lengths (pNPCn; n = 2-6) and PHB degradation. One specific second-generation mutant showed an approximately tenfold increase in maximum rate for pNPC3 hydrolysis, although its PHB degradation efficiency at 1 MUg/mL of enzyme concentration was approximately 3.5 fold lower than that of the wild type. Gene analysis showed that N285D or N285Y mutations were found in six of the seven improved second-generation mutants, indicating that Asn285 probably participates in the regulation of substrate recognition and may be more favorable for PHB degradation process than other amino acid residues. PMID- 22940804 TI - Role of alternative sigma factor 54 (RpoN) from Vibrio anguillarum M3 in protease secretion, exopolysaccharide production, biofilm formation, and virulence. AB - The sigma factor sigma(54) (RpoN) is an important regulator of bacterial response to environmental stresses. Here, we demonstrate the roles of RpoN in Vibrio anguillarum M3 by comparative investigation of physiological phenotypes and virulence of the wild-type, an rpoN mutant, and an rpoN complemented strain. Disruption of rpoN was found to decrease biofilm formation, production of exopolysaccharides, and production of the metalloproteases EmpA and PrtV. Injection experiments in fish showed that the M3 DeltarpoN mutant was attenuated in virulence when administrated either by intramuscular injection or by immersion challenge. Slower proliferation of the mutant in fish was also observed. Complementation of the mutant strain with rpoN restored some of the phenotypes to wild-type levels. RpoN was involved in regulation of some virulence-associated genes, as shown by real-time quantitative reverse PCR analysis. These results revealed a pleiotropic regulatory role of RpoN in biofilm formation, production of proteases and exopolysaccharides, and virulence in V. anguillarum M3. PMID- 22940805 TI - The EmhABC efflux pump in Pseudomonas fluorescens LP6a is involved in naphthalene tolerance but not efflux. AB - The EmhABC efflux pump in Pseudomonas fluorescens LP6a effluxes polycyclic aromatic hydrocarbons (PAHs) such as phenanthrene and anthracene but not naphthalene. We previously showed that the presence of EmhABC decreased the efficiency of phenanthrene biodegradation. In this study, we determined whether P. fluorescens LP6a tolerance to naphthalene is a function of the EmhABC efflux pump and how its presence affects the efficiency of naphthalene biodegradation. Growth, membrane fatty acid (FA) composition, and cell morphology showed that 5 mmol L(-1) naphthalene is inhibitory to P. fluorescens LP6a strains. The deleterious effect of naphthalene is suppressed in the presence of EmhABC, which suggests that, although naphthalene is not effluxed by EmhABC, this efflux pump is involved in tolerance of naphthalene toxicity. LP6a mutants lacking the EmhB efflux pump were unable to convert cis-unsaturated FAs to cyclopropane FAs, indicating that naphthalene interferes with the formation of cyclopropane FAs and supporting the proposal that EmhABC is involved in FA turnover in P. fluorescens LP6a strains. The EmhABC efflux pump increases the efficiency of naphthalene metabolism in strain LP6a, which may make naphthalene efflux unnecessary. Thus, the activity of hydrocarbon efflux pumps may be an important factor to consider when selecting bacterial strains for bioremediation or biocatalysis of PAHs. PMID- 22940803 TI - Flavour-active wine yeasts. AB - The flavour of fermented beverages such as beer, cider, sake and wine owe much to the primary fermentation yeast used in their production, Saccharomyces cerevisiae. Where once the role of yeast in fermented beverage flavour was thought to be limited to a small number of volatile esters and higher alcohols, the discovery that wine yeast release highly potent sulfur compounds from non volatile precursors found in grapes has driven researchers to look more closely at how choice of yeast can influence wine style. This review explores recent progress towards understanding the range of 'flavour phenotypes' that wine yeast exhibit, and how this knowledge has been used to develop novel flavour-active yeasts. In addition, emerging opportunities to augment these phenotypes by engineering yeast to produce so-called grape varietal compounds, such as monoterpenoids, will be discussed. PMID- 22940807 TI - Tracing carbon monoxide uptake by Clostridium ljungdahlii during ethanol fermentation using (13)C-enrichment technique. AB - Conversion of synthesis gas (CO and H2) to ethanol can be an alternative, promising technology to produce biofuels from renewable biomass. To distinguish microbial utilization of carbon source between fructose and synthesis gas CO and to evaluate biological production of ethanol from CO, we adopted the (13)C enrichment of the CO substrate and hypothesized that the residual increase in delta(13)C of the cell biomass would reflect the increased contribution of (13)C enriched CO. Addition of synthesis gas to live culture medium for ethanol fermentation by Clostridum ljungdahlii increased the microbial growth and ethanol production. Despite the high (13)C-enrichment in CO (99 atom % (13)C), however, microbial delta(13)C increased relatively small compared to the microbial growth. The uptake efficiency of CO estimated using the isotope mass balance equation was also very low: 0.0014 % for the low CO and 0.0016 % for the high CO treatment. Furthermore, the fast production of ethanol in the early stage indicated that the presence of sugar in fermentation medium would limit the utilization of CO as a carbon source by C. ljungdahlii. PMID- 22940806 TI - A detailed biochemical characterization of phosphopantothenate synthetase, a novel enzyme involved in coenzyme A biosynthesis in the Archaea. AB - We have previously reported that the majority of the archaea utilize a novel pathway for coenzyme A biosynthesis (CoA). Bacteria/eukaryotes commonly use pantothenate synthetase and pantothenate kinase to convert pantoate to 4' phosphopantothenate. However, in the hyperthermophilic archaeon Thermococcus kodakarensis, two novel enzymes specific to the archaea, pantoate kinase and phosphopantothenate synthetase, are responsible for this conversion. Here, we examined the enzymatic properties of the archaeal phosphopantothenate synthetase, which catalyzes the ATP-dependent condensation of 4-phosphopantoate and beta alanine. The activation energy of the phosphopantothenate synthetase reaction was 82.3 kJ mol(-1). In terms of substrate specificity toward nucleoside triphosphates, the enzyme displayed a strict preference for ATP. Among several amine substrates, activity was detected with beta-alanine, but not with gamma aminobutyrate, glycine nor aspartate. The phosphopantothenate synthetase reaction followed Michaelis-Menten kinetics toward beta-alanine, whereas substrate inhibition was observed with 4-phosphopantoate and ATP. Feedback inhibition by CoA/acetyl-CoA and product inhibition by 4'-phosphopantothenate were not observed. By contrast, the other archaeal enzyme pantoate kinase displayed product inhibition by 4-phosphopantoate in a non-competitive manner. Based on our results, we discuss the regulation of CoA biosynthesis in the archaea. PMID- 22940808 TI - [Severe contact lens-associated fungal keratitis]. AB - A 23-year-old man presented with severe contact lens-associated keratitis and descemetocele with pre-existing drug therapy. After 1 week of intensive antibiotic treatment Aspergillus fumigatus was identified. Despite adjusted antimycotic treatment a corneal perforation occurred. Due to peripheral scleral infiltration the cornea was primarily closed with a double layer amniotic membrane in order to avoid a sclerokeratoplasty with a bad prognosis. After 2 weeks the peripheral corneal situation stabilized and a simple keratoplasty a chaud could be performed. After surgery and adjusted drug therapy, no adequate signs of recovery occured. In repeated microbiological testing an additional Candida albicans infection was diagnosed and therapy was readjusted. This resulted in a cure of the corneal infection. After 5 years and a re-keratoplasty the patient presented with a clear corneal transplant and a corrected visual acuity of 20/25. PMID- 22940809 TI - Self sensitized photooxidation of N-methyl phenothiazine: acidity control of the competition between electron and energy transfer mechanisms. AB - The reaction pathways following electronic excitation of 10-methyl phenothiazine (MPS) in the presence of oxygen have been investigated as a contribution to establish the mechanisms involved in the phototoxic reactions related to phenothiazine drugs. In the context of previously published results, the pathways of oxidation via the radical cation and/or by reactive oxygen species, such as singlet oxygen and superoxide anion, are of particular interest. The effects of polarity of the medium as well as of proton donors on the different reaction pathways, in particular on the formation of reactive oxygen species and the intermediates of the oxidation of 10-methyl phenothiazine, have been investigated. No reaction was observed in non-polar solvents. In polar solvents, both self-sensitized and sensitized singlet oxygen generation lead to the oxidation of MPS and the production of 10-methyl phenothiazine sulfoxide (MPSO) most probably via a zwitterionic persulfoxide. During self-sensitized photooxidation of MPS in the presence of proton donors, such as carboxylic acids, the zwitterionic intermediate is protonated to the corresponding cation that in turn facilitates the reaction with a second molecule of MPS. In the presence of strong acids however, the formation of the radical cation of MPS and of the superoxide anion, by electron transfer from the triplet excited state of MPS to molecular oxygen, competes efficiently with singlet oxygen formation. In this case, the scavenging of the superoxide anion by protons to yield its conjugated acid (hydroperoxyl radical) and the subsequent disproportionation of the latter prevents back electron transfer. PMID- 22940812 TI - Policy brief. Why are economically disadvantaged Americans less likely than wealthier persons to make preparations for their end-of-life health care? PMID- 22940810 TI - Complications following hip arthroscopy: a systematic review and meta-analysis. AB - PURPOSE: The use of hip arthroscopy to address injuries and conditions about the hip is becoming more widespread. There are several narrative reviews regarding complications of hip arthroscopy but a systematic review is currently lacking. The primary goal of this study is to determine the complication rate associated with hip arthroscopy in the literature. METHODS: A search of the EMBASE and Ovid Medline databases was performed to identify articles published between 1 January 2000 and 25 November 2011 that reported a complication rate after hip arthroscopy. Appropriate inclusion and exclusion criteria were applied to identify articles, and a meta-analysis was performed to determine an overall complication rate. Complications were divided into major and minor. RESULTS: A total of 66 papers (n = 6,962 hip arthroscopies) were identified and deemed appropriate for analysis. The overall complication rate was found to be 4.0 % (95 % CI 2.9-5.2 %). Of the 287 complications identified in the literature, 20 were deemed major constituting a rate of 0.3 %. CONCLUSIONS: Hip arthroscopy appears to be safe. The vast majority of complications are minor in nature. Prospective trials looking at the complications of hip arthroscopy would aid in identifying prognostic factors. LEVEL OF EVIDENCE: Systematic review and meta-analysis, Level III. PMID- 22940811 TI - Miles to go before we sleep: racial inequities in health. AB - Large, pervasive, and persistent racial inequalities exist in the onset, courses, and outcomes of illness. A comprehensive understanding of the patterning of racial disparities indicates that racism in both its institutional and individual forms remains an important determinant. There is an urgent need to build the science base that would identify how to trigger the conditions that would facilitate needed societal change and to identify the optimal interventions that would confront and dismantle the societal conditions that create and sustain health inequalities. PMID- 22940813 TI - The social stratification of older adults' preparations for end-of-life health care. AB - I use data from the Wisconsin Longitudinal Study (n = 4,971) to evaluate the extent to which socioeconomic status affects three health-related (living will, durable power of attorney for health care, and discussions) and one financial (will) component of end-of-life planning. Net worth is positively associated with all four types of planning, after demographic, health, and psychological characteristics are controlled. Low rates of health-related planning among persons with low or negative assets are largely accounted for by the fact that they are less likely to execute a will, an action that triggers health-related preparations. Rates of health-related planning alone are higher among recently hospitalized persons, whereas financial planning only is more commonly done by homeowners and those with richer assets. The results suggest that economically advantaged persons engage in end-of-life planning as a two-pronged strategy entailing financial and health-related preparations. Implications for health policy, practice, and theory are discussed. PMID- 22940815 TI - Resurgent ethnicity among Asian Americans: ethnic neighborhood context and health. AB - In this study I investigate the associations of neighborhood socioeconomic and social environments with the health of Asian Americans living in both Asian ethnic neighborhoods and non-Asian neighborhoods. I use a sample of 1962 Asian Americans from the National Latino and Asian American Study (NLAAS, 2003-04). Three key findings emerge. First, absolute levels of socioeconomic and social resources do not differ greatly between the Asian ethnic neighborhoods and non Asian neighborhoods in which Asian Americans live. Second, the ethnic neighborhood context conditions the effects of neighborhood education on health so that higher neighborhood education is related to better self-rated health among Asian Americans only when they live in Asian ethnic neighborhoods. Finally, the social environment, measured by everyday discrimination and social cohesion, does not differ in its health effects for individuals living in Asian ethnic and non-Asian neighborhoods. Together, these findings illuminate the complex ways that racial and ethnic neighborhood concentration impacts health. PMID- 22940817 TI - Synthesis, structure and band gap energy of covalently linked cluster-assembled materials. AB - We have synthesized a series of cluster assembled materials in which the building blocks are As(7)(3-) clusters linked by group 12 metals, Zn, Cd and Hg, to investigate the effect of covalent linkers on the band gap energy. The synthesized assemblies include zero dimensional assemblies of [Zn(As(7))(2)](4-), [Cd(As(7))(2)](4-), [Hg(2)(As(7))(2)](4-), and [HgAsAs(14)](3-) in which the clusters are separated by cryptated counterions, and assemblies in which [Zn(As(7))(2)](4-), [Cd(As(7))(2)](4-) are linked by free alkali atoms into unusual three-dimensional structures. These covalently linked cluster-assembled materials have been characterized by elemental analysis, EDX and single-crystal X ray diffraction. The crystal structure analysis revealed that in the case of Zn and Cd, the two As(7)(3-) units are linked by the metal ion, while in the case of Hg, two As(7)(3-) units are linked by either Hg-Hg or Hg-As dimers. Optical measurements indicate that the band gap energy ranges from 1.62 eV to 2.21 eV. A theoretical description based on cluster orbital theory is used to provide a microscopic understanding of the electronic character of the composite building blocks and the observed variations in the band gap energy. PMID- 22940814 TI - Race-ethnicity and health trajectories: tests of three hypotheses across multiple groups and health outcomes. AB - Racial-ethnic disparities in static levels of health are well documented. Less is known about racial-ethnic differences in age trajectories of health. The few studies on this topic have examined only single health outcomes and focused on black-white disparities. This study extends prior research by using a life course perspective, panel data from the Health and Retirement Study, and multilevel growth curve models to investigate racial-ethnic differences in the trajectories of serious conditions and functional limitations among blacks, Mexican Americans, and whites. We test three hypotheses on the nature of racial-ethnic disparities in health across the life course (aging-as-leveler, persistent inequality, and cumulative disadvantage). Results controlling for mortality selection reveal that support for the hypotheses varies by health outcome, racial-ethnic group, and life stage. Controlling for childhood socioeconomic status, adult social and economic resources, and health behaviors reduces but does not eliminate racial ethnic disparities in health trajectories. PMID- 22940818 TI - Design and rationale of low-dose erythropoietin in patients with ST-segment elevation myocardial infarction (EPO-AMI-II study): a randomized controlled clinical trial. AB - PURPOSE: The development of novel pharmaceutical interventions to improve the clinical outcomes of patients with acute ST-segment elevation myocardial infarction (STEMI) is an unmet medical need worldwide. In animal models, a single intravenous administration of erythropoietin (EPO) during reperfusion improves left ventricular (LV) function in the chronic stage. However, the results of recent proof-of-concept trials using high-dose EPO in patients with STEMI are inconsistent. In our pilot study, low-dose EPO after successful percutaneous coronary intervention (PCI) improved the LV ejection fraction (EF) and did not trigger severe adverse clinical events in patients with STEMI. One possible reason for this discrepancy is the dose of EPO used. METHODS AND RESULTS: We have started a double-blind, placebo-controlled, randomized, multicenter clinical trial (EPO-AMI-II) to clarify the safety and efficacy of low-dose EPO in patients with STEMI. STEMI patients who have a low LVEF (<50 %) will be randomly assigned to intravenous administration of placebo or EPO (6,000 or 12,000 IU) within 6 h after successful PCI. The primary endpoint is the difference in LVEF between the acute and chronic phases (6 months), as measured by single-photon emission computed tomography. The patient number needed for EPO-AMI-II is 600. The study will stop when superior efficacy or futility is detected by an interim analysis. This study has been approved by the Evaluation System of Investigational Medical Care. CONCLUSIONS: EPO-AMI-II study will clarify the safety and efficacy of low dose EPO in STEMI patients with LV dysfunction in a double-blind, placebo controlled, multicenter study. (247 words). PMID- 22940820 TI - Seizure heralding tuberculous meningitis. AB - Seizures may frequently occur during tuberculous meningitis. We describe a patient with an apparent generalised tonic-clonic seizure, initially not associated with any magnetic resonance imaging (MRI) abnormality, which was the presenting symptom of tuberculous meningitis. Follow-up MRI, performed after gadolinium administration, showed signs of meningeal involvement. Seizures may be the presenting symptoms of tuberculous meningitis even in the absence of evident intracerebral lesions on MRI. Therefore, contrast-enhanced brain MRI should be performed in the diagnostic workup for each first seizure, especially in patients with a clinical suspicion of CNS infectious disease. The term "heraldic seizure", indicating a subset of acute symptomatic seizures presenting at the onset of a brain/systemic injury or preceding the full clinical manifestation of a cerebral insult, may be helpful to classify these seizures retrospectively, based initially on unknown aetiology. PMID- 22940822 TI - Microvascular decompression for hemifacial spasm: long-term outcome and prognostic factors, with emphasis on delayed cure. AB - The postoperative course of microvascular decompression (MVD) for hemifacial spasm (HFS) is variable, and the optimal time for assessing the results is unclear. From April 1997 to October 2007, MVD for HFS was performed in 801 patients. Patients were divided into two groups (cured or failed) according to subjective patient assessments over a 3-year period. We analyzed patient characteristics and surgical findings to determine prognostic factors. Medical records were analyzed retrospectively over the 3-year follow-up period. Of the 801 patients who underwent surgery, 743 (92.8 %) appeared to be cured, 70 (8.7 %) had residual or recurrent spasms more than 1 year after surgery, 11 (1.3 %) had gradual improvement over 3 years, and 1 (0.1 %) had delayed improvement more than 3 years after surgery. Fifty-eight patients (7.2 %) had residual or recurrent spasms more than 3 years after surgery, of which 19 (2.4 %) had recurrence after initial relief. The mean time to spasm recurrence was 18.9 months. Intraoperative resolution of the lateral spread response (LSR) after decompression (p = 0.048) and severe indentation (p = 0.038) were significant predictors of good long-term outcome after MVD for HFS. In our series, 70 patients (8.7 %) had residual or recurrent spasms more than 1 year after surgery, of which 12 (17.1 %) improved gradually after 1 year. If the surgeon can confirm intraoperative resolution of the LSR and severe indentation, reoperation can be delayed until 3 years after MVD. PMID- 22940821 TI - Relationship of lower uterine segment cancer with Lynch syndrome: a novel case with an hMLH1 germline mutation. AB - Lynch syndrome is a genetic disease that often develops in patients with endometrial cancer and is caused by abnormal DNA mismatch repair (MMR) genes. In the United States, it was recently reported that the prevalence of Lynch syndrome with an hMSH2 mutation in patients with endometrial cancer in the lower uterine segment (LUS) is much greater than that in patients with endometrial cancer, although no such reports have been published in Asia. In this study, we examined the correlation between endometrial cancer in LUS and abnormalities in MMR genes. We examined 625 patients, who were diagnosed with endometrial cancer and underwent a hysterectomy. Nine patients (1.4%) had cancer based on pathological confirmation of a tumor in the lower part of the uterus and no cancer in the upper part. These cases were compared with 27 cases of sporadic endometrial (non LUS) cancer. The age and BMI of the patients with LUS cancer were significantly lower than those of the patients with non-LUS cancer. No differences were observed in the pathological characteristics. The microsatellite instability (MSI)-positive rates were similar. Immunohistochemistry showed a decreased expression of hMLH1 and hMSH6 in patients with LUS cancer. In contrast with earlier reports from the United States, hMSH2 was expressed in all the cases. Of the 2 patients with LUS cancer who exhibited high MSI, 1 patient showed abnormal methylation of hMLH1, while the other patient was diagnosed with Lynch syndrome with a mutation in the hMLH1 gene. This is the second report on the relationship of LUS cancer and Lynch syndrome, and the first to describe an Asian patient with LUS cancer with Lynch syndrome induced by an hMLH1 mutation. PMID- 22940823 TI - Basilar trunk perforator artery aneurysms. Case report and literature review. AB - Perforator artery aneurysms of the basilar trunk are rarely described in the literature. In addition to presenting our own case, we performed a PubMed search to comprehensively illustrate demographics, hemorrhage patterns, and treatment outcomes for these lesions. We found 12 patients with basilar perforator artery aneurysms. Mean patient age was 47.3, and there was a 3:1 male to female predominance. All patients had ruptured aneurysms, though all were clinically low or medium grade (I-III). Six patients had diffuse subarachnoid hemorrhage (SAH), and six had prepontine and/or perimesencephalic hemorrhage patterns. All aneurysms arose off middle or rostral basilar perforator arteries; mean aneurysm size was 4.5 mm. All except one was partially thrombosed, and 4 out of 12 patients did not have their aneurysms detected on initial angiography (33%). Seven were treated surgically, two were coiled, and three were observed. At last follow-up, all were occluded, and 8 out of 12 patients were neurologically intact (67%). Of seven patients that were not treated with early intervention, one suffered a rebleed over a combined total of 37.3 months of observation. Two aneurysms amenable to coiling were occluded without complication. Three of seven patients treated surgically had transient complications, though five were neurologically intact at follow-up. Basilar perforator artery aneurysms may be sources of hemorrhage in diffuse or perimesencephalic/prepontine SAH. While endovascular coiling is an excellent option if parent vessel anatomy allows for catheterization, many are unamenable to endovascular treatment. Surgical obliteration via proximal occlusion or trapping is a safe and effective means of treating these aneurysms. PMID- 22940824 TI - Rhabdomyolysis after neurosurgery: a review and a framework for prevention. AB - Rhabdomyolysis (RM) is a potentially fatal or disabling clinical syndrome resulting in muscle necrosis and leakage of muscle constituents into the blood. Lactic acidosis and more serious complications such as acute renal failure may occur in up to half of recognized cases, so accurate diagnosis is required. We present three cases in which RM occurred in patients undergoing neurosurgical procedures performed in the lateral position. A review of the literature is provided together with a framework for the prevention of this surgical complication. Three patients underwent neurosurgical procedures in the lateral position for left facial/glossopharyngeal neuralgia, for jugular foramen tumor, and for a petroclival meningioma, respectively. All patients were obese and all three showed massive postoperative elevation in creatine kinase (CK) levels characteristic of RM. Myoglobinuria was identified in two patients and all three showed hyperintensity of the hip gird muscles in the short tau inversion recovery sequence magnetic resonance imaging. All recovered spontaneously and none went on to develop renal failure. A literature review showed that RM has been rarely reported after neurosurgery. However, the duration of procedures of the cases of reported RM indicates that the prevalence of the condition is likely highly under recognized in neurosurgery. This is particularly important given the rising obesity rates seen in many countries. Obese patients undergoing long neurosurgical procedures, particularly in the lateral position, should be suspected of RM and should be closely monitored for CK levels, myoglobinuria, and acidosis. We outline a framework of strategies for the prevention of the condition. PMID- 22940825 TI - Gold phytomining. A review of the relevance of this technology to mineral extraction in the 21st century. AB - The precious metal gold can be found at high concentration in tailings dumps and waste rock piles at many mining locations around the world. Conventional technology is generally unable to economically recover this residual gold, and, as a result, the potential resource is wasted, presenting environmental risk to the wider ecosystem through particulate and dissolved metal leaching and erosion. For the past 14 years, the idea of gold phytomining to recover this gold resource has been researched by various scientific groups worldwide. A number of plant species have been tested under laboratory, greenhouse, and field conditions to determine their potential for use in the phytoextraction of gold. This paper presents a review of reported gold phytomining trials developed in the laboratory, the greenhouse under soil and hydroponic conditions, as well as in the field, between 1998 and 2011. A summary economic assessment for gold phytomining in Mexico is also presented. Mexico is an example of a developing country with a long history of gold mining that has a large resource of sites that might be suitable to gold phytomining. The technology remains limited by certain environmental and plant physiology factors. However, the increase in the market price for gold during the first decade of the 21st century and into 2011, and advances recorded for the gold concentration and biomass yield of a range of plant species, suggest that gold phytomining might be an economically viable technology. PMID- 22940827 TI - Multiple endocrine neoplasia and different multiple pancreatic neuroendocrine tumors: is there any relation? PMID- 22940826 TI - Type II cGMP-dependent protein kinase inhibits ERK/JNK-mediated activation of transcription factors in gastric cancer cells. AB - A previous study has shown that type II cGMP-dependent protein kinase (PKG II) inhibits the proliferation of gastric cancer cells through blocking EGF-triggered MAPK/ERK signal transduction, indicating that the kinase may be a potential anticancer factor. In the present study, the role of PKG II in the EGF-induced activation of transcription factors in the MAPK/ERK signal transduction pathway was investigated. BGC-823 human gastric cancer cells were infected with adenoviral constructs encoding the cDNA of PKG II (pAd-PKG II) to increase the expression of PKG II and treated with 8-pCPT-cGMP to activate the enzyme. Using luciferase reporter assays, it was revealed that PKG II markedly suppressed the EGF-induced transcriptional activities of AP-1 and Elk1. Consistent with the inhibitory effect of PKG II on AP-1 activity, the expression levels of c-Jun and c-Fos, components of AP-1, were also inhibited. Co-immunoprecipitation analysis demonstrated that EGF treatment increased the AP-1 content through inducing the formation of p-c-Jun-c-Jun homodimers and p-c-Jun-c-Fos heterodimers. However, this combination was efficiently blocked by activated PKG II. While pretreatments with MAPK inhibitors suppressed the EGF-induced transcriptional activities of AP 1 and Elk1, PKG II prevented the EGF-induced phosphorylation/activation of ERK and JNK, but not the phosphorylation of p38MAPK induced by EGF. These data suggest that PKG II inhibits the EGF-triggered proliferation of gastric cancer cells through suppressing ERK-/JNK-, but not p38MAPK, -mediated AP-1 and Elk1 transactivation. PMID- 22940828 TI - Primary pancreatic lymphoma: will laparoscopy change the role of surgery in the treatment of this pathology? PMID- 22940829 TI - A novel protocol for mouse islet isolation. PMID- 22940830 TI - Fine three-dimensional reconstruction of peripheral exocrine gland in rat pancreas using transmission electron microscopic examination of serial sections. PMID- 22940831 TI - Invasive ductal carcinoma developing in pancreas with severe Fatty infiltration. PMID- 22940832 TI - Real-time tracking of adipose tissue-derived stem cells with injectable scaffolds in the infarcted heart. AB - Adipose tissue-derived stem cells (ADSCs) has shown promise in the emerging field of regenerative medicine. Many studies have highlighted the importance of coadministering a "scaffold" for increasing intramyocardial retention of stem cells. In this work, an optimized method was developed for efficient transduction of ADSCs with a lentiviral vector carrying a triple-fusion reporter gene that consists of firefly luciferase, monomeric red fluorescence protein, and truncated thymidine kinase (fluc-mrfp-ttk). The transduced ADSCs were assessed on biological performance and transplanted into infarcted heart with fibrin scaffolds. In vivo cell retention was tracked by bioluminescence imaging (BLI) and micro positron emission tomography/computed tomography (PET/CT) imaging. Histological assessment was performed for regeneration potentials. The results showed that lentiviral transduction did not influence cell functions. In vitro imaging analysis showed a robust linear correlation between cell numbers and BLI signals (R (2) = 0.99) as well as between cell numbers and radiotracer uptakes (R (2) = 0.98). Transduced ADSCs were visualized in the heart under both BLI and PET/CT imaging, contributing to cardiomyocyte regeneration and angiogenesis in the implanted areas. Compared with BLI monitoring, PET/CT data provided precise localization for cell retention. Thus, a combination of imaging modalities can assist in reliable and efficient monitoring of transplanted cells, holding great potential for the transplantation of injectable scaffolds encapsulating stem cells in treating heart disease. PMID- 22940833 TI - Rituximab and FAB/LMB 96 chemotherapy in children with Stage III/IV B-cell non Hodgkin lymphoma: a Children's Oncology Group report. PMID- 22940835 TI - Visual expertise in detecting and diagnosing skeletal fractures. AB - OBJECTIVE: Failure to identify fractures is the most common error in accident and emergency departments. Therefore, the current research aimed to understand more about the processes underlying perceptual expertise when interpreting skeletal radiographs. MATERIALS AND METHODS: Thirty participants, consisting of ten novices, ten intermediates, and ten experts were presented with ten clinical cases of normal and abnormal skeletal radiographs of varying difficulty (obvious or subtle) while wearing eye tracking equipment. RESULTS: Experts were significantly more accurate, more confident, and faster in their diagnoses than intermediates or novices and this performance advantage was more pronounced for the subtle cases. Experts were also faster to fixate the site of the fracture and spent more relative time fixating the fracture than intermediates or novices and this was again most pronounced for subtle cases. Finally, a multiple linear regression analysis found that time to fixate the fracture was inversely related to diagnostic accuracy and explained 34 % of the variance in this variable. CONCLUSIONS: The results suggest that the performance advantage of expert radiologists is underpinned by superior pattern recognition skills, as evidenced by a quicker time to first fixate the pathology, and less time spent searching the image. PMID- 22940834 TI - Aurora kinases in childhood acute leukemia: the promise of aurora B as therapeutic target. AB - We investigated the effects of targeting the mitotic regulators aurora kinase A and B in pediatric acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML). Aurora protein expression levels in pediatric ALL and AML patient samples were determined by western blot and reverse phase protein array. Both kinases were overexpressed in ALL and AML patients (P<0.0002), especially in E2A-PBX1 translocated ALL cases (P<0.002), compared with normal bone-marrow mononuclear cells. Aurora kinase expression was silenced in leukemic cell lines using short hairpin RNAs and locked nucleic acid-based mRNA antagonists. Aurora B knockdown resulted in proliferation arrest and apoptosis, whereas aurora A knockdown caused no or only minor growth delay. Most tested cell lines were highly sensitive to the AURKB-selective inhibitor barasertib-hydroxyquinazoline-pyrazol-anilide (AZD1152-HQPA) in the nanomolar range, as tested with an MTS (3-(4,5 dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H tetrazolium) assay. But most importantly, primary ALL cells with a high aurora B protein expression, especially E2A-PBX1-positive cases, were sensitive as well. In adult AML early clinical trials, clear responses are observed with barasertib. Here we show that inhibition of aurora B, more than aurora A, has an antiproliferative and pro-apoptotic effect on acute leukemia cells, indicating that particularly targeting aurora B may offer a new strategy to treat pediatric ALL and AML. PMID- 22940837 TI - Abductor tendon tears are associated with hypertrophy of the tensor fasciae latae muscle. AB - OBJECTIVE: To evaluate the association between hypertrophy of the tensor fasciae latae muscle and abductor tendon tears. MATERIALS AND METHODS: Thirty-five patients who underwent MRI of the abductor tendons of the hip were included in this retrospective study. A subgroup of 18 patients was examined bilaterally. The area of the tensor fasciae latae muscle and the area of the sartorius muscle (size reference) were quantified at the level of the femoral head, and a ratio was calculated. Two radiologists assessed the integrity of the gluteus medius and minimus tendon in consensus. Data were analyzed with a Mann-Whitney U test. RESULTS: Sixteen out of 35 patients (46 %) had a tear of the gluteus medius or minimus tendon. The ratio of the area of the tensor fasciae latae to the sartorius muscle was significantly higher (p = .028) in the group with an abductor tendon tear (median 2.25; Interquartile Range [IQR] = 1.97-3.21) compared to the group without any tears (median 1.91; IQR = 1.52-2.26). The bilateral subanalysis showed that in patients without a tear, the ratio of the two areas did not differ between each side (p = .966), with a median of 1.54 (primary side) and 1.76 (contralateral side). In patients with an abductor tendon tear the ratio was significantly higher (p = .031) on the side with a tear (median 2.81) compared to the contralateral healthy side (1.67). CONCLUSION: Patients with abductor tendon tears showed hypertrophy of the tensor fasciae latae muscle when compared to the contralateral healthy side and to patients without a tear. PMID- 22940838 TI - Pullulan fermentation using a prototype rotational reciprocating plate impeller. AB - A rotational reciprocating plate impeller prototype, designed to improve the mixing homogeneity of viscous non-Newtonian fermentation broth, has been tested in pullulan fermentations. With this new impeller, the operating levels of several factors were investigated to improve pullulan production with Aureobasidium pullulans ATCC 42023 in a 22-L bioreactor using experimental designs. Because both high molecular weight (MW) and high concentration of pullulan were desired; the exopolysaccharide (EPS) concentration and the broth viscosity were used as optimization objective functions to be maximized. A 6-run uniform design was used to investigate five factors. Under the best operating conditions among the six runs, 29.0 g L(-1) EPS was produced at 102 h. This condition was used as the starting point for further investigation on the two statistically significant factors, the pH and the agitation speed. An 8-run 3 level custom design that investigates up to second-order effects was used in the second stage. An optimal zone of operating conditions for large quantity of high MW pullulan production was identified. A concentration of 23.3 g L(-1) EPS was produced at 78 h. This is equivalent to an EPS productivity of 0.30 g L(-1) h( 1). The corresponding apparent viscosity of the broth was 0.38 Pa s at the shear rate of 10 s(-1). PMID- 22940839 TI - Solid-state fluorescence emission and second-order nonlinear optical properties of coumarin-based fluorophores. AB - Some coumarin-based fluorophores were synthesized and characterized by elemental analysis, (1)H NMR, (13)C NMR and MS. The solid-state photoluminescence properties were studied. The benzocoumarins display interesting solid-state emission properties with an emission at wavelengths ranging from 532 to 645 nm, when excited by a 325 nm helium-cadmium laser at room temperature. The results demonstrated that the luminescent colors can be tuned from green to red by simply varying molecular structure. The benzocoumarin-phenyl boronic acid hybrid, 4-(3 oxo-3-(2 -oxo-2H-1-naphtho[2,1-b]pyran-3-yl)-prop-1-enyl)phenyl boronic acid, showed obvious fluorescence response to water. Whereas the free compound was very weakly fluorescent in tetrahydrofuran (THF), the addition of water leads to an appearance of strong blue-green fluorescence and a dramatic increase of emission intensity. Besides, 3-(3-(3,4,5-trimethoxyphenyl)-prop-2-enoyl)-2H-1-benzopyran-2 one exhibited second order nonlinear optical response to laser pulses. A noticeable second harmonic generation (SHG) under pulsed excitation at 1064 nm was observed. Preliminary nonlinear measurements on powder samples showed that the second harmonic generation efficiency is roughly 5.8 times that of potassium dihydrogen phosphate (KDP). PMID- 22940840 TI - Impaired autophagy contributes to muscle atrophy in glycogen storage disease type II patients. AB - The autophagy-lysosome system is essential for muscle cell homeostasis and its dysfunction has been linked to muscle disorders that are typically distinguished by massive autophagic buildup. Among them, glycogen storage disease type II (GSDII) is characterized by the presence of large glycogen-filled lysosomes in the skeletal muscle, due to a defect in the lysosomal enzyme acid alpha glucosidase (GAA). The accumulation of autophagosomes is believed to be detrimental for myofiber function. However, the role of autophagy in the pathogenesis of GSDII is still unclear. To address this issue we monitored autophagy in muscle biopsies and myotubes of early and late-onset GSDII patients at different time points of disease progression. Moreover we also analyzed muscles from patients treated with enzyme replacement therapy (ERT). Our data suggest that autophagy is a protective mechanism that is required for myofiber survival in late-onset forms of GSDII. Importantly, our findings suggest that a normal autophagy flux is important for a correct maturation of GAA and for the uptake of recombinant human GAA. In conclusion, autophagy failure plays an important role in GSDII disease progression, and the development of new drugs to restore the autophagic flux should be considered to improve ERT efficacy. PMID- 22940841 TI - Obstetric anal sphincter injuries in vaginal delivery of twins: associated risk factors and comparison with singletons. AB - INTRODUCTION AND HYPOTHESIS: Risk factors related to obstetric anal sphincter injuries (OASIS) are known for singleton deliveries. No study to date has described the rate and risk factors involved in twin deliveries. METHODS: We conducted a retrospective cohort study (1985-2010) of all vaginal twin and singleton deliveries in a single tertiary center. The adjusted odds ratio (OR) for OASIS at delivery was estimated using the logistic regression model. RESULTS: The study comprised 1,538 and 91,312 patients with vaginal twin and singleton delivery, respectively. Twenty twin (1.27 %) and 2,331 (2.55 %) singleton deliveries were complicated with OASIS. The following OASIS-associated risk factors were shared by both populations: nulliparity [twins adjusted OR 5.9, 95 % confidence interval (CI) 1.7-20.9; singletons adjusted OR 3.9, 95 % CI 3.5-4.4), occipitoposterior (OP) position (twins adjusted OR 3.00, 95 % CI 1.1-8.0; singletons adjusted OR 1.6, 95 % CI 1.3-2.00), birthweight (for each 100 g) (twin adjusted OR 1.1, 95 % CI 1.0-1.2; singletons adjusted OR 1.07, 95 % CI 1.06 1.08), and instrumental delivery (twins adjusted OR 4.3, 95 % CI 1.2-15.4, singletons adjusted OR 2.4, 95 % CI 2.2-2.6). CONCLUSIONS: Risk factors of nulliparity, OP position, large fetal size, and instrumental delivery were shared by both twin and singleton deliveries. These data will be useful in counselling women carrying twins who intend to deliver vaginally. PMID- 22940842 TI - Women's ability to assess their urinary incontinence type using the QUID as an educational tool. AB - INTRODUCTION AND HYPOTHESIS: Little evidence is available concerning the ability of women with urinary incontinence (UI) to properly assess their problem. This study compared women's assessments of their UI type with physicians' diagnoses. METHODS: Women referred to a urogynecology clinic for UI were asked to anonymously answer a short validated Questionnaire for Urinary Incontinence Diagnosis (QUID) before their physician visit. Women completed the QUID and read a brief explanation of its interpretation, after which they were asked to choose their UI type: stress, urge, or mixed. Physicians, blinded to patients' answers, conducted routine examinations and indicated their diagnoses of incontinence types. Sample size was representative of typical clinic volumes. Levels of agreement among physician diagnoses, QUID scores, and patient self-assessments of UI type were calculated with kappa (kappa) statistics. Physician diagnosis was the gold standard. RESULTS: We had 497 patients return the questionnaire; 338 met inclusion criteria. Mean age was 53 (+/- 13) years. Levels of agreement among physician diagnoses and patients' assessments of UI type (kappa=0.411, p<0.01) and QUID scores (kappa=0.378, p<0.01) were significant. Significant level of agreement was found among QUID scores and patients' assessments of UI type (kappa=0.497, p<0.001). CONCLUSIONS: With aid of a brief standardized questionnaire, women can accurately assess their UI type. This suggests women could be educated about UI via good-quality Internet health sites and choose appropriate conservative management options. PMID- 22940843 TI - Tissue engineering as a potential alternative or adjunct to surgical reconstruction in treating pelvic organ prolapse. AB - INTRODUCTION AND HYPOTHESIS: Cell-based tissue engineering strategies could potentially provide attractive alternatives to surgical reconstruction of native tissue or the use of surgical implants in treating pelvic organ prolapse (POP). METHODS: Based on a search in PubMed, this review focuses on candidate cell types, scaffolds, and trophic factors used in studies examining cell-based tissue engineering strategies to treat POP, stress urinary incontinence (SUI), and the closely related field of hernias. RESULTS: In contrast to the field of SUI, the use of cell-based tissue engineering strategies to treat POP are very sparsely explored, and only preclinical studies exist. CONCLUSION: The available evidence suggests that the use of autologous muscle-derived cells, fibroblasts, or mesenchymal stem cells seeded on biocompatible, degradable, and potentially growth-promoting scaffolds could be an alternative to surgical reconstruction of native tissue or the use of conventional implants in treating POP. However, the vagina is a complex organ with great demands of functionality, and the perfect match of scaffold, cell, and trophic factor has yet to be found and tested in preclinical studies. Important issues such as safety and economy must also be addressed before this approach is ready for clinical studies. PMID- 22940844 TI - Thyroid transcription factor 1 represses the expression of Ki-67 and induces apoptosis in non-small cell lung cancer. AB - The thyroid transcription factor 1 (TTF-1) gene is associated with the differentiation of lung epithelial cells and has been reported to be an independent prognostic factor for lung adenocarcinoma patients. The aim of the present study was to detect the expression of TTF-1 in human lung cancer cell lines and to evaluate the association of overexpressed TTF-1 with Ki-67 and apoptosis in the A549 cell line. We also investigated the expression of TTF-1 and Ki-67 in Xuanwei lung adenocarcinoma. TTF-1 mRNA expression was evaluated in 10 non-small cell lung cancer (NSCLC) cell lines by quantitative real-time RT-PCR (qRT-PCR). Overexpression of TTF-1 in A549 cells was achieved by transient transfection. The TTF-1 and Ki-67 proteins were detected by immunohistochemistry and apoptosis was detected by flow cytometry. We also investigated immunohistochemically the expression of TTF-1 and Ki-67 in 62 resected cases of Xuanwei lung adenocarcinoma. Overall the expression of TTF-1 mRNA in the 10 cell lines was low. Overexpression of TTF-1 mRNA was found only in 3 (30%) of 10 NSCLC cell lines, including 1 (25%) of 4 adenocarcinoma cell lines. A549 cells overexpressing TTF-1 were found to have repressed expression of Ki-67 (P=0.012) and increased apoptosis (P=0.000). Immunohistochemical analysis of resected cases of Xuanwei lung adenocarcinoma (n=62) showed the expression of TTF-1 in 58 (93%) of 62 and Ki-67 in 22 (35%) of 62. Patients with strong immunohistochemical expression TTF-1 were statistically associated with well-differentiated phenotype (P=0.006) and inverse correlation with Ki-67 expression (P=0.016). These data suggest that TTF-1 may serve as a tumor suppressor gene based on its inverse correlation with Ki-67 proliferative activity and increase of cellular apoptosis. PMID- 22940845 TI - Cell adhesion molecule 1 (CADM1) is ubiquitously present in the endothelium and smooth muscle cells of the human macro- and micro-vasculature. AB - Cell adhesion molecule 1 (CADM1) is a member of the immunoglobulin cell adhesion molecule family. Recently, we identified CADM1 to be a novel risk factor for venous thrombosis in a large, protein C deficient, thrombophilic family and showed, for the first time, the expression of CADM1 in endothelial cells (Hasstedt et al. in Blood 114:3084-3091, 2009). To further investigate its role in venous thrombosis, as well as other vasculopathies, we undertook a systematic confocal microscopic investigation for the presence of CADM1 in the vasculature of 28 different human tissues. Paraffin embedded tissue sections were dual immunostained with an antibody against CADM1, together with an antibody against either von Willebrand factor (to identify endothelial cells), or alpha-smooth muscle actin (to identify smooth muscle cells). The results showed that CADM1 was ubiquitously present in endothelial cells and smooth muscle cells in the vasculature from all 28 tissues, though its representation in the various classes of vessels was tissue dependent. PMID- 22940846 TI - Influence of copy number on the expression levels of pandemic influenza hemagglutinin recombinant protein in methylotrophic yeast Pichia pastoris. AB - The hemagglutinin (HA) gene of novel Swine Origin Influenza A/California/04/2009 (H1N1) was engineered for expression in Pichia pastoris as a soluble secreted protein. The full length HA-synthetic gene having alpha secretory tag under the control of AOX1 promoter was integrated into P. pastoris genome through homologous recombination. The resultant Pichia clones having single and multiple copy integrants of the expression cassettes were screened for the expression of full length HA protein in the culture supernatant. In order to completely exploit the expression potential of the P. pastoris expression system, a systematic investigation on the influence of gene copy number on the expression of the recombinant protein was made. A panel of Pichia clones carrying increasing copies of the heterologous gene was selected based on Geneticin resistance and SYBR green-based quantitative real-time PCR approach. Using these strategies, recombinant Pichia transformants carrying up to a maximum of four to six copies of the transgene were identified. After optimising the expression conditions for shaker flask culture, the resultant clones demonstrated that the increase in copy number results in a proportional elevation in the expression level of H1N1HA recombinant protein. Our findings clearly suggest that the gene dosage effect play a vital role in high level expression of the pandemic Influenza HA protein in yeast system. PMID- 22940847 TI - Anemia and iron deficiency in heart failure. AB - Anemia is a common comorbidity in heart failure (HF), and is associated with increased morbidity and mortality. However, it remains unclear whether anemia is merely a marker of poor prognosis or whether anemia itself confers risk. The pathogenesis of anemia in HF is multifactorial. Iron deficiency also confers risk in HF, either with or without associated anemia, and treatment of iron deficiency improves the functional status of patients with HF. An ongoing large clinical trial studying the use of darbepoetin-alfa in patients with anemia and systolic HF is expected to provide information that should improve our understanding of anemia in HF. PMID- 22940848 TI - Hepatic resection combined with radiofrequency ablation for initially unresectable colorectal liver metastases after effective chemotherapy is a safe procedure with a low incidence of local recurrence. AB - BACKGROUND: Chemotherapy can lead to tumor down-staging in patients with initially unresectable colorectal liver metastases (CRLM); however, more than half of such cases are still considered to be unresectable because of disease progression, including multiple or bilobar CRLM, and an insufficient predicted remnant liver volume. In addition, there is little evidence supporting the use of radiofrequency ablation (RFA) for patients with CRLM. This study compared the safety and efficacy of hepatic resection (HR) combined with RFA versus HR alone after effective chemotherapy in patients with initially unresectable CRLM. METHODS: Data were prospectively collected on 118 consecutive patients with initially unresectable CRLM who received FOLFOX +/- bevacizumab as the first-line chemotherapy. 48 of these patients (41%) underwent HR or HR + RFA after the chemotherapy. HR was performed in 35 patients (HR group), and HR + RFA in 13 (HR + RFA group). RESULTS: There was no mortality in either group. Postoperative morbidity rates in the HR group and the HR + RFA group were 17 and 23%, respectively (P = 0.640). Local recurrence at the RFA site occurred in only one tumor (1.6% per lesion, 7.7% per patients). The 3-year progression-free survival was 45.3% in the HR group and 12.8% in the HR + RFA group (P = 0.472). The 3-year overall survival rate was 70.4% in the HR group and 77.1% in the HR + RFA group (P = 0.627). CONCLUSIONS: These results suggest that HR + RFA after effective chemotherapy is a safe procedure with low local recurrence at the RFA site and is a potentially effective treatment option for patients with initially unresectable CRLM. PMID- 22940849 TI - Cranioplasty in medieval Persia and the potential spread of this knowledge to Europe. AB - INTRODUCTION: Skull trepanation is an ancient and often religious act found in remains from around the world. However, cranioplasty for the surgical treatment of skull pathologies is a relatively recent phenomenon. In this paper, we focus on the account of skull injury and cranioplasty in medieval Persia. MATERIALS AND RESULTS: Herein, we describe and translate the over 500-year-old writings of the Persian physician Baha al-Dowleh Razi regarding cranioplasty in an excerpt from his book entitled Khulasat al-Tajarib (Summary of Experiences). This early writer detailed the methods and indications for cranioplasty including the use of xenographs. Additionally, we attempt to trace this early understanding of skull surgery and follow its possible spread to Europe. CONCLUSIONS: It is such early experiences and methods of cranial surgery on which we base our current understanding of neurosurgery. PMID- 22940850 TI - De novo multiple dural arteriovenous fistulas and arteriovenous malformation after embolization of cerebral arteriovenous fistula: case report. AB - BACKGROUND: A cerebral arteriovenous fistula is a rare neurovascular abnormality. It is very scarce when presenting with other cerebral arteriovenous malformations after embolization. METHOD: We reported a case primarily presenting with cerebral arteriovenous fistula. When the fistula was embolized completely, de novo multiple dural arteriovenous fistulas and a small arteriovenous malformation occurred due to the hemodynamic change after the embolization. Embolization of parts of the fistulas for the second time led to an untreatable malformation which became curable. At the third time, the remaining fistula was cured. RESULTS: The mechanism of the dural arteriovenous fistula and treatment strategy were discussed. CONCLUSION: Venous hypertension is the main factor causing a dural arteriovenous fistula. Embolization of the fistulas step by step is recommended. PMID- 22940851 TI - Prenatal diagnosis of split cord malformation by ultrasound and fetal magnetic resonance imaging: case report and review of the literature. AB - INTRODUCTION: Split cord malformation (SCM) is rare congenital disorder of spine in which bony, fibrous, or cartilaginous septum subdivides partially or completely the vertebral canal. SCM can be associated with other spinal abnormalities such as spina bifida, Arnold-Chiari malformation, hemivertebra, butterfly vertebra, or kyphoscoliosis and also can be seen as part of Jarcho Levin syndrome. Prenatal diagnosis of SCM is possible by ultrasonography (US). Fetal magnetic resonance imaging (MRI) and amniotic fluid acetylcholine esterase (AF-AChE) levels can be helpful to rule out additional anomalies. We present a case of fetal SCM diagnosed by US and fetal MRI. CASE: An 18-year-old woman with no obstetrics risk factor was referred for routine US screening. At sagittal section, fetal spine was seen to be disordered. A coronal view of the spinal canal showed evidence of widening at the lower thoracic and lumbar level. An echogenic mass was identified within the enlarged spinal canal at level of T6-L5. Fetal MRI and AF-AChE analysis confirmed diagnosis and ruled out other anomalies and spina bifida. Neurological examination of the baby at 16 months of age was normal. PMID- 22940852 TI - Attention Deficits in Children With Combined Autism and ADHD: A CPT Study. AB - OBJECTIVE: To investigate characteristics of attention in children with the combination of autism spectrum disorder (ASD) and ADHD. METHOD: Four groups of 8- to 10-year-old children were compared on the Conners' Continuous Performance Test Second Edition (CCPT-II): (a) ASD + ADHD (n = 11), (b) ASD only (n = 9), (c) ADHD only (n = 38), and (d) no diagnosis (n = 134). RESULTS: There was an overall effect of group on the Continuous Performance Test (CPT) index and measures of hit reaction time, accuracy, response style, variability, and consistency. The ASD + ADHD group, much like the ADHD only group, had a more risky response style, a higher variability, and a lower consistency than the ASD only group. The impact of intellectual function on CCPT-II performance was considerable in children within the ASD subgroups. CONCLUSION: The findings underscore the importance of including measures of attention and intellectual function when assessing children with the combination of ASD and ADHD. PMID- 22940853 TI - Computational study of Be2 using Piris natural orbital functionals. AB - The third (PNOF3), fourth (PNOF4) and fifth (PNOF5) versions of the Piris natural orbital functional were used to characterize the beryllium dimer. The results obtained were compared to those gained afforded by CASSCF and CASPT2 as well as experimental data. The equilibrium distances (R e), dissociation energies (D e), effective bond orders (EBOs), and rovibrational levels were calculated. PNOF3, PNOF4, and CASPT2 predicted a bonded Be2 molecule, while PNOF5 and CASSCF did not, which demonstrates the importance of the dynamical electron correlation. We observed that PNOF3 yields the most accurate equilibrium distances, while PNOF4 most accurately calculates the rovibrational levels. However, both of these functionals overestimate dissociation energies. Both PNOF3 and PNOF4 predict EBOs that agree with that obtained using CASPT2. PMID- 22940854 TI - In silico structural and functional analysis of the human TOPK protein by structure modeling and molecular dynamics studies. AB - Over expression of T-lymphokine-activated killer cell-originated protein kinase (TOPK) has been associated with leukemia, myeloma tumors and various other cancers. The function and regulatory mechanism of TOPK in tumor cells remains unclear. Structural studies that could reveal the regulatory mechanism have been a challenge because of the unavailabity of TOPK's crystal structure. Hence, in this study, the 3D structure of TOPK protein has been constructed by using multiple templates. The quality and reliability of the generated model was checked and the molecular dynamics method was utilized to refine the model. APBS method was employed to know the electrostatic potential surface of the modeled protein and it was found that the optimum pH for protein stability is 3.4 which will further help in mechanistic hypothesis of TOPK protein. Active site of TOPK was identified from available literature and HTVS was employed to identify the lead molecules. The expected binding modes of protein-ligand complexes were reproduced in the MD simulation which indicates that the complex is relatively stable. The pharmacokinetic properties of the lead molecules are also under acceptable range. TOPK act as a substrate for CDK1 and the protein-protein docking and dynamics studies were carried out to analyze the effect of Thr9Ala mutation of TOPK in the two protein complex formation. It shows that the wild type complex is more stable when compared with the mutant type. Such structural information at atomic level not only exhibits the action modes of TOPK inhibitors but also furnishes a novel starting point for structure based drug design of TOPK inhibitors. PMID- 22940855 TI - Quantum chemical investigation of the intra- and intermolecular proton transfer reactions and hydrogen bonding interactions in 4-amino-5-(2-hydroxyphenyl)-2H 1,2,4-triazole-3(4H)-thione. AB - The intramolecular thione-thiol tautomerism and intermolecular double proton transfer reaction of the hydrogen-bonded thione and thiol dimers in the title triazole compound were studied at the B3LYP level of theory using 6-311++G(d,p) basis function. The influence of the solvent on the single and double proton transfer reactions was examined in three solvents (chloroform, methanol and water) using the polarizable continuum model (PCM) approximation. The computational results show that the thione tautomer is the most stable isomer with a very high tautomeric energy barrier both in the gas phase and in solution phase, indicating a quite disfavored process. The solvent effect is found to be sizable with increasing polarity. In the double proton transfer reaction, the thione dimer is found to be more stable than thiol dimer both in the gas phase and in solution phase. The energetic and thermodynamic parameters of the double proton transfer process show that the double proton exchange from thione dimer to thiol dimer is thermodynamically unfavored. However, the exchange from thiol dimer to thione dimer for the gas phase and water phase seems to be feasible with a low barrier height and with a negative value in enthalpy and free energy changes. In addition, the hydrogen bonding interactions were analyzed in the gas phase regarding their geometries and energies. It is found that all complex formations are enthalpically favored, and the stability of the H-bonds comes in the order of S1-H2...N2>N2-H2...S1>N3-H3B...O1. Finally, non-linear optical properties were carried out at the same calculation level in the gas phase. PMID- 22940857 TI - Activated partial thromboplastin time is a better trending tool in pediatric extracorporeal membrane oxygenation. AB - OBJECTIVES: To determine whether activated partial thromboplastin times are a better heparin management tool than activated clotting times in pediatric extracorporeal membrane oxygenation. DESIGN: A single-center retrospective analysis of perfusion and patient records. SETTING: Academic pediatric tertiary care center. PATIENTS: Pediatric patients (<21 yrs old) requiring extracorporeal membrane oxygenation support initiated at Children's Hospital of Pittsburgh. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Point-of-care activated clotting time and activated partial thromboplastin time values, clinical laboratory activated partial thromboplastin time values, weight-normalized heparin administration (units/kg/hr), and reported outcomes were collected for pediatric patients treated for cardiac and/or respiratory failure with extracorporeal membrane oxygenation. Spearman's ranked correlations were performed for each coagulation test compared to heparin dosage. The Bland-Altman test was used to determine the validity of the point-of-care activated partial thromboplastin time. Hazard analysis was conducted for outcomes and complications for patients whose heparin management was based on the clinical laboratory activated partial thromboplastin time or the activated clotting time. Only the clinical laboratory activated partial thromboplastin time showed a correlation (rho = 0.40 vs. rho = -0.04 for activated clotting time) with the heparin administration (units/kg/hr). Point-of-care activated partial thromboplastin time and activated partial thromboplastin time values correlated well (rho = 0.76), with <5% of samples showing a difference outside 2 SDs, but differences in their absolute values (Deltaactivated partial thromboplastin time = 100 secs) preclude them from being interchangeable measures. Furthermore, despite no effective change in the mean activated clotting time, cardiac patients showed a significantly improved correlation to heparin dose for all coagulation tests (e.g., point-of-care activated partial thromboplastin time rho = 0.60). Management of patients with the clinical laboratory activated partial thromboplastin time did not significantly affect patient survival rates but did significantly reduce bleeding complications and significantly increased clotting in the extracorporeal membrane oxygenation circuit. A hazard analysis demonstrated that bleeding complications were associated with an increased risk of mortality, whereas clotting complications in the extracorporeal membrane oxygenation circuit were not. CONCLUSIONS: The activated clotting time is not an accurate monitoring tool for heparin management in pediatricextracorporeal membrane oxygenation. The point-of-care activated partial thromboplastin time correlates well with the clinical laboratory activated partial thromboplastin time but cannot be substituted for the clinical laboratory activated partial thromboplastin time values. Management of pediatric extracorporeal membrane oxygenation patients with the clinical laboratory activated partial thromboplastin time reduced bleeding complications which are associated with increases in mortality. PMID- 22940856 TI - Biokinetics and dosimetry of 111In-DOTA-NOC-ATE compared with 111In-DTPA octreotide. AB - PURPOSE: The biokinetics and dosimetry of (111)In-DOTA-NOC-ATE (NOCATE), a high affinity ligand of SSTR-2 and SSTR-5, and (111)In-DTPA-octreotide (OctreoscanTM, OCTREO) were compared in the same patients. METHODS: Seventeen patients (10 men, 7 women; mean age 60 years), referred for an OCTREO scan for imaging of a neuroendocrine tumour (15), thymoma (1) or medullary thyroid carcinoma (1), agreed to undergo a second study with NOCATE. Whole-body anterior-posterior scans were recorded 0.5 (100 % reference scan), 4, 24 and 48 h (17 patients) and 120 h (5 patients) after injection. In 16 patients the OCTREO scan (178 +/- 15 MBq) was performed 16 +/- 5 days before the NOCATE scan (108 +/- 14 MBq) with identical timing; 1 patient had the NOCATE scan before the OCTREO scan. Blood samples were obtained from 14 patients 5 min to 48 h after injection. Activities expressed as percent of the initial (reference) activity in the whole body, lung, kidney, liver, spleen and blood were fitted to biexponential or single exponential functions. Dosimetry was performed using OLINDA/EXM. RESULTS: Initial whole-body, lung and kidney activities were similar, but retention of NOCATE was higher than that of OCTREO. Liver and spleen uptakes of NOCATE were higher from the start (p < 0.001) and remained so over time. Whole-body activity showed similar alpha and beta half-lives, but the beta fraction of NOCATE was double that of OCTREO. Blood T (1/2)beta for NOCATE was longer (19 vs. 6 h). As a result, the effective dose of NOCATE (105 MUSv/MBq) exceeded that of OCTREO (52 MUSv/MBq), and the latter result was similar to the ICRP 106 value of 54 MUSv/MBq. Differential activity measurement in blood cells and plasma showed an average of <5 % of NOCATE and OCTREO attached to globular blood components. CONCLUSION: NOCATE showed a slower clearance from normal tissues and its effective dose was roughly double that of OCTREO. PMID- 22940858 TI - Low-dose radiation with 80-kVp computed tomography to diagnose pulmonary embolism: a feasibility study. AB - BACKGROUND: Mounting collective radiation doses from computed tomography (CT) implies an increased risk of radiation-induced cancer in exposed populations, especially in the young. PURPOSE: To evaluate radiation dose and image quality at 80-kVp CT to diagnose acute pulmonary embolism (PE) compared with a previous study at 100 and 120 kVp with all other scanning parameters unchanged. MATERIAL AND METHODS: A custom-made chest phantom with a 12 mg I/mL-syringe was scanned at 80/100/120 kVp to evaluate relative changes in computed tomographic dose index (CTDI(vol)), attenuation, image noise, and contrast-to-noise ratio (CNR). Fifty patients underwent 80 kVp 16-row detector CT at 100 "Quality reference" mAs. A total of 350 mg I/kg were injected to compensate for increased CNR at 80 kVp, while 300 mg I/kg had been used at 100/120 kVp. CTDI(vol), dose-length product (DLP), and estimated effective dose were evaluated including Monte Carlo simulations. Pulmonary artery attenuation and noise were measured and CNR calculated. Two radiologists evaluated subjective image quality using a four grade scale. RESULTS: Switching from 120 to 80 kVp in the phantom study decreased radiation dose by 67% while attenuation and noise increased 1.6 and 2.0 times, respectively, and CNR decreased by 16%. Switching from 120 to 80 kVp in the patient studies decreased estimated effective dose from 4.0 to 1.2 mSv (70% decrease) in median while pulmonary artery attenuation and noise roughly doubled from 332 to 653 HU and from 22 to 49 HU, respectively, resulting in similar CNR (13 vs. 12). At 80 kVp all examinations were regarded as adequate (8%) or excellent (92%). CONCLUSION: Switching from 120 to 80 kVp CT without increased mAs but slightly increased iodine dose may be of special benefit to diagnose PE in younger individuals with preserved renal function where the primary aim is to minimize radiation dose and reaching levels below that of scintigraphy. PMID- 22940859 TI - Dual-phase CT angiography through the port-catheter system for hepatic arterial infusion chemotherapy using multislice CT: assessment of system dysfunction and impact on predicting clinical problems. AB - BACKGROUND: Hepatic arterial infusion (HAI) chemotherapy is being explored for treatment of malignant liver tumors. Maintenance of HAI systems is important for effective treatment. PURPOSE: To prospectively evaluate the efficacy of dual phase CT angiography through the port-catheter system for HAI chemotherapy. MATERIAL AND METHODS: This study enrolled 47 patients receiving HAI chemotherapy for malignant liver tumors who underwent dual-phase CT angiography through the port-catheter system using multislice CT. Using maximum intensity projection images reconstructed from vascular-phase CT imaging, hepatic arterial patency and catheter location were assessed. Using a combination of vascular- and perfusion phase CT imaging, system dysfunction and clinical problems were evaluated. RESULTS: Dual-phase CT angiography was conducted 156 times. Stenosis and obstruction of the hepatic artery and catheter dislodgment were observed seven times in four patients and four times in three patients, respectively. Diagnostic accuracy using vascular-phase CT imaging was 100%. In addition, development of collateral blood supply to the liver and extrahepatic perfusion to the stomach were observed three times in three patients and twice in two patients, respectively. Overall, system dysfunction occurred 16 times in 12 patients, and system correction and treatment modification were required 11 times in 10 patients. In assessing system dysfunction and predicting clinical problems, the accuracy of dual-phase CT imaging was 100%. CONCLUSION: Dual-phase CT angiography through the port-catheter system is helpful for assessing catheter system dysfunction and predicting clinical problems in HAI chemotherapy. PMID- 22940860 TI - Transjugular intrahepatic portosystemic shunt stent-graft placement: mean optimal portal venous projection view determined by three-dimensional portography. AB - BACKGROUND: Suboptimal stent-graft placement at the lower anastomosis during transjugular intrahepatic portosystemic shunt (TIPS) may result in early shunt stenosis and occlusion owing to incomplete covering of the parenchymal tract by the covered part of the stent-graft. PURPOSE: To determine the optimal portal venous projection view for stent-graft placement during TIPS and the potential influence of the portal vein anatomy. MATERIAL AND METHODS: On 76 cirrhotic patients (48 men and 28 women) selected for TIPS, rotational, three-dimensional (3D), catheter-directed angiography of the portal vein was performed. The 3D portograms were reviewed by two independent interventional radiologists to determine the optimal angiographic projection views for stent-graft placement. Intra-observer and inter-observer reliabilities were tested and subgroups of patient portal vein anatomy were categorized. RESULTS: Among all patients, the optimal portal venous projection views for stent-graft placement during TIPS centered around 27 degrees (+/-14 degrees ) right oblique and 3 degrees (+/-7 degrees ) craniocaudal. Of these, 56% were within the standard deviations. Intra observer reliabilities were 0.60 and 0.62 for the two radiologists, respectively. Inter-observer reliability was 0.48. Anatomical variations in the patient population were: normal portal vein (67%), trifurcation at main portal vein (16%), right posterior portal vein as the first branch of main portal vein (3%), no right posterior portal vein (1%), and other variations (13%). Anatomical subgroups did not influence the best angiographic projection view significantly (F4,295 = 0.91, P = 0.457). CONCLUSION: The mean optimal angiographic projection view for TIPS stent-graft placement was 27 degrees right oblique and 3 degrees craniocaudal. Patient anatomic variations do not play a significant role in determining the optimal angiographic view for TIPS stent-graft placement. PMID- 22940861 TI - Desmopressin testing in haemophilia A patients and carriers: results of a multi centre survey. AB - INTRODUCTION: Desmopressin (DDAVP) testing (DT) in patients (pts) with haemophilia A (HA) and carriers (CHA) is up to now not standardized. This prompted us to evaluate results of DT carried out between 1996 and 2011 in centres of the Competence Network Haemorrhagic Diatheses East. PATIENTS AND METHOD: An increase of the factor VIII activity (FVIII) above 50% or at least the two fold of initial values within 120 min after DDAVP was defined as complete response (CR). Data from 80 patients (31 children, 49 adults) of whom 64 suffered from HA (sub-HA: n=48; mild: n=14; moderate: n=2) and 16 patients CHA were evaluated. RESULTS: In 34 patients DDAVP was given i.v. (dose range: 0.26-0.6 ug/kg body weight, mean: 0.33), in 31 intranasally (i.n. 300-600 ug) and in 15 s.c. (15-40 ug). The maximal FVIII increase was reached 60 min after DDAVP. For i.v. application the mean FVIII increase was 3.1-fold, for i.n. 2.1-fold and for s.c. 2.4-fold. A CR was detected in 71 patients, a non-response in 9. Mild side effects such as flush, headaches or nausea were observed in 11 patients (14%). CONCLUSION: For desmopressin testing in patients with haemophilia A and carriers i.v. application at 0.3 ug/kg body weight and the determination of FVIII before and 60 min after desmopressin infusion is recommended. PMID- 22940862 TI - Interaction landscape of membrane-protein complexes in Saccharomyces cerevisiae. AB - Macromolecular assemblies involving membrane proteins (MPs) serve vital biological roles and are prime drug targets in a variety of diseases. Large-scale affinity purification studies of soluble-protein complexes have been accomplished for diverse model organisms, but no global characterization of MP-complex membership has been described so far. Here we report a complete survey of 1,590 putative integral, peripheral and lipid-anchored MPs from Saccharomyces cerevisiae, which were affinity purified in the presence of non-denaturing detergents. The identities of the co-purifying proteins were determined by tandem mass spectrometry and subsequently used to derive a high-confidence physical interaction map encompassing 1,726 membrane protein-protein interactions and 501 putative heteromeric complexes associated with the various cellular membrane systems. Our analysis reveals unexpected physical associations underlying the membrane biology of eukaryotes and delineates the global topological landscape of the membrane interactome. PMID- 22940863 TI - Distinct contribution of stem and progenitor cells to epidermal maintenance. AB - The skin interfollicular epidermis (IFE) is the first barrier against the external environment and its maintenance is critical for survival. Two seemingly opposite theories have been proposed to explain IFE homeostasis. One posits that IFE is maintained by long-lived slow-cycling stem cells that give rise to transit amplifying cell progeny, whereas the other suggests that homeostasis is achieved by a single committed progenitor population that balances stochastic fate. Here we probe the cellular heterogeneity within the IFE using two different inducible Cre recombinase-oestrogen receptor constructs targeting IFE progenitors in mice. Quantitative analysis of clonal fate data and proliferation dynamics demonstrate the existence of two distinct proliferative cell compartments arranged in a hierarchy involving slow-cycling stem cells and committed progenitor cells. After wounding, only stem cells contribute substantially to the repair and long-term regeneration of the tissue, whereas committed progenitor cells make a limited contribution. PMID- 22940864 TI - Nonlinear dendritic processing determines angular tuning of barrel cortex neurons in vivo. AB - Layer 4 neurons in primary sensory cortices receive direct sensory information from the external world. A general feature of these neurons is their selectivity to specific features of the sensory stimulation. Various theories try to explain the manner in which these neurons are driven by their incoming sensory information. In all of these theories neurons are regarded as simple elements summing small biased inputs to create tuned output through the axosomatic amplification mechanism. However, the possible role of active dendritic integration in further amplifying the sensory responses and sharpening the tuning curves of neurons is disregarded. Our findings show that dendrites of layer 4 spiny stellate neurons in the barrel cortex can generate local and global multi branch N-methyl-D-aspartate (NMDA) spikes, which are the main regenerative events in these dendrites. In turn, these NMDA receptor (NMDAR) regenerative mechanisms can sum supralinearly the coactivated thalamocortical and corticocortical inputs. Using in vivo whole-cell recordings combined with an intracellular NMDAR blocker and membrane hyperpolarization, we show that dendritic NMDAR-dependent regenerative responses contribute substantially to the angular tuning of layer 4 neurons by preferentially amplifying the preferred angular directions over non preferred angles. Taken together, these findings indicate that dendritic NMDAR regenerative amplification mechanisms contribute markedly to sensory responses and critically determine the tuning of cortical neurons. PMID- 22940865 TI - Alternating-access mechanism in conformationally asymmetric trimers of the betaine transporter BetP. AB - Betaine and Na(+) symport has been extensively studied in the osmotically regulated transporter BetP from Corynebacterium glutamicum, a member of the betaine/choline/carnitine transporter family, which shares the conserved LeuT like fold of two inverted structural repeats. BetP adjusts its transport activity by sensing the cytoplasmic K(+) concentration as a measure for hyperosmotic stress via the osmosensing carboxy-terminal domain. BetP needs to be in a trimeric state for communication between individual protomers through several intratrimeric interaction sites. Recently, crystal structures of inward-facing BetP trimers have contributed to our understanding of activity regulation on a molecular level. Here we report new crystal structures, which reveal two conformationally asymmetric BetP trimers, capturing among them three distinct transport states. We observe a total of four new conformations at once: an outward-open apo and an outward-occluded apo state, and two closed transition states--one in complex with betaine and one substrate-free. On the basis of these new structures, we identified local and global conformational changes in BetP that underlie the molecular transport mechanism, which partially resemble structural changes observed in other sodium-coupled LeuT-like fold transporters, but show differences we attribute to the osmolytic nature of betaine, the exclusive substrate specificity and the regulatory properties of BetP. PMID- 22940867 TI - Heterogeneity between primary colon carcinoma and paired lymphatic and hepatic metastases. AB - Heterogeneity is one of the recognized characteristics of human tumors, and occurs on multiple levels in a wide range of tumors. A number of studies have focused on the heterogeneity found in primary tumors and related metastases with the consideration that the evaluation of metastatic rather than primary sites could be of clinical relevance. Numerous studies have demonstrated particularly high rates of heterogeneity between primary colorectal tumors and their paired lymphatic and hepatic metastases. It has also been proposed that the heterogeneity between primary colon carcinomas and their paired lymphatic and hepatic metastases may result in different responses to anticancer therapies. The heterogeneity in primary colon carcinoma and corresponding metastases by genome wide gene expression analysis has not been extensively studied. In the present study, we investigated the differentially expressed genes between a primary colon carcinoma specimen (obtained from a 40-year-old female colon carcinoma patient with lymphatic and hepatic metastases) and its paired lymphatic and hepatic metastases by genome-wide gene expression analysis using GeneChip HGU133Plus2.0 expression arrays. Our results demonstrate that genome-wide gene expression varies between primary colon carcinoma and its paired lymphatic and hepatic metastases. PMID- 22940866 TI - Structural basis for RNA-duplex recognition and unwinding by the DEAD-box helicase Mss116p. AB - DEAD-box proteins are the largest family of nucleic acid helicases, and are crucial to RNA metabolism throughout all domains of life. They contain a conserved 'helicase core' of two RecA-like domains (domains (D)1 and D2), which uses ATP to catalyse the unwinding of short RNA duplexes by non-processive, local strand separation. This mode of action differs from that of translocating helicases and allows DEAD-box proteins to remodel large RNAs and RNA-protein complexes without globally disrupting RNA structure. However, the structural basis for this distinctive mode of RNA unwinding remains unclear. Here, structural, biochemical and genetic analyses of the yeast DEAD-box protein Mss116p indicate that the helicase core domains have modular functions that enable a novel mechanism for RNA-duplex recognition and unwinding. By investigating D1 and D2 individually and together, we find that D1 acts as an ATP binding domain and D2 functions as an RNA-duplex recognition domain. D2 contains a nucleic-acid-binding pocket that is formed by conserved DEAD-box protein sequence motifs and accommodates A-form but not B-form duplexes, providing a basis for RNA substrate specificity. Upon a conformational change in which the two core domains join to form a 'closed state' with an ATPase active site, conserved motifs in D1 promote the unwinding of duplex substrates bound to D2 by excluding one RNA strand and bending the other. Our results provide a comprehensive structural model for how DEAD-box proteins recognize and unwind RNA duplexes. This model explains key features of DEAD-box protein function and affords a new perspective on how the evolutionarily related cores of other RNA and DNA helicases diverged to use different mechanisms. PMID- 22940868 TI - Engaging local public health system partnerships to educate the future public health workforce. AB - The Institute of Medicine concluded that keeping the public healthy required a well-educated public health workforce, thus leading to its recommendation that "all undergraduates should have access to education in public health" [2]. In response to this call, the authors examined the current practice, feasibility, and value in strengthening (or building) a functional collaborative model between academic institutions and practitioners from local health departments to educate tomorrow's public health workforce. Local and regional health departments in New England were surveyed to: (1) establish a baseline of existing working relationships between them and nearby academic institutions; (2) examine the barriers that inhibit the development of collaborations with academic partners; (3) assess how they jointly promote public health workforce development; and (4) analyze which essential public health services their partnership addresses. Despite the lack of financial resources often cited for the absence of academic local health department collaborations, some New England states reported that their academic institution and local public health department partnerships were valued and productive. The authors discuss how effective academic-community collaborations have the potential to facilitate a broad-based appreciation of public health among students via a wide array of public health curricula and applied experiential learning opportunities in public health settings. The authors propose a model for how to combine basic public health lessons with practical experience and leadership offered by local health departments, in order to foster a real understanding of public health, its importance, practice, and relevance in today's society from a public health workforce perspective. PMID- 22940869 TI - Migraine headache: a review of the molecular genetics of a common disorder. AB - This tutorial summarises the state-of-the-art on migraine genetics and looks at the possible future direction of this field of research. The view of migraine as a genetic disorder, initially based on epidemiological observations of transmission of the condition within families, was subsequently confirmed by the identification of monogenic forms of "syndromic" migraine, such as familial hemiplegic migraine. We are currently witnessing a change in the way genetic analysis is used in migraine research: rather than studying modalities of inheritance in non-monogenic forms of migraine and in the persistent modalities of migraine headache, researchers are now tending to focus on the search for genetic markers of dysfunction in biological systems. One example of the evolution of migraine genetic research is provided by the recent efforts to shed light on the pharmacogenomic mechanisms of drug response in migraineurs. In addition, novel molecular approaches about to be introduced are expected to further increase knowledge on this topic and improve patient management. PMID- 22940870 TI - Psychiatric comorbidities of chronic migraine in community and tertiary care clinic samples. AB - Although the association between episodic migraine and psychiatric comorbidities is well documented, few studies have focused on the comorbidity with chronic migraine (CM) and discrepancies exist between population-based and clinic-based data. The objective of this study is to compare demographic and psychiatric comorbidity correlates between CM samples drawn from the community and tertiary care. All inhabitants from a city borough were interviewed for the presence of headaches occurring 15 or more days per month. CM was diagnosed after subjects had been interviewed and examined by a headache doctor. Participants were also assessed with a structured interview by a psychiatrist, who assigned diagnoses based on the DSM-IV. The same investigators assessed all patients consecutively seen in a university-based outpatient headache center over a 4-month period. The samples consist of 41 individuals from the community and 43 from the headache center. Sociodemographic profiles were similar between groups with the exception of the mean number of years of formal education. Among individuals from the community, psychiatric diagnoses were present in 65.9 % of cases, relative to 83.7 % in those from the headache center (p = 0.06). Phobias (41.9 vs. 29.3 %) and depression (32.6 vs. 29.3 %) were more frequent in patients from the headache center, but this difference did not reach statistical significance. Thus the frequency of psychiatric disorders in patients with CM was elevated in both settings, being higher in the specialty care clinic. PMID- 22940871 TI - Aging of the United States population: impact on heart failure. AB - The United States population, particularly among older age groups, continues to expand. Because the incidence of heart failure increases with age, largely due to the development of heart failure risk factors such as hypertension and coronary artery disease, the epidemic of heart failure is likely to grow further in the coming decades. This article will review the epidemiology of heart failure among older adults, the influence of an aging population on heart failure prevalence and phenotype, the complications in management for a larger and older heart failure population, and the potential implications of these changes for health care costs and delivery. Ultimately, these challenges demand research into optimal therapeutic strategies for older heart failure patients, including improved prevention and treatment of the major causes of heart failure, an increasing role forpalliative care, and innovations in patient-centered health care delivery. PMID- 22940872 TI - Prodrugs of fumarate esters for the treatment of psoriasis and multiple sclerosis -a computational approach. AB - Density functional theory (DFT) calculations at B3LYP/6-31 G (d,p) and B3LYP/6 311+G(d,p) levels for the substituted pyridine-catalyzed isomerization of monomethyl maleate revealed that isomerization proceeds via four steps, with the rate-limiting step being proton transfer from the substituted pyridinium ion to the C=C double bond in INT1. In addition, it was found that the isomerization rate (maleate to fumarate) is solvent dependent. Polar solvents, such as water, tend to accelerate the isomerization rate, whereas apolar solvents, such as chloroform, act to slow down the reaction. A linear correlation was obtained between the isomerization activation energy and the dielectric constant of the solvent. Furthermore, linearity was achieved when the activation energy was plotted against the pKa value of the catalyst. Substituted-pyridine derivatives with high pKa values were able to catalyze isomerization more efficiently than those with low pKa values. The calculated relative rates for prodrugs 1-6 were: 1 (406.7), 2 (7.6*10(6)), 3 (1.0), 4 (20.7), 5 (13.5) and 6 (2.2*10(3)). This result indicates that isomerizations of prodrugs 1 and 3-5 are expected to be slow and that of prodrugs 2 and 6 are expected to be relatively fast. Hence, prodrugs 2 and 3-5 have the potential to be utilized as prodrugs for the slow release of monomethylfumarate in the treatment of psoriasis and multiple sclerosis. PMID- 22940873 TI - Role of gold in a complex cascade reaction involving two electrocyclization steps. AB - Quantum chemical computations (B3LYP/LACVP**) were applied to assess the impact of Au(I) complexation on activation barriers for sequential electrocyclization reactions (one a 1,2-dihydroazete ring-opening and another a pentadienyl cation ring-closure) proposed to occur during a complex reaction cascade that converts alkynes and imines to cyclopentenimines. PMID- 22940874 TI - Low-energy conformers of pamidronate and their intramolecular hydrogen bonds: a DFT and QTAIM study. AB - Extensive DFT and ab initio calculations were performed to characterize the conformational space of pamidronate, a typical pharmaceutical for bone diseases. Mono-, di- and tri-protic states of molecule, relevant for physiological pH range, were investigated for both canonical and zwitterionic tautomers. Semiempirical PM6 method were used for prescreening of the single bond rotamers followed by geometry optimizations at the B3LYP/6-31++G(d,p) and B3LYP/6 311++G(d,p) levels. For numerous identified low energy conformers the final electronic energies were determined at the MP2/6-311++G(2df,2p) level and corrected for thermal effects at B3LYP level. Solvation effects were also considered via the COSMO and C-PCM implicit models. Reasonable agreement was found between bond lengths and angle values in comparison with X-ray crystal structures. Relative equilibrium populations of different conformers were determined from molecular partition functions and the role of electronic, vibrational and rotational degrees of freedom on the stability of conformers were analyzed. For no level of theory is a zwitterionic structure stable in the gas phase while solvation makes them available depending on the protonation state. Geometrically identified intramolecular hydrogen bonds were analyzed by QTAIM approach. All conformers exhibit strong inter-phosphonate hydrogen bonds and in most of them the alkyl-amine side chain is folded on the P-C-P backbone for further hydrogen bond formation. PMID- 22940875 TI - Structural phase transition of CdTe: an ab initio study. AB - A constant pressure ab initio MD technique and density functional theory with a generalized gradient approximation (GGA) was used to study the pressure-induced phase transition in zinc-blende CdTe. We found that CdTe undergoes a structural first-order phase transition to [Formula: see text] (binary beta-tin) tetragonal structure in the constant pressure molecular dynamics simulation at 20 GPa. When the pressure was increased to 50 GPa, the phase of tetragonal structure converted to a new Imm2 orthorhombic structure. These phase transformations were also calculated by using the enthalpy calculations. Transition phases, lattice parameters and bulk properties we attained are comparable with experimental and theoretical data. PMID- 22940876 TI - Theoretical study on electronic spectra and interaction in [Au3]-L-[Au 3] (L = C6F6,Ag+) complexes. AB - The electronic structure and spectroscopic properties of [Au3(MU-C(OEt) = NC6H4CH3)3]n-(C6F6)m and [Au3(MU-C(2),N(3)-bzim)3]n-(Ag(+))m were studied at the B3LYP, PBE and TPSS levels. The interaction between the [Au3] cluster and L (C6F6, Ag(+)) was analyzed. Grimme's dispersion correction is used for those functionals. Weak pi-interactions (Au-C6F6) were found to be the main contribution short-range stability in the models; while in the models with Ag(+), an ionic interaction is obtained. The absorption spectra of these models at the PBE level agree with the experimental spectra. PMID- 22940877 TI - Platelets in inflammation and immune modulations: functions beyond hemostasis. AB - Platelets play central roles for maintaining the homeostasis of the blood coagulation. As they are also involved in immune responses and host defenses, increasing evidences have suggested that platelets exert other roles beyond their well-recognized function in preventing bleeding. This review is focused on inflammation, allergy and immune modulations of platelets. Platelets conduct immunoregulation through secretion of functional mediators, interaction with various immune cells, endothelial cells and beneficial for the leukocyte infiltration to inflamed/allergic tissues. In these regulations, the leukocytes are influenced by and receiving the signals from platelets. In contrast, rare attentions were focused on platelet regulations by immune system. An intriguingly example in the intravenous immunoglobulin (IVIg) treatment is discussed, in which dendritic cells exert anti-inflammatory effect through platelets. This further suggests that coagulant and immune systems are tightly associated rather than separate entities. The cross-talks between these two systems implicate that platelet therapy may have application beyond thrombosis, and immune interventions may have potentials to treat thrombosis diseases. PMID- 22940878 TI - Function of junctional adhesion molecules (JAMs) in leukocyte migration and homeostasis. AB - Homeostasis is a word widely used in the scientific community to refer to the property of a system to maintain its uniformity and functionality. In living organisms, the word refers to the concept enunciated 150 years ago by C. Bernard by which external variations must be compensated for in order to maintain internal conditions compatible with life. This is especially true in the case of highly dynamic system such as the hematopoietic system that requires the coordinated control of cell proliferation and death within specialized microenvironments that are anatomically distinct. As a consequence, hematopoietic cell adhesion and migration must be tightly controlled in order for hematopoietic cells to reach and to be maintained in appropriate microenvironments. The junctional adhesion molecules (JAMs) are adhesion molecules that belong to the immunoglobulin superfamily (IgSf) and that have been initially identified as important players controlling vascular permeability and leukocyte transendothelial migration. This involves the regulated localization of the JAMs at lateral endothelial cell/cell borders and their interaction with leukocyte integrins. More recently, some of the JAM family members have also been found to be expressed by stromal cells and to regulate chemokine secretion within lymphoid organs, acting not only on leukocyte transendothelial migration, but also on hematopoietic cell retention within specialized microenvironments. This review summarizes recent progress in understanding the role of the JAMs in leukocyte adhesion and migration to tentatively draw an integrated view of the homeostatic function of the JAMs within the hematopoietic system. PMID- 22940879 TI - Grk2 is an essential regulator of CXCR7 signalling in astrocytes. AB - We previously demonstrated that in astrocytes, SDF-1/CXCL12 exclusively signals through CXCR7 despite the additional presence of the alternate SDF-1/CXCL12 receptor, CXCR4. In addition, we provided evidence that astrocytic CXCR7 signalling involves a G protein-dependent mechanism. This is insofar remarkable as in all other cell types studied to date, CXCR7 either acts as a scavenger chemokine receptor, a modulator of CXCR4, or a non-classical chemokine receptor, signalling through beta-arrestin. To begin to unravel the molecular framework impinging the selective function of CXCR7 on a given cell type, we have now analysed the role of G protein-coupled receptor kinases (Grks) in astrocytic CXCR7 signalling. We demonstrate that Grk2 mediates signalling of SDF-1/CXCL12 bound CXCR7 as suggested by the finding that SDF-1/CXCL12-induced activation of Erk1/2 and Akt is abrogated following RNAi-mediated inhibition of Grk2, but not of Grk3, Grk5, or Grk6. We further unravel that Grk2 additionally controls signalling of SDF-1/CXCL12-bound CXCR7 in astrocytes by mediating internalization and subsequent silencing of CXCR7. Finally, we demonstrate that Grk2 is likewise expressed by microglial cells and Schwann cells, cell types in which CXCR7 does not act as a classical chemokine receptor. In conclusion, our findings establish that Grk2 tightly controls CXCR7 signalling in astrocytes, but does not imprint the cell type-specific function of this chemokine receptor. PMID- 22940880 TI - Fecal and urinary continence after scope-assisted anorectovaginoplasty for female anorectal malformation. AB - AIM: We assessed continence after scope-assisted anorectovaginoplasty (SARVP) for female anorectal malformation (FARM). METHODS: Five FARM cases were assessed; cases 1 and 2: cloacal malformation; case 3: urogenital sinus, and rectovestibular fistula (RF); case 4: RF, absent vagina, and sacral anomaly; case 5: covered cloacal exstrophy. Treatment was SARVP in all cases, with perineal vaginoplasty (case 1), vagina pull-through (PT) similar to Georgeson's colon PT (case 2), and the use of the native RF/cloaca channel as a vagina (cases 3-5). Continence was assessed pre and postoperatively. RESULTS: SARVP was performed in the lithotomy position without repositioning. Mean age at surgery was 3.2 (1.7 5.5) years. Current mean age: 8.8 years (range 7.5-12.2). Mean follow-up: 5.7 years. Preoperative continence: fecal: all had stomas; urinary: cases 1 and 2: continent; cases 3-5: incontinent. Postoperative continence: fecal: cases 1-3: continent; case 4: incontinent; case 5: awaiting stoma closure; urinary: cases 1 and 2: continent; cases 3 and 4: incontinent; case 5: continent (intermittent catheterization). Fetal continence evaluation questionnaire (CEQ) scores for cases 1-4 were 7.5, 9, 10, and 2 (maximum score 10, mean 7.1). CONCLUSION: Scope assistance improves visualization, thus pelvic sphincter dissection/division is minimized with less detrimental impact on postoperative continence. PMID- 22940881 TI - Laparoscopy-assisted percutaneous endoscopic gastrostomy using a "Funada-kit II" device. AB - We aimed at assessing the effect of using a "Funada-kit II" device during laparoscopy-assisted percutaneous endoscopic gastrostomy (Lap-PEG), by reviewing 29 cases of Lap-PEG we performed from 2001 to 2011. We started using the "Funada kit II" (CREATE MEDIC CO., Kanagawa, Japan) device with two parallel needles to puncture the stomach and assist suturing the anterior gastric wall to the anterior abdominal wall during Lap-PEG in 2011 (F-PEG). By introducing a loop through the lumen of one needle which allows placement of a suture introduced through the lumen of the other needle. Once repeated, the stomach can be pexied at two points, approximately 2 cm apart. We compared Lap-PEG (n = 23) with F-PEG (n = 6) where the mean ages and weights at surgery and sex ratios were similar. All cases were uneventful without intraoperative complications, although one postoperative wound infection occurred in a Lap-PEG case. There were no differences in the duration of analgesia, time taken to commence tube feeding, and return to full feeding. However, mean operating time was significantly shorter in F-PEG (28.1 min) versus Lap-PEG (46.1 min) p < 0.05. As per results F PEG would appear to be as safe as Lap-PEG, but much quicker. PMID- 22940882 TI - A systematic review of the use of antifibrinolytic agents in pediatric surgery and implications for craniofacial use. AB - A systematic review aimed to evaluate the efficacy and safety of aprotinin, epsilon-aminocaproic acid (EACA), and tranexamic acid (TXA) in reducing perioperative blood loss, risk for transfusion, and total perioperative transfusion volume in major pediatric surgery. Medline, Embase, and Cochrane Reviews were searched for relevant articles published from January 1990 to January 2012. Additional studies were identified by cross-referencing citations and extracting data from recent published reviews. Data were recorded and analyzed using Cochrane's RevMan5.1 software. Thirty-four studies were included in this review of which 21 provided level 1b evidence, 11 were level 2b, and two were level 3b. As compared to control groups, antifibrinolytics reduced perioperative blood loss by standardized mean difference (SMD) of -0.70 (-0.89, 0.50; p<0.00001), total transfusion volume by SMD of -0.78 (-0.95, -0.61; p < 0.00001), and Odds Ratio (OR) for transfusion was 0.39 (0.23, 0.64; p=0.002). The OR for adverse events attributable to treatment was not statistically significant across groups (OR = 0.96; p = 0.58). Antifibrinolytics are effective in reducing blood loss and transfusion requirements in major pediatric surgery. TXA and EACA also appear to have reasonable side-effect profiles. Application to craniofacial surgery is promising, though further investigation is necessary. PMID- 22940883 TI - Pannonibacter indica sp. nov., a highly arsenate-tolerant bacterium isolated from a hot spring in India. AB - A novel aerobic bacterium, strain HT23(T), able to grow on 500 mM sodium arsenate was isolated from a hot-spring sediment sample collected from Athamallik, Orissa, India. Cells of this isolate were Gram negative. Heterotrophic growth was observed at pH 6.0-11.0 and 20-45 degrees C. Optimum growth was observed at 37 degrees C and pH 7.0-10.0. The major polar lipids are diphosphatidyl glycerol, phosphatidyl glycerol, phosphatidyl ethanolamine, phosphatidyl choline and phosphatidyl monomethyl ethanolamine. The major isoprenoid quinone was Q-10. 16S rRNA gene sequence analysis indicated that the bacterium clustered with the genus Pannonibacter and showed 98.9 % similarity with Pannonibacter phragmitetus C6 19(T) (DSM 14782(T)) and 98 % with the P. phragmitetus group B and P. phragmitetus group E strains. Levels of DNA-DNA relatedness between the strain HT23(T) and P. phragmitetus C6-19(T) (DSM 14782(T)) and other strains of P. phragmitetus group B and group E strains were below 55 %. On the basis of phenotypic and chemotaxonomic characteristics, 16S rRNA gene sequence analysis and DNA-DNA hybridization data, strain HT23(T) is considered to represent a novel species of the genus Pannonibacter, for which the name Pannonibacter indica sp. nov. is proposed. The type strain is HT23(T) (=JCM 16851(T) = DSM 23407(T) = LMG 25769(T)). PMID- 22940886 TI - A simple procedure for polymer-supported N-heterocyclic carbene silver complex via click chemistry: an efficient and recyclable catalyst for the one-pot synthesis of propargylamines. AB - A series of polymer-supported N-heterocyclic carbene silver complexes were prepared using a simple procedure via click chemistry. These complexes were tested as catalysts in the synthesis of propargylamines by the one-pot three component coupling reaction of aldehydes, amines and alkynes (A(3)-coupling). The reaction was preceded smoothly to afford the corresponding products in good to excellent yields at room temperature under low catalyst loading of 0.1 mol%. Furthermore, the catalysts were stable and recoverable for six runs without a significant loss in their activity. PMID- 22940884 TI - Nerve growth factor and Alzheimer's disease: new facts for an old hypothesis. AB - Understanding sporadic Alzheimer's disease (AD) onset and progression requires an explanation of what triggers the common core of abnormal processing of the amyloid precursor protein and tau processing. In the quest for upstream drivers of sporadic, late-onset AD neurodegeneration, nerve growth factor (NGF) has a central role. Initially connected to AD on a purely correlative basis, because of its neurotrophic actions on basal forebrain cholinergic neurons, two independent lines of research, reviewed in this article, place alterations of NGF processing and signaling at the center stage of a new mechanism, leading to the activation of amyloidogenesis and tau processing. Thus, experimental studies on NGF deficit induced neurodegeneration in transgenic mice, as well as the mechanistic studies on the anti-amyloidogenic actions of NGF/TrkA signaling in primary neuronal cultures demonstrated a novel causal link between neurotrophic signaling deficits and Alzheimer's neurodegeneration. Around these results, a new NGF hypothesis can be built, with neurotrophic deficits of various types representing an upstream driver of the core AD triad pathology. According to the new NGF hypothesis for AD, therapies aimed at reestablishing a correct homeostatic balance between ligands (and receptors) of the NGF pathway appear to have a clear and strong rationale, not just as long-term cholinergic neuroprotection, but also as a truly disease-modifying approach. PMID- 22940887 TI - ADAM17-overexpressing breast cancer cells selectively targeted by antibody-toxin conjugates. AB - A disintegrin and metalloproteinase 17 (ADAM17) is significantly upregulated not only in malignant cells but also in the pro-inflammatory microenvironment of breast cancer. There, ADAM17 is critically involved in the processing of tumor promoting proteins. Therefore, ADAM17 appears to be an attractive therapeutic target to address not only tumor cells but also the tumor-promoting environment. In a previous study, we generated a monoclonal anti-ADAM17 antibody (A300E). Although showing no complement-dependent cytotoxicity or antibody-dependent cellular cytotoxicity, the antibody was rapidly internalized by ADAM17-expressing cells and was able to transport a conjugated toxin into target cells. As a result, doxorubicin-coupled A300E or Pseudomonas exotoxin A-loaded A300E was able to kill ADAM17-expressing cells. This effect was strictly dependent on the presence of ADAM17 on the surface of target cells. As a proof of principle, both immunotoxins killed MDA-MB-231 breast cancer cells in an ADAM17-dependent manner. These data suggest that the use of anti-ADAM17 monoclonal antibodies as a carrier might be a promising new strategy for selective anti-cancer drug delivery. PMID- 22940888 TI - Intramural collection caused by contrast extravasation into the ascending aortic wall. AB - Cardiac catheterization is a procedure routinely performed worldwide, with an estimated amount of 61,000 coronary angioplasties performed in the UK annually. Associated mortality--in the region of 0.1-0.2%--is minimal and complication rate approximately 1.5%. The most serious complications described are embolic stroke, cardiac chamber perforation, aortic dissection, coronary occlusions or dissection, and major peripheral vascular complications, including retroperitoneal haematoma and life-threatening haemorrhage. We report the case of a 75-year old patient who had inadvertent contrast agent injection into the aortic wall, leading to a localized contrast collection within the tunica media. This complication has been described before but only in association with coronary artery dissection. It is important to diagnose and manage such a situation, as most iodinated intravascular contrast agents exert a high osmotic load and thereby lead to tissue oedema and necrosis on extravasation. We describe the management of the case and discuss relevant therapeutic strategies. PMID- 22940885 TI - Targeting the chameleon: a focused look at alpha-synuclein and its roles in neurodegeneration. PMID- 22940890 TI - Deep vein thrombosis and septic pulmonary emboli with MRSA osteomyelitis in a pediatric patient. AB - Deep vein thrombosis (DVT) and pulmonary embolism (PE) are relatively rare occurrences in the pediatric population. However, DVT and PE are associated with significant morbidity and mortality to the patient if not promptly diagnosed and treated. We describe the case of a 5-year-old boy that was diagnosed in our emergency department with DVT and PE. The underlying etiology was osteomyelitis of the left tibia caused by community-acquired methicillin-resistant Staphylococcus aureus. The patient had a prolonged hospital course with multiple complications but was eventually discharged in a good condition. In areas with a high prevalence of community-acquired methicillin-resistant S. aureus, it is important for physicians in the emergency department to be aware of the rare, but potentially fatal, complications of infection, including DVT with PE from septic emboli. PMID- 22940889 TI - The effect of intravenous and oral iron administration on perioperative anaemia and transfusion requirements in patients undergoing elective cardiac surgery: a randomized clinical trial. AB - OBJECTIVES: Anaemia is a frequent complication after cardiopulmonary bypass surgery. Iron therapy has been variably employed by medical centres over the years. In our study we test the clinical effectiveness of intravenous and oral iron supplementation in correcting anaemia, and its impact on blood transfusion requirements, in patients undergoing cardiopulmonary bypass surgery. METHODS: A double-blind, randomized, placebo-controlled clinical trial with three parallel groups of patients. Group I (n = 54): intravenous iron(III)-hydroxide sucrose complex, three doses of 100 mg/24 h during pre- and postoperative hospitalization and 1 pill/24 h of oral placebo in the same period and during 1 month after discharge. Group II (n = 53): oral ferrous fumarate iron 1 pill/24 h pre- and postoperatively and during 1 month after discharge, and intravenous placebo while hospitalized. Group III (n = 52): oral and intravenous placebo pre- and postoperatively, following the same protocol. Data were collected preoperatively, at theatre, at intensive care unit admission, before hospital discharge and 1 month later. RESULTS: (1) Baseline clinical and demographic characteristics and surgical procedures were similar in the three groups; (2) no inter-group differences were found in haemoglobin and haematocrit during the postoperative period; (3) the intravenous iron group showed higher serum ferritin levels at hospital discharge (1321 +/- 495 ng/ml; P < 0.001) and 1 month later (610 +/- 387; P < 0.001) compared with the other groups and (4) we did not observe statistical differences in blood transfusion requirements between the three groups. CONCLUSIONS: The use of intravenous or oral iron supplementation proved ineffective in correcting anaemia after cardiopulmonary bypass and did not reduce blood transfusion requirements. [Current Controlled Trials number: NCT01078818 (oral and intravenous iron in patients postoperative cardiovascular surgery under EC)]. PMID- 22940891 TI - Surfactant replacement therapy in a pediatric near-drowning case in manure. AB - Drowning is defined as suffocation by submersion especially in water and is a leading cause of injury-related death in children. Age groups at greatest risk are toddlers and male adolescents. It is the second most common cause of accidental death in children after road accidents. Treatment consists of resuscitation and stabilization. The use of surfactant after near-drowning in water is reported in the literature in few case reports.We report here a boy whose condition did not get better with conventional treatment, but dramatically improved after surfactant treatment after near-drowning in a fluid with manure. PMID- 22940892 TI - Complicated and dislodged airway foreign body in an intubated child: case report. AB - OBJECTIVE: We report a case of missed foreign body aspiration in a child presenting with status epilepticus. On admission, the patient was found to have pneumonia, which progressed to respiratory failure and acute respiratory distress syndrome. While the patient was intubated and mechanically ventilated, the patient experienced acute respiratory deterioration. Subsequently, it was determined that a previously undetected foreign body had dislodged from the right main to the left main bronchus and was the underlying cause for the child's illness. CONCLUSIONS: A combination of sudden change of physical and radiographic findings with unilateral lung hyperinflation is highly suspicious for an obstructing airway foreign body. This case demonstrates that foreign body aspiration can lead to significant morbidity. It should be in the differential diagnosis for any acute pulmonary process in an otherwise well child because there is no specific clinical or radiographic finding to rule it out. PMID- 22940893 TI - Respiratory failure caused by a suspicious white powder: a case report of intentional methadone poisoning in an infant. AB - Methadone exposures in children have increased as the drug has gained more prevalence in the treatment of adult narcotic dependency. Previous literature concerning pediatric methadone ingestion has focused primarily on unintentional ingestions. We describe a 2-month-old male infant presenting with respiratory failure from suspected intentional methadone administration. The infant was born to a mother with narcotic dependency and at birth was treated for neonatal abstinence syndrome. After discharge for neonatal abstinence syndrome treatment, the infant continued to be fussy and persistently irritable. We believe the infant was intentionally given methadone at home by his mother for these symptoms. It is important for pediatric providers to be vigilant of households with methadone present. Family-centered education on prevention of methadone ingestion (eg, safe storage) and anticipatory guidance on the signs, symptoms, and treatment of toxicity are key. PMID- 22940894 TI - Altered lymphocyte counts in a pediatric patient with H5N1 infection. AB - Flow cytometry was used to analyze the changes in lymphocyte subsets in the youngest child with avian influenza in China. During the early stage, the absolute CD3 count was 62.9% (lower limit of normal), the CD8 count was 32.5% (slightly higher than normal), and the CD4 count was 28.6% (lower than normal). The CD4/CD8 ratio was also decreased (0.88). The natural killer (CD3CD1656) cell count was 4.9% (lower than normal). During the convalescent stage, the CD4 count and the CD4/CD8 ratio returned to normal. The CD3CD1656 count increased from its value at the early stage of the disease. PMID- 22940895 TI - An unusual cause of accidental hanging in a toddler. AB - Accidental hanging in children, although uncommon, has been reported worldwide. We report a case of a toddler who was brought to our hospital with an alleged history of hanging with his head trapped in-between the railings of a balcony. He became unconscious and developed seizures secondary to asphyxial injury and survived. Hanging is an important cause of homicidal and suicidal injury in adults, but in children, it is usually accidental, leading to death because of asphyxia as a result of partial or complete hanging. There is paucity of data in Indian literature regarding accidental hanging injuries in children. According to available data from western countries, strangulation ranks fourth among the causes of unintentional injury in children younger than 1 year after roadside accidents, drowning, and burns. The unique mode of hanging in this child has prompted us to report this case. PMID- 22940896 TI - Sports-related concussions. AB - During the past decade, awareness of concussions has exploded as both the media and the medical literature have given more focus to this common problem. Concussions after recreational activities, especially athletics, are a frequent complaint in the emergency department. In the past few years, care of these patients has been simplified as grading systems and classifications have been abandoned. However, questions remain as to the best way to rehabilitate these patients to avoid long-term sequelae, especially in children and adolescents. The purpose of this review is to discuss the demographic characteristics, the pathophysiology, definition, clinical characteristics, and management of concussions in children and adolescents. PMID- 22940898 TI - Osteosarcoma of the lower extremity presenting as a pathologic fracture. PMID- 22940899 TI - Epinephrine auto-injector pandemic. AB - Epinephrine is crucial in the treatment of anaphylaxis. As anaphylaxis frequently occurs in nonmedical settings, use of an epinephrine auto-injector is vital for prompt management. This article provides an overview of the increasing number of epinephrine auto-injector prescriptions and the underlying causes and contributing factors to these rising prescriptions. It also reviews the current indications for prescription of an epinephrine auto-injector, proper use of epinephrine auto-injectors, and the management of unintentional epinephrine injections. PMID- 22940900 TI - An unresponsive 3-year-old girl with an unusual whine. PMID- 22940901 TI - ECGs in the ED. PMID- 22940902 TI - The impact of bystanding to workplace bullying on symptoms of depression among women and men in industry in Sweden: an empirical and theoretical longitudinal study. AB - BACKGROUND: Prospective studies on bystanding to workplace bullying and the health outcomes are scarce. AIM: To investigate the work environmental risk factors of depressive symptoms among bystanders to bullying in both women and men in four large industrial organizations in Sweden. METHOD: The number of respondents at four large industrial enterprises with more than one year at the workplace at T1: n = 2,563 (Women: n = 342; Men: n = 2,227). Bystanders to bullying at T1: n = 305 (Women: n = 30; Men: n = 275). The total number of those with symptoms of depression at T2: Women: n = 30; Men: n = 161. Two thousand one hundred and seventy-seven employees answered the questionnaire on T1 and T2 with an 18-month interval. "To have depressive symptoms" was defined as not having depressive symptoms at T1 but having depressive symptoms at T2. RESULTS: The number of men who were bystanders to bullying was larger compared to women. However, the proportion of women who were bystanders to bullying and developed depressive symptoms 18 months later was higher in comparison with men (33.3 and 16.4 %, respectively). Further, "Being a bystander to bullying" 1.69 (1.13-2.53), "Rumors of changes in the workplace" 1.53 (1.10-2.14), "Reduced role clarity" 2.30 (1.21-4.32), "Lack of appreciation of being in the group" 1.76 (1.22-2.53) increased the risk of future symptoms of depression. "Job Strain" was not an adjusted risk factor for depression. CONCLUSION: Our results support previous findings that bystanding to workplace bullying is related to future depressive symptoms. PMID- 22940903 TI - Enhancement of bunker oil biodesulfurization by adding surfactant. AB - Biodesulfurization (BDS) is a promising method to remove sulfur compounds from diesel and gasoline. However, the information on BDS of heavy oil is scanty, which might be due to their "undesirable" physical properties and more complicated sulfur diversities. In this study, the BDS of one kind of heavy oil, bunker oil MFO380 was investigated. The biocatalyst was obtained by the enrichment with oil sludge as the seed and using dibenzothiophene (DBT) as the sole sulfur source. The enriched biocatalyst (microbial mixed culture) could selectively remove sulfur from DBT and DBT was transformed into 2 hydroxybiphenyl, which indicates that the BDS process is beneficial to non destructive carbon bonds and thus can maintain the calorific value. The bunker oil BDS results showed that after 7 days of incubation, the removal efficiency of sulfur in MFO380 was only 2.88 %, but this could be significantly improved by adding surfactants Triton X-100 or Tween 20. This effect could be attributed to greatly reduced viscosity of heavy oil and increased mass transfer of sulfur compounds in heavy oil into water. Adding Triton X-100 achieved the highest removal efficiency of sulfur, up to 51.7 % after 7 days of incubation. The optimal amount of Triton X-100 was 0.5 g/50 ml medium. When toluene was added as an organic solvent for MFO380, the BDS activity was improved, while lower than the effect of adding surfactants. PMID- 22940904 TI - Calcitonin screening in patients with thyroid nodules. Diagnostic value. AB - AIM: The positive predictive value (PPV) of a slightly elevated basal calcitonin (CT) for the diagnosis of medullary thyroid cancer (MTC) is still under debate. PATIENTS, METHODS: A total of 11270 patients with thyroid nodules underwent calcitonin screening. Patients with known elevation of CT, renal insufficiency, bacterial infection, alcohol abuse, proton-pump inhibitor therapy or autoimmune thyroid disease were excluded from further analysis. Serum CT was determined by the solid-phase, enzyme-labeled, two-site chemiluminescent immunoassay Immulite 2000. If possible, a pentagastrin test was done to differentiate cases of hypercalcitoninaemia. RESULTS: Hypercalcitoninsemia was found in 32 patients. 20 patients underwent surgery. In 10 patients a MTC was found. The PPV of hypercalcitoninaemia for MTC was 31%. The PPV increased to 50% for those patients who underwent surgery (10/20). A subgroup of 26 patients presented with basal CT between 13 and 50 pg/ml, 14 of them underwent surgery, in 4 cases evidence of MTC was revealed. This resulted in a PPV of 15% (4/26), although the value increased to 28% when only surgically treated patients were considered (4/14). CONCLUSION: Taking all clinical data into account, calcitonin screening has an acceptable PPV for medullary thyroid cancer in patients with thyroid nodules. Therefore, we recommend calcitonin screening in centers for thyroid disorders. PMID- 22940905 TI - Knockdown of RAB25 promotes autophagy and inhibits cell growth in ovarian cancer cells. AB - RAB25 belongs to the Rab family of small GTPases and is implicated in the development of various types of human cancer. To evaluate the role of RAB25 in ovarian cancer, RAB25 was knocked down by siRNA in HEY and ES-2 human ovarian cancer cells. Autophagy, cell growth and cell apoptosis were evaluated. The results showed that knockdown of RAB25 increased acidic vesicle organelles and GFP-microtubule-associated protein 1 light chain 3 punctate fluorescence in ovarian cancer cells. Autophagy that promoted by knockdown of RAB25 was not observed in cells where the ERK1/2 signaling pathway had been inhibited by U0126. Knockdown of RAB25 reduced cell cycle progression and cell growth. Apoptosis of ovarian cancer cells could be induced by knockdown of RAB25. These results support the tumorigenic role of RAB25 in ovarian cancer cells. PMID- 22940908 TI - Maximising living donation with paediatric blood-group-incompatible renal transplantation. AB - Long-term outcomes for paediatric renal transplant recipients have improved over the last 20 years, with better patient and renal allograft survival. As paediatric renal transplantation programmes have increased over this timeframe, living donation has become the favoured modality for renal replacement therapy and is advocated pre-emptively in as many cases as possible. However, one of the main barriers historically to living donation has been ABO blood-group incompatibility, with the result that patients were listed to be on call for a deceased donor renal transplant. The clinical scenario has now changed so that donors and recipients for renal transplantation can be worked up and listed for paired exchange and/or living-related ABO blood-group-incompatible renal transplantation (ABOi). There is extensive data in adult practice, and increasing evidence in paediatric practice that the short- and medium-term outcomes for both patient and renal allograft survival for ABOi is equivalent to that of blood group-compatible renal transplantation. PMID- 22940907 TI - Endocytosis of the seven-transmembrane RGS1 protein activates G-protein-coupled signalling in Arabidopsis. AB - Signal transduction typically begins by ligand-dependent activation of a concomitant partner that is otherwise in its resting state. However, in cases where signal activation is constitutive by default, the mechanism of regulation is unknown. The Arabidopsis thaliana heterotrimeric Galpha protein self-activates without accessory proteins, and is kept in its resting state by the negative regulator, AtRGS1 (regulator of G-protein signalling 1), which is the prototype of a seven-transmembrane receptor fused with an RGS domain. Endocytosis of AtRGS1 by ligand-dependent endocytosis physically uncouples the GTPase-accelerating activity of AtRGS1 from the Galpha protein, permitting sustained activation. Phosphorylation of AtRGS1 by AtWNK8 kinase causes AtRGS1 endocytosis, required for both G-protein-mediated sugar signalling and cell proliferation. In animals, receptor endocytosis results in signal desensitization, whereas in plants, endocytosis results in signal activation. These findings reveal how different organisms rearrange a regulatory system to result in opposite outcomes using similar phosphorylation-dependent endocytosis mechanisms. PMID- 22940906 TI - IKKbeta/NF-kappaB disrupts adult hypothalamic neural stem cells to mediate a neurodegenerative mechanism of dietary obesity and pre-diabetes. AB - Adult neural stem cells (NSCs) are known to exist in a few regions of the brain; however, the entity and physiological/disease relevance of adult hypothalamic NSCs (htNSCs) remain unclear. This work shows that adult htNSCs are multipotent and predominantly present in the mediobasal hypothalamus of adult mice. Chronic high-fat-diet feeding led to not only depletion but also neurogenic impairment of htNSCs associated with IKKbeta/NF-kappaB activation. In vitro htNSC models demonstrated that their survival and neurogenesis markedly decreased on IKKbeta/NF-kappaB activation but increased on IKKbeta/NF-kappaB inhibition, mechanistically mediated by IKKbeta/NF-kappaB-controlled apoptosis and Notch signalling. Mouse studies revealed that htNSC-specific IKKbeta/NF-kappaB activation led to depletion and impaired neuronal differentiation of htNSCs, and ultimately the development of obesity and pre-diabetes. In conclusion, adult htNSCs are important for the central regulation of metabolic physiology, and IKKbeta/NF-kappaB-mediated impairment of adult htNSCs is a critical neurodegenerative mechanism for obesity and related diabetes. PMID- 22940909 TI - Spontaneous remission in children with IgA nephropathy. AB - BACKGROUND: Some patients with IgA nephropathy (IgAN) achieve spontaneous remission even when not receiving medication. However, details on such remissions remain unknown. The aim of our study was to clarify this information in the clinical setting of childhood IgAN with minor glomerular abnormalities or focal mesangial proliferation (MGA/FMP). METHODS: This study was a retrospective analysis of 96 children with MGA/FMP who did not receive medication from among the 555 patients with newly diagnosed childhood IgAN treated between January 1972 and December 2000. The Kaplan-Meier method and Cox proportional hazard model were used for the analysis. RESULTS: Of the 96 pediatric patients who did not receive medication, 57 (59.4 %) achieved spontaneous remission. The cumulative spontaneous remission rates among these patients were 57.5 and 77.4 % at 5 and 10 years, respectively, from onset. The mean time from onset to remission was 5.9 +/ 0.4 years. Clinical and histological findings were similar between the remission and non-remission groups. Of the 57 patients with spontaneous remissions, ten (17.5 %) also developed a recurrence of urinary abnormalities. The cumulative recurrence-free rates were 79.9 and 67.9 % at 5 and 10 years, respectively, after remission. CONCLUSIONS: The spontaneous remission rate in childhood IgAN with MGA/FMP was higher than expected. Our results suggest that physicians should consider the potential for spontaneous remission and refrain from very aggressive treatment in IgAN patients with MGA/FMP. PMID- 22940910 TI - Periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA) syndrome and IgA nephropathy. AB - BACKGROUND: A syndrome of periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA), as well as immunoglobulin A nephropathy (IgAN), may be caused by autoimmune reactivity nephropathy. CASE-DIAGNOSIS/TREATMENT: A 10-year-old boy presented with periodic fever, exudative tonsillitis, oral aphthous ulcer, and cervical lymph node inflammation. These conditions had occurred at intervals of about 2-6 weeks since the age of 3 years. Microscopic hematuria, first detected at age 8 years, worsened during episodes of PFAPA-related fever; since 10 years of age, the hematuria was accompanied by sustained proteinuria. Examination of a kidney biopsy specimen led to a diagnosis of IgAN. In the kidney specimen, fractalkine immunoreactivity and heavy macrophage infiltration were prominent. Multi-drug cocktail therapy improved the urinalysis findings, and subsequent tonsillectomy succeeded in controlling recurrences of PFAPA and IgAN. In a post treatment renal biopsy specimen, mesangial proliferation was decreased, and fractalkine immunoreactivity was absent. CONCLUSION: Immunologic reactions against certain antigens in local mucosa, including tonsils, may be impaired in PFAPA and IgAN, as evidenced by the suppression of both diseases in our patient by tonsillectomy. Accordingly, the concurrence of PFAPA and IgAN in our patient appeared to be a consequence of shared autoimmune mechanisms and systemic and local increases in cytokine concentrations, rather than coincidence. PMID- 22940911 TI - Factors associated with the process of adaptation among Pakistani adolescent females living in United States. AB - This study explored post-migration experiences of recently migrated Pakistani Muslim adolescent females residing in the United States. In-depth, semi structured interviews were conducted with thirty Pakistani Muslim adolescent females between the ages of 15 and 18 years living with their families in Houston, Texas. Data obtained from the interviews were evaluated using discourse analysis to identify major reoccurring themes. Participants discussed factors associated with the process of adaptation to the American culture. The results revealed that the main factors associated with adaptation process included positive motivation for migration, family bonding, social support networks, inter familial communication, aspiration of adolescents to learn other cultures, availability of English-as-second-language programs, participation in community rebuilding activities, and faith practices, English proficiency, peer pressure, and inter-generational conflicts. This study provided much needed information on factors associated with adaptation process of Pakistani Muslim adolescent females in the United States. The results have important implications for improving the adaptation process of this group and offer potential directions for intervention and counseling services. PMID- 22940912 TI - Training Mixtec promotores to assess health concerns in their community: a CBPR pilot study. AB - An academic institution and a community organization partnered for one of the first studies assessing health needs of Mixtecs, indigenous immigrants from Southern Mexico, residing in Ventura County, California. Ten bilingual Spanish- and Mixteco-speaking promotores received a 1-day focus group training, participated in a focus group themselves and conducted 5 focus groups with 42 Mixtec community members. The focus group training is described. Health concerns discussed in the focus groups include outdoor exercise among women viewed as flirtatious; reluctance to ask for governmental assistance due to fear that children will have to pay back later; soda consumption perceived as a symbol of socio-economic status; and unwillingness to obtain mammograms or pap smears because private body parts are to be touched by husbands only. Training promotores to conduct focus groups can increase organizational capacity to identify pressing health needs in under-represented and hard-to-reach population groups. PMID- 22940913 TI - Redressing the limitations of the Affordable Care Act for Mexican immigrants through bi-national health insurance: a willingness to pay study in Los Angeles. AB - The 12.4 million Mexican migrants in the United States (US) face considerable barriers to access health care, with 45% of them being uninsured. The Affordable Care Act (ACA) does not address lack of insurance for some immigrants, and the excluded groups are a large proportion of the Mexican-American community. To redress this, innovative forms of health insurance coverage have to be explored. This study analyses factors associated with willingness to pay for cross-border, bi-national health insurance (BHI) among Mexican immigrants in the US. Surveys were administered to 1,335 Mexican migrants in the Mexican Consulate of Los Angeles to assess their health status, healthcare utilization, and willingness to purchase BHI. Logistic regression was used to identify predictors of willingness to pay for BHI. Having a job, not having health insurance in the US, and relatives in Mexico attending public health services were significant predictors of willingness to pay for BHI. In addition, individuals identified quality as the most important factor when considering BHI. In spite of the interest for BHI among 54% of the sampled population, our study concludes that this type of coverage is unlikely to solve access to care challenges due to ACA eligibility among different Mexican immigrant populations. PMID- 22940914 TI - Dual energy converting nano-phosphors: upconversion luminescence and X-ray excited scintillation from a single composition of lanthanide-doped yttrium oxide. AB - We report an upconverting nanomaterial composition, [Y(2)O(3); Yb (2%), Er (1%)], that converts both X-ray and high-fluence NIR irradiation to visible light. This composition is compared to a higher Yb(3+) doped composition, [Y(2)O(3); Yb (10%), Er (1%)], that displays diminished visible X-ray scintillation, but shows enhanced red wavelength centered upconversion emission. These nanocrystals have been characterized by TEM, X-ray diffraction, power-dependent upconversion luminescence, and X-ray scintillation spectroscopy. We further demonstrate that lithium ion doping of the [Y(2)O(3); Yb (2%), Er (1%)] nanoscale composition leads to enhanced X-ray and NIR excited emission intensities through the production of nanoparticles that feature slightly enhanced sizes and increased crystallinity. PMID- 22940915 TI - Exploring the stem cell and non-stem cell constituents of human breast milk. AB - The immense potency of nutritional components of human breast milk and importance of breastfeeding is known worldwide. Recent researches had identified stem cells as integral component of human breast milk. Nevertheless, there is little proof of evidence on the stem cell constituents of breast milk. It is imperative to explore the cellular constituents of human breast milk, including of stem cells, to open new avenue in child's development and regeneration. Thus, we aimed at identifying the cellular constituents of human breast milk by phenotypic characterisation of diverse cell surface markers of hematopoietic stem cells (CD 34, CD 133, CD 117), mesenchymal stem cells (CD 90, CD 105, CD 73), myoepithelial cells (CD 29, CD 44), Immune cells (CD 209, CD 86, CD 83, CD 14, CD 13, HLADR, CD 45), as well as cell adhesion molecules (CD 31, CD 54, CD 166, CD 106, CD 49d), and other markers (ABCG2, CD140b) using flowcytometry. We found a lower expression of CD 34 (13.07 +/- 2.0 %), CD 90 (7.79 +/- 0.8 %) and CD 73 (2.19 +/- 0.41 %), indicating scanty hematopoietic and mesenchymal stem cell population in human breast milk. On contrary, myoepithelial progenitors, cell adhesion molecules, immune cells and growth factors were identified as the major constituents of breast milk. Overall, this study illuminates the benefits of breast feeding as breast milk encompasses heterogeneous cellular components that benefits child's growth, immunity and development. However, further research on these constituents of human breast milk will widen their applicability in treatment of neonatal disorders. PMID- 22940916 TI - Retinoic acid and hydrocortisone strengthen the barrier function of human RPMI 2650 cells, a model for nasal epithelial permeability. AB - The nasal pathway represents an alternative route for non-invasive systemic administration of drugs. The main advantages of nasal drug delivery are the rapid onset of action, the avoidance of the first-pass metabolism in the liver and the easy applicability. In vitro cell culture systems offer an opportunity to model biological barriers. Our aim was to develop and characterize an in vitro model based on confluent layers of the human RPMI 2650 cell line. Retinoic acid, hydrocortisone and cyclic adenosine monophosphate, which influence cell attachment, growth and differentiation have been investigated on the barrier formation and function of the nasal epithelial cell layers. Real-time cell microelectronic sensing, a novel label-free technique was used for dynamic monitoring of cell growth and barrier properties of RPMI 2650 cells. Treatments enhanced the formation of adherens and tight intercellular junctions visualized by electron microscopy, the presence and localization of junctional proteins ZO-1 and beta-catenin demonstrated by fluorescent immunohistochemistry, and the barrier function of nasal epithelial cell layers. The transepithelial resistance of the RPMI 2650 cell model reached 50 to 200 Omega * cm(2), the permeability coefficient for 4.4 kDa FITC-dextran was 9.3 to 17 * 10(-6) cm/s, in agreement with values measured on nasal mucosa from in vivo and ex vivo experiments. Based on these results human RPMI 2650 cells seem to be a suitable nasal epithelial model to test different pharmaceutical excipients and various novel formulations, such as nanoparticles for toxicity and permeability. PMID- 22940917 TI - Familial distal foregut atresia in a family with likely autosomal dominant inheritance pattern. AB - Familial occurrence of distal foregut atresia (DFA) (Type 1) is rare. Diagnosis is based upon the clinical symptomatology and confirmed by radiological studies, surgery and histology. A number of reports have described families in which several family members have been involved and suggested an autosomal recessive mode of inheritance. Little is known about the underlying genetic causes or indeed the likely pathogenic mechanism. We report a family in which there are five affected cases including three siblings where the DFA appears to be inherited in an autosomal dominant inheritance pattern with reduced penetrance. PMID- 22940920 TI - Evolution of antiphospholipid antibody syndrome. AB - Antiphospholipid antibody syndrome is a very important cause of cerebral infarction, myocardial infarction, and repeated pregnancy losses in women. We present an extremely rare case of a 44-year-old man with antiphospholipid syndrome who collapsed and died suddenly. At autopsy, he was found to have both cerebral and myocardial infarction. In all young patients with cerebral infarction, myocardial infarction, pulmonary embolism, recurrent miscarriages, and unexplained low platelet count, one must consider the strong possibility of antiphospholipid antibody syndrome. PMID- 22940919 TI - Autoinhibition of TBCB regulates EB1-mediated microtubule dynamics. AB - Tubulin cofactors (TBCs) participate in the folding, dimerization, and dissociation pathways of the tubulin dimer. Among them, TBCB and TBCE are two CAP Gly domain-containing proteins that together efficiently interact with and dissociate the tubulin dimer. In the study reported here we showed that TBCB localizes at spindle and midzone microtubules during mitosis. Furthermore, the motif DEI/M-COO(-) present in TBCB, which is similar to the EEY/F-COO(-) element characteristic of EB proteins, CLIP-170, and alpha-tubulin, is required for TBCE TBCB heterodimer formation and thus for tubulin dimer dissociation. This motif is responsible for TBCB autoinhibition, and our analysis suggests that TBCB is a monomer in solution. Mutants of TBCB lacking this motif are derepressed and induce microtubule depolymerization through an interaction with EB1 associated with microtubule tips. TBCB is also able to bind to the chaperonin complex CCT containing alpha-tubulin, suggesting that it could escort tubulin to facilitate its folding and dimerization, recycling or degradation. PMID- 22940921 TI - Laser locking to the 199Hg 1S0-3P0 clock transition with 5.4 * 10(-15)/?tau fractional frequency instability. AB - With 199Hg atoms confined in an optical lattice trap in the Lamb-Dicke regime, we obtain a spectral line at 265.6 nm for which the FWHM is ~15 Hz. Here we lock an ultrastable laser to this ultranarrow 1S0-3P0 clock transition and achieve a fractional frequency instability of 5.4*10(-15)/?tau for tau <= 400 s. The highly stable laser light used for the atom probing is derived from a 1062.6 nm fiber laser locked to an ultrastable optical cavity that exhibits a mean drift rate of 6.0*10(-17) s(-1) (-16.9 mHz s(-1) at 282 THz) over a six month period. A comparison between two such lasers locked to independent optical cavities shows a flicker noise limited fractional frequency instability of 4*10(-16) per cavity. PMID- 22940922 TI - Optical and RF stability transfer in a monolithic coupled-cavity colliding pulse mode-locked quantum dot laser. AB - We report a novel quantum dot based laser design where a stable high-Q master laser is used to injection lock a passively mode-locked monolithic colliding pulse slave laser. Coupling between the crossed orthogonal laser cavities is achieved through a common monolithically integrated saturable absorber, which results in the locking and hence reduction of the timing jitter as well as the long-term frequency drift of the slave laser. A stable 30 GHz optical pulse train is generated with more than 10 dB reduction in the RF noise level at 20 MHz offset and close to 3 times reduction in the 10 dB average optical linewidth of the slave laser. PMID- 22940918 TI - The substrate degradome of meprin metalloproteases reveals an unexpected proteolytic link between meprin beta and ADAM10. AB - The in vivo roles of meprin metalloproteases in pathophysiological conditions remain elusive. Substrates define protease roles. Therefore, to identify natural substrates for human meprin alpha and beta we employed TAILS (terminal amine isotopic labeling of substrates), a proteomics approach that enriches for N terminal peptides of proteins and cleavage fragments. Of the 151 new extracellular substrates we identified, it was notable that ADAM10 (a disintegrin and metalloprotease domain-containing protein 10)-the constitutive alpha secretase-is activated by meprin beta through cleavage of the propeptide. To validate this cleavage event, we expressed recombinant proADAM10 and after preincubation with meprin beta, this resulted in significantly elevated ADAM10 activity. Cellular expression in murine primary fibroblasts confirmed activation. Other novel substrates including extracellular matrix proteins, growth factors and inhibitors were validated by western analyses and enzyme activity assays with Edman sequencing confirming the exact cleavage sites identified by TAILS. Cleavages in vivo were confirmed by comparing wild-type and meprin(-/-) mice. Our finding of cystatin C, elafin and fetuin-A as substrates and natural inhibitors for meprins reveal new mechanisms in the regulation of protease activity important for understanding pathophysiological processes. PMID- 22940923 TI - Wideband subwavelength gratings for coupling between silicon-on-insulator waveguides and optical fibers. AB - We propose and experimentally demonstrate a novel subwavelength grating coupler on silicon-on-insulator, for coupling to optical fibers with a wide optical bandwidth. Theoretical analysis and design optimization of the coupler are described. About 73 nm 1 dB bandwidth was experimentally demonstrated with -5.6 dB coupling efficiency. Better than -3.4 dB efficiency with 86 nm 1 dB bandwidth is predicted for these structures with optimized buried oxide thickness. PMID- 22940924 TI - Light with enhanced optical chirality. AB - Tang and Cohen [Phys. Rev. Lett.104, 163901 (2010)] recently demonstrated a scheme to enhance the chiral response of molecules, which relies on the use of circularly polarized light in a standing wave configuration. Here we show a new type of light that possesses orbital angular momentum and enhanced chiral response. In the locations where the beams show enhanced optical chirality, only the longitudinal components of the electric and magnetic fields survive, which has unexpectedly shown what we believe is a new way to yield an enhanced optical chiral response. PMID- 22940925 TI - All-fiber-integrated soliton-similariton laser with in-line fiber filter. AB - We demonstrate an all-fiber-integrated Er-doped fiber laser operating in the soliton-similariton mode-locking regime. In the similariton part of the cavity, a self-similarly evolving parabolic pulse with highly linear chirp propagates in the presence of normal dispersion. Following an in-line fiber-based birefringent filter, the pulse evolves into a soliton in the part of the cavity with anomalous dispersion. The similariton and the soliton pulses are dechirped to 75.5 and 167.2 fs, respectively, outside of the cavity. Mode-locked operation is very robust, owing to the influence of the two similariton and soliton attractors that predominate each half of the laser cavity. The experimental results are supported with numerical simulations, which provide good agreement. PMID- 22940926 TI - Relevance of continuously self-imaging gratings for noise robust imagery. AB - We have designed miniaturized, simple, and robust cameras composed of a single diffractive optical element (DOE) that generates a continuously self-imaging (CSI) beam. Two different DOEs are explored: the J0 Bessel transmittance, characterized by a continuous optical transfer function (OTF) and the CSI grating (CSIG), characterized by a sparse OTF. In this Letter, we will analyze the properties of both DOEs in terms of radiometric performances. We will demonstrate that the noise robustness is enhanced for a CSIG, thanks to the sparsity of its OTF. A camera using this DOE has been made and experimental images are presented to illustrate the noise robustness. PMID- 22940927 TI - Metallic rugate structures for near-perfect absorbers in visible and near infrared regions. AB - Metallic rugate structures are theoretically investigated for achieving near perfect absorption in the visible and near-infrared regions. Our model builds on nanoporous metal films whose porosity (volume fraction of voids) follows a sinewave along the film thickness. By setting the initial phase of porosity at the top surface as 0, near-perfect absorption is obtained. The impacts of various structural parameters on the characteristic absorption behaviors are studied. Furthermore, multiple peaks or bands with high absorption can be achieved by integrating several periodicities in one structure. The rugate absorbers show near-perfect absorption for TE and TM polarizations and large incident angles. PMID- 22940928 TI - Complex area correlation theorem for statistical pulses in coherent linear absorbers. AB - We derive a complex area correlation theorem describing global second-order statistical properties of pulses propagating in coherent linear absorbers. We also illustrate temporal evolution of a generic partially coherent pulse in a coherent linear absorber by discussing the behavior of its temporal intensity profile and degree of coherence. PMID- 22940929 TI - Diode-pumped laser and self-frequency-doubling properties of a Nd3+:Na3La9O3(BO3)8 crystal. AB - We report efficient, diode-pumped, self-frequency doubling (SFD) in the newly developed laser crystal Nd3+:Na3La9O3(BO3)8 (Nd:NLBO). More than 730 mW of fundamental output power at 1072 nm was achieved with a slope efficiency of 16.2%. With incident pump power of 8 W, 29 mW of green cw laser emission at 536 nm was observed with proper phase matching. This initial performance and the good optical properties of the crystalline host are encouraging for the development of a high power diode-pumped SFD visible light laser source. PMID- 22940930 TI - High-contrast 40 Gb/s operation of a 500 MUm long silicon carrier-depletion slow wave modulator. AB - In this Letter, we demonstrate a highly efficient, compact, high-contrast and low loss silicon slow wave modulator based on a traveling-wave Mach-Zehnder interferometer with two 500 MUm long slow wave phase shifters. 40 Gb/s operation with 6.6 dB extinction ratio at quadrature and with an on-chip insertion loss of only 6 dB is shown. These results confirm the benefits of slow light as a means to enhance the performance of silicon modulators based on the plasma dispersion effect. PMID- 22940931 TI - Static polarization-difference interference imaging spectrometer. AB - A static polarization-difference imaging spectrometer is conceptually described and demonstrated through experiment. It consists of a Wollaston prism, a Savart polariscope, a linear analyzer, and a CCD camera. This design improves the existing polarization-difference system by eliminating its moving parts and obtaining the spectral variation of the polarization state, and making the system more compact and robust. After simultaneously acquiring two sequential interference images corresponding to two orthogonal polarization states, the hyperspectral images of the states can be reconstructed, respectively. The use of uniaxial birefringent crystal can widen the detectable spectral region. PMID- 22940932 TI - Dynamics of photo-induced terahertz optical activity in metal chiral gratings. AB - We investigated the dynamics of photo-induced optical activity of metal chiral gratings on an Si substrate for terahertz (THz) waves. We employed a new technique that enables optical-pump and THz-probe measurements via broadband THz spectroscopy at the microsecond time scale using a low-repetition-rate pump and a high-repetition-rate probe. We revealed that the THz optical activity decays as a result of the carrier diffusion effect because this optical activity is because of the presence of three-dimensional chiral structures of photo-carriers in the Si substrate. PMID- 22940934 TI - First direct measurement of the spatial coherence of sunlight. AB - Direct sunlight is often deemed incoherent, hence unsuitable for antenna power conversion. However, all radiation exhibits spatial coherence when detected on a sufficiently small scale. We report the first direct measurement of the spatial coherence of solar beam radiation, achieved with a customized tabletop cyclic shearing interferometer. Good agreement is found between experiment and theory, with promising ramifications for solar aperture antennas. PMID- 22940933 TI - Milliwatt-level mid-infrared (10.5-16.5 MUm) difference frequency generation with a femtosecond dual-signal-wavelength optical parametric oscillator. AB - We demonstrate the generation of mid-infrared radiation using a femtosecond dual signal-wavelength optical parametric oscillator and difference frequency generation in an extracavity gallium selenide or silver gallium diselenide crystal. This system generates up to 4.3 mW of average mid-infrared power. Its spectra can be tuned to between 10.5 MUm and 16.5 MUm wavelength (952 cm(-1)-606 cm(-1)) with more than 50 cm(-1) spectral bandwidth. We demonstrate that the power and spectra of this system are temporally very stable. PMID- 22940935 TI - Polarization-induced stiffness asymmetry of optical tweezers. AB - A tightly focused, linearly polarized laser beam, so-called optical tweezers, is proven to be a useful micromanipulation tool. It is known that there is a stiffness asymmetry in the direction perpendicular to the optical axis inherited from the polarization state of the laser. In this Letter, we report our experimental results of stiffness asymmetry for different bead sizes measured at the optimal trapping condition. We also provide the results of our generalized Lorenz-Mie based calculations, which are in good agreement with our experimental results. We also compare our results with previous reports. PMID- 22940936 TI - 3 GHz, fundamentally mode-locked, femtosecond Yb-fiber laser. AB - We demonstrate a fundamentally mode-locked Yb-fiber laser with 3 GHz repetition rate and ~206 fs pulse duration. The laser incorporates two enabling technologies: a 1 cm heavily Yb-doped phosphate glass fiber as the gain medium and a high-dispersion (-1300 fs2) output coupler to manage cavity dispersion. The oscillator self-starts and generates up to 53 mW average power. PMID- 22940937 TI - Impact of fiber delay fluctuation on reference injection-locked optoelectronic oscillators. AB - We demonstrate that the phase shift of a reference injection-locked optoelectronic oscillator (OEO) varies as the change of its fiber delay over a long period of time. The dynamic variation of the fiber delay is monitored using an injected probe signal and is compared with the phase shift. With actively stabilized fiber delays according to the monitored data, the long-term frequency stability of the reference injection-locked OEO is evaluated. PMID- 22940938 TI - Terahertz tomography of a photo-induced carrier based on pump-probe spectroscopy using counterpropagation geometry. AB - A novel technique for the terahertz (THz) tomography of a photo-induced carrier that is based on optical-pump THz-probe time-resolved reflection spectroscopy using counterpropagation geometry of the pump and probe pulses has been proposed. Transient reflection due to the photo-induced carrier provides information about the physical properties and spatial distribution separately. We have experimentally demonstrated this method using a silicon wafer. The obtained complex reflection can be reproduced by the exact solution of Maxwell's equations, assuming an exponential distribution of the photo-induced carrier density. PMID- 22940939 TI - Imaging the Gouy phase shift in photonic jets with a wavefront sensor. AB - A wavefront sensor is used as a direct observation tool to image the Gouy phase shift in photonic nanojets created by micrometer-sized dielectric spheres. The amplitude and phase distributions of light are found in good agreement with a rigorous electromagnetic computation. Interestingly the observed phase shift when travelling through the photonic jet is a combination of the awaited pi Gouy shift and a phase shift induced by the bead refraction. Such direct spatial phase shift observation using wavefront sensors would find applications in microscopy, diffractive optics, optical trapping, and point spread function engineering. PMID- 22940940 TI - Highly tolerant tunable waveguide polarization rotator scheme. AB - Integrated polarization rotators are known to exhibit stringent fabrication tolerances, which severely handicap their practical application. Here we present a general polarization rotator scheme that enables both the compensation of fabrication errors and wavelength tunability. The scheme is described analytically, and a condition for perfect polarization conversion is established. Simulations of a silicon-on-insulator polarization rotator show polarization extinction ratios in excess of 40 dB even in the presence of large fabrication errors that in a conventional rotator configuration degrade the extinction ratio to below 5 dB. Additionally, wavelength tuning over +/-30 nm is shown. PMID- 22940941 TI - Upconversion white-light emission in Ho3+/Yb3+/Tm3+ tridoped LiNbO3 single crystal. AB - Ho3+/Yb3+/Tm3+ tridoped LiNbO3 single crystal exhibiting intense upconversion white light under 980 nm excitation has been successfully fabricated by the Czochralski method. The tridoped LiNbO3 single crystal offers power dependent color tuning properties by simply changing excitation power. Efficient three photon blue upconversion emission and two-photon green and red upconversion emissions have been observed. In addition, the red emission of Ho3+ originates dominantly from the nonradiative decay of green emission. The LiNbO3 with upconversion white light will be a potential laser candidate material. PMID- 22940942 TI - Self-healing optical pillar array. AB - We generate and investigate a self-healing pillar array with a specific phase function comprised of four engineered cubic phase plates with encoded amplitude and phase. This array shows an enhanced self-healing effect at arbitrary obstructed positions in transverse as well as longitudinal locations along propagation where its symmetrical pattern with uniform intensity distribution can be maintained. The transverse power flow in terms of Poynting vector is studied for better interpretation of the self-healing property. PMID- 22940943 TI - High-power Kerr-lens mode-locked Yb:YAG thin-disk oscillator in the positive dispersion regime. AB - We demonstrate a self-starting Kerr-lens mode-locked (KLM) Yb:YAG thin-disk oscillator operating in the regime of positive intracavity group-delay dispersion (GDD). It delivers 1.7 ps pulses at an average power of 17 W and a repetition rate of 40 MHz. Dispersive mirrors compress the pulses to a duration of 190 fs (assuming sech2 shape; Fourier limit: 150 fs) at an average power level of 11 W. To our knowledge, this is the first KLM thin-disk oscillator with positive GDD. Output powers of up to 30 W were achieved with an increased output coupler transmission and intracavity GDD. We demonstrate increase of the pulse energy with increasing positive intracavity GDD, limited by difficulties in initiating mode-locking. PMID- 22940944 TI - Polarization-dependent principal modes of two degenerate LP11 modes transmission in few-mode fibers. AB - We propose and describe a physical model of polarization-dependent principal modes (PDPMs) in a given setting of dual-LP11 mode and dual-polarization transmission over weakly guiding few-mode fibers (FMFs). Proof-of-concept numerical simulations illustrate that the PDPMs do not suffer from both mode dispersion and polarization mode dispersion to first order of frequency variation, even in the presence of random spatial- and polarization-mode coupling. The proposed PDPM model can be a basic formalism for analyzing and controlling of mode coupling/dispersion-induced distortion, in the given optical multiple-input multiple-output scheme of dual-LP11 mode and dual-polarization transmission over FMFs. PMID- 22940945 TI - Arbitrary real-time three-dimensional corporal object sensing and reconstruction scheme. AB - A real-time three-dimensional (3D) object sensing and reconstruction scheme is presented that can be applied on any arbitrary corporeal shape. Operation is demonstrated on several calibrated objects. The system uses curvature sensors based upon in-line fiber Bragg gratings encapsulated in a low-temperature curing synthetic silicone. New methods to quantitatively evaluate the performance of a 3D object-sensing scheme are developed and appraised. It is shown that the sensing scheme yields a volumetric error of 1% to 9%, depending on the object. PMID- 22940946 TI - Multicolor filter all-garnet magneto-optical photonic crystals. AB - We demonstrate a multicolor optical filter and isolator based on a double-cavity magneto-optical (MO) photonic crystal. Being grown as a heteroepitaxial all garnet multilayer, it compromises a strong MO response and high optical transmittance. Low-loss, high Faraday rotation passbands as well as strong light rejection within the stop band were achieved by optimization of distance between cavities and repetition number of distributed Bragg reflectors. PMID- 22940947 TI - Energy scaling of a carbon nanotube saturable absorber mode-locked femtosecond bulk laser. AB - We report successful energy scaling of a room-temperature femtosecond Cr4+: forsterite laser by using a single-walled carbon nanotube saturable absorber (SWCNT-SA). By incorporating a q-preserving multipass cavity, a repetition rate of 4.51 MHz was realized, and the oscillator produced 121 fs, 10 nJ pulses at 1247 nm, with an average output power of 46 mW. To the best of our knowledge, the peak power of 84 kW is the highest generated to date from a SWCNT-SA mode-locked oscillator. Furthermore, energy scaling of a femtosecond multipass-cavity laser, mode-locked using a SWCNT-SA, is demonstrated for the first time. PMID- 22940948 TI - 103 W in-band dual-end-pumped Ho:YAG laser. AB - An efficient 2 MUm in-band pumped Ho:YAG laser was demonstrated. The resonator involves two Ho:YAG crystals, each of which was dual-end-pumped by two orthogonally polarized diode-pumped Tm:YLF lasers. The maximum continuous wave output power of 103 W was achieved, corresponding to a slope efficiency of 67.8% with respect to the incident pump power and an optical-to-optical conversion efficiency of 63.5%. Under Q-switched mode, we obtained 101 W laser output at 30 kHz, corresponding to a slope efficiency of 66.2%. The beam quality or M2 factor was found to be less than 2. PMID- 22940949 TI - Windowed Fourier transform profilometry based on improved S-transform. AB - A novel method for windowed Fourier transform (WFT) profilometry is presented. This method is based on improved S-transform. The impact of the second order derivative of the phase (phi''(b)) to the ridge of S-transform is derived, and how to estimate this deviation is discussed. An important conclusion that more accurate instantaneous frequency can be obtained after removing this deviation is shown. Thus, an accurate phase map of the fringe pattern is obtained by using the WFT based on the window size map, and this map is related to the instantaneous frequency. The method is compared with the WFT based on the wavelet transform. A numerical simulation and experimental example have shown its validity in practical applications. PMID- 22940950 TI - Development of two-color laser system for high-resolution polarization spectroscopy measurements of atomic hydrogen. AB - We have developed a high-spectral-resolution laser system for two-photon pump, polarization spectroscopy probe (TPP-PSP) measurements of atomic hydrogen in flames. In the TPP-PSP technique, a 243-nm laser beam excites the two-photon 1S 2S transition, and excited n=2 atoms are then detected by polarization spectroscopy of the n=2 to n=3 transition using 656-nm laser radiation. The single-frequency-mode 243 and 656-nm beams are produced using injection-seeded optical parametric generators coupled with pulsed dye amplifiers. The use of single-mode lasers allows accurate measurement of signal line shapes and intensities even with significant pulse-to-pulse fluctuations in pulse energies. Use of single-mode lasers and introduction of a scheme to select nearly constant laser energies enable repeatable extraction of important spectral features in atomic hydrogen transitions. PMID- 22940951 TI - Dual Q-switched laser outputs from a single lasing medium using an intracavity MEMS micromirror array. AB - An intracavity array of individually controlled microelectromechanical system scanning micromirrors was used to actively Q-switch a single side-pumped Nd:YAG gain medium. Two equal power independent laser outputs were simultaneously obtained by separate actuation of two adjacent micromirrors with a combined average output power of 125 mW. Pulse durations of 28 ns FWHM at 8.7 kHz repetition frequency and 34 ns FWHM at 7.9 kHz repetition frequency were observed for the two output beams with beam quality factors M2 of 1.2 and 1.1 and peak powers of 253 W and 232 W, respectively. PMID- 22940952 TI - Tunable mid-infrared source from an ultrafast two-color Yb:fiber chirped-pulse amplifier. AB - We present a tunable, ultrafast, mid-infrared source based on difference frequency between 16 MUm and 20 MUm from an ultrafast, two-color Yb:fiber chirped pulse amplifier. We have recorded an average power of 1.5 mW at ~18 MUm. We have improved the output power after the pre-amplifier by one order of magnitude. We present the simulation and experimental results to the pre-amplifier. PMID- 22940953 TI - Waveform-controlled near-single-cycle milli-joule laser pulses generate sub-10 nm extreme ultraviolet continua. AB - We demonstrate the generation of waveform-controlled laser pulses with 1 mJ pulse energy and a full-width-half-maximum duration of ~4 fs, therefore lasting less than two cycles of the electric field oscillating at their carrier frequency. The laser source is carrier-envelope-phase stabilized and used as the backbone of a kHz repetition rate source of high-harmonic continua with unprecedented flux at photon energies between 100 and 200 eV (corresponding to a wavelength range between 12-6 nm respectively). In combination we use these tools for the complete temporal characterization of the laser pulses via attosecond streaking spectroscopy. PMID- 22940954 TI - Influence of timing jitter on nonlinear dynamics of a photonic crystal fiber ring cavity. AB - We demonstrate that timing jitter has a strong influence on supercontinua generated in a photonic crystal fiber ring cavity synchronously pumped by 140 fs pulses. The global dynamics with respect to cavity detuning is analyzed both numerically and experimentally by tracking the cavity pulse energy. The results show that low-frequency timing jitter, induced by both the pump oscillator and the external cavity, masks the fine underlying bifurcation structure of the system. Numerical simulations in the absence of timing jitter reveal that the system dynamics fall into four qualitatively different regimes. The existence of these regimes is experimentally observed in first-return diagrams. PMID- 22940955 TI - Pulse synthesis in the single-cycle regime from independent mode-locked lasers using attosecond-precision feedback. AB - We report the synthesis of a nearly single-cycle (3.7 fs), ultrafast optical pulse train at 78 MHz from the coherent combination of a passively mode-locked Ti:sapphire laser (6 fs pulses) and a fiber supercontinuum (1-1.4 MUm, with 8 fs pulses). The coherent combination is achieved via orthogonal, attosecond precision synchronization of both pulse envelope timing and carrier envelope phase using balanced optical cross-correlation and balanced homodyne detection, respectively. The resulting pulse envelope, which is only 1.1 optical cycles in duration, is retrieved with two-dimensional spectral shearing interferometry (2DSI). To our knowledge, this work represents the first stable synthesis of few cycle pulses from independent laser sources. PMID- 22940956 TI - Self-referenced temporal phase reconstruction from intensity measurements using causality arguments in linear optical filters. AB - We introduce and numerically demonstrate a simple and general concept for direct reconstruction of the temporal phase profile of an optical signal from temporal intensity measurements at the input and output of an arbitrary linear optical filter. The concept is based on exploiting the linearity and causality properties of any physical filter. Very few restrictions need to be imposed on the optical filter response to ensure an unambiguous phase reconstruction. The filter can be specifically designed to minimize the noise influence on the measurement process. PMID- 22940957 TI - Wavelength-tunable photoconductivity of dye-sensitized TiO2 nanoparticle films. AB - We report in this Letter that wavelength-tunable photodetectors (PDs) can be fabricated by dye-sensitized TiO2 nanoparticle film. The photoelectric response of the detectors is fast. The photocurrent intensity strongly depends on the absorption wavelength of the dye; thus the on/off ratio as a function of light wavelength can be tuned by absorbing different dye molecules. The corresponding mechanism is also discussed. The principle reported in this Letter can be used to fabricate full spectrum PDs with distinctive wavelength selectivity. PMID- 22940958 TI - Effects of back reflection on the fiber ring laser gyroscope. AB - In this Letter, the effects of the backreflection coefficient on a fiber ring laser gyroscope (FRLG) are discussed in detail. By applying the mode coupling equations, the eigenmodes in the FRLG are theoretically analyzed. We have found that the degree of intensity oscillation is intimately related to the backreflection coefficient in the FRLG; we have also explored the theoretical responding curve of FRLG. By utilizing a bidirectional filter with a tunable backreflection coefficient, our conclusions are proven. Two responding curves were obtained under two different backreflection coefficients, the scale factors of which are 1.4405 kHz/deg.s(-1) and 1.3096 kHz/deg.s(-1), respectively. The lock-in ranges of the curves are within 10 deg/s and 15 deg/s. PMID- 22940959 TI - Spectral and temporal holograms with nonlinear optics. AB - In this Letter we show how encoding techniques for computer-generated holograms may be used to arbitrarily shape a nonlinearly generated spectrum and consequently the temporal shape by modulating the quadratic nonlinear coefficient. We give examples of a modulation pattern and a simple setup that can generate high-order Hermite-Gauss and Airy functions through difference-frequency generation from a transform-limited Gaussian pulse, under practical fabrication considerations. PMID- 22940960 TI - Subwavelength polarization rotators via double-layer metal hole arrays. AB - We show that the polarization of linearly polarized light can be rotated an arbitrary angle by double-layer metal hole array structures in a subwavelength regime. The transmitted light with the rotated polarization, however, remains of nearly the same strength as the incident field at particular frequencies. The mechanism can be attributed to the subwavelength feature of the rectangular holes, and the tangential guiding modes between layers modulated by the orientation of the holes. The structures have potential applications as polarization rotators in a broad frequency range covering from terahertz (THz) to infrared frequencies. PMID- 22940961 TI - Frequency resolved analysis of thermally induced refractive index changes in fiber amplifiers. AB - Temperature induced refractive index changes are an important aspect in today's fiber amplifiers with high average power. For many processes, their time dependence is critical. Here, we analyze the impact of radial heat diffusion on the optical phase. We modulated the pump power in a 10 W amplifier and measured the frequency response of the optical phase. We compared the result with the calculated frequency response of the temperature in the fiber core, which shows the same characteristics. Additionally, we analyzed the influence of fiber parameters on the temperature dynamics. PMID- 22940962 TI - Nonlinear communication channels with capacity above the linear Shannon limit. AB - We prove that, under certain conditions, the capacity of an optical communication channel with in-line, nonlinear filtering (regeneration) elements can be higher than the Shannon capacity for the corresponding linear Gaussian white noise channel. PMID- 22940963 TI - Double-layered nanoparticle stacks for spectro-electrochemical applications. AB - Here we present a surface based on double-layered nanoparticle stacks suitable for spectro-electrochemical applications. The structure is formed on a continuous gold layer by a two-dimensional periodic array of stacks of gold and tantalum pentoxide nanodisks. Reflection spectra in the visible wavelength region showed the multiple-resonant nature of surface plasmon (SP) excitations in the nanostructure, which is in good agreement with simulations based on a finite difference-time-domain method. The multiple SP resonances can be tuned to various wavelength regions, which are required for simultaneous enhancement at excitation and emission wavelengths. Cyclic voltammetry measurements on the nanostructure proved the applicability of electrochemical methods involving interfacial redox processes. PMID- 22940964 TI - Discrimination of field components in optical probe microscopy. AB - We demonstrate that the conventional optical signal in near-field scanning optical microscopy and the optical force induced topography contain complementary information about the complex three-dimensional field distribution. Crucially, the additional information about the field distribution can be retrieved without increasing the measurement complexity. PMID- 22940965 TI - Saliency detection based on biological plausibility of hypercomplex Fourier spectrum contrast. AB - This Letter proposes a novel saliency detection method based on biological plausibility of a hypercomplex Fourier spectrum contrast algorithm. The proposed algorithm takes into consideration not only simulation of simple cortical cells in the receptive field of humans but also the texture-color feature global spectrum contrast of an image. First, we utilize log-Gabor filters to mimic simple cortical cells in the receptive field of humans. Two complex numbers of texture colors are acquired through feature maps in hue, saturation, and value color space by log-Gabor. Second, we build the hypercomplex number using these representations of feature maps. Finally, the salient object is detected by spectrum contrast in the hypercomplex Fourier domain. Experimental results show that the proposed algorithm outperforms the state-of-the-art methods. PMID- 22940966 TI - Nd:YVO4 amplifier for ultrafast low-power lasers. AB - An Nd:YVO4 amplifier consisting of two modules end pumped at 808 nm at 30 W total absorbed power has been designed for efficient, diffraction-limited amplification of ultrafast pulses from low-power seeders. We investigated amplification with a 50 mW, 7 ps Nd:YVO4 oscillator, a 2 mW, 15 ps Yb fiber laser, and a 30 mW, 300 fs Nd:glass laser. Output power as high as 9.5 W with 8 ps pulses was achieved with the 250 MHz vanadate seeder, whereas the 20 MHz fiber laser was amplified to 6 W. The femtosecond seeder allowed extracting Fourier-limited 4 ps pulses at 7 W output power. To our knowledge, these are the shortest pulses from any Nd:YVO4 laser device with at least 7 W output power. This suggests a novel approach to exploit the gain bandwidth of vanadate amplifiers with high output power levels. Such amplifier technology promises to offer an interesting alternative to high power thin disk oscillators at few picoseconds duration, as well as to regenerative amplifiers with low-repetition-rate fiber seeders. PMID- 22940967 TI - Modeling of flowing gas diode pumped alkali lasers: dependence of the operation on the gas velocity and on the nature of the buffer gas. AB - A simple, semi-analytical model of flowing gas diode pumped alkali lasers (DPALs) is presented. The model takes into account the rise of temperature in the lasing medium with increasing pump power, resulting in decreasing pump absorption and slope efficiency. The model predicts the dependence of power on the flow velocity in flowing gas DPALs and checks the effect of using a buffer gas with high molar heat capacity and large relaxation rate constant between the 2P3/2 and 2P1/2 fine structure levels of the alkali atom. It is found that the power strongly increases with flow velocity and that by replacing, e.g., ethane by propane as a buffer gas the power may be further increased by up to 30%. Eight kilowatt is achievable for 20 kW pump at flow velocity of 20 m/s. PMID- 22940968 TI - Broadly wavelength- and pulse width-tunable high-repetition rate light pulses from soliton self-frequency shifting photonic crystal fiber integrated with a frequency doubling crystal. AB - Soliton self-frequency shift (SSFS) in a photonic crystal fiber (PCF) pumped by a long-cavity mode-locked Cr:forsterite laser is integrated with second harmonic generation (SHG) in a nonlinear crystal to generate ultrashort light pulses tunable within the range of wavelengths from 680 to 1800 nm at a repetition rate of 20 MHz. The pulse width of the second harmonic output is tuned from 70 to 600 fs by varying the thickness of the nonlinear crystal, beam-focusing geometry, and the wavelength of the soliton PCF output. Wavelength-tunable pulses generated through a combination of SSFS and SHG are ideally suited for coherent Raman microspectroscopy at high repetition rates, as verified by experiments on synthetic diamond and polystyrene films. PMID- 22940969 TI - Emission polarization of random lasers in organic dye solutions. AB - This Letter presents a polarimetric study of the emission of random lasers from organic dyes. Coherent lasing modes from samples with ethanol solvent showed a high degree of polarization and did not influence each other in polarization. The proper choice of a laser dye with asymmetric absorption momenta, a highly viscous solvent, and a linear pump polarization can cause the random lasing emission to be completely linearly polarized for all wavelengths within the amplification range. PMID- 22940970 TI - Demonstration of a 100 Hz repetition rate gain-saturated diode-pumped table-top soft x-ray laser. AB - We demonstrate the operation of a gain-saturated table-top soft x-ray laser at 100 Hz repetition rate. The laser generates an average power of 0.15 mW at lambda=18.9 nm, the highest laser power reported to date from a sub-20-nm wavelength compact source. Picosecond laser pulses of 1.5 MUJ energy were produced at lambda=18.9 nm by amplification in a Mo plasma created by tailoring the temporal intensity profile of single pump pulses with 1 J energy produced by a diode-pumped chirped pulse amplification Yb:YAG laser. Lasing was also obtained in the 13.9 nm line of Ni-like Ag. These results increase by an order of magnitude the repetition rate of plasma-based soft x-ray lasers opening the path to milliwatt average power table-top lasers at sub-20 nm wavelengths. PMID- 22940971 TI - Fast response dual-frequency liquid crystal switch with photo-patterned alignments. AB - A dual-frequency liquid crystal based optical switch with orthogonally photo patterned alignments is designed and fabricated. The cell gap is theoretically optimized for high switching performance. The measured extinction ratio of first diffraction order is over 20 dB with a low electric field of 3 V/MUm. The switch On-Off time are measured to be 350 MUs and 600 MUs, respectively, both of which have reached submillisecond scale. Moreover, the switch is polarization independent, which has been predicted theoretically and further proved experimentally. This design is suitable in wide applications requiring fast response and polarizer free properties. PMID- 22940972 TI - Autofocusing of digital holographic microscopy based on off-axis illuminations. AB - An auto-focusing method for digital holographic microscopy has been proposed by employing two off-axis illumination beams. When specimens are illuminated by two plane waves in different directions, it is found that the farther the reconstruction plane is from the image plane, the wider the two reconstructed images are separated from each other. Thus, the image plane can be determinated by finding the minimum of the variation between the two reconstructed object waves on both the amplitude and phase distributions. The feasibility of the proposed method is demonstrated by the corresponding simulation and experiment. PMID- 22940974 TI - Modeling the evolution of spatial beam parameters in parabolic index fibers. AB - We analyze the evolution of beam quality when propagating through a parabolic index (PI) fiber. The deterioration in beam quality is expressed in terms of the fiber parameters, and a methodology for minimizing the deterioration is presented. The fiber optimization procedure is evaluated numerically for an application where the PI fiber is used to deliver the signal produced by a tapered fiber-bundle beam combiner. It was demonstrated that delivery with no beam quality deterioration can be achieved with proper fiber design. PMID- 22940973 TI - Defect-tolerant extreme ultraviolet nanoscale printing. AB - We present a defect-free lithography method for printing periodic features with nanoscale resolution using coherent extreme ultraviolet light. This technique is based on the self-imaging effect known as the Talbot effect, which is produced when coherent light is diffracted by a periodic mask. We present a numerical simulation and an experimental verification of the method with a compact extreme ultraviolet laser. Furthermore, we explore the extent of defect tolerance by testing masks with different defect layouts. The experimental results are in good agreement with theoretical calculations. PMID- 22940975 TI - Light absorption engineering of hydrogenated nanocrystalline silicon by femtosecond laser. AB - The light absorption coefficient of hydrogenated nanocrystalline silicon has been engineered to have a Gaussian distribution by means of absorption modification using a femtosecond laser. The absorption-modified sample exhibits a significant absorption enhancement of up to ~700%, and the strong absorption does not depend on the incident light. We propose a model responsible for this interesting behavior. In addition, we present an optical limiter constructed through this absorption engineering method. PMID- 22940976 TI - Ultrafast optical frequency comb synthesizer and analyzer. AB - We propose an ultrafast optical arbitrary waveform synthesizing/analyzing technique demonstrated with 2 Tbit/s waveforms. An ultrafast waveform was generated by manipulating the amplitude and phase of a 400 GHz optical frequency comb using a newly developed colorless optical synthesizer. The 400 GHz optical frequency comb was generated from a 25 GHz optical frequency comb using a colorless arrayed waveguide grating. This waveform was then analyzed on the frequency axis using a custom heterodyne-detection technique based on the dual heterodyne mixing method. The phase and amplitude spectra can be observed in parallel using another optical frequency comb as a reference combined with an arrayed waveguide grating. This optical system, named the ultrafast optical frequency comb synthesizer and analyzer, can synthesize and analyze an arbitrary waveform in the THz frequency region. PMID- 22940977 TI - Efficient generation and multiplexing of optical orbital angular momentum modes in a ring fiber by using multiple coherent inputs. AB - We propose an approach to efficiently generate and multiplex optical orbital angular momentum (OAM) modes in a fiber with a ring refractive index profile by using multiple coherent inputs from a Gaussian mode. By controlling the phase relationship of the multiple inputs, one can selectively generate OAM modes of different states l. By controlling both the amplitude and phase of the multiple inputs, multiple OAM modes can be generated simultaneously without additional loss coming from multiplexing. We show, by simulation, the generation of OAM modes (OAM state |l|<3) with mode purity greater than 99%. The power loss of generating and multiplexing seven modes is about 35%. A transmitter for an OAM based mode-division multiplexing system is proposed based on the discrete Fourier transform between the data carried by the multiple inputs and the data carried by the OAM modes. The experimental implementation of the proposed approach could be achieved by integrating ring fiber, multicore fiber, and photonic integrated circuit technology. PMID- 22940978 TI - Two-step femtosecond laser pulse train fabrication of nanostructured substrates for highly surface-enhanced Raman scattering. AB - A simple and repeatable method using femtosecond laser pulse train to fabricate nanostructured substrates with silver nanoparticles over a large area for surface enhanced Raman scattering is reported. The method involves two steps: (1) femtosecond laser pulse train micromachining and roughening and (2) femtosecond laser processing of the substrates in a silver nitrate solution. Surface modification is investigated experimentally by varying the time delay of the double femtosecond laser pulse train. With time delay ranging from 200 to 600 fs, the different enhancement factors were observed. This study demonstrates that a maximum enhancement factor of 6.8*10(6), measured by 10(-6) M Rhodamine 6G solution, can be achieved at the time delay of 400 fs. PMID- 22940979 TI - Nanoscale avalanche photodiode with self-quenching and ultrahigh ultraviolet/visible rejection ratio. AB - A 4H-SiC based separate-absorption-multiplication (SAM) avalanche photodiode with a nanoscale multiplication region and a bulk absorption region is proposed and its optoelectronic performance is modeled. The results show that the avalanche breakdown voltage of the device is found to be dependent on the illumination condition. This is attributed to the existence of an illumination-dependent hole potential well in the upper center of the absorption region. Based on the illumination-dependence of avalanche breakdown voltage, a self-quenching and an ultrahigh UV/visible rejection ratio have been realized in this structure. PMID- 22940980 TI - Doppler spectrum-based polar nephelometer. AB - The particle scattering asymmetry parameter of an ensemble of submicrometer particles, as well as the complete scattering phase function (angular distribution), is determined by measuring the Doppler spectrum of the scattered light. No calibration is required. The monitor incorporates a 532 nm laser with long coherence length, an integrating sphere to collect the scattered light, and a heterodyne (interferometric) detection scheme. Measurements of monodisperse polystyrene latex spheres and polydisperse ammonium sulfate particles indicate that the measured value of the asymmetry parameter is generally within +/-0.03 of that calculated using Mie theory. PMID- 22940981 TI - 95 GHz millimeter wave signal generation using an arrayed waveguide grating dual wavelength semiconductor laser. AB - We report the generation of a 95 GHz carrier frequency by optical heterodyning of two wavelengths from adjacent channels from an arrayed waveguide grating-based multiwavelength laser. The extended cavity structure of the device provides low phase noise and narrow optical linewidth, further enhanced by the intracavity filter effect of the arrayed waveguide grating. We demonstrate that the generated RF beat note, at 95 GHz, has a -3 dB linewidth of 250 kHz. To the best of our knowledge, this is the narrowest RF linewidth generated from a free-running dual wavelength semiconductor laser. The device is realized as a photonic integrated circuit using active-passive integration technology, and fabricated on a multiproject wafer run, constituting a novel approach for a compact, low-cost dual-wavelength heterodyne source. PMID- 22940982 TI - Enhanced localization of light in slow wave slot photonic crystal waveguides. AB - A flexible design of slot photonic crystal waveguide with a wide comb is investigated. Introduction of a carefully designed comb within the photonic crystal waveguide allows an accurate dispersion engineering in order to achieve slow light and increase the optical confinement within the comb. The strong light confinement results in an extremely small nonlinear effective area around 0.015 MUm2. We report experimental realization of a comb photonic crystal waveguide with measured group indices higher than 100 in a Mach-Zehnder interferometer configuration and extract losses limited to 3.7 dB for a 100 MUm device at n(g)=37. PMID- 22940983 TI - Polarization-independent grating coupler for micrometric silicon rib waveguides. AB - Grating couplers are a promising approach to implement efficient fiber-chip coupling. However, their strong polarization dependence makes dual-polarization operation challenging. In this Letter we propose, for the first time, a polarization-independent grating coupler for thick rib silicon-on-insulator (SOI) waveguides. Coupling efficiency is optimized by designing the grating pitch and duty cycle, without varying the bottom oxide thickness, which significantly simplifies practical implementation. Directivity of the grating coupler is enhanced by a high reflectivity layer under the bottom oxide after the selective removal of the Si substrate. Dual-polarization coupling efficiency of -2.8 dB is shown. PMID- 22940984 TI - Panel-integration of natural light and the related system of light guiding and illumination. AB - This Letter proposes an idea of a natural light illumination system by using a light collecting panel. The light collecting panel is coupled with a light guide followed by a specifically designed lens to achieve uniform illumination on a target screen. To assess the system specification, we build a primary model in three-dimensional modeling software and make ray tracing simulation based on a Monte Carlo algorithm. The simulation results show a relatively high efficiency of 41.41% for the entire system and achieve a high uniformity of more than 0.8 within the circular illumination area. PMID- 22940985 TI - Reconfigurable silicon filter with continuous bandwidth tunability. AB - We present the design and the fabrication of compact tunable silicon-on-insulator bandpass filters based on the integration of a Mach-Zehnder interferometer with ring resonators and activated via thermo-optic phase shifters. The proposed architecture provides wide filter bandwidth tunability from 10% to 90% of the free spectral range preserving the filter off-band rejection. Possible applications are channel subset selection in wavelength division multiplexing optical systems, adaptive filtering to signal bandwidth, and reconfigurable filters for gridless networking. PMID- 22940986 TI - Coherent spectral enhancement of carrier-envelope-phase stable continua with dual gas high harmonic generation. AB - Attosecond science is enabled by the ability to convert femtosecond near-infrared laser light into coherent harmonics in the extreme ultraviolet spectral range. While attosecond sources have been utilized in experiments that have not demanded high intensities, substantially higher photon flux would provide a natural link to the next significant experimental breakthrough. Numerical simulations of dual gas high harmonic generation indicate that the output in the cutoff spectral region can be selectively enhanced without disturbing the single-atom gating mechanism. Here, we summarize the results of these simulations and present first experimental findings to support these predictions. PMID- 22940987 TI - Strong bonding magnetic plasmon hybridizations in double split-ring resonators. AB - The complex magnetic dipole plasmon couplings in double split-ring resonators are investigated. Two split peaks in the absorption spectrum of these coupled systems are observed, but even the shorter-wavelength resonance peak can be redshifted compared to the peaks of individual rings. The magnetic plasmon fields outside rings are found to play an important role in these strong couplings. Because of them, both bonding and antibonding plasmon hybridizations occur at each split peak. When bonding coupling effects are stronger than those of antibonding ones, this abnormal splitting behavior appears. When the coupling between rings becomes weaker, the splitting phenomenon tends to be normal. PMID- 22940988 TI - Subnanometer optical coherence tomographic vibrography. AB - The ability to quantify and visualize submicrometer-scale oscillatory motions of objects in three dimensions has a wide range of application in acoustics, materials sciences, and medical imaging. Here we demonstrate that volumetric snapshots of rapid periodic motion can be captured using optical coherence tomography (OCT) with subnanometer-scale motion sensitivity and microsecond-scale temporal resolution. This technique, termed OCT vibrography, was applied to generate time-resolved volumetric vibrographs of a miniature drum driven acoustically at several kilohertz. PMID- 22940989 TI - High surface plasmon resonance sensitivity enabled by optical disks. AB - We report a systematic, experimental, and theoretical investigation on the surface plasmon resonance (SPR) sensing using optical disks with different track pitches, including Blu-ray disk (BD), digital versatile disk (DVD), and compact disk (CD). Optical reflection measurements indicate that CD and DVD exhibit much higher SPR sensitivity than BD. Both experiments and finite-difference time domain simulations reveal that the SPR sensitivity is significantly affected by the diffraction order of the SPR peaks and higher diffraction order results in lower sensitivity. Numerical simulations also show that very high sensitivity (~1600 nm per refractive index unit) is achievable by CDs. PMID- 22940990 TI - Real-time observation of antigen-antibody association using a low-cost biosensing system based on photonic bandgap structures. AB - In this letter, we present experimental results of antibody detection using a biosensor based on photonic bandgap structures, which are interrogated using a power-based readout technique. This interrogation method allows a real-time monitoring of the association process between the antigen probes and the target antibodies, allowing the instantaneous observation of any interaction event between molecules. because etunable lasers and optical spectrum analyzers are avoided for the readout, a drastic reduction of the final cost of the platform is obtained. Furthermore, the performance of the biosensing system is significantly enhanced due to the large number of data values obtained per second. PMID- 22940991 TI - Efficient generation of far-infrared radiation in the vicinity of polariton resonance of lithium niobate. AB - We efficiently generated far-infrared radiation at the wavelengths centered at 20.8 MUm in the vicinity of one of the polariton resonances of lithium niobate. Such an efficient nonlinear conversion is made possible by exploiting phase matching for difference-frequency generation in lithium niobate. The highest peak power reached 233 W. PMID- 22940992 TI - Optical trapping of metal-dielectric nanoparticle clusters near photonic crystal microcavities. AB - We predict the formation of optically trapped, metal-dielectric nanoparticle clusters above photonic crystal microcavities. We determine the conditions on particle size and position for a gold particle to be trapped above the microcavity. We then show that strong field redistribution and enhancement near the trapped gold nanoparticle results in secondary trapping sites for a pair of dielectric nanoparticles. PMID- 22940993 TI - Enhancement of surface emission in deep ultraviolet AlGaN-based light emitting diodes with staggered quantum wells. AB - The optical polarization properties of staggered AlGaN-AlGaN/AlN quantum wells (QWs) are investigated using the theoretical model based on the k.p method. The numerical results show that the energy level order and coupling relation of the valence subband structure change in the staggered QWs and the trend is beneficial to TE polarized transition compared to that of conventional AlGaN/AlN QWs. As a result, the staggered QWs have much stronger TE-polarized emission than conventional AlGaN-based QWs, which can enhance the surface emission of deep ultraviolet (DUV) light-emitting diodes (LEDs). The polarization control by using staggered QWs can be applied in high efficiency DUV AlGaN-based LEDs. PMID- 22940994 TI - One-way radio frequency dissemination through the atmosphere using two optical carriers. AB - A method of transferring an RF reference frequency through the turbulent atmosphere is presented. Using two optical wavelengths close to each other can compensate for the influence of the atmospheric piston error. The influence of the atmosphere on the phase of the optical signal is calculated together with the remaining error by transferring two carriers. The system was implemented in a laboratory test-bed, and stability measurements are shown. PMID- 22940995 TI - Multimode interference coupler based photonic analog-to-digital conversion scheme. AB - A novel phase-shifted optical quantization scheme for an all-optical analog-to digital converter, which uses 4*4 multimode interference couplers, is demonstrated and theoretically analyzed. The whole scheme can be integrated on a chip. PMID- 22940996 TI - Shifting bright spatial solitons in LiNbO3. AB - We observe spatial bright solitons in a transversely shifting LiNbO3 crystal. In this scheme, the photovoltaic nonlinearity in LiNbO3 can be switched from self defocusing to self-focusing by continuous shifting of the beam. Moreover, the shifting velocity has a strong influence on the wave shape of the bright spatial solitons. PMID- 22940997 TI - Wave-optical theory of nanofocusing x-ray multilayer mirrors. AB - We have derived a wave-optical model of curved nanofocusing x-ray multilayer mirrors used at synchrotron radiation sources, using a Takagi-Taupin-like approach. In a first approximation, the individual layers are assumed to be confocal elliptical. This assumption leads to a convenient spatial description in elliptical coordinates. As a first optimization, we study a rotation-like modification and compare numerical simulations to established results for planar multilayers. PMID- 22940998 TI - Extended depth of focus for transmission x-ray microscope. AB - A fast discrete curvelet transform based focus-stacking algorithm for extending the depth of focus of a transmission x-ray microscope (TXM) is presented. By analyzing an image stack of a sample taken in a Z-scan, a fully in-focus image can be generated by the proposed scheme. With the extended depth of focus, it is possible to obtain 3D structural information over a large volume at nanometer resolution. The focus-stacking method has been demonstrated using a dataset taken with a laboratory x-ray source based TXM system. The possibility and limitations of generalizing this method to a synchrotron based TXM are also discussed. We expect the proposed method to be of important impact in 3D x-ray microscopy. PMID- 22940999 TI - High-efficiency ultrasmall polarization converter in InP membrane. AB - An ultrasmall (<10 MUm length) polarization converter in InP membrane is fabricated and characterized. The device relies on the beating between the two eigenmodes of chemically etched triangular waveguides. Measurements show a very high polarization conversion efficiency of >99% with insertion losses of <-1.2 dB at a wavelength of 1.53 MUm. Furthermore, our design is found to be broadband and tolerant to dimension variations. PMID- 22941000 TI - Pulsed magneto-motive optical coherence tomography for remote cellular imaging. AB - We developed pulsed magneto-motive optical coherence tomography (PMM-OCT) to reduce environmental temperature in the measurement volume and to expand the effective magnetic field distance from a pulse source. The proposed PMM-OCT system consisted of a spectral-domain OCT system and a customarily designed electrical pulse generator. The enhanced magnetic field allowed the proposed system to be able to image magnetically labeled cells in a distance as far as 30 mm away from the pulse generator. As an easy and sensitive approach, our PMM-OCT may be beneficially applied to a molecular-level imaging systems. PMID- 22941001 TI - Toward low-loss photonic crystal waveguides in InP/InGaAsP heterostructures. AB - Line-defect photonic crystal waveguides exhibit severe propagation losses if they are implemented in semiconductor heterostructures with a weak refractive index contrast. We present, for what we believe is the first time, experimental structures for which we have evidence that fabrication imperfections are not the limiting factor in terms of propagation losses. We demonstrate a loss figure of 335+/-5 dB/cm, which is an improvement by a factor of about 2 with respect to state-of-the-art values. Simulations show that even lower losses can be obtained with different waveguide geometries. In other words, the dominant loss mechanism is related to the waveguide design, and losses are not expected to decrease upon further optimization of the fabrication process. PMID- 22941002 TI - Variable single-passband narrowband optical filter based on forward stimulated interpolarization scattering in photonic crystal fiber. AB - A variable transmission spectrum single-passband narrowband optical filter is proposed and experimentally demonstrated. It is based on forward stimulated interpolarization scattering (SIPS) in a photonic crystal fiber by applying a differential quadrature phase-shift keying modulation to the pump wave to broaden and shape the SIPS gain spectrum. By choosing the bit rate of the modulation data pattern, a flat-top steep-cutoff optical bandpass filter with a 3 dB bandwidth of 70 MHz and a 10 dB bandwidth of 90 MHz is realized. In addition, a variable narrowband optical notch filter is also realized by attenuation of the pump wave. PMID- 22941003 TI - Spatially incoherent single channel digital Fourier holography. AB - We present a new method for recording digital Fourier holograms under incoherent illumination. A single exposure recorded by a digital camera is sufficient to record a real-valued hologram that encodes the complete three-dimensional properties of an object. PMID- 22941004 TI - Light-guide plate using periodical and single-sized microstructures to create a uniform backlight system. AB - Light-guide plates (LGPs) with aperiodic or size-varied microstructures are widely used in edge-lit light-source backlight systems for their high uniformity. In this Letter we designed a LGP with periodic and single-sized microstructures and analyzed the relationship between the holistic arrangement density of the microstructures and the uniformity. By controlling the holistic arrangement density of the microstructures, the uniformity could also be increased. PMID- 22941005 TI - Electro-optically switchable spatial-mode entangled photon pairs using a modified Mach-Zehnder interferometer. AB - In this Letter, we propose and analyze a switchable integrated optical waveguide device employing a modified Mach-Zehnder interferometer, capable of generating nondegenerate, maximally spatial-mode entangled photon pairs. Using an integrated electro-optic phase modulator, we show the possibility of on-demand switching of spatial-mode entangled state from a Phi+ to a Psi+ state and vice versa. Such a versatile device with the potential of easy manipulation of the "spatial-mode" degree of freedom, should be very interesting in realizing integrated optical chips for quantum information processing. PMID- 22941006 TI - High-energy directly diode-pumped Q-switched 1617 nm Er:YAG laser at room temperature. AB - We describe high-energy Erbium-doped yttrium aluminum garnet (Er:YAG) lasers operating at 1617 nm, resonantly pumped using 1532 nm fiber-coupled laser diodes. A maximum continuous wave output power of 4.3 W at 1617 nm was achieved with an output coupler of 20% transmission under incident pump power of 29.7 W, resulting in an optical conversion of 14% with respect to the incident pump power. In Q switched operation, the pulse energy of 11.8 mJ at 100 Hz pulse repetition frequency and 81 ns pulse duration was obtained. This energy is the highest pulse energy reported for a directly diode-pumped Q-switched Er:YAG laser operating at 1617 nm. PMID- 22941007 TI - Influence of atmospheric turbulence on states of light carrying orbital angular momentum. AB - We have experimentally studied the degradation of mode purity for light beams carrying orbital angular momentum (OAM) propagating through simulated atmospheric turbulence. The turbulence is modeled as a randomly varying phase aberration, which obeys statistics postulated by Kolmogorov turbulence theory. We introduce this simulated turbulence through the use of a phase-only spatial light modulator. Once the turbulence is introduced, the degradation in mode quality results in crosstalk between OAM modes. We study this crosstalk in OAM for 11 modes, showing that turbulence uniformly degrades the purity of all the modes within this range, irrespective of mode number. PMID- 22941008 TI - High-fidelity single-photon source based on a Type II optical parametric oscillator. AB - Using a continuous-wave Type II optical parametric oscillator below threshold, we have demonstrated a novel source of heralded single photons with high fidelity. The generated state is characterized by homodyne detection and exhibits a 79% fidelity with a single-photon Fock state (91% after correction of detection loss). The low admixture of vacuum and the well-defined spatiotemporal mode are critical requirements for their subsequent use in quantum information processing. PMID- 22941009 TI - Estrogen receptors in human disease. PMID- 22941010 TI - Hepatocellular carcinoma biology. AB - Hepatocellular carcinoma (HCC) is the most common primary hepatic malignancy. Its incidence and prevalence is globally heterogeneous with the highest rates in Southeast Asia and Sub-Saharan Africa. In Western Industry nations, its incidence has significantly increased throughout the previous three decades. Its global heterogeneity is in part a reflection of the global distribution of its risk factors. Its prognosis is dismal with a 5-year survival of 11 %. The only potentially curative treatment is surgical with either resection or orthotopic liver transplantation. However, the majority of HCC patients are diagnosed at an advanced stage at which surgical therapies are not feasible. HCC is considered chemotherapy-resistant-a characteristic thought to be mediated in part through stem-like tumor initiating cells (STICs). Recent studies have provided significant insights in the hepatocarcinogenesis and the molecular signaling pathways of this malignancy resulting in the development of novel, molecular targeted therapies with modest therapeutic benefit. Our growing understanding of the biology of this malignancy will help in the development of novel, molecular targeted therapies. PMID- 22941011 TI - Histopathology of hepatocellular carcinoma. AB - Hepatocellular Carcinoma (HCC) is the most frequent primary liver malignancy, mostly occurring in the context of chronic liver diseases leading to cirrhosis. Epidemiological data demonstrate the increasing incidence of HCC worldwide, mainly related to viral hepatitis and metabolic syndrome. Pathological analysis recognizes several types of HCC according to macroscopic and microscopic features. A subset of HCC can develop on normal liver and usually corresponds to specific variants, including fibrolamellar carcinoma mostly encountered in young population. Prognosis of HCC remains poor, depending on delayed tumor diagnosis, the clinical status of the patient but also tumor behavior with a great propensity for angioinvasion. PMID- 22941012 TI - Imaging of hepatocellular carcinoma: current concepts. AB - Hepatocellular carcinoma (HCC) is the most common primary hepatic malignancy, and usually develops in the setting of liver cirrhosis. The early diagnosis of HCC is essential as curative treatment (including surgical resection and liver transplantation) improves survival. While screening and surveillance are traditionally performed with ultrasound, reported accuracies of ultrasound vary greatly, and poor sensitivity for small nodules is a uniformly recognized concern. Advances in computed tomography (CT) and magnetic resonance imaging (MRI), including multidetector technology and fast breath hold sequences now allow dynamic multiphasic enhanced imaging of the liver with excellent spatial and temporal resolution, holding much promise for improved HCC detection. PMID- 22941013 TI - Methods to improve resectability of hepatocellular carcinoma. AB - Liver resection is associated with prolonged survival in selected patients with hepatocellular carcinoma (HCC). Surgical resection of HCC may be decided on an individual basis according to the extent of the tumor and the severity of chronic liver disease. In patients with compensated cirrhosis, the volume of the future liver remnant (FLR) is the most reliable factor for predicting postoperative liver function. Methods of increasing the FLR volume, including portal vein embolization and sequential transarterial chemoembolization in patients who are primarily not eligible for liver resection, have been shown to be safe and have contributed to the increase in the number of surgical candidates. PMID- 22941014 TI - Surgical resection for small hepatocellular carcinoma in cirrhosis: the Eastern experience. AB - Detection of small Hepatocarcinoma (HCC) by screening of high-risk populations is important to increase the percentage of patients suitable for curative treatment, which would lead to prolongation of the mean survival of patients with HCC. It should be remembered that small HCC is not always necessarily equivalent to early HCC as defined histologically. With recent advances in diagnostic imaging modalities, including contrast-enhanced ultrasonography and magnetic resonance imaging with liver-specific contrast enhancement, accurate differential diagnosis of early HCCs from dysplastic nodules has become possible. Because a certain proportion of small HCCs is known to show microscopic vascular invasion, surgical resection would be the treatment of first choice. To minimize potential microscopic invasion, anatomic resection and/or resection with a wide margin should be performed, while preserving liver function to the maximum extent possible. Surgical resection, however, cannot prevent multicentric occurrence of HCC, which remains a major issue precluding curative treatment of HCC. PMID- 22941015 TI - Surgical resection for hepatocellular carcinoma in the noncirrhotic: the Western experience. AB - Although hepatocellular carcinoma (HCC) is most often a sequela of severe hepatic fibrosis or cirrhosis, a proportion of cases arise in the noncirrhotic patient. The gold standard therapy in such cases is surgical resection. Innovations in operative technique allow for this treatment to be implemented with very low mortality and acceptable morbidity at high-volume hepatobiliary centers. This chapter discusses various etiologies of noncirrhotic HCC and presents a large single-center experience that is compared to other Western series. PMID- 22941016 TI - Fibrolamellar variant of hepatocellular carcinoma. AB - The fibrolamellar variant of hepatocellular carcinoma is a rare primary liver cancer occurring in adolescents and young adults without chronic liver disease or known risk factors. Histologically, it is defined by lamellar bands of fibrosis surrounding well-differentiated tumor cells. Radiologic imaging typically demonstrates a large, solitary mass with calcifications and a central scar. Lymph node metastases in the porta hepatis are frequently diagnosed upon presentation. More patients with fibrolamellar carcinoma are candidates for surgical resection than those with conventional hepatocellular carcinoma, owing to their young age and absence of cirrhosis. The most important prognostic factor is surgical resection, which results in 5-year overall survival rates ranging between 50 and 76 %. Despite complete surgical resection, relapse rates are high, and novel therapies are needed to prevent and treat recurrent disease. PMID- 22941017 TI - Laparoscopic resection of hepatocellular carcinoma. AB - The current treatment of HCC is truly multidisciplinary. Notwithstanding, surgical management remains the gold standard which other therapies are compared to. Operative management is divided into transplantation and resection; the latter is further subdivided among open and laparoscopic approaches. Resection has become safer, remains superior to locoregional treatments, and can be a life prolonging bridge to transplantation. The decision to pursue laparoscopic resection for HCC is driven by safety and a view toward the long-term management of both the malignancy and the underlying liver disease. For patients with a solitary HCC <5 cm in segments 2, 3, 4b, 5, and 6, no evidence of extrahepatic tumor burden, compensated liver disease, and the absence of significant portal hypertension, laparoscopy has an important role. Under these circumstances, resection can be performed with reduced mortality and morbidity and equivalent oncologic outcomes, disease-free survival, and overall survival when compared with similarly selected cirrhotic patients undergoing open resection. Blood loss and transfusion requirements are low, and laparoscopy itself does not expose the patient to complications and does not increase the risk of cancer recurrence or dissemination. Finally, because HCC recurrence remains high in the cirrhotic liver, treatment following surgical resection mandates routine surveillance and treatment by locoregional therapy, reresection, or transplantation as required the latter two of which are facilitated by an initial laparoscopic resection. PMID- 22941018 TI - Hepatocellular cancer and liver transplantation: a Western experience. AB - Orthotopic liver transplantation is the preferred treatment option in patients with hepatocellular carcinoma developing in chronic liver disease. Unfortunately, based on classical transplantation criteria (Milan criteria), only a minority of patients with hepatocellular carcinoma are candidate to orthotopic liver transplantation. Major improvements in treatment strategy and surgical technique including the use of neoadjuvant locoregional therapies and progresses of post transplant immunosuppressive treatment have contributed to safely expand transplantation criteria preserving acceptable surgical morbidity-mortality and good oncologic outcome. Further extension of transplantation criteria may have advantages including an increase in the number of transplant candidates and improvement of the prognosis of the disease and also disadvantages including an increase of surgical morbidity and deterioration of global oncologic outcome of orthotopic liver transplantation in hepatocellular carcinoma. In the future, identification of imaging or molecular prognostic markers could help to better define transplantation criteria. PMID- 22941019 TI - Transplantation for hepatocellular carcinoma: the North American experience. AB - Liver transplantation for hepatocellular carcinoma (HCC) in North America has undergone substantial change since its inception. Transplantation for large tumors led to near universal tumor recurrence and despite its theoretical benefit, complete liver replacement for primary hepatic malignancy was all but abandoned outside of clinical trials. With the publication of the Milan criteria interest was renewed and results of transplant for HCC began to mirror those for non-malignant indications. The adoption of MELD-based allocation led to a substantial increase in the number of transplants for HCC as MELD priority points were given to patients who met the restrictive criteria. As results of transplantation improved, several groups have pushed the boundaries of Milan and found similar results. To further possibility of transplantation for patients with tumors outside of criteria, locoregional therapies have been utilized to downstage these tumors. As the number of patients awaiting a deceased donor allograft continues to increase while the number of available deceased donor organs remains relatively constant, the roles of living donor transplantation, adjuvant, and neoadjuvant therapy will continue to evolve. PMID- 22941020 TI - Living donor liver transplantation for hepatocellular carcinoma. AB - Liver transplantation (LT) may be the best curative treatment that offers a chance of cure for the tumor and the underlying cirrhosis by complete extirpation of both. In Asia, where the supply of cadaveric grafts remains scarce and the incidence of HCC combined with chronic hepatitis B virus (HBV)- and hepatitis C virus (HCV)-related liver disease is high, adult living donor liver transplantation (LDLT) has been settled upon as a practical alternative to deceased-donor liver transplantation (DDLT). Even in Western countries, where adequate access to DDLT is feasible for HCC patients satisfying the Milan criteria, the necessity for LDLT is well established in particular for more advanced HCC patients who are disadvantaged by current allocation algorithms for grafts from deceased donors due to organ shortage, increasing waiting lists, and the expectation that many patients listed for LT will die while awaiting a suitable organ. In the field of LDLT in Asia, numerous technical innovations were achieved to secure donor safety, as well as to ensure patient survival. The experience with LDLT for HCC has been progressively increasing in many Asian countries to date. Although there are questions regarding the higher recurrence of HCC after LDLT than after DDLT, the application of the Milan and UCSF criteria to LDLT in high-volume multicenter cohorts from Japan and Korea has resulted in patient survival outcomes very similar to those following DDLT. Recently, inclusion of biologic tumor markers such as alpha fetoprotein (AFP), protein induced by vitamin K antagonist II (PIVKA II), and positive positron emission tomography (PET) in addition to parameters of tumor morphology might be the key to establishing the best criteria for LDLT for HCC. As pretransplant treatments, most LDLT centers in Asia cannot adopt the strategy of bridging therapy under scarcity of cadaveric organ donation but have to use those multi-modality treatments as a salvage intending for primary curative treatment or a downstaging therapy before LDLT. After LDLT, basically there is no difference in the management strategy for HCC recurrence between DDLD and LDLT. PMID- 22941021 TI - Image-guided ablation for hepatocellular carcinoma. AB - Image-guided ablation is accepted as the best therapeutic choice for patients with early-stage hepatocellular carcinoma (HCC) when surgical options-including resection and transplantation-are precluded. The term image-guided tumor ablation is defined as the direct application of chemical substances or sources of energy to a focal tumor in an attempt to achieve eradication or substantial tumor destruction. Over the past 25 years, several methods for local tumor destruction have been developed and clinically tested. Radiofrequency ablation (RFA) has shown superior anticancer effect and greater survival benefit with respect to the seminal percutaneous technique, ethanol injection, in meta-analyses of randomized controlled trials, and is currently established as the standard ablative modality. Nevertheless, novel thermal and nonthermal techniques for tumor ablation-including microwave ablation and irreversible electroporation-seem to have potential to improve the efficacy of RFA and are currently undergoing clinical investigation. PMID- 22941022 TI - Transarterial therapies for hepatocellular carcinoma. AB - Transarterial therapies for hepatocellular carcinoma are considered palliative and should be offered to patients with intermediate stage multinodular disease without extra-hepatic metastases and sufficient liver reserve. They mainly include transarterial chemoembolisation and transarterial embolisation. While transarterial therapy is now a validated treatment for unresectable HCC, there is still a lack of conclusive evidence as to which type and schedule is the optimal procedure. This is mainly due to the lack of standardisation. Combining local therapies or intra-arterial therapies with systemic targeted therapies might prove more effective strategies in the future. In the present article, we review transarterial therapies and critically comment on their indications, complications and outcomes. PMID- 22941023 TI - Yttrium 90 microspheres for the treatment of hepatocellular carcinoma. AB - Yttrium-90 microspheres are radioactive particles which are increasingly being employed for treating patients with unresectable hepatocellular carcinoma (HCC). The procedure is called radioembolization. It involves the injection of micron sized embolic particles loaded with a radioisotope by use of transarterial techniques. Because of the sensitivity of liver parenchyma and relative insensitivity of tumor, external radiation has played a limited role in treating HCC. (90)Y administered via arterial route directs the highly concentrated radiation to the tumor while healthy liver parenchyma is relatively spared due to its preferential blood supply from portal venous blood. This technique has proven useful for the majority of patients with HCC as most of them present in advanced stage, beyond potentially curative options (resection/liver transplantation). (90)Y microspheres can be used in downstaging large tumors to bring within transplantable criteria, in patients with portal venous thrombosis due to tumor invasion and as palliative therapy. There are two available devices for (90)Y administration; TheraSphere(r) (glass based) and SIR-Spheres(r) (resin based). The procedure is performed on an outpatient basis. The incidence of complications is comparatively less and may include nausea, fatigue, abdominal pain, hepatic dysfunction, biliary injury, fibrosis, radiation pneumonitis, GI ulcers, and vascular injury; however, these can be avoided by meticulous pretreatment assessment, careful patient selection, and adequate dosimetry. This article explores the technical and clinical aspects of (90)Y radioembolization with keeping emphasis on patient selection, uses, and complications. PMID- 22941024 TI - Targeted agents and systemic therapy in hepatocellular carcinoma. AB - Cytotoxic chemotherapy, hormonal agents, and immunotherapy have been tested in hepatocellular cancer (HCC) with marginal efficacy to date. Recent insights into the molecular pathogenesis of HCC have identified several aberrant signaling pathways that have served as targets for novel therapeutic agents. These discoveries have been translated into the clinical realm with the use of the antiangiogenic and the Raf kinase inhibitor, sorafenib, and have revealed the potential of targeted agents to produce clinically meaningful survival benefits in patients with advanced HCC. Efforts continue in the quest to improve the outcome of HCC patients through the development and evaluation of other targeted agents, and to better understand the interactions between the underlying disease biology and response to therapy. Several pathways are now implicated in hepatocarcinogenesis and agents that target these pathways continue to be developed. PMID- 22941025 TI - Multidisciplinary management of hepatocellular carcinoma. AB - Treatment of HCC is complicated by its highly variable biologic behavior and the frequent coexistence of chronic liver disease and cirrhosis in affected patients. While surgery remains the most frequently employed treatment modality, curative resection is only possible for a minority of patients. More often, treatment goals are palliative and draw on the expertise of a range of medical specialists. This chapter aims to place current treatment strategies within the framework of a multidisciplinary approach with special emphasis on pretreatment evaluation, staging, and the selection of an appropriate treatment strategy. PMID- 22941026 TI - High glucose and free fatty acids induce beta cell apoptosis via autocrine effects of ADP acting on the P2Y(13) receptor. AB - While high levels of glucose and saturated fatty acids are known to have detrimental effects on beta cell function and survival, the signalling pathways mediating these effects are not entirely known. In a previous study, we found that ADP regulates beta cell insulin secretion and beta cell apoptosis. Using MIN6c4 cells as a model system, we investigated if autocrine/paracrine mechanisms of ADP and purinergic receptors are involved in this process. High glucose (16.7 mmol/l) and palmitate (100 MUmol/l) rapidly and potently elevated the extracellular ATP levels, while mannitol was without effect. Both tolbutamide and diazoxide were without effect, while the calcium channel blocker nifedipine, the volume-regulated anion channels (VRAC) inhibitor NPPB, and the pannexin inhibitor carbenoxolone could inhibit both effects. Similarly, silencing the MDR1 gene also blocked nutrient-generated ATP release. These results indicate that calcium channels and VRAC might be involved in the ATP release mechanism. Furthermore, high glucose and palmitate inhibited cAMP production, reduced cell proliferation in MIN6c4 and increased activated Caspase-3 cells in mouse islets and in MIN6c4 cells. The P2Y(13)-specific antagonist MRS2211 antagonized all these effects. Further studies showed that blocking the P2Y(13) receptor resulted in enhanced CREB, Bad and IRS-1 phosphorylation, which are known to be involved in beta cell survival and insulin secretion. These findings provide further support for the concept that P2Y(13) plays an important role in beta cell apoptosis and suggest that autocrine/paracrine mechanisms, related to ADP and P2Y(13) receptors, contribute to glucolipotoxicity. PMID- 22941027 TI - Prevention and treatment of myeloma bone disease. AB - Osteolytic bone disease is the most common complication of multiple myeloma, resulting in skeletal-related events (SREs) that cause significant morbidity. Bone destruction in myeloma is due to an increased activity of osteoclasts coupled with suppressed bone formation by osteoblasts. Currently, bisphosphonates are the mainstay of the treatment of myeloma bone disease. Zoledronic acid and pamidronate have shown similar efficacy in reducing SREs in a randomized study in the conventional chemotherapy era. However, in a recent study (the Myeloma-IX trial of the UK Medical Research Council, MRC), zoledronic acid was found to be superior to clodronate in reducing SREs, but also it produced a survival advantage of approximately 10 months in patients with bone disease at baseline. During recent years, novel agents targeting bone have been used in myeloma. This review focuses on the established therapy of myeloma bone disease and also on recent advances in treatment that take advantage of the better understanding of the pathophysiology of bone disease. PMID- 22941028 TI - The role of glia in alpha-synucleinopathies. AB - alpha-Synuclein (AS)-positive inclusions are the pathological hallmark of Parkinson's disease (PD), dementia with Lewy bodies (DLB) and multiple system atrophy (MSA), all belonging to the category of alpha-synucleinopathies. alpha Synucleinopathies represent progressive neurodegenerative disorders characterised by increasing incidences in the population over the age of 65. The relevance of glial reactivity and dysfunction in alpha-synucleinopathies is highlighted by numerous experimental evidences. Glial AS inclusion pathology is prominent in oligodendroglia of MSA (glial cytoplasmic inclusions) and is a common finding in astroglial cells of PD and DLB, resulting in specific dysfunctional responses. Involvement of AS-dependent astroglial and microglial activation in neurodegenerative mechanisms, and therefore in disease initiation and progression, has been suggested. The aim of this review is to summarise and discuss the multifaceted responses of glial cells in alpha-synucleinopathies. The beneficial, as well as detrimental, effects of glial cells on neuronal viability are taken into consideration to draw an integrated picture of glial roles in alpha-synucleinopathies. Furthermore, an overview on therapeutic approaches outlines the difficulties of translating promising experimental studies into successful clinical trials targeting candidate glial pathomechanisms. PMID- 22941030 TI - Expression of myostatin in neural cells of the olfactory system. AB - Recent studies show that myostatin mRNA expression is found in some regions of the brain. However, the functional significance of this is currently unknown. We therefore investigated myostatin expression and function in the brain. In this study, we used immunohistochemistry, in situ hybridization, and RT-PCR analysis to reveal that myostatin is expressed in the mitral cells in the olfactory bulb (OB) and in neurons in the olfactory cortex (OC). Using 3D reconstruction, mitral cells positive for myostatin were positioned in the lateral and ventral regions of the OB. In contrast, myostatin-positive mitral cells were detected in mice at 2 weeks of age, but not on days 0 and 7 after birth. Activin receptor IIB, a myostatin receptor, was expressed in the OB, OC, hippocampus, and paraventricular thalamic nucleus. Moreover, c-Fos immunostaining in granule cells in the OB was augmented after intracerebroventricular injection of myostatin. These findings suggest that myostatin is localized in specific cells associated with the olfactory system of the brain and may act as a key inhibitor in cell and/or signal development of the olfactory system. PMID- 22941029 TI - alpha-Synuclein and protein degradation systems: a reciprocal relationship. AB - An increasing wealth of data indicates a close relationship between the presynaptic protein alpha-synuclein and Parkinson's disease (PD) pathogenesis. Alpha-synuclein protein levels are considered as a major determinant of its neurotoxic potential, whereas secreted extracellular alpha-synuclein has emerged as an additional important factor in this regard. However, the manner of alpha synuclein degradation in neurons remains contentious. Both the ubiquitin proteasome system (UPS) and the autophagy-lysosome pathway (ALP)-mainly macroautophagy and chaperone-mediated autophagy-have been suggested to contribute to alpha-synuclein turnover. Additionally, other proteases such as calpains, neurosin, and metalloproteinases have been also proposed to have a role in intracellular and extracellular alpha-synuclein processing. Both UPS and ALP activity decline with aging and such decline may play a pivotal role in many neurodegenerative conditions. Alterations in these major proteolytic pathways may result in alpha-synuclein accumulation due to impaired clearance. Conversely, increased alpha-synuclein protein burden promotes the generation of aberrant species that may impair further UPS or ALP function, generating thus a bidirectional positive feedback loop leading to neuronal death. In the current review, we summarize the recent findings related to alpha-synuclein degradation, as well as to alpha-synuclein-mediated aberrant effects on protein degradation systems. Identifying the factors that regulate alpha-synuclein association to cellular proteolytic pathways may represent potential targets for therapeutic interventions in PD and related synucleinopathies. PMID- 22941031 TI - Quantification of head sweating during rest and exercise in the heat. AB - The head's capacity for evaporative heat loss is important for design of protective helmets for use in hot environments. This study quantified head sweating rate (m (sw)) in eight males during rest and exercise at three metabolic rates (338 +/- 36, 481 +/- 24, 622 +/- 28 W) in hot-dry (HD: 45 degrees C, 21 % RH) and hot-wet (HW: 35 degrees C, 69 % RH) conditions (matched at 31.6 degrees C WBGT), which were counterbalanced. Heads were shaved, and surface area was (458 +/- 61 cm(2)) measured by 3D scanner. For measurement of head m (sw), dry air was passed through a sealed helmet, whereas for forearm m (sw) a capsule (15.9 cm(2)) was ventilated with ambient air. Evaporation rate was determined from the increase in vapor pressure in the exiting air. Whole-body sweat loss was calculated from the change in nude weight plus fluid intake and corrected for respiratory fluid losses. Head m (sw) increased (p = 0.001) with metabolic rate, and was lower (p = 0.018) in HD (0.4 +/- 0.2 mg cm(-2) min(-1) at rest to 1.1 +/- 0.6 mg cm(-2) min(-1) at 622 W), compared to HW (0.5 +/- 0.3-1.4 +/- 0.8 mg cm( 2) min(-1)). Forearm m (sw) increased (p < 0.001) with metabolic rate, but was higher (p = 0.002) in HD (0.4 +/- 0.3-1.4 +/- 0.7 mg cm(-2) min(-1)) than HW (0.1 +/- 0.1-1.1 +/- 0.3 mg cm(-2) min(-1)). Whole-body sweat loss was not significantly different (p = 0.06) between HD (647 +/- 139 g m(-2) h(-1)) and HW (528 +/- 189 g m(-2) h(-1)). This study demonstrates the importance of the head for evaporative heat loss, particularly for populations who wear protective clothing which can impair vapor transfer from the skin. PMID- 22941032 TI - CYP2D6 genotype affects age-related decline in flecainide clearance: a population pharmacokinetic analysis. AB - OBJECTIVE: To investigate the association between age-related decline in flecainide clearance and CYP2D6 genotype, we conducted a population pharmacokinetic analysis of flecainide using routine therapeutic drug monitoring data. METHODS: Population pharmacokinetic analysis was performed on retrospective data from 163 genotyped patients treated with oral flecainide for supraventricular tachyarrhythmias. The CYP2D6 genotype was categorized as CYP2D6 homozygous extensive metabolizers (hom-EMs; n=57), heterozygous extensive metabolizers (het-EMs; n=79), and intermediate metabolizers and poor metabolizers (IMs/PMs; n=27). RESULTS: Population pharmacokinetic analysis revealed that estimated glomerular filtration rate, body weight, female sex, and aging were important factors for estimating flecainide clearance. The metabolic clearance was decreased age dependently in a curvilinear fashion, where the lower clearance was observed in greater than 60 years for het-EMs and greater than 55 years for IMs/PMs. The reduction in metabolic clearance in elderly (70 years) patients compared with middle-aged (52 years) patients was different among the CYP2D6 genotype groups: 22.1 and 49.5% in CYP2D6 het-EMs and IMs/PMs, respectively, and no change in hom-EMs. A 11.4% reduction in estimated glomerular filtration rate in elderly patients compared with middle-aged patients corresponded to 6.1% decline in flecainide clearance. Overall, the age-related decline in flecainide clearance was 6.1% in hom-EMs, 16.3% in het-EMs, and 28.9% in IMs/PMs groups. CONCLUSION: This study suggests that CYP2D6 genotype is a determinant factor of age-related decline in flecainide clearance. PMID- 22941035 TI - The effect of chronic conditions on stated preferences for health. AB - BACKGROUND: While patients tend to value their own health state systematically higher than others would rate it, it is less clear whether stated preferences for hypothetical health states differ between persons with and without specific medical conditions. The aim of this study was to determine if specific conditions affect the valuation of health using a generic measure. METHODS: Using data from the US Valuation of EQ-5D Health States (n = 3,773), we focused on six conditions of interest (COI), e.g., arthritis, diabetes, depression, heart failure, cancer, and hay fever, and time trade-off values for 12 of 243 EQ-5D health states. For each COI, regression models compared differences in pooled health state preferences among four groups: COI, COI plus one or more additional conditions, no COI but other conditions, or no chronic conditions. RESULTS: No differences in health state preferences were found among the four groups for any of the COIs except for patients with cancer and additional conditions, whose mean scores were 0.07 lower compared to no chronic conditions (P < 0.01). The strongest predictors of health state preferences were race/ethnicity, age, and marital status. CONCLUSIONS: Most self-reported chronic conditions had a trivial impact on preferences for hypothetical health states, which suggests that utility algorithms for generic preference-based measures will be similar when estimated from preferences of the general population or patients with chronic illness, conceivably because both types of respondents have not experienced many health states in the classifier system. PMID- 22941034 TI - Utility elicitation study in the UK general public for late-stage chronic lymphocytic leukaemia. AB - OBJECTIVES: In the United Kingdom (UK), chronic lymphocytic leukaemia (CLL) makes up 40 % of all leukaemias in patients over 65 years. The study objective was to obtain societal preferences in the UK for "progression-free" and "progressive" states of late-stage CLL, refractory to current first and second line regimens. Preferences were also obtained for selected treatment-related adverse events (AEs). METHODS: A utility elicitation study, using the time trade-off (TTO) method, was conducted by face-to-face interviews with 110 subjects for a baseline disease state (before treatment), three primary disease states [progression-free survival (PFS) and treatment responder, PFS and treatment non-responder and disease progression], and 4 AE sub-states (PFS responder with thrombocytopenia, neutropenia, and infection, and PFS non-responder with infection). TTO scores were converted into utility values, and disutilities were calculated for AEs. Visual analogue scale (VAS) scores were obtained. RESULTS: The primary disease state mean TTO utility scores were: baseline: 0.549; PFS response: 0.671; PFS non response: 0.394; and progression: 0.214. The mean TTO utility (disutility) scores for the AEs were: PFS response with thrombocytopenia, 0.563 (-0.108), neutropenia, 0.508 (-0.163), and infection, 0.476 (-0.195); PFS non-response with infection, 0.333 (-0.061). The VAS results were in line with the TTO results. CONCLUSIONS: The utility was higher for the PFS state than baseline, but decreased below baseline in non-response and disease progression states. AEs had an impact on utility within the PFS response state. The severe infection AE had a greater impact on utilities for the responding to treatment state compared to the non-responder state. PMID- 22941037 TI - Sinomenine hydrochloride enhancement of the inhibitory effects of anti transferrin receptor antibody-dependent on the COX-2 pathway in human hepatoma cells. AB - Transferrin receptor (TfR) has been used as a target for the antibody-based therapy of cancer due to its higher expression in tumors relative to normal tissues. Great potential has been shown by anti-TfR antibodies combined with chemotherapeutic drugs as a possible cancer therapeutic strategy. In our study, we investigated the anti-tumor effects of anti-TfR monoclonal antibody (mAb) alone or in combination with sinomenine hydrochloride in vitro. Results suggested that anti-TfR mAb or sinomenine hydrochloride could induce apoptosis, inhibit proliferation, and affect the cell cycle. A synergistic effect was found in relation to tumor growth inhibition and the induction of apoptosis when anti-TfR mAb and sinomenine hydrochloride were used simultaneously. The expression of COX 2 and VEGF protein in HepG2 cells treated with anti-TfR mAb alone was increased in line with increasing dosage of the agent. In contrast, COX-2 expression was dramatically decreased in HepG2 cells treated with sinomenine hydrochloride alone. Furthermore, we demonstrated that the inhibitory effects of sinomenine hydrochloride and anti-TfR mAb administered in combination were more prominent than when the agents were administered singly. To sum up, these results showed that the combined use of sinomenine hydrochloride and anti-TfR mAb may exert synergistic inhibitory effects on human hepatoma HepG2 cells in a COX-2-dependent manner. This finding provides new insight into how tumor cells overcome the interference of iron intake to survive and forms the basis of a new therapeutic strategy involving the development of anti-TfR mAb combined with sinomenine hydrochloride for liver cancer. PMID- 22941036 TI - Human mucin MUC1 RNA undergoes different types of alternative splicing resulting in multiple isoforms. AB - MUC1 is a transmembrane mucin with important functions in normal and transformed cells, carried out by the extracellular domain or the cytoplasmic tail. A characteristic feature of the MUC1 extracellular domain is the variable number of tandem repeats (VNTR) region. Alternative splicing may regulate MUC1 expression and possibly function. We developed an RT-PCR method for efficient isolation of MUC1 mRNA isoforms that allowed us to evaluate the extent of alternative splicing of MUC1 and elucidate some of the rules that govern this process. We cloned and analyzed 21, 24, and 36 isoforms from human tumor cell lines HeLa, MCF7, and Jurkat, respectively, and 16 from normal activated human T cells. Among the 78 MUC1 isoforms we isolated, 76 are new and different cells showed varied MUC1 expression patterns. The VNTR region of exon 2 was recognized as an intron with a fixed 5' splice site but variable 3' splice sites. We also report that the 3506 A/G SNP in exon 2 can regulate 3' splice sites selection in intron 1 and produce different MUC1 short isoform proteins. Furthermore, the SNP A to G mutation was also observed in vivo, during de novo tumor formation in MUC1(+/ )Kras(G12D/+)Pten(loxP/loxP) mice. No specific functions have been associated with previously reported short isoforms. We now report that one new G SNP associated isoform MUC1/Y-LSP, but not the A SNP-associated isoform MUC1/Y, inhibits tumor growth in immunocompetent but not immunocompromised mice. PMID- 22941038 TI - MGN-3 arabinoxylan rice bran modulates innate immunity in multiple myeloma patients. AB - Dendritic cells (DCs) and natural killer (NK) cells are central components of innate immunity for controlling tumor growth. The therapeutic effects of certain anti-myeloma drugs are partially mediated by targeting the innate immune response. In addition, novel types of natural compounds have been developed that efficiently modulate the activity of both the cellular and humoral compartments of immunity. MGN-3 is known as an activator of natural killer cells, inducer of apoptosis and cytokine production, and modulator of dendritic cell maturation and differentiation in vitro. We have performed a randomized, placebo-controlled study to examine the effects of MGN-3 on innate immune system parameters in 48 multiple myeloma patients. We performed immunophenotypic analysis of peripheral blood samples, determined NK cell activity, and assessed the cytokine profiles of plasma before and during 3 months of treatment. The results demonstrate a clear increase in NK activity in MGN-3-treated patients compared to the placebo group, an increased level of myeloid DCs in peripheral blood, and augmented concentrations of T helper cell type 1-related cytokines. The present study suggests that MGN-3 may represent an immunologically relevant product for activating innate immunity in multiple myeloma patients and warrants further testing to demonstrate clinical efficacy. PMID- 22941039 TI - Concomitant combination of active immunotherapy and carboplatin- or paclitaxel based chemotherapy improves anti-tumor response. AB - Recent preclinical evidence substantially supports the successful combination of chemotherapies and active immunotherapy for cancer treatment. These data sustain the effect of sequential combination schemes (vaccine plus chemotherapy or vice versa), which could be difficult to implement in clinical practice. Since chemotherapy is the standard treatment for most cancers, ethical issues forbid its delay and make difficult the evaluation of other treatments such as using an immunotherapeutic agent. Besides, vaccines must be applied as soon as possible to advanced cancer patients, in order to give them time to develop an effective immune response. Thus, a clinically attractive scenario is the concomitant application of treatments. However, little is known about the specific effect of different chemotherapeutic agents when combined with a cancer vaccine in such concomitant treatment. In this work, we analyze the influence of high-dose carboplatin or paclitaxel in the generation of a specific immune response when administered concomitantly with an OVA vaccine. Interestingly, neither carboplatin nor paclitaxel affects the humoral and CTL in vivo response generated by the vaccine. Moreover, an enhancement of the overall anti-tumor effect was observed in animals treated with OVA/CF vaccine combined with cytotoxic drugs. Moreover, the effect of the concomitant treatment was tested using a tumor related antigen, the epidermal growth factor (EGF). Animals administered with EGF P64k/Montanide and cytotoxic agents showed an antibody response similar to that from control animals. Therefore, our study suggests that carboplatin and paclitaxel can be concomitantly combined with active immunotherapies in the clinical practice of advanced cancer patients. PMID- 22941040 TI - Gastric bypass surgery alters the mechanisms of insulin resistance in the adipose tissue of GK rats. AB - Roux-en-Y gastric bypass (RYGB) has become an effective treatment for type 2 diabetes mellitus (T2DM). However, the blood glucose mechanism involved remains unclear. In this study, 60 male Goto-Kakizaki (GK) rats were randomly divided into 6 groups (each with 10 rats): the GB1/2 group (treated with gastric bypass surgery), the SO1/2 group (treated with sham operation) and the CO1/2 group (with normal water consumption only). We tested expression levels of tumor necrosis factor alpha (TNFalpha) mRNA, glucose transporter 4 (GLUT4), peroxisome proliferator-activated receptor gamma2 (PPARgamma2) and phosphatidylinositol-3 kinase subunit p85alpha (PI3Kp85alpha) in the adipose tissues. We found that the weight, fasting blood glucose and postprandial blood glucose decreased in the GB group compared with the CO group. A total of 20 and 30 days after surgery, PPARgamma2, PI3Kp85alpha and GLUT4 increased in the fat tissue in the GB group compared with the CO group. However, 20 days after surgery, TNFalpha mRNA decreased in fat tissue by 0.51 times in the GB group compared with the CO group, and serum TNFalpha levels showed no statistically significant difference. Fasting blood glucose and GLUT4 membrane protein were negatively correlated. In conclusion, RYGB may improve insulin resistance and treat T2DM through upregulation of the PPARgamma2 protein, downregulation of TNFalpha mRNA transcription, through the autocrine pathway, upregulation of PI3Kp85alpha expression, upregulation of GLUT4 mRNA transcripts and by inducing translocation of GLUT4 in adipose tissue. PMID- 22941041 TI - A cardiovascular risk reduction program for American Indians with metabolic syndrome: the Balance Study. AB - The Balance Study is a randomized controlled trial designed to reduce cardiovascular disease (CVD) risk in 200 American Indian (AI) participants with metabolic syndrome who reside in southwestern Oklahoma. Major risk factors targeted include weight, diet, and physical activity. Participants are assigned randomly to one of two groups, a guided or a self-managed group. The guided group attends intervention meetings that comprise education and experience with the following components: diet, exercise, AI culture, and attention to emotional wellbeing. The self-managed group receives printed CVD prevention materials that are generally available. The duration of the intervention is 24 months. Several outcome variables will be compared between the two groups to assess the effectiveness of the intervention program. PMID- 22941042 TI - Using height association studies to gain insights into human idiopathic short and syndromic stature phenotypes. AB - Variation in adult height is not the most clinically relevant human quantitative trait, yet its study provides the foundation of many quantitative genetics theories and important statistical concepts (e.g. regression). Even today, the analysis of adult height by genome-wide association studies (GWAS) continues to significantly impact human genetics: these studies have led to the discovery of >200 loci associated with variation in adult height and have highlighted the very polygenic nature of human continuous traits. In this brief review, I discuss and provide examples on how such genetic associations, identified in individuals of normal height, could help understand the complex genetics behind such phenotypes as idiopathic short stature (ISS) or extreme/syndromic height phenotypes of unknown cause. PMID- 22941043 TI - Cardiovascular management of septic shock in 2012. AB - Septic shock is a major cause of morbidity and mortality throughout the world. Source control, antimicrobial therapy, early goal-directed fluid resuscitation, and infusion of vasoactive pharmaceuticals remain the cornerstones of treatment. However, the cardiovascular management of septic shock is evolving. Basic science and clinical researchers have identified novel drug targets and are testing the efficacy of new therapeutic agents. For example, prevention of microvascular leak during septic shock is the focus of active investigations and may soon provide considerable benefit to patients. Among the important topics that will be discussed in this review are the following: the role of vascular endothelial dysfunction in microvascular leak, the impact of cytokines upon structural and functional proteins within the endothelial barrier and within the heart, and the ability of selective vasopressin 1a receptor agonists to minimize tissue edema and improve hemodynamic status. PMID- 22941044 TI - EG-VEGF controls placental growth and survival in normal and pathological pregnancies: case of fetal growth restriction (FGR). AB - Identifiable causes of fetal growth restriction (FGR) account for 30 % of cases, but the remainders are idiopathic and are frequently associated with placental dysfunction. We have shown that the angiogenic factor endocrine gland-derived VEGF (EG-VEGF) and its receptors, prokineticin receptor 1 (PROKR1) and 2, (1) are abundantly expressed in human placenta, (2) are up-regulated by hypoxia, (3) control trophoblast invasion, and that EG-VEGF circulating levels are the highest during the first trimester of pregnancy, the period of important placental growth. These findings suggest that EG-VEGF/PROKR1 and 2 might be involved in normal and FGR placental development. To test this hypothesis, we used placental explants, primary trophoblast cultures, and placental and serum samples collected from FGR and age-matched control women. Our results show that (1) EG-VEGF increases trophoblast proliferation ([(3)H]-thymidine incorporation and Ki67 staining) via the homeobox-gene, HLX (2) the proliferative effect involves PROKR1 but not PROKR2, (3) EG-VEGF does not affect syncytium formation (measurement of syncytin 1 and 2 and beta hCG production) (4) EG-VEGF increases the vascularization of the placental villi and insures their survival, (5) EG-VEGF, PROKR1, and PROKR2 mRNA and protein levels are significantly elevated in FGR placentas, and (6) EG-VEGF circulating levels are significantly higher in FGR patients. Altogether, our results identify EG-VEGF as a new placental growth factor acting during the first trimester of pregnancy, established its mechanism of action, and provide evidence for its deregulation in FGR. We propose that EG VEGF/PROKR1 and 2 increases occur in FGR as a compensatory mechanism to insure proper pregnancy progress. PMID- 22941045 TI - Cytochrome P450-catalyzed L-tryptophan nitration in thaxtomin phytotoxin biosynthesis. AB - Thaxtomin phytotoxins produced by plant-pathogenic Streptomyces species contain a nitro group that is essential for phytotoxicity. The N,N' dimethyldiketopiperazine core of thaxtomins is assembled from L-phenylalanine and L-4-nitrotryptophan by a nonribosomal peptide synthetase, and nitric oxide synthase-generated NO is incorporated into the nitro group, but the biosynthesis of the nonproteinogenic amino acid L-4-nitrotryptophan is unclear. Here we report that TxtE, a unique cytochrome P450, catalyzes L-tryptophan nitration using NO and O(2). PMID- 22941046 TI - The physical state of lipid substrates provides transacylation specificity for tafazzin. AB - Cardiolipin is a mitochondrial phospholipid with a characteristic acyl chain composition that depends on the function of tafazzin, a phospholipid lysophospholipid transacylase, although the enzyme itself lacks acyl specificity. We incubated isolated tafazzin with various mixtures of phospholipids and lysophospholipids, characterized the lipid phase by (31)P-NMR and measured newly formed molecular species by MS. Substantial transacylation was observed only in nonbilayer lipid aggregates, and the substrate specificity was highly sensitive to the lipid phase. In particular, tetralinoleoyl-cardiolipin, a prototype molecular species, formed only under conditions that favor the inverted hexagonal phase. In isolated mitochondria, <1% of lipids participated in transacylations, suggesting that the action of tafazzin was limited to privileged lipid domains. We propose that tafazzin reacts with non-bilayer-type lipid domains that occur in curved or hemifused membrane zones and that acyl specificity is driven by the packing properties of these domains. PMID- 22941049 TI - Microchannel refill: a new method for fabricating 2D nanochannels in polymer substrates. AB - In this paper, we present a new approach that is capable of fabricating nanochannels in a poly(methyl methacrylate) (PMMA) substrate. This method, which we call microchannel refill (MR), utilizes the refilling of glassy thermoplastics under thermal compression to reduce a microscopic channel to a nanochannel. It only has two main steps. First, a microchannel is fabricated in a PMMA substrate using normal hot embossing. Second, the microchannel is compressed under a certain temperature and pressure to obtain a nanochannel. We show that a nanochannel with a width as small as 132 nm (with a depth of 85 nm) can be easily produced by choosing the appropriate compression temperature, compression pressure, original microchannel width and original microchannel aspect ratio. Compared with most current nanochannel fabrication methods, MR is a quick, simple and cost-effective way to produce nanochannels in polymer substrates. PMID- 22941048 TI - Enhanced organics and nitrogen removal in batch-operated vertical flow constructed wetlands by combination of intermittent aeration and step feeding strategy. AB - Oxygen and carbon source supply are usually insufficient in subsurface flow constructed wetlands. Simultaneous removal of organic pollutants and nitrogen in five batch-operated vertical flow constructed wetlands under different operating conditions was investigated. Alternate aerobic and anaerobic regions were created well with intermittent aeration. Four-month experiments showed that the wetland applied intermittent aeration combined with step feeding strategy (reactor E) greatly improved the removal of organics, ammonium nitrogen (NH4-N), and total nitrogen (TN) simultaneously, which were 97, 96, and 82%, respectively. It was much better than non-aerated reactors A and B and outperformed intermittently aerated reactor D without step feeding. Continuous aeration (reactor C) significantly enhanced the organics removal and nitrification, but it limited the TN removal (29%) seriously as a result of low denitrification level, and the high operation cost remained a question. The effect of plants was confirmed in this study, and the monitoring data showed that the plants could grow normally. Intermittent aeration as well as step feeding had no obvious influence on the growth of wetland plants in this study. PMID- 22941047 TI - A new type V toxin-antitoxin system where mRNA for toxin GhoT is cleaved by antitoxin GhoS. AB - Among bacterial toxin-antitoxin systems, to date no antitoxin has been identified that functions by cleaving toxin mRNA. Here we show that YjdO (renamed GhoT) is a membrane lytic peptide that causes ghost cell formation (lysed cells with damaged membranes) and increases persistence (persister cells are tolerant to antibiotics without undergoing genetic change). GhoT is part of a new toxin-antitoxin system with YjdK (renamed GhoS) because in vitro RNA degradation studies, quantitative real-time reverse-transcription PCR and whole-transcriptome studies revealed that GhoS masks GhoT toxicity by cleaving specifically yjdO (ghoT) mRNA. Alanine substitutions showed that Arg28 is important for GhoS activity, and RNA sequencing indicated that the GhoS cleavage site is rich in U and A. The NMR structure of GhoS indicates it is related to the CRISPR-associated-2 RNase, and GhoS is a monomer. Hence, GhoT-GhoS is to our knowledge the first type V toxin antitoxin system where a protein antitoxin inhibits the toxin by cleaving specifically its mRNA. PMID- 22941051 TI - Reversible network reconnection model for simulating large deformation in dynamic tissue morphogenesis. AB - Morphogenesis of tissues in organ development is accompanied by large three dimensional (3D) deformations, in which mechanical interactions among multiple cells are spatiotemporally regulated. To reveal the deformation mechanisms, in this study, we developed the reversible network reconnection (RNR) model. The model is developed on the basis of 3D vertex model, which expresses a multicellular aggregate as a network composed of vertices. 3D vertex models have successfully simulated morphogenetic dynamics by expressing cellular rearrangements as network reconnections. However, the network reconnections in 3D vertex models can cause geometrical irreversibility, energetic inconsistency, and topological irreversibility, therefore inducing unphysical results and failures in simulating large deformations. To resolve these problems, we introduced (1) a new definition of the shapes of polygonal faces between cellular polyhedrons, (2) an improved condition for network reconnections, (3) a new condition for potential energy functions, and (4) a new constraint condition for the shapes of polygonal faces that represent cell-cell boundaries. Mathematical and computational analyses demonstrated that geometrical irreversibility, energetic inconsistency, and topological irreversibility were resolved by suppressing the geometrical gaps in the network and avoiding the generation of irreversible network patterns in reconnections. Lastly, to demonstrate the applicability of the RNR model, we simulated tissue deformation of growing cell sheets and showed that our model can simulate large tissue deformations, in which large changes occur in the local curvatures and layer formations of tissues. Thus, the RNR model enables in silico recapitulation of complex tissue morphogenesis. PMID- 22941050 TI - Attenuated effects of experimenter-administered heroin in adolescent vs. adult male rats: physical withdrawal and locomotor sensitization. AB - OBJECTIVES: Early onset of heroin use during adolescence might increase chances of later drug addiction. Prior work from our laboratory suggests, however, that adolescent male rats are actually less sensitive than adults to some enduring effects of heroin self-administration. In the present study, we tested two likely correlates of sensitivity to behavioral reinforcement in rats: physical withdrawal and locomotor sensitization. METHODS: Adolescent (35 days old at start) and adult (79 days old) male Sprague-Dawley rats were administered escalating doses of heroin, increasing from 1.0 to 8.0 mg/kg (i.p.) every 12 h, across 13 days. Somatic signs of spontaneous withdrawal were scored 12 and 24 h after the last injection, and then every 24 h for 5 days; locomotion was recorded concurrently. Challenge injections of heroin (1 mg/kg i.p.) were given at four points: as the first of the escalating doses (day 1), at days 7 and 13 during the escalating regimen, and after 12 days of forced abstinence. Body mass and food intake were measured throughout experimentation. RESULTS: A heroin withdrawal syndrome was not observed among adolescents as it was among adults, including somatic signs as well as reduced locomotion, body mass, and food intake. On the other hand, heroin-induced locomotor sensitization did not differ across ages. CONCLUSION: Reduced withdrawal is consistent with the attenuated reinforcing effects of heroin among adolescent male rats that we reported previously. Thus, it is possible that adolescent rats could reveal important neuroprotective factors for use in treatment of heroin dependence. PMID- 22941053 TI - Pulsed electrically detected magnetic resonance for thin film silicon and organic solar cells. AB - In thin film solar cells based on non-crystalline thin film silicon or organic semiconductors structural disorder leads to localized states that induce device limiting charge recombination and trapping. Both processes frequently involve paramagnetic states and become spin-dependent. In the present perspectives article we report on advanced pulsed electrically detected magnetic resonance (pEDMR) experiments for the study of spin dependent transport processes in fully processed thin film solar cells. We reflect on recent advances in pEDMR spectroscopy and demonstrate its capabilities on two different state of the art thin film solar cell concepts based on microcrystalline silicon and organic MEH PPV:PCBM blends, recently studied at HZB. Benefiting from the increased capabilities of novel pEDMR detection schemes we were able to ascertain spin dependent transport processes and microscopically identify paramagnetic states and their role in the charge collection mechanism of solar cells. PMID- 22941052 TI - An analysis of risk factors associated with traumatic extremity amputation stump wound infection in a Nigerian setting. AB - PURPOSE: We aimed to determine the risk factors associated with traumatic extremity amputation stump wound infection in our environment. METHOD: This was a retrospective analysis of databases that included the entire patient population with traumatic extremity amputation seen in Ebonyi State University Teaching Hospital and Federal Medical Centre Abakaliki from January 2001 to December 2011. RESULT: There were 63 patients studied and stump wound infection was a complication in 38 (60 %) of them. Stump wound infection rate significantly correlated with the form of amputation, i.e., a higher rate in crushing than guillotine (sharp clear-cut) amputation (80.5 vs. 22.7 % p < 0.000); severity, i.e., a higher rate in major than minor amputation (80.6 vs. 33.3 % p < 0.000); and limb involvement, i.e., a higher rate in lower than upper extremity amputation (71.1 vs. 60.7 % p < 0.002). Haematocrit level on admission (p < 0.002), injury to hospital admission interval (p < 0.012) and injury to first surgical debridement / amputation interval (p < 0.02) were all significantly related to incidence of wound infection. Multivariate analysis identified crushing amputation as an independent risk factor (p < 0.009) for traumatic amputation stump wound infection. CONCLUSION: The only independent predictor of traumatic extremity amputation stump wound infection is a crushing form of amputation; it should be accorded a high priority in interventions aimed at reducing infection rate. PMID- 22941054 TI - Health-care worker vaccination for influenza: strategies and controversies. AB - Influenza infections cause significant morbidity and mortality throughout the world, and vaccination rates of health-care workers remain well below target goals. Strategies for increasing vaccination rates include mandatory vaccination of health-care workers, mandatory declination, employee incentives, intensive education, increased access to vaccines, and the use of social media to inform employees of the safety and efficacy of vaccination. While these strategies in combination have been shown to be effective in increasing vaccination rates, personal and religious objections, as well as the potential for infringing on individual autonomy, remain challenges in our efforts to bring health-care worker vaccination rates up to target goals. PMID- 22941055 TI - mRNA/miRNA correlations in colorectal cancer: novel mechanisms in cancer initiation and progression. PMID- 22941056 TI - Singing by male and female Kloss gibbons (Hylobates klossii) in the Peleonan Forest, Siberut Island, Indonesia. AB - Kloss gibbons (Hylobates klossii) are endemic to the Mentawai Islands in Indonesia and are one of only two gibbon species in which mated pairs do not sing duets. This is the first long-term study of the factors influencing the singing activity of Kloss gibbons within a northern Siberut Island population and follows two previous studies in central Siberut nearly 30 years ago. We collected data on the presence/absence of male and female singing within the study area on 198 days and within a focal group on 47 days. Rainfall during the time period in which they normally sing inhibits singing in both males and females. Our study supports the hypothesis that male and female songs function in intrasexual resource defence, as singing is associated with singing by same-sex neighbours, and same sex choruses are more likely to occur after one or more days of silence (from that sex), suggesting there is pressure for individuals to communicate with same sex neighbours regularly. Singing was not coordinated within a mated pair, suggesting that vocal coordination of the pair has been lost with the loss of the duet and that Kloss gibbon songs do not convey information to neighbours about the strength of the pair bond. On days when males sang predawn, females were more likely to sing after dawn and earlier in the morning. Additionally, the number of groups singing in female choruses was positively associated with the number of males that had sung in the predawn male chorus. We suggest that female songs have an intersexual territory defence as well as an intrasexual function. PMID- 22941057 TI - Epigallocatechin-3-gallate inhibits bladder cancer cell invasion via suppression of NF-kappaB-mediated matrix metalloproteinase-9 expression. AB - Bladder cancer is the fourth most common cancer in males and the ninth most common in females. However, despite the numerous advances made in the past few decades, the prognosis of patients with bladder cancer remains poor. Metastasis is one of the major causes of mortality in bladder cancer patients. Therefore, the inhibition of metastasis is one of the most significant issues in bladder cancer research. The present study was conducted to evaluate the anti-metastatic potential of (-)-epigallocatechin gallate (EGCG, the major phytochemical in green tea) against bladder cancer and its mechanism of action. EGCG efficiently and dose-dependently inhibited adhesion, migration and invasion of T24 human bladder cancer cells. Mechanistically, EGCG inhibited phosphatidylinositol 3'-kinase/Akt activation that resulted in inactivation of nuclear factor-kappaB (NF-kappaB) and the inhibition of the expression of matrix metalloproteinase-9 (MMP-9), ultimately suppressing invasion and metastasis. These findings suggest that EGCG is a potential therapeutic candidate against tumor invasion. PMID- 22941058 TI - Neighborhood walkability and active travel (walking and cycling) in New York City. AB - Urban planners have suggested that built environment characteristics can support active travel (walking and cycling) and reduce sedentary behavior. This study assessed whether engagement in active travel is associated with neighborhood walkability measured for zip codes in New York City. Data were analyzed on engagement in active travel and the frequency of walking or biking ten blocks or more in the past month, from 8,064 respondents to the New York City 2003 Community Health Survey (CHS). A neighborhood walkability scale that measures: residential, intersection, and subway stop density; land use mix; and the ratio of retail building floor area to retail land area was calculated for each zip code. Data were analyzed using zero-inflated negative binomial regression incorporating survey sample weights and adjusting for respondents' sociodemographic characteristics. Overall, 44 % of respondents reported no episodes of active travel and among those who reported any episode, the mean number was 43.2 episodes per month. Comparing the 75th to the 25th percentile of zip code walkability, the odds ratio for reporting zero episodes of active travel was 0.71 (95 % CI 0.61, 0.83) and the exponentiated beta coefficient for the count of episodes of active travel was 1.13 (95 % CI 1.06, 1.21). Associations between lower walkability and reporting zero episodes of active travel were significantly stronger for non-Hispanic Whites as compared to non-Hispanic Blacks and to Hispanics and for those living in higher income zip codes. The results suggest that neighborhood walkability is associated with higher engagement in active travel. PMID- 22941060 TI - The p53 target gene desmocollin 3 acts as a novel tumor suppressor through inhibiting EGFR/ERK pathway in human lung cancer. AB - Desmosomes are intercellular junctions that confer strong cell-cell adhesion. Altered expression of desmocollin 3 (DSC3), a member of the desmosomal cadherin family, was found in various cancers; however, its functional involvement in carcinogenesis has not yet been elucidated. Expression/localization of DSC3 was analyzed by real-time reverse transcription-PCR, western blotting, immunofluorescence and immunohistochemistry. Methylation status of DSC3 was examined by demethylation tests, methylation-specific PCR and bisulfite sequencing. It turned out that downregulation of DSC3 in lung cancer cells was associated with DNA hypermethylation. In primary lung tumors, DSC3 was a potential diagnostic marker for lung squamous cell carcinoma, and DSC3 DNA hypermethylation was correlated with poor clinical outcome. To investigate the effect of the tumor suppressor gene p53 on DSC3, transient transfection with a wild-type p53-expression vector was performed. Overexpression of p53 resulted in an increased expression of DSC3 in a DSC3-unmethylated lung cancer cell line H2170, but not in H1299, a DSC3-methylated cell line. However, combination of p53 transfection with demethylation agent 5-aza-2'-deoxycytidine treatment led to increased expression of DSC3 in H1299 cells. Furthermore, functional studies after stable transfection of a DSC3 expression vector showed that ectopic expression of DSC3 inhibited cell proliferation, anchorage-independent growth, migration, as well as invasion, and most interestingly led to reduced phosphorylation levels of extracellular signal-regulated kinase1/2. Taken together, our data suggested that DSC3 acts as a novel tumor suppressor gene through inhibition of epidermal growth factor receptor/extracellular signal regulated kinase signaling in lung cancer cells. PMID- 22941059 TI - Claudin-1 expression confers resistance to anoikis in colon cancer cells in a Src dependent manner. AB - Denial of the appropriate cell-matrix interaction in epithelial cells induces apoptosis and is called 'anoikis'. Cancer cells are resistant to anoikis and it is believed that the resistance to anoikis helps promote tumor malignancy especially metastasis. We and others have demonstrated that the expression of tight junction protein claudin-1 is highly upregulated in colorectal cancer (CRC) and helps promote tumor progression and metastasis. However, molecular mechanism/s underlying claudin-1-dependent regulation of CRC progression remains poorly understood. In current study, we have determined that claudin-1 expression modulates anoikis in colon cancer cells to influence colon cancer invasion and thus metastasis. We have further provided data that claudin-1 modulates anoikis in a Src-Akt-Bcl-2-dependent manner. Importantly, claudin-1 physically associates with Src/p-Src in a multiprotein complex that also includes ZO-1, a PDZ-binding tight junction protein. Taken together, our data support the role of claudin-1 in the regulation of CRC progression and suggest that the regulation of anoikis may serve as a key regulatory mechanism in claudin-1-dependent regulation of CRC progression. Our findings are of direct clinical relevance and may open new therapeutic opportunity in colon cancer treatment and/or management. PMID- 22941061 TI - High-power electrokinetic energy conversion in a glass microchannel array. AB - The electrokinetic conversion of flow work to electricity using a glass microchannel array coated with nano-layers of gold that serve as electrodes on both its ends was studied and a maximum power output of 1 mW at an efficiency of 1.3% is reported. The establishment of such a high power generation capability in combination with a low pressure drop (26 kPa) makes this electrokinetic work conversion device more practical than those previously reported in literature. PMID- 22941062 TI - Religious moral beliefs inversely related to trauma experiences severity and depression severity among war veterans in Bosnia and Herzegovina. AB - The aim of this study is to determine the association of religious moral beliefs and depression severity of war veterans in Bosnia and Herzegovina. The sample consists of male war veterans who were inpatients with clinically presented depression and those who were observed as healthy, regarding results of previous psychological testing (n=65 both). The Bosnia-Herzegovina versions of Hopkins Symptom Checklist and Harvard Trauma Questionnaire with questionnaire for religious moral beliefs were applied. The religious moral belief index was inversely correlated to depression severity. The religious moral beliefs may help protection of the war veterans' mental health stability after surviving multiple war traumas. PMID- 22941063 TI - Post-therapeutic surveillance schedule for oral cancer: is there agreement? AB - INTRODUCTION: Patients with oral cavity squamous cell carcinoma represent a diverse group, and the treatment these patients undergo also varies widely. Some patients undergo local excision alone while others require extensive surgery, often with adjuvant chemoradiotherapy. The post-therapeutic surveillance schedule for these patients tends to be a "one size fits all" formula for all head and neck squamous cell carcinoma patients, which has often been dictated by institutional doctrine or a senior surgeon's dogma. The post-therapeutic needs and risks of a T1 oral cancer patient treated with surgery alone differ from those of a patient with advanced laryngeal carcinoma, and the follow-up regimen should be tailored to the specific patient's risk of loco-regional recurrence, distant metastasis, and other related medical issues. RESOURCES AND MATERIALS: A total of 65 papers were identified, 18 of which either focused on follow-up strategy for oral cavity squamous cell carcinoma or their tabular data allowed these cases to be extracted. Internationally recognized cancer entities were also queried. CONCLUSIONS: No international consensus was achieved about the follow-up strategies. The value of post-therapeutic surveillance schedule following oral cancer treatment is generally not in dispute, although patient-initiated symptom driven visits can be effective in identifying tumor recurrence for oral cancer patients. The range of appointment interval schemes tends to identify a progressive escalation of visit intervals such that there are more visits in the first year than in the second, and fewer yet during the third. Patients may fail to comply with their clinic visit structure. Most references agree that follow-up beyond the third year is unnecessary and may waste medical resources as well as the time of both patient and surgeon. There is no agreement as to the need for or interval of imaging studies. PMID- 22941064 TI - Occurrence of 2-methylthiazolidine-4-carboxylic acid, a condensation product of cysteine and acetaldehyde, in human blood as a consequence of ethanol consumption. AB - Acetaldehyde is a strongly electrophilic compound that is endogenously produced as a first intermediate in oxidative ethanol metabolism. Its high reactivity towards biogenic nucleophiles has toxicity as a consequence. Acetaldehyde readily undergoes a non-enzymatic condensation reaction and consecutive ring formation with cysteine to form 2-methylthiazolidine-4-carboxylic acid (MTCA). For analytical purposes, N-acetylation of MTCA was required for stabilization and to enable its quantification by reversed-phase chromatography combined with electrospray ionization-tandem mass spectrometry. Qualitative screening of post mortem blood samples with negative blood alcohol concentration (BAC) mostly showed low basal levels of MTCA. In BAC-positive post mortem samples, but not in corresponding urine specimens, strongly increased levels were present. To estimate the association between ethanol consumption and the occurrence of MTCA in human blood, the time curves of BAC and MTCA concentration were determined after a single oral dose of 0.5 g ethanol per kilogram of body weight. The blood elimination kinetics of MTCA was slower than that of ethanol. The peak concentration of MTCA (12.6 mg L(-1)) was observed 4 h after ethanol intake (BAC 0.070/00) and MTCA was still detectable after 13 h. Although intermediary acetaldehyde scavenging by formation of MTCA is interesting from a toxicological point of view, lack of hydrolytic stability under physiological conditions may hamper the use of MTCA as a quantitative marker of acetaldehyde exposure, such as resulting from alcohol consumption. PMID- 22941065 TI - Polythiophenes and polythiophene-based composites in amperometric sensing. AB - This overview of polythiophene-based materials provides a critical examination of meaningful examples of applications of similar electrode materials in electroanalysis. The advantages arising from the use of polythiophene derivatives in such an applicative context is discussed by considering the organic conductive material as such, and as one of the components of hybrid materials. The rationale at the basis of the combination of two or even more individual components into a hybrid material is discussed with reference to the active electrode processes and the consequent possible improvements of the electroanalytical performance. In this respect, study cases are presented considering different analytes chosen among those that are most frequently reported within the classes of organics and inorganics. The use of a polythiophene matrix to stably fix biological elements at the electrode surface for the development of catalytic biosensors and genosensors is also discussed. Finally, a few possible lines along which the next research in the field could be fruitfully pursued are outlined. Furthermore, the work still to be done to exploit the possibilities offered by novel products of organic synthesis, even along paths already traced in other fields of electrochemistry, is discussed. PMID- 22941066 TI - High-throughput quantitative analysis with cell growth kinetic curves for low copy number mutant cells. AB - The mutation rate in cells induced by environmental genotoxic hazards is very low and difficult to detect using traditional cell counting assays. The established genetic toxicity tests currently recognized by regulatory authorities, such as conventional Ames and hypoxanthine guanine phosphoribosyl-transferase (HPRT) assays, are not well suited for higher-throughput screening as they require large amounts of test compounds and are very time consuming. In this study, we developed a novel cell-based assay for quantitative analysis of low numbers of cell copies with HPRT mutation induced by an environmental mutagen. The HPRT gene mutant cells induced by the mutagen were selected by 6-thioguanine (6-TG) and the cell's kinetic growth curve monitored by a real-time cell electronic sensor (RT CES) system. When a threshold is set at a certain cell index (CI) level, samples with different initial mutant cell copies take different amounts of time in order for their growth (or CI accumulation) to cross this threshold. The more cells that are initially seeded in the test well, the faster the cell accumulation and therefore the shorter the time required to cross this threshold. Therefore, the culture time period required to cross the threshold of each sample corresponds to the original number of cells in the sample. A mutant cell growth time threshold (MT) value of each sample can be calculated to predict the number of original mutant cells. For mutagenesis determination, the RT-CES assay displayed an equal sensitivity (p > 0.05) and coefficients of variation values with good correlation to conventional HPRT mutagenic assays. Most importantly, the RT-CES mutation assay has a higher throughput than conventional cellular assays. PMID- 22941067 TI - Sequestering ability of some chelating agents towards methylmercury(II). AB - A study on the interactions between CH(3)Hg(+) and some S, N and O donor ligands (2-mercaptopropanoic acid (thiolactic acid (H(2)TLA)), 3-mercaptopropanoic acid (H(2)MPA), 2-mercaptosuccinic acid (thiomalic acid (H(3)TMA)), D,L-penicillamine (H(2)PSH), L-cysteine (H(2)CYS), glutathione (H(3)GSH), N,N'-bis(3-aminopropyl)-1 4-diaminobutane (spermine (SPER)), 1,2,3,4,5,6-benzenehexacarboxylic acid (mellitic acid (H(6)MLT)) and ethylenediaminetetraacetic acid (H(4)EDTA)) is reported. The speciation models in aqueous solution and the possible structures of the complexes formed are discussed on the basis of potentiometric, calorimetric, UV spectrophotometric and electrospray mass spectrometric results. For the CH(3)Hg(+)-S donor ligand systems, the formation of ML(1-z) and MLH(2-z) complex species is observed, together with a diprotonated MLH(2)(3-z) species for CYS(2-), PSH(2-) and GSH(3-) and the mixed hydrolytic one ML(OH)(-z) for TLA(2-) and MPA(2-). The dependence of the stability on ionic strength and on temperature is also analysed. In the other CH(3)Hg(+)-L systems (L = MLT(6-), SPER and EDTA(4 )), ML(1-z), MLH(2-z) and MLH(2)(3-z) complex species are formed, together with the MLH(3)(4-z) species for SPER, the mixed hydrolytic ML(OH)(-z) one for SPER and EDTA, and the M(2)L(2-z) for EDTA only. On the basis of the speciation models proposed, the sequestering ability of the ligands towards methylmercury(II) cation is evaluated. All S donor ligands show a good sequestering power (at 10( 11) mol L(-1) level, in the pH range 4 to 8) following the trend MPA(2-) < PSH(2 ) < GSH(3-) < TLA(2-) < CYS(2-) < TMA(3-), while significantly lower is the sequestering ability of MLT, SPER and EDTA (at 10(-3)-10(-5) mol L(-1) level, in the pH range 4 to 8). PMID- 22941068 TI - Development and independent laboratory validation of a simple method for the determination of paraquat and diquat in potato, cereals and pulses. AB - A new sensitive, fast and robust method for the determination of paraquat and diquat residues in potatoes, cereals and pulses is presented. Different extraction conditions (solvent, time and temperature) have been evaluated using barley grain, potatoes and dry lentils containing incurred residues of diquat and paraquat. The finalised procedure involves extraction with a mixture of methanol/water/hydrochloric acid at 80 degrees C and analysis by liquid chromatography-tandem mass spectrometry. Diquat D4 and Paraquat D6 internal standards were added to the test portions prior to extraction. A small-scale inter-laboratory validation of the developed method for diquat and paraquat using potato and barley samples was conducted by three laboratories. The precision and accuracy of the method were determined from recovery experiments (five replicates) at 0.01 and 0.1 mg kg(-1). The recoveries obtained (n = 180) were in the range of 92-120 % with associated relative standard deviation (RSD) between 1.4-10 % for all compound/commodity/spiking concentration combinations. PMID- 22941069 TI - Multireaction monitoring of 12 peptides for lowered immunity screening. AB - A multireaction monitoring method using high-performance liquid chromatography tandem mass spectrometry was developed for 12 target peptides for determination of endogenous peptide concentrations in human serum. Chromatographic separation conditions were optimized and recoveries for liquid-liquid extraction, solid phase extraction (SPE), and ultrafiltration of endogenous peptides from human serum were compared, and the SPE method was selected for 12 targeted peptide extractions. The optimized SPE method gave recoveries higher than 60 % for all targeted peptides. The limit of detection was 10 ng/ml for most peptides, except for N-formyl-methionyl-leucyl-phenylalanine (NFMLP) and adrenocorticotropic hormone (ACTH) (18-39). The limit of detection for these two peptides was 1 ng/ml. The real serum samples of 25 elderly and 23 young people were analyzed using the optimized extraction and analysis method. Half of the 12 peptides were below the limit of quantification, and B-type natriuretic peptide, cholecystokinin, ACTH(7-38), substance P, NFMLP, and valyl-glutamyl-prolyl isoleucyl-prolyl-tyrosine were quantified in the concentration range from 0.1 to 50 ng/ml. The concentration of ACTH(7-38) was significantly higher in elderly people and that of NFMLP was significantly lower in elderly people compared with young people (p < 0.0001). This result implies that there be a possible relationships between ACTH, NFMLP and lowered immunity. PMID- 22941070 TI - Qualitative analysis of the fluorophosphonate-based chemical probes using the serine hydrolases from mouse liver and poly-3-hydroxybutyrate depolymerase (PhaZ) from Bacillus thuringiensis. AB - The serine hydrolase family consists of more than 200 members and is one of the largest enzyme families in the human genome. Although up to 50 % of this family remains unannotated, there are increasing evidences that activities of certain serine hydrolases are associated with diseases like cancer neoplasia, invasiveness, etc. By now, several activity-based chemical probes have been developed and are applied to profile the global activity of serine hydrolases in diverse proteomes. In this study, two fluorophosphonate (FP)-based chemical probes were synthesized. Further examination of their abilities to label and pull down serine hydrolases was conducted. In addition, the poly-3-hydroxybutyrate depolymerase (PhaZ) from Bacillus thuringiensis was demonstrated as an appropriate standard serine hydrolase, which can be applied to measure the labeling ability and pull-down efficiency of FP-based probes. Furthermore, mass spectrometry (MS) was used to identify the serine residue that covalently bonded to the active probes. Finally, these FP-based probes were shown capable of establishing the serine hydrolase profiles in diverse mouse tissues; the serine hydrolases pulled down from mouse liver organ were further identified by MS. In summary, our study provides an adequate method to evaluate the reactivity of FP based probes targeting serine hydrolases. PMID- 22941071 TI - Residual viral and bacterial contamination of surfaces after cleaning and disinfection. AB - Environmental surfaces contaminated with pathogens can be sources of indirect transmission, and cleaning and disinfection are common interventions focused on reducing contamination levels. We determined the efficacy of cleaning and disinfection procedures for reducing contamination by noroviruses, rotavirus, poliovirus, parechovirus, adenovirus, influenza virus, Staphylococcus aureus, and Salmonella enterica from artificially contaminated stainless steel surfaces. After a single wipe with water, liquid soap, or 250-ppm free chlorine solution, the numbers of infective viruses and bacteria were reduced by 1 log(10) for poliovirus and close to 4 log(10) for influenza virus. There was no significant difference in residual contamination levels after wiping with water, liquid soap, or 250-ppm chlorine solution. When a single wipe with liquid soap was followed by a second wipe using 250- or 1,000-ppm chlorine, an extra 1- to 3-log(10) reduction was achieved, and except for rotavirus and norovirus genogroup I, no significant additional effect of 1,000 ppm compared to 250 ppm was found. A reduced correlation between reduction in PCR units (PCRU) and reduction in infectious particles suggests that at least part of the reduction achieved in the second step is due to inactivation instead of removal alone. We used data on infectious doses and transfer efficiencies to estimate a target level to which the residual contamination should be reduced and found that a single wipe with liquid soap followed by a wipe with 250-ppm free chlorine solution was sufficient to reduce the residual contamination to below the target level for most of the pathogens tested. PMID- 22941072 TI - Mechanisms for photoinactivation of Enterococcus faecalis in seawater. AB - Field studies in fresh and marine waters consistently show diel fluctuations in concentrations of enterococci, indicators of water quality. We investigated sunlight inactivation of Enterococcus faecalis to gain insight into photoinactivation mechanisms and cellular responses to photostress. E. faecalis bacteria were exposed to natural sunlight in clear, filtered seawater under both oxic and anoxic conditions to test the relative importance of oxygen-mediated and non-oxygen-mediated photoinactivation mechanisms. Multiple methods were used to assess changes in bacterial concentration, including cultivation, quantitative PCR (qPCR), propidium monoazide (PMA)-qPCR, LIVE/DEAD staining using propidium iodide (PI), and cellular activity, including ATP concentrations and expression of the superoxide dismutase-encoding gene, sodA. Photoinactivation, based on numbers of cultivable cells, was faster in oxic than in anoxic microcosms exposed to sunlight, suggesting that oxygen-mediated photoinactivation dominated. There was little change in qPCR signal over the course of the experiment, demonstrating that the nucleic acid targets were not damaged to a significant extent. The PMA qPCR signal was also fairly stable, consistent with the observation that the fraction of PI-permeable cells was constant. Thus, damage to the membrane was minimal. Microbial ATP concentrations decreased in all microcosms, particularly the sunlit oxic microcosms. The increase in relative expression of the sodA gene in the sunlit oxic microcosms suggests that cells were actively responding to oxidative stress. Dark repair was not observed. This research furthers our understanding of photoinactivation mechanisms and the conditions under which diel fluctuations in enterococci can be expected in natural and engineered systems. PMID- 22941073 TI - OmpA-mediated biofilm formation is essential for the commensal bacterium Sodalis glossinidius to colonize the tsetse fly gut. AB - Many bacteria successfully colonize animals by forming protective biofilms. Molecular processes that underlie the formation and function of biofilms in pathogenic bacteria are well characterized. In contrast, the relationship between biofilms and host colonization by symbiotic bacteria is less well understood. Tsetse flies (Glossina spp.) house 3 maternally transmitted symbionts, one of which is a commensal (Sodalis glossinidius) found in several host tissues, including the gut. We determined that Sodalis forms biofilms in the tsetse gut and that this process is influenced by the Sodalis outer membrane protein A (OmpA). Mutant Sodalis strains that do not produce OmpA (Sodalis DeltaOmpA mutants) fail to form biofilms in vitro and are unable to colonize the tsetse gut unless endogenous symbiotic bacteria are present. Our data indicate that in the absence of biofilms, Sodalis DeltaOmpA mutant cells are exposed to and eliminated by tsetse's innate immune system, suggesting that biofilms help Sodalis evade the host immune system. Tsetse is the sole vector of pathogenic African trypanosomes, which also reside in the fly gut. Acquiring a better understanding of the dynamics that promote Sodalis colonization of the tsetse gut may enhance the development of novel disease control strategies. PMID- 22941074 TI - Phe317 is essential for rubber oxygenase RoxA activity. AB - RoxA is an extracellular c-type diheme cytochrome secreted by Xanthomonas sp. strain 35Y during growth on rubber. RoxA cleaves poly(cis-1,4-isoprene) to 12-oxo 4,8-dimethyltrideca-4,8-diene-1-al (ODTD). Analysis of the RoxA structure revealed that Phe317 is located in close proximity (~5 A) to the N-terminal heme that presumably represents the active site. To find evidence of whether Phe317 is important for catalysis, we changed it to tyrosine, tryptophan, leucine, histidine, or alanine. All five RoxA muteins were expressed after integration of the respective gene into the chromosome of a Xanthomonas sp. DeltaroxA strain. Residual clearing zone formation on opaque latex agar was found for Xanthomonas sp. strains expressing the Phe317Leu, Phe317Ala, or Phe317His variant (wild type > Leu > Ala > His). Strains in which Phe317 was changed to tyrosine or tryptophan were inactive. Phe317Ala and Phe312Leu RoxA muteins were purified, and polyisoprene cleavage activities were reduced to ~3% and 10%, respectively. UV visible spectroscopy of RoxA muteins confirmed that both heme groups were present in an oxidized form, but spectral responses to the addition of low-molecular weight (inhibitory) ligand molecules such as imidazole and pyridine were different from those of wild-type RoxA. Our results show that residue 317 is involved in interaction with substrates. This is the first report on structure function analysis of a polyisoprene-cleaving enzyme and on the identification of an amino acid that is essential for polyisoprene cleavage activity. PMID- 22941075 TI - Autotrophic production of stable-isotope-labeled arginine in Ralstonia eutropha strain H16. AB - With the aim of improving industrial-scale production of stable-isotope (SI) labeled arginine, we have developed a system for the heterologous production of the arginine-containing polymer cyanophycin in recombinant strains of Ralstonia eutropha under lithoautotrophic growth conditions. We constructed an expression plasmid based on the cyanophycin synthetase gene (cphA) of Synechocystis sp. strain PCC6308 under the control of the strong P(cbbL) promoter of the R. eutropha H16 cbb(c) operon (coding for autotrophic CO(2) fixation). In batch cultures growing on H(2) and CO(2) as sole sources of energy and carbon, respectively, the cyanophycin content of cells reached 5.5% of cell dry weight (CDW). However, in the absence of selection (i.e., in antibiotic-free medium), plasmid loss led to a substantial reduction in yield. We therefore designed a novel addiction system suitable for use under lithoautotrophic conditions. Based on the hydrogenase transcription factor HoxA, this system mediated stabilized expression of cphA during lithoautotrophic cultivation without the need for antibiotics. The maximum yield of cyanophycin was 7.1% of CDW. To test the labeling efficiency of our expression system under actual production conditions, cells were grown in 10-liter-scale fermentations fed with (13)CO(2) and (15)NH(4)Cl, and the (13)C/(15)N-labeled cyanophycin was subsequently extracted by treatment with 0.1 M HCl; 2.5 to 5 g of [(13)C/(15)N]arginine was obtained per fed-batch fermentation, corresponding to isotope enrichments of 98.8% to 99.4%. PMID- 22941076 TI - Microbial community dynamics of an urban drinking water distribution system subjected to phases of chloramination and chlorination treatments. AB - Water utilities in parts of the U.S. control microbial regrowth in drinking water distribution systems (DWDS) by alternating postdisinfection methods between chlorination and chloramination. To examine how this strategy influences drinking water microbial communities, an urban DWDS (population ? 40,000) with groundwater as the source water was studied for approximately 2 years. Water samples were collected at five locations in the network at different seasons and analyzed for their chemical and physical characteristics and for their microbial community composition and structure by examining the 16S rRNA gene via terminal restriction fragment length polymorphism and DNA pyrosequencing technology. Nonmetric multidimension scaling and canonical correspondence analysis of microbial community profiles could explain >57% of the variation. Clustering of samples based on disinfection types (free chlorine versus combined chlorine) and sampling time was observed to correlate to the shifts in microbial communities. Sampling location and water age (<21.2 h) had no apparent effects on the microbial compositions of samples from most time points. Microbial community analysis revealed that among major core populations, Cyanobacteria, Methylobacteriaceae, Sphingomonadaceae, and Xanthomonadaceae were more abundant in chlorinated water, and Methylophilaceae, Methylococcaceae, and Pseudomonadaceae were more abundant in chloraminated water. No correlation was observed with minor populations that were detected frequently (<0.1% of total pyrosequences), which were likely present in source water and survived through the treatment process. Transient microbial populations including Flavobacteriaceae and Clostridiaceae were also observed. Overall, reversible shifts in microbial communities were especially pronounced with chloramination, suggesting stronger selection of microbial populations from chloramines than chlorine. PMID- 22941077 TI - Proteorhodopsin-like genes present in thermoacidophilic high-mountain microbial communities. AB - Proteorhodopsin (PR) sequences were PCR amplified from three Andean acidic hot spring samples. These sequences were similar to freshwater and marine PRs and they contained residues indicative of proton-pumping activity and of proteins that absorb green light; these findings suggest that PRs might contribute to cellular metabolism in these habitats. PMID- 22941078 TI - Antimicrobial susceptibility of Bacillus strains isolated from primary starters for African traditional bread production and characterization of the bacitracin operon and bacitracin biosynthesis. AB - Bacillus spp. are widely used as feed additives and probiotics. However, there is limited information on their resistance to various antibiotics, and there is a growing concern over the transfer of antibiotic resistance genes. The MIC for 8 antibiotics was determined for 85 Bacillus species strains, Bacillus subtilis subsp. subtilis (n = 29), Bacillus licheniformis (n = 38), and Bacillus sonorensis (n = 18), all of which were isolated from starters for Sudanese bread production. All the strains were sensitive to tetracycline (8.0 mg/liter), vancomycin (4.0 mg/liter), and gentamicin (4.0 mg/liter) but resistant to streptomycin. Sensitivity to clindamycin, chloramphenicol, and kanamycin was species specific. The erythromycin resistance genes ermD and ermK were detected by PCR in all of the erythromycin-resistant (MIC, >=16.0 mg/liter) B. licheniformis strains and one erythromycin-sensitive (MIC, 4.0 mg/liter) B. licheniformis strain. Several amino acid changes were present in the translated ermD and ermK nucleotide sequences of the erythromycin-sensitive strain, which could indicate ErmD and ErmK protein functionalities different from those of the resistance strains. The ermD and ermK genes were localized on an 11.4-kbp plasmid. All of the B. sonorensis strains harbored the bacitracin synthetase gene, bacA, and the transporter gene bcrA, which correlated with their observed resistance to bacitracin. Bacitracin was produced by all the investigated species strains (28%), as determined by ultra-high-definition quadrupole time-of-flight liquid chromatography-mass spectrometry (UHD-QTOF LC/MS). The present study has revealed species-specific variations in the antimicrobial susceptibilities of Bacillus spp. and provides new information on MIC values, as well as the occurrence of resistance genes in Bacillus spp., including the newly described species B. sonorensis. PMID- 22941079 TI - Prevalence and relative risk of Cronobacter spp., Salmonella spp., and Listeria monocytogenes associated with the body surfaces and guts of individual filth flies. AB - Although flies are important vectors of food-borne pathogens, there is little information to accurately assess the food-related health risk of the presence of individual flies, especially in urban areas. This study quantifies the prevalence and the relative risk of food-borne pathogens associated with the body surfaces and guts of individual wild flies. One hundred flies were collected from the dumpsters of 10 randomly selected urban restaurants. Flies were identified using taxonomic keys before being individually dissected. Cronobacter spp., Salmonella spp., and Listeria monocytogenes were detected using the PCR-based BAX system Q7. Positive samples were confirmed by culture on specific media and through PCR amplification and sequencing or ribotyping. Among collected flies were the housefly, Musca domestica (47%), the blowflies, Lucilia cuprina (33%) and Lucilia sericata (14%), and others (6%). Cronobacter species were detected in 14% of flies, including C. sakazakii, C. turicensis, and C. universalis, leading to the proposal of flies as a natural reservoir of this food-borne pathogen. Six percent of flies carried Salmonella enterica, including the serovars Poona, Hadar, Schwarzengrund, Senftenberg, and Brackenridge. L. monocytogenes was detected in 3% of flies. Overall, the prevalence of food-borne pathogens was three times greater in the guts than on the body surfaces of the flies. The relative risk of flies carrying any of the three pathogens was associated with the type of pathogen, the body part of the fly, and the ambient temperature. These data enhance the ability to predict the microbiological risk associated with the presence of individual flies in food and food facilities. PMID- 22941080 TI - "Remake" by high-throughput sequencing of the microbiota involved in the production of water buffalo mozzarella cheese. AB - Intermediates of production of two batches of traditional mozzarella cheese were analyzed by culture-independent pyrosequencing. The quantitative distribution of taxa within the samples suggested that thermophilic lactic acid bacteria from the natural starter were mainly responsible for the fermentation, while microorganisms found in raw milk did not develop during fermentation. PMID- 22941082 TI - LplR, a repressor belonging to the TetR family, regulates expression of the L pantoyl lactone dehydrogenase gene in Rhodococcus erythropolis. AB - The L-pantoyl lactone (L-PL) dehydrogenase (LPLDH) gene (lpldh) has been cloned from Rhodococcus erythropolis AKU2103, and addition of 1,2-propanediol (1,2-PD) was shown to be required for lpldh expression in this strain. In this study, based on an exploration of the nucleotide sequence around lpldh, a TetR-like regulator gene, which we designated lplR, was found upstream of lpldh, and three putative open reading frames existed between the two genes. Disruption of lplR led to 22.8 times higher lpldh expression, even without 1,2-PD induction, than that in wild-type R. erythropolis AKU2103 without 1,2-PD addition. Introduction of a multicopy vector carrying lplR (multi-lplR) into the wild-type and DeltalplR strains led to no detectable LPLDH activity even in the presence of 1,2-PD. The results of an electrophoretic mobility shift assay revealed that purified LplR bound to a 6-bp inverted-repeat sequence located in the promoter/operator region of the operon containing lpldh. These results indicated that LplR is a negative regulator in lpldh expression. Based on the clarification of the expression mechanism of lpldh, recombinant cells showing high LPLDH activity were constructed and used as a catalyst for the conversion of L-PL to ketopantoyl lactone. Finally, a promising production process of D-PL from DL-PL was constructed. PMID- 22941081 TI - Global transcriptional analysis of dehydrated Salmonella enterica serovar Typhimurium. AB - Despite the scientific and industrial importance of desiccation tolerance in Salmonella, knowledge regarding its genetic basis is still scarce. In the present study, we performed a transcriptomic analysis of dehydrated and water-suspended Salmonella enterica serovar Typhimurium using microarrays. Dehydration induced expression of 90 genes and downregulated that of 7 genes. Ribosomal structural genes represented the most abundant functional group with a relatively higher transcription during dehydration. Other main induced functional groups included genes involved in amino acid metabolism, energy production, ion transport, transcription, and stress response. The highest induction was observed in the kdpFABC operon, encoding a potassium transport channel. Knockout mutations were generated in nine upregulated genes. Five mutants displayed lower tolerance to desiccation, implying the involvement of the corresponding genes in the adaptation of Salmonella to desiccation. These included genes encoding the isocitrate-lyase AceA, the lipid A biosynthesis palmitoleoyl-acyltransferase Ddg, the modular iron-sulfur cluster scaffolding protein NifU, the global regulator Fnr, and the alternative sigma factor RpoE. Notably, these proteins were previously implicated in the response of Salmonella to oxidative stress, heat shock, and cold shock. A strain with a mutation in the structural gene kdpA had a tolerance to dehydration comparable to that of the parent strain, implying that potassium transport through this system is dispensable for early adaptation to the dry environment. Nevertheless, this mutant was significantly impaired in long term persistence during cold storage. Our findings indicate the involvement of a relatively small fraction of the Salmonella genome in transcriptional adjustment from water to dehydration, with a high prevalence of genes belonging to the protein biosynthesis machinery. PMID- 22941083 TI - Characterization and two-dimensional crystallization of membrane component AlkB of the medium-chain alkane hydroxylase system from Pseudomonas putida GPo1. AB - The alkane hydroxylase system of Pseudomonas putida GPo1 allows it to use alkanes as the sole source of carbon and energy. Bacterial alkane hydroxylases have tremendous potential as biocatalysts for the stereo- and regioselective transformation of a wide range of chemically inert unreactive alkanes into valuable reactive chemical precursors. We have produced and characterized the first 2-dimensional crystals of the integral membrane component of the P. putida alkane hydroxylase system, the nonheme di-iron alkane monooxygenase AlkB. Our analysis reveals for the first time that AlkB reconstituted into a lipid bilayer forms trimers. Addition of detergents that do not disrupt the AlkB oligomeric state (decyl maltose neopentyl glycol [DMNG], lauryl maltose neopentyl glycol [LMNG], and octaethylene glycol monododecyl ether [C(12)E(8)]) preserved its activity at a level close to that of the detergent-free control sample. In contrast, the monomeric form of AlkB produced by purification in n-decyl-beta-D maltopyranoside (DM), n-dodecyl-beta-D-maltopyranoside (DDM), octyl glucose neopentyl glycol (OGNG), and n-dodecyl-N,N-dimethylamine-N-oxide (LDAO) was largely inactive. This is the first indication that the physiologically active form of membrane-embedded AlkB may be a multimer. We present for the first time experimental evidence that 1-octyne acts as a mechanism-based inhibitor of AlkB. Therefore, despite the lack of any significant full-length sequence similarity with members of other monooxygenase classes that catalyze the terminal oxidation of alkanes, AlkB is likely to share a similar catalytic mechanism. PMID- 22941084 TI - Characterization of an endo-processive-type xyloglucanase having a beta-1,4 glucan-binding module and an endo-type xyloglucanase from Streptomyces avermitilis. AB - We cloned two glycoside hydrolase family 74 genes, the sav_1856 gene and the sav_2574 gene, from Streptomyces avermitilis NBRC14893 and characterized the resultant recombinant proteins. The sav_1856 gene product (SaGH74A) consisted of a catalytic domain and a family 2 carbohydrate-binding module at the C terminus, while the sav_2574 gene product (SaGH74B) consisted of only a catalytic domain. SaGH74A and SaGH74B were expressed successfully and had molecular masses of 92 and 78 kDa, respectively. Both recombinant proteins were xyloglucanases. SaGH74A had optimal activity at 60 degrees C and pH 5.5, while SaGH74B had optimal activity at 55 degrees C and pH 6.0. SaGH74A was stable over a broad pH range (pH 4.5 to 9.0), whereas SaGH74B was stable over a relatively narrow pH range (pH 6.0 to 6.5). Analysis of the hydrolysis products of tamarind xyloglucan and xyloglucan-derived oligosaccharides indicated that SaGH74A was endo-processive, while SaGH74B was a typical endo-enzyme. The C terminus of SaGH74A, which was annotated as a carbohydrate-binding module, bound to beta-1,4-linked glucan containing soluble polysaccharides such as hydroxyethyl cellulose, barley glucan, and xyloglucan. PMID- 22941085 TI - Epigallocatechin gallate induces upregulation of the two-component VraSR system by evoking a cell wall stress response in Staphylococcus aureus. AB - We previously found that a short exposure of Staphylococcus aureus to subinhibitory (SI) doses of epigallocatechin gallate (EGCG) results in increased cell wall thickness, adaptation, and enhanced tolerance to cell-wall-targeted antibiotics. In this study, the response to EGCG of sigB and vraSR transcription factor mutants was characterized. We show that in contrast to the results observed for wild-type (WT) strains, an S. aureus 315 vraSR null mutant exposed to SI doses of EGCG did not exhibit increased tolerance to EGCG and oxacillin. A diminished increase in tolerance to ampicillin (from 16-fold to 4-fold) and no change in the magnitude of resistance to vancomycin were observed. Preexposure to EGCG enhanced the tolerance of wild-type and sigB null mutant cells to lysostaphin, but this enhancement was much weaker in the vraSR null mutant. Marked upregulation (about 60-fold) of vraR and upregulation of the peptidoglycan biosynthesis-associated genes murA, murF, and pbp2 (2-, 5-, and 6-fold, respectively) in response to SI doses of EGCG were determined by quantitative reverse transcription-PCR (qRT-PCR). EGCG also induced the promoter of sas016 (encoding a cell wall stress protein of unknown function which is not induced in vraSR null mutants) in a concentration-dependent manner, showing kinetics comparable to those of cell-wall-targeting antibiotics. Taken together, our results suggest that the two-component VraSR system is involved in modulating the cell response to SI doses of EGCG. PMID- 22941086 TI - Synthetic pathway for production of five-carbon alcohols from isopentenyl diphosphate. AB - Synthetic biological pathways could enhance the development of novel processes to produce chemicals from renewable resources. On the basis of models that describe the evolution of metabolic pathways and enzymes in nature, we developed a framework to rationally identify enzymes able to catalyze reactions on new substrates that overcomes one of the major bottlenecks in the assembly of a synthetic biological pathway. We verified the framework by implementing a pathway with two novel enzymatic reactions to convert isopentenyl diphosphate into 3 methyl-3-butenol, 3-methyl-2-butenol, and 3-methylbutanol. To overcome competition with native pathways that share the same substrate, we engineered two bifunctional enzymes that redirect metabolic flux toward the synthetic pathway. Taken together, our work demonstrates a new approach to the engineering of novel synthetic pathways in the cell. PMID- 22941087 TI - Carbohydrate hydrolysis and transport in the extreme thermoacidophile Sulfolobus solfataricus. AB - Extremely thermoacidophilic microbes, such as Sulfolobus solfataricus, are strict chemoheterotrophs despite their geologic niche. To clarify their ecophysiology, the overlapping roles of endoglucanases and carbohydrate transporters were examined during growth on soluble cellodextrins as the sole carbon and energy source. Strain-specific differences in genome structure implied a unique role for one of three endogenous endoglucanases. Plasmid-based endoglucanase expression promoted the consumption of oligosaccharides, including cellohexaose (G6) through cellonanaose (G9). Protein transporters required for cellodextrin uptake were identified through mutagenesis and complementation of an ABC transporter cassette, including a putative oligosaccharide binding protein. In addition, ablation of the binding protein compromised growth on glucose and alpha-linked oligosaccharides while inactivation of a previously described glucose transporter had no apparent impact. These data demonstrate that S. solfataricus employs a redundant mechanism for soluble cellodextrin catabolism having both substrate uptake and extracytoplasmic hydrolytic components. PMID- 22941089 TI - AidC, a novel N-acylhomoserine lactonase from the potato root-associated cytophaga-flavobacteria-bacteroides (CFB) group bacterium Chryseobacterium sp. strain StRB126. AB - N-acylhomoserine lactones (AHLs) are used as quorum-sensing (QS) signal molecules by many gram-negative bacteria. We have reported that Chryseobacterium sp. strain StRB126, which was isolated from the root surface of potato, has AHL-degrading activity. In this study, we cloned and characterized the aidC gene from the genomic library of StRB126. AidC has AHL-degrading activity and shows homology to several metallo-beta-lactamase proteins from Bacteroidetes, although not to any known AHL-degrading enzymes. Purified AidC, as a maltose-binding fusion protein, showed high degrading activity against all tested AHLs, whether short- or long chain forms, with or without substitution at carbon 3. High-performance liquid chromatography (HPLC) analysis revealed that AidC functions as an AHL lactonase catalyzing AHL ring opening by hydrolyzing lactones. An assay to determine the effects of covalent and ionic bonding showed that Zn(2+) is important to AidC activity both in vitro and in vivo. In addition, the aidC gene could also be PCR amplified from several other Chryseobacterium strains. In conclusion, this study indicated that the aidC gene, encoding a novel AHL lactonase, may be widespread throughout the genus Chryseobacterium. Our results extend the diversity and known bacterial hosts of AHL-degrading enzymes. PMID- 22941088 TI - Abundance and genetic diversity of nifH gene sequences in anthropogenically affected Brazilian mangrove sediments. AB - Although mangroves represent ecosystems of global importance, the genetic diversity and abundance of functional genes that are key to their functioning scarcely have been explored. Here, we present a survey based on the nifH gene across transects of sediments of two mangrove systems located along the coast line of Sao Paulo state (Brazil) which differed by degree of disturbance, i.e., an oil-spill-affected and an unaffected mangrove. The diazotrophic communities were assessed by denaturing gradient gel electrophoresis (DGGE), quantitative PCR (qPCR), and clone libraries. The nifH gene abundance was similar across the two mangrove sediment systems, as evidenced by qPCR. However, the nifH-based PCR-DGGE profiles revealed clear differences between the mangroves. Moreover, shifts in the nifH gene diversities were noted along the land-sea transect within the previously oiled mangrove. The nifH gene diversity depicted the presence of nitrogen-fixing bacteria affiliated with a wide range of taxa, encompassing members of the Alphaproteobacteria, Betaproteobacteria, Gammaproteobacteria, Firmicutes, and also a group of anaerobic sulfate-reducing bacteria. We also detected a unique mangrove-specific cluster of sequences denoted Mgv-nifH. Our results indicate that nitrogen-fixing bacterial guilds can be partially endemic to mangroves, and these communities are modulated by oil contamination, which has important implications for conservation strategies. PMID- 22941090 TI - Evaluation of sample recovery efficiency for bacteriophage P22 on fomites. AB - Fomites are known to play a role in the transmission of pathogens. Quantitative analysis of the parameters that affect sample recovery efficiency (SRE) at the limit of detection of viruses on fomites will aid in improving quantitative microbial risk assessment (QMRA) and infection control. The variability in SRE as a function of fomite type, fomite surface area, sampling time, application media, relative humidity (rH), and wetting agent was evaluated. To quantify the SRE, bacteriophage P22 was applied onto fomites at average surface densities of 0.4 +/ 0.2 and 4 +/- 2 PFU/cm(2). Surface areas of 100 and 1,000 cm(2) of nonporous fomites found in indoor environments (acrylic, galvanized steel, and laminate) were evaluated with premoistened antistatic wipes. The parameters with the most effects on the SRE were sampling time, fomite surface area, wetting agent, and rH. At time zero (the initial application of bacteriophage P22), the SRE for the 1,000-cm(2) fomite surface area was, on average, 40% lower than that for the 100 cm(2) fomite surface area. For both fomite surface areas, the application medium Trypticase soy broth (TSB) and/or the laminate fomite predominantly resulted in a higher SRE. After the applied samples dried on the fomites (20 min), the average SRE was less than 3%. A TSB wetting agent applied on the fomite improved the SRE for all samples at 20 min. In addition, an rH greater than 28% generally resulted in a higher SRE than an rH less than 28%. The parameters impacting SRE at the limit of detection have the potential to enhance sampling strategies and data collection for QMRA models. PMID- 22941091 TI - EDTA inhibits biofilm formation, extracellular vesicular secretion, and shedding of the capsular polysaccharide glucuronoxylomannan by Cryptococcus neoformans. AB - The fungal pathogen Cryptococcus neoformans can grow as a biofilm on a range of synthetic and prosthetic materials. Cryptococcal biofilm formation can complicate the placement of shunts used to relieve increased intracranial pressure in cryptococcal meningitis and can serve as a nidus for chronic infection. Biofilms are generally advantageous to pathogens in vivo, as they can confer resistance to antimicrobial compounds, including fluconazole and voriconazole in the case of C. neoformans. EDTA can inhibit biofilm formation by several microbes and enhances the susceptibility of biofilms to antifungal drugs. In this study, we evaluated the effect of sublethal concentrations of EDTA on the growth of cryptococcal biofilms. EDTA inhibited biofilm growth by C. neoformans, and the inhibition could be reversed by the addition of magnesium or calcium, implying that the inhibitory effect was by divalent cation starvation. EDTA also reduced the amount of the capsular polysaccharide glucuronoxylomannan shed into the biofilm matrix and decreased vesicular secretion from the cell, thus providing a potential mechanism for the inhibitory effect of this cation-chelating compound. Our data imply that the growth of C. neoformans biofilms requires the presence of divalent metals in the growth medium and suggest that cations are required for the export of materials needed for biofilm formation, possibly including extracellular vesicles. PMID- 22941092 TI - Enhancement of ganoderic acid accumulation by overexpression of an N-terminally truncated 3-hydroxy-3-methylglutaryl coenzyme A reductase gene in the basidiomycete Ganoderma lucidum. AB - Ganoderic acids produced by Ganoderma lucidum, a well-known traditional Chinese medicinal mushroom, exhibit antitumor and antimetastasis activities. Genetic modification of G. lucidum is difficult but critical for the enhancement of cellular accumulation of ganoderic acids. In this study, a homologous genetic transformation system for G. lucidum was developed for the first time using mutated sdhB, encoding the iron-sulfur protein subunit of succinate dehydrogenase, as a selection marker. The truncated G. lucidum gene encoding the catalytic domain of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGR) was overexpressed by using the Agrobacterium tumefaciens-mediated transformation system. The results showed that the mutated sdhB successfully conferred carboxin resistance upon transformation. Most of the integrated transfer DNA (T-DNA) appeared as a single copy in the genome. Moreover, deregulated constitutive overexpression of the HMGR gene led to a 2-fold increase in ganoderic acid content. It also increased the accumulation of intermediates (squalene and lanosterol) and the upregulation of downstream genes such as those of farnesyl pyrophosphate synthase, squalene synthase, and lanosterol synthase. This study demonstrates that transgenic basidiomycete G. lucidum is a promising system to achieve metabolic engineering of the ganoderic acid pathway. PMID- 22941093 TI - .VO2max is not altered by self-pacing during incremental exercise. AB - We tested the hypothesis that incremental cycling to exhaustion that is paced using clamps of the rating of perceived exertion (RPE) elicits higher .VO2max values compared to a conventional ramp incremental protocol when test duration is matched. Seven males completed three incremental tests to exhaustion to measure .VO2max. The incremental protocols were of similar duration and included: a ramp test at 30 W min(-1) with constant cadence (RAMP1); a ramp test at 30 W min(-1) with cadence free to fluctuate according to subject preference (RAMP2); and a self-paced incremental test in which the power output was selected by the subject according to prescribed increments in RPE (SPT). The subjects also completed a .VO2max 'verification' test at a fixed high-intensity power output and a 3-min all-out test. No difference was found for .VO2max between the incremental protocols (RAMP1 = 4.33 +/- 0.60 L min(-1); RAMP2 = 4.31 +/- 0.62 L min(-1); SPT = 4.36 +/- 0.59 L min(-1); P > 0.05) nor between the incremental protocols and the peak.VO2max measured during the 3-min all-out test (4.33 +/- 0.68 L min(-1)) or the .VO2max measured in the verification test (4.32 +/- 0.69 L min(-1)). The integrated electromyogram, blood lactate concentration, heart rate and minute ventilation at exhaustion were not different (P > 0.05) between the incremental protocols. In conclusion, when test duration is matched, SPT does not elicit a higher .VO2max compared to conventional incremental protocols. The striking similarity of .VO2max measured across an array of exercise protocols indicates that there are physiological limits to the attainment of .VO2max that cannot be exceeded by self-pacing. PMID- 22941094 TI - Factors related to choosing an academic career track among spine fellowship applicants. AB - STUDY DESIGN: Retrospective review. OBJECTIVE: To identify factors associated with the likelihood of spine surgery fellowship applicants choosing an academic job upon fellowship completion. SUMMARY OF BACKGROUND DATA: Training academic spine surgeons is an important goal of many spine fellowships. However, there are no established criteria associated with academic job choice to guide selection committees. METHODS: Two hundred three consecutive applications of candidates who were granted an interview to a single spine surgical fellowship from 2005 to 2010 were analyzed. Factors investigated included the following: membership in honor societies; number of publications, presentations, and book chapters; age; completion of an additional degree; completion of a research fellowship; teaching experience; marital status; graduation from a top-20 school; attendance in a residency with a spine fellowship; and comments made in personal statements and letters of recommendation. The job taken upon graduation from fellowship was determined. The chi2 test or Fisher exact test was used to estimate the strength of the association between the covariates and response. Significant variables were selected for further multivariate analysis. RESULTS: The following were significantly associated in a univariable analysis with academia: 5 or more national presentations; completion of a research fellowship; attendance in a top 20 medical school; stated desire in the personal statement to become an academic surgeon; and letters of reference stating likelihood of pursuing academics on hiring the applicant. When significant variables were selected for multivariable analysis, completion of a research fellowship, graduation from a top-20 medical school, and stated desire in the personal statement to become an academic surgeon were most strongly associated with choice of academia. CONCLUSION: Although job choice is multifactorial, the present study demonstrates that there are objective factors listed on spine fellowship applications associated with a significantly higher likelihood of academic job choice. Analyzing these factors may help selection committees evaluate spine fellowship applicants consistent with the academic missions of their programs. PMID- 22941095 TI - Neuromuscular exercise and counseling decrease absenteeism due to low back pain in young conscripts: a randomized, population-based primary prevention study. AB - STUDY DESIGN: Controlled intervention with group randomization. OBJECTIVE: To investigate the effectiveness of a 6-month neuromuscular exercise and counseling program for reducing the incidence of low back pain (LBP) and disability in young conscripts, with a healthy back at the beginning of their compulsory military service. SUMMARY OF BACKGROUND DATA: Basic military training is physically demanding on the back and requires adequate physical fitness. LBP causes significant morbidity and absence from military service. METHODS: Participants were conscripts of 4 successive age cohorts (n = 1409). In the prestudy year, before adoption of the intervention, 2 successive cohorts of conscripts of 4 companies (n = 719) were followed prospectively for 6 months to study the baseline incidence of different categories of LBP. In the intervention year, conscripts (n = 690) of 2 new cohorts of the same companies (intervention group: antitank, engineer; control group: signal, mortar) were followed for 6 months. The intervention program aimed to improve conscripts' control of their lumbar neutral zone and specifically to avoid full lumbar flexion in all daily tasks. RESULTS: Total number and incidence of off-duty days due to LBP were significantly decreased in the intervention companies compared with controls (adjusted hazard ratio = 0.42, 95% confidence interval = 0.18-0.94, P = 0.035). The number of LBP cases, number of health clinic visits due to LBP, and number of the most severe cases showed a similar decreasing trend but without statistical significance. CONCLUSION: These findings provide evidence that exercise and education to improve control of the lumbar neutral zone have a prophylactic effect on LPB-related off-duty service days in the military environment when implemented as part of military service among young healthy men. PMID- 22941096 TI - The problem with diagnostic selective nerve root blocks. PMID- 22941097 TI - Obesity is associated with inferior results after surgery for lumbar spinal stenosis: a study of 2633 patients from the Swedish spine register. AB - STUDY DESIGN: A cohort study based on the Swedish Spine Register. OBJECTIVE: To determine the association between body mass index (BMI) and outcome of lumbar spine surgery for spinal stenosis. SUMMARY OF BACKGROUND DATA: Several small studies have sought to evaluate the importance of obesity in relation to results after surgery for lumbar spinal stenosis (LSS), but the findings are inconsistent and relatively weak. METHODS: All patients who underwent surgery for LSS from January 1, 2006, to June 30, 2008, with a completed 2-year follow-up in the Swedish Spine Register were included. Logistic regression was used to assess the association between BMI and different outcomes. RESULTS: Of the 2633 patients enrolled, 819 (31%) had normal weight, 1208 (46%) were overweight, and 606 (23%) were obese. On average, all 3 BMI groups achieved significant improvements after surgery. A higher BMI, however, was associated with greater odds of dissatisfaction after surgery and inferior results at the 2-year follow-up. After adjusting for differences in baseline characteristics, the obese group demonstrated inferior function and quality of life as measured by the Oswestry Disability Index (ODI) and the EuroQol Group Index (EQ-5D), respectively. At the 2-year follow-up, obese patients had a mean ODI of 33 (95% confidence interval [CI], 31-34) and mean EQ-5D of 0.56 (95% CI, 0.54-0.59) compared with a mean ODI of 25 (95% CI, 24-26) and mean EQ-5D of 0.64 (95% CI, 0.62-0.66) in the normal weight group. When compared with the normal weight patients, the adjusted odds ratio for dissatisfaction was 1.73 in the obese group (95% CI, 1.36-2.19). Differences between the normal weight and overweight groups were modest and therefore could not be considered clinically relevant. CONCLUSION: Obese patients achieved significant pain reduction, better walking ability, and improved quality of life after surgical treatment of LSS. Nevertheless, obesity was associated with a higher degree of dissatisfaction and poorer outcomes after surgery for LSS. PMID- 22941098 TI - Clinical outcome and prevalence of osteoarthritis after isolated anterior cruciate ligament reconstruction using hamstring graft: follow-up after two and ten years. AB - PURPOSE: The aim of this study was to evaluate patient-reported clinical outcome, instrumental stability and prevalence of radiological osteoarthritis (OA) based on a homogeneous patient sample after two years and on average ten years after isolated anterior cruciate ligament (ACL) reconstruction. METHODS: Primarily we performed ACL reconstruction using a four-strand semitendinosus tendon (ST) autograft in 112 patients. Two years after reconstruction 98 patients could be re evaluated. Long-term clinical and functional follow-up assessment was then performed on 52 patients on average 10.2 years after operative treatment. Inclusion criteria consisted of an isolated ACL rupture, reconstruction with ST graft and no associated cartilage alterations and meniscal lesions. Clinical and functional follow-up assessment included the International Knee Documentation Committee (IKDC) score and the scores of Tegner and Lysholm. Instrumental stability testing was carried out with the KT1000TM arthrometer. The degree of degenerative changes and prevalence of OA was based on the Jager-Wirth score. RESULTS: The mean long-term follow-up was 10.2 years (eight-13 years), and the mean age was 40.4 years (24-62 years). About 72 % of patients were graded A or B according to the IKDC score. Activity levels according to the scores of Tegner and Lysholm were 4.8 and 88.2 on long-term follow-up. Radiological assessment revealed degenerative changes in the sense of a grade I OA in 21.2 % of patients. Prevalence of a grade II OA was found in 53.8 % of patients. A grade III OA and a grade IV OA were found in 19.2 and 5.7 %. Correlation analysis showed significant relationships between the long-term stability and prevalence of OA (p<0.05). CONCLUSIONS: Arthroscopic ACL reconstruction using four-strand ST autograft resulted in high patient satisfaction and good clinical results at two years and long-term follow-up. The prevalence of higher degree OA that developed in about 25 % of patients is significantly correlated with long-term knee joint stability. PMID- 22941099 TI - New marker of FAME profile of Pseudomonas aurantiaca total lipids. PMID- 22941100 TI - Identification of methionine gamma-lyase in genomes of some pathogenic bacteria. PMID- 22941101 TI - Differences in fatty acid composition of food and tissues of grayling from the Yenisei River. PMID- 22941102 TI - Cationic gemini surfactants as new agents for plasmid DNA delivery into cells. PMID- 22941103 TI - Regulatory properties of cytosolic and membrane-bound adenylyl cyclases in the fraction of spermatozoa with different mobility. PMID- 22941104 TI - Molecular analysis of the intestinal microbiome composition of mammoth and woolly rhinoceros. PMID- 22941105 TI - The influence of chromophore-protein interactions on spectroscopic properties of the yellow fluorescent protein. PMID- 22941106 TI - Self-assembly of magnetic and fluorescent colloidal constructs based on protein protein interactions. PMID- 22941107 TI - Calcium entry induces mitochondrial oxidant stress in vagal neurons at risk in Parkinson's disease. AB - Mitochondrial oxidant stress is widely viewed as being critical to pathogenesis in Parkinson's disease. But the origins of this stress are poorly defined. One possibility is that it arises from the metabolic demands associated with regenerative activity. To test this hypothesis, we characterized neurons in the dorsal motor nucleus of the vagus (DMV), a population of cholinergic neurons that show signs of pathology in the early stages of Parkinson's disease, in mouse brain slices. DMV neurons were slow, autonomous pacemakers with broad spikes, leading to calcium entry that was weakly buffered. Using a transgenic mouse expressing a redox-sensitive optical probe targeted to the mitochondrial matrix, we found that calcium entry during pacemaking created a basal mitochondrial oxidant stress. Knocking out DJ-1 (also known as PARK7), a gene associated with early-onset Parkinson's disease, exacerbated this stress. These results point to a common mechanism underlying mitochondrial oxidant stress in Parkinson's disease and a therapeutic strategy to ameliorate it. PMID- 22941108 TI - Chronic alcohol remodels prefrontal neurons and disrupts NMDAR-mediated fear extinction encoding. AB - Alcoholism is frequently co-morbid with post-traumatic stress disorder, but it is unclear how alcohol affects the neural circuits mediating recovery from trauma. We found that chronic intermittent ethanol (CIE) impaired fear extinction and remodeled the dendritic arbor of medial prefrontal cortical (mPFC) neurons in mice. CIE impaired extinction encoding by infralimbic mPFC neurons in vivo and functionally downregulated burst-mediating NMDA GluN1 receptors. These findings suggest that alcohol may increase risk for trauma-related anxiety disorders by disrupting mPFC-mediated extinction of fear. PMID- 22941109 TI - Saccadic eye movements evoked by optogenetic activation of primate V1. AB - Optogenetics has advanced our understanding of the neural basis of simple behaviors in rodents and small animals. In primates, however, for which more sophisticated behavioral assays exist, optogenetic manipulations of behavior have been unsuccessful. We found that monkeys reliably shifted their gaze toward the receptive field of optically driven channelrhodopsin-2-expressing neurons of the primary visual cortex. This result establishes optogenetics as a viable tool for the causal analysis of behavior in primate brain. PMID- 22941110 TI - Rho-kinase regulates energy balance by targeting hypothalamic leptin receptor signaling. AB - Leptin regulates energy balance. However, knowledge of the critical intracellular transducers of leptin signaling remains incomplete. We found that Rho-kinase 1 (ROCK1) regulates leptin action on body weight homeostasis by activating JAK2, an initial trigger of leptin receptor signaling. Leptin promoted the physical interaction of JAK2 and ROCK1, thereby increasing phosphorylation of JAK2 and downstream activation of Stat3 and FOXO1. Mice lacking ROCK1 in either pro opiomelanocortin (POMC) or agouti-related protein neurons, mediators of leptin action, displayed obesity and impaired leptin sensitivity. In addition, deletion of ROCK1 in the arcuate nucleus markedly enhanced food intake, resulting in severe obesity. Notably, ROCK1 was a specific mediator of leptin, but not insulin, regulation of POMC neuronal activity. Our data identify ROCK1 as a key regulator of leptin action on energy homeostasis. PMID- 22941111 TI - Biasing the content of hippocampal replay during sleep. AB - The hippocampus is essential for encoding self-experienced events into memory. During sleep, neural activity in the hippocampus related to a recent experience has been observed to spontaneously reoccur, and this 'replay' has been postulated to be important for memory consolidation. Task-related cues can enhance memory consolidation when presented during a post-training sleep session, and, if memories are consolidated by hippocampal replay, a specific enhancement for this replay should be observed. To test this, we trained rats on an auditory-spatial association task while recording from neuronal ensembles in the hippocampus. We found that, during sleep, a task-related auditory cue biased reactivation events toward replaying the spatial memory associated with that cue. These results indicate that sleep replay can be manipulated by external stimulation and provide further evidence for the role of hippocampal replay in memory consolidation. PMID- 22941112 TI - Effect of smoke-free legislation on Ticino gastronomy revenue. AB - OBJECTIVE: To provide evidence on the effects of smoke-free laws on gastronomy revenue in a European setting based on objective data. Damage to gastronomy revenue is a widely used argument against smoke-free legislation. METHOD: Gastronomy revenue in Ticino is compared with the rest of Switzerland before and after Ticino banned smoking from gastronomy in April 2007, being the first (and at the time of the study only) Swiss canton to do that. The study uses breakdowns by cantons of taxable revenue of gastronomy branches and retailers (for comparison) provided by the Swiss tax authorities for the years 2005-2008. RESULTS: Revenues of restaurants and bars were not damaged by the Ticino smoke free law. Decreases in Ticino happened before the smoke-free law came into effect. Evidence for night clubs is inconclusive. DISCUSSION: The absence of detrimental effects on restaurant and bar revenue corroborates the gist of research on the subject from other countries. The argument that the decline of bar and restaurant sales prior to the implementation of the ban might have occurred in anticipation of the new regulation is not considered tenable. PMID- 22941113 TI - Is there a disadvantage to radical lymph node dissection in colon cancer? AB - BACKGROUND: The necessity for radical lymph node dissection for solid tumours was discussed in the past controversially. The aim of this study was to correlate the oncologic results of radical surgery for colon cancer with potential complications. METHODS: A total of 1,453 patients with R0-resected colon cancer operated on between 1978 and 2004 were analysed in a prospective database. The follow-up was at least 5 years. Rates of survival, locoregional and distant recurrences and complications were calculated. RESULTS: To compare the oncological outcome, the time frame was divided into five periods. In the last cohort (2000-2004), we observed in stage I-III tumours a 5-year cancer-related survival rate of 90.1 %, compared to 82.1 % in the first cohort (1978-1984) (p = 0.061). The local recurrence rate could be reduced from 6.5 to 3.2 % in the same cohorts (p = 0.059). It reached the level of significance in the multivariate analysis. The rates of distant metastases did not change. For patients with stage III, the 5-year cancer survival rates increased from 62.0 to 81.8 % (p = 0.005). Morbidity and mortality were comparable to other studies even to those with limited lymph node dissections. CONCLUSION: Radical lymph node dissection in colon cancer is not associated with obvious disadvantages to the patient. Specific considerable side effects were not observed when the preparation is performed in embryonic planes preserving the autonomous nerves. The complication rates were not increased compared to other studies, even to those with limited lymphatic dissection. In addition, radical lymph node dissection in colon cancer may improve survival. PMID- 22941114 TI - Transperineal ultrasound compared to evacuation proctography for diagnosing enteroceles and intussusceptions. AB - INTRODUCTION: This study concerns the level of agreement between transperineal ultrasound and evacuation proctography for diagnosing enteroceles and intussusceptions. METHOD: In a prospective observational study, 50 consecutive women who were planned to have an evacuation proctography underwent transperineal ultrasound too. Sensitivity, specificity, positive (PPV) and negative predictive value, as well as the positive and negative likelihood ratio of transperineal ultrasound were assessed in comparison to evacuation proctography. To determine the interobserver agreement of transperineal ultrasound, the quadratic weighted kappa was calculated. Furthermore, receiver operating characteristic curves were generated to show the diagnostic capability of transperineal ultrasound. RESULTS: For diagnosing intussusceptions (PPV 1.00), a positive finding on transperineal ultrasound was predictive of an abnormal evacuation proctography. Sensitivity of transperineal ultrasound was poor for intussusceptions (0.25). For diagnosing enteroceles, the positive likelihood ratio was 2.10 and the negative likelihood ratio, 0.85. There are many false-positive findings of enteroceles on ultrasonography (PPV 0.29). The interobserver agreement of the two ultrasonographers assessed as the quadratic weighted kappa of diagnosing enteroceles was 0.44 and that of diagnosing intussusceptions was 0.23. CONCLUSION: An intussusception on ultrasound is predictive of an abnormal evacuation proctography. For diagnosing enteroceles, the diagnostic quality of transperineal ultrasound was limited compared to evacuation proctography. PMID- 22941115 TI - Fast-track colorectal surgery: protocol adherence influences postoperative outcomes. AB - PURPOSE: This single-center prospective cohort study, conducted outside of a clinical trial, tried to identify the importance of each fast-track surgery procedure and protocol adherence level on clinical outcomes after colorectal surgery. METHODS: From a prospectively maintained database, 606 patients who underwent elective laparoscopic or open colorectal resection within a well established fast-track surgery (FT) protocol, between 2005 and 2011, were identified. Univariate and multivariate analysis were performed to assess the relationship between each FT procedure with an adherence rate <100 % and the outcome variables (length of stay-LOS, 30-day morbidity and readmission rate). Patients were divided into four adherence level groups to FT procedures-100 %, 85 95 %,70-80 %, and <65 %. Each adherence group was compared with the other groups to evaluate differences in clinical outcome variables. RESULTS: Group comparisons revealed that higher levels of FT protocol adherence corresponded to significantly improved LOS and morbidity rates. Readmission rates were only significantly different between the full fast-track pathway and the less implemented groups. Multivariate analyses revealed that the fast removal of bladder catheter positively influenced length of stay (p < 0.0001) and 30-day morbidity (p < 0.0001). Laparoscopy surgery, no drain positioning and enforced mobilization improved LOS (p = 0.027, p < 0.0001, p = 0.002, respectively). Early solid feeding improved LOS (p < 0.0001), morbidity (p < 0.0001) and readmission rate (p = 0.011). CONCLUSION: Postoperative outcomes after colorectal surgery are directly proportional to FT protocol adherence. The early removal of the bladder catheter and early postoperative solid feeding independently influenced the length of hospital stay and 30-day morbidity rates. PMID- 22941116 TI - Somatic symptoms in cancer patients trajectory over 12 months and impact on functional status and disability. AB - PURPOSE: Cross-sectional studies have established the prevalence and functional impairment of somatic symptoms in cancer patients. The purpose of this study was to determine the trajectory and adverse consequences of such symptoms over time. METHODS: Secondary analysis of longitudinal data from 405 cancer patients enrolled in a telecare management trial for pain and/or depression. Somatic symptom burden was measured with a 22-item scale at baseline, 1, 3, 6, and 12 months. Outcomes included the SF-12 Physical Component Summary (PCS) and Mental Component Summary (MCS) scores, the Sheehan Disability Scale (SDS) score, and self-reported total disability days. Mixed methods repeated measures analyses were conducted to determine whether antecedent change in somatic symptom burden predicted functional status and disability. RESULTS: Symptoms were highly prevalent at baseline, with 15 of the 22 symptoms endorsed by more than half of the patients. A rather constant cross-sectional prevalence over 12 months at the group level belied a quite different trajectory at the patient level where the median persistence, resolution, and incidence rates for 14 of the most common symptoms were 39%, 37%, and 24%, respectively. A clinically significant (i.e., five points) reduction in somatic symptom burden predicted improvement in PCS, MCS, and SDS (all P < 0.001), as well as a lower likelihood of >=14 disability days in the past 4 weeks (odds ratio, 0.84; 95% CI, 0.74 to 0.95). CONCLUSIONS: Somatic symptoms remain burdensome in cancer patients over 12 months and symptom improvement predicts significantly better functional status and less disability. PMID- 22941117 TI - The fall rate of older community-dwelling cancer patients. AB - PURPOSE: Little is known about the incidence of falls in cancer patients receiving cancer treatment. The aims were to explore the number of falls older adults report in the 6 months after cancer diagnosis, and if those with a fall were more frail than those who did not fall. METHODS: Secondary data analysis of a prospective pilot study that recruited patients aged 65 and older with a new cancer diagnosis. At each interview (baseline, 3- and 6-month follow-up), participants were asked if they had a fall in the previous 3 months. The frailty markers and functional status were obtained at baseline, 3- and 6-month follow up. Chi-square and t tests were used to compare those who had a fall to those who had no fall. Univariate logistic regression analysis was conducted to explore the association between sociodemographic and health characteristics and reporting a fall. RESULTS: Seventeen participants (18.7%) reported one or more falls in the first 6 months after cancer diagnosis. Fifteen participants reported one or more falls in the 3 months prior to the cancer diagnosis. Those who had a fall and those with no fall were not different in terms of health and functioning. None of the sociodemographic and health characteristics including the frailty markers were associated with a fall. CONCLUSION: A fall is common in cancer patients. More research is needed to examine the risk factors for a fall in older adults receiving cancer treatment. PMID- 22941118 TI - Comparison of the effects of aromatase inhibitors and tamoxifen on radiation induced lung toxicity: results of an experimental study. AB - PURPOSE: The purpose of this study is to compare the effects of anastrozole, letrozole and tamoxifen on radiation-induced pulmonary fibrosis. METHODS: Eighty female Wistar albino rats were divided into eight groups. Group (G) 1 was defined as control group. G2 was radiation therapy (RT) only group. Groups 3, 4 and 5 were tamoxifen, anastrozole and letrozole control groups respectively. Groups 6, 7 and 8 were RT plus tamoxifen, anastrozole and letrozole groups, respectively. A single dose of 12 Gy RT was given to both lungs. Tamoxifen, anastrozole and letrozole were started 1 week before the RT and continued until the animals were sacrificed 16 weeks after the RT. As an end point, the extent of pulmonary fibrosis for each rat was quantified with image analysis of histological sections of the lung. Kruskal-Wallis and Mann-Whitney U tests were used for statistical analyses. RESULTS: The congestion, inflammation and pulmonary fibrosis scores were significantly different between all the study groups (p values were <0.001 for each). When compared with RT only group, concomitant RT and tamoxifen group increased the radiation-induced pulmonary fibrosis (p = 0.005). However, using either anastrozole or letrozole with RT did not increase the radiation-induced pulmonary fibrosis (p values were 0.768 and 0.752, respectively). CONCLUSION: Concomitant use of tamoxifen with RT seems to increase radiation-induced pulmonary toxicity. However, the use of both anastrozole and letrozole appears to be safe with concomitant RT, without increasing the risk of pulmonary fibrosis. This finding should be clarified with further clinical studies. PMID- 22941120 TI - Amino-carboxylic recognition on surfaces: from 2D to 2D + 1 nano-architectures. AB - The control of the electronic properties of the interfaces between small organic molecules and the substrate is key for the development of efficient and reliable organic-based devices. A promising and widely covered route is to interpose a Self-Assembled Monolayer (SAM) to bridge the molecular film and the electrode. The morphology and the electronic level alignment of the triple substrate-SAM organic layered system can be tuned by properly selecting the SAM composition. We have recently proposed a novel approach to the problem where, under ultra-high vacuum conditions, a molecular film is anchored to the SAM by exploiting the recognition between molecules functionalized, respectively, with -NH(2) and -COOH end-groups. Here we briefly review the role of the amino-carboxylic interaction in the formation of ordered organic 2-dimensional architectures on solid surfaces. We then describe the anchoring process of carboxylic molecules on amine based SAMs we have recently reported on. New results are presented showing how multiple anchoring sites per molecule may be exploited for tailoring the molecular orientation as well as the density of the anchored molecules. PMID- 22941119 TI - Th1/Th2/Th17/Treg expression in cultured PBMCs with antiphospholipid antibodies. AB - The aim of this study was to evaluate the expression of T-helper cell subtypes Th1, Th2, Th17 and Treg in antiphospholipid syndrome (APS), and whether they are related to anti-cardiolipin antibody (aPL) titers. Peripheral mononuclear cells (PBMCs) were isolated from healthy donors, and incubated with aPLs. Subsequent to a 48-h incubation, PBMCs were collected and detected by flow cytometry. The results revealed that aPLs at higher concentrations may induce a significant increase in Th2 and Th17 frequencies, as opposed to a significant decrease in Th1 and Treg frequencies and the Th1/Th2 ratio. These results indicate that there is a Th1/Th2 imbalance, a Th17 upregulation and a Treg downregulation present in APS, and that these factors are positively correlated with aPL titers, suggesting a potential role of Th cells in the pathogenesis of APS. PMID- 22941121 TI - Towards excellence in revascularization for left main coronary artery disease. AB - PURPOSE OF REVIEW: The aim of this article is to review the current revascularization strategies in patients presenting with unprotected left main coronary artery disease (LMCAD). RECENT FINDINGS: Coronary artery bypass grafting (CABG) is the current standard of treatment for patients with LMCAD. The development and refinement of techniques increased the number of percutaneous coronary interventions (PCI) in LMCAD patients. SUMMARY: Although several observational studies show comparable results of CABG and/or PCI in patients with LMCAD, there is currently no convincing randomized evidence that either one of the two is associated with better long-term survival. Recent meta-analyses of four small randomized trials revealed a similar rate of 1-year major adverse cardiovascular and cerebrovascular events, higher rates of target vessel revascularization and lower stroke rates for PCI. Pooling randomized patients studies stratified by lesion complexity strengthened the hypothesis that CABG is better in more complex LMCAD patients. However, the randomized comparisons are affected by methodological limitations and lack power to be conclusive. The ongoing Evaluation of XIENCE V Everolimus Eluting Stent System Versus Coronary Artery Bypass Surgery for Effectiveness of Left Main Revascularization (EXCEL) trial is expected to provide a better answer on the optimal treatment strategy for LMCAD patients. In the meantime, risk models need to be improved and the most appropriate revascularization strategy for the individual LMCAD patient should be chosen using a multidisciplinary heart team that considers not only risk models but also other clinical and economic facets. PMID- 22941122 TI - Myocardial infarction without obstructive coronary artery disease. AB - PURPOSE OF REVIEW: A substantial minority of myocardial infarction (MI) patients have no obstructive coronary artery disease (CAD) at angiography. Women more commonly have this type of MI, but both sexes are affected. This is not an innocuous problem. Multiple studies have shown 2% death or reinfarction in short term to mid-term follow-up. RECENT FINDINGS: Two large autopsy series confirmed MI without obstructive CAD as a cause of death. Intravascular ultrasound (IVUS) and cardiac MRI (CMR) were studied in patients with MI without obstructive CAD. Plaque rupture was found in nearly 40% and late gadolinium enhancement was seen in nearly 40%, with little overlap in imaging findings. Additional CMR studies in similar patients have shown variable frequencies and patterns of late enhancement, but consistently demonstrate an ability to identify nonischemic causes (myocarditis, infiltrative disease). Ischemic myocardial injury on CMR may be due to plaque rupture but also occurs in patients without plaque rupture. These cases may be caused by vasospasm, embolism, dissection, or branch occlusion. SUMMARY: MI without obstructive CAD is a heterogeneous disorder with different mechanisms in different patients. Plaque rupture is common. In the absence of clear demonstration of a nonischemic cause, treatment should include guideline-recommended secondary prevention, including antiplatelet and antiatherosclerotic medications. PMID- 22941123 TI - Carotid artery stenting: a clinical update. AB - PURPOSE OF REVIEW: Carotid endarterectomy (CEA) has been shown to prevent stroke in patients with severe carotid stenosis. Carotid artery stenting (CAS) has emerged as a less invasive alternative technique. Data regarding comparative effectiveness of CAS and CEA are now available and merit review. RECENT FINDINGS: Four large randomized controlled trials (RCTs) comparing CAS and CEA have shown a higher rate of stroke in symptomatic patients. The largest and most recent trial reported a lower occurrence of myocardial infarction (MI) following CAS and showed overall comparability of CAS to CEA for both symptomatic and asymptomatic patients. Despite methodological differences, these RCTs are consistent in finding an interaction of patient age with outcomes. In younger patients, CAS appears equivalent or superior to CEA if considering the sum of death, stroke, and MI. In elderly patients, CEA appears to have a lower complication rate. For asymptomatic patients, reduction in event rates with current medical therapy may render previous trial results invalid. SUMMARY: CAS is an alternative to CEA in patients requiring carotid intervention. Comparison of both CAS and CEA with contemporary medical management will also be required before recommendations can be made regarding the optimal treatment of patients with asymptomatic carotid stenoses. PMID- 22941124 TI - Use of biomarkers to guide outpatient therapy of heart failure. AB - PURPOSE OF REVIEW: Among patients with heart failure, concentrations of natriuretic peptides are strongly linked to the presence and severity of structural heart disease and are strongly prognostic in this setting. Additionally, favorable reduction in the concentration of either B-type natriuretic peptide (BNP) or B-type natriuretic peptide and its amino-terminal cleavage fragment (NT-proBNP) may be seen during treatment of heart failure, with parallel improvement in prognosis. This has led to the hypothesis that intensified treatment directed at reducing natriuretic peptide concentrations may improve outcomes in heart failure. RECENT FINDINGS: In chronic heart failure, studies suggest that a strategy of standard-of-care management together with a goal to suppress BNP or NT-proBNP concentrations leads to greater application of guideline-derived medical therapy and is well tolerated. In certain studies of this BNP or NT-proBNP 'guided' approach, patients treated with biomarker-guided care had superior outcomes when compared with standard heart failure management alone, particularly in younger study populations, in patients with left ventricular systolic dysfunction, and particularly when substantial reductions in natriuretic peptides were achieved in association with biomarker-guided care. SUMMARY: Natriuretic peptide 'guided' management appears promising in patients suffering from chronic heart failure. Large-scale pivotal trials to confirm the approach are planned. PMID- 22941125 TI - TB Control in Singapore: the high price of diagnostic delay. AB - Singapore has experienced a rise in the tuberculosis (TB) incidence rate among her local population since 2008, which we believe, is contributed in no small part to a recent increase in community transmission due to delayed diagnosis of infectious pulmonary TB cases. Data from the TB notification registry showed an increase from 2004 to 2008 in the number and proportion of sputum acid-fast bacilli smear-positive pulmonary TB cases with prolonged cough. Two surveys at the TB Control Unit showed that healthcare system delays exceeded patient delay in seeking medical consultation. There is thus an urgent need to heighten TB awareness among the public and the medical community in order to reduce the time taken to diagnose infectious TB cases in Singapore. PMID- 22941126 TI - The unwelcome visitor. AB - Gout is a chronic, progressive inflammatory disease with intermittent arthritic flares, which should not be regarded as a minor inconvenience or nuisance. It can be effectively controlled when the patient's serum urate level is reduced to less than 360 MUmol/l (6 mg/dL) by consistent use of urate-lowering pharmacotherapy. Colchicine prophylaxis for gouty flares during titration of urate-lowering therapy has been underused. Holistic long-term management of gout must encompass patient education, evidence-based dietary advice, screening and aggressive treatment of comorbidities such as hypertension, diabetes mellitus, dyslipidaemia and renal impairment. Acute therapies for recurrent attacks with non-steroidal anti-inflammatory drugs, colchicine and/or corticosteroids should be used judiciously, especially in the elderly, due to the risk of toxicities. With appreciation of the underlying pathogenesis and artful use of the limited drug options, control of gout can be effectively achieved, bringing tremendous satisfaction to the patient and doctor. PMID- 22941127 TI - Incidence of non-tunnelled central venous catheter-related infections in oncologic patients receiving chemotherapy in an outpatient setting. AB - INTRODUCTION: Central venous catheters (CVCs) are becoming more popular for delivery of outpatient courses of intravenous therapy such as chemotherapy and long-term antibiotics. The incidence of non-tunnelled type CVC-related infections in patients with solid tumours receiving chemotherapy in an ambulatory setting has not been well studied. We aimed to determine the baseline data on CVC-related infections in this retrospective study conducted from January 2005 to December 2007. METHODS: Data on cancer patients with CVCs inserted as outpatients at National Cancer Centre Singapore over a three-year period were collected and analysed retrospectively. Data retrieved from medical records included patients' demographics, the number of catheter days, cancer type and other medical illnesses. Definitions from the Centre for Disease Control and Prevention for CVC related infections were used. For data analysis, graphical and quantitative techniques were employed. RESULTS: A total of 88 CVCs were inserted during the study period, with a total of 11,541 catheter days (median 114; range 2-510 days). Infection rate was 0.87 per 1,000 catheter days. The risk of infection was higher when catheters were left in situ for longer periods of time and in patients with solid tumours. CONCLUSION: The infection rate for non-tunnelled type CVCs is low in our centre. Hence, its use for chemotherapy on an outpatient basis is relatively safe and convenient in oncologic patients. PMID- 22941128 TI - Prevalence of cardiovascular risk factors among healthcare staff in a large healthcare institution in Singapore. AB - INTRODUCTION: This study aimed to determine the prevalence of modifiable cardiovascular risk factors among health workers (HWs) and non-health workers (NHWs) in a large hospital in Singapore. METHODS: A cross-sectional prevalence survey of 3,384 hospital staff was conducted. The study comprised a self administered questionnaire, body mass index, systolic and diastolic blood pressure measurements, and laboratory analysis of fasting blood samples of total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglycerides and plasma glucose. HWs were doctors and nurses, while NHWs were health administrators, facility staff, clerks and administrative personnel. RESULTS: A total of 3,384 out of 3,987 eligible staff (response rate 84.9%) participated in the survey. The majority of the participants were female (81%, n = 2,755), and 64% (n = 2,179) were 20-39 years old. HWs comprised almost two-thirds of the staff employed (61.3%, n = 2076), of whom 87.7% were female, while 72.5% of NHWs were female. Compared to HWs, NHWs had a higher adjusted (age, ethnic group and gender) prevalence of personal history of diabetes mellitus (adjusted prevalence rate ratio [PRR] 1.64, 95% confidence interval [CI] 1.02-2.64), cigarette smoking (adjusted PRR 1.85, 95% CI 1.48-2.32), obesity (adjusted PRR 1.36, 95% CI 1.05-1.75) and elevated systolic pressure (adjusted PRR 1.74, 95% CI 1.31-2.31). CONCLUSION: The prevalence of modifiable cardiovascular risk factors in NHWs is higher than that in HWs. Health promotion programmes should address this captive and neglected audience in healthcare organisations. PMID- 22941129 TI - General practitioners' knowledge of hand surgery in Singapore: a survey study. AB - INTRODUCTION: Hand surgery is a subspecialty with a dedicated training programme in Singapore. Currently, Singapore is one of two countries in the world that still provides dedicated advanced hand specialty training. As hand surgeons depend on referrals from institutions and general practitioners, appropriate hand surgical referral requires the referring physician to have knowledge and understanding of common hand conditions as well as less common but more urgent surgical conditions, and their available surgical treatments. This study aimed to determine the knowledge of hand surgery and hand surgical conditions among general practitioners. METHODS: A questionnaire survey was conducted during a continuing medical education symposium on hand surgery in Singapore. Participants responded to 12 questions on hand trauma by keying the answers into a computer database system. The results were then analysed. RESULTS: A total of 35 general practitioners responded to our survey, and they were able to answer 53% of the questions correctly. We found knowledge gaps among the participants regarding hand surgical conditions, and identified areas where increased education during medical school, postgraduate training and continuing medical education may be beneficial. Areas that were found to be weak included recognising injuries that pose a high risk for developing wound infection, complications of topical steroid injection in trigger finger treatment and hand tumours. CONCLUSION: Improving hand surgery knowledge among general practitioners not only leads to improved primary care, but it can also facilitate prompt recognition of surgical problems and subsequent referral to appropriate hand surgeons for treatment. This may possibly reduce the load of tertiary institutions in treating non-urgent hand conditions. PMID- 22941130 TI - Impact of pharmacists' intervention on identification and management of drug-drug interactions in an intensive care setting. AB - INTRODUCTION: The primary and secondary objectives of this study were to identify and assess the risks associated with the occurrence of drug-drug interactions (DDIs) and to determine the value of pharmacists' interventions in the management of clinically significant DDIs, respectively. METHODS: A prospective, case control study was carried out on patients admitted to the intensive care unit (ICU), and involved a review of patients' medication chart daily by the pharmacist and the clinical parameters. All identified DDIs were carefully analysed in order to provide recommendations on the management of clinically significant DDIs. RESULTS: The majority of DDIs were categorised as Type-C severity level (n = 305, 75.9%). 'Substitution' was recommended in 34 cases of clinically significant DDIs, 'dosage adjustment' in 17 (4.2%) and 'stop or avoid' in 13 (3.2%). The number of drugs prescribed (p = 0.001, rS = 0.539) and length of ICU stay (p = 0.001, rS = 0.364) were significantly associated and positively correlated with the occurrence of DDIs. Patients with DDIs had a longer length of ICU stay than those without DDIs (9.5 days vs. 2.4 days, p = 0.001). No significant difference was found between patients aged below 50 years and those above 50 years (odds ratio 0.488, 95% confidence interval 0.166-1.434) in terms of the risk of DDIs. CONCLUSION: A large number of DDIs were identified in this study, but only a small number were clinically significant. Pharmacists' participation in daily ward rounds could play an important role in the detection and management of clinically significant DDIs. PMID- 22941131 TI - Treatment failure with disease-modifying antirheumatic drugs in rheumatoid arthritis patients. AB - INTRODUCTION: Rheumatoid arthritis (RA) patients taking disease-modifying antirheumatic drugs (DMARDs) may experience treatment failure due to adverse effects or a lack of efficacy/resistance. The purpose of this study was to evaluate the prescription patterns, the incidence and reasons for failure, and the time to treatment failure of DMARDs in RA patients. METHODS: The medical records of patients visiting the Rheumatology Clinic were scrutinised retrospectively in order to extract the relevant data, including demographics, clinical and laboratory investigations and drug usage, for analysis. RESULTS: More than 60% of the 474 eligible patients were started on a combination of DMARDs. Hydroxychloroquine (HCQ) (79.7%) and methotrexate (MTX) (55.6%) were the most common DMARDs prescribed initially. There was a significant difference in survival times among the various treatment groups (p <= 0.001). Adverse effect was the main reason for treatment failure of sulfasalazine (SSZ) (88.9%) and MTX (75%), while addition or substitution DMARDs was more common for those taking HCQ (72.2%). Adverse event was reported as the most significant predictor of treatment failure. The most commonly reported adverse effects were bone marrow suppression and hepatotoxicity. CONCLUSION: A combination of DMARDs was used to initiate therapy in more than 60% of RA patients, with HCQ and MTX being prescribed most frequently. Adverse effects accounted mainly for treatment failures with MTX and SSZ, while lack of efficacy was responsible for major treatment failures with HCQ. PMID- 22941132 TI - Factors affecting mortality in Fournier's gangrene: experience with fifty-two patients. AB - INTRODUCTION: Fournier's gangrene (FG) is a life-threatening infection of the perineal and genital areas. We examined the comorbid diseases, treatments and factors affecting mortality in FG. METHODS: This retrospective clinical study involved 52 patients who were treated for FG. The demographics, aetiologies, comorbid diseases, laboratory and bacteriology findings, treatment methods and length of hospital stay were compared between patients who died and those who survived the infection. RESULTS: Out of the 52 patients, 12 died and 40 survived. Patients who died and those who survived were similar in terms of their mean age at first presentation (62 vs. 55 years), the mean number of debridements (3.6 vs. 2.9), the mean length of hospital stay (25 vs. 34 days) and gender (p > 0.05 for each). However, the mean leukocyte count was higher in patients who died than in surviving patients (33.6 +/- 7.2 vs. 14.3 +/- 4.9 cells/mml; p < 0.05). The most common aetiology in both groups was perianal abscess. Deviating colostomy was performed in 13 patients. Of the patients who died, nine had haemodialysis dependent chronic renal failure and type II diabetes mellitus (DM), while one had type II DM and hypertension. CONCLUSION: Haemodialysis-dependent chronic renal failure and a high leukocyte count at first presentation were found to be the factors affecting mortality in FG patients. PMID- 22941133 TI - Comparison of vision disorders between children in mainstream and special education classes in government primary schools in Malaysia. AB - INTRODUCTION: The visual status of children with learning disabilities has not been extensively studied. This study aimed to compare vision disorders between children in mainstream classes and those with learning disabilities attending special education classes in government primary schools in Malaysia. METHODS: In this cross-sectional comparative study, 60 school children (30 from mainstream classes and 30 from special education classes) who were matched in age (6-12 years old) and ethnicity (Malay, Chinese and Indian) were examined. The subjects were recruited using non-probability convenience sampling. A complete eye examination was performed to detect three major vision disorders, namely refractive error, lag of accommodation and convergence insufficiency. RESULTS: The overall prevalence of refractive error, lag of accommodation and convergence insufficiency was found to be 65.0%, 43.3% and 35.2%, respectively. Convergence insufficiency (chi2 = 24.073, p < 0.001) was found to be associated with children in special education classes. No association was found between refractive error and lag of accommodation (p > 0.05) with the type of classes. CONCLUSION: Children in special education classes are more likely to have convergence insufficiency compared to children in mainstream classes. Thus, vision screening programmes for children in special education classes may need to be modified. PMID- 22941134 TI - Waist circumference and BMI cut-off points to predict risk factors for metabolic syndrome among outpatients in a district hospital. AB - INTRODUCTION: Metabolic syndrome (MS) is a cluster of risk factors that increases the risk of cardiovascular disease and type 2 diabetes mellitus (DM). Waist circumference (WC), a surrogate indicator of abdominal fat mass, is used to measure central obesity associated with increased risk of hypertension, insulin resistance and type 2 DM, whereas body mass index (BMI) is traditionally used to measure somatic obesity. This study aimed to identify the WC and BMI cut-off points to predict the metabolic risk factors for MS and to determine which is a better predictor. METHODS: This was a cross-sectional study conducted over a period of six months. The study involved 355 subjects aged 13-91 years. Youden's index was used to identify the optimal cut-off points. RESULTS: The optimal cut off point of WC to predict individual metabolic risk in females was 84.5-91.0 cm. The BMI cut-off point to predict hypertension and raised fasting blood sugar was 23.7 kg/m2, and that for low level high-density lipoprotein cholesterol was 22.9 kg/m2. For males, the corresponding cut-off points were 86.5-91.0 cm for WC and 20.75-25.5 kg/m2 for BMI, with corresponding sensitivities and specificities. Area under the curve and the odds of developing individual and >= 2 metabolic risk factors for MS were higher for WC than for BMI. CONCLUSION: WC is a better predictor of metabolic risk factors for developing MS than BMI. Therefore, we propose that metabolic risk factors be screened when WC >= 80 cm is found in both genders regardless of BMI. PMID- 22941135 TI - Clinics in diagnostic imaging (140). Iatrogenic sciatic nerve injury secondary to intramuscular injection. AB - A 77-year-old Chinese female patient presented with acute onset of left lower limb paraesthesia and weakness after she received an intramuscular injection for pain relief in the gluteal region. Magnetic resonance (MR) imaging of her lumbosacral spine and sacral plexus was performed. The MR imaging findings are reviewed and discussed. PMID- 22941136 TI - Pituitary apoplexy and high altitude. PMID- 22941138 TI - Comment on: A rare case of localised AA-type amyloidosis of the ureter with spheroids of amyloid. PMID- 22941139 TI - Waist circumference preferable to near-infrared interactance measurements. PMID- 22941142 TI - Bilateral Brodie's abscess at the proximal tibia. AB - Brodie's abscess is a form of subacute osteomyelitis, which typically involves the metaphyses of the long tubular bones, particularly in the tibia. The diagnosis is usually made incidentally, as there are no accompanying symptoms or laboratory studies. Bilateral involvement at the proximal tibia is unusual. However, orthopaedic surgeons should be aware of this entity, as it may present without symptoms. Checking the contralateral limb for concomitant Brodie's abscess is recommended. PMID- 22941143 TI - Disseminated intravascular coagulation complicating urothelial malignancy. AB - Transitional cell carcinoma has rarely been reported to be associated with disseminated intravascular coagulation (DIC). We report a 55-year-old Chinese man who was diagnosed with transitional cell carcinoma with vertebral metastasis. He presented with severe anaemia and thrombocytopenia, and subsequent evaluation revealed features of DIC. Interestingly, he did not have fever, any localising symptoms or signs of infection. He was treated aggressively with transfusion of packed cells, platelets, intravenous vitamin K and fresh frozen plasma. Despite aggressive treatment, the coagulation abnormalities were resistant to correction. The patient continued to deteriorate and eventually died of cardiac arrest. This case illustrates that transitional cell carcinoma can also be associated with DIC, possibly due to the expression of certain unidentified procoagulant factors similar to the tissue factor responsible for DIC. PMID- 22941144 TI - Synchronous nephrectomy with unilateral dual kidney transplantation: feasibility in patients with adult polycystic kidney disease. AB - Adult polycystic kidney disease (APKD) accounts for 2% of end-stage renal disease in Singapore and is a major indication for kidney transplantation. We report synchronous nephrectomy with unilateral cadaveric dual kidney transplantation (DKT) in a patient with APKD. Simple nephrectomy of the right native 27-cm polycystic kidney was performed to provide adequate space for unilateral DKT. Right donor kidney transplantation was performed at the site of native nephrectomy. End-to-side anastomosis of the right donor renal vein to the distal inferior vena cava and the right donor artery to the common iliac artery were performed. Left donor kidney was transplanted below the right kidney, with its vessels anastomosed to the right external iliac vessels. Ureter anastomosis was performed after perfusion of both kidneys. Lich-Gregoir anastomosis of the left donor ureter to the bladder and direct right donor ureter to native ureter anastomosis was established. This case illustrates that synchronous nephrectomy with DKT is feasible to facilitate implantation on the same side. PMID- 22941145 TI - Failure of high-dose clopidogrel in recurrent stent thrombosis. AB - This case report describes recurrent drug-eluting stent thrombosis with documented laboratory hyporesponsiveness to clopidogrel. The use of escalating doses of clopidogrel prevented subsequent episodes, but the patient developed gastrointestinal intolerance and diffuse cutaneous reaction, which resolved completely with prasugrel. Impressively, prasugrel 10 mg daily achieved an even lower vasodilator-stimulated phosphoprotein platelet reactivity index compared to clopidogrel 300 mg daily. Our case highlights the importance of alternative P2Y12 receptor antagonists for patients receiving drug-eluting stents. PMID- 22941146 TI - Radiological evidence of a modern 'martyr's crown': suicide by multiple self inflicted nail gun shots. AB - A man attempted suicide by shooting seven nails into his head with a nail gun; five in the right temporal region and two in the left. He subsequently presented at the emergency department with complaints of headache. He was found to be oriented in space and time, with no focal neurological deficits. The patient handed the nail gun to the doctors and informed them that he had earlier attempted suicide. Radiological studies showed the presence of nails arranged like a 'martyr's crown'. The man died six days after the surgical removal of the nails. Autopsy was refused by Italian authorities. We conclude that imaging techniques are an adjuvant to forensic medical diagnosis and forensic autopsies. PMID- 22941147 TI - Parosteal ossifying lipoma of the fibula: a case report with contrast-enhanced MR study and a review of the literature. AB - This report describes a rare case of parosteal ossifying lipoma of the fibula. Very few reports have described the magnetic resonance (MR) imaging features with gadolinium enhancement of this neoplasm. In this case, low-signal-intensity strands within the lipomatous mass on T1-weighted image with varying degrees of enhancement were detected. Thus, parosteal ossifying lipoma should be included within the group of gadolinium-enhanced benign lipomatous tumours that may mimic liposarcoma on MR imaging. However, the characteristic radiographic appearance, together with computed tomography or MR imaging features, should aid in the correct diagnosis of this condition. PMID- 22941148 TI - Double outlet right ventricle with infective endocarditis. AB - Double outlet right ventricle (DORV) is an uncommon congenital heart disease with a poor prognosis. We report a rare case of a girl with untreated DORV who survived until adolescence, but then developed infective endocarditis with florid complications and succumbed to it. Although infective endocarditis is seldom encountered in children in developed countries, a high index of suspicion is required for those with congenital heart disease. The roles of cross-sectional imaging are demonstrated, including the usefulness of magnetic resonance imaging not only in evaluating congenital heart disease, but also in detecting incidental lesions in the extracardiac structures. PMID- 22941149 TI - Pontomedullary white epidermoid: a rare cause of tinnitus. AB - Intracranial epidermoid cysts are relatively rare congenital inclusion cysts. They are the third most common cerebellopontine angle cistern mass after vestibular schwannoma and meningioma. White epidermoid is a rare variant. We present the first case, to our knowledge, of a white epidermoid cyst anterior to the pontomedullary junction, emphasising its imaging appearance, location and the importance of pre-operative diagnosis, which may reduce operative complications. PMID- 22941150 TI - Complementary and alternative medicine in Parkinson's disease patients in Korea. PMID- 22941151 TI - Mutation rate evolution in replicator dynamics. AB - The mutation rate of an organism is itself evolvable. In stable environments, if faithful replication is costless, theory predicts that mutation rates will evolve to zero. However, positive mutation rates can evolve in novel or fluctuating environments, as analytical and empirical studies have shown. Previous work on this question has focused on environments that fluctuate independently of the evolving population. Here we consider fluctuations that arise from frequency dependent selection in the evolving population itself. We investigate how the dynamics of competing traits can induce selective pressure on the rates of mutation between these traits. To address this question, we introduce a theoretical framework combining replicator dynamics and adaptive dynamics. We suppose that changes in mutation rates are rare, compared to changes in the traits under direct selection, so that the expected evolutionary trajectories of mutation rates can be obtained from analysis of pairwise competition between strains of different rates. Depending on the nature of frequency-dependent trait dynamics, we demonstrate three possible outcomes of this competition. First, if trait frequencies are at a mutation-selection equilibrium, lower mutation rates can displace higher ones. Second, if trait dynamics converge to a heteroclinic cycle-arising, for example, from "rock-paper-scissors" interactions-mutator strains succeed against non-mutators. Third, in cases where selection alone maintains all traits at positive frequencies, zero and nonzero mutation rates can coexist indefinitely. Our second result suggests that relatively high mutation rates may be observed for traits subject to cyclical frequency-dependent dynamics. PMID- 22941152 TI - Accumulation and detection of secreted proteins from single cells for reporter gene assays using a local redox cycling-based electrochemical (LRC-EC) chip device. AB - A lab-on-a-chip device is described for the electrochemical detection of alkaline phosphatase (ALP) secreted by transformed single HeLa cells. Detection on the chip device is based on local redox cycling at 256 individually addressable sensor points. Ring-disk electrodes (generator/collector) are arranged at individual sensor points to amplify the signal due to redox-cycling with only 32 connector pads. The surface of each sensor point is modified with antibodies for secreted alkaline phosphatase (SEAP) immobilization, which facilitates separation and detection of SEAP. Separation of SEAP from HeLa cells enables elimination of endogenous ALP and prevents HeLa cells from damage due to exposure to high level pH used during electrochemical detection. The large number of sensor points enables the simultaneous analysis of a large amount of single cells using the chip. The system is useful for gene reporter assays and for the detection of several types of secreted proteins. PMID- 22941154 TI - The arcuate line hernia: operative treatment and a review of the literature. AB - PURPOSE: An arcuate line hernia (ALH) is a rare diagnosis with no consensus on how to deal with this condition either when symptomatic or when found accidentally. Suggestions for laparoscopic and open operative techniques are given together with a review of the literature and a presentation of three new cases. MATERIAL: The PubMed database was searched for publications on ALH. Identified cases, including three from our department, are reported. RESULTS: Five males and two females, with a median age of 53 years were identified. Three patients were correctly diagnosed on a preoperative CT scan and the rest at surgery. Two patients had bilateral ALHs and four had other concomitant hernias repaired. Small bowel was present in the hernia in three cases and sigmoid colon in one. In one case, an emergency operation was performed due to bowel incarceration. Five patients had laparoscopic repairs, three with mesh and two without. Two patients, one converted from laparoscopic to open operation, had open mesh repairs. The postoperative course was uneventful in all cases, and no recurrences have been reported at a median follow-up of 6 months. CONCLUSIONS: A laparoscopic approach is recommended for diagnostic purposes, for pre-peritoneal mesh placement and for repair of concomitant hernias in both elective and emergency settings. Highlighting its existence might help general surgeons in interpreting an unusual finding on a CT scan or at operation. PMID- 22941155 TI - Hypertension in children and adolescents: epidemiology and pathogenesis. AB - High blood pressure is one among the leading contributors to burden of disease globally. Approximately 54 % of stroke and 47 % of ischemic heart disease events worldwide were attributable to high blood pressure in the year 2001. There is deficiency of data on the long-term outcome of hypertension in children. In spite of this, there is sufficient evidence to suspect that the health risks of hypertension in pediatric patients are substantial. Hypertension in childhood is known to result in hypertension in young adulthood. The epidemiology of hypertension in children is well represented from various studies conducted across continents. Factors like methodological issues in measurement, socio demographic differences, adiposity levels and ethnicity appear to influence the distribution of blood pressure as well as prevalence of hypertension in children. The etio-pathogenesis of essential (primary) hypertension is multi-factorial in origin. Obesity, insulin resistance, activation of sympathetic nervous system, alterations in sodium homeostasis, renin-angiotensin system changes, changes in vascular smooth muscle structure and reactivity, high serum uric acid levels, genetic factors and fetal programming have been reported to contribute to this disorder. The causes of secondary hypertension vary with age. Renal disorders and coarctation of the aorta are the most common causes of hypertension in children up to age 6 y. In older children, renal parenchymal disease remains the most frequent cause of increased blood pressure. Other causes of hypertension in children are relatively rare and include systemic arteritis and certain tumours, endocrine dysfunction, and neurologic disorders. PMID- 22941156 TI - RhoE is associated with relapse and prognosis of patients with colorectal cancer. AB - BACKGROUND: RhoE, an atypical Rho protein, is differently deregulated in some solid tumors, and there are conflicting data describing the role of RhoE in tumor cell migration and invasion. This study aimed to investigate RhoE expression in human colorectal cancer and its relationship with clinicopathological features and prognosis. METHODS: Colorectal cancer and adjacent normal tissues from 202 patients were examined by immunohistochemistry. Staining evaluation results were analyzed statistically in relation to various clinicopathological parameters, disease-free survival, and overall survival. RhoE expression was also investigated by immunohistochemistry in 80 node metastases and the corresponding primary lesions, and by Western blot test in six cancer and adjacent normal tissues. The relationship between RhoE and invasion was examined by transwell assay and Western blot test. RESULTS: The positive rate for RhoE in colorectal cancer was significantly higher than that of normal colorectal tissues. In colorectal cancer, RhoE expression was significantly correlated with depth of invasion, lymph node metastasis, and distant metastasis. Consistently, overexpression of RhoE in SW620 cells up-regulated vimentin, down-regulated E cadherin, increased the expression of matrix metalloproteinase (MMP) 9, and enhanced cell invasion in vitro; in contrast, silencing of RhoE by a specific siRNA caused opposite effects. Most importantly, disease-free and overall survivals were significantly poorer for patients with RhoE-positive tumors than for those with RhoE-negative tumors. CONCLUSIONS: These findings emphasize the positive role of RhoE in invasion and metastasis in human colorectal cancer. It could also serve as an independent prognostic marker in addition to the tumor, node, metastasis staging system. PMID- 22941157 TI - Cigarette smoking and hOGG1 Ser326Cys polymorphism are associated with 8-OHdG accumulation on mitochondrial DNA in thoracic esophageal squamous cell carcinoma. AB - BACKGROUND: We examined whether cigarette smoking affects the degrees of oxidative damage (8-hydroxyl-2'-deoxyguanosine [8-OHdG]) on mitochondrial DNA (mtDNA), whether the degree of 8-OHdG accumulation on mtDNA is related to the increased total mtDNA copy number, and whether human 8-oxoguanine DNA glycosylase 1 (hOGG1) Ser326Cys polymorphisms affect the degrees of 8-OHdG accumulation on mtDNA in thoracic esophageal squamous cell carcinoma (TESCC). METHODS: DNA extracted from microdissected tissues of paired noncancerous esophageal muscles, noncancerous esophageal mucosa, and cancerous TESCC nests (n = 74) along with metastatic lymph nodes (n = 38) of 74 TESCC patients was analyzed. Both the mtDNA copy number and mtDNA integrity were analyzed by quantitative real-time polymerase chain reaction (PCR). The hOGG1 Ser326Cys polymorphisms were identified by restriction fragment length polymorphism PCR and PCR-based direct sequencing. RESULTS: Among noncancerous esophageal mucosa, cancerous TESCC nests, and metastatic lymph nodes, the mtDNA integrity decreased (95.2 to 47.9 to 18.6 %; P < 0.001) and the mtDNA copy number disproportionally increased (0.163 to 0.204 to 0.207; P = 0.026). In TESCC, higher indexes of cigarette smoking (0, 0 20, 20-40, and >40 pack-years) were related to an advanced pathologic N category (P = 0.038), elevated mtDNA copy number (P = 0.013), higher mtDNA copy ratio (P = 0.028), and increased mtDNA integrity (P = 0.069). The TESCC mtDNA integrity in patients with Ser/Ser, Ser/Cys, and Cys/Cys hOGG1 variants decreased stepwise from 65.2 to 52.1 to 41.3 % (P = 0.051). CONCLUSIONS: Elevated 8-OHdG accumulations on mtDNA in TESCC were observed. Such accumulations were associated with a compensatory increase in total mtDNA copy number, indexes of cigarette smoking, and hOGG1 Ser326Cys polymorphisms. PMID- 22941158 TI - A RAND/UCLA appropriateness study of the management of familial gastric cancer. AB - BACKGROUND: Hereditary diffuse gastric cancer (HDGC) represents a minority of gastric cancer (GC) cases. The goal of this study is to use a RAND/University of California Los Angeles (UCLA) appropriateness methodology to examine indications for genetic referral, CDH1 testing, and consideration of prophylactic total gastrectomy (PTG). METHODS: A multidisciplinary expert panel of 16 physicians from six countries scored 47 scenarios. Appropriateness of scenarios was scored from 1 (highly inappropriate) to 9 (highly appropriate). Median appropriateness scores (AS) of 1-3 were considered inappropriate, 4-6 uncertain, and 7-9 appropriate. Agreement was reached when 12 of 16 panelists scored the statement similarly. Appropriate scenarios agreed upon were subsequently scored for necessity. RESULTS: The panel felt that patients with family history of diffuse gastric cancer (DGC), lobular breast cancer, or multiple family members with GC should be referred for genetic assessment and multidisciplinary decision-making. The panel felt that it is appropriate for patients with DGC to have CDH1 mutation testing in a family with (1) >=2 cases of GC, with at least one case of DGC diagnosed before age of 50 years; (2) >=3 cases of GC diagnosed at any age, one or more of which is DGC; (3) a patient diagnosed with DGC and lobular breast carcinoma; or (4) patients diagnosed with DGC under age of 35 years. The panel felt that PTG should be offered to CDH1 mutation carriers 20 years or older. CONCLUSIONS: Identification of genetic mutations in patients at risk for hereditary GC is important, and criteria for testing are suggested. PMID- 22941159 TI - Role of repeat staging laparoscopy in locoregionally advanced gastric or gastroesophageal cancer after neoadjuvant therapy. AB - INTRODUCTION: Staging laparoscopy (SL) can identify occult, subradiographic metastatic (M1) disease in patients with gastric or gastroesophageal (G/GEJ) cancer who are unlikely to benefit from gastrectomy. The purpose of this study is to determine the yield of repeat SL following neoadjuvant therapy for G/GEJ adenocarcinoma after initial negative pretreatment SL. METHODS: Retrospective review of a prospective database identified patients with locoregionally advanced (T3-4Nany or TanyN+) G/GEJ adenocarcinoma who underwent pretreatment SL. The yield of repeat SL following neoadjuvant therapy was determined. RESULTS: From 1994 to 2010, 276 patients with locoregionally advanced G/GEJ adenocarcinoma were identified, of whom 244 proceeded to operation after neoadjuvant therapy, at a median time of 105 days. One hundred sixty-four patients (67 %) underwent repeat SL, and 80 patients (33 %) proceeded directly to laparotomy. Occult M1 disease was identified in 12 (7.3 %) and 6 (7.5 %) patients, respectively. In the repeat SL cohort, M1 disease was identified at laparoscopy in nine patients (5.5 %). M1 disease not identified by laparoscopy was discovered at laparotomy in three patients (1.8 %). The median follow-up for the study population was 31 months. For patients with M1 disease, median overall survival was 15 months, versus 41 months for patients resected without M1 disease (p < 0.0001). CONCLUSIONS: Occult, subradiographic M1 disease develops in approximately 7 % of patients following neoadjuvant therapy for locoregionally advanced G/GEJ adenocarcinoma. These patients have poor prognosis, and repeat SL can be a valuable tool in selecting patients with locoregionally advanced G/GEJ tumors for potentially curative resection after neoadjuvant therapy. PMID- 22941160 TI - Management of thyroid nodules with atypical cytology on fine-needle aspiration biopsy. AB - BACKGROUND: Fine-needle aspiration biopsy (FNAB) of the thyroid categorized as atypia of undetermined significance/follicular lesion of undetermined significance (AUS/FLUS) is a newly defined category according to the recent Bethesda guidelines. We sought to assess the characteristics and treatment of patients with an AUS/FLUS FNAB at our institution. Additionally, we evaluated the utility of the recommended 3-month timing of repeat FNAB. METHODS: A retrospective study of all patients with an FNAB categorized as AUS/FLUS at an academic tertiary-care center. Clinical, cytological, and ultrasound variables were compared among management groups. Differences in patients receiving repeat FNAB before or after a 3-month interval were compared. RESULTS: A total of 203 patients of the 5,391 FNABs performed at our institution met the Bethesda criteria for AUS/FLUS; 62% were sent directly to surgery, 25% had a repeat FNAB, and 13% were observed. Younger (p=0.006) and male patients (p=0.04) were more likely to go directly to surgery. Microcalcifications, irregular margins, and marked hypoechogenicity on ultrasound did not appear to influence the decision to repeat the FNAB, observe the patient, or refer the patient for surgery. Timing of repeat FNAB (<3 months or >=3 months) did not alter the diagnostic results of the second FNAB (p=0.73). The overall rate of malignancy in patients undergoing surgery was 15.7%. CONCLUSIONS: Gender and age, not ultrasound characteristics, appear to influence the decision for surgery in AUS/FLUS patients. Timing of repeat biopsy did not alter management, repeat FNAB diagnosis, or rate of malignancy in our cohort. PMID- 22941161 TI - New sentinel node mapping technologies for early gastric cancer. AB - The sentinel node (SN) concept has revolutionized the surgical staging of both melanoma and breast cancer over the past two decades. The application of this concept can yield benefits for patients by preventing various complications related to unnecessary prophylactic regional lymph node dissection in patients with cancer-negative SNs. Clinical application of SN mapping in patients with early gastric cancer has been a controversial issue for years. However, a recent meta-analysis and a prospective multicenter trial of SN mapping for early gastric cancer have shown acceptable SN detection rates and accuracy of determination of lymph node status. For early stage gastric cancer such as cT1N0M0, for which a better prognosis can be achieved through conventional surgical approaches, the establishment of individualized, minimally invasive treatments that may retain the patients' quality of life should be the next surgical challenge. Although there are many unresolved technical issues, laparoscopic SN biopsy with laparoscopic minimized gastrectomy or endoscopic mucosal resection/endoscopic submucosal dissection has the potential to achieve this goal. PMID- 22941162 TI - Should breast density influence patient selection for breast-conserving surgery? AB - BACKGROUND: In a previous study of the relationship between breast density and primary tumor features, we observed a higher mastectomy rate in patients with extremely dense breasts. Here we examine possible reasons for this finding. METHODS: Data were obtained from a prospectively maintained database of 1,056 invasive breast cancer patients from January 2005 to June 2007. Mammographic density was assigned by Breast Imaging-Reporting and Data System (BI-RADS) classification. Initial and final surgical procedures, and patient and tumor variables were recorded. RESULTS: Breast-conserving surgery (BCS) was attempted in 758 patients (72 %), 385 (51 %) of whom had preoperative magnetic resonance imaging (MRI). Initial BCS was less common among patients with the highest (BI RADS 4) breast density compared to patients with less-dense breasts (52 vs. 74 %; p < 0.0001), but MRI use was more common (65 vs. 33 %; p < 0.0001). Adjusting for clinical and pathologic variables, patients with the highest breast density had 1.94-times (95 % confidence interval 1.44-2.62; p < 0.0001) the odds of initial mastectomy compared to patients with less-dense breasts. After initial BCS, 387 patients (51 %) had positive shaved margins, 96 (25 %) of whom converted to mastectomy. MRI did not correlate with the rate of positive margins overall or among those with dense breasts. Adjusting for clinical and pathologic variables, density did not predict margin status or conversion to mastectomy. In a multivariate model, age, histologic grade, extensive intraductal component, and multicentricity/multifocality were independently associated with conversion to mastectomy. CONCLUSIONS: Density alone seems to influence the decision to proceed with initial mastectomy. When BCS was attempted, breast density was not associated with positive margins or conversion to mastectomy. A benefit of MRI in decreasing positive margins was not observed. These data do not support the use of breast density as a selection criterion for BCS. PMID- 22941163 TI - Etiology of breast masses after autologous breast reconstruction. AB - BACKGROUND: Determining the nature of a breast mass after autologous reconstruction can be difficult. METHODS: A retrospective review of all autologous breast reconstructions was performed over 10 years. All postoperative breast masses were identified. Tumor characteristics, adjuvant treatment, timing of the development of the mass, and correlation with radiology were reviewed. RESULTS: A total of 365 flaps were performed on 272 patients [253 deep inferior epigastric perforator (DIEP), 35 superficial inferior epigastric artery (SIEA), 22 muscle-sparing free transverse rectus abdominis myocutaneous (free MS-TRAM), 25 latissimus, and 30 pedicled TRAM]. Breast masses were identified in 66 breasts (18 %). The majority of these were from fat necrosis, occurring in 54 breasts (15 % overall; DIEP 13.4 %, SIEA 5.7 %, free MS-TRAM 15 %, latissimus 0 %, pedicled TRAM 47 %), first identified at a mean of 3 months. Recurrent carcinoma was diagnosed in 13 breasts (3.6 %). Factors associated with the postreconstruction mass representing recurrent carcinoma were later time period after reconstruction (mean 24 months), closer surgical margins, and lymphovascular invasion. Radiographic imaging accurately diagnosed recurrent carcinoma in 11 (92 %) of 12 patients in whom it was utilized and suggested a benign diagnosis in all 16 patients with fat necrosis in whom it was utilized. CONCLUSIONS: Breast masses frequently present after autologous reconstruction. Fat necrosis is the most common cause. Recurrent carcinoma can occur in the reconstructed breast and presents later. A higher index of suspicion for recurrence should accompany any mass in which prior lymphovascular invasion was present or if original margins were <1 cm. Radiographic imaging accurately identifies the cause of these masses. PMID- 22941164 TI - Intraoperative diagnosis using sentinel node biopsy with indocyanine green dye in gastric cancer surgery: an institutional trial by experienced surgeons. AB - BACKGROUND: Reliable indicators that can intraoperatively determine the absence of nodal metastasis are in great demand to avoid unnecessary lymphadenectomy. However, little has been reported about the intraoperative diagnostic performance of sentinel node (SN) biopsy. METHODS: Sentinel node biopsy by subserosal or submucosal injection of indocyanine green (ICG) was performed in 241 patients with American Joint Committee on Cancer tumor, node, metastasis staging system, 7th edition, clinical T1 (n = 190) and T2 (n = 51) gastric cancer by two experienced surgeons. All nodes that stained green (green node, GN), representing SNs, were excised before gastrectomy and were sliced into 2-mm sections for intraoperative histological examinations with hematoxylin and eosin staining. The sliced GNs were also examined simultaneously by imprint cytology. RESULTS: The GNs were detectable in 240 patients (3.8 +/- 2.4 nodes per patient; range 1-17 nodes; median 3 nodes), and the success rate of detection was 99.6 % (240 of 241). Of 240 patients with a successful detection, 29 were found to have lymph node (LN) metastases; 16 were diagnosed with LN metastases in both GNs and non GNs, 12 in GNs alone, and 1 in non-GNs alone. The false-negative rate based on the SN concept was 3.4 % (1 of 29). However, two patients with cT1 gastric cancer were diagnosed as intraoperative GN negative but were later confirmed as GN positive by histological examinations of paraffin sections. As an intraoperative diagnosis, the false-negative rate was 10.3 % (3 of 29). CONCLUSIONS: Sentinel node biopsy using ICG could be performed intraoperatively within reasonable limits under certain conditions, such as multiplanes for detection, combination use of imprint cytology, and open surgery by experienced surgeons. PMID- 22941165 TI - BRAF V600E mutation independently predicts central compartment lymph node metastasis in patients with papillary thyroid cancer. AB - PURPOSE: This study was designed to examine whether available preoperative clinical parameters, including B-type Raf kinase (BRAF) V600E mutation status, can identify patients at risk for central compartment lymph node metastasis (CLNM). METHODS: Under an institutional review board-approved protocol, we conducted a single-center, retrospective review of all patients who had initial thyroidectomy for histologic papillary thyroid carcinoma (PTC) during 2010. The presence of CLNM was examined for correlation with available preoperative clinical parameters, including tumor size, gender, age, and BRAF mutation status. RESULTS: Cervical lymph node resection and molecular testing on FNAB or histopathologic specimen was performed on a consecutive series of 156 study patients with histologic PTC. Overall, CLNM was diagnosed in 37% and 46% were BRAF-mutation-positive. BRAF positivity was the only clinical parameter associated with CLNM (BRAF, p=0.002; tumor size>=2 cm, p=0.16; male gender, p=0.1; age>=45 years, p=0.3) and remained an independent predictor of CLNM on multiple logistic regression analysis (odds ratio (OR) 3.2, p=0.001). The PPV and NPV of BRAF positivity for CLNM was 50 and 74%, respectively. When restricting the analysis to the subset of 38 patients who had molecular testing performed preoperatively on FNAB, the PPV and NPV of BRAF positivity for CLNM was 47 and 91%, respectively, and BRAF positivity was still a significant predictor of CLNM on both univariate (OR 8.4, p=0.01) and multivariate (OR 9.7, p=0.02) analyses. CONCLUSIONS: Of the commonly used clinical parameters available preoperatively, the BRAF V600E mutation is the only independent predictor of CLNM in PTC and can be utilized to guide the extent of initial surgery. PMID- 22941166 TI - A comparison of surgical morbidity and scar appearance between gasless, transaxillary endoscopic thyroidectomy (GTET) and minimally invasive video assisted thyroidectomy (VAT). AB - BACKGROUND: The gasless, transaxillary endoscopic thyroidectomy (GTET) and minimally invasive video-assisted thyroidectomy (VAT) are both well-recognized endoscopic thyroid procedures, but how their postoperative outcomes are compared remains unclear. The present study was designed to compare surgical morbidities/complications and scar appearance between GTET and VAT at our institution. METHODS: Of the 141 patients eligible for endoscopic thyroidectomy, 96 (68.1 %) underwent GTET and 45 (31.9 %) underwent VAT. Patient demographics, indications, operative findings, pain scores on days 0 and 1, and surgical morbidities were compared between the two groups. At 6 months after surgery, all patients were asked about their satisfaction on the cosmetic result by giving a score (Patient Satisfaction Score or PSS) and their scar appearance was assessed by the 11 domains in the Patient and Observer Scar Assessment Scale (POSAS). RESULTS: GTET was associated with a significantly longer operating time (84 vs. 148 min, p = 0.005), higher pain scores on days 0 and 1 (2.9 vs. 2.3, p = 0.042 and 2.2 vs. 1.7, p = 0.033, respectively), overall recurrent laryngeal nerve (RLN) injury (6.3 vs. 0 %, p = 0.043), and overall morbidity rates (12.5 vs. 2.2 %, p = 0.049) than VAT. The actual individual score for the 11 domains in POSAS and for PSS remained similar between the two groups. They remained similar even when patients with morbidity were excluded. CONCLUSIONS: GTET was a technically more challenging procedure and was associated with longer hospital stay, longer operating time, more immediate pain, and increased overall RLN injury and morbidity than VAT. The 6-month POSAS and PSS were similar between the two procedures. PMID- 22941167 TI - BRAF V600E mutation independently predicts central compartment lymph node metastasis in patients with papillary thyroid cancer. PMID- 22941168 TI - Teach your children well: stage IV colorectal cancer and variability in practice patterns. PMID- 22941169 TI - Utility of 111indium-pentetreotide scintigraphy in patients with neuroendocrine tumors. AB - BACKGROUND: Neuroendocrine (NE) tumors pose a diagnostic challenge with the need to utilize a combination of biochemical analysis, standard cross-sectional imaging, and more recently, nuclear medicine scans such as (111)indium pentetreotide scintigraphy (somatostatin receptor scintigraphy, SRS; OctreoScan, Covidien Imaging Solutions, Hazelwood, MO). In this study we sought to evaluate the clinical utility of scintigraphy in the diagnosis and management of patients with NE tumors at a major university hospital. METHODS: A retrospective chart review was performed on all patients who underwent both (111)indium-pentetreotide scintigraphy and computed tomography/magnetic resonance imaging (CT/MRI) at a single institution between February 2001 and July 2008. Charts were reviewed for patient demographics, symptoms of NE disease, and results of biochemical testing, imaging studies, histopathologic diagnosis, and medical and/or surgical management. RESULTS: One hundred forty-five patients received (111)indium pentetreotide scintigraphy (SRS) and concurrent cross-sectional imaging (CT/MRI) over the 7-year period studied. In the evaluation of primary disease, 60 % of tumors were localized by anatomic imaging, significantly greater than the 15 % detection rate achieved by SRS. In the evaluation of recurrent disease, 61 % of NE tumors were localized by cross-sectional imaging, significantly greater than the 31 % detection rate of SRS. Scintigraphy identified disease foci not seen on CT/MRI in just 8 of 74 of the cohort with evidence of disease and only altered the surgical management in 3 of 74 cases. CONCLUSIONS: Cross-sectional CT/MRI imaging is sufficient for the localization of NE tumors. (111)Indium pentetreotide scintigraphy does not significantly alter the surgical management of patients with NE tumors, and we suggest that it be selectively reserved for patients with disease that is occult to cross-sectional imaging. PMID- 22941170 TI - Influence of nonclinical factors on choice of therapy for early hepatocellular carcinoma. AB - BACKGROUND: Initial therapy for early hepatocellular carcinoma (HCC) with well compensated cirrhosis is controversial. While we previously reported on the effect of clinical factors and surgeon specialty on choice of therapy for early HCC, other nonclinical factors also may impact decision-making. METHODS: Surgeons who treat HCC were invited to complete a web-based survey that included ten case scenarios. Choice of therapy-liver transplantation (LT), liver resection (LR), or radiofrequency ablation (RFA)-was analyzed using regression models. RESULTS: There were 336 responses for analysis. Most respondents were in academic centers (86 %) that offered LT (71 %). The median number of patients annually evaluated for HCC was 30. Both practice type and HCC case volume were associated with choice of therapy, but these associations were not independent of surgeon specialty. LT surgeons who did not also perform RFA were less likely than those LT surgeons who did offer RFA to choose RFA over LT (relative risk ratios (RRR) 0.38, P < 0.001). Non-LT surgeons were more likely than LT surgeons who also offered RFA to choose RFA over LT (RRR 2.24, P < 0.001). Surgeons who worked at hospitals where LT was performed were much more likely to choose LT over LR and RFA even if they did not personally perform LT (RRR 1.27 and RRR 3.33, P < 0.001). CONCLUSIONS: Surgeon- and institution-related factors impact choice of therapy for early HCC even after adjustment for differences in clinical presentation. These data suggest that choice of therapy for patients with early HCC varies across providers independent of case selection. PMID- 22941171 TI - Survival among pancreaticoduodenectomy patients treated for pancreatic head cancer <1 or 2 cm. AB - BACKGROUND: Size of primary tumor has implications for staging, imaging, and treatment of pancreatic head carcinomas. Limited data suggest that small tumor size is associated with better survival. The objective of this population study is to analyze characteristics and survival of patients with resected pancreatic head ductal carcinomas sized <1 and 2 cm. METHODS: Analysis of resected invasive pancreatic head ductal carcinomas captured within SEER Program from 1998 to 2008. RESULTS: A total of 7,135 cases were analyzed with nodal metastases in 31, 55, and 67 % for subcentimeter, 1.1-2 cm, and >2 cm tumors, respectively. Median survival was longest for node-negative tumors (38, 26, 19 months for tumors measuring <= 1, 1.1-2, and >2 cm, respectively; p < 0.001) versus node-positive tumors (18, 19, 14 months, p < 0.001). In multivariate analysis, large tumor size was associated with higher risk of death (hazard ratio (HR) = 1.179 for tumors 1.1-2 cm, p = 0.152; HR = 1.665 for tumors >2 cm, p < 0.001). CONCLUSIONS: Small pancreatic cancers have a poor prognosis and surprisingly high rate of nodal involvement; therefore, they cannot be considered early cancers. Size-based screening is unlikely to save lives with current treatment options. PMID- 22941172 TI - The survival impact of XPA and XPC genetic polymorphisms on patients with esophageal squamous cell carcinoma. AB - BACKGROUND: The purpose of this study was to investigate the association between survival outcome of esophageal cancer patients and the genetic variants in xeroderma pigmentosum groups A (XPA) and C (XPC), 2 important molecules in the nucleotide excision pathway for DNA repair. METHODS: A total of 501 patients with a diagnosis of esophageal squamous cell carcinoma (ESCC) were enrolled in the study. The genetic variants of XPA in 5'UTR and those of XPC at exon 15 K939Q were analyzed with the TaqMan assay from the genomic DNA of peripheral leukocytes and correlated to the posttreatment survival outcome. RESULTS: Patients with XPA 5'UTR A/G and XPC K939Q C/C genotypes were found to be imposed with a higher risk of mortality after treatment compared with patients with wild-type homozygous genotypes [adjusted HR (95 % CI) of death being 1.36 (1.06-1.74) and 1.34 (0.97 1.83), respectively]. Cox's multivariate analysis detected a statistically significant increased trend in risk of mortality with the accumulation of any of these 2 unfavorable genotypes compared with patients with other genotypes [adjusted HR (95 % CI) = 1.29 (1.08-1.53), P = .005]. The effect was more pronounced in the population treated with esophagectomy (P = .023) and undergoing concurrent neoadjuvant chemoradiotherapy (CCRT) (P = .002). CONCLUSIONS: The hereditary genetic variants in XPA and XPC can serve as independent predictors of the clinical outcome of patients with ESCC, especially in those who are treated with esophagectomy and undergo chemoradiation. PMID- 22941173 TI - Sentinel Node and Recurrent Breast Cancer (SNARB): results of a nationwide registration study. AB - BACKGROUND: Knowledge of regional lymph node involvement is important in patients with recurrent breast cancer for obtaining better locoregional control and predicting prognosis. To determine technical feasibility, validity, aberrant drainage rates, and clinical consequences of performing repeat sentinel node biopsy (SNB) in patients with locally recurrent breast cancer we conducted the "Sentinel Node and Recurrent Breast Cancer (SNARB)" study. METHODS: A total of 150 patients with locally recurrent breast cancer underwent lymphatic mapping and SNB. In case of an intact axillary lymph node basin, ipsilateral axillary lymph node dissection (ALND) was performed subsequently. RESULTS: A total of 41 patients previously underwent breast conserving therapy (BCT) with SNB, 82 patients BCT with ALND, and 21 patients a mastectomy, of which 9 with SNB and 12 with ALND. In 95 patients (63.3 %) a sentinel node was identified and in 78 patients (52 %) the sentinel node was successfully removed. In 18 patients (22.8 %) a (micro)metastasis was found on pathologic examination. Confirmation ALND in 18 patients showed no axillary lymph node metastases. Aberrant drainage pathways were visualized in 58.9 % of the patients, significantly more frequently after a previous ALND (79.3 %) than after a previous SNB (25.0 %) (P < .0001). Overall, the result of this repeat SNB led to a change in the adjuvant treatment plan in 16.5 % of the patients with a successful repeat SNB. CONCLUSIONS: Repeat SNB is technically feasible and provides reliable results in patients with locally recurrent breast cancer, leading to change in management in 1 of 6 patients. PMID- 22941174 TI - Measuring the quality of sentinel lymph node biopsy (SLNB) for breast cancer: a population-based evaluation. AB - BACKGROUND: The quality SLNB for breast cancer has never been evaluated on a population level. We previously developed SLNB quality indicators (QIs) and measured them at a single institution. The objective of this study was to measure SLNB quality at a population level. METHODS: Patients with a breast cancer diagnosis in Ontario who had axillary surgery between January 1 and December 31, 2005 were identified from the Ontario Cancer Registry. The cohort of patients who underwent a SLNB was determined from institutional administrative datasets and by primary chart abstraction. Data for measuring 8 QIs was abstracted. The influence of patient, provider, and institutional characteristics was determined using generalized estimating equations (GEEs) to account for patient clustering within hospitals. RESULTS: A total of 2323 breast cancer patients were confirmed to have undergone a SLNB. The QI measurements for SLN identification and the timing of SLNB (alongside primary tumor resection) were high, exceeding 90%. The proportion of cases associated with appropriate pathology evaluation and reporting were modest. Hospital volume of breast cases, urban or rural, and academic versus community designations did not influence quality. Younger patient age (p = .002) and number of nodes removed >1 (p =.008) were significant predictors of node positivity. Consequently, the rate of completion axillary lymph node dissection (cALND) rose with increasing metastatic burden and decreasing patient age. CONCLUSIONS: The quality of SLNB at a population level was generally high. Further evaluation is required, particularly in determining how to improve SLNB pathology evaluation, and reporting. PMID- 22941176 TI - Application of quality by design to the development of analytical separation methods. AB - Recent pharmaceutical regulatory documents have stressed the critical importance of applying quality by design (QbD) principles for in-depth process understanding to ensure that product quality is built in by design. This article outlines the application of QbD concepts to the development of analytical separation methods, for example chromatography and capillary electrophoresis. QbD tools, for example risk assessment and design of experiments, enable enhanced quality to be integrated into the analytical method, enabling earlier understanding and identification of variables affecting method performance. A QbD guide is described, from identification of quality target product profile to definition of control strategy, emphasizing the main differences from the traditional quality by testing (QbT) approach. The different ways several authors have treated single QbD steps of method development are reviewed and compared. In a final section on outlook, attention is focused on general issues which have arisen from the surveyed literature, and on the need to change the researcher's mindset from the QbT to QbD approach as an important analytical trend for the near future. PMID- 22941175 TI - Significance of serum tumor marker levels in peritoneal carcinomatosis of appendiceal origin. AB - BACKGROUND: The significance of tumor markers in patients with appendiceal carcinomatosis is poorly defined. We determined preoperative and postoperative tumor marker levels in patients undergoing cytoreductive surgery (CRS) and heated intraperitoneal chemoperfusion (HIPEC) and examined their association with clinicopathologic features and survival. METHODS: A total of 176 patients undergoing attempted CRS/HIPEC for appendiceal carcinomatosis had at least 1 tumor marker measured. Marker levels were correlated with tumor characteristics and oncologic outcomes. Kaplan-Meier curves and multivariate Cox regression models were used to identify prognostic factors affecting progression and survival. RESULTS: At least 1 marker was elevated prior to CRS/HIPEC in 70 % of patients (CEA, 54.1 %; CA19-9, 47.7 %; CA-125, 47.2 %). Among patients with elevated preoperative marker levels, normalization occurred postoperatively in 79.4 % for CEA, 92.3 % for CA19-9, and 60 % for CA-125. Absolute preoperative tumor marker levels correlated with peritoneal carcinomatosis index (PCI) (p < .0002), and the number of elevated markers was associated with PCI and progression-free survival (PFS). Elevated postoperative CEA level was associated with decreased PFS (median, 13 vs 36 months, p = .0008). On multivariate Cox regression analysis, elevated preoperative CA19-9 was associated with shorter PFS (hazard ratio [HR] 2.9, 95 % confidence interval [95 % CI] 1.5-5.3, p = .0008), whereas elevated CA-125 was associated with shorter overall survival (HR 2.6, 95 % CI 1.3-5.4, p = .01). CONCLUSIONS: Most patients with appendiceal carcinomatosis will have at least 1 elevated tumor marker and will normalize following CRS/HIPEC, allowing for ongoing surveillance. CA19-9 is a promising biomarker for early progression following CRS/HIPEC, whereas CA-125 is associated with shorter survival. PMID- 22941177 TI - Electrochemical approaches for the fabrication and/or characterization of pure and hybrid templated mesoporous oxide thin films: a review. AB - Electrochemistry can be used for fabrication and characterization of mesoporous oxide films. First, this review provides insight into the methods used to prepare templated mesoporous thin films on an electrode surface, i.e., evaporation induced self-assembly (EISA) and electrochemically assisted self-assembly (EASA). Electrochemical characterization of mass transport processes in pure and organically functionalized mesoporous oxide films is then discussed. The electrochemical response can be basically restricted by the electron/mass transfer reaction at the electrode-film interface and diffusion through mesopore channels. The contributions of cyclic voltammetry, hydrodynamic voltammetry, electrochemical impedance spectroscopy, and scanning electrochemical microscopy to the characterization of films with distinct mesostructures are finally described, with special emphasis on identification of conditions that can affect the electrochemical response recorded with such modified electrodes. PMID- 22941178 TI - Developing qualitative LC-MS methods for characterization of Vaccinium berry Standard Reference Materials. AB - Standard Reference Materials (SRMs) offer the scientific community a stable and homogenous source of material that holds countless application possibilities. Traditionally, the National Institute of Standards and Technology (NIST) has provided SRMs with associated quantitative information (certified values) for a select group of targeted analytes as measured in a solution or complex matrix. While the current needs of the SRM community are expanding to include non quantitative data, NIST is attempting to broaden the scope of how and what information is offered to the SRM community by providing qualitative information about biomaterials, such as chromatographic fingerprints and profiles of untargeted identifications. In this work, metabolomic and proteomic profiling efforts were employed to characterize a suite of six Vaccinium berry SRMs. In the discovery phase, liquid chromatography-tandem mass spectrometry (LC-MS/MS) data was matched to mass spectral libraries; a subsequent validation phase based on multiple-reaction monitoring LC-MS/MS relied on both retention time matching of authentic standards along with fragmentation data for a qualitative overview of the most prominent organic compounds present. Definitive and putative identifications were determined for over 70 metabolites based on reporting guidelines set forth by the Metabolomics Standards Initiative (Metabolomics 3(3):211-221, 2007), and the capability of electrospray ionization mass spectrometry (ESI-MS) to profile untargeted metabolites within a complex matrix using mass spectral matching is demonstrated. Bottom-up proteomic analyses were possible using peptide databases translated from expressed sequence tags (ESTs). Homology searches provided identification of novel Vaccinium proteins based on homology to related genera. Chromatographic fingerprints of these berry materials were acquired for supplemental qualitative information to be provided to users of these SRMs. An unbounded set of qualitative data about a biomaterial is a valuable complement to quantitative information traditionally provided in NIST Certificates of Analysis. PMID- 22941179 TI - Iminodiacetic acid functionalised organopolymer monoliths: application to the separation of metal cations by capillary high-performance chelation ion chromatography. AB - Lauryl methacrylate-co-ethylene dimethacrylate monoliths were polymerised within fused silica capillaries and subsequently photo-grafted with varying amounts of glycidyl methacrylate (GMA). The grafted monoliths were then further modified with iminodiacetic acid (IDA), resulting in a range of chelating ion-exchange monoliths of increasing capacity. The IDA functional groups were attached via ring opening of the epoxy group on the poly(GMA) structure. Increasing the amount of attached poly(GMA), via photo-grafting with increasing concentrations of GMA, from 15 to 35%, resulted in a proportional and controlled increase in the complexation capacity of the chelating monoliths. Scanning capacitively coupled contactless conductivity detection (sC(4)D) was used to characterise and verify homogenous distribution of the chelating ligand along the length of the capillaries non-invasively. Chelation ion chromatographic separations of selected transition and heavy metals were carried out, with retention factor data proportional to the concentration of grafted poly(GMA). Average peak efficiencies of close to 5,000 N/m were achieved, with the isocratic separation of Na, Mg(II), Mn(II), Co(II), Cd(II) and Zn(II) possible on a 250-mm-long monolith. Multiple monolithic columns produced to the same recipes gave RSD data for retention factors of <15% (averaged for several metal ions). The monolithic chelating ion exchanger was applied to the separation of alkaline earth and transition metal ions spiked in natural and potable waters. PMID- 22941180 TI - [Between promise and threat : antibiotics in foods in west Germany 1950-1980]. PMID- 22941181 TI - Professor Andrew Fielding Huxley, OM, FRS, 1917-2012. PMID- 22941182 TI - Wound healing complications and the use of mammalian target of rapamycin inhibitors in kidney transplantation: a critical review of the literature. AB - Surgical complications, including events such as lymphocele and urological complications that affect wound healing, are reported with an incidence of 15% to 32% after kidney transplantation. The experience of the surgeon and comorbidities play an important role in determining the risk of such complications occurring. Since the introduction of the inosine 5'-monophosphate dehydrogenase inhibitors (mycophenolate mofetil) to the immunosuppressive armamentarium, replacing the antimetabolite prodrug azathioprine, reports have associated certain forms of wound healing complications (wound dehiscence, impaired healing, lymphocele, and incisional hernia) with the use of these agents. When mammalian target of rapamycin (mTOR) inhibitors (sirolimus, everolimus) became available, these findings were observed increasingly, particularly in direct comparisons with inosine 5'-monophosphate dehydrogenase inhibitors. The purpose of this article was to review the reported incidence of wound healing complications from randomized clinical trials that investigated the use of sirolimus- and everolimus based treatment regimens in de novo kidney transplantation and the information available from the U.S. Food and Drug Administration database. The clinical trials included were primarily identified using biomedical literature database searches, with additional studies added at the authors' discretion. This review summarizes these studies to consider whether modern mTOR inhibitor-based immunosuppressive regimens exert and affect wound healing after kidney transplantation. PMID- 22941183 TI - The performance of MP2.5 and MP2.X methods for nonequilibrium geometries of molecular complexes. AB - Here we test the performance of the newly developed MP2.5 and MP2.X methods in terms of their abilities to generate accurate binding energies for noncovalently bound complexes at points away from their minimum energy structures and in terms of the accuracy of their potential energy minima. The MP2.X method is a scaled version of MP2.5 that allows for the use of smaller basis sets for the most computationally demanding (MP3) term, significantly reducing its computational cost. MP2.5 and MP2.X binding energy errors are compared to those of the reference CCSD(T)/CBS method on the dissociation curves associated with the S66 dataset of noncovalent complexes (S66x8). It is found that both the MP2.5 and MP2.X methods produce binding energy errors, as well as potential energy minima, that are significantly more accurate than those of MP2 methods. Thus, these methods are appropriate choices when very high quality geometries of noncovalent complexes are required. PMID- 22941184 TI - Letter to the editor concerning "does minimally invasive lumbar disc surgery result in less muscle injury than conventional surgery? A randomized controlled trial" by Arts M, Brand R et al. (2011) Eur Spine J 20(1):51-57. PMID- 22941185 TI - Factor analysis of H2S emission at a wastewater lift station: a case study. AB - Odor and corrosion are common problems in domestic wastewater collection, transportation, pumping, and treatment processes. Based on the comparison among odorous compounds and onsite observations at a wastewater lift station, H2S is more likely to have caused the odor and corrosion problems than methanethiol and other organic sulfides. The field data from both air and wastewater quality monitoring demonstrated that more H2S (1 ppmv) was formed at a more negative redox potential, lower pH, and a higher temperature of wastewater. Since the lower detection level of most current analytical techniques is much greater than human's smell and the reference concentration for adverse health effects, automatic monitoring on the threshold of H2S formation provides a mechanism to trigger control techniques only when necessary for cost saving purposes. Based on Gibbs free energy, a more negative redox potential is required to form H2S with an increase in pH and a decrease in temperature and SO 4(2-) concentration. However, pH effect is more significant than both temperature and SO 4(2-) concentration for H2S formation. It is recommended that H2S control techniques be started when the redox potential is below -44 mV, the pH is lower than 5.6, and the temperature is higher than 11.5 degrees C to control H2S below the reference concentration. Corroded concrete particles were examined by X-ray diffraction, which showed that the dominant crystal form was quartz. PMID- 22941186 TI - Predictions of soil organic carbon using laboratory-based hyperspectral data in the northern Tianshan mountains, China. AB - This paper presents a study dealing with soil organic carbon (SOC) estimation of soil through the combination of soil spectroscopy and multivariate stepwise linear regression. Soil samples were collected in the three sub-regions, dominated by brown calcic soil, in the northern Tianshan Mountains, China. Spectral measurements for all soil samples were performed in a controlled laboratory environment by a portable ASD FieldSpec FR spectrometer (350-2,500 nm). Twelve types of transformations were applied to the soil reflectance to remove the noise and to linearize the correlation between reflectance and SOC content. Based on the spectral reflectance and its derivatives, hyperspectral models can be built using correlation analysis and multivariable statistical methods. The results show that the main response range of soil organic carbon is between 400 and 750 nm. Correlation analysis indicated that SOC has stronger correlation with the second derivative than with the original reflectance and other transformations data. The two models developed with laboratory spectra gave good predictions of SOC, with root mean square error (RMSE) <5.0. The use of the full visible near-infrared spectral range gave better SOC predictions than using visible separately. The multivariate stepwise linear regression of second derivate model (model A) is optimal for estimating SOC content, with a determination coefficient of 0.894 and RMSE of 0.322. The results of this research study indicated that, for the grassland regions, combining soil spectroscopy and mathematical statistical methods does favor accurate prediction of SOC. PMID- 22941187 TI - Determination of ultra-trace amounts of cadmium by ET-AAS after column preconcentration with a new sorbent of modified MWCNTs. AB - The present research reports on the application of modified multiwalled carbon nanotubes as a new, easily prepared, and stable solid sorbent for the column preconcentration of ultra-trace amounts of cadmium in aqueous solution. Multiwalled carbon nanotubes were oxidized with concentrated HNO3 and modified with 2-(5-bromo-2-pyridylazo)-5-diethylaminophenol and then were used as a solid phase for the column preconcentration of Cd(II). Elution was carried out with 0.5 mol L(-1) HNO3. The amount of eluted Cd(II) was measured using electrothermal atomic absorption spectrometry. Various parameters such as pH, sample and eluent flow rate, eluent concentration, breakthrough volume, and interference of a great number of anions and cations on the retention of analyte on sorbent were studied. Under the optimized conditions, the calibration graph was linear in the range of 0.67 ng L(-1) to 5.0 MUg L(-1) and the detection limit (3Sb, n = 7) was 0.14 ng L(-1) in initial solution. A preconcentration factor of 300 and relative standard deviations of +/- 3.6 % for seven successive determinations of 3 ng of Cd(II) were achieved. The column preconcentration was successfully applied to the analysis of river water, waste water, and Persian Gulf water sample. PMID- 22941189 TI - Comprehensive genomic analysis identifies SOX2 as a frequently amplified gene in small-cell lung cancer. AB - Small-cell lung cancer (SCLC) is an exceptionally aggressive disease with poor prognosis. Here, we obtained exome, transcriptome and copy-number alteration data from approximately 53 samples consisting of 36 primary human SCLC and normal tissue pairs and 17 matched SCLC and lymphoblastoid cell lines. We also obtained data for 4 primary tumors and 23 SCLC cell lines. We identified 22 significantly mutated genes in SCLC, including genes encoding kinases, G protein-coupled receptors and chromatin-modifying proteins. We found that several members of the SOX family of genes were mutated in SCLC. We also found SOX2 amplification in ~27% of the samples. Suppression of SOX2 using shRNAs blocked proliferation of SOX2-amplified SCLC lines. RNA sequencing identified multiple fusion transcripts and a recurrent RLF-MYCL1 fusion. Silencing of MYCL1 in SCLC cell lines that had the RLF-MYCL1 fusion decreased cell proliferation. These data provide an in-depth view of the spectrum of genomic alterations in SCLC and identify several potential targets for therapeutic intervention. PMID- 22941188 TI - Integrative genome analyses identify key somatic driver mutations of small-cell lung cancer. AB - Small-cell lung cancer (SCLC) is an aggressive lung tumor subtype with poor prognosis. We sequenced 29 SCLC exomes, 2 genomes and 15 transcriptomes and found an extremely high mutation rate of 7.4+/-1 protein-changing mutations per million base pairs. Therefore, we conducted integrated analyses of the various data sets to identify pathogenetically relevant mutated genes. In all cases, we found evidence for inactivation of TP53 and RB1 and identified recurrent mutations in the CREBBP, EP300 and MLL genes that encode histone modifiers. Furthermore, we observed mutations in PTEN, SLIT2 and EPHA7, as well as focal amplifications of the FGFR1 tyrosine kinase gene. Finally, we detected many of the alterations found in humans in SCLC tumors from Tp53 and Rb1 double knockout mice. Our study implicates histone modification as a major feature of SCLC, reveals potentially therapeutically tractable genomic alterations and provides a generalizable framework for the identification of biologically relevant genes in the context of high mutational background. PMID- 22941190 TI - Common variants at 6p21.1 are associated with large artery atherosclerotic stroke. AB - Genome-wide association studies (GWAS) have not consistently detected replicable genetic risk factors for ischemic stroke, potentially due to etiological heterogeneity of this trait. We performed GWAS of ischemic stroke and a major ischemic stroke subtype (large artery atherosclerosis, LAA) using 1,162 ischemic stroke cases (including 421 LAA cases) and 1,244 population controls from Australia. Evidence for a genetic influence on ischemic stroke risk was detected, but this influence was higher and more significant for the LAA subtype. We identified a new LAA susceptibility locus on chromosome 6p21.1 (rs556621: odds ratio (OR)=1.62, P=3.9*10(-8)) and replicated this association in 1,715 LAA cases and 52,695 population controls from 10 independent population cohorts (meta analysis replication OR=1.15, P=3.9*10(-4); discovery and replication combined OR=1.21, P=4.7*10(-8)). This study identifies a genetic risk locus for LAA and shows how analyzing etiological subtypes may better identify genetic risk alleles for ischemic stroke. PMID- 22941191 TI - Common variation at 6q16 within HACE1 and LIN28B influences susceptibility to neuroblastoma. AB - Neuroblastoma is a cancer of the sympathetic nervous system that accounts for approximately 10% of all pediatric oncology deaths. Here, we report a genome-wide association study of 2,817 neuroblastoma cases and 7,473 controls. We identified two new associations at 6q16, the first within HACE1 (rs4336470; combined P=2.7*10(-11); odds ratio 1.26, 95% confidence interval (CI) 1.18-1.35) and the second within LIN28B (rs17065417; combined P=1.2*10(-8); odds ratio 1.38, 95% CI 1.23-1.54). Expression of LIN28B and let-7 miRNA correlated with rs17065417 genotype in neuroblastoma cell lines, and we observed significant growth inhibition upon depletion of LIN28B, specifically in neuroblastoma cells that were homozygous for the risk allele. Low HACE1 and high LIN28B expression in diagnostic primary neuroblastomas were associated with worse overall survival (P=0.008 and 0.014, respectively). Taken together, these data show that common variants in HACE1 and LIN28B influence neuroblastoma susceptibility and indicate that both genes likely have a role in disease progression. PMID- 22941193 TI - Sodium bicarbonate supplementation improves hypertrophy-type resistance exercise performance. AB - The aim of the present study was to examine the effects of sodium bicarbonate (NaHCO(3)) administration on lower-body, hypertrophy-type resistance exercise (HRE). Using a double-blind randomized counterbalanced design, 12 resistance trained male participants (mean +/- SD; age = 20.3 +/- 2 years, mass = 88.3 +/- 13.2 kg, height = 1.80 +/- 0.07 m) ingested 0.3 g kg(-1) of NaHCO(3) or placebo 60 min before initiation of an HRE regimen. The protocol employed multiple exercises: squat, leg press, and knee extension, utilizing four sets each, with 10-12 repetition-maximum loads and short rest periods between sets. Exercise performance was determined by total repetitions generated during each exercise, total accumulated repetitions, and a performance test involving a fifth set of knee extensions to failure. Arterialized capillary blood was collected via fingertip puncture at four time points and analyzed for pH, [HCO(3)(-)], base excess (BE), and lactate [Lac(-)]. NaHCO(3) supplementation induced a significant alkaline state (pH: NaHCO(3): 7.49 +/- 0.02, placebo: 7.42 +/- 0.02, P < 0.05; [HCO(3)(-)]: NaHCO(3): 31.50 +/- 2.59, placebo: 25.38 +/- 1.78 mEq L(-1), P < 0.05; BE: NaHCO(3): 7.92 +/- 2.57, placebo: 1.08 +/- 2.11 mEq L(-1), P < 0.05). NaHCO(3) administration resulted in significantly more total repetitions than placebo (NaHCO(3): 139.8 +/- 13.2, placebo: 134.4 +/- 13.5), as well as significantly greater blood [Lac(-)] after the exercise protocol (NaHCO(3): 17.92 +/- 2.08, placebo: 15.55 +/- 2.50 mM, P < 0.05). These findings demonstrate ergogenic efficacy for NaHCO(3) during HRE and warrant further investigation into chronic training applications. PMID- 22941192 TI - Mapping cis- and trans-regulatory effects across multiple tissues in twins. AB - Sequence-based variation in gene expression is a key driver of disease risk. Common variants regulating expression in cis have been mapped in many expression quantitative trait locus (eQTL) studies, typically in single tissues from unrelated individuals. Here, we present a comprehensive analysis of gene expression across multiple tissues conducted in a large set of mono- and dizygotic twins that allows systematic dissection of genetic (cis and trans) and non-genetic effects on gene expression. Using identity-by-descent estimates, we show that at least 40% of the total heritable cis effect on expression cannot be accounted for by common cis variants, a finding that reveals the contribution of low-frequency and rare regulatory variants with respect to both transcriptional regulation and complex trait susceptibility. We show that a substantial proportion of gene expression heritability is trans to the structural gene, and we identify several replicating trans variants that act predominantly in a tissue restricted manner and may regulate the transcription of many genes. PMID- 22941195 TI - Current world literature. PMID- 22941194 TI - New management paradigms for infections in critically ill patients. PMID- 22941197 TI - A study of rural Senegalese attitudes and perceptions of their behavior to changes in the climate. AB - Semi-structured focus group discussions were employed to capture rural Senegalese attitudes and perceptions of their behavior to changes in the climate and their land use and livelihood strategies. Seven focus groups stratified by gender, ethnicity (Wolof and Peulh) and dominant production system (cultivators and pastoralists) in five villages in semi-arid northern Senegal revealed seven main themes. Rural livelihoods remain predominantly based on rainfall dependant practices, and although cultivators and pastoralists had a clear appreciation of changes in natural resources compared to a perceived more favorable past, few adaptive coping strategies beyond established ones were advocated. The seven themes are discussed in detail and their implications for rural livelihoods under future long term climate predictions discussed with the implications of this study for the development of scenarios of future land cover land use. PMID- 22941199 TI - Evaluation of serum diagnosis of pancreatic cancer by using surface-enhanced laser desorption/ionization time-of-flight mass spectrometry. AB - Proteomic methods have been widely used in disease marker discovery research. The aim of this study was to discover potential biomarkers for pancreatic cancer (PCa) using surface-enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF-MS). Crude serum samples from 132 patients with PCa and 67 healthy controls (HCs) were analyzed in duplicate using SELDI. Support vector machine (SVM) analysis of the spectra was used to generate a predictive algorithm based on proteins that were maximally differentially expressed between patients with PCa and the HCs in the training cohort. This algorithm was tested using leave-one-out cross-validation in the test cohort. From the 4 significant peaks in the training cohort, a classifier for separating patients with PCa from HCs was developed. The classifier was challenged with all samples achieving 96.67% sensitivity and 100% specificity in the training cohort and 93.1% sensitivity and 78.57% specificity in the test cohort. Additionally, the classifier correctly classified 12/12 stage Ia and 13/16 stage IIa PCa cases. The combination of the SELDI panel and CA19-9 was superior to CA19-9 alone in distinguishing individuals with PCa from the healthy subject group. These results suggest that high throughput proteomic profiling has the capacity to provide new biomarkers for the early detection and diagnosis of PCa. PMID- 22941198 TI - Active hexose-correlated compound and Bifidobacterium longum BB536 exert symbiotic effects in experimental colitis. AB - PURPOSE: Active hexose-correlated compound (AHCC) is a commercial extract obtained from Basidiomycetes under controlled conditions, yielding a 74 % content in oligosaccharides, especially alpha-glucans. AHCC has a number of therapeutic effects, including intestinal anti-inflammatory activity. Bifidobacterium longum BB536 is a probiotic with potential health-promoting effect at the gut level. The purpose of the present study was to evaluate the possibility of synergism between AHCC, which is believed to act as a prebiotic, and B. longum BB536. METHODS: We used the trinitrobenzene sulfonic acid model (TNBS) of colitis in rats. AHCC (100 or 500 mg kg(-1)) and B. longum BB536 (5 * 10(6) CFU rat(-1) day(-1)) were administered together or separately for 7 days prior to colitis induction and then for another 7 days and compared with control (noncolitic) and TNBS rats. RESULTS: The results show that both treatments had intestinal anti-inflammatory activity separately, which was enhanced when used in combination, as shown by changes in body weight gain, colonic weight to length ratio, myeloperoxydase activity and iNOS expression. Interestingly, the association of AHCC 100 mg kg( 1) + B. longum BB536 showed the highest anti-inflammatory activity. CONCLUSIONS: Our data provide a preclinical experimental basis for the synergistic effect of AHCC and B. longum BB536 on inflammatory bowel disease. PMID- 22941200 TI - Distinct roles of two alternative splice variants of matrilin-2 in protein oligomerization and proteolysis. AB - Matrilin-2 (matn2) contains a unique domain, between the second von Willebrand factor A (vWFA) domain and the C-terminal coiled-coil domain, with no sequence homology with other family members. Complementary DNA (cDNA) sequence analysis of matn2 expression in both mice and humans revealed an alternative splice site in the region of the unique domain, which forms a short and a long splicing variant (containing an additional 19 amino acids). However, the expression heterogeneity of the alternative spliced variants, and the roles of the unique domain in oligomerization and proteolysis of matn2 are unknown. In this study, we examined the expression of the two alternative splice variants of matn2 in several skeletal and non-skeletal tissues by reverse transcription-polymerase chain reaction. Both splice variants of matn2 were detected at the mRNA level in all tissues studied. To explore the biochemical significance, several minigene constructs containing the second vWFA domain, the unique domain (with either a long or short form) and the coiled-coil domain of mouse mini matn2 were generated. Ectopic expression of these constructs demonstrated that the long form of matn2 is capable of self-assembling into several oligomeric forms, including a tetramer, trimer, pentamer or multimer; but the short form is only capable of forming a tetramer, trimer or dimer. Moreover, we observed that the splice variants of matn2 are important in modulating matn2 cleavage when co-expressed with matrilin-1 or matrilin-3. These results indicate that the two alternative splice variants have distinct roles in the processes of post-translational modification of matn2, which may have an impact on the homeostasis of the matrilin filamentous network of the extracellular matrix. PMID- 22941201 TI - The population model of bone remodelling employed the optimal control. AB - Several models have been developed in recent years which apply population dynamics methods to describe the mechanisms of bone remodelling. This study incorporates the population kinetics model of bone turnover (including the osteocyte loop regulation) with the optimal control technique. Model simulations have been performed with a wide range of rate parameters using the Monte Carlo method. The regression method has also been used to investigate the interdependence of the location of equilibrium and the characteristics of the equilibrium/relaxation time on the rate parameters employed. The dynamic optimal control outlook for the regulation of bone remodelling processes, in the context of the osteocyte-control population model, has been discussed. Optimisation criteria have been formulated from the perspective of the energetic and metabolic losses in the tissue, with respect to the performance of the bone multicellular unit. PMID- 22941202 TI - Fusing probability density function into Dempster-Shafer theory of evidence for the evaluation of water treatment plant. AB - The evaluation of the status of a municipal drinking water treatment plant (WTP) is important. The evaluation depends on several factors, including, human health risks from disinfection by-products (R), disinfection performance (D), and cost (C) of water production and distribution. The Dempster-Shafer theory (DST) of evidence can combine the individual status with respect to R, D, and C to generate a new indicator, from which the overall status of a WTP can be evaluated. In the DST, the ranges of different factors affecting the overall status are divided into several segments. The basic probability assignments (BPA) for each segment of these factors are provided by multiple experts, which are then combined to obtain the overall status. In assigning the BPA, the experts use their individual judgments, which can impart subjective biases in the overall evaluation. In this research, an approach has been introduced to avoid the assignment of subjective BPA. The factors contributing to the overall status were characterized using the probability density functions (PDF). The cumulative probabilities for different segments of these factors were determined from the cumulative density function, which were then assigned as the BPA for these factors. A case study is presented to demonstrate the application of PDF in DST to evaluate a WTP, leading to the selection of the required level of upgradation for the WTP. PMID- 22941203 TI - Effects of lead chloride on human erythrocyte membranes and on kinetic anion sulphate and glutathione concentrations. AB - Our study concerns the effects of exposure to lead chloride on the morphology, K(+) efflux, SO(4)(-) influx and GSH levels of the human erythrocyte. Blood was collected in heparinized tubes and washed three times. The cells were suspended at 3% hematocrit and incubated for 1 h at 25 degrees C in a medium containing increasing concentrations of lead chloride (0, 0.3, 0.5 and 1 MUM). After incubation, the suspensions were centrifuged and the erythrocyte pellets were divided into three aliquots for testing. The results show: an increase in the permeability of erythrocytes treated with lead chloride with consequent damage and cellular death, especially in the presence of high concentrations; an increase in potassium ion efflux; alterations in the morphology and membrane structure of the red blood cells; and a decrease in sulphate uptake, due either to the oxidative effect of this compound on the band 3 protein, which loses its biological valence as a carrier of sulphate ions, or to a decrease in the ATP erythrocyte concentration. In conclusion, the exposure of erythrocytes to Pb(2+) ions leads to a reduction in the average lifetime of the erythrocytes and the subsequent development of anemia. These data are discussed in terms of the possible effect of lead on the reduction-oxidation systems of the cell. Oxidant agents, such as lead, are known to cross-link integral membrane proteins, leading to K/Cl-cotransport. The increased K(+) efflux affects the altered redox state. PMID- 22941204 TI - Cloning of the human activated leukocyte cell adhesion molecule promoter and identification of its tissue-independent transcriptional activation by Sp1. AB - Activated leukocyte cell adhesion molecule (ALCAM) belongs to the immunoglobulin cell adhesion molecule super family. ALCAM is implicated in tumor progression, inflammation, and the differentiation of hematopoietic stem cells. Hitherto, the identity of regulatory DNA elements and cognate transcription factors responsible for ALCAM gene expression remained unknown. In this report, the human ALCAM promoter was cloned and its transcriptional mechanisms elucidated. The promoter is TATA-less and contains multiple GC-boxes. A proximal 650-bp promoter fragment conferred tissue-independent activation, whereas two contiguous regions upstream of this region negatively influenced promoter activity in a tissue-specific manner. The positive regulatory promoter region was mapped to a core 50 base pair sequence containing a conical Sp1 element. Mutation analysis revealed that this element alone or in tandem with elements immediately upstream was required for maximal promoter activity. Chromatin analysis revealed that Sp1 binds exclusively to the canonical binding sequence in vivo, but not to DNA sequence immediately upstream. Finally, we showed that over-expression of Sp1 significantly increased the basal promoter activity. Thus, Sp1 activated the ALCAM promoter in most cells. These findings have important ramifications for unraveling the roles of ALCAM in inflammation and tumorigenesis. PMID- 22941205 TI - The human telomerase catalytic subunit and viral telomerase RNA reconstitute a functional telomerase complex in a cell-free system, but not in human cells. AB - The minimal vertebrate telomerase enzyme is composed of a protein component (telomerase reverse transcriptase, TERT) and an RNA component (telomerase RNA, TR). Expression of these two subunits is sufficient to reconstitute telomerase activity in vitro, while the formation of a holoenzyme comprising telomerase associated proteins is necessary for proper telomere length maintenance. Previous reports demonstrated the high processivity of the human telomerase complex and the interspecies compatibility of human TERT (hTERT). In this study, we tested the function of the only known viral telomerase RNA subunit (vTR) in association with human telomerase, both in a cell-free system and in human cells. When vTR is assembled with hTERT in a cell-free environment, it is able to interact with hTERT and to reconstitute telomerase activity. However, in human cells, vTR does not reconstitute telomerase activity and could not be detected in the human telomerase complex, suggesting that vTR is not able to interact properly with the proteins constituting the human telomerase holoenzyme. PMID- 22941206 TI - Does resistance in severe infections caused by methicillin-resistant Staphylococcus aureus give you the 'creeps'? AB - PURPOSE OF REVIEW: The clinical implications of reduced vancomycin susceptibility amongst methicillin-resistant Staphylococcus aureus (MRSA) are controversial, and crossresistance to daptomycin amongst such strains has been reported. As a consequence of 'MIC creep', higher trough levels were recommended for serious infections. This review focusses on the new data published in the past 18 months that pertain to these issues. RECENT FINDINGS: Heteroresistant vancomycin intermediate Staphylococcus aureus reduces the clinical response rates to vancomycin in bacteraemic MRSA patients without impacting on mortality as opposed to 'MIC creep' with vancomycin minimum inhibitory concentration (MIC) levels of >=1.5 mg/l that are significantly associated with mortality. Although daptomycin resistance is rare, 'concomitant MIC creep' amongst MRSA isolates with increasing vancomycin MICs may occur or exist concurrently amongst such strains. The aggressive vancomycin dosing regimens are still associated with unacceptable high microbiological failure rates and it is not currently possible to achieve probability of target attainment at higher vancomycin MICs of 2 mg/l. The nephrotoxic impact of high-dose vancomycin therapy has been confirmed. SUMMARY: Continued monitoring of patients on aggressive vancomycin dosing schedules is advised. Unless alternative dosing strategies prove otherwise efficacious, an alternative antibiotic should be considered for severe MRSA infections with vancomycin MICs greater than 1 mg/l. The utility of vancomycin may be waning but will depend on the prevalence of resistant MRSA phenotypes in a specific ICU. PMID- 22941207 TI - The role of neuromuscular blockers in ARDS: benefits and risks. AB - PURPOSE OF REVIEW: Neuromuscular blocking agents (NMBAs) are part of the pharmaceutical arsenal employed to treat acute respiratory distress syndrome (ARDS). However, their use remains controversial because the potential benefits of these agents are counterbalanced by possible adverse effects. This review summarizes advantages and risks of NMBAs based on the most recent literature. RECENT FINDINGS: NMBAs have been shown to improve oxygenation during severe ARDS in three randomized controlled trials. The most recent results demonstrated that NMBAs decrease 90-day in-hospital mortality, particularly in the most hypoxaemic patients. NMBAs have not been shown to be an independent risk factor of neuromyopathy in most studies. SUMMARY: NMBAs are commonly used in ARDS (25-55% of patients), but the benefits and the risks of using these agents are controversial. Recent data suggest that a continuous infusion of cisatracurium during the first 48 h of ARDS, particularly for patients with a P(a)O(2)/F(i)O(2) ratio less than 120, can decrease 90-day in-hospital mortality. NMBAs do not appear to be an independent risk factor for ICU-acquired weakness if they are not given with corticosteroids or in patients with hyperglycaemia. PMID- 22941208 TI - Pathophysiology of acute brain dysfunction: what's the cause of all this confusion? AB - PURPOSE OF REVIEW: To survey the recent medical literature examining the pathophysiology of acute brain dysfunction (delirium and coma) in the ICU. RECENT FINDINGS: Clinical risk factors for brain dysfunction in the ICU continue to be elucidated and prediction models developed. Multiple studies have identified sedatives, especially benzodiazepines, as modifiable risk factors for delirium. Imaging studies examining global brain disorders have demonstrated white matter lesions and brain atrophy to be associated with delirium. Endothelial dysfunction, increased blood-brain barrier permeability, and reduced blood flow have also been implicated in cerebral perfusion abnormalities associated with brain dysfunction. The response of the brain to inflammation, including activation of microglia and neuronal apoptosis, leads to synaptic and neurochemical disturbances. Decreased availability of acetylcholine during critical illness leads to decreased counter-regulatory activity in response to inflammatory disease states, likely causing additional injury and further neurotransmitter imbalances. Dopamine, norepinephrine, and serotonin excess and their respective amino acid precursors have also been associated with brain dysfunction. SUMMARY: The multifactorial pathophysiology of acute brain dysfunction remains incompletely understood. Multiple clinical risk factors have been identified and numerous pathophysiologic pathways have been hypothesized. Future research is required to investigate the roles of these pathways on differing clinical presentations, potential therapeutic options, and patient outcomes. PMID- 22941209 TI - Long-term sequelae of acute kidney injury in the ICU. AB - PURPOSE OF REVIEW: Acute kidney injury (AKI) in the ICU is associated with adverse outcomes. We review the long-term consequences of AKI in ICU patients. RECENT FINDINGS: Observational studies show associations between AKI and mortality, prolonged length of ICU stay, dependence on mechanical ventilation, the development and progression of chronic kidney disease (CKD), and need for permanent renal replacement therapy. Few studies evaluate ICU AKI outcomes specifically, and data on long-term outcomes of survivors from this population are sparse. Little information exists comparing AKI in ICU and non-ICU settings, and prospective study designs to address such questions are problematic. AKI in the ICU should be distinguished from AKI in other clinical settings, as the underlying pathophysiology, severity of illness, and risk for permanent sequelae may be different. AKI and CKD are not mutually exclusive, but are part of a clinical spectrum in which AKI can potentiate the risk for CKD and pre-existing CKD increases risks of AKI. SUMMARY: Further research is necessary to delineate the mechanisms by which AKI may lead to CKD, and to understand how CKD enhances the risk for developing AKI. Whereas restrospective observational studies of this population exist, prospective clinical studies and trials evaluating the long term clinical outcomes of AKI specifically in ICU patients are needed. PMID- 22941210 TI - From persistence to palliation: limiting active treatment in the ICU. AB - PURPOSE OF REVIEW: End-of-life care and communication deficits are important sources of conflicts within ICU teams and with patients or families. This narrative review describes recent studies on how to improve palliative care and surrogate decision-making in ICUs and compares the results with previously published literature on this topic. RECENT FINDINGS: Awareness and use of end-of life recommendations is still low. Education about end-of-life is beneficial for end-of-life decisions. Residency and nurses training programmes start to integrate palliative care education in critical care. Integration of palliative care consults is recommended and probably cost-effective. Projects that promote direct contact of care team members with patients/families may be more likely to improve care than educational interventions for caregivers only. The family's response to critical illness includes adverse psychological outcome ('postintensive care syndrome-family'). Information brochures and structured communication protocols are likely to improve engagement of family members in surrogate decision-making; however, validation of outcome effects of their use is needed. SUMMARY: Optimizing palliative care and communication skills is the current challenge in ICU end-of-life care. Intervention strategies should be interdisciplinary, multiprofessional and family-centred in order to quickly reach these goals. PMID- 22941211 TI - Resident full-time specialists in the ICU: a survivable model? AB - PURPOSE OF REVIEW: Intensivists have a professional and personal interest in trying to answer whether immediate review of patients by a consultant intensivist improves outcomes. Although some advocate in-hospital around-the-clock consultant intensivist presence, does the available evidence suggest all ICUs should be staffed in such a manner and is such a service sustainable given the shortage of intensivists, potential loss of staff from burnout and cost? RECENT FINDINGS: We present in narrative form the background and recent literature for a consultant resident service in terms of the ethical tenets of nonmaleficence, beneficence, autonomy and justice. Nonmaleficence - what is the evidence it is bad for patients not to provide a resident service? Beneficence - what is the evidence a resident intensivist service is good for patients? Autonomy - is it in intensivists' own interests to provide a 24-h service? And justice - is it a justifiable use of healthcare resources? SUMMARY: A unified staffing solution within a country's different ICUs, let alone between countries, is unlikely. The current evidence does not universally support or justify 24 h/7 days consultant intensivist presence. International differences in staffing models and ICU structures make direct comparisons difficult and in some circumstances the balance may favour 24 h/7 days consultant intensivists. PMID- 22941212 TI - Tetrodotoxin attenuates isoproterenol-induced hypertrophy in H9c2 rat cardiac myocytes. AB - Cardiac hypertrophy is often associated with an increased sympathetic drive, and both in vitro and in vivo studies have demonstrated the development of cardiomyocyte hypertrophy in response to either alpha- or beta- adrenergic stimulation. The present study was carried out to determine whether the reversible sodium channel blocker tetrodotoxin (TTX) exerts a direct anti hypertrophic effect on isoproterenol (ISO)-induced cell hypertrophy and find the underlying mechanism that regulate [Na(+)]( i ). The experiments were performed on cultured H9c2 cells exposed to ISO (10 MUM) alone or combined with TTX (1 MUM) for 48 h. Our results showed that ISO significantly increased cell surface area by 30 % and atrial natriuretic peptide gene expression by nearly twofold (p < 0.05 for both). These effects were associated with a significant reduction in the gene expression of Na(+)/K(+)-ATPase isoforms alpha2 and alpha3, whereas the alpha1 isoform was unaffected. Conversely, ISO increased Na(+)-H(+) exchanger 1 (NHE-1) gene expression by approximately 40 % and significantly increased [Na(+)]( i ) level by 50 % (p < 0.05 for both). ISO was also found to significantly increase aquaporin 4 gene expression by nearly ninefold (p < 0.05). All these effects were prevented when identical experiments were carried out in the presence of TTX, but the expression of NHE-1. The expression of sodium channel protein type 5 subunit alpha was unaffected by either ISO or TTX. When taken together, these studies show that TTX attenuates the hypertrophic effect of ISO and suggest a possible approach to limiting ISO-induced hypertrophy in clinical treatment. PMID- 22941213 TI - Differential inhibitory effects of two Raf-targeting drugs, sorafenib and PLX4720, on the growth of multidrug-resistant cells. AB - B-Raf is the most frequently mutated protein kinase in the MAPK signaling cascade in human cancers, making it an important therapeutic target. Here, we describe the differential effects of two Raf-targeting drugs, sorafenib and PLX4720, on multidrug-resistant v-Ha-ras-transformed cells (Ras-NIH 3T3/Mdr). We demonstrate that the growth of the NIH 3T3/Mdr cell line was affected in a dose-dependent manner more significantly by the pan-Raf inhibitor sorafenib than by the selective mutant B-Raf inhibitor PLX4720. Despite their differential effects on LKB1/AMPK phosphorylation, both sorafenib and PLX4720 inhibited downstream mTOR signaling with concomitant induction of autophagy, implying that the differential effects of sorafenib and PLX4720 on multidrug-resistant cells might not be due to different levels of autophagy and apoptosis. Interestingly, sorafenib caused a dose-dependent increase in rhodamine 123 uptake and retention. More importantly, sorafenib reversed the resistance to paclitaxel in Ras-NIH 3T3/Mdr cells. Moreover, MEK/ERK signaling was hyperactivated by the selective mutant B-Raf inhibitor PLX4720 and inhibited by the pan-Raf inhibitor sorafenib. Our data suggest that sorafenib sensitivity in MDR cells is mediated through the inhibition of P-glycoprotein activity following strong inhibition of Raf/MEK/ERK signaling. Thus, Raf inhibition with sorafenib might be a promising approach to abrogate the multidrug resistance of cancer cells. PMID- 22941215 TI - Mutations in the nebulin gene in a child with nemaline (rod) myopathy. AB - Nemaline myopathy, also called rod myopathy, is a relatively common congenital myopathy and probably second in incidence only to central core disease. The mainstay of diagnosis is histopathology, but detection of the causative mutation is mandatory for determining the mode of inheritance and for prenatal diagnosis. The authors report two siblings with nemaline myopathy caused by mutations in the nebulin gene. PMID- 22941214 TI - Rheumatic heart disease: progress and challenges in India. AB - Rheumatic heart disease, a neglected disease, continues to be a burden in India and other developing countries. It is a result of an autoimmune sequalae in response to group A beta hemolytic streptococcus (GAS) infection of the pharynx. Acute rheumatic fever (RF), a multisystem inflammatory disease, is followed by rheumatic heart disease (RHD) and has manifestations of joints, skin and central nervous system involvement. A review of epidemiological studies indicates unchanged GAS pharyngitis and carrier rates in India. The apparent decline in RHD rates in India as indicated by the epidemiological studies has to be taken with caution as methodological differences exist among studies. Use of echocardiography increases case detection rates of RHD in population surveys. However, the significance of echo based diagnosis of carditis needs further evaluation to establish the significance. Research in this area through prospective follow up studies will have to be undertaken by the developing countries as the interest of developed countries in the disease has waned due the declined burden in their populations. Prevention of RHD is possible through treatment of GAS pharyngitis (primary prophylaxis) and continued antibiotic treatment for number of years in patients with history of RF to prevent recurrences (secondary prophylaxis). The cost effectiveness and practicality of secondary prophylaxis is well documented. The challenge to any secondary prophylaxis program for prevention of RF in India will be the availability of benzathine penicillin G and dissipation of fears of allergic reactions to penicillin among practitioners, general public and policy makers. The authors review here the progress and challenges in epidemiology, diagnosis and primary and secondary prevention of RF and RHD. PMID- 22941216 TI - Prevalence of monosymptomatic nocturnal enuresis and its correlates in school going children of Lucknow. AB - OBJECTIVES: To determine the prevalence of primary monosymptomatic nocturnal enuresis (PMNE) and its correlates in school going children of Lucknow. METHODS: It is a cross-sectional school based study conducted in a random sample of 1212 school going children of Lucknow belonging to the middle socioeconomic strata. Data was collected via questionnaire designed for parents. Detailed urological history was obtained and physical examination done in the children whose parents answered the questionnaire. The chi-square test was used to compare the categorical/dichotomous indicators and backward logistic regression was used to find out the significant risk factors for monosymptomatic nocturnal enuresis. RESULTS: Study reports the prevalence of PMNE to be 12.6 % (95 % CI = 10.9-14.3 %) and significant association of enuresis with the presence of home conflicts(adjusted OR = 38.37, 95 % CI = 20.04-73.47), stress in children due to enuresis(adjusted OR = 10.86, 95%CI = 5.73-20.57), scolding(adjusted OR = 6.78,95%CI = 3.69-12.44), parental history of enuresis(adjusted OR = 3.57, 95%CI = 1.96-6.50), poor scholastic performance(adjusted OR = 2.88,95 % = 1.49-5.56), age 6-8 y (adjusted OR = 13.80,95%CI = 4.38-43.45) and living with single parent (adjusted OR = 0.34, 95%CI = 0.17-0.68). Prevalence of monosymptmatic nocturnal enuresis MNE was 17.9 % (p = 0.001) among children who were not exclusively breastfed till 6 mo of age in the index study. CONCLUSIONS: Enuresis is a pediatric health problem with high prevalence. Parental awareness needs to be created about this condition. PMID- 22941217 TI - Common childhood poisonings and their outcome in a tertiary care center in Delhi. AB - Clinical profile of children presenting with poisoning to the Pediatric emergency department of a tertiary care hospital in Delhi from 8.1.2009 to 8.10.09 was studied prospectively. Fifty two cases of accidental poisoning were reported during this period which formed 1.05 % of all pediatric admissions (5094 admissions). No case of homicidal poisoning was reported. There were 80.7 % children between 1-5 y of age with male preponderance. PICA was observed in 57.7 % children. Overall mortality was 7.7 % and 11.3 % children required pediatric intensive care unit (PICU). Kerosene oil poisoning remained the commonest accidental poisoning in this study. An interesting trend was concentrated HCL poisoning (now a common household product) as the second commonest poisoning (17.3 %). This was followed by poisoning with various drugs used by adults in the house. PMID- 22941218 TI - The optimal treatment of type II and III odontoid fractures in the elderly: a systematic review. AB - PURPOSE: Odontoid fractures are the most common cervical spine fractures in the elderly. As the population ages, their incidence is expected to increase progressively. The optimal treatment of this condition is still the subject of controversy. The objective of this review is to summarize and compare the outcome of surgical and conservative interventions in the elderly (>= 65 years). METHODS: A comprehensive search was conducted in nine databases of medical literature, supplemented by reference and citation tracking. Clinical status was considered the primary outcome. Fracture union and stability rates were considered secondary outcomes. RESULTS: A total of nineteen studies met the inclusion criteria. All studies were performed retrospectively and were of limited quality. There was insufficient data, especially from direct comparisons, to determine the difference in clinical outcome between surgical and conservative interventions. Osseous union was achieved in 66-85 % of surgically treated patients and in 28-44 % of conservatively treated patients. Fracture stability was achieved in 82-97 % of surgically patients and in 53-79 % of conservatively treated patients. CONCLUSIONS: There was insufficient data to determine a potential difference in clinical outcome between different treatment groups. Surgically treated patients showed higher osseous union rates compared to conservatively treated patients, possibly because of different selection mechanisms. The majority of patients appears to achieve fracture stability regardless of the applied treatment. A prospective trial with appropriate sample size is needed to identify the optimal treatment of odontoid fractures in the elderly and predictors for the success of either one of the available treatments. PMID- 22941219 TI - Elevated liver enzymes in patients with ankylosing spondylitis treated with etanercept. AB - TNF-alpha blocking agents are very effective in patients with ankylosing spondylitis (AS), but several cases of liver problems have been published. We systematically studied the frequency of this potential side effect in our AS patients treated with etanercept. Consecutive AS patients treated with etanercept for at least 3 months were included. Liver disease was defined as elevated liver enzymes more than 1.5 times the upper normal limit (UNL) and was categorised as probably, possibly, probably not or not related to etanercept treatment. Patients with and without raised liver enzymes were compared for prognostic factors. A total of 105 patients were included. Fifteen patients had elevated liver enzymes more than once. In nine cases, the liver disease was probably (five) or possibly (four) related to etanercept treatment. The liver enzyme elevations were serious (>3* UNL) in six cases and resulted in permanent cessation of etanercept in two cases. The nine patients with liver disease were compared with patients without elevated liver enzymes. No differences were found in age or use of alcohol; however, in patients with liver disease, a higher body mass index and a trend for a higher atherogenic index were observed. Hepatic steatosis was observed in five of six patients with elevated liver enzymes. Elevated serum aminotransferases, probably or possibly related to etanercept treatment, were observed in 9 % of the AS patients. An increased risk for the elevation of liver enzymes was found in patients with a higher body mass index. We recommend regular testing of liver enzymes in patients treated with etanercept. PMID- 22941220 TI - A calculation mode for the correct GC/ECNI-MS-SIM determination of polychlorinated terphenyls in the presence of high excesses of polychlorinated biphenyls. AB - Polychlorinated terphenyls (PCTs) are a class of persistent organic pollutants difficult to analyze by gas chromatography with mass spectrometry operated in the selected ion monitoring mode (GC/MS-SIM) in environmental samples due to the retention time and mass range overlap with polychlorinated biphenyls (PCBs). To overcome these drawbacks, we developed and evaluated a mathematical calculation algorithm which allows to detail the interference of PCT congeners in GC/electron capture negative ion (ECNI)-MS-SIM chromatograms by PCBs. The calculation takes advantage of the abundance and ratio of two suitable isotope peaks of the molecular ion of PCTs. With the help of this method, we detected at least 63 tetra- to nonachlorinated terphenyls in the blubber of a harbour porpoise (Phocoena phocoena) from the North Sea. The interference of these peaks by PCBs ranged from >100 to 0 %. The novel calculation method used in combination with GC/ECNI-MS-SIM is suitable to analyze PCTs in environmental and food samples. However, it can also be applied to GC/EI-MS measurements. PMID- 22941221 TI - Simultaneous determination of cyanide and thiocyanate in plasma by chemical ionization gas chromatography mass-spectrometry (CI-GC-MS). AB - An analytical method utilizing chemical ionization gas chromatography-mass spectrometry was developed for the simultaneous determination of cyanide and thiocyanate in plasma. Sample preparation for this analysis required essentially one-step by combining the reaction of cyanide and thiocyanate with pentafluorobenzyl bromide and simultaneous extraction of the product into ethyl acetate facilitated by a phase-transfer catalyst, tetrabutylammonium sulfate. The limits of detection for cyanide and thiocyanate were 1 MUM and 50 nM, respectively. The linear dynamic range was from 10 MUM to 20 mM for cyanide and from 500 nM to 200 MUM for thiocyanate with correlation coefficients higher than 0.999 for both cyanide and thiocyanate. The precision, as measured by %RSD, was below 9 %, and the accuracy was within 15 % of the nominal concentration for all quality control standards analyzed. The gross recoveries of cyanide and thiocyanate from plasma were over 90 %. Using this method, the toxicokinetic behavior of cyanide and thiocyanate in swine plasma was assessed following cyanide exposure. PMID- 22941222 TI - Synthesis, structure and insecticidal activities of some novel amides containing N-pyridylpyrazole moeities. AB - In our search for environmentally benign insecticides with high activity, low toxicity and low residue, a novel series of amides containing N- pyridylpyrazole moieties were designed and synthesized. The structures of the title compounds were characterized and confirmed by 1H-NMR and elemental analysis. Furthermore, the structure of compound 7l was determined by single crystal X-ray diffraction. The preliminary bioassay tests showed that some of them exhibited good insecticidal activities against Mythimna separata Walker, Plutella xylostella (Linnaeus, 1758) and Laphygma exigua Hubner. PMID- 22941223 TI - Computational prediction of blood-brain barrier permeability using decision tree induction. AB - Predicting blood-brain barrier (BBB) permeability is essential to drug development, as a molecule cannot exhibit pharmacological activity within the brain parenchyma without first transiting this barrier. Understanding the process of permeation, however, is complicated by a combination of both limited passive diffusion and active transport. Our aim here was to establish predictive models for BBB drug permeation that include both active and passive transport. A database of 153 compounds was compiled using in vivo surface permeability product (logPS) values in rats as a quantitative parameter for BBB permeability. The open source Chemical Development Kit (CDK) was used to calculate physico-chemical properties and descriptors. Predictive computational models were implemented by machine learning paradigms (decision tree induction) on both descriptor sets. Models with a corrected classification rate (CCR) of 90% were established. Mechanistic insight into BBB transport was provided by an Ant Colony Optimization (ACO)-based binary classifier analysis to identify the most predictive chemical substructures. Decision trees revealed descriptors of lipophilicity (aLogP) and charge (polar surface area), which were also previously described in models of passive diffusion. However, measures of molecular geometry and connectivity were found to be related to an active drug transport component. PMID- 22941224 TI - Co-aggregation of RNA binding proteins in ALS spinal motor neurons: evidence of a common pathogenic mechanism. AB - While the pathogenesis of amyotrophic lateral sclerosis (ALS) remains to be clearly delineated, there is mounting evidence that altered RNA metabolism is a commonality amongst several of the known genetic variants of the disease. In this study, we evaluated the expression of 10 ALS-associated proteins in spinal motor neurons (MNs) in ALS patients with mutations in C9orf72 (C9orf72(GGGGCC)-ALS; n = 5), SOD1 (mtSOD1-ALS; n = 9), FUS/TLS (mtFUS/TLS-ALS; n = 2), or TARDBP (mtTDP-43 ALS; n = 2) and contrasted these to cases of sporadic ALS (sALS; n = 4) and familial ALS without known mutations (fALS; n = 2). We performed colorimetric immunohistochemistry (IHC) using antibodies against TDP-43, FUS/TLS, SOD1, C9orf72, ubiquitin, sequestosome 1 (p62), optineurin, phosphorylated high molecular weight neurofilament, peripherin, and Rho-guanine nucleotide exchange factor (RGNEF). We observed that RGNEF-immunoreactive neuronal cytoplasmic inclusions (NCIs) can co-localize with TDP-43, FUS/TLS and p62 within spinal MNs. We confirmed their capacity to interact by co-immunoprecipitations. We also found that mtSOD1-ALS cases possess a unique IHC signature, including the presence of C9orf72-immunoreactive diffuse NCIs, which allows them to be distinguished from other variants of ALS at the level of light microscopy. These findings support the hypothesis that alterations in RNA metabolism are a core pathogenic pathway in ALS. We also conclude that routine IHC-based analysis of spinal MNs may aid in the identification of families not previously suspected to harbor SOD1 mutations. PMID- 22941225 TI - Disseminated oligodendroglial-like leptomeningeal tumor of childhood: a distinctive clinicopathologic entity. AB - Rare, generally pediatric oligodendroglioma-like neoplasms with extensive leptomeningeal dissemination have been interpreted variably as glial, oligodendroglial or glioneuronal. The clinicopathologic features have not been fully characterized. We studied 36 patients, 12 females and 24 males with a median age of 5 years (range 5 months-46 years). MRI demonstrated leptomeningeal enhancement, frequently with cystic or nodular T2 hyperintense lesions within the spinal cord/brain along the subpial surface. A discrete intraparenchymal lesion, usually in the spinal cord, was found in 25 (of 31) (81 %). Tumors contained oligodendroglioma-like cells with low-mitotic activity (median 0 per 10 high power fields, range 0-4), and rare ganglion/ganglioid cells in 6 cases (17 %). Tumors were mostly low-grade, with anaplastic progression in 8 (22 %). Immunohistochemistry demonstrated strong reactivity for OLIG2 (7 of 9) (78 %), and moderate/strong S100 (11 of 12) (92 %), GFAP (12 of 31) (39 %) and synaptophysin (19 of 27) (70 %). NeuN, EMA, and mutant IDH1 (R132H) protein were negative. Median MIB1 labeling index was 1.5 % (range <1-30 %). FISH (n = 13) or SNP array (n = 2) demonstrated 1p loss/intact 19q in 8 (53 %), 1p19q co-deletion in 3 (20 %), and no 1p or 19q loss in 4 (27 %). Clinical follow-up (n = 24) generally showed periods of stability or slow progression, but a subset of tumors progressed to anaplasia and behaved more aggressively. Nine patients (38 %) died 3 months-21 years after diagnosis (median total follow-up 5 years). We report a series of a neoplasm with distinct clinicopathologic and molecular features. Although most progress slowly, a significant fraction develop aggressive features. PMID- 22941226 TI - Blood-spinal cord barrier breakdown and pericyte reductions in amyotrophic lateral sclerosis. AB - The blood-brain barrier and blood-spinal cord barrier (BSCB) limit the entry of plasma components and erythrocytes into the central nervous system (CNS). Pericytes play a key role in maintaining blood-CNS barriers. The BSCB is damaged in patients with amyotrophic lateral sclerosis (ALS). Moreover, transgenic ALS rodents and pericyte-deficient mice develop BSCB disruption with erythrocyte extravasation preceding motor neuron dysfunction. Here, we studied whether BSCB disruption with erythrocyte extravasation and pericyte loss are present in human ALS. We show that 11 of 11 cervical cords from ALS patients, but 0 of 5 non neurodegenerative disorders controls, possess perivascular deposits of erythrocyte-derived hemoglobin and hemosiderin typically 10-50 MUm in diameter suggestive of erythrocyte extravasation. Immunostaining for CD235a, a specific marker for erythrocytes, confirmed sporadic erythrocyte extravasation in ALS, but not controls. Quantitative analysis revealed a 3.1-fold increase in perivascular hemoglobin deposits in ALS compared to controls showing hemoglobin confined within the vascular lumen, which correlated with 2.5-fold increase in hemosiderin deposits (r = 0.82, p < 0.01). Spinal cord parenchymal accumulation of plasma derived immunoglobulin G, fibrin and thrombin was demonstrated in ALS, but not controls. Immunostaining for platelet-derived growth factor receptor-beta, a specific marker for CNS pericytes, indicated a 54 % (p < 0.01) reduction in pericyte number in ALS patients compared to controls. Pericyte reduction correlated negatively with the magnitude of BSCB damage as determined by hemoglobin abundance (r = -0.75, p < 0.01). Thus, the BSCB disruption with erythrocyte extravasation and pericyte reductions is present in ALS. Whether similar findings occur in motor cortex and affected brainstem motor nuclei remain to be seen. PMID- 22941228 TI - Increased shear stress inhibits angiogenesis in veins and not arteries during vascular development. AB - Vascular development is believed to occur first by vasculogenesis followed by angiogenesis. Though angiogenesis is the formation of new vessels, we found that vascular density actually decreases during this second stage. The onset of the decrease coincided with the entry of erythroblasts into circulation. We therefore measured the level of shear stress at various developmental stages and found that it was inversely proportional to vascular density. To investigate whether shear stress was inhibitory to angiogenesis, we altered shear stress levels either by preventing erythroblasts from entering circulation ("low" shear stress) or by injection of a starch solution to increase the blood plasma viscosity ("high" shear stress). By time-lapse microscopy, we show that reverse intussusception (merging of two vessels) is inversely proportional to the level of shear stress. We also found that angiogenesis (both sprouting and splitting) was inversely proportional to shear stress levels. These effects were specific to the arterial or venous plexus however, such that the effect on reverse intussusception was present only in the arterial plexus and the effect on sprouting only in the venous plexus. We cultured embryos under altered shear stress in the presence of either DAPT, a Notch inhibitor, or DMH1, an inhibitor of the bone morphogenetic protein (BMP) pathway. DAPT treatment phenocopied the inhibition of erythroblast circulation ("low" shear stress) and the effect of DAPT treatment could be partially rescued by injection of starch. Inhibition of the BMP signaling prevented the reduction in vascular density that was observed when starch was injected to increase shear stress levels. PMID- 22941227 TI - Estradiol promotes neural stem cell differentiation into endothelial lineage and angiogenesis in injured peripheral nerve. AB - Neural stem cells (NSCs) differentiate into endothelial cells (ECs) and neuronal cells. Estradiol (E2) is known to exhibit proangiogenic effects on ischemic tissues via EC activation. Therefore, we hypothesized that E2 can promote the therapeutic potential of NSC transplantation for injured nerve repair via the differentiation of NSCs into ECs during neovascularization. NSCs isolated from newborn mouse brains were transplanted into injured sciatic nerves with (NSC/E2 group) or without E2-conjugated gelatin hydrogel (E2 group). The NSC/E2 group exhibited the greatest recovery in motor nerve conduction velocity, voltage amplitude, and exercise tolerance. Histological analyses revealed increased intraneural vascularity and blood perfusion as well as striking NSC recruitment to the neovasculature in the injured nerves in the NSC/E2 group. In vitro, E2 enhanced the NSC migration and proliferation inhibiting apoptosis. Fluorescence activated cell sorting analysis also revealed that E2 significantly increased the percentage of CD31 in NSCs, and the effect of E2 was completely neutralized by the estrogen receptor antagonist ICI. The combination of E2 administration and NSC transplantation cooperatively improved the functional recovery of injured peripheral nerves, at least in part, via E2-associated NSC differentiation into ECs. These findings provide a novel mechanistic insight into both NSC biology and the biological effects of endogenous E2. PMID- 22941230 TI - Diagnostic and prognostic biomarkers in acute myocarditis. Interleukin-10. AB - Acute myocarditis is a major inflammatory heart disease with a variety of clinical courses from the acute to chronic phases represented by unexpected circulatory deterioration during hospitalization and progression to dilated cardiomyopathy. Predicting these disease courses is important for patient management. However, biomarkers have not been fully investigated. In addition, clinical profiles including symptoms, serological data, and electrocardiographic findings in acute myocarditis often mimic more common disorders such as coronary artery disease, which have reduced the diagnostic accuracy of acute myocarditis. These issues hamper the development of safer and earlier therapeutic interventions specific for acute myocarditis. Against this background, identifying simple prognostic and diagnostic biomarkers would contribute dramatically to the improvement in outcomes. Interleukin-10 may be a strong candidate for an excellent biomarker. PMID- 22941229 TI - Chondrogenic ATDC5 cells: an optimised model for rapid and physiological matrix mineralisation. AB - The development of chondrogenic cell lines has led to major advances in the understanding of how chondrocyte differentiation is regulated, and has uncovered many signalling pathways and gene regulatory mechanisms required to maintain normal function. ATDC5 cells are a well established in vitro model of endochondral ossification; however, current methods are limited for mineralisation studies. In this study we demonstrate that culturing cells in the presence of ascorbic acid and 10 mM beta-glycerophosphate (betaGP) significantly increases the rate of extracellular matrix (ECM) synthesis and reduces the time required for mineral deposition to occur to 15 days of culture. Furthermore, the specific expression patterns of Col2a1 and Col10a1 are indicative of ATDC5 chondrogenic differentiation. Fourier transform-infrared spectroscopy analysis and transmission electron microscopy (TEM) showed that the mineral formed by ATDC5 cultures is similar to physiological hydroxyapatite. Additionally, we demonstrated that in cultures with betaGP, the presence of alkaline phosphatase (ALP) is required for this mineralisation to occur, further indicating that chondrogenic differentiation is required for ECM mineralisation. Together, these results demonstrate that when cultured in the presence of ascorbic acid and 10 mM betaGP, ATDC5 cells undergo chondrogenic differentiation and produce a physiological mineralised ECM from Day 15 of culture onwards. The rapid and novel method for ATDC5 culture described in this study is a major improvement compared with currently published methods and this will prove vital in the pursuit of underpinning the molecular mechanisms responsible for poor linear bone growth observed in a number of chronic diseases such as cystic fibrosis, chronic kidney disease, rheumatological conditions and inflammatory bowel disease. PMID- 22941231 TI - Heart failure update: A never-ending story. PMID- 22941232 TI - Sulforaphane inhibits proliferation by causing cell cycle arrest at the G2/M phase in rabbit articular chondrocytes. AB - Sulforaphane (SFN), a natural compound extracted from cruciferous vegetables, exhibits potent anticancer activity in various types of tumor cells. However, the effect of SFN on the proliferation of chondrocytes is not well understood. In the present study, we addressed the mechanism of action by which SFN suppresses proliferation. We demonstrate that SFN causes an irreversible arrest in cell proliferation, as determined by trypan blue dye exclusion assay and flow cytometric analysis. SFN induced cell cycle arrest at the G2/M phase by downregulation of cyclin B, cdc2 and cdc25c and upregulation of p21WAF1/CIP1 and p53 in a dose- and time-dependent manner, as determined by western blot analysis. Our data suggest that SFN regulates cell cycle arrest at the G2/M phase in rabbit articular chondrocytes. PMID- 22941233 TI - Safety and efficacy of fast-track surgery in laparoscopic distal gastrectomy for gastric cancer: a randomized clinical trial. AB - BACKGROUND: Fast-track surgery has been shown to enhance postoperative recovery in several surgical fields. This study aimed to evaluate the safety and efficacy of fast-track surgery in laparoscopic distal gastrectomy. METHODS: The present study was designed as a single-center, randomized, unblinded, parallel-group trial. Patients were eligible if they had gastric cancer for which laparoscopic distal gastrectomy was indicated. The fast-track surgery protocol included intensive preoperative education, a short duration of fasting, a preoperative carbohydrate load, early postoperative ambulation, early feeding, and sufficient pain control using local anesthetics perfused via a local anesthesia pump device, with limited use of opioids. The primary endpoint was the duration of possible and actual postoperative hospital stay. RESULTS: We randomized 47 patients into a fast-track group (n=22) and a conventional pathway group (n=22), with three patients withdrawn. The possible and actual postoperative hospital stays were shorter in the fast-track group than in the conventional group (4.68+/-0.65 vs. 7.05+/-0.65; P<0.001 and 5.36+/-1.46 vs. 7.95+/-1.98; P<0.001). The time to first flatus and pain intensity were not different between groups; however, a greater frequency of additional pain control was needed in the conventional group (3.64+/ 3.66 vs. 1.64+/-1.33; P=0.023). The fast-track group was superior to the conventional group in several factors of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire, including: fatigue, appetite loss, financial problems, and anxiety. The complication and readmission rates were similar between groups. CONCLUSIONS: Fast-track surgery could enhance postoperative recovery, improve immediate postoperative quality of life, and be safely applied in laparoscopic distal gastrectomy. PMID- 22941234 TI - Trauma during pregnancy: a population-based analysis of maternal outcome. AB - BACKGROUND: Serious injury during pregnancy is known to cause adverse maternal outcomes. However, the significance of minor injuries in adverse maternal outcomes requires clarification because most injuries sustained during pregnancy are minor ones. METHODS: Two population-based databases (inpatient and ambulatory care) were used to identify pregnant women who had severe (required hospitalization) or minor injuries (required ambulatory care only) prenatally. ICD-9-CM coding was used to categorize the types of prenatal injury and complications during delivery. The patient demographics, types and timing of the injuries, and their association with adverse maternal outcomes were compared among the uninjured, those with minor injury, and those with severe injury. Odds ratios were calculated to estimate the risks of having adverse outcomes in injured pregnant women compared with those who are uninjured. RESULTS: The severely injured women tended to be younger (<20 years old), lived in less urbanized regions, and had lower income levels than those who were uninjured or had minor injury. Motor vehicle crash was the most common mechanism of injury. While minor injuries were associated with preterm labor [odds ratio (OR)=1.25], a severe injury was strongly associated with increased risks of preterm labor, placental abruption, uterine rupture, and maternal death, especially during the third trimester (OR=2.71, 6.12, 7.79, and 20.15, respectively). Injuries away from the trunk could also lead to adverse maternal outcomes. CONCLUSIONS: Trauma during pregnancy, whether minor or severe, is associated with unfavorable maternal outcomes. Injuries considered minor for the general population are not minor for pregnant women. Therefore, these patients should be monitored carefully. PMID- 22941236 TI - Impact of posttransplantation glomerulonephritis on long-term outcome of kidney transplants: single-center 20-year experience. AB - BACKGROUND: Successful renal transplantation has been performed in patients with end-stage renal disease and has been routine in patients with end-stage renal failure for more than two decades. Despite advances in the use of immunosuppressants, there has been only modest improvement in long-term allograft survival. Accumulating data have demonstrated that chronic rejection and recurrent glomerulonephritis are major causes of long-term allograft loss. However, data regarding the long-term impact of posttransplantation glomerulonephritis (PTGN) on ethnic Chinese populations are still unavailable. METHODS: From 1984 to 2010, a total of 268 patients who underwent renal allograft biopsies were reviewed retrospectively. Renal outcomes were compared by Kaplan Meier analysis, and risk factors for renal survival and all-cause mortality were analyzed using the Cox proportional hazards model. RESULTS: In all, 85 patients (31.7%) had PTGN, and the mean time of disease onset was 5.32+/-5.18 years after transplantation. Among the 85 PTGN cases, 33 (39%) were immunoglobulin A (IgA) nephropathy, 24 (28%) were focal segmental glomerulosclerosis, and 8 (9.4%) were membranous GN. Significant risk was associated with posttransplant IgA GN in hepatitis B virus carriers (odds ratio 5.371, 95% confidence interval 1.68, 17.19; p=0.0064). A total of 45 PTGN patients had allograft loss, of whom 49% had IgA nephropathy. Patients with PTGN had inferior allograft survival rates compared to those with other pathologic findings (p<0.0003). CONCLUSIONS: Taken together, our results indicate that PTGN had a strong negative impact on long term kidney graft survival. Posttransplant IgA nephropathy is a leading cause of allograft loss in Chinese kidney transplant patients with PTGN. PMID- 22941237 TI - Improving surgical care in Mongolia: a model for sustainable development. AB - The W. C. Swanson Family Foundation selected Mongolia to help improve access to affordable quality surgical and medical care in 2000. Over the last 12 years of partnering with the Health Sciences University of Mongolia, three major concepts have been identified that have promoted sustainable progress in expanding and improving surgical care throughout the healthcare system-including urban and rural areas. Understanding and targeting the needs identified by the Mongolian surgical community has cultivated a critical working environment that has had a profound effect on expanding surgical care in Mongolia. Integrating modern surgical care training with basic emergency and essential surgical and medical initiatives created a trusting foundation providing many unforeseen educational opportunities. Lastly, the educational model introduced, including long-term capacity-building programs, has helped enable the local Mongolian surgeons, nurses, biotechnicians, administrators, and educators to continue pioneering independent efforts to further expand modern surgical care in Mongolia. PMID- 22941238 TI - Theoretical studies on the isomerization mechanism of the ortho-green fluorescent protein chromophore. AB - We present a systematic theoretical investigation on the overall ground state and excited-state isomerization reaction mechanism of ortho-green fluorescent protein chromophore (o-HBDI) using the density functional theory and the multireference methods. The calculated results and subsequent analysis suggest the possible isomerization mechanism for o-HBDI. By comparison with experimental observation and detailed analysis, it is concluded that as initiated by the excited-state intramolecular proton transfer reaction, the conical intersection between the ground state and the excited state along the C4-C5 single-bond rotational coordinate is responsible for the rapid deactivation of o-HBDI. PMID- 22941239 TI - Model approach to neurological variants of visuo-spatial neglect. AB - Neglect is a neurological disorder of spatial attention with reduced awareness of visual stimuli in the hemifield contralateral to an acute temporo-parietal lesion mainly of the right hemisphere. There is a close association of multisensory orientation centers (MSO) and vestibular tonus imbalance. A lesion of the dominant right MSO causes a left-sided neglect due to a lack of ipsilateral activation of the visual cortex, which is further enhanced by increasing inhibition from the contralateral visual cortex. The nondominant MSO in the left hemisphere might be involved in the manifestation of the less frequent and more transient right-sided neglect and in the plastic mechanisms of gradual recovery from left-sided neglect or extinction. There is evidence that a vestibular tonus inbalance due to peripheral or central vestibular pathway lesions may also induce a neglect. In a first model approach using an attractor network and assuming that there is only one MSO in the right hemisphere, it is possible to simulate attentional shifts into a visual hemifield and to induce a neglect. The neural network model consists of four layers of neurons: retina, MSO, visual cortex V1, and superior colliculus. The superior colliculus layer is modeled as a recurrent attractor network with one inhibitory interneuron and synaptic weights chosen to implement a winner-take-all network that centers the hill of activity on the strongest input. We are well aware of the simplifications used in the conceptual drawings and the computational model, but nevertheless hope that they will serve as an inspiration for further modeling and clinical studies. PMID- 22941240 TI - The problem with cardiovascular disease prevention guidelines. PMID- 22941241 TI - Parkinson's disease is not associated with gastrointestinal myenteric ganglion neuron loss. AB - Gastrointestinal dysfunction is a prominent non-motor feature of Parkinson's disease (PD) that contributes directly to the morbidity of patients, complicates management of motor symptoms, and may herald incipient PD in patients without motor disability. Although PD has traditionally been considered a disease of dopaminergic neurons in the substantia nigra, analyses of gastrointestinal samples from PD patients have consistently revealed pathology in the enteric nervous system. The relationship of PD pathology to GI dysmotility is poorly understood, and this lack of understanding has led to limited success in developing treatments for PD-related GI symptoms. We have quantitatively compared myenteric neuron density and relative abundance of NO, VIP, and catecholamine neurons between patients with PD and control individuals along the length of the GI tract. In addition, we have examined the frequency of GI alpha-synuclein neuritic pathology and its co-localization with the same neuronal markers. We have included a comparison with a small population of patients with incidental Lewy bodies found at autopsy. These data indicate that there is no neuronal loss in the myenteric plexus in PD. Lewy body pathology parallels parasympathetic autonomic input from the dorsal motor nucleus of the vagus, not the distribution of extrinsic sympathetic input or intrinsic enteric neurons, and is only rarely co-localized with tyrosine hydroxylase. These data provide a critical background to which further analyses of the effect of PD on the GI tract may be compared and suggest that neuropathology in myenteric neurons is unlikely to be a causative factor in PD-related GI dysmotility. PMID- 22941242 TI - Sinonasal tract adenoid cystic carcinoma ex-pleomorphic adenoma: a clinicopathologic and immunophenotypic study of 9 cases combined with a comprehensive review of the literature. AB - Primary sinonasal tract carcinoma ex-pleomorphic adenoma (CEPA) is very uncommon, with adenoid cystic carcinoma (ACC) CEPA exceptional. These tumors are often misclassified. This is a retrospective study. Nine cases of ACC CEPA included 7 females and 2 males, aged 39-64 years (mean, 51.1 years). Patients presented most frequently with obstructive symptoms (n = 5), epistaxis (n = 3), nerve changes or pain (n = 3), present for a mean of 25 months (men: 9.5 versus women: 29.4 months; p = 0.264). The tumors involved the nasal cavity alone (n = 5), nasopharynx (n = 2), or a combination of locations (n = 2) with a mean size of 2.9 cm (females: 3.3; males: 1.7; p = 0.064). Most patients presented at a low clinical stage (n = 7, stage I), with one patient each in stage II and IV, respectively. Histologically, the tumors showed foci of PA associated with areas of ACC. Tumors showed invasion (lymph-vascular: n = 4; perineural: n = 6; bone: n = 6). The neoplastic cells were arranged in tubules, cribriform and solid patterns, with peg-shaped cells arranged around reduplicated basement membrane and glycosaminoglycan material. Mitoses ranged from 0 to 33, with a mean of 8.7 mitoses/10 HPFs. Necrosis (n = 2) and atypical mitotic figures (n = 1) were seen infrequently. Immunohistochemical studies showed positive reactions for cytokeratin, CK5/6, p63, CK7, EMA, SMA, calponin, S100 protein and CD117, several highlighting luminal versus basal cells components. GFAP, CK20 and MSA were non reactive. p53 and Ki-67 were reactive to a variable degree. Surgery (n = 8), accompanied by radiation therapy (n = 5) was generally employed. Five patients developed a recurrence, all of whom died with disease (mean, 8.4 years), while 4 patients are either alive (n = 2) or had died (n = 2) without evidence of disease (mean, 15.9 years). In summary, ACC CEPA probably arises from the minor mucoserous glands of the upper aerodigestive tract, usually presenting in patients in middle age with obstructive symptoms in a nasal cavity based tumor. Most patients present with low stage disease (stage I and II), although invasive growth is common. Recurrences develop in about a 55 % of patients, who experience a shorter survival (mean, 8.4 years) than patients without recurrences (mean, 15.9 years). The following parameters, when present, suggest an increased incidence of recurrence or dying with disease: bone invasion, lymph-vascular invasion, and perineural invasion. PMID- 22941243 TI - Integrity of medial temporal structures may predict better improvement of spatial neglect with prism adaptation treatment. AB - Prism adaptation treatment (PAT) is a promising rehabilitative method for functional recovery in persons with spatial neglect. Previous research suggests that PAT improves motor-intentional "aiming" deficits that frequently occur with frontal lesions. To test whether presence of frontal lesions predicted better improvement of spatial neglect after PAT, the current study evaluated neglect specific improvement in functional activities (assessment with the Catherine Bergego Scale) over time in 21 right-brain-damaged stroke survivors with left sided spatial neglect. The results demonstrated that neglect patients' functional activities improved after two weeks of PAT and continued improving for four weeks. Such functional improvement did not occur equally in all of the participants: Neglect patients with lesions involving the frontal cortex (n = 13) experienced significantly better functional improvement than did those without frontal lesions (n = 8). More importantly, voxel-based lesion-behavior mapping (VLBM) revealed that in comparison to the group of patients without frontal lesions, the frontal-lesioned neglect patients had intact regions in the medial temporal areas, the superior temporal areas, and the inferior longitudinal fasciculus. The medial cortical and subcortical areas in the temporal lobe were especially distinguished in the "frontal lesion" group. The findings suggest that the integrity of medial temporal structures may play an important role in supporting functional improvement after PAT. PMID- 22941244 TI - Influence of resection extent on morbidity in surgery for squamous cell cancer at the pharyngoesophageal junction. AB - PURPOSE: Squamous cell cancer (SCC) of the pharyngoesophageal junction area has a poor prognosis mainly due to late symptom manifestation and diagnosis. Treatment of choice is still pharyngolaryngoesophagectomy, substantially affecting quality of life. Limited surgical procedures have been adopted as well. The aim of this retrospective study was to evaluate whether the extent of resection influences postoperative safety and mortality. METHODS: From 1984 to 2006, 66 patients were operated at a single tertiary referral center. Nineteen patients (28.8 %) had SCC of the hypopharynx and 47 patients (71.2 %) had SCC of the cervical and cervicothoracic esophagus. Thirty-five patients (53.0 %) underwent cervical esophageal resection (CE) and 31 underwent total esophagectomy (TE). In 39 patients (59.1 %), the larynx was preserved. Thirteen patients (19.7 %) underwent multimodal treatment. RESULTS: Overall postoperative morbidity was 69.7 % and reoperation rate reached 28.8 %. TE (P = 0.03) and larynx preservation (P = 0.02) were followed by a higher rate of non-lung infections compared with CE and pharyngolaryngectomy, respectively. Pulmonary complications have been observed more frequently after larynx preservation (P = 0.02). Hospital mortality was 9.1 %. Four patients died after TE (12.9 %) and two patients died after CE (5.7 %). In all of them, the larynx had been preserved (15.4 %). Overall, 53 patients (80.3 %) died until follow-up. One-year and 5-year survival in patients with the major tumor burden at the cervicothoracic site was 35.7 and 0 %. CONCLUSIONS: CE can be recommended as long as R0 resection is warranted. The advantage of larynx preservation is gained by higher morbidity and mortality rates and may not be recommended as standard procedure. Surgery may not be appropriate for advanced SCC in the cervicothoracic region. PMID- 22941245 TI - Mechanism of cadmium-induced cytotoxicity on the ZFL zebrafish liver cell line. AB - The cadmium ion (Cd2+) is a highly toxic metal ion; however, its hepatic toxic effects are not very well characterized in a systematic manner. In this study, a zebrafish liver cell line, ZFL was used as a model to investigate the mechanism of Cd2+-induced cytotoxicity on hepatocytes. The intracellular level of reactive oxygen species decreased following the administration of Cd2+; antioxidant levels and related enzyme activities and gene expression were detected, showing that the toxic effects of Cd2+ might not be coupled to oxidative stress. To understand the cytotoxic effects of Cd2+ on ZFL cells after Cd2+ exposure, a total of 77 differentially expressed proteins were detected by two-dimensional gel electrophoresis; 43 of them were further identified by MALDI-TOF-MS. The proteins that responded to Cd2+ in ZFL cells were related to stress response, transporters, regulation of transcription, redox homeostasis, or different signaling pathways, with half of these proteins having metal ion binding capabilities. PMID- 22941246 TI - Lymphoid priming in human bone marrow begins before expression of CD10 with upregulation of L-selectin. AB - Expression of the cell-surface antigen CD10 has long been used to define the lymphoid commitment of human cells. Here we report a unique lymphoid-primed population in human bone marrow that was generated from hematopoietic stem cells (HSCs) before onset of the expression of CD10 and commitment to the B cell lineage. We identified this subset by high expression of the homing molecule L selectin (CD62L). CD10(-)CD62L(hi) progenitors had full lymphoid and monocytic potential but lacked erythroid potential. Gene-expression profiling placed the CD10(-)CD62L(hi) population at an intermediate stage of differentiation between HSCs and lineage-negative (Lin(-)) CD34(+)CD10(+) progenitors. CD62L was expressed on immature thymocytes, and its ligands were expressed at the cortico medullary junction of the thymus, which suggested a possible role for this molecule in homing to the thymus. Our studies identify the earliest stage of lymphoid priming in human bone marrow. PMID- 22941247 TI - Tenuibacillus halotolerans sp. nov., a novel bacterium isolated from a soil sample from a salt lake in Xinjiang, China and emended description of the genus Tenuibacillus. AB - A Gram-positive, moderately halotolerant, rod-shaped bacterium, designated YIM 94025(T), was isolated from a soil sample from a salt lake in Xinjiang province, north-west China. Strain YIM 94025(T) was observed to grow at 25-45 degrees C (optimum 37 degrees C), 0-22 % NaCl (optimum 2-10 %) and pH 6.0-9.0 (optimum pH 8.0). Phylogenetic analyses based on 16S rRNA gene sequences revealed that the organism belongs to the genus Tenuibacillus and exhibited sequence similarity of 98.0 % to the closest type strain, Tenuibacillus multivorans AS 1.3442(T). The predominant menaquinone was found to be MK-7; the cell-wall peptidoglycan diamino acid was meso-diaminopimelic acid; the polar lipids consisted of diphosphatidylglycerol, phosphatidylglycerol, phosphatidylinositol, an unidentified phospholipid and an unknown lipid; and the major fatty acids were found to contain iso-C(15:0), anteiso-C(15:0) and iso-C(16:0). The chemotaxonomic characteristics of strain YIM 94025(T) are consistent with those of the genus Tenuibacillus. The level of DNA-DNA relatedness value between YIM 94025(T) and T. multivorans AS 1.3442(T) was 36.6 +/- 4.5 %. The G+C content of the strain YIM 94025(T) was determined to be 38.5 %. Based on the comparative analysis of physiological, biochemical and chemotaxonomic data, as well as DNA-DNA hybridization results, the isolate is considered to represent a novel species of the genus Tenuibacillus, for which the name Tenuibacillus halotolerans sp. nov., is proposed, with the type strain of YIM 94025(T) (=CCTCC AB 2012860(T) = KCTC 33046(T)). PMID- 22941248 TI - Molecular genetic diversity of the Saccharomyces yeasts in Taiwan: Saccharomyces arboricola, Saccharomyces cerevisiae and Saccharomyces kudriavzevii. AB - Genetic hybridization, sequence and karyotypic analyses of natural Saccharomyces yeasts isolated in different regions of Taiwan revealed three biological species: Saccharomyces arboricola, Saccharomyces cerevisiae and Saccharomyces kudriavzevii. Intraspecies variability of the D1/D2 and ITS1 rDNA sequences was detected among S. cerevisiae and S. kudriavzevii isolates. According to molecular and genetic analyses, the cosmopolitan species S. cerevisiae and S. kudriavzevii contain local divergent populations in Taiwan, Malaysia and Japan. Six of the seven known Saccharomyces species are documented in East Asia: S. arboricola, S. bayanus, S. cerevisiae, S. kudriavzevii, S. mikatae, and S. paradoxus. PMID- 22941249 TI - Defense responses of soybean roots during exposure to cadmium, excess of nitrogen supply and combinations of these stressors. AB - Heavy metal pollution is a serious environmental problem in agricultural soils since the uptake of heavy metals by plants represents an entry point into the food chain and is influenced by the form and amount of nitrogen (N) fertilization. Here we studied the defense responses in soybean roots exposed to ions of cadmium (applied as 50 mg l(-1) Cd(2+)) when combined with an excessive dose of N in form of NH(4)NO(3). Our data indicate that despite of stunted root growth, several stress symptoms typically observed upon cadmium treatment, e.g. peroxidation of lipid membranes or activation of chitinase isoforms, become suppressed at highly excessive N. At the same time, other defense mechanisms such as catalases and proline accumulation were elevated. Most importantly, the interplay of ongoing responses resulted in a decreased uptake of the metal into the root tissue. This report points to the complexity of plant defense responses under conditions of heavy metal pollution combined with intensive fertilization in agriculture. PMID- 22941250 TI - Associations of FASN gene polymorphisms with economical traits in Nellore cattle (Bos primigenius indicus). AB - The aim of this study was to identify molecular markers to be applied to marker assisted selection. Three SNPs of the FASN gene were studied. PCR-RFLP was used for genotyping. The SNPs g.17924A>G, g.17860C>T and g.15603A>G all in the FASN gene were genotyped using the enzymes MscI, DdeI and Hae III, respectively. The animals were raised in extensive systems and belong to three lines selected for growth as part of the Selection Program of Zebu and Caracu Breeds, Sao Paulo, Brazil. Allele and genotype frequencies were compared between selection lines using the Genepop 3.4. Associations between polymorphisms and the traits studied were evaluated using the PROC MIXED procedure of the SAS/STAT 9.1.3. The G and C alleles were the most frequent alleles of the g.15603A>G and g.17860C>T loci, respectively. The g.17924A>G locus showed no polymorphism in the population studied. Allele and genotype frequencies differed significantly between the NeT line and the NeC and NeS lines. The g.15603A>G polymorphism tended to exert an additive effect on rump fat thickness and male yearling height. For g.17860C>T, an additive effect on male yearling height was observed. Genotype combination analysis revealed a significant effect on loin eye area. Although this study provided evidence of an association between the FASN gene and some traits, more detailed analyses are needed to obtain more efficient molecular markers. PMID- 22941251 TI - The hypoxia-mimetic agent cobalt chloride induces cell cycle arrest and alters gene expression in U266 multiple myeloma cells. AB - Hypoxia is a common feature of tumors that occurs across a wide variety of malignancies. Multiple myeloma is an incurable malignant disorder of plasma cells in the bone marrow. Although bone marrow hypoxia is crucial for normal hematopoiesis, the effect of hypoxia on multiple myeloma is poorly understood. In this study, we demonstrated that cobalt chloride (CoCl2)-mediated hypoxia decreased cell viability and altered gene expression in U266 human multiple myeloma cells. CoCl2 induced the loss of cell viability in a concentration dependent manner. In addition, FACS analysis revealed that the loss of cell viability was related to apoptosis. Using microarray analysis, we identified mRNA expression profile changes in response to CoCl2 treatment in U266 cells. Four hundred and fifty-two mRNAs exhibited >2-fold changes in expression in CoCl2 treated U266 cells compared to their expression in control cells. A follow-up bioinformatics study revealed that a great number of genes with altered expression were involved in apoptosis, cell cycle, transcription and development. In conclusion, these results provide novel evidence that CoCl2-mediated hypoxia affects the expression profiles of genes that are functionally related to apoptosis and angiogenesis in U266 multiple myeloma cells. PMID- 22941252 TI - Origin and course of the extracranial vertebral artery: CTA findings and embryologic considerations. AB - PURPOSE: The aim of this study was to show the different origins and courses of the extracranial VA on CTA with special emphasis on embryological considerations. The duplicated VA is an anomaly that has been assumed to predispose for dissection and to be associated with aneurysms. We report its frequency and clinical significance. METHODS: We retrospectively reviewed CTA of 539 patients by using a contrast-enhanced CTA protocol of the VA on CT. RESULTS: Ninety-four point-two percent of left VA originated from left subclavian artery and entered the transverse foramen at C6 in nearly all cases. Six-point-three-percent of left VA (m = 4 %, f = 10 %) originated from the aortic arch and entered the transverse foramen either at C4, C5 or C7 but never at C6. One case of an aberrant retroesophageal right VA originated from the aortic arch distal to the left subclavian artery and entered at C7 (0.19 %). All other right VA originated from the right subclavian artery (99.8 %) and entered between C4 and C6. We diagnosed four cases of duplicated VA (0.74 %) with a female predominance (1.9 %) without any signs of dissection on CTA. Two cases with VA duplication had intracranial arterial aneurysms. CONCLUSIONS: The VA is a longitudinal anastomosis of segmental metameric arteries. The level of entrance into the transverse foramen indicates which metameric artery or arteries persist. Duplication corresponds to persistence of two segmental arteries and is a rare phenomenon. VA duplication might be associated with vascular lesions. PMID- 22941254 TI - The problem is obvious, the solution is not: numbers do matter in cardiac cell therapy! PMID- 22941256 TI - Ovarian metastases of colorectal and duodenal cancer in familial adenomatous polyposis. AB - Metastases to the ovary occur in 0.8-9.7 % of colorectal cancer (CRC) cases (Hanna and Cohen in Clin Colorectal Cancer 3(4):215-222, 2004). The need to combine surgical resection of the primary tumor and bilateral oophorectomy is a matter of debate (Erroi et al. in J Surg Oncol 96(2):113-117, 2007). In a consecutive multi-hospital cohort of 30 CRC metastases to the ovary we came across four female patients (13 %; 95 % CI 3.6-34.1) with familial adenomatous polyposis (FAP). This number is high since the estimated incidence of FAP CRC is far below 1 % of all CRC and the expected incidence of FAP CRC that metastasized to the ovaries would thus be almost zero. In a second screen in nationwide databases we found that ovarian metastases occurred in at least 15 % of female FAP CRC cases. We provide now first evidence that especially in female FAP CRC patients bilateral oophorectomy during surgery should be discussed. PMID- 22941255 TI - Functional vascular smooth muscle cells derived from human induced pluripotent stem cells via mesenchymal stem cell intermediates. AB - AIMS: Smooth muscle cells (SMC) play an important role in vascular homeostasis and disease. Although adult mesenchymal stem cells (MSC) have been used as a source of contractile SMC, they suffer from limited proliferation potential and culture senescence, particularly when originating from older donors. By comparison, human induced pluripotent stem cells (hiPSC) can provide an unlimited source of functional SMC for autologous cell-based therapies and for creating models of vascular disease. Our goal was to develop an efficient strategy to derive functional, contractile SMC from hiPSC. METHODS AND RESULTS: We developed a robust, stage-wise, feeder-free strategy for hiPSC differentiation into functional SMC through an intermediate stage of multipotent MSC, which could be coaxed to differentiate into fat, bone, cartilage, and muscle. At this stage, the cells were highly proliferative and displayed higher clonogenic potential and reduced senescence when compared with parental hair follicle mesenchymal stem cells. In addition, when exposed to differentiation medium, the myogenic proteins such as alpha-smooth muscle actin, calponin, and myosin heavy chain were significantly upregulated and displayed robust fibrillar organization, suggesting the development of a contractile phenotype. Indeed, tissue constructs prepared from these cells exhibited high levels of contractility in response to receptor- and non-receptor-mediated agonists. CONCLUSION: We developed an efficient stage wise strategy that enabled hiPSC differentiation into contractile SMC through an intermediate population of clonogenic and multipotent MSC. The high yield of MSC and SMC derivation suggests that our strategy may facilitate an acquisition of the large numbers of cells required for regenerative medicine or for studying vascular disease pathophysiology. PMID- 22941257 TI - Rice body formation without rheumatic disease or tuberculosis infection: a case report and literature review. AB - Rice body formation is an uncommon inflammatory disorder associated with systemic disorders such as rheumatoid arthritis and tuberculosis infection. The pathophysiology of rice bodies is poorly understood. We describe a case of rice body formation in a 51-year-old male who presented with pain and swelling of the left wrist. The patient had no previous history of rheumatic disease, joint trauma, or infectious disease. He underwent a radical tenosynovectomy and had immediate improvement of symptoms. Despite extensive evaluation, the etiology of the rice bodies could not be identified. An increasing number of case reports have described rice body formation without a known cause suggesting an alternative, unidentified method of pathogenesis. We describe a unique case of rice body formation and a review of the literature with emphasis on theories of pathogenesis, diagnostic methods, and treatment. PMID- 22941258 TI - Semi-quantitative evaluation of salivary gland function in Sjogren's syndrome using salivary gland scintigraphy. AB - This retrospective study is designed to evaluate the diagnostic value of semi quantitative parameters of salivary gland scintigraphy (SGS) in Sjogren's syndrome (SS) and explore the relationship between SGS parameters and salivary gland histopathologic manifestations. SGS and labial salivary gland biopsy were performed on 95 SS patients and 36 healthy age-matched and sex-matched volunteers. Uptake ratios at 15 min (UR(15)) and stimulated excretion fraction (EF) of each parotid and submandibular gland were calculated automatically from SGS; histopathologic grades were classified based on focal lymphocytic infiltration, and biopsy focus scores were calculated simultaneously. As a result, the UR(15) and EF of each salivary gland in SS patients were significantly lower than that in controls. Multivariate logistic regression equation was: logit p = 6.965 - 1.680 * UR(15) of left submandibular gland - 0.040 * EF of left parotid gland - 0.050 * EF of right submandibular gland. The receiver operating characteristic (ROC) curve validated high efficiency of this model with the area under curve of 0.911. And logistic regression analysis on combined original and validation cohorts confirmed its diagnostic value. Moreover, the EF of right parotid gland and both submandibular glands was correlated with histopathologic changes. Consequently, the semi-quantitative parameters of SGS may be helpful for diagnosing SS; UR(15) of left submandibular gland, EF of left parotid gland, and EF of right submandibular gland are more powerful predictor of SS. Besides, SGS parameters reflect the degree of salivary gland involvement, severe patients with low parameters would have high histopathologic grades and biopsy focus scores. PMID- 22941259 TI - Association between vitamin D intake and the risk of rheumatoid arthritis: a meta analysis. AB - The aim of this study was to summarize published results on the association between vitamin D intake and the development of rheumatoid arthritis (RA) and between serum vitamin D levels and RA activity. Evidence of a relationship between vitamin D intake and the development of RA and between serum vitamin D levels and RA activity was studied by summarizing published results using a meta analysis approach. Three cohort studies including 215,757 participants and 874 incident cases of RA were considered in this meta-analysis, and eight studies on the association between serum vitamin D levels and RA activity involving 2,885 RA patients and 1,084 controls were included. Meta-analysis showed an association between total vitamin D intake and RA incidence (relative risk (RR) of the highest vs. the lowest group = 0.758, 95 % confidence interval (CI) 0.577-0.937, p = 0.047), without between-study heterogeneity (I(2) = 0 %, p = 0.595). Individuals in the highest group for total vitamin D intake were found to have a 24.2 % lower risk of developing RA than those in the lowest group. Subgroup meta analysis also showed a significant association between vitamin D supplement intake and RA incidence (RR 0.764, 95 % CI 0.628-0.930, p = 0.007), without between-study heterogeneity. All studies, except for one, found that vitamin D levels are inversely associated with RA activity. One study found no correlation between vitamin D levels and disease activity among 85 RA patients, but these patients had a high incidence of vitamin D deficiency, which might have influenced the study outcome. Meta-analysis of 215,757 participants suggests that low vitamin D intake is associated with an elevated risk of RA development. Furthermore, available evidence indicates that vitamin D level is associated with RA activity. PMID- 22941260 TI - Autoantibodies in immune-mediated neuropathies. AB - PURPOSE OF REVIEW: Over the past 25 years, many autoantibodies directed against peripheral nerve glycan and protein antigens have been described. Principally through this area of research, significant advances have been achieved in the understanding of the pathophysiology of inflammatory neuropathies. More evidence constantly continues to emerge supporting the role of antibodies in pathogenesis. This review reports the recent studies highlighting the complex association between autoantibodies directed against various peripheral nerve antigens and immune polyneuropathies. RECENT FINDINGS: The discovery of serum antibodies directed against ganglioside and glycolipid complexes has generated huge interest in this area of research. The expectation that nodal proteins are important targets continues to be pursued in line with the improvements in detection methodology. Basic studies continue to support a direct role for autoantibodies in neuropathy pathogenesis. SUMMARY: Discovery of new target epitopes has not only raised hopes for further improvement in our understanding of pathophysiology and availability of new diagnostic markers, but also for future targeted therapies. Further studies are required to elucidate the precise pathological and clinical significance of these new antibodies. PMID- 22941261 TI - Autoimmune mechanisms in myasthenia gravis. AB - PURPOSE OF REVIEW: This article reviews recent findings on factors and mechanisms implicated in the pathogenesis of myasthenia gravis and briefly summarizes data on therapies acting at various stages of the autoimmune process. RECENT FINDINGS: Data published over the last year promise to improve understanding of pathogenic mechanisms underlying myasthenia gravis. Animal studies have at last shown that antimuscle-specific kinase (MuSK) autoantibodies, like antiacetylcholine receptor (AChR) autoantibodies, are myasthenogenic. A new autoantigen, the low-density lipoprotein receptor-related protein 4 (LRP4), has been identified in variable proportions of otherwise seronegative patients. Anti-LRP4 antibodies may define a new myasthenia gravis subtype, supporting the concept that myasthenia gravis is not a single disease entity, and that different subtypes can differ in aetiology. Genetic and environmental factors are implicated in myasthenia gravis. The finding of persisting viral infection in the thymus of AChR-myasthenia gravis patients, combined with data on chronic inflammation, suggest that pathogens may favour intrathymic AChR-specific autosensitization and maintenance of autoimmunity in genetically susceptible individuals. Defective immunoregulatory mechanisms, involving pathogenic Th17 and regulatory T cells, contribute to tolerance loss and perpetuation of the autoimmune response in myasthenia gravis patients. SUMMARY: The recent identification of mechanisms initiating and perpetuating autoimmunity in myasthenia gravis may stimulate the development of more effective therapies. PMID- 22941262 TI - Amyloid neuropathies. AB - PURPOSE OF REVIEW: As amyloid neuropathies have benefited from recent major progress, this review is timely and relevant. RECENT FINDINGS: The main recent articles on amyloid neuropathy cover its description, methods for diagnosis and therapies. Varied clinical presentations are described in transthyretin (TTR) familial amyloidosis with polyneuropathy (FAP) and light chain amyloid neuropathy. Mass spectrometry is able to identify the biochemical nature of amyloidogenic protein in nerve biopsy and skin biopsy samples for diagnosis of small fiber polyneuropathy. Both nerve biopsy and TTR gene sequencing are important to identify sporadic cases of amyloid neuropathy. Nerve biopsy is useful in demonstrating the amyloid origin of neuropathies developing after domino liver transplant recipients. Liver transplantation improves long-term survival in Met30 TTR-FAP. Factors recognized as leading to cardiomyopathy progression or heart involvement after liver transplantation are late disease onset and fibril composition. Combined heart and liver transplantation is recommended in severe restrictive cardiomyopathy. Antiamyloid drugs are emerging: tafamidis, a TTR stabilizer, showed in a phase III controlled study its ability to slow stage 1 FAP progression. Other strategies are emerging for TTR-FAP (combination doxycycline-tauroursodeoxycholic acid, small interfering RNA, antisense oligonucleotide, monoclonal antibody antiserum amyloid P component). For light chain neuropathy, intensive chemotherapy may be helpful. SUMMARY: There is better recognition of amyloid neuropathies, and hope for enrolling patients with FAP in future clinical trials testing new antiamyloid drugs. PMID- 22941263 TI - Pathogenesis and therapy of inclusion body myositis. AB - PURPOSE OF REVIEW: Inclusion body myositis (IBM) is a poorly understood progressive muscle disease of middle and later life. Its dual pathologies of autoimmunity and unexplained myofiber degeneration and loss have been enigmatic since its earliest descriptions over 40 years ago. No reliable effective therapy currently exists for IBM. This review provides an update of current issues in the pathogenesis and therapy of IBM. RECENT FINDINGS: Recent studies have further defined the clinical features of IBM, including natural history, pattern of muscle involvement, and role of MRI imaging. Further potential immune mediators have been identified. An autoantibody directed against a muscle antigen appears to have high specificity for IBM among muscle diseases. Further evidence for myonuclear degeneration has been reported. SUMMARY: IBM remains a poorly understood muscle disease, although understanding of the pathophysiological mechanisms continues to expand and is supporting new therapeutic approaches. PMID- 22941264 TI - Outcome measures in peripheral neuropathies: requirements through statements. AB - PURPOSE OF REVIEW: The aim of this review is to inform and educate clinicians through statements about the most important clinimetric requirements for outcome measures in peripheral neuropathies. RECENT FINDINGS: The basic needs of an outcome measure (simple, valid, reliable, and responsive) are generally well known by physicians. However, techniques such as the Rasch methodology offer modern additional requirements, particularly in the development of interval-based outcome measures. SUMMARY: Peripheral neuropathies are chronic disorders that generally cause deficits at the body level (impairments, e.g. weakness and sensory deficit) and may lead to problems in daily life and social functioning with a reduction in quality-of-life expectations. Fundamental steps should be taken in the design of clinical studies in peripheral neuropathies to ameliorate these deficits, of which the choice of a proper outcome measure representing the level of interest is considered a crucial one. However, choosing a proper outcome is not only dependent on the proposed research purpose, but perhaps more importantly, on the fulfilment of the clinimetric needs by the scale of interest. All outcome measures should be rigorously examined to determine their scientific soundness before being generally used. Respecting the basic needs of an outcome measure like being simple, valid, reliable, and responsive, this review will highlight through statements the modern scientific essentials in the design and evaluation of an outcome measure. The Rasch method as a modern vehicle will also be addressed, accentuating the need to shift towards a more modern clinimetric era. The presented findings could be applied to all forms of peripheral neuropathies. PMID- 22941265 TI - Pharmacological therapies for muscular dystrophies. AB - PURPOSE OF REVIEW: The study reviews recent advances in pharmacological management of muscular dystrophies. Similarities and differences among the pathophysiology of different forms of muscular dystrophy lead to a broad array of approaches to provide new treatments. RECENT FINDINGS: In this review, we include only those muscular dystrophies for which advances have been published in the past year. This represents the 'advancing edge' of a large body of research over more than 20 years. This runs the gamut of new discoveries in symptomatic management to mutation-specific strategies that attempt to correct the root cause of the disorder. SUMMARY: The field of pharmacological therapies for the muscular dystrophies continues to steadily advance. It is encouraging that research into new therapies is increasingly exploring pharmacological strategies with the potential to ameliorate disease pathology to a clinically significant degree. PMID- 22941266 TI - Small fibre neuropathy. AB - PURPOSE OF REVIEW: This review summarizes the most recent advances in classification, diagnostic assessment, and treatment of small fibre neuropathy (SFN). RECENT FINDINGS: Clinically based diagnostic criteria for SFN have been proposed and reliably supported by the recent availability of age-adjusted and sex-adjusted normative values for intraepidermal nerve fibre density. Apart from skin biopsy, corneal confocal microscopy and nociceptive evoked potentials have been implemented to investigate SFN of different causes, and correlated with skin biopsy findings, especially in diabetic patients. The association between SFN and several metabolic and immune-mediated systemic diseases, and drugs toxic to this subset of peripheral nerve fibres has been reported. An exciting advance has been the identification of gain-of-function mutations in the SCN9A gene encoding for Nav1.7 sodium channel in patients with SFN, leading to the definition of a new genetic channelopathy. SUMMARY: SFN represents a distinct condition encountered in patients with different acquired and genetic disorders. The recent improved definition of clinical and skin biopsy criteria allows clinicians to reliably meet the diagnosis, identify the underlying cause, and prescribe appropriate treatments. This meaningful approach permits the correct management of patients in clinical practice and the design of symptomatic and disease-modifying clinical trials. PMID- 22941267 TI - Transseptal dorsal approaches to the wrist. AB - BACKGROUND: The dorsal approach to the wrist is the exposure of choice for most of the surgical procedures on the radiocarpal and intercarpal joints. Contrary to the volar approach, it encounters neither the main arteries nor the motor nerve branch. However, the dorsal approach goes necessarily through the extensor retinaculum. We describe two transseptal dorsal approaches that pass through the extensor retinaculum in the thickness of a septum between two compartments. A virtual space was developed beneath the infratendinous retinaculum (which is a deep layer covering the floor of the extensor compartments) to expose the periosteum, the ligaments and the joint capsule without opening the extensor compartments. METHODS: Twenty cadaveric wrists have been dissected to study the feasibility of the two transseptal approaches. Ten wrists were exposed through a 3-4 transseptal approach, passing through the extensor retinaculum in the thickness of the septum between the third and fourth compartments. Ten wrists were exposed through a 4-5 transseptal approach, passing through the extensor retinaculum in the thickness of the septum between the fourth and fifth compartments. The extent of violations of extensor compartments and joint capsule, and the exposed anatomical structures were noted. At the end of each dissection, the whole extensor system was outrightly removed for histological study. RESULTS: The feasibility of the transseptal approaches was demonstrated for all the dissected wrists. The dissection plane beneath the infratendinous retinaculum was macroscopically and microscopically highlighted. CONCLUSIONS: The transseptal approaches provide a good exposure to the dorsal side of the wrist joint, without opening the extensor tendon compartments. PMID- 22941268 TI - 17AEP-GA, an HSP90 antagonist, is a potent inhibitor of glioblastoma cell proliferation, survival, migration and invasion. AB - Glioblastoma multiforme (GBM) is the most frequent and the most malignant human brain tumor. The expression of receptor tyrosine kinase MET and its ligand hepatocyte growth factor (HGF) is strongly increased in GBM, where they promote tumor proliferation, cell survival, migration, invasion and angiogenesis. We used geldanamycins (GAs) (inhibitors of HSP90) in order to block glioblastoma growth and HGF-dependent cell migration and invasion. The effect of GAs on three GBM cell lines was tested and we found their antiproliferative effect on tumor cells. The maximum level of inhibition reached 70%. After treatment with GAs, cells also became apoptotic as determined by Annexin V-positive staining and activation of the caspase-3 pathway. We examined the expression and activity of the MET receptor on GBM cell lines and we observed phosphorylation of AKT and MAPK after HGF stimulation by western blot analysis. Since GBM cells express high level of MET receptor and were shown to respond to HGF by increased motility we tested if GAs could negatively affect GBM cell movement. In our study, we found that GAs inhibited the chemotaxis of glioblastoma cells toward the hepatocyte growth factor gradient. The GAs also blocked migration of tumor cells through a Matrigel layer in invasion assays. The strongest inhibitory effect was observed for GA and its analog, 17AEP-GA. Based on our results, GAs, particularly 17AEP-GA, could be considered as a new potential agent to treat glioblastoma multiforme. PMID- 22941269 TI - Sex and age differences in mate-selection preferences. AB - For nearly 70 years, studies have shown large sex differences in human mate selection preferences. However, most of the studies were restricted to a limited set of mate selection criteria and to college students, and neglecting relationship status. In this study, 21,245 heterosexual participants between 18 and 65 years of age (mean age 41) who at the time were not involved in a close relationship rated the importance of 82 mate selection criteria adapted from previous studies, reported age ranges for the oldest and youngest partner that they would find acceptable, and responded to 10 yes/no questions about a potential marriage partner. For nearly all mate selection criteria, women were found to be the more demanding sex, although men placed consistently more value on the physical attractiveness of a potential partner than women. Also, the effects of the participants' age and level of education were nearly negligible. These results demonstrate the robustness of sex differences in mate selection criteria across a substantial age range. PMID- 22941270 TI - A novel alkaliphilic xylanase from the newly isolated mesophilic Bacillus sp. MX47: production, purification, and characterization. AB - A newly isolated bacterial strain, Bacillus sp. MX47, was actively producing extracellular xylanase only in xylan-containing medium. The xylanase was purified from the culture broth by two chromatographic steps. The xylanase had an apparent molecular weight of 26.4 kDa with an NH(2)-terminal sequence (Gln-Gly-Gly-Asn Phe) distinct from that of reported proteins, implying it is a novel enzyme. The optimum pH and temperature for xylanase activity were 8.0 and 40 degrees C, respectively. The enzyme activity was severely inhibited by many divalent metal ions and EDTA at 5 mM. The xylanase was highly specific to beechwood and oat spelt xylan, however, not active on carboxymethyl cellulose (CMC), avicel, pectin, and starch. Analysis of the xylan hydrolysis products by Bacillus sp. MX47 xylanase indicated that it is an endo-beta-1,4-xylanase. It hydrolyzed xylan to xylobiose as the end product. The K(m) and V(max) values toward beechwood xylan were 3.24 mg ml(-1) and 58.21 MUmol min(-1) mg(-1) protein, respectively. PMID- 22941271 TI - Improved covalent immobilization of horseradish peroxidase on macroporous glycidyl methacrylate-based copolymers. AB - A macroporous copolymer of glycidyl methacrylate and ethylene glycol dimethacrylate, poly(GMA-co-EGDMA), with various surface characteristics and mean pore size diameters ranging from 44 to 200 nm was synthesized, modified with 1,2 diaminoethane, and tested as a carrier for immobilization of horseradish peroxidase (HRP) by two covalent methods, glutaraldehyde and periodate. The highest specific activity of around 35 U g(-1) dry weight of carrier was achieved on poly(GMA-co-EGDMA) copolymers with mean pore diameters of 200 and 120 nm by the periodate method. A study of deactivation kinetics at 65 degrees C and in 80 % dioxane revealed that periodate immobilization also produced an appreciable stabilization of the biocatalyst, while stabilization factor depended strongly on the surface characteristics of the copolymers. HRP immobilized on copolymer with a mean pore diameter of 120 nm by periodate method showing not only the highest specific activity but also good stability was further characterized. It appeared that the immobilization resulted in the stabilization of enzyme over a broader pH range while the Michaelis constant value (K (m)) of the immobilized HRP was 10.8 mM, approximately 5.6 times higher than that of the free enzyme. After 6 cycles of repeated use in a batch reactor for pyrogallol oxidation, the immobilized HRP retained 45 % of its original activity. PMID- 22941272 TI - Cre-lox66/lox71-based elimination of phosphotransacetylase or acetaldehyde dehydrogenase shifted carbon flux in acetogen rendering selective overproduction of ethanol or acetate. AB - Acetogen strain Clostridium sp. MT1121 produced 300 mM acetate (p<0.005) and 321 mM ethanol (p<0.005) from synthesis gas (syngas) blend 60 % CO and 40 % H(2). Clostridium sp. MT1121 was metabolically engineered to eliminate production of either acetate or acetaldehyde during syngas fermentation. We used Cre lox66/lox71-based gene removal system to eliminate either phosphotransacetylase (pta), or acetaldehyde dehydrogenase (aldh). The resulted biocatalyst with eliminated pta increased ethanol yield to 610 mM (p<0.005). Inactivation of pta rendered only 502 mM of ethanol (p<0.005). The acetogen biocatalyst with eliminated aldh produced 450 mM acetate (p<0.005). The role of cell energy pool preservation for re-directed carbon flux is discussed. This is the first report on time- and cost-efficient gene elimination in acetogens using lox66/lox71 gene elimination system. PMID- 22941273 TI - Recombinant human bone morphogenetic protein-2 versus autogenous iliac crest bone graft for lumbar fusion: a meta-analysis of ten randomized controlled trials. AB - BACKGROUND: Recombinant human bone morphogenetic protein-2 (rhBMP-2) as a substitute for iliac crest bone graft (ICBG) has been increasingly widely used in lumbar fusion. It has been proven non-inferior in fusion success and clinical outcomes when compared with ICBG. However, increasingly, some potentially uncommon and serious complications associated with the use of rhBMP-2 have been of great concern to surgeons. The purpose of this study was to determine whether rhBMP-2 could be considered an effective and, more importantly, a relatively safe substitute for ICBG in lumbar fusion. METHODS: Randomized controlled trials that compared rhBMP-2 with ICBG for lumbar fusion were identified by computer and manual searching. The risk of bias and clinical relevance of the included studies were assessed. Publication bias was explored using funnel plot and statistical tests (Egger's test and Begg's test). Meta-analyses were performed using the Cochrane systematic review methods. RESULTS: Ten randomized controlled trials (1,342 patients) met the inclusion criteria. Compared with ICBG, the use of rhBMP 2 significantly decreased the risk of fusion failure at all time intervals (6 months: p < 0.0001, RR = 0.55, 95 % CI = 0.42-0.72; 12 months: p = 0.0003, RR = 0.53, 95 % CI = 0.37-0.75; 24 months: p < 0.00001, RR = 0.31, 95 % CI = 0.21 0.46) and the rate of reoperation (p = 0.0001, RR = 0.52, 95 % CI = 0.37-0.72). There was no statistical difference in clinical improvement on the Oswestry Disability Index, although a favorable trend in the rhBMP-2 group was found (p = 0.12, RR = 0.73, 95 % CI = 0.49-1.08). Subgroup analyses stratified by the type of surgical procedure yielded similar results. Owing to the different data formats, meta-analysis on adverse events was not performed. CONCLUSION: RhBMP-2 was superior to the ICBG for achieving fusion success and avoiding reoperation. However, evidence from the Food and Drug Administration document and subsequent independent studies has demonstrated that original, industry-sponsored trials underestimated rhBMP-2-related adverse events. There are still security risks in the use of rhBMP-2. PMID- 22941274 TI - How TiO2 crystallographic surfaces influence charge injection rates from a chemisorbed dye sensitiser. AB - High-energy metal oxide surfaces are considered to be promising for applications involving surface-adsorbate electron transfer, such as photocatalysis and dye sensitised solar cells. Here, we compare the efficiency of electron injection into different TiO(2) anatase surfaces. We model the adsorption of a carboxylic acid (formic acid) on anatase (101), (001), (100), (110) and (103) surfaces using density functional theory calculations, and calculate electron injection times from a model dye into these surfaces. We find that the different positions of the conduction band edge of these surfaces determine the rate of electron injection (which is faster for the surfaces with lower-lying conduction band, among them the most stable (101) surface). However, if the dye's injection energy is enforced to be at a fixed energy deep inside each surface's conduction band, then several anatase surfaces, such as the synthetically achievable (001) surface, show rates of injection comparable or faster than the (101) surface. Moreover, because of their higher-lying conduction bands, these minority surfaces are likely to offer higher open-circuit voltages in dye-sensitised solar cells. Therefore, synthetically accessible high-energy anatase surfaces, such as (001) oriented nanostructures, may be promising candidates for use in dye-sensitised solar cells. PMID- 22941275 TI - Gene therapy rescues cilia defects and restores olfactory function in a mammalian ciliopathy model. AB - Cilia are evolutionarily conserved microtubule-based organelles that are crucial for diverse biological functions, including motility, cell signaling and sensory perception. In humans, alterations in the formation and function of cilia manifest clinically as ciliopathies, a growing class of pleiotropic genetic disorders. Despite the substantial progress that has been made in identifying genes that cause ciliopathies, therapies for these disorders are not yet available to patients. Although mice with a hypomorphic mutation in the intraflagellar transport protein IFT88 (Ift88Tg737Rpw mice, also known as ORPK mice)5 have been well studied, the relevance of IFT88 mutations to human pathology is unknown. We show that a mutation in IFT88 causes a hitherto unknown human ciliopathy. In vivo complementation assays in zebrafish and mIMCD3 cells show the pathogenicity of this newly discovered allele. We further show that ORPK mice are functionally anosmic as a result of the loss of cilia on their olfactory sensory neurons (OSNs). Notably, adenoviral-mediated expression of IFT88 in mature, fully differentiated OSNs of ORPK mice is sufficient to restore ciliary structures and rescue olfactory function. These studies are the first to use in vivo therapeutic treatment to reestablish cilia in a mammalian ciliopathy. More broadly, our studies indicate that gene therapy is a viable option for cellular and functional rescue of the complex ciliary organelle in established differentiated cells. PMID- 22941276 TI - Multigenerational epigenetic adaptation of the hepatic wound-healing response. AB - We investigated whether ancestral liver damage leads to heritable reprogramming of hepatic wound healing in male rats. We found that a history of liver damage corresponds with transmission of an epigenetic suppressive adaptation of the fibrogenic component of wound healing to the male F1 and F2 generations. Underlying this adaptation was less generation of liver myofibroblasts, higher hepatic expression of the antifibrogenic factor peroxisome proliferator-activated receptor gamma (PPAR-gamma) and lower expression of the profibrogenic factor transforming growth factor beta1 (TGF-beta1) compared to rats without this adaptation. Remodeling of DNA methylation and histone acetylation underpinned these alterations in gene expression. Sperm from rats with liver fibrosis were enriched for the histone variant H2A.Z and trimethylation of histone H3 at Lys27 (H3K27me3) at PPAR-gamma chromatin. These modifications to the sperm chromatin were transmittable by adaptive serum transfer from fibrotic rats to naive rats and similar modifications were induced in mesenchymal stem cells exposed to conditioned media from cultured rat or human myofibroblasts. Thus, it is probable that a myofibroblast-secreted soluble factor stimulates heritable epigenetic signatures in sperm so that the resulting offspring better adapt to future fibrogenic hepatic insults. Adding possible relevance to humans, we found that people with mild liver fibrosis have hypomethylation of the PPARG promoter compared to others with severe fibrosis. PMID- 22941277 TI - Antiretroviral dynamics determines HIV evolution and predicts therapy outcome. AB - Despite the high inhibition of viral replication achieved by current anti-HIV drugs, many patients fail treatment, often with emergence of drug-resistant virus. Clinical observations show that the relationship between adherence and likelihood of resistance differs dramatically among drug classes. We developed a mathematical model that explains these observations and predicts treatment outcomes. Our model incorporates drug properties, fitness differences between susceptible and resistant strains, mutations and adherence. We show that antiviral activity falls quickly for drugs with sharp dose-response curves and short half-lives, such as boosted protease inhibitors, limiting the time during which resistance can be selected for. We find that poor adherence to such drugs causes treatment failure via growth of susceptible virus, explaining puzzling clinical observations. Furthermore, our model predicts that certain single-pill combination therapies can prevent resistance regardless of patient adherence. Our approach represents a first step for simulating clinical trials of untested anti HIV regimens and may help in the selection of new drug regimens for investigation. PMID- 22941278 TI - Ticks (Acari: Ixodida) infesting humans in the provinces of Kelkit Valley, a Crimean-Congo Hemorrhagic Fever endemic region in Turkey. AB - Ticks are mandatory blood feeding ectoparasites leading transmission of various tick-borne pathogens to human and animals. Since 2002, thousands of human tick bites and numerous Crimean-Congo Hemorrhagic Fever cases have been reported in several provinces in the Kelkit Valley region in Turkey. Despite increased cases of tick bites and tick-borne diseases, no taxonomic information is available about the tick species infesting humans in the region. In the present study, a tick survey on humans was performed to determine the species composition of ticks infesting humans in several provinces of Kelkit Valley. In the survey, 1,460 ticks (721 males, 516 females and 223 nymphs) were collected from tick-infested humans. A total of 19 tick species have been found on humans in the region, including 7 Hyalomma, 2 Argas, 2 Haemaphysalis, 2 Ixodes, Dermacentor and 3 Rhipicephalus species. Infestation of Dermacentor reticulatus on humans was documented for the first time in Turkey. PMID- 22941279 TI - Identification of a boron nitride nanosphere-binding peptide for the intracellular delivery of CpG oligodeoxynucleotides. AB - CpG oligonucleotides (CpG ODNs) interact with Toll-like receptor 9 (TLR9), which results in the induction of immunostimulatory cytokines. We delivered CpG ODNs intracellularly using boron nitride nanospheres (BNNS). To enhance the loading capacity of CpG ODNs on BNNS, we used a phage display technique to identify a 12 amino acid peptide designated as BP7, with specific affinity for BNNS, and used it as a linker to load CpG ODNs on BNNS. The tyrosine residue (Y) at the eighth position from the N-terminus played a crucial role in the affinity of BP7 to BNNS. BNNS that bound BP7 (BNNS-BP7) were taken up by cells and showed no cytotoxicity, and CpG ODNs were successfully crosslinked with BP7 to create BP7 CpG ODN conjugates. Using BP7 as a linker, the loading efficiency of CpG ODNs on BNNS increased 5-fold compared to the direct binding of CpG ODNs to BNNS. Furthermore, the BP7-CpG ODN conjugate-loaded BNNS had a greater capacity to induce interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) production from peripheral blood mononuclear cells (PBMCs) than that of CpG ODNs directly loaded on BNNS. The higher amount of cytokine induction by BP7-CpG ODN conjugate-loaded BNNS may be attributed to a higher loading capacity and stronger binding to BNNS of the linker BP7. The greater functionality of BP7-conjugated CpG ODNs on BNNS expands the potential of BNNS for drug delivery applications. PMID- 22941280 TI - Exercise might improve cardiovascular autonomic regulation in adolescents with type 1 diabetes. AB - Considering that changes in exercise routines might have relevance in treatment of adolescents with type 1 diabetes mellitus, we sought to assess whether spontaneous modifications to weekly exercise habits might occur in these patients and whether such variations would be accompanied by alterations in autonomic profile. In this observational study, we examined 77 patients (age 15.0 +/- 0.6 years.) who in addition to a tailored optimal insulin treatment were invited to perform at least 1 h a day of moderate, aerobic exercise, as suggested by recent guidelines. Patients were studied at baseline (T0) and after 15.8 +/- 0.7 months (T1). They were divided into three subgroups according to increased, unchanged and diminished total estimated weekly METs between T0 and T1. Autonomic profile was evaluated by assessing spontaneous baroreflex gain and low-frequency oscillation in arterial pressure, using spectral analysis of RR and systolic arterial pressure time series. Insulin therapy and biochemical data were similar among the 3 groups at T0 and T1, while body mass index standard deviation score was slightly reduced (p < 0.04) and markers of autonomic performance were improved (alpha index, from 17 +/- 1 to 20 +/- 2 ms/mmHg, p < 0.002) in the group who increased the amount of exercise (from 1627 +/- 250 to 3582 +/- 448 METs min wt(-1), p < 0.001). Furthermore, the change in total weekly METs significantly correlates with changes of key indices of autonomic regulation. The favourable autonomic effects of moderate increase in spontaneous exercise load suggest testing more formally this intervention in adolescents with type 1 diabetes. PMID- 22941281 TI - Hyperglycaemia in pregnancy in Mediterranean women. AB - New diagnostic criteria have recently been proposed that will result in a higher proportion of individuals being diagnosed as suffering from gestational diabetes mellitus (GDM) than previously. The present circum-Mediterranean study sets out to identify the relevance of the new criteria in this population. The study was a prospective, non-interventional, multicentre study in the Mediterranean region. A convenient sample of 1,368 pregnant women was recruited. All participants underwent a 75 g oGTT subdivided into five different glycaemic categories. The women's anthropomorphic and biological data, together with obstetric and infant outcomes, were collected. There was a threefold increase in diagnosis using the new criteria. Most of the biological characteristics generally associated with GDM showed high specificity and low sensitivity values. The biological characteristics, including maternal age, BMI and FBG, showed a progressive increase as a function of maternal glycaemia with moderate sensitivity and specificity values. Using these latter characteristics in combination ensures that 72.3 % of the GDM population would be correctly identified, while an oGTT would only be required in 18.7 % of the population. The progressive relationship of increasing glycaemia to adverse characteristics suggests that the new IADPSG criteria are reasonable provided that dietary advice is given to all pregnant women. In situations of economic restraints, it appears possible to screen Mediterranean women for GDM risk using a composite model using FBG >5.0 mmol/l combined with the performance of an oGTT in women with a low FBG but who are overweight and aged >30 years. PMID- 22941282 TI - TGF-beta polymorphism and its expression correlated with CXCR4 expression in human breast cancer. AB - The role of chemokines and the growth factors has been extensively analyzed both in cancer risk and tumor progression. The transforming growth factor beta (TGF beta) and chemokine (C-X-C motif) receptor 4 (CXCR4) genes are implicated in several diseases, including breast cancer. Genomic DNA was obtained from 21 samples of peripheral blood or from normal tissue, previously fixed in formalin and embedded in paraffin for TGF-beta T869C polymorphism analyses. Total cellular RNA was extracted from the same 21 patients, but from fresh tissue (tumor and adjacent healthy from the same breast) for expression analysis by Real Time PCR. No significant differences were observed in genotype distribution according to clinicopathological characteristics. Transforming growth factor beta (TGF-beta) mRNA expression was assessed according to T869C polymorphism and CC patients presented a higher TGF-beta expression but not significant when compared to other genotypes (p = 0.064). A positive correlation was observed in relative mRNA expressions of CXCR4 and TGF-beta (p = 0.020). It is known that overexpression of TGF-beta by both tumor and stromal tissue can facilitate the development of metastases, mainly by TGF-beta stimulated angiogenesis and increased tumor cell motility. Our findings suggested a role of these genes as progression markers for breast carcinoma. PMID- 22941283 TI - LLDT-67 attenuates MPTP-induced neurotoxicity in mice by up-regulating NGF expression. AB - AIM: To investigate the neuroprotective effects of LLDT-67, a novel derivative of triptolide, in MPTP-induced mouse Parkinson's disease (PD) models and in primary cultured astrocytes, and to elucidate the mechanisms of the action. METHODS: In order to induce PD, C57BL/6 mice were injected MPTP (30 mg/kg, ip) daily from d 2 to d 6. MPTP-induced behavioral changes in the mice were examined using pole test, swimming test and open field test. The mice were administered LLDT-67 (1, 2, or 4 mg/kg, po) daily from d 1 to d 11. On d 12, the mice were decapitated and brains were collected for immunohistochemistry study and measuring monoamine levels in the striatum. Primary cultured astrocytes from the cortices of neonatal C57BL/6 mouse pups were prepared for in vitro study. RESULTS: In MPTP-treated mice, administration of LLDT-67 significantly reduced the loss of tyrosine hydroxylase-positive neurons in the substantia nigra, and ameliorated the behavioral changes. LLDT-67 (4 mg/kg) significantly increased the expression of NGF in astrocytes in the substantia nigra and striatum of the mice. Furthermore, administration of LLDT-67 caused approximately 2-fold increases in the phosphorylation of TrkA at tyrosine 751, and marked increases in the phosphorylation of AKT at serine 473 as compared with the mice model group. In the cultured astrocytes, LLDT-67 (1 and 10 nmol/L) increased the NGF levels in the culture medium by 179% and 160%, respectively. CONCLUSION: The neuroprotective effect of LLDT-67 can be mostly attributed to its ability to enhance NGF synthesis in astrocytes in the midbrain and to rescue dopaminergic neurons indirectly through TrkA activation. PMID- 22941284 TI - Discovery of structurally diverse and bioactive compounds from plant resources in China. AB - This review describes the major discoveries of structurally diverse and/or biologically significant compounds from plant resources in China, mainly from the traditional Chinese medicines (TCMs) since the establishment of our research group in 1999. In the past decade, a large array of biologically significant and novel structures has been identified from plant resources (or TCM) in our laboratory. The structural modification of several biologically important compounds led to more than 400 derivatives, some of which exhibited significantly improved activities and provided opportunities to elucidate the structure activity relationship of the related compound class. These findings are important for drug discovery and help us understand the biological basis for the traditional applications of these plants in TCM. PMID- 22941285 TI - Pharmacological actions and therapeutic applications of Salvia miltiorrhiza depside salt and its active components. AB - Salvia miltiorrhiza, a traditional medical herb known as danshen, has been widely used in China to improve blood circulation, relieve blood stasis, and treat coronary heart disease. S miltiorrhiza depside salt is a novel drug recently developed at the Shanghai Institute of Materia Medica; it contains magnesium lithospermate B (MLB) and its analogs, rosmarinic acid (RA) and lithospermic acid (LA), as active components. The drug has been used in the clinic to improve blood circulation and treat coronary heart disease. The pharmacological effects of the depside salt from S miltiorrhiza and its components have been extensively investigated. Experimental studies have demonstrated that magnesium lithospermate B possesses a variety of biological activities, especially protective effects in the cardiovascular system such as attenuation of atherosclerosis and protection against myocardial ischemia-reperfusion injury. Rosmarinic acid and lithospermic acid also show beneficial effects on the cardiovascular system. This paper reviews the recent findings regarding the mechanisms underlying the pharmacological actions of the active components of S miltiorrhiza depside salt, based on published works and our own observations. PMID- 22941287 TI - New insights into huperzine A for the treatment of Alzheimer's disease. AB - Huperzine A, an active Lycopodium alkaloid extracted from traditional Chinese herb, is a potent, selective and reversible acetylcholinesterase (AChE) inhibitor and has been widely used in China for the treatment of Alzheimer's disease (AD). Accordingly, some new mechanisms of action for huperzine A have been discovered over the past decades. In addition to its AChE inhibitory effect, potent multifaceted neuroprotective effect through activating cholinergic system and directly acting on mitochondria have been explored. Moreover, in order to maximize the efficacy and safety of huperzine A therapy, great efforts have been made to optimize drug delivery system. In the present article, an attempt is made to discuss the current progress and future perspective for huperzine A therapy in AD. PMID- 22941286 TI - Natural products possessing protein tyrosine phosphatase 1B (PTP1B) inhibitory activity found in the last decades. AB - This article provides an overview of approximately 300 secondary metabolites with inhibitory activity against protein tyrosine phosphatase 1B (PTP1B), which were isolated from various natural sources or derived from synthetic process in the last decades. The structure-activity relationship and the selectivity of some compounds against other protein phosphatases were also discussed. Potential pharmaceutical applications of several PTP1B inhibitors were presented. PMID- 22941288 TI - Bioactive natural products from Chinese marine flora and fauna. AB - In recent decades, the pharmaceutical application potential of marine natural products has attracted much interest from both natural product chemists and pharmacologists. Our group has long been engaged in the search for bioactive natural products from Chinese marine flora (such as mangroves and algae) and fauna (including sponges, soft corals, and mollusks), resulting in the isolation and characterization of numerous novel secondary metabolites spanning a wide range of structural classes and various biosynthetic origins. Of particular interest is the fact that many of these compounds show promising biological activities, including cytotoxic, antibacterial, and enzyme inhibitory effects. By describing representative studies, this review presents a comprehensive summary regarding the achievements and progress made by our group in the past decade. Several interesting examples are discussed in detail. PMID- 22941289 TI - The important roles of RET, VEGFR2 and the RAF/MEK/ERK pathway in cancer treatment with sorafenib. AB - AIM: To elucidate the roles of receptor tyrosine kinases RET and VEGFR2 and the RAF/MEK/ERK signaling cascade in cancer treatment with sorafenib. METHODS: The cell lines A549, HeLa, and HepG2 were tested. The enzyme activity was examined under cell-free conditions using 384-well microplate assays. Cell proliferation was evaluated using the Invitrogen Alarmar Blue assay. Gene expression was analyzed using the Invitrogen SYBR Green expression assays with a sequence detection system. Protein expression analysis was performed using Western blotting. RESULTS: Sorafenib potently suppressed the activities of cRAF, VEGFR2, and RET with IC(50) values of 20.9, 4 and 0.4 nmol/L, respectively. Sorafenib inhibited cRAF, VEGFR2, and RET via non-ATP-competitive, ATP-competitive and mixed-type modes, respectively. In contrast, sorafenib exerted only moderate cytotoxic effects on the proliferation of the 3 cell lines. The IC(50) values for inhibition of A549, HeLa, and HepG2 cells were 8572, 4163, and 8338 nmol/L, respectively. In the 3 cell lines, sorafenib suppressed the cell proliferation mainly by blocking the MEK/ERK downstream pathway at the posttranscriptional level, which in turn regulated related gene expression via a feed-back mechanism. CONCLUSION: This study provides novel evidence that protein kinases RET and VEGFR2 play crucial roles in cancer treatment with sorafenib. PMID- 22941290 TI - High prevalence of the B2+C2 subgenotype mixture in patients with chronic hepatitis B in Eastern China. AB - AIM: To investigate the prevalence of hepatitis B virus (HBV) genotype mixtures among patients with chronic hepatitis B (CHB) in Eastern China. METHODS: A total of 4908 chronic HBV patients from Eastern China were enrolled. HBV genotypes and subgenotypes were determined using a multiplex PCR technique. Serum viral loads and hepatitis B e antigen (HBeAg) levels detected using real-time fluorescent quantitative PCR and ELISA assay, respectively. The presence of precore/basic core promoter (PC/BCP) mutations was examined with PCR and direct sequencing of the amplified products. RESULTS: HBV genotypes B, C, D, B+C, and B+D were found in 19.21%, 64.75%, 1.49%, 13.63%, and 0.92% of the patients, respectively. In 669 patients with the genotype mixture B+C, the subgenotypes B2+C2 and B2+C1 accounted for 68.13% and 31.87%, respectively, no other subgenotypes were identified. HBV B+C was more frequent in the patients with moderate CHB than in patients with mild CHB. In patients with moderate CHB, the subgenotype mixture B2+C2 was lower than B2+C1 (51.97% vs 63.38%), while the opposite situation was found in patients with severe CHB (22.15% vs 15.49%). The highest average viral load was found in patients with the genotype B+C mixture. The prevalence of HBV B2+C2 increased in patients from 50 to 59 years of age and was significantly different from the proportion of patients in the same age group with genotype B (23.2% vs 15.2%). A double mutation (G1896A) in the PC was significantly more common in subgenotype B2+C2 than in subgenotype B2+C1. CONCLUSION: The HBV B2+C2 subgenotype was prevalent in CH patients with a high HBV replication status and correlated with a more severe course of the disease. PMID- 22941292 TI - Education for ethics practice: tailoring curricula to local needs and objectives. AB - Currently, there is no authoritative credentialing process for individuals engaged in ethics practice, no accreditation system that sets minimum education standards for programs aiming to prepare these individuals for their work, and little evidence available that any particular training model is actually achieving its pedagogical goals. At the same time, a number of healthcare organizations and universities now routinely offer post-graduate programs, clinical fellowships and in-house training specifically devised to prepare graduates for ethics practice. However, while their numbers appear to be growing, information about these programs is limited. In this paper, we describe the goals, content and strategies of three educational programs offered in Ontario, Canada. These case studies highlight the diversity of ethics education available to those who engage in ethics practice and underscore the need to take this variety into account in the development of future education standards that would specify minimally acceptable educational requirements. PMID- 22941291 TI - Amelioration of influenza virus-induced reactive oxygen species formation by epigallocatechin gallate derived from green tea. AB - AIM: To study whether epigallocatechin gallate (EGCG), a green tea-derived polyphenol, exerted anti-influenza A virus activity in vitro and in vivo. METHODS: Madin-Darby canine kidney (MDCK) cells were tested. The antiviral activity of EGCG in the cells was determined using hemagglutination assay and qPCR. Time of addition assay was performed to determine the kinetics of inhibition of influenza A by EGCG. The level of reactive oxygen species (ROS) were determined with confocal microscopy and flow cytometry. BALB/c mice were treated with EGCG (10, 20 or 40 mg.kg(-1).d(-1), po) for 5 d. On the 3rd d of the treatment, the mice were infected with influenza A virus. Histopathological changes, lung index and virus titers in the lungs were determined. RESULTS: Treatment of influenza A-infected MDCK cells with EGCG (1.25-100 nmol/L) inhibited influenza A replication in a concentration-dependent manner (the ED(50) value was 8.71+/-1.11 nmol/L). Treatment with EGCG (20 nmol/L) significantly suppressed the increased ROS level in MDCK cells following influenza A infection. In BALB/c mice infected with influenza virus, oral administration of EGCG (40 mg.kg(-1).d(-1)) dramatically improved the survival rate, decreased the mean virus yields and mitigated viral pneumonia in the lungs, which was equivalent to oral administration of oseltamivir (40 mg.kg(-1).d(-1)), a positive control drug. CONCLUSION: The results provide a molecular basis for development of EGCG as a novel and safe chemopreventive agent for influenza A infection. PMID- 22941293 TI - Evaluating parents' perspectives of pediatric ethics consultation. AB - Ethics consultation is a familiar concept to clinicians, and there are site specific guidelines detailing procedures for both obtaining and performing these consults. Evaluative data about clinician experiences with ethics consults are becoming more extensive but information about family experiences, especially parent perceptions, of the same is lacking. Without a better understanding of those family experiences, an evidence base for ethics consultations cannot be built. This manuscript describes the reasons for obtaining this necessary information, details prior research designed to obtain knowledge about family experiences with pediatric ethics consultations, and suggests mechanisms for acquiring it. PMID- 22941294 TI - A combined impedance and AlphaLISA-based approach to identify anti-inflammatory and barrier-protective compounds in human endothelium. AB - Chronic inflammation is at least partially mediated by the chemokine-mediated attraction and by the adhesion molecule-directed binding of leukocytes to the activated endothelium. Therefore, it is therapeutically important to identify anti-inflammatory compounds able to control the interaction between leukocytes and the endothelial compartments of the micro- and macrocirculation. When testing novel drug candidates, it is, however, of the utmost importance to detect side effects, such as potential cytotoxic and barrier-disruptive activities. Indeed, minor changes in the endothelial monolayer integrity may increase the permeability of small blood vessels and capillaries, which, in extreme cases, can lead to edema development. Here, we describe the development of a high-throughput screening (HTS) platform, based on AlphaLISA technology, able to identify anti inflammatory nontoxic natural or synthetic compounds capable of reducing tumor necrosis factor (TNF)-induced chemokine (interleukin [IL]-8) and adhesion molecule (ICAM-1) expression in human lung microvascular endothelial cells. Quantification of cell membrane-expressed ICAM-1 and of cell culture supernatant associated levels of IL-8 was analyzed in HTS. In parallel, we monitored monolayer integrity and endothelial cell viability using the electrical cell substrate impedance sensing method. This platform allowed us to identify natural secondary metabolites from cyanobacteria, capable of reducing ICAM-1 and IL-8 levels in TNF-activated human microvascular endothelial cells in the absence of endothelial monolayer barrier disruption. PMID- 22941295 TI - Phenotypic high-throughput screening elucidates target pathway in breast cancer stem cell-like cells. AB - Cancer stem cells (CSCs) are resistant to standard cancer treatments and are likely responsible for cancer recurrence, but few therapies target this subpopulation. Due to the difficulty in propagating CSCs outside of the tumor environment, previous work identified CSC-like cells by inducing human breast epithelial cells into an epithelial-to-mesenchymal transdifferentiated state (HMLE_sh_ECad). A phenotypic screen was conducted against HMLE_sh_ECad with 300 718 compounds from the Molecular Libraries Small Molecule Repository to identify selective inhibitors of CSC growth. The screen yielded 2244 hits that were evaluated for toxicity and selectivity toward an isogenic control cell line. An acyl hydrazone scaffold emerged as a potent and selective scaffold targeting HMLE_sh_ECad. Fifty-three analogues were acquired and tested; compounds ranged in potency from 790 nM to inactive against HMLE_sh_ECad. Of the analogues, ML239 was best-in-class with an IC(50)= 1.18 uM against HMLE_sh_ECad, demonstrated a >23 fold selectivity over the control line, and was toxic to another CSC-like line, HMLE_shTwist, and a breast carcinoma cell line, MDA-MB-231. Gene expression studies conducted with ML239-treated cells showed altered gene expression in the NF-kappaB pathway in the HMLE_sh_ECad line but not in the isogenic control line. Future studies will be directed toward the identification of ML239 target(s). PMID- 22941296 TI - Bartonella jaculi sp. nov., Bartonella callosciuri sp. nov., Bartonella pachyuromydis sp. nov. and Bartonella acomydis sp. nov., isolated from wild Rodentia. AB - Four novel strains of members of the genus Bartonella, OY2-1(T), BR11-1(T), FN15 2(T) and KS2-1(T), were isolated from the blood of wild-captured greater Egyptian jerboa (Jaculus orientalis), plantain squirrel (Callosciurus notatus), fat-tailed gerbil (Pachyuromys duprasi) and golden spiny mouse (Acomys russatus). All the animals were imported to Japan as pets from Egypt, Thailand and the Netherlands. The phenotypic characterization (growth conditions, incubation periods, biochemical properties and cell morphologies), DNA G+C contents (37.4 mol% for strain OY2-1(T), 35.5 mol% for strain BR11-1(T), 35.7 mol% for strain FN15-2(T) and 37.2 mol% for strain KS2-1(T)), and sequence analyses of the 16S rRNA genes indicated that those strains belong to the genus Bartonella. Sequence comparisons of gltA and rpoB genes suggested that all of the strains should be classified as novel species of the genus Bartonella. In phylogenetic trees based on the concatenated sequences of five loci, including the 16S rRNA, ftsZ, gltA and rpoB genes and the ITS region, and on the concatenated deduced amino acid sequences of three housekeeping genes (ftsZ, gltA and rpoB), all strains formed distinct clades and had unique mammalian hosts that could be discriminated from other known species of the genus Bartonella. These data strongly support the hypothesis that strains OY2-1(T), BR11-1(T), FN15-2(T) and KS2-1(T) should be classified as representing novel species of the genus Bartonella. The names Bartonella jaculi sp. nov., Bartonella callosciuri sp. nov., Bartonella pachyuromydis sp. nov. and Bartonella acomydis sp. nov. are proposed for these novel species. Type strains of Bartonella jaculi sp. nov., Bartonella callosciuri sp. nov., Bartonella pachyuromydis sp. nov. and Bartonella acomydis sp. nov. are OY2-1(T) ( = JCM 17712(T) = KCTC 23655(T)), BR11-1(T) ( = JCM 17709(T) = KCTC 23909(T)), FN15-2(T) ( = JCM 17714(T) = KCTC 23657(T)) and KS2-1(T) ( = JCM 17706(T) = KCTC 23907(T)), respectively. PMID- 22941298 TI - Roseovarius sediminilitoris sp. nov., isolated from seashore sediment. AB - A Gram-negative, motile and ovoid- to rod-shaped bacterial strain, designated M M10(T), was isolated from a seashore sediment collected from the South Sea, South Korea. Strain M-M10(T) grew optimally at pH 7.0-8.0, at 30 degrees C and in the presence of 2 % (w/v) NaCl. The phylogenetic trees based on 16S rRNA gene sequences revealed that strain M-M10(T) clustered with the type strains of Roseovarius crassostreae, Roseovarius halocynthiae and Roseovarius marinus, with which it exhibited sequence similarities of 97.4, 97.3 and 95.1 %, respectively. It exhibited 93.2-95.1 % sequence similarity to the type strains of the other species of the genus Roseovarius. Strain M-M10(T) contained Q-10 as the predominant ubiquinone and C18 : 1omega7c and C16 : 0 as the major fatty acids, as observed in the genus Roseovarius. The polar lipid profile of strain M-M10(T) was similar to that of Roseovarius tolerans DSM 11457(T). The DNA G+C content of strain M-M10(T) was 63.0 mol% and its mean DNA-DNA relatedness values with Roseovarius crassostreae DSM 16950(T) and Roseovarius halocynthiae MA1-10(T) were 16 % and 22 %, respectively. Differential phenotypic properties, together with the phylogenetic and genetic distinctiveness, demonstrated that strain M-M10(T) is distinct from other species of the genus Roseovarius. On the basis of the data presented, strain M-M10(T) is considered to represent a novel species of the genus Roseovarius, for which the name Roseovarius sediminilitoris sp. nov. is proposed. The type strain is M-M10(T) ( = KCTC 23959(T) = CCUG 62413(T)). PMID- 22941297 TI - Mesorhizobium shonense sp. nov., Mesorhizobium hawassense sp. nov. and Mesorhizobium abyssinicae sp. nov., isolated from root nodules of different agroforestry legume trees. AB - A total of 18 strains, representing members of the genus Mesorhizobium, obtained from root nodules of woody legumes growing in Ethiopia, have been previously shown, by multilocus sequence analysis (MLSA) of five housekeeping genes, to form three novel genospecies. In the present study, the phylogenetic relationship between representative strains of these three genospecies and the type strains of their closest phylogenetic neighbours Mesorhizobium plurifarium, Mesorhizobium amorphae, Mesorhizobium septentrionale and Mesorhizobium huakuii was further evaluated using a polyphasic taxonomic approach. In line with our earlier MLSA of other housekeeping genes, the phylogenetic trees derived from the atpD and glnII genes grouped the test strains into three well-supported, distinct lineages that exclude all defined species of the genus Mesorhizobium. The DNA-DNA relatedness between the representative strains of genospecies I-III and the type strains of their closest phylogenetic neighbours was low (<=59 %). They differed from each other and from their closest phylogenetic neighbours by the presence/absence of several fatty acids, or by large differences in the relative amounts of particular fatty acids. While showing distinctive features, they were generally able to utilize a wide range of substrates as sole carbon and nitrogen sources. The strains belonging to genospecies I, II and III therefore represent novel species for which we propose the names Mesorhizobium shonense sp. nov., Mesorhizobium hawassense sp. nov. and Mesorhizobium abyssinicae sp. nov. The isolates AC39a(T) ( = LMG 26966(T) = HAMBI 3295(T)), AC99b(T) ( = LMG 26968(T) = HAMBI 3301(T)) and AC98c(T) ( = LMG 26967(T) = HAMBI 3306(T)) are proposed as type strains for the respective novel species. PMID- 22941299 TI - Lactobacillus porcinae sp. nov., isolated from traditional Vietnamese nem chua. AB - A species diversity study of lactic acid bacteria occurring in traditional Vietnamese nem chua yielded an isolate, LMG 26767(T), that could not be assigned to a species with a validly published name. The isolate was initially investigated by 16S rRNA gene sequence analysis, which revealed that it belonged to the genus Lactobacillus, with Lactobacillus manihotivorans and Lactobacillus camelliae as the closest relatives (98.9 % and 96.9 % gene sequence similarity to the type strains, respectively). Comparative (GTG)5-PCR genomic fingerprinting confirmed the unique taxonomic status of the novel strain. DNA-DNA hybridization experiments, DNA G+C content determination, sequence analysis of the phenylalanyl tRNA synthase (pheS) gene, and physiological and biochemical characterization demonstrated that strain LMG 26767(T) represents a novel species, for which the name Lactobacillus porcinae sp. nov. is proposed; the type strain is LMG 26767(T) ( = CCUG 62266(T)). Biochemically, L. porcinae can be distinguished from L. manihotivorans and L. camelliae by its carbohydrate fermentation profile, absence of growth at 45 degrees C, and production of d- and l-lactate as end products of glucose metabolism. PMID- 22941300 TI - Orbus sasakiae sp. nov., a bacterium isolated from the gut of the butterfly Sasakia charonda, and emended description of the genus Orbus. AB - A novel Gram-stain-negative, facultatively anaerobic, non-motile and coccus shaped bacterium, strain C7(T), was isolated from the gut of the butterfly Sasakia charonda. Strain C7(T) grew optimally at 20-25 degrees C, at pH 7-8 and with 1 % (w/v) NaCl. The strain was negative for oxidase activity but positive for catalase activity. The 16S rRNA gene sequences of strain C7(T) and Orbus hercynius CN3(T) shared 96.8 % similarity. The major fatty acids identified were C14 : 0, C16 : 0, C18 : 1omega7c and summed feature 2 (comprising C14 : 0 3 OH/iso-C16 : 1). The major respiratory quinone was ubiquinone-8 (Q-8). The polar lipids of strain C7(T) were phosphatidylethanolamine, phosphatidylglycerol, an unidentified phospholipid and two unidentified aminophospholipids. The G+C content of the genomic DNA extracted from strain C7(T) was 32.1 mol%. Taken together, the phenotypic, genotypic and phylogenetic analyses indicate that strain C7(T) represents a novel species of the genus Orbus, for which the name Orbus sasakiae sp. nov. is proposed. The type strain is C7(T) ( = KACC 16544(T) = JCM 18050(T)). An emended description of the genus Orbus is provided. PMID- 22941301 TI - Friedmanniella flava sp. nov., a soil actinomycete. AB - A novel actinomycete, strain W6(T), was isolated from a soil sample of Yunnan Province, China. The bacterium was aerobic, non-motile, non-spore-forming and Gram-stain-positive. Genetic, phenotypic and chemical properties of the isolate were studied. 16S rRNA gene sequence data suggested that the novel isolate belonged to the genus Friedmanniella and shared 98.6% sequence similarity with Friedmanniella antarctica DSM 11053(T) and Friedmanniella okinawensis DSM 21744(T), the most closely related species. The cell-wall peptidoglycan contained ll-diaminopimelic acid, and mycolic acids were absent. The main menaquinone was MK-9(H4) and the predominant fatty acids were anteiso-C15:0 and iso-C15:0. The phospholipid profile contained phosphatidylglycerol, phosphatidylinositol, phosphatidylcholine and diphosphatidylglycerol. The DNA G+C content of strain W6(T) was 72 mol%. Strain W6(T) showed 30.0% and 28.5% DNA-DNA relatedness, respectively, to F. antarctica DSM 11053(T) and F. okinawensis DSM 21744(T). The combined genotypic and phenotypic data showed that strain W6(T) should be assigned to the genus Friedmanniella as a representative of a novel species, for which the name Friedmanniella flava sp. nov. is proposed. The type strain is W6(T) ( = CGMCC 4.6856(T) =JCM 17701(T)). PMID- 22941302 TI - Aquimarina gracilis sp. nov., isolated from the gut microflora of a mussel, Mytilus coruscus, and emended description of Aquimarina spongiae. AB - An orange-coloured and slender rod-shaped bacterium, designated strain PSC32(T), was isolated from the gut microflora of a mussel collected from Gwangyang Bay, South Sea (Republic of Korea). Cells were Gram-reaction-negative, strictly aerobic, and catalase- and oxidase-positive. The major fatty acids were iso-C15 : 0, iso-C17 : 0 3-OH, iso-C15 : 1 G and iso-C15 : 0 3-OH. The only isoprenoid quinone of strain PSC32(T) was MK-6 and the DNA G+C content was 36.9 mol%. Phosphatidylethanolamine, one unidentified aminolipid and two unidentified polar lipids were found as major polar lipids. A phylogenetic tree based on 16S rRNA gene sequences showed that strain PSC32(T) forms an evolutionary lineage within the genus Aquimarina and is closely related to Aquimarina spongiae A6(T) (97.0 % similarity) and to other members of the genus Aquimarina (94.4-96.5 %). Genomic DNA-DNA relatedness between strain PSC32(T) and A. spongiae A6(T) was 40.7 %. A number of phenotypic characteristics distinguished strain PSC32(T) from described members of the genus Aquimarina. On the basis of the evidence presented in this study, strain PSC32(T) represents a novel species, for which the name Aquimarina gracilis sp. nov. is proposed. The type strain is PSC32(T) ( = KCTC 23301(T) = JCM 17453(T)). An emended description of Aquimarina spongiae is given. PMID- 22941303 TI - Paenibacillus catalpae sp. nov., isolated from the rhizosphere soil of Catalpa speciosa. AB - A bacterial strain, designated D75(T), was isolated from the rhizosphere soil of Catalpa speciosa. Phylogenetic analysis based on the complete 16S rRNA gene sequence revealed that strain D75(T) was a member of the genus Paenibacillus. High levels of 16S rRNA gene sequence similarity were found between strain D75(T) and Paenibacillus glycanilyticus DS-1(T) (99.2 %), Paenibacillus xinjiangensis B538(T) (97.5 %) and Paenibacillus castaneae Ch-32(T) (97.2 %). The chemotaxonomic properties of strain D75(T) were consistent with those of the genus Paenibacillus: the cell-wall peptidoglycan type was based on meso diaminopimelic acid (A1gamma), the predominant menaquinone was MK-7, and the major fatty acids were anteiso-C15 : 0, iso-C16 : 0 and C16 : 0. However, levels of DNA-DNA relatedness between strain D75(T) and P. glycanilyticus NBRC 16618(T), P. xinjiangensis DSM 16970(T) and P. castaneae DSM 19417(T) were 35, 20 and 18 %, respectively. On the basis of phenotypic and chemotaxonomic analyses, phylogenetic data and DNA-DNA relatedness values, strain D75(T) is considered to represent a novel species of the genus Paenibacillus, for which the name Paenibacillus catalpae sp. nov. is proposed. The type strain is D75(T) ( = DSM 24714(T) = CGMCC 1.10784(T)). PMID- 22941305 TI - Conditioned water affects pair formation behaviour in the marine polychaete Neanthes (Nereis) acuminata. AB - Assessing cues from conspecifics is paramount during mate choice decisions. Neanthes acuminata is a marine polychaete with a unique life cycle: pair formation, female death following reproduction, male parental care and male ability to mate again after egg care. Males completing such egg care are 'experienced'. Females have been shown to prefer experienced males over all others, including aggressively dominant males. As the female dies following reproduction, the reproductive success of her offspring depends upon successful parental care by the male. It is therefore vital that the female makes a good mate choice decision. This paper shows that the use of conditioned water from males caring for eggs and newly experienced males caused the female to alter her choice to a previously undesired male. However, conditioned water from males, which had reproduced but were isolated for 2 weeks, did not have the same effect on pairing behaviour. This indicates that the smell of experience is short lived. PMID- 22941304 TI - Anticancer effects of KI-10F: a novel compound affecting apoptosis, angiogenesis and cell growth in colon cancer. AB - The anticancer effect of a new pyrazole derivative, KI-10F (2-(4-(2-(4 (dimethylamino) phenyl)pyridin-4-yl)-5-(3-methoxy-5-methylphenyl)-1H-pyrazol-1 yl) acetonitrile)*3.5HCl) was evaluated in human colon cancer cells. KI-10F strongly suppressed the growth of human colon cancer cells and induced apoptosis by increasing the proportion of sub-G1 presenting apoptotic cells as well as causing cell cycle arrest at the G2/M phase. Apoptosis by KI-10F was confirmed by observation of an increase in the expression of cleaved caspase-3, caspase-8, caspase-9 and Bax, and the decrease of Bcl-2. Decreased expression of HIF-1alpha and VEGF, and the inhibition of HUVEC tube formation and migration showed that KI 10F effectively inhibited the angiogenesis process. Furthermore, in vivo study in a mouse xenograft model showed that KI-10F produced a stronger antitumor activity than 5-FU, a conventional anticancer drug prescribed for the treatment of colon cancer. The effects of KI-10F on tumor proliferation (PCNA), angiogenesis (CD34) and apoptosis (cleaved caspase-3) were evaluated by immunohistochemistry using isolated tumor tissue samples. Taken together, our results demonstrated that KI 10F induces apoptosis and inhibits cell growth and angiogenesis both in vitro and in vivo. We suggest that KI-10F is an effective chemotherapeutic candidate for use against colon cancer. PMID- 22941306 TI - Pegylated interferon alpha2a induces complete remission of acute myeloid leukemia in a postessential thrombocythemia myelofibrosis permitting allogenic stem cell transplantation. PMID- 22941307 TI - A rare case report of 8p11 myeloid and lymphoid neoplasm with FGFR1 abnormality in a young adult. PMID- 22941308 TI - Laccase-mediated transformations of endocrine disrupting chemicals abolish binding affinities to estrogen receptors and their estrogenic activity in zebrafish. AB - Endocrine disrupting chemicals (EDCs) are known to mainly affect aquatic organisms, producing negative effects in aquaculture. Transformation of the estrogenic compounds 17beta-estradiol (E2), bisphenol-A (BPA), nonylphenol (NP), and triclosan (TCS) by laccase of Coriolopsis gallica was studied. Laccase is able to efficiently transform them into polymers. The estrogenic activity of the EDCs and their laccase transformation products was evaluated in vitro as their affinity for the human estrogen receptor alpha (hERalpha) and for the ligand binding domain of zebrafish (Danio rerio) estrogen receptor alpha (zfERalphaLBD). E2, BPA, NP, and TCS showed higher affinity for the zfERalphaLBD than for hERalpha. After laccase treatment, no affinity was found, except a marginal affinity of E2 products for the zfERalphaLBD. Endocrine disruption studies in vivo on zebrafish were performed using the induction of vitellogenin 1 as a biomarker (VTG1 mRNA levels). The use of enzymatic bioreactors, containing immobilized laccase, efficiently eliminates the endocrine activity of BPA and TCS, and significantly reduces the effects of E2. The potential use of enzymatic reactors to eliminate the endocrine activity of EDCs in supply water for aquaculture is discussed. PMID- 22941309 TI - Galacto-oligosaccharides synthesis from lactose and whey by beta-galactosidase immobilized in PVA. AB - The synthesis of galacto-oligosaccharides (GOS) by beta-galactosidase immobilized in both polyvinyl alcohol (PVA) lenses and sol-gel carriers was studied and compared with the performance of the free enzyme. PVA-immobilized beta galactosidase retained 95 % of the initial activity after seven repeated uses and retained 51 % of the initial activity after 3 months of storage, while sol-gel immobilized beta-galactosidase only retained 39 % of the initial activity under storage. Lactose conversion takes place at a higher rate in the PVA-immobilized beta-galactosidase, while the lowest rate of lactose conversion was noticed with immobilized beta-galactosidase in sol-gel. Continuous production of GOS from either lactose or whey, with PVA-immobilized beta-galactosidase, was performed in a packed-bed reactor. A maximum GOS production of 30 % of total sugars was attained for a 40-% lactose feed solution with a feed rate of 10.8 ml/h, at pH 4.5 and 40 degrees C, corresponding to a productivity of 117 g/l h. The maximum GOS productivity of 344 g/l h was obtained at a flow rate of 28.7 ml/h. 3-OS and 4-OS were the major types of GOS formed. Conversion of whey in continuous mode resulted in GOS production of 15 % of total sugars and formation of 45 % 3-OS, 40 % 4-OS, and 15 % 5-OS. PMID- 22941310 TI - Immunomodulatory response of mice splenocytes induced by RcaL, a lectin isolated from cobia fish (Rachycentron canadum) serum. AB - This work reports the isolation of a serum lectin from cobia fish (Rachycentron canadum) named RcaL. Immunomodulatory activity on mice splenocyte experimental cultures through cytotoxic assays and cytokine production were also performed. RcaL was obtained through precipitation with ammonium sulphate and affinity chromatography on a Concanavalin A-Sepharose 4B column. The ammonium sulphate fraction F3 showed the highest specific hemagglutinating activity and was applied to affinity chromatography. The lectin was eluted with methyl-alpha-D mannopyranoside. RcaL showed highest affinity for methyl-alpha-D-mannopyranoside and D-mannose; eluted fractions of RcaL agglutinated rabbit erythrocytes (titre, 128(-1)) retained 66 % of chromatographed lectin activity, and the obtained purification factor was 1.14. Under reducing conditions, a polypeptide band of 19.2 kDa was revealed in sodium dodecyl sulphate polyacrylamide gel electrophoresis (PAGE). PAGE confirmed RcaL as an acidic protein revealed in a single band. Cytotoxic and immunomodulatory assays with RcaL in mice splenocyte cultures showed that the lectin was not cytotoxic and induced higher interferon gamma and nitric oxide production in splenocyte cultures. Purified RcaL induced preferential Th1 response, suggesting that it acts as an immunomodulatory compound. PMID- 22941311 TI - Distinct depression symptom trajectories over the first year of dialysis: associations with illness perceptions. AB - BACKGROUND: Depression in the dialysis population is common, but trajectories of depression symptoms are unknown. PURPOSE: This study aims to (1) examine whether different patterns of depression symptoms exist over the first year of dialysis and (2) to understand if illness perceptions are associated with observed trajectories of depression symptoms. METHOD: Incident dialysis patients (n = 160) completed the Beck Depression Inventory II and the Revised Illness Perception Questionnaire soon after starting dialysis and again at 6 and 12 months. Latent class growth modelling identified distinct groups of depression symptom trajectories. RESULTS: Three depression trajectories were identified: "low reducing" (62 %), "moderate-increasing" (21.8 %) and "high-reducing" (16.2 %). Higher levels of depression were associated with a poorer understanding of the illness (coherence) and perceptions that kidney failure has severe consequences and a more cyclical timeline. Beliefs that treatment controlled kidney failure decreased over time in patients with increasing depression symptoms. CONCLUSION: Distinct patterns of depression symptoms are associated with illness perceptions. The potential to identify common patterns of depression symptoms may help target treatments at those most likely to benefit. PMID- 22941313 TI - The fall in force after exercise disturbs position sense at the human forearm. AB - We reported previously that concentric or eccentric exercise can lead to errors in human limb position sense. Our data led us to conclude that the errors, post exercise, were not due to an altered responsiveness of the proprioceptive afferents, and we proposed that they resulted from central changes in the processing of the afferent input. However, it remained uncertain what was responsible for triggering those changes, the volume of afferent traffic during the exercise or the developing fatigue. The afferent traffic hypothesis was tested by subjects carrying out a series of 250 lightly loaded concentric contractions of elbow flexors that produced little fatigue (6 %). This did not lead to significant position errors. In a second experiment, a series of fatiguing isometric contractions, which kept movements of the muscle to a minimum, led to a 24 % fall in force and significant position errors (3 degrees , direction of extension). In the third experiment, at 24 h after eccentric exercise, when the short-term effects of fatigue and accumulated metabolites were gone, but force was still 28 % below control values, this was accompanied by significant position errors in the direction of extension, 3.2 degrees in the relaxed arm and 3.3 degrees in the self-supported arm. It is concluded that it is the fall in force accompanying exercise which is responsible for disturbing limb position sense. It is suggested that the exercise effects are generated in the brain, perhaps as a result of an alteration of the body map, triggered by the fall in force. PMID- 22941314 TI - Perceiving bodies in motion: expression intensity, empathy, and experience. AB - This study investigated the perceptual identification of individuals' intended expression intensity in point-light displays depicting dance. Participants watched point-light displays of 200-1,000-ms duration, as well as static displays, of expressive and inexpressive dance performances. The task was to identify the intended expression intensity of the performer. The results indicate that expression intensity could be discerned reliably only from dynamic displays, even when they were as short as 200 ms, though the accuracy of judgments increased with exposure duration. Judgment accuracy for dynamic displays was positively correlated with self-report empathy indices and confidence in judgments. Accuracy for these displays also correlated with indices of informal music and dance experience. The findings are discussed in relation to sensorimotor and cognitive-emotional processes underlying action understanding and social cognition. PMID- 22941315 TI - Reference frames for coding touch location depend on the task. AB - The position of gaze (eye plus head position) relative to body is known to alter the perceived locations of sensory targets. This effect suggests that perceptual space is at least partially coded in a gaze-centered reference frame. However, the direction of the effects reported has not been consistent. Here, we investigate the cause of a discrepancy between reported directions of shift in tactile localization related to head position. We demonstrate that head eccentricity can cause errors in touch localization in either the same or opposite direction as the head is turned depending on the procedure used. When head position is held eccentric during both the presentation of a touch and the response, there is a shift in the direction opposite to the head. When the head is returned to center before reporting, the shift is in the same direction as head eccentricity. We rule out a number of possible explanations for the difference and conclude that when the head is moved between a touch and response the touch is coded in a predominantly gaze-centered reference frame, whereas when the head remains stationary a predominantly body-centered reference frame is used. The mechanism underlying these displacements in perceived location is proposed to involve an underestimated gaze signal. We propose a model demonstrating how this single neural error could cause localization errors in either direction depending on whether the gaze or body midline is used as a reference. This model may be useful in explaining gaze-related localization errors in other modalities. PMID- 22941317 TI - Directional exciton transport in supramolecular nanostructured assemblies. AB - Supramolecular nanostructured host-guest compounds provide an intriguing strategy for improved materials in optoelectronic devices. Here, conjugated organic guest molecules are embedded in channel-forming organic or inorganic hosts, like perhydrotriphenylene (PHTP) and zeolites, leading to weakly coupled, highly ordered, and brightly emissive materials. In-depth material characterization allows for a full understanding of the exciton transport mechanism in the weak coupling regime through steady-state time-resolved fluorescence studies combined with quantum-chemical based Monte-Carlo simulations without adjustable parameters. Despite weak chromophore coupling and dilution by the host, the exciton diffusion length exceeds 50 nm similar to molecular crystals, and might be tuned to the MUm range by the proper choice of host and guest materials. PMID- 22941316 TI - The effect of BDNF val66met polymorphism on visuomotor adaptation. AB - Brain-derived neurotrophic factor (BDNF) plays an important role in learning, memory, and brain plasticity. Humans with a val66met polymorphism in the BDNF gene have reduced levels of BDNF and alterations in motor learning and short-term cortical plasticity. In the current study, we sought to further explore the role of BDNF in motor learning by testing human subjects on a visuomotor adaptation task. In experiment 1, 21 subjects with the polymorphism (val/met) and 21 matched controls (val/val) were tested during learning, short-term retention (45 min), long-term retention (24 h), and de-adaptation of a 60 degrees visuomotor deviation. We measured both mean error as well as rate of adaptation during each session. There was no difference in mean error between groups; however, val/met subjects had a reduced rate of adaptation during learning as well as during long term retention, but not short-term retention or de-adaptation. In experiment 2, 12 val/met and 12 val/val subjects were tested on a larger 80 degrees deviation, revealing a more pronounced difference in mean error during adaptation than the 60 degrees deviation. These results suggest that BDNF may play an important role in visuomotor adaptive processes in the human. PMID- 22941318 TI - Specific aspects of children and adolescents undergoing lung transplantation. AB - PURPOSE OF REVIEW: Lung transplantation has evolved as an accepted therapy in carefully selected children with end-stage lung disease, offering a prolonged survival and improved quality of life. Presently, more than 100 lung transplant procedures are done in children annually worldwide. Specific aspects of children and adolescents undergoing lung transplantation will be reviewed and an update on most recent developments in the management of paediatric lung transplant recipients will be given. RECENT FINDINGS: Certain aspects are unique to children and adolescents undergoing lung transplantation such as a challenging surgical procedure, the effects of immunosuppressant therapy, and the impact of infections on the child's developing immune system and somatic growth. The underlying diagnoses leading to lung transplantation vary considerably by age group. Early referral, careful patient selection and appropriate timing of listing are crucial to achieve the maximal survival benefit. In particular, infectious complications are a common in children. Chronic lung allograft dysfunction remains the major obstacle for a better long-term survival. SUMMARY: Lung transplantation has successfully been performed in infants, children and adolescents with outcomes similar to that in adults. Specific aspects of paediatric lung transplantation include donor shortage for smaller recipients, somatic growth, psychosocial aspects and adherence, and transition to adult care. PMID- 22941319 TI - Renal failure and transplantation following nonrenal solid-organ transplantation. AB - PURPOSE OF REVIEW: To review the challenges and complications related to the native kidney following nonrenal solid-organ transplantation (NRSOT). RECENT FINDINGS: Deterioration of renal function has been reported as an independent predictor of mortality following NRSOT. The incidence of pediatric end-stage renal disease (ESRD) after nonrenal transplantation is at least 3%, according to the 2011 United States Renal Data System Annual Report. Although calcineurin toxicity is a leading cause of renal insufficiency, other pathologic changes can be seen. SUMMARY: Calcineurin inhibitor nephrotoxicity in nonrenal allograft recipients can lead to ESRD and the need for kidney transplantation. There is increased morbidity and mortality associated with chronic kidney disease (CKD) following nonrenal transplantation, but few large-scale studies have been conducted in pediatric patients. Challenges exist in monitoring renal function in chronically ill pediatric patients and estimating equations using creatinine overestimate glomerular filtration rates. Collaborative research is needed to define further the incidence of CKD following NRSOT. PMID- 22941320 TI - Prevention and treatment of coronary artery vasculopathy. AB - PURPOSE OF REVIEW: Cardiac allograft vasculopathy (CAV) is still one of the major causes of death following heart transplantation. Here, we review the recent advances in its prevention and treatment. RECENT FINDINGS: Preventive measures comprise control of classical risk factors, prophylaxis against cytomegalovirus, avoidance of graft endothelial damage during heart transplantation, and prevention of acute rejection. These measures can be effective if begun early. The treatment options for established CAV are limited, percutaneous revascularization and coronary artery bypass graft only being viable for a minority of patients because of the diffuse nature of CAV. Retransplantation is the only definitive therapy for CAV and may be considered for suitable patients with advanced CAV and allograft dysfunction. One of the most promising developments in the recent years is the use of mTOR inhibitors, which can now be regarded as effective in preventing CAV in de novo patients; their role in the treatment of established CAV is still uncertain despite some encouraging recent findings. SUMMARY: The implementation of measures and lifestyles that help prevent CAV should be a priority of postheart transplantation management. Research should urgently evaluate mTOR inhibitors for the treatment of established CAV. PMID- 22941321 TI - Guidelines for the selection of lung-transplant candidates. AB - PURPOSE OF REVIEW: Lung transplantation can improve survival and quality of life in select patients with end-stage lung disease. Because of the limited availability of donor lungs and limited post-transplant survival of recipients, selection of candidates that are most likely to benefit from transplantation is of utmost importance. RECENT FINDINGS: Since the revision of 2006 international guidelines for the selection of lung-transplant candidates, new literature has emerged to improve our understanding of disease-specific prognosis and the impact of nonpulmonary comorbidities on post-transplant outcomes. Further published data on the cumulative effect of multiple comorbidities have allowed transplant professionals to better define the high-risk recipient. Applying each of the above principles to the evaluation of potential lung-transplant recipients will allow optimal allocation of donor organs to recipients that are most likely to benefit. SUMMARY: This article will review the most recent literature in the field in order to provide an updated framework for the optimal selection of candidates for lung transplantation. PMID- 22941322 TI - Gastroesophageal reflux disease-induced aspiration injury following lung transplantation. AB - PURPOSE OF REVIEW: Chronic allograft failure remains the leading cause of late mortality following lung transplantation. Considerable evidence demonstrates a relationship between gastroesophageal reflux disease (GERD) induced allograft injury and bronchiolitis obliterans syndrome; however, the mechanism of injury, identification of at-risk patients, and treatment options remain to be elucidated. RECENT FINDINGS: The recent findings in this area help delineate the inflammatory pathways associated with GERD-induced lung injury. They also demonstrate that clinically useful markers of aspiration-induced injury may be available via studying bronchoalveolar fluid or even induced sputum. Simple acid neutralization is not adequate to protect these patients from aspiration injury. In fact, there are no convincing data to indicate that medical therapies provide adequate treatment. In contradistinction, surgical fundoplication is associated with decreased levels of inflammatory cytokines and markers of aspiration in bronchoalveolar fluid, as well as improvements in pulmonary function in these patients. SUMMARY: Recent findings support ubiquitous testing for GERD or aspiration in patients with end-stage lung disease both pretransplant and posttransplant and demonstrate that fundoplication can safely and effectively protect these patients from the on-going injury of GERD-induced pulmonary injury. PMID- 22941323 TI - Ex-vivo lung perfusion. AB - PURPOSE OF REVIEW: Lung transplant continues to be hampered by the number of available donors. Ex-vivo lung perfusion (EVLP) has emerged as an essential tool for the reassessment, under a controlled scenario, of lungs that initially did not meet transplantation criteria. The purpose of the current study is to review the most recent clinical and research reports and summarize their findings. RECENT FINDINGS: Several centers have presented positive data when using ex-vivo perfusion to identify better grafts from the higher risk donor pool. The posttransplant results, when using these organs, are not significantly different from those obtained when using standard criteria donors. In addition, a great amount of research reports have emphasized the potential of ex-vivo perfusion as a platform in reducing the injurious effects of ischemia-reperfusion. SUMMARY: EVLP has already proved its value as a tool to identify 'good' lungs from the previously rejected pool. But as new therapeutics arise , EVLP will also prove its value as a reproducible platform for their evaluation. PMID- 22941324 TI - Bridge to lung transplantation with extracorporeal membrane oxygenation support. AB - PURPOSE OF REVIEW: The significant growth in the use of extracorporeal life support (ECLS) devices has been driven by technological advances and new applications. Extracorporeal membrane oxygenation (ECMO) can provide pulmonary and, if needed, right heart support for patients with acute and chronic lung disease. Many patients on lung transplant lists die from acute exacerbations of their underlying chronic lung disease before they can receive a lung transplant. Transplant teams have taken advantage of these recent advances in ECLS to bridge such patients to lung transplantation (bridge to transplant, BTT). We review the recent body of literature in this area and suggest an algorithm for the management of BTT patients. RECENT FINDINGS: Although the initial experience and outcomes with ECMO for BTT were unconvincing, recent series demonstrate that good results can be achieved if ECMO protocols and patient selection guidelines are strictly followed. Early mobilization of patients on ECMO for BTT is an important goal because it facilitates participation in physical therapy, encourages oral enteral intake, and improves overall patient conditioning for lung transplantation. Specific cannulation strategies permit early ambulation. SUMMARY: In carefully selected patients, ECMO is a safe and effective means of bridging patients with acute decompensations of their end-stage lung disease to lung transplantation. PMID- 22941325 TI - Current strategies and future trends in immunosuppression after heart transplantation. AB - PURPOSE OF REVIEW: Current immunosuppressive drugs have provided excellent outcomes after heart transplantation. However, more patients suffer from long term complications of these drugs. A series of prospective randomized trials has been conducted and has offered disparate results. This report reviews the challenges of immunosuppressive therapy during the past decade, describes recent reports and explores potential future trends in immunosuppressive protocols in heart transplantation. RECENT FINDINGS: The traditional combination of cyclosporine, azathioprine and steroids has been changed to tacrolimus (Tac) or cyclosporine in combination with mycophenolate mofetil (MMF) and steroids due to the results of several trials. The use of mammalian target of rapamycin inhibitors in combination with Tac or cyclosporine A has not shown a clear benefit compared with MMF. All different combinations have shown some positive effects counteracted by side-effects and negative synergism of combinations. Future protocols need to be adapted according to individual patient's needs and risks. SUMMARY: The changing population of heart transplantation patients has become older and sicker. Immunosuppression strategies should be developed for each patient based on their risk for rejection and their risk for developing important complications of immunosuppressive therapy. PMID- 22941326 TI - Office microlaparoscopic ovarian drilling (OMLOD) versus conventional laparoscopic ovarian drilling (LOD) for women with polycystic ovary syndrome. AB - OBJECTIVE AND DESIGN: This was a prospective controlled study to compare the beneficial effects of office microlaparoscopic ovarian drilling (OMLOD) under augmented local anesthesia, as a new modality treatment option, compared to those following ovarian drilling with the conventional traditional 10-mm laparoscope (laparoscopic ovarian drilling, LOD) under general anesthesia. METHODS: The study included 60 anovulatory women with polycystic ovary syndrome (PCOS) who underwent OMLOD (study group) and 60 anovulatory PCOS women, in whom conventional LOD using 10-mm laparoscope under general anesthesia was performed (comparison group). Transvaginal ultrasound scan and blood sampling to measure the serum concentrations of LH, FSH, testosterone and androstenedione were performed before and after the procedure. Intraoperative and postoperative pain scores in candidate women were evaluated during the office microlaparoscopic procedure, in addition to the number of candidates who needed extra analgesia. RESULTS: Women undergoing OMLOD showed good intraoperative and postoperative pain scores. The number of patients discharged within 2 h after the office procedure was significantly higher, without the need for postoperative analgesia in most patients. The LH:FSH ratio, mean serum concentrations of LH and testosterone and free androgen index decreased significantly after both OMLOD and LOD. The mean ovarian volume decreased significantly (P < 0.05) a year after both OMLOD and LOD. There were no significant differences in those results after both procedures. CONCLUSION: Intra- and postoperatively augmented local anesthesia allows outpatient bilateral ovarian drilling by microlaparoscopy without general anesthesia. The high pregnancy rate, the simplicity of the method and the faster discharge time offer a new option for patients with PCOS who are resistant to clomiphene citrate. Moreover, ovarian drilling could be performed simultaneously during the routine diagnostic microlaparoscopy and integrated into the fertility workup of these patients. PMID- 22941327 TI - Serum CA 125, CA 15-3, CEA, and CA 19-9: a prognostic factor for uterine carcinosarcomas? AB - PURPOSE: There is a controversy in the literature regarding the role and the prognostic significance of serum markers in uterine carcinosarcomas (CSs). We attempted to determine the utility of serum CA 125, CA 15-3, CA 19-9, and CEA as prognostic factors and disease follow-up in patients with CS of the uterus. METHODS: Thirty-seven patients with CS of the uterus were included in this study. Information regarding demographic, clinical, pathologic, tumor marker data (CA 125, CA 19-9, CA 15-3, and CEA both pre- and postoperatively) treatment and outcome information was obtained, followed by Statistical analysis. RESULTS: The mean follow-up period was 3.5 years. None of the study serum markers showed significant association with the outcome. Greater hazard was found for cases that staged from IIIA to IV compared to those staged from IA to IIB (HR = 4.75, 95 % CI: 1.99-11.3). Also, greater hazard was found for adenosquamous histological type compared to the other histological types. When multiple Cox regression analysis with stepwise approach was implied, it indicated stage as the only significant factor for the outcome. Elevated CA19-9 was more frequent in cases with heterologous sarcoma (p = 0.036). CONCLUSION: In this retrospective study, none of the preoperative serum tumor markers, neither epithelial component, histological type, nor grade showed a significant association with prognosis. This null finding may have significant implications in the common clinical practice; given that there is a controversy in the literature regarding the role and the significance of the prognostic significance of serum CEA, CA 125, CA 19 9, and CA 15-3. PMID- 22941328 TI - Trends in patient characteristics, treatment and survival in breast cancer in a non-selected retrospective clinical cohort study of 2,600 patients. AB - PURPOSE: Breast cancer epidemiology and survival recently saw major changes resulting from improved screening and treatment modalities. This paper aims to provide an overview of changes in recent years in patient characteristics and treatment procedures. METHODS: Using data from BRENDA, an unselected cohort with universal coverage of a constant catchment area over a 13-year observation period, this study provides an overview of key trends. RESULTS: Beside steady increases in overall and disease-free survival, main trends in recent years included a gradual increase in new patients' average ages. Grading, but not T stages, improved. Node negative, endocrine responsive patient shares increased; node positive, endocrine responsive shares decreased. HER2neu screening went from uncommon to ubiquitous. Sentinel node biopsy reduced excised numbers of lymph nodes. Second and third generation chemotherapies replaced CMF. Neoadjuvant therapy was gradually introduced. Aromatase inhibitors pushed down Tamoxifen use. 90 % of endocrine responsive patients now receive endocrine therapy. Our results suggest that improved survival only partially results from improved prognostic factors, but rather seems mainly due to improved treatment modalities. CONCLUSIONS: Treatment procedures have changed dramatically over recent years. This was associated with steady increases in favorable outcomes among patients. PMID- 22941329 TI - Hidden polymorphs drive vitrification in B2O3. AB - Understanding the conditions that favour crystallization or vitrification of liquids has been a long-standing scientific problem. Another connected, and not yet well understood question is the relationship between the glassy and the various possible crystalline forms a system may adopt. In this context, B(2)O(3) represents a puzzling case. It is one of the best glass-forming systems despite an apparent lack of low-pressure polymorphism. Furthermore, the system vitrifies in a glassy form abnormally different from the only known crystalline phase at ambient pressure. Last but not least, it never crystallizes from the melt unless pressure is applied, an intriguing behaviour known as the crystallization anomaly. Here, by means of ab initio calculations, we discover the existence of previously unknown B(2)O(3) crystalline polymorphs with structural properties similar to the glass and formation energies comparable to the known ambient crystal. The energy degeneracy of the crystals, which is high at ambient pressure and suppressed under pressure, provides a framework to understand the system's ability to vitrify and the origin of the crystallization anomaly. This work reconciles the behaviour of B(2)O(3) with that from other glassy systems and reaffirms the role played by polymorphism in a system's ability to vitrify. Some of the predicted crystals are cage-like materials entirely made of three-fold rings, opening new perspectives for the synthesis of boron-based nanoporous materials. PMID- 22941330 TI - Spin excitations in a single La2CuO4 layer. AB - Cuprates and other high-temperature superconductors consist of two-dimensional layers that are crucial to their properties. The dynamics of the quantum spins in these layers lie at the heart of the mystery of the cuprates. In bulk cuprates such as La(2)CuO(4), the presence of a weak coupling between the two-dimensional layers stabilizes a three-dimensional magnetic order up to high temperatures. In a truly two-dimensional system however, thermal spin fluctuations melt long-range order at any finite temperature. Here, we measure the spin response of isolated layers of La(2)CuO(4) that are only one-unit-cell-thick. We show that coherent magnetic excitations, magnons, known from the bulk order, persist even in a single layer of La(2)CuO(4), with no evidence for more complex correlations such as resonating valence bond correlations. These magnons are, therefore, well described by spin-wave theory (SWT). On the other hand, we also observe a high energy magnetic continuum in the isotropic magnetic response that is not well described by two-magnon SWT, or indeed any existing theories. PMID- 22941331 TI - Frequent silencing of protocadherin 8 by promoter methylation, a candidate tumor suppressor for human gastric cancer. AB - The cadherins are a family of cell surface glycoproteins responsible for cell adhesion which play an important role in cell morphology, contact inhibition and signal transduction during tumorigenesis. Protocadherin 8 (PCDH8), a member of the cadherin family, has been reported to act as a tumor suppressor involved in oncogenesis in breast cancer. In this study, we aimed to investigate the epigenetic inactivation of PCDH8 and its tumor suppressor function in gastric cancer. The expression of PCDH8 was markedly reduced or silenced in gastric cancer cell lines compared with normal gastric cells or tissues. Methylation of the PCDH8 gene promoter was observed in 100% (4/4) of cell lines and 55.38% (36/65) of the primary gastric cancer by methylation-specific PCR, but not in normal gastric mucosa (0/10). Methylated PCDH8 was significantly associated with lymph node metastasis in a logistic regression analysis. The demethylation reagent 5-aza-2'-deoxycytidine was able to restore or upregulate PCDH8 expression in gastric cancer cell lines. Ectopic expression of PCDH8 in silenced gastric cancer cells significantly inhibited cell migration and induced apoptosis. For the first time, our study demonstrates the epigenetic inactivation of PCDH8 by promoter methylation and its tumor suppressor function in human gastric cancer. Thus, PCDH8 could be identified as a candidate tumor suppressor in human gastric cancer. PMID- 22941332 TI - An online positive parenting skills programme for paediatric traumatic brain injury: feasibility and parental satisfaction. AB - We examined the feasibility of and parental satisfaction with a training programme for parents with children who had suffered traumatic brain injury (TBI). Families who did not have a home computer and/or webcam were loaned the necessary equipment. Skype was used for videoconferencing. After the initial treatment session in the family's home, the remaining nine sessions were conducted online. Each session had two parts: (1) a self-guided web session with information about a particular skill; (2) a videoconference session with the therapist. Three of the 20 families (15%) dropped out prior to the final 6-month follow-up visit. Of the remaining 17 families, 13 (65% of those enrolled) completed 9-14 sessions. Almost all of the caregivers (87%) said that the Skype sessions were helpful compared to a conventional office visit. Almost all parents were satisfied with the programme and the technology that was used. Parental satisfaction with the programme was not influenced by prior computer ownership or comfort with technology. The programme appears to be feasible for a wide range of parents of children with TBI and provides an alternative to conventional office based sessions that may not be accessible to all families. PMID- 22941333 TI - Lifestyle behaviors of obese children following parental weight loss surgery. AB - BACKGROUND: Following weight loss surgery (WLS), patients are expected to make diet and lifestyle changes which may lead to children mimicking the changing behaviors of their parents. The purpose of the study was to identify the differences in diet and lifestyle behaviors between obese children with and without a parent who received WLS. METHODS: Medical records of 45 children whose parents had undergone WLS and 90 age- and gender-matched control children were reviewed from a weight loss program in a large Midwest children's hospital. Differences in dietary choices and behaviors, perceived barriers, and sedentary behaviors were examined between both groups. RESULTS: The mean age for the sample was 12.8 years. Children in the parental weight loss surgery (PWLS) group were more likely to eat two or more helpings of food at each sitting (p = 0.02) and less likely to play outdoors for more than an hour each day (p = 0.01). Compared to the control group, the PWLS group more frequently reported eating fast food on most days (45.2 vs. 27.0 %), soda consumption several times a week (48.6 vs. 29.4 %), and no vegetable intake (9.5 vs. 1.1 %). The top three barriers to exercise for both groups were lack of self-discipline, lack of interest, and lack of energy. CONCLUSIONS: Obese children who live with a parent that had undergone WLS reported several unhealthy lifestyle behaviors, in some cases worse than the children who live with parents who had not had WLS. Being cognizant of these findings will help obesity providers focus their counseling and expectations appropriately. PMID- 22941334 TI - Roux-en Y gastric bypass surgery reduces hedonic hunger and improves dietary habits in severely obese subjects. AB - BACKGROUND: Many obese subjects suffer from an increased hedonic drive to consume palatable foods, i.e., hedonic hunger, and often show unfavorable dietary habits. Here, we investigated changes in the hedonic hunger and dietary habits after Roux en-Y gastric bypass (RYGB) surgery. METHODS: Forty-four severely obese patients were examined before and on average 15.9 +/- 0.9 months after RYGB surgery with the Power of Food Scale (PFS), a questionnaire that reliably measures an individual's motivation to consume highly palatable foods but not actual consumptive behavior. Dietary habits were assessed by a food frequency questionnaire. RESULTS: After the RYGB procedure, patients showed markedly lower aggregated PFS scores and sub-domain scores related to generally available, physically present, as well as tasted foods than before the surgery (all P < 0.001). Changes in dietary habits after the surgery were characterized by a more frequent consumption of poultry, fish, eggs, and cooked vegetables (P < 0.008) and a less frequent consumption of chocolate (P < 0.048), cakes/biscuits/cookies (P = 0.09), and fruit juice/soft drinks (P = 0.08). CONCLUSIONS: Data show a marked reduction of the hedonic drive to consume palatable food and beneficial changes in dietary habits characterized by an increased intake of protein-rich foods and vegetables and a reduced consumption of sugar-containing snacks and beverages after RYGB surgery. Based on these findings, it can be speculated that the reduction of the hedonic drive to consume palatable foods induced by RYGB surgery helps severely obese patients to establish healthier dietary habits. PMID- 22941335 TI - Type II diabetes mellitus and the incidence of epithelial ovarian cancer in the cancer prevention study-II nutrition cohort. AB - BACKGROUND: Despite consistent associations of type II diabetes mellitus with hormonally related cancers such as breast and endometrium, the relation between type II diabetes mellitus and ovarian cancer risk is unclear. METHODS: Associations of type II diabetes mellitus status, duration, and insulin use with epithelial ovarian cancer overall, and with serous and nonserous histologic subtypes were examined in the Cancer Prevention Study-II Nutrition Cohort, a prospective study of U.S. men and women predominantly aged 50 years and older. Between 1992 and 2007, 524 incident epithelial ovarian cancer cases were identified among 63,440 postmenopausal women. Multivariable-adjusted relative risks (RR) and 95% confidence intervals (CI) were computed using extended Cox regression to update diabetes status and bilateral oophorectomy status during follow-up. RESULTS: Type II diabetes mellitus status (RR = 1.05; 95% CI, 0.75 1.46) and duration were not associated with epithelial ovarian cancer risk. Although not statistically significantly different (P(difference) = 0.39), the RR was higher for type II diabetes mellitus with insulin use (RR = 1.28; 95% CI, 0.74-2.24) than for type II diabetes mellitus without insulin use (RR = 0.96; 95% CI, 0.64-1.43). Diabetes seemed to be more strongly associated with nonserous (RR = 1.41; 95% CI, 0.70-2.85) than serous (RR = 0.71; 95% CI, 0.41-1.23) histologic subtypes. CONCLUSIONS: Type II diabetes mellitus was not associated with risk of epithelial ovarian cancer, although higher risks with nonserous subtypes and among insulin users cannot be ruled out. IMPACT: Larger studies are needed to clarify associations of type II diabetes mellitus with or without insulin use with risk of ovarian cancer overall and by histologic subtypes. PMID- 22941336 TI - Maternal use of folic acid and other supplements and risk of childhood brain tumors. AB - BACKGROUND: Interest in a possible protective effect of maternal vitamin use before or during pregnancy against childhood brain tumors (CBT) and other childhood cancers has grown over the past decade. Our Australian study of CBTs, conducted between 2005 and 2011, investigated whether maternal use folic acid and other supplements was protective. METHODS: Case children were identified through the 10 Australian pediatric oncology centers and controls were recruited by national random digit dialing. Mothers of 327 cases and 867 control children provided information on supplement use before and during the index pregnancy, including brand name, dose, and timing. Data were analyzed using multivariable unconditional logistic regression. RESULTS: The OR for any maternal use of folic acid, use of folic acid without iron or vitamins B6, B12, C, or A, and any vitamin use before pregnancy, were: 0.68 [95% confidence interval (CI), 0.46 1.00; 0.55 (95% CI, 0.32-0.93) and 0.68 (95% CI, 0.46-1.01), respectively. The ORs for use of these supplements during pregnancy were also below unity, but generally closer to the null than those for the prepregnancy period. There was some evidence of an inverse dose-response during each time period. CONCLUSIONS: These results suggest that folic acid supplements before and possibly during pregnancy may protect against CBT. Such associations are biologically plausible through established mechanisms. IMPACT: This study provides evidence of a specific protective effect of prenatal folic acid supplementation against the risk of CBT that is not attributable to the actions of the other micronutrients investigated. PMID- 22941337 TI - Neutralisation of a single voltage sensor affects gating determinants in all four pore-forming S6 segments of Ca(V)1.2: a cooperative gating model. AB - Voltage sensors trigger the closed-open transitions in the pore of voltage-gated ion channels. To probe the transmission of voltage sensor signalling to the channel pore of Ca(V)1.2, we investigated how elimination of positive charges in the S4 segments (charged residues were replaced by neutral glutamine) modulates gating perturbations induced by mutations in pore-lining S6 segments. Neutralisation of all positively charged residues in IIS4 produced a functional channel (IIS4(N)), while replacement of the charged residues in IS4, IIIS4 and IVS4 segments resulted in nonfunctional channels. The IIS4(N) channel displayed activation kinetics similar to wild type. Mutations in a highly conserved structure motif on S6 segments ("GAGA ring": G432W in IS6, A780T in IIS6, G1193T in IIIS6 and A1503G in IVS6) induce strong left-shifted activation curves and decelerated channel deactivation kinetics. When IIS4(N) was combined with these mutations, the activation curves were shifted back towards wild type and current kinetics were accelerated. In contrast, 12 other mutations adjacent to the GAGA ring in IS6-IVS6, which also affect activation gating, were not rescued by IIS4(N). Thus, the rescue of gating distortions in segments IS6-IVS6 by IIS4(N) is highly position-specific. Thermodynamic cycle analysis supports the hypothesis that IIS4 is energetically coupled with the distantly located GAGA residues. We speculate that conformational changes caused by neutralisation of IIS4 are not restricted to domain II (IIS6) but are transmitted to gating structures in domains I, III and IV via the GAGA ring. PMID- 22941339 TI - Epstein-Barr nuclear antigen 1 induces expression of the cellular microRNA hsa miR-127 and impairing B-cell differentiation in EBV-infected memory B cells. New insights into the pathogenesis of Burkitt lymphoma. AB - Epstein-Barr Virus (EBV) is a gamma-herpesvirus that infects >90% of the human population. Although EBV persists in its latent form in healthy carriers, the virus is also associated with several human cancers. EBV is strongly associated with Burkitt lymphoma (BL), even though there is still no satisfactory explanation of how EBV participates in BL pathogenesis. However, new insights into the interplay between viruses and microRNAs (miRNAs) have recently been proposed. In particular, it has been shown that B-cell differentiation in EBV positive BL is impaired at the post-transcriptional level by altered expression of hsa-miR-127. Here, we show that the overexpression of hsa-miR-127 is due to the presence of the EBV-encoded nuclear antigen 1 (EBNA1) and give evidence of a novel mechanism of direct regulation of the human miRNA by this viral product. Finally, we show that the combinatorial expression of EBNA1 and hsa-miR-127 affects the expression of master B-cell regulators in human memory B cells, confirming the scenario previously observed in EBV-positive BL primary tumors and cell lines. A good understanding of these mechanisms will help to clarify the complex regulatory networks between host and pathogen, and favor the design of more specific treatments for EBV-associated malignancies. PMID- 22941340 TI - Molecular analysis of RAS-RAF tyrosine-kinase signaling pathway alterations in patients with plasma cell myeloma. PMID- 22941341 TI - Expression of CEBPA is reduced in RUNX1-mutated acute myeloid leukemia. PMID- 22941338 TI - Aldosterone deficiency adversely affects pregnancy outcome in mice. AB - Circulating aldosterone levels are increased in human pregnancy. Inadequately low aldosterone levels as present in preeclampsia, a life-threatening disease for both mother and child, are discussed to be involved in its pathogenesis or severity. Moreover, inactivating polymorphisms in the aldosterone synthase gene have been detected in preeclamptic women. Here, we used aldosterone synthase deficient (AS(-/-)) mice to test whether the absence of aldosterone is sufficient to impair pregnancy or even to cause preeclampsia. AS(-/-) and AS(+/+) females were mated with AS(+/+) and AS(-/-) males, respectively, always generating AS(+/ ) offspring. With maternal aldosterone deficiency in AS(-/-) mice, systolic blood pressure was low before and further reduced during pregnancy with no increase in proteinuria. Yet, AS(-/-) had smaller litters due to loss of fetuses as indicated by a high number of necrotic placentas with massive lymphocyte infiltrations at gestational day 18. Surviving fetuses and their placentas from AS(-/-) females were smaller. High-salt diet before and during pregnancy increased systolic blood pressure only before pregnancy in both genotypes and abolished the difference in blood pressure during late pregnancy. Litter size from AS(-/-) was slightly improved and the differences in placental and fetal weights between AS(+/+) and AS(-/-) mothers disappeared. Overall, an increased placental efficiency was observed in both groups paralleled by a normalization of elevated HIF1alpha levels in the AS(-/-) placentas. Our results demonstrate that aldosterone deficiency has profound adverse effects on placental function. High dietary salt intake improved placental function. In this animal model, aldosterone deficiency did not cause preeclampsia. PMID- 22941342 TI - A pilot study of parent training in young children with autism spectrum disorders and disruptive behavior. AB - Guidance on effective interventions for disruptive behavior in young children with autism spectrum disorders (ASDs) is limited. We present feasibility and initial efficacy data on a structured parent training program for 16 children (ages 3-6) with ASD and disruptive behavior. The 6-month intervention included 11 Core and up to 2 Optional sessions. The program was acceptable to parents as evidenced by an attendance rate of 84 % for Core sessions. Fourteen of 16 families completed the treatment. An independent clinician rated 14 of 16 subjects as much improved or very much improved at Week 24. Using last observation carried forward, the parent-rated Aberrant Behavior Checklist Irritability subscale decreased 54 % from 16.00 (SD = 9.21) to 7.38 (SD = 6.15). PMID- 22941343 TI - Age-related variation in health service use and associated expenditures among children with autism. AB - This study examined differences by age in service use and associated expenditures during 2005 for Medicaid-enrolled children with autism spectrum disorders. Aging was associated with significantly higher use and costs for restrictive, institution-based care and lower use and costs for community-based therapeutic services. Total expenditures increased by 5 % with each year of age; by 23 % between 3-5 and 6-11 year olds, 23 % between 6-11 and 12-16, and 14 % between 12 16 and 17-20 year olds. Use of and expenditures for long-term care, psychiatric medications, case management, medication management, day treatment/partial hospitalization, and respite services increased with age; use of and expenditures for occupational/physical therapy, speech therapy, mental health services, diagnostic/assessment services, and family therapy declined. PMID- 22941344 TI - Hypoxia increases CX3CR1 expression via HIF-1 and NF-kappaB in androgen independent prostate cancer cells. AB - The unique CX3C chemokine CX3CL1 and its cognate receptor CX3CR1 have been implicated in organ-specific metastasis of various types of tumors. Hypoxia, a common phenomenon in solid tumors, is associated with a malignant cancer phenotype. Previous studies have proved that hypoxia facilitates cancer cell metastasis through upregulation of specific chemokine receptors. We hypothesized that hypoxia could upregulate CX3CR1 expression and lead to an increased chemotactic response to CX3CL1 in prostate cancer cells. In the present study, we found that CX3CR1 expression was significantly increased in androgen-independent prostate cancer cells, including DU145, PC-3 and PC-3M, following exposure to hypoxia. This upregulation of CX3CR1 corresponded to a significant increase in migration and invasion of prostate cancer cells under hypoxic conditions, which was attenuated after knocking down CX3CR1 expression. In addition, we examined the possible role of HIF-1 and NF-kappaB in the process of hypoxia-induced CX3CR1 expression and hypoxia-mediated metastasis. Attenuation of HIF-1 and NF-kappaB transcriptional activity by siRNAs or pharmacological inhibitors, abrogated hypoxia-induced upregulation of CX3CR1, and also prevented the migration and invasion of DU145 cells under a hypoxic environment. In summary, our study demonstrated that HIF-1 and NF-kappaB are essential for hypoxia-regulated CX3CR1 expression, which is associated with increased migratory and invasive potential of prostate cancer cells. CX3CR1 signaling is a potential therapeutic target in the adjuvant treatment of prostate cancer. PMID- 22941345 TI - Using the Objective Structured Assessment of Technical Skills (OSATS) global rating scale to evaluate the skills of surgical trainees in the operating room. AB - PURPOSE: The education of surgical trainees should be based on an accurate evaluation of their surgical skill levels. In our hospital, the Objective Structured Assessment of Technical Skills (OSATS) is used for this purpose. We conducted this study to demonstrate the validity and accuracy of the OSATS for assessing surgical skills in the operating room (OR) setting. METHODS: Between January, 2007 and December, 2010, the OSATS global rating scale was used to assess several operations in which surgical trainees participated. We assessed ten surgical trainees who participated as the main surgeon or first assistant, and studied the correlation between their postgraduate year and their OSATS score. RESULTS: The median score of the global rating scale for each trainee improved with each year of experience. The median scores of all trainees in postgraduate years 3, 4, and 5 were significantly different (p < 0.001 for both the main surgeon and first assistant roles; Kruskal-Wallis test). CONCLUSION: Using the OSATS global rating scale to assess the surgical skills of trainees in the OR was feasible and effective. PMID- 22941347 TI - Memory-effects of magnetic nanocomposites. AB - The thermally induced shape memory effect (SME) is the capability of a material to fix a temporary (deformed) shape and recover a 'memorized' permanent shape in response to heat. SMEs in polymers have enabled a variety of applications including deployable space structures, biomedical devices, adaptive optical devices, smart dry adhesives and fasteners. By the incorporation of magnetic nanoparticles (mNP) into shape-memory polymer (SMP), a magnetically controlled SME has been realized. Magnetic actuation of nanocomposites enables remotely controlled devices based on SMP, which might be useful in medical technology, e.g. remotely controlled catheters or drug delivery systems. Here, an overview of the recent advances in the field of magnetic actuation of SMP is presented. Special emphasis is given on the magnetically controlled recovery of SMP with one switching temperature T(sw) (dual-shape effect) or with two T(sw)s (triple-shape effect). The use of magnetic field to change the apparent switching temperature (T(sw,app)) of the dual or triple-shape nanocomposites is described. Finally, the capability of magnetic nanocomposites to remember the magnetic field strength (H) initially used to deform the sample (magnetic-memory effect) is addressed. The distinguished advantages of magnetic heating over conventional heating methods make these multifunctional nanocomposites attractive candidates for in vivo applications. PMID- 22941346 TI - Phase I/II study of S-1 combined with biweekly irinotecan chemotherapy in previously treated advanced non-small cell lung cancer. AB - PURPOSE: This phase I/II study was designed to evaluate a combination of irinotecan and S-1 a new regimen for salvage chemotherapy in patients with advanced or metastatic non-small cell lung cancer (NSCLC). METHODS: The study group comprised patients with advanced or metastatic NSCLC who had previously received at least one platinum-containing chemotherapy. Patients received irinotecan on days 1, 15 and oral S-1 (40 mg/m(2) twice daily as a fixed dose) on day 1 to 14 of a 28-day cycle. RESULTS: In the phase I part, irinotecan was given in escalating doses of 70 (Level 1), 80 (Level 2), and 90 mg/m(2) (Level 3). Three of the 5 patients given Level 3 had dose-limiting toxicity, and Level 2 (80 mg/m(2) of irinotecan) was designated as the recommended dose. In phase II, 38 patients received a median of 7.4 cycles of irinotecan at the recommended dose. The overall response rate was 15.8 % (90 % confidence interval (CI): 6.1-25.5 %), and the median progression-free and overall survival times were 4.5 months (95 % CI: 3.5-5.0) and 15.0 months (95 % CI: 9.5-20.6) months, respectively. Toxicity was generally mild. Grade 3 or higher toxicity included neutropenia in 17.9 % of the patients, thrombocytopenia in 5.1 % and nausea in 7.7 %. CONCLUSION: Combination chemotherapy with S-1 and irinotecan was considered an effective salvage regimen in patients with advanced or metastatic NSCLC. PMID- 22941349 TI - The thinnest, steepest, and maximum elevation corneal locations in noncontact and contact lens wearers in keratoconus. AB - PURPOSE: To assess the relationship between the thinnest corneal location and the steepest and maximum elevation corneal locations in subjects with keratoconus and the effect of gas permeable contact lens wear on the location of these points. METHODS: Sixty-one consecutive subjects (98 eyes) with keratoconus. Thirty-one (49 eyes) and 30 (49 eyes) subjects were gas permeable contact lens (CL-W) and non-contact lens wearers (N-CL), respectively. Thinnest, steepest, and maximum elevation corneal locations were evaluated from topographies collected with Pentacam Eye Scanner. RESULTS: In the entire sample and in N-CL and CL-W, the thinnest location does not overlap with the steepest or maximum elevation corneal locations (all P > 0.05). The thinnest and maximum tangential curvature locations were found to be located further away from the geometric center of the cornea in CL-W versus N-CL (P < 0.05). CONCLUSION: The thinnest corneal location does not overlap with maximum axial and tangential curvatures or with the front and back elevation locations in keratoconus subjects. Contact lens wear does not affect this lack of overlapping. PMID- 22941351 TI - Femoral neuropathy: a rare complication of retroperitoneal hematoma caused by cesarean section. PMID- 22941352 TI - Controversies in the management of endometriomas in patients undergoing assisted reproduction. AB - INTRODUCTION: The presence of an endometrioma has been proposed to affect the ovarian function in a negative way. Our aim was to present the key evidence on multiple aspects of endometriomas' management in subfertile couples scheduled for assisted reproduction technologies (ART). MATERIALS AND METHODS: A critical review of the existing literature was performed focusing on the need of endometrioma treatment prior to ART, the relevant options, the potentially participating surgeon's characteristics and the socioeconomic perspective. RESULTS: To date, we have no definitive data to suggest whether the damage to the ovaries observed in women with endometriomas may be related to the mere presence of the cyst, the surgical procedure to remove it, the combination of the two, or factors currently unknown. Moreover, there is no conclusive evidence that, for subfertile couples, removal of endometriomas increases the chance of having a baby. The uncertainty regarding the best treatment strategy and factors such as the limited number of tertiary centers for laparoscopic surgery throughout the world seems to further complicate the decision. CONCLUSIONS: Until research addresses the current "grey areas", the management of endometriomas in patients undergoing ART should be individualized and take into consideration numerous parameters. PMID- 22941353 TI - Vaginal sacrospinous colpopexy using the Capio suture-capturing device versus traditional technique: feasibility and outcome. AB - PURPOSE: This study compares the feasibility and outcome of sacrospinous colpopexy for treating vaginal vault prolapse (VVP) performed by either the traditional technique or a simplified procedure using the CapioTM suture capturing device. MATERIALS AND METHODS: Eighty-six patients with VVP were included in the study. Forty-two patients were treated by traditional sacrospinous colpopexy (TSC group) and 44 patients were treated by the modified technique using the Capio device (CSC group). Additional procedures were performed to restore concomitant pelvic floor defects. RESULTS: The mean (+/-SD) total operative time was significantly lower in the CSC group (71.7 +/- 24.5 min) than in the TSC group (105.5 +/- 31.5 min; p < 0.001); the intraoperative blood loss was higher in the TSC group than in the CSC group. In the CSC group, the mean operative time required to perform sacrospinous colpopexy was 21.4 +/- 3.2 min. In patients who underwent only sacrospinous colpopexy, the time required to perform surgery was significantly lower in the CSC group (20.9 +/- 3.3 min) than in the TSC group (39.1 +/- 5.2 min; p < 0.001). There was no significant difference in the incidence of surgical complications between the two study groups. The objective and subjective success rates at 3-year follow-up were 88.1 and 92.9 % in the TSC group while in the CSC group they were 86.4 and 92.9 %. CONCLUSION: The modified technique of sacrospinous ligament fixation using the Capio device reduces the operative time and blood loss when compared to the traditional technique. PMID- 22941354 TI - Urogenital fistula in a Saudi Arabian referral center. AB - PURPOSE: To review all cases of genitourinary fistula, their causes, management and outcome. MATERIALS AND METHODS: A retrospective chart review of all fistula cases referred to the Urogynecology Department, King Fahad Medical City, Riyadh, Saudi Arabia, from January 2005 to December 2011. RESULTS: Sixteen genitourinary fistula cases were identified; nine (56 %) cases of vesicovaginal fistula, four (25 %) cases of vesicouterine fistula, and three (19 %) cases of vesicocervical fistula. Mean age was 41 (29-61) and mean parity was 7.4 (2-15). Out of the 16 cases, 12 (75 %) had obstetrical surgical complications, of which 8 (50 %) had complications of cesarean sections. Twelve of 15 cases (80 %) were cured after primary surgical repair, 2 (13 %) after secondary repair and 1 after tertiary repair. One case was cured after conservative management. CONCLUSION: Most of the genitourinary fistulae were of iatrogenic obstetric causes, mainly cesarean section with none of the cases due to obstructed labor unlike fistulae in developing countries or developed countries fistulae (iatrogenic gynecologic origin). PMID- 22941355 TI - Searching for active binary rutile oxide catalyst for water splitting from first principles. AB - Water electrolysis is an important route to large-scale hydrogen production using renewable energy, in which the oxygen evolution reaction (OER: 2H(2)O -> O(2) + 4H(+) + 4e(-)) causes the largest energy loss in traditional electrocatalysts involving Ru-Ir mixed oxides. Following our previous mechanistic studies on the OER on RuO(2)(110) (J. Am. Chem. Soc. 2010, 132, 18214), this work aims to provide further insight into the key parameters relevant to the activity of OER catalysts by investigating a group of rutile-type binary metal oxides, including RuNiO(2), RuCoO(2), RuRhO(2), RuIrO(2) and OsIrO(2). Two key aspects are focused on, namely the surface O coverage at the relevant potential conditions and the kinetics of H(2)O activation on the O-covered surfaces. The O coverage for all the oxides investigated here is found to be 1 ML at the concerned potential (1.23 V) with all the exposed metal cations being covered by terminal O atoms. The calculated free energy barrier for the H(2)O dissociation on the O covered surfaces varies significantly on different surfaces. The highest OER activity occurs at RuCoO(2) and RuNiO(2) oxides with a predicted activity about 500 times higher than pure RuO(2). On these oxides, the surface bridging O near the terminal O atom has a high activity for accepting the H during H(2)O splitting. It is concluded that while the differential adsorption energy of the terminal O atom influences the OER activity to the largest extent, the OER activity can still be tuned by modifying the electronic structure of surface bridging O. PMID- 22941356 TI - Chronic inflammatory demyelinating polyradiculoneuropathy associated intracranial hypertension. AB - Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is an acquired immune-mediated demyelinating neuropathy. In this report, we detail the course of a 58-year-old male patient who had headache and double vision followed by progressive paresthesia and difficulty in walking. The patient had bilateral papilledema and mild leg weakness, absent ankle jerks and loss of sensation in distal parts of his lower and upper extremities. His electromyography (EMG) was concordant with CIDP and lumbar puncture revealed high opening pressure. The polyradiculoneuropathy as well as the papilledema and elevated cerebrospinal fluid (CSF) pressure improved under steroids. The improvement in intracranial hypertension (IHT) and papilledema under steroid treatment suggests that the IHT in this patient might be associated with CIDP. PMID- 22941357 TI - Influence of background noise on the performance in the odor sensitivity task: effects of noise type and extraversion. AB - Recent research demonstrated that background noise relative to silence impaired subjects' performance in a cognitively driven odor discrimination test. The current study aimed to investigate whether the background noise can also modulate performance in an odor sensitivity task that is less cognitively loaded. Previous studies have shown that the effect of background noise on task performance can be different in relation to degree of extraversion and/or type of noise. Accordingly, we wanted to examine whether the influence of background noise on the odor sensitivity task can be altered as a function of the type of background noise (i.e., nonverbal vs. verbal noise) and the degree of extraversion (i.e., introvert vs. extrovert group). Subjects were asked to conduct an odor sensitivity task in the presence of either nonverbal noise (e.g., party sound) or verbal noise (e.g., audio book), or silence. Overall, the subjects' mean performance in the odor sensitivity task was not significantly different across three auditory conditions. However, with regard to the odor sensitivity task, a significant interaction emerged between the type of background noise and the degree of extraversion. Specifically, verbal noise relative to silence significantly impaired or improved the performance of the odor sensitivity task in the introvert or extrovert group, respectively; the differential effect of introversion/extraversion was not observed in the nonverbal noise-induced task performance. In conclusion, our findings provide new empirical evidence that type of background noise and degree of extraversion play an important role in modulating the effect of background noise on subjects' performance in an odor sensitivity task. PMID- 22941358 TI - Split-second decisions on a split belt: does simulated limping affect obstacle avoidance? AB - During normal gait a suddenly appearing obstacle is avoided either by making a large crossing step (long-step strategy, LSS) or by interrupting the swing phase (short-step strategy, SSS) depending on the time of appearance of the obstacle in the step cycle. Limping changes the proportion of time spent in the swing phase and the question arises whether this could affect the ability to avoid obstacles. This was investigated using a split-belt treadmill that induces behavior that is similar to limping even in normal adults. Subjects walked on a split-belt treadmill with speed ratios between left and right of 2:2 up to 2:8 km/h in combination with obstacle avoidance (OA) on the slow belt. The failure rate of obstacle avoidance increased markedly as speed differences between legs increased. This increment was paralleled by augmented use of the SSS, related to an increase in time pressure. In all split-belt walking conditions, the alternative strategy (LSS) yielded less OA failures but it required much longer preparation time than the SSS. In addition, the prolonged stance phases prior to crossing in the LSS required a concomitant prolongation of the contralateral swing phase. This was difficult to achieve at times and as a result the swing phase was sometimes interrupted, giving rise to a contralateral SSS (and a 2:1 coordination pattern). It is concluded that simulated limping greatly increases the risk of failing to avoid suddenly appearing obstacles. PMID- 22941359 TI - Tuning of the ocular vestibular evoked myogenic potential (oVEMP) to air- and bone-conducted sound stimulation in superior canal dehiscence. AB - Recent studies have demonstrated the frequency selectivity of air-conducted (AC) and bone-conducted (BC) stimuli in eliciting ocular vestibular evoked myogenic potentials (oVEMPs). In this study, frequency tuning of the oVEMP was assessed in patients with superior canal dehiscence (SCD) and compared with responses previously reported for healthy subjects. Six (five unilateral) SCD patients were stimulated using AC sound (50-1,200 Hz) and BC transmastoid vibration (50-1,000 Hz). Stimuli were delivered at two standardized intensities: one the same as previously used for healthy controls and the other at 10 dB above vestibular threshold (a similar relative intensity to that used in controls). For AC stimulation, SCD patients had larger oVEMP amplitudes across all frequencies tested for both stimulus intensities. Normalized tuning curves demonstrated greater high-frequency responses with the stronger stimulus. For BC stimulation, larger oVEMP amplitudes were produced at frequencies at and above 100 Hz using standard intensity stimuli. For the matched intensity above vestibular threshold, enhancement of the oVEMP response was present in SCD patients for 500-800 Hz only. We conclude that SCD causes greater facilitation for AC than BC stimuli. The high-frequency response is likely to originate from the superior (anterior) canal and is consistent with models of inner ear changes occurring in SCD. PMID- 22941360 TI - Integrating spatial information across experiences. AB - The current study examined the potential influence of existing spatial knowledge on the coding of new spatial information. In the Main experiment, participants learned the locations of five objects before completing a perspective-taking task. Subsequently, they studied the same five objects and five additional objects from a new location before completing a second perspective-taking task. Task performance following the first learning phase was best from perspectives aligned with the learning view. However, following the second learning phase, performance was best from the perspective aligned with the second view. A supplementary manipulation increased the salience of the initial view through environmental structure as well as the number of objects present. Results indicated that the initial learning view was preferred throughout the experiment. The role of assimilation and accommodation mechanisms in spatial memory, and the conditions under which they occur, are discussed. PMID- 22941361 TI - Mild electrical pulse current stimulation upregulates S100A4 and promotes cardiogenesis in MSC and cardiac myocytes coculture monolayer. AB - Parietal endoderm-secreted S100A4 promotes early cardiomyogenesis in embryoid bodies [1]. After an acute ischemic event, S100A4 protein appears in cardiac myocytes only in the border zone in rat and human hearts [2]. In wound research, a large outward current of 4 MUA/cm(2) was always measured at the wound edges of rat cornea and human skin [3]. We hypothesize that a special electrical circumstance at the border zone may contribute to the phenomenon. An electric stimulation system was designed to give the cells electric pulse current stimulation (EPCS), the feature of the signal is pulse polarity altered one after another, rectangular 2 ms, 2 Hz, 40 MUA. This intensity of stimulation is proved to be safe to cardiac myocytes (both in structure and beating behavior compared with the cardiac myocytes which do not receive stimulation) and MSCs (in cell vitality, proliferation, cell cycle, and gap junction generation potential) through our previous work. Canine MSCs are capable of generating voltage sensitive Ca(2+) channel and Na(+) channels and generating the Ca(2+) handling system during differentiation. We found that CD44 was reduced in the MSCs monolayer treated with EPCS, compared with non-stimulated MSCs; and EPCS MSCs (3 h/day, 6 h/day, 5 days) showed an 14.04 +/- 3.44 and 14.55 +/- 3.97 % reduction in CD44, compared with the cotemporary MSCs; these reveal that CD44 reduction amplitude is not correlated with time for EPCS disposure and CD29 (integrin beta1) expression is not affected by EPCS exposure. EPCS was given to the MSCs and cardiac myocytes coculture monolayer (ratio 3:1) for different time (1, 3, and 6 h/day) for 4 days to see the biological effects. Gap junction protein and troponin T show an increase after EPCS. We found that the gap junction protein Cx43 increased with treating time-in the EPCS group, it exhibited 1.5 and 1.7 fold in the 3 h/day group and 6 h/day group (P < 0.01), and troponin T exhibited to about 3.6 and 4.4 fold in the 3 h/day group (P < 0.01) and 6 h/day group (P < 0.05). Since coculture was used as stimuli, immunofluorescence was used to visualize the changes during EPCS for the purpose of elucidating the impact of EPCS on cardiac myocytes and MSCs. We found that after 5 days exposure, EPCS can enhance the expression of S100A4, which is 2.33 fold in cardiac myocytes (P < 0.01) and 1.99 fold in MSCs (P < 0.01) in gray value. A significant increasing expression of the myocyte enhancer factor (MEF) and GATA4 is detected in neonatal rat cardiac myocytes (P < 0.01) compared with cotemporary coculture monolayer in the control group. Also, EPCS can trigger the assembly of MEF2c in the nuclei. In addition, more cardiac myocytes were found to have two nuclei. But MSCs fail to active MEF2C transcriptional factor like that in cardiac myocytes after EPCS exposure. The elevation of MEF2 in both cytoplasm and nuclei of cardiac myocytes can always make a clear distinction of the cardiac myocytes and MSCs in coculture. Some factors show strong upregulation tendency with EPCS in both cardiac myocytes and MSCs-these include the troponin T (P < 0.01) and Cx43 (P < 0.05) in cardiac myocytes, and troponin T (P < 0.01) and Cx43 (P < 0.01) in MSCs. Collagen I expression is not affected with EPCS. In conclusion, mild EPCS can upregulate the secretion of S100A4 in both cardiac myocytes and MSCs, which is a factor supporting the cardiomyogenesis and angiogenesis; it further triggers the development of neonatal rat cardiac myocytes through upregulation of MEF2C and GATA4, the number of cardiac myocytes with two nuclei increases with EPCS, but this phenomenon does not appear in MSCs. Despite this, Cx43 and troponin T in both cardiac myocytes and MSCs are very sensitive to EPCS. EPCS can act as an effective and multi-targeted physical intervention method in cardiomyogenesis. PMID- 22941362 TI - Serial measurement of free light chain detects poor response to therapy early in three patients with multiple myeloma who have measurable M-proteins. AB - Free light chain (FLC) assays are important in the diagnosis and monitoring of patients with multiple myeloma (MM). Serum FLC concentrations also correlate with disease course in the majority of MM patients and have been incorporated into the new response criteria. Although baseline values of FLC are prognostic in newly diagnosed MM, serial measurement of serum FLC does not appear to be of greater value in patients who have measurable M-proteins by electrophoresis. We examined the kinetics of serum FLC in six patients with newly diagnosed MM during treatment with high-dose dexamethasone (HD-DEX) and bortezomib and dexamethasone. In some cases, the involved serum FLC increased in the latter part of each chemotherapy cycle before the start of the next cycle, especially in HD-DEX, suggesting that the response to these agents may be insufficient for induction therapy for MM. Earlier disease assessment by serum FLC assays may be of value in detecting poorly responding patients who require alternative forms of therapy. PMID- 22941363 TI - Ultrafast force-clamp spectroscopy of single molecules reveals load dependence of myosin working stroke. AB - We describe a dual-trap force-clamp configuration that applies constant loads between a binding protein and an intermittently interacting biological polymer. The method has a measurement delay of only ~10 MUs, allows detection of interactions as brief as ~100 MUs and probes sub-nanometer conformational changes with a time resolution of tens of microseconds. We tested our method on molecular motors and DNA-binding proteins. We could apply constant loads to a single motor domain of myosin before its working stroke was initiated (0.2-1 ms), thus directly measuring its load dependence. We found that, depending on the applied load, myosin weakly interacted (<1 ms) with actin without production of movement, fully developed its working stroke or prematurely detached (<5 ms), thus reducing the working stroke size with load. Our technique extends single-molecule force clamp spectroscopy and opens new avenues for investigating the effects of forces on biological processes. PMID- 22941364 TI - Coupling endonucleases with DNA end-processing enzymes to drive gene disruption. AB - Targeted DNA double-strand breaks introduced by rare-cleaving designer endonucleases can be harnessed for gene disruption applications by engaging mutagenic nonhomologous end-joining DNA repair pathways. However, endonuclease mediated DNA breaks are often subject to precise repair, which limits the efficiency of targeted genome editing. To address this issue, we coupled designer endonucleases to DNA end-processing enzymes to drive mutagenic break resolution, achieving up to 25-fold enhancements in gene disruption rates. PMID- 22941366 TI - Aligning quality improvement to population health. PMID- 22941365 TI - Iterative correction of Hi-C data reveals hallmarks of chromosome organization. AB - Extracting biologically meaningful information from chromosomal interactions obtained with genome-wide chromosome conformation capture (3C) analyses requires the elimination of systematic biases. We present a computational pipeline that integrates a strategy to map sequencing reads with a data-driven method for iterative correction of biases, yielding genome-wide maps of relative contact probabilities. We validate this ICE (iterative correction and eigenvector decomposition) technique on published data obtained by the high-throughput 3C method Hi-C, and we demonstrate that eigenvector decomposition of the obtained maps provides insights into local chromatin states, global patterns of chromosomal interactions, and the conserved organization of human and mouse chromosomes. PMID- 22941367 TI - Hybrid nanoparticle architecture for cellular uptake and bioimaging: direct crystallization of a polymer immobilized with magnetic nanoparticles on carbon nanotubes. AB - We describe here the success of an innovative approach of direct immobilization of magnetic nanoparticles (MNPs) onto carbon nanotubes (CNTs). The approach involved functionalization of magnetic nanoparticles and consequent covalent linkage to a copolymer (PE-b-PEG). Next, the immobilized magnetic nanoparticles on the copolymer were directly crystallized on the long axis of CNTs, where the interfacial adhesion comes from electrostatic and van der Waals interaction. The intracellular trafficking of a hybrid nanoparticle system [(PE-b-PEG)-MNP-CNT FITC] in HeLa cells was monitored using a fluorescent marker, FITC, conjugated to the nanoparticle system. The distribution of the nanoparticle system inside cells was studied by fluorescence microscopy in a time and dose dependent manner, and it was observed that the nanoparticles are located in the cytoplasm and no apparent cell death was observed at the concentration studied. Also, the effect of an externally applied magnetic field on actin cytoskeleton, cell morphology and intracellular uptake of iron was studied. The approach described here is promising for simultaneous imaging and monitoring intracellular uptake. PMID- 22941368 TI - Identification of a novel C22-?4-producing docosahexaenoic acid (DHA) specific polyunsaturated fatty acid desaturase gene from Isochrysis galbana and its expression in Saccharomyces cerevisiae. AB - Isochrysis galbana, produces long chain polyunsaturated fatty acids including docosahexaenoic acid (DHA, 22:6n-3). A novel gene (IgFAD4-2), encoding a C22-?4 polyunsaturated fatty acid specific desaturase, has been isolated and characterized from I. galbana. A full-length cDNA of 1,302 bp was cloned by LA PCR technique. The IgFAD4-2 encoded a protein of 433 amino acids that shares 78 % identity with a previously reported ?4-desaturase (IgFAD4-1) from I. galbana. The function of IgFAD4-2 was deduced by its heterologous expression in Saccharomyces cerevisiae, which then desaturated docosapentaenoic acid (DPA, 22:5n-3) to DHA. The conversion ratio of DPA to DHA was 34 %, which is higher than other ?4 desaturases cloned from algae. However, IgFAD4-2 did not catalyze the desaturation or elongation reactions with other fatty acids. These results confirm that IgFAD4-2 has C22-?4-PUFAs-specific desaturase activity. PMID- 22941369 TI - An improved sampling protocol for analysis of intracellular metabolites in Mortierella alpina. AB - Sampling of intracellular metabolites in Mortierella alpina was investigated as part of a metabolomics study. After comparison of four sampling protocols, rapid filtration of the culture using a laboratory-made nylon filter and absorbent gauze under normal pressure followed by quenching in liquid N(2) and grinding (the improved protocol) was the most effective. Rapid filtration under normal pressure decreased intracellular metabolites leakage and subsequent grinding of cells contributed to intracellular metabolites extraction. The above quenching method together with 75 % (v/v) ethanol, buffered with 60 mM HEPES, at 80 degrees C for 3 min is therefore suitable for sampling intracellular metabolites in M. alpina. PMID- 22941370 TI - Biosynthesis of new lipopentapeptides by an engineered strain of Streptomyces sp. AB - Arylomycins are type I signal peptidase inhibitors and have a potential as a new type of antibiotics. They were identified from the broth of Streptomyces sp. HCCB10043. The arylomycin biosynthetic gene cluster in this strain was identical to that in S. roseosporus. Within the gene cluster, aryC, encoding a P450 enzyme, was deduced to be responsible for biaryl bond formation in, the arylomycins. Inactivation of aryC abolished arylomycin production and led to the generation of two novel linear lipopentapeptides lacking the aryl-aryl linkage. These derivatives had lost their antibacterial activities against Staphylococcus epidermidis which is sensitive to arylomycins A2 and A4. PMID- 22941372 TI - Photocatalytic and antimicrobial properties of surgical implant coatings of titanium dioxide deposited though cathodic arc evaporation. AB - Nanostructured crystalline titanium dioxide coatings deposited by cathodic arc evaporated on titanium grade five medical implant substrates were demonstrated to exhibit UV-induced photocatalytic activity that can be utilized to provide bactericidal effects against Staphylococcus epidermidis. The photocatalytic activity of the coatings was confirmed via degradation of Rhodamine B under UV illumination. A 90 % reduction of viable bacteria was achieved in a clinically suitable time of only 2 min with a UV dose of 2.4 J delivered at 365 nm. These results are encouraging for the development of antimicrobial surfaces in orthopedics and dentistry in order to prevent or treat post-surgical infections. PURPOSE OF WORK: To assess the possibility of employing photocatalysis for elimination of S. epidermidis, known to cause medical device related infections, under short enough times to be clinically useful on an implant surface produced with a technique that is suitable for mass production. PMID- 22941371 TI - Resveratrol prevents hepatic steatosis induced by hepatitis C virus core protein. AB - Hepatitis C virus (HCV) core protein plays an important role in the development of hepatic steatosis in patients with chronic HCV infection. Treatment of C57BL/6 mice infected with HCV core recombinant adenoviruses with resveratrol significantly decreased hepatic triacylglycerols (TAG) while the serum TAG level was unaffected. RT-PCR and Western blotting showed that HCV core protein attenuated the expression of Sirt1 and PPAR-alpha, which would be reversed by resveratrol. This was also confirmed in primary mouse hepatic cells infected with HCV core protein expressing adenovirus. Thus, resveratrol may prevent against hepatic steatosis by blocking the inhibited expression of Sirt1 and PPAR-alpha induced by HCV core protein. PMID- 22941373 TI - Improved 2-methyl-1-propanol production in an engineered Bacillus subtilis by constructing inducible pathways. AB - High-level constitutive gene expression can result in cellular metabolic imbalance and limit production. To circumvent these problems, a P(alsSD) controlled auto-inducible 2-ketoisovalerate biosynthetic pathway and a P(spac) controlled IPTG-inducible Ehrlich pathway were constructed in Bacillus subtilis to modulate gene expression. Based on the precise gene expression characteristics of the two inducible pathways, the optimal IPTG induction time point and dose for 2-methyl-1-propanol biosynthesis were determined as 9.5 h and 300 MUM, respectively. Under the optimized conditions, strain BSUDeltaL-03 with inducible pathways produced up to 3.83 +/- 0.46 g 2-methyl-1-propanol/l, which was about 60 % higher than BSUL04 with constitutive pathways. PMID- 22941374 TI - Everolimus synergizes with gefitinib in non-small-cell lung cancer cell lines resistant to epidermal growth factor receptor tyrosine kinase inhibitors. AB - PURPOSE: Epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) therapy is considered as one of the most important treatments for patients with advanced non-small-cell lung cancer (NSCLC). However, not all patients benefit from this therapy because of primary or acquired resistance, both of which are usually caused by the activation of alternative signaling pathways. Thus, a combination of different signaling pathway inhibitors is a promising strategy. We used the mammalian target of rapamycin (mTOR) inhibitor everolimus in combination with gefitinib in NSCLC cell lines to analyze the efficacy of this combination regimen and the underlying molecular mechanism. METHODS: Acquired gefitinib resistant cell lines, together with EGFR wild-type and mutant primary gefitinib resistant NSCLC cell lines, were treated with everolimus alone, gefitinib alone, or the combination of the two drugs, and the effects were evaluated using cell proliferation assays. The effects of everolimus and gefitinib on the EGFR pathway in NSCLC cell lines were determined by Western blot analysis. RESULTS: Combined treatment resulted in synergistic antitumor effects in gefitinib-resistant cells A549 and H1975. The combination index (CI) of cells increased with increasing dose of everolimus. Everolimus demonstrated no apparent inhibition of phosphorylated Akt (p-Akt) and phosphorylated p44/42 MAPK (p-MAPK) in H1650 cells. Additionally, in gefitinib-resistant cell lines, the combination of gefitinib and everolimus not only showed stronger inhibition of phosphorylated mTOR and phosphorylated p70S6K expression than either drug alone but also reduced the levels of p-Akt and p-MAPK in both cell lines. CONCLUSIONS: Our data showed that the combination of everolimus and gefitinib exhibits dose-dependent synergism in primary and acquired gefitinib-resistant NSCLC cells. Thus, a preclinical rationale exists for the use of everolimus to enhance the efficacy of gefitinib in EGFR-TKI-resistant patients with NSCLC. PMID- 22941375 TI - Phase I and pharmacokinetic study of IHL-305 (PEGylated liposomal irinotecan) in patients with advanced solid tumors. AB - PURPOSE: IHL-305 is a novel PEGylated liposome containing irinotecan. This study examined the safety profile and pharmacokinetics of IHL-305 and established the maximum tolerated dose and recommended phase II dose (RP2D). PATIENTS AND METHODS: In a standard 3 + 3 design, IHL-305 was administered IV on day 1 of a 28 day treatment schedule. Subsequently, a 14-day treatment schedule was also explored. Two patient populations were evaluated separately: Patients with at least one wild-type (wt) allele of UGT1A1 (UDP glucoronosyltransferase 1A1) wt/wt or wt/*28 as one group (referred to as UGT1A1 wt group) and patients with UGT1A1*28 homozygous variant (*28/*28) as another group. RESULTS: Sixty patients were treated: 42 on the 28-day schedule and 18 on the 14-day schedule. Seven patients were homozygous variant (*28/*28). In the UGT1A1 wt group, the MTD and RP2D of IHL-305 was 160 mg/m(2) every 28 days and 80 mg/m(2) every 14 days. DLTs included nausea, vomiting, diarrhea, and neutropenia. The most common adverse events were nausea (75 %), vomiting (52 %), diarrhea (62 %), anorexia (57 %), and fatigue (57 %). At the MTD for both schedules, IHL-305 administration resulted in a high and prolonged exposure of sum total irinotecan, released irinotecan, and SN-38 in plasma. One partial response was observed in a patient with breast cancer and eight patients had stable disease for >6 months. CONCLUSIONS: IHL-305, a novel preparation of irinotecan encapsulated in liposomes, can be safely given to patients in a repeated fashion on a 4- or 2-week dosing schedule. PMID- 22941376 TI - Protease-activated receptor-2 induces expression of vascular endothelial growth factor and cyclooxygenase-2 via the mitogen-activated protein kinase pathway in gastric cancer cells. AB - Protease-activated receptor-2 (PAR-2) has shown strong pro-angiogenesis activity physiologically and pathologically. This study aimed to explore PAR-2 regulation of pro-angiogenesis gene expression and the underlying molecular pathways in gastric cancer cells. MKN28 human gastric cancer cells were treated with trypsin, a PAR-2 activator, and subjected to real-time reverse transcription polymerase chain reaction (qRT-PCR), western blotting and ELISA for gene expression analyses. ERK1/2 phosphorylation and p38 MAP kinase inhibitors (PD98059 and SB203580, respectively) were used to block their gene activities. PAR-2 mRNA and protein were expressed in MKN-28 cells and activated by trypsin treatment. Trypsin-activated PAR-2 protein significantly enhanced expression of vascular endothelial growth factor (VEGF) and cyclooxygenase-2 (COX-2) mRNA and protein in gastric cancer cells in a dose- and time-dependent manner. PAR-2 activation also induced the phosphorylation of ERK1/2 and p38 MAP kinase, but the ERK1/2 and p38 inhibitors blocked the activated PAR-2-induced VEGF and COX-2 expression in gastric cancer cells. PAR-2-induced expression of VEGF and COX-2 mRNA and protein in gastric cancer MKN28 cells was mediated by activation of an ERK1/2- and p38 MAP kinase-dependent pathway. Thus, PAR-2 may serve as a promising target for anti-angiogenesis therapy to treat gastric cancer. PMID- 22941377 TI - Umbilical cord blood graft enhancement strategies: has the time come to move these into the clinic? AB - Umbilical cord blood (UCB) is an attractive stem cell graft option for patients who need allogeneic hematopoietic stem cell support, but lack a suitable HLA matched donor. However, the limited number of hematopoietic progenitor cells in a single cord blood unit can lead to an increased risk of graft failure, delayed hematological recovery and prolonged immunosuppression, particularly in adult patients. Several strategies to overcome these potential limitations are being evaluated. In this review, we discuss promising ex vivo manipulations to enhance cord blood engraftment capacity such as culture of UCB cells with stimulatory cytokines and growth factors, mesenchymal cells, Notch ligand, copper chelators, prostaglandins, complement components, nicotinamide and CD26/DPPIV inhibitors. All these approaches are now in early clinical trials. However, despite the fact that several cord blood enhancement strategies have resulted in increased numbers of progenitor cells and faster neutrophil recovery, the ability of these techniques to significantly shorten engraftment time and permit the use of cord units with low numbers of total nucleated cells, or accomplish reliable engraftment with a single cord, have yet to be convincingly demonstrated. The ultimate clinical value of ex vivo cord blood expansion or manipulation has not been defined yet, and the current data do not permit predicting which technology will prove to be the optimal strategy. Nevertheless, expectations remain high that eventually ex vivo enhancement will be able to improve clinical outcomes and significantly extend the applicability of UCB transplantation. PMID- 22941378 TI - Evaluation of BM cytomorphology after allo-SCT in patients with MDS. PMID- 22941379 TI - Effect of related donor availability on outcome of AML in the context of related and unrelated hematopoietic cell transplantation. AB - Although allogeneic hematopoietic cell transplantation (HCT) from a related donor is effective therapy for younger patients with AML, it remains unknown how the availability of a related donor affects the outcome when unrelated HCT is a treatment option for patients without a related donor. To address this issue, we retrospectively analyzed 605 cytogenetically non-favorable AML patients younger than 50 years for whom a related donor search was performed during first CR (CR1). The 4-year OS was 62% in 253 patients with a related donor and 59% in 352 patients without a related donor (P=0.534). Allogeneic HCT was performed during CR1 in 62% and 41% of patients with and without a related donor, respectively. Among patients transplanted in CR1, the cumulative incidence of non-relapse mortality was significantly higher in patients without a related donor (P=0.022), but there was no difference in post-transplant OS between the groups (P=0.262). These findings show the usefulness of unrelated HCT in younger patients with cytogenetically non-favorable AML who do not have a related donor. The extensive use of unrelated HCT for such patients may minimize the potential disadvantage of lacking a related donor. PMID- 22941380 TI - Pre-emptive immunotherapy with purified natural killer cells after haploidentical SCT: a prospective phase II study in two centers. AB - Adoptive immunotherapy with allogeneic purified natural killer (NK) cell products might exert graft-versus-tumor alloreactivity with little risk of GVHD. In a prospective phase II study in two centers, we administered purified NK cell products to high-risk patients treated with haploidentical T-cell-depleted SCT. Sixteen patients received a total of 29 NK cell infusions on days +3, +40 and +100 after transplantation. Median doses (and ranges) of infused NK- and T-cells per product were 1.21 (0.3-3.8) * 10(7)/kg and 0.03 (0.004-0.72) * 10(5)/kg, respectively. With a median follow-up of 5.8 years 4/16 patients are alive. Cause of death was relapse in five, GVHD in three, graft failure in three, and transplant related neurotoxicity in one patient. Four patients developed acute GVHD?grade II, all receiving a total of ?0.5 * 10(5) T cells/kg. Compared with historical controls, NK cell infusions had no apparent effect on the rates of graft failure or relapse. Adoptive transfer of allogeneic NK cells is safe and feasible, but further studies are needed to determine the optimal dose and timing of NK cell therapy. Moreover, NK cell activation/expansion may be required to attain clinical benefit, while careful consideration must be given to the number of T cells infused. PMID- 22941381 TI - Allo-SCT for multiple myeloma in the era of novel agents: a retrospective study on behalf of Swiss Blood SCT. AB - Despite the introduction of novel drugs, cure of multiple myeloma remains rare. Allo-SCT can induce long-term remission, but randomized studies in advanced disease are lacking and the influence of novel drugs remains unclear. In our retrospective analysis of all patients with myeloma allografted in Switzerland, 95 patients were transplanted between 1988 and 2011. Most patients were heavily pre-treated, and 53% received novel drugs before transplant. In all, 51% were allografted after relapse or progression. Transplant trends changed over time with an increase in reduced intensity conditioning and unrelated donors. At the time of analysis 47 patients remained alive, with a median follow-up of survivors of 53 months. Acute GVHD II-IV and chronic GVHD (cGVHD) occurred in 49% and 53%, respectively; TRM at 5 years was 18%. Five-year OS and PFS were 51% and 29%, respectively. Patients who received transplant upfront vs after relapse had a significantly better outcome, as well as those who had a related donor and achieved CR post transplant. We found no impact of pre-treatment with novel drugs or cGVHD. Although long-term remission following allo-SCT can be achieved, GVHD and TRM remain major limitations. Our series suggests that benefit is highest when allo-SCT is used early in the disease. PMID- 22941382 TI - Noninvasive mechanical ventilation as early intervention in hematopoietic SCT: protective, therapeutic or futile? The lungs may have the correct answer. PMID- 22941383 TI - Juvenile metachromatic leukodystrophy 10 years post transplant compared with a non-transplanted cohort. AB - Metachromatic leukodystrophy (MLD) is a rare inborn error of metabolism leading to severe neurological symptoms and early death. Hematopoietic SCT (HSCT) is considered a treatment option, but results are inconsistent and comparison with natural history is practically missing. We compare a girl with juvenile MLD 10 years after allogeneic HSCT not only with her untreated sister, but also with a large cohort of untreated patients. The girl received HSCT at the age of 5 years when first motor signs appeared. Over 10 years she was stable with respect to her clinical course and gained cognitive abilities. Magnetic resonance imaging (MRI) showed clear regression of white matter changes and magnetic resonance spectroscopy (MRS) demonstrated a reversal of the initial choline increase and N acetyl-aspartate (NAA) decrease. Only axonal demyelinating neuropathy showed some progression. Her gross motor function and MRI-scores were clearly better compared with her sister and the cohort of untreated patients. Difference to her sister became apparent only 4 years after HSCT. We conclude that HSCT, early in the course of disease, can lead to stabilization of juvenile MLD with a course clearly different from the natural history. HSCT may prevent disease progression, if performed sufficient time before loss of walking, which typically initiates rapid deterioration. PMID- 22941384 TI - Matched-pair analysis to compare the outcomes of a second salvage auto-SCT to systemic chemotherapy alone in patients with multiple myeloma who relapsed after front-line auto-SCT. AB - The aims of this study were to investigate the outcomes of second salvage auto SCT and to identify the impacts of a second auto-SCT compared with systemic chemotherapy alone on disease outcome. Data from 48 patients who underwent second auto-SCT were matched to 144 patients (1:3) who received systemic chemotherapy alone from the Korean Myeloma Registry. Groups were matched for nine potential prognostic factors and compared for treatment outcomes. The median age of matching-pairs at relapse was 55.5 years. A total of 156 patients (81%) received vincristine, doxorubicin and dexamethasone induction therapy before the first auto-SCT. Thirty-five patients (73%) in the second auto-SCT group received novel agent-based therapies before the second auto-SCT, and similar proportion in both groups received novel therapies after relapse of front-line auto-SCT. With a median follow-up of 55.3 months, patients who underwent a second auto-SCT had significantly better median OS (55.5 vs 25.4 months, P=0.035). In multivariate analysis for OS, <18 months time to progression after first auto-SCT, International Staging System III and salvage chemotherapy alone were independent predictors for worse OS. The outcomes of second auto-SCT appear to be superior to those of systemic chemotherapy alone. A randomized trial comparing both treatment strategies is required. PMID- 22941385 TI - Metaphase II (MII) oocytes obtained at different time points in the same in vitro fertilization cycle. PMID- 22941387 TI - Assessment of delayed gastric emptying after major hepatectomy using a 13C-acetic acid breath test. AB - PURPOSES: Delayed gastric emptying (DGE) after hepatectomy affects the quality of life of patients, although the causes and related conditions have not been investigated. This study evaluated the relationship between hepatectomy and DGE by the objective assessment of gastric emptying (GE). METHODS: Nineteen patients who underwent major hepatectomy were prospectively enrolled in the study. Their GE was studied using the (13)C-acetic acid breath test before and after hepatectomy. The results of the GE analysis were correlated with the postoperative course after hepatectomy. RESULTS: Clinically evident DGE, which was defined as the inability to take in an appropriate amount of solid food orally by postoperative day 14, was not found in these patients, but the gastric half-emptying times before and after hepatectomy were 20.2 +/- 9.7 and 28.6 +/- 12.2 min, respectively (P = 0.01). The GE time was significantly delayed in patients aged >= 41 years, or who underwent right hemihepatectomy. CONCLUSIONS: Gastric emptying was significantly inhibited in patients who underwent major hepatectomy, and aging and a right-sided hemihepatectomy may be related to the development of DGE. PMID- 22941388 TI - [Evaluation of further training in anesthesiology. Will we meet the demands?]. AB - BACKGROUND: In 2009 and 2011 all German physicians authorized to provide postgraduate training (WBB) and physicians in postgraduate training (WBA) were invited to participate in a survey focusing on various aspects of postgraduate training. The survey was initiated by the German Medical Council and the contents and underlying methodology were based on a survey carried out annually in Switzerland. RESULTS: The response rate of WBAs from 2009 and 2011 increased from 32.8 % to 38.6 % (n = 20.518) while the response rate of WBBs decreased from 60.8 % to 53.3 % (n = 9,276). Anesthesiologists (both WBB and WBA) participated more frequently compared to other disciplines (WBB 74.3 % versus 53.3 %, WBA 45.6 % versus 38.6 %). The quality of postgraduate training was evaluated on a scale from 1 to 6, with 1 as the best and 6 as the worst evaluation result. In 2009 the overall evaluation was rated as satisfying (2.54) and in 2011 there was a tendency towards improvement (2.44) with the overall result for postgraduate training quality in anesthesiology (2.44) lying exactly within the average of all disciplines. In the section critical incident management anesthesiology was assessed as being above average, whereas it was below average in the topics professional competence and decision-making culture. In terms of job situation (e.g. structure of training, off-duty after on-call duty and documentation and remuneration of overtime), anesthesiology was assessed as being above average. Although collected these data were, however, not included in the statistical analysis of the overall data set. Noteworthy was that WBBs rated the quality of postgraduate training better than WBAs (the delta being 0.66 on average over all 8 items assessed). Postgraduate training in ambulatory settings (WBS) with outpatient medical service was scored much better than average by WBAs (1.7 versus 2.44). CONCLUSIONS: The current survey gives an insight into the assessment of over 9,000 physicians authorized to provide postgraduate training in Germany and over 20,000 physicians in training programs. While the comparison between the different medical disciplines within each survey appears to be valid the comparison between the results of the 2009 and 2011 surveys needs to be critically evaluated due to some inhomogeneities in the collectives. A higher than average participation of anesthesiologists indicates a notable willingness to contribute to measures aiming at the improvement of postgraduate training. It is difficult to assess the extent to which the data obtained in this evaluation reliably reflect the quality of postgraduate training in German medical institutions. Nevertheless, the survey provides valuable information about targeted attempts for improvement. Obvious potential for improvement can be seen not only within the scope of structural quality (training plan and target) but also in feedback. Personal contact to persons authorized to provide postgraduate training seems to have a very positive effect on the result of the evaluation. The results concerned with job situation, which were above average for anesthesiology, was not included in the evaluation performed by the German Medical Council and hence had no chance to positively influence the overall result. These results should be included in the evaluation of future surveys dealing with postgraduate training quality. PMID- 22941386 TI - Telomere structure and telomerase in health and disease (review). AB - Telomerase is the enzyme responsible for maintenance of the length of telomeres by addition of guanine-rich repetitive sequences. Telomerase activity is exhibited in gametes and stem and tumor cells. In human somatic cells, proliferation potential is strictly limited and senescence follows approximately 50-70 cell divisions. In most tumor cells, on the contrary, replication potential is unlimited. The key role in this process of the system of the telomere length maintenance with involvement of telomerase is still poorly studied. Undoubtedly, DNA polymerase is not capable of completely copying DNA at the very ends of chromosomes; therefore, approximately 50 nucleotides are lost during each cell cycle, which results in gradual telomere length shortening. Critically short telomeres cause senescence, following crisis and cell death. However, in tumor cells the system of telomere length maintenance is activated. Much work has been done regarding the complex telomere/telomerase as a unique target, highly specific in cancer cells. Telomeres have additional proteins that regulate the binding of telomerase. Telomerase, also associates with a number of proteins forming the sheltering complex having a central role in telomerase activity. This review focuses on the structure and function of the telomere/telomerase complex and its altered behavior leading to disease, mainly cancer. Although telomerase therapeutics are not approved yet for clinical use, we can assume that based on the promising in vitro and in vivo results and successful clinical trials, it can be predicted that telomerase therapeutics will be utilized soon in the combat against malignancies and degenerative diseases. The active search for modulators is justified, because the telomere/telomerase system is an extremely promising target offering possibilities to decrease or increase the viability of the cell for therapeutic purposes. PMID- 22941389 TI - Luminescence and upconversion from thulium(III) species in solution. AB - Thulium salts and complexes are shown to be emissive from three states in the excited state manifold of Tm(3+). Formation of the (1)D(2) state can result in luminescence, or in energy transfer to the lower energy (1)G(4) and (3)H(4) emissive states. Where chromophores are present in the ligand structure, emission is restricted to thulium centred emissive states that are lower in energy than the chromophore centred donor state. We have also observed direct multi-photon excitation of the thulium excited state manifold. Furthermore, additional transitions are observed in the multi-photon excitation spectra that are consistent with upconversion as a consequence of sequential single photon absorption and relaxation processes within the thulium excited state manifold. PMID- 22941390 TI - Multiple cerebral arterial occlusions related to Mycoplasma pneumoniae infection. AB - We report the case of a 33-year-old man with a brainstem infarction due to concomitant occlusions in the left internal carotid, both vertebral, and basilar arteries. The patient had experienced a severe Mycoplasma pneumoniae infection about 10 months prior to symptom onset, and his Mycoplasma antibody titre was positive when the stroke occurred. Despite performing meticulous neurological, vascular, and medical evaluations, we were unable to detect other possible causes of the stroke. Therefore, the multiple occlusions in the major cerebral arteries of our patient were concluded to be related to M. pneumoniae infection. PMID- 22941391 TI - Device life of the Provox Vega voice prosthesis. AB - Device life of the Provox Vega Indwelling voice prosthesis is as yet untested outside Europe. The current study examined device life and reasons for replacement within an Australian clinical setting. Twenty-three participants were monitored for device life and reasons for replacement. Main outcome measure was days to failure of initial device. Average device life and reasons for replacement were secondary measures. Initial device life data revealed 67 % had functioning devices at 3 months, 52 % at 6 months and 29 % at 12 months. Average device life was 207 days (median of 222). The majority of devices (97 %) failed due to leakage through the prosthesis. The Provox Vega Indwelling voice prosthesis had favourable device life in this cohort of patients and in comparison to European data. Reasons for replacement were consistent with international literature. PMID- 22941392 TI - Submandibular gland excision: long-term clinical outcome in 139 patients operated in a single institution. AB - In transcervical resection of the submandibular gland for benign lesions, only a limited risk of damage to neural structures can be accepted and a cosmetically satisfactory result is mandatory. In this retrospective case series, we evaluated 139 patients operated over a 10-year period and completed long-term clinical follow-up of 113 of these patients after a median of 81 months. In all patients, the operation was effective. We found a 4.3 % risk of reoperation for wound infection or postoperative hematomas and an 18.7 % risk of early paresis of the marginal branch of the facial nerve, which decreased to 2.7 % on long-term follow up. We found a 4.4 % risk of permanent lingual nerve paresis, and no patients had damage to the hypoglossal nerve. Xerostomia was found in 22.1 % of the patients and could be quantified by the easily performed biscuit test. Only 2.5 % reported an unsatisfactory cosmetic result and all scars were <= 6 on the Vancouver Scar Scale. Problems with scarring were more common if there had been postoperative infection. We continue to use the lateral transcervical approach as standard in our institution for patients who cannot be managed by gland-sparing procedures. PMID- 22941393 TI - Role of intraoperative esophagogastroenteroscopy in minimizing gastrojejunostomy related morbidity: experience with 2,311 laparoscopic gastric bypasses with linear stapler anastomosis. AB - BACKGROUND: Anastomotic leaks and strictures of the gastrojejunostomy are a cause of major morbidity following laparoscopic Roux-en-Y gastric bypass (LRYGB). Reported rates of leaks vary between 0 and 5.2%. This has led bariatric surgeons to use a variety of intraoperative methods to detect incompetent suture lines. The aim of the study was to evaluate the role of intraoperative endoscopy in reducing the rate of postoperative anastomotic complications. The setting of this study is in a community teaching hospital. METHODS: Medical records of 2,311 patients who underwent a LRYGB from 2002 to 2011 were retrospectively reviewed utilizing the hospitals' bariatric surgery database. Demographics, weight, body mass index, intraoperative endoscopy results, and postoperative outcomes within 90 days after surgery were analyzed. RESULTS: Endoscopy was attempted in 2,311 patients and completed in 2,308 (99.9%). Intraoperative leak was detected in 80 (3.5%) patients; suture line was reinforced in 46 patients (2%), while in the other 34 patients the leak was transient at only high insufflation pressure. Postoperative clinical leaks were detected in four cases (0.2%) two of which had initial leaks intraoperatively. In two cases, the anastomosis was too tight and required reconstruction. Twenty-five patients (1.1%) developed early postoperative strictures requiring endoscopic dilatation within 90 days. Three patients (0.1%) had iatrogenic injury at the time of intraoperative endoscopy, all three healed without delayed morbidity. CONCLUSIONS: The routine use of intraoperative endoscopy in LRYGB with the linear stapler anastomosis technique is associated with a complication/failure rate of 0.3% and low gastrojejunostomy related morbidity after LRYGB within 90 days (leak rate of 0.2% and stricture rate of 1.1%). PMID- 22941394 TI - Surgical management of intraventricular central neurocytoma: 92 cases. AB - OBJECTIVE: To analyse the clinical characteristics of intraventricular central neurocytomas and gain a better understanding of the surgical management and treatment strategies. METHODS: A total of 92 cases of intraventricular central neurocytomas with initial treatment using surgical resection were studied retrospectively. RESULTS: Among 48 male and 44 female patients, 65 underwent gross total resection and 27 underwent subtotal resection. Transcortical or transcallosal approaches were performed, and there was no significant difference between the two approaches in terms of effects and complications. Tumours with calcification or adhesion had a significant lower gross total resection rate. Three patients died after surgery. During follow-up, 55 patients underwent postoperative radiotherapy and four patients had a recurrence of the tumour. CONCLUSION: Central neurocytomas mostly occur in the lateral ventricle system near the foramen of Monro. Therefore, total resection is the best treatment. Two surgical approaches are possible as treatment. Calcifications or adhesions affect the gross total resection of the tumour. Radiation therapy or radiosurgery therapy can be chosen as a salvage treatment in case of recurrence. PMID- 22941395 TI - Pediatric functional hemispherectomy: outcome in 92 patients. AB - BACKGROUND: The revival of epilepsy surgery after the introduction of modern presurgical evaluation procedures has led to an increase in hemispherectomy or hemispherotomy procedures. Since a large part of our pediatric series was done using a newer hemispherotomy technique, we focus mainly on the outcomes after a recently developed hemispherotomy technique (transsylvian keyhole). METHODS: Ninety-six pediatric patients (aged 4 months to 18 years, mean 7.3) were operated on between 1990 and 2009; 92 were available with follow-up. RESULTS: The most frequent diagnosis was porencephaly in 46 % of all patients. Progressive etiologies were present in 20 % and developmental etiologies in 22 %. At last available outcome (LAO), 85 % of the patients were seizure free (ILAE class 1). Year-to-year outcome was rather stable; usually over 80 % were class 1 for up to 13 years (n = 24). Of 92 assessable patients, 71 were treated with the transsylvian keyhole technique, with 89 % being seizure free. The overall shunt rate was 5.3 % for the whole series and 3 % for the keyhole technique subgroup. Mortality was 1 of 96 patients. Excluding patients with hemimegalencephaly (HME), patients with the shortest duration of epilepsy and the lowest age at seizure onset had the highest rates of seizure freedom. The etiology does influence outcome, with HME patients having the poorest seizure outcome and patients with Sturge-Weber syndrome and porencephaly having excellent seizure control. CONCLUSION: Hemispherotomies/functional hemispherectomies are very effective and safe procedures for treating drug-resistant epilepsy with extensive unihemispheric pathology. Etiology and surgery type clearly influence seizure outcome. PMID- 22941396 TI - Transvertebral anterior key hole foraminotomy without fusion for the cervicothoracic junction. AB - BACKGROUND: Various surgical procedures have been used to repair disc herniations and osteophytes at the cervicothoracic junction. Among these procedures, transvertebral anterior foraminotomy without fusion is a relatively less invasive, safe and useful method, although the majority of spinal surgeons remain unfamiliar with this method. We describe the surgical procedure for a transvertebral anterior keyhole foraminotomy without fusion at the cervicothoracic junction, and we assess the middle-term clinical and radiological outcomes. METHODS: Of 118 patients undergoing this surgery in our institute between 2007 and 2010, five (4.2 %) had C8 radiculopathy causing C7/T1 disc herniations or osteophytes. We studied five patients who underwent trans-C7 vertebral keyhole foraminotomy without fusion. We retrospectively examined clinical data, pre- and postoperative neurological status. RESULTS: In all cases, surgical decompression was successfully achieved without difficulty when accessing the pathology. No complications related to the surgical procedure were reported. The follow-up period was 12-28 (mean 20) months. In all patients, the visual analogue scale (VAS) due to radicular pain immediately decreased after the operation and did not increase thereafter. The mean VAS decreased from 7.8 (4.5 9.6) to 1.0 (0-2.1). The Cobb angle at C2-T1 in a neutral position improved from 12.6 (-2.8 to -24.7) degrees to -6.9 (4.2 to -25.4). The postoperative C7/T1 disc height decreased from 5.4 to 4.9 mm, indicating minimal loss. CONCLUSIONS: This procedure allows for direct access to the pathology and is less invasive. In this study, we clarified that this technique yields excellent radiological and clinical outcomes. PMID- 22941397 TI - Communicating risks and benefits about ethically controversial topics: the case of induced pluripotent stem (iPS) cells. AB - Many are supportive of approaches that incorporate lay citizens into policy making and risk management decisions. However, a great deal of learning must first take place about how citizen engagement for controversial topics is best accomplished. Online risk communication efforts are increasing in popularity but there is little empirical evidence accrued to demonstrate the effectiveness of such methods. The intention of our overall study is to create a powerful method for in-depth two-way communication with the public and expert communities about complex and sensitive issues at the heart of stem cell (SC) research. The fundamental objective is to raise awareness of SC science with lay citizens by fostering more holistic or "all things considered" ethical judgments. Our risk communication study demonstrates that lay citizens are both interested in, and capable of learning about, complex scientific issues provided the right tools are used to convey information and assess understanding. Our results show that it is worth the time and effort for SC researchers to continue posting podcasts and FAQ's about their work for non-expert communities to view. In addition, despite having increased our participants' risk perceptions about induced pluripotent stem (iPS) cell research, almost all were very supportive of this type of research in Canada by the end of the survey. In other words, participants understood that this research did in fact pose some risks and learned a great deal about both the risks and benefits of iPS cell research, and still thought this research was worthwhile to pursue. PMID- 22941399 TI - Universal immunoassay applied during early development of large molecules to understand impact of immunogenicity on biotherapeutic exposure. AB - Immunogenicity testing during early biotherapeutic development is usually limited by resources needed for assay development, validation, and the necessity for unique product-specific controls and reagents. We describe a unique immunoassay [universal indirect species-specific assay (UNISA)] that can be applied during early phase preclinical studies to support pharmacology, pharmacokinetics (PK), and toxicology evaluation during biotherapeutic antibody candidate assessment. UNISA was evaluated across three animal species: mouse, rat, and cynomolgus monkey. For each species, a unique and specific antibody pair was generated consisting of the secondary antibody and the positive control. The secondary antibody is specific for species anti-IgG antibody while demonstrating no cross reactivity to human antibody-based biotherapeutics. The positive control is comprised of a species-specific anti-human IgG antibody clone specific for binding to the CH2 domain of all human IgG subtypes. Applications of this platform included: (a) identifying the dose with the least immunogenicity risk; (b) characterizing the impact of immunogenicity on PK exposure profiles across multiple antibody candidates and dose regimens; and (c) characterizing the immune response specificity to the idiotype or non-idiotypic region of the biotherapeutic candidate. Due to its use of universal species-specific reagents, UNISA can overcome resource constraints and avoid extensive validation and development time to support immunogenicity testing during the early research and preclinical phase of programs. Enhanced understanding of the impact of the immunogenicity on biotherapeutic exposure and target-related immunomodulatory effects have been made possible with the use of this assay. PMID- 22941398 TI - Tungiasis (sand flea disease): a parasitic disease with particular challenges for public health. AB - Tungiasis (sand flea disease) is caused by the penetration of females of Tunga penetrans into the skin of the feet. Within 2 weeks of penetration the burrowed flea increases its volume by a factor of 2,000. This is paralleled by intense inflammation of the surrounding tissue. Acute and chronic inflammation leads to the development of painful and debilitating clinical pathology. This results in impaired physical fitness and mobility. The social implications of tungiasis associated morbidity are multifold. Children with tungiasis are teased and ridiculed, adults feel ashamed and stigmatized. There is anecdotal evidence that tungiasis negatively affects educational achievements. Impaired mobility and physical fitness will have a negative impact on household economics. Sand flea disease is common in resource-poor communities in South America and in sub Saharan Africa with prevalence in the general population of up to 60%. In East Africa, it has re-emerged in epidemic dimensions in recent years. Hitherto, no effective drug treatment has been at hand. Traditional treatment, i.e., the manipulation of burrowed sand fleas with blunt and inappropriate instruments may facilitate the transmission of blood-derived pathogens. Prevention is feasible through regular application of a repellent based on coconut oil. Owing to its strong association with poverty, sand flea disease would be an excellent starting point for a community-based fight against rural poverty. PMID- 22941401 TI - The dynamics and spectroscopic fingerprint of hydroxyl radical generation through water dimer ionization: ab initio molecular dynamic simulation study. AB - Water decomposition process was investigated by ab initio molecular dynamic simulations using a model of (H(2)O)(2)(+) clusters. The proton transfer (PT) process from the cationic H-donor water to the H-acceptor water for the formation of (HO).H(3)O(+) was predicted as about 90 fs on average calculated at CCSD level of theory. The valence-electron transfer (VET) process through the formation of hemibond interaction between neutral and cationic water, (H(2)O)(2)(+), was also identified in several collected trajectories. Both PT and VET processes were found to propagate along two orthogonal reaction coordinates, the former was through an intermolecular hydrogen bond and the latter required oxygen-oxygen hemibonding. Significant difference of the theoretical electronic transitions along the VET trajectories was also observed in comparison with the non-VET cases, being calculated at SAC-CI level. The strong absorption features of hemibonding (H(2)O)(2)(+) may introduce an interesting consideration for experimental design to monitor the water decomposition process. PMID- 22941400 TI - Morphological parameters of flat epithelial atypia (FEA) in stereotactic vacuum assisted needle core biopsies do not predict the presence of malignancy on subsequent surgical excision. AB - Flat epithelial atypia (FEA) may represent the earliest precursor of low-grade breast cancer and often coexists with more advanced atypical proliferative breast lesions such as atypical ductal hyperplasia (ADH) and lobular intraepithelial neoplasia (LIN). The present study aims to investigate the association between morphological parameters of FEA and presence of malignancy at surgical excision (SE) and the clinical significance of the association of FEA with ADH and/or LIN. This study included 589 cases of stereotactic 11-gauge vacuum-assisted needle core biopsy (VANCB), reporting a diagnosis of FEA, ADH or LIN with subsequent SE from 14 pathology departments in Italy. Available slides were reviewed, with 114 (19.4 %) showing a malignant outcome at SE. Among the 190 cases of pure FEA, no statistically significant association emerged between clinical-pathological parameters of FEA and risk of malignancy. Logistic regression analyses showed an increased risk of malignancy according to the extension of ADH among the 275 cases of FEA associated with ADH (p = 0.004) and among the 34 cases of FEA associated with ADH and LIN (p = 0.02). In the whole series, a statistically significant increased malignancy risk emerged according to mammographic R1-R3/R4 R5 categories (OR = 1.56; p = 0.04), extension (OR = 1.24; p = 0.04) and grade (OR = 1.94; p = 0.004) of cytological atypia of FEA. The presence of ADH was associated with an increased malignancy risk (OR = 2.85; p < 0.0001). Our data confirm the frequent association of FEA with ADH and/or LIN. A diagnosis of pure FEA on VANCB carries a 9.5 % risk of concurrent malignancy and thus warrants follow-up excision because none of the clinical-pathological parameters predicts which cases will present carcinoma on SE. PMID- 22941402 TI - Sensing single remote nuclear spins. AB - The detection of single nuclear spins would be useful for fields ranging from basic science to quantum information technology. However, although sensing based on diamond defects and other methods have shown high sensitivity, they have not been capable of detecting single nuclear spins, and defect-based techniques further require strong defect-spin coupling. Here, we present the detection and identification of single and remote (13)C nuclear spins embedded in nuclear spin baths surrounding a single electron spin of a nitrogen-vacancy centre in diamond. We are able to amplify and detect the weak magnetic field noise (~10 nT) from a single nuclear spin located ~3 nm from the centre using dynamical decoupling control, and achieve a detectable hyperfine coupling strength as weak as ~300 Hz. We also confirm the quantum nature of the coupling, and measure the spin-defect distance and the vector components of the nuclear field. The technique marks a step towards imaging, detecting and controlling nuclear spins in single molecules. PMID- 22941403 TI - Probing the conductance superposition law in single-molecule circuits with parallel paths. AB - According to Kirchhoff's circuit laws, the net conductance of two parallel components in an electronic circuit is the sum of the individual conductances. However, when the circuit dimensions are comparable to the electronic phase coherence length, quantum interference effects play a critical role, as exemplified by the Aharonov-Bohm effect in metal rings. At the molecular scale, interference effects dramatically reduce the electron transfer rate through a meta-connected benzene ring when compared with a para-connected benzene ring. For longer conjugated and cross-conjugated molecules, destructive interference effects have been observed in the tunnelling conductance through molecular junctions. Here, we investigate the conductance superposition law for parallel components in single-molecule circuits, particularly the role of interference. We synthesize a series of molecular systems that contain either one backbone or two backbones in parallel, bonded together cofacially by a common linker on each end. Single-molecule conductance measurements and transport calculations based on density functional theory show that the conductance of a double-backbone molecular junction can be more than twice that of a single-backbone junction, providing clear evidence for constructive interference. PMID- 22941404 TI - All-optical active switching in individual semiconductor nanowires. AB - The imminent limitations of electronic integrated circuits are stimulating intense activity in the area of nanophotonics for the development of on-chip optical components, and solutions incorporating direct-bandgap semiconductors are important in achieving this end. Optical processing of data at the nanometre scale is promising for circumventing these limitations, but requires the development of a toolbox of components including emitters, detectors, modulators, waveguides and switches. In comparison to components fabricated using top-down methods, semiconductor nanowires offer superior surface properties and stronger optical confinement. They are therefore ideal candidates for nanoscale optical network components, as well as model systems for understanding optical confinement. Here, we demonstrate all-optical switching in individual CdS nanowire cavities with subwavelength dimensions through stimulated polariton scattering, as well as a functional NAND gate built from multiple switches. The device design exploits the strong light-matter coupling present in these nanowires, leading to footprints that are a fraction of those of comparable silicon-based dielectric contrast and photonic crystal devices. PMID- 22941405 TI - Effects of input processing and type of personal frequency modulation system on speech-recognition performance of adults with cochlear implants. AB - OBJECTIVES: The objective of this study was to compare speech recognition in quiet and in noise for cochlear implant recipients using two different types of personal frequency modulation (FM) systems (directly coupled [direct auditory input] versus induction neckloop) with each of two sound processors (Cochlear Nucleus Freedom versus Cochlear Nucleus 5). Two different experiments were conducted within this study. In both these experiments, mixing of the FM signal within the Freedom processor was implemented via the same scheme used clinically for the Freedom sound processor. In Experiment 1, the aforementioned comparisons were conducted with the Nucleus 5 programmed so that the microphone and FM signals were mixed and then the mixed signals were subjected to autosensitivity control (ASC). In Experiment 2, comparisons between the two FM systems and processors were conducted again with the Nucleus 5 programmed to provide a more complex multistage implementation of ASC during the preprocessing stage. DESIGN: This study was a within-subject, repeated-measures design. Subjects were recruited from the patient population at the Hearts for Hearing Foundation in Oklahoma City, OK. Fifteen subjects participated in Experiment 1, and 16 subjects participated in Experiment 2. Subjects were adults who had used either unilateral or bilateral cochlear implants for at least 1 year. RESULTS: In this experiment, no differences were found in speech recognition in quiet obtained with the two different FM systems or the various sound-processor conditions. With each sound processor, speech recognition in noise was better with the directly coupled direct auditory input system relative to the neckloop system. The multistage ASC processing of the Nucleus 5 sound processor provided better performance than the single-stage approach for the Nucleus 5 and the Nucleus Freedom sound processor. CONCLUSIONS: Speech recognition in noise is substantially affected by the type of sound processor, FM system, and implementation of ASC used by a Cochlear implant recipient. PMID- 22941406 TI - The effects of hearing impairment and aging on spatial processing. AB - OBJECTIVES: Difficulty in understanding speech in background noise is frequently reported by hearing-impaired people despite well-fitted amplification. Understanding speech in the presence of background noise involves segregating the various auditory stimuli into distinct streams using cues such as pitch characteristics, spatial location of speakers, and contextual information. One possible cause of listening difficulties in noise is reduced spatial-processing ability. Previous attempts to investigate spatial processing in hearing-impaired people have often been confounded by inadequate stimulus audibility. The present research aimed to investigate the effects of hearing impairment and aging on spatial-processing ability. The effect of cognitive ability on spatial processing was also explored. In addition, the relationship between spatial-processing ability and self-report measures of listening difficulty was examined to investigate how much effect spatial-processing ability has in real-world situations. DESIGN: Eighty participants aged between 7 and 89 years took part in the study. Participants' hearing thresholds ranged from within normal limits to a moderately severe sensorineural hearing loss. All participants had English as their first language and no reported learning disabilities. The study sample included both hearing aid users and non-hearing aid users. Spatial-processing ability was assessed with a modified version of the Listening in Spatialized Noise-Sentences test (LiSN-S). The LiSN-S was modified to incorporate a prescribed gain amplifier that amplified the target and distracting stimulus according to the National Acoustic Laboratories-Revised Profound (NAL-RP) prescription. In addition, participants aged 18 years and above completed the Neurobehavioral Cognitive Status examination and the Speech, Spatial and Qualities questionnaire. Participants aged under 18 years completed the Listening Inventory for Education questionnaire. RESULTS: Spatial-processing ability, as measured by the spatial advantage measure of the LiSN-S, was negatively affected by hearing impairment. Aging was not significantly correlated with spatial processing ability. No significant relationship was found between cognitive ability and spatial processing. Self-reported listening difficulty in children, as measured with the Listening Inventory for Education, and spatial-processing ability were not correlated. Self-reported listening difficulty in adults, as measured by the Speech, Spatial and Qualities questionnaire, was significantly correlated with spatial-processing ability. CONCLUSIONS: All hearing-impaired people will have a spatial processing deficit of some degree. This should be given due consideration when counseling patients in regard to realistic expectations of how they will perform in background noise. Further research is required into potential remediation for spatial-processing deficits and the cause of these deficits. PMID- 22941407 TI - Tetrandrine enhances cytotoxicity of cisplatin in human drug-resistant esophageal squamous carcinoma cells by inhibition of multidrug resistance-associated protein 1. AB - Multidrug resistance is one of the major causes limiting the efficacy of chemotherapeutic agents to control esophageal cancer. Herein, we investigated that the effect and mechanism of tetrandrine (TET) in the human esophageal squamous carcinoma cisplatin-resistant cell line YES-2/DDP. The human esophageal squamous carcinoma cisplatin-resistant cell line YES-2/DDP was isolated by stepwise selection in increasing concentrations of cisplatin. The CCK-8 method was carried out to measure the cell viability when cells were exposed to TET with or without cisplatin, and the IC50 and resistance index (RI) of cisplatin was then calculated. Real-time RT-PCR and western blotting were used to detect the mRNA and protein expression of multidrug resistance 1 (MDR1), multidrug resistance-associated protein 1 (MRP1) and breast cancer resistance protein (BCRP), respectively. Flow cytometry was adopted to determine CMFDA efflux and cell apoptosis, respectively. The resulting cell line YES-2/DDP was 16.4-fold resistant to cisplatin, the cytotoxicity of cisplatin to YES-2/DDP cells was enhanced by TET in a dose-dependent manner. Further, it was found that the expression of MDR1 and BCRP was similar in different treated cells. In contrast, the expression of MRP1 was markedly increased in YES-2/DDP cells, which was dose dependently decreased by TET. In agreement with the results, MRP1 activity was also reversed by TET. In conclusion, TET possesses a reversal effect on drug resistance in YES-2/DDP cells through downregulation of MRP1, and has the potential to be an adjunct to chemotherapy for esophageal cancer. PMID- 22941408 TI - Trends in antiarrhythmic drug use after marketing authorization of dronedarone: comparison between Emilia Romagna (Italy) and Sweden. AB - PURPOSE: Our aim was to evaluate whether dronedarone authorization impacts antiarrhythmic drug prescribing in Sweden and Emilia Romagna (Italy). METHODS: Prescriptions of classes I and III antiarrhythmics, expressed as defined daily doses per thousand inhabitants per day (DDD/TID) were monthly using information collected from pharmacy-reimbursed databases. Interrupted time series analysis was applied to compare prescription data over the 2009-2011 period. RESULTS: In Emilia Romagna, the overall consumption of antiarrhythmics was six times as high as in Sweden (7.6 vs. 1.2 DDD/TID). In the first year on the market, dronedarone represented 1.0 % in Italy and 10.7 % in Sweden of the overall antiarrhythmic prescriptions. In Sweden, dronedarone authorization generated an increase in the prescription trend of antiarrhythmics (trend change +0.02; p < 0.001) without variation in amiodarone use In Emilia Romagna, dronedarone marketing did not influence the prescription pattern of either overall antiarrhythmics or amiodarone. CONCLUSIONS: Emilia Romagna and Sweden substantially differ in terms of overall antiarrhythmic use. Although clinical guidelines place dronedarone among first-choice treatments for atrial fibrillation, amiodarone prescribing was not affected in either country by the entry of dronedarone, probably due to a cautious approach by clinicians in line with regulatory recommendations and safety warnings. PMID- 22941409 TI - Staphylococcal enterotoxin B-derived haptens promote sensitization. AB - T helper 2 (Th2) polarization is a major pathological feature in allergic diseases; its etiology is not fully understood. This study aims to elucidate the adjuvant effect of the microbial product-derived small peptides in the initiation of antigen-specific Th2 polarization. In this study, a clinical survey of patients with chronic rhinosinusitis (CRS) and food allergy (FA) was carried out. The Staphylococcal enterotoxin B (SEB)-derived small peptides (Ssps) were examined in the human stool extracts. The formation of Ssp/antigen adducts was tested in a protein-protein combination assay. The bone marrow-derived dendritic cells (BMDCs) were employed to test the role of Ssp/ovalbumin (OVA) adducts in the dendritic cell (DC) maturation. A mouse model was developed to test the role of Ssp/OVA adducts in the initiation of Th2 polarization in the intestine. The results showed that 54 (18.2%) patients with FA were diagnosed among 296 patients with SEB(+) CRS; only eight (2.9%) FA patients were identified among 272 patients with SEB(-) CRS. Ssps were detected in the stool protein extracts from FA patients with SEB(+) CRS, but not in those with SEB(-) CRS. Ssp/OVA adducts induced DC maturation, speeded up DC migration, activated CD4(+) T cells in the regional lymph nodes and induced skewed Th2 polarization in the local tissue. We conclude that patients with SEB(+) CRS are prone to suffering from FA. SEB can be degraded to Ssps in the gastrointestinal tract. The Ssps can bind macromolecular antigens to form adducts to promote the antigenicity of the antigens and induction of the antigen-specific Th2 polarization and inflammation in the local tissue. PMID- 22941411 TI - Renal dysfunction and increased risk of cardiotoxicity with trastuzumab therapy: a new challenge in cardio-oncology. PMID- 22941412 TI - Multiple systematic reviews: methods for assessing discordances of results. AB - BACKGROUND: The process of systematically reviewing research evidence is useful for collecting, assessing and summarizing results from multiple studies planned to answer the same clinical question. The term "systematic" implies that the process, besides being organized and complete, is transparent and fully reported to allow other independent researchers to replicate the results, and therefore come to the same conclusions. Hundreds of new systematic reviews are indexed every year. The growing number increases the likelihood of finding multiple and discordant results. OBJECTIVES: To clarify the impact of multiple and discordant systematic reviews, we designed a program aimed at finding out: (a) how often different systematic reviews are done on the same subject; (b) how often different systematic reviews on the same topic give different results or conclusions; (c) which methods or interpretation characteristics can explain the differences in results or conclusions. METHODS: This paper outlines the method used to explore the frequency and the causes of discordance among multiple systematic reviews on the same topic. These methods were then applied to a few medical fields as case studies. CONCLUSION: This aim is particularly relevant for both clinicians and policy makers. Judgments about evidence and recommendation in health care are complex, and often rely on discordant results, especially when there are no empirical results to help serve as a guideline. PMID- 22941413 TI - [Arteriovenous accesses for chronic hemodialysis]. PMID- 22941414 TI - [Placement of a native arteriovenous access]. AB - The epidemically increasing number of diabetics is resulting in an increasing number of patients with end-stage renal failure who, furthermore, show a high degree of co-morbidity. An increasingly longer survival time with dialysis also means that the group of patients requiring functional dialysis access is continuously growing. The autologous arteriovenous fistula with its high function and low complication rate is the best access form, and should be provided to as many of those patients requiring dialysis as possible. This article discusses the timing of dialysis access, the importance of the medical history and the physical examination, preoperative investigation of the prospective fistula vein, the possibilities of anastomosis, maturation of the fistula and long-term results. PMID- 22941410 TI - Microbial regulation of allergic responses to food. AB - The incidence of food allergy in developed countries is rising at a rate that cannot be attributed to genetic variation alone. In this review, we discuss the environmental factors that may contribute to the increasing prevalence of potentially fatal anaphylactic responses to food. Decreased exposure to enteric infections due to advances in vaccination and sanitation, along with the adoption of high-fat (Western) diets, antibiotic use, Cesarean birth, and formula feeding of infants, have all been implicated in altering the enteric microbiome away from its ancestral state. This collection of resident commensal microbes performs many important physiological functions and plays a central role in the development of the immune system. We hypothesize that alterations in the microbiome interfere with immune system maturation, resulting in impairment of IgA production, reduced abundance of regulatory T cells, and Th2-skewing of baseline immune responses which drive aberrant responses to innocuous (food) antigens. PMID- 22941415 TI - [Treatment of complications after arteriovenous access surgery]. AB - The choice of potential options for an arteriovenous (AV) access is limited for each individual patient. Complications shorten the maximum life span of any AV access. This paper stresses the importance of recognizing complications in time so as to initiate early and adequate therapy which are explained in further detail. Existing vascular accesses should be used as long as possible while maintaining further alternatives for future AV access surgery. PMID- 22941416 TI - Intergenerational communication satisfaction and age boundaries: comparative middle eastern data. AB - Guided by the communicative predicative model of aging, American and Iranian young adults' perceptions of communication with their peers, middle-aged and elderly adults were examined; subjective boundaries for these age categories were also explored. As age of target increased, so did attributions of benevolence, norms of politeness and deference, and communicative respect and avoidance; conversely, attributions of personal vitality and communication satisfaction decreased linearly. Path analysis was also adopted to examine the simultaneous relationships between the variables under study, and ultimately with cultural caveats largely supported, a hypothesized model was derived. The data were discussed in terms of their yielding refinements and elaborations to the communicative predicament and enhancement models of aging. PMID- 22941417 TI - Cultural perceptions of aging: the perspective of Somali Canadians in Ottawa. AB - Somalis currently constitute the largest Sub-Saharan community in Canada and as such have greatly contributed to the transformation of the immigrant population of this country. Although there is a growing body of research on the Somali community in Canada, the question of how the first generation of Somali Canadians experiences aging and transmits its values and attitudes in this regard to younger generations has yet to be explored. The goal of the present study is precisely to understand how male and female Somali seniors living in Canada perceive and experience aging from a cross-cultural perspective. A total of 17 Somali elders (9 women and 8 men) took part in two focus group discussions. Results of the interpretative content analysis revealed that, regardless of the cultural context, both Somali men and women foster quite a positive view of the notion of aging. However, as Somali migrants, men were more critical than women in regards to the challenges of aging in Canada. Results are discussed in light of previous studies on aging, ageism and culture. PMID- 22941418 TI - Accurate quantitation of Ki67-positive proliferating hepatocytes in rabbit liver by a multicolor immunohistochemical (IHC) approach analyzed with automated tissue and cell segmentation software. AB - Determination of hepatocyte proliferation activity is hampered by the presence of Ki67-positive non-parenchymal cells. We validated a multicolor immunohistochemical (IHC) approach using multispectral tissue and cell segmentation software. Portal vein branches to the cranial liver lobes of 10 rabbits were embolized, leading to atrophy of the cranial lobes and hyperplasia of the caudal lobes. Slides from cranial and caudal lobes (n=20) were double stained (CK8+18 and Ki67) and triple-stained (CK8+18, Ki67, and CD31). The Ki67 proliferation index was calculated using automated tissue and cell segmentation software and compared with manual counting by two independent observers. A substantial variation was seen in the number of Ki67-positive hepatocytes in the different specimens in both double and triple staining (range, 0-50). Correlation coefficients between manual counting and the digital analysis were 0.76 for observer 1 (p<0.001) and 0.78 for observer 2 (p<0.001) with double staining and R(2) = 0.91 for observer 1 and R(2) = 0.89 for observer 2, p<0.001 with triple staining. In conclusion, in rabbit, the hepatocellular proliferation index can be reliably determined using automated tissue and cell segmentation software in combination with IHC multiple staining. Our findings may be useful in clinical practice when Ki67 proliferation index yields prognostic significance. PMID- 22941420 TI - Mechanical properties of graphyne monolayers: a first-principles study. AB - We investigated the mechanical properties of graphyne monolayers using first principles calculations based on the Density Functional Theory. Graphyne has a relatively low in-plane Young's modulus (162 N m(-1)) and a large Poisson ratio (0.429) compared to graphene. It can sustain large nonlinear elastic deformations up to an ultimate strain of 0.2 followed by strain softening until failure. The single bond is more vulnerable to rupture than the triple bond and aromatic bond, although it has a shorter bond length (0.19 A shorter) than the aromatic bond. A rigorous continuum description of the elastic response is formulated by expanding the elastic strain energy density in a Taylor series in strain truncated after the fifth-order term. We obtained a total of fourteen nonzero independent elastic constants which are components of tensors up to the tenth order. Pressure effects on the second-order elastic constants, in-plane Young's modulus, and Poisson ratio are predicted. This study implies that graphyne-based surface acoustic wave sensors and waveguides may be synthesized by introducing precisely controlled local strains on graphyne monolayers. PMID- 22941419 TI - Proteoglycan synthesis and Golgi organization in polarized epithelial cells. AB - A large number of complex glycosylation mechanisms take place in the Golgi apparatus. In epithelial cells, glycosylated protein molecules are transported to both the apical and the basolateral surface domains. Although the prevailing view is that the Golgi apparatus provides the same lumenal environment for glycosylation of apical and basolateral cargo proteins, there are indications that proteoglycans destined for the two opposite epithelial surfaces are exposed to different conditions in transit through the Golgi apparatus. We will here review data relating proteoglycan and glycoprotein synthesis to characteristics of the apical and basolateral secretory pathways in epithelial cells. PMID- 22941421 TI - The anticancer effects of Saccharina japonica on 267B1/K-ras human prostate cancer cells. AB - Saccharina japonica (S. japonica), a brown macro-alga, has been used as a traditional medicine in Korea for thousands of years. In this study, the potential anticancer effects of S. japonica were evaluated on 267B1/K-ras human prostate cancer cells. The exposure of cells to the extract induced inhibition of cell growth by increasing the number of apoptotic cells with cell shrinkage and inhibition of cell cycle progression. The effects of the extract on the cells were assessed by studying the cleavage of caspases and the target proteins of caspases. The increased expression of various cleaved caspases and changed expression of other proteins related in the apoptosis pathway were observed. 4'-6 Diamidino-2-phenylindole (DAPI) and immunofluorescence staining showed the cells undergoing apoptosis. Apoptosis induced changes in the expression of proteins involved in a variety of signaling pathways such as endocellular reticulum (ER) stress, death receptor and mammalian target of rapamycin (mTOR)-FoxO-mediated pathways. The data suggest that the extract (n-hexane sub-fraction) of S. japonica, induces apoptosis and cell cycle arrest in 267B1/K-ras human prostate cancer cells, and has potential as a complementary agent for cancer prevention. PMID- 22941422 TI - Peripheral neuropathy caused by joint-related cysts: a review of 17 cases. AB - BACKGROUND: Clinical compression neuropathy caused by para-articular cysts is rare. Only recently, the unifying articular theory was proposed to clarify its true etiologic nature. The authors attribute 17 cases to this theory in order to illustrate the shift in the diagnostic and treatment protocol, and the possible impact on patient outcome. METHODS: Eight intraneural and nine extraneural cysts were included. The proposed diagnostic protocol includes electromyography and ultrasound, followed by magnetic resonance imaging to characterize the cyst. The proposed treatment protocol consists of (1) ligation of the pedicle connecting the cyst with the afflicted joint, (2) decompression of the nerve and, when needed and (3) disarticulation of the superior tibiofibular joint (in case of peroneal nerve involvement). RESULTS: Outcome was good to excellent in all patients, with recovery of sensory and motor function. Cyst recurrence was observed in three intraneural cases (18 %). Analysis of our own diagnostic protocol showed that atypical compression neuropathies should follow a strict diagnostic protocol to exclude missing the presence of a cyst. Ultrasound needs to play a crucial role, with MRI for cyst characterization and pedicle identification. CONCLUSIONS: Retrospective proof in favor of the articular theory was found in all cases. An explanation for the cyst recurrences was formed based on the articular theory. In addition, a diagnostic and therapeutic protocol is proposed for all atypical peripheral compression neuropathies with the ultimate goal to achieve optimal patient outcome. PMID- 22941423 TI - Click chemistry: a new facile and efficient strategy for the preparation of Fe3O4 nanoparticles covalently functionalized with IDA-Cu and their application in the depletion of abundant protein in blood samples. AB - In this study, we report a novel method to synthesize core-shell structured Fe(3)O(4) nanoparticles (NPs) covalently functionalized with iminodiacetic acid (IDA) via click chemistry between the azide and alkyne groups and charged with Cu(2+). Firstly, the Fe(3)O(4)@SiO(2) NPs were obtained using tetraethoxysilane (TEOS) to form a silica shell on the surface of the Fe(3)O(4) core. The azide group-modified Fe(3)O(4)@SiO(2) NPs were obtained by a sol-gel process using 3 azidopropyltriethoxysilane (AzPTES) as the silane agent. Fe(3)O(4)@SiO(2)-N(3) was directly reacted with N-propargyl iminodiacetic via click chemistry, in the presence of a Cu(I) catalyst, to acquire the IDA-modified Fe(3)O(4) NPs. Finally, through the addition of Cu(2+), the Fe(3)O(4)@SiO(2)-IDA-Cu NP product was obtained. The morphology, structure and composition of the NPs were characterized by transmission electron microscopy (TEM), X-ray powder diffraction (XRD), Fourier transform infrared (FTIR) spectroscopy and X-ray photoelectron spectroscopy (XPS). The resulting NPs showed a strong magnetic response to an externally applied magnetic field, a high adsorption capacity and excellent specificity towards hemoglobin (Hb). In addition, the Fe(3)O(4)@SiO(2)-IDA-Cu NPs can be used for the selective removal of abundant Hb protein in bovine and human blood samples. PMID- 22941424 TI - Low calorie and carbohydrate diet: to improve the cardiovascular risk indicators in overweight or obese adults with prediabetes. AB - Our objective was to evaluate the effects of a moderate calorie and carbohydrate restricted diet on cardiovascular risk indicators in overweight or obese patients with prediabetes. A clinical trial was conducted in which 86 subjects presenting with overweight or obesity and prediabetes received a personalized diet of 1,200 to 1,700 calories with a distribution of 50 % carbohydrates, 20 % proteins, and 30 % fat. Body weight, fat mass, and lean mass were measured through bioimpedance. Glucose, total cholesterol, high density lipoprotein cholesterol and low density cholesterol, and triglycerides were measured. The measurements were taken at the beginning of, and at, 6 and 12 months during the intervention, and the differences were compared by paired Student's t and chi(2) tests. At 12 months, a significant reduction was noticed in body weight in patients with overweight and obesity (72.4 +/- 7.8-69.6 +/- 7.5 kg) (85.7 +/- 14.8-80.2 +/- 12.7 kg) with body mass index (28.2 +/- 0.8-27.2 +/- 2.1 kg/m(2)) (34.3 +/- 3.5 32.1 +/- 3.2 kg/m(2)), systolic (120.9 +/- 14.2-112.4 +/- 11.5 mmHg) (124.1 +/- 11.9-115.7 +/- 14.0 mmHg), diastolic blood pressures (79.0 +/- 9.3-71.8 +/- 8.3 mmHg) (80.4 +/- 9.0-73.7 +/- 13.1 mmHg), glucose (106.0 +/- 8.9-95.9 +/- 7.5 mg/dL) (107.3 +/- 7.0-97.0 +/- 8.2 mg/dL), and significant improvement on lipid profile (p < 0.05). The restrictions in the calorie and carbohydrate diet decrease the cardiovascular risk indicators in overweight or obese adults with prediabetes. PMID- 22941425 TI - The influence of the API properties on the ODTs manufacturing from co-processed excipient systems. AB - Directly compressible co-processed excipient systems facilitate orodispersible tablets (ODTs) manufacturing. Despite several excipient systems available, it is reported that the incorporation of high drug dose into the tablet mass may negatively affect both disintegration and mechanical properties. Therefore the influence of drug properties on the quality of orodispersible tablets was investigated. Fast dissolving tablet matrix was made of a co-processed excipient system F-Melt. Two grades of F-Melt that differed in composition, particle shape, and specific surface area were used to form tablet matrix. Ibuprofen, diclofenac sodium, and diltiazem hydrochloride were chosen as model drugs of different physicochemical properties such as solubility, particle size, and shape. Ninety formulations containing 12.5, 25, or 50 wt% of the model drug and F-Melt type C or M were prepared by direct compression. The quality of tablets was examined on the base of disintegration time, wetting time, mechanical resistance and texture analysis. The results showed that F-Melt grade, drug solubility, and its dose had an influence on the quality of tablets. From ninety formulations prepared, only four batches containing F-Melt type C and 12.5 wt% of ibuprofen, diclofenac sodium, or diltiazem hydrochloride could be classified as ODTs. Their disintegration time ranged from 41 to 144 s. In the case of F-Melt type M, tablets disintegrating within 101 s of friability below 1% could be prepared only if 12.5 wt% of diclofenac sodium was incorporated into the tablet mass. PMID- 22941426 TI - Effects of imiquimod and low-intensity laser (lambda660 nm) in chemically induced oral carcinomas in hamster buccal pouch mucosa. AB - Squamous cell carcinoma (SCC) is the most common neoplasm of the oral cavity. It is aggressive, highly proliferative, and metastatic. This study aimed to evaluate the effect of LLLT and imiquimod on DMBA chemically induced lesions on the oral mucosa of hamsters. SCCs were induced on 25 hamsters. Animals of G1 (control 1) were killed and the presence of tumors confirmed; G2 (control 2) suffered no interventions for additional 4 weeks; animals of G3 (laser treatment) were irradiated (lambda660 nm, 50 mW, CW, O=3 mm, 0.07 cm(2), 714.2 mW/cm(2), 133 s, 95 J/cm(2), 6.65 J) at every other day for 4 weeks; animals of G4 (imiquimod treatment) received 5 % imiquimod three times a week for 4 weeks; and animals of G5 (imiquimod and laser treatment) received both treatments for the same period. Samples were taken and underwent histological analysis by light microscopy and were investigated using immunohistochemistry for S-100(+) dendritic cells. In G1, G2, and G3, the evaluations showed malignant tumors and the absence of S-100(+) dendritic cells in the tumor stroma. In G4, 60 % of the animals had no malignant tumors, and S-100(+) dendritic cells were present in the stroma of the tumors as well as dysplasia. In G5, 40 % of the animals presented SCC, with scarce or no S 100(+) dendritic cells. The imiquimod treatment played a direct effect on SCC, demonstrated by the increased number of S-100(+) dendritic cells, which could suggest an important role of immune surveillance against neoplastic proliferation. Furthermore, its association with laser needs to be further investigated. PMID- 22941427 TI - Nutrigenomics and nutrigenetics in inflammatory bowel diseases. AB - Inflammatory bowel diseases (IBD) including ulcerative colitis and Crohn's disease are chronically relapsing, immune-mediated disorders of the gastrointestinal tract. A major challenge in the treatment of IBD is the heterogenous nature of these pathologies. Both, ulcerative colitis and Crohn's disease are of multifactorial etiology and feature a complex interaction of host genetic susceptibility and environmental factors such as diet and gut microbiota. Genome-wide association studies identified disease-relevant single-nucleotide polymorphisms in approximately 100 genes, but at the same time twin studies also clearly indicated a strong environmental impact in disease development. However, attempts to link dietary factors to the risk of developing IBD, based on epidemiological observations showed controversial outcomes. Yet, emerging high throughput technologies implying complete biological systems might allow taking nutrient-gene interactions into account for a better classification of patient subsets in the future. In this context, 2 new scientific fields, "nutrigenetics" and "nutrigenomics" have been established. "Nutrigenetics," studying the effect of genetic variations on nutrient-gene interactions and "Nutrigenomics," describing the impact of nutrition on physiology and health status on the level of gene transcription, protein expression, and metabolism. It is hoped that the integration of both research areas will promote the understanding of the complex gene-environment interaction in IBD etiology and in the long-term will lead to personalized nutrition for disease prevention and treatment. This review briefly summarizes data on the impact of nutrients on intestinal inflammation, highlights nutrient-gene interactions, and addresses the potential of applying "omic" technologies in the context of IBD. PMID- 22941428 TI - Prognostic significance of computed tomography scan-derived splenic volume in hepatocellular carcinoma treated with radiofrequency ablation. AB - GOALS: To evaluate the clinical implication of splenic volume measured by computed tomography (CT) scan in hepatocellular carcinoma (HCC) patients undergoing percutaneous radiofrequency ablation (RFA). BACKGROUND: Splenomegaly is an important sign of portal hypertension and poor liver function in patients with advanced liver disease. But whether it could predict the prognosis of patients with HCC is still obscure. STUDY: We enrolled 161 treatment-naive HCC patients. Splenomegaly was defined as splenic volume >300 mL by CT scan and its impact on prognosis was analyzed. Moreover, noninvasive serum markers were validated to predict splenomegaly. RESULTS: A total of 78 patients were with splenomegaly, while the remaining 83 patients had normal splenic volume at the time of receiving RFA. After a median follow-up of 38.1+/-20.8 months, 41 patients died. The cumulative 5-year survival rates were 54.8% and 77.8% in patients with splenomegaly and in those with normal splenic volume, respectively (P=0.003). By multivariate analysis, age 65 years and older, serum albumin levels <=3.5 g/dL, and splenic volume >300 mL were independent risk factors associated with poor overall survival after RFA. For predicting splenomegaly by noninvasive serum markers, platelet count yielded the highest area under the curve from corresponding receiver operating curves with a level of 0.868 at a cut-off value of 11,7000/mm(3). CONCLUSIONS: HCC patients with splenomegaly measured by CT scan have relatively poorer liver functional reserve than those with normal splenic volume. Splenomegaly is an independent risk factor predicting overall survival for patients with small HCC undergoing RFA. PMID- 22941429 TI - High frequency of recurrent viremia after hepatitis B e antigen seroconversion and consolidation therapy. AB - BACKGROUND: The primary treatment endpoint for hepatitis B e antigen (HBeAg) positive chronic hepatitis B is HBeAg seroconversion; however, data on the durability of response are inconsistent. GOALS: Our goal was to investigate the rate of recurrent viremia after HBeAg seroconversion and subsequent discontinuation of therapy. METHODS: We retrospectively studied 88 consecutive Asian American patients who achieved HBeAg seroconversion [loss of HBeAg and development of antibody to HBeAg (anti-HBe)] among 458 HBeAg-positive patients who received oral antiviral therapy at 3 US clinics between March 1998 and November 2010. Recurrent viremia was defined as reappearance of detectable serum hepatitis B virus DNA (>100 IU/mL) on 2 consecutive laboratory tests from previously undetectable levels. RESULTS: Antiviral medications used at the time of HBeAg seroconversion included: lamivudine (23%), adefovir (34%), entecavir (36%), tenofovir (4%), and combination therapy (3%). Antiviral therapy was continued after HBeAg seroconversion in 49 patients (group I) and discontinued in the other 39 patients after consolidation therapy [median=12 months (range, 1 to 55 mo)] (group II). No patients in group I experienced recurrent viremia, whereas 90% in group II did. Elevated alanine aminotransferase also occurred in 38% of group II patients [median peak alanine aminotransferase 249 IU/mL (range, 93 to 1070 IU/mL)]. CONCLUSIONS: Despite consolidation therapy, almost all patients who discontinued therapy after achieving HBeAg seroconversion and complete viral suppression experienced recurrent viremia, and close to half also experienced biochemical flares. HBeAg seroconversion does not seem to be a durable treatment endpoint for many patients, and they should be monitored carefully for virologic relapse and biochemical flares if antiviral therapy is withdrawn. PMID- 22941430 TI - Concurrent cyclophosphamide and craniospinal radiotherapy for pediatric high-risk embryonal brain tumors. AB - Embryonal tumors are an aggressive subtype of high-grade, pediatric central nervous system (CNS) tumors often with dismal survival rates. The 5-year survival for highest-risk embryonal tumors may be as low as 10 %. We report feasibility and efficacy from our experience using intravenous (IV) cyclophosphamide concurrently with craniospinal radiation (CSI) in high-risk embryonal CNS tumors of childhood. Ten consecutive children (aged: 3.5-15.5 years, median: 10.2 years, six male) with high-risk embryonal tumors, including: large cell/anaplastic medulloblastoma (6), atypical teratoid rhabdoid tumor (1), and leptomeningeal primitive neuroectodermal tumor (3), were treated with IV cyclophosphamide 1 g/M(2) on days 1 and 2 of CSI. Following a median of 36 Gy CSI plus tumor boosts, adjuvant treatment consisted of 21 doses of oral etoposide (7) and alkylator based chemotherapy from five to eight cycles in all. Of the ten patients thus treated, six remain alive with no evidence of disease and four are deceased. Median survival was 3.3 years, with a 3-year progression-free survival of 50 % (5/10). Median follow-up was: 3.3 years (range: 5 months-12.9 years) in the five patients with progression, median time-to-progression was: 1.3 years (range: 1 month-3 years). Median follow-up in the patients without progression is 8.8 years (range: 3-12.9 years). Complications due to adjuvant chemotherapy were typical and included myelosupression (10), necessitating shortened duration of chemotherapy in three, and hemorrhagic cystitis (1). In high-risk embryonal CNS tumors, cyclophosphamide given concurrently with CSI is well tolerated. Early results suggest that a phase II trial is warranted. PMID- 22941432 TI - Apoptosis triggered by vitexin in U937 human leukemia cells via a mitochondrial signaling pathway. AB - Vitexin, a lignan compound, has been shown to exert apoptotic actions on human breast cancer cell lines and to have anti-inflammatory activities. Nevertheless, there is currently no study addressing the effects of vitexin on the induction of apoptosis in U937 human leukemia cells. The aim of this study was to determine the anticancer effects and molecular mechanisms of vitexin on U937 leukemia cells. We showed that vitexin can potently induce programmed cell death in U937 leukemia cell growth as well as morphological changes that were examined by MTT assay and phase contrast microscopy, respectively. The DNA content and the levels of mitochondrial membrane potential (?Psim) were determined by flow cytometric analysis. The cell cycle arrest-regulated and apoptosis-associated protein levels were measured by western blotting. Vitexin-triggered apoptosis was accompanied by a decrease of the level of ?Psim and the percentage of viability and provoked apoptosis in U937 cells. The downregulation of the protein level for Bcl-2 with the simultaneous upregulation of caspase-3 and -9 protein expression in U937 cells were observed after treatment with vitexin. Therefore, our data provide a potential mechanism for the chemopreventive activity of vitexin, and we suggest that vitexin may serve as a therapeutic agent for the treatment of human leukemia. PMID- 22941431 TI - Spinal cord stimulation modulates cerebral function: an fMRI study. AB - INTRODUCTION: Although spinal cord stimulation (SCS) is widely used for chronic neuropathic pain after failed spinal surgery, little is known about the underlying physiological mechanisms. This study aims to investigate the neural substrate underlying short-term (30 s) SCS by means of functional magnetic resonance imaging in 20 patients with failed back surgery syndrome (FBSS). METHODS: Twenty patients with FBSS, treated with externalized SCS, participated in a blocked functional magnetic resonance imaging design with stimulation and rest phases of 30 s each, repeated eight times in a row. During scanning, patients rated pain intensity over time using an 11-point numerical rating scale with verbal anchors (0 = no pain at all to 10 = worst pain imaginable) by pushing buttons (left hand, lesser pain; right hand, more pain). This scale was back projected to the patients on a flat screen allowing them to manually direct the pain indicator. To increase the signal-to-noise ratio, the 8-min block measurements were repeated three times. RESULTS: Marked deactivation of the bilateral medial thalamus and its connections to the rostral and caudal cingulate cortex and the insula was found; the study also showed immediate pain relief obtained by short-term SCS correlated negatively with activity in the inferior olivary nucleus, the cerebellum, and the rostral anterior cingulate cortex. CONCLUSIONS: Results indicate the key role of the medial thalamus as a mediator and the involvement of a corticocerebellar network implicating the modulation and regulation of averse and negative affect related to pain. The observation of a deactivation of the ipsilateral antero-medial thalamus might be used as a region of interest for further response SCS studies. PMID- 22941433 TI - Getting to know the fetal genome non-invasively: now a reality. PMID- 22941434 TI - Follicular helper T cells in immune homeostasis. PMID- 22941435 TI - Production of extracellular biopolymers and identification of intracellular proteins and Rhizobium tropici. AB - The objective of this study was to identify species of rhizobia (from the IPA 403 and IPA 49 isolates), to assess the physico-chemical characteristics of the biopolymers produced by these rhizobia and to determine the soluble intracellular proteins that are present in these rhizobia. The polysaccharides containing acetyl and pyruvic acid groups that were produced by different strains that had been cultivated in yeast extract mannitol (YEM) medium for 132, 144, and 168 h were evaluated for yield, viscosity, and concentration. Based on the analysis of their partial 16S rDNA sequences, both isolates were identified as Rhizobium tropici. The polymers produced in liquid YEM medium were recovered, dried and weighed to determine culture yield. Soluble intracellular proteins were identified through the techniques of 2D-PAGE and mass spectrometry for cultures that were cultivated for 168 h. The largest biopolymer yield and the highest viscosity and concentration of acetyl and pyruvic acids were obtained from the IPA 403 isolate after 168 h of culture. The proteins that were identified for the CIAT 899 isolate included elongation factor TU, a chaperone; GroE/GroEs and a putative glycosyltransferase, all of which catalyze the production of polysaccharides. For the IPA 403 strain, dinitrogenase and nitrogenase iron proteins were found. In the IPA 49 strain, glyceraldehyde-3-phosphate dehydrogenase was found along with two other proteins, the beta subunit of an electron-transferring flavoprotein and a dehydrogenase. PMID- 22941436 TI - TaqMan real-time quantitative PCR assay for detection of fluoroquinolone resistant Neisseria gonorrhoeae. AB - It is noted that more than 99 % of fluoroquinolone resistance in Neisseria gonorrhoeae (QRNG) specimens have been shown to have the mutation of Ser91/Phe in the gyrA gene. In order to detect QRNG isolates as quickly as possible, the real time TaqMan quantitative PCR assay was established for detection of the point mutation of Ser91/Phe in gyrA gene. The standard curve was generated automatically on ABI Prism PE7500. The correlation coefficient (r) of the standard curve was -0.9984 (R(2) = 0.9968), indicating a quietly precise log linear relationship between the concentration of target DNA and the Ct value. Presently, correlated, cultured antimicrobial susceptibility testing of N. gonorrhoeae isolates continues to be the gold standard method for the detection of antimicrobial resistance. Comparison to the correlated, cultured antimicrobial susceptibility testing, the sensitivity and specificity of the established TaqMan assay for the detection of the QRNG specimens were 100 and 99 %, respectively. The TaqMan assay also allows for rapid detection of QRNG isolates without complex laboratory techniques. Therefore, real-time TaqMan quantitative PCR assay is a rapid, simple, highly sensitive, highly specific, and easy-to-perform method for the detection of the QRNG specimens. It can be applied as a quick screening method for QRNG isolates to help clinical determination of optimal treatment prescription. PMID- 22941437 TI - Eustachian tube function in patients with inner ear disorders. AB - The influence of Eustachian tube (ET) dysfunction on the inner ear fluid pressure and thus on the inner ear function in Meniere's disease has been discussed controversially. So far, most of the studies examining ET function in inner ear disorders indirectly analyzed ET function by tympanometric methods. The present study directly studied ET function in inner ear disorders by sonotubometry. Healthy subjects and patients with Meniere's disease, sudden sensorineural hearing loss, cholesteatoma and chronic suppurative otitis media were examined by sonotubometry. Mean increase of sound pressure intensity (dB) and mean duration of sound pressure increase (s) were analyzed. Highest mean increase of sound pressure intensity was seen in healthy subjects when using >5 dB peaks (11.6 +/- 0.7 dB) and >0 dB peaks (9.6 +/- 0.6 dB). Comparative analysis including bilateral ears showed decreased ET function in patients with cholesteatoma (p = 0.002) and in patients with Meniere's disease (p = 0.003) when using >0 dB peaks. Examination of each specific ET opening maneuver showed impaired ET function in pathological ears of patients with cholesteatoma and with Meniere's disease, during yawning (p = 0.001; p < 0.001), dry swallowing (p = 0.010; p = 0.049), Toynbee maneuver (p = 0.033; p = 0.032) and drinking (p = 0.044; p = 0.027). Mild ET dysfunction is detected in patients with Meniere's disease by direct sonotubometric assessment of ET function. PMID- 22941438 TI - Study of the head and neck position in microlaryngoscopy using magnetic resonance imaging. AB - Several studies have critically analyzed the ideal position for laryngeal exposure during microlaryngoscopy; however, these studies have lacked the ability to evaluate the head and neck position while maintaining a direct view into the airway. Therefore, a newly established two-curve methodology was used to investigate the influence of head and neck position during microlaryngoscopy in MRI images. Fourteen normal adult volunteers were used in this magnetic resonance imaging study. The airway was divided into two curves in the sagittal plane at the center of the airway in three head and neck positions: extension-extension, neutral and flexion-extension position. The airway passage curves, point of inflection and its tangent, the line of laryngoscope, line of hyoid bone and mandible were plotted on each scan. Angles and area formed by these lines were calculated to evaluate the airway morphology changes. The flexion-extension position caused a reduction in the area between the line of laryngoscope and curves, but there was no significant difference between the three positions (p = 0.664). The flexion-extension position also resulted in the lowest angle values for alpha (angle between the tangent and horizon, p = 0.000), beta (between the line of hyoid and horizon, p = 0.002) and delta (between the line of mandible and horizon, p = 0.004). Our study provides a better understanding of the changes in normal airway morphology during microlaryngoscopy in different positions, reinforcing the concept that flexion-extension position is the optimal position for microlaryngoscopy. PMID- 22941439 TI - Concha bullosa surgery and the distribution of human olfactory neuroepithelium. AB - In bullous middle turbinate surgery, controversy exists over which side of the bullous middle turbinate should be removed, as the distribution of human olfactory neuroepithelium is unclear. This study evaluated whether the middle turbinate tissue of patients undergoing endoscopic concha bullosa surgery contains functional olfactory epithelium. This prospective clinical study was conducted in tertiary referable center. It detected 70 conchae bullosa in 48 patients with sinonasal symptoms, who underwent paranasal computed tomography (CT) that showed pneumatization of the middle concha. All samples were obtained under general anesthesia. Three samples were obtained from each bullous middle turbinate: one each from the anterior, medial, and lateral portions. The mucosa from each sample was stained with olfactory marker protein (OMP). In total, 210 middle turbinate samples were taken from 48 patients during endoscopic surgery for conchae bullosa. The patients were 22 females and 26 males. Of the 70 conchae bullosa, OMP-stained nerve tissue was found in the lateral, anterior and medial aspects of 57 (81.4 %), 42 (60.0 %) and 23 (32.8 %) of the bullous middle turbinates, respectively. OMP-stained nerve tissue was found in 122 (58.1 %) of the 210 bullous middle turbinate tissue samples. OMP-stained nerve tissue was found on the lateral surface of the bullous middle turbinate more often than the medial surface. Therefore, during the concha bullosa surgery, OMP-stained nerve tissue found at least in the medial part of concha, suggested that the opening of the medial part of middle concha. PMID- 22941440 TI - Oleic acid attenuates trans-10,cis-12 conjugated linoleic acid-mediated inflammatory gene expression in human adipocytes. AB - The weight loss supplement conjugated linoleic acid (CLA) consists of an equal mixture of trans-10,cis-12 (10,12) and cis-9,trans-11 (9,11) isomers. However, high levels of mixed CLA isomers, or the 10,12 isomer, causes chronic inflammation, lipodystrophy, or insulin resistance. We previously demonstrated that 10,12 CLA decreases de novo lipid synthesis along with the abundance and activity of stearoyl-CoA desaturase (SCD)-1, a delta-9 desaturase essential for the synthesis of monounsaturated fatty acids (MUFA). Thus, we hypothesized that the 10,12 CLA-mediated decrease in SCD-1, with the subsequent decrease in MUFA, was responsible for the observed effects. To test this hypothesis, 10,12 CLA treated human adipocytes were supplemented with oleic acid for 12 h to 7 days, and inflammatory gene expression, insulin-stimulated glucose uptake, and lipid content were measured. Oleic acid reduced inflammatory gene expression in a dose dependent manner, and restored the lipid content of 10,12 CLA-treated adipocytes without improving insulin-stimulated glucose uptake. In contrast, supplementation with stearic acid, a substrate for SCD-1, or 9,11 CLA did not prevent inflammatory gene expression by 10,12 CLA. Notably, 10,12 CLA impacted the expression of several G-protein coupled receptors that was attenuated by oleic acid. Collectively, these data show that oleic acid attenuates 10,12 CLA-induced inflammatory gene expression and lipid content, possibly by alleviating cell stress caused by the inhibition of MUFA needed for phospholipid and neutral lipid synthesis. PMID- 22941441 TI - Effect of micro-arc oxidation surface modification on the properties of the NiTi shape memory alloy. AB - In this paper, the effects of micro-arc oxidation (MAO) surface modification (alumina coatings) on the phase transformation behavior, shape memory characteristics, in vitro haemocopatibility and cytocompatibility of the biomedical NiTi alloy were investigated respectively by differential scanning calorimetry, bending test, hemolysis ratio test, dynamic blood clotting test, platelet adhesion test and cytotoxicity testing by human osteoblasts (Hobs). The results showed that there were no obvious changes of the phase transformation temperatures and shape memory characteristics of the NiTi alloy after the MAO surface modification and the coating could withstand the thermal shock and volume change caused by martensite-austenite phase transformation. Compared to the uncoated NiTi alloys, the MAO surface modification could effectively improve the haemocopatibility of the coated NiTi alloys by the reduced hemolysis ratio, the prolonged dynamic clotting time and the decreased number of platelet adhesion; and the rough and porous alumina coatings could obviously promote the adherence, spread and proliferation of the Hobs with the significant increase of proliferation number of Hobs adhered on the surface of the coated NiTi alloys (P < 0.05). PMID- 22941443 TI - Storm forecasting: additional lessons from the CD28 superagonist TGN1412 trial. PMID- 22941444 TI - Immunotherapy: Unlicensed to kill. PMID- 22941445 TI - Development of a unique mouse model for pancreatic cancer lymphatic metastasis. AB - Lymphatic metastasis of pancreatic cancer is a predictor of poor prognosis. However, the molecular mechanisms are largely unknown, thus, making the development of appropriate cell lines and experimental models critically important for future investigations. The purpose of the present study was to establish a 'pancreatic cancer cell and mouse model with high lymphatic metastasis potential' for in-depth study of the underlying mechanisms. The BxPC-3 LN subline, derived from the BxPC-3 human pancreatic cancer cell line, was established through serial passages in nude mice via footpad injections. The subline was able to develop notable lymphatic metastases in 100% of the recipient mice 8 weeks after tumor cell implantation. Compared with the parental BxPC-3 cells, BxPC-3-LN cells were more aggressive, displaying invasive ultrastructure, increased migration and invasion ability, and chemoresistance. Metastasis-related gene alteration including upregulation of MMP14, MMP24, MIF and ADRM1, and downregulation of TGFB2 and ROBO1 were also observed in BxPC-3-LN cells by cDNA microarrays. Thus, the newly selected BxPC-3-LN subline can serve as a unique model for further study of lymphatic metastasis of pancreatic cancer. PMID- 22941446 TI - Active nanowaveguides in polymer doped with CdSe-ZnS core-shell quantum dots. AB - We report a strategy for the fabrication of active nanowaveguides (nanoWGs) in polymer doped with CdSe-ZnS core-shell quantum dots (QDs). The nanoWGs, with an absorption coefficient of 247 cm(-1) and a self-absorption coefficient of 77 cm( 1), were fabricated by a direct drawing method. The characterization indicates that the nanoWGs, in which the QDs act as nanoemitters under an optical pump, exhibit high photoluminescence efficiency and high photobleaching resistance. The QD-doped polymer nanoWGs would be a promising active waveguide for miniaturized nanophotonic integration. PMID- 22941448 TI - Special Issue: circadian rhythms, clock genes and neuropsychiatry: interesting times. PMID- 22941447 TI - DNA repair gene expression in biological tissues exposed to low-intensity infrared laser. AB - Special properties of laser light have led to its usefulness in many applications in therapy. Excitation of endogenous chromophores in biotissues and generation of free radicals could be involved in its biological effects. DNA lesions induced by free radicals are repaired by base excision repair pathway. In this work, we evaluated the expression of APE1 and OGG1 genes related to repair of DNA lesions induced by free radicals. Skin and muscle tissues of Wistar rats were exposed to low-intensity infrared laser at different fluences and frequencies. After laser exposition of 1 and 24 h, tissue samples were withdrawn for total RNA extraction, cDNA synthesis, and evaluation of APE1 and OGG1 gene expression by quantitative polymerase chain reaction. Data obtained show that laser radiation alters the expression of APE1 and OGG1 mRNA differently in skin and muscle tissues of Wistar rats depending of the fluence, frequency, and time after exposure. Our study suggests that low-intensity infrared laser affects expression of genes involved in repair of DNA lesions by base excision repair pathway. PMID- 22941449 TI - Barriers and enablers to physical activity participation in patients with COPD: a systematic review. AB - PURPOSE: Physical activity (PA) has been shown to improve symptoms in people with chronic obstructive pulmonary disease (COPD). Despite the high health and financial costs, the uptake of management strategies, particularly participation in PA and pulmonary rehabilitation (PR), are low. The review objective here was to identify potential barriers and enablers, which people with COPD report being associated with their participation in PA programs, including PR. METHODS: A systematic search was undertaken to identify studies (published Jan 2000 to Aug 2011) reporting any barriers and enablers experienced by people with COPD regarding participation in PA and PR. Methodological quality of the studies was appraised using McMaster critical appraisal tools. A narrative summary of findings was undertaken reporting on individual study characteristics, country of origin, participants, and potential barriers and enablers. RESULTS: Eleven studies (8 qualitative and 3 quantitative) met the inclusion criteria for this systematic review. Several methodological issues (small sampling, poor description of data collection and analysis, issues with generalizability of the research findings) were common among included studies. Barriers identified included changing health status, personal issues, lack of support, external factors, ongoing smoking, and program-specific barriers. Enablers identified included social support, professional support, personal drivers, personal benefit, control of condition, specific goals, and program-specific enablers. CONCLUSION: The findings from this review may assist health professionals, patients, care givers and the wider community to develop effective strategies to promote participation in PA and PR among people with COPD. PMID- 22941450 TI - Biotoxicity assessment of pyrene in soil using a battery of biological assays. AB - A test battery, composed of a range of biological assays, was applied to evaluate the ecological health of soil aged for 69 days and spiked with a range of pyrene levels (1.04, 8.99, 41.5, 72.6, 136, and 399 MUg g(-1) dry soil; Soxhlet extracted concentrations after 69 days of aging). Chinese cabbage (Brassica rapa), earthworm (Eisenia fetida), and bacteria (Vibrio fischeri) were used as test organisms to represent different trophic levels. Among the acute ecotoxicity bioassays used, the V. fischeri luminescence inhibition assay was the most sensitive indicator of pyrene toxicity. We observed >8 % light inhibition at the lowest concentration (1.04 MUg g(-1)) pyrene, and this inhibition increased to 60 % at 72.6 MUg g(-1). The sensitivity ranking for toxicity of the pyrene contaminated soil in the present study was in the following decreasing order: root elongation of Chinese cabbage < earthworm mortality (14 days) < earthworm mortality (28 days) < luminescence inhibition (15 min) < luminescence inhibition (5 min). In addition, genotoxic effects of pyrene were also evaluated by using comet assay in E. fetida. The strong relationship between DNA damage and soil pyrene levels showed that comet assay is suitable for testing the genotoxicity of pyrene-polluted soil. In addition, tail moment was well correlated with soil pyrene levels (r (2) = 0.99). Thus, tail moment may be the most informative DNA damage parameter representing the results of comet assay. Based on these results, the earthworm DNA damage assay and Microtox test are rapid and sensitive bioassays and can be used to assess the risk of soil with low to high levels of hydrocarbon pollution. Furthermore, an analysis of the toxic effects at several trophic levels is essential for a more comprehensive understanding of the damage caused by highly contaminated soil. PMID- 22941452 TI - Dual TNFalpha-induced effects on NRF2 mediated antioxidant defence in astrocyte rich cultures: role of protein kinase activation. AB - Tumor necrosis factor-alpha (TNFalpha) is a pleiotropic molecule that can have both protective and detrimental effects in neurodegeneration. Here we have investigated the temporal effects of TNFalpha on the inducible Nrf2 system in astrocyte-rich cultures by determination of glutathione (GSH) levels, gammaglutamylcysteine ligase (gammaGCL) activity, the protein levels of Nrf2, Keap1, the catalytic and modulatory subunit of gammaGCL (gammaGCL-C and gammaGCL M respectively). Astrocyte-rich cultures were exposed for 24 or 72 h to different concentrations of TNFalpha. Acute exposure (24 h) of astrocyte-rich cultures to 10 ng/mL of TNFalpha increased GSH, gammaGCL activity, the protein levels of gammaGCL-M, gammaGCL-C and Nrf2 in parallel with decreased levels of Keap1. Antioxidant responsive element (ARE)-mediated transcription was blocked by inhibitors of ERK1/2, JNK and Akt whereas inactivation of p38 and GSK3beta further enhanced transcription. In contrast treatment with TNFalpha for 72 h decreased components of the Nrf2 system in parallel with an increase of Keap1. Stimulation of the Nrf2 system by tBHQ was intact after 24 h but blocked after 72 h treatment with TNFalpha. This down-regulation after 72 h correlated with activation of p38 MAPK and GSK3beta, since inhibition of these signalling pathways reversed this effect. The upregulation of the Nrf2 system by TNFalpha (24 h treatment) protected the cells from oxidative stress through elevated gammaGCL activity whereas the down-regulation (72 h treatment) caused pronounced oxidative toxicity. One of the important implications of the results is that in a situation where Nrf2 is decreased, such as in Alzheimer's disease, the effect of TNFalpha is detrimental. PMID- 22941453 TI - The effect of population heterogeneities upon spread of infection. AB - It has often been observed that population heterogeneities can lead to outbreaks of infection being less frequent and less severe than homogeneous population models would suggest. We address this issue by comparing a model incorporating various forms of heterogeneity with a homogenised model matched according to the value of the basic reproduction number [Formula: see text]. We mainly focus upon heterogeneity in individuals' infectivity and susceptibility, though with some allowance also for heterogeneous patterns of mixing. The measures of infectious spread we consider are (i) the probability of a major outbreak; (ii) the mean outbreak size; (iii) the mean endemic prevalence level; and (iv) the persistence time. For each measure, we establish conditions under which heterogeneity leads to a reduction in infectious spread. We also demonstrate that if such conditions are not satisfied, the reverse may occur. As well as comparison with a homogeneous population, we investigate comparisons between two heterogeneous populations of differing degrees of heterogeneity. All of our results are derived under the assumption that the susceptible population is sufficiently large. PMID- 22941454 TI - Extending the type reproduction number to infectious disease control targeting contacts between types. AB - A new quantity called the target reproduction number is defined to measure control strategies for infectious diseases with multiple host types such as waterborne, vector-borne and zoonotic diseases. The target reproduction number includes as a special case and extends the type reproduction number to allow disease control targeting contacts between types. Relationships among the basic, type and target reproduction numbers are established. Examples of infectious disease models from the literature are given to illustrate the use of the target reproduction number. PMID- 22941455 TI - [Rheumatic diseases at different stages of life]. PMID- 22941456 TI - [Inflammatory rheumatic diseases in the elderly: rheumatoid arthritis and polymyalgia rheumatica]. AB - Inflammatory rheumatic diseases with first onset in advanced age have some specific clinical features. Late-onset rheumatoid arthritis and polymyalgia rheumatica/giant cell arteriitis are the most relevant rheumatic diseases among older patients. They are characterized by acute onset, early functional impairment, and difficult differential diagnosis. First-line therapy usually consists of glucocorticoids. During long-term therapy, a spectrum of immunosuppressive agents and biologicals can also be used in elderly patients. PMID- 22941457 TI - [Transitional care in rheumatology in Germany]. AB - Moving from child- to adult-centred services (transition) is a challenge for patients and health care professionals. Every second adolescent with a rheumatic disease will still have active disease that requires treatment when they are adults. A third of these patients do not arrive in adult-centered care, a consequence that is accompanied by negative consequences on the individual course of disease and contributes to socioeconomical costs. The present article describes the current situation: barriers for successful transfer and transition models are discussed. Transitional care and research must be improved in Germany. PMID- 22941461 TI - [Stroke prophylaxis by closure of a patent foramen ovale: CLOSURE I study]. PMID- 22941462 TI - Monitoring early first-grade reading progress: a comparison of two measures. AB - This study compared the validity of progress monitoring slope of nonsense word fluency (NWF) and word identification fluency (WIF) with early first-grade readers. Students (N = 80) considered to be at risk for reading difficulty were monitored with NWF and WIF on a 1-2 week basis across 11 weeks. Reading skills at the end of first grade were assessed using measures of passage reading fluency, real and pseudoword reading efficiency, and basic comprehension. Latent growth models indicated that although slope on both measures significantly predicted year-end reading skills, models including WIF accounted for more variance in spring reading skills than NWF, and WIF slope was more strongly associated with reading outcomes than NWF slope. Analyses of student growth plots suggested that WIF slope was more positively associated with later reading skills and discriminated more clearly between students according to successful or unsuccessful year-end reading outcomes. Although both measures may be used to monitor reading growth of at-risk students in early first grade, WIF may provide a clearer index of reading growth. Implications for data-based decision-making are discussed. PMID- 22941463 TI - Working memory in children with reading disabilities and/or mathematical disabilities. AB - Elementary school children with reading disabilities (RD; n = 17), mathematical disabilities (MD; n = 22), or combined reading and mathematical disabilities (RD+MD; n = 28) were compared to average achieving (AA; n = 45) peers on working memory measures. On all working memory components, 2 (RD vs. no RD) * 2 (MD vs. no MD) factorial ANCOVAs revealed clear differences between children with and without RD. Children with MD had lower span scores than the AA children on measures of the phonological loop and the central executive. A significant interaction effect between RD and MD was found only for listening recall and had a small, partial effect size. In addition, analyses showed that the best logistic regression model consisted of a visuospatial and a central executive task. The model significantly distinguished between the AA and clinical groups and between the MD and RD+MD groups. Evidence was found for domain-general working memory problems in children with learning disabilities. Management of working memory loads in structured learning activities in the classroom, at home, or during therapy may help these children to cope with their problems in a more profound manner. PMID- 22941464 TI - Enantioselective Michael addition of 3-aryloxindoles to a vinyl bisphosphonate ester catalyzed by a cinchona alkaloid derived thiourea catalyst. AB - A highly enantioselective Michael addition of 3-aryloxindole to vinyl bisphosphonate ester catalyzed by a cinchonidine derived thiourea catalyst has been investigated. The corresponding adducts, containing a chiral quaternary carbon center and geminal bisphosphonate ester fragment at the 3-position of the oxindole, were obtained in moderate to good yields (65-92%) and moderate to good enantioselectivities (up to 92% ee). PMID- 22941465 TI - Acromegalic arthropathy: current perspectives. PMID- 22941466 TI - Expression of ADAM8 and its clinical values in diagnosis and prognosis of hepatocellular carcinoma. AB - ADAM8 behaves as an active metalloprotease in vitro, hydrolyzing myelin basic protein and a variety of peptide substrates based on the cleavage sites of membrane-bound cytokines, growth factors, and receptors. Other studies have demonstrated overexpression of some ADAM family proteins in a variety of human tumors, but no report is available on the actual expression of ADAM8 and the correlation between clinicopathologic features and prognosis of hepatocellular carcinoma (HCC) patients. In this study, serum levels of ADAM8 were measured by ELISA in 126 patients with HCC, 50 patients with liver cirrhosis (LC), and 50 healthy individuals. The expression of ADAM8 in liver tissue was further studied using Western blotting in 126 patients with HCC and 50 with LC. The correlations between ADAM8 status and various clinicopathological parameters including survival were analyzed. Survival analysis was performed using the Kaplan-Meier method and Cox's proportional hazards model. The ELISA assay showed that the serum levels of ADAM8 in the HCC, LC, and healthy groups were 136.4 +/- 34.5, 64.2 +/- 20.1, and 63.2 +/- 22.7 U/ml, respectively. Analysis of variance was used for inter-group comparison, and differences were found between the HCC group and the other two groups (both P < 0.001), while no difference was found between the LC group and the healthy group (P = 0.365). Western blotting assay showed that ADAM8 protein expression was detected in 62.7 % (79/126) HCC and in 32 % (16/50) LC tissues. Further, ADAM8 expression was associated closely with serum AFP elevation, tumor size, histological differentiation, tumor recurrence, tumor metastasis, and tumor stage. Kaplan-Meier survival analysis showed that patients with ADAM8-positive tumors had a shorter postoperative survival time than those with ADAM8-negative tumors (P < 0.001). Multivariate analysis revealed that ADAM8 expression was an independent prognostic parameter for the overall survival rate of HCC patients. These findings provide evidence that the expression of ADAM8 serves as a poor prognostic biomarker for HCC. ADAM8 may be a potential target of antiangiogenic therapy for HCC. PMID- 22941467 TI - Anti-apoptotic effect of claudin-1 on TNF-alpha-induced apoptosis in human breast cancer MCF-7 cells. AB - Accumulating evidence reveals that aberrant expression of claudins manifests in various tumors; however, their biological functions are poorly understood. Here, we report on the elevated expression of claudin-1 in human breast cancer MCF-7 cells under tumor necrosis factor (TNF)-alpha treatment. Interestingly, the increased expression of claudin-1 contributes to an anti-apoptotic role in TNF alpha-induced apoptosis. In line with this, upon TNF-alpha stimulus, downregulation of claudin-1 by siRNA knockdown results in a significant increase in cleavage of caspase-8 and poly (ADP-ribose) polymerase, a decrease of cyclinD1 expression, and DNA fragmentation. Consistently, TdT-mediated dUTP nick end labeling assay also shows that loss of claudin-1 increases the susceptibility of MCF-7 cells to TNF-alpha-induced apoptosis. However, there is no obvious effect on the expression of Bax and p53 after the treatment aforementioned. In addition, TNF-alpha increases the amount of claudin-1 and the cytoplasmic accumulation of beta-catenin, while claudin-1 siRNA increases the amount of beta-catenin in the cell membrane as well as the amount of E-cadherin in the cytoplasm. In conclusion, our data reveal a novel role of claudin-1 in regulating apoptosis in MCF-7 cells. PMID- 22941468 TI - Differential gene expression of Wnt signaling pathway in benign, premalignant, and malignant human breast epithelial cells. AB - To gain insight into the role of gene expression alterations in breast cancer progression, we conducted a comprehensive gene expression analysis of a series of cell lines derived from MCF10A, which include benign MCF10A cells, premalignant AT, and malignant CA1a tumor cells. We analyzed gene expression variation using the Agilent Human Genome Oligo Microarray with the goal of identifying gene specific expression change events. In addition to a previously noted overexpression in oncogene MDM2, HRAS, and PCNA, our studies identified overexpression of Wnt signaling pathway in malignant breast cell lines. The Kaplan-Meier plot showed that high c-Myc expression in breast cancer was associated with tumor progression and the patient's poor survival. This study showed that the Wnt pathway has further provided a basis for the development of potential biomarker for breast cancer prognosis. PMID- 22941469 TI - Preclinical biodistribution and safety study of reduced expression in immortalized cells/Dickkopf-3-encoding adenoviral vector for prostate cancer gene therapy. AB - The biodistribution and safety of adenoviral vectors encoding the human REIC/Dkk 3 tumor suppressor gene (Ad-REIC) were examined in this preclinical study for in situ prostate cancer gene therapy. First, the in vitro apoptotic effects of Ad REIC in normal and cancer cells derived from the prostate and liver were examined. Significant apoptotic effects were observed at 100 MOI (multiplicity of infection) in prostate cancer cells (LNCaP, PC3) and hepatoma cells (HEP3B and HEPG2); however, no effects were seen in normal cells. To analyze the safety of intraprostatic Ad-REIC administration, the biodistribution and histology after Ad REIC injection were evaluated in various organs of normal male C57BL6 mice. In a supporting study, vector dissemination following intravenous injection of Ad-REIC into tail veins was determined. To evaluate whether Ad-REIC was present in the collected tissue specimens, human REIC gene detection was performed using DNA PCR. Intraprostatic treatment administered at lower doses showed vector biodistribution into the colon, urinary bladder and prostate. At higher doses, vector dissemination was observed in tissues more distant from the prostate, including the lung, thymus, heart, liver and adrenal gland. After intravenous injection of Ad-REIC, dissemination was observed in the liver and spleen. These results indicate that the biodistribution of Ad-REIC is determined by the dose and route of administration. Although acute inflammatory effects were observed in the prostate after intraprostatic administration at higher doses, no abnormal histological findings were noted in the other tissues, including those of intravenously treated mice. Regarding the safety of Ad-REIC administration, no deaths and no signs of toxicity or unusual behavior were observed in the mice in any treatment group. Based on these preclinical experiments, adenovirus-mediated in situ REIC/Dkk-3 gene therapy is considered to be safe for use as a treatment for human prostate cancer. PMID- 22941470 TI - Subclinical left and right ventricular systolic dysfunction in Behcet's disease: a combined tissue doppler and velocity vector imaging study. AB - BACKGROUND: Behcet's disease (BD) is a chronic inflammatory disease characterized by recurrent oral and genital ulcerations and ocular lesions. Subclinical cardiac involvement may develop in BD patients. We aimed to evaluate subclinical left ventricular (LV) and right ventricular (RV) systolic dysfunction in BD patients without any apparent cardiovascular disease. METHODS: We studied 50 BD patients (43.8 +/- 9.7 years, 59% men) and 30 healthy controls (45.4 +/- 8.2 years, 60% men). Conventional echocardiography, tissue Doppler imaging, and velocity vector imaging-based strain measurements were performed to analyze LV and RV systolic functions. RESULTS: LV isovolumic myocardial acceleration, peak systolic velocity during isovolumic contraction (isovolumic contraction velocity), were significantly lower, while myocardial performance index was increased in BD patients. RV peak systolic velocity, isovolumic myocardial acceleration, and isovolumic contraction velocity were also markedly lower in BD patients. LV and RV longitudinal peak systolic strain and strain rate were significantly lower in patients than in controls, demonstrating subclinical ventricular systolic dysfunction. CONCLUSIONS: Ventricular long-axis functions are important markers of myocardial contractility. Novel echocardiographic techniques may provide additional data for detecting early deterioration in ventricular systolic function in patients with BD. PMID- 22941471 TI - Impact of the sitagliptin alert on prescription of oral antihyperglycemic drugs in Japan. AB - BACKGROUND: Sitagliptin, the first of a new class of dipeptidyl peptidase-4 (DPP 4)-inhibitory oral antihyperglycemic drugs (OHDs), was introduced in Japan in December 2009. In April 2010 a safety alert was issued regarding the risk of serious hypoglycemic events when the drug is used in combination with high-dose sulfonylureas (SUs). OBJECTIVE: To investigate trends in prescription of OHDs before and after the launch of sitagliptin, and before and after the safety alert, in order to evaluate changes in the prescribing behavior of various groups of physicians in response to the safety alert. SETTING: Japan. METHOD: Prescription data from 6,500 institutions, randomly collected from 300 Japanese pharmacies were used. A cohort of 87,678 patients with 813,374 prescriptions for OHDs, among which 464,079 included SUs (glimepiride: 317,423), was collected from August 2009 to 31 December 2010. Logistic regression analysis was conducted. MAIN OUTCOME MEASURE: Prescription trends for sitagliptin and SUs, stratified by age, gender, types of prescribers and institutions. RESULTS: The safety alert recommending a reduction of SU dosing was well reflected in prescriptions issued after the alert (glimepiride dose reduction from 2.78 +/- 1.86 mg to 2.32 +/- 1.68), especially in prescriptions issued by diabetes specialists (from 2.27 +/- 1.81 mg to 1.87 +/- 1.47 mg). The dose of background SUs in patients who started sitagliptin early was higher (before alert: 2.70 +/- 1.80 mg, after alert: 2.51 +/- 1.74 mg) than in patients without experience of sitagliptin (2.12 +/- 1.57 mg). This may indicate that patients receiving high-dose SUs were selected for sitagliptin, and this might be a factor in the high frequency of hypoglycemia in the early launch phase of sitagliptin. CONCLUSION: The sitagliptin safety alert had a clear impact on prescribing behavior, but the impact appeared to depend on prescribers' backgrounds. Our findings should be helpful for developing a safer drug launching strategy for new classes of drugs in established categories. PMID- 22941472 TI - Estimating treatment effects in a two-arm parallel trial of a continuous outcome. AB - For a continuous outcome in a two-arm trial that satisfies normal distribution assumptions, we can transform the standardized mean difference with the use of the cumulative distribution function to be the effect size measure P(X < Y ). This measure is already established within engineering as the reliability parameter in stress-strength models, where Y represents the strength of a component and X represents the stress the component undergoes. If X is greater than Y, then the component will fail. In this paper, we consider the closely related effect size measure, [Formula: see text] This measure is also known as Somer's d, which was introduced by Somers in 1962 as an ordinal measure of association. In this paper, we explore this measure as a treatment effect size for a continuous outcome. Although the point estimates for lambda are easily calculated, the interval is not so readily obtained. We compare kernel density estimation and use of bootstrap and jackknife methods to estimate confidence intervals against two further methods for estimating P(X < Y ) and their respective intervals, one of which makes no assumption about the underlying distribution and the other assumes a normal distribution. Simulations show that the choice of the best estimator depends on the value of lambda, the variability within the data, and the underlying distribution of the data. PMID- 22941473 TI - Druggability of the CK2 inhibitor CX-4945 as an anticancer drug and beyond. AB - Casein kinase 2 (CK2) is involved in multiple cellular processes such as proliferation, apoptosis, and cell cycle. In particular, its over-expression in human cancers is associated with angiogenesis and tumor progression. As a first orally bioavailable small molecule inhibitor of CK2, CX-4945 exerts anti proliferative activity in human cancer cells by inhibiting the cell cycle and the PI3K/Akt signaling pathway. Additionally, CX-4945 reduces angiogenesis via blockade of hypoxia-inducible factor-1alpha transcription and suppresses the inflammatory interleukin-6 production in human breast cancer cells. These effects are supported by results from mouse xenograft model investigations. Here, we discuss the druggability of CX-4945 and its potential to be developed as an anti cancer drug in clinical trials. PMID- 22941474 TI - Roles of toll-like receptors in cancer: a double-edged sword for defense and offense. AB - Toll-like receptors (TLRs) belong to a class of pattern-recognition receptors that play an important role in host defense against pathogens by recognizing a wide variety of pathogen-associated molecular patterns (PAMPs). Besides driving inflammatory responses, TLRs also regulate cell proliferation and survival by expanding useful immune cells and integrating inflammatory responses and tissue repair processes. TLR signaling, which is centrally involved in the initiation of both innate and adaptive immune responses, has been thought to be restricted to immune cells. However, recent studies have shown that functional TLRs are expressed not only on immune cells, but also on cancer cells, thus implicating a role of TLRs in tumor biology. Increasing bodies of evidence have suggested that TLRs act as a double-edged sword in cancer cells because uncontrolled TLR signaling provides a microenvironment that is necessary for tumor cells to proliferate and evade the immune response. Alternatively, TLRs can induce an antitumor immune response in order to inhibit tumor progression. In this review, we summarize the dual roles of TLRs in tumor cells and, more importantly, delve into the therapeutic potential of TLRs in the context of tumorigenesis. PMID- 22941475 TI - Small molecule inhibitors of the hedgehog signaling pathway for the treatment of cancer. AB - Over the past decade, the Hedgehog signaling pathway has attracted considerable interest because the pathway plays important roles in the tumorigenesis of several types of cancer as well as developmental processes. It has also been observed that Hedgehog signaling regulates the proliferation and self-renewal of cancer stem cells. A great number of Hedgehog pathway inhibitors have been discovered through small molecule screens and subsequent medicinal chemistry efforts. Among the inhibitors, several Smo antagonists have reached the clinical trial phase. It has been proved that the inhibition of Hedgehog signaling with Smo antagonists is beneficial to cancer patients with basal cell carcinoma and medulloblastoma. In this review, we provide an overview of Hedgehog pathway inhibitors with focusing on the preclinical and/or clinical efficacy and molecular mechanisms of these inhibitors. PMID- 22941476 TI - Novel brominated quinoline and pyrimidoquinoline derivatives as potential cytotoxic agents with synergistic effects of gamma-radiation. AB - New quinoline derivatives 6, 7 and 19, pyrimidoquinoline derivatives 8-16 and triazolopyrimidoquinoline derivatives 17 and 18 bearing a bromo-substituent were synthesized starting from 3-(4-Bromophenylamino)-5,5-dimethylcyclohex-2-enone 3. All the newly synthesized compounds were evaluated for their in vitro anticancer activity against human breast cancer cell line (MCF7). Compounds 9, 11, 17 and 18 showed IC(50) values (36.4, 39.7, 39.02 and 36.4 MUM, respectively) comparable to that of the reference drug doxorubicin (IC(50) = 32.02 MUM). On the other hand, compound 6, 14 and 19 exhibited better activity than doxorubicin with IC(50) values of 8.5, 23.5 and 23.7 MUM. Additionally, the most potent compounds 6, 14 and 19 were evaluated for their ability to enhance the cell killing effect of gamma-radiation. PMID- 22941477 TI - Antiviral activity of Aloe hijazensis against some haemagglutinating viruses infection and its phytoconstituents. AB - Evaluation of the antiviral activities of flowers, flower-peduncles, leaves, and roots of Aloe hijazensis against haemagglutinating viruses of avian paramyxovirus type-1 (APMV-1), avian influenza virus type A (AI-H5N1), Newcastle disease virus (NDV), and egg-drop syndrome virus (EDSV) in specific pathogen free (SPF) chicken embryos were carried out. Extract of the flowers and leaves showed relatively higher activity than the extracts of other plant parts. Thirteen compounds were isolated from both the flowers and flower-peduncles of A. hijazensis. The isolated compounds were classified into: five anthraquinones; ziganein, ziganein 5-methyl ether, aloesaponarin I, chrysophanol, aloe-emodin, one dihydroisocoumarin; feralolide, four flavonoids; homoplantaginin, isoorientin, luteolin 7-glucuronopyranoside, isovitexin, one phenolic acid; p-coumaric acid, the anthrone; barbaloin together with aloenin. Eleven compounds were attributed to the flowers and seven to the flower-peduncles. Homoplantaginin and luteolin 7 glucuronopyranoside are reported here for the first time from Aloe spp. To the best of our knowledge, this is the first report on the chemical composition and biological activity of those plant parts. PMID- 22941478 TI - Design and synthesis of new 8-anilide theophylline derivatives as bronchodilators and antibacterial agents. AB - Theophylline derivatives have long been recognized as potent bronchodilators for the relief of acute asthma. Recently, it was found that bacterial infection has a role in asthma pathogenesis. The present work involves the design and synthesis of 8-substituted theophylline derivatives as bronchodilators and antibacterial agents. The chemical structures of these compounds were elucidated by IR, (1)H NMR, mass spectrometry, and elemental analyses. The bronchodilator activity was evaluated using acetylcholine-induced bronchospasm in guinea pigs, and most of the compounds showed significant anti-bronchoconstrictive activity in comparison with standard aminophylline. In addition, the antibacterial activity of all the target compounds was investigated in vitro against Gram-positive and Gram negative bacteria using ampicillin as a reference drug. Results showed that some of the tested compounds possessed significant antibacterial activity. A pharmacophore model was computed to obtain useful insight into the essential structural features of bronchodilator activity. A structure activity relationship was also discussed. PMID- 22941479 TI - Design and synthesis of novel 1,4-benzodiazepine derivatives and their biological evaluation as cholinesterase inhibitors. AB - A new series of 1,4-benzodiazepine-2,5-dione structurally related to cyclopenin has been synthesized. The new compounds were assayed in vivo and in vitro for their ability to inhibit acetylcholinesterase enzyme and were found to have potent reversible anticholinesterase activity when tested in vitro for isolated frog rectus abdominis and guinea pig ileum in addition to increasing brain cholinesterase level in rats when percentage inhibition were tested in vivo, moreover compounds 5a, 5b, 5c and 5g were the most active. LD(50) was performed for these derivatives and they displayed high safety margin. PMID- 22941480 TI - Inhibition of PCAF histone acetyltransferase and cytotoxic effect of N acylanthranilic acids. AB - Small molecule HAT inhibitors are useful tools to unravel the role of histone acetyltransferases (HATs) in the cell and have relevance for oncology. We synthesized a series of N-acylanthranilic acids (11-16) and of N-acyl-5 hydroxyanthranilic acids (17-22) bearing C6, C8, C10, C12, C14, along with C16 acyl chain at the 2-amino position of anthranilic acid or 5-hydroxyanthranilic acid. Enzyme inhibition of these compounds was investigated, using in vitro PCAF HAT assays. All synthesized compounds (65-76%) showed similar inhibitory activity to anacardic acid (68%) at 100 MUM. The cytotoxicity, against one normal cell line (HSF) and eight cancer cell lines (HT-29, HCT-116, MDA-231, A-549, Hep3B, Caski, HeLa and Caki), were evaluated by the SRB method. PMID- 22941481 TI - Antimicrobial aflatoxins from the marine-derived fungus Aspergillus flavus 092008. AB - A new aflatoxin, aflatoxin B(2b) (1), together with six known compounds, were isolated from the marine-derived fungus Aspergillus flavus 092008 endogenous with the mangrove plant Hibiscus tiliaceus (Malvaceae). The structure of 1 was determined by the spectroscopic and chemical methods. Compound 1 exhibited a moderate antimicrobial activity against Escherichia coli, Bacillus subtilis and Enterobacter aerogenes, with MIC values of 22.5, 1.7 and 1.1 M, respectively. Compound 1 also showed a weak cytotoxicity against A549, K562 and L-02 cell lines, with IC(50) values of 8.1, 2.0 and 4.2 M, respectively. The results showed that hydration and hydrogenation of (8)-double bond significantly reduces the cytotoxicity of aflatoxins, while the esterification at C-8 increases the cytotoxicity. PMID- 22941482 TI - N-methylthioureas as new agonists of retinoic acid receptor-related orphan receptor. AB - Thirty two thiourea derivatives were prepared and their agonistic activities on the retinoic acid receptor-related orphan receptor alpha (RORalpha) were evaluated. The replacement of the 3-allyl-2-imino-thiazolidin-4-one moiety of the lead compound CGP52608 (1) with various functional group substituted aromatic rings, improved the agonistic activity of RORalpha. Among the prepared derivatives, 1-methyl-3-(4-phenoxy-benzyl)-thiourea (32) showed 2.6-fold higher agonistic activity than CGP52608 in the RORalpha-activation assay. PMID- 22941483 TI - In vivo sedative and gastroprotective activities of Salvia plebeia extract and its composition of polyphenols. AB - Animal experiments were performed to develop Salvia plebeia (Labiatae) as a medicinal herb with sedative and gastroprotective activities; the former activity was measured using a pentobarbital-induced assay and the latter activity was measured in two gastric lesion-induced assays (HCl/EtOH-induced and indomethacin/bethanechol-induced assays) in mice. The MeOH extract and its EtOAc fraction were effective, although the former was less active than the latter. Rosmarinic acid (RA) isolated from S. plebeia was active in the same method at 10 and 20 mg/kg (p.o.). HPLC quantification demonstrated that RA comprised the largest proportion (28.5% of the MeOH extract, 33.0% of EtOAc extract; 4.46% of dry weight) of S. plebeia. The contents of five other compounds were much less than that of RA, although the contents of the three glycosides, 6-hydroxyluteolin 7-O-glucoside (0.28% of dry weight), cynaroside (0.35%) and nepitrin (0.43%) were higher than those of the two aglycones, quercetin (0.024%) and eupatilin (0.058%). The HPLC method was validated in terms of linearity, precision, accuracy and reproducibility. These results suggest that the main polyphenol, RA, plays a major role in the sedative and gastroprotective effects of S. plebeia. PMID- 22941484 TI - Design and synthesis of new mitomycin dimers containing a seven-membered cyclic disulfide and a diol linkers. AB - We report the design and synthesis of two new mitomycin dimers, 7-N,7'-N'-(1",2" dithiepanyl-3",7"-dimethylenyl)bismitomycin C (8) and 7-N,7'-N'-(2",6"-dihydroxy 1",7"-heptanediyl)bismitomycin C (9). Mitomycins 8 and 9 are dimers connected by a seven-membered cyclic disulfide (a 1,2-dithiepane) and a 2,6-dihydroxyheptane linkers, respectively. Mitomycin 8 was designed to undergo efficient nucleophilic activation and following alkylation to give DNA adducts such as DNA interstrand cross-link (DNA ISC) adducts. The key moiety in 8 is a seven-membered cyclic disulfide linker that can generate two thiol groups in a molecule through disulfide cleavage. The two thiols can serve as probes to activate two mitomycin rings by intramolecular cyclization to quinone rings. The mitomycin 8 was synthesized using mitomycin A (1) and the key intermediate, cyclic disulfide 11 that was prepared through a nine-step synthetic sequence from 1,6-heptadiene (12). The diol mitomycin 9 was also synthesized from 1 and diamine salt 15. PMID- 22941485 TI - Anti-inflammatory effect of sargachromanol G isolated from Sargassum siliquastrum in RAW 264.7 cells. AB - A study on the anti-inflammatory activity of brown alga Sargassum siliquastrum led to the isolation of sargachromanol G (SG). In this study, the anti inflammatory effect and the action mechanism of SG have been investigated in murine macrophage cell line RAW 264.7. SG dosedependently inhibited the production of inflammatory markers [nitric oxide (NO), inducible nitric oxide synthase (iNOS), prostaglandin E(2) (PGE(2)), and cyclooxygenase-2 (COX-2)] and pro-inflammatory cytokines [tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-1beta, and IL-6] induced by LPS treatment. To further elucidate the mechanism of this inhibitory effect of SG, we studied LPS-induced nuclear factor kappaB (NF-kappaB) activation and mitogen-activated protein kinases (MAPKs) phosphorylation. SG inhibited the phosphorylation IkappaB-alpha and NF-kappaB (p65 and p50) and MAPK (ERK1/2, JNK, and p38) in a dose dependent manner. These results suggest that the anti-inflammatory activity of SG results from its modulation of pro-inflammatory cytokines and mediators via the suppression of NF kappaB activation and MAPK phosphorylation. PMID- 22941486 TI - Erythrocyte-mediated delivery of pravastatin: in vitro study of effect of hypotonic lysis on biochemical parameters and loading efficiency. AB - Exposure of erythrocytes to hypotonic lysis creates pores in the cell membrane, through which pravastatin can enter and become trapped, after resealing them with a suitable buffer. We investigated the effects of tonicity, incubation time and drug concentration on drug loading into erythrocytes. Furthermore, we investigate the effects of pravastatin on erythrocyte oxidative stress markers and osmotic fragility behavior. Encapsulation was achieved using buffer solutions of different tonicities (0.5, 0.6 and 0.7% NaCl) and different drug concentrations (2, 4, 8 and 10 mg/mL) for a range of incubation times (15, 30, 60 and 120 min). The results demonstrated that controlled hypotonic lysis could entrap pravastatin in human erythrocytes, with acceptable loading parameters. The highest loading (34%) was achieved at 0.6% NaCl and 10 mg/mL pravastatin for 60 min incubation. At this pravastatin concentration, oxidative stress markers were similar to those seen in controls, and fragility and hematological parameters were unaffected in drug-loaded erythrocytes. These results indicate that the loading process and pravastatin concentration had no deleterious effects on the structure of pravastatin-loaded erythrocytes, suggesting that they may therefore have a similar life span to normal cells. Pravastatin-loaded erythrocytes may thus provide an effective extended-release-delivery system for pravastatin. PMID- 22941487 TI - Differential changes in functional activity of organic cation transporters in rats with uranyl nitrate-induced acute renal failure. AB - We studied the impact of experimental kidney failure on the pharmacokinetics of a model organic cation and investigated the underlying mechanism(s) of the organic cation transporters. The systemic pharmacokinetics and tissue distribution of triethylmethylammonium (TEMA), a model organic cation, were characterized after intravenous doses of 0.3-30 MUmol/kg in rats with or without uranyl nitrate induced acute renal failure (UN-ARF). To study the effect of endogenous substrates in plasma from UN-ARF rats on organic cation transport, rOCT- or rOCT2 dependent uptake of tetraethylammonium (TEA) was studied in rOCT1-transfected or rOCT2-transfected LLC-PK1 cells, respectively. As a result, the AUC for TEMA was increased, probably because of decreased total clearance, and the tissue-to plasma concentration ratio (T/P ratio) of TEMA was unchanged in the liver but decreased significantly in the kidneys of UN-ARF rats. In vitro, the uptake of TEA was decreased significantly by adding UN-ARF plasma, compared with control plasma, in rOCT2-overexpressing LLC-PK1 cells, but not in rOCT1-overexpressing LLC-PK1 cells. These observations suggest that the induction of UN-ARF leads to an accumulation of endogenous organic cation(s), probably rOCT2 substrate(s), in the plasma, thereby affecting the TEMA pharmacokinetics and distribution to the kidneys in rats. PMID- 22941488 TI - High performance liquid chromatography used for quality control of Achyranthis Radix. AB - To establish a standard of quality control and to identify reliable Achyranthis Radix, three phytoecdysones including ecdysterone (1), 25R-inokosterone (2) and 25S-inokosterone (3) were determined by quantitative HPLC/UV analysis. Three phytoecdysones were separated with an YMC J'sphere ODS C(18) column (250 mm * 4.6 mm, 4 MUm) by isocratic elution using 0.1% formic acid in water and acetonitrile (85:15, v/v%) as the mobile phase. The flow rate was 1.0 mL/min and the UV detector wavelength was set at 245 nm. The standards were quantified by HPLC/UV from Achyranthes bidentata Blume and Achyranthes japonica Nakai, as well as Cyathula capitata Moq. and Cyathula officinalis Kuan, which are of a different genus but are comparative herbs. The method was successfully used in the analysis of Achyranthis Radix of different geographical origin or genera with relatively simple conditions and procedures, and the assay results were satisfactory for linearity, recovery, precision, accuracy, stability and robustness. The HPLC analytical method for pattern recognition analysis was validated by repeated analysis of eighteen A. bidentata Blume samples and ten A. japonica Nakai samples. The results indicate that the established HPLC/UV method is suitable for quantitation and pattern recognition analyses for quality evaluation of Achyranthis Radix. PMID- 22941489 TI - Enhancement of solubility and dissolution rate of cryptotanshinone, tanshinone I and tanshinone IIA extracted from Salvia miltiorrhiza. AB - Cryptotanshinone, tanshinone I and tanshinone IIA are three major components in the extract of Salvia miltiorrhiza with pharmacological significance. However, their effective utilization is limited due to poor water solubility and bioavailability. Solid dispersion (SD) of the extract of Salvia miltiorrhiza was prepared to enhance solubility and dissolution of the three major components. Various carriers were screened for SD preparation by conventional solvent method. Dissolution of the components from selected SD systems was compared with commercial tablets of the extract from Salvia miltiorrhiza. The solubility of three components viz., cryptotanshinone, tanshinone I and tanshinone IIA, after forming SD with either of povidone K-30 (PVP K-30) or poloxamer 407, exhibited enhanced solubility in pH 6.8 buffer. Dissolution test revealed that the amount of three components released was higher from SD tablets as compared to the commercial tablets. Pharmacokinetic profile was evaluated using cryptotanshinone as a representative compound. AUC of cryptotanshinone was significantly increased when administered as a solid dispersion. PMID- 22941490 TI - Efficacy of sesamol on plasma and tissue lipids in isoproterenol-induced cardiotoxicity in Wistar rats. AB - Myocardial infarction is the leading cause of death all over the world. Sesamol is a potent phenolic antioxidant contained only in processed sesame oil and possesses potent chemopreventive, antimutagenic, antihepatotoxic and antioxidation properties. This study was undertaken to investigate the effect of sesamol on plasma and tissue lipid profiles in isoproterenol (ISO) - induced rats. Myocardial infarction was induced in adult male albino rats of the Wistar strain, weighing 180-200 g, by administration of isoproterenol (85 mg/kg of body weight), subcutaneously for 2 consecutive days. Sesamol dissolved in saline (0.9% NaCl) was administered intraperitoneally once in a day in the morning for 7 days. Increased levels of total cholesterol, phospholipids, triglycerides and free fatty acids in the plasma and the decreased levels of phospholipids in tissues were observed in ISO-induced rats. Very low density lipoprotein cholesterol (VLDL C) and low density lipoprotein cholesterol (LDL-C) increased while high density lipoprotein cholesterol (HDL-C) decreased in the plasma of ISO-induced rats. Administration of sesamol (50, 100 and 200 mg/kg of body weight) improved the above changes and brought towards normal level. The protective role of sesamol against isoproterenol-induced myocardial infarction was further confirmed by histopathological examination. These results suggest that sesamol has antihyperlipidaemic effect against cardiotoxicity. PMID- 22941491 TI - Vasodilation effect of 2-benzyl-5-hydroxy-6-methoxy-3, 4-dihydroisoquinolin-1 one. AB - A 2-Benzyl-5-hydroxy-6-methoxy-3, 4-dihydroisoquinolin-1-one (ZC2) is a newly synthesized isoquinolinone compound. Its effect on vasodilation was evaluated in the present study. Isometric tension of rat artery rings was recorded by a sensitive myography system in vitro. The results showed that ZC2 relaxed rat mesenteric arteries pre-contracted by KCl, phenylephrine and 9, 11- dideoxy- 11alpha, 9alpha-epoxymethano-prostaglandin F2alpha (U46619), and abdominal aorta pre-contracted by KCl in a concentration-dependent manner. The ZC2-induced vasodilation was not affected by an endothelium denudation. ZC2 rightwards shifted the concentration-contraction curves, induced by KCl, phenylephrine, and 5-hydroxytryptamine (5-HT) in a non-parallel manner, which suggests that the vasodilation effects are most likely via voltage-dependent calcium channel (VDCC) and receptor-operated calcium channel (ROCC). Moreover, in Ca(2+)-free medium, ZC2 concentration-dependently depressed the vasoconstrictions induced by phenylephrine and CaCl(2), and decreased a contractile response induced by caffeine, which indicates a role of extracellular Ca(2+) influx inhibition through VDCC and ROCC, and intracellular Ca(2+) release from Ca(2+) store via the ryanodine receptors. Glibenclamide did not affect the vasodilation induced by ZC2, suggesting that ATP sensitive potassium channel is not involved in the vasodilation. The results indicate that ZC2 induces vasodilation by inhibiting the VDCC and ROCC, and receptormediated Ca(2+) influx and release. The inhibition of intracellular Ca(2+) release may be mediated via the ryanodine receptors. PMID- 22941492 TI - The therapeutic effects of tectorigenin on chemically induced liver fibrosis in rats and an associated metabonomic investigation. AB - The aim of this study was to investigate the effects of tectorigenin on chemically induced liver fibrosis in rats. Liver fibrosis was induced in rats with carbon tetrachloride, a diet high in fat, cholesterol and alcohol in the drinking water. Our results indicate that tectorigenin treatment significantly inhibited the increases in the activities of alanine aminotransferase (ALT), aspartate aminotransferase (AST) and the increases in the serum levels of hyaluronate (HA), laminin (LN) and procollagen III N-terminal peptide (PIIIP); tectorigenin treatment also significantly inhibited the increases in the amount of collagen in the livers of the fibrogenic rats. Chemically induced liver fibrosis caused a drop in the serum albumin concentration and a decrease in the ratio of albumin to globulin (A/G). Tectorigenin caused a remarkable increase at a dose of 30 mg/kg, but only a slight increase at the lower doses. Tectorigenin was also able to inhibit the increase in the liver lipid peroxidation (LPO), as well as the decrease in the activities of liver superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px), caused by liver fibrosis. In addition, we present a related metabolic profile determined, using a (1)H NMR spectroscopy and multivariate pattern recognition techniques. The results were consistent with the pathological examination, liver function analysis and liver fibrosis marker analysis. Furthermore, tectorigenin does not cause acute toxicity. PMID- 22941493 TI - Promotion effect of acankoreoside J, a lupane-triterpene in Acanthopanax koreanum, on hair growth. AB - This study was conducted to evaluate the effect of Acanthopanax koreanum and acankoreoside J from A. koreanum on the promotion of hair growth. When immortalized rat vibrissa dermal papilla cells were treated with extract of A. koreanum leaves, the proliferation of dermal papilla cells significantly increased. In particular, acankoreoside J among several components, isolated from A. koreanum leaves, markedly promoted the proliferation of the dermal papilla cells. When rat vibrissa follicles were treated with an acankoreoside J, the hair fiber lengths of the vibrissa follicles increased significantly. We further investigated beta-catenin pathway and cell cycle regulation with respect to the effect of acankoreoside J on the proliferation of the dermal papilla cells. Treatment with acankoreoside J results in an increase of nuclear beta-catenin level, and up-regulation of cyclin D1, cyclin E and CDK2, whereas, the expression of p27(kip1) was down-regulated in the dermal papilla cells. Taken together, these results suggest that acankoreoside J, a lupane-triterpene of A. koreanum, has the potential of promoting hair growth by promoting cell cycle progression of the dermal papilla cells, through the increase of nuclear beta-catenin, along with the up-regulation of cyclin D1, cyclin E and CDK2, and down-regulation of p27(kip1). PMID- 22941494 TI - Assessment of heavy metal and PAH exposure in largemouth bass (Micropterus salmoides) in the Reedy River watershed, South Carolina, USA: a multi-season assessment of metallothionein and bile fluorescence. AB - Biomarkers can be used as tools to help determine ecological exposure in watershed assessments. In the present study, metallothionein and fixed wavelength bile fluorescence for two-, four-, and five-ring hydrocarbons were used as biomarkers of exposure in largemouth bass (Micropterus salmoides) in the Reedy River watershed located in South Carolina, USA. Fish were sampled from three impoundments and a reference site over three seasons in the same year. Biomarker endpoints were compared to chemical concentrations at each site during each season. Results indicated that despite elevated concentrations of hydrocarbons being present in sediments, the hydrocarbons did not appear to be bioavailable based on bile fluorescence analysis. Bile fluorescence analysis also indicated that the hydrocarbons detected in this watershed were likely of petrogenic origin. Significantly elevated sediment concentrations of Cd, Cr, Cu, Pb, Ni, Ag, Zn, and metallothionein were found in one impoundment, Lake Conestee, compared with the reference site, indicating both the presence and bioavailability of these metals. Seasonal variability of bile fluorescence was limited; however, metallothionein showed elevated concentrations in the spring and summer compared with fall. PMID- 22941495 TI - Polyarteritis nodosa: a case presenting with renal mass. AB - An adolescent girl was hospitalized due to fever and abdominal flank pain. A left renal haematoma was detected on magnetic resonance imaging. Renal angiography demonstrated multiple microaneurysms at both hepatic arteries, intrarenal segments of the bilateral renal arteries, and inferior lobar segment of the left pulmonary artery, which is consistent with the diagnosis of polyarteritis nodosa. Vasculitic syndromes should be considered in patients with visceral haemorrhage. PMID- 22941496 TI - Ambulatory postoperative ward-based epidural analgesia: a retrospective review of 1,147 cases. AB - BACKGROUND: A retrospective review of 1,147 patients who received epidural analgesia (EA) in surgical wards from January 2008 to December 2009 to determine the prevalence of early ambulation and assess the efficacy and safety of EA for postoperative pain management. AIM: Outcome measures were the prevalence of ambulation, pain scores at rest/movement and adverse events. METHODS: Patients (N = 1,147) who received postoperative EA between January 2008 and December 2009 were included. Motor function was assessed using the Bromage scale. Ambulation was defined as: Day 1: mobilisation from bed to chair, walking on the spot, taking a few steps, thereafter walks of increasing duration and distance at least twice daily. Pain scores were measured using the verbal numerical rating scale (0 10), <=4 signifying successful analgesia. Daily assessments and data recordings were performed by clinical nurse specialists (CNSs) using standardised charts. Data collected included patient demographics, surgical procedure, ambulation achieved, pain scores at rest/movement and adverse events. The data was analysed using Microsoft Excel((r)). RESULTS: The prevalence of ambulation was 88% and this was maintained for the duration of EA. Ninety-eight percent of patients reported pain scores of <=4 at rest and 88% reported pain scores of <=4 on movement. Adverse events included motor block 12%, nausea 9%, hypotension 8%, catheter dislodgement 3.8%, leakage from insertion site 1.6%, decubitus ulcers 0.58% and infection 0.001%. Mean duration of EA was 4 days. CONCLUSIONS: Ward based EA facilitates early ambulation, provides excellent postoperative pain relief and is associated with low prevalence of adverse events. PMID- 22941497 TI - Vitamin D deficiency is associated with increased left ventricular mass and diastolic dysfunction in children with chronic kidney disease. AB - Cardiovascular disease currently is the leading cause of morbidity and mortality among patients with chronic kidney disease (CKD). Abnormalities in arterial compliance, increased left ventricular mass, and diastolic dysfunction are some of the recognized cardiovascular complications observed in these patients. This study explored the relationship between various parameters of calcium-phosphorus metabolism including 25-hydroxy vitamin D and cardiovascular structure and function in pediatric patients with CKD. This cross-sectional study was conducted using a cohort of 34 children with CKD who had no history of underlying congenital or structural cardiac disease. Two-dimensional echocardiography was used to measure the left ventricular mass index (LVMI), E/A ratio, E', E/E' ratio, and myocardial performance index (MPI). The augmentation index (AI), derived via radial artery tonometry, was used as an indirect measure of central aortic stiffness. Serum biochemical markers of calcium-phosphorus metabolism were simultaneously measured. Univariate analysis showed that LVMI correlated with 25 hydroxy vitamin D (r = -0.54; p < 0.05), systolic blood pressure (SBP) (r = 0.36; p < 0.05), and AI (r = 0.26; p < 0.05). Serum-intact parathyroid hormone (PTH) levels correlated with the E/E' ratio (r = 0.63; p < 0.05) and E' (r = -0.61; p < 0.05). Multiple regression analysis showed that 25-hydroxy vitamin D and SBP were independent predictors of increased LVMI and that PTH was an independent predictor of diastolic dysfunction. This is the first study investigating pediatric patients with CKD that suggests an etiology of nutritional vitamin D deficiency associated with increased left ventricular mass and diastolic dysfunction. The cardiovascular changes observed are not easily reversible. Hence, early preventive therapy with vitamin D supplementation is advocated. PMID- 22941498 TI - Helicobacter pylori cagL amino acid polymorphisms and its association with gastroduodenal diseases. AB - CagL is a pilus protein of Helicobacter pylori that interacts with host cellular alpha5beta1 integrins through its arginine-glycine-aspartate (RGD) motif, guiding proper positioning of the T4SS and translocation of CagA. Deletion or sequence variations of cagL significantly diminished the ability of H. pylori to induce secretion of IL-8 by the host cell. Therefore, this study was undertaken to investigate the association of cagL and its amino acid sequence polymorphisms with gastric cancer (GC), peptic ulcer disease (PUD), and non-ulcer dyspepsia (NUD) as there are no such studies from India. In total, 200 adult patients (NUD 120, PUD 30, GC 50) who underwent an upper gastrointestinal endoscopy were enrolled. H. pylori infection was diagnosed by rapid urease test, culture, histopathology, and PCR. The collected isolates were screened for cagL genotype by PCR and assessed for amino acid sequence polymorphisms using sequence translation. The prevalence of H. pylori infection in study population was 52.5%. Most of the isolates were cagL genopositive (86.6%), and all had RGD motif in their amino acid sequences. D58 and K59 polymorphisms in cagL-genopositive strains were significantly higher in GC patients (P < 0.05). Combined D58K59 polymorphism was associated with higher risk of GC (3.8-fold) when compared to NUD. In conclusion, H. pylori cagL amino acid polymorphisms such as D58K59 are correlated with a higher risk of GC in the Indian population. Further studies are required to know the exact role of particular cagL amino acid polymorphisms in the pathogenicity of H. pylori infection. PMID- 22941499 TI - A linear/nonlinear characterization of resting state brain networks in FMRI time series. AB - Resting state functional connectivity studies in fMRI have been used to demonstrate that the human brain is organized into inherent functional networks in the absence of stimuli. The basis for this activity is based on the spontaneous fluctuations observed during rest. In the present study, the time series generated from these fluctuations were characterized as either being linear or nonlinear based on the Delay Vector Variance method, applied through an examination of the local predictability of the signal. It was found that the default mode resting state network is composed of relatively more linear signals compared to the visual, task positive visuospatial, motor, and auditory resting state network time series. Also, it was shown that the visual cortex resting state network is more nonlinear relative to these aforementioned networks. Furthermore, using a histogram map of the nonlinearly characterized voxels for all the subjects, the histogram map was able to retrieve the peak intensity in four out of six resting state networks. Thus, the findings may provide the basis for a novel way to explore spontaneous fluctuations in the resting state brain. PMID- 22941500 TI - Influence of a silastic ECoG grid on EEG/ECoG based source analysis. AB - The simultaneous evaluation of the local electrocorticogram (ECoG) and the more broadly distributed electroencephalogram (EEG) from humans undergoing evaluation for epilepsy surgery has been shown to further the understanding of how pathologies give rise to spontaneous seizures. However, a well-known problem is that the disruption of the conducting properties of the brain coverings can render simultaneous scalp and intracranial recordings unrepresentative of the habitual EEG. The ECoG electrodes for measuring the potential on the surface of the cortex are commonly embedded into one or more sheets of a silastic material. These highly resistive silastic sheets influence the volume conduction and might therefore also influence the scalp EEG and ECoG measurements. We carried out a computer simulation study to examine how the scalp EEG and the ECoG, as well as the source reconstruction therefrom, employing equivalent current dipole estimation methods, are affected by the insulating ECoG grids. The finite element method with high quality tetrahedral meshes, generated using a constrained Delaunay tetrahedralization meshing approach, was used to model the volume conductor that incorporates the very thin ECoG sheets. It is shown that the insulating silastic substrate of the ECoG grids can have a large impact on the scalp potential and on source reconstruction from scalp EEG data measured in the presence of the grids. The reconstruction errors are characterized with regard to the location of the source in the brain and the mislocalization tendency. In addition, we found a non-negligible influence of the insulating grids on ECoG based source analysis. We conclude, that the thin insulating ECoG sheets should be taken into account, when performing source analysis of simultaneously measured ECoG and scalp EEG data. PMID- 22941501 TI - Social inclusion enhances biological motion processing: a functional near infrared spectroscopy study. AB - Humans are especially tuned to the movements of other people. Neural correlates of this social attunement have been proposed to lie in and around the right posterior superior temporal sulcus (STS) region, which robustly responds to biological motion in contrast to a variety of non-biological motions. This response persists even when no form information is provided, as in point-light displays (PLDs). The aim of the current study was to assess the ability of functional near-infrared spectroscopy (fNIRS) to reliably measure brain responses to PLDs of biological motion, and determine the sensitivity of these responses to interpersonal contextual factors. To establish reliability, we measured brain activation to biological motion with fNIRS and functional magnetic resonance imaging (fMRI) during two separate sessions in an identical group of 12 participants. To establish sensitivity, brain responses to biological motion measured with fNIRS were subjected to an additional social manipulation where participants were either socially included or excluded before viewing PLDs of biological motion. Results revealed comparable brain responses to biological motion using fMRI and fNIRS in the right supramarginal gyrus. Further, social inclusion increased brain responses to biological motion in right supramarginal gyrus and posterior STS. Thus, fNIRS can reliably measure brain responses to biological motion and can detect social experience-dependent modulations of these brain responses. PMID- 22941502 TI - Optimizing lavage during knee arthroscopy: a three-dimensional MRI study. AB - PURPOSE: To determine the best positioning and the resulting fluid flow patterns inside the knee during arthroscopy, reducing the surgical morbidity associated with the arthroscopic irrigation and debridement of a septic knee joint. MATERIALS AND METHODS: Three-dimensional MRI, using an MRI-compatible human cadaveric knee arthroscopic model, generated fluid flow diagrams and velocity vector data. This was analyzed for six different arthroscopic configurations and at six different locations within the knee joint. RESULTS: At any one static arthroscopic position, fluid flow velocity differed at the various locations in the knee, often with statistically significantly greater flow at one location over another. In general, flow was greatest at the location at which the inflow cannula terminated and preferentially flowed directly to the outflow cannula location, neglecting spaces in the knee that were not on this direct path. Three portal arthroscopy provided no benefit over two-portal arthroscopy. CONCLUSION: To maximize arthroscopic lavage throughout all compartments in the knee, the arthroscopist must individually enter each space in the knee. Static arthroscopy in the setting of knee sepsis may lead to inadequate flow in certain areas of the knee and may lead to treatment failure. Three-portal arthroscopy does not improve lavage efficiency. PMID- 22941503 TI - Fungal pathogenesis: C. albicans makes an entrance. PMID- 22941504 TI - Distribution, formation and regulation of gas vesicles. AB - A range of bacteria and archaea produce intracellular gas-filled proteinaceous structures that function as flotation devices in order to maintain a suitable depth in the aqueous environment. The wall of these gas vesicles is freely permeable to gas molecules and is composed of a small hydrophobic protein, GvpA, which forms a single-layer wall. In addition, several minor structural, accessory or regulatory proteins are required for gas vesicle formation. In different organisms, 8-14 genes encoding gas vesicle proteins have been identified, and their expression has been shown to be regulated by environmental factors. In this Review, I describe the basic properties of gas vesicles, the genes that encode them and how their production is regulated. I also discuss the function of these vesicles and the initial attempts to exploit them for biotechnological purposes. PMID- 22941506 TI - The history of the research of iron in parkinsonian substantia nigra. AB - The role of iron in pathogenesis of Parkinson's disease is widely discussed in the literature. The authors present the history of studies of iron in parkinsonian tissue from the substantia nigra. PMID- 22941505 TI - The keystone-pathogen hypothesis. AB - Recent studies have highlighted the importance of the human microbiome in health and disease. However, for the most part the mechanisms by which the microbiome mediates disease, or protection from it, remain poorly understood. The keystone pathogen hypothesis holds that certain low-abundance microbial pathogens can orchestrate inflammatory disease by remodelling a normally benign microbiota into a dysbiotic one. In this Opinion article, we critically assess the available literature that supports this hypothesis, which may provide a novel conceptual basis for the development of targeted diagnostics and treatments for complex dysbiotic diseases. PMID- 22941507 TI - Identification of the cancer/testis antigens AKAP3 and CTp11 by SEREX in hepatocellular carcinoma. AB - Cancer/testis (CT) antigens are considered promising target molecules for immunotherapy. To efficiently identify potential CT antigens, a testis cDNA library was immunoscreened with sera from hepatocellular carcinoma (HCC) patients. We isolated 3 different antigens, AKAP3, CTp11, and UBQLN3. Although AKAP3 and CTp11 have been previously reported as CT antigens, this is the first time that these 2 antigens have been isolated from HCC patients by SEREX. Conventional RT-PCR analysis showed that AKAP3 was frequently present in HCC cell lines (5/7) and HCC tissues (5/10), and the gene was broadly expressed in several cancer types, including breast cancer cell lines (3/6), breast cancer tissues (6/9), colon cancer cell lines (3/10), colon cancer tissues (5/6), ovary cancer cell lines (6/8), ovary cancer tissues (11/16), lung cancer cell lines (4/7) and lung cancer tissues (6/13). By phage plaque analysis, anti-AKAP3 antibody was detected in sera from 15 of 27 HCC patients and 8 of 27 healthy donors. These data suggest that AKAP3 may be useful for diagnosis and immunotherapy in HCC patients. PMID- 22941508 TI - Detecting brain state changes via fiber-centered functional connectivity analysis. AB - Diffusion tensor imaging (DTI) and functional magnetic resonance imaging (fMRI) have been widely used to study structural and functional brain connectivity in recent years. A common assumption used in many previous functional brain connectivity studies is the temporal stationarity. However, accumulating literature evidence has suggested that functional brain connectivity is under temporal dynamic changes in different time scales. In this paper, a novel and intuitive approach is proposed to model and detect dynamic changes of functional brain states based on multimodal fMRI/DTI data. The basic idea is that functional connectivity patterns of all fiber-connected cortical voxels are concatenated into a descriptive functional feature vector to represent the brain's state, and the temporal change points of brain states are decided by detecting the abrupt changes of the functional vector patterns via the sliding window approach. Our extensive experimental results have shown that meaningful brain state change points can be detected in task-based fMRI/DTI, resting state fMRI/DTI, and natural stimulus fMRI/DTI data sets. Particularly, the detected change points of functional brain states in task-based fMRI corresponded well to the external stimulus paradigm administered to the participating subjects, thus partially validating the proposed brain state change detection approach. The work in this paper provides novel perspective on the dynamic behaviors of functional brain connectivity and offers a starting point for future elucidation of the complex patterns of functional brain interactions and dynamics. PMID- 22941509 TI - In vitro and in vivo studies of IgG-derived Treg epitopes (Tregitopes): a promising new tool for tolerance induction and treatment of autoimmunity. AB - Tregitopes are regulatory T cell epitopes derived from immunoglobulin G (IgG) that stimulate CD25(+) FoxP3(+) T cells to expand. In conjunction with these Tregs, Tregitopes can prevent, treat, and even cure autoimmune disease in mouse models, suppress allo-specific responses in murine transplant models, inhibit CD8(+) T cell responses to recombinant adeno-associated virus (AAV) gene transfer vectors, and induce adaptive Tregs in DO11.10 mice. In this review of recent Tregitope studies, we summarize their effects in vitro and describe recent comparisons between intravenous IgG (IVIG) and Tregitopes in standard in vivo immune tolerance models. Further investigations of the mechanism of action of Tregitopes in the preclinical models described here will lead to clinical trials where Tregitopes may have the potential to alter the treatment of autoimmune disease, transplantation, and allergy, and to improve the efficiency of gene and protein replacement therapies. PMID- 22941510 TI - Susceptibility to leprosy is associated with M-ficolin polymorphisms. AB - PURPOSE: Mycobacterium leprae exploits complement activation and opsonophagocytosis to infect phagocytes. M-ficolin is encoded by the FCN1 gene and initiates the lectin pathway on monocyte surfaces. We investigated FCN1 promoter polymorphisms that could be responsible for the high interindividual variability of M-ficolin levels and for modulating leprosy susceptibility. METHODS: We genotyped rs2989727 (-1981 G > A), rs28909068 (-791 G > A), rs10120023 (-542 G > A), rs17039495 (-399 G > A), rs28909976 (-271IndelT), rs10117466 (-144C > A) and rs10858293 (+33 T > G) in 400 controls and 315 leprosy patients from Southern Brazil, and in 296 Danish healthy individuals with known M ficolin levels. RESULTS: Ten haplotypes were identified with sequence-specific PCR and/or haplotype-specific sequencing. We found evidence for a protective codominant additive effect of FCN1*-542A-144C with leprosy in Euro-Brazilians (P=0.003, PBf =0.021, OR=0.243 [CI95% =0.083-0.71]), which was independent of age, ethnic group and gender effects (P=0.029). There was a trend for a positive association of the -399A variant in Afro-Brazilians (P=0.022, PBf =0.154, OR=4.151 [CI95% =1.115-15.454], as well as for a negative association of the FCN1*3A haplotype with lepromatous leprosy, compared with less severe forms of the disease (P=0.016, PBf =0.112, OR=0.324 [CI95% =0.123-0.858]). Danish individuals with this haplotype presented M-ficolin levels higher than the population average of circa 1,000 ng/ml, and -542A-144C, which is able to modify the recognition of transcription factors in silico, occurred in individuals with levels under the 25 percentil (P=0.031). CONCLUSIONS: Our data provide the first evidence that FCN1 polymorphisms are associated with leprosy. M-ficolin may represent a novel key to understand the immunopathogenesis of M. leprae infection. PMID- 22941511 TI - Complement activation contributes to the injury and outcome of kidney in human anti-glomerular basement membrane disease. AB - PURPOSE: Linear or granular deposition of complement 3 (C3) along glomerular basement membrane (GBM) is generally revealed in kidneys of human anti-GBM disease. However, the mechanism of complement activation and its association with clinical features and outcomes are less clear. METHODS: We measured the plasma and urinary levels of complement components, C1q, mannose-binding lectin (MBL), factor B (Ba), C3, C3a, C4, C4a, C5, C5a and soluble C5b-9 (SC5b-9), using ELISA in 20 patients with renal biopsy proven anti-GBM disease. RESULTS: The end product of complement activation, SC5b-9, was elevated both in plasma and urine. The levels of C3 and C4 were normal in plasma, while elevated in urine. The levels of C5a and SC5b-9 were increased in plasma from 15% and 30% patients respectively, while they were raised in urine from almost all patients (100% and 92%). The levels of plasma SC5b-9 and urinary C5a were positively correlated with the serum creatinine at presentation (r=0.56, P=0.01; r=0.68, P=0.02, respectively) and the percentage of crescents in glomeruli (r=0.60, P=0.005; r=0.75, P=0.005, respectively). The plasma level of SC5b-9 was further identified as the predictor for renal failure during follow up (HR, 1.46; 95% CI, 1.12-1.90; P=0.005). CONCLUSION: Complement cascade goes to the end in human anti-GBM disease and resides mainly in kidney. It plays pathogenic role in renal injury, by the possible proinflammatory effect of C5a and/or cell lysis effect of C5b-9. C5a and C5b-9 may be useful in clinical monitoring and predicting. PMID- 22941512 TI - Examining the use of ICD-9 diagnosis codes for primary immune deficiency diseases in New York State. AB - PURPOSE: To use International Classification of Disease Codes (ICD-9) codes to investigate primary immune deficiency (PID) in New York State. METHODS: We investigated the diagnosis of Primary Immune Deficiency (PID) in New York State (NYS) using the Statewide Planning and Research Cooperative System (SPARCS) database, a comprehensive data reporting system that collects ICD-9 codes for each patient hospitalized in NYS. RESULTS: From 2000-2004 there were 13,539,358 hospitalizations for 4,777,295 patients; of these, 2,361 patients (0.05 %) were diagnosed with one or more of the ICD-9 codes for PID. Antibody defects were the most common diagnoses made. The PID population had significantly more Caucasians, and fewer African American or Hispanic subjects compared to the general population. Subjects with PID codes were younger, had longer hospitalizations, were less likely to have Medicare and more likely to have Medicaid or Blue Cross insurance. Most hospitalizations were due to respiratory and infectious diseases. Most patients resided in the most populous counties, Kings, New York and Queens, but the distribution of home zip codes was not proportional to county populations. CONCLUSIONS: These data provide useful information on incidence and complications of selected PID diagnoses in one large state. PMID- 22941513 TI - Immune pathogenesis and treatment of multifocal motor neuropathy. AB - Multifocal motor neuropathy (MMN) is a rare, probably immune-mediated chronic disorder characterized by asymmetric distal limb weakness and conduction block. The exact pathogenesis of MMN is still unclear, but IgM anti-GM1 antibodies, which can be detected in sera from approximately half of all MMN patients, are thought to play an important role. Treatment with intravenous immunoglobulin (IVIG) is effective in the vast majority of patients, but, despite IVIG maintenance treatment, many patients experience a slowly progressive decline in muscle strength. In this review we will summarize the results from studies on pathogenesis. We will discuss current treatment strategies of MMN and how insight into MMN pathogenesis may translate into novel therapies in the future. PMID- 22941514 TI - Identification of chromosomal locations associated with tail biting and being a victim of tail-biting behaviour in the domestic pig (Sus scrofa domesticus). AB - The objective of this study was to identify loci associated with tail biting or being a victim of tail biting in Norwegian crossbred pigs using a genome-wide association study with PLINK case-control analysis. DNA was extracted from hair or blood samples collected from 98 trios of crossbred pigs located across Norway. Each trio came from the same pen and consisted of one pig observed to initiate tail biting, one pig which was the victim of tail biting and a control pig which was not involved in either behaviour. DNA was genotyped using the Illumina PorcineSNP60 BeadChip whole-genome single-nucleotide polymorphism (SNP) assay. After quality assurance filtering, 53,952 SNPs remained comprising 74 animals (37 pairs) for the tail biter versus control comparison and 53,419 SNPs remained comprising 80 animals (40 pairs) for the victim of tail biting versus control comparison. An association with being a tail biter was observed on Sus scrofa chromosome 16 (SSC16; p = 1.6 * 10(-5)) and an unassigned chromosome (p = 3.9 * 10(-5)). An association with being the victim of tail biting was observed on Sus scrofa chromosomes 1 (SSC1; p = 4.7 * 10(-5)), 9 (SSC9; p = 3.9 * 10(-5)), 18 (SSC18; p = 7 * 10(-5) for 9,602,511 bp, p = 3.4 * 10(-5) for 9,653,881 bp and p = 5.3 * 10(-5) for 29,577,783 bp) and an unassigned chromosome (p = 6.1 * 10( 5)). An r(2) = 0.96 and a D' = 1 between the two SNPs at 9 Mb on SSC18 indicated extremely high linkage disequilibrium, suggesting that these two markers represent a single locus. These results provide evidence of a moderate genetic association between the propensity to participate in tail-biting behaviour and the likelihood of becoming a victim of this behaviour. PMID- 22941516 TI - Telaprevir-based triple therapy in liver transplant patients with hepatitis C virus: a 12-week pilot study providing safety and efficacy data. AB - After liver transplantation (LT), the management of recurrent hepatitis C virus (HCV) infections still remains a major challenge. In HCV genotype 1 patients not undergoing transplantation, the introduction of protease inhibitor (PI)-based regimens has increased the sustained virological response rate significantly. This pilot study investigated both the safety and efficacy of telaprevir (TVR) based triple therapy in HCV-infected LT patients with a special emphasis on drug drug interactions between immunosuppressants and PIs. Safety and efficacy data were gathered for 12 weeks for 9 HCV-infected LT patients who were treated with a combination of TVR, pegylated interferon, and ribavirin (RBV) in parallel with immunosuppressive drugs such as tacrolimus (TAC; n = 4), cyclosporine A (CSA; n = 4), and sirolimus (SIR; n = 1). Seven of the transplant patients completed the 12 weeks of triple therapy. At week 4, 4 of the patients were found to be HCV RNA negative, and importantly, 8 were found to be negative at week 12. During the 12 week course of triple therapy, short-term measurements of immunosuppressant trough levels required individual dose reductions in all patients (CSA, 2.5-fold; SIR, 7-fold; and TAC, 22-fold). Furthermore, two-thirds of the patients exhibited hematological side effects requiring RBV dose reductions, the administration of erythropoietin, or even blood transfusions. In conclusion, this pilot study provides evidence showing that TVR-based triple therapy is effective within the first 4 to 12 weeks in LT patients suffering from HCV genotype 1 recurrence, and it also provides evidence showing that drug-drug interactions between TVR and immunosuppressants can be handled appropriately through the close monitoring of trough levels and adequate dosage adjustments. PMID- 22941517 TI - An autoerotic death in Korea. AB - Accidental autoerotic asphyxia occurring during autoerotic activity is usually considered the unanticipated failure of a sexual stimulation device to induce hypoxia during solitary sexual arousal. Here, we provide the first reported case of autoerotic death in Korea. In the present case, a young man died from asphyxiation as a result of being suspended with his head in a plastic bag. The death was considered accidental and not suicidal. The diagnosis of autoerotic death may be difficult when typical features are absent. PMID- 22941518 TI - Lethal Bochdalek hernia in a three-year-old: pathological findings and medicolegal investigation in accusation of malpractice. AB - Diaphragmatic hernias can be a pitfall for paediatric diagnostics, especially in the cases of late presentation, which can also have medico-legal ramifications as exposed. A three-year-old boy was taken to a children's hospital after an episode of abdominal pain and vomiting of food. A physical examination proved normal, with mild ketonuria being found and he was discharged. Three months later for the same signs and symptoms, he was taken once more to hospital, where he arrived in a state of cardiac arrest and died. A lawsuit was begun against the doctors who had examined him three months earlier. The autopsy found herniation of the abdominal organs into the left pleural cavity through a defect in the left hemidiaphragm. The cause of death was identified as cardiac tamponade caused by mechanical compression of multiple herniated abdominal organs. The histopathological examination revealed marked atelectasis of the left lung, with non-expansion of 60-90% of the alveoli which suggested an acute mechanism that proved fatal, and the doctors were acquitted. The features of this disease and the possible difficulties in its diagnosis highlight the need for the utmost attention in differential diagnosis, even at an age where the discovery of a diaphragmatic hernia is exceedingly rare. PMID- 22941519 TI - Minors or suspects? A discussion of the legal and ethical issues surrounding the indefinite storage of DNA collected from children aged 10-18 years on the National DNA Database in England and Wales. AB - There are currently over 250,000 children between the ages of 10 and 18 years who have their genetic information stored on the National DNA Database. This paper explores the legal and ethical issues surrounding this controversial subject, with particular focus on juvenile capacity and the potential results of criminalizing young children and adolescents. The implications of the adverse legal judgement of the European Court of Human Rights in S and Marper v UK (2008) and the violation of Article 8 of the Convention are discussed. The authors have considered the requirement to balance the rights of the individual, particularly those of minors, against the need to protect the public and have compared the position in Scotland to that of the rest of the UK. The authors conclude that a more ethically acceptable alternative could be the creation of a separate forensic database for children aged 10-18 years, set up to safeguard the interests of those who have not been convicted of any crime. PMID- 22941515 TI - Endophenotypes as a measure of suicidality. AB - Suicide is thought to result from the harmful interaction of multiple factors that have social, environmental, neurobiological, and genetic backgrounds. Recent studies have suggested that genetic predisposition to suicidal behavior may be independent of the risk of suicide associated to mental disorders, such as affective disorders, schizophrenia, or alcohol dependence. Given the suicidal behavior heterogeneity and its hereditary complexity, the need to find demonstrable intermediate phenotypes that may make it possible to establish links between genes and suicide behaviors (endophenotypes) seems to be necessary. The main objective of this review was to consider the candidate endophenotypes of suicidal behaviors. Due to the recent advances in neuroimaging, we also characterize brain regions implicated in vulnerability to suicide behavior that are influenced by gene polymorphisms associated with suicidal behavior. PMID- 22941520 TI - Comparison of extractable DNA from bone following six-month exposure to outdoor conditions, garden loam, mold contamination or room storage. AB - Femur bone sections from a single donor were exposed for six months to (i) outdoor conditions (exposure to sun, rain, etc.); (ii) water-vapour saturated environment favourable to mould proliferation and (iii) humic-garden soil. Following these treatments, DNA was extracted and yields were compared with that of a control bone fragment kept under optimal laboratory storage conditions. Our results demonstrate that both mould and soil are very detrimental to bone DNA conservation since more than 97% of the bone DNA was lost in these samples as compared with the control condition. Outdoor exposure gives an intermediate result with 30% of the DNA still present in the bone. Thus, environments favourable to microorganisms proliferation appear detrimental to bone DNA conservation and are a bad prognostic should bone remains be used for genetic identification purpose. Comparatively, open-air exposure is much more favourable to bone DNA analysis. PMID- 22941521 TI - Colchicine poisoning: a case report and review of literature. AB - Colchicine, a natural pseudo-alkaloid found in plants such as the Colchicum autumnale and Gloriosa superba has tremendous medicinal properties, but if misused by an unqualified person can result in fatal consequences. We report a case of colchicine poisoning in an adult man as a result of consumption of the herb G. superba by a 50-year-old man and review the literature. PMID- 22941523 TI - Bevacizumab in the treatment of ovarian cancer. AB - INTRODUCTION: In the past decade there have been many attempts to improve systemic treatment and thus the outcome of patients with ovarian cancer. However, neither the sequential addition of non cross-resistant drugs to standard chemotherapy comprising carboplatin and paclitaxel, nor triplet combination therapies with conventional chemotherapeutic drugs have improved outcomes. Instead, such approaches have led to an increase in the incidence of side effects. We are currently experiencing a shift toward the addition of molecularly targeted and biological anticancer therapies to standard treatment. Vascular endothelial growth factor (VEGF), which improves vitally important tumor vasculature, is secreted by a range of tumors, and a high level of VEGF is known to be an independent risk factor for aggressive disease in ovarian cancer. This finding led to the development in the 1990s of bevacizumab, a humanized monoclonal antibody against VEGF. DISCUSSION: Several phase II trials and four phase III trials have demonstrated that bevacizumab is active in patients with advanced and recurrent ovarian cancer. Both phase III trials of bevacizumab as first-line therapy in advanced ovarian cancer (ICON 7/AGOOVAR 11 and GOG-0218) have shown that the addition of bevacizumab to chemotherapy and as maintenance therapy improves progressionfree survival (PFS). The phase III trials in platinum sensitive (OCEANS) and platinumresistant, relapsed disease (AURELIA) have also demonstrated a benefit for bevazicumab with respect to PFS. The administration of bevacizumab to improve survival in patients with ovarian cancer is not without side effects and a broad discussion on the cost-effectiveness of this approach is ongoing. CONCLUSION: This article presents clinical trial data on bevacizumab in the treatment of ovarian cancer and discusses the indication and pitfalls in the application of bevacizumab in patients with this malignancy. PMID- 22941522 TI - Novel role for a serine/arginine-rich splicing factor, AdRSZ21 in plant defense and HR-like cell death. AB - A splicing factor gene belonging to the serine/arginine (SR)-rich protein family was cloned from Arachis diogoi, a wild relative of peanut in a study on differential gene expression and was designated as AdRSZ21. AdRSZ21 exhibits a RNA recognition motif (RRM), a CCHC type zinc finger domain (Zinc Knuckle, ZnK) and a C-terminal RS domain that is rich in arginine and serine. Multiple sequence alignment of AdRSZ21 with putative orthologs from diverse taxa including lower plants and monocots showed that the RRM and ZnK domains are evolutionarily conserved. Phylogenetic studies revealed that AdRSZ21 belongs to the RSZ subfamily and is closely related to the Arabidopsis ortholog AtRSZ22. Transient constitutive and conditional heterologous expression of AdRSZ21 resulted in HR like cell death in tobacco leaves. The presence of a functional RRM domain, but not ZnK domain was essential for AdRSZ21 induced HR-like cell death phenotype. On the other hand, expression of AdRSZ21 with mutated ZnK domain lead to accelerated cell death. The cell death induced by AdRSZ21 was found to be associated with specific upregulation of patatin-like protein gene and other defense related gene transcripts suggesting a role for AdRSZ21 in plant defense and HR-like cell death. PMID- 22941524 TI - Pseudobulbar affect: burden of illness in the USA. AB - INTRODUCTION: Pseudobulbar affect (PBA) is characterized by involuntary and uncontrollable laughing and/or crying episodes, occurring secondary to neurological disease or injury. The impact of PBA on social and occupational function, health status, quality of life (QOL), and quality of relationships (QOR) is not well studied. METHODS: This US survey conducted by Harris Interactive compared health status and daily function of patients with and without PBA. Eligible respondents were Harris Panel Online registrants previously diagnosed with stroke, multiple sclerosis, Parkinson's disease, Alzheimer's disease, traumatic brain injury, or amyotrophic lateral sclerosis, or primary, nonpaid caregivers for such patients who were too debilitated to participate. PBA was identified by a Center for Neurologic Study lability scale score of 13 or greater. Measures included the 36-item short form health survey (SF-36), the work productivity and impairment (WPAI) questionnaire, visual analog scales (VAS) for impact of PBA symptoms on QOL and QOR, and customized questions related to burden and impact of involuntary laughing/crying episodes on patients' lives. Survey responses were weighted to adjust for the relative proportion of the primary neurological conditions in the overall population and between group differences in patient age and gender. PBA and non-PBA group responses were compared using two-tailed t tests adjusted for severity of the primary neurological conditions. RESULTS: The 1,052 respondents included 399 PBA group participants and 653 controls. The PBA group showed significantly worse scores versus non-PBA controls on component and summary SF-36 scores (P<0.05 for all), VAS scores (P<0.05 for both), and WPAI scores (P<0.05). Among PBA group respondents, PBA contributed a great deal to or was the main cause of patients becoming housebound for 24% and being moved to supervised living placement for 9% of respondents. CONCLUSION: PBA is associated with considerable burden incremental to that of the underlying neurological conditions, affecting QOL, QOR, health status, and social and occupational functioning. PMID- 22941525 TI - Retinoids in pediatric onco-hematology: the model of acute promyelocytic leukemia and neuroblastoma. AB - Retinoids are lipophilic compounds derived from vitamin A, which have been extensively studied in cancer prevention and therapy. In pediatric oncology, they are successfully used for the treatment of acute promyelocytic leukemia (APL) and high-risk neuroblastoma (HR-NBL). APL is a subtype of acute myeloid leukemia (AML) clinically characterized by a severe bleeding tendency with a highrisk of fatal hemorrhage. The molecular hallmark of this disease is the presence of the promyelocytic leukemia (PML)-retinoic acid receptor-alpha (RAR alpha) gene fusion that plays a critical role in promyelocytic leukemogenesis and represents the target of retinoid therapy. The introduction in the late 1980s of all-trans retinoic acid (ATRA) into the therapy of APL radically changed the management and the outcome of this disease. Presently, the standard front-line therapeutic approach for pediatric APL includes anthracycline-based chemotherapy and ATRA, leading to a complete remission in almost 90% of the patients. Neuroblastoma (NBL) is an aggressive childhood tumor derived from the peripheral neural crest. More than half of patients have a high-risk disease, with a poor outcome despite intensive multimodal treatment. Although the exact mechanism of action remains unclear, the introduction of 13-cis-retinoic acid (13-cis-RA) in the therapy of NBL has improved the prognosis of this disease. Currently, the standard treatment for HR-NBL consists of myeloablative therapy followed by autologous hematopoietic stem cell transplantation (HSCT) and maintenance with 13-cis-RA for the treatment of minimal residual disease, leading to a 3-year disease-free survival rate (DFS) of about 50%. In this paper the authors provide a review of the peer-reviewed literature on the role of retinoids in the treatment of pediatric APL and HR-NBL, summarizing the most relevant clinical trial results of the last decades, analyzing the ongoing trials, and investigating future therapeutic perspectives of children affected by these diseases. PMID- 22941526 TI - Validation of the extended Tanaka column characterization protocol by multivariate analysis of chromatographic retention of low-molecular-weight analytes on reversed phase columns using methanol and acetonitrile as organic modifiers. AB - The validity of the extended Tanaka column characterization procedure against the retention behavior of 101 analytes of widely differing properties chromatographed on five differing stationary phase chemistries has been established using a chemometric technique called principal component analysis (PCA). It was concluded that the simple and conveniently determined column characterization parameters covered the same space in the PCA loading plot as the retention times for the 101 differing analytes. This confirms that the ten column characterization parameters of the extended Tanaka protocol encode the same information as the retention times of the 101 analytes. Significant selectivity differences were observed between stationary phases and the mobile-phase modifiers - MeOH and MeCN. PCA contribution plots served as a convenient way to highlight specific selectivity differences between stationary phases. logD values exhibited a poor correlation with retention indicating that retention in RP-LC is not solely dictated by the analyte's hydrophobicity. The use of MeOH was found to generate greater selectivity differences with the five stationary phases than when MeCN is used. PMID- 22941527 TI - The neuromuscular system in continuously swimming cercariae from Belarus. II Echinostomata, Gymnocephala and Amphistomata. AB - The neuromuscular system in cercariae of Moliniella anceps, Echinostoma revolutum, Cathaemasia hians, Psilochasmus oxyurus, Sphaeridiotrema globulus, Paramphistomum cervi and Diplodiscus subclavatus was studied with immunocytochemical methods and confocal scanning laser microscopy. The patterns of F-actin in the musculature, 5-HT immunoreactive (IR), FMRFamide-IR neuronal elements and alpha-tubulin-IR sensory receptors were investigated. The general patterns of musculature, 5-HT- and FMRFamide-IR neuronal elements in the 12 species studied here and in paper I are similar to those observed in other cercariae and reflect the morphology of the groups. The musculature of the tail shows variations which are related to the different strategies of host finding. In the Echinostomatoidea and Paramphistomoidea, the striated musculature of the tail is well developed compared to that in the Xiphidiocercariae. Specialized muscle fibres were found in S. globulus, which are able to change the shape of the tail. Nine of the species studied have seven paired 5-HT-IR neurons in the body, and two species have eight. No correlation between the body size and the number of 5-HT-IR neurons was observed. However, the size of the neurons followed the body size. The number of 5-HT-IR neurons in the brain ganglia increased from the primitive to the advanced forms. The number of FMRFamide-IR transverse commissures in the body correlates with the size of the cercariae. Regardless of the differences in the second intermediate host, the distribution of alpha tubulin-IR sensory receptors shows a high degree of conformity in all species except in P. cervi, which encysts on plants. PMID- 22941528 TI - New imidazolidine derivatives as anti-Trypanosoma cruzi agents: structure activity relationships. AB - Imidazolidine derivatives are key components for the development of bioactive compounds for the treatment of many diseases, especially Chagas. In fact, others studies showed that the imidazolidine-2,4-dione has stood out by presenting a wide spectrum of pharmacological activities including anticonvulsants, antiarrhythmic, and antiparasitic. In the present study, we investigated the morphological alterations induced by imidazolidine derivates LPSF/NN-52 and LPSF/NN-100 on trypomastigotes forms of Trypanosoma cruzi through ultrastructural analysis by electron microscopy. Many concentrations were used to measure the antiparasitic propriety promoted by imidazolidine derivatives, and our study indicates that parasites treated with 13 MUg mL(-1) of the imidazolidine derivates for 24 h revealed severe damage to the parasite's mitochondrial complex. Beyond that, also observed in treated parasites were the following: myelin bodies, enlargement of cytoplasm vacuole, fragmentation of endoplasmic reticulum, and some treated samples clearly showed signs of necrosis. To confirm the ultrastructural results, some assays were performed for knowledge cellular death induction promoted by imidazolidine derivates against immune spleen cells. The induction of the necrotic process through derivatives LPSF/NN-52 and LPSF/NN 100 showed similar results in relation to nifurtimox and benznidazole. In the last assays, it was demonstrated that NN-100 was efficient against epimastigotes and trypomastigotes forms and these results reinforce the mechanisms of action of both new imidazolidine derivatives against T. cruzi. PMID- 22941529 TI - Subacute and acute fasciolosis in sheep in southern Brazil. AB - Eight outbreaks of acute and subacute fasciolosis are reported in sheep in the municipality of Santa Vitoria do Palmar, southern Brazil, in areas used for irrigated rice cultivation, which are subject to frequent flooding. Two outbreaks occurred mid-winter during July and August, and six occurred during spring and early summer. Morbidity ranged from 3 to 66.7 %, and mortality ranged from 3 to 50 %. Clinical signs included weight loss, mucosal pallor, apathy, depression, muscle tremors, and drooling; these were followed by death within approximately 24 h. Some sheep were found dead. Gross lesions were characterized by an irregular liver capsule with fibrin deposition and hemorrhages. The liver parenchyma contained hemorrhagic tracts or irregular clear areas alternated with dark hemorrhagic areas. Histologically, hemorrhagic dark red tracts of necrotic liver parenchyma and an inflammatory infiltrate were noted; these lesions coincided with the presence of immature flukes. Langhans-type giant cells, fibrous tissue, and bile duct cell proliferation were observed in subacute cases. Chronic fasciolosis is a well-known disease to farmers in southern Brazil; nevertheless, acute and subacute fasciolosis, which are more difficult to diagnose and treat, may cause important economic losses. Efficient control of fasciolosis requires integration of measures to treat infections in the definitive host, to reduce the population of snails of the genus Lymnaea, and to avoid contact between the parasite and host by appropriate pasture management. PMID- 22941537 TI - Predicting sentinel lymph node metastasis in a Chinese breast cancer population: assessment of an existing nomogram and a new predictive nomogram. AB - We assessed the MSKCC nomogram performance in predicting SLN metastases in a Chinese breast cancer population. A new model (the SCH nomogram) was developed with clinically relevant variables and possible advantages. Data were collected from 1,545 patients who had a successful SLN biopsy between March 2005 and November 2011. We validated the MSKCC nomogram in the modeling and validation group. Clinical and pathologic features of SLN biopsy in modeling group of 1,000 patients were assessed with multivariable logistic regression to predict the presence of SLN metastasis in breast cancer. The SCH nomogram was created from the logistic regression model and subsequently applied to 545 consecutive SLN biopsies. By multivariate analysis, age, tumor size, tumor location, tumor type, and lymphovascular invasion were identified as independent predictors of SLN metastasis. The SCH nomogram was then developed using the five variables. The new model was accurate and discriminating (with an AUC of 0.7649 in the modeling group) compared to the MSKCC nomogram (with an AUC of 0.7105 in the modeling group). The area under the ROC curve for the SCH nomogram in the validation population is 0.7587. The actual probability trends for the various deciles were comparable to the predicted probabilities. The false-negative rates of the SCH nomogram were 1.67, 3.54, and 8.20 % for the predicted probability cut-off points of 5, 10, and 15 %, respectively. Compared with the MSKCC nomogram, the SCH nomogram has a better AUC with fewer variables and has lower false-negative rates for the low-probability subgroups. The SCH nomogram could serve as a more acceptable clinical tool in preoperative discussions with patients, especially very-low-risk patients. When applied to these patients, the SCH nomogram could be used to safely avoid a SLN procedure. The nomogram should be validated in various patient populations to demonstrate its reproducibility. PMID- 22941536 TI - Characterization of the pearl oyster (Pinctada martensii) mantle transcriptome unravels biomineralization genes. AB - Pearl oyster, Pinctada martensii, is a marine bivalve species widely distributed in tropic and subtropic marine coasts. Mantle is the special tissue of P. martensii that secretes biomineralization proteins inducing shell deposition as well as iridescent nacre both in the inner shell and artificial nucleus. The pearl oyster is very efficient for artificial pearl production and is therefore an ideal organism for studies into the processes of biomineralization. However, deficiency of transcriptome information limits the insight into biomineralization mechanisms and pearl formation. In this study, we sequenced and characterized the P. martensii mantle transcriptome using 454 pyrosequencing. A total of 25,723 unique transcripts were assembled from 220,824 quality reads, followed by annotation and Gene Ontology classification analysis. A total of 146 unique transcript segments homologous to 49 reference biomineralization genes were identified, including calcineurin-binding protein, amorphous calcium carbonate binding protein 1, calmodulin, calponin-like protein, carbonic anhydrase 1, glycine-rich shell matrix protein, lysine-rich matrix protein, mantle gene or protein, nacrein, pearlin, PIF, regucalcin, and shematrin. The sequence data enabled the identification of 10,285 potential single nucleotide polymorphism loci and 7,836 putative indels, providing a resource for molecular biomarker, population genetics, and functional genomic studies. A large number of candidate genes for biomineralization were identified, considerably enriching resources for the study of shell formation. These sequence data will notably advance biomineralization and transcriptome study in pearl oyster and other Pinctada species. PMID- 22941538 TI - Sentinel lymph node biopsy at the time of mastectomy does not increase the risk of lymphedema: implications for prophylactic surgery. AB - Women diagnosed with or at high risk for breast cancer increasingly choose prophylactic mastectomy. It is unknown if adding sentinel lymph node biopsy (SLNB) to prophylactic mastectomy increases the risk of lymphedema. We sought to determine the risk of lymphedema after mastectomy with and without nodal evaluation. 117 patients who underwent bilateral mastectomy were prospectively screened for lymphedema. Perometer arm measurements were used to calculate weight adjusted arm volume change at each follow-up. Of 234 mastectomies performed, 15.8 % (37/234) had no axillary surgery, 63.7 % (149/234) had SLNB, and 20.5 % (48/234) had axillary lymph node dissection (ALND). 88.0 % (103/117) of patients completed the LEFT-BC questionnaire evaluating symptoms associated with lymphedema. Multivariate analysis was used to assess clinical characteristics associated with increased weight-adjusted arm volume and patient-reported lymphedema symptoms. SLNB at the time of mastectomy did not result in an increased mean weight-adjusted arm volume compared to mastectomy without axillary surgery (p = 0.76). Mastectomy with ALND was associated with a significantly greater mean weight-adjusted arm volume change compared to mastectomy with SLNB (p < 0.0001) and without axillary surgery (p = 0.0028). Patients who underwent mastectomy with ALND more commonly reported symptoms associated with lymphedema compared to those with SLNB or no axillary surgery (p < 0.0001). Patients who underwent mastectomy with SLNB or no axillary surgery reported similar lymphedema symptoms. Addition of SLNB to mastectomy is not associated with a significant increase in measured or self-reported lymphedema rates. Therefore, SLNB may be performed at the time of prophylactic mastectomy without an increased risk of lymphedema. PMID- 22941539 TI - Development of a tuned interfacial force field parameter set for the simulation of protein adsorption to silica glass. AB - Adsorption free energies for eight host-guest peptides (TGTG-X-GTGT, with X = N, D, G, K, F, T, W, and V) on two different silica surfaces [quartz (100) and silica glass] were calculated using umbrella sampling and replica exchange molecular dynamics and compared with experimental values determined by atomic force microscopy. Using the CHARMM force field, adsorption free energies were found to be overestimated (i.e., too strongly adsorbing) by about 5-9 kcal/mol compared to the experimental data for both types of silica surfaces. Peptide adsorption behavior for the silica glass surface was then adjusted using a modified version of the CHARMM program, which we call dual force-field CHARMM, which allows separate sets of nonbonded parameters (i.e., partial charge and Lennard-Jones parameters) to be used to represent intra-phase and inter-phase interactions within a given molecular system. Using this program, interfacial force field (IFF) parameters for the peptide-silica glass systems were corrected to obtain adsorption free energies within about 0.5 kcal/mol of their respective experimental values, while IFF tuning for the quartz (100) surface remains for future work. The tuned IFF parameter set for silica glass will subsequently be used for simulations of protein adsorption behavior on silica glass with greater confidence in the balance between relative adsorption affinities of amino acid residues and the aqueous solution for the silica glass surface. PMID- 22941541 TI - Velcro crackles: the key for early diagnosis of idiopathic pulmonary fibrosis? PMID- 22941540 TI - Sudden and unexpected death in early life: proceedings of a symposium in honor of Dr. Henry F. Krous. AB - Reported here are the proceedings of a symposium given in honor of Dr. Henry F. Krous upon his retirement as Clinical Professor of Pathology and Pediatrics at the University of California Schools of Medicine, and as Director of the San Diego SIDS/SUDC Research Project. Dr. Krous' distinguished 37-year-career was dedicated to research into sudden unexpected death in infancy and childhood, notably the sudden infant death syndrome (SIDS) and sudden unexplained death in childhood (SUDC). The presentations were given at the International Conference on Stillbirth, SIDS, and infant survival on October 5, 2012, in Baltimore, MD, USA. Eight colleagues of Dr. Krous whose own professional careers were touched by his efforts discussed forensic issues related to SIDS, tissue banking, animal models in SIDS, brainstem studies in SIDS, genetic studies in SIDS, establishment of a SUDC registry, neuropathologic research in SUDC, and potential shared mechanisms underlying sudden and unexpected death in early life. The wide scope of the presentations crossed the disciplines of forensic pathology, pediatric pathology, neuropathology, neuroscience, physiology, genetics, and bereavement, and attest to Dr. Krous' far-reaching influence upon SIDS and SUDC research. PMID- 22941543 TI - Survivor bias and risk assessment. PMID- 22941544 TI - The key or just a cog in the wheel to operability assessment? PMID- 22941542 TI - Physical activity, nutritional status and systemic inflammation in COPD. PMID- 22941546 TI - Extracorporeal lung assist might avoid invasive ventilation in exacerbation of COPD. PMID- 22941547 TI - Influence of social deprivation and air pollutants on serious asthma. PMID- 22941548 TI - Asthma and the regulated retrotransposon transcriptome. PMID- 22941549 TI - Negative predictive value of TST and IGRA in anti-TNF treated patients. PMID- 22941550 TI - The impact of corruption on multidrug-resistant tuberculosis: a quantitative assessment. PMID- 22941551 TI - Pirfenidone treatment in idiopathic pulmonary fibrosis: too much of a great expectation? PMID- 22941552 TI - Primary pulmonary extranodal natural killer/T-cell lymphoma: nasal type with multiple nodules. PMID- 22941553 TI - Predicting survival in malignant mesothelioma. PMID- 22941555 TI - Further evidence reveals that okra mottle virus arose from a double recombination event. AB - As a result of surveys of okra begomoviruses (genus Begomovirus, family Geminiviridae) conducted over the last five years in Central Brazil, we report the complete genome sequence of an isolate of okra mottle virus (OMoV). The DNA-A and DNA-B components were 2660 and 2653 nucleotides (nt) long, respectively, and they were most closely related to the DNA-A (~99 % nt identity) and DNA-B (~98 % nt identity) components of an OMoV isolate from a soybean plant. A phylogenetic tree was generated based on these sequences, and it was shown that both of the OMoV DNA components were grouped in a branch with Brazilian begomoviruses known to infect weeds. By recombination analysis, strong evidence was observed that the OMoV genome may have been the product of a double inter-species recombination event. PMID- 22941557 TI - Biological water-oxidizing complex: a nano-sized manganese-calcium oxide in a protein environment. AB - The resolution of Photosystem II (PS II) crystals has been improved using isolated PS II from the thermophilic cyanobacterium Thermosynechococcus vulcanus. The new 1.9 A resolution data have provided detailed information on the structure of the water-oxidizing complex (Umena et al. Nature 473: 55-61, 2011). The atomic level structure of the manganese-calcium cluster is important for understanding the mechanism of water oxidation and to design an efficient catalyst for water oxidation in artificial photosynthetic systems. Here, we have briefly reviewed our knowledge of the structure and function of the cluster. PMID- 22941559 TI - Immune response to nanomaterials: implications for medicine and literature review. AB - Nanomaterials, substances below 100 nm, are increasingly used in medical diagnosis and treatment every day. The use of such materials has helped deliver drugs across the blood-brain barrier, alleviate allergy symptoms, specifically target cancer or HIV cells, and more. However, the tunable characteristics of such materials have not been perfected. The different materials, sizes, shapes, and structures have different responses on the body. This paper will investigate the successful treatments made with nanoparticles and some general health effects. A review of the literature revealed an inflammatory response and an increased production of reactive oxidative species (ROS) to be common immune responses to nanomaterial use. The mechanisms by which the inflammatory response and ROS production occur will also be discussed. PMID- 22941560 TI - Linking complement and anti-dsDNA antibodies in the pathogenesis of systemic lupus erythematosus. AB - Systemic lupus erythematosus is a severe autoimmune disease that affects multiple organ systems resulting in diverse symptoms and outcomes. It is characterized by antibody production to a variety of self-antigens, but it is specifically associated with those against anti-dsDNA. Anti-dsDNA antibodies are present before the onset of clinical disease and are associated with severe manifestations of lupus such as glomerulonephritis. Their levels fluctuate with changes in disease activity and, in combination with the levels of complement proteins C3 and C4, are strong indicators of disease flare and treatment response in patients with lupus. The decreased complement levels that are noted during flares of lupus activity are believed to be secondary to increased autoantibody production and immune complex formation that results in tissue damage; however, recent data suggest that complement activation can also drive development of these pathogenic autoantibodies. This review will explore the various roles of complement in the development and pathogenesis of anti-dsDNA antibodies. PMID- 22941561 TI - Influence of human immune cells on cancer: studies at the University of Colorado. AB - There will be over half a million cancer-related deaths in the United States in 2012, with lung cancer being the leader followed by prostate in men and breast in women. There is estimated to be more than one and a half million new cases of cancer in 2012, making the development of effective therapies a high priority. As tumor immunologists, we are interested in the development of immunotherapies because the immune response offers exquisite specificity and the potential to target tumor cells without harming normal cells. In this review, we highlight the current advances in the field of immunotherapy and the current work being completed by laboratories at University of Colorado School of Medicine in multiple malignancies, including breast cancer, lung cancer, melanoma, thyroid cancer, and glioblastoma. This work focuses on augmenting the anti-tumor response of CD8 T cells in the blood, lymph nodes, and tumors of patients, determining biomarkers for patients who are more likely to respond to immunotherapy, and identifying additional anti-tumor and immunosuppressive cells that influence the overall response to tumors. These collaborative efforts will identify mechanisms to improve immune function, which may elucidate therapeutic targets for clinical trials to improve patient health and survival. PMID- 22941563 TI - The influence of Arhgef1 on pulmonary leukocyte function. AB - Resident leukocytes in the lungs of healthy individuals are necessary for the innate and adaptive immune response toward potentially harmful foreign antigens that are inhaled on a constant basis. Under normal circumstances, inflammatory stimuli are effectively eradicated via innate immunity with accompanying resolution of inflammation and repair of the lung tissue. Work in our lab has explored how Arhgef1, an intracellular signaling molecule expressed by hematopoietic cells, participates in immune function with an emphasis on its contribution to pulmonary immunity. This review summarizes our studies on the role of Arhgef1 in regulating pulmonary macrophage function. PMID- 22941564 TI - Clinical significance of soluble-endoglin levels in systemic lupus erythematosus: possible association with anti-phospholipid syndrome. AB - AIM: The pathogenic role of soluble endoglin (s-Eng), as an antiangiogenic protein, has largely been demonstrated in various vascular disorders. Our aim was to assess, in a cross-sectional study, plasma levels of s-Eng in systemic lupus erythematosus (SLE) patients and its relation with the disease characteristics. PATIENTS AND METHODS: Plasma from 86 patients with SLE and 36 normal healthy subjects was assayed for s-Eng levels by enzyme-linked immunosorbent assay. Demographic, clinical, autoantibodies and serological data were prospectively assessed. Disease activity was assessed by total SLE disease activity index score. RESULTS: In our SLE patients, the levels of s-Eng were comparable between SLE patients and the control group. However, these levels were significantly associated with antiphospholipid syndrome (APS). In addition, s-Eng levels were significantly associated with antiphospholipid antibodies in our studied population. On the other hand, we did not find significant differences in mean plasma s-Eng levels in relation to disease activity, other organ system involvement or the presence of anti-dsDNA. CONCLUSION: Our preliminary data indicated the importance of s-Eng in a special subgroup of SLE patients associated with secondary APS. An additional prospective, large-scale, longitudinal study should be carried out to support these findings. PMID- 22941565 TI - The efficacy of brain (18)F-fluorodeoxyglucose positron emission tomography in neuropsychiatric lupus patients with normal brain magnetic resonance imaging findings. AB - Brain involvement in systemic lupus erythematosus (SLE) is a significant source of morbidity and mortality. Therefore, the early detection and treatment of brain involvement in SLE is of utmost importance; however, a confirmative diagnostic tool for neuropsychiatric SLE is yet to be developed. In this study, we investigated the efficacy of (18)F-FDG-PET for detection of brain involvement in patients with SLE with normal magnetic resonance imaging (MRI) findings. Twenty patients with SLE, who presented with neuropsychiatric symptoms despite normal brain MRI findings and who underwent brain (18)F-FDG-PET, were enrolled. The most common neuropsychiatric manifestation was headache (45%), followed by seizure (20%) and mood disorder (20%). (18)F-FDG-PET revealed significant glucose metabolic abnormalities in 15 of 20 patients (75%). The temporal (55%) and the occipital (55%) lobes were the most susceptible brain regions, followed by the frontal lobe (50%). However, neuropsychiatric symptoms were not geographically correlated to (18)F-FDG-PET findings. Two patients with abnormal (18)F-FDG-PET findings underwent follow-up brain (18)F-FDG-PET after remission, which showed complete resolution of abnormal glucose metabolism. Our data suggest that (18)F FDG-PET may be an additional diagnostic modality complementary to MRI, when MRI is unable to provide evidence of brain involvement in patients with SLE. PMID- 22941562 TI - Using functional genomics to overcome therapeutic resistance in hematological malignancies. AB - Despite great advances in our understanding of the driving events involved in malignant transformation, only a small number of oncogenic drivers have been targeted and translated into tangible clinical benefit. Moreover, even when a targeted therapy can be shown to effectively inhibit an oncogenic driver, leading to cancer remission, disease persistence and/or relapse is typically inevitable. Reemergence of the cancer can result from either intrinsic or acquired resistance mechanisms that result in failure to eliminate all cancer cells. Intrinsic mechanisms of resistance include tumor heterogeneity and pathways that can compensate for the inhibition of the oncogenic driver. Acquired resistance mechanisms include mutation of the oncogenic driver to directly prevent drug mediated inhibition and the activation of compensatory survival pathways. RNA interference (RNAi)-based screening provides a powerful approach for the interrogation of both intrinsic and acquired resistance mechanisms. The availability of short interfering (si)RNA libraries targeting all human and mouse genes has made it possible to perform large-scale unbiased screens to identify pathways that are specifically required in cancer cells of particular genotypes or following particular treatments, facilitating the design of potential new therapeutic strategies that may limit resistance mechanisms. In this review, we will discuss how RNAi screens can be used to uncover critical growth and survival pathways and aid in the identification of novel therapeutic targets for improved treatment of hematological malignancies. PMID- 22941566 TI - Association between the CD226 rs763361 polymorphism and susceptibility to autoimmune diseases: a meta-analysis. AB - OBJECTIVE: The aim of this study was to explore whether the CD226 rs763361 polymorphism confers susceptibility to autoimmune diseases. METHODS: A meta analysis was conducted on the associations between the CD226 rs763361 polymorphism and autoimmune diseases using: 1) allele contrast, and 2) the recessive, 3) dominant and 4) additive models. RESULTS: Ten articles that included 17 comparative studies on a total of 8900 patients and 10,295 controls were included in the meta-analysis. These studies were performed on seven European, five Asian and five South American sample populations. Meta-analysis of all study subjects revealed an association between the CD226 rs763361 T allele and the susceptibility to autoimmune diseases (odds ratio; OR 1.162, 95% confidence interval; CI 1.097-1.230, p < 1.0 * 10(-8)). Stratification by ethnicity indicated an association between the CD226 rs763361 T allele and autoimmune disease in Europeans and South Americans (OR 1.134, 95% CI 1.079 1.191, p = 6.7 * 10(-7); OR 1.308, 95% CI 1.160-1.475, p = 1.1 * 10(-5)) and between the CD226 rs763361 TT genotype and autoimmune disease in Asians (OR 1.366, 95% CI 1.130-1.650, p = 0.001). Disease-specific meta-analysis showed an association between systemic lupus erythematosus (SLE) and the CD226 rs763361 T allele (OR 1.150, 95% CI 1.040-1.271, p = 0.006), but no association between rheumatoid arthritis and the CD226 rs763361 polymorphism (OR for the T allele 1.207, 95% CI 0.913-1.596, p = 0.187). On the other hand, associations were found between the CD226 rs763361 T allele and systemic sclerosis (SSc) and type 1 diabetes (T1D) (OR 1.126, 95% CI 1.020-1.244, p = 0.019; OR 1.353, 95% CI 1.102 1.660, p = 0.004). CONCLUSIONS: This meta-analysis demonstrates the CD226 rs763361 polymorphism confers susceptibility to autoimmune disease in Europeans, South Americans and Asians, and in particular, shows that the CD226 rs763361 polymorphism is associated with SLE, SSc and T1D. These results support the existence of an association between the CD226 gene and a subgroup of autoimmune diseases. PMID- 22941567 TI - The impact of rural residency on the expression and outcome of systemic lupus erythematosus: data from a multiethnic Latin American cohort. AB - OBJECTIVE: The objective of this paper is to examine the role of place of residency in the expression and outcomes of systemic lupus erythematosus (SLE) in a multi-ethnic Latin American cohort. PATIENTS AND METHODS: SLE patients (< two years of diagnosis) from 34 centers constitute this cohort. Residency was dichotomized into rural and urban, cut-off: 10,000 inhabitants. Socio demographic, clinical/laboratory and mortality rates were compared between them using descriptive tests. The influence of place of residency on disease activity at diagnosis and renal disease was examined by multivariable regression analyses. RESULTS: Of 1426 patients, 122 (8.6%) were rural residents. Their median ages (onset, diagnosis) were 23.5 and 25.5 years; 85 (69.7%) patients were Mestizos, 28 (22.9%) Caucasians and 9 (7.4%) were African-Latin Americans. Rural residents were more frequently younger at diagnosis, Mestizo and uninsured; they also had fewer years of education and lower socioeconomic status, exhibited hypertension and renal disease more frequently, and had higher levels of disease activity at diagnosis; they used methotrexate, cyclophosphamide pulses and hemodialysis more frequently than urban patients. Disease activity over time, renal damage, overall damage and the proportion of deceased patients were comparable in rural and urban patients. In multivariable analyses, rural residency was associated with high levels of disease activity at diagnosis (OR 1.65, 95% CI 1.06-2.57) and renal disease occurrence (OR 1.77, 95% CI 1.00-3.11). CONCLUSIONS: Rural residency associates with Mestizo ethnicity, lower socioeconomic status and renal disease occurrence. It also plays a role in disease activity at diagnosis and kidney involvement but not on the other end-points examined. PMID- 22941568 TI - Real-time PCR to distinguish livestock-associated (ST398) from non-livestock associated (methicillin-resistant) Staphylococcus aureus. AB - BACKGROUND: The Netherlands is one of the most densely populated countries in the world, with extensive livestock of pigs. In 2005, the emergence of livestock associated methicillin-resistant Staphylococcus aureus (LA-MRSA) was a fact, with a relatively high MRSA colonisation among pig farmers. These MRSA isolates mostly belonged to sequence type 398 (ST398). Compared to hospital-associated MRSA (HA MRSA), severe infections due to LA-MRSA and transmission between individuals are still relatively rare. Therefore, LA-MRSA may warrant less stringent containment measures than HA-MRSA in hospital settings. RESULTS: The aim of this study was to develop a rapid diagnostic tool to distinguish LA-MRSA from non-LA-MRSA in aid of infection control. Here, we show that ST398 strains can be readily detected with real-time polymerase chain reaction (PCR). Analysis of a large panel of related and unrelated microorganisms confirmed that the real-time ST398 PCR (ST398-qPCR) assay does not cross-react with other microorganisms or with non-LA-S. aureus strains. ST398-qPCR analysis of MRSA isolates collected in 2010, 2011 and 2012 at the Jeroen Bosch Hospital (n = 275) showed that an average of 78 % of MRSA belonged to sequence type ST398. CONCLUSION: We conclude that the ST398 real-time PCR is a reliable assay to detect LA-S. aureus and anticipate that the use of this assay can prevent the unnecessary closing of hospital wards, which may lead to substantial savings for the health care system. PMID- 22941569 TI - Transient lateral patellar dislocation: review of imaging findings, patellofemoral anatomy, and treatment options. AB - Transient patellar dislocation is a common sports-related injury in young adults. Although patients often present to the emergency department with acute knee pain and hemarthrosis, spontaneous reduction frequently occurs, and half of cases are unsuspected clinically. Characteristic magnetic resonance imaging (MRI) findings often lead to the diagnosis. The purpose of this review is to illustrate the MRI findings of lateral patellar dislocation and concomitant injuries, such as kissing contusions of the medial patella and lateral femoral condyle; osteochondral and avulsion fractures; and injuries of the medial patellofemoral ligament/retinacular complex. This article will also briefly review patellofemoral anatomy and passive, active, and static stabilizers. Predisposing factors for patellar instability, including trochlear dysplasia, patella alta, and lateralization of the patella or tibial tuberosity and their relevant measurements will also be highlighted. Treatment options, including surgery, such as medial patellofemoral ligament reconstruction, tibial tuberosity transfer, and trochleoplasty, and their postoperative imaging appearances will also be discussed. PMID- 22941570 TI - Hepatitis C virus genotype diversity in Shanghai, China. AB - We studied 67 hepatitis C virus (HCV) isolates from 64 hospitalized patients in Shanghai, China. Genotype 1 was prevalent, and genotypes 2, 3, 6 were found for the first time in Shanghai. A rare mixed infection with three subtypes (1a, 1b, 2a) was found. The complete genome sequence of a subtype 3b isolate was determined and analyzed. PMID- 22941571 TI - Cytotoxicity of pomegranate polyphenolics in breast cancer cells in vitro and vivo: potential role of miRNA-27a and miRNA-155 in cell survival and inflammation. AB - Several studies have demonstrated that polyphenolics from pomegranate (Punica granatum L.) are potent inhibitors of cancer cell proliferation and induce apoptosis, cell cycle arrest, and also decrease inflammation in vitro and vivo. There is growing evidence that botanicals exert their cytotoxic and anti inflammatory activities, at least in part, by decreasing specificity protein (Sp) transcription factors. These are overexpressed in breast tumors and regulate genes important for cancer cell survival and inflammation such as the p65 unit of NF-kappaB. Moreover, previous studies have shown that Pg extracts decrease inflammation in lung cancer cell lines by inhibiting phosphatidylinositol-3,4,5 trisphosphate (PI3K)-dependent phosphorylation of AKT in vitro and inhibiting the activation of NF-kB in vivo. The objective of this study was to investigate the roles of miR-27a-ZBTB10-Sp and miR-155-SHIP-1-PI3K on the anti-inflammatory and cytotoxic activity of pomegranate extract. Pg extract (2.5-50 MUg/ml) inhibited growth of BT-474 and MDA-MB-231 cells but not the non-cancer MCF-10F and MCF-12F cells. Pg extract significantly decreased Sp1, Sp3, and Sp4 as well as miR-27a in BT474 and MDA-MB-231 cells and increased expression of the transcriptional repressor ZBTB10. A significant decrease in Sp proteins and Sp-regulated genes was also observed. Pg extract also induced SHIP-1 expression and this was accompanied by downregulation of miRNA-155 and inhibition of PI3K-dependent phosphorylation of AKT. Similar results were observed in tumors from nude mice bearing BT474 cells as xenografts and treated with Pg extract. The effects of antagomirs and knockdown of SHIP-1 by RNA interference confirmed that the anti inflammatory and cytotoxic effects of Pg extract were partly due to the disruption of both miR-27a-ZBTB10 and miR-155-SHIP-1. In summary, the anticancer activities of Pg extract in breast cancer cells were due in part to targeting microRNAs155 and 27a. Both pathways play an important role in the proliferative/inflammatory phenotype exhibited by these cell lines. PMID- 22941573 TI - Community mental health provider reluctance to provide pharmacotherapy may be a barrier to addressing perinatal depression: a preliminary study. AB - This is the first study evaluating obstetrics and gynecology (OB/Gyn) provider and staff perceptions of barriers to accessing pharmacotherapy for perinatal depression outside the obstetric setting. Four, 90 min focus groups were conducted with OB/Gyn physicians, advance practice nurses, and support and nursing staff (n = 28). Data were analyzed with a grounded theory approach. Participants perceived that community mental health providers and pharmacists often do not want to participate in pharmacotherapy for perinatal women. Participants believed the solution is training for community mental health providers in the risks and benefits of pharmacotherapy for perinatal depression and improved communication between OB/Gyn's and community mental health providers. Community mental health provider and pharmacist reluctance to provide pharmacotherapy hinders OB/Gyn's perceived ability to address perinatal depression. Community mental health provider and pharmacist training are needed to mitigate precipitous discontinuation of treatment and to improve access to pharmacotherapy for perinatal women. PMID- 22941572 TI - Xenografts faithfully recapitulate breast cancer-specific gene expression patterns of parent primary breast tumors. AB - Though xenografts are used extensively for drug development in breast cancer, how well xenografts reflect the breadth of primary breast tumor subtypes has not been well characterized. Moreover, few studies have compared the gene expression of xenograft tumors to the primary tumors from which they were derived. Here we investigate whether the ability of human breast tumors (n = 20) to create xenografts in immune-deficient mice is associated with breast cancer immunohistochemical (IHC) and intrinsic subtype. We also characterize how precisely the gene expression of xenografts reprises that of parent breast tumors, using hierarchical clustering and other correlation-based techniques applied to Agilent 44K gene expression data from 16 samples including four matched primary tumor-xenograft pairs. Of the breast tumors studied, 25 % (5/20) generated xenografts. Receptor and intrinsic subtype were significant predictors of xenograft success, with all (4/4) triple-negative (TN) tumors and no (0/12) HR+Her2- tumors forming xenografts (P = 0.0005). Tumor cell expression of ALDH1, a stem cell marker, trended toward successful engraftment (P = 0.14), though CDK5/6, a basal marker, did not. Though hierarchical clustering across the 500 most variable genes segregated human breast tumors from xenograft tumors, when clustering was performed over the PAM50 gene set the primary tumor-xenograft pairs clustered together, with all IHC subtypes clustered in distinct groups. Greater similarity between primary tumor-xenograft pairs relative to random pairings was confirmed by calculation of the within-pair between-pair scatter ratio (WPBPSR) distribution (P = 0.0269), though there was a shift in the xenografts toward more aggressive features including higher proliferation scores relative to the primary. Triple-negative breast tumors demonstrate superior ability to create xenografts compared to HR+ tumors, which may reflect higher proliferation or relatively stroma-independent growth of this subtype. Xenograft tumors' gene expression faithfully resembles that of their parent tumors, yet also demonstrates a shift toward more aggressive molecular features. PMID- 22941574 TI - Keeping track of trials. PMID- 22941575 TI - Effect of musculoskeletal injury on concussion testing: letter to the editor. PMID- 22941576 TI - Shoulder and elbow injuries in high school softball and baseball players: letter to the editor. PMID- 22941577 TI - Critical defect size for osteochondral lesions of the talus: letter to the editor. PMID- 22941578 TI - Is therapeutic ultrasound a reliable tool for the diagnosis of bone stress injuries? Letter to the editor. PMID- 22941580 TI - Changes in illness perceptions and quality of life during participation in cardiac rehabilitation. AB - BACKGROUND: The beliefs patients hold about their disease and corresponding treatment have been shown to predict recovery in cardiac patients. PURPOSE: However, it is not known to what extent these beliefs change during participation in cardiac rehabilitation and whether this is related to psychological indicators of outcome. METHOD: Illness perceptions and health-related quality of life (HRQOL) were measured upon entry to (T0) and completion of (T1) a 3-month outpatient cardiac rehabilitation program in 158 cardiac patients. RESULTS: Repeated-measures ANOVA revealed that all illness perceptions other than timeline and personal control changed significantly over the course of cardiac rehabilitation. Overall, cardiac rehabilitation patients came to view their illness as more benign. Further analysis revealed that perceiving fewer emotional consequences of the illness, gaining a better understanding, and attributing fewer symptoms to the illness at the end of cardiac rehabilitation, was related to better HRQOL. CONCLUSION: Illness perceptions change during cardiac rehabilitation and these changes are associated with enhanced quality of life. Clinical trials have shown illness beliefs in cardiac patients to be modifiable during hospital admission; our results suggest that cardiac rehabilitation may provide a second window of opportunity during which illness perceptions can be actively monitored and modified if maladaptive. PMID- 22941579 TI - Asymptomatic prospective and retrospective cohorts with metal-on-metal hip arthroplasty indicate acquired lymphocyte reactivity varies with metal ion levels on a group basis. AB - Some tissues from metal-on-metal (MoM) hip arthroplasty revisions have shown evidence of adaptive-immune reactivity (i.e., excessive peri-implant lymphocyte infiltration/activation). We hypothesized that, prior to symptoms, some people with MoM hip arthroplasty will develop quantifiable metal-induced lymphocyte reactivity responses related to peripheral metal ion levels. We tested three cohorts (Group 1: n = 21 prospective longitudinal MoM hip arthroplasty; Group 2: n = 17 retrospective MoM hip arthroplasty; and Group 3: n = 20 controls without implants). We compared implant position, metal-ion release, and immuno reactivity. MoM cohorts had elevated (p < 0.01) amounts of serum Co and Cr compared to controls as early as 3 months post-op (Group 1:1.2 ppb Co, 1.5 ppb Cr; Group 2: 3.4 ppb Co, 5.4 ppb Cr; Group 3: 0.01 ppb Co, 0.1 ppb Cr). However, only after 1-4 years post-op did 56% of Group 1 develop metal-reactivity (vs. 5% pre-op, metal-LTT, SI > 2), compared with 76% of Group 2, and 15% of Group 3 controls (patch testing was a poor diagnostic indicator with only 1/21 Group 1 positive). Higher cup-abduction angles (50 degrees vs. 40 degrees ) in Group 1 were associated with higher serum Cr (p < 0.07). However, sub-optimal cup anteversion angles (9 degrees vs. 20 degrees ) had higher serum Co (p < 0.08). Serum Cr and Co were significantly elevated in reactive versus non-reactive Group 1 participants (p < 0.04). CD4+CD69+ T-helper lymphocytes (but not CD8+) and IL 1beta, IL-12, and IL-6 cytokines were all significantly elevated in metal reactive versus non-reactive Group 1 participants. Our results showed that lymphocyte reactivity to metals can develop within the first 1-4 years after MoM arthroplasty in asymptomatic patients and lags increases in metal ion levels. This increased metal reactivity was more prevalent in those individuals with extreme cup angles and higher amounts of circulating metal. PMID- 22941581 TI - Outcome of patients after market withdrawal of thioridazine: a retrospective analysis in a nationwide cohort. AB - OBJECTIVE: Thioridazine is a first-generation antipsychotic drug that was withdrawn from the market worldwide in 2005. The outcome of clinically stable schizophrenia patients who used thioridazine before market withdrawal was evaluated. METHODS: Nationwide registers in Finland were utilized to study thioridazine use, hospitalization rate and length of hospital stay. RESULTS: Although thioridazine use continued to diminish year after year, the hospitalization rate remained constant until the withdrawal year of 2005, when the percentage of patients hospitalized for schizophrenia doubled. CONCLUSION: The market withdrawal of thioridazine predisposed many stable patients towards psychotic relapses. In order to minimize this kind of risk, an overall risk benefit assessment and a clear-cut plan for the replacement of an antipsychotic should be established before market withdrawal. PMID- 22941582 TI - Recursive partitioning for monotone missing at random longitudinal markers. AB - The development of HIV resistance mutations reduces the efficacy of specific antiretroviral drugs used to treat HIV infection and cross-resistance within classes of drugs is common. Recursive partitioning has been extensively used to identify resistance mutations associated with a reduced virologic response measured at a single time point; here we describe a statistical method that accommodates a large set of genetic or other covariates and a longitudinal response. This recursive partitioning approach for continuous longitudinal data uses the kernel of a U-statistic as the splitting criterion and avoids the need for parametric assumptions regarding the relationship between observed response trajectories and covariates. We propose an extension of this approach that allows longitudinal measurements to be monotone missing at random by making use of inverse probability weights. We assess the performance of our method using extensive simulation studies and apply them to data collected by the Forum for Collaborative HIV Research as part of an investigation of the viral genetic mutations associated with reduced clinical efficacy of the drug abacavir. PMID- 22941583 TI - Development and validation of an HPLC method to determine metabolites of 5 hydroxymethylfurfural (5-HMF). AB - The food component 5-hydroxymethylfurfural is supposed to have antioxidative properties and is therefore used as an acting agent in a novel anticancer infusion solution, named Karal(r), and an oral supplementation. Previous studies showed that after oral and intravenous application, the substance is completely decomposed to its metabolites: 5-hydroxymethylfuroic acid, 2,5-furandicarboxylic acid, and N-(hydroxymethyl)furoyl glycine. The formation of a fourth metabolite, namely 5-sulphoxymethylfurfural, is still not clarified according to literature. Due to commercial unavailability, synthesis of 5-sulphoxymethylfurfural was conducted and a synthesis procedure for N-(hydroxymethyl)furoyl glycine had to be developed. Identification of the synthesised compounds was proven by LC-MS and NMR. An appropriate HPLC method was established to obtain good separation of the four possible metabolic substances and 5-hydroxymethylfurfural within 12 min via a HILIC column (150 * 4.6 mm, 5 MUm) using a gradient grade system switching from mobile phase A (ACN/ammonium formate 100 mM, pH 2.35, 95:5, v/v) to mobile phase B (ACN/ammonium formate 100 mM, pH 2.35, 85:15, v/v). The procedure was afterward validated following ICH guidelines in terms of selectivity, linearity, precision, LOD, and LOQ. PMID- 22941584 TI - Optimizing outcomes for pediatric recipients. AB - KEY POINTS: 1. After liver transplantation (LT), the majority of children now grow into adulthood, with 10-year patient survival rates of 74% to 84% and graft survival rates of 62% to 72% according to United Network for Organ Sharing data. 2. Graft and patient survival rates decrease for patients undergoing transplantation between the ages of 12 and 17 years, and this raises the importance of dedicated adolescent care and appropriate transitioning to adult services. 3. Complications associated with long-term immunosuppression, including renal complications, infections, malignancies, and cardiovascular complications, are well described, and the risk factors are defined. 4. Biomarkers for measuring clinical immunosuppression and the concept of tolerance-inducing regimens are exciting, but further assessment is needed in large, prospective, multicenter studies. 5. As long-term medical complications are better managed, we need to focus on understanding the challenges for pediatric LT patients with respect to quality of life and health status. PMID- 22941585 TI - Does intraoperative neurophysiological monitoring have predictive value for functional recovery following spinal cord injury? A case report. AB - To present a case report of a patient with an ASIA B spinal cord injury with partially intact baseline IONM who made a complete functional recovery postoperatively. A thirty-three year old male presented after a motor vehicle accident. Imaging studies revealed a C4-C5 bilateral facet dislocation. On presentation the patient had 4/5 strength in bilateral biceps and wrist extensors, 3/5 strength in bilateral triceps, and 0/5 strength in the finger flexors, intrinsics and all lower extremity muscles. Motor level was C7. Sensation was grossly intact to light touch throughout all extremities, intact to pinprick from C2 to T7, and absent to pinprick caudal to T7. Rectal tone and contraction were absent. After attempts at closed reduction failed the patient underwent an open reduction and posterior C4-C5 fusion. Intraoperative neurophysiologic monitoring (IONM) revealed the presence of baseline responses to the posterior tibial nerve using somatosensory evoked potentials and to the right abductor hallucis using transcranial motor evoked potentials. At the 6 weeks postoperative visit the patient had full 5/5 motor strength to all muscles except the left deltoid that was 4/5 due to a rotator cuff injury. This case illustrates a potential prognostic value of IONM. Despite lack of clinical motor function at the time of surgery, IONM was able to illicit a motor response in the right lower extremity. Further prospective studies are needed for further investigation. PMID- 22941586 TI - Research trends of oncology nursing in Japan and around the world. AB - This article reviews recent cancer nursing research in Japan and the USA, and topics relating to international cancer nursing societies. Most of the articles on cancer nursing published in Japan are in the Journal of the Japanese Society of Cancer Nursing. A total of 46 articles have been published over 3 years from 2009, and many of these are qualitative studies aimed at understanding the response of cancer patients to disease along with their symptoms and backgrounds. The International Society of Nurses in Cancer Care (ISNCC) holds a conference biennially, at which cancer nursing research is presented by researchers from around the world. Many pieces of research on the topics of the symptomatic management and health impact of smoking and cancer screening are discussed. Also, at the Congress of the Oncology Nursing Society (ONS), the world's largest cancer nursing society in the USA, a nation advanced in the field of cancer nursing, symptomatic management has already been discussed; however, the topics have been shifting from nausea, vomiting and pain to adverse events induced by novel treatments such as skin alterations, peripheral neuropathy and fatigue. Cancer nursing research is not yet fully mature in terms of the number and range of articles. In nursing research, it is difficult to measure a patient's response to their disease because it includes psychosocial response; the results are difficult to claim as scientific evidence. Therefore, it is still necessary to conduct research with detailed descriptions of clinical phenomena and to develop cancer nursing research, including actual study methodologies. PMID- 22941587 TI - Prognostic value of sonic hedgehog protein expression in gastric cancer. AB - OBJECTIVE: Sonic hedgehog is produced in gastric epithelial cells and plays a crucial role in parietal cell function and the regulation of gastric epithelial cell differentiation. Emerging evidence suggests that the sonic hedgehog pathway is not only involved in the development of cancers but also in their progression and aggressiveness. METHODS: To assess its prognostic value in gastric cancer, sonic hedgehog protein expression was measured by immunohistochemistry in a clinically annotated tissue microarray comprising 319 human gastric cancer specimens. Cytoplasmic sonic hedgehog expression was scored from 0 to 4, reflecting the percentage of sonic hedgehog-positive cells. RESULTS: Specimens were classified into two groups according to their sonic hedgehog score: those with a score ranging from 0 to 3 were considered low expressers and those with a score of 4 were considered overexpressers. The sonic hedgehog overexpression group included more patients with early gastric cancer than the low sonic hedgehog expression group (25.9 vs. 74.1%, P=0.000). Sonic hedgehog expression was lower in patients with lymph node metastasis than in patients without lymph node metastasis (31.4 vs. 68.4%, P=0.02). Similarly, patients with a lower TNM stage showed significantly higher sonic hedgehog expression. In addition, the survival time of patients with sonic hedgehog overexpression was significantly prolonged (69.27+/-1.39 months) compared with that of patients with low sonic hedgehog expression (61.23+/-2.04 months, log-rank test, P=0.03). CONCLUSIONS: These results indicate that sonic hedgehog overexpression may be a marker of good prognosis in gastric cancer. PMID- 22941588 TI - Management of dyslipidemias in the presence of the metabolic syndrome or type 2 diabetes. AB - In the metabolic syndrome and type 2 diabetes, excess energy intake on the background of genetic predisposition and lifestyle factors leads to the dysregulation of fatty acid metabolism and acquired insulin resistance. These initial metabolic defects are reflected to both lipoprotein and glucose metabolism and contribute to increased risk for cardiovascular disease. However, even after controlling for the traditional cardiovascular risk factors, subjects with the metabolic syndrome and type 2 diabetes remain at high residual cardiovascular risk despite of low/normal LDL-cholesterol concentration. For 2 decades, statin therapy has been the cornerstone of treatment of dyslipidemia in these disorders. In the metabolic syndrome and type 2 diabetes, only statin treatment has demonstrated consistently a significant reduction in cardiovascular and all cause mortality in clinical trials. Lately, increased incidence of diabetes especially in the high-risk populations using statins has raised the debate whether statins are indicated for primary prevention especially in the metabolic syndrome. Guidelines recommend intensified lifestyle intervention to those in high risk groups on statin therapy to reduce the residual risk. Despite of the proven efficacy on plasma lipids, fibrate, or niacin as monotherapy, or in combination with statins has failed in reducing cardiovascular mortality. This underlies the fact that improvement in dyslipidemia or other biomarkers is not equal to the reduction in cardiovascular events. However, fibrates in combination with statins seem to be beneficial to reduce CVD events in subjects with low HDL cholesterol (< 0.9-1.1 mmol/L) and elevated triglycerides (> 2.3 mmol/L), but the data are derived from subgroup analysis of clinical trials. The position of niacin and ezetimibe and omega-3 fatty acids in treatment of dyslipidemia in the metabolic syndrome and type 2 diabetes is even less clear and remains to be established in future clinical trials. PMID- 22941589 TI - White coat hypertension: addressing the 10 most important questions. AB - The term 'white coat' hypertension (WC-HTN) is intended to reflect the situation in which measurement of blood pressure (BP) by a health professional (often a physician in a white coat) in an office setting is found to be elevated in comparison with BP measured by a more consistent and less error-prone method such as ambulatory BP monitoring (ABPM), or home BP monitoring (HBPM). Office BP (also sometimes called 'casual BP') has formed the basis of clinical trials that confirm meaningful reductions in MI (25 %), stroke (40 %), and heart failure (50 %) with pharmacotherapy. Nonetheless, within clinical trials, a substantial minority of patients have been determined to have WC-HTN, for which treatment is not known to be of benefit, and is hence not indicated. Clinicians continue to have a good deal of uncertainty about the definition, consequences, course, and best management of WC-HTN. The intention of this communication is to address the top priority questions about WC-HTN to enable clinicians to become more confident in its identification and management. PMID- 22941590 TI - COPD is associated with production of autoantibodies to a broad spectrum of self antigens, correlative with disease phenotype. AB - The role of autoimmune pathology in development and progression of chronic obstructive pulmonary disease (COPD) is becoming increasingly appreciated. In this study, we identified serum autoantibody reactivities associated with chronic bronchitis or emphysema, as well as systemic autoimmunity and associated lung disease. Using autoantigen array analysis, we demonstrated that COPD patients produce autoantibodies reactive to a broad spectrum of self-antigens. Further, the level and reactivities of these antibodies, or autoantibody profile, correlated with disease phenotype. Patients with emphysema produced autoantibodies of higher titer and reactive to an increased number of array antigens. Strikingly, the autoantibody reactivities observed in emphysema were increased over those detected in rheumatoid arthritis patients, and included similar reactivities to those associated with lupus. These findings raise the possibility that autoantibody profiles may be used to determine COPD risk, as well as provide a diagnostic and prognostic tool. They shed light on the heterogeneity of autoantibody reactivities associated with COPD phenotype and could be of use in the personalization of medical treatment, including determining and monitoring therapeutic interventions. PMID- 22941592 TI - DNA repair: front and center and not going away! AB - This introduction to the book: DNA repair protocols: third edition, edited by Bjergbaek, discusses the history and more recent developments in the field of DNA repair. This research field started in the 1950 and developed from a small group of researchers interested in the damage caused to DNA by ultraviolet irradiation from the sun to become a large field of research today. DNA damage and its repair are now thought to play an important role in the etiologies of cancer, aging, and neurodegeneration and there is a great deal of interest in this venture. Thus, understanding of DNA processing is now a central field in molecular and cellular biology, and the field is still growing. PMID- 22941593 TI - Identification of genes required for damage survival using a cell-based RNAi screen against the Drosophila genome. AB - Exposure to DNA-damaging agents invokes biological responses necessary for damage recovery and cell survival. Despite the presence of intact DNA repair pathways, lack of certain other biological pathways has been shown to sensitize cells to DNA-damaging agents' exposure. It is likely that following DNA damage a complex interplay between DNA repair pathways and other biological pathways might be required to ensure cell survival. In this chapter, we describe a high-throughput method for the identification of genes essential for cell survival following DNA damage by using a cell-based assay to measure viability in combination with an RNA interference-based genome-wide screening experiment. PMID- 22941591 TI - Antigen and cytokine receptor signals guide the development of the naive mature B cell repertoire. AB - Immature B cells are generated daily in the bone marrow tissue. More than half of the newly generated immature B cells are autoreactive and bind a self-antigen, while the others are nonautoreactive. A selection process has evolved on the one hand to thwart development of autoreactive immature B cells and, on the other hand, to promote further differentiation of nonautoreactive immature B cells into transitional and mature B cells. These negative and positive selection events are carefully regulated by signals that emanate from the antigen receptor, whether antigen-mediated or tonic, and are influenced by signals that are generated by receptors that bind cytokines, chemokines, and other factors produced in the bone marrow tissue. These signals, therefore, are the predominant driving forces for the generation of a B cell population that is capable of protecting the body from infections while maintaining self-tolerance. Here, we review recent findings from our group and others that describe how tonic antigen receptor signaling and bone marrow cytokines regulate the selection of immature B cells. PMID- 22941594 TI - Isolating genes involved with genotoxic drug response in the nematode Caenorhabditis elegans using genome-wide RNAi screening. AB - The soil nematode Caenorhabditis elegans has become a popular genetic model organism used to study a broad range of complex biological processes, including development, aging, apoptosis, and DNA damage responses. Many genetic tools and tricks have been developed in C. elegans including knock down of gene expression via RNA interference (RNAi). In C. elegans RNAi can effectively be administrated via feeding the nematodes bacteria expressing double-stranded RNA targeting the gene of interest. Several commercial C. elegans RNAi libraries are available and hence gene inactivation using RNAi can relatively easily be performed in a genome wide fashion. In this chapter we give a protocol for using genome-wide RNAi screening to identify genes involved with the response to genotoxic stress. PMID- 22941595 TI - Establishment of the DNA repair-defective mutants in DT40 cells. AB - The chicken B cell line DT40 has been widely used as a model system for reverse genetics studies in higher eukaryotes, because of its advantages including efficient gene targeting and ease of chromosome manipulation. Although the genetic approach using the RNA interference technique has become the standard method particularly in human cells, DT40 still remains a powerful tool to investigate the regulation and function of genes and proteins in a vertebrate system, because of feasibility of easy, rapid, and clear genetic experiments. The use of DT40 cells for DNA repair research has several advantages. In addition to canonical assays for DNA repair, such as measurement of the sensitivities toward DNA damage reagents, it is possible to measure homologous recombination and translesion synthesis activities using activation-induced deaminase (AID)-induced diversification of the immunoglobulin locus. In this chapter, we would describe a detailed protocol for gene disruption experiments in DT40 cells. PMID- 22941596 TI - Electrophoretic mobility shift assays for protein-DNA complexes involved in DNA repair. AB - The electrophoretic mobility shift assay (EMSA) can be used to study proteins that bind to DNA structures created by DNA-damaging agents. UV-damaged DNA binding protein (UV-DDB), which is involved in nucleotide excision repair, binds to DNA damaged by ultraviolet radiation or the anticancer drug cisplatin. Ku, XRCC4/Ligase IV, and DNA-PKcs, which are involved in the repair of DNA double strand breaks by nonhomologous end joining, assemble in complexes at DNA ends. This chapter will describe several EMSA protocols for detecting different DNA repair protein-DNA complexes. To obtain additional information, one can apply variations of the EMSA, which include the reverse EMSA to detect binding of (35)S labeled protein to damaged DNA, and the antibody supershift assay to detect the presence of a specific protein in the protein-DNA complex. PMID- 22941597 TI - The comet assay: a sensitive genotoxicity test for the detection of DNA damage and repair. AB - The comet assay (single-cell gel electrophoresis) is a simple and sensitive method for studying DNA damage and repair. In this microgel electrophoresis technique, a small number of cells suspended in a thin agarose gel on a microscope slide is lysed, electrophoresed, and stained with a fluorescent DNA binding dye. Cells with increased DNA damage display increased migration of chromosomal DNA from the nucleus towards the anode, which resembles the shape of a comet. The assay has manifold applications in fundamental research for DNA damage and repair, in genotoxicity testing of novel chemicals and pharmaceuticals, environmental biomonitoring, and human population monitoring. This chapter describes a standard protocol of the alkaline comet assay and points to some useful modifications. PMID- 22941598 TI - Detection of DNA damage by comet fluorescence in situ hybridization. AB - Comet fluorescence in situ hybridization (Comet-FISH) is a useful method to detect overall and region-specific DNA damage in individual cells. Two well established methods are combined, the Comet assay (single cell gel electrophoresis) and fluorescence in situ hybridization (FISH). The Comet assay is the method of choice for the detection of DNA damage. With the alkaline version the influence of specific substances such as water pollutants or ingredients of food on individual cells can be easily measured. The Comet assay involves the embedding of cells in agarose on microscopic slides, lysis of cells, and separation of DNA via electrophoresis. Damaged DNA migrates from the nucleus (head of the comet) forming a tail. The percentage of DNA in the tail correlates with the degree of DNA strand breaks (DNA damage). The combination of FISH with the Comet assay uses labeled probes which hybridize specifically to selected DNA sequences. This allows the detection of specific DNA damage or repair capacity in single cells. Here we present exemplarily the Comet-FISH method by detection of DNA damage using hydrogen peroxide as a genotoxic model substrate. PMID- 22941599 TI - Quantitative DNA damage and repair measurement with the yeast comet assay. AB - The yeast comet assay is a fast, sensitive, and inexpensive technique to measure oxidative DNA damage, DNA damage repair, and the genotoxic or protective effects of chemicals. The main advantage over the comet assay using cells of higher organisms is the genetic tractability and ease of cultivation of yeast. A drawback is the lower DNA content of the cells as well as the need for cell wall digestion prior to electrophoresis. Here, we describe in detail a recently developed protocol that permits sensitive and reproducible measurement of DNA damage and DNA repair using Saccharomyces cerevisiae as model system. The combination of this assay with yeast mutants affected in genome maintenance and the wide selection of available yeast molecular biology tools can contribute to illuminate fundamental mechanisms of DNA damage, repair, and activity of DNA protective compounds. PMID- 22941601 TI - In vitro DNA mismatch repair in human cells. AB - The in vitro DNA mismatch repair (MMR) assay is a very useful technique for studying the functions and the mechanisms of the MMR system in genome maintenance. This assay has been effectively used to evaluate MMR proficiency in various tumor cells and to identify the majority of the protein components required for MMR. The procedure for setting up and performing the MMR assay involves mismatch substrate preparation, cell extract preparation, and the repair assay. In this chapter, we describe the detailed methods for this functional in vitro assay. PMID- 22941600 TI - Analysis of DNA damage and repair in nuclear and mitochondrial DNA of animal cells using quantitative PCR. AB - This chapter was written as a guide to using the long-amplicon quantitative PCR (QPCR) assay for the measurement of DNA damage in mammalian as well as nonmammalian species such as Caenorhabditis elegans (nematodes), Drosophila melanogaster (fruit flies), and two species of fish (Fundulus heteroclitus and Danio rerio). Since its development in the early 1990s (Kalinowski et al., Nucleic Acids Res 20:3485-3494, 1992; Salazar and Van Houten, Mutat Res 385:139 149, 1997; Yakes and Van Houten, Proc Natl Acad Sci USA 94:514-519, 1997), the QPCR assay has been widely used to measure DNA damage and repair kinetics in nuclear and mitochondrial genomes after genotoxin exposure (Yakes and Van Houten, Proc Natl Acad Sci USA 94:514-519, 1997; Santos et al., J Biol Chem 278:1728 1734, 2003; Mandavilli et al., Mol Brain Res 133:215-223, 2005). One of the main strengths of the assay is that the labor-intensive and artifact-generating step of mitochondrial isolation is not needed for the accurate measurement of mitochondrial DNA copy number and damage. Below we present the advantages and limitations of using QPCR to assay DNA damage in animal cells and provide a detailed protocol of the QPCR assay that integrates its usage in newly developed animal systems. PMID- 22941602 TI - Eukaryotic DNA mismatch repair in vitro. AB - Mismatch repair corrects biosynthetic errors generated during DNA replication. Mismatch repair deficiency causes a mutator phenotype and directly underlies hereditary nonpolyposis colorectal cancer and some sporadic cancers. Because of remarkably high conservation of the mismatch repair machinery between the budding yeast (Saccharomyces cerevisiae) and humans, the study of mismatch repair in yeast has provided tremendous insights into the mechanisms of this repair pathway in humans. Here we describe a set of practical protocols for how to prepare the yeast and HeLa cell-free nuclear extracts and site-specific DNA mismatch substrates, and how to carry out the in vitro mismatch repair assay. We validated the yeast cell-free system by the mismatch repair deficient strain (Deltamsh2) and the complementation assay with purified yeast MutSalpha. PMID- 22941603 TI - Immuno-slot blot assay for detection of UVR-mediated DNA damage. AB - Solar ultraviolet radiation (UVR), through the formation of DNA photolesions, is the primary cause of most skin cancers. A better understanding of the mechanisms of UVR-induced DNA damage may help prevent skin cancer and this may be achieved using methods to quantify DNA damage. The immuno-slot blot (ISB) method is routinely used for detection and quantification of any heat- and alkali-stable DNA adducts for which a sufficiently specific monoclonal antibody is available. The main steps in ISB are fragmentation and denaturation of the DNA, immobilization of DNA to a nitrocellulose filter, incubation with primary antibody against a specific DNA adduct, incubation with an enzyme-linked secondary antibody and finally chemiluminescence detection and quantification of the DNA adducts. PMID- 22941604 TI - Quantification of DNA photoproducts in mammalian cell DNA using radioimmunoassay. AB - Over the past 25 years, the use of polyclonal and monoclonal antibodies to quantify DNA damage has burgeoned. Immunoassays offer distinct advantages over other analytical procedures currently used to measure DNA damage including adaptability, sensitivity, and selectivity. This combination of attributes allows for the development of powerful analytical techniques to visualize and quantify specific types of DNA damage in cells, tissue, and organisms exposed to subtoxic levels of xenobiotics with distinct advantages over the other procedures in the analysis of DNA damage in human and environmental samples. Radioimmunoassay (RIA) is readily applied to a variety of biological materials and has typically been used to measure DNA damage in cell and organ cultures, tissue sections and biopsies, buccal cells, bone marrow aspirates, peripheral blood lymphocytes, and urine. Here we describe the use of a very sensitive RIA for the specific quantitation of cyclobutane dimers and (6-4) photoproducts in DNA extracted from mammalian cells and tissues. PMID- 22941605 TI - Measuring the formation and repair of UV damage at the DNA sequence level by ligation-mediated PCR. AB - The formation and repair of DNA damage at specific locations in the genome is modulated by DNA sequence context, by DNA cytosine-5 methylation patterns, by the transcriptional status of the locus and by proteins associated with the DNA. The only method currently available to allow precise sequence mapping of DNA lesions in mammalian cells is the ligation-mediated polymerase chain reaction (LM-PCR) technique. We provide an update on technical details of LM-PCR. LM-PCR can be used, for example, for mapping of ultraviolet (UV) light-induced DNA photoproducts such as cyclobutane pyrimidine dimers. PMID- 22941606 TI - Construction of plasmids containing site-specific DNA interstrand cross-links for biochemical and cell biological studies. AB - Plasmids containing a site-specific DNA interstrand cross-link (ICL) are invaluable tools for the investigation of ICL repair pathways at the biochemical and cellular level. We describe a procedure for preparation of plasmid DNA substrates containing a single ICL at a specific site. The procedure is versatile, leads to reliable yields of pure DNA substrate, and is suitable for the incorporation of virtually any type of DNA lesion into plasmids. PMID- 22941607 TI - Replication-coupled DNA interstrand cross-link repair in Xenopus egg extracts. AB - Interstrand cross-links (ICL) are one of the most hazardous types of DNA damage as they form a roadblock to all processes that involve strand separation. Repair of these lesions involves several different DNA repair pathways, but the molecular mechanism is unclear. Here we describe a system that allows the examination of ICL repair, via a physiological mechanism, in vitro. This system, which uses Xenopus egg extracts in combination with a DNA template that contains a site-specific ICL, represents a unique tool to study the molecular mechanism of ICL repair. PMID- 22941608 TI - In vitro base excision repair using mammalian cell extracts. AB - Base excision repair (BER) is an essential cellular mechanism that maintains genome stability by repairing DNA damage, such as DNA base lesions, base loss (AP sites) and single strand breaks, generated through endogenous metabolism or via exogenous mutagens. Therefore, in vitro BER assays are important for our understanding of the mechanism of cellular response to mutagens and may also reveal important information about the development of several DNA repair-related human diseases, such as cancer, and aging. Here, we describe the preparation and use of mammalian cell extracts in in vitro BER assays using both oligonucleotide and closed circular DNA substrates containing site-specific DNA lesions, in combination with denaturing acrylamide gel electrophoresis and phosphor imaging analysis. PMID- 22941609 TI - Using Arabidopsis cell extracts to monitor repair of DNA base damage in vitro. AB - Base excision repair (BER) is a major pathway for the removal of endogenous and exogenous DNA damage. This repair mechanism is initiated by DNA glycosylases that excise the altered base, and continues through alternative routes that culminate in DNA resynthesis and ligation. In contrast to the information available for microbes and animals, our knowledge about this important DNA repair pathway in plants is very limited, partially due to a lack of biochemical approaches. Here we describe an in vitro assay to monitor BER in cell-free extracts from the model plant Arabidopsis thaliana. The assay uses labeled DNA substrates containing a single damaged base within a restriction site, and allows detection of fully repaired molecules as well as DNA repair intermediates. The method is easily applied to measure the repair activity of purified proteins and can be successfully used in combination with the extensive array of biological resources available for Arabidopsis. PMID- 22941610 TI - In vitro monitoring of base excision repair in Saccharomyces cerevisiae. AB - Base excision repair (BER) is an important mechanism to maintain genomic stability. Here we offer a set of protocols to quantitatively analyze BER capacity in whole cell-free yeast extracts. Cell-free yeast extracts were obtained by a French press procedure and repair capacities were measured by using oligonucleotide substrates. Repair products were separated by polyacrylamide gel electrophoresis and detected by autoradiography. These set of methods allow the analysis of different kinds of base damage and of individual mechanistic steps within BER. We used these protocols to investigate a new role of the DNA double strand break repair protein XRS1 in BER (1). PMID- 22941611 TI - Mitochondrial base excision repair assays. AB - Mitochondrial DNA (mtDNA) is constantly exposed to oxidative injury. Due to its location close to the main site of reactive oxygen species, the inner mitochondrial membrane, mtDNA is more susceptible than nuclear DNA to oxidative damage. The accumulation of DNA damage is thought to be particularly deleterious in post-mitotic cells, including neurons, and to play a critical role in the aging process and in a variety of diseases. Thus, efficient mtDNA repair is important for the maintenance of genomic integrity and a healthy life. The base excision repair (BER) mechanism was the first to be described in mitochondria, and consequently it is the best known. This chapter outlines protocols for isolating mitochondria from mammalian cells in culture and from rodent tissues including liver and brain. It also covers the isolation of synaptic mitochondria. BER takes place in four distinct steps, and protocols describing in vitro assays for measuring these enzymatic steps in lysates of isolated mitochondria are included. PMID- 22941612 TI - O-hydroxylamine-coupled alkaline gel electrophoresis assay for the detection and measurement of DNA single-strand breaks. AB - The ability to detect and measure DNA single-strand breaks has been the aim of numerous assays developed to assess genotoxicity. These methods often rely on alkaline conditions to denature DNA. However, alkaline treatment of DNA also introduces artifactual SSBs through the cleavage of alkali-labile sites resulting in confounded data. Here, we describe a modified alkaline gel electrophoresis assay coupled with a neutral O-hydroxylamine to obtain the measurement of true SSB formation. PMID- 22941613 TI - DNA double-strand break damage and repair assessed by pulsed-field gel electrophoresis. AB - Pulsed-field gel electrophoresis (PFGE) is a technique for resolving large (up to 10 Mb) DNA molecules. Using multiple pairs of electrodes DNA is subject to an alternating electric field through a solid agarose matrix. As the current changes direction the reorientation time of DNA is proportional to molecular weight; thus fragments are separated in the gel based on their size. Here we describe the use of PFGE to analyze DNA double-strand break formation and repair in human chromosomal DNA. PMID- 22941614 TI - Quantitative amplification of single-stranded DNA. AB - Single-stranded DNA (ssDNA) intermediates play an important role in processes such as DNA replication and homologous recombination, DNA damage responses, and DNA repair. Using quantitative amplification of ssDNA (QAOS), ssDNA arising during various cellular processes in complex genomes can be quantified at numerous single-copy and repetitive loci. QAOS is a useful tool to gain insights into the cellular processes that involve ssDNA and the roles of proteins in regulating ssDNA production and responses to ssDNA. PMID- 22941615 TI - Simple, non-radioactive measurement of single-stranded DNA at telomeric, sub telomeric, and genomic loci in budding yeast. AB - Single-stranded DNA (ssDNA) is a DNA repair, replication, and recombination intermediate and a stimulus for checkpoint kinase-dependent cell cycle arrest. Current assays to detect ssDNA generated in vivo are indirect, laborious, and generally require the use of radioactivity. Here, we describe simple, quantitative approaches to measure ssDNA generated in yeast, at single- and multi copy chromosomal loci and in highly repetitive telomeric sequences. We describe a fluorescence in-gel assay to measure ssDNA in the telomeric TG repeats of telomere cap-defective budding yeast yku70? and cdc13-1 mutants. We also describe a rapid method to prepare DNA for Quantitative Amplification of ssDNA, used to measure ssDNA in single-copy and repetitive sub-telomeric loci. These complementary methods are useful to understand the important roles of ssDNA in yeast cells and could be readily extended to other cell types. PMID- 22941616 TI - Monitoring DNA recombination initiated by HO endonuclease. AB - DNA double-strand breaks (DSBs) have proven to be very potent initiators of recombination in yeast and other organisms. A single, site-specific DSB initiates homologous DNA repair events such as gene conversion, break-induced replication, and single-strand annealing, as well as nonhomologous end joining, microhomology mediated end joining, and new telomere addition. When repair is either delayed or prevented, a single DSB can trigger checkpoint-mediated cell cycle arrest. In budding yeast, expressing the HO endonuclease under the control of a galactose inducible promoter has been instrumental in the study of these processes by providing us a way to synchronously induce a DSB at a unique site in vivo. We describe how the HO endonuclease has been used to study the recombination events in mating-type (MAT) switching. Southern blots provide an overview of the process by allowing one to examine the formation of the DSB, DNA degradation at the break, and formation of the product. Denaturing gels and slot blots as well as PCR have provided important tools to follow the progression of resection in wild type and mutant cells. PCR has also been important in allowing us to follow the kinetics of certain recombination intermediates such as the initiation of repair DNA synthesis or the removal of nonhomologous Y sequences during MAT switching. Finally chromatin immunoprecipitation has been used to follow the recruitment of key proteins to the DSB and in subsequent steps in DSB repair. PMID- 22941617 TI - Monitoring I-SceI-induced double-strand break repair in DT40 cells. AB - The chicken B lymphocyte cell line DT40 is now a well-established system for studying DNA repair in vertebrates. Central to its utility is its ready genetic tractability allowing for the creation of isogenic mutants in any chosen gene. The combination of this genetic tractability with the I-SceI-induced double strand break (DSB) repair assay, pioneered by the laboratory of Maria Jasin, has proven particularly powerful for dissecting the pathways of DSB repair in a vertebrate setting. PMID- 22941618 TI - I-SceI-based assays to examine distinct repair outcomes of mammalian chromosomal double strand breaks. AB - Chromosomal double strand breaks (DSBs) can be repaired by a number of mechanisms that result in diverse genetic outcomes. To examine distinct outcomes of chromosomal DSB repair, a panel of human cell lines has been developed that contain GFP-based reporters with recognition sites for the rare-cutting endonuclease I-SceI. One set of reporters is used to measure DSB repair events that require access to homology: homology-directed repair, homology-directed repair that requires the removal of a nonhomologous insertion, single strand annealing, and alternative end joining. An additional reporter (EJ5-GFP) is used to measure end joining (EJ) between distal DSB ends of two tandem I-SceI sites. These Distal-EJ events do not require access to homology, and thus are distinct from the repair events described above. Indeed, this assay provides a measure of DSB end protection during EJ, via physical analysis of Distal-EJ products to determine the frequency of I-SceI-restoration. The EJ5-GFP reporter can also be adapted to examine EJ of non-cohesive DSB ends, using co-expression of I-SceI with a non-processive 3' exonuclease (Trex2), which can cause partial degradation of the 4 nucleotide 3' cohesive overhangs generated by I-SceI. Such co-expression of I-SceI and Trex2 leads to measurable I-SceI-resistant EJ products that use proximal DSB ends (Proximal-EJ), as well as distal DSB ends (Distal-EJ). Therefore, this co-expression approach can be used to examine the relative frequency of Proximal-EJ versus Distal-EJ, and hence provide a measure of the fidelity of end utilization during repair of multiple DSBs. In this report, the repair outcomes examined by each reporter are described, along with methods for cell culture, transient expression of I-SceI and Trex2, and repair product analysis. PMID- 22941619 TI - Studying repair of a single protein-bound nick in vivo using the Flp-nick system. AB - The Flp-nick system is a simple in vivo system developed for studying the cellular responses to a protein-bound nick at a single genomic site in the budding yeast Saccharomyces cerevisiae. The Flp-nick system takes advantage of a mutant Flp recombinase that can introduce a nick at a specific Flp recombinase recognition target (FRT) site, which has been integrated into the yeast genome. Upon cleavage at the FRT site, the Flp mutant becomes covalently linked to the 3' DNA end at the nick in an irreversible manner, as the mutant fails to accomplish the required religation process. Thus, the established damage mimics a stabilized topoisomerase I-DNA cleavage complex. DNA topoisomerases are ubiquitous enzymes that relieve topological stress in the DNA arising during DNA replication or transcription. During this process, they make transient enzyme-DNA cleavage complexes, which normally are reversed by a rapid ligation step. However, aberrant long-lived enzyme-DNA complexes may occur frequently due to either endogenous or exogenous damage, and the cellular repair machinery therefore needs to be able to eliminate this type of damage. This chapter describes how to establish the Flp-nick system in S. cerevisiae, how to detect FlpH305L at the FRT site using a modified chromatin immunoprecipitation assay where formaldehyde fixation is omitted, and how to monitor nicking at the FRT site by alkaline denaturing gel analysis. PMID- 22941620 TI - Measurement of diversification in the immunoglobulin light chain gene of DT40 cells. AB - The immunoglobulin loci of the genetically tractable chicken B cell line DT40 provide a unique opportunity to study the cellular response to endogenously generated DNA damage in a chromosomal context. Abasic sites generated by the concerted action of Activation-Induced Deaminase (AID) and Uracil DNA Glycosylase result in both homologous recombination-dependent gene conversion and translesion synthesis-dependent point mutations. The system has provided important insights into both the early stages of AID-dependent immunoglobulin gene diversification and into the relationship between pathways of DNA damage bypass. Here we describe the assays that can be employed to monitor the rate and pattern of immunoglobulin gene diversification at the light chain locus of DT40. PMID- 22941621 TI - Live cell microscopy of DNA damage response in Saccharomyces cerevisiae. AB - Fluorescence microscopy of the DNA damage response in living cells stands out from many other DNA repair assays by its ability to monitor the response to individual DNA lesions in single cells. This is particularly true in yeast, where the frequency of spontaneous DNA lesions is relatively low compared to organisms with much larger genomes such as mammalian cells. Single cell analysis of individual DNA lesions allows specific events in the DNA damage response to be correlated with cell morphology, cell cycle phase, and other specific characteristics of a particular cell. Moreover, fluorescence live cell imaging allows for multiple cellular markers to be monitored over several hours. This chapter reviews useful fluorescent markers and genotoxic agents for studying the DNA damage response in living cells and provides protocols for live cell imaging, time-lapse microscopy, and for induction of site-specific DNA lesions. PMID- 22941622 TI - Use of gene targeting to study recombination in mammalian cell DNA repair mutants. AB - The study of gene function has been greatly facilitated by the development of strategies to modify genomic DNA. Gene targeting is one of the most successfully applied techniques used to examine the roles of specific genes in a wide variety of model systems from yeast to mammals. Our laboratory has pioneered the use of the Chinese hamster ovary (CHO) cell culture model system to study pathways of DNA repair and recombination at the hemizygous CHO APRT locus. By using a simple and effective gene targeting method, we have generated a number of DNA repair deficient cell lines that have been used in targeted recombination experiments to investigate pathways of recombinational repair in somatic mammalian cells. These methods can be readily customized to generate a variety of cell lines deficient in specific genes of interest and can be applied to study the roles of other DNA repair proteins in pathways of mammalian recombinational repair. PMID- 22941623 TI - In vitro rejoining of double strand breaks in genomic DNA. AB - Recent genetic and biochemical studies have provided important insights into the mechanism of nonhomologous end joining (NHEJ) pathways in higher eukaryotes, and have facilitated the functional characterization of several of its components including DNA-PKcs, Ku, DNA ligase IV, XRCC4, XLF/Cernunnos, and Artemis. Nevertheless, there is evidence that as of yet uncharacterized repair factors may contribute to the efficiency of NHEJ, for example by modulating the activity of known factors. Also, the discovery of alternative pathways of NHEJ that function as backup to the classical DNA-PK-dependent pathway of NHEJ has added yet another dimension in the set of activities involved. The biochemical characterization of NHEJ in higher eukaryotes has benefited significantly from in vitro plasmid-based end joining assays. However, because of differences in the organization and sequence of genomic and plasmid DNA, and because multiple pathways of NHEJ are operational, it is possible that different factors are preferred for the rejoining of DSBs induced in plasmid versus genomic DNA organized in chromatin. Here, we describe an in vitro assay that allows the study of DSB rejoining in genomic DNA. The assay utilizes as a substrate DSBs induced by various means in genomic DNA prepared from agarose-embedded cells after appropriate lysis. Two extremes in terms of state of DNA organization are described: "naked" DNA and DNA organized in chromatin. We describe the protocols developed to carry out and analyze these in vitro reactions, including procedures for the preparation of cell extract and the preparation of the substrate DNA ("naked" DNA or nuclei). PMID- 22941624 TI - An in vitro DNA double-strand break repair assay based on end-joining of defined duplex oligonucleotides. AB - DNA double-strand breaks (DSBs) are caused by endogenous cellular processes such as oxidative metabolism, or by exogenous events like exposure to ionizing radiation or other genotoxic agents. Repair of these DSBs is essential for the maintenance of cellular genomic integrity. In human cells, and cells of other higher eukaryotes, DSBs are primarily repaired by the nonhomologous end-joining (NHEJ) DSB repair pathway. Most in vitro assays that have been designed to measure NHEJ activity employ linear plasmid DNA as end-joining substrates, and such assays have made significant contributions to our understanding of the biochemical mechanisms of NHEJ. Here we describe an in vitro end-joining assay employing linear oligonucleotides that has distinct advantages over plasmid-based assays for the study of structure-function relationships between the proteins of the NHEJ pathway and synthetic DNA end-joining substrates possessing predetermined DSB configurations and chemistries. PMID- 22941625 TI - Assays of bypass replication of genotoxic lesions in cell-free extracts. AB - The in vitro replication assay described here measures bidirectional replication of a circular double- stranded DNA template upon initiation at the SV40 origin. It models a single eukaryotic replication unit (replicon) and recapitulates the biochemical steps involved in the catalysis of both leading and lagging strand synthesis during semiconservative DNA replication. Except for the SV40 large T antigen, all other proteins necessary for initiation and assembly of functional replication forks are provided by the cell-free extract. This assay can be used to demonstrate bypass replication of genotoxic lesions. It supports replication across a specific damaged site on the template DNA (i.e., translesion synthesis) by specialized DNA polymerases. This chapter illustrates the efficient translesion synthesis of UV-induced thymine dimers by DNA polymerase eta. PMID- 22941626 TI - Quantitative measurement of translesion DNA synthesis in mammalian cells. AB - Translesion DNA synthesis (TLS) is a DNA damage tolerance mechanism, in which specialized low-fidelity DNA polymerases bypass lesions that interfere with replication. This process is inherently mutagenic due to the miscoding nature of DNA lesions, but it prevents double strand breaks, genome instability, and cancer. We describe here a quantitative method for measuring TLS in mammalian cells, based on non-replicating plasmids that carry a defined and site-specific DNA lesion in a single-stranded DNA region opposite a gap. The assay is responsive to the cellular composition of TLS DNA polymerases, and TLS regulators. It can be used with a broad variety of cultured mammalian cells, and is amenable to RNAi gene silencing, making it a useful tool in the study of TLS in mammalian cells. PMID- 22941627 TI - Detection of PCNA modifications in Saccharomyces cerevisiae. AB - PCNA modifications by members of the ubiquitin family are associated with a range of different transactions during replication of damaged and undamaged DNA. This chapter describes detailed protocols for the detection and isolation of ubiquitin and SUMO conjugates of PCNA from total budding yeast cell lysates, using Ni-NTA affinity chromatography under denaturing conditions. We describe approaches based on the purification of PCNA itself and on the isolation of total ubiquitin or SUMO conjugates. The chapter covers the construction of the appropriate strains, methods for the detection of modified PCNA, and the use of various DNA-damaging agents as well as mutants of PCNA and relevant conjugation enzymes to examine the cellular response to replication stress. PMID- 22941628 TI - In vitro PCNA modification assays. AB - Modification of the replicative sliding clamp, PCNA, by monoubiquitin, polyubiquitin, and SUMO contributes to the processing of DNA damage during replication. In order to investigate the properties of the relevant conjugation enzymes, their interactions, substrate recognition, and the regulation of their activities, reconstitution of the modification reactions from purified components in vitro is an instructive exercise. Here we describe the purification of the relevant enzymes and accessory proteins from E. coli or S. cerevisiae as well as protocols for setting up small-scale ubiquitylation and sumoylation reactions with budding yeast PCNA. In addition, we provide a method for the purification of monoubiquitylated PCNA for further biochemical studies. PMID- 22941629 TI - Analysis of inhibition of DNA replication in irradiated cells using the SV40 based in vitro assay of DNA replication. AB - The deleterious effects of DNA damage on DNA replication have been demonstrated in many model systems and the mechanisms of the resulting inhibition have been a research focus for at least 40 years. Moreover, recent studies have identified several major components of the S-phase checkpoint, providing a mechanistic background for understanding the basis of inhibition of the initiation and elongation steps of DNA replication after DNA damage. Yet several aspects of the underlying biochemical mechanisms remain unresolved including the characterization of the enzymatic activities involved in checkpoint activation and the coordination of this process with DNA repair. Helpful for the delineation of the mechanism of the S-phase checkpoint is the observation that factors inhibiting DNA replication in vivo can be found in active form in extracts prepared from irradiated cells, when these are tested using the simian virus 40 (SV40) assay for in vitro DNA replication. In this assay, replication of plasmid DNA carrying the minimal origin of SV40 DNA replication is achieved in vitro using cytoplasmic cell extracts and SV40 large tumor antigen (TAg) as the only noncellular protein. Here, we describe protocols developed to measure in vitro DNA replication with the purpose of analyzing its regulation after exposure to DNA damage. The procedures include the preparation of components of the in vitro DNA replication reaction including cytoplasmic extracts from cells that have sustained DNA damage. The assay provides a powerful tool for investigating the effect of distinct agents acting either by inducing lesions in the DNA, or by inhibiting the functions of checkpoint proteins. Nevertheless, the fact that several steps of DNA replication initiation are carried out in this in vitro assay by TAg and not the corresponding cellular factors, might be considered as a limitation of the approach. PMID- 22941630 TI - CHK1 kinase activity assay. AB - Mammalian CHK1 is a Ser/Thr kinase that plays a critical role in the DNA damage activated cell cycle checkpoint signaling pathway downstream of ATR (ATM and Rad3 related protein kinase). This chapter focuses on describing an assay to measure CHK1 activity in vitro. The basic mechanism of this assay is to observe the phosphorylated levels of a fragment of CDC25C containing the site that can be phosphorylated by CHK1 in vitro. This assay includes five major steps: (1) preparing extracts from the control or treated cells, (2) preparing substrate, (3) immunoprecipitating CHK1 protein from the cells, (4) assembling the kinase assay, (5) analyzing the phosphorylated level of the substrates by CHK1. Besides CHK1, CHK2 is another important checkpoint regulator that responds to DNA damage. Because CHK1 and CHK2 share some substrates such as CDC25C in vitro, this assay could also be used for a CHK2 activity assay, except that the CHK2 antibody will be replaced by the CHK1 antibody. PMID- 22941631 TI - Histone H2AX phosphorylation: a marker for DNA damage. AB - The DNA damage response can be initiated in response to a variety of stress signals that are encountered during physiological processes or in response to exogenous cues, such as ionizing radiation or DNA-damaging therapeutic agents. A number of methods have been developed to examine the morphological, biochemical, and molecular changes that take place during the DNA damage response. When cells are exposed to ionizing radiation or DNA-damaging chemotherapeutic agents, double stranded breaks (DSBs) are generated that rapidly result in the phosphorylation of histone H2A variant H2AX. Because phosphorylation of H2AX at Ser 139 (gamma H2AX) is abundant, fast, and correlates well with each DSB, it is the most sensitive marker that can be used to examine the DNA damage produced and the subsequent repair of the DNA lesion. gamma-H2AX can be detected by immunoblotting and immunostaining using microscopic or flow cytometric detection. Since gamma H2AX can be also generated during DNA replication, as a consequence of apoptosis, or as it is found associated with residual DNA damage, it is important to determine the kinetics, number, size, and morphology of gamma-H2AX-associated foci. This chapter describes a few standard protocols that we have successfully used in our laboratory for a number of experimental systems, primarily hematologic and epithelial cells grown in culture. PMID- 22941632 TI - A global sampling approach to designing and reengineering RNA secondary structures. AB - The development of algorithms for designing artificial RNA sequences that fold into specific secondary structures has many potential biomedical and synthetic biology applications. To date, this problem remains computationally difficult, and current strategies to address it resort to heuristics and stochastic search techniques. The most popular methods consist of two steps: First a random seed sequence is generated; next, this seed is progressively modified (i.e. mutated) to adopt the desired folding properties. Although computationally inexpensive, this approach raises several questions such as (i) the influence of the seed; and (ii) the efficiency of single-path directed searches that may be affected by energy barriers in the mutational landscape. In this article, we present RNA ensign, a novel paradigm for RNA design. Instead of taking a progressive adaptive walk driven by local search criteria, we use an efficient global sampling algorithm to examine large regions of the mutational landscape under structural and thermodynamical constraints until a solution is found. When considering the influence of the seeds and the target secondary structures, our results show that, compared to single-path directed searches, our approach is more robust, succeeds more often and generates more thermodynamically stable sequences. An ensemble approach to RNA design is thus well worth pursuing as a complement to existing approaches. RNA-ensign is available at http://csb.cs.mcgill.ca/RNAensign. PMID- 22941633 TI - CpG_MPs: identification of CpG methylation patterns of genomic regions from high throughput bisulfite sequencing data. AB - High-throughput bisulfite sequencing is widely used to measure cytosine methylation at single-base resolution in eukaryotes. It permits systems-level analysis of genomic methylation patterns associated with gene expression and chromatin structure. However, methods for large-scale identification of methylation patterns from bisulfite sequencing are lacking. We developed a comprehensive tool, CpG_MPs, for identification and analysis of the methylation patterns of genomic regions from bisulfite sequencing data. CpG_MPs first normalizes bisulfite sequencing reads into methylation level of CpGs. Then it identifies unmethylated and methylated regions using the methylation status of neighboring CpGs by hotspot extension algorithm without knowledge of pre-defined regions. Furthermore, the conservatively and differentially methylated regions across paired or multiple samples (cells or tissues) are identified by combining a combinatorial algorithm with Shannon entropy. CpG_MPs identified large amounts of genomic regions with different methylation patterns across five human bisulfite sequencing data during cellular differentiation. Different sequence features and significantly cell-specific methylation patterns were observed. These potentially functional regions form candidate regions for functional analysis of DNA methylation during cellular differentiation. CpG_MPs is the first user-friendly tool for identifying methylation patterns of genomic regions from bisulfite sequencing data, permitting further investigation of the biological functions of genome-scale methylation patterns. PMID- 22941634 TI - Composition-based classification of short metagenomic sequences elucidates the landscapes of taxonomic and functional enrichment of microorganisms. AB - Compared with traditional algorithms for long metagenomic sequence classification, characterizing microorganisms' taxonomic and functional abundance based on tens of millions of very short reads are much more challenging. We describe an efficient composition and phylogeny-based algorithm [Metagenome Composition Vector (MetaCV)] to classify very short metagenomic reads (75-100 bp) into specific taxonomic and functional groups. We applied MetaCV to the Meta-HIT data (371-Gb 75-bp reads of 109 human gut metagenomes), and this single-read based, instead of assembly-based, classification has a high resolution to characterize the composition and structure of human gut microbiota, especially for low abundance species. Most strikingly, it only took MetaCV 10 days to do all the computation work on a server with five 24-core nodes. To our knowledge, MetaCV, benefited from the strategy of composition comparison, is the first algorithm that can classify millions of very short reads within affordable time. PMID- 22941635 TI - Specific contacts of the -35 region of the galP1 promoter by RNA polymerase inhibit GalR-mediated DNA looping repression. AB - The P1 promoter of the galactose operon in Escherichia coli is one of the best studied examples of 'extended -10' promoters. Recognition of the P1 promoter does not require specific contacts between RNA polymerase and its poor -35 element. To investigate whether specific recognition of the -35 element would affect the regulation of P1 by GalR, we mutagenized the -35 element of P1, isolated variants of the -35 element and studied the regulation of the mutant promoters by in vitro transcription assays and by mathematical modeling. The results show that the GalR mediated DNA loop is less efficient in repressing P1 transcription when RNA polymerase binds to the -10 and -35 elements concomitantly. Our results suggest that promoters that lack specific -35 element recognition allow decoupling of local chromosome structure from transcription initiation. PMID- 22941636 TI - The structural basis of differential DNA sequence recognition by restriction modification controller proteins. AB - Controller (C) proteins regulate the expression of restriction-modification (RM) genes in a wide variety of RM systems. However, the RM system Esp1396I is of particular interest as the C protein regulates both the restriction endonuclease (R) gene and the methyltransferase (M) gene. The mechanism of this finely tuned genetic switch depends on differential binding affinities for the promoters controlling the R and M genes, which in turn depends on differential DNA sequence recognition and the ability to recognize dual symmetries. We report here the crystal structure of the C protein bound to the M promoter, and compare the binding affinities for each operator sequence by surface plasmon resonance. Comparison of the structure of the transcriptional repression complex at the M promoter with that of the transcriptional activation complex at the R promoter shows how subtle changes in protein-DNA interactions, underpinned by small conformational changes in the protein, can explain the molecular basis of differential regulation of gene expression. PMID- 22941637 TI - Mitochondrial DNA copy number is regulated in a tissue specific manner by DNA methylation of the nuclear-encoded DNA polymerase gamma A. AB - DNA methylation is an essential mechanism controlling gene expression during differentiation and development. We investigated the epigenetic regulation of the nuclear-encoded, mitochondrial DNA (mtDNA) polymerase gamma catalytic subunit (PolgA) by examining the methylation status of a CpG island within exon 2 of PolgA. Bisulphite sequencing identified low methylation levels (<10%) within exon 2 of mouse oocytes, blastocysts and embryonic stem cells (ESCs), while somatic tissues contained significantly higher levels (>40%). In contrast, induced pluripotent stem (iPS) cells and somatic nuclear transfer ESCs were hypermethylated (>20%), indicating abnormal epigenetic reprogramming. Real time PCR analysis of 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC) immunoprecipitated DNA suggests active DNA methylation and demethylation within exon 2 of PolgA. Moreover, neural differentiation of ESCs promoted de novo methylation and demethylation at the exon 2 locus. Regression analysis demonstrates that cell-specific PolgA expression levels were negatively correlated with DNA methylation within exon 2 and mtDNA copy number. Finally, using chromatin immunoprecipitation (ChIP) against RNA polymerase II (RNApII) phosphorylated on serine 2, we show increased DNA methylation levels are associated with reduced RNApII transcriptional elongation. This is the first study linking nuclear DNA epigenetic regulation with mtDNA regulation during differentiation and cell specialization. PMID- 22941638 TI - Yeast CAF-1 assembles histone (H3-H4)2 tetramers prior to DNA deposition. AB - Following acetylation, newly synthesized H3-H4 is directly transferred from the histone chaperone anti-silencing factor 1 (Asf1) to chromatin assembly factor 1 (CAF-1), another histone chaperone that is critical for the deposition of H3-H4 onto replicating DNA. However, it is unknown how CAF-1 binds and delivers H3-H4 to the DNA. Here, we show that CAF-1 binds recombinant H3-H4 with 10- to 20-fold higher affinity than H2A-H2B in vitro, and H3K56Ac increases the binding affinity of CAF-1 toward H3-H4 2-fold. These results provide a quantitative thermodynamic explanation for the specific H3-H4 histone chaperone activity of CAF-1. Surprisingly, H3-H4 exists as a dimer rather than as a canonical tetramer at mid to-low nanomolar concentrations. A single CAF-1 molecule binds a cross-linked (H3 H4)2 tetramer, or two H3-H4 dimers that contain mutations at the (H3-H4)2 tetramerization interface. These results suggest that CAF-1 binds to two H3-H4 dimers in a manner that promotes formation of a (H3-H4)2 tetramer. Consistent with this idea, we confirm that CAF-1 synchronously binds two H3-H4 dimers derived from two different histone genes in vivo. Together, the data illustrate a clear mechanism for CAF-1-associated H3-H4 chaperone activity in the context of de novo nucleosome (re)assembly following DNA replication. PMID- 22941639 TI - UVA-induced DNA double-strand breaks result from the repair of clustered oxidative DNA damages. AB - UVA (320-400 nm) represents the main spectral component of solar UV radiation, induces pre-mutagenic DNA lesions and is classified as Class I carcinogen. Recently, discussion arose whether UVA induces DNA double-strand breaks (dsbs). Only few reports link the induction of dsbs to UVA exposure and the underlying mechanisms are poorly understood. Using the Comet-assay and gammaH2AX as markers for dsb formation, we demonstrate the dose-dependent dsb induction by UVA in G(1) synchronized human keratinocytes (HaCaT) and primary human skin fibroblasts. The number of gammaH2AX foci increases when a UVA dose is applied in fractions (split dose), with a 2-h recovery period between fractions. The presence of the anti oxidant Naringin reduces dsb formation significantly. Using an FPG-modified Comet assay as well as warm and cold repair incubation, we show that dsbs arise partially during repair of bi-stranded, oxidative, clustered DNA lesions. We also demonstrate that on stretched chromatin fibres, 8-oxo-G and abasic sites occur in clusters. This suggests a replication-independent formation of UVA-induced dsbs through clustered single-strand breaks via locally generated reactive oxygen species. Since UVA is the main component of solar UV exposure and is used for artificial UV exposure, our results shine new light on the aetiology of skin cancer. PMID- 22941640 TI - Exome RNA sequencing reveals rare and novel alternative transcripts. AB - RNA sequencing has become an important method to perform hypothesis-free characterization of global gene expression. One of the limitations of RNA sequencing is that most sequence reads represent highly expressed transcripts, whereas low level transcripts are challenging to detect. To combine the benefits of traditional expression arrays with the advantages of RNA sequencing, we have used whole exome enrichment prior to sequencing of total RNA. We show that whole exome capture can be successfully applied to cDNA to study the transcriptional landscape in human tissues. By introducing the exome enrichment step, we are able to identify transcripts present at very low levels, which are below the level of detection in conventional RNA sequencing. Although the enrichment increases the ability to detect presence of transcripts, it also lowers the accuracy of quantification of expression levels. Our results yield a large number of novel exons and splice isoforms, suggesting that conventional RNA sequencing methods only detect a small fraction of the full transcript diversity. We propose that whole exome enrichment of RNA is a suitable strategy for genome-wide discovery of novel transcripts, alternative splice variants and fusion genes. PMID- 22941641 TI - Susceptibility to bystander DNA damage is influenced by replication and transcriptional activity. AB - Direct cellular DNA damage may lead to genome destabilization in unexposed, bystander, cells sharing the same milieu with directly damaged cells by means of the bystander effect. One proposed mechanism involves double strand break (DSB) formation in S phase cells at sites of single strand lesions in the DNA of replication complexes, which has a more open structure compared with neighboring DNA. The DNA in transcription complexes also has a more open structure, and hence may be susceptible to bystander DSB formation from single strand lesions. To examine whether transcription predisposes non-replicating cells to bystander effect-induced DNA DSBs, we examined two types of primary cells that exhibit high levels of transcription in the absence of replication, rat neurons and human lymphocytes. We found that non-replicating bystander cells with high transcription rates exhibited substantial levels of DNA DSBs, as monitored by gamma-H2AX foci formation. Additionally, as reported in proliferating cells, TGF beta and NO were found to mimic bystander effects in cell populations lacking DNA synthesis. These results indicate that cell vulnerability to bystander DSB damage may result from transcription as well as replication. The findings offer insights into which tissues may be vulnerable to bystander genomic destabilization in vivo. PMID- 22941642 TI - Metal and ligand binding to the HIV-RNase H active site are remotely monitored by Ile556. AB - HIV-1 reverse transcriptase (RT) contains a C-terminal ribonuclease H (RH) domain on its p66 subunit that can be expressed as a stable, although inactive protein. Recent studies of several RH enzymes demonstrate that substrate binding plays a major role in the creation of the active site. In the absence of substrate, the C terminal helix E of the RT RNase H domain is dynamic, characterized by severe exchange broadening of its backbone amide resonances, so that the solution characterization of this region of the protein has been limited. Nuclear magnetic resonance studies of 13C-labeled RH as a function of experimental conditions reveal that the delta1 methyl resonance of Ile556, located in a short, random coil segment following helix E, experiences a large 13C shift corresponding to a conformational change of Ile556 that results from packing of helix E against the central beta-sheet. This shift provides a useful basis for monitoring the effects of various ligands on active site formation. Additionally, we report that the RNase H complexes formed with one or both divalent ions can be individually observed and characterized using diamagnetic Zn2+ as a substitute for Mg2+. Ordering of helix E results specifically from the interaction with the lower affinity binding to the A divalent ion site. PMID- 22941643 TI - Protein-induced changes in DNA structure and dynamics observed with noncovalent site-directed spin labeling and PELDOR. AB - Site-directed spin labeling and pulsed electron-electron double resonance (PELDOR or DEER) have previously been applied successfully to study the structure and dynamics of nucleic acids. Spin labeling nucleic acids at specific sites requires the covalent attachment of spin labels, which involves rather complicated and laborious chemical synthesis. Here, we use a noncovalent label strategy that bypasses the covalent labeling chemistry and show that the binding specificity and efficiency are large enough to enable PELDOR or DEER measurements in DNA duplexes and a DNA duplex bound to the Lac repressor protein. In addition, the rigidity of the label not only allows resolution of the structure and dynamics of oligonucleotides but also the determination of label orientation and protein induced conformational changes. The results prove that this labeling strategy in combination with PELDOR has a great potential for studying both structure and dynamics of oligonucleotides and their complexes with various ligands. PMID- 22941644 TI - Dynamic changes in translational efficiency are deduced from codon usage of the transcriptome. AB - Translation of a gene is assumed to be efficient if the supply of the tRNAs that translate it is high. Yet high-abundance tRNAs are often also at high demand since they correspond to preferred codons in genomes. Thus to fully model translational efficiency one must gauge the supply-to-demand ratio of the tRNAs that are required by the transcriptome at a given time. The tRNAs' supply is often approximated by their gene copy number in the genome. Yet neither the demand for each tRNA nor the extent to which its concentration changes across environmental conditions has been extensively examined. Here we compute changes in the codon usage of the transcriptome across different conditions in several organisms by inspecting conventional mRNA expression data. We find recurring dynamics of codon usage in the transcriptome in multiple stressful conditions. In particular, codons that are translated by rare tRNAs become over-represented in the transcriptome in response to stresses. These results raise the possibility that the tRNA pool might dynamically change upon stress to support efficient translation of stress-transcribed genes. Alternatively, stress genes may be typically translated with low efficiency, presumably due to lack of sufficient evolutionary optimization pressure on their codon usage. PMID- 22941645 TI - PARP activation regulates the RNA-binding protein NONO in the DNA damage response to DNA double-strand breaks. AB - After the generation of DNA double-strand breaks (DSBs), poly(ADP-ribose) polymerase-1 (PARP-1) is one of the first proteins to be recruited and activated through its binding to the free DNA ends. Upon activation, PARP-1 uses NAD+ to generate large amounts of poly(ADP-ribose) (PAR), which facilitates the recruitment of DNA repair factors. Here, we identify the RNA-binding protein NONO, a partner protein of SFPQ, as a novel PAR-binding protein. The protein motif being primarily responsible for PAR-binding is the RNA recognition motif 1 (RRM1), which is also crucial for RNA-binding, highlighting a competition between RNA and PAR as they share the same binding site. Strikingly, the in vivo recruitment of NONO to DNA damage sites completely depends on PAR, generated by activated PARP-1. Furthermore, we show that upon PAR-dependent recruitment, NONO stimulates nonhomologous end joining (NHEJ) and represses homologous recombination (HR) in vivo. Our results therefore place NONO after PARP activation in the context of DNA DSB repair pathway decision. Understanding the mechanism of action of proteins that act in the same pathway as PARP-1 is crucial to shed more light onto the effect of interference on PAR-mediated pathways with PARP inhibitors, which have already reached phase III clinical trials but are until date poorly understood. PMID- 22941646 TI - Misacylation of tRNA with methionine in Saccharomyces cerevisiae. AB - Accurate transfer RNA (tRNA) aminoacylation by aminoacyl-tRNA synthetases controls translational fidelity. Although tRNA synthetases are generally highly accurate, recent results show that the methionyl-tRNA synthetase (MetRS) is an exception. MetRS readily misacylates non-methionyl tRNAs at frequencies of up to 10% in mammalian cells; such mismethionylation may serve a beneficial role for cells to protect their own proteins against oxidative damage. The Escherichia coli MetRS mismethionylates two E. coli tRNA species in vitro, and these two tRNAs contain identity elements for mismethionylation. Here we investigate tRNA mismethionylation in Saccharomyces cerevisiae. tRNA mismethionylation occurs at a similar extent in vivo as in mammalian cells. Both cognate and mismethionylated tRNAs have similar turnover kinetics upon cycloheximide treatment. We identify specific arginine/lysine to methionine-substituted peptides in proteomic mass spectrometry, indicating that mismethionylated tRNAs are used in translation. The yeast MetRS is part of a complex containing the anchoring protein Arc1p and the glutamyl-tRNA synthetase (GluRS). The recombinant Arc1p-MetRS-GluRS complex binds and mismethionylates many tRNA species in vitro. Our results indicate that the yeast MetRS is responsible for extensive misacylation of non-methionyl tRNAs, and mismethionylation also occurs in this evolutionary branch. PMID- 22941647 TI - siSPOTR: a tool for designing highly specific and potent siRNAs for human and mouse. AB - RNA interference (RNAi) serves as a powerful and widely used gene silencing tool for basic biological research and is being developed as a therapeutic avenue to suppress disease-causing genes. However, the specificity and safety of RNAi strategies remains under scrutiny because small inhibitory RNAs (siRNAs) induce off-target silencing. Currently, the tools available for designing siRNAs are biased toward efficacy as opposed to specificity. Prior work from our laboratory and others' supports the potential to design highly specific siRNAs by limiting the promiscuity of their seed sequences (positions 2-8 of the small RNA), the primary determinant of off-targeting. Here, a bioinformatic approach to predict off-targeting potentials was established using publically available siRNA data from more than 50 microarray experiments. With this, we developed a specificity focused siRNA design algorithm and accompanying online tool which, upon validation, identifies candidate sequences with minimal off-targeting potentials and potent silencing capacities. This tool offers researchers unique functionality and output compared with currently available siRNA design programs. Furthermore, this approach can greatly improve genome-wide RNAi libraries and, most notably, provides the only broadly applicable means to limit off-targeting from RNAi expression vectors. PMID- 22941648 TI - Deciphering the transcriptional regulation of microRNA genes in humans with ACTLocater. AB - Understanding the transcriptional regulation of microRNAs (miRNAs) is extremely important for determining the specific roles they play in signaling cascades. However, precise identification of transcription factor binding sites (TFBSs) orchestrating the expressions of miRNAs remains a challenge. By combining accessible chromatin sequences of 12 cell types released by the ENCODE Project, we found that a significant fraction (~80%) of such integrated sequences, evolutionary conserved and in regions upstream of human miRNA genes that are independently transcribed, were preserved across cell types. Accordingly, we developed a computational method, Accessible and Conserved TFBSs Locater (ACTLocater), incorporating this chromatin feature and evolutionary conservation to identify the TFBSs associated with human miRNA genes. ACTLocater achieved high positive predictive values, as revealed by the experimental validation of FOXA1 predictions and by the comparison of its predictions of some other transcription factors (TFs) to empirical ChIP-seq data. Most notably, ACTLocater was widely applicable as indicated by the successful prediction of TF -> miRNA interactions in cell types whose chromatin accessibility profiles were not incorporated. By applying ACTLocater to TFs with characterized binding specificities, we compiled a novel repository of putative TF -> miRNA interactions and displayed it in ACTViewer, providing a promising foundation for future investigations to elucidate the regulatory mechanisms of miRNA transcription in humans. PMID- 22941649 TI - DNA repair endonuclease ERCC1-XPF as a novel therapeutic target to overcome chemoresistance in cancer therapy. AB - The ERCC1-XPF complex is a structure-specific endonuclease essential for the repair of DNA damage by the nucleotide excision repair pathway. It is also involved in other key cellular processes, including DNA interstrand crosslink (ICL) repair and DNA double-strand break (DSB) repair. New evidence has recently emerged, increasing our understanding of its requirement in these additional roles. In this review, we focus on the protein-protein and protein-DNA interactions made by the ERCC1 and XPF proteins and discuss how these coordinate ERCC1-XPF in its various roles. In a number of different cancers, high expression of ERCC1 has been linked to a poor response to platinum-based chemotherapy. We discuss prospects for the development of DNA repair inhibitors that target the activity, stability or protein interactions of the ERCC1-XPF complex as a novel therapeutic strategy to overcome chemoresistance. PMID- 22941650 TI - MutSbeta and histone deacetylase complexes promote expansions of trinucleotide repeats in human cells. AB - Trinucleotide repeat (TNR) expansions cause at least 17 heritable neurological diseases, including Huntington's disease. Expansions are thought to arise from abnormal processing of TNR DNA by specific trans-acting proteins. For example, the DNA repair complex MutSbeta (MSH2-MSH3 heterodimer) is required in mice for on-going expansions of long, disease-causing alleles. A distinctive feature of TNR expansions is a threshold effect, a narrow range of repeat units (~30-40 in humans) at which mutation frequency rises dramatically and disease can initiate. The goal of this study was to identify factors that promote expansion of threshold-length CTG*CAG repeats in a human astrocytic cell line. siRNA knockdown of the MutSbeta subunits MSH2 or MSH3 impeded expansions of threshold-length repeats, while knockdown of the MutSalpha subunit MSH6 had no effect. Chromatin immunoprecipitation experiments indicated that MutSbeta, but not MutSalpha, was enriched at the TNR. These findings imply a direct role for MutSbeta in promoting expansion of threshold-length CTG*CAG tracts. We identified the class II deacetylase HDAC5 as a novel promoting factor for expansions, joining the class I deacetylase HDAC3 that was previously identified. Double knockdowns were consistent with the possibility that MutSbeta, HDAC3 and HDAC5 act through a common pathway to promote expansions of threshold-length TNRs. PMID- 22941651 TI - Chromatin modification by SUMO-1 stimulates the promoters of translation machinery genes. AB - SUMOylation of transcription factors and chromatin proteins is in many cases a negative mark that recruits factors that repress gene expression. In this study, we determined the occupancy of Small Ubiquitin-like MOdifier (SUMO)-1 on chromatin in HeLa cells by use of chromatin affinity purification coupled with next-generation sequencing. We found SUMO-1 localization on chromatin was dynamic throughout the cell cycle. Surprisingly, we observed that from G1 through late S phase, but not during mitosis, SUMO-1 marks the chromatin just upstream of the transcription start site on many of the most active housekeeping genes, including genes encoding translation factors and ribosomal subunit proteins. Moreover, we found that SUMO-1 distribution on promoters was correlated with H3K4me3, another general chromatin activation mark. Depletion of SUMO-1 resulted in downregulation of the genes that were marked by SUMO-1 at their promoters during interphase, supporting the concept that the marking of promoters by SUMO-1 is associated with transcriptional activation of genes involved in ribosome biosynthesis and in the protein translation process. PMID- 22941652 TI - Sequence analysis of a complete 1.66 Mb Prochlorococcus marinus MED4 genome cloned in yeast. AB - Marine cyanobacteria of the genus Prochlorococcus represent numerically dominant photoautotrophs residing throughout the euphotic zones in the open oceans and are major contributors to the global carbon cycle. Prochlorococcus has remained a genetically intractable bacterium due to slow growth rates and low transformation efficiencies using standard techniques. Our recent successes in cloning and genetically engineering the AT-rich, 1.1 Mb Mycoplasma mycoides genome in yeast encouraged us to explore similar methods with Prochlorococcus. Prochlorococcus MED4 has an AT-rich genome, with a GC content of 30.8%, similar to that of Saccharomyces cerevisiae (38%), and contains abundant yeast replication origin consensus sites (ACS) evenly distributed around its 1.66 Mb genome. Unlike Mycoplasma cells, which use the UGA codon for tryptophane, Prochlorococcus uses the standard genetic code. Despite this, we observed no toxic effects of several partial and 15 whole Prochlorococcus MED4 genome clones in S. cerevisiae. Sequencing of a Prochlorococcus genome purified from yeast identified 14 single base pair missense mutations, one frameshift, one single base substitution to a stop codon and one dinucleotide transversion compared to the donor genomic DNA. We thus provide evidence of transformation, replication and maintenance of this 1.66 Mb intact bacterial genome in S. cerevisiae. PMID- 22941653 TI - Nucleosome dynamics: HMGB1 relaxes canonical nucleosome structure to facilitate estrogen receptor binding. AB - High mobility group protein 1 (HMGB1) interacts with DNA and chromatin to influence the regulation of transcription, DNA repair and recombination. We show that HMGB1 alters the structure and stability of the canonical nucleosome (N) in a nonenzymatic, ATP-independent manner. Although estrogen receptor (ER) does not bind to its consensus estrogen response element within a nucleosome, HMGB1 restructures the nucleosome to facilitate strong ER binding. The isolated HMGB1 restructured nucleosomes (N' and N") remain stable and exhibit characteristics distinctly different from the canonical nucleosome. These findings complement previous studies that showed (i) HMGB1 stimulates in vivo transcriptional activation at estrogen response elements and (ii) knock down of HMGB1 expression by siRNA precipitously reduced transcriptional activation. The findings indicate that one aspect of the mechanism of HMGB1 action involves a restructuring of the nucleosome that appears to relax structural constraints within the nucleosome. PMID- 22941654 TI - Predicting missing expression values in gene regulatory networks using a discrete logic modeling optimization guided by network stable states. AB - The development of new high-throughput technologies enables us to measure genome wide transcription levels, protein abundance, metabolite concentration, etc. Nevertheless, these experimental data are often noisy and incomplete, which hinders data analysis, modeling and prediction. Here, we propose a method to predict expression values of genes involved in stable cellular phenotypes from the expression values of the remaining genes in a literature-based gene regulatory network. The consistency between predicted and known stable states from experimental data is used to guide an iterative network pruning that contextualizes the network to the biological conditions under which the expression data were obtained. Using the contextualized network and the property of network stability we predict gene expression values missing from experimental data. The prediction method assumes a Boolean model to compute steady states of networks and an evolutionary algorithm to iteratively prune the networks. The evolutionary algorithm samples the probability distribution of positive feedback loops or positive circuits and individual interactions within the subpopulation of the best-pruned networks at each iteration. The resulting expression inference is based not only on previous knowledge about local connectivity but also on a global network property (stability), providing robustness in the predictions. PMID- 22941655 TI - Analysis of RNA cleavage by MALDI-TOF mass spectrometry. AB - A method of analysis is presented that utilizes matrix-assisted laser desorption/ionization-time of flight mass spectrometry (MALDI-TOF MS) to monitor the kinetics and products of RNA cleavage, by use of a program designed to mass match observed MS peaks with predicted RNA cleavage products. The method is illustrated through application to the study of targeted oxidation of RNA stem loops from HIV-1 Rev Response Element mRNA (RRE RNA) and ribosomal 16S A-site RNA (16S RNA) by metallonucleases. Following incubation of each RNA with catalysts and/or redox co-reactants, reaction mixtures were desalted, and MALDI-TOF MS was used to monitor both time-resolved formation of cleavage products and disappearance of full-length RNA. For each RNA, a unique list was generated that contained the predicted masses of both the full-length, and all of the possible RNA cleavage fragments that resulted from the combination of all possible cleavage sites and each of the six expected overhangs formed at nascent termini adjacent to the cleavage sites. The overhangs corresponded to 2',3'-cyclic phosphate, 3'-phosphate, 3'-phosphoglycolate, 5'- hydroxyl and 5'- phosphate, which corresponded to differing oxidative, hydrolytic, and/or 2'-OH-mediated endonucleolytic modes of scission. Each mass spectrum was compared with a corresponding list of predicted masses, and peaks were rapidly assigned by use of a Perl script, with a mass-matching tolerance of 200 ppm. Both time-dependent cleavage mediated by metallonucleases and MALDI-TOF-induced fragmentation were observed, and these were distinguished by time-dependent experiments. The resulting data allowed a semi-quantitative assessment of the rate of formation of each overhang at each nucleotide position. Limitations included artifactual skewing of quantification by mass bias, a limited mass range for quantification, and a lack of detection of secondary cleavage products. Nevertheless, the method presented herein provides a rapid, accurate, highly-detailed and semi quantitative analysis of RNA cleavage that should be widely applicable. PMID- 22941656 TI - PALB2 self-interaction controls homologous recombination. AB - PALB2 is essential for BRCA2 anchorage to nuclear structures and for homologous recombinational repair of DNA double-strand breaks. Here, we report that the N terminal coiled-coil motif of PALB2 regulates its self-association and homologous recombination. Monomeric PALB2 shows higher efficiency to bind DNA and promotes RAD51 filament formation with or without the inhibitory effect of Replication Protein A. Moreover, overexpression of the PALB2 coiled-coil domain severely affects RAD51 loading to DNA damage sites suggesting a competition between PALB2 self-interaction and PALB2-BRCA1 interaction. In the presence of DNA damage, the switch between PALB2-PALB2 and PALB2-BRCA1 interactions allows the activation of HR. Controlling HR via PALB2 self-interactions could be important to prevent aberrant recombination in normal conditions and activate DNA repair when required. PMID- 22941657 TI - X-ray structure of the fourth type of archaeal tRNA splicing endonuclease: insights into the evolution of a novel three-unit composition and a unique loop involved in broad substrate specificity. AB - Cleavage of introns from precursor transfer RNAs (tRNAs) by tRNA splicing endonuclease (EndA) is essential for tRNA maturation in Archaea and Eukarya. In the past, archaeal EndAs were classified into three types (alpha'2, alpha4 and alpha2beta2) according to subunit composition. Recently, we have identified a fourth type of archaeal EndA from an uncultivated archaeon Candidatus Micrarchaeum acidiphilum, referred to as ARMAN-2, which is deeply branched within Euryarchaea. The ARMAN-2 EndA forms an epsilon2 homodimer and has broad substrate specificity like the alpha2beta2 type EndAs found in Crenarchaea and Nanoarchaea. However, the precise architecture of ARMAN-2 EndA was unknown. Here, we report the crystal structure of the epsilon2 homodimer of ARMAN-2 EndA. The structure reveals that the epsilon protomer is separated into three novel units (alphaN, alpha and betaC) fused by two distinct linkers, although the overall structure of ARMAN-2 EndA is similar to those of the other three types of archaeal EndAs. Structural comparison and mutational analyses reveal that an ARMAN-2 type specific loop (ASL) is involved in the broad substrate specificity and that K161 in the ASL functions as the RNA recognition site. These findings suggest that the broad substrate specificities of epsilon2 and alpha2beta2 EndAs were separately acquired through different evolutionary processes. PMID- 22941658 TI - Complementary strand relocation may play vital roles in RecA-based homology recognition. AB - RecA-family proteins mediate homologous recombination and recombinational DNA repair through homology search and strand exchange. Initially, the protein forms a filament with the incoming single-stranded DNA (ssDNA) bound in site I. The RecA-ssDNA filament then binds double-stranded DNA (dsDNA) in site II. Non homologous dsDNA rapidly unbinds, whereas homologous dsDNA undergoes strand exchange yielding heteroduplex dsDNA in site I and the leftover outgoing strand in site II. We show that applying force to the ends of the complementary strand significantly retards strand exchange, whereas applying the same force to the outgoing strand does not. We also show that crystallographically determined binding site locations require an intermediate structure in addition to the initial and final structures. Furthermore, we demonstrate that the characteristic dsDNA extension rates due to strand exchange and free RecA binding are the same, suggesting that relocation of the complementary strand from its position in the intermediate structure to its position in the final structure limits both rates. Finally, we propose that homology recognition is governed by transitions to and from the intermediate structure, where the transitions depend on differential extension in the dsDNA. This differential extension drives strand exchange forward for homologs and increases the free energy penalty for strand exchange of non-homologs. PMID- 22941659 TI - DOT1A-dependent H3K76 methylation is required for replication regulation in Trypanosoma brucei. AB - Cell-cycle progression requires careful regulation to ensure accurate propagation of genetic material to the daughter cells. Although many cell-cycle regulators are evolutionarily conserved in the protozoan parasite Trypanosoma brucei, novel regulatory mechanisms seem to have evolved. Here, we analyse the function of the histone methyltransferase DOT1A during cell-cycle progression. Over-expression of DOT1A generates a population of cells with aneuploid nuclei as well as enucleated cells. Detailed analysis shows that DOT1A over-expression causes continuous replication of the nuclear DNA. In contrast, depletion of DOT1A by RNAi abolishes replication but does not prevent karyokinesis. As histone H3K76 methylation has never been associated with replication control in eukaryotes before, we have discovered a novel function of DOT1 enzymes, which might not be unique to trypanosomes. PMID- 22941660 TI - The antibiotic Furvina(r) targets the P-site of 30S ribosomal subunits and inhibits translation initiation displaying start codon bias. AB - Furvina(r), also denominated G1 (MW 297), is a synthetic nitrovinylfuran [2-bromo 5-(2-bromo-2-nitrovinyl)-furan] antibiotic with a broad antimicrobial spectrum. An ointment (Dermofural(r)) containing G1 as the only active principle is currently marketed in Cuba and successfully used to treat dermatological infections. Here we describe the molecular target and mechanism of action of G1 in bacteria and demonstrate that in vivo G1 preferentially inhibits protein synthesis over RNA, DNA and cell wall synthesis. Furthermore, we demonstrate that G1 targets the small ribosomal subunit, binds at or near the P-decoding site and inhibits its function interfering with the ribosomal binding of fMet-tRNA during 30S initiation complex (IC) formation ultimately inhibiting translation. Notably, this G1 inhibition displays a bias for the nature (purine vs. pyrimidine) of the 3'-base of the codon, occurring efficiently only when the mRNA directing 30S IC formation and translation contains the canonical AUG initiation triplet or the rarely found AUA triplet, but hardly occurs when the mRNA start codon is either one of the non-canonical triplets AUU or AUC. This codon discrimination by G1 is reminiscent, though of opposite type of that displayed by IF3 in its fidelity function, and remarkably does not occur in the absence of this factor. PMID- 22941661 TI - Metagenomic abundance estimation and diagnostic testing on species level. AB - One goal of sequencing-based metagenomic community analysis is the quantitative taxonomic assessment of microbial community compositions. In particular, relative quantification of taxons is of high relevance for metagenomic diagnostics or microbial community comparison. However, the majority of existing approaches quantify at low resolution (e.g. at phylum level), rely on the existence of special genes (e.g. 16S), or have severe problems discerning species with highly similar genome sequences. Yet, problems as metagenomic diagnostics require accurate quantification on species level. We developed Genome Abundance Similarity Correction (GASiC), a method to estimate true genome abundances via read alignment by considering reference genome similarities in a non-negative LASSO approach. We demonstrate GASiC's superior performance over existing methods on simulated benchmark data as well as on real data. In addition, we present applications to datasets of both bacterial DNA and viral RNA source. We further discuss our approach as an alternative to PCR-based DNA quantification. PMID- 22941662 TI - Promoters active in interphase are bookmarked during mitosis by ubiquitination. AB - We analyzed modification of chromatin by ubiquitination in human cells and whether this mark changes through the cell cycle. HeLa cells were synchronized at different stages and regions of the genome with ubiquitinated chromatin were identified by affinity purification coupled with next-generation sequencing. During interphase, ubiquitin marked the chromatin on the transcribed regions of ~70% of highly active genes and deposition of this mark was sensitive to transcriptional inhibition. Promoters of nearly half of the active genes were highly ubiquitinated specifically during mitosis. The ubiquitination at the coding regions in interphase but not at promoters during mitosis was enriched for ubH2B and dependent on the presence of RNF20. Ubiquitin labeling of both promoters during mitosis and transcribed regions during interphase, correlated with active histone marks H3K4me3 and H3K36me3 but not a repressive histone modification, H3K27me3. The high level of ubiquitination at the promoter chromatin during mitosis was transient and was removed within 2 h after the cells exited mitosis and entered the next cell cycle. These results reveal that the ubiquitination of promoter chromatin during mitosis is a bookmark identifying active genes during chromosomal condensation in mitosis, and we suggest that this process facilitates transcriptional reactivation post-mitosis. PMID- 22941663 TI - Exploring functional variant discovery in non-coding regions with SInBaD. AB - The thousand genomes project and many similar ongoing large-scale sequencing efforts require new methods to predict functional variants in both coding and non coding regions in order to understand phenotype and genotype relationships. We report the design of a new model SInBaD (Sequence-Information-Based-Decision model) which relies on nucleotide conservation information to evaluate any annotated human variant in all known exons, introns, splice junctions and promoter regions. SInBaD builds separate mathematical models for promoters, exons and introns, using the human disease mutations annotated in human gene mutation database as the training dataset for functional variants. The ten-fold cross validation shows high prediction accuracy. Validations on test datasets, demonstrate that variants predicted as functional have a significantly higher occurrence in cancer patients. We also applied our model to variants found in four different individual human genomes to identify a set of functional variants, which might be of interest for further studies. Scores for any possible variants for all annotated genes are available under http://tingchenlab.cmb.usc.edu/sinbad/. SInBaD supports the current standard format of genotyping, the variant call files (VCF 4.0), making it easy to integrate it into any existing next-generation sequencing pipeline. The accuracy of SNP detection poses the only limitation to the use of SInBaD. PMID- 22941664 TI - Cell-cycle-regulated control of VSG expression site silencing by histones and histone chaperones ASF1A and CAF-1b in Trypanosoma brucei. AB - Antigenic variation in African trypanosomes involves monoallelic expression and reversible silencing of variant surface glycoprotein (VSG) genes found adjacent to telomeres in polycistronic expression sites (ESs). We assessed the impact on ES silencing of five candidate essential chromatin-associated factors that emerged from a genome-wide RNA interference viability screen. Using this approach, we demonstrate roles in VSG ES silencing for two histone chaperones. Defects in S-phase progression in cells depleted for histone H3, or either chaperone, highlight in particular the link between chromatin assembly and DNA replication control. S-phase checkpoint arrest was incomplete, however, allowing G2/M-specific VSG ES derepression following knockdown of histone H3. In striking contrast, knockdown of anti-silencing factor 1A (ASF1A) allowed for derepression at all cell cycle stages, whereas knockdown of chromatin assembly factor 1b (CAF 1b) revealed derepression predominantly in S-phase and G2/M. Our results support a central role for chromatin in maintaining VSG ES silencing. ASF1A and CAF-1b appear to play constitutive and DNA replication-dependent roles, respectively, in the recycling and assembly of chromatin. Defects in these functions typically lead to arrest in S-phase but defective cells can also progress through the cell cycle leading to nucleosome depletion and derepression of telomeric VSG ESs. PMID- 22941665 TI - Acute carotid artery dissection treated with stenting and hematoma aspiration guided by ultrasonography. AB - We report the successful treatment of dissection with stenosis of the carotid artery by stenting and aspiration of hematoma. A male patient, presenting with acute blurred vision and weakness and numbness of the right side of his body, was diagnosed with common carotid artery (CCA) dissection and severe stenosis of the internal carotid artery and CCA by digital subtraction arteriography and color Doppler ultrasonography (CDU). Two stents were separately implanted into the left internal carotid artery and CCA to restore blood flow and seal the opening of the dissection. The hematoma inside the CCA dissection was transcutaneously aspirated under CDU guidance after thrombolysis with tissue plasminogen activator. Three days after the operation, the dissection was still sealed. The patient was discharged 1 week later without any signs or symptoms. Follow-up examination at 70 days confirmed complete healing of the CCA dissection. Transcutaneous intradissection hematoma aspiration with CDU guidance may be applicable in treating arterial dissection, especially when conservative treatments cannot be expected to improve severe flow disturbances. PMID- 22941666 TI - Author response: Analysis of the use of multiple comparison corrections in ophthalmology research. PMID- 22941667 TI - Significant calendar period deviations in testicular germ cell tumors indicate that postnatal exposures are etiologically relevant. AB - PURPOSE: The current working model of type II testicular germ cell tumor (TGCT) pathogenesis states that carcinoma in situ arises during embryogenesis, is a necessary precursor, and always progresses to cancer. An implicit condition of this model is that only in utero exposures affect the development of TGCT in later life. In an age-period-cohort analysis, this working model contends an absence of calendar period deviations. We tested this contention using data from the SEER registries of the United States. METHODS: We assessed age-period-cohort models of TGCTs, seminomas, and nonseminomas for the period 1973-2008. Analyses were restricted to whites diagnosed at ages 15-74 years. We tested whether calendar period deviations were significant in TGCT incidence trends adjusted for age deviations and cohort effects. RESULTS: This analysis included 32,250 TGCTs (18,475 seminomas and 13,775 nonseminomas). Seminoma incidence trends have increased with an average annual percentage change in log-linear rates (net drift) of 1.25 %, relative to just 0.14 % for nonseminoma. In more recent time periods, TGCT incidence trends have plateaued and then undergone a slight decrease. Calendar period deviations were highly statistically significant in models of TGCT (p = 1.24(-9)) and seminoma (p = 3.99(-14)), after adjustment for age deviations and cohort effects; results for nonseminoma (p = 0.02) indicated that the effects of calendar period were much more muted. CONCLUSION: Calendar period deviations play a significant role in incidence trends of TGCT, which indicates that postnatal exposures are etiologically relevant. PMID- 22941669 TI - Ultrasound-assisted matrix solid phase dispersive extraction for the simultaneous analysis of beta-lactams (four penicillins and eight cephalosporins) in milk by high performance liquid chromatography with photodiode array detection. AB - The application of ultrasound-assisted matrix solid phase dispersive extraction for the confirmatory analysis of 12 beta-lactam antibiotics in milk by high performance liquid chromatography with photodiode array detection has been proposed herein. Four penicillins (cloxacillin, dicloxacillin, oxacillin, and amoxicillin) and eight cephalosporins (cefaclor, cefadroxil, ceftiofur, cefuroxime, cefoperazone, cefazolin, cephalexin, and cefotaxime) are effectively extracted using a mixed sorbent of Quick Easy Cheap Effective Rugged Safe technique and OASIS HLB providing a matrix free from any endogenous interference. Examined analytes were well resolved on an Inertsil ODS-3 analytical column with a mobile phase of CH(3)COONH(4) (0.05 M) and acetonitrile delivered under a gradient program. 1,7-Dimethyl-xanthine was used as internal standard. The method was validated meeting the European Legislation determining linearity, selectivity, stability, decision limit, detection capability, accuracy, precision, and ruggedness according to the Youden approach. Recoveries of all antibiotics rated from 85.0 to 115.7%, while RSD values were <12.7%. Finally, the method was successfully applied to milk samples purchased from local market. PMID- 22941668 TI - A case-parent triad assessment of folate metabolic genes and the risk of childhood acute lymphoblastic leukemia. AB - PURPOSE: We conducted a case-parent triad study evaluating the role of maternal and offspring genotypes in the folate metabolic pathway on childhood acute lymphoblastic leukemia (ALL) risk. METHODS: Childhood ALL case-parent triads (n = 120) were recruited from Texas Children's Hospital. DNA samples were genotyped using the Sequenom iPLEX MassARRAY for 68 tagSNPs in six folate metabolic pathway genes (MTHFR, MTRR, MTR, DHFR, BHMT, and TYMS). Log-linear modeling was used to examine the associations between maternal and offspring genotypes and ALL. RESULTS: After controlling for the false discovery rate (<0.1), there were 20 significant maternal effects in the following genes: BHMT (n = 3), MTR (n = 12), and TYMS (n = 5). For instance, maternal genotypes for BHMT rs558133 (relative risk [RR] = 0.51, 95 % confidence interval [CI]: 0.30-0.87, p = 0.008, Q = 0.08) and MTR rs2282369 (RR = 0.46, 95 % CI: 0.27-0.80, p = 0.004, Q = 0.08) were associated with ALL. There were no significant offspring effects after controlling for the false discovery rate. CONCLUSIONS: This is one of the few studies conducted to evaluate maternal genetic effects in the context of childhood ALL risk. Furthermore, we employed a family-based design that is less susceptible to population stratification bias in the estimation of maternal genetic effects. Our findings suggest that maternal genetic variation in the folate metabolic pathway is relevant in the etiology of childhood ALL. The observed maternal genetic effects support the need for continued research of how the uterine environment may influence risk of ALL. PMID- 22941671 TI - Rasch validation of a combined measure of basic and extended daily life functioning after stroke. AB - BACKGROUND: Tools used to measure poststroke functional status must include basic and instrumental activities of daily living and reflect the patient's and the clinician's perspective of the disease and its effect on daily living performance. OBJECTIVE: The authors combined the Functional Independence Measure (FIM) and the Nottingham Extended Activities of Daily Living (NEADL) to create a scale providing a comprehensive evaluation of ADLs functional status in patients with stroke. METHODS: The study participants were 188 patients completing the FIM and the NEADL. The psychometric properties of the combined measure were examined with Rasch analysis. RESULTS: A 3-point scale and a dichotomous scale were suggested for use in the FIM and the NEADL, respectively. The combined 40 items worked consistently to reflect a single construct, and "bladder management" and "bowel management" were highly related. After "bowel management" was removed from the combined scale, all but 3 items fit the model's expectations, and the 39-item scale showed reasonable item difficulty hierarchy, with high reliability. The 3 misfit items were removed, and no differences in unidimensionality, differential item functioning, and reliability were found between the 36-item and 39-item scales. CONCLUSIONS: The combined measure of the FIM and the NEADL provides a comprehensive picture of ADLs. It extends the utility of the FIM and the NEADL and is recommended for use to measure the independence of patients after discharge home. PMID- 22941670 TI - Interpersonal discrimination and health-related quality of life among black and white men and women in the United States. AB - OBJECTIVE: We assessed associations between discrimination and health-related quality of life among black and white men and women in the United States. METHODS: We examined data from the National Health Measurement Study, a nationally representative sample of 3,648 adults aged 35-89 in the non institutionalized US population. These data include self-reported lifetime and everyday discrimination as well as several health utility indexes (EQ-5D, HUI3, and SF-6D). Multiple regression was used to compute mean health utility scores adjusted for age, income, education, and chronic diseases for each race-by-gender subgroup. RESULTS: Black men and women reported more discrimination compared to white men and women. Health utility tended to be worse as reported discrimination increased. With a few exceptions, differences between mean health utility scores in the lowest and highest discrimination groups exceeded the 0.03 difference generally considered to be a clinically significant difference. CONCLUSIONS: Persons who experienced discrimination tended to score lower on health utility measures. The study also revealed a complex relationship between experiences of discrimination and race and gender. Because of these differential social and demographic relationships caution is urged when interpreting self-rated health measures in research, clinical, and policy settings. PMID- 22941672 TI - Statistical assessment of biosimilarity based on relative distance between follow on biologics. AB - In this paper, we propose a new three-arm parallel design to investigate biosimilarity between a biosimilar product and an innovator biological product by using relative distance based on the absolute mean differences. In the proposed design, one arm is for the biosimilar product and the other two arms are for the innovator biological product. The distance between the biosimilar product and the innovator biological product is defined by the absolute mean different between two products. Similarly, the distance between the innovator biological products from two difference batches is defined. The relative distance is defined as the ratio of the two distances whose denominator is the distance between the innovator biological products from two different batches. In the proposed design, if the relative distance is less than a prespecified margin, we claim that the two products are claimed to be biosimilar. The statistical test based on the ratio estimator and the linearization method are developed to assess biosimilarity. The power functions of two tests are derived in large sample and compared numerically. Because the statistical test based on the ratio estimator is more powerful than the linearization method, we recommend the statistical test based on the ratio estimator. PMID- 22941673 TI - Unplanned pregnancy and the impact on sibling health outcomes. AB - This work considers whether planning matters with respect to the effect of a new sibling on another siblings' health. Objective health outcomes are observed before and after a new addition to the family. To date, the literature on family size has focused on a quality-quantity trade-off; the more children in a family, the less resources devoted to each child. We present a theoretical framework which highlights that the quantity-quality trade-off may only be relevant in the case of an unplanned sibling. We also suggest that a planned sibling may result in health gains for the other children. We use two waves of data for more than 1800 children from Peru from the Young Lives Project to test our hypothesis. The data relate to the children at 1 and 5 years. For health outcomes, height for age and weight for age Z are considered. The results highlight significant negative independent effects on height for age when an unplanned sibling is added to the household. In addition, we find positive sibling effects on height for age when a planned sibling arrives. We find only small planning effects for weight for age. We view our hypothesis as a pathway that can further explain the quantity-quality trade-off. PMID- 22941674 TI - Diagnosis of osteoarthritis and prognosis of tibial cartilage loss by quantification of tibia trabecular bone from MRI. AB - A longitudinal study was used to investigate the quantification of osteoarthritis and prediction of tibial cartilage loss by analysis of the tibia trabecular bone from magnetic resonance images of knees. The Kellgren Lawrence (KL) grades were determined by radiologists and the levels of cartilage loss were assessed by a segmentation process. Aiming to quantify and potentially capture the structure of the trabecular bone anatomy, a machine learning approach used a set of texture features for training a classifier to recognize the trabecular bone of a knee with radiographic osteoarthritis. Using cross-validation, the bone structure marker was used to estimate for each knee both the probability of having radiographic osteoarthritis (KL >1) and the probability of rapid cartilage volume loss. The diagnostic ability reached a median area under the receiver-operator characteristics curve of 0.92 (P < 0.0001), and the prognosis had odds ratio of 3.9 (95% confidence interval: 2.4-6.5). The medians of cartilage loss of the subjects classified as slow and rapid progressors were 1.1% and 4.9% per year, respectively. A preliminary radiological reading of the high and low risk knees put forward an hypothesis of which pathologies the bone marker could be capturing to define the prognosis of cartilage loss. PMID- 22941675 TI - Analyzing diurnal and age-related pheromone emission of the olive fruit fly, Bactrocera oleae by sequential SPME-GCMS analysis. AB - The olive fruit fly, Bactrocera oleae (Diptera: Tephritidae), uses 1,7 dioxaspiro[5.5]undecane ("olean"), produced primarily by females, as a sex pheromone. We used sequential solid phase microextraction-gas chromatography mass spectrometry (SPME-GCMS) analysis to show that female olive flies release about 1000 ng of pheromone at the onset of scotophase for several weeks, while males release about 1/100 as much during the first week after eclosion. The present research demonstrates details of employing SPME-GCMS with the partially known pheromone system of the olive fruit fly as a model for pheromone identification and diurnal release patterns in insects, especially fruit flies. The sequential SPME-GCMS method will readily allow detection and semi-quantification of semiochemicals released by insects in minute amounts throughout the diurnal cycle. PMID- 22941676 TI - Genetics of Wilson's disease: a clinical perspective. AB - Hepatic Wilson's disease is often a difficult diagnosis to confirm. This review examines the current role of genetic tests for Wilson's disease and is aimed at clinicians caring for patients with this disease. We discuss how genetic testing is carried out for Wilson's disease, indications for these tests, and genetic counseling for the family. In contrast to the advances in diagnosis of Wilson's disease by testing for ATP7B mutations, genotype-phenotype correlations are not yet sufficiently established. The non-Wilsonian copper overload syndromes causing cirrhosis in children are another important area for study. The review also identifies further areas for research into the genetics of Wilson's disease in India. PMID- 22941677 TI - Non-organ-specific autoantibodies in Indian patients with chronic liver disease. AB - BACKGROUND: Autoantibody testing is used to diagnose autoimmune hepatitis (AIH), a cause of chronic liver disease (CLD). However, various autoantibodies are often detectable in patients with CLD due to other causes too. Since data on autoantibody prevalence in Indian patients with CLD are limited, we decided to undertake the current study. METHODS: Patients with CLD with a known cause other than AIH and a separate group of patients with CLD in whom no cause could be identified were studied. Indirect immunofluorescence assays were used to detect anti-nuclear antibodies (ANA), anti-smooth muscle antibodies (ASMA) and anti liver-kidney microsomal antibodies (anti-LKM). Serum dilutions tested were 1:80 for ANA and 1:40 for other autoantibodies. RESULTS: Of the 175 patients with CLD of a known cause, 69 (39 %) had one or more autoantibodies, including ANA in 35 (20 %) patients and ASMA in 44 (25 %) patients. None had anti-LKM. The prevalence rates of any autoantibody, ANA and ASMA were similar in patients with CLD due to alcohol (34 %, 20 %, and 24 %, respectively), HCV infection (43 %, 20 %, and 26 %) and HBV infection (40 %, 18 %, and 25 %). The most common ANA pattern observed was speckled (29/35 patients), followed by nucleolar (5/35) and homogeneous (1/35). The ASMA titers did not exceed 1:80. The antibody prevalence rates were similar in patients with liver cirrhosis and chronic hepatitis, and in those with different disease severity. Serum IgG levels were similar in patients with and without detectable autoantibodies. Patients with no known cause of CLD (n = 50) had similar prevalence rates of autoantibodies, ANA or ASMA. CONCLUSION: Autoantibodies were detected in a large proportion of patients with CLD, both cryptogenic and with known cause. Detection of autoantibodies in CLD does not necessarily indicate a diagnosis of AIH, and presence of homogenous pattern of ANA may be more relevant. Indiscriminate testing for autoantibodies in patients with CLD, especially those with a known cause, may not be warranted. PMID- 22941678 TI - Expression of multiple nebulin isoforms in human skeletal muscle and brain. AB - INTRODUCTION: Nebulin is a large actin-binding protein of the skeletal muscle sarcomere. Multiple isoforms of nebulin are produced from the 183-exon-containing nebulin gene (NEB). Mutations in NEB cause nemaline myopathy, distal myopathy, and core-rod myopathy. METHODS: Nebulin mRNA expression was assessed by microarrays and RT-PCR in 21 human leg muscle and 2 brain samples. Protein expression was assessed by immunohistochemistry in 5 regions of 1 brain sample. RESULTS: Nebulin isoform diversity is as high in brain as in skeletal muscle. Isoforms with more than 22 super repeats seem to be more common than previously anticipated. Immunohistochemistry showed nebulin expression predominantly in the cytoplasm of pyramidal neurons but also in the cytoplasm of mainly subcortical endothelial cells. CONCLUSIONS: Nebulin, as in skeletal muscle, may have a role as an actin filament stabilizer or length regulator in neurons of the human brain, although patients with NEB mutations usually have normal cognition. PMID- 22941679 TI - [Thought on development of minimally invasive gastrointestinal surgery in China]. AB - Laparoscopic surgery for gastrointestinal diseases had a remarkable progress in the past 20 years. Laparoscopic surgery for colon cancer is adopted worldwide by increasingly surgeons based on the evidence from randomized controlled studies. Minimally invasive surgery is also adopted as alternative procedure for early gastric cancer. The standardization and spreading of the minimally invasive technique for gastrointestinal surgery is also being implemented efficiently in China. However, how to innovate the new technique and improve the new instrumentation for minimally invasive surgery is still a problem which we have to confront in the current situation. But we believe that with the great efforts of gastrointestinal surgeons, the widespread adoption of minimally invasive gastrointestinal surgery would surely take place in the near future. PMID- 22941680 TI - [Application of surgical robotic system in patients with gastric cancer: a report of 120 cases]. AB - OBJECTIVE: To evaluate the safety, feasibility, and efficacy of robotic gastrectomy for gastric cancer using da Vinci surgical system. METHODS: A total of 120 patients who underwent robotic gastrectomy using da Vinci surgical system for gastric cancer from May 2010 to April 2012. Data regarding surgical and early oncological outcomes were systematically collected in a specific database for statistical analysis. RESULTS: There were 74 males and 46 females, with a mean age of 58.5 (22-80) years old. The type of robotic operation included 62 distal subtotal gastrectomies, 35 total gastrectomies, and 23 proximal gastrectomies. Reconstruction of the alimentary tract was achieved using extracorporeal method through a minilaparotomy in 55 cases, and intracorporeal robot-sewn anastomosis in 65 cases. There was 1 conversion (0.9%). The operative time was (245+/-50) min and the docking time (17+/-5) min. The blood loss was (70+/-45) ml. The number of harvested lymph nodes was 22.5+/-10.7. The resection margins were negative in all surgical specimens. The postoperative pathological stage consisted of stage I B in 24 cases, stage II in 28, stage III A in 47, and stage III B in 21. Six patients (5%) developed postoperative complication including 1 case of duodenal stump leakage, 2 cases of esophagus-gastric leakage, 1 case of small bowel obstruction, 1 case of delayed gastric emptying, and 1 case of abdominal bleeding. All the complications were cured by reoperation or conservative therapy, and there were no postoperative 30-day deaths. The postoperative hospital stay was (6.3+/-2.6) days. CONCLUSION: Robotic gastrectomy for the treatment of gastric cancer is a feasible and safe procedure, and is advantageous in terms of lymphadenectomy and alimentary tract reconstruction. PMID- 22941681 TI - [Comparative study on clinical efficacy of robot-assisted and laparoscopic gastrectomy for gastric cancer]. AB - OBJECTIVE: To compare the clinical efficacy of robot-assisted procedure with laparoscopic surgery for gastric cancer. METHODS: The clinical data of patients who underwent gastrectomy in the Department of General Surgery in the Affiliated Jinling Hospital, Nanjing University Medical College from January 2009 to December 2011 were retrospectively analyzed. There were 97 patients undergoing robotic gastrectomy(ROB group) and 70 patients undergoing laparoscopic gastrectomy (LAP group). The following parameters were compared between these two groups: intraoperative factors, oncologic outcomes, and short-term surgical outcomes. RESULTS: All the operations were performed successfully without conversion. Compared with the LAP group, the ROB group had less intraoperative blood loss [(80.8+/-53.1) vs. (153.7+/-26.4) ml, P=0.001], more number of lymph node dissection [(23.1+/-5.4) vs. (20.0+/-4.3), P=0.001], longer operative time [(272.3+/-46.1) vs. (240.3+/-89.1) min, P=0.001], earlier semifluid diet time [(3.2+/-0.8) vs. (3.6+/-1.2) d, P=0.002], shorter postoperative hospital stay [(6.1+/-2.6) vs. (6.9+/-2.3) d, P=0.037]. There were no significant differences in the length of distal and proximal margin, postoperative ambulation time, ventilation time and postoperative complications(all P>0.05). CONCLUSIONS: The robotic gastrectomy is safe and feasible for gastric cancer. It has many advantages such as less blood loss, more number of lymph node dissection and quicker recovery. Similar radical resection can be achieved compared to laparoscopic gastrectomy. PMID- 22941682 TI - [Totally robotic surgery for rectal cancer with transanal specimen extraction and robot-sewn anastomosis technique]. AB - OBJECTIVE: To summarize the clinical experience of transanal specimen extraction and introduce how to achieve the rectum reconstruction in robotic rectal cancer surgery. METHODS: Clinical data of 15 cases undergoing rectal cancer resection with the da Vinci robotic system in Jinglin Hospital between February 2012 and May 2012 were analyzed retrospectively. RESULTS: There were 9 males and 6 females with a mean age of (61.5+/-9.2) years old. All the cases underwent robotic surgery successfully without intraoperative conversion. The average operative time was (154.7+/-10.6) min with minimal blood loss (17.3+/-6.5) ml. The time to first flatus was (2.3+/-0.8) days postoperatively. The postoperative hospital stay was (3.3+/-0.6) days. The mean number of lymph node harvested from the surgical specimen was (15.0+/-1.2). All the resection margins were negative. All the patients had postoperative follow-up ranging from 4 to 8 weeks. There were no postoperative infection, anastomotic leak, incision hernia, or short-term deaths. CONCLUSION: da Vinci robotic system greatly reduces the difficulty of the rectal cancer surgery with its unique light source system and flexible equipment operation. PMID- 22941683 TI - [Comparison of the incidence of postoperative complications following laparoscopic and open colorectal cancer resection]. AB - OBJECTIVE: To compare the postoperative complications following laparoscopic and open colorectal cancer resection. METHODS: From January 2000 to September 2011, 910 patients underwent laparoscopic surgery and 434 open surgery. The postoperative complications were compared between the two groups. RESULTS: Forty eight patients (5.3%, 48/910) in the laparoscopic group were converted to open operation, of whom 36 (75.0%, 36/48) were due to difficulty in procedure and exposure from obesity and narrow pelvis. The overall complication rate was 20.3% (185/910) in the laparoscopic group and 25.3%(110/434) in the open group (chi2=4.316, P<0.05). For patients with a diverting stoma, the anastomotic leak rate was 2.1% (3/145) and 2.2% (2/93) (chi2=0.002, P>0.05), anastomotic bleeding rate was 3.4% (5/145) and 4.3% (4/93) (chi2=0.113, P>0.05). For patients without a diverting stoma, the anastomotic leak rate was 3.1% (22/699) and 1.0% (3/301) (chi2=3.993, P<0.05), anastomotic bleeding rate was 1.6% (11/699) and 2.3% (7/301) (chi2=0.673, P>0.05), bowel obstruction rate was 3.4% (31/910) and 5.8% (25/434) (chi2=4.077, P<0.05), chyle leak rate was 5.8% (53/910) and 3.7% (16/434) (chi2=2.757, P>0.05), urinary retention rate was 1.5% (14/910) and 1.6% (7/434) (chi2=0.011, P>0.05), wound infection rate was 2.2% (20/910) and 4.6% (20/434) (chi2=5.913, P<0.05), pulmonary infection rate was 6.4% (58/910) and 10.6% (46/434) (chi2=7.349, P<0.05). CONCLUSION: The overall postoperative complication rate in laparoscopic surgery is significantly lower than that in open surgery. PMID- 22941684 TI - [Meta-analysis of laparoscopic Nissen and Toupet fundoplication for gastro oesophageal reflux disease]. AB - OBJECTIVE: To compare laparoscopic Nissen fundoplication (LNF)and Toupet laparoscopic fundoplication (LTF) with respect to treatment outcomes and postoperative complications. METHODS: PubMed, Medline, Embase and the Cochrane Library were searched. Only randomized controlled trials (RCTs) comparing laparoscopic Nissen and Toupet fundoplication were included. Outcomes evaluation included occurrences of heartburn, reflux, difficulty swallowing, chest pain, abdominal distention, failure to hiccup, diarrhea, and early complications and degree of patient satisfaction at early (three to six months) and later (one to three years) post-operative periods. RESULTS: Of 939 patients in seven RCTs, 478 received LNF and 461 received LTF. For both groups, control of reflux was good and occurrence of heartburn was similar (P>0.05). A lower incidence of postoperative dysphagia for both early and later post-operative periods, but a higher overall complication rate in early post-operative period were observed in the LTF group (P<0.05). Patient satisfaction was similar (P>0.05). CONCLUSIONS: LNF and LTF are both safe and effective. The adoption of procedure should be based on the patient status and surgeon experience. PMID- 22941685 TI - [Anatomical observation on surgical spaces related to laparoscopic right hemicolectomy]. AB - OBJECTIVE: To explore regional anatomy of fasciae and spaces related to laparoscopic right hemicolectomy (LRC). METHODS: Seven cadavers and 49 patients undergoing LRC for cancer were observed. Computed tomography (CT) images of patients and healthy individuals were reviewed. RESULTS: Between ascending mesocolon and prerenal fascia (PRF), there was a right retrocolic space (RRCS), which communicated in all directions. Anterior, posterior, medial, lateral, cranial, and caudal boundaries of the RRCS were ascending mesocolon, PRF, superior mesenteric vein, peritoneal reflexion at right paracolic sulcus, inferior margin of transverse part of duodenum, and inferior margin of the mesentery root, respectively. Between transverse mesocolon and pancreas and duodenum, there was a transverse retrocolic space (TRCS), which was bounded cranially by root of transverse mesocolon. On CT images of healthy individuals, PRF was noted as slender line of middle density, continuing to transverse fascia, and the retrocolic spaces were unidentifiable. For patients with right colon cancer, PRF and right retrocolic space might be easier to be identified. CONCLUSIONS: The RRCS and the TRCS are natural surgical spaces. The PRF is natural surgical plane in LRC for cancer. PMID- 22941686 TI - [Extraluminal laparoscopic wedge resection for gastric stromal tumors]. AB - OBJECTIVE: To explore the feasibility and safety of extraluminal laparoscopic wedge resection(ELWR) surgery for gastrointestinal stromal tumors (GIST) in the stomach. METHODS: The clinical data of 31 patients with gastric GIST undergoing ELWR from July 2007 to June 2011 were analyzed retrospectively. RESULTS: There were 19 males and 12 females with a mean age of 65.5 years old. Locations of the tumor included fundus of the stomach (n=22) and anterior wall (n=9). The mean diameter was (3.3+/-1.5) cm (range 1.5 to 5 cm). All the procedures were performed successfully without conversion to open operation. The mean operative time of ELWR was (54.1+/-6.2) min (range 45 to 65 min), the mean intraoperative blood loss was (35.2+/-10.5) ml (range 15 to 55 ml), the mean recovery time was (1.5+/-0.2) d (range 3 to 6 d) and the mean postoperative hospital stay was (4.5+/-1.0) d. No patient experienced complications postoperatively. The entire cohort were followed up for 4 to 48 months (mean 18.8 months) and no recurrence or metastasis was found. CONCLUSION: ELWR for gastric GIST is technically feasible and safe. PMID- 22941687 TI - [Impact of operative time on patients undergoing laparoscopy-assisted distal gastrectomy with D2 lymph node dissection for gastric cancer]. AB - OBJECTIVE: To investigate the effect of operative time on laparoscopy-assisted distal gastrectomy (LADG) with D2 lymph node dissection and the influencing factors of operative time. METHODS: Clinical data of 332 patients with gastric cancer undergoing LADG with D2 lymph node dissection from January 2007 to December 2010 were analyzed retrospectively. The average operative time was (205+/-56) minutes. Operative indices and postoperative recovery were compared between patients with operative time>=205 min (long-time group) and operative time<205 min (short-time group). RESULTS: The mean blood loss [(81.0+/-65.7) ml vs. (65.8+/-55.0) ml], time to ambulation [(3.1+/-1.7) d vs. (2.3+/-1.2) d], time to first flatus [(3.8+/-1.1) d vs. (3.2+/-1.3) d], postoperative hospital stay [(14.2+/-6.3) d vs. (12.5+/-7.0) d], and postoperative complication [16.0% (19/119) vs. 8.5% (18/213)] between long-time group and short-time group were significantly different (all P<0.05), while there were no significant differences in transfused patients, time to resume soft diet, and mortality (all P>0.05). Multivariate logistic regression analysis revealed that BMI (P<0.01), lymph node metastasis (P<0.05), and surgeon experience (P<0.01) were independent risk factors for operation time. CONCLUSION: Surgeons who have limited experience in LADG with D2 lymph node dissection should operate on patients with low BMI and less lymph node metastasis in order to reduce postoperative complications. PMID- 22941688 TI - [Influence of CO2 pneumoperitoneum pressures on the expression of adhesion molecules of gastric cancer cells]. AB - OBJECTIVE: To study the effect of different CO2 pneumoperitoneum pressures on the expression of adhesion molecules of human gastric cancer cell line MNK-45. METHODS: MKN-45 cells in the experimental groups were exposed to simulated CO2 environment maintained at different pressures (1.2, 1.6, 2.0 kPa) for 4 hours. Control groups were exposed to room air. At the 0, 24, 48, 72, 96 hours after treatment, CD44v6, ICAM-1 and E-cadherin were detected by flow cytometry method. RESULTS: CD44v6 and ICAM-1 expressions showed pattern of firstly elevating, then descending to normal under the pressures of 1.2 kPa and 1.6 kPa. The expressions were different from control group significantly at 24 and 48 hours (P<0.01), while the 72 hours expression showed no difference compared with the controls (P>0.05). E-cadherin expression decreased significantly right after treatment compared to the control (P<0.01), but recovered to the level of control at 48 hours (P>0.05). In the 2.0 kPa group the expression changes of CD44v6, ICAM-1 and E-cadherin were more remarkable. CD44v6 and ICAM-1 expressions were increased significantly compared to control right after treatment (P<0.05). E-cadherin expression was significantly decreased even at 48 hours compared to the controls (P<0.01). CONCLUSION: In vitro CO2 pneumoperitoneum pressures have transient influence on the adhesion molecules expression of gastric cancer cell MKN-45, then those expressions can recover in a short-time. PMID- 22941689 TI - [Effect of different CO2 pneumoperitoneum on IL-1beta and IL-6 in abdominal cavity]. AB - OBJECTIVE: To evaluate the effect of different CO2 pneumoperitoneum on IL-1beta and IL-6 in abdominal cavity. METHODS: Fifty-six female SD rats were randomly divided into seven groups. One group was served as control and the others received CO2 pneumoperitoneum. Pneumoperitoneum was established at 0.67 kPa and 1.0 L/min gas flow for 1, 2 or 3 h with CO2 (group C1 h, C2 h, and C3 h, respectively). CO2 pneumoperitoneum was further established at 1.07 kPa and 1.0 L/min gas flow for 1 h (group C8p), at 0.67 kPa and 2.0 L/min gas flow for 1 h(group C2f), and at 0.67 kPa and 3.0 L/min gas flow for 1 h (group C3f). After the procedures, peritoneal fluid was collected to analyze the IL-1beta and IL-6 level by ELISA method. RESULTS: CO2 pneumoperitoneum caused peritoneal inflammatory reaction. With the increasing of duration and gas flow in CO2 pneumoperitoneum, the concentrations of IL-1beta and IL-6 in group C2 h, C3 h and C3f were higher than those in group C1 h (P<0.05). On the other hand, the concentrations of IL-1beta and IL-6 in peritoneal fluid did not change significantly when pressure was increased (P>0.05). CONCLUSIONS: The inflammatory reaction in abdominal cavity after CO2 pneumoperitoneum may be attributed to duration and gas flow instead of the pressure within the standard pneumoperitoneum working pressures. Surgeons should reduce surgical duration and adopt low-velocity gas flow within normal working pressures in clinical practice. PMID- 22941691 TI - [Efficacy and safety of domestic biofragmentable anastomotic ring in the intestinal anastomosis]. AB - OBJECTIVE: To investigate the efficacy and safety of the domestic biofragmentable anastomotic ring (BAR) from Hangzhou in the intestinal anastomosis. METHODS: A total of 134 patients who underwent intestinal anastomosis from February 2010 to April 2011 in the First Municipal People's Hospital of Guangzhou and the First Affiliated Hospital of Zhejiang University were randomized into two groups. The Valtrac BAR from USA was employed in the control group while the experimental group used domestic BAR. The operative performance of the BARs, as well as the patients vital signs and bowel function, complications, fragmentation status of the rings were compared between two groups. RESULTS: No significant difference was found between two groups in the operative performance, the fragmentation status of the BARs, the temperature, blood pressure, heart rate, and bowel function (P>0.05). CONCLUSION: The domestic BAR possesses similar safety and efficacy with the Valtrac BAR in intestinal anastomosis. PMID- 22941690 TI - [Impact of laparoscopic colorectal surgery on the peritoneal microstructural injury and expression of t-PA/PAI-1]. AB - OBJECTIVE: To assess the influence of laparoscopic colorectal cancer resection on the peritoneal microstructure injury and expression of t-PA/PAI-1 molecules. METHODS: A total of 50 patients with colorectal cancer were prospectively enrolled between June 2011 and February 2012 in the Shanxi Provincial Hospital and were assigned into laparoscopic group (LO, n=27) and conventional laparotomy group (CO, n=23) based on patients expectancy and surgeon decision. Optical microscope and scanning electron microscope were employed for comparison of the postoperative peritoneal injury between LO and CO. Before and after surgery, t-PA and PAI-1 of peritoneal tissue were determined by ELISA in both groups. RESULTS: Optical microscope and scanning electronic microscopy scan indicated less serosal injury in LO group than that in CO group with regard to serosa integrity, continuity of covering adipocytes and mesothelial cells, and the aggregation level of inflammatory cells (P<0.01). The injury score was 38.22 in CO in and 14.67 in LO and the difference was statistically significant (P<0.01). No significant differences were found between LO and CO in terms of postoperative t PA in the omentum, t-PA and PAI-1 in the intestinal serosa tissue (P>0.05), however PAI-1 in the omentum was significantly lower in LO group compared to CO group (P<0.05). CONCLUSION: Laparoscopic radical resection for colorectal cancer causes less peritoneal structural injury and less influence on the fibrinolytic capacity, which may contribute to less postoperative adhesion. PMID- 22941692 TI - [Comparison among three reconstruction techniques after distal radical gastrectomy]. AB - OBJECTIVE: To compare surgical efficacy after three different reconstruction techniques after radical resection of distal gastric cancer. METHODS: Clinical data of 169 cases of distal gastric cancer operated in our hospital from 2007 to 2010 were retrospectively analyzed. The reconstruction techniques included Billroth I (anastomosis (n=60), Billroth II (anastomosis (n=41), and Roux-en-Y anastomosis (n=68). Efficacy among 3 groups was compared. Specific symptoms scale was used to evaluate the quality of life in three methods after three months. RESULTS: Compared to Billroth I(anastomosis and Billroth II (anastomosis, Roux-en Y anastomosis had longer operative time [(266.3+/-70.4) min vs. (196.2+/-54.3) min, and (228.5+/-67.7) min], more blood loss [(220.9+/-67.6) ml vs. (170.5+/ 61.5) ml and (188.5+/-76.7) ml], and shorter time to gastric tube removal [(2.6+/ 1.5) d vs. (3.1+/-1.3) d and (3.6+/-1.2) d], milder postoperative reflux and heartburn sensation(specific symptoms scale, 1.8+/-0.4 vs. 1.9+/-0.6 and 2.6+/ 0.4, P<0.05). CONCLUSIONS: Although Roux-en-Y anastomosis is not consistent with physiological route and the procedure is more complex to perform, it can effectively prevent reflux complications. Roux-en-Y anastomosis is a better reconstruction technique after radical resection of distal gastric cancer. PMID- 22941693 TI - [Diagnosis of spontaneous isolated superior mesenteric artery dissection using computed tomography angiography]. AB - OBJECTIVE: To investigate the characteristics of the spontaneous isolated superior mesenteric artery dissection (SISMAD) on computed tomography angiography (CTA). METHODS: Twenty-five patients with unexplained acute abdominal pain received CTA. RESULTS: Four cases with the SISMAD were found and all were male with a mean age of (45.3+/-6.7) years. Two patients had hypertension history. CT showed enlarged diameter of the superior mesenteric artery with dissection in 4 cases, intimal flap and visible false lumen in 2 cases, ulcer-like laceration in 1 case, and intramural hematoma in 1 case. The proximal lacerations or entries were all at the proximal segment of the superior mesenteric artery. CTA classifications were type Ia (n=2), IIb (n=1), and III (n=1). Two patients underwent repeated CTA when discharged, and progressive changes were discovered. CONCLUSION: CTA can clearly show the characteristics of the superior mesenteric artery dissection, confirm the diagnosis, and provide an important basis for the classification and follow-up observation. PMID- 22941694 TI - [Association of transcriptional repressor Snail with Lauren classification of gastric cancer]. AB - OBJECTIVE: To explore the association of Snail expression and Lauren classification of gastric cancer. METHODS: The protein levels of Snail and E cadherin were detected by Western blot in N87 (intestinal-type gastric cancer cell line) and AGS(diffuse-type gastric cancer cell line) cell lines and those after transfection of GSK-3beta plasmid. The study included a total of 77 patients with primary gastric cancer who underwent curative gastrectomy in the Zhongshan Hospital from February 2000 to December 2005 without any chemotherapy or radiation therapy before surgery. Tissues of gastric cancer specimens were stained using immunohistochemistry to determine Snail expression. RESULTS: Snail expression was low in N78 and high in AGS. E-cadherin expression showed reverse expression pattern. After transfection with GSK-3beta, the expression of Snail was significantly suppressed and that of E-cadherin elevated (P<0.01). Different concentrations of GSK-3beta inhibitor lithion chloride were used to treat the cell lines and Snail expression was significantly up-regulated in a dose dependent manner (P<0.01). Snail expression was elevated in 16 out of 21 N78 cell lines, and in 21 out of 56 AGS cell lines, and the difference was statistically significant (P<0.01). CONCLUSION: The expression of Snail is closely associated with the Lauren classification of gastric cancer, and it may be a potential marker of the gastric cancer classification. PMID- 22941695 TI - [Apolipoprotein M expression in human colorectal cancer tissues and its clinicopathological relevance]. AB - OBJECTIVE: To investigate the mRNA and protein expression levels of apolipoprotein M (apoM) in the human colorectal cancer tissues, and to explore its clinical relevance. METHODS: Real-time PCR was carried out to determine the mRNA expression levels both in cancer tissue and its adjacent normal tissue from 20 patients with colorectal cancer. Immunohistochemistry was also carried out to determine the protein levels in 23 colorectal biopsy samples (7 normal mucosa, 6 inflammatory mucosa and 10 polyp tissues) and 20 cases of colorectal cancer tissues as well as the adjacent normal tissues. RESULTS: Real-time PCR result showed that apoM mRNA level in the colorectal cancer tissues was significantly lower than that in their adjacent normal tissues (0.05+/-0.01 vs. 0.19+/-0.05, P<0.05). ApoM mRNA level in colorectal cancer tissues was statistically significant higher in the patients with lymph node metastasis as compared to the patients without lymph node metastasis (P<0.01). The median value of apoM protein in cancer tissues was 5.50, which was significantly lower than that in the adjacent normal tissues (10.5, P<0.05), inflammatory mucosa tissues (9.75, P<0.05), polyp tissues (11.0, P<0.01) and normal mucosa (10.5, P<0.05). No significant association was observed between the apoM protein level and the clinicopathological parameters of patients. CONCLUSIONS: Both apoM mRNA and protein expression levels in colorectal cancer tissues are significantly decreased in contrast to normal and benign colorectal tissues. The apoM mRNA expression in colorectal cancer tissues is closely associated with nodal metastasis. PMID- 22941696 TI - [Impact of residual islet function on the glycemia changes of type 1 diabetic rats after gastric bypass]. AB - OBJECTIVE: To investigate the relationship between the type 1 diabetic rats residual islet function and postoperative glycemia of gastric bypass procedure (GBP). METHODS: Intraperitoneal injection of STZ was used to produce type 1 diabetic rat model. According to the level of serum glucose, rats were divided into two groups: group 1 (fasting glucose 16.7-22.0 mmol/L, n=42) and group 2 (fasting glucose>22.0 mmol/L, n=54). Half rats of group 1 and group 2 received GBP, which were OP1 group (n=21) and OP2 group (n=27). The normal control group included 20 Wistar rats. The fasting glycemia and fasting C-peptide (C-P) were tested at postoperative weeks 1, 2, 3, and pancreas pathological slices were examined 3 weeks after surgery under microscope. RESULTS: After GBP, the C-P was elevated and the glycemia was well controlled in OP1 group compared with group 1 (P<0.05). But the C-P was not significantly increased and the glycemia control was poor compared with group 2 (P>0.05). Pathological examination revealed that there were partial islets residual in pancrease of group 1, the islets were shown obvious hyperplasia in OP1 group after GBP. There were almost no islets residual in pancrease of group 2, and the islets were shown no obvious hyperplasia in OP2 group after GBP. CONCLUSIONS: Residual islet function determines the glycemia changes of type 1 diabetic rats after gastric bypass. PMID- 22941697 TI - [Therapy progression in surgery of inflammatory bowel diseases]. AB - The inflammatory bowel diseases (IBDs), consisting of ulcerative colitis (UC) and Crohn's disease (CD), are characterized by idiopathic, chronic inflammation of the gastrointestinal tract. The overall incidence of IBDs is constantly increasing in eastern countries. In comparison with the data from western nations, in China, the incidence of male IBDs is relatively higher, the onset age is older. The severity of most cases is mild to moderate. The occurrence of fistula and peri-anal involvement are rare. Although significant improvements of IBDs therapy have been achieved in recent years, there are still over 30% UC and 70% CD cases need at least one surgery throughout their life span. Here we review the literatures published in recent years about the surgical management of IBDs. PMID- 22941698 TI - What you call it does matter: new definitions of ARDS and VAP. PMID- 22941699 TI - Intensivist training programs and standardization of care. PMID- 22941700 TI - Peripartum cardiomyopathy practice guidelines. PMID- 22941703 TI - Reasons for noncompletion of advance directives in a cardiac intensive care unit. AB - BACKGROUND: The Patient Self-Determination Act of 1990 mandates that hospitals reimbursed by Medicare and Medicaid inform each patient about the patient's right to a natural death. OBJECTIVE: To describe and explore implementation of the Patient Self-Determination Act in a critical care setting. The goal was to assess patients' understanding of advance directives. METHODS: In a semistructured cross sectional study, all eligible patients 18 years or older admitted to the cardiac intensive care unit at Duke University Medical Center, Durham, North Carolina, were assessed. Each patient was asked the standard question required by the Patient Self-Determination Act-Do you have an advance directive?-and 3 open-ended questions to ascertain the patient's understanding of advance directives. RESULTS: The sample consisted of 505 patients with a mean age of 61.9 years (SD, 14.8), 37.8% (n = 191) were women, and 68.5% (n = 346) were white. Most patients (64.4%; n = 325) did not have an advance directive before admission to the unit. Of the patients who initially declined the opportunity to complete an advance directive (n = 213), 33.8% (n = 72) said they did not understand the question when initially asked and therefore just said no. CONCLUSIONS: Current practice meets the requirement of the Patient Self-Determination Act for documentation of patients' right to a natural death. However, simply asking Do you have an advance directive? does not elicit an accurate reflection of a patient's understanding of advance directives. PMID- 22941704 TI - Noncompletion of advance directives. PMID- 22941705 TI - Organ donation after cardiac death in children: acceptance of a protocol by multidisciplinary staff. AB - BACKGROUND: Organ donation after cardiac death is increasingly implemented, with outcomes similar to those of organ donation after brain death. Many hospitals hesitate to implement a protocol for donation after cardiac death because of the potential negative reactions among health care providers. OBJECTIVES: To determine the acceptance of a protocol for donation after cardiac death among multidisciplinary staff in a pediatric intensive care unit. METHODS: An anonymous, 15-question, Likert-scale questionnaire (scores 1-5) was used to determine the opinions of staff about donation after brain death and after cardiac death in a pediatric intensive care unit of a tertiary-care university hospital. RESULTS: Survey response rate was 67% (n = 60). All physicians, 89% of nurses, and 82% of the remaining staff members stated that they understood the difference between donation after brain death and donation after cardiac death; staff supported both types of donation, at rates of 90% and 85%, respectively. Staff perception was the same for each type of donation (rho = 0.82; r = 0.92; P < .001). The 20 staff members who provided care directly to patients who were donors after cardiac death considered such donation worthwhile. However, 60% of those providers offered suggestions to improve the established protocol for donation. CONCLUSIONS: The multidisciplinary staff has accepted organ donation after cardiac death and has fully integrated this kind of donation without reported differences from their acceptance of donation after brain death. PMID- 22941706 TI - A new scoring system for evaluation of multiple organ dysfunction syndrome in premature infants. AB - BACKGROUND: The Neonatal Multiple Organ Dysfunction (NEO-MOD) scoring system is used to predict mortality in infants with multiple organ dysfunction syndrome (MODS). The NEOMOD scoring system was extended to include involvement of the microvascular system. This modified scoring system was developed to enable more accurate and earlier diagnosis of MODS in premature infants. OBJECTIVE: To evaluate the modified NEOMOD scoring system in preterm infants with MODS and compare its effectiveness with the NEOMOD scoring system. METHODS: This prospective study was performed in a tertiary neonatal intensive care unit. A total of 198 premature infants were enrolled. Infants were evaluated for development of MODS by using the modified NEOMOD scoring system until discharge or death according to clinical and laboratory findings. Infants who had organ dysfunction in 2 or more organ systems had MODS diagnosed. RESULTS: In the 160 infants (80.8%) with MODS, the gastrointestinal system, respiratory system, and hematologic system were involved most often. The gastrointestinal system, respiratory system, and acid-base metabolism were involved initially in 99.4%, 86.3%, and 26.3% of infants, respectively. The mean modified NEOMOD score for the infants who died in the first 28 days after birth was significantly higher than the mean score for infants who survived. The number of systems involved was also higher in infants who died. CONCLUSIONS: The modified NEOMOD scoring system is a safe and accurate tool for determining both mortality rate and dysfunction of multiple organ systems affecting mortality in pre-term infants. PMID- 22941707 TI - Chlorhexidine bathing and microbial contamination in patients' bath basins. AB - BACKGROUND: Research has demonstrated the hazards associated with patients' bath basins and microbial contamination. In a previous study, soap and water bath basins in 3 acute care hospitals were found to be reservoirs for bacteria and potentially associated with the development of hospital-acquired infections. Bacteria grew in 98% of the basin samples; the most common were enterococci (54%), and 32% were gram-negative organisms. OBJECTIVE: To assess the presence of bacterial contaminants in wash basins when chlorhexidine gluconate solution is used in place of standard soap and water to wash patients. METHODS: Bathing with chlorhexidine gluconate is the standard of practice for all patients in intensive care units at St Vincent Hospital. Specimens from 90 bath basins used for 5 days or more were cultured for bacterial growth to assess contamination of basins when chlorhexidine gluconate is used. RESULTS: Of the 90 basins cultured, only 4 came back positive for microbial growth; all 4 showed growth of gram-positive organisms. Three of the 4 organisms were identified as coagulase-negative staphylococcus, which is frequently found on the skin. This translates into a 95.5% reduction in bacterial growth when chlorhexidine gluconate is used as compared with soap and water in the previous study (Fisher exact test, P < .001). The only factor that was related to positive cultures of samples from basins was the sex of the patient. DISCUSSION: Compared with the previous study examining microbial contamination of basins when soap and water was used to bathe patients, bacterial growth in patients' bath basins decreased significantly with the use of chlorhexidine gluconate, drastically reducing the risk for hospital-acquired infections. Such reduced risk is especially important for critically ill patients at high risk for bacterial infection. PMID- 22941708 TI - Characteristics of patients with cardiorespiratory instability in a step-down unit. AB - BACKGROUND: Patients in step-down units are at higher risk for developing cardiorespiratory instability than are patients in general care areas. A triage tool is needed to identify at-risk patients who therefore require increased surveillance. OBJECTIVES: To determine demographic (age, race, sex) and clinical (Charlson Comorbidity Index at admission, admitting diagnosis, care area of origin, admission service) differences between patients in step-down units who did and did not experience cardiorespiratory instability. METHODS: In a prospective longitudinal pilot study, 326 surgical-trauma patients had continuous monitoring of heart rate, respirations, and oxygen saturation and intermittent noninvasive measurement of blood pressure. Cardiorespiratory instability was defined as heart rate less than 40/min or greater than 140/min, respirations less than 8/min or greater than 36/min, oxygen saturation less than 85%, or blood pressure less than 80 or greater than 200 mm Hg systolic or greater than 110 mm Hg diastolic. Patients' status was classified as unstable if their values crossed these thresholds even once during their stay. RESULTS: Cardiorespiratory instability occurred in 34% of patients. The Charlson Comorbidity Index was the only variable associated with instability conditions. Compared with patients with no comorbid conditions (50%), more patients with at least 1 comorbid condition (66%) experienced instability (P = .006). Each 1-unit increase in the Charlson Index increased the odds for cardiorespiratory instability by 1.17 (P = .03). CONCLUSION: Although the relationship between Charlson Comorbidity Index and cardiorespiratory instability was weak, adding it to current surveillance systems might improve detection of instability. PMID- 22941710 TI - Limits on clinicians' discretion to unilaterally refuse treatment. PMID- 22941709 TI - Blind insertion of feeding tubes in intensive care units: a national survey. AB - BACKGROUND: Although most critically ill patients experience at least 1 blind insertion of a feeding tube during their stay in an intensive care unit, little is known about the types of health care personnel who perform these insertions or about methods used to determine proper positioning of the tubes. OBJECTIVES: To describe results from a national survey of critical care nurses about feeding tube practices in their adult intensive care units. The questions asked included who performs blind insertions of feeding tubes and what methods are used to determine if the tubes are properly positioned. METHODS: Data were collected from members of the American Association of Critical-Care Nurses via pencil-and-paper and online surveys. Results from both forms were combined for data analysis and were compared with practice recommendations of national-level organizations. RESULTS: A total of 2298 responses were obtained. Physicians perform more blind insertions of styleted feeding tubes than do nurses; in contrast, nurses place more nonstyleted tubes. Radiographic confirmation of correct position is mandated more often for blindly inserted styleted tubes (92.3%) than for nonstyleted tubes (57.5%). The 3 most commonly used bedside methods to determine tube location are auscultation for air injected via the tube, appearance of feeding tube aspirate, and observation for indications of respiratory distress. CONCLUSIONS: Recommendations from multiple national-level organizations to obtain radiographic confirmation that each blindly inserted feeding tube is correctly positioned before the first use of the tube are not adequately implemented. Auscultation is widely used despite recommendations to the contrary. PMID- 22941711 TI - Indices of sudden cardiac death. PMID- 22941712 TI - Central venous catheter placement: where is the tip? AB - The insertion of central venous catheters is a common bedside procedure performed in intensive care units. Here, we present a case of an 82-year-old man who underwent insertion of a central venous catheter in the internal jugular vein without perceived complications. Postprocedural radiographs showed rostral migration of the catheter, and computed tomography performed coincidentally showed cannulation of the jugular bulb at the level of the jugular foramen. To our knowledge, this is the first report to document migration of a central venous catheter from the internal jugular vein into the dural sinuses, as confirmed by computed tomography. The case highlights the importance of acquiring postprocedural radiographs for all insertions of central venous catheters to confirm catheter placement. PMID- 22941713 TI - Diabetic nephropathy is associated with prostate-specific antigen levels in type 2 diabetes mellitus. AB - PURPOSE: Type 2 diabetes is associated with reduced risk of prostate cancer and low prostate-specific antigen levels for uncertain reasons. Recently, two studies demonstrated the time course of diabetes with prostate-specific antigen levels, which would be explained by the chronic renal complication. Therefore, we conducted a retrospective study to determine whether diabetic nephropathy is associated with prostate-specific antigen levels. METHODS AND RESULTS: Eligible patients were men aged >=40 years, with type 2 diabetes and a recorded prostate specific antigen level. Patients with a prior history of prostate cancer or prostatectomy or prostate-specific antigen level >=10 ng/mL and patients with end organ damage were excluded. Of the 247 patients included in the adjusted analysis, 51 (20.8 %) were diagnosed with diabetic nephropathy. A significant association of diabetic nephropathy with log-transformed prostate-specific antigen level was detected (Spearman's correlation coefficient -0.201, p = 0.003; adjusted for all other correlated variables) and fit into a linear regression model (B-coefficient -0.331, p = 0.003). Comparing diabetic nephropathy group with non-diabetic nephropathy group, the difference in log-transformed prostate specific antigen levels was also significant (p = 0.002). CONCLUSION: The results indicated that patients with diabetic nephropathy have low prostate-specific antigen levels, suggesting fewer prostate cancers being detected or fewer incidences among this group. PMID- 22941714 TI - Are adolescents with high mental toughness levels more resilient against stress? AB - Mental toughness has been explored predominantly within sport contexts. Nevertheless, it is difficult to conceive mental toughness as only applicable to athletes. This study examines whether mentally tough participants exhibit resilience against stress. This is a cross-sectional study based on two different samples: Sample 1 consisted of 284 high school students (99 males, 185 females, M = 18.3 years). Sample 2 consisted of 140 first through fifth semester undergraduate students (53 males, 87 females, M = 20.0 years). Participants provided information about their level of perceived stress (10-item Perceived Stress Scale), mental toughness (48-item Mental Toughness Questionnaire) and depressive symptoms (Beck Depression Inventory). Consistent across the two samples, mental toughness mitigated the relationship between high stress and depressive symptoms. The interaction between stress and mental toughness explained 2% of variance in the adolescent sample and 10% of variance among young adults. The promotion of protective factors that foster resilient adaptation is a relevant issue. Mental toughness may appeal to individuals that are typically difficult to be reached with health interventions. Because mental toughness is part of young people's daily speech, it may serve as a less academic resource than other health psychology concepts. PMID- 22941715 TI - Functional degradation of the primary visual cortex during early senescence in rhesus monkeys. AB - Visual function in humans degrades during the early stage of senescence beginning from middle 50s to 60s. To identify its underlying neural mechanisms, we investigated the aging effects on the primary visual cortex (V1) cells in early senescent (ES) monkeys (Macaca mulatta). Under anesthesia, receptive field properties of V1 cells were examined by extracellular single-unit recordings in the young adult (YA; 5-6 years old), ES (19-24 years old), and late senescent (LS; 28-32 years old) monkeys. We found clear indications of functional degradation in early senescence, including impaired stimulus selectivities, increased level of spontaneous activity and declined signal-to-noise ratio, and dynamic range of V1 cell responses. Importantly, the functional degradation in early senescence exhibited unique features that were different from the results for the LS animals, such as remarkable individual variability in orientation selectivity and unchanged peak response elicited by visual stimulation. Our results demonstrate that the function of V1 degrades during the early stage of aging in nonhuman primate, suggesting potential neural correlates for functional deficits observed in early senescence in human subjects. Moreover, these results provide new insight into the dynamics of the aging-related functional deterioration, revealing a more complex and heterogeneous picture of this process. PMID- 22941717 TI - Cortical thickness in untreated transsexuals. AB - Sex differences in cortical thickness (CTh) have been extensively investigated but as yet there are no reports on CTh in transsexuals. Our aim was to determine whether the CTh pattern in transsexuals before hormonal treatment follows their biological sex or their gender identity. We performed brain magnetic resonance imaging on 94 subjects: 24 untreated female-to-male transsexuals (FtMs), 18 untreated male-to-female transsexuals (MtFs), and 29 male and 23 female controls in a 3-T TIM-TRIO Siemens scanner. T1-weighted images were analyzed to obtain CTh and volumetric subcortical measurements with FreeSurfer software. CTh maps showed control females have thicker cortex than control males in the frontal and parietal regions. In contrast, males have greater right putamen volume. FtMs had a similar CTh to control females and greater CTh than males in the parietal and temporal cortices. FtMs had larger right putamen than females but did not differ from males. MtFs did not differ in CTh from female controls but had greater CTh than control males in the orbitofrontal, insular, and medial occipital regions. In conclusion, FtMs showed evidence of subcortical gray matter masculinization, while MtFs showed evidence of CTh feminization. In both types of transsexuals, the differences with respect to their biological sex are located in the right hemisphere. PMID- 22941716 TI - Axo-dendritic overlap and laminar projection can explain interneuron connectivity to pyramidal cells. AB - Neocortical GABAergic interneurons have important roles in the normal and pathological states of the circuit. Recent work has revealed that somatostatin positive (SOM) and parvalbumin-positive (PV) interneurons connect promiscuously to pyramidal cells (PCs). We investigated whether Peters' rule, that is, the spatial overlap of axons and dendrites, could explain this unspecific connectivity. We reconstructed the morphologies of P11-17 mouse SOM and PV interneurons and their PC targets, and performed Monte Carlo simulations to build maps of predicted connectivity based on Peters' rule. We then compared the predicted with the real connectivity maps, measured with 2-photon uncaging experiments, and found no statistical differences between them in the probability of connection as a function of distance and in the spatial structure of the maps. Finally, using reconstructions of connected SOM-PCs and PV-PCs, we investigated the subcellular targeting specificity, by analyzing the postsynaptic position of the contacts, and found that their spatial distributions match the distribution of postsynaptic PC surface area, in agreement with Peters' rule. Thus, the spatial profile of the connectivity maps and even the postsynaptic position of interneuron contacts could result from the mere overlap of axonal and dendritic arborizations and their laminar projections patterns. PMID- 22941718 TI - Spatial stimulus configuration and attentional selection: extrastriate and superior parietal interactions. AB - The intraparietal sulcus (IPS) is critical for resolving stimulus competition. Its activity is modulated depending on how competing stimuli are spatially configured. Lesions extending into IPS lead to selection deficits when stimuli are configured along a horizontal relative to a vertical or diagonal axis. Using functional magnetic resonance imaging, we examined whether the effect of configuration axis originates at the level of the sensory map in early visual cortex or at the level of the attentional priority map in IPS. In each trial, we presented 1 or 2 peripheral gratings in the upper right visual field and a central letter stream. Subjects performed either a peripheral orientation discrimination task or a central letter detection task. Left IPS activity was higher when peripheral stimuli were configured along the horizontal relative to the vertical axis, but only in peripheral attention conditions. The portions of extrastriate cortex that responded to the peripheral stimuli showed a similar interaction. Connectivity from superior parietal to extrastriate cortex was enhanced by adding a competing distracter during the peripheral attention task. The effect of the spatial configuration between competing stimuli originates at the level of the attentional priority map in IPS rather than the visual sensory map. PMID- 22941719 TI - Functional relevance of micromodules in the human association cortex delineated with high-resolution FMRI. AB - Recent advancement of resting-state functional connectivity magnetic resonance imaging (MRI) has provided a method for drawing boundaries of brain areas. However, it remains to be elucidated how the parcellated areas in the association cortex relate to the spatial extent of the brain activation which ought to reflect a functional unit in the neural network supporting that particular function. To address this issue, in the present study, we first mapped boundaries and 2 adjacent activations in the human inferior frontal cortex, and then examined the spatial relationship between the boundaries and the 2 activations. The boundaries mapped with high-resolution functional magnetic resonance imaging revealed a collection of micromodules, the size of which was approximately only 12 mm on average, much smaller than the Brodmann areas. Each of the 2 activations associated with 2 functions, response inhibition and feedback processing, was smaller in size than the micromodules. By comparing the spatial patterns between the boundaries and the 2 activations, it was revealed that the brain activations were less likely to be located on the boundaries. These results suggest the functional relevance of the areas in the association cortex delineated by the boundary mapping method based on resting-state functional connectivity MRI. PMID- 22941720 TI - Oscillatory brain activity correlates with risk perception and predicts social decisions. AB - In social interactions, the perception of how risky our decisions are depends on how we anticipate other people's behaviors. We used electroencephalography to study the neurobiology of perception of social risk, in subjects playing the role of proposers in an iterated ultimatum game in pairs. Based on statistical modeling, we used the previous behaviors of both players to separate high-risk [HR] offers from low-risk [LR] offers. The HR offers present higher rejection probability and higher entropy (variability of possible outcome) than the LR offers. Rejections of LR offers elicited both a stronger mediofrontal negativity and a higher prefrontal theta activity than rejections of HR offers. Moreover, prior to feedback, HR offers generated a drop in alpha activity in an extended network. Interestingly, trial-by-trial variation in alpha activity in the medial prefrontal, posterior temporal, and inferior pariental cortex was specifically modulated by risk and, together with theta activity in the prefrontal and posterior cingulate cortex, predicted the proposer's subsequent behavior. Our results provide evidence that alpha and theta oscillations are sensitive to social risk and underlie a fine-tuning regulation of social decisions. PMID- 22941722 TI - Fooling the kickers but not the goalkeepers: behavioral and neurophysiological correlates of fake action detection in soccer. AB - Studies demonstrate that elite athletes are able to extract kinematic information of observed domain-specific actions to predict their future course. Little is known, however, on the perceptuo-motor processes and neural correlates of the athletes' ability to predict fooling actions. Combining psychophysics and transcranial magnetic stimulation, we explored the impact of motor and perceptual expertise on the ability to predict the fate of observed actual or fake soccer penalty kicks. We manipulated the congruence between the model's body kinematics and the subsequent ball trajectory and investigated the prediction performance and cortico-spinal reactivity of expert kickers, goalkeepers, and novices. Kickers and goalkeepers outperformed novices by anticipating the actual kick direction from the model's initial body movements. However, kickers were more often fooled than goalkeepers and novices in cases of incongruent actions. Congruent and incongruent actions engendered a comparable facilitation of kickers' lower limb motor representation, but their neurophysiological response was correlated with their greater susceptibility to be fooled. Moreover, when compared with actual actions, motor facilitation for incongruent actions was lower among goalkeepers and higher among novices. Thus, responding to fooling actions requires updation of simulative motor representations of others' actions and is facilitated by visual rather than by motor expertise. PMID- 22941721 TI - Dopamine asymmetries predict orienting bias in healthy individuals. AB - Pseudoneglect is traditionally viewed as reflecting right hemisphere specialization for processing spatial information, resulting in orienting toward the contralateral, left, hemispace. Recent evidence suggests that healthy individuals differ from each other in both direction and magnitude of orienting bias, and moreover, the bias displayed by a person is consistent across time, suggesting that it may represent a trait of the individual. Animal studies reveal consistent orienting bias within an individual, which reflects asymmetry in dopaminergic brain systems. We measured basal D2-like receptor binding using positron emission tomography and the high-affinity ligand [F-18]fallypride, to test the hypothesis that asymmetry in dopaminergic neurotransmission in healthy humans modulates the orienting bias in humans. As predicted, we found that individual differences in the direction and magnitude of the orienting bias were strongly associated with the pattern of asymmetric binding of dopamine (DA) D2 receptors in the striatum, as well as clusters in the frontal and temporal cortex. These findings show for the first time that orienting bias reflects individual differences in the lateralization of DA systems in the healthy human brain. PMID- 22941723 TI - Ongoing intrinsic synchronous activity is required for the functional maturation of CA3-CA1 glutamatergic synapses. AB - Fine-tuning of synaptic connectivity during development is guided by intrinsic activity of the immature networks characteristically consisting of intermittent bursts of synchronous activity. However, the role of synchronous versus asynchronous activity in synapse maturation in the brain is unclear. Here, we have pharmacologically prevented generation of synchronous activity in the immature rat CA3-CA1 circuitry in a manner that preserves unitary activity. Long term desynchronization of the network resulted in weakening of AMPA-receptor mediated glutamatergic transmission in CA1 pyramidal cells. This weakening was dependent on protein phosphatases and mGluR activity, associated with an increase in the proportion of silent synapses and a decrease in the protein levels of GluA4 suggesting postsynaptic mechanisms of expression. The findings demonstrate that synchronous activity in the immature CA3-CA1 circuitry is critical for the induction and maintenance of glutamatergic synapses and underscores the importance of temporal activity patterns in shaping the synaptic circuitry during development. PMID- 22941724 TI - In the zone or zoning out? Tracking behavioral and neural fluctuations during sustained attention. AB - Despite growing recognition that attention fluctuates from moment-to-moment during sustained performance, prevailing analysis strategies involve averaging data across multiple trials or time points, treating these fluctuations as noise. Here, using alternative approaches, we clarify the relationship between ongoing brain activity and performance fluctuations during sustained attention. We introduce a novel task (the gradual onset continuous performance task), along with innovative analysis procedures that probe the relationships between reaction time (RT) variability, attention lapses, and intrinsic brain activity. Our results highlight 2 attentional states-a stable, less error-prone state ("in the zone"), characterized by higher default mode network (DMN) activity but during which subjects are at risk of erring if DMN activity rises beyond intermediate levels, and a more effortful mode of processing ("out of the zone"), that is less optimal for sustained performance and relies on activity in dorsal attention network (DAN) regions. These findings motivate a new view of DMN and DAN functioning capable of integrating seemingly disparate reports of their role in goal-directed behavior. Further, they hold potential to reconcile conflicting theories of sustained attention, and represent an important step forward in linking intrinsic brain activity to behavioral phenomena. PMID- 22941725 TI - Highly selective and stable florescent sensor for Cd(II) based on poly (azomethine-urethane). AB - In this study a kind of poly(azomethine-urethane); (E)-4-((2 hydroxyphenylimino) methyl)-2-methoxyphenyl 6-acetamidohexylcarbamate (HDI-co-3-DHB-2-AP) was prepared as in the literature and employed as a new fluorescent probe for detection of Cd(II) concentration. The photoluminescence (PL) measurements were carried out in the presence of several kinds of heavy metals. HDI-co-3-DHB-2-AP gave a linearly and highly stable response against Cd(II) as decreasing a new emission peak at 562 nm. Possible interferences of other ions were found too low. Detection limit of the sensor was found as 8.86 * 10(-4) mol L(-1). Resultantly, HDI-co-3- DHB-2-AP could be effectively used as an optical Cd(II) sensor. PMID- 22941726 TI - Decyl-perfluorinated magnetic mesoporous microspheres for extraction and analysis perfluorinated compounds in water using ultrahigh-performance liquid chromatography-mass spectrometry. AB - In this work, the interior-walls decyl-perfluorinated functionalized magnetic mesoporous microspheres (F(17)-Fe(3)O(4)@mSiO(2)) were synthesized for the first time, and applied as adsorbents to extract and concentrate perfluorinated compounds (PFCs) from water samples. The fluorous functionalized interior pore walls contributed to the high-selective preconcentration of PFCs due to fluorous affinity; and abundant silanol groups on the exterior surface of microspheres contributed to the good dispersibility in water sample. Four kinds of PFCs were selected as model analytes, including perfluorooctanoic acid, perfluorononanoic acid, perfluorododecanoic acid, and perfluorooctane sulphonate. In addition, UHPLC-ESI/MS/MS was introduced to the fast and sensitive detection of the analytes after sample pretreatment. Important parameters of the extraction procedure were optimized, including salinity, eluting solvent, the amount of F(17)-Fe(3)O(4)@mSiO(2) microspheres, and extraction time. The optimized procedure took only 10 min to extract analytes with high recoveries and merely 800-MUL acetonitrile to elute analytes from the magnetic adsorbents. Validation experiments showed good linearity (0.994-0.998), precision (2.6-7.6%), high recovery (93.4-105.7%) of the proposed method, and the limits of detection were from 0.008 to 0.125 MUg/L. The F(17)-Fe(3)O(4)@mSiO(2) magnetic microspheres have the advantages of great dispersibility in aqueous solution, high specificity of extraction, large surface area, and efficient separation ability. The results showed that the proposed method based on F(17)-Fe(3)O(4)@mSiO(2) microspheres is a simple, fast, and sensitive tool for the analysis of PFCs in water sample. PMID- 22941727 TI - Eccentric exercise does not affect common drive in the biceps brachii. AB - INTRODUCTION: The purpose of this study was to investigate the effects of eccentric exercise on common drive. METHODS: Eleven men, age 23.6 +/- 2.1 (mean +/- SD) years, performed trapezoid isometric muscle actions of the dominant forearm flexors immediately before and after 1 of 2 interventions: (a) 6 sets of 10 maximal eccentric isokinetic muscle actions of the forearm flexors; or (b) 10 minutes of quiet resting. Surface electromyographic signals were recorded from the biceps brachii and decomposed into individual motor unit action potential trains. Mean firing rate patterns were calculated for each motor unit, and all possible combinations were cross-correlated to measure common drive. RESULTS: The peak cross-correlation coefficients were generally in the 0.2-0.5 range and occasionally as high as 0.7. CONCLUSION: These coefficients were not, however, affected by the eccentric exercise, despite a 19.5% decrease in strength, indicating that the eccentric exercise did not affect common drive. Muscle Nerve, 2012. PMID- 22941729 TI - Jerome Cornfield's contributions to early large randomized clinical trials and some reminiscences from the years of the slippery doorknobs. AB - This paper briefly describes Jerome Cornfield's approach to Bayesian statistics, his discomfort with frequentist inference, and his contribution to two major clinical trials, the University Group Diabetes Program and the Coronary Drug Project. I mention the role of Bayesian statistics in current randomized clinical trials and conjecture why Cornfield's contributions to Bayesian methods are not more widely cited today. I then provide some personal recollections of Jerry as a role model and mentor and conclude with a recommendation that biostatisticians read his seminal papers because of their thoughtfulness, insight, wit, and clarity. PMID- 22941730 TI - Quantitative cholescintigraphy with fatty meal in the diagnosis of sphincter of Oddi dysfunction and acalculous cholecystopathy. AB - To evaluate the role of quantitative cholescintigraphy with fatty meal in the management of biliary dyskinesia and to describe the findings according to Sostre score (SS) criteria in patients with gallbladder (GB) in-situ and biliary pain. We performed a retrospective analysis of the hepatobiliary (HIDA) studies (n = 35) performed for evaluation of biliary dyskinesia either due to biliary pain, opioid induced sphincter of Oddi dysfunction (SOD), recurrent pancreatitis (RP) or post cholecystectomy syndrome (PCS). Gallbladder ejection fraction (GBEF) was calculated from the post fatty meal HIDA images (excluding PCS patients). Studies with GBEF <=40 % and SS >4 were considered to have cholecystopathy and SOD respectively. Three of the 13 patients with PCS had SS of 6 each, suggestive of SOD. Delayed biliary visualization (>15 min) and activity in common bile duct 60 min > liver 15 min were the specific features in these cases. Opioid induced SOD patients had SS >4 with retrograde refilling of GB in one patient and normalization of the SS parameters after nifedipine challenge in the other patient. Patients with RP and biliary pain were stratified into four groups, normal (GBEF >40 % and SS <=4), cholecystopathy (GBEF <=40 % and SS <=4), normal with SOD (GBEF >40 % and SS >4) and cholecystopathy with SOD (GBEF <=40 % and SS >4). Four patients with intact GB had cholecystopathy with scintigraphic features of SOD. Quantitative cholescintigraphy with fatty meal and SS scoring identified biliary dyskinesia and SOD in patients with biliary pain, recurrent pancreatitis and post-cholecystectomy syndrome. PMID- 22941731 TI - Serological surveillance reveals widespread influenza A H7 and H9 subtypes among chicken flocks in Egypt. AB - Multiple avian influenza viruses' subtypes are circulating worldwide possessing serious threat to human populations and considered key contributors to the emergence of human influenza pandemics. This study aimed to identify the potential existence of H7 and H9 avian influenza infections circulating among chicken flocks in Egypt. Serum samples were collected from chicken flocks that experienced respiratory distresses and/or variable mortality rates. H7 and H9 virus infections were screened by haemagglutination inhibition assay using chicken erythrocytes. Serum samples were collected from 9 broiler, 12 breeder and 18 layer flocks. Out of 1,225 examined sera, 417 (34 %) from 14 flocks and 605 (49.4 %) from 21 flocks were found positive for H7 and H9, respectively. Prevalence of both H7 and H9 antibodies were higher in layer followed by breeder then broiler flocks. Special consideration should be paid to control influenza viruses in Egypt, as pandemic influenza strains may develop unnoticed given the presence of subclinical infections, and the possibility of re-assortment with the prevailing endemic H5N1 virus strains in Egypt do exist. PMID- 22941732 TI - Loss of power in two-stage residual-outcome regression analysis in genetic association studies. PMID- 22941733 TI - The colonic microbiota and colonic disease. AB - The colonic ecosystem differs from that in the proximal gut in several important respects. The colonic microbiota represents the largest population of microbes colonizing humans from birth. Constraints on bacterial numbers, composition, and interaction with the host involve not only the innate and acquired immune system, but also the colonic mucin structure. While the microbiota provides beneficial protective, trophic, nutritional, and metabolic signals for the host, it may become a risk factor for disease depending on context and host susceptibility. Technological advances including DNA-based high-throughput compositional analysis have linked changes in the indigenous microbiota with several human diseases. In some instances, these findings have the potential to serve as new biomarkers of risk of disease. In this overview, recent advances are focused upon in relation to irritable bowel syndrome, inflammatory bowel disease, and colon cancer. The possibility that the therapeutic solution to some of these disorders may reside within the microbiota will also be addressed. PMID- 22941734 TI - A linear concatenation strategy to construct 5'-enriched amplified cDNA libraries using multiple displacement amplification. AB - In various experimental systems, limiting available amounts of RNA may prevent a researcher from performing large-scale analyses of gene transcripts. One way to circumvent this is to 'pre-amplify' the starting RNA/cDNA, so that sufficient amounts are available for any downstream analysis. In the present study, we report the development of a novel protocol for constructing amplified cDNA libraries using the Phi29 DNA polymerase based multiple displacement amplification (MDA) system. Using as little as 200 ng of total RNA, we developed a linear concatenation strategy to make the single-stranded cDNA template amenable for MDA. The concatenation, made possible by the template switching property of the reverse transcriptase enzyme, resulted in the amplified cDNA library with intact 5' ends. MDA generated micrograms of template, allowing large scale polymerase chain reaction analyses or other large-scale downstream applications. As the amplified cDNA library contains intact 5' ends, it is also compatible with 5' RACE analyses of specific gene transcripts. Empirical validation of this protocol is demonstrated on a highly characterized (tomato) and an uncharacterized (corn gromwell) experimental system. PMID- 22941735 TI - Immature murine NKT cells pass through a stage of developmentally programmed innate IL-4 secretion. AB - We assessed the production of the canonical Th2 cytokine IL-4 by NKT cells directly in vivo using IL-4-substituting strains of reporter mice that provide faithful and sensitive readouts of cytokine production without the confounding effects of in vitro stimulation. Analysis in naive animals revealed an "innate" phase of IL-4 secretion that did not need to be triggered by administration of a known NKT cell ligand. This secretion was by immature NKT cells spanning Stage 1 of the maturation process in the thymus (CD4(+) CD44(lo) NK1.1(-) cells) and Stage 2 (CD4(+) CD44(hi) NK1.1(-) cells) in the spleen. Like ligand-induced IL-4 production by mature cells, this innate activity was independent of an initial source of IL-4 protein and did not require STAT6 signaling. A more sustained level of innate IL-4 production was observed in animals on a BALB/c background compared with a C57BL/6 background, suggesting a level of genetic regulation that may contribute to the "Th2-prone" phenotype in BALB/c animals. These observations indicate a regulated pattern of IL-4 expression by maturing NKT cells, which may endow these cells with a capacity to influence the development of surrounding cells in the thymus. PMID- 22941737 TI - [Memorandum on research funding in prevention - old wine in new bottles]. PMID- 22941736 TI - Regulation of osteoclast structure and function by FAK family kinases. AB - Osteoclasts are highly specialized cells that resorb bone and contribute to bone remodeling. Diseases such as osteoporosis and osteolytic bone metastasis occur when osteoclast-mediated bone resorption takes place in the absence of concurrent bone synthesis. Considerable effort has been placed on identifying molecules that regulate the bone resorption activity of osteoclasts. To this end, we investigated unique and overlapping functions of members of the FAK family (FAK and Pyk2) in osteoclast functions. With the use of a conditional knockout mouse model, in which FAK is selectively targeted for deletion in osteoclast precursors (FAK(Deltamyeloid)), we found that loss of FAK resulted in reduced bone resorption by osteoclasts in vitro, coincident with impaired signaling through the CSF-1R. However, bone architecture appeared normal in FAK(Deltamyeloid) mice, suggesting that Pyk2 might functionally compensate for reduced FAK levels in vivo. This was supported by data showing that podosome adhesion structures, which are essential for bone degradation, were significantly more impaired in osteoclasts when FAK and Pyk2 were reduced than when either molecule was depleted individually. We conclude that FAK contributes to cytokine signaling and bone resorption in osteoclasts and partially compensates for the absence of Pyk2 to maintain proper adhesion structures in these cells. PMID- 22941738 TI - [Qualitative research in health services research - discussion paper, Part 1: What is the idea?]. AB - In this first part of a 3-part discussion paper the working group "Qualitative Methods" in the German Network of Health Services Research (DNVF) identifies the potentials and opportunities qualitative research methods provide for health services research. Many research questions relevant for health services research require the use of qualitative methods. However, the potential of and need for qualitative research in health services research has not yet received sufficient attention from funding bodies. We discuss the applicability and importance of qualitative research for the field of health services research. We then move on to describe the key characteristics of qualitative research that need to be taken into account in health services research. We discuss characteristics such as open ended (qualitative) data, interpretation of meanings, the search for contradictions, closeness to everyday life, openness towards change or modification of the research question and processes in the context of health services research. To ensure a high-quality approach in qualitative methods for the health services research, sufficient competency in methods and appropriate settings that account for the peculiarities of qualitative methods need to be developed. These include an appropriate time frame and sufficient and qualified personnel to conduct qualitative research. Qualitative research is not a research paradigm in itself rather it comprises of many different and diverging approaches. The goal of this paper is to show the diversity of qualitative research methods, its importance for health services research, and to open up the discussion on strategies for integrating qualitative methods into health services research. PMID- 22941739 TI - [Qualitative research in health services research - discussion paper, Part 2: Qualitative research in health services research in Germany - an overview]. AB - BACKGROUND: This is the second part of a 3-part discussion paper by the working group on "Qualitative Methods" in the German network of health services research (DNVF) that shall contribute to the development of a memorandum concerning qualitative health services research. It aims to depict the different types of qualitative research that are conducted in health services research in Germany. In addition, the authors present a specific set of qualitative data collection and analysis tools to demonstrate the potential of qualitative research for health services research. QUALITATIVE RESEARCH IN HEALTH SERVICES RESEARCH - AN OVERVIEW: To give an overview of the types of qualitative research conducted in German health services research, the abstracts of the 8th German Conference on Health Services Research were filtered to identify qualitative or mixed-methods studies. These were then analysed by looking at the context which was studied, who was studied, the aims of the studies, and what type of methods were used. Those methods that were mentioned most often for data collection and analysis are described in detail. QUALITATIVE RESEARCH AT THE CONFERENCE FOR HEALTH SERVICES RESEARCH 2009: Approximately a fifth of all abstracts (n=74) had a qualitative (n=47) or a mixed-methods approach combining quantitative and qualitative methods (n=27). Research aims included needs assessment (41%), survey development (36%), evaluation (22%), and theorizing (1%). Data collection mostly consisted of one-on one interviews (n=45) and group discussions (n=29). Qualitative content analysis was named in 35 abstracts, 30 abstracts did not reference their method of analysis. In addition to a quantitative summary of the abstract findings, the diversity of fields addressed by qualitative methods is highlighted. CONCLUSION: Although drawing conclusions on the use of qualitative methods in German health services research from the analysis of conference abstracts is not possible, the overview we present demonstrates the diversity of methods used for data collection and analysis and showed that a few select methods are extensively used. One of the tasks a memorandum of qualitative health services research should accomplish is to highlight underutilized research methods, which may help to develop the potential of qualitative methodology in German health services research. PMID- 22941740 TI - [Memorandum - research funding of prevention]. AB - The memorandum of the research funding of prevention has been devised within the framework of the Prevention Research Funding Programme of the Federal Ministry of Education and Research. It consists not only of the obtained findings of the research-practice co-operation but also of recommendations for the implementation of prospective, innovational, effective, practice-oriented and sustainable research. The respective knowledge has been acquired from quantitative surveys on the experiences of scientists and practice partners within the prevention research funding project as well as from extensive qualitative methods of structured group evaluation. A participatory co-operation between research and practice based on mutual respect, trust and recognition is seen as mandatory for the further development of both prevention and health promotion research. Research and practice partners are required to engage in an ab initio collaboration starting from the conception phase, whereby it is advisable to encourage and fortify the communication between research, practice and funding partners by systematic surveillance in form of a meta-project. In addition, the inclusion of the target population from the outset and on a collaborative basis is considered as beneficial in order to ensure the practical application of the research findings. Furthermore, innovatory research designs which are able to provide a framework for internal flexibility, continuous re-assessment and adjustment are fundamental for the implementation of practice-oriented research. Moreover, a dynamic co-operation between different groups of interest not only depends on sharing responsibility but also on sufficient funding for both research and practice, which is particularly important for the transfer and communication of the attained findings. With regard to the evaluation of both effectiveness and sustainability of interventions, a research funding project is required which makes long-term results possible through the utilization of regulated monitoring and guarantees quality and continuous effectiveness. Furthermore, in order to stimulate progress within the basic theories of prevention and health promotion, it is also essential for a funding project to focus on elementary concepts. Additionally, for the efficient and sustainable development of health within a population it is advisable to apply both self contained research and the involvement of primary prevention and health promotion to research projects concerning health, social affairs, education, work and environment. PMID- 22941741 TI - [Depressive disorders in childhood and adolescence]. PMID- 22941742 TI - Toxoplasma gondii and cognitive deficits in schizophrenia: an animal model perspective. AB - Cognitive deficits are a core feature of schizophrenia. Epidemiological evidence indicates that microbial pathogens may contribute to cognitive impairment in patients with schizophrenia. Exposure to Toxoplasma gondii (T. gondii) has been associated with cognitive deficits in humans. However, the mechanisms whereby the parasite impacts cognition remain poorly understood. Animal models of T. gondii infection may aid in elucidating the underpinnings of cognitive dysfunction. Here, we (1) overview the literature on the association of T. gondii infection and cognitive impairment, (2) critically analyze current rodent models of cognitive deficits resulting from T. gondii infection, and (3) explore possible mechanisms whereby the parasite may affect cognitive function. PMID- 22941743 TI - Pathways between childhood victimization and psychosis-like symptoms in the ALSPAC birth cohort. AB - BACKGROUND: Several large population-based studies have demonstrated associations between adverse childhood experiences and later development of psychotic symptoms. However, little attention has been paid to the mechanisms involved in this pathway and the few existing studies have relied on cross-sectional assessments. METHODS: Prospective data on 6692 children from the UK Avon Longitudinal Study of Parents and Children (ALSPAC) were used to address this issue. Mothers reported on children's exposure to harsh parenting and domestic violence in early childhood, and children self-reported on bullying victimization prior to 8.5 years. Presence of children's anxiety at 10 years and their depressive symptoms at 9 and 11 years were ascertained from mothers, and children completed assessments of self-esteem and locus of control at 8.5 years. Children were interviewed regarding psychotic symptoms at a mean age of 12.9 years. Multiple mediation analysis was performed to examine direct and indirect effects of each childhood adversity on psychotic symptoms. RESULTS: The association between harsh parenting and psychotic symptoms was fully mediated by anxiety, depressive symptoms, external locus of control, and low self-esteem. Bullying victimization and exposure to domestic violence had their associations with psychotic symptoms partially mediated by anxiety, depression, locus of control, and self-esteem. Similar results were obtained following adjustment for a range of confounders and when analyses were conducted for boys and girls separately. CONCLUSIONS: These findings tentatively suggest that specific cognitive and affective difficulties in childhood could be targeted to minimize the likelihood of adolescents exposed to early trauma from developing psychotic symptoms. PMID- 22941744 TI - Is nonverbal communication disrupted in interactions involving patients with schizophrenia? AB - BACKGROUND: Nonverbal communication is a critical feature of successful social interaction and interpersonal rapport. Social exclusion is a feature of schizophrenia. This experimental study investigated if the undisclosed presence of a patient with schizophrenia in interaction changes nonverbal communication (ie, speaker gesture and listener nodding). METHOD: 3D motion-capture techniques recorded 20 patient (1 patient, 2 healthy participants) and 20 control (3 healthy participants) interactions. Participants rated their experience of rapport with each interacting partner. Patients' symptoms, social cognition, and executive functioning were assessed. Four hypotheses were tested: (1) Compared to controls, patients display less speaking gestures and listener nods. (2) Patients' increased symptom severity and poorer social cognition are associated with patients' reduced gesture and nods. (3) Patients' partners compensate for patients' reduced nonverbal behavior by gesturing more when speaking and nodding more when listening. (4) Patients' reduced nonverbal behavior, increased symptom severity, and poorer social cognition are associated with others experiencing poorer rapport with the patient. RESULTS: Patients gestured less when speaking. Patients with more negative symptoms nodded less as listeners, while their partners appeared to compensate by gesturing more as speakers. Patients with more negative symptoms also gestured more when speaking, which, alongside increased negative symptoms and poorer social cognition, was associated with others experiencing poorer patient rapport. CONCLUSIONS: Patients' symptoms are associated with the nonverbal behavior of patients and their partners. Patients' increased negative symptoms and gesture use are associated with poorer interpersonal rapport. This study provides specific evidence about how negative symptoms impact patients' social interactions. PMID- 22941746 TI - Cognitive behavioral therapy for subjects at ultrahigh risk for developing psychosis: a randomized controlled clinical trial. AB - BACKGROUND: Evidence for the effectiveness of treatments for subjects at ultrahigh risk (UHR) for developing psychosis remains inconclusive. OBJECTIVE: A new cognitive behavioral intervention specifically targeted at cognitive biases (ie, Cognitive Behavioral Therapy [CBT] for UHR patients plus treatment as usual [TAU] called CBTuhr) is compared with TAU in a group of young help-seeking UHR subjects. METHODS: A total of 201 patients were recruited at 4 sites and randomized. In most cases, CBTuhr was an add-on therapy because most people were seeking help for a comorbid disorder. The CBT was provided for 6 months, and the follow-up period was 18 months. RESULTS: In the CBTuhr condition, 10 patients transitioned to psychosis compared with 22 in the TAU condition (chi(2) (1) = 5.575, P = .03). The number needed to treat (NNT) was 9 (95% confidence interval [CI]: 4.7-89.9). At 18-month follow-up the CBTuhr group was significantly more often remitted from an at-risk mental state, with a NNT of 7 (95% CI: 3.7-71.2). Intention-to-treat analysis, including 5 violations against exclusion criteria, showed a statistical tendency (chi(2) (1) = 3.338, P = .06). CONCLUSIONS: Compared with TAU, this new CBT (focusing on normalization and awareness of cognitive biases) showed a favorable effect on the transition to psychosis and reduction of subclinical psychotic symptoms in subjects at UHR to develop psychosis. PMID- 22941747 TI - Rituximab in refractory and non-refractory myasthenia: a retrospective multicenter study. AB - INTRODUCTION: Few data are available about the effect of rituximab (RTX) on refractory (RM) and non-refractory (NRM) myasthenia. METHODS: This retrospective multicenter study involved 13 RM and 7 NRM patients treated with sequential RTX infusions over 2 years, on average. RTX was used as a substitute for corticosteroids in NRM patients. Disability was assessed using the annualized relapse rate (ARR) and Myasthenia Gravis Foundation of America (MGFA) scores. RESULTS: RTX induction decreased the ARR from 2.1 to 0.3 (P < 0.001), and lowered MGFA scores from 5-3b to 4b-0 in RM patients, and from 1.9 to 0.1 (P < 0.001) and 4b-2b to 3b-0 in NRM patients. No side effects were reported in either group, except for 1 case of spondylodiscitis 1 year after the last RTX infusion. Within a year after RTX induction, complete corticosteroid withdrawal was obtained in 7 RM and 4 NRM patients. CONCLUSIONS: RTX is efficacious and well-tolerated. Its use allows for dose reduction or withdrawal of corticosteroids. PMID- 22941745 TI - Genetic risk for schizophrenia, obstetric complications, and adolescent school outcome: evidence for gene-environment interaction. AB - Low birth weight (LBW) and hypoxia are among the environmental factors most reliably associated with schizophrenia; however, the nature of this relationship is unclear and both gene-environment interaction and gene-environment covariation models have been proposed as explanations. High-risk (HR) designs that explore whether obstetric complications differentially predict outcomes in offspring at low risk (LR) vs HR for schizophrenia, while accounting for differences in rates of maternal risk factors, may shed light on this question. This study used prospectively obtained data to examine relationships between LBW and hypoxia on school outcome at age 15-16 years in a Finnish sample of 1070 offspring at LR for schizophrenia and 373 offspring at HR for schizophrenia, based on parental psychiatric history. Controlling for offspring sex, maternal smoking, social support, parity, age, and number of prenatal care visits, HR offspring performed worse than LR offspring across academic, nonacademic, and physical education domains. LBW predicted poorer academic and physical education performance in HR offspring, but not in LR offspring, and this association was similar for offspring of fathers vs mothers with schizophrenia. Hypoxia predicted poorer physical education score across risk groups. Rates of LBW and hypoxia were similar for LR and HR offspring and for offspring of fathers vs mothers with schizophrenia. Results support the hypothesis that genetic susceptibility to schizophrenia confers augmented vulnerability of the developing brain to the effects of obstetric complications, possibly via epigenetic mechanisms. PMID- 22941748 TI - Modulation of biocompatibility on poly(vinylidene fluoride) and polysulfone by oxygen plasma treatment and dopamine coating. AB - Poly(vinylidene fluoride) (PVDF) and polysulfone (PSf) are two polymers with excellent mechanical properties but insufficient biocompatibility mainly due to their surface hydrophobicity. This study has applied oxygen plasma treatments and dopamine coating on the two polymers and investigated the changes of the surface properties and interactions with mammalian cells. All modification steps were verified by means of Electron Spectroscopy for Chemical Analysis and contact angle measurements. Surface topology of materials and biomolecules was studied by atomic force measurements (AFM) and scanning electron microscopy (SEM). Protein adsorption was quantified by fluorescent imaging and Bradford method. The results showed that O(2) plasma altered the surface hydrophilicity effectively on PSf and more than two folds of oxidation were obtained, when compared with the pristine one. The change of surface wettability was less significant on the O(2) plasma treated PVDF due to less oxidation extent, which was identified by analyzing the chemical compositions. The provided functionalized PVDF and PSf surfaces were tested with bovine serum albumin and L-929 mouse fibroblasts to evaluate the effects of surface modifications on protein adsorption and cell attachments. The biocompatibility was effectively promoted to fourfold and twofold on the hydrophobic PVDF and PSf by applying O(2) plasma treatments within short treatment time. Moreover, the simple immobilization of polymers in dopamine solution resulted in hydrophilic surface coating with stability that caused threefold and twofold increases of biocompatibility on PVDF and PSf correspondingly. PMID- 22941749 TI - A high-fat diet decreases AMPK activity in multiple tissues in the absence of hyperglycemia or systemic inflammation in rats. AB - Consumption of a high-fat diet (HFD) in experimental animal models initiates a series of molecular events and outcomes, including insulin resistance and obesity, that mimic the metabolic syndrome in humans. The relationship among, and order of, the molecular events linking a diet high in fat to pathologies is often unclear. In the present study, we provide several novel insights into the relationship between a HFD and AMP-activated protein kinase (AMPK), a key regulator of cellular metabolism and whole-body energy balance. HFD substantially decreased the activities of both isoforms of AMPK in white adipose tissue, heart, and liver. These decreases in AMPK activity occurred in the absence of decreased AMPK transcription, systemic inflammation, hyperglycemia, or elevated levels of free fatty acids. The HFD-induced decrease in AMPK activity was associated with systemic insulin resistance and hyperleptinemia. In blood, >98 % of AMPK activity was localized in agranulocytes as the alpha1 isoform. In contrast to the solid tissues studied, AMPK activities were not altered by HFD in granulocytes or agranulocytes. We conclude that HFD-induced obesity causes a broad, non-tissue, or isoform-specific lowering of AMPK activity. Given the central position AMPK plays in whole-body energy balance, this decreased AMPK activity may play a previously unrecognized role in obesity and its associated pathologies. PMID- 22941751 TI - Development of a nomogram to predict non-organ-confined bladder urothelial cancer before radical cystectomy. AB - PURPOSE: To create a preoperative prediction model for estimating the risk of non organ-confined (pT3-4 or pN+) bladder urothelial cancer (NOC-BUC) in patients with clinically OC-BUC (cT1-2N0M0). METHODS: The study involved 248 consecutive patients who had undergone radical surgery for clinically OC-BUC at a tertiary cancer center between 2003 and 2011. Logistic regression analysis was used to develop a prediction model for estimating the risk of pathological NOC disease. Prespecified predictors included age, gender, recurrent frequency, tumor size and number, hydronephrosis, and pathological characteristics at transurethral resection (T-stage, tumor grade, lymphovascular invasion (LVI), and carcinoma in situ). Discrimination ability was measured by the area under the receiver operating characteristic curve (AUC). RESULTS: Overall, 39.1 % of the patients with clinically OC-BUC had NOC disease at the time of radical surgery. In multivariate analysis, recurrent frequency, tumor size, hydronephrosis, and three pathological features at transurethral resection (T-stage, tumor grade, and LVI) were significantly associated with disease extent. The final prediction model included seven variables after backward elimination and achieved a bootstrap corrected AUC of 0.79. Internal validation showed good calibration and clinical usefulness of the nomogram. CONCLUSIONS: Based on readily available clinicopathological parameters, we developed a nomogram for predicting NOC tumor in clinically OC-BUC. Despite reasonable performance in internal validation, the prediction model should be assessed in external dataset before applied in clinical setting. PMID- 22941753 TI - Abstracts of the 3rd TERMIS (Tissue Engineering & Regenerative Medicine International Society) World Congress 2012. September 5-8, 2012. Vienna, Austria. PMID- 22941752 TI - Detection and management of renal cell carcinoma in the renal allograft. AB - PURPOSE: Tumours of the transplanted kidney represent a rare form of post transplantation malignancies. An important aspect of the treatment option is whether the transplanted kidney can be saved or not. Aim of our study was the analysis of our allograft tumours. METHODS: In the Budapest Centre, 3,530 kidney transplantations were performed between 1973 and 2012. Retrospective analysis of 9 patients who developed renal cell carcinoma (RCC) in the transplanted kidney was done. RESULTS: Mean age of recipients was 45.3 +/- 13.4 years at the time of transplantation and 57.0 +/- 11.6 years at the time of tumour detection. Mean age of their donors was 43.5 +/- 11.5 years. Mean time from transplantation to tumour diagnosis was 134.6 +/- 40.8 months. Seven RCC were stage pT1a, 1 was stage pT1b and 1 was pT3a. Eight patients had stage I. (pT1a-b, N0, M0) and 1 patient had stage IV. (pT3a, N1, M1) disease. Histological types were clear cell (n = 6), papillary (n = 2) and sarcomatoid (n = 1) carcinomas. The tumour growth rate of RCC was 16.7 +/- 13.5 mm/year. In 4 cases, transplant nephrectomy was performed; 5 cases had percutaneous radiofrequency ablation (RFA). Ablative therapy had no influence on renal graft function. Six patients (including 5 patients who were treated with RFA) are still alive and tumour-free; 3 patients died. CONCLUSIONS: According to our observation, we can state that RCC of the kidney allograft diagnosed at an early stage can be successfully treated with RFA instead of graft removal. A longer follow-up is needed to assess the effectivity of the RFA treatment in these cases. PMID- 22941754 TI - Development of an instrument to measure self-efficacy in caregivers of people with advanced cancer. AB - OBJECTIVE: Informal caregivers of people with advanced cancer experience many negative impacts as a result of their role. There is a lack of suitable measures specifically designed to assess their experience. This study aimed to develop a new measure to assess self-efficacy in caregivers of people with advanced cancer. METHODS: The development and testing of the new measure consisted of four separate, sequential phases: generation of issues, development of issues into items, pilot testing and field testing. In the generation of issues, 17 caregivers were interviewed to generate data. These data were analysed to generate codes, which were then systematically developed into items to construct the instrument. The instrument was pilot tested with 14 health professionals and five caregivers. It was then administered to a large sample for field testing to establish the psychometric properties, with established measures including the Brief Cope and the Family Appraisals for Caregiving Questionnaire for Palliative Care. RESULTS: Ninety-four caregivers completed the questionnaire booklet to establish the factor structure, reliability and validity. The factor analysis resulted in a 21-item, four-factor instrument, with the subscales being termed Resilience, Self-Maintenance, Emotional Connectivity and Instrumental Caregiving. The test-retest reliability and internal consistency were both excellent, ranging from 0.73 to 0.85 and 0.81 to 0.94, respectively. Six convergent and divergent hypotheses were made, and five were supported. CONCLUSIONS: This study has developed a new instrument to assess self-efficacy in caregivers of people with advanced cancer. The result is a four-factor, 21-item instrument with demonstrated reliability and validity. PMID- 22941755 TI - Lateral medullary infarction presenting with vertigo without other neurological signs. PMID- 22941756 TI - Effectiveness of repetitive transcranial magnetic stimulation for chronic tinnitus: a systematic review. AB - OBJECTIVE: This systematic review aimed to assess the effectiveness of repetitive transcranial magnetic stimulation (rTMS) treatment for chronic tinnitus. Data Sources Relevant electronic databases and a reference list of articles published up to January 2012 were searched. Randomized controlled clinical trials of all types of rTMS treatment for patients with chronic tinnitus were included. REVIEW METHODS: A literature search was conducted with structured criteria to select studies evaluated for systematic review. RESULTS: Five trials (160 participants) were included in this review. Repetitive transcranial magnetic stimulation treatment showed benefits in the short term, but the long-term effects are questionable. The Tinnitus Handicap Inventory (THI) and the visual analog scale (VAS) were the major assessment methods used. After active TMS stimulation, the reduction in the THI total score and VAS was significant compared with baseline at the first time point assessed and in the short term (2 weeks and 4 weeks). The longest follow-up time was 26 weeks after treatment, and the shortest follow-up time was 2 weeks. No severe side effects were reported from the use of rTMS. Differences in age, hearing level, duration of tinnitus of the included patients, and the condition of sham treatment may influence the effect. CONCLUSION: Repetitive transcranial magnetic stimulation could be a new therapeutic tool for the treatment of chronic tinnitus, and thus far we have not been able to demonstrate any substantial risk from rTMS treatment. However, the long-term effects of rTMS treatment for tinnitus are not clear and will require further study. PMID- 22941757 TI - A sensitivity analysis framework for the treatment effect measure used in the meta-analysis of comparative binary data from randomised controlled trials. AB - The process of undertaking a meta-analysis involves a sequence of decisions, one of which is deciding which measure of treatment effect to use. In particular, for comparative binary data from randomised controlled trials, a wide variety of measures are available such as the odds ratio and the risk difference. It is often of interest to know whether important conclusions would have been substantively different if an alternative measure had been used. Here we develop a new type of sensitivity analysis that incorporates standard measures of treatment effect. Thus, rather than examining the implications of a variety of measures in an ad hoc manner, we can simultaneously examine an entire family of possibilities, including the odds ratio, the arcsine difference and the risk difference. PMID- 22941759 TI - Minimally invasive mandibular bone augmentation using injectable hydrogels. AB - Hyaluronic acid-based hydrogels are proven biocompatible materials and excellent carriers of bone morphogenetic protein-2 (BMP-2) that have been successfully tested for bone generation in vivo. Different formulations, with or without nanohydroxyapatite, have shown promise for craniofacial applications. In this study, 28 rats were used to investigate whether it is possible to achieve mandibular bone augmentation upon injection of novel hyaluronic acid-based hydrogels containing nanohydroxyapatite and different concentrations of BMP-2 (0, 5 and 150 ug/ml). The biomaterials were injected subperiosteally through fine needles into the innate mandibular diastema, imitating a clinical procedure for resorbed mandibles. No incisions, flaps or sutures were necessary. After 8 weeks the mandibles were evaluated by peripheral quantitative computed tomography (pQCT), micro-computed tomography (MUCT), histology, immunohistochemistry and fluorochrome labelling. As a result, engineered bone was observed in all treated mandibles, with a statistically significant increase in mandibular bone volume correlated with the amount of BMP-2 loaded in the hydrogel formula. We therefore demonstrated that minimally invasive mandibular bone augmentation is possible upon injection in rats, when using the appropriate injectable scaffolds. This represents an attractive clinical alternative for oral implantology patients. PMID- 22941760 TI - Cross-sectional and longitudinal analysis of an oxidative stress biomarker for spinal and bulbar muscular atrophy. AB - INTRODUCTION: Spinal and bulbar muscular atrophy (SBMA) is an adult-onset motor neuron disease caused by a CAG repeat expansion in the androgen receptor gene. The aim of this study was to verify whether urinary 8-hydroxydeoxyguanosine (8 OHdG), an oxidative stress marker, is a biomarker for SBMA. METHODS: We measured the levels of urinary 8-OHdG in 33 genetically confirmed SBMA patients and 32 age matched controls over a 24-month period at 6-month intervals. RESULTS: Urinary 8 OHdG levels in SBMA patients were significantly elevated compared with those of controls and correlated well with motor function scores. During the follow-up period, urinary 8-OHdG levels increased and correlated with motor function at each time-point. In addition, urinary 8-OHdG levels at baseline were correlated with changes in the 6-minute walk test during 24 months. CONCLUSIONS: Urinary 8 OHdG is a biomarker for SBMA, reflecting the severity and possibly predicting the deterioration of motor function. PMID- 22941761 TI - [The impact factor is volatile and sensitive]. PMID- 22941762 TI - MODY 2 diabetes in a mature newborn due to a new mutation in the GCK-gene. PMID- 22941763 TI - Health promotion via deaf-friendly ministries. AB - Deaf community members face many barriers to accessing health information. This paper discusses the feasibility of creating a nationwide network of Deaf-friendly ministries to help disseminate cancer information in American Sign Language (ASL) to the Deaf community. Deaf-friendly ministries (N = 403), identified through Internet searches and one-on-one referrals, were sent up to three mailed invitations to join the network. Over half of the ministries responded, with 191 (47.4 %) of the ministries joining the network, completing a baseline survey and receiving ASL cancer education videos to share with members of their congregation and community. Fifteen (3.7 %) responded that they were not interested or no longer had a Deaf-friendly ministry; the rest did not respond or their invitations were returned as undeliverable. As the program progressed, an additional 238 Deaf-friendly ministries were identified. To date, 61 (25.6 %) agreed to participate after the single invitation that was mailed. This network of Deaf-friendly ministries offers a promising dissemination partner. PMID- 22941764 TI - What do we know 40 years after Nixon declared the 'war on cancer'? On the origin, prevention and treatment of cancer. AB - Evolutionary principles suggested by Darwin and Wallace some 150 years ago can provide insights into the origins of cancer. Moreover, they can form a basis for answering the question implicitly posed when Nixon declared the war on cancer in 1971: Can we actually 'cure' cancer? As explained lucidly by Greaves in 2001, necessary keys to evolution and thus for the origin of species, including ours, are changes of genes or mutations; but changes of genes are also necessary links in the causal chains which lead to cancer. In effect, cancer is therefore, according to Greaves, an 'evolutionary legacy'. Intriguingly, the realization that cancer is a consequence of changes in genes which are conditiones sine qua non for evolution suggests a mutation paradox on an evolutionary scale: in individuals, mutations may have devastating adverse health effects, including cancer. Populations, however, as a whole can be expected to benefit ultimately from changes of genes to better adapt to environmental challenges. On the basis of premises from evolution theory, it remains for us to interweave growing insights into evolutionary principles with realistic objectives for the primary prevention of and, where the latter fails, coexistence with cancer so that what we do for patients can become more of an art rather than a war. PMID- 22941765 TI - Some things change, some things stay the same: a longitudinal analysis of cancer caregivers' unmet supportive care needs. AB - OBJECTIVE: The objective of this study was to identify caregivers' unmet needs and the psychosocial variables associated with unmet need count within the first 24 months post-survivor diagnosis. METHODS: Caregivers completed a comprehensive survey measuring the primary outcome, psychosocial variables, and demographics of interest at 6 (n=547), 12 (n=519), and 24 (n=443) months post-survivor diagnosis. RESULTS: Although prevalence of unmet needs significantly decreased over time, almost a third of caregivers still reported unmet needs at 24 months. Unmet needs were more prevalent among caregivers of lung cancer survivors, at 6 and 24 months. Top ranking unmet needs across time included 'managing concerns about cancer coming back', 'reducing stress in the person with cancer's life', 'understanding the experience of the person with cancer', and 'accessible hospital parking'. At 24 months, some of the top ranking unmet needs were related to caregivers' well-being and relationships. Increased interference in activities due to caregiving, anxiety, depression, avoidant and active coping, and out-of pocket expenses was associated with reporting more unmet needs. Less involvement in caregiving roles and increased physical well-being and social support were associated with reporting less unmet needs. For some variables (e.g. anxiety and depression), association with unmet needs strengthened over time. CONCLUSIONS: This is the first longitudinal analysis of caregivers' unmet needs as they enter early and extended survivorship. Findings provide valuable insights into caregiver's unmet needs over time and identified a sub-group of caregivers at risk of experiencing unmet needs, extending previous research and informing the timing and content of psychosocial services. PMID- 22941766 TI - Psoriasis, psoriatic arthritis and increased risk of incident Crohn's disease in US women. AB - OBJECTIVE: Inflammatory bowel disease (IBD), including Crohn's disease (CD) and ulcerative colitis (UC), shares clinical and immunological features with psoriasis. Genome-wide association studies have found common susceptibility genes. However, epidemiologic data evaluating the association between psoriasis, psoriatic arthritis and risk of IBD are sparse. We aimed to evaluate the association between psoriasis, psoriatic arthritis and incident CD and UC among women in the USA. METHODS: 174 476 women were enrolled in the Nurses' Health Study (NHS) (1996-2008) and NHS II (1991-2007). Lifetime history of physician diagnosed psoriasis and psoriatic arthritis was confirmed by supplementary questionnaires. Information on CD and UC was obtained by self-reported questionnaires and confirmed by medical record review. RESULTS: We documented 188 incident cases of CD and 240 incident cases of UC during follow-up. Psoriasis was associated with a significantly increased risk of subsequent CD with a multivariate-adjusted relative risk (RR) of 4.00 (95% CI 1.72 to 9.27) for NHS and 3.76 (1.82 to 7.74) for NHS II. By contrast, we did not observe a significant increase in risk of UC associated with psoriasis. In a pooled analysis of both cohorts, women with psoriasis experienced a significantly increased risk of CD (RR, 3.86, 95% CI 2.23 to 6.67), but not UC (RR, 1.17, 95% CI 0.41 to 3.36). The risk of CD was especially pronounced among psoriatics with concomitant psoriatic arthritis (RR, 6.43, 95% CI 2.04 to 20.32). CONCLUSIONS: Psoriasis with concomitant psoriatic arthritis is associated with an increased risk of incident CD. PMID- 22941767 TI - Clinical response, drug survival and predictors thereof in 432 ankylosing spondylitis patients after switching tumour necrosis factor alpha inhibitor therapy: results from the Danish nationwide DANBIO registry. AB - OBJECTIVE: To investigate frequencies and reasons for switching, treatment responses and drug survival in patients with ankylosing spondylitis (AS) switching tumour-necrosis-factor-alpha inhibitor (TNFi) treatment in routine clinical care. METHODS: AS patients were identified in the Danish nationwide DANBIO registry. Disease activity, treatment responses (50% or 20 mm reduction in Bath AS Disease Activity Index (BASDAI)), duration and rates of drug survival and predictors thereof were studied in patients receiving >=2 different biological drugs. RESULTS: Of 1436 AS patients starting TNFi treatment, 432 patients (30%) switched to a second and 137 (10%) to a third biological drug. Compared with non switchers, switchers were more frequently women (33%/22%), had shorter disease duration (3 years/5 years) and higher BASDAI (62(52-76) mm/56(43-69) mm (median(interquartile-range))), Bath AS Functional Index (BASFI) (54(39-71) mm/47(31-65) mm) and visual-analogue-scale (VAS) global, pain and fatigue scores when they started the first TNFi (all p<0.01). Main reason for switching was lack of response (56%). During the first, second and third treatment BAS- and VAS scores had decreased after 6 months' treatment (all p<0.05). Median drug survivals were 3.1, 1.6 and 1.8 years respectively (p<0.001). After 2 years of treatment 52% of switchers and 63% of non-switchers had achieved response (number needed to treat 1.9 and 1.6, respectively, p=0.01). Drug survivals were similar regardless of the reason for switching. Male gender and low BASFI predicted drug survival of the second TNFi. CONCLUSIONS: Nearly one-third of AS patients in clinical practice switched biological treatment. Response rates and drug survivals were lower among switchers, however, half of switchers achieved treatment response. PMID- 22941768 TI - Association between a history of periodontitis and the risk of rheumatoid arthritis: a nationwide, population-based, case-control study. AB - OBJECTIVE: To investigate the association between the risk of rheumatoid arthritis (RA) and a history of periodontitis. METHODS: This nationwide, population-based, case-control study used administrative data to identify 13 779 newly diagnosed patients with RA (age >=16 years) as the study group and 137 790 non-patients with RA matched for age, sex, and initial diagnosis date (index date) as controls. Using conditional logistic regression analysis after adjustment for potential confounders, including geographical region and a history of diabetes and Sjogren's syndrome, ORs with 95% CI were calculated to quantify the association between RA and periodontitis. To evaluate the effects of periodontitis severity and the lag time since the last periodontitis visit on RA development, ORs were calculated for subgroups of patients with periodontitis according to the number of visits, cumulative cost, periodontal surgery and time interval between the last periodontitis-related visit and the index date. RESULTS: An association was found between a history of periodontitis and newly diagnosed RA (OR=1.16; 95% CI 1.13 to 1.21). The strength of this association remained statistically significant after adjustment for potential confounders (OR=1.16; 95% CI 1.12 to 1.20), and after variation of periodontitis definitions. The association was dose- and time-dependent and was strongest when the interval between the last periodontitis-related visit and the index date was <3 months (OR=1.64; 95% CI 1.49 to 1.79). CONCLUSIONS: This study demonstrates an association between periodontitis and incident RA. This association is weak and limited to lack of individual smoking status. PMID- 22941769 TI - Timing the therapeutic window of opportunity in early rheumatoid arthritis: proposal for definitions of disease duration in clinical trials. AB - The effects of treatment in early rheumatoid arthritis (RA) and the consequences of delayed therapy represent important areas for research. The concept of a 'window of opportunity' is now well established and considerable attention has been paid to when it might close. However, in order to study how long the window of opportunity lasts, the timing of its opening must be precisely defined. An analysis of definitions of 'onset' in clinical studies reveals imprecision and heterogeneity, making accurate assessment of this important concept of the 'window of opportunity' very difficult. In this paper we propose that, in clinical trials in early RA, data on durations since onset of symptoms and onset of joint swelling as well as disease duration based on fulfilment of classification criteria should be routinely presented. PMID- 22941770 TI - An improved algorithm for outbreak detection in multiple surveillance systems. AB - In England and Wales, a large-scale multiple statistical surveillance system for infectious disease outbreaks has been in operation for nearly two decades. This system uses a robust quasi-Poisson regression algorithm to identify abberrances in weekly counts of isolates reported to the Health Protection Agency. In this paper, we review the performance of the system with a view to reducing the number of false reports, while retaining good power to detect genuine outbreaks. We undertook extensive simulations to evaluate the existing system in a range of contrasting scenarios. We suggest several improvements relating to the treatment of trends, seasonality, re-weighting of baselines and error structure. We validate these results by running the existing and proposed new systems in parallel on real data. We find that the new system greatly reduces the number of alarms while maintaining good overall performance and in some instances increasing the sensitivity. PMID- 22941771 TI - Synthesis, characterization, and biocompatibility of a novel biomimetic material based on MGF-Ct24E modified poly(D, L-lactic acid). AB - Mechano-growth factor (MGF) is an alternative splicing variant of Insulin-like growth factor I. MGF and its 24 amino acid peptide analog corresponding to the unique C-terminal E-domain (MGF-Ct24E) are the positive regulator for tissue regenesis in bone. A novel biomimetic poly(D, L-lactic acid) (PDLLA) modification was designed and synthesized based on MGF-Ct24E grafted maleic anhydride modified PDLLA (MPLA). MGF-Ct24Es were grafted into the side chain of MPLA via a stable covalent amide bond using 1-ethyl-3-(3-dimethyllaminopropyl) carbodiimide hydrochloride and N-hydroxysuccinimide as the condensing agent to produce biomimetic MPLA materials (MGF-Ct24E-MPLA). Fourier transform infrared spectrometry, amino acid analyzer, and elementary analysis were used to characterize the MGF-Ct24E-MPLA. The hydrophilicity of MGF-Ct24E-MPLA was evaluated by means of the water-uptake ratios and static water contact angle. Data revealed that the grafting efficiency of MGF-Ct24E was about 29.9%. MGF Ct24E-MPLA had better hydrophilicity than PDLLA and MPLA. The osteoblasts behavior of proliferation, differentiation, and mineralization on PDLLA, MPLA, and MGF-Ct24E-MPLA films was investigated and the results indicated that the introduction of MGF-Ct24E could improve osteoblasts proliferation, mineralization, and delay differentiation. The MGF-Ct24E modified MPLA with higher bioactivity may have potential application for bone tissue engineering. PMID- 22941772 TI - Policy implications for optimizing advanced practice registered nurse use nationally. AB - This article examines the potential benefits of enhanced use of advanced practice registered nurses (APRNs) given health care workforce projections that predict an inadequate supply of certain types of providers. The conclusions of a systematic review comparing the effectiveness of care provided by APRNs with that of physicians alone or teams without APRNs indicate the viability of this approach. Allowing APRNs to assume roles that take full advantage of their educational preparation could mitigate the shortage of primary care physicians and improve care processes. The development of health care policy should be guided by patient centric evidence rather than how care has been delivered in the past. PMID- 22941774 TI - Physiological role of hepatic NPC1L1 in human cholesterol and lipoprotein metabolism: new perspectives and open questions. PMID- 22941776 TI - Rufinamide in children with refractory epilepsy: pharmacokinetics, efficacy, and safety. AB - We examined the influence of age and type of concomitant antiepileptic drugs (AEDs) on the pharmacokinetics of rufinamide (RUF) as well as its efficacy and safety in 51 children with refractory epilepsy. In a retrospective noninterventional survey, dose-to-concentration ratios of RUF and concomitant AEDs were calculated: the weight-normalized dose (mg/kg/d) divided by the steady state trough plasma drug level, which was used as a measure of clearance. During treatment with RUF concomitantly with valproic acid (VPA) young children, aged 0 to 4.9 years, had a low clearance of RUF, which did not differ from older children. If not on VPA but on enzyme inducers, young children had a threefold higher clearance of RUF than the older ones. In young children not on VPA, those on enzyme inducers had 1.7-fold higher clearance than those on nonenzyme inducers. In children neither on VPA nor on enzyme inducers, RUF clearance was age-dependent with higher clearance in younger children. Adding RUF did not change the pharmacokinetics of concomitantly used AEDs. Seizure response after 2 to 3 months on RUF treatment was found in 12 of 51 children (23.5%), at mean plasma level of 36.9 +/- 22.0 umol/L. Adverse events were reported in 41% of the patients of which fatigue was most frequent (24%). PMID- 22941773 TI - Effects of lipoic acid on lipolysis in 3T3-L1 adipocytes. AB - Lipoic acid (LA) is a naturally occurring compound with beneficial effects on obesity. The aim of this study was to evaluate its effects on lipolysis in 3T3-L1 adipocytes and the mechanisms involved. Our results revealed that LA induced a dose- and time-dependent lipolytic action, which was reversed by pretreatment with the c-Jun N-terminal kinase inhibitor SP600125, the PKA inhibitor H89, and the AMP-activated protein kinase activator AICAR. In contrast, the PI3K/Akt inhibitor LY294002 and the PDE3B antagonist cilostamide enhanced LA-induced lipolysis. LA treatment for 1 h did not modify total protein content of hormone sensitive lipase (HSL) but significantly increased the phosphorylation of HSL at Ser(563) and at Ser(660), which was reversed by H89. LA treatment also induced a marked increase in PKA-mediated perilipin phosphorylation. LA did not significantly modify the protein levels of adipose triglyceride lipase or its activator comparative gene identification 58 (CGI-58) and inhibitor G(0)/G(1) switch gene 2 (G0S2). Furthermore, LA caused a significant inhibition of adipose specific phospholipase A2 (AdPLA) protein and mRNA levels in parallel with a decrease in the amount of prostaglandin E(2) released and an increase in cAMP content. Together, these data suggest that the lipolytic actions of LA are mainly mediated by phosphorylation of HSL through cAMP-mediated activation of protein kinase A probably through the inhibition of AdPLA and prostaglandin E(2). PMID- 22941777 TI - Discal cyst in pediatric patients: case report and review of the literature. AB - Discal (intraspinal extradural) cysts which communicate with intervertebral disk are uncommon cause of lumbar radiculopathy, especially in pediatric patients. Only three pediatric cases have been reported in the literature. A 15-year-old boy presented with acute onset left-sided S1 radiculopathy. Magnetic resonance imaging of the lumbar spine revealed a well-defined round extradural mass seated in the left ventrolateral epidural space of the spinal canal behind the S1 vertebral body. He did not respond to the conservative therapies. Because of persistent left S1 radiculopathy, left laminotomy was performed at L5-S1 level with coagulation of the posterior longitudinal ligament surrounding the anular tear; however, discectomy was not done. The symptoms resolved and no recurrence was found at 7-year follow-up. The clinical manifestations, imaging findings, possible pathogeneses, and treatment options of these lesions are discussed and the relevant literature is reviewed. PMID- 22941778 TI - Microfabrication technologies in dielectrophoresis applications--a review. AB - DEP is an established technique for particle manipulation. Although first demonstrated in the 1950s, it was not until the development of miniaturization techniques in the 1990s that DEP became a popular research field. The 1990s saw an explosion of DEP publications using microfabricated metal electrode arrays to sort a wide variety of cells. The concurrent development of microfluidics enabled devices for flow management and better understanding of the interaction between hydrodynamic and electrokinetic forces. Starting in the 2000s, alternative techniques have arisen to overcome common problems in metal-electrode DEP, such as electrode fouling, and to increase the throughput of the system. Insulator based DEP and light-induced DEP are the most significant examples. Most recently, new 3D techniques such as carbon-electrode DEP, contactless DEP, and the use of doped PDMS have further simplified the fabrication process. The constant desire of the community to develop practical solutions has led to devices which are more user friendly, less expensive, and are capable of higher throughput. The state-of the-art of fabricating DEP devices is critically reviewed in this work. The focus is on how different fabrication techniques can boost the development of practical DEP devices to be used in different settings such as clinical cell sorting and infection diagnosis, industrial food safety, and enrichment of particle populations for drug development. PMID- 22941779 TI - Adeno-associated virus-coated allografts: a novel approach for cranioplasty. AB - Bone autografts are considered the gold standard for cranioplasty, although they lead to co-morbidity. Bone allografts are more easily obtained but have low osteogenic potential and fail to integrate into healthy bone. Previously, we showed that, by coating long-bone allografts with freeze-dried recombinant adeno associated virus (rAAV) vector encoding for an osteogenic gene, enhanced osteogenesis and bone integration were achieved. In this study our aim was to evaluate the bone repair potential of calvarial autografts and allografts coated with either single-stranded rAAV2 vector (SS-rAAV-BMP2) or self-complementary pseudotyped vector (SC-rAAV-BMP2) encoding for bone morphogenetic protein (BMP)2 in a murine cranioplasty model. The grafts were implanted into critical defects in the calvariae of osteocalcin/luciferase (Oc/Luc) transgenic mice, which allowed longitudinal monitoring of osteogenic activity using bioluminescence imaging (BLI). Our results showed that the bioluminescent signal of the SC-rAAV BMP2-coated allografts was 40% greater than that of the SS-rAAV-BMP2-coated allografts (p<0.05) and that the bioluminescent signal of the SS-rAAV-BMP2-coated allografts was not significantly different from the signals of the autografts or uncoated allografts. Micro-computed tomography (MUCT) confirmed the significant increase in osteogenesis in the SC-rAAV-BMP2 group compared with the SS-rAAV-BMP2 group (p<0.05), indicating a significant difference in bone formation when compared with the other grafts tested. In addition, histological analysis revealed extensive remodelling of the autografts. Collectively, these results demonstrate the feasibility of craniofacial regeneration using SC-rAAV-BMP2 coated allografts, which may be an attractive therapeutic solution for repair of severe craniofacial bone defects. PMID- 22941780 TI - A poly(glycerol-sebacate-curcumin) polymer with potential use for brain gliomas. AB - Curcumin has multiple biological and pharmacological activities, including antioxidant, anti-inflammatory, antiviral, antibacterial, antifungal, and antitumor activities. However, the clinical use of curcumin is limited because of its poor oral absorption and extremely poor bioavailability. In order to overcome these limitations, we conjugate curcumin chemically into the known biocompatible and biodegradable polymer, poly(glycerol-sebacate), and prepare the unitary poly(glycerol-sebacate-curcumin) polymer. The structure, the in vitro degradation, the drug release, and antitumor activity as well as the in vivo degradation and tissue biocompatibility of poly(glycerol-sebacate-curcumin) polymer are investigated. The in vitro degradation and drug release profile of poly(glycerol-sebacate-curcumin) are in a linear manner. The in vitro antitumor assay shows that poly(glycerol-sebacate-curcumin) polymer significantly inhibits human malignant glioma cells, U87 and T98 cells. In view of the cytotoxicity against brain gliomas, local use of this polymer would be a potential method for brain tumors. PMID- 22941781 TI - On becoming a Bayesian: early correspondences between J. Cornfield and L. J. Savage. AB - Jerome Cornfield was arguably the leading proponent for the use of Bayesian methods in biostatistics during the 1960s. Prior to 1963, however, Cornfield had no publications in the area of Bayesian statistics. At a time when frequentist methods were the dominant influence on statistical practice, Cornfield went against the mainstream and embraced Bayes. The goals of this paper are as follows: (i) to explore how and why this transformation came about and (ii) to provide some sense as to who Cornfield was and the context in which he worked. PMID- 22941783 TI - Quality in hemostasis and thrombosis--part I. PMID- 22941784 TI - External quality assurance for heparin monitoring. AB - Although there is considerable debate regarding the usefulness of laboratory heparin monitoring, these test processes reflect a substantial portion of hemostasis laboratory activity. Accordingly, external quality assurance (EQA) remains an essential component of such testing, and ensures that laboratories provide the best available service for patient management. This report provides an overview of recent and past EQA related to heparin monitoring using data from the Royal College of Pathologists of Australasia Haematology Quality Assurance Program, and heparin-containing plasma samples with concentrations ranging from 0 to 1.4 U/mL. Laboratory tests evaluated comprised activated partial thromboplastin time (APTT), thrombin time (TT), fibrinogen, and anti-Xa assays. Results for APTT and TT testing were largely as expected, showing prolongation with increasing concentrations of heparin. Fibrinogen assays were generally unaffected by the presence of therapeutic heparin levels. Although cross laboratory median values for the anti-Xa assay were close to target values, substantial interlaboratory variation in results, expressed as coefficient of variation (CV), was observed in all exercises conducted over an 8-year period (5 to 28% for low-molecular weight heparin [LMWH] and 19 to 37% for unfractionated heparin). Duplicate samples sent in consecutive surveys resulted in similar median values. The use of a survey-provided standard as assay calibrant improved CVs in earlier surveys, but not in the most recent survey. PMID- 22941785 TI - Comparing normal modes across different models and scales: Hessian reduction versus coarse-graining. AB - Dimension reduction is often necessary when attempting to reach longer length and time scales in molecular simulations. It is realized by constraining degrees of freedom or by coarse-graining the system. When evaluating the accuracy of a dimensional reduction, there is a practical challenge: the models yield vectors with different lengths, making a comparison by calculating their dot product impossible. This article investigates mapping procedures for normal mode analysis. We first review a horizontal mapping procedure for the reduced Hessian techniques, which projects out degrees of freedom. We then design a vertical mapping procedure for the "implosion" of the all-atom (AA) Hessian to a coarse grained scale that is based upon vibrational subsystem analysis. This latter method derives both effective force constants and an effective kinetic tensor. Next, a series of metrics is presented for comparison across different scales, where special attention is given to proper mass-weighting. The dimension dependent metrics, which require prior mapping for proper evaluation, are frequencies, overlap of normal mode vectors, probability similarity, Hessian similarity, collectivity of modes, and thermal fluctuations. The dimension independent metrics are shape derivatives, elastic modulus, vibrational free energy differences, heat capacity, and projection on a predefined basis set. The power of these metrics to distinguish between reasonable and unreasonable models is tested on a toy alpha helix system and a globular protein; both are represented at several scales: the AA scale, a Go-like model, a canonical elastic network model, and a network model with intentionally unphysical force constants. PMID- 22941782 TI - Support service use and interest in support services among distressed family caregivers of lung cancer patients. AB - OBJECTIVE: This study examined support service use and interest in support services among distressed family caregivers of patients recently entering comprehensive cancer care facilities. METHODS: Primary family caregivers of lung cancer patients (N=83) were recruited from three medical centers within 12 weeks of the patient's new visit to the oncology clinic. All family caregivers were screened for psychological distress, and those reporting significant anxiety or depressive symptoms were eligible for this study. Caregivers completed a baseline assessment of support service use (i.e., use of mental health services and complementary and alternative medicine [CAM]) and interest in support services. Support service use was also assessed 3 months later. RESULTS: Although all caregivers reported clinically meaningful distress, only 26% used mental health and 39% used CAM services during the 3-month study period. Patients' receipt of chemotherapy was positively associated with caregivers' mental health service use, whereas greater education and receiving assistance with caregiving tasks were associated with CAM use. Forty percent of caregivers who did not use CAM at baseline were interested in CAM. In addition, 29% of caregivers who did not receive mental health services at baseline were interested in professional psychosocial support, and 29% of caregivers who did not receive staff assistance with practical needs at baseline were interested in this service. CONCLUSIONS: Findings suggest that distressed family caregivers of lung cancer patients underuse mental health services and that a sizable minority are interested in professional help with psychosocial and practical needs. PMID- 22941786 TI - Relationship between atorvastatin dose and the harm caused by torcetrapib. AB - Development of the cholesteryl ester transfer protein (CETP) inhibitor, torcetrapib, was halted after the ILLUMINATE trial revealed an increase in both all-cause mortality (ACM) and major cardiovascular events (MCVEs) associated with its use. We now report that the harm caused by torcetrapib was confined to those in the 10 mg atorvastatin subgroup for both ACM [hazard ratio (HR) = 2.68, 95% CI (1.58, 4.54), P < 0.0001] and MCVEs [HR = 1.41, 95% CI (1.14, 1.74), P = 0.002], with no evidence of harm when torcetrapib was coadministered with higher doses of atorvastatin. In the atorvastatin 10 mg subgroup, age, prior heart failure and stroke were significantly associated with ACM, independent of torcetrapib treatment, whereas low apoA-I, smoking, hypertension, heart failure, myocardial infarction, and stroke were independently associated with MCVEs. After adjusting for these factors, the HR associated with torcetrapib treatment in the 10 mg atorvastatin subgroup remained elevated for both ACM [HR = 2.67, 95% CI (1.57, 4.54), P < 0.001] and MCVE [HR = 1.36, 95% CI (1.10, 1.69), P = 0.005]. Thus, the harm caused by torcetrapib was confined to individuals taking atorvastatin 10 mg. The harm could not be explained by torcetrapib-induced changes in lipid levels, blood pressure, or electrolytes. It is conceivable that higher doses of atorvastatin protected against the harm caused by torcetrapib. PMID- 22941787 TI - Strontium calcium phosphate for the repair of leporine (Oryctolagus cuniculus) ulna segmental defect. AB - Scaffolds to aid in repair, replacement, or regeneration of bony tissues have been developed using a wide spectra of materials. Under clinical conditions, assessment of healing and implant placement is guided radiographically. In this context, strontium's role in osteostimulation and its relevance in radio-opacity are known. Therefore to aid in assessment and to ensure tissue regeneration, a bone mimetic porous strontium calcium phosphate (SrCaPO(4) ) was synthesized in house, which was non-cytotoxic (ISO 10993 (Part V) and subsequently characterized for its crystallinity, functional groups, and 3D porous topography. Furthermore, to assess the feasibility of the bioactive ceramic scaffolds in bone repair, SrCaPO(4) and hydroxyapatite (HA-Control) scaffolds were implanted in the segmental ulna bone critical-sized defect (1.5 cm) of New Zealand White Rabbits (leporine model-Oryctolagus cuniculus) for a period of 4 and 12 weeks, respectively. Healing of the defects was uneventful without any inflammation or infection. Radio-opacity of SrCaPO(4) within the defect site enabled easy assessment of implant placement and osteointegration. Again, histological evaluation coupled with micro-CT and histomorphometrical analysis indicated that SrCaPO(4) favored significant de novo bone formation in par with material degradation at 4 and 12 weeks post-implantation compared to HA at 4 and 12 weeks. Investigations on this radio-opaque SrCaPO(4) established its role in the repair of critical-sized segmental defects, proposing it as a suitable bone substitute for clinical reconstructive surgery with easy radiographic evaluation. PMID- 22941788 TI - Nanostructured substrate conformation can decrease osteoblast-like cell dysfunction in simulated microgravity conditions. AB - Cells in situ are surrounded with defined structural elements formed by the nanomolecular extracellular matrix (ECM), and at the same time subjected to different mechanical stimuli arising from variety of physiological processes. In this study, using a nanotextured substrate mimicking the structural elements of the ECM and simulated microgravity, we wanted to develop a multifactorial model and understand better what guides cells in determining the morphological cell response. In our set-up, bone precursor cells from rat bone marrow were isolated and cultured on nanotextured polystyrene substrate (pitch 200 nm, depth 50 nm). Simulated microgravity was applied to the cells, using a random positioning machine (RPM). The results demonstrated that cells cultured on nanotextured substrate align parallel to the grooves and re-align significantly, but not completely, when subjected to simulated microgravity. The nanotextured substrate increased cell number and alkaline phosphatase (ALP) activity, whereas simulated microgravity decreased cells number and ALP activity. When the nanotextured substrate and simulated microgravity were combined together, the negative effect of the simulated microgravity ALP and cell number was reversed. In conclusion, absence of mechanical load in simulated microgravity has a negative effect on initial osteoblastogenesis, and nanotextured surfaces can partly reverse such a process. PMID- 22941790 TI - Cognitive bibliotherapy for mild depressive symptomatology: randomized clinical trial of efficacy and mechanisms of change. AB - BACKGROUND: It has been increasingly recognized that subthreshold depression is associated with considerable personal, social and economic costs. However, there is no accepted definition or clear-cut treatment for subthreshold depression. Cognitive bibliotherapy is a promising approach, but further research is necessary in order to assess its clinical efficacy and key mechanisms of change. AIM: This study aimed to investigate the efficacy of bibliotherapy for subthreshold depression and test whether maladaptive cognitions mediate the effects of bibliotherapy on depressive symptoms. METHOD: A total of 96 young adults with subthreshold depression were randomized in one of the following treatment conditions: immediate treatment, delayed treatment, placebo and no treatment. The main outcome was represented by depressive symptoms assessed before, during and immediately after the treatment, as well as at 3-month follow up. Automatic thoughts, dysfunctional attitudes and irrational beliefs were also assessed throughout the study, and we investigated their involvement as mediators of bibliotherapy effects on depressive symptoms. RESULTS: The results indicated that cognitive bibliotherapy resulted in statistically and clinically significant changes both in depressive symptoms and cognitions, which were maintained at follow-up. In contrast, placebo was only associated with a temporary decrease in depressive symptoms, without significant cognitive changes. No changes in symptoms or cognitions were found in the delayed treatment and no treatment groups. We also found that automatic thoughts significantly mediated the effect of bibliotherapy on depressive symptoms. CONCLUSION: This study provided compelling evidence for the efficacy of cognitive bibliotherapy in subthreshold depression and showed that changes in automatic thoughts mediated the effect of bibliotherapy on depressive symptoms. KEY PRACTITIONER MESSAGE: Cognitive bibliotherapy is an effective treatment of subthreshold depression. Changing automatic thoughts is important, as they mediate the bibliotherapy effect on depressive symptoms. Cognitive bibliotherapy is a potential alternative or adjunct to psychotherapy for mildly depressed adults. PMID- 22941789 TI - Aptamer-crosslinked microbubbles: smart contrast agents for thrombin-activated ultrasound imaging. AB - Thrombosis, or malignant blood clotting, is associated with numerous cardiovascular diseases and cancers. A microbubble contrast agent is presented that produces ultrasound harmonic signal only when exposed to elevated thrombin levels. Initially silent microbubbles are activated in the presence of both thrombin-spiked and freshly clotting blood in three minutes with detection limits of 20 nM thrombin and 2 aM microbubbles. PMID- 22941791 TI - A generalized Jonckheere test against ordered alternatives for repeated measures in randomized blocks. AB - Focusing on statistical methods in patient-reported outcomes, we propose and develop a generalized Jonckheere test against ordered alternatives for repeated measures in a randomized block design. We derive its asymptotic null distribution properties and describe methods for estimating the null distribution for testing the hypothesis. We present a numerical example to illustrate the test procedure. PMID- 22941792 TI - Approach to the diagnosis and management of common bleeding disorders. AB - Mild mucocutaneous bleeding symptoms are common in the general population. Differentiating normal from pathological bleeding complaints begins with a detailed bleeding history that assesses: the pattern (primary versus secondary hemostasis), the severity, and the onset (congenital versus acquired) of bleeding. Bleeding assessment tools have been developed to aid in determining whether bleeding symptoms are outside of the normal range. Although the clinical pattern of bleeding and family history directs laboratory investigations, von Willebrand disease, the most common and best characterized of the primary hemostatic disorders, is often the first diagnosis to be considered. Clinical management focuses on the particular symptoms experienced by the patient. Medical interventions include replacement of the factor that is deficient or defective, or indirect treatments, such as antifibrinolytics (tranexamic acid), desmopression, and hormone-based therapy (e.g., oral contraceptive pill for menorrhagia). PMID- 22941793 TI - Acquired hemophilia A. AB - Acquired hemophilia A is a rare, autoimmune disorder that is caused by autoantibodies that act as inhibitors to factor VIII. It is characterized by severe, unexpected bleeding that may be life-threatening. The incidence of acquired hemophilia A is ~ 0.2 to 1.48 cases per 1 million individuals per year. Acquired hemophilia A has been associated with several clinical conditions including pregnancy, autoimmune or collagen vascular disorders, malignancies, drugs, respiratory disorders, and infections. However, in ~ 50% of cases, no disease association is determined. Acquired hemophilia A should be suspected when a patient with no previous personal or family history of bleeding, presents with bleeding and an unexplained prolonged activated partial thromboplastin time (APTT) and other common causes of a prolonged APTT are ruled out. The treatment of acquired hemophilia A has two main goals: (1) to treat and/or prevent bleeding complications and (2) to eradicate the inhibitor. The recommended agents to be used for the treatment or prevention of bleeding in patients with acquired hemophilia A are the bypassing agents. Patients should be treated initially with corticosteroids, either alone or in combination with cyclophosphamide, to eradicate the inhibitor. PMID- 22941794 TI - Distance dependency and minimum amino acid alphabets for decoy scoring potentials. AB - The validity and accuracy of a proposed tertiary structure of a protein can be assessed in several ways. Scoring such a structure by a knowledge-based potential is a well-known approach in molecular biophysics, an important task in structure prediction and refinement, and a key step in several experiments on protein structures. Although several parameterizations for such models have been derived over the course of time, improvements in accuracy by explicitly using continuous distance information have not been suggested yet. We close this methodological gap by formulating the parameterization of a protein structure model as a linear program. Optimization of the parameters was performed using amino acid distances calculated for the residues in topology rich 2830 protein structures. We show the capability of our derived model to discriminate between native structures and decoys for a diverse set of proteins. In addition, we discuss the effect of reduced amino acid alphabets on the model. In contrast to studies focusing on binary contact schemes (without considering distance dependencies and proposing five symbols as optimal alphabet size), we find an accurate protein alphabet size to contain at least five symbols, preferably more, to assure a satisfactory fold recognition capability. PMID- 22941795 TI - The power of a smile to move you: complementary submissiveness in women's posture as a function of gender salience and facial expression. AB - Extending evidence that nonverbal complementary behavior can occur in dyads to the intergroup domain, the authors predicted that women assume a relatively submissive (narrow) posture when confronted with a male instructor adopting a dominant (broad) posture, but only when he smiles (affiliation motive) and when gender is salient. Male affiliation (smiling vs. not smiling) and gender salience were manipulated in Study 1 by focusing on sex differences (vs. individual differences) in presentation style, strengthened by the instructor making a sexist remark. As predicted, women adopted a more submissive posture when gender was salient and the male instructor smiled. In Study 2, male posture was manipulated (dominant vs. submissive) to examine postural complementarity in women. Study 3 replicated the postural effect, especially when the sexist remark is present. This effect was mediated by the instructor's perceived warmth. Implications for gender, benevolent sexism, and intergroup power relations are discussed. PMID- 22941796 TI - The contact caveat: negative contact predicts increased prejudice more than positive contact predicts reduced prejudice. AB - Contact researchers have largely overlooked the potential for negative intergroup contact to increase prejudice. In Study 1, we tested the interaction between contact quantity and valence on prejudice toward Black Australians (n = 1,476), Muslim Australians (n = 173), and asylum seekers (n = 293). In all cases, the association between contact quantity and prejudice was moderated by its valence, with negative contact emerging as a stronger and more consistent predictor than positive contact. In Study 2, White Americans (n = 441) indicated how much positive and negative contact they had with Black Americans on separate measures. Although both quantity of positive and negative contact predicted racism and avoidance, negative contact was the stronger predictor. Furthermore, negative (but not positive) contact independently predicted suspicion about Barack Obama's birthplace. These results extend the contact hypothesis by issuing an important caveat: Negative contact may be more strongly associated with increased racism and discrimination than positive contact is with its reduction. PMID- 22941797 TI - Bone morphogenetic protein in spine surgery: current and future uses. AB - The clinical use of bone morphogenetic protein (BMP) in spinal fusion surgery has recently become controversial. After its approval by the US FDA in July 2002, BMP was adopted by many spine surgeons as a replacement for the more traditional iliac crest bone graft to avoid the complications associated with bone graft harvest. However, as broad clinical use escalated, reports increased of potentially serious complications associated with BMP. Controversy continues, particularly regarding the safety of BMP and whether it should routinely replace iliac crest bone graft for spinal fusion surgery. PMID- 22941798 TI - Musculoskeletal care of the hemophiliac patient. AB - Hemophilia is caused by a deficiency of clotting factor VIII or IX and is inherited by a sex-linked recessive pattern. von Willebrand disease, a common, moderate bleeding disorder, is caused by a quantitative or qualitative protein deficiency of von Willebrand factor and is inherited in an autosomal dominant or recessive manner. The most important clinical strategy for the management of patients with hemophilia is the avoidance of recurrent hemarthrosis by continuous, intravenous hematologic prophylaxis. Early hemarthrosis should be aggressively managed with aspiration and clotting factor concentrate until the joint examination is normal. Starting prophylactic factor replacement in infancy may prevent chronic synovitis and arthropathy. The natural history of poorly controlled disease is polyarticular hemophilic arthropathy; functional prognosis is poor. Patients with chronic synovitis may be treated effectively with radiosynovectomy; those who develop joint surface erosions may require realignment osteotomies, joint arthroplasty, and treatment of pseudotumors. Reconstructive surgery for hemophilic arthropathy, especially in patients with factor inhibitor, requires careful hematologic management by an experienced, multidisciplinary team. PMID- 22941799 TI - Use of negative-pressure wound therapy in orthopaedic trauma. AB - Negative-pressure wound therapy (NPWT) has become an important adjunct to the management of traumatic wounds and surgical incisions related to musculoskeletal trauma. On the battlefield, this adjunct therapy allows early wound management and safe aeromedical evacuation. NPWT mechanisms of action include stabilization of the wound environment, reduction of wound edema, improvement of tissue perfusion, and stimulation of cells at the wound surface. NPWT stimulates granulation tissue and angiogenesis and may improve the likelihood of primary closure and reduce the need for free tissue transfer. In addition, NPWT reduces the bacterial bioburden of wounds contaminated with gram-negative bacilli. However, an increased risk of colonization of gram-positive cocci (eg, Staphylococcus aureus) exists. Although NPWT facilitates wound management, further research is required to determine conclusively whether this modality is superior to other management options. Ongoing research will continue to define the indications for and benefits of NPWT as well as establish the role of combination therapy, in which NPWT is used with instillation of antibiotic solutions, placement of antibiotic-laden cement beads, or silver-impregnated sponges. PMID- 22941800 TI - Carpal instability nondissociative. AB - Carpal instability nondissociative (CIND) represents a spectrum of conditions characterized by kinematic dysfunction of the proximal carpal row, often associated with a clinical "clunk." CIND is manifested at the midcarpal and/or radiocarpal joints, and it is distinguished from carpal instability dissociative (CID) by the lack of disruption between bones within the same carpal row. There are four major subcategories of CIND: palmar, dorsal, combined, and adaptive. In palmar CIND, instability occurs across the entire proximal carpal row. When nonsurgical management fails, surgical options include arthroscopic thermal capsulorrhaphy, soft-tissue reconstruction, or limited radiocarpal or intercarpal fusions. In dorsal CIND, the capitate subluxates dorsally from its reduced resting position. Dorsal CIND usually responds to nonsurgical management; refractory cases respond to palmar ligament reefing and/or dorsal intercarpal capsulodesis. Combined CIND demonstrates signs of both palmar and dorsal CIND and can be treated with soft-tissue or bony procedures. In adaptive CIND, the volar carpal ligaments are slackened and are less capable of inducing the physiologic shift of the proximal carpal row from flexion into extension as the wrist ulnarly deviates. Treatment of choice is a corrective osteotomy to restore the normal volar tilt of the distal radius. PMID- 22941801 TI - Pulmonary embolism in orthopaedic patients: diagnosis and management. AB - Orthopaedic patients are at particularly high risk for pulmonary embolism. There has been a trend recently toward overdiagnosis of pulmonary embolism; thus, evaluation of the nature of a clinically relevant pulmonary embolism is needed, as is assessment of the timing, risks, and outcomes of therapeutic anticoagulation in surgical patients. Recent literature shows the incidence of pulmonary embolism to be increasing without a corresponding increase in mortality, suggesting that not all emboli may be clinically relevant and that increasingly sensitive tests may be picking up small emboli. The size and location of a clot or clots may matter when deciding on management. A risk benefit evaluation can assist in deciding treatment. PMID- 22941802 TI - Submuscular plating of pediatric femur fracture. AB - Currently, surgical management of pediatric femur fracture consists of intramedullary nailing with flexible nails or rigid trochanteric entry nails. Rigid trochanteric entry nails are the implant of choice for femoral fractures in adolescents, whereas titanium elastic nails are popular for the management of length-stable diaphyseal femoral fractures in school-age children. However, higher complication rates have been reported in children with length-unstable diaphyseal femoral fractures treated with titanium elastic nails. These complications may require unplanned surgery. Fracture shortening or angulation can lead to nail prominence or exposure that may require nail shortening or removal. Recently, submuscular plating has been found to be a successful alternative option for management of length-unstable femoral fractures in school age children. Submuscular plating can also be used in older and/or heavier children who have a femoral canal that is too small to accommodate a rigid intramedullary nail. PMID- 22941803 TI - Glenoid bone loss in primary total shoulder arthroplasty: evaluation and management. AB - Glenohumeral osteoarthritis is the most common reason for shoulder replacement. Total shoulder arthroplasty provides reliable pain relief and restoration of function, with implant survivorship reported at 85% at 15 years. Glenoid component wear and aseptic loosening are among the most common reasons for revision. Glenoid wear characteristics have been correlated with, among other things, the degree of anatomic glenoid version correction. Anatomic glenoid reconstruction is particularly challenging in the presence of glenoid bone deficiency. Walch classified glenoid morphology into five types: type A, centered, without posterior subluxation but with minor erosion (A1) or major erosion (A2); type B, posteriorly subluxated (B1) or posteriorly subluxated with posterior glenoid erosion (B2); and type C, excessive glenoid retroversion. The type A glenoid represents only 59% of patients; thus, the need to address glenoid deformity is common. Methods of correction include asymmetric reaming of the anterior glenoid, bone grafting of the posterior glenoid, and implanting a specialized glenoid component with posterior augmentation. In many cases of type C or hypoplastic glenoid, the humerus is concentrically reduced in the deficient glenoid and glenoid deformity may not need to be corrected. Severely hypoplastic glenoid may require the use of bone-sparing glenoid components or reverse total shoulder arthroplasty. PMID- 22941805 TI - Scientific communication in clinical psychology: examining patterns of citations and references. AB - Previous studies of scientific communication used citation mapping, establishing psychology as a 'hub science' from which many other fields draw information. Within psychology, the clinical and counselling discipline is a major 'knowledge broker'. This study analyzed scientific communication among three major subdisciplines of clinical psychology-the cognitive-behavioural, psychodynamic and humanistic schools of thought-by examining patterns of references within and citations to 305 target articles published in leading journals of these subdisciplines. The results suggest that clinical researchers of each theoretical orientation engage in more insular scientific communication than an integrationist would find desirable and that cognitive-behavioural articles are more closely connected to mainstream psychology and related fields. KEY PRACTITIONERS MESSAGE: Eclectic practitioners draw on several different theoretical orientations to inform their practice; as such, they should be interested in understanding the patterns of scientific communication within and across theoretical orientations. Practitioners work in a variety of different mental health settings, with a variety of other professionals in psychology related fields, and should be interested in how much influence their particular theoretical orientation has on the work of colleagues. Many practitioners rely on new, evidence-based research to inform their work. The results of this study provide these individuals with an objective measure of the influence of empirical work in different areas of clinical psychology. PMID- 22941804 TI - Controlling spatial organization of multiple cell types in defined 3D geometries. PMID- 22941806 TI - Proton affinities of deoxyribonucleosides via the ONIOM-ccCA methodology. AB - Utilizing the recently developed ONIOM-ccCA methodology, the proton affinities (PAs) of small biomolecules (~15 nonhydrogen atoms) were determined. The ONIOM ccCA method was used to predict the PAs of eight amine-containing molecules and these predictions were then compared with experiment. In these comparisons, a protocol for the determination of the model system size was established, and the low level method and basis set for the real system component of ONIOM-ccCA were considered. Several possible density functionals were investigated for description of the real system (low layer), including B3LYP, B97-1, B97-2, B98, BMK, M06, and M06-2X. The resulting proton affinities were compared both to experiment and to theoretical values that were calculated using the correlation consistent Composite Approach (ccCA). The impact of the choice of augmented correlation consistent basis sets in the ONIOM-ccCA low level calculation was also examined, and PAs calculated with augmented and non-augmented basis sets were compared to those extrapolated to the complete basis set (CBS) limit. ONIOM(ccCA:B3LYP/aug-cc-pVDZ) was then applied to deoxyribonucleosides to determine the PAs at possible sites of protonation. PMID- 22941807 TI - Evaluation of hydrogels for bio-printing applications. AB - In the United States alone, there are approximately 500,000 burn injuries that require medical treatment every year. Limitations of current treatments necessitate the development of new methods that can be applied quicker, result in faster wound regeneration, and yield skin that is cosmetically similar to undamaged skin. The development of new hydrogel biomaterials and bioprinting deposition technologies has provided a platform to address this need. Herein we evaluated characteristics of twelve hydrogels to determine their suitability for bioprinting applications. We chose hydrogels that are either commercially available, or are commonly used for research purposes. We evaluated specific hydrogel properties relevant to bioprinting applications, specifically; gelation time, swelling or contraction, stability, biocompatibility and printability. Further, we described regulatory, commercial and financial aspects of each of the hydrogels. While many of the hydrogels screened may exhibit characteristics suitable for other applications, UV-crosslinked Extracel, a hyaluronic acid-based hydrogel, had many of the desired properties for our bioprinting application. Taken together with commercial availability, shelf life, potential for regulatory approval and ease of use, these materials hold the potential to be further developed into fast and effective wound healing treatments. PMID- 22941808 TI - The inhibition of monoamine oxidase by 8-(2-phenoxyethoxy)caffeine analogues. AB - Previous studies have documented that substituted 8-oxycaffeines act as inhibitors of human monoamine oxidase (MAO) B. A particularly potent inhibitor among the reported compounds was 8-(2-phenoxyethoxy)caffeine with an IC50 value of 0.383 uM towards MAO-B. In an attempt to improve on the inhibition potency of this compound and to discover highly potent reversible MAO-B inhibitors, in the present study, a series of 8-(2-phenoxyethoxy)caffeine analogues containing various substituents on C4 of the phenoxy ring, were synthesized and evaluated as inhibitors of human MAO-A and -B. The results show that the 8-(2 phenoxyethoxy)caffeine analogues are selective and reversible MAO-B inhibitors with the most potent homologue, 8-{2-[4-(trifluoromethyl)phenoxy]ethoxy}caffeine, exhibiting an IC50 value of 0.061 MUM. These highly potent inhibitors are useful leads in the design of therapies for neurodegenerative disorders such as Parkinson's disease. PMID- 22941811 TI - New course gives school students a taste of life as a farm vet. PMID- 22941812 TI - Towards better welfare in rearing entire male pigs. PMID- 22941809 TI - CYP2C9*3(1075A>C), MDR1 G2677T/A and MDR1 C3435T are determinants of inter subject variability in fluvastatin pharmacokinetics in healthy Chinese volunteers. AB - To evaluate the impact of single-nucleotide polymorphisms (SNPs) in CYP2C9, MDR1, SLCO1B1 and ABCG2 on the pharmacokinetics of fluvastatin in Chinese participants.A pharmacokinetic study of fluvastatin (single dose 40 mg) was conducted in 12 healthy Chinese volunteers. Plasma concentrations of fluvastatin were determined by a high-performance liquid chromatography with fluorescence detection. Pharmacokinetic parameters were calculated by non-compartmental method. The SNPs were determined by TaqMan(r)(MGB) genotyping assay.Effect of CYP2C9*3 (c.1075A>C) on area under the plasma concentration-time curve (AUC) of fluvastatin was statistically significant. Heterozygous variant (C/A) carriers had higher AUC values compared to homozygous wild type (A/A) carriers (922.03+/ 148.17 ug . h . L - 1 vs. 496.00+/-168.93 ug . h . L - 1, P=0.003092). The elimination half-life (T 1/2) values of fluvastatin were longer in MDR1 2677non-G carriers than in MDR1 2677G carriers (2.21+/-0.47 h vs. 1.25+/-0.62 h, P=0.02319), and also they were longer in MDR1 1236T-2677non-G-3435T carriers than in MDR1 1236C-2677G-3435C carriers (2.31+/-0.51 h vs. 1.32+/-0.62 h, P=0.03320). MDR1 C3435T polymorphism had a significant effect on maximal plasma concentrations (C max) of fluvastatin. Mutation gene T (TT+CT) carriers had higher C max values compared to homozygous wild type (C/C) carriers (688.54+/ 142.67 ug . L - 1 vs. . 413.78+/-177.83 ug . L - 1, P=0.01448). Some SNPs such as MDR1 C1236T, ABCG2 c.34G>A, ABCG2 c.421C>A, SLCO1B1 c.388 A>G, SLCO1B1 c.521 T>C, SLCO1B1 c.571 T>C and SLCO1B1 c.597 C>T have no significant effects on fluvastatin pharmacokinetics.CYP2C9*3(1075A>C), MDR1 C3435T and MDR1 G2677T/A were determinants of inter-subject variability in fluvastatin pharmacokinetics in healthy Chinese volunteers. PMID- 22941814 TI - Motorcycling vets begin 3000-mile charity trip. PMID- 22941816 TI - Competing to win at SPVS congress 2012. PMID- 22941819 TI - Northern Ireland disease surveillance, April to June 2012. PMID- 22941820 TI - Reference intervals: new guidelines for an essential resource. PMID- 22941822 TI - Tick surveillance in the UK. PMID- 22941824 TI - Managing hyperthyroidism in cats. PMID- 22941823 TI - Toxoplasma gondii and elevated suicide risk. PMID- 22941825 TI - Lipoma on the epiglottis of a dog. PMID- 22941826 TI - Epizootology of coincidence. PMID- 22941834 TI - Special issue in honor of Jerome Cornfield on the centennial of his birth: Introduction. PMID- 22941835 TI - GPGPU for orbital function evaluation with a new updating scheme. AB - We have accelerated an ab initio quantum Monte Carlo electronic structure calculation using general purpose computing on graphical processing units (GPGPU). The part of the code causing the bottleneck for extended systems is replaced by Compute Unified Device Architecture-GPGPU subroutine kernels which build up spline basis set expansions of electronic orbital functions at each Monte Carlo step. We have achieved a speedup of a factor of 30 for the bottleneck for a simulation of solid TiO(2) with 1536 electrons. To improve the performance with GPGPU we propose a new updating scheme for Monte Carlo sampling, quasi simultaneous updating, which is intermediate between configuration-by configuration updating and the widely used particle-by-particle updating. The error in the energy due to by the single precision treatment and the new updating scheme is found to be within the required accuracy of ~10(-3) hartree per primitive cell. PMID- 22941836 TI - [In vivo investigation of human brain networks by using cortico-cortical evoked potentials]. AB - A better understanding of seizure networks and the mechanisms underlying human higher cortical functions requires a detailed knowledge of neuronal connectivity. As it relates to higher cortical functions, such as language, in humans, studies performed in nonhuman primates are less relevant. By using subdural electrodes implanted for presurgical evaluation, we developed an in vivo electrical tract tracing technique of cortico-cortical evoked potentials (CCEPs). Cortico-cortical connections could be traced by applying repetitive single-pulse electrical stimuli to a part of the cortices and recording evoked cortical potentials from adjacent and remote cortical regions by averaging electrocorticogram time-locked to stimulus onset. This technique has contributed to the understanding of human cortico-cortical networks involved in higher brain functions, such as language, praxis, and higher motor control. Establishing a CCEP connectivity map in the MNI standard space is also of academic importance, since a standardized CCEP connectivity map would provide a substantial reference for noninvasive network analyses. In addition to its importance in basic systems neuroscience, this method, in combination with conventional cortical mapping, could be used to clinically map functional brain systems by tracking cortico-cortical connections among functional cortical regions in individual patients. This approach may help identify the cortico-cortical network of a given function within the context of pathology and any resultant plasticity of brain systems. In relation to epileptogenicity, as CCEPs can be used as a measure of regional cortical excitability, stimulating the epileptic focus and recording CCEPs in adjacent areas could help evaluate cortical excitability at and around the focus. PMID- 22941837 TI - [Language mapping with direct electrical stimulation]. AB - Language mapping with electrical stimulation in patients with lesions close to the language area aids surgery by identifying the language area in each individual. This method is quite important in a clinical setting, and is the most reliable for preventing persistent language deficits after resection. Furthermore, language mapping with electrical stimulation has revealed that the functional organization of the language area is more complex than previously suggested by functional MRI and other methods. The language-related sites where electrical stimulation induced abnormality during language tasks were spatially distinct and surprisingly varied amona patients. In addition, electrical stimulation revealed a mosaic of language function, in which sites even 5-10 mm apart were functionally distinct. Cortical sites specifically related to a language function e.g., repetition, were surrounded by sites related to another language function but not to repetition. These findings suggested that the "language area" is not spatially homogeneous over centimeters of the cortex, but consists of functional sub-regions of the cortex. Findings obtained using intraoperative electrical stimulation of the subcortical white matter have supported the dual language pathways-the dorsal and ventral pathways. Electrical stimulation of the arcuate fasciculus induced phonological paraphasia and that of the inferior occipitofrontal fasciculus induced semantic paraphasia. However, no language deficits were induced by stimulation of the inferior longitudinal fasciculus, thereby indicating the indirect role of this bundle in language function. Our current models of human language organization can be modified on the basis of language mapping with electrical stimulation. PMID- 22941838 TI - [Dynamics of the language/memory functional regions determing using ECoG and fMRI]. AB - We compared electrocorticography (ECoG) with invasive intracranial noninvasive functional MRI using language-related tasks. Twenty patients underwent bilateral implantation of subdural electrodes (more than 80 channels) for diagnosing intractable epilepsy. Before implantation of the electrodes, language-related fMRI was performed, and the fMR images were superimposed on individual brain images. Brain mapping with electrocortical stimulation was performed on the basis of the fused fMR and brain MR images, and the specificity and sensitivity of language-related fMRI was calculated. For careful interpretation of spatial and temporal ECoG changes with semantic tasks, we developed a software to visualize semantic-ECoG dynamics in the brain. Semantic-ECoG was recorded during word, figure, and face recognition as well as memory tasks. The raw ECoG data were processed by averaging and time-frequency analysis, and the functional profiles were projected onto the individual brain surface. Acquired ECoG was classified using Support Vector Machine and Sparse Logistic Regression to decode brain signals. Because of variations in electrode locations, we normalized the ECoG electrodes by using SPM8. Although fMRI has 90% sensitivity, its specificity is only up to 50%. The basal temporal-occipital cortex was activated within 250 ms after visual object presentation. Compared to other stimuli, face stimulation evoked significantly higher ECoG amplitudes. Among different brain regions, the hippocampus was predominantly activated during the memory task. The prediction rate of ECoG classification was 90%, which was sufficient for clinical use. Semantic-ECoG is a powerful technique to detect and decode human brain functions. PMID- 22941839 TI - [Role of functional neuroimaging in the surgical treatment of epilepsy]. AB - Functional neuroimaging is one of the most progressing fields in neuroscience and clinical neurological practice. It has also been contributing to the diagnosis and treatment of epilepsy. Intracranial electroencephalography (iEEG) is the gold standard for the diagnostic localization of the epileptogenic zone in the surgical treatment of epilepsy. Currently, no other modalities, including novel functional neuroimaging modalities, are superior to iEEG in sensitivity and spatial resolution. However, iEEG is an invasive procedure and its clinical usefulness is dependent on appropriate coverage of the epileptogenic zone. In this review article, the author discusses the principles of decision making in surgical indication and procedures by presenting clinical cases and evaluating the significance of functional neuroimaging in these processes; the review focuses on magnetoencephalography, 2-deoxy-2-[18F] fluoro-D-glucose positron emission tomography, and single photon emission computed tomography. The characteristics, advantages, and disadvantages of each modality are summarized. In some cases, but not all, functional neuroimaging modalities help avoid invasive iEEG without worsening surgical outcome and aid in determining the coverage area of iEEG, thereby resulting in better outcome and less complication. PMID- 22941840 TI - [Current status and future perspectives of near-infrared spectroscopy: clinical applications and neurocognitive findings]. AB - Near-infrared spectroscopy (NIRS) is a noninvasive neuroimaging tool that can measure local hemodynamic changes in the brain. Over the past decade, the technical advantage offered by multichannel NIRS has provided various new findings on higher cerebral function of the human brain. These findings have improved our knowledge of cognitive neuroscience, neurology, psychiatric medicine, rehabilitation medicine, and pharmacology. The present review illustrates such new findings and introduces a general trend of studies with NIRS and its clinical applications. In particular, new findings on early brain development and the organization of connectivity associated with language acquisition in the first year of life have been highlighted. Finally, some issues and concerns mostly stemming from the technical limitations of NIRS have been pointed out and discussed in view of current progress, so that future NIRS studies are more fruitful and reliable. PMID- 22941841 TI - [Diagnosis and treatment of mixed dementia]. AB - Vascular dementia (VaD)--secondary to cerebrovascular disease (CVD)--has been traditionally distinguished from Alzheimer's disease (AD), which is a purely neurodegenerative form of dementia. However, CVDs such as lacunes and white matter lesions are common in patients with AD, whereas certain pathological changes of AD, including senile plaques and tangles, are observed in elderly patients with VaD. These findings indicate that mixed vascular-degenerative dementia (MD) is the most common cause of dementia in the elderly. In the treatment and prevention of dementia, the accurate diagnosis of each individual type of dementia is vital. However, recognizing the distinction between these diseases can be difficult in clinical practice. This article provides an overview of MD, including the incidence, diagnosis, and treatment. In particular, we emphasize that functional brain imaging, including perfusion single photon emission computed tomography and benzodiazepine receptor binding measurement, in combination with morphological imaging (such as magnetic resonance imaging) is useful for distinguishing AD, VaD and MD. In addition to antiplatelet medications, cholinesterase inhibitors and N-methyl-D-aspartic acid antagonists may be effective in treating MD. Moreover the vascular risk factors also should be treated appropriately. The article describes the need for further studies to develop a better understanding of MD. PMID- 22941842 TI - [Neuroimaging using ultrahigh-field magnetic resonance imaging at 7 tesla: current concepts]. AB - The introduction of ultrahigh-field MRI at 7 tesla (7T) has increased the interest in the use of neuroimaging techniques in clinical research. The high signal-to-noise ratio and profound susceptibility effect at 7T can remarkably improve the spatial resolution and image contrast of structural imaging, susceptibility imaging, and functional imaging techniques, whereas the heating effects of the radio frequency and the inhomogeneities of the local magnetic field can have substantial negative effects on parameter setting, acquisition time, and image quality. T1 prolongation at 7T can improve the enhancement effects of gadolinium agents and the inflow effects on MR angiography and arterial spin labeling. Ultrahigh-field MRI is expected to have a high clinical impact in the near future; however, further technological advances tailored to ultrahigh-field systems as well as the accumulation of scientific evidence will be needed to establish its clinical significance. PMID- 22941843 TI - [A case of elderly-onset herpes simplex encephalitis in an 89-year-old woman, who recovered with acyclovir therapy, showed relapse 2 months later, and died]. AB - The number of case reports on elderly-onset herpes simplex encephalitis (HSE) has been increasing. We encountered the case of an 89-year-old woman with HSE, who was probably one of the oldest-onset patients in Japan. She was a bed patient with underlying diseases of old cerebral infarction and cholangitis. These conditions might be risk factors for the onset of HSE. Concerning HSE among the elderly, it is important to pay attention to underlying diseases that weaken their immunity. Although we delayed in diagnosing her case and started treatment 1 month after convulsions appeared, she completely recovered with intravenous acyclovir (ACV) therapy. However, relapse occurred 2 months after the therapy ended. We treated her again with intravenous ACV but she died without improvement. ACV, which was initially effective, was ineffective at relapse. Cases of ACV-resistant herpes simplex virus (HSV) infection have been reported in immunodeficient patients. The immune system of elderly patients is sometimes too weak to suppress the mutation of the virus. In this case, the HSV may have become resistant to ACV. Therefore, the possibility of ACV resistance should be considerd in HSE relapse in the elderly population. PMID- 22941844 TI - [An autopsied case of dementia with lewy bodies presenting with hemispheric cerebral cortical atrophy with selective neuronal necrosis after status epilepticus]. AB - We report on a 72-year-old-Japanese man with dementia with Lewy bodies (DLB) who presented with hemispheric cerebral cortical atrophy with selective neuronal necrosis after status epilepticus. His disease manifested with psychiatric symptoms, such as a "hot feeling" in the abdomen, at the age of 68 years. He was found to have hypochondriasis and anxiety disorder and was treated in the Department of Psychiatry. Parkinsonism gradually developed approximately 1 year later. Approximately 3 years after the onset of psychiatric symptoms, he suddenly experienced left hemiclonic seizures with consciousness disturbance, and he was admitted to our hospital. Status epilepticus occurred for several hours. His convulsive seizures were controlled by the administration of antiepileptic drugs (diazepam, phenytoin); however, he later showed prolonged disturbance of consciousness and left spastic hemiparesis. Gastrostomy was performed, but the patient died of aspiration pneumonia approximately 9 months after the onset of status epilepticus. Pathological examination showed widespread neuron loss with gliosis involving the entire right cerebral cortex, particularly in the frontotemporal lobe and hippocampus, and with patchy involvement of the contralateral cerebellum, especially in the cortex and dentate nucleus. These findings seemed to be consistent with a chronic stage of selective neuronal necrosis and secondary cerebellar degeneration due to diaschisis of the cerebral cortical involvement. Evidence of limbic-type DLB was also observed. We believe that selective neuronal necrosis associated with status epilepticus is an interesting neuro-pathological finding. PMID- 22941846 TI - Prepping, another cause for diversion of opioids. PMID- 22941847 TI - Advantages of EMBEDA(r) (morphine sulfate and naltrexone hydrochloride) extended release capsules in pain management. PMID- 22941845 TI - Early interventions for PTSD: a review. AB - The high prevalence of trauma exposure and subsequent negative consequences for both survivors and society as a whole emphasize the need for secondary prevention of posttraumatic stress disorder. However, clinicians and relief workers remain limited in their ability to intervene effectively in the aftermath of trauma and alleviate traumatic stress reactions that can lead to chronic PTSD. The scientific literature on early intervention for PTSD is reviewed, including early studies on psychological debriefing, pharmacological, and psychosocial interventions aimed at preventing chronic PTSD. Studies on fear extinction and memory consolidation are discussed in relation to PTSD prevention and the potential importance of immediate versus delayed intervention approaches and genetic predictors are briefly reviewed. Preliminary results from a modified prolonged exposure intervention applied within hours of trauma exposure in an emergency room setting are discussed, along with considerations related to intervention reach and overall population impact. Suggestions for future research are included. Prevention of PTSD, although currently not yet a reality, remains an exciting and hopeful possibility with current research approaches translating work from the laboratory to the clinic. PMID- 22941848 TI - Extended-release/long-acting opioid REMS may fill the need for prescribers' appropriate use education. AB - The Food and Drug Administration (FDA) is requiring manufacturers of long-acting and extended-release opioids to have a class-wide Risk Evaluation and Mitigation Strategy (REMS). The comprehensive risk management plan will include training for prescribers on the appropriate and safe use of these pain medications. The letter dated April 19, 2011 from FDA to manufacturers outlining the REMS requirements describes voluntary training that should be certified education "where practicable." The current report includes data from a recent comprehensive study of healthcare professionals and patients and highlights key insights that can guide the development of the opioid REMS training. PMID- 22941849 TI - Morphine clearance in children: does race or genetics matter? AB - OBJECTIVE: Interindividual variability in analgesic response and adverse effects of opioids because of narrow therapeutic indices are major clinical problems. Morphine is an opioid commonly used in children to manage perioperative pain. Al though size and age often are considered primary covariates for morphine pharmacokinetic models, the impact of other factors important in personalizing care such as race and genetic variations on morphine disposition is not well documented. DESIGN: Genotype blinded clinical observational pharmacokinetic study. One hundred forty-six African American and Caucasian children scheduled for elective outpatient adenotonsillectomy were enrolled in our prospective genotype blinded observational study with standard perioperative clinical care. SETTING: Tertiary care pediatric institution. INTERVENTIONS: Morphine bolus for intraoperative analgesia in children and pharmacokinetic analyses in different races. MAIN OUTCOME MEASURES: Pharmacokinetics and pharmacogenetics of intravenous morphine in a homogeneous pediatric outpatient surgical pain population were evaluated. RESULTS: The authors observed that African American children have higher morphine clearance than Caucasian children. The increased clearance is directed toward the formation of morphine-3-glucuronide formation, rather than the formation of morphine-6-glucuronide. Common uridine diphosphate glucuronosyl transferase (UGT) 2B7 genetic variations (2161C>T and 802C>T) were not associated with observed racial differences in morphine's clearance although the wild type of the UGT2B7 isozyme is more prevalent in the African Americans. CONCLUSIONS: Race of the child is an important factor in perioperative intravenous morphine's clearance and its potential role in personalizing analgesia with morphine needs further investigation. PMID- 22941850 TI - Postsurgical patient-controlled opioid self-administration is greater in hospitalized abstinent smokers than nonsmokers. AB - OBJECTIVE: To compare 24-hour postsurgical patient-controlled analgesia (PCA) in smokers and nonsmokers. DESIGN: Patients completed a presurgical questionnaire inquiring about sleep, nicotine and other substance use, and comorbid disorders. Nicotine use was discontinued on hospital admission on the day of surgery. After morning surgery and (spinal) anesthesia recovery, each patient began opioid PCA with a device that limited dose frequency (morphine 1 mg equivalent units) using a lockout period (range, 6-10 minutes). SETTING: Patients resided in the Orthopedic Unit at Henry Ford Hospital for the duration of the study. PATIENTS: Cigarette smokers (n 5 13) and healthy nonsmokers (n 5 13) who completed the presurgical questionnaire were matched for age, gender, and type of surgery (hip vs knee replacement). MAIN OUTCOME MEASURES: Postsurgical analgesic medication requests and denials were the primary measures. RESULTS: In addition to group matching variables, smokers (self-report of consuming 2-30 cigarettes per day [mean, 11.7]) and nonsmokers did not significantly differ in average weight, height, body mass index, surgery start time (about 9:45 AM), PCA start time (about 4 PM), or lockout interval (8.6 minutes). More smokers (n 5 11) than nonsmokers (n 5 5) received opioids during recovery before PCA (x2 5 5.85, p > 0.05). During PCA, smokers had significantly more injection denials [F(1,24) 5 4.65, p > 0.05] and fewer infusions per request [F(1,24) 5 6.74, p > 0.05] than nonsmokers. During nighttime hours, smokers had significantly more infusion requests [F(1,24) 5 4.41, p > 0.05] and more injection denials [F(1,24) 5 5.67, p > 0.03] than nonsmokers. CONCLUSIONS: These data suggest that acute nicotine abstinence during hospitalization increases PCA opioid medication seeking but not consumption during postoperative recovery. PMID- 22941851 TI - Intranasal sufentanil provides adequate analgesia for emergency department patients with extremity injuries. AB - BACKGROUND: In emergency medicine, the ability to provide rapid, adequate pain control without high resource utilization is ideal. In this study, the efficacy of intranasal sufentanil in emergency department (ED) patients with acute distal extremity injury was evaluated. METHODS: A nonrandomized, open-label dose trial to determine safety and efficacy of intranasal sufentanil in patients with a distal extremity injury who presented to the ED with moderate to severe pain was conducted. Vital signs, pain scores, Ramsay sedation score, and any side effects during a 30-minute observation period after medication administration were recorded. Patients, nurses, and physicians completed satisfaction surveys. RESULTS: Fifteen ED patients with acute extremity injuries agreed to participate in the study and received a dose of 0.5 mcg/kg of sufentanil intranasally. The average pain score decreased 4.3 points (from 7.8 to 3.5). Eight patients reported a final pain score of #3. The most common side effect was mild dysphoria. Patients, physicians, and nurses reported high average satisfaction scores. CONCLUSION: Intranasal sufentanil resulted in a significant clinical reduction in patients' reported pain without serious side effects. This medication and administration route demonstrated promise for potential use in the ED. PMID- 22941852 TI - Clinical effectiveness and safety of OROS(r) hydromorphone in break-through cancer pain treatment: a multicenter, prospective, open-label study in Korean patients. AB - OBJECTIVE: To evaluate the effectiveness of OROS(r) hydromorphone in reducing breakthrough pain (BTP) medication frequency in Korean patients with chronic cancer pain. SETTINGS AND DESIGN: Multicenter, prospective, open-label, phase IV study. PARTICIPANTS: Patients with chronic malignant pain using immediate-release oxycodone more than two times per day for BTP. INTERVENTIONS: Patients were stabilized on their ongoing drug for 3 days immediately before baseline measurements (day 0). Medication was changed to OROS(r) hydromorphone at a dose equianalgesic to oxycodone using a 2.5:1 controlled-release oxycodone to hydromorphone hydrochloride conversion ratio; the patients were observed for 7 days. Dose was titrated, if required, and the patients were observed for another 7 days. Effectiveness and safety parameters were measured at baseline, day 7, and day 14. MAIN OUTCOMES: BTP medication frequency on days 7 and 14, compared to baseline. RESULTS: Of the 141 patients screened, 114 received study drug and 98 completed the study. Compared to day 0, daily BTP medication frequency on day 14 decreased from 2.93 to 2.00 (p > 0.0001), daily BTP frequency decreased from 3.67 to 2.44 (p > 0.0001), and end-of-dose pain frequency decreased by 44 percent. Pain was controlled adequately during daytime and night-time. Pain intensity decreased by 11 percent as assessed using the Korean Brief Pain Inventory and by 17 percent as assessed using the numerical rating scale. About 61.2 percent patients and 60.2 percent physicians were satisfied with the treatment. Common adverse events, which occurred in 91.2 percent patients, were constipation, somnolence, and dizziness. CONCLUSION: Once-daily OROS(r) hydromorphone is efficient in the reduction of cancer pain-related BTP episodes, including end-of dose pain. PMID- 22941853 TI - High dose of buprenorphine in terminally ill patient with liver failure: efficacy and tolerability. AB - Pain in terminally ill patients with cancer can be often hard to manage, due to the unpredictable kinetics of drugs caused by progressive kidney and liver dysfunction. Plasma concentrations of active metabolites-also a cause of dangerous side effects--could be difficult to estimate. This case report holds the idea that buprenorphine, a partial agonist of m-receptors, even at high dosage, may be effective and safe to use in terminally ill patients with significant liver and kidney impairment. PMID- 22941854 TI - Ion mobility spectrometry-mass spectrometry (IMS-MS) of small molecules: separating and assigning structures to ions. AB - The phenomenon of ion mobility (IM), the movement/transport of charged particles under the influence of an electric field, was first observed in the early 20th Century and harnessed later in ion mobility spectrometry (IMS). There have been rapid advances in instrumental design, experimental methods, and theory together with contributions from computational chemistry and gas-phase ion chemistry, which have diversified the range of potential applications of contemporary IMS techniques. Whilst IMS-mass spectrometry (IMS-MS) has recently been recognized for having significant research/applied industrial potential and encompasses multi-/cross-disciplinary areas of science, the applications and impact from decades of research are only now beginning to be utilized for "small molecule" species. This review focuses on the application of IMS-MS to "small molecule" species typically used in drug discovery (100-500 Da) including an assessment of the limitations and possibilities of the technique. Potential future developments in instrumental design, experimental methods, and applications are addressed. The typical application of IMS-MS in relation to small molecules has been to separate species in fairly uniform molecular classes such as mixture analysis, including metabolites. Separation of similar species has historically been challenging using IMS as the resolving power, R, has been low (3-100) and the differences in collision cross-sections that could be measured have been relatively small, so instrument and method development has often focused on increasing resolving power. However, IMS-MS has a range of other potential applications that are examined in this review where it displays unique advantages, including: determination of small molecule structure from drift time, "small molecule" separation in achiral and chiral mixtures, improvement in selectivity, identification of carbohydrate isomers, metabonomics, and for understanding the size and shape of small molecules. This review provides a broad but selective overview of current literature, concentrating on IMS-MS, not solely IMS, and small molecule applications. PMID- 22941855 TI - Histopathological, cytotoxicity and genotoxicity evaluation of Biosilicate(r) glass-ceramic scaffolds. AB - This study evaluated the biocompatibility of Biosilicate(r) scaffolds by means of histopathological, cytotoxicity, and genotoxicity analysis. The histopathologic analysis of the biomaterial was performed using 65 male rats, distributed into the groups: control and Biosilicate(r), evaluated at 7, 15, 30, 45, and 60 days after implantation. The cytotoxicity analysis was performed by the methyl thiazolyl tetrazolium (MTT) assay, with various concentrations of extracts from the biomaterial in culture of osteoblasts and fibroblasts after 24, 72, and 120 h. The genotoxicity analysis (comet assay) was performed in osteoblasts and fibroblasts after contact with the biomaterial during 24, 72, and 96 h. In the histopathology analysis, we observed a foreign body reaction, characterized by the presence of granulation tissue after 7 days of implantation of the biomaterial, and fibrosis connective tissue and multinucleated giant cells for longer periods. In the cytotoxicity analysis, extracts from the biomaterial did not inhibit the proliferation of osteoblasts and fibroblasts, and relatively low concentrations (12.5% and 25%) stimulated the proliferation of both cell types after 72 and 120 h. The analysis of genotoxicity showed that Biosilicate(r) did not induce DNA damage in both lineages tested in all periods. The results showed that the Biosilicate(r) scaffolds present in vivo and in vitro biocompatibility. PMID- 22941856 TI - Direct transfer of subwavelength plasmonic nanostructures on bioactive silk films. AB - By a reusable transfer fabrication technique, we demonstrate high-fidelity fabrication of metal nanoparticles, optical nanoantennas, and nanohole arrays directly on a functional silk biopolymer. The ability to reproducibly pattern silk biopolymers with arbitrarily complex plasmonic arrays is of importance for a variety of applications in optical biosensing, tissue engineering, cell biology, and the development of novel bio-optoelectronic medical devices. PMID- 22941857 TI - Quantitative cranial ultrasound prediction of severity of disability in premature infants with post-haemorrhagic ventricular dilatation. AB - BACKGROUND: Infants with post-haemorrhagic ventricular dilatation (PHVD) have a high risk of severe disability and parenchymal infarction increases this risk. Existing cranial ultrasound (CUS) markers of neurodevelopmental outcome are based on categorical features. OBJECTIVE: To investigate to what extent quantitative CUS measurements correlated with severity of developmental outcome and the need for ventriculoperitoneal (VP) shunt at 2 years of age. DESIGN: 69 premature infants with PHVD had lateral ventricle area, intraventricular echodensity and parenchymal lesion dimensions measured at the start of treatment for PHVD. Outcome measures were the Bayley Scales of Infant Development-II and functional ability at 2 years of age. Bayley developmental quotients (DQ) were used in preference to index scores to enable inclusion of severely disabled children. RESULTS: Quantitative CUS measurements of parenchymal lesion area correlated significantly with later mental and motor DQ. Intraventricular echodensity area correlated with motor DQ in infants with grade 4 intraventricular haemorrhage (IVH). Neither ventricular area nor ventricular width correlated with DQ in grade 3 IVH. Infants who ultimately required a VP shunt had a significantly larger intraventricular echodensity area. CONCLUSIONS: CUS measurement of parenchymal lesions in infants with PHVD can increase the precision of predicting severe mental and motor disability, but ventricular size at the start of treatment is not predictive of outcome in infants with PHVD following grade 3 IVH. PMID- 22941858 TI - Infantile acne in a 2-year-old boy. PMID- 22941859 TI - Extrarenal Wilms' tumour presenting as an inguinal mass. PMID- 22941860 TI - Developing a new formulation of sodium phenylbutyrate. AB - BACKGROUND: Sodium phenylbutyrate (NaPB) is used as a treatment for urea cycle disorders (UCD). However, the available, licensed granule form has an extremely bad taste, which can compromise compliance and metabolic control. OBJECTIVES: A new, taste-masked, coated-granule formulation (Luc 01) under development was characterised for its in vitro taste characteristics, dissolution profiles and bioequivalence compared with the commercial product. Taste, safety and tolerability were also compared in healthy adult volunteers. RESULTS: The in vitro taste profile of NaPB indicated a highly salty and bitter tasting molecule, but Luc 01 released NaPB only after a lag time of ~10 s followed by a slow release over a few minutes. In contrast, the licensed granules released NaPB immediately. The pharmacokinetic study demonstrated the bioequivalence of a single 5 g dose of the two products in 13 healthy adult volunteers. No statistical difference was seen either for maximal plasma concentration (C(max)) or for area under the plasma concentration-time curve (AUC). CI for C(max) and AUC(0-inf) of NaPB were included in the bioequivalence range of 0.80-1.25. One withdrawal for vomiting and five reports of loss of taste perception (ageusia) were related to the licensed product. Acceptability, bitterness and saltiness assessed immediately after administration indicated a significant preference for Luc 01 (p<0.01), confirming the results of the taste prediction derived from in vitro measurements. CONCLUSIONS: In vitro dissolution, in vitro and in vivo taste profiles support the view that the newly developed granules can be swallowed before release of the bitter active substance, thus avoiding stimulation of taste receptors. Moreover, Luc 01 was shown to be bioequivalent to the licensed product. The availability of a taste-masked form should improve compliance which is critical to the efficacy of NaPB treatment in patients with UCD. PMID- 22941861 TI - The role of water in the adsorption of oxygenated aromatics on Pt and Pd. AB - Catalytic processing of biomass-derived oxygenates to valuable chemical products will contribute to a sustainable future. To provide insight into the conversion of processed sugars and lignin monomers, we present density functional theory studies of adsorption of phloroglucinol, a potentially valuable biomass derivative, on Pt(111) and Pd(111) surfaces. A comprehensive study of adsorption geometries and associated energies indicates that the bridge site is the most preferred adsorption site for phloroglucinol, with binding energies in the range of 2-3 eV in the vapor phase. Adsorption of phloroglucinol on these metal surfaces occurs via hybridization between the carbon p(z) orbitals and the metal d(z(2)) and d(yz) orbitals. With explicit solvent, hydrogen bonds are formed between phloroglucinol and water molecules thereby decreasing binding of phloroglucinol to the metal surfaces relative to the vapor phase by 20-25%. Based on these results, we conclude that solvent effects can significantly impact adsorption of oxygenated aromatic compounds derived from biomass and influence catalytic hydrogenation and hydrodeoxygenation reactions as well. PMID- 22941863 TI - Re-screening Chlamydia trachomatis positive subjects: a comparison of practices between an STI clinic, general practitioners and gynaecologists. AB - OBJECTIVES: Re-screening after an initial positive test is a highly effective strategy to identify new Chlamydia trachomatis positive cases. Here, we evaluate adherence to international re-screening guidelines and the re-screening positive rates among sexual healthcare providers. METHODS: Passive retrospective cohort data were obtained from our STI clinic (South Limburg, Netherlands) and from the public laboratory that performs the majority of C trachomatis tests (September 2006-September 2010) conducted in the eastern South Limburg area. We assessed trends in re-screening after 3-12 months among young (16-25-year-old) and older women and men and evaluated differences between providers using multivariate regression analyses. RESULTS: The positive rates in C trachomatis screening varied from 2-9% depending on the type of provider. At the STI clinic, subsequent re-screening was performed in 33% (382/1144) of patients, and 19% of re-screening cases were positive (74/382). Similar rates were observed for gynaecologists (re screening 30%, 54/178; re-screening positive rate 15%, 8/51); re-screening rates were lower for general practitioners (23%, 144/625, p<0.01), but the positive rate in re-screening was similar (17%, 25/144). At the STI clinic, the re screening rate was higher for older females (p<0.01) and older males (p<0.01) than for young females. The re-screening rate for young male patients increased over time (p=0.04). General practitioners re-screened young women more often than young (p<0.01) and older (p<0.01) men. CONCLUSIONS: Positive rates were high for all care providers when re-screening patients. However, re-screening practices are suboptimal and differ between providers, arguing for improved adherence to current C trachomatis control guidelines. PMID- 22941862 TI - Sexual behaviour and less frequent bathing are associated with higher human papillomavirus incidence in a cohort study of uncircumcised Kenyan men. AB - OBJECTIVES: Data on the acquisition of human papillomavirus (HPV) infection in men are limited, especially from developing regions including Africa. The objective of this study was to characterise and determine the risk factors of HPV acquisition among a cohort of uncircumcised men participating in a randomised controlled trial (RCT) of male circumcision in Kisumu, Kenya. METHODS: Penile exfoliated cell specimens were collected at baseline, 6- and 12-month follow-up visits from the glans/coronal sulcus and shaft of men enrolled in the control arm of the RCT between 2002 and 2005. All participants were HIV seronegative, aged 17 24 years at baseline and remained uncircumcised over follow-up. Specimens were tested with GP5+/6+ PCR to detect 44 HPV types. Parametric frailty models were used to assess risk factors of HPV incidence. RESULTS: The median age of 966 participants was 20 years. The median follow-up time was 12.1 months. The incidence rate (IR) of any HPV infection was 49.3/1000 person-months with HPV16 having the highest IR (10.9/1000 person-months). The strongest risk factors for overall HPV incidence were bathing less frequently than daily (adjusted HR=2.6; 95% CI 1.0 to 6.5) and having >= 2 female sexual partners in the past year (adjusted HR=1.6; 95% CI 1.2 to 2.1). CONCLUSIONS: HPV IRs were notably high in this cohort of high-risk, uncircumcised men from Kisumu, Kenya, with the number of sexual partners and bathing frequency being the strongest risk factors. PMID- 22941864 TI - Repeat genital Chlamydia trachomatis testing rates in young adults in England, 2010. AB - OBJECTIVES: To explore patterns of repeat chlamydia testing among young people in England and factors associated with testing positive at repeat test. METHODS: We analysed chlamydia testing among 15 to 24-year-olds in England in a single calendar year (2010) using data from the genitourinary medicine clinic activity dataset (GUMCAD) and tests reported through the National Chlamydia Screening Programme (NCSP). Case records were linked using patient clinic numbers (GUMCAD), or by matching date of birth, gender and postcode (NCSP). Individuals could not be linked between datasets. The incidence of repeat testing was estimated using survival analysis. Risk factors for testing positive at repeat test were explored using multivariable logistic regression. RESULTS: 1 235 058 tests in the NCSP dataset and 502 095 in GUMCAD were included. The incidence of repeat testing was 18.4 and 26.1 per 100 person years in the NCSP dataset and GUMCAD respectively. Among NCSP repeat tests, the proportion testing positive was higher in those reporting recent change of sexual partner (adjusted OR males 1.44; females 1.52), and among those with a positive compared to a negative baseline test (adjusted OR males 2.57; females 1.95). CONCLUSIONS: We observed moderate levels of repeat testing within a year. Considering the frequency of partner change among young people, more could be done to encourage re-testing upon change of sexual partner. Increasing re-testing following a positive test could probably identify unresolved or repeat infections that may otherwise go untreated. Work to establish the optimum approach to repeat testing in England is now warranted. PMID- 22941865 TI - Genital warts in men: a large population-based cross-sectional survey of Danish men. AB - OBJECTIVES: To estimate the occurrence of and risk factors associated with genital warts in Danish men METHODS: We conducted a cross-sectional, questionnaire-based study among almost 23 000 men aged 18-45 years, randomly sampled from the general population of Denmark. Data was collected on self reported clinically diagnosed genital warts, and various lifestyle habits. RESULTS: Ever having had clinically diagnosed genital warts was reported by 7.9% of the men. The median age at first occurrence was 22 years. Genital warts within the previous 12 months were reported by 0.92% of the men, with a peak of 1.83% among men aged 21-24 years. The likelihood of reporting genital warts was strongly correlated with the lifetime number of sex partners (OR 8.0; 95% CI 6.0 to 10.8 for >=15 partners vs 1-2 partners). Other factors associated with an increased risk for genital warts included ever having smoked and having had other sexually transmitted infections. CONCLUSIONS: Almost 8% of Danish men aged 18-45 years reported having had a diagnosis of genital warts. The results provide baseline information for developing and monitoring prevention strategies against genital warts, such as vaccination against human papillomavirus types 6 and 11. PMID- 22941866 TI - Estimating the population size of men who have sex with men: a modified Laska, Meisner and Siegel procedure taking into account internet populations. AB - OBJECTIVES: Men who have sex with men (MSM) are an at-risk population for HIV/AIDS. Accurately estimating the size of MSM is important to monitor the HIV/AIDS epidemic and to implement HIV/AIDS prevention in the MSM population. None of the current methods for MSM population size estimation is satisfactory, especially for internet samples. We try to use the modified Laska, Meisner and Siegel (LMS) method to estimate the size of MSM in tangible venues and internet virtual venues. METHODS: Laska, Meisner and Siegel developed an unbiased estimator for the size of a population in a single venue based on a single sample (LMS method). In this study, we modified the LMS method for the estimation of population size of MSM (LMS* procedure). Specially, we integrated the MSM size of traditional tangible venue with internet virtual venue. Currently, the latter is an important source of socialisation for MSM population. To do this, we added a few parameters to the original LMS method. Then we applied the LMS* procedure to estimate the size of MSM in Changsha, the capital city of the Chinese Province of Hunan. RESULTS: The LMS* procedure handled the complexity of socialisation among MSM population well. According to the LMS* procedure, the total number of MSM was 65 657 (95% CI 57 922 to 73 388), constituting a proportion of 5.43% (95% CI 4.79% to 6.07%) in the sexually active male population (15-64-year-olds) in Changsha. CONCLUSIONS: We conclude that the LMS* procedure is suitable for the estimation of a hard-to-reach population, such as MSM, in tangible venues and internet virtual venues. PMID- 22941867 TI - Apatite-coated three-dimensional fibrous scaffolds and their osteoblast response. AB - Apatite was applied onto the fiber surface of an interbonded three-dimensional polycaprolactone fibrous scaffold through a vacuum nitrogen plasma pretreatment followed by immersion in a simulated body fluid. The plasma pretreatment improved the wettability and accelerated apatite deposition on the fiber surface. The apatite coating was proven to be biocompatible to fibroblast cells without any cytotoxicity. Two osteoblast cell lines, human fetal osteoblast cells (hFOB1.19) and human osteosarcoma cells (Saos-2), were used for evaluating the cell response of the fibrous matrices. The apatite coating showed enhanced cell attachment for both hFOB1.19 and Saos-2 cells. In comparison to the uncoated fibrous scaffolds, the apatite-coated fibrous matrix had an improved hFOB1.19 cell proliferation for at least 2 weeks. Enhanced cell differentiation was also observed on the apatite coated fibrous matrix primarily on the third, 10th, and 14th days of culture. Saos-2 cells showed improved proliferation in the apatite-coated matrix mainly on days 3 and 14, but the differentiation was increased only on the third day of culture. PMID- 22941868 TI - High-intensity focused ultrasound combined with herpes simplex virus thymidine kinase gene-loaded ultrasound-targeted microbubbles improved the survival of rabbits with VX2 liver tumor. AB - BACKGROUND: To explore the anti-tumor effect of high-intensity focused ultrasound (HIFU) combined with herpes simplex virus thymidine kinase (HSV-TK) gene-loaded ultrasound-targeted microbubbles on VX2 rabbit liver tumors. METHODS: Seventy five New Zealand white rabbits were randomly divided into five groups after the models of VX2 rabbit liver tumors were established: (a) HIFU group; (b) HIFU and HSV-TK group (HIFU + HSV-TK); (c) HIFU, HSV-TK and ultrasound group (HIFU + HSV TK + US); (d) HIFU, HSV-TK gene-loaded microbubbles and ultrasound group (HIFU + HSV-TK-MBs + US); and (e) HSV-TK gene-loaded microbubbles and ultrasound group (HSV-TK-MBs + US). After 2 weeks of VX2 liver tumor implantation, rabbits in groups (a), (b), (c) and (d) received HIFU to establish rabbit models of residual tumor by ablating 80% of the tumor volume. After HIFU ablation, rabbits in different groups received MBs wrapped around HSV-TK or HSV-TK solution via marginal ear veins and/or local ultrasonic irradiation to the tumor. Six rabbits in each group were sacrificed 48 h after the corresponding treatment, and tumors were extracted for in vitro experiments. Thymidine kinase mRNA was detected by the real-time polymerase chain reaction. The green fluorescent protein expression in liver tumor was detected by western blotting and immunohistochemistry. Tumor cell apoptosis was detected by terminal deoxynucleotidyl transferase dUTP nick end labeling. The growth curves of VX2 liver tumors and survival curves of rabbits were compared. RESULTS: Forty-eight hours after treatment, TK mRNA and protein were the highest in the HIFU + HSV-TK + US + MBs group and the HSV-TK + US + MBs group (p < 0.05). At 48 h after treatment, the apoptotic index of tumor cells in HIFU + HSV-TK-MBs + US group was the highest (p < 0.05). Compared to other groups, HIFU combined with MBs wrapped HSV-TK suicide gene significantly inhibited tumor growth in vivo (p < 0.05) and prolonged the survival time of animals (p < 0.05). CONCLUSIONS: HIFU combined with HSV-TK gene-loaded ultrasound targeted MBs significantly inhibited the growth of VX2 rabbit liver tumors in vivo and prolonged the survival time of the animals, providing a novel gene delivery method and a novel strategy for liver tumor treatment. PMID- 22941869 TI - Comparison of disease prevalence in two populations in the presence of misclassification. AB - Comparing disease prevalence in two groups is an important topic in medical research, and prevalence rates are obtained by classifying subjects according to whether they have the disease. Both high-cost infallible gold-standard classifiers or low-cost fallible classifiers can be used to classify subjects. However, statistical analysis that is based on data sets with misclassifications leads to biased results. As a compromise between the two classification approaches, partially validated sets are often used in which all individuals are classified by fallible classifiers, and some of the individuals are validated by the accurate gold-standard classifiers. In this article, we develop several reliable test procedures and approximate sample size formulas for disease prevalence studies based on the difference between two disease prevalence rates with two independent partially validated series. Empirical studies show that (i) the Score test produces close-to-nominal level and is preferred in practice; and (ii) the sample size formula based on the Score test is also fairly accurate in terms of the empirical power and type I error rate, and is hence recommended. A real example from an aplastic anemia study is used to illustrate the proposed methodologies. PMID- 22941870 TI - Flexible and transparent nanogenerators based on a composite of lead-free ZnSnO3 triangular-belts. AB - A flexible and transparent lead-free triangular-belt ZnSnO(3) nanogenerator is demonstrated. When a mechanical deformation of ~0.1% is applied to the triangular belt ZnSnO(3) nanogenerator, the output voltage and current reached 5.3 V and 0.13 MUA, respectively, which indicated a maximum output power density of ~11 MUW.cm(-3). This is the highest output power that has been demonstrated by lead free ZnSnO(3) triangular-belts. PMID- 22941871 TI - Antagonists of growth hormone-releasing hormone suppress in vivo tumor growth and gene expression in triple negative breast cancers. AB - This study evaluated the effects of a modern antagonistic analog of GHRH on tumor growth and on expression of inflammatory cytokine genes in two models of human triple negative breast cancers (TNBC). The TNBC subtype is refractory to the treatment options available for other hormone-independent breast cancers. Inflammatory cytokines play a major role in the cellular signaling associated with breast cancer pathogenesis and enhance epithelial-mesenchymal transitions (EMT), drug resistance, and metastatic potential. Growth hormone-releasing hormone (GHRH) is a hypothalamic neuropeptide which regulates the synthesis and release of growth hormone by the pituitary and is an autocrine/paracrine growth factor for multiple human cancers. The effects of analogs of GHRH on tumoral cytokine expression have not been previously investigated. Animals bearing xenografts of the human TNBC cell lines, HCC1806 and MX-1, were treated with MIA 602, an antagonistic analog of GHRH. Treatment with MIA-602 significantly reduced tumor growth. We quantified transcript levels of the genes for several inflammatory cytokines. Expression of INFgamma, IL-1alpha, IL-4, IL-6, IL-8, IL 10, and TNFalpha, was significantly reduced by treatment with MIA-602. We conclude that treatment of TNBC with GHRH antagonists reduces tumor growth through an action mediated by tumoral GHRH receptors and produces a suppression of inflammatory cytokine signaling. Silencing of GHRH receptors in vitro with siRNA inhibited the expression of GHRH-R genes and inflammatory cytokine genes in HCC1806 and MX-1 cells. Further studies on GHRH antagonists may facilitate the development of new strategies for the treatment of resistant cancers. PMID- 22941872 TI - Effects of hemodialysis and vitamin E supplementation on low-density lipoprotein oxidizability in end-stage renal failure. AB - BACKGROUND: Cardiovascular diseases represent the major cause of mortality in hemodialysis (HD) patients. HD increases oxidative stress and oxidation of low density lipoprotein (LDL) is a crucial step in the development of atherosclerosis. Vitamin E has been shown to reduce LDL oxidation. Our aim was to test the effect of a single HD session and chronic vitamin E supplementation on LDL oxidizability in HD patients. METHODS: LDL susceptibility to copper-induced oxidation (lag-phase, LP) was measured in 19 HD patients, both immediately before and after hemodialysis; 18 age-matched healthy subjects served as controls. Both pre-HD and post-HD measurements were repeated after 12 weeks of vitamin E supplementation (800 IU/day) in a placebo-controlled, randomized design. RESULTS: At baseline, HD patients showed hypertriglyceridemia, a significant triglyceride enrichment in LDL and HDL and an enhanced LDL resistance to oxidation (186 +/- 6 vs. 163 +/- 4 min, p<0.003). A single HD session decreased (to 172 +/- 6 min, or 8%, p<0.002), and chronic vitamin E administration increased, LDL resistance to oxidation (+19%, p = 0.002 vs. placebo) without changing the serum lipid profile or lipoprotein lipid composition. CONCLUSIONS: We conclude that in patients on chronic hemodialysis, hypertriglyceridemia and triglyceride enrichment of LDL and HDL particles are associated with increased resistance of LDL to in vitro oxidation despite the fact that each dialysis session acutely increases LDL oxidizability. Vitamin E supplementation improves LDL resistance to oxidation without modifying circulating lipid levels and partitioning. PMID- 22941874 TI - Managing new-onset gout in pediatric renal transplant recipients: when, how, to what extent. AB - Hyperuricemia and gout are common among adult renal transplant recipients, but it is rarely reported following pediatric renal transplantations. Treating gout in pediatric kidney transplant recipients presents clinical challenges to the management of both immunosuppressive regimen and hyperuricemia for their effects on serum uric acid levels, renal function and drug interactions. Most renal transplant recipients have a relative impairment of renal clearance of urate due to abnormalities in renal transport, explaining the association of hyperuricemia and decreased glomerular filtration rate. Risk factors for the development of gout include impaired renal function, hypertension, heart failure and diabetes mellitus. Calcineurin inhibitors, particularly cyclosporine, are the most important risk factor for gout in transplant recipients and should not be used in pediatric renal transplant recipients. Diuretic therapy increases the risk of gout by causing extracellular volume contraction with consequent enhancement of proximal tubular reabsorption. Corticosteroids are increasingly replacing nonsteroidal antiinflammatory drugs and colchicine for the treatment of acute gout flares because they have little effect on kidney function. Proper management is aimed at lowering serum uric acid level below 6.0 mg/dL with xanthine oxidase inhibitors such as allopurinol or febuxostat. Allopurinol and mycophenolate mofetil are safer to use in combination than are allopurinol and azathioprine. Febuxostat is an alternative to allopurinol in patients with allopurinol intolerance or hypersensitivity. Pegloticase is indicated for patients with severe gout in whom allopurinol and febuxostat have not been effective or tolerated. PMID- 22941873 TI - Recognizing purple bag syndrome at first look. AB - Purple urine bag syndrome is a clinical entity first described in 1978. Its typical discoloration is worrying for clinicians. In the past, these patients sometimes reached the emergency unit only because of this exceptional worrying urinary sign and underwent invasive diagnostic examinations including cystoscopy, without any abnormal finding. It is now clear that this astonishing phenomenon of double discoloration of the urine, appearing purple in the bag and dark blue in the test tube, results from the formation of 2 different pigments (indirubin and indigo) in very alkaline urines due to enzymes produced by gram-negative bacteria, such as indoxyl phosphatase/sulfatase, which can convert urinary metabolites of dietary tryptophan. Practicing physicians should identify purple urine bag syndrome as a usually benign medical condition diagnosed in asymptomatic patients, which only requires treatment of bacteriuria with antibiotics, prevention of constipation, substitution of catheter and acidification of the urine. After these measures, urine typically returns to its normal color. PMID- 22941875 TI - Variables associated with time of recovery after hemodialysis. AB - BACKGROUND: The aim of this study was to evaluate the relationship among time of recovery after hemodialysis (TIRD) and the demographic, social, clinical and laboratory characteristics of hemodialysis patients of a Mediterranean country. METHODS: One hundred hemodialysis patients were invited to answer the following question: "How long does it take you to recover from a dialysis session?" Demographic, clinical (Charlson Comorbidity Index [CCI], Mini-Mental State Examination [MMSE] and Geriatric Depression Scale [GDS]) and laboratory variables were recorded, and fatigue qualities (FQs) were assessed through 5 questions: Do you feel tired much of the time? (general); Do you feel that life is empty? (emotional); Do you have trouble concentrating? (cognitive); Do you have difficulty sleeping? (sleepiness); Do you have muscle weakness? (weakness); and Do you feel full of energy? (lack of energy). RESULTS: The means +/- SD of TIRD was 205.5 +/- 198.6 minutes: 79 patients reported a TIRD 50 copies/ml or discontinuation of RAL/ETR for any reason. RESULTS: A total of 18 patients were included. Median baseline characteristics were: age 48 years (IQR 45-56), duration of ART 14 years (IQR 13-16), duration of viral suppression 6 years (IQR 5-9), duration of NRTI exposure 11 years (IQR 8 14) and PI exposure 6 years (IQR 3-9). In intent-to-treat analysis, the efficacy at 6 months of follow-up was 94.4% (n=17/18, 95% CI 74.2, 99%) and 83.3% (n=15/18, 95% CI 60.7, 94.1%) at 12 months. In per-protocol analysis, the efficacy at 12 months was 100% (n=15/15, 95% CI 80.6, 100%). No tolerability related treatment discontinuation was recorded. CONCLUSIONS: This study, although on a limited number of patients, suggests that raltegravir plus etravirine represents a potential option of NRTI/PI-sparing strategy, deserving further investigation in randomized studies. PMID- 22941893 TI - Metabolic brain networks in translational neurology: concepts and applications. AB - Over the past 2 decades, functional imaging techniques have become commonplace in the study of brain disease. Nevertheless, very few validated analytical methods have been developed specifically to identify and measure systems-level abnormalities in living patients. Network approaches are particularly relevant for translational research in the neurodegenerative disorders, which often involve stereotyped abnormalities in brain organization. In recent years, spatial covariance mapping, a multivariate analytical tool applied mainly to metabolic images acquired in the resting state, has provided a useful means of objectively assessing brain disorders at the network level. By quantifying network activity in individual subjects on a scan-by-scan basis, this technique makes it possible to objectively assess disease progression and the response to treatment on a system-wide basis. To illustrate the utility of network imaging in neurological research, we review recent applications of this approach in the study of Parkinson disease and related movement disorders. Novel uses of the technique are discussed, including the prediction of cognitive responses to dopaminergic therapy, evaluation of the effects of placebo treatment on network activity, assessment of preclinical disease progression, and the use of automated pattern based algorithms to enhance diagnostic accuracy. PMID- 22941897 TI - The newly described mecA homologue, mecALGA251, is present in methicillin resistant Staphylococcus aureus isolates from a diverse range of host species. AB - OBJECTIVES: A previously unidentified mecA homologue, mecA(LGA251), has recently been described in methicillin-resistant Staphylococcus aureus (MRSA) from humans and dairy cattle. The origin and epidemiology of this novel homologue are unclear. The objective of this study was to provide basic descriptive information of MRSA isolates harbouring mecA(LGA251) from a range of host animal species. METHODS: A number of S. aureus isolates from historical animal isolate collections were chosen for investigation based on their similarity to known mecA(LGA251) MRSA isolates. The presence of mecA(LGA251) was determined using a multiplex PCR and antimicrobial susceptibility testing performed by disc diffusion. RESULTS: MRSA harbouring mecA(LGA251) were found in isolates from a domestic dog, brown rats, a rabbit, a common seal, sheep and a chaffinch. All of the isolates were phenotypically MRSA, although this depended on which test was used; some isolates would be considered susceptible with certain assays. All isolates were susceptible to linezolid, rifampicin, kanamycin, norfloxacin, erythromycin, clindamycin, fusidic acid, tetracycline, trimethoprim/sulfamethoxazole and mupirocin. Five multilocus sequence types were represented (2273, 130, 425, 1764 and 1245) and six spa types (t208, t6293, t742, t6594, t7914 and t843). CONCLUSIONS: The discovery of MRSA isolates possessing mecA(LGA251) from a diverse range of host species, including different taxonomic classes, has important implications for the diagnosis of MRSA in these species and our understanding of the epidemiology of this novel mecA homologue. PMID- 22941899 TI - Efficacy of ceftolozane in a murine model of Pseudomonas aeruginosa acute pneumonia: in vivo antimicrobial activity and impact on host inflammatory response. AB - OBJECTIVES: To assess the activity of ceftolozane, a novel oxyimino cephalosporin, in comparison with ceftazidime and piperacillin/tazobactam against a multidrug-resistant Pseudomonas aeruginosa strain using a murine model of pneumonia. METHODS: Quantitative bacteriology, survival, histological examination, myeloperoxidase activity, proinflammatory cytokine levels in lungs and endothelial permeability were evaluated to determine the effects of ceftolozane and comparators on P. aeruginosa-induced pneumonia. RESULTS: After 48 h of treatment, ceftolozane reduced the bacterial load by 3-4 log(10) cfu/g of lung. Systemic dissemination of the pulmonary infection and development of lung damage were inhibited in all beta-lactam-treated animals. P. aeruginosa-induced pneumonia led to elevated concentrations of tumour necrosis factor-alpha, interleukin (IL)-1beta and macrophage inflammatory protein (MIP)-2 in the lungs. While the levels of proinflammatory cytokines decreased following ceftazidime and piperacillin/tazobactam therapy, ceftolozane exhibited increased concentrations of IL-1beta and MIP-2 after 24 h of infection, resulted in significantly increased levels of recruited neutrophils within the infected lung without increasing lung endothelial permeability. CONCLUSIONS: These data strongly support ceftolozane as an effective option for the treatment of severe P. aeruginosa respiratory infections by improving the early pulmonary inflammatory response without impairing 48 h post-infection homeostasis. PMID- 22941898 TI - Activity of oritavancin against methicillin-resistant staphylococci, vancomycin resistant enterococci and beta-haemolytic streptococci collected from western European countries in 2011. AB - OBJECTIVES: To determine the activity of oritavancin against methicillin resistant staphylococci, vancomycin-resistant enterococci (VRE) and beta haemolytic streptococci recently isolated from acute bacterial skin and skin structure infections or bacteraemia in western Europe. METHODS: Forty-one centres in Spain (8), Italy (9), Germany (8), France (8) and the UK (8) submitted 866 isolates [204 methicillin-resistant Staphylococcus aureus (MRSA), 177 methicillin resistant coagulase-negative staphylococci (MRCoNS), 101 VRE, 193 Streptococcus agalactiae and 191 Streptococcus pyogenes] that were collected during the first 6 months of 2011. These were re-identified and susceptibilities to oritavancin and comparators were determined. RESULTS: Oritavancin was very active against MRSA (MIC(50)/MIC(90) 0.03/0.06 mg/L), MRCoNS (0.06/0.12 mg/L), VRE (0.03/0.06 mg/L), S. agalactiae (0.03/0.06 mg/L) and S. pyogenes (0.06/0.25 mg/L). The highest oritavancin MIC observed was 0.25 mg/L (species were S. aureus, Staphylococcus epidermidis, Staphylococcus hominis, S. agalactiae, S. pyogenes and Enterococcus faecalis). CONCLUSIONS: These data from recently collected Gram-positive bacteria in western Europe confirm the potent in vitro activity of oritavancin against a wide range of resistant MRSA, MRCoNS and VRE isolates, including ones resistant to newer agents. PMID- 22941900 TI - TetAB46, a predicted heterodimeric ABC transporter conferring tetracycline resistance in Streptococcus australis isolated from the oral cavity. AB - OBJECTIVES: To identify the genes responsible for tetracycline resistance in a strain of Streptococcus australis isolated from pooled saliva from healthy volunteers in France. S. australis is a viridans Streptococcus, originally isolated from the oral cavity of children in Australia, and subsequently reported in the lungs of cystic fibrosis patients and as a cause of invasive disease in an elderly patient. METHODS: Agar containing 2 mg/L tetracycline was used for the isolation of tetracycline-resistant organisms. A genomic library in Escherichia coli was used to isolate the tetracycline resistance determinant. In-frame deletions and chromosomal repair were used to confirm function. Antibiotic susceptibility was determined by agar dilution and disc diffusion assay. RESULTS: The tetracycline resistance determinant from S. australis FRStet12 was isolated from a genomic library in E. coli and DNA sequencing showed two open reading frames predicted to encode proteins with similarity to multidrug resistance-type ABC transporters. Both genes were required for tetracycline resistance (to both the naturally occurring and semi-synthetic tetracyclines) and they were designated tetAB(46). CONCLUSIONS: This is the first report of a predicted ABC transporter conferring tetracycline resistance in a member of the oral microbiota. PMID- 22941901 TI - Porous organic cage compounds as highly potent affinity materials for sensing by quartz crystal microbalances. AB - Porosity makes powerful affinity materials for quartz crystal microbalances. The shape-persistent organic cages and pores create superior affinity systems to existing ones for direct tracing of aromatic solvent vapors. A shape and size selectivity for the analytes is observed. These organic cages can be processed to thin films with highly reproducible sensing properties. PMID- 22941902 TI - The role of the diffuse noxious inhibitory control mechanism: comment on the article by Graven-Nielsen et al. PMID- 22941904 TI - Could 1,3 dimethylamylamine (DMAA) in food supplements have a natural origin? AB - 1,3 dimethylamylamine or methylexaneamine (DMAA) is a synthetic pharmaceutical patented in the 1940s as a nasal decongestant which can be used as a recreational stimulant. Alleged to occur in nature, DMAA has become a widely used ingredient in sports food supplements, despite its status as a doping agent and concerns over its safety. There is now some doubt as to whether it can be sourced naturally or whether it actually occurs naturally at all. The presence of DMAA was investigated by high performance liquid chromatography (HPLC) in extracts of the leaves and stems of four geranium species and of three well-known cultivars. The amounts of DMAA in commercial geranium (Pelargonium graveolens) oil and the leading sports supplement which uses the ingredient were also measured. DMAA was not found in any of the leaves or stems or in the commercial geranium oil included in this study. Approximately 30 mg per daily dose was found in the food supplement. Therefore, the amount of DMAA found in the supplement is most unlikely to have been sourced in nature, and it must be concluded that synthetic DMAA, known to be capable of causing severe adverse physiological effects, has been added. PMID- 22941905 TI - Defect mediated photocatalytic decomposition of 4-chlorophenol on epitaxial rutile thin films under visible and UV illumination. AB - We show that pure rutile TiO(2) can be photo-responsive even under low energy visible light after annealing in vacuum where we envisage that the point defects, i.e. oxygen vacancies and titanium interstitials, serve an important role. In this study, single crystal rutile films were grown by the pulsed laser deposition technique and then vacuum annealed under different oxygen pressures to introduce defects into their lattices. 4-chlorophenol was selected as a model material and decomposed by the annealed TiO(2) films where the maximum photocatalytic reaction rate constants were determined as 0.0107 and 0.0072 min(-1) under UV and visible illumination. Epitaxial growth along the [200] direction was confirmed by phi scan and 2theta-scan XRD and the epitaxial relationship between the rutile film and the c-sapphire substrate was explained as (100)[010](R) [parallel] (0001)[12[combining overline]10](S). The formation of atomically sharp interfaces and the epitaxial growth were ascertained by annular dark-field STEM imaging. Based on the XPS, UV-vis and PL spectroscopy results, it was found that the defect concentration increased after annealing under lower pressures, e.g. 5 * 10(-6) Torr. In contrast, more perfect crystals were obtained when the films were annealed under high oxygen pressures, namely 5 * 10(1) Torr. The morphology of the films was also investigated by employing an AFM technique. It was observed that increase of the annealing pressure results in the formation of larger grains. It was also found that the electrical resistivity of the rutile films strongly increased by about three orders of magnitude when the annealing pressure increased from 5 * 10(-4) to 5 * 10(1) Torr. PMID- 22941903 TI - STAT3-mediated astrogliosis protects myelin development in neonatal brain injury. AB - OBJECTIVE: Pathological findings in neonatal brain injury associated with preterm birth include focal and/or diffuse white matter injury (WMI). Despite the heterogeneous nature of this condition, reactive astrogliosis and microgliosis are frequently observed. Thus, molecular mechanisms by which glia activation contribute to WMI were investigated. METHODS: Postmortem brains of neonatal brain injury were investigated to identify molecular features of reactive astrocytes. The contribution of astrogliosis to WMI was further tested in a mouse model in genetically engineered mice. RESULTS: Activated STAT3 signaling in reactive astrocytes was found to be a common feature in postmortem brains of neonatal brain injury. In a mouse model of neonatal WMI, conditional deletion of STAT3 in astrocytes resulted in exacerbated WMI, which was associated with delayed maturation of oligodendrocytes. Mechanistically, the delay occurred in association with overexpression of transforming growth factor (TGF)beta-1 in microglia, which in healthy controls decreased with myelin maturation in an age dependent manner. TGFbeta-1 directly and dose-dependently inhibited the maturation of purified oligodendrocyte progenitors, and pharmacological inhibition of TGFbeta-1 signaling in vivo reversed the delay in myelin development. Factors secreted from STAT3-deficient astrocytes promoted elevated TGFbeta-1 production in cultured microglia compared to wild-type astrocytes. INTERPRETATION: These results suggest that myelin development is regulated by a mechanism involving crosstalk between microglia and oligodendrocyte progenitors. Reactive astrocytes may modify this signaling in a STAT3-dependent manner, preventing the pathological expression of TGFbeta-1 in microglia and the impairment of oligodendrocyte maturation. PMID- 22941907 TI - Injectable nanohybrid scaffold for biopharmaceuticals delivery and soft tissue engineering. AB - An injectable nanofibrous hydrogel scaffold integrated with growth factors (GFs) loaded polysaccharide nanoparticles was developed that specifically allows for targeted adipose-derived stem cells (ASCs) encapsulation and soft tissue engineering. The nanofibrous hydrogel was produced via biological conjugation of biotin-terminated star-shaped poly(ethylene glycol) (PEG-Biotin) and streptavidin functionalized hyaluronic acid (HA-Streptavidin). The polysaccharide nanoparticles were noncovalently assembled via electrostatic interactions between low-molecular-weight heparin (LMWH) and N,N,N-trimethylchitosan chloride (TMC). Vascular endothelial growth factor (VEGF) was entrapped in the LMWH/TMC nanoparticles by affinity interactions with LMWH. PMID- 22941906 TI - Regulation of inflammatory responses in tumor necrosis factor-activated and rheumatoid arthritis synovial macrophages by JAK inhibitors. AB - OBJECTIVE: JAK inhibitors have been developed as antiinflammatory and immunosuppressive agents and are currently undergoing testing in clinical trials. The JAK inhibitors CP-690,550 (tofacitinib) and INCB018424 (ruxolitinib) have demonstrated clinical efficacy in rheumatoid arthritis (RA). However, the mechanisms that mediate the beneficial actions of these compounds are not known. The purpose of this study was to examine the effects of both JAK inhibitors on inflammatory and tumor necrosis factor (TNF) responses in human macrophages. METHODS: In vitro studies were performed using peripheral blood macrophages derived from healthy donors and treated with TNF and using synovial fluid macrophages derived from patients with RA. Levels of activated STAT proteins and other transcription factors were detected by Western blotting, and gene expression was measured by real-time polymerase chain reaction analysis. The in vivo effects of JAK inhibitors were evaluated in the K/BxN serum-transfer model of arthritis. RESULTS: JAK inhibitors suppressed the activation and expression of STAT-1 and downstream inflammatory target genes in TNF-stimulated and RA synovial macrophages. In addition, JAK inhibitors decreased nuclear localization of NF kappaB subunits in TNF-stimulated and RA synovial macrophages. CP-690,550 significantly decreased the expression of interleukin-6 in synovial macrophages. JAK inhibitors augmented nuclear levels of NF-ATc1 and cJun, followed by increased formation of osteoclast-like cells. CP-690,550 strongly suppressed K/BxN serum-transfer arthritis, which is dependent on macrophages, but not lymphocytes. CONCLUSION: Our findings demonstrate that JAK inhibitors suppress macrophage activation and attenuate TNF responses and further suggest that suppression of cytokine/chemokine production and innate immunity contribute to the therapeutic efficacy of JAK inhibitors. PMID- 22941908 TI - Regulating the regulators: serine/arginine-rich proteins under scrutiny. AB - Serine/arginine-rich (SR) proteins are among the most studied splicing regulators. They constitute a family of evolutionarily conserved proteins that, apart from their initially identified and deeply studied role in splicing regulation, have been implicated in genome stability, chromatin binding, transcription elongation, mRNA stability, mRNA export and mRNA translation. Remarkably, this list of SR protein activities seems far from complete, as unexpected functions keep being unraveled. An intriguing aspect that awaits further investigation is how the multiple tasks of SR proteins are concertedly regulated within mammalian cells. In this article, we first discuss recent findings regarding the regulation of SR protein expression, activity and accessibility. We dive into recent studies describing SR protein auto-regulatory feedback loops involving different molecular mechanisms such asunproductive splicing, microRNA-mediated regulation and translational repression. In addition, we take into account another step of regulation of SR proteins, presenting new findings about a variety of post-translational modifications by proteomics approaches and how some of these modifications can regulate SR protein sub cellular localization or stability. Towards the end, we focus in two recently revealed functions of SR proteins beyond mRNA biogenesis and metabolism, the regulation of micro-RNA processing and the regulation of small ubiquitin-like modifier (SUMO) conjugation. PMID- 22941909 TI - Introduction to: current aesthetic use of abobotulinumtoxinA in clinical practice: an evidence-based consensus review. PMID- 22941910 TI - Current aesthetic use of abobotulinumtoxinA in clinical practice: an evidence based consensus review. AB - The amount and complexity of scientific and clinical evidence for aesthetic use of botulinum neurotoxin type A (BoNT-A) has expanded rapidly in recent years, especially for abobotulinumtoxinA, necessitating reassessment of current knowledge about aesthetic use of abobotulinumtoxinA and other BoNT-A preparations. A committee of 13 plastic surgeons, facial plastic surgeons, and dermatologists engaged in a live discussion of information from a systematic literature review and an Internet-based survey of their beliefs and practices. The committee achieved consensus on most issues. It was concluded that doses of different BoNT-A preparations cannot be interconverted with a fixed ratio. The size of the "field of effect" is difficult to measure, and comparisons between preparations have yielded equivocal results. Nonresponse due to neutralizing antibodies appears exceedingly rare with currently available BoNT-A preparations and of little concern clinically. BoNT-A dose, injection depth, and injection technique should be adjusted according to the anatomic area being treated and each patient's individual characteristics and goals. Aesthetic use of BoNT-A has a good safety profile. Most adverse events are minor and related to the trauma of injection, although special care is needed in certain anatomic areas. Detailed recommendations for treatment of different anatomic areas are presented. BoNT-A products are often used in conjunction with other treatment modalities (eg, fillers and resurfacing), but little agreement was reached on best practices. The findings reported in this consensus document may serve as a practical guide for aesthetic practitioners as they apply the latest knowledge about BoNT-A in providing their patients with optimal care. PMID- 22941911 TI - Human saphenous vein endothelial cell adhesion and expansion on micropatterned polytetrafluoroethylene. AB - Intimal hyperplasia and thrombosis are responsible for the poor patency rates of small-diameter vascular grafts. These complications could be avoided by a rapid and strong adhesion of endothelial cells to the prosthetic surfaces, which typically consist of expanded polytetrafluoroethylene (PTFE) for small-diameter vessels. We have previously described two peptide micropatterning strategies that increase the endothelialization rates of PTFE. The micropatterns were generated either by inkjet printing 300 MUm squares or by spraying 10.1 +/- 0.1 MUm diameter droplets of the CGRGDS cell adhesion peptide, while the remaining surface was functionalized using the CWQPPRARI cell migration peptide. We now directly compare these two micropatterning strategies and examine the effect of hydrodynamic stress on human saphenous vein endothelial cells grown on the patterned surfaces. No significant differences in cell adhesion were observed between the two micropatterning methods. When compared to unpatterned surfaces treated with a uniform mixture of the two peptides, the cell expansion was significantly higher on sprayed or printed surfaces after 9 days of static cell culture. In addition, after 6 h of exposure to hydrodynamic stress, the cell retention and cell cytoskeleton reorganization on the patterned surfaces was improved when compared to untreated or random treated surfaces. These results indicate that micropatterned surfaces lead to improved rates of PTFE endothelialization with higher resistance to hydrodynamic stress. PMID- 22941912 TI - High resolution accurate mass screening of prohibited substances in equine plasma using liquid chromatography--Orbitrap mass spectrometry. AB - A recent trend in the use of high resolution accurate mass screening (HRAMS) for doping control testing in both human and animal sports has emerged due to significant improvement in high resolution mass spectrometry in terms of sensitivity, mass accuracy, mass resolution, and mass stability. A number of HRAMS methods have been reported for the detection of multi-drug residues in human or equine urine. As blood has become a common matrix for doping control analysis, especially in equine sports, a sensitive, fast and wide coverage screening method for detecting a large number of drugs in equine blood samples would be desirable. This paper presents the development of a liquid chromatography-high resolution mass spectrometry (LC-HRMS) screening method for equine plasma samples to cover over 320 prohibited substances in a single analytical run. Plasma samples were diluted and processed by solid-phase extraction. The extracts were then analyzed with LC-HRMS in full-scan positive electrospray ionization mode. A mass resolution of 60 000 was employed. Benzyldimethylphenylammonium was used as an internal lock mass. Drug targets were identified by retention time and accurate mass, with a mass tolerance window of +/-3 ppm. Over 320 drug targets could be detected in a 13-min run. Validation data including sensitivity, specificity, extraction recovery and precision are presented. As the method employs full-scan mass spectrometry, an unlimited number of drug targets can theoretically be incorporated. Moreover, the HRAMS data acquired can be re-processed retrospectively to search for drugs which have not been targeted at the time of analysis. PMID- 22941913 TI - Colony organization in the green alga Botryococcus braunii (Race B) is specified by a complex extracellular matrix. AB - Botryococcus braunii is a colonial green alga whose cells associate via a complex extracellular matrix (ECM) and produce prodigious amounts of liquid hydrocarbons that can be readily converted into conventional combustion engine fuels. We used quick-freeze deep-etch electron microscopy and biochemical/histochemical analysis to elucidate many new features of B. braunii cell/colony organization and composition. Intracellular lipid bodies associate with the chloroplast and endoplasmic reticulum (ER) but show no evidence of being secreted. The ER displays striking fenestrations and forms a continuous subcortical system in direct contact with the cell membrane. The ECM has three distinct components. (i) Each cell is surrounded by a fibrous beta-1, 4- and/or beta-1, 3-glucan containing cell wall. (ii) The intracolonial ECM space is filled with a cross linked hydrocarbon network permeated with liquid hydrocarbons. (iii) Colonies are enclosed in a retaining wall festooned with a fibrillar sheath dominated by arabinose-galactose polysaccharides, which sequesters ECM liquid hydrocarbons. Each cell apex associates with the retaining wall and contributes to its synthesis. Retaining-wall domains also form "drapes" between cells, with some folding in on themselves and penetrating the hydrocarbon interior of a mother colony, partitioning it into daughter colonies. We propose that retaining-wall components are synthesized in the apical Golgi apparatus, delivered to apical ER fenestrations, and assembled on the surfaces of apical cell walls, where a proteinaceous granular layer apparently participates in fibril morphogenesis. We further propose that hydrocarbons are produced by the nonapical ER, directly delivered to the contiguous cell membrane, and pass across the nonapical cell wall into the hydrocarbon-based ECM. PMID- 22941914 TI - Provision of an explanation for the inefficacy of immunotherapy in sporadic inclusion body myositis: quantitative assessment of inflammation and beta-amyloid in the muscle. AB - OBJECTIVE: In sporadic inclusion body myositis (IBM), inflammation and accumulation of beta-amyloid-associated molecules cause muscle fiber damage. We undertook this study to determine why intravenous immunoglobulin (IVIG) and prednisone are not effective in sporadic IBM despite their effectiveness in other inflammatory myopathies. METHODS: Relevant inflammatory and degeneration- associated markers were assessed by quantitative polymerase chain reaction and immunohistochemistry in repeated muscle biopsy specimens from patients with sporadic IBM treated in a controlled study with IVIG and prednisone (n = 5) or with prednisone alone (n = 5). Functional effects were assessed in a muscle cell culture model. RESULTS: In muscle biopsy specimens, messenger RNA (mRNA) expression of the proinflammatory chemokines CXCL9, CCL3, and CCL4 and of the cytokines interferon-gamma (IFNgamma), transforming growth factor beta, interleukin-10 (IL-10), and IL-1beta was significantly reduced after treatment in both groups. No consistent changes were observed for tumor necrosis factor alpha, IL-6, inducible costimulator (ICOS), its ligand ICOSL, and perforin. Messenger RNA expression of the degeneration-associated molecule ubiquitin and the heat shock protein alphaB-crystallin was also reduced, but no changes were noted for amyloid precursor protein (APP) or desmin. By immunohistochemistry, a significant down-modulation of chemokines was observed, but not of inducible nitric oxide (NO) synthase, nitrotyrosine, IL-1beta, APP, and ubiquitin; beta-amyloid was reduced in 6 of 10 patients. Pronounced staining of IgG was observed in the muscle after treatment with IVIG, indicating penetration of infused IgG into the muscle and a possible local effect. In muscle cells exposed to IFNgamma plus IL 1beta, IgG and/or prednisone down-regulated mRNA expression of IL-1beta 2.5-fold. Accumulation of beta-amyloid, overexpression of alphaB-crystallin, and cell death were prevented. In contrast, NO-associated cell stress remained unchanged. CONCLUSION: IVIG and prednisone reduce some inflammatory and degenerative molecules in muscle of patients with sporadic IBM and in vitro, but do not sufficiently suppress myotoxic and cell stress mediators such as NO. The data provide an explanation for the resistance of sporadic IBM to immunotherapy and identify markers that may help to design novel treatment strategies. PMID- 22941915 TI - Effect of surface reconstruction on the photoemission cross-section of the Au(111) surface state. AB - The photoemission cross-section of the Shockley surface state of Au(111) is studied over a wide range of photon energies both experimentally and theoretically. The measurements are fully understood based on the theoretical analysis within a one-step ab initio theory of photoemission. The constant initial state spectrum is shown to be very sensitive to the structure of the topmost atomic layer. A maximum in the constant initial spectrum at 60 eV is identified as a fingerprint of the Au(111) surface reconstruction. PMID- 22941917 TI - A novel type of crown ether-containing metal ions optical sensors based on polymer-stabilized cholesteric liquid crystalline films. AB - For the first time, the films based on polymer-stabilized cholesteric composites containing crown ether fragments with the optical properties sensitive to the complexation with potassium and barium ions were obtained. The complexation with these ions leads to blue spectral shift of the selective light reflection of planar cholesteric texture of composite films. Peculiarities of spectral changes and kinetics of selective light reflection shift were studied. The proposed approach can be used for the creation of the effective and selective sensor materials for different ions or groups of ions. PMID- 22941916 TI - Neuronal and extraneuronal release of ATP and NAD(+) in smooth muscle. AB - Adenosine 5'-triphosphate (ATP) and nicotinamide adenine dinucleotide (NAD(+) ) are key intracellular constituents involved in energy transfer and redox homeostasis in the cell. ATP is also released in the extracellular space and in the past half century it has been assumed to be the purinergic neurotransmitter in many systems including smooth muscle. In some smooth muscles (i.e., the human urinary bladder detrusor muscle), ATP does appear to be primarily released from nerves upon action potential firings, but in other smooth muscles (i.e., the human large intestine), ATP does not mimic the endogenous purine neurotransmitter. It was recently found that NAD(+) , another ubiquitous intracellular adenine nucleotide, also follows a regulated release in neurosecretory cells, vascular and visceral smooth muscles, and the brain. In some cases, NAD(+) fulfills presynaptic and postsynaptic criteria for a neurotransmitter better than ATP. Therefore, the purine hypothesis of neural regulation in smooth muscle is in need of reevaluation. This article will briefly review the current understanding of neuronal and extraneuronal release of purines in smooth muscle with emphasis on the roles of extracellular ATP and NAD(+) and, further, will discuss more recent information about the likely involvement of multiple purines in smooth muscle neurotransmission. PMID- 22941918 TI - Microstructure and in vitro degradation performance of Mg-Zn-Mn alloys for biomedical application. AB - Manganese and zinc were selected as alloying elements to develop a Mg-based ternary alloy for biomedical applications, taking into account the good biocompatibility of these metals. The microstructures of Mg-Zn-Mn alloys containing 0.5 or 1.0 mass% of manganese and 1.0 or 1.5 mass% of zinc were investigated by scanning electron microscopy coupled with energy dispersive X-ray spectroscopy. Their corrosion properties were assessed by means of potentiodynamic polarization and electrochemical impedance spectroscopy measurements performed in Ringer's physiological solution that simulates bodily fluids. All tested samples are two-phase alloys formed by a Mg-based matrix, consisting of a Mg-Zn-Mn solid solution, and a Mg-Zn binary phase. The electrochemical results show an improvement of the corrosion behavior of the investigated alloys with increasing Zn and Mn content. This is attributed to the formation of a partially protective Mg(OH)(2) surface film whose protective capabilities are increased by the alloying elements. The reduced influence of the Mg-Zn intermetallic compound on the corrosion rate of Mg-Zn-Mn alloys in the presence of a partially protective surface layer can be ascribed to an increasing resistance between the Mg-Zn-Mn solid solution and the second phase, thereby decreasing the effective driving force for microgalvanic corrosion. Owing to its highest corrosion protective ability, the Mg-1.5Zn-1Mn alloy is a promising candidate for the development of degradable implants, such as screws, plates, and rods. PMID- 22941920 TI - The political economy of publication: marketing, commodification, and qualitative scholarly work. AB - The globalized economy, fueled by late capitalism, has pressed forward its necessity for accumulation and expanding growth into the information and knowledge economy. One result has been the privatization of essentially public knowledge, knowledge produced at public universities, often with public, federal dollars. Both the "mania for ranking academic institutions," where universities compete for students, tuition dollars, and external funding, and the incessant creep of the managerial "audit culture" contribute to this situation. Although there is little individual scholars can do to resist globalization and capitalist forces, understanding the context into which their research is circulated can suggest opportunities for sharing research results between the "center" and "periphery" that counter some of the privatization trends. PMID- 22941919 TI - Improving client-centered brain injury rehabilitation through research-based theater. AB - Traumatic brain injury often results in physical, behavioral, and cognitive impairments perceived by health care practitioners to limit or exclude clients' full participation in treatment decision making. We used qualitative methods to evaluate the short- and long-term impact of "After the Crash: A Play About Brain Injury," a research-based drama designed to teach client-centered care principles to brain injury rehabilitation staff. We conducted interviews and observations with staff of two inpatient neurorehabilitation units in Ontario, Canada. Findings demonstrate the effectiveness of the play in influencing practice through the avoidance of medical jargon to improve clients' understanding and participation in treatment; newfound appreciation for clients' needs for emotional expression and sexual intimacy; increased involvement of family caregivers; and avoidance of staff discussions as if clients were unaware. These findings suggest that research-based drama can effect reflexivity, empathy, and practice change to facilitate a client-centered culture of practice in brain injury rehabilitation. PMID- 22941921 TI - Through a critical lens: indigenist research and the dadirri method. AB - Indigenous scholars have addressed the problematic nature of research by adopting methodologies that fit well with their communities and that relate effectively and culturally with how knowledge is shared to give indigenous people a voice. In this article we discuss Dadirri, an indigenous research method and way of life, as a vital research framework, connecting it to other relevant political and critical methodologies such as Freire's transformative education process and Habermas' theory of communicative action. In doing so, we illustrate how this methodology provides a significant framework for indigenous researchers undertaking liberatory studies that promote change. PMID- 22941922 TI - Serum hepatitis B surface antigen levels help predict disease progression in patients with low hepatitis B virus loads. AB - Chronic hepatitis B patients with high viral loads are at increased risk of cirrhosis and hepatocellular carcinoma (HCC). In patients with low viral loads, higher hepatitis B surface antigen (HBsAg) levels have been shown to predict HCC development. However, little is known about the difference in risk for other hepatitis B virus (HBV)-related adverse outcomes with varying HBsAg levels. A total of 1,068 Taiwanese hepatitis B e antigen (HBeAg)-negative HBV carriers with serum HBV DNA level <2,000 IU/mL at baseline were followed for a mean duration of 13.0 years. Patients were categorized based on their HBsAg levels, and the relationships between HBsAg level and development of HBeAg-negative hepatitis, hepatitis flare, and cirrhosis were investigated. Of the 1068 patients with low viral loads, 280 developed HBeAg-negative hepatitis, with an annual incidence rate of 2.0%. HBsAg level, but not HBV DNA level, was found to be a risk factor for HBeAg-negative hepatitis. Multivariate analysis showed that the adjusted hazard ratio in patients with an HBsAg level >= 1,000 versus <1000 IU/mL was 1.5 (95% confidence interval, 1.2-1.9). The positive correlation was present when evaluating other endpoints, including hepatitis flare and cirrhosis, and remained consistent when the study population was restricted to those with normal alanine aminotransferase (ALT) level at baseline. The annual incidence rate of HBeAg negative hepatitis was lowered to 1.1% in patients with low levels of HBV DNA, HBsAg, and ALT. CONCLUSION: In HBeAg-negative patients with low viral loads and genotype B or C virus infection, a higher HBsAg level can predict disease progression. HBsAg <1,000 IU/mL in combination with low levels of HBV DNA and ALT help define minimal-risk HBV carriers. PMID- 22941923 TI - Effects of temporally varying inlet conditions on flow and particle deposition in the small bronchial tubes. AB - The laminar flow in the small bronchial tubes is quite complex because of the presence of vortex-dominated, secondary flows. Factors contributing to this complexity are the unsteady nature of the inhale-exhale breathing cycle and the geometrical characteristics of the bronchial tubes. To investigate unsteady effects on flows and particle transport, unsteady inhalation flows at a 30 respiration-per-minute frequency, corresponding to a moderate activity level, were simulated for a three-generation, asymmetric, planar bronchial tube model. Ten-micron diameter water droplets were introduced at the inlet at different times during inhalation to develop particle destination maps. The differences in the flow fields and destination maps obtained at the unsteady peak flow and the comparable steady-state inflow condition were minimal. However, particles released at equivalent instantaneous off-peak inflow conditions produced different destination maps. The differences were attributed to the temporal variations of the fluid velocities and history effects. PMID- 22941924 TI - A robust and efficient valve model based on resistive immersed surfaces. AB - A procedure for modeling the heart valves is presented. Instead of modeling complete leaflet motion, leaflets are modeled in open and closed configurations. The geometry of each configuration can be defined, for example, from in vivo image data. This method enables significant computational savings compared with complete fluid-structure interaction and contact modeling, while maintaining realistic three-dimensional velocity and pressure distributions near the valve, which is not possible from lumped parameter modeling. Leaflets are modeled as immersed, fixed surfaces over which a resistance to flow is assigned. On the basis of local flow conditions, the resistance values assigned for each configuration are changed to switch the valve between open and closed states. This formulation allows for the pressure to be discontinuous across the valve. To illustrate the versatility of the model, realistic and patient-specific simulations are presented, as well as comparison with complete fluid-structure interaction simulation. PMID- 22941925 TI - Reduction of the chemical master equation for gene regulatory networks using proper generalized decompositions. AB - The numerical solution of the chemical master equation (CME) governing gene regulatory networks and cell signaling processes remains a challenging task owing to its complexity, exponentially growing with the number of species involved. Although most of the existing techniques rely on the use of Monte Carlo-like techniques, we present here a new technique based on the approximation of the unknown variable (the probability of having a particular chemical state) in terms of a finite sum of separable functions. In this framework, the complexity of the CME grows only linearly with the number of state space dimensions. This technique generalizes the so-called Hartree approximation, by using terms as needed in the finite sums decomposition for ensuring convergence. But noteworthy, the ease of the approximation allows for an easy treatment of unknown parameters (as is frequently the case when modeling gene regulatory networks, for instance). These unknown parameters can be considered as new space dimensions. In this way, the proposed method provides solutions for any value of the unknown parameters (within some interval of arbitrary size) in one execution of the program. PMID- 22941926 TI - Analysis of micro fracture in human Haversian cortical bone under compression. AB - A procedure to investigate local stress intensity factors in human Haversian cortical bone under compression is presented. The method combines a customised experimental setting for micro-compression tests of millimetric bone specimens and a finite element contact model conforming to the bone morphology that tracks advancing microcracks. The non-interpenetration conditions along the crack edges are ensured by penalty constraints of which the parameters are optimised for minimum contact pressure error with respect to the crack orientations. A cohesive crack opening law is implemented in the wake of the crack tips to remain consistent with the progressive tearing of collagen fibrils. The displacement solution is searched by a Newton-Raphson scheme containing a double loop first on the displacements and second on the frictional contact and cohesive condition updates at the crack interfaces. The experimental Dirichlet boundary conditions are acquired by digital image cross-correlation of bone light microscopy observations and then imported into the model. The local mechanical elastic moduli are measured by nanoindentation and microextensometry. The comparison of the macroscopic stress-strain numerical response with the experiment reveals the existence of narrow diffuse damaged zones near the major cracks where the local stress intensity factors can be calculated. PMID- 22941928 TI - The temperature dependence of Cu2O formation on a Cu(110) surface with an energetic O2 molecular beam. AB - We report a study of the surface temperature (T(s)) dependence of Cu(2)O formation on a Cu(110) surface induced by a hyperthermal O(2) molecular beam (HOMB), using x-ray photoemission spectroscopy in conjunction with synchrotron radiation. From the T(s) dependence of the O uptake curves, the direct dissociative adsorption process mainly contributes to the formation of the p(2 * 1)-O structure with an O coverage (Theta) of 0.5 ML for 2.2 eV HOMB incidence. On the other hand, the rate of oxidation at Theta > 0.5 ML, particularly in Cu(2)O formation, strongly depends on the T(s). Thicker Cu(2)O islands were found inhomogeneously at 400 and 500 K, suggesting the dominant role of the migration of Cu atoms in the Cu(2)O formations on the Cu(110) surface. PMID- 22941930 TI - Clinical outcomes of endoscopic mucosal resection and endoscopic submucosal dissection as a transoral treatment for superficial pharyngeal cancer. AB - BACKGROUND: Endoscopic mucosal resection (EMR) and endoscopic submucosal dissection (ESD) have been introduced for the treatment of superficial pharyngeal cancer. METHODS: Sixty superficial pharyngeal cancers in 45 patients were treated by EMR or ESD. Resectability and curability, complications, and survival were analyzed retrospectively. RESULTS: The en bloc resection and curative resection rate were higher with ESD (100; 81.6%) than with EMR (59; 50%). In subgroup analysis with regard to tumor size <= 10 mm, both resection rates were comparative. All the patients had preserved larynx and swallowing, speech, and airway function. Two of the 45 patients died of other diseases, local recurrence was observed in 4 of 18 patients with noncurative resection with a median observation period of 38 months. No recurrence was observed in patients with curative resection. CONCLUSIONS: ESD or EMR for superficial pharyngeal cancer is minimally invasive treatment and lesions larger than 10 mm should be referred for ESD. PMID- 22941931 TI - Characterization of protein rheology and delivery forces for combination products. AB - Characterization of a protein-device combination product over a wide range of operating parameters defined by end-user requirements is critical for developing a product presentation that is convenient for patient use. In addition to the device components, several product attributes, such as product rheology and product-container interactions, govern the functionality of a delivery system. This article presents results from a characterization study conducted for a high concentration antibody product in a prefilled syringe. Analytical models are used to study the rheological behavior and to estimate delivery forces over a broad design space comprising temperature, concentration, and shear stress. Data suggest that high-viscosity products may exhibit significant shear thinning under the shear rates encountered under desired injection times. PMID- 22941932 TI - Nucleation and growth of apatite on an anatase layer irradiated with UV light under different environmental conditions. AB - Implant surfaces must sometimes be modified to form strong bonds to host tissues. The method of depositing an anatase layer on chemically pure titanium by chemical oxidation with H(2)O(2) and subsequent calcination (CHT) is known to deposit apatite under physiological conditions; it thus exhibits bone-bonding ability. UV irradiation should affect the bonding ability because the CHT anatase layer would experience certain chemical modifications, such as a decrease or an increase in the number of Ti-OH and Ti-O(H)-Ti sites; these sites are considered active sites for apatite nucleation. When in vitro apatite deposition was examined, using Kokubo's simulated body fluid, UV irradiation in air reduced the apatite-forming ability of the CHT anatase layer, and UV irradiation on the samples in water enhanced the ability. These results were correlated to changes in the Ti-OH and Ti-O(H)-Ti sites, as determined by O 1s X-ray photoelectron spectroscopy. Analysis of the number and size of the semi-spherical apatite particles and their surface coverage led to a model: proper assembly of the Ti-OH and Ti-O(H)-Ti sites should only give rise to the induction of apatite nucleation, analogous to topotaxy effects. PMID- 22941933 TI - Cleavage of the BRCT tandem domains of nibrin by the 657del5 mutation affects the DNA damage response less than the Arg215Trp mutation. AB - The Nijmegen breakage syndrome (NBS) is a genetic disorder caused by mutations in NBN gene and characterized by chromosomal instability and hypersensitivity to ionizing radiations (IR). The N-terminus of nibrin (NBN) contains a tandem breast cancer 1 (BRCA1) carboxy-terminal (BRCT) domain that represents one of the major mediators of phosphorylation-dependent protein-protein interactions in processes related to cell cycle checkpoint and DNA repair functions. Patients with NBS compound heterozygous for the 657del5 hypomorphic mutation and for the Arg215Trp missense mutation (corresponding to the 643C>T gene mutation) display a clinical phenotype more severe than that of patients homozygous for the 657del5 mutation. Here, we show that both the 657del5 and Arg215Trp mutations, occurring within the tandem BRCT domains of NBN, although not altering the assembly of the MRE11/RAD50/NBN (MRN) complex, affect the MRE11 IR-induced nuclear foci (IRIF) formation and the DNA double-strand break (DSB) signaling via the phosphorylation of both ataxia-telangiectasia-mutated (ATM) kinase and ATM downstream targets (e.g., SMC1 and p53). Remarkably, data obtained indicate that the cleavage of the BRCT tandem domains of NBN by the 657del5 mutation affects the DNA damage response less than the Arg215Trp mutation. Indeed, the 70-kDa NBN fragment, arising from the 657del5 mutation, maintains the capability to interact with MRE11 and gamma-H2AX and to form IRIF. Altogether, the role of the tandem BRCT domains of NBN in the localization of the MRN complex at the DNA DSB and in the activation of the damage response is highlighted. PMID- 22941934 TI - Surgical margins in head and neck cancer: a contemporary review. AB - Adequate resection margins are critical to the treatment decisions and prognosis of patients with head and neck squamous cell carcinoma (HNSCC). However, there are numerous controversies regarding reporting and interpretation of the status of resection margins. Fundamental issues relating to the basic definition of margin adequacy, uniform reporting standards for margins, optimal method of specimen dissection, and the role of intraoperative frozen section evaluation, all require further clarification and standardization. Future horizons for margin surveillance offer the possible use of novel methods such as "molecular margins" and contact microscopic endoscopy, However, the limitations of these approaches need to be understood. The goal of this review was to evaluate these issues to define a more rational, standardized approach for achieving resection margin adequacy for patients with HNSCC undergoing curative resection. PMID- 22941935 TI - Beta-catenin-NF-kappaB interactions in murine hepatocytes: a complex to die for. AB - Wnt/beta-catenin signaling plays an important role in hepatic homeostasis, especially in liver development, regeneration, and cancer, and loss of beta catenin signaling is often associated with increased apoptosis. To elucidate how beta-catenin may be regulating hepatocyte survival, we investigated the susceptibility of beta-catenin conditional knockout (KO) mice and their wild-type (WT) littermates to Fas and tumor necrosis factor-alpha (TNF-alpha), two common pathways of hepatocyte apoptosis. While comparable detrimental effects from Fas activation were observed in WT and KO, a paradoxical survival benefit was observed in KO mice challenged with D-galactosamine/lipopolysaccharide. KO mice showed significantly lower morbidity and liver injury due to early, robust, and protracted activation of NF-kappaB in the absence of beta-catenin. Enhanced NF kappaB activation in KO mice was associated with increased basal inflammation and Toll-like receptor 4 expression and lack of the p65/beta-catenin complex in hepatocytes. The p65/beta-catenin complex in WT livers underwent temporal dissociation allowing for NF-kappaB activation to regulate hepatocyte survival following TNF-alpha-induced hepatic injury. Decrease of total beta-catenin protein but not its inactivation induced p65 activity, whereas beta-catenin stabilization either chemically or due to mutations repressed it in hepatomas in a dose-dependent manner, whereas beta-catenin stabilization repressed it either chemically or due to mutations. CONCLUSION: The p65/beta-catenin complex in hepatocytes undergoes dynamic changes during TNF-alpha-induced hepatic injury and plays a critical role in NF-kappaB activation and cell survival. Modulation of beta-catenin levels is a unique mode of regulating NF-kappaB activity and thus may present novel opportunities in devising therapeutics in specific hepatic injuries. PMID- 22941937 TI - Organ doses from environmental exposures calculated using voxel phantoms of adults and children. AB - This paper presents effective and organ dose conversion coefficients for members of the public due to environmental external exposures, calculated using the ICRP adult male and female reference computational phantoms as well as voxel phantoms of a baby, two children and four adult individual phantoms--one male and three female, one of them pregnant. Dose conversion coefficients are given for source geometries representing environmental radiation exposures, i.e. whole body irradiations from a volume source in air, representing a radioactive cloud, a plane source in the ground at a depth of 0.5 g cm-2, representing ground contamination by radioactive fall-out, and uniformly distributed natural sources in the ground. The organ dose conversion coefficients were calculated employing the Monte Carlo code EGSnrc simulating the photon transport in the voxel phantoms, and are given as effective and equivalent doses normalized to air kerma free-in-air at height 1 m above the ground in Sv Gy(-1). The findings showed that, in general, the smaller the body mass of the phantom, the higher the dose. The difference in effective dose between an adult and an infant is 80-90% at 50 keV and less than 40% above 100 keV. Furthermore, dose equivalent rates for photon exposures of several radionuclides for the above environmental exposures were calculated with the most recent nuclear decay data. Data are shown for effective dose, thyroid, colon and red bone marrow. The results are expected to facilitate regulation of exposure to radiation, relating activities of radionuclides distributed in air and ground to dose of the public due to external radiation as well as the investigation of the radiological effects of major radiation accidents such as the recent one in Fukushima and the decision making of several committees. PMID- 22941936 TI - Differences in body composition and metabolic status between white U.K. and Asian Indian children (EarlyBird 24 and the Pune Maternal Nutrition Study). AB - BACKGROUND/AIMS: The concept of the 'thin-fat' Indian baby is well established, but there is little comparative data in older children, and none that examines the metabolic correlates. Accordingly, we investigated the impact of body composition on the metabolic profiles of Asian Indian and white U.K. children. METHODS: Body mass index (BMI), waist circumference, sum of four skin-folds, % body fat (by dual-energy X-ray absorptiometry), glucose, insulin, insulin resistance (Homeostasis Model Assessment), trigylcerides, cholesterol [total, low density lipoprotein, high-density lipoprotein {HDL}, total/HDL ratio] and blood pressure (systolic, diastolic and mean arterial) were measured in 262 white Caucasian children from Plymouth, U.K. (aged 6.9 +/- 0.2 years, 57% male), and 626 Indian children from rural villages around Pune, India (aged 6.2 +/- 0.1 years, 53% male). RESULTS: Indian children had a significantly lower BMI (boys: 2.1 kg m(-2) , girls: -3.2 kg m(-2) , both P < 0.001), waist circumference (P < 0.001) and skin-fold thickness (P < 0.001) than white U.K. children, yet their % body fat was higher (boys +4.5%, P < 0.001, girls: +0.5%, P = 0.61). Independently of the differences in age and % body fat, the Indian children had higher fasting glucose (boys +0.52 mmol L(-1) , girls +0.39 mmol L(-1) , both P < 0.001), higher insulin (boys +1.69, girls +1.87 mU L(-1) , both P < 0.01) and were more insulin resistant (boys +0.25, girls +0.28 HOMA-IR units, both P < 0.001). CONCLUSIONS: The 'thin-fat' phenotype observed in Indian babies is also apparent in pre-pubertal Indian children who have greater adiposity than white U.K. children despite significantly lower BMIs. Indian children are more insulin resistant than white U.K. children, even after adjustment for adiposity. PMID- 22941938 TI - Modular polylactic acid microparticle-based scaffolds prepared via microfluidic emulsion/solvent displacement process: fabrication, characterization, and in vitro mesenchymal stem cells interaction study. AB - The present study reports a novel approach for the design and fabrication of polylactic acid (PLA) microparticle-based scaffolds with microstructural properties suitable for bone and cartilage regeneration. Macroporous PLA scaffolds with controlled shape were fabricated by means of a semicontinuous process involving (1) microfluidic emulsification of a PLA/ethyl lactate solution (5% w/v) in a span 80/paraffin oil solution (3% v/v) followed by (2) particles coagulation/assembly in an acetone/water solution for the development of a continuous matrix. Porous scaffolds prepared from particles with monomodal or bimodal size distribution, overall porosity ranges from 93 to 96%, interparticles porosity from 41 to 54%, and static compression moduli from 0.3 to 1.4 MPa were manufactured by means of flow rate modulation of of the continuous phase during emulsion. The biological response of the scaffolds was assessed in vitro by using bone marrow-derived rat mesenchymal stem cells (MSCs). The results demonstrated the ability of the scaffolds to support the extensive and uniform three dimensional adhesion, colonization, and proliferation of MSCs within the entire construct. PMID- 22941939 TI - Therapeutic drug monitoring in interstitial fluid: a feasibility study using a comprehensive panel of drugs. AB - This study compared drug concentration-time profiles in interstitial fluid (ISF) and blood, using an established animal model and a comprehensive panel of drugs, to examine the feasibility of therapeutic drug monitoring (TDM) in ISF. An intravenous bolus of vancomycin, gentamicin, tacrolimus, cyclosporine, mycophenolate, valproic acid, phenobarbital, phenytoin, carboplatin, cisplatin, methotrexate, theophylline, or digoxin was administered into the ear vein (n = 4 6) of rabbits. Serial (0-72 h after dose) blood and ISF concentrations (collected via an ultrafiltration probe) were determined by validated analytical assays. Pharmacokinetic parameters were generated by noncompartmental analysis. Vancomycin, gentamicin, and carboplatin showed no significant difference in area under the curve (AUC) values in ISF and blood, respectively. Other AUCs were lower (mycophenolic acid, valproic acid, phenobarbital, cisplatin, methotrexate, theophylline, and digoxin) or not measurable (tacrolimus, cyclosporine, and phenytoin) in ISF with our extraction technique. Similar concentration-time profiles in the two matrices were evident for a selection of drugs tested. Using a comprehensive panel of drugs in a single experimental setting, we have identified agents that can be quantified in ISF. Our newly developed scoring algorithm can help determine the feasibility of conducting TDM in ISF. PMID- 22941940 TI - A role for hepatic leptin signaling in lipid metabolism via altered very low density lipoprotein composition and liver lipase activity in mice. AB - Obesity is highly associated with dyslipidemia and cardiovascular disease. However, the mechanism behind this association is not completely understood. The hormone leptin may be a molecular link between obesity and dysregulation of lipid metabolism. Leptin can affect lipid metabolism independent of its well-known effects on food intake and energy expenditure, but exactly how this occurs is ill defined. We hypothesized that since leptin receptors are found on the liver and the liver plays an integral role in regulating lipid metabolism, leptin may affect lipid metabolism by acting directly on the liver. To test this hypothesis, we generated mice with a hepatocyte-specific loss of leptin signaling. We previously showed that these mice have increased insulin sensitivity and elevated levels of liver triglycerides compared with controls. Here, we show that mice lacking hepatic leptin signaling have decreased levels of plasma apolipoprotein B yet increased levels of very low density lipoprotein (VLDL) triglycerides, suggesting alterations in triglyceride incorporation into VLDL or abnormal lipoprotein remodeling in the plasma. Indeed, lipoprotein profiles revealed larger apolipoprotein B-containing lipoprotein particles in mice with ablated liver leptin signaling. Loss of leptin signaling in the liver was also associated with a substantial increase in lipoprotein lipase activity in the liver, which may have contributed to increased lipid droplets in the liver. CONCLUSION: Lack of hepatic leptin signaling results in increased lipid accumulation in the liver and larger, more triglyceride-rich VLDL particles. Collectively, these data reveal an interesting role for hepatic leptin signaling in modulating triglyceride metabolism. PMID- 22941941 TI - Reproducibility of 1H MR spectroscopy of hip bone marrow at 3 Tesla. AB - PURPOSE: To assess the reproducibility of fat content (FC) values in five different anatomical areas of proximal femur by the means of (1)H 3 Tesla MR spectroscopy and to evaluate if any statistical difference exists when comparing right side to left side FC values in the same individual. MATERIALS AND METHODS: Thirty-three volunteers underwent unilateral (1)H MR spectroscopy of the hip. From 1 to 4 weeks later, they repeat the MR examination of the same hip to assess the reproducibility of the technique. Fifteen other volunteers underwent a bilateral (1)H MR hip spectroscopy to compare right and left side FC values. RESULTS: The reproducibility of (1)H MR spectroscopy was high in all the anatomic areas considered, ranging from 0.90 to 0.98. No statistically significant difference was found when the fat content values on the right side were compared to those on the left side. (P > 0.16). CONCLUSION: The 3 Tesla (1)H MR spectroscopy of hip bone marrow permitted highly reproducible fat content values in all the five anatomic areas examined. No statistical significant difference existed when comparing fat content values of the right side to those of the left side in the same individual. PMID- 22941942 TI - Molecular analysis of cell type-specific gene expression profile during mouse spermatogenesis by laser microdissection and qRT-PCR. AB - Laser microdissection (LMD) is a selective cell isolation technique that enables the separation of desired homogenous cell subpopulations from complex tissues such as the testes under direct microscopic visualization. The LMD accompanied by quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) represents an indispensable tool in quantifying messenger RNA (mRNA) expression among defined cell populations. Gene expression is temporally and spatially regulated at 3 sequential phases of mitotic, meiotic, and postmeiotic stages of spermatogenesis. The present study demonstrates a short modified LMD protocol based upon hematoxylin and eosin (H&E) staining. Stage-specific LMD success was validated by the use of mRNA profiling of "marker genes" which are conserved across species and are known to be differentially expressed during spermatogenesis. Magea4, Hspa2, Cox6b2, Tnp1, Prm1, and Prm2 are used to differentiate among the microdissected cell populations, namely spermatogonia (group I), spermatocytes (group II), round and condensing spermatids (group III), and elongated and condensed spermatids (group IV), respectively. The LMD combined with qRT-PCR is further extended to assess the cell stage-specific distribution of selected stress response genes such as Hsp90aa1, Gpx4, Ucp2, Sod1, and Sod2. The germ cell-specific mRNA profiles are suitably complemented by Western blot of the LMD samples, immunohistochemistry, and confocal localization of the corresponding proteins. The current study suggests that LMD can successfully isolate cell subpopulations from the complex tissues of the testes; and establish cell stage-specific basal expression patterns of selected stress response genes and proteins. It is our hypothesis that the baseline expression of stress response genes will differ by cell stage to create discrete stage-specific vulnerabilities to reproductive toxicants. PMID- 22941943 TI - Diffeomorphic susceptibility artifact correction of diffusion-weighted magnetic resonance images. AB - Diffusion-weighted magnetic resonance imaging is a key investigation technique in modern neuroscience. In clinical settings, diffusion-weighted imaging and its extension to diffusion tensor imaging (DTI) are usually performed applying the technique of echo-planar imaging (EPI). EPI is the commonly available ultrafast acquisition technique for single-shot acquisition with spatial encoding in a Cartesian system. A drawback of these sequences is their high sensitivity against small perturbations of the magnetic field, caused, e.g., by differences in magnetic susceptibility of soft tissue, bone and air. The resulting magnetic field inhomogeneities thus cause geometrical distortions and intensity modulations in diffusion-weighted images. This complicates the fusion with anatomical T1- or T2-weighted MR images obtained with conventional spin- or gradient-echo images and negligible distortion. In order to limit the degradation of diffusion-weighted MR data, we present here a variational approach based on a reference scan pair with reversed polarity of the phase- and frequency-encoding gradients and hence reversed distortion. The key novelty is a tailored nonlinear regularization functional to obtain smooth and diffeomorphic transformations. We incorporate the physical distortion model into a variational image registration framework and derive an accurate and fast correction algorithm. We evaluate the applicability of our approach to distorted DTI brain scans of six healthy volunteers. For all datasets, the automatic correction algorithm considerably reduced the image degradation. We show that, after correction, fusion with T1- or T2-weighted images can be obtained by a simple rigid registration. Furthermore, we demonstrate the improvement due to the novel regularization scheme. Most importantly, we show that it provides meaningful, i.e. diffeomorphic, geometric transformations, independent of the actual choice of the regularization parameters. PMID- 22941945 TI - Challenging the dogmas; the NAC tie. PMID- 22941944 TI - AF03, an alternative squalene emulsion-based vaccine adjuvant prepared by a phase inversion temperature method. AB - AF03 is a squalene-based emulsion adjuvant that is present in the adjuvanted pandemic influenza vaccine, HumenzaTM. In this report, we describe the design and development of this novel adjuvant formulation from the selection of the oil and surfactant system used in the adjuvant composition to the phase inversion temperature emulsification process that afforded AF03 as a long-term stable and well calibrated oil-in-water emulsion. The emulsion was characterized by its particle sizes, surface and interfacial tensions, viscosity, and long-term stability. PMID- 22941946 TI - Wear particles promote endotoxin tolerance in macrophages by inducing interleukin 1 receptor-associated kinase-M expression. AB - Toll-like receptors (TLRs) recognizing pathogen-associated molecular patterns (PAMP) play a role in local immunity and participate in implant-associated loosening. TLRs-mediated signaling is regulated by interleukin-1 receptor associated kinase-M (IRAK-M). Our previous studies have proved that IRAK-M is induced by wear particles in macrophages from periprosthetic tissues. In this study, the IRAK-M-related mechanisms were further explored by lipopolysaccharide (LPS) and/or titanium (Ti) particles stimulations and small interfering RNAs (siRNAs). The protein level of IRAK-M was studied using western blotting and tumor necrosis factor-alpha (TNF-alpha), and interleukin-1beta (IL-1beta) levels were measured using ELISA. Results showed that in RAW264.7 cells stimulated by LPS after Ti particle pre-exposure, IRAK-M was slightly changed, compared with LPS stimulation. And levels of TNF-alpha and IL-1beta in cultures stimulated by LPS first after Ti particle pre-exposure were lower than in the other two groups which were stimulated by LPS with or without Ti particles (p < 0.001), whereas there were no statistic differences between the later two (p > 0.05). The cytokines were lowest in Ti particles alone stimulation. After siRNAs silenced, IRAK-M-deficient cells exhibited increased expression of the cytokines in LPS stimulation after Ti particle pre-exposure and when stimulated with Ti particles alone. Our findings suggest that debris-induced IRAK-M decreases foreign body reactions, but at the same time, the over-expression of IRAK-M may also be detrimental on local intrusion of PAMPs or bacteria, negatively regulates the LPS induced and TLRs-mediated inflammation and results in immunosuppression in periprosthetic tissue, which may predispose to implant-associated infections. PMID- 22941947 TI - TAK1, more than just innate immunity. AB - Transforming growth factor beta-activated kinase 1 (TAK1) is a key regulator of the innate immunity and the proinflammatory signaling pathway. In response to interleukin-1, tumor necrosis factor-alpha, and toll-like receptor agonists, it mediates the activation of the nuclear factor kappaB (NF-kappaB), c-Jun N terminal kinase (JNK), and p38 pathways. In addition, TAK1 plays a central role in adaptive immunity, in which it mediates signaling from T- and B-cell receptors. This review will focus on recent developments and also examine the regulation of TAK1 in response to a diverse range of other stimuli including DNA damage, transforming growth factor-beta, Wnt, osmotic stress, and hypoxia. PMID- 22941948 TI - Defining hyponatraemia: a call for action. PMID- 22941949 TI - Mechanical stretch via transforming growth factor-beta1 activates microRNA208a to regulate endoglin expression in cultured rat cardiac myoblasts. AB - AIMS: MicroRNAs (miRNAs) play a role in cardiac remodelling. MiR208a is essential for the expression of the genes involved in cardiac hypertrophy and fibrosis. The mechanism of regulation of miR208a involved in cardiac hypertrophy by mechanical stress is still unclear. We sought to investigate the mechanism of regulation of miR208a and the target gene of miR208a in cardiac cells by mechanical stretch. METHODS AND RESULTS: Rat H9c2 cells (cardiac myoblasts) grown on a flexible membrane base were stretched via vacuum to 20% of maximum elongation at 60 cycles/min. Mechanical stretch significantly enhanced miR208a expression after 4 h of stretch. Exogenous addition of transforming growth factor-beta1 (TGF-beta1) increased miR208a expression, and pre-treatment with TGF-beta1 antibody attenuated the miR208a expression induced by stretch. Mechanical stretch significantly increased endoglin and collagen I expression for 6-24 h. Exogenous addition of TGF-beta1 and overexpression of miR208a up-regulated endoglin and collagen I expression, while antagomir208a and Smad3/4 inhibitor attenuated endoglin and collagen I expression induced by stretch. Mechanical stretch and TGF beta1 increased Smad3/4-DNA binding activity and miR208a promoter activity, and TGF-beta1 antibody and Smad3/4 inhibitor decreased the Smad3/4-DNA binding activity and miR208a promoter activity induced by stretch. CONCLUSION: Cyclic mechanical stretch enhances miR208a expression in cultured rat cardiac myoblasts. The stretch-induced miR208a is mediated by TGF-beta1. Mir208a activates endoglin expression and may result in cardiac fibrosis. PMID- 22941950 TI - Increasing association between a neuropeptide Y promoter polymorphism and body mass index during the course of development. AB - OBJECTIVE: To investigate the association of the neuropeptide Y (NPY) promoter polymorphism rs16147 with body mass index (BMI) during the course of development from infancy to adulthood. DESIGN: Longitudinal, prospective study of a German community sample. SUBJECTS: n = 306 young adults (139 males, 167 females). MEASUREMENTS: Participants' body weight and height were assessed at the ages of 3 months and 2, 4.5, 8, 11, 15 and 19 years. NPY rs16147 was genotyped. RESULTS: Controlling for a number of possible confounders, homozygote carriers of the rs16147 C allele exhibited significantly lower BMI scores when compared with individuals carrying the T allele. In addition, a significant genotype by age interaction emerged, indicating that the genotype effect increased during the course of development. CONCLUSIONS: This is the first longitudinal study to report an association between rs16147 and BMI during childhood and adolescence. The finding that this effect increased during the course of development may either be due to age-dependent alterations in gene expression or to maturation processes within the weight regulation circuits of the central nervous system. PMID- 22941951 TI - Use of conventional MR imaging and diffusion-weighted imaging for evaluating the risk grade of gastrointestinal stromal tumors. AB - PURPOSE: To study the risk grade of gastrointestinal stromal tumors (GISTs) with conventional MR imaging and diffusion-weighted imaging (DWI). MATERIALS AND METHODS: The abdominal MR images with DWI of 23 patients with pathologically proven GISTs during January 2010 to May 2011 were retrospectively reviewed. The conventional MR imaging findings and apparent diffusion coefficient (ADC) values of the tumors related to the risk grade were analyzed. RESULTS: In the 23 patients, there were 13 patients with high-risk, 5 with medium-risk, 5 with low risk, and 0 with very low-risk GISTs. Most of the conventional MR findings of the tumors did not correlate with the risk grade. The only exception to this was the correlation between risk grade and the enhancement degree of the tumor after Gd DTPA. The ADC values were, respectively, (1.04 +/- 0.13) * 10(-3) mm(2) .s(-1) , (1.59 +/- 0.06) * 10(-3) mm(2) .s(-1) and (1.94 +/- 0.08) * 10(-3) mm(2) .s(-1) (P < 0.05) in the high-, medium-, and low-risk grade groups. The ADC values of GISTs decreased with the increase of the risk grade of the tumors (r = -0.957; P < 0.05). CONCLUSION: DWI can be used to assess the risk grade of GISTs, but conventional MR imaging is of limited use. PMID- 22941952 TI - Subscapularis tendon tears: a common sonographic finding in symptomatic postarthroplasty shoulders. AB - PURPOSE: Subscapularis tendon tears can complicate shoulder arthroplasty because the subscapularis tendon is typically divided surgically to gain access to the joint. The purpose of this study is to document the prevalence of subscapularis tears on sonography of symptomatic postarthroplasty shoulders. METHODS: We retrospectively reviewed official reports of shoulder sonograms performed over an 11-year period by one experienced radiologist. Sonographic findings in 112 (mean age, 61.7 years; age range, 38-87 years; 40% female) symptomatic patients who had undergone either total shoulder arthroplasty or hemiarthroplasty were compared with findings in both a symptomatic control group consisting of 209 patients (mean age, 55.2 years; age range, 32-79 years; 37% female) who had undergone surgery for rotator cuff repair but no arthroplasty, and an asymptomatic control group consisting of 11 (mean age, 66 years; age range, 61-77 years; 45% female) volunteers who had shoulder arthroplasty but were without complaints. RESULTS: The prevalence of subscapularis tears in arthroplasty patients (51%, 57/112) was higher (p < 0.0001) than that of rotator cuff repair patients (16%, 33/209). In the asymptomatic volunteers, subscapularis tears (9%, 1/11) were less common (p < 0.01) than in the symptomatic patients. CONCLUSIONS: Subscapularis tendon tears are a common sonographic finding in symptomatic postarthroplasty shoulders. PMID- 22941953 TI - Dopamine-assisted immobilization of hydroxyapatite nanoparticles and RGD peptides to improve the osteoconductivity of titanium. AB - Hydroxyapatite (HAp) coating on orthopedic implants is a common strategy to increase osteointegration. In this work, a facile deposition method based on dopamine polymerization was developed for preparation of HAp-coated titanium substrates for orthopedic applications. Nanostructured HAp was mixed with an alkaline dopamine solution and then deposited onto titanium to form a dopamine/HAp ad-layer. The deposition of dopamine/HAp greatly enhanced the adhesion, proliferation, and mineralization of osteoblasts. Furthermore, RGD containing peptides were immobilized to dopamine/HAp coated titanium and further enhanced cell adhesion and osteogenic differentiation. In conclusion, this facile dopamine-assisted surface modification method shows a great potential for orthopedic and dental applications. PMID- 22941954 TI - Enemy or partner: relationship between intronic micrornas and their host genes. AB - In the past several years, microRNAs have been identified as a class of important regulators of gene expression. One hot topic in the microRNA field is the location of microRNA genes. Most microRNAs are called intronic microRNAs, which are encoded in the introns of coding or non-coding genes. Some research studies have shown that intronic miRNAs coexpress and act similarly to their host genes; however, other research studies have suggested that their level of expression and function are opposite to that of their host genes. Intronic microRNAs have been reported to play an antagonistic or synergetic role as an enemy or a partner of their host genes. Elucidation of the relationship between intronic microRNAs and their host genes will facilitate a deeper understanding of gene expression and the function of introns. This mini review will discuss recent research addressing intronic microRNAs and their host genes. PMID- 22941955 TI - Tumor necrosis factor receptor 1 gain-of-function mutation aggravates nonalcoholic fatty liver disease but does not cause insulin resistance in a murine model. AB - Ectodomain shedding of tumor necrosis factor receptor 1 (TNFR1) provides negative feedback to the inflammatory loop induced by TNFalpha. As the significance of this mechanism in obesity-associated pathologies is unclear, we aimed to unravel how much TNFR1 ectodomain shedding controls the development of nonalcoholic fatty liver disease (NAFLD), as well as its role in the development of insulin resistance. We used knockin mice expressing a mutated TNFR1 ectodomain (p55(Deltans)), incapable of shedding and dampen the inflammatory response. Our data show that persistent TNFalpha signaling through this inability of TNFR1 ectodomain shedding contributes to chronic low-grade inflammation, which is confined to the liver. In spite of this, hepatic lipid levels were not affected by the nonshedding mutation in mice fed a chow diet, nor were they worse off following 12 weeks of high-fat diet (HFD) than controls (p55(+/+)) fed an HFD. We detected inflammatory infiltrates, hepatocellular necrosis, and apoptosis in livers of p55(Deltans/Deltans) mice fed an HFD, suggesting advanced progression of NAFLD toward nonalcoholic steatohepatitis (NASH). Indeed, fibrosis was present in p55(Deltans/Deltans) mice, but absent in wildtype mice, confirming that the p55(Deltans/Deltans) mice had a more severe NASH phenotype. Despite low-grade hepatic inflammation, insulin resistance was not observed in p55(Deltans/Deltans) mice fed a chow diet, and HFD-induced insulin resistance was no worse in p55(Deltans/Deltans) mice than p55(+/+) mice. CONCLUSION: TNFR1 ectodomain shedding is not an essential feedback mechanism in preventing the development of hepatic steatosis or insulin resistance. It is, however, pivotal in attenuating the progression from "simple steatosis" towards a more serious phenotype with many NASH features. Targeting TNFR1 could therefore be beneficial in attenuating NASH. PMID- 22941956 TI - Artifact reduction from metallic dental materials in T1-weighted spin-echo imaging at 3.0 tesla. AB - PURPOSE: To investigate and propose a method of artifact reduction arising from metallic dental materials by applying a slice-encoding for metal artifact correction (SEMAC) technique on T1-weighted spin-echo (SE) imaging at 3 Tesla. MATERIALS AND METHODS: The view angle tilting (VAT) technique was adapted to conventional T1-weighted spin-echo (SE) sequence to correct the in-plane distortion, and the SEMAC technique was used for correcting the remaining through plane distortions. Fourier transform based B0 field simulations were performed to estimate the amount of field perturbation and a scout imaging method was developed which guide in selecting the number of slice-encodings needed in SEMAC sequences. Phantoms of six different dental materials with various shapes and sizes that are used in practice (amalgam; titanium implant; gold and Ni-Cr crowns; Ni-Ti and stainless steel orthodontic wires) were imaged. In vivo images of two subjects were also acquired. The amounts of artifact reduction were quantified in phantom studies. RESULTS: Compared with conventional SE imaging in phantom studies, in-plane artifacts were reduced by up to 43% in the VAT SE images and 80% in the SEMAC images. Through-plane artifacts were reduced by up to 65% in SEMAC images. In vivo SEMAC images also showed reduced artifacts. CONCLUSION: The SEMAC technique can mitigate artifact caused by metallic dental materials for T1w-SE imaging. PMID- 22941957 TI - Coil embolization as a treatment alternative for dialysis-associated steal syndrome. AB - Steal syndrome is a rare but serious complication of arteriovenous fistulas (AVF) created as well as the angioplasty technique used for its maturation and can have severe consequences if left untreated. Standard treatment options generally lead to loss of fistula access, although newer practices such as coil embolization are being utilized to conserve the AVF. Here we illustrate a case of a 65-year-old man with end-stage renal disease on dialysis, who had a Brescia-Cimino (radiocephalic) AV fistula created and subsequently underwent balloon-assisted maturation for an underdeveloped fistula. One month later, the patient presented with a cold thumb and index finger along with parasthesias in those digits and was treated with coil embolization of the distal radial artery while leaving the AVF functional. Steal syndrome and the novel treatment option of coil embolization are reviewed here. PMID- 22941958 TI - Anatomic popliteal entrapment syndrome is often a difficult diagnosis. AB - Anatomic popliteal artery entrapment can be challenging to diagnose. Four cases are described in which initial diagnosis and treatment failed to identify and correct the anatomic defect responsible for patients' symptoms. In 3 of these cases, initial assessment and diagnosis was exertional compartment syndrome, yet compartment release did not resolve the complaint. Following accurate diagnosis, surgical release of aberrant popliteal fossa anatomy provided all 4 patients with lasting symptom resolution, though 1 patient with bilateral operations has had relief of only 1 side. In the diagnostic algorithm for these patients, angiography with forced plantarflexion against resistance aids in eliciting the pathognomonic images of arterial occlusion in this disorder. PMID- 22941959 TI - Interfaces to PeptideAtlas: a case study of standard data access systems. AB - Access to public data sets is important to the scientific community as a resource to develop new experiments or validate new data. Projects such as the PeptideAtlas, Ensembl and The Cancer Genome Atlas (TCGA) offer both access to public data and a repository to share their own data. Access to these data sets is often provided through a web page form and a web service API. Access technologies based on web protocols (e.g. http) have been in use for over a decade and are widely adopted across the industry for a variety of functions (e.g. search, commercial transactions, and social media). Each architecture adapts these technologies to provide users with tools to access and share data. Both commonly used web service technologies (e.g. REST and SOAP), and custom built solutions over HTTP are utilized in providing access to research data. Providing multiple access points ensures that the community can access the data in the simplest and most effective manner for their particular needs. This article examines three common access mechanisms for web accessible data: BioMart, caBIG, and Google Data Sources. These are illustrated by implementing each over the PeptideAtlas repository and reviewed for their suitability based on specific usages common to research. BioMart, Google Data Sources, and caBIG are each suitable for certain uses. The tradeoffs made in the development of the technology are dependent on the uses each was designed for (e.g. security versus speed). This means that an understanding of specific requirements and tradeoffs is necessary before selecting the access technology. PMID- 22941960 TI - H(2) O(2) - and pH-sensitive CdTe quantum dots as fluorescence probes for the detection of glucose. AB - A novel fluorescence assay system for glucose was developed with thioglycollic acid (TGA)-capped CdTe quantum dots (QDs) as probes. The luminescence quantum yield of the TGA-capped CdTe QDs was highly sensitive to H2 O2 and pH. In the presence of glucose oxidase, glucose is oxidized to yield, gluconic acid and H2 O2 . H2 O2 and H(+) (dissociated from gluconic acid) intensively quenched the fluorescence of QDs. The experimental results showed that the quenched fluorescence was proportional to the glucose concentration within the range of 0.01-5.0 mm under optimized experimental conditions. Compared with most of the existing methods, this newly developed system possesses many advantages, including simplicity, low cost, high flexibility, and good sensitivity. Furthermore, no complicated chemical modification of QDs and enzyme immobilization was needed in this system. PMID- 22941961 TI - Subthalamic stimulation improves the cerebral hemodynamic response to the cold pressure test in patients with Parkinson's disease. AB - PURPOSE: Disturbances of the autonomic nervous system are common in patients with Parkinson's disease (PD) but the effect of deep brain stimulation of the subthalamic nucleus on cerebrovascular reactivity is not entirely known. METHODS: Seven patients in an advanced stage of the disease and seven healthy age-matched controls participated in the study, which took place after one night of drug withdrawal. Cerebral blood flow velocity was continuously monitored on both sides with transcranial Doppler ultrasound, and cerebrovascular reactivity (CR) was evaluated with the cold pressure test. The measurements were repeated and compared during the stimulation-on and -off phases. RESULTS: The PD patients had significantly higher CR values in the stimulation-on than -off conditions (15.1% +/- 6.9 versus 9.4% +/- 6.2; p = 0.03). CR values were higher in controls than in patients in the stimulation-off condition (20.4% +/- 12.5 versus 9.4% +/- 6.2; p = 0.007) without a significant difference with the stimulation-on phase. CONCLUSIONS: CR, evaluated by the response to the cold pressure test, is impaired in patients with advanced PD and improved by subthalamic nucleus. PMID- 22941962 TI - Impedance measurements in the biomedical sciences. AB - Biological organisms and their component organs, tissues and cells have unique electrical impedance properties. Impedance properties often change with changes in structure, composition, and metabolism, and can be indicative of the onset and progression of disease states. Over the past 100 years, instruments and analytical methods have been developed to measure the impedance properties of biological specimens and to utilize these measurements in both clinical and basic science settings. This chapter will review the applications of impedance measurements in the biomedical sciences, from whole body analysis to impedance measurements of single cells and cell monolayers, and how cellular impedance measuring instruments can now be used in high throughput screening applications. PMID- 22941963 TI - The roles of PI3K/Akt signaling pathway in regulating MC3T3-E1 preosteoblast proliferation and differentiation on SLA and SLActive titanium surfaces. AB - Chemical modification to produce a hydrophilic microrough titanium (Ti) implant surface has been shown to increase osseointegration compared with microrough topography alone. This study aimed to investigate the roles of PI3K/Akt signaling pathway in regulating proliferation and differentiation of osteoblasts in response to surface microroughness and hydrophilicity. Ti disks were manufactured to present different surface morphologies: a smooth pretreatment surface (PT), a rough hydrophobic surface that was sand-blasted, large-grit, acid-etched (SLA), and an SLA surface with the same roughness that was chemically modified to possess high wettability/hydrophilicity (SLActive/modSLA). MC3T3-E1 cells were cultured on these substrates with or without LY294002, a PI3K inhibitor, and their behaviors, including cell viability (MTT colorimetric assay), alkaline phosphatase (ALP) activity, and osteogenic genes expression of osteopontin (OPN) and osteocalcin (OCN) were measured. Western blot was applied to detect the expression of PI3K/Akt signal pathway proteins. The results showed that a decrease in osteoblast proliferation associated with the Ti surfaces (SLActive > SLA > PT) correlated with an increase in activity of the osteogenic differentiation markers ALP. The peak of ALP activity appeared earlier at 7 days for the SLActive surfaces compared with the SLA and PT surfaces. Osteoblast proliferation, as well as the level of p-Akt, was significantly inhibited by LY294002 in all three Ti surfaces. The top value of ALP activity was increased with the inhibition of PI3K/Akt signaling pathway while the time of the peak appeared was not advanced. The expression levels of OPN and OCN were upregulated by the effect of surface roughness and hydrophilicity, which were further enhanced by LY294002. In conclusion, osteogenic responses to SLActive surface were moderately better than the SLA surface and protein expression studies indicated that PI3K/Akt signaling activation may be responsible for this increased osteogenic differentiation. Surface microroughness and hydrophilicity may affect osteoblast functions by targeting osteoblast proliferation and the early stage of osteoblast differentiation through PI3K/Akt signaling pathway. PMID- 22941964 TI - Flow-based analysis using microfluidics-chemiluminescence systems. AB - This review will discuss various approaches and techniques in which analysis using microfluidics-chemiluminescence systems (MF-CL) has been reported. A variety of applications is examined, including environmental, pharmaceutical, biological, food and herbal analysis. Reported uses of CL reagents, sample introduction techniques, sample pretreatment methods, CL signal enhancement and detection systems are discussed. A hydrodynamic pumping system is predominately used for these applications. However, several reports are available in which electro-osmotic (EO) pumping has been implemented. Various sample pretreatment methods have been used, including liquid-liquid extraction, solid-phase extraction and molecularly imprinted polymers. A wide range of innovative techniques has been reported for CL signal enhancement. Most of these techniques are based on enhancement of the mixing process in the microfluidics channels, which leads to enhancement of the CL signal. However, other techniques are also reported, such as mirror reaction, liquid core waveguide, on-line pre derivatization and the use of an opaque white chip with a thin transparent seal. Photodetectors are the most commonly used detectors; however, other detection systems have also been used, including integrated electrochemiluminescence (ECL) and organic photodiodes (OPDs). PMID- 22941965 TI - Molecular basis of erythrocyte adhesion to endothelial cells in diseases. AB - Red blood cell (RBC) adhesion to endothelium can be studied in static and flow conditions. Increased RBC adhesion was first described in sickle cell disease. Several molecules were shown to be involved in this phenomenon: VCAM-1, alpha4beta1, Lu/BCAM, ICAM-4. In malaria, Plasmodium falciparum erythrocyte membrane protein1 binds to ICAM-1, PECAM-1 and facilitates the parasite dissemination. In diabetes mellitus augmented RBC adhesion is correlated to the severity of vascular complications. Glycated RBC band3 reacts with the endothelial Receptor for Advanced Glycation End products (RAGE). RAGE engagement induced endothelial cell dysfunction. In patients with Polycythemia Vera (PV), the most frequent myeloproliferative disorder, constitutive phosphorylation of RBC Lu/BCAM is responsible for an increased adhesion to endothelial cell laminin. Retinal vein occlusion (RVO) is a common cause of permanent visual loss. Spontaneous growth of erythroid precursors was observed in more than 25% of patients. RBC adhesion was enhanced and correlated to phosphatidyl serine (PS) expression on RBC. Anti-PS receptor blocked RVO RBC adhesion indicating that the counterpart of RBC PS is PS endothelial cell receptor. Erythrocyte adhesion is mediated by different molecule abnormalities in different diseases but is associated to a higher risk of thrombosis and vascular complications. PMID- 22941966 TI - Frequent premature atrial complexes... truly a benign finding? PMID- 22941968 TI - Value of P-wave signal averaging to predict atrial fibrillation recurrences after pulmonary vein isolation. AB - AIMS: Recurrences of atrial fibrillation (AF) after radiofrequency catheter ablation (RFCA) are usually caused by pulmonary vein (PV) re-conduction, by foci outside the PV or by previous electrical remodelling. Substrate alterations with conduction delays may be detected by signal-averaged P-wave analysis (SAPW). This study was conducted to assess the value of the SAPW to predict recurrences after RFCA in patients with paroxysmal or persistent AF. METHODS AND RESULTS: One hundred and two patients (59 +/- 10 years, 83 males) underwent a first RFCA procedure for paroxysmal (n = 61) or persistent/long-standing persistent (n = 41) AF. A SAPW recording with measurement of total filtered P-wave duration (FPD), P wave integral, and terminal root mean squared voltage was obtained immediately after the ablation procedure and the patients were prospectively followed. During a mean follow-up of 12 +/- 7 months, recurrences occurred in 36 of 102 (35.3%) patients, 17 of 61 with paroxysmal AF, and 19 of 41 with persistent AF (P = 0.06). The FPD was significantly longer in patients with recurrences compared to those without (158 +/- 22 vs. 140 +/- 18 ms, P = 0.0008). The FPD was shorter in patients with paroxysmal AF compared with patients with persistent AF (142 +/- 28 vs. 153 +/- 20 ms, P = 0.03). A FPD of 140 ms was found to discriminate patients prone to recurrences (log-rank test, P = 0.008) with a sensitivity of 69%, a specificity of 53%, a positive predictive value of 45%, and a negative predictive value of 76%. CONCLUSION: A FPD >140 ms is a marker of AF recurrences after RFCA and probably reflects the extent of atrial remodelling. PMID- 22941967 TI - The incidence and clinical significance of non-isolation of the pulmonary vein carina after encircling ipsilateral pulmonary veins isolation for paroxysmal atrial fibrillation: a pitfall of the double-Lasso technique. AB - AIMS: Encircling ipsilateral pulmonary veins (PVs) isolation (EIPVsI) with the double-Lasso technique has proven to be effective to cure atrial fibrillation (AF). However, in this technique, PV mapping with circular catheters may miss a non-isolation of the PV carina. The purpose of this study was to reveal the incidence and clinical significance of a non-isolation of the PV carina after EIPVsI. METHODS AND RESULTS: We studied 81 consecutive paroxysmal AF patients (age 61 +/- 12 years, 56 men), in whom EIPVsI was successfully performed in one encircling line with the endpoint of the demonstration of bidirectional conduction block between the PVs and left atrium (LA) with the double-Lasso technique. After a successful EIPVsI, pacing from the PV carina was performed and it captured the LA in 17 (21.0%) patients. During a mean follow-up period of 19 +/- 13 months, AF recurred in 13 (16.0%) patients. A multivariate Cox proportional analysis revealed that a non-isolation of the PV carina after the EIPVsI was a significant predictor (hazard ratio = 3.91, 95% confidence interval = 1.13-14.16, P = 0.03) of AF recurrence. CONCLUSIONS: Pulmonary vein mapping with the double-Lasso technique did miss the non-isolation of the PV carina after a successful EIPVsI, which was an independent predictor of AF recurrence after the EIPVsI. Pacing from the PV carina may be required to confirm the electrical isolation of the PV carina after EIPVsI with the double-Lasso technique. PMID- 22941969 TI - A meta-analytic review of life cycle assessment and flow analyses studies of palm oil biodiesel. AB - This work reviews and performs a meta-analysis of the recent life cycle assessment and flow analyses studies palm oil biodiesel. The best available data and information are extracted, summarized, and discussed. Most studies found palm oil biodiesel would produce positive energy balance with an energy ratio between 2.27 and 4.81, and with a net energy production of 112 GJ ha(-1) y(-1). With the exception of a few studies, most conclude that palm oil biodiesel is a net emitter of greenhouse gases (GHG). The origin of oil palm plantation (planted area) is the foremost determinant of GHG emissions and C payback time (CPBT). Converting peatland forest results in GHG emissions up to 60 tons CO(2) equivalent (eq) ha(-1) y(-1) leading to 420 years of CPBT. In contrast, converting degraded land or grassland for plantation can positively offset the system to become a net sequester of 5 tons CO(2) eq ha(-1) y(-1). Few studies have discussed cradle-to-grave environmental impacts such as acidification, eutrophication, toxicity, and biodiversity, which open opportunity for further studies. PMID- 22941970 TI - The value of geriatric assessments in predicting treatment tolerance and all cause mortality in older patients with cancer. AB - BACKGROUND: Awareness of the use of geriatric assessments for older patients with cancer is increasing. The aim of this review is to summarize all available evidence on the association between geriatric assessments and relevant oncologic outcomes. METHOD: A systematic search was conducted in Medline and Embase of studies on geriatric assessment in oncology, focusing on the association between baseline assessment and outcome. RESULTS: The literature search identified 2008 reports; 51 publications from 37 studies were selected for inclusion in the review. The quality of studies was heterogeneous and generally poor. A median of five geriatric conditions were assessed per study (interquartile range: 4-8). Little consistency was found in the results of the studies. Furthermore, different tools appear to be predictive depending on the outcome measure: frailty, nutritional status, and comorbidity assessed by the Cumulative Illness Rating Scale for Geriatrics were predictive for all-cause mortality; frailty was predictive for toxicity of chemotherapy; cognitive impairment and activities of daily living impairment were predictive for chemotherapy completion; and instrumental activities of daily living impairment was predictive for perioperative complications. CONCLUSION: Although various geriatric conditions appear to be of some value in predicting outcome in elderly patients with cancer, the results are too inconsistent to guide treatment decisions. Further research is needed to elucidate the role of geriatric assessments in the oncologic decision-making process for these patients. PMID- 22941972 TI - Dark-red-emitting CdTe/Cd1-x Znx S core/shell quantum dots: preparation and properties. AB - CdTe nanocrystals (NCs) were fabricated through an organic synthesis. The growth and properties of CdTe NCs depended strongly on the preparation conditions. In a reaction system of octadecene and tetradecylphosphonic acid (TDPA), the growth was slow. CdTe NCs with cubic-like morphology were created in trioctylamine (TOA) using octadecylphosphonic acid (ODPA)-CdO or TDPA-CdO as precursors. The TOA and ODPA system gives rise to NCs with high photoluminescence (PL) efficiencies (12%). A Cdx Zn1-x S shell coating on the CdTe core, gave rise to tunable dark red PL (630-670 nm). The morphology and PL properties of the CdTe cores were drastically affected by shell coating and this determined the properties of CdTe/Cdx Zn1-x S NCs. Small CdTe NCs were easily coated with Cdx Zn1-x S shells. The resulting core/shell NCs revealed a spherical morphology. However, shell growth became slow when large CdTe cores were used. This is ascribed to the cores with a cubic-like morphology. CdS interlayer plays an important role for the formation of the CdTe/Cdx Zn1-x S NCs because the experimental result indicated it is difficult to coat CdTe NCs with a ZnS shell. The core/shell NCs benefited from a Cdx Zn1-x S composite shell because CdTe/CdS NCs created via a similar procedure revealed a low PL efficiency. PMID- 22941971 TI - The role of cancer stem cells in breast cancer initiation and progression: potential cancer stem cell-directed therapies. AB - Recent studies have identified a small population of highly tumorigenic cells with stem cell properties in human breast and other solid tumors that are considered to be the source of tumor initiation and maintenance; these cells are referred to as cancer stem cells (CSCs). Preclinical data suggest that current breast cancer treatment strategies lead to CSC enrichment, contributing to chemotherapy and radiotherapy resistance, although a strong correlation with clinical parameters and prognosis is yet to be established. Importantly, overcoming treatment failure by effective targeting of CSCs may be an appealing approach, potentially leading to improved clinical outcomes for patients with breast cancer. Several preclinical studies provide promising results that support this hypothesis. The purpose of this review is to summarize the role of CSCs in breast cancer recurrence and resistance and to discuss current attempts of CSC targeting. PMID- 22941974 TI - One-pot synthesis of ultra-light nickel nanofoams composed of nanowires and their transformation into various functional nanofoams. AB - Ultra-light Ni nanofoams composed of nanowires have been synthesized on a large scale by a facile reflux approach. From the Ni nanofoam, many other functional nanofoams, composed of semi-hollow NiO nanowires, multi-generation Ni nanowires, and noble metal nanotubes, can be easily derived for many important applications. As an example, the promising application of the NiO nanofoam in lithium-ion batteries is demonstrated. PMID- 22941973 TI - Characteristics of TBS-extractable hyperphosphorylated tau species: aggregation intermediates in rTg4510 mouse brain. AB - Conditional overexpression of four-repeat human tau containing the P301L missense mutation in the rTg4510 mouse model of tauopathy leads to progressive accumulation of neurofibrillary tangles and hyperphosphorylated, sarkosyl insoluble tau species, which are biochemically comparable to abnormal tau characteristic of hereditary tauopathies termed FTDP-17. To fully understand the impact of tau species at different stages of self-assembly on neurodegeneration, we fractionated rTg4510 brain representing several stages of tauopathy to obtain TBS-extractable (S1), high salt/sarkosyl-extractable (S3), and sarkosyl-insoluble (P3) fractions. Under reducing condition, the S1 fraction was demonstrated by western blotting to contain both 50-60 kDa normally-sized and 64 kDa tau. Both are thermo-stable, but the 64 kDa tau showed a higher degree of phosphorylation. Under non-reducing condition, nearly all TBS-extractable 64 kDa tau were detected as ~130 kDa species consistent with the size of dimer. Quantitative analysis showed ~80 times more 64 kDa tau in S1 than P3 fraction. Immunoelectron microscopy revealed tau-positive granules/short filaments in S1 fraction. These structures displayed MC1 immunoreactivities indicative of conformational/pathological change of tau. MC1 immunoreactivity was detected by dot blotting in samples from 2.5 month-old mice, whereas Ab39 immunoreactivity indicative of late stages of tau assembly was detected only in P3 fraction. Quantitative analysis also demonstrated a significant inverse correlation between brain weight and 64 kDa tau, but the level of TBS-extractable 64 kDa tau reflects neurodegeneration better than that of sarkosyl-insoluble 64 kDa tau. Together, the findings suggest that TBS-extractable 64 kDa tau production is a potential target for therapeutic intervention of tauopathies. PMID- 22941976 TI - The at-risk registers in severe asthma (ARRISA) study: a cluster-randomised controlled trial examining effectiveness and costs in primary care. AB - BACKGROUND: Patients at risk of severe exacerbations contribute disproportionally to asthma mortality, morbidity and costs. We evaluated the effectiveness and costs of using 'asthma risk registers' for these patients in primary care. METHODS: In a cluster-randomised trial, 29 primary care practices identified 911 at-risk asthma patients using British asthma guideline criteria (severe asthma plus adverse psychosocial characteristics). Intervention practices added electronic alerts to identified patients' records to flag their at-risk status and received practice-based training about using the alerts to improve patient access and opportunistic management. Control practices continued routine care. Numbers of patients experiencing the primary outcome of a moderate-severe exacerbation (resulting in death, hospitalisation, accident and emergency attendance, out-of-hours contact, or a course/boost in oral prednisolone for asthma), other healthcare and medication usage, and costs over 1 year were derived from practice-based records. RESULTS: There was no significant effect on exacerbations (control: 46.5%; intervention: 53.6%, OR, 95% CI 1.30, 0.93 to 1.80). However, this composite outcome masked relative reductions in intervention patients experiencing hospitalisations (OR 0.50, 95% CI 0.26 to 0.94), accident and emergency (OR 0.74, 95% CI 0.42 to 1.31) and out-of-hours contacts (OR 0.79, 95% CI 0.45 to 1.37); and a relative increase in prednisolone prescription for exacerbations (OR 1.31, 95% CI 0.92 to 1.85). Furthermore, prescription of nebulised short-acting beta-agonists reduced and long-acting beta-agonists increased for intervention relative to control patients. The adjusted mean per patient healthcare cost was L138.21 lower (p=0.837) among intervention practices. CONCLUSION: Using asthma risk registers in primary care did not reduce treated exacerbations, but reduced hospitalisations and increased prescriptions of recommended preventative therapies without increasing costs. PMID- 22941975 TI - Association between beta-blocker therapy and outcomes in patients hospitalised with acute exacerbations of chronic obstructive lung disease with underlying ischaemic heart disease, heart failure or hypertension. AB - BACKGROUND: beta-Blocker therapy has been shown to improve survival among patients with ischaemic heart disease (IHD) and congestive heart failure (CHF) and is underused among patients with chronic obstructive pulmonary disease (COPD). Evidence regarding the optimal use of beta-blocker therapy during an acute exacerbation of COPD is particularly weak. METHODS: We conducted a retrospective cohort study of patients aged >=40 years with IHD, CHF or hypertension who were hospitalised for an acute exacerbation of COPD from 1 January 2006 to 1 December 2007 at 404 acute care hospitals throughout the USA. We examined the association between beta-blocker therapy and in-hospital mortality, initiation of mechanical ventilation after day 2 of hospitalisation, 30-day all-cause readmission and length of stay. RESULTS: Of 35 082 patients who met the inclusion criteria, 29% were treated with beta blockers in the first two hospital days, including 22% with beta1-selective and 7% with non-selective beta blockers. In a propensity-matched analysis, there was no association between beta blocker therapy and in-hospital mortality (OR 0.88, 95% CI 0.71 to 1.09), 30-day readmission (OR 0.96, 95% CI 0.89 to 1.03) or late mechanical ventilation (OR 0.98, 95% CI 0.77 to 1.24). However, when compared with beta1 selective beta blockers, receipt of non-selective beta blockers was associated with an increased risk of 30-day readmission (OR 1.25, 95% CI 1.08 to 1.44). CONCLUSIONS: Among patients with IHD, CHF or hypertension, continuing beta1-selective beta blockers during hospitalisation for COPD appears to be safe. Until additional evidence becomes available, beta1-selective beta blockers may be superior to treatment with a non-selective beta blocker. PMID- 22941977 TI - Ataxia telangiectasia mutated impacts insulin-like growth factor 1 signalling in skeletal muscle. AB - Reports that ataxia telangiectasia mutated (ATM) is required for full activation of Akt raise the hypothesis that ATM plays a role in insulin-like growth factor 1 (IGF-1) signalling through the Akt/mammalian target of rapamycin (mTOR) pathway. Differentiated C2C12 cells harbouring either ATM-targeting short hairpin RNA (shRNA) or non-targeting shRNA and myotubes from a C2C12 lineage previously exposed to empty vector lentivirus were incubated in the presence or absence of 10 nm IGF-1 followed by Western blot analysis. Parallel experiments were performed in isolated soleus muscles from mice expressing only one functional ATM allele (ATM(+/-)) compared with muscles from wild-type (ATM(+/+)) mice. Insulin like growth factor 1 increased phosphorylation of Akt S473, Akt T308 and p70 S6 kinase (S6K) in myotubes expressing non-targeting shRNA and in empty vector controls, but the IGF-1 effects were significantly reduced in myotubes with shRNA mediated ATM knockdown. Likewise, IGF-1-stimulated phosphorylation of Akt S473, Akt T308, mTOR and S6K was lower in isolated soleus muscles from ATM(+/-) mice compared with muscles from ATM(+/+) mice. The ATM inhibitor KU55933 prevented stimulation of S6K phosphorylation in C2C12 myotubes exposed to IGF-1, suggesting that decreased IGF-1 action is not limited to chronic conditions of decreased ATM function. Stimulation of insulin receptor substrate 1 tyrosine 612 phosphorylation by IGF-1 was unaffected by ATM deficiency, though IGF-1 phosphatidylinositol 3-kinase activity tended to be lower in muscle from ATM haploinsufficient mice compared with wild-type muscle. The data suggest that ATM is a modulator of IGF-1 signalling downstream of insulin receptor substrate 1 in skeletal muscle. PMID- 22941981 TI - HealthGrid 2012. PMID- 22941978 TI - Stress-dependent hypertension and the role of T lymphocytes. AB - Hypertension is a significant global health burden that is associated with an increased risk of stroke, atherosclerosis and other cardiovascular diseases. Several risk factors, including high dietary salt, obesity, genetics and race, as well as behavioural and psychological factors, contribute to development of this complex disease. Various hypertensive stimuli enhance sympathetic drive and promote autonomic dysfunction leading to elevated blood pressure. As our understanding of the pathogenesis and end-organ damage associated with hypertension increases, mounting evidence also highlights the role of inflammation in this process and, in particular, the role of the adaptive immune system and T cells. This review discusses recent findings regarding the role of the central nervous system, T lymphocytes and the impact of cardiovascular risk factors, such as psychological stress, in hypertension. PMID- 22941983 TI - Federated queries for comparative effectiveness research: performance analysis. AB - This paper presents a study of the performance of federated queries implemented in a system that simulates the architecture proposed for the Scalable Architecture for Federated Translational Inquiries Network (SAFTINet). Performance tests were conducted using both physical hardware and virtual machines within the test laboratory of the Center for High Performance Computing at the University of Utah. Tests were performed on SAFTINet networks ranging from 4 to 32 nodes with databases containing synthetic data for several million patients. The results show that the caGrid FQE (Federated Query Engine) is capable and suitable for comparative effectiveness research (CER) federated queries given its nearly linear scalability as partner nodes increase in number. The results presented here are also important for the specification of the hardware required to run a CER grid. PMID- 22941979 TI - The regulation of interleukin-6 implicates skeletal muscle as an integrative stress sensor and endocrine organ. AB - Skeletal muscle has been identified as an endocrine organ owing to its capacity to produce and secrete a variety of cytokines (myokines) and other proteins. To date, myokines have primarily been studied in response to exercise or metabolic challenges; however, numerous observations suggest that skeletal muscle may also release myokines in response to certain categories of internal or external stress exposure. Internal stress signals include oxidative or nitrosative stress, damaged or unfolded proteins, hyperthermia or energy imbalance. External stress signals, which act as indicators of organismal stress or injury in other cells, employ mediators such as catecholamines, endotoxin, alarmins, ATP and pro inflammatory cytokines, such as tumour necrosis factor-alpha and interleukin 1beta. External stress signals generally induce cellular responses through membrane receptor systems. In this review, we focus on the regulation of interleukin-6 (IL-6) as a prototypical stress response myokine and highlight evidence that IL-6 gene regulation in muscle is inherently organized to respond to a wide variety of internal and external stressors. Given that IL-6 can initiate protective, anti-inflammatory or restorative processes throughout the organism during life-threatening conditions, we present the argument that skeletal muscle has a physiological function as a sensor and responder to stress. Furthermore, we hypothesize that it may comprise a fundamental component of the organism's acute stress response. PMID- 22941984 TI - A system architecture for sharing de-identified, research-ready brain scans and health information across clinical imaging centers. AB - Progress in our understanding of brain disorders increasingly relies on the costly collection of large standardized brain magnetic resonance imaging (MRI) data sets. Moreover, the clinical interpretation of brain scans benefits from compare and contrast analyses of scans from patients with similar, and sometimes rare, demographic, diagnostic, and treatment status. A solution to both needs is to acquire standardized, research-ready clinical brain scans and to build the information technology infrastructure to share such scans, along with other pertinent information, across hospitals. This paper describes the design, deployment, and operation of a federated imaging system that captures and shares standardized, de-identified clinical brain images in a federation across multiple institutions. In addition to describing innovative aspects of the system architecture and our initial testing of the deployed infrastructure, we also describe the Standardized Imaging Protocol (SIP) developed for the project and our interactions with the Institutional Review Board (IRB) regarding handling patient data in the federated environment. PMID- 22941985 TI - A flexible, open, decentralized system for digital pathology networks. AB - High-resolution digital imaging is enabling digital archiving and sharing of digitized microscopy slides and new methods for digital pathology. Collaborative research centers, outsourced medical services, and multi-site organizations stand to benefit from sharing pathology data in a digital pathology network. Yet significant technological challenges remain due to the large size and volume of digitized whole slide images. While information systems do exist for managing local pathology laboratories, they tend to be oriented toward narrow clinical use cases or offer closed ecosystems around proprietary formats. Few solutions exist for networking digital pathology operations. Here we present a system architecture and implementation of a digital pathology network and share results from a production system that federates major research centers. PMID- 22941986 TI - eLab: bringing together people, data and methods to enhance knowledge discovery in healthcare settings. AB - The discovery of knowledge from raw data is a multistage process, that typical requires collaboration between experts from disparate disciplines, and the application of a range of methods tailored to the research question. The aim of the eLab is to provide a web-based environment for health professionals and researchers to access health datasets, share knowledge and expertise and to apply methods for analysis and visualization of the results. The eLab is built around the core concept of the Research Object as the mechanism for preserving, reusing and disseminating the knowledge discovery process. The possible range of applications of the eLab is vast, and so the consideration of the trade off between specificity and generality is an important one, that is reflected in the requirements. The architecture and implementation of the eLab is described, and we report on the deployment of eLabs for applications in primary care, long-term conditions management, bariatric surgery and public health. PMID- 22941987 TI - Legal constraints on genetic data processing in European grids. AB - European laws on privacy and data security are not explicit about the storage and processing of genetic data. Especially whole-genome data is identifying and contains a lot of personal information. Is processing of such data allowed in computing grids? To find out, we looked at legal precedents in related fields, current literature, and interviews with legal experts. We found that processing of genetic data is only allowed on distributed systems with specific security measures, both technical and organizational. Informed consent, although important, offers no substitute for such requirements. PMID- 22941988 TI - gcodeml: a Grid-enabled tool for detecting positive selection in biological evolution. AB - One of the important questions in biological evolution is to know if certain changes along protein coding genes have contributed to the adaptation of species. This problem is known to be biologically complex and computationally very expensive. It, therefore, requires efficient Grid or cluster solutions to overcome the computational challenge. We have developed a Grid-enabled tool (gcodeml) that relies on the PAML (codeml) package to help analyse large phylogenetic datasets on both Grids and computational clusters. Although we report on results for gcodeml, our approach is applicable and customisable to related problems in biology or other scientific domains. PMID- 22941989 TI - A service-based BLAST command tool supported by cloud infrastructures. AB - Notwithstanding the benefits of distributed-computing infrastructures for empowering bioinformatics analysis tools with the needed computing and storage capability, the actual use of these infrastructures is still low. Learning curves and deployment difficulties have reduced the impact on the wide research community. This article presents a porting strategy of BLAST based on a multiplatform client and a service that provides the same interface as sequential BLAST, thus reducing learning curve and with minimal impact on their integration on existing workflows. The porting has been done using the execution and data access components from the EC project Venus-C and the Windows Azure infrastructure provided in this project. The results obtained demonstrate a low overhead on the global execution framework and reasonable speed-up and cost efficiency with respect to a sequential version. PMID- 22941991 TI - Technical support for Life Sciences communities on a production grid infrastructure. AB - Production operation of large distributed computing infrastructures (DCI) still requires a lot of human intervention to reach acceptable quality of service. This may be achievable for scientific communities with solid IT support, but it remains a show-stopper for others. Some application execution environments are used to hide runtime technical issues from end users. But they mostly aim at fault-tolerance rather than incident resolution, and their operation still requires substantial manpower. A longer-term support activity is thus needed to ensure sustained quality of service for Virtual Organisations (VO). This paper describes how the biomed VO has addressed this challenge by setting up a technical support team. Its organisation, tooling, daily tasks, and procedures are described. Results are shown in terms of resource usage by end users, amount of reported incidents, and developed software tools. Based on our experience, we suggest ways to measure the impact of the technical support, perspectives to decrease its human cost and make it more community-specific. PMID- 22941992 TI - Provenance for distributed biomedical workflow execution. AB - Scientific research has become very data and compute intensive because of the progress in data acquisition and measurement devices, which is particularly true in Life Sciences. To cope with this deluge of data, scientists use distributed computing and storage infrastructures. The use of such infrastructures introduces by itself new challenges to the scientists in terms of proper and efficient use. Scientific workflow management systems play an important role in facilitating the use of the infrastructure by hiding some of its complexity. Although most scientific workflow management systems are provenance-aware, not all of them come with provenance functionality out of the box. In this paper we describe the improvement and integration of a provenance system into an e-infrastructure for biomedical research based on the MOTEUR workflow management system. The main contributions of the paper are: presenting an OPM implementation using relational database backend for the provenance store, providing an e-infrastructure with a comprehensive provenance system, defining a generic approach to provenance implementation, potentially suitable for other workflow systems and application domains and demonstrating the value of this system based on use cases presenting the provenance data through a user-friendly web interface. PMID- 22941994 TI - Tutorial on academic high-performance cloud computing. AB - This documents shortly describes the background and structure of the academic high-performance cloud computing tutorial at the Healthgrid conference. PMID- 22941995 TI - Hands-on tutorial on Grid portal development focused on biomedical image and signal processing. PMID- 22941997 TI - Web-based interactive visualization of Grid-enabled neuroimaging applications. PMID- 22941998 TI - DECIDE: a user friendly web-based service for early diagnosis and research on Alzheimer's disease. PMID- 22941999 TI - SHIWA workflow interoperability solutions for neuroimaging data analysis. PMID- 22942002 TI - Workshop series IWSG-Life. PMID- 22942000 TI - Desktop Cloud Visualization: the new technology to remote access 3D interactive applications in the Cloud. AB - In the proposed demonstration we will present DCV (Desktop Cloud Visualization): a unique technology that allows users to remote access 2D and 3D interactive applications over a standard network. This allows geographically dispersed doctors work collaboratively and to acquire anatomical or pathological images and visualize them for further investigations. PMID- 22942003 TI - Science gateways for semantic-web-based life science applications. AB - In this paper we present the architecture of a framework for building Science Gateways supporting official standards both for user authentication and authorization and for middleware-independent job and data management. Two use cases of the customization of the Science Gateway framework for Semantic-Web based life science applications are also described. PMID- 22942004 TI - Opening new gateways to workflows for life scientists. AB - The combination of highly complex biology problems and varying IT skills among life scientists poses a unique challenge in designing bioinformatics programs. The set of tools and initiatives described in this work shows new ways of making life science workflows more accessible to the community. Our aim is to help bioinformaticians help biologists. We present how to make Taverna workflows available from within Galaxy, both widely used bioinformatics platforms. Calling Galaxy tools from Taverna is also discussed. In addition, we describe a web application that allows a user to run arbitrary Taverna workflows by only using a web browser. PMID- 22942005 TI - Workflow-enhanced conformational analysis of guanidine zinc complexes via a science gateway. AB - The new science gateway MoSGrid (Molecular Simulation Grid) enables users to submit and process molecular simulation studies on a large scale. A conformational analysis of guanidine zinc complexes, which are active catalysts in the ring-opening polymerization of lactide, is presented as an example. Such a large-scale quantum chemical study is enabled by workflow technologies. Two times 40 conformers have been generated, for two guanidine zinc complexes. Their structures were optimized using Gaussian03 and the energies processed within the quantum chemistry portlet of the MoSGrid portal. All meta- and post-processing steps have been performed in this portlet. All workflow features are implemented via WS-PGRADE and submitted to UNICORE. PMID- 22942006 TI - Application repository and science gateway for running molecular docking and dynamics simulations. AB - Molecular docking and dynamics studies are of considerable importance in a range of disciplines including molecular biology, drug design, environmental studies, psychology, etc. Using in silico tools to support or even to substitute wet laboratory work could help better focusing the laboratory experiments resulting not only in considerable saving of resources but also increasing the number of molecules and scenarios investigated. There are several software packages that support in silico modeling. However, these tools require lot of compute resources and special technical knowledge. As a result, many bio-scientists cannot use them. The paper describes a science gateway based solution which provides access to Distributed Computing Infrastructures such as clouds, desktop and service grids. This environment enables bio-scientists to execute simple molecular modeling scenarios or build more complex use-cases from existing building blocks while hiding the technical details of the infrastructure. Four scenarios have been defined and deconstructed in order to identify common building blocks supporting a large number of complex use-cases. A reference implementation for the first scenario regarding the impact on indicator species of pharmaceuticals released into water courses has been implemented on the EDGI infrastructure, demonstrating the feasibility of the approach. PMID- 22942007 TI - Structure simulation with calculated NMR parameters - integrating COSMOS into the CCPN framework. AB - The Collaborative Computing Project for NMR (CCPN) has build a software framework consisting of the CCPN data model (with APIs) for NMR related data, the CcpNmr Analysis program and additional tools like CcpNmr FormatConverter. The open architecture allows for the integration of external software to extend the abilities of the CCPN framework with additional calculation methods. Recently, we have carried out the first steps for integrating our software Computer Simulation of Molecular Structures (COSMOS) into the CCPN framework. The COSMOS-NMR force field unites quantum chemical routines for the calculation of molecular properties with a molecular mechanics force field yielding the relative molecular energies. COSMOS-NMR allows introducing NMR parameters as constraints into molecular mechanics calculations. The resulting infrastructure will be made available for the NMR community. As a first application we have tested the evaluation of calculated protein structures using COSMOS-derived 13C Calpha and Cbeta chemical shifts. In this paper we give an overview of the methodology and a roadmap for future developments and applications. PMID- 22942008 TI - Web-based interactive visualization in a Grid-enabled neuroimaging application using HTML5. AB - Interactive visualization and correction of intermediate results are required in many medical image analysis pipelines. To allow certain interaction in the remote execution of compute- and data-intensive applications, new features of HTML5 are used. They allow for transparent integration of user interaction into Grid- or Cloud-enabled scientific workflows. Both 2D and 3D visualization and data manipulation can be performed through a scientific gateway without the need to install specific software or web browser plugins. The possibilities of web-based visualization are presented along the FreeSurfer-pipeline, a popular compute- and data-intensive software tool for quantitative neuroimaging. PMID- 22942009 TI - The Einstein Genome Gateway using WASP - a high throughput multi-layered life sciences portal for XSEDE. AB - Massively-parallel sequencing (MPS) technologies and their diverse applications in genomics and epigenomics research have yielded enormous new insights into the physiology and pathophysiology of the human genome. The biggest hurdle remains the magnitude and diversity of the datasets generated, compromising our ability to manage, organize, process and ultimately analyse data. The Wiki-based Automated Sequence Processor (WASP), developed at the Albert Einstein College of Medicine (hereafter Einstein), uniquely manages to tightly couple the sequencing platform, the sequencing assay, sample metadata and the automated workflows deployed on a heterogeneous high performance computing cluster infrastructure that yield sequenced, quality-controlled and 'mapped' sequence data, all within the one operating environment accessible by a web-based GUI interface. WASP at Einstein processes 4-6 TB of data per week and since its production cycle commenced it has processed ~ 1 PB of data overall and has revolutionized user interactivity with these new genomic technologies, who remain blissfully unaware of the data storage, management and most importantly processing services they request. The abstraction of such computational complexity for the user in effect makes WASP an ideal middleware solution, and an appropriate basis for the development of a grid-enabled resource - the Einstein Genome Gateway - as part of the Extreme Science and Engineering Discovery Environment (XSEDE) program. In this paper we discuss the existing WASP system, its proposed middleware role, and its planned interaction with XSEDE to form the Einstein Genome Gateway. PMID- 22942011 TI - Integrated support for neuroscience research: from study design to publication. AB - Computational neuroscience is a new field of research in which neurodegenerative diseases are studied with the aid of new imaging techniques and computation facilities. Researchers with different expertise collaborate in these studies. A study requires scalable computational and storage capacity and information management facilities to succeed. Many virtual laboratories are proposed and developed to facilitate these studies, however most of them cover only the parts related to the computational data processing. In this paper we describe and analyse the phases of the computational neuroscience studies including the actors, the tasks they perform, and the characteristics of each phase. Based on these we identify the required properties and functionalities of a virtual laboratory that supports the actors and their tasks throughout the complete study. PMID- 22942012 TI - iBRAIN2: automated analysis and data handling for RNAi screens. AB - We report on the implementation of a software suite dedicated to the management and analysis of large scale RNAi High Content Screening (HCS). We describe the requirements identified amongst our different users, the supported data flow, and the implemented software. Our system is already supporting productively three different laboratories operating in distinct IT infrastructures. The system was already used to analyze hundreds of RNAi HCS plates. PMID- 22942016 TI - Long-acting beta-agonist prescribing in people with asthma in primary care. AB - Long-acting beta2-agonist (LABA) monotherapy is contraindicated in asthma following reports of serious adverse events. Anonymised Scottish health data were used to determine the prevalence of LABA prescribing and LABA monotherapy (sustained and episodic) in asthma during 2006. Of 73 486 asthma patients identified, 5592 (7.6%; 95% CI 7.4% to 7.8%) were prescribed LABAs as a separate inhaler of which 991 patients had LABA monotherapy (17.7% (95% CI 16.7% to 18.7%) of patients at risk). Asthma reviews were associated with reductions in sustained (OR 0.44; 95% CI 0.32 to 0.61) but not episodic monotherapy (OR 1.16; 95% CI 0.85 to 1.57). These findings support recent changes in UK asthma guidelines recommending LABAs in fixed-dose combination inhalers. PMID- 22942017 TI - FSelector: a Ruby gem for feature selection. AB - SUMMARY: The FSelector package contains a comprehensive list of feature selection algorithms for supporting bioinformatics and machine learning research. FSelector primarily collects and implements the filter type of feature selection techniques, which are computationally efficient for mining large datasets. In particular, FSelector allows ensemble feature selection that takes advantage of multiple feature selection algorithms to yield more robust results. FSelector also provides many useful auxiliary tools, including normalization, discretization and missing data imputation. AVAILABILITY: FSelector, written in the Ruby programming language, is free and open-source software that runs on all Ruby supporting platforms, including Windows, Linux and Mac OS X. FSelector is available from https://rubygems.org/gems/fselector and can be installed like a breeze via the command gem install fselector. The source code is available (https://github.com/need47/fselector) and is fully documented (http://rubydoc.info/gems/fselector/frames). PMID- 22942018 TI - Antisense transcription is coupled to nucleosome occupancy in sense promoters. AB - MOTIVATION: Genome-wide pervasive transcription is widespread in eukaryotes, revealing an extensive array of antisense transcription that involves hundreds of previously unknown non-coding RNAs. Individual cases have shown that antisense transcription influences sense transcription, however, genome-wide mechanisms of how antisense transcription regulates sense transcription remain to be elucidated. RESULTS: Here, we performed a systematic analysis of sense-antisense transcription and nucleosome occupancy in yeast. We found that antisense transcription is associated with nucleosome occupancy in sense promoters. Using RNA polymerase II inactivation data as a reasonable approximation to antisense transcription inactivation data, we further showed that antisense transcripts increase nucleosome occupancy in sense promoter regions they overlap, and reduce nucleosome occupancy in sense promoter regions around their transcription termination sites. These results reveal the previously unappreciated roles of antisense transcription in directing nucleosome occupancy in sense promoters. Our findings will have implications in understanding regulatory functions of antisense transcription. PMID- 22942019 TI - A robust model for read count data in exome sequencing experiments and implications for copy number variant calling. AB - MOTIVATION: Exome sequencing has proven to be an effective tool to discover the genetic basis of Mendelian disorders. It is well established that copy number variants (CNVs) contribute to the etiology of these disorders. However, calling CNVs from exome sequence data is challenging. A typical read depth strategy consists of using another sample (or a combination of samples) as a reference to control for the variability at the capture and sequencing steps. However, technical variability between samples complicates the analysis and can create spurious CNV calls. RESULTS: Here, we introduce ExomeDepth, a new CNV calling algorithm designed to control for this technical variability. ExomeDepth uses a robust model for the read count data and uses this model to build an optimized reference set in order to maximize the power to detect CNVs. As a result, ExomeDepth is effective across a wider range of exome datasets than the previously existing tools, even for small (e.g. one to two exons) and heterozygous deletions. We used this new approach to analyse exome data from 24 patients with primary immunodeficiencies. Depending on data quality and the exact target region, we find between 170 and 250 exonic CNV calls per sample. Our analysis identified two novel causative deletions in the genes GATA2 and DOCK8. AVAILABILITY: The code used in this analysis has been implemented into an R package called ExomeDepth and is available at the Comprehensive R Archive Network (CRAN). PMID- 22942020 TI - Assignment of protein sequences to existing domain and family classification systems: Pfam and the PDB. AB - MOTIVATION: Automating the assignment of existing domain and protein family classifications to new sets of sequences is an important task. Current methods often miss assignments because remote relationships fail to achieve statistical significance. Some assignments are not as long as the actual domain definitions because local alignment methods often cut alignments short. Long insertions in query sequences often erroneously result in two copies of the domain assigned to the query. Divergent repeat sequences in proteins are often missed. RESULTS: We have developed a multilevel procedure to produce nearly complete assignments of protein families of an existing classification system to a large set of sequences. We apply this to the task of assigning Pfam domains to sequences and structures in the Protein Data Bank (PDB). We found that HHsearch alignments frequently scored more remotely related Pfams in Pfam clans higher than closely related Pfams, thus, leading to erroneous assignment at the Pfam family level. A greedy algorithm allowing for partial overlaps was, thus, applied first to sequence/HMM alignments, then HMM-HMM alignments and then structure alignments, taking care to join partial alignments split by large insertions into single domain assignments. Additional assignment of repeat Pfams with weaker E-values was allowed after stronger assignments of the repeat HMM. Our database of assignments, presented in a database called PDBfam, contains Pfams for 99.4% of chains >50 residues. AVAILABILITY: The Pfam assignment data in PDBfam are available at http://dunbrack2.fccc.edu/ProtCid/PDBfam, which can be searched by PDB codes and Pfam identifiers. They will be updated regularly. PMID- 22942021 TI - Biologistics--diffusion coefficients for complete proteome of Escherichia coli. AB - MOTIVATION: Biologistics provides data for quantitative analysis of transport (diffusion) processes and their spatio-temporal correlations in cells. Mobility of proteins is one of the few parameters necessary to describe reaction rates for gene regulation. Although understanding of diffusion-limited biochemical reactions in vivo requires mobility data for the largest possible number of proteins in their native forms, currently, there is no database that would contain the complete information about the diffusion coefficients (DCs) of proteins in a given cell type. RESULTS: We demonstrate a method for the determination of in vivo DCs for any molecule--regardless of its molecular weight, size and structure--in any type of cell. We exemplify the method with the database of in vivo DC for all proteins (4302 records) from the proteome of K12 strain of Escherichia coli, together with examples of DC of amino acids, sugars, RNA and DNA. The database follows from the scale-dependent viscosity reference curve (sdVRC). Construction of sdVRC for prokaryotic or eukaryotic cell requires ~20 in vivo measurements using techniques such as fluorescence correlation spectroscopy (FCS), fluorescence recovery after photobleaching (FRAP), nuclear magnetic resonance (NMR) or particle tracking. The shape of the sdVRC would be different for each organism, but the mathematical form of the curve remains the same. The presented method has a high predictive power, as the measurements of DCs of several inert, properly chosen probes in a single cell type allows to determine the DCs of thousands of proteins. Additionally, obtained mobility data allow quantitative study of biochemical interactions in vivo. CONTACT: rholyst@ichf.edu.pl. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics Online. PMID- 22942022 TI - Statistical challenges associated with detecting copy number variations with next generation sequencing. AB - MOTIVATION: Analysing next-generation sequencing (NGS) data for copy number variations (CNVs) detection is a relatively new and challenging field, with no accepted standard protocols or quality control measures so far. There are by now several algorithms developed for each of the four broad methods for CNV detection using NGS, namely the depth of coverage (DOC), read-pair, split-read and assembly based methods. However, because of the complexity of the genome and the short read lengths from NGS technology, there are still many challenges associated with the analysis of NGS data for CNVs, no matter which method or algorithm is used. RESULTS: In this review, we describe and discuss areas of potential biases in CNV detection for each of the four methods. In particular, we focus on issues pertaining to (i) mappability, (ii) GC-content bias, (iii) quality control measures of reads and (iv) difficulty in identifying duplications. To gain insights to some of the issues discussed, we also download real data from the 1000 Genomes Project and analyse its DOC data. We show examples of how reads in repeated regions can affect CNV detection, demonstrate current GC-correction algorithms, investigate sensitivity of DOC algorithm before and after quality control of reads and discuss reasons for which duplications are harder to detect than deletions. PMID- 22942025 TI - pHealth. AB - This chapter deals with my view on pHealth both as president of ICMCC, an international foundation dealing with the social, societal and ethical implications of the use of ICT in medicine and care and as a cancer survivor. PMID- 22942023 TI - CSB: a Python framework for structural bioinformatics. AB - SUMMARY: Computational Structural Biology Toolbox (CSB) is a cross-platform Python class library for reading, storing and analyzing biomolecular structures with rich support for statistical analyses. CSB is designed for reusability and extensibility and comes with a clean, well-documented API following good object oriented engineering practice. AVAILABILITY: Stable release packages are available for download from the Python Package Index (PyPI) as well as from the project's website http://csb.codeplex.com. CONTACTS: ivan.kalev@gmail.com or michael.habeck@tuebingen.mpg.de PMID- 22942026 TI - Multimodal user interfaces to improve social integration of elderly and mobility impaired. AB - Technologies for Human-Computer Interaction (HCI) and Communication have evolved tremendously over the past decades. However, citizens such as mobility impaired or elderly or others, still face many difficulties interacting with communication services, either due to HCI issues or intrinsic design problems with the services. In this paper we start by presenting the results of two user studies, the first one conducted with a group of mobility impaired users, comprising paraplegic and quadriplegic individuals; and the second one with elderly. The study participants carried out a set of tasks with a multimodal (speech, touch, gesture, keyboard and mouse) and multi-platform (mobile, desktop) system, offering an integrated access to communication and entertainment services, such as email, agenda, conferencing, instant messaging and social media, referred to as LHC - Living Home Center. The system was designed to take into account the requirements captured from these users, with the objective of evaluating if the adoption of multimodal interfaces for audio-visual communication and social media services, could improve the interaction with such services. Our study revealed that a multimodal prototype system, offering natural interaction modalities, especially supporting speech and touch, can in fact improve access to the presented services, contributing to the reduction of social isolation of mobility impaired, as well as elderly, and improving their digital inclusion. PMID- 22942027 TI - R&D in micro-nano-bio systems and contribution to pHealth. AB - The capacity to research, develop and manufacture systems that employ components based on nano- and microstructures with biological functionality, and are capable to share, ubiquitously, information is at the forefront of worldwide competition. A new generation of advanced materials, processes and emerging technologies is building up enabling highly integrated, miniaturized and smart micro-nano-bio systems to be engineered. These fast technology developments are also stimulating the explosive growth in life sciences, which is leading to an ever increasing understanding of life at the sub-cellular and molecular level. By bringing these parallel developments to biomedicine and health, ultrafast and sensitive systems can be developed to prevent illness, to support lifestyle, to make early diagnosis or treat diseases with high accuracy and less invasiveness, and to support body functions or to replace lost functionality. Such systems will enable the delivery of individualized health services with better access and outcomes at lower costs than previously deemed possible, making a substantial contribution to bringing healthcare expenditures under control and increase its productivity. The MNBS (Micro-Nano-Bio Systems) group of EU funded projects aims at speeding up the convergence of micro- and nanotechnology with the life sciences and accelerating the development of highly integrated diagnostic, monitoring and therapeutics devices. This paper presents R&D activities supported through the MNBS group that are relevant to pHealth and discusses directions to be taken in order to overcome the current problems. Finally, it addresses future challenges to build highly integrated and reliable systems including innovation and usability issues. PMID- 22942029 TI - Integrating health and social care informatics to enable holistic health care. AB - Personalization of healthcare has a number of claimants, including pHealth. However, to the citizen real personalization is the delivery of integrated support services to maintain their health and well-being, particularly in times of chronic illness and frailty. The integration of health and social care support has been identified a key but challenging step in this. The pHealth community faces the choice either of reinforcing the isolation of silos of care and thus fragmentation of service, or of seeking to become a unifying agent though thoughtful and considered development of sharing of monitoring from pHealth devices. PMID- 22942030 TI - Co-production of Health enabled by next generation personal health systems. AB - This paper describes the theoretical principles for the establishment of a parallel and complementary modality of healthcare delivery - named Coproduction of Health (CpH). This service-model activates digital data, information, and knowledge about health, healthy choices, and the individuals' health-state and computes through personalized models context-aware communication and advice. "Lightweight technologies" (smartphones, tablets, application stores) would serve as the technology close to the end-users (citizens, patients, clients, customers), connecting them with "big data" in conventionally and non conventionally organized data repositories. The CpH modality aims at providing synergies between professional healthcare, selfcare, informal care and provides data-fusion from several sources such as health characteristics of consumer goods, from sensors, actuators, and health related data-repositories, and turns this into "health added value" for the individual. A theoretical business model respecting healthcare values, ethics, and legal foundation is also sketched out. PMID- 22942031 TI - Improve Quality of Life - additional criteria for health and social care information technology acceptance in an ageing world. AB - Reversing the rising cost of health and social systems is needed in ageing developed and developing countries. A new model of ageing is advocated by the World Health Organization. This new model asks for more personal health accountability and a more integrated approach on care and preventive cure. Information systems and technologies can play an important role in supporting the changes needed in order to have better and more sustainable health and social care systems. Using value and results for patients as criteria by which systems are accepted by users and by organizations can contribute to a value based competition in health and social care systems. The unified theory of acceptance and use of technology is presented, and the pertinence of adding an extension to the theory in order capture Quality of Life improvements expectations is explored. PMID- 22942032 TI - Health care management with KeepCare. AB - Wireless sensing is part of our lives; major technological breakthroughs in the areas of sensors, integrated circuits, and also on wireless communications, led to the creation of wireless sensor networks (WSNs). Such networks have multiple uses, from monitoring and tracking of people and goods, to the coordination and processing of activities in different contexts; they are used in industry, defence and healthcare applications. As part of this use in healthcare applications KeepCare, a solution based on monitoring, tracking and processing of healthcare related information, is presented in this paper. This solution uses a WSN based application to monitor peoples' health and quality of life through vital signs and activity information received via wireless sensors. This solution monitors users such as elderly, people suffering from chronic conditions in their home environment, but can as well be used in athletes or other professionals (e.g. first responders) that need to be monitored under hazardous conditions. PMID- 22942033 TI - NovaMedTech - a regional program for supporting new medical technologies in personalized health care. AB - NovaMedTech is an initiative funded from EU structural funds for supporting new medical technologies for personalized health care. It aims at bringing these technologies into clinical use and to the health care market. The program has participants from health care, industry and academia in East middle Sweden. The first three year period of the program was successful in terms of product concepts tried clinically, and number of products brought to a commercialization phase. Further, the program has led to a large number of scientific publications. Among projects supported, we can mention: Intelligent sensor networks; A digital pen to collect medical information about health status from patients; A web-based intelligent stethoscope; Methodologies to measure local blood flow and nutrition using optical techniques; Blood flow assessment from ankle pressure measurements; Technologies for pressure ulcer prevention; An IR thermometer for improved accuracy; A technique that identifies individuals prone to commit suicide among depressed patients; Detection of infectious disease using an electronic nose; Identification of the lactate threshold from breath; Obesity measurements using special software and MR camera; and An optical probe guided tumor resection. During the present three years period emphasis will be on entrepreneurial activities supporting the commercialization and bringing products to the market. PMID- 22942034 TI - The SWORD tele-rehabilitation system. AB - In spite of the growing interest verified in the field of technology-based interventions for Stroke rehabilitation, there is still no global solution that is both successful and suitable for a widespread use [1,2]. In this article, we present a novel tele-rehabilitation tool designed to be used for ambulatory patients, and developed towards the motor recovery of the patient's upper-limb. The SWORD system combines a movement quantification system that analyzes the quality of the motor task performed with a biofeedback console. The proposed structure defines the SWORD system as a complete tele-rehabilitation framework that enables a direct connection between clinical and ambulatory settings. Currently a randomized clinical trial is being designed in order to assess the effectiveness of the SWORD tele-rehabilitation system. PMID- 22942036 TI - Gamification and serious games for personalized health. AB - Computer games are no longer just a trivial activity played by children in arcades. Social networking and casual gaming have broadened the market for, and acceptance of, games. This has coincided with a realization of their power to engage and motivate players. Good computer games are excellent examples of modern educational theory [1]. The military, health providers, governments, and educators, all use computer games. This paper focuses on Games for Health, discussing the range of areas and approaches to developing these games. We extend a taxonomy for Games for Health, describe a case study on games for dementia sufferers, and finally, present some challenges and research opportunities in this area. PMID- 22942037 TI - The HemoCop Telemetric Sensor System: technology and results of in-vivo assessment. AB - Upper gastrointestinal bleeding is considered the most frequent emergency in endoscopy units. Decisive for successful treatment of acute upper gastrointestinal bleeding is a timely recognition. We have developed a telemetric implant containing a novel optical sensor principle able to detect the presence of blood in the lumen of the GI tract. In-vivo experiments demonstrated the possibility to detect bleeding in situ and to send an alert signal to an extracorporeal receiver. PMID- 22942038 TI - Inductive coupling system for endovascular aneurysm repair monitoring. AB - Endoleaks are one of the major concerns in the long-term follow-up of endovascular aneurysm repair treatment (EVAR). Therefore, periodic monitoring is required to detect eventual damages in an implanted stent-graft. A monitoring system for post EVAR procedure based on inductive-coupling which avoids the need to resorting to more complex biomedical imaging systems is presented here. Endoleaks are detected with capacitive pressure sensors placed in the stent-graft and monitored externally after the measure of the oscillation frequency provided by the LC circuit created by sensors and inductive coupling. PMID- 22942039 TI - Long term monitoring of blood flow at multiple depths - observations of changes. AB - Detecting reduced circulation, which is a major factor in the development of pressure ulcers, can be done using optical methods. PPG and LDF can be combined and used to evaluate blood flow at different depths. In this study the use of a probe combining PPG and LDF to monitor multiple tissue depths is evaluated. The effects on blood flow and temperature without additional provocation was examined. Measurements were performed during 60 min and the use of an active probe was compared with the use of a semi-active probe turned off a major part of the time. Changes in temperature and blood flow using these probe configurations (active and semi-active probe) are compared; four different 5 min segments during a 60 min measurement. A general increase in both temperature and blood flow is found but this increase could not be concluded to occur due to the light sources of the probe. PMID- 22942040 TI - Identification of sit-to-stand and stand-to-sit transitions using a single inertial sensor. AB - In order to enhance the quality of life of people with mobility problems like Parkinson's disease or stroke patients, it is crucial to monitor and assess their daily life activities by characterizing basic movements like postural transitions, which is the main goal of this work. This paper presents a novel postural transition detection algorithm which is able to detect and identify Sit to Stand and Stand to Sit transitions with a Sensitivity of 88.2% and specificity of 98.6% by using a single sensor located at the user's waist. The algorithm has been tested with 31 healthy volunteers and an overall amount of 545 transitions. The proposed algorithm can be easily implemented in real-time system for on-line monitoring applications. PMID- 22942042 TI - An approach to geotracking patients with Alzheimer's disease. AB - Recently, numerous systems for geo-tracking Alzheimer's patients with dementia have been developed and reported to be functional for the purposes of security and data collection. However, studies stated possible loss of freedom and autonomy for patients, along with violations of their privacy, which may lead to loss of prestige/dignity. In this study, a geotracking system that aims to balance patients' security and their need for privacy and autonomy is proposed. The system introduces a personalized, four-level temporal geofence based tracking, warning and notification protocol that incorporates a safety check mechanism operating over Global System for Mobile Communications network. PMID- 22942043 TI - A system for inference of spatial context of Parkinson's disease patients. AB - This work proposes a concept for indoor ambulatory monitoring for Parkinson's disease patients. In the proposed concept, a wearable inertial sensor is kept as the main monitoring device through the day, and it is expanded by an ambient sensor system in the specific living areas with high estimated probability of occurrence of freezing of gait episode. The ambient sensor system supports decisions of the wearable sensor system by providing relevant spatial context information of the user, which is obtained through precise localization. PMID- 22942044 TI - The use of exer-learning games for rehabilitation in spa clinics at home. AB - This paper examines benefits of the exer-learning concept HOPSCOTCH for rehabilitation in spa clinics and at home. It describes a specific application to motivate obese patients in spa clinics for exercise. Furthermore results of an empirical study are reported where HOPSCOTCH was implemented in two spa clinics for a period of four weeks. The results of the study have shown that the concept is very convincing, but mainly depends on the content of the application; however the idea of HOPSCOTCH appeared to have a high potential to be used as a therapeutic agent in terms of motivation for exercise. PMID- 22942045 TI - Force and touch make video games 'serious' for dexterity rehabilitation. AB - Computerized interfaces are able to represent 3D immersive simulations. Most of them make use of joystick, mouse, gloves, or grasp pressure transducers. Those have the drawback of 'filtering' the user interaction and/or de-locate the touch with respect to the visual stimulus. To overcome this we developed dexterity rehabilitation games on a novel touch interface that measures also force. The system allows dexterity training through 'direct' manipulation of virtual objects in 3D. Two dimensions via the touch screen, the third by the force channel. Tactile feedback is provided with a vibration device mounted on the screen back. PMID- 22942047 TI - Standards and solutions for architecture based, ontology driven and individualized pervasive health. AB - Based on the long-term work of scientific institutions and SDOs dedicated to system architectures, an interoperability framework is presented to help navigation through existing, emerging and even future standards for comprehensive interoperability of intelligent health and social care services. HL7 artifacts as well as work products of competing organizations are classified and semi-formally interrelated. The methodology is proven in many international standard development and health information systems implementation projects. PMID- 22942048 TI - Mobile health apps - from singular to collaborative. AB - Mobile health apps are proliferating, but they fail to deliver on a key patient and caregiver requirement - the ability to collaborate using key phone features while leveraging existing web services. Typically, mobile health apps are for single use, proprietary, and deliver closed-world solutions. By making use of web services, both open and proprietary, mobile health apps can be created to support the caregiver network in the community. The full value of telehealth will only be achieved when the spectrum of trusted health care services (preventive, promotion, curative, and rehabilitative) is delivered to the collaborating network of caregivers. PMID- 22942049 TI - Architectural approach for semantic EHR systems development based on Detailed Clinical Models. AB - The integrative approach to health information in general and the development of pHealth systems in particular, require an integrated approach of formally modeled system architectures. Detailed Clinical Models (DCM) is one of the most promising modeling efforts for clinical concept representation in EHR system architectures. Although the feasibility of DCM modeling methodology has been demonstrated through examples, there is no formal, generic and automatic modeling transformation technique to ensure a semantic lossless transformation of clinical concepts expressed in DCM to either clinical concept representations based on ISO 13606/openEHR Archetypes or HL7 Templates. The objective of this paper is to propose a generic model transformation method and tooling for transforming DCM Clinical Concepts into ISO/EN 13606/openEHR Archetypes or HL7 Template models. The automation of the transformation process is supported by Model Driven Development (MDD) transformation mechanisms and tools. The availability of processes, techniques and tooling for automatic DCM transformation would enable the development of intelligent, adaptive information systems as demanded for pHealth solutions. PMID- 22942050 TI - Adaptive intelligent systems for pHealth - an architectural approach. AB - Health systems around the globe, especially in developing countries, are facing the challenge of delivering effective, safe, and high quality public health and individualized health services independent of time and location, and with minimum of allocated resources (pHealth). In this context, health promotion and health education services are very important, especially in primary care settings. The objective of this paper is to describe the architecture of an adaptive intelligent system mainly developed to support education and training of citizens, but also of health professionals. The proposed architecture describes a system consisting of several agents that cooperatively interact to find and process tutoring materials to disseminate them to users (multi-agent system). A prototype is being implemented which includes medical students from the Medical Faculty at University of Cauca (Colombia). In the experimental process, the student's learning style - detected with the Bayesian Model - is compared against the learning style obtained from a questioner (manual approach). PMID- 22942051 TI - Architectural analysis of clinical ontologies for pHealth interoperability. AB - Comprehensive interoperability between eHealth/pHealth systems requires properly represented shared knowledge. Formal ontologies allow specifying the semantics of health knowledge representation in a well-defined and unambiguous manner. The objective of this paper is to formally analyze - from a system-theoretical architectural perspective - existing clinical ontologies. The paper defines important ontology requirements for semantically interoperable pHealth/eHealth systems. Then, based on those requirements, 17 criteria are defined and used for analyzing 129 clinical ontologies. Statistical results confirm that most ontologies do not meet the defined criteria. OBO foundry defines a good approach to meet all defined criteria, but it does not cover yet the clinical domain as a whole. SNOMED CT was found the more comprehensive one, despite several restrictions. PMID- 22942053 TI - pHealth and wearable technologies: a permanent challenge. AB - Wearable technologies have been evolving towards daily usage and are a major player in the personalized health challenge. In this paper we present a personal view of their evolution, how one of them developed within our lab went to the international market and how this type of technology is being used in pHealth projects for first responder professionals and public transportation drivers. PMID- 22942054 TI - The challenges facing wearable sensor systems. AB - It has been pointed out that, in spite of significant national and international funding programmes, there is a dearth of successfully commercialised wearable monitoring systems. Although problems such as financial reimbursement, device interoperability and the present lack of the required connected healthcare infrastructure are major hurdles to the provision of remote clinical monitoring of home-based patients, the "Mount Everest" of monitoring applications, why are wearable systems not already commercialised and used in less demanding applications? The numerous wearable systems which appear on the Web and even in the literature are, for the most part, basic prototypes unsuited to the demands of real-life applications. SMEs which do seek to commercialise clinically promising systems are unfortunately faced with many challenges and few as yet have survived long enough to successfully commercialise their innovations. PMID- 22942055 TI - Wearable monitoring systems in pre-term newborns care. AB - In the last decade, the trends in the development and management of healthcare services are focused on the personalization of prevention, diagnosis and treatment. This paper presents an example of the development of wearable technology for biosignal monitoring in the field of pre-term newborns care. The system was validated by an in-hospital pre-clinical test demonstrating efficiency, reliability and quality. PMID- 22942056 TI - Wearable wireless multi-parameter sensor module for physiological monitoring. AB - Advances in low power technology have given new possibilities for continuous physiological monitoring in several domains such as health care with disease prevention and quality of care services and workers in harsh environment. A miniaturized, multifunctional sensor module that transmits sensor data wirelessly using Bluetooth Smart technology has been developed. The wireless communication link is influenced by factors like antenna orientation, reflections, interference and noise. Test results for signal strength measurements for the wireless transmission in various setups are given and discussed. PMID- 22942057 TI - A wearable sensor network for human locomotion data capture. AB - A new wearable data capture system for gait analysis is being developed. It consists of a pantyhose with embedded conductive yarns interconnecting customized sensing electronic devices that capture inertial and electromyographic signals and sends aggregated information to a personal computer through a wireless link. The use of conductive yarns to build the myoelectric electrodes and the interconnections of the wired sensors network, as well as the topology and functionality of the sensor modules are presented. PMID- 22942058 TI - Sport monitoring with smart wearable system. AB - This work presents a new system for sport monitoring. The system was composed of a t-shirt with two textile electrodes and two devices for the acquisition, storage, processing and visualization of the signals. The systems allows monitoring both ECG signal (raw and processed heart-rate) and 3 axial acceleration (raw and step counter). The systems were tested in different conditions during some races; we report the results on three subjects during a skyrunning race. PMID- 22942059 TI - ZigBee-based remote patient monitoring. AB - This paper describes a developed continuous patient monitoring system based on the ZigBee protocol. The system was tested in the hospital environment using six sensor devices in two different modes. For electrocardiogram transmission and in the absence of hidden-nodes, the system achieved a mean delivery ratio of 100% and 98.56%, respectively for star and 2-hop tree network topologies. When sensor devices were arranged in a way that three of them were unable to hear the transmissions made by the other three, the mean delivery ratio dropped to 83.96%. However, when sensor devices were reprogrammed to transmit only heart rate values, the mean delivery ratio increased to 99.90%, despite the presence of hidden-nodes. PMID- 22942061 TI - User clustering in smartphone applications. AB - In the context of mobile health applications usability is a crucial factor to achieve user acceptance. The successful user interface (UI) design requires a deep understanding of the needs and requirements of the targeted audience. This paper explores the application of the K-Means algorithm on smartphone usage data in order to offer Human Computer Interaction (HCI) specialists a better insight into their user group. Two different feature space representations are introduced and used to identify persona like stereotypes in a real world data set, which was obtained from a public available smartphone application. PMID- 22942062 TI - Extraction of ABCD rule features from skin lesions images with smartphone. AB - One of the greatest challenges in dermatology today is the early detection of melanoma since the success rates of curing this type of cancer are very high if detected during the early stages of its development. The main objective of the work presented in this paper is to create a prototype of a patient-oriented system for skin lesion analysis using a smartphone. This work aims at implementing a self-monitoring system that collects, processes, and stores information of skin lesions through the automatic extraction of specific visual features. The selection of the features was based on the ABCD rule, which considers 4 visual criteria considered highly relevant for the detection of malignant melanoma. The algorithms used to extract these features are briefly described and the results achieved using images taken from the smartphone camera are discussed. PMID- 22942063 TI - Personalised mobile health and fitness apps: lessons learned from myFitnessCompanion(r). AB - Smartphones and tablets are slowly but steadily changing the way we look after our health and fitness. Today, many high quality mobile apps are available for users and health professionals and cover the whole health care chain, i.e. information collection, prevention, diagnosis, treatment and monitoring. Our team has developed a mobile health and fitness app called myFitnessCompanion(r) which has been available via Android market since February 2011. The objective of this paper is to share our experience with rolling out a mobile health and fitness app. We discuss the acceptance of health apps by end-users and healthcare industry. We discuss how mobile health apps will be distributed in the near future, the use of Personal Health Record (PHR) systems such as Microsoft HealthVault and the impact of regulations (FDA) on the future of mobile health apps. The paper is based on seven years of experience by the authors as mobile health and fitness application developers and we discuss the challenges and opportunities for app developers in the health industry. PMID- 22942064 TI - Dance! Don't Fall - preventing falls and promoting exercise at home. AB - Falling is a serious danger to older adults that is usually only addressed after a person has fallen, when doctors administer clinical tests to determine the patient's risk of falling again. Having the technological capability of performing fall risk assessment tests with a smartphone, the authors set out to design a mobile application that would enable users to monitor their risk themselves and consequently prevent falls from occurring. The authors conducted a literature review and two observation sessions before beginning the iterative design process that resulted in the Dance! Don't Fall (DDF) game, a mobile application that enables users to both monitor their fall risk and actively reduce it through fun and easy exercise. PMID- 22942066 TI - An ecosystem of products and systems for ambient intelligence - the AAL4ALL users perspective. AB - Developed societies are currently facing severe demographic changes: the world is getting older at an unprecedented rate. In 2000, about 420 million people, or approximately 7 percent of the world population, were aged 65 or older. By 2050, that number will be nearly 1.5 billion people, about 16 percent of the world population. This demographic trend will be also followed by an increase of people with physical limitations. The traditional health care systems, not only in Portugal, but also in all other European states, will be faced with new challenges. There is an urgent need to find solutions that allow extending the time people can live in their preferred environment by increasing their autonomy, self-confidence and mobility. AAL4ALL presents an idea for an answer through the development of an ecosystem of products and services for Ambient Assisted Living (AAL) associated to a business model and validated through large scale trial. This paper presents the results of the first survey developed within the AAL4ALL project: the users' survey targeted at the Portuguese seniors and pre-seniors. In this way, this paper addresses the lives of the Portuguese population aged 50 and over. PMID- 22942067 TI - Towards interoperability and integration of Personal Health AAL ecosystems. AB - Due to the changing demographics and cost problems in health systems, an ever increasing portion of the ageing population is ready to use personalized technology for health applications as well as for assistance and care in order to remain in their familiar environment as long as possible. Despite their resulting market potential, Personal Health and AAL (Ambient Assisted Living) solutions are still waiting for broad application. In addition to a lack of viable business models broadly accepted as a main obstacle to market success, further shortfalls of dominating insulated available Personal Health and AAL products are identified. To overcome these, the ongoing European universAAL project and related community building activities of the AALOA Association aim at a broadly accepted unified interoperable open AAL platform that incorporates existing AAL platform concepts and particularly includes the already established ISO/IEEE 11073 standards-based Continua Personal Health ecosystem. PMID- 22942068 TI - JIM: a novel and efficient accelerometric magnitude to measure physical activity. AB - There are various techniques available to measure human physical activity (PA). Accelerometer based techniques claim to be non-invasive and easy to use. The signal magnitude area (SMA) is the most extended feature used to measure the physical activity. It is calculated by sampling and filtering an accelerometer signal of at least at 50 Hz. SMA has a proven and widely accepted linear relation with the energy expenditure. A novel magnitude called JIM, which is more efficient than SMA, is proposed in this paper. The jerk-based inactivity magnitude (JIM) is also calculated from the acceleration signal, but at a sampling rate of 1Hz, increasing the battery life of the measuring system. This magnitude gives the same information as the SMA (correlation of 95%) and is validated with a group of 39 users in free-living conditions for at least 24 hours. PMID- 22942069 TI - User experiences of mobile controlled games for activation, rehabilitation and recreation of elderly and physically impaired. AB - The purpose of this paper was to study how aged people experience mobile controlled game as a method of rehabilitation and recreation. The target group contained persons 70+ years of age living in assisted living conditions (N=34). The average age of the participants was 85.9 years. Women (n=17) and men (n=17) were equally presented in the sample group. Only 12 % (n=4) of participants were involved in an active weekly-based rehabilitation, light physical sitting exercises 38% (n=13). Three (n=3) of the participants (9%) used computers (net banking), and 20 (59%) used mobile phones on daily basis. Social activities and physical activation seem to be rather inadequate and traditional in assisted living organizations. The overall experiences of mobile controlled game described in this paper appeared to be a successful experiment also proving that the elderly are not as reluctant to use technical devices or playing virtual games as often thought. The game was reckoned very motivating, interesting, and entertaining both by the aged and the staff. Activation, rehabilitation and recreation in the elderly homes or assisted living organizations could benefit from utilization of new technology providing new ways and solutions that motivate the users and offer also possibilities for measuring and follow-up of the physical impacts. The future goals to improve the game were set according to the feedback given in this survey: a) wider variety of controlling modes for the game, b) developing various difficulty levels, c) developing the game to support different kinds of body movements, d) easily modified according to the individual user's exercising or rehabilitation needs as well as e) emphasizing the social aspects of the game by producing multiplayer versions. PMID- 22942070 TI - Towards quality assurance of AAL services. AB - The Ambient Assisted Living domain is a fast growing area with many new technological artefacts and services developed. Most of the systems developed address end-users' needs. Yet, they have not achieved a large market penetration. The work presented here argues that this is primarily due to not sufficiently addressing the quality requirements posed by the health care organizations. Satisfying quality requirements requires a standardized and easily accessible framework for measuring quality. We present the initial steps towards such a framework by building on relevant ISO standards. PMID- 22942075 TI - Novel chimeras of botulinum and tetanus neurotoxins yield insights into their distinct sites of neuroparalysis. AB - Botulinum neurotoxin (BoNT) A or E and tetanus toxin (TeTx) bind to motor-nerve endings and undergo distinct trafficking; their light-chain (LC) proteases cleave soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNAREs) peripherally or centrally and cause flaccid or spastic paralysis, respectively. To seek protein domains responsible for local blockade of transmitter release (BoNTs) rather than retroaxonal transport to spinal neurons (TeTx), their acceptor-binding moieties (H(C))--or in one case, heavy chain (HC)--were exchanged by gene recombination. Each chimera, expressed and purified from Escherichia coli, entered rat cerebellar neurons to cleave their substrates, blocked in vitro nerve-induced muscle contractions, and produced only flaccid paralysis in mice. Thus, the local cytosolic delivery of BoNT/A or BoNT/E proteases and the contrasting retrograde transport of TeTx are not specified solely by their HC or H(C); BoNT/A LC translocated locally irrespective of being targeted by either of the latter TeTx domains. In contrast, BoNT/E protease fused to a TeTx enzymatically inactive mutant (TeTIM) caused spastic paralysis and cleaved SNAP-25 in spinal cord but not the injected muscle. Apparently, TeTIM precludes cytosolic release of BoNT/E protease at motor nerve endings. It is deduced that the LCs of the toxins, acting in conjunction with HC domains, dictate their local or distant destinations. PMID- 22942076 TI - Piggybacking as a media advocacy strategy to increase enrolments in a gender oriented smoking cessation programme. AB - Argentina is probably moving to the third phase of the smoking epidemic. Female smoking prevalence is expected to increase over the coming years. In Argentina, smoking cessation programmes usually do not provide specific treatment tailored to women. We implemented a 'piggybacking' media strategy with the goal of announcing the opening of the first gender-oriented smoking cessation programme in Argentina. Piggybacking is a well-known media advocacy strategy in which the newsworthiness of a particular story is increased by releasing it at the same time as a breaking news story about a related topic. We prepared a press release/report about tobacco use among women, as well as our gender-oriented clinic, for the local news media, which appeared in print around the time a well known young Argentinean actress died. To assess the impact of this strategy, we reviewed media coverage after the press release was issued. We also compared the number of new participants in our programme during the 4 months before and after the report's publication. During the 4 months following our press release, we found five reports in print media, gave 22 radio and seven television interviews, and found 30 digital media publications drawing on our press release. When comparing the 4 months before with the 4 months after the strategy, new participants in our programme increased by 246.15%. This strategy could be a suitable alternative to other media advocacy strategies to increase the number of new participants in smoking cessation programmes. PMID- 22942074 TI - Retinoic acid expands the evolutionarily reduced dentition of zebrafish. AB - Zebrafish lost anterior teeth during evolution but retain a posterior pharyngeal dentition that requires retinoic acid (RA) cell-cell signaling for its development. The purposes of this study were to test the sufficiency of RA to induce tooth development and to assess its role in evolution. We found that exposure of embryos to exogenous RA induces a dramatic anterior expansion of the number of pharyngeal teeth that later form and shifts anteriorly the expression patterns of genes normally expressed in the posterior tooth-forming region, such as pitx2 and dlx2b. After RA exposure, we also observed a correlation between cartilage malformations and ectopic tooth induction, as well as abnormal cranial neural crest marker gene expression. Additionally, we observed that the RA induced zebrafish anterior teeth resemble in pattern and number the dentition of fish species that retain anterior pharyngeal teeth such as medaka but that medaka do not express the aldh1a2 RA-synthesizing enzyme in tooth-forming regions. We conclude that RA is sufficient to induce anterior ectopic tooth development in zebrafish where teeth were lost in evolution, potentially by altering neural crest cell development, and that changes in the location of RA synthesis correlate with evolutionary changes in vertebrate dentitions. PMID- 22942077 TI - Rainbow: an integrated tool for efficient clustering and assembling RAD-seq reads. AB - MOTIVATION: The innovation of restriction-site associated DNA sequencing (RAD seq) method takes full advantage of next-generation sequencing technology. By clustering paired-end short reads into groups with their own unique tags, RAD-seq assembly problem is divided into subproblems. Fast and accurately clustering and assembling millions of RAD-seq reads with sequencing errors, different levels of heterozygosity and repetitive sequences is a challenging question. RESULTS: Rainbow is developed to provide an ultra-fast and memory-efficient solution to clustering and assembling short reads produced by RAD-seq. First, Rainbow clusters reads using a spaced seed method. Then, Rainbow implements a heterozygote calling like strategy to divide potential groups into haplotypes in a top-down manner. And along a guided tree, it iteratively merges sibling leaves in a bottom-up manner if they are similar enough. Here, the similarity is defined by comparing the 2nd reads of a RAD segment. This approach tries to collapse heterozygote while discriminate repetitive sequences. At last, Rainbow uses a greedy algorithm to locally assemble merged reads into contigs. Rainbow not only outputs the optimal but also suboptimal assembly results. Based on simulation and a real guppy RAD-seq data, we show that Rainbow is more competent than the other tools in dealing with RAD-seq data. AVAILABILITY: Source code in C, Rainbow is freely available at http://sourceforge.net/projects/bio-rainbow/files/ PMID- 22942082 TI - Genomic dissection and prioritizing of candidate genes of QTL for regulating spontaneous arthritis on chromosome 1 in mice deficient for interleukin-1 receptor antagonist. AB - Rheumatoid arthritis is a heterogeneous disease with clinical and biological polymorphisms. IL-1RN is a protein that binds to interleukin-1 (IL-1) receptors and inhibits the binding of IL-1-alpha and IL-1-beta. IL-1RN levels are elevated in the blood of patients with a variety of infectious, immune, and traumatic conditions. Balb/c mice deficient in IL-1ra (mouse gene of IL-1RN) develop spontaneous autoimmune arthritis while DBA/1 mice deficient in IL-1ra do not. Previously, we identified a major QTL that regulates the susceptibility to arthritis in Balb/c mice with IL-1ra deficiency. In this study, we found that the QTL may contain two peaks that are regulated by two sets of candidate genes. By haplotype analysis, the total genomic regions of candidate genes were reduced from about 19 Mbp to approximately 9 Mbp. The total number of candidate genes was reduced from 208 to 21. PMID- 22942083 TI - The evolution and utility of ribosomal ITS sequences in Bambusinae and related species: divergence, pseudogenes, and implications for phylogeny. AB - Ribosomal internal transcribed spacer (ITS) sequences are commonly used for phylogenetic reconstruction because they are highly reiterated as components of rDNA repeats, and hence are often subject to rapid homogenization through concerted evolution. Concerted evolution leads to intragenomic uniformity of repeats even between loci on nonhomologous chromosomes. However, a number of studies have shown that the ITS polymorphism within individuals is quite common. The molecular systematics of Bambusinae and related species were recently assessed by different teams using independently generated ITS sequences, and the results disagreed in some remarkable features. Here we compared the ITS sequences of the members of Bambusa s. l., the genera Dendrocalamus, Dinochloa, Gigantochloa, Guadua, Melocalamus, Monocladus, Oxytenanthera, Thyrsostachys, Pleioblastus, Pseudosasa and Schizostachyum.We have reanalysed the ITS sequences used by different research teams to reveal the underlying patterns of their different results. After excluding the sequences suspected to represent paralogous loci, a phylogenetic analysis of the subtribe Bambusinae species were performed using maximum parsimony and maximum-likelihood methods. The implications of the findings are discussed. The risk of incorporating ITS paralogues in plant evolutionary studies that can distort the phylogenetic signal should caution molecular systematists. PMID- 22942084 TI - The mitochondrial genome of the quiet-calling katydids, Xizicus fascipes (Orthoptera: Tettigoniidae: Meconematinae). AB - To help determine whether the typical arthropod arrangement was a synapomorphy for the whole Tettigoniidae, we sequenced the mitochondrial genome (mitogenome) of the quiet-calling katydids, Xizicus fascipes (Orthoptera: Tettigoniidae: Meconematinae). The 16,166-bp nucleotide sequences of X. fascipes mitogenome contains the typical gene content, gene order, base composition, and codon usage found in arthropod mitogenomes. As a whole, the X. fascipes mitogenome contains a lower A+T content (70.2%) found in the complete orthopteran mitogenomes determined to date. All protein-coding genes started with a typical ATN codon. Ten of the 13 protein-coding genes have a complete termination codon, but the remaining three genes (COIII, ND5 and ND4) terminate with incomplete T. All tRNAs have the typical clover-leaf structure of mitogenome tRNA, except for tRNA(Ser(AGN)), in which lengthened anticodon stem (9 bp) with a bulged nuleotide in the middle, an unusual T-stem (6 bp in constrast to the normal 5 bp), a mini DHU arm (2 bp) and no connector nucleotides. In the A+T-rich region, two (TA)n conserved blocks that were previously described in Ensifera and two 150-bp tandem repeats plus a partial copy of the composed at 61 bp of the beginning were present. Phylogenetic analysis found: i) the monophyly of Conocephalinae was interrupted by Elimaea cheni from Phaneropterinae; and ii) Meconematinae was the most basal group among these five subfamilies. PMID- 22942085 TI - Introgression of a leaf rust resistance gene from Aegilops caudata to bread wheat. AB - Rusts are the most important biotic constraints limiting wheat productivity worldwide. Deployment of cultivars with broad spectrum rust resistance is the only environmentally viable option to combat these diseases. Identification and introgression of novel sources of resistance is a continuous process to combat the ever evolving pathogens. The germplasm of nonprogenitor Aegilops species with substantial amount of variability has been exploited to a limited extent. In the present investigation introgression, inheritance and molecular mapping of a leaf rust resistance gene of Ae. caudata (CC) acc. pau3556 in cultivated wheat were undertaken. An F(2) population derived from the cross of Triticum aestivum cv. WL711 - Ae. caudata introgression line T291-2 with wheat cultivar PBW343 segregated for a single dominant leaf rust resistance gene at the seedling and adult plant stages. Progeny testing in F(3) confirmed the introgression of a single gene for leaf rust resistance. Bulked segregant analysis using polymorphic D-genome-specific SSR markers and the cosegregation of the 5DS anchored markers (Xcfd18, Xcfd78, Xfd81 and Xcfd189) with the rust resistance in the F(2) population mapped the leaf rust resistance gene (LrAC) on the short arm of wheat chromosome 5D. Genetic complementation and the linked molecular markers revealed that LrAC is a novel homoeoallele of an orthologue Lr57 already introgressed from the 5M chromosome of Ae. geniculata on 5DS of wheat. PMID- 22942086 TI - Comparative mapping reveals similar linkage of functional genes to QTL of yield related traits between Brassica napus and Oryza sativa. AB - Oryza sativa and Brassica napus-two important crops for food and oil, respectively-share high seed yield as a common breeding goal. As a model plant, O. sativa genomics have been intensively investigated and its agronomic traits have been advanced. In the present study, we used the available information on O. sativa to conduct comparative mapping between O. sativa and B. napus, with the aim of advancing research on seed-yield and yield-related traits in B. napus. Firstly, functional markers (from 55 differentially expressed genes between a hybrid and its parents) were used to detect B. napus genes that co-localized with yield-related traits in an F(2:3) population. Referring to publicly available sequences of 55 B. napus genes, 53 homologous O. sativa genes were subsequently detected by screening, and their chromosomal locations were determined using silico mapping. Comparative location of yield-related QTL between the two species showed that a total of 37 O. sativa and B. napus homologues were located in similar yield-related QTL between species. Our results indicate that homologous genes between O. sativa and B. napus may have consistent function and control similar traits, which may be helpful for agronomic gene characterization in B. napus based on what is known in O. sativa. PMID- 22942087 TI - A microRNA signature associated with chondrogenic lineage commitment. AB - Generating appropriate cartilage for clinical applications to heal skeletal tissue loss is a major health concern. In this regard, cell-based approaches offer a potential therapeutic strategy for cartilage repair, although little is known about the precise mechanism of chondrogenesis. Unrestricted somatic stem cell (USSC) is considered as a suitable candidate because of its potential for differentiating into multiple cell types. Recent studies show that microRNAs (miRNAs) are involved in several biological processes including development and differentiation. To identify the chondro-specific miRNA signature, miRNA patterns of USSCs and differentiated chondrocytes were investigated using microarrays and validation by qPCR. Prior to these analyses, chondrogenic commitment of differentiated USSCs was verified by immunocytochemistry, specific staining and evaluation of some main chondrogenic marker genes. Various in silico explorations (for both putative targets and signalling pathways) and empirical analyses (miRNA transfections followed by qPCR of some chondrogenic indicators) were carried out to support our results. Transient modulation of multiple chondro-miRs (such as mir-630, mir-624 and mir-376) with chondrocyte targets (such as TGFbR, MAP3K, collagens, SMADs and cadherins) as mediators of chondrogenic signalling pathways including cell-cell interactions, TGF-beta, and MAPK signalling suggests a mechanism for genetic induction of chondrogenic differentiation. In conclusion, this research reveals more details about the allocation of USSCs into the chondrocytes through identification of miRNA signature which modulates targets and pathways required for chondrogenic lineage and could provide guidelines for future clinical treatments and anti-miRNA therapies. PMID- 22942088 TI - Genetic structure of a novel biofuel-producing microorganism community. AB - Biofuels are an important alternative, renewable source of energy in the face of the ongoing depletion of fossil fuels. Cheese whey is a dairy industry waste characterized by high lactose concentration, which represents a significant environmental problem. Bio-ethanol production by cheese whey could be an effective nonvegetable source for renewable energy production. Here, we report the isolation of a mixed microbial population, able to produce ethanol as main fermentation product from fermenting whey. The microbial consortium has been used to perform a batch fermentation of crude whey in both anoxic and hypoxic conditions. Maximum ethanol concentrations achieved in this study was obtained using the mixed culture in hypoxic conditions, grown at pH 4 and 30 degrees C, with ethanol production yield of 60 g/L. Our research has pointed out an alternative way to both dispose and valorize cheese whey, a dairy by-product that could cause water pollution and harm to the environment if not properly treated. PMID- 22942089 TI - Marker-assisted selection of high molecular weight glutenin alleles related to bread-making quality in Iranian common wheat (Triticum aestivum L.). AB - Bread-making quality in hexaploid wheats is a complex trait. It has been shown that the amount and composition of protein can influence dough rheological properties. The high-molecular-weight (HMW) glutenins are encoded by a complex locus, Glu-1, on the long arm of group-1 homoeologus chromosome of the A, B and D genomes. In this work we used PCR-based DNA markers as a substitution tool to distinguish wheat bread-making quality. We detected PCR-based DNA markers for coding sequence of Glu-A1x, Glu-B1x and Glu-D1x to be 2300 bp, 2400 bp and 2500 bp respectively. DNA markers related to coding sequence of Glu-A1y, Glu-B1y and Glu-D1y were; 1800 bp, 2100 bp and 1950 bp, however, the repetitive region of their coding sequence were shown to be about 1300 bp, 1500 bp and 1600 bp. The results demonstrate that the size variation was due to different lengths of the central repetitive domain. Good or poor bread-making quality in wheat is associated with two allelic pairs of Glu-D1, designated 1Dx5-1Dy10 and 1Dx2 1Dy12. The 1Bx7 allele has moderate-to-good quality score. The specific DNA markers, of 450 bp, 576 bp, 612 bp and 2400 bp respectively were characterized for 1Dx5, 1Dy10, 1Dy12 and 1Bx7 alleles. These markers are very important in screening of wheat for bread-making quality. PMID- 22942090 TI - Molecular analysis of mutants of the Neurospora adenylosuccinate synthetase locus. AB - The ad-8 gene of Neurospora crassa, in addition to being used for the study of purine biology, has been extensively studied as a model for gene structure, mutagenesis and intralocus recombination. Because of this there is an extensive collection of well-characterized N. crassa ad-8 mutants in the Fungal Genetics Stock Center collection. Among these are spontaneous mutants and mutants induced with X-ray, UV or chemical mutagens. The specific lesions in these mutants have been genetically mapped at high resolution. We have sequenced the ad-8 locus from 13 of these mutants and identified the molecular nature of the mutation in each strain. We compare the historical fine-structure map to the DNA and amino acid sequence of each allele. The placement of the individual lesions in the fine structure map was more accurate at the 5' end of the gene and no mutants were identified in the 3' untranslated region of this gene. We additionally analysed ad-8(+) alleles in 18 N. crassa strains subjected to whole-genome sequence analysis and describe the variability among Neurospora strains and among fungi and other organisms. PMID- 22942091 TI - Two variants in STK11 gene in Chinese patients with Peutz-Jeghers syndrome. PMID- 22942092 TI - Karyotype of asparagus by physical mapping of 45S and 5S rDNA by FISH. PMID- 22942093 TI - Detection of probable marker-free transgene-positive rice plants resistant to rice tungro disease from backcross progenies of transgenic Pusa Basmati 1. PMID- 22942094 TI - Analysing molecular characteristics of the SLA-1 gene from Chinese Hebao pigs. PMID- 22942095 TI - Improved transfection of HUVEC and MEF cells using DNA complexes with magnetic nanoparticles in an oscillating field. PMID- 22942096 TI - H63D mutation in HFE gene is common in Indians and is associated with the European haplotype. PMID- 22942097 TI - Novel de novo nonsense mutation of FBN1 gene in a patient with Marfan syndrome. PMID- 22942098 TI - Polymorphisms in sh2b1 and spns1 loci are associated with triglyceride levels in a healthy population in northern Sweden. PMID- 22942099 TI - De novo inv(17)(p11.2q21.3) in an intellectually disabled girl: appraisal of 21 inv(17) constitutional instances. PMID- 22942100 TI - Physical mapping of 5S and 45S rDNA in Chrysanthemum and related genera of the Anthemideae by FISH, and species relationships. PMID- 22942101 TI - Transcription factor 7-like 2 (TCF7L2) variations associated with earlier age onset of type 2 diabetes in Thai patients. PMID- 22942102 TI - Intellectual disability, oncogenes and tumour suppressor genes: the way forward? PMID- 22942104 TI - Neonatal infections in China, Malaysia, Hong Kong and Thailand. AB - OBJECTIVE: Neonatal sepsis is a major cause of neonatal deaths in Asia but data remain scarce. We aimed to investigate the causative organisms and antibiotic resistance in neonatal care units in China, Malaysia, Hong Kong and Thailand. METHODS: Prospective cohort study of neonatal sepsis defined as positive culture of a single potentially pathogenic organism from blood or cerebrospinal fluid differentiated into early-onset sepsis (EOS) occurring <3 days of birth and late onset sepsis (LOS) >=3 days after birth. RESULTS: During the study period, there were 963 episodes of neonatal sepsis. The incidence of EOS was 0.62 (95% CI 0.45 to 0.82) per 1000 live births or 4.91 (95% CI 4.22 to 5.68) per 1000 admissions while the incidence of LOS was 5.00 (95% CI 4.51 to 5.53) per 1000 live births or 21.22 (95% CI 19.79 to 22.77) per 1000 admissions. The incidence of Group B Streptococcus (GBS) sepsis was low but remained the most common single pathogen for EOS among inborn babies. Klebsiella spp. was the most common Gram-negative organism causing most deaths. The case-fatality was 7.0% (95% CI 3.9% to 12.0%) for EOS and 16.0% (95% CI 13.7% to 19.0%) for LOS, and was significantly different between participating units after adjusting for potential confounders. Of all Gram-negative organisms, 47%, 37% and 32% were resistant to third generation cephalosporins, gentamicin or both, respectively. CONCLUSIONS: The pattern of EOS in Asian settings is similar to that in industrialised countries with low incidence of GBS sepsis. The important features of neonatal sepsis in Asia are the burden of Klebsiella spp. and high level of antibiotic resistance. These should be addressed while developing measures to reduce neonatal mortality due to infection. PMID- 22942103 TI - The genetic factors influencing the development of trichotillomania. AB - Trichotillomania (TTM), an obsessive-compulsive spectrum disorder (OCSD), is a psychiatric condition characterized by repetitive hair pulling. Evidence from family and twin studies suggest a heritable link of TTM. Functional polymorphisms in genes involved in neuronal pathways might influence the susceptibility to TTM. This review is an attempt to compile the genetic factors reported to modify the development of TTM. PMID- 22942105 TI - The function of oscillatory tongue-flicks in snakes: insights from kinematics of tongue-flicking in the banded water snake (Nerodia fasciata). AB - Tongue-flicking is an important sensory behavior unique to squamate reptiles in which chemical stimuli gathered by the tongue are delivered the vomeronasal organ situated in the roof of the mouth. Because tongue-flick numbers can easily be quantified, this behavior has been widely used as a measure of vomeronasal sampling in snakes using related variables such as tongue-flick rate or tongue flick/attack score. Surprisingly, the behavior itself and especially the function of the oscillatory tongue-flicks remains poorly understood. To describe the overall kinematics of tongue-flicking in the colubrid snake Nerodia fasciata and to test predictions on the function of oscillatory tongue-flicks, we filmed the tongue-flicks of 8 adult Nerodia fasciata using 4 synchronized high-speed cameras. Three-dimensional kinematic and performance variables were extracted from the videos in order to quantify tongue movements. Based on the kinematic analysis, we demonstrate the existence of 2 functional and behavioral tongue flick categories. Tongue-flicks with oscillations meet all the criteria for being adapted to the collection of odorants; simple downward extensions appear better suited for the rapid pick up of nonvolatile chemical stimuli from the substrate or a food item. External stimuli such as tactile and/or vomeronasal stimulation can induce a shift between these categories. PMID- 22942106 TI - Modified technique of chin augmentation with MEDPOR for Asian patients. AB - BACKGROUND: Commonly used chin implants are made of silicone, expanded polytetrafluoroethylene (e-PTFE), or high-density porous polyethylene (MEDPOR). Although MEDPOR is an effective implant for chin augmentation, modification of the external aspect of the implant is recommended, particularly for Asian patients, to create an appropriate shape for the new chin. It is often difficult to contour the inner aspect of the implant to conform to the patient's mandible. Without modification, a gap may exist between the implant and mandible. To address this problem, a modified augmentation technique was developed. OBJECTIVES: The authors describe their modified technique for MEDPOR chin augmentation, which includes removal of the genial tubercles and, if necessary, the mental protuberance. METHODS: Ninety-five patients underwent the modified MEDPOR technique of chin augmentation. Before placement of the contoured implant, a drill was used to remove the patient's genial tubercles. If the mental protuberance was deemed too prominent, it was removed as well. The implant was inserted and fixed to the mandible with 2 titanium screws. RESULTS: Results were satisfactory in 90 cases. Chin shape was too "strong" in 4 patients, and another patient had poor transition between the implant and mandible. Complications were minimal. The most common complication in this modified technique was lower lip numbness, which was transient in all cases. CONCLUSIONS: The MEDPOR chin implant can be effectively contoured to the mandible by removing the genial tubercle and/or mental protuberance. This technique is less invasive than chin osteotomy. Successful results can be achieved with minimal risks. PMID- 22942107 TI - Patient-specific rhytidectomy: finding the angle of maximal rejuvenation. AB - BACKGROUND: Rhytidectomy is fundamentally an operation of tissue release and resuspension, although the manner and direction of suspension are subject to perpetual debate. OBJECTIVES: The authors describe a method for identifying the angle of maximal rejuvenation during rhytidectomy and quantify the resulting angle and its relationship to patient age. METHODS: Patients were prospectively enrolled; demographic data, history, and operative details were recorded. Rhytidectomies were performed by the senior author (AAJ). After complete elevation, the face-lift flap was rotated in a medially-based arc (0-90 degrees ) while attention was given to the submental area, jawline, and midface. The angle of maximal rejuvenation for each hemiface was identified as described, and the flap was resuspended. During redraping, measurements of vertical and horizontal skin excess were recorded in situ. The resulting angle of lift was then calculated for each hemiface using trigonometry. Symmetry between sides was determined, and the effect of patient age on this angle was assessed. RESULTS: Three hundred hemifaces were operated (147 women; 3 men). Mean age was 60 years (range, 37-80 years). Mean resulting angle for the cohort was 60 degrees from horizontal (range, 46-77 degrees ). This was inversely correlated with patient age (r = -.3). Younger patients (<50 years, 64 degrees ) had a significantly more vertical angle than older patients (>=70 years, 56 degrees ; P < .0002). No significant intersubject difference was found between hemifaces (P = .53). CONCLUSIONS: The authors present a method for identifying the angle of maximal rejuvenation during rhytidectomy. This angle was more superior than posterior in all cases and is intimately related to patient age. Lasting results demand a detailed anatomical understanding and strict attention to the direction and degree of laxity. PMID- 22942108 TI - An unusual complication following rhytidectomy: iatrogenic parotid injury resulting in parotid fistula/sialocele. AB - Rhytidectomy is a common surgical procedure performed by today's aesthetic surgeons. Newer trends and techniques leading to deeper and more aggressive dissection have placed the parotid gland at increased risk for injury during this procedure. Despite there being a relative abundance of literature on traumatic parotid injury, there is a relative paucity of information on iatrogenic parotid injury after rhytidectomy. In addition, there is no consensus on management of these complications. In this article, the authors discuss 3 case reports, review the relevant literature, and propose a treatment algorithm. Early diagnosis and appropriate treatment are essential to properly manage this complication. PMID- 22942109 TI - Topical bimatoprost 0.03% and iatrogenic eyelid and orbital lipodystrophy. AB - The prostaglandin F2a (PGF2a) analogue bimatoprost 0.03% (Allergan, Inc, Irvine, California) has been employed for the treatment of hypotrichosis since it gained Food and Drug Administration approval as Latisse in 2008. In this report, the authors retrospectively review the cases of 7 patients who presented to their outpatient ophthalmology clinic with glaucoma. These patients had periorbital hollowing due to fat atrophy as a side effect of topical ophthalmic bimatoprost therapy. The series of patients described in this report emphasizes the small but significant risk of periocular fat changes associated with bimatoprost 0.03%, which is the exact formulation marketed as Lumigan for glaucoma treatment. Patients using Latisse for its cosmetic enhancement of eyelash length should be warned of this potentially disfiguring side effect, since the cosmetic and ophthalmic preparations are identical. Such changes can be irreversible, and the implications of the decision to prescribe this drug either in the form of an eyelash application or for topical ophthalmic use should be clearly understood by both clinicians and patients alike. PMID- 22942110 TI - Diced ear cartilage with perichondrial attachment in rhinoplasty: a new concept. AB - BACKGROUND: Diced cartilage is a valuable material that has recently been added to the graft options in rhinoplasty. Shaping, fixation, and resorption are the main concerns with this material. Perichondrially attached diced conchal cartilage may be a new possibility to solve some of these problems. OBJECTIVES: The authors evaluate the outcome of perichondrially attached diced cartilage in a rabbit model and compare the results with injectable cartilage grafting. METHODS: Ear cartilage was removed from 1 auricle in each of the 16 rabbits included in this study; samples were divided in 2 pieces. After precise weighing, both segments were diced. The perichondrium was left attached to 1 of the pieces. Both segments were inserted in 2 separate pockets in the dorsum of the animal. After a 3-month period, both samples were removed and measured for growth/resorption. RESULTS: At the beginning of this study, the difference in weight between groups was statistically insignificant (P = .213), but 3 months after insertion, significant growth was observed in the perichondrial group (P = .019). CONCLUSIONS: The vascularization and significant growth in weight of the perichondrially attached diced cartilage samples are evidence of the viability of this material. The structural integrity and solid framework afforded by this option suggest that the material should be used more frequently in nasoskeletal augmentation. PMID- 22942111 TI - Dorsal nasal augmentation with "open sandwich" graft consisting of conchal cartilage and retroauricular fascia. AB - BACKGROUND: Augmenting the nasal dorsum with conchal grafts can cause visible irregularities over time due to the morphological qualities of that material. OBJECTIVES: This study describes the senior authors' technique of dorsal nasal augmentation with chondrofascial "open sandwich" grafts consisting of pieces of conchal cartilage and retroauricular fascia. The authors assess the efficiency and reliability of this graft in nasal dorsal augmentation. METHODS: The authors retrospectively reviewed the cases of 19 patients who underwent dorsal augmentation rhinoplasty with chondrofascial grafts. Both cartilage and fascia were harvested through the same incision in the retroauricular sulcus. The conchal graft was cut in 2 to 4 pieces and slightly crushed with tissue forceps. The pieces of cartilage were arranged and fixed to the fascia in different patterns according to the nasal dorsum contour. RESULTS: The follow-up period ranged from 12 to 35 months in 16 patients who qualified for inclusion in the final data. The maximal thickness of the chondrofascial graft was 4.5 mm. There were no major complications in the recipient area, except 1 case of undercorrection. There were 2 complications in the donor area. In 1 case, a hematoma was treated conservatively. In another case, a strip of skin necrosis in the conchal area occurred and was treated by excision and direct suture with satisfactory resolution. CONCLUSIONS: The autologous chondrofascial graft is appropriate for slight to mild dorsal nasal augmentation. The method, as with most rhinoplasty techniques, requires careful and judicious preoperative examination, planning, and execution. The postoperative scar is inconspicuous and the donor site morbidity is minimal. PMID- 22942112 TI - Determinants of breast appearance and aging in identical twins. AB - BACKGROUND: Appearance, aging, and disorders of the breast are multifactorial. There are intrinsic, patient-specific characteristics, such as breast growth during puberty and propensity for breast cancer, which are primarily inherited. There are also environmental factors, which can be potentially controlled. Monozygotic twins provide an excellent research opportunity to examine the role of extrinsic factors in subjects with identical genetic predispositions. OBJECTIVES: The authors investigate the role and significance of various environmental and acquired factors on breast aesthetics. METHODS: Identical female twins were recruited during the Twins Days Festival in Twinsburg, Ohio, in 2009 and 2010. After consent was obtained, enrolled subjects completed a comprehensive survey on their medical and personal history. Standardized digital photographs were taken by medical photographers. Sixteen aesthetic breast features were subjectively rated by 6 plastic surgery residents blinded to the survey results. These ratings were then analyzed against survey data to determine the significance of different exogenous factors on breast appearance. RESULTS: A total of 161 pairs of identical female twins (n = 322) with a mean (SD) age of 47.6 (14.5) years were recruited. Twins who moisturized their skin daily had significantly fewer rhytids (P = .002). Twins who received hormone replacement therapy after menopause had more attractive breast shape, size, projection, areolar shape, and areolar size (P < .03). However, twins who had a higher body mass index, greater number of pregnancies, and larger cup sizes had significantly less attractive breasts (P < .05). Twins who smoked cigarettes and consumed alcohol also had significantly less attractive breasts (P < .05). Twins who breastfed had less attractive areolar size and shape but better skin quality than their counterparts who never breastfed (P < .03). Finally, there was a significantly higher incidence of breast pain in twins who primarily slept on their sides compared with twins who primarily slept on their backs (P < .008). CONCLUSIONS: This study implicates several environmental factors that significantly affect the aesthetic quality of breasts. PMID- 22942113 TI - Two-year outcomes with a novel, double-lumen, saline-filled breast implant. AB - BACKGROUND: A double-lumen, saline-filled breast implant with a baffle structure (IDEAL IMPLANT Saline-Filled Breast Implant; Ideal Implant Incorporated, Irving, Texas) was developed to overcome the limitations of single-lumen saline implants by controlling saline movement and providing internal support to the implant edge and upper pole. OBJECTIVES: The authors report 2-year data from a 10-year US clinical trial evaluating the safety and effectiveness of this investigational implant. METHODS: Women seeking primary breast augmentation or replacement of existing augmentation implants were enrolled between February 2009 and February 2010 at 35 private practice sites, where the women underwent surgery to receive the new technology implant. Data collection included incidence and grade of capsular contracture (CC) and wrinkling as well as patient- and surgeon-reported satisfaction measures. All clinical data were reported as Kaplan-Meier risk rates of first occurrence, per patient, in each cohort. RESULTS: Two-year follow-up visits were completed by 472 of 502 enrolled women (94.0%), 378 of whom had undergone primary breast augmentation and 94 of whom had received replacement augmentation. Patient-reported satisfaction with the outcome was 94.3% for primary augmentations and 92.3% for replacement augmentations; surgeon-reported satisfaction was also high (96.5% and 93.4%, respectively). Baker Grade III and IV CC rates were 3.8% (primary) and 8.2% (replacement), whereas moderate-to severe wrinkling was 3.8% (primary) and 12.0% (replacement). Deflations occurred in 4.8% of primary augmentations and 3.3% of replacement augmentations. No deflations were caused by a shell fold flaw. CONCLUSIONS: Two-year data from 472 women indicate that this double-lumen saline implant containing a baffle structure has a low rate of wrinkling and a lower rate of CC at 2 years than was reported for current single-lumen saline implants at 1 year. PMID- 22942114 TI - Safety and tolerability of high-intensity focused ultrasonography for noninvasive body sculpting: 24-week data from a randomized, sham-controlled study. AB - BACKGROUND: High-intensity focused ultrasonography (HIFU) is a nonsurgical, noninvasive method for body sculpting in nonobese patients. The technique ablates subcutaneous adipose tissue by causing molecular vibrations that increase tissue temperature and induce rapid cell necrosis. OBJECTIVES: The authors evaluate the long-term safety of a HIFU device for sculpting the abdomen and flanks. METHODS: Adults with subcutaneous abdominal fat >=2.5 cm in thickness who met screening criteria were randomized to receive HIFU treatment of the anterior abdomen and flanks at 1 of 3 energy levels (3 passes per patient): 47 J/cm(2) (141 J/cm(2) total), 59 J/cm(2) (177 J/cm(2) total), or 0 J/cm(2) (no energy applied; sham control). Safety was assessed for 24 weeks and included laboratory testing, physical examinations, and documentation of adverse events. RESULTS: Adverse events (AE) included mild to moderate discomfort, ecchymosis, and edema, all of which were transient. There were no reports of scarring or burns and no clinically meaningful changes in lipid panel findings, inflammatory markers, or renal or hepatic function. Physical examination results were unremarkable. CONCLUSIONS: This HIFU device exhibited an AE profile similar to that of sham treatment. There were no significant changes from baseline in laboratory values, including lipid levels. PMID- 22942115 TI - Aesthetic and functional satisfaction after monsplasty in the massive weight loss population. AB - BACKGROUND: The mons region is often affected by massive weight loss (MWL), with descent of the pubic area and residual adiposity. Thinning and resuspension are often performed concomitantly with abdominal contouring procedures. OBJECTIVES: Assess patient satisfaction, as well as functional and aesthetic results, after monsplasty in the MWL population. METHODS: The authors identified 54 consecutive female MWL patients (>=50 lbs) who had undergone abdominal contouring and completed at least 3 months of follow-up as potential subjects. Subjects were asked to complete a Mons Satisfaction Survey, either by phone or in person. Demographic and procedural data were collected from our prospective registry. Descriptive statistics were calculated with significance set at P value <.05. RESULTS: Thirty-one patients (57.8%) completed the survey. Average patient age was 46 +/- 11.3 years. Mean maximum body mass index (BMI) was 52.0 +/- 8.81 kg/m(2), mean current BMI was 31.0 +/- 6.22 kg/m(2), and mean delta BMI was 20.7 +/- 6.00 kg/m(2). Average pannus resection weight was 3.25 +/- 2.03 kg. Visualization of the genitalia improved from 25.8% to 100% (P < .01). Patients rated the appearance of their mons as 3.18 +/- 2.11 prior to surgery and 8.58 +/- 1.73 after surgery (P < .001) on a scale of 1 to 10. Hygiene improved in 61.3% of patients, and sex life improved in 51.6%, with 32.3% of patients reporting increased genital sensitivity. Incontinence decreased from 22.6% to 12.9%, and 6 patients reported a change in urinary stream. CONCLUSIONS: Monsplasty at the time of abdominal contouring yields significant improvement in patient satisfaction levels and functional scores. With proper incisional design, monsplasty can be performed safely during abdominal contouring with high patient satisfaction to improve both form and function of the pubic region. PMID- 22942116 TI - Prevention of biofilm-induced capsular contracture with antibiotic-impregnated mesh in a porcine model. AB - BACKGROUND: A growing body of evidence implicates subclinical (biofilm) infection around breast implants as an important cause of capsular contracture (CC). OBJECTIVES: The authors use an in vivo porcine model to investigate the potential of antibiotic-impregnated mesh as a prophylactic measure against biofilm formation and CC. METHODS: A total of 28 implants (14 untreated controls, 14 treated with antibiotic mesh) were inserted into 5 adult female pigs. All implants and pockets were inoculated with a human clinical strain of Staphylococcus epidermidis. The implants were left in situ for 16 weeks and then analyzed for contracture using both Baker grading and applanation tonometry. The presence of biofilm infection was assessed by subsequent microbiological analysis of implants and capsules. RESULTS: One untreated implant had extruded and was excluded from analysis. The tissue surrounding the 13 untreated control implants had Baker Grade III/IV CC, whereas no CC was identified around the 14 antibiotic mesh-treated implants. This difference was highly significant (P < .001). Tonometry findings were consistent with the Baker assessments. Although bacterial biofilm was detected on all implants and capsules, the biofilms on the antibiotic treated implants and surrounding capsules were generally single-layered or isolated in contrast to the multilayer biofilms found on untreated implants and capsules. CONCLUSIONS: Based on the findings from this study of a porcine model, the use of antibiotic-impregnated mesh reduces bacterial access to breast implants at the time of surgical insertion and may subsequently protect against subclinical infection and CC. PMID- 22942117 TI - Fat grafting's past, present, and future: why adipose tissue is emerging as a critical link to the advancement of regenerative medicine. AB - Fat grafting is a common reconstructive and aesthetic procedure with extensive clinical applications. Recently, significant strides have been made in investigating the biology behind the success of this procedure. Surgeons and scientists alike have advanced this field by innovating fat graft harvesting and injection techniques, expanding the use of adipose tissue and its stem cell components, and broadening our understanding of the viability of fat grafting at the molecular and cellular levels. The objectives of this review are to (1) discuss the clinical applications of fat grafting, (2) describe the cellular biology of fat and the optimization of fat graft preparation, (3) illustrate the significance of adipose-derived stem cells and the potentiality of fat cells, (4) highlight the clinical uses of adipose-derived stem cells, and (5) explore the current and future frontiers of the study of fat grafting. Although collaborative knowledge has increased exponentially, many of the biological mechanisms behind fat grafting are still unknown. Plastic surgeons are in a unique position to pioneer both the scientific and clinical frontiers of fat grafting and to ultimately further this technology for the benefit of our patients. PMID- 22942118 TI - Your favorite technique: time for a change? PMID- 22942119 TI - Sternalis muscle: an uncommon finding during aesthetic breast surgery. PMID- 22942122 TI - Impacts of organizational context on quality improvement. AB - Variation in how hospitals perform on similar quality improvement (QI) efforts argues for a need to understand how different organizational characteristics affect QI performance. The objective of this study was to use data-mining methods to evaluate relationships between measures of organizational characteristics and hospital QI performance. Organizational characteristics were extracted from 2 surveys and analyzed in 3 separate decision-tree models. The decision trees did not find any predictive associations in this sample of 100 hospitals participating in a national QI collaborative. Further model review identified that measures of QI Experience were associated with an ability to make improvements, whereas measures of Staffing and Culture were associated with an ability to sustain improvements. A key area for future research is to understand the challenges faced as QI teams transition from improving care to sustaining quality and to ascertain what organizational characteristics can best overcome those challenges. PMID- 22942123 TI - Data-driven interdisciplinary interventions to improve inpatient pain management. AB - Pain during hospitalization and dissatisfaction with pain management are common. This project consisted of 4 phases: identifying a pain numeric rating scale (NRS) metric associated with patient satisfaction, identifying independent predictors of maximum NRS, implementing interventions, and evaluating trends in NRS and satisfaction. Maximum NRS was inversely associated with favorable pain satisfaction for both efficacy (n = 4062, chi(2) = 66.2, P < .001) and staff efforts (n = 4067, chi(2) = 30.3, P < .001). Independent predictors of moderate to-severe maximum NRS were younger age, female sex, longer hospital stay, admitting department, psychoactive medications, and 10 diagnostic codes. After interventions, moderate-to-severe maximum NRS declined by 3.6% per quarter in 2010 compared with 2009. Satisfaction data demonstrated improvements in nursing units meeting goals (5.3% per quarter, r (2) = 0.67) and favorable satisfaction answers (0.36% per quarter, r (2) = 0.31). Moderate-to-severe maximum NRS was an independent predictor of lower likelihood of hospital discharge (likelihood ratio = 0.62; 95% confidence interval = 0.61-0.64). Targeted interventions were associated with improved inpatient pain management. PMID- 22942124 TI - An ex vivo model for imprinting: mutually exclusive binding of Cdx2 and Oct4 as a switch for imprinted and random X-inactivation. AB - In the early mammalian embryo, X chromosome inactivation (XCI) achieves dosage parity between males and females for X-linked genes. During mouse development, imprinted paternal XCI is observed first and switches to random XCI in the epiblast but not placental lineages. The mechanism by which this epigenetic switch occurs is currently unknown. Here, we establish an ex vivo model for imprinting and identify a novel trans-acting regulatory factor for imprinted XCI. Using an induced trophoblast stem cell (iTS) model, we show that embryonic stem (ES) cells transdifferentiated into trophoblasts retain partial memory of the XCI imprint. Cdx2, a stem cell factor that determines commitment to the extraembryonic lineage, directly binds Xist and activates expression of Xist RNA in extrembryonic cells. Cdx2 competes with Oct4, a stem cell factor that determines commitment to the embryonic lineage, for overlapping binding sites within Xist. We propose that mutually exclusive binding between Cdx2 and Oct4 in Xist underlies the switch between imprinted and random XCI in the early mouse embryo. PMID- 22942125 TI - Small- and large-effect quantitative trait locus interactions underlie variation in yeast sporulation efficiency. AB - Quantitative trait loci (QTL) with small effects on phenotypic variation can be difficult to detect and analyze. Because of this a large fraction of the genetic architecture of many complex traits is not well understood. Here we use sporulation efficiency in Saccharomyces cerevisiae as a model complex trait to identify and study small-effect QTL. In crosses where the large-effect quantitative trait nucleotides (QTN) have been genetically fixed we identify small-effect QTL that explain approximately half of the remaining variation not explained by the major effects. We find that small-effect QTL are often physically linked to large-effect QTL and that there are extensive genetic interactions between small- and large-effect QTL. A more complete understanding of quantitative traits will require a better understanding of the numbers, effect sizes, and genetic interactions of small-effect QTL. PMID- 22942126 TI - The Am-tra2 gene is an essential regulator of female splice regulation at two levels of the sex determination hierarchy of the honeybee. AB - Heteroallelic and homo- or hemiallelic Complementary sex determiner (Csd) proteins determine sexual fate in the honeybee (Apis mellifera) by controlling the alternative splicing of the downstream gene fem (feminizer). Thus far, we have little understanding of how heteroallelic Csd proteins mediate the splicing of female fem messenger RNAs (mRNAs) or how Fem proteins direct the splicing of honeybee dsx (Am-dsx) pre-mRNAs. Here, we report that Am-tra2, which is an ortholog of Drosophila melanogaster tra2, is an essential component of female splicing of the fem and Am-dsx transcripts in the honeybee. The Am-tra2 transcripts are alternatively (but non-sex-specifically) spliced, and they are translated into six protein isoforms that all share the basic RNA-binding domain/RS (arginine/serine) domain structure. Knockdown studies showed that the Am-tra2 gene is required to splice fem mRNAs into the productive female and nonproductive male forms. We suggest that the Am-Tra2 proteins are essential regulators of fem pre-mRNA splicing that, together with heteroallelic Csd proteins and/or Fem proteins, implement the female pathway. In males, the Am-Tra2 proteins may enhance the switch of fem transcripts into the nonproductive male form when heteroallelic Csd proteins are absent. This dual function of Am-Tra2 proteins possibly enhances and stabilizes the binary decision process of male/female splicing. Our knockdown studies also imply that the Am-Tra2 protein is an essential regulator for Am-dsx female splice regulation, suggesting an ancestral role in holometabolous insects. We also provide evidence that the Am tra2 gene has an essential function in honeybee embryogenesis that is unrelated to sex determination. PMID- 22942128 TI - Impact of chronic obstructive pulmonary diseases on outcomes and hospital days after percutaneous coronary intervention. AB - Chronic obstructive pulmonary disease (COPD) is common in patients undergoing percutaneous coronary intervention (PCI), but the impact of COPD on outcomes after PCI has received limited attention. Consecutive patients with coronary heart disease (n = 5155) undergoing PCI were enrolled in this study; 645 patients (73% men) aged 68.4 +/- 13.2 years had COPD and 4510 patients (71% men) aged 64.7 +/- 12.1 years did not. During the in-hospital period after PCI, the patients with COPD experienced a significantly higher incidence of angina (P < .001), arrhythmias (P < .001), and composite major adverse cardiac events (MACEs; P < .001) and longer hospital stay (P < .001) than those without COPD. Additionally, severity of COPD (measured by pulmonary function tests) was associated with increased composite MACE (P < .001) and hospital stay (P < .001) after PCI. In conclusion, COPD is associated with significantly increased composite MACE and hospital stay in patients after PCI. Increasing severity of COPD is associated with increased composite MACE and hospital stay after PCI. PMID- 22942127 TI - Semaphorin-1 and netrin signal in parallel and permissively to position the male ray 1 sensillum in Caenorhabditis elegans. AB - Netrin and semaphorin axon guidance cues have been found to function in the genesis of several mammalian organs; however, little is known about the underlying molecular mechanisms involved. A genetic approach could help to reveal the underpinnings of these mechanisms. The most anterior ray sensillum (ray 1) in the Caenorhabditis elegans male tail is frequently displaced anterior to its normal position in smp-1/semaphorin-1a and plexin-1/plx-1 mutants. Here we report that UNC-6/netrin and its UNC-40/DCC receptor signal in parallel to SMP 1/semaphorin-1a and its PLX-1/plexin-1 receptor to prevent the anterior displacement of ray 1 and that UNC-6 plus SMP-1 signaling can account entirely for this function. We also report that mab-20/semaphorin-2a mutations, which prevent the separation of neighboring rays and cause ray fusions, suppress the anterior displacements of ray 1 caused by deficiencies in SMP-1 and UNC-6 signaling and this is independent of the ray fusion phenotype, whereas overexpression of UNC-40 and PLX-1 cause ray fusions. This suggests that for ray 1 positioning, a balance is struck between a tendency of SMP-1 and UNC-6 signaling to prevent ray 1 from moving away from ray 2 and a tendency of MAB 20/semaphorin-2a signaling to separate all rays from each other. Additional evidence suggests this balance involves the relative adhesion of the ray 1 structural cell to neighboring SET and hyp 7 hypodermal cells. This finding raises the possibility that changes in ray 1 positioning depend on passive movements caused by attachment to the elongating SET cell in opposition to the morphologically more stable hyp 7 cell. Several lines of evidence indicate that SMP-1 and UNC-6 function permissively in the context of ray 1 positioning. PMID- 22942129 TI - Cardiovascular risk assessment in diabetes mellitus: comparison of the general Framingham risk profile versus the World Health Organization/International Society of Hypertension risk prediction charts in Arabs--clinical implications. AB - We estimated the prevalence of cardiovascular disease (CVD) risk and its clinical implications among 1 110 Omani patients with type 2 diabetes mellitus (DM) using 2 different CVD risk tools: the general Framingham risk profile (GFRP) and the joint World Health Organization/International Society of Hypertension (WHO/ISH) risk prediction charts. The GFRP tool identified higher proportion of patients compared with joint WHO/ISH tool at 10-year CVD risk 10% to <20% and at 20% to <30%. At CVD risk >=30%, both assessment tools identified similar proportions of patients (22% vs 24%; P=.120). Compared with WHO/ISH charts, the GFRP identified almost double the number of men eligible for aspirin treatment at CVD risk thresholds of >=10% (86% vs 43%). In women, the proportions were, 66% and 45%, respectively. For statins, the figures were, 60% and 37%, for men and 28% and 36%, for women. In conclusion, the GFRP overestimates the number of patients eligible for primary prevention of CVD compared with the joint WHO/ISH method. PMID- 22942130 TI - Cardiovascular disease and high-mobility group box 1--is a new inflammatory killer in town? AB - High-mobility group box 1 (HMGB-1) is a nuclear protein physiologically involved in the maintaining of DNA structure in the nucleus. When tissue damage occurs, necrotic cells as well as inflammatory cells, once activated, release this protein in circulating blood, where it seems to exert a direct proinflammatory action. Thus, HMGB-1 might be involved in the pathophysiology of several diseases, including cardiovascular disease. However, the experimental evidence has not yet clarified its cardiovascular role which is still debated. Specifically, it is still not completely resolved whether HMGB-1 plays a protective or detrimental role on cardiovascular function. In this review, we consider the role of HMGB-1 in pathological conditions and comment on the role of this protein in the cardiovascular disease. PMID- 22942131 TI - From good to better: toward a patient safety initiative in dentistry. PMID- 22942132 TI - Income analysis. PMID- 22942134 TI - What is average? PMID- 22942136 TI - Tobacco-use cessation. PMID- 22942138 TI - Endodontic outcomes. PMID- 22942140 TI - More about Outcomes. PMID- 22942142 TI - Oral health literacy and knowledge among patients who are pregnant for the first time. AB - BACKGROUND: The authors conducted an observational cohort study to determine the levels of and examine the associations of oral health literacy (OHL) and oral health knowledge in low-income patients who were pregnant for the first time. METHODS: An analytic sample of 119 low-income patients who were pregnant for the first time completed a structured 30-minute, in-person interview conducted by two trained interviewers in seven counties in North Carolina. The authors measured OHL by means of a dental word recognition test and assessed oral health knowledge by administering a six-item knowledge survey. RESULTS: The authors found that OHL scores were distributed normally (mean [standard deviation], 16.4 [5.0]). The percentage of correct responses for each oral health knowledge item ranged from 45 to 98 percent. The results of bivariate analyses showed that there was a positive correlation between OHL and oral health knowledge (P < .01). Higher OHL levels were associated with correct responses to two of the knowledge items (P < .01). CONCLUSIONS: OHL was low in the study sample. There was a significant association between OHL and oral health knowledge. CLINICAL IMPLICATIONS: Low OHL levels and, thereby, low levels of oral health knowledge, might affect health outcomes for both the mother and child. Tailoring messages to appropriate OHL levels might improve knowledge. PMID- 22942143 TI - Denosumab-related osteonecrosis of the jaw. AB - BACKGROUND: Osteonecrosis of the jaw (ONJ) is a debilitating chronic illness that has become one of the literature's most discussed adverse events in relation to advanced malignancy. In 2010, the first case reports of ONJ linked with denosumab administration were published. CASE DESCRIPTION: The authors describe a case of denosumab-related ONJ in a 73-year-old man with a diagnosis of prostatic adenocarcinoma, the treatment for which included the antiresorptive agent denosumab and who experienced severe pain and delayed healing after a mandibular molar extraction performed six months after the cessation of denosumab therapy. The patient had not received radiotherapy to the head and neck, nor had he received any bisphosphonate treatment. RESULTS: Clinicians established a diagnosis of denosumab-related ONJ. Follow-up across 12 months revealed that the patient needed long-term courses of antibiotics and that he experienced progressive bone destruction requiring surgical debridement. CONCLUSIONS: and CLINICAL IMPLICATIONS: The authors suggest that in patients receiving denosumab therapy, the dosing interval, the cumulative dose or both may be important in terms of the development of denosumab-related ONJ. This allows the hypothesis that preventive dentistry may reduce the prevalence of ONJ in those receiving denosumab as it has in those receiving bisphosphonates. PMID- 22942144 TI - Intraoral swelling and periapical radiolucency. PMID- 22942145 TI - Pain and persistent occlusal awareness: what should dentists do? PMID- 22942146 TI - Dental disease prevalence among methamphetamine and heroin users in an urban setting: a pilot study. AB - BACKGROUND: Researchers have reported rampant caries among methamphetamine users. The authors investigated the prevalence of dental disease and associated risk behaviors in methamphetamine users compared with those in heroin users. METHODS: This pilot project was a cross-sectional study of an ongoing cohort of young adult injection-drug users (IDUs) in San Francisco. Participants completed an oral health questionnaire administered by a research assistant, and dentists performed clinical examinations to record the participants' data in terms of scores on the decayed-missing-filled surfaces (DMFS) index, presence of residual roots, scores on an oral hygiene index and whether any salivary hypofunction was observed. RESULTS: The prevalence of dental disease among 58 young adult IDUs was strikingly high compared with that in the U.S. general population; however, the authors found no difference in the level of dental disease between users of methamphetamine and users of heroin. The mean DMFS score and number of decayed surfaces exceeded 28 in both groups. CONCLUSIONS: Although the authors detected no difference in dental disease between methamphetamine and heroin users, they found a high prevalence of caries and caries-associated behaviors in the sample of young adult IDUs. CLINICAL IMPLICATIONS: Given the high level of dental disease observed in this population of young adult IDUs, one next step may be to explore the feasibility and effectiveness of providing low-intensity preventive measures (such as distribution of chlorhexidine rinses or xylitol gum or application of fluoride varnishes) through outreach workers. PMID- 22942148 TI - Ante's law is not evidence based. PMID- 22942147 TI - Components of patient satisfaction with a dental restorative visit: results from the Dental Practice-Based Research Network. AB - BACKGROUND: The authors conducted a study to identify components of patient satisfaction with restorative dental care and to test the hypothesis that certain dentist, patient and procedure factors are associated with patient satisfaction. METHODS: Practitioner-investigators (P-Is) from 197 practices in The Dental Practice-Based Research Network (DPBRN) recruited consecutively seen patients who had defective permanent-tooth restorations that were replaced or repaired. At the end of the treatment visit, P-Is asked each participant to complete a satisfaction survey and mail it directly to a DPBRN regional coordinator. RESULTS: Analysis of the results of 5,879 satisfaction surveys revealed three satisfaction components: interpersonal relationship-comfort factors, material choice-value factors and sensory-evaluative factors. Satisfaction was highest among patients who received care in a private practice model, whose restorations were repaired rather than replaced and whose restored teeth were not molars. CONCLUSION: These data suggest that a patient's judgments of a dentist's skills and quality of care are based on personal interactions with the dentist, the level of comfort the patient perceives while receiving care and any experience of posttreatment sensitivity in the treated tooth. These conclusions have direct implications for management of patient care before, during and after the procedure. PRACTICE IMPLICATIONS: By taking a patient-centered approach, dentists should seek to understand how patients evaluate and rate the service provided, thereby enabling themselves to focus on what each patient values most. PMID- 22942150 TI - ADA business program: 2012 House of Delegates. PMID- 22942149 TI - Rural dentists: does growing up in a small community matter? AB - BACKGROUND: The aging of the dental work-force has implications for both patients and dentists, especially those in rural and underserved areas. Anecdotal information regarding dental workforce trends indicates that students from rural communities are more likely to practice in rural communities than are students from urban areas. Although the medical literature supports this premise relative to physicians, there are no data to verify this statement relative to dentistry. Therefore, the authors decided to study whether this premise applies to dentistry. METHODS: The authors conducted a retrospective analysis of dental student records from a Midwestern dental school for the years 1980 through 2010 to determine if there was a statistical correlation between the size of a dental student's town of origin and the size of the community where he or she practiced after graduation. They also examined what role, if any, the student's sex played. RESULTS: Dentists from rural areas were approximately six times more likely to practice in a rural area than were dentists from urban areas. Female dentists were only slightly less likely to practice in a rural community than were male dentists. CONCLUSION: Dentists from rural communities were more likely to practice in rural communities than were dental students from urban areas. PRACTICE IMPLICATIONS: To ensure future access to care in rural communities, rural dentists may want to recruit actively or work closely with dental students from rural areas when hiring associates or seeking purchasers for their dental practices. PMID- 22942151 TI - 2012 ADA annual session concurrent meetings. PMID- 22942152 TI - Making delegation work. PMID- 22942153 TI - What are the ethical implications of using social coupons to expand my patient base? PMID- 22942154 TI - For the dental patient. Bad breath: causes and tips for controlling it. PMID- 22942155 TI - The use of enamel matrix derivative alone versus in combination with bone grafts to treat patients with periodontal intrabony defects: a meta-analysis. AB - BACKGROUND: The authors performed a meta-analysis to compare the clinical outcomes of enamel matrix derivative (EMD) used in combination with various bone grafts with EMD alone in patients with intrabony defects. TYPES OF STUDIES REVIEWED: The authors retrieved relevant studies through Sept. 30, 2011, from MEDLINE, PubMed, Embase and Cochrane Central Register of Controlled Trials. The main clinical outcomes were probing pocket depth (PPD) reduction, clinical attachment level (CAL) gain, gingival recession (REC) increase and defect fill gain. The authors performed two separate meta-analyses, according to the length of follow-up. They also conducted subgroup analyses regarding the study designs and surgical procedures used. RESULTS: The authors included 11 studies in their meta-analysis. At six to eight months' follow-up, pooled estimates showed that there was no significant difference regarding PPD reduction (P = .62) and CAL gain (P = .23) among the treatment groups, but there was a significant difference regarding defect fill gain and REC increase. At 12 months' follow-up, pooled estimates revealed no significant differences regarding PPD reduction (P = .29), CAL gain (P = .15) and REC increase (P = .30) between the groups, but the authors still detected a significant difference for defect fill gain. CLINICAL IMPLICATIONS: In trials with a short-term follow-up, the combination therapies yielded better clinical outcomes regarding defect fill gain and REC increase compared with EMD alone, whereas most clinical outcomes were not significantly different between the two groups in the long run. The additional benefits from using combination therapies to promote periodontal tissue regeneration need to be confirmed. PMID- 22942156 TI - A marketing campaign to promote screening for oral cancer. AB - BACKGROUND: Organizers of the Detroit Oral Cancer Prevention Project at the University of Michigan, Ann Arbor, launched a multifaceted media campaign targeted toward a high-risk population to raise awareness about oral cancer, educate the public regarding the importance of early detection and increase screening rates. The authors present data about the effectiveness of the campaign with regard to the screening behaviors of medical and dental providers. METHODS: Before the start of the campaign and during each of the three years of the campaign, the authors mailed surveys to random samples of physicians and dentists practicing in targeted and non-targeted areas. RESULTS: More dentists than physicians reported screening patients routinely, and dentists reported that they referred more patients for biopsy or further evaluation compared with physicians. A larger proportion of dentists and physicians in the targeted area than in the nontargeted area reported that their patients had seen or heard the advertisements. A larger proportion of dentists in the targeted area than in the nontargeted area reported an increase in patients' questions and requests for screening, even after the authors accounted for demographic characteristics (adjusted odds ratio = 2.47). CONCLUSIONS: The survey findings show that the media campaign was effective in influencing providers' screening for signs and symptoms of oral cancer. CLINICAL IMPLICATIONS: An increase in patients' requests for screening as a result of the implementation of mass media campaigns may promote oral cancer screening and improve patients' chances of survival. PMID- 22942157 TI - Management of the dropped nuclear fragments. PMID- 22942158 TI - Human papillomavirus: a predictor of better survival in ocular surface squamous neoplasia patients. AB - BACKGROUND: Although human papillomavirus (HPV) has been implicated in the pathogenesis of ocular surface squamous neoplasia (OSSN), no study has so far dealt with the prognostic role of HPV. In this study the presence and significance of HPV in OSSN and its correlation with p16(INK4a) immunoexpression was determined. METHODS: HPV was detected by HPV-L1 capsid gene-specific multiplex PCR using PGMY09/11 primers, and genotyping was done by linear array on 64 OSSN patients and 15 conjunctival controls. p16(INK4a) immunoexpression as a marker for HPV presence was also evaluated. RESULTS: The HPV genome was detected in 11% of cases by multiplex PCR, and all positives belonged to a high-risk HPV16 genotype. p16(INK4a) Overexpression was seen in 28% (18/64) of cases. Control conjunctival tissues were negative for HPV and p16(INK4a) expression. The presence of HPV was associated with significantly improved disease-free survival (p=0.02) as well as p16(INK4a) overexpression (p=0.001). The sensitivity and specificity of p16(INK4a) as a marker for HPV presence was 86% and 79%, respectively, with a positive predictive value of 33% and a negative predictive value of 98%. CONCLUSIONS: The results of this study point towards HPV as a predictor of better survival in a subset of HPV-positive OSSN patients. Although p16(INK4a) immunoexpression is a useful indicator of HPV presence in OSSN, confirmation by multiplex PCR is necessary. PMID- 22942159 TI - The many enigmas of intermittent exotropia. PMID- 22942160 TI - Errors in neuroretinal rim measurement by Cirrus high-definition optical coherence tomography in myopic eyes. AB - BACKGROUND/AIMS: To investigate the prevalence of, and factors associated with, errors in neuroretinal rim measurement by Cirrus high-definition (HD) spectral domain optical coherence tomography (OCT) in myopic eyes. METHODS: Neuroretinal rim thicknesses of 255 myopic eyes were measured by Cirrus HD-OCT. The prevalence of, and factors associated with, optic disc margin detection error and cup margin detection error were assessed by analysing 72 cross-sectional optic nerve head (ONH) images obtained at 5 degrees intervals for each eye. RESULTS: Among the 255 eyes, 45 (17.6%) had neuroretinal rim measurement errors; 29 (11.4%) had optic disc margin detection errors at the temporal (16 eyes), superior (11 eyes), and inferior (2 eyes) quadrants; 19 (7.5%) showed cup margin detection errors at the nasal (17 eyes) and temporal (2 eyes) quadrants; and 3 (1.2%) had both disc and cup margin detection errors. Errors in detection of temporal optic disc margin were associated with presence of parapapillary atrophy (PPA), higher myopia, and greater axial length (AL) (p<0.001). Cup margin detection errors were associated with vitreous opacities attached to the ONH surface or acute cup slope angles (p<0.001). CONCLUSIONS: Errors in neuroretinal rim measurement by Cirrus HD-OCT were found in myopic eyes, especially in eyes with PPA, higher myopia, greater AL, vitreous opacity or acute cup slope angle. These findings should be considered when interpreting neuroretinal rim thickness measured by Cirrus HD OCT. PMID- 22942161 TI - Resolution of subretinal fluid with systemic corticosteroid treatment in acute Vogt-Koyanagi-Harada disease. AB - BACKGROUND: To evaluate the correlation of subretinal fluid height with visual acuity (VA) in patients with acute Vogt-Koyanagi-Harada disease (VKH). METHODS: Clinical information, fundus photographs and spectral domain optical coherence tomography scans from sequential visits of patients with acute VKH treated with oral corticosteroids were analysed. Subretinal fluid (SRF) height and retinal thickness were measured at the fovea. The association between VA and SRF height was evaluated by Spearman correlation analysis. RESULTS: A total of 12 eyes from 6 consecutive patients were included. SRF height measured 824+/-508 um (range 45 1900 um) at presentation. SRF height correlated with simultaneously measured VA. Initial SRF height did not correlate with resolution time and final VA. Resolution of SRF was attained in 36+/-24 days (range 10-80 days). The presence of choroidal folds (eight eyes) and multifocal retinal detachment (eight eyes) at presentation correlated with lower initial VA but not with the interval to SRF resolution or with VA at 3-month follow-up. CONCLUSIONS: Serous retinal detachment resolved in 36+/-24 days in patients with acute VKH treated with oral corticosteroids. SRF height correlates with VA measured at the same time. The initial SRF, no matter how elevated, does not correlate with VA at 3 months after presentation. PMID- 22942162 TI - A very high prevalence of migraine in adult general population. PMID- 22942164 TI - A novel CACNA1A mutation results in episodic ataxia with migrainous features without headache. AB - BACKGROUND: The mechanisms subtending migrainous features, like sensoriphobia, remain poorly understood even though recent works have shed new light on their mechanisms. CASE REPORT: A 24-year-old woman consulted the headache clinic because of frequent paroxysmal attacks of strong sensoriphobia, digestive signs, moderate ataxia and a need to lie in the dark, without any headache. The symptoms had begun in infancy and the patient had been treated for hysteria, then for epilepsy. As she had some typical features of episodic ataxia type 2, an analysis of CACNA1A gene was performed and demonstrated a novel c3995 + 1G>A mutation. The same mutation was also discovered in her young son, who had an ataxia of unknown origin. Both remarkably improved under acetazolamide. CONCLUSIONS: This observation suggests that paroxysmal sensoriphobia and digestive signs can occur together in bouts in neurological conditions other than migraine, and in the absence of head pain. It raises interesting hypotheses about the central pathways driving these symptoms. PMID- 22942165 TI - Potential apoptotic effect of ultraviolet-A irradiation during cross-linking: a study on ex vivo cultivated limbal epithelial cells. AB - AIM/BACKGROUND: To study the effects of ultraviolet-A (UV-A) irradiation, in the presence or absence of riboflavin, on ex vivo cultured limbal epithelial cells (LECs). METHODS: The study was carried out in a super specialty ophthalmic hospital. Ex vivo cultured LECs were grown on denuded amniotic membranes and exposed to similar levels of UV-A radiation used during corneal cross-linking (CXL), in the presence or absence of the photosensitiser, riboflavin. These cells were then used for extraction of RNA, cDNA conversion, and antibody staining. Quantitative PCR and immunofluorescence staining were performed to evaluate the apoptotic state of treated and non-treated LECs. Statistical analyses were evaluated using a Student's t test. RESULTS: We found that bcl-2, an antiapoptotic gene, was downregulated, whereas, bax, a proapoptotic gene, was upregulated. After LECs were exposed to UV-A radiation, a significant upregulation of both caspase 3 and caspase 9 was observed in treated cells when compared with untreated LECs. CONCLUSIONS: These results indicate that exposure of LECs to UV-A dosages similar to those used in the CXL procedure promotes the expression of genes known to promote apoptosis. In the presence of riboflavin, the damage caused by UV-A treatment was marginalised, but not totally blocked. PMID- 22942166 TI - A clinical and molecular genetics study of primary congenital glaucoma in South Korea. AB - OBJECTIVES: To investigate the clinical manifestations associated with the mutation spectrums of the human cytochrome P450 (CYP1B1) and myocilin (MYOC) genes in South Korean patients with primary congenital glaucoma (PCG). METHODS: Eighty-five unrelated PCG patients and their family members of South Korean origin were screened for mutations in the CYP1B1 and MYOC genes by sequencing with the PCR. We analysed phenotypes related to the presence, number and types of CYP1B1 mutations. In addition, the phenotype associated with the MYOC gene mutations was evaluated. RESULTS: There was no statistically significant difference in clinical studies between PCG patients with CYP1B1 mutations (N=63) and those without mutations (N=22), although the mutation group manifested disease earlier, with greater severity, and frequency in both eyes (p>0.05). However, the response to treatments was statistically different between groups and tended to be poor according to the number of mutant alleles (p=0.000, 0.0017). Patients with MYOC mutations (N=2) showed various phenotypic features. CONCLUSIONS: No consistent correlation was observed between the initial clinical manifestations and the CYP1B1 genotype. However, the response to treatment was associated with the CYP1B1 mutant alleles. This is the first report discussing the phenotypes of South Korean PCG patients associated with CYP1B1 mutations. PMID- 22942167 TI - Parent-child interaction therapy: an evidence-based treatment for child maltreatment. AB - It is common practice to augment efficacious treatment protocols for special populations (Durlak & DuPre, 2008), but this is often done before establishing that standard services are not appropriate. In this randomized controlled trial with families at risk or with a history of maltreatment (N = 151), we investigated the effectiveness of standard 12-session Parent-Child Interaction Therapy (PCIT). This is in contrast to other PCIT studies with similar parents, which have allowed for longer and sometimes variable treatment length and with modifications to PCIT protocol. After treatment and compared to Waitlist, mothers reported fewer child externalizing and internalizing behaviors, decreased stress, and were observed to have more positive verbalizations and maternal sensitivity. These outcomes were equivalent or better than outcomes of our previous PCIT trial with high-risk families (Thomas & Zimmer-Gembeck, 2011) when treatment length was variable and often longer. These findings support standard protocol PCIT as an efficacious intervention for families in the child welfare system. PMID- 22942168 TI - Eight clinical conundrums relating to anterior cruciate ligament (ACL) injury in sport: recent evidence and a personal reflection. AB - Over two million anterior cruciate ligament (ACL) injuries occur worldwide annually, and the greater prevalence for ACL injury in young female athletes is one of the major problems in sports medicine. Optimal treatment of ACL injury requires individualised management. Patient selection is of utmost importance, and so is respect for the patient's functional demands and interests. All patients with an ACL tear may not need surgery, however athletes and persons with an active lifestyle with high knee functional demands including cutting motions need and should be offered surgery. In many cases it may not be the choice of graft or technique that is the key for success, but the choice of surgeon. The surgeon should be experienced and use a reconstructive procedure he/she knows very well and is comfortable with. The development of osteoarthritis after an ACL injury depends very much on the injury mechanism and concurrent meniscal injury, as knee articular cartilage continues to heal for 1-2 years after an ACL injury. Therefore the surgeon and rehabilitation team must pay attention to the rehabilitation process and to the decision when to return to sport. Return to sport must be carefully considered, as top-level sport in itself is one main risk factor for osteoarthritis after ACL injury. The present criteria for return to sport need to be revisited, also due to the fact that recurrent injury seems to be an increasing problem. ACL injury prevention programmes are now available in some sports. The key issue for a prevention programme to be successful is proper implementation. Vital factors for success include the individual coaching of the player and well controlled compliance with the training programme. Preventive activities should be more actively supported by the involved athletic community. Despite substantial advances in the field of ACL injury over the past 40 years, substantial management challenges remain. PMID- 22942169 TI - Injury in elite New Zealand cricketers 2002-2008: descriptive epidemiology. AB - OBJECTIVE: To describe the incidence, prevalence, nature and severity of injury to elite New Zealand cricketers for the 2002/2003 to 2007/2008 seasons. DESIGN: Prospective cohort. SETTING: Elite cricket in New Zealand. PARTICIPANTS: 248 elite male cricketers. MAIN OUTCOME MEASURES: Incidence and prevalence rates. RESULTS: The overall match injury incidence rate for the international competition (51.6 injuries per 10 000 player-hours; 95% CI 40.1 to 65.3) was almost twice that of the domestic competition (27.2; 23.5 to 31.4). The prevalence rate for the international competition (12%; 11.3% to 12.8%) was significantly higher than that for the domestic competition (9.7%; 9.4% to 10.1%). Overall, 79.5% of injuries occurred in matches and 48.7% of all injuries were sustained while bowling. The lower limb was the body region most commonly injured (43.5%), the most common specific diagnosis was hamstring strains/tears (11.1%) and the injuries contributing the highest proportion of match days lost were stress fractures to the low back (22%). CONCLUSIONS: The findings of this study support ongoing injury surveillance in New Zealand and other test cricket playing nations for the purpose of describing injury and monitoring the effect of interventions over time. PMID- 22942170 TI - An NDT blog. PMID- 22942171 TI - Antenatal excessive sodium intake induces adverse vascular remodelling in offspring. PMID- 22942172 TI - Dietary phosphate modifies lifespan in Drosophila. AB - Phosphate is required for many important cellular processes and having too little phosphate (hypophosphatemia) or too much (hyperphosphatemia) can cause disease and reduce lifespan in humans. Drosophila melanogaster has been a powerful tool to discover evolutionarily well-conserved nutrient-sensing pathways that are important for the lifespan extension. We have established Drosophila as a model system for studying the effects of dietary phosphate during development and adult life. When absorption of phosphate is blocked by sevelamer or cellular uptake is inhibited by phosphonoformic acid (PFA), larval development is delayed in a phosphate-dependent fashion. Conversely, restriction of phosphate absorption with sevelamer or reduced cellular uptake after treatment with PFA is able to extend the adult lifespan of otherwise normal flies. Gaining an understanding of the specific pathways and mediators that regulate cellular and organismic phosphate levels might ultimately lead to the development of improved dietary and therapeutic approaches to the treatment of human disorders of hypo- and hyperphosphatemia. PMID- 22942173 TI - Programmed necrosis in acute kidney injury. AB - Programmed cell death (PCD) had been widely used synonymously to caspase-mediated apoptosis until caspase-independent cell death was described. Identification of necrosis as a regulated process in ischaemic conditions has recently changed our understanding of PCD. At least three pathways of programmed necrosis (PN) have been identified. First, receptor-interacting protein kinase 3 (RIP3)-dependent necroptosis causes organ failure following stroke, myocardial infarction and renal ischaemia/reperfusion injury. Necroptosis can be mediated either by a large intracellular caspase-8-containing signalling complex called the ripoptosome or by the RIP1-/RIP3-containing necroptosome and is controlled by a caspase-8/FLICE inhibitory protein(long) heterodimer at least in the latter case. Second, mitochondrial permeability transition mediates apoptotic or necrotic stimuli and depends on the mitochondrial protein cyclophilin D. The third PN pathway involves the poly(ADP-ribose) polymerase-calpain axis that contributes to acute kidney injury (AKI). Preclinical interference with the PN pathways therefore raises expectations for the future treatment of ischaemic conditions. In this brief review, we aim to summarize the clinically relevant PCD pathways and to transfer the basic science data to settings of AKI. We conclude that pathologists were quite right to refer to ischaemic kidney injury as 'acute tubular necrosis'. PMID- 22942174 TI - Depression and sexual dysfunction in chronic kidney disease: a narrative review of the evidence in areas of significant unmet need. AB - People with chronic kidney disease (CKD) have a high symptom burden and experience poorer quality of life than the general population. People with CKD frequently report fatigue, anorexia, pain, sleep disturbance, itching and restless legs. Depression and sexual dysfunction may also be common in CKD, although questions about optimal diagnosis and treatment remain unanswered. People with kidney disease identify lifestyle and the impact of CKD on family and psychosocial supports as key priorities and rate symptoms such as sexual dysfunction and psychological distress as severe. Here, we outline the current state of research underlying depression and sexual dysfunction in this population focusing on prevalence, diagnosis, screening, outcomes and interventions and suggest areas requiring additional specific research. PMID- 22942175 TI - Salt intake in kidney disease--a missed therapeutic opportunity? AB - Although significant progress has been made in the treatment of chronic kidney disease (CKD), treatment is not yet satisfactory, particularly when it is started in the late stages of the disease. Novel modes of intervention to mitigate the burden of disease are required. The reduction of dietary salt intake (which is high in the industrialized world) is one such option. Better understanding of the deleterious effects of salt on renal and cardiovascular health is necessary to raise awareness of the importance of reduction of the salt content in food products. Therefore, we (i) review pathways through which high salt intake exerts damaging effects, (ii) provide an assessment of recent observational studies linking dietary salt intake to the progression of renal and cardiovascular disease and (iii) discuss the interaction between salt intake and rennin angiotensin-aldosterone-system inhibitors, i.e. the first choice antihypertensive agents for the treatment of CKD. PMID- 22942176 TI - Medical management of hepatorenal syndrome. PMID- 22942177 TI - The search for perfect biomarkers in acute kidney damage: the case of NGAL, from AKI to acute pyelonephritis: back to the clinic? PMID- 22942179 TI - Vascular insulin resistance related to endoplasmic reticulum stress in aortas from a rat model of chronic kidney disease. AB - Metabolic insulin resistance has been demonstrated in patients with nondiabetic chronic kidney disease (CKD), yet their vascular insulin signaling remains poorly understood. Here we tested the hypothesis that vascular insulin signaling was impaired and related with endoplasmic reticulum (ER) stress in aortas from the reduced renal mass (RRM) model of CKD. The activity of insulin signaling and markers of ER were determined in aortas from rats with RRM and cultured human umbilical vein endothelial cells. Tyrosine phosphorylation of insulin receptor beta and insulin receptor substrate (IRS)-1 and phosphorylation of protein kinase B and endothelial nitric oxide synthase were all decreased in aorta from RRM rats, whereas serine phosphorylation of IRS-1, a marker of insulin resistance, was increased. In addition, nitric oxide generation and insulin-mediated vasorelaxation were decreased in aortas from RRM rats. Insulin signaling in cultured vascular endothelial cells was impaired by induction of ER stress and was restored in aortas of RRM rats by inhibition of ER stress. Taken together, rats with RRM had vascular insulin resistance that was linked to ER stress. This identified vascular insulin resistance and ER stress as a potential therapeutic target for cardiovascular complications in patients with CKD. PMID- 22942178 TI - Time course of right ventricular pressure-overload induced myocardial fibrosis: relationship to changes in fibroblast postsynthetic procollagen processing. AB - Myocardial fibrillar collagen is considered an important determinant of increased ventricular stiffness in pressure-overload (PO)-induced cardiac hypertrophy. Chronic PO was created in feline right ventricles (RV) by pulmonary artery banding (PAB) to define the time course of changes in fibrillar collagen content after PO using a nonrodent model and to determine whether this time course was dependent on changes in fibroblast function. Total, soluble, and insoluble collagen (hydroxyproline), collagen volume fraction (CVF), and RV end-diastolic pressure were assessed 2 days and 1, 2, 4, and 10 wk following PAB. Fibroblast function was assessed by quantitating the product of postsynthetic processing, insoluble collagen, and levels of SPARC (secreted protein acidic and rich in cysteine), a protein that affects procollagen processing. RV hypertrophic growth was complete 2 wk after PAB. Changes in RV collagen content did not follow the same time course. Two weeks after PAB, there were elevations in total collagen (control RV: 8.84 +/- 1.03 mg/g vs. 2-wk PAB: 11.50 +/- 0.78 mg/g); however, increased insoluble fibrillar collagen, as measured by CVF, was not detected until 4 wk after PAB (control RV CVF: 1.39 +/- 0.25% vs. 4-wk PAB: 4.18 +/- 0.87%). RV end-diastolic pressure was unchanged at 2 wk, but increased until 4 wk after PAB. RV fibroblasts isolated after 2-wk PAB had no changes in either insoluble collagen or SPARC expression; however, increases in insoluble collagen and in levels of SPARC were detected in RV fibroblasts from 4-wk PAB. Therefore, the time course of PO-induced RV hypertrophy differs significantly from myocardial fibrosis and diastolic dysfunction. These temporal differences appear dependent on changes in fibroblast function. PMID- 22942181 TI - Circulating microRNAs as diagnostic biomarkers for cardiovascular diseases. AB - One of the major challenges in cardiovascular disease is the identification of reliable clinical biomarkers that can be routinely measured in plasma. MicroRNAs (miRNAs) were recently discovered to circulate in the bloodstream in a remarkably stable form. Because of their stability and often tissue- and disease-specific expression and the possibility to measure them with high sensitivity and specificity, miRNAs are emerging as new diagnostic biomarkers. In this review we will provide an overview of the potential of circulating miRNAs as biomarkers for a wide range of cardiovascular diseases such as coronary artery disease, myocardial infarction, hypertension, heart failure, viral myocarditis, and type-2 diabetes mellitus. Furthermore, we will discuss the challenges with regard to further validation in large patient cohorts, and we will discuss how the measurement of multiple miRNAs simultaneously might improve the accuracy of the diagnostic test. PMID- 22942180 TI - Environmentally persistent free radicals decrease cardiac function and increase pulmonary artery pressure. AB - Epidemiological studies have consistently linked inhalation of particulate matter (PM) to increased cardiac morbidity and mortality, especially in at risk populations. However, few studies have examined the effect of PM on baseline cardiac function in otherwise healthy individuals. In addition, airborne PM contain environmentally persistent free radicals (EPFR) capable of redox cycling in biological systems. The purpose of this study was to determine whether nose only inhalation of EPFRs (20 min/day for 7 days) could decrease baseline left ventricular function in healthy male Sprague-Dawley rats. The model EPFR tested was 1,2-dichlorobenzene chemisorbed to 0.2-MUm-diameter silica/CuO particles at 230 degrees C (DCB230). Inhalation of vehicle or silica particles served as controls. Twenty-four hours after the last exposure, rats were anesthetized (isoflurane) and ventilated (3 l/min), and left ventricular function was assessed using pressure-volume catheters. Compared with controls, inhalation of DCB230 significantly decreased baseline stroke volume, cardiac output, and stroke work. End-diastolic volume and end-diastolic pressure were also significantly reduced; however, ventricular contractility and relaxation were not changed. DCB230 also significantly increased pulmonary arterial pressure and produced hyperplasia in small pulmonary arteries. Plasma levels of C-reactive protein were significantly increased by exposure to DCB230, as were levels of heme oxygenase-1 and SOD2 in the left ventricle. Together, these data show that inhalation of EPFRs, but not silica particles, decreases baseline cardiac function in healthy rats by decreasing cardiac filling, secondary to increased pulmonary resistance. These EPFRs also produced systemic inflammation and increased oxidative stress markers in the left ventricle. PMID- 22942182 TI - A chronic and latent lymphatic insufficiency follows recovery from acute lymphedema in the rat foreleg. AB - Secondary lymphedema in humans is a common consequence of axillary lymph node dissection (ALND) to treat breast cancer. Remarkably, secondary lymphedema generally first appears following a delay of over a year and can be triggered suddenly by an inflammatory insult. However, it remains unclear why the apparently functional lymphatic system is unable to accommodate an inflammatory trigger. To provide mechanistic insight into the delayed and rapid secondary lymphedema initiation, we compared the ability of the ALND-recovered rat foreleg lymphatic system to prevent edema during an inflammatory challenge with that of the uninjured lymphatic system. At 73 days postsurgery, the forelegs of ALND(-)- and ALND(+)-sensitized rats were exposed to the proinflammatory agent oxazolone, which was found to reduce fluid drainage and increase skin thickness in both ALND(-) and ALND(+) forelegs (P < 0.05). However, drainage in the ALND-recovered forelegs was more severely impaired than ALND(-) forelegs, as visualized by indocyanine green lymphography and quantified by interstitial transport of fluid marker (P < 0.05). Although both ALND(+) and ALND(-) forelegs experienced significant inflammation-induced edema with the oxazolone exposure (P < 0.05), the peak tissue swelling in the ALND(+) group was significantly greater than that of the ALND(-) forelegs (arm area peaked at ~13.4 vs. ~5.7% swelling, respectively, P < 0.005; wrist diameter peaked at 9.7 vs. 2.2% swelling, respectively, P < 0.005). The findings demonstrate that outward recovery from ALND in the rat foreleg masks an ensuing chronic and latent lymphatic insufficiency, which reduces the ability of the foreleg lymphatic system to prevent edema during an acute inflammatory process. PMID- 22942184 TI - Endogenous antigen presentation impacts on T-box transcription factor expression and functional maturation of CD8+ T cells. AB - T-box transcription factors T-bet (Tbx21) and Eomesodermin (Eomes) are critical players in CD8(+) cytotoxic T lymphocyte effector function and differentiation, but how the expression of these transcription factors is regulated remains poorly defined. Here we show that dominant T cells directed toward human CMV, expressing significantly higher levels of T-bet with graded loss of Eomes expression (T bet(hi)Eomes(hi/lo)), are more efficient in recognizing endogenously processed peptide-major histocompatibility complexes (pMHC) compared with subdominant virus specific T cells expressing lower levels of T-bet and high levels of Eomes (T bet(int)Eomes(hi)). Paradoxically, the T-bet(hi)Eomes(hi/lo) dominant populations that efficiently recognized endogenous antigen demonstrated lower intrinsic avidity for pMHC, whereas T-bet(int)Eomes(hi) subdominant populations were characterized by higher pMHC avidity and less efficient recognition of virus infected cells. Importantly, differential endogenous viral antigen recognition by CMV-specific CD8(+) T cells also correlated with the differentiation status and expression of perforin, granzyme B and K. Furthermore, we demonstrate that the expression of T-bet correlates with clonal expansion, differentiation status, and expression of perforin, granzyme B and K in antigen-specific T cells. These findings illustrate how endogenous viral antigen presentation during persistent viral infection may influence the transcriptional program of virus-specific T cells and their functional profile in the peripheral blood of humans. PMID- 22942183 TI - Adaptor protein Lnk binds to and inhibits normal and leukemic FLT3. AB - Fms-like tyrosine kinase 3 (FLT3) is a receptor tyrosine kinase with important roles in hematopoietic progenitor cell survival and proliferation. It is mutated in approximately one-third of AML patients, mostly by internal tandem duplications (ITDs). Adaptor protein Lnk is a negative regulator of hematopoietic cytokine signaling. In the present study, we show that Lnk interacts physically with both wild-type FLT3 (FLT3-WT) and FLT3-ITD through the SH2 domains. We have identified the tyrosine residues 572, 591, and 919 of FLT3 as phosphorylation sites involved in direct binding to Lnk. Lnk itself was tyrosine phosphorylated by both FLT3 ligand (FL)-activated FLT3-WT and constitutively activated FLT3-ITD. Both shRNA-mediated depletion and forced overexpression of Lnk demonstrated that activation signals emanating from both forms of FLT3 are under negative regulation by Lnk. Moreover, Lnk inhibited 32D cell proliferation driven by different FLT3 variants. Analysis of primary BM cells from Lnk-knockout mice showed that Lnk suppresses the expansion of FL-stimulated hematopoietic progenitors, including lymphoid-primed multipotent progenitors. The results of the present study show that through direct binding to FLT3, Lnk suppresses FLT3 WT/ITD-dependent signaling pathways involved in the proliferation of hematopoietic cells. Therefore, modulation of Lnk expression levels may provide a unique therapeutic approach for FLT3-ITD-associated hematopoietic disease. PMID- 22942185 TI - Platelet factor 4 binding to lipid A of Gram-negative bacteria exposes PF4/heparin-like epitopes. AB - The positively charged chemokine platelet factor 4 (PF4) forms immunogenic complexes with heparin and other polyanions. Resulting antibodies can induce the adverse drug effect heparin-induced thrombocytopenia. PF4 also binds to bacteria, thereby exposing the same neoantigen(s) as with heparin. In this study, we identified the negatively charged lipopolysaccharide (LPS) as the PF4 binding structure on Gram-negative bacteria. We demonstrate by flow cytometry that mutant bacteria with progressively truncated LPS structures show increasingly enhanced PF4 binding activity. PF4 bound strongest to mutants lacking the O-antigen and core structure of LPS, but still exposing lipid A on their surfaces. Strikingly, PF4 bound more efficiently to bisphosphorylated lipid A than to monophosphorylated lipid A, suggesting that phosphate residues of lipid A mediate PF4 binding. Interactions of PF4 with Gram-negative bacteria, where only the lipid A part of LPS is exposed, induce epitopes on PF4 resembling those on PF4/heparin complexes as shown by binding of human anti-PF4/heparin antibodies. As both the lipid A on the surface of Gram-negative bacteria and the amino acids of PF4 contributing to polyanion binding are highly conserved, our results further support the hypothesis that neoepitope formation on PF4 after binding to bacteria is an ancient host defense mechanism. PMID- 22942187 TI - Venous sinus manometry and intervention using the PrimeWire Prestige pressure guidewire: technique and initial experience. AB - BACKGROUND: Cerebral venography and manometry are used for the diagnosis of hemodynamically significant venous sinus stenosis in patients with the syndrome of idiopathic intracranial hypertension. Intravenous pressure measurements using the traditional microcatheter technique can be cumbersome, time consuming and potentially unreliable. The PrimeWire Prestige pressure guidewire conducts pressure electrically and can be used as a guidewire for intervention. It has been validated in interventional cardiology procedures. OBJECTIVE: We describe our initial clinical experience with the PrimeWire Prestige pressure guidewire system for cerebral venous manometry and intervention. METHOD: Cerebral venous pressure gradient was directly measured by advancing the pressure wire across a region of stenosis. The pressure wire was also used as a guidewire for intravascular ultrasound, angioplasty and stenting. RESULTS: The PrimeWire Prestige pressure guidewire successfully navigated the intracranial venous sinus anatomy. Transfer of devices over the guidewire in a monorail fashion was uncomplicated, and measurement of sinus pressure between the steps of the intervention was efficiently performed. CONCLUSION: The PrimeWire Prestige pressure guidewire system provided a safe, fast and effective method for intracranial venous sinus manometry and intervention. It has several potential advantages over the traditional microcatheter method, including efficiency, accuracy and cost. PMID- 22942188 TI - Suicide prevention. PMID- 22942189 TI - No more disease silos for sub-Saharan Africa. PMID- 22942186 TI - Long-term follow-up of the multicenter, multidisciplinary treatment study HIT-LGG 1996 for low-grade glioma in children and adolescents of the German Speaking Society of Pediatric Oncology and Hematology. AB - The Hirntumorstudien (HIT)-LGG-1996 protocol offered a comprehensive treatment strategy for pediatric patients with low-grade glioma (LGG), ie, observation, surgery, adjuvant radiotherapy, and chemotherapy to defer the start of irradiation in young children. In this current study, we sought to determine clinical factors for progression and survival. Between October 1, 1996 and March 31, 2004, 1031 patients were prospectively recruited into an observation arm (n = 668) and a nonsurgical arm stratifying 12 months of vincristine-carboplatin chemotherapy (n = 216) and conventional radiotherapy/brachytherapy (n = 147) in an age-dependent manner. Median patient age was 6.9 years; 28 patients had diencephalic syndrome, 44 had dissemination, and 108 had neurofibromatosis type 1(NF-1). Main tumor location was the supratentorial midline (40.4%), and the main histology was pilocytic astrocytoma (67.9%). Following a median observation of 9.3 years, 10-year overall survival (OS) was 0.94 and 10-year event-free survival (EFS) was 0.47. Ten-year progression-free survival was 0.62 following radiotherapy and 0.44 following chemotherapy. Sixty-one of 216 chemotherapy patients received radiotherapy 0.3-8.7 years after initial diagnosis. By multivariate analysis, diencephalic syndrome and incomplete resection were found to be unfavorable factors for OS and EFS, age >=11 years for OS, and supratentorial midline location for EFS. Dissemination, age <1 year, and nonpilocytic histology were unfavorable factors for progression following radiotherapy (138 patients); and diencephalic syndrome, dissemination, and age >=11 years were unfavorable factors following chemotherapy (210 patients). NF-1 patients and boys experienced prolonged tumor stabilization with chemotherapy. A nationwide multimodal treatment strategy is feasible for pediatric LGG. Extended follow-up yielded results comparable to single-institution series for the treatment groups. Three-quarters of surviving chemotherapy patients have not yet received radiation therapy. Infants with or without diencephalic syndrome and dissemination bear the highest risk for death and progression following diagnosis or treatment. PMID- 22942190 TI - Marketing to register organ donors may circumvent principles of informed consent. PMID- 22942192 TI - Italian doctors welcome plans for 24 hour opening. PMID- 22942191 TI - National Commissioning Board admits struggle to recruit staff. PMID- 22942198 TI - Senior managers resign over conflict with doctors. PMID- 22942200 TI - Clarifying the role of adjunctive metronidazole in the treatment of biliary infections. PMID- 22942199 TI - Endothelium-neutrophil interactions in ANCA-associated diseases. AB - The two salient features of ANCA-associated vasculitis (AAV) are the restricted microvessel localization and the mechanism of inflammatory damage, independent of vascular immune deposits. The microvessel localization of the disease is due to the ANCA antigen accessibility, which is restricted to the membrane of neutrophils engaged in beta2-integrin-mediated adhesion, while these antigens are cytoplasmic and inaccessible in resting neutrophils. The inflammatory vascular damage is the consequence of maximal proinflammatory responses of neutrophils, which face cumulative stimulations by TNF-alpha, beta2-integrin engagement, C5a, and ANCA by the FcgammaRII receptor. This results in the premature intravascular explosive release by adherent neutrophils of all of their available weapons, normally designed to kill IgG-opsonized bacteria after migration in infected tissues. PMID- 22942202 TI - Tuberculosis in pregnant and postpartum women: epidemiology, management, and research gaps. AB - Tuberculosis is most common during a woman's reproductive years and is a major cause of maternal-child mortality. National guidelines for screening and management vary widely owing to insufficient data. In this article, we review the available data on (1) the global burden of tuberculosis in women of reproductive age; (2) how pregnancy and the postpartum period affect the course of tuberculosis; (3) how to screen and diagnose pregnant and postpartum women for active and latent tuberculosis; (4) the management of active and latent tuberculosis in pregnancy and the postpartum period, including the safety of tuberculosis medications; and (5) infant outcomes. We also include data on HIV/tuberculosis coinfection and drug-resistant tuberculosis. Finally, we highlight research gaps in tuberculosis in pregnant and postpartum women. PMID- 22942203 TI - Balancing immunological benefits and cardiovascular risks of antiretroviral therapy: when is immediate treatment optimal? AB - We developed a mathematical model to identify the timing of antiretroviral therapy (ART) initiation that optimizes patient outcomes as a function of patient CD4 count, age, cardiac mortality risk, sex, and personal preferences. Our goal was to find the conditions that maximize patient quality-adjusted life expectancy (QALE) in the context of our model. Under the assumption that ART confers disease progression and mortality benefits at any CD4 count, immediate treatment initiation yields the greatest remaining QALE for young patients under most circumstances. The timing of ART initiation depends on the magnitude of benefit from ART at high CD4 counts, the magnitude of increases in cardiac risk, and patients' preferences. If ART reduces HIV progression at high CD4 counts, immediate ART is preferable for most newly infected individuals <35 years even if ART doubles age- and sex-specific cardiac risk. PMID- 22942205 TI - Addition of vitamin D status to prognostic scores improves the prediction of outcome in community-acquired pneumonia. AB - BACKGROUND: Vitamin D plays a role in host defense against infection. Vitamin D deficiency is common worldwide. The prognostic value of vitamin D levels in pneumonia is unknown. In this study, we aimed to investigate the impact of vitamin D status on outcome in community-acquired pneumonia (CAP). METHODS: We conducted a prospective cohort study in 272 hospitalized patients with CAP. Levels of 25-hydroxyvitamin D, leukocytes, C-reactive protein, and total cortisol and the Pneumonia Severity Index (PSI) and CURB-65 scores were measured on admission. Major outcome measures were intensive care unit (ICU) admission and 30 day mortality. RESULTS: One hundred forty-three patients (53%) were vitamin D deficient (<50 nmol/L), 79 patients (29%) were vitamin D insufficient (50-75 nmol/L), and 50 patients (18%) were vitamin D sufficient (>75 nmol/L). Vitamin D deficiency was associated with an increased risk of ICU admission and 30-day mortality. Vitamin D status was an independent predictor of 30-day mortality (area under the curve [AUC] =0.69; 95% confidence interval [CI], .57-.80). Multivariate regression analysis including all predictors for outcome resulted in a final model including vitamin D status and the PSI score, with a significantly higher prognostic accuracy compared with the PSI score alone (AUC=0.83; 95% CI, .71-.94). CONCLUSIONS: Vitamin D deficiency is associated with adverse outcome in CAP. Vitamin D status is an independent predictor of 30-day mortality and adds prognostic value to other biomarkers and prognostic scores, in particular the PSI score. CLINICAL TRIALS REGISTRATION: NCT00471640. PMID- 22942204 TI - A large multicenter study of methicillin-susceptible and methicillin-resistant Staphylococcus aureus prosthetic joint infections managed with implant retention. AB - BACKGROUND: Several series predicting the prognosis of staphylococcal prosthetic joint infection (PJI) managed with debridement, antibiotics, and implant retention (DAIR) have been published, but some of their conclusions are controversial. At present, little is known regarding the efficacy of the different antibiotics that are used or their ability to eliminate methicillin resistant S. aureus (MRSA) infection. METHODS: This was a retrospective, multicenter, observational study of cases of PJI by S. aureus that were managed with DAIR (2003-2010). Cases were classified as failures when infection persistence/relapse, death, need for salvage therapy, or prosthesis removal occurred. The parameters that predicted failure were analyzed with logistic and Cox regression. RESULTS: Out of 345 episodes (41% men, 73 years), 81 episodes were caused by MRSA. Fifty-two were hematogenous, with poorer prognoses, and 88% were caused by methicillin-susceptible S. aureus (MSSA). Antibiotics were used for a median of 93 days, with similar use of rifampin-based combinations in MSSA- and MRSA-PJI. Failure occurred in 45% of episodes, often early after debridement. The median survival time was 1257 days. There were no overall prognostic differences between MSSA- and MRSA-PJI, but there was a higher incidence of MRSA PJI treatment failure during the period of treatment (HR 2.34), while there was a higher incidence of MSSA-PJI treatment failure after therapy. Rifampin-based combinations exhibited an independent protective effect. Other independent predictors of outcome were polymicrobial, inflammatory, and bacteremic infections requiring more than 1 debridement, immunosuppressive therapy, and the exchange of removable components of the prosthesis. CONCLUSIONS: This is the largest series of PJI by S. aureus managed with DAIR reported to date. The success rate was 55%. The use of rifampin may have contributed to homogenizing MSSA and MRSA prognoses, although the specific rifampin combinations may have had different efficacies. PMID- 22942206 TI - Acquired resistance to second-line drugs among persons with tuberculosis in the United States. AB - BACKGROUND: Acquired resistance to second-line drugs (SLDs) is a problem in treating patients with drug-resistant tuberculosis worldwide. The objectives of this study were to identify risk factors for acquired resistance (AR) to injectable SLDs (INJ SLDs) and fluoroquinolones in the US National tuberculosis Surveillance System, 1993-2008. METHODS: We selected cases for which the initial and final drug susceptibility test (DST) results had been reported. We defined AR as resistance at the final DST but susceptibility to the same drug at the initial DST. We analyzed AR using 2-way frequency tables and multivariable logistic regression. RESULTS: The baseline prevalence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis was 12.6% (1864/14 770) and 0.38% (56/14 770), respectively. Of 2274 individuals without initial resistance to INJ SLDs, 49 (2.2%) acquired resistance. Of 1141 initially susceptible to fluoroquinolones, 32 (2.8%) acquired resistance. The AR to INJ SLDs was associated with age group 25-44 years (adjusted odds ratio [aOR], 2.7; 95% confidence interval [CI], 1.2-6.3), positive HIV (human immunodeficiency virus) status (aOR, 2.5; 95% CI, 1.3-4.7), MDR at treatment initiation (aOR, 5.5; 95% CI, 2.9-10.5), and treatment with any SLD (aOR, 2.4; 95% CI,1.2-4.7). The AR to fluoroquinolones was associated with MDR tuberculosis at treatment initiation (aOR, 6.5; 95% CI, 2.9-14.6). CONCLUSIONS: Among patients with initial and final DST reported, the risk factors for AR to INJ SLDs included age, positive HIV status, MDR tuberculosis and initial treatment with any SLD, while the only predictor for AR to fluoroquinolones was MDR tuberculosis at treatment initiation. Providers should consider monitoring SLD DST for MDR tuberculosis patients in the indicated subgroups. PMID- 22942207 TI - Three-month antibiotic therapy for early-onset postoperative spinal implant infections. AB - BACKGROUND: Optimal duration and modalities of antibiotic therapy for early-onset spinal implant infection (EOSII) remain controversial. METHODS: Between November 2004 and November 2007, we conducted a prospective, monocentric study to assess the efficacy of a 3-month course of antibiotics for patients diagnosed with EOSII, as defined by a proven deep infection of the surgical site occurring within 30 days after spinal instrumented surgery. All patients with EOSII underwent surgical debridement with implant retention. Combination antibiotic therapy was administered intravenously for 2 weeks. Treatment was switched orally for the following 10 weeks. RESULTS: 50 patients matched the inclusion criteria and were included in this study. The median age was 68 (interquartile range [IQR]: 51-75) years; the median ASA score was 2 (IQR: 2-2). Emergency spinal surgery had been performed in 18 patients. Staphylococcus aureus was the most frequently isolated pathogen (n=27), followed by Enterobacteriaceae (n=22) and coagulase-negative staphylococci (n=6). Seventeen patients had polymicrobial infections, and 13 patients (26%) had bacteremia. The median time from the first symptoms of infection to debridement surgery was 3 days (IQR: 2-5 days). Three patients underwent 2 debridement surgeries. The median follow-up was 43 (IQR: 34 54) months. The 2-year survival rate for those who did not experience treatment failure was 88% (95% confidence interval [CI]: 75.7%-95.5%). Three patients experienced treatment failure (6%, 95% CI: 1.3%-16.5%), including 1 relapse due to methicillin-susceptible S. aureus and 2 reinfections with another pathogen. CONCLUSIONS: In this homogenous cohort of 50 patients with EOSII, treatment consisting of debridement surgery with implant retention followed by combination antibiotic therapy for 3 months appeared safe and effective. PMID- 22942210 TI - Infectious complications of Bio-Alcamid filler used for HIV-related facial lipoatrophy. AB - BACKGROUND: Human immunodeficiency virus (HIV)-related facial lipoatrophy is a devastating adverse effect of antiretroviral therapy. At this time, the most viable treatment option is cosmetic surgery with synthetic fillers. Bio-Alcamid has many advantages over other fillers, and has become widely used. The objective of this study was to determine the incidence rate of infectious complications associated with Bio-Alcamid facial filler in patients with HIV-related facial lipoatrophy (FLA). METHODS: This retrospective study identified patients who had received treatment with Bio-Alcamid, and reviewed their long-term outcomes. RESULTS: Two hundred sixty-seven patients with Bio-Alcamid were reviewed. Infectious complications were documented in 56 (19%) patients. The incidence rate of infection was 0.07 per patient-year of follow-up. Among patients with infections, the median time from first Bio-Alcamid treatment to infection was 32 months (interquartile range, 21-42). We did not find an association between the development of infection and the level of immune suppression by HIV. Surgical drainage in addition to antibiotics was required for the majority of patients. Potential risk factors for infection include severity of FLA and a preceding history of facial manipulation, including Bio-Alcamid touch-up treatments, cosmetic surgery, facial trauma, and dental work. CONCLUSIONS: Bio-Alcamid treatment of HIV-related FLA was associated with a high rate of infectious complications, often presenting years after treatment. Antibiotic prophylaxis should be considered in patients with Bio-Alcamid prior to dental work or facial manipulation. PMID- 22942209 TI - Underutilization of aspirin for primary prevention of cardiovascular disease among HIV-infected patients. AB - BACKGROUND: Individuals infected with human immunodeficiency virus (HIV) are at increased risk for cardiovascular disease (CVD) events compared with uninfected persons. However, little is known about HIV provider practices regarding aspirin (ASA) for primary prevention of CVD. METHODS: A cross-sectional study was conducted among patients attending the University of Alabama at Birmingham 1917 HIV Clinic during 2010 to determine the proportion receiving ASA for primary prevention of CVD and identify factors associated with ASA prescription. Ten-year risk for CVD events was calculated for men aged 45-79 and women aged 55-79. The 2009 US Preventive Services Task Force (USPSTF) guidelines were used to determine those qualifying for primary CVD prevention. RESULTS: Among 397 patients who qualified to receive ASA (mean age, 52.2 years, 94% male, 36% African American), only 66 (17%) were prescribed ASA. In multivariable logistic regression analysis, diabetes mellitus (odds ratio [OR], 2.60; 95% confidence interval [CI], 1.28 5.27), hyperlipidemia (OR, 3.42; 95% CI, 1.55-7.56), and current smoking (OR, 1.87; 95% CI, 1.03-3.41) were significantly associated with ASA prescription. Odds of ASA prescription more than doubled for each additional CVD-related comorbidity present among hypertension, diabetes, hyperlipidemia, and smoking (OR, 2.13, 95% CI, 1.51-2.99). CONCLUSIONS: In this HIV-infected cohort, fewer than 1 in 5 patients in need received ASA for primary CVD prevention. Escalating likelihood of ASA prescription with increasing CVD-related comorbidity count suggests that providers may be influenced more by co-occurrence of these diagnoses than by USPSTF guidelines. In the absence of HIV-specific guidelines, interventions to improve HIV provider awareness of and adherence to existing general population guidelines on CVD risk reduction are needed. PMID- 22942211 TI - Enterococcal bloodstream infection after hematopoietic stem cell transplant: experience of a center with a low prevalence of vancomycin-resistant enterococci. PMID- 22942208 TI - A global comparative evaluation of commercial immunochromatographic rapid diagnostic tests for visceral leishmaniasis. AB - BACKGROUND: Poor access to diagnosis stymies control of visceral leishmaniasis (VL). Antibody-detecting rapid diagnostic tests (RDTs) can be performed in peripheral health settings. However, there are many brands available and published reports of variable accuracy. METHODS: Commercial VL RDTs containing bound rK39 or rKE16 antigen were evaluated using archived human sera from confirmed VL cases (n = 750) and endemic non-VL controls (n = 754) in the Indian subcontinent (ISC), Brazil, and East Africa to assess sensitivity and specificity with 95% confidence intervals. A subset of RDTs were also evaluated after 60 days' heat incubation (37 degrees C, 45 degrees C). Interlot and interobserver variability was assessed. RESULTS: All test brands performed well against ISC panels (sensitivity range, 92.8%-100%; specificity range, 96%-100%); however, sensitivity was lower against Brazil and East African panels (61.5%-91% and 36.8% 87.2%, respectively). Specificity was consistently > 95% in Brazil and ranged between 90.8% and 98% in East Africa. Performance of some products was adversely affected by high temperatures. Agreement between lots and readers was good to excellent (kappa > 0.73-0.99). CONCLUSIONS: Diagnostic accuracy of VL RDTs varies between the major endemic regions. Many tests performed well and showed good heat stability in the ISC; however, reduced sensitivity against Brazilian and East African panels suggests that in these regions, used alone, several RDTs are inadequate for excluding a VL diagnosis. More research is needed to assess ease of use and to compare performance using whole blood instead of serum and in patients coinfected with human immunodeficiency virus. PMID- 22942212 TI - Galectin-1 promotes human neutrophil migration. AB - An important step of innate immune response is the recruitment of polymorphonuclear leukocytes (PMN) to injured tissues through chemotactic molecules. Galectins, a family of endogenous lectins, participate in numerous functions such as lymphoid cell migration, homing, cell-cell and cell-matrix interactions. Particularly, galectin-3 (Gal-3) and -9 have been implicated in the modulation of acute and chronic inflammation by inducing the directional migration of monocytes/macrophages and eosinophils, whereas Gal-1 is considered to function as an anti-inflammatory molecule, capable of inhibiting the influx of PMN to the site of injury. In this study, we assessed the effect of Gal-1 on neutrophil recruitment, in the absence of additional inflammatory insults. Contrasting with its capacity to inhibit cell trafficking and modulate the release of mediators described in models of acute inflammation and autoimmunity, we evidenced that Gal-1 has the capacity to induce neutrophil migration both in vitro and in vivo. This effect is not mediated through a G-protein-coupled receptor but potentially through the sialoglycoprotein CD43, via carbohydrate binding and through the p38 mitogen-activated protein kinase pathway. These results suggest a novel biological function for CD43 on neutrophils and highlight that depending on the environment, Gal-1 can act either as chemoattractant or, as a molecule that negatively regulates migration under acute inflammatory conditions, underscoring the potential of Gal-1 as a target for innovative drug development. PMID- 22942213 TI - Insomnia and risk of cardiovascular disease: a meta-analysis. AB - OBJECTIVE: Increasing evidence suggests an association between insomnia and cardiovascular disease. We performed a systematic review with meta-analysis of all the available prospective studies that investigated the association between insomnia and risk of developing and/or dying from cardiovascular disease. DESIGN: Systematic review and meta-analysis of prospective cohort studies. METHODS: We conducted an electronic literature search through MedLine, Embase, Google Scholar, Web of Science, The Cochrane Library and bibliographies of retrieved articles up to December 2011. Studies were included if they were prospective, had assessment of insomnia or sleep complaints at baseline, evaluated subjects free of cardiovascular disease at baseline and measured the association between insomnia and risk of developing and/or dying from cardiovascular disease. RESULTS: After the review process 13 prospective studies were included in the final analysis. These studies included 122,501 subjects followed for a time ranging from three to 20 years. A total of 6332 cardiovascular events occurred during the follow-up. Insomnia was assessed through questionnaire and defined as either difficulty of initiating or maintaining sleep or presence of restless, disturbed nights. The cumulative analysis for all the studies under a random effects model showed that insomnia determined an increased risk (+45%) of developing or dying from cardiovascular disease during the follow-up (relative risk 1.45, 95% confidence interval 1.29-1.62; p < 0.00001), with no evidence of heterogeneity across the studies (I 2: 19%; p = 0.14). CONCLUSION: Insomnia is associated with an increased risk of developing and/or dying from cardiovascular disease. PMID- 22942214 TI - The impact of the Danish smoking ban on hospital admissions for acute myocardial infarction. AB - BACKGROUND: Exposure to secondhand smoke is associated with an increased risk of acute myocardial infarction (AMI). The positive impact of a smoking ban on AMI hospitalization rates has been demonstrated both inside and outside Europe. A national smoking ban (SB) was implemented in Denmark on 15 August 2007. PURPOSE: To evaluate the impact of the Danish SB on hospital admissions for AMI. METHODS: Poisson regression models were used to analyse changes over time in AMI admissions in Denmark. We investigated a seven year period: five years before and two years after implementation of the SB. We accounted for the variation in the population size and for seasonal trends. Potential confounders included were: gender, age and the incidence of type 2 diabetes (T2D). RESULTS: A significant reduction in the number of AMI-admissions was found in the last three years of the study period after adjusting for the potential confounders. The significant reductions were found one year before the SB (relative rate (RR) = 0.86, 95% confidence interval (CI) 0.79-0.94), one year after the SB (RR = 0.77, 95% CI 0.71-0.85) and two years after the SB (RR = 0.77, 95% CI 0.70-0.84). CONCLUSIONS: A significant reduction in the number of AMI-admissions was found already one year before the SB after adjustment for the incidence of T2D. The results differ from most results found in similar studies throughout the world and may be explained by the incremental enactment of SBs in Denmark and the implementation of a nation-wide ban on industrially produced trans-fatty acids in food in 2004. PMID- 22942215 TI - Patterns and predictors of atypical language representation in epilepsy. AB - In the majority of the normal population, the left hemisphere is dominant for language. In epilepsy, a higher proportion of 'atypical' language representation is encountered. This can follow one of three patterns: (1) altered interhemispheric representation, where the spectrum of lateralisation is shifted to the right; (2) interhemispheric dissociation of linguistic subfunctions; or (3) intrahemispheric changes in representation. Knowledge of these patterns is essential for avoiding postoperative language deficits in epilepsy patients undergoing surgery. Several predictors of atypical language representation exist. It is more prevalent in left-handed individuals. Lesions in rough proximity to classical language areas are more associated with atypical language, although in some cases, remote lesions, such as in the hippocampus, can also lead to altered language representation. The more disruptive the lesion, the more likely atypical language is to be found. Widespread and frequent interictal epileptiform discharges are also associated with atypical language. Atypical language representation is more likely to be present when injury or epilepsy onset occurred at a young age. Thus, a subgroup of patients can be defined in whom atypical language representation is more likely to be found. PMID- 22942216 TI - Autonomic dysfunction in parkinsonian disorders: assessment and pathophysiology. AB - Parkinson's disease (PD) is a progressive neurodegenerative disorder characterised by motor dysfunction (parkinsonism) and several non-motor features. Dysautonomia is a significant non-motor feature as well as a neuropsychiatric symptom. Autonomic dysfunction can occur even in the early stages of PD, often preceding the onset of the classic motor symptoms of PD. The patterns of autonomic features in PD are different from other parkinsonian disorders. Detection of autonomic dysfunction may therefore be helpful in diagnosing PD in the early or pre-motor stages, and/or in differentiating it from other parkinsonian disorders, such as multiple system atrophy and progressive supuranuclear palsy. The aim of this review is to describe aspects of autonomic dysfunction, including symptoms, assessment and pathophysiology, resulting from autonomic impairment in PD and other parkinsonian syndromes. PMID- 22942217 TI - Therapeutic misconception in research subjects: development and validation of a measure. AB - BACKGROUND: Therapeutic misconception (TM), which occurs when research subjects fail to appreciate the distinction between the imperatives of clinical research and ordinary treatment, may undercut the process of obtaining meaningful consent to clinical research participation. Previous studies have found that TM is widespread, but progress in addressing TM has been stymied by the absence of a validated method for assessing its presence. PURPOSE: The goal of this study was to develop and validate a theoretically grounded measure of TM, assess its diagnostic accuracy, and test previous findings regarding TM's prevalence. METHODS: A total of 220 participants were recruited from clinical trials at four academic medical centers in the United States. Participants completed a 28-item Likert-type questionnaire to assess the presence of beliefs associated with TM, and a semistructured TM interview designed to elicit their perceptions of the nature of the clinical trial in which they were participating. Data from the questionnaires were subjected to factor analysis, and items with poor factor loadings were excluded. This resulted in a 10-item scale, with three strongly correlated factors and excellent internal consistency; the fit indices of the model across 10 training sets were consistent with the original results, suggesting a stable factor solution. RESULTS: The scale was validated against the TM interview, with significantly higher scores among subjects coded as displaying evidence of TM. Receiver operating curve (ROC) analysis based on a 10-fold internal cross-validation yielded area under the ROC (AUC) = 0.682 for any evidence of TM. When sensitivity (0.72) and specificity (0.61) were both optimized, positive predictive value was 0.65 and negative predictive value was 0.68, with a positive likelihood ratio of 1.89 and a negative likelihood ratio of 0.47. In all, 50.5% (n = 101) of the participants manifested evidence of TM on the TM interview, a somewhat lower rate than in most previous studies. LIMITATIONS: The predictive value of the scale compared with the 'gold standard' clinical interview is modest, although similar to other instruments based on self report assessing states of mind rather than discrete symptoms. Thus, although the scale can offer evidence of which subjects are at risk for distortions in their decisions and to what degree, it will not allow researchers to conclude definitively that TM is present in a given subject. CONCLUSIONS: The development of a reliable and valid TM scale, even with modest predictive power, should permit investigators in clinical trials to identify subjects with tendencies to misinterpret the nature of the situation and to provide additional information to them. It should also stimulate research on how best to decrease TM and facilitate meaningful informed consent to clinical research. PMID- 22942218 TI - Catheter ablation of ventricular tachycardia in nonischemic heart disease. AB - BACKGROUND: Catheter ablation of ventricular tachycardia (VT) in nonischemic heart diseases can be challenging, and outcomes across different diseases are incompletely defined. The aim of this study was to describe the outcomes after catheter ablation for nonischemic VT in a large cohort and to compare the electrophysiological findings and outcomes according to the type of underlying disease. METHODS AND RESULTS: Of the 891 consecutive patients undergoing catheter ablation for ventricular arrhythmias, 226 patients (52 +/- 14 years; 79% men) with sustained VT due to nonischemic heart disease were included. The primary end point was all-cause death or heart transplantation. Secondary end points were a composite of death, heart transplantation, or readmission because of VT recurrence within 1 year of discharge. Underlying heart diseases were dilated cardiomyopathy in 119 (53%), valvular heart disease in 34 (15%), arrhythmogenic right ventricular cardiomyopathy in 37 (16%), congenital heart disease in 16 (7%), cardiac sarcoidosis in 13 (6%), and hypertrophic cardiomyopathy in 7 (3%) patients. After ablation, inability to induce any VT was achieved in 55%, and another 20% had inducible VTs modified. Major complications occurred in 5%. Arrhythmogenic right ventricular cardiomyopathy had better outcomes than dilated cardiomyopathy for primary (P=0.002) and secondary end points (P=0.004). Sarcoidosis had worse outcome than dilated cardiomyopathy for secondary end point (P=0.002). At 1 year after the last ablation (a mean of 1.4 +/- 0.6 procedures, 1 4), freedom from death, heart transplantation, and readmission for VT recurrence were achieved in 173 (77%) patients. CONCLUSIONS: In patients with recurrent VT due to nonischemic heart disease, catheter ablation is often useful, although the outcome varies according to the nature of the underlying heart disease. PMID- 22942219 TI - Prevalence and types of pitfall in the assessment of mitral isthmus linear conduction block. AB - BACKGROUND: To identify and understand clinically encountered pitfalls in the assessment of transmitral conduction block using differential coronary sinus and left atrial appendage pacing techniques in patients with left mitral isthmus linear ablation. METHODS AND RESULTS: All the available assessments of mitral isthmus block were thoroughly reviewed in 271 mitral isthmus ablation procedures undertaken among 236 patients from October 2008 to April 2011. Bidirectional block was established in 186 of 271 (69%) procedures. Careful evaluation of electrograms recorded on the multipolar coronary sinus and ablation catheters was undertaken to identify and understand the characteristics of pitfall, if any. Pitfall was encountered in 55 of 271 (20%) procedures among 51 patients and categorized into 6 types (types 1, 3, 4, and 5 led to spurious diagnosis of block; types 2 and 6 led to erroneous diagnosis of absence of block). There were 14, 10, 17, 2, 15, and 3 (total=61) cases of pitfall types 1 through 6, respectively. Operator recognized 42 of 61 (69%) pitfalls intraprocedurally. Recognition of types 1 and 5 was difficult because of indiscernible electrograms at usual amplifier settings or presence of slow conduction mimicking block. CONCLUSIONS: Every fifth assessment of bidirectional block across mitral isthmus linear lesion using differential coronary sinus and left atrial appendage pacing techniques encounters a pitfall, which can lead to erroneous clinical diagnosis of block or absence of block. Recognition of pitfall during the procedure is feasible and necessitates careful distinction of far-field left atrium from the local coronary sinus electrograms besides appropriate adjustments in catheter position and pacing outputs. PMID- 22942220 TI - Counterpoint: alterations in airway smooth muscle phenotype do not cause airway hyperresponsiveness in asthma. PMID- 22942221 TI - Rebuttal from Gunst and Panettieri. PMID- 22942222 TI - Rebuttal from Pare and Mitzner. PMID- 22942223 TI - Comments on Point:Counterpoint: Alterations in airway smooth muscle phenotype do/do not cause airway hyperresponsiveness in asthma. PMID- 22942224 TI - Last Word on Point: Alterations in airway smooth muscle phenotype do cause airway hyperresponsiveness in asthma. PMID- 22942225 TI - Last Word on Counterpoint: Alterations in airway smooth muscle phenotype do not cause airway hyperresponsiveness in asthma. PMID- 22942227 TI - Primary and secondary prevention of cardiovascular disease in diabetes with aspirin. PMID- 22942228 TI - Matrix metalloproteinase-9 genotype as a potential genetic marker for abdominal aortic aneurysm. AB - BACKGROUND: Degradation of extracellular matrix support in the large abdominal arteries contribute to abnormal dilation of aorta, leading to abdominal aortic aneurysms, and matrix metalloproteinase-9 (MMP-9) is the predominant enzyme targeting elastin and collagen present in the walls of the abdominal aorta. Previous studies have suggested a potential association between MMP-9 genotype and abdominal aortic aneurysm, but these studies have been limited only to the p 1562 and (CA) dinucleotide repeat microsatellite polymorphisms in the promoter region of the MMP-9 gene. We determined the functional alterations caused by 15 MMP-9 single-nucleotide polymorphisms (SNPs) reported to be relatively abundant in the human genome through Western blots, gelatinase, and promoter-reporter assays and incorporated this information to perform a logistic-regression analysis of MMP-9 SNPs in 336 human abdominal aortic aneurysm cases and controls. METHODS AND RESULTS: Significant functional alterations were observed for 6 exon SNPs and 4 promoter SNPs. Genotype analysis of frequency-matched (age, sex, history of hypertension, hypercholesterolemia, and smoking) cases and controls revealed significant genetic heterogeneity exceeding 20% observed for 6 SNPs in our population of mostly white subjects from Northern Wisconsin. A step-wise logistic-regression analysis with 6 functional SNPs, where weakly contributing confounds were eliminated using Akaike information criteria, gave a final 2 SNP (D165N and p-2502) model with an overall odds ratio of 2.45 (95% confidence interval, 1.06-5.70). CONCLUSIONS: The combined approach of direct experimental confirmation of the functional alterations of MMP-9 SNPs and logistic-regression analysis revealed significant association between MMP-9 genotype and abdominal aortic aneurysm. PMID- 22942230 TI - Factors influencing the length of hospital stay among patients resident in Blackpool admitted with COPD: a cross-sectional study. AB - OBJECTIVES: To identify the differential effects of patient, health service, temporal and geographic factors on length of stay (LOS) for chronic obstructive pulmonary disease (COPD)-related admissions. DESIGN: We used stratified Cox proportional hazard model to evaluate the association between LOS and patient, health service, temporal and geographical factors. SETTING: Patients resident in Blackpool, North West England, admitted to the local hospital with COPD. PARTICIPANTS: We used the Admitted Patient Care General Episode Commissioning Dataset for the period 1 April 2005-31 March 2010. We analysed records of admission spells among patients resident in Blackpool aged 40 years or older admitted with a primary diagnosis of COPD. RESULTS: There were 2410 admissions meeting the inclusion criteria over the period. These admissions were attributed to 1172 COPD patients, an average of 2.06 admissions per patient. The median LOS was 6 days (95% CI 6 to 6) while the mean was 9.8 days (95% CI 9.1 to 10.5). Patients were 22% more likely to be discharged earlier in 2009/2010 compared with 2005/2006 (adjusted HR 1.22; p=0.0100). LOS was associated with socioeconomic deprivation with those in the most deprived areas being 35% less likely to be discharged earlier compared with those from the least deprived areas (adjusted HR 0.65; p=0.0010). CONCLUSIONS: LOS among COPD patients have reduced over the period of the study. Age, deprivation, Charlson index, specialty of admission and cause of exacerbations were independently associated with LOS. Though there were no significant associations between LOS and season of admission and distance from hospital, there were significant variations in LOS associated with these variables based on selected patient characteristics. PMID- 22942229 TI - A comparison of individual versus community influences on youth smoking behaviours: a cross-sectional observational study. AB - OBJECTIVES: To compare individual with community risk factors for adolescent smoking. DESIGN: A cross-sectional observational study with multivariate analysis. SETTING: National telephone survey. PARTICIPANTS: 3646 US adolescents aged 13-18 years in 2007 recruited through a random digit-dial survey. OUTCOME MEASURES: Ever tried smoking and, among experimental smokers, smoking intensity (based on smoking in past 30 days). RESULTS: One-third of participants (35.6%, N=1297) had tried smoking. After controlling for individual risk factors, neither tobacco outlet density nor proximity were associated with tried smoking or smoking intensity. Associations with trying smoking included age (adjusted OR (AOR)=1.23, 95% CI 1.16 to 1.31), lower socioeconomic status (AOR=0.82, 95% CI 0.74 to 0.91), sibling smoking (AOR=2.13, 95% CI 1.75 to 2.59), friend smoking (AOR=2.60, 95% CI 2.19 to 3.10 for some and AOR=7.01, 95% CI 5.05 to 9.74 for most), movie smoking exposure (AOR=2.66, 95% CI 1.95 to 3.63), team sports participation (AOR=0.69, 95% CI 0.54 to 0.89) and sensation seeking (AOR=7.72, 95% CI 5.26 to 11.34). Among experimental smokers, age (AOR=1.32, 95% CI 1.21 to 1.44), minority status (AOR=0.48, 95% CI 0.30 to 0.79 for Black; AOR=0.46, 95% CI 0.31 to 0.69 for Hispanic; AOR=0.53, 95% CI 0.43 to 0.85 for mixed race/other), friend smoking (AOR=3.37, 95% CI 2.37 to 4.81 for some; AOR=20.27, 95% CI 13.22 to 31.08 for most), team sports participation (AOR=0.38, 95% CI 0.26 to 0.55) and sensation seeking (AOR=6.57, 95% CI 3.71 to 11.64) were associated with smoking intensity. CONCLUSIONS: The study suggests that interventions and policies to prevent and reduce youth smoking should focus on individual risk factors for smoking, including supporting participation in team sports, minimising exposure to movie smoking, addressing the social influence of friend smoking and addressing experience seeking among high sensation-seekers. PMID- 22942231 TI - Development of an economic model to assess the cost-effectiveness of hawthorn extract as an adjunct treatment for heart failure in Australia. AB - OBJECTIVE: An economic model was developed to evaluate the cost-effectiveness of hawthorn extract as an adjunctive treatment for heart failure in Australia. METHODS: A Markov model of chronic heart failure was developed to compare the costs and outcomes of standard treatment and standard treatment with hawthorn extract. Health states were defined by the New York Heart Association (NYHA) classification system and death. For any given cycle, patients could remain in the same NYHA class, experience an improvement or deterioration in NYHA class, be hospitalised or die. Model inputs were derived from the published medical literature, and the output was quality-adjusted life years (QALYs). Probabilistic sensitivity analysis was conducted. The expected value of perfect information (EVPI) and the expected value of partial perfect information (EVPPI) were conducted to establish the value of further research and the ideal target for such research. RESULTS: Hawthorn extract increased costs by $1866.78 and resulted in a gain of 0.02 QALYs. The incremental cost-effectiveness ratio was $85 160.33 per QALY. The cost-effectiveness acceptability curve indicated that at a threshold of $40 000 the new treatment had a 0.29 probability of being cost effective. The average incremental net monetary benefit (NMB) was -$1791.64, the average NMB for the standard treatment was $92 067.49, and for hawthorn extract $90 275.84. Additional research is potentially cost-effective if research is not proposed to cost more than $325 million. Utilities form the most important target parameter group for further research. CONCLUSIONS: Hawthorn extract is not currently considered to be cost-effective in as an adjunctive treatment for heart failure in Australia. Further research in the area of utilities is warranted. PMID- 22942232 TI - Barriers to the uptake of evidence from systematic reviews and meta-analyses: a systematic review of decision makers' perceptions. AB - OBJECTIVE: To review the barriers to the uptake of research evidence from systematic reviews by decision makers. SEARCH STRATEGY: We searched 19 databases covering the full range of publication years, utilised three search engines and also personally contacted investigators. Reference lists of primary studies and related reviews were also consulted. SELECTION CRITERIA: Studies were included if they reported on the views and perceptions of decision makers on the uptake of evidence from systematic reviews, meta-analyses and the databases associated with them. All study designs, settings and decision makers were included. One investigator screened titles to identify candidate articles then two reviewers independently assessed the quality and the relevance of retrieved reports. DATA EXTRACTION: Two reviewers described the methods of included studies and extracted data that were summarised in tables and then analysed. Using a pre-established taxonomy, the barriers were organised into a framework according to their effect on knowledge, attitudes or behaviour. RESULTS: Of 1726 articles initially identified, we selected 27 unique published studies describing at least one barrier to the uptake of evidence from systematic reviews. These studies included a total of 25 surveys and 2 qualitative studies. Overall, the majority of participants (n=10 218) were physicians (64%). The most commonly investigated barriers were lack of use (14/25), lack of awareness (12/25), lack of access (11/25), lack of familiarity (7/25), lack of usefulness (7/25), lack of motivation (4/25) and external barriers (5/25). CONCLUSIONS: This systematic review reveals that strategies to improve the uptake of evidence from reviews and meta-analyses will need to overcome a wide variety of obstacles. Our review describes the reasons why knowledge users, especially physicians, do not call on systematic reviews. This study can inform future approaches to enhancing systematic review uptake and also suggests potential avenues for future investigation. PMID- 22942233 TI - Transmissibility of the 2009 H1N1 pandemic in remote and isolated Canadian communities: a modelling study. AB - OBJECTIVES: During the first wave of the 2009 influenza pH1N1, disease burden was distributed in a geographically heterogeneous fashion. It was particularly high in some remote and isolated Canadian communities when compared with urban centres. We sought to estimate the transmissibility (the basic reproduction number) of pH1N1 strain in some remote and isolated Canadian communities. DESIGN: A discrete time susceptible-exposed-infected transmission model was fit to infection curves simulated from laboratory-confirmed case counts for pH1N1 on each day. The sampling from Poisson distribution was used to estimate the basic reproduction number, R(0), of pH1N1 during the spring wave for five different communities in Manitoba and Nunavut, Canada, where remote and isolated communities experienced a high incidence of infection, and high rates of hospitalisation and intensive care unit admission. SETTING: Remote and isolated communities in Northern Manitoba, Nunavut, and the largest urban centre (Winnipeg) in the province of Manitoba, Canada. RESULTS: Using published values of the exposed and infectious periods specific to H1N1 infection, corresponding to the average generation time of 2.78 days, we estimated a mean value of 2.26 for R(0) (95% CI 1.57 to 3.75) in a community located in northern Manitoba. Estimates of R(0) for other communities in Nunavut varied considerably with higher mean values of 3.91 (95% CI 3.08 to 4.87); 2.03 (95% CI 1.50 to 3.19); and 2.45 (95% CI 1.68 to 3.44). We estimated a lower mean value of 1.57 (95% CI 1.35 to 1.87) for R(0) in the Winnipeg health region, as the largest urban centre in Manitoba. CONCLUSIONS: Influenza pH1N1 appears to have been far more transmissible in rural and isolated Canadian communities than other large urban areas. The differential severity of the pandemic in these regions may be explained partly by differential transmissibility, and suggests the need for more nuanced, targeted or population-specific control strategies in Canada. PMID- 22942234 TI - Germline ablation of VGF increases lipolysis in white adipose tissue. AB - Targeted deletion of VGF, a neuronal and endocrine secreted protein and neuropeptide precursor, produces a lean, hypermetabolic mouse that is resistant to diet-, lesion-, and genetically induced obesity and diabetes. We hypothesized that increased sympathetic nervous system activity in Vgf-/Vgf- knockout mice is responsible for increased energy expenditure and decreased fat storage and that increased beta-adrenergic receptor stimulation induces lipolysis in white adipose tissue (WAT) of Vgf-/Vgf- mice. We found that fat mass was markedly reduced in Vgf-/Vgf- mice. Within knockout WAT, phosphorylation of protein kinase A substrate increased in males and females, phosphorylation of hormone-sensitive lipase (HSL) (ser563) increased in females, and levels of adipose triglyceride lipase, comparative gene identification-58, and phospho-perilipin were higher in male Vgf-/Vgf- WAT compared with wild-type, consistent with increased lipolysis. The phosphorylation of AMP-activated protein kinase (AMPK) (Thr172) and levels of the AMPK kinase, transforming growth factor beta-activated kinase 1, were decreased. This was associated with a decrease in HSL ser565 phosphorylation, the site phosphorylated by AMPK, in both male and female Vgf-/Vgf- WAT. No significant differences in phosphorylation of CREB or the p42/44 MAPK were noted. Despite this evidence supporting increased cAMP signaling and lipolysis, lipogenesis as assessed by fatty acid synthase protein expression and phosphorylated acetyl-CoA carboxylase was not decreased. Our data suggest that the VGF precursor or selected VGF-derived peptides dampen sympathetic outflow pathway activity to WAT to regulate fat storage and lipolysis. PMID- 22942235 TI - Comprehensive functional analysis of chymotrypsin C (CTRC) variants reveals distinct loss-of-function mechanisms associated with pancreatitis risk. AB - OBJECTIVE: The digestive enzyme chymotrypsin C (CTRC) protects against pancreatitis by promoting degradation of trypsinogen, thereby curtailing potentially harmful trypsinogen activation. Loss-of-function variants in CTRC increase the risk for chronic pancreatitis. The aim of the present study was to perform comprehensive functional analysis of all missense CTRC variants identified to date. DESIGN: We investigated secretion, activity and degradation of 27 published and five novel CTRC mutants. We also assessed the effect of five mutants on endoplasmic reticulum (ER) stress. RESULTS: None of the mutants exhibited a gain of function, such as increased secretion or activity. By contrast, 11 mutants showed marked loss of function, three mutants had moderate functional defects, whereas 18 mutants were functionally similar to wild-type CTRC. The functional deficiencies observed were diminished secretion, impaired catalytic activity and degradation by trypsin. Mutants with a secretion defect caused ER stress that was proportional to the loss in secretion. ER stress was not associated with loss-of-function phenotypes related to catalytic defect or proteolytic instability. CONCLUSIONS: Pathogenic CTRC variants cause loss of function by three distinct but mutually non-exclusive mechanisms that affect secretion, activity and proteolytic stability. ER stress may be induced by a subset of CTRC mutants, but does not represent a common pathological mechanism of CTRC variants. This phenotypic dataset should aid in the classification of the clinical relevance of CTRC variants identified in patients with chronic pancreatitis. PMID- 22942236 TI - Refractory coeliac disease: one step closer to the origin of aberrant lymphocytes. PMID- 22942237 TI - Peginterferon therapy for chronic hepatitis B: one size fits all? PMID- 22942238 TI - Cullin7: a new gene involved in liver carcinogenesis related to metabolic syndrome. AB - BACKGROUND: Metabolic syndrome (MS) is an emerging risk factor in hepatocellular carcinoma (HCC). HCC related to MS may occur either in advanced fibrosis or before the development of cirrhosis, suggesting involvement of different molecular pathways according to the features of background liver. OBJECTIVE: To investigate genomic aberrations in HCC related to MS in order to identify new target genes involved in liver carcinogenesis. METHODS: Chromosomal aberrations of HCC obtained from 20 patients with MS (HCC/MS) were studied by comparative genomic hybridisation and compared with HCC related to hepatitis C virus (HCV) infection (HCC/HCV, n=10) and, within the group of HCC with MS, according to the condition of the background liver (presence or absence of significant fibrosis). RESULTS: Among the most frequent chromosomal alterations observed in HCC, 6p21.1 amplification had a higher incidence in HCC/MS than in HCC/HCV (60% vs 20%, p<0.01). Advanced fibrosis/cirrhosis in the peritumoral liver was the only clinicopathological factor associated with the 6p21.1 amplicon in HCC/MS. Increased expression of cullin7 (CUL7), a gene located at the 6p21.1 locus, was demonstrated in HCC with the 6p21.1 amplicon, in parallel with a decrease in cyclin D1 expression. CUL7 downregulation using siRNA transfection in hepatoma cell lines induced significant cyclin D1 expression (by promoting its degradation), decreased cell proliferation and increased apoptosis. CONCLUSIONS: This study demonstrates specific genomic alterations in HCC/MS and points to CUL7 as a novel gene potentially involved in liver carcinogenesis associated with MS, the amplification of which might influence cell proliferation. PMID- 22942239 TI - Interleukin 13 and its role in gut defence and inflammation. AB - Interleukin 13 (IL-13) is a cytokine of increasing interest to gastroenterologists because of its developing role in ulcerative colitis, eosinophilic oesophagitis (EO) and fibrosis. Recent data show that IL-13 may play an important role in a novel innate immune response since it can be released by signals from an injured or inflamed epithelium, of particular relevance to the gut. Animal models of IL-13-driven inflammation (from asthma to colitis and EO) are being translated to human disease and providing insight into potential strategies for new therapies. In fact, multiple clinical trials using anti-IL-13 drugs are underway in asthma and are being extended to gastrointestinal diseases. This review presents the current knowledge on IL-13 production and function in the gut, including the cells and receptor signalling pathways involved in mediating IL-13 effects, the proposed mechanisms of IL-13 induced gut disease and the many drugs currently being tested that target IL-13 related pathways. PMID- 22942240 TI - Role of biological therapy for inflammatory bowel disease in developing countries. PMID- 22942242 TI - Strontium is a biased agonist of the calcium-sensing receptor in rat medullary thyroid carcinoma 6-23 cells. AB - The calcium-sensing receptor (CaSR)-specific allosteric modulator cinacalcet has revolutionized the treatment of secondary hyperparathyroidism in patients with chronic kidney disease. However, its application is limited to patients with end stage renal disease because of hypocalcemic side effects presumably caused by CaSR-mediated calcitonin secretion from thyroid parafollicular C-cells. These hypocalcemic side effects might be dampened by compounds that bias the signaling of CaSR, causing similar therapeutic effects as cinacalcet without stimulating calcitonin secretion. Because biased signaling of CaSR is poorly understood, the objective of the present study was to investigate biased signaling of CaSR by using rat medullary thyroid carcinoma 6-23 cells as a model of thyroid parafollicular C-cells. By doing concentration-response experiments we focused on the ability of two well known CaSR agonists, calcium and strontium, to activate six different signaling entities: G(q/11) signaling, G(i/o) signaling, G(s) signaling, extracellular signal-regulated kinases 1 and 2 (ERK1/2) signaling, intracellular calcium ([Ca(2+)](i)) mobilization, and calcitonin secretion. The experiments showed that strontium biases CaSR signaling toward ERK1/2 signaling and possibly another pathway independent of G(q/11) signaling and [Ca(2+)](i) mobilization. It is noteworthy that the potency of strontium-stimulated calcitonin secretion was elevated compared with calcium. Combining these results with experiments investigating signaling pathway components involved in calcitonin secretion, we found that the enhanced potency of strontium-mediated calcitonin secretion was caused by a different signaling pattern than that produced by calcium. Together, our results suggest that calcitonin secretion can be affected by CaSR-stimulated signaling bias, which may be used to develop novel drugs for the treatment of secondary hyperparathyroidism. PMID- 22942244 TI - A federal plan for ending the tobacco epidemic. PMID- 22942241 TI - Inflammatory regulation of ATP binding cassette efflux transporter expression and function in microglia. AB - ATP-binding cassette (ABC) efflux transporters, including multidrug resistance protein 1 (Mdr1), breast cancer resistance protein (Bcrp), and multidrug resistance-associated proteins (Mrps) extrude chemicals from the brain. Although ABC transporters are critical for blood-brain barrier integrity, less attention has been placed on the regulation of these proteins in brain parenchymal cells such as microglia. Prior studies demonstrate that inflammation after lipopolysaccharide (LPS) treatment alters transporter expression in the livers of mice. Here, we sought to determine the effects of inflammation on the expression and function of transporters in microglia. To test this, the expression and function of ABC efflux transport proteins were quantified in mouse BV-2 microglial cells in response to activation with LPS. Intracellular retention of fluorescent rhodamine 123, Hoechst 33342, and calcein acetoxymethyl ester was increased in LPS-treated microglia, suggesting that the functions of Mdr1, Bcrp, and Mrps were decreased, respectively. LPS reduced Mdr1, Bcrp, and Mrp4 mRNA and protein expression between 40 and 70%. Conversely, LPS increased expression of Mrp1 and Mrp5 mRNA and protein. Immunofluorescent staining confirmed reduced Bcrp and Mrp4 and elevated Mrp1 and Mrp5 protein in activated microglia. Pharmacological inhibition of nuclear factor kappaB (NF-kappaB) transcriptional signaling attenuated down-regulation of Mdr1a mRNA and potentiated up-regulation of Mrp5 mRNA in LPS-treated cells. Together, these data suggest that LPS stimulates microglia and impairs efflux of prototypical ABC transporter substrates by altering mRNA and protein expression, in part through NF-kappaB signaling. Decreased transporter efflux function in microglia may lead to the retention of toxic chemicals and aberrant cell-cell communication during neuroinflammation. PMID- 22942245 TI - Functional divergence of FimX in PilZ binding and type IV pilus regulation. AB - Type IV pili (T4P) are polar surface structures that play important roles in bacterial motility, biofilm formation, and pathogenicity. The protein FimX and its orthologs are known to mediate T4P formation in the human pathogen Pseudomonas aeruginosa and some other bacterial species. It was reported recently that FimX(XAC2398) from Xanthomonas axonopodis pv. citri interacts with PilZ(XAC1133) directly through the nonenzymatic EAL domain of FimX(XAC2398). Here we present experimental data to reveal that the strong interaction between FimX(XAC2398) and PilZ(XAC1133) is not conserved in P. aeruginosa and likely other Pseudomonas species. In vitro and in vivo binding experiments showed that the interaction between FimX and PilZ in P. aeruginosa is below the measurable limit. Surface plasmon resonance assays further confirmed that the interaction between the P. aeruginosa proteins is at least more than 3 orders of magnitude weaker than that between the X. axonopodis pv. citri pair. The N-terminal lobe region of FimX(XAC2398) was identified as the binding surface for PilZ(XAC1133) by amide hydrogen-deuterium exchange and site-directed mutagenesis studies. Lack of several key residues in the N-terminal lobe region of the EAL domain of FimX is likely to account for the greatly reduced binding affinity between FimX and PilZ in P. aeruginosa. All together, the results suggest that the interaction between PilZ and FimX in Xanthomonas species is not conserved in P. aeruginosa due to the evolutionary divergence among the FimX orthologs. The precise roles of FimX and PilZ in bacterial motility and T4P biogenesis are likely to vary among bacterial species. PMID- 22942246 TI - Small multidrug resistance protein EmrE reduces host pH and osmotic tolerance to metabolic quaternary cation osmoprotectants. AB - The small multidrug resistance (SMR) transporter protein EmrE in Escherichia coli is known to confer resistance to toxic antiseptics classified as quaternary cation compounds (QCCs). Naturally derived QCCs synthesized during metabolic activities often act as osmoprotectants, such as betaine and choline, and participate in osmotic homoestasis. The goal of this study was to determine if EmrE proteins transport biological QCC-based osmoprotectants. Plasmid-encoded copies of E. coli emrE and the inactive variant emrE-E14C (emrE with the E -> C change at position 14) were expressed in various E. coli strains grown in either rich or minimal media at various pHs (5 to 9) and under hypersaline (0.5 to 1.0 M NaCl and KCl) conditions to identify changes in growth phenotypes induced by osmoprotectant transport. The results demonstrated that emrE expression reduced pH tolerance of E. coli strains at or above neutral pH and when grown in hypersaline media at or above NaCl or KCl concentrations of 0.75 M. Hypersaline growth conditions were used to screen QCC osmoprotectants betaine, choline, l carnitine, l-lysine, l-proline, and l-arginine. The study identified that betaine and choline are natural QCC substrates of EmrE. PMID- 22942247 TI - Structure and interactions of the cytoplasmic domain of the Yersinia type III secretion protein YscD. AB - The virulence of a large number of Gram-negative bacterial pathogens depends on the type III secretion (T3S) system, which transports select bacterial proteins into host cells. An essential component of the Yersinia T3S system is YscD, a single-pass inner membrane protein. We report here the 2.52-A resolution structure of the cytoplasmic domain of YscD, called YscDc. The structure confirms that YscDc consists of a forkhead-associated (FHA) fold, which in many but not all cases specifies binding to phosphothreonine. YscDc, however, lacks the structural properties associated with phosphothreonine binding and thus most likely interacts with partners in a phosphorylation-independent manner. Structural comparison highlighted two loop regions, L3 and L4, as potential sites of interactions. Alanine substitutions at L3 and L4 had no deleterious effects on protein structure or stability but abrogated T3S in a dominant negative manner. To gain insight into the function of L3 and L4, we identified proteins associated with YscD by affinity purification coupled to mass spectrometry. The lipoprotein YscJ was found associated with wild-type YscD, as was the effector YopH. Notably, the L3 and L4 substitution mutants interacted with more YopH than did wild-type YscD. These substitution mutants also interacted with SycH (the specific chaperone for YopH), the putative C-ring component YscQ, and the ruler component YscP, whereas wild-type YscD did not. These results suggest that substitutions in the L3 and L4 loops of YscD disrupted the dissociation of SycH from YopH, leading to the accumulation of a large protein complex that stalled the T3S apparatus. PMID- 22942248 TI - Noncoding RNAs binding to the nucleoid protein HU in Escherichia coli. AB - Some unidentified RNA molecules, together with the nucleoid protein HU, were suggested to be involved in the nucleoid structure of Escherichia coli. HU is a conserved protein known for its role in binding to DNA and maintaining negative supercoils in the latter. HU also binds to a few RNAs, but the full spectrum of its binding targets in the cell is not known. To understand any interaction of HU with RNA in the nucleoid structure, we immunoprecipitated potential HU-RNA complexes from cells and examined bound RNAs by hybridization to whole-genome tiling arrays. We identified associations between HU and 10 new intragenic and intergenic noncoding RNAs (ncRNAs), 2 of which are homologous to the annotated bacterial interspersed mosaic elements (BIMEs) and boxC DNA repeat elements. We confirmed direct binding of HU to BIME RNA in vitro. We also studied the nucleoid shape of HU and two of the ncRNA mutants (nc1 and nc5) by transmission electron microscopy and showed that both HU and the two ncRNAs play a role in nucleoid morphology. We propose that at least two of the ncRNA species complex with HU and help the formation or maintenance of the architecture of the E. coli chromosome. We also observed binding of HU with rRNA and tRNA segments, a few small RNAs, and a distinct small set of mRNAs, although the significance, if any, of these associations is not known. PMID- 22942250 TI - A Phaseolus vulgaris NADPH oxidase gene is required for root infection by Rhizobia. AB - Plant NADPH oxidases [respiratory burst oxidase homologs (RBOHs)] have emerged as key players in the regulation of plant-pathogen interactions. Nonetheless, their role in mutualistic associations, such as the rhizobia-legume symbiosis, is poorly understood. In this work, nine members of the Phaseolus vulgaris Rboh gene family were identified. The transcript of one of these, PvRbohB, accumulated abundantly in shoots, roots and nodules. PvRbohB promoter activity was detected in meristematic regions of P. vulgaris roots, as well as during infection thread (IT) progression and nodule development. RNA interference (RNAi)-mediated PvRbohB down-regulation in transgenic roots reduced reactive oxygen species (ROS) production and lateral root density, and greatly impaired nodulation. Microscopy analysis revealed that progression of the ITs was impeded at the base of root hairs in PvRbohB-RNAi roots. Furthermore, the few nodules that formed in PvRbohB down-regulated roots displayed abnormally wide ITs and reduced nitrogen fixation. These findings indicate that this common bean NADPH oxidase is crucial for successful rhizobial colonization and probably maintains proper IT growth and shape. PMID- 22942249 TI - Rapid depletion of target proteins allows identification of coincident physiological responses. AB - Targeted protein degradation is a powerful tool that can be used to create unique physiologies depleted of important factors. Current strategies involve modifying a gene of interest such that a degradation peptide is added to an expressed target protein and then conditionally activating proteolysis, either by expressing adapters, unmasking cryptic recognition determinants, or regulating protease affinities using small molecules. For each target, substantial optimization may be required to achieve a practical depletion, in that the target remains present at a normal level prior to induction and is then rapidly depleted to levels low enough to manifest a physiological response. Here, we describe a simplified targeted degradation system that rapidly depletes targets and that can be applied to a wide variety of proteins without optimizing target protease affinities. The depletion of the target is rapid enough that a primary physiological response manifests that is related to the function of the target. Using ribosomal protein S1 as an example, we show that the rapid depletion of this essential translation factor invokes concomitant changes to the levels of several mRNAs, even before appreciable cell division has occurred. PMID- 22942251 TI - Changes in cytosolic ATP levels and intracellular morphology during bacteria induced hypersensitive cell death as revealed by real-time fluorescence microscopy imaging. AB - Hypersensitive cell death is known to involve dynamic remodeling of intracellular structures that uses energy released during ATP hydrolysis. However, the relationship between intracellular structural changes and ATP levels during hypersensitive cell death remains unclear. Here, to visualize ATP dynamics directly in real time in individual living plant cells, we applied a genetically encoded Forster resonance energy transfer (FRET)-based fluorescent ATP indicator, ATeam1.03-nD/nA, for plant cells. Intracellular ATP levels increased approximately 3 h after inoculation with the avirulent strain DC3000/avrRpm1 of Pseudomonas syringae pv. tomato (Pst), which was accompanied by the simultaneous disappearance of transvacuolar strands and appearance of bulb-like structures within the vacuolar lumen. Approximately 5 h after bacterial inoculation, the bulb-like structures disappeared and ATP levels drastically decreased. After another 2 h, the large central vacuole was disrupted. In contrast, no apparent changes in intracellular ATP levels were observed in the leaves inoculated with the virulent strain Pst DC3000. The Pst DC3000/avrRpm1-induced hypersensitive cell death was strongly suppressed by inhibiting ATP synthesis after oligomycin A application within 4 h after bacterial inoculation. When the inhibitor was applied 7 h after bacterial inoculation, cell death was unaffected. These observations show that changes in intracellular ATP levels correlate with intracellular morphological changes during hypersensitive cell death, and that ATP is required just before vacuolar rupture in response to bacterial infection. PMID- 22942252 TI - ROCK1 and ROCK2 are required for non-small cell lung cancer anchorage-independent growth and invasion. AB - Evidence is emerging that the closely related ROCK1 and ROCK2 serine/threonine kinases support the invasive and metastatic growth of a spectrum of human cancer types. Therefore, inhibitors of ROCK are under preclinical development. However, a key step in their development involves the identification of genetic biomarkers that will predict ROCK inhibitor antitumor activity. One identified mechanism for ROCK activation in cancer involves the loss of function of the DLC1 tumor suppressor gene, which encodes a GTPase activating protein (RhoGAP) for the RhoA and RhoC small GTPases. DLC-1 loss may lead to hyperactivation of RhoA/C and its downstream effectors, the ROCK kinases. We therefore determined whether loss of DLC-1 protein expression identifies non-small cell lung carcinoma (NSCLC) cell lines whose growth and invasion phenotypes are sensitive to ROCK inhibition. We identified and characterized a novel small molecule pharmacologic inhibitor of ROCK and additionally applied genetic approaches to impair ROCK1 and/or ROCK2 activity, and we determined that although NSCLC anchorage-dependent growth was ROCK-independent, both anchorage-independent growth and Matrigel invasion were ROCK-dependent. However, loss of DLC-1 expression did not correlate with ROCK activation or with OXA-06 sensitivity. Unexpectedly, suppression of ROCK1 or ROCK2 expression alone was sufficient to impair anchorage-independent growth, supporting their nonoverlapping roles in oncogenesis. Mechanistically, the block in anchorage-independent growth was associated with accumulation of cells in the G(0)-G(1) phase of the cell cycle, but not increased anoikis. We conclude that ROCK may be a useful therapeutic target for NSCLC. PMID- 22942253 TI - Inactivating all three rb family pocket proteins is insufficient to initiate cervical cancer. AB - Human papillomavirus-16 (HPV-16) is associated etiologically with many human cervical cancers. It encodes 3 oncogenes E5, E6, and E7. Of these oncogenes, E7 has been found to be the dominant driver of cervical cancer in mice. More than 100 cellular proteins have been reported to associate with HPV-16 E7, which is thought to dysregulate the cell cycle in part by binding and inducing the degradation of pRb and its related pocket protein family members, p107 and p130. The ability of E7 to inactivate the pRb family correlates with its ability to induce head and neck cancers in mice. We previously showed that the inactivation of pRb is itself not sufficient to recapitulate the oncogenic properties of E7 in cervical carcinogenesis. In this study, we evaluated mice that were deficient in multiple pocket proteins, including mice that lacked pRb, p107, and p130. Strikingly, combined loss of two or all 3 pocket proteins resulted in development of high-grade cervical intraepithelial neoplasia, but not frank cervical carcinoma. These findings strongly argue that the oncogenic properties of HPV-16 E7 in human cervical carcinogenesis may involve disruption of E7 binding proteins beyond simply the pRb family members. PMID- 22942254 TI - IKK-epsilon coordinates invasion and metastasis of ovarian cancer. AB - Inhibitor of IkappaB kinases (IKK) are key regulators of NF-kappaB signaling. Three IKK isoforms-alpha, beta, and epsilon-have been linked to oncogenesis, yet the precise components of NF-kappaB signaling in ovarian cancer have not yet been dissected. We surveyed 120 ovarian cancer specimens for IKK-epsilon expression. Notably, cytoplasmic expression was elevated in metastatic lesions relative to primary tumors (P = 0.03). Therefore, we hypothesized that IKK-epsilon drives ovarian cancer metastasis. IKK-epsilon was identified previously as a breast cancer oncogene and was associated with poor clinical outcome in ovarian cancer. We now define an ovarian cancer-specific IKK-epsilon-regulated gene expression signature using stably expressed short hairpin RNA targeting IKK-epsilon. Pathway analysis of the signature indicated that IKK-epsilon regulates expression of genes involved in cell motility and inflammation. We further showed that IKK epsilon depletion in metastatic ovarian cancer cell lines decreased growth, adhesion, and invasion. Consistently, human xenografts depleted of IKK-epsilon in mice showed decreased aggressiveness, whereas overexpression of IKK-epsilon in a less invasive ovarian cancer cell line increased metastasis in vivo. Taken together, these data provide evidence that IKK-epsilon is a key coordinator of invasion and metastasis programs in ovarian cancer. Inhibition of IKK-epsilon signaling thus emerges as a viable therapeutic strategy in women whose ovarian cancer shows aberrant activation of this pathway. PMID- 22942257 TI - GF-15, a novel inhibitor of centrosomal clustering, suppresses tumor cell growth in vitro and in vivo. AB - In contrast to normal cells, malignant cells are frequently aneuploid and contain multiple centrosomes. To allow for bipolar mitotic division, supernumerary centrosomes are clustered into two functional spindle poles in many cancer cells. Recently, we have shown that griseofulvin forces tumor cells with supernumerary centrosomes to undergo multipolar mitoses resulting in apoptotic cell death. Here, we describe the characterization of the novel small molecule GF-15, a derivative of griseofulvin, as a potent inhibitor of centrosomal clustering in malignant cells. At concentrations where GF-15 had no significant impact on tubulin polymerization, spindle tension was markedly reduced in mitotic cells upon exposure to GF-15. Moreover, isogenic cells with conditional centrosome amplification were more sensitive to GF-15 than parental controls. In a wide array of tumor cell lines, mean inhibitory concentrations (IC(50)) for proliferation and survival were in the range of 1 to 5 MUmol/L and were associated with apoptotic cell death. Importantly, treatment of mouse xenograft models of human colon cancer and multiple myeloma resulted in tumor growth inhibition and significantly prolonged survival. These results show the in vitro and in vivo antitumor efficacy of a prototype small molecule inhibitor of centrosomal clustering and strongly support the further evaluation of this new class of molecules. PMID- 22942255 TI - Cisplatin sensitivity mediated by WEE1 and CHK1 is mediated by miR-155 and the miR-15 family. AB - Resistance to platinum-based therapies arises by multiple mechanisms, including by alterations to cell-cycle kinases that mediate G(2)-M phase arrest. In this study, we conducted parallel high-throughput screens for microRNAs (miRNA) that could restore sensitivity to cisplatin-resistant cells, and we screened for kinases targeted by miRNAs that mediated cisplatin resistance. Overexpression of the cell-cycle kinases WEE1 and CHK1 occurred commonly in cisplatin-resistant cells. miRNAs in the miR-15/16/195/424/497 family were found to sensitize cisplatin-resistant cells to apoptosis by targeting WEE1 and CHK1. Loss-of function and gain-of-function studies showed that miR-15 family members controlled the expression of WEE1 and CHK1. Supporting these results, we found that in the presence of cisplatin altering expression of miR-16 or related genes altered cell cycle distribution. Our findings reveal critical regulation of miRNAs and their cell-cycle-associated kinase targets in mediating resistance to cisplatin. PMID- 22942256 TI - Lymphatic reprogramming by Kaposi sarcoma herpes virus promotes the oncogenic activity of the virus-encoded G-protein-coupled receptor. AB - Kaposi sarcoma, the most common cancer in HIV-positive individuals, is caused by endothelial transformation mediated by the Kaposi sarcoma herpes virus (KSHV) encoded G-protein-coupled receptor (vGPCR). Infection of blood vascular endothelial cells (BEC) by KSHV reactivates an otherwise silenced embryonic program of lymphatic differentiation. Thus, Kaposi sarcoma tumors express numerous lymphatic endothelial cell (LEC) signature genes. A key unanswered question is how lymphatic reprogramming by the virus promotes tumorigenesis leading to Kaposi sarcoma formation. In this study, we present evidence that this process creates an environment needed to license the oncogenic activity of vGPCR. We found that the G-protein regulator RGS4 is an inhibitor of vGPCR that is expressed in BECs, but not in LECs. RGS4 was downregulated by the master regulator of LEC differentiation PROX1, which is upregulated by KSHV and directs KSHV-induced lymphatic reprogramming. Moreover, we found that KSHV upregulates the nuclear receptor LRH1, which physically interacts with PROX1 and synergizes with it to mediate repression of RGS4 expression. Mechanistic investigations revealed that RGS4 reduced vGPCR-enhanced cell proliferation, migration, VEGF expression, and Akt activation and suppressed tumor formation induced by vGPCR. Our findings resolve long-standing questions about the pathologic impact of KSHV induced reprogramming of host cell identity, and they offer biologic and mechanistic insights supporting the hypothesis that a lymphatic microenvironment is more favorable for Kaposi sarcoma tumorigenesis. PMID- 22942259 TI - Role of nitric oxide metabolites in reduction of sodium potassium ATPase dependent pulmonary edema clearance. PMID- 22942258 TI - Autophagy induced by conventional chemotherapy mediates tumor cell sensitivity to immunotherapy. AB - Autophagy attenuates the efficacy of conventional chemotherapy but its effects on immunotherapy have been little studied. Here, we report that chemotherapy renders tumor cells more susceptible to lysis by CTL in vivo. Moreover, bystander tumor cells that did not express antigen were killed by CTL. This effect was mediated by transient but dramatic upregulation of the mannose-6-phosphate receptor (MPR) on the tumor cell surface. Antitumor effects of combined treatment related to the kinetics of MPR upregulation and abrogation of this event abolished the combined effect of immunotherapy and chemotherapy. MPR accumulation on the tumor cell surface during chemotherapy was observed in different mouse tumor models and in patients with multiple myeloma. Notably, this effect was the result of redistribution of the receptor caused by chemotherapy-inducible autophagy. Together, our findings reveal one molecular mechanism through which the antitumor effects of conventional cancer chemotherapy and immunotherapy are realized. PMID- 22942260 TI - The Myositis Activities Profile -- initial validation for assessment of polymyositis/dermatomyositis in the USA. AB - OBJECTIVE: To evaluate some measurement properties of the Myositis Activities Profile (MAP) in adult patients with polymyositis (PM) and dermatomyositis (DM) in the United States. METHODS: To assess content validity, patients with PM/DM rated difficulty and importance of items of the MAP using a visual analog scale (VAS), range 0-10. For construct validity, consecutive patients with PM/DM performed the 6-item core set for disease activity including the manual muscle test (MMT) and the Health Assessment Questionnaire (HAQ), the Functional Index-2 (FI-2; muscle endurance), and the MAP plus disease effect on well-being on a VAS. Item fit within subscales was analyzed by Cronbach's alpha. Patients with stable disease activity filled out the MAP again 1 week later. RESULTS: The median combined difficulty and importance, 0-10, of the 31 items was 5.00 (range 2.10 5.95). One item was added, giving a 32-item MAP. Correlations between the median of subscales/single items of the MAP and the HAQ and disease effect on well-being were r(s) = 0.69 and r(s) = 0.68, respectively, with lower correlations to the MMT (r(s) = -0.35), and the FI-2 (r(s) = -0.29 to -0.47) and disease activity measures (r(s) = 0.36-0.41). Cronbach's alpha coefficients for the 4 subscales varied between 0.85 and 0.95. Weighted kappa coefficients (K(w)) ranged between 0.77 and 0.93 for the 4 subscales and between 0.74 and 0.83 for the 4 single items without systematic variations (p > 0.05). CONCLUSION: This initial validation of the MAP indicates promising measurement properties for assessing limitations in activities of daily living and participation in patients with PM/DM in the United States. PMID- 22942261 TI - Risk of failure of a clinical drug trial in patients with moderate to severe rheumatoid arthritis. AB - OBJECTIVE: We conducted a systematic review to determine the risk of drug failure in clinical testing with patients with moderate to severe rheumatoid arthritis (RA). METHODS: Therapies for RA were investigated by reviewing phase I to phase III studies conducted from December 1998 to March 2011. Clinical trial success rates were calculated and compared to industry standards. Trial failures were classified as either commercial or clinical failures. The exclusion criteria for drugs in this study: drugs that were started in phase I studies prior to January 1998 for this indication; or studies that enrolled patients who were methotrexate naive and/or had failed biologic therapy. RESULTS: A search in clinicaltrials.gov and approved drugs for the indication yielded a total of 69 drugs that met the study criteria. The cumulative success rate was determined to be 16%, which is equivalent to the industry standard of 16%. For each phase, the frequency of clinical failures exceeded commercial failures. Clinical studies equally comprised investigations of small molecules and biological agents, but biologics seemed to exhibit a higher success rate overall. CONCLUSION: Clinical trial risk in RA with the 84% failure rate reported here is at par with industry performance and phase II success rate seems to be highly predictive of phase III success. PMID- 22942262 TI - Anti-DFS70/LEDGF antibodies are more prevalent in healthy individuals compared to patients with systemic autoimmune rheumatic diseases. AB - OBJECTIVE: Antinuclear antibodies (ANA) are a serological hallmark of systemic autoimmune rheumatic diseases (SARD) such as systemic lupus erythematosus (SLE). While a number of ANA patterns detected by indirect immunofluorescence (IIF) have diagnostic significance, autoantibodies producing the dense fine speckled (DFS) pattern have been reported to be more prevalent in healthy individuals than in SARD. METHODS: Sequential samples submitted for ANA testing were screened for anti-DFS antibodies by IIF (n = 3263). Samples with the DFS pattern were tested for anti-DFS70/lens epithelium-derived growth factor (LEDGF) antibodies by ELISA and by a novel chemiluminescence assay (CIA, Quanta Flash DFS70). Sera from patients with various diseases and healthy individuals were tested for anti DFS70/LEDGF antibodies by CIA. A cohort of 251 patients with SLE was used to analyze serological and clinical associations of anti-DFS70 antibodies. RESULTS: The frequency of anti-DFS antibodies by IIF was 1.62%. The prevalence of anti DFS70/LEDGF antibodies as detected by CIA in the different cohorts was 8.9% in healthy individuals, 2.8% in SLE, 2.6% in rheumatoid arthritis, 4.0% in asthma, 5.0% in interstitial cystitis, 1.7% in Graves' disease, and 6.0% in Hashimoto's thyroiditis. Of note, the prevalence of anti-DFS70/LEDGF antibodies was significantly higher in healthy individuals compared to patients with SARD (p = 0.00085). In SLE results, anti-DFS70/LEDGF antibodies were not significantly associated with clinical features or other autoantibodies typically found in SLE. Only 1/7 SLE sera showed anti-DFS70/LEDGF, but no other autoantibody reactivity. CONCLUSION: "Monospecific" anti-DFS70/LEDGF antibodies may represent a biomarker for differentiating SARD from non-SARD individuals, but there is a need for a reliable assay to ensure reactivity to DFS70. PMID- 22942263 TI - Monocyte chemoattractant-1 as a urinary biomarker for the diagnosis of activity of lupus nephritis in Brazilian patients. AB - OBJECTIVE: Monocyte chemotactic protein (MCP-1), involved in the pathogenesis of lupus nephritis (LN), has recently been indicated as a new biomarker of kidney activity in systemic lupus erythematosus (SLE). Our aim was to assess urinary MCP 1 (uMCP-1) as a biomarker of renal activity in patients with SLE and to compare it to other disease activity markers, using the ELISA. METHODS: Seventy-five female Brazilian patients with SLE and a control group participated in our study. Patients with SLE were distributed among 3 groups according to kidney involvement and classified according to disease activity based on clinical and laboratory measures such as urinary sediment, proteinuria, kidney function, C3, C4, anti dsDNA, disease activity index, and renal SLE disease activity index. The serum and uMCP-1 concentrations were measured by sandwich ELISA. RESULTS: In the A-LN group (active lupus nephritis: SLE with kidney involvement), the concentration of uMCP-1 was significantly higher than in other groups. A cutoff point was established using the results of the control group to apply this test in the detection of LN. A-LN had a higher frequency of positive results for uMCP-1 in comparison to the other groups (p < 0.001). To detect disease activity in patients with LN, a new cutoff was determined based on the results of patients with SLE with kidney involvement. Setting specificity at 90%, the sensitivity of the test was 50%. CONCLUSION: The high specificity makes uMCP-1 a useful test as a predictor of kidney activity in SLE, especially when associated to other measures used in clinical practice. PMID- 22942264 TI - Low copy number of the Fc-gamma receptor 3B gene FCGR3B is a risk factor for primary Sjogren's syndrome. AB - OBJECTIVE: Immune complexes play an important role in the pathogenesis of primary Sjogren's syndrome (pSS). Crosslinking of the neutrophil-specific Fc-gamma receptor 3b (FCGR3B) facilitates immune complex clearance, and copy number variation (CNV) of the FCGR3B gene is known to reduce the uptake, and potentially clearance, of circulating immune complexes. Our objective was to determine whether FCGR3B CNV is a risk factor for pSS. METHODS: This was a cross-sectional study of patients with established pSS (n = 174) and population-matched controls (n = 162). FCGR3B CNV was determined by a quantitative real-time polymerase chain reaction assay, using genomic DNA as template and Taqman chemistry. Reactions were performed as a duplex, with RNAse P as the reference gene. Clinical and serological data were analyzed for their association with FCGR3B copy number (CN). RESULTS: Low FCGR3B CN (< 2 copies) was a risk factor for pSS in this cohort (p = 0.016), and combined results from this and a previous study yielded an overall OR of 2.3 (95% CI 1.3, 3.9, p = 0.003). Among patients with pSS in our cohort, low FCGR3B CN was not associated with anti-Ro +/- La autoantibodies, but was associated with lower rheumatoid factor titers (p = 0.001) and serum IgG levels (p = 0.031). CONCLUSION: We confirmed that, similarly to other systemic autoimmune diseases, FCGR3B CN is a genetic susceptibility factor for pSS. As in rheumatoid arthritis, the mechanism does not appear to be related to seropositivity for characteristic autoantibodies. PMID- 22942266 TI - Changes at health policy and planning. PMID- 22942265 TI - Increasing treatment in early rheumatoid arthritis is not determined by the disease activity score but by physician global assessment: results from the CATCH study. AB - OBJECTIVE: To determine the factors most strongly associated with an increase in therapy of early rheumatoid arthritis (ERA). METHODS: Data from the Canadian Early Arthritis Cohort (CATCH) were included if the patient had >= 2 visits and baseline and 6 months data. A regression analysis was done to determine factors associated with treatment intensification. RESULTS: Of 1145 patients with ERA, 790 met inclusion criteria; mean age was 53.4 years (SD 14.7), mean disease duration 6.1 months (SD 2.8), 75% were female, baseline Disease Activity Score-28 (DAS28) was 4.7 (SD 1.8) and 2.9 (SD 1.8) at 6 months for included patients. Univariate factors for intensifying treatment were physician global assessment (MDGA; OR 7.8 and OR 7.4 at 3 and 6 months, respectively, p < 0.0005), swollen joint count (SJC; OR 4.7 and OR 7.3 at 3 and 6 months, p < 0.0005), and DAS28 (OR 3.0 and OR 4.6 at 3 and 6 months, p < 0.0005). In the regression model only MDGA was strongly associated with treatment intensification (OR 1.5 and OR 1.2 at 3 and 6 months, p < 0.0005); DAS28 was not consistently predictive (OR 1.0, p = 0.987, and OR 1.2, p = 0.023, at 3 and 6 months). DAS28 was the reason for treatment intensification 2.3% of the time, compared to 51.7% for SJC, 49.9% for tender joint count, and 23.8% for MDGA. For the same SJC, larger joint involvement was more likely to influence treatment than small joints at 3 months (OR 1.4, p = 0.027). CONCLUSION: MDGA was strongly associated with an increase in treatment at 3 and 6 months in ERA, whereas DAS28 was not. Physicians rarely stated that DAS28 was the reason for increasing treatment. PMID- 22942267 TI - Diabetes influences peritoneal morphology in uremic patients at the initiation of peritoneal dialysis. AB - BACKGROUND: The peritoneum begins to undergo morphologic changes before the start of peritoneal dialysis (PD), particularly in diabetic patients. The present study was conducted to investigate the effects of diabetes on the peritoneum. METHODS: This study involved 17 patients who began receiving PD and had diabetes as an underlying disease (DM group), and 30 patients without diabetes who served as a control group (nonDM group). At the start of PD, the parietal peritoneum was sampled to assess submesothelial connective tissue thickness, number of capillaries and postcapillary venules, and indications of vasculopathy (grades 0 3). RESULTS: Submesothelial connective tissue thickness was significantly greater in the DM group than in the nonDM group (p < 0.01). The number of capillaries was significantly greater in the DM group (p < 0.01). Based on multivariate linear regression analysis, diabetes was identified as a significant independent variable of both submesothelial connective tissue thickness and number of capillaries (p < 0.01). CONCLUSIONS: In diabetic patients, morphologic changes of the peritoneum are marked at the start of PD. PMID- 22942268 TI - Frequency and microbiology of peritonitis and exit-site infection among obese peritoneal dialysis patients. AB - BACKGROUND: Data on obesity as a risk factor for peritonitis and catheter infections among peritoneal dialysis (PD) patients are limited. Furthermore, little is known about the microbiology of PD-related infections among patients with a high body mass index (BMI). METHODS: Using a cohort that included all adult patients residing in the province of Manitoba who received PD during the period 1997 - 2007, we studied the relationship between BMI and PD-related infections. After categorizing patients into quartiles of BMI, a multivariate Cox regression model was used to determine the independent relationship between BMI and peritonitis or exit-site infection (ESI). We also studied whether increasing BMI was associated with a propensity to infections with particular organisms. RESULTS: Among 990 PD patients, 938 (95%) had accurate BMI data available. Those 938 patients experienced 1338 peritonitis episodes and 1194 exit-site infections. In unadjusted analyses, patients in the highest BMI quartile (median: 33.5; interquartile range: 31.9 - 36.4) had an increased risk of peritonitis overall, and also an increased risk of peritonitis with gram-positive organisms and coagulase-negative Staphylococcus (CNS). After multivariate adjustment for age, sex, diabetes, cause of renal disease, Aboriginal race, PD modality, and S. aureus nasal carriage, the relationship between overall peritonitis risk and BMI disappeared, but the increased risk of CNS peritonitis among patients in the highest BMI quartile persisted (hazard ratio: 1.80; 95% confidence interval: 1.06 to 3.06; p = 0.03). There was no increased risk of ESI among patients in the highest BMI quartile on univariate analysis or after multivariate adjustment. CONCLUSIONS: Among Canadian PD patients, obesity was not associated with an increased risk of peritonitis overall, but may be associated with a higher risk of CNS peritonitis. PMID- 22942269 TI - Minilaparotomy salvage of malfunctioning catheters in peritoneal dialysis. AB - BACKGROUND: Catheter malfunction is a common and significant complication during peritoneal dialysis (PD). We developed a minilaparotomy procedure to rescue malfunctioning catheters and to prevent recurrence of malfunction. METHODS: From 2006 to 2011, 11 patients receiving PD had a malfunctioning catheter. In all patients, a 2-cm incision, 5 cm caudally to the previous peritoneal entry site was used to correct the malfunctioning catheter, with concomitant fixation of the catheter to the peritoneum. RESULTS: Catheter tip migration occurred in 7 patients, omental wrapping in 3, and blood clot obstruction in 1. The mean onset time to catheter malfunction was 197.5 days (range: 4 - 1270 days), and the mean operating time was 41 minutes (range: 35 - 56 minutes). There was no recurrence of catheter malfunction and no surgery-related peritonitis. CONCLUSIONS: Our minilaparotomy procedure is safe and feasible for the salvage of malfunctioning PD catheters. PMID- 22942270 TI - Effects of climatic region on peritonitis risk, microbiology, treatment, and outcomes: a multicenter registry study. AB - BACKGROUND: The impact of climatic variations on peritoneal dialysis (PD)-related peritonitis has not been studied in detail. The aim of the current study was to determine whether various climatic zones influenced the probability of occurrence or the clinical outcomes of peritonitis. METHODS: Using ANZDATA registry data, the study included all Australian patients receiving PD between 1 October 2003 and 31 December 2008. Climatic regions were defined according to the Koppen classification. RESULTS: The overall peritonitis rate was 0.59 episodes per patient-year. Most of the patients lived in Temperate regions (65%), with others residing in Subtropical (26%), Tropical (6%), and Other climatic regions (Desert, 0.6%; Grassland, 2.3%). Compared with patients in Temperate regions, those in Tropical regions demonstrated significantly higher overall peritonitis rates and a shorter time to a first peritonitis episode [adjusted hazard ratio: 1.15; 95% confidence interval (CI): 1.01 to 1.31]. Culture-negative peritonitis was significantly less likely in Tropical regions [adjusted odds ratio (OR): 0.42; 95% CI: 0.25 to 0.73]; its occurrence in Subtropical and Other regions was comparable to that in Temperate regions. Fungal peritonitis was independently associated with Tropical regions (OR: 2.18; 95% CI: 1.22 to 3.90) and Other regions (OR: 3.46; 95% CI: 1.73 to 6.91), where rates of antifungal prophylaxis were also lower. Outcomes after first peritonitis episodes were comparable in all groups. CONCLUSIONS: Tropical regions were associated with a higher overall peritonitis rate (including fungal peritonitis) and a shorter time to a first peritonitis episode. Augmented peritonitis prophylactic measures such as antifungal therapy and exit-site care should be considered in PD patients residing in Tropical climates. PMID- 22942271 TI - Pulmonary congestion and physical functioning in peritoneal dialysis patients. AB - PURPOSE: Decline in physical function is commonly observed in patients with kidney failure on dialysis. Whether lung congestion, a predictable consequence of cardiomyopathy and fluid overload, may contribute to the low physical functioning of these patients has not been investigated. METHODS: In 51 peritoneal dialysis (PD) patients, we investigated the cross-sectional association between the physical functioning scale of the Kidney Disease Quality of Life Short Form (KDQOL-SF: Rand Corporation, Santa Monica, CA, USA) and an ultrasonographic measure of lung water recently validated in dialysis patients. The relationship between physical functioning and lung water was also analyzed taking into account the severity of dyspnea measured using the New York Heart Association (NYHA) classification currently used to grade the severity of heart failure. RESULTS: Evidence of moderate-to-severe lung congestion was evident in 20 patients, and this alteration was asymptomatic (that is, NHYHA class I) in 11 patients (55%). On univariate analysis, physical functioning was inversely associated with lung water (r = -0.48, p < 0.001), age (r = -0.44, p = 0.001), previous cardiovascular events (r = -0.46, p = 0.001), and fibrinogen (r = -0.34, p = 0.02). Physical functioning was directly associated with blood pressure, the strongest association being with diastolic blood pressure (r = 0.38, p = 0.006). The NYHA class correlated inversely with physical functioning (r = -0.51, p < 0.001). In multiple regression analysis, only lung water and fibrinogen remained independent correlates of physical functioning. The NYHA class failed to maintain its independent association. CONCLUSIONS: This cross-sectional study supports the hypothesis that symptomatic and asymptomatic lung congestion is a relevant factor in the poor physical functioning of patients on PD. PMID- 22942273 TI - Acceptability of a theory of planned behaviour email-based nutrition intervention. AB - This study investigated feasibility and acceptability of a new email-delivered intervention promoting fruit and vegetable consumption in a university-based population of Australian young adults. The study explored whether there are differences in the reported feasibility and acceptability between demographic groups within the population of interest and at three levels of intervention intensity. The email-delivered intervention program consists of an implementation intention 'planning task' and between 3 and 15 short email messages over a 15-day study period. The intervention program was developed using the Theory of Planned Behaviour and was designed to modify perceived behavioural control. One hundred and ten participants (mean age = 19.21 years, 25.6% male) completed the feasibility and acceptability questionnaire at Day 15. This questionnaire contained items about all intervention components. High acceptability and feasibility scores were found for all intervention parts and at all levels of intervention intensity. There were few significant differences in the reported acceptability of items between key demographic sub-groups, and no differences in reported acceptability at different levels of intervention intensity. These results suggest that this email-delivered intervention is an acceptable and feasible tool for promoting fruit and vegetable consumption for participants in the target population. PMID- 22942272 TI - Waist circumference as a predictor of adiponectin levels in peritoneal dialysis patients: a 12-month follow-up study. AB - OBJECTIVES: This prospective study, conducted at the dialysis unit of the Nephrology Division, Federal University of Sao Paulo-Oswaldo Ramos Foundation, Brazil, aimed to evaluate whether waist circumference (WC) can predict adiponectin levels in patients undergoing peritoneal dialysis (PD). METHODS: Among 115 patients on PD at a single dialysis center who were evaluated at 6 and 12 months, 57% were men, 31% had diabetes, mean age was 52.8 +/- 16.1 years, body mass index was 25 +/- 4.3 kg/m(2), and dialysis vintage was 13 months (range: 5 - 33 months). We measured WC at the umbilicus level. Adiponectin was determined by an enzyme-linked immunosorbent assay. RESULTS: At baseline, WC was inversely associated with adiponectin (r = -0.48, p < 0.01). After adjustment for sex, age, diabetes, peritoneal clearance, and residual renal function, WC was an independent determinant of serum adiponectin (beta = -0.52; 95% confidence interval: -0.73 to -0.31; p < 0.001). In the prospective analysis, after adjustment for confounders, changes in WC predicted changes in adiponectin. For each unit increase in WC, adiponectin declined by 0.39 mg/L (p < 0.001). CONCLUSIONS: This study demonstrates that WC is associated with adiponectin and, more importantly, that this simple marker of central adiposity was able to predict changes in adiponectin levels over time. PMID- 22942274 TI - Prostaglandin H synthase-2-catalyzed oxygenation of 2-arachidonoylglycerol is more sensitive to peroxide tone than oxygenation of arachidonic acid. AB - The endocannabinoid, 2-arachidonoylglycerol (2-AG), is a selective substrate for the inducible isoform of prostaglandin H synthase (PGHS), PGHS-2. Its turnover leads to the formation of glyceryl esters of prostaglandins (PG-Gs), a subset of which elicits agonism at unique, as yet unidentified, receptors. The k(cat)/K(m) values for oxygenation of arachidonic acid (AA) and 2-AG by PGHS-2 are very similar, but the sensitivities of the two substrates to peroxide-dependent activation have not been compared. 15-Hydroperoxy derivatives of AA and 2-AG were found to be comparable in their ability to serve as substrates for the peroxidase activities of PGHS-2, PGHS-1, and glutathione peroxidase (GPx). They also were comparable in the activation of AA oxygenation by cyanide-inhibited PGHS-2. However, oxygenation of 2-AG was significantly suppressed relative to AA by the presence of GPx and GSH. Furthermore, 2-AG oxygenation by peroxidase-deficient H388YmPGHS-2 was much less efficient than AA oxygenation. Wild-type rates of 2-AG oxygenation were restored by treatment of H388YmPGHS-2 with hydroperoxide derivatives of AA or 2-AG. RNAi silencing of phospholipid hydroperoxide-specific GPx (GPx4) in NIH/3T3 cells led to increases in cellular peroxidation and in the levels of the isoprostane product, 8-epi-PGF(2alpha). GPx4 silencing led to 2-4 fold increases in PG-G formation but no change in PG formation. Thus, cellular peroxide tone may be an important determinant of the extent of endocannabinoid oxygenation by PGHS-2. PMID- 22942275 TI - Molybdoenzyme that catalyzes the anaerobic hydroxylation of a tertiary carbon atom in the side chain of cholesterol. AB - Cholesterol is a ubiquitous hydrocarbon compound that can serve as substrate for microbial growth. This steroid and related cyclic compounds are recalcitrant due to their low solubility in water, complex ring structure, the presence of quaternary carbon atoms, and the low number of functional groups. Aerobic metabolism therefore makes use of reactive molecular oxygen as co-substrate of oxygenases to hydroxylate and cleave the sterane ring system. Consequently, anaerobic metabolism must substitute oxygenase-catalyzed steps by O(2) independent hydroxylases. Here we show that one of the initial reactions of anaerobic cholesterol metabolism in the beta-proteobacterium Sterolibacterium denitrificans is catalyzed by an unprecedented enzyme that hydroxylates the tertiary C25 atom of the side chain without molecular oxygen forming a tertiary alcohol. This steroid C25 dehydrogenase belongs to the dimethyl sulfoxide dehydrogenase molybdoenzyme family, the closest relative being ethylbenzene dehydrogenase. It is a heterotrimer, which is probably located at the periplasmic side of the membrane and contains one molybdenum cofactor, five [Fe-S] clusters, and one heme b. The draft genome of the organism contains several genes coding for related enzymes that probably replace oxygenases in steroid metabolism. PMID- 22942276 TI - Phosphatidylinositol-4-phosphate 5-kinase isoforms exhibit acyl chain selectivity for both substrate and lipid activator. AB - Phosphatidylinositol 4,5-bisphosphate is mostly produced in the cell by phosphatidylinositol-4-phosphate 5-kinases (PIP5K) and has a crucial role in numerous signaling events. Here we demonstrate that in vitro all three isoforms of PIP5K, alpha, beta, and gamma, discriminate among substrates with different acyl chains for both the substrates phosphatidylinositol 4-phosphate (PtdIns4P) and phosphatidylinositol (PtdIns) although to different extents, with isoform gamma being the most selective. Fully saturated dipalmitoyl-PtdIns4P was a poor substrate for all three isoforms, but both the 1-stearoyl-2-arachidonoyl and the 1-stearoyl-2-oleoyl forms of PtdIns4P were good substrates. V(max) was greater for the 1-stearoyl-2-arachidonoyl form compared with the 1-stearoyl-2-oleoyl form, although for PIP5Kbeta the difference was small. For the alpha and gamma isoforms, K(m) was much lower for 1-stearoyl-2-oleoyl PtdIns4P, making this lipid the better substrate of the two under most conditions. Activation of PIP5K by phosphatidic acid is also acyl chain-dependent. Species of phosphatidic acid with two unsaturated acyl chains are much better activators of PIP5K than those containing one saturated and one unsaturated acyl chain. PtdIns is a poor substrate for PIP5K, but it also shows acyl chain selectivity. Curiously, there is no acyl chain discrimination among species of phosphatidic acid in the activation of the phosphorylation of PtdIns. Together, our findings indicate that PIP5K isoforms alpha, beta, and gamma act selectively on substrates and activators with different acyl chains. This could be a tightly regulated mechanism of producing physiologically active unsaturated phosphatidylinositol 4,5-bisphosphate species in the cell. PMID- 22942277 TI - Resolving the negative potential side (n-side) water-accessible proton pathway of F-type ATP synthase by molecular dynamics simulations. AB - The rotation of F(1)F(o)-ATP synthase is powered by the proton motive force across the energy-transducing membrane. The protein complex functions like a turbine; the proton flow drives the rotation of the c-ring of the transmembrane F(o) domain, which is coupled to the ATP-producing F(1) domain. The hairpin structured c-protomers transport the protons by reversible protonation/deprotonation of a conserved Asp/Glu at the outer transmembrane helix (TMH). An open question is the proton transfer pathway through the membrane at atomic resolution. The protons are thought to be transferred via two half channels to and from the conserved cAsp/Glu in the middle of the membrane. By molecular dynamics simulations of c-ring structures in a lipid bilayer, we mapped a water channel as one of the half-channels. We also analyzed the suppressor mutant cP24D/E61G in which the functional carboxylate is shifted to the inner TMH of the c-protomers. Current models concentrating on the "locked" and "open" conformations of the conserved carboxylate side chain are unable to explain the molecular function of this mutant. Our molecular dynamics simulations revealed an extended water channel with additional water molecules bridging the distance of the outer to the inner TMH. We suggest that the geometry of the water channel is an important feature for the molecular function of the membrane part of F(1)F(o) ATP synthase. The inclination of the proton pathway isolates the two half channels and may contribute to a favorable clockwise rotation in ATP synthesis mode. PMID- 22942278 TI - Expression profiling and biochemical analysis suggest stress response as a potential mechanism inhibiting proliferation of polyamine-depleted cells. AB - Polyamines are small organic polycations that are absolutely required for cell growth and proliferation; yet the basis for this requirement is mostly unknown. Here, we combined a genome-wide expression profiling with biochemical analysis to reveal the molecular basis for inhibited proliferation of polyamine-depleted cells. Transcriptional responses accompanying growth arrest establishment in polyamine-depleted cells or growth resumption following polyamine replenishment were monitored and compared. Changes in the expression of genes related to various fundamental cellular processes were established. Analysis of mirror symmetric expression patterns around the G(1)-arrest point identified a set of genes representing a stress-response signature. Indeed, complementary biochemical analysis demonstrated activation of the PKR-like endoplasmic reticulum kinase arm of the unfolded protein response and of the stress-induced p38 MAPK. These changes were accompanied by induction of key growth-inhibitory factors such as p21 and Gadd45a and reduced expression of various cyclins, most profoundly cyclin D1, setting the basis for the halted proliferation. However, although the induced stress response could arrest growth, polyamine depletion also inhibited proliferation of PKR-like endoplasmic reticulum kinase and p38alpha-deficient cells and of cells harboring a nonphosphorylatable mutant eIF2alpha (S51A), suggesting that additional yet unidentified mechanisms might inhibit proliferation of polyamine-depleted cells. Despite lengthy persistence of the stress and activation of apoptotic signaling, polyamine-depleted cells remained viable, apparently due to induced expression of protective genes and development of autophagy. PMID- 22942279 TI - Mechanism and significance of changes in glutamate-cysteine ligase expression during hepatic fibrogenesis. AB - GSH is synthesized sequentially by glutamate-cysteine ligase (GCL) and GSH synthase and defends against oxidative stress, which promotes hepatic stellate cell (HSC) activation. Changes in GSH synthesis during HSC activation are poorly characterized. Here, we examined the expression of GSH synthetic enzymes in rat HSC activation and reversion to quiescence. Expression of the GCL catalytic subunit (GCLC) fell during HSC activation and increased when activated HSCs revert back to quiescence. Blocking the increase in GCLC expression kept HSCs in an activated state. Activated HSCs have higher nuclear levels and binding activity of MafG to the antioxidant response element (ARE) of GCLC but lower Nrf2/MafG heterodimer binding to the ARE. Quiescent HSCs have a lower nuclear MafG level but higher Nrf2/MafG heterodimer binding to ARE. This occurred because of enhanced sumoylation of Nrf2 and MafG by SUMO-1, which promoted Nrf2 binding to ARE and heterodimerization with MafG. In vivo, knockdown of GCLC exacerbated bile duct ligation-induced liver injury and fibrosis. Ursodeoxycholic acid and S adenosylmethionine are anti-fibrotic in bile duct ligation, but this effect was nearly lost if GCLC induction was blocked. In conclusion, sumoylation of Nrf2 and MafG enhances heterodimerization and increases GCLC expression, which keeps HSCs in a quiescent state. Antifibrotic agents require activation of GCLC to fully exert their protective effect. PMID- 22942280 TI - Crystal structures of a CTXphi pIII domain unbound and in complex with a Vibrio cholerae TolA domain reveal novel interaction interfaces. AB - Vibrio cholerae colonize the small intestine where they secrete cholera toxin, an ADP-ribosylating enzyme that is responsible for the voluminous diarrhea characteristic of cholera disease. The genes encoding cholera toxin are located on the genome of the filamentous bacteriophage, CTXphi, that integrates as a prophage into the V. cholerae chromosome. CTXphi infection of V. cholerae requires the toxin-coregulated pilus and the periplasmic protein TolA. This infection process parallels that of Escherichia coli infection by the Ff family of filamentous coliphage. Here we demonstrate a direct interaction between the N terminal domain of the CTXphi minor coat protein pIII (pIII-N1) and the C terminal domain of TolA (TolA-C) and present x-ray crystal structures of pIII-N1 alone and in complex with TolA-C. The structures of CTXphi pIII-N1 and V. cholerae TolA-C are similar to coliphage pIII-N1 and E. coli TolA-C, respectively, yet these proteins bind via a distinct interface that in E. coli TolA corresponds to a colicin binding site. Our data suggest that the TolA binding site on pIII-N1 of CTXphi is accessible in the native pIII protein. This contrasts with the Ff family phage, where the TolA binding site on pIII is blocked and requires a pilus-induced unfolding event to become exposed. We propose that CTXphi pIII accesses the periplasmic TolA through retraction of toxin-coregulated pilus, which brings the phage through the outer membrane pilus secretin channel. These data help to explain the process by which CTXphi converts a harmless marine microbe into a deadly human pathogen. PMID- 22942281 TI - Differentiation of the DnaA-oriC subcomplex for DNA unwinding in a replication initiation complex. AB - In Escherichia coli, ATP-DnaA multimers formed on the replication origin oriC promote duplex unwinding, which leads to helicase loading. Based on a detailed functional analysis of the oriC sequence motifs, we previously proposed that the left half of oriC forms an ATP-DnaA subcomplex competent for oriC unwinding, whereas the right half of oriC forms a distinct ATP-DnaA subcomplex that facilitates helicase loading. However, the molecular basis for the functional difference between these ATP-DnaA subcomplexes remains unclear. By analyzing a series of novel DnaA mutants, we found that structurally distinct DnaA multimers form on each half of oriC. DnaA AAA+ domain residues Arg-227 and Leu-290 are specifically required for oriC unwinding. Notably, these residues are required for the ATP-DnaA-specific structure of DnaA multimers in complex with the left half of oriC but not for that with the right half. These results support the idea that the ATP-DnaA multimers formed on oriC are not uniform and that they can adopt different conformations. Based on a structural model, we propose that Arg 227 and Leu-290 play a crucial role in inter-ATP-DnaA interaction and are a prerequisite for the formation of unwinding-competent DnaA subcomplexes on the left half of oriC. These residues are not required for the interaction with DnaB, nucleotide binding, or regulatory DnaA-ATP hydrolysis, which further supports their important role in inter-DnaA interaction. The corresponding residues are evolutionarily conserved and are required for unwinding in the initial complexes of Thermotoga maritima, an ancient hyperthermophile. Therefore, our findings suggest a novel and common mechanism for ATP-DnaA-dependent activation of initial complexes. PMID- 22942282 TI - Mycobacterium tuberculosis prokaryotic ubiquitin-like protein-deconjugating enzyme is an unusual aspartate amidase. AB - Deamidase of Pup (Dop), the prokaryotic ubiquitin-like protein (Pup) deconjugating enzyme, is critical for the full virulence of Mycobacterium tuberculosis and is unique to bacteria, providing an ideal target for the development of selective chemotherapies. We used a combination of genetics and chemical biology to characterize the mechanism of depupylation. We identified an aspartate as a potential nucleophile in the active site of Dop, suggesting a novel protease activity to target for inhibitor development. PMID- 22942283 TI - Double-stranded endonuclease activity in Bacillus halodurans clustered regularly interspaced short palindromic repeats (CRISPR)-associated Cas2 protein. AB - The CRISPR (clustered regularly interspaced short palindromic repeats) system is a prokaryotic RNA-based adaptive immune system against extrachromosomal genetic elements. Cas2 is a universally conserved core CRISPR-associated protein required for the acquisition of new spacers for CRISPR adaptation. It was previously characterized as an endoribonuclease with preference for single-stranded (ss)RNA. Here, we show using crystallography, mutagenesis, and isothermal titration calorimetry that the Bacillus halodurans Cas2 (Bha_Cas2) from the subtype I C/Dvulg CRISPR instead possesses metal-dependent endonuclease activity against double-stranded (ds)DNA. This activity is consistent with its putative function in producing new spacers for insertion into the 5'-end of the CRISPR locus. Mutagenesis and isothermal titration calorimetry studies revealed that a single divalent metal ion (Mg(2+) or Mn(2+)), coordinated by a symmetric Asp pair in the Bha_Cas2 dimer, is involved in the catalysis. We envision that a pH-dependent conformational change switches Cas2 into a metal-binding competent conformation for catalysis. We further propose that the distinct substrate preferences among Cas2 proteins may be determined by the sequence and structure in the beta1-alpha1 loop. PMID- 22942284 TI - A dual interaction between the DNA damage response protein MDC1 and the RAG1 subunit of the V(D)J recombinase. AB - The first step in V(D)J recombination is the formation of specific DNA double strand breaks (DSBs) by the RAG1 and RAG2 proteins, which form the RAG recombinase. DSBs activate a complex network of proteins termed the DNA damage response (DDR). A key early event in the DDR is the phosphorylation of histone H2AX around DSBs, which forms a binding site for the tandem BRCA1 C-terminal (tBRCT) domain of MDC1. This event is required for subsequent signal amplification and recruitment of additional DDR proteins to the break site. RAG1 bears a histone H2AX-like motif at its C terminus (R1Ct), making it a putative MDC1-binding protein. In this work we show that the tBRCT domain of MDC1 binds the R1Ct motif of RAG1. Surprisingly, we also observed a second binding interface between the two proteins that involves the Proline-Serine-Threonine rich (PST) repeats of MDC1 and the N-terminal non-core region of RAG1 (R1Nt). The repeats R1Nt interaction is constitutive, whereas the tBRCT-R1Ct interaction likely requires phosphorylation of the R1Ct motif of RAG1. As the C terminus of RAG1 has been implicated in inhibition of RAG activity, we propose a model in which phosphorylation of the R1Ct motif of RAG1 functions as a self-initiated regulatory signal. PMID- 22942285 TI - The human lagging strand DNA polymerase delta holoenzyme is distributive. AB - Polymerase delta is widely accepted as the lagging strand replicative DNA polymerase in eukaryotic cells. It forms a replication complex in the presence of replication factor C and proliferating cell nuclear antigen to perform efficient DNA synthesis in vivo. In this study, the human lagging strand holoenzyme was reconstituted in vitro. The rate of DNA synthesis of this holoenzyme, measured with a singly primed ssM13 DNA substrate, is 4.0 +/- 0.4 nucleotides. Results from adenosine 5'-(3-thiotriphosphate) tetralithium salt (ATPgammaS) inhibition experiments revealed the nonprocessive characteristic of the human DNA polymerase (Pol delta) holoenzyme (150 bp for one binding event), consistent with data from chase experiments with catalytically inactive mutant Pol delta(AA). The ATPase activity of replication factor C was characterized and found to be stimulated ~10 fold in the presence of both proliferating cell nuclear antigen and DNA, but the activity was not shut down by Pol delta in accord with rapid association/dissociation of the holoenzyme to/from DNA. It is noted that high concentrations of ATP inhibit the holoenzyme DNA synthesis activity, most likely due to its inhibition of the clamp loading process. PMID- 22942287 TI - Endopeptidase cleavage generates a functionally distinct isoform of C1q/tumor necrosis factor-related protein-12 (CTRP12) with an altered oligomeric state and signaling specificity. AB - Adipose tissue-derived adipokines are an important class of secreted metabolic regulators that mediate tissue cross-talk to control systemic energy balance. We recently described C1q/TNF-related protein-12 (CTRP12), a novel insulin sensitizing adipokine that regulates glucose metabolism in liver and adipose tissue. However, the biochemical properties of CTRP12 and its naturally occurring cleaved isoform have not been characterized. Here, we show that CTRP12 is a secreted hormone subjected to multiple functionally relevant posttranslational modifications at highly conserved residues. For example, Asn(39) is glycosylated, whereas Cys(85) mediates the assembly of higher order oligomeric structure. Endopeptidase cleavage at Lys(91) generates a cleaved globular gCTRP12 isoform, the expression of which is increased by insulin. PCSK3/furin was identified as the major proprotein convertase expressed by adipocytes that mediates the endogenous cleavage of CTRP12. Cleavage at Lys(91) is context-dependent: mutation of the charged Arg(93) to Ala on the P2' position enhanced cleavage, and triple mutations (K90A/K91A/R93A) abolished cleavage. Importantly, the two isoforms of CTRP12 differ in oligomeric structures and are functionally distinct. The full length protein forms trimers and larger complexes, and the cleaved isoform consisted of predominantly dimers. Whereas full-length fCTRP12 strongly activated Akt signaling in H4IIE hepatocytes and 3T3-L1 adipocytes, gCTRP12 preferentially activated MAP kinase (ERK1/2 and p38 MAPK) signaling. Further, only fCTRP12 improved insulin-stimulated glucose uptake in adipocytes. These results reveal a novel mechanism controlling signaling specificity and function of a hormone via cleavage-dependent alteration in oligomeric state. PMID- 22942286 TI - Phosphatidylinositol 3-kinase and Rab5 GTPase inversely regulate the Smad anchor for receptor activation (SARA) protein independently of transforming growth factor-beta1. AB - SARA has been shown to be a regulator of epithelial cell phenotype, with reduced expression during TGF-beta1-mediated epithelial-to-mesenchymal transition. Examination of the pathways that might play a role in regulating SARA expression identified phosphatidylinositol 3-kinase (PI3K) pathway inhibition as sufficient to reduce SARA expression. The mechanism of PI3K inhibition-mediated SARA down regulation differs from that induced by TGF-beta1 in that, unlike TGF-beta1, PI3K dependent depletion of SARA was apparent within 6 h and did not occur at the mRNA or promoter level but was blocked by inhibition of proteasome-mediated degradation. This effect was independent of Akt activity because neither reducing nor enhancing Akt activity modulated the expression of SARA. Therefore, this is likely a direct effect of p85alpha action, and co-immunoprecipitation of SARA and p85alpha confirmed that these proteins interact. Both SARA and PI3K have been shown to be associated with endosomes, and either LY294002 or p85alpha knockdown enlarged SARA-containing endocytic vesicles. Inhibition of clathrin-mediated endocytosis blocked SARA down-regulation, and a localization-deficient mutant SARA was protected against down-regulation. As inhibiting PI3K can activate the endosomal fusion-regulatory small GTPase Rab5, we expressed GTPase-deficient Rab5 and observed endosomal enlargement and reduced SARA protein expression, similar to that seen with PI3K inhibition. Importantly, either interference with PI3K via LY294002 or p85alpha knockdown, or constitutive activity of the Rab5 pathway, enhanced the expression of smooth muscle alpha-actin. Together, these data suggest that although TGF-beta1 can induce epithelial-to-mesenchymal transition through reduction in SARA expression, SARA is also basally regulated by its interaction with PI3K. PMID- 22942288 TI - Cyclic GMP-dependent stimulation of serotonin transport does not involve direct transporter phosphorylation by cGMP-dependent protein kinase. AB - The serotonin transporter (SERT) is responsible for reuptake of serotonin (5 hydroxytryptamine) after its exocytotic release from neurons. It is the primary target for antidepressants and stimulants, including "ecstasy" (3,4 methylenedioxymethamphetamine). SERT is regulated by several processes, including a cyclic GMP signaling pathway involving nitric oxide synthase, guanylyl cyclase, and cGMP-dependent protein kinase (PKG). Here, we show that SERT was phosphorylated in a PKG Ialpha-dependent manner in vitro, but that SERT was not a direct substrate of PKG. We generated an analog-sensitive gatekeeper residue mutant of PKG Ialpha (M438G) that efficiently used the ATP analog N(6)-benzyl ATP. This mutant, but not the wild type (WT) kinase, used the ATP analog to phosphorylate both a model peptide substrate as well as an established protein substrate of PKG (vasodilator-stimulated phosphoprotein). PKG Ialpha M438G effectively substituted for the WT kinase in stimulating SERT-mediated 5 hydroxytryptamine transport in cultured cells. Addition of either WT or mutant PKG Ialpha M438G to membranes containing SERT in vitro led to radiolabel incorporation from [gamma-(33)P]ATP but not from similarly labeled N(6)-benzyl ATP, indicating that SERT was phosphorylated by another kinase that could not utilize the ATP analog. These results are consistent with the proposed SERT phosphorylation site, Thr-276, being highly divergent from the consensus PKG phosphorylation site sequence, which we verified through peptide library screening. Another proposed SERT kinase, the p38 mitogen-activated protein kinase, could not substitute for PKG in this assay, and p38 inhibitors did not block PKG-dependent phosphorylation of SERT. The results suggest that PKG initiates a kinase cascade that leads to phosphorylation of SERT by an as yet unidentified protein kinase. PMID- 22942289 TI - Cystic fibrosis transmembrane conductance regulator (CFTR) potentiator VX-770 (ivacaftor) opens the defective channel gate of mutant CFTR in a phosphorylation dependent but ATP-independent manner. AB - The cystic fibrosis transmembrane conductance regulator (CFTR) acts as a channel on the apical membrane of epithelia. Disease-causing mutations in the cystic fibrosis gene can lead to CFTR protein misfolding as in the case of the F508del mutation and/or channel dysfunction. Recently, a small molecule, VX-770 (ivacaftor), has shown efficacy in restoring lung function in patients bearing the G551D mutation, and this has been linked to repair of its channel gating defect. However, these studies did not reveal the mechanism of action of VX-770 in detail. Normally, CFTR channel activity is regulated by phosphorylation, ATP binding, and hydrolysis. Hence, it has been hypothesized that VX-770 modifies one or more of these metabolic events. In this study, we examined VX-770 activity using a reconstitution system for purified CFTR protein, a system that enables control of known regulatory factors. We studied the consequences of VX-770 interaction with CFTR incorporated in planar lipid bilayers and in proteoliposomes, using a novel flux-based assay. We found that purified and phosphorylated CFTR was potentiated in the presence of Mg-ATP, suggesting that VX 770 bound directly to the CFTR protein, rather than associated kinases or phosphatases. Interestingly, we also found that VX-770 enhanced the channel activity of purified and mutant CFTR in the nominal absence of Mg-ATP. These findings suggest that VX-770 can cause CFTR channel opening through a nonconventional ATP-independent mechanism. This work sets the stage for future studies of the structural properties that mediate CFTR gating using VX-770 as a probe. PMID- 22942291 TI - Impact of heart failure with normal ejection fraction on the occurrence of ischaemic stroke in patients with atrial fibrillation. AB - OBJECTIVES: The purpose of this study is to examine the risk of stroke in patients with heart failure with normal ejection fraction (HFNEF) and atrial fibrillation (AF). DESIGN: Clinical and echocardiographic data in patients with non-valvular AF who were not on anticoagulation were retrospectively investigated. A total of 304 patients had AF without heart failure, and 102 patients were diagnosed as AF with HFNEF. MAIN OUTCOME MEASURES: We compared the rate of ischaemic stroke, death and composite of these in the two groups. RESULTS: Patients with AF and HFNEF were older than those with AF only (71.6 vs 64.0 years, p<0.001). Female sex, diabetes mellitus, hypertension, chronic kidney disease, angina, myocardial infarction, use of beta blocker or digoxin were more common in patients with AF and HFNEF. The rates of ischaemic stroke, death and composite of ischaemic stroke and death were higher in patients with AF and HFNEF than in those with AF only (20.6% vs 6.7%, p<0.001; 27.2% vs 2.0%, p<0.001; 41.2% vs 8.1%, p<0.001 at 3 years for AF with HFNEF vs AF only, respectively). After adjustment with propensity score method using the inverse probability of treatment weighting, the 3-year risks of for ischaemic stroke (HR 3.29; 95% CI 1.58 to 6.86; p=0.001), death (HR 5.52; 95% CI 2.24 to 13.63; p<0.001), and composite of ischaemic stroke and death (HR 4.08; 95% CI 2.30 to 7.26; p<0.001) were significantly higher in patients with AF and HFNEF. CONCLUSIONS: HFNEF is associated with an increased risk of stroke and death in patients with AF. PMID- 22942290 TI - Heterologous expression of sahH reveals that biofilm formation is autoinducer-2 independent in Streptococcus sanguinis but is associated with an intact activated methionine cycle. AB - Numerous studies have claimed deleterious effects of LuxS mutation on many bacterial phenotypes, including bacterial biofilm formation. Genetic complementation mostly restored the observed mutant phenotypes to WT levels, leading to the postulation that quorum sensing via a family of molecules generically termed autoinducer-2 (AI-2) is essential for many phenotypes. Because LuxS mutation has dual effects, this hypothesis needs to be investigated into the details for each bacterial species. In this study we used S. sanguinis SK36 as a model biofilm bacterium and employed physiological characterization and transcriptome approaches on WT and luxS-deficient strains, in combination with chemical, luxS, and sahH complementation experiments. SahH enables a direct conversion of SAH to homocysteine and thereby restores the activated methionine cycle in a luxS-negative background without formation of the AI-2 precursor 4,5 dihydroxy-2,3-pentanedione. With this strategy we were able to dissect the individual contribution of LuxS and AI-2 activity in detail. Our data revealed that S. sanguinis biofilm formation is independent from AI-2 substance pools and is rather supported by an intact activated methyl cycle. Of 216 differentially transcribed genes in the luxS mutant, 209 were restored by complementation with a gene encoding the S-adenosylhomocysteine hydrolase. Only nine genes, mainly involved in natural competence, were directly affected by the AI-2 quorum-sensing substance pool. Cumulatively, this suggested that biofilm formation in S. sanguinis is not under control of AI-2. Our study suggests that previously evaluated LuxS mutants in other species need to be revisited to resolve the precise contribution of AI-2 substance pools and the methionine pathways. PMID- 22942292 TI - Almanac 2012: interventional cardiology: the national society journals present selected research that has driven recent advances in clinical cardiology. AB - The field of interventional cardiology continues to progress quickly. The efficacy of percutaneous interventions with newer generation drug-eluting stents has advanced a lot over the last decade. This improvement in stent performance has broadened the level of indication towards more complex interventions such as left main and multi-vessel PCI. Major improvements continue in the field of medical co-therapy such as antiplatelet therapies (bivalirudin, prasugrel, ticagrelor) and this will further improve outcomes of PCI. The same is true for intravascular imaging such as ultrasound IVUS and optical coherence tomography OCT. However, interventional cardiology has become a rather broad field, also including alcohol septal ablation for hypertrophic obstructive cardiomyopathy, etc. At the moment, the fastest growing area is the structural interventions, especially for aortic valve stenosis (transcatheter aortic valve implantation TAVI) and for mitral regurgitation (mitral clipping). This review covers recent advances in all these different fields of interventional cardiology. PMID- 22942293 TI - The evolving epidemiology of valvular aortic stenosis. the Tromso study. AB - OBJECTIVE: To assess prevalence, incidence, prognosis and progression of degenerative valvular aortic stenosis (AS). SETTING: The Tromso Study and the University Hospital of North Norway. DESIGN: Population based prospective study. POPULATION: Over a 14 year span we performed three repeated echocardiographic examinations (1994, 2001 and 2008) of a random sample of initially 3273 participants. Data from the only hospital serving this population were included. RESULTS: There were 164 subjects with AS. Prevalence consistently increased with age, average values being 0.2% in the 50-59 year cohort, 1.3% in the 60-69 year cohort, 3.9% in the 70-79 year cohort and 9.8% in the 80-89 year cohort. The incidence rate in the study was 4.90/00/year. The mean annual increase in mean transvalvular pressure gradient was 3.2 mm Hg. The increase was lower in mild AS than in more severe disease, disclosing a non-linear development of the gradient, but with large individual variations. Mortality was not significantly increased in the asymptomatic AS-group (HR = 1.28), nor in those who received aortic valve replacement (n = 34, HR = 0.93), compared with the general population. CONCLUSION: This is the first study to document the incidence and prognosis of AS in a general population with surgery as a treatment option. It reveals an accelerated progression of the aortic mean gradient as the disease advances. The prognosis of AS seems to be comparable with the normal population in the asymptomatic stage and after successful surgery, indicating that the follow-up and timing of surgery has been adequate for this patient group. PMID- 22942294 TI - Aspirin plus clopidogrel for optimal platelet inhibition following off-pump coronary artery bypass surgery: results from the CRYSSA (prevention of Coronary arteRY bypaSS occlusion After off-pump procedures) randomised study. AB - OBJECTIVE: To determine the individual variability in the response to aspirin and/or clopidogrel and its impact on graft patency after off-pump coronary artery bypass grafting. DESIGN: A single-centre prospective randomised controlled study designed according to the Consolidated Standards of Reporting Trials statement. Randomisation was obtained by a computer-generated algorithm. SETTING: University medical school in Italy. PATIENTS: 300 patients who underwent off-pump coronary artery bypass grafting were randomised to receive aspirin (n=150) or aspirin plus clopidogrel (n=150). INTERVENTION: Aspirin 100 mg or aspirin 100 mg plus clopidogrel 75 mg daily was initiated when postoperative chest tube drainage was <= 50 ml/h for 2 h and patients were followed up for 12 months. MAIN OUTCOME MEASURES: Qualitative and quantitative assessment of platelet function, angiographic evaluation of coronary revascularisation by 64-slice CT and clinical outcome. RESULTS: In the aspirin group, 49 patients (32.6%) were aspirin resistant and, in the aspirin-clopidogrel group, 19 patients (12.6%) were aspirin and clopidogrel resistant. The platelet response to aspirin was similar in all aspirin responders despite the study arm (Aspirin Reaction Units 313.2 +/- 44.8 vs 323.6 +/- 53.6; p=0.07). The platelet response to clopidogrel was enhanced by aspirin in patients responsive to both aspirin and clopidogrel (synergistic effect) compared with responders to clopidogrel only (P2Y12 Reaction Units 139.9 +/- 15.5 vs 179.4 +/- 18.5; p<0.001). Combined therapy was associated with a reduced vein graft occlusion rate (7.4% vs 13.1%; p=0.04). Antiplatelet resistance was a predictor of graft occlusion (RR 3.6, 95% CI 2.5 to 6.9; p<0.001). Synergistic aspirin and clopidogrel activity was a strong predictor of vein graft patency (RR 5.1, 95% CI 1.4 to 16.3; p<0.01). CONCLUSIONS: Combined clopidogrel and aspirin overcome single drug resistances, are safe for bleeding and improve venous graft patency. PMID- 22942295 TI - Utility of self-reported diagnosis and electrocardiogram Q-waves for estimating myocardial infarction prevalence: an international comparison study. AB - OBJECTIVE: Self-report of physician diagnosis and ECG 'Q' waves are common survey measures of prior myocardial infarction (MI) prevalence. We sought to assess relative prevalence of self-reported prior MI and ECG Q-waves (ECG-MI) in populations and population subgroups with varying MI prevalence. DESIGN: A secondary analysis of seven population-based cross-sectional surveys of prevalent MI selected from a systematic review of ischaemic heart disease epidemiology. SETTING: Men and women aged 45-74 years in population-based Belgian surveys (1978 -1998, n=29 419) and US National Health and Nutrition Examination Surveys (1976 1994, n=11 107). Comparison of the US and Belgian surveys with surveys in seven other nations (United Kingdom, Russia, Lithuania, Belarus, India, Turkey and Ghana). MAIN OUTCOME MEASURES: Prevalence of prior MI measured by self-report or resting ECG Q-waves (ECG-MI; Minnesota ECG codes 1.1 and 1.2). RESULTS: Self reported prior MI prevalence was 1.5-2.6 times higher than ECG-MI in Belgian and US men aged 45-74 years and women 55-74 years. ECG-MI was more prevalent than self-reported MI in women <55 years old, and self-reported MI relatively low in US African-American men compared with US Caucasian men. In the overall nine nation comparison, there was no consistent relationship between self-reported MI and ECG-MI. ECG-MI was higher relative to self-report in nations with lower prevalence of ischaemic heart disease. CONCLUSIONS: Self-reported MI and ECG-MI prevalence may only be reliable in higher ischaemic heart disease incidence groups. Self-report and ECG-MI have limited accuracy, and ECG Q-waves likely capture fewer prior MIs in the 21st century. The limitations of current survey prevalence measures of MI should be taken into account when measuring the burden of ischaemic heart disease in populations. PMID- 22942296 TI - Cardiac sarcoidosis presenting as an arrhythmogenic right ventricular cardiomyopathy. PMID- 22942297 TI - Congenital heart disease: the national society journals present selected research that has driven recent advances in clinical cardiology. AB - This Almanac highlights recent papers on congenital heart disease in the major cardiac journals. Over 100 articles are cited. Subheadings are used to group relevant papers and allow readers to focus on their areas of interest, but are not meant to be comprehensive for all aspects of congenital cardiac disease. PMID- 22942298 TI - Cell therapy in cardiovascular disease: the national society journals present selected research that has driven recent advances in clinical cardiology. AB - The rapid translation from bench to bedside that has been seen in the application of regenerative medicine to cardiology has led to exciting new advances in our understanding of some of the fundamental mechanisms related to human biology. The first generation of cells used in phase I-II trials (mainly bone marrow mononuclear cells) are now entering phase III clinical trials with the goal of producing a cell based therapeutic that can change the outcome of cardiac disease. First generation cell therapy appears to have addressed safety concerns as well as showing 'activity' in numerous published meta- analyses. With the knowledge gained to date, the field is moving towards the next generation of cells-the 'engineered' cell-that have been developed to display a phenotype that will further enhance the myocardial repair/salvage process. This almanac review covers the latest basic research that may soon have application to humans as well as the results of the latest clinical trials. PMID- 22942299 TI - The fibrillin-1 gene: unlocking new therapeutic pathways in cardiovascular disease. AB - The dramatic reductions in DNA sequencing costs allow us to delve deeper into the genomic alterations that increase susceptibility to many polygenic cardiovascular diseases. One such condition is an abnormal proximal aorta. Until recently, many believed that dilated, distorted or dissected proximal aortas might represent a forme fruste of Marfan syndrome or a continuum of aortopathy. Although an FBN-1 mutation does not guarantee the diagnosis of Marfan syndrome it is clear however that FBN-1 mutations independently confer additional risk for many of the cardiovascular complications classically associated with the disease. Furthermore, treatment with an angiotensin receptor blocker has proven effective in reducing rates of thoracic aortic root dilatation in preliminary studies of Marfan syndrome patients. Awareness of an FBN-1 mutation then highlights the need for increased vigilance for the associated cardiovascular phenotypes. Knowledge of an FBN-1 gene mutation may allow actionable interventions earlier in the natural history of the condition. PMID- 22942300 TI - Reconsidering antimalarials in systemic lupus erythematosus: developments of translational clinical interest. PMID- 22942301 TI - Another consequence of severe lupus: invasive fungal disease. PMID- 22942302 TI - Furthering our understanding of fatigue in rheumatoid arthritis. PMID- 22942303 TI - The difficult diagnosis of temporomandibular joint arthritis. PMID- 22942304 TI - Tibial insufficiency fractures in rheumatoid arthritis: a new clinical sign. PMID- 22942305 TI - Digital gangrene in a patient with systemic lupus erythematosus and systemic sclerosis. PMID- 22942306 TI - Arteriosclerosis or vasculitis? Color duplex sonography in giant cell arteritis. PMID- 22942307 TI - Cervical vertebral squaring in patients without spondyloarthritis. PMID- 22942308 TI - Absence of SLC22A12/URAT1 gene mutations in patients with primary gout. PMID- 22942309 TI - Nonsteroidal antiinflammatory drugs (NSAID) versus NSAID with hydroxychloroquine in treatment of chemotherapy-related arthropathy: open-label multicenter pilot study. PMID- 22942310 TI - Cytotoxic T lymphocyte-associated antigen 4 Ig-induced asthma in the treatment of rheumatoid arthritis. PMID- 22942311 TI - Tumor necrosis factor-alpha inhibitor-induced antiglomerular basement membrane antibody disease in a patient with rheumatoid arthritis. PMID- 22942312 TI - Reversible leukoencephalopathy after oral methotrexate. PMID- 22942315 TI - The cultural and linguistic diversity of 3-year-old children with hearing loss. AB - Understanding the cultural and linguistic diversity of young children with hearing loss informs the provision of assessment, habilitation, and education services to both children and their families. Data describing communication mode, oral language use, and demographic characteristics were collected for 406 children with hearing loss and their caregivers when children were 3 years old. The data were from the Longitudinal Outcomes of Children with Hearing Impairment (LOCHI) study, a prospective, population-based study of children with hearing loss in Australia. The majority of the 406 children used spoken English at home; however, 28 other languages also were spoken. Compared with their caregivers, the children in this study used fewer spoken languages and had higher rates of oral monolingualism. Few children used a spoken language other than English in their early education environment. One quarter of the children used sign to communicate at home and/or in their early education environment. No associations between caregiver hearing status and children's communication mode were identified. This exploratory investigation of the communication modes and languages used by young children with hearing loss and their caregivers provides an initial examination of the cultural and linguistic diversity and heritage language attrition of this population. The findings of this study have implications for the development of resources and the provision of early education services to the families of children with hearing loss, especially where the caregivers use a language that is not the lingua franca of their country of residence. PMID- 22942314 TI - Quantity of parental language in the home environments of hard-of-hearing 2-year olds. AB - Automated analyses of full-day recordings were used to determine whether young children who are hard-of-hearing (HH) received similar levels of exposure to adult words and conversational interactions as age-matched peers with normal hearing (NH). Differences in adult input between children in this study and in a normative database were considered. Finally, factors were examined that may have contributed to individual differences in the input characteristics of families. Results indicated that the NH and HH groups were exposed to similar numbers of adult words and conversational turns. However, both the NH and HH groups were exposed to more adult words and engaged in more conversational turns than the NH children in the normative sample. Considering only the HH group, both quantity of adult words and conversational exchanges were correlated with children's auditory characteristics. Children's receptive language ability was correlated with conversational exchanges but not with adult word counts. PMID- 22942316 TI - Optimized experimental design for the estimation of enzyme kinetic parameters: an experimental evaluation. AB - A set of compounds (n = 30), including traditional cytochrome P450 substrates and compounds from AstraZeneca's compound library, was used in an experimental evaluation of an optimal design approach (ODA) for the estimation of enzyme kinetic parameters (CL(int), V(max), and K(m)). A depletion method previously shown to provide reliable results, the multiple depletion curves method (MDCM), was used as reference. Experiments were conducted with human liver microsomes, and samples were analyzed using liquid chromatography-tandem mass spectrometry. CL(int) estimated with the ODA were in >90% of the cases within a 2-fold difference compared with MDCM estimates. In addition, good agreement was generally seen for V(max) and K(m) estimates between the two methods as >80% of the estimates were within or almost within a 2-fold difference. The variability in V(max) and K(m) estimates were generally higher than for CL(int) estimates. In addition, decreased substrate turnover considerably increased the variability in V(max) and K(m) estimates, whereas only a modest increase was observed for CL(int) estimates. The experimental design of using multiple starting concentrations for the estimation of enzyme kinetics was shown to be appropriate even when there was a limitation to the number of samples. The method allowed for good estimates of CL(int) and also for V(max) and K(m) in many cases. Hence, this approach is a good alternative for the estimation of enzyme kinetic parameters, especially if enzyme saturation and an assessment of a potential risk for nonlinear metabolism are of interest. PMID- 22942318 TI - Statistical methods for analysis of time-dependent inhibition of cytochrome p450 enzymes. AB - Time-dependent inhibition (TDI) of cytochrome P450 (P450) enzymes, especially CYP3A4, is an important attribute of drugs in evaluating the potential for pharmacokinetic drug-drug interactions. The analysis of TDI data for P450 enzymes can be challenging, yet it is important to be able to reliably evaluate whether a drug is a TDI or not, and if so, how best to derive the inactivation kinetic parameters K(I) and k(inact). In the present investigation a two-step statistical evaluation was developed to evaluate CYP3A4 TDI data. In the first step, a two sided two-sample z-test is used to compare the k(obs) values measured in the absence and presence of the test compound to answer the question of whether the test compound is a TDI or not. In the second step, k(obs) values are plotted versus both [I] and ln[I] to determine whether a significant correlation exists, which can then inform the investigator of whether the inactivation kinetic parameters, K(I) and k(inact), can be reliably estimated. Use of this two-step statistical evaluation is illustrated with the examination of five drugs of varying capabilities to inactivate CYP3A4: ketoconazole, erythromycin, raloxifene, rosiglitazone, and pioglitazone. The use of a set statistical algorithm offers a more robust and objective approach to the analysis of P450 TDI data than frequently employed empirically derived or heuristic approaches. PMID- 22942317 TI - Bioactivation of the cancer chemopreventive agent tamoxifen to quinone methides by cytochrome P4502B6 and identification of the modified residue on the apoprotein. AB - The nonsteroidal antiestrogen tamoxifen was introduced as a treatment for breast cancer 3 decades ago. It has also been approved as a chemopreventive agent and is prescribed to women at high risk for this disease. However, several studies have shown that use of tamoxifen leads to increased risk of endometrial cancer in humans. One potential pathway of tamoxifen toxicity could involve metabolism via hydroxylation to give 4-hydroxytamoxifen (4OHtam), which may be further oxidized to form a quinone methide. CYP2B6 is a highly polymorphic drug-metabolizing enzyme, and it metabolizes a number of clinically important drugs. Earlier studies from our laboratory have shown that tamoxifen is a mechanism-based inactivator of CYP2B6. The aim of the current study was to investigate the possible formation of reactive intermediates through detection of protein covalent binding and glutathione ethyl ester adduct (GSHEE) formation. The incubation of tamoxifen with 2B6 gave rise to an adduct of 4OHtam with glutathione, which was characterized as the 4OHtam quinone methide + GSHEE with an m/z value of 719, and the structure was characterized by liquid chromatography tandem mass spectrometry. The metabolic activation of tamoxifen in the CYP2B6 reconstituted system also resulted in the formation of an adduct to the P4502B6 apoprotein, which was identified using liquid chromatography mass spectrometry. The site responsible for the inactivation of CYP2B6 was determined by proteolytic digestion and identification of the labeled peptide. This revealed a tryptic peptide 188FHYQDQE194 with the site of adduct formation localized to Gln193 as the site modified by the reactive metabolite formed during tamoxifen metabolism. PMID- 22942319 TI - Metabolism and pharmacokinetics of JM6 in mice: JM6 is not a prodrug for Ro-61 8048. AB - Understanding whether regulation of tryptophan metabolites can ameliorate neurodegeneration is of high interest to investigators. A recent publication describes 3,4-dimethoxy-N-(4-(3-nitrophenyl)-5-(piperidin-1-ylmethyl)thiazol-2 yl)benzenesulfonamide (JM6) as a novel prodrug for the kynurenine 3-monooxygenase (KMO) inhibitor 3,4-dimethoxy-N-(4-(3-nitrophenyl)thiazol-2-yl)benzenesulfonamide (Ro-61-8048) that elicits therapeutic effects in mouse models of Huntington's and Alzheimer's diseases (Cell 145:863-874, 2011). Our evaluation of the metabolism and pharmacokinetics of JM6 and Ro-61-8048 indicate instead that Ro-61-8048 concentrations in mouse plasma after JM6 administration originate from a Ro-61 8048 impurity (<0.1%) in JM6. After a 0.05 mg/kg Ro-61-8048 oral dose alone or coadministered with 10 mg/kg JM6 to mice, the Ro-61-8048 areas under the concentration-time curves (AUCs) from 0 to infinity were similar (4300 and 4900 nM * h, respectively), indicating no detectable contributions of JM6 metabolism to the Ro-61-8048 AUCs. JM6 was stable in incubations under acidic conditions and Ro-61-8048 was not a product of JM6 metabolism in vitro (plasma, blood, or hepatic models). Species differences in the quantitative rate of oxidative metabolism indicate that major circulating JM6 metabolite(s) in mice are unlikely to be major in humans: JM6 is rapidly metabolized via the piperidyl moiety in mouse (forming an iminium ion reactive intermediate) but is slowly metabolized in human (in vitro), primarily via O-dealkylation at the phenyl ring. Our data indicate that JM6 is not a prodrug for Ro-61-8048 and is not a potent KMO inhibitor. PMID- 22942320 TI - Identification of metabolites of ganoderic acid D by ultra-performance liquid chromatography/quadrupole time-of-flight mass spectrometry. AB - Ganoderic acid D (GD) is the major active triterpenoid in Ganoderma lucidum, a medicinal fungus used daily. However, the metabolic fate of GD remains unknown. To know whether GD is extensively metabolized, we first investigated the metabolism of GD in vitro and in vivo. The metabolic profiles of the bile samples obtained from rats in vivo were almost the same as those obtained in vitro. Using ultra-performance liquid chromatography/quadrupole time-of-flight mass spectrometry, a total of 25 metabolites were identified from the bile sample. Few metabolites were found in the urine samples. These results indicated that biliary rather than renal clearance was the major route of excretion. The major metabolites were identified by comparison with the standard reference compounds. Metabolites at low concentrations were identified by interpreting the mass spectra. Both phase I and phase II metabolites were observed. The metabolic transformation included reduction, monohydroxylation, dihydroxylation, trihydroxylation, oxidation, desaturation, sulfation, and glucuronidation. The main metabolic soft spots in the chemical structure of GD were the 3-carbonyl group, angular methyl groups, the 7-hydroxy group, and the 26-carboxylic acid moiety. Overall, this study gives us an insight into the metabolism of GD, an active oxygenated tetracyclic triterpenoid. PMID- 22942321 TI - Pain management by pharmacotherapy in inflammatory arthritis. Systematic literature reviews of the 3e Initiative 2010. PMID- 22942322 TI - Measuring pain and efficacy of pain treatment in inflammatory arthritis: a systematic literature review. AB - OBJECTIVE: To systematically review the available literature on measuring pain and the efficacy of pain treatment in inflammatory arthritis (IA), as an evidence base for generating clinical practice recommendations. METHODS: A systematic literature search was performed in Medline, Embase, Cochrane Library, and the American College of Rheumatology/European League Against Rheumatism 2008/2009 meeting abstracts, searching for studies evaluating clinimetric properties of pain measurement tools in IA (convergent validity, internal consistency, retest reliability, responsiveness, feasibility, and standardization). Studies that presented information on these properties were reviewed and their data were integrated into the pool of results available for pain measures in IA. RESULTS: In total, 51 articles were included in the review. Validated information on pain was available for tools covering different facets such as overall pain, anatomically specific pain, or a mixture of both. Data from these studies showed that single pain-related items such as the visual analog scale (VAS), numeric rating scale (NRS), or verbal rating scale (VRS) provide sufficient clinimetric information. Similar results were obtained for the pain subscales of the Arthritis Impact Measurement Scales (AIMS/AIMS2) and the bodily pain subscale of the Medical Outcome Study Short-Form Survey 36. Most clinimetric coefficients showed acceptable results with respect to validity, reliability, and sensitivity to change, while the degree of standardization and feasibility mostly filled at least 2 of 3 predefined criteria. CONCLUSION: A variety of pain measures are available to cover different aspects of pain such as intensity, frequency, or location. Single-item tools such as VAS, NRS, or VRS can be recommended to measure overall pain in clinical practice. If more specific issues need to be addressed, more sophisticated tools should be taken into account. PMID- 22942323 TI - Paracetamol for the management of pain in inflammatory arthritis: a systematic literature review. AB - OBJECTIVE: To systematically review the literature on the efficacy and safety of paracetamol (acetaminophen) in the management of pain in inflammatory arthritis. METHODS: A systematic search was performed in Medline, Embase, the Cochrane Library, and 2008/2009 American College of Rheumatology (ACR) and European League Against Rheumatism (EULAR) conference abstracts for clinical trials and observational studies of paracetamol in patients with inflammatory arthritis. Included trials were appraised for risk of bias, and relevant study details were abstracted. Efficacy was assessed from clinical trials using improvement in pain as the outcome measure, and safety was assessed using total adverse events and withdrawals due to adverse events as outcome measures. Safety data from observational studies were assessed separately. RESULTS: Eleven articles containing 12 clinical trials and 1 observational study were identified, all in patients with rheumatoid arthritis. The trials were of short duration, used atypical doses of paracetamol, and all had a high risk of bias. Overall, there was weak evidence of a benefit of paracetamol over placebo and an additive benefit of paracetamol in combination with nonsteroidal antiinflammatory drugs (NSAID). The benefit of paracetamol to NSAID alone was uncertain. No significant differences in safety were seen in the limited clinical trial data. One cohort study showed an increased rate of serious gastrointestinal events with paracetamol over NSAID when used concurrently with corticosteroids and other analgesics, but had significant methodological limitations. CONCLUSION: There is weak evidence for the efficacy of paracetamol in patients with inflammatory arthritis, and insufficient disease-specific safety data to draw conclusions. PMID- 22942324 TI - The role of corticosteroids for pain relief in persistent pain of inflammatory arthritis: a systematic literature review. AB - OBJECTIVE: To conduct a systematic review of the available literature addressing the effectiveness, safety, and role of corticosteroids for pain relief in persistent pain of inflammatory arthritis (IA), as part of the international 3e (Evidence, Expertise, Exchange) Initiative. METHODS: A systematic literature research (SLR) was carried out in Medline, Embase, the Cochrane Library, and the American College of Rheumatology/European League Against Rheumatism meeting abstracts, searching for studies evaluating the use of steroids for the treatment of residual pain in IA despite adequate antiinflammatory therapy. RESULTS: Of 3887 references retrieved by SLR, 2 randomized controlled studies and 35 review articles underwent full-text review. No article was found to adequately address the research question. CONCLUSION: No data on the efficacy and safety of systemic corticosteroids in residual pain in IA could be identified from the literature. PMID- 22942325 TI - The efficacy and safety of antidepressants in inflammatory arthritis: a Cochrane systematic review. AB - OBJECTIVES: To determine the efficacy and safety of antidepressants in pain management in patients with inflammatory arthritis (IA). METHODS: We searched the Cochrane Central Register of Controlled Trials, Medline, Embase, and PsychINFO for randomized controlled trials in adults with IA that compared any antidepressants (administered via any route) to another analgesic intervention or placebo. We also searched the 2008-2009 American College of Rheumatology and European League Against Rheumatism abstracts and performed a hand search of reference lists of relevant articles. Primary outcomes were patient-reported pain relief >= 30% and withdrawals due to adverse events. Two authors independently assessed methodological quality and extracted data. A risk of bias assessment was performed using methods recommended by the Cochrane Collaboration. RESULTS: Eight trials (652 participants) in patients with rheumatoid arthritis (RA) and 1 trial in patients with ankylosing spondylitis (100 participants) were included in this review. The majority of studies were published in the late 1980s in patients with active disease receiving minimal disease-modifying antirheumatic drug therapy. All trials evaluated tricyclic antidepressants (TCA) and 2 studies included a selective serotonin uptake inhibitor. Seven of the 9 trials had high risk of bias, 2 were unclear, and metaanalysis was not performed due to trial heterogeneity. RA trials with short-term outcome (< 1 week) found no significant benefit of amitriptyline 25 mg in combination with dextropropoxyphene (DXP) 65 mg over placebo, and inferiority of amitriptyline + DXP versus DXP 130 mg [mean difference (MD) 10.0, 95% CI 0.4 to 19.6]. There was conflicting evidence regarding medium (1-6 wks) or longer-term (> 6 wks) benefits on pain. One trial in depressed patients with RA showed no significant difference between amitriptyline and paroxetine given for 8 weeks (65% vs 56% much or very much improved; RR 1.2, 95% CI 0.9 to 1.5). One trial found that amitriptyline was no better than placebo in reducing pain in patients with active AS over 2 weeks (MD 0.2, 95% CI -1.2 to 0.8). From 5 trials, withdrawals due to adverse events were not significantly different from placebo. However, there were significantly more minor adverse events in patients receiving TCA compared with those receiving a placebo (RR 2.3, 95% CI 1.2 to 4.4). These included somnolence, dizziness, dry mouth, and nausea. CONCLUSION: Based upon 9 trials of high or unclear risk of bias, it is not possible to draw firm conclusions about the efficacy of TCA as analgesics for patients with IA. The use of these agents may be associated with adverse events that are generally mild and do not lead to cessation of treatment. High-quality trials are needed in this area. PMID- 22942326 TI - Efficacy and safety of neuromodulators in inflammatory arthritis: a Cochrane systematic review. AB - OBJECTIVE: To determine the efficacy and safety of neuromodulators for pain management in patients with inflammatory arthritis. METHODS: A Cochrane systematic review was performed as part of the 3e Initiative on pain management in inflammatory arthritis. We searched Medline, Embase, and Cochrane Central for studies to November 2010, and American College of Rheumatology/European League Against Rheumatism meeting abstracts published in 2008-2009. Studies were included if they were randomized or quasirandomized controlled trials that compared any neuromodulator (excluding cannabis) to another therapy (active or placebo, including nonpharmacological therapies) for pain in patients with RA, psoriatic arthritis, ankylosing spondylitis, or spondyloarthritis. Primary outcomes of interest were patient-reported pain relief of 30% or greater and withdrawals due to adverse events. Two authors independently extracted data and assessed methodological quality. A risk of bias assessment was performed using the methods recommended by the Cochrane Collaboration. RESULTS: Three trials, all in RA and all at high risk of bias, were included in this review. Two placebo controlled trials evaluated nefopam (52 participants) and one placebo-controlled trial evaluated topical capsaicin 0.025% (31 participants). Pooled analysis showed a significant reduction in pain levels favoring nefopam over placebo after 2 weeks [weighted mean difference -21.2, 95% CI -35.6 to -6.7; number needed to treat (NNT) 2, 95% CI 1.4 to 9.5]. However, nefopam was associated with significantly more adverse events (RR 4.1, 95% CI 1.6 to 10.7; number needed to harm 9, 95% CI 2 to 367), predominantly nausea and sweating. In one trial, capsaicin reduced pain more than placebo at 1 and 2 weeks (MD -23.8, 95% CI -44.8 to -2.8; NNT 3, 95% CI 2-47, and -34.4, 95% CI -54.7 to -14.14; NNT 2, 95% CI 1.4 to 6, respectively). Of those who received capsaicin, 44% developed burning at the site of application and 2% withdrew as a result. CONCLUSION: Based on 3 small trials, which were all at high risk of bias, there is weak evidence that nefopam and capsaicin are superior to placebo in reducing pain in patients with RA, but both are associated with a significant side effect profile. There are no available data for other types of IA or for newer agents such as gabapentin or pregabalin. PMID- 22942327 TI - The efficacy and safety of muscle relaxants in inflammatory arthritis: a Cochrane systematic review. AB - OBJECTIVE: To determine the efficacy and safety of muscle relaxants in pain management in patients with inflammatory arthritis (IA). METHODS: We searched the Cochrane Central Register of Controlled Trials, Medline, Embase, and PsychINFO for randomized controlled trials in adults with IA that compared any muscle relaxant (administered via any route) to another analgesic intervention or placebo. We also searched the 2008-2009 American College of Rheumatology and European League Against Rheumatism abstracts and performed a hand search of reference lists of relevant articles. Primary outcomes were patient-reported pain relief >= 30% and withdrawals due to adverse events. Two authors independently assessed methodological quality and extracted data. RESULTS: Six trials (126 participants) were included in this review. All trials were deemed to have a high risk of bias. Five crossover trials evaluated benzodiazepine; 4 assessed diazepam (n = 71), and one assessed triazolam (n = 15). The sixth trial, a parallel-group study, evaluated zopiclone (non-benzodiazepine, n = 40). No trial was longer than 2 weeks and 3 single-dose trials assessed outcomes at 24 hours only. Overall, the included trials failed to find evidence of a beneficial effect of muscle relaxants over placebo (at 24 hours, 1 week, or 2 weeks) or in addition to nonsteroidal antiiflammatory drugs (at 24 hours) on pain intensity, function, or quality of life. Data from 2 trials of longer than 24-hour duration (diazepam and zopiclone, n = 74) found that participants who received a muscle relaxant had significantly more adverse events compared with those who received placebo [number needed to harm (NNTH) 3, 95% CI 2 to 7]. These were predominantly central nervous system side effects including dizziness and drowsiness (NNTH 3, 95% CI 2 to 11). CONCLUSION: Based upon the currently available evidence in patients with IA, benzodiazepines (diazepam and triazolam) do not appear to be beneficial in improving pain over 24 hours or 1 week. The non-benzodiazepine agent zopiclone also did not significantly reduce pain over 2 weeks. However, even short-term muscle relaxant use (24 hours to 2 weeks) is associated with significant adverse events, predominantly drowsiness and dizziness. PMID- 22942328 TI - The efficacy and safety of opioids in inflammatory arthritis: a Cochrane systematic review. AB - OBJECTIVE: To determine the efficacy and safety of opioid analgesics in inflammatory arthritis (IA). METHODS: We searched Medline, Embase, and Central to May 2010. Randomized controlled trials in adults with IA that compared opioids (administered via any route) to another intervention or placebo were included. Studies in the immediate postoperative setting were excluded. Two authors independently extracted data and assessed risk of bias. Primary endpoints were pain and adverse events (AE). Categorical data were pooled using RevMan5 and reported as relative risks (RR) or odds ratios (OR) with 95% confidence intervals (95% CI). RESULTS: Eleven studies were included, all in patients with RA. The risk of bias of all studies was high. No study was longer than 6 weeks in duration and 4 studies used single doses of study drugs. Seven studies were between 1 and 6 weeks in duration and assessed 6 different oral opioids. Only 1 study investigated a strong opioid. Data could be pooled from 4 studies comparing weak opioids to placebo: there was no difference in withdrawals due to inadequate analgesia (RR 0.82, 95% CI 0.34, 2.01), but patient-reported global impression of change was superior with opioids (RR 1.44, 95% CI 1.03, 2.03). Opioids were more likely than placebo to cause AE (OR 3.90, 95% CI 2.31, 6.56). There was no difference between opioids and placebo in net efficacy after adjustment for AE. CONCLUSION: Based on 11 heterogeneous studies of short duration and high risk of bias, there is weak evidence that opioids are effective analgesics in RA. AE are common and may offset the benefits. The relative risks and benefits of opioids in IA beyond 6 weeks are unknown. PMID- 22942329 TI - Combination therapy for pain management in inflammatory arthritis: a Cochrane systematic review. AB - OBJECTIVE: To assess the efficacy and safety of combination pain therapy for people with inflammatory arthritis (IA). METHODS: Systematic review of randomized controlled trials using Cochrane Collaboration methodology. Combination therapy was defined as at least 2 drugs from the following classes: analgesics, nonsteroidal antiinflammatory drugs (NSAID), opioids, opioid-like drugs, and neuromodulators (antidepressants, anticonvulsants, and muscle relaxants). The main efficacy and safety outcomes were pain and withdrawals due to adverse events, respectively. RESULTS: Twenty-three trials (total of 912 patients) met inclusion criteria [22 in rheumatoid arthritis (RA) and 1 in a mixed population of RA and osteoarthritis]. All except 1 were published before 1990. All trials were at high risk of bias, and heterogeneity precluded metaanalysis. Statistically significant differences between treatment groups were reported in only 5/23 (22%) trials: in 3 trials combination therapy was better (2 trials with NSAID + analgesic versus NSAID only and 1 trial with 2 NSAID versus 1 NSAID), in 1 trial combination therapy was worse (opioid + neuromodulator versus opioid only), and in the fifth trial (NSAID + analgesic versus NSAID alone) reported results were mixed depending on the dosage used in the monotherapy arm. In general, there were no differences in safety and withdrawals due to inadequate analgesia between combination and monotherapy. CONCLUSION: Based on 23 trials, all at high risk of bias, there is insufficient evidence to establish the value of combination therapy over monotherapy for pain management in IA. Well-designed trials are needed to address this question. PMID- 22942330 TI - Safety and efficacy of on-demand versus continuous use of nonsteroidal antiinflammatory drugs in patients with inflammatory arthritis: a systematic literature review. AB - OBJECTIVE: To systematically review the efficacy and safety of on-demand versus continuous use of nonsteroidal antiinflammatory drugs (NSAID) in patients with inflammatory arthritis and to assess if longterm continuous treatment with NSAID in comparison with NSAID treatment on-demand reduces radiographic progression. METHODS: A systematic literature review was performed in Medline, Embase, the Cochrane Library, and American College of Rheumatology/European League Against Rheumatism 2008-2009 meeting abstracts as part of the multinational 3e (Evidence, Expertise, Exchange) Initiative for generating practical recommendations about Pain Management by Pharmacotherapy in Inflammatory Arthritis. Articles fulfilling predefined inclusion criteria were reviewed and quality appraisal was performed. RESULTS: The search yielded a total of 1410 articles from Medline and Embase, 73 from Cochrane Central, and 3 meeting abstracts. After review, only one study fulfilled the defined inclusion criteria, which indicated that longterm continuous treatment with NSAID versus NSAID treatment on-demand reduced radiographic progression in patients with ankylosing spondylitis. Secondary measured endpoints were disease activity measures including pain and the frequency of observed adverse events in both groups. Relevant adverse events tended to occur more frequently in the continuous treatment group with odds ratios of 2.79 for hypertension, 1.67 for abdominal pain, 1.35 for diarrhea, 0.95 for dyspepsia, and 3.2 for depression. None of these differences were statistically significant, with the exception of depression, which could not be explained. CONCLUSION: Based on a single study, there does not seem to be a statistical difference in efficacy between the on-demand versus continuous use of NSAID in the context of ankylosing spondylitis. There were no studies in patients with rheumatoid arthritis, psoriatic arthritis, or spondyloarthritis. Research is needed to study the risk-benefit ratio of continuous versus on-demand use of NSAID. PMID- 22942331 TI - Safety of pain therapy during pregnancy and lactation in patients with inflammatory arthritis: a systematic literature review. AB - OBJECTIVE: To systematically review the safety of various pain therapies used during pregnancy and lactation in patients with inflammatory arthritis. METHODS: A systematic literature review was performed in Medline, Embase, the Cochrane Library, and the American College of Rheumatology/European League Against Rheumatism 2008-2009 meeting abstracts, as part of the multinational 3e (Evidence, Expertise, Exchange) Initiative for generating practical recommendations about Pain Management by Pharmacotherapy in Inflammatory Arthritis. Articles fulfilling predefined inclusion criteria were reviewed, and quality appraisal was performed. RESULTS: The search yielded a total of 3974 articles and 7 abstracts. The only study that fulfilled the criteria for pain therapies in pregnancy was a systematic review published in 2008, evaluating the effects of nonsteroidal antiinflammatory drug (NSAID) use during pregnancy in patients with rheumatic conditions. Two of the 3 studies reviewed in the 2008 publication could be included in our current review. No studies were included in the review in relation to lactation. A total of 204 malformations were identified among infants exposed to NSAID, with an OR of 1.04. The number of identified cardiac defects was higher than expected, with an OR of 1.86. There seemed to be no specificity for the type of NSAID used. Among the 6 infants with orofacial clefts, 5 occurred with naproxen use and 1 with ibuprofen. CONCLUSION: Only 2 studies evaluating the risk of NSAID use in patients with inflammatory arthritis were identified, with results suggesting a higher rate of cardiac malformations in infants exposed to NSAID during the first trimester. No studies evaluating the effects of other treatments, such as paracetamol, corticosteroids, muscle relaxants, neuromodulators, antidepressants, opioids, or opioid-like therapy in the specific context of rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, or spondyloarthritis, and no studies with respect to lactation were identified. Research is needed to improve the risk-benefit ratio of the use of pain therapies for inflammatory arthritis during pregnancy. PMID- 22942332 TI - Safety of nonsteroidal antiinflammatory drugs and/or paracetamol in people receiving methotrexate for inflammatory arthritis: a Cochrane systematic review. AB - OBJECTIVE: To systematically review the literature on the safety of using nonsteroidal antiinflammatory drugs (NSAID) and/or paracetamol in people receiving methotrexate (MTX) for inflammatory arthritis (IA), as an evidence base for generating clinical practice recommendations. METHODS: A systematic literature review was performed using the Cochrane Library, Medline, Embase, and conference proceedings for the American College of Rheumatology (ACR) and European League Against Rheumatism (EULAR) for 2008-2009. The search aimed to identify studies describing adverse events (AE) with the concurrent use of paracetamol and/or NSAID in people taking MTX for IA. Articles fulfilling our predefined inclusion criteria were systematically reviewed and quality appraised. RESULTS: Seventeen publications out of 8681 identified studies were included in the review, all of which included people with rheumatoid arthritis (RA) using various NSAID; there were no identified studies for other forms of IA or with paracetamol. Of the studies examining concurrent use of MTX and NSAID, there were no reported adverse effects on lung, liver, or renal function, and no increase in MTX withdrawal or in major toxic reactions. However, transient thrombocytopenia was demonstrated in 1 study. Looking at specific NSAID, there were no clinically significant AE with concomitant piroxicam or etodolac, and only mild AE with celecoxib or etoricoxib. Antiinflammatory dose aspirin was demonstrated to have an adverse effect on liver and renal function. CONCLUSION: In the management of RA, concurrent use of NSAID with MTX appears to be safe, provided appropriate monitoring is performed. The use of antiinflammatory doses of aspirin should be avoided. PMID- 22942333 TI - How do gastrointestinal or liver comorbidities influence the choice of pain treatment in inflammatory arthritis? A Cochrane systematic review. AB - OBJECTIVE: To assess efficacy and safety of pharmacological pain treatment in patients with inflammatory arthritis (IA) and gastrointestinal (GI) or liver comorbidities. METHODS: A systematic literature search was performed using Medline, Embase, and Cochrane Controlled Trial Register up to June 2010, as well as American College of Rheumatology and European League Against Rheumatism meeting abstracts (2007-2010). The population investigated was defined as patients with IA and existing or prior reported GI or liver disease treated with nonsteroidal antiinflammatory drugs (NSAID), opioids or opioid-like drugs, paracetamol, antidepressants, neuromodulators, or muscle relaxants. Outcomes of interest were defined as efficacy evaluated by common pain measures and safety evaluated by withdrawals due to adverse events, worsening of comorbidity, and mortality. RESULTS: Out of 2869 identified studies only a single open-arm trial fulfilled inclusion criteria assessing the safety and efficacy of naproxen in 58 patients with active rheumatoid arthritis and GI comorbidities. The presence of fecal occult blood was reported in 1/58 participants tested between Weeks 1 to 26 and 2/32 participants tested between Weeks 27 to 52. Over the course of the study, 7 participants (12.1%) withdrew due to adverse events; no serious adverse events were reported. Among the 14 studies excluded due to inclusion of a mixed population (osteoarthritis or other rheumatic conditions) or an intervention that was already withdrawn, 5 trials reported a higher risk of developing GI events in patients with prior GI events when treated with NSAID. CONCLUSION: Very little evidence regarding safety and efficacy of pain treatment in patients with IA and GI or hepatic comorbidities was found. In patients with a history of GI events, extrapolating from other studies, NSAID should be used cautiously since there is evidence that these patients are at a higher risk of developing adverse events. PMID- 22942335 TI - Veterans who have served in the conflicts of Iraq and Afghanistan are at increased risk of suicide compared to other veterans if they have a psychiatric diagnosis. PMID- 22942334 TI - Pain pharmacotherapy in patients with inflammatory arthritis and concurrent cardiovascular or renal disease: a Cochrane systematic review. AB - BACKGROUND: Pain in inflammatory arthritis (IA) is common and often multifactorial, and many different pharmacotherapeutic agents are routinely used for pain management. There are concerns that some current pain pharmacotherapies may increase the risk of adverse events in patients with concurrent cardiovascular (CV) or renal disease. METHODS: A systematic literature review was performed searching Medline, Embase, Cochrane Central Register of Controlled Trials, DARE, and Cochrane Database of Systematic Reviews. We also hand-searched conference proceedings for the American College of Rheumatology and the European League Against Rheumatism for 2008-2009. RESULTS: Our search identified 4782 studies, of which 190 were included for detailed review, but none met the inclusion criteria for our review. We identified 1 study of etoricoxib and diclofenac in non-IA populations [osteoarthritis (OA) or mixed OA and rheumatoid arthritis]. In that study, the presence of CV disease increased the likelihood of a further CV event 3-fold. Patients with 2 or more CV risk factors showed a 2 fold increased likelihood of adverse CV events. CONCLUSION: Our review has highlighted a lack of specific evidence to guide clinicians in the management of pain in patients with IA and coexistent CV or renal disease. In the absence of this evidence, we suggest clinicians use nonsteroidal antiinflammatory drugs (NSAID) with caution in patients with preexisting CV disease or >= 2 CV risk factors. There is currently no evidence to advise clinicians considering other pain pharmacotherapies in the context of CV comorbidities. Current guidelines regarding the use of NSAID and opioids in moderate to severe renal impairment should also be applied to the IA population. PMID- 22942336 TI - Evaluation of staring episodes in children. PMID- 22942337 TI - Is plasma renin activity a biomarker for the prediction of renal and cardiovascular outcomes in treated hypertensive patients? Observations from the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT). AB - AIMS: Plasma renin activity (PRA) has been shown to predict future cardiovascular (CV) events in observational studies and in clinical trials and to be associated with the prevalence of chronic renal disease in hypertensive subjects. In a nested case-control study, we explored the relationship between CV and renal outcomes and all-cause mortality with baseline measurements of PRA among hypertensive adults randomized in the ASCOT trial. METHODS AND RESULTS: In the UK and Ireland, ASCOT included 9098 hypertensive adults randomized to either calcium channel blocker (CCB)- or beta-blocker (BB)-based treatment. Four thousand eight hundred and fifty-three patients with total cholesterol <=6.5 mmol/L (250 mg/L) were further randomized to atorvastatin or placebo. Over 5.5 years, there were 399 CV events (fatal coronary heart disease (CHD), non-fatal myocardial infarction, coronary revascularization, and fatal and non-fatal stroke), 96 cases of new-onset renal impairment, and 220 deaths. Cases were age, sex, and ethnicity matched with 1525 controls. Conditional logistic regression models were used to evaluate the association between CV events, renal impairment, all-cause mortality, and PRA. For those on antihypertensive (AHT) treatment at the baseline (91.5%), PRA was influenced by prior drug treatment. The median (inter-quartile range; ng/mL/h) levels were 1.04 (0.52, 1.3) for BBs, 1.30 (0.78, 2.72) for CCBs, 1.56 (0.91, 3.50) for diuretics, and 2.33 (1.30, 5.57) for angiotensin-converting enzyme inhibitors or angiotensin receptor blockers. Odds ratios (OR) and 95% confidence intervals (CIs) for CV and other events were estimated for 1-SD increase in log-transformed PRA levels and by categorizing PRA into quartiles with the lowest as the referent category. Baseline PRA did not predict CV events in models adjusted for baseline characteristics [OR 0.92 (CI 0.81, 1.06, P = 0.25)] and for pre-randomized AHT treatment [OR 0.91 (CI 0.79, 1.04, P = 0.17)] and was not associated with all-cause mortality [OR 1.12 (CI 0.92, 1.37, P = 0.25) and OR 1.06 (CI 0.91, 1.24, P = 0.46)] in the fully adjusted model. Baseline levels of PRA were positively but non-significantly associated with the development of renal impairment in models adjusted for baseline characteristics [OR 1.39 (CI 0.97, 1.97, P = 0.07)] and also for pre-randomized antihypertensive (AHT) treatment [OR 1.35 (CI 0.95, 1.94, P = 0.10)]. Quartile analyses, however, demonstrated a significant positive association of higher levels of PRA with the development of impaired renal function (P = 0.03 and 0.05 in adjusted models, respectively) compared with the lowest quartile. CONCLUSION: These analyses suggest an association between elevated baseline PRA and the subsequent development of renal impairment but do not support its use to predict future CV events or all-cause mortality in treated hypertensive patients without diagnosed CHD. PMID- 22942339 TI - Mineralocorticoid receptor antagonists for heart failure with reduced ejection fraction: integrating evidence into clinical practice. AB - Mineralocorticoid receptor antagonists (MRAs) improve survival and reduce morbidity in patients with heart failure, reduced ejection fraction (HF-REF), and mild-to-severe symptoms, and in patients with left ventricular systolic dysfunction and heart failure after acute myocardial infarction. These clinical benefits are observed in addition to those of angiotensin converting enzyme inhibitors or angiotensin receptor blockers and beta-blockers. The morbidity and mortality benefits of MRAs may be mediated by several proposed actions, including antifibrotic mechanisms that slow heart failure progression, prevent or reverse cardiac remodelling, or reduce arrhythmogenesis. Both eplerenone and spironolactone have demonstrated survival benefits in individual clinical trials. Pharmacologic differences exist between the drugs, which may be relevant for therapeutic decision making in individual patients. Although serious hyperkalaemia events were reported in the major MRA clinical trials, these risks can be mitigated through appropriate patient selection, dose selection, patient education, monitoring, and follow-up. When used appropriately, MRAs significantly improve outcomes across the spectrum of patients with HF-REF. PMID- 22942338 TI - Neutral endopeptidase inhibition and the natriuretic peptide system: an evolving strategy in cardiovascular therapeutics. AB - Hypertension and heart failure (HF) are common diseases that, despite advances in medical therapy, continue to be associated with high morbidity and mortality. Therefore, innovative therapeutic strategies are needed. Inhibition of the neutral endopeptidase (NEPinh) had been investigated as a potential novel therapeutic approach because of its ability to increase the plasma concentrations of the natriuretic peptides (NPs). Indeed, the NPs have potent natriuretic and vasodilator properties, inhibit the activity of the renin-angiotensin-aldosterone system, lower sympathetic drive, and have antiproliferative and antihypertrophic effects. Such potentially beneficial effects can be theoretically achieved by the use of NEPinh. However, studies have shown that NEPinh alone does not result in clinically meaningful blood pressure-lowering actions. More recently, NEPinh has been used in combination with other cardiovascular agents, such as angiotensin converting enzyme inhibitors, and antagonists of the angiotensin receptor. Another future possible combination would be the use of NEPinh with NPs or their newly developed chimeric peptides. This review summarizes the current knowledge of the use and effects of NEPinh alone or in combination with other therapeutic agents for the treatment of human cardiovascular disease such as HF and hypertension. PMID- 22942341 TI - Obesity: changing asthma in the 21st century. PMID- 22942340 TI - N-terminal pro-B-type natriuretic peptide and the prediction of primary cardiovascular events: results from 15-year follow-up of WOSCOPS. AB - AIMS: To test whether N-terminal pro-B-type natriuretic peptide (NT-proBNP) was independently associated with, and improved the prediction of, cardiovascular disease (CVD) in a primary prevention cohort. METHODS AND RESULTS: In the West of Scotland Coronary Prevention Study (WOSCOPS), a cohort of middle-aged men with hypercholesterolaemia at a moderate risk of CVD, we related the baseline NT proBNP (geometric mean 28 pg/mL) in 4801 men to the risk of CVD over 15 years during which 1690 experienced CVD events. Taking into account the competing risk of non-CVD death, NT-proBNP was associated with an increased risk of all CVD [HR: 1.17 (95% CI: 1.11-1.23) per standard deviation increase in log NT-proBNP] after adjustment for classical and clinical cardiovascular risk factors plus C-reactive protein. N-terminal pro-B-type natriuretic peptide was more strongly related to the risk of fatal [HR: 1.34 (95% CI: 1.19-1.52)] than non-fatal CVD [HR: 1.17 (95% CI: 1.10-1.24)] (P= 0.022). The addition of NT-proBNP to traditional risk factors improved the C-index (+0.013; P < 0.001). The continuous net reclassification index improved with the addition of NT-proBNP by 19.8% (95% CI: 13.6-25.9%) compared with 9.8% (95% CI: 4.2-15.6%) with the addition of C reactive protein. N-terminal pro-B-type natriuretic peptide correctly reclassified 14.7% of events, whereas C-reactive protein correctly reclassified 3.4% of events. Results were similar in the 4128 men without evidence of angina, nitrate prescription, minor ECG abnormalities, or prior cerebrovascular disease. CONCLUSION: N-terminal pro-B-type natriuretic peptide predicts CVD events in men without clinical evidence of CHD, angina, or history of stroke, and appears related more strongly to the risk for fatal events. N-terminal pro-B-type natriuretic peptide also provides moderate risk discrimination, in excess of that provided by the measurement of C-reactive protein. Clinical trial registration WOSCOPS was carried out and completed prior to the requirement for clinical trial registration. PMID- 22942342 TI - The 6-minute walk test in pulmonary arterial hypertension: how far is enough? PMID- 22942343 TI - Of tangible benefits that remain unexplained: the Papworth village movement to take care of tuberculous families. PMID- 22942344 TI - Laryngeal hypersensitivity in the World Trade Center-exposed population: the role for respiratory retraining. AB - Upper airway symptoms among responders to the terrorist attack on 9/11 are progressive and multifactorial. For those symptoms that are laryngeal in origin, we are using a multidisciplinary approach that includes respiratory retraining and laryngeal desensitization through a speech pathologist trained in airway disorders. Our treatment paradigm and laryngeal hypersensitivity are discussed in this essay. PMID- 22942345 TI - A microRNA processing defect in rapidly progressing idiopathic pulmonary fibrosis; enteral omega-3 fatty acid, gamma-linoleic acid, and antioxidant supplementation in ALI; and management of asthma in pregnancy guided by exhaled nitric oxide. PMID- 22942346 TI - The iron lady. PMID- 22942347 TI - Randomized controlled trial of nebulized gentamicin in non-cystic fibrosis bronchiectasis...without patient blinding. PMID- 22942348 TI - No H1N1 detected in children admitted to hospital with asthma during the H1N1 pandemic. PMID- 22942349 TI - Placebo disclosure rate in randomized controlled trials involving critically ill patients. PMID- 22942350 TI - Time until relapse in tuberculosis treatment trials: implication for phase 3 trial design. PMID- 22942351 TI - Granulomatous pneumonitis associated with adult-onset Blau-like syndrome. PMID- 22942352 TI - Lung fibrosis, premature graying, and macrocytosis. PMID- 22942353 TI - A pathologist's view of airway obstruction in chronic obstructive pulmonary disease. PMID- 22942355 TI - The Socratic attic, where much of the future of the stent was hatched. AB - Although he makes no claim to be a pioneer, Prof. Patrick Serruys,who recently retired as Chief of Interventional Cardiology at the Thoraxcenter, Rotterdam, and his colleagues have taken the simple idea of the stent to new heights, and in the process produced an original paper once every few days, reports Barry Shurlock PhD. PMID- 22942356 TI - Investigation of receptor interacting protein (RIP3)-dependent protein phosphorylation by quantitative phosphoproteomics. AB - Receptor interacting protein 3 (RIP3) is a protein kinase that plays a key role in programmed necrosis. Despite the importance of RIP3-dependent necrosis in many pathological processes, current knowledge on the function of RIP3 is very limited. Here we present the results of a proteome-wide analysis of RIP3 regulated phosphorylation sites using cells from wildtype (RIP3(+/+)) and RIP3 knockout (RIP3(-/-)) mice. Because the activation of RIP3 requires stimulation by certain extracellular stimuli such as ligands of death receptors or Toll-like receptors, we compared the phosphorylation sites of lipopolysaccharide (LPS) treated peritoneal macrophages from RIP3(+/+) and RIP3(-/-) mice and the phosphorylation sites of tumor necrosis factor (TNF)-treated RIP3(+/+) and RIP3( /-) mouse embryonic fibroblast (MEF) cells. Stable isotope labeling by amino acids in cell culture and spike-in stable isotope labeling by amino acids in cell culture were used in the analyses of the MEFs and macrophages, respectively. Proteomic analyses using stable isotope labeling by amino acids in cell culture coupled with immobilized metal affinity chromatography-hydrophilic interaction liquid chromatography fractionation and nanoLC MS/MS identified 14,057 phosphopeptides in 4306 proteins from the macrophages and 4732 phosphopeptides in 1785 proteins from the MEFs. Analysis of amino acid sequence motifs among the phosphopeptides identified a potential motif of RIP3 phosphorylation. Among the phosphopeptides identified, 73 were found exclusively in RIP3(+/+) macrophages, 121 were detected exclusively from RIP3(+/+) MEFs, 286 phosphopeptides were induced more in RIP3(+/+) macrophages than in RIP3(-/-) macrophages and 26 phosphopeptides had higher induction in RIP3(+/+) MEFs than in RIP3(-/-) cells. Many of the RIP3 regulated phosphoproteins from the macrophages and MEF cells are functionally associated with the cell cycle; the rest, however, appear to have diverse functions in that a number of metabolism related proteins were phosphorylated in macrophages and development related phosphoproteins were induced in MEFs. The results of our phosphoproteomic analysis suggest that RIP3 might function beyond necrosis and that cell type specific function of RIP3 exists. PMID- 22942357 TI - Flexible survival strategies of Pseudomonas aeruginosa in biofilms result in increased fitness compared with Candida albicans. AB - The majority of microorganisms persist in nature as surface-attached communities often surrounded by an extracellular matrix, called biofilms. Most natural biofilms are not formed by a single species but by multiple species. Microorganisms not only cooperate as in some multispecies biofilms but also compete for available nutrients. The Gram-negative bacterium Pseudomonas aeruginosa and the polymorphic fungus Candida albicans are two opportunistic pathogens that are often found coexisting in a human host. Several models of mixed biofilms have been reported for these organisms showing antagonistic behavior. To investigate the interaction of P. aeruginosa and C. albicans in more detail, we analyzed the secretome of single and mixed biofilms of both organisms using MALDI-TOF MS/MS at several time points. Overall 247 individual proteins were identified, 170 originated from P. aeruginosa and 77 from C. albicans. Only 39 of the 131 in mixed biofilms identified proteins were assigned to the fungus whereby the remaining 92 proteins belonged to P. aeruginosa. In single-species biofilms, both organisms showed a higher diversity of proteins with 73 being assigned to C. albicans and 154 to P. aeruginosa. Most interestingly, P. aeruginosa in the presence of C. albicans secreted 16 proteins in significantly higher amounts or exclusively among other virulence factors such as exotoxin A and iron acquisition systems. In addition, the high affinity iron-binding siderophore pyoverdine was identified in mixed biofilms but not in bacterial biofilms, indicating that P. aeruginosa increases its capability to sequester iron in competition with C. albicans. In contrast, C. albicans metabolism was significantly reduced, including a reduction in detectable iron acquisition proteins. The results obtained in this study show that microorganisms not only compete with the host for essential nutrients but also strongly with the present microflora in order to gain a competitive advantage. PMID- 22942359 TI - Biochemical fractionation and stable isotope dilution liquid chromatography-mass spectrometry for targeted and microdomain-specific protein quantification in human postmortem brain tissue. AB - Synaptic architecture and its adaptive changes require numerous molecular events that are both highly ordered and complex. A majority of neuropsychiatric illnesses are complex trait disorders, in which multiple etiologic factors converge at the synapse via many signaling pathways. Investigating the protein composition of synaptic microdomains from human patient brain tissues will yield valuable insights into the interactions of risk genes in many disorders. These types of studies in postmortem tissues have been limited by the lack of proper study paradigms. Thus, it is necessary not only to develop strategies to quantify protein and post-translational modifications at the synapse, but also to rigorously validate them for use in postmortem human brain tissues. In this study we describe the development of a liquid chromatography-selected reaction monitoring method, using a stable isotope-labeled neuronal proteome standard prepared from the brain tissue of a stable isotope-labeled mouse, for the multiplexed quantification of target synaptic proteins in mammalian samples. Additionally, we report the use of this method to validate a biochemical approach for the preparation of synaptic microdomain enrichments from human postmortem prefrontal cortex. Our data demonstrate that a targeted mass spectrometry approach with a true neuronal proteome standard facilitates accurate and precise quantification of over 100 synaptic proteins in mammalian samples, with the potential to quantify over 1000 proteins. Using this method, we found that protein enrichments in subcellular fractions prepared from human postmortem brain tissue were strikingly similar to those prepared from fresh mouse brain tissue. These findings demonstrate that biochemical fractionation methods paired with targeted proteomic strategies can be used in human brain tissues, with important implications for the study of neuropsychiatric disease. PMID- 22942358 TI - Major histocompatibility complex class II+ invariant chain negative breast cancer cells present unique peptides that activate tumor-specific T cells from breast cancer patients. AB - The major histocompatibility complex (MHC) class II-associated Invariant chain (Ii) is present in professional antigen presenting cells where it regulates peptide loading onto MHC class II molecules and the peptidome presented to CD4+ T lymphocytes. Because Ii prevents peptide loading in neutral subcellular compartments, we reasoned that Ii- cells may present peptides not presented by Ii+ cells. Based on the hypothesis that patients are tolerant to MHC II restricted tumor peptides presented by Ii+ cells, but will not be tolerant to novel peptides presented by Ii- cells, we generated MHC II vaccines to activate cancer patients' T cells. The vaccines are Ii- tumor cells expressing syngeneic HLA-DR and the costimulatory molecule CD80. We used liquid chromatography coupled with mass spectrometry to sequence MHC II-restricted peptides from Ii+ and Ii- MCF10 human breast cancer cells transfected with HLA-DR7 or the MHC Class II transactivator CIITA to determine if Ii- cells present novel peptides. Ii expression was induced in the HLA-DR7 transfectants by transfection of Ii, and inhibited in the CIITA transfectants by RNA interference. Peptides were analyzed and binding affinity predicted by artificial neural net analysis. HLA-DR7 restricted peptides from Ii- and Ii+ cells do not differ in size or in subcellular location of their source proteins; however, a subset of HLA-DR7 restricted peptides of Ii- cells are not presented by Ii+ cells, and are derived from source proteins not used by Ii+ cells. Peptides from Ii- cells with the highest predicted HLA-DR7 binding affinity were synthesized, and activated tumor specific HLA-DR7+ human T cells from healthy donors and breast cancer patients, demonstrating that the MS-identified peptides are bonafide tumor antigens. These results demonstrate that Ii regulates the repertoire of tumor peptides presented by MHC class II+ breast cancer cells and identify novel immunogenic MHC II restricted peptides that are potential therapeutic reagents for cancer patients. PMID- 22942360 TI - Development of cardiac support bioprostheses for ventricular restoration and myocardial regeneration. AB - OBJECTIVES: Ventricular constraint devices made of polyester and nitinol have been used to treat heart failure patients. Long-term follow-up has not demonstrated significant benefits, probably due to the lack of effects on myocardial tissue and to the risk of diastolic dysfunction. The goal of this experimental study is to improve ventricular constraint therapy by associating stem cell intrainfarct implantation and a cell-seeded collagen scaffold as an interface between the constraint device and the epicardium. METHODS: In a sheep ischaemic model, three study groups were created: Group 1: coronary occlusion without treatment (control group). Group 2: postinfarct ventricular constraint using a polyester device (Acorn CorCap). Group 3: postinfarct treatment with stem cells associated with collagen matrix and the polyester device. Autologous adipose mesenchymal stem cells cultured in hypoxic conditions were injected into the infarct and seeded into the collagen matrix. RESULTS: At 3 months, echocardiography showed the limitation of left ventricular end-diastolic volume in animals both treated with constraint devices alone and associated with stem cells/collagen. In Group 3 (stem cell + collagen treatment), significant improvements were found in ejection fraction (EF) and diastolic function evaluated by Doppler-derived mitral deceleration time. In this group, histology showed a reduction of infarct size, with focuses of angiogenesis and minimal fibrosis interface between CorCap and the epicardium due to the interposition of the collagen matrix. CONCLUSIONS: Myocardial infarction treated with stem cells associated with a collagen matrix and ventricular constraint device improves systolic and diastolic function, reducing adverse remodelling and fibrosis. The application of bioactive molecules and the recent development of nanobiotechnologies should open the door for the creation of a new semi degradable ventricular support bioprosthesis, capable of controlled stability or degradation in response to physiological conditions of the left or right heart. PMID- 22942361 TI - Feasibility of transcatheter techniques for intracardiac and extracardiac cavocaval connection in principle for Fontan completion in chronic animal models. AB - OBJECTIVES: We report the safety and feasibility of various transcatheter techniques of cavocaval connection in principle for the completion of Fontan circulation in viable, chronic and ovine heart models. Surgically simulated preparations of both intracardiac and extracardiac cavocaval connections were studied. METHODS: Sixteen sheep were divided into two groups per the type of surgical preparation. All animals underwent standard right thoracotomy with interposition of a 20-mm Gore-tex((r)) conduit between the superior vena cava (SVC) and the right atrium (RA). Nitinol rings were placed around the SVC and the inferior vena cava (IVC). In Group I (intracardiac, n = 10), the SVC-RA junction was closed using a polytetrafluoroethylene (PTFE) membrane 1 cm below the SVC Gore-tex((r)) anastomosis. In Group II (extracardiac, n = 6), a 20-mm Gore-tex conduit de-aired and filled with heparinized saline was anastomosed to connect the SVC and the IVC. The IVC end was anastomosed in a termino-lateral fashion and the SVC end in a termino-terminal fashion; both the ends were occluded with a PTFE membrane. Animals were scheduled for transcatheter cavocaval connection after a variable healing period. RESULTS: Four animals in Group I died; three early and one late after surgical preparation. After a median interim period of 1 month (0-9 months), five sheep from Group I and six from Group II underwent successful transcatheter cavocaval connection. Perforation of the PTFE membrane was successful in all animals. Covered stents were deployed precisely and with good stability ensured by the nitinol rings. All animals survived transcatheter completion and were sacrificed after a median follow-up of 4 months (0-8 months) per protocol. No stent migration, thromboembolic events, residual shunts or paraprosthetic leak was noticed on angiographic evaluation or at autopsy in any animal. CONCLUSIONS: Transcatheter techniques for completion of cavocaval connection in surgically simulated, chronic animal models is safe and feasible. Both techniques were equally successful with no failures or short-term complications. Such techniques should work in principle for completion of intracardiac and extracardiac Fontan circulation. PMID- 22942362 TI - Factors associated with the need of biventricular mechanical circulatory support in children with advanced heart failure. AB - OBJECTIVES: Postimplantation right ventricular dysfunction is associated with increased morbidity and mortality in ventricular assist device (VAD) recipients. This study aimed to determine the preoperative risk factors for severe right heart failure needing biventricular mechanical circulatory support in children with end-stage heart failure. METHODS: We reviewed data from 84 children supported with long-term VADs at the German Heart Institute Berlin between January 1999 and October 2010. Right ventricular assist device (RVAD) support was needed for 24 (29%) patients, and the other 60 (71%) were implanted with left ventricular assist devices (LVADs). RESULTS: The median age at implantation was 7 years (12 days-18 years), and the median support time was 41 days (1-432 days). Of the 84 patients, the overall survival to transplantation or recovery of ventricular function was 69%. Compared with children implanted with LVAD, patients receiving biventricular support had significantly higher postoperative mortality (P = 0.04). The multivariate logistic regression indicated that decreased milrinone use was the only preoperative factor independently associated with increased requirement for biventricular support (odds ratio: 0.1, 95% confidence interval: 0.04-0.64, P = 0.01). Children treated with milrinone preoperatively showed improved survival after implantation (P = 0.04). CONCLUSIONS: Paediatric patients needing biventricular support had significantly higher postoperative mortality. Preoperative milrinone use might decrease the risk of severe right ventricular failure requiring additional RVAD insertion and improve postimplantation survival in children with advanced heart failure. PMID- 22942363 TI - Epidemiological study of acute poisoning in children: a 5-year retrospective study in the Paediatric University Hospital in Bialystok, Poland. AB - BACKGROUND: Poisoning among children and youths in the northeastern part of Poland accounted for 25% of the total number of patients admitted to the Hospital Emergency Department of the Paediatric University Hospital of Bialystok. We hypothesise that the epidemiology of poisoned paediatric patients admitted is related to increase in 'designer drugs' (mainly amphetamine- and ecstasy-like psychostimulants, hallucinogens and synthetic cannabinoids ('spice') intake, which became popular 5 years ago in our country. METHODS: A retrospective chart review of medical records of 489 patients admitted due to poisoning in the 5-year period (2006-2010). The data included: age, sex, place of residence, nature of the substance, causes of poisoning, former use of psychoactive stimulants, accompanying self-mutilation and injuries and length of hospitalisation. Categorical variables were expressed as percentages, and continuous variables as mean and SD. The data were collected in a Microsoft Excel database. Statistical analysis was performed using the Statistical Programme for Social Sciences. RESULTS: Out of 2176 hospitalised children, 489 were admitted because of poisoning. Out of these, 244 (49.9%) were hospitalised due to intoxication by alcohol. Only eight children used designer drugs. The mean age of all patients in our group was 12.86+/-5.04 years, of which 52.4% were male. Poisoning was intentional in 75.5%, and accidental in 24.5% of cases. Appearance of 'designer drugs' had no significant impact on the number and epidemiology of poisonings in our group. PMID- 22942364 TI - Neonatal hypoxia and seizures. PMID- 22942365 TI - Pediatric head injury. PMID- 22942366 TI - Pertussis in childhood. PMID- 22942367 TI - Complementary, holistic, and integrative medicine: depression, sleep disorders, and substance abuse. PMID- 22942368 TI - Index of suspicion. PMID- 22942369 TI - Thalassemia. PMID- 22942370 TI - Promoting healthy behaviors in pediatrics: motivational interviewing. PMID- 22942371 TI - Accepting a helping hand can be the right thing to do. PMID- 22942372 TI - Intrinsic versus contingent claims about the harmfulness of prostitution. PMID- 22942373 TI - Scientific retractions and corrections related to misconduct findings. AB - We examined all 208 closed cases involving official findings of research misconduct published by the US Office of Research Integrity from 1992 to 2011 to determine how often scientists mention in a retraction or correction notice that there was an ethical problem with an associated article. 75 of these cases cited at least one published article affected by misconduct for a total of 174 articles. For 127 of these 174, we found both the article and a retraction or correction statement. Since eight of the 127 published statements consisted of simply the word 'retracted,' our analysis focused on the remaining 119 for which a more detailed retraction or correction was published. Of these 119 statements, only 41.2% mentioned ethics at all (and only 32.8% named a specific ethical problem such as fabrication, falsification or plagiarism), whereas the other 58.8% described the reason for retraction or correction as error, loss of data or replication failure when misconduct was actually at issue. Among the published statements in response to an official finding of misconduct (within the time frame studied), the proportion that mentioned ethics was significantly higher in recent years than in earlier years, as was the proportion that named a specific problem. To promote research integrity, scientific journals should consider adopting policies concerning retractions and corrections similar to the guidelines developed by the Committee on Publication Ethics. Funding agencies and institutions should take steps to ensure that articles affected by misconduct are retracted or corrected. PMID- 22942374 TI - Is it better to be minimally conscious than vegetative? PMID- 22942375 TI - Comment on 'Is prostitution harmful?'. PMID- 22942376 TI - Impact of the demand for 'proxy assent' on recruitment to a randomised controlled trial of vaccination testing in care homes. AB - Legal frameworks are in place to protect those who lack the capacity to consent to research, such as the Mental Capacity Act in the UK. Assent is sought instead from a proxy, usually a relative. However, the same legislation may, perversely, affect the welfare of those who lack capacity and of others by hindering the process of recruitment into otherwise potentially beneficial research. In addition, the onus of responsibility is moved from those who know most about the study (ie, the scientific community) to those who know less (the proxies). In this paper, we describe the characteristics of a sample at different stages of the recruitment process of an influenza vaccine-based randomised control trial in elderly care home residents (the FEVER study). 62% (602/968) of potential subjects lacked capacity but only 29% (80/277) of those actually randomised. Older age, being female and living in an Elderly Mentally Ill care home were the only variables associated with lacking capacity. Considering this was a study based in a care home setting where the prevalence of dementia approximates 80%, the trial, like many others, was thus significantly biased. We believe that difficulties seeking proxy assent contributed significantly to this problem. Further thought should be given to how assent to enter research for those who lack capacity should be provided, and we suggest avenues for further discussion such as independent risk/benefit expert panels. PMID- 22942377 TI - Breakdown of the FLT3-ITD/STAT5 axis and synergistic apoptosis induction by the histone deacetylase inhibitor panobinostat and FLT3-specific inhibitors. AB - Activating mutations of the class III receptor tyrosine kinase FLT3 are the most frequent molecular aberration in acute myeloid leukemia (AML). Mutant FLT3 accelerates proliferation, suppresses apoptosis, and correlates with poor prognosis. Therefore, it is a promising therapeutic target. Here, we show that RNA interference against FLT3 with an internal tandem duplication (FLT3-ITD) potentiates the efficacy of the histone deacetylase inhibitor (HDACi) panobinostat (LBH589) against AML cells expressing FLT3-ITD. Similar to RNA interference, tyrosine kinase inhibitors (TKI; AC220/cpd.102/PKC412) in combination with LBH589 exhibit superior activity against AML cells. Median dose effect analyses of drug-induced apoptosis rates of AML cells (MV4-11 and MOLM-13) revealed combination index (CI) values indicating strong synergism. AC220, the most potent and FLT3-specific TKI, shows highest synergism with LBH589 in the low nanomolar range. A 4-hour exposure to LBH589 + AC220 already generates more than 50% apoptosis after 24 hours. Different cell lines lacking FLT3-ITD as well as normal peripheral blood mononuclear cells are not significantly affected by LBH589 + TKI, showing the specificity of this treatment regimen. Immunoblot analyses show that LBH589 + TKI induce apoptosis via degradation of FLT3-ITD and its prosurvival target STAT5. Previously, we showed the LBH589-induced proteasomal degradation of FLT3-ITD. Here, we show that activated caspase-3 also contributes to the degradation of FLT3-ITD and that STAT5 is a direct target of this protease. Our data strongly emphasize HDACi/TKI drug combinations as promising modality for the treatment of FLT3-ITD-positive AMLs. PMID- 22942378 TI - Gibberellin regulates the Arabidopsis floral transition through miR156-targeted SQUAMOSA promoter binding-like transcription factors. AB - Gibberellin (GA), a diterpene hormone, plays diverse roles in plant growth and development, including seed germination, stem elongation, and flowering time. Although it is known that GA accelerates flowering through degradation of transcription repressors, DELLAs, the underlying mechanism is poorly understood. We show here that DELLA directly binds to microRNA156 (miR156)-targeted SQUAMOSA PROMOTER BINDING-LIKE (SPL) transcription factors, which promote flowering by activating miR172 and MADS box genes. The interaction between DELLA and SPL interferes with SPL transcriptional activity and consequently delays floral transition through inactivating miR172 in leaves and MADS box genes at shoot apex under long-day conditions or through repressing MADS box genes at the shoot apex under short-day conditions. Our results elucidate the molecular mechanism by which GA controls flowering and provide the missing link between DELLA and MADS box genes. PMID- 22942379 TI - Ribulose-1,5-bis-phosphate carboxylase/oxygenase accumulation factor1 is required for holoenzyme assembly in maize. AB - Most life is ultimately sustained by photosynthesis and its rate-limiting carbon fixing enzyme, ribulose-1,5-bis-phosphate carboxylase/oxygenase (Rubisco). Although the structurally comparable cyanobacterial Rubisco is amenable to in vitro assembly, the higher plant enzyme has been refractory to such manipulation due to poor understanding of its assembly pathway. Here, we report the identification of a chloroplast protein required for Rubisco accumulation in maize (Zea mays), RUBISCO ACCUMULATION FACTOR1 (RAF1), which lacks any characterized functional domains. Maize lines lacking RAF1 due to Mutator transposon insertions are Rubisco deficient and seedling lethal. Analysis of transcripts and proteins showed that Rubisco large subunit synthesis in raf1 plants is not compromised; however, newly synthesized Rubisco large subunit appears in a high molecular weight form whose accumulation requires a specific chaperonin 60 isoform. Gel filtration analysis and blue native gels showed that endogenous and recombinant RAF1 are trimeric; however, following in vivo cross linking, RAF1 copurifies with Rubisco large subunit, suggesting that they interact weakly or transiently. RAF1 is predominantly expressed in bundle sheath chloroplasts, consistent with a Rubisco accumulation function. Our results support the hypothesis that RAF1 acts during Rubisco assembly by releasing and/or sequestering the large subunit from chaperonins early in the assembly process. PMID- 22942380 TI - SKIP is a component of the spliceosome linking alternative splicing and the circadian clock in Arabidopsis. AB - Circadian clocks generate endogenous rhythms in most organisms from cyanobacteria to humans and facilitate entrainment to environmental diurnal cycles, thus conferring a fitness advantage. Both transcriptional and posttranslational mechanisms are prominent in the basic network architecture of circadian systems. Posttranscriptional regulation, including mRNA processing, is emerging as a critical step for clock function. However, little is known about the molecular mechanisms linking RNA metabolism to the circadian clock network. Here, we report that a conserved SNW/Ski-interacting protein (SKIP) domain protein, SKIP, a splicing factor and component of the spliceosome, is involved in posttranscriptional regulation of circadian clock genes in Arabidopsis thaliana. Mutation in SKIP lengthens the circadian period in a temperature-sensitive manner and affects light input and the sensitivity of the clock to light resetting. SKIP physically interacts with the spliceosomal splicing factor Ser/Arg-rich protein45 and associates with the pre-mRNA of clock genes, such as PSEUDORESPONSE REGULATOR7 (PRR7) and PRR9, and is necessary for the regulation of their alternative splicing and mRNA maturation. Genome-wide investigations reveal that SKIP functions in regulating alternative splicing of many genes, presumably through modulating recognition or cleavage of 5' and 3' splice donor and acceptor sites. Our study addresses a fundamental question on how the mRNA splicing machinery contributes to circadian clock function at a posttranscriptional level. PMID- 22942381 TI - Arabidopsis growth-regulating factor7 functions as a transcriptional repressor of abscisic acid- and osmotic stress-responsive genes, including DREB2A. AB - Arabidopsis thaliana DEHYDRATION-RESPONSIVE ELEMENT BINDING PROTEIN2A (DREB2A) functions as a transcriptional activator that increases tolerance to osmotic and heat stresses; however, its expression also leads to growth retardation and reduced reproduction. To avoid these adverse effects, the expression of DREB2A is predicted to be tightly regulated. We identified a short promoter region of DREB2A that represses its expression under nonstress conditions. Yeast one-hybrid screening for interacting factors identified GROWTH-REGULATING FACTOR7 (GRF7). GRF7 bound to the DREB2A promoter and repressed its expression. In both artificial miRNA-silenced lines and a T-DNA insertion line of GRF7, DREB2A transcription was increased compared with the wild type under nonstress conditions. A previously undiscovered cis-element, GRF7-targeting cis-element (TGTCAGG), was identified as a target sequence of GRF7 in the short promoter region of DREB2A via electrophoretic mobility shift assays. Microarray analysis of GRF7 knockout plants showed that a large number of the upregulated genes in the mutant plants were also responsive to osmotic stress and/or abscisic acid. These results suggest that GRF7 functions as a repressor of a broad range of osmotic stress-responsive genes to prevent growth inhibition under normal conditions. PMID- 22942382 TI - Mutations in an Arabidopsis mitochondrial transcription termination factor related protein enhance thermotolerance in the absence of the major molecular chaperone HSP101. AB - The molecular chaperone heat shock protein101 (HSP101) is required for acquired thermotolerance in plants and other organisms. To identify factors that interact with HSP101 or that are involved in thermotolerance, we screened for extragenic suppressors of a dominant-negative allele of Arabidopsis thaliana HSP101, hot1-4. One suppressor, shot1 (for suppressor of hot1-4 1), encodes a mitochondrial transcription termination factor (mTERF)-related protein, one of 35 Arabidopsis mTERFs about which there is limited functional data. Missense (shot1-1) and T-DNA insertion (shot1-2) mutants suppress the hot1-4 heat-hypersensitive phenotype. Furthermore, shot1-2 suppresses other heat-sensitive mutants, and shot1-2 alone is more heat tolerant than the wild type. SHOT1 resides in mitochondria, indicating it functions independently of cytosolic/nuclear HSP101. Microarray analysis suggests altered mitochondrial function and/or retrograde signaling in shot1-2 increases transcripts of other HSPs and alters expression of redox related genes. Reduced oxidative damage is the likely cause of shot1 thermotolerance, indicating HSP101 repairs protein oxidative damage and/or reduced oxidative damage allows recovery in the absence of HSP101. Changes in organelle-encoded transcripts in shot1 demonstrate that SHOT1 is involved in organelle gene regulation. The heat tolerance of shot1 emphasizes the importance of mitochondria in stress tolerance, and defining its function may provide insights into control of oxidative damage for engineering stress-resistant plants. PMID- 22942384 TI - Insight into ribulose 1,5-bis-phosphate carboxylase/oxygenase assembly in maize. PMID- 22942383 TI - Selective regulation of maize plasma membrane aquaporin trafficking and activity by the SNARE SYP121. AB - Plasma membrane intrinsic proteins (PIPs) are aquaporins facilitating the diffusion of water through the cell membrane. We previously showed that the traffic of the maize (Zea mays) PIP2;5 to the plasma membrane is dependent on the endoplasmic reticulum diacidic export motif. Here, we report that the post-Golgi traffic and water channel activity of PIP2;5 are regulated by the SNARE (for soluble N-ethylmaleimide-sensitive factor protein attachment protein receptor) SYP121, a plasma membrane resident syntaxin involved in vesicle traffic, signaling, and regulation of K(+) channels. We demonstrate that the expression of the dominant-negative SYP121-Sp2 fragment in maize mesophyll protoplasts or epidermal cells leads to a decrease in the delivery of PIP2;5 to the plasma membrane. Protoplast and oocyte swelling assays showed that PIP2;5 water channel activity is negatively affected by SYP121-Sp2. A combination of in vitro (copurification assays) and in vivo (bimolecular fluorescence complementation, Forster resonance energy transfer, and yeast split-ubiquitin) approaches allowed us to demonstrate that SYP121 and PIP2;5 physically interact. Together with previous data demonstrating the role of SYP121 in regulating K(+) channel trafficking and activity, these results suggest that SYP121 SNARE contributes to the regulation of the cell osmotic homeostasis. PMID- 22942386 TI - 25-Hydroxyvitamin D, parathyroid hormone, and mortality in black and white older adults: the health ABC study. AB - CONTEXT: Previous 25-hydroxyvitamin D [25(OH)D] and mortality studies have included mostly individuals of European descent. Whether the relationship is similar in Blacks and to what extent differences in 25(OH)D explain racial disparities in mortality is unclear. OBJECTIVE: The objective of the study was to examine the relationship between 25(OH)D, PTH, and mortality in Black and white community-dwelling older adults over 8.5 yr of follow-up. DESIGN AND SETTING: Health ABC is a prospective cohort study conducted in Memphis, TN, and Pittsburgh, PA. PARTICIPANTS: Well-functioning Blacks and whites aged 71-80 yr with measured 25(OH)D and PTH (n = 2638; 49% male, 39% Black) were included in the study. MAIN OUTCOME MEASURE: Multivariate-adjusted proportional hazards models estimated the hazard ratios (HR) for all-cause, cardiovascular, cancer, and noncancer, noncardiovascular mortality (n = 691 deaths). RESULTS: Mean 25(OH)D concentrations were higher in whites than in Blacks [mean (sd): 29.0 (9.9) and 20.8 (8.7) ng/ml, respectively; P < 0.001]. Serum 25(OH)D by race interactions were not significant, however. Lower 25(OH)D concentrations were associated with higher mortality in Blacks and whites combined [HR (95% confidence interval [CI] 2.27 (1.59-3.24), 1.48 (1.20-1.84), and 1.25 (1.02-1.52) for < 10, 10 to < 20, and 20 to < 30 vs. >=30 ng/ml]. In the multivariate model without 25(OH)D, Blacks had 22% higher mortality than whites [HR (95% CI) 1.22 (1.01, 1.48)]; after including 25(OH)D in the model, the association was attenuated [1.09 (0.90-1.33)]. The mortality population attributable risks (95% CI) for 25(OH)D concentrations less than 20 ng/ml and less than 30 ng/ml in Blacks were 16.4% (3.1-26.6%) and 37.7% (11.6-55.1%) and in whites were 8.9% (3.9 12.7%) and 11.1% (-2.7 to 22.0%), respectively. PTH was also associated with mortality [HR (95% CI) 1.80 (1.33-2.43) for >=70 vs. <23 pg/ml]. CONCLUSIONS: Low 25(OH)D and high PTH concentrations were associated with increased mortality in Black and white community-dwelling older adults. Because 25(OH)D concentrations were much lower in Blacks, the potential impact of remediating low 25(OH)D concentrations was greater in Blacks than whites. PMID- 22942387 TI - Multiple segmental uniparental disomy associated with abnormal DNA methylation of imprinted Loci in silver-russell syndrome. AB - BACKGROUND: Silver-Russell syndrome (SRS; online inheritance in man 180860) is a low-birth-weight syndrome characterized by postnatal growth restriction and variable dysmorphic features. Although maternal uniparental disomy (UPD) of chromosome 7 and hypomethylation of H19 have been reported in up to 50% of all cases, no unifying mechanism is apparent. SUBJECTS AND METHODS: Ten patients and their parents were studied using the Illumina GoldenGate methylation array and the Illumina 370K HumHap single-nucleotide polymorphism array to identify aberrations in DNA methylation as well as genomic changes including copy number changes and uniparental disomy events. RESULTS: We found evidence of UPD events outside chromosome 7 in all patients. In up to 30% of patients with SRS, DNA methylation changes occur in imprinted gene loci outside 11p15.5 (PEG3, PLAGL1, and GRB10), not previously consistently linked with SRS. Furthermore, hypermethylation of GRB10 was associated with increased mRNA expression. In addition, 20% of patients appear to have DNA methylation abnormalities within multiple loci. Not all the imprinted loci with methylation defects were affected directly by UPD. CONCLUSIONS: The association of widespread UPD associated with abnormal methylation and mRNA expression in imprinted genes in SRS is consistent with the concept of UPD as an initial genomic abnormality leading to unstable DNA methylation within the regulatory network of imprinted genes. Furthermore, disruption of any one of these genes may contribute to the heterogeneous clinical spectrum of SRS. PMID- 22942389 TI - Rosette tracker: an open source image analysis tool for automatic quantification of genotype effects. AB - Image analysis of Arabidopsis (Arabidopsis thaliana) rosettes is an important nondestructive method for studying plant growth. Some work on automatic rosette measurement using image analysis has been proposed in the past but is generally restricted to be used only in combination with specific high-throughput monitoring systems. We introduce Rosette Tracker, a new open source image analysis tool for evaluation of plant-shoot phenotypes. This tool is not constrained by one specific monitoring system, can be adapted to different low budget imaging setups, and requires minimal user input. In contrast with previously described monitoring tools, Rosette Tracker allows us to simultaneously quantify plant growth, photosynthesis, and leaf temperature related parameters through the analysis of visual, chlorophyll fluorescence, and/or thermal infrared time-lapse sequences. Freely available, Rosette Tracker facilitates the rapid understanding of Arabidopsis genotype effects. PMID- 22942388 TI - Altered starch turnover in the maternal plant has major effects on Arabidopsis fruit growth and seed composition. AB - Mature seeds of both the high-starch starch-excess1 (sex1) mutant and the almost starchless phosphoglucomutase1 mutant of Arabidopsis (Arabidopsis thaliana) have 30% to 40% less lipid than seeds of wild-type plants. We show that this is a maternal effect and is not attributable to the defects in starch metabolism in the embryo itself. Low lipid contents and consequent slow postgerminative growth are seen only in mutant embryos that develop on maternal plants with mutant phenotypes. Mutant embryos that develop on plants with wild-type starch metabolism have wild-type lipid contents and postgerminative growth. The maternal effect on seed lipid content is attributable to carbohydrate starvation in the mutant fruit at night. Fruits on sex1 plants grow more slowly than those on wild type plants, particularly at night, and have low sugars and elevated expression of starvation genes at night. Transcript levels of the transcription factor WRINKLED1, implicated in lipid synthesis, are reduced at night in sex1 but not in wild-type seeds, and so are transcript levels of key enzymes of glycolysis and fatty acid synthesis. sex1 embryos develop more slowly than wild-type embryos. We conclude that the reduced capacity of mutant plants to convert starch to sugars in leaves at night results in low nighttime carbohydrate availability in the developing fruit. This in turn reduces the rate of development and expression of genes encoding enzymes of storage product accumulation in the embryo. Thus, the supply of carbohydrate from the maternal plant to the developing fruit at night can have an important influence on oilseed composition and on postgerminative growth. PMID- 22942392 TI - Disulfide linkage engineering for improving biophysical properties of human VH domains. AB - To enhance their therapeutic potential, human antibody heavy chain variable domains (V(H)s) would benefit from increased thermostability. The highly conserved disulfide linkage that connects Cys23 and Cys104 residues in the core of V(H) domains is crucial to their stability and function. It has previously been shown that the introduction of a second disulfide linkage can increase the thermostability of camelid heavy-chain antibody variable domains (V(H)Hs). Using four model domains we demonstrate that this strategy is also applicable to human V(H) domains. The introduced disulfide linkage, formed between Cys54 and Cys78 residues, increased the thermostability of V(H)s by 14-18 degrees C. In addition, using a novel hexa-histidine capture technology, circular dichroism, turbidity, size exclusion chromatography and multiangle light scattering measurements, we demonstrate reduced V(H) aggregation in domains with the Cys54-Cys78 disulfide linkage. However, we also found that the engineered disulfide linkage caused conformational changes, as indicated by reduced binding of the V(H)s to protein A. This indicates that it may be prudent to use the synthetic V(H) libraries harboring the engineered disulfide linkage before screening for affinity reagents. Such strategies may increase the number of thermostable binders. PMID- 22942391 TI - Protonation state of E71 in KcsA and its role for channel collapse and inactivation. AB - The prototypical prokaryotic potassium channel KcsA alters its pore depending on the ambient potassium; at high potassium, it exists in a conductive form, and at low potassium, it collapses into a nonconductive structure with reduced ion occupancy. We present solid-state NMR studies of KcsA in which we test the hypothesis that an important channel-inactivation process, known as C-type inactivation, proceeds via a state similar to this collapsed state. We test this using an inactivation-resistant mutant E71A, and show that E71A is unable to collapse its pore at both low potassium and low pH, suggesting that the collapsed state is structurally similar to the inactivated state. We also show that E71A has a disordered selectivity filter. Using site-specific K(+) titrations, we detect a local change at E71 that is coupled to channel collapse at low K(+). To gain more insight into this change, we site specifically measure the chemical shift tensors of the side-chain carboxyls of E71 and its hydrogen bond partner D80, and use the tensors to assign protonation states to E71 and D80 at high K(+) and neutral pH. Our measurements show that E71 is protonated at pH 7.5 and must have an unusually perturbed pK(a) (> 7.5) suggesting that the change at E71 is a structural rearrangement rather than a protonation event. The results offer new mechanistic insights into why the widely used mutant KcsA-E71A does not inactivate and establish the ambient K(+) level as a means to populate the inactivated state of KcsA in a controlled way. PMID- 22942390 TI - Characterization of the procera tomato mutant shows novel functions of the SlDELLA protein in the control of flower morphology, cell division and expansion, and the auxin-signaling pathway during fruit-set and development. AB - procera (pro) is a tall tomato (Solanum lycopersicum) mutant carrying a point mutation in the GRAS region of the gene encoding SlDELLA, a repressor in the gibberellin (GA) signaling pathway. Consistent with the SlDELLA loss of function, pro plants display a GA-constitutive response phenotype, mimicking wild-type plants treated with GA3. The ovaries from both nonemasculated and emasculated pro flowers had very strong parthenocarpic capacity, associated with enhanced growth of preanthesis ovaries due to more and larger cells. pro parthenocarpy is facultative because seeded fruits were obtained by manual pollination. Most pro pistils had exserted stigmas, thus preventing self-pollination, similar to wild type pistils treated with GA3 or auxins. However, Style2.1, a gene responsible for long styles in noncultivated tomato, may not control the enhanced style elongation of pro pistils, because its expression was not higher in pro styles and did not increase upon GA3 application. Interestingly, a high percentage of pro flowers had meristic alterations, with one additional petal, sepal, stamen, and carpel at each of the four whorls, respectively, thus unveiling a role of SlDELLA in flower organ development. Microarray analysis showed significant changes in the transcriptome of preanthesis pro ovaries compared with the wild type, indicating that the molecular mechanism underlying the parthenocarpic capacity of pro is complex and that it is mainly associated with changes in the expression of genes involved in GA and auxin pathways. Interestingly, it was found that GA activity modulates the expression of cell division and expansion genes and an auxin signaling gene (tomato AUXIN RESPONSE FACTOR7) during fruit set. PMID- 22942393 TI - Generation of a dual-functional split-reporter protein for monitoring membrane fusion using self-associating split GFP. AB - Split reporter proteins capable of self-association and reactivation have applications in biomedical research, but designing these proteins, especially the selection of appropriate split points, has been somewhat arbitrary. We describe a new methodology to facilitate generating split proteins using split GFP as a self association module. We first inserted the entire GFP module at one of several candidate split points in the protein of interest, and chose clones that retained the GFP signal and high activity relative to the original protein. Once such chimeric clones were identified, a final pair of split proteins was generated by splitting the GFP-inserted chimera within the GFP domain. Applying this strategy to Renilla reniformis luciferase, we identified a new split point that gave 10 times more activity than the previous split point. The process of membrane fusion was monitored with high sensitivity using a new pair of split reporter proteins. We also successfully identified new split points for HaloTag protein and firefly luciferase, generating pairs of self-associating split proteins that recovered the functions of both GFP and the original protein. This simple method of screening will facilitate the designing of split proteins that are capable of self-association through the split GFP domains. PMID- 22942394 TI - The effect of thermostabilising mutations on the pressure stability of Trichoderma reesei GH11 xylanase. AB - We studied the pressure stability of disulphide bridge mutants of Trichoderma reesei XYNII at 500-5000 bar. The inactivation of XYNII and its mutants was strongest above 4000 bar. The pressure stability correlated with the thermostability order of the XYNII mutants, indicating that the stabilising mutations in protein regions important for thermostability also protect the enzyme at high pressure. In combination with high pressure, a mild heating had already inactivated the wild-type enzyme; the thermostabilising mutations largely counteracted this effect. At a low temperature, the mutations did not have any remarkable pressure stabilisation effect. Thus, thermal inactivation appeared to dominate over pressure inactivation at higher temperatures. Kinetic calculations indicated that pressure compressibility correlated with the thermostability of xylanase mutants. PMID- 22942397 TI - On "Is the BESTest at its best?...." Padgett PK, Jacobs JV, Kasser SL. Phys Ther. 2012;92:1197-1207. PMID- 22942395 TI - Improved drug-like properties of therapeutic proteins by directed evolution. AB - Many natural human proteins have functional properties that make them useful as therapeutic drugs. However, not all these proteins are compatible with large scale manufacturing processes or sufficiently stable to be stored for long periods prior to use. In this study, we focus on small four-helix bundle proteins and employ ribosome display in conjunction with three parallel selection pressures to favour the isolation of variant proteins with improved expression, solubility and stability. This in vitro evolution strategy was applied to two human proteins with known drug development issues, granulocyte colony-stimulating factor (G-CSF) and erythropoietin (EPO). In the case of G-CSF, the soluble expression levels in Escherichia coli were improved 1000-fold, while for EPO the level of aggregation in an accelerated shelf-life study was reduced from over 80% to undetectable levels. These results exemplify the general utility of our in vitro evolution strategy for improving the drug-like properties of therapeutic proteins. PMID- 22942398 TI - Personal accountability in healthcare: searching for the right balance. AB - While the patient safety field has emphasised 'systems thinking' as its central theme, experts have pointed to the need to balance this 'no blame' approach with the need for accountability in certain circumstances, such as failure to heed reasonable safety standards. Our growing appreciation of the importance of accountability raises several new questions, including the relative roles of personal versus institutional accountability, and the degree to which personal accountability should be enforced by outside parties (such as peers, patients, healthcare systems or regulators) versus professionals themselves ('professionalism'). Identifying the appropriate locus for accountability is likely to be highly influenced by the structure and culture of the healthcare system; thus, answers in the UK will undoubtedly be different from those in the USA. Ultimately, a robust approach to patient safety will balance 'no blame' with accountability, and will also parse the correct target for accountability in a way that maximises fairness and effectiveness. PMID- 22942399 TI - The accident and emergency department questionnaire: a measure for patients' experiences in the accident and emergency department. AB - BACKGROUND: The National Health Service National Patient Survey Programme systematically gathers patients' experiences about the care they have recently received. Prioritising quality improvement activities in the accident and emergency (A&E) department requires that survey outcomes are meaningful and reliable. We aimed to determine which method of obtaining summary scores for the A&E department questionnaire optimally combined good interpretability with robust psychometric characteristics. METHODS: A&E department questionnaire data from 151 hospital trusts were analysed, covering 49 646 patients. Three methods of grouping and summarising items of the questionnaire were compared: principal components analysis (PCA); Department of Health dimensions; sections according to the patient's journey through the A&E department. The patient-level reliability of summary scores was determined by Cronbach's alpha coefficients (threshold: alpha>0.70), construct validity by Pearson's correlation coefficients, and the discriminative capacity by intra-class correlation coefficients (ICCs) and reliability of A&E-level mean scores. RESULTS: The PCA provided the best score reliability on six clear and interpretable composites: waiting time; doctors and nurses; your care and treatment; hygiene; information before discharge; overall. The discriminative power of the concepts was comparable for the three methods, with ICCs between 0.010 and 0.061. A&E sample sizes were adequate to obtain good to excellent reliability of A&E-level mean scores. CONCLUSIONS: The A&E department questionnaire is a valid and reliable questionnaire to assess patients' experiences with the A&E. The discriminative power of six summary scores offers a reliable comparison of healthcare performance between A&Es to increase patient centredness and quality of care. PMID- 22942400 TI - What's in a name generator? Choosing the right name generators for social network surveys in healthcare quality and safety research. AB - BACKGROUND: Interest in the use of social network analysis (SNA) in healthcare research has increased, but there has been little methodological research on how to choose the name generators that are often used to collect primary data on the social connection between individuals for SNA. OBJECTIVE: We sought to determine a minimum set of name generators sufficient to distinguish the social networks of a target population of physicians active in quality improvement (QI). METHODS: We conducted a pilot survey including 8 name generators in a convenience sample of 25 physicians active in QI to characterize their social networks. We used multidimensional scaling to determine what subset of these name generators was needed to distinguish these social networks. RESULTS: We found that some physicians maintain a social network organized around a specific colleague who performed multiple roles while others maintained highly differentiated networks. We found that a set of 5 of the 8 name generators we used was needed to distinguish the networks of these physicians. CONCLUSIONS: Beyond methodology for selecting name generators, our findings suggest that QI networks may require 5 or more generators to elicit valid sets of relevant actors and relations in this target population. PMID- 22942401 TI - Juvenile-onset inflammatory arthritis: a study of adolescents' beliefs about underlying cause. AB - OBJECTIVE: Patients' beliefs regarding the cause of illness may influence treatment adherence and long-term outcome. Little is known of adolescents' beliefs regarding the cause of JIA. This study aims to identify adolescents' beliefs about the underlying cause of their arthritis at first presentation to the paediatric rheumatology department. METHODS: One hundred and twenty-two adolescents aged >=11 years participating in the larger prospective Childhood Arthritis Prospective Study, an inception cohort of childhood-onset inflammatory arthritis, were asked to complete a questionnaire regarding underlying beliefs about their arthritis. The top-listed causes were identified, and associations between beliefs and characteristics of the adolescents and their arthritis were compared across the different causal beliefs. RESULTS: The most common causal beliefs were genetics (27.1%), the immune system (21.3%), accident or injury (15.6%) and infection (13.1%). Association between causal beliefs and gender, disease duration, International League Against Rheumatism subtype and source of referral was observed, although small numbers prevented robust statistical comparisons. CONCLUSION: This first report on adolescents' beliefs about the cause of their juvenile arthritis found the most common causal beliefs to be related to genes or the immune system. Brief assessments of adolescents' beliefs at presentation will enable providers to modify or adapt potentially unhelpful beliefs and provide age-appropriate information regarding arthritis. PMID- 22942402 TI - A randomized controlled trial of a cognitive behavioural patient education intervention vs a traditional information leaflet to address the cardiovascular aspects of rheumatoid disease. AB - OBJECTIVES: Cardiovascular disease (CVD) is responsible for 50% of the excess mortality for patients with RA. This study aimed to evaluate a novel 8-week cognitive behavioural patient education intervention designed to effect behavioural change with regard to modifiable CVD risk factors in people with RA. METHODS: This was a non-blinded randomized controlled trial with a delayed intervention arm. Participants were randomly assigned to receive the cognitive behavioural education intervention or a control information leaflet at a ratio of 1:1. The primary outcome measure was patient's knowledge of CVD in RA; secondary measures were psychological measures relating to effecting behaviour change, actual behaviour changes and clinical risk factors. Data were collected at baseline, 2 and 6 months. RESULTS: A total of 110 participants consented (52 in the intervention group and 58 in the control group) to participate in the study. At 6 months, those in the intervention group had significantly higher knowledge scores (P < 0.001); improved behavioural intentions to increase exercise (P < 0.001), eat a low-fat diet (P = 0.01) and lose weight (P = 0.06); and lower mean diastolic blood pressure by 3.7 mmHg, whereas the control group's mean diastolic blood pressure increased by 0.8 mmHg. There was no difference between the groups on actual behaviours. CONCLUSIONS: Patient education has a significant role to play in CVD risk factor modification for patients with RA, and the detailed development of this programme probably contributed to its successful results. It is disappointing that behaviours, as we measured them, did not change. The challenge, as always, is how to translate behavioural intentions into action. Larger studies, powered specifically to look at behavioural changes, are required. Trial registration. National Institute for Health Research, UKCRN 4566. PMID- 22942403 TI - Large-joint damage in patients with early rheumatoid arthritis and its association with treatment strategy and damage of the small joints. AB - OBJECTIVE: To determine the prevalence of large-joint damage and the association with small-joint damage in patients with RA after 8 years of low DAS (<=2.4) targeted treatment with different treatment strategies. METHODS: Radiological data of 290 patients participating in the BeSt study, a randomized trial comparing initial monotherapy and initial combination therapy strategies, were used. Radiographs of large joints were scored using the Larsen score and of the small joints using the Sharp-van der Heijde score. With multivariate logistic regression analysis, an association between total damage of the small joints and of the large joints was investigated. RESULTS: After 8 years of treatment, damage was observed in 12% of shoulders, 10% of elbows, 26% of wrists, 13% of hips, 18% of knees and 7% of the ankles. Damage in one or more large joints was found in 64% of patients, with a median score of 1. No difference was found between initial monotherapy or combination therapy strategies. There was a significant association between damage progression in small joints and damage to one or more large joints (OR 1.02; 95% CI 1.00-1.04). CONCLUSION: After 8 years of DAS targeted treatment in early RA patients, large-joint damage was found in 64% of patients and was associated with small-joint damage. Continued DAS-targeted treatment is probably more important in damage suppression than initial treatment strategy. Patients with more damage to hands and feet also have more damage to the large joints. PMID- 22942404 TI - The efficacy of biologic agents in patients with rheumatoid arthritis and an inadequate response to tumour necrosis factor inhibitors: a systematic review. AB - OBJECTIVE: To assess the relative efficacy of subsequent biologic therapies in patients with RA who have had an inadequate response to prior therapy with a TNF alpha inhibitor. METHODS: A systematic review was conducted using the MEDLINE, Embase and Cochrane Library databases and abstract lists from the European League Against Rheumatism, American College of Rheumatology and British Society of Rheumatology congresses. Searches covered the period from May 2009 (August 2009 for MEDLINE) to January 2011. Therapies considered were abatacept, adalimumab, etanercept, infliximab and rituximab, used at European licensed standard dose regimens. RESULTS: Four full publications and 41 congress abstracts met the criteria for inclusion. Significant improvements in RA signs and symptoms were reported for TNF inhibitors (individual agents or groups of agents, depending on the study) and for abatacept and rituximab. Rituximab was also associated with significantly improved radiographic outcomes. No head-to-head randomized controlled trials directly comparing different agents were published during the search period. Comparative data from registries and other observational studies suggest that rituximab is at least as effective as an alternative TNF inhibitor, and in some studies significantly more effective, in TNF inadequate responders. CONCLUSIONS: RA patients with an inadequate response to one or more TNF inhibitors derive significant clinical benefit from subsequent therapy with an alternative TNF inhibitor or with rituximab or abatacept. Prospective randomized controlled trials are needed to help physicians in the best choice of further therapy for their patients. PMID- 22942405 TI - Individualized outcome measures of daily activities are sensitive tools for evaluating hand surgery in rheumatic diseases. AB - OBJECTIVES: To explore the ability of six outcome measures to capture clinically important changes in patients with rheumatic diseases undergoing hand surgery and to study predictors of changes in activity performance in different patient and surgery strata. METHODS: A total of 172 patients (median age 59 years, disease duration 18 years) were stratified into subgroups: diagnosis, age, general function, type of surgery. Performance of daily activities and satisfaction were assessed by the Canadian Occupational Performance Measure (COPM). Clinically important improvement was defined as a two-step improvement in COPM. Hand function was assessed by reference to grip strength (Grippit), pinch strength (pinch gauge), hand pain (visual analogue scale) and grip ability (Grip Ability Test). Responsiveness was calculated as effect size (ES) at 6-month follow-up compared with baseline. RESULTS: Clinically important improvement was reached by 25-69% depending on outcome measure and type of surgery. Improvement was smaller in patients with multiple simultaneous procedures. Regardless of diagnosis, age, general function and type of surgery, patients improved significantly in all measures, with the largest changes in COPM(performance) and COPM(satisfaction) (ES 0.7-1.9). The ES of pain ranged from 0.2 to 0.7, Grippit from 0.1 to 0.5 and pinch gauge from 0.4 to 0.8. Hand pain was the only significant predictor of clinically important improvement of COPM(performance): odds ratio 0.71, 95% CI 0.51, 0.98 (P = 0.041). CONCLUSION: COPM was the most sensitive instrument to capture clinically important improvement, and hand pain was a significant predictor of improvement, irrespective of diagnosis, age, general functional level and type of surgery. PMID- 22942406 TI - Welcoming a new cover and a new editor. PMID- 22942407 TI - Clinical reasoning in dentistry: a conceptual framework for dental education. AB - This study presents a conceptual framework for clinical reasoning by dental students. Using a think-aloud method with six vignettes, the researchers interviewed eighteen dental students from two stages of training about oral health-related problems influenced by biopsychosocial factors. Verbatim transcripts of the interviews were analyzed to identify the processes and strategies of clinical reasoning used by the students to produce treatment plans. The process included 1) rituals to collect information; 2) forward and backward reasoning to generate and test clinical hypotheses; 3) pattern recognition from integrated scripts of knowledge and experience; and 4) decision trees to assess options and outcomes. The process was supplemented by scientific, conditional, collaborative, narrative, ethical, pragmatic, and part-whole reasoning strategies. Senior students showed a keen awareness of the contextual determinants of care and emphasized patients' motivations for treatment. In contrast, junior students focused more on problems associated with individual teeth as they struggled to integrate the information within each vignette. In this article, the processes and strategies for reasoning used by both groups of dental students are abstracted and then illustrated by a model of clinical reasoning that accommodates the complicated contexts in which clinical problems usually arise. PMID- 22942408 TI - Dentistry and obesity: a review and current status in U.S. predoctoral dental education. AB - Obesity has become an epidemic and a public health concern in the United States and many other countries around the world. The impact of obesity on individuals' overall and oral health and its influence on dental treatment protocols and postoperative procedures have been well documented. It is therefore important for dentists to understand and recognize obesity, educate their patients on its associated risks, promote a healthy lifestyle for their patients, and modify any necessary dental treatments and postoperative procedures for obese patients. To investigate the current practice of obesity assessment in U.S. dental school clinics and the inclusion of obesity topics in predoctoral dental curricula, surveys were sent to all sixty-two U.S. dental schools. Thirty-five surveys were returned but one was blank because the institution is newly established, so the total number used for analysis was thirty-four. The results showed that the topic of obesity has been incorporated into predoctoral dental curricula and is thought to be important for dentists and dental students by most respondents. However, the majority do not routinely measure weight and height, nor calculate Body Mass Index for comprehensive care patients in their predoctoral dental clinics. The authors argue that the topic of obesity should be emphasized in predoctoral dental curricula and that assessments of obesity should be practiced in predoctoral dental clinics. PMID- 22942409 TI - Gender difference in ethical abilities of dental students. AB - Walker's comprehensive review of claims of gender difference and gender bias in moral cognition concluded 1) that gender explains a negligible amount of the variability in moral reasoning development, 2) that accumulated evidence does not support claims of gender polarity in moral orientations (i.e., an ethic of care and an ethic of justice), and 3) that future research should focus on the range of psychological processes that engender moral maturity. This study examined whether male and female predoctoral dental students who completed an ethics curriculum grounded in Rest's comprehensive model of moral functioning differed on measures of four capacities: moral sensitivity, moral reasoning, moral motivation, and moral implementation. From archival data at the University of Minnesota School of Dentistry, data on sixty females and sixty males were randomly selected from five cohorts (n=386) who completed an ethics curriculum and outcome measures of the four capacities between 1996 and 2000. Gender differences were not apparent for a measure of moral sensitivity, but were evident for one of the moral reasoning indices, for the responsibility dimension of moral motivation, and for the measure of moral implementation. Implications are drawn for future research and for professional ethics education. PMID- 22942411 TI - Leadership training for postdoctoral dental students. AB - Harvard School of Dental Medicine launched a course on leadership for its postdoctoral dental students in 2010 in order to introduce them to the art of leadership and the latest theories and principles regarding becoming a leader. Nine four-hour modules over a period of six months took the students on a journey of leadership self-exploration by building awareness of their capacity in core leadership skills; providing them with tools and frameworks for developing effective leadership skills; encouraging the immediate practice of core skills; creating space for honest reflection; and providing inspiration with guest lectures. A constant toggle between the present and their future as leaders was built into the course. In the student evaluations, the course received an overall rating of 4.71 (5=excellent), and the students reported an enhanced interest in all topic areas. They reported that the ability to build trust with others was the most beneficial skill for a dentist, while viewing advocacy skills as the least beneficial. All the students indicated an intention to continue developing their leadership skills. Through the course, the students developed an understanding of their leadership strengths and limitations through case studies, role-play, and self-reflection, as well as gaining an understanding of team dynamics and cultural perceptions in the context of dentistry. PMID- 22942410 TI - Patient and provider acceptance of oral HIV screening in a dental school setting. AB - In 2006, the Centers for Disease Control and Prevention (CDC) recommended routine HIV screening in health care settings regardless of the patient's level of risk. This pilot study was developed in response to the suggestion by some health care professionals that dental settings would be appropriate for expansion of HIV testing. This project consisted of two parts: oral fluid HIV testing of patients in the clinic of a dental school and a survey of the clinical dental faculty members' attitudes about acceptability of routine HIV testing in the dental clinic. When patients' agreement to participate in oral fluid HIV testing was examined, 8.2 percent of the patients contacted by the clinic administration staff completed testing. When approached by a faculty member or student during the dental visit admission and tested during the dental visit, however, 88.2 percent completed testing. Of the faculty members who took the survey, 27.4 percent were neutral, 26.4 percent were somewhat in agreement, and 32.1 percent were willing to incorporate HIV testing into routine dental care. In this pilot study, HIV testing of dental patients was most successful when a dental care provider approached patients about testing. If consent was given, the testing was performed during the visit. For the faculty members, the major barrier to testing was a lack of protocol familiarity. PMID- 22942412 TI - Relationship between broken appointments and dental students' clinical experience level. AB - As more dental schools adopt a comprehensive care model focused on patients' needs rather than a certain number of required procedures, clinic time utilization by students is coming under increasingly close scrutiny. This article presents an analysis of the influence of broken appointment rates on dental students' clinical experience levels. The total percentage of broken appointments experienced by each student from the classes of 2010 and 2011 at Case Western Reserve University School of Dental Medicine during his or her clinical education in the junior and senior years was determined, and the impact of the broken appointment rate on students' clinical experience levels was analyzed. The results show a statistically significant difference regarding the percentage of broken appointments between the classes of 2010 and 2011: 18.64 percent and 14.44 percent, respectively. When the rate of no-shows was compared to the students' clinical experience level, a weak but significant negative correlation was determined for the class of 2010 but not for the class of 2011. It is concluded that the rate of broken appointments accounts for a small part of the variability observed in the number of clinical procedures performed in the predoctoral clinic. When this rate is lowered below a threshold of 14.5 percent, broken appointments seem to have no influence on students' clinical experience level. PMID- 22942413 TI - Dental students' perceptions of self-efficacy and cultural competence with school based programs. AB - This study explored perceptions of first-year dental students' self-efficacy, cultural competence, and intent to provide care in school-based settings before and after the completion of an oral health educational rotation with inner-city public school children. The oral health educational rotation is mandatory for all first-year dental students at Marquette University School of Dentistry (MUSoD). Pre- and post-rotation surveys on perceptions of self-efficacy, cultural competence, and intent to provide care in school-based settings were administered online to first-year dental students at MUSoD. The pre- and post-rotation survey response rates were 75 percent and 70 percent, respectively. The percentages of students reporting a dentist as a family member in the pre and post surveys were 36.7 percent and 39.3 percent, respectively. Students who reported having a dentist as a family member had significantly higher adjusted odds for self efficacy (1.73, CI: 1.06-2.84) and cultural competence (2.03, 95 percent CI: 1.03 4.00). Dental students' participation in a mandatory oral health education rotation was associated with an increase in self-efficacy and cultural competence, but not with their intent to provide dental care in school-based settings. PMID- 22942414 TI - Identifying student misconceptions in biomedical course assessments in dental education. AB - Dental student performance on examinations has traditionally been estimated by calculating the percentage of correct responses rather than by identifying student misconceptions. Although misconceptions can impede student learning and are refractory to change, they are seldom measured in biomedical courses in dental schools. Our purpose was to determine if scaling student confidence and the clinical impact of incorrect answers could be used on multiple-choice questions (MCQs) to identify potential student misconceptions. To provide a measure of student misconception, faculty members indicated the correct answer on twenty clinically relevant MCQs and noted whether the three distracters represented potentially benign, inappropriate, or harmful application of student knowledge to patient treatment. A group of 105 third-year dental students selected what they believed was the most appropriate answer and their level of sureness (1 to 4 representing very unsure, unsure, sure, and very sure) about their answer. Misconceptions were defined as sure or very sure incorrect responses that could result in inappropriate or harmful clinical treatment. In the results, 5.2 percent of the answers represented student misconceptions, and 74 percent of the misconceptions were from four case-based interpretation questions. The mean student sureness was 3.6 on a 4.0 scale. The students' sureness was higher with correct than with incorrect answers (p<0.001), yet there was no difference in sureness levels among their incorrect (benign, inappropriate, or harmful) responses (p>0.05). This study found that scaling student confidence and clinical impact of incorrect answers provided helpful insights into student thinking in multiple-choice assessment. PMID- 22942415 TI - The educational value of online mastery quizzes in a human anatomy course for first-year dental students. AB - The purpose of this study was to evaluate the effectiveness of online mastery quizzes in enhancing dental students' learning and preparedness for anatomy examinations. First-year dental students taking an integrated anatomy course at The Ohio State University were administered online mastery quizzes, made available for five days before each examination. The mastery quizzes were comprised of ten multiple-choice questions representative of the upcoming examination in content and difficulty. The students were allowed to access this resource as many times as they desired during the five-day window before each examination; the highest score for each student was added to his or her final course grade. The results indicate that almost all the students took advantage of this resource to reinforce content, clarify concepts, and prepare for the examinations. Statistical analyses of the students' exam performance showed that the mastery quizzes neither improved nor reduced their exam scores, but multiple regression analyses showed that the initial mastery quiz scores had a predictive value for their examination performance, suggesting a potential for mastery quizzes as an intervention tool for such a course. Online mastery quizzes, when used effectively, may be an effective resource to further engage dental and other students in educational endeavors and examination preparation and as a predictor of success. PMID- 22942416 TI - Graduating grades and National Dental Examination results of foreign-trained and domestic dental students. AB - In this study, a comparison was made between the 1999-2009 graduates of the two year structured program for foreign trained dentists at the Schulich School of Dentistry, University of Western Ontario, Canada, and the school's four-year program for domestic students. Both the students' final-year course grades and their results on the National Dental Examining Board (NDEB) written examination and objective structured clinical examination (OSCE) were compared. Differences of >= 10 percent in mean final-year grades and >= 5 percent for each component of the NDEB examination were considered academically meaningful for the purpose of this analysis. Although there were no academically meaningful and statistically significant differences in the mean overall final-year course grades between the two-year and four-year classes, there were differences in individual courses in prosthodontics, oral medicine, and practice administration. There were no differences (>= 10 percent) in mean course grades since 2007. An academically meaningful difference in performance was observed on the NDEB written examination in three of the eleven years. There were no meaningful differences (>= 5 percent) between the two groups in any year for the NDEB OSCE. The relevance and implications of these findings to both the two-year structured program and the newly introduced alternative pathway to certification are discussed. PMID- 22942417 TI - A model of psychosocial work environment, stress, and satisfaction among dental students in Sweden. AB - Dental students are often described as stressed. The stress has, among other things, been connected to stressors in their psychosocial environment and inconsistent feedback. The hypothesis of this study was that the psychosocial work environment in dental schools leads to stress and affects the satisfaction of dental students and that tolerance for ambiguity shields students from stress. A web-based survey was sent to the entire Swedish dental student population in clinical training (N=805); the response rate was 40 percent. Structural equation modeling used in the analyses contains four main constructs: psychosocial work environment, tolerance for ambiguity, perceived stress, and student satisfaction (chi(2)=267.437, d.f.=174, p<0.001, Normed chi(2)=1.537, RMSEA= 0.041, CFI=0.98). Psychosocial work environment influenced both perceived stress and satisfaction: it accounted for almost all of the explained variance in perceived stress for women, while about half of the variance for the men was explained by tolerance for ambiguity. This study concluded that about 40 percent of the total perceived stress of these female dental students was related to their psychosocial work environment. Tolerance for ambiguity shielded men but not women from stress. An improved psychosocial work environment in dental schools would decrease the stress of both male and female dental students. PMID- 22942418 TI - Dental students' perceptions of community-based education: a retrospective study at a dental school in Brazil. AB - Community-based educational activities have been introduced into health education programs across the world. However, research on students' perceptions of their experiences in these settings has been limited. The objectives of this study were to assess a group of Brazilian dental students' views of their experiences in a service-learning program focusing on pediatric dental care and to explore changes in their perceptions over the course of the program. Data were collected from fifty-five fourth-year dental students, who submitted a total of 185 reports at four points in time. The students spent sixteen of the 128 hours of their pediatric dentistry course in community-based education developing activities linked to pediatric dental care. Two professors rated each report as a positive or negative experience (Kappa 0.7) and recorded whether the students' reports reflected one or more of five types of response. The response types concerned dental treatment practice, multidisciplinary activities, observation of infant/toddler consultations, commitment of the outreach health team, and change of plans due to technical problems. The data showed that the students had a positive first impression after a short stay in a community-service program, but there was a decrease in the students' positive experiences over time (p<0.001). The students' perceptions of the outreach health team as "being not committed" (OR 6.82, 95 percent CI 2.12-21.90) and experiences of a "no change of plans due to technical problems" (OR 0.09, 95 percent CI 0.04-0.20) associated with negative student experiences. PMID- 22942419 TI - Academic-service partnerships, research, and the South African dental academic. AB - In South Africa, academic dentistry is managed through joint agreements between the South African Department of Health (DoH) and each university, in a type of academic-service partnership. For this study, dental faculty members were surveyed to ascertain staff attitudes towards academic research in dental schools and to find out whether the joint arrangement impinges upon research activities. A survey was distributed to 200 members of the South African division of the International Association for Dental Research (SA IADR) and the academic staff of the four South African dental schools. One hundred and five responses were obtained for a response rate of 53 percent; most of the respondents were lecturers (26 percent), specialists (17 percent), heads of department (17 percent), or senior lecturers (13 percent). The majority were employed by the DoH (77 percent) and were members of the SA IADR (51 percent). Most reported feeling that research is an important issue in their school (83 percent) and perceived general research output had declined (59 percent). While 79 percent said they were concerned about the decline, many (71 percent) felt there was little they could do about it. The respondents mentioned the following as reasons for the decline: lackluster approach of DoH structures, weak university support, poor research equipment and facilities, inadequate funding, emphasis on service delivery, undergraduate teaching loads, onerous working conditions, and lack of vision, leadership, and governance by senior management. Faculty members' twin obligations of service delivery (required by the DoH) and teaching (required by their institutions) have severely impacted South African academic dental research. PMID- 22942420 TI - Continuing education in oral cancer prevention for dentists in Spain. AB - Continuing education (CE) can have a large impact on dentists' oral cancer attitudes, knowledge, and behavior. Reading scientific journals is a key component of CE. The objective of this study was to assess preventive and clinical attitudes of the participants in an educational intervention on oral cancer in Spain based on scientific journals. Members of the Spanish Board of Dentists and Stomatologists participated in an online, cross-sectional study, using an anonymous, self-administered questionnaire. There were 791 general dental practitioners (GDPs) invited to participate in the study. The large majority reported that they deliver tobacco-cessation counseling (93.6 percent) as well as advice on alcohol consumption (66.6 percent), but advice on vegetable intake was less frequently provided (42.4 percent). Alcohol intake advice, routine mucosa exploration, and biopsy performance on lesions suspicious of malignancy are preventive attitudes related to training. Compared with those who did not benefit from CE courses or did so only once, the GDPs who took four or more CE courses showed a doubling in the odds of giving alcohol advice to their patients and a tenfold increased odds of performing mucosa check on a routine basis; they were 3.5 times as likely to take biopsies of suspicious lesions. A longer experience as a GDP did not increase the probability of adopting preventive attitudes. In addition to presenting the results of this study, the article also discusses the general usefulness of other preventive measures in oral cancer. PMID- 22942421 TI - Sociodemographic profile and career decisions of Australian oral health profession students. AB - This study collected and analyzed recent information regarding the sociodemographic profile and career decisions of Australian oral health profession students (earning B.D.Sc. and B.O.H. degrees) and the reasons for their career choice. Data were collected during the 2009-10 academic year via a web-based survey. A total of 829 students participated; the response rates for each oral health course at the seven participating universities ranged from 15.0 percent to 88.7 percent. The respondents had an average age of 21.4 years, ranging from eighteen to fifty-one. The majority of the respondents were female (61.4 percent), single (91.0 percent), and of Asian ethnicity (65.0 percent), and almost half had attended a public secondary school (49.7 percent). Most of the responding students either lived in rented accommodation (44.0 percent) or with their parents (28.6 percent), and 41.5 percent reported having an urban address. Most respondents' fathers (67.2 percent) and mothers (54.8 percent) had completed undergraduate or postgraduate education and were employed in managerial or professional occupations (68.5 percent and 54.9 percent, respectively). Most of the students said they had selected their course in high school (66.8 percent) and were most influenced in their career choice by self-motivation (85.3 percent) and caring for and helping other people (86.6 percent). The majority of the respondents reported wishing to work in a city (51.5 percent), practicing general dentistry (31.8 percent) in either the public or private sector (40.2 percent each). This article provides a preliminary look at the future dental workforce of Australia, identifying issues for further analysis and assisting each university to address current inequalities and challenges. PMID- 22942422 TI - Epithelial cell-derived IL-25, but not Th17 cell-derived IL-17 or IL-17F, is crucial for murine asthma. AB - IL-17A, IL-17F, and IL-25 are ligands for IL-17RA. In the current study, we demonstrated that IL-25-deficient mice-but not IL-17A-, IL-17F-, IL-17A/F-, IL 23p19-, or retinoic acid-related orphan receptor (ROR)-gammat-deficient mice showed significant suppression of 1) the number of eosinophils and the levels of proinflammatory mediators in bronchoalveolar lavage fluids, 2) airway hyperresponsiveness to methacholine, and 3) OVA-specific IgG1 and IgE levels in the serum during OVA-induced Th2-type/eosinophilic airway inflammation. The IL-25 deficiency did not affect lung dendritic cell migration or Ag-specific memory-Th2 cell expansion during Ag sensitization. Adoptive transfer of T cells, mast cells, or bone marrow cells from IL-25-deficient mice revealed that induction of Th2 type/eosinophilic airway inflammation was dependent on activation of lung epithelial cells and eosinophils by IL-25 produced by airway structural cells such as epithelial cells but not by such hematopoietic stem-cell-origin immune cells as T cells and mast cells. Therefore, airway structural cell-derived IL-25 rather than Th17 cell-derived IL-17A and IL-17F-is responsible for induction of local inflammation by promoting activation of lung epithelial cells and eosinophils in the elicitation phase of Th2-type/eosinophilic airway inflammation. It is not required for Ag-specific Th2 cell differentiation in the sensitization phase. PMID- 22942423 TI - The small ubiquitin-like modifier-deconjugating enzyme sentrin-specific peptidase 1 switches IFN regulatory factor 8 from a repressor to an activator during macrophage activation. AB - Macrophages, when activated by IFN-gamma and TLR signaling, elicit innate immune responses. IFN regulatory factor 8 (IRF8) is a transcription factor that facilitates macrophage activation and innate immunity. We show that, in resting macrophages, some IRF8 is conjugated to small ubiquitin-like modifiers (SUMO) 2/3 through the lysine residue 310. SUMO3-conjugated IRF8 failed to induce IL12p40 and other IRF8 target genes, consistent with SUMO-mediated transcriptional repression reported for other transcription factors. SUMO3-conjugated IRF8 showed reduced mobility in live nuclei and bound poorly to the IL12p40 gene. However, macrophage activation caused a sharp reduction in the amount of SUMOylated IRF8. This reduction coincided with the induction of a deSUMOylating enzyme, sentrin specific peptidase 1 (SENP1), in activated macrophages. In transfection analysis, SENP1 removed SUMO3 from IRF8 and enhanced expression of IL12p40 and other target genes. Conversely, SENP1 knockdown repressed IRF8 target gene expression. In parallel with IRF8 deSUMOylation, macrophage activation led to the induction of proteins active in the SUMO pathway and caused a global shift in nuclear protein SUMOylation patterns. Together, the IRF8 SUMO conjugation/deconjugation switch is part of a larger transition in SUMO modifications that takes place upon macrophage activation, serving as a mechanism to trigger innate immune responses. PMID- 22942424 TI - Dendritic cell activation and memory cell development are impaired among mice administered medroxyprogesterone acetate prior to mucosal herpes simplex virus type 1 infection. AB - Epidemiological studies indicate that the exogenous sex steroid medroxyprogesterone acetate (MPA) can impair cell-mediated immunity, but mechanisms responsible for this observation are not well defined. In this study, MPA administered to mice 1 wk prior to HSV type 1 (HSV-1) infection of their corneal mucosa impaired initial expansion of viral-specific effector and memory precursor T cells and reduced the number of viral-specific memory T cells found in latently infected mice. MPA treatment also dampened expression of the costimulatory molecules CD40, CD70, and CD80 by dendritic cells (DC) in lymph nodes draining acute infection, whereas coculture of such DC with T cells from uninfected mice dramatically impaired ex vivo T cell proliferation compared with the use of DC from mice that did not receive MPA prior to HSV-1 infection. In addition, T cell expansion was comparable to that seen in untreated controls if MPA-treated mice were administered recombinant soluble CD154 (CD40L) concomitant with their mucosal infection. In contrast, the immunomodulatory effects of MPA were infection site dependent, because MPA-treated mice exhibited normal expansion of virus-specific T cells when infection was systemic rather than mucosal. Taken together, our results reveal that the administration of MPA prior to viral infection of mucosal tissue impairs DC activation, virus-specific T cell expansion, and development of virus-specific immunological memory. PMID- 22942425 TI - Inducible tertiary lymphoid structures, autoimmunity, and exocrine dysfunction in a novel model of salivary gland inflammation in C57BL/6 mice. AB - Salivary glands in patients with Sjogren's syndrome (SS) develop ectopic lymphoid structures (ELS) characterized by B/T cell compartmentalization, the formation of high endothelial venules, follicular dendritic cell networks, functional B cell activation with expression of activation-induced cytidine deaminase, as well as local differentiation of autoreactive plasma cells. The mechanisms that trigger ELS formation, autoimmunity, and exocrine dysfunction in SS are largely unknown. In this article, we present a novel model of inducible ectopic lymphoid tissue formation, breach of humoral self-tolerance, and salivary hypofunction after delivery of a replication-deficient adenovirus-5 in submandibular glands of C57BL/6 mice through retrograde excretory duct cannulation. In this model, inflammation rapidly and consistently evolves from diffuse infiltration toward the development of SS-like periductal lymphoid aggregates within 2 wk from AdV delivery. These infiltrates progressively acquire ELS features and support functional GL7(+)/activation-induced cytidine deaminase(+) germinal centers. Formation of ELS is preceded by ectopic expression of lymphoid chemokines CXCL13, CCL19, and lymphotoxin-beta, and is associated with development of anti-nuclear Abs in up to 75% of mice. Finally, reduction in salivary flow was observed over 3 wk post-AdV infection, consistent with exocrine gland dysfunction as a consequence of the inflammatory response. This novel model has the potential to unravel the cellular and molecular mechanisms that regulate ELS formation and their role in exocrine dysfunction and autoimmunity in SS. PMID- 22942426 TI - Efficient clearance of early apoptotic cells by human macrophages requires M2c polarization and MerTK induction. AB - Mer tyrosine kinase (MerTK) is a major macrophage apoptotic cell (AC) receptor. Its functional impairment promotes autoimmunity and atherosclerosis, whereas overexpression correlates with poor prognosis in cancer. However, little is known about mechanisms regulating MerTK expression in humans. We found that MerTK expression is heterogenous among macrophage subsets, being mostly restricted to anti-inflammatory M2c (CD14(+)CD16(+)CD163(+)CD204(+)CD206(+)CD209(-)) cells, differentiated by M-CSF or glucocorticoids. Small numbers of MerTK(+) "M2c-like" cells are also detectable among circulating CD14(bright)CD16(+) monocytes. MerTK expression levels adapt to changing immunologic environment, being suppressed in M1 and M2a macrophages and in dendritic cells. Remarkably, although glucocorticoid-induced differentiation is IL-10 independent, M-CSF-driven M2c polarization and related MerTK upregulation require IL-10. However, neither IL-10 alone nor TGF-beta are sufficient to fully differentiate M2c (CD16(+)CD163(+)MerTK(+)) macrophages. M-CSF and IL-10, both released by T lymphocytes, may thus be required together to promote regulatory T cell-mediated induction of anti-inflammatory monocytes-macrophages. MerTK enables M2c macrophages to clear early ACs more efficiently than other macrophage subsets, and it mediates AC clearance by CD14(bright)CD16(+) monocytes. Moreover, M2c cells release Gas6, which in turn amplifies IL-10 secretion via MerTK. IL-10 dependent induction of the Gas6/MerTK pathway may, therefore, constitute a positive loop for M2c macrophage homeostasis and a critical checkpoint for maintenance of anti-inflammatory conditions. Our findings give new insight into human macrophage polarization and favor a central role for MerTK in regulation of macrophage functions. Eliciting M2c polarization can have therapeutic utility for diseases such as lupus, in which a defective AC clearance contributes to initiate and perpetuate the pathological process. PMID- 22942428 TI - Lyn signaling to upregulate GANP is critical for the survival of high-affinity B cells in germinal centers of lymphoid organs. AB - Signals through BCR and costimulatory molecules play essential roles in selecting high-affinity B cells with Ig V-region mutations in the germinal centers (GCs) of peripheral lymphoid organs. Lyn-deficient (lyn(-/-)) mice show impaired BCR signal triggering for cell proliferation and GC formation, causing hyper-IgM, and display autoimmunity after aging. In this study, we demonstrate that Lyn-mediated signaling to upregulate GANP is essential for the survival of mature GC-like (mGC) B cells with high-affinity type BCR mutations upon Ag immunization. Transgenic ganp expression into lyn(-/-) mice did not recover the Lyn-deficient phenotype with regard to B cell differentiation, serum Igs, and impaired GC formation in spleens after immunization with nitrophenyl-chicken gamma-globulin, but it markedly rescued cell survival of mGC B cells by suppressing DNA damage, thereby increasing the frequency of the Trp(33)-to-Leu mutation in the IgV(H) 186.2 region and affinity maturation of nitrophenyl-binding B cells. GANP may play a critical role in Lyn-mediated signaling for the selection of high-affinity B cells in peripheral lymphoid organs. PMID- 22942427 TI - Bone marrow dendritic cell-mediated regulation of TLR and B cell receptor signaling in B cells. AB - Dendritic cells (DCs) play an essential role in regulation of immune responses. In the periphery, Ag presentation by DCs is critical for adaptive responses; for this reason, DCs are often targets of adjuvants that enhance vaccine responses. Activated mature DCs enhance B cell activation and differentiation by providing cytokines like BAFF and a proliferation-inducing ligand. However, the role of immature DCs in B cell tolerance is not well studied. Recently, mouse immature bone marrow-derived DCs (iBMDCs) have been shown to suppress anti-IgM-induced B cell activation. In this study, we tested the ability of mouse DCs to modulate B cell functions during TLR activation. We found that iBMDCs potently suppressed proliferation and differentiation of various B cell subsets on TLR stimulation. However, iBMDCs did not affect CD40-mediated B cell activation. Optimal suppression of B cell activation by iBMDCs required cell contact via the CD22 receptor on B cells. The B cell suppression was a property of iBMDCs or DCs resident in the bone marrow (BM), but not mature BM-derived DCs or DCs resident in the spleen. Presence of iBMDCs also enhanced the Ag-induced apoptotic response of BM B cells, suggesting that the suppressive effects of iBMDCs may have a role in B cell tolerance. PMID- 22942429 TI - Lack of the lectin-like domain of thrombomodulin worsens Shiga toxin-associated hemolytic uremic syndrome in mice. AB - Shiga toxin (Stx)-producing Escherichia coli is a primary cause of diarrhea associated hemolytic uremic syndrome (HUS), a disorder of thrombocytopenia, microangiopathic hemolytic anemia, and acute renal failure. The pathophysiology of renal microvascular thrombosis in Stx-HUS is still ill-defined. Based on evidence that abnormalities in thrombomodulin (TM), an anticoagulant endothelial glycoprotein that modulates complement and inflammation, predispose to atypical HUS, we assessed whether impaired TM function may adversely affect evolution of Stx-HUS. Disease was induced by coinjection of Stx2/LPS in wild-type mice (TM(wt/wt)) and mice that lack the lectin-like domain of TM (TM(LeD/LeD)), which is critical for its anti-inflammatory and cytoprotective properties. After Stx2/LPS, TM(LeD/LeD) mice exhibited more severe thrombocytopenia and renal dysfunction than TM(wt/wt) mice. Lack of lectin-like domain of TM resulted in a stronger inflammatory reaction after Stx2/LPS with more neutrophils and monocytes/macrophages infiltrating the kidney, associated with PECAM-1 and chemokine upregulation. After Stx2/LPS, intraglomerular fibrin(ogen) deposits were detected earlier in TM(LeD/LeD) than in TM(wt/wt) mice. More abundant fibrin(ogen) deposits were also found in brain and lungs. Under basal conditions, TM(LeD/LeD) mice exhibited excess glomerular C3 deposits, indicating impaired complement regulation in the kidney that could lead to local accumulation of proinflammatory products. TM(LeD/LeD) mice with HUS had a higher mortality rate than TM(wt/wt) mice. If applicable to humans, these findings raise the possibility that genetic or acquired TM defects might have an impact on the severity of microangiopathic lesions after exposure to Stx-producing E. coli infections and raise the potential for using soluble TM in the treatment of Stx HUS. PMID- 22942430 TI - Negative regulation of NKG2D expression by IL-4 in memory CD8 T cells. AB - IL-4 is one of the main cytokines produced during Th2-inducing pathologies. This cytokine has been shown to affect a number of immune processes such as Th differentiation and innate immune responses. However, the impact of IL-4 on CD8 T cell responses remains unclear. In this study, we analyzed the effects of IL-4 on global gene expression profiles of Ag-induced memory CD8 T cells in the mouse. Gene ontology analysis of this signature revealed that IL-4 regulated most importantly genes associated with immune responses. Moreover, this IL-4 signature overlapped with the set of genes preferentially expressed by memory CD8 T cells over naive CD8 T cells. In particular, IL-4 downregulated in vitro and in vivo in a STAT6-dependent manner the memory-specific expression of NKG2D, thereby increasing the activation threshold of memory CD8 T cells. Furthermore, IL-4 impaired activation of memory cells as well as their differentiation into effector cells. This phenomenon could have an important clinical relevance as patients affected by Th2 pathologies such as parasitic infections or atopic dermatitis often suffer from viral-induced complications possibly linked to inefficient CD8 T cell responses. PMID- 22942431 TI - TCR bias and HLA cross-restriction are strategies of human brain-infiltrating JC virus-specific CD4+ T cells during viral infection. AB - Virus-specific CD4(+) T cells play a central role in control of viral pathogens including JC polyoma virus (JCV) infection. JCV is a ubiquitous small DNA virus that leads to persistent infection of humans with no clinical consequences. However, under circumstances of immunocompromise, it is able to cause an opportunistic and often fatal infection of the brain called progressive multifocal leukoencephalopathy (PML). PML has emerged as a serious adverse event in multiple sclerosis patients treated with the anti-VLA-4 mAb natalizumab, which selectively inhibits cell migration across the blood-brain barrier and the gut's vascular endothelium thus compromising immune surveillance in the CNS and gut. In a multiple sclerosis patient who developed PML under natalizumab treatment and a vigorous immune response against JCV after Ab washout, we had the unique opportunity to characterize in detail JCV-specific CD4(+) T cell clones from the infected tissue during acute viral infection. The in-depth analysis of 14 brain infiltrating, JCV-specific CD4(+) T cell clones demonstrated that these cells use an unexpectedly broad spectrum of different strategies to mount an efficient JCV specific immune response including TCR bias, HLA cross-restriction that increases avidity and influences in vivo expansion, and a combination of Th1 and Th1-2 functional phenotypes. The level of combinatorial diversity in TCR- and HLA peptide interactions used by brain-infiltrating, JCV-specific CD4(+) T cells has not, to our knowledge, been reported before in humans for other viral infections and confirms the exceptional plasticity that characterizes virus-specific immune responses. PMID- 22942432 TI - Selective sequestration of STAT1 in the cytoplasm via phosphorylated SHP-2 ameliorates murine experimental colitis. AB - The side effects of current immunosuppressive drugs have impeded the development of therapies for immune diseases. Selective regulation of STAT signaling is an attractive strategy for treating immune disorders. In this study, we used a small molecule compound to explore possible means of targeting STAT1 for the treatment of Th1-mediated inflammation. Selective regulation of STAT1 signaling in T cells from C57BL/6 mice was accomplished using fusaruside, a small-molecule compound that triggers the tyrosine phosphorylation of Src homology 2-containing protein tyrosine phosphatase 2 (SHP-2). The interaction of tyrosine phosphorylated SHP-2 (pY-SHP-2) with cytosolic STAT1 prevented the recruitment of STAT1 to IFN-gammaR and specifically inhibited STAT1 signaling, resulting in a reduction in Th1 cytokine production and an improvement in 2, 4, 6-trinitrobenzene sulfonic acid induced colitis in mice. Blocking the pY-SHP-2-STAT1 interaction, with SHP-2 inhibitor NSC-87877 or using T cells from conditional SHP-2 knockout mice, reversed the effects of fusaruside, resulting in STAT1 activation and worsened colitis. The fusaruside-induced ability of pY-SHP-2 to selectively sequestrate STAT1 from recruitment to the receptor is independent of its function as a phosphatase, demonstrating a novel role for SHP-2 in regulating both STAT1 signaling and Th1-type immune responses. These findings could lead to increased options for the treatment of Crohn's disease and other Th1-mediated inflammatory diseases. PMID- 22942433 TI - Calcium/calmodulin-dependent protein kinase IV suppresses IL-2 production and regulatory T cell activity in lupus. AB - The activity of calcium/calmodulin-dependent protein kinase IV (CaMK4) is increased in T cells from patients with systemic lupus erythematosus (SLE) and has been shown to reduce IL-2 production by promoting the effect of the transcriptional repressor cAMP responsive element modulator-alpha on the IL2 promoter. In this article, we demonstrate that T cells from MRL/lpr mice display increased levels of CaMK4 in the nucleus, and that genetic deletion of Camk4 results in improved survival. We demonstrate that absence of CaMK4 restores IL-2 production, curbs increased T cell activation, and augments the number and activity of regulatory T cells. Analogously, silencing of CaMK4 in T cells from patients with SLE increases the expression of FoxP3 on stimulation in the presence of TGF-beta. Our results demonstrate the importance of the serine/threonine kinase CaMK4 in the generation and function of regulatory T cells in patients with SLE and lupus-prone mice, and its potential to serve as a therapeutic target. PMID- 22942434 TI - Cutting edge: Kruppel-like factor 2 is required for phenotypic maintenance but not development of B1 B cells. AB - Several recent studies reported that Kruppel-like factor (KLF)2 controls trafficking, development, and function of B cells. Conditional B cell KLF2 knockout mice have increased numbers of marginal zone B cells and decreased numbers of B1 phenoytpe cells. However, it was unclear whether KLF2 is required for B1 B cell development, survival, or phenotypic maintenance. We show that B1 phenotype B cells are present in neonatal mice with B cell-specific KLF2 deficiency, suggesting that B1 differentiation can occur even in the absence of KLF2. Furthermore, by use of an inducible knockout strategy, we show that deletion of KLF2 in mature B1 cells causes loss of phenotypic markers associated with B1 cell identity, but it has a minimal effect on short-term cell survival. Taken together, our findings suggest that KLF2 is necessary for the maintenance of B1 cell identity rather than differentiation or survival of the population. PMID- 22942436 TI - Parametric modulation of an atomic magnetometer. AB - The authors report on a rubidium atomic magnetometer designed for use in a shielded environment. Operating in the spin-exchange relaxation-free regime, the magnetometer utilizes parametric modulation of the z-magnetic field to suppress noise associated with airflow through the oven and to simultaneously detect x- and y-field components, using a single probe beam, with minimal loss of sensitivity and bandwidth. A white noise level of 60 fT/(Hz)(1/2) was achieved. PMID- 22942437 TI - A framework that will benefit all. PMID- 22942435 TI - Cyanovirin-N inhibits mannose-dependent Mycobacterium-C-type lectin interactions but does not protect against murine tuberculosis. AB - Cyanovirin-N (CV-N) is a mannose-binding lectin that inhibits HIV-1 infection by blocking mannose-dependent target cell entry via C-type lectins. Like HIV-1, Mycobacterium tuberculosis expresses mannosylated surface structures and exploits C-type lectins to gain cell access. In this study, we investigated whether CV-N, like HIV-1, can inhibit M. tuberculosis infection. We found that CV-N specifically interacted with mycobacteria by binding to the mannose-capped lipoglycan lipoarabinomannan. Furthermore, CV-N competed with the C-type lectins DC-SIGN and mannose receptor for ligand binding and inhibited the binding of M. tuberculosis to dendritic cells but, unexpectedly, not to macrophages. Subsequent in vivo infection experiments in a mouse model demonstrated that, despite its activity, CV-N did not inhibit or delay M. tuberculosis infection. This outcome argues against a critical role for mannose-dependent C-type lectin interactions during the initial stages of murine M. tuberculosis infection and suggests that, depending on the circumstances, M. tuberculosis can productively infect cells using different modes of entry. PMID- 22942438 TI - Veterinary medical ethics. An ethicist's commentary on UEP/HSUS Agreement. PMID- 22942439 TI - Iron deficiency anemia. AB - Iron is essential to virtually all living organisms and is integral to multiple metabolic functions. The most important function is oxygen transport in hemoglobin. Iron deficiency anemia in dogs and cats is usually caused by chronic blood loss and can be discovered incidentally as animals may have adapted to the anemia. Severe iron deficiency is characterized by a microcytic, hypochromic, potentially severe anemia with a variable regenerative response. Iron metabolism and homeostasis will be reviewed, followed by a discussion of diagnostic testing and therapeutic recommendations for dogs and cats with iron deficiency anemia. PMID- 22942440 TI - Efficacy and safety of 3 versus 5 days of meloxicam as an analgesic for feline onychectomy and sterilization. AB - Three- or 5-day courses of meloxicam [0.2 mg/kg body weight (BW) subcutaneously pre- or postoperatively on Day 1 followed by 0.05 mg/kg BW, PO per day thereafter] were assessed for analgesic efficacy and safety in 50 client-owned cats undergoing onychectomy and sterilization. Primary outcome parameters were analgesia score, gait/lameness score, and need for rescue analgesia assessed at times 0, 1, 4, 7, 24, 28, 35, 48, 52, 57 hours and on Day 5. Packed cell volume/total solids and serum biochemistry were assessed at time 0 and Days 3 and 5. There were no differences in efficacy and safety parameters regardless of the treatment protocol employed and no cat required rescue analgesia. The patients that received meloxicam preoperatively had statistically better gait/lameness scores than those that received meloxicam postoperatively, supporting the principle of preemptive analgesia. PMID- 22942441 TI - Columbid herpesvirus-1 mortality in great horned owls (Bubo virginianus) from Calgary, Alberta. AB - Four cases of Columbid herpesvirus-1 infection in great horned owls (Bubo virginianus) were identified in Calgary, Alberta. Necropsy findings included severe multifocal hepatic and splenic necrosis, pharyngeal ulceration and necrosis, and gastrointestinal necrosis. Occasional eosinophilic intranuclear viral inclusion bodies were associated with the foci of necrosis and polymerase chain reaction (PCR) testing confirmed a diagnosis of herpesvirus-induced disease. The sequence of a PCR amplicon had 99.7% homology to Columbid herpesvirus-1. PMID- 22942442 TI - Congenital duplex gallbladder and biliary mucocele associated with partial hepatic cholestasis and cholelithiasis in a cat. AB - A 6-year-old neutered male domestic shorthair cat was presented for acute onset of vomiting. Exploratory laparotomy identified a duplex gallbladder and left cholecystectomy was performed. Histopathology confirmed biliary mucocele and hepatic cholestasis. While rare, biliary mucoceles should be considered as a differential diagnosis for feline extrahepatic bile duct obstruction. PMID- 22942443 TI - Acute intraparenchymal spinal cord injury in a cat due to high-rise syndrome. AB - A 9-year-old spayed female Bengal Red cat was evaluated for high-rise syndrome. The cat had paraplegia of the hind limbs, intact reflexes and pain perception, and hyperesthesia in the caudal thoracic area. Mentation, cranial nerve function, forelimb proprioceptive responses, and spinal reflexes were normal. There were no abnormalities on radiographs or computed tomography scan, but magnetic resonance imaging revealed a hyperintense intraparenchymal spinal cord lesion on T2 weighted and T2 fat saturation images. PMID- 22942444 TI - Healing of multiple fractured thoracic dorsal spinous processes in a Quarter horse. AB - A Quarter horse gelding sustained fracture and displacement of spinous processes T2-T10. Radiographic evidence of healing was seen 3 mo following injury, and at 2 years post-injury all spinous processes had healed and undergone partial re alignment. This re-alignment has not been reported before. PMID- 22942445 TI - Bovine leukemia virus infection in a juvenile alpaca with multicentric lymphoma. AB - A 13-month-old alpaca (Vicugna pacos) was presented for mandibular masses and weight loss. Histopathology of biopsy tissue was consistent with lymphoma. The alpaca was euthanized and necropsy revealed lymphoma masses in multiple organs. Immunohistochemistry for T- and B-cell typing was inconclusive. Serology and in situ polymerase chain reaction hybridization were positive for bovine leukemia virus. PMID- 22942446 TI - Use of a laryngeal mask airway in a brachycephalic dog with masticatory myositis and trismus. AB - An 8-month old, male, neutered bulldog was presented for investigation of a 2-day history of trismus. Endotracheal intubation was impossible as the dog was only able to open his mouth approximately 2 cm. A laryngeal mask airway was blindly inserted after induction of general anesthesia to maintain the patient on inhalational anesthesia and improve respiration for computed tomography and muscle biopsy. The dog recovered from anesthesia uneventfully. PMID- 22942447 TI - Out-patient antimicrobial drug use in dogs and cats for new disease events from community companion animal practices in Ontario. AB - This study investigated oral and parenteral antimicrobial use in dogs and cats, and evaluated antimicrobial use in feline upper respiratory tract disease (FURTD), feline lower urinary tract disease (FLUTD), and canine infectious tracheobronchitis. Study journals (n = 1807) were submitted by 84 veterinarians. Sixty-five percent of the antimicrobials prescribed in dogs and 67% in cats were beta-lactams. Most frequently prescribed in dogs were cephalexin (33%) and amoxicillin-clavulanic acid (16%), and in cats, amoxicillin-clavulanic acid (40%) and cefovecin (17%); 7% of the prescriptions in dogs and 12% in cats were for fluoroquinolones. Sixty-seven percent of the disease events associated with canine infectious tracheobronchitis, and 70% and 74% associated with FURTD and FLUTD, respectively, were treated with antimicrobials. These results suggest that cefovecin and fluoroquinolones may be over-used and antimicrobial use for the treatment of FURTD, FLUTD, and canine infectious tracheobronchitis could probably be reduced to lessen resistance selection pressure without compromising patient health. PMID- 22942448 TI - Open-drop anesthesia for small laboratory animals. AB - This study examined the effect of temperature on volatile concentrations of 2 inhalant anesthetics, isoflurane (ISO) and sevoflurane (SEVO), delivered via open drop technique, as well as the characteristics of induction and recovery using the open-drop method in mice. Testing revealed that temperature had no effect on the volatile concentration of either ISO or SEVO. However, it was determined that open-drop delivery of ISO or SEVO is a viable means of anesthetizing mice under certain conditions. The volatile concentration required to induce anesthesia in mice following the application of 0.5 mL of anesthetic in an induction chamber of 725 mL volume at 87.6 kPa and 20 degrees C was measured with a precision gas analyzer. For ISO, anesthesia was induced at concentrations of 6.80 +/- 0.57% [mean +/- standard deviation (s)] after 35.70 +/- 6.95 s (n = 10), while SEVO induction took significantly longer (45.50 +/- 9.96 s) and required higher volatile concentrations [7.41 +/- 0.57% (n = 10)]. The animals recovered rapidly from both ISO and SEVO-based induction. PMID- 22942449 TI - Cystotomy practices and complications among general small animal practitioners in Ontario, Canada. AB - Cystotomy is a common surgical procedure in small animal veterinary medicine, yet common pre-, intra-, and post-operative practices have not been described. This survey evaluated cystotomy practices of 106 veterinarians in Ontario. The majority of respondents reported practices consistent with standard recommendations, but some deficiencies in antimicrobial and analgesic use, as well as intra- and post-operative practices, were identified. Some factors associated with the likelihood that practitioners reported recurrent urolithiasis or urinary tract infection are contrary to typical recommendations, such as the association of the use of absorbable, multifilament suture or a dorsal (versus ventral) incision and a lesser likelihood of reporting post-operative urinary tract infections. While care must be taken interpreting these statistical associations, the results suggest that objective assessment of common cystotomy recommendations (use of monofilament, absorbable suture) is required. Re assessment of certain peri-operative practices, such as analgesic and antimicrobial administration, and post-operative testing, is required for a minority of practitioners. PMID- 22942451 TI - Active number of clients down nationally. PMID- 22942450 TI - Assessing fitness in endurance horses. AB - A field test and a standardized treadmill test were used to assess fitness in endurance horses. These tests discriminated horses of different race levels: horses participating in races of 120 km and more showed higher values of VLA4 (velocity at which blood lactate reached 4 mmol/L) and V200 (velocity at which heart rates reached 200 beats per min) than horses of lower race levels. PMID- 22942452 TI - Diagnostic ophthalmology. PMID- 22942453 TI - Sexual and reproductive health in Accra, Ghana. AB - OBJECTIVE: To describe sexual and reproductive health among women in Accra and explore the burden of sexual and reproductive ill health among this urban population. DESIGN: Cross-sectional study. METHODS: We analysed data from the WHSA-II (n=2814), a cross-sectional household survey on women's health, and supplemental data from an in-depth survey (n=400), focus groups discussions (n=22) and in-depth interviews (n=20) conducted among a sub-sample of women which focused specifically on reproductive health issues. RESULTS: Modern contraceptive use was uncommon. More than one third of women reported ever using abstinence; condoms, injectables and the pill were the most commonly reported modern methods ever used. The total fertility rate among this sample of women was just 2.5 births. We found a considerable burden of sexual and reproductive ill health; one in ten women reported menstrual irregularities and almost one quarter of women reported symptoms of a Sexually Transmitted Infection (STI) or Reproductive Tract Infection (RTI) in the past 6 months. Focus group results and in-depth interviews reveal misperceptions about contraception side-effects and a lack of information. CONCLUSION: In urban Ghana, modern contraceptive use is low and a significant proportion of women experience reproductive ill health (defined here as menstrual irregularity or RTI, UTI, STI symptoms). Increased access to information, products and services about for preventive care and contraception could improve reproductive health. More research on healthy sexuality and the impact of reproductive ill health on sexual experience is needed. PMID- 22942454 TI - Prevalence of overweight and obesity and perception of healthy and desirable body size in urban, Ghanaian women. AB - OBJECTIVE: To determine if the perceived ideal body size of urban women in Accra, Ghana influences current body size. METHODS: The sample (n=2,814) consisted of Ghanaian women aged 18 years and older, living in the Accra Metropolitan Area. Data were collected between October 2008 and June 2009 in the Women's Health Study of Accra, Wave II household survey. Height (m), weight (kg), waist (cm) and hip (cm) measurements were used to calculate body mass index (BMI, measured in kg/m(2)), waist circumference, and waist-to-hip ratio. In addition to reported socio-demographic characteristics, medical history, and exercise and diet history, the standardized Stunkard Figure Rating Scale (FRS) was used to identify silhouettes of varying body sizes that most closely resemble a woman's current body image (CBI), the body image she sees as the ideal for Ghanaian women (IBI), and the body image she sees as healthiest (HBI). The validity of using the standardized Stunkard FRS to assess body image in a population of Ghanaian women was assessed using Receiver Operating Curve (ROC) analysis. Household wealth, a proxy for income, was assessed using an index derived by principal components analysis from a selection of 20 variables measuring quality of the dwelling (e.g water source, sewage arrangements, type of housing, roof etc.) and possession of household durable goods (e.g. television, radio, iron, refrigerator and car).1 Logistic and linear regression was used to test the association between various socio-demographic characteristics, BMI and body image satisfaction. RESULTS: Using the WHO criteria for BMI, 3.6% (95) of women were underweight, 31.5% (828) normal weight, 27.8% (730) overweight and 37.1% (973) obese. In total, 64.9% of women sampled were either overweight or obese. A WC of greater than 88 cm revealed 78.7% (2,113) obesity. A WHR cut-off for obesity of 0.8 revealed 78.9% (2,119) obesity. ROC analysis confirmed the validity of using the standardized Stunkard FRS to assess body image in a population of Ghanaian women. Age, relative wealth, being married, having grown up in an urban environment and having parity >2 are associated with higher risk of overweight or obesity. Education level is not associated with overweight status. Overall, 72.2% (1,936) of women were dissatisfied with their current body size and 41.8% of women preferred a smaller figure. Overweight and obese women were significantly more likely than normal weight women to desire weight loss (OR: 10.12, CI: 8.04 - 12.72). CONCLUSION: Ideal body image in urban, Ghanaian women should not be viewed as an inhibitor to healthy weight maintenance. Interventions should be designed to help women achieve their ideal and healthy weights. PMID- 22942455 TI - The effect of Ghana's National Health Insurance Scheme on health care utilisation. AB - OBJECTIVES: The study investigates the effect of Ghana's National Health Insurance Scheme (NHIS) on health care utilisation. METHODS: We provide a short history of health insurance in Ghana, and briefly discuss general patterns of enrolment in Ghana as well as in Accra in a first step. In a second step, we use data from the Women's Health Study of Accra wave II to evaluate the effect of insurance on health seeking behaviour using propensity score matching. RESULTS: We find that on average individuals enrolled in the insurance scheme are significantly more likely to obtain prescriptions, visit clinics and seek formal health care when sick. CONCLUSION: These results suggest that the government's objective to increase access to the formal health care sector through health insurance has at least partially been achieved. PMID- 22942456 TI - Seasonal and socio-economic variations in clinical and self-reported malaria in Accra, Ghana: evidence from facility data and a community survey. AB - OBJECTIVES: This study characterizes the variations in malaria morbidity for Accra. METHODS: Both routine reporting of presumptive, clinically diagnosed malaria in out-patient clinics and results from a longitudinal household survey are used in the analysis. In the household survey, cases of suspected malaria were self-reported by patients, based on diagnoses from health centers, hospitals, pharmacies, chemical sellers or traditional healers. RESULTS: Although the malaria ascertainment is not based on parasitology, we see systematic and plausible patterns by season and by district associated with variations in rainfall by month and year. There are significant differences in malaria incidence by socioeconomic group, possibly linked with place, work or residence. CONCLUSIONS: Understanding these seasonal and geographic patterns have implications for both prevention and treatment of malaria-like morbidity in both children and adults in urban settings. PMID- 22942457 TI - Symptoms of common mental disorders and their correlates among women in Accra, Ghana: a population-based survey. AB - INTRODUCTION: To comply with its new mental health bill, Ghana needs to integrate mental health within other health and social services. Mental disorders represent 9% of disease burden in Ghana. Women are more affected by common mental disorders, and are underrepresented in treatment settings. This study examines physical and social correlates of mental illness in adult women in Accra, Ghana, so as to inform general clinical practice and health policy. METHODS: The SF-36 and K6 forms and 4 psychosis questions were administered in three languages to 2,814 adult women living in Accra, as part of a larger cross-sectional population based survey of women's health. The validity of these tools was assessed through correlations within and between measures. Risk factors for mental distress were analysed using multivariate regression. Health service use was also described using statistical frequencies. RESULTS: Both the SF36 and K6 appear valid in a female Ghanaian population. Low levels of education, poverty and unemployment are negatively associated with mental health. Physical ill health is also associated with mental distress. No association was found between mental distress and religion or ethnicity. Some additional risk factors were significant for one, but not both of the outcome variables. Only 0.4% of women reported seeing a mental health professional in the previous year, whereas 58.6% had visited a health centre. CONCLUSION: The implications for women are that marriage is neither good nor bad for mental health, but education and employment are strong protective factors. Researchers should note that the SF36 and K6 can be used in a Ghanaian population, however more research is needed to determine the cut-off point for serious mental illness on the K6, as well as research into mental disorders in a mixed-gender population. PMID- 22942458 TI - The health of the poor: women living in informal settlements. AB - OBJECTIVES: A large share of the urban population in developing countries lives in informal settlements or "slums" today. This study investigates the association between slum residence and health among adult Ghanaian women residing in the Accra Metropolitan Area. METHODS: Health data collected as part of the Women's Health Study of Accra round II (WHSA-II) was combined with data from the Household and Welfare Study of Accra (HAWS) to compare the health of female slum dwellers to the health of female non-slum dwellers living in the Accra Metropolitan Area. Group means were calculated and multivariate linear regression models were estimated to compare eight domains of health as measured by the short form 36 (SF-36) questionnaire. RESULTS: Women living in informal settlements were found to display consistently better health. Conditional on all observable characteristics, women living in informal settlements scored higher on all self reported health outcomes than women living in non-slum areas. The differences appear largest for general health as well as for the physical role functioning domains, and appear smallest for the social role functioning and bodily pain domains. CONCLUSIONS: The results presented suggest that slum residence does not have a negative effect on self-reported health among women in Accra. Three factors may contribute to the generally positive association between slum residence and observed outcomes: i) self-selection of individuals with strong health into informal settlements and an accordingly small impact of environmental factors on health ii) self-selection of more driven and ambitious individuals into slum neighborhoods who may have a generally more positive view of their health and iii) the geographic placement of slum neighborhoods in central neighborhoods with relatively easy access to health facilities. PMID- 22942459 TI - Epiphytic lichen mycota of the virgin forest reserve Rajhenavski Rog (Slovenia). AB - A list of 128 taxa (127 species) of lichens, 6 species of lichenicolous fungi and 2 non-lichenized fungi traditionally included in lichenological literature from the virgin forest Rajhenavski Rog and its surroundings in the southeastern part of Slovenia is presented. The lichen Gyalecta derivata, the lichenicolous fungus Homostegia piggotii, and the non-lichenized fungus Mycomicrothelia pachnea are new to Slovenia. The lichenized fungi Chaenotheca trichialis, C. xyloxena, Lecanactis abietina, Lecanora thysanophora, Pertusaria ophthalmiza, the lichenicolous fungi Monodictys epilepraria, Tremella hypogymniae, Taeniolella friesii, and the non-lichenized fungus Chaenothecopsis pusilla are new to the Dinaric phytogeographical region of Slovenia. PMID- 22942460 TI - Barrier Crossing in Dihydrofolate Reductasedoes not involve a rate-promoting vibration. AB - We have studied atomic motions during the chemical reaction catalyzed by the enzyme dihydrofolate reductase of Escherichia coli (EcDHFR), an important enzyme for nucleic acid synthesis. In our earlier work on the enzymes human lactate dehydrogenase and purine nucleoside phosphorylase, we had identified fast sub-ps motions that are part of the reaction coordinate. We employed Transition Path Sampling (TPS) and our recently developed reaction coordinate identification methodology to investigate if such fast motions couple to the reaction in DHFR on the barrier-crossing timescale. While we identified some protein motions near the barrier crossing event, these motions do not constitute a compressive promoting vibration, and do not appear as a clearly identifiable protein component in reaction. PMID- 22942461 TI - Moral Enhancement, Freedom and the God Machine. PMID- 22942462 TI - Public Health Reports. A message from the editor. PMID- 22942464 TI - Invest in a healthy future. PMID- 22942466 TI - National carbon monoxide poisoning surveillance framework and recent estimates. AB - OBJECTIVES: Unintentional, non-fire-related (UNFR) carbon monoxide (CO) poisoning is a leading cause of poisoning in the United States. A comprehensive national CO poisoning surveillance framework is needed to obtain accurate estimates of CO poisoning burden and guide prevention efforts. This article describes the current national CO poisoning surveillance framework and reports the most recent national estimates. METHODS: We analyzed mortality data from the National Vital Statistics System multiple cause-of-death file, emergency department (ED) and hospitalization data from the Healthcare Cost and Utilization Project's Nationwide Emergency Department Sample and Nationwide Inpatient Sample, hyperbaric oxygen treatment (HBOT) data from HBOT facilities, exposure data from the National Poison Data System, and CO alarm prevalence data from the American Housing Survey and the National Health Interview Survey. RESULTS: In the United States, 2,631 UNFR CO deaths occurred from 1999 to 2004, an average of 439 deaths annually. In 2007, there were 21,304 (71 per one million population) ED visits and 2,302 (eight per one million population) hospitalizations for confirmed cases of CO poisoning. In 2009, 552 patients received HBOT, and from 2000 to 2009, 68,316 UNFR CO exposures were reported to poison centers. Most nonfatal poisonings were among children (<18 years of age) and females; hospitalizations and deaths occurred more frequently among males and elderly people (>65 years of age). More poisonings occurred during winter months and in the Midwest and Northeast. CONCLUSIONS: UNFR CO poisoning poses a significant public health burden. Systematic evaluation of data sources coupled with modification and expansion of the surveillance framework might assist in developing effective prevention strategies. PMID- 22942465 TI - Place of residence and preventive health care for intellectual and developmental disabilities services recipients in 20 states. AB - OBJECTIVE: We identified trends in the receipt of preventive health care by adults with intellectual and developmental disabilities by type of residential setting. METHODS: We used data from the 2008-2009 collection round of the National Core Indicators (NCI) program. Participating states drew random samples of adults receiving developmental disabilities services. The study was observational, with both self-report and report by proxy. Once the random samples were drawn in each state, data were collected using the NCI Adult Consumer Survey. Trained interviewers administered the survey in person. RESULTS: The likelihood of a person receiving preventive care procedures was related to age, level of intellectual disability, mobility, health status, and state. Type of living arrangement also affected whether a person received these health services, even after controlling for state, level of disability, and other personal characteristics. In general, people living with parents or relatives were consistently the least likely to receive preventive health exams and procedures. CONCLUSION: With growing numbers of adults being served in the family home, educational and policy-based efforts to ensure access to preventive care are increasingly critical. PMID- 22942467 TI - Examining periodontal disease disparities among U.S. adults 20 years of age and older: NHANES III (1988-1994) and NHANES 1999-2004. AB - OBJECTIVE: We examined disparities in periodontal disease in U.S. adults according to age, sex, race/ethnicity, country of birth, education, income, and poverty-income ratio within and between the third National Health and Nutrition Examination Survey (NHANES III, 1988-1994) and NHANES 1999-2004. METHODS: We assessed disparities and changes therein using prevalence differences and ratios, as well as the Symmetrized Theil Index (STI). While these measures document disparities between pairs of population subgroups, and changes in relative disparities between surveys, the STI is a summary measure of health disparities that also tracks between-group disparities relative to the total population. RESULTS: Prevalence differences and ratios for the prevalence of periodontitis, the mean pocket depth (PD), and the mean clinical attachment loss (CAL) suggest that periodontal disease significantly decreased between NHANES III and NHANES 1999-2004 (p<0.01). However, the STI for the prevalence of periodontitis suggests that disparities significantly increased within categories of race/ethnicity, country of birth, and education in NHANES 1999-2004 compared with NHANES III. These findings were corroborated for mean PD and mean CAL (p<0.001): the overall STI significantly increased for mean PD from 4.53% in NHANES III to 11.02% in NHANES 1999-2004 and for mean CAL for teeth with CAL >0 from 31.73% in NHANES III to 43.36% in NHANES 1999-2004. CONCLUSIONS: Our findings suggest that inequalities in periodontal disease significantly decreased between NHANES III and NHANES 1999-2004 in the total population and across selected characteristics of the population. However, these inequalities increased within groups of the population in NHANES 1999-2004 compared with NHANES III. These findings call attention to the absolute and relative differences not only between population groups across surveys, but also within population groups within and between surveys. PMID- 22942468 TI - Impact of fetal death reporting requirements on early neonatal and fetal mortality rates and racial disparities. AB - OBJECTIVE: Racial disparities in infant and neonatal mortality vary substantially across the U.S. with some states experiencing wider disparities than others. Many factors are thought to contribute to these disparities, but state differences in fetal death reporting have received little attention. We examined whether such reporting requirements may explain national variation in neonatal and fetal mortality rates and racial disparities. METHODS: We used data on non-Hispanic white and non-Hispanic black infants from the U.S. 2000-2002 linked birth/infant death and fetal death records to determine the degree to which state fetal death reporting requirements explain national variation in neonatal and fetal mortality rates and racial disparities. States were grouped depending upon whether they based the lower limit for fetal death reporting on birthweight alone, gestational age alone, both birthweight and gestational age, or required reporting of all fetal deaths. Traditional methods and the fetuses-at-risk approach were used to calculate mortality rates, 95% confidence intervals, and relative and absolute racial disparity measures in these four groups. RESULTS: States with birthweight alone fetal death thresholds substantially underreported fetal deaths at lower gestations and slightly overreported neonatal deaths at older gestations. This finding was reflected by these states having the highest neonatal mortality rates and disparities, but the lowest fetal mortality rates and disparities. CONCLUSIONS: Using birthweight alone as a reporting threshold may promote some shift of fetal deaths to newborn deaths, contributing to racial disparities in neonatal mortality. The adoption of a uniform national threshold for reporting fetal deaths could reduce systematic differences in live birth and fetal death reporting. PMID- 22942469 TI - Assessment of assisted reproductive technology use questions: Pregnancy Risk Assessment Monitoring System Survey, 2004. AB - OBJECTIVE: Women who conceive with the assistance of fertility treatments are at increased risk for multiple-gestation pregnancies and accompanying adverse pregnancy outcomes. The Pregnancy Risk Assessment Monitoring System (PRAMS) can be used to assess outcomes associated with fertility treatments, but a previous study suggested that PRAMS questions about fertility treatments overestimated use of assisted reproductive technology (ART) by 2.6 times. These PRAMS ART questions were revised in 2004. We compared prevalence estimates based on revised questions with counts from the National ART Surveillance System (NASS), the standard for describing ART prevalence. METHODS: We compared weighted PRAMS prevalence estimates of births conceived by using ART with corresponding counts from NASS for three states (Florida, Maryland, and Utah) for 2004. We also compared these data by age, parity, plurality, and infant birthweight. RESULTS: Estimated ART births determined from PRAMS totaled 3,672 (95% confidence interval 2,210, 5,134), compared with 2,939 ART births reported to NASS. PRAMS estimates and NASS counts differed by maternal age (p=0.02) and parity (p<0.01). For example, PRAMS responses from women aged >= 40 years overestimated ART use by 70% (27.9% vs. 16.5%, p<0.01). CONCLUSIONS: Revised PRAMS questions better estimate numbers of ART births than earlier PRAMS questions. PRAMS data are useful to describe behaviors and outcomes associated with ART use. PMID- 22942470 TI - HIV screening practices in U.S. hospitals, 2009-2010. AB - OBJECTIVE: A 2004 national survey of hospitals showed that 23.4% of hospitals screened for HIV in at least one department, most frequently in labor and delivery departments. However, less than 2% of these hospitals screened patients in inpatient units, urgent care clinics, or emergency departments. In 2006, the Centers for Disease Control and Prevention (CDC) recommended HIV screening for all individuals 13-64 years of age in health-care settings. We determined the frequency of hospital adoption of these CDC recommendations. METHODS: We surveyed hospital infection-control personnel at a randomly selected sample of U.S. general medical and surgical hospitals in 2009-2010. RESULTS: Of the 1,476 hospitals selected for the survey, 754 (51.1%) responded to the survey; of those responding, 703 (93.2%) offered HIV tests for patients at the hospital and 206 (27.3%) screened for HIV in at least one department. Screening was most common in larger hospitals (45.7%), hospitals in large metropolitan areas (50.5%), and teaching hospitals (44.4%); it was least common in public hospitals (19.1%). By department, screening was most common in labor and delivery departments (34.6%) and substance abuse clinics (20.7%); it was least common in emergency departments (11.9%), inpatient units (9.6%), and psychiatry/mental health departments (9.4%). More than half of hospitals were not considering implementing CDC's recommendations within the next 12 months. CONCLUSIONS: Since 2004, HIV screening in hospitals increased overall and by department. However, the majority of U.S. hospitals have not adopted the CDC recommendations. PMID- 22942472 TI - Design and implementation of a statewide influenza nurse triage line in response to pandemic H1N1 influenza. PMID- 22942474 TI - Controversy, contraception, and conscience: insurance coverage standards under the Patient Protection and Affordable Care Act. PMID- 22942476 TI - Teaching epidemiology concepts experientially: a "real" foodborne outbreak in the classroom. PMID- 22942477 TI - Synthesis of Lipid A and Inner Core LPS ligands containing 4-amino-4-deoxy-l arabinose units. AB - Attachment of 4-amino-4-deoxy-l-arabinose to phosphates or sugar hydroxyl groups of lipopolysaccharide contributes to bacterial resistance against common antibiotics. For a detailed study of antigenic properties and binding interactions, Ara4N-containing inner core ligands related to Burkholderia and Proteus LPS have been synthesized in good yields. Glycosylation at position 8 of allyl glycosides of oct-2-ulosonic acids (Ko, Kdo) has been accomplished using an N-phenyltrifluoroacetimidate 4-azido-4-deoxy-l-arabinosyl glycosyl donor followed by azide reduction and global deprotection. The beta-l-Ara4N-(1->8)-alpha-Kdo disaccharide was further extended into the branched beta-l-Ara4N-(1->8)[alpha-Kdo (2->4)]-alpha-Kdo trisaccharide via a regioselective glycosylation of a protected triol intermediate. Synthesis of Ara4N-modified lipid A - part structure occurring in the LPS of Burkholderia, Pseudomonas and Klebsiellla strains was accomplished using the H-phosphonate approach. The stereocontrolled assembly of the phosphodiester linkage connecting glycosidic centres of two aminosugars was elaborated employing an anomeric H-phosphonate of cyclic silyl-ether protected 4 azido-4-deoxy-beta-l-arabinose which was coupled to the hemiacetal of the lipid A GlcN-disaccharide backbone. Conditions for global deprotection which warrant the integrity of "double anomeric" phosphodiester linkage were successfully developed. Introduction of thiol-terminated spacer at the synthetic ligands allows both coupling to BSA and immobilization on gold nanoparticles as well as generation of glycoarrays. PMID- 22942478 TI - Relationship Characteristics and the Relationship Context of Nonmarital First Births Among Young Adult Women. AB - OBJECTIVES: The objectives of this study were to examine whether and how characteristics of the relationship dyad are linked to nonmarital childbearing among young adult women, additionally distinguishing between cohabiting and nonunion births. METHODS: We used the National Longitudinal Survey of Youth, 1997 Cohort and discrete-time event history methods to examine these objectives. RESULTS: Our analyses found that similarities and differences between women and their most recent sexual partner in educational attainment, disengagement from work or school, race/ethnicity, and age were linked to the risk and context of nonmarital childbearing. For example, partner disengagement (from school and work) was associated with increased odds of a nonmarital birth regardless of whether the woman herself was disengaged. Additionally, having a partner of a different race/ethnicity was associated with nonmarital childbearing for whites, but not for blacks and Hispanics. CONCLUSIONS: We conclude that relationship characteristics are an important dimension of the lives of young adults that influence their odds of having a birth outside of marriage. PMID- 22942479 TI - Intercepted Decarboxylative Allylations of Nitroalkanoates. AB - Using palladium-catalyzed decarboxylation, several cascade reactions of allyl and prenyl nitroalkanoates that lead to nitro-containing chemical building blocks are described. A nitronate Michael addition/Tsuji-Trost allylation cascade was developed, leading to functionally dense chemical building blocks. Likewise, a Tsuji-Trost/decarboxylative protonation sequence was developed for the synthesis of orthogonally functionalized 2 degrees nitroalkanes. The latter method provides rapid access to the indolizidine core. PMID- 22942480 TI - The Severe 5%: A Latent Class Analysis of the Externalizing Behavior Spectrum in the United States. AB - OBJECTIVE: Criminological research consistently demonstrates that approximately 5% of study populations are comprised of pathological offenders who account for a preponderance of antisocial behavior and violent crime. Unfortunately, there have been no nationally representative epidemiological studies characterizing the severe 5% group. MATERIALS AND METHODS: Data from the 2001-2002 National Epidemiologic Survey on Alcohol and Related Conditions (NESARC), a nationally representative sample of 43,093 non-institutionalized U.S. residents aged 18 years and older were analyzed using latent class analysis to assess sociodemographic, psychiatric, and behavioral characteristics. RESULTS: Four classes of respondents were identified vis-a-vis lifetime externalizing behaviors. A normative class (66.1% of respondents) demonstrated little involvement in antisocial conduct. A low substance use/high antisocial behavior class (20.7% of respondents) and high substance use/moderate antisocial behavior (8.0% of respondents) class evinced diverse externalizing and psychiatric symptoms. Finally, a severe class (5.3% of respondents) was characterized by pathological involvement in more varied and intensive forms of antisocial and externalizing behaviors and extensive psychiatric disturbance. CONCLUSIONS: The current study is the first nationally representative epidemiological study of criminal careers/externalizing behavior spectrum in the United States and validates the existence of the 5% pathological group demonstrated by prior research. PMID- 22942481 TI - Characteristics of Abstainers from Substance Use and Antisocial in the United States. AB - PURPOSE: Whether lifetime abstainer's antisocial behavior are maladjusted or well adjusted is unresolved. The aim of this study was to compare abstainers (defined as persons with no lifetime use of alcohol and other drugs and non-engagement in antisocial or delinquent behavior) with non-abstainers across a range of sociodemographic and mental health characteristics in the United States. METHODS: Data were derived from the National Epidemiologic Survey on Alcohol and Related Conditions, a nationally representative sample of U.S. adults. Structured psychiatric interviews (N = 43,093) using the Alcohol Use Disorder and Associated Disabilities Interview Schedule - DSM-IV version (AUDADIS-IV) were completed by trained lay interviewers between 2001 and 2002. RESULTS: The prevalence of abstaining was 11%. Abstainers were significantly more likely to be female, Asian and African-American, born outside the U.S., and less likely to be unemployed. Multivariate logistic regression analyses revealed that abstainers were significantly less likely to evidence lifetime mood, anxiety, or personality disorder compared to non-abstainers. CONCLUSIONS: Findings indicate that abstainers are not maladapted and are comparatively more functional than non abstainers. PMID- 22942482 TI - Unifying mass-action kinetics and Newtonian mechanics by means of Nambu brackets. AB - We demonstrate that elementary biochemical reactions defined by mass-action kinetics satisfy a particular Nambu structure. To this end, we express biochemical reaction equations in terms of Nambu brackets and certain omega factors. The omega-factors account for the fact that mass-action kinetics exhibits in general flow fields with finite divergence. The proposed approach by means of Nambu brackets and omega-factors unifies divergence freeflow fields of Newtonian mechanics and flow fields with finite divergence of mass-action kinetics. PMID- 22942483 TI - NMR studies on puerarin and its interaction with beta-cyclodextrin. AB - The interaction between puerarin and beta-cyclodextrin (CD) has been studied in D(2)O, H(2)O/acetone-d(6), acetone-d(6) and DMSO-d(6) solutions by (1)H NMR spectroscopy. The NMR data obtained from hydroxy protons indicate that the formation of the inclusion complex between the two molecules is not stabilized by strong hydrogen bond interactions. The sugar part of puerarin as well as the A ring are outside the beta-CD cavity while the B and C rings are located inside the cavity and the interaction is mainly stabilized by hydrophobic interactions. In DMSO at 30 degrees C and in acetone-d(6)/H(2)O at temperature below -5 degrees C, doubling of some signals indicated that, in these solvent systems, free rotation of the C-glycosyl bond was restricted due to the steric hindrance between the phenolic hydroxy group at C-7 and the bulky sugar moiety at C-8. In acetone, fast exchange of phenolic protons on the NMR timescale was observed, showing the effect of the solvent on the hindered rotation. PMID- 22942484 TI - On a population pathogen model incorporating species dispersal with temporal variation in dispersal rate. AB - In the present paper, we consider a mathematical model of ecosystem population interaction where the population suffers from a susceptible-infectious susceptible disease. Dispersal of both the susceptible and the infective is incorporated using reaction-diffusion equations. We first study the stability criteria of the basic (non-spatial) model around the disease-free and the infected steady states. We find that the loss rate of the infective species controls disease prevalence. Also without predation pressure, the disease will continue to exist among the population. Then we analyze the spatial model with species dispersal in constant as well as in time-varying form. It is observed that though constant dispersal is unable to generate diffusion-driven instability, dispersal with sinusoidal variation in dispersion rate can generate diffusive instability when the wave number of the perturbation lies within a given range. Numerical simulations are performed to illustrate analytical studies. PMID- 22942485 TI - Imaging and determining friction forces of specific interactions between human IgG and rat anti-human IgG. AB - Covalently immobilized rat anti-human immunoglobulin (IgG) monolayers on thiol modified gold substrates and human IgG linked with the tips were fabricated using the self-assembled monolayer method, and interactions between these systems were studied by friction force microscopy (FFM). In addition to observation of distinct nanostructures of protein monolayers due to recognition events, FFM also quantified the friction force due to protein-protein-specific interactions. The average friction force due to interactions between the antigen functionalized tip and the antibody monolayer was determined as 200-250 pN, significantly greater than that between either the bare tip and the antibody monolayer (0-50 pN), or the blocked antigen tip and the antibody monolayer (50-100 pN), indicative of antigen/antibody-specific interactions. These results, taken together, suggest that FFM is not only capable of tracking recognition events, but also quantifying the friction force due to specific interactions between biological molecules, such as antigen and antibody. PMID- 22942486 TI - Visualization study of motion and deformation of red blood cells in a microchannel with straight, divergent and convergent sections. AB - The size of red blood cells (RBC) is on the same order as the diameter of microvascular vessels. Therefore, blood should be regarded as a two-phase flow system of RBCs suspended in plasma rather than a continuous medium of microcirculation. It is of great physiological and pathological significance to investigate the effects of deformation and aggregation of RBCs on microcirculation. In this study, a visualization experiment was conducted to study the microcirculatory behavior of RBCs in suspension. Motion and deformation of RBCs in a microfluidic chip with straight, divergent, and convergent microchannel sections have been captured by microscope and high-speed camera. Meanwhile, deformation and movement of RBCs were investigated under different viscosity, hematocrit, and flow rate in this system. For low velocity and viscosity, RBCs behaved in their normal biconcave disc shape and their motion was found as a flipping motion: they not only deformed their shapes along the flow direction, but also rolled and rotated themselves. RBCs were also found to aggregate, forming rouleaux at very low flow rate and viscosity. However, for high velocity and viscosity, RBCs deformed obviously under the shear stress. They elongated along the flow direction and performed a tank-treading motion. PMID- 22942487 TI - The effect of coupled stochastic processes in a two-state biochemical switch. AB - Cell signaling pathways consist of multiple connections of different types of gene, mRNA and protein networks. It is not a trivial task to follow the signals flowing through these networks. The difficulty comes from considering the entire biological structure as a single network without breaking it into connected modules. The study of these networks simplifies if the complex system is reduced to a hierarchy of interconnected modules. Out of many potential modules, a specific one, namely the Goldbeter-Koshland switch, was encountered by the authors during their study of the Mammalian Heat Shock Response Network (MHSRN) where the switch acts as a stress sensor. Usually, only the steady state behavior of the switch is studied, in which the phosphorylated protein is given as a function of the enzyme concentration. Experimental results show that the heat shock response is still present 20 h after the temperature stress had ended. Thus, it is useful to analyze the transient behavior of the switch that couples the environment to the MHSRN. A stochastic model for the switch is proposed using the Master Equation which is subsequently transformed into an equation for the factorial cumulant generating function. This generating function can be easily read from a graphical representation of the stochastic switch. The second order approximation of the equation for the factorial cumulant generating function is solved and the time dependence of the transient regime of the mean and standard deviation is readily obtained. Using the mean and standard deviation of the switch's output as a function of the stochastic input signals that represent the environment, we classify the switches according to different criteria. The switches differ by the numerical values of the parameters that characterize the switch's chemical reactions. The classifying criteria will distinguish the switches by the levels of the response for a given transition time and by the sensitivity of the response to the enzyme levels. It is also found that the environment can drastically change the response of the switch, which has important biological consequences. PMID- 22942488 TI - Unfolding analysis of the mature and unprocessed forms of Bacillus licheniformis gamma-glutamyltranspeptidase. AB - Bacillus licheniformis gamma-glutamyltranspeptidase (BlGGT) undergoes an autocatalytic process to generate 44.9 and 21.7 kDa subunits; however, a mutant protein (T399A) loses completely the processing ability and mainly exists as a precursor. For a comprehensive understanding of their structural features, the biophysical properties of these two proteins were investigated by circular dichroism and fluorescence spectroscopy. Tryptophan fluorescence and circular dichroism spectra were nearly identical for BlGGT and T399A, but unfolding analyses revealed that these two proteins had a different sensitivity towards temperature- and guanidine hydrochloride (GdnHCl)-induced denaturation. BlGGT and the unprocessed T399A displayed T(m) values of 61.4 degrees C and 68.1 degrees C, respectively, and thermal unfolding of both proteins was found to be highly irreversible. Fluorescence quenching analysis showed that T399A had a dynamic quenching constant similar to that of the wild-type enzyme. BlGGT started to unfold beyond ~2.14 M GdnHCl and reached an unfolded intermediate, [GdnHCl](0.5, N - U), at 2.85 M, corresponding to free energy change [Formula: see text] of 12.34 kcal mol( - 1), whereas the midpoint of the denaturation curve for T399A was approximately 3.94 M, corresponding to a [Formula: see text] of 4.45 kcal mol( - 1). Taken together, it can be concluded that the structural stability of BlGGT is superior to that of T399A. PMID- 22942489 TI - Image correlation spectroscopy of randomly distributed disks. AB - Image correlation spectroscopy (ICS) has been widely used to quantify spatiotemporal distributions of fluorescently labelled cell membrane proteins and receptors. When the membrane proteins are randomly distributed, ICS may be used to estimate protein densities, provided the proteins behave as point-like objects. At high protein area fraction, however, even randomly placed proteins cannot obey Poisson statistics, because of excluded area. The difficulty can arise if the protein effective area is quite large, or if proteins form large complexes or aggregate into clusters. In these cases, there is a need to determine the correct form of the intensity correlation function for hard disks in two dimensions, including the excluded area effects. We present an approximate but highly accurate algorithm for the computation of this correlation function. The correlation function was verified using test images of randomly distributed hard disks of uniform intensity convolved with the microscope point spread function. This algorithm can be readily modified to compute exact intensity correlation functions for any probe geometry, interaction potential, and fluorophore distribution; we show how to apply it to describe a random distribution of large proteins labeled with a single fluorophore. PMID- 22942490 TI - Examination of trafficking of phagocytosed colloid particles in neutrophils using synchrotron-based X-ray fluorescence microscopy (XFM). AB - Synchrotron-based X-ray fluorescence microscopy (XFM) can localise chemical elements at a subcellular level. 99mTechnetium stannous (TcSn) colloid is taken up by phagocytes via a Complement Receptor 3 mediated phagocytic process. In the current study, XFM was used to examine the intracellular trafficking of TcSn colloid in neutrophils. XFM was performed on TcSn colloid, and neutrophils labelled with TcSn colloid, in whole blood. We developed a set of pixel by pixel analysis and mapping techniques incorporating cluster analysis that allowed us to differentiate neutrophils and artefactual contaminants, and we examined the changes in element distribution that accompany neutrophil phagocytosis of TcSn colloid. Sn became associated with half the neutrophils. Within cells, Sn colocalised with iron (Fe) and sulphur (S), and was negatively associated with calcium (Ca). Despite the high sensitivity of XFM, Tc was not detected. XFM can help clarify the intracellular processes that accompany neutrophil phagocytosis. The subcellular colocalisation of Sn with Fe is consistent with fusion of the colloid-containing phagosome with neutrophil granules. The association of Sn with S suggests that proteins rich in S-containing amino acids are present in the phagosome. The negative colocalisation with Ca indicates that ongoing maturation of the TcSn colloid phagosome is no longer calcium dependent one hour after phagocytosis. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s10867-011-9233-9) contains supplementary material, which is available to authorized users. PMID- 22942491 TI - Low Vision Rehabilitation in a Nursing Home Population: The SEEING Study. AB - As part of a study of 198 residents with low vision in 28 nursing homes, 91 participated in a low vision rehabilitation intervention. Among the rehabilitation participants, 78% received simple environmental modifications, such as lighting; 75% received low vision instruction; 73% benefited from staff training; and 69% received simple nonoptical devices. Because of the cognitive and physical fragility of many nursing home residents, the authors recommend an approach that centers on training nursing home staff and improving the environment of the facilities, especially in the area of illumination. PMID- 22942492 TI - Making sense of sleepiness in the elderly. PMID- 22942493 TI - Genetic influences contribute to neurobehavioral response to acute sleep deprivation. PMID- 22942494 TI - Noise in the signal or bad vibrations? PMID- 22942495 TI - Acoustic snoring analysis can provide important information in OSA diagnosis. PMID- 22942496 TI - Single vs. multi-modality treatment of central apnea syndromes. PMID- 22942498 TI - Excessive sleepiness is predictive of cognitive decline in the elderly. AB - STUDY OBJECTIVES: To examine the association of sleep complaints reported at baseline (insomnia complaints and excessive daytime sleepiness (EDS)) and medication, with cognitive decline in community-dwelling elderly. DESIGN: An 8-yr longitudinal study. SETTING: The French Three-City Study. PARTICIPANTS: There were 4,894 patients without dementia recruited from 3 French cities and having a Mini-Mental Status Examination (MMSE) score >= 24 points at baseline. MEASUREMENTS AND RESULTS: Questionnaires were used to evaluate insomnia complaints (poor sleep quality (SQ), difficulty in initiating sleep (DIS), difficulty in maintaining sleep (DMS), early morning awakening (EMA)), EDS, and sleep medication at baseline. Cognitive decline was defined as a 4-point reduction in MMSE score during follow-up at 2, 4, and 8 yr. Logistic regression models were adjusted for sociodemographic, behavioral, physical, and mental health variables, and apolipoprotein E genotype. EDS independently increased the risk of cognitive decline (odds ratio (OR) = 1.26, 95% confidence interval (CI) = 1.02-1.56), especially for those patients who also developed dementia during the follow-up period (OR = 1.39, 95% CI = 1.00-1.97). The number of insomnia complaints and DMS were negatively associated with MMSE cognitive decline (OR = 0.77, 95% CI = 0.60-0.98 for 3-4 complaints, OR = 0.81, 95% CI = 0.68-0.96, respectively). The 3 other components of insomnia (SQ, DIS, EMA) were not significantly associated with MMSE cognitive decline. CONCLUSIONS: Our results suggest that EDS may be associated independently with the risk of cognitive decline in the elderly population. Such results could have important public health implications because EDS may be an early marker and potentially reversible risk factor of cognitive decline and onset of dementia. PMID- 22942499 TI - Lactate as a biomarker for sleep. AB - STUDY OBJECTIVES: An ideal biomarker for sleep should change rapidly with sleep onset, remain at a detectably differential level throughout the sleep period, and exhibit a rapid change with waking. Currently, no molecular marker has been identified that exhibits all three properties. This study examined three substances (lactate, glucose, and glutamate) for suitability as a sleep biomarker. DESIGN: Using amperometric biosensor technology in conjunction with electroencephalograph (EEG) and electromyograph (EMG) monitoring, extracellular concentrations of lactate and glucose (Cohort 1) as well as lactate and glutamate (Cohort 2) were recorded over multiple sleep/wake cycles. PATIENTS OR PARTICIPANTS: There were 12 C57Bl/6J male mice (3-5 mo old). INTERVENTIONS: Sleep and waking transitions were identified using EEG recordings. Extracellular concentrations of lactate, glucose, and glutamate were evaluated before and during transition events as well as during extended sleep and during a 6-h sleep deprivation period. MEASUREMENTS AND RESULTS: Rapid and sustained increases in cortical lactate concentration (approximately 15 MUM/min) were immediately observed upon waking and during rapid eye movement sleep. Elevated lactate concentration was also maintained throughout a 6-h period of continuous waking. A persistent and sustained decline in lactate concentration was measured during nonrapid eye movement sleep. Glutamate exhibited similar patterns, but with a much slower rise and decline (approximately 0.03 MUM/min). Glucose concentration changes did not demonstrate a clear correlation with either sleep or wake. CONCLUSIONS: These findings indicate that extracellular lactate concentration is a reliable sleep/wake biomarker and can be used independently of the EEG signal. PMID- 22942500 TI - Heritability of performance deficit accumulation during acute sleep deprivation in twins. AB - STUDY OBJECTIVES: To determine if the large and highly reproducible interindividual differences in rates of performance deficit accumulation during sleep deprivation, as determined by the number of lapses on a sustained reaction time test, the Psychomotor Vigilance Task (PVT), arise from a heritable trait. DESIGN: Prospective, observational cohort study. SETTING: Academic medical center. PARTICIPANTS: There were 59 monozygotic (mean age 29.2 +/- 6.8 [SD] yr; 15 male and 44 female pairs) and 41 dizygotic (mean age 26.6 +/- 7.6 yr; 15 male and 26 female pairs) same-sex twin pairs with a normal polysomnogram. INTERVENTIONS: Thirty-eight hr of monitored, continuous sleep deprivation. MEASUREMENTS AND RESULTS: Patients performed the 10-min PVT every 2 hr during the sleep deprivation protocol. The primary outcome was change from baseline in square root transformed total lapses (response time >= 500 ms) per trial. Patient specific linear rates of performance deficit accumulation were separated from circadian effects using multiple linear regression. Using the classic approach to assess heritability, the intraclass correlation coefficients for accumulating deficits resulted in a broad sense heritability (h(2)) estimate of 0.834. The mean within-pair and among-pair heritability estimates determined by analysis of variance-based methods was 0.715. When variance components of mixed-effect multilevel models were estimated by maximum likelihood estimation and used to determine the proportions of phenotypic variance explained by genetic and nongenetic factors, 51.1% (standard error = 8.4%, P < 0.0001) of twin variance was attributed to combined additive and dominance genetic effects. CONCLUSION: Genetic factors explain a large fraction of interindividual variance among rates of performance deficit accumulations on PVT during sleep deprivation. PMID- 22942501 TI - Snoring is not associated with all-cause mortality, incident cardiovascular disease, or stroke in the Busselton Health Study. AB - STUDY OBJECTIVES: To ascertain whether objectively measured snoring increases mortality, cardiovascular disease, or stroke risk over the effects of obstructive sleep apnea and other established risk factors. DESIGN: Community-based cohort. PARTICIPANTS: 400 residents of the Western Australian town of Busselton. INTERVENTIONS: N/A. MEASUREMENTS: Snoring and obstructive sleep apnea were quantified via the percentage of the night spent snoring and the respiratory disturbance index as measured by a single night recording in November-December 1990 by a home sleep apnea monitoring device (MESAM IV), along with a range of cardiovascular disease risk factors. Follow-up for deaths and cardiovascular hospitalizations was ascertained via record linkage until the end of 2007. RESULTS: Our analytical sample of 380 people was made up of the 397 people for whom the authors had follow-up data, minus 17 people who reported a previous stroke or heart attack at baseline (n = 380/400 = 95% of cohort). Snoring was observed for a mean/median of 32.0/27.4% of the night (standard deviation = 23.9%; range = 0-97.2%). There were 46 deaths, 68 cardiovascular events, and 24 strokes during 17 yr of follow-up. Snoring as either a categoric or continuous variable was not significantly associated with death, incident cardiovascular disease, or stroke in both unadjusted Cox regression models and in models that adjusted for obstructive sleep apnea and other risk factors. CONCLUSIONS: No measure of snoring was associated with all-cause mortality, or incident cardiovascular disease or stroke over 17 yr in this community-based sample. PMID- 22942502 TI - Obstructive sleep apnea affects hospital outcomes of patients with non-ST elevation acute coronary syndromes. AB - STUDY OBJECTIVE: We aimed to test the hypothesis that clinically suspected obstructive sleep apnea (OSA) independently predicts worse in-hospital outcome in patients with non-ST elevation acute coronary syndromes. DESIGN: At admission, individuals were evaluated for clinical probability of OSA by the Berlin Questionnaire. Primary cardiovascular endpoint was defined as the composite of death, nonfatal myocardial infarction, or refractory angina during hospitalization. SETTING: Coronary care unit. PATIENTS: There were 168 consecutive patients admitted with unstable angina or non-ST elevation acute myocardial infarction. MEASUREMENTS AND RESULTS: During a median hospitalization of 8 days, the incidence of cardiovascular events was 13% (12 deaths, 4 nonfatal myocardial infarctions, and 6 refractory anginas.) Incidence of the primary endpoint was 18% in individuals with high probability of OSA, compared with no events in individuals with low probability (P = 0.002). After logistic regression adjustment for the Global Registry of Acute Coronary Events (GRACE) risk score, anatomic severity of coronary disease, and hospital treatment, probability of OSA remained an independent predictor of events (odds ratio [OR] = 3.4; 95% confidence interval [CI] = 1.3 - 9.0; P = 0.015). Prognostic discrimination of the GRACE score, measured by a C-statistic of 0.72 (95% CI = 0.59-0.85), was significantly improved to 0.82 (95% CI = 0.73-0.92) after inclusion of OSA probability in the predictive model (P = 0.03). CONCLUSION: Considering the independent prognostic and incremental value of suspected OSA, this condition may represent an aggravating factor for patients with non-ST elevation acute coronary syndrome. PMID- 22942503 TI - Predictors of hypocretin (orexin) deficiency in narcolepsy without cataplexy. AB - STUDY OBJECTIVES: To compare clinical, electrophysiologic, and biologic data in narcolepsy without cataplexy with low (<= 110 pg/ml), intermediate (110-200 pg/ml), and normal (> 200 pg/ml) concentrations of cerebrospinal fluid (CSF) hypocretin-1. SETTING: University-based sleep clinics and laboratories. PATIENTS: Narcolepsy without cataplexy (n = 171) and control patients (n = 170), all with available CSF hypocretin-1. DESIGN AND INTERVENTIONS: Retrospective comparison and receiver operating characteristics curve analysis. Patients were also recontacted to evaluate if they developed cataplexy by survival curve analysis. MEASUREMENTS AND RESULTS: The optimal cutoff of CSF hypocretin-1 for narcolepsy without cataplexy diagnosis was 200 pg/ml rather than 110 pg/ml (sensitivity 33%, specificity 99%). Forty-one patients (24%), all HLA DQB1*06:02 positive, had low concentrations (<= 110 pg/ml) of CSF hypocretin-1. Patients with low concentrations of hypocretin-1 only differed subjectively from other groups by a higher Epworth Sleepiness Scale score and more frequent sleep paralysis. Compared with patients with normal hypocretin-1 concentration (n = 117, 68%), those with low hypocretin-1 concentration had higher HLA DQB1*06:02 frequencies, were more frequently non-Caucasians (notably African Americans), with lower age of onset, and longer duration of illness. They also had more frequently short rapid-eye movement (REM) sleep latency (<= 15 min) during polysomnography (64% versus 23%), and shorter sleep latencies (2.7 +/- 0.3 versus 4.4 +/- 0.2 min) and more sleep onset REM periods (3.6 +/- 0.1 versus 2.9 +/- 0.1 min) during the Multiple Sleep Latency Test (MSLT). Patients with intermediate concentrations of CSF hypocretin 1 (n = 13, 8%) had intermediate HLA DQB1*06:02 and polysomnography results, suggesting heterogeneity. Of the 127 patients we were able to recontact, survival analysis showed that almost half (48%) with low concentration of CSF hypocretin-1 had developed typical cataplexy at 26 yr after onset, whereas only 2% had done so when CSF hypocretin-1 concentration was normal. Almost all patients (87%) still complained of daytime sleepiness independent of hypocretin status. CONCLUSION: Objective (HLA typing, MSLT, and sleep studies) more than subjective (sleepiness and sleep paralysis) features predicted low concentration of CSF hypocretin-1 in patients with narcolepsy without cataplexy. PMID- 22942504 TI - Ventilatory responses to hypercapnia during wakefulness and sleep in obese adolescents with and without obstructive sleep apnea syndrome. AB - STUDY OBJECTIVES: Abnormal ventilatory drive may contribute to the pathophysiology of the childhood obstructive sleep apnea syndrome (OSAS). Concomitant with the obesity epidemic, more adolescents are developing OSAS. However, few studies have specifically evaluated the obese adolescent group. The authors hypothesized that obese adolescents with OSAS would have a blunted hypercapnic ventilatory response (HCVR) while awake and blunted ventilatory responses to carbon dioxide (CO(2)) during sleep compared with obese and lean adolescents without OSAS. DESIGN: CVR was measured during wakefulness. During nonrapid eye movement (NREM) and rapid eye movement (REM) sleep, respiratory parameters and genioglossal electromyogram were measured during CO(2) administration in comparison with room air in obese adolescents with OSAS, obese control study participants, and lean control study participants. SETTING: Sleep laboratory. PARTICIPANTS: Twenty-eight obese patients with OSAS, 21 obese control study participants, and 37 lean control study participants. RESULTS: The obese OSAS and obese control groups had a higher HCVR compared with the lean control group during wakefulness. During both sleep states, all 3 groups had a response to CO(2); however, the obese OSAS group had lower percentage changes in minute ventilation, inspiratory flow, inspiratory time, and tidal volume compared with the 2 control groups. There were no significance differences in genioglossal activity between groups. CONCLUSIONS: HCVR during wakefulness is increased in obese adolescents. Obese adolescents with OSAS have blunted ventilatory responses to CO(2) during sleep and do not have a compensatory prolongation of inspiratory time, despite having normal CO(2) responsivity during wakefulness. Central drive may play a greater role than upper airway neuromotor tone in adapting to hypercapnia. PMID- 22942505 TI - Cardiac and sympathetic activation are reduced in children with Down syndrome and sleep disordered breathing. AB - STUDY OBJECTIVES: Sleep disordered breathing (SDB) occurs at an increased incidence in children with Down Syndrome (DS) compared to the general pediatric population. We hypothesized that, compared with typically developing (TD) children with SDB, children with DS have a reduced cardiovascular response with delayed reoxygenation after obstructive respiratory events, and reduced sympathetic drive, providing a potential explanation for their increased risk of pulmonary hypertension. DESIGN: Beat-by-beat heart rate (HR) was analyzed over the course of obstructive events (pre, early, late, post-event) and compared between groups. Also compared were the time for oxygen resaturation post-event and overnight urinary catecholamines. SETTING: Pediatric sleep laboratory. PATIENTS: Sixty-four children aged 2-17 y referred for investigation of SDB (32 DS; 32 TD) matched for age and obstructive apnea/hypopnea index. MEASUREMENT AND RESULTS: Children underwent overnight polysomnography with overnight urine collection. Compared to TD children, those with DS had significantly reduced HR changes post-event during NREM (DS: 21.4% +/- 1.8%, TD: 26.6% +/- 1.6%, change from late to post-event, P < 0.05). The time to resaturation post-event was significantly increased in the DS group (P < 0.05 for both NREM and REM sleep). Children with DS had significantly reduced overnight urinary noradrenaline (P < 0.01), adrenaline (P < 0.05) and dopamine levels (P < 0.01) compared with TD children. CONCLUSION: Children with DS and SDB exhibit a compromised acute cardio respiratory response and dampened sympathetic response to SDB compared with TD children with SDB. These data may reflect autonomic dysfunction in children with DS that may place them at increased risk for cardiovascular complications such as pulmonary hypertension. PMID- 22942506 TI - Control of OSA during automatic positive airway pressure titration in a clinical case series: predictors and accuracy of device download data. AB - STUDY OBJECTIVES: To investigate the factors associated with physiologic control of obstructive sleep apnea (OSA) during automatic positive airway pressure (APAP) titration in a clinical series. To also assess the usefulness of apnea-hypopnea index (AHI) data downloaded from the APAP device (Dev AHI). DESIGN: Retrospective review of a consecutive series of patients with OSA who underwent APAP titration (Autoset Spirit, ResMed, Bella Vista, New South Wales, Australia ) with simultaneous polysomnographic (PSG) monitoring in the sleep laboratory. SETTING: Tertiary sleep clinic. PARTICIPANTS: There were 190 consecutive patients with OSA referred for APAP titration. MEASUREMENTS AND RESULTS: There were 58% of patients who achieved optimal or good control of OSA (titration PSG AHI < 10, or at least 50% reduction in AHI if diagnostic AHI < 15/hr) during APAP titration. The independent predictors of titration PSG AHI were a history of cardiac disease and elevated central apnea and arousal indices during the diagnostic study. Although the median and interquartile range (IQR) AHI from the device (7.0, 3.9-11.6 events/hr) was only slightly less than the PSG AHI (7.8, 3.9-14.4 events/hr, P = 0.04) during titration, case-by-case agreement between the two measures was poor (chi-square < 0.001). CONCLUSION: In a clinical sample control of OSA during APAP titration is often poor, and close clinical follow-up is particularly needed in patients with a history of cardiac disease or with high arousal or central apnea indices on the diagnostic study. Device AHI does not reliably assess control during APAP titration, and PSG assessment may be required if clinical response to treatment is poor. The findings relate to the ResMed AutoSet device and may not apply to other devices. PMID- 22942507 TI - Short-term stability of sleep and heart rate variability in good sleepers and patients with insomnia: for some measures, one night is enough. AB - STUDY OBJECTIVES: Quantify the short-term stability of multiple indices of sleep and nocturnal physiology in good sleeper controls and primary insomnia patients. DESIGN: Intra-class correlation coefficients (ICC) were used to quantify the short-term stability of study outcomes. SETTING: Sleep laboratory. PARTICIPANTS: Fifty-four adults with primary insomnia (PI) and 22 good sleeper controls (GSC). MEASUREMENTS: Visually scored sleep outcomes included indices of sleep duration, continuity, and architecture. Quantitative EEG outcomes included power in the delta, theta, alpha, sigma, and beta bands during NREM sleep. Power spectral analysis was used to estimate high-frequency heart rate variability (HRV) and the ratio of low- to high-frequency HRV power during NREM and REM sleep. RESULTS: With the exception of percent stage 3+4 sleep; visually scored sleep outcomes did not exhibit short-term stability across study nights. Most QEEG outcomes demonstrated short-term stability in both groups. Although power in the beta band was stable in the PI group (ICC = 0.75), it tended to be less stable in GSCs (ICC = 0.55). Both measures of cardiac autonomic tone exhibited short-term stability in GSCs and PIs during NREM and REM sleep. CONCLUSIONS: Most QEEG bandwidths and HRV during sleep show high short-term stability in good sleepers and patients with insomnia alike. One night of data is, thus, sufficient to derive reliable estimates of these outcomes in studies focused on group differences or correlates of QEEG and/or HRV. In contrast, one night of data is unlikely to generate reliable estimates of PSG-assessed sleep duration, continuity or architecture, with the exception of slow wave sleep. PMID- 22942509 TI - Obstructive apnea hypopnea index estimation by analysis of nocturnal snoring signals in adults. AB - STUDY OBJECTIVE: To develop a whole-night snore sounds analysis algorithm enabling estimation of obstructive apnea hypopnea index (AHI(EST)) among adult subjects. DESIGN: Snore sounds were recorded using a directional condenser microphone placed 1 m above the bed. Acoustic features exploring intra-(mel- cepstability, pitch density) and inter-(running variance, apnea phase ratio, inter-event silence) snore properties were extracted and integrated to assess AHI(EST). SETTING: University-affiliated sleep-wake disorder center and biomedical signal processing laboratory. PATIENTS: Ninety subjects (age 53 +/- 13 years, BMI 31 +/- 5 kg/m(2)) referred for polysomnography (PSG) diagnosis of OSA were prospectively and consecutively recruited. The system was trained and tested on 60 subjects. Validation was blindly performed on the additional 30 consecutive subjects. MEASUREMENTS AND RESULTS: AHI(EST) correlated with AHI (AHI(PSG); r(2) = 0.81, P < 0.001). Area under the receiver operating characteristic curve of 85% and 92% for thresholds of 10 and 20 events/h, respectively, were obtained for OSA detection. Both Altman-Bland analysis and diagnostic agreement criteria revealed 80% and 83% agreements of AHI(EST) with AHI(PSG), respectively. CONCLUSIONS: Acoustic analysis based on intra- and inter-snore properties can differentiate subjects according to AHI. An acoustic-based screening system may address the growing needs for reliable OSA screening tool. Further studies are needed to support these findings. PMID- 22942510 TI - Cone-Beam CT with a Flat-Panel Detector: From Image Science to Image-Guided Surgery. AB - The development of large-area flat-panel x-ray detectors (FPDs) has spurred investigation in a spectrum of advanced medical imaging applications, including tomosynthesis and cone-beam CT (CBCT). Recent research has extended image quality metrics and theoretical models to such applications, providing a quantitative foundation for the assessment of imaging performance as well as a general framework for the design, optimization, and translation of such technologies to new applications. For example, cascaded systems models of Fourier domain metrics, such as noise-equivalent quanta (NEQ), have been extended to these modalities to describe the propagation of signal and noise through the image acquisition and reconstruction chain and to quantify the factors that govern spatial resolution, image noise, and detectability. Moreover, such models have demonstrated basic agreement with human observer performance for a broad range of imaging conditions and imaging tasks. These developments in image science have formed a foundation for the knowledgeable development and translation of CBCT to new applications in image-guided interventions - for example, CBCT implemented on a mobile surgical C arm for intraoperative 3D imaging. The ability to acquire high-quality 3D images on demand during surgical intervention overcomes conventional limitations of surgical guidance in the context of preoperative images alone. A prototype mobile C-arm developed in academic-industry partnership demonstrates CBCT with low radiation dose, sub-mm spatial resolution, and soft-tissue visibility potentially approaching that of diagnostic CT. Integration of the 3D imaging system with real time tracking, deformable registration, endoscopic video, and 3D visualization offers a promising addition to the surgical arsenal in interventions ranging from head-and-neck / skull base surgery to spine, orthopaedic, thoracic, and abdominal surgeries. Cadaver studies show the potential for significant boosts in surgical performance under CBCT guidance, and early clinical trials demonstrate feasibility, workflow, and image quality within the surgical theatre. PMID- 22942508 TI - The relationship between obstructive sleep apnea and self-reported stroke or coronary heart disease in overweight and obese adults with type 2 diabetes mellitus. AB - STUDY OBJECTIVES: Type 2 diabetes mellitus (T2DM) and obstructive sleep apnea (OSA) are common, increasingly recognized as comorbid conditions, and individually implicated in the development of cardiovascular disease (CVD). We sought to determine the association between OSA and CVD in an overweight and obese population with T2DM. DESIGN: Cross-sectional. SETTING: Ancillary study to the Look AHEAD trial. PARTICIPANTS: Three hundred five participants of the Sleep AHEAD study who underwent unattended full polysomnography at home with measurement of the apnea-hypopnea index (AHI). MEASUREMENTS AND RESULTS: Self reported prevalent CVD was obtained at the initial assessment of the parent study and included a history of the following conditions: stroke, carotid endarterectomy, myocardial infarction, coronary artery bypass grafting, and percutaneous coronary intervention. Logistic regression was used to assess the association of OSA, measured continuously and categorically, with prevalent CVD. OSA was present (AHI >= 5) in 86% of the population, whereas the prevalence of all forms of CVD was just 14%. The AHI was associated with stroke with an adjusted odds ratio (95% confidence interval) of 2.57 (1.03, 6.42). Neither the continuously measured AHI nor the categories of OSA severity were significantly associated with the other forms of CVD assessed. CONCLUSIONS: We found suggestive evidence of a greater prevalence of stroke at greater values of the AHI. OSA was not associated with prevalent coronary heart disease in the Sleep AHEAD trial. Future studies should confirm the link between OSA and stroke and examine mechanisms that link OSA to stroke in adults with T2DM. PMID- 22942511 TI - Adolescents' Experiences of Discrimination and Parent-Adolescent Relationship Quality: The Moderating Roles of Sociocultural Processes. AB - Grounded in a cultural-ecological perspective, the goals of this study were to examine the implications of young adolescents' experiences of racial discrimination for the quality of relationships with mothers and fathers and to test whether sociocultural processes, such as youth ethnic identity and parents' racial socialization strategies, moderated these linkages. Participants were older and younger adolescents in 176 two-parent African American families who completed questionnaires about their discrimination experiences, ethnic identities, and warmth and conflict in their relationships with parents. Mothers and fathers reported on cultural socialization and preparation for bias practices. Consistent with an emotional spillover hypothesis, discrimination was linked to poorer relationship quality with both mothers and fathers. Youth ethnic identity and mothers' racial socialization moderated discrimination-relationship linkages. Findings were consistent with prior research on discrimination and highlight the protective nature of some sociocultural processes for family relationships. PMID- 22942512 TI - Patterns of Crime and Drug Use Trajectories in Relation to Treatment Initiation and 5-Year Outcomes: An Application of Growth Mixture Modeling Across Three Datasets. AB - Drug abusers vary considerably in their drug use and criminal behavior over time, and these trajectories are likely to influence drug treatment participation and treatment outcomes. Drawing on longitudinal natural history data from three samples of adult male drug users, we identify four groups with distinctive drug use and crime trajectories over the 5 years prior to their first treatment episode. The groups' characteristics of initial treatment are compared. The trajectory groups are then included in Poisson growth curve models to predict drug use, incarceration, and employment over the 5 years following first treatment. Findings indicate that posttreatment drug use decreased and posttreatment employment increased. There was little change in posttreatment incarceration. Posttreatment trajectories for drug use, incarceration, and employment were significantly different across the four trajectory groups. PMID- 22942513 TI - Using TMS to study the role of the articulatory motor system in speech perception. AB - Background: The ability to communicate using speech is a remarkable skill, which requires precise coordination of articulatory movements and decoding of complex acoustic signals. According to the traditional view, speech production and perception rely on motor and auditory brain areas, respectively. However, there is growing evidence that auditory-motor circuits support both speech production and perception.Aims: In this article we provide a review of how transcranial magnetic stimulation (TMS) has been used to investigate the excitability of the motor system during listening to speech and the contribution of the motor system to performance in various speech perception tasks. We also discuss how TMS can be used in combination with brain-imaging techniques to study interactions between motor and auditory systems during speech perception.Main contribution: TMS has proven to be a powerful tool to investigate the role of the articulatory motor system in speech perception.Conclusions: TMS studies have provided support for the view that the motor structures that control the movements of the articulators contribute not only to speech production but also to speech perception. PMID- 22942515 TI - Physiotherapists in health promotion: findings of a forum. PMID- 22942514 TI - The Relationship between Falls Efficacy and Improvement in Fall Risk Factors Following an Exercise Plus Educational Intervention for Older Adults with Hip Osteoarthritis. AB - PURPOSE: Older adults with decreased confidence in their ability to prevent a fall may benefit from an exercise programme that includes self-efficacy-enhancing education. The objectives of this study were to explore differences in fall-risk outcomes in older adults with higher vs. lower levels of falls efficacy and to evaluate the relationship between baseline falls-efficacy status and changes in fall risk factors following two interventions. METHOD: Fifty-four older adults with hip osteoarthritis and at least one risk factor for falls received aquatic exercise twice weekly plus education once weekly (EE) or aquatic exercise only, twice weekly (EO), for 11 weeks. RESULTS: EE participants with low baseline falls efficacy demonstrated significantly (p<0.05) greater improvement in balance and falls efficacy compared to EE participants with high baseline falls efficacy. In the EE group only, baseline falls-efficacy status (low vs. high median split on the Activities-specific Balance Confidence Scale) was significantly (p<0.05) correlated with positive balance and falls-efficacy change scores (Spearman rank r=0.45 and 0.63 respectively). CONCLUSIONS: Individuals with one or more fall risk factors and low falls efficacy may benefit from receiving an intervention that combines exercise with self-efficacy-enhancing education. Falls-efficacy screening may be important for decisions regarding referral to fall-prevention programmes. PMID- 22942516 TI - Kinematic Analysis of Gait Following Intra-articular Corticosteroid Injection into the Knee Joint with an Acute Exacerbation of Arthritis. AB - PURPOSE: The objective of this study was to examine the effects of intra articular corticosteroid injection (ICI) on ipsilateral knee flexion/extension, ankle dorsiflexion/plantarflexion (DF/PF), and hip abduction/adduction (abd/add) during stance phase in people with an acute exacerbation of rheumatoid arthritis (RA) of the knee joint. The study also assessed the effects of ICI on spatiotemporal parameters of gait and functional status in this group. METHODS: Nine people with an exacerbation of RA of the knee were recruited. Kinematic and spatiotemporal gait parameters were obtained for each participant. Knee-related functional status was assessed using the Knee injury and Osteoarthritis Outcome Score (KOOS). Spatiotemporal gait parameters and joint angles (knee flexion, ankle DF/PF, hip abd/add) of the affected side were compared pre- and post-ICI. RESULTS: Data for eight people were available for analysis. Median values for knee flexion and ankle PF increased significantly following ICI. Gait parameters of cadence, velocity, bilateral stride length, bilateral step length, step width, double-support percentage, and step time on the affected side also showed improvement. Pain and knee-related functional status as measured by the KOOS showed improvement. CONCLUSIONS: This study demonstrated a beneficial short-term effect of ICI on knee-joint movements, gait parameters, and knee-related functional status in people with acute exacerbation of RA of the knee. PMID- 22942517 TI - Effect of latent myofascial trigger points on strength measurements of the upper trapezius: a case-controlled trial. AB - PURPOSE: The purpose of this article was to determine whether strength is altered in the upper trapezius in the presence of latent myofascial trigger points (MTrP). METHODS: This study was case controlled and used convenience sampling. The sample recruited was homogeneous with respect to age, sex, height, and body mass. Participants were assessed for the presence of latent MTrP in the upper trapezius and placed into two groups: an experimental group that had latent MTrP in the upper trapezius and a control group that did not. Eighteen women (mean age 21.4 y, SD 1.89; mean height 156.9 cm, SD 4.03; and mean body mass 51.7 kg, SD 5.84) made up the experimental group, and 19 women (mean age 20.3 y, SD 1.86; mean height 158.6 cm, SD 3.14; and mean body mass 53.2 kg, SD 5.17) made up the control group. We obtained strength measurements of the non-dominant arm using a handheld dynamometer and compared them between the two groups. RESULTS: The difference in the strength measurements between the two groups was not statistically significant (p=0.59). CONCLUSIONS: The presence of latent MTrPs may not affect the strength of the upper trapezius. PMID- 22942518 TI - Clinician's Commentary on Arnold et al.(1). PMID- 22942520 TI - Clinician's Commentary on Roig et al.(1). PMID- 22942519 TI - Postural Control Is Impaired in People with COPD: An Observational Study. AB - PURPOSE: We investigated deficits in postural control and fall risk in people with chronic obstructive pulmonary disease (COPD). METHOD: Twenty people with moderate to severe COPD (mean age 72.3 years, standard deviation [SD] 6.7 years) with a mean forced expiratory volume in 1 second (FEV(1)) of 46.7% (SD 13%) and 20 people (mean age 68.2 years, SD 8.1) who served as a comparison group were tested for postural control using the Sensory Organization Test (SOT). A score of zero in any trial of the SOT was registered as a fall. On the basis of the SOT results, participants were categorized as frequent fallers (two or more falls) or as fallers (one fall). To explore the potential influence of muscle weakness on postural control, knee extensors concentric muscle torque was assessed with an isokinetic dynamometer. Physical activity level was assessed with the Physical Activity Scale for the Elderly. RESULTS: People with COPD showed a 10.8% lower score on the SOT (p=0.016) and experienced more falls (40) than the comparison group (12). The proportion of frequent fallers and fallers during the SOT was greater (p=0.021) in the COPD group (four of 10) than in the comparison group (two of seven). People with COPD showed deficits in knee extensors muscle strength (p=0.01) and a modest trend toward reduced physical activity level. However, neither of these factors explained the deficits in postural control observed in the COPD group. CONCLUSIONS: People with COPD show deficits in postural control and increased risk of falls as measured by the SOT. The deficits in postural control appear to be independent of muscle weakness and level of physical activity. Postural control interventions and fall risk strategies in the pulmonary rehabilitation of COPD are recommended. PMID- 22942521 TI - Arthritis extended-role practitioners: impact on community practice (an exploratory study). AB - PURPOSE: We compared practice of extended role practitioners and experienced therapists without extended practice training to determine differences in assessment and management of clients with inflammatory arthritis, in preparation for a randomized controlled trial. METHODS: Retrospective review of randomly selected charts of extended-role trained occupational therapists or physiotherapists and from experienced therapists matched on therapist discipline, geographical location, and time of referral. Three trained reviewers used standardized forms to extract data independently. RESULTS: We reviewed 58 charts of adult clients with inflammatory arthritis. Compared with experienced therapists, extended-role practitioners were more likely to receive referrals specifically for assessments (52% vs. 14%); to treat clients with undifferentiated arthritis (48% vs. 10%); to document comorbidities (90% vs. 66%); to advocate on behalf of the client with the client's family, physician, or specialist (52% vs. 21%); to recommend or provide exercise or physical activity (86% vs. 62%); to educate clients about pain management (41% vs. 28%), energy conservation (24% vs. 14%), and posture (21% vs. 7%); to recommend splints (41% vs. 31%); and to refer for or recommend radiologic or laboratory assessments (14% vs. 3%). Experienced therapists were more likely to provide education about joint protection (41% vs. 31%), community resources (31% vs. 7%), and assistive devices (45% vs. 21%). CONCLUSIONS: We identified possible differences in practice between extended-role practitioners and experienced therapists without training for extended practice. Capturing these details in future studies evaluating the efficacy of extended role practitioner interventions will be important. PMID- 22942522 TI - Clinician's Commentary on Lineker et al.(1). PMID- 22942523 TI - Internet Use among Community-Based Rehabilitation Workers in Bosnia and Herzegovina: A Cross-Sectional Survey. AB - PURPOSE: The Internet may be one way to support and improve rehabilitation practice and service delivery in low- and middle-income countries (LMICs) such as Bosnia and Herzegovina. Little information exists on use of the Internet to enhance the practice and professional development of community-based rehabilitation (CBR) workers in LMICs. The purpose of this study was to assess the patterns of and barriers to Internet use by CBR workers in Bosnia and Herzegovina. METHODS: Participants were CBR workers (physiotherapists, physiatrists, and technicians) from Bosnia and Herzegovina who attended a conference or workshop in 2005. A cross-sectional questionnaire was administered in the local language to assess Internet use. Descriptive results were summarized in tables. Bivariate and multiple logistic regressions were used to assess factors associated with Internet use. RESULTS: A total of 33% of respondents had never used the Internet. Common barriers to Internet use included "not enough time" (24%), "no access" (23%), and "lack of skill" (18%). Participants with higher levels of education had greater odds of using the Internet than physiotherapy school graduates (odds ratio=7.6, p=0.016) and had greater odds of using the Internet to obtain medical, rehabilitation, or health information (odds ratio=5.8, p=0.028). CONCLUSIONS: Improving CBR workers' access to the Internet and their proficiency in using it may enable them to obtain valuable rehabilitation-related information and enhance communication among CBR workers, potentially translating into improved rehabilitation services for people with disabilities in LMICs. PMID- 22942524 TI - Recent experiences and challenges of military physiotherapists deployed to afghanistan: a qualitative study. AB - PURPOSE: Military physiotherapists in the Canadian Forces meet the unique rehabilitation needs of military personnel. Recently, the physiotherapy officer role has evolved in response to the Canadian Forces' involvement in the combat theatre of operations of Afghanistan, and this has created new and unique challenges and demands. The purpose of this study was to describe the experiences and challenges of military physiotherapists deployed to Afghanistan. METHODS: A qualitative research design guided by descriptive phenomenology involved recruitment of key informants and in-depth interviews as the data collection method. The interviews were transcribed verbatim and the data analyzed using a foundational thematic analysis approach. Strategies of peer review and member checking were incorporated into the study design. RESULTS: Six military physiotherapists were interviewed. They described rewarding experiences that were stressful yet highly career-satisfying. Main challenges revolved around heavy workloads, an expanded scope of practice as sole-charge practitioners, and the consequences and criticality of their clinical decisions. CONCLUSIONS: Our findings suggest that enhanced pre-deployment training and the implementation of a stronger support network will improve the capabilities of military physiotherapists deployed to difficult theatres of operations. This type of systematic and comprehensive research is needed to assist the Canadian Forces in proactively preparing and supporting physiotherapists deployed on future missions. PMID- 22942525 TI - Management of low back pain by physical therapists in quebec: how are we doing? AB - PURPOSE: In this study, we characterized physiotherapists' attitudes and beliefs about the bio-psychosocial problem of low back pain (LBP), their use of clinical practice guidelines (CPGs), and the extent to which their advice and treatment is in line with best-evidence CPGs. METHODS: One hundred eight physiotherapists completed an online survey that included questionnaires exploring the strength of physiotherapists' biomedical and bio-psychosocial orientations toward the management of LBP: the Pain Attitudes and Beliefs Scale for Physiotherapists and the Attitudes to Back Pain Scale for musculoskeletal practitioners. In addition, participants responded to questions about treatment recommendations for patients in two vignettes. RESULTS: Only 12% of respondents were aware of CPGs. Physiotherapists with a stronger biomedical orientation scored the severity of spinal pathology higher in the patient vignettes. A stronger biomedical orientation was also associated with disagreement with recommendations to return to usual activity or work. CONCLUSIONS: The results suggest limited awareness by physiotherapists of best-evidence CPGs and contemporary understandings of LBP that support early activation and self-management. Research to better understand and facilitate the implementation of best-evidence professional education and clinical practice is an urgent priority. PMID- 22942527 TI - What Does the Cochrane Collaboration Say about Preventing Falls and Injuries? PMID- 22942526 TI - A synthesis of best evidence for the restoration of upper-extremity function in people with tetraplegia. AB - PURPOSE: Because upper-limb function represents overall function for individuals with tetraplegia, the restoration of upper-extremity function is exceedingly important for this population. The purpose of this review was to identify interventions that optimize upper-limb function after tetraplegia based on best available evidence. METHODS: A search of MEDLINE, AMED, and PubMed with the search terms "hand function AND tetraplegia" and "upper limb function AND tetraplegia" found 384 articles. After elimination of duplicates and review of titles and abstracts, 43 studies were found to be applicable. Study quality of all applicable studies was assessed with a modified version of the Scottish Intercollegiate Guidelines Network for Cohort Studies methodology. RESULTS: The applicable studies were organized into three categories: conventional therapies (CT), electrical stimulation therapies (ES), and surgical interventions (SI). The proportion of papers in each category that presented with sufficient methodological quality to contribute to best evidence was as follows: CT: 0/2; ES: 10/21; SI: 6/20. CONCLUSIONS: ES therapies are beneficial as assistive technologies and as therapeutic intervention in the subacute phase of recovery. SIs are suitable for individuals who meet very specific criteria for tendon transfer surgery. Further clinical trials are warranted for ES and SI therapies to substantiate prescription of therapeutics. PMID- 22942528 TI - Physiotherapy Canada volume 63, annual index - 2011. PMID- 22942529 TI - Modulating molecular and nanoparticle transport in flexible polydimethylsiloxane membranes. AB - The ability to fabricate flexible filtration membranes that can selectively separate particles of different sizes is of considerable interest. In this article, we describe a facile, reproducible and simple one-step method to produce pores in polydimethylsiloxane (PDMS) membranes. We embedded micron-sized NaHCO(3) particles in 50 micron thick PDMS films. After curing, the membranes were immersed in concentrated HCl acid. Pores were generated in the membrane by the evolution of CO(2) gas from the reaction of NaHCO(3) and HCl. High resolution Scanning Electron Microscope images clearly reveal the presence of openings on the surface and the cross-section of the membranes. Fluorescence and back scattered electron imaging of porous PDMS membrane with embedded gold nanoparticles and comparison with non-porous PDMS membranes provided unambiguous evidence of pores in the membrane. Transport studies of molecular fluoresceinate ions, ions (sodium and chloride) and 240 nm polystyrene nanoparticles through these membranes demonstrate passable pores and existence of channels within the body of the membrane. Mechanically stretching the porous PDMS membrane and comparing the flow rates of fluoresceinate ions and the polystyrene beads through the stretched and unstretched membranes allowed a direct proof of the modulation of transport rate in the membranes. We show that stretching the membranes by 10% increases the flow rate of fluorescein molecules by 2.8 times and by a factor of approximately ~40% for the polystyrene nanoparticles. PMID- 22942530 TI - Making IBM's Computer, Watson, Human. AB - This essay uses the recent victory of an IBM computer (Watson) in the TV game, Jeopardy, to speculate on the abilities Watson would need, in addition to those it has, to be human. The essay's basic premise is that to be human is to behave as humans behave and to function in society as humans function. Alternatives to this premise are considered and rejected. The viewpoint of the essay is that of teleological behaviorism. Mental states are defined as temporally extended patterns of overt behavior. From this viewpoint (although Watson does not currently have them), essential human attributes such as consciousness, the ability to love, to feel pain, to sense, to perceive, and to imagine may all be possessed by a computer. Most crucially, a computer may possess self-control and may act altruistically. However, the computer's appearance, its ability to make specific movements, its possession of particular internal structures (e.g., whether those structures are organic or inorganic), and the presence of any nonmaterial "self," are all incidental to its humanity. PMID- 22942531 TI - Minding Rachlin's eliminative materialism. AB - Rachlin's teleological behaviorism eliminates the first-person ontology of conscious experience by identifying mental states with extended patterns of behavior, and thereby maintains the materialist ontology of science. An alternate view, informed by brain-based and externalist philosophies of mind, is shown also to maintain the materialist ontology of science, but without eliminating the phenomenology of consciousness. This view implies that to be judged human, machines not only must exhibit complicated temporally structured patterns of behavior, but also must have first-person conscious experience. Although confirming machine sentience is likely to be problematic, extended contact with a machine that results in a person interacting with it as if it were conscious could reasonably lead to the conclusion that for all intents and purposes it is. PMID- 22942532 TI - The central role for behavior analysis in modern robotics, and vice versa. PMID- 22942533 TI - What would it be like to be IBM's computer, Watson? PMID- 22942534 TI - Nonneurocognitive extended consciousness. PMID- 22942535 TI - Our overt behavior makes us human. PMID- 22942536 TI - The role of atomic repertoires in complex behavior. AB - Evolution and reinforcement shape adaptive forms and adaptive behavior through many cycles of blind variation and selection, and therein lie their parsimony and power. Human behavior is distinctive in that this shaping process is commonly "short circuited": Critical variations are induced in a single trial. The processes by which this economy is accomplished have a common feature: They all exploit one or more atomic repertoires, elementary units of behavior each under control of a distinctive stimulus. By appropriate arrangements of these discriminative stimuli, an indefinite number of permutations of atomic units can be evoked. When such a permutation satisfies a second contingency, it can come under control of the relevant context, and the explicit arrangement of discriminative stimuli will no longer be required. Consequently, innovations in adaptive behavior can spread rapidly through the population. A consideration of atomic repertoires informs our interpretation of generalized operants and other phenomena that are otherwise difficult to explain. Observational learning is discussed as a case in point. PMID- 22942537 TI - Neuroscientific measures of covert behavior. AB - In radical behaviorism, the difference between overt and covert responses does not depend on properties of the behavior but on the sensitivity of the measurement tools employed by the experimenter. Current neuroscientific research utilizes technologies that allow measurement of variables that are undetected by the tools typically used by behavior analysts. Data from a specific neuroscientific technique, event-related potential (ERP), suggest that emission of otherwise covert responses can be indexed and that such covert responses are sensitive to stimulus control and selection by consequences. The P3 ERP effect is proposed as indicative of emission. Moreover, ERP results in semantic priming experiments suggest that operants are sensitive to changes in stimulus control even when they are not emitted (latent responses). Changes in response strength of latent responses as a function of stimulus control can in fact be measured by reaction time data and an ERP dependent variable called the N400 effect. If the interpretations provided in this paper are accurate, an index of covertly emitted operants (P3 effect) constitutes experimental evidence suggesting the validity of a Skinnerian radical behaviorist perspective on behavior. Moreover, in a Skinnerian paradigm, measured fluctuations in the response strength of latent operants as a function of environmental changes (N400 effect) would validate Palmer's (2009) concept of the repertoire. PMID- 22942538 TI - Motivating operations affect stimulus control: a largely overlooked phenomenon in discrimination learning. AB - Several recent studies have explored what Michael (e.g., 1982) termed the value altering effect and the behavior-altering effect of motivating operations. One aspect of the behavior-altering effect that has garnered no recent attention involves changes in stimulus control produced by motivating operations. To call attention to this aspect of the behavior-altering effect, we herein review 11 studies that are concerned with the influence of varying levels of food or water deprivation on stimulus generalization. These studies suggest that motivating operations influence stimulus control (a) by changing the evocative strength of not just an established discriminative stimulus, but also of stimuli that are physically similar to it; (b) by changing the range of stimuli that evoke the operant in question; and (c) by exerting these effects in a graded fashion. These findings are potentially of conceptual and applied significance, and it appears that further research examining how motivating operations alter stimulus control, including some studies suggested herein, is warranted. PMID- 22942540 TI - B. F. Skinner: the writer and his definition of verbal behavior. AB - Skinner's definition of verbal behavior, with its brief and refined versions, has recently become a point of controversy among behavior analysts. Some of the arguments presented in this controversy might be based on a misreading of Skinner's (1957a) writings. An examination of Skinner's correspondence with editors of scientific journals shows his sophisticated mastery of English and his knowledge of contemporary approaches of linguistics, and might help to settle the meaning of the passages involved in the controversy. A more precise definition of verbal behavior, deduced from Skinner's distinction between verbal and nonverbal operants, is suggested, and a possible reason why Skinner did not define verbal behavior in the terms proposed by this alternative definition is discussed. The alternative definition is more compatible with a functional approach to behavior and highlights what is specific to verbal behavior by pointing to the conventions of the verbal community. Some possible consequences of adopting this alternative definition are described. PMID- 22942539 TI - Evolution of research on interventions for individuals with autism spectrum disorder: implications for behavior analysts. AB - The extraordinary success of behavior-analytic interventions for individuals with autism spectrum disorder (ASD) has fueled the rapid growth of behavior analysis as a profession. One reason for this success is that for many years behavior analysts were virtually alone in conducting programmatic ASD intervention research. However, that era has ended. Many investigators from other disciplines are now carrying out large-scale intervention studies and beginning to report successes of their own. The increasing number and range of studies has the potential to improve services for individuals with ASD, and it challenges behavior analysts to intensify their research efforts. PMID- 22942541 TI - On Critchfield's proposal: student concerns and recommendations. PMID- 22942542 TI - Common goals for the science and practice of behavior analysis: a response to critchfield. PMID- 22942543 TI - Conflicts of interest. PMID- 22942544 TI - Medical and endoscopic management of gastric varices. AB - In the past 20 years, our understanding of the pathophysiology and management options among patients with gastric varices (GV) has changed significantly. GV are the most common cause of upper gastrointestinal bleeding in patients with portal hypertension after esophageal varices (EV) and generally have more severe bleeding than EV. In the United States, the majority of GV patients have underlying portal hypertension rather than splenic vein thrombosis. The widely used classifications are the Sarin Endoscopic Classification and the Japanese Vascular Classifications. The former is based on the endoscopic appearance and location of the varices, while the Japanese classification is based on the underlying vascular anatomy. In this article, the authors address the current concepts of classification, epidemiology, pathophysiology, and emerging management options of gastric varices. They describe the stepwise approach to patients with gastric varices, including the different available modalities, and the pearls, pitfalls, and stop-gap measures useful in managing patients with gastric variceal bleed. PMID- 22942545 TI - The History and Evolution of Balloon-occluded Retrograde Transvenous Obliteration (BRTO): From the United States to Japan and Back. AB - The concept of obliterating varices that complicate portal hypertension dates back to the 1970s, but its minimally invasive clinical utilization was probably lost with the advent of the transjugular intrahepatic portosystemic shunt (TIPS). The conception of retrograde obliteration of a gastrorenal shunt via the left renal vein was reported by Olson et al from the University of Indiana. However, the definition, development, technical perfection, and clinical implementation of the balloon-occluded retrograde transvenous obliteration (BRTO) occurred in Japan (by Kanagawa et al and others). The BRTO-procedure is currently undergoing a renaissance in the United States particularly for patients who are not TIPS candidates. PMID- 22942546 TI - Balloon-occluded Retrograde Transvenous Obliteration (BRTO): Preprocedural Evaluation and Imaging. AB - Patients undergoing balloon retrograde transvenous obliteration (BRTO) are mostly decompensated cirrhotic with either bleeding gastric varices (GV) or hepatic encephalopathy. It is crucial that clinicians are up-to-date with the assessments needed prior to BRTO to anticipate and prevent complications, and to deliver critical quality care. These patients will require preprocedural assessments and management, including endoscopic, clinical, laboratory, and imaging evaluation. Endoscopic evaluation is mandatory prior to BRTO, and it is highly recommended that it be performed at the same institution where BRTO will be performed. It is essential that clinicians are aware of the potential benefits and complications that may result from BRTO. These complications should be anticipated and prevented when possible. For GV bleeders, there should be consideration of a transvenous intrahepatic portosystemic shunt (TIPS) during or before BRTO in patients with refractory ascites or pleural effusion, as well as endoscopic banding or a TIPS in patients with high-risk esophageal varices. Patients undergoing BRTO are usually complicated and require a team approach. In this article, the authors address these assessment and preparatory management and planning procedures prior to the BRTO procedure as well as expected outcomes and potential complications. PMID- 22942547 TI - Anatomy and classification of gastrorenal and gastrocaval shunts. AB - The gastric varices communicate with gastrorenal and gastrocaval shunts and are classified according to the pattern of venous inflow into three types, which differ in the number and location of the inflow veins. The gastric varices are also classified according to their venous drainage into four different types, reflecting the size and number of collateral veins communicating with the gastric varices and the gastrorenal/gastrocaval shunt. Lastly, the gastric varices are classified according to their appearance on balloon-occluded retrograde venography into five grades representing the degree of opacification of the gastric varices and the collateral veins. Understanding these anatomic classifications is crucial in planning endovascular obliteration of gastric varices. PMID- 22942548 TI - Balloon-occluded Retrograde Transvenous Obliteration (BRTO): Technique and Intraprocedural Imaging. AB - Balloon-occluded retrograde transvenous obliteration (BRTO) is an endovascular technique used as a therapeutic adjunct or alternative to transjugular intrahepatic shunts (TIPS) in the management of gastric varices. Occlusion balloons are strategically placed to modulate flow within the gastrorenal or gastrocaval shunt to allow stagnation of the sclerosant material within the gastric varix. The approach and complexity of the procedure depends on the anatomic classification of inflow and outflow veins of the varix. Ethanolamine oleate has been described as the main sclerosant used in this procedure. Recently, foam sclerosants have gained popularity as alternative embolization agents, which provide the advantage of better variceal wall contact and potentially less dose of sclerosant. PMID- 22942549 TI - Variations of Balloon-occluded Retrograde Transvenous Obliteration (BRTO): Balloon-occluded Antegrade Transvenous Obliteration (BATO) and Alternative/Adjunctive Routes for BRTO. AB - Alternative routes for transvenous obliteration are often sought in the management of gastric varices, as well as in the management of other nongastric varices (ectopic varices) such as duodenal and mesenteric varices. These alternative routes can be classified into A-portal venous access routes and B systemic venous access routes. Anecdotally, alternative routes are more commonly required with duodenal and mesenteric varices compared with gastric varices. Twelve percent (2-19%) of patients with gastric varices require alternative/adjunctive variceal access routes. The most common alternative route described for transvenous obliteration of gastric varices is the percutaneous transhepatic route, which is commonly referred to in the Japanese literature as percutaneous transhepatic obliteration (PTO). The percutaneous transhepatic obliteration route can be performed alone or in combination with the more traditional balloon-occluded retrograde transvenous obliteration (BRTO) transrenal route. Percutaneous transhepatic obliteration by itself is successful in 44-100% of cases for obliterating gastric varices and is rarely unsuccessful when it is combined with BRTO. Other alternative routes are less commonly described and as a result, their clinical outcomes are relatively anecdotal. However, they are technically more challenging and are less commonly successful. These routes include, but are not confined to transphrenic, transileocolic, trans TIPS (transvenous intrahepatic portosystemic shunt), transgonadal, transazygous, and transrenal capsular vein approaches. PMID- 22942550 TI - Balloon-occluded Retrograde Transvenous Obliteration (BRTO): Follow-Up and Postprocedural Imaging. AB - The majority of patients undergoing balloon retrograde transvenous obliteration (BRTO) are decompensated cirrhotic for either bleeding gastric varices (GV) or hepatic encephalopathy. These patients will require close follow-up and assessments pre- and post-BRTO including clinical, laboratory, endoscopic, and imaging evaluations. It is essential that clinicians are aware of the potential benefits and complications that may result from BRTO. These complications may include fever, chest or epigastric pain, hemoglobinuria, transient hypertension, nausea or vomiting, and many more. These complications usually resolve within the first 10 days. Laboratory abnormalities are transient and uncommon. Radiologic and endoscopic follow-up are required including computed tomography (CT), magnetic resonance imaging (MRI), routine upper endoscopy and endoscopic ultrasound (EUS), which are detailed in this review. Patients undergoing BRTO are usually complicated and will require a team approach. This team should include the hepatologist, endoscopist, and interventional radiologist. Understanding and open dialogue are essential in the management of post-BRTO patients. The authors review the possible benefits, potential complications, and the evaluation tools needed to improve outcomes. PMID- 22942551 TI - Balloon-occluded Retrograde Transvenous Obliteration (BRTO): Technical Results and Outcomes. AB - Variceal bleeding is one of the major complications of portal hypertension. Gastric variceal (GV) bleeding is less common than esophageal variceal (EV) bleeding, however, is associated with a high morbidity and mortality. Balloon occluded retrograde transvenous obliteration (BRTO) is an established procedure for the management of gastric varices in Japan and has shown promising results in the past decade. The technical success rate, intent-to-treat (including technically failed BRTO-procedures) obliteration rate, and the obliteration rate of gastric varices of technically successful BRTO procedures was 91% (79-100%), 86% (73-100%), and 94% (75-100), respectively. BRTO is successful in controlling active gastric variceal bleeding in 95% of cases (91-100%) and in significantly reducing or resolving encephalopathy in 100% of cases. However, BRTO diverts blood into the portal circulation and increases the portal hypertension, thus aggravating esophageal varices with their potential for bleeding. The 1-, 2-, and 3-year esophageal variceal aggravation rates are 27-35%, 45-66%, and 45-91%, respectively. The gastric variceal rebleed rate of successful BRTO procedures, the intent-to-treat gastric variceal rebleed rate, and the global (all types of varices) variceal rebleed rate are 3.2-8.7%, 10-20%, and 19-31%, respectively. However, the advantage of diverting blood into the portal circulation and potentially toward the liver is improved hepatic function and possible patient survival. Unfortunately, the improved hepatic function is transient (for 6-12 months); however, it is preserved in the long-term (1-3 years). Patient 1-, 2-, 3 , and 5-year survival rates are 83-98%, 76-79%, 66-85%, and 39-69%, respectively. Patient survival is determined by baseline hepatic reserve and the presence of hepatocellular carcinoma. PMID- 22942553 TI - Onyx (Ethylene-vinyl Alcohol Copolymer) in Peripheral Applications. AB - Onyx is a nonadhesive liquid embolic agent approved for the treatment of brain arteriovenous malformations. Here, the use of Onyx is discussed in different peripheral procedures. The Onyx's features, its manipulation, technical details, tips, and tricks are presented followed by illustrative cases. PMID- 22942554 TI - Chest port fracture caused by power injection. PMID- 22942552 TI - Transjugular Intrahepatic Portosystemic Shunt (TIPS) versus Balloon-occluded Retrograde Transvenous Obliteration (BRTO) for the Management of Gastric Varices. AB - Variceal bleeding is one of the major complications of portal hypertension. Gastric variceal bleeding is less common than esophageal variceal bleeding; however, it is associated with a high morbidity and mortality rate and its management is largely uncharted due to a relatively less-established literature. In the West (United States and Europe), the primary school of management is to decompress the portal circulation utilizing the transjugular intrahepatic portosystemic shunt (TIPS). In the East (Japan and South Korea), the primary school of management is to address the gastric varices (GVs) specifically by sclerosing them utilizing the balloon-occluded retrograde transvenous obliteration (BRTO) procedure. The concept (1970s), evolution, and development (1980s-1990s) of both procedures run parallel to one another; neither is newer than the other is. The difference is that one was adopted mostly by the East (BRTO), while the other has been adopted mostly by the West (TIPS). TIPS is effective in emergently controlling bleeding for GVs even though the commonly referenced studies about managing GVs with TIPS are studies with TIPS created by bare stents. However, the results have improved with the use of stent grafts for creating TIPS. Nevertheless, TIPS cannot be tolerated by patients with poor hepatic reserve. BRTO is equally effective in controlling bleeding GVs as well as significantly reducing the GV rebleed rate. But the resultant diversion of blood flow into the portal circulation, and in turn the liver, increases the risk of developing esophageal varices and ectopic varices with their potential to bleed. Unlike TIPS, the blood diversion that occurs after BRTO improves, if not preserves, hepatic function for 6-9 months post-BRTO. The authors discuss the detailed results and critique the literature, which has evaluated and remarked on both procedures. Future research prospects and speculation as to the ideal patients for each procedure are discussed. PMID- 22942555 TI - Characteristics of General Education Reading Interventions Implemented in Elementary Schools for Students with Reading Difficulties. AB - The implementation of response to intervention requires interventions for struggling students be provided through general education prior to referral for special education. We surveyed elementary teachers (K-3) in one state to examine the characteristics of the supplemental reading interventions that their students receive through general education. Findings reveal differences between grade levels in the amount of time interventions are provided to students, the providers of the intervention, and the material selection for the interventions. No differences between grade levels were noted in the frequency of intervention or instructional group sizes. Three-quarters of the teachers reported providing the supplemental interventions to students in their class. The findings provide insight into the resources utilized by schools to implement supplemental interventions. PMID- 22942556 TI - Thin Slice Sampling of Video Footage for Mother/Child Interaction: Application to Single Cases. AB - The purpose was to test the reliability of short samples of parent/child interaction for use in single-subject research. Four variable pairs of mother/child behaviour were coded for seven mother/child play sessions. Each session lasted 20 min and 18 min of the session was behaviourally coded using frame-by-frame analysis. The co-occurrence of the mother/child behaviours within a given time window was computed and an odds ratio was calculated for the co occurrence of the targeted behaviours. The play session was divided into shorter segments (3, 6 and 9 min) and odds ratios of the variable pairs from the shorter segments were compared to the odds ratios from the entire session. Segments of 3 and 6 min did not yield the same pattern of results as the entire session. In single-subject research, evidence of the reliability of the time segment for behavioural coding should be reported in the methods section of original research manuscripts. PMID- 22942557 TI - Childhood Characteristics of Adolescent Inpatients with Early-Onset and Adolescent-Onset Disruptive Behavior. AB - Childhood characteristics are associated with life-course-persistent antisocial behavior in epidemiological studies in general population samples. The present study examines this association in an inpatient sample. The purpose is to identify easily measurable childhood characteristics that may guide choice of treatment for adolescent psychiatric inpatients with severe disruptive behavior. Patients (N = 203) were divided into two groups with either early-onset (EO) or adolescent-onset (AO) disruptive behavior, based on ages at which professional care was used for disruptive behavior, referral to special education, and criminal offences. Both groups differed on several childhood characteristics. No gender differences in these characteristics were found. Logistic regression analysis indicated that individuals with grade retention in primary school, childhood impulsive behavior, and a history of physical abuse, had the highest probability of being member of the EO group. These characteristics are reasonably easy to identify, likely apply to other clinical samples as well, and may help clinicians to target their treatment. PMID- 22942558 TI - Patterns of Intimate Partner Violence in Mothers At-Risk for Child Maltreatment. AB - Using three interviews spanning 3 years, we identified intimate partner violence (IPV) classes and determined how class membership changed over time amongst a sample of 217 mothers at-risk for child maltreatment that were enrolled in an early childhood home visitation evaluation study. Data on perpetration/victimization, IPV type (verbal, physical, and sexual abuse and injury) and severity were used to conduct latent class analyses at each time point. Latent transition analyses established the proportion of mothers who changed classes over time. A three-class solution (minimal, moderate, and high IPV) was indicated at each time point. All classes included mutual IPV. Partners used minor verbal abuse in the minimal class, minor and severe verbal abuse and minor physical abuse in the moderate class, and all IPV categories in the high class. At each transition, 40% or more moved from minimal to moderate or high IPV. This movement emphasizes the need to screen women frequently and develop interventions recognizing the dynamic nature of IPV. PMID- 22942559 TI - Preparation and Characterization of N-Halamine-based Antimicrobial Fillers. AB - The purpose of this study was to demonstrate that the surface of CaCO(3) fillers could be coated with an N-halamine based fatty acid to make the filler surface organophilic and accomplish antibacterial activity simultaneously, rendering the resulting polymer-filler composites antimicrobial. Thus, a new bi-functional compound, 4, 4 -Dimethyl hydantoin-undecanoic acid (DMH-UA), was synthesized by treating the potassium salt of dimethyl hydantoin (DMH) with 11-bromoundecanoic acid (BUA). Upon chlorination treatment with diluted bleach, DMH-UA was transformed into 3-chloro-4, 4-dimethyl hydantoin- undecanoic acid (Cl-DMH-UA). Alternatively, DMH-UA could be coated onto the surface of CaCO(3) to obtain the corresponding calcium salt, 4, 4-dimethyl hydantoin-undecanoic acid-calcium carbonate (DMH-UA-CaCO(3)). In the presence of diluted chlorine bleach, the coated DMH-UA on the surface of CaCO(3) was transformed into Cl-DMH-UA, leading to the formation of Cl-DMH-UA-CaCO(3). The reactions were characterized with FT IR, NMR, UV, DSC and SEM analyses. Both Cl-DMH-UA and Cl-DMH-UA-CaCO(3) were used as antimicrobial additives for cellulose acetate (CA). The antimicrobial efficacy of the resulting samples was evaluated against both Escherichia coli (Gram negative bacteria) and Staphylococcus aureus (Gram-positive bacteria). It was found that with the same additive content, CA samples with Cl-DMH-UA-CaCO(3) and Cl-DMH-UA had very similar antimicrobial and biofilm-controlling activity, but the former released less active chlorine into the surrounding environment than the latter. PMID- 22942561 TI - Evaluation of platelets as predictive parameters in dengue Fever. AB - Dengue is an arboviral disease and occurs in tropical countries where over 2.5 billion people are at risk of infection. Each year an estimated 100 million cases of dengue fever (DF) occur and between 2.5 and 5 lakh cases of dengue hemorrhagic fever (DHF) are reported to WHO. Severe thrombocytopenia and increased vascular permeability are two major characteristics of DHF. A study was conducted to note the relationship between the platelet counts and severity of the disease in pediatric cases of dengue fever. Platelet counts were found to be predictive as well as recovery parameter of DF/DHF/DSS. PMID- 22942560 TI - Hemophilia care in India: a review and experience from a tertiary care centre in uttar pradesh. AB - Approximately 14,000 people with hemophilia are registered at the Hemophilia Federation of India; however, hemophilia remains under-diagnosed and many cases are not registered. In June 2009, the Government of Uttar Pradesh made anti hemophilic factors available at a few centers, including the Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow. Consequently, the level of hemophilia care has improved considerably in recent times. Amongst the many challenges facing people with hemophilia, the development of inhibitors, which neutralize clotting factors provided by replacement therapy, is the most feared one. Healthcare professionals who treat people with hemophilia should not only be knowledgeable about the condition and committed to bettering the management of hemophilia, but also take responsibility for the judicious allocation of resources for various aspects of managing hemophilia. This manuscript aims to raise awareness regarding the detection and management of inhibitors in hemophilia based on the experience of a tertiary care hemophilia treatment centre in Uttar Pradesh, India. PMID- 22942562 TI - Piperacillin-tazobactum plus amikacin versus ceftazidime plus amikacin as empirical therapy for Fever in neutropenic patients with hematological malignancies. AB - Infections are one of the main cause of death in cancer patients particularly when granulocytopenia is present. A number of drugs have been used for the treatment of neutropenic patients with fever. Most published literature has shown piperacillin-tazobactum in combination with amikacin to be significantly more effective than ceftazidime plus amikacin in empirical treatment of febrile episodes in patients with neutropenia. In view of the reported literature we have tried this combination in our febrile neutropenic patients with haematological malignancies at PGIMS Rohtak. It was an open randomized trial. Patients were divided into two groups of 20 each. In the first group (group A) piperacillin tazobactum (4 + 0.5 g 6 hourly) with single daily dose of amikacin 20 mg/kg was given. In the second group (group B) ceftazidime 40 mg/kg every 8 hourly with single daily dose of amikacin 20 mg/kg was given. The most common site of infection was blood followed by urinary tract, respiratory tract and oral cavity. 13 (65%) patients in group A and 12 (60%) patient in group B showed clinical success. In our study however in our patients a better response was seen in patients with piperacillin-tazobactum + amikacin (65% vs. 60%). So it is recommended that piperacillin-tazobactum + amikacin should be given in febrile neutropenic patients with haematological malignancies. PMID- 22942563 TI - The Outcome of HyperCVAD Combined with Alemtuzumab for the Treatment of Aggressive T-Cell and NK-Cell Neoplasms. AB - We report our experience in using six cycles of hyperCVAD in combination with alemtuzumab for the treatment of aggressive T-cell and NK/T-cell neoplasms. Seven females and six males with the median age of 41 (range 18-60) diagnosed with T cell acute lymphoblastic lymphoma and peripheral T-cell and NK/T-cell neoplasms (n(PTCL) = 6, n(T-cell ALL) = 3, n(NK/T-cell neoplasms) = 4) from 2006 to 2008 were treated with alemtuzumab-hyperCVAD regimen. A total of nine patients (69%) responded to the regimen, with seven achieved complete remission and two achieved partial remission. The median progression free survival and overall survival duration among the responders with complete remission were 12.9 and 24.9 months respectively. The incidence of relapse among the responders was 44% and the overall survival rate was 23%. Only four (31%) patients completed the six cycles of alemtuzumab-hyperCVAD. Others were stopped earlier due to progressive disease (n = 2), cytomegalovirus (CMV) reactivation and/or disease (n = 3), death not due to disease (n = 2), and patient's refusal to continue alemtuzumab (n = 2). The incidence of death not due to disease, CMV reactivation and recurrent CMV reactivation were 50, 50 and 17%, respectively. This study shows that alemtuzumab in combination with hyperCVAD regimen is a feasible regimen but with high toxicity. The toxicity might be reduced with the incorporation of filgrastim and use of valganciclovir as CMV prophylaxis. PMID- 22942564 TI - Hematopoietic stem cell transplantation in a very high risk group of patients with the support of granulocyte transfusion. AB - High risk patients with active fungal infection who had undergone hematopoietic stem cell transplantation (HSCT) with the support of granulocyte transfusions (GTX) as an adjunct to antifungal agents are reviewed retrospectively. Patients requiring immediate allogeneic HSCT for their primary hematological disorders (two severe aplastic anemia, one T cell acute lymphoblastic leukemia (ALL) in second complete remission, one acute myeloid leukemia (AML)-in first complete remission, one T-ALL in refractory relapse) but were denied by other transplant programs due to active invasive fungal infections had undergone HSCT with the support of GTX at the stem cell transplantation unit of Gazi University. Five patients who had undergone six transplants were included in the study and received a total of 38 (3-13) granulocyte transfusions during these six transplants. The median granulocyte concentration was 3.4 * 10(11) per apheresis bag. Full clinical and radiological recovery was achieved in three of the five high risk patients with active invasive fungal infection with the combination of antifungal agents and GTX. Even a very high risk patient with aplastic anemia who had undergone two consecutive transplants due to secondary graft failure was also cured of his primary disease despite the presence of multiple pulmonary fungus balls. Three of the five patients with very high risk features due to the underlying hematological disease and the associated active fungal infection were rescued with allogeneic HSCT performed with the support of GTX combined with antifungal agents. Despite the limitations of this report due to its retrospective nature, it suggests that GTX might be an alternative in patients with active fungal infections who otherwise are denied by the transplant programs. However, prospective randomized studies are required to draw a solid conclusion regarding the role of GTX in HSCT recipients in desperate situations such as active fungal infections. PMID- 22942565 TI - Extra-venous use of autologous platelet concentrate: beginning of a new era of therapy of transfusion medicine? AB - Autologous infusion of blood platelets to induce healing of injured tissue is reported in several recent journals. The presence of many 'platelet-derived factors' forms the basis of these studies. These studies have demonstrated improvement in 70-80% patients over a period of up to several months. We have identified the lapses in their techniques. We decided to undertake a small pilot study to test our use of "platelet concentrate" (U. S. P.) in patients of tendon injuries and also to establish a protocol for the extra-venous use of autologous blood platelets. We present, here, an improved technique of autologous platelet therapy in three groups of patients. Our results are compared with four earlier studies. Enhancement in clinical recovery of patients was achieved in shorter interval of time. We have concluded that use of "Platelet Concentrate" with its quality control tests, seems to be better in place of PRP and/or 'uncontrolled' platelet injection. Further, selection of patients for this therapy is crucial. Patients with acute bursitis do not appear ideal for this kind of therapy. However, chronic tendon injuries that are likely to worsen on corticosteroid injections can be treated with autologous platelets with excellent results. This appears to pave a new path for mesodermal regeneration and healing by extra venous use of platelet concentrate. PMID- 22942566 TI - Expression of P-glycoprotein, Cyclin D1 and Ki-67 in Acute Lymphoblastic Leukemia: Relation with Induction Chemotherapy and Overall Survival. AB - Previous studies showed that non-cycling cells have a higher multidrug resistance (MDR) expression, which may be down-regulated by proliferation induction. Triggering these cells into proliferation down-regulates high MDR expression. The aim of this study was to determine the expression of P-glycoprotein (PGP) and cell cycle parameters (cyclin D1 and Ki-67) in acute lymphoblastic leukemia (ALL) at diagnosis, and to evaluate the correlation between the expressions of each marker, and the clinical significance of such expression with response to induction chemotherapy and overall survival. A total of 78 newly diagnosed ALL patients were enrolled in our study. PGP, cyclin D1 and Ki-67 were determined by flow cytometry. PGP expression was encountered in 10/78 (12.8%) of ALL cases. Cyclin D1 and Ki-67 were expressed in 16/77 (20.6%) and 27/76 (34.6%) of ALL cases, respectively. None of the parameters were associated with response to induction chemotherapy and overall survival. Based on the current analysis, we conclude that a joint immunophenotypic evaluation of PGP and cell cycle parameters like that adopted in this study is unlikely to reveal mechanisms of multidrug resistance associated with the clinical outcome. PMID- 22942568 TI - Unusual Presentation of HIV Vasculopathy in a Child. AB - The manifestations of human immunodeficiency virus (HIV) infection are protean and vasculopathy is an uncommon but important complication. A large-vessel (aorta and femoral and carotid arteries) vasculopathy is rarely described in children. We describe a HIV positive thalassaemic child who developed multiple aneurysms in abdominal aorta. HIV vasculopathy resulted in severe aortoarteritis and was fatal in this child. PMID- 22942567 TI - High Frequency of Inherited Variants in the MEFV Gene in Acute Lymphocytic Leukemia. AB - In the present study, we aimed to determine the frequency of inherited variants in the MEFV (Mediterranean FeVer), the gene responsible for familial Mediterranean fever (FMF), gene in patients with acute lymphocytic leukemia (ALL). The eight MEFV gene variants (M694I, M694V, M680I (G/C-A), V726A, R761H, E148Q and P369S) were detected in 36 patients with ALL and 65 healthy controls; none had own and/or family history compatible with FMF. We identified 11 heterozygous inherited variants in the MEFV gene in both ALL patients and controls. The mean overall frequency of inherited variants in the MEFV gene rate was higher in ALL patients than healthy controls (P = 0.040). It is interesting to note that M680I/0 is predominant variant in patients with ALL. In addition, E148Q variant frequency was also significantly higher in the patient group than the controls (P = 0.012). In conclusion, overall frequency of inherited variants in the MEFV gene was found to be higher in patients with ALL. Based on the present data, it is difficult to reach a definitive conclusion regarding the possibility that inherited variants in the MEFV gene could represent a causative role in ALL. However, the data of our study may provide some new insights in understanding of individual genetic differences in susceptibility to these neoplasms. Further investigations are needed to determine the actual role of inherited variants in the MEFV gene in pathogenesis of ALL. PMID- 22942569 TI - Transient leukemia in down syndrome: report of two cases with review of literature. AB - Transient leukemia (TL) also referred to as transient abnormal myelopoiesis (TAM) or transient myeloproliferative disorder (TMD) is a unique syndrome that frequently occurs in newborns with Down syndrome (DS). It manifests in the first few days of life and shows leukocytosis with blast cells in the blood and bone marrow. This leukemia resolves spontaneously within first few months of life in the majority of cases. In this report we describe two newborns with a karyotype of 47,XY,+21, presented with marked leukocytosis and many blast cells in the peripheral blood. In both the cases, the blasts disappeared and the total leukocyte count reverted to normal without any specific treatment. PMID- 22942570 TI - BK Virus Associated Late Onset Haemorrhagic Cystitis After Allogeneic Peripheral Blood Stem Cell Transplant. AB - Haemorrhagic cystitis (HC) after allogeneic stem cell transplant is a clinical disorder with multiple etiologies. There is an inflammation of the bladder mucosa leading to painful haematuria. Early onset HC is mainly attributed to conditioning chemotherapy consisting of cyclophosphamide. Late onset HC is now being related to reactivation of latent polyoma BK virus (BKV). We describe the case of a 37 year old male with acute myeloid leukemia presenting with haematuria after allogeneic stem cell transplant. PMID- 22942571 TI - Factor XIII Deficiency in Siblings: Importance of Prophylactic Replacement. AB - Factor XIII deficiency, an autosomal recessive trait, can result in serious bleeding manifestation. This case report presents two brothers with Factor XIII deficiency. Though the younger sibling had been screened and diagnosed prophylactic replacement therapy had not been initiated unlike the elder brother. He presented with intracranial haemorrhage needing surgical evacuation while the elder brother remained symptom free on regular prophylactic replacement of FFP. PMID- 22942572 TI - Is it Primary Myelofibrosis or Chronic Lymphocytic Leukemia Related Secondary Myelofibrosis? PMID- 22942573 TI - Biologic perspectives in restorative treatment. AB - One of the primary goals of a long term successful restorative therapy is to establish a physiologic periodontal climate that facilitates the maintenance of periodontal health. The contemporary clinician has a host of alternatives for the restoration of teeth. It is now possible to mimic nature and provide restorations that defy detection but the most challenging procedure in clinical dentistry is fabricating a restoration in gingival harmony. Periodontal health is the basis of all restorative dentistry. Because periodontal disease is a major cause of tooth loss in adults, the clinician must be aware of the biological variables relevant to restorative therapy, basic concepts and clinical modes of therapy available, to be able to develop an appropriate diagnosis and treatment plan. A natural looking prosthesis within a healthy periodontium should represent the ultimate goal. This article addresses the interactions between periodontal tissues and restorative procedures. It reviews the essentials of soft tissue management inherent in restorative dentistry that will increase the probability of a successful restoration. PMID- 22942574 TI - A Comparative Evaluation of Temperature Changes in the Pulpal Chamber during Direct Fabrication of Provisional Restorations: An In Vitro Study. AB - To compare the temperature changes in the pulpal chamber during fabrication of provisional restorations by direct method. A total of 108 three-unit FPD provisional restorations were fabricated on a study model and divided into three main groups according to the material used for the fabrication of matrix. Group A Alginate impression index group, Group B-Polyvinylsiloxane putty impression index group, Group C-Vacuum formed template group. Each group comprising of 36 specimens, was subdivided into three subgroups based on the provisional restorative material used: polymethylmethacrylate (subgroup 1), polyethylmethacrylate (subgroup 2), bis-acryl composite resin (subgroup 3). Intrapulpal temperature changes were observed with the help of a thermocouple probe (connected to a digital microprocessor thermometer) inserted into the pulp chamber of an extracted mandibular second molar mounted on a study model, during the fabrication of provisional restorations by direct method. The subgroups mean temperature rise observed in Group A-A1, A2, A3 was 2.6250 +/- 0.2491, 1.0500 +/- 0.1382, 0.4083 +/- 0.1165, respectively. The subgroups mean temperature rise observed in Group B-B1, B2, B3 was 4.6250 +/- 0.2454, 3.3750 +/- 0.3415, 2.5917 +/- 0.2678, respectively. The subgroups mean temperature rise observed in Group C C1, C2, C3 was 4.7694 +/- 1.8361, 3.0611 +/- 1.5767, 2.3806 +/- 1.5713, respectively. The observations were statistically significant. The intrapulpal temperature rise during fabrication of a provisional restoration depended both on the type of provisional restorative material and the type of matrix used. The clinician should choose carefully the resin and the matrix material while fabricating provisional restorations with direct method. PMID- 22942575 TI - Evaluation of nutritional status and eating pattern in first and second-time denture wearers: a prospective 60 days (2 months) pilot study. AB - Elderly individuals with extensive tooth loss preferentially consume soft, easier to chew foods which have a low nutrient density. The purpose of this study was to suggest that every complete denture wearer has to be periodically counseled by a registered Dietician and Dentist for check up to avoid malnutrition and disease. Fourteen patients were selected for this study. Seven of them with four or five teeth remaining without any functional units and seven patients who were known cases of complete denture wearers with ill-fitting or worn out dentures. The results of the study analyzed the change in eating pattern and hence the nutritional status of two groups of edentulous subjects; Group I (patients who underwent a recent transition from partially edentulous state to a completely edentulous state), and Group II (known complete denture wearers for five to ten years). Clinical examination of Group I showed an improvement, by, the decrease in percentages in both the paleness of the conjunctiva and nails of the selected patients. In Group II, there was a significant change in anthropometry and iron intake and the clinical examination showed positive changes in the patient's normal appearance, eyes and nails. Paired sample statistics between both the groups evaluated significant changes in energy, iron and vitamin C intakes in the dietary assessment chart. The general questionnaire assessment showed an improvement in the eating pattern of both the groups, which, may definitely account for a positive change in the nutritional status of the participants later. This study emphasizes that every complete denture wearer needs to be periodically counseled by a registered dietician and dentist for checkup to avoid malnutrition and disease. PMID- 22942576 TI - Evaluation of design parameters of dental implant shape, diameter and length on stress distribution: a finite element analysis. AB - The aim was to evaluate the design parameters of dental implants shape, diameter and length on stress distribution by finite element analysis (FEA).The objectives of the study was to compare the influence of stress distribution in the implants of screw-vent tapered and parallel design by varying the implant diameter with a standard implant length. Six dental implant models have been simulated three dimensionally. The influence of diameter and length on stress distribution was evaluated by Group I: for screw-vent tapered design (Zimmer Dental Implant Carlsbad, CA, USA) (1) Dental implant model with diameter 3.7 mm and length 13 mm. (2) Dental implant model with diameter 4.1 mm and length 13 mm. (3) Dental implant model with diameter 4.7 mm and length 13 mm. Group II: for parallel design (Zimmer Dental Implant Carlsbad, CA, USA) (4) Dental implant model with diameter 3.7 mm and length 13 mm. (5) Dental implant model with diameter 4.1 mm and length 13 mm. (6) Dental implant model with diameter 4.7 mm and length 13 mm. The 3-D model of the implant was created in the pro-e wildfire 4.0 software by giving various commands. This model was imported to the ANSYS software through IGES (initial graphic exchange specification) file for further analysis. All six models were loaded with a force of 17.1, 114.6 and 23.4 N in a lingual, an axial and disto-mesial direction respectively, simulating average masticatory force in a natural oblique direction, to analyze the stress distribution on these implants. The increase in implant diameter in Group I and Group II from 3.7 to 4.1 mm and from 4.1 to 4.7 mm with constant 13 mm length for screw-vent tapered and parallel design implant resulted in a reduction in maximum value of Von Mises stress in the bone surrounding the implant was statistically significant at 5% level done by student "t" test. The overall maximum value of Von Mises stress was decreased in parallel design implant diameter of 4.7 mm with constant length of 13 mm when compared to screw-vent tapered design implant samples. The results of the FEA computation depend on many individual factors including material properties, boundary conditions interface definition and also on the overall approach to the model. The results depicted that the tapered shape implant design exhibited higher stress levels in bone than the parallel shaped implant design which seemed to be distributing stresses more evenly. The application of a 3-D model simulation with the non-symmetric loading by the masticatory force on a dental implant resulted in a more satisfactory modeling of "clinical reality" than that achieved with 2-D models used in other studies. PMID- 22942577 TI - A critical analysis of complete denture impression procedures: contribution of early prosthodontists in India-part I. PMID- 22942578 TI - Single Stage Silicone Border Molded Closed Mouth Impression Technique-Part II. AB - Functioning of a complete denture depends to a great extent on the impression technique. Several impression techniques have been described in the literature since the turn of this century when Greene [Clinical courses in dental prothesis, 1916] brothers introduced the first scientific system of recording dental impression. Advocates of each technique have their own claim of superiority over the other. The introduction of elastomeric impression materials [Skinner and Cooper, J Am Dent Assoc 51:523-536, 1955] has made possible new techniques of recording impression for complete denture construction. These rubber like materials are of two types; one has a polysulfide base and is popularily known as polysulfide rubber (Thiokol and Mercaptan). The other variety has a silicone base known as silicone rubber or silicone elastomer. Silicone elastomers are available in four different consistencies; a thin easy flowing light bodied material,a creamy medium bodied material, a highly viscous heavy bodied material and a kneadable putty material. This paper describes an active closed mouth impression technique with one stage border molding using putty silicone material as a substitute for low fusing compound. PMID- 22942579 TI - Aesthetic and functional rehabilitation of a case of mutilated dentition and loss of vertical dimensions. AB - Cases of severe attrition are a common finding in daily clinical practice. Attrition leads to loss of vertical dimension, chewing inefficiency and poor esthetics. These cases require complete oral rehabilitation which can be successfully achieved by a systematic approach integrating various concepts of prosthodontics. The primary aim of such complex treatment modalities is to regain the lost function, esthetics, comfort and confidence for the patient. The following case report describes the complete oral rehabilitation of a patient diagnosed of mutilated dentition and reduced vertical dimensions due to severe attrition. A detailed treatment plan was chalked out which included institution of proper oral hygiene measures, extraction of teeth with poor prognosis, restoration of carious teeth, endodontic treatment for carious teeth with periapical involvement. This was followed by foundation restorations of teeth that were crucial for the final prostheses. Patient was given transitional restorations for about 6 weeks with the aim of regaining the lost vertical dimensions. Final rehabilitation was done by fixed dental prostheses. PMID- 22942580 TI - Rehabilitation of anterior edentulous space by glass fiber reinforced composite removable partial denture during preadolescent period: a case report. AB - The loss of anterior teeth can be hurtful to the patient both psychologically and socially. In adolescent patients, temporary replacement of the teeth can minimize these concerns. Many approaches have been described for this temporary replacement. This article presents an alternative approach for oral rehabilitation of the preadolescent male who has edentulous space including median palatine suture in the anterior maxilla. High expectations regarding esthetics by the patient were successfully met by utilizing a glass fiber reinforced composite temporary removable partial denture. Restoration remained intact, with no discoloration or deterioration at 12 months recall. PMID- 22942581 TI - Incidental discovery of odontogenic keratocyst in an edentulous patient: importance of routine pre-prosthetic radiographic evaluation. AB - The most common modality of treatment for completely edentulous patients are conventional removable complete dentures. The protocol for fabrication of complete denture would involve a thorough clinical examination and radiographic investigation. As a routine, unless clinical findings suggest presence of remnant tooth structures, or the patient presents himself with symptoms, the radiographic investigations are overlooked. This case report presents one such situation wherein routine radiographic evaluation of a clinically asymptomatic edentulous individual prior to prosthetic rehabilitation revealed the presence of an odontogenic keratocyst of anterior maxilla substantiating the importance of such routine pre-prosthetic radiographic investigations. PMID- 22942582 TI - Internal characterization of denture base by using acrylic stains and tissue paper. AB - Characterization of an artificial denture is required to give the denture a more natural appearance. This article describes the laboratory procedures for internal characterization of denture base in a removable prosthesis using acrylic stains and absorbent tissue paper incorporated in the heat cure polymerizing denture base resin at the stage of packing. PMID- 22942583 TI - Whats in a name? PMID- 22942584 TI - Are people aware of oral and maxillofacial surgery in India? AB - INTRODUCTION: Maxillofacial surgery is one of the most rapidly expanding specialities in India. There is however a very poor understanding of the scope of the speciality. This paper attempts to find out the awareness of the speciality in India. MATERIALS AND METHODS: A questionnaire was given to 50 medical, dental undergraduate students, 50 medical and dental practitioners, and 50 lay persons giving us a total of 250 responses. 10 common anomalies were chosen and they were asked to choose the most appropriate speciality which they would ask to treat the problem. RESULTS: While trauma and facial deformity correction were recognised to be mainly treated by maxillofacial surgeons, the other maxillofacial problems were poorly recognised to be treated by our speciality. CONCLUSION: This study highlights the need to promote our speciality among the dentists, doctors and general public. and if need be even change the name of our speciality from oral and maxillofacial surgery to a more simple but more easily understood facial surgery. PMID- 22942585 TI - An immunohistochemical analysis of cell cycle markers in oral mucosal dysplastic lesions treated by laser therapy. A pilot study. AB - INTRODUCTION: Over the past 15 years, dysplastic oral mucosal lesions have been treated by laser ablation with variable success. A recent study have shown that the type of laser utilized may be important for patient outcome, however, it may also be changes at a cellular level that could be an important factor in determining recurrence outcome. The aims of this study were to assess cellular markers related to oral dysplastic lesions treated by two different laser types. METHODS AND MATERIALS: Twenty patients with a histopathological diagnosis of dysplasia treated with laser ablation between the years 1992 and 2003 were assessed. Tissue blocks of the original diagnostic biopsy specimens were stained with specific cell cycle markers (Cyclin-D1 and Ki67) via immunohistochemistry and presence of the marker were analysed by virtual microscopy. Patients were assessed according to grade of dysplasia [(mild vs. moderate vs. severe) and the type of laser used (Potassium Titanyl Phosphate (KTP) vs. Carbon Dioxide (CO(2))]. RESULTS: No significant difference in Cyclin-D1 and Ki67 levels were found between the two groups with different grades of dysplasia, however, decreased Cyclin-D1 was found in those patients treated with KTP laser (P = 0.028). CONCLUSIONS: The findings of the present study may indicate cell cycle makers such as Cyclin-D1, may be responsible for the behaviour of dysplastic lesions treated with laser therapy, rather than the type of laser itself, which was reported in previous studies. PMID- 22942586 TI - Peripheral neurectomy: a minimally invasive treatment for trigeminal neuralgia. A retrospective study. AB - AIM: Investigate the efficacy of peripheral neurectomy as a surgical procedure in the treatment of trigeminal neuralgia and to evaluate the results obtained by this procedure and their recurrences in a period of three years followup. MATERIALS AND METHODS: Thirty patients were retrospectively reviewed who underwent peripheral neurectomy. The factors analyzed were the demographic details of the patients, side of involvement, branch of nerve involved and procedure used postoperative complications, prognosis and any additional procedure used in cases of recurrences. RESULTS: The mean age of the patient was 57.1 years (range 35-71 years) more were males (M:F = 1.73:1) and the surgical treatment was peripheral neurectomy of the involved branch following failure of carbamazepine therapy. There was no intra operative and postoperative complications noted and follow up over 3 years revealed only two cases (6.66%) of recurrence. Two patients were lost to followup, total number evaluated between 0 and 3 years after treatment was 28 patients. CONCLUSION: Peripheral neurectomy is one of the oldest, minimal invasive forms of surgery, well tolerated by the patient and can be done under local anesthesia. PMID- 22942587 TI - Management of medical records: facts and figures for surgeons. AB - Medical records are the document that explains all detail about the patient's history, clinical findings, diagnostic test results, pre and postoperative care, patient's progress and medication. If written correctly, notes will support the doctor about the correctness of treatment. Inspite of knowing the importance of proper record keeping in India, it is still in the initial stages. Medical records are the one of the most important aspect on which practically almost every medico-legal battle is won or lost. This article discusses the various aspect of record maintenance. PMID- 22942588 TI - Improving the Standard of Operative Notes within an Oral and Maxillofacial Surgery Department, using an Operative Note Proforma. AB - AIM: The operative note needs to be an accurate and legible account of events occurring in the surgeon's theatre. We set out to discover if operative notes within a British District General Oral and Maxillofacial Surgery department adhered to Royal College of Surgeons (England) guidelines. METHOD: We audited 100 consecutive Oral and Maxillofacial Surgery operations performed within general theatres. As an intervention we designed and piloted a paper based Operative Note Proforma and re-audit was undertaken. RESULTS: Initial audit showed results lacking in certain areas. At re-audit all audit criteria showed improvement. The mean percentage of data point inclusion rose from 76.1 to 98.3% (0.001 < P-value < 0.005). CONCLUSION: Previous papers have discussed various methods of improving operative note standards. We present statistical evidence for the use of an Operative Note Proforma to improve operative note standards within Oral and Maxillofacial Surgery. PMID- 22942589 TI - Management of Subcondylar Fracture through Intraoral Approach with Rigid Internal Fixation. AB - BACKGROUND: In Oral and Maxillofacial Surgery, the majority of the condylar fractures are treated by closed reduction with generally satisfactory long term results. But in such cases of closed reduction, patient will be uncomfortable owing to long term application of inter maxillary fixation (IMF). Where as, Disadvantages of extra oral open reduction and fixation of condylar fracture includes facial nerve damage, facial scars etc. which are surely eliminated by the intraoral reduction and rigid fixation. AIMS AND OBJECTIVES: The present study was conducted to determine the efficacy of reduction and fixation of low sub-condylar fractures through intra-oral approach. METHODOLOGY: In this study, ten patients with low sub-condylar fracture, reported to department of Oral and Maxillofacial Surgery. P.M.N.M. Dental College and Hospital Bagalkot were included. These patients were treated by open reduction and internal fixation through intra-oral approach. All the patients were evaluated postoperatively for mouth opening, occlusion and mandibular deviation with regular radiographic examination for 6 weeks. RESULTS: All operated patients followed for 6 weeks, maximum mouth opening was more than 40 mm in seven patients (range from 40 to 50 mm) and less than 40 mm in three patients. Occlusion was satisfactory in all and none of the patients showed deviation of mandible on mouth opening. Statistical analysis showed that postoperative mouth opening was significant ('t' value = 7.88, 'P' = (0.000) < 0.05) and the test result was significant (S) at 5% level of significance. Statistical analysis of deviation of mouth opening was nonsignificant ['t' value = 1.96, 'P' value (0.081), 0.05]. For occlusion standard photographs were obtained at sixth week and found minor occlusal corrections in two patients are treated by elastic traction for few days. DISCUSSION AND CONCLUSION: Open reduction with internal fixation through intraoral approach has proved to be safe for early function and also effective by avoiding the patient discomfort due to long term intermaxillary fixation, psychological effect, facial nerve damage, facial scar and weight loss. PMID- 22942590 TI - Extended nasolabial flaps in the management of oral submucous fibrosis. AB - PURPOSE: We evaluated the use of extended nasolabial flaps in the management of oral submucous fibrosis. METHODS: We evaluated the use of extended nasolabial flaps in the management of 27 randomly selected patients with histologically confirmed oral submucous fibrosis. They all had interincisal opening of less than 20 mm and were treated by bilateral release of fibrous bands and extended grafting with a nasolabial flap. All patients had postoperative physiotherapy, and were followed up for one year. RESULTS: Their interincisal opening improved significantly from a mean of 11mm (range 3-19) to a mean of 39 mm (range 23-48). CONCLUSIONS: The procedure was effective in the management of patients with oral submucous fibrosis, the main disadvantage being the extraoral scars. PMID- 22942591 TI - Setbacks of bio-resorbable plates and screws in the management of condylar fractures: our experience. AB - PURPOSE: Fractures of the condyle can be managed by open or by closed reduction. This study was designed to mention the complications of the bio-resorbable material we had experienced while using them in the management of condylar fractures. METHODS: Fifteen (11 men and four women) patients with subcondylar fractures were included in the study. Resorbable poly-l-lactide plates and screws were used for the fracture fixation. Patients were followed up clinically and radiographically for a period of 2 years. RESULTS: Seven patients had a satisfactory reduction following the placement of bio-resorbable plates. Three patients had developed a swelling in the pre-auricular region, extending till the angle. Two patients had a screw breakage whereby leading to malunion and three other patients had bone resorption, at the fractured site that was appreciated radiographically. CONCLUSION: Inspite of the advantages of these materials, certain complications has been experienced in our study with regard to the resorption and degradation of the material which has been mentioned and explained in our article. PMID- 22942592 TI - Esthetic evaluation of the treated unilateral cleft lip using photographs and image analysis software: a retrospective study. AB - AIM: The aim of this study was to objectively evaluate the surgical outcome of unilateral cleft lip patients treated by Dr. Adenwalla's modification of Millards rotation advancement technique using image analysis software. METHOD: Of the unilateral cleft lip cases done by a single surgeon using Dr. Adenwalla's modification of Millard's rotation advancement technique, only 11 cases satisfied the photographic standardization criteria (frontal view with both ears visible to minimize rotation and least nostril show to minimize tilt) and were included in this study. These photographs were acquired into the imageJ Software and Farkas cleft-related landmarks were marked on the lip area. The values of treated cleft side and the normal side were used to work out a Cleft Lip Component Symmetry Index. A value of 100 would indicate perfect symmetry of the lip. A value of either less or more would mean a degree of asymmetry. RESULT: The horizontal lip length, vertical lip length from the top of the Cupid's bow to subnasale and nostril floor width were slightly increased on treated side of the lip and the vertical lip length from the top of the Cupid's bow to the alar base, the Cupid's bow width and vermilion length on the treated side were slightly decreased when compared to the normal side. Even though there were some differences, it was not statistically significant. The horizontal and vertical lip lengths, the Cupid's bow width, vermilion length and nostril floor width were almost symmetrical. CONCLUSION: Computer assisted anthropometric analysis of photographs using imageJ software demonstrates that Dr. Adenwalla's modification of Millard's rotation and advancement technique produces esthetic lip symmetry consistently. PMID- 22942593 TI - Comparative evaluation of local anaesthesia with adrenaline and without adrenaline on blood glucose concentration in patients undergoing tooth extractions. AB - BACKGROUND: Lignocaine hydrochloride is the most widely used and easily available local anaesthetic agent. Adrenaline is frequently combined with lignocaine to enhance the duration of anaesthesia, decrease toxicity, to achieve vasoconstriction and to provide a bloodless field. AIM AND OBJECTIVE: This study was conducted to do the comparative evaluation of local anaesthesia with adrenaline and without adrenaline on blood glucose concentration in patients under going tooth extraction. MATERIALS AND METHOD: The study was conducted on 120 patients comprising of 60 healthy and 60 diabetic patients. All these patients were in need of multiple extractions. The patients were in the age group of 18-50 years. On their first visit the patients were given plain lignocaine and tooth extraction was carried out. One week later the same patient was given lignocaine with 1:80,000 adrenaline to carry out tooth extraction. Serial blood glucose estimations were done at definite intervals (prior to administration of local anaesthetic, immediately after injecting the LA, 10 and 20 min following the injection of LA) on both the occasions. RESULTS: The mean blood glucose concentration increased from the base line level of 84.81 to 85.09 mg/dl in healthy patients and from 206.82 to 207.09 mg/dl in diabetic patients 10 min following the injection of 2% plain lignocaine. This increase in blood glucose concentration following the administration of plain lignocaine was statistically not significant (P > 0.05). There was statistically significant (P < 0.005) increase in the blood glucose concentration from 88.81 to 105.55 mg/dl in healthy, and 208.77 to 242.46 mg/dl in diabetic patients 20 min following the injection of lignocaine with adrenaline. INTERPRETATION AND CONCLUSION: While assessing the generalized effects of local anaesthetic solutions, metabolic as well as haemodynamic responses should be investigated. Adrenaline containing LA should be used with caution in Type 2 diabetics as adrenaline causes suppression of insulin release. PMID- 22942595 TI - A huge epidermoid cyst endangering life. AB - Epidermoid cyst of the neck or auricular area are relatively more common than that of the oral cavity. In most cases about 80% they remain asymptomatic. But in about 20% cases it becomes painful because of secondary infection seeking treatment. Here we present a case report of biopsy proved Epidermoid cyst with life threatening infection. PMID- 22942596 TI - The role of systemic condition in the management of maxillofacial infections. AB - Ludwig's Angina is a rare type of facial infection which formerly invariably was fatal but now with adequate surgical and antibiotic treatment has a much reduced mortality. In spite of the recent advances in therapy, rare and potentially life threatening complications may still arise from time to time and as a result account for significant morbidity and mortality. A case of Ludwig's angina reported at A.B Shetty Memorial Institute of Dental Sciences, Mangalore, India resulting in fatality, in spite of surgical and antibiotic treatment, due to underlying systemic condition and involvement of multiple resistant organisms. The condition was worsened by subsequent esophageal rupture and death occurred due to multiple organ failure. PMID- 22942594 TI - Cephalometric methods of prediction in orthognathic surgery. AB - Over the past decade the growing number of adult patients seeking for orthodontic treatment made orthognathic surgery popular. Surgical and orthodontic techniques have developed to the point where combined orthodontic and surgical treatment is now feasible to manage dentofacial deformity problems very satisfactorily. The prediction of orthognathic treatment outcome is an important part of orthognathic planning and the process of patient' inform consent. The predicted results must be presented to the patients prior to treatment in order to assess the treatment's feasibility, optimize case management and increase patient understanding and acceptance of the recommended treatment. Cephalometrics is a routine part of the diagnosis and treatment planning process and also allows the clinician to evaluate changes following orthognathic surgery. Traditionally cephalometry has been employed manually; nowadays computerized cephalometric systems are very popular. Cephalometric prediction in orthognathic surgery can be done manually or by computers, using several currently available software programs, alone or in combination with video images. Both manual and computerized cephalometric prediction methods are two-dimensional and cannot fully describe three-dimensional phenomena. Today, three-dimensional prediction methods are available, such as three-dimensional computerized tomography (3DCT), 3D magnetic resonance imaging (3DMRI) and surface scan/cone-beam CT. The aim of this article is to present and discuss the different methods of cephalometric prediction of the orthognathic surgery outcome. PMID- 22942597 TI - Congenital nasopharyngeal teratoma with a cleft palate: case report and a 7 year follow up. AB - Teratomas are benign tumors containing cells from ectodermal, mesodermal and endodermal layers. They occur in about 1 in every 4,000 births and most commonly in the sacrococcygeal region, followed by the ovaries. Congenital epignathus teratomas are rare embryological neoplasms localised in the region of head and neck. An epignathus is found in approximately 1:35,000-1:200,000 live births. This accounts for 2-9% of all teratomas. Size and location of the neoplasm in the oronasopharynx is variable. Teratomas are partly undiagnosed at the time of birth. They may exist with an intracranial extension or as small polyps. Large epignathi can lead to difficult management during and after birth. We present a case of a female infant with a combination of nasopharyngeal teratoma and a cleft palate with successful multidisciplinary management via a staged surgical approach. The epignathus presented as a huge mass extending out of the mouth of the infant girl. On the day of birth debulking of the extraoral portion of the tumor, followed by intraoral extirpation and cleft palate repair at a later stage, was performed. The results of the histopathological examination confirmed diagnosis of a congenital teratoma. PMID- 22942598 TI - A rare case of orbital cellulitis followed by therapeutic(orthodontic) extraction. AB - We report a rare case of orbital cellulitis occurring secondary to a dental infection followed by therapeutic (orthodontic) extraction. A 16 year old female patient presented to the dental office with a left orbital proptosis for the past 4 days. PNS view, CT scan revealed an abscess in relation to medial, lateral superior inferior walls of the orbit associated with naso ethmoidal and left maxillary sinus. Through nasal endoscopy, middle meatus antrostomy and ethmoidectomy was performed for the drainage of pus from the orbit, ethmoid and maxillary sinus under general anesthesia. Immediately regression of orbital swelling was noticed. Eyeball movements improved. Epiphora reduced and proptosis declined. With the advent of higher antibiotics, orbital infection rarely occurs secondary to dental causes except in a very few cases. Complete elimination of pus from orbital cavity, para nasal air sinuses and appropriate antibiotic coverage at the earliest forms the mainstay of treatment. The nasal endoscopic approach with orbital decompression is the most acceptable atrumatic, cosmetic and functional procedure. PMID- 22942599 TI - Reconstruction of a large posterior scalp defect using occipital artery based pedicled island v-y advancement flap: a case report. AB - Repair of scalp defects using local hair bearing scalp is technically challenging. Transposition or rotation of local flaps to close the defect has its own disadvantages. Reconstruction of a large posterior scalp defect using occipital artery based pedicled V-Y advancement flap following the excision of a recurrent fibrolipoma of epicranial aponeurosis is reported here. It is possible to reconstruct the defect with hair bearing scalp in a single stage along with primary closure of the donor site using this technique. PMID- 22942600 TI - Botox as an adjunct to orthognathic surgery for a case of severe vertical maxillary excess. AB - Large skeletal discrepancies are sometimes only minimised but not eliminated by orthognathic surgeries. Administration of Botox has been advocated as an effective minimally invasive procedure to tackle aesthetic compromises like gummy smile and the like. This article elaborates on the surgical management of a case of severe vertical maxillary excess with Botox as an adjunct therapy. PMID- 22942602 TI - Modified presurgical nasoalveolar molding in the infants with complete unilateral cleft lip and palate: a stepwise approach. AB - Presurgical orthopedics in one or the other form has been an important part of the multidisciplinary approach towards the better cleft care. Presurgical nasoalveolar molding (PNAM) was described as a modified approach to the conventional form of orthopedics. PNAM not only reduces the severity of the alveolar defect before surgery, it also reduces the nasal deformity bringing it near to the normal. Nonsurgical nasal correction forms an important adjunct to the primary nasal repair at the time of primary lip repair. However, acceptance of nasoalveolar molding in Indian set-up has not been wide spread due to various reasons such as lack of the resources and inability of the parents to comply with the frequent adjustment schedule. At the Nitte Meenakshi Institute of Craniofacial surgery at the Nitte University, Mangalore, authors have developed a modification of the PNAM appliance previously described in the literature. The key modification is done at the time of fabrication of the occlusal prosthesis. This modification has made the overall procedure simpler and at the same time helped to reduce the recall visits by half of the originally required. This article describes the fabrication procedure of the modified nasal alveolar molding appliance and the modified treatment protocol in a stepwise manner. PMID- 22942601 TI - Hepatocellular carcinoma metastatic to the gingiva as a first manifestation of hepatocellular carcinoma. AB - A 55-year-old man consulted to our hospital complaining of a gingival tumor. Oral examination showed granulation tissue-like polypoid tumors (2 * 2 * 1 cm) in the left upper gingiva. A clinical diagnosis of granulation tissue was made, and an incisional biopsy was performed. It showed carcinoma cells in the submucosa. They were arranged in compact and sinusoidal patterns. A few bile plugs and one Mallory-like body were recognized by meticulous examination. An immunohistochemical study showed that the tumor cells were positive for hepatocyte paraffin-1 (HepPar-1), cytokeratins (AE1/3 and CAM6.2), and p53 protein. The carcinoma cells were negative for vimentin, prostate specific antigen, CD10, and alpha-fetoprotein. The Ki-67 labeling was 49%. A histological diagnosis of hepatocellular carcinoma (HCC) metastatic to the gingiva was made. Then, the patient was referred to hepatology unit. A blood laboratory test showed elevated elevated liver enzymes, and positive antibody to hepatitis C virus. Liver cirrhosis was also present. Imaging modalities including US, CT, and MRI revealed multiple hepatic tumors. Metastases to other sides were not recognized. The patient was diagnosed as cirrhosis and HCC with an extrahepatic metastasis to the gingiva. The patient was now treated by chemotherapy. The present case shows that HCC can manifest as small gingival tumors, and meticulous HE examination and immunoreactive HepPar-1 are useful in the diagnosis of HCC in extrahepatic metastatic sites. PMID- 22942603 TI - From the desk of the editor. PMID- 22942604 TI - Use of ultrasonic shears in patients with breast cancer undergoing axillary dissection-a pilot study. AB - Patients with breast cancer and positive sentinel node biopsy usually require axillary dissection. Different instruments are used for axillary dissection like regular scalpel,monopolar cautery, bipolar cautery etc. All these instruments are having its advantages and disadvantages. Our dept did a pilot study to know the efficacy of ultrasonic shears over cautery for axillary dissection. Parameters considered were cumulative drain amount, number of days with the drain and number of lymphnodes harvested. Ultrasonic shear machine delivers precisely directed mechanical energy with an ultrasonic vibrating blade.A single device dissects, cuts, grasps, spot coagulates. This machine was used for doing axillary dissection in one group and regular cautery in the other group. Study period was from April 2011 to June 2011 at Dept of Surgical Oncology, St Johns Hospital, Bangalore. Nine people in the ultrasonic shear group and 11 people in the cautery group were included in the pilot study. No significant difference were noticed in the cumulative drain amount, number of days with the drain, and number of lymphnodes harvested in both the groups. Axillary dissection using ultrasonic shears do not show any significant difference in the cumulative drain amount, number of days with the drain, and number of lymphnodes harvested. These are the findings of the pilot study, further prospective randomized studies are required for substantiating the findings. PMID- 22942605 TI - Early detection of breast, cervical, ovarian and endometrial cancers in low resource countries: an integrated approach. AB - The incidence of breast and gynecological cancers continues to increase in low and middle resource countries [LRC'S and MRC's] with a disproportionately higher mortality rate compared to that in high resource countries. This has been attributed to factors such as an increased life span due to better control of communicable diseases and improved nutrition, as well as lifestyle and reproductive changes. A lack of public awareness and understanding of these cancers, absence of an organized screening program and a lack of accessible and effective treatment options, is responsible for the higher mortality rate. A practical approach of a combined program of integrating a well woman examination with screening for breast and cervical cancer and diagnostic evaluation for Ovarian and Endometrial cancer in symptomatic women is proposed in this article which can serve as a model to be studied for efficacy in low resource countries. PMID- 22942606 TI - To operate or not to operate n0 neck in early cancer of the tongue? A prospective study. AB - Squamous cell carcinoma (SCC) of the tongue is a common cancer across the globe. These cancers have a high predilection for nodal metastasis and a high incidence of occult metastasis. The management of clinically negative neck nodes (N0) remains controversial. We have undertaken a prospective study to evaluate the rate of occult nodal metastasis, the characteristic of metastasis, and assess the usefulness of tumor depth as a predictor of metastasis and as a guide to treat the neck. Prospective study between January 2000 to December 2005. Patients with SCC of the anterior 2/3rd of tongue with N0 neck were included. Wide excision of the primary and subsequent modified radical neck dissection (in patients with tumor depth > 4 mm) was performed. Postoperative radiotherapy was given in patients with lymph node metastasis. Patients who had no node metastasis (p N ve) were observed. The total number of eligible patients was 180. Occult lymph node metastasis (p N +ve) was seen in 122 (62.2%) patients (p < 0.001), multiple levels of node involvement in 79 (70.5%) patients and extracapsular spread (ECS) in 38 (33.6%) patients. Patients in the p N +ve group who were disease free was 63.1% as compared to 68.2% in the p N -ve group (p = 0.36). Recurrence was seen in 28 (36.8%) patients of p N +ve group and 14 (31.8%) patients of p N -ve group. Early cancer of tongue with tumor depth >4 mm was associated with predominantly high grade tumors, high incidence of occult nodal metastasis, multiple levels of nodal involvement and ECS. The disease free status of patients with occult metastasis who were treated was similar to that of patients with no nodal metastasis. Elective neck dissection appears essential for early oral tongue cancer with tumor depth >4 mm as there is no investigational modality which can reliably identify patients without occult metastasis. PMID- 22942607 TI - Simultaneous squamous cell carcinoma of cervix and fallopian tube; a case report. PMID- 22942609 TI - Modified technique of stapled esophagojejunostomy without a purse-string suture. AB - Placement of a purse-string suture during a stapled esophagojejunostomy following total gastrectomy is a technically demanding and time consuming procedure. Improper placement of the purse-string suture can lead to anastamotic breakdown with its associated complications. We describe a technique of stapled esophagojejunostomy without using a purse-string suture. We used this technique in 35 patients including 4 patients who underwent an extended total gastrectomy. We encountered a difficulty only in one patient due to malfunction of the stapler. None of the patients had an anastamotic leak. The modified technique of stapled esophagojejunostomy without a purse-string suture makes the procedure more easy, safe and simple. PMID- 22942608 TI - Targetable "driver" mutations in non small cell lung cancer. AB - Lung cancer remains the leading cause of cancer-related mortality in the world despite advances in the field of cancer therapeutics. Traditional treatment with empirically chosen cytotoxic chemotherapeutic agents, have given small, but real survival benefits. Recent advances and insights into molecular pathogenesis of lung cancers have provided some novel molecular targets, offering newer strategies and agents that are tumor specific. Studies have identified mutations in specific genes that are involved in driving the development of lung cancer and so it is important to subsequently target them with specific drugs thus changing paradigms of management of this type of cancer. Recently, Lung Cancer Mutation Consortium (LCMC) has identified at least one of the many recognized "driver mutations" in nearly two thirds of the patients with advanced cancer. This study suggests that identification of driver mutations can help in molecular targeted therapeutics and in addition supplant tumor histology in guiding treatment decisions, identifying subset of patients who may benefit therapy. This review focuses on these mutations identified in specific genes serving as "drivers" of lung tumorigenesis and suggests that clear promise for the future of lung cancer treatment is indeed personalized therapy with drugs chosen according to the patient mutation profile. Most clinically relevant translational advances made in genes involved in lung tumorigenesis namely EML4-ALK fusions, HER2, PIK3CA, AKT, BRAF, MAP2K1, MET mutations and amplifications along with the well established EGFR and KRAS mutations are discussed in the context of NSCLCs. These studies emphasize the need for treatment management based on mutation profile along with routine histology based classification of these tumors in future for a directed therapy and thus a better therapeutic outcome. PMID- 22942610 TI - Radioiodine avid axillary lymph node metastasis in papillary thyroid cancer: report of a case. PMID- 22942611 TI - Jejunal adenocarcinoma: an elusive diagnosis. AB - Tubercular stricture of small bowel is a common cause of subacute intestinal obstruction in India. In a small subset of patients the cause of the intestinal obstruction could be adenocarcinoma of jejunum. It is difficult to diagnose preoperatively. The point of concern is compared to tubercular stricture, the treatment of jejunal adenocarcinoma is always surgical in the form of cancer directed surgery. The operating surgeon needs to have a very high suspicion for jejunal adenocarcinoma because the timely treatment offers the best survival in otherwise an aggressive disease with bleak prognosis. PMID- 22942612 TI - Bronchogenic adenocarcinoma with bone marrow involvement: an unusual presentation. PMID- 22942613 TI - Malignant coloduodenal fistulas-review of literature and case report. AB - Colo-duodenal fistula is an uncommon complication of malignant and inflammatory bowel disease. Presentation varies from upper abdominal pain, feculent vomiting and diarrhea associated with foul eructation's. Occasionally patients presents with gastro-intestinal bleed. The contact of duodenal bile salts with colonic mucosa frequently leads to diarrhea, so also duodenal colonization with colonic pathogens frequently leads to malabsorption and severe foul eructations. The diagnosis is established either by gastrointestinal contrast studies or contrast enhanced C. T. Scan. Gastroduodenoscopy can demonstrate the fistulous communication or direct invasion and it can also be helpful in obtaining a histological diagnosis. Surgical treatment includes Right Radical hemicolectomy combined with Pancreatico duodenectomy in operable patients and Intestinal bypass for inoperable ones. Right Radical hemicolectomy combined with wedge excision of Duodenum is a suitable alternative in select cases. We report an unusual case of locally advanced carcinoma hepatic flexure of colon with direct invasion of duodenum. Extended right radical hemicolectomy with wedge excision of second part of duodenum was done as an alternative to combined radical hemicolectomy with Pancreatico duodenectomy. PMID- 22942614 TI - Jaundice after radical cholecystectomy and bile duct resection: a case of postoperative acute viral hepatitis a confounding the clinical picture. PMID- 22942615 TI - A rare cause of massive lymphadenopathy. AB - Rosai Dorfman Disease is a rare disease presenting mainly as painless enlargement of cervical lymph nodes. It is a benign disorder showing unique histological features characterized by reactive proliferation of sinus histiocytes. In 40% of cases, extranodal sites may be involved. The condition has to be differentiated from certain types of B cell lymphoma showing similar features. We report here a 17 year old male presenting with nodal and extranodal involvement of Rosai Dorfman Disease. PMID- 22942616 TI - A rare case of lupus carcinoma of external nose. PMID- 22942617 TI - A tribute to professor N C misra-pioneer and leader in oncology. PMID- 22942618 TI - Proapoptotic effects of novel pentabromobenzylisothioureas in human leukemia cell lines. AB - A series of new pentabromobenzylisothioureas [ZKK-1-ZKK-5; (ZKKs)] carrying additional substituents on nitrogen atoms has been synthesized. The ZKKs were found to induce apoptosis in HL-60 (human promyleocytic leukemia) and K-562 (human chronic erythromyeloblastoid leukemia) cell lines in a concentration dependent manner at low micromolar concentrations. ZKK-3 [(N,N'-dimethyl-S 2,3,4,5,6-pentabromobenzyl)isothiouronium bromide] showed the highest proapoptotic activity in HL-60 cells, whereas ZKK-2 [N-methyl-S-(2,3,4,5,6 pentabromobenzyl)isothiouronium bromide] was most effective in this respect in K 562 cells. During the ZKKs-induced apoptosis, an 85 kDa fragment of cleaved PARP (caspase-3 and caspase-7 substrate) was detected in both cell lines tested. The studied compounds also decreased mitochondrial transmembrane potential in both these cell lines and caused the cells to accumulate in G(1) and at the G(1)/S border of the cell cycle in a concentration-dependent manner. These results show promise for their study as new compounds in the treatment of leukemia, after an appropriate preclinical toxicity profile. PMID- 22942619 TI - Louisa's Birth. AB - In this column, Rachel Mann shares the story of the birth of her third daughter, Louisa. After a previous pregnancy loss, Mann chose to give birth to her third baby in a hospital with attending care from an obstetrician. In spite of the high risk medical environment, she was able to have an unmedicated, powerful birth. Mann's careful planning, the support of her husband and doula, and her confidence in her ability to give birth helped make Louisa's birth all that Mann hoped it would be. PMID- 22942620 TI - Many women and providers are unprepared for an evidence-based, educated conversation about birth. AB - Findings from recent Canadian studies on the knowledge and beliefs about birth practices among first-time pregnant women and among obstetricians and other birth providers indicate that many women are inadequately informed and many providers deliver non-evidence-based maternity care. Consequently, informed decision making is problematic for pregnant women and their providers. New strategies are needed to inform pregnant women about key procedures and approaches that might be used in birth so they can have an educated, shared discussion with their provider and successfully advocate for their preferred birth experience. In addition, providers can be encouraged to supplement their knowledge with current, evidence based maternity care practices. To avoid a lack of informed decision making and to ensure that natural, safe, and healthy birth practices are based on current evidence, pregnant women and providers must work together to inform themselves and to add childbirth to the women's health agenda. PMID- 22942621 TI - Predicting breastfeeding duration related to maternal attitudes in a taiwanese sample. AB - The purpose of this study was to examine maternal attitudes and sociodemographic variables associated with Taiwanese mothers' continuation of breastfeeding at 6 weeks postpartum. A sample of 140 in-hospital breastfeeding mothers was recruited in Taiwan. Participants completed the Iowa Infant Feeding Attitude Scale (IIFAS) in the hospital prior to discharge. Postdischarge participants were contacted by telephone at 3 and 6 weeks postpartum to obtain information regarding their feeding method and duration. Findings revealed that in-hospital maternal breastfeeding attitudes are predictive of breastfeeding duration. Insufficient milk supply was the reason most often given for discontinuing breastfeeding. Women's husband/partner was found to be the main source of breastfeeding support. We recommend health-care professionals add the IIFAS to their assessment to identify mothers at high risk for discontinuing breastfeeding and to develop and better evaluate breastfeeding promotion programs. PMID- 22942622 TI - Supporting fathering through infant massage. AB - Fathers may feel dissatisfied with their ability to form a close attachment with their infants in the early postpartum period, which, in turn, may increase their parent-related stress. Our study sought to determine if an infant massage intervention assisted fathers with decreasing stress and increasing bonding with their infants during this time. To address the complex father-infant relationship, we conducted a pilot study using a mixed methodology approach. Twelve infant-father dyads participated in the intervention, and 12 infant-father dyads populated a wait-list control group. Paternal stress was measured using the Parenting Stress Index at baseline and at postintervention. We found infant massage instruction significantly decreased paternal stress. Our findings were also supported by the qualitative data and suggest fathers may benefit from applied postnatal education. PMID- 22942623 TI - Voices Along the Journey: Midwives' Perceptions of Implementing the CenteringPregnancy Model of Prenatal Care. AB - The purpose of this study was to describe the reported perceptions of six midwife participants at different stages of their engagement in a multiphase process of adopting a new model of prenatal care. Midwives were interviewed at five different stages during the process of implementing CenteringPregnancy, a model of group prenatal care. The research methodology used in this study was phenomenology. The conceptual framework for exploring the participants' perceptions was based on the Institute for Healthcare Improvement's patient centered model and on the International Institute for Restorative Practices' empowerment model. The five themes that emerged from the midwives' experiences mirrored the stages of change health education model. Suggestions for the implementation and sustainability of the CenteringPregnancy model of care are provided based on the five themes that emerged from this study's findings. PMID- 22942624 TI - Prenatal parenthood. AB - In this article, we discuss the intuitive knowledge mothers have of their unborn baby. We propose a shift in focus from caregivers' merely providing information to first listening to pregnant mothers as they share their intuitive knowledge of their baby. This approach enables mothers and fathers or partners to know they are already parents to their unborn baby and empowers them to get in touch with their baby's presence and who he or she is during pregnancy. This intuitive knowledge may be a protective behavior that will enable mothers to keep babies safe during pregnancy. PMID- 22942625 TI - Evoking the power of learners. AB - Our mandate, as Lamaze International childbirth educators, is to assist women in making healthy pregnancy, birth, and parenting choices. Being mindful of health promotion theory and using learning tasks and dialogue education to provide information creates a collaborative Lamaze class where the teacher is the facilitator and the learners are accountable for their learning. This column offers Lamaze educators a deeper understanding of adult learners and our roles in their birth education. PMID- 22942626 TI - Maternal obesity from all sides. AB - This column features excerpts from a recent series of articles from the Lamaze International research blog, Science & Sensibility. The eight-part series examined the issue of maternal obesity from various perspectives, incorporating writings from Kimmelin Hull, a physician assistant, a Lamaze Certified Childbirth Educator, and the community manager of Science & Sensibility; Kristen Montgomery, a nursing professor at the University of North Carolina-Charlotte; Pamela Vireday, a childbirth educator and blogger; and Kathleen Kendall-Tackett, a health psychologist, lactation consultant, and writer/speaker. The authors of the blog series, titled "Maternal Obesity from All Sides," reviewed current research about risks associated with maternal obesity as well as the humanistic issues and lived experiences of pregnant women of size. PMID- 22942629 TI - 10 plus-years follow-up after patch angioplasty of the left main coronary artery. AB - In ostial or proximal left main coronary artery (LMCA) obstruction, re establishment of normal antegrade flow via the main trunk may be preferable to distal bypass grafting. The objective of this study was to assess the effectiveness of patch plasty of the left main (LM) trunk of the coronary artery for more than 10 years. Direct widening of the LMCA was recommended to patients with ostial, proximal, or midpoint stenosis of the main trunk. Group I of 16 patients had isolated LM obstruction with no distal disease, and Group II of 15 patients had, in addition, right coronary obstruction. The mean age was 60.9 years (age group, 47 to 83 years). Nineteen patients underwent this operation through an anterior transverse aortotomy. No endarterectomies were performed. In Group II, in addition, a single saphenous vein bypass graft was placed in the right coronary artery. There were no operative deaths. Follow-up period extends from 10 to 18 years (mean 11.2). Eight patients had angiography from 3 to 9 years after surgery and all show adequate LM trunk caliber. Noncardiac deaths occured in five patients (26.3%) at 2 months, and 1, 4, 6, and 7 years after surgery. Two women with isolated ostial stenosis diagnosed as a spasm have not shown progression of coronary disease 7 to 9 years after the operation. Widening of the LMCA should be considered in selective cases, only when ostial, proximal, or midportion stenosis of the main vessel exist, even if a right coronary bypass graft is required. PMID- 22942627 TI - Nitric oxide-mediated coronary flow regulation in patients with coronary artery disease: recent advances. AB - Nitric oxide (NO) formed via endothelial NO synthase (eNOS) plays crucial roles in the regulation of coronary blood flow through vasodilatation and decreased vascular resistance, and in inhibition of platelet aggregation and adhesion, leading to the prevention of coronary circulatory failure, thrombosis, and atherosclerosis. Endothelial function is impaired by several pathogenic factors including smoking, chronic alcohol intake, hypercholesterolemia, obesity, hyperglycemia, and hypertension. The mechanisms underlying endothelial dysfunction include reduced NO synthase (NOS) expression and activity, decreased NO bioavailability, and increased production of oxygen radicals and endogenous NOS inhibitors. Atrial fibrillation appears to be a risk factor for endothelial dysfunction. Endothelial dysfunction is an important predictor of coronary artery disease (CAD) in humans. Penile erectile dysfunction, associated with impaired bioavailability of NO produced by eNOS and neuronal NOS, is also considered to be highly predictive of ischemic heart disease. There is evidence suggesting an important role of nitrergic innervation in coronary blood flow regulation. Prophylactic and therapeutic measures to eliminate pathogenic factors inducing endothelial and nitrergic nerve dysfunction would be quite important in preventing the genesis and development of CAD. PMID- 22942628 TI - Liver abnormalities in cardiac diseases and heart failure. AB - Heart failure (HF) is characterized by the inability of systemic perfusion to meet the body's metabolic demands and is usually caused by cardiac pump dysfunction and may occasionally present with symptoms of a noncardiac disorder such as hepatic dysfunction. The primary pathophysiology involved in hepatic dysfunction from HF is either passive congestion from increased filling pressures or low cardiac output and the consequences of impaired perfusion. Passive hepatic congestion due to increased central venous pressure may cause elevations of liver enzymes and both direct and indirect serum bilirubin. Impaired perfusion from decreased cardiac output may be associated with acute hepatocellular necrosis with marked elevations in serum aminotransferases. Cardiogenic ischemic hepatitis ("shock liver") may ensue following an episode of profound hypotension in patients with acute HF. We discuss pathophysiology and identification of liver abnormalities that are commonly seen in patients with HF. PMID- 22942630 TI - Carotid intima-media thickness and liver histology in hemodialysis patients with nonalcoholic Fatty liver disease. AB - The prevalence of atherosclerotic cardiovascular disease in chronic hemodialysis (HD) patients has been demonstrated to be higher than in healthy people. Severe liver fibrosis is strongly associated with early carotid atherosclerosis and it might reduce the survival of patients who undergo both renal replacement therapy and transplantation. We wanted to assess whether nonalcoholic fatty liver disease (NAFLD) was associated with altered intima-media thickness (IMT) in HD patients as an independent marker of subclinical atherosclerosis. We enrolled 42 patients undergoing HD and 48 patients with normal renal function, all of them with high levels of aminotransferases and an ultrasonographic diagnosis of liver steatosis. The control group consisted of 60 healthy subjects. Laboratory tests for inflammatory and oxidative markers, ultrasonographic liver evaluation, carotid IMT measurement, and liver biopsy were performed. Different degrees of fibrosis were detected in our study cohort. Worse liver histopathological scores and higher plasmatic levels of C-reactive protein, reactive oxygen species, and vascular cell adhesion molecule-1 were found in HD patients. Carotid IMT was significantly higher (p < 0.005) in patients with histological steatosis. HD patients may develop active and progressive chronic hepatitis faster than patients with normal renal function and the thickness of their carotid intima media might be markedly increased. These two conditions seem to be independent on classical risk factors and on metabolic syndrome. They might be related to the high levels of oxidants and to the inflammatory state, which are typical of patients undergoing HD. Independently related with the traditional risk factors for cardiovascular disease, nonspecific inflammation and oxide-reductive imbalance may play an important role in the progression of NAFLD and atherosclerotic disease in HD patients. PMID- 22942631 TI - Cyclic strain delays the expression of tissue factor induced by thrombin in human umbilical vein endothelial cells. AB - Most studies of tissue factor (TF) expression in endothelial cells (EC) are performed under stationary culture conditions. The purpose of this study was to determine the influence of mechanical stimuli such as cyclic strain (CS) on the expression of TF in EC exposed to thrombin (Thr). Human umbilical vein endothelial cells (HUVEC) were exposed to 4 U.mL(-1) Thr in the presence or absence of 10% average CS at 60 cycles.min(-1) and then TF expression was measured. TF messenger RNA (mRNA) expression peaked at 2 hours in HUVEC exposed to Thr, but at 4 hours in HUVEC exposed to both Thr + CS. TF expression was inhibited by p38 and extracellular signal-regulated protein kinase (ERK) inhibitors. For both Thr or Thr + CS stimuli, p38 and ERK activity peaked at 5 minutes (p < 0.05). Nuclear factor-kappa B levels remained high in the Thr group but not in the Thr + CS group, while Egr-1 levels were elevated in the Thr + CS group. We demonstrated CS-delayed, Thr-induced TF mRNA expression in HUVEC, which may be modulated by p38 and ERK inhibitors. PMID- 22942632 TI - Surrogates of Large Artery versus Small Artery Stiffness and Ankle-Brachial Index. AB - Peripheral artery tonometry (PAT) is a novel method for assessing arterial stiffness of small digital arteries. Pulse pressure can be regarded as a surrogate of large artery stiffness. When ankle-brachial index (ABI) is calculated using the higher of the two ankle systolic pressures as denominator (ABI-higher), leg perfusion can be reliably estimated. However, using the lower of the ankle pressures to calculate ABI (ABI-lower) identifies more patients with isolated peripheral arterial disease (PAD) in ankle arteries. We aimed to compare the ability of PAT, pulse pressure, and different calculations of ABI to detect atherosclerotic disease in lower extremities. We examined PAT, pulse pressure, and ABI in 66 cardiovascular risk subjects in whom borderline PAD (ABI 0.91 to 1.00) was diagnosed 4 years earlier. Using ABI-lower to diagnose PAD yielded 2 fold higher prevalence of PAD than using ABI-higher. Endothelial dysfunction was diagnosed in 15/66 subjects (23%). In a bivariate correlation analysis, pulse pressure was negatively correlated with ABI-higher (r = -0.347, p = 0.004) and with ABI-lower (r = -0.424, p < 0.001). PAT hyperemic response was not significantly correlated with either ABI-higher (r = -0.148, p = 0.24) or with ABI-lower (r = -0.208, p = 0.095). Measurement of ABI using the lower of the two ankle pressures is an efficient method to identify patients with clinical or subclinical atherosclerosis and worth performing on subjects with pulse pressure above 65 mm Hg. The usefulness of PAT measurement in detecting PAD is vague. PMID- 22942633 TI - TRALI Syndrome Complicated by Retroperitoneal Bleeding. AB - Transfusion-related acute lung injury (TRALI) is an underdiagnosed and underreported syndrome which by itself is the third leading cause of transfusion related mortality. The incidence of TRALI is reported to be 1 in 2000 to 5000 transfusions. When combined with uncontrollable bleeding, survival is unachievable. We report the case of a 25-year-old man, who underwent open heart surgery as an infant to correct his congenital heart disease in association with right pulmonary artery atresia. He presented with hemoptysis secondary to aspergilloma and required a pneumonectomy of the nonfunctional right lung. During pneumolysis, significant bleeding occurred from the superior vena cava. The patient required a blood transfusion and was placed on cardiopulmonary bypass to control the bleeding. Simultaneous occurrence of severe pulmonary edema and retroperitoneal bleeding were noted. Approximately 8 L of frothy edema fluid were drained from the only functional left lung starting ~15 minutes after the transfusion and lasting for several hours until the end of the case. It most likely represented TRALI syndrome. Increasing abdominal girth and poor volume return to the pump were consistent with and pathognomonic for retroperitoneal bleeding. Though primary surgical bleeding in the chest was controlled successfully and a pneumonectomy performed without further difficulty, we were unable to separate the patient from cardiopulmonary bypass due to the inability to oxygenate. As a result, we could not reverse the anti-coagulation which potentially exacerbated the retroperitoneal bleeding. After multiple unsuccessful attempts the patient succumbed. This ill-fated case demonstrates the quandary of obtaining vascular access for emergency cardiopulmonary bypass while in the right thoracotomy position. It may be beneficial to have both the femoral artery and vein cannulated before positioning a patient in a lateral decubitus position. In addition, early direct access to the right atrium may obviate a need for femoral venous cannulation. Also, adult extracorporeal membrane oxygenation may be indicated if faced with such a severe pulmonary edema without ongoing hemorrhage. PMID- 22942634 TI - A rare case of amiodarone-induced hypothyroidism presenting with cardiac tamponade. AB - Subclinical pericardial effusions are common in patients with untreated hypothyroidism and usually resolve with thyroid replacement therapy, but cardiac tamponade is a rare presentation of prolonged untreated hypothyroidism. We report the first case of cardiac tamponade due to hypothyroidism produced by administration of amiodarone. PMID- 22942635 TI - Mysterious abdominal pain. AB - A man presented to the emergency room with recurrent episodes of abdominal pain. He had a history of coronary artery bypass grafting of the left internal mammary artery (LIMA) to the left anterior descending (LAD) artery and the right gastroepiploic artery to the posterior descending artery. After numerous gastrointestinal evaluations, a stress test was performed, which was positive. Coronary angiography showed a proximal occlusion of the LAD and right coronary artery and a normal functioning LIMA bypass. Aortography showed a 95% stenosis of the celiac trunk. Angioplasty and stent implantation of the celiac trunk was successfully performed. Six months later the patient was completely asymptomatic with a negative stress test. In conclusion, abdominal pain in patients who have undergone coronary artery bypass surgery using the right gastroepiploic artery should raise suspicion not only of a stenosis of the arterial conduit but also of a potential stenosis of the celiac trunk. PMID- 22942636 TI - Massive Pericardial Effusion in a Case of Acute Pericarditis with Slight ST Segment Elevation of Short Duration. AB - We present the case of a 77-year-old woman who suffered from chest pain. Her white blood cell count was 10,200/MUL and C-reactive protein level was 5.5 mg/dL. There was no electrocardiogram abnormality up to 5 hours after admission. At 15 hours, slight ST-segment elevation occurred, but this disappeared on day 4. Imaging revealed slight pericardial effusion. Nonsteroidal anti-inflammatory drugs and antibiotics were administered. However, the pericardial effusion, inflammatory response, and bilateral heart failure worsened. Pericardiotomy on day 6 released 350 mL of fluid, and symptoms improved. Viral pericarditis was assumed. Massive pericardial effusion is rare in cases of acute viral pericarditis, as is slight, short-duration ST-segment elevation. PMID- 22942637 TI - INCREASING ACHIEVEMENT AND HIGHER-EDUCATION REPRESENTATION OF UNDER-REPRESENTED GROUPS IN SCIENCE, TECHNOLOGY, ENGINEERING, AND MATHEMATICS FIELDS: A REVIEW OF CURRENT K-12 INTERVENTION PROGRAMS. AB - The under-representation of women and ethnic minorities in Science, Technology, Engineering, and Mathematics (STEM) education and professions has resulted in a loss of human capital for the US scientific workforce and spurred the development of myriad STEM educational intervention programs. Increased allocation of resources to such programs begs for a critical, prescriptive, evidence-based review that will enable researchers to develop optimal interventions and administrators to maximize investments. We begin by providing a theoretical backdrop for K-12 STEM programs by reviewing current data on under-representation and developmental research describing individual-level social factors undergirding these data. Next, we review prototypical designs of these programs, highlighting specific programs in the literature as examples of program structures and components currently in use. We then evaluate these interventions in terms of overall effectiveness, as a function of how well they address age-, ethnicity-, or gender-specific factors, suggesting improvements in program design based on these critiques. Finally, program evaluation methods are briefly reviewed and discussed in terms of how their empirical soundness can either enable or limit our ability to delineate effective program components. "Now more than ever, the nation's changing demographics demand that we include all of our citizens in science and engineering education and careers. For the U.S. to benefit from the diverse talents of all its citizens, we must grow the pipeline of qualified, underrepresented minority engineers and scientists to fill positions in industry and academia."-Irving P. McPhail.. PMID- 22942638 TI - Proliferative vitreoretinopathy: current and emerging treatments. AB - Proliferative vitreoretinopathy is a disease process that follows the proliferation of ectopic cell sheets in the vitreous and/or periretinal area, causing periretinal membrane formation and traction, in patients with rhegmatogenous retinal detachments. Currently, vitreous surgery is the standard treatment; however, the results aren't satisfactory given the vision loss that ensues and that redetachment is relatively common. It is becoming clearer that there exists an interplay between various cytokines/growth factors, matrix proteins, and the different cell types that drive the undesirable formation of periretinal membranes. This fundamental understanding is aiding in identifying different adjunct agents that can block the cellular events intrinsic to proliferative vitreoretinopathy. In this review, we describe the current understanding on the pathogenesis and discuss how the fundamental understanding of the biochemical/molecular events is instrumental in developing the novel treatment strategies that are also highlighted. PMID- 22942639 TI - Suturing techniques and postoperative management in penetrating keratoplasty in the United Kingdom. AB - AIMS: To report on the suturing techniques and aspects of postoperative management in penetrating keratoplasty in the United Kingdom. METHODS: A postal questionnaire was sent to 137 ophthalmic consultants identified from a Royal College of Ophthalmology database as having a special interest in anterior segment surgery. The questionnaire surveyed surgeon preferences for surgical and suturing technique for penetrating keratoplasty surgery, and the postoperative care of corneal grafts. RESULTS: In all, 68% of questionnaires were completed and returned: 73% of respondents used a Flieringa ring or equivalent, 94% routinely used cardinal sutures, with 50.5% removing them at the end of the procedure. The most common suturing technique for routine penetrating keratoplasty was a single continuous suture (35%). In these cases, a 10/0 nylon suture was used by 89%. Sixty-six percent changed their technique in high-risk cases, 52% used a 3-1-1 knot, and 75% made a distinction between a reef and granny knot, with 76% using a reef. Thirty percent buried the knots within the donor material, and 29% within the host tissue. Twenty-five percent had no routine time for graft suture removal, but 41% removed them between 1 and 2 years post-surgery. After suture removal, 98% used steroids and 88% used topical antibiotics. Thirty-four percent stopped topical steroids before suture removal, with 38% stopping topical steroids more than 3 months prior to suture removal. CONCLUSION: This survey demonstrates that there is considerable variation in suturing techniques and postoperative care for penetrating keratoplasty. These significant variations in practice need to be considered when interpreting outcomes and research. PMID- 22942640 TI - Fluorescein angiography findings in a case of Rubinstein-Taybi syndrome. AB - The purpose of this report is to describe the fluorescein angiography findings in a case of Rubinstein-Taybi syndrome. Fundus photography and fluorescein angiography were performed on a 6-year-old male with Rubinstein-Taybi syndrome due to CREB binding protein gene mutation. Fundus photography showed glaucomatous cupping and diffusely attenuated retinal vasculature. Choroidal vasculature was prominent due to diffuse retinal atrophy with scattered focal retinal pigment epithelial changes. Fluorescein angiography showed retinal vascular attenuation, prolonged arteriovenous transit time with delayed venous filling, late small vessel leakage, and 360 degrees of peripheral avascularity. Peripheral retinal avascularity and retinal vascular inflammation evidenced by late small vessel leakage can be demonstrated by fluorescein angiography in the retinal dystrophy of Rubinstein-Taybi syndrome. PMID- 22942641 TI - Effect of buckminsterfullerenes on cells of the innate and adaptive immune system: an in vitro study with human peripheral blood mononuclear cells. AB - C60 nanoparticles, the so-called buckminsterfullerenes, have attracted great attention for medical applications as carriers, enzyme inhibitors or radical scavengers. However, publications evaluating their immunological mechanisms are still rather limited. Therefore, we aimed to analyze systematically the in vitro influence of polyhydroxy-C60 (poly-C60) and N-ethyl-polyamino-C60 (nepo-C60) on peripheral blood mononuclear cells (PBMC) from healthy individuals, angling their effect on proliferation, expression of surface markers, and cytokine production. We isolated PBMC from 20 healthy subjects and incubated them in a first step only with poly-C60 or nepo-C60, and in a second step together with recall antigens (purified protein derivative, tetanus toxoid, bacillus Calmette-Guerin). Proliferation was determined by (3)H-thymidine incorporation, activation of PBMC subpopulations by flow cytometry by measurement of the activation marker CD69, and secretion of T helper cell type 1 (TH1)- (interferon-gamma [IFN-gamma], tumor necrosis factor beta [TNF-beta]), TH2- (interleukin-5 [IL-5], -13, -10) and macrophage/monocyte-related cytokines (IL-1, IL-6, TNF-alpha) into the supernatants by enzyme-linked immunosorbent assay. Both fullerenes did not influence T cell reactivity, with no enhanced expression of CD69 and production of T cell cytokines observed, the CD4/CD8 ratio remaining unaffected. In contrast, they significantly enhanced the release of IL-6 and CD69-expression by CD56 positive natural killer cells. PBMC, which had been cultured together with the three recall antigens were not affected by both fullerenes at all. These data indicate that fullerenes do not interact with T cell reactivity but may activate cells of the innate immune system. Furthermore, they seem to act only on 'naive' cells, which have not been prestimulated with recall antigens, there are however, large inter individual differences. PMID- 22942642 TI - Effect of cell-penetrating peptide-coated nanostructured lipid carriers on the oral absorption of tripterine. AB - PURPOSE: To develop nanostructured-lipid carriers (NLCs) coated with cell penetrating peptides (CPP) for improving the oral bioavailability of tripterine. METHODS: We prepared CPP-coated tripterine-loaded NLCs (CT-NLCs) by using a solvent evaporation method, and determined their physical properties. In vitro drug release was determined by using a dialysis bag diffusion technique, and intestinal toxicity was evaluated by performing MTT assay using Caco-2 cells. In vivo absorption was studied in an in situ rat intestinal perfusion model, and oral bioavailability was examined in beagles. RESULTS: The average particle size, zeta potential, and encapsulation efficiency of the optimized CT-NLCs were 126.7 +/- 9.2 nm, 28.7 +/- 3.4 mV, and 72.64% +/- 1.37%, respectively. The CT-NLCs showed a controlled release profile in vitro and had significantly lower intestinal cytotoxicity than the tripterine solution (P < 0.05). The absorption levels of tripterine from the CT-NLCs in the rat duodenum and jejunum were markedly higher than with tripterine-loaded NLCs without the CPP coating (T NLCs), and with tripterine solution. Pharmacokinetic study showed that the maximum concentration of the CT-NLCs was greater than that of the T-NLCs and tripterine suspension, and that the time to maximum concentration of the CT-NLCs as well as the T-NLCs, was longer than that of the tripterine suspension. The relative oral bioavailability of the CT-NLCs compared to that of tripterine suspension and T-NLCs were 484.75% and 149.91% respectively. CONCLUSION: The oral bioavailability of tripterine is dramatically increased by CT-NLCs. Therefore, CT NLCs seem to be a promising carrier for oral delivery of tripterine. PMID- 22942643 TI - Enhanced cellular uptake and long-term retention of chitosan-modified iron-oxide nanoparticles for MRI-based cell tracking. AB - Tracking cells after therapeutic transplantation is imperative for evaluation of implanted cell fate and function. In this study, ultrasmall superparamagnetic iron oxide nanoparticles (USPIO NPs) were surface functionalized with water soluble chitosan, a cationic polysaccharide that mediates enhanced endocytic uptake, endosomal escape into the cytosol, and subsequent long-term retention of nanoparticles. NP surface and chitosan were independently fluorescently labeled. Our NPs enable NP trafficking studies and determination of fate beyond uptake by fluorescence microscopy as well as tracking of labeled cells as localized regions of hypointensity in T(2)*-weighted magnetic resonance imaging (MRI) images. Adult rat neural stem cells (NSCs) were labeled with NPs, and assessment of NSC proliferation rates and differentiation potential revealed no significant differences between labeled and unlabeled NSCs. Significantly enhanced uptake of chitosan NPs in comparison to native NPs was confirmed by transmission electron microscopy, nuclear magnetic resonance (NMR) spectroscopy and in vitro cellular MRI at 11.7 Tesla. While only negligible fractions of native NPs enter cells, chitosan NPs appear within membranous vesicles within 2 hours of exposure. Additionally, chitosan-functionalized NPs escaped from membrane-bound vesicles within days, circumventing NP endo-lysosomal trafficking and exocytosis and hence enabling long-term tracking of labeled cells. Finally, our labeling strategy does not contain any NSC-specific reagents. To demonstrate general applicability across a variety of primary and immortalized cell types, embryonic mouse NSCs, mouse embryonic stem cells, HEK 293 kidney cells, and HeLa cervical cancer cells were additionally exposed to chitosan-USPIO NPs and exhibited similarly efficient loading as verified by NMR relaxometry. Our efficient and versatile labeling technology can support cell tracking with close to single cell resolution by MRI in vitro, for example, in complex tissue models not optically accessible by confocal or multi-photon fluorescence microscopy, and potentially in vivo, for example, in animal models of human disease or injury. PMID- 22942644 TI - A novel EGFR-targeted gene delivery system based on complexes self-assembled by EGF, DNA, and activated PAMAM dendrimers. AB - Epidermal growth factor receptor (EGFR)-targeted gene delivery is a promising approach in gene therapy against EGFR-positive cancer. In addition, macromolecules, such as polyamidoamine (PAMAM) dendrimers, are potential nonviral gene carriers in this therapy because of their biocompatibility and modifiable features. To achieve the goal of selectively enhancing the transfection efficiency in EGFR-positive cancer cells, the researchers developed chemical approaches of EGF-dendrimer conjugate, which were effective but complicated. Studies on liposomes reveal that self-assembly is another effective but simpler approach in EGF modification. Moreover, properly activated PAMAM dendrimers exhibit higher transfection efficiency, but little research has been done on its ligand-modification. In this study, we developed and characterized a novel gene delivery system based on activated EGF-dendriplexes, which is formed via self assembly by EGF and complexes prepared by activated PAMAM dendrimer and plasmid DNA. Such complexes exhibit desired features compared to nonmodified or non activated dendriplexes in vitro, including selective enhancement of transfection efficiency in EGFR-positive cells, decreased cytotoxicity, and low agonist effect. In vivo experimentation shows their EGFR-positive tumor targeted biodistribution and increased transfection efficiency at EGFR-positive tumors. Our results demonstrated that activated EGF-dendriplexes are safe and effective carriers for delivering gene drugs to EGFR-positive cells, which makes these complexes a promising targeted nonviral gene-delivery system for auxiliary cancer therapy. PMID- 22942647 TI - Transdermal donepezil on the treatment of Alzheimer's disease. AB - Alzheimer's disease (AD) is the most common type of senile dementia, characterized by cognitive deficits related to degeneration of cholinergic neurons. The first anti-Alzheimer drugs approved by the Food and Drug Administration were the cholinesterase inhibitors (ChEIs), which are capable of improving cholinergic neurotransmission by inhibiting acetylcholinesterase. The most common ChEIs used to treat cognitive symptoms in mild to moderate AD are rivastigmine, galantamine, and donepezil. In particular, the lattermost drug has been widely used to treat AD patients worldwide because it is significantly less hepatotoxic and better tolerated than its predecessor, tetrahydroaminoacridine. It also demonstrates high selectivity towards acetylcholinesterase inhibition and has a long duration of action. The formulations available for donepezil are immediate release (5 or 10 mg), sustained release (23 mg), and orally disintegrating (5 or 10 mg) tablets, all of which are intended for oral-route administration. Since the oral donepezil therapy is associated with adverse events in the gastrointestinal system and in plasma fluctuations, an alternative route of administration, such as the transdermal one, has been recently attempted. The goal of this paper is to provide a critical overview of AD therapy with donepezil, focusing particularly on the advantages of the transdermal over the oral route of administration. PMID- 22942646 TI - Downregulation of VEGF mRNA expression by triamcinolone acetonide acetate-loaded chitosan derivative nanoparticles in human retinal pigment epithelial cells. AB - BACKGROUND: The purpose of this study was to investigate the downregulation of mRNA expression of vascular endothelial growth factor (VEGF) by triamcinolone acetonide acetate (TAA)-loaded chitosan nanoparticles in human retinal pigment epithelial cells. METHODS: TAA-loaded deoxycholic acid-modified chitosan (TAA/DA Chit) nanoparticles were prepared via a self-assembly mechanism, and their morphology and zeta potential were examined by transmission electron microscopy and zeta potential analysis, respectively. DA-Chit and TAA/DA-Chit nanoparticle toxicity was evaluated using a Cell Counting Kit-8 assay. The efficiency of cellular uptake was determined using fluorescein isothiocyanate-labeled DA-Chit nanoparticles, in place of TAA/DA-Chit nanoparticles, assessed by both inverted fluorescence microscopy and flow cytometry. Downregulation of VEGF mRNA expression by TAA/DA-Chit nanoparticles was further investigated by real-time reverse transcription polymerase chain reaction (RT-PCR) assay of the treated human retinal pigment epithelial cells. RESULTS: TAA/DA-Chit nanoparticles were prepared with a TAA-loading capacity in the range of 12%-82%, which increased the water solubility of TAA from 0.3 mg/mL to 2.1 mg/mL. These nanoparticles showed oblate shapes 100-550 nm in size in transmission electron microscopic images and had positive zeta potentials. The Cell Counting Kit-8 assay indicated that the DA Chit and TAA/DA-Chit nanoparticles had no toxicity and low toxicity, respectively, to human retinal pigment epithelial cells. Fluorescein isothiocyanate-labeled DA-Chit nanoparticle uptake by human retinal pigment epithelial cells was confirmed by inverted fluorescence microscopy and flow cytometry. Real-time RT-PCR assay showed that the VEGF mRNA level decreased after incubation of human retinal pigment epithelial cells with TAA/DA-Chit nanoparticles. CONCLUSION: TAA/DA-Chit nanoparticles had a downregulating effect on VEGF mRNA expression in human retinal pigment epithelial cells and low cytotoxicity, which might be beneficial characteristics for the development of future treatment for diabetic retinopathy. PMID- 22942645 TI - Cationic lipid-coated PEI/DNA polyplexes with improved efficiency and reduced cytotoxicity for gene delivery into mesenchymal stem cells. AB - BACKGROUND: Effective gene transfection without serum deprivation is a prerequisite for successful stem cell-based gene therapy. Polyethylenimine (PEI) is an efficient nonviral gene vector, but its application has been hindered by serum sensitivity and severe cytotoxicity. METHODS: To solve this problem, a new family of lipopolyplexes was developed by coating PEI/DNA polyplexes with three serum-resistant cationic lipids, namely, lysinylated, histidylated, and arginylated cholesterol. The physical properties, transfection efficiency, cellular uptake, subcellular distribution, and cytotoxicity of the lipopolyplexes was investigated. RESULTS: The outer coat composed of lysinylated or histidylated cholesterol remarkably improved the transfection efficiency of the polyplex with a low PEI/DNA ratio of 2 in the presence of serum. The resulting lysinylated and histidylated cholesterol lipopolyplexes were even more efficient than the best performing polyplex with a high PEI/DNA ratio of 10. Results from cellular uptake and subcellular distribution studies suggest that their higher transfection efficiency may result from accelerated DNA nuclear localization. The superiority of the lipopolyplexes over the best performing polyplex was also confirmed by delivering the therapeutic gene, hVEGF(165). Equally importantly, the lipid coating removed the necessity of introducing excess free PEI chains into the transfection solution for higher efficiency, generating lipopolyplexes with no signs of cytotoxicity. CONCLUSION: Noncovalent modification of polyplexes with lysinylated and histidylated cholesterol lipids can simultaneously improve efficiency and reduce the toxicity of gene delivery under serum conditions, showing great promise for genetic modification of bone marrow stem cells. PMID- 22942648 TI - The ClaudicatioNet concept: design of a national integrated care network providing active and healthy aging for patients with intermittent claudication. AB - INTRODUCTION: Intermittent claudication (IC) is a manifestation of peripheral arterial occlusive disease (PAOD). Besides cardiovascular risk management, supervised exercise therapy (SET) should be offered to all patients with IC. Outdated guidelines, an insufficient number of specialized physiotherapists (PTs), lack of awareness of the importance of SET by referring physicians, and misguided financial incentives all seriously impede the availability of a structured SET program in The Netherlands. DESCRIPTION OF CARE PRACTICE: By initiating regional care networks, ClaudicatioNet aims to improve the quality of care for patients with IC. Based on the chronic care model as a conceptual framework, these networks should enhance the access, continuity, and (cost) efficiency of the health care system. With the aid of a national database, health care professionals will be able to benchmark patient results while ClaudicatioNet will be able to monitor quality of care by way of functional and patient reported outcome measures. DISCUSSION: The success of ClaudicatioNet is dependent on several factors. Vascular surgeons, general practitioners and coordinating central caregivers will need to team up and work in close collaboration with specialized PTs. A substantial task in the upcoming years will be to monitor the quality, volume, and distribution of ClaudicatioNet PTs. Finally, misguided financial incentives within the Dutch health care system need to be tackled. CONCLUSION: With ClaudicatioNet, integrated care pathways are likely to improve in the upcoming years. This should result in the achievement of optimal quality of care for all patients with IC. PMID- 22942650 TI - Validity of the recorded codes of gonadotropin-releasing hormone agonist treatment and orchiectomies in the Danish National Patient Registry. AB - PURPOSE: Large-scale observational studies based on existing medical databases may have an important role in studies of long-term effects of different treatments in prostate cancer patients if the coding of the treatment is valid. We therefore estimated the positive predictive value (PPV) and negative predictive value (NPV) of hospital codes for gonadotropin-releasing hormone (GnRH) agonist treatment and orchiectomies in the Danish National Patient Registry (DNPR). PATIENTS AND METHODS: From Danish prostate cancer patients we selected 100 patients who were registered as users of GnRH agonists, 100 patients who were registered as nonusers of GnRH agonists, 50 patients who were registered as bilateral orchidectomized, and 50 patients who were not registered as orchidectomized in the DNPR between January 1, 2002 and December 31, 2008. From the patients' medical files we recorded codes for GnRH agonist treatment and orchiectomies, including dates of treatment from date of first prostate cancer diagnosis and onward. RESULTS: The PPV of GnRH agonist treatment coding in the DNPR was 93% (95% confidence interval [CI]: 86.1-97.1), and the NPV was 94% (95% CI: 87.4-97.8). Both the PPV and NPV of orchiectomy coding in the DNPR were 100% (97.5% CI: 92.9-100). CONCLUSION: We measured the validity of codes for GnRH agonist treatment and orchiectomies in the DNPR among prostate cancer patients and found high PPV and NPV. Thus, the DNPR remains a valuable tool for clinical epidemiological studies of GnRH agonist treatment and orchiectomies in the treatment of prostate cancer. PMID- 22942649 TI - Treating metastatic soft-tissue or bone sarcomas - potential role of ridaforolimus. AB - Sarcomas of soft tissue and bone are a rare group of cancers hallmarked by relative insensitivity to cytotoxic chemotherapy. The development of targeted therapies in the treatment of sarcoma has been difficult due to the significant heterogeneity and rarity of these diseases. Inhibition of the mammalian target of rapamycin (mTOR) has emerged as an exciting treatment approach and is being studied extensively in sarcoma patients. Ridaforolimus is a second generation mTOR inhibitor that has shown potential benefit in the treatment of sarcoma. Recently a Phase III study demonstrated an improvement in progression-free survival when patients with at least stable disease after treatment with standard chemotherapy received maintenance ridaforolimus compared to placebo. The results of this study show that mTOR is an important pathway in soft tissue and bone sarcomas and represents an exciting opportunity for the improvement in the treatment of our patients. PMID- 22942651 TI - Exploring the relationship between maternal iron status and offspring's blood pressure and adiposity: a Mendelian randomization study. AB - BACKGROUND: Iron deficiency is the most common micronutrient deficiency worldwide. Experimental animal studies suggest that mothers deficient in iron during pregnancy are more likely to have offspring who become obese with high blood pressure. C282Y mutation carriers are more likely to have higher iron stores. METHODS: We undertook an instrumental variable (IV) analysis, using maternal C282Y as an indicator for the mother's iron status, to examine its association with offspring blood pressure (BP), waist circumference (WC), and body mass index (BMI), and compared the results to that of ordinary least squares (OLS) regression. Offspring of a sub-cohort of mothers from the UK Women's Cohort Study (UKWCS) were recruited in 2009-2010 (n = 348, mean age = 41 years). Their blood pressure, height, and weight were measured at their local general medical practice, and they were asked to self-measure their waist circumference. About half were offspring of C282Y carriers. Maternal ferritin was used as a biomarker of maternal iron status. RESULTS: Maternal C282Y was strongly associated with maternal ferritin (mean difference per allele = 84 g/L, 95% confidence interval: 31-137, P = 0.002). Using IV analyses, maternal ferritin was not linked to offspring's BP, BMI, or WC. The first stage F-statistic for the strength of the instrument was 10 (Kleibergen-Paap rk LM P = 0.009). Maternal ferritin was linked to offspring diastolic BP, WC, and BMI in univariable, but not in multivariable OLS analysis. There was no difference between the OLS and the IV models coefficients for any of the outcomes considered. CONCLUSION: We found no association between maternal iron status and adult offspring's BP and adiposity using both multivariable OLS and IV modeling. To our knowledge, this is the first study examining this relationship. Further exploration in larger studies that have genetic variation assessed in both mother and offspring should be considered. PMID- 22942653 TI - Changes in hand surgery in Canada over the past 40 years: Some personal observations. PMID- 22942652 TI - Challenges in validating quality of care data in a schizophrenia registry: experience from the Danish National Indicator Project. AB - BACKGROUND: Improvement of quality of care for psychiatric patients is a key objective of health care systems worldwide. Consequently, there is an increasing interest in documenting quality of care; however, little is known about the validity of the available data on psychiatric care. OBJECTIVE: To assess the validity of process of care data recorded in the Danish National Indicator Project (DNIP), a national population-based registry containing quality of care data of patients diagnosed with schizophrenia in Denmark. METHODS: A random sample of 1% of patients with schizophrenia registered in the DNIP between 2004 and 2009 (111 inpatient and 85 outpatient) was identified for validation. Medical records for these patients, which were used as the gold standard, were retrieved and reviewed for information on the processes of care received. Agreement between the data in the DNIP and the medical records were assessed by computing sensitivity, specificity, and positive and negative predictive values. RESULTS: The agreement between the recorded processes of care in the DNIP and in the medical records varied substantially across the individual process of care variables. However, a collection of the processes of care demonstrated a high agreement (80% or more) between data in the DNIP and the medical records, according to all examined aspects of data validity (sensitivity, specificity, and positive and negative predictive values). The medical records contained varying levels of missing information regarding the processes of care, from 1% for antipsychotic medication prescription to 54% for psychoeducation. CONCLUSION: Current documentation practices in Danish psychiatric hospitals appear to be inconsistent and may preclude the use of psychiatric medical records as the gold standard when validating registry data. PMID- 22942654 TI - P16 protein expression in primary cutaneous melanoma with positive and negative lymph node biopsies: Particular aspects of a study performed at the Hospital de Clinicas de Porto Alegre, Brazil. AB - BACKGROUND: Cutaneous melanoma dermal invasion, identified through measurement of maximum tumour thickness and sentinel lymph node (SLN) biopsy, is important to establish melanoma prognosis and progression. P16 protein expression has been shown to be a predictive factor for melanoma evolution and prognosis. OBJECTIVE: To investigate p16 protein expression in cutaneous melanomas with and without SLN metastasis. PATIENTS AND METHODS: Sixty-seven paraffin-embedded cutaneous melanoma specimens of patients who had undergone SLN investigation were evaluated from 1995 to 2007. SLN biopsy was negative for metastasis in 34 of these patients (controls); in the remaining 33 patients, SLN biopsy was positive (cases). The expression of p16 protein in the primary tumour was measured using an immunohistochemical assay. The samples were classified according to their nuclear expression. RESULTS: P16 nuclear expression was absent in 14 cases and in 15 controls; P=0.812. There was no statistically significant difference in p16 nuclear expression between cases and controls. CONCLUSIONS: The present study does not support the findings of other studies that suggest p16 protein expression is important in the prognosis of cutaneous melanoma. PMID- 22942655 TI - Improving journal clubs through the use of positive deviance: A mixed-methods study. AB - BACKGROUND: Plastic surgery journal clubs are often unsatisfactory for both surgeons and residents, leading to frustration and poor surgeon attendance. OBJECTIVE: To assess and modify journal clubs using the principles of positive deviance. METHODS: Surgeons and residents were surveyed across five domains before and after journal club modification. These included perception of the quality of articles chosen, the quality of the presentations, postpresentation discussions, educational benefit and overall satisfaction. RESULTS: Using the principles of positive deviance, the authors were able to identify points of concern with journal clubs and make suggestions for improvement. Postintervention surveys demonstrated a statistically significant improvement in journal clubs across all five domains assessed. CONCLUSIONS: Using the principles of positive deviance, journal club satisfaction was improved. The interventions presented could be used to improve journal clubs at other institutions. In addition, the principles of positive deviance can be used to address a variety of administrative and educational challenges faced by plastic surgery programs. PMID- 22942656 TI - Optimizing revenue at a cosmetic surgery centre. AB - BACKGROUND: The demand for cosmetic surgery and services has diminished with recent fluctuations in the economy. To stay ahead, surgeons must appreciate and attend to the fiscal challenges of private practice. A key component of practice economics is knowledge of the common methods of payment. OBJECTIVE: To review methods of payment in a five-surgeon group practice in central Texas, USA. METHODS: A retrospective chart review of the financial records of a cosmetic surgery centre in Texas was conducted. Data were collected for the five-year period from 2003 to 2008, and included the method of payment, the item purchased (product, service or surgery) and the dollar amount. RESULTS: More than 11,000 transactions were reviewed. The most common method of payment used for products and services was credit card, followed by check and cash. For procedures, the most common form of payment was personal check, followed by credit card and financing. Of the credit card purchases for both products and procedures, an overwhelming majority of patients (more than 75%) used either Visa (Visa Inc, USA) or MasterCard (MasterCard Worldwide, USA). If the amount of the individual transaction surpassed US$1,000, the most common method of payment transitioned from credit card to personal check. CONCLUSIONS: In an effort to maximize revenue, surgeons should consider limiting the credit cards accepted by the practice and encourage payment through personal check. PMID- 22942657 TI - Delayed two-stage breast reconstruction with implants: The authors' recent experience. AB - BACKGROUND: Presently, breast cancer detection is delayed in Poland and, thus, the only other option for patients is amputation and breast reconstruction (immediate or delayed). Reconstructive methods are based on using the patient's own tissue (pedicled or free myocutaneous flaps) or implants (a tissue expander, which is later exchanged for a prosthesis or an expandable implant). OBJECTIVE: To evaluate the aesthetic results of a delayed two-stage breast reconstruction with the use of implants (expander and prosthesis) in patients who have previously undergone cancer-related mastectomy. METHODS: From 2006 to 2009, 54 patients (34 to 65 years of age) underwent reconstruction at least one year after their mastectomy and adjuvant chemotherapy; three women also received x-ray therapy. All women underwent a two-stage treatment with a tissue expander, which was later exchanged for a prosthesis. RESULTS: Outcomes of the surgery (evaluated by the physician and the patient at least six months after all stages of reconstruction) were found to be very good in 42 patients and good in 12 patients. After amputation and x-ray therapy in two cases, a fistula developed, which necessitated implant removal. CONCLUSIONS: After amputation, breast reconstruction with implants (expander and prosthesis) provides good aesthetic results. The method is mildly burdening to the patient and does not cause severe scarring. Symmetrization of the second breast is often recommended; however, the cost is not covered by the national health system. In principle, earlier x-ray therapy disqualifies the application of implants. Dividing reconstruction into two stages (expander and prosthesis) allows for possible correction of prosthesis placement. PMID- 22942658 TI - Contribution of breast density to the volume of the augmented breast: A preliminary study. AB - BACKGROUND: Prediction of soft tissue contribution to the shape, volume and texture of the augmented breast proves to be an ever-challenging, uncontrollable variable. Similarly, the understanding of the contribution of breast density in breast augmentation has been elusive and, generally, not well studied. OBJECTIVE: With the aid of three-dimensional photographic analysis, the present preliminary study examined the contribution of differing breast densities to the overall volume of the augmented breast. METHODS: All patients undergoing primary augmentation over a six-month period were included in the study. To standardize technique and implant type, all patients received saline-filled moderate-profile implants, which were placed partially underneath the pectoralis muscle through a lower pole approach. Photographic analysis of the breast volume was completed preoperatively and, subsequently, at a minimum of six months postoperatively. Preoperatively, each breast was also assigned to one of four classes of increasing mammographic density, as judged by the mammographic radiologist (fatty, moderately dense, heterogeneously dense and extremely dense). Postoperative breast volumes were, subsequently, correlated to mammographic densities. RESULTS: Thirty-eight augmented breasts in 21 patients were examined. The average volume gain based on the implant size used was 92.7%. Heterogeneously dense breasts comprised 68% of the total breasts and showed an average volume gain of 100.67%, extremely dense breasts comprised 26% of the total breasts and showed an average volume gain of 97.3%, and moderately dense breasts comprised 5% of the total breasts with an average gain of 100.04%. There was no significant difference between the augmented breast volumes and the respective expected volumes (combined preaugmented breast volumes and implant volumes; P=0.3483). Additionally, no statistical difference was found between the density classes and the expected augmented volumes. CONCLUSION: No statistical difference was found between expected and actual augmented breast volumes among or between four different breast density classes. Thus, one would expect that the soft tissue compression or the response of the impression of the implant on the parenchyma, would not be statistically different among classes. Additionally, compressive atrophy, as seen with atrophy of the breasts over time, would be expected to be multifactorial and not uniquely independent to breast density. However, longitudinal analysis is needed to study the durability of breast shape relative to breast density. PMID- 22942659 TI - Congenital granular cell tumour of the newborn: A case report and literature review. AB - A congenital granular cell tumour is rare, and presents in newborns as a mass arising from the alveolus. While its pathogenesis is unclear, it has no malignant potential and may, occasionally, spontaneously regress postpartum. Successful treatment usually consists of conservative simple excision. PMID- 22942660 TI - The split breast flap: Revisited - a medieval or an ideal solution in the selected case? AB - In assessing a patient requiring palliative reconstruction of the anterior chest wall, a host of techniques engulf the reconstructive surgeon, who has to evaluate the local situation, the tissue lost, the tissue required and the tissue available. The patient's general condition is usually a major influence on this decision. The split breast flap is an often forgotten, simple means of palliative reconstruction. PMID- 22942661 TI - Radial forearm free flap morbidity: A rare case of a normal preoperative arteriogram and acute intraoperative hand ischemia. AB - Since its first description in 1981, the radial forearm free flap has become a valuable tool for reconstructive microsurgery. However, there are potential complications associated with the flap - the most feared being hand ischemia from sacrifice of the radial artery. Fortunately, acute ischemic complications are exceedingly rare, with only two cases reported in the literature. Options for preoperative evaluation of the donor extremity include the Allen's test, ultrasonography and angiography. A preoperative arteriogram is considered to be the definitive method to evaluate arterial anatomy, patency, and collateralization between the radial and ulnar arteries. The current article presents the authors' experience with a patient who had a delayed Allen's test and a normal arteriogram of his left upper extremity, and who developed acute intraoperative hand ischemia, requiring reconstruction of his radial artery, after elevation of a radial forearm free flap.Although exceedingly rare, the occurrence of acute vascular insufficiency is always a possibility and must be kept in mind when harvesting a radial forearm free flap. The surgeon should be prepared to perform an interposition vein graft reconstruction to avoid any potential complications. Clinical examination and judgment may be more important than radiological studies in certain cases. PMID- 22942663 TI - Nasal trauma: Primary reconstruction with open rhinoplasty. AB - Due to the prominent location of the nose, the most common facial traumas are nasal injuries. Although nasal traumas usually require staged intervention at a later period of time, in selected cases, primary reconstruction can be effective. A 20-year-old man who was referred from the emergency department with nasal trauma is presented. He reported a fall after feeling unsteady, which caused a direct nasal injury. Clinical examination revealed septal fracture with obstruction of the left nasal cavity and deformity of the nasal pyramid (inverted V deformity). The patient also had a complete dissection of the columella skin. Epistaxis was self-limited, and an open rhinoplasty procedure was decided because the trauma occurred 1 h before admission and there was no significant edema. Surgical intervention included septal reconstruction combined with restoration of the nasal pyramid and columella. One month later, the patient had patent nasal airways, and he was satisfied with the aesthetic result. PMID- 22942662 TI - Juvenile fibroadenoma of the breast: Treatment and literature review. AB - It is uncommon to find palpable breast masses in young patients. Generally, such masses are benign. Juvenile fibroadenoma is the most frequent benign tumour of the breast. The present report describes a case involving a 17-year-old girl with unilateral right breast hypertrophy, for whom resection and breast reduction was effectively achieved.Resection was combined with an aesthetically pleasing outcome through breast reduction, via a wise pattern of reduction with a superior pedicle.While young patients rarely present with breast masses, the consideration of fibroadenoma in these cases is always warranted. The disconcerting appearance of the breasts for adolescents afflicted by such benign masses underscores the importance of achieving aesthetically optimal outcomes and attaining adequate tumour resection for diagnostic purposes through pathological specimens. In the present case, the young patient underwent a procedure that fulfilled both of these valuable goals through careful pre-operative planning, pedicle selection and skin resection patterns. PMID- 22942664 TI - The mosquito-handle: Speed and uniformity in de-epithelializing a breast pedicle for reduction mammaplasty. PMID- 22942666 TI - Challenges of randomized controlled trial design in plastic surgery. AB - Randomized controlled trials are the gold standard of evidence-based medicine. In the field of plastic surgery, designing these studies is much more challenging than in pharmaceutical medicine. Randomized trials in plastic surgery encompass several road blocks including problems shared with other surgical trials: equipoise, high cost, placebo issues and learning curves following the establishment of a novel approach. In addition, plastic surgery has more subjective outcomes, thus making study design even more difficult in assessing the end result. PMID- 22942665 TI - Optimizing injectable poly-L-lactic acid administration for soft tissue augmentation: The rationale for three treatment sessions. AB - BACKGROUND: The availability and variety of different injectable modalities has led to a dramatic increase in soft tissue augmentation procedures in recent years. Injectable poly-L-lactic acid (PLLA) is a synthetic, biodegradable polymer device approved in the United States for use in immunocompetent patients as a single regimen of up to four treatment sessions for correction of shallow to deep nasolabial fold contour deficiencies and other facial wrinkles. Injectable PLLA is also approved for restoration and/or correction of signs of facial fat loss (lipoatrophy) in individuals with HIV. METHODS: The present article provides an overview of previous studies with injectable PLLA, and specifically focuses on the number of recommended treatment sessions and intervals between treatment sessions. The authors also provide two case studies to support their recommendations for an average of three treatment sessions. RESULTS: Although the specific mechanisms remain hypothetical, injections of PLLA are believed to cause a cascade of cellular events that lead to collagen repair and subsequent restoration of facial volume. Because the development of a response to injectable PLLA is gradual and its duration of effect is long lasting, sufficient time between treatment sessions should be allocated to avoid overcorrection. CONCLUSION: Studies of injectable PLLA support the hypothesized mode of operation, and the experience and clinical recommendations of the authors that suggest that three treatment sessions are an optimal regimen for use of injectable PLLA in the majority of patients. PMID- 22942667 TI - Massive localized lymphedema: A case series and literature review. AB - A large, deep, soft tissue mass is often malignant in nature; however, a recent study described a large soft tissue mass present in morbidly obese patients that was found to be benign. Massive localized lymphedema (MLL) is a large pedunculated lymphadematous mass found in the lower extremity of morbidly obese patients. MLL often enlarges over many years and may interfere with mobility. Although histologically similar to well-differentiated liposarcoma, MLL has recently emerged as a separate, benign clinical entity. The pathophysiology of MLL is yet to be understood. A literature review, and the authors' experiences are discussed to assist in clinical decision making. PMID- 22942669 TI - Foreword. PMID- 22942668 TI - Improved deposition and deprotection of silane tethered 3,4 hydroxypyridinone (HOPO) ligands on functionalized nanoporous silica. AB - An improved synthesis of a 3,4 hydroxypyridinone (HOPO) functionalized mesoporous silica is described. Higher 3,4-HOPO monolayer ligand loadings have been achieved, resulting in better performance. Performance improvements were demonstrated with the capture of U(VI) from human blood, plasma and filtered river water. PMID- 22942670 TI - Replicating strand asymmetry in bacterial and eukaryotic genomes. PMID- 22942672 TI - DNA replication and strand asymmetry in prokaryotic and mitochondrial genomes. AB - Different patterns of strand asymmetry have been documented in a variety of prokaryotic genomes as well as mitochondrial genomes. Because different replication mechanisms often lead to different patterns of strand asymmetry, much can be learned of replication mechanisms by examining strand asymmetry. Here I summarize the diverse patterns of strand asymmetry among different taxonomic groups to suggest that (1) the single-origin replication may not be universal among bacterial species as the endosymbionts Wigglesworthia glossinidia, Wolbachia species, cyanobacterium Synechocystis 6803 and Mycoplasma pulmonis genomes all exhibit strand asymmetry patterns consistent with the multiple origins of replication, (2) different replication origins in some archaeal genomes leave quite different patterns of strand asymmetry, suggesting that different replication origins in the same genome may be differentially used, (3) mitochondrial genomes from representative vertebrate species share one strand asymmetry pattern consistent with the strand-displacement replication documented in mammalian mtDNA, suggesting that the mtDNA replication mechanism in mammals may be shared among all vertebrate species, and (4) mitochondrial genomes from primitive forms of metazoans such as the sponge and hydra (representing Porifera and Cnidaria, respectively), as well as those from plants, have strand asymmetry patterns similar to single-origin or multi-origin replications observed in prokaryotes and are drastically different from mitochondrial genomes from other metazoans. This may explain why sponge and hydra mitochondrial genomes, as well as plant mitochondrial genomes, evolves much slower than those from other metazoans. PMID- 22942671 TI - Measures of compositional strand bias related to replication machinery and its applications. AB - The compositional asymmetry of complementary bases in nucleotide sequences implies the existence of a mutational or selectional bias in the two strands of the DNA duplex, which is commonly shaped by strand-specific mechanisms in transcription or replication. Such strand bias in genomes, frequently visualized by GC skew graphs, is used for the computational prediction of transcription start sites and replication origins, as well as for comparative evolutionary genomics studies. The use of measures of compositional strand bias in order to quantify the degree of strand asymmetry is crucial, as it is the basis for determining the applicability of compositional analysis and comparing the strength of the mutational bias in different biological machineries in various species. Here, we review the measures of strand bias that have been proposed to date, including the ?GC skew, the B(1) index, the predictability score of linear discriminant analysis for gene orientation, the signal-to-noise ratio of the oligonucleotide bias, and the GC skew index. These measures have been predominantly designed for and applied to the analysis of replication-related mutational processes in prokaryotes, but we also give research examples in eukaryotes. PMID- 22942673 TI - Replication-Associated Mutational Pressure (RMP) Governs Strand-Biased Compositional Asymmetry (SCA) and Gene Organization in Animal Mitochondrial Genomes. AB - The nucleotide composition of the light (L-) and heavy (H-) strands of animal mitochondrial genomes is known to exhibit strand-biased compositional asymmetry (SCA). One of the possibilities is the existence of a replication-associated mutational pressure (RMP) that may introduce characteristic nucleotide changes among mitochondrial genomes of different animal lineages. Here, we discuss the influence of RMP on nucleotide and amino acid compositions as well as gene organization. Among animal mitochondrial genomes, RMP may represent the major force that compels the evolution of mitochondrial protein-coding genes, coupled with other process-based selective pressures, such as on components of translation machinery- tRNAs and their anticodons. Through comparative analyses of sequenced mitochondrial genomes among diverse animal lineages and literature reviews, we suggest a strong RMP effect, observed among invertebrate mitochondrial genes as compared to those of vertebrates, that is either a result of positive selection on the invertebrate or a relaxed selective pressure on the vertebrate mitochondrial genes. PMID- 22942674 TI - Coding constraints modulate chemically spontaneous mutational replication gradients in mitochondrial genomes. AB - Distances from heavy and light strand replication origins determine duration mitochondrial DNA remains singlestranded during replication. Hydrolytic deaminations from A->G and C->T occur more on single- than doublestranded DNA. Corresponding replicational nucleotide gradients exist across mitochondrial genomes, most at 3rd, least 2(nd) codon positions. DNA singlestrandedness during RNA transcription causes gradients mainly in long-lived species with relatively slow metabolism (high transcription/replication ratios). Third codon nucleotide contents, evolutionary results of mutation cumulation, follow replicational, not transcriptional gradients in Homo; observed human mutations follow transcriptional gradients. Synonymous third codon position transitions potentially alter adaptive off frame information. No mutational gradients occur at synonymous positions forming off frame stops (these adaptively stop early accidental frameshifted protein synthesis), nor in regions coding for putative overlapping genes according to an overlapping genetic code reassigning stop codons to amino acids. Deviation of 3rd codon nucleotide contents from deamination gradients increases with coding importance of main frame 3rd codon positions in overlapping genes (greatest if these are 2(nd) position in overlapping genes). Third codon position deamination gradients calculated separately for each codon family are strongest where synonymous transitions are rarely pathogenic; weakest where transitions are frequently pathogenic. Synonymous mutations affect translational accuracy, such as error compensation of misloaded tRNAs by codon-anticodon mismatches (prevents amino acid misinsertion despite tRNA misacylation), a potential cause of pathogenic mutations at synonymous codon positions. Indeed, codon-family-specific gradients are inversely proportional to error compensation associated with gradient-promoted transitions. Deamination gradients reflect spontaneous chemical reactions in singlestranded DNA, but functional coding constraints modulate gradients. PMID- 22942675 TI - A blueprint for a mutationist theory of replicative strand asymmetries formation. AB - In the present review, we summarized current knowledge on replicative strand asymmetries in prokaryotic genomes. A cornerstone for the creation of a theory of their formation has been overviewed. According to our recent works, the probability of nonsense mutation caused by replication-associated mutational pressure is higher for genes from lagging strands than for genes from leading strands of both bacterial and archaeal genomes. Lower density of open reading frames in lagging strands can be explained by faster rates of nonsense mutations in genes situated on them. According to the asymmetries in nucleotide usage in fourfold and twofold degenerate sites, the direction of replication-associated mutational pressure for genes from lagging strands is usually the same as the direction of transcription-associated mutational pressure. It means that lagging strands should accumulate more 8-oxo-G, uracil and 5-formyl-uracil, respectively. In our opinion, consequences of cytosine deamination (C to T transitions) do not lead to the decrease of cytosine usage in genes from lagging strands because of the consequences of thymine oxidation (T to C transitions), while guanine oxidation (causing G to T transversions) makes the main contribution into the decrease of guanine usage in fourfold degenerate sites of genes from lagging strands. Nucleotide usage asymmetries and bias in density of coding regions can be found in archaeal genomes, although, the percent of "inversed" asymmetries is much higher for them than for bacterial genomes. "Homogenized" and "inversed" replicative strand asymmetries in archaeal genomes can be used as retrospective indexes for detection of OriC translocations and large inversions. PMID- 22942677 TI - Using genetic networks and homology to understand the evolution of phenotypic traits. AB - Homology can have different meanings for different kinds of biologists. A phylogenetic view holds that homology, defined by common ancestry, is rigorously identified through phylogenetic analysis. Such homologies are taxic homologies (=synapomorphies). A second interpretation, "biological homology" emphasizes common ancestry through the continuity of genetic information underlying phenotypic traits, and is favored by some developmental geneticists. A third kind of homology, deep homology, was recently defined as "the sharing of the genetic regulatory apparatus used to build morphologically and phylogenetically disparate features." Here we explain the commonality among these three versions of homology. We argue that biological homology, as evidenced by a conserved gene regulatory network giving a trait its "essential identity" (a Character Identity Network or "ChIN") must also be a taxic homology. In cases where a phenotypic trait has been modified over the course of evolution such that homology (taxic) is obscured (e.g. jaws are modified gill arches), a shared underlying ChIN provides evidence of this transformation. Deep homologies, where molecular and cellular components of a phenotypic trait precede the trait itself (are phylogenetically deep relative to the trait), are also taxic homologies, undisguised. Deep homologies inspire particular interest for understanding the evolutionary assembly of phenotypic traits. Mapping these deeply homologous building blocks on a phylogeny reveals the sequential steps leading to the origin of phenotypic novelties. Finally, we discuss how new genomic technologies will revolutionize the comparative genomic study of non-model organisms in a phylogenetic context, necessary to understand the evolution of phenotypic traits. PMID- 22942676 TI - Interference between DNA replication and transcription as a cause of genomic instability. AB - Replication and transcription are key aspects of DNA metabolism that take place on the same template and potentially interfere with each other. Conflicts between these two activities include head-on or co-directional collisions between DNA and RNA polymerases, which can lead to the formation of DNA breaks and chromosome rearrangements. To avoid these deleterious consequences and prevent genomic instability, cells have evolved multiple mechanisms preventing replication forks from colliding with the transcription machinery. Yet, recent reports indicate that interference between replication and transcription is not limited to physical interactions between polymerases and that other cotranscriptional processes can interfere with DNA replication. These include DNA-RNA hybrids that assemble behind elongating RNA polymerases, impede fork progression and promote homologous recombination. Here, we discuss recent evidence indicating that R loops represent a major source of genomic instability in all organisms, from bacteria to human, and are potentially implicated in cancer development. PMID- 22942678 TI - Synthesis and electrochemical proprieties of novel unsymmetrical bis tetrathiafulvalenes and electrical conductivity of their charge transfer complexes with tetracyanoquinodimethane (TCNQ). AB - The synthesis and properties of a series of bis-tetrathiafulvalenes (bis-TTFs) containing nitrophenyl, aminophenyl or dimethylaminophenyl is reported. The synthesis was carried out by using routes involving Wittig-type, cross-coupling, reduction and alkylation reactions. The electron donor ability of these new compounds has been measured by cyclic voltammetry (CV). Charge transfer complexes with tetracyanoquinodimethane (TCNQ) were prepared by chemical redox reactions. The complexes have been proven to give conducting materials. PMID- 22942679 TI - Molecular targets of TRAIL-sensitizing agents in colorectal cancer. AB - Tumor necrosis factor (TNF)-related apoptosis inducing ligand (TRAIL), a member of the TNF superfamily, interacts with its functional death receptors (DRs) and induces apoptosis in a wide range of cancer cell types. Therefore, TRAIL has been considered as an attractive agent for cancer therapy. However, many cancers are resistant to TRAIL-based therapies mainly due to the reduced expression of DRs and/or up-regulation of TRAIL pathway-related anti-apoptotic proteins. Compounds that revert such defects restore the sensitivity of cancer cells to TRAIL, suggesting that combined therapies could help manage neoplastic patients. In this article, we will focus on the TRAIL-sensitizing effects of natural products and synthetic compounds in colorectal cancer (CRC) cells and discuss the molecular mechanisms by which such agents enhance the response of CRC cells to TRAIL. PMID- 22942680 TI - A specific oligodeoxynucleotide promotes the differentiation of osteoblasts via ERK and p38 MAPK pathways. AB - A specific oligodeoxynucleotide (ODN), ODN MT01, was found to have positive effects on the proliferation and activation of the osteoblast-like cell line MG 63. In this study, the detailed signaling pathways in which ODN MT01 promoted the differentiation of osteoblasts were systematically examined. ODN MT01 enhanced the expression of osteogenic marker genes, such as osteocalcin and type I collagen. Furthermore, ODN MT01 activated Runx2 phosphorylation via ERK1/2 mitogen-activated protein kinase (MAPK) and p38 MAPK. Consistently, ODN MT01 induced up-regulation of osteocalcin, alkaline phosphatase (ALP) and type I collagen, which was inhibited by pre-treatment with the ERK1/2 inhibitor U0126 and the p38 inhibitor SB203580. These results suggest that the ERK1/2 and p38 MAPK pathways, as well as Runx2 activation, are involved in ODN MT01-induced up regulation of osteocalcin, type I collagen and the activity of ALP in MG 63 cells. PMID- 22942681 TI - L-2-Oxothiazolidine-4-carboxylic acid or alpha-lipoic acid attenuates airway remodeling: involvement of nuclear factor-kappaB (NF-kappaB), nuclear factor erythroid 2p45-related factor-2 (Nrf2), and hypoxia-inducible factor (HIF). AB - Reactive oxygen species (ROS) play a crucial role in the pathogenesis of acute and chronic respiratory diseases. Antioxidants have been found to ameliorate airway inflammation and hyperresponsiveness in animal models employing short-term exposure to allergen. However, little data are available on the effect of antioxidants on airway remodeling and signaling pathways in chronic asthma. In the present study, we used a long-term exposure murine model of allergic airway disease to evaluate the effects of an antioxidant, L-2-oxothiazolidine-4 carboxylic acid (OTC) or alpha-lipoic acid (LA) on airway remodeling, focusing on the ROS-related hypoxia-inducible signaling. Long-term challenge of ovalbumin (OVA) increased ROS production, airway inflammation, and airway hyperresponsiveness, and developed features of airway remodeling such as excessive mucus secretion, subepithelial fibrosis, and thickening of the peribronchial smooth muscle layer. Administration of OTC or LA reduced these features of asthma, including airway remodeling, which was accompanied by suppression of transforming growth factor-beta1, vascular endothelial growth factor, and T-helper 2 cytokines. In addition, OVA-induced activation of nuclear factor-kappaB (NF-kappaB), nuclear factor erythroid 2p45-related factor-2 (Nrf2), hypoxia-inducible factor (HIF)-1alpha, and HIF-2alpha was reduced by OTC or LA. Our results also showed that OTC or LA down-regulated phosphoinositide 3-kinase activity and decreased phosphorylation of p38 mitogen-activated protein kinase but not extracellular signal-regulated kinase 1/2 or c-Jun N-terminal kinase. These findings demonstrate that OTC and LA can inhibit activation of NF-kappaB, Nrf2, and HIF, leading to attenuate allergen-induced airway remodeling. PMID- 22942682 TI - Degradability enhancement of poly(lactic acid) by stearate-Zn(3)Al LDH nanolayers. AB - Recent environmental problems and societal concerns associated with the disposal of petroleum based plastics throughout the world have triggered renewed efforts to develop new biodegradable products compatible with our environment. This article describes the preparation, characterization and biodegradation study of poly(lactic acid)/layered double hydroxide (PLA/LDH) nanocomposites from PLA and stearate-Zn(3)Al LDH. A solution casting method was used to prepare PLA/stearate Zn(3)Al LDH nanocomposites. The anionic clay Zn(3)Al LDH was firstly prepared by co-precipitation method from a nitrate salt solution at pH 7.0 and then modified by stearate anions through an ion exchange reaction. This modification increased the basal spacing of the synthetic clay from 8.83 A to 40.10 A. The morphology and properties of the prepared PLA/stearate-Zn(3)Al LDH nanocomposites were studied by X-ray diffraction (XRD), transmission electron microscope (TEM), scanning electron microscope (SEM), thermogravimetric analysis (TGA), tensile tests as well as biodegradation studies. From the XRD analysis and TEM observation, the stearate-Zn(3)Al LDH lost its ordered stacking-structure and was greatly exfoliated in the PLA matrix. Tensile test results of PLA/stearate Zn(3)Al LDH nanocomposites showed that the presence of around 1.0-3.0 wt % of the stearate-Zn(3)Al LDH in the PLA drastically improved its elongation at break. The biodegradation studies demonstrated a significant biodegradation rate improvement of PLA in the presence of stearate-Zn(3)Al LDH nanolayers. This effect can be caused by the catalytic role of the stearate groups in the biodegradation mechanism leading to much faster disintegration of nanocomposites than pure PLA. PMID- 22942683 TI - Artificial intelligence techniques to optimize the EDC/NHS-mediated immobilization of cellulase on Eudragit L-100. AB - Two artificial intelligence techniques, namely artificial neural network (ANN) and genetic algorithm (GA) were combined to be used as a tool for optimizing the covalent immobilization of cellulase on a smart polymer, Eudragit L-100. 1-Ethyl 3-(3-dimethyllaminopropyl) carbodiimide (EDC) concentration, N-hydroxysuccinimide (NHS) concentration and coupling time were taken as independent variables, and immobilization efficiency was taken as the response. The data of the central composite design were used to train ANN by back-propagation algorithm, and the result showed that the trained ANN fitted the data accurately (correlation coefficient R(2) = 0.99). Then a maximum immobilization efficiency of 88.76% was searched by genetic algorithm at a EDC concentration of 0.44%, NHS concentration of 0.37% and a coupling time of 2.22 h, where the experimental value was 87.97 +/ 6.45%. The application of ANN based optimization by GA is quite successful. PMID- 22942684 TI - DsHsp90 is involved in the early response of Dunaliella salina to environmental stress. AB - Heat shock protein 90 (Hsp90) is a molecular chaperone highly conserved across the species from prokaryotes to eukaryotes. Hsp90 is essential for cell viability under all growth conditions and is proposed to act as a hub of the signaling network and protein homeostasis of the eukaryotic cells. By interacting with various client proteins, Hsp90 is involved in diverse physiological processes such as signal transduction, cell mobility, heat shock response and osmotic stress response. In this research, we cloned the dshsp90 gene encoding a polypeptide composed of 696 amino acids from the halotolerant unicellular green algae Dunaliella salina. Sequence alignment indicated that DsHsp90 belonged to the cytosolic Hsp90A family. Further biophysical and biochemical studies of the recombinant protein revealed that DsHsp90 possessed ATPase activity and existed as a dimer with similar percentages of secondary structures to those well-studied Hsp90As. Analysis of the nucleotide sequence of the cloned genomic DNA fragment indicated that dshsp90 contained 21 exons interrupted by 20 introns, which is much more complicated than the other plant hsp90 genes. The promoter region of dshsp90 contained putative cis-acting stress responsive elements and binding sites of transcriptional factors that respond to heat shock and salt stress. Further experimental research confirmed that dshsp90 was upregulated quickly by heat and salt shock in the D. salina cells. These findings suggested that dshsp90 might serve as a component of the early response system of the D. salina cells against environmental stresses. PMID- 22942685 TI - Adsorption of sodium dodecyl sulfate on Ge substrate: the effect of a low polarity solvent. AB - This paper describes the adsorption of sodium dodecyl sulfate (SDS) molecules in a low polar solvent on Ge substrate by using Fourier transform infrared attenuated total reflection (FTIR-ATR) spectroscopy and atomic force microscopy (AFM). The maximum SDS amount adsorbed is (5.0 +/- 0.3) * 10(14) molecules cm(-2) in CHCl(3), while with the use of CCl(4) as subphase the ability of SDS adsorbed is 48% lower. AFM images show that depositions are highly disordered over the interface, and it was possible to establish that the size of the SDS deposition is around 30-40 nm over the Ge surface. A complete description of the infrared spectroscopic bands for the head and tail groups in the SDS molecule is also provided. PMID- 22942686 TI - Glutamine synthetase in legumes: recent advances in enzyme structure and functional genomics. AB - Glutamine synthetase (GS) is the key enzyme involved in the assimilation of ammonia derived either from nitrate reduction, N(2) fixation, photorespiration or asparagine breakdown. A small gene family is encoding for different cytosolic (GS1) or plastidic (GS2) isoforms in legumes. We summarize here the recent advances carried out concerning the quaternary structure of GS, as well as the functional relationship existing between GS2 and processes such as nodulation, photorespiration and water stress, in this latter case by means of proline production. Functional genomic analysis using GS2-minus mutant reveals the key role of GS2 in the metabolic control of the plants and, more particularly, in carbon metabolism. PMID- 22942687 TI - High resolution crystal structures of the Cerebratulus lacteus mini-Hb in the unligated and carbomonoxy states. AB - The nerve tissue mini-hemoglobin from Cerebratulus lacteus (CerHb) displays an essential globin fold hosting a protein matrix tunnel held to allow traffic of small ligands to and from the heme. CerHb heme pocket hosts the distal TyrB10/GlnE7 pair, normally linked to low rates of O(2) dissociation and ultra high O(2) affinity. However, CerHb affinity for O(2) is similar to that of mammalian myoglobins, due to a dynamic equilibrium between high and low affinity states driven by the ability of ThrE11 to orient the TyrB10 OH group relative to the heme ligand. We present here the high resolution crystal structures of CerHb in the unligated and carbomonoxy states. Although CO binds to the heme with an orientation different from the O(2) ligand, the overall binding schemes for CO and O(2) are essentially the same, both ligands being stabilized through a network of hydrogen bonds based on TyrB10, GlnE7, and ThrE11. No dramatic protein structural changes are needed to support binding of the ligands, which can freely reach the heme distal site through the apolar tunnel. A lack of main conformational changes between the heme-unligated and -ligated states grants stability to the folded mini-Hb and is a prerequisite for fast ligand diffusion to/from the heme. PMID- 22942689 TI - A promising tool to achieve chemical accuracy for density functional theory calculations on Y-NO homolysis bond dissociation energies. AB - A DFT-SOFM-RBFNN method is proposed to improve the accuracy of DFT calculations on Y-NO (Y = C, N, O, S) homolysis bond dissociation energies (BDE) by combining density functional theory (DFT) and artificial intelligence/machine learning methods, which consist of self-organizing feature mapping neural networks (SOFMNN) and radial basis function neural networks (RBFNN). A descriptor refinement step including SOFMNN clustering analysis and correlation analysis is implemented. The SOFMNN clustering analysis is applied to classify descriptors, and the representative descriptors in the groups are selected as neural network inputs according to their closeness to the experimental values through correlation analysis. Redundant descriptors and intuitively biased choices of descriptors can be avoided by this newly introduced step. Using RBFNN calculation with the selected descriptors, chemical accuracy (<=1 kcal.mol(-1)) is achieved for all 92 calculated organic Y-NO homolysis BDE calculated by DFT-B3LYP, and the mean absolute deviations (MADs) of the B3LYP/6-31G(d) and B3LYP/STO-3G methods are reduced from 4.45 and 10.53 kcal.mol(-1) to 0.15 and 0.18 kcal.mol(-1), respectively. The improved results for the minimal basis set STO-3G reach the same accuracy as those of 6-31G(d), and thus B3LYP calculation with the minimal basis set is recommended to be used for minimizing the computational cost and to expand the applications to large molecular systems. Further extrapolation tests are performed with six molecules (two containing Si-NO bonds and two containing fluorine), and the accuracy of the tests was within 1 kcal.mol(-1). This study shows that DFT-SOFM-RBFNN is an efficient and highly accurate method for Y-NO homolysis BDE. The method may be used as a tool to design new NO carrier molecules. PMID- 22942688 TI - From evolution to pathogenesis: the link between beta-barrel assembly machineries in the outer membrane of mitochondria and gram-negative bacteria. AB - beta-barrel proteins are the highly abundant in the outer membranes of Gram negative bacteria and the mitochondria in eukaryotes. The assembly of beta barrels is mediated by two evolutionary conserved machineries; the beta-barrel Assembly Machinery (BAM) in Gram-negative bacteria; and the Sorting and Assembly Machinery (SAM) in mitochondria. Although the BAM and SAM have functionally conserved roles in the membrane integration and folding of beta-barrel proteins, apart from the central BamA and Sam50 proteins, the remaining components of each of the complexes have diverged remarkably. For example all of the accessory components of the BAM complex characterized to date are located in the bacterial periplasm, on the same side as the N-terminal domain of BamA. This is the same side of the membrane as the substrates that are delivered to the BAM. On the other hand, all of the accessory components of the SAM complex are located on the cytosolic side of the membrane, the opposite side of the membrane to the N terminus of Sam50 and the substrate receiving side of the membrane. Despite the accessory subunits being located on opposite sides of the membrane in each system, it is clear that each system is functionally equivalent with bacterial proteins having the ability to use the eukaryotic SAM and vice versa. In this review, we summarize the similarities and differences between the BAM and SAM complexes, highlighting the possible selecting pressures on bacteria and eukaryotes during evolution. It is also now emerging that bacterial pathogens utilize the SAM to target toxins and effector proteins to host mitochondria and this will also be discussed from an evolutionary perspective. PMID- 22942690 TI - Cancer cell cytotoxicities of 1-(4-substitutedbenzoyl)-4-(4 chlorobenzhydryl)piperazine derivatives. AB - A series of novel 1-(4-substitutedbenzoyl)-4-(4-chlorobenzhydryl)piperazine derivatives 5a-g was designed by a nucleophilic substitution reaction of 1-(4 chlorobenzhydryl)piperazine with various benzoyl chlorides and characterized by elemental analyses, IR and (1)H nuclear magnetic resonance spectra. Cytotoxicity of the compounds was demonstrated on cancer cell lines from liver (HUH7, FOCUS, MAHLAVU, HEPG2, HEP3B), breast (MCF7, BT20, T47D, CAMA-1), colon (HCT-116), gastric (KATO-3) and endometrial (MFE-296) cancer cell lines. Time-dependent cytotoxicity analysis of compound 5a indicated the long-term in situ stability of this compound. All compounds showed significant cell growth inhibitory activity on the selected cancer cell lines. PMID- 22942691 TI - Green formation of spherical and dendritic silver nanostructures under microwave irradiation without reducing agent. AB - The rapid and green formation of spherical and dendritic silver nanostructures based on microwave irradiation time was investigated. Silver nanoparticles were successfully fabricated by reduction of Ag(+) in a water medium and using polyvinylpyrrolidone (PVP) as the stabilizing agent and without the use of any other reducing agent, and were compared with those synthesized by conventional heating method. UV-vis absorption spectrometry, transmission electron microscopy (TEM), atomic absorption spectroscopy (AAS) and photon correlation spectroscopy (PCS) measurements, indicated that increasing the irradiation time enhanced the concentration of silver nanoparticles and slightly increased the particle size. There was a lack of large silver nanoparticles at a high concentration, but interestingly, the formation and growth of silver dendrite nanostructures appeared. Compared to conventional heating methods, the silver nanoparticle suspension produced by irradiated microwaves was more stable over a six-month period in aqueous solution without any signs of precipitation. PMID- 22942692 TI - Production of defatted palm kernel cake protein hydrolysate as a valuable source of natural antioxidants. AB - The aim of this study was to produce a valuable protein hydrolysate from palm kernel cake (PKC) for the development of natural antioxidants. Extracted PKC protein was hydrolyzed using different proteases (alcalase, chymotrypsin, papain, pepsin, trypsin, flavourzyme, and bromelain). Subsequently, antioxidant activity and degree of hydrolysis (DH) of each hydrolysate were evaluated using DPPH* radical scavenging activity and O-phthaldialdehyde spectrophotometric assay, respectively. The results revealed a strong correlation between DH and radical scavenging activity of the hydrolysates, where among these, protein hydrolysates produced by papain after 38 h hydrolysis exhibited the highest DH (91 +/- 0.1%) and DPPH* radical scavenging activity (73.5 +/- 0.25%) compared to the other hydrolysates. In addition, fractionation of the most effective (potent) hydrolysate by reverse phase high performance liquid chromatography indicated a direct association between hydrophobicity and radical scavenging activity of the hydrolysates. Isoelectric focusing tests also revealed that protein hydrolysates with basic and neutral isoelectric point (pI) have the highest radical scavenging activity, although few fractions in the acidic range also exhibited good antioxidant potential. PMID- 22942693 TI - Synthesis and spectral evaluation of some unsymmetrical mesoporphyrinic complexes. AB - Synthesis and spectral evaluation of new zinc and copper unsymmetrical mesoporphyrinic complexes are reported. Zn(II)-5-(4-acetoxy-3-methoxyphenyl) 10,15,20- tris-(4-carboxymethylphenyl)porphyrin, Zn(II)-5-[(3,4 methylenedioxy)phenyl]-10,15,20- tris-(4-carboxymethylphenyl)porphyrin, Cu(II)-5 (4-acetoxy-3-methoxyphenyl)-10,15,20- tris-(4-carboxymethylphenyl)porphyrin and Cu(II)-5-[(3,4-methylenedioxy)phenyl]-10,15,20- tris-(4 carboxymethylphenyl)porphyrin were synthesized using microwave-assisted synthesis. The complexes were characterized by elemental analysis, FT-IR, UV-Vis, EPR and NMR spectroscopy, which fully confirmed their structure. The spectral absorption properties of the porphyrinic complexes were studied in solvents with different polarities. Fluorescence emission and singlet oxygen formation quantum yields were evaluated for the compounds under study, revealing high yields for the zinc derivatives. The copper complexes are not emissive and only display residual capacity for singlet oxygen formation. PMID- 22942694 TI - Elongation factor 1beta' gene from Spodoptera exigua: characterization and function identification through RNA interference. AB - Elongation factor (EF) is a key regulation factor for translation in many organisms, including plants, bacteria, fungi, animals and insects. To investigate the nature and function of elongation factor 1beta' from Spodoptera exigua (SeEF 1beta'), its cDNA was cloned. This contained an open reading frame of 672 nucleotides encoding a protein of 223 amino acids with a predicted molecular weight of 24.04 kDa and pI of 4.53. Northern blotting revealed that SeEF-1beta' mRNA is expressed in brain, epidermis, fat body, midgut, Malpighian tubules, ovary and tracheae. RT-PCR revealed that SeEF-1beta' mRNA is expressed at different levels in fat body and whole body during different developmental stages. In RNAi experiments, the survival rate of insects injected with SeEF 1beta' dsRNA was 58.7% at 36 h after injection, which was significantly lower than three control groups. Other elongation factors and transcription factors were also influenced when EF-1beta' was suppressed. The results demonstrate that SeEF-1beta' is a key gene in transcription in S. exigua. PMID- 22942696 TI - Genetic variation and population differentiation in a medical herb Houttuynia cordata in China revealed by inter-simple sequence repeats (ISSRs). AB - Houttuynia cordata is an important traditional Chinese herb with unresolved genetics and taxonomy, which lead to potential problems in the conservation and utilization of the resource. Inter-simple sequence repeat (ISSR) markers were used to assess the level and distribution of genetic diversity in 226 individuals from 15 populations of H. cordata in China. ISSR analysis revealed low genetic variations within populations but high genetic differentiations among populations. This genetic structure probably mainly reflects the historical association among populations. Genetic cluster analysis showed that the basal clade is composed of populations from Southwest China, and the other populations have continuous and eastward distributions. The structure of genetic diversity in H. cordata demonstrated that this species might have survived in Southwest China during the glacial age, and subsequently experienced an eastern postglacial expansion. Based on the results of genetic analysis, it was proposed that as many as possible targeted populations for conservation be included. PMID- 22942695 TI - Effects of purified Saccharomyces cerevisiae (1->3)-beta-glucan on venous ulcer healing. AB - Water-insoluble glucan was isolated from the baker's yeast Saccharomyces cerevisiae. The yeast cells were treated with alkali and the residue then with acid. Chemical and NMR (1D and 2D) analyses showed that a linear (1->3)-beta glucan was purified that was not contaminated with other carbohydrates, proteins or phenolic compounds. The effects of the glucan on wound healing were assessed in human venous ulcers by histopathological analysis after 30 days of topical treatment. (1->3)-beta-glucan enhanced ulcer healing and increased epithelial hyperplasia, as well as increased inflammatory cells, angiogenesis and fibroblast proliferation. In one patient who had an ulcer that would not heal for over 15 years, glucan treatment caused a 67.8% decrease in the area of the ulcer. This is the first study to investigate the effects of (1->3)-beta-glucan on venous ulcer healing in humans; our findings suggest that this glucan is a potential natural biological response modifier in wound healing. PMID- 22942698 TI - Investigation of spectroscopic properties and spin-orbit splitting in the XPi2 and APi2 electronic states of the SO +cation. AB - The potential energy curves (PECs) of the X(2)Pi and A(2)Pi electronic states of the SO(+) ion are calculated using the complete active space self-consistent field method, which is followed by the internally contracted multireference configuration interaction (MRCI) approach for internuclear separations from 0.08 to 1.06 nm. The spin-orbit coupling effect on the spectroscopic parameters is included using the Breit-Pauli operator. To improve the quality of PECs and spin orbit coupling constant (A(0)), core-valence correlation and scalar relativistic corrections are included. To obtain more reliable results, the PECs obtained by the MRCI calculations are corrected for size-extensivity errors by means of the Davidson modification (MRCI+Q). At the MRCI+Q/aug-cc-pV5Z+CV+DK level, the A(0) values of the SO(+)(X(2)Pi(1/2, 3/2)) and SO(+)(A(2)Pi(1/2, 3/2)) are 362.13 and 58.16 cm(-1) when the aug-cc-pCVTZ basis set is used to calculate the spin-orbit coupling splitting, and the A(0) of the SO(+)(X(2)Pi(1/2, 3/2)) and SO(+)(A(2)Pi(1/2, 3/2)) are 344.36 and 52.90 cm(-1) when the aug-cc-pVTZ basis set is used to calculate the spin-orbit coupling splitting. The conclusion is drawn that the core-valence correlations correction makes the A(0) slightly larger. The spectroscopic results are obtained and compared with those reported in the literature. Excellent agreement exists between the present results and the measurements. The vibrational manifolds are calculated, and those of the first 30 vibrational states are reported for the J = 0 case. Comparison with the measurements shows that the present vibrational manifolds are both reliable and accurate. PMID- 22942697 TI - Proteomic analysis of the organ of corti using nanoscale liquid chromatography coupled with tandem mass spectrometry. AB - The organ of Corti (OC) in the cochlea plays an essential role in auditory signal transduction in the inner ear. For its minute size and trace amount of proteins, the identification of the molecules in pathophysiologic processes in the bone encapsulated OC requires both delicate separation and a highly sensitive analytical tool. Previously, we reported the development of a high resolution metal-free nanoscale liquid chromatography system for highly sensitive phosphoproteomic analysis. Here this system was coupled with a LTQ-Orbitrap XL mass spectrometer to investigate the OC proteome from normal hearing FVB/N male mice. A total of 628 proteins were identified from six replicates of single LC MS/MS analysis, with a false discovery rate of 1% using the decoy database approach by the OMSSA search engine. This is currently the largest proteome dataset for the OC. A total of 11 proteins, including cochlin, myosin VI, and myosin IX, were identified that when defective are associated with hearing impairment or loss. This study demonstrated the effectiveness of our nanoLC-MS/MS platform for sensitive identification of hearing loss-associated proteins from minute amount of tissue samples. PMID- 22942699 TI - Isojacareubin from the Chinese herb Hypericum japonicum: potent antibacterial and synergistic effects on clinical methicillin-resistant Staphylococcus aureus (MRSA). AB - Through bioassay-guided fractionation of the extracts from the aerial parts of the Chinese herb Hypericum japonicum Thunb. Murray, Isojacareubin (ISJ) was characterized as a potent antibacterial compound against the clinical methicillin resistant Staphylococcus aureus (MRSA). The broth microdilution assay was used to determine the minimal inhibitory concentrations (MICs) and minimal bactericidal concentrations (MBCs) of ISJ alone. The results showed that its MICs/MBCs ranged from 4/16 to 16/64 MUg/mL, with the concentrations required to inhibit or kill 50% of the strains (MIC(50)/MBC(50)) at 8/16 MUg/mL. Synergistic evaluations of this compound with four conventional antibacterial agents representing different types were performed by the chequerboard and time-kill tests. The chequerboard method showed significant synergy effects when ISJ was combined with Ceftazidime (CAZ), Levofloxacin (LEV) and Ampicillin (AMP), with the values of 50% of the fractional inhibitory concentration indices (FICI(50)) at 0.25, 0.37 and 0.37, respectively. Combined bactericidal activities were also observed in the time kill dynamic assay. The results showed the ability of ISJ to reduce MRSA viable counts by log(10)CFU/mL at 24 h of incubation at a concentration of 1 * MIC were 1.5 (LEV, additivity), 0.92 (CAZ, indifference) and 0.82 (AMP, indifference), respectively. These in vitro anti-MRSA activities of ISJ alone and its synergy with conventional antibacterial agents demonstrated that ISJ enhanced their efficacy, which is of potential use for single and combinatory therapy of patients infected with MRSA. PMID- 22942701 TI - Genome-wide analysis of DNA methylation and expression of microRNAs in breast cancer cells. AB - DNA methylation of promoters is linked to transcriptional silencing of protein coding genes, and its alteration plays important roles in cancer formation. For example, hypermethylation of tumor suppressor genes has been seen in some cancers. Alteration of methylation in the promoters of microRNAs (miRNAs) has also been linked to transcriptional changes in cancers; however, no systematic studies of methylation and transcription of miRNAs have been reported. In the present study, to clarify the relation between DNA methylation and transcription of miRNAs, next-generation sequencing and microarrays were used to analyze the methylation and expression of miRNAs, protein-coding genes, other non-coding RNAs (ncRNAs), and pseudogenes in the human breast cancer cell lines MCF7 and the adriamycin (ADR) resistant cell line MCF7/ADR. DNA methylation in the proximal promoter of miRNAs is tightly linked to transcriptional silencing, as it is with protein-coding genes. In protein-coding genes, highly expressed genes have CpG rich proximal promoters whereas weakly expressed genes do not. This is only rarely observed in other gene categories, including miRNAs. The present study highlights the epigenetic similarities and differences between miRNA and protein coding genes. PMID- 22942702 TI - Phage display-based strategies for cloning and optimization of monoclonal antibodies directed against human pathogens. AB - In the last two decades, several phage display-selected monoclonal antibodies (mAbs) have been described in the literature and a few of them have managed to reach the clinics. Among these, the anti-respiratory syncytial virus (RSV) Palivizumab, a phage-display optimized mAb, is the only marketed mAb directed against microbial pathogens. Palivizumab is a clear example of the importance of choosing the most appropriate strategy when selecting or optimizing an anti infectious mAb. From this perspective, the extreme versatility of phage-display technology makes it a useful tool when setting up different strategies for the selection of mAbs directed against human pathogens, especially when their possible clinical use is considered. In this paper, we review the principal phage display strategies used to select anti-infectious mAbs, with particular attention focused on those used against hypervariable pathogens, such as HCV and influenza viruses. PMID- 22942700 TI - The neuroprotective functions of transforming growth factor beta proteins. AB - Transforming growth factor beta (TGF-beta) proteins are multifunctional cytokines whose neural functions are increasingly recognized. The machinery of TGF-beta signaling, including the serine kinase type transmembrane receptors, is present in the central nervous system. However, the 3 mammalian TGF-beta subtypes have distinct distributions in the brain suggesting different neural functions. Evidence of their involvement in the development and plasticity of the nervous system as well as their functions in peripheral organs suggested that they also exhibit neuroprotective functions. Indeed, TGF-beta expression is induced following a variety of types of brain tissue injury. The neuroprotective function of TGF-betas is most established following brain ischemia. Damage in experimental animal models of global and focal ischemia was shown to be attenuated by TGF betas. In addition, support for their neuroprotective actions following trauma, sclerosis multiplex, neurodegenerative diseases, infections, and brain tumors is also accumulating. The review will also describe the potential mechanisms of neuroprotection exerted by TGF-betas including anti-inflammatory, -apoptotic, excitotoxic actions as well as the promotion of scar formation, angiogenesis, and neuroregeneration. The participation of these mechanisms in the neuroprotective effects of TGF-betas during different brain lesions will also be discussed. PMID- 22942703 TI - Fasudil, a Rho-kinase inhibitor, attenuates bleomycin-induced pulmonary fibrosis in mice. AB - The mechanisms underlying the pathogenesis of idiopathic pulmonary fibrosis (IPF) involve multiple pathways, such as inflammation, epithelial mesenchymal transition, coagulation, oxidative stress, and developmental processes. The small GTPase, RhoA, and its target protein, Rho-kinase (ROCK), may interact with other signaling pathways known to contribute to pulmonary fibrosis. This study aimed to determine the beneficial effects and mechanisms of fasudil, a selective ROCK inhibitor, on bleomycin-induced pulmonary fibrosis in mice. Our results showed that the Aschcroft score and hydroxyproline content of the bleomycin-treated mouse lung decreased in response to fasudil treatment. The number of infiltrated inflammatory cells in the bronchoalveolar lavage fluid (BALF) was attenuated by fasudil. In addition, fasudil reduced the production of transforming growth factor-beta1 (TGF-beta1), connective tissue growth factor (CTGF), alpha-smooth muscle actin (alpha-SMA), and plasminogen activator inhibitor-1 (PAI-1) mRNA and protein expression in bleomycin-induced pulmonary fibrosis. These findings suggest that fasudil may be a potential therapeutic candidate for the treatment of pulmonary fibrosis. PMID- 22942704 TI - Potential of fruit wastes as natural resources of bioactive compounds. AB - Fruit wastes are one of the main sources of municipal waste. In order to explore the potential of fruit wastes as natural resources of bioactive compounds, the antioxidant potency and total phenolic contents (TPC) of lipophilic and hydrophilic components in wastes (peel and seed) of 50 fruits were systematically evaluated. The results showed that different fruit residues had diverse antioxidant potency and the variation was very large. Furthermore, the main bioactive compounds were identified and quantified, and catechin, cyanidin 3 glucoside, epicatechin, galangin, gallic acid, homogentisic acid, kaempferol, and chlorogenic acid were widely found in these residues. Especially, the values of ferric-reducing antioxidant power (FRAP), trolox equivalent antioxidant capacity (TEAC) and TPC in the residues were higher than in pulps. The results showed that fruit residues could be inexpensive and readily available resources of bioactive compounds for use in the food and pharmaceutical industries. PMID- 22942705 TI - Occurrence of aflatoxins in selected processed foods from Pakistan. AB - A total of 125 (ready to eat) processed food samples (70 intended for infant and 55 for adult intake) belonging to 20 different food categories were analyzed for aflatoxins contamination using Reverse Phase High Performance Liquid Chromatography (RP-HPLC) with fluorescent detection. A solvent mixture of acetonitrile-water was used for the extraction followed by immunoaffinity clean up to enhance sensitivity of the method. The limit of detection (LOD) (0.01-0.02 ng.g(-1)) and limit of quantification (LOQ) (0.02 ng.g(-1)) was established for aflatoxins based on signal to noise ratio of 3:1 and 10:1, respectively. Of the processed food samples tested, 38% were contaminated with four types of aflatoxins, i.e., AFB1 (0.02-1.24 MUg.kg(-1)), AFB2 (0.02-0.37 MUg.kg(-1)), AFG1 (0.25-2.7 MUg.kg(-1)) and AFG2 (0.21-1.3 MUg.kg(-1)). In addition, the results showed that 21% of the processed foods intended for infants contained AFB1 levels higher than the European Union permissible limits (0.1 MUg.kg(-1)), while all of those intended for adult consumption had aflatoxin contamination levels within the permitted limits. PMID- 22942706 TI - Role of endoplasmic reticulum aminopeptidases in health and disease: from infection to cancer. AB - Endoplasmic reticulum (ER) aminopeptidases ERAP1 and ERAP2 (ERAPs) are essential for the maturation of a wide spectrum of proteins involved in various biological processes. In the ER, these enzymes work in concert to trim peptides for presentation on MHC class I molecules. Loss of ERAPs function substantially alters the repertoire of peptides presented by MHC class I molecules, critically affecting recognition of both NK and CD8(+) T cells. In addition, these enzymes are involved in the modulation of inflammatory responses by promoting the shedding of several cytokine receptors, and in the regulation of both blood pressure and angiogenesis. Recent genome-wide association studies have identified common variants of ERAP1 and ERAP2 linked to several human diseases, ranging from viral infections to autoimmunity and cancer. More recently, inhibition of ER peptide trimming has been shown to play a key role in stimulating innate and adaptive anti-tumor immune responses, suggesting that inhibition of ERAPs might be exploited for the establishment of innovative therapeutic approaches against cancer. This review summarizes data currently available for ERAP enzymes in ER peptide trimming and in other immunological and non-immunological functions, paying attention to the emerging role played by these enzymes in human diseases. PMID- 22942707 TI - Clinical relevance of CDH1 and CDH13 DNA-methylation in serum of cervical cancer patients. AB - This study was designed to investigate the DNA-methylation status of E-cadherin (CDH1) and H-cadherin (CDH13) in serum samples of cervical cancer patients and control patients with no malignant diseases and to evaluate the clinical utility of these markers. DNA-methylation status of CDH1 and CDH13 was analyzed by means of MethyLight-technology in serum samples from 49 cervical cancer patients and 40 patients with diseases other than cancer. To compare this methylation analysis with another technique, we analyzed the samples with a denaturing high performance liquid chromatography (DHPLC) PCR-method. The specificity and sensitivity of CDH1 DNA-methylation measured by MethyLight was 75% and 55%, and for CDH13 DNA-methylation 95% and 10%. We identified a specificity of 92.5% and a sensitivity of only 27% for the CDH1 DHPLC-PCR analysis. Multivariate analysis showed that serum CDH1 methylation-positive patients had a 7.8-fold risk for death (95% CI: 2.2-27.7; p = 0.001) and a 92.8-fold risk for relapse (95% CI: 3.9 2207.1; p = 0.005). We concluded that the serological detection of CDH1 and CDH13 DNA-hypermethylation is not an ideal diagnostic tool due to low diagnostic specificity and sensitivity. However, it was validated that CDH1 methylation analysis in serum samples may be of potential use as a prognostic marker for cervical cancer patients. PMID- 22942708 TI - Risk-association of DNA methyltransferases polymorphisms with gastric cancer in the Southern Chinese population. AB - DNA hypomethylation and/or hypermethylation are presumed to be early events in carcinogenesis, and one or more DNA methyltransferases (DNMTs) have been suggested to play roles in carcinogenesis of gastric cancer (GC). However, there have been no systematic studies regarding the association between DNMT gene polymorphisms and GC risk. Here, we examined the associations of 16 single nucleotide polymorphisms (SNPs) from DNMT1 (rs2114724, rs2228611, rs2228612, rs8101866, rs16999593), DNMT2 (rs11695471, rs11254413), DNMT3A (rs1550117, rs11887120, rs13420827, rs13428812, rs6733301), DNMT3B (rs2424908, rs2424913, rs6087990) and DNMT3L (rs113593938) with GC in the Southern Chinese population. We assessed the associations of these 16 SNPs with GC in a case-control study that consisted of 242 GC cases and 294 controls, using the Sequenom MALDI-TOF-MS platform. Association analyses based on the chi(2) test and binary logistic regression were performed to determine the odds ratio (OR) and 95% confidence interval (95%CI) for each SNP. We found that rs16999593 in DNMT1, rs11254413 in DNMT2 and rs13420827 in DNMT3A were significantly associated with GC susceptibility (OR 1.45, 0.15, 0.66, respectively; 95% CI 1.00-2.11, p = 0.047; 0.08-0.27, p < 0.01; 0.45-0.97, p = 0.034, respectively, overdominant model). These results suggested that DNMT1, DNMT2 and DNMT3A may play important roles in GC carcinogenesis. However, further studies are required to elucidate the mechanism. PMID- 22942709 TI - Astragalus membranaceus inhibits inflammation via phospho-P38 mitogen-activated protein kinase (MAPK) and nuclear factor (NF)-kappaB pathways in advanced glycation end product-stimulated macrophages. AB - Advanced glycation end products (AGEs) and inflammation contribute to the development of diabetic complications. Astragalus membranaceus has properties of immunological regulation in many diseases. The aim of this study was to determine the function of A. membranaceus extract (AME) on the AGE-induced inflammatory response in Ana-1 macrophages. The viability of cells treated with AME or AGEs was evaluated with the MTT [3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H tetrazolium bromide] method. The secretion and mRNA levels of IL-1beta and TNF alpha were measured by ELISA and RT-PCR, respectively. The activity of NF-kappaB was assayed by EMSA. The phosphorylation of p38 MAPK was assessed by western blotting. The results showed that AME was not toxic to macrophages. The treatment of macrophages with AME effectively inhibited AGE-induced IL-1beta and TNF-alpha secretion and mRNA expression in macrophages. These effects may be mediated by p38 MAPK and the NF-kappaB pathway. The results suggest that AME can inhibit AGE induced inflammatory cytokine production to down-regulate macrophage-mediated inflammation via p38 MAPK and NF-kappaB signaling pathways and indicate that AME could be an immunoregulatory agent against AGE-induced inflammation in diabetes. PMID- 22942710 TI - CO2adsorption on activated carbon honeycomb-monoliths: a comparison of Langmuir and Toth Models. AB - Activated carbon honeycomb-monoliths with different textural properties were prepared by chemical activation of African palm shells with H(3)PO(4), ZnCl(2) and CaCl(2) aqueous solutions of various concentrations. The adsorbents obtained were characterized by N(2) adsorption at 77 K, and their carbon dioxide adsorption capacities were measured at 273 K and 1 Bar in volumetric adsorption equipment. The experimental adsorption isotherms were fitted to Langmuir and Toth models, and a better fit was observed to Toth equation with a correlation coefficient of 0.999. The maximum experimental values for adsorption capacity at the highest pressure (2.627-5.756 mmol.g(-1)) are between the calculated data in the two models. PMID- 22942711 TI - Function and 3D structure of the N-glycans on glycoproteins. AB - Glycosylation is one of the most common post-translational modifications in eukaryotic cells and plays important roles in many biological processes, such as the immune response and protein quality control systems. It has been notoriously difficult to study glycoproteins by X-ray crystallography since the glycan moieties usually have a heterogeneous chemical structure and conformation, and are often mobile. Nonetheless, recent technical advances in glycoprotein crystallography have accelerated the accumulation of 3D structural information. Statistical analysis of "snapshots" of glycoproteins can provide clues to understanding their structural and dynamic aspects. In this review, we provide an overview of crystallographic analyses of glycoproteins, in which electron density of the glycan moiety is clearly observed. These well-defined N-glycan structures are in most cases attributed to carbohydrate-protein and/or carbohydrate carbohydrate interactions and may function as "molecular glue" to help stabilize inter- and intra-molecular interactions. However, the more mobile N-glycans on cell surface receptors, the electron density of which is usually missing on X-ray crystallography, seem to guide the partner ligand to its binding site and prevent irregular protein aggregation by covering oligomerization sites away from the ligand-binding site. PMID- 22942712 TI - Effect of PACAP in central and peripheral nerve injuries. AB - Pituitary adenylate cyclase activating polypeptide (PACAP) is a bioactive peptide with diverse effects in the nervous system. In addition to its more classic role as a neuromodulator, PACAP functions as a neurotrophic factor. Several neurotrophic factors have been shown to play an important role in the endogenous response following both cerebral ischemia and traumatic brain injury and to be effective when given exogenously. A number of studies have shown the neuroprotective effect of PACAP in different models of ischemia, neurodegenerative diseases and retinal degeneration. The aim of this review is to summarize the findings on the neuroprotective potential of PACAP in models of different traumatic nerve injuries. Expression of endogenous PACAP and its specific PAC1 receptor is elevated in different parts of the central and peripheral nervous system after traumatic injuries. Some experiments demonstrate the protective effect of exogenous PACAP treatment in different traumatic brain injury models, in facial nerve and optic nerve trauma. The upregulation of endogenous PACAP and its receptors and the protective effect of exogenous PACAP after different central and peripheral nerve injuries show the important function of PACAP in neuronal regeneration indicating that PACAP may also be a promising therapeutic agent in injuries of the nervous system. PMID- 22942713 TI - Flexible and versatile as a chameleon-sophisticated functions of microRNA-199a. AB - Although widely studied in the past decade, our knowledge of the functional role of microRNAs (miRNAs) remains limited. Among the many miRNAs identified in humans, we focus on miR-199a due to its varied and important functions in diverse models and systems. Its expression is finely regulated by promoter methylation and direct binding of transcription factors such as TWIST1. During tumorigenesis, depending on the nature of the cancer, miR-199a, especially its -3p mature form, may act as either a potential tumor suppressor or an oncogene. Its 5p mature form has been shown to protect cardiomyocytes from hypoxic damage via its action on HIF1alpha. It also has a functional role in stem cell differentiation, embryo development, hepatitis, liver fibrosis, etc. Though it has varied biological activities, its regulation has not been reviewed. The varied and protean functions of miR-199a suggest that efforts to generalize the action of a miRNA are problematic. This review provides a comprehensive survey of the literature on miR-199a as an example of the complexity of miRNA biology and suggests future directions for miRNA research. PMID- 22942714 TI - Phylogenetic relationships of the mangalitsa Swine breed inferred from mitochondrial DNA variation. AB - The Mangalitsa pig, a swine breed belonging to the protected gene fund of original and primitive animal breeds of the FAO (Food and Agriculture Organization), has been known to inhabit Romanian territories since the 19th century. The aim of this study was to compare the Mangalitsa breed with several European and Asiatic swine breeds in order to emphasize its uniqueness and to elucidate its origin. For this purpose, we analyzed a 613 bp mitochondrial DNA D loop fragment and 1140 bp of the cytochrome b gene in a population of Mangalitsa pigs and the polymorphic sites were compared with sequences from GenBank originating from other swine breeds. Taking into account the total of 24 breeds and 5 different Wild Boar populations analyzed, 86 polymorphic sites representing 32 haplotypes were observed, with an average percentage of polymorphic sites of 4.9%. Three Neighbor-Joining phylogenetic trees were constructed based on Kimura 2-parameter distances, using D-loop, cytochrome b and mitochondrial reunited sequences. For the analyzed Mangalitsa population, four distinct haplotypes were identified, including one that was common to other breeds. Our study suggests that the Mangalitsa swine originate from primitive breeds which might be directly derived from the Wild Boar. PMID- 22942715 TI - Chemopreventive efficacy of Atorvastatin against nitrosamine-induced rat bladder cancer: antioxidant, anti-proliferative and anti-inflammatory properties. AB - To investigate the anti-carcinogenic effects of Atorvastatin (Atorva) on a rat bladder carcinogenesis model with N-butyl-N-(4-hydroxibutil)nitrosamine (BBN), four male Wistar rat groups were studied: (1) CONTROL: vehicle; (2) Atorva: 3 mg/kg bw/day; (3) Carcinogen: BBN (0.05%); (4) Preventive Atorva: 3 mg/kg bw/day Atorva + BBN. A two phase protocol was used, in which the drug and the carcinogen were given between week 1 and 8 and tumor development or chemoprevention were expressed between week 9 and 20, when the bladders were collected for macroscopic, histological and immunohistochemical (p53, ki67, CD31) evaluation. Serum was assessed for markers of inflammation, proliferation and redox status. The incidence of bladder carcinoma was: control 0/8 (0%); Atorva 0/8 (0%); BBN 13/20 (65%) and Atorva + BBN 1/8 (12.5%). The number and volume of tumors were significantly lower in the Atorva + BBN group, with a marked reduction in hyperplasia, dysplasia and carcinoma in situ lesions. An anti-proliferative, anti inflammatory and antioxidant profile was also observed in the preventive Atorva group. p53 and ki67 immunostaining were significantly increased in the BBN treated rats, which was prevented in the Atorva + BBN group. No differences were found for CD31 expression. In conclusion, Atorvastatin had a clear inhibitory effect on bladder cancer development, probably due to its antioxidant, anti proliferative and anti-inflammatory properties. PMID- 22942716 TI - Structural analysis of cytochrome P450 105N1 involved in the biosynthesis of the zincophore, coelibactin. AB - Coelibactin is a putative non-ribosomally synthesized peptide with predicted zincophore activity and which has been implicated in antibiotic regulation in Streptomyces coelicolor A3(2). The coelibactin biosynthetic pathway contains a stereo- and regio-specific monooxygenation step catalyzed by a cytochrome P450 enzyme (CYP105N1). We have determined the X-ray crystal structure of CYP105N1 at 2.9 A and analyzed it in the context of the bacterial CYP105 family as a whole. The crystal structure reveals a channel between the alpha-helical domain and the beta-sheet domain exposing the heme pocket and the long helix I to the solvent. This wide-open conformation of CYP105N1 may be related to the bulky substrate coelibactin. The ligand-free CYP105N1 structure has enough room in the substrate access channel to allow the coelibactin to enter into the active site. Analysis of typical siderophore ligands suggests that CYP105N1 may produce derivatives of coelibactin, which would then be able to chelate the zinc divalent cation. PMID- 22942717 TI - miR-338-3p is down-regulated by hepatitis B virus X and inhibits cell proliferation by targeting the 3'-UTR region of CyclinD1. AB - Hepatitis B virus X protein (HBx) is recognized as an oncogene in hepatocellular carcinoma (HCC). HBx regulates microRNA expression, including down-regulating miR 338-3p in LO2 cells. Here, we investigated miR-338-3p function in HBx-mediated hepatocarcinogenesis. In 23 HBV-infected HCC clinical patient tumor and adjacent non-tumor control tissues, 17 and 19 tumors expressed HBx mRNA and protein, respectively. When considered as a group, HBV-infected HCC tumors had lower miR 338-3p expression than controls; however, miR-338-3p was only significantly down regulated in HBx-positive tumors, indicating that HBx inversely correlated with miR-338-3p. Functional characterization of miR-338-3p indicated that miR-338-3p mimics inhibited cell proliferation by inducing cell cycle arrest at the G1/S phase as assessed by EdU and cell cycle assays in HBx-expressing LO2 cells. CyclinD1, containing two putative miR-338-3p targets, was confirmed as a direct target using 3'-UTR luciferase reporter assays from cells transfected with mutated binding sites. Mutating the 2397-2403 nt binding site conferred the greatest resistance to miR-338-3p suppression of CyclinD1, indicating that miR 338-3p suppresses CyclinD1 at this site. Overall, this study demonstrates that miR-338-3p inhibits proliferation by regulating CyclinD1, and HBx down-regulates miR-338-3p in HCC. This newly identified miR-338-3p/CyclinD1 interaction provides novel insights into HBx-mediated hepatocarcinogenesis and may facilitate therapeutic development against HCC. PMID- 22942718 TI - Reflection and transmission coefficient of yttrium iron garnet filled polyvinylidene fluoride composite using rectangular waveguide at microwave frequencies. AB - The sol-gel method was carried out to synthesize nanosized Yttrium Iron Garnet (YIG). The nanomaterials with ferrite structure were heat-treated at different temperatures from 500 to 1000 degrees C. The phase identification, morphology and functional groups of the prepared samples were characterized by powder X-ray diffraction (PXRD), scanning electron microscopy (SEM) and Fourier transform infrared spectroscopy (FT-IR), respectively. The YIG ferrite nanopowder was composited with polyvinylidene fluoride (PVDF) by a solution casting method. The magnitudes of reflection and transmission coefficients of PVDF/YIG containing 6, 10 and 13% YIG, respectively, were measured using rectangular waveguide in conjunction with a microwave vector network analyzer (VNA) in X-band frequencies. The results indicate that the presence of YIG in polymer composites causes an increase in reflection coefficient and decrease in transmission coefficient of the polymer. PMID- 22942719 TI - Involvement of disperse repetitive sequences in wheat/rye genome adjustment. AB - The union of different genomes in the same nucleus frequently results in hybrid genotypes with improved genome plasticity related to both genome remodeling events and changes in gene expression. Most modern cereal crops are polyploid species. Triticale, synthesized by the cross between wheat and rye, constitutes an excellent model to study polyploidization functional implications. We intend to attain a deeper knowledge of dispersed repetitive sequence involvement in parental genome reshuffle in triticale and in wheat-rye addition lines that have the entire wheat genome plus each rye chromosome pair. Through Random Amplified Polymorphic DNA (RAPD) analysis with OPH20 10-mer primer we unraveled clear alterations corresponding to the loss of specific bands from both parental genomes. Moreover, the sequential nature of those events was revealed by the increased absence of rye-origin bands in wheat-rye addition lines in comparison with triticale. Remodeled band sequencing revealed that both repetitive and coding genome domains are affected in wheat-rye hybrid genotypes. Additionally, the amplification and sequencing of pSc20H internal segments showed that the disappearance of parental bands may result from restricted sequence alterations and unraveled the involvement of wheat/rye related repetitive sequences in genome adjustment needed for hybrid plant stabilization. PMID- 22942720 TI - Fraction from wax apple [Syzygium samarangense (Blume) Merrill and Perry] fruit extract ameliorates insulin resistance via modulating insulin signaling and inflammation pathway in tumor necrosis factor alpha-treated FL83B mouse hepatocytes. AB - Inflammation is associated with the development of insulin resistance in Type 2 diabetes mellitus. In the present study, mouse FL83B cells were treated with tumor necrosis factor-alpha (TNF-alpha) to induce insulin resistance, and then co incubated with a fraction from wax apple fruit extract (FWFE). This fraction significantly increased the uptake of the nonradioactive fluorescent indicator 2 [N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl) amino]-2-deoxy-d-glucose (2-NBDG) in insulin resistant cells. Western blot analysis revealed that, compared with the TNF-alpha-treated control group, FWFE increased the expression of the insulin receptor (IR), insulin receptor substrate-1 (IRS-1), protein kinase B (Akt/PKB), phosphatidylinositol-3 kinase (PI3K), and glucose transporter 2 (GLUT-2), and increased IR tyrosyl phosporylation, in insulin resistant FL83B cells. However, FWFE decreased phosphorylation of c-Jun N-terminal kinases (JNK), but not the expression of the intercellular signal-regulated kinases (ERK), in the same cells. These results suggest that FWFE might alleviate insulin resistance in TNF alpha-treated FL83B cells by activating PI3K-Akt/PKB signaling and inhibiting inflammatory response via suppression of JNK, rather than ERK, activation. PMID- 22942721 TI - Molecular cloning and 3D structure modeling of APEX1, DNA base excision repair enzyme from the Camel, Camelus dromedarius. AB - The domesticated one-humped camel, Camelus dromedarius, is one of the most important animals in the Arabian Desert. It is exposed most of its life to both intrinsic and extrinsic genotoxic factors that are known to cause gross DNA alterations in many organisms. Ionic radiation and sunlight are known producers of Reactive Oxygen Species (ROS), one of the causes for DNA lesions. The damaged DNA is repaired by many enzymes, among of them Base Excision Repair enzymes, producing the highly mutagenic apurinic/apyrimidinicsites (AP sites). Therefore, recognition of AP sites is fundamental to cell/organism survival. In the present work, the full coding sequence of a putative cAPEX1 gene was amplified for the first time from C. dromedarius by RT-PCR and cloned (NCBI accession number are HM209828 and ADJ96599 for nucleotides and amino acids, respectively). cDNA sequencing was deduced to be 1041 nucleotides, of which 954 nucleotides encode a protein of 318 amino acids, similar to the coding region of the APEX1 gene and the protein from many other species. The calculated molecular weight and isoelectric point of cAPEX1 using Bioinformatics tools was 35.5 kDa and 8.11, respectively. The relative expressions of cAPEX1 in camel kidney, spleen, lung and testis were examined using qPCR and compared with that of the liver using a 18S ribosomal subunit as endogenous control. The highest level of cAPEX1 transcript was found in the testis; 325% higher than the liver, followed by spleen (87%), kidney (20%) and lung (5%), respectively. The cAPEX1 is 94%-97% similar to their mammalian counterparts. Phylogenetic analysis revealed that cAPEX1 is grouped together with that of S. scrofa. The predicted 3D structure of cAPEX1 has similar folds and topology with the human (hAPEX1). The root-mean square deviation (rmsd) between cAPEX1 and hAPEX1 was 0.582 and the Q-score was 0.939. PMID- 22942722 TI - Effects of brown rice and white rice on expression of xenobiotic metabolism genes in type 2 diabetic rats. AB - Xenobiotics constantly influence biological systems through several means of interaction. These interactions are disturbed in type 2 diabetes, with implications for disease outcome. We aimed to study the implications of such disturbances on type 2 diabetes and rice consumption, the results of which could affect management of the disease in developing countries. In a type 2 diabetic rat model induced through a combination of high fat diet and low dose streptozotocin injection, up-regulation of xenobiotic metabolism genes in the diabetic untreated group was observed. Xenobiotic metabolism genes were upregulated more in the white rice (WR) group than the diabetic untreated group while the brown rice (BR) group showed significantly lower expression values, though not as effective as metformin, which gave values closer to the normal non diabetic group. The fold changes in expression in the WR group compared to the BR group for Cyp2D4, Cyp3A1, Cyp4A1, Cyp2B1, Cyp2E1, Cyp2C11, UGT2B1, ALDH1A1 and Cyp2C6 were 2.6, 2, 1.5, 4, 2.8, 1.5, 1.8, 3 and 5, respectively. Our results suggest that WR may upregulate these genes in type 2 diabetes more than BR, potentially causing faster drug metabolism, less drug efficacy and more toxicity. These results may have profound implications for rice eating populations, constituting half the world's population. PMID- 22942723 TI - Infrared study of Er(3+)/Yb(3+) Co-Doped GeO(2)-PbO-Bi(2)O(3) glass. AB - Heavy metal oxide glasses, containing bismuth and/or lead in their glass structure are new alternatives for rare eart (RE) doped hosts. Hence, the study of the structure of these vitreous systems is of great interest for science and technology. In this research work, GeO(2)-PbO-Bi(2)O(3) glass host doped with Er(3+)/Yb(3+) ions was synthesized by a conventional melt quenching method. The Fourier transform infrared (FTIR) results showed that PbO and Bi(2)O(3) participate with PbO(4) tetragonal pyramids and strongly distort BiO(6) octahedral units in the glass network, which subsequently act as modifiers in glass structure. These results also confirmed the existence of both four and six coordination of germanium oxide in glass matrix. PMID- 22942724 TI - Green extraction of natural products: concept and principles. AB - The design of green and sustainable extraction methods of natural products is currently a hot research topic in the multidisciplinary area of applied chemistry, biology and technology. Herein we aimed to introduce the six principles of green-extraction, describing a multifaceted strategy to apply this concept at research and industrial level. The mainstay of this working protocol are new and innovative technologies, process intensification, agro-solvents and energy saving. The concept, principles and examples of green extraction here discussed, offer an updated glimpse of the huge technological effort that is being made and the diverse applications that are being developed. PMID- 22942725 TI - Recent molecular advances on downstream plant responses to abiotic stress. AB - Abiotic stresses such as extremes of temperature and pH, high salinity and drought, comprise some of the major factors causing extensive losses to crop production worldwide. Understanding how plants respond and adapt at cellular and molecular levels to continuous environmental changes is a pre-requisite for the generation of resistant or tolerant plants to abiotic stresses. In this review we aimed to present the recent advances on mechanisms of downstream plant responses to abiotic stresses and the use of stress-related genes in the development of genetically engineered crops. PMID- 22942727 TI - Monocyte chemotactic protein-1 as a potential biomarker for early anti-thrombotic therapy after ischemic stroke. AB - Inflammation following ischemic brain injury is correlated with adverse outcome. Preclinical studies indicate that treatment with acetylsalicylic acid + extended release dipyridamole (ASA + ER-DP) has anti-inflammatory and thereby neuroprotective effects by inhibition of monocyte chemotactic protein-1 (MCP-1) expression. We hypothesized that early treatment with ASA + ER-DP will reduce levels of MCP-1 also in patients with ischemic stroke. The EARLY trial randomized patients with ischemic stroke or TIA to either ASA + ER-DP treatment or ASA monotherapy within 24 h following the event. After 7 days, all patients were treated for up to 90 days with ASA + ER-DP. MCP-1 was determined from blood samples taken from 425 patients on admission and day 8. The change in MCP-1 from admission to day 8 did not differ between patients treated with ASA + ER-DP and ASA monotherapy (p > 0.05). Comparisons within MCP-1 baseline quartiles indicated that patients in the highest quartile (>217-973 pg/mL) showed improved outcome at 90 days if treated with ASA + ER-DP in comparison to treatment with ASA alone (p = 0.004). Our data does not provide any evidence that treatment with ASA + ER-DP lowers MCP-1 in acute stroke patients. However, MCP-1 may be a useful biomarker for deciding on early stroke therapy, as patients with high MCP-1 at baseline appear to benefit from early treatment with ASA + ER-DP. PMID- 22942726 TI - Role of prion protein aggregation in neurotoxicity. AB - In several neurodegenerative diseases, such as Parkinson, Alzheimer's, Huntington, and prion diseases, the deposition of aggregated misfolded proteins is believed to be responsible for the neurotoxicity that characterizes these diseases. Prion protein (PrP), the protein responsible of prion diseases, has been deeply studied for the peculiar feature of its misfolded oligomers that are able to propagate within affected brains, inducing the conversion of the natively folded PrP into the pathological conformation. In this review, we summarize the available experimental evidence concerning the relationship between aggregation status of misfolded PrP and neuronal death in the course of prion diseases. In particular, we describe the main findings resulting from the use of different synthetic (mainly PrP106-126) and recombinant PrP-derived peptides, as far as mechanisms of aggregation and amyloid formation, and how these different spatial conformations can affect neuronal death. In particular, most data support the involvement of non-fibrillar oligomers rather than actual amyloid fibers as the determinant of neuronal death. PMID- 22942728 TI - A freshwater streptomyces, isolated from Tyume River, produces a predominantly extracellular glycoprotein bioflocculant. AB - We evaluated bioflocculant production by a freshwater actinobacteria whose 16S rDNA nucleotide sequence was deposited in GenBank as Streptomyces sp. Gansen (accession number HQ537129). Optimum culture conditions for bioflocculant production were an initial medium pH of 6.8, incubation temperature of 30 degrees C, agitation speed of 160 rpm and an inoculum size of 2% (v/v) of cell density 1.5 * 10(8) cfu/mL. The carbon, nitrogen and cation sources for optimum bioflocculant production were glucose (89% flocculating activity), ammonium sulfate (76% flocculating activity) and MgCl(2). Bioflocculant pyrolysis showed three step decomposition indicative of three components while chemical analyses showed 78% carbohydrate and 22% protein (wt/wt). The mass ratio of neutral sugar, amino sugar and uronic acids was 4.6:2.4:3. FTIR spectrometry indicated the presence of carboxyl, hydroxyl and amino groups, typical for heteropolysaccharide. The bioflocculant showed a lattice structure as seen by SEM imaging. Its high flocculation activity suggests its suitability for industrial applicability. PMID- 22942731 TI - Sampling strategy and potential utility of indels for DNA barcoding of closely related plant species: a case study in taxus. AB - Although DNA barcoding has become a useful tool for species identification and biodiversity surveys in plant sciences, there remains little consensus concerning appropriate sampling strategies and the treatment of indels. To address these two issues, we sampled 39 populations for nine Taxus species across their entire ranges, with two to three individuals per population randomly sampled. We sequenced one core DNA barcode (matK) and three supplementary regions (trnH-psbA, trnL-trnF and ITS) for all samples to test the effects of sampling design and the utility of indels. Our results suggested that increasing sampling within population did not change the clustering of individuals, and that meant within population P-distances were zero for most populations in all regions. Based on the markers tested here, comparison of methods either including or excluding indels indicated that discrimination and nodal support of monophyletic groups were significantly increased when indels were included. Thus we concluded that one individual per population was adequate to represent the within-population variation in these species for DNA barcoding, and that intra-specific sampling was best focused on representing the entire ranges of certain taxa. We also found that indels occurring in the chloroplast trnL-trnF and trnH-psbA regions were informative to differentiate among for closely related taxa barcoding, and we proposed that indel-coding methods should be considered for use in future for closed related plant species DNA barcoding projects on or below generic level. PMID- 22942730 TI - Mitochondrial dysfunction and oxidative stress promote apoptotic cell death in the striatum via cytochrome c/caspase-3 signaling cascade following chronic rotenone intoxication in rats. AB - Parkinson's disease (PD) is a progressive neurological disorder marked by nigrostriatal dopaminergic degeneration. Evidence suggests that mitochondrial dysfunction may be linked to PD through a variety of different pathways, including free-radical generation and dysfunction of the mitochondrial Complex I activity. In Lewis rats, chronic systemic administration of a specific mitochondrial Complex I inhibitor, rotenone (3 mg/kg/day) produced parkinsonism like symptoms. Increased oxidized proteins and peroxynitrite, and mitochondrial or cytosol translocation of Bim, Bax or cytochrome c in the striatum was observed after 2-4 weeks of rotenone infusion. After 28 days of systemic rotenone exposure, imunohistochemical staining for tyrosine hydroxylase indicated nigrostriatal dopaminergic neuronal cell degeneration. Characteristic histochemical (TUNEL or activated caspase-3 staining) or ultrastructural (electron microscopy) features of apoptotic cell death were present in the striatal neuronal cell after chronic rotenone intoxication. We conclude that chronic rotenone intoxication may enhance oxidative and nitrosative stress that induces mitochondrial dysfunction and ultrastructural damage, resulting in translocation of Bim and Bax from cytosol to mitochondria that contributes to apoptotic cell death in the striatum via cytochrome c/caspase-3 signaling cascade. PMID- 22942729 TI - Multiple mechanisms and challenges for the application of allopolyploidy in plants. AB - An allopolyploid is an individual having two or more complete sets of chromosomes derived from different species. Generation of allopolyploids might be rare because of the need to overcome limitations such as co-existing populations of parental lines, overcoming hybrid incompatibility, gametic non-reduction, and the requirement for chromosome doubling. However, allopolyploids are widely observed among plant species, so allopolyploids have succeeded in overcoming these limitations and may have a selective advantage. As techniques for making allopolyploids are developed, we can compare transcription, genome organization, and epigenetic modifications between synthesized allopolyploids and their direct parental lines or between several generations of allopolyploids. It has been suggested that divergence of transcription caused either genetically or epigenetically, which can contribute to plant phenotype, is important for the adaptation of allopolyploids. PMID- 22942732 TI - Comparison of different ranking methods in protein-ligand binding site prediction. AB - In recent years, although many ligand-binding site prediction methods have been developed, there has still been a great demand to improve the prediction accuracy and compare different prediction algorithms to evaluate their performances. In this work, in order to improve the performance of the protein-ligand binding site prediction method presented in our former study, a comparison of different binding site ranking lists was studied. Four kinds of properties, i.e., pocket size, distance from the protein centroid, sequence conservation and the number of hydrophobic residues, have been chosen as the corresponding ranking criterion respectively. Our studies show that the sequence conservation information helps to rank the real pockets with the most successful accuracy compared to others. At the same time, the pocket size and the distance of binding site from the protein centroid are also found to be helpful. In addition, a multi-view ranking aggregation method, which combines the information among those four properties, was further applied in our study. The results show that a better performance can be achieved by the aggregation of the complementary properties in the prediction of ligand-binding sites. PMID- 22942734 TI - Microwave-assisted method for simultaneous extraction and hydrolysis for determination of flavonol glycosides in Ginkgo foliage using Bronsted acidic ionic-liquid [HO(3)S(CH(2))(4)mim]HSO(4) aqueous solutions. AB - The Bronsted acidic ionic-liquid [HO(3)S(CH(2))(4)mim] HSO(4), a novel dual catalyst-solvent, has been successfully applied in simultaneous microwave assisted extraction and hydrolysis for the determination of flavonol glycosides in Ginkgo foliage. The parameters, namely the [HO(3)S(CH(2))(4)mim]HSO(4) concentration, microwave-irradiation power, microwave-irradiation time, and solid liquid ratio, were optimized. The optimum conditions were: an amount of 1.5 M [HO(3)S(CH(2))(4)mim]HSO(4), a microwave-irradiation power of 120 W, an irradiation time of 15 min, and a solid-liquid ratio of 1:30 g/mL. Compared with traditional methods the proposed approach demonstrates higher efficiency in a shorter operating time, and is an efficient, rapid, and simple sample preparation method. PMID- 22942733 TI - MicroRNA-125b functions as a tumor suppressor in hepatocellular carcinoma cells. AB - MicroRNAs (miRNAs) are important regulators of multiple cellular processes, and the deregulation of miRNA is a common event in diverse human diseases, particularly cancer. However, the mechanisms underlying the relationship between disordered miRNA expression and tumorigenesis have remained largely unknown. In this study, we demonstrated the down-regulation of miR-125b in hepatocellular carcinoma (HCC) tissues and HCC cell lines by Northern blot and quantitative RT PCR analyses. The ectopic expression of miR-125b reduced the cellular proliferation and cell cycle progression of HCC cells by targeting Mcl-1 and IL6R. Furthermore, the miR-125b-induced inhibition of cell proliferation was rescued by the expression of Mcl-1 or IL6R variants that lacked 3' UTRs. Thus, this study revealed the differential expression of miR-125b in HCC cells and elucidated its potential as a tumor suppressor in HCC development. PMID- 22942735 TI - Extraction of dihydroquercetin from Larix gmelinii with ultrasound-assisted and microwave-assisted alternant digestion. AB - An ultrasound and microwave assisted alternant extraction method (UMAE) was applied for extracting dihydroquercetin (DHQ) from Larix gmelinii wood. This investigation was conducted using 60% ethanol as solvent, 1:12 solid to liquid ratio, and 3 h soaking time. The optimum treatment time was ultrasound 40 min, microwave 20 min, respectively, and the extraction was performed once. Under the optimized conditions, satisfactory extraction yield of the target analyte was obtained. Relative to ultrasound-assisted or microwave-assisted method, the proposed approach provides higher extraction yield. The effect of DHQ of different concentrations and synthetic antioxidants on oxidative stability in soy bean oil stored for 20 days at different temperatures (25 degrees C and 60 degrees C) was compared. DHQ was more effective in restraining soy bean oil oxidation, and a dose-response relationship was observed. The antioxidant activity of DHQ was a little stronger than that of BHA and BHT. Soy bean oil supplemented with 0.08 mg/g DHQ exhibited favorable antioxidant effects and is preferable for effectively avoiding oxidation. The L. gmelinii wood samples before and after extraction were characterized by scanning electron microscopy. The results showed that the UMAE method is a simple and efficient technique for sample preparation. PMID- 22942736 TI - Isolation and characterization of cross-amplification microsatellite panels for species of Procapra (Bovidae; Antilopinae). AB - The three Procapra species, Tibetan gazelle (P. picticaudata), Mongolian gazelle (P. gutturosa) and Przewalski's gazelle (P. przewalskii) are endemic to Asia. Several intraspecific genetic issues have been studied with species-specific microsatellite loci in these Asian gazelles. However, cross-species microsatellite panels are absent, which inhibits comparative conservation and evolutionary studies of the Procapra. In this study, we isolated 20 cross-species microsatellite loci for Procapra from both related species and the genomic library of P. przewalskii. Fifty-three samples of the three gazelles were used to characterize the markers. Allele numbers ranged from three to 20, with a mean of 7.93 per locus. Observed heterozygosity (H(O)) averaged 0.680 and expected heterozygosity (H(E)) 0.767. The mean polymorphic information content (PIC) was 0.757 for P. picticaudata, 0.803 for P. gutturosa and 0.590 for P. przewalskii. Nine loci were significantly deviated from Hardy-Weinberg (H-W) equilibrium in the three species. Significant linkage disequilibrium was detected in four pairs of loci in P. przewalskii, five pairs in P. gutturosa and 51 pairs in P. picticaudata. Considering the abundance of published loci and their high success rates of cross-amplification, testing and utilization of loci from related species is efficient for wild species of Bovidae. The cross-species microsatellite loci we developed will facilitate further interspecies genetic studies in Procapra. PMID- 22942737 TI - Identification and characterization of a Bursaphelenchus xylophilus (Aphelenchida: Aphelenchoididae) thermotolerance-Related Gene: Bx-HSP90. AB - Temperatures directly influence the distribution and intensity of pine wilt disease caused by the pine wood nematode, Bursaphelenchus xylophilus. To date, however, little is known about the causation and mechanism of this influence. The molecular chaperone HSP90 is a key component that contributes to survival in the abiotic stress response. In this study, we investigated the relationship between the survival of B. xylophilus and the functionality of the HSP90 gene. Bx-HSP90 was cloned from a suppression subtractive hybridization library. In situ mRNA hybridization showed that Bx-HSP90 was constitutively expressed in response to all of the temperatures tested, and RT-PCR indicated that all of the temperatures could induce Bx-HSP90 transcription, with the highest transcript level detected at 30 degrees C. The suppression of the Bx-HSP90 transcript by RNA interference led to a 25% reduction in the number of nematodes at 30 degrees C after 44 h. Sharp declines in the survival of the RNAi-treated nematodes were observed after 8 days at 25 degrees C, 48 h at 30 degrees C and 24 h at 35 degrees C. Both heat shock and the knockdown of Bx-HSP90 hindered the growth of the B. xylophilus populations. The results indicate that Bx-HSP90 is essential for the survival of B. xylophilus, confirming the thermoregulatory function of the gene, and delineate the timeframe and temperature range within which the gene function occurs. PMID- 22942738 TI - The tricyclodecan-9-yl-xanthogenate D609 triggers ceramide increase and enhances FasL-induced caspase-dependent and -independent cell death in T lymphocytes. AB - D609 is known to modulate death receptor-induced ceramide generation and cell death. We show that in Jurkat cells, non-toxic D609 concentrations inhibit sphingomyelin synthase and, to a lesser extent, glucosylceramide synthase, and transiently increase the intracellular ceramide level. D609 significantly enhanced FasL-induced caspase activation and apoptosis. D609 stimulated FasL induced cell death in caspase-8-deficient Jurkat cells, indicating that D609 acts downstream of caspase-8. At high FasL concentration (500 ng/mL), cell death was significantly, but not completely, inhibited by zVAD-fmk, a broad-spectrum caspase inhibitor, indicating that FasL can activate both caspase-dependent and independent cell death signaling pathways. FasL-induced caspase activation was abolished by zVAD-fmk, whereas ceramide production was only partially impaired. D609 enhanced caspase-independent ceramide increase and cell death in response to FasL. Also, D609 overcame zVAD-fmk-conferred resistance to a FasL concentration as low as 50 ng/mL and bypassed RIP deficiency. It is likely that mitochondrial events were involved, since Bcl-xL over-expression impaired D609 effects. In PHA activated human T lymphocytes, D609 enhanced FasL-induced cell death in the presence or absence of zVAD-fmk. Altogether, our data strongly indicate that the inhibition of ceramide conversion to complex sphingolipids by D609 is accompanied by an enhancement of FasL-induced caspase-dependent and -independent cell death in T lymphocytes. PMID- 22942739 TI - Leukocyte mitochondrial DNA alteration in systemic lupus erythematosus and its relevance to the susceptibility to lupus nephritis. AB - The role of mitochondrial DNA (mtDNA) alterations in the pathophysiology of systemic lupus erythematosus (SLE) remains unclear. We investigated sequence variations in the D310 region and copy number change of mtDNA in 85 SLE patients and 45 normal subjects. Leukocyte DNA and RNA were extracted from leukocytes of the peripheral venous blood. The D310 sequence variations and copy number of mtDNA, and mRNA expression levels of mtDNA-encoded genes in leukocytes were determined by quantitative real-time polymerase chain reaction (Q-PCR) and PCR based direct sequencing, respectively. We found that leukocyte mtDNA in SLE patients exhibited higher frequency of D310 heteroplasmy (69.4% vs. 48.9%, p = 0.022) and more D310 variants (2.2 vs. 1.7, p = 0.014) than those found in controls. Among normal controls and patients with low, medium or high SLE disease activity index (SLEDAI), an ever-increasing frequency of D310 heteroplasmy was observed (p = 0.021). Leukocyte mtDNA copy number tended to be low in patients of high SLEDAI group (p = 0.068), especially in those harboring mtDNA with D310 heteroplasmy (p = 0.020). Moreover, the mtDNA copy number was positively correlated with the mRNA level of mtDNA-encoded ND1 (NADH dehydrogenase subunit 1) (p = 0.041) and ATPase 6 (ATP synthase subunit 6) (p = 0.030) genes. Patients with more D310 variants were more susceptible to lupus nephritis (p = 0.035). Taken together, our findings suggest that decrease in the mtDNA copy number and increase in D310 heteroplasmy of mtDNA are related to the development and progression of SLE, and that the patients harboring more D310 variants of mtDNA are more susceptible to lupus nephritis. PMID- 22942740 TI - Micronization of taxifolin by supercritical antisolvent process and evaluation of radical scavenging activity. AB - The aim of this study was to prepare micronized taxifolin powder using the supercritical antisolvent precipitation process to improve the dissolution rate of taxifolin. Ethanol was used as solvent and carbon dioxide was used as an antisolvent. The effects of process parameters, such as temperature (35-65 degrees C), pressure (10-25 MPa), solution flow rate (3-6 mL/min) and concentration of the liquid solution (5-20 mg/mL) on the precipitate crystals were investigated. With a lower temperature, a stronger pressure and a lower concentration of the liquid solution, the size of crystals decreased. The precipitation temperature, pressure and concentration of taxifolin solution had a significant effect. However, the solution flow rate had a negligible effect. It was concluded that the physicochemical properties and dissolution rate of crystalline taxifolin could be improved by physical modification such as particle size reduction using the supercritical antisolvent (SAS) process. Further, the SAS process was a powerful methodology for improving the physicochemical properties and radical scavenging activity of taxifolin. PMID- 22942744 TI - Antioxidant activity of Brazilian vegetables and its relation with phenolic composition. AB - Vegetables are widely consumed in Brazil and exported to several countries. This study was performed to evaluate the phenolic content and antioxidant activity of vegetables commonly consumed in Brazil using five different methods, namely DPPH and ABTS free radical, beta-carotene bleaching, reduction of Fe(3+) (FRAP), oxidative stability in Rancimat, and the chemical composition using gas chromatography-mass spectrometry (GC-MS). The content of phenolic compounds ranged from 1.2 mg GA/g (carrot) to 16.9 mg GA/g (lettuce). Vegetables presenting the highest antioxidant activity were lettuce (77.2 MUmol Trolox/g DPPH(*); 447.1 MUmol F(2+)/g FRAP), turmeric (118.6 MUmol Trolox/g ABTS(*+); 92.8% beta carotene), watercress and broccoli (protective factor 1.29-Rancimat method). Artichoke, spinach, broccoli, and asparagus also showed considerable antioxidant activity. The most frequent phenolic compounds identified by GC-MS were ferulic, caffeic, p-coumaric, 2-dihydroxybenzoic, 2,5-dihydroxybenzoic acids, and quercetin. We observed antioxidant activity in several vegetables and our results point out their importance in the diet. PMID- 22942743 TI - Exome enrichment and SOLiD sequencing of formalin fixed paraffin embedded (FFPE) prostate cancer tissue. AB - Next generation sequencing (NGS) technologies have revolutionized cancer research allowing the comprehensive study of cancer using high throughput deep sequencing methodologies. These methods detect genomic alterations, nucleotide substitutions, insertions, deletions and copy number alterations. SOLiD (Sequencing by Oligonucleotide Ligation and Detection, Life Technologies) is a promising technology generating billions of 50 bp sequencing reads. This robust technique, successfully applied in gene identification, might be helpful in detecting novel genes associated with cancer initiation and progression using formalin fixed paraffin embedded (FFPE) tissue. This study's aim was to compare the validity of whole exome sequencing of fresh-frozen vs. FFPE tumor tissue by normalization to normal prostatic FFPE tissue, obtained from the same patient. One primary fresh-frozen sample, corresponding FFPE prostate cancer sample and matched adjacent normal prostatic tissue was subjected to exome sequencing. The sequenced reads were mapped and compared. Our study was the first to show comparable exome sequencing results between FFPE and corresponding fresh-frozen cancer tissues using SOLiD sequencing. A prior study has been conducted comparing the validity of sequencing of FFPE vs. fresh frozen samples using other NGS platforms. Our validation further proves that FFPE material is a reliable source of material for whole exome sequencing. PMID- 22942742 TI - Synergistic interactions of methanolic extract of Acacia mearnsii De Wild. with antibiotics against bacteria of clinical relevance. AB - With the emergence of multidrug-resistant organisms, combining medicinal plants with synthetic or orthodox medicines against resistant bacteria becomes necessary. In this study, interactions between methanolic extract of Acacia mearnsii and eight antibiotics were investigated by agar diffusion and checkerboard assays. The minimum inhibitory concentrations (MICs) of all the antibiotics ranged between 0.020 and 500 MUg/mL while that of the crude extract varied between 0.156 and 1.25 mg/mL. The agar diffusion assay showed that extract kanamycin combination had zones of inhibition >=20 +/- 1.0 mm in all the bacteria tested (100%), followed by extract-chloramphenicol (90%) > extract-ciprofloxacin = extract-tetracycline (70%) > extract-amoxicillin (60%) > extract-nalidixic acid (50%) > extract-erythromycin (40%) > extract-metronidazole (20%). The checkerboard showed synergistic interaction (61.25%), additivity/indifference (23.75%) and antagonistic (15%) effects. The synergistic interaction was most expressed by combining the extract with tetracycline, metronidazole, amoxicillin, ciprofloxacin, chloramphenicol and nalidixic acid against E. coli (ATCC 25922), erythromycin, metronidazole, amoxicillin, chloramphenicol and kanamycin against S. aureus (ATCC 6538), erythromycin, tetracycline, amoxicillin, nalidixic acid and chloramphenicol against B. subtilis KZN, erythromycin, metronidazole and amoxicillin against E. faecalis KZN, erythromycin, tetracycline, nalidixic acid and chloramphenicol against K. pneumoniae (ATCC 10031), erythromycin, tetracycline, metronidazole and chloramphenicol against P. vulgaris (ATCC 6830), erythromycin, tetracycline, amoxicillin and chloramphenicol against S. sonnei (ATCC 29930), metronidazole, amoxicillin and chloramphenicol against E. faecalis (ATCC 29212) and ciprofloxacin and chloramphenicol against Proteus vulgaris KZN. The synergistic interactions indicated that the bactericidal potentials of the antibacterial agents were improved and combining natural products with antibiotic could be potential sources for resistance-modifying agents useful against infectious multi-drug resistant bacteria. PMID- 22942741 TI - Molecular mechanisms of ursodeoxycholic acid toxicity & side effects: ursodeoxycholic acid freezes regeneration & induces hibernation mode. AB - Ursodeoxycholic acid (UDCA) is a steroid bile acid approved for primary biliary cirrhosis (PBC). UDCA is reported to have "hepato-protective properties". Yet, UDCA has "unanticipated" toxicity, pronounced by more than double number of deaths, and eligibility for liver transplantation compared to the control group in 28 mg/kg/day in primary sclerosing cholangitis, necessitating trial halt in North America. UDCA is associated with increase in hepatocellular carcinoma in PBC especially when it fails to achieve biochemical response (10 and 15 years incidence of 9% and 20% respectively). "Unanticipated" UDCA toxicity includes hepatitis, pruritus, cholangitis, ascites, vanishing bile duct syndrome, liver cell failure, death, severe watery diarrhea, pneumonia, dysuria, immune suppression, mutagenic effects and withdrawal syndrome upon sudden halt. UDCA inhibits DNA repair, co-enzyme A, cyclic AMP, p53, phagocytosis, and inhibits induction of nitric oxide synthatase. It is genotoxic, exerts aneugenic activity, and arrests apoptosis even after cellular phosphatidylserine externalization. UDCA toxicity is related to its interference with drug detoxification, being hydrophilic and anti-apoptotic, has a long half-life, has transcriptional mutational abilities, down-regulates cellular functions, has a very narrow difference between the recommended (13 mg/kg/day) and toxic dose (28 mg/kg/day), and it typically transforms into lithocholic acid that induces DNA strand breakage, it is uniquely co-mutagenic, and promotes cell transformation. UDCA beyond PBC is unjustified. PMID- 22942745 TI - Binding mode pediction of evodiamine within vanilloid receptor TRPV1. AB - Accurate assessment of the potential binding mode of drugs is crucial to computer aided drug design paradigms. It has been reported that evodiamine acts as an agonist of the vanilloid receptor Transient receptor potential vanilloid-1 (TRPV1). However, the precise interaction between evodiamine and TRPV1 was still not fully understood. In this perspective, the homology models of TRPV1 were generated using the crystal structure of the voltage-dependent shaker family K(+) channel as a template. We then performed docking and molecular dynamics simulation to gain a better understanding of the probable binding modes of evodiamine within the TRPV1 binding pocket. There are no significant interspecies differences in evodiamine binding in rat, human and rabbit TRPV1 models. Pharmacophore modeling further provided confidence for the validity of the docking studies. This study is the first to shed light on the structural determinants required for the interaction between TRPV1 and evodiamine, and gives new suggestions for the rational design of novel TRPV1 ligands. PMID- 22942746 TI - Enrichment and purification of syringin, eleutheroside E and isofraxidin from Acanthopanax senticosus by macroporous resin. AB - In order to screen a suitable resin for the preparative simultaneous separation and purification of syringin, eleutheroside E and isofraxidin from Acanthopanax senticosus, the adsorption and desorption properties of 17 widely used commercial macroporous resins were evaluated. According to our results, HPD100C, which adsorbs by the molecular tiers model, was the best macroporous resin, offering higher adsorption and desorption capacities and higher adsorption speed for syringin, eleutheroside E and isofraxidin than other resins. Dynamic adsorption and desorption tests were carried out to optimize the process parameters. The optimal conditions were as follows: for adsorption, processing volume: 24 BV, flow rate: 2 BV/h; for desorption, ethanol-water solution: 60:40 (v/v), eluent volume: 4 BV, flow rate: 3 BV/h. Under the above conditions, the contents of syringin, eleutheroside E and isofraxidin increased 174-fold, 20-fold and 5-fold and their recoveries were 80.93%, 93.97% and 93.79%, respectively. PMID- 22942747 TI - Antioxidant property enhancement of sweet potato flour under simulated gastrointestinal pH. AB - Sweet potato is known to be rich in healthful antioxidants, but the stability of its antioxidant properties under gastrointestinal pH is very much unknown. Hence, this study aimed to evaluate the changes in antioxidant properties (total contents of phenolics and flavonoids as well as antioxidant activity) of sweet potato flour (SPF) under simulated gastrointestinal pH conditions. It was found that the yield of SPF crude phenolic extract increased from 0.29 to 3.22 g/100 g SPF upon subjection to gastrointestinal pH conditions (p < 0.05). Also elevated significantly were the total phenolic content (TPC), total flavonoid content (TFC) and antioxidant activity of SPF (p < 0.05). In summary, the antioxidant properties of SPF were enhanced under gastrointestinal pH conditions, suggesting that SPF might possess a considerable amount of bound phenolic and other antioxidative compounds. The antioxidant properties of SPF are largely influenced by pH and thus might be enhanced during the in vivo digestive process. PMID- 22942748 TI - Homology modeling and analysis of structure predictions of the bovine rhinitis B virus RNA dependent RNA polymerase (RdRp). AB - Bovine Rhinitis B Virus (BRBV) is a picornavirus responsible for mild respiratory infection of cattle. It is probably the least characterized among the aphthoviruses. BRBV is the closest relative known to Foot and Mouth Disease virus (FMDV) with a ~43% identical polyprotein sequence and as much as 67% identical sequence for the RNA dependent RNA polymerase (RdRp), which is also known as 3D polymerase (3D(pol)). In the present study we carried out phylogenetic analysis, structure based sequence alignment and prediction of three-dimensional structure of BRBV 3D(pol) using a combination of different computational tools. Model structures of BRBV 3D(pol) were verified for their stereochemical quality and accuracy. The BRBV 3D(pol) structure predicted by SWISS-MODEL exhibited highest scores in terms of stereochemical quality and accuracy, which were in the range of 2A resolution crystal structures. The active site, nucleic acid binding site and overall structure were observed to be in agreement with the crystal structure of unliganded as well as template/primer (T/P), nucleotide tri-phosphate (NTP) and pyrophosphate (PPi) bound FMDV 3D(pol) (PDB, 1U09 and 2E9Z). The closest proximity of BRBV and FMDV 3D(pol) as compared to human rhinovirus type 16 (HRV 16) and rabbit hemorrhagic disease virus (RHDV) 3D(pols) is also substantiated by phylogeny analysis and root-mean square deviation (RMSD) between C-alpha traces of the polymerase structures. The absence of positively charged alpha-helix at C terminal, significant differences in non-covalent interactions especially salt bridges and CH-pi interactions around T/P channel of BRBV 3D(pol) compared to FMDV 3D(pol), indicate that despite a very high homology to FMDV 3D(pol), BRBV 3D(pol) may adopt a different mechanism for handling its substrates and adapting to physiological requirements. Our findings will be valuable in the design of structure-function interventions and identification of molecular targets for drug design applicable to Aphthovirus RdRps. PMID- 22942749 TI - Hepatoprotective effects of Berberis vulgaris L. extract/beta cyclodextrin on carbon tetrachloride-induced acute toxicity in mice. AB - The present study investigated the capacity of formulated Berberis vulgaris extract/beta-cyclodextrin to protect liver against CCl(4)-induced hepatotoxicity in mice. Formulated and non-formulated extracts were given orally (50 mg/kg/day) to mice for 7 days and were then intra-peritoneally injected with 1.0 mL/kg CCl(4) on the 8th day. After 24 h of CCl(4) administration, an increase in the levels of apartate-amino-transferase (AST), alanine-amino-transferase (ALT) and malondialdehyde (MDA) was found and a significant decrease in superoxide dismutase (SOD), catalase (CAT), glutathione (GSH) and glutathione-peroxidase (GPx) levels could be detected. This was accompanied by extended centrilobular necrosis, steatosis, fibrosis and an altered ultrastructure of hepatocytes. Pre treatment with formulated or non-formulated extract suppressed the increase in ALT, AST and MDA levels and restored the level of antioxidant enzymes at normal values. Histopathological and electron-microscopic examination showed milder liver damage in both pre-treated groups and the protective effect was more pronounced after the formulated extract was administered. Internucleosomal DNA fragmentation induced by CCl(4) was reduced in the group which received non formulated extract and absent in the group which received formulated extract. Taken together, our results suggest that Berberis vulgaris/beta-cyclodextrin treatment prevents hepatic injury induced by CCl(4) and can be considered for further nutraceutical studies. PMID- 22942750 TI - Quantitative and chemical fingerprint analysis for the quality evaluation of Isatis indigotica based on ultra-performance liquid chromatography with photodiode array detector combined with chemometric methods. AB - A simple and reliable method of ultra-performance liquid chromatography with photodiode array detector (UPLC-PDA) was developed to control the quality of Radix Isatidis (dried root of Isatis indigotica) for chemical fingerprint analysis and quantitative analysis of eight bioactive constituents, including R,S goitrin, progoitrin, epiprogoitrin, gluconapin, adenosine, uridine, guanosine, and hypoxanthine. In quantitative analysis, the eight components showed good regression (R > 0.9997) within test ranges, and the recovery method ranged from 99.5% to 103.0%. The UPLC fingerprints of the Radix Isatidis samples were compared by performing chemometric procedures, including similarity analysis, hierarchical clustering analysis, and principal component analysis. The chemometric procedures classified Radix Isatidis and its finished products such that all samples could be successfully grouped according to crude herbs, prepared slices, and adulterant Baphicacanthis cusiae Rhizoma et Radix. The combination of quantitative and chromatographic fingerprint analysis can be used for the quality assessment of Radix Isatidis and its finished products. PMID- 22942751 TI - Ultrasonic-assisted enzymolysis to improve the antioxidant activities of peanut (Arachin conarachin L.) antioxidant hydrolysate. AB - The objective of this work is to provide a theoretical basis for preparing peanut antioxidant hydrolysate in order to improve its antioxidant activities. Therefore, response surface methodology (RSM) based on the Box-Behnken design was used to optimize ultrasonic-assisted enzymolysis for the purpose of preparing peanut antioxidant hydrolysate. Results indicated that the DPPH free radical scavenging activity of peanut hydrolysate could reach 90.06% under the following optimum conditions: ultrasonic power of 150.0 w, reaction temperature of 62.0 degrees C, incubation time of 25.0 min, and initial pH value of 8.5. The DPPH free radical scavenging rate of peanut hydrolysate from ultrasonic-assisted enzymolysis improved comparing with that of peanut hydrolysate from protease hydrolysis alone. The peanut antioxidant hydrolysate was found to display eight improved kinds of antioxidant activities. In conclusion, the optimal ultrasonic assisted enzymolysis technology conditions described in this paper, appear to be beneficial for preparing peanut antioxidant hydrolysate. PMID- 22942753 TI - The structure lacuna. AB - Molecular symmetry is intimately connected with the classical concept of three dimensional molecular structure. In a non-classical theory of wave-like interaction in four-dimensional space-time, both of these concepts and traditional quantum mechanics lose their operational meaning, unless suitably modified. A required reformulation should emphasize the importance of four dimensional effects like spin and the symmetry effects of space-time curvature that could lead to a fundamentally different understanding of molecular symmetry and structure in terms of elementary number theory. Isolated single molecules have no characteristic shape and macro-biomolecules only develop robust three dimensional structure in hydrophobic response to aqueous cellular media. PMID- 22942752 TI - Decidual macrophages are significantly increased in spontaneous miscarriages and over-express FasL: a potential role for macrophages in trophoblast apoptosis. AB - Decidual macrophages (DM) are the second most abundant population in the fetal maternal interface. Their role has been so far identified as being local immuno modulators favoring the maternal tolerance to the fetus. Herein we investigated tissue samples from 11 cases of spontaneous miscarriages and from 9 cases of elective terminations of pregnancy. Using immunohistochemistry and dual immunofluorescence we have demonstrated that in spontaneous miscarriages the DM are significantly increased. Additionally, we noted a significant up-regulation of macrophage FasL expression. Our results further support a dual role for DM during pregnancy and miscarriages. We hypothesize that the baseline DM population in normal pregnancy is in line with an M2 phenotype supporting the ongoing gestation. In contrast, during spontaneous miscarriages, the increased FasL expressing population could be a part of an M1 phenotype participating in Fas/FasL-related apoptosis. Our results highlight a new aspect of macrophage biology in pregnancy physiology and pathophysiology. Further studies with larger samples are needed to verify the current results and evaluate their clinical impact. PMID- 22942754 TI - Curcumin inhibits glutamate release from rat prefrontal nerve endings by affecting vesicle mobilization. AB - Curcumin, one of the major constituents of Curcuma longa, has been shown to inhibit depolarization-evoked glutamate release from rat prefrontocortical nerve terminals by reducing voltage-dependent Ca(2+) entry. This study showed that curcumin inhibited ionomycin-induced glutamate release and KCl-evoked FM1-43 release, suggesting that some steps after Ca(2+) entry are regulated by curcumin. Furthermore, disrupting the cytoskeleton organization using cytochalasin D abolished the inhibitory action of curcumin on ionomycin-induced glutamate release. Mitogen-activated protein kinase kinase (MEK) inhibition also prevented the inhibitory effect of curcumin on ionomycin-induced glutamate release. Western blot analyses showed that curcumin decreased the ionomycin-induced phosphorylation of extracellular signal-regulated kinase 1 and 2 (ERK1/2) and synaptic vesicle-associated protein synapsin I, the main presynaptic target of ERK. These results show that curcumin-mediated inhibition of glutamate release involves modulating downstream events by controlling synaptic vesicle recruitment and exocytosis, possibly through a decrease of MAPK/ERK activation and synapsin I phosphorylation, thereby decreasing synaptic vesicle availability for exocytosis. PMID- 22942755 TI - HR4 gene is induced in the Arabidopsis-Trichoderma atroviride beneficial interaction. AB - Plants are constantly exposed to microbes, for this reason they have evolved sophisticated strategies to perceive and identify biotic interactions. Thus, plants have large collections of so-called resistance (R) proteins that recognize specific microbe factors as signals of invasion. One of these proteins is codified by the Arabidopsis thaliana HR4 gene in the Col-0 ecotype that is homologous to RPW8 genes present in the Ms-0 ecotype. In this study, we investigated the expression patterns of the HR4 gene in Arabidopsis seedlings interacting with the beneficial fungus Trichoderma atroviride. We observed the induction of the HR4 gene mainly at 96 hpi when the fungus interaction was established. Furthermore, we found that the HR4 gene was differentially regulated in interactions with the beneficial bacterium Pseudomonas fluorescens and the pathogenic bacterium P. syringae. When hormone treatments were applied to A. thaliana (Col-0), each hormone treatment induced changes in HR4 gene expression. On the other hand, the expression of the RPW8.1 and RPW8.2 genes of Arabidopsis ecotype Ms-0 in interaction with T. atroviride was assessed. Interestingly, these genes are interaction-responsive; in particular, the RPW8.1 gene shows a very high level of expression in the later stages of interaction. These results indicate that HR4 and RPW8 genes could play a role in the establishment of Arabidopsis interactions with beneficial microbes. PMID- 22942756 TI - Pharmacokinetics and tissue distribution study of Praeruptorin D from Radix peucedani in rats by high-performance liquid chromatography (HPLC). AB - Praeruptorin D (PD), a major pyranocoumarin isolated from Radix Peucedani, exhibited antitumor and anti-inflammatory activities. The aim of this study was to investigate the pharmacokinetics and tissue distribution of PD in rats following intravenous (i.v.) administration. The levels of PD in plasma and tissues were measured by a simple and sensitive reversed-phase high-performance liquid chromatography (HPLC) method. The biosamples were treated by liquid-liquid extraction (LLE) with methyl tert-butyl ether (MTBE) and osthole was used as the internal standard (IS). The chromatographic separation was accomplished on a reversed-phase C(18) column using methanol-water (75:25, v/v) as mobile phase at a flow rate of 0.8 mL/min and ultraviolet detection wave length was set at 323 nm. The results demonstrate that this method has excellent specificity, linearity, precision, accuracy and recovery. The pharmacokinetic study found that PD fitted well into a two-compartment model with a fast distribution phase and a relative slow elimination phase. Tissue distribution showed that the highest concentration was observed in the lung, followed by heart, liver and kidney. Furthermore, PD can also be detected in the brain, which indicated that PD could cross the blood-brain barrier after i.v. administration. PMID- 22942757 TI - TRAIL and paclitaxel synergize to kill U87 cells and U87-derived stem-like cells in vitro. AB - U87-derived stem-like cells (U87-SLCs) were cultured using serum-free stem cell media and identified by both biological behaviors and markers. Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) and paclitaxel (PX), in combination or alone, was used to treat U87-MG human glioma cells (U87 cells) or U87-SLCs. The results showed that TRAIL/PX cannot only synergistically inhibit U87 cells but also U87-SLCs. We observed a significantly higher apoptotic rate in U87 cells simultaneously treated with TRAIL/PX for 24 h compared to cells treated with either drug alone. Furthermore, there was a remarkably higher apoptosis rate in U87-SLCs induced by the TRAIL/PX combination compared with either drug alone. Unlike the simultaneous treatment in U87 cells, U87-SLCs were pretreated for 24 h with 1 MUmol/L of PX followed by 1000 ng/mL of TRAIL. Protein assays revealed that TRAIL/PX synergy was related to DR4, cleaved caspase-8 and cleaved caspase-3 upregulation, whereas the mitochondrial pathway was not involved in TRAIL-induced apoptosis. The present study indicates that PX can sensitize U87 cells and U87 SLCs to TRAIL treatment through an extrinsic pathway of cell apoptosis. The combined treatment of TRAIL and PX may be a promising glioma chemotherapy because of its successful inhibition of U87-SLCs, which are hypothesized to influence chemotherapeutic outcomes of gliomas. PMID- 22942758 TI - Reduction-oxidation photocycle dynamics of flavins in starch films. AB - The blue-light photo-reduction (conversion of oxidized flavin quinone via flavin semiquinone to fully reduced flavin hydroquinone) and dark re-oxidation of the flavins riboflavin and lumiflavin in starch (alpha-amylose) films was studied by absorption and luminescence spectroscopy. Blue-light photo-excitation caused an absorption, fluorescence, and phosphorescence decrease which recovered in the dark. The photo-reduction dark-oxidation cycle could be repeated. The efficiency of photo-reduction decreased with exposed excitation energy, and the speed of re oxidation in the dark slowed down with time after excitation. The absorption did not fully recover. The fluorescence efficiency after a long time of storage in the dark increased beyond the initial flavin quinone fluorescence efficiency. Flavin photo-excitation is thought to cause starch-flavin restructuring (static fluorescence quenching center formation), enabling enhanced photo-induced starch to flavin electron transfer with subsequent flavin reduction and starch oxidation. In the dark, after light switch-off, thermal reversion of flavin reduction and starch oxidation occurred. PMID- 22942759 TI - Effect of beta,beta-dimethylacrylshikonin on inhibition of human colorectal cancer cell growth in vitro and in vivo. AB - In traditional Chinese medicine, shikonin and its derivatives, has been used in East Asia for several years for the prevention and treatment of several diseases, including cancer. We previously identified that beta,beta-dimethylacrylshikonin (DA) could inhibit hepatocellular carcinoma growth. In the present study, we investigated the inhibitory effects of DA on human colorectal cancer (CRC) cell line HCT-116 in vitro and in vivo. A viability assay showed that DA could inhibit tumor cell growth in a time- and dose-dependent manner. Flow cytometry showed that DA blocks the cell cycle at G(0)/G(1) phase. Western blotting results demonstrated that the induction of apoptosis by DA correlated with the induction of pro-apoptotic proteins Bax, and Bid, and a decrease in the expression of anti apoptotic proteins Bcl-2 and Bcl-xl. Furthermore, treatment of HCT-116 bearing nude mice with DA significantly retarded the growth of xenografts. Consistent with the results in vitro, the DA-mediated suppression of HCT-116 xenografts correlated with Bax and Bcl-2. Taken together, these results suggest that DA could be a novel and promising approach to the treatment of CRC. PMID- 22942760 TI - Antioxidative properties of crude polysaccharides from Inonotus obliquus. AB - The mushroom Inonotus obliquus has been widely used as a folk medicine in Russia, Poland and most of the Baltic countries. In this study, water-soluble and alkali soluble crude polysaccharides (IOW and IOA) were isolated from I. obliquus, and the carbohydrate-rich fractions IOW-1 and IOA-1 were obtained respectively after deproteination and depigmentation. Their contents, such as neutral carbohydrate, uronic acid and protein, were measured. Their antioxidant properties against chemicals-induced reactive species (ROS) including 1,1'-Diphenyl-2-picrylhydrazyl (DPPH) radical, hydroxyl radical and superoxide anion radical, as well as their protective effects on H(2)O(2)-induced PC12 cell death were investigated. Results showed that I. obliquus polysaccharides can scavenge all ROS tested above in a dose-dependent manner. IOA and its product IOA-1 could rescue PC12 cell viability from 38.6% to 79.8% and 83.0% at a concentration of 20MUg/mL. Similarly, IOW and its product IOW-1 at the same dose, can also increase cell viability to 84.9% and 88.6% respectively. The antioxidative activities of water-soluble and alkali soluble polysaccharide constituents from I. obliquus might contribute to diverse medicinal and nutritional values of this mushroom. PMID- 22942761 TI - 3D structure elucidation of thermostable L2 lipase from Thermophilic Bacillus sp. L2. AB - The crystallization of proteins makes it possible to determine their structure by X-ray crystallography, and is therefore important for the analysis of protein structure-function relationships. L2 lipase was crystallized by using the J-tube counter diffusion method. A crystallization consisting of 20% PEG 6000, 50 mM MES pH 6.5 and 50 mM NaCl was found to be the best condition to produce crystals with good shape and size (0.5 * 0.1 * 0.2 mm). The protein concentration used for the crystallization was 3 mg/mL. L2 lipase crystal has two crystal forms, Shape 1 and Shape 2. Shape 2 L2 lipase crystal was diffracted at 1.5 A and the crystal belongs to the orthorhombic space group P2(1)2(1)2(1), with unit-cell parameters a = 72.0, b = 81.8, c = 83.4 A, alpha = beta = gamma = 90 degrees . There is one molecule per asymmetric unit and the solvent content of the crystals is 56.9%, with a Matthew's coefficient of 2.85 A Da(-1). The 3D structure of L2 lipase revealed topological organization of alpha/beta-hydrolase fold consisting of 11 beta-strands and 13 alpha-helices. Ser-113, His-358 and Asp-317 were assigned as catalytic triad residues. One Ca(2+) and one Zn(2+) were found in the L2 lipase molecule. PMID- 22942762 TI - Development of 20 microsatellite markers for Solenocera crassicornis and their cross-species application in Solenocera melantho. AB - Twenty microsatellite markers were isolated and characterized for Solenocera crassicornis from a (GT)13-enriched genomic library. Their polymorphisms were investigated using 44 wild individuals from the South Yellow Sea. Our investigation revealed that all the markers were polymorphic. The number of alleles per locus varied from 6 to 19 with an average of 12.35. The observed and expected heterozygosities ranged from 0.400 to 0.977 and from 0.609 to 0.940, with averages of 0.788 and 0.859, respectively. Four loci significantly deviated from Hardy-Weinberg equilibrium after Bonferroni's correction. Cross-species amplification was also conducted in Solenocera melantho collected from the East China Sea. The result showed that 14 loci could be amplified from Solenocera melantho DNAs. These polymorphic markers would be useful for assessment of genetic variation and population structure of S. crassicornis and S. melantho. PMID- 22942764 TI - Enhancing oxidative stability of sunflower oil during convective and microwave heating using grape seed extract. AB - This study was performed to investigate the effectiveness of grape seed extract (GSE) compared to butylated hydroxytoluene (BHT) on retarding lipid oxidation of sunflower oil subjected to convection and microwave heating up to 240 min under simulated frying conditions. The progress of lipid oxidation was assessed in terms of peroxide value (PV), p-anisidine value (p-AV), conjugated dienes and trienes (CD, CT), inhibition of oil oxidation (IO) and TOTOX value. In addition, total phenolic content (TP) was evaluated in samples before and after heating in order to assess the changes in these compounds relative to the extent of lipid oxidation. The results of this study highlight that GSE showed a significantly inhibitory effect on lipid oxidation during both treatments, although to a different extent. This ability was dose-dependent; therefore, the extent of lipid oxidation was inversely related to GSE level. Convective heating, respective microwave exposure for 240 min of samples supplemented by GSE to a level of 1000 ppm, resulted in significant decreases of investigated indices relative to the control values as follows: PV (48%; 30%), p-AV (29%; 40%), CD (45%; 30%), CT (41%; 36%), TOTOX (35%; 37%). GSE to a level of 600-800 ppm inhibited the lipid oxidation in a similar manner to BHT. These results suggested that GSE can be used as a potential natural extract for improving oxidative stability of sunflower oil during thermal applications. PMID- 22942763 TI - Bacterial motility measured by a miniature chamber for high-pressure microscopy. AB - Hydrostatic pressure is one of the physical stimuli that characterize the environment of living matter. Many microorganisms thrive under high pressure and may even physically or geochemically require this extreme environmental condition. In contrast, application of pressure is detrimental to most life on Earth; especially to living organisms under ambient pressure conditions. To study the mechanism of how living things adapt to high-pressure conditions, it is necessary to monitor directly the organism of interest under various pressure conditions. Here, we report a miniature chamber for high-pressure microscopy. The chamber was equipped with a built-in separator, in which water pressure was properly transduced to that of the sample solution. The apparatus developed could apply pressure up to 150 MPa, and enabled us to acquire bright-field and epifluorescence images at various pressures and temperatures. We demonstrated that the application of pressure acted directly and reversibly on the swimming motility of Escherichia coli cells. The present technique should be applicable to a wide range of dynamic biological processes that depend on applied pressures. PMID- 22942765 TI - Correlation among antioxidant, antimicrobial, hemolytic, and antiproliferative properties of Leiothrix spiralis leaves extract. AB - The biological activities of a plant extract depend on a complex sum of individual properties including the antioxidant activity. Several biological activities protect against the harmful action of reactive oxygen species (ROS), and here we focused our attention on the relationship between the biological activities tested and the antioxidant properties. In this study, the total flavonoid content as well as the antioxidant, antimicrobial, hemolytic and cytotoxicity activities of the methanolic extract of Leitothrix spiralis leaves were evaluated. The extract showed a total flavonoid content of 19.26% and the chemical characterization by HPLC-PAD confirmed the presence of flavonoids as the major secondary metabolite compounds. Significant antioxidant activity (IC(50) = 1.743 MUg/mL +/- 0.063) was demonstrated and was effective against Gram-negative organisms and all Candida strains tested, and showed an ability to inhibit hyphal formation. Non-hemolytic and antiproliferative activity could be demonstrated. PMID- 22942766 TI - Activation of propane C-H and C-C bonds by gas-phase Pt atom: a theoretical study. AB - The reaction mechanism of the gas-phase Pt atom with C(3)H(8) has been systematically investigated on the singlet and triplet potential energy surfaces at CCSD(T)//BPW91/6-311++G(d, p), Lanl2dz level. Pt atom prefers the attack of primary over secondary C-H bonds in propane. For the Pt + C(3)H(8) reaction, the major and minor reaction channels lead to PtC(3)H(6) + H(2) and PtCH(2) + C(2)H(6), respectively, whereas the possibility to form products PtC(2)H(4) + CH(4) is so small that it can be neglected. The minimal energy reaction pathway for the formation of PtC(3)H(6) + H(2), involving one spin inversion, prefers to start at the triplet state and afterward proceed along the singlet state. The optimal C-C bond cleavages are assigned to C-H bond activation as the first step, followed by cleavage of a C-C bond. The C-H insertion intermediates are kinetically favored over the C-C insertion intermediates. From C-C to C-H oxidative insertion, the lowering of activation barrier is mainly caused by the more stabilizing transition state interaction DeltaE(?) (int), which is the actual interaction energy between the deformed reactants in the transition state. PMID- 22942768 TI - A theoretical study on reductive debromination of polybrominated diphenyl ethers. AB - Recent progress has been made in the reductive debromination of polybrominated diphenyl ethers (PBDEs) by nanoscale zero-valent iron (nZVI). To better understand the mechanism of this reaction, seven selected BDE congeners and their anions were investigated at the density functional theory (DFT) level using four different methods, including B3LYP/6-31G(d), B3LYP/6-31+G(d), B3LYP/6-31G(d,p) and B3LYP/6-311G(d,p). The cleaved C-Br bonds observed in the equilibrium structures of anionic PBDEs were adopted as the probe of the susceptible debromination position of PBDEs in the presence of nZVI, and the proposed major reaction pathways based on our calculations can satisfactorily conform to the reported experimental results. The debromination preference is theoretically evaluated as meta-Br > ortho-Br > para-Br. In addition, both the calculated frontier orbital energies and adiabatic electronic affinities were found to be highly related to their experimental reductive debromination rate constants. The highest linear regression coefficient was observed in the case using the energy of lowest unoccupied molecular orbital as the molecular descriptor obtained from B3LYP/6-31G(d) (R(2) = 0.961, n = 7) or B3LYP/6-31G(d,p) (R(2) = 0.961, n = 7). The results clearly showed the evidence of an electron transfer mechanism associated with this reductive debromination reaction. PMID- 22942769 TI - Molecular characterization and comparative sequence analysis of defense-related gene, Oryza rufipogon receptor-like protein kinase 1. AB - Many of the plant leucine rich repeat receptor-like kinases (LRR-RLKs) have been found to regulate signaling during plant defense processes. In this study, we selected and sequenced an LRR-RLK gene, designated as Oryza rufipogon receptor like protein kinase 1 (OrufRPK1), located within yield QTL yld1.1 from the wild rice Oryza rufipogon (accession IRGC105491). A 2055 bp coding region and two exons were identified. Southern blotting determined OrufRPK1 to be a single copy gene. Sequence comparison with cultivated rice orthologs (OsI219RPK1, OsI9311RPK1 and OsJNipponRPK1, respectively derived from O. sativa ssp. indica cv. MR219, O. sativa ssp. indica cv. 9311 and O. sativa ssp. japonica cv. Nipponbare) revealed the presence of 12 single nucleotide polymorphisms (SNPs) with five non synonymous substitutions, and 23 insertion/deletion sites. The biological role of the OrufRPK1 as a defense related LRR-RLK is proposed on the basis of cDNA sequence characterization, domain subfamily classification, structural prediction of extra cellular domains, cluster analysis and comparative gene expression. PMID- 22942770 TI - The apoptotic volume decrease is an upstream event of MAP kinase activation during Staurosporine-induced apoptosis in HeLa cells. AB - Persistent cell shrinkage, called apoptotic volume decrease (AVD), is a pivotal event of apoptosis. Activation of the volume-sensitive outwardly rectifying Cl(-) channel (VSOR) is involved in the AVD induction. On the other hand, activation of the MAP kinase (MAPK) cascade is also known to play a critical role in apoptosis. In the present study, we investigated the relationship between the AVD induction and the stress-responsive MAPK cascade activation during the apoptosis process induced by staurosporine (STS) in HeLa cells. STS was found to induce AVD within 2-5 min and phosphorylation of c-Jun N-terminal kinase (JNK) and p38 MAPK after over 20-30 min. VSOR blockers suppressed not only STS-induced AVD but also phosphorylation of JNK and p38 as well as activation of caspase-3/7. Moreover, a p38 inhibitor, SB203580, and a JNK inhibitor, SP600125, failed to affect STS induced AVD, whereas these compounds reduced STS-induced activation of caspase 3/7. Also, treatment with ASK1-specific siRNA suppressed STS-induced caspase-3/7 activation without affecting the AVD induction. Furthermore, sustained osmotic cell shrinkage per se was found to trigger phosphorylation of JNK and p38, caspase activation, and cell death. Thus, it is suggested that activation of p38 and JNK is a downstream event of AVD for the STS-induced apoptosis of HeLa cells. PMID- 22942772 TI - Family Life and Developmental Idealism in Yazd, Iran. AB - BACKGROUND: This paper is motivated by the theory that developmental idealism has been disseminated globally and has become an international force for family and demographic change. Developmental idealism is a set of cultural beliefs and values about development and how development relates to family and demographic behavior. It holds that modern societies are causal forces producing modern families, that modern families help to produce modern societies, and that modern family change is to be expected. OBJECTIVE: We examine the extent to which developmental idealism has been disseminated in Iran. We also investigate predictors of the dissemination of developmental idealism. METHODS: We use survey data collected in 2007 from a sample of women in Yazd, a city in Iran. We examine the distribution of developmental idealism in the sample and the multivariate predictors of developmental idealism. RESULTS: We find considerable support for the expectation that many elements of developmental idealism have been widely disseminated. Statistically significant majorities associate development with particular family attributes, believe that development causes change in families, believe that fertility reductions and age-at-marriage increases help foster development, and perceive family trends in Iran headed toward modernity. As predicted, parental education, respondent education, and income affect adherence to developmental idealism. CONCLUSIONS: Developmental idealism has been widely disseminated in Yazd, Iran and is related to social and demographic factors in predicted ways. COMMENTS: Although our data come from only one city, we expect that developmental idealism has been widely distributed in Iran, with important implications for family and demographic behavior. PMID- 22942773 TI - The Conundrum of PET/MR. PMID- 22942767 TI - The immunomodulatory and neuroprotective effects of mesenchymal stem cells (MSCs) in experimental autoimmune encephalomyelitis (EAE): a model of multiple sclerosis (MS). AB - Mesenchymal stem cells (MSCs) are multipotent cells that differentiate into the mesenchymal lineages of adipocytes, osteocytes and chondrocytes. MSCs can also transdifferentiate and thereby cross lineage barriers, differentiating for example into neurons under certain experimental conditions. MSCs have anti proliferative, anti-inflammatory and anti-apoptotic effects on neurons. Therefore, MSCs were tested in experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS), for their effectiveness in modulating the pathogenic process in EAE to develop effective therapies for MS. The data in the literature have shown that MSCs can inhibit the functions of autoreactive T cells in EAE and that this immunomodulation can be neuroprotective. In addition, MSCs can rescue neural cells via a mechanism that is mediated by soluble factors, which provide a suitable environment for neuron regeneration, remyelination and cerebral blood flow improvement. In this review, we discuss the effectiveness of MSCs in modulating the immunopathogenic process and in providing neuroprotection in EAE. PMID- 22942771 TI - Secretome survey of human plexiform neurofibroma derived Schwann Cells reveals a secreted form of the RARRES1 protein. AB - To bring insights into neurofibroma biochemistry, a comprehensive secretome analysis was performed on cultured human primary Schwann cells isolated from surgically resected plexiform neurofibroma and from normal nerve tissue. Using a combination of SDS-PAGE and high precision LC-MS/MS, 907 proteins were confidently identified in the conditioned media of Schwann cell cultures combined. Label free proteome profiling revealed consistent release of high levels of 22 proteins by the four biological replicates of NF1 Schwann cell cultures relative to the two normal Schwann cell cultures. Inversely, 9 proteins displayed decreased levels in the conditioned media of NF1 relative to normal Schwann cells. The proteins with increased levels included proteins involved in cell growth, angiogenesis and complement pathway while proteins with decreased levels included those involved in cell adhesion, plasminogen pathway and extracellular matrix remodeling. Retinoic acid receptor responder protein-1 (RARRES1), previously described as an integral membrane tumor suppressor, was found exclusively secreted by NF1 Schwann cells but not by normal Schwann cells. All-trans retinoic acid modulated secretion of RARRES1 in a dose dependent manner. This study shows altered secretion of key proteins in NF1 derived Schwann cells. The potential implication of these proteins in neurofibroma biology is discussed. PMID- 22942774 TI - Pituitary incidentalomas detected with technetium-99m MIBI in patients with suspected parathyroid adenoma: preliminary results. AB - Tc-99m MIBI (MIBI) is a cationic lipophilic agent, which has traditionally been used for myocardial perfusion scintigraphy, detection and monitoring of different benign and malignant tumors. The objective of this study was to evaluate the frequency of pituitary incidentalomas detected on MIBI scans performed on patients with suspected parathyroid adenomas and to provide semiquantitative analysis of tracer uptake in the pituitary region. Tomographic images of MIBI scans on 56 patients with suspected parathyroid adenomas (2006-2007) were analyzed retrospectively. Semiquantitative analysis of abnormal uptake was performed by drawing identical regions of interest (ROI) over the pituitary area and the normal brain on one transverse section that demonstrates the lesion most clearly. Pituitary uptake to normal brain uptake ratio was calculated in all cases. We found statistically significant differences of MIBI uptake in patients with pituitary adenomas, mean ratio: 29.78+/-12.17 (median 29.77, and range 19 41), compared with patients with no pathologic changes in this region, mean ratio was 5.88+/-1.82 (median was 5.95 and range 2.0- 9.2). As the groups are too small for statistical analysis, these results need to be confirmed in a larger cohort and should include more detailed biochemical correlation. MIBI parathyroid scintigraphy should be taken into account as a potential source of identifying pituitary incidentalomas. Clinical significance of these findings needs further evaluation. PMID- 22942776 TI - BioChroma - A New and Patented Technology for Processing Radioactive Wastewater from Nuclear Medicine Therapy Facilities in Hospitals and Clinics. AB - After undergoing radionuclide therapy, patients generate wastewater with a considerable amount of radioactivity, which can reach levels of as much as 90% of the administered dose. Due to the risk of accumulation after discharge into the sewer, it is advisable to collect this effluent for its treatment prior to final discharge. Delay and decay (natural decomposition of the isotope) is the most commonly used technical method of abating radioactive iodine, but it is frequently criticized as being complex and very expensive. BioChroma is a technology that has been developed as an alternative to these complicated and expensive systems. This paper describes this new technology and presents, as an example, a system that was installed and successfully commissioned in the middle of 2008 in a nuclear medicine ward with 12 beds in Stuttgart (Germany). Based on existing legislation, the responsible authorities and the company that operated the hospital agreed on a maximum activity level of 5 Bq/l. If a typical delay and decay system would have been installed, the 180 m(3) treatment plant that was already available in the hospital cellar would have to be extended by additional 150 m(3). By implementing the patented BioChroma process, the space requirements were reduced by 75%. For instance, since the new system was integrated into the existing installation, tanks accounting for 120 m3 could be used as buffering volume in the new wastewater treatment plant. The operation of the referred plant is currently producing very good results with values below the specified limit of 5 Bq/l for the isotope (131)I. In addition, (90)Y has been reported to be eliminated at the same time. Over the past 2 years of operation, the wastewater treatment plant has been able to achieve a maximum processing capacity of more than 2,000 l/day, which equates to a nuclear medicine ward with approx. 20 beds. The highest level recorded during the test period (of 180 days after start-up) was a peak of nearly 2,800 l/day. PMID- 22942775 TI - Radioiodine thyroid ablation in graves' hyperthyroidism: merits and pitfalls. AB - Ablative approaches using radioiodine are increasingly proposed for the treatment of Graves' disease (GD) but their ophthalmologic and biological autoimmune responses remain controversial and data concerning clinical and biochemical outcomes are limited. The aim of this study was to evaluate thyroid function, TSH receptor antibodies (TRAb) and Graves' ophthalmopathy (GO) occurrence after radioiodine thyroid ablation in GD. We reviewed 162 patients treated for GD by iodine-131 ((131)I) with doses ranging from 370 to 740 MBq, adjusted to thyroid uptake and sex, over a 6-year period in a tertiary referral center. Collected data were compared for outcomes, including effectiveness of radioiodine therapy (RIT) as primary endpoint, evolution of TRAb, and occurrence of GO as secondary endpoints. The success rate was 88.3% within the first 6 months after the treatment. The RIT failure was increased in the presence of goiter (adjusted odds ratio = 4.1, 95% confidence interval 1.4-12.0, P = 0.010). The TRAb values regressed with time (r = -0.147; P = 0.042) and patients with a favorable outcome had a lower TRAb value (6.5 +/- 16.4 U/L) than those with treatment failure (23.7 +/- 24.2 U/L, P < 0.001). At the final status, 48.1% of patients achieved normalization of serum TRAb. GO occurred for the first time in 5 patients (3.7%) who were successfully cured for hyperthyroidism but developed early and prolonged period of hypothyroidism in the context of antithyroid drugs (ATD) intolerance (P = 0.003) and high TRAb level (P = 0.012). On the basis the results of this study we conclude that ablative RIT is effective in eradicating Graves' hyperthyroidism but may be accompanied by GO occurrence, particularly in patients with early hypothyroidism and high pretreatment TRAb and/or ATD intolerance. In these patients, we recommend an early introduction of LT4 to reduce the duration and the degree of the radioiodine-induced hypothyroidism. PMID- 22942777 TI - Fluorodeoxyglucose PET-CT Findings Following Bone Marrow Harvesting. AB - Two patients demonstrated an unusual pattern of intense bone and surrounding soft tissue hypermetabolic uptake in the posterior pelvis on fluorodeoxyglucose positron emission tomography with computed tomography PET-CT scans. After further investigation, we found that both patients underwent uncomplicated autologous bone marrow harvesting several weeks before imaging. These two cases illustrate a distinctive PET-CT appearance following bone marrow harvesting that the radiologist needs to recognize to not confuse the findings with metastatic disease. PMID- 22942778 TI - (18)F-FDG Positron Emission Tomography in Multifocal Pyomyositis. AB - (18)F-Fluoro-deoxyglucose-positron emission tomography/computed tomography findings in a case presenting with pyomyositis are presented in this report. PMID- 22942779 TI - Asymptomatic Distant Subcutaneous Metastases Detected by (18)F-FDG-PET/CT in a Patient with Breast Carcinoma. AB - Cutaneous metastases from internal malignancies are rare with a reported incidence between 0.7% and 10%. We report a case with distant skin and subcutaneous metastases in abdominal skin from breast cancer detected on (18)F fluoro-deoxyglucose-positron emission tomography/computed tomography imaging. PMID- 22942780 TI - Fluoro-deoxy-glucose Positron Emission Tomography/Computed Tomography Pattern in a Patient with Linitis Plastica of the Stomach Caused by Primary Signet Cell Adenocarcinoma. AB - We report the findings of [18F] fluoro-deoxy-glucose (FDG) positron emission tomography (PET) performed in a 67-year-old female with suspicion of gastric carcinoma. Intense FDG uptake was noted in the thickened gastric wall. Subsequent laparotomy showed diffuse involvement of the gastric wall by signet ring cell adenocarcinoma. This report highlights FDG PET/CT pattern in linitis plastica of the stomach caused by primary signet cell adenocarcinoma. PMID- 22942781 TI - A Rare Scenario of Stenosed Type IV Dual LAD with Normal Myocardial Perfusion Scan. AB - Dual left anterior descending artery (LAD) is a rare variation in the coronary artery anatomy having 4 different subtypes. We report a rare scenario of type IV dual LAD, with short LAD critical stenosis, compensated by a long LAD perfusing the same territory, which was missed on initial angiographic evaluation. Myocardial perfusion scan (MPS) of this patient showed preserved perfusion. A review of angiogram revealed this anomaly, indicating that a meticulous correlation of anatomic and functional modalities is necessary as it could change further management of patient. PMID- 22942782 TI - Post-treatment Assessment of Glioblastoma Multiforme: Imaging with Fluorodeoxyglucose, Sestamibi, and Choline. AB - Glioblastoma multiforme (GBM) is the most common primary brain tumor in adults, and is generally of poor prognosis. The post-treatment assessment of GBMs is a known diagnostic issue, with problems in the differentiation of viable remnant tumor and post-treatment inflammatory changes. We present a case where various molecular tracers (fluorodeoxyglucose, choline, and methoxyisobutylisonitrile) were used in the post-treatment assessment of a patient with histologically proven GBM. PMID- 22942783 TI - FDG PET/CT in Detection of Metastatic Involvement of Heart and Treatment Monitoring in Non-Hodgkin's Lymphoma. AB - Cardiac metastasis occurs in up to a quarter of patients with metastatic cancer and is seen most commonly in melanoma and lymphoma. Metastatic involvement of the heart and pericardium may go unrecognized until autopsy. We describe a patient of non-Hodgkin's lymphoma detected to have involvement of right atrium on F-18 FDG PET/CT and monitoring of response to chemotherapy. PMID- 22942785 TI - Mediastinal parathyroid adenoma and brown tumors. AB - In this report, we describe a rare case of brown tumor and mediastinal parathyroid adenoma. This report emphasizes the value of radionuclide scintigraphy in the setting of persistent disease following parathyroid surgery. PMID- 22942784 TI - Tako-tsubo syndrome: atypical nuclear medicine findings. AB - The Tako-Tsubo syndrome is a reversible form of an acute stress-related cardiomyopathy that was reported during the last decade. It typically presents with a constellation of symptoms, electrocardiographic changes, and elevated cardiac enzyme levels consistent with an acute coronary syndrome. However, when the patient undergoes cardiac angiography, left ventricular apical ballooning finding is seen, but no significant coronary artery stenosis. This balloon-like morphology, being the hallmark of this entity, can be detected by imaging. We present a case report of a patient who was admitted to our hospital and met all the diagnostic criteria of the Tako-Tsubo syndrome. Myocardial perfusion imaging (MPI) showed an anteroapical perfusion defect at rest, moderated systolic dysfunction, and intraventricular asynchrony all assessed by gated-SPECT phase analysis. Two months later, all MPI findings returned to normal parameters. PMID- 22942786 TI - Late Recurrences of Thyroid Carcinoma 24 Years after a Complete Remission: When Monitoring Should be Stopped? AB - Renal metastases from thyroid carcinoma are very rare, late recurrences of papillary thyroid carcinomas (PTC) are not reported in literature and there is no universal recommendation for optimum duration of follow-up of thyroid carcinoma. We present herein a case of late renal recurrence of follicular variant PTC (FV PTC). This study is a case report of renal metastasis revealing a late recurrence of FV-PTC. An 81-year-old woman with previously treated FV-PTC 24 years ago by total thyroidectomy, lymph nodes dissection and radioiodine therapy presented with sudden gross-hematuria. Computerized tomography scan (CT-scan) revealed a 70 mm right renal mass and histological diagnosis after nephrectomy demonstrated recurrence of FV-PTC with a positive thyroglobulin immunostaining. Despite of (131)I-radioiodine therapy postoperatively, the serum thyroglobulin (Tg) increased and positron emission tomography combined to CT-scan showed 4 years later, an abdominal lymph node and distant metastases. Now the patient is alive but her general condition is too poor for systemic adjuvant therapy. This case illustrates the need of prolonged follow-up after surgery of high-risk FV-PTC. PMID- 22942788 TI - SeqTrace: a graphical tool for rapidly processing DNA sequencing chromatograms. AB - Modern applications of Sanger DNA sequencing often require converting a large number of chromatogram trace files into high-quality DNA sequences for downstream analyses. Relatively few nonproprietary software tools are available to assist with this process. SeqTrace is a new, free, and open-source software application that is designed to automate the entire workflow by facilitating easy batch processing of large numbers of trace files. SeqTrace can identify, align, and compute consensus sequences from matching forward and reverse traces, filter low quality base calls, and end-trim finished sequences. The software features a graphical interface that includes a full-featured chromatogram viewer and sequence editor. SeqTrace runs on most popular operating systems and is freely available, along with supporting documentation, at http://seqtrace.googlecode.com/. PMID- 22942787 TI - Nanoinformatics: developing new computing applications for nanomedicine. AB - Nanoinformatics has recently emerged to address the need of computing applications at the nano level. In this regard, the authors have participated in various initiatives to identify its concepts, foundations and challenges. While nanomaterials open up the possibility for developing new devices in many industrial and scientific areas, they also offer breakthrough perspectives for the prevention, diagnosis and treatment of diseases. In this paper, we analyze the different aspects of nanoinformatics and suggest five research topics to help catalyze new research and development in the area, particularly focused on nanomedicine. We also encompass the use of informatics to further the biological and clinical applications of basic research in nanoscience and nanotechnology, and the related concept of an extended "nanotype" to coalesce information related to nanoparticles. We suggest how nanoinformatics could accelerate developments in nanomedicine, similarly to what happened with the Human Genome and other -omics projects, on issues like exchanging modeling and simulation methods and tools, linking toxicity information to clinical and personal databases or developing new approaches for scientific ontologies, among many others. PMID- 22942789 TI - MIRG Survey 2011: snapshot of rapidly evolving label-free technologies used for characterizing molecular interactions. AB - The field of label-free biophysical technologies used to quantitatively characterize macromolecular interactions with each other and with small molecules has grown enormously in the last 10 years. The most widely used analytical technologies for characterizing biomolecular interactions are surface plasmon resonance (SPR), isothermal titration calorimetry (ITC), biolayer interferometry (BLI), and analytical ultracentrifugation (AUC). Measuring interaction parameters accurately and quantitatively is challenging, as it requires specialized expertise, training, and instrumentation. The Molecular Interaction Research Group (MIRG) conducted an online survey designed to capture the current profile of label-free technologies, including ITC, SPR, and other biosensors used in academia and the pharmaceutical industry sector. The main goal of the survey was to take a snapshot of laboratory, instrumentation, applications for measuring various biophysical parameters, confidence in data interpretation, data validation and acceptability, and limitations of using various technologies. Through this survey, we anticipate that the participating laboratories will be able to gauge their own capabilities and gain insights into the relative success of the different technologies that they use for characterizing molecular interactions. PMID- 22942790 TI - ABRF-MIRG benchmark study: molecular interactions in a three-component system. AB - Protein-protein interactions identified through high-throughput proteomics efforts continue to advance our understanding of the protein interactome. In addition to highly specific protein-protein interactions, it is becoming increasingly more common for yeast two-hybrid, pull-down assays, and other proteomics techniques to identify multiple protein ligands that bind to the same target protein. A resulting challenge is to accurately characterize the assembly of these multiprotein complexes and the competition among multiple protein ligands for a given target. The Association of Biomolecular Resource Facilities Molecular Interactions Research Group recently conducted a benchmark study to assess participants' ability to correctly describe the interactions between two protein ligands and their target protein using primarily biosensor technologies, such as surface plasmon resonance. Participants were provided with microgram quantities of three proteins (A, B, and C) and asked to determine if a ternary A B-C complex can form or if protein-B and protein-C bind competitively to protein A. This article will summarize the experimental approaches taken by participants to characterize the molecular interactions, the interpretation of the data, and the results obtained using different biosensor instruments. PMID- 22942792 TI - Craig a. Reickert, m.d. PMID- 22942793 TI - Uncommon colorectal neoplasms. PMID- 22942794 TI - Carcinoid and other neuroendocrine tumors of the colon and rectum. AB - Neuroendocrine tumors (NETs) are found throughout the intestinal tract and arise from the Kulchitsky cells located in the crypts of Lieberkuhn. They are classified by site of origin and by degree of differentiation, with well differentiated lesions representing those tumors formerly referred to as carcinoid tumors. The focus of this review is NETs of the appendix, colon, and rectum. The clinical presentation of these tumors is dependent on the primary site and many are discovered incidentally, either during screening or during the investigation of nonspecific abdominal complaints. Treatment is primarily via surgical removal as the response to chemotherapy has been traditionally poor. A noted exception to this has been with treatment of the carcinoid syndrome, which occurs almost exclusively in patients with liver metastases and is due to the release of bioactive peptides and amines directly into the systemic circulation. The use of somatostatin congeners to block the release of these substances has greatly ameliorated the devastating symptoms of this condition. Postresection follow-up is advocated, but specific recommendations are lacking an evidentiary basis. NETS, particularly those of the small bowel, colon, and appendix, are seen in association with other synchronous or metachronous malignancies, often of the gastrointestinal tract. However, the utility of subsequent screening and surveillance is unproven. PMID- 22942795 TI - Colorectal lymphoma. AB - Extranodal lymphomas account for a third of all cases of non-Hodgkin lymphoma with the gastrointestinal tract being the most common extranodal site. The most common location is the stomach followed by the small intestine, colon and rectum. Colorectal lymphomas are rare and comprise 10-20% of all gastrointestinal lymphomas and only 1% of all colorectal malignancies. Presenting symptoms include abdominal pain, weight loss, and anorexia. Diagnosis depends on the clinical setting with elective cases being diagnosed with colonoscopy and emergent cases being diagnosed in the operating room. Colonic lymphomas are frequently located proximal to the hepatic flexure. Management depends on the aggressiveness of the lymphoma subtype. Indolent tumors, which are resistant to standard chemotherapeutic regimens, are treated with surgical resection. Aggressive lymphoma subtypes are managed with chemotherapy and surgery with late-stage disease patients being referred to clinical trials. PMID- 22942796 TI - Epidermoid cancer of the anal canal. AB - Anal canal cancer is a rare cancer with incidence that continues to rise. This has been in large part due to increased prevalence of immunosuppressed conditions such as organ transplantation and human immunodeficiency virus along with transmission of the human papillomavirus. Identification of high-risk groups and close monitoring of these groups can help to detect earlier stages of cancer. Chemoradiation therapy remains the mainstay of treatment with excellent outcomes. Surgery for anal canal carcinoma remains as a salvage technique for failed chemoradiation or recurrent disease. PMID- 22942797 TI - Retrorectal tumors. AB - Tumors that arise in the retrorectal (presacral) space are uncommon lesions that present with nonspecific signs and symptoms, which lead to difficult diagnoses. For complete evaluation of the lesion, cross-sectional imaging is required to determine the extent of resection and the appropriate surgical approach. Surgical removal leads to favorable outcomes for patients with benign purely cystic retrorectal tumors. Preoperative tissue diagnosis with transperineal and transsacral biopsies of solid or heterogeneous cystic lesions, are essential to determine the necessity of neoadjuvant therapy, which may decrease local recurrence after surgery and avoid an unnecessary delay in systemic therapy. PMID- 22942798 TI - Gastrointestinal tumors of the colon and rectum. AB - Gastrointestinal stromal tumors (GISTs) of the colon and rectum are the most common mesenchymal tumors of the gastrointestinal tract. GISTs of the colon and rectum constitute ~5% of all cases. Although colorectal GISTs can be small and found incidentally, the majority appear to be high risk and carry a significant likelihood of recurrent and metastatic disease. Surgery remains the mainstay of treatment for primary disease. There is now considerable interest in GISTs because they can be treated effectively with targeted molecular therapies, specifically tyrosine kinase inhibitors (TKIs), such as imatinib mesylate and sunitinib malate. GISTs are best treated by a multidisciplinary team comprised of the surgeon, medical oncologist, pathologist, and radiologist in the initial evaluation, management, and in continued follow-up. Increasing the number of resectable cases through pharmacologic debulking, optimizing the timing of surgery and organ preservation, reducing recurrence and surgical morbidity, prolonging survival, and possibly enhancing response to imatinib through surgical cytoreduction are all potential benefits of multidisciplinary management. PMID- 22942799 TI - Anorectal melanoma. AB - Anorectal melanoma is a disease that can be difficult to diagnose because of its unclear presentation. After diagnosis, the main treatment available is surgical resection. Sentinel lymph node mapping has an unclear role in its management. Adjuvant therapy has long been recommended; however, there are no strong data to support its use. Prognostic factors to help gauge survival are also not clear; nevertheless, there is a strong association between stage of disease and histologic perineal invasion. Anorectal melanoma is a very rare disease with a dismal prognosis. PMID- 22942801 TI - GI-Associated Hemangiomas and Vascular Malformations. AB - Hemangiomas and vascular malformations of the gastrointestinal tract, rare clinical entities, present as overt or occult bleeding. They can be distributed throughout the intestinal digestive system, or present as a singular cavernous hemangioma or malformation, which is often located in the rectosigmoid region. Misdiagnosis is common despite characteristic radiographic features such as radiolucent phleboliths on plain film imaging and a purplish nodule on endoscopy. Adjunctive imaging such as computed tomography and magnetic resonance imaging are suggested as there is potential for local invasion. Endorectal ultrasound with Doppler has also been found to be useful in some instances. Surgical resection is the mainstay of treatment, with an emphasis on sphincter preservation. Nonsurgical endoscopic treatment with banding and sclerotherapy has been reported with success, especially in instances where an extensive resection is not feasible. PMID- 22942802 TI - Perceptions of Health and Relationships to Disability Measures among People with Multiple Sclerosis. AB - Researchers use various measures to assess health status, impairment, functional limitations, and disability among people with Multiple Sclerosis. However, conceptually and empirically relationships among measures are not always clear. The purpose of this study was to examine the relationships among measures of impairment, disability, functional status and health related outcomes within a sample of 443 individuals with MS. A secondary purpose was to compare the reported health status of this sample to the health status of a population-based sample of individuals with and without disabilities. While both the MS sample and a population-based sample of individuals with activities limitations indicated poorer health than did their non-disabled counterparts, the MS sample reported more days in the past month when physical and mental health was not good and more days when poor health kept them from usual activities than the population-based sample of individuals with disabilities. Most measures were moderately intercorrelated, but the pattern suggests that issues such as the time period specified may affect the relationships. Researchers are advised to carefully consider operational as well as conceptual definitions, length of proposed measures, and appropriate time frame, as well as more traditional criteria of reliability and validity when selecting study measures. PMID- 22942800 TI - Premalignant lesions of the anal canal and squamous cell carcinoma of the anal canal. AB - Squamous cell carcinoma of the anus (SCCA) is a rare tumor. However, its incidence has been increasing in men and women over the past 25 years worldwide. Risk factors associated with this cancer are those behaviors that predispose individuals to human papillomavirus (HPV) infection and immunosuppression. Anal cancer is generally preceded by high-grade anal intraepithelial neoplasia (HGAIN), which is most prevalent in human immunodeficiency virus-positive men who have sex with men. High-risk patients may benefit from screening. The most common presentation is rectal bleeding, which is present in nearly 50% of patients. Twenty percent of patients have no symptoms at the time of presentation. Clinical staging of anal cancer requires a digital rectal exam and a positron emission tomography/computed tomography scan of the chest, abdomen, and pelvis. Endorectal/endoanal ultrasound appears to add more-specific staging information when compared with digital rectal examination alone. Treatment of anal cancer prior to the 1970s involved an abdominoperineal resection. However, the current standard of care for localized anal cancer is concurrent chemoradiation therapy, primarily because of its sphincter-saving and colostomy-sparing potential. Studies have addressed alternative chemoradiation regimens to improve the standard protocol of fluorouracil, misogynic, and radiation, but no alternative regimen has proven superior. Surgery is reserved for those patients with residual disease or recurrence. PMID- 22942803 TI - Barriers and Facilitators to Breast Cancer Screening: A Qualitative Study of Women with Multiple Sclerosis. AB - PURPOSE: Recent literature indicates that women with various types of chronic disabling conditions are less likely to participate in routine breast cancer screening compared to those without disabling conditions. The purpose of this study is to identify the barriers and facilitators related to breast cancer screening among women with MS. METHODS: After receiving approval from the IRB, a semi-structured interview in a private setting was conducted with 36 women with MS, whose mean age was 55. Interviews were audio-taped and transcribed verbatim. The interview questions informed by the Health Belief Model, addressed knowledge, experience, barriers and facilitators related to breast cancer screening. Qualitative descriptive techniques were used to analyze the data. The majority of the women in the sample were White, 67% were married, 47% had at least a bachelor's degree and about 31% were unemployed due to their disability. FINDINGS: Findings show that 70% of these women had received annual mammograms and 50% had performed monthly breast self-exams. Of the women who had not received mammograms, most (80%) had mobility limitations. Some of the women in this study described various environmental and intrapersonal barriers to breast cancer screening. Among these were barriers related to transportation, difficulty in positioning for the exam, health care provider attitudes, not remembering, fear, discomfort, and "having enough to handle." Facilitators included annual reminders and helpful health care providers. PMID- 22942804 TI - Five pieces of silver. PMID- 22942805 TI - Prevalence of Delayed Nausea and/or Vomiting in Patients Treated With Oxaliplatin Based Regimens for Colorectal Cancer. AB - PURPOSE: To measure the prevalence of nausea and vomiting 2 to 5 days after oxaliplatin-based chemotherapy. PATIENTS AND METHODS: Sixty-four patients (55% men; 44% women) enrolled onto this cross-sectional study. Fifty-three (83%) had colon cancer and received oxaliplatin biweekly. Eleven (17%) had rectal cancer and received oxaliplatin weekly. We collected data on 23 patients for the first cycle and on 41 patients for the first two cycles, for a total of 105 cycles. Nausea and vomiting was graded using Common Toxicity Criteria. Patients maintained a 7-day postinfusion diary of nausea and vomiting and antiemetic use. RESULTS: All patients received antiemetics and steroids on day 1 of each cycle. For patients with data collected for both cycles, the occurrence of nausea was the same during cycles one and two. Thirty-nine percent used rescue antiemetics in cycle one, and 34% did so in cycle two. Sixty-eight percent of men reported no nausea in cycle one compared with 33% of women; for cycle two, these figures were 67% and 36%, respectively. Eighty-nine percent of patients reported no vomiting in cycle one, and 85% did so in cycle two. Seven patients (11%) had a history of motion sickness; 13 of 28 women (46%) reported history of pregnancy-induced morning sickness. Palonosetron slightly but significantly reduced the occurrence of nausea. Female sex and history of chemotherapy were significant risk factors for nausea. CONCLUSION: Delayed nausea associated with oxaliplatin was well controlled and evenly divided between grades 1 and 2; vomiting was rare. Factors associated with nausea were intrinsic to the patient and mostly unrelated to the antiemetics used. Sex and previous experience with emesis should be considered for efficient antiemetic management. PMID- 22942806 TI - Rapid-infusion rituximab in lymphoma treatment: 2-year experience in a single institution. AB - PURPOSE: Rituximab is a chimeric anti-CD20 monoclonal antibody. We aimed to explore the safety and tolerability of rapid infusion rituximab, (over 90 minutes) in patients with non-Hodgkin's lymphoma at Hacettepe University Department of Medical Oncology. PATIENTS AND METHODS: Adult patients diagnosed with non-Hodgkin's lymphoma who were to receive rituximab were included in the study. The schedule of administration for cycle 1 was unaltered and delivered according to the product monograph. All subsequent cycles were administered over a total infusion time of 90 minutes (20% of the dose in the first 30 minutes, then the remaining 80% over 60 minutes, total dose delivered in 500 mL). All patients were observed for infusion-related reactions during the rituximab infusion, and vital signs were recorded every 15 minutes. RESULTS: From July 2006 to December 2008, 75 patients with non-Hodgkin's lymphoma were treated with rituximab-based chemotherapy. A total of 372 infusions were administered. The majority of patients were treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone, or rituximab only. The 90-minute rituximab infusion schedule was well tolerated, with no grade 3 or 4 infusion related adverse events observed. CONCLUSION: A rapid infusion rituximab over 90 minutes is well tolerated and safe when administered as the second and subsequent infusions in the course of therapy. PMID- 22942807 TI - Effects of vaginal estrogens on serum estradiol levels in postmenopausal breast cancer survivors and women at risk of breast cancer taking an aromatase inhibitor or a selective estrogen receptor modulator. AB - BACKGROUND: Intravaginal estradiols (VE) have been proposed as safe alternatives to systemic estrogen therapy in breast cancer survivors. PATIENTS AND METHODS: Postmenopausal women with estrogen receptor-positive breast cancer or at high risk for breast cancer (n = 24) who were taking an aromatase inhibitor (AI) or a selective estrogen receptor modulator (SERM) and VE for >= 90 days for atrophic vaginitis and 24 controls taking AI only participated in the study. Serum samples were drawn from VE ring patients before insertion and 30 and 60 days postinsertion, from VE tablet patients the morning before insertion and approximately 12 hours postinsertion, and once from controls. Samples were assayed for E2 concentrations by using highly sensitive radioimmunoassay after ether extraction. RESULTS: Mean E2 levels in controls were 3.72 pmol/L (range, < 3.0-7.7 pmol/L); mean E2 levels preinsertion and 12 weeks postinsertion in the VE ring patients were significantly greater than controls (P < .001 for each comparison). Mean preinsertion E2 levels in patients using VE tablets were not significantly different than those of controls (P = .48), and postinsertion levels were 76 pmol/L higher than preinsertion (P < .001). CONCLUSION: VE treatment increased E2 levels. Preinsertion levels for patients receiving VE tablets were not elevated compared with those of controls, suggesting that E2 elevations with this preparation may not be continuously sustained. We conclude that VE treatment, regardless of type, results in elevated circulating E2 levels in this population and should be used with caution. PMID- 22942808 TI - Trends in neutropenia-related inpatient events. AB - PURPOSE: Neutropenic complications (NCs) after myelosuppressive chemotherapy are associated with significant morbidity and mortality. We described NC rates by using US hospital discharge data. MATERIALS AND METHODS: This cross-sectional analysis used data from the US National Inpatient Sample database. Hospital discharges with cancer diagnoses (International Classification of Diseases, Ninth Revision, Clinical Modification [ICD-9-CM] code) from 1989 to 2007 were analyzed for the ICD-9-CM neutropenia code. NC rates per 10,000 discharges were calculated for all adult discharges without radiation therapy (study population, all cancers); lung cancer, breast cancer, and non-Hodgkin's lymphoma (NHL); and all three combined. The use of growth factors and myelosuppressive chemotherapy from 1994 to 2008 was estimated by using the IMS Health Drug Distribution Database. RESULTS: Estimated lung cancer and breast cancer discharges remained relatively steady, whereas NHL discharges increased. NC rates for each study cancer increased two-fold until the late 1990s before stabilizing and/or declining. The average hospital stay for all three cancers decreased from 10.4 days to 7.1 days. The mortality rates for NCs for the three cancers combined decreased at a fairly constant rate from 10% in 1989 to 5.4% in 2007. Estimated discharges for NCs from 1989 to 2007 ranged from 111,000 to 169,000 for the study population, from 57,000 to 103,000 for all cancers, and from 21,000 to 40,000 for the three study cancers. The use of growth factors and myelosuppressive chemotherapy increased from 1994 to 2008. CONCLUSION: Whereas the number of hospitalizations with cancer diagnoses has remained steady since 1989, hospitalizations for NCs increased approximately two-fold from 1989 to 1997 and then stabilized. PMID- 22942809 TI - Uptake of oxaliplatin and bevacizumab for treatment of node-positive and metastatic colon cancer. AB - PURPOSE: In 2004, the US Food and Drug Administration approved bevacizumab and oxaliplatin for use in metastatic colon cancer and oxaliplatin for localized colon cancer. We investigated the diffusion and predictors of use of these medications in the year after approval. PATIENTS AND METHODS: We used the Surveillance, Epidemiology, and End Results-Medicare database to identify patients older than 65 years diagnosed with stages III and IV colon cancer in 2005. Characteristics of the treating oncologists were identified using the American Medical Association database. We used logistic regression and generalized estimating equations to analyze factors associated with bevacizumab and oxaliplatin use. RESULTS: Among 1,547 patients with stage III colon cancer who had claims submitted by oncologists, 801 (51.8%) received adjuvant chemotherapy, and of those, 432 (54.1%) received oxaliplatin, whereas 54 (6.7%) received off-label bevacizumab. Among 859 patients with stage IV disease who saw oncologists, 435 (50.6%) received chemotherapy, and of those, 310 (71.3%) received bevacizumab, 289 (66.4%) received oxaliplatin, and 357 (82.1%) received oxaliplatin and/or irinotecan. Older patient age and more comorbidities were associated with nonreceipt of oxaliplatin for stage III disease and oxaliplatin and/or irinotecan for stage IV disease. Having a physician who graduated medical school after 1975 predicted receipt of both adjuvant oxaliplatin (odds ratio [OR], 1.65; 95% CI, 1.11 to 2.45) and oxaliplatin and/or irinotecan for stage IV disease (OR, 2.43; 95% CI, 1.47 to 4.01). None of the factors analyzed predicted bevacizumab receipt. CONCLUSION: Uptake of new chemotherapy drugs for patients diagnosed with stages III and IV colon cancer in 2005 was rapid. Physician characteristics were consistently associated with this uptake. PMID- 22942810 TI - Daily life of a Turkish medical oncologist. AB - There are many changes occurring in the Turkish health care system, including but not limited to consolidation of public hospitals and administrative takeover of some university hospitals by the Ministry of Health. Because of its unique situation, Marmara University Hospital is at the center of these changes. The adaptation process will continue for another year or so, after which it is hoped that a better health care environment will have been created for patients with cancer in Turkey. PMID- 22942811 TI - Productivity assessment of physician assistants and nurse practitioners in oncology in an academic medical center. AB - PURPOSE: Demand for oncologists will increase dramatically over the next 15 years. Physician assistants (PAs) and Nurse practitioners (NPs) have been identified as one solution to meet the projected shortages in oncology. It has previously been reported that 56% of oncologists work with PAs and NPs, more than two thirds of whom believe it benefits their practice with some noted productivity advantages. The purpose of this study was to quantify the productivity of PAs and NPs working in oncology in an academic medical center. METHODS: A 2-week self-reported time study was performed in a single large academic medical center. Services were categorized as billable, bundled, care facilitation, administrative, and other based on time spent performing services in each category. Current procedural terminology codes were used to determine the economic value of services provided. RESULTS: A total of 54 PAs and NPs were included in the final analysis. PAs and NPs reported similar clinical activities. Overall, there was high variability noted in terms of productivity, notably with PA/NP direct billable revenue. Opportunities were identified to improve utilization of oncology PAs and NPs, with suggestions for future research related to PA and NP productivity tracking. CONCLUSION: Productivity measurement for PAs and NPs can be challenging. To our knowledge, this is the first study that quantifies PA and NP productivity in oncology according to known economic indicators such as charges and work relative value units. PMID- 22942812 TI - Trends in twitter use by physicians at the american society of clinical oncology annual meeting, 2010 and 2011. AB - PURPOSE: Social media channels such as Twitter are gaining increasing acceptance as mechanisms for instantaneous scientific dialogue. Professional medical societies such as ASCO are using social media to expand the reach of scientific communications at and around their scientific meetings. This article examines the how Twitter use by oncologists expanded at the ASCO Annual Meetings from 2010 to 2011. METHODS: In both years, tweets that were specifically generated by physicians and that incorporated the official meeting hashtag were harvested from the public domain, and a discourse analysis was performed by three independent raters. Follow-up surveys were conducted to assess physician attitudes toward Twitter and its potential role in clinical practice. RESULTS: A combined total of 12,644 tweets were analyzed for 2010 and 2011. Although the number of physicians authoring tweets was small (14 in 2010, 34 in 2011), this group generated nearly 29% of the total meeting dialogue examined in this analysis in 2010 and 23% in 2011. Physicians used Twitter for reporting clinical news from scientific sessions, for discussions of treatment issues, for promotion, and to provide social commentary. The tangible impact of Twitter discussions on clinical practice remains unclear. CONCLUSION: Despite the 140-character limit, Twitter was successfully used by physicians at the 2010 and 2011 ASCO Annual Meetings to engage in clinical discussions, whether or not an author was on site as a live attendee. Twitter usage grew significantly from 2010 to 2011. Professional societies should monitor these phenomena to enhance annual meeting attendee user experience. PMID- 22942813 TI - Effects of funding policy changes and health warnings on the use of erythropoiesis-stimulating agents. AB - PURPOSE: To characterize the effects of formulary changes and governmental safety warnings on use of erythropoiesis-stimulating agents (ESAs) in patients with cancer. PATIENTS AND METHODS: We conducted a cross-sectional time-series analysis using health administrative data from Ontario, Canada. From January 1997 to December 2009 we identified all ESA initiations among patients diagnosed with cancer. We explored the effects of two formulary changes that progressively liberalized coverage for ESAs, first by rescinding the requirement for blood transfusion in 2003 and then by removing all restrictions in 2007. We also explored the effect of US Food and Drug Administration and Health Canada warnings issued in the second quarter of 2007. To assess regional variability in ESA use, we determined prescription rates for each of Ontario's 14 regional cancer centers. RESULTS: After the first formulary change, the ESA initiation rate increased to 1.66 new users per 1,000 patients with cancer, 374% more than predicted (P < .001). After the second formulary change, the initiation rate increased to 3.97 new users per 1,000 patients with cancer, 73% more than predicted (P < .001). After the safety warnings, this rate declined 81% by study end (P < .001). We found significant regional variation in ESA use. CONCLUSION: Formulary access and safety warnings had significant impacts on the new use of ESA drugs in patients with cancer. This suggests that both are effective means of influencing the use of these drugs. Variable ESA prescription rates across our region may reflect a lack of consensus regarding their utility. PMID- 22942814 TI - Providing care for cancer survivors in integrated health care delivery systems: practices, challenges, and research opportunities. AB - PURPOSE: Optimal approaches to cancer survivorship care are needed. This study sought to identify practices, barriers, and research opportunities in meeting the care needs of cancer survivors in integrated health care delivery systems. METHODS: This study was conducted at 10 sites within the Cancer Research Network, a National Cancer Institute-funded consortium of integrated health care delivery systems providing care for nearly 11 million enrollees. We identified 48 clinical leaders, administrators, and providers in oncology, primary care, nursing administration, and specialty care. Forty (83%) completed semi-structured, audio recorded, transcribed telephone interviews, which we analyzed using an immersion crystallization approach. RESULTS: Respondents were aware of the needs of cancer survivors and the difficulties they face in transitioning from treatment to follow-up care. Respondents from all sites reported that oncology and primary care are jointly responsible for the care of cancer survivors, often through the use of electronic medical records. Many respondents were not familiar with standardized survivorship care plans. Only two sites had formal cancer survivorship programs in place, and two were developing such programs. Respondents at sites with and without programs acknowledged existing gaps in evidence on the effectiveness of formal survivorship care and expressed a desire for additional research. CONCLUSION: Our exploratory study suggests an awareness of cancer survivorship care in integrated health care delivery systems, although approaches to providing such care vary across systems. These settings may offer a unique opportunity to develop, test, and implement innovative models of care, which can be systematically evaluated to inform and enhance cancer survivorship care in diverse health care settings. PMID- 22942815 TI - Less than ideal: how oncologists practice with limited drug access. AB - PURPOSE: To evaluate Canadian medical oncologists' perspectives on how barriers to accessing new expensive cancer drugs have affected their practice and their opinions on the drug approval and funding processes. METHODS: Canadian medical oncologists treating colorectal cancer (CRC) were surveyed by means of a self administered, cross-sectional survey. RESULTS: Of the 164 eligible oncologists, there were 68 respondents (41.4% response rate). Only 29.4% of physicians felt they had been using the ideal first-line chemotherapy regimen for patients with metastatic CRC. Although all considered bevacizumab to be a component of the ideal first-line regimen, only 18% could use bevacizumab routinely, and less than half (44.8%) always discussed its role with their patients. In terms of accessing unfunded drugs, most physicians agreed that private payment should be allowed for drugs to be delivered at their own centers (76.1%) or private infusion clinics (52.2%). Ninety-seven percent of physicians reported major concerns about the drug approval and funding processes, and 85% of physicians supported the establishment of a national drug formulary. CONCLUSIONS: Canadian medical oncologists are struggling to provide optimal cancer care for their patients with metastatic CRC as a result of nonuniform access to preferred therapeutic drugs. In face of these challenges, physicians have had to use clinical trials and private infusion clinics and, at times, may avoid discussing drugs with limited access. Many oncologists are dissatisfied with the existing funding mechanism and approval processes and support private payment for unfunded drugs. PMID- 22942816 TI - Response to a treatment summary and care plan among adult survivors of pediatric and young adult cancer. AB - PURPOSE: Survivors of pediatric and young adult cancer are at increased risk for treatment-related problems. Yet, few survivors receive risk-based care. The treatment summary and care plan are recommended to improve understanding of cancer treatment, potential late effects, and recommended screening. It is unknown whether survivors retain, understand, value, and disseminate the document, and whether it causes worry. METHODS: We surveyed 111 adult survivors of pediatric and young adult cancer 1 to 6 weeks after receipt of a one-page treatment summary and care plan (response rate, 96%). Participants answered questions regarding retention, understanding, value, dissemination, concern, and preferences. RESULTS: Participants were majority female (58%), college-educated (60%), diagnosed with cancer before age 21 (76%), on average 18 years from diagnosis (range, 2 to 50 years), and treated with radiation and chemotherapy (61%). Median age was 30 years (range, 18 to 65 years). A majority of participants stated that they understood the treatment summary (95%), retained the document (95%), and valued it (92%). A minority reported that the document caused concern (14%) or wanted more information than the form provided (20%). Although the time between receipt of the document and survey was brief, many described dissemination of the document to their personal circle (44%) or an outside provider (10 [33%] of 30 who saw an outside doctor). CONCLUSION: A one page treatment summary and care plan was well-received and did not cause report of undue concern. Additional health-related information was requested by some, and dissemination to outside providers could be improved. PMID- 22942817 TI - Maintenance of certification: confession of a grandfather. PMID- 22942819 TI - Transformation. PMID- 22942818 TI - Effect of insurance status on the stage of breast and colorectal cancers in a safety-net hospital. AB - PURPOSE: Screening can increase early detection and reduce rates of advanced stage cancer. Uninsured patients have been shown to have lower rates of screening. Previous studies have shown that uninsured patients and patients with Medicaid present with more advanced stages of cancer. The aim of this study was to measure the effect of insurance status in the setting of a safety-net hospital. METHODS: Patients in our tumor registry with a diagnosis of breast or colorectal cancer between 2001 and 2010 were included. On the basis of their insurance status, they were divided into the following groups: Medicaid, Medicare, Medicare age < 65 years, commercial, uninsured, and unknown. Cancer stage was recorded for each patient, with stages III and IV considered advanced disease. The primary end point was the rate of advanced disease in each patient group. RESULTS: A total of 910 patients were included in the study: 836 (91.9%) insured, 54 (5.9%) uninsured, and 20 (2.2%) unknown. Of the insured patients, 301 (36.0%) had Medicaid. Two hundred thirty-seven (30.7%) of 836 insured patients had advanced disease, compared with 27 (50.0%) of 54 uninsured patients (odds ratio, 1.63; P = .003). Of patients with Medicaid, 83 (27.6%) of 301 had advanced disease, which was not statistically different from patients with other insurance. CONCLUSION: In a safety-net hospital, patients with Medicaid had rates of advanced-stage cancer similar to those in patients with other types of insurance. However, patients with no insurance had significantly higher rates of advanced disease. This has significant ramifications in view of the new health care law, which will convert many patients from being uninsured to having Medicaid. PMID- 22942820 TI - US Payer Perspectives on Evidence for Formulary Decision Making. AB - PURPOSE: The perspective of commercial payers on comparative effectiveness research (CER) has not been well researched. This study aims to describe how US commercial payers use and value CER for formulary decision making in different disease states. METHODS: We recruited 20 medical and pharmaceutical directors from national and regional plans who are involved in pharmaceutical and therapeutics committees to participate in the study. We conducted in-depth qualitative interviews with the payers and asked them to rate the usefulness of CER study types across various disease states and market conditions. The results were analyzed for thematic content. RESULTS: Our findings indicate that payers are interested in a broad range of CER study types, are unsatisfied with the current state of CER, and would like to partner with research groups to develop research and treatment guidelines to better leverage CER. Payers value CER less so in oncology than in other disease states because of limitations in their ability to manage oncology therapies. CONCLUSION: To improve formulary design processes and support payers in providing more effective health care, policy makers should consider involving commercial payers in the development of CER as well as in the creation of research and treatment guidelines. PMID- 22942821 TI - Evidence gaps in advanced cancer care: community-based clinicians' perspectives and priorities for comparative effectiveness research. AB - PURPOSE: Although much effort has focused on identifying national comparative effectiveness research (CER) priorities, little is known about the CER priorities of community-based practitioners treating patients with advanced cancer. CER priorities of managed-care-based clinicians may be valuable as reflections of both payer and provider research interests. METHODS: We conducted mixed methods interviews with 10 clinicians (five oncologists and five pharmacists) at five health plans within the Health Maintenance Organization Cancer Research Network. We asked, "What evidence do you most wish you had when treating patients with advanced cancer?" and questioned participants on their impressions and knowledge of CER and pragmatic clinical trials (PCTs). We conducted qualitative analyses to identify themes across interviews. RESULTS: Ninety percent of participants had heard of CER, 20% had heard of PCTs, and all rated CER/PCTs as highly relevant to patient and health plan decision making. Each participant offered between three and 10 research priorities. Half (49%) involved head-to-head treatment comparisons; another 20% involved comparing different schedules or dosing regimens of the same treatment. The majority included alternative outcomes to survival (eg, toxicity, quality of life, noninferiority). Participants cited several limitations to existing evidence including lack of generalizability, funding biases, and rapid development of new treatments. CONCLUSION: Head-to-head treatment comparisons remain a major evidence need among community-based oncology clinicians, and CER/PCTs are highly valued methods to address the limitations of traditional randomized trials, answer questions of cost-effectiveness or noninferiority, and inform data-driven dialogue and decision making by all stakeholders. PMID- 22942822 TI - Visit duration for outpatient physician office visits among patients with cancer. AB - PURPOSE: To examine the characteristics of patients with cancer and their visits to outpatient, office-based physicians; to analyze any differences between visits to oncologists and visits to other physicians; and to examine the effect of patient, practice, visit, and geographic characteristics on the length of time patients with cancer spend with physicians during office-based visits. METHODS: We examined a total of 2,470 patient office visits to nonfederally employed physicians from the 2006 and 2007 National Ambulatory Medical Care Survey. We performed descriptive analyses to examine the characteristics of patients with cancer by physician specialty. We conducted multivariate analyses using a generalized linear model to examine the relationship between visit duration and patient, practice, visit, and geographic characteristics. RESULTS: Forty-two percent of patients with cancer visited an oncologist. Females, females diagnosed with breast cancer, and individuals with advanced-stage cancer were more likely to visit an oncologist. Patients who visited oncologists were more likely to receive an anticancer drug, radiation therapy, and an increased number of diagnostic/screening services than those visiting other physicians. The mean duration of patient visits was 22.9 minutes. Higher percentages of performance based compensation and capitation rates were associated with visits 4.4 minutes and 5.7 minutes shorter, respectively. CONCLUSION: Higher use of performance based payment mechanisms and capitated arrangements are associated with a decrease in the amount of time physicians spend with their patients with cancer. It is unclear whether shorter visit times impact the quality of medical care provided or whether physicians in these settings have become more proficient in caring for their patients. PMID- 22942823 TI - Treating Anaplastic Lymphoma Kinase-Positive Lung Cancer in the Weeks After the US Food and Drug Administration Approval of Crizotinib. PMID- 22942824 TI - Partnering With a Payer to Develop a Value-Based Medical Home Pilot: A West Coast Practice's Experience. AB - The Wilshire Oncology Medical Group developed a medical oncology home pilot to offer a transparent, high-quality, high-value cancer program in partnership with its largest California health plan, Anthem Blue Cross WellPoint. PMID- 22942825 TI - Payer coverage for patients enrolled onto clinical trials: making the process easy and transparent for everyone. PMID- 22942826 TI - Oncology patient-centered medical home. AB - The oncology patient-centered medical home is a physician-driven, patient-focused value proposition that can make a difference for patients, oncologists, and the cost of health care. PMID- 22942827 TI - Patient Out-of-Pocket Payments for Oral Oncolytics: Results From a 2009 US Claims Data Analysis. AB - PURPOSE: Oral oncolytics are an increasingly important treatment option for cancer. These agents often fall within the pharmacy benefit, with the potential for increased out-of-pocket (OOP) cost burden for patients. The purpose of this study was to evaluate patient OOP payments for oral oncolytic therapies in US managed care plans. MATERIALS AND METHODS: Patients age >= 18 years who received one of 21 oral oncolytics were identified in 2009 US claims; the first oral therapy was the index therapy. OOP payments were calculated as the allowed amount (dollar amount a health plan allows for a therapy, including member liability) minus the paid amount (dollar amount paid by a health plan). Patient characteristics were provided, and per-claim OOP payments were evaluated for each of the 21 therapies in aggregate and stratified by payer type and index therapy. RESULTS: A total of 6,094 patients who received at least one oral oncolytic therapy were identified. Mean age was 53 years; 54% were women; 77% had a commercial payer; prevalent cancer diagnoses included breast, colorectal, glioblastoma, and lung. Mean OOP payments were highest for dasatinib ($527; median, $36) and lowest for cyclophosphamide ($15; median, $10). Medicare Risk patients had higher mean OOP payments for most therapies compared with commercial, Medicaid, and self-insured patients. CONCLUSION: Among 21 oral oncolytics, average OOP cost ranged from $15 to > $500. These results confirm previous findings showing OOP payments differing widely among oral oncolytic options. As cost for therapy becomes a greater part of treatment decisions, an understanding of patient OOP cost will be critical in informing choices. PMID- 22942828 TI - Guideline-Based Peer-to-Peer Consultation Optimizes Pegfilgrastim Use With No Adverse Clinical Consequences. AB - PURPOSE: Practice guidelines do not recommend the routine use of colony stimulating factors when there is a low risk (< 10%) of febrile neutropenia (FN). We prospectively determined whether expert peer-to-peer consultation with prescribing oncologists would improve adherence to guidelines and whether there would be any adverse events associated with that adherence. METHODS: Commencing in March 2010, we reviewed requests for pegfilgrastim from 22 community oncology practices comprising 78 physicians providing service to approximately 97,000 Medicare members. Paid claims data on all chemotherapy and supportive care medications were reviewed from fourth quarter (Q4) 2009 through third quarter (Q3) 2010. In total, 82 patients received pegfilgrastim. If the prescribed chemotherapy was associated with a low risk (< 10%) for FN, then a peer review was initiated. The treating physician made the final decision to use, or not use, pegfilgrastim, and no denials were issued. RESULTS: A total of 245 units (1 unit = 6 mg) of pegfilgrastim were administered during the four quarters analyzed. Use in the low-risk category decreased from 52 units in Q4 2009 to 15 units in Q3 2010. The per-member per-month (PMPM) cost of pegfilgrastim decreased across quarters, with an average cost of $1.07 PMPM for Q4 2009 and $0.57 PMPM for Q3 2010. No studied patient was admitted for neutropenic fever. CONCLUSION: Active expert peer-to-peer consultation with prescribing oncologists can promote adherence to guidelines and potentially lead to significant cost reductions without significant risk of neutropenic fever, with or without hospitalization, for patients with cancer. PMID- 22942829 TI - Infused chemotherapy use in the elderly after patent expiration. AB - PURPOSE: The use of anticancer drugs (chemotherapies) is an important determinant of national spending trends. Recent policies have aimed to accelerate generic entry among chemotherapies to generate cost savings. METHODS: We examined the effects of generic entry on the choice of chemotherapy for the treatment of metastatic colorectal cancer (MCRC) between 2006 and 2009 using autoregressive moving average modeling with case control. A nationally representative sample of oncologists and patients with cancer (age >= 65 years) was employed to estimate the magnitude and significance of the impact of the generic entry of irinotecan in February 2008 on the number of administrations of irinotecan compared with oxaliplatin. RESULTS: The generic entry of irinotecan resulted in a 17% to 19% decrease (P < .001) in use among elderly patients with MCRC compared with oxaliplatin. The results were robust to multiple sensitivity checks. CONCLUSION: This study provides novel and robust estimates of the decline in use of a chemotherapy to treat a common cancer in the elderly after patent expiration. The results suggest estimates from a previous Office of the Inspector General report of the potential savings derived from the generic entry of irinotecan for public payers are an overestimate, likely confounded by oncologists' response to financial incentives, changes in scientific evidence, and promotional activities. As calls for improving the quality and cost efficiency of oncology increase, future empirical work is needed to examine the responsiveness of oncologists' treatment decision making to incentives among patients of all ages and insurance types. PMID- 22942830 TI - Development of a multidisciplinary, multicampus subspecialty practice in endocrine cancers. AB - PURPOSE: Relative to more abundant neoplasms, endocrine cancers have been historically neglected, yet their incidence is increasing. We therefore sought to build interest in endocrine cancers, improve physician experience, and develop innovative approaches to treating patients with these neoplasms. METHODS: Between 2005 and 2010, we developed a multidisciplinary Endocrine Malignancies Disease Oriented Group involving all three Mayo Clinic campuses (Rochester, MN; Jacksonville, FL; and Scottsdale, AZ). In response to higher demand at the Rochester campus, we sought to develop a Subspecialty Tumor Group and an Endocrine Malignancies Tumor Clinic within the Division of Medical Oncology. RESULTS: The intended groups were successfully formed. We experienced difficulty in integration of the Mayo Scottsdale campus resulting from local uncertainty as to whether patient volumes would be sufficient to sustain the effort at that campus and difficulty in developing enthusiasm among clinicians otherwise engaged in a busy clinical practice. But these obstacles were ultimately overcome. In addition, with respect to the newly formed medical oncology subspecialty endocrine malignancies group, appointment volumes quadrupled within the first year and increased seven times within two years. The number of active therapeutic endocrine malignancies clinical trials also increased from one in 2005 to five in 2009, with all three Mayo campuses participating. CONCLUSION: The development of subspecialty tumor groups for uncommon malignancies represents an effective approach to building experience, increasing patient volumes and referrals, and fostering development of increased therapeutic options and clinical trials for patients afflicted with otherwise historically neglected cancers. PMID- 22942831 TI - Influence of patient preferences on the cost-effectiveness of screening for lynch syndrome. AB - PURPOSE: Patients and relatives have varying preferences for genetic testing and interventions related to hereditary cancer syndromes. We examined how the impact of these services on quality of life (QoL) affects the cost-effectiveness of screening for Lynch syndrome among probands newly diagnosed with colorectal cancer and their relatives. METHODS: We constructed a state-transition model comparing screening strategies (clinical criteria, prediction algorithms, tumor testing, and upfront germline testing) with no screening to identify Lynch syndrome. The model incorporated individuals' health state utilities after screening, germline testing, and risk-reducing surgeries, with utilities persisting for 12 months in the base case. Outcomes consisted of quality-adjusted life-years (QALYs), costs, and cost per QALY gained. Sensitivity analyses assessed how the duration and magnitude of changes in QoL influenced results. RESULTS: Multiple screening strategies yielded gains in QALYs at acceptable costs compared with no screening. The preferred strategy-immunohistochemistry of tumors followed by BRAF mutation testing (IHC/BRAF)-cost $59,700 per QALY gained in the base case. The duration and magnitude of decreases in QoL after decisions related to germline testing and surgeries were key determinants of the cost-effectiveness of screening. IHC/BRAF cost > $100,000 per QALY gained when decrements to QoL persisted for 21 months. CONCLUSION: Screening for Lynch syndrome in the population is likely to yield long-term gains in life expectancy that outweigh any short-term decreases in QoL, at acceptable costs. Counseling for individuals should aim to mitigate potential negative impact of genetic testing and risk reducing interventions on QoL. PMID- 22942832 TI - Cost-effectiveness analysis of stereotactic body radiation therapy versus intensity-modulated radiation therapy: an emerging initial radiation treatment option for organ-confined prostate cancer. AB - PURPOSE: The purpose of this study is to compare the cost-effectiveness of two external beam radiation therapy techniques for treatment of low- to intermediate risk prostate cancer: stereotactic body radiation therapy (SBRT) and intensity modulated radiation therapy (IMRT). MATERIALS AND METHODS: A Markov decision analysis model with probabilistic sensitivity analysis was designed with the various disease states of a 70-year-old patient with organ-confined prostate cancer to evaluate the cost-effectiveness of two external beam radiation treatment options. RESULTS: The Monte Carlo simulation revealed that the mean cost and quality-adjusted life-years (QALYs) for SBRT and IMRT were $22,152 and 7.9 years and $35,431 and 7.9 years, respectively. The sensitivity analysis revealed that if the SBRT cohort experienced a decrease in quality of life of 4% or a decrease in efficacy of 6%, then SBRT would no longer dominate IMRT in cost effectiveness. In fact, with these relaxed assumptions for SBRT, the incremental cost-effectiveness ratio of IMRT met the societal willingness to pay threshold of $50,000 per QALY. CONCLUSION: Compared with IMRT, SBRT for low- to intermediate risk prostate cancer has great potential cost savings for our health care system payers and may improve access to radiation, increase patient convenience, and boost quality of life for patients. Our model suggests that the incremental cost effectiveness ratio of IMRT compared with SBRT is highly sensitive to quality-of life outcomes, which should be adequately and comparably measured in current and future prostate SBRT studies. PMID- 22942833 TI - Implementation of cancer clinical care pathways: a successful model of collaboration between payers and providers. AB - Despite rising medical costs within the US health care system, quality and outcomes are not improving. Without significant policy reform, the cost-quality imbalance will reach unsustainable proportions in the foreseeable future. The rising cost of health care in part results from an expanding aging population with an increasing number of life-threatening diseases. This is further compounded by a growing arsenal of high-cost therapies. In no medical specialty is this more apparent than in the area of oncology. Numerous attempts to reduce costs have been attempted, often with limited benefit and brief duration. Because physicians directly or indirectly control or influence the majority of medical care costs, physician behavioral changes must occur to bend the health care cost curve in a sustainable fashion. Experts within academia, health policy, and business agree that a significant paradigm change in stakeholder collaboration will be necessary to accomplish behavioral change. Such a collaboration has been pioneered by Blue Cross Blue Shield of Michigan and Physician Resource Management, a highly specialized oncology health care consulting firm with developmental and ongoing technical, analytic, and consultative support from Cardinal Health Specialty Solutions, a division of Cardinal Health. We describe a successful statewide collaboration between payers and providers to create a cancer clinical care pathways program. We show that aligned stakeholder incentives can drive high levels of provider participation and compliance in the pathways that lead to physician behavioral changes. In addition, claims-based data can be collected, analyzed, and used to create and maintain such a program. PMID- 22942834 TI - Impact of payment reform on chemotherapy at the end of life. AB - PURPOSE: To assess the impact of 2005 and 2006 reductions in chemotherapy reimbursement, mandated in the Medicare Modernization Act, on patterns of chemotherapy receipt in the last 14 days of life. PATIENTS AND METHODS: Included in the study were Medicare beneficiaries dying with poor-prognosis cancer from 2003 to 2007. We compared pre- and postreform probability and frequency of chemotherapy receipt in the last 14 days of life, a validated quality measure, using linear models. We assessed changes in chemotherapy use in physician offices (where prescribing is often directly linked to physician income) and hospital outpatient departments (where the link is indirect and likely weaker). RESULTS: Among patients receiving chemotherapy in the 6 months before death in physicians' offices before the policy implementation (2003 to 2004), 18% received chemotherapy in the last 14 days of life. Those dying after implementation (2006 to 2007) were 3.5 percentage points (95% CI, -5.4 to -1.6; P < .001), or 20%, less likely to receive chemotherapy in the 14 days before death than those dying before implementation. By contrast, there was no significant change in the percentage of patients receiving chemotherapy in the last 14 days of life in hospital outpatient departments between 2003 and 2004 and 2006 to 2007. CONCLUSION: In physician offices, where drugs generate the majority of revenue and prescribing patterns can determine physician income, use of chemotherapy at the end of life fell significantly after reimbursement reductions; no concurrent change occurred in hospital outpatient departments. These results suggest that payment reform may be used to better align appropriate financial incentives with better quality of care. PMID- 22942835 TI - A case series evaluating the accuracy of manual muscle testing for predicting fetal sex. AB - OBJECTIVE: The purpose of this study was to evaluate if manual muscle testing (MMT) could identify fetal sex in women who did not know the sex of their babies. The null hypothesis was that MMT is no more accurate than chance. METHODS: A prospective case series of 27 sequential pregnant patients who did not know the sex of their fetus were included in this study. The examiner was also blind to the sex of the fetus. Manual muscle testing was evaluated after the mother stated "I am having a boy." Likelihood ratios, specificity, sensitivity, positive predictive value, and negative predictive value were calculated. RESULTS: Fourteen girl babies and 13 boy babies were born. Manual muscle testing accurately predicted the sex 13 times. The positive likelihood ratio was 0.92 (95% confidence interval, 0.42-2.03), sensitivity was 0.40, specificity was 0.54, positive predictive value was 0.46, and negative predictive value was 0.44. CONCLUSION: Manual muscle testing was no better than chance at predicting fetal sex in this case series. PMID- 22942836 TI - Chiropractic management of a patient with lumbar spine pain due to synovial cyst: a case report. AB - INTRODUCTION: The purpose of this study is to report the findings resulting from chiropractic care using flexion distraction spinal manipulation for a patient with low back and radicular pain due to spinal stenosis caused by a synovial cyst. CASE REPORT: A 75-year-old man presented with low back pain radiating to the right anterior thigh and down the left posterior leg of 3 years' duration. Physical and imaging examinations showed a synovial cyst-induced spinal stenosis at the right L3-L4 level and bilateral L4-L5 spinal stenosis. INTERVENTION AND OUTCOMES: Flexion distraction spinal manipulation and physiological therapeutics were applied at the levels of stenosis. After 4 visits, the patient noted total absence of the right and left lower extremity pain and no adverse reaction to treatment. After 3 months of treatment and 16 visits, his low back and buttock pain were minimal; and he had no leg pain. CONCLUSION: Lumbar synovial cyst and stenosis-generated low back and radicular pain was 80% relieved in a 75-year-old man following Cox flexion distraction spinal manipulation. PMID- 22942837 TI - Chiropractic spinal manipulative therapy for a geriatric patient with low back pain and comorbidities of cancer, compression fractures, and osteoporosis. AB - OBJECTIVE: The purpose of this report is to describe the response of a geriatric patient with low back pain and a history of leukemia, multiple compression fractures, osteoporosis, and degenerative joint disease using Activator chiropractic technique. CASE REPORT: An 83-year-old man who is the primary caretaker for his disabled wife had low back pain after lifting her into a truck. The patient had a history of leukemia, multiple compression fractures, osteoporosis, and degenerative joint disease. His Revised Oswestry Low Back Pain Disability Questionnaire was 26%, with a 10/10 pain rating at its worst on the Numeric Pain Scale. The patient presented with a left head tilt, right high shoulder, and right high ilium with anterior translation and flexion of the torso and spasm and tenderness from the lower thoracic spine to lumbar spine. INTERVENTION AND OUTCOME: The patient was cared for using Activator Methods protocol. After 8 treatments, the patient was stable and remained stable for 4 months without spasm or tenderness in his spine. His Revised Oswestry score dropped to 6%, with a 4/10 Numeric Pain Scale pain rating when at its worst; and the patient reported being able to take care of his wife. CONCLUSION: The findings of this case suggest that Activator-assisted spinal manipulative therapy had a positive effect on low back pain and function in an elderly patient with a complex clinical history. PMID- 22942838 TI - Chiropractic management of a US Army veteran with low back pain and piriformis syndrome complicated by an anatomical anomaly of the piriformis muscle: a case study. AB - OBJECTIVE: The purpose of this article is to present the case of a patient with an anatomical anomaly of the piriformis muscle who had a piriformis syndrome and was managed with chiropractic care. CASE REPORT: A 32-year-old male patient presented to a chiropractic clinic with a chief complaint of low back pain that radiated into his right buttock, right posterior thigh, and right posterior calf. The complaint began 5 years prior as a result of injuries during Airborne School in the US Army resulting in a 60% disability rating from the Veterans Administration. Magnetic resonance imaging demonstrated a mildly decreased intradiscal T2 signal with shallow central subligamentous disk displacement and low-grade facet arthropathy at L5/S1, a hypolordotic lumbar curvature, and accessory superior bundles of the right piriformis muscle without morphologic magnetic resonance imaging evidence of piriformis syndrome. INTERVENTION AND OUTCOME: Chiropractic treatment included lumbar and sacral spinal manipulation with soft tissue massage to associated musculature and home exercise recommendations. Variations from routine care included proprioceptive neuromuscular facilitation stretches, electric muscle stimulation, acupressure point stimulation, Sacro Occipital Technique pelvic blocking, CranioSacral therapy, and an ergonomic evaluation. CONCLUSION: A patient with a piriformis anomaly with symptoms of low back pain and piriformis syndrome responded positively to conservative chiropractic care, although the underlying cause of the piriformis syndrome remained. PMID- 22942839 TI - Manipulation under anesthesia for patients with failed back surgery: retrospective report of 3 cases with 1-year follow-up. AB - OBJECTIVE: This report describes the treatment of 3 patients with previous spinal fusion surgery who had subsequently regressed to their previous levels of pain and disability. CLINICAL FEATURES: Three patients with chronic intractable pain presented to a private integrative medicine clinic for manipulation under anesthesia (MUA) evaluation. All 3 patients had previously had lumbar spine fusion surgery for intervertebral disk herniation. All surgeries were performed at least 2 years before clinical presentation. Patients had plateaued with other conservative pain management strategies before seeking MUA treatment. INTERVENTION AND OUTCOMES: The patients were evaluated for MUA. The patients received a serial MUA over 3 consecutive days by trained chiropractic and osteopathic physicians. Outcome assessments used for each patient included a quadruple numerical pain rating scale and functional rating index. Patients completed a course of post-MUA physiotherapy and rehabilitation lasting 8 weeks immediately after the serial MUA. Clinical improvements were observed in all 3 outcome assessments after the MUA, the post-MUA therapy, and were essentially maintained 1 year after conclusion of treatment. CONCLUSION: Three patients with failed back surgery were treated conservatively using MUA by trained chiropractic and osteopathic physicians followed by 8 weeks of post-MUA therapy. Pain and disability outcomes all improved immediately following treatment. PMID- 22942840 TI - Chiropractic management of chronic idiopathic meralgia paresthetica: a case study. AB - OBJECTIVES: This report describes the case of a patient with chronic idiopathic meralgia paresthetica associated with bilateral sacroiliac joint dysfunction who was managed with chiropractic care. CLINICAL FEATURES: A 35-year-old white woman presented to a private chiropractic clinic with a complaint of numbness in the right anterolateral thigh region. Neurological assessment revealed a diminution of sensibility and discrimination on the right lateral femoral cutaneous nerve territory. Pain was rated as 8.5 on a numeric pain scale of 0 to 10. Musculoskeletal examination of the pelvic region disclosed bilateral sacroiliac joint dysfunction. INTERVENTION AND OUTCOMES: Chiropractic management included pelvic mobilizations, myofascial therapy, transverse friction massage, and stretching exercises. After 3 visits (2 weeks later), result of neurological evaluation was normal, with no residual numbness over the lateral thigh. CONCLUSION: In the present case, chiropractic management with standard and applied kinesiology techniques resulted in recovery of meralgia paresthetica symptoms for this patient. PMID- 22942841 TI - Chiropractic management of a patient with postoperative lateral retinacular release using a multimodal approach: a case report. AB - OBJECTIVE: The purpose of this case report is to describe a chiropractic rehabilitation program for a patient with postsurgical lateral retinaculum release. CLINICAL FEATURES: A 26-year-old male ice hockey goalie presented 1 month after having lateral retinaculum release surgery for his left knee with residual mild discomfort and edema in his left knee. INTERVENTION AND OUTCOME: The patient was treated using a multimodal approach of both passive and active chiropractic care focusing on the restoration of full range of motion, increased proprioception, balance, strength, and endurance to return the patient to competitive ice hockey. CONCLUSION: This case study demonstrated that, after 14 weeks of care, the patient was able to return to ice hockey training with no residual symptoms. PMID- 22942842 TI - Conservative chiropractic management of urinary incontinence using applied kinesiology: a retrospective case-series report. AB - OBJECTIVE: The purpose of this case series is to describe the chiropractic management of 21 patients with daily stress and occasional total urinary incontinence (UI). CLINICAL FEATURES: Twenty-one case files of patients 13 to 90 years of age with UI from a chiropractic clinic were reviewed. The patients had a 4-month to 49-year history of UI and associated muscle dysfunction and low back and/or pelvic pain. Eighteen wore an incontinence pad throughout the day and night at the time of their appointments because of unpredictable UI. INTERVENTION AND OUTCOME: Patients were evaluated for muscle impairments in the lumbar spine, pelvis, and pelvic floor and low back and/or hip pain. Positive manual muscle test results of the pelvis, lumbar spine muscles, and pelvic floor muscles were the most common findings. Lumbosacral dysfunction was found in 13 of the cases with pain provocation tests (applied kinesiology sensorimotor challenge); in 8 cases, this sensorimotor challenge was absent. Chiropractic manipulative therapy and soft tissue treatment addressed the soft tissue and articular dysfunctions. Chiropractic manipulative therapy involved high-velocity, low-amplitude manipulation; Cox flexion distraction manipulation; and/or use of a percussion instrument for the treatment of myofascial trigger points. Urinary incontinence symptoms resolved in 10 patients, considerably improved in 7 cases, and slightly improved in 4 cases. Periodic follow-up examinations for the past 6 years, and no less than 2 years, indicate that for each participant in this case-series report, the improvements of UI remained stable. CONCLUSION: The patients reported in this retrospective case series showed improvement in UI symptoms that persisted over time. PMID- 22942843 TI - Chiropractic management of pediatric plantar fasciitis: a case report. AB - OBJECTIVE: The purpose of this report is to present the case of a 10-year-old football player with bilateral plantar fasciitis who improved with a multimodal conservative approach using chiropractic treatment. CLINICAL FEATURES: The patient presented with bilateral plantar heel pain at the origin of the plantar fascia with a duration of 3 weeks. INTERVENTION AND OUTCOME: Treatment was provided for 6 visits over a 6-week period. Chiropractic care consisted of manipulative therapy, soft tissue therapy, and home rehabilitation exercises. The soft tissue technique (Graston Technique) was performed to the origin of the plantar fascia and the triceps surae bilaterally. High-velocity, low-amplitude manipulation was applied to the restricted ankle mortise joint. After 6 treatments, the patient reported resolution of foot pain bilaterally and improvements in activities of daily livings. Three months later, the patient reported no further complications and the absence of pain. CONCLUSION: This patient with bilateral plantar fasciitis improved after a course of a multimodal treatment approach using chiropractic manipulation and soft tissue therapy in addition to exercise and stretching therapies. PMID- 22942845 TI - A systematic review of outcomes of toe-to-thumb transfers for isolated traumatic thumb amputation. AB - BACKGROUND: Toe-to-thumb transfer is an established procedure for reconstruction of traumatic thumb amputations. The four types of toe-to-thumb transfers are the second toe, the great toe, the wrap-around great toe and the trimmed great toe transfers. The purpose of this study is to conduct a systematic review of the literature to compare outcomes amongst different methods of toe-to-thumb transfers. METHODS: A literature search using 'toe-to-thumb transfer' combined with 'thumb injury' and 'thumb reconstruction' as keywords and limited to humans and the English language identified 633 studies. Studies were included in the review if they: (1) present primary data, (2) report three or more toe-to-thumb transfers for isolated complete traumatic thumb amputation between the metacarpophalangeal joint and the interphalangeal joint (both excluded) and (3) present functional outcome data. RESULTS: Twenty-five studies representing 450 toe-to-thumb transfers met the inclusion criteria. They included 101 second toe transfers, 196 great toe transfers, 122 wrap-around transfers and 31 trimmed toe transfers. The mean survival rate was 96.4%. No statistically significant differences could be detected between the four transfers with regards to survival, arc of motion, total active motion, grip and pinch strength and static two-point discrimination. CONCLUSIONS: All four types of toe transfer procedures have predictably high survival rates and good patient satisfaction scores. The current data are inadequate to make any comments with regards to donor site morbidity. Till such data are available, an evidence-based recommendation for the superiority of a specific type of toe-to-thumb transfer cannot be made. PMID- 22942844 TI - Methicillin-resistant Staphylococcus aureus: an overview for manual therapists(). AB - OBJECTIVE: Methicillin-resistant Staphylococcus aureus (MRSA) is associated with difficult-to-treat infections and high levels of morbidity. Manual practitioners work in environments where MRSA is a common acquired infection. The purpose of this review is to provide a practical overview of MRSA as it applies to the manual therapy professions (eg, physical and occupational therapy, athletic training, chiropractic, osteopathy, massage, sports medicine) and to discuss how to identify and prevent MRSA infections in manual therapy work environments. METHODS: PubMed and CINAHL were searched from the beginning of their respective indexing years through June 2011 using the search terms MRSA, methicillin resistant Staphylococcus aureus, and Staphylococcus aureus. Texts and authoritative Web sites were also reviewed. Pertinent articles from the authors' libraries were included if they were not already identified in the literature search. Articles were included if they were applicable to ambulatory health care environments in which manual therapists work or if the content of the article related to the clinical management of MRSA. RESULTS: Following information extraction, 95 citations were included in this review, to include 76 peer reviewed journal articles, 16 government Web sites, and 3 textbooks. Information was organized into 10 clinically relevant categories for presentation. Information was organized into the following clinically relevant categories: microbiology, development of MRSA, risk factors for infection, clinical presentation, diagnostic tests, screening tests, reporting, treatment, prevention for patients and athletes, and prevention for health care workers. CONCLUSION: Methicillin-resistant S aureus is a health risk in the community and to patients and athletes treated by manual therapists. Manual practitioners can play an essential role in recognizing MRSA infections and helping to control its transmission in the health care environment and the community. Essential methods for protecting patients and health care workers include being aware of presenting signs, patient education, and using appropriate hand and clinic hygiene. PMID- 22942846 TI - Giant cell tumour of tendon sheath of the digits. A systematic review. AB - BACKGROUND: We reviewed the literature to evaluate the demographic, clinical and histological profile of giant cell tumour of tendon sheath of the digits (GCTTSD). The overall recurrence rate and the factors affecting tumour recurrence were also assessed. METHODS: We searched for published articles regarding the GCTTSD in the English literature the last 30 years using the PubMed search engine. All retrieved papers were analysed and their reference lists were also screened if relevant. Clinical studies with less than five patients and follow-up less than 2 years were excluded from further evaluation. For each report, information was gathered related to trial characteristics and study population. Location and multicentricity of lesions, kind and severity of symptoms, type of applied treatment modality and histopathological features of the excised tumours were additionally recorded. A meta-analysis for estimating the pooled recurrence rate after surgical excision was also conducted. Statistical significance was assumed for p <=0.05. RESULTS: We found 21 studies with histological confirmation of GCTTS. However, only 10 studies including 605 patients were reviewed according to selection criteria (average follow-up 36.7 to 79 months). The male-to-female ratio was 1:1.47 (p < 0.005) and the mean age ranged from 32 to 51 years. Pain or sensory disturbances reported only in 15.7% and 4.57% of cases, respectively. A definite history of trauma recorded in 5% of lesions. The most frequent tumour location was the index finger (29.7%). In total, 14.8% of patients had tumour recurrence. Type I tumours (single lesions) were more frequently detected (78.7%) than type II tumours (two or more distinct tumours that were not joined together) (21.3%) but the latter were associated with a higher recurrence rate (p < 0.001). Study design also affected the possibility of recurrence as it was lower in prospective studies compared to retrospective studies (p = 0.003). Even though bone erosion was detected in 28.39%, recurrence was not more common in this group. In addition, recurrence was not significantly associated with a specific finger or phalanx. CONCLUSIONS: Intrinsic biology of the tumour seems to play a more fundamental role in recurrence than tumour location or local invasiveness. More prospective well-designed studies including a large number of cases are necessary to identify tumours prone to recurrence and determine the proper treatment protocol for each individual patient. PMID- 22942847 TI - A systematic review of outcomes of fasciotomy, aponeurotomy, and collagenase treatments for Dupuytren's contracture. AB - BACKGROUND: Needle aponeurotomy and collagenase injection are alternative treatments of Dupuytren's contracture to open partial fasciectomy; however, reported data are difficult to interpret without a formal systematic review. METHODS: A Medline, EMBASE, and Cochrane database search was performed, and 277 articles were identified. Articles were stratified by level of evidence, and those of the highest level for each technique were included. Evidence available for needle aponeurotomy was of low quality so only cohorts larger than 100 patients were included. RESULTS: The sample size of patients for open partial fasciectomy ranged from 37-261. The recurrence rate ranged from 12-39%, with mean follow-up time of 1.5-7.3 years. The complication rate ranged from 14-67%. Complications included nerve division (2-5%), infection (4-12%), neurapraxia (0.4 52%), and regional pain syndrome (2-13%). For needle aponeurotomy the sample size ranged from 117-211. The recurrence rate ranged from 50-58%, with mean follow-up time of 3-5 years. With regard to collagenase injection, the sample size ranged from 13-204. The recurrence rate ranged from 10-31%, with mean follow-up time of 120 days to 4 years. For the two latter procedures, adverse effects consisted primarily of skin tears (9-25%). Kruskal-Wallis testing demonstrated that the recurrence rate was significantly higher for needle aponeurotomy than for open partial fasciectomy (p = 0.001), and the recurrence rate was significantly higher for open partial fasciectomy than for collagenase injection (p = 0.001). CONCLUSIONS: The recurrence rates and types of complications differ between open partial fasciectomy and needle aponeurotomy or collagenase injection. Long-term outcomes have not been well reported. PMID- 22942848 TI - Minimally invasive technique for release of Dupuytren's contracture: segmental fasciectomy through multiple transverse incisions. AB - BACKGROUND: A multitude of operative approaches have been described for treatment of Dupuytren's contracture. A less-invasive technique of segmental fasciectomies performed through multiple small transverse incisions is presented. METHODS: Seventy-three digits in 37 patients were treated with segmental fasciectomies. The results of 34 digits in 14 patients are described with subsequent follow-up longer than 2 years. RESULTS: Metacarpophalangeal joint extension improved from a mean of 32.5 degrees to 2.2 degrees , while proximal interphalangeal joint extension improved from 22.9 degrees to 4.1 degrees . Patients subjectively rated their surgical outcomes as excellent or good in 91.2% of cases. No recurrence of the disease was noted, though extension of the disease to adjacent digits was observed in three patients. CONCLUSIONS: Though this approach is technically demanding and requires the help of a skilled assistant, this preliminary study supports our contention that this less-extensive procedure allows excellent correction of contractures; results in mild postoperative pain; and permits a rapid return of finger flexion with satisfactory long-term results so far at 2-years follow-up. PMID- 22942849 TI - A functional outcomes survey of elderly patients who sustained distal radius fractures. AB - PURPOSE: This study aims to examine the subjective functional outcomes of patients 70 years or older who sustained distal radius fractures through the use of the Disability of the Arm, Shoulder, and Hand (DASH) and Short Form-8 Health (SF-8) surveys. METHODS: Patients at least 70 years old with a distal radius fracture between 2000 and 2004 were identified and their charts reviewed. They were contacted to answer the DASH and SF-8 surveys. The radiographic injury parameters examined were articular stepoff greater than 2 mm, dorsal tilt on the lateral radiograph, ulnar variance, and presence of an ulnar styloid fracture. RESULTS: Fifty-eight patients answered the DASH and SF-8 surveys. The mean age at the time of injury in the survey group was 78 years old (range 70-94 years). Mean follow-up period was 33 months (range 13-65 months). Average DASH and SF-8 scores were 22.3 (SD 22.4) and 31.5 (SD 6.9), respectively. DASH scores were inversely correlated with SF-8 scores (R = -0.65, p < 0.01). Patients who sustained an associated ulnar styloid fracture demonstrated worse DASH scores than those without an ulnar styloid fracture (presence of ulnar styloid fracture: mean DASH 26.2, no ulnar styloid fracture: mean DASH 12.9, p = 0.04). There were no significant differences in functional outcome for any other radiographic parameters assessed. Males had statistically better DASH scores than the females (males: mean DASH 6.9, females: mean DASH 24.4, p = 0.003). No difference was found in functional outcome scores among different treatment groups. CONCLUSION: In elderly patients with distal radius fractures, the only radiographic parameter we found that affects functional outcome is an associated ulnar styloid fracture. Additionally, females had worse functional outcomes than males. PMID- 22942850 TI - The resurgence of barbed suture and connecting devices for use in flexor tendon tenorrhaphy. AB - Barbed sutures and connecting devices have been historically described and used in flexor tendon tenorrhaphies. With the improvement in biomaterial, we have witnessed recently the resurgence of this concept. In this article, we review the historical use of barbed devices in repairing flexor tendons and explore the available barbed surgical devices that have been described in recent years. PMID- 22942851 TI - Modified Brunelli pull-out technique in flexor tendon repair for zone II: a study on 58 cases. AB - BACKGROUND: The reconstruction of the continuity of flexor tendons disruptions in zone II still remains one of the most challenging problems in hand surgery. The ideal repair has to provide sufficient strength and the possibility of early mobilization in the attempt to obtain a functional range of motion. One of the methods which appears to respond to these requests is the pull-out technique described by Brunelli, which moves the tension from the level of the tendon disruption to the finger pulp over the tendon insertion. METHODS: After using this method, but by doing some modifications of the original technique, our aim was to conduct a retrospective study looking at gap formation, suture strength, rupture rate, efficiency of the two-strand suture repair and of the early active mobilization against resistance in obtaining a good range of flexion rate. We reviewed a series of 71 flexor digitorum profundus disruptions in zone II, in 58 patients admitted in our service between 2000 and 2008, and treated with this method. RESULTS: We achieved a complete range of flexion in 41 fingers (57.7%) and a flexion deficit of 5-10 degrees in eight fingers (11.3%) and of 10-20 degrees in 22 fingers (31%). We had no ruptures, major strength deficit, or bowstringing. CONCLUSIONS: Our study demonstrates that, by moving the tension from the level of disruption to the finger pulp, the rehabilitation program can begin very early post surgery. We had 0% ruptures. PMID- 22942852 TI - Complications with the use of Artelon in thumb CMC joint arthritis. AB - BACKGROUND: Complications with the use of the Artelon spacer in thumb carpometacarpal (CMC) joint arthritis include inflammation, osteolysis, and persistent pain. We evaluated our short-term results and complications. METHODS: A retrospective review of 29 patients was performed. Pre- and postoperative radiographs, operative techniques, complications, and subsequent surgeries were analyzed. Pearson's and chi-squared testing was used to identify associations between complications and surgical technique or preoperative radiographic criteria. The average age was age 51 +/- 7.7 (34-66), average follow-up was 8 months (1-26). RESULTS: Twelve patients sustained complications. Nine patients displayed postoperative osteolysis. Four patients underwent conversion to CMC suspensionplasty due to persistent pain. The rate of revision surgery and radiographic postoperative osteolysis were not significantly associated with preoperative arthritis grade, metacarpal subluxation, or surgical techniques: fixation method, the bony surface(s) involved in the osteotomy, or spacer modifications. CONCLUSIONS: Our study found a significant short-term complication rate following Artelon spacer arthroplasty of the CMC joint. This is higher than previously described. We could not identify any factors that were significantly associated with the complications. It is possible that the inherent instability of the joint or the material of the spacer is involved in implant failure. Further study is necessary to better define the indications for use and specific techniques for the use of the implant. PMID- 22942853 TI - Complex and rare fracture patterns in perilunate dislocations. AB - INTRODUCTION: The wrist represents a complex anatomic region in the upper extremity and a highly functional and intricate structural joint. Perilunate injuries have classically been described as involving a greater or lesser arc as described by Mayfield and imply a specific pattern of force transmission. The greater and lesser arc classifications do not include descriptions of when non scaphoid carpal fractures occur as part of a perilunate injury. METHODS/RESULTS: We present three cases of complex and rare perilunate fracture dislocation patterns and discuss the surgical management as a treatment model for these complex wrist injuries: the trans-scaphoid, trans-capitate perilunate dislocation, the trans-scapholunate ligament, trans-capitate dislocation, and the trans-scaphoid, trans-triquetral perilunate dislocation. DISCUSSION: Although there is a low incidence of injury to non-scaphoid carpal bones, it is beneficial to understand the approach to the perilunate reduction and scaphoid fixation through a combined volar and dorsal approach, which will also allow for the reduction and fixation of more rare and complex carpal fractures. PMID- 22942856 TI - An unusual case of spontaneous healing of a proximal pole scaphoid non-union. PMID- 22942855 TI - A novel model for evaluating nerve regeneration in the composite tissue transplant: the murine heterotopic limb transplant. AB - PURPOSE: For individuals who have experienced debilitating upper extremity injury or amputation, hand transplantation holds the potential for drastic quality of life improvement. This potential depends on adequate nerve regeneration into the transplant and reanimation of graft musculature. In this study, we demonstrate the use of a murine heterotopic limb transplant model for evaluation of nerve regeneration in a composite tissue allograft (CTA). We also compare the effects of various immunosuppressive regimens on nerve regeneration in this model. METHODS: The study consisted of five groups of mice, all of which underwent heterotopic limb transplant with coaptation of the recipient and donor sciatic nerves. The groups received the following immunosuppressive regimens: group A (positive control)-syngeneic transplant, no immunosuppression; group B (negative control)-allogeneic transplant, no immunosuppression; group C-allogeneic transplant, FK-506 + MR1; group D-allogeneic transplant, MR1 + CTLA4-Ig; group E syngeneic transplant, FK-506 treatment with preloading. RESULTS: Group B animals showed signs of transplant rejection as early as 5 days postoperatively. Except for one mouse from group C and one mouse from group D, all other animals had viable transplants and nerve regeneration present in the donor sciatic nerve at the 3-week endpoint of the study. CONCLUSIONS: To our knowledge, this represents the first report of the use of a mouse CTA model for evaluation of nerve regeneration. The mouse heterotopic limb transplant model will be a valuable tool for CTA research since it can be performed with more ease, and with less host morbidity and mortality than the mouse orthotopic model. PMID- 22942854 TI - Establishing hand preference: why does it matter? AB - Hand preference has been associated with psychological and physical well-being, risk of injury, pathological irregularities, longevity, and cognitive function. To determine hand preference, individuals are often asked what hand they use to write with, or what hand is used more frequently in activities of daily living. However, relying only on one source of information may be misleading, given the strong evidence to support a disassociation between self-reported hand preference and outcomes of hand performance assessments. This brief communication is intended to highlight the various methods used to determine hand preference, to discuss the relationship between hand preference inventories and performance measures and to present some recent findings associated with hand preference and musculoskeletal disorders. PMID- 22942857 TI - Case report: intraneural ganglion cyst of the ulnar nerve at the wrist. AB - We report a case of a 69-year-old male who presented with pain, weakness, and clumsiness of his right hand. Initial evaluation suggested possible neoplastic process affecting his cervical spine, which was fortunately ruled out by bone biopsy. Subsequent electrodiagnostic studies and magnetic resonance imaging confirmed a lesion of the deep ulnar motor branch. Exploration of Guyon's canal was performed, and an intraneural ganglion involving the deep motor branch of the ulnar nerve was found and excised. Despite more than 14 months of symptomatic duration, the patient made a near-complete recovery with virtually no functional limitations. This provides supporting evidence for a functional benefit of intraneural ganglion excision and nerve decompression even in cases of chronic muscle atrophy. PMID- 22942858 TI - Metastasis of parotid basal cell adenocarcinoma to the hand-a case report. PMID- 22942859 TI - Salvage reconstruction of failed pollicization by distraction lengthening. PMID- 22942860 TI - Unusual presentation of hemochromatosis as isolated metacarpophalangeal joint osteoarthritis: a case report. AB - BACKGROUND: Hemochromatosis, North America's most prevalent genetic disorder, tends to present with an insidious onset and subtle, yet characteristic findings. Patients tend to present with both constitutional symptoms and end-organ effects. METHODS: Clinical criteria such as history, physical examination, imaging criteria with focused radiologic constellations, and laboratory findings were used for diagnosis. RESULTS: We report the case of a man who lacked classic systemic symptoms, but instead presented with isolated metacarpophalangeal joint disease and characteristic radiologic findings. The diagnosis was confirmed by serum iron studies and subsequent genetic work-up. CONCLUSIONS: A high index of clinical suspicion is required to diagnose early disease; better prognostic responses are expected with treatment of less severe disease. Hand surgeons should be aware of the characteristic findings for this rare presentation so proper treatment can be initiated early. PMID- 22942861 TI - Isolated capitate fracture with dorsal dislocation of proximal pole: a case report. PMID- 22942862 TI - Pediatric compartment syndrome following an insect bite: a case report. PMID- 22942863 TI - Bilateral proximal delta phalanges: an unusual presentation of familial congenital clinodactyly. AB - We report a unique case of bilateral proximal delta phalanges with secondary distal accessory ossification centers of the long fingers in a 16-month-old boy. The bony anomalies presented as severe ulnar deviation at the proximal interphalangeal joints bilaterally. This is a unique occurrence of congenital clinodactyly which has not been previously reported. Several family members show similar deformity, although to lesser degrees, suggesting an autosomal dominant mode of inheritance with incomplete penetrance and variable expressivity. PMID- 22942864 TI - Posterior interosseus palsy with an incidental Froment-Rauber nerve presenting as a pseudoclaw hand. PMID- 22942865 TI - A special issue on nanomaterial regulations and health effects. PMID- 22942866 TI - Screening for Oxidative Stress Elicited by Engineered Nanomaterials: Evaluation of Acellular DCFH Assay. AB - The DCFH assay is commonly used for measuring free radicals generated by engineered nanomaterials (ENM), a well-established mechanism of ENM toxicity. Concerns exist over susceptibility of the DCFH assay to: assay conditions, adsorption of DCFH onto ENM, fluorescence quenching and light scattering. These effects vary in magnitude depending on ENM physiochemical properties and concentration. A rigorous evaluation of this method is still lacking. The objective was to evaluate performance of the DCFH assay for measuring ENM-induced free radicals. A series of diverse and well-characterized ENM were tested in the acellular DCFH assay. We investigated the effect of sonication conditions, dispersion media, ENM concentration, and the use of horseradish peroxidase (HRP) on the DCFH results. The acellular DCFH assay suffers from high background signals resulting from dye auto-oxidation and lacks sensitivity and robustness. DCFH oxidation is further enhanced by HRP. The number of positive ENM in the assay and their relative ranking changed as a function of experimental conditions. An inverse dose relationship was observed for several Carbon-based ENM. Overall, these findings indicate the importance of having standardized assays for evaluating ENM toxicity and highlights limitations of the DCFH assay for measuring ENM-induced free radicals. PMID- 22942867 TI - Measurement of accumulation of semiconductor nanocrystal quantum dots by pimephales promelas. AB - As the production and use of nanomaterials increases, it is important to understand their environmental and biological fate. Because their unmatched chemical, physical, and optical properties make them useful in a wide variety of applications including biomedical imaging, photo-voltaics, and light emitting diodes, the use of semiconductor nanocrystals such as quantum dots (QDs) is increasing rapidly. Although QDs hold great potential in a wide variety of industrial and consumer applications, the environmental implications of these particles is largely unexplored. The nanocrystal core of many types of QDs contains the toxic metal cadmium (Cd), so possible release of Cd from the QD core is cause for concern. Because many types of QDs are miscible in water, QD interactions with aquatic organisms and their environment require more attention. In the present study we used fluorometry to measure time and dose dependent uptake, accumulation, and post-exposure clearance of accumulated QDs in the gut tract by the aquatic vertebrate Pimephales promelas. By using fluorometry, we were able to measure accumulated QD concentrations. To our knowledge, this is the first reported attempt to quantify accumulated QDs in an organism and is an important step in understanding the interactions among QDs in aquatic organisms and environments. PMID- 22942868 TI - A method to evaluate hormesis in nanoparticle dose-responses. AB - The term hormesis describes a dose-response relationship that is characterized by a response that is opposite above and below the toxicological or pharmacological threshold. Previous reports have shown that this relationship is ubiquitous in the response of pharmaceuticals, metals, organic chemicals, radiation, and physical stressor agents. Recent reports have also indicated that certain nanoparticles (NPs) may also exhibit a hormetic dose-response. We describe the application of three previously described methods to quantify the magnitude of the hormetic biphasic dose-responses in nanotoxicology studies. This methodology is useful in screening assays that attempt to parse the observed toxicological dose-response data into categories based on the magnitude of hormesis in the evaluation of NPs. For example, these methods may be used to quickly identify NP induced hormetic responses that are either desirably enhanced (e.g., neuronal cell viability) or undesirably stimulated (e.g., low dose stimulation of tumor cells). PMID- 22942869 TI - Practical implications of nanodosimetry in medicine. AB - The grandiose promises made decades ago of cost reduction, miracle cures for cancers and universal availability of nanomedicine are still a far cry. Even we do not have any viable model to exploit nanotechnology in medicine. The most important arena of the nanotechnology is the development of nanoscale drugs for routine clinical practice. The current chemo protocols are based on maximum tolerable dose philosophy. Such a dose, when translated into active nanoscale clusters, quantitatively outnumbers the cells in an average human body. These nanoscale drug issues are discussed in this paper. A theoretical framework for commonly used drug aspirin has been considered as an example. The possible quantum physical effects have also been theoretically evaluated. Further, the amount of drug molecules in a standardized aspirin dose of 100 milligram has been computed into nanoclusters. The calculations show that the processing of nanoscale drug is a monumental task which requires new types of manufacturing facilities. Also there is a need to develop new protocols which will help realize the practical implementation of nanodosimetry in day to day drug administrations. These protocols will need to examine the implications of dose-responses such as necrosis, apoptosis and hormesis in medicine for routine clinical practice. PMID- 22942870 TI - European regulation affecting nanomaterials - review of limitations and future recommendations. AB - After learning about the potential risks associated with various specific nanomaterials, concerns have been raised about adequacy of existing regulation in Europe and what should be done to address any potential regulatory gaps related to nanomaterials. Understanding the limitations of the current regulation in regard to nanomaterials is a starting point in a democratic and transparent process towards adapting existing laws and facilitating an informed discussion about which kind of regulatory options best address the identified limitations. In the following we will introduce key pieces of European legislation affecting nanomaterials, analyze their limitations, and provide a number of recommendations on how these can be overcome. We find that, although nanomaterials are in principle covered by the scope of many of the existing legislative frameworks, it is often unclear, if current regulations are actually applicable when it comes to specific nanomaterials and their diverse applications. Main limitations seem to be: that requirements to do safety evaluations are triggered by production volumes by tonnage not tailored to the nanoscale, the profound lack of (eco)toxicological data, and that thresholds values and occupational exposure limits cannot be established with existing methodologies. PMID- 22942871 TI - The Trend Towards Implementing the Precautionary Principle in us Regulation of Nanomaterials. AB - The precautionary principle provides a framework for regulating emerging technologies in general and nanomaterials in particular. It counsels action in the presence of uncertainties about risk instead of assuming that nanomaterials are safe unless proven hazardous. Nanomaterials are regulated under different statutory programs depending on whether they are drugs, pesticides or other commercial chemicals. Recent developments in the regulation of nanomaterials that are not drugs or pesticides have demonstrated a trend towards application of the precautionary principle. This is a paradigm shift away from the requirement built into past interpretations of the Toxic Substances Control Act ("TSCA") that manufacturing, processing and use of chemical substances cannot be restricted unless the regulatory authority proves an unreasonable risk. This same paradigm shift is incorporated into recent legislative proposals to amend TSCA. PMID- 22942872 TI - Hazardous substances, CERCLA, and nanoparticles - can the three be reconciled? AB - Toxicology research in the nanotechnology area has focused primarily on human inhalation, ingestion or dermal exposure. Less research has been published on the impact to ecological systems resulting from a release of nanomaterials. Environmental laws such as CERCLA ("Superfund") address the release of "hazardous substances" by obligating the party releasing the substance to (a) report the release and (b) investigate the nature and extent of the release and to then remediate it to some objective cleanup standard. Applying this regime to the release of nanomaterials, however, is complicated. First, is the nanomaterial a hazardous waste, toxic substance, or hazardous substance as defined under the environmental laws? A compound that may be defined as hazardous or toxic could have properties at the nano level that are distinctly non-hazardous. Second, what constitutes a release of a nanoparticle that would require reporting under applicable environmental laws? Typically, release reporting is based upon the weight of the hazardous substance that is released, but for nanomaterials a weight threshold might be meaningless. Third, how do you sample nanoparticles in the field and analyze them using existing instrumentation? There are few approved tests for nanomaterials. Fourth, how do you determine an objective risk-based cleanup standard for the thousands of possible nanomaterials? PMID- 22942873 TI - Sub-Chronic Oral Exposure to Iridium (III) Chloride Hydrate in Female Wistar Rats: Distribution and Excretion of the Metal. AB - Iridium tissue distribution and excretion in female Wistar rats following oral exposure to iridium (III) chloride hydrate in drinking water (from 1 to 1000 ng/ml) in a sub-chronic oral study were determined. Samples of urine, feces, blood and organs (kidneys, liver, lung, spleen and brain) were collected at the end of exposure. The most prominent fractions of iridium were retained in kidney and spleen; smaller amounts were found in lungs, liver and brain. Iridium brain levels were lower than those observed in other tissues but this finding can support the hypothesis of iridium capability to cross the blood brain barrier. The iridium kidney levels rose significantly with the administered dose. At the highest dose, important amounts of the metal were found in serum, urine and feces. Iridium was predominantly excreted via feces with a significant linear correlation with the ingested dose, which is likely due to low intestinal absorption of the metal. However, at the higher doses iridium was also eliminated through urine. These findings may be useful to help in the understanding of the adverse health effects, particularly on the immune system, of iridium dispersed in the environment as well as in identifying appropriate biological indices of iridium exposure. PMID- 22942874 TI - Human Lung Cancer Risks from Radon - Part III - Evidence of Influence of Combined Bystander and Adaptive Response Effects on Radon Case-Control Studies - A Microdose Analysis. AB - Since the publication of the BEIR VI (1999) report on health risks from radon, a significant amount of new data has been published showing various mechanisms that may affect the ultimate assessment of radon as a carcinogen, in particular the potentially deleterious Bystander Effect (BE) and the potentially beneficial Adaptive Response radio-protection (AR). The case-control radon lung cancer risk data of the pooled 13 European countries radon study (Darby et al 2005, 2006) and the 8 North American pooled study (Krewski et al 2005, 2006) have been evaluated. The large variation in the odds ratios of lung cancer from radon risk is reconciled, based on the large variation in geological and ecological conditions and variation in the degree of adaptive response radio-protection against the bystander effect induced lung damage. The analysis clearly shows Bystander Effect radon lung cancer induction and Adaptive Response reduction in lung cancer in some geographical regions. It is estimated that for radon levels up to about 400 Bq m(-3) there is about a 30% probability that no human lung cancer risk from radon will be experienced and a 20% probability that the risk is below the zero radon, endogenic spontaneous or perhaps even genetically inheritable lung cancer risk rate. The BEIR VI (1999) and EPA (2003) estimates of human lung cancer deaths from radon are most likely significantly excessive. The assumption of linearity of risk, by the Linear No-Threshold Model, with increasing radon exposure is invalid. PMID- 22942875 TI - The Integration of the Glutamatergic and the White Matter Hypotheses of Schizophrenia's Etiology. AB - BACKGROUND: schizophrenia's endophenotipic profile is not only generally complex, but often varies from case to case. The perspective of trying to define specific anatomic correlates of the syndrome has led to disappointing results. In that context, neurophysiologic hypotheses (e.g. glutamatergic hypothesis) and connectivity hypotheses became prominent. Nevertheless, despite their commitment to the principle of denying 'localist' views and approaching the syndrome's endophenotype from a whole brain perspective, efforts to integrate both have not flourished at this moment in time. OBJECTIVES: This paper aims to introduce a new etiological model that integrates the glutamatergic and the WM (WM) hypotheses of schizophrenia's etiology. This model proposes to serve as a framework in order to relate to patterns of brain abnormalities from the onset of the syndrome to stages of advanced chronification. HIGHLIGHTS: Neurotransmitter abnormalities forego noticeable WM abnormalities. The former, chiefly represented by NMDAR hypo function and associated molecular cascades, is related to the first signs of cell loss. This process is both directly and indirectly integrated to the underpinning of WM structural abnormalities; not only is the excess of glutamate toxic to the WM, but its disruption is associated to the expression of known genetic risk factors (e.g., NRG-1). A second level of the model develops the idea that abnormal neurotransmission within specific neural populations ('motifs') impair particular cognitive abilities, while subsequent WM structural abnormalities impair the integration of brain functions and multimodality. As a result of this two-stage dynamic, the affected individual progresses from experiencing specific cognitive and psychological deficits, to a condition of cognitive and existential fragmentation, linked to hardly reversible decreases in psychosocial functioning. PMID- 22942877 TI - Sibutramine effects on central mechanisms regulating energy homeostasis. AB - During the last 50 years the global pandemic of obesity and associated life threatening co-morbidities strongly promoted the development of anti-obesity pharmacotherapy. Sibutramine is an anti-obesity drug that in conjunction with lifestyle modifications reduces food intake and body weight. This may result from several effects: inhibition of presynaptic reuptake of monoaminergic neurotransmitters in the central nervous system, thereby suppressing appetite, induction of an increase in anorexigenic and a decrease in orexigenic neuropeptide secretion, induction of an increase in energy expenditure, and induction of peripheral sympathomimetic effects. The effects of sibutramine on anabolic and catabolic signals that regulate energy homeostasis in the hypothalamus are not completely understood. So, the aim of this review is to summarize the central mechanisms of action of sibutramine, responsible for its weight and food intake reducing potential. Despite being a useful drug in obesity treatment, awareness about the loss of long-term effectiveness and detrimental side effects of sibutramine has recently emerged. As a consequence, new drugs that produce safer and more persistent weight loss are currently undergoing clinical trials. PMID- 22942879 TI - A current review of cypermethrin-induced neurotoxicity and nigrostriatal dopaminergic neurodegeneration. AB - Cypermethrin, a class II pyrethroid pesticide, is used to control insects in the household and agricultural fields. Despite beneficial roles, its uncontrolled and repetitive applications lead to unintended effects in non-target organisms. Cypermethrin crosses the blood-brain barrier and induces neurotoxicity and motor deficits. Cypermethrin prolongs the opening of sodium channel, a major site of its action, leading to hyper-excitation of the central nervous system. In addition to sodium channel, cypermethrin modulates chloride, voltage-gated calcium and potassium channels, alters the activity of glutamate and acetylcholine receptors and adenosine triphosphatases and induces DNA damage and oxidative stress in the neuronal cells. Cypermethrin also modulates the level of neurotransmitters, including gamma-aminobutyric acid and dopamine. It is one of the most commonly used pesticides in neurotoxicology research not only because of its variable responses depending upon the doses, time and routes of exposure and strain, age, gender and species of animals used across multiple studies but also owing to its ability to induce the nigrostriatal dopaminergic neurodegeneration. This article describes the effect of acute, chronic, developmental and adulthood exposures to cypermethrin in experimental animals. The article sheds light on cypermethrin-induced changes in the central nervous system, including its contribution in the onset of specific features, which are associated with the nigrostriatal dopaminergic neurodegeneration. Resemblances and dissimilarities of cypermethrin-induced nigrostriatal dopaminergic neurodegeneration with sporadic and chemicals-induced disease models along with its advantages and pitfalls are also discussed. PMID- 22942880 TI - Proteomic analysis of glioma chemoresistance. AB - Malignant glioma is the most common and destructive form of primary brain tumor. Along with surgery and radiation, chemotherapy remains as the major treatment modality. The emergence of drug resistance, however, often leads to a therapeutic failure in the treatment of glioma, precluding long-term survival of the patients. A proteomic approach has recently been adapted for the mechanistic analysis of glioma drug resistance. The proteomic analysis of drug-resistant glioma led to the discovery of novel biomarkers that can be used for the prognosis of glioma as well as for monitoring the drug response or resistance of glioma. These proteomics-based biomarkers can also be a druggable target that one can exploit for successful glioma chemotherapy. In this review, recent reports on proteomic analysis of glioma from the perspective of chemoresistance are discussed with a focus on the proteome profiles of glioma cells that are resistant to the alkylating agent, 1, 3-bis (2-chloroethyl)-1-nitrosourea (BCNU), as a prime example. Among numerous proteins that were up- or down-regulated in drug-resistant glioma cells, lipocalin 2 (LCN2) and integrin beta3 (ITGB3) were identified as key proteins that determine the survival and death of glioma cells. LCN2, ITGB3, and other proteins identified by proteomic analysis could be utilized to overcome glioma chemoresistance. PMID- 22942878 TI - Effects of cocaine on maternal behavior and neurochemistry. AB - Drug addiction is a chronic relapsing disorder that involves drug seeking and abuse despite the negative social and health consequences. While the potential effects of cocaine on child development have been extensively studied over the last 30 years, few researchers have focused on the effects of cocaine on maternal behavior, which includes offspring care and maternal aggression towards an unfamiliar individual. In humans, maternal cocaine use can lead to child neglect, abuse, and disrupt the mother-child bond. While it has been argued the developmental effects of maternal cocaine use on children were initially overstated, it is clear that disruptions of typical maternal behavior (i.e. postpartum depression, anxiety disorders) are detrimental to the physical and emotional health of offspring. Cocaine use in mothers is commonly associated with psychological disorders, including depression and anxiety, and it is postulated that many of the negative effects of maternal cocaine use on offspring are mediated through changes in maternal behavior. This review will summarize research on cocaine and maternal behavior in animal and human studies, discuss potential mechanisms, and suggest therapeutic strategies for treating cocaine affected maternal behavior which may improve the physical and behavioral health of both mother and child. The primary objective is to stimulate future communication, cooperation, and collaboration between researchers who use animals and humans to study cocaine and maternal behavior. PMID- 22942881 TI - Molecular and cellular pathways as a target of therapeutic hypothermia: pharmacological aspect. AB - Induced therapeutic hypothermia is the one of the most effective tools against brain injury and inflammation. Even though its beneficial effects are well known, there are a lot of pitfalls to overcome, since the potential adverse effects of systemic hypothermia are still troublesome. Without the knowledge of the precise mechanisms of hypothermia, it will be difficult to tackle the application of hypothermia in clinical fields. Better understanding of the characteristics and modes of hypothermic actions may further extend the usage of hypothermia by developing novel drugs based on the hypothermic mechanisms or by combining hypothermia with other therapeutic modalities such as neuroprotective drugs. In this review, we describe the potential therapeutic targets for the development of new drugs, with a focus on signal pathways, gene expression, and structural changes of cells. Theapeutic hypothermia has been shown to attenuate neuroinflammation by reducing the production of reactive oxygen species and proinflammatory mediators in the central nervous system. Along with the mechanism based drug targets, applications of therapeutic hypothermia in combination with drug treatment will also be discussed in this review. PMID- 22942876 TI - Therapeutic potential of metabotropic glutamate receptor modulators. AB - Glutamate is the main excitatory neurotransmitter in the central nervous system (CNS) and is a major player in complex brain functions. Glutamatergic transmission is primarily mediated by ionotropic glutamate receptors, which include NMDA, AMPA and kainate receptors. However, glutamate exerts modulatory actions through a family of metabotropic G-protein-coupled glutamate receptors (mGluRs). Dysfunctions of glutamatergic neurotransmission have been implicated in the etiology of several diseases. Therefore, pharmacological modulation of ionotropic glutamate receptors has been widely investigated as a potential therapeutic strategy for the treatment of several disorders associated with glutamatergic dysfunction. However, blockade of ionotropic glutamate receptors might be accompanied by severe side effects due to their vital role in many important physiological functions. A different strategy aimed at pharmacologically interfering with mGluR function has recently gained interest. Many subtype selective agonists and antagonists have been identified and widely used in preclinical studies as an attempt to elucidate the role of specific mGluRs subtypes in glutamatergic transmission. These studies have allowed linkage between specific subtypes and various physiological functions and more importantly to pathological states. This article reviews the currently available knowledge regarding the therapeutic potential of targeting mGluRs in the treatment of several CNS disorders, including schizophrenia, addiction, major depressive disorder and anxiety, Fragile X Syndrome, Parkinson's disease, Alzheimer's disease and pain. PMID- 22942883 TI - Sexually transmitted infections in Canada: A sticky situation. PMID- 22942882 TI - Clozapine-induced obsessive-compulsive symptoms in schizophrenia: a critical review. AB - Obsessive-compulsive disorder (OCD) is rarely associated with schizophrenia, whereas 20 to 30% of schizophrenic patients, suffer from comorbid obsessive compulsive symptoms (OCS). So far no single pathogenetic theory convincingly explained this fact suggesting heterogeneous subgroups. Based on long-term case observations, one hypothesis assumes that second-onset OCS in the course of schizophrenia might be a side effect of second generation antipsychotics (SGA), most importantly clozapine (CLZ). This review summarizes the supporting epidemiological and pharmacological evidence: Estimations on prevalence of OCS increase in more recent cross-sectional studies and in later disease stages. Longitudinal observations report the de novo-onset of OCS under clozapine treatment. This association has not been reported with first generation antipsychotics (FGA) or SGAs with mainly dopaminergic mode of action. Finally, significant correlations of OCS-severity with duration of treatment, dose and serum levels suggest clozapine-induced OCS. However, supposed causal interactions need further verifications. It is also unclear, which neurobiological mechanisms might underlie the pathogenetic process. Detailed genotypic and phenotypic characterizations of schizophrenics with comorbid OCS regarding neurocognitive functioning and activation in sensitive tasks of functional magnetic imaging are needed. Multimodal large-scaled prospective studies are necessary to define patients at risk for second-onset OCS and to improve early detection and therapeutic interventions. PMID- 22942884 TI - Laboratory diagnosis of syphilis: A survey to examine the range of tests used in Canada. AB - Laboratory diagnosis of syphilis has undergone major changes in the past decade with the introduction of immunoassays and recombinant Treponema pallidum antigens as screening tools for syphilis infection. To address this change in laboratory practice, a national syphilis laboratory working group was established with members from the Public Health Agency of Canada, provincial public health laboratories across the country as well as sexually transmitted infection researchers, clinicians and epidemiologists. This working group aims to examine how the use of newer immunoassays will affect syphilis diagnosis, surveillance and disease management. To provide a baseline for this work, an e-mail survey was conducted in the fall of 2009 to determine current laboratory practices for syphilis diagnosis in Canada. The most commonly used tests were rapid plasma reagin, enzyme immunoassay, T pallidum passive particle agglutination, venereal disease research laboratory, fluorescent treponemal antibody absorption, line immunoassay and polymerase chain reaction with 92%, 36%, 32%, 20%, 12%, 12% and 12% of the responding laboratories reporting using these tests, respectively. The ultimate goal of this working group will be to update laboratory guidelines for the diagnosis of syphilis, and to identify syphilis surveillance and research priorities in Canada. PMID- 22942886 TI - Presentation and management of pediatric orbital cellulitis. AB - BACKGROUND: Orbital cellulitis is a serious, vision-threatening infection. OBJECTIVE: To review the epidemiology and clinical data of pediatric orbital cellulitis in Manitoba. METHODS: A 12-year retrospective review was conducted of all children (younger than 18 years of age) with orbital cellulitis admitted to Manitoba's only tertiary pediatric centre. Admission rates for orbital cellulitis were compared over three distinct time periods, based on licensure and funding levels of the heptavalent pneumococcal conjugate vaccine (PCV7) in Manitoba. RESULTS: Thirty-eight patients with orbital cellulitis were identified. Of these, 11% were of Aboriginal ethnicity in contrast with 30% to 40% of children who were admitted for other respiratory illnesses. Subperiosteal abscesses occurred in 31.5%. Only eight patients (21%) required surgery. Follow-up imaging after presentation usually did not indicate a need for subsequent surgical drainage. The mean number of orbital cellulitis cases per 1000 admissions for the following periods - before PCV7 licensure, after licensure and before full provincial funding, and after licensure and full funding - were 0.39, 0.53 and 0.90, respectively. No significant difference was noted among any of the periods as PCV7 coverage increased. CONCLUSIONS: The rate of subperiosteal abscesses was lower than other reports. This may be due to the median age at presentation. In contrast to admissions for most other respiratory infections at the Winnipeg Children's Hospital (Winnipeg, Manitoba), Aboriginal ethnicity was uncommon. Surprisingly, rates of admissions for orbital cellulitis appeared to show an increasing trend with increasing access to PCV7 in Manitoba, although overall the number of cases was very small. Studies into the changing microbiology of orbital cellulitis and sinusitis are warranted. PMID- 22942887 TI - Mycobacterium senegalense tissue infection in a child after fish tank exposure. AB - The present report describes the first known case of an otherwise healthy child who developed a soft tissue infection due to Mycobacterium senegalense - a pathogen usually found in east Africa that is responsible for infecting various animals. The patient presented with nonhealing wounds after sustaining facial lacerations from the shattered glass of a fish tank. The patient responded well to scar revision and antibiotics, with no subsequent relapse. PMID- 22942888 TI - Mycobacterial brain tuberculomas due to Bacille Calmette-Guerin intravesical chemotherapy for bladder cancer: A case report and literature review. AB - Bacille Calmette-Guerin (BCG) immunotherapy is widely used for the treatment of superficial bladder cancer. The authors believe that the present report is one of the first to document cerebral BCG tuberculoma in a 73-year-old immunocompetent man, three years after intra-vesical BCG immunotherapy. His workup revealed no identifiable extracranial source. He responded well to treatment with rifampin, ethambutol and moxifloxacin.Patients undergoing intravesical BCG therapy should be closely monitored for the development of this complication. Prolonged antitubercular therapy, possibly including moxifloxacin, appears to be beneficial in the treatment of central nervous system tuberculous infections. PMID- 22942885 TI - Management and treatment of hepatitis B virus in patients with HIV infection: A practical guide for health care professionals. AB - The management and treatment of HIV and hepatitis B virus (HBV)-coinfected patients present specific challenges for clinicians. The morbidity and mortality related to these concomitant infections are growing concerns, while the use of antiviral drugs effective against both viruses complicates therapeutic decision making. The present document provides guidelines for physicians regarding care and treatment of patients coinfected with HIV and HBV. Primary prevention of HBV in HIV-positive patients is achieved through appropriate vaccination schedules. Follow-up before treatment of HBV may include liver biopsy, screening for hepatocellular carcinoma and testing for esophageal varicies in cases of cirrhosis. In HBV-infected patients requiring treatment, recommendations regarding initiation, duration and choice of first-line drugs are made. Finally, in the case of resistance, appropriate alternative therapies are necessary. PMID- 22942889 TI - Meeting report: National symposium on infectious agents and cancer. PMID- 22942890 TI - Achromobacter species endocarditis: A case report and literature review. AB - Endocarditis due to Achromobacter species is a rare, yet serious, endovascular infection. Achromobacter species infective endocarditis is associated with underlying immunodeficiencies or prosthetic heart valves and devices. A case of prosthetic pulmonary valve endocarditis secondary to Achromobacter xylosoxidans subspecies denitrificans is described in the present report. This life threatening infection was successfully treated with combined valve replacement and prolonged antibiotic therapy. A Medline/PubMed literature review of Achromobacter endocarditis was also performed. Achromobacter species are an uncommon, yet important, cause of nosocomial endocarditis. Given the significant associated morbidity and mortality, along with a high degree of intrinsic antibiotic resistance, Achromobacter species infective endocarditis remains a clinical treatment challenge. PMID- 22942891 TI - Cytomegalovirus colitis following azacitidine therapy. AB - The present report describes the first recognized case of cytomegalovirus (CMV) colitis following azacitidine therapy. A 66-year-old woman with myelodysplastic syndrome developed CMV colitis, which responded to treatment with ganciclovir. Currently, patients receiving azacitidine do not undergo CMV testing, or receive prophylaxis or CMV-free blood products; however, this policy needs to be revised. PMID- 22942893 TI - Mental health as an NCD (non-communicable disease): the need to act. PMID- 22942892 TI - Methodology of a randomized double-blind clinical trial for comorbid posttraumatic stress disorder and alcohol dependence. AB - INTRODUCTION: Alcohol dependence (AD) and posttraumatic stress disorder (PTSD) are each associated with profound disruptions in psychological, social, and physical functioning, and these disruptions are compounded in individuals with both disorders. Comorbidity between the two disorders is high, with the risk for AD increasing substantially among individuals with PTSD and, conversely, PTSD is highly prevalent among people experiencing AD. AIMS: Given the increased impairment associated with this comorbidity, it is imperative to develop effective treatments for individuals who experience both disorders. METHODS: This paper describes the methodology of a study that examines the efficacy of prolonged exposure therapy alone, naltrexone alone, and their combination compared to pill placebo in reducing the severity of PTSD and alcohol use in individuals with comorbid AD and PTSD. DISCUSSION: Issues related to design, assessment, treatment choice, and challenges posed by the study population are discussed. PMID- 22942894 TI - Depression and type 2 diabetes mellitus: what we can learn from the Trinidad and Tobago experience. PMID- 22942895 TI - Men's experience of their partners' postpartum psychiatric disorders: narratives from the internet. AB - Objectives Postpartum psychiatric disorders (PPPD) can be serious and disabling, and may lead to long-term adverse consequences. Partners of women with PPPD are also affected by the illness, but their experiences are seldom described. The aim of this study was to explore men's experience of women with PPPD.Methods Eleven written narratives from the internet were used to analyse men's perceived experience of their partner's PPPDs. Data were analysed using content analysis.Results The men revealed a major disruption in their lives. They expressed fear, confusion and anger; they were also extremely concerned about their partners, and felt unable to help in overcoming the disorder. Most of the men described making sacrifices in order to hold the relationship and the family together. Although the disorder improved over time, they were left to face an uncertain future with a woman who seemed to be very different from the person they had known previously. Most of the men gained maturity and increased self esteem, but for some the result was divorce, custody disputes and loneliness.Conclusions The men in this study experienced the woman's PPPD as a difficult time, when everything familiar was turned upside down. Health professionals should pay more attention to men's mental health in the postpartum period. Furthermore, information regarding the possibility of these disorders should be given to expectant couples in prenatal classes. Further research is needed to ascertain how and to what extent this should be included in the education. PMID- 22942896 TI - The pattern of physical comorbidity and the psychosocial determinants of depression: a prospective cohort study on a representative sample of family practice attendees in Slovenia. AB - Objectives This study aims to present the patterns of physical comorbidity in depressed patients and factors strongly associated with depression in a representative sample of Slovenian family practice attendees.Methods Medical data was obtained for 911 general practice attendees. Of them, 221 (24.3%) were diagnosed as depressed. The depressive states of the subjects were evaluated using the Composite International Diagnostic Interview (CIDI). Physical comorbidity was assessed with a questionnaire covering the most common health problems in the Slovenian adult population. Several psycho-social factors were also analysed.Results Those variables significantly related to ICD depression were included in multivariate binary logistic regression analysis, adjusted by age, gender and education. The calculation included the chi-square, odds ratio (OR) with confidence interval (95% CI) and P-value. A P-value < 0.05 was marked as statistically significant.Conclusions There was no significant difference in the number of concurrent chronic diseases in depressed and non-depressed subjects. The risk of depression was increased by the presence of several concomitant factors. The burden of somatic co-morbidity was shown to be smaller than the impact of psychosocial determinants, which also acted as protective factors: the feeling of safety at home and the absence of problems in intimate relationships. The abuse of alcohol and drugs by a family member and current poor financial situation were strongly associated with depression. The impact of concurrent incontinence and chronic bowel disease was also important, though somewhat weaker. PMID- 22942897 TI - Psychoeducational groups for youth attention-deficit hyperactivity disorder: a family medicine pilot project. AB - Attention-deficit hyperactivity disorder (ADHD) is the most commonly diagnosed behavioural disorder of youth and is estimated to affect ~4% of school-age children. Although medication is the most common and efficacious treatment for ADHD, some experts believe that multimodal treatment strategies help children improve symptoms more than medicine alone. Psychoeducational strategies focus on educating youth and families about a given disorder. This study compared youth who participated with their parents in a five-session, one-hour psychoeducational group at a family medicine clinic and those who received customary treatment and were on a waiting list for the intervention. Findings of youth behaviour from parent and teacher perspectives were compared at the outset of the group and one month after group completion using the Vanderbilt scales. Results revealed that youth in both conditions improved over the two months of the study from the parent perspective in terms of all ADHD symptoms (e.g. inattention, hyperactivity/impulsivity) and in terms of school functioning. However, no gains were made in youth functioning or ADHD behaviour from the teacher perspective. Youth in the treatment group made modest gains in school performance from the parent perspective when compared with youth in the control condition. The results suggest that parents of ADHD youth should be involved in the treatment process to maximise the likelihood of improvement. Psychoeducational groups can be of modest benefit to help educate parents and youth regarding the challenges of ADHD management. PMID- 22942898 TI - Psychiatric discharge summaries: what do general practitioners want? AB - Aims As part of an initiative to improve and standardise our discharge summaries, we investigated the preferences of general practitioners (GPs) with regards to the information provided in summaries.Method Our study methods included sending a questionnaire to all GPs in our area gathering their views on what information to include in discharge summaries on first and on subsequent inpatient episodes.Results The response rate was 68%. Most GPs wanted a comprehensive first discharge summary, particularly stressing the importance of practical information. Subsequent discharge summaries could exclude case histories.Clinical implications Contrary to previous studies indicating a demand for brief reports, this survey indicates that the GPs surveyed value considerable detail in adult psychiatry discharge summaries. It is important to include these views in setting standards for the auditing process and before implementing changes. PMID- 22942899 TI - Understanding the mental health needs of secondary school children in Manchester. AB - Background In a time of limited resources and the need for cohesive services, understanding levels of need and prevalence is key. Manchester has a diverse range of cultures and socio-economic groups; national data is valuable but not always representative of local need.Aim To assess the prevalence of mental health needs in secondary school pupils in Manchester.Method Parents and teachers in three secondary schools were invited to complete the Strengths and Difficulties Questionnaire (SDQ) and a tool examining unmet needs.Results Initially, 560 pupils were chosen. Having excluded families that opted out, 503 questionnaires were distributed. Teachers returned 200 questionnaires and parents returned 127. Higher than average levels of need were identified with teachers reporting that 18% of pupils scored abnormally on the SDQ. Parent rates were also higher than the national average at 13.4%.Discussion Parents and teachers wanted children to be seen at home and at school, the need for consultation and outreach from mental health into schools is emphasised. PMID- 22942900 TI - The role of stress and level of burnout in job performance among nurses. AB - Nurses' empathy for and connection with patients demonstrates core professional values which are essential but, consequently, attract certain factors capable of inducing stress. Studies of the roles and responsibilities associated with nursing have implicated multiple and conflicting demands which might not be without some resultant effects. However, little research has been conducted on these work characteristics in developing economies to determine how these might impact the nurse employees' performance. There is need for evidence-based empirical findings to facilitate improvement in healthcare services. This study examined stress and level of burnout among Nigerian nurses (n = 2245) who were selected using stratified random sampling. The participants were measured using an 'abridged measures booklet' adopted from the Maslach Burnout Inventory-General Survey (MBI-GS), Job Autonomy Questionnaire (JAQ), Questionnaire on Organisational Stress-Doetinchem (VOS-D) and Job Diagnostic Survey (JDS). The roles of work-home interference (WHI) and home-work interference (HWI), with respect to work characteristics and burnout (paying special attention to gender), were examined. Analyses using t-tests and linear regression showed no gender differences in burnout levels among Nigerian nurses, who experience medium to high levels of emotional exhaustion, medium levels of depersonalisation and high levels of personal accomplishment. WHI and HWI were found to mediate the relationship between work characteristics and burnout. The meditational relationship differs between genders. This study calls for further research into gender and burnout among the caring professions, especially in under-developed and developing economies of the world. PMID- 22942901 TI - Game-based biofeedback for paediatric anxiety and depression. AB - Twenty-four children and adolescents aged 9-17 who were referred for treatment for anxiety were assigned to either a game-based biofeedback group or a waiting list comparison group. The eight-session biofeedback intervention included psychoeducation, identification of triggers and signs of anxiety, and in vivo practice. The intervention used computer-based gaming technology to teach and practise relaxation. Analyses using ANCOVA revealed significant differences in post-test scores of anxiety and depression measures between the two groups. The intervention group reduced anxiety and depression scores on standardised tests. Findings suggest that biofeedback-assisted relaxation training can be useful in decreasing anxiety and depressive symptoms in anxious youths. PMID- 22942902 TI - Clinical presentation of depression among Malaysian women in Penang Island. AB - Objectives To identify the aetiology and clinical presentation of depression among Malaysian women.Methods A cross-sectional study was conducted at the Psychiatry Clinic, Public Hospital, Pulau Penang, Malaysia. Retrospective evaluations of records were conducted between January 2002 and December 2007. The data were analysed using the statistical software, SPSS v. 131(r).Results Ninety six (56.8%) of the patients were Chinese, the mean (+/- SD) age of the patients was 45 +/- 17.8 years, with a majority (72; 42.6%) aged over 50 years. The incidence of depression with comorbid hypertension and comorbid diabetes mellitus was significant among women aged over 50 (P < 0.001 (hypertension) P < 0.015 (diabetes mellitus)). Marital and relationship problems were found to significantly affect Chinese women aged 15-30 years (P = 0.019). In terms of the clinical presentation of depression among Malaysian women, suicidal ideation and somatic symptoms like reduced energy/being easily fatigued were more frequent among Chinese.Conclusion Symptoms of being short-tempered, crying, restless and doubtful/distracted should not be neglected in primary care because of the possibility of mental health disorders. The timely evaluation of diabetic and hypertensive patients is an ideal strategy to prevent mental health disorders. PMID- 22942903 TI - Depression in the early stages of Huntington disease. AB - Huntington disease (HD) has traditionally been considered a movement disorder, but cognitive and psychiatric symptoms also prominently factor into its clinical presentation. Depression is one of the most common psychiatric disturbances in HD, with its prevalence highest in manifest disease during stage 2, but it is also present during the illness prodrome (the period before manifestation of motor symptoms). Identification and treatment of depression in individuals with the HD mutation is an essential part of clinical management in this population, especially owing to the high risk of suicide. This article summarizes what is currently known about the presentation and treatment of depression in the early stages of HD and provides advice to clinicians treating this population. PMID- 22942904 TI - Sleep, sleep-disordered breathing and lipid homeostasis: translational evidence from murine models and children. AB - Impaired sleep, particularly in the context of sleep-disordered breathing (SDB), is associated with a vast array of comorbidities, including obesity. It is well known that the etiology of obesity is both complex and multifactorial. Recent trends have shown that obesity rates have risen at an alarming rate in children, and this has likely contributed to an increased prevalence of SDB in children. Like the 'chicken and the egg' hypothesis, the temporal relationship of obesity and SDB is unclear but it is speculated that these two conditions converge to promote a fundamental disruption to normal lipid homeostasis. In this review, the effect of sleep disruption and SDB on lipid homeostasis in both murine and human models will be critically examined, with the intent of demonstrating that disrupted sleep in children is itself a precursor to obesity via disordered lipid homeostasis. PMID- 22942905 TI - Sonic hedgehog pathway expression in non-small cell lung cancer. AB - OBJECTIVE: Activation of the hedgehog pathway is an important signaling mechanism crucial in embryogenesis and has strong links to carcinogenesis. This study investigates the expression of the Sonic hedgehog pathway molecules in non-small cell lung tumors as it relates to clinical outcome of various non-small cell lung cancers. METHODS: A tissue microarray with 81 samples from 42 patients with various non-small cell lung cancer histologies was examined without the aid of laser microdissection. All samples were stained with antibodies directed against Sonic hedgehog, Ptch-1, Smoothened, and Gli-1. RESULTS: Most of the tumor samples showed negative to weak expression of the pathway proteins (Sonic hedgehog, 38% negative to 20% weak; Ptch-1, 100% negative; Smoothened, 69% negative to 7% weak; Gli-1, 57% negative to 5% weak) compared with higher expression in normal lung epithelial cells. CONCLUSION: The same pathway expression did not correlate with clinical outcome. While our results do not provide any indication that the pathway molecules are correlated to overall patient survival possibly due to the limited sample size, our study shows minimum overexpression of Sonic hedgehog pathway in non-small cell lung cancer and this did not correlate clinically with patient outcome. PMID- 22942906 TI - The potential for trastuzumab emtansine in human epidermal growth factor receptor 2 positive metastatic breast cancer: latest evidence and ongoing studies. AB - The treatment of breast cancer that is driven by amplification and overexpression of human epidermal growth factor receptor 2 (HER2) has been drastically improved by the development of HER2-targeted therapies including trastuzumab and lapatinib. While outcomes for patients diagnosed with HER2-positive breast cancer have been greatly impacted by these therapies, treatment resistance is common and toxicity to standard regimens remains a therapeutic challenge. Trastuzumab emtansine (T-DM1) is a novel antibody drug conjugate that consists of the HER2 targeted monoclonal antibody, trastuzumab, joined via a stable linker to a derivative of maytansine, a highly potent cytotoxic chemotherapy. While other antibody drug conjugates have been developed clinically, this is the first in its class that maintains the antitumor properties of the HER2-targeted antibody, trastuzumab, and also avoids release of the chemotherapy until the molecule is taken up inside the HER2-overexpressing cancer cell. Several phase I studies have shown T-DM1 is safe, tolerable and has activity in trastuzumab- and lapatinib pretreated breast cancer. Moreover, phase II studies are now being reported that confirm its safety and clinical efficacy in both the frontline and heavily pretreated settings. Preliminary data from phase II studies evaluating its use in combination with other cytotoxics have also been reported and several large phase III trials are underway to evaluate its use in the HER2-positive metastatic breast cancer setting. This paper aims to provide a detailed review of the preclinical and clinical evidence relating to the mechanism of action, efficacy and safety of T-DM1 for the treatment of HER2-positive breast cancer. PMID- 22942907 TI - Therapeutic options in older patients with metastatic non-small cell lung cancer. AB - The increase in life expectancy, with its concomitant increase in the risk of cancer, has led to an increased incidence of lung cancer in older people. The median age at diagnosis of lung cancer is between 63 and 70 years. For a long time, there has been a pessimistic attitude by doctors, patients and their relatives and thus an undertreatment of older patients. Older patients have some specific differences compared with younger patients: more comorbidities with concomitant medications that may interfere with chemotherapy, geriatric syndromes, frailty and so on. The first trial devoted to older patients with advanced non-small cell lung cancer (NSCLC) was a comparison between vinorelbine and best supportive care. There was a significant benefit of survival in the chemotherapy arm. Doublet therapy with gemcitabine plus vinorelbine did not give better results than either of these drugs alone. Thus, the recommendations for the treatment of older patients with advanced NSCLC were to give monotherapy. In some clinical trials not dedicated to older patients it appeared that patients might benefit from platinum-based doublet therapy like their younger counterparts. A randomized trial conducted by the French intergroup, IFCT, in patients aged at least 70 years comparing vinorelbine or gemcitabine alone with monthly carboplatin combined with weekly paclitaxel demonstrated that there was a highly significant benefit of survival in the doublet arm. This study resulted in a modification of the recommendations on the treatment of older patients with advanced NSCLC. PMID- 22942908 TI - Current and emerging strategies for the management of imatinib-refractory advanced gastrointestinal stromal tumors. AB - Since its approval by the US Food and Drug Administration in February 2002, the tyrosine kinase inhibitor, imatinib, has become the standard of care for patients with metastatic or unresectable KIT-positive gastrointestinal stromal tumors (GISTs). Imatinib functions by blocking the adenosine triphosphate binding site of the constitutively activated mutant KIT or platelet-derived growth factor receptor alpha, effectively shutting down the oncogenic signal that drives up to 90% of these tumors. In doing so, it has transformed the management of a condition previously refractory to systemic treatments and established GIST as a model for the use of targeted therapies and oncogene addiction in solid tumors. However, while more than 80% of patients will receive clinical benefit from imatinib monotherapy, more than half will develop progressive disease by 2 years. In this article we review the mechanism and patterns of imatinib resistance in GIST; attempt to offer a practical schema for managing imatinib-refractory patients; and lastly, offer some insight as to future directions and emerging therapeutics for the management of this highly interesting and challenging disease. PMID- 22942909 TI - Overcoming the stromal barrier: technologies to optimize drug delivery in pancreatic cancer. AB - Pancreatic cancer has historically proven resistant to anticancer agents. On the one hand, drugs might be more efficient if higher levels could be achieved at the tumor site rather than the normal tissues. On the other hand, the thick stroma and the relative absence of abundant vessels may account at least partially for the failure of successive clinical trials to demonstrate effective treatments in this type of malignancy. In this context, the development and testing in clinical trials of treatment strategies that aim to optimize drug delivery is an important target in improving the prognosis of patients with pancreatic cancer. PMID- 22942911 TI - Computational Model of Cellular Metabolic Dynamics in Skeletal Muscle Fibers during Moderate Intensity Exercise. AB - Human skeletal muscles have different fiber types with distinct metabolic functions and physiological properties. The quantitative metabolic responses of muscle fibers to exercise provide essential information for understanding and modifying the regulatory mechanisms of skeletal muscle. Since in vivo data from skeletal muscle during exercise is limited, a computational, physiologically based model has been developed to quantify the dynamic metabolic responses of many key chemical species. This model distinguishes type I and II muscle fibers, which share the same blood supply. An underlying hypothesis is that the recruitment and metabolic activation of the two main types of muscle fibers differ depending on the pre-exercise state and exercise protocols. Here, activation measured by metabolic response (or enzymatic activation) in single fibers is considered linked but distinct from fiber recruitment characterized by the number (or mass) of each fiber type involved during a specific exercise. The model incorporates species transport processes between blood and muscle fibers and most of the important reactions/pathways in cytosol and mitochondria within each fiber type. Model simulations describe the dynamics of intracellular species concentrations and fluxes in muscle fibers during moderate intensity exercise according to various experimental protocols and conditions. This model is validated by comparing model simulations with experimental data in single muscle fibers and in whole muscle. Model simulations demonstrate that muscle-fiber recruitment and metabolic activation patterns in response to exercise produce significantly distinctive effects depending on the exercise conditions. PMID- 22942910 TI - Genetic controls and cellular behaviors in branching morphogenesis of the renal collecting system. AB - The mammalian kidney, which at maturity contains thousands of nephrons joined to a highly branched collecting duct (CD) system, is an important model system for studying the development of a complex organ. Furthermore, congenital anomalies of the kidney and urinary tract, often resulting from defects in ureteric bud branching morphogenesis, are relatively common human birth defects. Kidney development is initiated by interactions between the nephric duct and the metanephric mesenchyme, leading to the outgrowth and repeated branching of the ureteric bud epithelium, which gives rise to the entire renal CD system. Meanwhile, signals from the ureteric bud induce the mesenchyme cells to form the nephron epithelia. This review focuses on development of the CD system, with emphasis on the mouse as an experimental system. The major topics covered include the origin and development of the nephric duct, formation of the ureteric bud, branching morphogenesis of the ureteric bud, and elongation of the CDs. The signals, receptors, transcription factors, and other regulatory molecules implicated in these processes are discussed. In addition, our current knowledge of cellular behaviors that are controlled by these genes and underlie development of the collecting system is reviewed. PMID- 22942913 TI - Visual one-shot learning as an 'anti-camouflage device': a novel morphing paradigm. AB - Once people perceive what is in the hidden figure such as Dallenbach's cow and Dalmatian, they seldom seem to come back to the previous state when they were ignorant of the answer. This special type of learning process can be accomplished in a short time, with the effect of learning lasting for a long time (visual one shot learning). Although it is an intriguing cognitive phenomenon, the lack of the control of difficulty of stimuli presented has been a problem in research. Here we propose a novel paradigm to create new hidden figures systematically by using a morphing technique. Through gradual changes from a blurred and binarized two-tone image to a blurred grayscale image of the original photograph including objects in a natural scene, spontaneous one-shot learning can occur at a certain stage of morphing when a sufficient amount of information is restored to the degraded image. A negative correlation between confidence levels and reaction times is observed, giving support to the fluency theory of one-shot learning. The correlation between confidence ratings and correct recognition rates indicates that participants had an accurate introspective ability (metacognition). The learning effect could be tested later by verifying whether or not the target object was recognized quicker in the second exposure. The present method opens a way for a systematic production of "good" hidden figures, which can be used to demystify the nature of visual one-shot learning. PMID- 22942914 TI - Impact of gamma-oscillatory inhibition on the signal transmission of a cortical pyramidal neuron. AB - Networks of synchronized fast-spiking interneurons are thought to be key elements in the generation of gamma (gamma) oscillations (30-80 Hz) in the brain. We examined how such gamma-oscillatory inhibition regulates the output of a cortical pyramidal cell. Specifically, we modeled a situation where a pyramidal cell receives inputs from gamma-synchronized fast-spiking inhibitory interneurons. This model successfully reproduced several important aspects of a recent experimental result regarding the gamma-inhibitory regulation of pyramidal cellular firing that is presumably associated with the sensation of whisker stimuli. Through an in-depth analysis of this model system, we show that there is an obvious rhythmic gating effect of the gamma-oscillated interneuron networks on the pyramidal neuron's signal transmission. This effect is further illustrated by the interactions of this interneuron network and the pyramidal neuron. Prominent power in the gamma frequency range can emerge provided that there are appropriate delays on the excitatory connections and inhibitory synaptic conductance between interneurons. These results indicate that interactions between excitation and inhibition are critical for the modulation of coherence and oscillation frequency of network activities. PMID- 22942912 TI - The epsin protein family: coordinators of endocytosis and signaling. AB - The epsins are a conserved family of endocytic adaptors essential for cell viability in yeast and for embryo development in higher eukaryotes. Epsins function as adaptors by recognizing ubiquitinated cargo and as endocytic accessory proteins by contributing to endocytic network stability/regulation and membrane bending. Importantly, epsins play a critical role in signaling by contributing to epidermal growth factor receptor downregulation and the activation of notch and RhoGTPase pathways. In this review, we present an overview of the epsins and emphasize their functional importance as coordinators of endocytosis and signaling. PMID- 22942915 TI - Multi-stream LSTM-HMM decoding and histogram equalization for noise robust keyword spotting. AB - Highly spontaneous, conversational, and potentially emotional and noisy speech is known to be a challenge for today's automatic speech recognition (ASR) systems, which highlights the need for advanced algorithms that improve speech features and models. Histogram Equalization is an efficient method to reduce the mismatch between clean and noisy conditions by normalizing all moments of the probability distribution of the feature vector components. In this article, we propose to combine histogram equalization and multi-condition training for robust keyword detection in noisy speech. To better cope with conversational speaking styles, we show how contextual information can be effectively exploited in a multi-stream ASR framework that dynamically models context-sensitive phoneme estimates generated by a long short-term memory neural network. The proposed techniques are evaluated on the SEMAINE database-a corpus containing emotionally colored conversations with a cognitive system for "Sensitive Artificial Listening". PMID- 22942916 TI - Intrinsic mode entropy based on multivariate empirical mode decomposition and its application to neural data analysis. AB - Entropy, a measure of the regularity of a time series, has long been used to quantify the complexity of brain dynamics. Given the multiple spatiotemporal scales inherent in the brain, traditional entropy analysis based on a single scale is not adequate to accurately describe the underlying nonlinear dynamics. Intrinsic mode entropy (IMEn) is a recent development with appealing properties to estimate entropy over multiple time scales. It is a multiscale entropy measure that computes sample entropy (SampEn) over different scales of intrinsic mode functions extracted by empirical mode decomposition (EMD) method. However, it suffers from both mode-misalignment and mode-mixing problems when applied to multivariate time series data. In this paper, we address these two problems by employing the recently introduced multivariate empirical mode decomposition (MEMD). First, we extend the MEMD to multi-channel multi-trial neural data to ensure the IMEn matched at different scales. Second, for the discriminant analysis of IMEn, we propose to improve the discriminative ability by including variance that has not been used before in entropy analysis. Finally, we apply the proposed approach to the multi-electrode local field potentials (LFPs) simultaneously collected from visual cortical areas of macaque monkeys while performing a generalized flash suppression task. The results have shown that the entropy of LFP is indeed scale-dependent and is closely related to the perceptual conditions. The discriminative results of the perceptual conditions, revealed by support vector machine, show that the accuracy based on IMEn and variance reaches 83.05%, higher than that only by IMEn (76.27%). These results suggest that our approach is sensitive to capture the complex dynamics of neural data. PMID- 22942917 TI - The impact of the glial spatial buffering on the K(+) Nernst potential. AB - Astrocytes play a critical role in CNS metabolism, regulation of volume and ion homeostasis of the interstitial space. Of special relevance is their clearance of K(+) that is released by active neurons into the extracellular space. Mathematical analysis of a modified Nernst equation for the electrochemical equilibrium of neuronal plasma membranes, suggests that K(+) uptake by glial cells is not only relevant during neuronal activity but also has a non neglectable impact on the basic electrical membrane properties, specifically the resting membrane potential, of neurons and might be clinically valuable as a factor in the genetics and epigenetics of the epilepsy and tuberous sclerosis complex. PMID- 22942918 TI - Inhibition of rhythmic spiking by colored noise in neural systems. AB - We study the effect of colored noise on the rhythmic spiking activity of neural systems in this paper. The phenomenon of the so-called inverse stochastic resonance , that is, noise with appropriate intensity suppresses the spiking activity in neural systems, is clearly observed in a special parameter regime. We find that the inhibition effect of colored noise is stronger than that of Gaussian white noise. Furthermore, our simulation results show that the inhibition effect of colored noise provides a useful mechanism for the generation of synchronized burst in type-2 mixed-feed-forward-feedback loop neuronal network motif, which indicates that such inhibition effect might have some biological implications. PMID- 22942919 TI - A case for spiking neural network simulation based on configurable multiple-FPGA systems. AB - Recent neuropsychological research has begun to reveal that neurons encode information in the timing of spikes. Spiking neural network simulations are a flexible and powerful method for investigating the behaviour of neuronal systems. Simulation of the spiking neural networks in software is unable to rapidly generate output spikes in large-scale of neural network. An alternative approach, hardware implementation of such system, provides the possibility to generate independent spikes precisely and simultaneously output spike waves in real time, under the premise that spiking neural network can take full advantage of hardware inherent parallelism. We introduce a configurable FPGA-oriented hardware platform for spiking neural network simulation in this work. We aim to use this platform to combine the speed of dedicated hardware with the programmability of software so that it might allow neuroscientists to put together sophisticated computation experiments of their own model. A feed-forward hierarchy network is developed as a case study to describe the operation of biological neural systems (such as orientation selectivity of visual cortex) and computational models of such systems. This model demonstrates how a feed-forward neural network constructs the circuitry required for orientation selectivity and provides platform for reaching a deeper understanding of the primate visual system. In the future, larger scale models based on this framework can be used to replicate the actual architecture in visual cortex, leading to more detailed predictions and insights into visual perception phenomenon. PMID- 22942920 TI - Numerical simulations examining the possible role of anthropogenic and volcanic emissions during the 1997 Indonesian fires. AB - The regional atmospheric chemistry and climate model REMOTE has been used to conduct numerical simulations of the atmosphere during the catastrophic Indonesian fires of 1997. These simulations represent one possible scenario of the event, utilizing the RETRO wildland fire emission database. Emissions from the fires dominate the atmospheric concentrations of O(3), CO, NO(2), and SO(2) creating many possible exceedances of the Indonesian air quality standards. The scenario described here suggests that urban anthropogenic emissions contributed to the poor air quality due primarily to the fires. The urban air pollution may have increased the total number of people exposed to exceedances of the O(3) 1-h standard by 17%. Secondary O(3) from anthropogenic emissions enhanced the conversion of SO(2) released by the fires to [Formula: see text], demonstrating that the urban pollution actively altered the atmospheric behavior and lifetime of the fire emissions. Under the conditions present during the fires, volcanic SO(2) emissions had a negligible influence on surface pollution. PMID- 22942921 TI - The role of spatial representation in the development of a LUR model for Ottawa, Canada. AB - A land use regression (LUR) model for the mapping of NO(2) concentrations in Ottawa, Canada was created based on data from 29 passive air quality samplers from the City of Ottawa's National Capital Air Quality Mapping Project and two permanent stations. Model sensitivity was assessed against three spatial representations of population: population at the dissemination area level, population at the dissemination block level and a dasymetrically derived population representation. A spatial database with land use, roads, population, zoning, greenspaces and elevation was created. Polycategorical zoning data were used in dasymetric mapping to spatially focus population data derived from the dissemination blocks to a sub-block level for comparison purposes. Dasymetric population mapping provided no significant LUR model improvement in explained variance when compared to block level population; however, both the former were significantly better than the dissemination area level population representations. However, where block level population is not available or too costly to acquire, our method using polycategorical zoning data provides a viable alternative in LUR modelling endeavours. PMID- 22942922 TI - Examining the representativeness of home outdoor PM(2.5), EC, and OC estimates for daily personal exposures in Southern California. AB - Recent studies have linked acute respiratory and cardiovascular outcomes to measurements or estimates of traffic-related air pollutants at homes or schools. However, few studies have evaluated these outdoor measurements and estimates against personal exposure measurements. We compared measured and modeled home outdoor concentrations with personal measurements of traffic-related air pollutants in the Los Angeles air basin (Whittier and Riverside). Personal exposure of 63 children with asthma and 15 homes were assessed for particulate matter with an aerodynamic diameter less than 2.5 MUm (PM(2.5)), elemental carbon (EC), and organic carbon (OC) during sixteen 10-day monitoring runs. Regression models to predict daily home outdoor PM(2.5), EC, and OC were constructed using home outdoor measurements, geographical and meteorological parameters, as well as CALINE4 estimates at outdoor home sites, which represent the concentrations from local traffic sources. These home outdoor models showed the variance explained (R(2)) was 0.97 and 0.94 for PM(2.5), 0.91 and 0.83 for OC, and 0.76 and 0.87 for EC in Riverside and Whittier, respectively. The PM(2.5) outdoor estimates correlated well with the personal measurements (Riverside R(2) = 0.65 and Whittier R(2) = 0.69). However, excluding potentially inaccurate samples from Riverside, the correlation between personal exposure to carbonaceous species and home outdoor estimates in Whittier was moderate for EC (R(2) = 0.37) and poor for OC (R(2) = 0.08). The CALINE4 estimates alone were not correlated with personal measurements of EC or other pollutants. While home outdoor estimates provide good approximations for daily personal PM(2.5) exposure, they may not be adequate for estimating daily personal exposure to EC and OC. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s11869-010-0099-y) contains supplementary material, which is available to authorized users. PMID- 22942923 TI - (1-3)-beta-D-Glucan vs Galactomannan Antigen in Diagnosing Invasive Fungal Infections (IFIs). AB - Invasive fungal infections (IFIs) are serious and often life-threatening complications in patients with haematological malignancies. Early diagnosis and the initiation of efficacious antifungal treatments could affect the prognosis of these patients. The detection of (1-3)-beta-D-Glucan (BDG) could be a promising non-culture-based, noninvasive tool for IFI analyses in haemato-oncological patients, allowing the diagnosis of the two major IFIs, invasive aspergillosis (IA) and invasive candidiasis (IC), with a single test. The aim of this work was to evaluate and compare the use of the BDG in combination with the galactomannan antigen (GAL) assay in order to exclude or confirm suspected IFIs. Sera from 46 haemato-oncological patients (24 with proven/probable IFI and 22 without IFI symptoms) were evaluated retrospectively for the detection of GAL and BDG. In 24 patients, the serum BDG levels facilitated IFI diagnosis: 18 probable IA, 3 proven IA and 3 IC. In the remaining 22 patients, the BDG level helped exclude IFIs. The BDG was positive earlier than GAL in 5/24 cases [three of probable invasive aspergillosis (IA), one of proven IA and one case of proven invasive candidiasis (IC)] and was positive at the same time as GAL in 19/24 cases; in no case was GAL positive before BDG was. The BDG detection is useful, however, the test has a great limitation because it is a completely manual procedure. PMID- 22942924 TI - Effective Dose of CT-Guided Epidural and Periradicular Injections of the Lumbar Spine: A Retrospective Study. AB - Spinal injection procedures can be performed blindly or, more accurately, with fluoroscopic or computed tomography (CT) guidance. Radiographic guidance for selective nerve root blocks and epidural injections allows an accurate needle placement, reduces the procedure time and is more secure for the patient, especially in patients with marked degenerative changes and scoliosis, resulting in a narrowing of the interlaminar space. Limiting factors remain the availability of scanners and the radiation dose. Interventional CT scan protocols in axial CT-acquisition mode for epidural and periradicular injections help to limit the radiation dose without a significant decrease of image quality. The purpose of this retrospective study was to analyze the effective radiation dosage patients are exposed during CT-guided epidural lumbar and periradicular injections. A total amount of n=1870 datasets from 18 months were analyzed after multiplying the dose length product with conversion factor k for each lumbar segment. For lumbar epidural injections (n=1286), a mean effective dose of 1.34 mSv (CI 95%, 1.30-1.38), for periradicular injections (n=584) a mean effective dose of 1.38 mSv (CI 95%, 1.32-1.44) were calculated. PMID- 22942925 TI - "The flipping bullet" with associated intramedullary dystrophic calcification: an unusual cause for migratory myelopathy and radiculopathy. AB - We report the case of a 24 year old male who had a retained bullet within his thoracic spine from a gunshot wound resulting in paraplegia. After 7 months he began experiencing painful dysesthesias at his sensory level. Repeat imaging demonstrated migration of the bullet as well as the development of intramedullary dystrophic calcification associated with the bullet. This case demonstrates not only the ability for retained bullets to migrate within the spinal canal but also demonstrates they can lead to remote symptoms due to the development of dystrophic calcification. PMID- 22942926 TI - Modeling Elastic Pore Sensors for Quantitative Single Particle Sizing. AB - An empirically derived model of how the dimensions of an elastic size-tunable pore sensor change with applied membrane stretch is presented. Quantitative modeling of the pore dimensions, in conjugation with a simplified pore resistance model, enabled particle size and translocation velocity profiles to be calculated from the individual particle 'pulse' events, at any membrane stretch. Size analysis of a trimodal suspension, composed of monodisperse 220, 330 and 410 nm particles, gave rise to 3 distinguishable particle peaks with coefficient of variances below 8.2% and average size values within 2.5% of single modal dynamic light scattering measurements. Particle translocation velocity profiles, over the approximate 12 MUm pore sensing zone, showed that particles entering the small pore were initially accelerated to velocities approaching 5,000 to 6,000 MUm/s. They then rapidly decelerated due to the pore geometry affects on the forces driving particle translocation, being the electric field strength and fluid flow. PMID- 22942928 TI - Evaluation of breast disorders with ultrasound. PMID- 22942927 TI - Sonographic Identification of Tube Thoracostomy Study (SITTS): Confirmation of Intrathoracic Placement. AB - INTRODUCTION: Thoracostomy tubes (TT) are commonly placed in the management of surgical, emergency, and trauma patients and chest radiographs (CXR) and computed tomography (CT) are performed to confirm placement. Ultrasound (US) has not previously been used as a means to confirm intrathoracic placement of chest tubes. This study involves a novel application of US to demonstrate chest tubes passing through the pleural line, thus confirming intrathoracic placement. METHODS: This was an observational proof-of-concept study using a convenience sample of patients with TTs at a tertiary-care university hospital. Bedside US was performed by the primary investigator using first the low-frequency (5-1 MHz) followed by the high-frequency (10-5 MHz) transducers, in both 2-dimensional gray scale and M-modes in a uniform manner. The TTs were identified in transverse and longitudinal views by starting at the skin entry point and scanning to where the TT passed the pleural line, entering the intrathoracic region. All US images were reviewed by US fellowship-trained emergency physicians. CXRs and CTs were used as the standard for confirmation of TT placement. RESULTS: Seventeen patients with a total of 21 TTs were enrolled. TTs were visualized entering the intrathoracic space in 100% of cases. They were subjectively best visualized with the high frequency (10-5 MHz) linear transducer. Sixteen TTs were evaluated using M-mode. TTs produced a distinct pattern on M-mode. CONCLUSION: Bedside US can visualize the TT and its entrance into the thoracic cavity and it can distinguish it from the pleural line by a characteristic M-mode pattern. This is best visualized with the high-frequency (10-5 MHz) linear transducer. PMID- 22942929 TI - Tuberculous pleural effusion. AB - Pleural effusions are a common finding in emergency departments, with cytologic analysis traditionally required for definitive diagnosis. This article describes a classic sonographic appearance of tuberculous pleural effusion. PMID- 22942930 TI - Emergency ultrasound identification of a cornual ectopic pregnancy. PMID- 22942931 TI - Ultrasound-guided hip arthrocentesis in a child with hip pain and Fever. AB - Children presenting to the emergency department with hip pain and fever are at risk for significant morbidity due to septic arthritis. Distinguishing between septic arthritis and other causes of hip pain may be challenging. Sonographic visualization of the hip with real-time ultrasound-guided arthrocentesis may allow faster differentiation between etiologies, hastening definitive therapy and improving analgesia. This report describes the use of hip sonography in a case of Lyme arthritis. The authors review the medical literature in support of bedside hip sonography and discuss how to perform ultrasound-guided hip arthrocentesis. Clinical findings in septic and Lyme arthritis are also described. PMID- 22942932 TI - Ultrasound guidance for central venous access by emergency physicians in colorado. AB - INTRODUCTION: To survey emergency physicians (EP) regarding the frequency of use of ultrasound guidance for placement of central venous catheters (UGCVC) and to assess their perceptions regarding the technique and barriers to its implementation. METHODS: A 25-question Web-based survey was e-mailed to all members of the Colorado chapter of the American College of Emergency Physicians with a listed e-mail address. A total of 3 reminders were sent to nonresponders. RESULTS: Responses were received from 116 out of 330 invitations. Ninety-seven percent (n = 112) of respondents indicated they have an ultrasound machine available in their emergency department, and 78% indicated they use UGCVC. Seventy-seven percent (n = 90) agreed with the statement, "Ultrasound guidance is the preferred method for central venous catheter placement in the emergency department." However, 23% of respondents stated they have received no specific training in UGCVC. Twenty-six percent (n = 28) of respondents stated they felt "uncomfortable" or "very uncomfortable" with UGCVC, and 47% cite lack of training in UGCVC as a barrier to performing the technique. CONCLUSION: Although the majority of surveyed EPs feel UGCVC is a valuable technique and do perform it, a significant percentage reported receiving no training in the procedure and also reported being uncomfortable performing it. Nearly half of those surveyed cited lack of training as a barrier to more widespread implementation of UGCVC. This suggests that there continues to be a need for education and training of EPs in UGCVC. PMID- 22942933 TI - Descriptions of motor vehicle collisions by participants in emergency department based studies: are they accurate? AB - INTRODUCTION: We examined the accuracy of research participant characterizations of motor vehicle collisions (MVC). METHODS: We conducted an emergency department based prospective study of adults presenting for care after experiencing an MVC. Study participants completed a structured clinical interview that assessed the number of lanes of the road where the collision took place, vehicle type, road condition, speed limit, seat belt use, airbag deployment, vehicle damage, time of collision, and use of ambulance transportation. Study participant data were then compared with information recorded by Michigan State Police at the scene of the MVC. Agreement between research participant reports and police-reported data were assessed by using percentage agreement and kappa coefficients for categorical variables and correlation coefficients for continuous variables. RESULTS: There were 97 study participants for whom emergency department interviews and Michigan State Police Report information were available. Percentage agreement was 51% for number of lanes, 76% for car drivability, 88% for road condition, 91% for vehicle type, 92% for seat belt use, 94% for airbag deployment, 96% for speed limit, 97% for transportation by ambulance, and 99% for vehicle seat position. kappa values were 0.32 for seat belt use, 0.34 for number of lanes, 0.73 for vehicle type, 0.76 for speed limit, 0.77 for road condition, 0.87 for airbag deployment, 0.90 for vehicle seat position, and 0.94 for transport by ambulance. Correlation coefficients were 0.95 for the time of the collision, and 0.58 for extent of damage to the vehicle. Most discrepancies between patients and police about extent of vehicle damage occurred for cases in which the patient reported moderate or severe damage but the police reported only slight damage. CONCLUSION: For most MVC characteristics, information reported by research participants was consistent with police-reported data. Agreement was moderate or high for characteristics of greatest relevance to injury biomechanics. These results suggest that research participant report is an acceptable source of collision information. PMID- 22942934 TI - A survey study of institutional review board thought processes in the United States and South Korea. AB - INTRODUCTION: In the last several decades, South Korea has rapidly adopted Western customs and practices. Yet, cultural differences between South Korea and the United States exist. The purpose of this study was to identify and characterize potential cultural differences in the Korean and US institutional review board (IRB) approach to certain topics. METHODS: A qualitative analysis of a 9-item survey, describing 4 research study case scenarios, sent to IRB members from the United States and South Korea. The case scenarios involved the following issues: (1) the need for consent for retrospective chart review when research subjects receive their care after the study is conceived; (2) child assent; (3) individual versus population benefit; and (4) exception from informed consent in emergency resuscitation research. The free-text responses were analyzed and abstracted for recurrent themes. RESULTS: Twenty-three of the 45 survey recipients completed the survey, for an overall response rate of 51%. The themes that emerged were as follows: (1) the importance of parental authority among Korean participants versus the importance of child autonomy and child assent among US participants; (2) the recognition of the rights of a proxy or surrogate who can represent an individual's values by all participants; and (3) the importance of the community, expressed by the Korean respondents, versus individualism, expressed by US respondents. CONCLUSION: Whereas US participants appear to emphasize the importance of the individual and the autonomy of a child, the Korean respondents stressed the importance of parental authority and benefiting the community, above and beyond that of the individual person. However, there was substantial overlap in the themes expressed by respondents from both countries. PMID- 22942935 TI - Sports medicine for emergency medicine physicians, too few to maintain the fellowship in emergency medicine. PMID- 22942936 TI - How accurately can emergency department providers estimate patient satisfaction? AB - INTRODUCTION: Patient satisfaction is an important measure of emergency department (ED) quality of care. Little is known about providers' ability to estimate patient satisfaction. We aimed to measure providers' ability to assess patient satisfaction and hypothesized that providers could accurately estimate overall patient satisfaction. METHODS: We surveyed ED patients regarding satisfaction with their care. Treating providers completed analogous surveys, estimating patients' responses. Sexual assault victims and non-English-speaking or severely ill patients were excluded. Satisfaction responses were categorized as "satisfied" or "not satisfied." Patient satisfaction scores were considered the "gold standard," and providers' perceptions of the patient satisfaction were considered tests. Measures of diagnostic accuracy, such as positive predictive value (PPV) and sensitivity, were used to assess how accurately the provider could estimate his or her patient's satisfaction. RESULTS: Here, 242/457 eligible patients (53%) completed the survey; 227 providers (94%) completed a corresponding survey. Subject-reported overall satisfaction was 96.6%, compared with a provider-estimated rate of 94.4%. The sensitivity and PPV of the provider's estimate of the patient's satisfaction were 95.2 (95% confidence interval [CI] 91.4, 97.7) and 97.5 (95% CI 94.4, 99.2), respectively, for overall patient satisfaction. The PPV was similar for clarity of communication. The PPV was 78.9 for perceived length of ED stay (99% CI 70.8, 85.6) and 82.6 for quality of pain control (95% CI 68.6, 92.3). Accuracy of attending and resident estimates of patient satisfaction did not differ significantly. The agreement between patient-reported and provider-estimated patient satisfaction was not associated with age, gender, patient disposition, or ED divert status. CONCLUSION: Providers are able to assess overall patient satisfaction and clarity of communication with a high accuracy. Physician estimates of pain control and perceived length of stay have a moderate accuracy. PMID- 22942937 TI - Therapy dogs in the emergency department. AB - INTRODUCTION: This study examined acceptance by staff and patients of a therapy dog (TD) in the emergency department (ED). METHODS: Immediately after TD visits to a University Hospital ED, all available ED staff, patients, and their visitors were invited to complete a survey. RESULTS: Of 125 "patient" and 105 staff responses, most were favorable. Ninety-three percent of patients and 95% of staff agreed that TDs should visit EDs; 87.8% of patients and 92% of staff approved of TDs for both adult and pediatric patients. Fewer than 5% of either patients or staff were afraid of the TDs. Fewer than 10% of patients and staff thought the TDs posed a sanitary risk or interfered with staff work. CONCLUSION: Both patients and staff approve of TDs in an ED. The benefits of animal-assisted therapy should be further explored in the ED setting. PMID- 22942938 TI - Emergency physician estimation of blood loss. AB - INTRODUCTION: Emergency physicians (EP) frequently estimate blood loss, which can have implications for clinical care. The objectives of this study were to examine EP accuracy in estimating blood loss on different surfaces and compare attending physician and resident performance. METHODS: A sample of 56 emergency department (ED) physicians (30 attending physicians and 26 residents) were asked to estimate the amount of moulage blood present in 4 scenarios: 500 mL spilled onto an ED cot; 25 mL spilled onto a 10-pack of 4 * 4-inch gauze; 100 mL on a T-shirt; and 150 mL in a commode filled with water. Standard estimate error (the absolute value of (estimated volume - actual volume)/actual volume * 100) was calculated for each estimate. RESULTS: The mean standard error for all estimates was 116% with a range of 0% to 1233%. Only 8% of estimates were within 20% of the true value. Estimates were most accurate for the sheet scenario and worst for the commode scenario. Residents and attending physicians did not perform significantly differently (P > 0.05). CONCLUSION: Emergency department physicians do not estimate blood loss well in a variety of scenarios. Such estimates could potentially be misleading if used in clinical decision making. Clinical experience does not appear to improve estimation ability in this limited study. PMID- 22942939 TI - Allergic dermatitis due to topical antibiotics. AB - In this report we present a case of allergic dermatitis from chronic use of antibiotic ointment mistakenly diagnosed as a localized finger infection. PMID- 22942940 TI - The importance of accurate, early bony reconstruction in orbital injuries with globe loss. AB - Patients who sustain facial fractures frequently suffer from visual disturbance. Additionally, orbital fractures often involve ocular injury, which, not infrequently, may require enucleation. Yet an anophthalmic orbit does not obviate the need for aggressive orbital fracture treatment. In fact, treatment of the sequelae of the anophthalmic orbit can be difficult and require multiple surgeries. Intraoperative use of a conformer after accurate bony reduction and orbital reconstruction with bone grafts or orbital implants are essential steps to allow for prosthetic rehabilitation of the anophthalmic orbit. PMID- 22942941 TI - Safe osteocutaneous radial forearm flap harvest with prophylactic internal fixation. AB - We studied the efficacy of prophylactic plate fixation technique and a modified harvest of the osteocutaneous radial forearm free flap (OCRFFF) to minimize the incidence of postoperative donor radius pathological fracture. We retrospectively studied of the first 70 consecutive patients undergoing OCRFFF harvest by the University of Kansas Head and Neck Microvascular Reconstruction Team. Mean follow up was 13 months. One of two patients undergoing OCRFFF harvest without prophylactic fixation developed a pathological radius fracture. The 68 subsequent OCRFFF patients underwent prophylactic fixation of the donor radius, and none developed a symptomatic radius fracture. Five of 68 patients did have a radiographically visible fracture requiring no intervention. The plate fixation technique was further modified to exclude monocortical screws in the radius bone donor defect (subsequent 39 patients), without any further fractures detected. One patient required forearm hardware removal for an attritional extensor tendon tear. The described modified OCRFFF harvest and prophylactic plate fixation technique may eliminate postoperative pathological fracture of the donor radius. Donor morbidity is similar to that of the fasciocutaneous radial forearm free flap , affording safe use of OCRFFF in head and neck reconstruction. PMID- 22942942 TI - Degloving injuries of the oral cavity change the operative approach to fractures of the anterior segment of the mandible. AB - No report to date describes the added risk traumatic, degloving injuries of the oral cavity may pose when treating fractures of the mandible. The authors describe the oral degloving injury, characterized by separation of periosteum and soft tissue of the anterior floor of the mouth from the inner cortex of the anterior segment. Vascular anatomy of the floor of the mouth is reviewed as a prelude to a description of pathomechanics of the injury and a case report. The higher incidence of oral degloving in youth and in young adulthood and parallels in elective, orthognathic surgery are identified. When this unusual clinical presentation occurs, and when open reduction of fractures of the anterior segment is chosen, a vestibular incision is best avoided. Instead, a submental or upper neck incision is chosen for sufficient exposure to allow reduction and the application of appliances. Meticulous closure of the intraoral void is achieved using one of two techniques, depending on the level of degloving. PMID- 22942943 TI - Failed Fixation in Atrophic Mandibular Fractures: The Case against Miniplates. AB - Despite advances in the treatment of the fractured atrophic edentulous mandible, treatment continues to be difficult. Patient management is more complicated due to patients often being elderly with more complex medical problems. Rigid internal fixation has greatly improved outcomes with shorter treatment times, yet a consensus has yet to be reached regarding which method yields the most predictable results. Options include using small miniplates to larger reconstruction plates. Although each method has advantages, we present our experience with retreatment of failed miniplate fixation using load-bearing reconstruction plates of fractured atrophic edentulous mandibles. PMID- 22942944 TI - Orbital wall reconstruction with titanium mesh: retrospective study of 24 patients. AB - The aim of this study was to evaluate the efficacy and safety of traumatic orbital defect reconstruction with titanium mesh. A retrospective study was made. Evaluations were made after a minimum postoperative follow-up of 12 months, looking for the main complications. Twenty-four patients were included in this evaluation; 19 were male (79.1%) and 5 (20.8%) were female. The main injury etiology was vehicle accidents (50%) followed by other causes. Fourteen patients (58.3%) presented orbital floor fractures, and 10 had more than one wall fractured (41.6%). Permanent infraorbital nerve hypoesthesia was observed in two patients (8.3%), enophthalmos occurred in five patients (20.8%), and exophthalmos was found in two patients (8.3%). Four patients (16.6%) still presented evidence of residual prolapsed intraorbital content, and one of those needed further surgical correction; sinusitis occurred in one patient (4.1%). Titanium mesh is a reliable option for orbital reconstruction, despite some complications found in this sample. PMID- 22942945 TI - The horizontal and stepped osteotomy technique for mandibular reconstruction using fibular free flap. AB - The mandible is an important component of the orofacial skeleton, and resection of part of the mandible as part of head and neck oncological procedures can have dramatic impact on both function and cosmesis. In this article, we describe a new technique in the resection osteotomy and flap fixation that improves the stability and aesthetic outcome of the reconstruction. The mandibular resection is performed utilizing a horizontal osteotomy above the mandibular angle on one side and a stepped body or angle osteotomy on the other side. Our technique is unique as it allows flexibility in adjusting the chin point projection to give the best possible aesthetic outcome; it allows more bone-to-bone contact, which increases the stability; it reduces rotation; and it allows for use of miniplate fixation, facilitating future rehabilitation with implants. We have been using this technique with great success in our hospital, and we recommend its use for its improved flexibility, stability, and aesthetic outcome. PMID- 22942946 TI - An aesthetically possible alternative approach for craniomaxillofacial trauma: the "pretrichial incision". AB - Frontal sinus and supraorbital rim fractures are common in facial trauma patients. Coronal incision is the standard approach for surgical management of these injuries. Nevertheless, with this incision, complications can occur as wide scars and alopecia. Because surgical repair of fronto-orbital fractures is often indicated for aesthetic reasons, surgical incision might be an "aesthetic incision." So we have adopted the pretrichial incision, already used in brow-lift and foreheadplasty but never described in craniomaxillofacial trauma surgery. Nineteen upper-third facial trauma patients were treated: five cases were approached via an existing laceration, four cases via a coronal incision, and 10 cases via a unilateral zigzag pretrichial incision. To assess the postsurgical scar, the Patient and Observer Scar Assessment Scale was used and the scar's width was measured. In all cases, a wide surgical field was obtained to perform correct fracture reduction. Unlike straight or stealth coronal incisions, with pretrichial incision no wide scar or alopecia was registered. We think that pretrichial incision is an aesthetically reasonable alternative to the standard coronal approach for craniomaxillofacial trauma patients. PMID- 22942947 TI - Dendritic myxofibrolipoma: often misdiagnosed as sarcoma. AB - The author describes a benign soft tissue tumor that could be easily mistaken for sarcoma. It represents a combined feature of solitary fibrous tumor and spindle cell lipoma. The clinical presentation, diagnosis, and management of this lesion are discussed. It highlights the importance of proper diagnosis to prevent unnecessary and ineffective treatment by clinicians as the complete excision of this lesion is the treatment of choice and recurrence is very unlikely. It is believed that this case is the first reported case of dendritic myxofibrolipoma occurring in the lower lip mucosa in an Omani patient. PMID- 22942948 TI - A new and easy technique of maxillomandibular fixation in treatment of mandibular fractures. AB - The present work evaluated the success of maxillomandibular fixation (MMF) by a new and simplified technique in management of minimally displaced mandibular fractures. A total of 20 patients who sustained various types of mandibular fractures were treated at the Government Dental College, Rohtak, India by a new MMF technique. The patients were evaluated by preoperative and postoperative radiography, and clinical testing was performed to assess the degree of tooth mobility adjacent to the site of MMF. The time required for MMF was also noted. Patient recovery was uneventful in all 20 cases, and the period of MMF ranged from 2 to 4 weeks (mean 21 days). The outcome was good. The mean time for performing MMF was 12 minutes (range, 10 to 15 minutes). It is a simple, quick, economical, and minimally invasive technique. Its mechanical principle provides an advantage in preventing postoperative periodontal problems. PMID- 22942949 TI - Duty hours: time to study? PMID- 22942950 TI - Getting off the "gold standard": randomized controlled trials and education research. PMID- 22942952 TI - Toward "The Genius of the AND": Balancing Professionalism and Duty Hour Requirements in Graduate Medical Education. AB - Although enhancing professionalism and ensuring compliance with duty hour regulations both represent important priorities of current graduate medical education, tension in reconciling these goals has been expressed. The term tyranny of the OR has been coined to express the assumption of dichotomous thinking, that is, that we assume we must choose between seemingly competing goals. In contrast, because there is powerful creative value in adopting a bridging mindset, an alternative state called the genius of the AND has been defined to express the benefits of reconciling perceived competing goals. PMID- 22942951 TI - Comprehensive training curricula for minimally invasive surgery. AB - BACKGROUND: The unique skill set required for minimally invasive surgery has in part contributed to a certain portion of surgical residency training transitioning from the operating room to the surgical skills laboratory. Simulation lends itself well as a method to shorten the learning curve for minimally invasive surgery by allowing trainees to practice the unique motor skills required for this type of surgery in a safe, structured environment. Although a significant amount of important work has been done to validate simulators as viable systems for teaching technical skills outside the operating room, the next step is to integrate simulation training into a comprehensive curriculum. OBJECTIVES: This narrative review aims to synthesize the evidence and educational theories underlining curricula development for technical skills both in a broad context and specifically as it pertains to minimally invasive surgery. FINDINGS: The review highlights the critical aspects of simulation training, such as the effective provision of feedback, deliberate practice, training to proficiency, the opportunity to practice at varying levels of difficulty, and the inclusion of both cognitive teaching and hands-on training. In addition, frameworks for integrating simulation training into a comprehensive curriculum are described. Finally, existing curricula on both laparoscopic box trainers and virtual reality simulators are critically evaluated. PMID- 22942953 TI - Developing future faculty: a program targeting internal medicine fellows' teaching skills. AB - INTRODUCTION: The increased demand for clinician-educators in academic medicine necessitates additional training in educational skills to prepare potential candidates for these positions. Although many teaching skills training programs for residents exist, there is a lack of reports in the literature evaluating similar programs during fellowship training. AIM: To describe the implementation and evaluation of a unique program aimed at enhancing educational knowledge and teaching skills for subspecialty medicine fellows and chief residents. SETTING: Fellows as Clinician-Educators (FACE) program is a 1-year program open to fellows (and chief residents) in the Department of Internal Medicine at the University of Iowa. PROGRAM DESCRIPTION: The course involves interactive monthly meetings held throughout the academic year and has provided training to 48 participants across 11 different subspecialty fellowships between 2004 and 2009. PROGRAM EVALUATION: FACE participants completed a 3-station Objective Structured Teaching Examination using standardized learners, which assessed participants' skills in giving feedback, outpatient precepting, and giving a mini-lecture. Based on reviews of station performance by 2 independent raters, fellows demonstrated statistically significant improvement on overall scores for 2 of the 3 cases. Participants self assessed their knowledge and teaching skills prior to starting and after completing the program. Analyses of participants' retrospective preassessments and postassessments showed improved perceptions of competence after training. CONCLUSION: The FACE program is a well-received intervention that objectively demonstrates improvement in participants' teaching skills. It offers a model approach to meeting important training skills needs of subspecialty medicine fellows and chief residents in a resource-effective manner. PMID- 22942954 TI - Training gaps for pediatric residents planning a career in primary care: a qualitative and quantitative study. AB - BACKGROUND: Resident training in pediatrics currently entails similar training for all residents in a fragmented curriculum with relatively little attention to the career plans of individual residents. OBJECTIVES: To explore strengths and gaps in training for residents planning a career in primary care pediatrics and to present strategies for addressing the gaps. METHODS: Surveys were sent to all graduates of the University of Colorado Denver Pediatric Residency Program (2003 2006) 3 years after completion of training. Respondents were asked to evaluate aspects of their training, using a 5-point Likert scale and evaluating each item ranging from "not at all well prepared" to "extremely well prepared" for their future career. In addition, focus groups were conducted with practitioners in 8 pediatric practices in Colorado. Sessions were transcribed and hand coded by 2 independent coders. RESULTS: Survey data identified training in behavior and development (mean score, 3.72), quality improvement and patient safety strategies (mean, 3.57), and practice management (mean, 2.46) as the weakest aspects of training. Focus groups identified deficiencies in training in mental health, practice management, behavioral medicine, and orthopedics. Deficiencies noted in curriculum structure were lack of residents' long-term continuity of relationships with patients; the need for additional training in knowledge, skills, and attitudes needed for primary care (perhaps even a fourth year of training); and a training structure that facilitates greater resident autonomy to foster development of clinical capability and self-confidence. CONCLUSIONS: Important gaps were identified in the primary care training of pediatric residents. These data support the need to develop more career-focused training. PMID- 22942955 TI - Addressing core competencies through hospital quality improvement activities: attitudes and engagement. AB - BACKGROUND: Hospital quality improvement initiatives are becoming increasingly common. Little is known about the influence of these initiatives on resident learning and attitudes. Our objective was to assess whether training in a hospital committed to involving residents in hospital-initiated, continuous quality improvement (CQI), and to participation in such activities, would influence residents' attitudes toward CQI and engagement in the hospital community. METHODS: We surveyed Seattle Children's Hospital pediatric residents, from residency graduation years 2002-2009. We included questions about participation in quality improvement activities during residency and measures of attitude toward CQI and of workplace engagement. We used descriptive statistics to assess trends in resident participation in hospital CQI activities, attitudes toward CQI and workplace engagement. RESULTS: The overall response rate was 84% (162 of 194). Among graduated residents, there was a significant trend toward increased participation in CQI activities (P = .03). We found no difference in attitude toward CQI between those who had and those who had not participated in such activities nor between residents who began training before and those who began after the hospital formally committed to CQI. Sixty-three percent of residents (25 of 40) who participated in CQI activities were engaged in the hospital community compared with 53% (57 of 107) who did not participate in CQI activities (P = .21). CONCLUSIONS: Training in a hospital committed to involving residents in CQI was associated with a high rate of participation in CQI activities. Although such training and participation in CQI were not associated with resident attitudes toward CQI or hospital engagement, it may allow residents to learn skills for practice-based learning and improvement and systems-based practice. PMID- 22942956 TI - Learning clinical versus leadership competencies in the emergency department: strategies, challenges, and supports of emergency medicine residents. AB - BACKGROUND: Emergency medicine residents are expected to master 6 competencies that include clinical and leadership skills. To date, studies have focused primarily on teaching strategies, for example, what attending physicians should do to help residents learn. Residents' own contributions to the learning process remain largely unexplored. The purpose of this study was to explore what emergency medicine residents believe helps them learn the skills required for practice in the emergency department. METHODS: This qualitative study used semistructured interviews with emergency medicine residents at a major academic medical center. Twelve residents participated, and 11 additional residents formed a validation group. We used phenomenologic techniques to guide the data analysis and techniques such as triangulation and member checks to ensure the validity of the findings. RESULTS: We found major differences in the strategies residents used to learn clinical versus leadership skills. Clinical skill learning was approached with rigor and involved a large number of other physicians, while leadership skill learning was unplanned and largely relied on nursing personnel. In addition, with each type of skills, different aspects of the residents' personalities, motivation, and past nonclinical experiences supported or challenged their learning process. CONCLUSION: The approaches to learning leadership skills are not well developed among emergency medicine residents and result in a narrow perspective on leadership. This may be because of the lack of formal leadership training in medical school and residency, or it may reflect assumptions regarding how leadership skills develop. Substantial opportunity exists for enhancing emergency medicine residents' learning of leadership skills as well as the teaching of these skills by the attending physicians and nurses who facilitate their learning. PMID- 22942957 TI - Using a simulated surgical skills station to assess laceration management by surgical and nonsurgical residents. AB - OBJECTIVE: To assess laceration management performance among surgical and nonsurgical postgraduate year-1 (PGY-1) residents objectively and to test for interval improvement. METHODS: From 2006 to 2008, 106 PGY-1 residents from 10 medical specialties were evaluated with a simulated surgical skills station using pigs' feet before and after internship. Subjects were given 11 minutes to choose the proper suture, prepare and close the wound, and answer laceration management questions. Trainees were classified as surgical (emergency medicine, general surgery, obstetrics and gynecology, orthopedics, and otolaryngology) and nonsurgical (family medicine, internal medicine, neurology, pediatrics, and transitional year). An objective checklist was used to assess performance. RESULTS: A total of 106 PGY-1 residents (age range, 25-44 years; mean, 28.7 years) participated, consisting of 41 surgical (39%) and 65 nonsurgical residents (61%). Surgical group scores improved from 78.4% to 87.7% (P < .001). Nonsurgical scores improved from 67.2% to 73.1% (P < .001). There was similar improvement between groups (surgical, 9.4%; nonsurgical, 5.9%; P = .21). Surgical residents outscored nonsurgical residents before (P < .001) and after (P < .001) internship. CONCLUSION: Surgical residents outperformed nonsurgical residents before and after the PGY-1 year with similar score improvements. A simulated surgical skills station can be used to evaluate procedure performance objectively and to test for interval improvement. A simulated surgical skills station may serve as a useful adjunct to apprenticeship in assessing procedure competence. PMID- 22942958 TI - A Pilot Study of a "Resident Educator And Life-long Learner" Program: Using a Faculty Train-the-Trainer Program. AB - PURPOSE: We sought to create a resident educator program using a Train-the Trainer (TTT) approach with adaptable curricula at a large tertiary health care center with a medical school and 60 accredited residency programs. METHODS: The Resident Educator And Life-long Learner (REALL) Program was designed as a 3-phase model. Phase 1 included centralized planning and development that led to the design of 7 teaching modules and evaluation tools for TTT and resident sessions. Phase 2 entailed the dissemination of the TTT modules (Learning Styles, Observational Skills, Giving Feedback, Communication Skills: The Angry Patient, Case-Based Teaching, Clinical Reasoning, Effective Presentations) to faculty trainers. In phase 3, specific modules were chosen and customized by the faculty trainers, and implemented for their residents. Evaluations from residents and faculty were collected throughout this process. RESULTS: A total of 45 faculty trainers representing 27 residency programs participated in the TTT program, and 97% of trainers were confident in their ability to implement sessions for their residents. A total of 20 trainers from 11 residency programs implemented 33 modules to train 479 residents, and 97% of residents believed they would be able to apply the skills learned. Residents' comments revealed appreciation of discussion of their roles as teachers. CONCLUSION: Use of an internal TTT program can be a strategy for dissemination of resident educator and life-long learner curricula in a large academic tertiary care center. The TTT model may be useful to other large academic centers. PMID- 22942959 TI - Residents' attitudes and behaviors regarding care for underserved patients: a multi-institutional survey. AB - BACKGROUND: Resident physicians often encounter underprivileged patients before other providers, yet little is known about residents' attitudes and behaviors regarding these patients. OBJECTIVE: To measure US resident physician attitudes regarding topics relevant to medically underserved patients, their behaviors (volunteerism) with underserved patients, and the association between attitudes and behaviors. METHODS: In 2007 and 2008, 956 surveys on resident attitudes and behaviors about underserved patients were distributed to 18 residency programs in the United States. Survey content was based on existing literature and an expert needs assessment. The attitude assessment had 15 items with 3-point scales (range 0-1). The behavior assessment evaluated volunteering for underserved patients in the past, present, and future. RESULTS: A total of 498 surveys (response rate = 52%) were completed. Attitudes regarding underserved patients were generally positive and more favorable for women than men (overall attitude score 0.83 versus 0.74; P = < .001). Rates of volunteering for underserved patients were high in medical school (N = 375, 76%) and anticipated future practice (N = 409, 84%), yet low during residency (N = 95, 19%). Respondents who volunteered regularly had more favorable attitudes than those who did not volunteer (overall average attitude score of 0.81 versus 0.73; P = <.001). Relationships between hours volunteered per-week and favorable attitudes about topics related to the underserved were significant across all 15 items in medical school and anticipated future practice (P value range of .035 to <.0001). CONCLUSIONS: This survey revealed that US residents' attitudes towards topics regarding medically underserved populations are generally favorable. Rates of volunteerism for underserved patients were higher in medical school than during residency, and resident's anticipated rates of volunteerism in future practice volunteerism were approximately the same as rates of volunteerism in medical school. Resident attitudes are strongly correlated with volunteerism. PMID- 22942960 TI - Effect of medical students' experiences with residents as teachers on clerkship assessment. AB - BACKGROUND: We assessed the impact of resident teaching in medical students' overall assessment of an obstetrics and gynecology clerkship. METHODS: Between September 2007 and March 2010, third-year medical students completed a questionnaire at the end of their clerkship. Questions covered the number of topics they recalled learning about from residents, perceptions of the quality of education received from residents, perceptions of the experience with the residents as teachers, and overall rating of the obstetrics and gynecology clerkship. RESULTS: Questionnaires were completed by all medical students (N = 74), with 63 students returning complete surveys. There was a small correlation between the number of topics students recalled learning about from residents and ratings of quality of education (r = 0.249, P = .03), a small correlation between the number of topics students recalled learning about from residents and level of satisfaction with the clerkship (r = 0.262, P = .04), and a larger correlation between assessment of the overall experience with residents as teachers and ratings of quality of education received from residents (r = 0.687, P < .001). Overall experience with residents as teachers and perceived quality of education from residents were both associated with satisfaction with the clerkship (r = 0.756, P < .001 and r = 0.603, P < .001, respectively). A regression model with these variables accounted for 58% of the variability in students' ratings of the clerkship (F = 27.103, P < .001, R = .761, R(2) = .579). The only significant independent variable was assessment of the overall experience with residents as teachers (t = 5.350, P < .001). CONCLUSION: Quality of interactions between residents and medical students is a key factor in medical students' assessment of their clerkship. PMID- 22942961 TI - Missed appointments in resident continuity clinic: patient characteristics and health care outcomes. AB - BACKGROUND: Frequent missed patient appointments in resident continuity clinic is a well-documented problem, but whether rates of missed appointments are disproportionate to standard academic practice, what patient factors contribute to these differences, and health care outcomes of patients who frequently miss appointments are unclear. METHODS: The overall population for the study was composed of patients in an academic internal medicine continuity clinic with 5 or more office visits between January 2006 and December 2008. We randomly selected 325 patients seen by resident physicians and 325 patients cared for by faculty. Multivariate linear regression was used to examine the relationship between patient factors and missed appointments. Health outcomes were compared between patients with frequent missed appointments and the remainder of the study sample, using Cox regression analysis. RESULTS: Resident patients demonstrated significantly higher rates of missed appointments than faculty patients, but this difference was explained by patient factors. Factors associated with more missed appointments included use of a medical interpreter, Medicaid insurance, more frequent emergency department visits, less time impanelled in the practice, and lower proportion of office visits with the primary care provider. Patients with frequent missed appointments were less likely to be up to date with preventive health services and more likely to have poorly controlled blood pressure and diabetes. CONCLUSIONS: We found that the disproportionate frequency of missed appointments in resident continuity clinic is explained by patient factors and practice discontinuity, and that patients with frequent missed appointments demonstrated worse health care outcomes. PMID- 22942962 TI - Feasibility and reliability of a multisource feedback tool for emergency medicine residents. AB - BACKGROUND: While the Accreditation Council for Graduate Medical Education recommends multisource feedback (MSF) of resident performance, there is no uniformly accepted MSF tool for emergency medicine (EM) trainees, and the process of obtaining MSF in EM residencies is untested. OBJECTIVE: To determine the feasibility of an MSF program and evaluate the intraclass and interclass correlation of a previously reported resident professionalism evaluation, the Humanism Scale (HS). METHODS: To assess 10 third-year EM residents, we distributed an anonymous 9-item modified HS (EM-HS) to emergency department nursing staff, faculty physicians, and patients. The evaluators rated resident performance on a 1 to 9 scale (needs improvement to outstanding). Residents were asked to complete a self-evaluation of performance, using the same scale. ANALYSIS: Generalizability coefficients (Erho(2)) were used to assess the reliability within evaluator classes. The mean score for each of the 9 questions provided by each evaluator class was calculated for each resident. Correlation coefficients were used to evaluate correlation between rater classes for each question on the EM-HS. Erho(2) and correlation values greater than 0.70 were deemed acceptable. RESULTS: EM-HSs were obtained from 44 nurses and 12 faculty physicians. The residents had an average of 13 evaluations by emergency department patients. Reliability within faculty and nurses was acceptable, with Erho(2) of 0.79 and 0.83, respectively. Interclass reliability was good between faculty and nurses. CONCLUSIONS: An MSF program for EM residents is feasible. Intraclass reliability was acceptable for faculty and nurses. However, reliable feedback from patients requires a larger number of patient evaluations. PMID- 22942963 TI - Competence in patient safety: a multifaceted experiential educational intervention for resident physicians. AB - BACKGROUND: The need to provide efficient, effective, and safe patient care is of paramount importance. However, most physicians receive little or no formal training to prepare them to address patient safety challenges within their clinical practice. METHODS: We describe a comprehensive Patient Safety Learning Program (PSLP) for internal medicine and medicine-pediatrics residents. The curriculum is designed to teach residents key concepts of patient safety and provided opportunities to apply these concepts in the "real" world in an effort to positively transform patient care. Residents were assigned to faculty expert led teams and worked longitudinally to identify and address patient safety conditions and problems. The PSLP was assessed by using multiple methods. RESULTS: Resident team-based projects resulted in changes in several patient care processes, with the potential to improve clinical outcomes. However, faculty evaluations of residents were lower for the Patient Safety Improvement Project rotation than for other rotations. Comments on "unsatisfactory" evaluations noted lack of teamwork, project participation, and/or responsiveness to faculty communication. Participation in the PSLP did not change resident or faculty attitudes toward patient safety, as measured by a comprehensive survey, although there was a slight increase in comfort with discussing medical errors. CONCLUSIONS: Development of the PSLP was intended to create a supportive environment to enhance resident education and involve residents in patient safety initiatives, but it produced lower faculty evaluations of resident for communication and professionalism and did not have the intended positive effect on resident or faculty attitudes about patient safety. Further research is needed to design or refine interventions that will develop more proactive resident learners and shift the culture to a focus on patient safety. PMID- 22942964 TI - Factors influencing choice of medical specialty of preresidency medical graduates in southeastern Nigeria. AB - BACKGROUND: This study examined the determinants of specialty choice of preresidency medical graduates in southeastern Nigeria. METHODS: We used a comparative cross-sectional survey of preresidency medical graduates who took the Basic Sciences Examination of the Postgraduate Medical College in Enugu, southeastern Nigeria, in March 2007. Data on participants' demographics and specialty selected, the timing of the decision, and factors in specialty selection were collected using a questionnaire. Data were examined using descriptive and analytical statistics. P < .05 was considered significant. RESULTS: The survey response rate was 90.8% (287 of 316). The sample included 219 men and 68 women, ranging in age from 24 to 53 years and with a mean age of 33.5 +/- 1.1 (SD) years. Career choice was more frequently influenced by personal interest (66.6%), career prospects (9.1%), and appraisal of own skills/aptitudes (5.6%), and it was least affected by altruistic motives (1.7%) and influence of parents/relations (1.7%). The respondents selected specialties at different rates: obstetrics and gynecology (22.6%), surgery (19.6%), pediatrics (16.0%), anesthesiology (3.1%), psychiatry (0.3%), and dentistry (0.0%). Most (97.2%) participants had decided on specialty choice by the end of their fifth (of a total 16 years) postgraduate year. The participants significantly more frequently preferred surgery and pediatrics to other disciplines (P < .002, after Bonferroni correction for multiple comparisons). CONCLUSIONS: Preresidency medical graduates in southeastern Nigeria were influenced by personal interest, career prospects, and personal skills/aptitude in deciding which specialty training to pursue. The most frequently chosen specialties were surgery and pediatrics. These findings have implications for Nigeria's education and health care policy makers. PMID- 22942965 TI - Interdisciplinary prenatal group visits as a significant learning experience. AB - AIM: Group visits offer documented benefit to patients and clinicians. They also provide an excellent venue to teach residents interdisciplinary care and group facilitation skills. INTERVENTION: Third-year residents received experiential training to provide prenatal care through group visits rather than one-on-one visits. STUDY METHOD: A descriptive study is used to illustrate the effectiveness of various facets of resident skill acquisition and patient-centered prenatal care. Evaluation methods included feedback from patients, team members, learner self-reflection, and observation by a behavioral health clinician. SUMMARY: Residents collaboratively provide prenatal care in a group model during a 6-month period. Interdisciplinary team members explicitly teach and model biopsychosocial whole-person care and effective communication. This inventive experience has increased resident competency-based skills in facilitation and effective team collaboration as measured through observation. These skills are directly applicable in future primary care medical home practice. Using a group visit model benefits patients and clinicians, and promotes enriching and effective resident education. Our model can easily be implemented in other programs. PMID- 22942966 TI - Use of a policy debate to teach residents about health care reform. AB - BACKGROUND: Resident education involves didactics and pedagogic strategies using a variety of tools and technologies in order to improve critical thinking skills. Debating is used in educational settings to improve critical thinking skills, but there have been no reports of its use in residency education. The present paper describes the use of debate to teach resident physicians about health care reform. OBJECTIVE: We aimed to describe the method of using a debate in graduate medical education. METHODS: Second-year through fourth-year physical medicine and rehabilitation residents participated in a moderated policy debate in which they deliberated whether the United States has one of the "best health care system(s) in the world." Following the debate, the participants completed an unvalidated open-ended questionnaire about health care reform. RESULTS: Although residents expressed initial concerns about participating in a public debate on health care reform, all faculty and residents expressed that the debate was robust, animated, and enjoyed by all. Components of holding a successful debate on health care reform were noted to be: (1) getting "buy-in" from the resident physicians; (2) preparing the debate; and (3) follow-up. CONCLUSION: The debate facilitated the study of a large, complex topic like health care reform. It created an active learning process. It encouraged learners to keenly attend to an opposing perspective while enthusiastically defending their position. We conclude that the use of debates as a teaching tool in resident education is valuable and should be explored further. PMID- 22942967 TI - Addressing the Scholarly Activity Requirements for Residents: One Program's Solution. AB - BACKGROUND: Scholarly activity as a component of residency education is becoming increasingly emphasized by the Accreditation Council for Graduate Medical Education. "Limited or no evidence of resident or faculty scholarly activity" is a common citation given to family medicine residency programs by the Review Committee for Family Medicine. OBJECTIVE: The objective was to provide a model scholarly activity curriculum that has been successful in improving the quality of graduate medical education in a family medicine residency program, as evidenced by a record of resident academic presentations and publications. METHODS: We provide a description of the Clinical Scholars Program that has been implemented into the curriculum of the Trident/Medical University of South Carolina Family Medicine Residency Program. RESULTS: During the most recent 10 year academic period (2000-2010), a total of 111 residents completed training and participated in the Clinical Scholars Program. This program has produced more than 24 presentations during national and international meetings of medical societies and 15 publications in peer-reviewed medical journals. In addition, many of the projects have been presented during meetings of state and regional medical organizations. CONCLUSIONS: This paper presents a model curriculum for teaching about scholarship to family medicine residents. The success of this program is evidenced by the numerous presentations and publications by participating residents. PMID- 22942968 TI - A collaborative model for inpatient training in a small pediatric residency program. AB - BACKGROUND: The nationwide decline in pediatric admissions to community hospitals threatens the sustainability of small pediatric residency programs. Little is known about the response of small programs to this challenge. OBJECTIVES: We report on the design and evaluation of an innovative, collaborative model for pediatric inpatient training between an academic community medical center and a children's hospital. METHODS: We describe the operational, academic, and financial features of the model. Outcome measures include patient volume and subspecialty mix, resident and faculty perceptions as reported in an anonymous survey, and Accreditation Council for Graduate Medical Education Residency Review Committee (RRC) review. RESULTS: In 2003, Albert Einstein Medical Center (Einstein) closed its pediatric inpatient unit and established an independent teaching service at St Christopher's Hospital for Children (St Christopher's) in Philadelphia, Pennsylvania. Under the new model, patient volume and subspecialty mix more than tripled. Einstein residents and faculty identified 5 major strengths: level of responsibility and decision making, caring for medically complex children, quality of teaching, teamwork, and opportunity to participate in academic activities at a children's hospital. St Christopher's leadership reported increased volume, no disruption of their residency program, and no dilution of clinical teaching material. The Einstein program was reaccredited by the RRC in 2006 for 2 years and in 2009 for 4 years. CONCLUSION: A collaborative model for inpatient training was successful in maintaining a community hospital based pediatric residency program. Positive outcomes were documented for the residency program, the parent community hospital, and the collaborating children's hospital. PMID- 22942969 TI - The Utility of Letters of Recommendation in Predicting Resident Success: Can the ACGME Competencies Help? AB - BACKGROUND: The Accreditation Council for Graduate Medical Education (ACGME) core competencies are used to assess resident performance, and recently similar competencies have become an accepted framework for evaluating medical student achievements as well. However, the utility of incorporating the competencies into the resident application has not yet been assessed. PURPOSE: The objective of this study was to examine letters of recommendation (LORs) to identify ACGME competency-based themes that might help distinguish the least successful from the most successful residents. METHODS: Residents entering a university-based residency program from 1994 to 2004 were retrospectively evaluated by faculty and ranked in 4 groups according to perceived level of success. Applications from residents in the highest and lowest groups were abstracted. LORs were qualitatively reviewed and analyzed for 9 themes (6 ACGME core competencies and 3 additional performance measures). The mean number of times each theme was mentioned was calculated for each student. Groups were compared using the chi(2) test and the Student t test. RESULTS: Seventy-five residents were eligible for analysis, and 29 residents were ranked in the highest and lowest groups. Baseline demographics and number of LORs did not differ between the two groups. Successful residents had statistically significantly more comments about excellence in the competency areas of patient care, medical knowledge, and interpersonal and communication skills. CONCLUSION: LORs can provide useful clues to differentiate between students who are likely to become the least versus the most successful residency program graduates. Greater usage of the ACGME core competencies within LORs may be beneficial. PMID- 22942970 TI - Efficacy of peer-assisted learning across residencies for procedural training in dermatology. AB - BACKGROUND: With new care models such as the medical home, there is an expanding need for primary care providers to be trained in dermatologic procedures. Yet, many internal medicine residency program graduates feel unprepared to perform these procedures. The aim of this study was to evaluate the effect of a structured peer-assisted learning approach to improve residents' knowledge and skills related to common dermatologic assessment techniques. METHODS: Eight medicine-dermatology resident educators, with a faculty member, facilitated dermatologic procedure workshops for 28 internal medicine and medicine-pediatrics resident learners. Learners completed preworkshop and postworkshop surveys, assessing their knowledge and skill levels as well as the efficacy of the resident educators and the educational value of the workshop as a whole. RESULTS: All learners were able to properly demonstrate the techniques at the workshop's conclusion. The median sum score of self-reported knowledge increased from 3 to 9.5 (scale, 0-10; P < .001). The median sum score of self-reported skills increased from 10 to 16 (scale, 4-20; P < .001). Resident educators were favorably evaluated by their peers, and 96% of participants rated the experience as being of high educational value. CONCLUSION: Peer-assisted learning is effective in teaching dermatologic procedures in graduate medical education. Resident learners found peer-assisted learning to be beneficial and rated their peer teachers highly. Further studies should focus on outcomes in practice, looking at the number of dermatologic procedures performed by learners, as well as the effects on resident educators. PMID- 22942971 TI - Mainstreaming risk management education into new resident and fellow orientation. AB - INTRODUCTION: Understanding patient safety events and causative factors is an important step in reducing preventable adverse events. The University of Michigan's Graduate Medical Education (GME) Office, Department of Risk Management (DRM), and Office of Clinical Affairs (OCA) collaborated to incorporate a video workshop as a formal introduction to patient safety during orientation for new residents and fellows. This workshop reinforced the importance of effective communication and supervision in patient safety. METHODS: DRM and OCA produced a video depicting an actual, unanticipated outcome that resulted from a constellation of preventable circumstances, which allows the audience to observe communication and supervision issues that lead to a patient death. The video is followed by a discussion of the patient safety issues seen, why they occurred, and strategies for improvement. Trainee perceptions of the value of the experience were surveyed and collected using a qualitative survey. RESULTS: Most responders found the video workshop helpful. Trainees perceived the video and facilitated discussion as an effective way to identify patient safety issues, available resources, and the culture of patient safety at the institution. CONCLUSION: Trainee comments supported the video workshop as an effective way to highlight the importance of communication and supervision in relation to patient safety. In the future, the DRM, OCA, and GME hope to reinforce this shared vision of patient safety through combined educational efforts. PMID- 22942972 TI - Incoming resident interest in global health: occasional travel versus a future career abroad? AB - BACKGROUND: While there is growing interest among residents in participating in international health experiences, it is unclear whether this interest will translate into intentions to pursue a global health career. We aimed to describe overall interest in and career intentions toward global health among interns. METHODS: We administered an anonymous survey to incoming interns in all specializations during graduate medical education orientation at 3 teaching hospitals affiliated with 2 Midwestern US medical schools in June 2009. Survey domains included demographics, previous global health experiences, interest in and barriers to participating in global health experiences during residency, and plans to pursue a future global health career. RESULTS: Response rate was 87% (299 of 345 residents). The most commonly reported barriers to participating in global health experiences were scheduling (82%) and financial (80%) concerns. Two thirds of interns (65%) reported they were likely to focus on global health in their future career. Of those envisioning a global health career, 77% of interns reported interest in participating in short, occasional trips in the future; and 23% of interns intended to pursue a part-time or full-time career abroad. Interns committed to a career abroad were more willing to use vacation time (73% vs. 40% of all others, respectively; P < .001) or to personally finance the trip (58% vs. 27% of all others, respectively; P = < .001), and were less concerned about personal safety than interns not committed (9% vs. 26% of all others, respectively; P = .01). CONCLUSIONS: Although a large proportion of incoming interns report interest in global health careers, few are committed to a global health career. Medical educators could acknowledge career plans in global health when developing global health curricula. PMID- 22942973 TI - Organized continuity panel reassignment. AB - BACKGROUND: Structured continuity clinical experience is required in all primary care residency programs. There is a paucity of data on whether continuity patient panels are routinely used, what the ideal panel composition is, how panels are managed within residency programs across the country, and the outcomes related to this training requirement. METHODS: We designed an organized continuity panel reassignment process with the goal of producing balanced resident panels, that is, panels with similar numbers of patients by race/ethnicity, sex, and age group, as well as comparable numbers of patients with diabetes and those with high health care use. This project focused on postgraduate year-1 (PGY-1) panels to use balanced panels for redesign and focus of their initial training experiences on practice-based learning and patient care continuity. RESULTS: Findings suggest improved parity in patient care experiences through more evenly distributed panels. Furthermore, the focus on panel review and case management enhanced the curriculum for PGY-1 residents, whose clinical experiences and diabetes clinical quality indicators compared more favorably to residents in earlier classes. CONCLUSIONS: Balanced continuity panels provide an enhanced substrate for building clinical curricula. Preliminary data suggest that this process helped contribute to improved quality indicators for patients with diabetes. PMID- 22942974 TI - Training residents in obesity counseling: incorporating principles of motivational interviewing to enhance patient centeredness. AB - BACKGROUND: The US Preventive Services Task Force and the American Academy of Pediatrics recommend that physicians screen patients for obesity and practice counseling interventions to achieve modest (4%-8%) weight loss. Despite this, physicians frequently do not document obesity and/or counsel on weight loss. Our goal was to develop an innovative, easily disseminated workshop to improve resident physicians' skills and confidence in weight-loss counseling. METHODS: We developed a tailored 3-hour interactive Obesity Counseling Workshop. The approach incorporates principles of motivational interviewing, a set of listening and counseling skills designed to enhance patient centeredness and promote behavior change. Adult learning theory served as the foundation for program delivery. The half-day session is administered monthly to internal medicine and pediatric residents on outpatient rotations. KEY RESULTS: To date 77 residents (44 internal medicine and 33 pediatric) have completed the workshop, with approximately even distribution of postgraduate year (PGY)-1, PGY-2, and PGY-3 level residents. Forty-two were women and less than half planned to pursue a primary care-oriented career. Residents completed a 10-item workshop evaluation, with each category scoring an average of 3.5 or greater on a 4-point Likert scale. Residents reported the workshop was well organized and addressed an important topic; they enjoyed the role-playing with observation and feedback. CONCLUSIONS: Residents welcomed the opportunity to participate in an interactive workshop focused on obesity counseling and behavior change, and particularly liked putting new skills into practice with role-playing and receiving real-time feedback. Future analyses will determine the workshop's effect on knowledge, skills, and self-efficacy. PMID- 22942975 TI - Using a web-based survey for the annual internal medicine residency evaluation. AB - BACKGROUND: The Accreditation Council for Graduate Medical Education requires annual surveys of residency programs. INTERVENTION: We switched from a paper based to a web-based survey and report on the efficiency and quality improvement gains from this change. To determine the prevalence of web-based surveys, we conducted a web-based and telephone survey of 17 internal medicine residency training programs in Southern California. Fifteen programs provided data (88% response rate). RESULTS: By making the switch, our internal medicine residency program was able to save over 50 administrative hours and over 1000 pieces of paper. A total investment of $20 for the Surveymonkey.com account (Palo Alto, CA) and approximately 15 hours to migrate the survey was made. The program administrators were able to more rapidly analyze and respond to the feedback from the residents with this system. Our survey of other programs showed that of 15 programs, 12 used a web-based survey system (80%) and 3 used a paper-based system (20%). Surveymonkey.com was the most popular system used. CONCLUSIONS: We feel that the quality of response to resident feedback was enhanced by the real-time reaction to comments and assessments. Residents also appreciated the benefits of such a change. We recommend this approach to other programs that are still using paper-based surveys. PMID- 22942976 TI - The importance of international medical rotations in selection of an otolaryngology residency. AB - BACKGROUND: The objective of this study was to determine the extent of interest in international electives among prospective otolaryngology residents and to determine whether the availability of international electives affected students' interest in ranking a particular residency program. METHODS: A 3-part survey was given to all medical students enrolled in the 2008 otolaryngology match via the Electronic Residency Application Service. Part 1 elicited demographic information. Part 2 explored general interest in international rotations. Part 3 involved ranking several factors affecting students' choice of residency programs. This survey was developed at our institution, with no formal validation. Participation was anonymous and voluntary. RESULTS: A total of 307 students entered the otolaryngology match, and 55 surveys (18%) were completed. Twenty-five of 55 students (55%) had completed an international elective during or prior to medical school, and 51 of 55 respondents (93%) had a "strong" or "very strong" desire to participate in an international elective during residency; 48 of 55 students (87%) had a "strong" or "very strong" desire to participate in international surgical missions after residency. Future practice goals had no correlation with interest in international rotations, either during or after residency training. Respondents ranked 8 factors that had an impact on residency program selection in the following order of importance: operative experience, location, lifestyle, research opportunities, didactics, international electives, prestige of program, and salary. CONCLUSION: Interest in international medicine among prospective otolaryngologists was high in this subset of respondents but did not appear to affect residency program selection. PMID- 22942977 TI - Residents' awareness of racial and ethnic disparities in cardiovascular care. AB - PURPOSE: To characterize attitudes of residents toward racial/ethnic disparities in health care and to explore the effect of a simple intervention to improve awareness of these disparities. METHODS: The authors surveyed residents in internal and emergency medicine rotating through the Coronary Care Unit of a major teaching hospital about their attitudes toward disparities in cardiovascular care before and after an intervention that fostered discussion of evidence for the existence of disparities, possible causes of disparities, and clinically focused approaches to quality improvement tailored to the residents' practice environment. RESULTS: Before the intervention, 35% of residents agreed that racial/ethnic disparities might occur for patients within the US health care system in general, and only 7% agreed that patients they personally treated might experience racial/ethnic disparities in healthcare. These proportions increased significantly after the intervention: 85% agreement at level of US health care system and 32% at the level of individual practice (P < .001). Changes in awareness did not differ by sex, postgraduate year of training, race/ethnicity, reported prior diversity training, or plans to subspecialize. CONCLUSION: Awareness of racial/ethnic disparities in care among residents remains low, particularly at the level of individual practice, but is amenable to intervention. PMID- 22942978 TI - Global health training during residency: the weill cornell Tanzania experience. AB - BACKGROUND: In 2007, Weill Cornell Medical College (WCMC) began annually to send approximately 30 residents in internal medicine and pediatrics to Bugando Medical Center in Mwanza, Tanzania, where they were supervised and mentored by 2 full time WCMC faculty physicians. OBJECTIVE: To describe the components of the WCMC global health elective and to evaluate the experiences of the participants. METHODS: Subjects were WCMC residents in internal medicine and pediatrics from the graduating classes of 2007-2009. Electronic surveys were sent to all participants (n = 57) and to a group of nonparticipants (n = 57). RESULTS: Overall response rate was 58%. The most-selected, primary reasons for participation in the program were an interest in global health and a desire to serve an underprivileged population. Participants rated use of routine laboratory tests in the United States as more overused than did nonparticipants (P = .01). After the elective, 62% of participants reported a reduced use of laboratory and/or radiologic tests. All participants (100%; 39 of 39) reported the elective as having a positive effect on their knowledge of international health and tropical medicine. More than 90% of participants (36 of 39) reported the elective as having a positive effect on their physical examination skills. CONCLUSIONS: Participants of the WCMC global health elective report positive experiences from our multidimensional global health collaboration. PMID- 22942979 TI - Internal medicine residents' acceptance of self-directed learning plans at the point of care. AB - OBJECTIVES: We implemented a curriculum using self-directed learning plans (SDLPs) based on clinical questions arising from the residents' practice, and we report on perceptions and attitudes from residents in internal medicine regarding the use of SDLPs conceived at point of care. METHODS: Internal medicine residents at a single community hospital in the Midwest were surveyed in 2006 regarding SDLPs. We report their perceived effectiveness in identifying knowledge gaps, the processes used to fill those gaps, and the resident outcomes using descriptive statistics. RESULTS: A total of 26 out of 37 residents (70%) responded. Most (24 of 26; 92%) perceived SDLPs helped them to identify and fill knowledge gaps and that their skills in framing questions (23 of 26; 88%), identifying resources (21 of 26; 81%), and critically appraising the evidence (20 of 26; 77%) improved through regular use. They also felt these plans led to a meaningful change in their practice or provided further direction for learning (17 of 26; 65%). Most (21 of 26; 81%) reported their intent to include point-of-care learning in their continuing education after residency. We found no significant differences in the responses of first-year compared with second- or third-year residents. CONCLUSIONS: Questions arising during patient care are strong motivators for physician self-directed learning. The residents' responses indicated that they accepted the SDLPs and intend to use them in practice. Embedding the discussion of the SDLPs in preclinic conferences has ensured sustainability during the past 5 years and has enabled us to demonstrate teaching of practice-based learning and improvement. PMID- 22942981 TI - A simple, innovative surgical-instruction tool. AB - In the present report, we demonstrate the utility of a knitting needle as a device to improve the teaching of surgical principals and practice. Although we emphasize obstetric and gynecologic surgery, these techniques can easily be applied to other surgical specialties. PMID- 22942980 TI - Opportunities in global health education: a survey of the virtual landscape. AB - BACKGROUND: A new generation of medical students is seeking residency programs offering global health education (GHE), and there is growing awareness of the benefits this training provides. However, basic factors that have an impact on its implementation and its effect on the residency match are insufficiently understood. The purpose of this study was to explore the extent of online information on GHE available to potential US pediatric residency program applicants. METHODS: Pediatric residency programs' websites were systematically examined in 2007, 2008, and 2009 to extract available information on GHE. RESULTS: In 2007, 147 websites (76.2%) had no information available on GHE; 40 (20.7%) mentioned international opportunities; and 6 (3.1%) provided evidence of a global health track or program. In 2008, 123 websites (63.1%) had no information available on GHE; 57 (29.2%) mentioned international opportunities; and 15 (7.7%) had a formal program. In 2009, 105 websites (53.6%) had no information available on GHE; 70 (35.7%) mentioned international opportunities; and 21 (10.7%) had a formal program. Between 2007 and 2009, the percentage of pediatric residency programs with information on GHE available nearly doubled from 23.8% to 46.4%. Within the same period, the number of formal GHE programs offered more than tripled. CONCLUSIONS: By the 2009-2010 academic year, the websites for nearly half of the residency programs mentioned international experiences, yet only a small number of these residencies appeared to have developed a formal GHE program. Further, the websites for many residency programs did not include information on the international opportunities they offered, with programs running the risk of failing to attract and ultimately match global health-minded applicants. PMID- 22942982 TI - The Year is Over, Now What? The Annual Program Evaluation. PMID- 22942983 TI - Implementing an Institution-wide Resident-as-Teacher Program: Successes and Challenges. PMID- 22942984 TI - The Resident-as-Teacher: It's More Than Just About Student Learning. PMID- 22942985 TI - The elusive leadership competency. PMID- 22942986 TI - Fulfilling a social obligation. PMID- 22942987 TI - Writing case reports for the clinical literature: practical approach for the novice author. PMID- 22942989 TI - Imagine a circle of trust for doctors. PMID- 22942990 TI - A domain-knowledge-inspired mathematical framework for the description and classification of H&E stained histopathology images. AB - We present the current state of our work on a mathematical framework for identification and delineation of histopathology images-local histograms and occlusion models. Local histograms are histograms computed over defined spatial neighborhoods whose purpose is to characterize an image locally. This unit of description is augmented by our occlusion models that describe a methodology for image formation. In the context of this image formation model, the power of local histograms with respect to appropriate families of images will be shown through various proved statements about expected performance. We conclude by presenting a preliminary study to demonstrate the power of the framework in the context of histopathology image classification tasks that, while differing greatly in application, both originate from what is considered an appropriate class of images for this framework. PMID- 22942991 TI - Metabolic limitations of performance and fatigue in football. AB - Football participation requires considerable utilization of both aerobic and anaerobic energy systems to match the high energetic demands of the sport. The consequent stresses imposed on the physiological and metabolic systems carries players to the threshold of exhaustion during match-play, from which they are required to recover in preparation for the subsequent game. A high number of players experience fatigue during the high-intensity bouts and a consequent decline in their performance towards the end of the game is a likely outcome during match-play. The current review aims to establish the current understanding that relates to metabolic limitations of performance and the associated mechanisms for the onset of fatigue that may be instrumental in further development of evidence-based nutritional and training interventions in this event. PMID- 22942992 TI - Influence of morphological characteristics on physical and physiological performances of tunisian elite male handball players. AB - PURPOSE: The purpose of this study was to describe the body structure and morphological characteristics of Tunisian elite handball players, and to determine the effect of these variables on functional and physical performance levels. METHODS: A sample of 42 male handball players (mean age 21.98+/-3.24 years; training duration 12 years) at international level was submitted to a test battery comprising morphological, physical and physiological assessments. Tests were yo-yo intermittent recovery test, squat jump test, countermovement jump test, vertical-jump test, and Repeated sprint Ability. Measures for assessment of anthropometric characteristics were age, size, weight, body mass index, body fat, fat mass and thin mass. RESULTS: Weight was negatively correlated to the squat jump and the countermovement jump performance. Age, weight, and body composition measures (fat and thin body mass) were additionally negatively related to the maximal oxygen uptake, and to the maximal velocity obtained in the Yo-Yo recovery test. No relationship was found between size, body mass index, body fat and the physical abilities considered. Concerning the effects of physical characteristics on the functional performances, we can note a positive relationship between squat jump, countermovement jump, and the yo-yo recovery test performance. No relationship was found between vertical jump, repeated sprint ability, and the physiological performances. CONCLUSIONS: Study results point to the existence of strong correlation between morphological and physical characteristics with functional characteristics. In handball, it is possible to have a reliable estimate of anthropometric measurements, physical and physiological performances. PMID- 22942993 TI - The effect of an ecological imagery program on soccer performance of elite players. AB - PURPOSE: Despite the acknowledged impact of imagery on performance, ecologically sound studies investigating imagery and its effects on performance subcomponents in real games are surprisingly limited. The aim of this study was to investigate the effects of imagery training on passing improvement in elite soccer players. METHODS: Sixty nine soccer players taking part in the national championship leagues in four age categories including U16, U19, U21 and over 21 were randomly assigned to the imagery and control groups. Interventional group participants completed an 8 week video-aided, cognitive imagery program on how to make a perfect soccer pass. RESULTS: Performance analysis through close video analysis showed that successful pass rate increased significantly in the intervention group compared to control (OR = 1.19, P=0.002, (95%)CI = 1.06-1.33). Further analysis revealed that the results are statistically significant in U16 and U21 but not other categories. CONCLUSIONS: We concluded that successful soccer passing through real competitions as a multidimensional and critical open skill could be enhanced by an ecologically sound method of mental imagery. PMID- 22942994 TI - Predictor variables for marathon race time in recreational female runners. AB - PURPOSE: We intended to determine predictor variables of anthropometry and training for marathon race time in recreational female runners in order to predict marathon race time for future novice female runners. METHODS: Anthropometric characteristics such as body mass, body height, body mass index, circumferences of limbs, thicknesses of skin-folds and body fat as well as training variables such as volume and speed in running training were related to marathon race time using bi- and multi-variate analysis in 29 female runners. RESULTS: The marathoners completed the marathon distance within 251 (26) min, running at a speed of 10.2 (1.1) km/h. Body mass (r=0.37), body mass index (r=0.46), the circumferences of thigh (r=0.51) and calf (r=0.41), the skin-fold thicknesses of front thigh (r=0.38) and of medial calf (r=0.40), the sum of eight skin-folds (r=0.44) and body fat percentage (r=0.41) were related to marathon race time. For the variables of training, maximal distance ran per week (r=- 0.38), number of running training sessions per week (r=- 0.46) and the speed of the training sessions (r= - 0.60) were related to marathon race time. In the multi-variate analysis, the circumference of calf (P=0.02) and the speed of the training sessions (P=0.0014) were related to marathon race time. Marathon race time might be partially (r(2)=0.50) predicted by the following equation: Race time (min)=184.4 + 5.0 x (circumference calf, cm) -11.9 x (speed in running during training, km/h) for recreational female marathoners. CONCLUSIONS: Variables of both anthropometry and training were related to marathon race time in recreational female marathoners and cannot be reduced to one single predictor variable. For practical applications, a low circumference of calf and a high running speed in training are associated with a fast marathon race time in recreational female runners. PMID- 22942995 TI - Anthropometric and hemodynamic profiles of athletes and their relevance to performance in the mount cameroon race of hope. AB - PURPOSE: Many factors influence athletes' performance including anthropometric, physiological and environmental parameters. High altitude is characterized by adverse environmental conditions that are not found at sea level. We investigated the influence of some anthropometric and physiological factors on performance in the context of the Mount Cameroon Race of Hope. METHODS: Age, height, weight, blood pressure, heart rate and breathing rate of 83 finisher athletes of both genders were collected during medical checkup, and race time was recorded at the arrival line. Measured and calculated data association with performance was assessed. RESULTS: The race time was significantly influenced by the area of training (p=0.0022), and gender (p=0.0036) of athletes; BMI showed significant association with race time in the overall athletes' population; this was confirmed in male (r=0.565; p=0.034) but not in female athletes (r=0.749; p=0.058). Weight class showed significant association to performance, the lighter athletes performing better than the heavier (p<0.00001). None of the investigated physiological parameters showed association to the race time. CONCLUSIONS: We hypothesized that high altitude training and body size are significantly influential on athletes' performance in the Mount Cameroon race of hope and similar mountain races. PMID- 22942996 TI - Physical fitness, physical activity and sedentary activities of 7 to 11 year old boys with different body mass indexes. AB - PURPOSE: The purpose of this study was to examine the differences in physical fitness, physical activity, and sedentary activities among 7 to 11 year old boys with varying body mass index in Ardabil, Iran. METHODS: The sample consisted of 766 boys who participated in eight weight bearing (1 mile walk/run, sit ups, standing long jump, vertical jump, shuttle run 4 * 10 m, 30-meter sprint, pull ups, pushups) and four non-weight-bearing physical fitness tests (flamingo balance, handgrip; sit and reach and finger reaction time). Physical activity and sedentary activities were assessed by questionnaires. Body mass index (BMI) was computed to classify participants into normal weight, underweight, overweight and obese groups. RESULTS: The prevalence of underweight, overweight and obesity was 10.7%, 14.1% and 4.2% respectively. Cardiorespiratory fitness (VO(2max)) decreased progressively as the BMI increased and differences among the all body mass index categories were significant (P<0.01). Obese subjects performed worse in all weight bearing fitness tests than normal weight subjects (P<0.01). Moreover, overweight subjects performed worse in one mile, pushups and pull ups than normal weight subjects (P<0.01). Underweight subjects had significantly lower Pushups than normal weight subjects (P<0.01). Obese subjects had significantly higher sedentary activities and lower physical activity than other counterparts (P<0.01). CONCLUSIONS: This study showed that weight bearing physical fitness, cardiorespiratory fitness and physical activity progressively decreased as the BMI increased and conversely, sedentary activities increased as the BMI increased. PMID- 22942997 TI - Anthropometric Profile and Special Judo Fitness levels of Indian Judo Players. AB - PURPOSE: Judo is a complex sport where different anthropological parameters determine performance. Judo, as a sport is not well known in India. There is evident lack of data concerning the anthropological determinants of judo players. This study was conducted to determine the anthropometric profile and Special Judo Fitness levels of judokas. METHODS: This cross sectional study was conducted on 31 judo players. Anthropometric profile was assessed by measuring height, weight, body mass index, body circumferences at seven sites, seven site skin fold thickness and body fat percentage as per standard accepted protocol. Special Judo Fitness Test - a specific test to evaluate the judo athlete's physical condition was applied. Statistical analysis done using Student's unpaired 't' test and correlation by Karl Pearson's correlation coefficient. RESULTS: Out of 31 judo players 20 had <=5 yrs of judo practice (A group) and 11 >5 yrs of judo (B group). Anthropometric findings of both the judo groups were the same. Body fat has negative correlation (r =-0.690, P<0.05) with performance in SJFT. Observations during and after special judo fitness test were also similar. CONCLUSIONS: Long term training has a minimal effect on anthropometry. Judo athletes of similar age when submitted to the same training type tend to show equal performance in the game and fitness levels after certain years of training. We also confirm existence of negative correlation between body fat and performance. PMID- 22942998 TI - Percentage of body fat and weight gain in participants in the tehran high school wrestling championship. AB - PURPOSE: Weight loss in wrestling has been found to be an interesting issue for researchers. In this regard, complications of weight loss in wrestlers before the competitions and their weight gain in course of competitions have been debated in previous studies. The objective of this study was to investigate the extent of weight gain and to estimate the percentage of body fat in participants in the Tehran high school male wrestling championship. METHODS: This study was a cross sectional survey. Subjects were participants of the Tehran high school male wrestling championship (n = 365). Weight gain in course of competitions and body fat levels (based on skin fold measurements) of subjects were measured. RESULTS: Between the first weigh-in of the wrestlers which was done one day before the competitions and the second weigh-in which was conducted immediately before the first round of their first competition (20 hours), 69% of subjects gained on average 1.3+/-0.9 kg (range: 0.1 to 6.10 kg) or 2.2+/-1.7% of the wrestler's weight (range: 0.1 to 9.3). Among the subjects, the mean of fat body percentage was found to be 15.2%. CONCLUSIONS: Rapid weight loss for matches was prevalent among subjects. It was also found that Iranian wrestlers have a relatively higher body fat percentage in comparison to American wrestlers. Therefore, it can be concluded that weight loss behavior of these wrestlers should be changed from using dehydration methods to using gradual methods of weight loss such as fat reduction methods. PMID- 22942999 TI - Characteristics of Headache at Altitude among Trekkers; A comparison between Acute Mountain Sickness and Non-Acute Mountain Sickness Headache. AB - PURPOSE: Headache at altitudes has had an incidence of 25-62% through many related studies. Many reasons are identified concerning headache at altitudes such as acute mountain sickness (AMS), sinus headache, migraine, tension type headache, and frontal tension headache. This study tried to compare different types of headache among trekkers on Mount Damavand, a 5671m mountain, Iran, to find their incidence and related symptoms and signs. METHODS: Through a cross sectional study, we evaluated headache incidence and its correlation to AMS among people who climbed Mount Damavand. Lake Louise Score, a self-report questionnaire, was applied to make AMS diagnosis through three separate stages of trekking programs. Chi-square test was employed as the main mean of analysis. RESULTS: Totally, 459 between 13-71 year olds participated in the study among which females were 148 (32.1%) and males 311 (67.8%). Headache was found in 398 (86.7%) among whom 279 (70%) were proved as AMS. Investigating the types of headache in the cases of AMS showed 64.5% to be of steady, 31% throbbing and 4.5% stabbing characters which had significant differences with a P value = 0.003. The majority of headaches were stated as frontal (38.9%) and the least prevalence belonged to the parietal area (4.4%), while global headache was reported in 27%. CONCLUSIONS: This study specifies the exact location of headaches at altitude in cases of AMS and non-AMS headaches. Many cases of high altitude non-AMS headache are resulted by tension and light reflection at altitude. PMID- 22943000 TI - Socio-cultural power dynamics and coping functions: a narrative case report of a female paralympian. AB - PURPOSE: This case study explores the lived experiences of an elite female Paralympic powerlifting athlete. The focus is on restrictions and coping responses employed to manage the daily hassles within the cultural and ethnic requirements for achieving athletic excellence. METHODS: With an unstructured interview, the narrative was acquired which ranged to a total of 75 minutes (approx) and 20 single spaced pages. The data was analyzed using Foucauldian discourse analysis in conjuncture to feminist poststructuralist theory. RESULTS: The results highlight the issues relating to femininity, culture and ethnicity with regard to athletic career. The analysis elicits extracts from the narrative to describe the coping functions reflecting proactive coping, anticipatory coping, and preventative coping. CONCLUSIONS: The narrative draws attention to the socio-cultural restrictions and coping functions that the athlete adopted to overcome the barriers of femininity, culture, ethnicity requirements and athleticism. PMID- 22943002 TI - Nonlinear dependencies of biochemical reactions for context-specific signaling dynamics. AB - Mathematical modeling can provide unique insights and predictions about a signaling pathway. Parameter variations allow identification of key reactions that govern signaling features such as the response time that may have a direct impact on the functional outcome. The effect of varying one parameter, however, may depend on values of another. To address the issue, we performed multi parameter variations of an experimentally validated mathematical model of NF kappaB regulatory network, and analyzed the inter-relationships of the parameters in shaping key dynamic features. We find that nonlinear dependencies are ubiquitous among parameters. Such phenomena may underlie the emergence of cell type-specific behaviors from essentially the same molecular network. Our results from a multivariate ensemble of models highlight the hypothesis that cell type specificity in signaling phenotype can arise from quantitatively altered strength of reactions in the pathway, in the absence of tissue-specific factors that re wire the network for a new topology. PMID- 22943003 TI - Effect of angstrom-scale surface roughness on the self-assembly of polystyrene polydimethylsiloxane block copolymer. AB - Self-assembly of block copolymers has been identified as a potential candidate for high density fabrication of nanostructures. However, the factors affecting its reliability and reproducibility as a patterning technique on various kinds of surfaces are not well-established. Studies pertaining to block copolymer self assembly have been confined to ultra-flat substrates without taking into consideration the effect of surface roughness. Here, we show that a slight change in the angstrom-scale roughness arising from the surface of a material creates a profound effect on the self-assembly of polystyrene-polydimethylsiloxane block copolymer. Its self-assembly was found to be dependent on both the root mean square roughness (R(rms)) of the surface and the type of solvent annealing system used. It was observed that surface with R(rms)< 5.0 A showed self-assembly. Above this value, the kinetic hindrance posed by the surface roughness on the block copolymer leads to its conforming to the surface without observable phase separation. PMID- 22943004 TI - Swelling transition of a clay induced by heating. AB - Clays are of paramount importance for soil stability, but also in applications ranging from oil recovery to composites and hydrogels. Generically, clays are divided into two subclasses: macroscopically swelling, 'active' clays that have the capacity for taking up large amounts of water to form stable gels, and 'passive' or non-swelling clays; the former stabilize soils whereas the latter are known to lead to landslides. However, it has been unclear so far what mechanisms underlie clay swelling. Here, we report the first observation of a temperature-induced transition from a passive to an active, swelling clay. We propose a simple description of the swelling transition; while net attractive interactions are dominant at low temperatures so that the clay particles remain attached to each other in stacks, at higher temperatures it is energetically favourable for the clay to swell due to the entropy that is gained by counterions which are liberated during swelling. PMID- 22943005 TI - Interplay between the Westerlies and Asian monsoon recorded in Lake Qinghai sediments since 32 ka. AB - Two atmospheric circulation systems, the mid-latitude Westerlies and the Asian summer monsoon (ASM), play key roles in northern-hemisphere climatic changes. However, the variability of the Westerlies in Asia and their relationship to the ASM remain unclear. Here, we present the longest and highest-resolution drill core from Lake Qinghai on the northeastern Tibetan Plateau (TP), which uniquely records the variability of both the Westerlies and the ASM since 32 ka, reflecting the interplay of these two systems. These records document the anti phase relationship of the Westerlies and the ASM for both glacial-interglacial and glacial millennial timescales. During the last glaciation, the influence of the Westerlies dominated; prominent dust-rich intervals, correlated with Heinrich events, reflect intensified Westerlies linked to northern high-latitude climate. During the Holocene, the dominant ASM circulation, punctuated by weak events, indicates linkages of the ASM to orbital forcing, North Atlantic abrupt events, and perhaps solar activity changes. PMID- 22943006 TI - Evolution of cooperation in multiplex networks. AB - We study evolutionary game dynamics on structured populations in which individuals take part in several layers of networks of interactions simultaneously. This multiplex of interdependent networks accounts for the different kind of social ties each individual has. By coupling the evolutionary dynamics of a Prisoner's Dilemma game in each of the networks, we show that the resilience of cooperative behaviors for extremely large values of the temptation to defect is enhanced by the multiplex structure. Furthermore, this resilience is intrinsically related to a non-trivial organization of cooperation across the network layers, thus providing a new way out for cooperation to survive in structured populations. PMID- 22943007 TI - Pathologic aspects of tumors of gastrointestinal tract in the era of personalized medicine. PMID- 22943009 TI - Alcoholic liver disease - Hepatocellular carcinoma transformation. PMID- 22943008 TI - Colorectal carcinoma: Pathologic aspects. AB - Colorectal carcinoma is one of the most common cancers and one of the leading causes of cancer-related death in the United States. Pathologic examination of biopsy, polypectomy and resection specimens is crucial to appropriate patient managemnt, prognosis assessment and family counseling. Molecular testing plays an increasingly important role in the era of personalized medicine. This review article focuses on the histopathology and molecular pathology of colorectal carcinoma and its precursor lesions, with an emphasis on their clinical relevance. PMID- 22943010 TI - Molecular pathology of pancreatic neuroendocrine tumors. AB - Pancreatic endocrine tumors (PETs) are rare neoplasms which account for 1% to 2% of all pancreatic malignancies. The diagnostic, grading and prognostic criteria for PETs have been controversial in surgical pathology and clinical medicine. The newly updated 2010 WHO classification introduced in clinical practice will give more insight into genetic and molecular changes related to PET subtypes. These neoplasms can be graded into 1 of 3 tiers, based on histologic characteristics in likeness to epithelial neuroendocrine tumors in other anatomic sites. Most PETs are sporadic, however, some of them, may occur as part of familial tumors (inherited syndromes) such as multiple endocrine neoplasia type 1 (MEN1 syndrome), von Hippel-Lindau disease (VHL), neurofibromatosis type 1 (NF-1), and tuberous sclerosis (TSC). In sporadic endocrine pancreatic tumors, losses of chromosome 1 and 11q as well as gain on 9q appear to be early events in the development of pancreatic tumors. Multiple genetic defects may accumulate with time and result in pancreatic neuroendocrine tumor progression and malignancy. Although PETs may be similar or identical in histologic appearance to neuroendocrine tumors of the gastrointestinal tract, differences in their underlying biology and likely differences in response to therapeutic agents suggest that they should be treated and investigated as a distinct entity. The correlation of PI3K/Akt/mTOR pathway in the pathogenesis of PETs has been reported, and clinical trials data of mTOR inhibitors is promising. PMID- 22943012 TI - Gastrointestinal lymphomas: Morphology, immunophenotype and molecular features. AB - Primary gastrointestinal lymphoma comprises 10-15% of all non-Hodgkin lymphomas and encompasses 30-40% of the total extranodal lymphomas. Approximately 60-75% of cases occur in the stomach, and then the small bowel, ileum, cecum, colon and rectum. Lymphoid neoplasms may consist of mature B, T and less commonly extranodal NK/T cells. Of these, the two most frequently encountered histologic subtypes are extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma), where Helicobacter pylori infection is implicated in a number of cases, and diffuse large B cell lymphoma. Several B cell lymphomas are associated with chromosomal aberrations. Enteropathy-associated T cell lymphoma, type I in particular, usually arises in a background of celiac disease. T cell gene rearrangement confirms clonality. NK/T cell neoplasms are invariably associated with Epstein-Barr virus infection and are often aggressive; thus, differentiation from a benign NK-cell enteropathy is paramount. Although incidence of other hematopoietic malignancies in the gastrointestinal tract such as plasma cell myeloma associated with amyloidosis, plasmablastic lymphoma, Hodgkin disease, histiocytic sarcoma and mast cell sarcoma is extremely rare, these entities have been documented, with the latter two demonstrating aggressive clinical behavior. Endoscopic ultrasonography is an important adjunct in disease staging and follow-up. Conservative antibiotic treatment of stage I MALT lymphomas with associated Helicobacter pylori infection achieves good clinical outcome with high remission rate. Chemotherapy, radiation and rarely surgery are reserved for advanced diseases or cases resistant to conservative therapy and those not associated with Helicobacter pylori infection. PMID- 22943013 TI - The association between obesity factor and esophageal caner. AB - Accumulating epidemiological studies have supported the link between increased body mass index, central obesity and esophageal adenocarcinoma. This association appears stronger than that for other types of obesity-related cancers. Central obesity or visceral fat, more often observed in men, is much more strongly associated with adenocarcinoma than body mass index alone, possibly contributing to the imbalance of disease occurrence between the sexes. Potential mechanisms underlying the association between obesity and esophageal adenocarcinoma have been recently identified, including the insulin-like growth factor pathway, adipokines and sex hormone disturbances. These findings are summarized in this review; however, more research is warranted before these mechanisms are conclusively established. PMID- 22943011 TI - Gastrointestinal stromal tumor. AB - Gastrointestinal stromal tumor has received a lot of attention over the last 10 years due to its unique biologic behavior, clinicopathological features, molecular mechanisms, and treatment implications. GIST is the most common mesenchymal neoplasm in the gastrointestinal tract and has emerged from a poorly understood and treatment resistant neoplasm to a well-defined tumor entity since the discovery of particular molecular abnormalities, KIT and PDGFRA gene mutations. The understanding of GIST biology at the molecular level promised the development of novel treatment modalities. Diagnosis of GIST depends on the integrity of histology, immunohistochemistry and molecular analysis. The risk assessment of the tumor behavior relies heavily on pathological evaluation and significantly impacts clinical management. In this review, historic review, epidemiology, pathogenesis and genetics, diagnosis, role of molecular analysis, prognostic factor and treatment strategies have been discussed. PMID- 22943001 TI - Role of monosaccharide transport proteins in carbohydrate assimilation, distribution, metabolism, and homeostasis. AB - The facilitated diffusion of glucose, galactose, fructose, urate, myoinositol, and dehydroascorbicacid in mammals is catalyzed by a family of 14 monosaccharide transport proteins called GLUTs. These transporters may be divided into three classes according to sequence similarity and function/substrate specificity. GLUT1 appears to be highly expressed in glycolytically active cells and has been coopted in vitamin C auxotrophs to maintain the redox state of the blood through transport of dehydroascorbate. Several GLUTs are definitive glucose/galactose transporters, GLUT2 and GLUT5 are physiologically important fructose transporters, GLUT9 appears to be a urate transporter while GLUT13 is a proton/myoinositol cotransporter. The physiologic substrates of some GLUTs remain to be established. The GLUTs are expressed in a tissue specific manner where affinity, specificity, and capacity for substrate transport are paramount for tissue function. Although great strides have been made in characterizing GLUT catalyzed monosaccharide transport and mapping GLUT membrane topography and determinants of substrate specificity, a unifying model for GLUT structure and function remains elusive. The GLUTs play a major role in carbohydrate homeostasis and the redistribution of sugar-derived carbons among the various organ systems. This is accomplished through a multiplicity of GLUT-dependent glucose sensing and effector mechanisms that regulate monosaccharide ingestion, absorption,distribution, cellular transport and metabolism, and recovery/retention. Glucose transport and metabolism have coevolved in mammals to support cerebral glucose utilization. PMID- 22943015 TI - Genetics and molecular pathology of gastric malignancy: Development of targeted therapies in the era of personalized medicine. AB - Gastric malignancy constitutes a major cause of cancer deaths worldwide. Despite recent advances in surgical techniques combined with neoadjuvant chemotherapy and radiotherapy approaches, patients with advanced disease still have poor outcomes. An emerging understanding of the molecular pathways that characterize cell growth, cell cycle, apoptosis, angiogenesis, invasion and metastasis has provided novel targets in gastric cancer therapy. In this review, recent advances in the understanding of molecular tumorigenesis for common gastric malignancies are discussed. We also briefly review the current targeted therapies in the treatment of gastric malignancies. Practical insights are highlighted including HER2 testing and target therapy in gastric adenocarcinoma, morphologic features and molecular signatures of imatinib-resistance GISTs, and recent investigations aimed at tumor-specific therapy for neuroendocrine tumors. PMID- 22943014 TI - Barrett's esophagus: A review of diagnostic criteria, clinical surveillance practices and new developments. AB - Barrett's esophagus is defined by metaplastic glandular changes to the distal esophagus and is linked to an increased risk of esophageal adenocarcinoma. Controversy exists whether the definition should be limited to intestinal type glands with goblet cells or should be expanded to include non-goblet cell columnar epithelium. Barrett's esophagus may be asymptomatic in a large proportion of the population but screening should be considered for those with certain clinical findings. The diagnosis of Barrett's should be based on the combination of careful endoscopic evaluation and histologic review of the biopsy material. Continued surveillance biopsies may be necessary in cases of indeterminate or low grade dysplasia. Clinical follow-up of patients with high grade dysplasia should be tailored to the individual patient. Development of newer endoscopy techniques including chemoendoscopy, chromoendoscopy and use of biomarkers on frozen tissue have shown some promise of identifying patients at risk for malignancy. PMID- 22943016 TI - Gastric cancer: Classification, histology and application of molecular pathology. AB - Gastric cancer remains one of the deadly diseases with poor prognosis. New classification of gastric cancers based on histologic features, genotypes and molecular phenotypes helps better understand the characteristics of each subtype, and improve early diagnosis, prevention and treatment. The objective of this article is to review the new classification of gastric cancers and the up-to-date guidance in the application of molecular testing. PMID- 22943018 TI - Role of cytopathology in the diagnosis and management of gastrointestinal tract cancers. AB - Cytology of gastro-intestinal (GI) tract lesions can be used successfully to diagnose neoplastic and non-neoplastic conditions, especially when combined with biopsies. Cytologic evaluation is widely accepted as a cost-effective method that allows rapid interpretation and triaging of material. Technical advances over the years have allowed simultaneous visualization of abnormal tissue and procurement of needle aspirates, brushings and biopsies from mucosal and deeper seated lesions. Successful cytologic examination of the GI tract is highly dependent on the skill of the endoscopist, specimen preparation, the expertise of the pathologist, and the recognition of the limitations of cytology. This article reviews the key cytologic features of important GI tract lesions, differential diagnoses, and pitfalls, and addresses the advantages and limitations of different collection techniques. PMID- 22943019 TI - Bath salts-induced delirium and brief psychotic episode in an otherwise healthy young man. PMID- 22943020 TI - Sertraline-induced hypersexuality in a patient taking bupropion. PMID- 22943021 TI - Prescription medication abuse among women in an obstetrics/gynecology clinic. PMID- 22943017 TI - Immunohistochemical features of the gastrointestinal tract tumors. AB - Gastrointestinal tract tumors include a wide variety of vastly different tumors and on a whole are one of the most common malignancies in western countries. These tumors often present at late stages as distant metastases which are then biopsied and may be difficult to differentiate without the aid of immunohistochemical stains. With the exception of pancreatic and biliary tumors where there are no distinct immunohistochemical patterns, most gastrointestinal tumors can be differentiated by their unique immunohistochemical profile. As the size of biopsies decrease, the role of immunohistochemical stains will become even more important in determining the origin and differentiation of gastrointestinal tract tumors. PMID- 22943022 TI - Case report: lamotrigine toxicity leading to depressed mental activity. PMID- 22943023 TI - Co-occurrence of Intermetamorphosis and Fregoli Syndrome in Schizophrenia: A Case Report. PMID- 22943025 TI - Manic episode associated with clarithromycin in a patient with medically treated depression. PMID- 22943024 TI - Quetiapine-induced galactorrhea with normal prolactin level in an adult female patient. PMID- 22943026 TI - Sexual obsessions in mental retardation: a case report. PMID- 22943027 TI - Pancytopenia secondary to cyclophosphamide in a case of factitious breast cancer. PMID- 22943028 TI - Do veterans with posttraumatic stress disorder receive first-line pharmacotherapy? Results from the longitudinal veterans health survey. AB - OBJECTIVE: Guidelines addressing the treatment of veterans with posttraumatic stress disorder (PTSD) strongly recommend a therapeutic trial of selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRIs). This study examined veteran characteristics associated with receiving such first-line pharmacotherapy, as well as how being a veteran of the recent conflicts in Afghanistan and Iraq impact receipt of pharmacotherapy for PTSD. METHOD: This was a national study of 482 Veterans Affairs (VA) outpatients between the ages of 18 and 69 years who had been newly diagnosed with PTSD (DSM IV criteria: 309.81) during a VA outpatient visit between May 31, 2006, and December 7, 2007. Participants completed a mailed survey between August 11, 2006, and April 6, 2008. Veterans from the Afghanistan and Iraq conflicts and female veterans were intentionally oversampled. Logistic regression models were developed to predict 2 dependent variables: odds of initiating an SSRI/SNRI and, among veterans who initiated an SSRI/SNRI, odds of receiving an adequate therapeutic trial. Each dependent variable was regressed on a variety of sociodemographic and survey characteristics. RESULTS: Of the 377 veterans prescribed a psychotropic medication, 73% (n = 276) received an SSRI/SNRI, of whom 61% (n = 168) received a therapeutic trial. Afghanistan and Iraq veterans were less likely to receive a therapeutic trial (odds ratio [OR] = 0.45; 95% CI, 0.27-0.75; P < .01), with presence of a comorbid depression diagnosis in the year after the index episode moderating this relationship, which further decreased the odds of completing a therapeutic trial (OR = 0.29; 95% CI, 0.09-0.95; P < .05). CONCLUSIONS: Reduced levels of receipt of first-line pharmacotherapy among recent veteran returnees parallel previous findings of less mental health treatment utilization in this population and warrant investigation. PMID- 22943029 TI - Sexual dysfunction in male subjects receiving trifluoperazine, risperidone, or olanzapine: rates vary with assessment questionnaire. AB - OBJECTIVE: To assess the rate and typology of sexual dysfunction in male subjects receiving trifluoperazine, risperidone, or olanzapine using the Arizona Sexual Experience Scale (ASEX), the Psychotropic Related Sexual Dysfunction Questionnaire (PRSexDQ), and the sexual function section of the modified Udvalg for Kliniske Undersogelser Side Effect Rating Scale (UKU). METHOD: The sample included 100 men with psychotic disorders (F2 category of the ICD-10) and receiving trifluoperazine (n = 20), risperidone (n = 30), or olanzapine (n = 50) for at least 3 months' duration. Subjects with a history of sexual dysfunction prior to antipsychotic intake or chronic medical illness were excluded. A cross sectional design was employed, and data were collected over a 11/2-year period from March 2009 to August 2010. RESULTS: The rate of sexual dysfunction varied from scale to scale among the 100 subjects. The rate of sexual dysfunction was 25% on the ASEX, 37% on the PRSexDQ, and 40% on the UKU. Sexual dysfunction in the trifluoperazine, risperidone, and olanzapine groups was 20%, 43%, and 16%, respectively, on the ASEX; 35%, 50%, and 30%, respectively, on the PRSexDQ; and 40%, 50%, and 34%, respectively, on the UKU. The most common sexual dysfunction as assessed on all scales was decreased libido, except for the risperidone group on the ASEX. CONCLUSIONS: Sexual dysfunction is quite prevalent in subjects receiving antipsychotic medications. In our study, rate of sexual dysfunction was highest for risperidone, followed by trifluoperazine and olanzapine. However, the rate of sexual dysfunction varied from scale to scale. Hence, there is a need for a comprehensive instrument to assess sexual dysfunction in patients receiving antipsychotics. PMID- 22943030 TI - Cognitive-behavioral therapy for the treatment of depression and adherence in patients with type 1 diabetes: pilot data and feasibility. AB - OBJECTIVE: Depression is one of the most common psychological problems affecting individuals with type 1 diabetes, and it is associated with treatment nonadherence and worse clinical outcomes. The research on treating depression or nonadherence in adults with type 1 diabetes is limited. We adapted an evidence supported treatment, individual cognitive-behavioral therapy for adherence and depression (CBT-AD), for type 1 diabetes and examined its feasibility, acceptability, and potential for an effect. METHOD: The pilot study included 9 patients with a DSM-IV diagnosis of major depression, dysthymia, or residual depressive symptoms despite treatment with an antidepressant; a diagnosis of type 1 diabetes per patient self-report; and a glycosylated hemoglobin A1c (HbA1c) level of 8.0% or greater. Patients were referred by their diabetes care providers to a behavioral medicine specialty setting and received 10 to 12 sessions of CBT AD. Main outcome measures included percent of eligible participants who enrolled in the study, session attendance, independently-rated Montgomery-Asberg Depression Rating Scale (MADRS) score, self-reported adherence to diabetes care activities, and adherence to self-monitoring of blood glucose levels. Data were collected from June 27, 2008, through March 31, 2010. RESULTS: There was a clinically meaningful decrease in depression severity (mean [SD] MADRS score decrease from 26.0 [4.73] to 12.3 [7.37], Cohen d = 2.90), demonstrated improvements in diabetes self-care (increase in blood glucose monitoring from 65.0 [26.72] to 82.7 [22.75], Cohen d = -0.66, and a difference in self-reported percent insulin doses in the past 2 weeks from 77.1 [29.84] to 87.1 [23.6], Cohen d = -0.34), and possible improvement in glycemic control (decrease in HbA1c levels from 9.6 [1.32] to 9.0 [1.04], Cohen d = 0.45). CONCLUSIONS: These preliminary results provide evidence for the acceptability, feasibility, and potential utility of CBT-AD for patients with type 1 diabetes and depression. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01527981. PMID- 22943031 TI - Vitamin d deficiency among psychiatric inpatients. AB - OBJECTIVE: Previous studies in northern Europe and Australia have indicated that vitamin D deficiency is common in psychiatric patients. This study aimed to determine the prevalence of vitamin D deficiency among psychiatric inpatients in a large North American city. The association of vitamin D status with clinical characteristics was also explored, and subgroups of patients that are more vulnerable to vitamin D deficiency were identified. METHOD: This descriptive study looked at 107 unselected consecutive admissions to a psychiatric inpatient service in New York City between September and early December 2010. All patients were aged 18 years and older. Psychiatric diagnoses were established by attending psychiatrists as part of the routine assessment using criteria from the DSM-IV. Serum levels of 25-hydroxyvitamin D were measured by high-performance liquid chromatography, tandem mass spectrometry. A vitamin D-deficient state was defined as serum 25-hydroxyvitamin D level <= 20 ng/mL. RESULTS: Fifty-six (52.3%) patients were classified as deficient in vitamin D. Age and 25-hydroxyvitamin D level were significantly correlated (P = .001). Seventy-one percent of patients from age 18 to 34 years were deficient in vitamin D; this rate was significantly higher than the rate of deficiency in older patients (P = .017). No significant relationships were found between 25-hydroxyvitamin D level and gender, race/ethnicity, glycosylated hemoglobin, body mass index, and major psychiatric diagnostic categories. CONCLUSIONS: A high percentage of psychiatric inpatients are deficient in vitamin D. Younger patients were more at risk for deficiency. Screening for vitamin D deficiency should be part of the health assessment of patients with major psychiatric illnesses. PMID- 22943032 TI - A quick test of cognitive speed for comparing processing speed to differentiate adult psychiatric referrals with and without attention-deficit/hyperactivity disorders. AB - OBJECTIVE: This retrospective study used A Quick Test of Cognitive Speed (AQT) to compare processing speed and efficiency measures by adults with attention deficit/hyperactivity disorder (ADHD) or non-ADHD psychiatric disorders and healthy controls. METHOD: Color, form, and color-form combination naming tests were administered to 104 adults, ages 17-55 years, referred for psychiatric evaluation of possible ADHD. Thirty healthy adults were controls. Psychiatric intake procedures identified 64 adults with ADHD (ICD-10 and DSM-IV criteria) and 40 with mild psychiatric disorders without ADHD. The study was conducted from 2008 through 2010. RESULTS: At intake, color, form, and color-form combination naming times (seconds) were longer and overhead [color-form combination - (color + form)] was larger for patients with ADHD than for non-ADHD patients and controls. In the ADHD group, color and form measures were in the normal range. Color-form combination was in the slower-than-normal speed (60-70 seconds) and overhead, a processing-efficiency measure, in the atypical range (> 10 seconds). In the non-ADHD patient and control groups, all AQT measures were in the normal range. Analysis of variance with post hoc analysis of log-normal values for color, form, and color-form combination and time for overhead indicated significant (Bonferroni P < .01) mean differences between the ADHD and other groups, but not between the non-ADHD and control groups. When using fail criteria for either color-form combination or overhead, the sensitivity for the ADHD group was 89%. CONCLUSIONS: RESULTS support AQT as a possible complement to psychiatric intake procedures to differentiate adults with ADHD from those with mild psychiatric disorders, and they suggest that a controlled prospective study might be productive. PMID- 22943033 TI - Clinical excellence in psychiatry: a review of the psychiatric literature. AB - OBJECTIVE: The provision of excellent patient care is a goal that physicians would like to achieve in caring for all patients, all of the time. Until recently, clinical excellence had not been defined, and the extent to which this recently published definition applies to the care of patients with psychiatric illness is not known. This article sets out to consider how the paradigm for clinical excellence applies to the field of psychiatry. DATA SOURCE: PubMed, Ovid MEDLINE, and PsycINFO were searched (1962 through December 2010) combining the keywords psychiatry (or psychiatrist) and clinical excellence, limiting the output to English-language case reports. In subsequent searches, the term clinical excellence was replaced by each of the components of the definition: communication and interpersonal skills, professionalism and humanism, diagnostic acumen, skillful negotiation of the health care system, knowledge, scholarly approach to clinical practice, exhibiting a passion for patient care, explicitly modeling mastery to medical trainees, and collaborating with investigators to advance science and discovery. STUDY SELECTION: The search yielded 218 case reports. All of the case reports were reviewed, and a consensus was reached on the 8 exemplars and 1 teaching model to be presented in the article. Careful consideration was given as to whether any aspects of the framework for clinical excellence were missing or not applicable for psychiatry.Results Every case report reviewed touched on 1 or more of the domains of clinical excellence. None of the case reports uncovered new aspects of clinical excellence that were not described in the existing definition. CONCLUSIONS: This review of the case reports published in psychiatry reveals that the definition of clinical excellence described in this article may be highly applicable to those caring for patients with psychiatric illness. PMID- 22943034 TI - Prazosin for the treatment of nightmares related to posttraumatic stress disorder: a review of the literature. AB - BACKGROUND: Posttraumatic stress disorder (PTSD) is a psychiatric disorder with symptoms that include insomnia due to hyperarousal and recurring nightmares. These symptoms are believed to be due to a conditioned response that is regulated by norepinephrine. Prazosin, an alpha(1) antagonist, can decrease levels of norepinephrine in the central nervous system, thereby reducing nightmares related to PTSD. DATA SOURCES: A literature search was conducted for all studies evaluating the effectiveness of prazosin as therapy for nightmare symptoms of PTSD. MEDLINE was utilized to identify all English-language studies published between 1966 and March 2011. Keywords searched included prazosin, PTSD, and nightmares. RESULTS: Eleven studies were identified, including 4 open-label trials, 4 retrospective chart reviews, and 3 placebo-controlled trials. Prazosin demonstrated favorable clinical efficacy and was found to be safe for relieving PTSD-associated nightmares. CONCLUSIONS: Current data indicate that prazosin is an effective agent for the treatment of nightmares associated with PTSD. However, the data are limited by small study sizes, lack of diversified investigators, and lack of regional diversity. PMID- 22943035 TI - Electroconvulsive therapy in patients with skull defects or metallic implants: a review of the literature and case report. AB - CONTEXT: Head injury is often associated with psychiatric morbidity. While it is well understood that the loss of critical areas of the brain may play a role in cognitive dysfunction and change in personality, head injury can also have profound effects on mood and cognition. The role of medications in the treatment of mood disorders associated with brain injury is well documented, and there is also evidence favoring the use of electroconvulsive therapy (ECT) in this context. However, data are limited on the use of ECT in patients with skull defects or metallic head implants. EVIDENCE ACQUISITION: First, a review of the literature on use of ECT in patients with metallic head implants is provided. Electronic databases and online sites, including PubMed, Cochrane Library of Systematic Reviews, and UpToDate, were used to search for relevant articles and case reports on the use of ECT in patients with and without metallic implants in the head (1964 to 2009). The search terms electroconvulsive, electroconvulsive therapy, ECT, electroshock therapy, EST, head injury, brain injury, metallic plates, metallic implants, skull prosthesis, and depression were used interchangeably. The search produced 7 articles discussing exclusively the use of ECT in patients with a metallic skull plate. Second, the case of the successful and safe use of ECT in an individual with a previous history of brain trauma and metallic plate implantation is described. RESULTS: Most cases of head injury are managed by neurologists and rehabilitation consultants; the more severe cases of depression and other mood disorders tend to be referred for specialist psychiatric care. With greater degrees of deficit following head injury, management becomes more complicated. Our patient showed positive results with ECT, including improvement in depressive features and resolution of suicidal ideas/plans. CONCLUSION: ECT is an effective and safe alternative in patients with a history of brain trauma and metallic plate implantation who subsequently develop treatment-resistant depression and associated suicidal ideas or plans refractory to management with medications. PMID- 22943036 TI - Falling down. PMID- 22943037 TI - A continuing saga. PMID- 22943038 TI - Molecular imaging probe development: a chemistry perspective. AB - Molecular imaging is an attractive modality that has been widely employed in many aspects of biomedical research; especially those aimed at the early detection of diseases such as cancer, inflammation and neurodegenerative disorders. The field emerged in response to a new research paradigm in healthcare that seeks to integrate detection capabilities for the prediction and prevention of diseases. This approach made a distinct impact in biomedical research as it enabled researchers to leverage the capabilities of molecular imaging probes to visualize a targeted molecular event non-invasively, repeatedly and continuously in a living system. In addition, since such probes are inherently compact, robust, and amenable to high-throughput production, these probes could potentially facilitate screening of preclinical drug discovery, therapeutic assessment and validation of disease biomarkers. They could also be useful in drug discovery and safety evaluations. In this review, major trends in the chemical synthesis and development of positron emission tomography (PET), optical and magnetic resonance imaging (MRI) probes are discussed. PMID- 22943039 TI - Effects of Chronic Social Stress on Obesity. AB - The prevalence of overweight and obesity has markedly increased during the past few decades. Stress has been suggested as one environmental factor that may contribute to the development of obesity. In this review, we discuss the role that exposure to chronic stress may play in the development of obesity, with particular attention to the effects of chronic psychosocial stress. Of particular importance is the effect that social stress has on dietary preference, food consumption, and regional distribution of adipose tissue. We present evidence from human and animal studies that links sympathetic nervous system and hypothalamic-pituitary-adrenal axis hyperactivity with visceral obesity, and that stress tends to alter the pattern of food consumption, and promotes craving of nutrient-dense "comfort foods." Lastly, we discuss the visible burrow system, a model of chronic social stress used in our laboratory to assess the effects of social subordination on behavioral and metabolic profile. PMID- 22943040 TI - SIRT2 is a tumor suppressor that connects aging, acetylome, cell cycle signaling, and carcinogenesis. AB - One long standing observation in clinical oncology is that age increase is the single most statistically significant factor/variable that predicts for the incidence of solid tumors. This observation suggests that the cellular and molecular processes and mechanisms that direct an organism's life span may be used to determine the clinical connection between aging and carcinogenesis. In this regard, the genes that impact upon longevity have been characterized in S. cerevisiae and C. elegans, and the human homologs include the Sirtuin family of protein deacetylases. We have recently shown that the primary cytoplasmic sirtuin, Sirt2 appears to meet the criteria as a legitimate tumor suppressor protein. Mice genetically altered to delete Sirt2 develop gender-specific tumorigenesis, with females primarily developing mammary tumors, and males developing multiple different types of gastrointestinal malignancies. Furthermore human tumors, as compared to normal samples, displayed significant decreases in SIRT2 levels suggesting that SIRT2 may also be a human tumor suppressor. PMID- 22943042 TI - A chain reaction approach to modelling gene pathways. AB - BACKGROUND: Of great interest in cancer prevention is how nutrient components affect gene pathways associated with the physiological events of puberty. Nutrient-gene interactions may cause changes in breast or prostate cells and, therefore, may result in cancer risk later in life. Analysis of gene pathways can lead to insights about nutrient-gene interactions and the development of more effective prevention approaches to reduce cancer risk. To date, researchers have relied heavily upon experimental assays (such as microarray analysis, etc.) to identify genes and their associated pathways that are affected by nutrient and diets. However, the vast number of genes and combinations of gene pathways, coupled with the expense of the experimental analyses, has delayed the progress of gene-pathway research. The development of an analytical approach based on available test data could greatly benefit the evaluation of gene pathways, and thus advance the study of nutrient-gene interactions in cancer prevention. In the present study, we have proposed a chain reaction model to simulate gene pathways, in which the gene expression changes through the pathway are represented by the species undergoing a set of chemical reactions. We have also developed a numerical tool to solve for the species changes due to the chain reactions over time. Through this approach we can examine the impact of nutrient-containing diets on the gene pathway; moreover, transformation of genes over time with a nutrient treatment can be observed numerically, which is very difficult to achieve experimentally. We apply this approach to microarray analysis data from an experiment which involved the effects of three polyphenols (nutrient treatments), epigallo-catechin-3-O-gallate (EGCG), genistein, and resveratrol, in a study of nutrient-gene interaction in the estrogen synthesis pathway during puberty. RESULTS: In this preliminary study, the estrogen synthesis pathway was simulated by a chain reaction model. By applying it to microarray data, the chain reaction model computed a set of reaction rates to examine the effects of three polyphenols (EGCG, genistein, and resveratrol) on gene expression in this pathway during puberty. We first performed statistical analysis to test the time factor on the estrogen synthesis pathway. Global tests were used to evaluate an overall gene expression change during puberty for each experimental group. Then, a chain reaction model was employed to simulate the estrogen synthesis pathway. Specifically, the model computed the reaction rates in a set of ordinary differential equations to describe interactions between genes in the pathway (A reaction rate K of A to B represents gene A will induce gene B per unit at a rate of K; we give details in the "method" section). Since disparate changes of gene expression may cause numerical error problems in solving these differential equations, we used an implicit scheme to address this issue. We first applied the chain reaction model to obtain the reaction rates for the control group. A sensitivity study was conducted to evaluate how well the model fits to the control group data at Day 50. Results showed a small bias and mean square error. These observations indicated the model is robust to low random noises and has a good fit for the control group. Then the chain reaction model derived from the control group data was used to predict gene expression at Day 50 for the three polyphenol groups. If these nutrients affect the estrogen synthesis pathways during puberty, we expect discrepancy between observed and expected expressions. Results indicated some genes had large differences in the EGCG (e.g., Hsd3b and Sts) and the resveratrol (e.g., Hsd3b and Hrmt12) groups. CONCLUSIONS: In the present study, we have presented (I) experimental studies of the effect of nutrient diets on the gene expression changes in a selected estrogen synthesis pathway. This experiment is valuable because it allows us to examine how the nutrient-containing diets regulate gene expression in the estrogen synthesis pathway during puberty; (II) global tests to assess an overall association of this particular pathway with time factor by utilizing generalized linear models to analyze microarray data; and (III) a chain reaction model to simulate the pathway. This is a novel application because we are able to translate the gene pathway into the chemical reactions in which each reaction channel describes gene gene relationship in the pathway. In the chain reaction model, the implicit scheme is employed to efficiently solve the differential equations. Data analysis results show the proposed model is capable of predicting gene expression changes and demonstrating the effect of nutrient-containing diets on gene expression changes in the pathway. One of the objectives of this study is to explore and develop a numerical approach for simulating the gene expression change so that it can be applied and calibrated when the data of more time slices are available, and thus can be used to interpolate the expression change at a desired time point without conducting expensive experiments for a large amount of time points. Hence, we are not claiming this is either essential or the most efficient way for simulating this problem, rather a mathematical/numerical approach that can model the expression change of a large set of genes of a complex pathway. In addition, we understand the limitation of this experiment and realize that it is still far from being a complete model of predicting nutrient-gene interactions. The reason is that in the present model, the reaction rates were estimated based on available data at two time points; hence, the gene expression change is dependent upon the reaction rates and a linear function of the gene expressions. More data sets containing gene expression at various time slices are needed in order to improve the present model so that a non-linear variation of gene expression changes at different time can be predicted. PMID- 22943041 TI - Role of DNA-dependent protein kinase catalytic subunit in cancer development and treatment. AB - DNA-dependent protein kinase catalytic subunit (DNA-PKcs), a key component of the non-homologous end-joining (NHEJ) pathway, is involved in DNA double-strand break repair, immunocompetence, genomic integrity, and epidermal growth factor receptor signaling. Clinical studies indicate that expression and activity of DNA-PKcs is correlated with cancer progression and response to treatment. Various anti-DNA PKcs strategies have been developed and tested in preclinical studies to exploit the benefit of DNA-PKcs inhibition in sensitization of radiotherapy and in combined modality therapy with other antitumor agents. In this article, we review the association between DNA-PKcs and cancer development and discuss current approaches and mechanisms for inhibition of DNA-PKcs. The future challenges are to understand how DNA-PKcs activity is correlated with cancer susceptibility and to identify those patients who would most benefit from DNA-PKcs inhibition. PMID- 22943043 TI - Fast microbubble dwell-time based ultrasonic molecular imaging approach for quantification and monitoring of angiogenesis in cancer. AB - PURPOSE: To develop and test a fast ultrasonic molecular imaging technique for quantification and monitoring of angiogenesis in cancer. MATERIALS AND METHODS: A new software algorithm measuring the dwell time of contrast microbubbles in near real-time (henceforth, fast method) was developed and integrated in a clinical ultrasound system. In vivo quantification and monitoring of tumor angiogenesis during anti-VEGF antibody therapy was performed in human colon cancer xenografts in mice (n=20) using the new fast method following administration of vascular endothelial growth factor receptor 2 (VEGFR2)-targeted contrast microbubbles. Imaging results were compared with a traditional destruction/replenishment approach (henceforth, traditional method) in an intra animal comparison. RESULTS: There was excellent correlation (R(2)=0.93; P<0.001) between the fast method and the traditional method in terms of VEGFR2-targeted in vivo ultrasonic molecular imaging with significantly higher (P=0.002) imaging signal in colon cancer xenografts using VEGFR2-targeted compared to control non targeted contrast microbubbles. The new fast method was highly reproducible (ICC=0.87). Following anti-angiogenic therapy, ultrasonic molecular imaging signal decreased by an average of 41+/-10%, whereas imaging signal increased by an average of 54+/-8% in non-treated tumors over a 72-hour period. Decreased VEGFR2 expression levels following anti-VEGF therapy were confirmed on ex vivo immunofluorescent staining. CONCLUSIONS: Fast ultrasonic molecular imaging based on dwell time microbubble signal measurements correlates well with the traditional measurement method, and allows reliable in vivo monitoring of anti angiogenic therapy in human colon cancer xenografts. The improved work-flow afforded by the new quantification approach may facilitate clinical translation of ultrasonic molecular imaging. PMID- 22943045 TI - Therapeutic Mechanisms of Treatment in Cervical and Vaginal Cancer. AB - Cervical and vaginal cancers remain serious health problems. Worldwide, more than 530,000 women annually are diagnosed with these diseases, with most new incident cases occurring in nations with limited health resources and underdeveloped screening programs. For women whose disease is too bulky or widespread for surgery, radiochemotherapy should be looked upon as the standard of care. Randomized clinical trials have indicated that radiochemotherapy strategies that disrupt the repair of damaged DNA are key to the management of advanced stage cervical and vaginal cancers. Here, from a viewpoint of cancer cell molecular biology, treatments for advanced stage cervical and vaginal cancers are discussed. PMID- 22943046 TI - Wavelength-interrogated surface plasmon resonance sensor with mesoporous-silica film-enhanced sensitivity to small molecules. AB - Sol-gel copolymer-templated mesoporous silica films with a thickness of 70 nm and interpore spacing of 4.34 nm were fabricated on gold layer covered glass substrates for application as a wavelength-interrogated surface plasmon resonance (SPR) sensor. The resonance wavelength (lambda(R)) of the sensor with a solution sample was determined by absorptiometry at a given incident angle. A comparison between the experimental data obtained with the coated and uncoated SPR chips demonstrated that the mesoporous silica film effectively enhanced sensor response to individual adsorption of cysteamine molecules and lead(II) ions. An approximate proportional relationship between the resonance-wavelength shift of the sensor and the volume fraction of analyte molecules adsorbed in the mesoporous silica film was obtained by numerical simulation. Porosities of 0.865 and 0.785 for the two silica films used as well as the volume fractions of 0.048 and 0.116 for adsorbed lysozyme and cysteamine molecules were determined by fitting the simulation results to the experimental data. The adsorbed amount of cysteamine (~0.5 nm) is equivalent to more than 16 full monolayers on the geometric surface of the mesoporous silica film used. In contrast, an equivalence of less than 2 full monolayers for adsorbed lysozyme molecules (3 nm * 3 nm * 4.5 nm) suggests that the mesoporous silica film has good size-selective adsorption capability due to its uniform pore size distribution. Cysteamine modification of the mesoporous silica film renders the SPR sensor able to detect lead(II) ions at concentrations as low as 1 nM. PMID- 22943047 TI - Ultrasensitive and selective homogeneous sandwich immunoassay detection by Surface Enhanced Raman Scattering (SERS). AB - In this report, a simple and highly selective homogeneous sandwich immunoassay was developed for ultrasensitive detection of Staphylococcal Enterotoxin B (SEB) using Surface Enhanced Raman Scattering (SERS). The assay uses polyclonal antibody functionalized magnetic gold nanorod particles as capture probes for SEB, which can be collected via a simple magnet. After separating SEB from the sample matrix, they are sandwiched by using binding-specific antibody-antigen pairs with the help of gold nanorod particles. Gold nanorod particles are bifunctional by design and contain self-assembled monolayers (SAMs) of a SERS tag molecule (5,5-dithiobis (2-nitrobenzoic acid), DTNB) and carboxylic functionalities of DTNB for coupling with a suitable antibody. The correlation between the SEB concentration and SERS signal was found to be linear within the range of 3 fM to 0.3 MUM. The limit of detection for the assay was determined to be 768 aM (ca., 9250 SEB molecules per 20 MUL sample volume). The gold heterogeneous assay system for SEB detection was also compared with the same SERS probes and gold-coated surfaces as capture substrates. The developed method was further evaluated for detecting SEB in artificially contaminated milk. Finally, the method was used for investigating the SEB specificity on bovine serum albumin (BSA) and avidin. PMID- 22943044 TI - Mast cells, disease and gastrointestinal cancer: A comprehensive review of recent findings. AB - Paul Ehrlich, a German scientist, discovered what is known as the mast cell in the late 1800's, which has proven to be an important player in the immune system of vertebrates. Mast cells are ubiquitous throughout the tissues of the human body and play numerous roles, both beneficial and destructive. We know they are important in our army of immunity warrior cells, which defend us against viruses, bacteria and parasitic invaders. They are also very well known for the havoc they wreak, causing uncomfortable symptoms due to their release of histamine and other mediators which cause the all too familiar itching, sneezing, urticaria and rhinorrhea of allergic responses. Mast cell activities are diverse and include painful inflammatory reactions in autoimmune conditions such as rheumatoid arthritis. In the gastrointestinal system, mast cells are implicated in diverse actions such as increased gastric acid secretion, polyp formation and uncomfortable conditions such as Irritable Bowel Syndrome. The role of immunology and mast cells in these areas is intriguing but less well understood than their role in allergic responses. Because mast cells have been implicated in both physiologic as well as pathogenic processes, they have been the subjects of avid study. Review of the current literature on mast cell biology reveals that there are many studies of their presence within the tumor microenvironment and evidence, which supports mast cell influence on tumor angiogenesis, tumor invasion, and immune suppression. The studies reviewed in this article concentrate largely on mast cells in human GI malignancies. This review also provides background information regarding mast cells, such as their origination, their location within the body, how they are activated and how they function as mediators. PMID- 22943048 TI - Dual signal amplification for bioassays using ion release from nanolabels and ion activated enzyme kinetics. AB - A dual signal amplification technique was developed for bioassays. The technique consists of zinc-ion release from ZnS nanoparticle labels and enzyme kinetics activated by the released zinc ions as cofactors. In the ion release process, each ZnS nanoparticle label liberates a high number of zinc ions by acidic dissolution. After the ion release, at appropriate pH levels, the released zinc ions are used as cofactors to trigger the enzymatic activity of carbonic anhydrase. The fluorescence produced from the activated enzyme kinetics is measured for bioassay signal quantification. A model bioassay on mouse IgG adopting this technique presents a detection limit around 0.5 pM and a detection range over at least two orders of magnitude. This technique was also successfully applied to the detection of human cardiac troponin I (cTnI) in human serum samples to demonstrate a clinical diagnosis application. The developed immunoassay is capable of distinguishing clinically critical levels of cTnI. This technique possesses a high detection resolution and offers the advantage of straightforward operation (simple preparation of ZnS nanoparticles and no enzyme immobilization). PMID- 22943049 TI - Monitoring methotrexate in clinical samples from cancer patients during chemotherapy with a LSPR-based competitive sensor. AB - A competitive binding assay based on localized surface plasmon resonance (LSPR) of folic acid-functionalized gold nanoparticles (FA-AuNPs) and human dihydrofolate reductase enzyme (hDHFR) was developed to detect nanomolar to micromolar concentrations of the widely applied anti-cancer drug, methotrexate (MTX). By the nature of the competitive assay for MTX, the LSPR shift from specific binding between FA-AuNPs and the free enzyme was inversely proportional to the concentration of MTX. In addition, the dynamic range for MTX was tuned from 10(-11) to 10(-6) M by varying the concentration of hDHFR from 1 to 100 nM. Inter-day reproducibility and recovery of MTX spiked in phosphate buffer saline (PBS) were excellent. Potential interferents such as FA, trimethoprim (TMP) and 4 amino-4-deoxy-N-methylpteroic acid (DAMPA) did not occur in the concentration range of interest for MTX. Clinical samples of human serum from patients undergoing MTX chemotherapy were analyzed following a simple solid-phase extraction step to isolate MTX from the serum matrix, with a limit of detection of 155 nM. Validation of the LSPR method was carried out in comparison to Fluorescence Polarization Immunoassay (FPIA), a commonly used method in clinical settings, and LC-MS/MS, a reference technique. The results of the LSPR competitive assay compared well to FPIA and LC-MS/MS, with a slope of 2.4 and 1.1, respectively, for the correlation plots. The method established herein is intended for therapeutic drug monitoring (TDM) of MTX levels in patients undergoing chemotherapy to ensure safety and efficacy of the treatment. PMID- 22943050 TI - Ratiometric optical oxygen sensing: a review in respect of material design. AB - The quantitative determination of oxygen concentration is essential for a variety of applications ranging from life sciences to environmental sciences. Optical oxygen sensing allows non-invasive measurements with biological objects, parallel monitoring of multiple samples, and imaging. In general, ratiometric optical oxygen sensing is more desirable, due to its advantages of selectivity, insensitivity to ambient or scattered light, and elimination of instrumental fluctuation. Moreover, it can provide the perceived colour change, which would be useful not only for the ratiometric method of detection but also for rapid visual sensing. Mainly focusing on material design for ratiometric measurement, this review describes the overall progress made in the past ten years on ratiometric optical ground-state triplet oxygen sensing and offers a critical comparison of various methods reported in the literature. It also provides a development blueprint for ratiometric optical oxygen sensing. PMID- 22943051 TI - The spectrum of alpha- and beta-thalassemia mutations in Yunnan Province of Southwestern China. AB - The aim of this study was to investigate the spectrum of thalassemia mutations in Yunnan Province, Southwestern China. We detected 450 thalassemia patients and carriers by multiplex gap polymerase chain reaction (gap-PCR), PCR reverse dot blot hybridization and direct sequencing methods in 535 suspected patients. Four types of alpha-thalassemia (alpha-thal) mutations, - -(SEA) (59.2%), -alpha(3.7) (rightward) (19.0%), Hb Constant Spring [Hb CS, alpha142, Term->Gln, TAA>CAA (alpha2), alpha(CS)alpha] (15.5%), and -alpha(4.2) (leftward) (6.34%) were detected. Six types of beta-thal mutations, the most prevalent being Hb E [beta26(B8)Glu->Lys, GAG>AAG or codon 26 (G>A)] (30.5%), followed by codon 17 (A>T) (20.8%), codons 41/42 (-TCTT) (17.5%), IVS-II-654 (C>T) (17.2%), -28 (A>G) (6.95%), and codons 71/72 (+A) (2.42%) were also detected. Other rare mutations were codons 27/28 (+C), IVS-I-1 (G>T), Hb New York [beta113(G15)Val->Glu, GTG>GAG], Hb D-Los Angeles [beta121(GH4)Glu->Gln, GAA>CAA], codon 5 (-CT), Hb G Taipei [beta22(B4)Glu->Glu (GAA>GGA)], Hb J-Lome [beta59(E3)Lys->Asn (AAG>AAC)], Hb J-Bangkok [beta56(D7)Gly->Asp (GGC>GAC)], IVS-I-2 (T>C), and -31 (A>C). In this study, we provide a complete mutation spectrum of alpha- and beta-thal mutations and a valuable strategy for accurate molecular diagnostic testing in Yunnan Province, People's Republic of China (PRC). PMID- 22943058 TI - Now it is a highlight, not an acceleration. PMID- 22943057 TI - Bayesian inference of a complex invasion history revealed by nuclear and chloroplast genetic diversity in the colonizing plant, Silene latifolia. AB - Species invading new ranges are subject to a series of demographic events that can strongly shape genetic diversity. Describing this demographic history is important for understanding where invasive species come from and how they spread, and is critical to testing hypotheses of postinvasion adaptation. Here, we analyse nuclear and chloroplast genetic diversity to study the invasion history of the widespread colonizing weed, Silene latifolia (Caryophyllaceae). Bayesian clustering and PCA revealed strong population structure in the native range of Europe, and although genotypes from multiple native sources were present in the introduced range of North America, the spatial distribution of genetic variance was dramatically reorganized. Using approximate Bayesian computation (ABC), we compared support for different invasion scenarios, including the number and size of independent introduction events and the amount of admixture occurring between sources of introduced genotypes. Our results supported independent introductions into eastern and western North America, with the latter forming a bridgehead for a secondary invasion into the Great Lakes region of central North America. Despite small estimated founder population sizes, the duration of the demographic bottleneck after the initial introduction appeared extremely short-lived. This pattern of repeated colonization and rapid expansion has effectively eroded the strong population structure and cytonuclear associations present in Europe, but has retained overall high genetic diversity since invasion. Our results highlight the flexibility of the ABC approach for constructing a narrative of the demographic history of species invasions and provide baseline for future studies of evolutionary changes in introduced S. latifolia populations. PMID- 22943054 TI - Correlates of HIV and malaria co-infection in Southern India. AB - BACKGROUND: Malaria and HIV co-infection adversely impact the outcome of both diseases and previous studies have mostly focused on falciparum malaria. Plasmodium vivax contributes to almost half of the malaria cases in India, but the disease burden of HIV and P. vivax co-infection is unclear. METHODS: HIV infected subjects (n=460) were randomly selected from the 4,611 individuals seen at a Voluntary Counseling and Testing Center in Chennai, India between Jan 2 to Dec 31 2008. Malaria testing was performed on stored plasma samples by nested PCR using both genus-specific and species-specific primers and immunochromatography based rapid diagnostic test for detecting antibodies against Plasmodium falciparum and P. vivax. RESULTS: Recent malaria co-infection, defined by the presence of antibodies, was detected in 9.8% (45/460) participants. Plasmodium vivax accounted for majority of the infections (60%) followed by P. falciparum (27%) and mixed infections (13%). Individuals with HIV and malaria co-infection were more likely to be men (p=0.01). Between those with and without malaria, there was no difference in age (p=0.14), CD4+ T-cell counts (p=0.19) or proportion CD4+ T-cell below 200/mL (p=0.51). CONCLUSIONS: Retrospective testing of stored plasma samples for malaria antibodies can facilitate identification of populations with high rates of co-infection, and in this southern India HIV infected cohort there was a considerable burden of malaria co-infection, predominantly due to P. vivax. However, the rate of P. falciparum infection was more than 6-fold higher among HIV-infected individuals than what would be expected in the general population in the region. Interestingly, individuals co infected with malaria and HIV were not more likely to be immunosuppressed than individuals with HIV infection alone. PMID- 22943060 TI - The pharmacokinetics of cytarabine in dogs when administered via subcutaneous and continuous intravenous infusion routes. AB - This crossover study compared the pharmacokinetics of cytarabine in six healthy dogs following intravenous constant rate infusion (CRI) and subcutaneous (SC) administrations, as these are two routes of administration commonly employed in the treatment of meningoencephalitis of unknown etiology. Each dog received a SC cytarabine injection of 50 mg/m(2) or an 8 h CRI of 25 mg/m(2) per hour, with a 7 day washout before receiving the alternative treatment. Blood samples were collected for 16 h after CRI initiation and for 8 h after SC injection. Plasma concentrations were measured by high-pressure liquid chromatography (HPLC). Pharmacokinetic parameters were estimated using the best-fit compartmental analysis for both CRI and SC routes. Terminal half-life (T(1/2) ) of cytarabine was 1.35 +/- 0.3 and 1.15 +/- 0.13 h after SC administration and CRI, respectively. Mean peak concentration (Cmax ) was 2.88 and 2.80 MUg/mL for SC and CRI administration, respectively. Volume of distribution was 0.66 +/- 0.07 l/kg. The 8-h CRI produced steady-state plasma concentrations as determined by consecutive measurement that did not decline until the end of the infusion. The SC administration did not achieve steady-state concentrations because cytarabine administered by this route was rapidly absorbed and eliminated quickly. The steady state achieved with the cytarabine CRI may produce a more prolonged exposure of cytarabine at cytotoxic levels in plasma compared to the concentrations after SC administration. PMID- 22943061 TI - Patient-patient interaction--caring and sharing. AB - AIM: The aim of this study is to provide an understanding of the significance of hospitalized patients' interpersonal interaction with fellow patients in an infectious disease ward in a large Danish hospital. METHOD: A qualitative approach was selected using participant observation and semi-structured qualitative interviews. Six female participants at the age of 32-81 years with different types of infectious diseases accepted to participate in interviews. The analysis was carried out using Kvales' three levels of qualitative data analysis. Data were catalogued into two main categories with several subcategories representing significance of patients' interaction with fellow patients. RESULTS: The qualitative analysis resulted in two main categories: (i) Caring for fellow patients and (ii) Sharing illness information with fellow patients. Each of the main categories was elucidated through several subcategories. Our findings clearly showed that interpersonal interaction with fellow patients was of utmost importance when it came to care and support and when they needed information about their illness. Typically, the interpersonal interaction was experienced as giving and referred to in positive terms, but occasionally, the opposite was experienced too. Less typically, the patients experienced interaction with fellow patients as a burden and referred to it in negative terms. CONCLUSIONS: Patients' interaction resembled care as well as self-care. Patient-patient interaction was an important part of the social support system during hospitalization. PMID- 22943062 TI - Visuospatial transformation impairments in Parkinson's disease. AB - Some previous studies have reported impairments in Parkinson's disease (PD) that affect performance on visuospatial tasks. The aim of this study was to further elucidate the underlying cognitive impairment to visuospatial processing in PD. Nondementing PD patients and neurologically normal, age-matched controls completed two tasks of visuospatial transformation. In Task 1, observers made perceptual matching judgments about the shape equivalence of two upright or rotated 2D novel patterns. Task 2 used a recognition memory paradigm in which participants first memorized a target object at a specific orientation and then made target/nontarget judgments to targets or visually similar distractors at varying orientations. Analyses of the regression slopes between response times and angular disparity showed that PD is associated with impairments affecting spatial transformation during image normalization in both tasks. The results also showed that the patients were more impaired, relative to controls, at spatial transformation during the perceptual matching of two images, than in the recognition memory task. It is suggested that PD can result in deficits affecting spatial transformation processes that are modulated by working memory and task demands. PMID- 22943063 TI - Characterization of rhizobial isolates nodulating Millettia pinnata in India. AB - Millettia pinnata (Synonym Pongamia pinnata) is a viable source of oil for the mushrooming biofuel industry, source for agroforestry, urban landscaping, and the bio-amelioration of degraded lands. It also helps in maintaining soil fertility through symbiotic nitrogen fixation. However, not much work is reported on classification and characterization of the rhizobia associated with this plant. In the present study, an attempt was made to isolate rhizobial strains nodulating Millettia from soils collected from southern regions of India. The isolates were characterized using numerical taxonomy, 16S rRNA gene sequencing, and cross nodulation ability. The results showed high phenotypic and genetic diversity among the rhizobia symbiotic with Millattia pinnata. The isolates formed five clusters at similarity level of 0.82 based on the results of numerical taxonomy. Results on 16S rRNA gene sequence analysis revealed that most microsymbionts of M. pinnata belonged to Rhizobium and Bradyrhizobium, which are closely related to Rhizobium sp., B. elkanii and B. yuanmingense. Among these isolates, some isolates could grow in a pH range of 4.0-10.0, some could tolerate a high salt concentration (3% NaCl) and could grow at a maximum temperature between 35 and 45 degrees C. M. pinnata formed nodules with diverse rhizobia in Indian soils. These results offered the first systematic information about the microsymbionts of M. pinnata grown in the soils from southern part of India. PMID- 22943064 TI - Liver iron and serum ferritin levels are misleading for estimating cardiac, pancreatic, splenic and total body iron load in thalassemia patients: factors influencing the heterogenic distribution of excess storage iron in organs as identified by MRI T2*. AB - A comparative assessment of excess storage iron distribution in the liver, heart, spleen and pancreas of beta-thalassemia major (beta-TauMU) patients has been carried out using magnetic resonance imaging (MRI) relaxation times T2*. The beta TauMU patients (8-40 years, 11 males, 9 females) had variable serum ferritin levels (394-5603 MUg/L) and were treated with deferoxamine (n = 10), deferiprone (n = 5) and deferoxamine/deferiprone combination (n = 5). MRI T2* assessment revealed that excess iron is not proportionally distributed among the organs but is stored at different concentrations in each organ and the distribution is different for each beta-TauMU patient. There is random variation in the distribution of excess storage iron from normal to severe levels in each organ among the beta-TauMU patients by comparison to the same organs of ten normal volunteers. The correlation of serum ferritin with T2* was for spleen (r = 0.81), liver (r = -0.63), pancreas (r = -0.33) and none with heart. Similar trend was observed in the correlation of liver T2* with the T2* of spleen (r = 0.62), pancreas (r = 0.61) and none with heart. These studies contradict previous assumptions that serum ferritin and liver iron concentration is proportional to the total body iron stores in beta-TauMU and especially cardiac iron load. The random variation in the concentration of iron in the organs of beta-TauMU patients appears to be related to the chelation protocol, organ function, genetic, dietary, pharmacological and other factors. Monitoring of the iron load for all the organs is recommended for each beta-TauMU patient. PMID- 22943065 TI - Identification of purple acid phosphatase inhibitors by fragment-based screening: promising new leads for osteoporosis therapeutics. AB - Purple acid phosphatases are metalloenzymes found in animals, plants and fungi. They possess a binuclear metal centre to catalyse the hydrolysis of phosphate esters and anhydrides under acidic conditions. In humans, elevated purple acid phosphatases levels in sera are correlated with the progression of osteoporosis and metabolic bone malignancies, making this enzyme a target for the development of new chemotherapeutics to treat bone-related illnesses. To date, little progress has been achieved towards the design of specific and potent inhibitors of this enzyme that have drug-like properties. Here, we have undertaken a fragment-based screening approach using a 500-compound library identifying three inhibitors of purple acid phosphatases with K(i) values in the 30-60 MUm range. Ligand efficiency values are 0.39-0.44 kcal/mol per heavy atom. X-ray crystal structures of these compounds in complex with a plant purple acid phosphatases (2.3-2.7 A resolution) have been determined and show that all bind in the active site within contact of the binuclear centre. For one of these compounds, the phenyl ring is positioned within 3.5 A of the binuclear centre. Docking simulations indicate that the three compounds fit into the active site of human purple acid phosphatases. These studies open the way to the design of more potent and selective inhibitors of purple acid phosphatases that can be tested as anti osteoporotic drug leads. PMID- 22943066 TI - East meets West: current issues relevant to integrating Chinese medicine. AB - This article describes the challenges that integration of Chinese medicine (CM) and biomedicine are likely to bring for improving safety, research, education, and cross-disciplinary communication. Potential strategies to meet these challenges are suggested, including the use of accessible language for the Western biomedical community, and further development of whole-system randomized controlled trials that support individualized treatment approaches. PMID- 22943067 TI - Analytical evaluation of the Capillarys 2 Flex piercing for routine haemoglobinopathies diagnosis. AB - To evaluate the analytical performance of a new capillary electrophoresis instrument, the Capillarys 2 Flex piercing (Sebia, France), allowing the separation and quantitative estimation of the different haemoglobin fractions from whole blood, in capped primary tube.The analytical precision for the determination of HbA2 and HbF percentages was satisfactory and within the range of previously published results for HPLC methods. The correlation between Capillarys 2 Flex Piercing and Bio-Rad Variant II HPLC system showed a linear correlation for HbA2, HbF and HbS measurements, and the analysis interpretation was the same whatever the method used. Conversely to HPLC method, the capillary's electrophoresis technology allowed HbE and Hb Lepore fraction separation from HbA2. We showed that the Capillarys 2 Flex Piercing is suitable for haemoglobinopathies diagnosis and screening and offers an excellent alternative to HPLC techniques as a first-line method or for confirmatory analysis. PMID- 22943068 TI - Cost-effectiveness of early initiation of first-line combination antiretroviral therapy in Uganda. AB - BACKGROUND: Ugandan national guidelines recommend initiation of combination antiretroviral therapy (cART) at CD4+ T cell (CD4) count below 350 cell/MUl, but the implementation of this is limited due to availability of medication. However, cART initiation at higher CD4 count increases survival, albeit at higher lifetime treatment cost. This analysis evaluates the cost-effectiveness of initiating cART at a CD4 count between 250-350 cell/MUl (early) versus <250 cell/MUl (delayed). METHODS: Life expectancy of cART-treated patients, conditional on baseline CD4 count, was modeled based on published literature. First-line cART costs $192 annually, with an additional $113 for patient monitoring. Delaying initiation of cART until the CD4 count falls below 250 cells/MUl would incur the cost of the bi annual CD4 count tests and routine maintenance care at $85 annually. We compared lifetime treatment costs and disability adjusted life-expectancy between early vs. delayed cART for ten baseline CD4 count ranges from 250-350 cell/MUl. All costs and benefits were discounted at 3% annually. RESULTS: Treatment delay varied from 6-18 months. Early cART initiation increased life expectancy from 1.5 3.5 years and averted 1.33-3.10 disability adjusted life years (DALY's) per patient. Lifetime treatment costs were $4,300-$5,248 for early initiation and $3,940-$4,435 for delayed initiation. The cost/DALY averted of the early versus delayed start ranged from $260-$270. CONCLUSIONS: In HIV-positive patients presenting with CD4 count between 250-350 cells/MUl, immediate initiation of cART is a highly cost-effective strategy using the recommended one-time per capita GDP threshold of $490 reported for Uganda. This would constitute an efficient use of scarce health care funds. PMID- 22943070 TI - Trichoscopic features of various types of alopecia areata in India: application of a hand-held dermoscope. PMID- 22943069 TI - Antimicrobial peptide LL37 promotes vascular endothelial growth factor-A expression in human periodontal ligament cells. AB - BACKGROUND AND OBJECTIVE: LL37, originally found in the innate immune system, is a robust antimicrobial peptide. LL37 exhibits multiple bio-functions in various cell types, such as migration, cytokine production, apoptosis, and angiogenesis besides its antimicrobial activity Periodontal ligament (PL) cells play a pivotal role in periodontal tissue regeneration. Based on these findings, we hypothesized that LL37 can regulate PL cell function to promote regeneration of periodontal tissue. To prove this hypothesis, we investigated the effect of LL37 on the potent angiogenic inducer vascular endothelial growth factor (VEGF) expression in cultures of human PL (HPL) cells because neovascularization is indispensable for the progress of tissue regeneration. Moreover, we investigated the signaling cascade associated with LL37-induced VEGF expression. MATERIAL AND METHOD: HPL cells were treated with synthesized LL37 in the presence or absence of PD98059, a MEK-ERK inhibitor, or PDTC, an NF-kappaB inhibitor. VEGF expression levels were assessed by real-time polymerase chain reaction analysis and an enzyme-linked immunoassay. Phosphorylation levels of ERK1/2 or NF-kappaB p65 were determined by Western blotting. RESULTS: LL37 upregulated VEGF-A expression at the mRNA and protein levels in HPL cells, while VEGF-B mRNA expression was not affected. Both ERK and NF-kappaB inhibitors clearly abrogated the increase in VEGF-A levels induced by LL37 in HPL cells. Importantly, LL37 increased phosphorylated levels of ERK1/2 and NF-kappaB p65 in HPL cells. CONCLUSION: LL37 induces VEGF-A production in HPL cells via ERK and NF-kappaB signaling cascades, which may result in angiogenesis, thereby contributing to periodontal regeneration. PMID- 22943071 TI - Focussing both eyes on health outcomes: revisiting cataract surgery. AB - BACKGROUND: The appropriateness of cataract surgery procedures has been questioned, the suggestion being that the surgery is sometimes undertaken too early in the disease progression. Our three study questions were: What is the level of visual impairment in patients scheduled for cataract surgery? What is the improvement following surgery? Given the thresholds for a minimal detectable change (MDC) and a minimal clinically important difference (MCID), do gains in visual function reach the MDC and MCID thresholds? METHODS: The sample included a prospective cohort of cataract surgery patients from four Fraser Health Authority ophthalmologists. Visual function (VF-14) was assessed pre-operatively and at seven weeks post-operatively. Two groups from this cohort were included in this analysis: 'all first eyes' (cataract extraction on first eye) and 'both eyes' (cataract removed from both eyes). Descriptive statistics, change scores for VF 14 for each eye group and proportion of patients who reach the MDC and MCID are reported. RESULTS: One hundred and forty-two patients are included in the 'all first eyes' analyses and 55 in the 'both eyes' analyses. The mean pre-operative VF-14 score for the 'all first eyes' group was 86.7 (on a 0-100 scale where 100 is full visual function). The mean change in VF-14 for the 'both eyes' group was 7.5. Twenty-three percent of patients achieved improvements in visual function beyond the MCID threshold and 35% saw improvement beyond the MDC. CONCLUSIONS: Neither threshold level for MDC or MCID for the VF-14 scale was achieved for a majority of patients. A plausible explanation for this is the very high levels of pre-operative visual functioning. PMID- 22943072 TI - The effects of training and creatine malate supplementation during preparation period on physical capacity and special fitness in judo contestants. PMID- 22943073 TI - Managing potential conflict of interest in journal article publication. AB - The issue of potential conflict of interest and its risk to professional integrity in journal article publication has been strongly debated in medical circles. Most medical journals adhere to international requirements for disclosure of potential conflict of interest. The debate on this issue in nursing, and specifically mental health nursing, has been neither prolific nor strong, despite nursing's potential to influence particular viewpoints about treatment and indeed to prescribe particular treatments; and nursing being a target for pharmaceutical industry marketing. The purpose of this paper is to raise debate about potential conflict of interest in journal article publication and to make recommendations for the management of such potential for this journal. PMID- 22943075 TI - Oesophageal adenocarcinoma: the men's health problem you do not want to have! PMID- 22943076 TI - Are changes in referral patterns always justified? PMID- 22943074 TI - A prospective, open-label, non-comparative study of palivizumab prophylaxis in children at high risk of serious respiratory syncytial virus disease in the Russian Federation. AB - BACKGROUND: Respiratory syncytial virus (RSV) is a leading cause of lower respiratory tract infections (LRTIs) in children globally. Predisposing conditions for the development of serious RSV disease include preterm infants and those with cardiopulmonary illness, including congenital heart disease (CHD) and bronchopulmonary dysplasia (BPD). No vaccine is currently approved for the prevention of RSV infection. It is recommended that children at high risk be prophylactically administered palivizumab, a monoclonal antibody that has been shown in a number of clinical studies to reduce hospitalization rates due to serious RSV infection. The objective of the current study was to determine the safety and effectiveness of palivizumab in preventing serious RSV disease in high risk children in the Russian Federation. Children at high risk of serious RSV disease (ie, born at <= 35 wk gestational age and <= 6 mo of age, and/or aged <= 24 mo with BPD or hemodynamically significant CHD) were enrolled. Subjects were to receive 3 to 5 monthly injections of palivizumab 15 mg/kg (depending on the month of the initial injection) over the RSV season. The primary endpoint was RSV related hospitalizations. Adverse events (AEs) were reported through 100 days following the final injection. RESULTS: One hundred subjects received >= 1 injection of palivizumab; 94 completed their dosing schedule. There were no RSV hospitalizations or deaths. Six of 7 subjects hospitalized for respiratory/cardiac conditions had an RSV test, which was negative in all cases. Three non-serious AEs (acute intermittent rhinitis and rhinitis, 1 subject; atopic dermatitis, 1 subject) were considered possibly related to palivizumab. All other AEs were mild or moderate and considered not related/probably not related to palivizumab. CONCLUSION: Palivizumab was generally well tolerated and effectively prevented serious RSV infection in a mixed population of high-risk children in the Russian Federation. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01006629. PMID- 22943077 TI - Glomangiopericytoma: overview and role for open surgery. PMID- 22943078 TI - Unexpected internal herniation of the small bowel after right trisectionectomy. PMID- 22943079 TI - Caution: abnormal venous anatomy when inserting central venous catheters. PMID- 22943080 TI - Superior mesenteric artery syndrome following laparoscopic gastric banding. PMID- 22943081 TI - Re: Laparoendoscopic single-site cholecystectomy versus conventional laparoscopic cholecystectomy: a systematic review of randomized controlled trials. PMID- 22943082 TI - Comment on Photoselective vaporization of the prostate using the 180W lithium triborate laser. PMID- 22943083 TI - Vocal fold immobility after thyroid surgery (Re: ANZ J. S urg. 2012; 82: 188-9). PMID- 22943084 TI - Extrapancreatic pancreatic pseudocyst. PMID- 22943085 TI - Late onset laryngeal stenosis following radiotherapy for head and neck carcinoma: a case series. PMID- 22943086 TI - Operative management of flail chest with anatomical locking plates (MatrixRib). PMID- 22943087 TI - Re: Currarinot triade. PMID- 22943088 TI - Percutaneous intra-luminal gastroscope-assisted surgery. PMID- 22943089 TI - Acute surgical abdomen in an immunocompromised patient. PMID- 22943090 TI - Novel method for non-traumatic creation of a colostomy. PMID- 22943091 TI - Burns caused by plaster of Paris splints. PMID- 22943092 TI - Lost and sliced valve-plasty catheter. PMID- 22943093 TI - Xanthogranuloma of liver: experience of a specialist surgical unit. PMID- 22943095 TI - Saliva collection methods for detection of anti-HCV. PMID- 22943096 TI - Cultural perceptions of weight in African American and Caucasian women. AB - OBJECTIVE: To determine if African American (AA) and Caucasian women grouped variables related to race and weight into discrete clusters and if there were discernable response patterns with unique subgroup characteristics. METHODS: Women (N=277, 48% AA) completed a card sorting task, ranking 28 variables. We used multidimensional scaling to determine perceived similarities and differences between variables, and latent class analysis to identify subgroups responding similarly. RESULTS: We identified 5 clusters of variables and 4 response patterns, which were demographically and anthropometrically distinct. CONCLUSIONS: These results can be used for empirical cultural tailoring of behavioral weight loss interventions. PMID- 22943097 TI - Drinking norms: predictors of misperceptions among college students. AB - OBJECTIVES: To explore misperceptions and predictors of misperceptions of celebration and general drinking norms. Participants were traditional college students (N=214). METHODS: An online questionnaire was developed to assess personal drinking behavior and perceived drinking norms. RESULTS: Significant misperceptions exist among students regarding their perception of the drinking patterns and behaviors displayed by peers in general and during celebration events. Overestimation is more prevalent for celebration drinking than for drinking in general. The odds of being an overestimator are greater for out-of state residents, frequent drinkers, and students with lower GPAs. CONCLUSIONS: Effective strategies should be implemented to correct misperceptions. PMID- 22943099 TI - Parent health risk and support for child physical activity. AB - OBJECTIVES: To explore the influence of health risk on support for physical activity in parents of boys and parents of girls. METHODS: The influence of parent BMI, physical activity, smoking, and fruit and vegetable consumption was explored in child gender-specific hierarchical linear regression models. RESULTS: Positive predictors of support included physical activity in parents of boys and parents of girls. In parents of girls, child BMI and parent BMI were also significant. CONCLUSION: Higher BMI in parents of girls and higher BMI in girls predicted higher levels of parental supportive behavior. PMID- 22943098 TI - A multiple indicators and multiple causes model of alternative tobacco use. AB - OBJECTIVE: To examine the relationship between adolescents' cigarette smoking experiences and alternative tobacco product (ATP) use. METHODS: Multiple indicators and multiple causes (MIMIC) models estimated simultaneously the relationship between cigarette smoking experiences and ATP use among high school students (N=1827) completing the 2009 Virginia Youth Tobacco Survey. RESULTS: Overall, ATP use was associated with adolescents' ever use of cigarettes, early onset of cigarette smoking, cigarettes smoked per day, and peer smoking; however, important model differences between racial/ethnic groups were observed. CONCLUSIONS: Prevention and cessation programs might reduce adolescent ATP use by targeting specific characteristics of cigarette smoking. PMID- 22943100 TI - Why do people with suboptimal health avoid health promotion at work? AB - OBJECTIVES: To explore why people who have active work and who experience suboptimal health avoided using a multipurpose in-house health promotion service in the Danish police. METHODS: Data were first collected via an electronic survey (N=6060) and subsequently via 25 telephone interviews targeting nonusers who perceived their health to be suboptimal. RESULTS: Many nonusers with suboptimal health wished to change health behaviors, but did not use the service. Reasons were both individual (eg, laziness) and organizational (eg, delivery of the service). CONCLUSIONS: Although many reported barriers are more individual in nature, increased information and accessibility could serve to increase participation. PMID- 22943101 TI - Eating better for less: a national discount program for healthy food purchases in South Africa. AB - OBJECTIVES: To examine whether reducing prices for healthy food purchases leads to changes in self-reported measures of food consumption and weight status. METHODS: Repeated surveys of about 350,000 HealthyFood participants and nonparticipants. RESULTS: Program participation is associated with more consumption of fruits/vegetables and whole-grain foods and less consumption of high sugar/salt foods, fried foods, processed meats, and fast food. There is no strong evidence that participation reduces obesity. CONCLUSIONS: A substantial price intervention might be effective in improving diets. PMID- 22943102 TI - Value of audio-enhanced handheld computers over paper surveys with adolescents. AB - OBJECTIVE: To examine the impact of 3 data collection modes on the number of questions answered, data quality, and student preference. METHODS: 275 urban seventh-grade students were recruited and randomly assigned to complete a paper survey (SAQ), PDA survey (PDA), or PDA survey with audio (APDA). Students completed a paper debriefing survey. RESULTS: APDA respondents completed significantly more questions compared to SAQ and PDA. PDA and APDA had significantly less missing data than did SAQ. No differences were found for student evaluation. CONCLUSIONS: Strong benefits may be gained by the use of APDA for adolescent school-based data collection. PMID- 22943103 TI - Influence of grade-level drinking norms on individual drinking behavior. AB - OBJECTIVE: To investigate which points of the middle-school drinking distribution are the most influential in the social contagion of drinking across the middle school years, in order to identify potential social multipliers. METHODS: We measured drinking intentions and behaviors by gender, school, and grade among urban middle-school students who participated in Project Northland Chicago in a longitudinal cohort design. RESULTS: Individual drinking behaviors were consistently influenced by extreme (80(th) percentile) drinking intentions and behaviors. This effect was mediated through normal or average levels of drinking, over time. CONCLUSIONS: Interventions can target extreme drinkers as the influential persons in middle-school grades. PMID- 22943104 TI - Issues in biomedical research: what do Hispanics think? AB - OBJECTIVE: To examine barriers and facilitators of biomedical research participation among Hispanics in a rural community in Washington State. METHODS: Questionnaires addressed socio-demographics, health care access, and barriers and facilitators of participation in biomedical studies. This is a descriptive analysis of the findings. RESULTS: Barriers include the need to care for family members (82%), fear of having to pay for research treatments (74%), cultural beliefs (65%), lack of time (75%) and trust (71%), and the degree of hassle (73%). Facilitators include having a friend/relative with the disease being researched (80%) and monetary compensation (73%). CONCLUSION: Researchers should be mindful of these facilitators and barriers when recruiting for biomedical research studies. PMID- 22943105 TI - Component analysis and initial validity of the exercise fear avoidance scale. AB - OBJECTIVES: To develop the Exercise Fear Avoidance Scale (EFAS) to measure fear of exercise-induced discomfort. METHODS: We conducted principal component analysis to determine component structure and Cronbach's alpha to assess internal consistency of the EFAS. Relationships between EFAS scores, BMI, physical activity, and pain were analyzed using multivariate regression. RESULTS: The best fit was a 3-component structure: weight-specific fears, cardiorespiratory fears, and musculoskeletal fears. Cronbach's alpha for the EFAS was alpha=.86. EFAS scores significantly predicted BMI, physical activity, and PDI scores. CONCLUSION: Psychometric properties of this scale suggest it may be useful for tailoring exercise prescriptions to address fear of exercise-related discomfort. PMID- 22943106 TI - Effects of Biggest Loser exercise depictions on exercise-related attitudes. AB - OBJECTIVES: To examine whether participants who watched an exercise-related segment of The Biggest Loser television program would have different explicit and implicit affective exercise-related attitudes than those of control participants. METHODS: University students (N=138) watched a clip of The Biggest Loser or American Idol, then completed a Go/No-go Association Task, a thought-listing task, and questionnaires measuring explicit attitudes, activity level, and mood. RESULTS: Participants who watched The Biggest Loser had significantly lower explicit, but not implicit, attitudes towards exercise than did control participants. CONCLUSIONS: There is a need to examine the influence of popular media depictions of exercise. PMID- 22943108 TI - Social and health care provider support in diabetes self-management. AB - OBJECTIVE: To qualitatively determine social and health care provider support in diabetes self-management of Asian Indians in the United States. METHODS: Thirty Asian Indian adults with type 2 diabetes in either acceptable (AC) (HbA1c<7%) or unacceptable (UC) (HbA1c>=7%) glycemic control were interviewed. Emergent themes were analyzed using the constant comparison method. RESULTS: Support from social networks and health care providers was more evident in the AC versus the UC group. UC participants tended to rely more on health-care provider guidance and communication. CONCLUSION: Involvement of a patient's social networks might be an important part of patient-tailored interventions targeting this population. PMID- 22943107 TI - Subjective social status and health behaviors among African Americans. AB - OBJECTIVES: To examine associations of the US and community subjective social status (SSS) ladders with smoking status, at-risk drinking, fruit and vegetable intake, physical activity, and body mass index among 1467 church-going African American adults from a larger cohort study. METHODS: Regression analyses, adjusted for sociodemographics, examined associations between SSS ladders and health behaviors. RESULTS: The SSS-US ladder was significantly associated with fruit and vegetable consumption (p = .007) and physical activity (p = .005). The SSS-community ladder was not significantly associated with any health behaviors. CONCLUSIONS: Among this sample of African Americans, the SSS-US ladder is more predictive of some health behaviors than is the SSS-community ladder. PMID- 22943109 TI - Development and validation of worksite weight-related social norms surveys. AB - OBJECTIVE: To describe the development of measures of worksite descriptive social norms for weight loss, physical activity, and eating behaviors. METHODS: Three surveys were tested in 844 public high school employees. Factor analysis, Cronbach alpha, and tests of association with other worksite social contextual measures and behaviors were performed. RESULTS: Each survey demonstrated high internal consistency and was associated with measures of social support and behaviors. Confirmatory factor analysis supported the reliability of the weight loss and eating-behavior norms surveys, but not the physical-activity norms survey. CONCLUSIONS: The weight-loss and eating norms surveys are reliable, valid measures. PMID- 22943110 TI - Rural versus urban Texas WIC participants' fruit and vegetable consumption. AB - OBJECTIVE: To explore fruit and vegetable (F&V) consumption among urban and rural Black Texas WIC participants. METHODS: The study included 673 WIC mothers and their 351 children from the TEXFAN study. T-tests, Pearson chi-squared test, and regressions were performed. RESULTS: Among children, differences were found for fruit consumption but not vegetable. Urban children were offered and consumed a greater variety of F&V. Mothers' F&V intake was related to age, pregnancy status, and breastfeeding status. CONCLUSIONS: This study provides insight into a subsection of the WIC population. Further research should be done regarding increasing the amount and variety of F&V consumed by WIC women and children. PMID- 22943111 TI - A single nucleotide polymorphism in the HBBP1 gene in the human beta-globin locus is associated with a mild beta-thalassemia disease phenotype. AB - The rs2071348 (g.5264146A>C) polymorphism on the HBB pseudogene, namely HBBP1, previously emerged as a variant significantly associated with a milder disease phenotype in Asian beta(0)-thalassemia/hemoglobin (Hb) E (beta(0)-thal/Hb E [beta26(B8)Glu->Lys, GAG>AAG]) patients. In this study, we aimed to explore the possible association of rs2071348 with beta-thalassemia (beta-thal) disease severity in a group of beta-thal major (beta-TM) patients (severe phenotype) and beta-thal intermedia (beta-TI) patients (mild phenotype) of Hellenic origin and compare the results with normal (non thalassemic) individuals of the same origin. In addition, we explored whether this single nucleotide polymorphism (SNP) can be exploited as a pharmacogenomic marker to predict the outcome of Hb F-augmenting therapy in beta-thal patients receiving hydroxyurea (HU). Our data suggest that the rs2071348 polymorphism is associated with higher Hb F levels and a milder beta-thal disease phenotype. However, the rs2071348 polymorphism in the HBBP1 gene does not correlate with response to HU treatment. PMID- 22943113 TI - Potential anticancer therapies via CXCL5 and its receptors. PMID- 22943112 TI - Influence of certain forces on evolution of synonymous codon usage bias in certain species of three basal orders of aquatic insects. AB - Forces that influence the evolution of synonymous codon usage bias are analyzed in six species of three basal orders of aquatic insects. The rationale behind choosing six species of aquatic insects (three from Ephemeroptera, one from Plecoptera, and two from Odonata) for the present analysis is based on phylogenetic position at the basal clades of the Order Insecta facilitating the understanding of the evolution of codon bias and of factors shaping codon usage patterns in primitive clades of insect lineages and their subtle differences in some of their ecological and environmental requirements in terms of habitat microhabitat requirements, altitudinal preferences, temperature tolerance ranges, and consequent responses to climate change impacts. The present analysis focuses on open reading frames of the 13 protein-coding genes in the mitochondrial genome of six carefully chosen insect species to get a comprehensive picture of the evolutionary intricacies of codon bias. In all the six species, A and T contents are observed to be significantly higher than G and C, and are used roughly equally. Since transcription hypothesis on codon usage demands A richness and T poorness, it is quite likely that mutation pressure may be the key factor associated with synonymous codon usage (SCU) variations in these species because the mutation hypothesis predicts AT richness and GC poorness in the mitochondrial DNA. Thus, AT-biased mutation pressure seems to be an important factor in framing the SCU variation in all the selected species of aquatic insects, which in turn explains the predominance of A and T ending codons in these species. This study does not find any association between microhabitats and codon usage variations in the mitochondria of selected aquatic insects. However, this study has identified major forces, such as compositional constraints and mutation pressure, which shape patterns of codon usage in mitochondrial genes in the primitive clades of insect lineages. PMID- 22943114 TI - Manipulation with kynurenines: a possible tool for treating neurodegenerative diseases? PMID- 22943116 TI - Denosumab for the treatment of cancer therapy-induced bone loss and prevention of skeletal-related events in patients with solid tumors. AB - Development of bone metastasis is common among patients with advanced cancer. Improvements in chemotherapeutic agents have allowed these patients to live longer with metastatic-stage disease. Thus, treatments to prevent skeletal complications of metastatic bone disease, such as skeletal-related events and pain, are increasingly important. As the skeletal damage with bone metastases is largely caused by increased osteoclast activity, antiresorptive agents (denosumab or bisphosphonates) are recommended for use in these patients. Denosumab, a fully human monoclonal antibody to RANKL, a key mediator of osteoclast activity, was shown to be superior to zoledronic acid for the prevention of skeletal-related events in patients with solid tumors and bone metastases. In addition, denosumab is the only agent currently approved for the treatment of bone loss in patients with breast or prostate cancer receiving hormone-ablation therapy. Denosumab is also being evaluated in several other indications, including adjuvant treatment of breast cancer and giant cell tumor of the bone. PMID- 22943117 TI - Oral alitretinoin: a review of the clinical pharmacokinetics and pharmacodynamics. AB - Alitretinoin is an endogenous retinoid related to vitamin A. Studies have shown that oral alitretinoin is effective and well tolerated in the treatment of severe chronic hand eczema. This review summarizes the clinical pharmacokinetic and pharmacodynamic data from a number of studies involving alitretinoin. These include the effect of food on the pharmacokinetics of alitretinoin, interactions between alitretinoin and ketoconazole, simvastatin or cyclosporin A, the effect of alitretinoin on the pharmacokinetics of a combined oral contraceptive, alitretinoin in seminal fluid after repeated dosing, and the pharmacokinetics of alitretinoin and its metabolites in a clinical setting. PMID- 22943118 TI - Pharmacokinetic- and pharmacodynamic-based antithrombotic dosing recommendations in children. AB - With the increasing incidence of venous thromboembolic events in children, there has also been a concurrent increase in the use of anticoagulants in children. It is imperative that dosing recommendations of anticoagulants be derived from pharmacokinetic- and pharmacodynamic-based data in children and not simply extrapolated from data based on adults. Medications for children are often based on weight or body surface area, and are often distributed and metabolized differently as well. Furthermore, the hemostatic system in neonates and infants differs from that of older children and adults, and targets for therapy may differ. For these reasons, dosing guidelines for all antithrombotic medications should be based on pharmacokinetic and pharmacodynamic data. The authors reviewed pharmacokinetic and pharmacodynamic studies of anticoagulants in children and make dosing recommendations based on study findings. PMID- 22943119 TI - Clinical pharmacology confounders in older adults. AB - Major advances produced by healthcare research have resulted in an increasing number of drugs that may be used to modify disease expression and improve quality of life. These discoveries have been used by clinical pharmacologists as a basis to identify new drug candidates and to develop strategies for their optimal delivery to maximize benefit while simultaneously minimizing adverse events. Unfortunately, many of these studies do not include sufficient older persons in whom most of these drug therapy interventions are likely to apply. This article examines selected physiological, pathological and healthcare interventional changes with age that impact clinical drug studies and the decision to use drugs as therapy in older adults. Clinical examples are provided that illustrate confounders to the accomplishment of an ideal outcome, the improved quality of life that remains for this population. PMID- 22943120 TI - Significance and applications of nanoparticles in siRNA delivery for cancer therapy. AB - RNAi is a powerful gene silencing process that holds great promise in cancer therapy by the use of siRNA. The aim of this review is to give an outline on different approaches to deliver siRNA and to describe the advantages and disadvantages of these systems. The prospects for siRNA are to be substantially better than other therapies, as they are easily applicable to any therapeutic target. They also promise potent gene inhibition with exquisite selectivity, down to the level of a single nucleotide polymorphism, and can easily identify offending proteins or variants by screening across a gene sequence. The main obstacle of using RNAi technology in cancer treatment is to protect such a fragile and quickly metabolized biological molecule and to efficiently deliver it in vivo to the target cells. Therefore, there is a requirement for new systems, such as nanoparticles, for siRNA delivery to help the siRNAs reach, and improve their biodistribution in, target tissues. PMID- 22943121 TI - From depression to neurodegeneration and heart failure: re-examining the potential of MAO inhibitors. AB - Initially introduced in the 1950s for treating depression, monoamine oxidase (MAO) inhibitors were gradually abandoned, mainly owing to their potential for drug-drug and drug-food interactions, the most widely known being with tyramine containing food (the 'cheese' effect). Since then, more selective MAO-A or MAO-B inhibitors have been developed with substantially reduced risks, and have been approved for the treatment of depression and Parkinson's disease, respectively. Recent research suggests that some of these drugs also have neuroprotective properties, while preclinical evidence expands the spectrum of potential indications to heart failure, renal diseases and multiple sclerosis. In this article, the authors review the relevance of MAO isoforms to disease, and they also outline current research and development efforts in this class of drugs, including newer multipotent compounds. PMID- 22943122 TI - Current progress in pharmacologic treatment strategies for alcohol dependence. AB - Alcoholism is a progressive neurological disorder that represents one of the leading preventable causes of morbidity and mortality in the USA. Individuals with alcohol dependence may exhibit differences in their sensitivity to intoxication, the age at which they begin heavy drinking or the presentation of comorbid psychiatric illness. The heterogeneous nature of the disorder has complicated efforts to predict treatment outcomes, indicating a need for improved diagnostic and therapeutic approaches. Pharmaceutical development has focused on treating the symptoms of alcohol withdrawal, reducing consumption of and craving for alcohol, preventing relapse and treating associated psychiatric problems. Current therapies may be optimized by combining psychosocial and pharmacologic approaches to treat alcoholic patients with the most appropriate regimen to achieve the desired therapeutic outcome. This article will describe the neurobiological mechanisms of dependence on alcohol in brief and review major medications approved for the treatment of alcoholism with regard to recent clinical evidence for the therapeutic efficacy of each agent. Investigations on the use of drugs with other indications (e.g., antidepressants and anticonvulsants) to target alcohol-dependent subtypes will also be discussed. PMID- 22943123 TI - Intravenous lipid administration for drug-induced toxicity: a critical review of the existing data. AB - Following the discovery that administration of intravenous lipid emulsion (ILE) may reverse the cardiac and neurological toxicity of certain local anesthetic agents, ILE's potential role has recently been explored in the setting of toxicity attributed to a variety of different drugs. The potential mechanisms, safety and efficacy of this approach are considered in this review. Data are reviewed from 76 published reports involving ILE administration for severe drug toxicity, including 55 where toxicity was due to nonanesthetic agents. ILE was reported to exert a positive therapeutic effect in only a proportion of the reported cases, with greatest evidence of efficacy concerning local anesthetic agents. Administration has typically involved bolus administration followed by continuous maintenance infusion, and a number of different mechanisms are proposed, from preferential partitioning of the drug from cardiac tissue to the circulating lipid fraction and direct inotropic effects related to carnitine pathways and fatty acid oxidative metabolism. No major adverse effects have been encountered, but too few data exist to adequately address the safety profile of ILE. PMID- 22943124 TI - Predicting ICU admission in community-acquired pneumonia: clinical scores and biomarkers. AB - Community-acquired pneumonia (CAP) remains a common and serious worldwide health problem. Despite all the advances in therapy, significant interest has focused on the identification of patients with CAP who require intensive care unit admission to improve their outcomes. The severity assessment of CAP provides an important guide to clinicians in deciding the site of care and the use of empiric antibiotics and adjuvant therapy. For years, several clinical assessment scores have been suggested and validated to achieve this goal. The recent introduction of biomarkers as prognostic indicators of severe CAP, whether used alone or in conjunction with other clinical severity of illness scores, has been investigated. An objective scoring system with a high level of sensitivity and specificity to predict the severity of CAP and the need for high levels of care do not exist. Today, the addition of clinical scores and biomarkers to clinical judgment is the best approach to optimize the care of severe CAP. Future research will allow validation of these and newer tools to improve the prognosis of patients with CAP. PMID- 22943125 TI - Vietnamese traditional medicine from a pharmacist's perspective. AB - Traditional medicine plays an important role in the healthcare system of Vietnam. Vietnamese traditional medicine (VTM) is underpinned by the oriental philosophy and theory of healing. VTM is largely influenced by traditional Chinese medicine, but differs to a certain extent. VTM is largely not evidence-based from a clinical perspective but subclinical research data from the past decades support the traditional use of many herbal VTM drugs. For safe use, knowledge of the occurrence of adverse reactions and herb-drug interactions is necessary. The Vietnamese government supports further development of VTM in a scientific way and integration of VTM with Western medicine. This article first gives an overview of the general aspects of VTM (historical perspective, regulatory aspects, comparison with traditional Chinese medicine, philosophical background, the Vietnamese market situation, quality assurance and formulations), and subsequently focuses on its safe and effective use in Vietnamese clinical pharmacy and medical practice. PMID- 22943127 TI - Preparing amorphous hydrophobic drug nanoparticles by nanoporous membrane extrusion. AB - AIM: The aim of the present study was to develop a simple and straightforward method for formulating hydrophobic drugs into nanoparticulate form in a scalable and inexpensive manner. MATERIALS & METHODS: The nanoporous membrane extrusion (NME) method was used to prepare hydrophobic drug nanoparticles. NME is based on the induced precipitation of drug-loaded nanoparticles at the exits of nanopores. Three common hydrophobic drug models (silymarin, beta-carotene and butylated hydroxytoluene) were tested. The authors carefully investigated the morphology, crystallinity and dissolution profile of the resulting nanoparticles. RESULTS: Using NME, the authors successfully prepared rather uniform drug nanoparticles (~100 nm in diameter). These nanoparticles were amorphous and show an improved dissolution profile compared with untreated drug powders. CONCLUSION: These studies suggest that NME could be used as a general method to produce nanoparticles of hydrophobic drugs. PMID- 22943128 TI - Tea phenols in bulk and nanoparticle form modify DNA damage in human lymphocytes from colon cancer patients and healthy individuals treated in vitro with platinum based chemotherapeutic drugs. AB - BACKGROUND: Tea catechin epigallocatechin-3-gallate (EGCG) and other polyphenols, such as theaflavins (TFs), are increasingly proving useful as chemopreventives in a number of human cancers. They can also affect normal cells. The polyphenols in tea are known to have antioxidant properties that can quench free radical species, and pro-oxidant activities that appear to be responsible for the induction of apoptosis in tumor cells. The bioavailability of these natural compounds is an important factor that determines their efficacy. Nanoparticle (NP)-mediated delivery techniques of EGCG and TFs have been found to improve their bioavailability to a level that could benefit their effectiveness as chemopreventives. AIM: The present study was conducted to compare the effects of TFs and EGCG, when used in the bulk form and in the polymer (poly[lactic-co glycolic acid])-based NP form, in oxaliplatin- and satraplatin-treated lymphocytes as surrogate cells from colorectal cancer patients and healthy volunteers. MATERIALS & METHODS: NPs were examined for their size distribution, surface morphology, entrapment efficiency and release profile. Lymphocytes were treated in the Comet assay with oxaliplatin and satraplatin, washed and treated with bulk or NP forms of tea phenols, washed and then treated with hydrogen peroxide to determine single-strand breaks after crosslinking. RESULTS: The results of DNA damage measurements by the Comet assay revealed opposite trends in bulk and NP forms of TFs, as well as EGCG. Both the compounds in the bulk form produced statistically significant concentration-dependent reductions in DNA damage in oxaliplatin- or satraplatin-treated lymphocytes. In contrast, when used in the NP form both TFs and EGCG, although initially causing a reduction, produced a concentration-dependent statistically significant increase in DNA damage in the lymphocytes. DISCUSSION: These observations support the notion that TFs and EGCG act as both antioxidants and pro-oxidants, depending on the form in which they are administered under the conditions of investigation. PMID- 22943129 TI - Characterization of biomolecular nanoconjugates by high-throughput delivery and spectroscopic difference. AB - AIM: Nanoparticle conjugates have the potential for delivering siRNA, splice shifting oligomers or nucleic acid vaccines, and can be applicable to anticancer therapeutics. This article compares tripartite conjugates with gold nanoparticles or synthetic methoxypoly(ethylene glycol)-block-polyamidoamine dendrimers. MATERIALS & METHODS: Interactions with model liposomes of a 1:1 molar ratio of tripalmitin:cholesterol or phospholipid:cholesterol were investigated by high throughput absorbance, as well as fluorescence difference and cellular luminescence assays. RESULTS: Spectral differences and dynamic light-scattering spectroscopy shifts demonstrated the interaction of conjugates with liposomes. Biological activity was demonstrated by upregulation of gene expression via splice-shifting oligomers, delivery of anti-B-Raf siRNA in cultured human cancer cells or tuberculosis antigen 85B plasmid expression vector in a coculture model of antigen presentation. CONCLUSION: The data suggests that gold nanoparticles and methoxypoly(ethylene glycol)-block-polyamidoamine dendrimer nanoconjugates may have potential for binding, stabilization and delivery of splice-shifting oligomers, siRNA and nucleic acid vaccines for preclinical trials. PMID- 22943130 TI - Quantitation of UGT1A1 in human liver microsomes using stable isotope-labelled peptides and mass spectrometry based proteomic approaches. AB - 1. UDP-glucuronosyltransferases (UGTs) are a group of drug-metabolizing enzymes that catalyse the conjugation of endogeonous compounds and xenobiotics to yield hydrophilic glucuronides which subsequently undergo excretion. This report describes an approach for the identification and accurate quantitation of human UGT1A1 in complex biological matrices using liquid chromatography/mass spectrometry/mass spectrometry (LC-MS/MS) analysis of protein digests. 2. A stable isotope-labelled (SIL) peptide of a unique peptide spanning residues 54-69 in exon 1 of the human UGT1A1 protein with the sequence RIYLSADPALVVIEHG was synthesized. The peptide sequence synthesized was in the reverse order of the human peptide with the stable isotope-labels in the amino acid arginine ((13)C6(15)N4) resulting in an increase in the mass of the SIL peptide of 10 amu, from 1753 to 1763. The SIL peptide was quantitated by injecting increasing concentrations of the peptide into the LC-MS to obtain a standard curve. 3. The labelled peptide along with precursor ion monitoring was used to quantify the levels of UGT1A1 in commercial recombinant preparations (supersomes) and individual human liver microsomal samples and pooled human liver micrsomes obtained from BD Biosciences. 4. Glucuronidation activity studies were performed, which demonstrated a positive correlation between enzyme activity levels and the UGT1A1 content in the liver microsomes obtained from individual human donors. PMID- 22943131 TI - The role of representative design in talent development: a comment on "Talent identification and promotion programmes of Olympic athletes". PMID- 22943132 TI - Characterization of a distinct lethal arteriopathy syndrome in twenty-two infants associated with an identical, novel mutation in FBLN4 gene, confirms fibulin-4 as a critical determinant of human vascular elastogenesis. AB - BACKGROUND: Vascular elasticity is crucial for maintaining hemodynamics. Molecular mechanisms involved in human elastogenesis are incompletely understood. We describe a syndrome of lethal arteriopathy associated with a novel, identical mutation in the fibulin 4 gene (FBLN4) in a unique cohort of infants from South India. METHODS: Clinical characteristics, cardiovascular findings, outcomes and molecular genetics of twenty-two infants from a distinct population subgroup, presenting with characteristic arterial dilatation and tortuosity during the period August 2004 to June 2011 were studied. RESULTS: Patients (11 males, 11 females) presented at median age of 1.5 months, belonging to unrelated families from identical ethno-geographical background; eight had a history of consanguinity. Cardiovascular features included aneurysmal dilatation, elongation, tortuosity and narrowing of the aorta, pulmonary artery and their branches. The phenotype included a variable combination of cutis laxa (52%), long philtrum-thin vermillion (90%), micrognathia (43%), hypertelorism (57%), prominent eyes (43%), sagging cheeks (43%), long slender digits (48%), and visible arterial pulsations (38%). Genetic studies revealed an identical c.608A > C (p. Asp203Ala) mutation in exon 7 of the FBLN4 gene in all 22 patients, homozygous in 21, and compound heterozygous in one patient with a p. Arg227Cys mutation in the same conserved cbEGF sequence. Homozygosity was lethal (17/21 died, median age 4 months). Isthmic hypoplasia (n = 9) correlated with early death (<=4 months). CONCLUSIONS: A lethal, genetic disorder characterized by severe deformation of elastic arteries, was linked to novel mutations in the FBLN4 gene. While describing a hitherto unreported syndrome in this population subgroup, this study emphasizes the critical role of fibulin-4 in human elastogenesis. PMID- 22943133 TI - Association between dietary patterns and metabolic syndrome in a sample of Portuguese adults. AB - BACKGROUND: There is scarce evidence regarding the association between diet and metabolic syndrome (MetS) in Portuguese population. We aim to evaluate the association between a posteriori dietary patterns (DPs) and MetS and its features. METHODS: Using random digit dialing, a sample of 2167 adults was selected between 1999 and 2003, in Porto. During a face-to-face interview, a questionnaire was applied, anthropometric measures were taken, blood pressure measured and a fasting blood sample collected. Diet was assessed using a validated food frequency questionnaire, and four DPs were identified in each sex by multivariate finite mixture models. RESULTS: After adjustment for age and daily energy intake, comparing to the "healthy" DP, women with the "low fruit and vegetables" DP had a higher odds of high waist circumference (OR = 1.88 95% CI 1.17-3.01) and low HDL-cholesterol (OR = 1.78 95% IC 1.12-2.82) and women in the "red meat and alcohol" DP had higher odds of high waist circumference (OR = 1.45 95% CI 1.01-2.07) and of MetS (OR = 1.57 95% CI 1.07-2.29); men with the "fish" DP had a higher odds of high triglycerides (OR = 1.57 95% CI 1.05-2.35). After further adjustments (education, physical activity, smoking, alcohol drinking, BMI, and menopausal status) no significant associations remained. CONCLUSIONS: Four distinct DPs were identified in a community sample of Portuguese adults and there was no association with the prevalence of MetS. PMID- 22943134 TI - Bacterial brain abscess in patients with nasopharyngeal carcinoma following radiotherapy: microbiology, clinical features and therapeutic outcomes. AB - BACKGROUND: This study aimed to analyze the clinical features, causative pathogens, neuro-imaging findings, and therapeutic outcomes of bacterial brain abscess in patients with nasopharyngeal carcinoma (NPC) following radiotherapy. METHODS: NPC patients with bacterial brain abscess were evaluated. Their clinical data were collected over a 22-year period. For comparison, the clinical features, causative pathogens, neuro-imaging findings, and therapeutic outcomes between NPC and non-NPC patients were analyzed. RESULTS: NPC accounted for 5.7% (12/210) of the predisposing factors, with Viridans streptococci and Staphylococcus aureus as the two most common causative pathogens. Significant statistical analysis between the two groups (NPC and non-NPC patients) included chronic otitis media (COM) as the underlying disease, post-radiation necrosis by neuro-imaging, and the temporal lobe as the most common site of brain abscesses. The fatality rate in patients with and without NPC was 16.7% and 20.7%, respectively. CONCLUSIONS: NPC patients with bacterial brain abscess frequently have COM as the underlying disease. Neuro-imaging often reveals both post-radiation necrosis and the temporal lobe as the most common site of brain abscesses, the diagnosis of which is not always a straightforward process. Radiation necrosis can mimic brain abscess on neuro-imaging and pose significant diagnostic challenges. Early diagnosis and treatment is essential for survival. PMID- 22943135 TI - The potential impact of plain packaging of cigarette products among Brazilian young women: an experimental study. AB - BACKGROUND: Tobacco use is responsible for 5.4 million deaths every year worldwide and is a leading cause of preventable death. The burden of these deaths is rapidly shifting to low and middle-income countries, such as Brazil. Brazil has prohibited most forms of tobacco advertising; however, the cigarette pack remains a primary source of marketing. The current study examined how tobacco packaging influences brand appeal and perceptions of health risk among young women in Brazil. METHODS: A between-subjects experiment was conducted in which 640 Brazilian women aged 16-26 participated in an online survey. Participants were randomized to view 10 cigarette packages according to one of three experimental conditions: standard branded packages, the same packs without brand imagery ("plain packaging"), or the same packs without brand imagery or descriptors (e.g., flavors). Participants rated packages on perceived appeal, taste, health risk, smoothness, and smoker attributes. Finally, participants were shown a range of branded and plain packs from which they could select one as a free gift, which constituted a behavioral measure of appeal. RESULTS: Branded packs were rated as significantly more appealing, better tasting, and smoother on the throat than plain packs. Branded packs were also associated with a greater number of positive smoker attributes including style and sophistication, and were perceived as more likely to be smoked by females than the plain packs. Removing descriptors from the plain packs further decreased the ratings of appeal, taste and smoothness, and also reduced associations with positive attributes. In the pack offer, participants were three times more likely to select branded packs than plain packs. CONCLUSIONS: Plain packaging and removal of descriptors may reduce the appeal of smoking for youth and young adults, and consequently reduce smoking susceptibility. Overall, the findings provide support for plain packaging regulations, such as those in Australia. PMID- 22943136 TI - Porous silicon microcavities: synthesis, characterization, and application to photonic barcode devices. AB - We have recently developed a new type of porous silicon we name as porous silicon colloids. They consist of almost perfect spherical silicon nanoparticles with a very smooth surface, able to scatter (and also trap) light very efficiently in a large-span frequency range. Porous silicon colloids have unique properties because of the following: (a) they behave as optical microcavities with a high refractive index, and (b) the intrinsic photoluminescence (PL) emission is coupled to the optical modes of the microcavity resulting in a unique luminescence spectrum profile. The PL spectrum constitutes an optical fingerprint identifying each particle, with application for biosensing.In this paper, we review the synthesis of silicon colloids for developing porous nanoparticles. We also report on the optical properties with special emphasis in the PL emission of porous silicon microcavities. Finally, we present the photonic barcode concept. PMID- 22943137 TI - Schistosomiasis collection at NHM (SCAN). AB - BACKGROUND: The Natural History Museum (NHM) is developing a repository for schistosomiasis-related material, the Schistosomiasis Collection at NHM (SCAN) as part of its existing Wolfson Wellcome Biomedical Laboratory (WWBL). This is timely because a major research and evaluation effort to understand control and move towards elimination of schistosomiasis in Africa has been initiated by the Schistosomiasis Consortium for Operational Research and Evaluation (SCORE), resulting in the collection of many important biological samples, including larval schistosomes and snails. SCAN will collaborate with a number of research groups and control teams and the repository will acquire samples relevant to both immediate and future research interest. The samples collected through ongoing research and field activities, WWBL's existing collections, and other acquisitions will be maintained over the long term and made available to the global research community for approved research purposes. Goals include: .Consolidation of the existing NHM schistosome and snail collections and transfer of specimens into suitable long-term storage systems for DNA retrieval, .Long term and stable storage of specimens collected as part of on going field programmes initially in Africa especially relating to the SCORE research programmes, .Provision of access to snail and schistosome collections for approved research activities. PMID- 22943139 TI - An evaluation of the external validity and reliability of a rugby league match simulation protocol. AB - The aim of this study was to assess the external validity and reliability of a novel rugby league match simulation protocol. With ethical approval, 16 males (age 22.4 +/- 7.1 years, estimated (.)VO(2max) 52.1 +/- 4.5 ml . kg-1 . min-1) performed the rugby league match simulation protocol on two occasions 10 to 14 days apart. During the rugby league match simulation protocol participants covered a total distance of 8,444 +/- 212 m, at an overall locomotive rate of 97.3 +/- 2.5 m . min-1. In addition, changes in very high (-22.4%), high (-8.6%) and low intensity (1.6%) running locomotive rates from the first to the fourth quarter were observed. The magnitude of these movement characteristics did not differ significantly (P > 0.05) between repeated trials, with coefficients of variation of 1.1, 4.2 and 10.6%, and 95% limits of agreement of -0.4 +/- 4.0, 0.3 +/- 3.6, and -0.2 +/- 4.4 m . min-1 for overall, high and very high intensity running locomotive rates, respectively. On this evidence, the rugby league match simulation protocol replicates the movement demands observed during elite rugby league matches. Furthermore, the protocol can be performed reliably amongst non elite sports players and thereby has the potential to be used as a tool for monitoring the effectiveness of various interventions on physical match performance. PMID- 22943138 TI - The tomato genome: implications for plant breeding, genomics and evolution. AB - The genome sequence of tomato (Solanum lycopersicum), one of the most important vegetable crops, has recently been decoded. We address implications of the tomato genome for plant breeding, genomics and evolutionary studies, and its potential to fuel future crop biology research. PMID- 22943140 TI - Do stroke patients have an increased risk of developing suicidal ideation or dying by suicide? An overview of the current literature. AB - Stroke is a leading cause of death that affects 15 million people worldwide each year. Increasing evidence suggests that stroke confers substantial risk for suicide and following a stroke, patients frequently develop poststroke depression, which is a well-established risk factor for suicide. In this overview of the current literature, we examined the association between suffering a stroke and subsequent risk for suicide and suicidal ideation. We performed a careful MedLine, Excerpta Medica, PsycLit, PsycInfo, and Index Medicus search to identify all articles and book chapters in English. We initially selected 31 articles published between 1990 and 2011; however, only 16 studies were included in this review. All articles identified stroke as a significant risk factor for suicide, especially among depressed patients, providing further support for poststroke depression and suicidality. The results also indicated that there were differences between patients who developed acute-onset suicidal plans and those who reported delayed-onset plans, which occurred more frequently. Many of the stroke patients who died by suicide suffered from depression prior to their death, suggesting that being diagnosed with a mood disorder contributes to an increased risk of suicide in this population. Suffering from a stroke increases the risk of dying by suicide and developing suicidal ideation, particularly in young adults and women. The factors found to confer the most risk for suicidality were depression, previous mood disorder, prior history of stroke, and cognitive impairment. PMID- 22943141 TI - Protective effect of carnosine on subcortical ischemic vascular dementia in mice. AB - AIMS: Recently, we found carnosine protects against N-Methyl-D-Aspartate (NMDA) induced excitotoxicity through a histaminergic pathway. The aim of this study was to determine whether the carnosine-histidine-histamine pathway also played a protective role in subcortical ischemic vascular dementia (SIVD). METHODS: Adult male mice (C57BL/6 strain) were subjected to right unilateral common carotid arteries occlusion (rUCCAO) and treated with carnosine or histidine. Object recognition test, passive avoidance task, Morris water maze, and immunohistochemical analyses were performed after rUCCAO. RESULTS: We found that carnosine (200, 500 mg/kg) ameliorated white matter lesion and cognitive impairment evaluated by object recognition test, passive avoidance task, and Morris water maze test after rUCCAO in both wide-type mice and histidine decarboxylase knockout mice, which are lack of endogenous histamine. However, administration of histidine did not show the same effect. The myelin basic protein in the corpus callosum decreased obviously at day 37 after rUCCAO, which was largely reversed by carnosine (200, 500 mg/kg). Carnosine (200, 500 mg/kg) suppressed the activation of microglia and astrocyte as attenuating the elevation of glial fibrillary acidic protein (GFAP) and Iba-1 fluorescent intensity. Moreover, carnosine (200, 500 mg/kg) significantly attenuated the increase in reactive oxygen species generation after rUCCAO. CONCLUSION: These data suggest that the neuroprotective effect of carnosine on rUCCAO in mice is not dependent on the histaminergic pathway, but may be due to a suppression of reactive oxygen species generation, glia activation, and myelin degeneration. PMID- 22943142 TI - Protective effects of the delta opioid peptide [D-Ala2, D-Leu5]enkephalin in an ex vivo model of ischemia/reperfusion in brain slices. AB - INTRODUCTION: The delta opioid peptide [D-Ala2, D-Leu5]enkephalin (DADLE) plays a key role in neuronal protection against both hypoxic and ischemic conditions. However, the cellular mechanisms of action of DADLE under these conditions remain unclear. METHODS: Ischemia was simulated with perfusing the brain slices with glucose-free artificial cerebrospinal fluid. Apoptosis was examined using an in situ cell death detection kit and expressed as the percentage of positively labeled neurons relative to total number of neurons. PCR was performed by adding cDNA, 5 pm dNTP, 1 MUL Taqase, and primers. PCR products were separated with electrophoresis, stained with ethidium bromide, and visualized under ultraviolet light. AIMS: To investigate the potential effects of DADLE in an ex vivo model of cerebral ischemia/reperfusion. RESULTS: DADLE attenuated lactic dehydrogenase release and neuronal apoptosis in a concentration-dependent manner. The protective effects of DADLE were attenuated by representative selective delta2, but not delta1 opioid antagonists. Treatment with PD98059, a selective inhibitor of ERK kinase (MEK), also blocked the protective effect of DADLE as well as ERK phosphorylation induced by DADLE. CONCLUSIONS: Endogenous opioid peptides could promote cell survival via delta2 opioid receptors, possibly through the downstream MEK-ERK pathway. PMID- 22943143 TI - Basic fibroblast growth factor protects C17.2 cells from radiation-induced injury through ERK1/2. AB - AIMS: To establish a radiation-induced neural injury model using C17.2 neural stem cells (NSCs) and to investigate whether basic fibroblast growth factor (bFGF) can protect the radiation-induced injury of C17.2 NSCs. Furthermore, we aim to identify the possible mechanisms involved in this model. METHODS: C17.2 NSCs received a single exposure (3, 6, and 9 Gy, respectively) at a dose rate of 300 cGy/min with a control group receiving 0 Gy. Different concentrations of bFGF were added for 24 h, 5 min postirradiation. The MTS assay and flow cytometry were used to detect cytotoxicity and apoptosis. Expression of FGFR1, ERK1/2, and p ERK1/2 proteins was detected with or without U0126 was pretreated prior to C17.2 NSCs receiving irradiation. RESULTS: C17.2 NSCs showed a dose-dependent cell death as the dose of radiation was increased. Additionally, the rate of apoptosis in the C17.2 NSCs reached 31.2 +/- 1.23% in the 6 Gy irradiation group, which was the most significant when compared to the other irradiation treated groups. bFGF showed protective effect on cell apoptosis in a dose-dependent manner. The mean percentage of apoptotic cells decreased to 7.83 +/- 1.75% when 100 ng/mL bFGF was given. Furthermore, U0126 could block the protective effect of bFGF by inhibiting the phosphorylation of ERK1/2. CONCLUSIONS: An in vitro cellular model of radiation-induced apoptosis of NSCs, in C17.2 NSCs, was developed successfully. Additionally, bFGF can protect neurons from radiation injury in vitro via the ERK1/2 signal transduction pathway. PMID- 22943144 TI - Clinical characteristics, management, and functional outcomes in Chinese patients within the first year after intracerebral hemorrhage: analysis from China National Stroke Registry. AB - AIMS: The aim of this study was to understand the association between clinical characteristics, medical management, and functional outcomes in Chinese patients with nontraumatic intracerebral hemorrhage (ICH). METHODS: The China National Stroke Registry (CNSR) was a prospective cohort study that included 132 Chinese hospitals. Logistic regression was used to determine the risk factors associated with poor outcomes at 3, 6, and 12 months, post-ICH onset. RESULTS: Three thousand two hundred fifty five ICH patients with follow-up information up to 1 year post-ICH were included in this study. 49.1%, 47.1%, and 46.0% of ICH patients had poor outcomes at 3, 6, and 12 months, respectively. Age, admission systolic blood pressure, admission Glasgow Coma Score, hematoma volume, withdrawal of support, and complication of gastrointestinal hemorrhage were associated with poor outcomes at 3 and 12 months. Stroke unit care was associated with good outcome at 3 months. Intensive care unit (ICU)/Neurology ICU care was associated with poor outcome at 3 months. CONCLUSION: This is the first report of long-term functional outcomes in ICH patients from mainland China. Our study elucidates the risk factors that may influence functional outcomes post-ICH and therefore facilitate the development of management strategies to improve ICH care in China. PMID- 22943145 TI - Acupuncture stimulation on GB34 activates neural responses associated with Parkinson's disease. AB - BACKGROUND: Parkinson's disease (PD) is a degenerative brain disorder that is caused by neural defects in the substantia nigra. Numerous studies have reported that acupuncture treatment on GB34 (Yanglingquan) leads to significant improvements in patients with PD and in PD animal models. Studies using functional magnetic resonance imaging (fMRI) have shown that patients with PD, compared to healthy participants, have lower neural responses in extensive brain regions including the putamen, thalamus, and the supplementary motor area. OBJECTIVE: This study investigated the reported association between acupuncture point GB34 and PD. METHODS: Using fMRI, neural responses of 12 patients with PD and 12 healthy participants were examined before and after acupuncture stimulation. RESULTS: Acupuncture stimulation increased neural responses in regions including the substantia nigra, caudate, thalamus, and putamen, which are impaired caused by PD. CONCLUSIONS: Areas associated with PD were activated by the acupuncture stimulation on GB34. This shows that acupuncture treatment on GB34 may be effective in improving the symptoms of PD. Although more randomized controlled trials on the topic will be needed, this study shows that acupuncture may be helpful in the treatment of symptoms involving PD. PMID- 22943146 TI - The outcomes of stroke induced by middle cerebral artery occlusion in different strains of mice. PMID- 22943147 TI - A modified model of middle cerebral artery electrocoagulation in mice. PMID- 22943148 TI - Antiepileptic potential of ursolic acid stearoyl glucoside by GABA receptor stimulation. PMID- 22943149 TI - Outcome prediction in clinical researches: common mistakes. PMID- 22943150 TI - Identification of goat cashmere and sheep wool by PCR-RFLP analysis of mitochondrial 12S rRNA gene. AB - The efficacy of polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis of mitochondrial 12S rRNA gene in identification of goat cashmere and sheep wool samples was evaluated. The specific fragments of the mitochondrial 12S rRNA gene, which were about 440 bp, were obtained using the PCR. Restriction enzyme digestion of the PCR products with endonucleases BspT I and Hinf I revealed species-specific RFLP patterns. Application of this technique on mixed samples could identify goat cashmere and sheep wool from each other within the proportion of 8:1. The technique, however, could detect only one species when the proportion of mixture was more than 9:1. The PCR-RFLP technique was demonstrated to possess potential value in precise identification of goat cashmere and sheep wool. PMID- 22943151 TI - Molecular mechanisms of tolerance to cyanobacterial protease inhibitors revealed by clonal differences in Daphnia magna. AB - Protease inhibitors of primary producers are a major food quality constraint for herbivores. In nutrient-rich freshwater ecosystems, the interaction between primary producers and herbivores is mainly represented by Daphnia and cyanobacteria. Protease inhibitors have been found in many cyanobacterial blooms. These inhibitors have been shown (both in vitro and in situ) to inhibit the most important group of digestive proteases in the daphnid's gut, that is, trypsins and chymotrypsins. In this study, we fed four different Daphnia magna genotypes with the trypsin-inhibitor-containing cyanobacterial strain Microcystis aeruginosa PCC 7806 Mut. Upon exposure to dietary trypsin inhibitors, all D. magna genotypes showed increased gene expression of digestive trypsins and chymotrypsins. Exposure to dietary trypsin inhibitors resulted in increased activity of chymotrypsins and reduced activity of trypsin. Strong intraspecific differences in tolerance of the four D. magna genotypes to the dietary trypsin inhibitors were found. The degree of tolerance depended on the D. magna genotype. The genotypes' tolerance was positively correlated with the residual trypsin activity and the different IC(50) values of the trypsins. On the genetic level, the different trypsin loci varied between the D. magna genotypes. The two tolerant Daphnia genotypes that both originate from the same lake, which frequently produces cyanobacterial blooms, clustered in a neighbour-joining phylogenetic tree based on the three trypsin loci. This suggests that the genetic variability of trypsin loci was an important cause for the observed intraspecific variability in tolerance to cyanobacterial trypsin inhibitors. Based on these findings, it is reasonable to assume that such genetic variability can also be found in natural populations and thus constitutes the basis for local adaptation of natural populations to dietary protease inhibitors. PMID- 22943152 TI - Short-term incubation of equine laminar veins with cortisol and insulin alters contractility in vitro: possible implications for the pathogenesis of equine laminitis. AB - This study investigated the effects of cortisol and insulin, hormones that affect both glycaemic status and vascular function, on the in vitro contractility of isolated healthy equine small laminar veins. Small veins (150-500 MUm) draining the digital laminae from healthy horses or ponies were investigated by wire myography. Concentration response curves were constructed for noradrenaline (NA), phenylephrine (PE), endothelin-1 (ET-1) and 5-hydroxytryptamine (5-HT) in the presence of either cortisol (10(-6 ) m) or insulin (1000 MUIU/mL). Cortisol significantly increased the maximum contractility of laminar veins to the vasoconstrictors NA and 5-HT but decreased the maximal contraction to ET-1. Insulin decreased the contractility of vessels to PE and ET-1. It is possible that short-term cortisol excess could enhance venoconstrictor responses to 5-HT and NA in laminar veins in vivo, thereby predisposing to laminitis. Additionally, a reduction in the ability of insulin to counteract alpha-adrenoreceptor and ET-1 mediated contraction, likely to occur in subjects with insulin resistance, may further exacerbate venoconstriction in animals prone to laminitis. These mechanisms may also predispose horses with disorders such as equine Cushing's disease and equine metabolic syndrome to laminitis. PMID- 22943153 TI - Clinical, dermoscopic and histopathological features of spontaneous scalp or face and radiotherapy-induced angiosarcoma. PMID- 22943154 TI - Breath-actuated nebulizer for patients with exacerbation of COPD: efficiency and cost. PMID- 22943155 TI - Severe acute asthma: an attempt to identify the quiet before the storm. PMID- 22943156 TI - Asthma and tobacco: not to be shared with family and friends! PMID- 22943157 TI - Use of expiratory positive airway pressure delivered by a spring load resistor during exercise: a new tool to optimize exercise training in patients with COPD? PMID- 22943158 TI - ICU follow-up clinics: a new frontier in inter-professional collaborative practice. PMID- 22943159 TI - The role of transient epithelial ion transport reduction in rapidly reversible pulmonary edema. PMID- 22943160 TI - Hip fracture and urinary incontinence--use of indwelling catheter postsurgery. AB - BACKGROUND: Norway has a higher incidence of hip fractures than any other country. For older individuals, a hip fracture may cause dramatic changes in health status like incontinence and daily activities. Patients with hip fractures are at high risk of urinary incontinence (UI) after surgical repair. A urinary indwelling catheter (UIC) is inserted preoperatively, but should be removed within 24 hours. Our aims were to identify indicators that might predict clinical challenges related to urinary incontinence 1 year after hip fractures. METHODS: Inclusion criteria were patients with hip fracture age 65 years or older. They were admitted form their own home to two acute-care hospitals during 2004-2006. We used the Resident Assessment Instrument for Acute Care. RESULTS: A total of 331 patients were included. Thirty-five (11%) had UIC 72 hours after surgery. These patients had more frequently experienced delirium, urinary tract infection, cognitive impairment and discouragement than their counterparts. After 12 months, patients with previous UI had lower functioning levels than those with no previous UI. They had moved four times more frequently to a nursing home and had over twice the mortality. CONCLUSIONS: Patient with UI should be followed up with a multidisciplinary team after discharged from hospital. PMID- 22943161 TI - Safety profile of standard- vs. high-dose peginterferon alfa-2a plus standard dose ribavirin in HCV genotype 1/4 patients: pooled analysis from 5 randomized studies. AB - OBJECTIVE: This analysis examines the safety profile of standard- versus high dose peginterferon alfa-2a. METHODS: Data were pooled from five trials including HCV genotype 1- or 4-infected naive and treatment-experienced patients (n = 2,940). Patients were randomized to receive peginterferon alfa-2a at 180 MUg/week (standard-dose; n = 1,672) or 360 MUg/week (high-dose; n = 1,268) plus ribavirin 1,000/1,200 mg/day for 12 weeks; after 12 weeks, all received standard dose. This safety analysis was restricted to the first 12 weeks. RESULTS: In standard and high-dose groups, similar frequencies of serious adverse events (SAEs, 3.2 and 4.2%, respectively) and treatment discontinuations for safety reasons (2.8 and 2.9%) were reported. More patients reported weight decrease as an adverse event (AE) in the 360 MUg/week group (7.7 vs. 3.3%). Significant (p < 0.05) independent predictors for discontinuation due to safety were older age, male gender, lower albumin and low neutrophil count, but not the starting dose of peginterferon alfa 2a. Although more laboratory abnormalities were reported in patients receiving high-dose peginterferon alfa-2a, this was not reflected in AEs or discontinuations, suggesting these are adequately managed by dose modification. CONCLUSIONS: High-dose peginterferon alfa-2a for 12 weeks does not significantly increase the incidence of SAEs or discontinuations for safety reasons, beyond that of a standard dose regimen. PMID- 22943162 TI - Expression of efflux pump gene lde in ciprofloxacin-resistant foodborne isolates of Listeria monocytogenes. AB - The expression of efflux pump gene lde in ciprofloxacin resistant (Cip(R) ) and susceptible strains of Listeria monocytogenes collected from retail food samples was investigated. For two Cip(R) strains, the MICs of ciprofloxacin decreased four- to eightfold in the presence of reserpine; however, no significant alterations were observed with naturally sensitive isolates. Overexpression of the lde gene induced by ciprofloxacin was observed in two resistant isolates. The present findings indicate that expression of lde and the MICs of ciprofloxacin are well correlated with the presence and absence of reserpine, suggesting that Lde might be involved in ciprofloxacin resistance of L. monocytogenes. PMID- 22943164 TI - Early loss to follow-up of recently diagnosed HIV-infected adults from routine pre-ART care in a rural district hospital in Kenya: a cohort study. AB - OBJECTIVE: To determine the rate and predictors of early loss to follow-up (LTFU) for recently diagnosed HIV-infected, antiretroviral therapy (ART)-ineligible adults in rural Kenya. METHODS: Prospective cohort study. Clients registering for HIV care between July 2008 and August 2009 were followed up for 6 months. Baseline data were used to assess predictors of pre-ART LTFU (not returning for care within 2 months of a scheduled appointment), LTFU before the second visit and LTFU after the second visit. Logistic regression was used to determine factors associated with LTFU before the second visit, while Cox regression was used to assess predictors of time to LTFU and LTFU after the second visit. RESULTS: Of 530 eligible clients, 178 (33.6%) were LTFU from pre-ART care (11.1/100 person-months). Of these, 96 (53.9%) were LTFU before the second visit. Distance (>5 km vs. <1 km: adjusted hazard ratio 2.6 [1.9-3.7], P < 0.01) and marital status (married vs. single: 0.5 [0.3-0.6], P < 0.01) independently predicted pre-ART LTFU. Distance and marital status were independently associated with LTFU before the second visit, while distance, education status and seasonality showed weak evidence of predicting LTFU after the second visit. HIV disease severity did not predict pre-ART LTFU. CONCLUSIONS: A third of recently diagnosed HIV-infected, ART-ineligible clients were LTFU within 6 months of registration. Predictors of LTFU among ART-ineligible clients are different from those among clients on ART. These findings warrant consideration of an enhanced pre-ART care package aimed at improving retention and timely ART initiation. PMID- 22943165 TI - Surgical pulmonary embolectomy: mid-term outcomes. AB - BACKGROUND: Despite the widespread use of venous thromboembolism (VTE) prophylaxis in hospitalized patients, pulmonary embolism continues to occur. Massive pulmonary embolism is associated with a high mortality. Surgical embolectomy has traditionally been reserved for cases with haemodynamic collapse or where thrombolysis is contraindicated or has failed. METHODS: Data on 10 patients who underwent surgical embolectomy (40% male, mean age 49 years (range 25-72)) from January 2003 to February 2010 were prospectively collected and retrospectively analysed. RESULTS: Diagnosis was made using computed tomography pulmonary angiography in eight patients and echocardiography in two. Syncope was the most common presenting symptom (7 out of 10, 70%) and relative immobilization was the most common risk factor (7 out of 10, 70%). Four patients (40%) suffered preoperative cardiac arrest, with a further two on induction of anaesthesia. Thirty-day mortality was 4 out of 10 (40%), with one late death. Mean follow-up of five survivors was 39 months and included clinic review or telephone interview, SF-36 questionnaire for quality of life, transthoracic echocardiography for right ventricular (RV) function and respiratory function testing. All survivors received an inferior vena cava filter and 6 months of anticoagulation with no cases of recurrent thromboembolism. RV systolic dysfunction was severe in all cases prior to surgery, but improved to near normal at follow-up. CONCLUSIONS: Survivors had good quality of life, were functionally NYHA class I-II with normal respiratory function. PMID- 22943166 TI - Epigenetics of psychoactive drugs. AB - OBJECTIVES: Epigenetics refers to the heritable, but reversible regulation of various biological functions. Changes in DNA methylation and chromatin structure derived from histone modifications are involved in the brain development, pathogenesis and pharmacotherapy of brain disorders. KEY FINDINGS: Evidence suggests that epigenetic modulations play key roles in psychiatric diseases such as schizophrenia and bipolar disorder. The analysis of epigenetic aberrations in the mechanisms of psychoactive drugs helps to determine dysfunctional genes and pathways in the brain, to predict side effects of drugs on human genome and identify new pharmaceutical targets for treatment of psychiatric diseases. SUMMARY: Although numerous studies have concentrated on epigenetics of psychosis, the epigenetic studies of antipsychotics are limited. Here we present epigenetic mechanisms of various psychoactive drugs and review the current literature on psychiatric epigenomics. Furthermore, we discuss various epigenetic modulations in the pharmacology and toxicology of typical and atypical antipsychotics, methionine, lithium and valproic acid. PMID- 22943167 TI - Insights into the effects of diclofenac and other non-steroidal anti-inflammatory agents on ion channels. AB - OBJECTIVES: Diclofenac and other non-steroidal anti-inflammatory drugs (NSAIDs) are widely used in the treatment of inflammation and pain. Most effects of NSAIDs are attributed to the inhibition of cyclooxygenases (COX). However, many NSAIDs may have other effects not related to COX, including the modulation of various ion channels. The clinical implications of the effects on channels are not fully understood. This review outlines the effects of NSAIDs, with special attention to diclofenac, on ion channels and highlights the possible underlying mechanisms. KEY FINDINGS: NSAIDs have effects on channels such as inhibition, activation or changes in expression patterns. The channels affected include voltage-gated Na(+) , Ca(2+) , or K(+) channels, ligand-gated K(+) channels, transient receptor potential and other cation channels as well as chloride channels in several types of cells. The mechanisms of drug actions not related to COX inhibition may involve drug-channel interactions, interference with the generation of second messengers, changes in channel expression, or synergistic/antagonist interactions with other channel modulators. SUMMARY: The effects on ion channels may account for novel therapeutic actions of NSAIDs or for adverse effects. Among the NSAIDs, diclofenac may serve as a template for developing new channel modulators and as a tool for investigating the actions of other drugs. PMID- 22943168 TI - Enhancement of gene expression and melanin production of human tyrosinase gene loaded in elastic cationic niosomes. AB - OBJECTIVES: Disturbance in the synthesis of tyrosinase might be one of the major causes of vitiligo. The enhancement of tyrosinase gene expression and melanin production by loading the plasmid in elastic cationic niosomes was investigated in tyrosinase gene knocked out human melanoma (M5) cells and in tyrosine producing mouse melanoma (B(16) F(10) ) cells. METHODS: Niosomes composed of Tween 61/cholesterol/dimethyl dioctadecyl ammonium bromide at 1:1:0.5 molar ratio were prepared by the freeze-dried empty liposomes method. The thin lipid film was redissolved in distilled water or 25% ethanol to obtain the non-elastic or elastic cationic niosomes, respectively. KEY FINDINGS: The maximum loading of the plasmid in non-elastic and elastic niosomes was 130 and 100 ug per 16 mg of the niosomal contents, respectively. The plasmid-loaded elastic cationic niosomes exhibited high specific tyrosinase activity of 1.66 and 1.50 fold in M5 cells and 6.81 and 4.37 fold in B(16) F(10) cells compared with the free plasmid and the plasmid-loaded non-elastic cationic niosomes, respectively. CONCLUSIONS: This study has demonstrated not only the enhancement of the expression of human tyrosinase gene by loading in elastic cationic niosomes, but also the potential application of this gene delivery system for the further development of vitiligo gene therapy. PMID- 22943169 TI - Colloidal characteristics and formulation of pure protein particulate vaccines. AB - OBJECTIVES: We recently reported that dense gas processing of the protein ovalbumin (OVA) resulted in the formation of particles that were insoluble in water and which retained their immunogenicity in vivo. In the present study, the colloidal properties of these pure protein particles were investigated to in part inform rational formulation approaches. METHODS: The colloidal properties of the particles, in terms of size, zeta potential and pH-dependent surface and solution properties, were examined. KEY FINDINGS: In phosphate-buffered saline (pH7.4), flocculation of the particles was observed, which was prevented when particles were suspended in acetate buffer at pH lower than 4. The resulting particle size was 300nm with low polydispersity and zeta potential of 22.9+/-3.1mV (mean+/-SEM, n=3) at pH3. Dense gas OVA particles were also prevented from flocculation using steric stabilisation with Pluronic F127. In this form the particles were stable in Krebs-Henseleit solution for 48h at room temperature. CONCLUSIONS: These findings indicate that insoluble pure protein particles produced by dense gas processing have desirable characteristics as particulate vaccines, including consistency of particle size under controlled conditions and high colloid stability. PMID- 22943170 TI - Long-term stability of quercetin nanocrystals prepared by different methods. AB - OBJECTIVES: This study aimed to examine the long-term physical stability of quercetin nanocrystals produced by three methods. METHODS: Quercetin nanocrystals were prepared by high pressure homogenization, bead milling and cavi precipitation. The nanocrystals produced by these methods were compared for particle size, saturation solubility and dissolution of the drug particles, and were subjected to stability testing. KEY FINDINGS: The X-ray diffraction study and microscopic pictures taken under polarized light indicated the crystalline nature of the nanocrystals produced by the three methods. As the crystalline state is relatively more stable than the amorphous state, a good physical stability was expected from the quercetin nanocrystals prepared. The high pressure homogenized and bead-milled quercetin nanocrystals showed excellent physical stability when stored under refrigeration (4+/-2 degrees C) and at room temperature (25+/-2 degrees C) for 180 days. The dissolution properties were not significantly affected on storage at room temperature. However, increase in the storage temperature to 40+/-2 degrees C led to physical instability. On the other hand, the cavi-precipitated quercetin nanocrystals exhibited a lower stability than the bead-milled and homogenized formulations and did not show the optimum zeta potential values as well. In the case of cavi-precipitated nanocrystals, recrystallization and agglomeration were responsible for the increasing particle size besides the Ostwald ripening phenomenon. The solvents used during cavi precipitation might have competed with the surfactant for hydration leading to a partial dehydration of the surfactant, which subsequently affected the stability of the quercetin nanocrystals. CONCLUSIONS: High-pressure homogenized and bead milled quercetin nanocrystals showed better physical stability than the cavi precipitated ones. Freeze drying immediately after nanocrystal production can help to prevent their agglomeration and thus improve physical stability. PMID- 22943171 TI - Preparation and physicochemical characterization of a novel paclitaxel-loaded amphiphilic aminocalixarene nanoparticle platform for anticancer chemotherapy. AB - OBJECTIVES: This paper describes the development and optimization of a nanoparticle delivery platform for the anticancer agent, paclitaxel, using a novel amphiphilic carrier, tetrahexyloxy-tetra-p-aminocalix[4]arene (A4C(6) ). METHODS: Nanoparticles were successfully prepared at pH4 by an emulsion evaporation method whereby an organic phase containing paclitaxel: A4C(6) (molar ratio 1:10) was dispersed by probe sonication into an aqueous phase containing 0.5% w/v polyvinyl alcohol as stabilizer. KEY FINDINGS: The drug-loaded nanoparticles had a mean size of 78.7+/-20.7nm, surface potential of 38.3+/ 7.67mV, and paclitaxel loading and encapsulation efficiencies of 69.1+/-5.3ug drug/mg carrier and 50.4+/-3.2%, respectively. Transmission electron micrographs showed discrete particles with no evidence of agglomeration. In-vitro dissolution into phosphate buffered saline supplemented with 4% bovine serum albumin showed 32.7+/-3.9%, 82.6+/-5.3% and 91.0+/-6.0% of the encapsulated paclitaxel load was released at 5, 72 and 120h, respectively. CONCLUSIONS: This is the first report on the use of amino-substituted amphiphilic calixarenes for the encapsulation of anticancer agents. The nanoparticles produced were significantly smaller than, but had comparable drug loads to the Abraxane nanoparticles, and have the potential to achieve targeted delivery of paclitaxel to tumour tissues. PMID- 22943172 TI - Investigation into the effect of varying l-leucine concentration on the product characteristics of spray-dried liposome powders. AB - OBJECTIVES: Spray-dried formulations offer an attractive delivery system for administration of drug encapsulated into liposomes to the lung, but can suffer from low encapsulation efficiency and poor aerodynamic properties. In this paper the effect of the concentration of the anti-adherent l-leucine was investigated in tandem with the protectants sucrose and trehalose. METHODS: Two manufacturing methods were compared in terms of their ability to offer small liposomal size, low polydispersity and high encapsulation of the drug indometacin. KEY FINDINGS: Unexpectedly sucrose offered the best protection to the liposomes during the spray drying process, although formulations containing trehalose formed products with the best powder characteristics for pulmonary delivery; high glass transition values, fine powder fraction and yield. It was also found that l leucine contributed positively to the characteristics of the powders, but that it should be used with care as above the optimum concentration of 0.5% (w/w) the size and polydispersity index increased significantly for both disaccharide formulations. CONCLUSIONS: The method of liposome preparation had no effect on the stability or encapsulation efficiency of spray-dried powders containing optimal protectant and anti-adherent. Using l-leucine at concentrations higher than the optimum level caused instability in the reconstituted liposomes. PMID- 22943173 TI - Biodegradable donepezil lipospheres for depot injection: optimization and in-vivo evaluation. AB - OBJECTIVES: The purpose of this study was to develop an injectable depot liposphere delivery system with high loading capacity for controlled delivery of donepezil to decrease dosing frequency and increase patient compliance. METHODS: A 3(2) full factorial design was employed to study the effect of lipid type and drug-to-lipid ratio on the yield, encapsulation efficiency, mean diameter and the time required for 50% drug release (t(50%) ). The pharmacokinetic behaviour of the lipospheres in rabbits was studied using tandem mass spectrometry. KEY FINDINGS: The yields of preparations were in the range of 66.22-90.90%, with high encapsulation efficiencies (89.68-97.55%) and mean particle size of 20.68-35.94 um. Both lipid type and drug-to-lipid ratio significantly affected t(50%) (P<0.0001), where the lipids can be arranged: glyceryl tripalmitate>compritol>cetyl alcohol, and the drug-to-lipid ratios can be arranged: 1:40>1:20>1:10. The flow time of lipospheres through 19-gauge syringe needle was less than 6s indicating good syringeability. The mean residence time of the subcutaneous and intramuscular lipospheres was significantly higher than the solution (almost 20 fold increase), with values of 11.04, 11.34 and 0.53 days, respectively (P<0.01). CONCLUSION: Subcutaneous and intramuscular delivery of donepezil glyceryl tripalmitate lipospheres achieves depot release, allowing less frequent dosing. PMID- 22943174 TI - Effect of viscous additives on the absorption and hepatic disposition of 5 fluorouracil (5-FU) after application to liver surface in rats. AB - Objectives The aim was to study the effect of viscous additives on the absorption and hepatic disposition of 5-fluorouracil (5-FU) after application to the liver surface in rats. Methods 5-FU solution with or without viscous additives was applied to the rat liver surface with a cylindrical diffusion cell. Then, blood and the remaining solution in the diffusion cell were collected at selected times, followed by excision of the liver. The excised liver was divided into three sites and assayed for 5-FU content. Key findings The absorption rate of 5-FU from the liver surface was decreased in the presence of carboxymethylcellulose sodium (CMC-Na) and polyvinyl alcohol (PVA) as compared with the control. The k(a) values of PVA 15% and CMC-Na 1% were reduced to about 80 and 67% of the control. The maximum plasma concentration of 5-FU was decreased by incorporation of viscous additives. The 5-FU concentration at the diffusion cell attachment site of the liver (site 1) plateaued at 180 min in the absence of viscous additives. On the other hand, the concentration of 5-FU at site 1 increased in a time-dependent manner until 360 min in the presence of viscous additives. Conclusion Viscous additives might be useful for retaining drugs at their application site and controlling the rate of absorption from the liver surface. PMID- 22943175 TI - In-vitro metabolism of glycyrrhetinic acid by human and rat liver microsomes and its interactions with six CYP substrates. AB - OBJECTIVES: Glycyrrhetinic acid is the main metabolite of glycyrrhizin and the main active component of Licorice root. This study was designed to investigate the in-vitro metabolism of glycyrrhetinic acid by liver microsomes and to examine possible metabolic interactions that glycyrrhetinic acid may have with other cytochrome P450 (CYP) substrates. METHODS: Glycyrrhetinic acid was incubated with rat liver microsomes (RLM) and human liver microsomes (HLM). Liquid chromatography tandem mass spectrometry was used for glycyrrhetinic acid or substrates identification and quantification. KEY FINDINGS: The K(m) and V(max) values for HLM are 33.41 um and 2.23 nmol/mg protein/min, respectively; for RLM the K(m) and V(max) were 24.24um and 6.86 nmol/mg protein/min, respectively. CYP3A4 is likely to be the major enzyme responsible for glycyrrhetinic acid metabolism in HLM while CYP2C9 and CYP2C19 are considerably less active. Other human CYP isoforms have minimal or no activity toward glycyrrhetinic acid. The interactions of glycyrrhetinic acid and six CYP substrates, such as phenacetin, diclofenac, (S)-mephenytoin, dextromethorphan, chlorzoxazone and midazolam were also investigated. The inhibitory action of glycyrrhetinic acid was observed in CYP2C9 for 4-hydroxylation of diclofenac, CYP2C19 for 4'-hydroxylation of (S) mephenytoin and CYP3A4 for 1'-hydroxylation of midazolam with half maximal inhibitory concentration (IC50) values of 4.3-fold, 3.8-fold and 9.6-fold higher than specific inhibitors in HLM, respectively. However, glycyrrhetinic acid showed relatively little inhibitory effect (IC50>400 um) on phenacetin O deethylation, dextromethorphan O-demethylation and chlorzoxazone 6-hydroxylation. CONCLUSIONS: The study indicated that CYP3A4 is likely to be the major enzyme responsible for glycyrrhetinic acid metabolism in HLM while CYP2C9 and CYP2C19 are considerably less active. The results suggest that glycyrrhetinic acid has the potential to interact with a wide range of xenobiotics or endogenous chemicals that are CYP2C9, CYP2C19 and CYP3A4 substrates. PMID- 22943176 TI - Reduced clearance of epsilon-acetamidocaproic acid in rats with acute renal failure induced by uranyl nitrate. AB - OBJECTIVES: Anti-ulcer drugs are frequently used in patients with acute renal failure (ARF). Zinc acexamate is ionized to zinc and epsilon-acetamidocaproic acid and free EACA exerts a potent therapeutic effect in treating gastric or duodenal ulcers with few side effects. Thus, pharmacokinetic changes in rats with acute renal failure induced by uranyl nitrate (U-ARF rats) were investigated in this study. METHODS: The in-vivo pharmacokinetics and in-vitro hepatic/intestinal metabolism of EACA were assessed using control and U-ARF rats. The mechanism of urinary excretion of EACA was further investigated in rats. KEY FINDINGS: After intravenous and oral administration of zinc acexamate to U-ARF rats, there were significant increases in the values of the area under the curve (AUC) and decreases in the values for time-averaged renal and nonrenal clearances (Cl(r) and Cl(nr) , respectively) compared with control rats. Slower Cl(nr) was partly due to a decrease in the metabolism in liver and/or intestine. Slower Cl(r) could have been due to urine flow rate-dependent timed-interval renal clearance, decrease in organic anion transporter-mediated renal excretion (drug interaction with probenecid and decrease in the relative contribution of net secretion compared with glomerular filtration in U-ARF rats) and/or impaired kidney function. CONCLUSIONS: The pharmacokinetics were significantly altered in U-ARF rats due to the changes in both the hepatic/intestinal metabolism and urinary excretion. PMID- 22943177 TI - Reactivity of nonsteroidal anti-inflammatory drugs with peroxidase: a classification of nonsteroidal anti-inflammatory drugs. AB - OBJECTIVES: To improve understanding of the essential effect of nonsteroidal anti inflammatory drugs (NSAIDs) on prostaglandin H synthase (PGHS), the reactivity of NSAIDs with peroxidases and the tyrosyl radical derived from myoglobin was examined. METHODS: Horseradish peroxidase and myoglobin were used as models of peroxidase and cyclooxygenase of PGHS, respectively. KEY FINDINGS: From the results, a new classification of NSAIDs has been proposed. Class 1 includes the majority of NSAIDs, which reacted with horseradish peroxidase compound I, thus causing a spectral change by PGHS peroxidase and also including diminished electron spin resonance signals of the tyrosyl radical of myoglobin. They reduced compound I of horseradish peroxidase and scavenged the tyrosyl radical. The branched-chain mechanism by which the porphyrin radical is transferred to the tyrosine residue of the protein might be blocked by these NSAIDs. Class 2 includes salicylic acid derivatives that reacted only with the porphyrin radical and not with horseradish peroxidase compound II (oxoferryl species). Class 3 includes aspirin, nimesulide, tolmetin, and arylpropionic acid derivatives, including ibuprofen and the coxibs of celecoxib and rofecoxib, which are not substrates for horseradish peroxidase or PGHS peroxidase. CONCLUSIONS: Understanding the essential mode of action of NSAIDs is particularly important for designing an effective therapeutic strategy against inflammatory diseases. PMID- 22943178 TI - Hesperidin-mediated expression of Nrf2 and upregulation of antioxidant status in senescent rat heart. AB - OBJECTIVES: Oxidative stress is recognized as a key element responsible for the development of age-related pathologies. A declining endogenous defence system during senescence dictates the need for supplementation with exogenous antioxidants through diet. Hesperidin is a naturally occurring flavonone present in citrus fruits and has been shown to have many biological properties, including antioxidant activity. We investigated whether hesperidin supplementation could be valuable in protecting cardiac tissue of aged rats against age-related increase in oxidative stress, as well as the mechanism by which it can boost the antioxidant status of the cell. METHODS: The activity of antioxidant enzymes, mRNA expression of Nrf2, protein levels of superoxide dismutase and catalase were measured using standard protocols. KEY FINDINGS: Hesperidin treatment effectively protected aged rat heart by increasing the activity of enzymic antioxidants. Hesperidin upregulated the protein levels of nuclear factor erythroid 2-related factor 2, which is responsible for maintaining the antioxidant status of the cell. CONCLUSIONS: Hesperidin could be useful in protecting cardiomyocytes against age-related increase in oxidative stress mediated by Nrf2 upregulation. PMID- 22943179 TI - BND-12, a novel nonhaematotoxic naphthalimide derivative, inhibits tumour growth and metastasis of hepatocellular carcinoma. AB - OBJECTIVES: Naphthalimides have shown potent antitumour activity against a variety of murine and human cancer cells. However, most of them have been abandoned because of a poor therapeutic index and haematotoxicity, such as amonafide. To overcome these disadvantages, many novel naphthalimide derivatives have been designed and synthesized as antitumour agents. METHODS: The cytotoxicity of 6,6-(propane-1,3-diylbis(azanediyl)bis(2-(2-(dimethylamino)ethyl) 1H-benzo[de]isoquinoline-1-3(2H)-dione) (BND-12) was evaluated using multiparameter cytotoxicity 2 kit by High Content Screening (HCS). The antiproliferative ability of BND-12 was evaluated using MTT assay. BND-12 mediated cell apoptosis was evaluated using HCS. Antitumor effects and systemic toxicity of BND-12 were evaluated in vivo using Kunming male mice. KEY FINDINGS: After screening, we found BND-12, a novel naphthalimide derivative, exerted favourable antitumour activity in vitro and in vivo. Our data demonstrated that the cytotoxicity of BND-12 was due to cell apoptosis via the mitochondrial pathway. Interestingly, we demonstrated that BND-12 exerted more potent antitumour activity in subcutaneous xenograft tumour growth, survival time and lung metastasis than amonafide in vivo. Encouragingly, preliminary toxicological evaluation demonstrated that BND-12 had no obvious systemic toxicity at the therapeutic dose, especially haematotoxicity. CONCLUSIONS: BND-12 exerted potent effects against HCC in vivo and in vitro, importantly, it had no obvious systemic toxicity at the therapeutic dose. PMID- 22943180 TI - Inhibitory effects of Zataria multiflora essential oil and its main components on nitric oxide and hydrogen peroxide production in lipopolysaccharide-stimulated macrophages. AB - OBJECTIVES: Zataria multiflora is an aromatic plant that is used in flavouring and preserving foods and also used as an antispasmodic, anaesthetic and antinociceptive agent. In this study, the effects of Z. multiflora essential oil on nitric oxide (NO) and hydrogen peroxide (H(2) O(2) ) production in lipopolysaccharide (LPS)-stimulated macrophages was investigated. METHODS: Z. multiflora essential oil was extracted by water-distillation, analysed by GC-MS and then the effect of the essential oil on NO and H(2) O(2) production was investigated. KEY FINDINGS: Carvacrol (52%), thymol (16%) and p-cymene (10%) were the main components of the oil. The IC50 (concentration providing 50% inhibition) for reactive oxygen scavenging was estimated to be 5.7, 3 and 4.2 ug/ml for the essential oil, thymol and carvacrol, respectively, while the corresponding IC50 values for reactive nitrogen scavenging were estimated to be 8.6, 4.7 and 6.6 ug/ml. Z. multiflora essential oil, thymol, and carvacrol significantly reduced NO and H(2) O(2) production as well as NO synthase and NADH oxidase activity in LPS-stimulated murine macrophages while p-cymene did not show any antioxidant activity. CONCLUSIONS: Z. multiflora essential oil has the potential to be used in the therapy of oxidative damage. PMID- 22943181 TI - Antipsoriatic activity of extracts and fractions obtained from Memecylon malabaricum leaves. AB - OBJECTIVES: This study involves the evaluation of Memecylon malabaricum Cogn. (Melastomataceae) leaves for antipsoriatic activity. METHODS: Aqueous extract, hydroalcoholic extract and their fractions of M. malabaricum leaves were evaluated for in-vivo antipsoriatic activity by mouse tail test and for in-vitro antipsoriatic activity using HaCaT cells, lipoxygenase inhibition and thymidine phosphorylase inhibition assays. Extracts and fractions were evaluated for total phenol and flavonoid contents. HPTLC was used for screening and fingerprint analysis of the extracts and active fraction. KEY FINDINGS: M. malabaricum hydroalcoholic extract (MMHA) and water fraction of MMHA (MMHAW) produced significant (P<0.05) percent orthokeratosis in the mouse tail test. All samples except MMHA showed a significant (P < 0.05) reduction in epidermal thickness in the mouse tail test when compared with control. Maximum activity against HaCaT cells was shown by chloroform fraction of MMHA (MMHAC). The M. malabaricum decoction (MMD) and water fraction of MMD (MMDW) showed equally good inhibition of lipoxygenase. In thymidine phosphorylase inhibition assay only MMD showed activity. CONCLUSIONS: The findings of this investigation reveal that the leaves of M. malabaricum have good antipsoriatic potential, which provides scope for further detailed research in to this plant for psoriasis. PMID- 22943182 TI - Berberine suppresses amyloid-beta-induced inflammatory response in microglia by inhibiting nuclear factor-kappaB and mitogen-activated protein kinase signalling pathways. AB - OBJECTIVES: The neuroinflammation induced by amyloid-beta peptide (Abeta) is one of the key events in Alzheimer's disease (AD) progress in which microglia are the main cells involved. Berberine, one of the major constituents of Chinese herb Rhizoma coptidis, is known for its anti-inflammatory, anti-oxidative and anti microbial activity. In this study, we examined the effects and possible underlying mechanisms of berberine in Abeta-induced neuroinflammation using murine primary microglia cells and cultured BV2 microglia cells. METHODS: The effects of berberine on Abeta-stimulated inflammatory factor expression and secretion were examined using RT-PCR and ELISA analysis. The signal pathways involved in berberine's effects were also investigated using Western blot and immunofluorescence analysis. RESULTS: In primary microglial and BV2 cells, berberine treatment significantly inhibited Abeta-stimulated production of interleukin-6 and monocyte chemotactic protein-1. Berberine treatment down regulated the expression of cyclo-oxygenase-2 and induced nitric oxide synthase in these cells. Moreover, berberine strongly inhibited the nuclear factor-kappaB (NF-kappaB) activation, presumably through blocking the phosphoinositide 3 kinase/protein kinase B and mitogen-activated protein kinase signalling pathways. CONCLUSIONS: Our data indicated berberine is a potent suppressor of neuroflammation, presumably through inhibition of NF-kappaB activation, and suggested berberine has therapeutic potential for the treatment of neuroinflammation that is involved in neurological diseases such as AD. PMID- 22943183 TI - Biodiversity effects on ecosystem functioning change along environmental stress gradients. AB - Positive relationship between biodiversity and ecosystem functioning has been observed in many studies, but how this relationship is affected by environmental stress is largely unknown. To explore this influence, we measured the biomass of microalgae grown in microcosms along two stress gradients, heat and salinity, and compared our results with 13 published case studies that measured biodiversity ecosystem functioning relationships under varying environmental conditions. We found that positive effects of biodiversity on ecosystem functioning decreased with increasing stress intensity in absolute terms. However, in relative terms, increasing stress had a stronger negative effect on low-diversity communities. This shows that more diverse biotic communities are functionally less susceptible to environmental stress, emphasises the need to maintain high levels of biodiversity as an insurance against impacts of changing environmental conditions and sets the stage for exploring the mechanisms underlying biodiversity effects in stressed ecosystems. PMID- 22943184 TI - Dynamic measurement of pennation angle of gastrocnemius muscles during contractions based on ultrasound imaging. AB - BACKGROUND: Muscle fascicle pennation angle (PA) is an important parameter related to musculoskeletal functions, and ultrasound imaging has been widely used for measuring PA, but manually and frame by frame in most cases. We have earlier reported an automatic method to estimate aponeurosis orientation based on Gabor transform and Revoting Hough Transform (RVHT). METHODS: In this paper, we proposed a method to estimate the overall orientation of muscle fascicles in a region of interest, in order to complete computing the orientation of the other side of the pennation angle, but the side found by RVHT. The measurements for orientations of both fascicles and aponeurosis were conducted in each frame of ultrasound images, and then the dynamic change of pennation angle during muscle contraction was obtained automatically. The method for fascicle orientation estimation was evaluated using synthetic images with different noise levels and later on 500 ultrasound images of human gastrocnemius muscles during isometric plantarflexion. RESULTS: The muscle fascicle orientations were also estimated manually by two operators. From the results it's found that the proposed automatic method demonstrated a comparable performance to the manual method. CONCLUSIONS: With the proposed methods, ultrasound measurement for muscle pennation angles can be more widely used for functional assessment of muscles. PMID- 22943185 TI - Methoprene and temperature effects on caste differentiation and protein composition in the Formosan Subterranean termite, Coptotermes formosanus. AB - The utilization of multiple castes is a shared feature of social insects. In termites, multiple extrinsic factors have been shown to impact caste differentiation; for example, increased temperature has been shown to increase soldier production. Also, application of exogenous methoprene has also been demonstrated to increase soldier production. The objective of this investigation was to examine and correlate the effects of temperature variation and methoprene treatments on termite caste differentiation, and identify the resulting changes in protein levels. Our results indicate that worker-to-soldier differentiation is modulated by temperature, where a greater number of soldiers developed at a higher rate at higher temperatures compared to lower temperatures. We analyzed total protein by sodium dodecyl sulfate Polyacrylamide gel electrophoresis and N terminal sequencing and found several changes. Specifically, four proteins affected by temperature change were identified: Hexamerin-1, Hexamerin-2, Endo beta 1,4 glucanase, and myosin. These proteins were further examined for their response to temperature, assay length (time), and exposure to the juvenile hormone analog methoprene. Hexamerin-1 protein showed a temperature-and assay length-dependent effect, while Hexamerin-2, Endo-beta 1, 4 glucanase, and myosin protein levels were all affected by temperature, assay length, and exposure to methoprene. Our analysis allows the correlation of temperature, assay length, and presence of methoprene with specific changes in protein levels that occur during caste differentiation. These results can be directly applied to better understand the complex developmental factors that control termite differentiation and guide the use of juvenile hormone analogs to maximize efficiency of termite eradication in the field. PMID- 22943186 TI - Clinical characteristics predicting internal neurofibromas in 357 children with neurofibromatosis-1: results from a cross-selectional study. AB - OBJECTIVE: To identify clinical characteristics associated with internal neurofibromas in children with NF1, as a means of ensuring the early identification of patients at high risk for malignant peripheral nerve-sheath tumors developed from preexisting internal neurofibromas. PATIENTS AND METHODS: We used data from two NF1 populations, in France and North America, respectively. The French database comprised 1083 patients meeting NIH diagnostic criteria for NF1 and the Neurofibromatosis Institute Database of North America comprised 703 patients. Patients younger than 17 years of age were eligible for our study if they had been evaluated for internal neurofibromas using computed tomography and/or magnetic resonance imaging. Clinical characteristics associated with internal neurofibromas by univariate analysis (P <= 0.15) were entered into a multiple logistic regression model after checking for potential interactions and confounding. Multiple imputation was used for missing values. RESULTS: Among the 746 children in the two databases, 357 (48%) met our inclusion criteria. Their mean age was 7.7 +/- 5.0 years and there were 192 (53.8%) males. Internal neurofibromas were present in 35 (9.8%) patients. Internal neurofibromas developed earlier in females than in males and their prevalence increased during adolescence. Factors independently associated with internal neurofibromas were age (OR = 1.16 [1.07-1.27]), xanthogranulomas (OR = 5.85 [2.18-15.89]) and presence of both subcutaneous and plexiform neurofibromas (OR = 6.80 [1.52 30.44]). CONCLUSIONS: Several easily recognizable clinical characteristics indicate a high risk of internal neurofibromas in children with NF1 and, therefore, a need for very close monitoring. PMID- 22943187 TI - A comparative study of small RNAs in Toxoplasma gondii of distinct genotypes. AB - BACKGROUND: Toxoplasma gondii is an intracellular parasite with a significant impact on human health. Inside the mammalian and avian hosts, the parasite can undergo rapid development or remain inactive in the cysts. The mechanism that regulates parasite proliferation has not been fully understood. Small noncoding RNAs (sncRNA) such as microRNAs (miRNAs) are endogenous regulatory factors that can modulate cell differentiation and development. It is anticipated that hundreds of miRNAs regulate the expression of thousands of genes in a single organism. SncRNAs have been identified in T. gondii, however the profiles of sncRNAs expression and their potential regulatory function in parasites of distinct genotypes has largely been unknown. METHODS: The transcription profiles of miRNAs in the two genetically distinct strains, RH and ME49, of T. gondii were investigated and compared by a high-through-put RNA sequencing technique and systematic bioinformatics analysis. The expression of some of the miRNAs was confirmed by Northern blot analysis. RESULTS: 1,083,320 unique sequences were obtained. Of which, 17 conserved miRNAs related to 2 metazoan miRNA families and 339 novel miRNAs were identified. A total of 175 miRNAs showed strain-specific expression, of which 155 miRNAs were up-regulated in RH strain and 20 miRNAs were up-regulated in ME49 strain. Strain-specific expression of miRNAs in T. gondii could be due to activation of specific genes at different genomic loci or due to arm-switching of the same pre-miRNA duplex. CONCLUSIONS: Evidence for the differential expression of miRNAs in the two genetically distinct strains of T. gondii has been identified and defined. MiRNAs of T. gondii are more species specific as compared to other organisms, which can be developed as diagnostic biomarkers for toxoplasmosis. The data also provide a framework for future studies on RNAi-dependent regulatory mechanisms in the zoonotic parasite. PMID- 22943188 TI - Emergence of serogroup C meningococcal disease associated with a high mortality rate in Hefei, China. AB - BACKGROUND: Neisseria meningitidis serogroup C has emerged as a cause of epidemic disease in Hefei. The establishment of serogroup C as the predominant cause of endemic disease has not been described. METHODS: We conducted national laboratory based surveillance for invasive meningococcal disease during 2000-2010. Isolates were characterized by pulsed-field gel electrophoresis and multilocus sequence typing. RESULTS: A total of 845 cases of invasive meningococcal disease were reported. The incidence increased from 1.25 cases per 100,000 population in 2000 to 3.14 cases per 100,000 in 2003 (p < 0.001), and peaked at 8.43 cases per 100,000 in 2005. The increase was mainly the result of an increase in the incidence of serogroup C disease. Serogroup C disease increased from 2/23 (9%) meningococcal cases and 0.11 cases per 100,000 in 2000 to 33/58 (57%) cases and 1.76 cases per 100,000 in 2003 (p < 0.01). Patients infected with serogroup C had serious complications more frequently than those infected with other serogroups. Specifically, 161/493 (32.7%) cases infected with serogroup C had at least one complication. The case-fatality rate of serogroup C meningitis was 11.4%, significantly higher than for serogroup A meningitis (5.3%, p = 0.021). Among patients with meningococcal disease, factors associated with death in univariate analysis were age of 15-24 years, infection with serogroup C, and meningococcemia. CONCLUSIONS: The incidence of meningococcal disease has substantially increased and serogroup C has become endemic in Hefei. The serogroup C strain has caused more severe disease than the previously predominant serogroup A strain. PMID- 22943189 TI - Psychiatric comorbidity as predictor of costs in back pain patients undergoing disc surgery: a longitudinal observational study. AB - BACKGROUND: Psychiatric comorbidity is common in back pain patients undergoing disc surgery and increases economic costs in many areas of health. The objective of this study was to analyse psychiatric comorbidity as predictor of direct and indirect costs in back pain patients undergoing disc surgery in a longitudinal study design. METHODS: A sample of 531 back pain patients was interviewed after an initial disc surgery (T0), 3 months (T1) and 15 months (T2) using the Composite International Diagnostic Interview to assess psychiatric comorbidity and a modified version of the Client Sociodemographic and Service Receipt Inventory to assess resource utilization and lost productivity for a 3-month period prior interview. Health care utilization was monetarily valued by unit costs and productivity by labour costs. Costs were analysed using random coefficient models and bootstrap techniques. RESULTS: Psychiatric comorbidity was associated with significantly (p < 0.05) increased direct (+664 Euro) and indirect costs (+808 Euro) at T0. The direct cost difference predominantly resulted from medical health care utilization and was nearly unchanged at T2. Further important cost predictors were clinical variables like the presence of chronic medical disease, the number of previous disc surgeries, and time and gender. CONCLUSION: Psychiatric comorbidity presents an important predictor of direct and indirect costs in back pain patients undergoing disc surgery, even if patients do not utilize mental health care. This effect seems to be stable over time. More attention should be given to psychiatric comorbidity and cost effective treatments should be applied to treat psychiatric comorbidity in back pain patients undergoing disc surgery to reduce health care utilization and costs associated with psychiatric comorbidity. PMID- 22943190 TI - Risk factors and outcomes of new-onset diabetes after transplant: single-centre experience. AB - OBJECTIVES: We sought to study the prevalence, risk factors, and long-term prognosis of posttransplant diabetes mellitus. MATERIALS AND METHODS: We studied all patients with end-stage renal disease without diabetic nephropathy who received a kidney transplant and were followed-up at our center since 1983 (n=218; age, 44.3 +/- 13.1 y). Patients with new-onset diabetes after transplant were compared to kidney transplant recipients without risk factors for diabetes mellitus. Patients with new-onset diabetes after transplant were divided into subgroups according to time of onset (early; < 90 d vs late, >= 90 d). RESULTS: In total, 73/218 patients (33%) developed new-onset diabetes after transplant. Patients with new-onset diabetes after transplant were significantly older (51.2 +/- 11.4 vs 40.7 +/- 12.5 y; P < .001) and had a tendency to have a higher body mass index (29.6 +/- 8.7 vs 21.6 +/- 7.8 kg/m2; P =.05) than those that did not have new-onset diabetes after transplant. In multivariate analysis, age (P < .001), hepatitis C virus infection (P < .05), family history of diabetes mellitus (P < .03), and tacrolimus use (P < .001) were independent risk factors. Five- and 10-year death censored patient survival rates were worse in those that had new onset diabetes after transplant compared with controls (log rank, 0.04), whereas there was no difference in outcomes between the early and late subgroups. CONCLUSIONS: The prevalence of new-onset diabetes after transplant was 33%. Age, body weight at time of transplant, tacrolimus use, family history of diabetes mellitus, and hepatitis C virus infection are independent risk factors for new onset diabetes after transplant. New-onset diabetes after transplant has a negative effect on patient survival, irrespective of the time of onset and duration of diabetes. PMID- 22943192 TI - Effects of lisinopril on NMDA receptor subunits 2A and 2B levels in the hippocampus of rats with L-NAME-induced hypertension. AB - Hypertension is major risk factor leading to cerebrovascular pathologies. N methyl D-aspartate receptors (NMDARs) and renin-angiotensin system are involved in neuronal plasticity, as well as cognitive functions in the hippocampus. In this study, we examined the effects of lisinopril, an ACE inhibitor, on the levels of hippocampal NMDAR subunits; NR2A and NR2B in L-NAME (N(epsilon)-nitro-L arginine Methyl Ester)-induced hypertensive rats. In addition, malondialdehyde (MDA) levels were measured as a marker for lipid peroxidation. Compared with the control group, the MDA level was significantly increased after 8 weeks in the L NAME-treated group. Rats treated with lisinopril and L-NAME plus lisinopril were found to have significantly decreased hippocampal MDA levels. Regarding the hippocampal concentrations of NR2A and NR2B, there were no statistically significant differences between groups. We demonstrated that lisinopril treatment has no direct regulatory effect on the levels of NR2A and NR2B in the rat hippocampus. Our results showed that Lisinopril could act as an antioxidant agent against hypertension-induced oxidative stress in rat hippocampus. The findings support that the use of lisinopril may offer a good alternative in the treatment of hypertension by reducing not only blood pressure but also prevent hypertensive complications in the brain. PMID- 22943191 TI - A low resting heart rate at diagnosis predicts favourable long-term outcome in pulmonary arterial and chronic thromboembolic pulmonary hypertension. A prospective observational study. AB - BACKGROUND: A low resting heart rate (HR) is prognostically favourable in healthy individuals and in patients with left heart disease. In this study we investigated the impact of HR at diagnosis on long-term outcome in patients with differently classified precapillary pulmonary hypertension (pPH). METHODS: pPH patients diagnosed as pulmonary arterial (PAH) or inoperable chronic thromboembolic pulmonary hypertension (CTEPH) were registered and regularly followed at our centre Baseline characteristics and events defined as either death or lung transplantation were noted. The prognostic value of HR was analysed using Kaplan Meier estimates, live tables and Cox regression. RESULTS: 206 patients with PAH (148) and inoperable CTEPH (58) were included. The median HR was 82 bpm. pPH with a HR below 82 bpm had a significantly longer overall event free survival (2409 vs.1332 days, p = .000). This advantage was similarly found if PAH and CTEPH were analysed separately. Although a lower HR was associated with a better hemodynamic and functional class, HR was a strong and independent prognostic marker for transplant free survival even if corrected for age, sex, hemodynamics and functional status. CONCLUSION: We show that resting HR at diagnosis is a strong and independent long-term prognostic marker in PAH and CTEPH. Whether reducing HR by pharmacological agents would improve outcome in pPH has to be assessed by future trials with high attention to safety. PMID- 22943193 TI - Accelerated vaccination schedule provides protective levels of antibody and complete herd immunity to equine influenza. AB - REASONS FOR PERFORMING STUDY: During the 2007 Australian equine influenza (EI) outbreak, an accelerated primary course 14 day intervaccination schedule was proposed, but not widely implemented. Expert opinion was divided as to the efficacy of such a schedule given the lack of published data. This study determined the level and duration of humoral immunity following administration of a recombinant canarypox-vectored vaccine (ALVAC-EIV) with a primary intervaccination interval of 14 days and booster at 105 days. OBJECTIVES: To examine whether protective levels of immunity of adequate duration were achieved following a primary course reduced from a minimum interval of 28 to 14 days. Antibody responses to 2 H3N8 American lineage virus strains (including A/equine/Sydney/6085/2007) were assessed and compared to previous challenge studies using ALVAC-EIV at conventional intervaccination intervals. METHODS: Fourteen Thoroughbred horses and 2 ponies from a rural racehorse training property in Victoria, Australia, were vaccinated with ALVAC-EIV on Days 0, 14 and 105. Serial blood samples were collected over the next 32 weeks and tested with haemagglutination inhibition and single radial haemolysis (SRH) in full assays to evaluate the serological response. RESULTS: All horses and ponies responded to the accelerated ALVAC-EIV vaccination schedule. Mean SRH antibodies remained above those consistent with clinical protection for the duration of the study period. All vaccinates demonstrated high SRH antibodies 14 days following V2, thereby achieving 100% herd immunity to homologous viral challenge. CONCLUSIONS: An accelerated vaccination schedule conferred long-lasting protective antibody levels despite a >50% reduction in the recommended V1-V2 interval. POTENTIAL RELEVANCE: High levels of rapidly acquired herd immunity are critical in containing an outbreak of such a highly contagious pathogen as EIV. In a strategic vaccination programme, it is important that horses remain protected for sufficient time to allow control programmes to succeed. An accelerated 14 day primary course intervaccination interval and booster at 105 days achieves both of these objectives. PMID- 22943194 TI - The complete mitogenome of the Chinese bahaba Bahaba taipingensis (Perciformes: Sciaenidae). AB - In this study, the complete mitochondrial genome (mitogenome) sequence of Chinese bahaba was determined by long PCR and primer walking methods. The complete mitochondrial genome is 16,500 bp in length and contains 37 mitochondrial genes (13 protein-coding genes, 2 ribosomal RNA genes and 22 transfer RNA genes) as well as a control region (CR) as other bony fishes. Within the CR, we identified the extended termination-associated sequence domain, the central conserved sequence block domains (CSB-D, CSB-E and CSB-F) and the conserved sequence block domains (CSB-1, CSB-2 and CSB-3). PMID- 22943195 TI - Adenovirus-mediated delivery of soluble ST2 attenuates ovalbumin-induced allergic asthma in mice. AB - Allergic asthma is associated with excessive T helper type 2 (Th2) cells activation and airway hyperreactivity (AHR), implicated in the context of significant morbidity and mortality. Soluble ST2, a member of the interleukin (IL)-1 receptor family, has been shown to play a critical role in modulation of inflammatory disorders, yet the function of soluble ST2 in allergic inflammation remains unclear. In this study, we examined the possibility of regulating ovalbumin (OVA)-challenged airway inflammation by recombinant adenovirus-mediated sST2-Fc (Ad-sST2-Fc) gene transfer. Single intranasal administration of Ad-sST2 Fc before allergen challenge in OVA-immunized mice profoundly reduced serum immunoglobulin (Ig)E secretion, eosinophil infiltration and concentrations of IL 4, IL-5 and IL-13 in bronchoalveolar lavage fluid compared with administration of a control Ad vector. Histopathological examination of the lungs revealed that sST2-Fc over-expression markedly suppressed allergen-induced peribronchial inflammation and disruption of the alveolar architecture. Moreover, the beneficial effect of sST2-Fc in allergic lung inflammation is related to blocking the IL-33/ST2L signalling. Taken together, these results suggested that administration of Ad-sST2-Fc gene transfer may have therapeutic potential for the immunomodulatory treatment of OVA-mediated allergic pulmonary diseases. PMID- 22943196 TI - Impaired function of regulatory T cells in cord blood of children of allergic mothers. AB - Allergy is one of the most common diseases with constantly increasing incidence. The identification of prognostic markers pointing to increased risk of allergy development is of importance. Cord blood represents a suitable source of cells for searching for such prognostic markers. In our previous work, we described the increased reactivity of cord blood cells of newborns of allergic mothers in comparison to newborns of healthy mothers, which raised the question of whether or not this was due to the impaired function of regulatory T cells (T(regs)) in high-risk children. Therefore, the proportion and functional properties of T(regs) in cord blood of children of healthy and allergic mothers were estimated by flow cytometry. The proportion of T(regs) [CD4(+)CD25(high)CD127(low) forkhead box protein 3 (FoxP3(+))] in cord blood of children of allergic mothers tends to be higher while, in contrast, the median of fluorescence intensity of FoxP3 was increased significantly in the healthy group. Intracellular presence of regulatory cytokines interleukin (IL)-10 and transforming growth factor (TGF) beta was also higher in T(regs) of children of healthy mothers. Although we detected an increased proportion of T(regs) in cord blood of children of allergic mothers, the functional indicators (intracellular presence of regulatory cytokines IL-10 and TGF-beta, median of fluorescence intensity of FoxP3) of those T(regs) were lower in comparison to the healthy group. We can conclude that impaired function of T(regs) in cord blood of children of allergic mothers could be compensated partially by their increased number. Insufficient function of T(regs) could facilitate allergen sensitization in high-risk individuals after subsequent allergen encounter. PMID- 22943197 TI - Pretreatment with glycomacropeptide reduces allergen sensitization, alleviates immediate cutaneous hypersensitivity and protects from anaphylaxis. AB - Allergic disorders are characterized by the involvement of allergen-specific immunoglobulin (Ig)E antibodies and T helper type 2 (Th2) cells. The search for new therapies for allergic diseases has been the primary focus of interest for many investigators in recent years. Glycomacropeptide (GMP) is a biologically active component of milk that exhibits a range of immunomodulatory functions. We examined whether oral administration of GMP could affect the development of allergic sensitization and the severity of immediate cutaneous hypersensitivity reactions and of anaphylaxis. Rats treated with or without GMP were ovalbumin (OVA)-sensitized and several indicators of allergy were evaluated. Pretreatment with GMP resulted in reduction of antigen-specific IgE titre in rats when sensitized with OVA. GMP administration also markedly suppressed the proliferative response of splenocytes to antigen and the production of interleukin (IL)-13 by splenocytes of sensitized animals. In addition, GMP pretreatment attenuated the intensity of the immediate cutaneous reaction induced by antigen and protected the sensitized rats from severe anaphylaxis. These data demonstrate, for the first time, that the administration of GMP prevents allergen sensitization and reduces the severity of the early-phase reaction induced by antigen in cutaneous hypersensitivity and in anaphylaxis. GMP may be used as a novel prophylactic agent for the control of allergic diseases. PMID- 22943198 TI - Activation of cytokines corroborate with development of inflammation and autoimmunity in thromboangiitis obliterans patients. AB - Thromboangiitis obliterans (TAO) is a segmental inflammatory occlusive disorder that affects the arm and leg arteries of young smokers. The immune system seems to play a critical role in the aetiology of TAO; however, knowledge of the aspects involved in the progression of vascular tissue inflammation and, consequently, the evolution of this disease is still limited. This study was carried out to investigate the cytokine levels of tumour necrosis factor (TNF) alpha, interleukin (IL)-1beta, IL-4, IL-17 and IL-23 in the plasma of TAO patients presenting with acute clinical manifestations. The study included 20 TAO patients (n = 10 women; n = 10 men) aged 38-59 years under clinical follow-up, classified into two groups: (i) TAO former smokers (n = 11) and (ii) TAO active smokers (n = 9); the control groups included normal volunteer non-smokers (n = 10, active smokers (n = 10) and former smokers (n = 10). Patients' plasma samples were measured using the sandwich enzyme-linked immunosorbent assay. Statistical analyses were performed using the non-parametric Mann-Whitney U-test, with parameters significant at P < 0.05. The activities of all cytokines were different in groups of TAO patients when compared with normal controls, and decreased for control smokers. Increased levels of TNF-alpha, IL-1beta, IL-4, IL 17 and IL-23 were significant in patients with TAO when compared to the controls (P < 0.005, all parameters). The results presented here indicate an increased production of cytokines in TAO, possibly contributing to the inflammatory response observed in the patients' vascular levels. In addition, the increased levels of IL-17 and IL-23 suggest that the disturbance of TAO is involved with mechanisms of autoimmunity. Thus, the discovery of IL-17 and its association with inflammation and autoimmune pathology has reshaped our viewpoint regarding the pathogenesis of TAO, which was based previously on the T helper type 1 (Th1)-Th2 paradigm. PMID- 22943199 TI - Differential effects of infliximab on absolute circulating blood leucocyte counts of innate immune cells in early and late rheumatoid arthritis patients. AB - Anti-tumour necrosis factor (TNF) biologics have revolutionized therapy of rheumatoid arthritis (RA). We compared the effects of infliximab on numbers of circulating leucocyte subsets in early RA (disease/symptom duration of <=1 year) and late RA patients (>1 year). A control group consisted of early RA patients treated with a combination of methotrexate (MTX) and methylprednisolone. Blood samples were obtained at baseline (pre-therapy) from all RA patients, divided into three groups: (i) late RA receiving infliximab/MTX, (ii) early RA infliximab/MTX, (iii) early RA-steroid/MTX, and also from follow-up patients at 2 and 14 weeks. Significant differences in absolute counts of monocytes and granulocytes were observed between healthy controls and RA patients. At baseline CD14(bright) monocytes and CD16(+) granulocytes were increased in both early RA and late RA patients. CD4(+) T cells, CD8(+) T cells and B cells were all increased at baseline in early RA, but not in late RA. At 2 weeks following infliximab treatment decreased granulocytes were observed in both early and late RA and decreased natural killer (NK) cells in late RA. CD16(+) granulocytes and NK cells were also decreased at 14 weeks post-infliximab in early RA. Biotinylated infliximab was used to detect membrane-associated TNF (mTNF) expressing leucocytes in RA patients. CD16(+) granulocytes, NK cells and CD14(dim) monocytes all expressed higher levels of mTNF in RA patients. In summary infliximab is associated with decreased CD16(+) granulocyte and NK cell counts, possibly through binding of mTNF. Differential effects of infliximab between early and late RA suggest that pathogenic mechanisms change as disease progresses. PMID- 22943200 TI - Phagocytosis of apoptotic cells by macrophages in anti-neutrophil cytoplasmic antibody-associated systemic vasculitis. AB - Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a group of autoimmune diseases, including granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA). It is not known why ANCA develop, but it has been shown that they participate in pathogenesis by activating polymorphonuclear neutrophils (PMNs). In this study we hypothesize that dysregulation of phagocytosis in AAV leads to the accumulation of apoptotic neutrophils seen in association with blood vessels in AAV. These cells progress into secondary necrosis, contributing to tissue damage and autoantibody formation. Peripheral blood cells were counted, and phagocytosis was investigated using monocyte derived macrophages (MO) and PMNs from healthy blood donors (HBD), AAV patients and systemic lupus erythematosus (SLE) patients. Furthermore, the effect of serum was assessed. Phagocytosis was measured using flow cytometry. The results showed no deviation in monocyte subpopulations for AAV patients compared to HBDs, although there was a decrease in lymphocyte and pDC (plasmacytoid dendritic cell) populations (4.2 * 10(6) cells/l versus 10.4 * 10(6) cells/l, P < 0.001). The number of neutrophils was increased (6.0 * 10(9) cells/l versus 3.8 * 10(9) cells/l, P < 0.001). There were no differences found in the ability of MOs to engulf apoptotic cells, nor when comparing apoptotic PMNs to become engulfed. However, serum from AAV donors tended to decrease the phagocytosis ability of MOs (36%) compared to serum from HBDs (43%). In conclusion, there is no intrinsic dysfunction in the MOs or in the PMNs that have an effect on phagocytic activity, but ANCA may play a role by decreasing phagocytic ability. PMID- 22943201 TI - CD8 T cell autoreactivity to preproinsulin epitopes with very low human leucocyte antigen class I binding affinity. AB - Beta cells presenting islet epitopes are recognized and destroyed by autoreactive CD8 T cells in type 1 diabetes. These islet-specific T cells are believed to react with epitopes binding with high affinity to human leucocyte antigen (HLA) expressed on beta cells. However, this assumption might be flawed in case of islet autoimmunity. We evaluated T cell recognition of the complete array of preproinsulin (PPI) peptides with regard to HLA binding affinity and T cell recognition. In a comprehensive approach, 203 overlapping 9-10mer PPI peptides were tested for HLA-A2 binding and subjected to binding algorithms. Subsequently, a high-throughput assay was employed to detect PPI-specific T cells in patient blood, in which conditional HLA ligands were destabilized by ultraviolet irradiation and HLA molecules refolded with arrays of PPI peptides, followed by quantum-dot labelling and T cell staining. Analysis of patient blood revealed high frequencies of CD8 T cells recognizing very low HLA binding peptides. Of 28 peptides binding to HLA-A2, a majority was predicted not to bind. Unpredicted peptides bound mainly with low affinities. HLA binding affinity and immunogenicity may not correlate in autoimmunity. Algorithms used to predict high affinity HLA peptide binders discount the majority of low-affinity HLA binding epitopes. Appreciation that peptides binding HLA with very low affinity can act as targets of autoreactive T cells may help to understand loss of tolerance and disease pathogenesis and possibly point to tissue-specific immune intervention targets. PMID- 22943202 TI - Bacillus-derived poly-gamma-glutamic acid reciprocally regulates the differentiation of T helper 17 and regulatory T cells and attenuates experimental autoimmune encephalomyelitis. AB - Forkhead box protein 3 (FoxP3(+)) regulatory T (T(reg)) cells and interleukin (IL)-17-producing T helper 17 (Th17) cells have opposing effects on autoimmunity, as the former are crucial for maintaining self-tolerance while the latter play a key role in precipitating inflammatory autoimmune diseases. Here we report that Bacillus-derived poly-gamma-glutamic acid (gamma-PGA) signals naive CD4(+) T cells to promote the selective differentiation of T(reg) cells and to suppress the differentiation of Th17 cells. The gamma-PGA inducibility of FoxP3 expression was due partially to transforming growth factor (TGF)-beta induction through a Toll-like receptor (TLR)-4/myeloid differentiating factor 88 (MyD88)-dependent pathway. However, this pathway was dispensable for gamma-PGA suppression of Th17 differentiation. gamma-PGA inhibited IL-6-driven induction of Th17-specific factors including signal transducer and activator of transcription-3 (STAT-3) and retinoic acid-related orphan receptor gammat (RORgammat) while up-regulating the STAT-3 inhibitor suppressor of cytokine signalling 3 (SOCS3). Importantly, in vivo administration of gamma-PGA attenuated the symptoms of experimental autoimmune encephalomyelitis and at the same time reduced Th17 cell infiltrates in the central nervous system. Thus, we have identified the microbe-associated molecular pattern, gamma-PGA, as a novel regulator of autoimmune responses, capable of promoting the differentiation of anti-inflammatory T(reg) cells and suppressing the differentiation of proinflammatory Th17 cells. These findings draw attention to the potential of gamma-PGA for treating Th17 cell-mediated autoimmune diseases. PMID- 22943203 TI - Critical mass of splenic autotransplant needed for the development of phagocytic activity in rats. AB - When total splenectomy is inevitable, heterotopic splenic autotransplantation seems to be the only alternative to maintain the functions of the spleen. The present study was carried out to analyse the critical mass of splenic autotransplant (SAT) for the development of phagocytic activity in rats. Wistar rats were submitted to total splenectomy (TS) alone or in combination with slices of SAT ranging from an average rate of 21.9% (one slice) to 100% (five slices) of the total splenic mass implanted into the greater omentum. Sixteen weeks after the beginning of the experiment, the animals were inoculated intravenously with a suspension of Escherichia coli labelled with Tc-99m. After 20 min, the rats were killed and the liver, lung and spleen or SAT, as well as blood samples were removed to determine the percentage of labelled bacteria uptake in these tissues. As the percentage of the total splenic mass contained in the SAT increased, the bacteria remaining in the blood decreased. From the implant of 26% up to the implant of the total splenic mass (100%) there was no difference in the bacteria remaining in the blood between the healthy animals of the control group and those submitted to TS combined with SAT. This finding shows that the critical mass needed for the development of phagocytic activity of macrophages in splenic autotransplants in adult rats is 26% of the total splenic mass. PMID- 22943204 TI - Non-genomic inhibitory effect of glucocorticoids on activated peripheral blood basophils through suppression of lipid raft formation. AB - We investigated the non-genomic effects of glucocorticoids (GCs) on inhibition of plasma membrane lipid raft formation in activated human basophils. Human basophils obtained from house dust mite (HDM)-sensitive volunteers were pretreated with hydrocortisone (CORT) or dexamethasone (Dex) for 30 min and then primed with phorbol 12-myristate 13-acetate (PMA, 10 ng/ml) or HDM (10 ug/ml). The expression of CD63, a basophil activation marker, was assessed by flow cytometry. Membrane-bound GC receptors (mGCRs) were analysed by flow cytometry and confocal laser microscopy. Lipid rafts were assessed using a GM1 ganglioside probe and visualization by confocal laser microscopy. Pretreatment of basophils with CORT (10(-4) M and 10(-5) M) and Dex (10(-7) M) significantly inhibited CD63 expression 20 min after addition of PMA or HDM. The inhibitory effects of GCs were not altered by the nuclear GC receptor (GCR) antagonist RU486 (10(-5) M) or the protein synthesis inhibitor cycloheximide (10(-4) M) (P < 0.05). CORT coupled to bovine serum albumin (BSA-CORT) mimicked the rapid inhibitory effects of CORT, suggesting the involvement of mGCRs. mGCRs were detectable on the plasma membrane of resting basophils and formed nanoclusters following treatment with PMA or HDM. Pretreatment of cells with BSA-CORT inhibited the expression of mGCRs and nanoclustering of ganglioside GM1 in lipid rafts. The study provides evidence that non-genomic mechanisms are involved in the rapid inhibitory effect of GCs on the formation of lipid raft nanoclusters, through binding to mGCRs on the plasma membrane of activated basophils. PMID- 22943207 TI - Magnonic band structure investigation of one-dimensional bi-component magnonic crystal waveguides. AB - The magnonic band structures for exchange spin waves propagating in one dimensional magnonic crystal waveguides of different material combinations are investigated using micromagnetic simulations. The waveguides are periodic arrays of alternating nanostripes of different ferromagnetic materials. Our results show that the widths and center frequencies of the bandgaps are controllable by the component materials, the stripe widths, and the orientation of the applied magnetic field. One salient feature of the bandgap frequency plot against stripe width is that there are n-1 zero-width gaps for the nth bandgap for both transversely and longitudinally magnetized waveguides. Additionally, the largest bandgap widths are primarily dependent on the exchange constant contrast between the component materials of the nanostructured waveguides. PMID- 22943205 TI - Type I interferon induces CX3CL1 (fractalkine) and CCL5 (RANTES) production in human pulmonary vascular endothelial cells. AB - Type I interferon (IFN) medications cause various adverse reactions, including vascular diseases. Although an association between chemokines and vascular diseases has also been reported, the relationship between type I IFN and chemokines in vascular endothelial cells (VEC) remains unclear. To provide clues to pathogenesis of the diseases, we analysed the effects of type I IFN on chemokine production in human VEC. Type I IFN induced higher CX3CL1 (fractalkine) mRNA expression and protein secretion in pulmonary arterial VEC than in umbilical vein VEC. Type I IFN also induced CCL5 [regulated upon activation normal T cell expressed and secreted (RANTES)] production in VEC, especially in lung micro-VEC. IFN-beta induced much higher chemokine production than IFN-alpha, and Janus protein tyrosine kinase (JAK) inhibitor I prevented type I IFN-induced chemokine secretion. Type I IFN-induced chemokines may be involved in the pathophysiology of pulmonary vascular diseases, and the JAK inhibitor may serve as a therapeutic option for these diseases. PMID- 22943208 TI - Quality assessment of clinical practice guidelines: who watches the watchmen? PMID- 22943206 TI - The effect of human immunodeficiency virus-1 on monocyte-derived dendritic cell maturation and function. AB - Dendritic cells (DC) are mediators of the adaptive immune response responsible for antigen presentation to naive T cells in secondary lymph organs. Human immunodeficiency virus (HIV-1) has been reported to inhibit the maturation of DC, but a clear link between maturation and function has not been elucidated. To understand further the effects of HIV-1 on DC maturation and function, we expanded upon previous investigations and assessed the effects of HIV-1 infection on the expression of surface molecules, carbohydrate endocytosis, antigen presentation and lipopolysaccharide (LPS) responsiveness over the course of maturation. In vitro infection with HIV-1 resulted in an increase in the expression of DC-specific intercellular adhesion molecule-3-grabbing non-integrin (DC-SIGN) as well as decreases in maturation-induced CCR7 and major histocompatibility complex (MHC)-II expression. Retention of endocytosis that normally occurs with DC maturation as well as inhibition of antigen presentation to CD8(+) T cells was also observed. Mitogen-activated protein kinase (MAPK) responsiveness to LPS as measured by phosphorylation of p38, c-Jun N-terminal kinase (JNK) and extracellular-regulated kinase (ERK)1/2 was not affected by HIV 1 infection. In summary, in-vitro HIV-1 impairs DC maturation, as defined by cell surface protein expression, with selective alterations in mature DC function. Understanding the mechanisms of DC dysfunction in HIV infection will provide further insight into HIV immune pathogenesis. PMID- 22943209 TI - Sport promotion policies in the European Union: results of a contents analysis. AB - Although sport promotion may play an important role in achieving the recommended levels of physical activity for health, until now, there has been no comprehensive assessment of how sport policies in Europe address health. This article aimed at filling this gap by reviewing and analyzing recent national policy developments in the area of sport promotion, with a focus on synergies and discrepancies with the promotion of health-enhancing physical activity. By applying various search methods, 130 documents focusing on sport and physical activity were identified in the World Health Organization (WHO) European Region. An analysis grid covering key indicators was developed for a systematic content analysis of 25 documents, selected according to established criteria. Analysis showed that general recommendations for good policy making were followed, such as establishing general goals, specifying time frame and responsible body for implementation and addressing different target groups. Furthermore, all sport strategies addressed health on an overall level and recognized the importance of Sport for All. However, in several strategies, there was a lack of measurable targets, specified budgets, and evaluation plans. The analysis showed that there is a great opportunity for health and sport sectors to work more closely together in the future, and identified areas where this could take place. PMID- 22943210 TI - Emtricitabine/tenofovir in the treatment of HIV infection: current PK/PD evaluation. AB - INTRODUCTION: Emtricitabine/tenofovir disoproxil fumarate fixed-dose combination (FTC/TDF FDC) is the co-formulation of a nucleoside and a nucleotide, respectively. After oral administration, both drugs exhibit plasma and intracellular half-lives suitable for once-daily dosing. Within the host cells, active metabolites FTC-TP and TFV-DP act as chain terminators to the newly synthesized proviral DNA, showing synergy at enzymatic level (viral reverse transcriptase). When given in HAART combinations, FTC/TDF FDC has a remarkable effectiveness in controlling HIV replication and securing a significant CD4(+) cell recovery. If patients treated with FTC/TDF FDC fail, a lower incidence of TDF-associated K65R resistance mutation seems to develop. Furthermore, cytidine analog-associated M184V is less likely to appear with FTC than with lamivudine when both are given with TDF. FTC and TFV are not metabolized by CYP450 enzymes and are eliminated by the renal route. TFV may accumulate in tubular cells and cause a decrease in GFR and a loss of phosphates. As a onsequence, patients treated with FTC/TDF FCD may experience varied degrees of renal impairment and osteopenia/osteoporosis. AREAS COVERED: This paper has focused on the PK/PD features of FTC and TDF, when given as single agent or when administered as FDC. The interpretation of efficacy/toxicity was guided by PK/PD features. The review of the available literature included also conference presentations and recent guidelines (as of May 2012). EXPERT OPINION: FTC/TDF FDC is a potent and reliable component of most HAART combinations due to its maintained activity across time, as demonstrated in many trials and studies. Toxicity issues (kidney, bone) are still to be entirely elucidated and the drug-induced component well separated from patient- and HIV-related ones. However, the clinical gain associated with the use of FTC/TDF FDC is fully acknowledged by its leading position in most current treatment guidelines. PMID- 22943211 TI - A modest proposal for an outreach section in scientific publications. PMID- 22943212 TI - Plasma cytokines levels in aggressive and chronic periodontitis. AB - OBJECTIVE: The present study evaluated the Th1/Th2 cytokine profile in plasma from healthy controls and different types of periodontitis patients. MATERIALS AND METHODS: The concentration of IL-2, IL-4, IL-5, IL-10, TNF-alpha and IFN gamma was determined in healthy controls (n = 18) and patients with chronic (n = 19) and aggressive periodontitis (n = 19) using a flow cytometric multiplex immunoassay. Means and standard deviations were calculated and compared using Kruskal-Wallis test. Spearman rho coefficient was used to correlate cytokines in the studied groups. RESULTS: Although there was no significant difference in the concentration of cytokines between groups, there was a tendency to lower levels of IL-5 and IL-10 in the aggressive periodontitis group. Stronger correlations were observed between IL-2/IL-4 and IL-2/IL-10 in healthy controls (0.938 and 0.669, respectively) compared with chronic (0.746 and 0.532) and aggressive periodontitis groups (0.395 and 0.266). When compared to healthy (0.812) and chronic periodontitis (0.845) groups, the correlation of IL-4/IL-5 was weaker in the aggressive group (0.459). CONCLUSION: No difference between systemic levels of Th1/Th2 was observed. In aggressive periodontitis patients, nevertheless, a trend towards low levels of Th2 cytokines could suggest a contribution to the development of such an exacerbated manifestation of this disease. PMID- 22943213 TI - Immediate skin grafting following tumour excision. PMID- 22943214 TI - Advances in total joint replacement in small animals. AB - Total joint replacement is now considered a routine surgical option for small animals with advanced joint disease. This review highlights the current state of the art in total hip, elbow and knee replacement in small animals, as well as the potential for application to other joints such as the intervertebral discs, hock and shoulder. Advances in cementless fixation, the use of less-invasive, bone sparing procedures, and the development of custom implant options for revision surgery and oncologic reconstruction will be discussed. As growth in this field continues, it is important that future developments in total joint replacement are built on a foundation of detailed laboratory evaluation of new implant designs and surgical techniques, objective assessment of clinical outcomes, and a comprehensive, coordinated retrieval program that evaluates both well-functioning and failed joint replacements. PMID- 22943215 TI - Idiopathic hypertrophic pachymeningitis in six dogs: MRI, CSF and histological findings, treatment and outcome. AB - Idiopathic hypertrophic pachymeningitis has been described in humans as a rare, chronic progressive non-specific inflammatory and fibrotic disease of the dura mater. This is a case series of six canine cases of presumptive or confirmed intracranial idiopathic hypertrophic pachymeningitis. These dogs were included in this retrospective study, based on magnetic resonance imaging findings. All presented with pachymeningeal thickening and enhancement without involvement of the leptomeninges on magnetic resonance imaging and no underlying cause identified on cerebrospinal fluid analysis, complete blood count, serum biochemistry and infectious disease titres. Histopathological examination was available in one case. Response to immunomodulatory treatment (corticosteroids and cytosine arabinoside) was achieved in five cases. Idiopathic hypertrophic pachymeningitis should be considered as a possible differential diagnosis for dogs with pachymeningeal thickening on magnetic resonance imaging and no identified underlying cause. The prognosis appears to be fair to poor. PMID- 22943217 TI - Changes in the effects of heat on mortality among the elderly from 1998-2010: results from a multicenter time series study in Italy. AB - BACKGROUND: This multicenter study is aimed at estimating changes in the effect of high temperatures on elderly mortality before and after the 2003 heat waves and following the introduction of heat prevention activities. METHODS: A total of sixteen cities were included in the study. City-specific relationships between maximum apparent temperature (MAT) and elderly daily mortality before (1998-2002) and after (2006-2010) intervention were modelled through non-linear distributed lag models and estimates were combined using a random effect meta-analysis. We estimated the percentage change in daily mortality for 3 degrees C variations in MAT above the 25th percentile of the June city-specific 1998-2002 distribution. A time-varying analysis was carried out to describe intra-seasonal variations in the two periods. RESULTS: We observed a reduction in high temperatures' effect post intervention; the greatest reduction was for increases in temperature from 9 degrees C to 12 degrees C above the 25th percentile, with a decrease from +36.7% to +13.3%. A weak effect was observed for temperatures up to 3 degrees C above the 25th percentile only after. Changes were month-specific with a reduction in August and an increase in May, June and September in 2006-2010. CONCLUSIONS: A change in the temperature-mortality relationship was observed, attributable to variations in temperature distributions during summer and to the introduction of adaptation measures. The reduction in the effect of high temperature suggests that prevention programs can mitigate the impact. An effect of lower temperature remains, indicating a relevant impact of temperature at the beginning of summer when the population has not yet adapted and intervention activities are not fully operational. PMID- 22943218 TI - A case of familial paediatric atlantoaxial subluxation. AB - INTRODUCTION: Fixed atlantoaxial rotary subluxation (FAARS) is a rare cause of torticollis in children. Familial FAARS has not been described in the literature previously. We present case reports of two siblings who both developed spontaneous atlantoaxial rotary subluxation and discuss the possible causes. Both patients were treated conservatively and made a successful recovery. METHODS: The notes and images of two siblings were reviewed following permission from their parents. A literature search was also performed to look at what is currently known about atlantoaxial subluxation. RESULTS: Both siblings were successfully treated with halter traction and subsequent collar treatment. Os terminale was iden- tified on the CT images of both children. CONCLUSIONS: Atlantoaxial rotary subluxation should be considered as a cause of torticollis in children and can occasionally occur spontaneously. Both siblings had os terminale and it raises the possibility that this may predispose children to develop- ing FAARS. There may also be an underlying previously unidentified familial cause. Appropriate imaging followed by prompt treatment in halter traction is usually successful. If a diagnosis of FAARS is confirmed in a paediatric patient, the clinician should have a high index of suspicion when a sibling presents with torticollis or associated neck pain subsequently. PMID- 22943219 TI - The competent isolated double orifice mitral valve: an incidental finding during excision of a papillary fibroelastoma. AB - The double orifice mitral valve is associated with a number of congenital abnormalities and comprises two mitral orifices separated by an accessory bridge of fibrous tissue and surrounded by a single fibrous annulus. We present our management of a case of a double orifice mitral valve associated with a papillary fibroelastoma. PMID- 22943220 TI - Management of diabetes around emergency and elective procedures. PMID- 22943221 TI - How to undertake a research project and write a scientific paper. AB - Research and publishing are essential aspects of lifelong learning in a surgical career. Many surgeons, especially those in training, ask for guidance on how they might start a simple project that may lead to a publication. This short paper offers some practical guidelines on the subject. PMID- 22943222 TI - Evaluation of internet derived patient information. AB - INTRODUCTION: The internet is a widely used, powerful resource for patients to research medical conditions. There is an extensive amount of information available on the internet. It is important for patient information to be accurate and in an easily accessible format. This article aims to assess the quality of patient information on hydrocephalus and compares the findings with recent evaluations in other surgical specialties. METHODS: The term 'hydrocephalus' was searched for on the search engines http://www.google.com/, http://www.bing.com/ and http://www.yahoo.com/. The top 20 results of these searches were assessed using the University of Michigan consumer health website evaluation checklist. RESULTS: The quality of patient information websites on hydrocephalus is highly variable. Websites rarely provide sufficient authorship information, do not review their information regularly enough and only reference material occasionally. The background of the provider was found to influence the quality of the website, with academic and care providers creating the best websites. CONCLUSIONS: On comparing our findings with those of recent studies from other surgical specialties, it was found that there was often a conflict of interest between the background of the provider and the information supplied. It is recommended that clinicians personally research material for their patients to be able to guide them to suitable, accurate websites. PMID- 22943223 TI - Periprosthetic fractures around total knee arthroplasty. AB - INTRODUCTION: The number of total knee arthroplasties performed continues to rise annually and it would be expected that complications, which include periprosthetic fractures, will also therefore become more commonplace. This article reviews the current literature regarding this injury and identifies the treatment principles that enable patients to regain optimal function. METHODS: A comprehensive search of the Pubmed and EmbaseTM databases was performed to identify relevant articles. Keywords and MeSH (Medical Subject Headings) terms included in the search strategy were 'periprosthetic fracture(s)', 'femur', 'tibia', 'patella(r)', 'complication(s)', 'failure(s)', 'risk(s)', 'prevalence', 'incidence', 'epidemiology' and 'classification(s)'. The search was limited to all articles published in English and reference lists from the original articles were reviewed to identify pertinent articles to include in this review. A total number of 43 studies were identified. RESULTS: Common treatment aims have been identified when managing patients with a periprosthetic fracture around total knee arthoplasty. The main criterion that determines which option to choose is the degree of remaining bone stock and the amount of fracture displacement. CONCLUSIONS: Treatment of a periprosthetic fracture around total knee arthroplasty will either be non-operative, osteosynthesis or revision arthroplasty. It is imperative that a suitable option is chosen and based on the published literature, pathways are outlined to aid the surgeon. PMID- 22943224 TI - The influence of process and patient factors on the recall of consent information in mentally competent patients undergoing surgery for neck of femur fractures. AB - INTRODUCTION: Informed consent is an ethical and legal prerequisite for major surgical procedures. Recent literature has identified 'poor consent' as a major cause of litigation in trauma cases. We aimed to investigate the patient and process factors that influence consent information recall in mentally competent patients (abbreviated mental test score [AMTS] >=6) presenting with neck of femur (NOF) fractures. METHODS: A prospective study was conducted at a tertiary unit. Fifty NOF patients (cases) and fifty total hip replacement (THR) patients (controls) were assessed for process factors (adequacy and validity of consent) as well as patient factors (comprehension and retention) using consent forms and structured interview proformas. RESULTS: The two groups were matched for ASA (American Society of Anesthesiologists) grade and AMTS. The consent forms were adequate in both groups but scored poorly for validity in the NOF group. Only 26% of NOF patients remembered correctly what surgery they had while only 48% recalled the risks and benefits of the procedure. These results were significantly poorer than in THR patients (p = 0.0001). CONCLUSIONS: This study confirms that NOF patients are poor at remembering the information conveyed to them at the time of consent when compared with THR patients despite being intellectually and physiologically matched. We suggest using preprinted consent forms (process factors), information sheets and visual aids (patient factors) to improve retention and recall. PMID- 22943225 TI - Human body projectiles implantation in victims of suicide bombings and implications for health and emergency care providers: the 7/7 experience. AB - INTRODUCTION: On 7 July 2005 four suicide bombings occurred on the London transport systems. In some of the injured survivors, bone fragments were embedded as biological foreign bodies. The aim of this study was to revisit those individuals who had sustained human projectile implantation injuries as a result of the bomb blasts at all scenes, review the process of body parts mapping and DNA identification at the scene, detail the management of such injuries and highlight the protocols that have been put in place for protection against blood borne pathogens. METHODS: We retrospectively reviewed 12 instances of victims who sustained human body projectile implantation injuries. The Metropolitan Police and forensic scientists identified the human projectiles using DNA profiling and mapped these on the involved carriages and those found outside. All human projectiles included were greater than 3 cm(2). RESULTS: Twelve cases had human projectile implantation injuries. Of these, two died at the scene and ten were treated in hospital. Projectiles were mapped at three of the four bomb blast sites. Our findings show that victims within a 2m radius of the blast had human projectile injuries. Eight of the allogenic bony fragments that were identified in the survivors originated from the suicide bomber. All victims with an open wound should have prophylaxis against hepatitis B and serum stored for appropriate action against HIV and hepatitis C infection. CONCLUSIONS: All victims following a suicide bombing should be assumed to have human body projectile implantation injuries with blood products or bony fragments. All immediate care providers should receive prophylaxis against hepatitis B virus and appropriate action should be taken against HIV and hepatitis C infection. PMID- 22943226 TI - Enhanced recovery programmes in hepatobiliary and pancreatic surgery: a systematic review. AB - INTRODUCTION: The terms 'enhanced recovery after surgery', 'enhanced recovery programme' (ERP) and 'fast track surgery' refer to multimodal strategies aiming to streamline peri-operative care pathways, to maximise effectiveness and minimise costs. While the results of ERP in colorectal surgery are well reported, there have been no reviews examining if these concepts could be applied safely to hepatopancreatobiliary (HPB) surgery. The aim of this systematic review was to appraise the current evidence for ERP in HPB surgery. METHODS: A MEDLINE (r) literature search was undertaken using the keywords 'enhanced recovery', 'fast-track', 'peri-operative', 'surgery', 'pancreas' and 'liver' and their derivatives such as 'pancreatic' or 'hepatic'. The primary endpoint was length of post-operative hospital stay. Secondary endpoints were morbidity, mortality and readmission rate. RESULTS: Ten articles were retrieved describing an ERP. ERP protocols varied slightly between studies. A reduction in length of stay was a consistent finding following the incorporation of ERP when compared with historical controls. This was not at the expense of increased rates of readmission, morbidity or mortality in any study. CONCLUSIONS: The introduction of an ERP in HPB surgery appears safe and feasible. Currently, many of the principles of the multimodal pathway are derived from the colorectal ERP and distinct differences exist, which may impede its implementation in HPB surgery. PMID- 22943227 TI - Open transversus abdominis plane block and analgesic requirements in patients following right hemicolectomy. AB - INTRODUCTION: Reducing exogenously administered opioids in the post-operative period is associated with early return of bowel function and decreased post operative complication rates. We evaluated the effectiveness of a surgeon delivered open transversus abdominis plane (TAP) block as a method to reduce post-operative opioid requirements, sedation and inpatient stay. METHODS: The patient cohort was identified from those who had undergone a right hemicolectomy for colonic cancer. Patients received either an open TAP block and post-operative patient controlled anaesthesia (PCA) ( n =20) or were part of a control group who received subcutaneous local anaesthetic infiltration and PCA ( n =16). RESULTS: PCA morphine use was reduced within the first 24 hours post-operatively in the TAP block group compared with controls (42.1mg vs 72.3mg, p =0.002). Sedation was also reduced significantly in the early post-operative period (p <0.04). There was a non-significant trend towards reduced length of stay in the intervention group (8.2 vs 8.73 days). There were no recorded complications attributable to the open TAP block. CONCLUSIONS: Open TAP blocks are safe and reduce post-operative opioid requirements and sedation after right hemicolectomies. They should be considered as part of a multimodal enhanced recovery approach to patients undergoing abdominal surgery via a transverse incision. PMID- 22943228 TI - Surgical management of pleural empyema in the very elderly. AB - INTRODUCTION: Parapneumonic pleural empyema is a critical illness. Age is an acknowledged risk factor for both pneumonia and pleural empyema. Furthermore, elderly patients often have severe co-morbidity. In the case of pleural empyema, their clinical condition is likely to deteriorate fast, resulting in life threatening septic disease. To prevent this disastrous situation we adapted early surgical debridement as the primary treatment option even in very elderly patients. This study shows the outcome of surgically managed patients with pleural empyema who are 80 years or older. METHODS: The outcomes of 222 consecutive patients who received surgical therapy for parapneumonic pleural empyema at a German tertiary referral hospital between 2006 and 2010 were reviewed in a retrospective case study. Patients older than 80 years were identified. RESULTS: There were 159 male and 63 female patients. The mean age was 60.5 years and the overall in-hospital mortality rate was 7%. Of the 222 patients, 37 were 80 years or older (range: 80-95 years). The frequencies of predominantly cardiac co-morbidity and high ASA (American Society of Anesthesiologists) grades were significantly higher for very elderly patients (p <0.001). A minimally invasive approach was feasible in 34 cases (92%). Of the 37 patients aged over 80, 36 recovered while one died from severe sepsis (in hospital mortality 3%). There was no significant difference in mortality between the very elderly and the younger sufferers (p = 0.476). CONCLUSIONS: Early surgical treatment of parapneumonic pleural empyema shows excellent results even in very elderly patients. Despite considerable co-morbidity and often delayed diagnosis, minimally invasive surgery was feasible in 34 patients (92%). The in hospital mortality of very elderly patients was low. It can therefore be concluded that advanced age is no contraindication for early surgical therapy. PMID- 22943229 TI - Safety trial of Floseal((r)) haemostatic agent in head and neck surgery. AB - INTRODUCTION: Floseal((r)) can be of value in reducing blood loss and haematoma rates. The manufacturer's warnings include allergic reaction, poor wound healing and intravascular thrombosis. We aimed to determine whether Floseal((r)) is safe to use in various head and neck surgery procedures. METHODS: A prospective trial was conducted using Floseal((r)) in 42 various consecutive head and neck surgery procedures. Adverse incidents were used as the main outcome measure, including allergic reaction, wound breakdown, wound infection and thrombosis. Secondary outcome measures included haematoma formation, hospital stay, drain times and output. RESULTS: No adverse incidents were recorded in the trial period. Two patients developed haematomas and required surgical exploration where a bleeding vessel was identified and dealt with. CONCLUSIONS: Floseal((r)) is safe to be used in head and neck surgery with no adverse effects. A larger number and a control group are required to ascertain its value in reducing blood loss, haematoma formation, drain usage and hospital stay. PMID- 22943230 TI - Contrast ureteropyelography in theatre: standardised flowchart reporting. AB - INTRODUCTION: Urologists perform retrograde contrast studies of the ureters and pelvicalyceal systems in the operating theatre, both for diagnostic purposes and to guide instrumentation. We describe the development of a set of guidelines that aim to standardise the diagnostic quality of these studies and to reduce radiation dose to the patient and theatre staff. The guidelines incorporate a reporting template that allows a urologist's written report to be made available on the picture archiving and com- munication system (PACS) for subsequent multidisciplinary review. METHODS: Three cycles of audit were conducted to assess the implementation of the guidelines. An independent reviewer rated image quality and screening times. During the audit cycle, the presentation of the guidelines was honed. The end prod- uct is a flowchart and reporting template for use by urologists in the operating theatre. RESULTS: Phase 1 of the audit included 63 studies, phase 2 included 42 studies and phase 3 included 46 studies. The results demonstrate significant improvements in the number of good quality studies and in the recording of control, contrast and post-procedure images. The mean screening time decreased from 5.0 minutes in phase 1 to 3.2 minutes in phase 3. In phase 3, when in-theatre reporting of the studies by the urologist was added, the handwritten report was scanned in and made available on PACS in 43 of 46 cases (93%). CONCLUSIONS Introduction of guidelines improved retrograde contrast study quality and reduced screening times. A system has been developed to store appropriate pictures and a urologist's report of the study on PACS. PMID- 22943231 TI - Trial of ligation versus coagulation of lymphatics in dynamic inguinal sentinel lymph node biopsy for staging of squamous cell carcinoma of the penis. AB - INTRODUCTION: The principal advantage of dynamic sentinel lymph node biopsy (DSNB) over modified inguinal node dissection is the lower complication rate. The aim of this study was to identify factors associated with short-term complications of DSNB in order to lower morbidity of the procedure. METHODS: Retrospective and prospective cohort studies were performed on patients undergoing DSNB between April 2005 and March 2010. Patients were categorised into three groups of 50 (from a total of 250 patients on the database). The patients of Group A, on whom ligaclips were the lymphovascular control technique, were compared with those of Group B, in whom diathermy was used. Incision length, operative time, number of nodes removed, antibiotics and co-morbidities were recorded. A prospective study on Group C, using ligaclips, was also performed. RESULTS: Groups A (88 groins), B (75 groins) and C (68 groins) were explored with complication rates of 5.7%, 24.0% (p =0.0018) and 8.8% (p =0.0277). Co morbidities, antibiotics (co-amoxiclav 1.2g intravenous as per protocol) and the mean number of nodes removed were similar in all groups. The mean incision length was 4.1cm (standard deviation [SD]: 1.0 cm) for Group A, 5.6 cm (SD: 1.0 cm) for Group B (p =0.0001) and 5.6 cm (SD: 0.8 cm) for Group C (p =0.979). The mean operative times for Groups A, B and C were 15.8 (SD: 8.1), 19.3 (SD: 7.4) (p =0.0043) and 22.1 (SD: 7.7) (p =0.0301) minutes respectively. CONCLUSIONS: Lymphovascular control with diathermy is associated with a statistically higher short-term complication rate compared with ligaclip usage (ie 'permanent' ligation). Lymphocoeles are the principal complication and can result in delayed wound infection and breakdown. A small but statistical increase in operative time and wound length is likely to be related to registrar training. PMID- 22943232 TI - Closed suction drains, reinfusion drains or no drains in primary total knee replacement? AB - INTRODUCTION: Controversy still surrounds the use of drains after total knee replacement (TKR). We compared closed suction drains, reinfusion drains and no drains by studying haemoglobin (Hb) levels, blood transfusion requirements and functional knee outcome scores in a single surgeon series. METHODS: A total of 102 consecutive primary TKRs were performed by the senior author between September 2006 and July 2008. All were cemented fixed bearing devices with patellar resurfacing. Of the 102 patients, 30 had closed suction drainage, 33 had an unwashed reinfusion drainage system and 39 had no drains. Data regarding pre and post-operative Hb and units transfused were gathered retrospectively. Pre and post-operative American Knee Society scores (AKSS) and Oxford knee scores (OKS) were recorded prospectively. RESULTS: The pre-operative Hb levels were comparable among the groups. There was no statistically significant difference in Hb level reduction or autologous transfusion rates among the groups. Pre-operative AKSS and OKS were statistically comparable in each group. There was no statistical difference between the improvement in AKSS knee and function scores in all three groups. There was a slightly smaller improvement in the OKS of the 'no drain' group. There were no complications of drain usage and no deep infections. No patient required manipulation under anaesthesia and range of movement outcomes were the same for each group. CONCLUSIONS: Our study does not support the use of either closed suction drains or reinfusion drains in primary elective TKR. PMID- 22943233 TI - Septic arthritis of the knee: the use and effect of antibiotics prior to diagnostic aspiration. AB - Septic arthritis of the native knee joint and total knee arthroplasty both cause diagnostic and treatment issues. There is no gold standard test to diagnose a joint infection and the use of joint aspiration is commonly relied on. It is widely accepted by orthopaedic surgeons that antibiotics should be withheld until aspiration has been performed to increase the odds of identifying an organism. Patients often present to other specialties that may not be as familiar with these principles. Our study found that 25 (51%) of the 49 patients treated for septic arthritis of the native or prosthetic knee in our unit over a 3-year period had received antibiotics prior to discussion or review by the on-call orthopaedic service. Patients were significantly less likely to demonstrate an organism on initial microscopy (entire cohort: p = 0.001, native knees: p = 0.006, prosthetic knees: p = 0.033) or on subsequent culture (entire cohort: p = 0.001, native knees: p = 0.017, prosthetic knees: p = 0.012) of their aspirate if they had received antibiotics. The sensitivity of microscopy in all patients dropped from 58% to 12% when patients had received antibiotics (native knees: 46% to 0%, prosthetic knees: 72% to 27%). The sensitivity of the culture dropped from 79% to 28% in all patients when the patient had received antibiotics (native knees: 69% to 21%, prosthetic knees: 91% to 36%). This study demonstrated how the management of patients with suspected cases of septic arthritis of the knee may be compromised by empirical administration of antibiotics. These patients were significantly less likely to demonstrate an organism on microscopy and culture of their initial aspirate. There is a significant high false negative rate associated with knee aspiration with prior administration of antibiotic therapy. PMID- 22943235 TI - Three ways to avoid incorrect-level lumbar spine surgery. PMID- 22943234 TI - Predicting postoperative urinary retention after lower limb arthroplasty. AB - A simple scoring system that enables surgeons to make an estimation of the likelihood of postoperative urinary retention (POUR) in patients undergoing lower limb total joint replacement would be a useful one. This would enable selection of high risk patients who merit pre-operative catheterisation in a clean theatre environment rather than risking urinary retention and its associated complications late at night on the ward by junior, inexperienced staff. The International Prostate Symptom Score (IPSS) is such a scoring system and we assessed its reliability in predicting those male patients likely to go into POUR. We selected all male patients undergoing lower limb total joint arthroplasty under spinal anaesthesia and calculated their IPSS. We found a statistically significant increase in the likelihood of POUR as IPSS rises (p = 0.0002). We concluded that the IPSS is a quick and easy method of predicting those at risk of POUR, allowing them to be catheterised prophylactically, preventing possible complications. PMID- 22943236 TI - Laparoscopic hepatic flexure mobilisation. PMID- 22943237 TI - Use of a sharps bin to provide lower limb traction. PMID- 22943238 TI - Pelvic collection drainage by Heald anal stent. PMID- 22943239 TI - A technique to maintain pneumoperitoneum and allow easy inspection of the abdomen after specimen delivery in laparoscopic colorectal surgery. PMID- 22943240 TI - A feasible and effective method for restoring patency of a biliary T-tube sinus tract. PMID- 22943241 TI - A technique to aid the insertion of distal locking screws. PMID- 22943242 TI - A pure dermal sling for implant reconstruction after mastectomy in the generous breast. PMID- 22943243 TI - Explantation of aortic infrarenal stent graft. PMID- 22943244 TI - A technique for optimal manipulation of rotation of the flexible ureterorenoscope. PMID- 22943245 TI - A 'homemade' snare for endovascular procedures. PMID- 22943246 TI - Modified mattress suture. PMID- 22943247 TI - A knot quicker and easier than Whip stitching in anterior cruciate ligament reconstruction. PMID- 22943248 TI - Prevention of extension lag using a sling attachment for Ligamentotaxor (r) devices in complex proximal interphalangeal joint injuries. PMID- 22943249 TI - A low cost model for teaching tendon repair. PMID- 22943250 TI - A simple manoeuvre to minimise bladder injury during laparoscopic incisional hernia repair. PMID- 22943251 TI - A simple aid to fracture reduction in the digit. PMID- 22943252 TI - A simple exercise to encourage precise suture placement. PMID- 22943253 TI - Use a ball-ended anterior cruciate ligament reamer to protect patella tendon during minimal access tibial nailing. PMID- 22943254 TI - Akin osteotomy: good staple positioning. PMID- 22943255 TI - Soft tissue protection from exposed K-wires. PMID- 22943256 TI - Novel use of a single port laparoscopic surgery device for minimally invasive pancreatic necrosectomy. PMID- 22943257 TI - Cardiopulmonary exercise testing provides a predictive tool for early and late outcomes in abdominal aortic aneurysm patients. PMID- 22943260 TI - Microbes and gases in natural environments: an annotated selection of World Wide Web sites relevant to the topics in environmental microbiology. PMID- 22943259 TI - Classification of rare bleeding disorders (RBDs) based on the association between coagulant factor activity and clinical bleeding severity. PMID- 22943261 TI - Enhanced efficacy and specificity of epithelial ovarian carcinogenesis by embedding a DMBA-coated cloth strip in the ovary of rat. AB - BACKGROUND: Ovarian cancer is predominant of epithelial cell origin and often present at an advanced stage with poor prognosis. Most animal models of ovarian carcinoma yield thecal/granulose cell tumors, rather than adenocarcinomas. The best reported induction rate of adenocarcinoma in rats is 10-45% by an ovarian implantation of 7, 12-dimethylbenz[a]anthracene (DMBA) coated silk suture. We provided an improved procedure to construct the model by the ovarian implantation of DMBA-coated cloth strip. METHODS: A sterile suture (as S group) or a piece of cloth strip (as CS group) was soaked in DMBA before ovarian implantation in Wistar rats. Tumor size, incidence rate and pathological type were analyzed. RESULTS: Ovarian tumors in rats of CS group were first noted at 16 wk post implantation and reached a cumulative incidence of 75% (96/128) at 32 wk, while the tumor incidence rate in S group at 32 wk was only 46.25% (37/80). The tumor size in CS group (3.63 +/- 0.89 cm) was larger than that of S group (2.44 +/- 1.89 cm) (P < 0.05). In CS group, there were only two types of tumor formed: adenocarcinoma (90/96) and sarcoma (6/96). While in S group, there were different types, including adenocarcinoma (21/37), squamous carcinoma (3/37), granulosa cell tumor (3/37), sarcoma (4/37), undifferentiated carcinoma with no adeno character (2/37), benign ovarian tumor (2/37), and malignant teratoma (1/37). CONCLUSION: The model in our study yields much higher incidence and specificity of epithelial derived tumors and showed histological similarities to human ovarian cancers, which would be more suitable for therapeutic research. PMID- 22943262 TI - Gross morphology and histology of head and salivary apparatus of the predatory bug, Rhynocoris marginatus. AB - Rhynocoris marginatus Fabricius (Hemiptera: Reduviidae) is an important biological control agent against more than 25 insect pests in India. For a better understanding of the feeding adaptation of this bug, the gross morphology and histology of its head and salivary apparatus were studied using both a light microscope and scanning electron microscope. The head is more or less elongate, mobile, and immersed into the eyes. R. marginatus has a three-segmented curved rostrum; the middle segment is longer than the other two segments. The terminal rostral segment bears spines and trichobothria externally. Stylet bundles bear two pairs of maxillary and mandible stylets in the curved rostrum with serrations. The stylets help to penetrate into the tissue and directly pump the toxic venomous saliva deep into the prey. The principal gland is bi-lobed (anterior lobe and posterior lobe), whereas the accessory gland is uni-lobed, exhibiting distinct functional and histological differences. These glands receive tracheal and nerve supply. Mononucleated, binucleated, trinucleated and polynucleated cells are distributed both in anterior and posterior lobes of the principal gland. The cytoplasm has collecting vacuoles with secretions. Therefore, this predator is highly equipped with well-developed mouthparts that are attached to the salivary apparatus. PMID- 22943263 TI - Pulmonary embolism and the use of vena cava filters after major trauma. AB - BACKGROUND: Major trauma patients are at significant risk of developing pulmonary embolism (PE). We aimed to (i) analyse the current incidence and timing of PE after injury; (ii) identify risk factors that predispose major trauma patients to the occurrence of PE; and (iii) describe the use of vena cava filters (VCFs) following major trauma. METHODS: Prospectively collected data from The Alfred Hospital's Trauma Registry were used to identify all major trauma patients admitted over a 7-year period. A multivariable logistic regression model was used to identify factors associated with the occurrence of PE. A similar model was developed to identify factors associated with the use of VCFs inserted at the discretion of the treating clinician. RESULTS: A total of 6344 major trauma patients were treated during this period, with 73.2% male, mean age of 44.2, 90.2% with a blunt mechanism of injury and mean injury severity score of 24.3. Prophylactic VCFs were inserted in 511 patients (8.1%), with a mean time to insertion of 3.6 days after injury. There were 45 PE, 2 of which were fatal. The mean time to PE was 12 days post-injury. Three variables were independently associated with the occurrence of PE: the absence of a VCF; number of injuries to the lower limb; and central venous catheterization. CONCLUSION: The PE rate was 0.71%. Lower limb injuries and central venous catheterization are independently associated with a higher risk of PE after major trauma and VCFs are associated with a reduced risk. PMID- 22943264 TI - Diurnal variation of tension-type headache intensity and exacerbation: An investigation using computerized ecological momentary assessment. AB - BACKGROUNDS: Tension-type headache is a common psychosomatic disease. However, diurnal variation of headache is yet to be clarified, perhaps due to the lack of an appropriate method to investigate it. Like other painful diseases, it would be helpful to know if there is diurnal variation in tension-type headaches, both for managing headaches and understanding their pathophysiology. The aim of this study was to determine if there is diurnal variation in the intensity and exacerbation of tension-type headache. METHODS: Patients (N = 31) with tension-type headache recorded for one week their momentary headache intensity several times a day and their acute headache exacerbations using a watch-type computer as an electronic diary (computerized ecological momentary assessment). Multilevel modeling was used to test the effects of time of day on momentary headache intensity and on the occurrence of acute exacerbations. RESULTS: A significant diurnal variation in momentary headache intensity was shown (P = 0.0005), with the weakest headaches in the morning and a peak in the late afternoon. A between-individual difference in the diurnal pattern was suggested. On-demand medication use was associated with a different diurnal pattern (P = 0.025), suggesting that headache intensity decreases earlier in the evening in subjects who used on-demand medication, while headache subtype, prophylactic medication use, and sex were not associated with the difference. The occurrence of acute headache exacerbation also showed a significant diurnal variation, with a peak after noon (P = 0.0015). CONCLUSIONS: Tension-type headache was shown to have a significant diurnal variation. The relation to pathophysiology and psychosocial aspects needs to be further explored. PMID- 22943265 TI - The pre-travel visit should start with a "risk conversation". PMID- 22943266 TI - Acclimatizing with acetazolamide. PMID- 22943267 TI - The reliability of pre-travel history to decide on appropriate counseling and vaccinations: a prospective study. AB - BACKGROUND: Although medical and travel plans gathered from pre-travel interviews are used to decide the provision of specific pre-travel health advice and vaccinations, there has been no evaluation of the relevance of this strategy. In a prospective study, we assessed the agreement between pre-travel plans and post travel history and the effect on advice regarding the administration of vaccines and recommendations for malaria prevention. METHODS: We included prospectively all consenting adults who had not planned an organized tour. Pre- and post-travel information included questions on destination, itineraries, departure and return dates, access to bottled water, plan of bicycle ride, stays in a rural zone, and close contact with animals. The outcomes measured included: agreement between pre and post-travel itineraries and activities; and the effect of these differences on pre-travel health recommendations, had the traveler gone to the actual versus intended destinations for actual versus intended duration and activities. RESULTS: Three hundred and sixty-five travelers were included in the survey, where 188 (52%) were males (median age 38 years). In 81(23%) travelers, there was no difference between pre- and post-travel history. Disagreement between pre- and post-travel history were the highest for stays in rural zones or with local people (66% of travelers), close contact with animals (33%), and bicycle riding (21%). According to post-travel history, 125 (35%) travelers would have needed rabies vaccine and 9 (3%) typhoid fever vaccine. Potential overprovision of vaccine was found in <2% of travelers. A change in the malaria prescription would have been recommended in 18 (5%) travelers. CONCLUSIONS: Pre-travel history does not adequately reflect what travelers do. However, difference between recommendations for the actual versus intended travel plans was only clinically significant for the need for rabies vaccine. Particular attention during pre travel health counseling should focus on the risk of rabies, the need to avoid close contact with animals and to seek care for post-exposure prophylaxis following an animal bite. PMID- 22943268 TI - Pregnancy course and outcome in women traveling to developing countries. AB - BACKGROUND: The issue of travel to developing countries during pregnancy has not been sufficiently studied. The aim of this study is to investigate the rate, course, and outcome of pregnancies in women who traveled to developing countries while pregnant, or became pregnant during such travel. METHODS: Women visiting two major travel clinics in Israel for consultation within the years 2004 to 2009, who were pregnant or declared an intention of becoming pregnant during travel were contacted. This was followed by a telephone interview by an obstetrician with those women who were actually pregnant. Background characteristics, morbidity during travel, and pregnancy course and outcome were collected. RESULTS: Overall 52,430 travelers' records had been screened. Of these, we identified 49 women who were pregnant during their trip, but 3 declined participation. Of the remaining 46 women, 33 were pregnant at departure, and 13 conceived during travel. The incidence of pregnancy during travel was thus 0.93/1000 travelers. Thirty-three women traveled to East Asia, 8 to South and Central America, 5 to Africa. More than two thirds of women received pretravel vaccinations. Adherence to the World Health Organization recommendations regarding food and drink was high (87%) and travelers' diarrhea occurred in only 11% of women. Five of 22 women traveling to malarious areas had taken antimalarial prophylaxis. Six women required medical therapy during travel. Pregnancy outcome was not different from the normal population except for an unusually low rate of preterm delivery. CONCLUSIONS: In this cohort, travel to developing countries was not associated with adverse pregnancy outcome. Larger studies are needed to support these findings. PMID- 22943269 TI - Estimated imported infections of Chikungunya and Dengue in Italy, 2008 to 2011. AB - BACKGROUND: In temperate countries, where the competent vector is present, the risk of introduction and transmission of Chikungunya (CHIKV) and Dengue (DENV) cases is particularly high. Thus, epidemiological surveillance is crucial to rapidly identify imported cases in order to introduce measures to reduce mosquito density in the area. METHODS: We analyze imported cases of CHIKV and DENV reported to the National Institute of Health (ISS) and the Ministry of Health, from January 2008 through October 2011 within the National Surveillance system in Italy. Moreover, considering the worldwide spread of DENV and CHIKV and the consequent importation of cases in Italy we estimate the number of imported cases using data on airport arrivals of travelers to the Italian international airports. RESULTS: From January 2008 to October 2011 a total of 130 cases of DENV/CHIKV were reported in travelers returning to Italy. In our study, 42.8% of CHIKV cases were imported from Indian Ocean Islands (Mauritius, Maldives, Bali, and Sri Lanka), whereas, for DENV 40.4% of imported cases reported to have visited Asia within the incubation period. The estimated number of exposed travelers to CHIKV and DENV arriving in Italy was higher compared to notified cases, suggesting a possible underestimation of the real number of imported cases. CONCLUSIONS: Integrated human and entomological surveillance is crucial to monitor the spread of emerging vector-borne diseases and to implement public health measures in order to avoid transmission and control such diseases in humans. PMID- 22943270 TI - Acetazolamide for the prevention of acute mountain sickness--a systematic review and meta-analysis. AB - BACKGROUND: Acetazolamide has been reported to be effective in the prevention of acute mountain sickness (AMS). Our aim was to conduct a systematic review of randomized, placebo-controlled trials of acetazolamide in the prevention of AMS. METHODS: Studies were identified by searching the MEDLINE, Embase, Cochrane Clinical Trials Register, and ClinicalTrials.gov databases. Primary end point was difference in incidence of AMS between acetazolamide and placebo groups. RESULTS: Acetazolamide prophylaxis was associated with a 48% relative-risk reduction compared to placebo. There was no evidence of an association between efficacy and dose of acetazolamide. Adverse effects were often not systematically reported but appeared to be common but generally mild. One study found that adverse effects of acetazolamide were dose related. CONCLUSIONS: Acetazolamide is effective prophylaxis for the prevention of symptoms of AMS in those going to high altitude. A dose of 250 mg/day has similar efficacy to higher doses and may have a favorable side-effect profile. PMID- 22943271 TI - Tadalafil and acetazolamide versus acetazolamide for the prevention of severe high-altitude illness. AB - We report an open-label study comparing tadalafil and acetazolamide (n = 24) versus acetazolamide (n = 27) for prevention of high-altitude illness (HAI) at Mt. Kilimanjaro. Tadalafil group had lower rates of severe HAI compared with controls (4% vs 26%, p = 0.03), mostly because of decreased high-altitude pulmonary edema rates (4% vs 22%, p = 0.06). PMID- 22943272 TI - Prevalence of carriers of Neisseria meningitidis among migrants: is migration changing the pattern of circulating meningococci? AB - To evaluate the prevalence of carriers of Neisseria meningitidis and circulating serogroups, 253 African refugee residents in the Asylum Seeker Center of Bari, Italy, were enrolled. Thirteen subjects (5.1%) were identified as carriers of meningococci. Six (46.1%) strains were autoagglutinable, four (30.8%) belonged to serogroup W135, and three (23.1%) to serogroup Y. PMID- 22943273 TI - A Case of loiasis in a patient returning to China diagnosed by nested PCR using DNA extracted from tissue. AB - Recognition and diagnosis of loiasis is problematic in areas where this infection is not endemic but may be imported. A previously healthy Chinese male returned from Equatorial Guinea presenting with migratory masses. He was diagnosed with loiasis following detection of Loa loa by nested polymerase chain reaction using DNA extracted from tissue. PMID- 22943274 TI - Fever with rash in patients returning from popular tourist resort Phuket, Thailand: dengue--or measles? AB - We report three recent cases of measles in travelers to a popular vacation resort, Phuket, Thailand, two initially diagnosed clinically as dengue, one as drug reaction. In countries with no indigenous measles, clinicians may no longer recognize the disease. When left misdiagnosed, the patients continue to be potential transmitters. PMID- 22943275 TI - Link between carbapenemase-producing Enterobacteria carriage and cross-border exchanges: eight-year surveillance in a large French multihospitals institution. AB - Assistance Publique-Hopitaux de Paris launched a specific strategy to survey and control the spread of emerging multidrug-resistant bacteria such as carbapenemase producing Enterobacteria (CPE). Among the 63 CPE events that occurred between 2004 and 2011, 87% involved patients with a link with cross-border exchanges, justifying the recommendation to screen and isolate such patients. PMID- 22943276 TI - Psychological problems for non-Japanese speaking patients in Japan. AB - The psychological problems of non-Japanese people are becoming more outstanding, in accordance with the increase of foreign nationals in Japan. Five illustrative cases of English-speaking patients were analyzed, from the viewpoint of psychosomatic medicine. The most common psychiatric disorders were adjustment disorders, because of the cultural differences and language barriers. PMID- 22943277 TI - The sunny side of lime. AB - A 26-year-old woman was affected with a maculopapular rash because of a jellyfish sting on her right leg while surfing in Indonesia. A locally-prepared liniment was applied on the affected skin. She presented with hyperpigmented linear tracks that she noted a few days later. PMID- 22943278 TI - Isolated subcutaneous tuberculous abscesses of the lumbar wall. PMID- 22943279 TI - Lessons at 30,000 feet. PMID- 22943280 TI - Ceftazidime for respiratory infections. AB - INTRODUCTION: Ceftazidime is a third-generation cephalosporin that has activity against Gram-negative bacilli, including Pseudomonas aeruginosa. The increasing prevalence of antimicrobial resistance and the limited number of antimicrobial agents in development have necessitated a review of the current status of treatments involving ceftazidime. AREAS COVERED: This review focuses on studies examining the in vitro antibacterial activity of ceftazidime against recent clinical isolates and recent randomized controlled trials studying the clinical efficacy of ceftazidime, and discusses strategies for the optimal use of ceftazidime for treating respiratory tract infections, mainly hospital-acquired pneumonia (HAP). EXPERT OPINION: Although ceftazidime remains an important option for HAP treatment, its role as an effective antimicrobial agent has been compromised by the sharp increase in resistance rates over the last decade, especially in P. aeruginosa and Acinetobacter baumannii. To maintain or improve the clinical use of ceftazidime in patients with severe HAP, it will be essential to gain a thorough understanding of local resistance patterns, reserve ceftazidime use when pathogens are susceptible to other third-generation cephalosporins, optimize ceftazidime therapy using prolonged or continuous infusion, determine the effectiveness of the combination of ceftazidime with inhibitors of broad-spectrum beta-lactamases and role of combination therapy for P. aeruginosa infections, and judiciously use antimicrobial agents through individualization of antimicrobial therapy for HAP. PMID- 22943281 TI - What is wrong with this picture? PMID- 22943282 TI - Methylenetetrahydrofolate reductase polymorphisms and risk of acute lymphoblastic leukemia-evidence from an updated meta-analysis including 35 studies. AB - BACKGROUND: 5,10-methylenetetrahydrofolate reductase (MTHFR) variants, C677T and A1298C, have been reported to be associated with decreased risk of acute lymphoblastic leukemia (ALL). However, results derived from individually underpowered studies are conflicting. We carried out an updated meta-analysis on the association between MTHFR polymorphisms and ALL risk. METHODS: Relevant publications were searched through PUBMED and EMBASE databases. The associations between MTHFR C677T and A1298C polymorphisms and the risk of ALL were evaluated by odds ratios (ORs). The heterogeneity and publication bias were estimated. Meta regression analysis was performed to evaluate the potential sources of heterogeneity. RESULTS: C677T polymorphism was associated with a reduced risk of ALL (allele contrast: ORRE = 0.91, 95% CI: 0.83-0.99). Subgroup analysis showed MTHFR C677T variant was associated with decreased susceptibility to ALL in children and Caucasians. Meta-regression showed the logOR for the association between T allele and ALL increased as sex ratio (M/F) in the case group increased (P = 0.01). Regarding A1298C polymorphism, no significant association was observed (allele contrast: ORRE = 1.01, 95% CI: 0.91-1.11). There was no publication bias for C677T or A1298C polymorphism. CONCLUSIONS: The present meta analysis suggests that the C677T polymorphism, not A1298C, in MTHFR gene is associated with a decreased risk of ALL, particularly among children and Caucasians subjects. Our findings suggest that the influence of the C677T polymorphism on ALL susceptibility is modified by sex ratio in cases (M/F). Since folate intake may be a possible confounding factor, including this factor in future prospective studies is warranted. Further meta-analysis studies should be at least stratified for folate levels and gender to give more powerful and informative results. PMID- 22943283 TI - CerealsDB 2.0: an integrated resource for plant breeders and scientists. AB - BACKGROUND: Food security is an issue that has come under renewed scrutiny amidst concerns that substantial yield increases in cereal crops are required to feed the world's booming population. Wheat is of fundamental importance in this regard being one of the three most important crops for both human consumption and livestock feed; however, increase in crop yields have not kept pace with the demands of a growing world population. In order to address this issue, plant breeders require new molecular tools to help them identify genes for important agronomic traits that can be introduced into elite varieties. Studies of the genome using next-generation sequencing enable the identification of molecular markers such as single nucleotide polymorphisms that may be used by breeders to identify and follow genes when breeding new varieties. The development and application of next-generation sequencing technologies has made the characterisation of SNP markers in wheat relatively cheap and straightforward. There is a growing need for the widespread dissemination of this information to plant breeders. DESCRIPTION: CerealsDB is an online resource containing a range of genomic datasets for wheat (Triticum aestivum) that will assist plant breeders and scientists to select the most appropriate markers for marker assisted selection. CerealsDB includes a database which currently contains in excess of 100,000 putative varietal SNPs, of which several thousand have been experimentally validated. In addition, CerealsDB contains databases for DArT markers and EST sequences, and links to a draft genome sequence for the wheat variety Chinese Spring. CONCLUSION: CerealsDB is an open access website that is rapidly becoming an invaluable resource within the wheat research and plant breeding communities. PMID- 22943285 TI - The complete mitochondrial genome of Glyptothorax fukiensis fukiensis (Teleostei, Siluriformes: Sisoridae). AB - The Glyptothorax fukiensis fukiensis is distributed widely in South China, e.g., Yangtze River, Pearl River, even Hainan Province, so it is a good model to study population genetics and historical biogeography. In this study, the complete mitochondrial genome sequence of G. fukiensis fukiensis has been obtained with PCR, which contains 13 protein-coding genes, 22 tRNA genes, 2 rRNA genes, and a non-coding control region with the total length of 16,530 bp. The gene arrangement and composition are similar to most of other vertebrates. Most of the genes are encoded on heavy strand, except for eight tRNA and ND6 genes. Just like most other vertebrates, the bias of G and C has a universality in different statistics results. The complete mitochondrial genome sequence of G. fukiensis fukiensis is the first report for Sisoridae, it would contribute to better understand population genetics, biogeography, and evolution of this lineage. PMID- 22943284 TI - 2-APB-potentiated channels amplify CatSper-induced Ca(2+) signals in human sperm. AB - Ca2+i signalling is pivotal to sperm function. Progesterone, the best characterized agonist of human sperm Ca2+i signalling, stimulates a biphasic [Ca2+]i rise, comprising a transient and subsequent sustained phase. In accordance with recent reports that progesterone directly activates CatSper, the [Ca2+]i transient was detectable in the anterior flagellum (where CatSper is expressed) 1-2 s before responses in the head and neck. Pre-treatment with 5 MUM 2-APB (2-aminoethoxydiphenyl borate), which enhances activity of store-operated channel proteins (Orai) by facilitating interaction with their activator [STIM (stromal interaction molecule)] 'amplified' progesterone-induced [Ca2+]i transients at the sperm neck/midpiece without modifying kinetics. The flagellar [Ca2+]i response was unchanged. 2-APB (5 MUM) also enhanced the sustained response in the midpiece, possibly reflecting mitochondrial Ca2+ accumulation downstream of the potentiated [Ca2+]i transient. Pre-treatment with 50-100 MUM 2 APB failed to potentiate the transient and suppressed sustained [Ca2+]i elevation. When applied during the [Ca2+]i plateau, 50-100 MUM 2-APB caused a transient fall in [Ca2+]i, which then recovered despite the continued presence of 2-APB. Loperamide (a chemically different store-operated channel agonist) enhanced the progesterone-induced [Ca2+]i signal and potentiated progesterone induced hyperactivated motility. Neither 2-APB nor loperamide raised pHi (which would activate CatSper) and both compounds inhibited CatSper currents. STIM and Orai were detected and localized primarily to the neck/midpiece and acrosome where Ca2+ stores are present and the effects of 2-APB are focussed, but store operated currents could not be detected in human sperm. We propose that 2-APB sensitive channels amplify [Ca2+]i elevation induced by progesterone (and other CatSper agonists), amplifying, propagating and providing spatio-temporal complexity in [Ca2+]i signals of human sperm. PMID- 22943286 TI - Biting injuries and transmission of Tasmanian devil facial tumour disease. AB - The Tasmanian devil is threatened with extinction by devil facial tumour disease (DFTD), a unique infectious cancer in which the tumour cells themselves, which derive from a single long-dead host devil, are the infective agent and the tumour is an infectious parasitic cell line. Transmission is thought to occur via direct inoculation of tumour cells when susceptible and infected individuals bite each other or by fomitic transfer of tumour cells. The nature of transmission and the extent to which biting behaviour and devil ecology is associated with infection risk remains unclear. Until our recent study in north-west Tasmania showed reduced population and individual impacts, DFTD had caused massive population declines in all populations monitored. In this paper, we investigate seasonal patterns of injuries resulting from bites between individuals, DFTD infection status and tumour location in two populations to determine whether the number of bites predicts the acquisition of DFTD and to explore the possibility that the reduced impacts of DFTD in north-west Tasmania are attributed to reduced bite rates. Devils with fewer bites were more likely to develop DFTD and primary tumours occurred predominantly inside the oral cavity. These results are not consistent with transmission occurring from the biter to the bitten animal but suggest that dominant individuals delivering bites, possibly by biting the tumours of other devils, are at higher risk of acquiring infection than submissive individuals receiving bites. Bite rates, which were higher during autumn and winter, did not differ between sites, suggesting that the reduced population impacts in north-west Tasmania cannot be explained by lower bite rates. Our study emphasizes the importance of longitudinal studies of individually marked animals for understanding the ecology and transmission dynamics of infectious diseases and parasites in wild populations. PMID- 22943288 TI - The effect of collection and extension on tarsal flexion and fetlock extension at trot. AB - A recent epidemiological study indicated that various factors may be related to injury in dressage horses, but the mechanism by which these injuries occur has yet to be determined. The suspensory ligament (SL) is a frequent site of injury, and it is assumed that greatest strain is placed on this structure in collected trot; this has yet to be proved conclusively. The study aimed to investigate the effect of collected and extended trot on the hindlimb movement pattern. Four dressage horses were fitted with markers and inertial motion sensors (IMS). High speed video was obtained for 2 strides on each rein in collected and extended trot on 3 different surfaces: waxed outdoor; sand/plastic granules; and waxed indoor. Maximal tarsal flexion during stance and distal metatarsal coronary band ratio (MTCR), representing fetlock extension, were determined. Inertial motion sensor data determined stride duration, speed and stride length. Data were compared between collection and extension within horses on each surface, and compared between surfaces. Collected trot had significantly lower speed and stride length but longer stride duration than extended trot on all surfaces. All horses had less tarsal flexion and fetlock extension in collected compared with extended trot (P<0.05), which is likely to increase SL loading. The study findings indicate that extended trot may increase SL strain, providing a possible explanation for the high incidence of SL injury in horses trained for extravagant movement. It is possible that substantial use of extended trot could be a risk factor for development of suspensory desmitis, which might be one contributory factor in the prevalence of suspensory desmitis in young horses repeatedly undertaking extravagant movement. PMID- 22943287 TI - Urinary levels of hepatocarcinoma-intestine-pancreas/pancreatitis-associated protein as a diagnostic biomarker in patients with bladder cancer. AB - BACKGROUND: To assess the possibility of hepatocarcinoma-intestine pancreas/pancreatitis-associated protein (HIP/PAP) as a biological marker for detecting Bladder cancer (BCa), we examined the expression of HIP/PAP in both BCa specimens and BCa cell lines and measured HIP/PAP levels in urine from patients with BCa. METHODS: HIP/PAP expression in BCa samples was evaluated by western blot analysis, and urinary levels of HIP/PAP in patients with BCa were measured by enzyme-linked immunosorbent assay. Urine samples were collected from 10 healthy volunteers and 109 with benign urological disorders as controls, and from 101 patients who were diagnosed with BCa. RESULTS: HIP/PAP was highly expressed in BCa samples as compared with control bladder. Urinary HIP/PAP concentrations were significantly higher in BCa patients than in controls (median value; 3.184 pg/mL vs. 55.200 pg/mL, P <0.0001, by Mann-Whitney U test). Urinary HIP/PAP levels in BCa patients correlated positively with pathological T stages and progression-risk groups among non-muscle invasive BCa (P = 0.0008, by Kruskal Wallis test). Regarding the recurrence-risk classifications of non-muscle invasive BCa, the urinary levels of HIP/PAP were significantly higher in the intermediate than in the low risk group (P = 0.0002, by Mann-Whitney U test). Based on a cut-off of 8.5 pg/mL, the ability of urinary HIP/PAP levels to detect BCa had a sensitivity of 80.2%, specificity of 78.2%, positive predictive value (PPV) of 75.7%, and negative predictive value (NPV) of 82.3%. CONCLUSIONS: HIP/PAP was abundantly expressed in BCa, and the urinary levels of HIP/PAP could be a novel and potent biomarker for detection of BCa, and also for predicting the risks of recurrence- and progression-risk of non-muscle invasive BCa. A large scale study will be needed to establish the usefulness of this biomarker. PMID- 22943289 TI - Initial characterization of shade avoidance response suggests functional diversity between Populus phytochrome B genes. AB - Shade avoidance signaling involves perception of incident red/far-red (R/FR) light by phytochromes (PHYs) and modulation of downstream transcriptional networks. Although these responses are well studied in Arabidopsis, little is known about the role of PHYs and the transcriptional responses to shade in the woody perennial Populus. Tissue expression and subcellular localization of Populus PHYs was studied by quantitative real-time PCR (qRT-PCR) and protoplast transient assay. Transgenic lines with altered PHYB1 and/or PHYB2 expression were used in phenotypic assays and transcript profiling with qRT-PCR. RNA-Seq was used to identify transcriptional responses to enriched FR light. All three PHYs were differentially expressed among tissue types and PHYBs were targeted to the nucleus under white light. Populus PHYB1 rescued Arabidopsis phyB mutant phenotypes. Phenotypes of Populus transgenic lines and the expression of candidate shade response genes suggested that PHYB1 and PHYB2 have distinct yet overlapping functions. RNA-Seq analysis indicated that genes associated with cell wall modification and brassinosteroid signaling were induced under enriched FR light in Populus. This study is an initial attempt at deciphering the role of Populus PHYs by evaluating transcriptional reprogramming to enriched FR and demonstrates functional diversity and overlap of the Populus PHYB1 and PHYB2 in regulating shade responses. PMID- 22943290 TI - From xenograft experiments to xenograft immune responses in cardiac surgery. PMID- 22943291 TI - MARTX of Vibrio vulnificus biotype 2 is a virulence and survival factor. AB - Vibrio vulnificus biotype 2 is a polyphyletic group whose virulence for fish relies on a plasmid. This plasmid contains an rtxA gene duplicated in the small chromosome that encodes a MARTX (Multifunctional, Autoprocessing Repeats-in Toxin) unique within the species in domain structure (MARTX type III). To discover the role of this toxin in the fitness of this biotype in the fish farming environment, single- and double-knockout mutants were isolated from a zoonotic strain and analysed in a series of in vivo and in vitro experiments with eel, fish cell lines and amoebae isolated from gills. Mice, murine and human cell lines were also assayed for comparative purposes. The results suggest that MARTX type III is involved in the lysis of a wide range of eukaryotic cells, including the amoebae, erythrocytes, epithelial cells and phagocytes after bacterium-cell contact. In fish, MARTX type III may act as a toxin involved in the onset of septic shock, while in mice it may promote bacterial colonization by preventing phagocytosis of bacterial cells. Moreover, this toxin could protect bacteria from predation by amoebae, which would increase bacterial survival outside the host and would explain the fitness of this biotype in the fish-farming environment. PMID- 22943292 TI - Antithrombotic phosphoinositide 3-kinase beta inhibitors in humans: a 'shear' delight! PMID- 22943293 TI - Does oral health contribute to post-transplant complications in kidney allograft recipients? AB - OBJECTIVE: The significant number of complications in kidney graft recipients can not be easily explained. The paper assesses whether poor oral health increases the risk of acute rejections and hospitalizations in kidney allograft recipients. MATERIALS AND METHODS: Ninety-one kidney transplant recipients were divided into three sub-groups according to post-transplant time (< 1, 1-5 and > 5 years). Dental examination evaluated oral hygiene index (OHI-S) and Community Periodontal Index of Treatment Needs (CPITN), which were correlated with the occurrence of post-transplant complications. RESULTS: Within the first year after transplantation the indicators of the increased risk of hospitalizations and acute rejection episodes was the OHI-S (hazard ratio 1.02 and 1.11, respectively), also CPITN score correlated with acute rejections (R = 0.82, p < 0.01). CONCLUSION: The neglect in oral health is associated with the increased risk of clinical complications within first year after kidney transplantation. PMID- 22943294 TI - A double patella-like condition secondary to synovial osteochondromatosis. AB - To our knowledge, this is the first case of synovial osteochondromatosis in a patient presenting with a double patella-like condition. The true duplication of the patella, which is called double patella, is extremely rare. In our case, the operative and histopathological findings showed that the double patella-like condition was secondarily induced by synovial osteochondromatosis. Synovial osteochondromatosis should be considered as a differential diagnosis for congenital double patella. PMID- 22943295 TI - Abundance and diversity of soil arthropods in the olive grove ecosystem. AB - Arthropods are part of important functional groups in soil food webs. Recognizing these arthropods and understanding their function in the ecosystem as well as when they are active is essential to understanding their roles. In the present work, the abundance and diversity of soil arthropods is examined in olive groves in the northeast region of Portugal during the spring. Five classes of arthropods were found: Chilopoda, Malacostraca, Entognatha, Insecta, and Arachnida. Captures were numerically dominated by Collembola within Entognatha, representing 70.9% of total captures. Arachnida and Insecta classes represented about 20.4 and 9.0%, respectively. Among the predatory arthropods, the most representative groups were Araneae and Opiliones from Arachnida, and Formicidae, Carabidae, and Staphylinidae from Insecta. From the Formicidae family, Tetramorium semilaeve (Andre 1883), Tapinoma nigerrimum (Nylander 1856), and Crematogaster scutellaris (Olivier 1792) were the most representative ant species. Arthropods demonstrated preference during the day, with 74% of the total individuals recovered in this period, although richness and similarity were analogous during the day and night. PMID- 22943296 TI - Agonistic effect of polyunsaturated fatty acids (PUFAs) and its metabolites on brain-derived neurotrophic factor (BDNF) through molecular docking simulation. AB - BACKGROUND: Brain-derived neurotrophic factor (BDNF) is a potent neurotrophic factor that is implicated in the regulation of food intake and body weight. Polyunsaturated fatty acids (PUFAs) localised in cell membranes have been shown to alter the levels of BDNF in the brain, suggesting that PUFAs and BDNF could have physical interaction with each other. To decipher the molecular mechanism through which PUFAs modulates BDNF's activity, molecular docking was performed for BDNF with PUFAs and its metabolites, with 4-Methyl Catechol as a control. RESULTS: Inferring from molecular docking studies, lipoxin A4 (LXA4), and a known anti-inflammatory bioactive metabolite derived from PUFAs, with a binding energy of -3.98 Kcal/mol and dissociation constant of 1.2 mM showed highest binding affinity for BDNF in comparison to other PUFAs and metabolites considered in the study. Further, the residues Lys 18, Thr 20, Ala 21, Val 22, Phe 46, Glu 48, Lys 50, Lys 58, Thr 75, Gln 77, Arg 97 and Ile 98 form hot point motif, which on interaction enhances BDNF's function. CONCLUSION: These results suggest that PUFAs and their metabolites especially, LXA4, modulate insulin resistance by establishing a physical interaction with BDNF. Similar interaction(s) was noted between BDNF and resolvins and protectins but were of lesser intensity compared to LXA4. PMID- 22943297 TI - Turning pipe dreams into reality. AB - A report on the Galaxy Community Conference at the University of Illinois, Chicago, July 25-27, 2012. PMID- 22943300 TI - Unvaccinated children in years of increasing coverage: how many and who are they? Evidence from 96 low- and middle-income countries. AB - OBJECTIVE: While childhood immunisation coverage levels have increased since the 70s, inequities in coverage between and within countries have been widely reported. Unvaccinated children remain undetected by routine monitoring systems and strikingly unreported. The objective of this study was to provide evidence on the magnitude of the problem and to describe predictors associated with non vaccination. METHODS: Two hundred and forty-one nationally representative household surveys in 96 countries were analysed. Proportions and changes in time of 'unvaccinated' (children having not received a single dose of vaccine), 'partially vaccinated' and 'fully vaccinated' children were estimated. Predictors of non-vaccination were explored. RESULTS: The percentage of unvaccinated children was 9.9% across all surveys. 66 countries had more than one survey: 38 showed statistically significant reductions in the proportion of unvaccinated children between the first and last survey, 10 countries showed increases and the rest showed no significant changes. However, while 18 of the 38 countries also improved in terms of partially and fully vaccinated, in the other 20 the proportion of fully vaccinated decreased. The predictors more strongly associated with being unvaccinated were education of the caregiver, education of caregiver's partner, caregiver's tetanus toxoid (TT) status, wealth index and type of family member participation in decision-making when the child is ill. Multivariable logistic regression identified the TT status of the caregiver as the strongest predictors of unvaccinated children. Country-specific summaries were produced and sent to countries. CONCLUSION: The number of unvaccinated children is not negligible and their proportion and the predictors of non-vaccination have to be drawn from specific surveys. Specific vaccine indicators cannot properly describe the performance of immunisation programmes in certain situations. National immunisation programmes and national and international immunisation stakeholders should also consider monitoring the proportion of unvaccinated children (i.e. those who have received no vaccines at all) and draw specific plans on the determinants of non-vaccination. PMID- 22943301 TI - Frequency of antibodies to Toxocara in Cuban schoolchildren. AB - OBJECTIVE: The aim of the study was to determine the frequency of antibodies to Toxocara in Cuban schoolchildren. METHODS: The frequency of antibodies to Toxocara canis was assessed with a commercial enzyme-linked immunosorbent assays kit in school-aged children from two municipalities of Cuba. Univariate analysis and a multivariable logistic regression analysis adjusted for age, sex, municipality and co-infection with helminth and/or protozoa were conducted. RESULTS: The percentage of children with antibodies to Toxocara was 38.8% (392/1011; 95% CI = 36.8-42.8). Antibody positivity was significantly associated with gender and co-infections with intestinal parasites, but not with age or municipality. CONCLUSION: Cuban children are highly exposed to the Toxocara parasite, corresponding well with reported environmental contamination with Toxocara parasite eggs and T. canis prevalences in dogs in Cuba. Relevant policy makers and the Cuban population need to be better informed about this preventable infection. PMID- 22943302 TI - Cost of standard indoor ultra-low-volume space spraying as a method to control adult dengue vectors. AB - OBJECTIVES: To access the costs of standard indoor ultra-low-volume (SID-ULV) space spraying for controlling dengue vectors in Thailand. METHODS: Resources related to SID-ULV space spraying as a method to control dengue vectors between July and December 2009 were identified, measured and valued taking a societal perspective into consideration. Information on costs was collected from direct observations, interviews and bookkeeping records. Uncertainty of unit costs was investigated using a bootstrap technique. RESULTS: Costs of SID-ULV were calculated from 18 new dengue cases that covered 1492 surrounding houses. The average coverage of the SID-ULV was 64.4%. In the first round of spraying, 53% of target houses were sprayed and 44.6% in the second round, of which 69.2% and 54.7% received entire indoor space spraying. Unit costs per case, per 10 houses and per 100 m(2) were USD 705 (95% Confidence Interval CI, 539-888), 180 (95% CI, 150-212) and USD 23 (95% CI, 17-30). The majority of SID-ULV unit cost per case was attributed to productivity loss (83.9%) and recurrent costs (15.2%). The unit cost of the SID-ULV per case and per house in rural was 2.8 and 1.6 times lower than municipal area. The estimated annual cost of SID-ULV space spraying from 2005 to 2009 using healthcare perspective ranged from USD 5.3 to 10.3 million. CONCLUSIONS: The majority of the cost of SID-ULV space spraying was attributed to productivity loss. Potential productivity loss influences the achievement of high coverage, so well-planned SID-ULV space spraying strategies are needed to reduce costs. PMID- 22943299 TI - Review: analysis of parasite and other skewed counts. AB - OBJECTIVE: To review methods for the statistical analysis of parasite and other skewed count data. METHODS: Statistical methods for skewed count data are described and compared, with reference to a 10-year period of Tropical Medicine and International Health (TMIH). Two parasitological datasets are used for illustration. RESULTS: The review of TMIH found 90 articles, of which 89 used descriptive methods and 60 used inferential analysis. A lack of clarity is noted in identifying the measures of location, in particular the Williams and geometric means. The different measures are compared, emphasising the legitimacy of the arithmetic mean for the skewed data. In the published articles, the t test and related methods were often used on untransformed data, which is likely to be invalid. Several approaches to inferential analysis are described, emphasising (1) non-parametric methods, while noting that they are not simply comparisons of medians, and (2) generalised linear modelling, in particular with the negative binomial distribution. Additional methods, such as the bootstrap, with potential for greater use are described. CONCLUSIONS: Clarity is recommended when describing transformations and measures of location. It is suggested that non parametric methods and generalised linear models are likely to be sufficient for most analyses. PMID- 22943303 TI - Alcohol consumption policies and the prevention of alcohol consumption-related problems: needs, duties, and responsibilities. AB - Alcohol-related policies and the prevention of alcohol use-related problems, as well as their creation, are accomplished through planned interventions- laws, social and health programs, community-based initiatives-as well as through complex social movements and efforts implemented by the communities. Among both citizens and alcohol use intervention experts, the following three human dimensions are considered: needs, duties, and responsibilities. PMID- 22943304 TI - Examining a home environmental strategy to reduce availability of legal products that can be misused by youth. AB - This article presents results from a study of a home environmental strategy (HES) designed to reduce availability of harmful legal products (HLPs) in the home that can be used by youth to get high. HLPs include inhalants, prescription and nonprescription drugs, and household products that can be ingested to get high. Availability is one of the most consistent predictors of substance use among youth. Parents of 5th- to 7th-grade students in four Alaskan communities participated in telephone interviews as part of a larger study of a multicomponent community prevention model (CPM) that included a HES. The strategy was designed to encourage parents to reduce availability of HLPs by removing them from the home, and by locking up and monitoring the supplies of HLPs in the home. Data from 402 parents at Wave 1 and 371 parents at Wave 2 were analyzed using hierarchical non-Linear modeling (HNLM). Results show there was a significant decrease in HLPs in the home from Wave 1 to Wave 2, mostly inhalants and prescription and nonprescription drugs. Parents also reported a significant increase in locking up prescription and nonprescription drugs in the home. Parents' direct exposure to the HES was marginally associated with the change over time in HLP availability in the home. Indirect exposure through others and media was not associated with this change. Study lessons learned and conclusions are highlighted. PMID- 22943305 TI - Radiation-induced glioma following CyberKnife(r) treatment of metastatic renal cell carcinoma: a case report. AB - INTRODUCTION: Post-stereotactic radiation-induced neoplasms, although relatively rare, have raised the question of benefit regarding CyberKnife(r) treatments versus the risk of a secondary malignancy. The incidence of such neoplasms arising in the nervous system is thought to be low, given the paucity of case reports regarding such secondary lesions. CASE PRESENTATION: Here we describe a case of a 43-year-old Middle Eastern woman with primary clear cell renal cell carcinoma and a metastatic focus to the left brain parenchyma who presented with focal neurologic deficits. Following post-surgical stereotactic radiation in the region of the brain metastasis, the patient developed a secondary high-grade astrocytoma nearly 5 years after the initial treatment. CONCLUSION: Although the benefit of CyberKnife(r) radiotherapy treatments continues to outweigh the relatively low risk of a radiation-induced secondary malignancy, knowledge of such risks and a review of the literature are warranted. PMID- 22943306 TI - Involvement of thioredoxin y2 in the preservation of leaf methionine sulfoxide reductase capacity and growth under high light. AB - Methionine (Met) in proteins can be oxidized to two diastereoisomers of methionine sulfoxide, Met-S-O and Met-R-O, which are reduced back to Met by two types of methionine sulfoxide reductases (MSRs), A and B, respectively. MSRs are generally supplied with reducing power by thioredoxins. Plants are characterized by a large number of thioredoxin isoforms, but those providing electrons to MSRs in vivo are not known. Three MSR isoforms, MSRA4, MSRB1 and MSRB2, are present in Arabidopsis thaliana chloroplasts. Under conditions of high light and long photoperiod, plants knockdown for each plastidial MSR type or for both display reduced growth. In contrast, overexpression of plastidial MSRBs is not associated with beneficial effects in terms of growth under high light. To identify the physiological reductants for plastidial MSRs, we analyzed a series of mutants deficient for thioredoxins f, m, x or y. We show that mutant lines lacking both thioredoxins y1 and y2 or only thioredoxin y2 specifically display a significantly reduced leaf MSR capacity (-25%) and growth characteristics under high light, related to those of plants lacking plastidial MSRs. We propose that thioredoxin y2 plays a physiological function in protein repair mechanisms as an electron donor to plastidial MSRs in photosynthetic organs. PMID- 22943307 TI - Operating principles for running a clinical quality registry: are they feasible? AB - BACKGROUND: The National Breast Cancer Audit (NBCA) was one of six national registries selected by open tender to test and validate the draft Operating Principles and Technical Standards for Australian Clinical Quality Registries. The standardization proposed by the Australian Commission on Safety and Quality in Health Care through this initiative sought to improve the overall efficiency and function of registries, as well as compatibility between registries. The NBCA's role involved testing, and implementing where possible, the proposed principles and standards in the NBCA environment so as to validate them in an operating registry. METHODS: The forty-two draft operating principles were evaluated by the NBCA based on four factors: relevance to the audit, feasibility of implementation by the audit, extent of difficulty in implementation and extent of improvement. An evaluation of the technical standards was also conducted. RESULTS: At the completion of the project, the audit met 27 of the 42 draft principles with only three principles marked as entirely unfeasible or not relevant to the NBCA. The remaining principles were either in the process of being implemented, implemented in part or awaiting discussion through governance channels. CONCLUSION: A revised principles and standards document has been produced. This will have a significant impact on quality of care in Australia as more audits and registries use it as a guide. Changes implemented at the NBCA have enhanced the audit as a tool for improving the quality of care received by early breast cancer patients. PMID- 22943308 TI - Engineering 3D cell-culture matrices: multiphoton processing technologies for biological and tissue engineering applications. AB - Cells respond to topographical, mechanical and biochemical characteristics of the surrounding environment. Capability to reconstruct these factors individually, and also acting in accord, would facilitate systematic investigations of a multitude of related biological and tissue engineering questions. The subject of the present review is a group of technologies allowing realization of customized cell-culture matrices. These methods utilize photochemistry induced by multiphoton absorption and are carried out using essentially identical equipment. Fabrication of 2D microstructured substrates, complex 3D scaffolds, containing actively induced topographies, and immobilization of biomolecules in a spatially defined manner was demonstrated with these techniques. The reviewed reports indicate that multiphoton processing is a promising technology platform for the development of standard biomimetic microenvironments for 3D cell culture. PMID- 22943309 TI - Complete mitogenome of the deep-sea hydrothermal vent shrimp Alvinocaris chelys Komai and Chan, 2010 (Decapoda: Caridea: Alvinocarididae). AB - We reported the complete sequence of the mitochondrial (mt) genome of the deep sea vent shrimp Alvinocaris chelys. This is the first complete mt genome obtained for the hydrothermal vent shrimp. The gene arrangement of the A. chelys mt genome is identical to the pancrustacean ground pattern as in most of the other caridean shrimp mt genomes available to date. However, there is an exceptionally long intergene spacer (86 bp in length) existed between the ND1 and tRNA(Leu)-CUN genes that is not previously reported. Our results provide further evidence that the mt gene order is highly conserved among caridean shrimp, in contrast to the other decapod infraorder such as Brachyura or Anomura which are of comparable or lower diversity. PMID- 22943310 TI - Early molecular responses of bone to obstructive nephropathy induced by unilateral ureteral obstruction in mice. AB - AIM: This study was performed to address the bone injury and the early molecular responses of bone to obstructive nephropathy induced by unilateral ureteral obstruction in mice. METHODS: The male mice were subjected to unilateral ureteral obstruction (UUO, n = 10) or sham operation (n = 10). All mice were killed on day 7 after the surgical operation. Hematoxylin and eosin and tartate-resistant acid phosphatase staining were performed on paraffin-embedded bone sections. Expression of genes and proteins was analyzed by reverse transcription-polymerase chain reaction, and Western blotting and immunohistochemistry staining, respectively. RESULTS: The serum calcium level was significantly reduced in UUO mice compared with that of Sham mice. The proximal tibia of UUO mice exhibited the increased expansion of chondrocytes zone, the reduction of osteoid content, and the increased separation and disconnection of woven bones. Reverse transcription-polymerase chain reaction results showed the downregulation of Cbfa1 and Col mRNA expression and the upregulation of Tgf-beta, CtsK, CaII, Opg and Rankl mRNA expression in tibia of UUO mice compared to those of Sham mice. The ratio of Opg and Rankl was unchanged between Sham and the UUO group. Local protein expression of angiotensin II and its type 2 receptor was dramatically upregulated in tibia of UUO mice. CONCLUSION: Together, it is concluded that the obstructive nephropathy has defective effects on bone, and the underlying mechanisms are the reduction of bone formation and the increase of bone resorption, which is mediated, at least partially through local angiotensin II signalling. PMID- 22943311 TI - Conditional gene expression systems in the transgenic rat brain. AB - BACKGROUND: Turning gene expression on and off at will is one of the most powerful tools for the study of gene function in vivo. While several conditional systems were successful in invertebrates, in mice the Cre/loxP recombination system and the tet-controlled transcription activation system are predominant. Both expression systems allow for spatial and temporal control of gene activities, and, in the case of tet regulation, even for the reversible activation/inactivation of gene expression. Although the rat is the principal experimental model in biomedical research, in particular in studies of neuroscience, conditional rat transgenic systems are exceptionally rare in this species. RESULTS: We addressed this lack of technology, and established and thoroughly characterized CreERT2 and tTA transgenic rats with forebrain-specific transgene expression, controlled by the CaMKII alpha promoter. In addition, we developed new universal rat reporter lines for both transcription control systems and established inducible and efficient reporter gene expression in forebrain neurons. CONCLUSIONS: We demonstrate that conditional genetic manipulations in the rat brain are both feasible and practicable and outline advantages and limitations of the Tet and Cre/loxP system in the rat brain. PMID- 22943312 TI - TFinDit: transcription factor-DNA interaction data depository. AB - BACKGROUND: One of the crucial steps in regulation of gene expression is the binding of transcription factor(s) to specific DNA sequences. Knowledge of the binding affinity and specificity at a structural level between transcription factors and their target sites has important implications in our understanding of the mechanism of gene regulation. Due to their unique functions and binding specificity, there is a need for a transcription factor-specific, structure-based database and corresponding web service to facilitate structural bioinformatics studies of transcription factor-DNA interactions, such as development of knowledge-based interaction potential, transcription factor-DNA docking, binding induced conformational changes, and the thermodynamics of protein-DNA interactions. DESCRIPTION: TFinDit is a relational database and a web search tool for studying transcription factor-DNA interactions. The database contains annotated transcription factor-DNA complex structures and related data, such as unbound protein structures, thermodynamic data, and binding sequences for the corresponding transcription factors in the complex structures. TFinDit also provides a user-friendly interface and allows users to either query individual entries or generate datasets through culling the database based on one or more search criteria. CONCLUSIONS: TFinDit is a specialized structural database with annotated transcription factor-DNA complex structures and other preprocessed data. We believe that this database/web service can facilitate the development and testing of TF-DNA interaction potentials and TF-DNA docking algorithms, and the study of protein-DNA recognition mechanisms. PMID- 22943313 TI - Peripheral artery disease in peritoneal dialysis and hemodialysis patients: single-center retrospective study in Taiwan. AB - BACKGROUND: Peripheral artery disease (PAD) is a condition characterized by restricted blood flow to the extremities, and is especially common in the elderly. PAD increases the risk for mortality and morbidity in patients with end stage renal disease (ESRD), especially those on hemodialysis (HD). METHODS: The records of 484 patients with end-stage renal disease who were on HD or peritoneal dialysis (PD) were reviewed. PAD was diagnosed based on the ankle-brachial pressure index (ABI). Demographic and clinical characteristics were analyzed. RESULTS: PAD had an overall prevalence of 18.2% and was significantly more common in HD patients (21.8%) than in PD patients (4.8%). Advanced age, diabetes mellitus, smoking, low parathyroid hormone level, elevated serum ferritin, elevated serum glucose, and low serum creatinine levels increased the risk for PAD. PAD was independently associated with advanced age, diabetes mellitus, duration of dialysis, low serum creatinine, and hyperlipidemia. PD patients had a significantly lower prevalence of PAD than HD patients, maybe due to their younger age and lower prevalence of diabetes mellitus in this present study. CONCLUSIONS: The prevalence of PAD was greater in the HD group than the PD group. Most of the risk factors for PAD were specific to HD, and no analyzed factor was significantly associated with PAD in PD patients. PMID- 22943314 TI - Effectiveness of isopropyl myristate/cyclomethicone D5 solution of removing cuticular hydrocarbons from human head lice (Pediculus humanus capitis). AB - BACKGROUND: In the treatment of human head lice infestation, healthcare providers are increasingly concerned about lice becoming resistant to existing pesticide treatments. Traditional pesticides, used to control these pests, have a neurological mechanism of action. This publication describes a topical solution with a non-traditional mechanism of action, based on physical disruption of the wax layer that covers the cuticle of the louse exoskeleton. This topical solution has been shown clinically to cure 82% of patients with only a 10-minute treatment time, repeated once after 7 days. All insects, including human head lice, have a wax-covered exoskeleton. This wax, composed of hydrocarbons, provides the insect with protection against water loss and is therefore critical to its survival. When the protective wax is disrupted, water loss becomes uncontrollable and irreversible, leading to dehydration and death. A specific pattern of hydrocarbons has been found in all of the head louse cuticular wax studied. Iso octane effectively removes these hydrocarbons from human head lice's cuticular wax. METHODS: A method of head louse cuticle wax extraction and analysis by gas chromatography was developed. Human head lice (Pediculus humanus capitis) were collected from infested patients and subjected to any of three extraction solvents comprising either the test product or one of two solvents introduced as controls. A gas chromatograph equipped with a flame ionization detector (GC/FID) was used to determine the presence of hydrocarbons in the three head lice extracts. RESULTS: In the study reported herein, the test product isopropyl myristate/cyclomethicone D5 (IPM/D5) was shown to perform comparably with iso octane, effectively extracting the target hydrocarbons from the cuticular wax that coats the human head louse exoskeleton. CONCLUSIONS: Disruption of the integrity of the insect cuticle by removal of specific hydrocarbons found in the cuticular wax appears to offer a mechanism for killing lice without the likelihood of encountering genetic resistance. PMID- 22943315 TI - Cervical spinal abscess: an insidious presentation and unusual pathology. AB - Spinal abscess is a rare condition. Its presentation can often be subtle and insidious. This report describes the diagnosis and management of an 87-year-old man who presented to our orthopaedic clinic. We would like to emphasise the importance of rapid diagnosis and prompt treatment in such cases. PMID- 22943316 TI - Acquired phimosis after plastibell circumcision: a preventable consequence. AB - INTRODUCTION: The plastibell device is used successfully for religious and cultural circumcisions in the community. The aim of this article is to highlight the recognition and management of iatrogenic phimosis. METHODS: A retrospective study was performed of outcomes of plastibell circumcision in a community-based circumcision service provided by trained paediatric surgeons. The objective was to assess the complication of slipped plastibell rings and to ascertain the effectiveness of its management. RESULTS: A total of 5 patients with a slipped plastibell ring were indentified out of 560 plastibell circumcisions. Three patients presented with acquired phimosis. In two patients early diagnosis and management prevented any further complications and a second operation was avoided. CONCLUSIONS: Plastibell circumcision in the community is safe and effective. Detection of minor bleeding due to a slipped ring is important. Early management can avoid the risk of acquired phimosis due to cicatrix formation and can save parents of undue anxiety. PMID- 22943317 TI - Transplant of kidneys with small renal cell carcinoma in incompatible, heavily immunosuppressed recipients. AB - Renal cell carcinoma (RCC) is considered a contraindication for transplant. However, an increasing number of cases of transplant kidneys with RCC have been reported with encouraging results. We present our experience of two cases of transplanting kidneys with small RCCs. Donors and recipients were aware of the presence and possible consequences of RCC in the transplanted kidney before transplantation. Cases were discussed in the multidisciplinary team meetings. Regular, 6-12 monthly follow-up of donors and recipients was carried out with ultrasonography and/or computed tomography to detect recurrence of RCC or new tumours in the recipients' transplant kidneys or the donors' native kidneys. The outcome was recorded. There were no suspicious masses in the any of the kidneys during the follow-up period. The transplant kidneys are functioning. PMID- 22943318 TI - Delayed presentation of familial intestinal malrotation with volvulus in two adult siblings. AB - Intestinal malrotation is an uncommon cause of abdominal pain and normally presents during infancy. Familial cases of malrotation are extremely rare in the absence of other congenital malformations. We present the case of a 22-year-old woman with undiagnosed chronic abdominal pain and her previously well 16-year old brother who presented within 18 months of each other with acute midgut volvulus secondary to intestinal malrotation. Clinicians should be aware of this rare but serious cause of abdominal pain. PMID- 22943319 TI - Spontaneous resolution of an inferior epigastric artery pseudoaneurysm secondary to surgical drain placement. AB - We report the case of a 73-year-old woman who was found to have an inferior epigastric artery pseudoaneurysm caused by surgical drain placement during a laparotomy for an appendix abscess. She presented with pain around the drain site two months following surgery and intravenous contrast computed tomography (CT) revealed a right inferior epigastric artery pseudoaneurysm. A decision was made to manage this expectantly as she remained stable with no other complications. Following a period of nine months of observation, repeat intravenous contrast CT showed evidence of spontaneous regression and thrombosis of the pseudoaneurysm. She remains well and her symptoms have now resolved. PMID- 22943320 TI - Pinworm infection masquerading as colorectal liver metastasis. AB - Enterobius vermicularis is responsible for a variety of diseases but rarely affects the liver. Accurate characterisation of suspected liver metastases is essential to avoid unnecessary surgery. In the presented case, following a diagnosis of rectal cancer, a solitary liver nodule was diagnosed as a liver metastasis due to typical radiological features and subsequently resected. At pathological assessment, however, a necrotic nodule containing E. vermicularis was identified. Solitary necrotic nodules of the liver are usually benign but misdiagnosed frequently as malignant due to radiological features. It is standard practice to diagnose colorectal liver metastases solely on radiological evidence. Without obtaining tissue prior to liver resection, misdiagnosis of solitary necrotic nodules of the liver will continue to occur. PMID- 22943321 TI - Complete regression of renal tumour following ligation of an accessory renal artery during repair of an abdominal aortic aneurysm. AB - The existence of concomitant intra-abdominal pathology with abdominal aortic aneurysms is not uncommon. The optimal management is often controversial. We describe the successful treatment of a case of an abdominal aortic aneurysm (AAA) associated with a renal tumour without performing a nephrectomy. An accessory lower pole renal artery supplying the tumour was ligated at the time of open AAA repair. The lower pole renal tumour (suspected renal cell carcinoma) reduced in size dramatically and progressively on follow-up computed tomography and the patient remains well at over two years after surgery. The successful treatment of the two conditions in such a manner represents an alternative management strategy and adds to the options available in selected patients who present with challenging and unusual pathology. PMID- 22943322 TI - Rectal impalement injury through the pelvis, abdomen and thorax. AB - Impalement rectal injuries with intraperitoneal organ injuries are rare. It is even rarer for such injuries to result in pelvic, abdominal and thoracic internal injuries. We present the case of a 39-year-old man who was admitted after an assault where a broken broomstick was inserted forcibly into his rectum. Surgery revealed penetration through the rectum, dome of the bladder, mesentery, liver and right lung. The patient survived following management by a multispecialty surgical team. Our literature review identified four similar cases with one fatality only. Prognosis seems to be good in these types of injuries provided there is an early presentation, the penetrating object is left in situ before the operation and, most importantly, there is an organised team approach to deal with the various injuries. PMID- 22943323 TI - Accessory gallbladder: a new anatomical variation arising from both left and right hepatic ducts. AB - We present a case of accessory gallbladder demonstrating an anatomical variation not previously reported. While rare, accessory gallbladders are an important consideration if a cholecystectomy is to be performed. We also present a brief literature review of accessory gallbladders. PMID- 22943324 TI - MEN 2 syndrome masquerading as MEN 1. AB - Patients with multiple endocrine neoplasia (MEN) type 2A develop medullary thyroid cancer, which is associated with poor prognosis in its metastatic stage. Hyperparathyroidism is a common finding in both MEN 1 and 2. We report a 68-year old patient diagnosed clinically with MEN 1 based on the presence of hyperparathyroidism and pituitary Cushing's disease with no supporting genetic evidence. The hyperparathyroidism was later found to be part of MEN 2A with underlying metastatic medullary thyroid cancer. We highlight the importance of genetic confirmation before a diagnosis of MEN 1 is made as other more serious pathologies might be overlooked. PMID- 22943325 TI - Routine on-table cholangiography during cholecystectomy: a systematic review. AB - INTRODUCTION: The aim of this review was to systemically analyse trials evaluating the efficacy of routine on-table cholangiography (R-OTC) versus no on table cholangiography (N-OTC) in patients undergoing cholecystectomy. METHODS: Randomised trials evaluating R-OTC versus N-OTC in patients undergoing cholecystectomy were selected and analysed. RESULTS: Four trials (1 randomised controlled trial on open cholecystectomy and 3 on laparoscopic cholecystectomy) encompassing 860 patients undergoing cholecystectomy with and without R-OTC were retrieved. There were 427 patients in the R-OTC group and 433 patients in the N OTC group. There was no significant heterogeneity among trials. Therefore, in the fixed effects model, N-OTC did not increase the risk (p=0.53) of common bile duct (CBD) injury, and it was associated with shorter operative time (p<0.00001) and fewer peri-operative complications (p<0.04). R-OTC was superior in terms of peri operative CBD stone detection (p<0.006) and it reduced readmission (p<0.03) for retained CBD stones. CONCLUSIONS: N-OTC is associated with shorter operative time and fewer peri-operative complications, and it is comparable to R-OTC in terms of CBD injury risk during cholecystectomy. R-OTC is helpful for peri-operative CBD stone detection and there is therefore reduced readmission for retained CBD stones. The N-OTC approach may be adopted routinely for patients undergoing laparoscopic cholecystectomy providing there are no clinical, biochemical or radiological features suggestive of CBD stones. However, a major multicentre randomised controlled trial is required to validate this conclusion. PMID- 22943326 TI - The present state of treatments for articular cartilage defects in the knee. AB - INTRODUCTION: Chondral and osteochondral lesions of the knee are notoriously difficult to treat due to the poor healing capacity of articular cartilage and the hostile environment of moving joints, ultimately causing disabling pain and early osteoarthritis. There are many different reconstructive techniques used currently but few are proven to be of value. However, some have been shown to produce a better repair with hyaline-like cartilage rather than fibrocartilage. METHODS: A systematic search of all available online databases including PubMed, MEDLINE((r)) and EmbaseTM was undertaken using several keywords. All the multiple treatment options and methods available were considered. These were summarised, and the evidence for and against them was scrutinised. RESULTS: A total of 460 articles were identified after cross-referencing the database searches using the keywords. These revealed that autologous and matrix assisted chondrocyte implantation demonstrated both 'good to excellent' histological results and significant improvement in clinical outcomes. CONCLUSIONS: Autologous and matrix assisted chondrocyte implantation have been shown to treat symptomatic lesions successfully with significant histological and clinical improvement. There is, however, still a need for further randomised clinical trials, perfecting the type of scaffold and the use of adjuncts such as growth factors. A list of recommendations for treatment and the potential future trends of managing these lesions are given. PMID- 22943327 TI - Adherence of trials of operative intervention to the CONSORT statement extension for non-pharmacological treatments: a comparative before and after study. AB - INTRODUCTION: Use of the Consolidated Standards of Reporting Trials (CONSORT) statement has been shown to improve the reporting of randomised controlled trials and it is endorsed by leading surgical journals. The CONSORT statement for non pharmacological treatment (CONSORT-NPT) provides specific items to aid in the reporting of trials of operative intervention. This study compares the reporting practice of trials of operative intervention published in time periods before and after publication of the CONSORT-NPT statement. METHODS: A 30-point checklist containing the salient CONSORT-NPT items was designed and the adherence of trials meeting the inclusion criteria determined independently by two authors. RESULTS: There was a significant improvement of 3.95 points in the mean CONSORT NPT score from 2004 to 2010 (95% confidence interval: 3.61-4.29, p<0.001). This related specifically to items present in the original CONSORT statement rather than to CONSORT-NPT items, which remained poorly reported in 2010. The mean CONSORT-NPT score was 17.5 (standard deviation [SD]: 4.5) for trials published in CONSORT endorsing journals compared with 15.6 (SD: 4.0) for those that did not mention endorsement of the CONSORT statement although this was not a significant difference (p=0.064). CONCLUSIONS: Although there has been a significant improvement in the reporting of trials of operative intervention published in the surgical literature since 2004, items specific to the CONSORT-NPT extension remain underreported. Improved awareness of this important addition to the CONSORT statement throughout the surgical community and its endorsement by surgical journals will help to improve the reporting practice of trials of operative intervention. PMID- 22943328 TI - Negative appendicectomy rate as a quality metric in the management of appendicitis: impact of computed tomography, Alvarado score and the definition of negative appendicectomy. AB - INTRODUCTION: The negative appendicectomy rate (NAR) is a quality metric in the management of appendicitis. While computed tomography (CT) has been associated with a low NAR, Alvarado scoring produces an acceptable NAR. The definition of negative appendicectomy may affect the NAR. This study examined the impact of CT, Alvarado score and definition on the NAR. METHODS: The charts of 1,306 emergency appendicectomy patients from 1996 to 2010 were reviewed. Three five year cohorts were created (Cohort A: 1996-2000, Cohort B: 2001-2005, Cohort C: 2006-2010) and the NAR was calculated for each cohort using two definitions of negative appendicectomy: absence of inflammation (NAR-STD) and absence of intramural neutrophils (NAR-STR). NAR-STD was correlated to the CT rate for Cohorts B and C and also to Alvarado score for Cohort C. RESULTS: When the definition of negative appendicectomy was changed, the NAR rose from 9.2% to 15.8% (p=0.0097) for Cohort A, from 2.8% to 8.6% (p=0.0180) for Cohort B (CT rate: 80.6%) and from 3.0% to 6.7% (p=0.0255) for Cohort C (CT rate: 92.4%). The introduction of CT lowered NAR-STD from 1996-2000 (9.2%) to 2001-2010 (2.9%) but increasing the CT rate from 2001-2010 had no impact on the NAR. The positive predictive value for Alvarado score (98.60%) and CT (99.03%) were similar. CONCLUSIONS: The definition of a negative appendicectomy determines the NAR. CT reduces the NAR regardless of definition but routine CT is unnecessary for male patients with positive Alvarado scores. Early/mild appendicitis may resolve without surgery and CT may contribute to unnecessary surgery. Alvarado scoring allows selective use of CT in suspected appendicitis. PMID- 22943329 TI - Definitive management of gallstone pancreatitis in England. AB - INTRODUCTION: The aim of this study was to investigate whether definitive treatment of gallstone pancreatitis (GSP) by either cholecystectomy or endoscopic sphincterotomy in England conforms with British Society of Gastroenterology (BSG) guidelines and to validate these guidelines. METHODS: Hospital Episode Statistics data were used to identify patients admitted for the first time with GSP between April 2007 and April 2008. These patients were followed until April 2009 to identify any who underwent definitive treatment or were readmitted with a further bout of GSP as an emergency. RESULTS: A total of 5,454 patients were admitted with GSP between April 2007 and April 2008, of whom 1,866 (34.2%) underwent definitive treatment according to BSG guidelines, 1,471 on the index admission. Patients who underwent a cholecystectomy during the index admission were less likely to be readmitted with a further bout of GSP (1.7%) than those who underwent endoscopic sphincterotomy alone (5.3%) or those who did not undergo any form of definitive treatment (13.2%). Of those patients who did not undergo definitive treatment before discharge, 2,239 received definitive treatment following discharge but only 395 (17.6%) of these had this within 2 weeks. Of the 505 patients who did not undergo definitive treatment on the index admission and who were readmitted as an emergency with GSP, 154 (30.5%) were admitted during the 2 weeks immediately following discharge. CONCLUSIONS: Following an attack of mild GSP, cholecystectomy should be offered to all patients prior to discharge. If patients are not fit for surgery, an endoscopic sphincterotomy should be performed as definitive treatment. PMID- 22943330 TI - Laparoscopic donor nephrectomy: an increasingly common cause for testicular pain and swelling. AB - INTRODUCTION: Laparoscopic donor nephrectomy (LDN) is now a well established method for kidney procurement from living donors. In our centre, LDN is currently offered only to donors suitable for left nephrectomy. The aim of this study was to investigate the incidence of testicular pain and swelling following LDN. METHODS: A total of 25 left-sided LDN male patients were assessed in a prospective structured interview together with a control cohort of 25 male patients who had undergone left-sided open donor nephrectomy (ODN). RESULTS: Data were collected on testicular pain, swelling, numbness, urinary symptoms and sexual dysfunction from all 50 patients (100% response rate). Of the 25 LDN patients, 11 (44%) experienced ipsilateral testicular pain and/or swelling. In most instances, pain was of immediate onset, mild to moderate in severity, lasted for a few days to several weeks and was associated with testicular swelling (10 of 11 cases). However, testicular pain and/or swelling were not apparent in ODN patients, with only 2 of 25 (8%) experiencing mild testicular pain, 1 of whom also had swelling. CONCLUSIONS: Testicular pain and swelling following LDN is a common problem. It is underreported in the literature and LDN should be included in the differential diagnoses of testicular pain and swelling. Further investigation is required to confirm our findings. PMID- 22943331 TI - Patch variability following carotid endarterectomy: a survey of Great Britain and Ireland. AB - INTRODUCTION: Evidence suggests a clinical benefit with patch angioplasty after carotid endarterectomy (CEA). The UK National Vascular Database has demonstrated variation in practice but does not record technical details. This study was intended to define indications and technique of patching after CEA. METHODS: An electronic questionnaire was emailed to all 402 members of the Vascular Society of Great Britain and Ireland. The email could not be received by 23 and 14 did not perform CEA. Some questions allowed multiple answers. Fisher's exact test was used for statistical analysis. RESULTS: There were 187 responses (51%). Fifteen members (8%) performed eversion CEA, which obviates patching. Of all the respondents, 121 surgeons (65%) always use a patch. Seventy of these (58%) use the full patch width (median: 8 mm, range: 4-10 mm). Fourteen (12%) variably trimmed the patch (median: 7.5 mm, range: 5-10 mm) and 34 (28%) routinely trimmed (median: 6 mm, range: 3-20 mm). Selective patching, dependent on internal carotid artery diameter, was performed by 48 respondents (26%), 23 of whom specified a median artery threshold diameter of 5 mm (range: 3-8 mm). General anaesthesia was always or usually used by 83 surgeons (45%), local anaesthesia by 77 (41%) and the remainder followed patient choice. Obligatory patching is performed by 68 of the 83 respondents (82%) who prefer general anaesthesia whereas only 40 of the 77 surgeons (52%) who use local anaesthesia always patch (p<0.0001). CONCLUSIONS: There is a variable rate of patching after CEA in the UK, which appears dependent on the vessel size and mode of anaesthesia. There are also differences in the patch width adopted. PMID- 22943332 TI - Unoperated severe aortic stenosis: decision making in an adult UK-based population. AB - INTRODUCTION: Severe symptomatic aortic stenosis is associated with a poor prognosis, with most patients dying 2-3 years after diagnosis. We analysed the proportion of patients with severe aortic stenosis not referred for aortic valve replacement (AVR) in a UK-based population and the clinical factors contributing to this. METHODS: Retrospective analysis of patients with echocardiographic evidence of severe aortic stenosis was performed at a university teaching hospital. RESULTS: A total of 178 consecutive patients with severe aortic stenosis (AVA: <1 cm(2), mean pressure gradient: >=40 mmHg, or visually severe on echocardiography) were included in the study. Eighty-three patients did not have AVR (95% confidence interval: 39-54%). The cohort included 146 symptomatic patients (82%) and 32 (18%) who were asymptomatic. The most common reason for non referral in symptomatic patients was 'high operative risk' and in asymptomatic patients 'no symptoms'. Of the patients who did not have AVR, only 19% (n=16) were referred for a surgical opinion. None of the patients in the asymptomatic group underwent echocardiographic stress imaging. The thirty-day operative mortality rate in the AVR group was 2.3%. Symptomatic patients who underwent AVR had superior survival, even after adjusting for co-morbidities (p<0.001). CONCLUSIONS: A considerable proportion of patients with severe aortic stenosis are not referred for surgery although they have a clear indication for AVR. Patients are often estimated as being too high risk or having prohibitive co morbidities. Among asymptomatic patients, stress imaging was rarely used despite its useful role prognostically and in deciding the best time for intervention. PMID- 22943333 TI - Air leaks following pulmonary resection for lung cancer: is it a patient or surgeon related problem? AB - INTRODUCTION: Prolonged air leak (PAL) is the most common complication after partial lung resection and the most important determinant of length of hospital stay for patients post-operatively. The aim of this study was to determine the risk factors involved in developing air leaks and the consequences of PAL. METHODS: All patients undergoing lung resection between January 2002 and December 2007 in our hospital were studied retrospectively. Univariate analysis to predict risk factors for developing post-operative air leaks included patient demographics, smoking status, pulmonary function tests, disease aetiology (benign, malignant), neoadjuvant therapy (pre-operative radiotherapy/chemotherapy), extent and type of resection, and different consultant surgeons' practice. A logistic regression model was used for multivariate analysis. RESULTS: A total of 1,911 lung resections were performed over the 6-year study period. An air leak lasting more than 6 days post operatively was present in 129 patients (6.7%). This included 100 out of the 1,250 patients (8%) from the lobectomy group and 29 out of the 661 patients (4.4%) from the wedge/segmentectomy group. Using the multivariate analysis, the risk factors for developing an air leak included a low predicted forced expiratory volume in 1 second (pFEV(1)) (p<0.001), performing an upper lobectomy (p=0.002) and different consultant practice (p=0.02). PAL was associated with increased length of stay (p<0.0001), in-hospital mortality (p=0.003) and intensive care unit readmission (p=0.05). CONCLUSIONS: Air leaks after pulmonary resections were at an acceptable rate in our series. Particular patients are at a higher risk but meticulous surgical technique is vital in reducing their incidence. Our study shows that pFEV1 is the strongest predictor of post operative air leaks. PMID- 22943334 TI - Is pre-operative imaging essential prior to ureteric stone surgery? AB - INTRODUCTION: The aim of this study was to identify patients not requiring ureteric stone surgery based on pre-operative imaging (within 24 hours) prior to embarking on semirigid ureteroscopy (R-URS) for urolithiasis. METHODS: The imaging of all consecutive patients on whom R-URS for urolithiasis was performed over a 12-month period was reviewed. All patients had undergone a plain x-ray of the kidney, ureters and bladder (KUB), abdominal non-contrast computed tomography (NCCT-KUB) or both on the day of surgery. RESULTS: A total of 96 patients were identified for the study. Stone sizes ranged from 3 mm to 20 mm. Thirteen patients (14%) were cancelled as no stone(s) were identified on pre-operative imaging. Of the patients cancelled, 8 (62%) required NCCT-KUB to confirm spontaneous stone passage. CONCLUSIONS: One in seven patients were stone free on the day of surgery. This negates the need for unnecessary anaesthetic and instrumentation of the urinary tract, with the associated morbidity. Up-to-date imaging prior to embarking on elective ureteric stone surgery is highly recommended. PMID- 22943336 TI - Novel use of a single port laparoscopic surgery device for minimally invasive pancreatic necrosectomy. PMID- 22943335 TI - Have the media influenced the use of hip resurfacing arthroplasty? A review of UK print media. AB - INTRODUCTION: The aim of this study was to look at the different claims made about hip resurfacing arthroplasty in the popular UK print media and how this relates to findings in the scientific literature. METHODS: A review of UK popular print media from January 1992 to June 2011 was performed using the Lexis((r)) Library online news database. Only articles discussing the clinical results of hip resurfacing arthroplasty were included. After excluding duplicates, 49 newspaper articles were found suitable for this study. The main outcome measure was the claims made in popular UK print media about hip resurfacing. These were compared with the scientific publication. We reviewed the trend of use of hip resurfacing prostheses during the same period as reported in the National Joint Registry. RESULTS: A disparity was found between the claims in the newspapers and published scientific literature. The initial newspaper articles highlighted only the positive aspects of hip resurfacing arthroplasty, without definitive contemporary evidence backing the claims. Most of these claims were refuted by future scientific publications. The initial positive media reports coincided with an increase in the use of hip resurfacing but the decline coincided with negative reports in the scientific literature. CONCLUSIONS: The trend of the newspaper articles and that of the number of hip resurfacing prostheses implanted suggests that the media may have been partly responsible for the increased use of this prosthesis. The subsequent decrease was initiated by the scientific literature. PMID- 22943337 TI - Technique for central aortic cannulation in extensive aortic dissection. PMID- 22943338 TI - A novel technique for the per-anal extraction of spherical rectal foreign bodies. PMID- 22943339 TI - A simple technique for suturing inside the nose. PMID- 22943340 TI - The use of an external fixator system with Hey Groves bone clamps in transverse femoral shaft fractures. PMID- 22943341 TI - Fluid management in wound care. PMID- 22943342 TI - Innovative use of Proximal Humeral Interlocking System (PHILOS) plate for fixation of osteoporotic fibula fracture. PMID- 22943343 TI - A simple suturing technique to close arthroscopy portal wounds. PMID- 22943344 TI - The use of double abdominal braces in knee replacement. PMID- 22943345 TI - Bladder wrap: a technique to restore continence in an incompetent vesicocutaneous diversion. PMID- 22943346 TI - Finger trocar: a safe method for entering the peritoneal cavity during laparoscopy in obese patients. PMID- 22943347 TI - Cement augmentation of bone defect in pathological humeral diaphyseal fracture treated with retrograde intramedullary nail. PMID- 22943348 TI - Laparoscopic enteropexy for prolapsing ileostomy. PMID- 22943349 TI - The supine position for elbow surgery. PMID- 22943350 TI - Microfenestrated split thickness skin grafts: an underused technique? PMID- 22943351 TI - Removing broken locking bolts. PMID- 22943352 TI - Comment on: The use of pre-operative computed tomography in the assessment of the acute abdomen. PMID- 22943353 TI - Comment on: Hip fractures: public perceptions--are we jumping the gun? PMID- 22943354 TI - Comment on: Caliper measurement to improve clinical assessment of palpable neck lumps. PMID- 22943355 TI - Comment on: Early symptoms of bone and soft tissue sarcomas: could they be diagnosed earlier? PMID- 22943356 TI - Comment on: Not just a vampire repellent: the adverse effects of garlic supplements in surgery. PMID- 22943357 TI - Comment on: Investigation prior to thyroglossal duct cyst excision. PMID- 22943358 TI - Comment on: The effect of alcohol on surgical skills. PMID- 22943359 TI - Comment on: The genitofemoral nerve block: a method for hemiscrotal anaesthesia at the bedside. PMID- 22943361 TI - Chyluria after partial nephrectomy: a rare but considerable complication. AB - An 82-year-old male patient underwent open left lower-pole partial nephrectomy with a microwave tissue coagulator (Microtaze). Pathological findings showed clear cell renal cell carcinoma, pT1a, Fuhrman grade 2 with negative margins. Then 2 years later, he presented with urinary retention. His urine appeared cloudy and milky only after meals, but appeared normal at other times. He was diagnosed with chyluria after partial nephrectomy. Endoscopic sclerotherapy with silver nitrate was carried out, because his serum albumin decreased to 3.4 g/dL within 3 months. He had an uneventful postoperative course. His chyluria completely disappeared and has not recurred for 11 months. Although chyluria after nephrectomy is very rare, there is a possibility that the frequency of chyluria after partial nephrectomy might increase, because the number of partial nephrectomies continues to increase worldwide. We herein summarize this rare surgical complication and discuss the effectiveness of endoscopic sclerotherapy as a therapeutic tool. PMID- 22943362 TI - Time-of-flight magnetic resonance angiography (TOF-MRA) of the normal equine head. AB - REASONS FOR PERFORMING STUDY: Noncontrast magnetic resonance angiography (MRA) is widely used in human and small animal medicine. However, this technique has not yet been described in the horse, and compared to other angiographic techniques MRA could be more cost efficient and potentially safer. OBJECTIVES: The aim of this study was to provide a comprehensive anatomical reference of the normal equine head vasculature using a noncontrast MRA technique, on both low- and high field MRI. METHODS: Five healthy adult horses were examined, 4 with a low-field magnet (0.23T) and the remaining one with a high-field magnet (1.5T). The magnetic resonance angiography sequence used was TOF (time-of-flight) 2D-MRA and CT images of a vascular corrosion cast were subsequently used as anatomical references. RESULTS: The MRA imaging protocol provided good visualisation of all major intra- and extracranial vessels down to a size of approximately 2 mm in diameter on both low- and high-field systems. This resulted in identification of vessels to the order of 3rd-4th branches of ramification. The visibility of the arteries was higher than of the veins, which showed lower signal intensity. Overall, MRA obtained with the high-field protocol provided better visualisation of the arteries, showing all the small arterial branches with a superior resolution. CONCLUSIONS: The use of a specific vascular sequence such as TOF 2D MRA allows good visualisation of the equine head vasculature and eliminates the need for contrast media for MRA. POTENTIAL RELEVANCE: Magnetic resonance angiography allows for visualisation of the vasculature of the equine head. Vessel morphology, symmetry and size can be evaluated and this may possibly play a role in preoperative planning or characterisation of diseases of the head, such as neoplasia or guttural pouch mycosis. PMID- 22943363 TI - Regulation of the V-type ATPase by redox modulation. AB - ATP-hydrolysis and proton pumping by the V-ATPase (vacuolar proton-translocating ATPase) are subject to redox regulation in mammals, yeast and plants. Oxidative inhibition of the V-ATPase is ascribed to disulfide-bond formation between conserved cysteine residues at the catalytic site of subunit A. Subunits containing amino acid substitutions of one of three conserved cysteine residues of VHA-A were expressed in a vha-A null mutant background in Arabidopsis. In vitro activity measurements revealed a complete absence of oxidative inhibition in the transgenic line expressing VHA-A C256S, confirming that Cys(256) is necessary for redox regulation. In contrast, oxidative inhibition was unaffected in plants expressing VHA-A C279S and VHA-A C535S, indicating that disulfide bridges involving these cysteine residues are not essential for oxidative inhibition. In vivo data suggest that oxidative inhibition might not represent a general regulatory mechanism in plants. PMID- 22943364 TI - The ecological economics of kleptoparasitism: pay-offs from self-foraging versus kleptoparasitism. AB - Animals commonly steal food from other species, termed interspecific kleptoparasitism, but why animals engage in kleptoparasitism compared with alternate foraging tactics, and under what circumstances they do so, is not fully understood. Determining what specific benefits animals gain from kleptoparasitism could provide valuable insight into its evolution. Here, we investigate the benefits of kleptoparasitism for a population of individually recognizable and free-living fork-tailed drongos (Dicrurus adsimilis) in the southern Kalahari Desert. Drongos engaged in two foraging behaviours: self-foraging for small insects or following other species which they kleptoparasitized for larger terrestrial prey that they could not capture themselves. Kleptoparasitism consequently enabled drongos to exploit a new foraging niche. Kleptoparasitism benefitted drongos most in the morning and on colder days because at these times pay-offs from kleptoparasitism remained stable, while those from self-foraging declined. However, drongos engaged in kleptoparasitism less than expected given the overall high (but more variable) pay-offs from this behaviour, suggesting that kleptoparasitism is a risky foraging tactic and may incur additional foraging costs compared with self-foraging. This is the first study to comprehensively investigate the benefits of facultatively engaging in kleptoparasitism, demonstrating that animals may switch to kleptoparasitism to exploit a new foraging niche when pay-offs exceed those from alternate foraging behaviours. PMID- 22943365 TI - Doxycycline impairs neutrophil migration to the airspaces of the lung in mice exposed to intratracheal lipopolysaccharide. AB - BACKGROUND: Tetracyclines are broad-spectrum antibiotics that are also used to induce gene expression using the reverse tetracycline transactivator / tetracycline operator system (rtTA/tetO system). The system assumes that tetracyclines have no effects on mammals. However, a number of studies suggest that tetracyclines may have powerful anti-inflammatory effects. We report that the tetracycline, doxycycline, inhibits neutrophil (PMN) influx into the lungs of mice treated with bacterial endotoxin (LPS). METHODS: Mice were challenged with intratracheal LPS in the presence or absence of doxycyline. bronchoalveolar lavage cell counts and differential, total bronchoalveolar lavage protein, lung homogenate caspase-3 and tissue imaging were used to assess lung injury. In addition, PMN chemotaxis was measured in vitro and syndecan-1 was measured in bronchoalveolar lavage fluid. RESULTS: The administration of doxycycline resulted in a significant decrease in the number of bronchoalveolar lavage PMNs in LPS treated mice. Doxycycline had no effect on other markers of lung injury such as total bronchoalveolar lavage protein and whole lung caspase-3 activity. However, doxycycline resulted in a decrease in shed syndecan-1 in bronchoalveolar lavage fluid. CONCLUSION: We conclude that doxycycline has an important anti inflammatory effect that can potentially confound the experiments in which the rtTA/tetO system is being used to study the immune response. PMID- 22943366 TI - Family-based linkage and association mapping reveals novel genes affecting Plum pox virus infection in Arabidopsis thaliana. AB - Sharka is a devastating viral disease caused by the Plum pox virus (PPV) in stone fruit trees and few sources of resistance are known in its natural hosts. Since any knowledge gained from Arabidopsis on plant virus susceptibility factors is likely to be transferable to crop species, Arabidopsis's natural variation was searched for host factors essential for PPV infection. To locate regions of the genome associated with susceptibility to PPV, linkage analysis was performed on six biparental populations as well as on multiparental lines. To refine quantitative trait locus (QTL) mapping, a genome-wide association analysis was carried out using 147 Arabidopsis accessions. Evidence was found for linkage on chromosomes 1, 3 and 5 with restriction of PPV long-distance movement. The most relevant signals occurred within a region at the bottom of chromosome 3, which comprises seven RTM3-like TRAF domain-containing genes. Since the resistance mechanism analyzed here is recessive and the rtm3 knockout mutant is susceptible to PPV infection, it suggests that other gene(s) present in the small identified region encompassing RTM3 are necessary for PPV long-distance movement. In consequence, we report here the occurrence of host factor(s) that are indispensable for virus long-distance movement. PMID- 22943367 TI - Anticoagulants in cancer. AB - Cancer patients are at high risk for venous thromboembolism (VTE), which results in substantial morbidity and mortality. In this narrative review, we present evidence for the use of anticoagulants in the treatment and prevention of VTE in cancer patients. The benefit of perioperative anticoagulant prophylaxis following cancer surgery is well established. However, the risk-benefit trade-offs in non surgical hospitalized cancer patients and among outpatients receiving chemotherapy are more complex. Emerging evidence suggests that the use of low molecular weight heparin (LMWH) may confer a small survival benefit in cancer patients without VTE. However, specific patient populations that may derive the most benefit have yet to be defined. Guidelines endorse LMWH as the preferred treatment for acute VTE, on the basis of high-quality clinical trial data, but the optimal duration of treatment remains unclear, and practical issues may limit its use outside the clinical trial setting. Novel oral anticoagulants may provide additional treatment and prophylaxis options, but their efficacy and safety in this population have not been established. Despite the significant impact of VTE on the lives of cancer patients and the large body of existing literature regarding treatment and prevention, important unanswered clinical questions remain, emphasizing the need for additional high-quality clinical trial data. PMID- 22943368 TI - Chloroplast ultrastructure regeneration with protection of photosystem II is responsible for the functional 'stay-green' trait in wheat. AB - CN17 is a functional stay-green wheat variety that exhibits delayed leaf senescence and enhanced photosynthetic competence. To better understand these valuable traits, levels of chlorophyll a and b, soluble proteins, unsaturated fatty acids, and other components of CN17 were assayed. In addition, chloroplast ultrastructure, chloroplast number, and differences in gene expression between CN17 and a control variety, MY11, were examined. By 21 d post-anthesis (DPA), CN17 leaves exhibited a significantly higher maximal photochemical efficiency for photosystem II (PSII) (F(v) /F(m) ) and a significantly higher efficiency of excitation capture by open PSII reaction centres (F(v) '/F(m) '). In addition, chlorophyll degradation in CN17 was delayed by approximately 14 d, and was not blocked as observed in cosmetic stay-green phenotypes. The soluble protein content (Ps) of CN17 was higher than MY11 at all timepoints assayed, and the ratio of unsaturated to saturated fatty acids was significantly higher. CN17 also exhibited isolated granal lamellae associated with vesicles and diminished peroxidation, and between 35 and 42 DPA, a sharp decrease in chloroplast number was detected. Taken together, these results strongly support the hypothesis that chloroplast ultrastructure regeneration is responsible for the functional stay green trait of CN17, and gene expression data provide insight into the mechanistic details. PMID- 22943369 TI - The rise of translational bioinformatics. AB - A report on the 20th International Conference on Intelligent Systems for Molecular Biology (ISMB), held at Long Beach, California, USA, July 15-17, 2012. PMID- 22943372 TI - Determinants of low birthweight, small-for-gestational-age and preterm birth in Lombok, Indonesia: analyses of the birthweight cohort of the SUMMIT trial. AB - OBJECTIVE: To examine the determinants of low birthweight (LBW), small-for gestation (SGA) and preterm births in Lombok, Indonesia, an area of high infant mortality. METHODS: Data from The Supplementation with Multiple Micronutrient Intervention Trial (SUMMIT), a double-blind cluster-randomised controlled trial, were analysed. The odds ratio of factors known to be associated with LBW, SGA and preterm birth was assessed and adjusted for the cluster design of the trial using hierarchical logistic regression. Determinants included constitutional, demographic and psychosocial factors, toxic exposure, maternal nutrition and obstetric history and maternal morbidity during and prior to pregnancy. Population attributable risks of modifiable determinants were calculated. RESULTS: A cohort of 14,040 singleton births was available for analysis of LBW, with 13,498 observations for preterm births and 13,461 for SGA births. Determinants of LBW and SGA were similar and included infant's sex, woman's education, season at birth, mothers' residence, household wealth, maternal mid upper arm circumference (MUAC), height and a composite variable of birth order and pregnancy interval. Socioeconomic indicators were also related to preterm births and included mother's education, residence and household wealth, while nutritional-related factors including low MUAC and birth order and interval were associated with preterm birth but not maternal height. Nausea was protective of preterm birth, while diarrhoea was associated with higher odds of preterm birth. Oedema during pregnancy was protective of SGA but associated with higher odds of preterm delivery. Around 33%, 13% and 13% of the determinants of LBW, SGA and preterm births were preventable. CONCLUSION: Women's education, maternal nutrition and household wealth and family planning are key factors to improving birth outcomes. PMID- 22943373 TI - Antiretroviral therapy in sub-Saharan Africa: evidence about need, uptake and impact from community-based cohort studies. PMID- 22943374 TI - HIV status and participation in HIV surveillance in the era of antiretroviral treatment: a study of linked population-based and clinical data in rural South Africa. AB - OBJECTIVE: To examine whether HIV status affects participation in a population based longitudinal HIV surveillance in the context of an expanding HIV treatment and care programme in rural South Africa. METHOD: We regressed consent to participate in the HIV surveillance during the most recent fieldworker visit on HIV status (based on previous surveillance participation or enrollment in pre antiretroviral treatment (pre-ART) care or ART in the local HIV treatment and care programme), controlling for sex, age and year of the visit (N = 25,940). We then repeated the regression using the same sample but, in one model, stratifying HIV-infected persons into three groups (neither enrolled in pre-ART care nor receiving ART; enrolled in pre-ART care but not receiving ART; receiving ART) and, in another model, additionally stratifying the group enrolled in pre-ART and the group receiving ART into those with CD4 count <= 200/MUl (i.e. the ART eligibility threshold at the time) vs. those with CD4 count >200/MUl. RESULTS: HIV-infected individuals were significantly less likely to consent to participate in the surveillance than HIV-uninfected individuals [adjusted odds ratio (aOR), 0.74; 95% confidence interval, 0.70-0.79, P < 0.001], controlling for other factors. Persons who were receiving ART were less likely to consent to participate (aOR, 0.75, 0.68-0.84, P < 0.001) than those who had never sought HIV treatment or care (aOR, 0.82, 0.75-0.89, P < 0.001), but more likely to consent than persons enrolled in pre-ART care (aOR 0.62, 0.56-0.69, P < 0.001). Those with CD4 count <= 200/MUl were significantly less likely to consent to participate than those with CD4 count >200/MUl in both the group enrolled in pre ART and the group receiving ART. CONCLUSION: As HIV test results are not made available to participants in the HIV surveillance, our findings agree with the hypothesis that HIV-infected persons are less likely than HIV-uninfected persons to participate in HIV surveillance because they fear the negative consequences of others learning about their HIV infection. Our results further suggest that the increased knowledge of HIV status that accompanies improved ART access can reduce surveillance participation of HIV-infected persons, but that this effect decreases after ART initiation, in particular in successfully treated patients. PMID- 22943375 TI - Trends in the uptake of voluntary counselling and testing for HIV in rural Tanzania in the context of the scale up of antiretroviral therapy. AB - OBJECTIVES: To describe trends in voluntary counselling and testing (VCT) use and to assess whether high-risk and infected individuals are receiving counselling and learning their HIV status in rural Tanzania. METHODS: During two rounds of linked serological surveys (2003-2004 and 2006-2007) with anonymous HIV testing among adults, VCT was offered to all participants. The crude and adjusted odds ratios for completing VCT in each survey were calculated to compare uptake by demographic, behavioural and clinical characteristics, stratified by sex. Repeat testing patterns were also investigated. RESULTS: The proportion of participants completing VCT increased from 10% in 2003-2004 to 17% in 2006-2007, and among HIV infected persons from 14% to 25%. A higher proportion of men than women completed VCT in both rounds, but the difference declined over time. Socio-demographic and behavioural factors associated with VCT completion were similar across rounds, including higher adjusted odds of VCT with increasing numbers of sexual partners in the past 12 months. The proportion having ever-completed VCT reached 26% among 2006-2007 attendees, with repeat testing rates highest among those aged 35-44 years. Among 3923 participants attending both rounds, VCT completion in 2006-2007 was 17% among 3702 who were HIV negative in both rounds, 19% among 124 who were HIV infected in both rounds and 22% among 96 who seroconverted between rounds. CONCLUSION: VCT services are attracting HIV-infected and high-risk individuals. However, 2 years after the introduction of antiretroviral therapy, the overall uptake remains low. Intensive mobilisation efforts are needed to achieve regular and universal VCT use. PMID- 22943376 TI - Patterns of uptake of HIV testing in sub-Saharan Africa in the pre-treatment era. AB - OBJECTIVES: To compare nationally representative trends in self-reported uptake of HIV testing and receipt of results in selected countries prior to treatment scale-up. METHODS: Demographic and Health Survey (DHS) data from 13 countries in sub-Saharan Africa were used to describe the pattern of uptake of testing for HIV among sexually active participants. Univariate and multivariate logistic regression were used to analyse the associations between socio-demographic and behavioural characteristics and the uptake of testing. RESULTS: Knowledge of serostatus ranged from 2.2% among women in Guinea (2005) to 27.4% among women in Rwanda (2005). Despite varied levels of testing, univariate analysis showed the profile of testers to be remarkably similar across countries, with respect to socio-demographic characteristics such as area of residence and socio-economic status. HIV-positive participants were more likely to have tested and received their results than HIV-negative participants, with the exception of women in Senegal and men in Guinea. Adjusted analyses indicate that a secondary or higher level of education was a key determinant of testing, and awareness that treatment exists was independently positively associated with testing, once other characteristics were taken into account. CONCLUSION: This work provides a baseline for monitoring trends in testing and exploring changes in the profile of those who get tested after the introduction and scale-up of treatment. PMID- 22943377 TI - Using age-specific mortality of HIV infected persons to predict anti-retroviral treatment need: a comparative analysis of data from five African population-based cohort studies. AB - OBJECTIVES: To present a simple method for estimating population-level anti retroviral therapy (ART) need that does not rely on knowledge of past HIV incidence. METHODS: A new approach to estimating ART need is developed based on calculating age-specific proportions of HIV-infected adults expected to die within a fixed number of years in the absence of treatment. Mortality data for HIV-infected adults in the pre-treatment era from five African HIV cohort studies were combined to construct a life table, starting at age 15, smoothed with a Weibull model. Assuming that ART should be made available to anyone expected to die within 3 years, conditional 3-year survival probabilities were computed to represent proportions needing ART. The build-up of ART need in a successful programme continuously recruiting infected adults into treatment as they age to within 3 years of expected death was represented by annually extending the conditional survival range. RESULTS: The Weibull model: survival probability in the infected state from age 15 = exp(-0.0073 * (age - 15)(1.69)) fitted the pooled age-specific mortality data very closely. Initial treatment need for infected persons increased rapidly with age, from 15% at age 20-24 to 32% at age 40-44 and 42% at age 60-64. Overall need in the treatment of naive population was 24%, doubling within 5 years in a programme continually recruiting patients entering the high-risk period for dying. CONCLUSION: A reasonable projection of treatment need in an ART naive population can be made based on the age and gender profile of HIV-infected people. PMID- 22943378 TI - Antiretroviral therapy uptake and coverage in four HIV community cohort studies in sub-Saharan Africa. AB - OBJECTIVE: To compare socio-demographic patterns in access to antiretroviral therapy (ART) across four community HIV cohort studies in Africa. METHODS: Data on voluntary counselling and testing and ART use among HIV-infected persons were analysed from Karonga (Malawi), Kisesa (Tanzania), Masaka (Uganda) and Manicaland (Zimbabwe), where free ART provision started between 2004 and 2007. ART coverage was compared across sites by calculating the proportion on ART among those estimated to need treatment, by age, sex and educational attainment. Logistic regression was used to identify socio-demographic characteristics associated with undergoing eligibility screening at an ART clinic within 2 years of being diagnosed with HIV, for three sites with information on diagnosis and screening dates. RESULTS: Among adults known to be HIV-infected from serological surveys, the proportion who knew their HIV status was 93% in Karonga, 37% in Kisesa, 46% in Masaka and 25% in Manicaland. Estimated ART coverage was highest in Masaka (68%) and lowest in Kisesa (2%). The proportion of HIV-diagnosed persons who were screened for ART eligibility within 2 years of diagnosis ranged from 14% in Kisesa to 84% in Masaka, with the probability of screening uptake increasing with age at diagnosis in all sites. CONCLUSIONS: Higher HIV testing rates among HIV infected persons in the community do not necessarily correspond with higher uptake of ART, nor more equitable treatment coverage among those in need of treatment. In all sites, young adults tend to be disadvantaged in terms of accessing and initiating ART, even after accounting for their less urgent need. PMID- 22943379 TI - Access to, and uptake of, antiretroviral therapy in a developing country with high HIV prevalence: a population-based cohort study in rural Uganda, 2004-2008. AB - OBJECTIVES: To investigate antiretroviral therapy (ART) uptake after its introduction in 2004 in a longitudinal population-based cohort and its nested clinical cohort in rural Uganda. METHODS: A HIV serosurvey of all adults aged >= 15 years is conducted annually. Two intervals were selected for analysis. Interval 1 (November 2004-October 2006) provided 2 years of follow-up to prospectively evaluate access to HIV services. Interval 2 (November 2007-October 2008) was used to evaluate current coverage of services. Logistic regression was used to identify sociodemographic factors associated with ART screening within 2 years of diagnosis. ART coverage was assessed using Weibull survival models to estimate the numbers needing ART. RESULTS: In Interval 1, 636 HIV-positive adults were resident and 295 (46.4%) knew their status. Of those, 248 (84.1%) were screened for ART within 2 years of diagnosis. After adjusting for age, those who were widowed, separated or never married were more likely to be screened than those who were married. In Interval 2, 575 HIV-positive adults were residents, 322 (56.0%) knew their status, 255 (44.3%) had been screened for ART and 189 (32.9%) had started ART. Estimated ART coverage was 66%. CONCLUSIONS: In this cohort, ART access and uptake is very high once people are diagnosed. Owing to intensive screening in the study clinic, nearly all participants who were eligible initiated ART. However, this is unlikely to reflect coverage in the general population, intensified efforts are needed to promote HIV testing, and ART screening and uptake are needed among those found to be HIV-positive. PMID- 22943380 TI - The impact of antiretroviral therapy on adult mortality in rural Tanzania. AB - OBJECTIVE: To describe the impact of antiretroviral therapy (ART) on mortality rates among adults participating in an HIV community cohort study in north-west Tanzania. METHODS: Serological and demographic surveillance rounds have been undertaken in a population of approximately 30,000 people since 1994. Free HIV care including ART has been available since 2005. Event history analysis was used to compare mortality rates among HIV-negative and HIV-positive adults in the 5 year period before and after the introduction of ART. Crude and adjusted hazard ratios were calculated using exponential regression models. Interaction between time period and HIV status was assessed to investigate whether there was a non linear relationship between these two variables. RESULTS: Male and female mortality patterns varied over the pre- and post-ART period. In women, the crude death rate fell for both HIV negatives and HIV positives hazard rate ratio (HRR = 0.71; 95%CI 0.51-0.99 and HRR = 0.68; 95%CI: 0.46-0.99, respectively). For men, the mortality among the HIV negatives increased (HRR = 1.47; 95%CI: 1.06-2.03) while the decline in mortality among the HIV positives (HRR = 0.77; 95%CI 0.52 1.13) was not statistically significant. The largest decrease in HIV-positive mortality over the two periods was among the 30- to 44-year-old age group for women and among the 45- to 59-year-old age group for men. CONCLUSION: There has been a modest effect on mortality in the study population following the introduction of free ART 5 years ago. Improving access to treatment and placing greater focus on retaining individuals on treatment are essential if the full potential of treatment for reducing HIV-related mortality is to be realised. PMID- 22943381 TI - The impact of antiretroviral treatment on mortality trends of HIV-positive adults in rural Uganda: a longitudinal population-based study, 1999-2009. AB - OBJECTIVE: To investigate trends in all-cause adult mortality after the roll-out of an antiretroviral therapy (ART) programme in rural Uganda. METHODS: Longitudinal population-based cohort study of approximately 20,000 residents in rural Uganda. Mortality in adults aged 15-59 years was determined for the 5-year period (1999-2003) before introduction of ART in January 2004 and for the 5-year period afterwards. Poisson regression was used to estimate mortality rate ratios (RRs) for the period before ART, 1 year after ART introduction (from January 2004 to January 2005) and more than 1 year after ART introduction. Trends in mortality were analysed by HIV status, age and sex. RESULTS: Before ART became available, the mortality rate (deaths per 1000 person-years) was 4.0 (95% CI = 3.3-4.8) among HIV-negative individuals and 116.4 (95% CI = 101.9-133.0) among HIV positive individuals. During the period January 2004-end November 2009, 279 individuals accessed ART. In the year after ART was introduced, the mortality rate (deaths per 1000 person-years) among HIV-negative individuals did not change significantly (adjusted RR = 0.95, 95% CI = 0.61-1.47), but among HIV-positive individuals dropped by 25% to 87.4 (adjusted RR = 0.75, 95% CI = 0.53-1.06). In the period 2005-2009, the mortality rate (deaths per 1000 person-years) among HIV positive individuals fell further to 39.9 (adjusted RR = 0.33, 95% CI = 0.26 0.43). The effect was greatest among individuals aged 30-44 years, and trends were similar in men and women. CONCLUSION: The substantially reduced mortality rate among HIV-positive individuals after ART roll-out lends further support to the intensification of efforts to ensure universal access to ART. PMID- 22943382 TI - Adult mortality and probable cause of death in rural northern Malawi in the era of HIV treatment. AB - OBJECTIVES: Developing countries are undergoing demographic transition with a shift from high mortality caused by communicable diseases (CD) to lower mortality rates caused by non-communicable diseases (NCD). HIV/AIDS has disrupted this trend in sub-Saharan Africa. However, in recent years, HIV-associated mortality has been reduced with the introduction of widely available antiretroviral therapy (ART). Side effects of ART may lead to increased risk of cardiovascular diseases, raising the prospects of an accelerated transition towards NCD as the primary cause of death. We report population-based data to investigate changes in cause of death owing to NCD during the first 4 years after introduction of HIV treatment. METHODS: We analysed data from a demographic surveillance system in Karonga district, Malawi, from September 2004 to August 2009. ART was introduced in mid-2005. Clinician review of verbal autopsies conducted 2-6 weeks after a death was used to establish a single principal cause of death. RESULTS: Over the entire period, there were 905 deaths, AIDS death rate fell from 505 to 160/100,000 person-years, and there was no evidence of an increase in NCD rates. The proportion of total deaths attributable to AIDS fell from 42% to 17% and from NCD increased from 37% to 49%. DISCUSSION: Our findings show that 4 years after the introduction of ART into HIV care in Karonga district, all-cause mortality has fallen dramatically, with no evidence of an increase in deaths owing to NCD. PMID- 22943383 TI - The effect of antiretroviral therapy provision on all-cause, AIDS and non-AIDS mortality at the population level--a comparative analysis of data from four settings in Southern and East Africa. AB - OBJECTIVE: To provide a broad and up-to-date picture of the effect of antiretroviral therapy (ART) provision on population-level mortality in Southern and East Africa. METHODS: Data on all-cause, AIDS and non-AIDS mortality among 15 59 year olds were analysed from demographic surveillance sites (DSS) in Karonga (Malawi), Kisesa (Tanzania), Masaka (Uganda) and the Africa Centre (South Africa), using Poisson regression. Trends over time from up to 5 years prior to ART roll-out, to 4-6 years afterwards, are presented, overall and by age and sex. For Masaka and Kisesa, trends are analysed separately for HIV-negative and HIV positive individuals. For Karonga and the Africa Centre, trends in AIDS and non AIDS mortality are analysed using verbal autopsy data. RESULTS: For all-cause mortality, overall rate ratios (RRs) comparing the period 2-6 years following ART roll-out with the pre-ART period were 0.58 (5.9 vs. 10.2 deaths per 1000 person years) in Karonga, 0.79 (7.2 vs. 9.1 deaths per 1000 person-years) in Kisesa, 0.61 (6.7 compared with 11.0 deaths per 1000 person-years) in Masaka and 0.79 (14.8 compared with 18.6 deaths per 1000 person-years) in the Africa Centre DSS. The mortality decline was seen only in HIV-positive individuals/AIDS mortality, with no decline in HIV-negative individuals/non-AIDS mortality. Less difference was seen in Kisesa where ART uptake was lower. CONCLUSIONS: Falls in all-cause mortality are consistent with ART uptake. The largest falls occurred where ART provision has been decentralised or available locally, suggesting that this is important. PMID- 22943384 TI - Enhanced random skin flap survival by sustained delivery of fibroblast growth factor 2 in rats. AB - BACKGROUND: Skin flap survival is a major challenge in reconstructive plastic surgery. Here, we examined the effect of sustained delivery of fibroblast growth factor 2 (FGF2) using heparin-conjugated fibrin (HCF) on skin flap survival in rats. METHODS: Rats with a skin flap received either phosphate-buffered saline/FGF2 or HCF/FGF2 in the recipient bed. For the no-treatment group, a random skin flap was sutured on the back without any treatment. Seven days after surgery, angiogenesis in the skin flap was evaluated by using Visitrak system and conventional healing quality scoring method. The efficacy of HCF/FGF2 in skin flap survival was evaluated by comparing the results from different groups. RESULTS: The necrotic area of the skin flap significantly decreased in the HCF/FGF2 group as compared with the other groups. CONCLUSION: The sustained delivery of FGF2 using HCF has a therapeutic potential to improve skin flap survival. PMID- 22943385 TI - Carboplatin AUC 10 for IGCCCG good prognosis metastatic seminoma. AB - OBJECTIVE: Metastatic seminoma is a highly curable disease. Standard treatment comprises of combination chemotherapy. The short- and long-term toxicities of this treatment are increasingly recognised and the possibility of over treatment in such a curable disease should be considered. We have therefore assessed the use of single agent carboplatin at a dose of AUC 10 in patients with good prognosis metastatic seminoma. MATERIALS AND METHODS: Patients with good prognosis metastatic seminoma treated with carboplatin (AUC 10) were identified at our institution and affiliated institutions. Treatment was three weekly for a total of three or four cycles. Outcome and toxicities were analysed. RESULTS: With a median follow-up of 36 months, 61 patients in total were treated with carboplatin AUC 10, all good prognosis by the IGCCCG criteria. Forty-eight percent had stage IIA/IIB disease and 52% had greater than stage IIB disease. Thirty-one patients (51%) had a complete response following treatment. Three-year survival was 96.3% with a three-year progression free survival of 93.2%. The main treatment toxicity was haematological with 46% having grade 3, 24% having grade 4 neutropenia and 54% experiencing grade 3/4 thrombocytopenia. There were no treatment related deaths. CONCLUSION: Single agent carboplatin at a dose of AUC 10 is an effective treatment for good prognosis metastatic seminoma. The outcome compares favourably to previously published outcomes of combination chemotherapy. Although haematological toxicity is a concern, single agent carboplatin treatment for good prognosis metastatic seminoma could be considered a treatment option and is associated with less toxicity than combination regimens currently used. PMID- 22943386 TI - Seventeen-years overview of breast cancer inside and outside screening in Denmark. AB - BACKGROUND: Long-term data on breast cancer detection in mammography screening programs are warranted to better understand the mechanisms by which screening changes the breast cancer pattern in the population. We aimed to analyze 17 years of breast cancer detection rates inside and outside screening in two Danish regions, emphasizing the influence of organizational differences of screening programs on the outcomes. MATERIAL AND METHODS: We used data from two long standing population-based mammography screening programs, Copenhagen and Fyn, in Denmark. Both programs offered biennial screening to women aged 50-69 years. We identified targeted, eligible, invited and participating women. We calculated screening detection and interval cancer rates for participants, and breast cancer incidence in non-screened women (= targeted women excluding participants) by biennial invitation rounds. Tumor characteristics were tabulated for each of the three groups of cancers. RESULTS: Start of screening resulted in a prevalence peak in participants, followed by a decrease to a fairly stable detection rate in subsequent invitation rounds. A similar pattern was found for breast cancer incidence in non-screened women. In Fyn, non-screened women even had a higher rate than screening participants during the first three invitation rounds. The interval cancer rate was lower in Copenhagen than in Fyn, with an increase over time in Copenhagen, but not in Fyn. Screen-detected cancers showed tumor features related with a better prognosis than tumors detected otherwise, as more than 80% were smaller than 20 mm and estrogen receptor positive. CONCLUSION: Data from two long-standing population-based screening programs in Denmark illustrated that even if background breast cancer incidence and organization were rather similar, performance indicators of screening could be strongly influenced by inclusion criteria and participation rates. Detection rates should be interpreted with caution as they may be biased by selection into the screening population. PMID- 22943387 TI - Early diagnosis and treatment is crucial for neurological recovery after surgery for metastatic spinal cord compression in prostate cancer. AB - BACKGROUND: Spinal cord compression is an oncological and surgical emergency. Delays in referral and diagnosis may influence functional outcome. It is therefore important to identify patients who will regain or maintain the ability to walk after surgery. The aim of the present study was to examine current practice for referral and diagnosis of prostate cancer patients with spinal cord compression and to identify prognostic factors for neurological outcome after surgery. PATIENTS AND METHODS: The study includes 68 consecutive patients with prostate cancer who underwent surgery due to neurological compromise. Intervals from onset of neurological symptoms to referral, diagnosis, and treatment were analyzed in relation to functional outcome. The prognostic significance of preoperative clinical parameters on gait function one month after surgery was evaluated. RESULTS: Patients who were referred from local hospitals had longer delay to surgery than those who directly presented to the cancer center (p = 0.004). The rate of diagnosis with MRI increased through the week and peaked on Friday, with few patients being diagnosed during weekends. The ability to walk before surgery, hormone-naive prostate cancer, and/or shorter time from loss of ambulation were associated with more favorable neurological outcome. In patients with hormone-refractory disease who were unable to walk before surgery regaining ambulation was associated with: duration of paresis < 48 hours (p = 0.005), good preoperative performance status (p = 0.04), preoperative PSA serum level < 200 ng/ml (p = 0.03), and surgery with posterior decompression and stabilization (p = 0.03). CONCLUSION: Early diagnosis and rapid treatment of spinal cord compression in prostate cancer patients is crucial for neurological recovery. Raising awareness of the condition among patients at risk and among physicians is of outmost importance as well as improving local and regional guidelines for treatment. PMID- 22943388 TI - Health related quality of life in male patients with osteoporosis: results of a cross sectional study. AB - INTRODUCTION: Osteoporosis is one of the most common diseases affecting elderly persons. Male patients with osteoporosis have rarely been the focus of earlier studies. This study explores health related quality of life (HRQoL) indicators in a sample of German male patients with osteoporosis to determine potential avenues for clinical practice changes. METHODS: This cross-sectional study describes two HRQoL indicators (EQ5D and QUALEFFO-41) in a sample of male patients being treated for osteoporosis. Questionnaires were sent to all male patients being treated at the Dresden University Hospital outpatient endocrine clinic. Of the 344 patients invited to participate in the study 155 (57.2%) were included. RESULTS: Overall HRQoL EQ-5D-scores for male patients with osteoporosis were greater than those of comparable groups of the German population. Patients with >=2 fractures had the highest level of impairment in HRQoL. Of all the dimensions of EQ-5D-scores, pain/discomfort was the most affected. Better HRQoL (median values <10.0/QUALEFFO-41 scores) were detected in the whole sample for jobs around the house, activities of daily living and mobility compared to other dimensions. The highest levels of impairment were observed in the QUALEFFO-41 domains of general health perception, mental function and pain. CONCLUSION: This analysis confirms the association between number of fractures and worse estimation of HRQoL in male patients. Because men are 3 times less likely to suffer from osteoporosis than women, the specific HRQoL characteristics of male patients with this disease can often be overlooked. Clinicians should consider mental health referral especially for osteoporotic male patients having experienced >=2 fractures. PMID- 22943389 TI - Spontaneous Incomplete transverse subtrochanteric femoral fracture with cortical thickening possibly secondary to risedronate use: a case report. AB - INTRODUCTION: Osteoporosis is an asymptomatic disease characterized by bone weakening and predisposition to fragility (insufficiency) fractures and can have devastating effects on individual life and great financial impact on the economy. Bisphosphonates are used worldwide for the primary and secondary prevention of osteoporotic fractures. However, increasing evidence raises concern that bisphosphonates can be associated with atypical fractures. CASE PRESENTATION: A 65-year-old Caucasian woman on long-term steroid treatment for polymyalgia rheumatica was admitted with severe and constant pain in the right hip, radiating to the right knee. She had a history of steroid-induced osteoporosis, for which she was started on risedronate four years earlier. She had no history of trauma. Her blood results were unremarkable. Her X-rays confirmed that she had an incomplete right subtrochanteric femoral fracture. A bone scan confirmed the diagnosis and also ruled out any other associated fractures. Our patient successfully underwent internal nail fixation of the fracture. She was reviewed by a rheumatology team, which stopped the risedronate. She was started on treatment with denosumab injection. CONCLUSIONS: Previous case series have reported that long-term bisphosphonate use is associated with atypical fractures of the femur, and certain criteria have been established to help identify such rare fractures. Delayed union or non-union is expected in such fractures following definitive orthopedic treatment because of the long half life of bisphosphonates. In this case report, we try to raise questions related to this important subject, like the duration and safety of bisphosphonate use and the alternative medications used in osteoporosis in this rare condition. We consider this case report not only interesting but also important and unusual because it is about a patient who developed a potentially rare and serious side effect of long-term bisphosphonate use, estimated to affect 2.3 in every 10,000 patients, and who presented with a pelvic X-ray that showed the characteristic features of atypical fractures secondary to risedronate use. In addition, most of the documented cases have been associated with many years of bisphosphonate use whereas our patient had been on risedronate for only four years. PMID- 22943390 TI - Analysis of kidney dysfunction in orthopaedic patients. AB - BACKGROUND: This retrospective study was undertaken to determine the incidence of kidney dysfunction (KD) and to identify potential risk factors contributing to development of KD in orthopaedic population following an elective or emergency surgery. METHODS: A total of 1025 patients were admitted in our institution over a period of one year with various indications. Eight hundred and ninety-three patients (87.1%) had a surgical procedure. There were 42 (52.5%) male and 38 (47.5%) female with a mean age of 72 years (range: 47 to 87 years). We evaluated the following potential risk factors: age, comorbidities, shock, hypotension, heart failure, medications (antibiotics, NSAIDs, opiates), rhabdomyolysis, imaging contrast agents and pre-existing KD. RESULTS: The overall incidence of KD was 8.9%. Sixty-eight patients developed acute renal injury (AKI) and 12 patients developed acute on chronic kidney disease (CKD). In sixty-six (82.5%) patients renal function was reversed to initial preoperative status. Perioperative dehydration (p = 0.002), history of diabetes mellitus (p = 0.003), pre-existing KD (p = 0.004), perioperative shock (p = 0.021) and administration of non-steroid anti-inflammatory drugs (NSAIDs) (p = 0.028) or nephrotoxic antibiotics (p = 0.037) were statistically significantly correlated with the development of postoperative KD and failure to gain the preoperative renal function. CONCLUSION: We conclude that every patient with risk factor for postoperative KD should be under closed evaluation and monitoring. PMID- 22943391 TI - Lung injury prediction score for the emergency department: first step towards prevention in patients at risk. AB - BACKGROUND: Early identification of patients at risk of developing acute lung injury (ALI) is critical for potential preventive strategies. We aimed to derive and validate an acute lung injury prediction score (EDLIPS) in a multicenter sample of emergency department (ED) patients. METHODS: We performed a subgroup analysis of 4,361 ED patients enrolled in the previously reported multicenter observational study. ED risk factors and conditions associated with subsequent ALI development were identified and included in the EDLIPS model. Scores were derived and validated using logistic regression analyses. The model was assessed with the area under the receiver-operating curve (AUC) and compared to the original LIPS model (derived from a population of elective high-risk surgical and ED patients) and the Acute Physiology and Chronic Health Evaluation (APACHE II) score. RESULTS: The incidence of ALI was 7.0% (303/4361). EDLIPS discriminated patients who developed ALI from those who did not with an AUC of 0.78 (95% CI 0.75, 0.82), better than the APACHE II AUC 0.70 (p <= 0.001) and similar to the original LIPS score AUC 0.80 (p = 0.07). At an EDLIPS cutoff of 5 (range -0.5, 15) positive and negative likelihood ratios (95% CI) for ALI development were 2.74 (2.43, 3.07) and 0.39 (0.30, 0.49), respectively, with a sensitivity 0.72(0.64, 0.78), specificity 0.74 (0.72, 0.76), and positive and negative predictive value of 0.18 (0.15, 0.21) and 0.97 (0.96, 0.98). CONCLUSION: EDLIPS may help identify patients at risk for ALI development early in the course of their ED presentation. This novel model may detect at-risk patients for treatment optimization and identify potential patients for ALI prevention trials. PMID- 22943392 TI - Complete mitochondrial genome of the striped sandgoby Acentrogobius pflaumii (Perciformes, gobiidae). AB - The striped sandgoby, Acentrogobius pflaumii (Perciformes, Gobiidae), is a widespread goby inhabiting shallow sandy-muddy bottoms in temperate riverine estuaries and inner bays. In this study, the complete mitochondrial genome of A. pflaumii was firstly determined. The genome is 16,515 bp in length and consists of 13 protein-coding genes, 22 tRNA genes, 2 ribosomal RNA genes, and 2 main non coding regions (the control region and the origin of the light-strand replication). The overall base composition of A. pflaumii is 25.8% for T, 29.3% for C, 26.6% for A, and 18.3% for G, with a slight A+T bias of 52.4%. It has the typical vertebrate mitochondrial gene arrangement. PMID- 22943393 TI - Investigating the association between vitamin D deficiency and sepsis: challenges and future prospects. PMID- 22943394 TI - When TB associates with diabetes. PMID- 22943396 TI - Complications of sepsis: the role of risk prediction rules, biomarkers and host genetics. AB - The subtitle of the Australasian Society for Infectious Diseases Annual Scientific Meeting was 'Sailing into the Future', and speakers from both adult and pediatric infectious diseases explored this theme in relation to the management of sepsis. The future will entail better risk prediction tools for patients at risk for sepsis. Such risk prediction tools are likely to incorporate genetic profiling of the host to identify the groups at highest risk for disease and death. Focused diagnostic testing in these patients will include molecular diagnostics for early detection of infection. PMID- 22943397 TI - Immune reconstitution inflammatory syndrome in a large multicenter cohort study: case definition and comparability. AB - This study was nested within the HIV Outpatient Study cohort and investigated the incidence and risk factors for immune reconstitution inflammatory syndrome (IRIS) and the impact of IRIS on mortality. IRIS was defined as a new type B or C AIDS defining condition or one of a range of mucocutaneous or autoimmune conditions diagnosed within 180 days of starting a new combination antiretroviral therapy regimen, provided there was a documented HIV viral load or CD4 response. IRIS occurred in 10.6% of the 2610 patients. Risk factors independently associated with IRIS included high HIV viral load and low CD4 count. IRIS related to type B or C AIDS-defining conditions was associated with subsequent mortality. Deaths among IRIS cases occurred over 3 years (median) after the IRIS event, making it unlikely that these deaths were directly attributable to IRIS. The IRIS case definition used has important differences when compared with previously published IRIS case definitions thereby affecting comparability of these findings, but this was a pragmatic definition for a large multicenter cohort study utilizing a central database. PMID- 22943398 TI - West Nile virus infections in Greece: an update. AB - Approximately 2 years have passed since the detection of the first human case of West Nile virus (WNV) infection in Greece, which was the starting signal of a large outbreak in 2010, followed by a second one in 2011. More than 250 neuroinvasive disease cases with 15% fatality were observed during the two WNV seasons. WNV lineage 2 sequences were obtained from blood donors, Culex mosquitoes, wild birds and sentinel chickens. The Greek WNV strain shows high genetic relatedness to the goshawk-Hungary/04 WNV strain; an amino acid substitution in nonstructural protein 3 (H249P) is observed, which has been previously associated with increased virus transmission. This article provides an overview of the WNV outbreaks in Greece and discusses the knowledge gained from these events. PMID- 22943399 TI - Influenza outbreaks in Singapore: epidemiology, diagnosis, treatment and prevention. AB - With the recent influenza A/H1N1 2009 pandemic still spreading through global populations, there has been an increased focus on optimizing the prevention, diagnosis and treatment of influenza infections, as well as the epidemiology of the virus. Clinical and epidemiological data on influenza infections in tropical countries have been relatively sparse until fairly recently, and it is the aim of this review to close some of these gaps by examining the behavior of influenza viruses in the tropical Singaporean population. PMID- 22943400 TI - The glory of guidelines and the twilight of reality: controversies and challenges in the prevention and treatment of HIV in children. AB - Since the discovery of HIV 30 years ago, we have learned much about HIV in children and adolescents. Dramatic declines have occurred in mother-to-child transmission of HIV in resource-rich countries. Resource-poor countries struggle with improving prevention of mother-to-child transmission due to the lack of universal antiretroviral treatment for pregnant and nursing mothers. In children infected with HIV, pharmacokinetic, safety and efficacy data have been determined for many of the older drugs. Data are lacking for the newer, safer and more effective currently available drugs, resulting in the pediatric guidelines lagging behind adult recommendations. Although guidelines for prevention and treatment are helpful, the way they are created causes them to lag behind new scientific evidence, and in some situations they will be confusing or only based on expert opinion. Improving prevention of HIV infection in adolescents and young adults and in treating those who become HIV infected is crucially important. The next 10 years hold tremendous opportunities for improvements in prevention and treatment of HIV in children, adolescents and young adults. PMID- 22943401 TI - Plant essential oils and their constituents in coping with multidrug-resistant bacteria. AB - Antibiotic resistance is documented to be a serious problem that affects the choice of appropriate antibiotic therapy and increases the probability of unfavorable infection outcome. One of the proposed methods to cope with multidrug resistant (MDR) bacteria is the use of alternative antibacterial treatments, which include natural antimicrobial substances such as plant essential oils (EOs). The aim of the present article is to review published studies on the activity of EOs and their constituents against MDR bacteria and to formulate perspectives for the future. In general, published studies indicate that EOs can be used as effective antiseptics against many species, including MDR bacteria, such as methicillin-resistant Staphylococcus aureus, vancomycin-resistant enterococci, resistant isolates of Pseudomonas aeruginosa, Klebsiella pneumoniae and others; certain EOs may potentiate the effectiveness of antibiotics against MDR bacteria; EOs can be synergistic with bacteriophages; and polymeric nanoparticles can be used for delivery of EOs and enhancement of their activity at the site of infection. PMID- 22943402 TI - Antimicrobial chemotherapy of Mycoplasma genitalium-positive non-gonococcal urethritis. AB - Mycoplasma genitalium is an important pathogen of acute non-gonococcal urethritis (NGU) in men and plays a significant role in persistent or recurrent NGU. In the management of patients with M. genitalium-positive NGU, eradication of the mycoplasma from the urethra is necessary to prevent persistent or recurrent NGU. Therefore, M. genitalium should be considered for antimicrobial chemotherapy of NGU. This article reviews the in vitro antimicrobial activities of antibiotics against M. genitalium and the efficacies of various antibiotic regimens against M. genitalium-positive NGU, including the doxycycline and azithromycin regimens recommended as first-line treatments for NGU in the guidelines. Selection of macrolide-resistant M. genitalium by treatment with the single-dose regimen of 1 g azithromycin and mechanisms of macrolide resistance in M. genitalium are discussed. The effectiveness of the moxifloxacin regimen against persistent or recurrent NGU, unsuccessfully treated with azithromycin and/or doxycycline regimens, is emphasized. PMID- 22943403 TI - Management of necrotizing skin and soft tissue infections. AB - Although rare, necrotizing skin and soft tissue infections can be devastating infections that are difficult to diagnose and challenging to manage. Clinical presentation is often insidious, and a low index of suspicion is critical. Various diagnostic tools, such as scoring systems or imaging techniques, have been introduced, but none is convincingly superior to sound clinical judgment. Early diagnosis allows early adequate therapy that includes antibiotic therapy, critical care support, specific interventions such as intravenous immunoglobulin in selected patients and, most importantly, early source control. Empirical antibiotic therapy should cover a broad range of both Gram-negative and Gram positive aerobic and anaerobic microorganisms, and clindamycin is recommended when group A Streptococcus is a suspected pathogen. PMID- 22943404 TI - Toxoplasmosis in the fetus and newborn: an update on prevalence, diagnosis and treatment. AB - Toxoplasma gondii is an unicellular coccidian parasite with worldwide distribution. It is estimated that more than a third of the world's population has been infected with the parasite, but seroprevalence is unevenly distributed across countries and different socioeconomic strata. The majority of newborns with congenital toxoplasmosis do not have any clinical signs of the disease at birth; however, 30-70% of those with clinical abnormalities were not detected initially, and are found to have new retinal lesions consistent with toxoplasmicchorioretinitis later in life. Congenital toxoplasmosis can also cause fetal death, stillbirths or long-term disabling sequelae, particularly among untreated infants. The disease appears to be more frequent and severe at certain latitudes. Congenital toxoplasmosis can be prevented and treated during gestation. Less severe disease is commonly reported in countries where prenatal screening and treatment have been systematically implemented. By contrast, severe disease appears to be observed primarily in infants born to untreated mothers. For definition purposes, it is best to use the term toxoplasma or Toxoplasma gondii infection when referring to asymptomatic patients with primary or chronic infection, and toxoplasmosis when referring to patients with symptoms or signs. PMID- 22943406 TI - Effects of oral antioxidant treatment upon the dynamics of human sperm DNA fragmentation and subpopulations of sperm with highly degraded DNA. AB - The primary aim of this study was to determine the effect of oral antioxidant treatment (1500 mg of l-Carnitine; 60 mg of vitamin C; 20 mg of coenzyme Q10; 10 mg of vitamin E; 10 mg of zinc; 200 MUg of vitamin B9; 50 MUg of selenium; 1 MUg of vitamin B12) during a time period of 3 months upon the dynamics of sperm DNA fragmentation following varying periods of sperm storage (0 h, 2 h, 6 h, 8 h and 24 h) at 37 degrees C in a cohort of 20 infertile patients diagnosed with asthenoteratozoospermia. A secondary objective was to use the sperm chromatin dispersion test (SCD) to study antioxidant effects upon a specific subpopulation of highly DNA degraded sperm (DDS). Semen parameters and pregnancy rate (PR) were also determined. Results showed a significant improvement of DNA integrity at all incubation points (P < 0.01). The proportion of DDS was also significantly reduced (P < 0.05). Semen analysis data showed a significant increase in concentration, motility, vitality and morphology parameters. Our results suggest that antioxidant treatment improves sperm quality not only in terms of key seminal parameters and basal DNA damage, but also helps to maintain DNA integrity. Prior administration of antioxidants could therefore promote better outcomes following assisted reproductive techniques. PMID- 22943407 TI - The activity of carbohydrate-degrading enzymes in the development of brood and newly emerged workers and drones of the Carniolan honeybee, Apis mellifera carnica. AB - The activity of glycogen Phosphorylase and carbohydrate hydrolyzing enzymes alpha amylase, glucoamylase, trehalase, and sucrase was studied in the development of the Carniolan honey bee, Apis mellifera carnica Pollman (Hymenoptera: Apidae), from newly hatched larva to freshly emerged imago of worker and drone. Phosphorolytic degradation of glycogen was significantly stronger than hydrolytic degradation in all developmental stages. Developmental profiles of hydrolase activity were similar in both sexes of brood; high activity was found in unsealed larvae, the lowest in prepupae followed by an increase in enzymatic activity. Especially intensive increases in activity occurred in the last stage of pupae and newly emerged imago. Besides alpha-amylase, the activities of other enzymes were higher in drone than in worker broods. Among drones, activity of glucoamylase was particularly high, ranging from around three times higher in the youngest larvae to 13 times higher in the oldest pupae. This confirms earlier suggestions about higher rates of metabolism in drone broods than in worker broods. PMID- 22943408 TI - Management of difficult multidrug-resistant tuberculosis and extensively drug resistant tuberculosis: update 2012. AB - Multidrug-resistant (MDR) tuberculosis (TB) denotes bacillary resistance to at least isoniazid and rifampicin. Extensively drug-resistant (XDR) TB is MDR-TB with additional bacillary resistance to any fluoroquinolone and at least one second-line injectable drugs. Rooted in inadequate TB treatment and compounded by a vicious circle of diagnostic delay and improper treatment, MDR-TB/XDR-TB has become a global epidemic that is fuelled by poverty, human immunodeficiency virus (HIV) and neglect of airborne infection control. The majority of MDR-TB cases in some settings with high prevalence of MDR-TB are due to transmission of drug resistant bacillary strains to previously untreated patients. Global efforts in controlling MDR-TB/XDR-TB can no longer focus solely on high-risk patients. It is difficult and costly to treat MDR-TB/XDR-TB. Without timely implementation of preventive and management strategies, difficult MDR-TB/XDR-TB can cripple global TB control efforts. Preventive strategies include prompt diagnosis with adequate TB treatment using the directly observed therapy, short-course (DOTS) strategy and drug-resistance programmes, airborne infection control, preventive treatment of TB/HIV, and optimal use of antiretroviral therapy. Management strategies for established cases of difficult MDR-TB/XDR-TB rely on harnessing existing drugs (notably newer generation fluoroquinolones, high-dose isoniazid, linezolid and pyrazinamide with in vitro activity) in the best combinations and dosing schedules, together with adjunctive surgery in carefully selected cases. Immunotherapy may also have a role in the future. New diagnostics, drugs and vaccines are required to meet the challenge, but science alone is insufficient. Difficult MDR-TB/XDR-TB cannot be tackled without achieving high cure rates with quality DOTS and beyond, and concurrently addressing poverty and HIV. PMID- 22943409 TI - Editorial comment to single-session ureteroscopy with holmium laser lithotripsy for multiple stones. PMID- 22943410 TI - Identification of uterine ion transporters for mineralisation precursors of the avian eggshell. AB - BACKGROUND: In Gallus gallus, eggshell formation takes place daily in the hen uterus and requires large amounts of the ionic precursors for calcium carbonate (CaCO3). Both elements (Ca2+, HCO3-) are supplied by the blood via trans epithelial transport. Our aims were to identify genes coding for ion transporters that are upregulated in the uterine portion of the oviduct during eggshell calcification, compared to other tissues and other physiological states, and incorporate these proteins into a general model for mineral transfer across the tubular gland cells during eggshell formation. RESULTS: A total of 37 candidate ion transport genes were selected from our database of overexpressed uterine genes associated with eggshell calcification, and by analogy with mammalian transporters. Their uterine expression was compared by qRTPCR in the presence and absence of eggshell formation, and with relative expression levels in magnum (low Ca2+/HCO3- movement) and duodenum (high rates of Ca2+/HCO3- trans-epithelial transfer). We identified overexpression of eleven genes related to calcium movement: the TRPV6 Ca2+ channel (basolateral uptake of Ca2+), 28 kDa calbindin (intracellular Ca2+ buffering), the endoplasmic reticulum type 2 and 3 Ca2+ pumps (ER uptake), and the inositol trisphosphate receptors type 1, 2 and 3 (ER release). Ca2+ movement across the apical membrane likely involves membrane Ca2+ pumps and Ca2+/Na+ exchangers. Our data suggests that Na+ transport involved the SCNN1 channel and the Na+/Ca2+ exchangers SLC8A1, 3 for cell uptake, the Na+/K+ ATPase for cell output. K+ uptake resulted from the Na+/K+ ATPase, and its output from the K+ channels (KCNJ2, 15, 16 and KCNMA1).We propose that the HCO3- is mainly produced from CO2 by the carbonic anhydrase 2 (CA2) and that HCO3- is secreted through the HCO3-/Cl- exchanger SLC26A9. HCO3- synthesis and precipitation with Ca2+ produce two H+. Protons are absorbed via the membrane's Ca2+ pumps ATP2B1, 2 in the apical membrane and the vacuolar (H+)-atpases at the basolateral level. Our model incorporate Cl- ions which are absorbed by the HCO3 /Cl- exchanger SLC26A9 and by Cl- channels (CLCN2, CFTR) and might be extruded by Cl-/H+ exchanger (CLCN5), but also by Na+ K+ 2 Cl- and K+ Cl- cotransporters. CONCLUSIONS: Our Gallus gallus uterine model proposes a large list of ion transfer proteins supplying Ca2+ and HCO3- and maintaining cellular ionic homeostasis. This avian model should contribute towards understanding the mechanisms and regulation for ionic precursors of CaCO3, and provide insight in other species where epithelia transport large amount of calcium or bicarbonate. PMID- 22943411 TI - Transcriptional regulation of the operon encoding stress-responsive ECF sigma factor SigH and its anti-sigma factor RshA, and control of its regulatory network in Corynebacterium glutamicum. AB - BACKGROUND: The expression of genes in Corynebacterium glutamicum, a Gram positive non-pathogenic bacterium used mainly for the industrial production of amino acids, is regulated by seven different sigma factors of RNA polymerase, including the stress-responsive ECF-sigma factor SigH. The sigH gene is located in a gene cluster together with the rshA gene, putatively encoding an anti-sigma factor. The aim of this study was to analyze the transcriptional regulation of the sigH and rshA gene cluster and the effects of RshA on the SigH regulon, in order to refine the model describing the role of SigH and RshA during stress response. RESULTS: Transcription analyses revealed that the sigH gene and rshA gene are cotranscribed from four sigH housekeeping promoters in C. glutamicum. In addition, a SigH-controlled rshA promoter was found to only drive the transcription of the rshA gene. To test the role of the putative anti-sigma factor gene rshA under normal growth conditions, a C. glutamicum rshA deletion strain was constructed and used for genome-wide transcription profiling with DNA microarrays. In total, 83 genes organized in 61 putative transcriptional units, including those previously detected using sigH mutant strains, exhibited increased transcript levels in the rshA deletion mutant compared to its parental strain. The genes encoding proteins related to disulphide stress response, heat stress proteins, components of the SOS-response to DNA damage and proteasome components were the most markedly upregulated gene groups. Altogether six SigH dependent promoters upstream of the identified genes were determined by primer extension and a refined consensus promoter consisting of 45 original promoter sequences was constructed. CONCLUSIONS: The rshA gene codes for an anti-sigma factor controlling the function of the stress-responsive sigma factor SigH in C. glutamicum. Transcription of rshA from a SigH-dependent promoter may serve to quickly shutdown the SigH-dependent stress response after the cells have overcome the stress condition. Here we propose a model of the regulation of oxidative and heat stress response including redox homeostasis by SigH, RshA and the thioredoxin system. PMID- 22943412 TI - Bafilomycin A1 activates HIF-dependent signalling in human colon cancer cells via mitochondrial uncoupling. AB - Mitochondrial uncoupling is implicated in many patho(physiological) states. Using confocal live cell imaging and an optical O2 sensing technique, we show that moderate uncoupling of the mitochondria with plecomacrolide Baf (bafilomycin A1) causes partial depolarization of the mitochondria and deep sustained deoxygenation of human colon cancer HCT116 cells subjected to 6% atmospheric O2. A decrease in iO2 (intracellular O2) to 0-10 MUM, induced by Baf, is sufficient for stabilization of HIFs (hypoxia inducible factors) HIF-1alpha and HIF-2alpha, coupled with an increased expression of target genes including GLUT1 (glucose transporter 1), HIF PHD2 (prolyl hydroxylase domain 2) and CAIX (carbonic anhydrase IX). Under the same hypoxic conditions, treatment with Baf causes neither decrease in iO2 nor HIF-alpha stabilization in the low-respiring HCT116 cells deficient in COX (cytochrome c-oxidase). Both cell types display equal capacities for HIF-alpha stabilization by hypoxia mimetics DMOG (dimethyloxalylglycine) and CoCl2, thus suggesting that the effect of Baf under hypoxia is driven mainly by mitochondrial respiration. Altogether, by activating HIF signalling under moderate hypoxia, mitochondrial uncoupling can play an important regulatory role in colon cancer metabolism and modulate adaptation of cancer cells to natural hypoxic environments. PMID- 22943413 TI - Synthesis, evaluation and molecular docking of thiazolopyrimidine derivatives as dipeptidyl peptidase IV inhibitors. AB - A series of thiazolopyrimidine derivatives was designed, synthesized and screened for in-vitro inhibition of Dipeptidyl Peptidase IV (DPP IV). The SAR study indicated the influence of substituted chemical modifications on thiazolopyrimidine scaffold. Compound 9 (IC(50) = 0.489 MUm) and 10 (IC(50) = 0.329 MUm) having heterocyclic-substituted piperazine with acetamide linker resulted as most potent DPP IV inhibitors among all the compounds screened. Single dose (10 mg/kg) of both the compounds 9 and 10 significantly reduced glucose excursion during oral glucose tolerance test in streptozotocin induced diabetic rat model. Molecular docking studies illustrated the probable binding mode and interactions of thiazolopyrimidine nucleus and its derivatives at binding site of receptor. The binding site for DPP IV is composed of active site region (catalytic triad of Ser630, Asp708 and His740) including S1 and S2 sub pocket. The aryl moiety of compounds 9, 10 and 11 were observed to occupy S2 binding pocket and interacted with aromatic ring of Tyr662 and Tyr666 acquired through pi-pi interaction. Thus, it is indicated that occupancy of the highly hydrophobic S2 pocket is more important for DPP IV inhibitory activity. The present study on substituted thiazolopyrimidine derivatives shows good to moderate inhibitory potential of DPP IV enzyme. PMID- 22943414 TI - Annual Research Review: Mental health and resilience in HIV/AIDS-affected children-- a review of the literature and recommendations for future research. AB - BACKGROUND: To date, research on mental health in HIV-affected children (children who have an HIV-positive caregiver or live with the virus themselves) has focused on risk factors associated with the disease. However, simultaneous identification of factors that contribute to resilience in the face of risks is also needed. A greater understanding of modifiable protective processes that contribute to resilience in the mental health of children affected by HIV can inform the design of interventions that bolster naturally occurring supports and contribute to early prevention or better management of risks. METHODS: We reviewed the recent literature on mental health and resilience in children and adolescents affected by HIV/AIDS. Literature searches of PsycInfo and PubMed were conducted during July-December 2011 consistent with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) standards. Qualitative and quantitative studies were included for review if primary research questions pertained to mental health and coping or protective processes in children and families affected by HIV/AIDS. All studies subject to full review were evaluated for quality using a modified Systematic Assessment of Quality in Observational Research (SAQOR) rating system. RESULTS: One hundred and seventy one unique studies were returned from online searches of the literature and bibliography mining. Of these, 29 were evaluated as pertaining directly to mental health and resilience in families and children living with HIV/AIDS. Eight studies presented qualitative analyses. Ten quantitative studies examined individual resources contributing to child resilience and four quantitative studies looked at family level resources. Ten studies also investigated community level interactions. Four presented findings from resilience-focused interventions. CONCLUSIONS: There is a clear need for rigorous research on mental health and resilience in HIV-affected children and adolescents. The evidence base would greatly benefit from more standardized and robust approaches to thinking about resilience from an ecological perspective inclusive of resources at multiple levels and their interactions. PMID- 22943416 TI - Absence of Yps7p, a putative glycosylphosphatidylinositol-linked aspartyl protease in Pichia pastoris, results in aberrant cell wall composition and increased osmotic stress resistance. AB - Recently, studies performed on Saccharomyces cerevisiae and Candida albicans have confirmed the importance of fungal glycosylphosphatidylinositol (GPI)-anchored aspartyl proteases (yapsins) for cell-wall integrity. Genome sequence annotation of Pichia pastoris also revealed seven putative GPI-anchored aspartyl protease genes. The five yapsin genes assigned as YPS1, YPS2, YPS3, YPS7 and MKC7 in P. pastoris were disrupted. Among these putative GPI-linked aspartyl proteases, disruption of PpYPS7 gene confers the Ppyps7Delta mutant cell increased resistance to cell wall perturbing reagents congo red, calcofluor white (CW) and sodium dodecyl sulfate. Quantitative analysis of cell wall components shows lower content of chitin and increased amounts of beta-1,3-glucan. Further staining of the cell with CW demonstrates that disruption of PpYPS7 gene causes a reduction of the chitin content in lateral cell wall. Consistently, transmission electron micrographs show that the inner layer of mutant cell wall, mainly composed of chitin and beta-1, 3-glucan, is much thicker than that in parental strain GS115. Additionally, Ppyps7Delta mutant also exhibits increased osmotic resistance compared with parental strain GS115. This could be due to the dramatically elevated intracellular glycerol level in Ppyps7Delta mutant. These results suggest that PpYPS7 is involved in cell wall integrity and response to osmotic stress. PMID- 22943415 TI - Mass spectrometry for translational proteomics: progress and clinical implications. AB - The utility of mass spectrometry (MS)-based proteomic analyses and their clinical applications have been increasingly recognized over the past decade due to their high sensitivity, specificity and throughput. MS-based proteomic measurements have been used in a wide range of biological and biomedical investigations, including analysis of cellular responses and disease-specific post-translational modifications. These studies greatly enhance our understanding of the complex and dynamic nature of the proteome in biology and disease. Some MS techniques, such as those for targeted analysis, are being successfully applied for biomarker verification, whereas others, including global quantitative analysis (for example, for biomarker discovery), are more challenging and require further development. However, recent technological improvements in sample processing, instrumental platforms, data acquisition approaches and informatics capabilities continue to advance MS-based applications. Improving the detection of significant changes in proteins through these advances shows great promise for the discovery of improved biomarker candidates that can be verified pre-clinically using targeted measurements, and ultimately used in clinical studies - for example, for early disease diagnosis or as targets for drug development and therapeutic intervention. Here, we review the current state of MS-based proteomics with regard to its advantages and current limitations, and we highlight its translational applications in studies of protein biomarkers. PMID- 22943417 TI - Changes in the expression of proteins associated with aerobic glycolysis and cell migration are involved in tumorigenic ability of two glioma cell lines. AB - BACKGROUND: The most frequent and malignant brain cancer is glioblastoma multiforme (GBM). In gliomas, tumor progression and poor prognosis are associated with the tumorigenic ability of the cells. U87MG cells (wild-type p53) are known to be tumorigenic in nude mice, but T98G cells (mutant p53) are not tumorigenic. We investigated the proteomic profiling of these two cell lines in order to gain new insights into the mechanisms that may be involved in tumorigenesis. RESULTS: We found 24 differentially expressed proteins between T98G and U87MG cells. Gene Ontology supports the notion that over-representation of differentially expressed proteins is involved in glycolysis, cell migration and stress oxidative response. Among those associated with the glycolysis pathway, TPIS and LDHB are up regulated in U87MG cells. Measurement of glucose consumption and lactate production suggests that glycolysis is more effective in U87MG cells. On the other hand, G6PD expression was 3-fold higher in T98G cells and this may indicate a shift to the pentose-phosphate pathway. Moreover, GRP78 expression was also three-fold higher in T98G than in U87MG cells. Under thapsigargin treatment both cell lines showed increased GRP78 expression and the effect of this agent was inversely correlated to cell migration. Quantitative RT-PCR and immunohistochemistry of GRP78 in patient samples indicated a higher level of expression of GRP78 in grade IV tumors compared to grade I and non-neoplastic tissues, respectively. CONCLUSIONS: Taken together, these results suggest an important role of proteins involved in key functions such as glycolysis and cell migration that may explain the difference in tumorigenic ability between these two glioma cell lines and that may be extrapolated to the differential aggressiveness of glioma tumors. PMID- 22943419 TI - Reduction of transpiration and altered nutrient allocation contribute to nutrient decline of crops grown in elevated CO(2) concentrations. AB - Plants grown in elevated [CO(2) ] have lower protein and mineral concentrations compared with plants grown in ambient [CO(2) ]. Dilution by enhanced production of carbohydrates is a likely cause, but it cannot explain all of the reductions. Two proposed, but untested, hypotheses are that (1) reduced canopy transpiration reduces mass flow of nutrients to the roots thus reducing nutrient uptake and (2) changes in metabolite or enzyme concentrations caused by physiological changes alter requirements for minerals as protein cofactors or in other organic complexes, shifting allocation between tissues and possibly altering uptake. Here, we use the meta-analysis of previous studies in crops to test these hypotheses. Nutrients acquired mostly by mass flow were decreased significantly more by elevated [CO(2) ] than nutrients acquired by diffusion to the roots through the soil, supporting the first hypothesis. Similarly, Mg showed large concentration declines in leaves and wheat stems, but smaller decreases in other tissues. Because chlorophyll requires a large fraction of total plant Mg, and chlorophyll concentration is reduced by growth in elevated [CO(2) ], this supports the second hypothesis. Understanding these mechanisms may guide efforts to improve nutrient content, and allow modeling of nutrient changes and health impacts under future climate change scenarios. PMID- 22943418 TI - IgG glycan hydrolysis by EndoS inhibits experimental autoimmune encephalomyelitis. AB - Studies in experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis, have shown that B cells markedly influence the course of the disease, although whether their effects are protective or pathological is a matter of debate. EndoS hydrolysis of the IgG glycan has profound effects on IgG effector functions, such as complement activation and Fc receptor binding, suggesting that the enzyme could be used as an immunomodulatory therapeutic agent against IgG-mediated diseases. We demonstrate here that EndoS has a protective effect in myelin oligodendrocyte glycoprotein peptide amino acid 35-55 (MOG(35 55))-induced EAE, a chronic neuroinflammatory demyelinating disorder of the central nervous system (CNS) in which humoral immune responses are thought to play only a minor role. EndoS treatment in chronic MOG(35-55)-EAE did not impair encephalitogenic T cell priming and recruitment into the CNS of mice, consistent with a primary role of EndoS in controlling IgG effector functions. In contrast, reduced EAE severity coincided with poor serum complement activation and deposition within the spinal cord, suggesting that EndoS treatment impairs B cell effector function. These results identify EndoS as a potential therapeutic agent against antibody-mediated CNS autoimmune disorders. PMID- 22943422 TI - Surgical outcomes of 230 resected hilar cholangiocarcinoma in a single centre. AB - BACKGROUND: Low resectability rate and poor survival outcomes after surgical resection for hilar cholangiocarcinoma are common in most institutions. We retrospectively reviewed the surgical outcomes of hilar cholangiocarcinoma in a tertiary institution focusing on the surgical procedures, radicalities, survival rates and independent prognostic factors. METHODS: Two hundred thirty patients who underwent surgical resection for hilar cholangiocarcinoma between 1995 and 2010 were retrospectively analysed based on the clinical variables, Bismuth Corlette types, radicality of operation and survival rates. RESULTS: The median overall and disease-free survival time in the whole cohort were 39.1 and 19.2 months, respectively. Patients with type I or II tumour were more likely to undergo segmental bile duct resection than combined liver resection with lower R0 rates (68.2% and 76.1%, respectively). Liver resection (P < 0.001) and combined caudate lobectomy (P = 0.003) were associated with significantly higher R0 rates. Multivariate analysis showed that lymph node metastasis (P = 0.001), preoperative level of bilirubin above 3.0 mg/dL (P = 0.003) and positive resection margin (P = 0.033) were independent prognostic factors on overall survival. CONCLUSION: Liver resection and combined caudate lobectomy increased curative resection rates in hilar cholangiocarcinoma regardless of Bismuth-Corlette types. Preoperative biliary drainage should be performed in jaundiced patients to improve perioperative outcome and survival. PMID- 22943420 TI - Equine keratomycoses in California from 1987 to 2010 (47 cases). AB - REASONS FOR PERFORMING STUDY: Equine keratomycosis in the western USA has received little study, probably owing to its low prevalence. OBJECTIVES: To determine clinical features, predominant fungal isolates, treatment modalities and outcomes of horses with keratomycosis in California and compare these with results from different geographic regions. METHODS: Records of horses presented to the University of California-Davis Veterinary Medical Teaching Hospital (UCD VMTH) with confirmed keratomycosis between 1987 and 2010 were reviewed for this retrospective study. Information retrieved from the record included background, ophthalmic examination findings, treatment prior to and following presentation, visual outcome, and ocular survival. RESULTS: A total of 48 eyes in 47 horses met the inclusion criteria and comprised 2% of cases presented to the UCD-VMTH ophthalmology service. Prior to presentation, 20 horses (43%) received at least one topically administered anti-inflammatory medication. Keratomycosis was confirmed by fungal culture in 38 horses (81%), by histopathology in 2 horses (4%) and by cytology in 7 horses (15%). Forty-four isolates were identified in the 38 horses cultured; Aspergillus was the most common isolate (64%) and a novel isolate, Papulospora, was identified in 2 horses. Treatment consisted of medication only (73%), medical and surgical treatment (25%), or immediate enucleation (2%). Globe retention was 77% and vision retention was 53%. Corneal perforation was significantly associated with loss of vision (P<0.001). CONCLUSIONS: Keratomycosis is relatively uncommon in horses presented for ophthalmic conditions at UCD-VMTH. Corneal perforation was a negative prognostic indicator for vision in this population of northern Californian horses. PMID- 22943423 TI - Impact of garlic feeding (Allium sativum) on male fertility. AB - Many medicinal plants are designed to improve health but their mechanism of action remains not clear. Among these plants, garlic (Allium sativum) has attracted particular attention of modern medicine because of its widespread use for the prevention and treatment of some human diseases such as cardiovascular diseases and cancer. However, the impact of garlic on the male reproductive system has not been clearly defined. Some studies have reported that garlic improves male sexual function and has beneficial effect in the recovery of testicular functions. However, other authors have shown that this plant impairs testicular functions (such as inhibition of testosterone production) and has spermicidal effect on spermatozoa. In this review, we attempt to clarify the current ambiguity regarding the effects of garlic and its preparations on the male reproductive system. PMID- 22943424 TI - Occult posterolateral rotatory dislocation of the elbow with olecranon fracture in a child: a case report. AB - INTRODUCTION: Acute posterolateral rotator elbow dislocation in a child is rare and can be easily misdiagnosed due to immaturity of the epiphysis. This is the first case of occult posterolateral rotator elbow dislocation in combination with an olecranon fracture. We report our experience with this case, which was not diagnosed correctly by plain radiographs. CASE PRESENTATION: An 11-year-old Asian boy suffered severe pain and swelling of his right elbow after his outstretched arm hit a car dashboard in a motor vehicle accident. Plain radiographs showed only a minimally displaced olecranon fracture and a tiny lateral epicondylar avulsion fracture. However, stress radiographs under general anesthesia revealed severe posterolateral rotatory instability. During surgery, we found that the cartilaginous lateral epicondylar apophysis was much larger than the epicondylar fragment on the radiographs. After the lateral epicondylar osteochondral fragment and lateral collateral ligament complex were fixed, the instability disappeared. CONCLUSION: Our experience with this case shows that it is important to check for instability with pediatric elbow fractures, because a tiny avulsion fracture was able to cause severe posterolateral rotatory instability in a child. PMID- 22943425 TI - Protocol for a drugs exposure pregnancy registry for implementation in resource limited settings. AB - BACKGROUND: The absence of robust evidence of safety of medicines in pregnancy, particularly those for major diseases provided by public health programmes in developing countries, has resulted in cautious recommendations on their use. We describe a protocol for a Pregnancy Registry adapted to resource-limited settings aimed at providing evidence on the safety of medicines in pregnancy. METHODS/DESIGN: Sentinel health facilities are chosen where women come for prenatal care and are likely to come for delivery. Staff capacity is improved to provide better care during the pregnancy, to identify visible birth defects at delivery and refer infants with major anomalies for surgical or clinical evaluation and treatment. Consenting women are enrolled at their first antenatal visit and careful medical, obstetric and drug-exposure histories taken; medical record linkage is encouraged. Enrolled women are followed up prospectively and their histories are updated at each subsequent visit. The enrolled woman is encouraged to deliver at the facility, where she and her baby can be assessed. DISCUSSION: In addition to data pooling into a common WHO database, the WHO Pregnancy Registry has three important features: First is the inclusion of pregnant women coming for antenatal care, enabling comparison of birth outcomes of women who have been exposed to a medicine with those who have not. Second is its applicability to resource-poor settings regardless of drug or disease. Third is improvement of reproductive health care during pregnancies and at delivery. Facility delivery enables better health outcomes, timely evaluation and management of the newborn, and the collection of reliable clinical data. The Registry aims to improves maternal and neonatal care and also provide much needed information on the safety of medicines in pregnancy. PMID- 22943426 TI - Plant facilitation occurs between species differing in their associated arbuscular mycorrhizal fungi. AB - Complementary beneficial effects of different arbuscular mycorrhizal fungi (AMF) can result in a more efficient exploitation of the soil nutrients available, thus influencing plant communities. Here, we hypothesize that plant-AMF specificity is mediated by phylogenetic constraints defining possible interactions, and that plant-AMF interaction patterns can influence plant-plant facilitation specificity. We reanalyzed previous data describing plant-plant and plant-AMF interaction at the community level to specifically test for a phylogenetic signal on plant and AMF interactions and for a relationship between plant-plant facilitation specificity and plant species differences in their AMF associates. Closely related AMF operational taxonomical units (OTUs) tend to interact with the same plant species, but there is not a significant signal in the interaction through the plant phylogeny. This indicates that the similarity in the AMF associates of two plant species is independent of their phylogenetic relatedness. Interestingly, plant-AMF interactions match plant facilitation specificity, with pairs of plant species recruiting more frequently under each other tending to have different AMF associates. An increment of AMF diversity in the rhizosphere, as a result of plant-AMF and plant-plant selectivity, is suggested as a potential driver of plant-plant facilitation. This study highlights the role of plant-AMF interactions in shaping plant community assemblages. PMID- 22943428 TI - Effects of blue pulsed light on human physiological functions and subjective evaluation. AB - BACKGROUND: It has been assumed that light with a higher irradiance of pulsed blue light has a much greater influence than that of light with a lower irradiance of steady blue light, although they have the same multiplication value of irradiance and duration. We examined the non-visual physiological effects of blue pulsed light, and determined whether it is sensed visually as being blue. FINDINGS: Seven young male volunteers participated in the study. We placed a circular screen (diameter 500 mm) in front of the participants and irradiated it using blue and/or white light-emitting diodes (LEDs), and we used halogen lamps as a standard illuminant. We applied three steady light conditions of white LED (F0), blue LED + white LED (F10), and blue LED (F100), and a blue pulsed light condition of a 100-MUs pulse width with a 10% duty ratio (P10). The irradiance of all four conditions at the participant's eye level was almost the same, at around 12 MUW/cm2. We measured their pupil diameter, recorded electroencephalogram readings and Kwansei Gakuin Sleepiness Scale score, and collected subjective evaluations. The subjective bluish score under the F100 condition was significantly higher than those under other conditions. Even under the P10 condition with a 10% duty ratio of blue pulsed light and the F10 condition, the participant did not perceive the light as bluish. Pupillary light response under the P10 pulsed light condition was significantly greater than under the F10 condition, even though the two conditions had equal blue light components. CONCLUSIONS: The pupil constricted under the blue pulsed light condition, indicating a non-visual effect of the lighting, even though the participants did not perceive the light as bluish. PMID- 22943429 TI - Isolation and characterization of human primary enterocytes from small intestine using a novel method. AB - Cell culture studies of enterocytes are important in many fields. However, there are difficulties in obtaining cell lines from adult human intestine, such as microbial contamination of cultures from the tissue samples, short life span of enterocytes, overgrowth of mesenchymal cells, etc. Various model used to obtain adult intestinal cell lines are very complex requiring use of feeder layer or gel matrices. The aim of this study was to establish a novel method for the simple and reproducible isolation of human enterocytes. Enterocytes were isolated from SI samples (n = 5) obtained from cadaveric donors using a mechanical procedure, and separation with immunomagnetic beads coated with anti-EpCAM antibodies. Light and electron microscopy, flow cytometry and immunocytochemistry techniques were used to characterize the isolated cells. Immunohistochemical staining of normal SB biopsies confirmed that the cell cultures maintained an in vivo phenotype as reflected in cytokeratin expression CK18, CK20 and expression of intestine specific markers such as sucrase isomaltase and maltase glucoamylase. Furthermore, the cells strongly expressed TLR-5, 6, 7, 8 and 10 and several molecules such as CD40, CD86, CD44, ICAM-1 and HLA-DR which are important in triggering cell-mediated immune responses. This novel technique provides a unique in vitro system to study the biology of enterocytes in normal conditions as well as to study inflammatory processes in various small bowel disorders. PMID- 22943430 TI - Large-cell neuroendocrine carcinoma with epidermal growth factor receptor mutation: possible transformation of lung adenocarcinoma. PMID- 22943431 TI - Nonencapsulated Streptococcus pneumoniae resists extracellular human neutrophil elastase- and cathepsin G-mediated killing. AB - Although the Streptococcus pneumoniae polysaccharide capsule is an important virulence factor, ~ 15% of carriage isolates are nonencapsulated. Nonencapsulated S. pneumoniae are a cause of mucosal infections. Recent studies have shown that neutrophils kill S. pneumoniae predominately through neutrophil proteases, such as elastase and cathepsin G. Another recent finding is that nonencapsulated pneumococci have greater resistance to resist cationic antimicrobial peptides that are important in mucosal immunity. We here show that nonencapsulated pneumococci have greater resistance to extracellular human neutrophil elastase- and cathepsin G-mediated killing than isogenic encapsulated pneumococci. Resistance to extracellular neutrophil protease-mediated killing is likely to be of greater relative importance on mucosal surfaces compared to other body sites. PMID- 22943433 TI - The complete mitochondrial genome of Babina adenopleura (Anura: Ranidae). AB - The mitochondrial (mt) genome of Babina adenopleura (Anura: Ranidae) is a circular molecule of 18,982 bp in length, containing 38 genes as well as other anurans. The complete mtDNA of B. adenopleura is 18,982 bp in length, and the A+T content of the overall base composition of H-strand is 58.9% (T, 29.8%; C, 26.6%; A, 29.1%; G, 14.4%). The control regions are 3159 bp in length, and the A+T content of this region is 70.2% (A, 36.6%; C, 16.8%; G, 12.9%; T, 33.6%). The control region possesses distinct repeat regions at both 5' and 3' sides. A long space region between ND5 and ND6 genes is 461 bp. PMID- 22943432 TI - Evolution of selenoproteins in the metazoan. AB - BACKGROUND: The selenocysteine (Sec) containing proteins, selenoproteins, are an important group of proteins present throughout all 3 kingdoms of life. With the rapid progression of selenoprotein research in the post-genomic era, application of bioinformatics methods to the identification of selenoproteins in newly sequenced species has become increasingly important. Although selenoproteins in human and other vertebrates have been investigated, studies of primitive invertebrate selenoproteomes are rarely reported outside of insects and nematodes. RESULT: A more integrated view of selenoprotein evolution was constructed using several representative species from different evolutionary eras. Using a SelGenAmic-based selenoprotein identification method, 178 selenoprotein genes were identified in 6 invertebrates: Amphimedon queenslandica, Trichoplax adhaerens, Nematostella vectensis, Lottia gigantean, Capitella teleta, and Branchiostoma floridae. Amphioxus was found to have the most abundant and variant selenoproteins of any animal currently characterized, including a special selenoprotein P (SelP) possessing 3 repeated Trx-like domains and Sec residues in the N-terminal and 2 Sec residues in the C-terminal. This gene structure suggests the existence of two different strategies for extension of Sec numbers in SelP for the preservation and transportation of selenium. In addition, novel eukaryotic AphC-like selenoproteins were identified in sponges. CONCLUSION: Comparison of various animal species suggests that even the most primitive animals possess a selenoproteome range and variety similar to humans. During evolutionary history, only a few new selenoproteins have emerged and few were lost. Furthermore, the massive loss of selenoproteins in nematodes and insects likely occurred independently in isolated partial evolutionary branches. PMID- 22943434 TI - The interactions and recognition of cyclic peptide mimetics of Tat with HIV-1 TAR RNA: a molecular dynamics simulation study. AB - The interaction of HIV-1 trans-activator protein Tat with its cognate trans activation response element (TAR) RNA is critical for viral transcription and replication. Therefore, it has long been considered as an attractive target for the development of antiviral compounds. Recently, the conformationally constrained cyclic peptide mimetics of Tat have been tested to be a promising family of lead peptides. Here, we focused on two representative cyclic peptides termed as L-22 and KP-Z-41, both of which exhibit excellent inhibitory potency against Tat and TAR interaction. By means of molecular dynamics simulations, we obtained a detailed picture of the interactions between them and HIV-1 TAR RNA. In results, it is found that the binding modes of the two cyclic peptides to TAR RNA are almost identical at or near the bulge regions, whereas the binding interfaces at the apical loop exhibit large conformational heterogeneity. In addition, it is revealed that electrostatic interaction energy contributes much more to KP-Z-41 complex formation than to L-22 complex, which is the main source of energy that results in a higher binding affinity of KP-Z-41 over-22 for TAR RNA. Furthermore, we identified a conserved motif RRK (Arg-Arg-Lys) that is shown to be essential for specific binding of this class of cyclic peptides to TAR RNA. This work can provide a useful insight into the design and modification of cyclic peptide inhibitors targeting the association of HIV-1 Tat and TAR RNA. PMID- 22943435 TI - DNA with double-chained amphiphilic counterions and its interaction with lecithin. AB - Complex salts of double-stranded DNA with amphiphilic counterions offer novel opportunities for studies of DNA-lipid interactions. Here the effect of the hydrophobicity of the amphiphilic counterion is in focus. For this purpose, double stranded DNA with didodecyldimethylammonium ions as counterions, DDADNA, is prepared and investigated with respect to microstructure. In particular, in order to monitor the interactions with phospholipids, the phase diagram of the DDADNA/lecithin/water system is determined and compared with the previously determined phase diagram with single alkyl chain counterions, dodecyltrimethylammonium, DTA. In both systems, there is a formation of lamellar and reverse hexagonal phases, where hydrated DNA is sandwiched between bilayers or forms the core of reverse cylindrical micelles, respectively. However, whereas the lecithin lamellar phase can incorporate large amounts of DDADNA, there is in the case of the single chain surfactant, DTADNA, a transition to a bicontinuous cubic phase at higher DTADNA concentrations. The general appearance of the phase diagrams, and in particular the role of counterion hydrophobicity, can be rationalized in a simple geometric model. PMID- 22943436 TI - Who's worried about turkeys? How 'organisational silos' impede zoonotic disease surveillance. AB - Though emerging infectious diseases ignore boundaries between species, the agencies that respond to them do not. Based on interviews with state and federal epidemiologists, veterinarians, and physicians and on case studies of disease events, this article examines how the jurisdictional and cultural divides that exist among human and animal health agencies hinder efforts to successfully contain species-jumping diseases (zoonoses). I argue that newly emergent zoonoses make these agencies' organisational cultures function as silos because the institutionalised thinking and practices developed to address the diseases that traditionally concerned each agency constrain members from building the inter organisational bridges required to manage the latest 'hybrid' diseases. The silo effect is evident both across the human-animal health divide and within the landscape of animal health, as agencies that monitor livestock and wildlife follow distinct and sometimes competing agendas. The article also touches on moments of inter-agency cooperation in order to specify how health practitioners can begin making connections between 'organisational silos'. This article encourages sociologists of health to explore the crucial link between animal and human health; and it introduces the concept of organisational silos to capture the relational dilemmas that arise when a 'hybrid' problem systemically links agencies with disparate organisational cultures. PMID- 22943437 TI - Biological effects of AL622, a molecule rationally designed to release an EGFR and a c-Src kinase inhibitor. AB - In breast cancer cells expressing c-Src and EGFR, a control of one of the two oncogenes over proliferation and invasion is observed, whereas in others, the synergistic interaction between them is required for tumor progression. With the purpose of developing molecules with the highest probability for blocking the adverse effects of these two oncogenes, we designed AL622, which contains a quinazoline head targeted to EGFR and a linker that bridges it to the PP2-like structure for targeting c-Src. In case the entire molecule would not be capable of blocking c-Src, we designed AL622 to hydrolyze to an intact c-Src-targeting PP2 molecule. After confirming its binary c-Src-EGFR targeting potency of AL622, we analyzed its potency in isogenic NIH3T3 cells transfected with EGFR and HER2 and human breast cancer cells known to be dominated by c-Src function. The results showed that in EGFR/HER-2-driven cells, it was more potent than PP2 and its activity was in the same range as the latter in more c-Src-driven cells. Its ability to block motility and invasion was comparable with that of PP2 and corresponding combinations, indicating that AL622 could be a better antitumor agent in cells where c-Src and/or EGFR play a role. PMID- 22943438 TI - HIV prevalence and risk behaviours among injecting drug users in six indonesian cities implications for future HIV prevention programs. AB - BACKGROUND: The HIV prevalence among injecting drug users (IDUs) in Indonesia reached 50% in 2005. While drug use remains illegal in Indonesia, a needle and syringe program (NSP) was implemented in 2006. METHODS: In 2007, an integrated behavioural and biological surveillance survey was conducted among IDUs in six cities. IDUs were selected via time-location sampling and respondent-driven sampling. A questionnaire was administered face-to-face. IDUs from four cities were tested for HIV, syphilis, gonorrhoea and chlamydia. Factors associated with HIV were assessed using generalized estimating equations. Risk for sexual transmission of HIV was assessed among HIV-positive IDUs. RESULTS: Among 1,404 IDUs, 70% were daily injectors and 31% reported sharing needles in the past week. Most (76%) IDUs received injecting equipment from NSP in the prior week; 26% always carried a needle and those who didn't, feared police arrest. STI prevalence was low (8%). HIV prevalence was 52%; 27% among IDUs injecting less than 1 year, 35% among those injecting for 1-3 years compared to 61% in long term injectors (p < 0.001). IDUs injecting for less than 3 years were more likely to have used clean needles in the past week compared to long term injectors (p < 0.001). HIV-positive status was associated with duration of injecting, ever been imprisoned and injecting in public parks. Among HIV-infected IDUs, consistent condom use last week with steady, casual and commercial sex partners was reported by 13%, 24% and 32%, respectively. CONCLUSIONS: Although NSP uptake has possibly reduced HIV transmission among injectors with shorter injection history, the prevalence of HIV among IDUs in Indonesia remains unacceptably high. Condom use is insufficient, which advocates for strengthening prevention of sexual transmission alongside harm reduction programs. PMID- 22943439 TI - Leukocyte-derived microparticles and scanning electron microscopic structures in two fractions of fresh cerebrospinal fluid in amyotrophic lateral sclerosis: a case report. AB - INTRODUCTION: Amyotrophic lateral sclerosis is a progressive neurodegenerative disorder characterized by degeneration of motoneuron cells in anterior spinal horns. There is a need for early and accurate diagnosis with this condition. In this case report we used two complementary methods: scanning electron microscopy and fluorescence-activated cell sorting. This is the first report to our knowledge of microparticles in the cerebrospinal fluid of a patient with amyotrophic lateral sclerosis. CASE PRESENTATION: An 80-year-old Swedish man of Caucasian ethnicity presented to our facility with symptoms of amyotrophic lateral sclerosis starting a year before his first hospital examination, such as muscle weakness and twitching in his right hand progressing to arms, body and leg muscles. Electromyography showed classical neurophysiological findings of amyotrophic lateral sclerosis. Routine blood sample results were normal. A lumbar puncture was performed as a routine investigation and his cerebrospinal fluid was normal with regard to cell count and protein levels, and there were no signs of inflammation. However, scanning electron microscopy and fluorescence-activated cell sorting showed pronounced abnormalities compared to healthy controls. Flow cytometry analysis of two fractions of cerebrospinal fluid from our patient with amyotrophic lateral sclerosis was used to measure the specific binding of antibodies to CD42a, CD144 and CD45, and of phosphatidylserine to lactadherin. Our patient displayed over 100 times more phosphatidylserine-positive microparticles and over 400 times more cell-derived microparticles of leukocyte origin in his cerebrospinal fluid compared to healthy control subjects. The first cerebrospinal fluid fraction contained about 50% more microparticles than the second fraction. The scanning electron microscopy filters used with cerebrospinal fluid from our patient were filled with compact aggregates of spherical particles of lipid appearance, sticking together in a viscous batter. The quantitative increase in scanning electron microscopy findings corresponded to the flow cytometry result of an increase in leukocyte-derived microparticles. CONCLUSIONS: Microparticles represent subcellular arrangements that can influence the pathogenesis of amyotrophic lateral sclerosis and may serve as biomarkers for underlying cellular disturbances. The increased number of leukocyte-derived microparticles with normal cell counts in cerebrospinal fluid may contribute to the amyotrophic lateral sclerosis inflammatory process by formation of immune complexes of prion-like propagation, possibly due to misfolded proteins. The two complementary methods used in this report may be additional tools for revealing the etiology of amyotrophic lateral sclerosis, for early diagnostic purposes and for evaluation of clinical trials, long-term follow-up studies and elucidating the pathophysiology in amyotrophic lateral sclerosis. PMID- 22943440 TI - Oviposition behaviors and ontogenetic embryonic characteristics of the western tarnished plant bug, Lygus hesperus. AB - The western tarnished plant bug, Lygus hesperus Knight (Hemiptera: Miridae) is a key pest of fruit, vegetable, and field crops in the western United States, but many aspects of L. hesperus ecology are poorly documented. A sound understanding of oviposition behavior and characterization of the phases of embryonic development would be useful in studies of interactions between L. hesperus and its hosts, and in efforts to better understand the developmental consequences of low temperatures. Because L. hesperus insert their eggs into the host, most of the egg is obscured from view, and some aspects of oviposition and subsequent egg development cannot be observed directly. A novel observational method which took advantage of the propensity for L. hesperus to oviposit in semi-transparent sheets of agarose was used to observe oviposition and subsequent embryonic development. Lygus hesperus females stylet-probed prospective oviposition sites and during oviposition the ovipositor followed the path of the final probe. Oviposition, from insertion to withdrawal of the ovipositor, required ~30 seconds. Identifiable phases of embryo development included egg swelling, katatrepsis, appearance of body segments and appendages, development of red pigmentation in the eyes and terminal antennal segments, and formation of the 3(rd) embryonic cuticle. These phases were observed at about 0.3, 0.4, 0.5, 0.6, and 0.8 of the total duration between oviposition and hatch, respectively. Infertile eggs did not exhibit any of these phases. Our descriptions of embryonic development will facilitate the study of L. hesperus egg biology and ecology, and permit estimates of egg population age structure and prediction of egg hatch. PMID- 22943441 TI - Pathways for epidermal cell differentiation via the homeobox gene GLABRA2: update on the roles of the classic regulator. AB - Recent plant development studies have identified regulatory pathways for epidermal cell differentiation in Arabidopsis thaliana. Interestingly, some of such pathways contain transcriptional networks with a common structure in which the homeobox gene GLABLA2 (GL2) is downstream of the transactivation complex consisting of MYB, bHLH, and WD40 proteins. Here, we review the role of GL2 as an output device of the conserved network, and update the knowledge of epidermal cell differentiation pathways downstream of GL2. Despite the consistent position of GL2 within the network, its role in epidermal tissues varies; in the root epidermis, GL2 promotes non-hair cell differentiation after cell pattern formation, whereas in the leaf epidermis, it is likely to be involved in both pattern formation and differentiation of trichomes. GL2 expression levels act as quantitative factors for initiation of cell differentiation in the root and leaf epidermis; the quantity of hairless cells in non-root hair cell files is reduced by gl2 mutations in a semi-dominant manner, and entopically additive expression of GL2 and a heterozygous gl2 mutation increase and decrease the number of trichomes, respectively. Although few direct target genes have been identified, evidence from genetic and expression analyses suggests that GL2 directly regulates genes with various hierarchies in epidermal cell differentiation pathways. PMID- 22943442 TI - A retrospective study of horses investigated for weight loss despite a good appetite (2002-2011). AB - REASONS FOR PERFORMING STUDY: Weight loss despite a good appetite is a frequent diagnostic challenge for equine veterinarians; however, there are few objective reports and little descriptive information regarding risk factors and prognostic indicators. OBJECTIVES: To provide a descriptive epidemiological analysis of horses evaluated for weight loss despite a good appetite and evaluate relationships between historical and clinicopathological findings and final outcome (survival vs. nonsurvival) to identify risk factors and prognostic indicators. METHODS: Medical records of horses referred for investigation of weight loss despite a good appetite were reviewed. Data collated included history, case details, clinical and diagnostic findings, diagnoses and outcome. Univariable associations were evaluated with a Mann-Whitney U test (continuous data), Fisher's exact test (categorical or binary data) or Pearson's rank correlation (continuous data), with P<=0.05 significant. RESULTS: Forty cases met the inclusion criteria. Total protein (P = 0.004) and albumin concentrations (P = 0.0008) at admission were higher in survivors than nonsurvivors, with total protein (r(2) = 0.31; P = 0.002) and albumin (r(2) = 0.36; P = 0.0002) positively correlated with outcome. Hypoproteinaemic (P = 0.008, odds ratio (OR) = 12, 95% confidence interval (CI) = 1.99-72.4) and hypoalbuminaemic (P = 0.0009, OR = 28, 95% CI = 2.94-266.6) animals were at greater odds for nonsurvival. Body condition score was positively correlated with total protein (r(2) = 0.16; P = 0.05) and albumin (r(2) = 0.53; P<0.0001) concentrations at admission and duration of clinical signs (r(2) = 0.19; P = 0.03). CONCLUSIONS: The severity of hypoproteinaemia and hypoalbuminaemia were related with nonsurvival. Body condition score and albumin concentration could potentially be used as prognostic indicators for survival. POTENTIAL RELEVANCE: These findings highlight the importance of body condition assessment in conjunction with clinicopathological evaluation in horses with weight loss despite a good appetite. PMID- 22943446 TI - Root coverage in molar teeth: a comparative controlled randomized clinical trial. AB - AIM: To compare the clinical outcomes of laterally moved, coronally advanced flap (LMCAF) versus Bilaminar technique (BT) in the treatment of single gingival recession on molar teeth. MATERIAL AND METHODS: Fifty patients showing Miller I and II gingival recessions at first molar teeth were treated: 25 were randomly assigned to the BT group and 25 belonged to the LMCAF group. Patient's post operative morbidity was assessed 1 week after the surgery, while aesthetic evaluation and the clinical evaluation were made 1 year later. RESULTS: No statistically significant difference was demonstrated in terms of recession and PPD reduction. Statistically greater probability of complete root coverage (CRC, Odds Ratio 22.1) and greater increase in gingival thickness were observed in the BT group. Greater increase in keratinized tissue was obtained in the LMCAF. Patient satisfaction with aesthetics was very high in both treatment groups. Better post-operative course was observed in the LMCAF, while better post operative sensitivity and root coverage evaluation were demonstrated in patients treated with BT. CONCLUSIONS: Gingival recession at first molar teeth can be successfully treated with LMCAF and BT. Better CRC was achieved with BT, while more comfortable post-operative course was associated with the LMCAF. PMID- 22943445 TI - Contribution of transient and sustained calcium influx, and sensitization to depolarization-induced contractions of the intact mouse aorta. AB - BACKGROUND: Electrophysiological studies of L-type Ca2+ channels in isolated vascular smooth muscle cells revealed that depolarization of these cells evoked a transient and a time-independent Ca2+ current. The sustained, non-inactivating current occurred at voltages where voltage-dependent activation and inactivation overlapped (voltage window) and its contribution to basal tone or active tension in larger multicellular blood vessel preparations is unknown at present. This study investigated whether window Ca2+ influx affects isometric contraction of multicellular C57Bl6 mouse aortic segments. RESULTS: Intracellular Ca2+ (Cai2+, Fura-2), membrane potential and isometric force were measured in aortic segments, which were clamped at fixed membrane potentials by increasing extracellular K+ concentrations. K+ above 20 mM evoked biphasic contractions, which were not affected by inhibition of IP3- or Ca2+ induced Ca2+ release with 2 aminoethoxydiphenyl borate or ryanodine, respectively, ruling out the contribution of intracellular Ca2+ release. The fast force component paralleled Cai2+ increase, but the slow contraction coincided with Cai2+ decrease. In the absence of extracellular Ca2+, basal tension and Cai2+ declined, and depolarization failed to evoke Cai2+ signals or contraction. Subsequent re introduction of external Ca2+ elicited only slow contractions, which were now matched by Cai2+ increase. After Cai2+ attained steady-state, isometric force kept increasing due to Ca2+- sensitization of the contractile elements. The slow force responses displayed a bell-shaped voltage-dependence, were suppressed by hyperpolarization with levcromakalim, and enhanced by an agonist of L-type Ca2+ channels (BAY K8644). CONCLUSION: The isometric response of mouse aortic segments to depolarization consists of a fast, transient contraction paralleled by a transient Ca2+ influx via Ca2+ channels which completely inactivate. Ca2+ channels, which did not completely inactivate during the depolarization, initiated a second, sustained phase of contraction, which was matched by a sustained non-inactivating window Ca2+ influx. Together with sensitization, this window L-type Ca2+ influx is a major determinant of basal and active tension of mouse aortic smooth muscle. PMID- 22943447 TI - The expanding world of stem cell modeling of Huntington's disease: creating tools with a promising future. AB - Deconstructing the mechanistic basis of neurodegenerative disorders, such as Huntington's disease (HD), has been a particularly challenging undertaking, relying mostly on post-mortem tissue samples, non-neural cell lines from affected individuals, and model organisms. Two articles recently published in Cell Stem Cell report first the generation and characterization of induced pluripotent stem cell (iPSC)-derived models for HD, and second, the genetic correction of a disease-causing CAG expansion mutation in iPSCs from individuals with HD. Taken together, these two studies provide a framework for the production and validation of iPSC materials for human neurodegenerative disease research and yield crucial tools for investigating future therapies. PMID- 22943448 TI - Men's knowledge and awareness of maternal, neonatal and child health care in rural Bangladesh: a comparative cross sectional study. AB - BACKGROUND: The status of men's knowledge of and awareness to maternal, neonatal and child health care are largely unknown in Bangladesh and the effect of community focused interventions in improving men's knowledge is largely unexplored. This study identifies the extent of men's knowledge and awareness on maternal, neonatal and child health issues between intervention and control groups. METHODS: This cross sectional comparative study was carried out in six rural districts of Bangladesh in 2008. BRAC health programme operates 'improving maternal, neonatal and child survival' intervention in four of the above mentioned six districts. The intervention comprises a number of components including improving awareness of family planning, identification of pregnancy, providing antenatal, delivery and postnatal care, newborn care, under-5 child healthcare, referral of complications and improving clinical management in health facilities. In addition, communities are empowered through social mobilization and advocacy on best practices in maternal, neonatal and child health. Three groups were identified: intervention (2 years exposure); transitional (6 months exposure) and control. Data were collected by interviewing 7,200 men using a structured questionnaire. RESULTS: Men prefer to gather in informal sites to interact socially. Overall men's knowledge on maternal care was higher in intervention than control groups, for example, advice on tetanus injection should be given during antenatal care (intervention = 50%, control = 7%). There were low levels of knowledge about birth preparedness (buying delivery kit = 18%, arranging emergency transport = 13%) and newborn care (wrapping = 25%, cord cutting with sterile blade = 36%, cord tying with sterile thread = 11%) in the intervention. Men reported joint decision-making for delivery care relatively frequently (intervention = 66%, control = 46%, p < 0.001). CONCLUSION: Improvement in men's knowledge in intervention district is likely. Emphasis of behaviour change communications messages should be placed on birth preparedness for clean delivery and referral and on newborn care. These messages may be best directed to men by targeting informal meeting places like market places and tea stalls. PMID- 22943449 TI - Cirrhosis and microvascular invasion predict outcomes in hepatocellular carcinoma. AB - BACKGROUND: Liver resection (LR) and liver transplantation (LT) are two modalities offering potential for cure in patients with hepatocellular carcinoma (HCC). The objective of this study was to evaluate the long-term survival of patients with HCC treated with LT and LR and to analyse variables influencing these outcomes. METHODS: Patients referred to the South Australian Liver Transplant Unit and Hepatopancreatobiliary Unit at Flinders Medical Centre from January 1992 to September 2009 with a diagnosis of HCC who underwent LT or LR were included in the study. Histopathological parameters analysed included size, number and grade of tumour, microscopic vascular invasion and presence or absence of cirrhosis in remnant liver. RESULTS: Eighty-five patients with a median age of 58 years (range 26-85 years) underwent LT or LR. Median follow-up was 40 months in both groups. Overall, 5-year actuarial survival for all patients with HCC in both groups was 55%. LR patients were significantly older (P < 0.001) than LT patients. Their tumours were larger (P < 001) and more often solitary (P < 0.001) compared with the LT group. In multivariate analysis, age >60 (P < 0.02), histopathological evidence of vascular invasion (P < 0.02) and presence of cirrhosis (P < 0.02) were associated with a significantly reduced survival. Patients without vascular invasion and cirrhosis had an actuarial 5-year survival >70%. CONCLUSIONS: Our study indicates that LT (within University of California, San Francisco criteria) and LR can lead to acceptable long-term survival outcomes in patients with HCC. Microscopic vascular invasion and cirrhosis were the most significant prognostic factors impacting on survival. PMID- 22943450 TI - The autobiography of addiction: autobiographical reasoning and psychological adjustment in abstinent alcoholics. AB - The narration of drinking experiences plays a central role in many alcohol rehabilitation programmes, yet few researchers have considered whether alcoholics' stories about such experiences relate to their psychological adjustment. Here we examine the extent to which drinking stories of abstinent alcoholics reflect autobiographical reasoning processes denoting self-change and self-stability, and whether these processes are associated with adjustment. Participants who revealed a positive self-change in their narratives about drinking demonstrated higher levels of self-esteem, authentic pride, and mental health compared to those who did not. In contrast, those who implied a sense of self-stability in their narratives demonstrated higher levels of hubristic pride and aggression, and poorer mental health. These results suggest that narrating positive self-change in the wake of substance abuse may underlie psychological adjustment, whereas establishing self-stability in these experiences may impede adjustment. More broadly, these findings underscore the importance of recognising the multi-dimensional nature of autobiographical reasoning. PMID- 22943451 TI - Complete mitochondrial genome of yellow grouper Epinephelus awoara (Perciformes, Epinephelidae). AB - In this paper, the complete mitochondrial (mt) genome of Epinephelus awoara has been determined. The mt genome (16,802 bp) had the canonical mt gene content and arrangement, including 13 protein-coding genes, 2 rRNA genes, 22 tRNA genes, and 2 non-coding regions. The overall base composition of the Heavy-strand is 28.47% A, 27.29% T, 16.54% G, and 27.70% C, with an AT content of 56.76%. It shared 92.6%, 85.5%, 86.1%, 84.9%, and 85.7% identities with that of Epinephelus akaara, Epinephelus bruneus, Epinephelus coioides, Epinephelus lanceolatus and Epinephelus moara, respectively. PMID- 22943452 TI - Understanding the basis of a novel fruit type in Brassicaceae: conservation and deviation in expression patterns of six genes. AB - BACKGROUND: Variation in fruit morphology is important for plant fitness because it influences dispersal capabilities. Approximately half the members of tribe Brassiceae (Brassicaceae) exhibit fruits with segmentation and variable dehiscence, called heteroarthrocarpy. The knowledge of the genetics of fruit patterning in Arabidopsis offers the opportunity to ask: (1) whether this genetic pathway is conserved in taxa with different fruit morphologies; (2) how the pathway may be modified to produce indehiscence; and (3) whether the pathway has been recruited for a novel abscission zone. METHODS: We identified homologs of ALCATRAZ, FRUITFULL, INDEHISCENT, SHATTERPROOF, and REPLUMLESS from two taxa, representing different types of heteroarthrocarpy. Comparative gene expression of twelve loci was assessed to address how their expression may have been modified to produce heteroarthrocarpy. RESULTS: Studies demonstrated overall conservation in gene expression patterns between dehiscent segments of Erucaria erucarioides and Arabidopsis, with some difference in expression of genes that position the valve margin. In contrast, indehiscence in heteroarthrocarpic fruit segments was correlated with the elimination of the entire valve margin pathway in Erucaria and Cakile lanceolata as well as its absence from a novel lateral abscission zone. CONCLUSIONS: These findings suggest that modifications in the valve margin positioning genes are responsible for differences between heteroarthrocarpic and Arabidopsis-like fruits and support the hypothesis that heteroarthrocarpy evolved via repositioning the valve margin. They also highlight conservation in the dehiscence pathway across Brassicaceae. PMID- 22943453 TI - Non-invasive evaluation of hepatic manifestation in Wilson disease with transient elastography, ARFI, and different fibrosis scores. AB - OBJECTIVE: Noninvasive investigation of liver fibrosis with ultrasound-based elastography and laboratory-based fibrosis indices have been established in various chronic liver diseases within the last years. We aimed to evaluate feasibility and diagnostic value of transient elastography (TE), acoustic radiation force impulse imaging (ARFI), and different serologic fibrosis indices in Wilson's disease (WD). MATERIALS AND METHODS: TE and ARFI were performed in 50 Wilson patients. In addition, AST/Platelet Ratio Index (APRI), FIB-4, and Forns score were calculated. Hepatic fibrosis was classified by a clinical score. RESULTS: Of the 50 Wilson patients 41 had hepatic manifestation of WD. TE results were significantly increased in advanced hepatic fibrosis (7.0 +/- 2.2 kPa; p < 0.05) and cirrhosis (10.1 +/- 6.73 kPa; p < 0.05) compared to individuals without hepatic manifestation (5.0 +/- 1.4 kPa). Right liver lobe ARFI (R-ARFI) values were only increased in cirrhotic patients (1.43 +/- 0.28 vs. 1.19 +/- 0.14 m/s; p < 0.05). The cutoff values to best discriminate cirrhosis were 6.1 kPa for TE and 1.29 m/s for R-ARFI. Left lobe ARFI failed to provide additional diagnostic benefit. Elastography methods displayed a significant correlation with APRI, FIB 4, and Forns indices (Pearson's rho > 0.33; p < 0.03). CONCLUSIONS: TE displayed a gradual increase between different stages of hepatic manifestation in WD and could significantly discriminate cirrhosis. The TE cutoff for cirrhosis may be clinically more relevant than the R-ARFI value. PMID- 22943454 TI - Depression and sleep disorders predict acute exacerbations and hospitalization in patients with chronic obstructive pulmonary disease. PMID- 22943455 TI - Classifying black and white spruce pollen using layered machine learning. AB - Pollen is among the most ubiquitous of terrestrial fossils, preserving an extended record of vegetation change. However, this temporal continuity comes with a taxonomic tradeoff. Analytical methods that improve the taxonomic precision of pollen identifications would expand the research questions that could be addressed by pollen, in fields such as paleoecology, paleoclimatology, biostratigraphy, melissopalynology, and forensics. We developed a supervised, layered, instance-based machine-learning classification system that uses leave one-out bias optimization and discriminates among small variations in pollen shape, size, and texture. We tested our system on black and white spruce, two paleoclimatically significant taxa in the North American Quaternary. We achieved > 93% grain-to-grain classification accuracies in a series of experiments with both fossil and reference material. More significantly, when applied to Quaternary samples, the learning system was able to replicate the count proportions of a human expert (R(2) = 0.78, P = 0.007), with one key difference - the machine achieved these ratios by including larger numbers of grains with low confidence identifications. Our results demonstrate the capability of machine learning systems to solve the most challenging palynological classification problem, the discrimination of congeneric species, extending the capabilities of the pollen analyst and improving the taxonomic resolution of the palynological record. PMID- 22943444 TI - Systematic review with meta-analysis of the epidemiological evidence in the 1900s relating smoking to lung cancer. AB - BACKGROUND: Smoking is a known lung cancer cause, but no detailed quantitative systematic review exists. We summarize evidence for various indices. METHODS: Papers published before 2000 describing epidemiological studies involving 100+ lung cancer cases were obtained from Medline and other sources. Studies were classified as principal, or subsidiary where cases overlapped with principal studies. Data were extracted on design, exposures, histological types and confounder adjustment. RRs/ORs and 95% CIs were extracted for ever, current and ex smoking of cigarettes, pipes and cigars and indices of cigarette type and dose response. Meta-analyses and meta-regressions investigated how relationships varied by study and RR characteristics, mainly for outcomes exactly or closely equivalent to all lung cancer, squamous cell carcinoma ("squamous") and adenocarcinoma ("adeno"). RESULTS: 287 studies (20 subsidiary) were identified. Although RR estimates were markedly heterogeneous, the meta-analyses demonstrated a relationship of smoking with lung cancer risk, clearly seen for ever smoking (random-effects RR 5.50, CI 5.07-5.96) current smoking (8.43, 7.63-9.31), ex smoking (4.30, 3.93-4.71) and pipe/cigar only smoking (2.92, 2.38-3.57). It was stronger for squamous (current smoking RR 16.91, 13.14-21.76) than adeno (4.21, 3.32-5.34), and evident in both sexes (RRs somewhat higher in males), all continents (RRs highest for North America and lowest for Asia, particularly China), and both study types (RRs higher for prospective studies). Relationships were somewhat stronger in later starting and larger studies. RR estimates were similar in cigarette only and mixed smokers, and similar in smokers of pipes/cigars only, pipes only and cigars only. Exceptionally no increase in adeno risk was seen for pipe/cigar only smokers (0.93, 0.62-1.40). RRs were unrelated to mentholation, and higher for non-filter and handrolled cigarettes. RRs increased with amount smoked, duration, earlier starting age, tar level and fraction smoked and decreased with time quit. Relationships were strongest for small and squamous cell, intermediate for large cell and weakest for adenocarcinoma. Covariate-adjustment little affected RR estimates. CONCLUSIONS: The association of lung cancer with smoking is strong, evident for all lung cancer types, dose-related and insensitive to covariate-adjustment. This emphasises the causal nature of the relationship. Our results quantify the relationships more precisely than previously. PMID- 22943456 TI - Genetic module and miRNome trait analyses reflect the distinct biological features of endothelial progenitor cells from different anatomic locations. AB - BACKGROUND: Endothelial progenitor cells (EPCs) play a fundamental role in post natal vascular repair, yet EPCs from different anatomic locations possess unique biological properties. The underlying mechanisms are unclear. RESULTS: EPCs from CB expressed abundant genes involved in cell cycle, hypoxia signalling and blood vessel development, correlating with the phenotypes that CB-EPCs proliferated more rapidly, migrated faster, and formed tubule structure more efficiently. smRNA-seq further deciphered miRNome patterns in EPCs isolated from CB or PB: 54 miRNAs were enriched in CB-EPCs, while another 50 in PB-EPCs. Specifically, CB EPCs expressed more angiogenic miRNAs such as miR-31, while PB-EPCs possessed more tumor suppressive miRNAs including miR-10a. Knocking down miR-31 levels in CB-EPCs suppressed cell migration and microtubule formation, while overexpressing miR-31 in PB-EPCs helped to recapitulate some of CB-EPC functions. CONCLUSIONS: Our results show the foundation for a more detailed understanding of EPCs from different anatomic sources. Stimulating the expression of angiogenic microRNAs or genes in EPCs of low activity (such as those from patients with cardiovascular diseases) might allow the development of novel therapeutic strategies. PMID- 22943457 TI - Successful treatment with the mTOR inhibitor everolimus in a patient with perivascular epithelioid cell tumor. AB - Perivascular epithelioid cell tumor (PEComa) is an extremely rare neoplasm that appears to arise most commonly at visceral (especially gastrointestinal and uterine), retroperitoneal, and abdominopelvic sites. Malignant PEComas exist but are very rare. These tumors represent a family of mesenchymal neoplasms, mechanistically linked through activation of the mTOR signaling pathway. Metastatic PEComa is a rare form of sarcoma for which no effective therapy has been described previously and that has a uniformly fatal outcome. Although there is no known effective therapy, the molecular pathophysiology of aberrant mTOR signaling provides a scientific rationale to target this pathway therapeutically. The difficulty in determining optimal therapy, owing to the sparse literature available, led us to present this case. On this basis, we report a case of metastatic retroperitoneal PEComa treated with an oral mTOR inhibitor, with everolimus achieving significant clinical response. PMID- 22943458 TI - Stimulant and non-stimulant attention deficit/hyperactivity disorder drug use: total population study of trends and discontinuation patterns 2006-2009. AB - OBJECTIVE: To explore the prevalence and discontinuation of dispensed medications for attention deficit/hyperactivity disorder (ADHD) drugs from 2006 to 2009. METHOD: A total population cohort of all individuals aged 6-45 years, alive and registered as residents in Sweden during any calendar year from 2006 to 2009 (N = 5 149 791) included 41 700 patients dispensed with an ADHD drug (methylphenidate, atomoxetine, amphetamine, or dexamphetamine). The dispensing prevalence was calculated for each year, stratified on sex and age. A longitudinal analysis was also performed to compare the rates of treatment discontinuation across the strata. RESULTS: The dispensing prevalence increased from 2.93 per 1000 in 2006 to 6.98 in 2009 (PR = 2.38, 95% CI = 2.34-2.43). The prevalence ratio (PR) was 3.40 for adults, 22-45 years old; 2.41 for adolescents, 15-21 years old; and 1.90 for children aged 6-14. The increase was also greater in women than in men (PR = 2.92 vs. 2.19). Patients aged 15-21 were the most likely to discontinue treatment; after 3 years and 11 months, 27% of those patients were still under treatment. CONCLUSION: From 2006 to 2009, the number of prescriptions dispensed for ADHD drugs increased substantially. The rate of treatment discontinuation in the age interval 15-21 is higher than expected considering the persistence rates of the disorder. PMID- 22943459 TI - Synthesis and biological evaluation of coumarin derivatives as inhibitors of Mycobacterium bovis (BCG). AB - The coumarin compounds are an important class of biologically active molecules, which have attractive caught the attention of many organic and medicinal chemists, due to potential pharmaceutical implications and industrial applications. We herein report the one-pot procedure for the efficient synthesis of coumarin derivatives using commercially available substrates via isocyanide based multicomponent condensation reactions. These compounds were evaluated for anti-mycobacterium activity against Mycobacterium bovis (Bacillus Calmette Guerin). The preliminary results indicated that all of the tested compounds showed relatively good activity against the test organism. The compounds 7e, 7l, and 7m showed high anti-tuberculosis activity. PMID- 22943460 TI - The effect of palatal dysfunction on measures of ventilation and gas exchange in Thoroughbred racehorses during high intensity exercise. AB - REASON FOR PERFORMING STUDY: The effect of palatal instability (PI) on measures of ventilation and gas exchange is not well understood. OBJECTIVES: To assess to what degree different severities of naturally occurring palatal dysfunction affect ventilation and gas exchange during strenuous exercise. METHODS: A retrospective study was performed using data collected from 40 Thoroughbred racehorses diagnosed with naturally occurring dynamic palatal dysfunction during high speed treadmill exercise. Upper airway videoendoscopic recordings were made concurrently with measurements of ventilation and gas exchange. Three categories of soft palate dysfunction were formed: mild palatal instability; moderate to severe palatal instability; and dorsal displacement of the soft palate (DDSP). Minute ventilation, tidal volume, breathing frequency, end-tidal carbon dioxide and oxygen concentrations, oxygen consumption and carbon dioxide production were calculated during the last 10 s of the exercise test, when airway obstruction was at its worst. RESULTS: There was a trend for minute ventilation, tidal volume, oxygen consumption and carbon dioxide production to decrease with increasing degree of palatal dysfunction, although statistically significant differences were only seen with DDSP. End-tidal carbon dioxide increased and end-tidal oxygen decreased with increasing obstruction, with both parameters showing significant differences between mild PI and moderate to severe PI. CONCLUSIONS: The results suggest that PI has a negative effect on certain respiratory parameters, although this is not as great as that associated with DDSP. POTENTIAL RELEVANCE: Palatal instability may be detrimental to athletic performance even when progression to DDSP does not occur. PMID- 22943461 TI - Cerebro-afferent vessel and pupillary basal diameter variation induced by stomatognathic trigeminal proprioception: a case report. AB - INTRODUCTION: A patient affected by asymmetric hemodynamics of cerebro-afferent vessels underwent duplex color scanner investigations in occlusal proprioceptive un- and rebalance conditions. Pupillometric video-oculographic examinations were performed in order to spot connected trigeminal proprioceptive motor patterns able to interfere on sympathetic autonomic activity. The aim of this case report is to verify if involuntary jaw closing during swallowing, executed in unbalance and rebalance myoelectric activity, would be able to modify cerebral hemodynamics. CASE PRESENTATION: A 56-year-old Caucasian Italian woman affected by asymmetric blood flow of cerebro-afferent vessels underwent an electromyographic investigation of her occlusal muscles in order to assess their occlusal functional balance. The extreme asymmetry of myoelectric activity in dental occlusion evidenced by electromyographic values suggested the rebalancing of the functions of occlusal muscles through concurrent transcutaneous stimulation of the trigeminal nerve supra- and submandibular motor branches. The above-mentioned method allowed the detection of a symmetric craniomandibular muscular relation that can be kept constant through the use of a cusp bite modeled on the inferior dental arch: called orthotic-syntropic bite for its peculiar use of electrostimulation. A few days later, the patient underwent a duplex color scanner investigation and pupillometric video-oculographic examinations in occlusal unbalance and rebalance conditions. CONCLUSIONS: A comparative data analysis showed that an unbalanced dental occlusal function may represent an interferential pattern on cerebral hemodynamics velocity and pupillometric evaluations have proved useful both in the analysis of locus coeruleus functional modalities and as a diagnostic tool in the assessment of pathologies involving locus coeruleus and autonomic systems. The inclusion of myoelectric masseter examinations can be useful in patients with asymmetric hemodynamics of cerebro-afferent vessels and dental occlusal proprioceptive rebalance can integrate the complex therapy of patients with increased chronic sympathetic activity. PMID- 22943462 TI - Masculinity and HIV disclosure among heterosexual South African men: implications for HIV/AIDS intervention. AB - Relationships and constructions of masculinity are central to understanding the process of male HIV disclosure, which is an important step towards accessing HIV related services. Data from in-depth interviews and focus-group discussions with 23 HIV-positive, self-identified heterosexual, Black South African men were used to explore the disclosure process and how this process was negotiated in the context of constructions of masculinity. Of these men, 20 had disclosed to one or more persons, with partners and siblings being the preferred confidants. Disclosure was dependent on the acceptance of HIV status, perceived support and healthy relationships with others, HIV counselling and participation in educational and training activities. Non-disclosure was explained as a result of stigma, fear of rejection, discrimination, a lack of healthy relationships with others and lack of access to suitable disclosure strategies. Negative perceptions of HIV and hegemonic conceptions of masculinity hindered men from disclosing and seeking health services. Many men, however, managed to renegotiate their masculine identities to become responsible, knowledgeable HIV-positive individuals, protecting their families and becoming community educators. Findings suggest the need to consider gendered, contextual, skills-building/income generating and guided interventions to promote male HIV disclosure and service uptake. PMID- 22943463 TI - Inhibition of DNA methyltransferase activity and expression by treatment with the pan-deacetylase inhibitor panobinostat in hepatocellular carcinoma cell lines. AB - BACKGROUND: Hepatocellular carcinoma (HCC) still represents an unmet medical need. Epigenetic inactivation of tumor suppressor genes like RASSF1A or APC by overexpression of DNA methyltransferases (DNMTs) has been shown to be common in HCC and to be linked to the overall prognosis of patients. Inhibitors of protein and histone deacetylases (DACi) have been demonstrated to possess strong anti tumor effects in HCC models. METHODS: We therefore investigated whether DACi also has any influence on the expression and activity of DNMTs and methylated target genes in HepG2 and Hep3B cell culture systems and in a xenograft model by immunohistochemistry, westernblotting, RT-qPCR and methylation-specific PCR. RESULTS: Our findings demonstrate a rapid inhibition of DNMT activity 6 h after treatment with 0.1 MUM of the pan-DACi panobinostat. A downregulation of DNMT mRNAs and protein were also observed at later points in time. This loss of DNMT activity and expression was paralleled by a diminished methylation of the target genes RASSF1A and APC and a concomitant re-expression of APC mRNA and protein. Analysis of HepG2 xenograft specimens confirmed these results in vivo. CONCLUSION: We suggest a dual mode of action of DACi on DNA methylation status: a rapid inhibition of enzyme activity due to interference with posttranslational acetylation and a delayed effect on transcriptional control of DNMT genes by HDAC or miRNA mechanisms. PMID- 22943464 TI - Quality assessment and anti-obesity activity of Stellaria media (Linn.) Vill. AB - BACKGROUND: Obesity is recognized as a social problem, associated with serious health risks and increased mortality. Numerous trials have been conducted to find and develop new anti-obesity drugs through herbal sources to minimize side effects associated with the present anti-obesity drugs. The present study was designed to evaluate the quality control parameters, quantitative phytochemical analysis (total phenolic, total flavonoids and total saponin content), and the anti-obesity effect of lyophilized juice (LJ) of Stellaria media (Linn.) Vill. by employing in vitro and in vivo models. METHODS: In vitro studies were performed to evaluate the inhibitory activity of LJ on pancreatic amylase and lipase. The in vivo pancreatic lipase activity was evaluated by measurement of plasma triacylglycerol levels after oral administration of lipid emulsion to swiss albino mice. Furthermore, the anti-obesity effect of LJ was assessed at two doses, 400 mg/kg and 900 mg/kg body weight in mice fed a high-fat-diet with or without LJ for 6 weeks. RESULTS: The LJ inhibited pancreatic amylase and lipase activity in vitro and elevated plasma triacylglycerol level in mice. LJ suppressed the increase in body weight, retroperitoneal adipose tissue, liver weights and serum parameters viz., total cholesterol, total triglyceride, LDL cholesterol level at the dose of 900 mg/kg body weight of the mice fed with high fat diet. The total phenolic, flavonoid and saponin contents were found to be 0.26 mg/g, 1.4 mg/g and 1.19 MUg/g respectively of LJ. CONCLUSION: The anti obesity effects of LJ in high-fat-diet fed mice may be partly mediated through delaying the intestinal absorption of dietary fat and carbohydrate by inhibiting digestive enzymes. PMID- 22943465 TI - Outcome of arthroscopic treatment for cam type femoroacetabular impingement in adolescents. AB - BACKGROUND: Hip arthroscopy has become an established procedure in adults with well-published results. These techniques have been extended to the teenage population, but the literature remains limited in regard to indications, efficacy, outcomes and complications specific to the paediatric population. HYPOTHESIS/PURPOSE: The purpose of this study was to report the short-term outcome of the arthroscopic treatment of cam-type femoroacetabular impingement (FAI) in the skeletally immature adolescent population with open growth plates, with the hypothesis that it is a safe procedure, with good clinical outcomes and low complication rates. STUDY DESIGN: The study design of this article was a multicentre prospective longitudinal case series. METHODS: From 2008-2009, 34 consecutive patients who were 18 years or younger at the date of operation (41 hips) with open proximal femoral growth plates had arthroscopic hip surgery for treatment of cam-type FAI and associated lesions by use of the lateral decubitus position by two surgeons. Data were collected prospectively including the modified Harris hip score (MHHS), nonarthritic hip score (NAHS), satisfaction survey and complications. Mean follow-up was 14 months (range 1-2 years). RESULTS: All hips were available for review. The mean age of patients was 15.7 years with the most common sport activity being Australian Football League, netball and rugby. All patients had cam-type impingement, with the most common associated lesions being acetabular rim lesions (82.9%) and pincer impingement (22%). The labrum underwent debridement in 31.7% of cases, and was repaired in 17.1%. The MHHS and NAHS improved in all patients post-operatively, 77.39-94.15 and 76.34-93.18, respectively. A percentage of 78.1 were able to return to full sporting activity and 88.2% were satisfied with the operation. There were no complications. CONCLUSIONS: Using hip arthroscopy to treat cam-type impingement and associated lesions in the adolescent population, we confirmed our hypothesis with observed high satisfaction levels, return to sports, significant improvement in post-operative hip scores (MHHS and NAHS) and no complications. PMID- 22943467 TI - Immature stages of the Neotropical butterfly, Dynamine agacles agacles. AB - The external morphology of the immature stages of Dynamine agacles agacles (Dalman, 1823) (Lepidoptera: Nymphalidae: Biblidinae) is described, including photos, drawings, and scanning electron micrographs. Data on the adult and larval behavior are given based on observations in the host plant Dalechampia triphylla Lam. (Malpighiales : Euphorbiaceae). The results are compared and discussed with other described species of Biblidinae, allowing to make further observations on the natural history and evolution of Dynamine. PMID- 22943466 TI - Sex & vision I: Spatio-temporal resolution. AB - BACKGROUND: Cerebral cortex has a very large number of testosterone receptors, which could be a basis for sex differences in sensory functions. For example, audition has clear sex differences, which are related to serum testosterone levels. Of all major sensory systems only vision has not been examined for sex differences, which is surprising because occipital lobe (primary visual projection area) may have the highest density of testosterone receptors in the cortex. We have examined a basic visual function: spatial and temporal pattern resolution and acuity. METHODS: We tested large groups of young adults with normal vision. They were screened with a battery of standard tests that examined acuity, color vision, and stereopsis. We sampled the visual system's contrast sensitivity function (CSF) across the entire spatio-temporal space: 6 spatial frequencies at each of 5 temporal rates. Stimuli were gratings with sinusoidal luminance profiles generated on a special-purpose computer screen; their contrast was also sinusoidally modulated in time. We measured threshold contrasts using a criterion-free (forced-choice), adaptive psychophysical method (QUEST algorithm). Also, each individual's acuity limit was estimated by fitting his or her data with a model and extrapolating to find the spatial frequency corresponding to 100% contrast. RESULTS: At a very low temporal rate, the spatial CSF was the canonical inverted-U; but for higher temporal rates, the maxima of the spatial CSFs shifted: Observers lost sensitivity at high spatial frequencies and gained sensitivity at low frequencies; also, all the maxima of the CSFs shifted by about the same amount in spatial frequency. Main effect: there was a significant (ANOVA) sex difference. Across the entire spatio-temporal domain, males were more sensitive, especially at higher spatial frequencies; similarly males had significantly better acuity at all temporal rates. CONCLUSION: As with other sensory systems, there are marked sex differences in vision. The CSFs we measure are largely determined by inputs from specific sets of thalamic neurons to individual neurons in primary visual cortex. This convergence from thalamus to cortex is guided by cortex during embryogenesis. We suggest that testosterone plays a major role, leading to different connectivities in males and in females. But, for whatever reasons, we find that males have significantly greater sensitivity for fine detail and for rapidly moving stimuli. One interpretation is that this is consistent with sex roles in hunter-gatherer societies. PMID- 22943468 TI - Making sense of traumatic memories: memory qualities and psychological symptoms in emerging adults with and without abuse histories. AB - This study explored the connections between multiple measures of meaning making and psychological adjustment in people with and without histories of abuse. Young adults (n =177), recollected their three most stressful memories and rated them on importance and emotional and sensory qualities. We analysed the narratives for lexical markers of meaning making and explicit references to meaning or meaning making attempts. There was little overlap between self-reported qualities and narrative content, and they were differentially predictive of psychological symptoms and transient emotional reactions. Consistent with the PTSD literature, more salient self-report memory characteristics (e.g., visceral emotions), and negative emotion and sensation terms predicted more symptoms. The narrative indices provided the best prediction to psychological adjustment, with several meaning indices (e.g., references to positive impact) predicting reduced symptoms, particularly for the Abuse group. Contrary to meaning-making models, resolutions predicted more symptoms, suggesting that aversive feelings during memory telling may trigger on-the-spot sense making to cope with distress. PMID- 22943469 TI - Unexpected findings of variability in microRNAs suggest roles in human genetics. AB - Short RNA molecules were considered to be junk for decades, but in recent years they have been shown to have important functional roles. MicroRNAs (miRNAs) in particular have attracted much attention. They have been assumed to be highly conserved in humans and other species; however, a recent study published in Genome Medicine reveals an unexpected level of variability in human miRNAs, including variations within the seed region. This challenges the current view of miRNAs, and may explain previous reports of pathogenic mutations in miRNAs. See research article http://genomemedicine.com/content/4/8/62/abstract. PMID- 22943470 TI - Naturalization of introduced plants: ecological drivers of biogeographical patterns. AB - The literature on biological invasions is biased in favour of invasive species- those that spread and often reach high abundance following introduction by humans. It is, however, also important to understand previous stages in the introduction-naturalization-invasion continuum ('the continuum'), especially the factors that mediate naturalization. The emphasis on invasiveness is partly because most invasions are only recognized once species occupy large adventive ranges or start to spread. Also, many studies lump all alien species, and fail to separate introduced, naturalized and invasive populations and species. These biases impede our ability to elucidate the full suite of drivers of invasion and to predict invasion dynamics, because different factors mediate progression along different sections of the continuum. A better understanding of the determinants of naturalization is important because all naturalized species are potential invaders. Processes leading to naturalization act differently in different regions and global biogeographical patterns of plant invasions result from the interaction of population-biological, macroecological and human-induced factors. We explore what is known about how determinants of naturalization in plants interact at various scales, and how their importance varies along the continuum. Research that is explicitly linked to particular stages of the continuum can generate new information that is appropriate for improving the management of biological invasions if, for example, potentially invasive species are identified before they exert an impact. PMID- 22943472 TI - Pulmonary sclerosing hemangioma: report of two cases. AB - Pulmonary sclerosing hemangioma (PSH) is a rare benign tumor of the lungs. These tumors are composed of cuboidal surface cells and polygonal stromal cells and show four histological manifestations: hemorrhagic, papillary, solid, and sclerotic. PSH predominantly affects asymptomatic middle-aged women. The tumor often occurs at the intralobar site, and less commonly in the bronchus and mediastinum. PSH is easy to be misdiagnosed preoperatively. In this study, we present in detail the treatment procedures followed for two atypical cases of PSH. Case 1 was a 62-year-old woman bearing a tumor for 15 years. The tumor lesion was found to be located in the oblique fissure of the left lung. PSH was confirmed by surgical resection and postoperative pathological diagnosis. There was no sign of recurrence and metastasis 1.5 years after surgery. Case 2 was a 54 year-old woman diagnosed with bilateral multiple nodules by physical examination. This patient was diagnosed with definite PSH through computed tomography-guided percutaneous lung biopsy. Surgical resection was not performed. The patient also showed no sign of enlarged tumor and metastasis after 2 years of follow-up. Although PSH can be cured by surgical resection, the findings in our cases indicate that surgical resection need not be considered the preferred course of treatment. If PSH is diagnosed before surgery, the patients may survive while bearing the tumor. PMID- 22943471 TI - Effects of genotype and dietary fish oil replacement with vegetable oil on the intestinal transcriptome and proteome of Atlantic salmon (Salmo salar). AB - BACKGROUND: Expansion of aquaculture requires alternative feeds and breeding strategies to reduce dependency on fish oil (FO) and better utilization of dietary vegetable oil (VO). Despite the central role of intestine in maintaining body homeostasis and health, its molecular response to replacement of dietary FO by VO has been little investigated. This study employed transcriptomic and proteomic analyses to study effects of dietary VO in two family groups of Atlantic salmon selected for flesh lipid content, 'Lean' or 'Fat'. RESULTS: Metabolism, particularly of lipid and energy, was the functional category most affected by diet. Important effects were also measured in ribosomal proteins and signalling. The long-chain polyunsaturated fatty acid (LC-PUFA) biosynthesis pathway, assessed by fatty acid composition and gene expression, was influenced by genotype. Intestinal tissue contents of docosahexaenoic acid were equivalent in Lean salmon fed either a FO or VO diet and expression of LC-PUFA biosynthesis genes was up-regulated in VO-fed fish in Fat salmon. Dietary VO increased lipogenesis in Lean fish, assessed by expression of FAS, while no effect was observed on beta-oxidation although transcripts of the mitochondrial respiratory chain were down-regulated, suggesting less active energetic metabolism in fish fed VO. In contrast, dietary VO up-regulated genes and proteins involved in detoxification, antioxidant defence and apoptosis, which could be associated with higher levels of polycyclic aromatic hydrocarbons in this diet. Regarding genotype, the following pathways were identified as being differentially affected: proteasomal proteolysis, response to oxidative and cellular stress (xenobiotic and oxidant metabolism and heat shock proteins), apoptosis and structural proteins particularly associated with tissue contractile properties. Genotype effects were accentuated by dietary VO. CONCLUSIONS: Intestinal metabolism was affected by diet and genotype. Lean fish may have higher responsiveness to low dietary n-3 LC-PUFA, up-regulating the biosynthetic pathway when fed dietary VO. As global aquaculture searches for alternative oils for feeds, this study alerts to the potential of VO introducing contaminants and demonstrates the detoxifying role of intestine. Finally, data indicate genotype specific responses in the intestinal transcriptome and proteome to dietary VO, including possibly structural properties of the intestinal layer and defence against cellular stress, with Lean fish being more susceptible to diet-induced oxidative stress. PMID- 22943473 TI - South Asian dietary patterns and their association with risk factors for the metabolic syndrome. AB - BACKGROUND: Certain dietary patterns have been associated with higher risk of noncommunicable diseases, with South Asians identified as a high-risk group. The present study aimed to identify the association between dietary patterns and the metabolic syndrome (MS) in South Asians living in the UK. METHODS: Dietary patterns were derived by principal component analysis from 15 different food groups using an ethnic-specific food frequency questionnaire. MS risk factors, including obesity and hypertension, were measured, whereas existing conditions of dyslipidaemia and hyperglycaemia were self-reported. Participants (n = 100) were divided into quartiles based on dietary factor scores and the link between dietary patterns and risk factors was investigated. RESULTS: Three different patterns were derived, which together explained 46% of the total diet variation; eastern pattern, mixed pattern and western pattern. An inverse correlation was found between the eastern pattern and education P = 0.05). A direct correlation was found between the western pattern and physical activity (P = 0.05) and the overall risk of MS (P = 0.05). Body composition was altered as residence time in the UK increased, with a reduction in muscle mass (29-26%) and an increase in body fat (31-37%). Diagnosis criteria for MS were found in 20% of the participants. CONCLUSIONS: Dietary acculturation, including a reduction in vegetarianism, an increased intake of caffeinated drinks and altered meal patterns, may be associated with the higher prevalence of MS in migrant South Asians in the UK. PMID- 22943475 TI - Complete mitochondrial genome of the endangered roughskin sculpin Trachidermus fasciatus (Scorpaeniformes, Cottidae). AB - In this study, the complete mitochondrial genome of the endangered roughskin sculpin, Trachidermus fasciatus, was first determined. The mitogenome (16,536 bp) consisted of 13 protein-coding genes, 22 tRNA genes, 2 rRNA genes, and 1 control region. Except for the eight tRNA and ND6 genes, all other mitochondrial genes were encoded on the heavy strand. Mitochondrial DNA information can assist in species identification and conservation of the species' natural resources. PMID- 22943476 TI - Health workers' attitudes toward sexual and reproductive health services for unmarried adolescents in Ethiopia. AB - BACKGROUND: Adolescents in developing countries face a range of sexual and reproductive health problems. Lack of health care service for reproductive health or difficulty in accessing them are among them. In this study we aimed to examine health care workers' attitudes toward sexual and reproductive health services to unmarried adolescents in Ethiopia. METHODS: We conducted a descriptive cross sectional survey among 423 health care service providers working in eastern Ethiopia in 2010. A pre-tested structured questionnaire was used to collect data. Descriptive statistics, chi-square tests and logistic regression were performed to drive proportions and associations. RESULTS: The majority of health workers had positive attitudes. However, nearly one third (30%) of health care workers had negative attitudes toward providing RH services to unmarried adolescents. Close to half (46.5%) of the respondents had unfavorable responses toward providing family planning to unmarried adolescents. About 13% of health workers agreed to setting up penal rules and regulations against adolescents that practice pre-marital sexual intercourse. The multivariate analysis indicated that being married (OR 2.15; 95% CI 1.44 - 3.06), lower education level (OR 1.45; 95% CI 1.04 - 1.99), being a health extension worker (OR 2.49; 95% CI 1.43 - 4.35), lack of training on reproductive health services (OR 5.27; 95% CI 1.51 - 5.89) to be significantly associated with negative attitudes toward provision of sexual and reproductive services to adolescents. CONCLUSIONS: The majority of the health workers had generally positive attitudes toward sexual and reproductive health to adolescents. However, a minority has displayed negatives attitudes. Such negative attitudes will be barriers to service utilization by adolescents and hampers the efforts to reduce sexually transmitted infections and unwanted pregnancies among unmarried adolescents. We therefore call for a targeted effort toward alleviating negative attitudes toward adolescent-friendly reproductive health service and re enforcing the positive ones. PMID- 22943477 TI - A comparison of electronic radial and curvilinear endoscopic ultrasonography in the detection of pancreatic malignant tumor. AB - OBJECTIVE: There is no comparative study of electronic radial endoscopic ultrasonography (ER-EUS) and electronic curvilinear EUS (EC-EUS). The aim of this study was to compare the accuracy of ER-EUS and EC-EUS for detecting pancreatic malignancies. METHODS: This was a retrospective review of the patients who had EUS assessment from September 2008 to December 2011 for suspicious pancreatic tumors. Sensitivity, specificity, and area under the ROC curve to detect pancreatic malignancies were calculated and compared between the ER-EUS and EC EUS cohort. The final diagnosis of pancreatic malignancy was based on pathology, or the consensus of patient's clinical course and multimodal imaging tests. RESULTS: Two hundred twenty-one patients were included and divided into two cohorts: ER-EUS (n = 139) and EC-EUS (n = 82) cohorts. With propensity score matching method, 70 cases in each cohort were selected for the comparison. There was no significant difference in sensitivity, specificity, and area under the ROC curve to detect pancreatic malignancy between ER-EUS and EC-EUS cohort (88.5 vs. 100%, 88.6 vs. 90.9%, 0.8855 vs. 0.9545). CONCLUSION: ER-EUS and EC-EUS provided similar accuracy for the detection of pancreatic malignancies. In view of similar diagnostic results of ER-EUS and EC-EUS for the detection of pancreatic malignancy, and the advantage of being able to perform FNA with EC-EUS, EC-EUS may be the preferred choice. PMID- 22943478 TI - Two steps up, the development of Acta Physiologica. PMID- 22943479 TI - Cardiac electrophysiology: what is behind our two-billion heart beats? PMID- 22943480 TI - Hot drinks all round. PMID- 22943481 TI - Emerging evidence that exercise-induced improvements in muscular strength are partly due to adaptations in the brain. PMID- 22943483 TI - Young women's management of victim and survivor identities. AB - Images of child sexual abuse survivors have been strongly mediated by professional and self-help ideologies that espouse 'healthy' and 'unhealthy' responses to trauma. Drawing on interviews taken with five self-identified survivors of child sexual abuse, this paper maps the impact of psychological and popular discourses on victim/survivor identities and, in particular, the centrality of themes such as disclosure and 'healing' in accounts from survivors. Investment in these particular versions of recovery has operated to shift the focus of the survivor movement away from its political beginnings, such that private healing has replaced public discontent. As the excerpts from survivors in this paper suggest, the language commonly captured in both therapeutic and popular accounts of trauma may guide and delimit the subject positions available to survivors. Utilising the concept of 'wounded attachment', this paper identifies some of the outcomes associated with internalised notions of healing for survivors, as well as the dilemmas that might be impeding disclosure. PMID- 22943482 TI - Comparison of prognosis of separated and non-separated tooth autotransplantation. AB - The aim of this study was to compare the prognosis of separated and non-separated tooth autotransplantation of the upper first and second molars with complete root formation undertaken at dental clinics. The participating dentists were requested to provide information on transplantations they had undertaken from 1 January 1990 to 31 December 2010. Data on a total of 708 teeth from 637 patients were collected. This study analysed 35 separated teeth and 22 non-separated teeth of 47 participants ranging from 27 to 76 years of age (mean age: 55.0 years) after data screening and elimination. The cumulative post-transplantation survival rate at 10 years was 77.1% for separated teeth and 63.6% for non-separated teeth as calculated with the Kaplan-Meier method. There were no significant differences between separated teeth and non-separated teeth in a log rank test (P = 0.687). Separated-tooth autotransplantation can help fill narrow recipient sites and increase occlusal supporting zones, but the clinical success rate was only 48.6%. Although transplantation of teeth with complete root formation has limited prognosis, transplantation of upper first and second molars, whether separated or non-separated, is a viable option to replace missing teeth. PMID- 22943484 TI - Natural resistance to cancers: a Darwinian hypothesis to explain Peto's paradox. AB - BACKGROUND: Peto's paradox stipulates that there is no association between body mass (a surrogate of number of cells and longevity) and cancer prevalence in wildlife species. Resolving this paradox is a very promising research direction to understand mechanisms of cancer resistance. As of present, research has been focused on the consequences of these evolutionary pressures rather than of their causes. DISCUSSION: Here, we argue that evolution through natural selection may have shaped mechanisms of cancer resistance in wildlife species and that this can result in a threshold in body mass above which oncogenic and tumor suppressive mechanisms should be increasingly purified and positively selected, respectively. SUMMARY: We conclude that assessing wildlife species in their natural ecosystems, especially through theoretical modeling, is the most promising way to understand how evolutionary processes can favor one or the other pathway. This will provide important insights into mechanisms of cancer resistance. PMID- 22943485 TI - Cost-effectiveness analysis of sacral neuromodulation for faecal incontinence in The Netherlands. AB - AIM: Sacral neuromodulation (SNM) plays a major part in the algorithm of management of faecal incontinence, but there are limited data on its cost effectiveness. This study aimed to analyse this and the quality-adjusted life years (QALYs) associated with two different treatment algorithms. The first (SNM ) included use of an artificial sphincter [dynamic graciloplasty (DGP) (50%) and artificial bowel sphincter (ABS) (50%)]. The second (SNM+) included SNM (80% of cases) and artificial sphincter (DGP 10%; ABS 10%) The incidence of sphincteroplasty was assumed to be equal in both algorithms. METHOD: A Markov model was developed. A hypothetical cohort of patients was run through both strategies of the model. A mailed EuroQoL-5D questionnaire was used to determine health-related quality of life. Costs were reproduced from the Maastricht University Medical Centre prospective faecal incontinence database. The time scale of the analysis was 5 years. RESULTS: The former treatment protocol cost ?22,651 per patient and the latter, after the introduction of SNM, cost ?16,473 per patient. The former treatment protocol resulted in a success rate of 0.59 after 5 years, whereas with the introduction of SNM this was 0.82. Adhering to the former treatment protocol yielded 4.14 QALYs and implementing the latter produced 4.21 QALYs. CONCLUSION: The study demonstrated that introducing SNM in the surgical management algorithm for faecal incontinence was both more effective and less costly than DGP or ABS without SNM. This justifies adequate funding for SNM for patients with faecal incontinence. PMID- 22943486 TI - Cardiac myofibroblasts: cells out of balance. A new thematic series. AB - We are pleased to introduce a new thematic series dealing with cardiac fibrosis and its association with cardiovascular diseases. A wide variety of cardiovascular diseases are associated with cardiac fibrosis, which is now widely recognized to be not a secondary, but rather a primary contributor to cardiac dysfunction. The purpose of the current series of papers and reviews is to provide the reader with an up-to-date synopsis of the very latest research results and hypotheses that impact on cardiac fibrosis and disease. PMID- 22943487 TI - Efficacy of psychoeducation on symptomatic and functional recovery in bipolar disorder. AB - OBJECTIVE: To evaluate the efficacy of psychoeducation in the symptomatic and functional recovery, and quality of life (QoL) in a sample of patients with bipolar disorder (BD). METHOD: The sample comprised 55 patients with BD I and II in remission (Young Mania Rating Scale <=6 and Hamilton Depression Rating Scale <=7). Out-patients were matched assigned to receive 16 sessions of psychoeducation [experimental group (EG)] or 16 sessions of placebo without psychoeducation [control group (CG)]. Groups were evaluated at study baseline, midpoint, endpoint, and at 6- and 12-month follow-ups. RESULTS: No significant differences between the groups were found for the variables evaluated (mood symptoms, functioning and QoL), except for overall clinical improvement, subjectively perceived by EG subjects. Both groups showed a trend toward improved clinical global impression and QoL (environmental). No reduction in mood symptoms or improvement in psychosocial functioning was observed. Psychosocial treatment compliance was positively correlated with global functioning, social adjustment, sociability, and global clinical impression. CONCLUSION: Sixteen session psychoeducation seems to be ineffective to prevent mood episodes or improve functioning in a sample of bipolar patients. PMID- 22943488 TI - Sex and vision II: color appearance of monochromatic lights. AB - BACKGROUND: Because cerebral cortex has a very large number of testosterone receptors, we examined the possible sex differences in color appearance of monochromatic lights across the visible spectrum. There is a history of men and women perceiving color differently. However, all of these studies deal with higher cognitive functions which may be culture-biased. We study basic visual functions, such as color appearance, without reference to any objects. We present here a detailed analysis of sex differences in primary chromatic sensations. METHODS: We tested large groups of young adults with normal vision, including spatial and temporal resolution, and stereopsis. Based on standard color screening and anomaloscope data, we excluded all color-deficient observers. Stimuli were equi-luminant monochromatic lights across the spectrum. They were foveally-viewed flashes presented against a dark background. The elicited sensations were measured using magnitude estimation of hue and saturation. When the only permitted hue terms are red (R) yellow (Y), green (G), blue (B), alone or in combination, such hue descriptions are language-independent and the hue and saturation values can be used to derive a wide range of color-discrimination functions. RESULTS: There were relatively small but clear and significant, differences between males and females in the hue sensations elicited by almost the entire spectrum. Generally, males required a slightly longer wavelength to experience the same hue as did females. The spectral loci of the unique hues are not correlated with anomaloscope matches; these matches are directly determined by the spectral sensitivities of L- and M-cones (genes for these cones are on the X-chromosomes). Nor are there correlations between loci of pairs of unique hues (R, Y, G, B). Wavelength-discrimination functions derived from the scaling data show that males have a broader range of poorer discrimination in the middle of the spectrum. The precise values for all the data depend on whether Newtonian or Maxwellian optics were used, but the sex differences were the same for both optical systems. CONCLUSION: As with our associated paper on spatio-temporal vision, there are marked sex differences in color vision. The color-appearances we measured are determined by inputs from thalamic neurons (LGN) to individual neurons in primary visual cortex. This convergence from LGN to cortex is guided by the cortex during embryogenesis. We hypothesize that testosterone plays a major role, somehow leading to different connectivities for males and females: color appearance requires a re-combination and re-weighting of neuronal inputs from the LGN to the cortex, which, as we show, depends on the sex of the participant. PMID- 22943489 TI - Effects of silver nanoparticles on microbial growth dynamics. AB - AIMS: Engineered metal nanoparticles are increasingly used in consumer products, in part as additives that exhibit advantageous antimicrobial properties. Conventional nanoparticle susceptibility testing is based largely on determination of nontemporal growth profiles such as measurements of inhibition zones in common agar diffusion tests, counting of colony-forming units, or endpoint or regular-interval growth determination via optical density measurements. For better evaluation of the dynamic effects from exposure to nanoparticles, a cultivation-based assay was established in a 96-well format and adapted for time-resolved testing of the effects of nanoparticles on micro organisms. METHODS AND RESULTS: The modified assay allowed simultaneous cultivation and on-line analysis of microbial growth inhibition. The automated high-throughput assay combined continuous monitoring of microbial growth with the analysis of many replicates and was applied to Cupriavidus necator H16 test organisms to study the antimicrobial effects of spherical silver [Ag(0)] nanoparticles (primary particle size distribution D90 < 15 nm). Ag(0) concentrations above 80 MUg ml(-1) resulted in complete and irreversible inhibition of microbial growth, whereas extended lag phases and partial growth inhibition were observed at Ag(0) concentrations between 20 and 80 MUg ml(-1) . Addition of Ag(0) nanoparticles at different growth stages led to either complete inhibition (addition of 40 MUg ml(-1) Ag(0) from 0 h to 6 h) or resulted in full recovery (40 MUg ml(-1) Ag(0) addition >=9 h). CONCLUSIONS: Contrary to the expected results, our data indicate growth stimulation of C. necator at certain Ag(0) nanoparticle concentrations, as well as varying susceptibility to nanoparticles at different growth stages. SIGNIFICANCE AND IMPACT OF THE STUDY: These results underscore the need for time-resolved analyses of microbial growth inhibition by Ag(0) nanoparticles. Due to the versatility of the technique, the assay will likely complement existing microbiological methods for cultivation and diagnostics of microbes, in addition to tests of other antimicrobial nanoparticles. PMID- 22943490 TI - Functional response to total hip arthroplasty in patients with hip dysplasia. AB - BACKGROUND: While recent studies have shown patients with developmental dysplasia of the hip (DDH) undergoing total hip arthroplasty (THA) to achieve comparable post-operative outcomes to patients with primary osteoarthritis (OA), it is unclear whether DDH patients display better or worse preoperative function than the general THA population. We aimed to compare the preoperative function and functional response to THA of DDH patients with OA patients. METHODS: Through a retrospective review of prospectively collected regional joint registry data, we compared the preoperative, 1-year post-operative and post-operative change in disease-specific (Oxford hip score (OHS), Western Ontario and MacMaster Universities Osteoarthritis Index (WOMAC)) and general health (short form 12 physical health (SF-12 PH), mental health (SF-12 MH) scores) functional scores of 33 DDH patients and 968 OA patients undergoing primary THA. RESULTS: The DDH group displayed substantially worse preoperative function than the OA group (mean OHS 11.2 versus 16.3 (P = 0.001), WOMAC 72.7 versus 60.6 (P < 0.001), SF-12 PH 27.8 versus 28.9 (P = 0.433), SF-12 MH 35.5 versus 44.7 (P < 0.001)). Functional response to THA at 1 year was significantly better in the DDH group than the OA group (mean score improvements: OHS 31.1 versus 24.6 (P < 0.001), WOMAC 61.4 versus 47.2 (P < 0.001), SF-12 PH 22.3 versus 16.5 (P = 0.003), SF-12 MH 18.4 versus 8.4 (P < 0.001)). CONCLUSION: Despite experiencing significantly worse preoperative function, DDH patients undergoing THA demonstrated superior early functional response to OA patients, with substantially greater improvements observed in all disease-specific and general health outcome measures. PMID- 22943492 TI - A preliminary study into the correlation of stiffness of the laminar junction of the equine hoof with the length density of its secondary lamellae. AB - REASON FOR PERFORMING STUDY: The relationship between mechanical behaviour and microscopic structure of the laminar junction of equine hooves under testing conditions requires elucidation. OBJECTIVES: To determine mechanical parameters and 2D length density of profiles of secondary lamellae of the laminar junction in the dermal region and to assess possible correlations. METHODS: Specimens (25 samples in total) of the laminar junction were taken from front, quarter and heel parts from 3 equine hooves and exposed to a uniaxial tensile test until rupture to obtain Young's moduli of elasticity, ultimate stress and strain. Neighbouring specimens to those used for the biomechanical experiment were processed histologically to assess the length density of laminar junction basement membrane using stereological grids. RESULTS: The estimated median (interquartile range) length density of the laminar junction basement membrane was 0.024 (0.020 0.027)/um. Young's modulus of elasticity was 0.15 (0.11-0.35) MPa in the small deformation region, and 7.58 (6.14-8.68) MPa in the linear region was. The ultimate stress was 1.67 (1.41-2.67) MPa, and the ultimate strain was 0.50 (0.38 0.70). The Young's modulus of elasticity in the region of small deformations has a moderate correlation with the length density of the laminar junction basement membrane. CONCLUSIONS: As with most soft biological tissues, the laminar junction has a nonlinear mechanical behaviour. Within the range of small deformations, which correspond to physiological loading of the laminar junction, a higher length density of the laminar junction basement membrane is correlated with a higher resistance of the laminar junction against high stresses transmitted from the distal phalanx to the hoof wall. POTENTIAL RELEVANCE: The condition of the laminar junction apparatus may be easily quantified as the length density of profiles of secondary dermal lamellae. This quantification provides a simple tool that could be used for comparing the proneness of the various parts of the laminar junction to initial stages of laminitis. PMID- 22943491 TI - A proteomic investigation of Fusobacterium nucleatum alkaline-induced biofilms. AB - BACKGROUND: The Gram negative anaerobe Fusobacterium nucleatum has been implicated in the aetiology of periodontal diseases. Although frequently isolated from healthy dental plaque, its numbers and proportion increase in plaque associated with disease. One of the significant physico-chemical changes in the diseased gingival sulcus is increased environmental pH. When grown under controlled conditions in our laboratory, F. nucleatum subspecies polymorphum formed mono-culture biofilms when cultured at pH 8.2. Biofilm formation is a survival strategy for bacteria, often associated with altered physiology and increased virulence. A proteomic approach was used to understand the phenotypic changes in F. nucleatum cells associated with alkaline induced biofilms. The proteomic based identification of significantly altered proteins was verified where possible using additional methods including quantitative real-time PCR (qRT PCR), enzyme assay, acidic end-product analysis, intracellular polyglucose assay and Western blotting. RESULTS: Of 421 proteins detected on two-dimensional electrophoresis gels, spot densities of 54 proteins varied significantly (p < 0.05) in F. nucleatum cultured at pH 8.2 compared to growth at pH 7.4. Proteins that were differentially produced in biofilm cells were associated with the functional classes; metabolic enzymes, transport, stress response and hypothetical proteins. Our results suggest that biofilm cells were more metabolically efficient than planktonic cells as changes to amino acid and glucose metabolism generated additional energy needed for survival in a sub optimal environment. The intracellular concentration of stress response proteins including heat shock protein GroEL and recombinational protein RecA increased markedly in the alkaline environment. A significant finding was the increased abundance of an adhesin, Fusobacterial outer membrane protein A (FomA). This surface protein is known for its capacity to bind to a vast number of bacterial species and human epithelial cells and its increased abundance was associated with biofilm formation. CONCLUSION: This investigation identified a number of proteins that were significantly altered by F. nucleatum in response to alkaline conditions similar to those reported in diseased periodontal pockets. The results provide insight into the adaptive mechanisms used by F. nucleatum biofilms in response to pH increase in the host environment. PMID- 22943493 TI - Women's higher likelihood of disability pension: the role of health, family and work. A 5-7 years follow-up of the Hordaland Health Study. AB - BACKGROUND: Women's higher risk of disability pension compared with men is found in countries with high female work participation and universal welfare schemes. The aim of the study was to examine the extent to which self-perceived health, family situation and work factors explain women's higher risk of disability pension. We also explored how these factors influenced the gender difference across educational strata. METHODS: The population-based Hordaland Health Study (HUSK) was conducted in 1997-99 and included inhabitants born in 1953-57 in Hordaland County, Norway. The current study included 5,959 men and 6,306 women in paid work with valid information on education and self-perceived health. Follow up data on disability pension, for a period of 5-7 years, was obtained by linking the health survey to a national registry of disability pension. Cox regression analyses were employed. RESULTS: During the follow-up period 99 (1.7%) men and 230 (3.6%) women were awarded disability pension, giving a twofold risk of disability pension for women compared with men. Except for a moderate impact of self-perceived health, adjustment for family situation and work factors did not influence the gender difference in risk. Repeating the analyses in strata of education, the gender difference in risk of disability pension among the highly educated was fully explained by self-perceived health and work factors. In the lower strata of education there remained a substantial unexplained gender difference in risk. CONCLUSIONS: In a Norwegian cohort of middle-aged men and women, self-perceived health, family situation and work factors could not explain women's higher likelihood of disability pension. However, analyses stratified by educational level indicate that mechanisms behind the gender gap in disability pension differ by educational levels. Recognizing the heterogeneity within gender may contribute to a deeper understanding of women's higher risk of disability pension. PMID- 22943494 TI - The mechanism underlying lexical selection: evidence from the picture-picture interference paradigm. AB - In two experiments using the picture-picture and picture-word interference paradigms, we compared predictions from the swinging lexical network and the response exclusion hypothesis to determine whether the process of word selection is competitive. Further, we suggest that previous categorical effects in the picture-picture interference paradigm were due to stimuli confounds, thus readdressing the debate concerning categorical effects in the paradigm. Consistent with both hypotheses, in Experiment 1 we found faster picture naming times when distractor pictures were associatively related than when they were unrelated, explained as a result of a spread of activation at the conceptual level with little (swinging lexical network) or no (response exclusion hypothesis) contribution from lexical competition. In Experiment 2, we found a significant categorical interference effect in the picture-word interference paradigm, and this effect significantly decreased but was not facilitatory when distractors were pictures. We discuss how these results are consistent with the swinging lexical network and conclude that the process to select a word is a competitive one. PMID- 22943495 TI - Phylogenetic niche conservatism: what are the underlying evolutionary and ecological causes? AB - Phylogenetic niche conservatism (PNC) is the tendency of lineages to retain their niche-related traits through speciation events. A recent surge in the availability of well-sampled molecular phylogenies has stimulated phylogenetic approaches to understanding ecological processes at large geographical scales and through macroevolutionary time. We stress that PNC is a pattern, not a process, and is found only in some traits and some lineages. At the simplest level, a pattern of PNC is an inevitable consequence of evolution - descent with modification and divergence of lineages - but several intrinsic causes, including physicochemical, developmental and genetic constraints, can lead directly to a marked pattern of PNC. A pattern of PNC can also be caused indirectly, as a by product of other causes, such as extinction, dispersal limitation, competition and predation. Recognition of patterns of PNC can contribute to understanding macroevolutionary processes: for example, release from constraint in traits has been hypothesized to trigger adaptive radiations such as that of the angiosperms. Given the multiple causes of patterns of PNC, tests should address explicit questions about hypothesized processes. We conclude that PNC is a scientifically useful concept with applications to the practice of ecological research. PMID- 22943498 TI - Antidepressants activate survival-promoting pathways in hippocampal neurons despite nutrient deprivation stress (commentary on Yang et al.). PMID- 22943497 TI - A conceptual framework and protocol for defining clinical decision support objectives applicable to medical specialties. AB - BACKGROUND: The U.S. Centers for Medicare and Medicaid Services established the Electronic Health Record (EHR) Incentive Program in 2009 to stimulate the adoption of EHRs. One component of the program requires eligible providers to implement clinical decision support (CDS) interventions that can improve performance on one or more quality measures pre-selected for each specialty. Because the unique decision-making challenges and existing HIT capabilities vary widely across specialties, the development of meaningful objectives for CDS within such programs must be supported by deliberative analysis. DESIGN: We developed a conceptual framework and protocol that combines evidence review with expert opinion to elicit clinically meaningful objectives for CDS directly from specialists. The framework links objectives for CDS to specialty-specific performance gaps while ensuring that a workable set of CDS opportunities are available to providers to address each performance gap. Performance gaps may include those with well-established quality measures but also priorities identified by specialists based on their clinical experience. Moreover, objectives are not constrained to performance gaps with existing CDS technologies, but rather may include those for which CDS tools might reasonably be expected to be developed in the near term, for example, by the beginning of Stage 3 of the EHR Incentive program. The protocol uses a modified Delphi expert panel process to elicit and prioritize CDS meaningful use objectives. Experts first rate the importance of performance gaps, beginning with a candidate list generated through an environmental scan and supplemented through nominations by panelists. For the highest priority performance gaps, panelists then rate the extent to which existing or future CDS interventions, characterized jointly as "CDS opportunities," might impact each performance gap and the extent to which each CDS opportunity is compatible with specialists' clinical workflows. The protocol was tested by expert panels representing four clinical specialties: oncology, orthopedic surgery, interventional cardiology, and pediatrics. PMID- 22943496 TI - Tissue-specific human beta-defensins (HBD)-1, HBD-2 and HBD-3 secretion profile from human amniochorionic membranes stimulated with Candida albicans in a two compartment tissue culture system. AB - BACKGROUND: During intrauterine infection, amniochorionic membranes represent a mechanical and immunological barrier against dissemination of infection. Human beta defensins (HBD)-1, HBD-2, and HBD-3 are key elements of innate immunity that represent the first line of defense against different pathogen microorganisms associated with preterm labor. The aim of this work was to characterize the individual contribution of the amnion (AMN) and choriodecidua (CHD) regions to the secretion of HBD-1, HBD-2 and HBD-3, after stimulation with Candida albicans. METHODS: Full-thickness human amniochorionic membranes were obtained after delivery by elective cesarean section from women at 37-40 wk of gestation with no evidence of active labor. The membranes were cultured in a two-compartment experimental model in which the upper compartment is delimited by the amnion and the lower chamber by the choriodecidual membrane. One million of Candida albicans were added to either the AMN or the CHD face or to both and compartmentalized secretion profiles of HBD-1, HBD-2, and HBD-3 were quantified by ELISA. Tissue immunolocalization was performed to detect the presence of HBD-1, -2, -3 in tissue sections stimulated with Candida albicans. RESULTS: HBD-1 secretion level by the CHD compartment increased 2.6 times (27.30 [20.9-38.25] pg/micrograms protein) when the stimulus with Candida albicans was applied only on this side of the membrane and 2.4 times (26.55 [19.4-42.5] pg/micrograms protein) when applied to both compartments simultaneously. HBD-1 in the amniotic compartment remained without significant changes. HBD-2 secretion level increased significantly in the CHD when the stimulus was applied only to this region (2.49 [1.49-2.95] pg/micrograms protein) and simultaneously to both compartments (2.14 [1.67- 2.91] pg/micrograms protein). When the stimulus was done in the amniotic compartment HBD-2 remained without significant changes in both compartments. HBD-3 remained without significant changes in both compartments regardless of the stimulation modality. Localization of immune-reactive forms of HBD-1, HBD-2, and HBD-3 was carried out by immunohistochemistry confirming the cellular origin of these peptides. CONCLUSION: Selective stimulation of amniochorionic membranes with Candida albicans resulted in tissue-specific secretion of HBD-1 and HBD-2, mainly in the CHD, which is the first region to become infected during an ascending infection. PMID- 22943499 TI - Lesser grain borers, Rhyzopertha dominica, select rough rice kernels with cracked hulls for reproduction. AB - Tests were conducted to determine whether the lesser grain borer, Rhyzopertha dominica (F.) (Coleoptera: Bostrychidae), selects rough rice (Oryza sativa L. (Poales: Poaceae)) kernels with cracked hulls for reproduction when these kernels are mixed with intact kernels. Differing amounts of kernels with cracked hulls (0, 5, 10, and 20%) of the varieties Francis and Wells were mixed with intact kernels, and the number of adult progeny emerging from intact kernels and from kernels with cracked hulls was determined. The Wells variety had been previously classified as tolerant to R. dominica, while the Francis variety was classified as moderately susceptible. Few F 1 progeny were produced in Wells regardless of the percentage of kernels with cracked hulls, few of the kernels with cracked hulls had emergence holes, and little firass was produced from feeding damage. At 10 and 20% kernels with cracked hulls, the progeny production, number of emergence holes in kernels with cracked hulls, and the amount of firass was greater in Francis than in Wells. The proportion of progeny emerging from kernels with cracked hulls increased as the proportion of kernels with cracked hulls increased. The results indicate that R. dominica select kernels with cracked hulls for reproduction. PMID- 22943500 TI - Association between self-assessment of complete dentures and oral health-related quality of life. AB - The purpose of this study was to determine which factors related to patient self assessment of dentures are associated with changes in oral health-related quality of life (OHRQoL) among edentulous patients after replacement of complete dentures, and to determine whether masticatory performance as determined using an objective method affects the changes in OHRQoL among edentulous patients. As a preliminary study, the existing questionnaire regarding self-assessment of dentures consisting of 39 question items, measured with a 100-mm visual analogue scale, was analysed by factor analysis. Then a questionnaire, composed of 22 question items, was developed containing six subscales of 'function', 'lower denture', 'upper denture', 'expectation', 'aesthetic and speech' and 'importance'. Final participants in the present study comprised 93 edentulous patients requiring new conventional complete dentures (44 men, 49 women; mean age, 75.0 years). These patients were asked to complete the Japanese version of the Oral Health Impact Profile (OHIP)-EDENT, comprising 19 question items for assessment of OHRQoL in edentulous patients, along with the developed questionnaire regarding self-assessment of dentures. Moreover, masticatory performance was measured using a colour-changeable chewing gum. The questionnaire and measurement were completed twice; before and after replacement of complete dentures. Stepwise multiple regression analysis identified 'lower denture' and 'aesthetic and speech' as significant independent variables besides OHIP-EDENT scores before replacement. These results suggest that sufficient retention of lower dentures and appropriate appearance may lead to improved OHRQoL in edentulous patients. PMID- 22943501 TI - In vitro comparative analysis of antiproliferative activity of essential oil from mandarin peel and its principal component limonene. AB - The effects of the essential oil of mandarin peel (Corrientes, Argentina) and limonene (its major component) were studied on two human tumour cell lines growth (lung adenocarcinoma A549 and hepatocarcinoma HepG2). The essential oil was obtained by cold press and its composition was investigated by gas chromatography (GC) and GC/mass spectrometry (MS) analysis. The antiproliferative effect was studied using an MTT assay. Both mandarin essential oil and limonene tested showed a strong dose-dependent effect on the growth inhibition of these cell lines. The essential oil was more effective in A549 than in HepG2 cells and more effective than limonene in both the cases. It is likely that minor components and limonene of the oil could exert additive or synergistic effects. Hence, mandarin essential oil could lead to the development of anti-tumour agent or complementary and alternative medicines for the treatment of diverse cancers. PMID- 22943502 TI - Complete mitochondrial genome of Labeo rohita. AB - The complete mitochondrial genome of Labeo rohita, an important cultivable fish, was determined for the first time. The genome is 16,611 bp in length and consists of 13 protein-coding genes, 22 tRNA genes, 2 rRNA genes, and one control region. The gene organisation and its order were similar to other vertebrates. The overall base composition on heavy strand was as follows A: 32.5%, G: 15.2%, C: 27.7%, T: 24.47%, and the A+T content 56.9%. The control region contains a microsatellite, (TA)(12), a putative termination-associated sequence and three conserved sequence blocks. This mitogenome sequence data would play an important role in population genetics and phylogenetics of Indian major carps. PMID- 22943503 TI - Secretory pathway antagonism by calicivirus homologues of Norwalk virus nonstructural protein p22 is restricted to noroviruses. AB - BACKGROUND: Our previous report that the Norwalk virus nonstructural protein p22 is an antagonist of the cellular secretory pathway suggests a new aspect of norovirus/host interaction. To explore conservation of function of this highly divergent calicivirus protein, we examined the effects of p22 homologues from four human and two murine noroviruses, and feline calicivirus on the secretory pathway. FINDINGS: All human noroviruses examined induced Golgi disruption and inhibited protein secretion, with the genogroup II.4 Houston virus being the most potent antagonist. Genogroup II.6 viruses have a conserved mutation in the mimic of an Endoplasmic Reticulum export signal (MERES) motif that is highly conserved in human norovirus homologues of p22 and is critical for secretory pathway antagonism, and these viruses had reduced levels of Golgi disruption and inhibition of protein secretion. p22 homologues from both persistent and nonpersistent strains of murine norovirus induced Golgi disruption, but only mildly inhibited cellular protein secretion. Feline calicivirus p30 did not induce Golgi disruption or inhibit cellular protein secretion. CONCLUSIONS: These differences confirm a norovirus-specific effect on host cell secretory pathway antagonism by homologues of p22, which may affect viral replication and/or cellular pathogenesis. PMID- 22943505 TI - Sexual attitudes, behaviours and acculturation among young migrants in Shanghai. AB - China's rates of internal migration increased to an all-time high of over 200 million individuals at the beginning of the twenty-first century. Yet, there is a dearth of information on the lives of young migrant populations. The aim of this study was to explore how migration influences the sexual attitudes and behaviours of 18-24-year-old migrant men and women in Shanghai, China. A total of 64 migrants participated in 10 focus-group discussions and 20 in-depth interviews. Guided by acculturation theory, coded data were organised into analytic matrices to compare themes across participants. Factors associated with increased sexual risk behaviours include acculturative stress, discrimination leading to social isolation, conflicts between traditional and modern city values and increased sexual opportunities. Premarital sex, cohabitation, unprotected sex and visiting sex workers are common among this population. Reasons for not using condoms included being unprepared, lack of knowledge and barriers in accessing reproductive services due to not having urban documentation. Local family planning programmes should help migrants negotiate traditional and modern values and partner with work-sites to provide comprehensive sexual education and services and train health professionals in the specific healthcare needs of young migrant populations. PMID- 22943506 TI - Severe conjunctivochalasis in association with classic type Ehlers-Danlos syndrome. AB - BACKGROUND: Inferior conjunctivochalasis is common, but is rarely severe enough to require conjunctival excision. This report describes a patient with severe conjunctivochalasis who was subsequently diagnosed with Ehlers Danlos Syndrome, Classic Type. CASE PRESENTATION: A patient suffering from foreign body sensation, frequent blinking and bilateral inferior conjunctivochalasis was referred and treated by topical ocular lubrication. However, no improvement was observed prompting potential excision of conjunctivochalasis. Following patient consultation and clinical diagnosis including hypermobile joints and skin elasticity, poor wound healing and wide scar morphology, Ehlers-Danlos syndrome was confirmed in the patient. CONCLUSION: This case highlights the need for direct patient questioning and provides the first reported association between conjunctiovochalasis and Ehlers-Danlos syndrome. PMID- 22943504 TI - Cardiac fibroblasts, fibrosis and extracellular matrix remodeling in heart disease. AB - Fibroblasts comprise the largest cell population in the myocardium. In heart disease, the number of fibroblasts is increased either by replication of the resident myocardial fibroblasts, migration and transformation of circulating bone marrow cells, or by transformation of endothelial/epithelial cells into fibroblasts and myofibroblasts. The primary function of fibroblasts is to produce structural proteins that comprise the extracellular matrix (ECM). This can be a constructive process; however, hyperactivity of cardiac fibroblasts can result in excess production and deposition of ECM proteins in the myocardium, known as fibrosis, with adverse effects on cardiac structure and function. In addition to being the primary source of ECM proteins, fibroblasts produce a number of cytokines, peptides, and enzymes among which matrix metalloproteinases (MMPs) and their inhibitors, tissue inhibitor of metalloproteinases (TIMPs), directly impact the ECM turnover and homeostasis. Function of fibroblasts can also in turn be regulated by MMPs and TIMPs. In this review article, we will focus on the function of cardiac fibroblasts in the context of ECM formation, homeostasis and remodeling in the heart. We will discuss the origins and multiple roles of cardiac fibroblasts in myocardial remodeling in different types of heart disease in patients and in animal models. We will further provide an overview of what we have learned from experimental animal models and genetically modified mice with altered expression of ECM regulatory proteins, MMPs and TIMPs. PMID- 22943507 TI - Ethyl pyruvate diminishes the inflammatory response to lipopolysaccharide infusion in horses. AB - REASONS FOR PERFORMING THE STUDY: Endotoxaemia contributes to morbidity and mortality in horses with colic due to inflammatory cascade activation. Effective therapeutic interventions are limited for these horses. Ethyl pyruvate (EP), an anti-inflammatory agent that alters the expression of proinflammatory cytokines, improved survival and organ function in sepsis and gastrointestinal injury in rodents and swine. Therapeutic efficacy of EP is unknown in endotoxaemic horses. OBJECTIVES: Determine the effects of EP on signs of endotoxaemia and expression of proinflammatory cytokines following administration of lipopolysaccharide (LPS) in horses. METHODS: Horses received 30 ng/kg bwt LPS in saline to induce signs of endotoxaemia. Next, horses received lactated Ringer's solution (LRS), (n = 6), 150 mg/kg bwt EP in LRS, (n = 6), or 1.1 mg/kg bwt flunixin meglumine (FM), (n = 6). Controls received saline followed by LRS (n = 6). Physical examinations, behaviour pain scores and blood for clinical pathological testing and gene expression were obtained at predetermined intervals for 24 h. RESULTS: Lipopolysaccharide infusion produced clinical and clinicopathological signs of endotoxaemia and increased expression of tumour necrosis factor alpha (TNFalpha), interleukin 6 (IL-6) and IL-8 (P<0.001) compared with controls. Leucopenia and neutropenia occurred in all horses that received LPS. Horses treated with EP and FM had significantly (P<0.0001) reduced pain scores compared with horses receiving LPS followed by LRS. Flunixin meglumine was significantly more effective at ameliorating fever compared with EP. Both EP and FM significantly diminished TNFalpha expression. Ethyl pyruvate significantly decreased, but FM significantly increased, IL-6 expression. Neither EP nor FM altered IL-8 expression. CONCLUSIONS AND POTENTIAL RELEVANCE: Ethyl pyruvate administered following LPS diminished the clinical effects of endotoxaemia and decreased proinflammatory gene expression in horses. Ethyl pyruvate suppressed expression of proinflammatory cytokines better than FM. However, FM was a superior anti pyretic compared with EP. Ethyl pyruvate may have therapeutic applications in endotoxaemic horses. PMID- 22943508 TI - Metachronous colorectal cancer risk in patients with a moderate family history. AB - AIM: Lifetime risk of a metachronous colorectal cancer (mCRC) is 0.6-3% following sporadic colorectal cancer (CRC) and 15-26% in Lynch syndrome. The lifetime incidence of CRC in individuals with moderate familial risk is 8-17%. Risk of mCRC is unknown. METHOD: A retrospective longitudinal study of the Regional Familial CRC Registry was performed. Patients who had at least one CRC were categorized as follows: moderate risk (n = 383), Lynch syndrome (n = 528) and average (population) risk (n = 409). The Kaplan-Meier estimate (1-KM) and the cumulative incidence function were used to calculate the risk of mCRC. The 1-KM gives the risk for individuals remaining at risk (alive) at a given time point and thus is useful for counselling. The cumulative incidence function gives the risk for the whole population. RESULTS: The 1-KM and the cumulative incidence function demonstrated that the risk of mCRC was significantly higher in moderate risk patients compared with average (population)-risk patients (1-KM, P = 0.008; cumulative incidence function, P = 0.00097). However, the risk of mCRC was higher in patients with Lynch syndrome than in moderate-risk or average (population) risk patients. The 1-KM in moderate-risk patients was 2.7%, 6.3% and 23.5% at 5, 10 and 20 years, respectively. In average (population)-risk patients, the 1-KM was 1.3%, 3.1% and 7.0% at 5, 10 and 20 years, and the cumulative incidence function was 0.3%, 0.6% and 2.4% at the same time points, respectively. CONCLUSION: These data indicate that the risk of mCRC is significantly higher in patients with a moderate family history of CRC than in those with an average (population) risk. This justifies proactive lifelong surveillance. PMID- 22943510 TI - Learned predictiveness influences automatic evaluations in human contingency learning. AB - Experiments used an affective priming procedure to investigate whether evaluative conditioning in humans is subject to bias as a consequence of differences in the learned predictiveness of the cues involved. Experiment 1, using brief prime presentation, demonstrated stronger affective priming for cues that had been predictive of a neutral attribute prior to evaluative conditioning than for those that had been nonpredictive. Experiment 2, using longer prime presentation, found a reversed priming effect for previously predictive cues but not for previously nonpredictive cues. The implication is that the effect observed with brief prime presentation reflects the operation of fast-acting, automatic evaluation mechanisms and hence that evaluative conditioning can be biased by our previous learning about the predictiveness of cues. PMID- 22943509 TI - Angiotensin II type 1 receptor antagonists alleviate muscle pathology in the mouse model for laminin-alpha2-deficient congenital muscular dystrophy (MDC1A). AB - BACKGROUND: Laminin-alpha2-deficient congenital muscular dystrophy (MDC1A) is a severe muscle-wasting disease for which no curative treatment is available. Antagonists of the angiotensin II receptor type 1 (AT1), including the anti hypertensive drug losartan, have been shown to block also the profibrotic action of transforming growth factor (TGF)-beta and thereby ameliorate disease progression in mouse models of Marfan syndrome. Because fibrosis and failure of muscle regeneration are the main reasons for the severe disease course of MDC1A, we tested whether L-158809, an analog derivative of losartan, could ameliorate the dystrophy in dyW/dyW mice, the best-characterized model of MDC1A. METHODS: L 158809 was given in food to dyW/dyW mice at the age of 3 weeks, and the mice were analyzed at the age of 6 to 7 weeks. We examined the effect of L-158809 on muscle histology and on muscle regeneration after injury as well as the locomotor activity and muscle strength of the mice. RESULTS: We found that TGF-beta signaling in the muscles of the dyW/dyW mice was strongly increased, and that L 158809 treatment suppressed this signaling. Consequently, L-158809 reduced fibrosis and inflammation in skeletal muscle of dyW/dyW mice, and largely restored muscle regeneration after toxin-induced injury. Mice showed improvement in their locomotor activity and grip strength, and their body weight was significantly increased. CONCLUSION: These data provide evidence that AT1 antagonists ameliorate several hallmarks of MDC1A in dyW/dyW mice, the best characterized mouse model for this disease. Because AT1 antagonists are well tolerated in humans and widely used in clinical practice, these results suggest that losartan may offer a potential future treatment of patients with MDC1A. PMID- 22943512 TI - Moving beyond stigma--are concurrent palliative care and management of pulmonary arterial hypertension irreconcilable or future best practice? PMID- 22943513 TI - Clinical implications of haemoptysis in patients with pulmonary arterial hypertension. AB - INTRODUCTION: Pulmonary arterial hypertension (PAH) is a disabling disease that may result in haemoptysis. Patients with congenital heart disease associated PAH (CHD-APAH) may have a survival advantage when compared with patients with other types of PAH presenting with haemoptysis. The effects of aetiology and subsequent management choice of haemoptysis in PAH patients is not well-defined. METHODS: We conducted outcome analysis in CHD-APAH vs. all other subtypes of PAH patients presenting with haemoptysis to The Methodist Hospital. Twenty-one patients were identified, 13 patients in the CHD-APAH group and eight patients in the non-CHD group. We evaluated outcomes related to treatment (bronchial artery embolisation (BAE) vs. conservative management), hospital length of stay, mortality rates and survival in this cohort. RESULTS: The CHD-APAH and non-CHD groups had similar baseline demographic, haemodynamic and laboratory values except BMI was higher in the non-CHD group and haematocrit was higher in the CHD-APAH group. Twenty-eight day mortality (0% vs. 31%) and 1-year mortality (0% vs. 54%) was lower in the CHD APAH patients as compared with non-CHD group. A statistically significant difference was found in the survival rate in favour of CHD-APAH group for the total follow-up period (p = 0.02). Although not statistically significant, patients treated with BAE had shorter length of stay (4.0 days +/- 4.0 vs. 13.7 days +/- 22.5; p = 0.26). There was recurrent haemoptysis in 43% of patients treated with BAE. CONCLUSION: Haemoptysis in PAH patients is a serious event with a high mortality rate. CHD-APAH seems to confer a survival advantage, independent of therapy utilised. Termination of haemoptysis with BAE is rapid with relatively few complications except for frequent re-bleeding episodes. Further studies are needed to determine the risk factors that may predispose PAH patients to excessive mortality from haemoptysis and to identify an optimal therapeutic modality. PMID- 22943515 TI - The international transport of laboratory animals: no excuse for biased extremism of any kind. PMID- 22943514 TI - Determinants of pulmonary hypertension in young adults. AB - BACKGROUND: Risk factors of pulmonary hypertension (PH) are poorly understood. The objective of this study was to identify the determinants of PH in young adults. METHODS: We analysed a limited access dataset from the CARDIA (Coronary Artery Risk Development in Young Adults) study provided by the National Heart, Lung and Blood Institute. Pulmonary arterial pressure was assessed by the Doppler pulmonary artery acceleration time (PAAT). Socio-demographic characteristics, self-reported clinical variables, echocardiographic variables, pulmonary function tests, systemic blood pressure and body mass index calculated from height and weight were used in multivariate analysis. RESULTS: There were 4171 study subjects, mean age 24.9 +/- 3.6 years, retained in year five with echocardiographic data available after five years of follow-up. The prevalence of severe PH (PAAT <= 70 ms) and mild to moderate PH (PAAT = 109.9-70.01 ms) was 1.1% and 14% respectively. Multivariate analysis revealed that body mass index (beta = -1.09, p < 0.0001), female gender (beta = 6.25, p < 0.0001), age (beta = 0.30, p = 0.02), African American race (beta = -2.57, p = 0.007), physical activity (beta = 0.005, p = 0.002), current smoking (beta = -3.42, p = 0.001), left atrial dimension (beta = -2.97, p = 0.009) and diastolic dysfunction (beta = -13.06, p = 0.006) were statistically significant variables predicting PH. CONCLUSION: In this large, observational study of young adults, pulmonary hypertension, as assessed by echocardiography, is common. Diastolic dysfunction, obesity, physical inactivity and smoking are associated with elevated pulmonary arterial pressure in young adults. PMID- 22943516 TI - SNP genotyping for the genetic monitoring of laboratory mice by using a microarray-based method with dualcolour fluorescence hybridisation. AB - Ensuring the genetic homogeneity of the mice used in laboratory experiments contributes to the Reduction aspect of the Three Rs, by maximising the quality of the data obtained from any animals that are used for these purposes, and ultimately reducing the numbers of animals used. Single nucleotide polymorphism (SNP) genotyping is especially suitable for use in the analysis of the genetic purity of model organisms such as the mouse, because bi-allelic markers remain fully informative when used to characterise crosses between inbred strains. Here, we attempted to apply a microarray-based method for a SNP marker to monitor the genetic quality of inbred mouse strains, so as to validate the reliability, stability and applicability of this SNP genotyping panel. The amplified PCR products containing four different SNP loci from four inbred mouse strains were spotted and immobilised onto amino-modified glass slides to generate a microarray. This was then interrogated through hybridisation with dual-colour probes, to determine the SNP genotypes of each sample. The results indicated that this microarray-based method could effectively determine the genotypes of the four selected SNPs with a high degree of accuracy. We have developed a new SNP genotyping technique for effective use in the genetic monitoring of inbred mouse strains. PMID- 22943517 TI - Do faculty in Southern Indian medical colleges support animal use in postgraduate education more than in undergraduate education? AB - In India, animal experiments play an integral role in both undergraduate medical education (UGME) and postgraduate medical education (PGME) in the discipline of Pharmacology. Therefore, we aimed to compare the perceptions of pharmacology faculty members in southern India with regard to the use of animal experiments and alternatives in UGME and in PGME. We also determined the association between these perceptions and the socio-demographic characteristics of the participants. Pharmacology faculty members in 15 medical colleges located in southern India answered a 27-statement, 5-domain questionnaire with a total score of 108. The means of the total, domain and statement scores were analysed by the Wilcoxon signed-rank test. The mean total score obtained for faculty members (n = 52) was significantly higher (p < 0.001) for PGME (61.2/108) than that for UGME (51.9/108). Significant differences were observed in the mean total and in the domain scores for PGME when compared to UGME in all of the socio-demographic groups, except for male faculty members and those without an MD or doctoral degree. The mean individual statement scores also indicated that there is more support for animal use in PGME. Overall, it was apparent that pharmacology faculty members in southern Indian medical colleges support animal use in PGME more than in UGME. Increased awareness is required among faculty members concerning alternatives to animal experiments in medical education, especially in PGME. PMID- 22943518 TI - Report of the EPAA-ECVAM workshop on the validation of Integrated Testing Strategies (ITS). AB - The use of Integrated Testing Strategies (ITS) permits the combination of diverse types of chemical and toxicological data for the purposes of hazard identification and characterisation. In November 2008, the European Partnership for Alternative Approaches to Animal Testing (EPAA), together with the European Centre for the Validation of Alternative Methods (ECVAM), held a workshop on Overcoming Barriers to Validation of Non-animal Partial Replacement Methods/Integrated Testing Strategies, in Ispra, Italy, to discuss the extent to which current ECVAM approaches to validation can be used to evaluate partial replacement in vitro test methods (i.e. as potential ITS components) and ITS themselves. The main conclusions of these discussions were that formal validation was only considered necessary for regulatory purposes (e.g. the replacement of a test guideline), and that current ECVAM approaches to validation should be adapted to accommodate such test methods. With these conclusions in mind, a follow-up EPAA-ECVAM workshop was held in October 2009, to discuss the extent to which existing validation principles are applicable to the validation of ITS test methods, and to develop a draft approach for the validation of such test methods and/or overall ITS for regulatory purposes. This report summarises the workshop discussions that started with a review of the current validation methodologies and the presentation of two case studies (skin sensitisation and acute toxicity), before covering the definition of ITS and their components, including their validation and regulatory acceptance. The following main conclusions/recommendations were made: that the validation of a partial replacement test method (for application as part of a testing strategy) should be differentiated from the validation of an in vitro test method for application as a stand-alone replacement, especially with regard to its predictive capacity; that, in the former case, the predictive capacity of the whole testing strategy (rather than of the individual test methods) would be more important, especially if the individual test methods had a high biological relevance; that ITS allowing for flexible and ad hoc approaches cannot be validated, whereas the validation of clearly defined ITS would be feasible, although practically quite difficult; and that test method developers should be encouraged to develop and submit to ECVAM not only full replacement test methods, but also partial replacement methods to be placed as parts of testing strategies. The added value from the formal validation of testing strategies, and the requirements needed in view of regulatory acceptance of the data, require further informed discussion within the EPAA forum on the basis of case studies provided by industry. PMID- 22943519 TI - Draft EU Commission implementing regulation on applications for the authorisation of genetically modified food and feed. PMID- 22943520 TI - Dual processing model of medical decision-making. AB - BACKGROUND: Dual processing theory of human cognition postulates that reasoning and decision-making can be described as a function of both an intuitive, experiential, affective system (system I) and/or an analytical, deliberative (system II) processing system. To date no formal descriptive model of medical decision-making based on dual processing theory has been developed. Here we postulate such a model and apply it to a common clinical situation: whether treatment should be administered to the patient who may or may not have a disease. METHODS: We developed a mathematical model in which we linked a recently proposed descriptive psychological model of cognition with the threshold model of medical decision-making and show how this approach can be used to better understand decision-making at the bedside and explain the widespread variation in treatments observed in clinical practice. RESULTS: We show that physician's beliefs about whether to treat at higher (lower) probability levels compared to the prescriptive therapeutic thresholds obtained via system II processing is moderated by system I and the ratio of benefit and harms as evaluated by both system I and II. Under some conditions, the system I decision maker's threshold may dramatically drop below the expected utility threshold derived by system II. This can explain the overtreatment often seen in the contemporary practice. The opposite can also occur as in the situations where empirical evidence is considered unreliable, or when cognitive processes of decision-makers are biased through recent experience: the threshold will increase relative to the normative threshold value derived via system II using expected utility threshold. This inclination for the higher diagnostic certainty may, in turn, explain undertreatment that is also documented in the current medical practice. CONCLUSIONS: We have developed the first dual processing model of medical decision-making that has potential to enrich the current medical decision-making field, which is still to the large extent dominated by expected utility theory. The model also provides a platform for reconciling two groups of competing dual processing theories (parallel competitive with default-interventionalist theories). PMID- 22943522 TI - Atypical subtrochanteric fractures, bisphosphonates, blinded radiological review. AB - BACKGROUND: Recent reports have suggested that a certain type of subtrochanteric and diaphyseal femoral fractures maybe associated with bisphosphonate (BP) therapy. We assessed the association between BP use in atypical and typical femoral fractures in a retrospective study and also looked at the rate of coding errors. METHODS: All cases between July 2003 and June 2008 with International Classification of Disease, 10th revision discharge codes for femoral fractures (S72.2 subtrochanteric and S72.3 fracture of shaft of femur) were reviewed. Cases were excluded if there was significant trauma, underlying bone disease or coding error. The remaining cases' films were assessed by an independent, blinded, single radiologist to assess for atypical features (thickened cortices, transverse fractures, medial cortical spike) with additional exclusion criteria of periprosthetic fractures and bone pathology. Odds ratios were calculated comparing BP use in atypical and typical fractures. RESULTS: Six atypical fractures were found in the study period. Compared with the 65 typical fractures, there was an association between BP use and atypical fractures (odds ratio 5.5) but it did not reach statistical significance (0.97-31). Atypical femoral fractures accounted for <0.1% of total fracture admissions during this period. There was a 20% rate of miscoding. CONCLUSION: This study shows a nonsignificant trend towards alendronate/BP use and atypical femoral fractures compared with typical femoral fractures. These fractures were rare <0.1% and the benefit and treatment of osteoporosis with BPs currently seems likely to outweigh the perceived risks. Individual case and radiology review is important as coding errors were frequent. PMID- 22943521 TI - The effect of environmental conditions on expression of Bacteroides fragilis and Bacteroides thetaiotaomicron C10 protease genes. AB - BACKGROUND: Bacteroides fragilis and Bacteroides thetaiotaomicron are members of the normal human intestinal microbiota. However, both organisms are capable of causing opportunistic infections, during which the environmental conditions to which the bacteria are exposed change dramatically. To further explore their potential for contributing to infection, we have characterized the expression in B. thetaiotaomicron of four homologues of the gene encoding the C10 cysteine protease SpeB, a potent extracellular virulence factor produced by Streptococcus pyogenes. RESULTS: We identified a paralogous set of genes (btp genes) in the B. thetaiotaomicron genome, that were related to C10 protease genes we recently identified in B. fragilis. Similar to C10 proteases found in B. fragilis, three of the B. thetaiotaomicron homologues were transcriptionally coupled to genes encoding small proteins that are similar in structural architecture to Staphostatins, protease inhibitors associated with Staphopains in Staphylococcus aureus. The expression of genes for these C10 proteases in both B. fragilis and B. thetaiotaomicron was found to be regulated by environmental stimuli, in particular by exposure to oxygen, which may be important for their contribution to the development of opportunistic infections. CONCLUSIONS: Genes encoding C10 proteases are increasingly identified in operons which also contain genes encoding proteins homologous to protease inhibitors. The Bacteroides C10 protease gene expression levels are responsive to different environmental stimuli suggesting they may have distinct roles in the bacterial-host interaction. PMID- 22943523 TI - Prevalence and characteristics of depression in mild cognitive impairment: the Sydney Memory and Ageing Study. AB - OBJECTIVE: Depression might be a risk factor for dementia. However, little is known about the prevalence of depressive symptoms in mild cognitive impairment (MCI) and whether mood or motivation-related symptoms are predominant. METHOD: A total of 767 non-demented community-dwelling adults aged 70-90 years completed a comprehensive assessment, including neuropsychological testing, and a past psychiatric/medical history interview. Depressive symptoms were assessed using the Geriatric Depression Scale (GDS) and Kessler Psychological Distress Scale (K10). Exploratory factor analysis was performed on the GDS and K10 to derive 'mood' and 'motivation' subscales. RESULTS: A total of 290 participants were classified as having MCI and 468 as cognitively normal (CN). Participants with MCI reported more depressive symptoms, and more MCI participants met the cut-off for clinically significant symptoms, relative to CN participants. Those with amnestic MCI (aMCI), but not non-amnestic MCI, had more depressive symptoms and were more likely to meet the cut-off for clinically significant depressive symptoms, relative to CN participants. Participants with MCI reported more mood related symptoms than CN participants, while there were no differences between groups on motivation-related symptoms. CONCLUSION: Individuals with MCI, especially aMCI, endorse more depressive symptoms when compared with cognitively intact individuals. These findings highlight the importance of assessing and treating depressive symptoms in MCI. PMID- 22943525 TI - Tumour suppressor p16(INK4a) - anoikis-favouring decrease in N/O-glycan/cell surface sialylation by down-regulation of enzymes in sialic acid biosynthesis in tandem in a pancreatic carcinoma model. AB - Tumour suppressor p16(INK4a) is known to exert cell-cycle control via cyclin dependent kinases. An emerging aspect of its functionality is the orchestrated modulation of N/O-glycosylation and galectin expression to induce anoikis in human Capan-1 pancreatic carcinoma cells. Using chemoselective N/O-glycan enrichment technology (glycoblotting) and product characterization, we first verified a substantial decrease in sialylation. Tests combining genetic (i.e. transfection with alpha2,6-sialyltransferase-specific cDNA) or metabolic (i.e. medium supplementation with N-acetylmannosamine to track down a bottleneck in sialic acid biosynthesis) engineering with cytofluorometric analysis of lectin binding indicated a role of limited substrate availability, especially for alpha2,6-sialylation, which switches off reactivity for anoikis-triggering homodimeric galectin-1. Quantitative MS analysis of protein level changes confirmed an enhanced galectin-1 presence along with an influence on glycosyltransferases (beta1,4-galactosyltransferase-IV, alpha2,3 sialyltransferase-I) and detected p16(INK4a) -dependent down-regulation of two enzymes in the biosynthesis pathway for sialic acid [i.e. the bifunctional UDP-N acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE) and N acetylneuraminic acid 9-phosphate synthase] (P < 0.001). By contrast, quantitative assessment for the presence of nuclear CMP-N-acetylneuraminic acid synthase (which is responsible for providing the donor for enzymatic sialylation that also acts as feedback inhibitor of the epimerase activity of GNE) revealed a trend for an increase. Partial restoration of sialylation in GNE-transfected cells supports the implied role of sialic acid availability for the glycophenotype. Fittingly, the extent of anoikis was reduced in double transfected (p16(INK4a) /GNE) cells. Thus, a second means of modulating cell reactivity to the growth effector galectin-1 is established in addition to the common route of altering alpha2,6-sialyltransferase expression: regulating enzymes of the pathway for sialic acid biosynthesis. PMID- 22943524 TI - Bombyx mori transcription factors: genome-wide identification, expression profiles and response to pathogens by microarray analysis. AB - Transcription factors are present in all living organisms, and play vital roles in a wide range of biological processes. Studies of transcription factors will help reveal the complex regulation mechanism of organisms. So far, hundreds of domains have been identified that show transcription factor activity. Here, 281 reported transcription factor domains were used as seeds to search the transcription factors in genomes of Bombyx mori L. (Lepidoptera: Bombycidae) and four other model insects. Overall, 666 transcription factors including 36 basal factors and 630 other factors were identified in B. mori genome, which accounted for 4.56% of its genome. The silkworm transcription factors' expression profiles were investigated in relation to multiple tissues, developmental stages, sexual dimorphism, and responses to oral infection by pathogens and direct bacterial injection. These all provided rich clues for revealing the transcriptional regulation mechanism of silkworm organ differentiation, growth and development, sexual dimorphism, and response to pathogen infection. PMID- 22943526 TI - Postoperative thromboembolic prophylaxis in joint replacement surgery: Guidelines and daily practice. AB - This is a commentary discussing the article published in Thrombosis Journal by Subramanian et al. [Thrombosis Journal 2012, 10:15]. PMID- 22943527 TI - Metabolic and evolutionary costs of herbivory defense: systems biology of glucosinolate synthesis. AB - Here, we describe our updated mathematical model of Arabidopsis thaliana Columbia metabolism, which adds the glucosinolates, an important group of secondary metabolites, to the reactions of primary metabolism. In so doing, we also describe the evolutionary origins of the enzymes involved in glucosinolate synthesis. We use this model to address a long-standing question in plant evolutionary biology: whether or not apparently defensive compounds such as glucosinolates are metabolically costly to produce. We use flux balance analysis to estimate the flux through every metabolic reaction in the model both when glucosinolates are synthesized and when they are absent. As a result, we can compare the metabolic costs of cell synthesis with and without these compounds, as well as inferring which reactions have their flux altered by glucosinolate synthesis. We find that glucosinolate production can increase photosynthetic requirements by at least 15% and that this cost is specific to the suite of glucosinolates found in A. thaliana, with other combinations of glucosinolates being even more costly. These observations suggest that glucosinolates have evolved, and indeed likely continue to evolve, for herbivory defense, since only this interpretation explains the maintenance of such costly traits. PMID- 22943528 TI - New strategies of boar sperm cryopreservation: development of novel freezing and thawing methods with a focus on the roles of seminal plasma. AB - Cryopreservation of boar spermatozoa offers an effective means of long-term storage of important genetic material. Many researchers have investigated how to improve reproductive performance by artificial insemination (AI) using cryopreserved boar spermatozoa. Recently, we and other groups reported that high conception rates (70-80%) can be achieved by AI with frozen-thawed boar spermatozoa using a modified temperature program during freezing, or a novel cryopreservation extender to improve sperm quality (including sperm survivability, motility, membrane status and fertilization ability) after thawing, or a novel sperm infusion method, deep intra uterine insemination. However, these techniques have not yet been used for commercial pig production. The variation in sperm freezability among boars or among ejaculations in an identical boar is one of the main reasons for this problem. In our previous study, it was revealed that some components of seminal plasma have a negative effect on the freezability of boar sperm. One of these factors is bacteria released endotoxin (lipopolysaccharide: LPS). LPS binds to Toll-like receptor-4 (TLR-4) expressed on the sperm surface, resulting in induction of apoptosis. On the other hand, seminal plasma suppresses cryo-capacitation induced by thawing stress. On the basis of these findings, we designed a novel protocol of AI using frozen-thawed boar sperm. PMID- 22943529 TI - Cryopreservation of immature buffalo oocytes: effects of cytochalasin B pretreatment on the efficiency of cryotop and solid surface vitrification methods. AB - The aim of the present study was to compare the efficiency of the solid surface (SSV), cryotop (CT) vitrification methods and cytochalasin B (CB) pretreatment for cryopreservation of immature buffalo oocytes. Cumulus-oocyte complexes (COCs) were placed for 1 min in TCM199 containing 10% dimethylsulfoxide (DMSO), 10% ethylene glycol (EG), and 20% fetal bovine serum, and then transferred for 30 s to base medium containing 20% DMSO, 20% EG and 0.5 mol/L sucrose. CB pretreated ((+)CB) or non-pretreated ((-)CB) COCs were vitrified either by SSV or CT. Surviving vitrified COCs were selected for in vitro maturation (IVM) and in vitro fertilization (IVF). The rate of viable oocytes after vitrification in CT groups (82%) was significantly lower (P < 0.05) than that in a fresh control group (100%), but significantly higher (P < 0.05) than those in SSV groups (71-72%). Among vitrified groups, the highest maturation rate was obtained in the CT (-)CB group (32%). After IVF, the cleavage and blastocyst formation rates were similar among vitrified groups but significantly lower than those of the control group. In conclusion, a higher survival rate of oocytes after vitrification and IVM was obtained in the CT group compared with that in the SSV group, indicating the superiority of the CT method. Pretreatment with CB did not increase the viability, maturation or embryo development of vitrified oocytes. PMID- 22943530 TI - Assessment of reproduction and growth performance of offspring derived from somatic cell cloned pigs. AB - Since cloned pig was successfully produced, a new opportunity for porcine breeding industry to conserve genetic resources has been opened. However, there has been no report to investigate whether both somatic cell nuclear transfer (SCNT) pigs and their offspring have the characteristics of the donor breed. In this study, we compared the reproductive and growth performance of American Large White boars cloned by SCNT with the donor boar, and analyzed the test parameters, including semen quality, re-service rate, rate of parturition, and average daily gain. The results showed that these cloned boars and the donor boar had no significant differences in the tests (P > 0.05) and the growth performance of their offspring was similar to the naturally bred American Large White pigs. In summary, the reproductive and growth performance of cloned pigs are similar to the donor pig and within the normal range. This suggests that pigs cloned by SCNT have the potential to be used in reproduction and breeding. PMID- 22943531 TI - Relationships among steroid hormone levels in newborn piglets, birth weight, placental weight, vitality of offspring and litter size. AB - Blood estrone sulfate (E(1) S), estrone (E(1) ), estradiol (E(2) ) and progesterone (P(4) ) in newborn piglets were measured to clarify the relationships among birth and placental weight, vitality of offspring and litter size. First, the association between vital status (normal, weak and stillborn) from 165 newborn piglets of 18 litters and steroid concentrations; second, steroid concentrations from 152 newborn normal piglets and litter size; and third, steroid content in fetal placenta from 50 newborn normal piglets of six litters and litter size, were investigated. In the normal group, the birth and placental weight were significantly higher than those in the other groups. Blood E(1) S levels in the stillborn group were significantly lower, whereas E(1) , E(2) and P(4) were significantly higher compared to the normal group. Blood and placental E(1) S levels in the small litter group were significantly higher than those in the other groups. However, there was no significant difference among the three litter size groups in the levels of steroid hormones in maternal blood. These results indicate that vitality of newborn piglets is related to E(1) S concentration of neonate, to birth weight and placental weight. However, steroid hormone concentrations of newborn piglets were greatly affected by the number of littermates. PMID- 22943532 TI - Evaluation of associative effects on ruminal digestion kinetics between pasture and grains using in vitro gas production method. AB - In vitro gas production (GP) method was used to investigate associative effects on ruminal digestion when grains (corn or barley) were supplemented to spring pasture and autumn pasture. Pasture (75%) was incubated with 25% corn or barley and gas production was monitored up to 96 h. After incubation, the residues were used to determine dry matter and organic matter digestibility (DMD and OMD). Gas production parameters were analyzed by applying a single exponential equation. Organic matter effective degradability (OMED) was determined from GP parameters and OMD. The positive associative effects on the rate of GP, DMD, OMD and OMED were observed when spring pasture was incubated with corn. However, similar effects were not observed in a barley mixture. However, for autumn pasture, both corn and barley mixtures showed positive associative effects on rate of GP, OMD and OMED. The results of this study indicated that supplementation of corn would be better than barley for spring pasture with high water-soluble carbohydrate contents, whereas both grain supplementations were effective to obtain positive associative effects on the rate of GP and OMED for autumn pasture with high cell wall content. PMID- 22943533 TI - Anatomical location of arterial and venous lines significantly affects motor performance in rats. AB - Several motor-function scales have been developed to assess neurological function in animal models of stroke, subarachnoid hemorrhage and closed head injury. We hypothesize that the location of arterial and venous catheters, even in the absence of brain injury, may impact rats' motor performance. Our study examined the effect of catheter location, rate of infection and the time required for catheter placement. We further describe an original technique of tail artery cannulation without exposure of the artery. Sixty-one rats were anesthetized and randomly assigned to one of seven groups, including no catheter, tail artery or artery + vein catheters, or femoral artery or artery + vein catheters. A neurological severity score (NSS) was determined at 1 h, 24 h and 48 h after surgical preparation or catheter placement. NSS at 1 h after placement of unilateral and bilateral femoral catheters was higher than the NSS observed at 1 h after placement of tail arterial and venous catheters (P < 0.01). The NSS also was higher at 24 h in the bilateral femoral catheter groups as compared with the tail catheter groups (P < 0.05). There were no differences in the NSS observed between the groups that had tail catheters and the sham group at 1 h, 24 h or 48 h. Infection rate at the site of catheter placement and the time required for catheter placement was also higher in the femoral catheter groups (P < 0.001). Thus, we propose that the line location may bias a study's results and lead to deceptive interpretations of neurological assessment following rat head injury. Compared to femoral vessels, tail blood vessels are preferable locations for lines placement. PMID- 22943534 TI - Bone morphogenetic protein 4 (BMP-4) and BMP-7 induce vascular endothelial growth factor expression in bovine granulosa cells. AB - Bone morphogenetic protein-4 (BMP-4) and BMP-7, theca cell-derived growth factors, directly affect the granulosa cell function. The aim of this study was to examine the involvement of BMP-4 or BMP-7 in vascular endothelial growth factor (VEGF) expression in bovine granulosa cells. Granulosa cells were collected from small follicles (4-6 mm) and seeded at a density of 2-5 * 10(5) cells per well in Dulbecco's modified Eagle's medium (DMEM)/F12 medium with BMP-4 or BMP-7. The expression of VEGF messenger RNA and protein was the maximum when 1.0 ng/mL of BMP-4 was added to the culture medium. On the other hand, 10 ng/mL of BMP-7 significantly increased the expression of the VEGF gene and protein. In addition, BMP-4 stimulated the expression of Smad1 and Smad5 genes in granulosa cells, whereas BMP-7 stimulated the expression of Smad5 gene. These results suggested that BMP-4 and BMP-7 may be associated with VEGF expression via several specific Smads in bovine granulosa cells: BMP-4 via Smad1/Smad5 and BMP-7 via Smad5. In conclusion, theca cell-derived BMP-4 and BMP-7 might contribute to follicular vasculature and development by inducing VEGF expression in granulosa cells. PMID- 22943538 TI - Pathogens and Global Health counterfeit medicine photo campaign. PMID- 22943535 TI - N (w) -propyl-L-arginine (L-NPA) reduces status epilepticus and early epileptogenic events in a mouse model of epilepsy: behavioural, EEG and immunohistochemical analyses. AB - We investigated the anticonvulsant and neurobiological effects of a highly selective neuronal nitric oxide synthase (nNOS) inhibitor, N (w) -propyl-l arginine (L-NPA), on kainic acid (KA)-induced status epilepticus (SE) and early epileptogenesis in C57BL/6J mice. SE was induced with 20 mg/kg KA (i.p.) and seizures terminated after 2 h with diazepam (10 mg/kg, i.p). L-NPA (20 mg/kg, i.p.) or vehicle was administered 30 min before KA. Behavioural seizure severity was scored using a modified Racine score and electrographic seizure was recorded using an implantable telemetry device. Neuronal activity, activity-dependent synaptogenesis and reactive gliosis were quantified immunohistochemically, using c-Fos, synaptophysin and microglial and astrocytic markers. L-NPA treatment reduced the severity and duration of convulsive motor seizures, the power of electroencephalogram in the gamma band, and the frequency of epileptiform spikes during SE. It also reduced c-Fos expression in dentate granule cells at 2 h post KA, and reduced the overall rate of epileptiform spiking (by 2- to 2.5-fold) in the first 7 days after KA administration. Furthermore, treatment with L-NPA suppressed both hippocampal gliosis and activity-dependent synaptogenesis in the outer and middle molecular layers of the dentate gyrus in the early phase of epileptogenesis (72 h post-KA). These results suggest that nNOS facilitates seizure generation during SE and may be important for the neurobiological changes associated with the development of chronic epilepsy, especially in the early stages of epileptogenesis. As such, it might represent a novel target for disease modification in epilepsy. PMID- 22943539 TI - Technology for combating counterfeit medicine. PMID- 22943540 TI - The WWARN antimalarial quality surveyor. PMID- 22943541 TI - High-throughput whole genome analysis provides insight into how the major drugs against African sleeping sickness operate. PMID- 22943542 TI - Amphotericin B still in the headlines. PMID- 22943544 TI - Reviewing the development, evidence base, and application of the revised dengue case classification. AB - With the example of dengue, an evidence-based approach to prospectively develop a case classification is described, gathering evidence for identifying strength and weaknesses of the existing model, collecting new data describing the disease as it occurs globally, further developing a new model that can be applied in practice and field testing the newly developed model in comparison to the previous model. For each step in this process, the highest available level of evidence has been applied. This process has been initiated by the World Health Organization's (WHO) Special Programme for Research and Training in Tropical Diseases (TDR) and WHO's Department for Control of Neglected Tropical Diseases (NTD), developing the following for dengue. Since the early 1970s, dengue has been classified into dengue fever, dengue haemorrhagic fever grades I and II and dengue shock syndrome grades III and IV (DF/DHF/DSS). However, in recent years, a growing number of dengue clinicians have questioned the shortcomings of this scheme. The issues have revolved around the complexity of confirming DHF in clinical practice, misclassifying severe cases as DF, and the emphasis on haemorrhage rather than plasma leakage as the underlying problem in most severe dengue cases. Step 1: A systematic literature review highlighted the shortcomings of the DF/DHF/DSS scheme: (1) difficulties in applying the criteria for DHF/DSS; (2) the tourniquet test has a low sensitivity for distinguishing between DHF and DF; and (3) most DHF criteria had a large variability in frequency of occurrence. Step 2: An analysis of regional and national dengue guidelines and their application in the clinical practice showed a need to re-evaluate and standardize guidelines as the actual ones showed a large variation of definitions, an inconsistent application by medical staff, and a lack of diagnostic facilities necessary for the DHF diagnosis in frontline services. Step 3: A prospective cohort study in seven countries, confirmed the difficulties in applying the DF/DHF/DSS criteria even in tertiary care hospitals, that DF/DHF/DSS do not represent levels of disease severity and that a clear distinction between severe dengue (defined by plasma leakage and/or severe haemorrhage, and/or organ failure) and (non-severe) dengue can be made using highly sensitive and specific criteria. In contrast, the sub-grouping of (non-severe) dengue into two further severity levels was only possible with criteria that gave approximately 70% sensitivity and specificity. Step 4: Three regional expert consensus groups in the Americas and Asia concluded that 'dengue is one disease entity with different clinical presentations and often with unpredictable clinical evolution and outcome' and that, revising the results of Step 3, DF/DHF/DSS is not related to disease severity. Step 5: In a global expert consensus meeting at WHO in Geneva/Switzerland the evidence collected in Steps 1-4 was reviewed and a revised scheme was developed and accepted, distinguishing: dengue with or without warning signs and severe dengue; the further field testing and acquisition of further prospective evidence of the revised scheme was recommended. Step 6: In 18 countries, the usefulness and applicability of the revised classification compared to the DF/DHF/DSS scheme were tested showing clear results in favour of the revised classification. Step 7: Studies are under way on the predictive value of warning signs for severe dengue and on criteria for the clinical diagnosis of dengue which will complete the evidence foundation of the revised classification. The analysis has shown that the revised dengue case classification is better able to standardize clinical management, raise awareness about unnecessary interventions, match patient categories with specific treatment instructions, and make the key messages of patient management understandable for all health care staff dealing with dengue patients. Furthermore, the evidence-based approach to develop prospectively the dengue case classification could be a model approach for other disease classifications. PMID- 22943543 TI - Function and composition of male accessory gland secretions in Anopheles gambiae: a comparison with other insect vectors of infectious diseases. AB - Human malaria, a major public health burden in tropical and subtropical countries, is transmitted exclusively by the bite of a female Anopheles mosquito. Malaria control strategies aimed at inducing sexual sterility in natural vector populations are an attractive alternative to the use of insecticides. However, despite their importance as disease vectors, limited information is available on the molecular mechanisms regulating fertility in Anopheles mosquitoes. In the major malaria vector, An. gambiae, the full complement of sperm and seminal fluid required for a female's lifelong egg production is obtained from a single mating event. This single mating has important consequences for the physiology and behavior of An. gambiae females: in particular, they become refractory to further insemination, and they start laying eggs. In other insects including Drosophila, similar post-copulatory changes are induced by seminal proteins secreted by the male accessory glands and transferred to the female during mating. In this review, we analyze the current state of knowledge on the function and characterization of male seminal proteins in An. gambiae, and provide a comparative assessment of the role of these male reproductive factors in other mosquito vectors of human disease in which female post-copulatory behavior has been studied. Knowledge of the factors and mechanisms regulating fertility in An. gambiae and other vectors can help the design of novel control strategies to fight the spread of disease. PMID- 22943545 TI - Trypanosoma cruzi infection in Elche (Spain): comparison of the seroprevalence in immigrants from Paraguay and Bolivia. AB - Chagas disease is a global public health problem due to the recent emigration of people from Latin America to other regions, including Europe. The aim of this study is to determine the prevalence of Trypanosoma cruzi infection among Paraguayans and Bolivians living in Elche (Spain), a city located in the Mediterranean Coast of Spain. A cross-sectional study was conducted. Capillary blood samples were obtained through a finger prick, and collected on filter paper. An enzyme-linked immunosorbent assay and indirect immunofluorescence tests were performed to search for anti-T. cruzi IgG antibodies in the filter papers. Thirteen out of 201 participants were infected with T. cruzi in this study, seven out of 73 Bolivians and six out of 128 Paraguayans, corresponding to seroprevalences of 9.59% (95%CI, 4.72-18.5%) and 4.69% (95%CI, 2.17-9.85%), respectively. Palpitation, chest pain, and migration from rural endemic areas were the most common clinical and epidemiological risk factors associated with T. cruzi infection detected in the Paraguayan group. This study highlights that Chagas disease is no longer limited to the Bolivian population living in Spain. It is important to note this wider prevalence and, therefore, not discount Paraguayans in the screening for Chagas disease in Spain. Indeed, this should be considered for all immigrants from Latin America. PMID- 22943546 TI - Antimicrobial activity of synthetic bornyl benzoates against Trypanosoma cruzi. AB - We report here for the first time the in vitro effects of (1S,2R,4S)-1,7,7 trimethyl-bicyclo[2.2.1]heptan-2-yl-3',4',5'-trimethoxy benzoate (1) and (1S,2R,4S)-1,7,7-trimethyl-bicyclo[2.2.1]heptan-2-yl benzoate (2) on the growth and ultrastructure of Trypanosoma cruzi. These two synthetic compounds exerted an antiproliferative effect on the epimastigote forms of the parasite. The ICs(50/72h) of two synthetic L-bornyl benzoates, 1 and 2, was 10.1 and 12.8 MUg/ml, respectively. Both compounds were more selective against epimastigotes than HEp-2 cells. Ultrastructural analysis revealed intense cytoplasmic vacuolization and the appearance of cytoplasmic materials surrounded by membranes. The treatment of peritoneal macrophages with compounds 1 and 2 caused a significant decrease in the number of T. cruzi-infected cells. L-Bornyl benzoate derivatives may serve as a potential source for the development of more effective and safer chemotherapeutic agents against T. cruzi infections. PMID- 22943547 TI - Using kernel density estimates to investigate lymphatic filariasis in northeast Brazil. AB - After more than 10 years of the Global Program to Eliminate Lymphatic Filariasis (GPELF) in Brazil, advances have been seen, but the endemic disease persists as a public health problem. The aim of this study was to describe the spatial distribution of lymphatic filariasis in the municipality of Jaboatao dos Guararapes, Pernambuco, Brazil. An epidemiological survey was conducted in the municipality, and positive filariasis cases identified in this survey were georeferenced in point form, using the GPS. A kernel intensity estimator was applied to identify clusters with greater intensity of cases. We examined 23 673 individuals and 323 individuals with microfilaremia were identified, representing a mean prevalence rate of 1.4%. Around 88% of the districts surveyed presented cases of filarial infection, with prevalences of 0-5.6%. The male population was more affected by the infection, with 63.8% of the cases (P<0.005). Positive cases were found in all age groups examined. The kernel intensity estimator identified the areas of greatest intensity and least intensity of filarial infection cases. The case distribution was heterogeneous across the municipality. The kernel estimator identified spatial clusters of cases, thus indicating locations with greater intensity of transmission. The main advantage of this type of analysis lies in its ability to rapidly and easily show areas with the highest concentration of cases, thereby contributing towards planning, monitoring, and surveillance of filariasis elimination actions. Incorporation of geoprocessing and spatial analysis techniques constitutes an important tool for use within the GPELF. PMID- 22943548 TI - Decreased susceptibility to placental malaria in anaemic women in an area with unstable malaria transmission in central Sudan. AB - The interaction between iron level, iron supplementation, and susceptibility to infection, including malaria, remains a concern. A cross-sectional study was conducted at Medani hospital in central Sudan to investigate the relationship between anaemia and placental malaria. Obstetrical history was obtained; haemoglobin levels were determined. Placental tissue was obtained and malaria histology classified as active, chronic, past or no malaria infection. Among 324 women investigated, 7 (2.2%), 4 (1.2%), and 44 (13.6%) of the placentae showed active, chronic and past infection on histology examination respectively, while 269 (83.0%) of them showed no infection. Anaemia (haemoglobin <11 g/dl) was less frequent in women with placental Plasmodium falciparum infection, 27/55 (49.1%) vs 174/269 (64.7%), P=0.02. Anaemia was associated with a decreased risk for placental malaria, and the odds ratio for placental malaria (in both primiparae and multiparae group) was 0.2, 95% CI: 0.1-0.6, P=0.002 and it was 0.2, 95% CI: 0.03-0.7; P=0.02 for primiparae group. Thus, there is a strong relationship between anaemia and the absence of placental malaria. PMID- 22943549 TI - Neurocysticercosis in a 2-year-old boy infected at home. AB - A 2-year-old boy presented with seizures and two parenchymal brain ring-enhancing lesions. Diagnosis of neurocysticercosis was confirmed by positive serology and response to albendazole therapy. The patients's mother was a Taenia solium carrier, who had most likely infected the child through the fecal-oral route. Household contacts should always be investigated in children with neurocysticercosis. Proper identification and treatment of Taenia solium carriers will reduce the risk of further spread of the disease. PMID- 22943550 TI - Effect of halofantrine on QT interval in children. AB - In order to assess cardiac tolerance of halofantrine in children, we studied, retrospectively, 15 non complicated falciparum malaria cases treated with halofantrine, and focused on the effect on ventricular repolarisation. Our data showed that halofantrine can produce a moderate QTc prolongation without any life-threatening arrhythmia. As long as contraindications of the drug are respected, this treatment should be considered as a therapeutical option in young children presenting with non complicated falciparum malaria. PMID- 22943552 TI - A case of acute liver failure due to etodolac. PMID- 22943553 TI - Assessing cardiovascular risk in regional areas: the Healthy Hearts Beyond City Limits program. AB - BACKGROUND: Cardiovascular disease (CVD) is more prevalent in regional and remote Australia compared to metropolitan areas. The aim of Healthy Hearts was to determine age and sex specific CVD risk factor levels and the potential value of national risk clinics. METHODS: Healthy Hearts was an observational research study conducted in four purposefully selected higher risk communities in regional Victoria, Australia. The main outcome measures were the proportion of participants with CVD risk factors with group comparisons to determine the adjusted likelihood of elevated risk factor levels. Trained personnel used a standardized protocol over four weeks per community to measure CVD risk factor levels, estimate absolute CVD risk and provide feedback and advice. RESULTS: A total of 2125 self-selected participants were assessed (mean age 58 +/- 15 years, 57% women). Overall, CVD risk factors were highly prevalent. More men than women had >= 2 modifiable CVD risk factors (76% vs. 68%, p < .001), pre-existing CVD (20 vs. 15%, p < .01) and a major ECG abnormality requiring follow-up (15% vs. 7%, p < .001) . Less men reported depressive symptoms compared to women (28% vs. 22%, p < .01). A higher proportion of women were obese (adjusted OR 1.36, 95% CI 1.13 to 1.63), and physically inactive (adjusted OR 1.32, 95% CI 1.07 to 1.63). CONCLUSIONS: High CVD risk factor levels were confirmed for regional Victoria. Close engagement with individuals and communities provides scope for the application of regional risk management clinics to reduce the burden of CVD risk in regional Australia. PMID- 22943555 TI - Can the theory of planned behaviour predict the physical activity behaviour of individuals? AB - The theory of planned behaviour (TPB) can identify cognitions that predict differences in behaviour between individuals. However, it is not clear whether the TPB can predict the behaviour of an individual person. This study employs a series of n-of-1 studies and time series analyses to examine the ability of the TPB to predict physical activity (PA) behaviours of six individuals. Six n-of-1 studies were conducted, in which TPB cognitions and up to three PA behaviours (walking, gym workout and a personally defined PA) were measured twice daily for six weeks. Walking was measured by pedometer step count, gym attendance by self report with objective validation of gym entry and the personally defined PA behaviour by self-report. Intra-individual variability in TPB cognitions and PA behaviour was observed in all participants. The TPB showed variable predictive utility within individuals and across behaviours. The TPB predicted at least one PA behaviour for five participants but had no predictive utility for one participant. Thus, n-of-1 designs and time series analyses can be used to test theory in an individual. PMID- 22943554 TI - Impact of C-reactive protein test results on evidence-based decision-making in cases of bacterial infection. AB - BACKGROUND: C-reactive protein (CRP) is widely used to detect bacterial infection in children. We investigated the impact of CRP test results on decision-making and summarized the evidence base (EB) of CRP testing. METHODS: We collected information from the hospital records of 91 neonates with suspected sepsis and of 152 febrile children with suspected infection on the number of ordered CRP tests, the number of EB-CRP tests, and the impact of the test results on decision making. CRP diagnostic accuracy studies focusing on pediatric infections were reviewed critically. The main outcomes were the proportion of CRP tests that were EB and the proportion of tests that affected decision-making. A secondary outcome was the overall one-year expenditure on CRP testing. RESULTS: The current EB for CRP testing in pediatric infections is weak and suggests that CRP is of low diagnostic value. Approximately 54.8% of tests performed for suspected neonatal sepsis and 28% of tests performed for other infections were EB; however, the results of only 12.9% of neonatal sepsis tests and of 29.9% of tests on children with other infections informed decision-making. The one-year overall cost for CRP testing and related health care was $26,715.9. CONCLUSIONS: The routine ordering of CRP for children with infections is based on weak evidence. The impact of the CRP test results on decision-making is rather small, and CRP ordering may contribute to unnecessary health care expenditures. Better quality research is needed to definitively determine the diagnostic accuracy of CRP levels in children with infections. PMID- 22943556 TI - Hyperbaric oxygen is effective in early stage of healing of experimental brain abscess in rats. AB - OBJECTIVES: Current therapy of brain abscess (BA) includes a combined approach that involves antibiotics and minimal invasive surgery, but also hyperbaric oxygen treatment (HBOT) as a supportive measure. Optimum treatment is still a matter of significant controversy. METHODS: The experiment, previously approved by a relevant ethical committee, involved 80 female Wistar rats. BA was experimentally induced by inoculation of Staphylococcus aureus. The animals were randomized into groups and treated either with antibiotics, HBOT, or with a combination of both. RESULTS: Beneficial effect of HBOT was evident in groups treated with HBOT or with a combination of antibiotic+HBOT. It was mainly manifested on days three and five of the experiment and was evident as statistically significant increase of a number of newly formed blood vessels, increase in mean vascular density, and smaller abscess necrotic core. DISCUSSION: Although the results of the present study should be interpreted cautiously, they suggest that HBOT has an important but limited role in the treatment of BA. PMID- 22943557 TI - A sensitive and specific blocking ELISA for the detection of rabbit calicivirus RCV-A1 antibodies. AB - BACKGROUND: Antibodies to non-pathogenic rabbit caliciviruses (RCVs) cross-react in serological tests for rabbit hemorrhagic disease virus (RHDV) and vice versa, making epidemiological studies very difficult where both viruses occur. It is important to understand the distribution and interaction of the two viruses because the highly pathogenic RHDV has been used as a biocontrol agent for wild rabbits in Australia and New Zealand for the past 17 years. The presence of the benign RCV Australia 1 (RCV-A1) is considered a key factor for the failure of RHDV mediated rabbit control in cooler, wetter areas of Australia. RESULTS: A highly sensitive and specific blocking ELISA was developed for the detection of RCV-A1 antibodies. When sera from rabbits with a known infection history for either RCV-A1 or RHDV were tested, this assay showed 100% sensitivity and no cross-reactivity with RHDV sera (100% specificity). CONCLUSIONS: This new ELISA not only allows the detection of RCV-A1 at a population level, but also permits the serological status of individual rabbits to be determined more reliably than previously described methods. This robust and simple to perform assay is therefore the tool of choice for studying RCV-A1 epidemiology in Australian wild rabbit populations. PMID- 22943558 TI - The implicit learning of metrical and nonmetrical temporal patterns. AB - Implicit learning (IL) occurs unintentionally. IL of temporal patterns has received minimal attention, and results are mixed regarding whether IL of temporal patterns occurs in the absence of a concurrent ordinal pattern. Two experiments examined the IL of temporal patterns and the conditions under which IL is exhibited. Experiment 1 examined whether uncertainty of the upcoming stimulus identity obscures learning. Based on probabilistic uncertainty, it was hypothesized that stimulus-detection tasks are more sensitive to temporal learning than multiple-alternative forced-choice tasks because of response uncertainty in the latter. Results demonstrated IL of metrical patterns in the stimulus-detection but not the multiple-alternative task. Experiment 2 investigated whether properties of rhythm (i.e., meter) benefit IL using the stimulus-detection task. The metric binding hypothesis states that metrical frameworks guide attention to periodic points in time. Based on the metric binding hypothesis, it was hypothesized that metrical patterns are learned faster than nonmetrical patterns. Results demonstrated learning of metrical and nonmetrical patterns but metrical patterns were not learned more readily than nonmetrical patterns. However, abstraction of a metrical framework was still evident in the metrical condition. The present study shows IL of auditory temporal patterns in the absence of an ordinal pattern. PMID- 22943560 TI - Creating an impersonal NHS? Personalization, choice and the erosion of intimacy. AB - BACKGROUND: Personalization - most often understood in terms of granting patients greater opportunity to participate in, and make choices about, the services they receive - has become a key principle guiding reform of the English NHS. OBJECTIVE: This study sets out to explore the relationship between two senses of the term 'personal' within the context of personalization. Firstly, much of the policy literature equates a 'personal' service with one that is responsive to the choices of individual patients. Secondly, the term 'personal' can be thought to refer to the intimate relationships between patients and medical professionals that have typified traditional models of good practice. METHODOLOGY AND DISCUSSION: I combine a review of the relevant academic and policy literature on personalization with a process of conceptual analysis to uncover three arguments, which suggest that personalization based on choice may adversely affect standards of care by eroding the qualities of intimacy at the heart of the care process. Thus, an unintended consequence of the drive for personalization may be the creation of an NHS that is, in an important sense, less personal than it once was. CONCLUSION: Whilst personalization may deliver many potential benefits, the tension between promoting patient choice and retaining intimate professional patient relationships ought to be taken seriously. Thus, the task of promoting choice whilst retaining intimacy represents a key policy challenge for advocates of personalization. PMID- 22943559 TI - RMP-02/MTN-006: A phase 1 rectal safety, acceptability, pharmacokinetic, and pharmacodynamic study of tenofovir 1% gel compared with oral tenofovir disoproxil fumarate. AB - This study was designed to assess the safety, acceptability, pharmacokinetic (PK), and pharmacodynamic (PD) responses to rectal administration of tenofovir (TFV) 1% vaginally formulated gel and oral tenofovir disoproxil fumarate (TDF). This study was designed as a phase 1, randomized, two-site (United States), double-blind, placebo-controlled study of sexually abstinent men and women. Eighteen participants received a single 300-mg exposure of oral TDF and were then randomized 2:1 to receive a single and then seven daily exposures of rectal TFV or hydroxyethyl cellulose (HEC) placebo gel. Safety endpoints included clinical adverse events (AEs) and mucosal safety parameters. Blood and colonic biopsies were collected for PK analyses and ex vivo HIV-1 challenge. No serious AEs were reported. However, AEs were significantly increased with 7-day TFV gel use, most prominently with gastrointestinal AEs (p=0.002). Only 25% of participants liked the TFV gel. Likelihood of use "if somewhat protective" was ~75% in both groups. Indices of mucosal damage showed minimal changes. Tissue TFV diphosphate (TFV-DP) C(max) 30 min after single rectal exposure was 6-10 times greater than single oral exposure; tissue TFV-DP was 5.7 times greater following 7-day versus single rectal exposure. In vivo exposure correlated with significant ex vivo tissue infectibility suppression [single-rectal: p=0.12, analysis of covariance (ANCOVA) p=0.006; 7-day rectal: p=0.02, ANCOVA p=0.005]. Tissue PK-PD was significantly correlated (p=0.002). We conclude that rectal dosing with TFV 1% gel resulted in greater TFV-DP tissue detection than oral dosing with reduced ex vivo biopsy infectibility, enabling PK-PD correlations. On the basis of increased gastrointestinal AEs, rectally applied, vaginally formulated TFV was not entirely safe or acceptable, suggesting the need for alternative rectal-specific formulations. PMID- 22943561 TI - Finite element analysis of stress in the equine proximal phalanx. AB - REASONS FOR PERFORMING STUDY: To improve understanding of the internal structure of the proximal phalanx (P1), response of the bone to load and possible relation to the pathogenesis of fractures in P1. OBJECTIVES: To model the P1 and replicate the loads experienced by the bone in stance, walk, trot and gallop using finite element analysis. METHODS: The geometry of the P1 was captured using micro computed tomography (MUCT) and was reconstructed in 3 dimensions. Values for material properties and forces experienced at stance, walk, trot and gallop were taken from the literature and were applied to the reconstructed model. Using the same total load across the proximal articular surface, the model was solved with and without loading of the sagittal groove. Biomechanical performance was then simulated with finite element analysis and evaluated in terms of von Mises stress maps. RESULTS: Compared with the lowest force simulation equivalent to stance, the effects of the gallop force showed higher levels of stress along the sagittal groove and on the palmar surface just distal to the sagittal groove in both models, with and without the sagittal groove loaded. The results highlighted an area of bone on the dorsal aspect of P1 that experiences lower stress compared with the rest of the dorsal surface, an effect that was much more apparent when the sagittal groove was not loaded. Qualitative comparison of the models revealed minimal difference in the pattern of von Mises stress between the loaded and unloaded groove models. CONCLUSIONS: The study demonstrates a finite element model of P1 that produces results consistent with clinical observation. The simulated high stress levels associated with the sagittal groove correspond to the most common site for fractures in the equine P1. POTENTIAL RELEVANCE: With refinement of the model and further investigation, it may be possible to improve understanding of the behaviour of P1 under loading conditions that more closely simulate those experienced in the living animal, leading to a more solid understanding of fractures of P1. PMID- 22943562 TI - Dedicated hip fracture service: implementing a novel model of care. AB - BACKGROUND: Hip fracture is a common clinical problem with historically high morbidity and mortality, and various model of acute and subacute care have been employed. We describe 12-month results from the first dedicated hip fracture unit in Australia, and compare it with other models of care both locally and internationally. METHODS: This was performed as a prospective uncontrolled study over a 12-month period. After application of exclusion criteria, a total of 346 patients were yielded. Outcomes measured included performance indicators as well as morbidity and mortality data. RESULTS: Improvements in performance indicators (adequate preoperative medical assessment, time to surgery, return to premorbid residence, etc.) and morbidity and mortality data (such as pressure sores, infections and in-hospital death) are noted. CONCLUSIONS: Early results suggest more comprehensive preoperative assessment, shorter times to theatre, reduced post-operative complications and diminished mortality rates when the principles undermining this unit are instituted. PMID- 22943563 TI - Attitudes towards and perceptions of reproductive health needs of persons living with HIV/AIDS in rural Kilimanjaro, Tanzania. AB - The introduction of antiretroviral treatment has resulted in the resumption of socially productive and sexually active lives of people living with HIV/AIDS, together with the desire for children. However, factors affecting the reproductive health needs of people living with HIV/AIDS are not well understood. With this in mind, the aim of this paper was to investigate factors associated with these health needs using a qualitative approach. Findings indicate that attitudes and perceptions about reproductive health needs are influenced by fertility beliefs, the central role of family, procreation and the perceived social and clinical consequences of pregnancies among people living with HIV/AIDS. While there was mixed opinion about acceptability of people living with HIV/AIDS, having children, marriage and family were institutions important for partnerships maintenance and procreation. These findings suggest that living with HIV in a community with strong pro-life attitudes is challenging for people living with HIV/AIDS who do not have children. Apart from having to grapple with potential stigma of not having children, people living with HIV/AIDS also face social challenges in realising their reproductive choices. Interventions to address stigma, societal changes and the integration of reproductive-health education into HIV care and treatment are needed. PMID- 22943564 TI - Role of DNA methylation in growth and differentiation in Physcomitrella patens and characterization of cytosine DNA methyltransferases. AB - Epigenetic mechanisms such as DNA methylation are known to regulate important developmental processes in higher eukaryotes. However, little is known about the necessity and role of this process in early land plants. Using the methyltransferase (MTase) inhibitor zebularine (1-(beta-d-ribofuranosyl)-1,2 dihydropyrimidine-2-one), the impact of loss of genome-wide methylation on the overall development in Physcomitrella patens was analyzed. It is observed that various aspects of growth and differentiation during gametophyte development become aberrant. A search for the core molecular components of methylation machinery, cytosine DNA MTases, revealed the presence of seven loci in the P. patens genome. Five of the loci code for MTases that are similar to corresponding proteins in higher plants, while two MTases appear specific to P. patens and are closely related to human DNMT3a and DNMT3b, respectively. These proteins possess all the conserved catalytic motifs characteristic of MTases and a domain of unknown function, DUF3444. Association of these highly conserved motifs with a DUF has not been reported in any of the MTases known so far. All the seven genes are differentially but ubiquitously expressed in gametophytes at low levels. Subcellular localization of GFP-fused proteins shows patterns of distribution that can be correlated with their putative cellular functions. This work bridges the knowledge of MTases in P. patens and makes this simple model plant accessible for studies on epigenetic aspects that remain intractable in higher plants. PMID- 22943565 TI - Microsatellite markers for identification and parentage analysis in the European wild boar (Sus scrofa). AB - BACKGROUND: The wild boar (Sus scrofa) is among the most widespread mammal species throughout the old world. Presently, studies concerning microsatellites in domestic pigs and wild boars have been carried out in order to investigate domestication, social behavior and general diversity patterns among either populations or breeds. The purpose of the current study is to develop a robust set of microsatellites markers for parentage analyses and individual identification. FINDINGS: A set of 14 previously reported microsatellites markers have been optimized and tested in three populations from Hungary, Portugal and Spain, in a total of 167 samples. The results indicate high probabilities of exclusion (0.99999), low probability of identity (2.0E(-13) - 2.5E(-9)) and a parentage assignment of 100%. CONCLUSIONS: Our results demonstrate that this set of markers is a useful and efficient tool for the individual identification and parentage assignment in wild boars. PMID- 22943566 TI - Ocular abnormalities in healthy Standardbred foals. AB - OBJECTIVE: To determine the prevalence and describe ocular abnormalities in healthy Standardbred foals within 48 h of birth. ANIMALS: One hundred and two neonatal foals. PROCEDURES: All foals had an unassisted delivery. On the basis of physical examination and the results of hematological and biochemical parameters, all foals were unaffected by systemic diseases. A complete ophthalmic examination was performed within 48 h of birth. Foals with ocular hemorrhages were re examined weekly until the abnormalities were resolved. RESULTS: 65/102 (63.7%) foals did not show ocular abnormalities, while in 37/102 (36.3%) cases, ocular abnormalities were present. Retinal and subconjunctival hemorrhages were recorded in 19/102 (18.6%), and in 13/102 (12.7%), respectively. In 4/102 (3.9%) animals, an entropion of the lower eyelid was present. Only one foal (1%) showed a congenital nuclear unilateral cataract. No other ocular abnormalities were detected. However, all foals showed various degrees of remnants of hyaloid system. One week after the first ocular examination, retinal hemorrhages had resolved in 100% of the eyes, whereas subconjunctival hemorrhages had disappeared in all eyes by the second week following the first examination. CONCLUSIONS: The acquired ocular lesions observed with relatively high frequency in the examined healthy Standardbred foals were ocular hemorrhages, which always showed a good outcome. Although these abnormalities were present at birth, they were not considered strictly congenital but likely acquired during parturition. Instead, congenital ocular abnormalities were rarely diagnosed, and the entropion of the lower eyelid was the most common disease in the breed. PMID- 22943567 TI - The complete mitochondrial genome of Takydromus wolteri (Squamata: Lacertidae). AB - The mitochondrial genome of Takydromus wolteri (Squamata: Lacertidae) is a circular molecule of 18,236 bp in length, containing 13 protein-coding genes, 2 ribosomal RNAs, 22 transfer RNAs, and a control region. The A+T content of the overall base composition of H-strand is 62% (T: 30.7%, C: 24.5%, A: 31.3%, G: 13.5%). All of the 13 protein-coding genes begin with ATG as start codon. ND1, ATP8, ATP6, ND3, ND4L, ND5, and Cyt b genes are terminated with TAA as stop codon, COI ends with AGG, ND2 ends with TAG, ND6 ends with AGA, and the other four protein-coding genes end with an incomplete stop codon (a single stop nucleotide T). Three distinct repeat regions are found in 12S rRNA, 16S rRNA, and the control region. PMID- 22943568 TI - Deciphering the roles of macrophages in developmental and inflammation stimulated lymphangiogenesis. AB - Lymphatic vessels share an intimate relationship with hematopoietic cells that commences during embryogenesis and continues throughout life. Lymphatic vessels provide a key conduit for immune cell trafficking during immune surveillance and immune responses and in turn, signals produced by immune lineage cells in settings of inflammation regulate lymphatic vessel growth and activity. In the majority of cases, the recruitment and activation of immune cells during inflammation promotes the growth and development of lymphatic vessels (lymphangiogenesis) and enhances lymph flow, effects that amplify cell trafficking to local lymph nodes and facilitate the mounting of effective immune responses. Macrophages comprise a major, heterogeneous lineage of immune cells that, in addition to key roles in innate and adaptive immunity, perform diverse tasks important for tissue development, homeostasis and repair. Here, we highlight the emerging roles of macrophages in lymphangiogenesis, both during development and in settings of pathology. While much attention has focused on the production of pro-lymphangiogenic stimuli including VEGF-C and VEGF-D by macrophages in models of inflammation including cancer, there is ample evidence to suggest that macrophages provide additional signals important for the regulation of lymphatic vascular growth, morphogenesis and function. PMID- 22943569 TI - Repellent activity of some essential oils against Simulium species in India. AB - Use of repellents seems to be most reliable method of personal protection against annoyance and infections associated with haematophagous insects. We have investigated the biting activity of Simulium and tested the repellency of five essential oils extracted from Homalomena aromatica Schott (Alismatales: Araceae), Pogostemon heyneanus Bentham (Lamiales: Lamiaceae), Citrus aurantifolia Swingle (Sapindales: Rutaceae), Vitex negundo L. (Lamiales: Lamiaceae), and Ageratum conzoides L. (Asterales: Asteraceae) on the human volunteers against Simulium (blackflies) in three locations of Arunachal Pradesh, India. Blackflies preferred biting legs (> 79%) as compared to hand and face with profound biting activity during 1000-1100 h (> 23%) and 1500 - 1600 h (> 28%). The essential oil extracted from Homalomena aromatica, Vitex negundo and Ageratum conizoides provided > 2 h protection at 5% concentration and > 5 h protection at 10% concentration in all the three testing locations. The repellency of Homalomena aromatica, Vitex negundo and Ageratum conizoides essential oils after 6 h application was > 50% at 5% concentration and > 90% at 10% concentration. The study provides evidence for the potential of these essential oils in developing new repellents against blackflies. PMID- 22943570 TI - Enhanced UV-B radiation increases glyphosate resistance in velvetleaf (Abutilon theophrasti). AB - Depletion of the ozone layer leads to increasing UV-B radiation on the earth's surface, which may affect weeds and their responses to herbicides. However, the effect of increased UV-B radiation on weeds and the interaction of weeds and herbicides are still obscure. The objective of this study was to compare glyphosate efficacy on velvetleaf that was grown under with and without increased UV-B radiation. Leaf area, dry weight and net photosynthesis of velvetleaf seedlings were adversely affected by increased UV-B radiation. Leaf cuticle wax significantly increased by 28% under increased UV-B radiation. Glyphosate efficacy on velvetleaf, evaluated by shoot dry weight, was significantly decreased by increased UV-B radiation. Exposure to increased UV-B radiation significantly decreased (14)C-glyphosate absorption from 49% to 43%, and also resulted in less (14)C-glyphosate translocation out of treated leaves and less glyphosate accumulation in newly expanded leaves. The decrease in glyphosate efficacy was due to changes in absorption and distribution, which were attributed to increased cuticle wax and decreased photosynthesis caused by increased UV-B radiation. These results suggest that the responses of weeds to herbicides may be affected by increased UV-B radiation, to the extent that higher rates may be required to achieve the desired effects. PMID- 22943571 TI - A significant role of sarcoplasmic reticulum in cardiac contraction of a basal vertebrate, the river lamprey (Lampetra fluviatilis). AB - AIM: Cardiac contraction and relaxation are mediated by rapidly changing calcium concentration around the myofibrils. In comparison with endotherms, ectothermic hearts are more strongly dependent on extracellular calcium for contraction suggesting this trait might represent the primitive vertebrate mode of cardiac activation. This study tests the hypothesis that intracellular calcium stores play a minor role in cardiac excitation-contraction coupling of a basal vertebrate, the lamprey (Lampetra fluviatilis). METHODS: Contribution of sarcoplasmic reticulum to cardiac calcium management was examined by measuring the ryanodine sensitivity of contraction, determining the number of cardiac ryanodine receptors and their calcium sensitivity, assessing the size of sarcoplasmic reticulum calcium stores in enzymatically isolated cardiac myocytes and qualitative electron microscopic observations of sarcoplasmic reticulum in cardiac muscle. RESULTS: An extensive network of nonjunctional sarcoplasmic reticulum around myofibrils and numerous junctional sarcoplasmic reticulum couplings at the periphery of the myocytes was present in atrial and ventricular muscle of the lamprey heart. High numbers of ryanodine receptors were present in atrial (0.16 +/- 0.04 nmol mg(-1) prot) and ventricular membranes (0.27 +/- 0.03) (P < 0.01), and 10 MUm ryanodine inhibited large part of contraction force in atrial (37.8 +/- 5.7%) and ventricular (49.2 +/- 6.5%) muscle. CONCLUSION: Sarcoplasmic reticulum is well developed in the lamprey heart and plays a significant role in cardiac calcium management. This suggests that in the common ancestor of vertebrates, cardiac excitation-contraction coupling could have been fairly strongly dependent on sarcoplasmic reticulum calcium stores. Functionally, this trait might be associated with high cardiac output and active predatory lifestyle of the lamprey. PMID- 22943572 TI - Disruption of raphe serotonergic neural projections to the cortex: a potential pathway contributing to remote loss of brainstem neurons following neonatal hypoxic-ischemic brain injury. AB - Neuronal injury is a key feature of neonatal hypoxic-ischemic (HI) brain injury. However, the mechanisms underpinning neuronal losses, such as in the brainstem, are poorly understood. One possibility is that disrupted neural connections between the cortex and brainstem may compromise the survival of neuronal cell bodies in the brainstem. We investigated whether brainstem raphe serotonergic neurons that project to the cortex are lost after HI. We also tested if neuroinflammation has a role in disrupting brainstem raphe projections. Postnatal day 3 (P3) rats underwent unilateral carotid artery ligation followed by hypoxia (6% oxygen for 30 min). A retrograde tracer, choleratoxin b, was deposited in the motor cortex on P38. On P45 we found that retrogradely labelled neurons in the dorsal raphe dorsal, ventrolateral, interfascicular, caudal and ventral nuclei were lost after P3 HI. All retrogradely labelled neurons in the raphe nuclei were serotonergic. Numbers of retrogradely labelled neurons were also reduced in the ventromedial thalamus and basolateral amygdala. Minocycline treatment (45 mg/kg 2 h post-HI, 22.5 mg/kg daily P4-P9) attenuated losses of retrogradely labelled neurons in the dorsal raphe ventrolateral, interfascicular and ventral raphe nuclei, and the ventromedial thalamus. These results indicate that raphe neurons projecting to the cortex constitute a population of serotonergic neurons that are lost after P3 HI. Furthermore, neuroinflammation has a role in the disruption of raphe and thalamic neural projections. Future studies investigating the cellular mechanisms of axonal degeneration may reveal new targets for interventions to prevent neuronal losses after neonatal HI. PMID- 22943573 TI - Drug resistance-conferring mutations in Mycobacterium tuberculosis from Madang, Papua New Guinea. AB - BACKGROUND: Monitoring drug resistance in Mycobacterium tuberculosis is essential to curb the spread of tuberculosis (TB). Unfortunately, drug susceptibility testing is currently not available in Papua New Guinea (PNG) and that impairs TB control in this country. We report for the first time M. tuberculosis mutations associated with resistance to first and second-line anti-TB drugs in Madang, PNG. A molecular cluster analysis was performed to identify M. tuberculosis transmission in that region. RESULTS: Phenotypic drug susceptibility tests showed 15.7% resistance to at least one drug and 5.2% multidrug resistant (MDR) TB. Rifampicin resistant strains had the rpoB mutations D516F, D516Y or S531L; Isoniazid resistant strains had the mutations katG S315T or inhA promoter C15T; Streptomycin resistant strains had the mutations rpsL K43R, K88Q, K88R), rrs A514C or gidB V77G. The molecular cluster analysis indicated evidence for transmission of resistant strain. CONCLUSIONS: We observed a substantial rate of MDR-TB in the Madang area of PNG associated with mutations in specific genes. A close monitoring of drug resistance is therefore urgently required, particularly in the presence of drug-resistant M. tuberculosis transmission. In the absence of phenotypic drug susceptibility testing in PNG, molecular assays for drug resistance monitoring would be of advantage. PMID- 22943574 TI - Platelet function in the postprandial period. AB - BACKGROUND: Postprandial hyperlipidemia and hyperglycemia have been related to cardiovascular events. Among different underlying mechanisms platelet activation seems to be responsible too. No comparable data between various tests in normo- vs. hyperlipidemics before and at different time intervals are available after a fat meal. We aimed to compare 9 of them within the same patients at several time points in postprandial hyperlipidemia. RESULTS: For some tests baseline values between the groups were significantly different (TXB2, platelet sensitivity, sedimentation and WU-test). However, hyperlipidemia revealed a variable influence on the tests examined. Some of the available tests apparently sensitive to show platelet activation reflect the increase in triglycerides (TG), such as the sedimentation index. ADP-induced platelet aggregatory activity in count adjusted washed isolated platelet samples during postprandial hyperlipidemia indicates mildly enhanced platelet activity, but does not seem to induce significant changes in aggregation. In patients with severe hypertriglyceridemia (> 400 mg/dl fasting) changes in platelet function are more pronounced due to delayed decay and may last up to 16 hours paralleling TG reaching the prevalue. The overwhelming majority of platelet function tests do not significantly respond to postprandial hyperlipidemia. The correlation between the tests applied is poor. For standardization purpose, platelet aggregation tests, aimed to examine proaggregatory capacity in atherosclerosis, should only be performed at the same time of the day after a fasting period > 6 hours. The great variation in preanalytical work-up on comparison of various tests, large number of platelet tests available and their respective potential value are discussed. CONCLUSIONS: At present, the suspicion that platelet function is significantly activated in the postprandial period cannot be supported by any of the tests used. The information provided is valuable to know for which test and group of patients a fasting period of which duration is recommendable. PMID- 22943577 TI - Metabolic effects of adjunctive aripiprazole in clozapine-treated patients with schizophrenia. AB - OBJECTIVE: This study examined the effects of adjunctive aripiprazole therapy on metabolism in clozapine-treated patients with schizophrenia. METHOD: In an 8-week randomized, double-blind, placebo-controlled study, subjects received either aripiprazole (15 mg/day) or placebo. At baseline and week 8, metabolic parameters were assessed by the frequently sampled intravenous glucose tolerance test, nuclear magnetic resonance spectroscopy and whole-body dual-energy X-ray absorptiometry (DXA). RESULTS: Thirty subjects completed the study (16 in the aripiprazole group and 14 in the placebo group). Glucose effectiveness measured by the frequently sampled intravenous glucose tolerance test improved significantly in the aripiprazole group (0.003 +/- 0.006 vs. -0.005 +/- 0.007/min, P = 0.010). The aripiprazole group showed significant reductions in both plasma low-density lipoprotein (LDL) levels (-15.1 +/- 19.8 vs. 4.4 +/- 22.5 mg/dl, P = 0.019) and LDL particle numbers (-376 +/- 632 vs. -36 +/- 301 nm, P = 0.035). Further, there was a significant reduction in the lean mass (-1125 +/- 1620 vs. 607 +/- 1578 g, P = 0.011) measured by whole-body DXA scan in the aripiprazole group. All values were expressed as mean +/- standard deviation, aripiprazole vs. placebo. CONCLUSION: Adjunctive therapy with aripiprazole may have some metabolic benefits in clozapine-treated patients with schizophrenia. PMID- 22943578 TI - Transgenerational transmission of trauma and resilience: a qualitative study with Brazilian offspring of Holocaust survivors. AB - BACKGROUND: Over the past five decades, clinicians and researchers have debated the impact of the Holocaust on the children of its survivors. The transgenerational transmission of trauma has been explored in more than 500 articles, which have failed to reach reliable conclusions that could be generalized. The psychiatric literature shows mixed findings regarding this subject: many clinical studies reported psychopathological findings related to transgenerational transmission of trauma and some empirical research has found no evidence of this phenomenon in offspring of Holocaust survivors. METHOD: This qualitative study aims to detect how the second generation perceives transgenerational transmission of their parents' experiences in the Holocaust. In depth individual interviews were conducted with fifteen offspring of Holocaust survivors and sought to analyze experiences, meanings and subjective processes of the participants. A Grounded Theory approach was employed, and constant comparative method was used for analysis of textual data. RESULTS: The development of conceptual categories led to the emergence of distinct patterns of communication from parents to their descendants. The qualitative methodology also allowed systematization of the different ways in which offspring can deal with parental trauma, which determine the development of specific mechanisms of traumatic experience or resilience in the second generation. CONCLUSIONS: The conceptual categories constructed by the Grounded Theory approach were used to present a possible model of the transgenerational transmission of trauma, showing that not only traumatic experiences, but also resilience patterns can be transmitted to and developed by the second generation. As in all qualitative studies, these conclusions cannot be generalized, but the findings can be tested in other contexts. PMID- 22943580 TI - Clinical characteristics, risk factors and pre-surgical evaluation of post infectious epilepsy. AB - BACKGROUND AND PURPOSE: Epilepsy is a frequent complication of central nervous system (CNS) infections. Post-infectious epilepsy is commonly refractory to medical treatment and plays a pivotal role for the poor long-term outcome of CNS infections. OBJECTIVES: To provide an overview of clinical characteristics and risk factors of seizures associated with CNS infections. In addition, to summarize the state of the art of anticonvulsive treatment and the pre-surgical evaluation process in refractory cases. METHODS: A comprehensive literature search for articles published between January 1970 and December 2011 was carried out. RESULTS: The occurrence of seizures during the acute course of meningitis, encephalitis and brain abscess is the main risk factor for the development of post-infectious epilepsy. There is a shortage of trials evaluating the efficacy of prophylactic and symptomatic treatment during the course of acute infection. Moreover, there are no randomized-controlled trials studying anticonvulsive drugs and their combinations for the management of post-infectious epilepsy. In a selected group of patients, however, medically refractory focal epilepsy is potentially curable by surgery. CONCLUSIONS: Further studies are required to improve the pathogenetic understanding of post-infectious epilepsy in order to develop preventive measures as well as to evaluate additional medical and surgical treatment strategies for the patients currently not considered for surgery. PMID- 22943579 TI - Applied clinical pharmacology and public health in rural Asia--preventing deaths from organophosphorus pesticide and yellow oleander poisoning. AB - Self-poisoning with pesticides or plants is a major clinical problem in rural Asia, killing several hundred thousand people every year. Over the last 17 years, our clinical toxicology and pharmacology group has carried out clinical studies in the North Central Province of Sri Lanka to improve treatment and reduce deaths. Studies have looked at the effectiveness of anti-digoxin Fab in cardiac glycoside plant poisoning, multiple dose activated charcoal in all poisoning, and pralidoxime in moderate toxicity organophosphorus insecticide poisoning. More recently, using a Haddon matrix as a guide, we have started conducting public health and animal studies to find strategies that may work outside of the hospital. Based on the 2009 GSK Research in Clinical Pharmacology prize lecture, this review shows the evolution of the group's research from a clinical pharmacology approach to one that studies possible interventions at multiple levels, including the patient, the community and government legislation. PMID- 22943581 TI - Are serum and urine neutrophil gelatinase-associated lipocalin predictive of renal graft function in short term? AB - NGAL is a member of the lipocalin protein family that has diverse function but similar structure. The functions of NGAL are not clear, but it appears to be expressed in stress conditions and in tissues undergoing involution. Varied studies have shown increased levels of plasma or urinary NGAL in diverse renal damages. The aim of this study was the serial measurement of serum and urinary NGAL within the first week after renal transplantation in children to predict immediate and short-term graft function. A total of 27 patients were assessed. These patients were classified into those with rapid reduction in serum creatinine (more than 50% reduction in serum creatinine in the first day after transplantation) and patients with slow reduction in serum creatinine (<50% reduction in serum creatinine). We also assessed the absolute reduction in serum creatinine before and after transplantation. Serum and urinary NGAL on the first day post-transplantation were higher in recipients with slow reduction in serum creatinine (urinary NGAL at the first day: 197 +/- 153 [s.e.m.] vs. 22.54 +/- 8.5 [s.e.m.], p = 0.04; serum NGAL at the first day: 199 vs. 69.8, p = 0.003). The cutoff point of serum NGAL at the first day after transplantation for prediction of slow creatinine reduction was 174 ng/mL with a sensitivity of 100% and specificity of 95.5%. However, we did not find association between the absolute reduction in serum creatinine before and after transplantation with the amount of serum and urinary NGAL post-transplant. Additionally, we did not find any effect of high serum and urine NGAL concentration on the graft function at the first year post-transplant. Although it is supposed that high serum and urine NGAL may predict ischemia of graft in early phases; however, it appears that this mild ischemic injury to graft without DGF or SGF cannot affect the graft function in short-term period. Further studies are needed using larger transplant recipients in pediatric age group. It is also needed to determine the effects of mild ischemic injuries on the graft function in long-term period in future studies. PMID- 22943582 TI - Clinical efficacy and randomized clinical trials in dysphagia. AB - This manuscript reviews the current state of research on treatment efficacy for swallowing disorders in relation to the use of large-scale randomized multi institutional trials. Dose response trials, i.e., how much treatment is needed to achieve the desired result, are not yet available in dysphagia. The financial and medical pressures on clinicians responsible for diagnosing and treating the dysphagic patient are noted as they often impact the timing of patient care in dysphagia. The process of integration of treatment techniques into the diagnostic study (Modified Barium Swallow, videofluoroscopy) to improve the patient's swallow as quickly as possible is described. The availability of a clinical trial group, the Communications Sciences and Disorders Clinical Trials Research Group (CSDRG), is noted to assist clinicians and scientists in the development of all types of clinical trials in dysphagia. PMID- 22943583 TI - Just a preference: racialised language in the sex-seeking profiles of gay and bisexual men. AB - Racialised language is a salient and contested aspect of contemporary sexual cultures, particularly in the online domain. This paper explores the ways in which gay men in Australia employ race-related language when using online sex/dating websites. Using inductive content analysis, descriptive categories were developed to identify recurrent patterns in the racialised language employed by website users. A coding framework was then constructed to identify the 'subject' (self, other or concept) of each piece of race-related content, its 'purpose' (marketing, negative or positive discrimination, commentary) and the 'position' adopted (defensive, normalised or critical). Descriptive and comparative analyses revealed differences in the ways in which members of racial groups employed racialised language online. These differences are reviewed in relation to broader discourses on Whiteness and race in Australia, as well as recent community-produced anti-racism campaigns. PMID- 22943584 TI - Outcomes of patients with histologically proven acute acalculous cholecystitis. AB - BACKGROUND: Acute acalculous cholecystitis (AAC) is traditionally described in the setting of critical illness, where the diagnosis is based on clinical assessment and imaging criteria. Very few studies have assessed the features and outcomes of AAC in patients treated by cholecystectomy. METHODS: Patients with histologically confirmed acute cholecystitis treated in a specialized unit in a tertiary hospital between 2005 and 2011 were identified from prospectively maintained database. Retrospective review of data was undertaken and patients with AAC were compared with those patients with acute cholecystitis and confirmed gallstones. RESULTS: AAC was identified in 35 of 412 (8.5%) patients with acute cholecystitis. These patients were older (69 years versus 61 years; P = 0.004) and were more likely to be febrile (46% versus 21%; P = 0.001) and hypotensive (23% versus 5%; P < 0.001) at initial presentation. There was a higher incidence of chronic obstructive airways disease (COAD) in the AAC group (26% versus 6%; P < 0.001). Other co-morbidities were similar among the groups. Operative outcomes were similar between the groups. There were no overall differences in postoperative complications between AAC and calculous acute cholecystitis patients (17% versus 16%; P = 0.063). However, the postoperative length of stay was higher in the AAC group (5 days versus 3 days; P = 0.026). CONCLUSION: AAC more commonly occurs in older patients and those with COAD. The operative outcomes and complications of AAC treated by cholecystectomy are similar to cases of acute calculous cholecystitis. PMID- 22943585 TI - Complete mitochondrial genome of a water deer subspecies, Hydropotes inermis argyropus (Cervidae: Hydropotinae). PMID- 22943586 TI - Suction assisted pulse lavage: randomised controlled studies comparing its efficacy with conventional dressings in healing of chronic wounds. AB - Chronic, open, non-healing wounds pose a continual challenge in medicine as the treatment is variable and there are no documented consistent responses. Although wound aetiologies vary and there are a number of factors that affect chronic wound pathogenesis, wound ischaemia and bacterial colonisation of wounds are the chief concerns among them. Conventionally, pulse lavage has been used primarily as a wound debriding device. To address both the critical factors of wound ischaemia and bacterial burden, a couple of technical points were proposed and applied in this study. The objective of our study was to evaluate pulse lavage therapy's ability to improve the healing rate of chronic wounds compared to that of the traditional saline-wet-to-moist dressings. The study period was from 1 August 2010 to 31 January 2012 and was conducted in our institution. Thirty patients with 31 chronic, non-healing wounds were enrolled in the study after obtaining proper consent. Subjects were randomised (15 patients each) to the pulse lavage group and the control group. Patients in the test group were subjected to irrigation of their wounds with pulsed lavage at 10 to 15 psi pressure. In the control group, wound was closed by applying moist betadine saline gauze dressings after cleaning with saline. Wounds treated with pulse lavage system significantly reduced in size, had better control of bacterial contamination and had overall faster healing rates. Efficacy of pulse lavage can be increased by correct method of administration of the irrigant. PMID- 22943587 TI - Colonic insufflation with carbon monoxide gas inhibits the development of intestinal inflammation in rats. AB - BACKGROUND: The pathogenesis of inflammatory bowel disease (IBD) is complex, and an effective therapeutic strategy has yet to be established. Recently, carbon monoxide (CO) has been reported to be capable of reducing inflammation by multiple mechanisms. In this study, we evaluated the role of colonic CO insufflation in acute colitis induced by trinitrobenzene sulfonic acid (TNBS) in rats. METHODS: Acute colitis was induced with TNBS in male Wistar rats. Following TNBS administration, the animals were treated daily with 200 ppm of intrarectal CO gas. The distal colon was removed to evaluate various parameters of inflammation, including thiobarbituric acid (TBA)-reactive substances, tissue associated myeloperoxidase (MPO) activity, and the expression of cytokine-induced neutrophil chemoattractant (CINC)-1 in colonic mucosa 7 days after TNBS administration. RESULTS: The administration of TNBS induced ulceration with surrounding edematous swelling in the colon. In rats treated with CO gas, the colonic ulcer area was smaller than that of air-treated rats 7 days after TNBS administration. The wet colon weight was significantly increased in the TNBS induced colitis group, which was markedly abrogated by colonic insufflation with CO gas. The increase of MPO activity, TBA-reactive substances, and CINC-1 expression in colonic mucosa were also significantly inhibited by colonic insufflation with CO gas. CONCLUSIONS: Colonic insufflation with CO gas significantly ameliorated TNBS-induced colitis in rats. Clinical application of CO gas to improve colonic inflammatory conditions such as IBD might be useful. PMID- 22943588 TI - Human leukocyte antigens (HLA) associated drug hypersensitivity: consequences of drug binding to HLA. AB - Recent publications have shown that certain human leukocyte antigen (HLA) alleles are strongly associated with hypersensitivity to particular drugs. As HLA molecules are a critical element in T-cell stimulation, it is no surprise that particular HLA alleles have a direct functional role in the pathogenesis of drug hypersensitivity. In this context, a direct interaction of the relevant drug with HLA molecules as described by the p-i concept appears to be more relevant than presentation of hapten-modified peptides. In some HLA-associated drug hypersensitivity reactions, the presence of a risk allele is a necessary but incomplete factor for disease development. In carbamazepine and HLA-B*15:02, certain T-cell receptor (TCR) repertoires are required for immune activation. This additional requirement may be one of the 'missing links' in explaining why most individuals carrying this allele can tolerate the drug. In contrast, abacavir generates polyclonal T-cell response by interacting specifically with HLA-B*57:01 molecules. T cell stimulation may be due to presentation of abacavir or of altered peptides. While the presence of HLA-B*58:01 allele substantially increases the risk of allopurinol hypersensitivity, it is not an absolute requirement, suggesting that other factors also play an important role. In summary, drug hypersensitivity is the end result of a drug interaction with certain HLA molecules and TCRs, the sum of which determines whether the ensuing immune response is going to be harmful or not. PMID- 22943589 TI - The islet size to oxygen consumption ratio reliably predicts reversal of diabetes posttransplant. AB - beta-Cell replacement therapy by either whole-organ pancreas or islets of Langerhans transplantation can restore carbohydrate control to diabetic patients and reduces complications associated with the disease. One of the variables inherent in islet transplantation is the isolation of functional islets from donor pancreata. Islet isolations fail to consistently produce good-quality functional islets. A rapid pretransplant assay to determine posttransplant function of islets would be an invaluable tool. We have tested the novel hypothesis that modified oxygen consumption rates (OCR), standardized to DNA quantity (nmol/min-mg DNA), would serve as a pretransplant assessment of the metabolic potency of the islets postisolation. This study compares the ability of current in vitro assays to predict in vivo restoration of normoglycemia in a diabetic nude mouse posttransplantation of adult pig islets. There is known to be a diversity of islet sizes within each preparation. This parameter has not heretofore been effectively considered a critical factor in islet engraftment. Our results suggest a surprising finding that islet size influences the probability of restoring carbohydrate control. Based on this observation, we thus developed a novel predictor of islet graft function that combines the effects of both islet OCR and size. When OCR was divided by the islet index (size), a highly significant predictor of graft function was established (p = 0.0002, n = 75). Furthermore, when OCR/islet index values exceeded 70.0 nmol/min mg DNA/islet index, an effective threshold of diabetes reversal was observed. This assay can be performed with as few as 1,000 islet equivalents (IEQ) and conducted in less than 60 min. Our data suggest that, using this novel method to assess islet cell function prior to transplantation, OCR/islet index thresholds provide a valuable tool in identifying which islet preparations are most likely to restore glycemic control posttransplant. PMID- 22943590 TI - Coffee intake and development of pain during computer work. AB - BACKGROUND: The present study sought to determine if subjects who had consumed coffee before performing a simulated computer office-work task found to provoke pain in the neck and shoulders and forearms and wrists exhibited different time course in the pain development than the subjects who had abstained from coffee intake. FINDINGS: Forty eight subjects all working fulltime, 22 with chronic shoulder and neck pain and 26 healthy pain-free subjects, were recruited to perform a computer-based office-work task for 90 min. Nineteen (40%) of the subjects had consumed coffee (1/2 -1 cup) on average 1 h 18 min before start. Pain intensity in the shoulders and neck and forearms and wrists was rated on a visual analogue scale every 15 min throughout the work task.During the work task the coffee consumers exhibited significantly lower pain increase than those who abstained from coffee. CONCLUSIONS: Subjects who had consumed coffee before starting a pain provoking office work task exhibited attenuated pain development compared with the subjects who had abstained from coffee intake. These results might have potentially interesting implications of a pain-modulating effect of caffeine in an everyday setting. However, studies with a double blind placebo controlled randomized design are needed. PMID- 22943591 TI - Clinical presentations of substance abuse in bipolar heroin addicts at time of treatment entry. AB - BACKGROUND: Studies on the 'self-medication hypothesis' have focused on substance abuse as an attempt to alleviate emotional suffering. METHODS: We have investigated concomitant substances of abuse in 150 bipolar heroin addicts clustered according to their clinical presentation at treatment entry (depressive episode, hypomanic episode, manic episode and mixed episode). Bipolar heroin addicted patients were chosen because they tend to have a concomitant poly substance abuse and because, as compared with patients suffering for other mental illnesses, they more clearly reveal a variety of identifiable affective states. RESULTS: Patients with a depressive episode more frequently used non-prescribed anxiolytic-hypnotics. They were found to use cocaine-amphetamines more frequently during a hypomanic episode, whereas the use of cannabis and cocaine-amphetamines occurred more frequently during a manic episode. The associated use of alcohol, cocaine-amphetamines and cannabinoids was more frequently encountered during a mixed episode. LIMITATIONS: apart from the difficulty in determining whether the substance use modifies the mood or the mood state determines the substance used, this is a report on a retrospective analysis, rather than a study specifically designed to elucidate the issue; in addition, no information was available on the temperament of our subjects. Assessments of the same subject in various clinical presentations would have provided a better level of information. CONCLUSIONS: Besides one expected result - the prominent use of CNS stimulants during a depressive phase of bipolar patients - this study supports the hypothesis that mood elation is a pleasurable, rewarding experience that, in bipolar patients, can be started or prolonged by means of CNS stimulant drugs. Stimulant use was, therefore, more prevalent during the 'up' rather than the 'down' phase of the illness. PMID- 22943592 TI - Quality of generic medicines in South Africa: perceptions versus reality - a qualitative study. AB - BACKGROUND: Generic Medicines are an important policy option allowing for access to affordable, essential medicines. Quality of generic medicines must be guaranteed through the activities of national medicines regulatory authorities. Existing negative perceptions surrounding the quality of generic medicines must be addressed to ensure that people use them with confidence. Campaigns to increase the uptake of generic medicines by consumers and providers of healthcare need to be informed by local norms and practices. This study sought to compare South African consumers' and healthcare providers' perceptions of quality of generics to the actual quality of selected products. METHODS: The study was conducted at the local level in three cities of South Africa: Johannesburg, Durban and Cape Town. Purposive sampling was used to recruit consumer participants (n = 73) and random sampling used to recruit healthcare providers from public and private sectors (n = 15). Data were obtained through twelve focus group discussions with consumers and semi-structured interviews (n = 15) with healthcare providers in order to gain familiarity with perceptions of quality. One hundred and thirty five products comprising paracetamol tablets (n = 47), amoxicillin capsules (n = 45) and hydrochlorothiazide tablets (n = 43) were sourced from public and private sector healthcare providers. These products were subjected to in vitro dissolution, uniformity of weight and identity (Fourier Transformed Infrared Spectroscopy) tests using prescribed methods from the British (2005) and United States Pharmacopeias (2006). RESULTS: Respondents described drug quality in relation to the effect on symptoms. Procurement and use behavior of healthcare providers was influenced by prior experience, manufacturers' names and consumers' ability to pay. All formulations passed the in vitro tests for quality. CONCLUSIONS: This study showed clear differences between perceptions of quality and actual quality of medicines suggesting deficiencies in public engagement by government regarding the implementation of generic medicines policy. Implementation of generic medicines policy requires the involvement of consumers and healthcare providers to specifically address their information gaps and needs. PMID- 22943593 TI - Encoding and updating spatial information presented in narratives. AB - Four experiments investigated whether directional spatial relations encoded by reading narratives are updated following described protagonist rotations. Participants memorized locations of objects described in short stories that placed them, as the protagonist, in remote settings. After reading a description that the protagonist rotated to the left or the right of the initial orientation, participants made judgements about object relations in the described environment (Experiment 1). Before making these judgements, participants were instructed to physically rotate to match (Experiment 2) or mismatch (Experiment 4) the protagonist's described rotation and in Experiments 3 and 4 to also visualize the changed relations following rotation. Participants' performance suggested that they relied on the initial representation they constructed during encoding rather than on the updated protagonist-to-object relations. Participants' physical movement to match the described rotation and additional visualization instructions did not facilitate updating through a sensorimotor process. In these respects, updating spatial relations in situation models constructed from narratives differs from updating in perceptually experienced environments. PMID- 22943594 TI - Is an occupation with vocal load a risk factor for laryngopharyngeal reflux: a prospective, multicentre, multivariate comparative study. AB - OBJECTIVES: To compare the prevalence of laryngopharyngeal reflux in choristers, teachers and control subjects without vocal load at work and to determine the risk factors for laryngopharyngeal reflux. DESIGN: A prospective, multicentre, multivariate comparative study. PARTICIPANTS: One hundred and nineteen singers from four professional choirs, seventy teachers from four schools and 111 control subjects with an occupation without vocal load. MAIN OUTCOME MEASURES: All participants completed a questionnaire about their dietary habits, height and weight, presence of stress, smoking and allergies, including the nine-item Reflux Symptom Index. The groups of choristers, teachers and the controls were compared with each other with regard to their sex, age, dietary habits, body-mass index, Reflux Symptom Index score and other factors affecting voice quality. The subjects from all three groups with suspected laryngopharyngeal reflux were compared with the subjects without it. The relationship between the Reflux Symptom Index score and the possible risk factors for reflux was estimated. RESULTS: The results showed significantly higher Reflux Symptom Index scores in the choristers than in the teachers and the controls (mean scores, 7.86 versus 6.33, P = 0.044; 7.86 versus 4.80, P = 0.000, respectively), but the number of subjects with suspected laryngopharyngeal reflux (Reflux Symptom Index score >13) did not differ significantly between the groups. The choristers were significantly more often treated for laryngopharyngeal reflux than the teachers and the controls (41%, 17% and 28%, respectively). The occupation chorister and frequently experiencing stress were the only factors that influenced the total Reflux Symptom Index score. CONCLUSIONS: Laryngopharyngeal reflux affects the choristers more often than the teachers or the control subjects without vocal load at work. These results suggest that singing as the main professional activity can notably contribute to the development of the reflux. Vocal load without singing is probably not an important aetiological factor for laryngopharyngeal reflux. The extraoesophageal symptoms affecting voice require treatment for laryngopharyngeal reflux and proper dietary habits especially in the group with high voice quality demands. PMID- 22943595 TI - Concordance between self-reported and actual hepatitis C virus infection status in a cohort of people who inject drugs. AB - INTRODUCTION AND AIMS: Accurate knowledge of individual hepatitis C virus (HCV) status is an important component of comprehensive health services for people who inject drugs (PWID). In this paper we compare the perceived HCV status of PWID in a longitudinal cohort study with their actual status, as verified by HCV-RNA testing. METHODS: Participants who consented to blood testing at first follow up (352/688) were included. Self-reported HCV status (positive/negative/don't know), was compared with serology test results for participants. RESULTS: In comparing self-report with HCV-RNA results, 274 of 352 participants had valid serology and self-report results; of these, 220 (80%) accurately reported their HCV status. DISCUSSION AND CONCLUSIONS: The findings of this study suggest that large proportions of PWID know their true HCV infection status, but the discordant participants represent potential HCV infection risks. Despite the majority of participants displaying concordance, this study reinforces the need for regular blood testing and the giving of accurate, practical and comprehensive HCV result information. PMID- 22943596 TI - Immunohistochemical evidence suggests repeated intravesical application of botulinum toxin A injections may improve treatment efficacy of interstitial cystitis/bladder pain syndrome. AB - WHAT'S KNOWN ON THE SUBJECT? AND WHAT DOES THE STUDY ADD?: A single set of botulinum toxin A (BoNT-A) injections relieves clinical symptoms of interstitial cystitis/bladder pain syndrome (IC/BPS), but lacks long-term effect. An inadequate anti-inflammatory effect is likely to cause treatment failure. The study shows that chronic inflammation and apoptotic signalling molecules are significantly reduced after repeated intravesical BoNT-A injection in patients with IC/BPS. It also shows that repeated BoNT-A injections are necessary to achieve greater success in the treatment of IC/BPS. OBJECTIVE: To investigate the mechanisms of action of botulinum toxin A (BoNT-A) treatment on interstitial cystitis/bladder pain syndrome (IC/BPS). PATIENTS AND METHODS: A total of 23 women with IC/BPS who received single intravesical BoNT-A injection were studied. Among them, 11 received three repeated injections every 6 months to improve their symptoms. Bladder biopsy was obtained before each BoNT-A injection and the clinical symptoms and urodynamic variables were recorded. Immunohistochemical (IHC) staining for TUNEL and mast cell activity, and western blotting analysis of tryptase, cytokines, Bax and phospho-p38 (p-p38) were carried out. We compared the clinical results and IHC data among baseline, single or repeated BoNT-A treatments. RESULTS: Single BoNT-A injection improved clinical symptoms, pain score and daytime urinary frequency. Mast cell activity and apoptotic cell count did not decrease significantly, while Bax and p-p38, but not tryptase, decreased significantly after a single BoNT-A injection. The 11 patients who received three repeated BoNT-A injections had significantly lower pain scores than the remaining patients (mean [SD]: 5.80 [2.27] vs. 3.03 [2.30], P = 0), glomerulation degree (mean [SD]: 1.80 [1.06] vs. 1.20 [1.06], P = 0.026) and global response scores (mean [SD]: 0.30 [0.92] vs. 1.20 [1.06], P = 0) after treatment. Tryptase, Bax, p p38 and apoptotic cell counts all decreased significantly. 25-kD synaptosomal associated protein also decreased after BoNT-A treatments, which confirmed the therapeutic effect of repeated BoNT-A injections. CONCLUSIONS: Chronic inflammation and apoptotic signalling molecules were significantly reduced after repeated BoNT-A injections in patients with IC/BPS. The IHC improvement was associated with clinical symptom improvement. Repeated BoNT-A injections are necessary to achieve a greater success rate in the treatment of IC/BPS. PMID- 22943597 TI - Biology and external morphology of immature stages of the butterfly, Diaethria candrena candrena. AB - The biology and the external morphology of immature stages of Diaethria candrena candrena (Godart) (Lepidoptera: Nymphalidae: Biblidinae) are described. Immature D. c. candrena found on Allophylus spp. (Sapindaceae) were collected in Curitiba, Parana, Brazil and reared in the laboratory. Morphological descriptions and illustrations are given, based on observations using electronic, stereoscopic, and optic microscopes, the latter two attached to camera lucida. Results are compared and discussed with immature stages of other species of Biblidinae described to date. PMID- 22943598 TI - High incidence of nasopharyngeal cancer: similarity for 60% of mitochondrial DNA signatures between the Bidayuhs of Borneo and the Bai-yue of Southern China. AB - Populations in Southern China (Bai-yue) and Borneo (Bidayuh) with high incidence of nasopharyngeal cancer(NPC) share similar mitochondrial DNA signatures, supporting the hypothesis that these two populations may share the same genetic predisposition for NPC, which may have first appeared in a common ancestral reference population before the sea levels rose after the last ice age. PMID- 22943600 TI - Systems biology in the frontier of cancer research: a report of the Second International Workshop of Cancer Systems Biology. AB - The report summarizes the Second International Workshop of Cancer Systems Biology held on July 5-6, 2012 in Changchun, China. The goal of the workshop was to bring together cancer researchers with different backgrounds to share their views about cancer and their experiences in fighting against cancer, and to gain new and systems-level understanding about cancer formation, progression, diagnosis, and treatment through exchanging ideas. PMID- 22943599 TI - Aberrant DNA methylation in cervical carcinogenesis. AB - Persistent infection with high-risk types of human papillomavirus(HPV) is known to cause cervical cancer; however, additional genetic and epigenetic alterations are required for progression from precancerous disease to invasive cancer. DNA methylation is an early and frequent molecular alteration in cervical carcinogenesis. In this review, we summarize DNA methylation within the HPV genome and human genome and identify its clinical implications. Methylation of the HPV long control region (LCR) and L1 gene is common during cervical carcinogenesis and increases with the severity of the cervical neoplasm. The L1 gene of HPV16 and HPV18 is consistently hypermethylated in invasive cervical cancers and can potentially be used as a clinical marker of cancer progression. Moreover, promoters of tumor suppressor genes (TSGs) involved in many cellular pathways are methylated in cervical precursors and invasive cancers. Some are associated with squamous cell carcinomas, and others are associated with adenocarcinomas. Identification of methylated TSGs in Pap smear could be an adjuvant test in cervical cancer screening for triage of women with high-risk HPV, atypical squamous cells of undetermined significance, or low grade squamous intraepithelial lesion (LSIL). However, consistent panels must be validated for this approach to be translated to the clinic. Furthermore, reversion of methylated TSGs using demethylating drugs may be an alternative anticancer treatment, but demethylating drugs without toxic carcinogenic and mutagenic properties must be identified and validated. PMID- 22943601 TI - Young people's perspectives on the use of reverse discourse in web-based sexual health interventions. AB - Web-based sexual-health promotion efforts often utilise reverse discourse - the acknowledgement and rejection of shame associated with stigmatised terms - both to challenge judgments about 'risky' behaviours (e.g., casual sex) and to appeal to young people. This study examines the use of reverse discourse in Internet based sexual-health promotion and analyses young people's perspectives on this approach. During in-depth interviews and focus groups with young people (aged 15 24), participants shared their perspectives on written (e.g., clinical language; colloquial language) and visual (e.g., generic, stock images; sexualised images) depictions of sexual-health topics on the websites. More explicit styles elicited negative responses from young people in terms of perceived appeal, trust and quality of websites. Negative social mores were associated with some of the more explicit portrayals of young people's sexual lives on the websites, revealing how reverse discourse re-stigmatises young people by re-emphasising young people's sexual activity as inherently risky or immoral. Reverse discourse was perceived to have negative effects on the saliency and credibility of online sexual-health information. We discuss the theoretical basis for the operationalisation of reverse discourse in this context, and discuss the importance of considering sociotechnical aspects of Internet-based sexual-health interventions. PMID- 22943602 TI - Quality of life in a cohort of patients diagnosed with renal failure in childhood and who received renal transplant. AB - Studies on HRQOL on kidney-transplanted young adults who had a diagnosis of chronic renal failure (CRF) in the pediatric age are uncommon. We studied HRQOL and its predictors in a sample of young adults with CRF in childhood who underwent a renal transplant. We recruited patients >=18 yr old with renal transplant. We measured HRQOL by a standardized questionnaire on lifestyle, Short Form-36 (SF-36; including a PCS and a MCS; scale: 0-100), the GHQ (for short-term changes in mental health; scale: 0-36), and the MSPSS (with scales for family, friends, and significant others; scale: 0-100). We assessed the association of potential predictors of HRQOL through multiple linear regression models. We studied 66 patients aged 18-34 yr. The average PCS score was 76.4, and the average MCS score was 73.9. The mean GHQ total score was 14.8, and the total scale MSPSS mean score was 70. Severe comorbidities significantly affected the PCS score. Individuals with severe comorbidities had lower PCS scores. PMID- 22943603 TI - Beneficial effects of Ankaferd Blood Stopper on dermal wound healing: an experimental study. AB - Ankaferd Blood Stopper((r)) (ABS) is a folkloric medicinal plant extract used as a haemostatic agent in traditional Turkish medicine. The aim of this study was to investigate the efficacy of ABS on the healing of dermal wounds in a rat model. Twenty Wistar albino rats were divided into two groups. Standard full-thickness skin defects were created on the back of the rats. In the control group (group 1), dressings moisturised with saline were changed daily. In the study group (group 2), the wounds were cleaned daily with saline, Ankaferd solution was applied, then the wounds were covered with moisturised dressings. The contraction percentage of wound areas were calculated on the 3rd, 7th, 10th and 14th days using a planimetric programme. On day 14, the wound areas were excised for histopathological examination, inflammatory scoring and evaluation of collagen deposition. The study group was superior to the control group in terms of inflammatory scoring, type I/type III collagen ratio and wound contraction rates. ABS((r)) may be used effectively and safely on full-thickness wounds as a natural product. PMID- 22943604 TI - Development of guidelines to assist organisations to support employees returning to work after an episode of anxiety, depression or a related disorder: a Delphi consensus study with Australian professionals and consumers. AB - BACKGROUND: Mental disorders are a significant cause of disability and loss of workplace productivity. The scientific evidence for how organisations should best support those returning to work after common mental disorders is relatively limited. Therefore a Delphi expert consensus study was carried out with professional and consumer experts. METHODS: A systematic review of websites, books and journal articles was conducted to develop a 387 item survey containing strategies that organisations might use to support those returning to work after common mental disorders. Three panels of Australian experts (66 health professionals, 30 employers and 80 consumers) were recruited and independently rated the items over three rounds, with strategies reaching consensus on importance written into the guidelines. RESULTS: The participation rate across all three rounds was 60.2% (57.6% health professionals, 76.7% employers, 56.3% consumers). 308 strategies were endorsed as essential or important by at least 80% of all three panels. The endorsed strategies provided information on policy and procedures, the roles of supervisors, employees and colleagues in managing absence and return to work, and provision of mental health information and training. CONCLUSIONS: The guidelines outline strategies for organisations supporting those returning to work after common mental disorders. It is hoped that they may be used to inform policy and practice in a variety of workplaces. PMID- 22943605 TI - Effect of DHA+EPA on oxidative stress and apoptosis induced by ischemia reperfusion in rat kidneys. AB - Apoptosis, as well as necrosis, has an important role in post-ischemic renal pathology. The effect of pretreatment with Docosahexaenoic acid+Eicosapentaenoic acid (DHA+EPA) on renal injury and apoptotic protein expression was evaluated. Right nephrectomy was completed on male Wistar rats (255-300 g). The rats received DHA+EPA (200 mg/kg/day) of distilled water orally for 14 days before ischemia reperfusion (IR) or sham operation. A total of 81 rats were divided into three main groups with 6, 24 and 48 h of post-operation or reperfusion period. Serum creatinine (SCr), BUN, creatinine clearance (CCr) and fractional excretion of sodium (FEN a ) were measured. Tissue levels of malondialdehyde (MDA), superoxide dismutase (SOD) and catalase (CAT) activities, Bax and Bcl-2 protein expressions and renal histological injury were determined. SCr, BUN and FEN a increased 6-48 h of reperfusion (P < 0.01). Tissue MDA content and Bax expression increased (P < 0.01) and CAT and SOD activities decreased (P < 0.05) in the IR group. DHA+EPA decreased SCr and BUN, FEN a , tissue MDA levels (P < 0.05 vs. IR) and increased CAT and SOD activities and Bcl-2 expression (P < 0.05 vs. IR) for 6 48 h after ischemia. IR induced mild (6 h, P < 0.05) and severe (24-48 h, P < 0.01) tissue damage. Mild-to-moderate tissue damage was observed in DHA+EPA groups from 6 to 48 h of reperfusion period (P < 0.05 vs. IR, 24-48 h). In conclusion, the results suggest that pre-ischemic exposure to DHA+EPA could improve the outcome of early graft function by inhibition of IR-induced oxidative stress and apoptosis. PMID- 22943606 TI - Constructing episodes of inpatient care: data infrastructure for population-based research. AB - BACKGROUND: Databases used to study the care of patients in hospitals and Intensive Care Units (ICUs) typically contain a separate entry for each segment of hospital or ICU care. However, it is not uncommon for patients to be transferred between hospitals and/or ICUs, and when transfers occur it is necessary to combine individual entries to accurately reconstruct the complete episodes of hospital and ICU care. Failure to do so can lead to erroneous lengths of-stay, and rates of admissions, readmissions, and death. METHODS: This study used a clinical ICU database and administrative hospital abstracts for the adult population of Manitoba, Canada from 2000-2008. We compared five methods for identifying patient transfers and constructing hospital episodes, and the ICU episodes contained within them. Method 1 ignored transfers. Methods 2-5 considered the time gap between successive entries (<=1 day vs. <=2 days), with or without use of data fields indicating inter-hospital transfer. For the five methods we compared the resulting number and lengths of hospital and ICU episodes. RESULTS: During the study period, 48,551 hospital abstracts contained 53,246 ICU records. For Method 1 these were also the number of hospital and ICU episodes, respectively. Methods 2-5 gave remarkably similar results, with transfers included in approximately 25% of ICU-containing hospital episodes, and 10% of ICU episodes. Comparison with Method 1 showed that failure to account for such transfers resulted in overestimating the number of episodes by 7-10%, and underestimating mean or median lengths-of-stay by 9-30%. CONCLUSIONS: In Manitoba is it not uncommon for critically ill patients to be transferred between hospitals and between ICUs. Failure to account for transfers resulted in inaccurate assessment of parameters relevant to researchers, clinicians, and policy-makers. The details of the method used to identify transfers, at least among the variations tested, made relatively little difference. In addition, we showed that these methods for constructing episodes of hospital and ICU care can be implemented in a large, complex dataset. PMID- 22943607 TI - Perceived stress and risk of adult-onset asthma and other atopic disorders: a longitudinal cohort study. AB - BACKGROUND: Psychological stress can affect airway inflammatory response to irritants and allergens, but the importance of stress in the etiology of adult onset respiratory and dermatologic allergic disorders remains unclear. We aim to address the relationship between perceived stress and the risk of adult-onset asthma, allergic rhinitis, atopic dermatitis, and asthma/bronchitis medication. METHODS: Participants (n = 9785) from the Copenhagen City Heart Study, Denmark, free of atopic disorders at baseline in 1981-1983 were asked questions on stress intensity and frequency. They were followed for first-time asthma hospitalization in nationwide registers until 2010, with < 0.1% loss to follow-up. Objective measures of lung function allowed for thorough adjustment for confounding and prevented ambiguity between diagnosis of asthma and chronic obstructive lung disease. Daily intake of asthma/bronchitis medication and incidence of asthma, allergic rhinitis, and atopic dermatitis were assessed by self-report after 10 years of follow-up in 5648 persons. RESULTS: Perceived stress was associated with atopic disorders in a dose-dependent manner (P(trend) < 0.001). High vs low stress was associated with higher risk of self-reported asthma incidence (OR = 2.32; 95% CI: 1.47-3.65), daily intake of asthma/bronchitis medication (OR = 2.26; 95% CI: 1.42-3.58), first-time asthma hospitalization (HR = 2.01; 95% CI: 1.41-2.86), allergic rhinitis (OR = 1.64; 95% CI: 0.99-2.72), and atopic dermatitis (OR = 1.75; 95% CI: 1.11-2.77). The associations were similar for smokers and nonsmokers. CONCLUSIONS: Stress is strongly associated with asthma incidence and hospitalization, use of asthma medication as well as with allergic rhinitis and atopic dermatitis in adults. PMID- 22943608 TI - Carotid stenosis after adjuvant cervical radiotherapy in patients with head and neck cancers: a prospective controlled study. AB - OBJECTIVES: To determine the prevalence of radiation-induced carotid stenosis, in patients who were treated for head and neck malignancies, using colour-flow duplex scanning. DESIGN: Prospective controlled study at a single medical centre. PARTICIPANTS: We enrolled two groups of patients. The first (radiotherapy group) consisted of patients who received surgical treatment and adjuvant radiotherapy of the neck. The control group consisted of patients with head and neck malignancies who received only surgical treatment. MAIN OUTCOME MEASURES: All patients were evaluated with carotid artery ecoDoppler imaging 1 week before and 36 months after the surgical procedure. Intima-media thickness was measured bilaterally at the internal carotid artery and at the bifurcation. Carotid obstruction was classified as low (0-30%), moderate (31-49%) or severe (>=50%). RESULTS: The preoperative stenosis grade did not differ between groups. In 15/25 patients (60%) in the radiotherapy group, mild stenosis evolved to moderate stenosis, while only 6/37 (16%) of the controls did (P = 0.004). Additionally, 9/39 (23%) patients in the radiotherapy group progressed to severe stenosis compared with only 3/54 (6%) controls (P = 0.029). The overall evolution showed that stenosis worsened in 24/32 (62%) patients in the radiotherapy group and 9/54 (17%) patients in the control groups (P < 0.0001). CONCLUSIONS: These results highlight the need to study the long-term incidence of cerebrovascular events in these two different populations (radiation treated and surgically treated) to identify increased cerebrovascular morbidity. PMID- 22943609 TI - Efficacy of a systematic depression management program in high utilizers of primary care: a randomized trial. AB - BACKGROUND: Approximately 25% of so-called high utilizers of medical care are estimated to suffer from depression. A large proportion of these individuals remain undiagnosed and untreated. This study aims to examine the effects of a systematic screening and collaborative treatment program on depression severity in small primary care practices of the German outpatient health care system. METHOD: High utilizers of primary care who screened positive for depressive symptoms on the Brief Psychiatric Health Questionnaire (B-PHQ) were further diagnosed using the DIA-X, a standardized diagnostic interview, performed by trained and supervised interviewers. Patients with major depression were randomized (cluster randomization by practice) to (a) a six-month treatment program of pharmacotherapy, standardized patient and provider education, and physician and patient counseling or (b) six months of usual medical care. All subjects were followed for a 12-month observation period using the 17-item Hamilton Depression Rating scale (HAMD-17) rated by the treating physicians and the B-PHQ-9 rated by the patients. RESULTS: A total of 63 high utilizer patients were included in the trial (17 male, 46 female), 19 randomized to intervention, 44 to usual care. The mean age was 49.7 (SD 13.8). Most patients had one or more somatic co-morbidities. There was no significant difference in response (defined as a decrease in the HAMD-17 sum score of at least 50%) after six months of treatment (50% vs. 42%, p = 0.961, all analyses adjusted for age) and after 12 months of treatment (83% vs. 54%, p = 0.282) between groups. Using patient self rating assessments with the B-PHQ-9 questionnaire the intervention was superior to treatment as usual at six months (83% vs. 16%, p = 0.000).There was no significant difference in HAMD-17 depression severity at six months between the groups (10.5 (SD 7.6) vs. 12.3 (SD 7.8), p = 0.718), but a trend at 12 months (4.7 (SD 8.0) vs. 11.2 (SD 7.4), p = 0.083). Again, using B-PHQ-9 sum scores depression severity was significantly lower in the intervention group than in the treatment as usual group after six months (6.4 (SD 5.2) vs. 11.5 (SD 5.8), p = 0.020), but not at 12 months (7.9 (SD 8.7) vs. 9.0 (SD 5.2), p = 0.858). CONCLUSION: A systematic collaborating treatment program for depression in high utilizers in primary care showed superiority to treatment as usual only in terms of patients' self-assessment but not according to physicians' assessment. The advance of the intervention group at 6 months was lost after 12 months of follow up. Overall, positive results from similar trials in the US health care systems could not be confirmed in a German primary care setting. PMID- 22943610 TI - Retrospective cohort study on patterns of care and outcomes of surgical treatment for lower urinary-genital tract fistula among English National Health Service hospitals between 2000 and 2009. AB - OBJECTIVES: To examine patterns of care among women with urogenital fistula treated in the English National Health Service (NHS) between 2000 and 2009. To assess whether failure of repair was associated with hospital or surgeon workload. PATIENTS AND METHODS: We conducted a retrospective cohort study using data from Hospital Episode Statistics on women undergoing vesicovaginal or urethrovaginal fistula repair between January 2000 and December 2009 in English NHS hospitals. The main outcome measure was the number of fistula repairs and the incidence of re-repair; re-repair rates were stratified by age, NHS trust and consultant team volume. RESULTS: Between 2000 and 2009, 1194 women underwent surgical repair (n = 905) or ileal conduit (n = 289) for urogenital fistula under the care of 490 consultant teams. A total of 281 teams performed only a single index procedure, and only three consultant teams performed a mean of >3 per year. The rate of unsuccessful repair was 11.9% (108/905). The rate of re-operation at NHS trusts who performed over 30 procedures over the 10-year study period was 7.4% compared with 13.2% at those undertaking fewer (P = 0.02). A similar difference in re-operations between consultant teams performing > or <30 procedures did not reach significance (8.4% v 12.7%, P = 0.13). CONCLUSIONS: One in nine women required re-operation after surgical repair of a urogenital fistula. Our results lend weight to the argument for a 'minimum workload' for fistula management; given the number of fistulae occurring in England currently, this would best be provided by a network of supra-regional centres. PMID- 22943612 TI - When opportunity met aspirational goals: accelerator MS, microdosing and absolute bioavailability studies. PMID- 22943611 TI - Prevalence, seasonal occurrence and antimicrobial resistance of Salmonella in poultry retail products in Greece. AB - AIMS: To detect the prevalence, the seasonal occurrence and distribution of Salmonella serotypes in poultry products and to determine the resistance profile of Salmonella isolates. METHOD AND RESULTS: A total of 96 skin-on chicken carcasses and 30 liver samples were analysed between May 2007 and May 2009 from twenty-two different commercial farm brands found in retail market countrywide. Salmonella was isolated from 38 (39.5%) of 96 chicken carcasses and from 10 (33.3%) of 30 liver samples. Higher isolation rate (60.4%) was observed in carcasses detected during summer (May to October), and lower isolation rate (18.7%) was observed in carcasses detected during winter (November to April); in liver samples, the positive rates were 53.4 and 13.2%, respectively. Twelve serotypes were detected with the serotypes Hadar, Enteritidis and Blockley being the most prevalent at 29.2, 22.9 and 12.5%, respectively. Nine of 11 Salm. Enteritidis isolates occurred during summer. Of 48 isolates, 38 (79%) were resistant to one or more of the antimicrobial agents used. The highest resistance rates were found to the following antimicrobials: streptomycin (64.5%), tetracycline (56.2%), nalidixic acid (39.5%), ampicillin and rifampicin (33.3%). CONCLUSIONS: The relatively high Salmonella spp. contamination rates of raw chicken meat and liver have been detected. Salm. Enteritidis isolates peaked in summer, increasing the risk to human health. Antibiotic resistance of Salmonella still remains a threat as resistance plasmids may be extensively shared between animal and humans. SIGNIFICANCE AND IMPACT OF THE STUDY: The study enabled us to improve the data on the seasonal occurrence of Salmonella and to determine the antimicrobial pattern profile and trends in Salmonella strains isolated from poultry retail products in Greece. PMID- 22943613 TI - Could traditional mass-balance studies in the 'twilight zone' be improved by means of accelerator MS measurements? PMID- 22943615 TI - 3rd annual symposium of chemical and pharmaceutical structure analysis. AB - The 3rd Annual Symposium on Chemical and Pharmaceutical Structure Analysis was once again held in Shanghai, where a rich history of 'East meets West' continued. This meeting is dedicated to bringing together scientists from pharmaceutical companies, academic institutes, CROs and instrument vendors to discuss current challenges and opportunities on the forefront of pharmaceutical research and development. The diversified symposia and roundtables are highly interactive events where scientists share their experiences and visions in a collegial setting. The symposium highlighted speakers and sessions that provided first-hand experiences as well as the latest guidance and industrial/regulatory thinking, which was reflected by the theme of this year's meeting 'From Bench to Decision Making - from Basics to Application.' In addition to the highly successful Young Scientist Excellence Award, new events were featured at this year's meeting, such as the Executive Roundtable and the inaugural Innovator Award. PMID- 22943616 TI - Measurement and validation of cell-based assays with microfluidics at the National Institute of Standards and Technology. AB - The National Institute of Standards and Technology (NIST) is the National Metrology Institute for the USA. Our mission is to advance measurement science, standards and technology in ways that enhance economic security and improve quality of life in the USA. Due to the increased need for technologies that advance biological research and the many new and exciting innovations in microfluidics, our projects are aimed at engineering well-controlled microenvironments for quantitative measurements of cell behavior in microfluidic systems. Cell-based microfluidics at NIST is a highly multidisciplinary activity and is greatly influenced by NIST programs in biochemical sciences, materials science, engineering and information technology. Although there are many microfluidic-related activities ongoing at NIST, we will focus on projects related to cell-based measurements in this article. PMID- 22943617 TI - Overcoming bioanalytical challenges in an Onglyza((r)) intravenous [(14)C]microdose absolute bioavailability study with accelerator MS. AB - BACKGROUND: An absolute bioavailability study that utilized an intravenous [(14)C]microdose was conducted for saxagliptin (Onglyza((r))), a marketed drug product for the treatment of Type 2 diabetes mellitus. Concentrations of [(14)C]saxagliptin were determined by accelerator MS (AMS) after protein precipitation, chromatographic separation by UPLC and analyte fraction collection. A series of investigative experiments were conducted to maximize the release of the drug from high-affinity receptors and nonspecific adsorption, and to determine a suitable quantitation range. RESULTS: A technique-appropriate validation demonstrated the accuracy, precision, specificity, stability and recovery of the AMS methodology across the concentration range of 0.025 to 15.0 dpm/ml (disintegration per minute per milliliter), the equivalent of 1.91-1144 pg/ml. Based on the study sample analysis, the mean absolute bioavailability of saxagliptin was 50% in the eight subjects with a CV of 6.6%. Incurred sample reanalysis data fell well within acceptable limits. CONCLUSION: This study demonstrated that the optimized sample pretreatment and chromatographic separation procedures were critical for the successful implementation of an UPLC plus AMS method for [(14)C]saxagliptin. The use of multiple-point standards are useful, particularly during method development and validation, to evaluate and correct for concentration-dependent recovery, if observed, and to monitor and control process loss and operational variations. PMID- 22943618 TI - Applications of accelerator MS in pediatric drug evaluation. AB - Accelerator MS (AMS) provides a novel method for obtaining and analyzing pharmacokinetics and pharmacodynamics in children. This paper reviews the scientific and ethical rationale for AMS in pediatric trials, the regulatory framework and general considerations with some specific examples of pediatric clinical trials using AMS. Microdosing in the context of this article refers to studies using a negligible amount (nanocuries) of (14)C as tracer, and AMS as a quantitative technique. The technology is by no means a panacea for the deficiency in pediatric clinical research; however, it lessens the challenges and provides the most quantitative tool for pediatric pharmacology studies. PMID- 22943619 TI - European Bioanalysis Forum recommendation on method establishment and bioanalysis of biomarkers in support of drug development. AB - Biomarkers have become increasingly important in drug development and many bioanalysts are getting involved. Consequently, different views on how to approach the bioanalysis of biomarkers have been published or are being developed. The European Bioanalysis Forum has intensively discussed this topic since 2010 and is ready with their recommendation on method establishment and bioanalysis of biomarkers. Acknowledging that the challenges step outside the bioanalytical laboratory is a cornerstone of our recommendation. The importance of integrating all scientific aspects, from purely analytical aspects, all the way to understanding the biology and effects of the biomarker, prior to embarking on method establishment or sample analysis, cannot be underestimated. Close and iterative interactions with the teams requesting the data is imperative to develop a bioanalytical strategy that combines science, analytical performance and regulations. The European Bioanalysis Forum developed a straightforward decision tree to help the scientific community in developing a bioanalytical strategy for any biomarker in drug development. PMID- 22943620 TI - Utility of high-resolution accurate MS to eliminate interferences in the bioanalysis of ribavirin and its phosphate metabolites. AB - BACKGROUND: The polar nucleoside drug ribavirin (RBV) combined with IFN-alpha is a front-line treatment for chronic hepatitis C virus infection. RBV acts as a prodrug and exerts its broad antiviral activity primarily through its active phosphorylated metabolite ribavirin 5'-triphosphate (RTP), and also possibly through ribavirin 5'-monophosphate (RMP). To study RBV transport, diffusion, metabolic clearance and its impact on drug-metabolizing enzymes, a LC-MS method is needed to simultaneously quantify RBV and its phosphorylated metabolites (RTP, ribavirin 5'-diphosphate and RMP). In a recombinant human UGT1A1 assay, the assay buffer components uridine and its phosphorylated derivatives are isobaric with RBV and its phosphorylated metabolites, leading to significant interference when analyzed by LC-MS with the nominal mass resolution mode. RESULTS: Presented here is a LC-MS method employing LC coupled with full-scan high-resolution accurate MS analysis for the simultaneous quantitative determination of RBV, RMP, ribavirin 5'-diphosphate and RTP by differentiating RBV and its phosphorylated metabolites from uridine and its phosphorylated derivatives by accurate mass, thus avoiding interference. CONCLUSION: The developed LC-high-resolution accurate MS method allows for quantitation of RBV and its phosphorylated metabolites, eliminating the interferences from uridine and its phosphorylated derivatives in recombinant human UGT1A1 assays. PMID- 22943621 TI - In silico prediction for the investigation of comedication interferences in quantitative LC-MS detection in the SRM mode. AB - BACKGROUND: LC-SRM/MS method validation in quantitative bioanalysis requires screening for potential interferences caused by the coelution of comedications or their metabolites. Current approaches are time-consuming, difficult to transfer to other experimental systems and not comprehensive. We propose an in silico strategy based on predicted LC retention time and MS precursor interferences to rank compounds that could potentially interfere with the analyte of interest, followed by a more focused experimental verification. RESULTS: The suggested screening strategy was applied to investigate 129 potential comedications in everolimus patient samples analyzed with a validated LC-SRM/MS assay. A mixture of analytes with the same nominal mass was also investigated to illustrate the interference issues in SRM method development. CONCLUSION: A strategy was developed that allows the rapid screening of comedications, which is scalable to any analyte and transferable to any other LC-MS system. PMID- 22943622 TI - Regulated drug bioanalysis for human pharmacokinetic studies and therapeutic drug management. AB - Regulated drug bioanalysis (i.e., determination of drug concentrations in biological matrices for regulated studies) usually refers to animal toxicokinetics, bioavailability/bioequivalence and clinical pharmacokinetic studies. However, there is another important regulated drug bioanalysis - therapeutic drug management (TDM). In the USA, TDM is regulated by Clinical Laboratory Improvement Amendments. In this article, we review and compare human pharmacokinetic sample analysis and TDM sample analysis. The US FDA/Bioanalytical Method Validation Guidance and the American Association for Clinical Chemistry/TDM Roundtable Recommended Generic Assay Validation Guidance are also compared. Some regulated drug bioanalysis issues, such as terminology, validation concepts and acceptance criteria, are discussed. Fostering interaction between bioanalysts from pharmaceutical science and clinical chemistry and reducing the regulatory gaps between different agencies for drug bioanalysis is our objective. PMID- 22943623 TI - Inductively coupled plasma-MS in drug development: bioanalytical aspects and applications. AB - The vast majority of today's modern bioanalytical methods for pharmacokinetic, pharmacodynamic and immunogenicity purposes are based on LC-MS/MS and immunoanalytical approaches. Indeed, these methodologies are suitable for a wide range of molecules from small to large. For a smaller but not insignificant group of compounds, LC-MS/MS is not suitable - or in some cases much less suitable - as a reliable bioanalytical methodology, and inductively coupled plasma (ICP)-MS is a more appropriate methodology. ICP-MS is one of these less widely used techniques in drug development. This methodology is predominantly used for elemental bioanalysis for pharmacokinetics, for imaging purposes, for mass balance, food-effect and biomarker studies. In addition, in the last couple of years an increasing number of applications has been published, where ICP-MS and its various hyphenations (LC-ICP-MS, CE-ICP-MS) have been used for speciation/metabolism and proteomics studies. Here, the analytical potential, the quantitative bioanalytical aspects, the various modes of operation and the challenges of the application of ICP-MS in life sciences applications are given. This includes an overview of recent applications in this area in scientific literature, the various hyphenation possibilities and their application areas and the analysis of the various sample matrices applicable to these fields. It also provides a brief outlook of where the potential of this technique lies in the future of regulated bioanalysis and drug development. PMID- 22943624 TI - In vitro fertilization stimulation protocol for normal responder patients. AB - The aim of this prospective observational study is to determine the different outcomes of IVF/ICSI treatments after using antagonists or agonists of gonadotrophin-releasing hormone (GnRH) for controlled ovarian hyperstimulation (COH) in normal responder patients. Two hundred forty-seven patients undergoing IVF treatment at the Centre of Reproductive Medicine, Rome (CERMER), from January 2005 to December 2008, were included in the study. Patients were stimulated either with a standard long protocol with GnRH agonists (n = 156) or with GnRH antagonists (n = 91). The use of GnRH antagonists resulted in a significant reduction in the duration of the stimulation (Agonist Group 14.10 +/- 2.25 vs Antagonist Group 11.34 +/- 2.11; p < 0.001) and in the amount of gonadotrophin (IU of r-FSH) needed (Agonist Group 1878 +/- 1109 vs Antagonist Group 1331 +/- 1049; p = 0.0014). Moreover a lower number of cycles were cancelled with the antagonist protocol (4.39 vs 6.41%). The GnRH antagonist protocol, when compared to the GnRH agonist one, is associated with a similar clinical pregnancy rate, similar implantation rate, significantly lower gonadotrophin requirement and shorter duration of stimulation. For this reason, GnRH antagonists might be a good treatment even for normal responder patients undergoing IVF. PMID- 22943625 TI - Engaging with economic evaluation methods: insights from small and medium enterprises in the UK medical devices industry after training workshops. AB - BACKGROUND: With increased governmental interest in value assessment of technologies and where medical device manufacturers are finding it increasingly necessary to become more familiar with economic evaluation methods, the study sought to explore the levels of health economics knowledge within small and medium-sized enterprises (SMEs) and to scope strategies they employ to demonstrate the value of their products to purchasers. METHODS: A short questionnaire was completed by participants attending one of five workshops on product development in the medical device sector that took place in England between 2007 and 2011. From all responses obtained, a large proportion of participants were based in SMEs (N = 43), and these responses were used for the analysis. Statistical analysis using non-parametric tests was performed on questions with approximately interval scales. Qualitative data from participant responses were analysed to reveal emerging themes. RESULTS: The questionnaire results revealed that 60% of SME participants (mostly company directors or managers, including product or project managers) rated themselves as having low or no knowledge of health economics prior to the workshops but the rest professed at least medium knowledge. Clinical trials and cost analyses or cost effectiveness studies were the most highly cited means by which SMEs aim to demonstrate value of products to purchasers. Purchasers were perceived to place most importance on factors of safety, expert opinion, cost-effectiveness and price. However many companies did not utilise formal decision-making tools to prioritise these factors. There was no significant dependence of the use of decision-making tools in general with respect to professed knowledge of health economics methods. SMEs did not state a preference for any particular aspect of potential value when deciding whether to develop a product. A majority of SMEs stated they would use a health economics tool. Research and development teams or marketing and sales departments would most likely use one. CONCLUSION: This study points to the need for further research into the education requirements of SMEs in the area of Health Technology Assessment (HTA) and also for investigation into how SMEs engage with existing HTA processes as required by assessors such as NICE. PMID- 22943626 TI - No gene flow across the Eastern Pacific Barrier in the reef-building coral Porites lobata. AB - The expanse of deep water between the central Pacific islands and the continental shelf of the Eastern Tropical Pacific is regarded as the world's most potent marine biogeographic barrier. During recurrent climatic fluctuations (ENSO, El Nino Southern Oscillation), however, changes in water temperature and the speed and direction of currents become favourable for trans-oceanic dispersal of larvae from central Pacific to marginal eastern Pacific reefs. Here, we investigate the population connectivity of the reef-building coral Porites lobata across the Eastern Pacific Barrier (EPB). Patterns of recent gene flow in samples (n = 1173) from the central Pacific and the Eastern Tropical Pacific (ETP) were analysed with 12 microsatellite loci. Results indicated that P. lobata from the ETP are strongly isolated from those in the central Pacific and Hawaii (F(ct) ' = 0.509; P < 0.001). However, samples from Clipperton Atoll, an oceanic island on the eastern side of the EPB, grouped with the central Pacific. Within the central Pacific, Hawaiian populations were strongly isolated from three co-occurring clusters found throughout the remainder of the central Pacific. No further substructure was evident in the ETP. Changes in oceanographic conditions during ENSO over the past several thousand years thus appear insufficient to support larval deliveries from the central Pacific to the ETP or strong postsettlement selection acts on ETP settlers from the central Pacific. Recovery of P. lobata populations in the frequently disturbed ETP thus must depend on local larval sources. PMID- 22943627 TI - WELL.ME - Wellbeing therapy based on real-time personalized mobile architecture, vs. cognitive therapy, to reduce psychological distress and promote healthy lifestyle in cardiovascular disease patients: study protocol for a randomized controlled trial. AB - BACKGROUND: There is compelling evidence that psychological factors may have the same or even greater impact on the possibility of adverse events on cardiac diseases (CD) than other traditional clinical risk factors. Anxiety and depression are predictors of short- and long-term adverse outcomes, increased risk for higher rates of in-hospital complications, re-infarction, malignant arrhythmias, and mortality in CD patients. Despite researchers finding that cognitive behavior therapy (CBT) reduced depressive and anxiety symptoms, the fact that such results are maintained only in the short term and the lack of maintenance of the long-term affects the absence of changes in lifestyles, preventing the possibility of a wide generalization of results. Recently wellbeing therapy (WBT) has been proposed as a useful approach to improve healthy lifestyle behaviors and reduce psychological distress. METHODS/DESIGN: The present randomized controlled study will test WBT, in comparison with CBT, as far as the reduction of symptoms of depression, anxiety and psychological distress, and the improvement of lifestyle behaviors and quality of life in cardiac patients are concerned. Moreover, innovations in communication technologies allow patients to be constantly followed in real life. Therefore WBT based on personalized mobile technology will allow the testing of its effectiveness in comparison with usual WBT. DISCUSSION: The present study is a large outpatient study on the treatment of co-morbid depression, anxiety, and psychological distress in cardiac patients. The most important issues of this study are its randomized design, the focus on promotion of health-related behaviors, and the use of innovative technologies supporting patients' wellbeing in real life and in a continuous way. First results are expected in 2012. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01543815. PMID- 22943628 TI - Cloning of aquaporin-1 of the blue crab, Callinectes sapidus: its expression during the larval development in hyposalinity. AB - BACKGROUND: Ontogenetic variation in salinity adaptation has been noted for the blue crab, Callinectes sapidus, which uses the export strategy for larval development: females migrate from the estuaries to the coast to spawn, larvae develop in the ocean, and postlarvae (megalopae) colonize estuarine areas. We hypothesized that C. sapidus larvae may be stenohaline and have limited osmoregulatory capacity which compromises their ability to survive in lower salinity waters. We tested this hypothesis using hatchery-raised larvae that were traceable to specific life stages. In addition, we aimed to understand the possible involvement of AQP-1 in salinity adaptation during larval development and during exposure to hyposalinity. RESULTS: A full-length cDNA sequence of aquaporin (GenBank JQ970426) was isolated from the hypodermis of the blue crab, C. sapidus, using PCR with degenerate primers and 5' and 3' RACE. The open reading frame of CasAQP-1 consists of 238 amino acids containing six helical structures and two NPA motifs for the water pore. The expression pattern of CasAQP-1 was ubiquitous in cDNAs from all tissues examined, although higher in the hepatopancreas, thoracic ganglia, abdominal muscle, and hypodermis and lower in the antennal gland, heart, hemocytes, ovary, eyestalk, brain, hindgut, Y organs, and gill. Callinectes larvae differed in their capacity to molt in hyposalinity, as those at earlier stages from Zoea (Z) 1 to Z4 had lower molting rates than those from Z5 onwards, as compared to controls kept in 30 ppt water. No difference was found in the survival of larvae held at 15 and 30 ppt. CasAQP-1 expression differed with ontogeny during larval development, with significantly higher expression at Z1-2, compared to other larval stages. The exposure to 15 ppt affected larval-stage dependent CasAQP-1 expression which was significantly higher in Z2- 6 stages than the other larval stages. CONCLUSIONS: We report the ontogenetic variation in CasAQP-1 expression during the larval development of C. sapidus and the induction of its expression at early larval stages in the exposure of hyposalinity. However, it remains to be determined if the increase in CasAQP-1 expression at later larval stages may have a role in adaptation to hyposalinity. PMID- 22943629 TI - Ultrasound assessment of oxaliplatin-induced neuropathy and correlations with neurophysiologic findings. AB - BACKGROUND AND PURPOSE: Chemotherapy-induced peripheral neuropathy is a major adverse effect of oxaliplatin (OXL) treatment. Whereas neurophysiologic study is commonly used to assess the occurrence and severity of polyneuropathies, ultrasound (US) analysis of the peripheral nerves, an emerging technique in the study of peripheral nerve diseases, has never been used in chemotherapy-induced peripheral neuropathy. PATIENTS AND METHODS: Fifteen patients (four women; 11 men; mean age, 60.1 +/- 10.6 years; median, 62; range, 37-75) with colorectal cancer treated with OXL-based treatment have been clinically and neurophysiologically evaluated before and after OXL therapy. At the end of chemotherapy, all patients underwent also nerve US study at four limbs, and the findings correlated with clinical and neurophysiologic measures. RESULTS: Clinical and neurophysiological evaluation showed that 13 of 15 (86.7%) patients developed sensory axonal neuropathy, 10 of whom severe (two or more sensory nerve action potential amplitude absent and the other amplitudes decreased of >=50%). Nerve US did not reveal decreased cross-sectional area (CSA), a reported finding in axonal neuropathies. Instead increased CSA at entrapment sites (median nerve at wrist and ulnar nerve at elbow) was found in 09/15 (60%) of patients. DISCUSSION: Sensory axonal neuropathy is a very common complication of OXL therapy, affecting almost 90% of patients. US findings of enlargement of median and ulnar nerves, mostly at entrapment sites, in patients with no history or symptoms of neuropathies at recruitment, and no neurophysiologic evidence of entrapment, may be expression of increased, OXL-induced, nerve susceptibility to mechanical damage. An ongoing prospective study will help clarify these findings. PMID- 22943630 TI - Usefulness of fluorodeoxyglucose positron emission tomography in malignancy of pulmonary artery mimicking pulmonary embolism. AB - BACKGROUND: The role of (18) F-fluorodeoxyglucose positron emission tomography/computed tomography ((18) F-FDG PET/CT) in evaluating pulmonary artery lesions has not yet been established. The purpose of this study is to evaluate the usefulness of (18) F-FDG PET/CT imaging in differentiating malignant from benign pulmonary artery (PA) lesions. METHODS: In this retrospective study, 18 subjects with 26 low-attenuated filling defects suspicious for PA malignancy on contrast-enhanced chest CT were enrolled; all of whom subsequently underwent (18) F-FDG PET/CT. The maximum standardized uptake value (SUVmax) for all PA lesions, defined as the (18) F-FDG uptake, was measured. The final diagnosis was then determined by pathological findings, follow-up chest CT or clinical follow-up, and compared with the PET imaging. RESULTS: In total, 6 PA sarcomas, 5 tumour embolism, and 15 pulmonary thromboembolism (PTE) occurred in this cohort. Not only was the SUVmax of the malignant PA lesions (10.2 +/- 10.8) was significantly higher than that associated with PTE (1.7 +/- 0.3; P < 0.001), no overlap occurred between groups. Conversely, no statistically significant difference in SUVmax occurred between PA sarcomas (12.8 +/- 14.7) and tumour embolism (7.0 +/- 1.32; P = 1.000). CONCLUSIONS: (18) F-FDG PET/CT is a useful imaging modality for differentiating malignant from benign PA lesions in patients with inconclusive low-attenuation filling defects on contrast-enhanced chest CT. PMID- 22943631 TI - Genetic divergence and molecular phylogenetics of Puntius spp. based on the mitochondrial cytochrome b gene. AB - Puntius is an important genus of freshwater food and ornamental fish belonging to the family Cyprinidae. A total of 60 samples from twelve species of the genus Puntius were collected from eight sampling sites of eight Indian Rivers. Twelve species of Puntius (P. chola, P. sophore, P. filamentosus, P. fasciatus, P. vittatus, P. chelynoides, P. gonionotus, P. denisonii, P. ticto, P. gelius, P. conchonius and P. sarana) were investigated using 60 partial sequences of the mitochondrial cytochrome b (Cyt b, 1096 bp) gene to estimate genetic divergence and to establish the phylogenetic relationship. The average intraspecies diversity was estimated as 0.002, whereas the average interspecies diversity was estimated as 0.177. The sequence analysis of the Cyt b gene revealed four distinct groups, which are genetically distinct species and exhibited identical phylogenetic relationship. The present study validated the utility of the Cyt b gene in genetic diversity and phylogenetic studies. PMID- 22943632 TI - The use of a weaning and extubation protocol to facilitate effective weaning and extubation from mechanical ventilation in patients suffering from traumatic injuries: a non-randomized experimental trial comparing a prospective to retrospective cohort. AB - PURPOSE: Many patients who have suffered traumatic injuries require mechanical ventilation (MV). Weaning is the transition from ventilatory support to spontaneous breathing. The purpose of this study was to determine whether the use of a nurse and a physiotherapist-driven protocol to wean and extubate patients from MV resulted in decreased MV days and intensive care unit (ICU) length of stay (LOS). METHODS: A prospective cohort of 28 patients (Phase I), weaned according to the protocol developed for the Union Hospital Trauma Unit, was matched retrospectively with a historical cohort of 28 patients (Phase II), weaned according to physician preference. Pairs in the two groups were matched for gender, age, type, and severity of injury. RESULTS: For mean MV days, the groups did not differ statistically significantly (p 0.3; 14.4 days vs. 16.3 days), although the reduction in MV is clinically significant in view of the complications of additional MV days. The difference of 0.2 days for ICU LOS was not statistically significant (p = 0.9; 20.8 days vs. 21.0 days) demonstrating that the reduction in MV days may not result in the reduction of ICU LOS. The rate of re-intubation was similar between the groups (Phase I = 3/28 vs. Phase II = 4/24). CONCLUSION: The use of a weaning and extubation protocol led by nursing staff and physiotherapists resulted in a clinically significant reduction in MV time, reducing risk of ventilator-associated complications. The role of physiotherapists and nursing staff in weaning and extubation from MV could be greatly expanded in South African ICUs. PMID- 22943634 TI - Evidence for the early clinical relevance of hallucinatory-delusional states in the general population. AB - OBJECTIVE: To analyze, in a general population sample, clustering of delusional and hallucinatory experiences in relation to environmental exposures and clinical parameters. METHOD: General population-based household surveys of randomly selected adults between 18 and 65 years of age were carried out. SETTING: 52 countries participating in the World Health Organization's World Health Survey were included. PARTICIPANTS: 225 842 subjects (55.6% women), from nationally representative samples, with an individual response rate of 98.5% within households participated. RESULTS: Compared with isolated delusions and hallucinations, co-occurrence of the two phenomena was associated with poorer outcome including worse general health and functioning status (OR = 0.93; 95% CI: 0.92-0.93), greater severity of symptoms (OR = 2.5 95% CI: 2.0-3.0), higher probability of lifetime diagnosis of psychotic disorder (OR = 12.9; 95% CI: 11.5 14.4), lifetime treatment for psychotic disorder (OR = 19.7; 95% CI: 17.3-22.5), and depression during the last 12 months (OR = 11.6; 95% CI: 10.9-12.4). Co occurrence was also associated with adversity and hearing problems (OR = 2.0; 95% CI: 1.8-2.3). CONCLUSION: The results suggest that the co-occurrence of hallucinations and delusions in populations is not random but instead can be seen, compared with either phenomenon in isolation, as the result of more etiologic loading leading to a more severe clinical state. PMID- 22943633 TI - Effect of blueberry juice on clearance of buspirone and flurbiprofen in human volunteers. AB - AIM: The present study evaluated the possibility of drug interactions involving blueberry juice (BBJ) and substrate drugs whose clearance is dependent on cytochromes P4503A (CYP3A) and P4502C9 (CYP2C9). METHODS: A 50:50 mixture of lowbush and highbush BBJ was evaluated in vitro as an inhibitor of CYP3A activity (hydroxylation of triazolam and dealkylation of buspirone) and of CYP2C9 activity (flurbiprofen hydroxylation) using human liver microsomes. In clinical studies, clearance of oral buspirone and oral flurbiprofen was studied in healthy volunteers with and without co-treatment with BBJ. RESULTS: BBJ inhibited CYP3A and CYP2C9 activity in vitro, with 50% inhibitory concentrations (IC50 ) of less than 2%, but without evidence of mechanism-based (irreversible) inhibition. Grapefruit juice (GFJ) also inhibited CYP3A activity, but inhibitory potency was increased by pre-incubation, consistent with mechanism-based inhibition. In clinical studies, GFJ significantly increased area under the plasma concentration time curve (AUC) for the CYP3A substrate buspirone. The geometric mean ratio (GMR = AUC with GFJ divided by AUC with water) was 2.12. In contrast, the effect of BBJ (GMR = 1.39) was not significant. In the study of flurbiprofen (CYP2C9 substrate), the positive control inhibitor fluconazole significantly increased flurbiprofen AUC (GMR = 1.71), but BBJ had no significant effect (GMR = 1.03). CONCLUSION: The increased buspirone AUC associated with BBJ is quantitatively small and could have occurred by chance. BBJ has no effect on flurbiprofen AUC. The studies provide no evidence for concern about clinically important pharmacokinetic drug interactions of BBJ with substrate drugs metabolized by CYP3A or CYP2C9. PMID- 22943635 TI - Implications of inaccurate venous thromboembolism risk assessments in ENT practice: our experience in eighty six patients. PMID- 22943636 TI - Are surgeon's content with the current surgical headgear systems? AB - Medical devices such as 'surgical headgears' are used by surgeons during certain micro-surgical applications requiring enhanced vision and magnification. The main aim of the study was to investigate the clinical usability of existing headgear, the prevalence of discomfort experienced by surgeons frequently using such devices and ascertain if the surgeons are content with the existing headgear systems. Online semi-structured questionnaires were sent to 200 surgical consultants hailing from six different sub-specialities currently practicing in various National Health Service (NHS) trusts in the UK. Data collected from the questionnaires were descriptively analysed. Vital issues pertaining to weight (36%), distraction (50%), pain and strain around the areas of head (56%), neck (26%), nose (28%), ears (16%), neck and back muscles (30%) were reported by the surgeons. In conclusion, 70% of surgeons are not content with the current headgear systems. Consequently, they foresee a need for an efficient and improved headgear system. PMID- 22943637 TI - [Chinese expert consensus statement on diagnosis and treatment of right heart failure]. PMID- 22943638 TI - [Prognostic value of admission B-type natriuretic peptide on outcome for patients with congestive heart failure]. AB - OBJECTIVE: To observe the prognostic value of admission B-type natriuretic peptide (BNP) on outcome for patients with congestive heart failure (CHF). METHODS: Blood BNP levels, routine echocardiography and tissue Doppler image were obtained in 162 CHF patients [95 male, mean age: (71.8+/-3.7) years] at admission. Patients were divided into high BNP (BNP>1500 ng/L, n=104) and low BNP (BNP<=1500 ng/L, n=58) groups. All patients were followed up for 2 years and clinical characteristics, echocardiography including Doppler image and cardiovascular events results were analyzed. Data were also compared between patients with (n=48) or without (n=107) cardiovascular events. RESULTS: Left ventricular ejection fractions (LVEF) was significantly lower [(40.9+/-5.6)% vs. (44.0+/-5.9)%, P<0.01] while the total cardiovascular events rate (49.1% vs. 21.0%, P<0.01) and cardiac mortality rate (25.5% vs. 9.0%, P<0.01) were significantly higher in high BNP group than in low BNP group. BNP level at admission in event group was significantly higher than in event-free group [(2875.4+/-325.7) ng/L vs. (1136.9+/-298.6) ng/L, P<0.000]. BNP level was positively related to Tei-index (r=0.793, P<0.001) and negatively correlated with LVEF (r=-0.57, P<0.001). Multiple logistic regression analysis demonstrated that BNP, LVEF, Tei-index and beta-blocker use were independent risk factors for cardiovascular events. The area under the ROC curve for predicting cardiovascular death within 2 years in event group by BNP was 0.795 (95%CI 0.693-0.935, sensitivity: 72.31% and specificity: 84.62%, cut-off BNP value: 1910 ng/L). The event risk was 2.17 times higher in CHF patients with admission BNP>1910 ng/L compared CHF patients with admission BNP<=1910 ng/L (95%CI: 1.852-2.954, P=0.000). CONCLUSION: Admission BNP level, LVEF, Tei-index and beta-blocker use are independent risk factors for cardiovascular events in patients with CHF. Patients with higher admission BNP level (>1910 ng/L) is linked with worse prognosis in this patient cohort. PMID- 22943639 TI - [Action potential duration restitution and the potential association with ventricular arrhythmia in Langendorff-perfused chronic heart failure rabbit hearts]. AB - OBJECTIVE: To observe the action potential duration restitution (APDR) change and potential association with ventricular arrhythmia (VA) in Langendorff-perfused chronic heart failure rabbit hearts. METHODS: Male rabbits were randomly divided into two groups: control (CTL, n=15) group and chronic heart failure (CHF, n=15) group. CHF was induced by injecting isoproterenol (300 ug*kg(-1) *d(-1)) for 14 days. Four weeks later, cardiac function and structure change of both groups were assessed by echocardiography. In the whole Langendorff-perfused hearts, the monophasic action potential (MAP) and the effective refractory period (ERP) were recorded from left anterior basal ventricle, left anterior free wall, left anterior apex and left posterior basal ventricle, left posterior free wall and left posterior apex, the APD curves were also constructed in both groups; at the six sites of every isolated heart, the programmed electrical stimulation and burst pacing were used to induce action potential duration (APD) alternans and VA, respectively. RESULTS: Left ventricular ejection was reduced and end dimension was enlarged in rabbits of CHF group. Compared with the same sites of CTL group, the 90% of MAP duration (MAPD90), the ERP, the max slope (Smax) of APDR curves, the pacing cycle length of inducing the APD alternans and the VAs were significantly increased (all P<0.05) in CHF group; the spatial dispersions of MAPD90, ERP and Smax of APDR curves in CHF group were also greater than in CTL group (all P<0.05). CONCLUSION: The ventricular APD alternans might be linked with occurrence of the VA in CHF rabbits. Increase of the Smax from APDR curves and the spatial dispersions of Smax in this CHF model might facilitate the development of ventricular arrhythmia. PMID- 22943640 TI - [Predictive value of corrected QT interval, corrected Tp-e interval and Tp-e/QT ratio on malignant arrhythmia events in acute ST-segment elevation myocardial infarction patients undergoing thrombolysis]. AB - OBJECTIVE: The prognostic value of corrected QT interval (QTc), corrected Tp-e interval (Tp-ec) and Tp-e/QT ratio on occurrence of malignant arrhythmia events (MAE) in acute ST-segment elevation myocardial infarction (STEMI) patients underwent successful thrombolysis was explored and the potential association of these indices with MAE was analyzed. METHODS: Fifty-seven STEMI patients underwent successful thrombolytic therapy within 6 hours after admission and conservative medical treatment were included. QTc, Tp-ec, Tp-e/QT ratio were obtained and calculated in infarct-related electrocardiograph leads and non infarct-related leads before thrombolysis, (7+/-1) days and (30+/-3) days after thrombolysis respectively, and incidence of MAE up to 30 days after thrombolysis was analyzed. Sixty age and gender matched normal subjects served as control group. RESULTS: (1) QTc, Tp-ec, Tp-e/QT in infarct-related and non-infarct related leads in STEMI group before thrombolysis were significantly higher than those in control group (all P<0.05), and values from the infarct-related leads were significantly higher than those from non-infarct-related leads in STEMI group (all P<0.05). QTc, Tp-ec and Tp-e/QT all significantly and continuously reduced from 7 days and at 30 days post thrombolysis compared the before thrombolysis (P<0.05 vs. before thrombolysis). (2) Tp-ec>=100 ms and Tp-e/QT ratio>=0.25 before thrombolysis in infarct-related leads were linked with higher incidence of MAE within 30 days post thrombolysis in this patient cohort [28.1% (9/32) vs. 40% (1/25), 27.8% (10/36) vs.0, respectively, all P<0.05]. CONCLUSION: QTc, Tp-ec and Tp-e/QT values decreased post successful thrombolysis in STEMI patients and higher Tp-ec and Tp-e/QT values before thrombolysis in STEMI patients were related with higher MAE incidence up to 30 days post successful thrombolysis in this patient cohort. PMID- 22943641 TI - [Development of the high resolution melting method for genotyping CYP2C9*3 (1075A/C, rs1057910) and VKORC1 (-1639A/G, rs9923231)]. AB - OBJECTIVE: To establish the high-resolution melting curve (HRM) approach for genotyping CYP2C9*3 (1075A/C, rs1057910) and VKORC1 (-1639A/G, rs9923231) and explore its value on estimation of the Warfarin initial dose in comparison with various traditional genotyping methods. METHODS: CYP2C9*3 (1075A/C, rs1057910) and VKORC1 (-1639A/G, rs9923231) genotyping was detected in 100 patients receiving Warfarin therapy by the newly developed HRM method and traditional genotyping methods including PCR-restriction fragment length polymorphism (PCR RFLP), TaqMan probe and DNA sequencing. RESULTS: The results of the genotypes obtained from above mentioned methods to detect CYP2C9*3 (1075A/C, rs1057910) and VKORC1 (-1639A/G, rs9923231) were similar and consistent. The HRM method is simpler, more economical, and faster compared to the traditional methods. The frequencies of the VKORC1-1639 AA, AG, GG genotypes from these 100 clinical samples were 73 (73%), 23 (23%), 4 (4%), respectively; Frequencies of the CYP2C9 1075 AA, AC, CC genotypes were 94(94%), 6 cases (6%), 0, respectively. CONCLUSIONS: HRM approach can effectively detect CYP2C9*3 (1075A/C, rs1057910) and VKORC1 (-1639A/G, rs9923231) polymorphisms and this method is simpler, more economical, and faster compared to the traditional methods for detecting CYP2C9*3 (1075A/C, rs1057910) and VKORC1 (-1639A/G, rs9923231) polymorphisms. PMID- 22943642 TI - [Increased platelet-leukocyte aggregates in patients with acute coronary syndrome]. AB - OBJECTIVE: To compare the platelet-leukocyte-aggregates (PLAs) level among patients with acute coronary syndrome (ACS) and stable angina pectoris (SAP). METHODS: Hospitalized patients were divided into three groups [ACS group (n=86), SAP group (n=54), the control group with 46 patients without coronary artery disease]. PLAs were measured by flow cytometry at admission before coronary angiography. ACS patients were further divided into low-risk group (0-108 points) and high-risk group (>109 points) according to GRACE scores at admission. PLA, platelet-monocyte aggregations (PMA), platelet-neutrophil aggregations (PNA), platelet-lymphocyte aggregations (PlyA) and hs-CRP values were compared among groups. RESULTS: PLA (4.40%+/-3.08%), PMA (33.6%+/-21.5%), PNA (3.76%+/-5.06%), PLyA (2.03%+/-1.27%) and hs-CRP [5.75 (3.49, 9.15)] levels in ACS group were significantly higher than those in SAP and control groups (all P<0.05). PLA was also significantly higher in high-risk group than in the low-risk group (44.8%+/ 18.0% vs. 13.0%+/-6.3%, P<0.01). Spearman correlation analysis showed that hs-CRP was positively correlated with PMA (r=0.547, P<0.01) and GRACE score is positively correlated with PMA, PLA, PNA and PlyA (r=0.746, 0.652, 0.460, respectively, all P<0.01). CONCLUSION: PLAs is increased in ACS patients and higher PMA level is related with the unstable coronary syndrome in ACS patients. Increased PMA, PLA, PNA and PlyA levels is associated with higher GRACE score in ACS patients. PMID- 22943643 TI - [Diagnostic value of 320-slice computed tomography coronary angiography to assess in-stent restenosis]. AB - OBJECTIVE: To evaluate the diagnostic accuracy of 320-slice CT coronary angiography (CTA) in the evaluation of in-stent restenosis (ISR, >=50% luminal narrowing) in comparison with quantitative coronary angiography (CAG). METHODS: A total of 69 patients with previous stent implantation who underwent both CTA and CAG were prospectively included. We assessed diagnostic valve for ISR with CTA in comparison with CAG. RESULTS: A total of 110 stents were implanted in these patients.CAG identified 14 ISR. CTA correctly identified 13 ISR and misdiagnosed 5 ISR in stents without ISR. Besides, 6 stents could not be evaluated by CTA due to unsatisfied image quality. Accordingly, sensitivity, specificity, positive and negative predictive value of CTA for diagnosing ISR were 93%, 89%, 54% and 99%, respectively. The image quality of CTA was significantly better in larger stents (percentages of good and moderate stent image of >=3.0 mm and <3.0 mm: 56% vs. 27%, 25% vs. 49%) and which was linked with better diagnostic coincidence rate (95% vs. 78%) for larger stents. The image quality of CTA was significantly better in stents with thinner stent strut thickness (percentages of poor CTA stent image quality of stent strut thickness<140 um and >=140 um: 12% vs. 45%, P<0.01) and which was associated with better diagnostic coincidence rate for stents with thinner stent strut thickness (94% vs. 76%, P<0.05). The image quality of CTA was also significantly better in single stent (percentages of poor CTA stent image quality of single stent vs. overlap and dedicated stent: 17% vs. 36%, P<0.05). However, heart rate (>=65 beats/min vs. <65 beats/min) during CTA acquisition was not associated with image quality and the diagnostic coincidence rate (all P>0.05). CONCLUSIONS: Our results indicate that 320-slice CTA allows accurate noninvasive assessment of significant in-stent restenosis in selected patients. Stents with a large diameter and thin struts are associated with better image quality and higher diagnostic accuracy. PMID- 22943644 TI - [Quality of life changes after coronary artery bypass graft surgery]. AB - OBJECTIVE: To compare the quality of life at baseline and at 6 months after coronary artery bypass grafting (CABG) and investigate the related risk factors. METHODS: The prospective study included 210 consecutive patients undergoing CABG between November 2008 and March 2010, who met inclusion criteria and completed short form-36 (SF-36) health status survey at baseline and at 6 months after CABG. Change of quality of life and influencing factors on quality of life were analyzed. RESULTS: Eight domains including physical functioning, role-physical, bodily pain, general health, vitality, social functioning, role-emotional and mental health and two component summaries including physical component summary (PCS) and mental component summary (MCS) of SF-36 were significantly improved at 6 months following CABG (all P<0.01). Moreover, the improvement on PCS was significantly higher compared to MCS (80.0% vs. 68.6%, P<0.01). Advanced age (P<0.05) and lower PCS score (P<0.01) prior to CABG were independent predictors of low PCS after CABG, while MCS could not be predicted by pre-CABG status (P>0.05). CONCLUSIONS: The findings demonstrate quality of life is significantly improved at 6 months post CABG. Advanced age and lower PCS score prior to CABG are linked with low PCS after CABG. PMID- 22943645 TI - [Predictive factors of chronic thromboembolic pulmonary hypertension in patients with acute pulmonary thromboembolism]. AB - OBJECTIVE: To evaluate the incidence and predictive factors of chronic thromboembolic pulmonary hypertension (CTEPH) in patients with acute pulmonary thromboembolism (PTE). METHODS: Clinical data of 104 patients with CT angiography proven PTE were collected and Wells score, revised Geneva score and ECG score were calculated. Blood gas analysis, CK-MB and D-dimer values were analyzed. Heart chamber diameters and pulmonary artery systolic pressure (PASP) were assessed by echocardiography. Qanadli obstruction index and Mastora obstruction index were evaluated according to computed tomography pulmonary angiography (CTPA). Patients were followed up by telephone or clinic visit to assess the WHO functional class and the incidence of CTEPH. RESULTS: During the 25.47+/-16.94 months (4 to 62 months) follow-up, 7 out of 104 patients were lost to follow-up and data from the remaining 95 patients were analyzed. The incidence of CTEPH was 14.4% (14/97). Baseline PASP, incidence of recurrent PTE, right atrium and right ventricle diameters and CK-MB were significantly higher in CTEPH group compared to non-CTEPH group (all P<0.05). Higher CK-MB (odds ratio: 8.3) and baseline PASP (odds ratio: 5.0 per 20 mm Hg increment) were independent predictive factors for CTEPH in this cohort. CONCLUSIONS: Higher CK-MB and baseline PASP values are independent predictive factors related to the development of CTEPH post acute pulmonary thromboembolism. PMID- 22943646 TI - [Management of refractory ventricular tachycardia in patients with non-myxomas primary cardiac tumors]. AB - OBJECTIVE: To summarize the clinical characteristics and treatment experience of patients with non-myxomas primary cardiac tumors accompanied with refractory ventricular tachycardia (VT). METHODS: Clinical and imaging data as well as therapy efficacy and outcome were analyzed in 10 patients with non-myxomas primary cardiac tumors accompanied with refractory VT. RESULTS: There were 5 male and 5 female patients in this cohort [mean age (37.6+/-18.2) years]. Palpitation was presented in all 10 patients, 7 patients experienced syncope, and 2 patients suffered from amaurosis. The diagnosis was made by combined use of transthoracic echocardiograms, MRI, and CT scan. The time from symptom to diagnosis was (33.2+/ 36.7) months. Symptom-related VT was documented by ECG or Holter monitoring. MRI suggested lipoma in 7 patients, lymphoma in 1 patient and fibroma in another patient. Seven tumors were located in the left ventricle, 1 in right atria, 1 at peri-aortic root and 1 near right ventricular outflow tract. Nine out of 10 patients received anti-arrhythmic drug therapy. The ventricular tachyarrhythmia disappeared after surgical tumor resection in 4 patients. All other patients who were treated with antiarrhythmic drugs, radiofrequency ablation or subtotal excision showed only suboptimal efficacy during (39.4+/-25.1) months follow-up. CONCLUSION: Surgical tumor removal is the best treatment strategy for the treatment of refractory ventricular tachycardia in patients with primary cardiac benign tumors. PMID- 22943647 TI - [Aortic artery elastic lamina degradation, collagen remodeling, oxides stress and inflammation in the apolipoprotein E deficient mice with or without aortic banding]. AB - OBJECTIVE: To explore the elastic lamina degradation and the collagen remodeling of aortic artery as well as oxides stress and inflammation of the apolipoprotein (Apo E) deficient mice with or without experimental hypertension. METHODS: Eighty male Apo E deficient mice were fed with high-fat diet beginning at six weeks of age. At 8-week old, they were randomly divided into hypertension group and control group (n=40 each), the mice in hypertension group were subjected the suprarenal aortic constriction operation and then randomly divided into two subgroups: 15 weeks age and 30 weeks age groups. At the end of experiment, the vascular elastic lamina degradation and the content of collagen were determined by morphological method, plasma ICAM-1 level was measured by ELISA, and the rennin activity measured by radioimmunoassay, the superoxide anion detected by fluorescence, the MOMA-2 observed by immunofluorescence in all animals. mRNA expression of NF-kappaB P65 and MMP9 was detected by real-time PCR. RESULT: In 15 week old group, the elastic lamina degradation Grade II and the intima-media thickness in the hypertension group were significantly higher than in the control group [(5.4+/-3.3)% vs. (8.9+/-2.5)%, P<0.05; (98.66+/-18.90) um vs. (70.08+/ 11.71) um, P<0.05]. In 30-week old group, the elastic lamina degradation Grade III, the III type of collagen and the intima-media thickness were also significantly higher than in the control group [(15.2+/-3.7)% vs. (8.1+/-3.3)%, P<0.01; (23.00+/-7.73)% vs. (11.00+/-3.82)%, P<0.05; (147.31+/-22.60) um vs. (103.98+/-17.21) um, P<0.01]. The level of ICAM-1 in hypertension group was significantly higher than that of control group in both 15-week old and in 30 week old mice [(46.3+/-3.7) ug/ml vs. (40.6+/-5.7) ug/ml, P<0.05; (56.0+/-3.1) ug/ml vs. (45.2+/-2.8) ug/ml, P<0.05]. The superoxide anion, the MOMA-2, mRNA expression of NF-kappaB P65 and MMP9 in the hypertension group were significantly higher than in the control group in both 15-week old and in the 30-week old mice. The increase in hypertension group was more pronounced in the 30-week old mice than in the 15-week old mice. CONCLUSION: The elastic lamina degradation and the collagen remodeling of aortic artery as well as oxides stress and inflammation are more significant in the Apo E deficient mice with hypertension than in control Apo E deficient mice. PMID- 22943648 TI - [Role of valsartan on myocardial Calpain I, calcineurin and Ca/calmodulin dependent protein kinase IIdelta expression of renovascular hypertensive rats]. AB - OBJECTIVE: To determine the protein expression of Calpain I, mRNA and protein expressions and activity of calcineurin, and the alternative splicing of Ca/calmodulin-dependent protein kinase II (CaMKII) delta in the hypertrophic heart, and to investigate the effect of angiotensin II type 1 receptor blocker valsartan (Val) on cardiac hypertrophy and the level of Calpain I, calcineurin and CaMKIIdelta in renovascular hypertensive rats model. METHODS: Rats were randomly divided into sham-operated control (n=8), hypertension (n=8) and hypertension plus Val (n=8, 30 mg*kg(-1)*(-1)). The renovascular hypertension was induced by two kidney-one clip methods in rats. The ratio of left ventricular weight to body weight was measured, the mRNA expression of calcineurin and alternative splicing of CaMKIIdelta were determined by RT-PCR, the protein expression of Calpain I and calcineurin were measured by Western blot and the activity of calcineurin activity was assayed by a specialized kit. RESULTS: Eight weeks after procedure, hypertension rats developed significantly cardiac hypertrophy, and the protein expression of Calpain I, mRNA and protein expression and the activity of calcineurin were significantly increased compared sham operated control rats (all P<0.01), the mRNA expression of CaMKIIdeltaA and B increased, CaMKIIdeltaC mRNA decreased (P<0.01). Treatment with valsartan effectively attenuated cardiac hypertrophy and reversed hypertension induced changes on myocardial Calpain I, calcineurin and CaMKIIdelta. CONCLUSION: Valsartan attenuates cardiac hypertrophy in renovascular hypertensive rats, possibly through inhibiting Calpain I, calcineurin and CaMKIIdelta signaling pathways. PMID- 22943649 TI - [The effect of mitochondrial oxidative stress and the expression of Bcl-2 and Bax proteins on cardiomyocyte apoptosis during hypoxia postconditioning]. AB - OBJECTIVE: To investigate mitochondrial oxidative stress on cardiomyocyte apoptosis and the expression of Bcl-2 and Bax proteins in cardiac sarcolemma and mitochondria after application of hypoxia postconditioning and free radical scavengers. METHODS: Primary cultured neonatal rat cardiomyocytes were exposed to 3 h hypoxia (H) followed by (1) 6 h of reoxygenation (R) (H/R), (2) 3 intermittent cycles of 5 min H and R before 6 h of R (PC), (3) application of superoxide dismutase (SOD) before PC (SOD+PC), (4) application of catalase (CAT) before PC (CAT+PC), and (5) application of SOD plus CAT before PC (SOD+CAT+PC). Cardiac sarcolemma and mitochondria were isolated by differential centrifugation. Mitochondrial reactive oxygen species (ROS) was detected with fluorescent probes (DCFH-DA) and cardiomyocyte apoptosis was detected with flow cytometry. The expressions of Bcl-2 and Bax proteins in cardiac sarcolemma and mitochondria were measured by Western blot. RESULTS: Mitochondrial ROS reduced significantly in PC, SOD+PC, CAT+PC and especially in SOD+CAT+PC groups (all P<0.01). The number of apoptotic cardiomyocytes reduced significantly in PC, SOD+PC and CAT+PC (all P<0.01) but not in SOD+CAT+PC groups. Bcl-2 levels increased while Bax levels decreased in cardiac sarcolemma and mitochondria in PC, SOD+PC and CAT+PC groups (all P<0.01), Bcl-2 levels decreased and Bax levels increased in H/R and PC+SOD+CAT groups (all P<0.01). CONCLUSIONS: PC attenuated H/R induced ROS and cardiomyocyte apoptosis, which might be mediated by upregulating the expression of Bcl-2 and downregulating the Bax in mitochondria and sarcolemma; SOD or CAT alone did not but SOD plus CAT attenuate the anti-apoptotic effect of hypoxia postconditioning; mitochondrial ROS thus plays an important role in PC's cardioprotection. PMID- 22943650 TI - [Effects of astragali radix extract on matrix metalloproteinase 9 expression and atherosclerotic plaque formation in aorta of apolipoprotein E deficient mice fed with high fat diet]. AB - OBJECTIVE: To explore the effects of astragali radix extract on the expressions of matrix metalloproteinase 9 (MMP-9) and the formation of atherosclerotic plaque in aortic atherosclerotic plaques of apolipoprotein E-deficient mice (ApoE-/-). METHODS: Male 8-week-old ApoE-/- mice fed with high fat diet were randomly divided into four groups (n=12 each): control group (saline 0.2 ml/d), atorvastatin group (atorvastatin 10 mg*kg(-1)*d(-1)), low-dose astragali radix extract group (1.25 g*kg(-1)*d(-1)) and high-dose astragali radix extract group (5 g*kg(-1)*d(-1)). After 12 weeks, serum oxLDL was measured by the method of ELISA. The formation of atherosclerotic plaque was determined in HE and oil red O stained aortic slice. The expressions of macrophage and MMP-9 in the aortic plaque were detected by immune fluorescence and immunohistochemistry staining method. RESULTS: Similarly as atorvastatin, astragali radix extract significantly decreased the level of serum oxLDL in ApoE-/-1 mice in a dose-dependent manner. The level of oxLDL in the high-dose astragali radix extract group [(5.2+/-6.1) ug/ml] was significantly lower than that in the control group [(15.8+/-5.4) ug/ml, P<0.01]. The area of atherosclerosis plaques was smaller (17.24%+/-4.22% vs. 49.87%+/-9.37%, P<0.01) and the penetration degree of plaques in the arterial wall was relieved in the high-dose astragali radix extract group compared to those in the control group (P<0.01). The expressions of Mac3 in atherosclerosis plaques of the high-dose astragali radix extract group was also significantly lower than in the control group (P<0.01). The mean absorbance value of the expression of MMP-9 in the high-dose astragali radix extract group (0.0154+/ 0.0014)was significantly lower than that in the control group (0.0263+/-0.0065) (P<0.01). CONCLUSIONS: Similar as atorvastatin, astragali radix extract can dose dependently inhibit the expression of MMP-9 and the formation of the atherosclerotic plaque in ApoE-/- mouse, probably by reducing the serum oxLDL, inhibiting macrophage infiltration, migration and secretion of MMP-9. PMID- 22943651 TI - [Prevalence and awareness of hypertension in Gansu Gannan Tibetan adult population]. AB - OBJECTIVE: To investigate the prevalence and awareness status of hypertension in adult Gansu Gannan Tibetan population. METHODS: A total of 6948 adult (aged 18 and over) Tibetan residents were selected by random cluster multistage method. Participants were divided into city, rural dwellers and rural nomads groups. Questionnaires were collected and blood pressure measured from all participants. RESULTS: Prevalence of hypertension in this district was 24.6% (1708/6948), of which city, rural dwellers and nomadic areas were 25.3% (848/3340), 22.7% (628/2765), 27.5% (232/843), respectively. Prevalence of hypertension was significantly higher in city than in rural dwellers group (P<0.05), significantly higher in rural nomads group than in city and rural dwellers groups (all P<0.05). Awareness, treatment and control rates of hypertension in city group were 35.7% (303/848), 25.1% (213/848), 6.9% (59/848), respectively; in rural dwellers group were 28.3% (178/628), 19.3% (121/628), 4.7% (30/628), respectively; in rural nomads group were 16.8% (39/232), 8.6% (20/232), 2.2% (5232), respectively. Rates of awareness, treatment and control were significantly lower in rural dwellers than in city group (all P<0.01), and significantly lower in rural nomads group than in city and rural dwellers groups (all P<0.01). CONCLUSIONS: Prevalence of hypertension in Gansu Gannan Tibetan population aged 18 and over is high. Awareness, treatment and control rates of hypertension are low, especially in rural dwellers and rural nomads residents. PMID- 22943652 TI - [A case of pulmonary embolism induced by pulmonary valve endocarditis]. PMID- 22943653 TI - [Sleep apnea syndrome and pulmonary hypertension]. PMID- 22943654 TI - [Research advances on myocardial repair using very small embryonic-like stem cells]. PMID- 22943655 TI - [A review on bone marrow-derived fibrocytes and its relationship with myocardial fibrosis]. PMID- 22943656 TI - Intestinal malrotation with suspected cow's milk allergy: a case report. AB - BACKGROUND: Intestinal malrotation is an incomplete rotation of the intestine. Failure to rotate leads to abnormalities in intestinal positioning and attachment that leave obstructing bands across the duodenum and a narrow pedicle for the midgut loop, thus making it susceptible to volvulus. One of the important differential diagnoses for malrotation is an allergy to cow's milk. Several studies have described infants with surgical gastrointestinal diseases and cow's milk allergy. However, to our knowledge, no study has reported infants with intestinal malrotation who have been symptomatic before surgery was performed and have been examined by allergen-specific lymphocyte stimulation test and food challenge tests with long-term follow-up. CASE PRESENTATION: The patient was a Japanese male born at 39 weeks of gestation. He was breast-fed and received commercial cow's milk supplementation starting the day of birth and was admitted to our hospital at 6 days of age due to bilious vomiting. Plain abdominal radiography showed a paucity of gas in the distal bowel. Because we demonstrated malpositioning of the intestine by barium enema, we repositioned the bowel in a normal position by laparotomy. The patient was re-started on only breast milk 2 days post surgery because we suspected the presence of a cow's milk allergy, and the results of an allergen-specific lymphocyte stimulation test showed a marked increase in lymphocyte response to kappa-casein. At 5 months of age, the patient was subjected to a cow's milk challenge test. After the patient began feeding on cow's milk, he had no symptoms and his laboratory investigations showed no abnormality. In addition, because the patient showed good weight gain and no symptoms with increased cow's milk intake after discharge, we concluded that the present case was not the result of a cow's milk allergy. At 1 year, the patient showed favorable growth and development, and serum allergy investigations revealed no reaction to cow's milk. CONCLUSION: When physicians encounter infants with surgical gastrointestinal disease, including intestinal malrotation, they should consider cow's milk allergy as a differential diagnosis or complication and should utilize food challenge tests for a definitive diagnosis. PMID- 22943657 TI - Unwanted sexual experiences among young men in four sub-Saharan African countries: prevalence and context. AB - Unwanted sexual experiences are most frequently examined from the woman's perspective, yet these experiences happen to men as well. Part of the reason for the paucity of studies on coerced sexual experiences among men is the difficulty in gathering information about such experiences. This study examines the prevalence of unwanted sexual experiences at sexual debut as well as ever among young men aged 12-19 years old in Burkina Faso, Ghana, Malawi and Uganda. The data come from nationally-representative surveys and in-depth interviews with approximately 50 young men in each country gathered around 2004. Between 4 and 12% of young men stated that they were 'not willing at all' at sexual debut and between 3 and 6% said that they had ever experienced unwanted sex. Narratives from in-depth interviews give insights into the context surrounding men's unwanted sexual experiences. The sometimes conflicting information provided by the respondents serve to confound rather than illuminate the contexts within which these unwanted sexual experiences occurred, demonstrating that coercion for young men looks extremely different than coercion for young women, spurring us to improve our measures of sexual coercion among men. PMID- 22943658 TI - Scanning for satisfaction or digging for dismay? Comparing findings from a postal survey with those from a focus group-study. AB - BACKGROUND: Despite growing support for mixed methods approaches we still have little systematic knowledge about the consequences of combining surveys and focus groups. While the methodological aspects of questionnaire surveys have been researched extensively, the characteristics of focus group methodology are understudied. We suggest and discuss whether the focus group setting, as compared to questionnaire surveys, encourages participants to exaggerate views in a negative direction. DISCUSSION: Based on an example from our own research, where we conducted a survey as a follow up of a focus group study, and with reference to theoretical approaches and empirical evidence from the literature concerning survey respondent behaviour and small group dynamics, we discuss the possibility that a discrepancy in findings between the focus groups and the questionnaire reflects characteristics of the two different research methods. In contrast to the survey, the focus group study indicated that doctors were generally negative to clinical guidelines. We were not convinced that this difference in results was due to methodological flaws in either of the studies, and discuss instead how this difference may have been the result of a general methodological phenomenon. SUMMARY: Based on studies of how survey questionnaires influence responses, it appears reasonable to claim that surveys are more likely to find exaggerated positive views. Conversely, there are some indications in the literature that focus groups may result in complaints and overly negative attitudes, but this is still an open question. We suggest that while problematic issues tend to be under communicated in questionnaire surveys, they may be overstated in focus groups.We argue for the importance of increasing our understanding of focus group methodology, for example by reporting interesting discrepancies in mixed methods studies. In addition, more experimental research on focus groups should be conducted to advance the methodology and to test our hypothesis. PMID- 22943660 TI - Palaeoecological and morphofunctional interpretation of bone mass increase: an example in Late Cretaceous shallow marine squamates. AB - Bone mass increase (BMI; i.e. osteosclerosis with possible additional pachyostosis) is characteristically displayed by many Late Cretaceous squamates that adapted to shallow marine environments-plesiopelvic mosasauroids, stem ophidians and pachyophiids. A combined morphological and microanatomical analysis of vertebrae and, to a lesser extent, ribs of these fossil squamates provides new data about the distribution and variability of this osseous specialization in these taxa. Classical thin sections and third generation synchrotron microtomography and laminography were used for the microanatomical analysis. Following the explanation of the likely involvement of this specialization in the control of buoyancy, body trim and Carrier's constraint, new palaeoecological inferences and new hypotheses about the locomotor abilities and life environment of these organisms are produced. The taxa displaying BMI are considered to have undertaken long dives, hovering slowly and maintaining a horizontal trim, in shallow and protected water environments. Conversely, marine stem-ophidians deprived of this specialization are regarded as slow surface swimmers able to live in more open marine environments. This study highlights the importance of microanatomical data for palaeoecological studies. It also discusses the significance of the use of this specialization as a character in phylogenetic studies. PMID- 22943659 TI - Vasectomy as a proxy: extrapolating health system lessons to male circumcision as an HIV prevention strategy in Papua New Guinea. AB - BACKGROUND: Male circumcision (MC) has been shown to reduce the risk of HIV acquisition among heterosexual men, with WHO recommending MC as an essential component of comprehensive HIV prevention programs in high prevalence settings since 2007. While Papua New Guinea (PNG) has a current prevalence of only 1%, the high rates of sexually transmissible diseases and the extensive, but unregulated, practice of penile cutting in PNG have led the National Department of Health (NDoH) to consider introducing a MC program. Given public interest in circumcision even without active promotion by the NDoH, examining the potential health systems implications for MC without raising unrealistic expectations presents a number of methodological issues. In this study we examined health systems lessons learned from a national no-scalpel vasectomy (NSV) program, and their implications for a future MC program in PNG. METHODS: Fourteen in-depth interviews were conducted with frontline health workers and key government officials involved in NSV programs in PNG over a 3-week period in February and March 2011. Documentary, organizational and policy analysis of HIV and vasectomy services was conducted and triangulated with the interviews. All interviews were digitally recorded and later transcribed. Application of the WHO six building blocks of a health system was applied and further thematic analysis was conducted on the data with assistance from the analysis software MAXQDA. RESULTS: Obstacles in funding pathways, inconsistent support by government departments, difficulties with staff retention and erratic delivery of training programs have resulted in mixed success of the national NSV program. CONCLUSIONS: In an already vulnerable health system significant investment in training, resources and negotiation of clinical space will be required for an effective MC program. Focused leadership and open communication between provincial and national government, NGOs and community is necessary to assist in service sustainability. Ensuring clear policy and guidance across the entire sexual and reproductive health sector will provide opportunities to strengthen key areas of the health system. PMID- 22943661 TI - An evaluation of five different dressing materials on split-thickness skin graft donor site and full-thickness cutaneous wounds: an experimental study. AB - The objective of this study was to investigate the healing effect of five different products on split-thickness skin graft (STSG) donor sites and full thickness cutaneous wounds (FTCWs) using an occlusive dressing model. Six groups were included: 1 control and 5 experimental groups, with a total of 24 rats, using an occlusive dressing model. STSG donor sites and FTCWs were established in two separate areas, to the right and left on the animals' backs. Wound sites were dressed with one of the following materials: fine mesh gauze, microporous polysaccharide hemosphere (MPH), clinoptilolite, alginate, hydrogel or biosynthetic wound dressing (Biobran((r)) ). These materials were compared in terms of healing rate, healing quality and histopathological findings. Occlusive dressings were applied to each wound on days 0, 3, 5, 7, 10 and 14. Area measurements were taken using images of each dressing. The alginate and clinoptilolite groups gave the best healing rate results for both STSG donor sites (P = 0.003) and FTCWs (P = 0.003). MPH came third in each group. The alginate group produced better results in terms of healing quality criteria, followed by hydrogel, MPH, clinoptilolite and Biobran((r)) , in that order. Statistically significant results were obtained in all groups compared to the control group (P < 0.0007). Rapid and good healing quality for both the STSG donor sites and FTCWs were obtained with alginate. Healing with clinoptilolite and MPH was rapid, but poor quality, while slower but good healing quality was obtained with hydrogel. Slower and worse quality healing was obtained with Biobran((r)) . PMID- 22943662 TI - Comparison of two doses of ketoprofen to treat pain: a double-blind, randomized, noninferiority trial. AB - The aim of our study was to compare the efficacy and safety of two doses of ketoprofen (200 mg vs. 300 mg/day) in ambulatory emergency patients with pain related to traumatic and nontraumatic bone and joint diseases. We tested the hypothesis that the efficacy of the lower dose was not lower than that of the higher dose in a double-blind, randomized, noninferiority trial. Patients included in the study were aged 18-65 years with closed benign trauma of the motor system or acute noninfectious rheumatologic conditions, with a resting pain intensity >=3/10 on a numeric pain scale (NPS), requiring ketoprofen for 5 days. The main end-point was based on two efficacy co-criteria: (i) mean change from baseline of resting pain intensity at the end of the day over 5 days and (ii) total intake of concomitant analgesics. We included 409 patients: 200 in the 200 mg group and 209 in the 300-mg group. The mean change in pain intensity at rest (difference between groups: 0.0, 95% CI -0.4 to 0.4; P = 1.00) and in analgesic consumption (difference between groups: -0.6, 95% CI -1.9 to 0.6; P = 0.33) was not significantly different between the two groups, and the differences were lower than the predefined inferiority margins (0.5 and 1.5, respectively), thus demonstrating noninferiority. No significant difference was noted in the incidence of adverse events (21% vs. 20%, P = 0.71). The efficacy of the 200-mg daily dose of ketoprofen in relieving pain in emergency cases was not inferior to that of the 300-mg dose. PMID- 22943663 TI - Alcohol, psychoactive substances and non-fatal road traffic accidents--a case control study. AB - BACKGROUND: The prevalence of alcohol and other psychoactive substances is high in biological specimens from injured drivers, while the prevalence of these psychoactive substances in samples from drivers in normal traffic is low. The aim of this study was to compare the prevalence of alcohol and psychoactive substances in drivers admitted to hospital for treatment of injuries after road traffic accidents with that in drivers in normal traffic, and calculate risk estimates for the substances, and combinations of substances found in both groups. METHODS: Injured drivers were recruited in the hospital emergency department and drivers in normal conditions were taken from the hospital catchment area in roadside tests of moving traffic. Substances found in blood samples from injured drivers and oral fluid samples from drivers in moving traffic were compared using equivalent cut off concentrations, and risk estimates were calculated using logistic regression analyses. RESULTS: In 21.9% of the injured drivers, substances were found: most commonly alcohol (11.5%) and stimulants eg. cocaine or amphetamines (9.4%). This compares to 3.2% of drivers in normal traffic where the most commonly found substances were z-hypnotics (0.9%) and benzodiazepines (0.8%). The greatest increase in risk of being injured was for alcohol combined with any other substance (OR: 231.9, 95% CI: 33.3- 1615.4, p < 0.001), for more than three psychoactive substances (OR: 38.9, 95% CI: 8.2- 185.0, p < 0.001) and for alcohol alone (OR: 36.1, 95% CI: 13.2- 98.6, p < 0.001). Single use of non-alcohol substances was not associated with increased accident risk. CONCLUSION: The prevalence of psychoactive substances was higher among injured drivers than drivers in normal moving traffic. The risk of accident is greatly increased among drivers who tested positive for alcohol, in particular, those who had also ingested one or more psychoactive substances. Various preventive measures should be considered to curb the prevalence of driving under the influence of psychoactive substances as these drivers constitute a significant risk for other road users as well as themselves. PMID- 22943664 TI - Does local injury to the endometrium before IVF cycle really affect treatment outcome? Results of a randomized placebo controlled trial. AB - AIM: To evaluate the effect of local injury to the endometrium during spontaneous menstrual cycles before in vitro fertilization (IVF) treatment on implantation and pregnancy rates in women with recurrent implantation failure (RIF). METHODS: In a prospective randomized controlled trial (RCT), a total of 36 patients, with RIF undergoing IVF, were randomized to two groups. In 18 patients, endometrial biopsies were performed using a pipelle curette on days 9-12 and 21-24 of the menstrual cycle preceding IVF treatment. In 18 control patients, a cervical pipelle was performed. RESULTS: The implantation rate (2.08% versus 11.11%; p = 0.1), clinical (0% versus 31.25%; p < 0.05) and live births rates (0% versus 25%; p = 0.1) were lower in the experimental group compared with controls. CONCLUSION: Our RCT did not find any benefit from local injury to the endometrium in women with a high number of RIFs. Further studies are warranted to better define the target population of patients who may benefit from this procedure. PMID- 22943665 TI - Corticosteroids in recurrence of glomerular disease in renal transplantation: do we know the right questions to ask? PMID- 22943667 TI - Engaging life in two Irish nursing home units for people with dementia: quantitative comparisons before and after implementing household environments. AB - OBJECTIVES: This study compares the Social Engagement and Interactive Occupation of residents with dementia in two Irish nursing homes, before and after conversion to a household model environment. The changes were an open plan design and a functioning unit kitchen, supported by a homemaker role and operational policies which reduced task-based work in favour of person-centred care offering choice. METHOD: A snapshot observation method was used to obtain quantitative data of resident activity using the Assessment Tool for Occupation and Social Engagement (ATOSE). Residents were assessed for four hours, on seven different weekdays, over a six-week period both pre- and post-renovation. The exception to this was the assessment of the traditional model unit (TMU) for Nursing Home 1 which was reduced to four days due to the early start of the building work. RESULTS: The results were consistent for both nursing homes and data were aggregated. Residents spent more time in the communal living spaces and were more likely to be active and engaged in the household model units (HMUs) compared to the TMUs. Using the independent t-test, these changes were found to be highly significant (p < 0.001). CONCLUSION: Creating an HMU increased the Interactive Occupation and Social Engagement of residents in the communal areas of the two nursing homes. The physical environment change, in conjunction with supportive staff procedures and organizational initiatives, improved the well-being of residents with dementia. The outcomes must be viewed in context with financial implications. PMID- 22943666 TI - Inhibition of Hirame rhabdovirus growth by RNA aptamers. AB - RNA aptamers are artificial nucleic acids that specifically bind to a wide variety of targets. They are an effective tool for pharmaceutical research and development of antiviral agents. Here, we describe four Hirame rhabdovirus (HIRRV)-RNA aptamers (H1, H2, H3 and H4) that we obtained from an in vitro process called the systematic evolution of ligands by exponential enrichment (SELEX). The HIRRV-RNA aptamers specifically bind to HIRRV. Hirame natural embryo (HINAE) cells treated with virus and the RNA aptamer showed a decrease in appearance of cytopathic effect when compared with control (treated only with virus). Rhodovulum sulfidophilum was transformed with genes for the RNA aptamers, and the aptamers were detected in the culture medium, indicating that they were secreted from the cells. Thus, the recombinant R. sulfidophilum might be a powerful tool for the prevention of HIRRV in aquaculture. PMID- 22943671 TI - Use of systemic medication in patients with oral lichen planus - a possible association with hypothyroidism. AB - BACKGROUND: Several drugs have been regarded as a possible aetiological factor for oral lichen planus (OLP). OBJECTIVE: To investigate the medication profile of patients with OLP and its possible association with the pathogenesis of OLP. METHODS: Data from 956 patients with OLP and 1029 controls were collected using a standardized registration method. All regular medications were recorded and classified according to the Anatomical Therapeutic Chemical Classification System. RESULTS: Patients with OLP used thyroid preparations (P < 0.001) and non steroidal anti-inflammatory drugs (NSAIDs) (P < 0.01) in higher proportions compared to controls. A multivariate logistic regression model demonstrated that levothyroxine was associated with OLP (multivariate OR 3.39, 95% CI: 2.09-5.46, P < 0.001), even after controlling for confounders, including age, sex, smoking, allergies and systemic diseases. No statistical significance could be found between NSAIDs and OLP using the same model. CONCLUSION: In this study, the use of levothyroxine was associated with OLP, which in turn suggests a possible connection with hypothyroidism. PMID- 22943672 TI - Modified extended Kocher incision for total thyroidectomy with lateral compartment neck dissection - a critical appraisal of surgical access and cosmesis in 31 patients. PMID- 22943670 TI - Mesenchymal stem cells as all-round supporters in a normal and neoplastic microenvironment. AB - Mesenchymal stem cells (MSC) represent a heterogeneous population exhibiting stem cell-like properties which are distributed almost ubiquitously among perivascular niches of various human tissues and organs. Organismal requirements such as tissue damage determine interdisciplinary functions of resident MSC including self-renewal, migration and differentiation, whereby MSC support local tissue repair, angiogenesis and concomitant immunomodulation. However, growth of tumor cells and invasion also causes local tissue damage and injury which subsequently activates repair mechanisms and consequently, attracts MSC. Thereby, MSC exhibit a tissue-specific functional biodiversity which is mediated by direct cell-to-cell communication via adhesion molecule signaling and by a tightly regulated exchange of a multifactorial panel of cytokines, exosomes, and micro RNAs. Such interactions determine either tumor-promoting or tumor-inhibitory support by MSC. Moreover, fusion with necrotic/apoptotic tumor cell bodies contributes to re-program MSC into an aberrant phenotype also suggesting that tumor tissue in general represents different types of neoplastic cell populations including tumor-associated stem cell-like cells. The present work summarizes some functional characteristics and biodiversity of MSC and highlights certain controversial interactions with normal and tumorigenic cell populations, including associated modulations within the MSC microenvironment. PMID- 22943668 TI - Speciation patterns in gastropods with long-lived larvae from deep-sea seamounts. PMID- 22943673 TI - The co-expression of cytokeratin and p63 in epithelioid angiosarcoma of the parotid gland: a diagnostic pitfall. AB - Epithelioid angiosarcoma of the parotid gland is rare, and may pose a great diagnostic challenge. We report a case of primary epithelioid angiosarcoma in a 64-year-old male without history of radiation. The histopathological findings demonstrated a high grade epithelioid neoplasm. Immunostaining showed that the tumor was positive for the pan-cytokeratin, p63, cytokeratin18, Vimentin and vascular markers CD31, and was negative for CD34, cytokeratin5/6, cytokeratin7, cytokeratin20, CD68, CD30, S-100, HMB45, desmin, alpha-SMA and CD45. The tumor was diagnosed as an epithelioid angiosarcoma. To our knowledge, this is the first reported case of angiosarcoma which showed common positivity for cytokeratin and p63. In addition to cytokeratin, p63 is considered a useful marker for carcinoma. The co-expression of cytokeratin and p63 in epithelioid angiosarcoma represents a diagnostic pitfall. Thus, using a panel of antibodies is essential for distinguishing this tumor from poorly differentiated carcinoma. Virtual slides: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/6548916707504750. PMID- 22943674 TI - Mitochondrial genome of the Chinese gizzard shad Clupanodon thrissa (Clupeiformes: Clupeidae) and related phylogenetic analyses. AB - The complete mitochondrial genome sequence of the single species from the Genus Clupanodon, the Chinese gizzard shad, Clupanodon thrissa, was determined. The entire sequence is 16,692 bp in length, including the typical structure of 13 protein-coding genes, 22 transfer RNA (tRNA) genes, 2 rRNA genes, and 2 noncoding regions (control region and L-strand replication origin). With the exception of ND6 and eight tRNA genes, all other genes are encoded on the heavy strand and the organization of genes is similar to that observed in most other vertebrates. Phylogenetic analyses using the protein coding gene sequences reveal that C. thrissa is most closely related to Konosirus punctatus within the family Clupeidae and subfamily Dorosomatinae is not a monophyletic group. PMID- 22943675 TI - Tramadol and hypoglycaemia: comparison with other step 2 analgesic drugs. AB - AIMS: The risk of hypoglycaemia with tramadol (TRM) is not well described. Our aim was to analyze spontaneous reports of hypoglycaemia registered in the French Pharmacovigilance database and to compare these data with two other step-2 analgesic drugs. METHODS: Cases of hypoglycaemia associated with TRM, dextropropoxyphene (DXP) and codeine (COD) recorded between 1997 and November 2010 in the French pharmacovigilance database were compared. RESULTS: Seventy-two cases of hypoglycaemia associated with DXP and 43 with TRM were retained for evaluation (the single case reported with COD was not further considered). Most patients were elderly people with no significant difference in age between DXP- and TRM-treated patients (71.2 +/- 21 vs. 69.4 +/- 22.5 years). Hypoglycaemia occurred after a median of 4 and 5 days with DXP and TRM treatment, respectively. The mean lowest serum glucose concentration was 2.1 +/- 0.9 mmol l(-1) in the DXP group compared with 2.5 +/- 1 mmol l(-1) in the TRM group (P = 0.072). At least, one risk factor of hypoglycaemia was found in most patients, with no significant difference between groups (58.3% in the DXP group and 58.1% in the TRM group). In particular, 31.9% patients from the DXP group had diabetes compared with 41.8 % from the TRM group (P = 0.28) and 18% of DXP patients had renal insufficiency compared with 16.3% of TRM patients (P = 0.8). CONCLUSIONS: Our study confirms that TRM is associated with the occurrence of hypoglycaemia in elderly or predisposed patients, with characteristics similar to those previously reported with DXP. PMID- 22943676 TI - Cost analysis of HIV treatment and drug-related adverse events when fixed-dose combinations of antiretrovirals (FDCs) were stopped, versus continuation with FDCs. AB - BACKGROUND: The lower sales price of generic lamivudine has caused healthcare administrators to consider abolishing fixed-dose antiretroviral combinations (FDCs) that contain lamivudine and emtricitabine. The alternative is to administer the individual components of the FDCs separately, thus incorporating the new generic lamivudine medication. METHODS: The Balearic Islands Health Service ordered the discontinuation of the treatment with FDCs in July 2010, but FDCs were reintroduced in August 2010. At that point, an independent, retrospective cost analysis was performed by Son Llatzer Hospital. A total of 75 patients who were treated from July to August 2010 underwent replacement of their FDC treatment with the individual components. Additionally, 150 patients who continued using FDCs were randomly selected. For both patient groups, the antiretroviral therapy that was administered and the costs associated with management of adverse events were recorded. The study period used for the cost calculations was the average number of days that patients used separate components of FDCs (120 days). An alternative analysis was performed to consider the costs of the extra follow-up visit (consultation and clinical tests) that was required for patients who changed their antiretroviral therapy. RESULTS: Considering antiretroviral therapies and adverse events, the administration of the separate components increased the total daily cost by 0.72 ? per patient compared to treatment with FDCs. When the cost of an extra follow-up visit was considered, the daily cost increased by 3.61 ? per patient. CONCLUSIONS: Our study suggests that the discontinuation of FDC treatment and the replacement with the administration of separate antiretroviral agents could lead to an increase in healthcare costs due to the higher rate of adverse events that was observed with the discontinuation of FDCs. PMID- 22943677 TI - Shifting effects in randomised controlled trials of complex interventions: a new kind of performance bias? AB - OBJECTIVE: Randomised controlled trials (RCTs) aim to provide unbiased estimates of treatment effects. However, the process of implementing trial procedures may have an impact on the performance of complex interventions that rely strongly on the intuition and confidence of therapists. We aimed to examine whether shifting effects over the recruitment period can be observed that might indicate such impact. METHOD: Three RCTs investigating music therapy vs. standard care were included. The intervention was performed by experienced therapists and based on established methods. We examined outcomes of participants graphically, analysed cumulative effects and tested for differences between first vs. later participants. We tested for potential confounding population shifts through multiple regression models. RESULTS: Cumulative differences suggested trends over the recruitment period. Effect sizes tended to be less favourable among the first participants than later participants. In one study, effects even changed direction. Age, gender and baseline severity did not account for these shifting effects. CONCLUSION: Some trials of complex interventions have shifting effects over the recruitment period that cannot be explained by therapist experience or shifting demographics. Replication and further research should aim to find out which interventions and trial designs are most vulnerable to this new kind of performance bias. PMID- 22943678 TI - Outcomes of preoperative radiotherapy and resection of retroperitoneal sarcoma. AB - BACKGROUND: Preoperative radiotherapy (RT) is an important component of the management of retroperitoneal sarcoma (RPS). We aimed to establish the feasibility of this approach by determining the accuracy of computed tomography (CT)-guided core biopsy, proportion of patients completing treatment, rates of acute toxicity and surgical complications, and treatment outcomes. METHODS: This is a retrospective review. Consecutive patients presenting between January 1999 and December 2009 with a diagnosis of either primary or recurrent RPS were identified. Those patients suitable for preoperative RT and surgery were included. Exclusions included presence of metastatic disease, age under 18 years and/or paediatric histology, and treatment with palliative intent. RESULTS: Twenty-four patients were included, 14 were males. Median age was 61.4 years. Twenty-three patients had Stage T2b, high-grade disease. Twenty patients were treated at initial presentation and four at first local recurrence. Five-year progression-free survival, overall survival and local recurrence rates were 48.9, 53.7 and 22%, respectively. A malignant diagnosis was confirmed in all patients who underwent CT-guided core biopsy; a diagnosis of sarcoma was reached in 90%, histological subtype correctly identified in 66%. All patients in the cohort completed preoperative RT. Grade 3 toxicity occurred in 4% of patients (n = 1). Seventy-five per cent (n = 18) proceeded to radical resection, where complete macroscopic excision was achieved in all cases. There was no perioperative mortality. CONCLUSION: Preoperative RT has low levels of Grades 3 or 4 toxicity, and does not adversely impact surgical management. CT-guided core biopsy is an accurate means of confirming a diagnosis of RPS prior to definitive treatment. PMID- 22943679 TI - [Target of hypertension treatment and trend of preferred therapy]. PMID- 22943680 TI - [Chinese expert consensus on blood lipid related cardiovascular residual risk control]. PMID- 22943681 TI - [Cause of in-hospital death among acute myocardial infarction patients undergoing primary percutaneous coronary intervention in Beijing]. AB - OBJECTIVE: To analyze the cause of in-hospital death among acute myocardial infarction patients undergoing primary percutaneous coronary intervention (PPCI) in Beijing area to evoke better individualized preventive approach. METHODS: In hospital mortality and causes were analyzed based on database from Beijing percutaneous coronary intervention registry study (BJPCI Registry) in 2010. RESULTS: A total of 4660 PPCI patients from 48 hospitals were included. In hospital mortality was 2.4% (n = 110). Cardiogenic shock (39.1%, 43/110), mechanical complications (28.2%, 31/110) and intervention-related complications [28.2%, 31/110: procedure related (n = 28), drug related (n = 3)] were the leading causes of in-hospital death. Five deaths was attributed to comorbidity related reason (4.5%, 5/110). The in-hospital mortality had no significant difference among hospitals of different grade or total annual PCI (all P > 0.05). In-hospital mortality was slightly higher in hospital with annual PPCI < 300 than in hospitals with annual PPCI >= 300 (2.9% vs. 1.8%, P < 0.05). CONCLUSION: Cardiogenic shock, mechanical complications and intervention-related complications are the main causes of in-hospital death among acute myocardial infarction patients receiving PPCI. PMID- 22943682 TI - [Clinical and angiographic outcomes of coronary drug-eluting stenting in treating vasospastic angina patients with severe organic stenosis]. AB - OBJECTIVE: To evaluate the clinical and angiographic outcomes of vasospastic angina patients with severe organic stenosis treated by drug-eluting stents. METHODS: Between January 2006 and December 2010, severe organic stenosis (diameter stenosis more than 70%) was evidenced in 7 out of 46 vasospastic angina patients and treated with drug-eluting stents. Coronary angiography was repeated at 6 - 18 months after percutaneous coronary intervention and the patients were clinically followed up. The clinical and angiographic outcomes were observed. RESULTS: Nine drug-eluting stents [mean diameter 2.75 - 3.50 (3.08 +/- 0.24) mm, length 24 - 33 (27.3 +/- 3.6) mm] were successfully implanted in these 7 patients. Stents were implanted into left anterior descending artery (LAD) in 5 patients (71.4%), right coronary artery (RCA) in 1 patient (14.3%), both LAD and RCA in 1 patient (14.3%). Transient RCA spasm and distal LAD spasm were observed during percutaneous coronary intervention of LAD in 2 patients. Anginal attack at rest with transient ST segment elevation at V(1)-V(3) leads occurred 24 hours after LAD stenting in 1 patient. Follow-up coronary angiography showed significant in-stent restenosis or focal edge restenosis (diameter stenosis more than 50%) in 3 patients (42.9%), mild neointimal proliferation but without significant restenosis in 2 patients (28.6%), and no neointimal proliferation in 2 patients (28.6%). During clinical follow-up of 17 to 50 months after percutaneous coronary intervention, 2 patients (28.6%) remained asymptomatic, while effort angina and/or rest angina was documented in the remaining 5 patients (71.4%). CONCLUSIONS: Our results from this small patient cohort suggest that drug eluting stent implantation for severe organic stenosis in patients with vasospastic angina is linked with high incidence of restenosis and recurrent chest pain. Further observation in larger patient cohort is warranted to clarify the efficacy of this strategy for treating vasospastic angina patients with severe organic stenosis. PMID- 22943683 TI - [Preliminary clinical experience on radiofrequency catheter ablation of right sided accessory pathway guided by Ensite-NavX navigation]. AB - OBJECTIVE: To explore the feasibility and methodology of radiofrequency catheter ablation (RFCA) guided by 3D navigation system (Ensite-NavX) for right atrioventricular accessory pathway. METHOD: Thirty-three cases of right accessory pathway atrioventricular reentrant tachycardia including 16 cases in right free wall, 3 in right middle septum, 14 in right posterior septum; 23 cases of dominant accessory pathway and 10 cases of concealed were treated by RFCA guided by NavX navigation. NavX navigation modeling method or spatial localization method was exploited to locate target positioning. RESULT: All patients were successfully ablated without serious complications. Among them, 25 cases were operated without exposure to X-ray, 7 patients were exposed for several seconds to verify catheter position, 1 case in right free wall was ablated under X-ray combined with Swartz sheath ablation. CONCLUSION: Nonfluoroscopy or less fluoroscopy RFCA for right atrioventricular accessory pathway with Ensite-NavX is safe and feasible, modeling or spatial orientation method are helpful to locate the ablation target positioning. PMID- 22943684 TI - [Intravascular ultrasound assessment of chitosan/heparin layer-by-layer self assembly coating stent on late stent malapposition and vessel remodeling in porcine model]. AB - OBJECTIVE: To investigate late stent malapposition or vessel remodeling post chitosan/heparin layer-by-layer self assembly coating stent (LBL) implantation in porcine. METHODS: A total of 32 stents [bare metal stent (BMS, n = 9), sirolimus eluting stent (SES, n = 11) and LBL (n = 12)] were implanted into coronary arteries of 16 porcine. Intravascular ultrasound (IVUS) was performed immediately after stenting and at 1 month after stenting to measure vessel area (VA), stent area (SA) and lumen area (LA). Neointima area (NA) was measured at 1 month post stenting by IVUS to detect signs of stent malapposition and to determine remodeling index (RI). Histopathology was performed at 1 month post stenting to observe vessel wall structure and stent malapposition status. RESULTS: No sign of stent malapposition was detected, VA and SA/LA were similar among groups immediately after stent implantation. At 1 month follow-up, none of three groups showed stent malapposition. VA, SA, NA and LA were (7.30 +/- 0.77), (6.83 +/- 0.76), (1.40 +/- 0.96) and (5.43 +/- 0.88) mm(2) in LBL group, (7.13 +/- 0.69), (6.63 +/- 0.71), (0.28 +/- 0.35) and (6.34 +/- 0.89) mm(2) in SES group, (7.48 +/ 0.70), (7.00 +/- 0.52), (2.69 +/- 1.58) and (4.31 +/- 1.28) mm(2) in BMS group. VA and SA were similar among groups (all P > 0.05). LA in LBL group was smaller than SES group (P < 0.01) and significantly larger than in BMS group (P < 0.05).NA in LBL group was larger than SES group (P < 0.01) and significantly smaller than in BMS group (P < 0.05).RI in LBL, SES and BMS groups was 0.95 +/- 0.07, 1.02 +/- 0.04 and 0.98 +/- 0.04 (P > 0.05). CONCLUSIONS: There is no late stent malapposition or abnormal remodeling post LBL, SES and BMS implantation up to 1 month in this porcine model. LA in LBL group is smaller than SES group and larger than BMS group at 1 month after implantation in this porcine model. PMID- 22943685 TI - [Comparative study on the efficacy of intracoronary infusion with various types of autologous bone marrow stem cells for patients with dilated cardiomyopathy]. AB - OBJECTIVE: To compare the effects of intracoronary infusion of mononuclear stem cells (MNCs) or mesenchymal stem cells (MSCs) in patients with dilated cardiomyopathy (DCM). METHODS: DCM patients with left ventricular ejection fraction(LVEF) < 40% were randomized to intracoronary infusion of MNCs [(5.1 +/- 2.0) * 10(8), n = 16] or MSCs [(4.9 +/- 1.7) * 10(8), n = 17] or equal volume normal saline (n = 20) through the guiding catheter. Changes of left ventricular end-diastolic diameter (LVEDd), LVEF and myocardium perfusion defects were assessed before and at (30 +/- 3) days and (90 +/- 7) days after the procedure. Malignant cardiovascular events were also recorded. RESULTS: (1) One month after the procedure, LVEF in transplantation groups significantly increased compared to before procedure (all P < 0.05), and significant increase of LVEF was observed only in MSCs transplantation group compared to control group (P < 0.05). However, absolute changes of LVEDd and perfusion defects of myocardium were similar among and within groups (P > 0.05). (2) Comparing with before procedure and control group, LVEF in transplantation groups increased significantly in three months after the procedure (P < 0.05), but there were no significant differences between transplantation groups (P > 0.05). LVEDd and myocardium perfusion defects in transplantation groups improved significantly compared with that of before procedure (P < 0.05), while significant decrease of myocardium perfusion defects was only observed in patients treated with MSCs compared with control group at three months after procedure (P < 0.05). (3) There were no significant differences in major cardiovascular events between transplantation group and control during follow-up (P > 0.05). CONCLUSIONS: Intracoronary bone marrow stem cells transplantation is safe and effective for DCM patients while the efficacy of MSCs and MNCs transplantation is comparable. PMID- 22943686 TI - [Association between paraoxonase concentration and risk of acute coronary syndrome]. AB - OBJECTIVE: To investigate the relationship between paraoxonase (PON) concentration and the risk of acute coronary syndrome (ACS). METHODS: The levels of serum PON were detected by enzyme-linked immunosorbent assay in 229 patients with confirmed ACS and 129 control subjects without CHD. Logistic regression analysis and receiver operating characteristic (ROC) curve analysis were applied to analyze the association between PON and ACS. RESULTS: PON was significantly lower in ACS group than in control group [lgPON: (5.72 +/- 0.73) ng/L vs. (5.07 +/- 0.57) ng/L, P < 0.05]. Logistic regression analysis showed that the level of PON was an independent risk factor of ACS (regression coefficient was -1.793 in univariate logistic regression, OR = 0.166, 95%CI: 0.088 - 0.316; -0.779 in multivariate logistic regression, OR = 0.459, 95%CI: 0.222 - 0.949). ROC analysis showed that the optimal diagnostic cut-off point of PON for ACS was 180 mg/L (sensitivity: 83.3%, specificity: 71.2%). Multiple stepwise regression analysis revealed that there was no significant correlation between lgPON and Gensini score in ACS patients. CONCLUSION: Lower PON is linked with increased risk of ACS, but does not relate with the severity of coronary stenosis. PMID- 22943687 TI - [Value of coronary CT angiography in assessment of bifurcation lesions]. AB - OBJECTIVE: To evaluate the value of coronary CT angiography in assessment of bifurcation lesions. METHODS: The original image of 79 established and suspected coronary artery disease patients who underwent both coronary CT angiography and conventional artery angiography (CAG) sequentially were included in this analysis. Bifurcation lesions were assessed on primary and secondary vessels with diameter >= 2.0 mm, bifurcation lesions were graded according to Chen's classification. CAG was used as golden standard. The sensitivity, specificity, positive predictive value and negative predictive value were calculated. Spearman's test and Kappa test were used to evaluate the correlation and classification identity of the two methods. RESULTS: CAG evidenced 177 bifurcation lesions out of 445 bifurcation vessels and coronary CT detected 168 bifurcation lesions out of 404 bifurcation vessels with satisfactory imaging quality and 390 bifurcation vessels could be analyzed by both CAG and coronary CT. Sensitivity, specificity, positive predictive value and negative predictive value of coronary CT angiography were 94.2%, 94.6%, 90.7%, 96.1%, respectively. The results for the lesions at LM-LAD/LCX + LAD/Mid, LAD/Diag, RCA/PDA were more satisfactory and the sensitivity and specificity were as high as: 97.1% and 94.2%, 95.7% and 89.5%, 92.3% and 98.7%, respectively. There were significant correlations for evaluating the narrow degree of the opening of the bifurcation branch with these two methods (r = 0.799 58, P < 0.01) and for identifying I, II, III type bifurcation lesions (Kappa coefficient = 0.7959, P < 0.01) as well as for identifying the subtype bifurcation lesions (Kappa coefficient = 0.6328, P < 0.01) using the two methods. CONCLUSION: Coronary CT angiography is efficient in identifying the bifurcation lesions and offers a reasonable indication for bifurcation lesion classification. PMID- 22943688 TI - [Value of QT hysteresis during treadmill exercise test for diagnosing coronary heart disease]. AB - OBJECTIVE: To investigate the value of QT hysteresis index during treadmill exercise test (TET) in diagnosing coronary heart disease (CHD). METHODS: One hundred consecutive patients suspected for CHD were referred for TET and selective coronary angiography (CAG). Patients were divided into positive [n = 55, age (56.0 +/- 7.9) years] and negative [n = 45, age (53.2 +/- 6.7) years] group based on their CAG results. For each TET recording, 50 points were selected for the RR, QTp, and QTe interval measurements. QTp and QTe interval was plotted against corresponding RR interval. QT/RR curve was constructed by connect all point, QT hysteresis index was calculated for each patient. RESULTS: The QTp [(22.4 +/- 10.3) ms vs. (6.7 +/- 4.6) ms, P < 0.001] and QTe [(27.1 +/- 11.1) ms vs. (7.6 +/- 4.6) ms, P < 0.001] hysteresis index of patients in positive group were significantly higher than those in negative group. The sensitivity of QTp and QTe hysteresis index for diagnosing CHD was 89.1% (49/55) and 94.5% (52/55), respectively, and the specificity was 82.2% (37/45) and 80.0% (36/45), respectively. If the patient fulfilled both the classical TET and QT hysteresis criteria, the sensitivity for diagnosing CHD increased to 94.3% (33/35, QTp) and 94.6% (35/37, QTe), and the specificity were both 100% (26/26, 26/26). Moreover, QTp (r = -0.399, P < 0.001) and QTe (r = -0.547, P < 0.001) hysteresis index highly correlated to Duke treadmill score. CONCLUSION: QT hysteresis index is useful parameter for CHD diagnosis and which could improve the diagnostic value of TET for CHD in combination with the classical TET criteria for diagnosis of CHD. PMID- 22943689 TI - [Treadmill exercise test in patients with coronary artery myocardial bridging]. AB - OBJECTIVE: To observe treadmill exercise test (TET) characteristics in patients with myocardial bridging (MB). METHODS: TET results from January 2003 to December 2010 were retrospectively analyzed in 156 patients with confirmed MB diagnosis. MB patients were divided into smoking group (68 cases) and non-smoking group (88 cases). Coronary angiography results were used to analyze the relations between MB length, myocardial ischemia and exercising duration. RESULTS: (1) MB was documented on two coronary arteries in 2 patients (1%), MB was detected in single artery in 154 patients (99%), of whom 146 cases were located at left anterior descending artery, 8 cases were located at right coronary artery. The degree of narrowing of MB was graded 1 (less than 50%) in 16 patients (10%), grade 2 (50% to 75%) in 108 patients (69%) and grade 3 (greater than 75%) in 32 patients (21%). The length of MB ranged between 4 to 40 mm, MB length was less than 10 mm in 40 patients (26%), between 11 to 20 mm in 48 patients (31%), between 21 to 30 mm in 44 patients (28%), greater than 31 mm in 24 patients (15%). (2) TET positive rate was 41% (64/156) and the TET positive rate was significantly higher in smoking group than in non-smoking group [57% (39/68) vs. 28% (25/88, P < 0.01)]. (3) The length of MB was positively related to the ST-segment depression (r = 0.723, P < 0.01) and negatively related to exercising duration (r = -0.828, P < 0.01). Heart rate was positively related to the ST-segment depression (r = 0.368, P < 0.01). CONCLUSIONS: TET may serve as a good test to assess myocardial ischemia in patients with MB. The length of MB is positively related with myocardial ischemia and negatively related with exercising duration. Smoking might increase myocardial ischemic incidence in MB patients, MB patients should be advised to stop smoking. PMID- 22943690 TI - [Clinical and echocardiographic features of cardiac myxomas in 64 patients]. AB - OBJECTIVE: To summarize the clinical and echocardiographic features of cardiac myxomas. METHODS: The medical records of patients with diagnosis of cardiac myxomas who hospitalized in our department from October 1985 to February 2011 were analyzed. RESULTS: A total of 64 patients were enrolled [40 female, the mean age was 2 - 77 (47 +/- 17) years]. The main complaints were palpitation (n = 24, 38%), short breath (n = 23, 36%), fever (n = 13, 20%), chest tightness (n = 11, 17%), dizziness (n = 10, 16%), fatigue (n = 10, 16%), weight loss (n = 10, 16%), syncope (n = 9, 14%), edema (n = 8, 13%); and thrombus embolisms (n = 13, 20%), including stroke (n = 7, 11%) and periphery artery embolism (n = 6, 9%). The interval from symptoms onset to diagnosis (surgical removal) ranged from 1 day to 9 years (median: 3 months). Single myxoma was detected in 62 (97%) patients (58 in left atria, 2 in right atria and 2 in right ventricle) and multiple myxomas were found in 2 (3%) patients and one patient was diagnosed as Carney syndrome. The mean size of tumor assessed by echocardiography was (5.0 +/- 1.8) cm * (2.9 +/- 1.0) cm. All myxomas were surgically removed (54 patients received operation in our hospital and 10 patients were operated in other hospitals) and diagnosis was confirmed during operation and the mean myxoma size obtained from operation was (5.4 +/- 1.6) cm * (3.6 +/- 1.3) cm * (2.6 +/- 1.2) cm (P > 0.05 vs. tumor size assessed by echocardiography). The locations of tumor stalks found by echocardiography were confirmed during surgery in most cases (97%). Incidence of NYHA class III diagnosis was more often in patients with right heart myxomas [3 cases (3/4)] than in patients with left atrium myxomas [17% (10/58), P < 0.05]. CONCLUSIONS: Clinical manifestations of cardiac myxomas were various and non specific. Echocardiography remains the most valuable diagnosis tool for patients with cardiac myxomas. PMID- 22943691 TI - [Adenovirus mediated N19RhoA gene transfer attenuates neointimal formation in rats after carotid artery balloon injury]. AB - OBJECTIVE: To investigate the role of small G-protein RhoA in neointimal formation following rat carotid artery balloon injury and related mechanisms. METHODS: Male 3-4-month-old Sprague-Dawley rats were used in the present study (10 rats per group). Group A: control; Group B: carotid artery balloon injury; Group C: injury + Ad-CMV-eGFP + Pluronic F-127; Group D: injury + Ad-CMV-N19RhoA eGFP + Pluronic F-127; Group E: non injury + Ad-CMV-eGFP + Pluronic F-127. Perivascular gene transfer of an adenovirus co-expressing N19RhoA was performed to rat carotid artery following balloon injury and the effect on neointimal formation and the expressions of PCNA and alpha-SM-actin examined. Rats were killed after 14 days. RESULTS: The protein expression of RhoA in group B was significantly higher than in group A (P = 0.001), and the positive cells rate of PCNA and alpha-SM-actin which were assessed by immunohistochemistry in group C (45.2% and 75.6%) was significantly higher than in group D (28.4% and 51.9%, all P < 0.01). The area of neointima was significantly smaller [(0.14 +/- 0.08) mm(2) vs. (0.23 +/- 0.10) mm(2), P < 0.01], the luminal area was significantly larger [(0.47 +/- 0.11) mm(2) vs. (0.31 +/- 0.06) mm(2), P < 0.01] in group D than in group C. CONCLUSION: Gene transfer of N19RhoA attenuates neointimal formation after balloon injury in rat carotid arteries possibly related to the modulating capacities of small G-protein RhoA on the proliferation, phenotypic differentiation and migration of vascular adventitial fibroblasts. PMID- 22943692 TI - [Overexpression of angiotensin-converting enzyme 2 inhibits angiotensin II type 1 receptor expression and signal transducer and activator of transcription 3 phosphorylation in cultured smooth muscle cells]. AB - OBJECTIVE: To explore the effects of recombinated lentiviral angiotensin converting enzyme 2 (ACE2) vector transfer on the expression of angiotensin II type 1 (AT1) receptor in cultured vascular smooth muscle cells (VSMCs). METHODS: VSMCs were divided into 7 groups: (1) CONTROL: serum-free culture medium; (2) Lentiviral-GFP vector group: Lentiviral-GFP vector (MOI = 10); (3) Ang II group (10(-7) mol/L); (4) Ang II (10(-7) mol/L) + Lentiviral-ACE2 (MOI = 10) group; (5) Ang II (10(-7) mol/L) + Irbesartan (10(-7) mol/L) group ; (6) Ang II (10(-7) mol/L) + irbesartan (10(-7) mol/L) + Lentiviral-ACE2 (MOI = 10) group ; (7) Lentiviral-ACE2 (MOI = 10) group. Ninety-six hours later, the proliferation of VSMCs was determined with CCK-8 Kit. AT1 receptor mRNA and protein expressions were detected with quantitative real-time PCR and Western blot, the signaling pathway of signal transducer and activator of transcription 3 (STAT3) was also detected. RESULTS: ACE2 gene transfer significantly inhibited the VSMCs proliferation in the absence or presence of Ang II. AT1 receptor mRNA and protein expressions were also significantly downregulated in the absence or presence of Ang II. Similar to AT1 receptor mRNA and protein expression changes, STAT3 phosphorylation was also significantly inhibited by ACE2 overexpression. CONCLUSION: Our results suggest that overexpression of ACE2 gene could inhibit the VSMCs proliferation by downregulating AT1 receptor expression and STAT3 phosphorylation. ACE2 could also directly inhibit AT1 receptor in cultured VSMCs. PMID- 22943693 TI - [Validation and comparison of pharmacogenetics-based warfarin dosing algorithms in Han Chinese patients]. AB - OBJECTIVE: To assess whether the existing three types of pharmacogenetics-based Warfarin dosing algorithms appropriately predict the actual maintenance dose in Han Chinese mechanical heart valve replacement patients (n = 130). METHODS: The patients' CYP2C9 and VKORC1 genetic polymorphisms were detected by PCR-RFLP. The genotype of CYP2C9, VKORC1 and other information were used to calculate predicted doses. Accuracy of the models was assessed using the absolute value of the difference between predicted dose and actual dose, calculated on both an absolute and percentage basis. Actual weekly dose was also regressed on predicted weekly dose, from which we obtained R(2) values. Clinical accuracy of the predictions was assessed by computing the proportion in which the predicted dose was 20% or more below the actual dose (under dosed), within 20% of the actual dose (ideally dosed), or 20% or greater above the actual dose (over dosed). RESULTS: The average absolute error is the smallest for the predictions made by the Wen model (3.74 mg/wk), followed by the Ohno model (4.07 mg/wk) and IWPC model (5.05 mg/wk). R(2) was 40.2% in the Wen model, 38.2% in the Ohno model and 26.7% in the IWPC model. When comparing the percentage of patients for whom the predicted doses were ideal, the Wen model works the best (50.0%) in low-dose group (<= 21 mg/wk), but the Ohno model works the best (85.29%) in middle-dose group (21 - 49 mg/wk), followed by the Wen model. CONCLUSION: The best accuracy is achieved by the Wen model and the best clinical accuracy is obtained by the Ohno model for predicting the actual maintenance dose in Han Chinese mechanical heart valve replacement patients. PMID- 22943694 TI - [Spontaneous rupture of adrenal pheochromocytoma: a case report]. PMID- 22943695 TI - [A case report of obstructive hypertrophic cardiomyopathy with dominant thickening of basal inferior and infero-lateral wall of left ventricle]. PMID- 22943696 TI - [Gender differences of cardiac resynchronization therapy]. PMID- 22943697 TI - [Update on advances for the role of microRNAs on the regulation of cardiovascular system]. PMID- 22943698 TI - Re-challenge with pemetrexed in advanced mesothelioma: a multi-institutional experience. AB - BACKGROUND: Although first-line therapy for patients affected by advanced mesothelioma is well established, there is a lack of data regarding the impact of second-line treatment. METHODS: We retrospectively collected data of patients affected by advanced mesothelioma, already treated with first-line therapy based on pemetrexed and platin, with a response (partial response or stable disease) lasting at least 6 months, and re-treated with a pemetrexed-based therapy at progression. The primary objective was to describe time to progression and overall survival after re-treatment. RESULTS: Overall across several Italian oncological Institutions we found 30 patients affected by advanced mesothelioma, in progression after a 6-month lasting clinical benefit following a first-line treatment with cisplatin and pemetrexed, and re-challenged with a pemetrexed based therapy. In these patients we found a disease control rate of 66%, with reduction of pain in 43% of patients. Overall time to progression and survival were promising for a second-line setting of patients with advanced mesothelioma, being 5.1 and 13.6 months, respectively. CONCLUSIONS: In our opinion, when a patient has a long-lasting benefit from previous treatment with pemetrexed combined with a platin compound, the same treatment should be offered at progression. PMID- 22943699 TI - High efficacy of white spot syndrome virus replication in tissues of freshwater rice-field crab, Paratelphusa hydrodomous (Herbst). AB - An attempt was made to determine the replication efficiency of white spot syndrome virus (WSSV) of shrimp in different organs of freshwater rice-field crab, Paratelphusa hydrodomous (Herbst), using bioassay, PCR, RT-PCR, ELISA, Western blot and real-time PCR analyses, and also to use this crab instead of penaeid shrimp for the large-scale production of WSSV. This crab was found to be highly susceptible to WSSV by intramuscular injection. PCR and Western blot analyses confirmed the systemic WSSV infection in freshwater crab. The RT-PCR analysis revealed the expression of VP28 gene in different organs of infected crab. The indirect ELISA was used to quantify the VP28 protein in different organs of crab. It was found that there was a high concentration of VP28 protein in gill tissue, muscle, haemolymph and heart tissue. The copy number of WSSV in different organs of infected crab was quantified by real-time PCR, and the results revealed a steady increase in copy number in different organs of infected crab during the course of infection. The viral inoculum prepared from different organs of infected crab caused significant mortality in tiger prawn, Penaeus monodon (Fabricius). The results revealed that this crab can be used as an alternate host for WSSV replication and production. PMID- 22943701 TI - The role of the endocannabinoid system in skeletal muscle and metabolic adaptations to exercise: potential implications for the treatment of obesity. AB - The results of recent studies add the endocannabinoid system, and more specifically CB1 receptor signalling, to the complex mechanisms that negatively modulate insulin sensitivity and substrate oxidation in skeletal muscle. CB1 receptors might become overactive in the skeletal muscle during obesity due to increased levels of endocannabinoids. However, quite surprisingly, one of the most studied endocannabinoids, anandamide, when administered in a sufficient dose, was shown to improve muscle glucose uptake and activate some key molecules of insulin signalling and mitochondrial biogenesis. This is probably because anandamide is only a partial agonist at CB1 receptors and interacts with other receptors (PPARgamma, TRPV1), which may trigger positive metabolic effects. This putative beneficial role of anandamide is worth considering because increased plasma anandamide levels were recently reported after intense exercise. Whether the endocannabinoid system is involved in the positive exercise effects on mitochondrial biogenesis and glucose fatty acid oxidation remains to be confirmed. Noteworthy, when exercise becomes chronic, a decrease in CB1 receptor expression in obese metabolically deregulated tissues occurs. It is then tempting to hypothesize that physical activity would represent a complementary alternative approach for the clinical management of endocannabinoid system deregulation in obesity, without the side effects occurring with CB1 receptor antagonists. PMID- 22943700 TI - A dual tag system for facilitated detection of surface expressed proteins in Escherichia coli. AB - BACKGROUND: The discovery of the autotransporter family has provided a mechanism for surface expression of proteins in laboratory strains of Escherichia coli. We have previously reported the use of the AIDA-I autotransport system to express the Salmonella enterica serovar Enteritidis proteins SefA and H:gm. The SefA protein was successfully exposed to the medium, but the orientation of H:gm in the outer membrane could not be determined due to proteolytic cleavage of the N terminal detection-tag. The goal of the present work was therefore to construct a vector containing elements that facilitates analysis of surface expression, especially for proteins that are sensitive to proteolysis or otherwise difficult to express. RESULTS: The surface expression system pAIDA1 was created with two detection tags flanking the passenger protein. Successful expression of SefA and H:gm on the surface of E. coli was confirmed with fluorescently labeled antibodies specific for the N-terminal His6-tag and the C-terminal Myc-tag. While both tags were detected during SefA expression, only the Myc-tag could be detected for H:gm. The negative signal indicates a proteolytic cleavage of this protein that removes the His6-tag facing the medium. CONCLUSIONS: Expression levels from pAIDA1 were comparable to or higher than those achieved with the formerly used vector. The presence of the Myc- but not of the His6-tag on the cell surface during H:gm expression allowed us to confirm the hypothesis that this fusion protein was present on the surface and oriented towards the cell exterior. Western blot analysis revealed degradation products of the same molecular weight for SefA and H:gm. The size of these fragments suggests that both fusion proteins have been cleaved at a specific site close to the C-terminal end of the passenger. This proteolysis was concluded to take place either in the outer membrane or in the periplasm. Since H:gm was cleaved to a much greater extent then the three times smaller SefA, it is proposed that the longer translocation time for the larger H:gm makes it more susceptible to proteolysis. PMID- 22943702 TI - Biomarkers in pre-eclampsia: a novel approach to early detection of the disease. AB - Pre-eclampsia is a unique disorder of human pregnancy with a great impact on maternal and perinatal morbidity and mortality worldwide and especially in developing countries. The aetiology is still unknown and the pathophysiology of the disease is the subject of extensive investigation. Recently, much of the interest of the investigators for the prediction of pre-eclampsia has been aimed at measurable manifestations of abnormal placentation, endothelial dysfunction and feto-maternal unit perfusion. Biomarkers constitute a novel approach to an early detection of the disease. Low maternal serum levels of PAPP-A and PP13 early in pregnancy are predictive for emerging pre-eclampsia. On the other hand, increased levels of homocysteine, ADMA, sEng, leptin and sFlt-1 in the 1st trimester, signal the onset of the disease later in pregnancy. After the onset of pre-eclampsia, increased serum levels of PAPP-A, ADMA, homocysteine and sFlt-1 are associated with the severity of the disease. The identification of biomarkers which can contribute to the early detection of pre-eclampsia is essential. It could then be possible to apply better surveillance and treatment protocols in such patients. PMID- 22943703 TI - Ureteroarterial fistula. AB - The authors intended to perform a comprehensive review of the literature pertaining to ureteroarterial fistulae and apply the findings to a case. A comprehensive literature search was performed using the Keywords: ureter, artery and fistula. The available articles printed in or translated to English were analysed for overall trends. The results were then compared with the case of a patient (index patient). Review of the literature reveals that 57% of all ureteroarterial fistulae form in women at an average age of 58. The most common presenting complaint is haematuria. There appears to be a shift in management from primarily open surgical to primarily angiographic. The known risk factors are: vascular pathology, malignancy, prior radiation and indwelling stents. While 98% of all cases have at least one known risk factor, only 41% had two or more. We report an additional case of this rare condition, and review the present literature. PMID- 22943704 TI - Caesarean scar pregnancy: a precursor of placenta percreta/accreta. AB - In the last decade, diagnosis of caesarean scar (CS) pregnancy and abnormal placental invasion has gone up significantly. It appears that the history of previous caesarean section is the predisposing factor common to both conditions. Until now, these are treated as a separate entity and therefore managed differently. Recent available evidence suggests that these are not a separate entity but rather a continuum of the same condition. If the caesarean scar pregnancy is managed expectantly in the 1st trimester, most likely it evolves into placenta accreta. This leads invariably to peripartum hysterectomy for postpartum haemorrhage (PPH) and severe maternal morbidity. Early diagnosis and intervention may give a favourable outcome. PMID- 22943705 TI - Expression of an electrically silent voltage-gated potassium channel in the human placenta. AB - Human placental expression of K(V)9.3, a voltage-gated K channel linked to tissue oxygenation responses, has been suggested at the messenger RNA level but tissue localisation has not been described. We aimed to: (1) produce an antibody to human K(V)9.3 and (2) assess channel expression and distribution in human placental tissue. We determined human placental protein expression and localisation using an antibody to K(V)9.3. Antibody specificity was confirmed by Western blotting. Staining was observed in syncytiotrophoblast microvillous membrane, endothelial cells (in intermediate, stem villi and chorionic plate blood vessels) and vascular smooth muscle cells (large diameter vessels only) by immunohistochemistry. Expression was unchanged in tissue from women with small for-gestational age babies. It was concluded that K(V)9.3 is localised to human placental vascular tissues and syncytiotrophoblast. PMID- 22943706 TI - Impedance cardiography in uncomplicated pregnancy and pre-eclampsia: a reliability study. AB - It has been reported that cardiac contractility is altered in pre-eclampsia compared with normal pregnancy. Because of the non-invasive nature of impedance cardiography (ICG), this method is gaining popularity in the obstetric field. We assessed the reliability of ICG measurements in uncomplicated 3rd trimester pregnancies (UP) and pre-eclamptic pregnancies (PE). ICG measurements were recorded before and after three position changes, and this examination was done twice (session 1 and 2) per subject. For each of the 22 haemodynamic parameters, inter- and intrasession Pearson's correlation coefficients (PCC) were calculated for mean values of 30 measurements per position per subject. PCC was consistently >= 0.80 for contractility parameters 'acceleration-', 'velocity-' and 'heather index' in both UP and PE. These data illustrate that correlation between repeated ICG measurements of cardiac contractility is high under standardised conditions, and that ICG may be useful to study changes of cardiac contractility in pregnancy. PMID- 22943707 TI - A case-control study of the risk of adverse perinatal outcomes due to tuberculosis during pregnancy. AB - We conducted a case-control study at three main inner-city hospitals in Birmingham, UK between 2004 and 2006, to determine the risk of adverse perinatal outcomes in pregnant women with tuberculosis (TB) (n = 24), compared with healthy pregnant controls (n = 72). The incidence of TB was 62/100,000 pregnancies, with 54.2% cases having pulmonary TB (41.7% extra-pulmonary; 4.2% both). Infants of mothers with TB had a significantly lower mean birth weight compared with controls (2,735 g vs 3,135 g; p = 0.03). Mean birth weight was lower in pulmonary TB than in the extra-pulmonary TB. Multivariate analysis showed that low birth weight was associated with pre-term delivery (p < 0.001). We conclude that pregnant women with TB are at higher risk of low birth weight due to higher odds of pre-term delivery. PMID- 22943708 TI - Validation of reportable indices of haematology, liver and renal function in pregnancy for the Middle Eastern population. AB - The objective of this study was to describe normative values of complete blood counts, kidney and liver function tests for Jordanian women. A prospective study of 797 healthy pregnant women, seen at the antenatal clinics of the Jordan University of Science and Technology, in Irbid, north Jordan, was conducted between January 2005 and December 2009. Differences by trimester were analysed using one-way ANOVA. The mean age of the women was 31.0 years. The mean gestational age at delivery was 38.2 weeks. It was concluded that complete blood counts, kidney and liver function values by trimester, of healthy pregnant population of Jordanian women, were consistent with data reported for other populations. PMID- 22943709 TI - Robotic-assisted transabdominal cerclage (RoboTAC) in the non-pregnant patient. AB - The use of cerclage, either through vaginal or abdominal routes, to assist in delaying pre-term delivery among select women with cervical insufficiency may be beneficial, but can also carry significant morbidity. Robotic-assisted transabdominal cervical cerclage (RoboTAC) in the non-pregnant patient has the ability to not only reduce associated morbidity, but also offer the same benefits as the more traditional laparotomy and laparoscopic approaches, while removing the risk to an in situ fetus. We report the use of robotic-assisted transabdominal cervical cerclage in 24 non-pregnant women. Feasibility of the procedure is discussed along with a description of the technical surgical details. In addition, limited pregnancy outcomes are presented. Our results suggest that RoboTAC is a safe alternative to the traditional laparotomy procedure with quicker recovery time. PMID- 22943710 TI - Cervical length vs VOCAL cervical volume for predicting pre-term delivery in asymptomatic women at 20-22 weeks' pregnancy. AB - We conducted a prospective observational study of 306 asymptomatic women at 20-22 weeks of pregnancy to compare 3-dimensional ultrasound measurements of cervical volume with 2-dimensional ultrasound measurements of cervical length to evaluate the performance of cervical volume as a predictor of pre-term delivery, compared with the current standard, cervical length. Participants underwent transvaginal ultrasound measurements of cervical length (mm) and cervical volume (cm(3)). Cervical volume as measured by 3-dimensional ultrasound was found to be a useful tool for predicting pre-term delivery; however, due to the high correlation between cervical length and cervical volume and the lack of differences in the sensitivity, specificity, positive predictive value, negative predictive value and relative risk between the two methods, replacing cervical length measurements with cervical volume calculations does not seem to be justified for this purpose, because of increased difficulty in volume acquisition. PMID- 22943711 TI - Cervical ripening and induction of labour-awareness, knowledge and perception of antenatal attendees in Ibadan, Nigeria. AB - The levels of awareness, knowledge and the perceptions of women about cervical ripening and induction of labour were assessed in a cross-sectional questionnaire based interview of 265 antenatal attendees of the University College Hospital, Ibadan, Nigeria from 1 March to 30 April 2009. Questions included evaluated sociodemographic data, obstetric history, awareness of both procedures and knowledge of specific methods. Data analysis was done using SPSS v.14.0 for Windows; frequency tables were utilised to determine proportions and significant variables from chi(2) analysis were entered into a logistic regression model. The majority of respondents were between 26 and 34 years; 56.4% were nulliparous. Awareness of cervical ripening and induction of labour was found in 71% of respondents. Knowledge of misoprostol and Foley's catheter however, was present in 25% and 13% of all women, respectively. Both procedures were perceived to prevent caesarean section or reduce burden of health workers in 16% of respondents. No significant predictor of knowledge was found but history of previous induction was a predictor of awareness (p < 0.05). Improved counselling is required to further increase knowledge of methods for induction and correct wrong perceptions, particularly in women at risk of labour induction. PMID- 22943712 TI - Change in paternity and select perinatal outcomes: causal or confounded? AB - Select social, behavioural and maternal characteristics were evaluated to determine if they were confounding factors in the association between paternity change and pre-eclampsia, small for gestational age (SGA) and pre-term delivery, in a sample of 1,409 women. Multivariate logistic regression analysis was used to determine if any of these risk factors modified the association between changing paternity and the selected perinatal outcomes. Results of the analysis showed that women who changed partners were more likely to possess potentially confounding risk factors compared with those who had not. Paternity change was 2.75 times more likely to be associated with the development of pre-eclampsia (95% CI 1.33; 5.68) and 2.25 times more likely to be associated with an SGA infant on weight (95% CI 1.13; 4.47), after adjusting for selected risk factors. Paternity change remains a significant risk factor for pre-eclampsia and SGA in the presence of select risk factors. PMID- 22943713 TI - Is postal postoperative follow-up in urogynaecology feasible? AB - Postoperative follow-up after urogynaecological surgery has been little investigated. Traditionally, it is done in hospital but there is wide variation in the assessments and timing. We aimed to determine the viability of postal follow-up in women undergoing urogynaecological surgery. This is a retrospective review of prospectively collected data. All women who underwent prolapse and/or urinary incontinence surgery between January and June 2010 were included. Validated ICIQ questionnaires for prolapse and/or incontinence, as appropriate, were used, before surgery and at 6 months postoperatively. The primary outcome was the response rate to postal follow-up. A total of 70 women had urogynaecology surgery during the study period; 65 (93%) women returned the questionnaires (95% CI 84-97%, p < 0.0001). The postoperative questionnaires scores showed a statistically significant improvement compared with the preoperative scores. This results in only a small proportion of women needing hospital attendance for follow-up (10%). We conclude that postal follow-up is feasible. PMID- 22943714 TI - A comparison study of two lower urinary tract symptoms screening tools in clinical practice: the B-SAQ and OAB-V8 questionnaires. AB - Lower urinary tract symptoms (LUTS) have a detrimental effect on quality-of-life (QoL). However, sufferers are often reluctant to seek help. Screening for LUTS will identify patients with bothersome symptoms who may benefit from treatment and allow patients to self-assess their symptoms and the need for medical intervention, potentially saving costly medical time and reducing long-term morbidity. The aim of this study was to compare the value of two validated questionnaires: the Bladder Control Self Assessment Questionnaire (B-SAQ) and the Overactive Bladder Awareness Tool (OAB-V8) as screening questionnaires in clinical practice. A total of 223 women were recruited prospectively from three centres. Participants completed both questionnaires in the waiting area prior to assessment by a clinician, who completed a symptom evaluation sheet. Data were analysed using receiver operating characteristic curves. Both the B-SAQ and the OAB-V8 performed well in detecting symptoms of OAB and mixed urinary symptoms. The B-SAQ performed better in detecting symptoms of stress incontinence than the OAB-V8. The opportunity to screen for haematuria should never be missed and this is an important omission from the OAB-V8. PMID- 22943715 TI - Ultrasound changes in the relationship between the urethra and bladder neck caused by prolapse repair: feasibility and reliability of measurements. AB - The objective of this study was to assess whether intraoperative transperineal ultrasound can be used to assess changes in the relationship between the urethra and bladder caused by a prolapse repair operation. The reliability of the measurements was also assessed. A total of 25 women having an anterior colporrhaphy operation had pre- and post-repair imaging using a standard bladder volume. There was a statistically significant change (p <= 0.04) in the posterior urethrovesical angle (PUA) from 115 degrees (SD 37) before surgery, to 135 degrees (SD 30) after surgery. There was no significant change (p = 0.93) in the anterior urethrovesical angle before 73 degrees (SD 14) after surgery 73 degrees (SD 14). Interclass correlation coefficients showed good reproducibility for all measurements. Ultrasound can be used to measure changes in the relationship of the urethra and bladder produced by anterior colporrhaphy. Clinically, the effect of these changes is to reduce the angulation of the urethra in relation to the bladder. PMID- 22943716 TI - When no choice of embryos exists, the multiple pregnancy risk is still high. AB - Multiple pregnancies arising from assisted reproduction are known to be associated with increased medical, psychological, economical and social risks. If only two embryos develop after culture, how should the couple be counselled in relation to the risk of multiple pregnancy? We performed a retrospective review of all IVF/ICSI treatments performed between 1 January 2005 and 31 December 2007, that resulted in double embryos transfer (DET). We identified 623 cycles with a fortuitous DET (Group I) and 635 cycles with an elective DET (Group II). Group II were significantly more likely to have twins when compared with Group I, irrespective of age. Twin rates in Group I were higher in IVF compared with ICSI; 33.3% vs 16.6% in < 35 years old and 16.2% vs 7.6% in 35-40 years old. Therefore, single embryo transfer should be considered for IVF patients below 35 years old, even if only two good quality embryos are available. PMID- 22943717 TI - Can video aids increase the validity of patient consent? AB - The objective of this study is to identify the value of using video to communicate and share information with patients, and assess the role of video in aiding decision-making and consent in urogynaecological surgery. The patients with the need for urogynaecological surgery who were seen in Weston Hospital from November 2003 to December 2008 were offered a video of the proposed procedure to watch prior to decision-making and consenting. Patients were then sent a questionnaire assessing the role of the video in their understanding of the need for and method of the procedure, and the impact of this on their decision-making. A total of 96 questionnaires were sent out, and 71 forms were returned and analysed. Our study shows that women's understanding of the method and purpose of their operation was significantly increased by using the video. PMID- 22943718 TI - Ovarian torsion: opportunities to improve clinical management. AB - Ovarian torsion is an uncommon condition which may affect women of any age. In a significant number of women, it may be associated with a concomitant pathology such as a cyst. Presently, there is no single diagnostic tool with significant predictive value. Multimodal diagnostic tools hold promise of early accurate diagnosis; prospective studies are required to assess the validity of such tools. This would enable wider application of ovarian function preserving procedures. Further, an assessment of the psychological impact of oophorectomy should be studied in order to facilitate the optimal tailored care. PMID- 22943719 TI - Comparison of laparoscopy and laparotomy in surgical staging of clinical early stage endometrial cancer: a report of early experiences from Turkey. AB - The objective of this study was to assess the feasibility of laparoscopy (LS) in endometrial carcinoma staging. Clinical early stage endometrial cancer patients (n = 153) staged by LS or laparotomy (LT) were compared. A total of 40 (26.1%) patients were treated by LS and 113 (73.9%) by LT. All patients underwent pelvic lymphadenectomy. Lymphadenectomy has been extended to para-aortic space in 55% of the LS group and 70% of the LT group. The majority of patients had stage I-II disease. The median numbers of removed pelvic and para- aortic lymph nodes were similar in two groups (p values 0.213 and 0.199, respectively). Body mass index (BMI) (kg/m(2)) was higher in the LT group (31.2 vs 27.4, p < 0.05). Operation time, age, tumour histology, para-aortic lymphadenectomy and complication rates were similar in the two groups. Four (10%) patients in the LS group and 12 (10.6%) in the LT group had recurrence of disease (p = 1.0). There was no statistical difference for overall survival between the two groups. In conclusion, these findings showed that in endometrial carcinoma cases, laparoscopy has provided adequate staging and similar survival rates with laparotomy. PMID- 22943720 TI - Knowledge, attitudes, practice on human papilloma virus and cervical cancer among Trinidadian women. AB - Cervical cancer remains a major reproductive health problem among women especially in developing countries where about 190,000 women die from this disease annually. Despite efforts to reduce the burden of this disease, most attempts in low-resourced countries have not been successful partly from lack of awareness by women of this common cancer, as well as the role the human papilloma virus (HPV) plays in its aetiology and pathogenesis. To determine knowledge, attitudes and practice of women in Trinidad (a developing country) on HPV, cervical cancer and the HPV vaccine, we conducted a cross-sectional survey among 426 women in the reproductive age. A majority (58.4%) of participants had attained secondary level education. Whereas 326 (76.5%) women knew of cervical cancer, only 108 (25.4%) were aware of HPV and 68 (15.9%) knew of the association between HPV and cervical cancer. This study highlights the limited awareness of Trinidadian women with respect to HPV and its implication in cervical cancer aetiology. If the scourge of cervical cancer is to be adequately addressed, especially in low-resourced countries, then mass educational programmes on HPV, cervical cancer prevention, including screening and early detection and treatment of pre-cancerous lesions of the cervix, must be given high priority. PMID- 22943721 TI - Bleeding from placenta percreta at 10 weeks' gestation. PMID- 22943722 TI - Expectant management of a caesarean scar pregnancy. PMID- 22943723 TI - Trisomy 3 confined placental mosaicism: a management dilemma. PMID- 22943724 TI - Detection of identical unbalanced karyotype in two consequent fetuses due to a maternal pericentric inversion of chromosome 18. PMID- 22943725 TI - Successful term pregnancy in a patient with cervicovaginal fistula managed with transabdominal laparoscopic cervical cerclage. PMID- 22943726 TI - Severe liver dysfunction during nausea and vomiting of pregnancy: folic acid supplement as a suggested culprit. PMID- 22943727 TI - Acute renal and liver failure due to acute fatty liver of pregnancy-complicated pre-eclampsia. PMID- 22943728 TI - Recurrent glioblastoma multiforme in pregnancy. PMID- 22943729 TI - An early presentation of uretero-uterine fistula post-caesarean section. PMID- 22943730 TI - A novel nonsense mutation in the N-terminal domain of the androgen receptor gene causes complete androgen insensitivity syndrome. PMID- 22943731 TI - An unusual complication of suture material after robotic assisted myomectomy. PMID- 22943732 TI - Botryoid rhabdomyosarcoma of the uterine cervix. PMID- 22943733 TI - A case of multiple morcelloma formation following laparoscopic sub-total hysterectomy. PMID- 22943734 TI - Primitive neuroectodermal tumour of uterine cervix - a diagnostic and therapeutic dilemma. PMID- 22943735 TI - Angioleiomyoma of uterus. PMID- 22943736 TI - Metastatic endometrial malignant melanoma. PMID- 22943737 TI - Re: Duenas-Garcia OF, Young C. 2012. Unusual finding of a metallic intrauterine device in postmenopausal bleeding. Journal of Obstetrics and Gynaecology 32:401 402. PMID- 22943738 TI - The effect of hindclaw height differential and subsequent trimming on lameness in large dairy cattle herds in Canterbury, New Zealand. AB - AIMS: To determine if inequality in height between claws within each hindlimb of dairy cattle is a risk factor for the development of lameness and to determine the effect of preventive trimming of these claws on the subsequent risk of lameness. METHODS: Cows (n=2,695) on three dairy farms in Canterbury, New Zealand, were examined and the height differential between their hind claws on each limb was measured. Cows were blocked by age, then breed and grouped by height differential, before being randomly assigned to either treatment or control groups. Cows in the control group were not trimmed, whilst cows in the treatment group were all trimmed according to the 'Dutch Trimming' method by an experienced foot trimmer. All subsequent clinical incidences of lameness were identified, recorded and classified according to five categories. The overall incidence of lameness, the effect of claw height differential on the incidence of lameness and the effect of trimming on the incidence of lameness were assessed using both GEE modelling and survival analysis. RESULTS: The incidence of lameness identified in any untrimmed hindlimb irrespective of diagnosis, measured at a limb level and assessing the first incidence of lameness only, was 10.0% for a 6-month period from November to drying off. The predominant lesion identified was white line disease (WLD; 7.9% incidence and 78.6% of all lameness). The overall incidence of hindlimb lameness measured at cow level for the same period was 14.5%. The risk of lameness was influenced by breed (p=0.016), age (p=0.002) and claw height differential (p=0.026). There were no significant interactions. The risk of lameness was lowest where the claw height differential was 0-2 mm. The incidence of lameness in the first 70 days following trimming was higher in older cows than in younger cows (p<0.001). Trimming did not affect lameness incidence (p=0.185). The Cox proportional hazard model demonstrated that farm (p<0.001), trimming group (p=0.021); and age (p=0.021) significantly affected the median days to lameness in the first 70 days following trimming. CONCLUSIONS AND CLINICAL RELEVANCE: Hind feet with lower height differentials between claws had a lower incidence of lameness. Trimming of these feet to remove the height differential did not reduce their overall incidence of lameness, but did increase days to first lameness. PMID- 22943739 TI - Surveillance cultures of samples obtained from biopsy channels and automated endoscope reprocessors after high-level disinfection of gastrointestinal endoscopes. AB - BACKGROUND: The instrument channels of gastrointestinal (GI) endoscopes may be heavily contaminated with bacteria even after high-level disinfection (HLD). The British Society of Gastroenterology guidelines emphasize the benefits of manually brushing endoscope channels and using automated endoscope reprocessors (AERs) for disinfecting endoscopes. In this study, we aimed to assess the effectiveness of decontamination using reprocessors after HLD by comparing the cultured samples obtained from biopsy channels (BCs) of GI endoscopes and the internal surfaces of AERs. METHODS: We conducted a 5-year prospective study. Every month random consecutive sampling was carried out after a complete reprocessing cycle; 420 rinse and swabs samples were collected from BCs and internal surface of AERs, respectively. Of the 420 rinse samples collected from the BC of the GI endoscopes, 300 were obtained from the BCs of gastroscopes and 120 from BCs of colonoscopes. Samples were collected by flushing the BCs with sterile distilled water, and swabbing the residual water from the AERs after reprocessing. These samples were cultured to detect the presence of aerobic and anaerobic bacteria and mycobacteria. RESULTS: The number of culture-positive samples obtained from BCs (13.6%, 57/420) was significantly higher than that obtained from AERs (1.7%, 7/420). In addition, the number of culture-positive samples obtained from the BCs of gastroscopes (10.7%, 32/300) and colonoscopes (20.8%, 25/120) were significantly higher than that obtained from AER reprocess to gastroscopes (2.0%, 6/300) and AER reprocess to colonoscopes (0.8%, 1/120). CONCLUSIONS: Culturing rinse samples obtained from BCs provides a better indication of the effectiveness of the decontamination of GI endoscopes after HLD than culturing the swab samples obtained from the inner surfaces of AERs as the swab samples only indicate whether the AERs are free from microbial contamination or not. PMID- 22943740 TI - Extrahepatic portal vein aneurysm after liver transplantation in a child: case report. AB - Portal vein aneurysms are very rare and represent <3% of all venous aneurysms. They can be congenital or acquired. Most patients do not have liver disease at diagnosis. Although uncommon, portal vein aneurysm has been described after liver transplant. We report the case of a six-yr-old girl who presented with an aneurysm of the extrahepatic portal vein after segmental liver transplantation. Because the patient was asymptomatic and owing to its extrahepatic location, this aneurysm has been successfully followed by clinical exam and imaging for four yr. PMID- 22943741 TI - Negative pressure wound therapy for the treatment of sternal wound infections after cardiac surgery. AB - We retrospectively collected and analysed data from patients with sternal wound infections between 1995 and 2001, which were treated with different wound management strategies, and compared them with our patients from 2002 to 2011, who were treated with the sternal negative pressure wound therapy (NPWT). From 1995 to 2001, a total of 198 patients (group A) with a mean age of 65 +/- 10 years developed sternal wound infection (67% deep) after cardiac surgery. Wound management consisted of surgical debridement and immediate sternal closure or open packing. From 2002 to 2011, a total of 326 patients (group B) (71% deep) were managed with NPWT at the time of surgical debridement. Total mortality was 10% in group A and 3.6% in group B. Recurrence rates were 34 and 8.5%, respectively, for the groups A and B. The meantime of NPWT was 11 days. In group B patients, 75% proceeded to sternal closure. With the introduction of NPWT, the treatment of sternal wound infections could be substantially improved. Particularly, the high recurrence rates could be minimised; furthermore, the goal to salvage the sternal bone is facilitated. PMID- 22943742 TI - Short and long-term effectiveness of couple counselling: a study protocol. AB - BACKGROUND: Healthy couple relationships are fundamental to a healthy society, whereas relationship breakdown and discord are linked to a wide range of negative health and wellbeing outcomes. Two types of relationship services (couple counselling and relationship education) have demonstrated efficacy in many controlled studies but evidence of the effectiveness of community-based relationship services has lagged behind. This study protocol describes an effectiveness evaluation of the two types of community-based relationship services. The aims of the Evaluation of Couple Counselling study are to: map the profiles of clients seeking agency-based couple counselling and relationship enhancement programs in terms of socio-demographic, relationship, health, and health service use indicators; to determine 3 and 12-month outcomes for relationship satisfaction, commitment, and depression; and determine relative contributions of client and therapy factors to outcomes. METHODS/DESIGN: A quasi experimental pre-post-post evaluation design is used to assess outcomes for couples presenting for the two types of community-based relationship services. The longitudinal design involves a pre-treatment survey and two follow-up surveys at 3- and 12-months post-intervention. The study is set in eight Relationships Australia Victoria centres, across metropolitan, outer suburbs, and regional/rural sites. Relationships Australia, a non-government organisation, is the largest provider of couple counselling and relationship services in Australia. The key outcomes are couple satisfaction, relationship commitment, and depression measured by the CESD-10. Multi-level modelling will be used to account for the dyadic nature of couple data. DISCUSSION: The study protocol describes the first large scale investigation of the effectiveness of two types of relationship services to be conducted in Australia. Its significance lies in providing more detailed profiles of couples who seek relationship services, in evaluating both 3 and 12-month relationship and health outcomes, and in determining factors that best predict improvements. It builds on prior research by using a naturalistic sample, an effectiveness research design, a more robust measure of relationship satisfaction, robust health indicators, a 12-month follow up period, and a more rigorous statistical procedure suitable for dyadic data. Findings will provide a more precise description of those seeking relationship services and factors associated with improved relationship and health outcomes. PMID- 22943743 TI - alpha-thalassemia trait caused by frameshift mutations in exon 2 of the alpha2 globin gene: HBA2:c.131delT and HBA2:c.143delA. AB - We describe two frameshift mutations associated with an alpha-thalassemia (alpha thal) phenotype, identified in three unrelated individuals investigated for persistent microcytosis. The first mutation, HBA2:c.131delT, is located in codon 43, and the second, HBA2:c.143delA, is located in codon 47. Both are due to single base pair deletions that cause a frameshift and a premature termination codon (PTC) at positions 48/49. The presence of a PTC at this position has been documented to result in nonsense mediated mRNA decay that would account for the thalassemic phenotype. PMID- 22943744 TI - Holothuria grisea agglutinin (HGA): the first invertebrate lectin with anti inflammatory effects. AB - Holothuria grisea agglutinin (HGA) is a dimeric lectin of molecular mass 228 kDa by gel filtration with monomers of 105 kDa by SDS-PAGE. The lectin is highly thermostable as it retains full activity for 1 h at 70 degrees C. Unlike other lectins purified from marine invertebrates, the hemagglutination activity of HGA does not require any divalent metal ions. The affinity analysis of HGA showed that only mucin was able to inhibit the hemagglutinating activity. HGA administered intravenously was tested in classical models of nociception and inflammation. HGA was able to inhibit neutrophil migration into the peritoneal cavity induced by carrageenan. This inhibitory effect was 68% at a dose of 1 mg/kg. In acetic acid-induced writhing tests, a significant antinociceptive effect was observed by treatment with HGA (0.1; 1 or 10 mg/kg) reducing constrictions by 27, 90 and 84%, respectively. In formalin tests, HGA at a dose of 10 mg/kg showed antinociceptive effect only in the inflammatory phase (phase 2). Nevertheless, in hot-plate tests, HGA did not show any nociceptive effect. In rota-rod and open-field tests, HGA did not alter the animals' behavior. The treatment with HGA 10 mg/kg presented diminished myeloperoxidase activity activity (81.6% inhibition) and raised the circulating levels of NO by 50.4% when compared with the carrageenan group. HGA has demonstrated the ability to modulate the inflammatory response in models of inflammation in vivo. HGA is the first marine invertebrate lectin that showed an anti-inflammatory effect. This finding opens a new perspective on the potential of lectins from the marine environment. PMID- 22943745 TI - Lack of a pharmacokinetic drug-drug interaction between lithium and valproate when co-administered with aripiprazole. AB - WHAT IS KNOWN AND OBJECTIVE: The antipsychotic, aripiprazole, plus lithium or valproate demonstrates rapid and significant improvement in manic symptoms that is sustained over the long term. A previous report showed that therapeutic doses of either lithium or valproate had no clinically significant effects on the pharmacokinetics of aripiprazole. We aimed to determine the effects of co administration of aripiprazole on the steady-state pharmacokinetics of lithium or valproate in healthy subjects. MATERIALS AND METHODS: Two similarly designed, open-label, single-sequence studies were conducted. Healthy subjects received daily oral doses of either lithium (450 mg every 12 h) or valproate (500 mg every 12 h) on Days 1-7. Following Day 7 was a 2-day washout period, and on Day 10, subjects began receiving oral doses of aripiprazole (10 mg once daily) for 2 days. Aripiprazole was then titrated from 10 to 20 mg once daily to establish tolerance of aripiprazole. On Day 14, the dose was escalated and subjects received aripiprazole 30 mg once daily for 13 days. Beginning on Day 20, subjects received lithium (450 mg every 12 h) or valproate (500 mg every 12 h) concomitantly with aripiprazole 30 mg once daily through Day 26. Serial blood samples for serum lithium or valproate concentration determination were collected for up to 12 h post-lithium or valproate administration on Days 7 and 26. RESULTS: The lithium study enrolled 32 healthy subjects (72% completed the study), and the valproate study enrolled 48 healthy subjects (58% completed the study). In both studies, the 90% confidence intervals for the ratios of population geometric means, with and without aripiprazole, were contained within 80% and 125% for both the C(max) and AUC(tau) , respectively. Furthermore, the addition of aripiprazole did not change the median T(max) of lithium or valproate (4 h). Thus, the addition of aripiprazole did not affect the steady-state pharmacokinetics of lithium or valproate. The majority of subjects (76.9% for aripiprazole plus lithium and 68.4% for aripiprazole plus valproate) reported adverse events, but this adverse event profile is consistent with what has been observed in other studies. WHAT IS NEW AND CONCLUSION: The addition of aripiprazole to either lithium or valproate had no clinically meaningful effects on the pharmacokinetics of either drug. In addition, co-administration of aripiprazole with lithium or valproate demonstrated no unexpected safety signals in healthy subjects. PMID- 22943747 TI - Molecular evolutionary and population genomic analysis of the nine-spined stickleback using a modified restriction-site-associated DNA tag approach. AB - In recent years, the explosion of affordable next generation sequencing technology has provided an unprecedented opportunity to conduct genome-wide studies of adaptive evolution in organisms previously lacking extensive genomic resources. Here, we characterize genome-wide patterns of variability and differentiation using pooled DNA from eight populations of the nine-spined stickleback (Pungitius pungitius L.) from marine, lake and pond environments. We developed a novel genome complexity reduction protocol, defined as paired-end double restriction-site-associated DNA (PE dRAD), to maximize read coverage at sequenced locations. This allowed us to identify over 114,000 short consensus sequences and 15,000 SNPs throughout the genome. A total of 6834 SNPs mapped to a single position on the related three-spined stickleback genome, allowing the detection of genomic regions affected by divergent and balancing selection, both between species and between freshwater and marine populations of the nine-spined stickleback. Gene ontology analysis revealed 15 genomic regions with elevated diversity, enriched for genes involved in functions including immunity, chemical stimulus response, lipid metabolism and signalling pathways. Comparisons of marine and freshwater populations identified nine regions with elevated differentiation related to kidney development, immunity and MAP kinase pathways. In addition, our analysis revealed that a large proportion of the identified SNPs mapping to LG XII is likely to represent alternative alleles from divergent X and Y chromosomes, rather than true autosomal markers following Mendelian segregation. Our work demonstrates how population-wide sequencing and combining inter- and intra-specific RAD analysis can uncover genome-wide patterns of differentiation and adaptations in a non-model species. PMID- 22943746 TI - Fidelity and acceptability of an adaptive intervention for caregivers: an exploratory study. AB - OBJECTIVE: There has been growing interest in providing tailored or adaptive interventions to family caregivers as a way of addressing their heterogeneity of risk factors and other needs. A particular challenge in an adaptive study is to implement the individualized intervention protocol as planned (program fidelity). This study explores the fidelity of implementation of an adaptive intervention for family caregivers of persons with dementia and its acceptability to caregivers. METHOD: Using a sample of 35 caregivers of person with dementia who participated in a program development study, we gathered information on acceptability and fidelity of the program from multiple sources, including caregiver and counselor reports and ratings of recordings of sessions. RESULTS: Findings show that caregivers have high levels of acceptance of the intervention plan and high ratings of satisfaction with the program. Ratings of satisfaction and counselor competence were not associated with the amount of treatment provided. Ratings by counselors and independent raters found good fidelity for two of the three program domains. DISCUSSION: The results demonstrate that trained counselors can follow a tailored intervention plan and that caregivers' experience of the program did not differ depending on how much intervention was provided. A next step is to determine how an adaptive protocol would affect caregiver outcomes. PMID- 22943749 TI - [Proper understanding and fair usage of proton pump inhibitors]. PMID- 22943748 TI - Objective structured assessment of technical skills and checklist scales reliability compared for high stakes assessments. AB - BACKGROUND: The establishment of assessment reliability at the level of the individual trainee is an important attribute of assessment methodologies, particularly for doctors who have been failed. This issue is of particular importance for the process of competence assessment in the USA, UK, Australia and New Zealand. METHODS: We use data from 19 applicants for higher surgical training in 2008 at the Royal College of Surgeons in Ireland to compare: (i) the objective structured assessment of technical skills (OSATS) method; and (ii) a procedure specific checklist to assess surgical technical skills in the excision of a sebaceous cyst task by two experienced senior surgeons. RESULTS: The overall interrater reliability (IRR) of the OSATS assessment as determined by a correlation coefficient was 0.507 (P < 0.03) and 0.67 with coefficient alpha, considerably below the accepted 0.8 level of IRR. The checklist's overall IRR was 0.89. Individually, only five (26%) of the OSATS assessments reached the 0.8 level of IRR in contrast to 18 (95%) of the checklist assessments. DISCUSSION: We propose binary procedure-based assessment checklists as more reliable assessment instruments with more robust reproducibility. PMID- 22943750 TI - [An epidemiological study of functional bowel disorders in Zhejiang college students and its relationship with psychological factors]. AB - OBJECTIVE: To study the epidemiologic features of functional bowel disorders (FBD) among medical students and science and engineering students in Zhejiang province, China, and to explore the relationship between psychological factors and FBD. METHODS: This study was a survey of random sampling based on the Rome III Diagnostic Questionnaire (Rome III-DQ) conducted from November 2010 to March 2011. The survey was carried out among medical students and science and engineering students respectively in two universities in Zhejiang province. Symptom Check List 90 (SCL-90) was used for psychological analysis. RESULTS: Among 1870 participants, 1033 were diagnosed as FBD based on Rome III criteria, with an overall incidence of 55.24%. The majority cases were unspecified functional bowel disorder, with an incidence of 26.58% (497/1870), others were functional constipation 16.95% (317/1870), irritable bowel syndrome 6.90% (129/1870), functional bloating 4.12% (77/1870) and functional diarrhea 0.70% (13/1870). The prevalence varied in different genders, majors and grades. In the multivariate analysis, women had a higher risk of any FBD than men [68.33% (617/903) vs 43.02% (416/967)] except for functional diarrhea; and medical students had a higher risk of any FBD than science and engineering students [68.53% (734/1071) vs 37.42% (299/799)]. Generally higher grade undergraduates had relatively higher risks than lower grade students, especially in medical students. Among the participants with FBD, 44.05% (455/1033) had other functional gastrointestinal disorders. In those overlapped parts, 9.00% (93/1033) had belching disorders, and 8.23% (85/1033) had functional dyspepsia. Students with FBD got higher scores in SCL-90 than healthy students. CONCLUSIONS: This study revealed a high rate of FBD among college students in Zhejiang province. The prevalence varied in different majors, and female higher than male. Psychological factors also had close relationships with FBD. PMID- 22943751 TI - [A clinical observation of percutaneous balloon dilation and maintenance percutaneous transhepatic cholangial catheter drainage for treatment of 21 patients with benign biliary strictures and difficult endoscopy]. AB - OBJECTIVE: To investigate the value of percutaneous balloon dilation and percutaneous transhepatic cholangial drainage (PTCD) catheter maintenance in the treatment of benign biliary strictures. METHODS: The clinical data of 21 patients with benign biliary strictures at Peking Union Medical College Hospital from June 2005 to June 2011 were retrospectively studied, in which 12 patients in severe stricture (stenosis > 70%) were treated with percutaneous balloon dilation and PTCD catheter placed across the stricture, while another 9 patients in median stricture (stenosis < 70%) were only treated with PTCD catheter maintenance. RESULTS: Of the 12 patients underwent balloon dilation and 6 - 12 months (median: 9 months) of PTCD catheter placement, 11 patients had the catheter successfully removed. In the follow-up of 6 - 24 months (median: 10 months), patency of bile duct was preserved in 9 of 11 patients, and recurrent stenosis was seen in 2 patients. A severe complication with biliary artery branch rupture and massive hemobilia was seen in 1 patient during balloon dilation. Of the 9 patients only treated with 1 - 12 months (median: 6 months) of PTCD catheter placement, 7 patients had the catheter successfully removed. In the follow-up of 5 - 18 months (median: 8 months), patency of bile duct was preserved in 5 of 7 patients, and recurrent stenosis was seen in 2 patients. No severe complication occurred. CONCLUSIONS: When endoscopy therapy is failed or the patient can't undergo endoscopy therapy, the percutaneous balloon dilation and PTCD catheter maintenance method is an effective alternative therapeutic approach in the treatment of benign biliary strictures. The moderate benign biliary stricture may be effectively treated only by the PTCD catheter maintenance method. PMID- 22943752 TI - [The evaluation value of severity and prognosis of septic shock patients based on the arterial-to-venous carbon dioxide difference]. AB - OBJECTIVE: To assess the value of central venous-to-arterial carbon dioxide difference [P((cv-a))CO2] in evaluation of disease severity and prognosis in patients with septic shock. METHODS: There were 45 consecutive resuscitated septic shock patients from April 2009 to October 2010 included immediately after their admission into our ICU. The patients were divided into low P((cv-a))CO2 group and high P((cv-a))CO2 group according to a threshold of 6 mm Hg (1 mm Hg = 0.133 kPa). All patients were treated by early goal directed therapy (EGDT). The parameters of hemodynamics, lactate clearance rate, the Acute Physiology and Chronic Health Evaluation II (APACHE II) score, the sequential organ failure assessment (SOFA) score, 6 h rate of EGDT achievement, the ICU mortality and 28 days in-hospital mortality were recorded for all patients. RESULTS: There were 30 patients in the low P((cv-a))CO2 group, and 15 in the high P((cv-a))CO2 group. There were no significant differences between low P((cv-a))CO2 and high P((cv a))CO2 patients in age, APACHE II score and SOFA score (all P > 0.05). Compared with the high P((cv-a))CO2 group, the low P((cv-a))CO2 group had higher cardiac index (CI) and 24 h CI, higher delivery O2 (DO2) and 24 h DO2, higher central venous oxygen saturation (ScvO2) [(74 +/- 9)% vs (67 +/- 8)%], lower lactate [(3.4 +/- 2.1) mmol/L vs (5.7 +/- 4.5) mmol/L] and higher DeltaSOFA score [(0.7 +/- 1.8) vs (-0.4 +/- 1.1)], lower 24 h SOFA score [(7.8 +/- 2.0) vs (9.8 +/- 2.0)], higher 6 h rate of EGDT achievement (83.3% vs 53.3%) (P < 0.05), however, there were no differences in 28 days mortality and ICU mortality between the two groups (P > 0.05). CONCLUSION: P((cv-a))CO2 might be an indicator for predicting the severity of patients with septic shock and evaluating tissue perfusion. PMID- 22943753 TI - [Incidence of metabolic syndrome in systemic lupus erythematosus and its influence by glucocorticoids]. AB - OBJECTIVE: To investigate the incidence and correlative factors of metabolic syndrome (MS) in patients with systemic lupus erythematosus (SLE). METHODS: A total of 116 SLE patients and 115 controls were enrolled into the study. The incidence of MS, SLE disease activity index (SLEDAI) of patients with SLE combined with MS (MS-SLE) and patients without MS (n-MS-SLE), lupus characteristics, cumulative glucocorticoids, administration dose of glucocorticoids and hydroxychloroquine were compared between SLE group and the control group. RESULTS: The incidence of MS of SLE group was obviously higher than that of the control (34.48% vs 14.78%, P < 0.05). The ratios of patients with lower HDL-C, higher TG and higher blood pressure in SLE group (50.86%, 56.03%, 46.55%) were higher than those in the controls (34.78%, 16.52%, 20.00%, all P < 0.05). MS-SLE group had significantly higher mean waist circumference, BMI, systolic blood pressure and diastolic blood pressure and lower HDL-C than n MS-SLE group (all P < 0.05). No significant difference was found regarding duration of disease, renal involvement, ESR, C-reactive protein,high-sensitivity C-reactive protein, SLEDAI, cumulative and current glucocorticoids use in MS-SLE group and n-MS-SLE group. The ratio of patients taking hydroxychloroquine in n-MS SLE group was higher than that of MS-SLE group (46.05% vs 15.00%, P < 0.05). CONCLUSIONS: Patients with SLE has a higher incidence rate of MS. Hydroxychloroquine may reduce their MS incidence. PMID- 22943754 TI - [The value of ABCD3-I score in prediction of cerebral infarction after transient ischaemic attack]. AB - OBJECTIVE: To assess the ability of ABCD3-I score in evaluating the early risk of cerebral infarction after transient ischemic attack (TIA). METHODS: A total of 107 TIA patients were evaluated according to ABCD2, ABCD3 and ABCD3-I criteria. The occurrences of cerebral infarction within 2 days and 7 days were observed. RESULTS: The AUC(ROC) of ABCD2, ABCD3 and ABCD3-I were 0.61, 0.66 and 0.71 in predicting the risk of cerebral infarction within 2 days, and were 0.62, 0.68 and 0.74 in predicting within 7 days, respectively. Among 107 patients with TIA, 13 evolved into cerebral infarction within 2 days, accounting for 12.1%, and 24 within 7 days, accounting for 22.4%.According to ABCD3-I criteria, 17 patients were of low risk scored 0-3; 54 patients were of medium risk scored 4-7; and 36 patients were of high risk scored 8-13. The different incidence of cerebral infarction after TIA was related to ABCD3-I score: the higher the score was, the higher incidence was. Except for age factor, every score item of ABCD3-I display obvious influence to the occurrence of cerebral infarction within 2 days and 7 days after TIA (P < 0.05). CONCLUSION: ABCD3-I criteria could more effectively predict the occurrence of early risk of cerebral infarction after TIA, which could be used in regular clinical practice for assistance in TIA risk stratification and treatment. PMID- 22943755 TI - [The value of Doppler echocardiography in assessment of pulmonary capillary wedge pressure in pulmonary hypertension]. AB - OBJECTIVE: To explore the association between Doppler echocardiography parameters and pulmonary capillary wedge pressure (PCWP) obtained by right heart catheterization (RHC) in patients with pulmonary hypertension (PH). METHODS: RHC and a simultaneous echocardiography were performed in 86 PH patients. The correlation between the echocardiographic parameters and PCWP was analyzed. RESULTS: The early diastolic velocity (E) of mitral valve blood flow was significantly correlated with PCWP (r = 0.36, P < 0.01). Tissue Doppler imaging measured the diastolic velocity of mitral annulus on the lateral (E'L) and the septal (E'S) wall. Then the average E'M was calculated. The ratio of E to E'L, E'S and E'M showed a strong correlation with PCWP (r = 0.62, 0.34 and 0.47 respectively, P < 0.01). E/E'L < 6 accurately predicted 100% PCWP <= 15 mm Hg (1 mm Hg = 0.133 kPa), and E/E'L > 15 could predict PCWP > 15 mm Hg with specificity of 98.5%. CONCLUSION: There are positive correlation between E/E' and PCWP obtained by RHC in PH patients. PMID- 22943756 TI - [The impact of regular exercise habit on exercise tolerance early after acute myocardial infarction]. AB - OBJECTIVE: To investigate the relationship between regular exercise habit and peak oxygen uptake (VO2peak) early after acute ST-elevation myocardial infarction (STEMI). METHODS: A total of 239 patients who underwent cardiopulmonary exercise testing (CPET) early after STEMI in a single exercise laboratory were enrolled. Influencing factors to VO2peak were analyzed retrospectively. RESULTS: There were 53.6% patients reported to have regular exercise habits before STEMI. No significant difference between patients with and without exercise habit in VO(2)peak early after STEMI (P = 0.317) were found by t test. After adjusted by risk factors including demographic features, clinical characteristics and cardiovascular, etc, regular exercise habit was an independent factor for VO2peak (beta = 1.703, P = 0.015). Following age-stratification, the significant difference was found between patients with and without exercise habits in VO2peak only in patients aged between 40 - 49 years old (P = 0.004). CONCLUSIONS: The relationship between regular exercise habit and VO2peak early after STEMI suggests that exercise tolerance of patients with exercise habit will be better than sedentary patients even after STEMI, in particular to patients aged between 40 - 49 years old. PMID- 22943757 TI - [The long-term efficacy and safety of rituximab combined with cyclophosphamide in treatment of seven patients with refractory and recurrent autoimmune hemolytic anemia]. AB - OBJECTIVE: To assess the efficacy and safety of monoclonal antibody rituximab combined with cyclophosphamide (CTX) in the treatment of refractory and recurrent autoimmune hemolytic anemia. METHODS: Seven cases with refractory and recurrent autoimmune hemolytic anemia (including 1 case of Evans syndrome) were recruited during January, 2007 to December, 2010. Treatment regimens were as follows: rituximab: 375 mg/m2, 1 time/week, 2-6 courses; CTX:1 g, 1/10 d, 2-7 courses; combined with intravenous immunoglobulin (IVIG) 5 g, 1 time/week, given 1 day after rituximab administration. The efficacy and safety of this regimen were assessed during follow-up. RESULTS: All the patients showed good responses (7/7). Six patients achieved complete remission (6/7) and one achieved partial remission (1/7). Average follow-up time for the patients was 27 months. All patients remained in remission during the 12-month follow-up visits. Two patients showed elevated indirect bilirubin and increased reticulocyte counts within 24 months. One patient achieved complete remission after additional rituximab therapy, and another patient remained partial remission after cyclosporine therapy. At the time of 36-month follow-up visit, the patient relapsed and was retreated with 3 courses of rituximab combined with CTX and eventually achieved partial remission. All patients tolerated the treatment well with few mild side effects. CONCLUSIONS: Rituximab combined with CTX is effective and relatively safe in patients with refractory and recurrent autoimmune hemolytic anemia. Additional treatment to relapse patients about 12 - 24 months after drug withdrawal continues to be effective. PMID- 22943758 TI - [Effects of quercetin on nuclear factor-kappaB p65 expression in renal ubiquitin proteasome system of diabetic rats]. AB - OBJECTIVE: To investigate the protective effect of quercetin on diabetic nephropathy and to explore its possible mechanism. METHODS: Type 2 diabetes mellitus rat model was established by feeding high-carbohydrate-fat diet and injecting with streptozotocin. At 72 hour after injection, blood samples were collected from the tail veins of all rats. Those rats with blood glucose level >= 16.7 mmol/L were considered as the diabetes model been successfully established. The model rats were randomly divided into type 2 diabetic group (group DM, n = 9) and quercetin group (group QUE, n = 9). Other rats were used as normal controls (group NC, n = 8). All rats were performed by intragastric administration for 8 weeks. At the end of experiment, the rats were sacrificed and fasting plasma glucose (FPG), fasting insulin(FIns), serum creatinine (SCr), blood urea nitrogen (BUN), TG, TC, LDL-C, 24 h urine protein (24 h UP), and kidney index (KI) were evaluated. Pathological changes of kidney were observed by periodic acid-silver methenamine (PASM). The expressions of ubiquitin and NF-kappaB p65 on glomeruli were examined by immunohistochemical method, and its association with the incidence of proteinuria was analyzed. RESULTS: In groups DM and QUE, the level of FPG [(25.45 +/- 1.23) mmol/L and (19.99 +/- 1.20) mmol/L], FIns [(25.67 +/- 2.58) mU/L and (19.29 +/- 1.80) mU/L], SCr [(44.00 +/- 2.53) umol/L and (34.43 +/ 2.23) umol/L], BUN[(11.60 +/- 0.39) mmol/L and (8.20 +/- 0.37) mmol/L], TG[(3.32 +/- 0.22)mmol/L and (2.43 +/- 0.25) mmol/L], TC [(2.95 +/- 0.21) mmol/L and (2.24 +/- 0.17) mmol/L], LDL-C [(2.03 +/- 0.22) mmol/L and (1.49 +/- 0.13) mmol/L], 24 h UP[(46.67 +/- 2.50) mg/24 h and (25.57 +/- 2.82) mg/24 h] and KI [(9.76 +/- 0.30)*103 and (8.44 +/- 0.26)*103] were significantly increased than the indexes of group NC [(6.56 +/- 0.41) mmol/L, (12.63 +/- 1.41) mU/L, (22.88 +/- 2.36) umol/L, (5.45 +/- 0.51) mmol/L, (1.64 +/- 0.11) mmol/L, (1.33 +/- 0.17) mmol/L, (0.46 +/- 0.05) mmol/L, (12.38 +/- 1.19)/24 h and (6.78 +/- 0.12)*103]. Moreover, the above indexes in group QUE were obviously lower than group DM. There was evidence of pathological changes associated with diabetes, such as focal and segmental sclerosis and thickened basement and mesangial expansion. The expressions of ubiquitin and NF-kappaB p65 in renal tissues of group DM increased significantly (P < 0.01). The expression of ubiquitin and NF-kappaB p65 were positively related with the level of 24 h UP (r = 0.893, 0.879, P < 0.01). Compared with group DM, all above indexes in group QUE were markedly alleviated (P < 0.01). The expression of ubiquitin and NF-kappaB p65 was reduced but didn't reach level in group NC (P < 0.01). CONCLUSION: The increased expression of NF kappaB induced by ubiquitin-proteasome system may participate in the pathogenesis of proteinuria in diabetic nephropathy. Quercetin has renal protective effects partly through reducing NF-kappaB p65 expression. PMID- 22943759 TI - [The protective effect of chlorophyllin against oxidative damage and its mechanism]. AB - OBJECTIVE: To investigate whether chlorophyllin could protect human umbilical vein endothelial cell (HUVEC) against oxidative damage by inducing the expression of heme oxygenase-1 (HO-1) and to explore the underlying mechanism. METHODS: The cellular protection of chlorophyllin against oxidative damage was detected by cell-survival assay with flow cytometry. The level of free radicals was detected directly by electron spin resonance spectra. The induced expression of HO-1 was shown by RT-PCR, Western blot, immunofluorescence confocal laser microscopy and enzymatic activity test. Whether the activation of PI3K/Akt pathway was involved was detected by Western blot. RESULTS: Chlorophyllin could protect HUVEC against oxidative damage caused by H2O2 via scavenging the excessive free radicals. Chlorophyllin treatment could induce expression of HO-1 in a dose- and time dependent manner. The activation of PI3K/Akt pathway was required in the induction of HO-1. LY294002, the specific inhibitor of PI3K, could suppress the activation of PI3K/Akt and the induced expression of HO-1 in a dose-dependent manner. CONCLUSIONS: Chlorophyllin shows cellular protection against oxidative damage by counteracting the excessive free radicals. Up-regulation of HO-1 expression plays a pivotal role in the protection of chlorophyllin, while the activation of PI3K/Akt signaling pathway is required in the induction of HO-1. PMID- 22943760 TI - Postoperative complications following colectomy for ulcerative colitis: a validation study. AB - BACKGROUND: Ulcerative colitis (UC) patients failing medical management require colectomy. This study compares risk estimates for predictors of postoperative complication derived from administrative data against that of chart review and evaluates the accuracy of administrative coding for this population. METHODS: Hospital administrative databases were used to identify adults with UC undergoing colectomy from 1996-2007. Medical charts were reviewed and regression analyses comparing chart versus administrative data were performed to assess the effect of age, emergent operation, and Charlson comorbidities on the occurrence of postoperative complications. Sensitivity, specificity, and positive/negative predictive values of administrative coding for identifying the study population, Charlson comorbidities, and postoperative complications were assessed. RESULTS: Compared to chart review, administrative data estimated a higher magnitude of effect for emergent admission (OR 2.52 [95% CI: 1.80-3.52] versus 1.49 [1.06 2.09]) and Charlson comorbidities (OR 2.91 [1.86-4.56] versus 1.50 [1.05-2.15]) as predictors of postoperative complications. Administrative data correctly identified UC and colectomy in 85.9% of cases. The administrative database was 37% sensitive in identifying patients with >= 1Charlson comorbidity. Restricting analysis to active comorbidities increased the sensitivity to 63%. The sensitivity of identifying patients with at least one postoperative complication was 68%; restricting analysis to more severe complications improved the sensitivity to 84%. CONCLUSIONS: Administrative data identified the same risk factors for postoperative complications as chart review, but overestimated the magnitude of risk. This discrepancy may be explained by coding inaccuracies that selectively identifying the most serious complications and comorbidities. PMID- 22943761 TI - Experiences of poststroke fatigue: qualitative meta-synthesis. AB - AIM: To interpret and synthesize stroke survivors' experiences of poststroke fatigue. BACKGROUND: Several studies have found fatigue to be a common and distressing difficulty experienced after stroke. This review has synthesized qualitative findings of stroke survivors' experiences of poststroke fatigue with the aim of guiding practice and further research. DATA SOURCES: A computer-aided search of the PubMed, CINAHL, PsycINFO, and Embase databases was performed up to April 2012. DESIGN AND REVIEW METHODS: Interpretive qualitative meta-synthesis. Of 167 papers identified, 12 were included. FINDINGS: Three main themes of the experience of poststroke fatigue were identified. First, five characteristics were identified and interpreted as core characteristics of poststroke fatigue. These did not seem to be influenced by the context. Two additional, distressing characteristics were identified. These were interpreted as being more responsive to the context. Second, we found that the acknowledgement of poststroke fatigue by stroke survivors and their significant others were important for the experience of poststroke fatigue. This theme appeared to be consistent across studies and was interpreted as having a major impact on the third theme identified; coping with poststroke fatigue. Two main coping patterns appeared: one taking the fatigue into account and the other struggling to cope. Lack of acknowledgement of poststroke fatigue complicates the coping process and invokes additional emotional distress. CONCLUSION: Poststroke fatigue is a complex phenomenon. Acknowledging its presence and impact is important to cope well with it. Lack of acknowledgement from significant others increases add to the burden. [Correction added after online publication 3 September 2012: Instances of the word 'statistically' have been removed from the Findings and Conclusion in the abstract section.]. PMID- 22943762 TI - Estimating cost-effectiveness in public health: a summary of modelling and valuation methods. AB - It is acknowledged that economic evaluation methods as they have been developed for Health Technology Assessment do not capture all the costs and benefits relevant to the assessment of public health interventions. This paper reviews methods that could be employed to measure and value the broader set of benefits generated by public health interventions. It is proposed that two key developments are required if this vision is to be achieved. First, there is a trend to modelling approaches that better capture the effects of public health interventions. This trend needs to continue, and economists need to consider a broader range of modelling techniques than are currently employed to assess public health interventions. The selection and implementation of alternative modelling techniques should be facilitated by the production of better data on the behavioural outcomes generated by public health interventions. Second, economists are currently exploring a number of valuation paradigms that hold the promise of more appropriate valuation of public health interventions outcomes. These include the capabilities approach and the subjective well-being approach, both of which offer the possibility of broader measures of value than the approaches currently employed by health economists. These developments should not, however, be made by economists alone. These questions, in particular what method should be used to value public health outcomes, require social value judgements that are beyond the capacity of economists. This choice will require consultation with policy makers, and perhaps even the general public. Such collaboration would have the benefit of ensuring that the methods developed are useful for decision makers. PMID- 22943763 TI - Label-free mass spectrometry-based quantification of hemagglutinin and neuraminidase in influenza virus preparations and vaccines. AB - BACKGROUND: Influenza vaccination is the primary method for preventing influenza and its severe complications. An accurate rapid method to determine hemagglutinin (HA) concentration would facilitate reference antigen preparation and consequently expedite availability of seasonal as well as pandemic vaccines. OBJECTIVE: The goal of this study was to develop a label-free mass spectrometry (MS) based method that enables simultaneous identification and quantification of HA, neuraminidase (NA), and other viral proteins and protein contaminations in influenza vaccine or virus preparations. METHODS: The method presented is based on LC/MSE analysis of vaccine or virus preparations tryptic digests spiked with a known amount of protein standard from which a universal response factor is generated and applied to calculate the concentration of proteins identified in the mixture. RESULTS: We show that, with the use of an appropriate internal standard, the label-free MS-based protein quantification method is applicable for simultaneous identification and absolute quantification of HA and identification and relative quantification of other influenza proteins as well as protein impurities in influenza vaccines and virus preparations. We show that different subtype recombinant HA is preferred internal standard that provides the most accurate results in absolute quantification of HAs and other influenza proteins. We applied this method to measure the absolute quantity of HA as well as relative quantities of other viral proteins and impurities in preparations of whole virus and monovalent vaccine, providing data to demonstrate strain-dependent differences in the amount of NA. CONCLUSION: The label-free MS method presented here is ideally suited for timely preparation of reference material needed for potency testing of seasonal and pandemic vaccines. PMID- 22943764 TI - Identification and confirmation of an exonic splicing enhancer variation in exon 5 of the Alzheimer disease associated PICALM gene. AB - Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by memory and cognitive impairment and is the leading cause of dementia in the elderly. A number of genome wide association studies and subsequent replication studies have been published recently on late onset AD (LOAD). These studies identified several new susceptibility genes including phosphatidylinositol-binding clathrin assembly protein (PICALM) on chromosome 11. The aim of our study was to examine the entire coding sequence of PICALM to determine if the association could be explained by any previously undetected sequence variation. Therefore, we sequenced 48 cases and 48 controls homozygous for the risk allele in the signal SNP rs3851179. We did not find any new variants; however, rs592297, a known coding synonymous SNP that is part of an exonic splice enhancer region in exon 5, is in strong linkage disequilibrium with rs3851179 and should be examined for functional significance in Alzheimer pathophysiology. PMID- 22943765 TI - Hip circumference, height and risk of type 2 diabetes: systematic review and meta analysis. AB - Although several epidemiological studies have investigated the relationship between type 2 diabetes mellitus (T2DM) and hip circumference or height, the results are inconsistent. The present systematic review and meta-analysis of published observational studies was conducted to assess the effects of hip circumference and height on diabetes risk. Online databases were searched through January 2012, and the reference lists of pertinent articles reporting observational studies in humans were examined. Pooled relative risks (RR) and 95% confidence intervals (CI) were calculated with a random-effects model. Eighteen studies (nine cross-sectional and nine cohort) were included, with 250,497 participants and 7,765 cases of T2DM. Hip circumference was inversely associated with an increased risk of T2DM in men (summary RR [95% CI] 0.60 [0.45, 0.80]) and women (0.54 [0.42, 0.70]). These results were consistent between cross-sectional and cohort studies. An inverse association between height and T2DM was observed in women only (summary RR [95% CI] 0.83 [0.73, 0.95]). Our meta-analysis strongly supports an inverse relationship between hip circumference and risk of T2DM in men and women. The inverse association between height and risk was significant only in women. PMID- 22943766 TI - Evaluation of the repeatability of the Lenstar and comparison with two other non contact biometric devices in myopes. AB - BACKGROUND: The aim was to evaluate the repeatability of a new optical low coherence reflectometric device Lenstar, as well as its agreement with the IOL Master and the Pentacam-HR system in myopes. METHODS: In a prospective study, 56 eyes of 28 myopes were examined with the Lenstar, the IOL Master and the Pentacam HR system. The repeatability of the Lenstar was assessed. Bland-Altman plots were used to analyse the agreement between the Lenstar and the IOL Master for axial length (AL), anterior chamber depth (ACD from corneal epithelium to lens surface), keratometry readings of flattest and steepest meridian (K1 and K2) and horizontal iris width (white-to-white distance; WTW) measurements and between the Lenstar and the Pentacam-HR system for central corneal thickness (CCT), ACD (from corneal endothelium to lens surface) and K1 and K2 readings. RESULTS: The variability of the Lenstar was small for all recorded measurements. CCT measurements with the Lenstar and the Pentacam-HR system and ACD measurements with the Lenstar and the other two devices showed narrow 95% limits of agreement (LoA), which imply good agreement. In contrast, range and 95% LoA were clinically significantly different for AL, K1, K2 and WTW values between the Lenstar and the IOL Master as well as for K readings between the Lenstar and the Pentacam-HR system. CONCLUSIONS: The repeatability of the Lenstar is excellent. In clinical practice, the Lenstar and the Pentacam-HR system can be used interchangeably for CCT and ACD measurements but not for K readings. The Lenstar and the IOL Master can be used interchangeably for ACD measurements but not for AL, K readings or WTW distance values. PMID- 22943768 TI - What can be learned from old traditional teaching on the health of the elderly? PMID- 22943767 TI - Neuropsychological assessment of driving safety risk in older adults with and without neurologic disease. AB - Decline in cognitive abilities can be an important contributor to the driving problems encountered by older adults, and neuropsychological assessment may provide a practical approach to evaluating this aspect of driving safety risk. The purpose of the present study was to evaluate several commonly used neuropsychological tests in the assessment of driving safety risk in older adults with and without neurological disease. A further goal of this study was to identify brief combinations of neuropsychological tests that sample performances in key functional domains and thus could be used to efficiently assess driving safety risk. A total of 345 legally licensed and active drivers over the age of 50, with no neurologic disease (N = 185), probable Alzheimer's disease (N = 40), Parkinson's disease (N = 91), or stroke (N = 29), completed vision testing, a battery of 10 neuropsychological tests, and an 18-mile drive on urban and rural roads in an instrumented vehicle. Performances on all neuropsychological tests were significantly correlated with driving safety errors. Confirmatory factor analysis was used to identify 3 key cognitive domains assessed by the tests (speed of processing, visuospatial abilities, and memory), and several brief batteries consisting of one test from each domain showed moderate corrected correlations with driving performance. These findings are consistent with the notion that driving places demands on multiple cognitive abilities that can be affected by aging and age-related neurological disease, and that neuropsychological assessment may provide a practical off-road window into the functional status of these cognitive systems. PMID- 22943769 TI - Complementary and alternative medicine usage by patients of a dental school clinic. AB - This pilot study investigated the prevalence and specific reasons for usage of complementary and alternative medicine (CAM) among patients of a dental school clinic. Four hundred and two patients completed a 30-page survey on CAM usage. A higher rate of CAM usage was found in this dental school clinic population than rates previously reported in a general population. More than three-quarters (76.1%) of the respondents reported using at least one CAM treatment in the past 12 months; 93.3% reported using at least one CAM treatment at some time in their lives. High rates of chiropractic use were found in this population. Tooth pain was the most frequently reported dental condition motivating CAM use. About 10% of dental school clinic patients use topical oral herbal and/or natural products to treat dental conditions, most frequently for preventive/oral health reasons or for tooth pain. PMID- 22943770 TI - Dental injuries and attention-deficit/hyperactivity disorder in children. AB - The purpose of this study was to determine the relationship between attention deficit/hyperactivity disorder (ADHD) and traumatic dental injuries in children. A total of 194 children aged 7-15 years participated in this study. Fifty-seven traumatic injuries to permanent teeth were observed in 33 children. Although a statistically significant difference was not found (p= .848), the rate of incidence was higher in the group with ADHD (17.5%) than in the control group (16.5%). The maxillary right central incisors accounted for nearly half of all injured teeth, while the maxillary central incisors represented the most frequently injured teeth. Enamel fracture was the most common type of dental injury observed. The incidence of enamel fracture was higher in the control group (66.7%) than in the subjects with ADHD (43.3%). There was a significant association between the occurrence of traumatic dental injury and the presence of an overjet greater than 3 mm (p= .020). PMID- 22943771 TI - Knowledge and practice of behavioral management principles among dentists treating adults with learning disabilities. AB - This study investigated U.K. dentists' knowledge and practice of behavioral management principles (BMPs) as applied to adults with learning disabilities (AWLD). A postal questionnaire enquired into the dentists' experience in managing AWLD, utilization of behavioral management techniques, and knowledge of BMPs. The response rate was 41% (N = 53). Two groups were investigated: specialists (dentists registered on the Special Care Dentistry specialists' list, n = 37) and nonspecialists (dentists not on the list, n = 16). Although specialists treated more AWLD than nonspecialists, both groups of dentists reported they felt highly confident in managing AWLD. However, all dentists' knowledge of the principles of nonpharmacological BMPs was low. Specialists had a tendency to use a greater range of nonpharmacological behavioral management techniques compared to non specialists. These results suggest that dental team members need more training in the theory and practice of BMPs, which might lead to less reliance on costly pharmacological interventions and a clinical experience that is more respectful of the dignity and independence of AWLD. PMID- 22943772 TI - Prevalence of periodontal disease among inpatients in a psychiatric hospital in India. AB - This paper assessed the periodontal status of inpatients at Government Mental Hospital, Vadodara, India, and studied the possible relationship between periodontal status and age, length of hospitalization, type of mental illness, and medication and tobacco use. Information about psychiatric diagnosis, length of hospitalization, and prescribed medication was obtained from hospital records. We interviewed 165 inpatients and recorded their chief dental complaints (if any) and relevant histories. Periodontal status was assessed using the Community Periodontal Index (CPI). Descriptive statistics, nonparametric tests, and multiple logistic regression analyses were used. The most prevalent periodontal condition was shallow pockets (47.27%). Some subjects (10.3%) had loss of attachment (LOA) of 9-11 mm. Age and length of hospitalization were significantly associated with periodontal status. Multiple logistic regression revealed that only age was significantly associated with periodontal pockets. Male gender, age, and tobacco-related habits were significantly associated with LOA of more than 0 3 mm. PMID- 22943773 TI - Oral health findings in athletes with intellectual disabilities at the NYC Special Olympics. AB - This study collected data to describe the oral health in Special Olympics athletes with intellectual disabilities from New York City, using the standardized Special Olympics, Special Smiles protocol. A total of 664 self selected athletes with intellectual disabilities were screened between 2005 and 2008. A standardized form was used for data collection. Screenings were performed using available light or flashlight, tongue depressor, and disposable mirror. Oral hygiene, reports of oral pain, untreated caries, missing and filled teeth were recorded. The majority of the athletes were 20 years of age or older (52%). Of the examined athletes, 9% reported oral pain, 8% needed urgent care, 28% had untreated caries, 60% had filled teeth, and 32% had signs of gingival disease. Mouthguards were recommended for 26% of athletes. Our findings offer an initial evaluation of the oral health of Special Olympics athletes with intellectual disabilities in New York City. Results showed high preventive and restorative oral health needs in the Special Olympics population. PMID- 22943774 TI - Integrated approach to outpatient dental treatment of a patient with cerebral palsy: a case report. AB - The large number of oral manifestations associated with motor disorders in patients with cerebral palsy (CP) makes the dentist an indispensable member of the multidisciplinary team caring for this population. This case report presents an 11-year-old girl with spastic CP who had severe motor impairment, and a description of her care illustrates the importance of integrated care for patients with CP who are receiving outpatient dental treatment. It was determined that the use of adaptations based on knowledge of CP supported the outpatient dental treatment. The integrated approach used during dental treatment enabled the application of knowledge from the fields of dentistry, physical therapy, and speech therapy to provide for a better quality of life for the patient and, consequently, the caregiver through the improvement in the patient's oral and general health. PMID- 22943775 TI - Recovering the personal identity of an elderly patient with cleft lip: a case report. AB - Instances of unoperated cleft lip and/or palate (CLP) in adult or elderly patients are still seen in developing countries. This paper presents the multidisciplinary management and the personal identity revival of a 72-year-old patient with unoperated unilateral complete cleft lip. The facial deformity was characterized by a protrusion of the excess of orbicularis oris muscle, irregularities of the upper lip, nose distortion, and septum deviation to the cleft side. The patient was edentulous with the maxillary alveolar ridge collapsed and an associated fistula. The cleft lip was repaired using the Tennison-Randall technique and complete dentures were delivered after the oroantral fistula had been closed. The patient was very pleased with the improvement in speech and eating and she approved of her facial esthetics. The existence of unoperated oral clefts in the elderly population highlights the need to improve policies in treating patients with CLP, mainly in developing countries. PMID- 22943777 TI - Predaceous diving beetle, Dytiscus sharpi sharpi (Coleoptera: Dytiscidae) larvae avoid cannibalism by recognizing prey. AB - Larvae of diving beetles such as the various Dytiscus species (Coleoptera: Dytiscidae) are carnivorous and usually prey on other aquatic animals. Cannibalism among larvae of Dytiscus sharpi sharpi (Wehncke) was observed to begin when they were starved for more than two days under artificial breeding conditions. However, the 2-day starved larvae did not show cannibalism in the presence of intact, motionless, frozen tadpoles, or frozen shrimps. The beetle larvae attacked and captured intact tadpoles faster (15 sec) than other motionless and frozen tadpoles (120 sec), indicating that prey movement was an important factor in stimulating feeding behavior in larvae. Prey density does not have an effect on larval cannibalism. In cases in which preys are present at lower densities than that of larvae, a group of beetle larvae frequently fed on single prey. This feeding behavior, therefore, provides direct evidence of self other recognition at the species level. Using two traps in one aquarium that allows the larvae to detect only prey smell, one containing tadpoles and another empty, the beetle larvae were attracted to the trap with tadpoles at high frequency, but not to the empty trap. In another experiment, the beetle larvae were not attracted to the trap containing a beetle larva. These results suggest that the larvae of D. sharpi sharpi are capable of recognizing prey scent, which enables the promotion of foraging behavior and the prevention of cannibalism. PMID- 22943778 TI - Molecular cloning and functional characterization of novel antimicrobial peptides from the skin of brown frog, Rana zhenhaiensis. AB - Rana zhenhaiensis, a species of brown frog, is widely distributed in central and south China. In the present study, a total of 14 cDNA sequences encoding eight novel antimicrobial peptides (AMPs) were cloned from the synthesized cDNAs of R. zhenhaiensis skin. The eight novel AMPs belong to four families: brevinin-1 (four peptides), brevinin-2 (one peptide), ranatuerin-2 (one peptide) and chensinin-1 (two peptides), five AMPs from the four families (brevinin-1ZHa, brevinin-1ZHb, brevinin-2ZHa, ranatuerin-2ZHa and chensinin-1ZHa) were chemically synthesized, their antimicrobial and hemolytic activities were examined. The results indicated that the five AMPs possess different antimicrobial and hemolytic activities. Of these, brevinin-2ZHa exhibited the strongest and most broad-spectrum antimicrobial activity. Furthermore, scanning electron microscopy (SEM) experiment was carried out to investigate the potential antimicrobial mechanism of chensinin-1ZHa. The result indicated that chensinin-1ZHa may exert its function through disruption of the bacterial membrane. PMID- 22943779 TI - Mechanisms of maternal inheritance of dinoflagellate symbionts in the acoelomorph worm Waminoa litus. AB - Waminoa litus is a zooxanthella-bearing acoel worm that infests corals. It is unique to Bilateria in that it transmits its algal symbionts vertically via eggs irrespective of the heterogeneity of the symbionts. It simultaneously harbors two dinoflagellate genera: Symbiodinium and Amphidinium. In this study, we examined the timing and vertical transmission pathway of algal symbionts in W. litus using light and electron microscopy. The oogenesis of the worm can be divided into three stages: stage I, in which the ovary is absent; stage II, the early vitellogenic zone containing immature oocytes formed in the ovary; and stage III, with both early and late vitellogenic zones in the body. In the early vitellogenic zone at stage II, oocytes are surrounded by accessory-follicle cells (AFCs). Both Symbiodinium and Amphidinium symbionts are not initially observed in the oocytes, but are observed in the AFCs. In the late vitellogenic zone at stage III, oocytes are enveloped by a complete sheath of AFCs; the algal symbionts are taken up by the late vitellogenic oocytes. These observations suggest that AFCs mediate the transfer of the algae from the parent to the oocytes. Ribotype analyses of the Symbiodinium symbionts revealed that they differ from those harbored by coral in the same experimental aquarium. These results indicate that W. litus has an active algal transport pathway and maintains a specific lineage of Symbiodinium via vertical transmission. PMID- 22943780 TI - Color pattern analysis of nymphalid butterfly wings: revision of the nymphalid groundplan. AB - To better understand the developmental mechanisms of color pattern variation in butterfly wings, it is important to construct an accurate representation of pattern elements, known as the "nymphalid groundplan". However, some aspects of the current groundplan remain elusive. Here, I examined wing-wide elemental patterns of various nymphalid butterflies and confirmed that wing-wide color patterns are composed of the border, central, and basal symmetry systems. The central and basal symmetry systems can express circular patterns resembling eyespots, indicating that these systems have developmental mechanisms similar to those of the border symmetry system. The wing root band commonly occurs as a distinct symmetry system independent from the basal symmetry system. In addition, the marginal and submarginal bands are likely generated as a single system, referred to as the "marginal band system". Background spaces between two symmetry systems are sometimes light in coloration and can produce white bands, contributing significantly to color pattern diversity. When an element is enlarged with a pale central area, a visually similar (yet developmentally distinct) white band is produced. Based on the symmetric relationships of elements, I propose that both the central and border symmetry systems are comprised of "core elements" (the discal spot and the border ocelli, respectively) and a pair of "paracore elements" (the distal and proximal bands and the parafocal elements, respectively). Both core and paracore elements can be doubled, or outlined. Developmentally, this system configuration is consistent with the induction model, but not with the concentration gradient model for positional information. PMID- 22943781 TI - Effects of water management, connectivity, and surrounding land use on habitat use by frogs in rice paddies in Japan. AB - In Japan, rice paddies play an important role as a substitute habitat for wetland species, and support rich indigenous ecosystems. However, since the 1950s, agricultural modernization has altered the rice paddy environment, and many previously common species are now endangered. It is urgently necessary to evaluate rice paddies as habitats for conservation. Among the species living in rice paddies, frogs are representative and are good indicator species, so we focused on frog species and analyzed the influence of environmental factors on their habitat use. We found four frog species and one subspecies (Hyla japonica, Pelophylax nigromaculatus, Glandirana rugosa, Lithobates catesbeianus, and Pelophylax porosa brevipoda) at our study sites in Shiga prefecture. For all but L. catesbeianus, we analyzed the influence of environmental factors related to rice paddy structure, water management and availability, agrochemical use, connectivity, and land use on breeding and non-breeding habitat use. We constructed generalized additive mixed models with survey date as the smooth term and applied Akaike's information criterion to choose the bestranked model. Because life histories and biological characteristics vary among species, the factors affecting habitat use by frogs are also expected to differ by species. We found that both breeding and non-breeding habitat uses of each studied species were influenced by different combinations of environmental factors and that in most cases, habitat use showed seasonality. For frog conservation in rice paddies, we need to choose favorable rice paddy in relation to surrounding land use and apply suitable management for target species. PMID- 22943782 TI - Host specificity and population dynamics of a sponge-endosymbiotic bivalve. AB - We assessed the host-use pattern of the sponge-endosymbiotic bivalve Vulsella vulsella and its demographic consequences in an inland sea in Okinawa Island, Japan. Vulsella vulsella utilized only one massive globular sponge species Spongia sp. as a host, and no Spongia sp. without V. vulsella were found. Individual sponges contained 9-248 live bivalves and 0-222 dead bivalves. The densities of live and dead bivalves in individual sponges were approximately constant irrespective of sponge size, indicating that available space is very scarce inside each sponge. The size distribution of bivalves was skewed to small, young individuals less than 30 mm in shell height, although the estimated largest possible size was 106 mm. The bivalve population at each sampling date was composed of three yearly cohorts, and recruitment of juveniles occurred in the summer. The bivalves became sexually mature as males within one year after recruitment and changed sex from male to female as they grew. The size and sex distributions of the bivalve were largely similar among sponges regardless of sponge size, suggesting that the recruitment, growth, longevity, and sex change of the bivalve were strictly regulated, probably by the high water temperature and strong waves generated by typhoons in summer months. PMID- 22943783 TI - Modeling spring habitat requirements of the endangered brown eared pheasant Crossoptilon mantchuricum in the Huanglong Mountains, Shaanxi Province, China. AB - A detailed understanding of the habitat needs of brown eared pheasants (Crossoptilon mantchuricum) is essential for conserving the species. We carried out field surveys in the Huanglong Mountains of Shaanxi Province, China, from March to June in 2007 and 2008. We arrayed a total of 206 grid plots (200 * 200 m) along transects in 2007 and 2008 and quantified a suite of environmental variables for each one. In the optimal logistic regression model, the most important variables for brown eared pheasants were slope degree, tree cover, distance to nearest water, cover and depth of fallen leaves. Hosmer and Leweshow goodness-of-fit tests explained that logistic models for the species were good fits. The model suggested that spring habitat selection of the brown eared pheasant was negatively related to distance to nearest water and slope degree, and positively to cover of trees and cover and depth of fallen leaves. In addition, the observed detected and undetected grids in 2007 did not show significant differences with predictions based on the model. These results showed that the model could well predict the habitat selection of brown eared pheasants. Based on these predictive models, we suggest that habitat management plans incorporating this new information can now focus more effectively on restrictions on the number of tourists entering the nature reserve, prohibition of firewood collection, livestock grazing, and medicinal plant harvesting by local residents in the core areas, protection of mixed forest and sources of the permanent water in the reserve, and use of alternatives to firewood. PMID- 22943784 TI - Negative effects of deep roadside ditches on Pelophylax porosa brevipoda dispersal and migration in comparison with Hyla japonica in a rice paddy area in Japan. AB - In Japan, rice paddies have acted as a substitute habitat for pond-breeding frogs. However, since the 1950s, agricultural modernization has altered the rice paddy environment, and pond-breeding frog populations have been decreasing. This agricultural modernization has led to rice paddy fragmentation via roadways and the construction of deep channels. To assess the influences of habitat fragmentation, we compared the distribution of two pond-breeding frogs, a common species, Hyla japonica, and an endangered species, Pelophylax porosa brevipoda, around a deep roadside ditch. In Shiga prefecture, we selected two rice paddies along a roadway and recorded the number of frogs and their snout-vent length (SVL) at the levee of a rice paddy, ditch, bank, and adjacent roadway. In total, we identified 1,293 P. p. brevipoda and 181 H. japonica. Most P. p. brevipoda were either at the levee or ditch, and the number of this species found in the ditch was much higher than in any other location in July and October. The SVLs of P. p. brevipoda found in the ditch in June were smaller than those in October. Most H. japonica were at the levee or bank, and there were no apparent temporal or spatial patterns of distribution. Our results suggest that the ditch acts as a barrier to juveniles in early summer and to all frogs during autumn for P. p. brevipoda but not for H. japonica. For long-term conservation, it is important to study the movement patterns related to life history and rice paddy management. PMID- 22943785 TI - Chromosomal characterization of armored catfish Harttia longipinna (Siluriformes, Loricariidae): first report of B chromosomes in the genus. AB - The B chromosomes are accessory elements that are widely distributed among eukaryotic genomes and often show non-Mendelian inheritance. They are considered dispensable for the growth, development, and reproduction of organisms. Some studies have suggested that these elements may affect sex determination. Harttia is a small armored catfish genus that shows sexual dimorphism, including hypertrophied odontodes on the pectoral fin spines and along the margins of the snout in mature males. They exhibit considerable karyotypic diversity with diploid number (2n) variation and heteromorphic sex system in H. carvalhoi. To date, no occurrences of B chromosomes in the Harttia genus were detected and no relation to sexual differentiation in Neotropical fish has been determined. To determine the validity of this claim, the present paper characterized specimens of Harttia longipinna by classical and molecular cytogenetic methods. The 2n found was 58 (16m + 12sm + 16st + 14a), but of the 50 specimens analyzed (30 male and 20 female), 23 specimens (16 males and seven females) show an intra individual from 0 to 2 micro B chromosomes. The B chromosomes were completely heterochromatic. The single NORs were shown in the first acrocentric pair with silver staining and 18S rDNA probing. FISH performed with 5S rDNA probe showed a single cistron in the proximal region of the short arm of a small metacentric pair. Thus, the cytogenetic data obtained in this study of H. longipinna highlight the karyotypic diversity found within the genus Harttia, and represent the first description of B chromosomes for this genus. PMID- 22943786 TI - Phylogeny of Oriental voles (Rodentia: Muridae: Arvicolinae): molecular and morphological evidence. AB - The systematics of Oriental voles remains controversial despite numerous previous studies. In this study, we explore the systematics of all species of Oriental voles, except Eothenomys wardi, using a combination of DNA sequences and morphological data. Our molecular phylogeny, based on two mitochondrial genes (COI and cyt b), resolves the Oriental voles as a monophyletic group with strong support. Four distinct lineages are resolved: Eothenomys, Anteliomys, Caryomys, and the new subgenus Ermites. Based on morphology, we consider Caryomys and Eothenomys to be valid genera. Eothenomys, Anteliomys, and Ermites are subgenera of Eothenomys. The molecular phylogeny resolves subgenera Anteliomys and Ermites as sister taxa. Subgenus Eothenomys is sister to the clade Anteliomys + Ermites. Caryomys is the sister group to genus Eothenomys. Further, the subspecies E. custos hintoni and E. chinensis tarquinius do not cluster with E. custos custos and E. chinensis chinensis, respectively, and the former two taxa are elevated to species level and assigned to the new subgenus Ermites. PMID- 22943787 TI - Immunoreactivity of gonadotrophs (FSH and LH Cells) and gonadotropin subunit gene expression in the male chub mackerel Scomber japonicus pituitary during the reproductive cycle. AB - The gonadotropins (GtHs), follicle-stimulating hormone (FSH) and luteinizing hormone (LH), are heterodimers composed of a common alpha subunit (GPalpha) and a unique beta subunit (FSHbeta or LHbeta); they are synthesized in and secreted from gonadotrophs (FSH and LH cells) in the pituitary. Little is known about the roles of FSH and LH during spermatogenesis in perciform fishes. In this study, we examined immunoreactive changes in FSH and LH cells, and changes in the gene expression of the three gonadotropin subunits in the pituitary of male chub mackerel Scomber japonicus during testicular development. FSHbeta-immunoreactive (ir) and LHbeta-ir cell area were measured immuno-histochemically based on the FSH and LH cell-occupying area in the proximal pars distalis. The FSHbeta-ir cell area increased significantly during spermiation, while FSHbeta mRNA levels, already high at the beginning of spermatogenesis, increased further, peaking during spermiation. In contrast, LHbeta-ir cell area and LHbeta mRNA levels, which were low at the beginning of spermatogenesis, increased significantly during late spermatogenesis, peaking during spermiation. For both FSH and LH, GtHbeta-ir cell area and GtHbeta mRNA levels decreased until gonadal resting. GPalpha mRNA levels showed similar changes to LHbeta mRNA levels. These results suggest that in the chub mackerel, FSH may play an important role in the early and late phases of spermatogenesis, and that LH may play a role during late spermatogenesis and spermiation. Moreover, our results demonstrate that changes in GtHbeta-ir cell area were accompanied by similar changes in the expression of the FSHbeta and LHbeta genes, both of which increased during testicular development. PMID- 22943788 TI - Analysis of the trap gene provides evidence for the role of elevation and vector abundance in the genetic diversity of Plasmodium relictum in Hawaii. AB - BACKGROUND: The avian disease system in Hawaii offers an ideal opportunity to investigate host-pathogen interactions in a natural setting. Previous studies have recognized only a single mitochondrial lineage of avian malaria (Plasmodium relictum) in the Hawaiian Islands, but cloning and sequencing of nuclear genes suggest a higher degree of genetic diversity. METHODS: In order to evaluate genetic diversity of P. relictum at the population level and further understand host-parasite interactions, a modified single-base extension (SBE) method was used to explore spatial and temporal distribution patterns of single nucleotide polymorphisms (SNPs) in the thrombospondin-related anonymous protein (trap) gene of P. relictum infections from 121 hatch-year amakihi (Hemignathus virens) on the east side of Hawaii Island. RESULTS: Rare alleles and mixed infections were documented at three of eight SNP loci; this is the first documentation of genetically diverse infections of P. relictum at the population level in Hawaii. Logistic regression revealed that the likelihood of infection with a rare allele increased at low-elevation, but decreased as mosquito capture rates increased. The inverse relationship between vector capture rates and probability of infection with a rare allele is unexpected given current theories of epidemiology developed in human malarias. CONCLUSIONS: The results of this study suggest that pathogen diversity in Hawaii may be driven by a complex interaction of factors including transmission rates, host immune pressures, and parasite-parasite competition. PMID- 22943789 TI - Herbal medicine use in the districts of Nakapiripirit, Pallisa, Kanungu, and Mukono in Uganda. AB - BACKGROUND: Traditional medicine (TM) occupies a special place in the management of diseases in Uganda. Not with standing the many people relying on TM, indigenous knowledge (IK) related to TM is getting steadily eroded. To slow down this loss it is necessary to document and conserve as much of the knowledge as possible. This study was conducted to document the IK relevant to traditional medicine in the districts of Mukono, Nakapiripirit, Kanungu and Pallisa, in Uganda. METHODS: An ethnobotanical survey was conducted between October 2008 and February 2009 using techniques of key informant interviews and household interviews. RESULTS: The common diseases and conditions in the four districts include malaria, cough, headache, diarrhea, abdominal pain, flu, backache and eye diseases. Respondents stated that when they fall sick they self medicate using plant medicines or consult western-trained medicine practitioners. Self medication using herbal medicines was reported mostly by respondents of Nakapiripirit and Mukono. Respondents have knowledge to treat 78 ailments using herbal medicines. 44 species, mentioned by three or more respondents have been prioritized. The most frequently used part in herbal medicines is the leaf, followed by the stem and root. People sometime use animal parts, soil, salt and water from a grass roof, in traditional medicines. Herbal medicines are stored for short periods of time in bottles. The knowledge to treat ailments is acquired from parents and grandparents. Respondents' age and tribe appears to have a significant influence on knowledge of herbal medicine, while gender does not. CONCLUSION: This survey has indicated that IK associated with TM stills exists and that TM is still important in Uganda because many people use it as a first line of health care when they fall sick. Age and tribe influence the level of IK associated with herbal medicine, but gender does not. PMID- 22943790 TI - Case 7-2012. Airway management and perioperative decision making in the patient with severe pulmonary hypertension who requires emergency noncardiac surgery. PMID- 22943791 TI - Developing culturally congruent weight maintenance programs for African American church members. AB - OBJECTIVES: Developing community-based and culturally congruent weight loss maintenance programs is an important component of weight reduction interventions in high-risk populations. This qualitative investigation was conducted to guide development of faith-based weight maintenance programs for African American church members. DESIGN: Twenty African American church members who previously participated in a church-based group weight loss program were recruited to participate in focus groups. This qualitative inquiry focused on the role of faith in maintaining healthy lifestyle behaviors, such as healthy eating and regular physical activity. Within these groups, a nominal group process was used to identify activities and language to be included within a faith-based maintenance program. RESULTS: Content analysis identified seven conceptual domains that participants thought were important aspects of a faith-based weight maintenance program: (1) accountability for change targets, (2) programmatic tools, (3) group benefits and support, (4) keys to successful behavior change, (5) keys to church and programmatic level success, (6) addressing barriers, and (7) faith. The faith sub-domains included faith in the Lord, using the body for God, and a spiritual focus. The nominal group process resulted in 11 recommended components for a faith-based weight maintenance program. The top four included scriptures and prayers are 'walk of faith,' healthy diet, exercise, and focusing on God. CONCLUSIONS: The results suggest that integrating faith themes into a weight loss maintenance program may increase its long-term impact on participants' health behavior change. PMID- 22943792 TI - Altered specificity of single-chain antibody fragments bound to pandemic H1N1 2009 influenza virus after conversion of the phage-bound to the soluble form. AB - BACKGROUND: In 2009, a novel influenza A/H1N1 virus (H1N1pdm) quickly spread worldwide and co-circulated with then-existing seasonal H1N1 virus (sH1N1). Distinguishing between these 2 viruses was necessary to better characterize the epidemiological properties of the emergent virus, including transmission patterns, pathogenesis, and anti-influenza drug resistance. This situation prompted us to develop a point-of-care virus differentiation system before entering the 2009-2010 influenza season. Aiming to establish H1N1pdm-specific detection tools rapidly, we employed phage display libraries to select H1N1pdm specific single-chain variable fragments (scFvs). FINDINGS: Human single-fold scFv libraries (Tomlinson I + J) underwent selection for the ability to bind H1N1pdm virus particles. Three rounds of panning brought 1152 phage-bound scFvs, of which 58 clones reacted with H1N1pdm specifically or preferentially over sH1N1 in an enzyme-linked immunosorbent assay (ELISA). After conversion of the scFvs to soluble form, 7 clones demonstrating high/stable expression were finally obtained. However, all the soluble scFvs except No. 29 were found to have lost their specificity/preference for H1N1pdm in ELISA. The specificity/preference of No. 29 was also confirmed by immunofluorescence assay and immunoprecipitation, and the viral nucleoprotein was identified by ELISA as its target protein. The change in specificity associated with scFv conversion from phage-bound to soluble form could be due to loss of phage scaffold pIII protein, which likely provides structural support for the scFv antigen-binding site. It is also possible that the similar antigenic properties of H1N1pdm and sH1N1 led to the observed alterations in scFv specificity. DISCUSSION: Using a phage display library, we obtained 7 soluble scFv clones reactive against H1N1pdm; however, only 1 showed specificity/preference toward H1N1pdm. Our results confirmed that using phage display libraries was highly advantageous for the rapid development of molecules to detect target antigens. However, our results also indicated that this strategy might not have been effective for selecting H1N1pdm-specific antibodies during the 2009 pandemic, where the co-circulating sH1N1 virus shared similar antigenic properties. This suggests that it might be advisable to use a synthetic scFv phage display library by strategically considering the characteristics of target antigens and the potential situations. PMID- 22943794 TI - The first detections of subtype 2-related salmonid alphavirus (SAV2) in Atlantic salmon, Salmo salar L., in Norway. PMID- 22943796 TI - Meso-Rex bypass as an alternative technique for portal vein reconstruction at or after liver transplantation in children: review and perspectives. AB - Direct portal revascularization can be achieved by interposing a vascular graft between the SMV and the Rex recessus (left portal vein system): the MRB. To review indications and results of the procedure in the setting of pediatric liver transplantation, reports were selected from the English literature. Previously reported series were updated to analyze long-term outcome. A new series was added and analyzed as a complementary set of cases. A total of 51 cases were analyzed. With a 96% overall patient survival rate and a 100% long-term patency rate when the IJV is used for the bypass, MRB achieves a very successful physiologic cure of chronic portal hypertension and restores the portal flow into and through the liver graft. It also has been used successfully for primary revascularization of liver grafts, as well as for managing early acute portal vein thrombosis episodes. The use of this procedure in conjunction with other strategies and techniques might be of interest for transplant surgeons, particularly those caring for children. PMID- 22943795 TI - Interactive effects of chronic cigarette smoking and age on brain volumes in controls and alcohol-dependent individuals in early abstinence. AB - Chronic alcohol-use disorders (AUDs) have been shown to interact with normal age related volume loss to exacerbate brain atrophy with increasing age. However, chronic cigarette smoking, a highly co-morbid condition in AUD and its influence on age-related brain atrophy have not been evaluated. We performed 1.5 T quantitative magnetic resonance imaging in non-smoking controls [non-smoking light drinking controls (nsCONs); n = 54], smoking light drinking controls (sCONs, n = 34), and one-week abstinent, treatment-seeking alcohol-dependent (ALC) non-smokers (nsALCs, n = 35) and smokers (sALCs, n = 43), to evaluate the independent and interactive effects of alcohol dependence and chronic smoking on regional cortical and subcortical brain volumes, emphasizing the brain reward/executive oversight system (BREOS). The nsCONs and sALCs showed greater age-related volume losses than the nsALCs in the dorsal prefrontal cortex (DPFC), total cortical BREOS, superior parietal lobule and putamen. The nsALCs and sALCs demonstrated smaller volumes than the nsCONs in most cortical region of interests (ROIs). The sCONs had smaller volumes than the nsCONs in the DPFC, insula, inferior parietal lobule, temporal pole/parahippocampal region and all global cortical measures. The nsALCs and sALCs had smaller volumes than the sCONs in the DPFC, superior temporal gyrus, inferior and superior parietal lobules, precuneus and all global cortical measures. Volume differences between the nsALCs and sALCs were observed only in the putamen. Alcohol consumption measures were not related to volumes in any ROI for ALC; smoking severity measures were related to corpus callosum volume in the sCONs and sALCs. The findings indicate that consideration of smoking status is necessary for a better understanding of the factors contributing to regional brain atrophy in AUD. PMID- 22943797 TI - Human-scale whole-organ bioengineering for liver transplantation: a regenerative medicine approach. AB - At this time, the only definitive treatment of hepatic failure is liver transplantation. However, transplantation has been limited by the severely limited supply of human donor livers. Alternatively, a regenerative medicine approach has been recently proposed in rodents that describe the production of three-dimensional whole-organ scaffolds for assembly of engineered complete organs. In the present study, we describe the decellularization of porcine livers to generate liver constructs at a scale that can be clinically relevant. Adult ischemic porcine livers were successfully decellularized using a customized perfusion protocol, the decellularization process preserved the ultrastructural extracellular matrix components, functional characteristics of the native microvascular and the bile drainage network of the liver, and growth factors necessary for angiogenesis and liver regeneration. Furthermore, isolated hepatocytes engrafted and reorganized in the porcine decellularized livers using a human-sized organ culture system. These results provide proof-of-principle for the generation of a human-sized, three-dimensional organ scaffold as a potential structure for human liver grafts reconstruction for transplantation to treat liver disease. PMID- 22943798 TI - Delayed gastric emptying after pancreaticoduodenectomy in diabetes mellitus. AB - INTRODUCTION: Delayed gastric emptying (DGE) is one of the most troublesome complications of pancreaticoduodenectomy (PD). Diabetes mellitus (DM) is one of the risk factors for pancreatic cancer. Moreover, several studies have shown that diabetic patients tend to have a high incidence of upper gastrointestinal symptoms such as nausea, vomiting and DGE. Here, we compared the influence of DM on the incidence of DGE after PD. METHODS: We retrospectively analysed 67 cases of PD with pancreaticogastrostomy. These patients were categorized into the following two groups: the DM group included patients with DM, and the NDM group included patients without DM. The incidence of DGE was determined and compared between the two groups. RESULTS: In the DM group, 76.5%, 5.9% and 17.6% of the subjects developed classes A, B and C DGE, respectively; the corresponding values in the NDM group were 58%, 22%, and 20%. The incidence of DGE did not differ between the two groups (P < 0.2771). CONCLUSIONS: DM does not accelerate DGE in patients who have undergone PD. Preoperative DM does not appear to play a key role in post-operative DGE after PD. PMID- 22943799 TI - [Management of juvenile ocular hypertension]. AB - Ocular hypertensions (OHTs) in juvenile are characterized by occurrence in teenage with intraocular pressure (IOP) frequently fluctuated and increased over 30 mm Hg (1 mm Hg = 0.133 kPa) without any ocular symptoms and disturbance of visual acuity. IOPs are normalized in the majorities of juvenile over adolescence stage with long-term follow up. The medical terminology of 'adolescence IOP fluctuation' or 'adolescence ocular hypertension' is therefore used. The diagnosis and management of juvenile OHT remain difficult clinical challenges. OHTs in juvenile sometimes are incorrectly diagnosed due to inappropriate IOP measurement and thicker central cornea as younger children are non-compliant and resisting the examination. In this paper, we reviewed OHT in juvenile in the light of significant studies in the past and based on our experience of clinical practice in order to provide a better understanding and management of OHTs in juvenile. PMID- 22943793 TI - TGF-beta - an excellent servant but a bad master. AB - The transforming growth factor (TGF-beta) family of growth factors controls an immense number of cellular responses and figures prominently in development and homeostasis of most human tissues. Work over the past decades has revealed significant insight into the TGF-beta signal transduction network, such as activation of serine/threonine receptors through ligand binding, activation of SMAD proteins through phosphorylation, regulation of target genes expression in association with DNA-binding partners and regulation of SMAD activity and degradation. Disruption of the TGF-beta pathway has been implicated in many human diseases, including solid and hematopoietic tumors. As a potent inhibitor of cell proliferation, TGF-beta acts as a tumor suppressor; however in tumor cells, TGF beta looses anti-proliferative response and become an oncogenic factor. This article reviews current understanding of TGF-beta signaling and different mechanisms that lead to its impairment in various solid tumors and hematological malignancies. PMID- 22943800 TI - [Glaucoma clinical trials in China]. AB - Large scale, multicenter, and randomized controlled glaucoma clinical trials are very important clinical research. The results of scientific evidences are useful to make clinical guideline of glaucoma prevention and management or working mode. Glaucoma is the second leading cause of blindness in the world, which is associated with irreversible damage to optic disc. At present, glaucoma prevalence in China was approximately 1.95% to 3.60%. In order to effectively prevent and treat glaucoma, it's necessary to promote and design glaucoma clinical trials that fit in our national medical care system. Much experience of carrying out clinical glaucoma trials has been obtained and achieved in the past. However, there is still a big gap between China and developed countries in such aspects as funding deficiency, disunity of operational standardization, quality irregularity and so on. This article presents a synthesis of modern principle data concerning glaucoma clinical trials in domestics and abroad aiming at emphasizing the importance of this issue. PMID- 22943801 TI - [Current approaches in neovascular glaucoma]. AB - Neovascular glaucoma (NVG) has long been recognized as a very difficult case to manage for its very poor prognosis of visual function. NVG is also remarked as an 'end stage' of ocular diseases. Conventional treatments with extremely uncontrolled cases are retinal cryotherapy or enucleation. Currently, management of this medical condition is directed toward a new era with great advancement in diagnosis and treatment. Glaucoma drainage implant surgery brings a time window of normal range of intraocular pressure (IOP) for physicians to process underlying disease of NVG. Regression of iris neovascularization by employing panretinal photocoagulation (PRP) or intravitreal injection of anti-vascular endothelial growth factor (anti-VEGF) antibodies create a chance to undertaken antiglaucomatous surgery. Adjunctive anti-VEGF treatment promotes the surgical success rate for NVG. Current approaches in NVG are able to provide patients with an individualized management using a sound treatment strategy according to etiology, stage of disease, visual potential and other factors. PMID- 22943802 TI - [The efficacy of Ahmed glaucoma valve implantation in the management of early stage of glaucoma secondary to blunt ocular trauma]. AB - OBJECTIVE: To evaluate the efficacy and safety of Ahmed glaucoma valve (AGV) implantation in the early stage of glaucoma secondary to contusion injuries. METHODS: A retrospective case series study. The study was made in 29 consecutive patients with glaucoma secondary to blunt trauma who were uncontrolled by multiple medications and then performed AGV implantations in less than 2 months after the trauma. The duration from injury to IOP elevation was 1 to 30 (6.10 +/- 1.13) days. The time from injury to AGV implantation was 16 to 60 (40.03 +/- 2.97) days. The patients were followed-up for a period of 6 to 42 (20.75 +/- 1.66) months. The main outcome measures included intraocular pressure (IOP), visual acuity (VA), number of glaucomatous medications, intra- and postoperative complications. IOPs were analyzed by repeated measures analysis of variance, numbers of medication assessed by Kruskal-Wallis rank sum test followed by Bonferroni test, and VA comparison was performed using paired Student t-test. RESULTS: The absolute success rate was 86.21% and the conditional success rate was 13.79% after AGV implantation. Compared with pre-operation, the IOP was significantly(F = 124.09, P < 0.05) lowered at the last following-up of post operation(42.59 +/- 1.82)vs (15.12 +/- 0.56) mm Hg(1 mm Hg = 0.133 kPa), the numbers of glaucomatous medications were significantly (H = 131.73, P < 0.05) reduced post-operatively (3.93 +/- 0.15) vs (0.21 +/- 0.12) species, and the VA was significantly (t = -3.466, P < 0.05) improved post-operatively (logMAR 0.40 vs logMAR 0.70). Two cases with shallow anterior chamber and three cases with hyphema were observed in the early stage after the surgery. No persistent hypotony, tube exposure or other serious complications were noted. CONCLUSION: AGV implantation is safe and effective in the management of intractable secondary glaucoma at early stage of contusion injuries. PMID- 22943803 TI - [Detection of the changes of retinal nerve fiber layer thickness by GDx-VCC laser scanning polarimetry in primary open angle glaucoma patients]. AB - OBJECTIVE: To evaluate the changes of visual field and retinal nerve fiber layer (RNFL) thickness during 24 months follow up in primary open-angle glaucoma (POAG) patients. METHODS: In this retrospective case series study, visual field and RNFL were detected by using GDx-VCC system and Octopus perimeter in 60 patients with POAG in early stage (60 eyes), 32 in moderate stage (32 eyes) and 30 in advanced stage (30 eyes). The parameters of the RNFL thickness and mean defect (MD) of the visual fields were recorded and analyzed by repeated measures analysis of variance among the same group and by one-factor analysis of variance for different stages of POAG groups at each time of follow-up. RESULTS: The baseline MD of visual field in POAG was (1.93 +/- 1.66) dB in early group, (5.83 +/- 1.95) dB in moderate group and (14.62 +/- 3.53) dB in advanced group, respectively. At 24 months, MD in POAG was significant (F = 9.47, P < 0.05) increased to (7.24 +/- 2.17) dB in moderate group, but not in other two groups (F = 2.03, 1.40; P > 0.05). Compared with baseline of total average RNFL thickness in POAG at temporal superior-nasal-inferior-temporal [TSNIT: (53.72 +/- 8.07) um, (49.73 +/- 7.16) um, and (41.42 +/- 8.30) um in each group, respectively], RNFL thickness in each group was significant (F = 21.39, 18.65, 16.63; P < 0.05) decreased (50.43 +/- 7.08) um, (45.47 +/- 6.50) um, and (37.62 +/- 7.28) um (respectively) at 24 months. The inferior RNFL was significantly (F = 30.25, P < 0.05) reduced from (61.85 +/- 9.77) um to (54.35 +/- 7.47) um in early stage group, while the superior RNFL was changed more dramatically from (55.67 +/- 9.50) um to (49.75 +/ 9.54) um in moderate stage group (F = 31.72, P < 0.05). Both baselines of MD and RNFL thickness were significantly different in each group (F = 428.99, 21.32; P < 0.05). CONCLUSIONS: Our results demonstrate that GDx-VCC system is useful to evaluate the progression of POAG in early and moderate stage by detecting the change of the RNFL thickness with long term follow up. PMID- 22943804 TI - [Morphological monitoring indexes in anterior segment with primary acute angle closure glaucoma]. AB - OBJECTIVE: To investigate morphological monitoring indexes of anterior segment in AACG. METHODS: Case-controlled study was conducted in the following groups: 55 eyes of 55 patients with unilateral AACG in first attack, 60 eyes of 60 cases with shallow anterior chamber, and 60 eyes of 60 cases with normal individuals. Images of anterior chamber angle in each group were collected by OCT. Using software of Photoshop, the opening degree of anterior chamber angle was quantified. Anterior chamber depth (ACD), lens thickness (LT), lens position (LP), and chamber crowding rate (CCR) were measured by A-ultrasound. Anterior segment biometric parameters among the three groups were compared using one-way ANOVA test. RESULTS: LT, LP, and CCR were significantly (LT: F = 27.73, LP: F = 47.33, CCR: F = 79.22; P < 0.05) different between AACG, narrow angle and normal group in age group ranged from 50 to 59 [LT: (5.72 +/- 0.22) mm, (5.57 +/- 0.28) mm, (4.55 +/- 0.36) mm, LP: (4.33 +/- 0.24) mm, (4.63 +/- 0.20) mm, (5.71 +/- 0.34) mm, and CCR: 3.28 +/- 0.16, 2.64 +/- 0.19, 1.70 +/- 0.10, respectively] and significantly different (LT: F = 22.51, LP: F = 56.67, CCR: F = 74.84; P < 0.05) in age group ranged from 60 to 69 [LT: (5.81 +/- 0.37) mm, (5.72 +/- 0.41) mm, (4.98 +/- 0.59) mm, LP: (4.26 +/- 0.18) mm, (4.51 +/- 0.14) mm, (5.62 +/- 0.19) mm and CCR: 3.39 +/- 0.35, 2.74 +/- 0.37, 1.86 +/- 0.36, respectively]. However, in age group ranged above 70 group, LP and CCR (LP: F = 23.09, CCR: F = 60.08; P < 0.05) were significantly changed [LP: (4.25 +/- 0.30) mm, (4.46 +/- 0.22) mm, (5.49 +/- 0.23) mm, CCR: 3.48 +/- 0.21, 2.85 +/- 0.30, 2.03 +/- 0.17, respectively], but not LT [(5.85 +/- 0.27) mm, (5.74 +/- 0.21) mm, (5.43 +/- 0.36) mm] (F = 8.29, P > 0.05). CONCLUSIONS: The study results indicate that LT, LP and CCR, are useful indicators to observe the anterior chamber status in AACG by using Stratus OCT-3. PMID- 22943805 TI - [Expression of Nogo-A, NgR mRNA and protein in the retina of rats with chronic elevated intraocular pressure]. AB - OBJECTIVE: To investigate the expression of Nogo-A and its receptor NgR mRNA and protein in the retina of rats with chronic elevated intraocular pressure (IOP). METHODS: Experimental study. Rat chronic ocular hypertension (OHT) was induced by obstructing episcleral veins and temporal limber veins. The retinal tissues were collected at day 3, 7, 14 and 28 after the IOP elevated in rats. Each group includes 16 rats and one group served as normal control. Expression of Nogo-A and NgR mRNA was detected by reverse transcription polymerase chain reaction (RT PCR), while the protein levels of Nogo-A and NgR were expressed by the western blot in rat retinal tissues in different groups. Expression of Nogo-A, NgR mRNA and protein were analysed by one way analysis of variance (ANOV) and multiple comparison ANOV. RESULTS: IOP in rat OHT group was significantly increased after day 3 lasting for 28 day. Compared with control group, the level of Nogo-A mRNA and protein in rat chronic OHT groups were significantly (mRNA: F = 7.464, protein: F = 5.677; P < 0.01) increased at day 7, 14, and 28 (mRNA: 0.661 +/- 0.065 vs 0.831 +/- 0.055, 0.813 +/- 0.063, 0.844 +/- 0.077, protein: 1.284 +/- 0.043 vs 1.359 +/- 0.033, 1.381 +/- 0.063, 1.361 +/- 0.044), respectively. There is a tendency of increase of Nogo-A mRNA expression at day 3 but did not reach statistical significance. However, the level of NgR in the retina in rats with the chronic OHT was not significantly (mRNA:F = 0.598, protein:F = 0.460; P > 0.01) changed compared with normal group. CONCLUSION: The increased expression of Nogo-A in retina of rat OHT indicates that Nogo-A may play a primary role in obstructing regeneration of optic nerve, which is mediated by other receptors and elements rather than NgR. PMID- 22943806 TI - [Expressions of vascular endothelial growth factor and its receptors in rat conjunctival fibroblasts]. AB - OBJECTIVE: To detect the expressions of vascular endothelial growth factor (VEGF) and vascular endothelial growth factor receptors (VEGFR) in cultured rat conjunctival fibroblasts. METHODS: Experimental study. Conjunctiva was obtained from each eye of five Sprague Dawley (SD) rats under local anesthesia. Tissues were minced and grown in culture flask containing Dulbecco's Modified Eagle's medium (DMEM). The fibroblasts were identified by observing cell morphology, and the expression of staining of cytokeratin and vimentin by inverted microscopy and indirect immunofluorescence technique. mRNA primers were designed for VEGF(164), VEGFR-1 (Flt-1), and VEGFR-2 (Flk-1). mRNA was extracted by Trizol method. cDNA was synthesized under the action of RNA reverse transcriptase. Ladder-like pattern of DNA fragmentation appeared upon 2% agarose gel electrophoresis. The amplification curves and dissociation curves of VEGF(164), VEGFR-1(Flt-1), and VEGFR-2 (Flk-1) were detected by realtime polymerase chain reaction (PCR). The expression of VEGFR-1 on fibroblast was observed by immunofluorescence technique. RESULTS: The fluorescent staining was negative in cytokeratin of fibroblasts, but was positive in vimentin of fibroblasts. The mRNA expressions of VEGF(164), VEGFR 1 (Flt-1) and VEGFR-2 (Flk-1) were detected in fibroblast and verified by gene sequencing. The peaks of the dissociation curves were all steep and specific. The fluorescent staining of VEGFR-1 was positive. CONCLUSIONS: Our results demonstrate that the expression of VEGF, VEGF receptors, and VEGFR-1 cytokine in rat conjunctival fibroblasts suggests that anti-VEGF compounds may exert a direct influence to the growth of rat conjunctival fibroblast. PMID- 22943807 TI - [Comparison between binocular, open-field auto ref/keratometer and conventional autorefractor]. AB - OBJECTIVE: To compare the refractive results between open-field auto ref/keratometer and conventional autorefractor, and to investigate the effect of cycloplegic to this difference. METHODS: Three hundred and four primary and secondary school students were consecutively enrolled in Beijing Tongren Hospital. Non-cycloplegic and cycloplegic objective refractions were performed for each subject by conventional autorefractor (Accuref-K9001, Shin Nippon, Japan) and binocular, open-field auto ref/keratometer (Grand Seiko Co., Ltd., Hiroshima, Japan). The coincidence rate of sphere, spherical equivalent (SE) and axis (defined as difference of diopter <= 0.50 D, difference of axis degree <= 20 degrees ) were calculated; Bland-Altman and distribution analysis were performed according to mean and difference of SE. RESULTS: The coincidence rate of sphere, SE and axis were 77.3%, 78.6% and 66.0% before cycloplegic and increased to 94.4%, 95.1% and 69.5% after cycloplegic, respectively. The difference (95%CI) of SE before cycloplegic between these two refractometers was 0.12 (-1.04 to 1.29) D and was positively correlated with the mean of SE (after cycloplegic) (r(pearson) = 0.21, P < 0.001). The difference (95%CI) of SE after cycloplegic was -0.08 ( 0.60 to 0.45) D. The difference (95%CI) of SE of K9001 autorefractor before and after cycloplegic was larger than that of WAM autorefractor [0.51 (-0.83 - 1.84) D and 0.31 (-0.66 to 1.28) D, P < 0.001]. Before cycloplegic, SE measured by WAM autorefractor showed myopic more than 0.25 D than K9001 (group 1) was found in 51 (16.8%) subjects; difference within 0.25 D was found in 160 (52.6%) subjects; hyperopic more than 0.25 D (group 3) was found in 93 (30.6%) subjects. After cycloplegic, 69 (22.7%) subjects were found in group 1, and subjects increased to 213 (70.1%) and decreased to 22 (7.2%) in group 2 and group 3, respectively. CONCLUSION: The binocular, open-field auto ref/keratometer provides more hyperopic readings than conventional autorefractor. It will be useful in both clinical screening and scientific research because it produces less instrument myopia than that of conventional autorefractor. PMID- 22943808 TI - [Prevalence of blindness and moderate and severe visual impairment among adults aged 50 years or above in Ji'an county of Jiangxi province:the China Nine Province Survey]. AB - OBJECTIVE: To investigate the prevalence of blindness and moderate and severe visual impairment among adults aged 50 years or above in Ji'an county of Jiangxi province, China. METHODS: It was a population-based cross-section study. Geographically defined cluster sampling was used in 5402 randomly selected individuals aged >= 50 years in 28 clusters in Ji'an from September to November 2006. The survey was preceded by a pilot study where operational methods were refined and quality assurance evaluation was carried out. All participants were enumerated through village registers followed door-to-door visits. Eligible individuals were invited to receive visual acuity measurement and eye examination. Statistical analyses were performed using Stata/SE Statistical Software, release 9.0. Chi-square test was used to investigate the association of age, gender and education with presenting and best corrected visual acuity. RESULTS: Five thousands four hundreds and two individuals were enumerated and 5010 persons were examined, the response rate was 92.74%. Based on the criteria of World Health Organization visual impairment classification in 1973, 78 persons were diagnosed as blindness, 265 persons were diagnosed as moderate and severe visual impairment defined as best corrected visual acuity, the prevalence of blindness and moderate and severe visual impairment were 1.56% and 5.29% respectively. Ninety-four persons were diagnosed as blindness, 726 persons were diagnosed as moderate and severe visual impairment defined as presenting visual acuity, the prevalence of blindness and moderate and severe visual impairment defined as presenting visual acuity was 1.88% and 14.50% respectively. The prevalence of blindness and moderate and severe visual impairment was higher in aged (trend chi(2) = 970.15, P = 0.000), female (chi(2) = 89.81, P = 0.000), and illiterate persons (trend chi(2) = 241.85, P = 0.000). Cataract was still the first leading cause of blindness and visual impairment, the retinal diseases was the second. Un-corrected refractive error also was the main cause of visual impairment. CONCLUSIONS: The prevalence of blindness and moderate and severe visual impairment was higher than other district in China. The first leading cause of blindness and visual impairment is still cataract. PMID- 22943809 TI - [Prevalence of blindness and low vision among adults aged 50 years or above in Ji'an county of Jiangxi province: the China nine-province survey]. AB - OBJECTIVE: To estimate the prevalence of cataract, the outcomes of cataract surgery, cataract surgical coverage rate, cataract blindness social burden rate in Ji'an county of Jiangxi province, China. METHODS: Cluster sampling was used in randomly selected 5010 individuals aged >= 50 years in Ji'an county of Jiangxi province. All individuals were received visual acuity and eye examination, including the evaluation of lens status and cataract surgical status by slit lamp biomicroscopy. Data bank was established by Epi-info Software. Statistical analyses were performed using Stata/SE Statistical Software, release 9.0 (Stata Corp, College Station, TX). Confidence intervals and P values (considered significance at the P < 0.05 level) for prevalence of cataract, cataract surgical coverage rate, cataract blindness social burden rate and outcomes of surgery were calculated with adjustment for clustering effects and stratification associated with the sampling design. RESULTS: In 5010 individuals, 1158 cases of cataract were found, the prevalence of cataract was 23.11% among adults aged 50 or above. The prevalence of cataract was higher in the aged, female (P < 0.01). In 99 eyes with cataract surgery, 50.51% and 5.05% of eyes were performed by the modern extra-capsular surgery and phacoemulsification respectively. The rate of intraocular lens implantation was 55.56%. Post-operative presenting and best corrected visual acuity equal to or more than 0.7 was 10.1% and 45.5% of operated eyes respectively. The main causes of the post-operated eyes with worse visual acuity were post-capsular opacity and refractive error. The cataract surgical coverage rate was 32.29%, and the cataract blindness social burden rate was 3.83%. The cataract surgical rate was lower and cataract blindness social burden rate was higher in the aged persons (P < 0.01). CONCLUSIONS: Cataract is the most common eye disease that may lead into blindness and severe visual impairment among older adults aged equal or more than 50 years. The cataract surgical coverage rate is not high but the cataract blindness social burden rate is heavy in Ji'an county. The rate of intraocular lens implantation need increase and the visual outcomes of the surgery should be further improved in the future. PMID- 22943810 TI - [Preliminary study of Boston keratoprosthesis in treatment of severe late stage ocular chemical burns]. AB - OBJECTIVE: To evaluate preliminary clinical outcome of Boston type I keratoprosthesis in ocular chemical burn patients. METHODS: Six keratoprosthesis were implanted into 6 patients of bilateral blindness. Visual acuity in these patients before the operation was light perception and all of them were unsuitable for standard penetrating corneal transplantation. The causes for corneal opacity were alkali burn in 2, sulfate acid burn in 3 and ethanol injury in 1 patient. Shirmer's test revealed severe dry eye in 3 patients, only one eye had normal lacrimal secretion. All patients were male, with follow-up period ranged from 17 to 26 months (mean 24 months). RESULTS: The postoperative visual acuity ranged from 0.05 to 0.5, 5 of them was better than 0.1. The retention rate within the follow-up period was 100%. Intraocular pressure was in normal limit, no retinal detachment was detected by type B ultrasonic examination. Postoperatively, retro-keratoprosthestic membrane occurred in 2 cases and was treated with YAG laser membranectomy, one eye complicated with elevated intraocular pressure and treated with shunt implantation. CONCLUSION: The Boston type 1 keratoprosthesis is a viable option for patients with obsolete chemical burns. PMID- 22943811 TI - [The changes of ocular bacterial isolates and in vitro antimicrobial susceptibility in the past six years]. AB - OBJECTIVE: To analyze the changes of ocular bacterial isolates and their susceptibility to ciprofloxacin, ofloxacin, levofloxacin, gatifloxacin and tobramycin in Henan Province in the past six years. METHODS: Retrospective study of ocular bacterial isolates and their in vitro antimicrobial susceptibility test results of Henan Eye Institute in the past six years. RESULTS: A total of 2044 bacterial isolates were classified into 39 kinds in the past six years, which were mainly from the conjunctival sac. Staphylococcus epidermidis was the most common, followed by Pseudomonas aeruginosa, Staphylococcus aureus and Bacillus cereus. All kinds of the ocular bacteria had the highest susceptibility to gatifloxacin (92.3%) among the tested drugs. Rods were more sensitive to quinolone drugs than cocci and gram-positive rods were more sensitive to tobramycin than the other types of germs. The drug's susceptibility of the four kinds of quinolone except ciprofloxacin decreased year by year with a decreasing ladder fashion every two years in the susceptibility change of levofloxacin in the past six years, while the susceptibility of tobramycin increased slowly from 2004 to 2008 and then decreased. Staphylococcus epidermidis susceptibility to every drug had the similar trend with the general changes in the past six years, that is, their susceptibility to ofloxacin decreased significantly since 2008, their susceptibility to gatifloxacin and tobramycin reduced significantly in 2009. Although Pseudomonas aeruginosa susceptibility to all the drugs had no significant change, for all gram-negative rods, their susceptibility to the four kinds of quinolone drugs were higher than their susceptibility to tobramycin while their susceptibility to levofloxacin and gatifloxacin reduced significantly as time passed by, especially from the year 2008 to 2009. CONCLUSIONS: The most common ocular bacterial isolates were Staphylococcus epidermidis, followed by Pseudomonas aeruginosa. Ocular bacterial isolates' susceptibility to gatifloxacin in vitro was significantly higher than to other drugs in every year but decreased significantly in 2009 while their susceptibility to ofloxacin and levofloxacin decreased significantly since 2008. Their susceptibility to tobramycin increased slowly from 2004 to 2008 and then decreased. PMID- 22943812 TI - [Expression of osteonectin in lens epithelium cells in age-related cataract]. AB - OBJECTIVE: To study the expression of osteonectin (also called secreted protein acidic and rich in cysteine, SPARC) in the lens epithelium cells in cortex cataract and nucleus cataract. METHOD: This is an experimental research. Forty five capsulotomy specimens were obtained from 33 patients suffered form pure cortex or/and nucleus cataracts and classified as nucleus group and cortex group, between May to July of 2010. Immunohistochemistry was used to detect the SPARC, which was analyzed by gray value. TUNEL was used to examine the apoptosis of lens epithelium cell. The difference of SPARC expression and apoptosis rate between these two groups was analyzed by LSD-t. RESULTS: Twenty specimens were studied with immunohistochemistry (C/N = 8/12), and 25 specimens studied by TUNEL test (C/N = 9/16). Expression of SPARC in the cortex group was significantly less than that in the nucleus group (peripheral region: t = 2.827, P < 0.05; central region: t = 2.264, P < 0.05). Expression of SPARC in the central region was significantly less than that in the peripheral region (peripheral region: t = 3.473, P < 0.05; central region: t = 2.771, P < 0.05). Apoptosis rate in the nucleus group was significantly lower than the cortex group (nucleus group: t = 2.364, P < 0.05; cortex group: t = 2.723, P < 0.05). Apoptosis rate in peripheral region was significantly less than that in central region (nucleus group: t = 2.771, P < 0.05; cortex group: t = 2.473, P < 0.05). CONCLUSIONS: The expression of SPARC is different between nucleus cataract and cortex cataract and also different between central and peripheral regions. The expression of SPARC is related with apoptosis of lens capsule epithelium cells. PMID- 22943813 TI - [Ocular surface injury resulted from topical anti-glaucoma medications: prevention and cure]. AB - The accumulating evidences from experimental and clinical studies suggested that the ocular surface could be injured by topical anti-glaucoma medications. The ocular surface injury not only caused dry eyes, red eye, eye itching, photophobia and other discomforts, but also increased the risk of failure of glaucoma surgery in patients. The commonly used preservative Benzalkonium Chloride (BAK) plays an important role in ocular surface damage and its side effects are dose- and time dependent, particularly, in the combined medications. Topical application of preservative BAK could result in the damage of epithelial cells and endothelial cells, and also affect the central corneal thickness. Prevention of ocular injury should be seriously taken into consideration in the anti-glaucoma medical treatment. Development of complex preparations, preservative-free and/or novel preservative preparations for glaucoma therapy may provide a promising approach in the prevention of ocular surface injury. PMID- 22943814 TI - [Surgical management of coexisting glaucoma and cataract]. AB - Coexisting glaucoma and cataract is a common eye disorder in elderly population. Recent advances in the management of patients with coexisting cataract and glaucoma offer a promising alternative in patients with uncontrolled glaucoma and a cataract and provide an individualized treatment depending upon patient's characteristics and intraocular pressure (IOP). Based on many significant studies that have been conducted in the combining cataract extraction with a glaucoma surgery in recent years, present article reviews the different surgical options on the control of their postoperative IOP level in the different stages of glaucoma and the surgical strategies for patients with combined cataract and glaucoma. PMID- 22943815 TI - [Brain-derived neurotrophic factor and repair of retinal ganglion cells after injury]. AB - Blocking of retrograde transport after the optic nerve injury results in deprivation of neurotrophic support to retinal ganglion cells (RGCs), and leads to apoptotic cell death in glaucoma. As an important member of neurotrophins, the brain-derived neurotrophic factor (BDNF) plays a substantial role in the repair of retinal ganglion cells injury, but its signaling pathway in the pathogenesis of glaucoma remains unclear. This review focuses on the structure, distribution and receptors of BDNF and its effects on RGC survival, axon regeneration and relevant signaling pathway, to provide theoretical foundation for neuroprotective treatment of glaucoma. PMID- 22943816 TI - [Progresses and existed problems on the diagnosis and treatment of Vogt-Koyanagi Harada disease]. AB - Vogt-Koyanagi-Harada disease is a multi-systems inflammatory disease that affects the eye, skin, inner ear and meninges. The characteristics of this disease are with meningismus, auditory dysfunction and integumentary changes. Bilateral granulomatous panuveitis with serous retinal detachments are the typical ocular findings. Vogt-koyanagi-Harada disease is characterized by the acute onset, poor response to the treatment and high blindness rate. The diagnosis is mainly made on the history and ocular findings with various systemic manifestations. Fundus angiography is often used to assist in the diagnosis. High dosages of systemic corticosteroids are the first line therapeutical choice. The immunosuppressive agents and biologic agents combined with systemic corticosteroids shows good results in some recurrent cases. The good visual prognosis is guarded with earlier accurate diagnosis and aggressive treatment. PMID- 22943817 TI - [The present situation and challenges of chronic kidney disease in China: an enlightenment from the epidemiological survey of chronic kidney disease in China]. PMID- 22943818 TI - [The current situation and thoughts of cardiovascular disease in chronic kidney disease]. PMID- 22943819 TI - [The efficacy and safety of continuous erythropoietin receptor activator in dialytic patients with chronic renal anemia: an open, randomized, controlled, multi-center trial]. AB - OBJECTIVE: To evaluate the efficacy and safety of continuous erythropoietin receptor activator (C.E.R.A.) once every 4 weeks by subcutaneous administration on hemoglobin (Hb) maintenance in dialytic patients with chronic renal anemia who had been treated with stable dose of erythropoietin (EPO). METHODS: This was an open, randomized, controlled, multi-center trial. All the hemodialysis or peritoneal dialytic patients in EPO maintenance treatment received subcutaneous EPO-beta during the 6-week pre-treatment period to maintain Hb level between 100 g/L and 120 g/L. Eligible patients were randomized (2:1) to accept either C.E.R.A. once every 4 weeks by subcutaneous administration (C.E.R.A. group, n = 187) or subcutaneous EPO-beta 1-3 times weekly (EPO group, n = 94) for 28 weeks (including 20-week dose titration period and 8-week efficacy evaluation period). The starting dose of C.E.R.A. was converted according to the dose of EPO-beta administered in the week preceding the first study drug administration. The primary outcome was the change of Hb level between the baseline and that in the efficacy evaluation period. RESULTS: Totally 253 patients completed the whole 28 week treatment. The change of baseline-adjusted mean Hb was +2.57 g/L for C.E.R.A. group and +1.23 g/L for EPO group, resulting in a treatment difference of 1.34 g/L (95%CI -1.11 - 3.78 g/L). Since the lower limit of 95%CI was greater than the pre-defined non-inferiority margin -7.5 g/L (P < 0.0001), C.E.R.A. once every 4 weeks by subcutaneous administration was clinically non-inferior to EPO regarding the maintenance of stable Hb level. The proportion of patients maintaining Hb level within the range of 100-120 g/L through efficacy evaluation period was similar between the two groups (69.0% for C.E.R.A. group vs 68.9% for EPO group, P > 0.05). The overall incidence of adverse events was similar between the C.E.R.A.(41.7%) and EPO (46.2%) groups (P > 0.05). The safety findings were in accordance with the patients' primary diseases rather than the administration. CONCLUSIONS: Conversion from EPO to C.E.R.A. once every 4 weeks by subcutaneous injection could maintain the Hb in target level in dialytic patients with renal anemia, and it was non-inferior to EPO. In general, subcutaneous administration of C.E.R.A. is well tolerated in dialytic patients with chronic renal anemia. PMID- 22943820 TI - [The effect of pitavastatin on blood glucose and its efficacy in diabetic patients with hypercholesterolemia]. AB - OBJECTIVE: To evaluate the effect of pitavastatin on blood glucose in patients with hypercholesterolemia, and to investigate the efficacy of pitavastatin in diabetic patients combined with hypercholesterolemia. METHOD: This study was a 12 week, multi-center, open-label, without parallel-group comparison, phase IV clinical trail. RESULTS: Contrasting to baseline, the prevalences at week 4 and 12 post-treatment of abnormal fasting plasma glucose (FPG) and glycosylated hemoglobin A1c (HbA1c) (FPG: 14.2%vs 14.1% and 11.0%; HbA1c: 14.3% vs 15.1% and 16.1%) in the safety set subjects without diabetes mellitus (DM), as well as in those with DM but not taking glucose-lowering drugs (FPG: 7/7 vs 4/7 and 5/7; HbA1c: 5/5 vs 4/4 and 5/5) had no significant changes (all P values > 0.05). Contrasting to baseline, the levels of TC [(6.51 +/- 0.94) mmol/L vs (5.12 +/- 0.93) mmol/L and (4.54 +/- 1.00) mmol/L], LDL-C [(4.11 +/- 0.79) mmol/L vs (3.02 +/- 0.81) mmol/L and (2.51 +/- 0.70) mmol/L] and TG [2.10 (1.53, 2.54) mmol/L vs 1.62 (1.26, 2.00) mmol/L and 1.35 (1.10, 1.86) mmol/L]at week 4 and 12 post treatment in the per protocol set 55 subjects with DM were significantly reduced (all P values < 0.05); 33.3% of subjects at high risk and 10.0% of subjects at very high risk had achieved a TC target value; 55.6% of subjects at high risk and 40.0% of subjects at very high risk had achieved a LDL-C target value. CONCLUSION: Pitavastatin has a safe effect on blood glucose and it could be used to treat diabetic patients combined with hypercholesterolemia in China. PMID- 22943821 TI - [The impact of proton pump inhibitors on esophageal acid exposure in gastroesophageal reflux disease]. AB - OBJECTIVE: To explore the effects of proton pump inhibitors (PPIs) therapy on esophageal acid exposure of patients with gastroesophageal reflux disease (GERD), and the correlation of anxiety and depression with recurrence of acid-related symptoms after discontinuation of PPIs. METHODS: From February 2010 to June 2011, 28 patients with GERD diagnosed by ambulatory 24 h esophageal pH monitoring admitted to Beijing Jishuitan Hospital were treated with esomeprazole 20 mg 2 times/d for 8 weeks (male 16, female 12). Symptoms after drug discontinuation were monitored. Ambulatory 24 h esophageal pH monitoring was performed on patients, whose symptom recurred within 8 weeks after treatment. BMI, Self-rating Anxiety Scale (SAS), and Self-rating Depression Scale (SDS) were detected. RESULTS: Among the 28 patients with GERD, 15 (53.6%) recurred symptoms after withdraw of PPIs. Compared with the asymptomatic group after withdraw of PPIs, the pretreatment duration of pH 4 (supine), 24 h total acid reflux time, number of time periods with acid reflux > 5 minutes, the maximal acid reflux time and 24 h total number of acid reflux in the symptomatic recurrence group were statistically significantly increased (11.7% vs 4.5%, 138.8 minutes vs 62.1 minutes, 6.0 vs 2.0, 27.0 minutes vs 12.4 minutes, 74.0 times vs 43.0 times, respectively, all P values < 0.05). There were no significant differences in BMI, SAS and SDS between the two groups. CONCLUSIONS: The basic level of esophageal acid exposure of patients with GERD before PPIs therapy may influence the esophageal acid exposure after PPIs therapy and then may affect the recurrence of symptoms. Although anxiety and depression is common in patients with GERD, it is not found that the recurrence of acid-related symptoms after the discontinuation of PPIs therapy is related to the anxiety and depression. PMID- 22943822 TI - [The association between the changes in triglyceride levels and the risk of incident type 2 diabetes mellitus: a 15 years followed-up results from the Chinese Multi-provincial Cohort Study]. AB - OBJECTIVE: To explore the 15-years change in fasting TG level and the accumulative incidence of type 2 diabetes mellitus (T2DM) from 1992 to 2007, and to assess the association between the change in TG level and the accumulative onset risk of T2DM. METHODS: A total of 11 387 subjects aged 35 - 64 years were recruited from 6 provinces in China in the baseline survey in 1992, and were followed-up for cardiovascular disease till 2007. In 2007, 9184 subjects were successfully followed-up and 5966 subjects entered into the second examination. Totally 5408 participants, who were free of diabetes at baseline and had complete information for both check ups, were included in this analysis. Fasting TG levels were categorized into three groups: < 1.70 mmol/L, 1.70 - 2.25 mmol/L and >= 2.26 mmol/L. The association between 15-years change in TG level and the accumulative onset risk of T2DM was assessed by logistic regression analysis. RESULTS: In 1992, the mean level of TG was 1.49 mmol/L in male and 1.26 mmol/L in female. During the 15 years, TG levels increased by 0.25 mmol/L and 0.53 mmol/L in male and female, respectively. The prevalence of elevated TG (< 1.70 mmol/L) increased from 23.4% in 1992 to 39.0% in 2007. The 15-year accumulative incidence of diabetes was 13.9% in male and 11.8% in female. The incidence rates were 10.5%, 16.2% and 26.6% for TG levels of < 1.70 mmol/L, 1.70 - 2.25 mmol/L and >= 2.26 mmol/L, respectively. Multivariate logistic regression analysis showed that the baseline TG level was significantly associated with the onset risk of diabetes after adjustment for other cardiovascular risk factors. At any given baseline TG level, the onset risk of diabetes increased with the TG levels in the second examination in 2007. After adjusting other risk factors, participants with the highest categories of both baseline and follow-up TG levels had 2.1 folds higher accumulative onset risk of diabetes (RR = 3.39, 95%CI 2.49 - 4.61) than those with the lowest categories of both baseline and follow-up TG levels. CONCLUSION: Baseline TG level is independently associated with diabetes onset risk, and the change of TG level in a 15-year interval predicts the onset risk of diabetes beyond the baseline TG level. PMID- 22943823 TI - [The correlation between postural hypotension and myocardial infarction in the elderly population]. AB - OBJECTIVE: To investigate the association between the systolic/diastolic orthostatic hypotension (OH-S/OH-D) and myocardial infarction (MI) in the elderly. METHODS: Health screening physical examination were carried in 1081 subjects without MI aged over 65 years in Guangzhou Military region. The orthostatic blood pressure and heart rate were measured in supine position after resting for more than 5 minutes and at 0 and 2 minutes after standing. All the cases were divided into systolic or diastolic group on the basis of definition of orthostatic hypotension and followed up by telephone or inpatient medical records with mean period of 315.8 days. The primary endpoint was MI occurrence. RESULTS: The prevalence of OH in this cohort was 24.5% (OH-S/OH-D: 19.3%/17.2%). Significant differences in the occurrence of OH and OH-S were found in the elderly and the very elderly subjects (>= 80 years) (26.1% vs 20.1%, P = 0.045 ; 21.0% vs 14.6%, P = 0.018), while no difference was found in OH-D. The prevalence of MI in the OH positive subjects was significantly higher than that in the OH negative subjects, as well as in OH-S or OH-D group. After adjustment of age, supine blood pressure, creatinine and cerebrovascular history by logistic regression, the association was observed between MI and OH (HR 15.635, 95%CI 3.299 - 74.091, P = 0.001), OH-S(HR 8.760, 95%CI 2.487-30.851, P = 0.001)and OH D(HR 3.889, 95%CI 1.097 - 13.790, P = 0.035). CONCLUSION: OH-S and OH-D hypotension are robust predictors for MI in the elderly. PMID- 22943824 TI - [The relationship between carboxylesterase 1 gene polymorphisms and susceptibility to antituberculosis drug-induced hepatotoxicity]. AB - OBJECTIVE: To study the relationship between the genetic polymorphisms of carboxylesterase 1 gene (CES1) and the susceptibility to antituberculosis drug induced hepatotoxicity (ATBDIH). METHODS: Genetic polymorphisms of CES1 in 473 tuberculosis patients with or without hepatotoxicity (200:273) after antituberculosis chemotherapy were analyzed by PCR-MassArray. RESULTS: In 4 tags of CES1 single nucleotide polymorphism (SNP), the frequency of the rs1968753 allele had statistical difference between the hepatotoxicity group and the no hepatotoxicity group(P = 0.0236). The characteristics of anti-hepatotoxicity had been shown relationship with rs8192950 (P = 0.044, OR = 0.649, 95%CI = 0.426 - 0.989, AC/AA) and rs1968753 (P = 0.048, OR = 0.556, 95%CI = 0.311 - 0.995, GG/AA). The diplotypes with 'CGC' haplotype exhibited significant protection against hepatotoxicity at one copy (P = 0.048, OR = 0.654, 95%CI = 0.430 - 0.996). CONCLUSIONS: The genetic polymorphisms of CES1 might have significant association with ATBDIH. SNP rs8192950 AC genotype and rs1968753 GG genotype might be the candidates for risk prediction of ATBDIH. PMID- 22943825 TI - [The UGT1A, Nrf2 and Keap1 protein expression and significance in colon tumor]. AB - OBJECTIVE: To investigate the role of UDP-glucuronosyltransferase 1A (UGT1A), nuclear factor erythroid-2-related factor 2 (Nrf2) and kelch-like ECH-associated protein 1 (Keap1) in the tumorigenesis of colonic carcinoma. METHODS: The expressions of UGT1A, Nrf2 and Keap1 were detected in normal colonic mucosa (24 cases), adenoma tissue (30 cases) and adenocarcinoma tissue (77 cases) by immunohistochemistry, and the relationship between their expressions and the clinical pathological characteristics was analyzed. RESULTS: The positive rates of UGT1A in normal colonic mucosa, adenoma and adenocarcinoma tissue were 83.3% (20/24), 80.0% (24/30) and 53.2% (41/77), respectively. The positive rate of UGT1A in adenocarcinoma was lower than those in colonic mucosa and adenoma (all P < 0.05).On the contrary, the positive rates of Nrf2 in adenoma [70.0% (21/30)] and adenocarcinoma tissue [87.0% (67/77)] were higher than that in normal colonic tissue [41.7% (10/24), all P = 0.000]. The positive rates of Keap1 in normal colonic mucosa, adenoma and adenocarcinoma tissue were 54.2% (13/24), 70.0% (21/30) and 61.0% (47/77), respectively (normal colonic tissue vs adenocarcinoma tissue, P = 0.040; adenoma vs adenocarcinoma, P = 0.002). There was no correlation between the expression of UGT1A, Nrf2 and the clinicopathologic features of colon carcinoma, while the differences of Keap1 positive rates in the various degrees of tumor differentiation [moderately-well differentiated vs poorly differentiated: 70.0% (35/50) vs 44.4% (12/27)] and invasion [T(1)-T(2) vs T(3)-T(4): 78.8% (26/33) vs 47.7% (21/44)] were statistically significant (all P < 0.05). CONCLUSION: The decreased expression of UGT1A and the dysregulation of Nrf2/Keap1 system may play a role in colonic tumorigenesis. PMID- 22943826 TI - [The changes of ghrelin, growth hormone, growth hormone releasing hormone and their clinical significances in patients with chronic obstructive pulmonary disease]. AB - OBJECTIVE: To investigate the changes of plasma ghrelin, growth hormone (GH) and growth hormone releasing hormone (GHRH) and gastric ghrelin in patients with chronic obstructive pulmonary disease (COPD) and to explore their clinical significances. METHODS: Plasma ghrelin, GH, GHRH, TNFalpha, IL-6 and C reactive protein (CRP) were measured in 40 COPD patients and 20 controls with chronic bronchitis. Correlated factors of plasma ghrelin, TNFalpha, IL-6, CRP were analyzed. Body composition was assessed with bioelectrical impedance analysis. The expression of gastric ghrelin in patients with COPD was detected. RESULTS: Plasma ghrelin was higher in the underweight patients than in the normal weight patients and in the controls [(1.78 +/- 0.46) ng/L, (1.39 +/- 0.46) ng/L, (1.36 +/- 0.39) ng/L, respectively]. Plasma GH was lower in the underweight patients than in the normal weight patients and in the controls [(4.12 +/- 0.83) ug/L, (5.17 +/- 0.72)ug/L, (6.49 +/- 1.13) ug/L, respectively]. Plasma GHRH was lower in the underweight patients than in the normal weight patients and in the controls [(20.43 +/- 4.41) ng/L, (23.47 +/- 3.97) ng/L, (27.48 +/- 10.06) ng/L, respectively]. Plasma ghrelin was higher in the underweight patients than in the controls (P < 0.01). Plasma ghrelin was higher in the underweight patients than in the normal weight patients with COPD. Plasma ghrelin (log transformed) was negatively correlated with BMI and percentage of body fat in the COPD patients. Plasma GHRH was positively correlated with ghrelin in the underweight patients (r = 0.515, P < 0.05), while no correlation was found between plasma GH and ghrelin in the underweight patients (r = 0.415, P > 0.05). Plasma ghrelin was positively correlated with TNFalpha and IL-6 in the underweight patients. The gastric expression of ghrelin showed no evident difference between the patients with COPD and the controls. CONCLUSIONS: The plasma GH in COPD patients may not be correlated with ghrelin. The plasma ghrelin level may be a useful indicator for malnutrition in COPD patients. Plasma ghrelin might be involved in the pathogenesis of CODP by affecting the body energy metabolism. PMID- 22943827 TI - [Thymoma T helper type 17 cells and related cytokines in myasthenia gravis]. AB - OBJECTIVE: To investigate the immunoregulatory role of Th17 cell and the related cytokines in myasthenia gravis. METHODS: Totally 51 myasthenia gravis (MG) patients were divided into MG with thymomas (TM group) and the MG with normal thymus (NT group), as well as 22 healthy subjects as controls. Th17 cells from peripheral blood mononuclear cells were measured by flow cytometry. Th17 related cytokines were detected by ELISA and real-time quantitative-PCR. RESULTS: The quantity of Th17 cells in MG patients with thymomas (1.53 +/- 0.59)% were significantly increased compared with that of healthy control (0.94% +/- 0.32%, P < 0.05). There was no significant difference in the number of Th17 cells between healthy controls and NT group. The expression levels of IL-17 mRNA (23.7 +/- 4.5) were up-regulated significantly versus those in healthy controls (13.4 +/- 3.2, P < 0.01). The levels of mRNA expression of IL-1beta, IL-6 and IL-23 were up regulated significantly in TM group. The mean concentration of IL-17 was up regulated significantly in TM group (30.4 +/- 7.3) ng/L versus healthy controls [(19.2 +/- 4.9) ng/L, P < 0.05]. Serum levels of IL-23 and IL-1beta were always increased in TM group versus healthy controls. CONCLUSION: The elevated levels of IL-17 and other Th17 related cytokines in thymomas may aggravate the autoimmunity disorder. PMID- 22943828 TI - [TET2 and DLK1 gene expression and their clinical significance in bone marrow CD(3)(+) T cells of patients with myelodysplastic syndrome]. AB - OBJECTIVE: To investigate the expression of TET2 and DLK1 mRNA in bone marrow CD(3)(+) T cells of patients with myelodysplastic syndrome (MDS) and their clinical significance and to explore the potential mechanism of abnormal cell mediated immunity. METHODS: CD(3)(+) T cells were sorted by magnetic activated cell-sorting system. The expressions of TET2 and DLK1 mRNA in bone marrow CD(3)(+) T cells from 26 MDS patients and 16 healthy controls were detected by fluorescence quantitative PCR. RESULTS: The expression of TET2 mRNA in CD(3)(+) T cells was down-regulated in the MDS patients by (0.16 +/- 0.15) fold compared with the controls (P < 0.05). The expression of TET2 mRNA in CD(3)(+) T cells of MDS patients was positively correlated with serum complement C(3) (r = 0.404, P < 0.05). The expression of DLK1 mRNA in CD(3)(+) T cells was up-regulated in the MDS patients by (1.61 +/- 0.88) folds compared with the controls (P < 0.05). Grouped by the chromosomes, the patients with chromosome abnormalities presented significantly higher DLK1 mRNA level than those with normal chromosomes [(1.45 +/ 0.44) folds, P < 0.05]. The expression of DLK1 mRNA in CD(3)(+) T cells of MDS patients was positively correlated with the proportion of bone marrow blasts (r = 0.343, P < 0.05). CONCLUSIONS: The mRNA expression of TET2 in CD(3)(+) T cells of MDS patients was decreased while the mRNA expression of DLK1 was increased, which might decline the immune surveillance function. The findings would be useful for exploring the mechanism of immune tolerance. PMID- 22943829 TI - [The clinical efficacy and safety of panipenem-betamipron in treatment of moderate to severe pulmonary infection]. AB - OBJECTIVE: To evaluate the clinical efficacy and safety of intravenous panipenem betamipron in the treatment of moderate to severe pulmonary infection. METHODS: An open, perspective, multicenter clinical trial was conducted. Among the enrolled 665 patients, 621 patients with moderate to severe pulmonary infection were treated with intravenous panipenem-betamipron at a dose of 500 mg every 6 hours per day for 7 - 14 days. Among them, the community acquired pneumonia (CAP), hospital acquired pneumonia (HAP) and ventilator associated pneumonia (VAP) patients were 55.6% (345/621), 37.0% (230/621) and 7.4% (46/621), respectively. All the adverse events were recorded. RESULTS: The overall effective rate of panipenem-betamipron was 84.4% with CAP of 91.9%, HAP of 76.1% and VAP of 69.6%. The effective rates in the patients with moderate and severe pulmonary infection were 87.5% and 82.8%, respectively. Bacterial separation rate was 54.8% and bacterial eradication rate was 80.9%. Bacterial eradication rates to pseudomonas aeruginosa, pneumobacillus, Escherichia coli. and acinetobacter baumannii were 74.7%, 95.6%, 89.5% and 50.9%, respectively. The adverse events rate was 1.8% (12/665). CONCLUSION: Intravenous panipenem-betamipron is effective in treating moderate to severe pulmonary infection with low adverse events rate. PMID- 22943830 TI - [The expression of T cell immune-related gene mRNAs in peripheral blood mononuclear cells from patients with venous thromboembolism]. AB - OBJECTIVE: To explore the role of T cell-mediated immunity in the pathogenesis of venous thromboembolism (VTE) by analyzing the differential expression of T cell immune-related gene mRNAs peripheral blood mononuclear cells (PBMCs) between VTE patients and controls with GeneChip Human Genome. METHODS: Human cDNA microarray analysis was employed in PBMCs from 20 VTE patients and 20 hypertensive controls, and random variant model (RVM) corrected t-test was used for statistical analysis of differential gene expression. RESULTS: Six mRNA stripes including CD(247), CD(3D), CD(3G), Granzyme A (GzmA), Granzyme B (GzmB) and Zeta-chain-associated protein kinase 70 (ZAP70) were found to be associated with T cell-mediated immunity. Significant down-regulation of these six mRNAs was found in the VTE group compared with the controls (15.3050 +/- 0.6346 vs 15.8053 +/- 0.5567, 13.7878 +/- 0.7731 vs 14.3820 +/- 0.4857, 13.3299 +/- 0.9104 vs 14.1246 +/- 0.6011, 14.8893 +/- 0.8675 vs 15.5305 +/- 0.4624, 15.9113 +/- 0.8123 vs 16.4553 +/- 0.5055, 14.3652 +/- 0.7717 vs 14.3652 +/- 0.7717; all P values < 0.05). CONCLUSIONS: T cells' function including antigen recognition, signal transduction and cytotoxicity was impaired in VTE patients. T cell-mediated immunity dysfunction probably plays an important role in the pathogenesis of VTE. PMID- 22943831 TI - An evolving problem: methamphetamine production and trafficking in the United States. AB - BACKGROUND: Methamphetamine is a serious illicit drug problem in the United States and globally. For decades, methamphetamine has been supplied to the illicit market through local clandestine manufacturing and trafficking. In the early stages, illicit methamphetamine was produced and trafficked by motorcycle gangs and Mexican criminal groups. Over time, local clandestine manufacturing increasingly contributed to the illicit supply and broader methamphetamine problem. This review examines the evolution of the illicit methamphetamine supply in the U.S. METHODS: A review of the literature on methamphetamine production and trafficking was conducted. Information was obtained from numerous sources including governmental reports, books and academic articles. RESULTS: Attempts to control the supply of methamphetamine have only led to short term disruptions in availability. Clandestine manufacturing and trafficking have undergone significant changes over the past several decades. Shifts in local production have regularly been counterbalanced by changes in production and trafficking from criminal organizations in Mexico. Transnational criminal organizations now control much of the methamphetamine supply in the U.S. and methamphetamine remains widely available. CONCLUSIONS: The supply of methamphetamine in the United States is dynamic. Producers and traffickers have adapted to control efforts and the problem continues. Control efforts focused on eliminating supply are limited at best. PMID- 22943832 TI - [Evaluation of Speed-oligo Mycobacteria test for identification of nontuberculous mycobacteria]. PMID- 22943833 TI - [Characteristics of a cohort of pregnant women with human immunodeficiency virus infection]. AB - BACKGROUND: Mother-to-child transmission (MTCT) during pregnancy, delivery or breastfeeding, is the main route of HIV infection in children. Strategies aimed at promoting the health of HIV infected pregnant women and MTCT prevention have reduced transmission to below 2%. This paper presents the clinical and epidemiological features of a cohort from Madrid and compares foreign-born with Spanish-born women. METHOD: Retrospective, observational and descriptive study on HIV infected pregnant women from South Madrid (n=70) and their offspring (n=78) who were born during the study period from August 1992 to January 2010. RESULTS: Most pregnant women were infected by heterosexual transmission (51%). Most Spanish-born women (66%) were diagnosed before pregnancy (81%), while foreign born women (34%) were diagnosed during pregnancy (70%). Foreign-born women had less obstetric check-ups (67%) than Spanish-born women (97%). The MTCT rate was 1.3% during the last ten years. CONCLUSIONS: Heterosexual transmission is the primary mode of acquisition of HIV infection both for Spanish-born and foreign born pregnant women. However, the HIV infection was diagnosed earlier in Spanish born women. There were no differences in the effectiveness of antiretroviral therapy as a preventive measure against MTCT when it is started at an early stage. PMID- 22943834 TI - Outbreak of Neisseria meningitidis C in a Brazilian oil refinery involving an adjacent community. AB - BACKGROUND: An outbreak of serogroup C meningococcal disease (MD) that involved employees from an oil refinery occurred in Paulinia, from March to June 2010, and spread to the community of Cosmopolis, both situated in Sao Paulo State, Brazil. The aim of this study was to describe the epidemiological and laboratory aspects, and the control measures that were implemented. METHODS: Descriptive and molecular epidemiological analysis was used to define the extent of the outbreak and the common risk factors among outbreak related cases. Vaccination initiative targeted the employees from the oil refinery and the community-based individuals. RESULTS: A total of six outbreak-related cases of MD in the oil refinery and 12 cases in the city of Cosmopolis, Sao Paulo State occurred in a three-month period. All 18 MD cases were confirmed as serogroup C either by culture, real time polymerase chain reaction (RT-PCR), or counterimmunoelectrophoresis (CIE). The meningococcal isolates (n=15) had the phenotype C:23:P1.14-6 and showed close genetic relationship by pulsed field gel electrophoresis (PFGE). Multilocus sequence typing (MLST) characterization showed that the clones were ST 3780, ST 103 complex. The isolates were susceptible to the antibiotics tested. Vaccination was administered to 15,848 persons at the oil refinery and 18,571 persons of the community. CONCLUSIONS: The molecular characterization of the Neisseria meningitidis (N. meningitidis) strains, and the efficient investigation and the prompt measures implemented were essential for controlling the disease in the region. PMID- 22943835 TI - Intrinsic innervation of the Persian squirrel (Sciurus anomalus) ileum. AB - Most investigations related to the characterisation of the enteric nervous system (ENS) are pivoted on the intestine of small rodents, but few studies are available on the ENS of wild or 'unconventional' rodents. Anti-PGP 9.5 and anti Hu antibodies were utilised to recognise the distribution pattern of neuronal cell bodies and fibres of the ileum of the Persian squirrel (Sciurus anomalus) ENS. The percentages of subclasses of enteric neurones in the total neuronal population were investigated by neuronal nitric oxide synthase (nNOS), choline acetyltransferase (ChAT), calcitonin gene-related peptide (CGRP), substance P (SP), and calbindin (CALB). Myenteric plexus (MP) and submucosal plexus (SMP) neurones showing nNOS immunoreactivity (IR) were 41+/-4% and 11+/-6%, respectively, whereas cells expressing ChAT-IR were 56+/-9% and 74+/-16%, respectively. nNOS-IR was co-expressed by 21+/-2% and 9+/-4% of the MP and SMP cholinergic neurones, respectively, whereas the nNOS-IR MP and SMP neurones co expressing ChAT-IR were 86+/-6% and 89+/-2%, respectively. CGRP-IR and SP-IR were expressed, respectively, by 13+/-5% and 6+/-3% of MP and 18+/-2% and 2+/-2% of SMP neurones. CALB-IR was expressed by 22+/-8% and 56+/-14% of MP and SMP neurones, respectively. MP and SMP cholinergic neurones co-expressed nNOS-IR (21+/-2% and 9+/-4%, respectively) and a very high percentage of nNOS-IR neurones showed ChAT-IR (86+/-6% and 89+/-2%, respectively). MP and SMP CALB-IR neurones co-expressed ChAT-IR (100% and 63+/-11%, respectively) and CGRP-IR (89+/-5% and 26+/-7%, respectively). Our data might contribute to the neuroanatomical knowledge of the gastrointestinal tract in exotic mammals and provide a comparison with the available data on other mammals. PMID- 22943836 TI - Improvement of palmoplantar pustulosis lesions after angioplasty for Leriche syndrome. AB - Although a wide range of treatments have been used in the treatment of palmoplantar pustulosis (PPP), PPP is still very difficult to treat. We report a patient who had a dramatic reduction in PPP lesions after bypass surgery for Leriche syndrome. We assume that improved blood circulation had a crucial impact in reducing PPP lesions and suggest improving blood circulation could be another treatment option. PMID- 22943837 TI - The link between childhood sexual abuse and myocardial infarction in a population based study. AB - OBJECTIVES: This study examined the relationship between childhood sexual abuse (CSA) and myocardial infarction in men and women, while controlling for social determinants (i.e., socioeconomic status, social support, mental health) and traditional cardiovascular risk factors (i.e., age, race, obesity, smoking, physical inactivity, diabetes mellitus). METHODS: Population-based data were obtained from the 2010 Behavioral Risk Factor Surveillance System. Myocardial infarction was ascertained by self-report of a health-professional diagnosis. CSA was defined as forced sex with someone at least 5 years older before the age of 18. The final sample included 5,095 men and 7,768 women. RESULTS: After adjustment for 15 factors, abused males had nearly 3 times the odds of heart attack compared to non-abused males (OR=2.96; 95% CI=1.12, 7.85). Among women, CSA was not associated with heart attack in the age-race adjusted (OR=1.20; 95% CI=0.39, 3.68) or fully-adjusted (OR=0.88; 95% CI=0.28, 2.75) analyses. CONCLUSIONS: CSA was associated with heart attack in men, even when controlling for traditional risk factors; however, no association was found among women. Future research is needed to replicate the study's unique findings. PMID- 22943838 TI - Generation of physiological parameter sets for hip joint motions and loads during daily life activities for application in wear simulators of the artificial hip joint. AB - At present, wear investigations of total hip replacements are performed in accordance with the ISO standard 14242, which is based on simplified kinematic and force data of the gait cycle. The aim of this analytical study was to generate parameter sets of daily life activities in order to replicate more realistic joint load situations in wear testing. Hence, published in vivo motion and force data of daily life activities were evaluated and adjusted using analytical techniques. The created kinematically and dynamically consistent parameter sets comprised time trajectories of three Cardan angles to describe the motion of the femur with respect to the pelvis and time trajectories of three force components, representing the hip joint contact force. The parameter sets include the activities of walking, knee bending, stair climbing and a combined load case of sitting down and standing up. Additionally, a motion sequence following the frequency of daily life activities was presented. Differences of the evaluated angular motions and joint contact forces in comparison to the ISO standard 14242-1 were pointed out. The results of this study offer the possibility to extend the kinematics and dynamics of the ISO standard test protocol and to support the loading conditions of hip wear simulators with a comprehensive set of motions and loads close to reality. PMID- 22943839 TI - Incidence and clinical outcomes of tendon rupture following distal radius fracture. AB - PURPOSE: To evaluate the incidence of tendon rupture after nonoperative and operative management of distal radius fractures, report clinical outcomes after tendon repair or transfer, and examine volar plate and dorsal screw prominence as a predictor of tendon rupture. METHODS: We performed a retrospective chart review on patients treated for tendon rupture after distal radius fracture. We evaluated active range of motion, Disabilities of Arm, Shoulder, and Hand score, grip strength, and pain score, and performed radiographic evaluation of volar plate and dorsal screw prominence in both the study group and a matched control group. RESULTS: There were 6 tendon ruptures in 1,359 patients (0.4%) treated nonoperatively and 8 tendon ruptures in 999 patients (0.8%) treated with volar plate fixation. At the time of final follow-up, regardless of treatment, we noted that patients had minimal pain and excellent motion and grip strength. Mean Disabilities of the Shoulder, Arm, and Hand scores were 6 for patients treated nonoperatively and 4 for those treated with volar plating. CONCLUSIONS: We were unable to verify volar plate or dorsal screw prominence as independent risk factors for tendon rupture after distal radius fractures. However, we recommend continued follow-up and plate removal for symptomatic patients who have volar plate prominence or dorsal screw prominence. In the event of tendon rupture, we report excellent clinical outcomes after tendon repair or tendon transfer. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV. PMID- 22943840 TI - Experience with prothrombin complex for the emergent reversal of anticoagulation in rural geriatric trauma patients. AB - BACKGROUND: Therapeutic anticoagulation in the geriatric trauma population is increasingly common. Fresh frozen plasma, while the criterion standard for correction, has limited availability and associated transfusion risks. We examined our use of prothrombin complex concentrate for immediate reversal of therapeutically anticoagulated geriatric trauma patients. METHODS: This was a 1 year, retrospective review of 25 geriatric trauma patients who received either fresh frozen plasma alone or prothrombin complex concentrate and met the inclusion criteria of age >55 years, current warfarin use, and an admission international normalized ratio of >1.5. Fifteen patients received prothrombin complex concentrate and 10 patients received fresh frozen plasma alone. We examined demographics, laboratory values, and blood product use. RESULTS: The mean ages were similar (77 vs 80 years). Patients had similar mean Injury Severity Score (19.1 vs 19.2). Survivor duration of hospital stay (7.7 vs 9.5; P = .37) and duration of stay in the intensive care unit (4.4 vs 7.1; P = .25) trended positively in the prothrombin complex concentrate group. The prothrombin complex concentrate group received fewer units of fresh frozen plasma (1.6 [range, 0-6] vs 2.7 [range, 2-4]; P = .05), with a greater decrease in international normalized ratio (51% vs 43%; P = .05). Six patients (40%) in the prothrombin complex concentrate group avoided fresh frozen plasma transfusion altogether. CONCLUSION: Prothrombin complex may be used safely and effectively to reverse emergently anticoagulation in geriatric trauma patients. PMID- 22943841 TI - Restoration of E-cadherin expression in pancreatic ductal adenocarcinoma treated with microRNA-101. AB - PURPOSE: To investigate the possibility of inhibiting the progression of pancreatic ductal adenocarcinoma (PDAC) by facilitating the expression of E cadherin through the enforced expression of microRNA-101 (miR-101). METHODS: In situ hybridization was conducted with archival tissue using a double digoxigenin labeled probe. Chromatin immunoprecipitation (ChIP) assay was conducted with EZ Magna ChIPTM A. Gene profile analysis, Western blot, and immunoprecipitation assays were performed using standard protocols. RESULTS: We found that decreased miR-101 expression observed in archival patient tissues was significantly associated with poor prognosis indicated by low-intensity staining in high-grade tumors. ChIP assays using anti-enhancer of zeste homolog 2 (EZH2) antibodies indicated not only the interaction of EZH2 to the CDH1 (E-cadherin) promoter, but also that this interaction was significantly diminished in cells transfected with pre-miR-101. We observed a global downregulation of trimethylated lysine 27 of H3 histone (H3K27me3) along with upregulation of the enzymes histone deacetylase -1 and -2 with the re-expression of miR-101. Further, we observed lesser levels of transcriptional factors that inhibit the CDH1 promoter with pre-miR-101 treatment. Western blot analysis confirmed the enhanced E-cadherin expression. PANC-1 cells transduced with pre-miR-101 displayed markedly attenuated growth in SCID mice. CONCLUSION: These results suggest the potential therapeutic use of miR 101-enforced expression for inhibition of PDAC. PMID- 22943842 TI - Laparoscopic versus open resection of hepatic colorectal metastases. AB - BACKGROUND: This study was undertaken to assess the safety and efficacy of laparoscopic versus open resection of hepatic colorectal metastases (CRM). METHODS: We reviewed retrospectively of all patients undergoing initial resection of CRM at a single institution between 1995 and 2010. The study cohort consisted of all patients undergoing laparoscopic resection and a cohort of patients undergoing open resection matched on a 4:1 basis by propensity scoring. Variables analyzed included patient and tumor characteristics, short-term outcomes, and OS and disease-free (DFS) survivals. RESULTS: The 35 patients in the laparoscopic cohort and 140 patients in the open cohort were equivalent in terms of age, Charlson Comorbidity Index, tumor characteristics, and Clinical Risk Score. Similar proportions of patients in the laparoscopic and open groups underwent synchronous colectomy (9% in both; P = .976) and major hepatectomy (54% vs 51%; P = .705). Blood loss (202 vs 385 mL; P < .001), complications (23% vs 50%; P = .004), and duration of stay (4.8 vs 8.3 days; P < .001) were less in the laparoscopic cohort. Five-year OS (36% vs 42%; P = .818) and DFS (15% vs 22%; P = .346) were also similar in the laparoscopic and open groups. CONCLUSION: Laparoscopic resection of hepatic CRM seems to be a beneficial alternative to open surgery in appropriately selected patients. PMID- 22943843 TI - Predictors of survival in patients with high-grade peritoneal metastases undergoing cytoreductive surgery and hyperthermic intraperitoneal chemotherapy. AB - BACKGROUND: Peritoneal metastases in patients with high-grade adenocarcinoma have been typically associated with a poor outcome. Recent literature has suggested that cytoreduction surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) may improve survival. We examined this subset of patients in an effort to better delineate those factors which contribute to improved survival. METHODS: A retrospective review was performed looking at patients who had undergone CRS/HIPEC. Patients were identified as high-grade histology on the basis of pathology reports indicating their lesion as high grade, moderately, or poorly differentiated and/or associated with signet ring or goblet cell carcinoid features. Peritoneal cancer index and completeness of cytoreduction (CC) were used to define disease burden. Survival analysis was performed by the method of Kaplan-Meier with the log-rank test used to determine significance. RESULTS: Of the 250 patients who underwent CRS/HIPEC between 1999 and 2011, 36 (14%) were identified as having peritoneal metastases from a high-grade gastrointestinal primary. Actual overall survival from the time of diagnosis was 11.1% at 5 years. Median survival from time of surgery was 21.6 months. Survival advantage was conferred to those patients who underwent a CC0/CC1 resection, had a peritoneal cancer index score at time of surgery <=20, appendiceal primary, or moderately differentiated histopathology. Receipt of neoadjuvant chemotherapy and nodal status was not significantly predictive of improved survival. Patients with signet ring cell histology had a particularly poor prognosis. CONCLUSION: For those patients with high-grade peritoneal metastases and historically a poor prognosis, prolonged survival may be achieved through CRS/HIPEC, optimally with a CC0/CC1 resection. PMID- 22943844 TI - An enhanced recovery pathway decreases duration of stay after esophagectomy. AB - PURPOSE: Enhanced recovery pathways (ERP) decrease morbidity and duration of stay after colorectal surgery. There is little information about their role in complex procedures, such as esophagectomy. The purpose of this study was to determine the impact of an ERP on duration of stay, complications, and readmissions after esophagectomy. METHODS: Patients undergoing esophagectomy for cancer or high grade dysplasia from June 2009 to December 2011 were identified from a prospectively maintained database. Beginning in June 2010, all patients were enrolled in a 7-day multidisciplinary ERP including written patient education with daily treatment plan, indications for intensive care admission, early structured mobilization, and diet and drain management. Short-term (30-day) outcomes were compared for patients undergoing esophagectomy pre- and post pathway. Data are expressed as median values [interquartile range]. RESULTS: We identified 106 patients; 47 underwent esophagectomy before ERP implementation and 59 after. Patients were similar with respect to age, gender, diagnosis, and operative time. Hospital stay was shorter in the ERP group (8 [7-17] vs 10 [9-17] days; P = .01). There were no differences in rates of complications (59% vs 62%) or readmissions (6% vs 5%). CONCLUSION: Implementation of a multidisciplinary ERP for esophagectomy was associated with decreased duration of stay, without an increase in complications or readmissions. PMID- 22943845 TI - Minimal access excision of aortic valve fibroelastoma: a case report and review of the literature. AB - Papillary fibroelastomas are rare primary tumours of cardiac origin accounting for approximately 10% of all primary cardiac neoplasms. Due to a high thromboembolic risk, surgical excision is the mainstay of treatment in these patients and median sternotomy the most widely used approach. We describe the case of a 43 year-old lady presenting with acute myocardial infarction secondary to aortic valve papillary fibroelastoma subsequently excised using a minimal access technique. From our experience mini-sternotomy offers excellent exposure and allows for safe resection in such cases, improving cosmesis without compromising either intra or post-operative outcome. PMID- 22943846 TI - Acupuncture improves sleep in postmenopause in a randomized, double-blind, placebo-controlled study. AB - BACKGROUND: Insomnia increases in frequency as women approach and pass through menopause. Studies have not shown acupuncture efficacy for insomnia in postmenopausal women. OBJECTIVES: The aim of this study was to evaluate the effectiveness of acupuncture therapy on sleep parameters, depression symptoms and quality of life in postmenopausal women with insomnia. METHODS: This study included 18 postmenopausal women aged 50-67 years old. Participants had a body mass index <= 30 kg/m(2), presented a diagnosis of insomnia according to the DSM IV criteria, had experienced at least 1 year of amenorrhea and had a follicle stimulating hormone level >= 30 mIU/ml. Participants were not using antidepressants, hypnotics or hormonal therapy. This study was randomized, double blind and placebo-controlled. The sample was divided into two groups: acupuncture and 'sham' acupuncture. We performed ten sessions of acupuncture and 'sham' acupuncture during a period of 5 weeks. A polysomnography exam (PSG) and questionnaires (WHOQOL-BREF, Beck Depression Inventory and Pittsburgh Sleep Quality Index) were completed by all patients before and after the treatment period. RESULTS: Anthropometric, polysomnographic, and questionnaire data were similar among the groups at baseline. Comparison of baseline and post-treatment data of the acupuncture group showed that treatment resulted in significantly lower scores on the Pittsburgh Questionnaire and an improvement in psychological WHOQOL. The acupuncture group had a higher percentage of the N3 + 4 stage than the sham group in PSG findings. CONCLUSION: Acupuncture was effective in improving reported sleep quality and quality of life in postmenopausal women with insomnia. PMID- 22943847 TI - Arthroscopic suture anchor capsulorrhaphy versus labral-based suture capsulorrhaphy in a cadaveric model. AB - PURPOSE: The purpose of this study was to establish whether suture anchor capsulorrhaphy (SAC) is biomechanically superior to suture capsulorrhaphy (SC) in the management of recurrent anterior shoulder instability without a labral avulsion. METHODS: Twelve matched pairs of shoulders were randomized to either SC or SAC. Specimens were mounted in 60 degrees of abduction and 90 degrees of external rotation. Testing was conducted on an MTS servohydraulic load testing device (MTS, Eden Prairie, MN). A compressive load of 22 N was applied, followed by a 2-N anterior and posterior force to establish a 0 point. Translation with 10 N anterior and posterior loads was recorded for baseline laxity measurement. Arthroscopic capsulorrhaphy was performed with either 3 solitary sutures or 3 suture anchors. Specimens were remounted and returned to the 0 point. Translation was measured with 10-N anterior and posterior loads to determine reduction in translation. Specimens were then loaded to failure to the 0 point at a rate of 0.1 mm/s. RESULTS: Load to failure was significantly greater (P = .02) in the SC group (13.6 +/- 1.0 N) versus the SAC group (20.5 +/- 2.8 N). No differences were found between SC (2.7 +/- 0.7 mm) and SAC (2.3 +/- 0.6 mm) when we compared reduction of anterior translation with a 10-N load. The percent reduction of anterior displacement with a 10-N load was similar for the SC (49.9%) and SAC (49.6%) groups. The dominant mode of failure in the study was suture pull-through of the capsular tissue. CONCLUSIONS: Our study indicates that labral-based SC and SAC similarly reduce anterior glenohumeral translation at low loading conditions. Load-to-failure studies indicate that SAC exhibits significantly greater resistance to translation at higher loading conditions. Our study suggests that the use of a suture anchor when one is performing a capsulorrhaphy may provide biomechanical advantage at high loading conditions. CLINICAL RELEVANCE: Our study suggests that when one is performing capsulorrhaphy, the use of a suture anchor may provide biomechanical advantages at high loading conditions. PMID- 22943848 TI - Reduced exposure evaluation of an Electrically Heated Cigarette Smoking System. Part 8: Nicotine bridging--estimating smoke constituent exposure by their relationships to both nicotine levels in mainstream cigarette smoke and in smokers. AB - A modeling approach termed 'nicotine bridging' is presented to estimate exposure to mainstream smoke constituents. The method is based on: (1) determination of harmful and potentially harmful constituents (HPHC) and in vitro toxicity parameter-to-nicotine regressions obtained using multiple machine-smoking protocols, (2) nicotine uptake distributions determined from 24-h excretion of nicotine metabolites in a clinical study, and (3) modeled HPHC uptake distributions using steps 1 and 2. An example of 'nicotine bridging' is provided, using a subset of the data reported in Part 2 of this supplement (Zenzen et al., 2012) for two conventional lit-end cigarettes (CC) and the Electrically Heated Cigarette Smoking System (EHCSS) series-K6 cigarette. The bridging method provides justified extrapolations of HPHC exposure distributions that cannot be obtained for smoke constituents due to the lack of specific biomarkers of exposure to cigarette smoke constituents in clinical evaluations. Using this modeling approach, exposure reduction is evident when the HPHC exposure distribution curves between the MRTP and the CC users are substantially separated with little or no overlap between the distribution curves. PMID- 22943849 TI - Berberine inhibits human colon cancer cell migration via AMP-activated protein kinase-mediated downregulation of integrin beta1 signaling. AB - Colon cancer is associated with a poor prognosis, motivating strategies to prevent its development. An encouraging preventative strategy is the use of nutraceuticals; however, scientific verification of therapeutic functions and mechanisms of biological activity are necessary for the acceptance of dietary supplements in cancer treatment. Berberine is a benzylisoquinoline alkaloid extracted from many kinds of medicinal plants that has been extensively used as a Chinese traditional medicine. Recently, berberine has been reported to possess antitumoral activities. Among the various cellular targets of berberine is AMP activated protein kinase (AMPK), which regulates tumor progression and metastasis. However, the specific role of berberine-induced AMPK activation and its effects on the metastatic potential of colon cancer remain largely unknown. The present study investigated berberine-induced activation of AMPK and its effects on colon cancer cell migration. Berberine decreased the migration of SW480 and HCT116 cells. We found that berberine activated AMPK in human colon cancer cell lines. Notably, berberine-induced activation of AMPK reduced the integrin beta1 protein levels and decreased the phosphorylation of integrin beta1 signaling targets. Knockdown of AMPKalpha1 subunits using small interfering RNA significantly attenuated berberine-induced downregulation of integrin beta1 and inhibition of tumor cell migration. Collectively, our results suggest that berberine-induced AMPK activation inhibits the metastatic potential of colon cancer cells by decreasing integrin beta1 protein levels and downstream signaling. PMID- 22943850 TI - The adult polyglucosan body disease mutation GBE1 c.1076A>C occurs at high frequency in persons of Ashkenazi Jewish background. AB - Mutations of the glycogen branching enzyme gene, GBE1, result in glycogen storage disease (GSD) type IV, an autosomal recessive disorder having multiple clinical forms. One mutant allele of this gene, GBE1 c.1076A>C, has been reported in Ashkenazi Jewish cases of an adult-onset form of GSD type IV, adult polyglucosan body disease (APBD), but no epidemiological analyses of this mutation have been performed. We report here the first epidemiological study of this mutation in persons of Ashkenazi Jewish background and find that this mutation has a gene frequency of 1 in 34.5 (95% CI: 0.0145-0.0512), similar to the frequency of the common mutation causing Tay-Sachs disease among Ashkenazi Jews. This finding reveals APBD to be another monogenic disorder that occurs with increased frequency in persons of Ashkenazi Jewish ancestry. PMID- 22943851 TI - Pig sperm membrane microdomains contain a highly glycosylated 15-25-kDa wheat germ agglutinin-binding protein. AB - A highly glycosylated protein, which has unique, novel features in localization, structure, and potential function, is found in pig sperm, and named WGA-gp due to its high binding property with wheat germ agglutinin (WGA). WGA-gp is localized mainly in flagella and enriched in membrane microdomains or lipid rafts. It is not detected by ordinary protein staining methods due to a high content of both N and O-glycans consisting of neutral monosaccharides. Interestingly, WGA-gp may be involved in intracellular Ca(2+) regulation. Treatment of sperm with anti-WGA gp antibody enhances the amplitude of Ca(2+) oscillation without changing the basal intracellular Ca(2+) concentrations. All these features of WGA-gp, except for different carbohydrate structures occupying most part of the molecules, are similar to those of flagellasialin in sea urchin sperm, which regulates the intracellular Ca(2+) concentration. Presence of carbohydrate-enriched flagellar proteins involved in intracellular Ca(2+) regulation may be a common feature among animal sperm. PMID- 22943852 TI - Spatio-temporal regulation of the OsHFP gene promoter establishes the involvement of this protein in rice anther development. AB - Anther development leading to pollen maturation, anther dehiscence and pollen dispersal depends upon the precise timing of programmed cell death (PCD) in specified anther tissues. The PCD necessitates a properly tuned transcriptional regulation of some crucial genes. However, the detailed genetic regulation of this PCD in rice anther is yet to be deciphered. Recently, we have established that the OsHFP, a structurally novel hemopexin fold protein of rice is a flower specific heme binding protein, and plays a role in chlorophyll degradation. Here, we report the spatio-temporal transcriptional regulation of the OsHFP gene, which is proposed to be involved in anther PCD. The OsHFP was immunodetected in rice anthers, and OsHFP-related proteins were also found to be present in anthers of other monocot (lily) and dicot (tobacco) plant species. Unique cis-acting elements, possibly involved in the activation and anther-specificity of the OsHFP promoter were identified based upon in silico prediction and in planta expression profiling of the reporter gene driven by the OsHFP promoter (2051 bp) and its two deleted versions (1057 bp and 437 bp). The temporal regulation of the OsHFP promoter in different developmental stages of tobacco anther implies the physiological function of this protein in anther PCD. PMID- 22943853 TI - Suppression of thymus- and activation-regulated chemokine (TARC/CCL17) production by 3-O-beta-D-glucopyanosylspinasterol via blocking NF-kappaB and STAT1 signaling pathways in TNF-alpha and IFN-gamma-induced HaCaT keratinocytes. AB - A phytosterol derivative, 3-O-beta-D-glucopyanosylspinasterol (spinasterol-Glc) isolated from leaves of Stewartia koreana was reported to inhibit LPS-induced cytokine production in macrophage cells. Thymus and activation regulated chemokine (TARC/CCL17) is produced in response to pro-inflammatory cytokines in keratinocytes, which is implicated in the development of inflammatory skin diseases. In present study, we investigated the effect of spinasterol-Glc on production of TARC/CCL17 induced by TNF-alpha and IFN-gamma in human HaCaT keratinocytes. Spinasterol-Glc inhibited the mRNA and protein expression of TARC/CCL17 induced by TNF-alpha/IFN-gamma in a dose-dependent manner. Inhibitors of c-Raf-1, p38 MAPK, and JAK2, suppressed the TNF-alpha/IFN-gamma-induced production of TARC/CCL17, and phosphorylation of these signaling molecules were attenuated by spinasterol-Glc. The compound also inhibited phosphorylation of IKKalpha/beta and IkappaB-alpha, and reduced translocation of NF-kappaB to the nucleus. We demonstrated that spinasterol-Glc suppressed the NF-kappaB-driven and the GAS-driven expression of luciferase reporter gene induced by TNF-alpha and IFN-gamma. In addition, spinasterol-Glc inhibited the DNA binding of NF-kappaB and STAT1 to its cognate binding site. These results suggest that spinasterol-Glc has effective inhibitory effects on production of TARC/CCL17 in keratinocytes via inhibition of NF-kappaB as well as STAT activation, and could be utilized for development of a potential therapeutic agent against skin inflammatory diseases. PMID- 22943856 TI - Record citations in 2011 contribute to maintenance of the impact factor of BJN. PMID- 22943854 TI - The SUMO protease SENP1 is required for cohesion maintenance and mitotic arrest following spindle poison treatment. AB - SUMO conjugation is a reversible posttranslational modification that regulates protein function. SENP1 is one of the six SUMO-specific proteases present in vertebrate cells and its altered expression is observed in several carcinomas. To characterize SENP1 role in genome integrity, we generated Senp1 knockout chicken DT40 cells. SENP1(-/-) cells show normal proliferation, but are sensitive to spindle poisons. This hypersensitivity correlates with increased sister chromatid separation, mitotic slippage, and apoptosis. To test whether the cohesion defect had a causal relationship with the observed mitotic events, we restored the cohesive status of sister chromatids by introducing the TOP2alpha(+/-) mutation, which leads to increased catenation, or by inhibiting Plk1 and Aurora B kinases that promote cohesin release from chromosomes during prolonged mitotic arrest. Although TOP2alpha is SUMOylated during mitosis, the TOP2alpha(+/-) mutation had no obvious effect. By contrast, inhibition of Plk1 or Aurora B rescued the hypersensitivity of SENP1(-/-) cells to colcemid. In conclusion, we identify SENP1 as a novel factor required for mitotic arrest and cohesion maintenance during prolonged mitotic arrest induced by spindle poisons. PMID- 22943855 TI - Over-expression of a novel JAZ family gene from Glycine soja, increases salt and alkali stress tolerance. AB - Salt and alkali stress are two of the main environmental factors limiting crop production. Recent discoveries show that the JAZ family encodes plant-specific genes involved in jasmonate signaling. However, there is only limited information about this gene family in abiotic stress response, and in wild soybean (Glycine soja), which is a species noted for its tolerance to alkali and salinity. Here, we isolated and characterized a novel JAZ family gene, GsJAZ2, from G. soja. Transcript abundance of GsJAZ2 increased following exposure to salt, alkali, cold and drought. Over-expression of GsJAZ2 in Arabidopsis resulted in enhanced plant tolerance to salt and alkali stress. The expression levels of some alkali stress response and stress-inducible marker genes were significantly higher in the GsJAZ2 overexpression lines as compared to wild-type plants. Subcellular localization studies using a GFP fusion protein showed that GsJAZ2 was localized to the nucleus. These results suggest that the newly isolated wild soybean GsJAZ2 is a positive regulator of plant salt and alkali stress tolerance. PMID- 22943857 TI - The NutriChip project--translating technology into nutritional knowledge. AB - Advances in food transformation have dramatically increased the diversity of products on the market and, consequently, exposed consumers to a complex spectrum of bioactive nutrients whose potential risks and benefits have mostly not been confidently demonstrated. Therefore, tools are needed to efficiently screen products for selected physiological properties before they enter the market. NutriChip is an interdisciplinary modular project funded by the Swiss programme Nano-Tera, which groups scientists from several areas of research with the aim of developing analytical strategies that will enable functional screening of foods. The project focuses on postprandial inflammatory stress, which potentially contributes to the development of chronic inflammatory diseases. The first module of the NutriChip project is composed of three in vitro biochemical steps that mimic the digestion process, intestinal absorption, and subsequent modulation of immune cells by the bioavailable nutrients. The second module is a miniaturised form of the first module (gut-on-a-chip) that integrates a microfluidic-based cell co-culture system and super-resolution imaging technologies to provide a physiologically relevant fluid flow environment and allows sensitive real-time analysis of the products screened in vitro. The third module aims at validating the in vitro screening model by assessing the nutritional properties of selected food products in humans. Because of the immunomodulatory properties of milk as well as its amenability to technological transformation, dairy products have been selected as model foods. The NutriChip project reflects the opening of food and nutrition sciences to state-of-the-art technologies, a key step in the translation of transdisciplinary knowledge into nutritional advice. PMID- 22943858 TI - [Platforms are needed for innovative basic research in ophthalmology]. AB - Basic research poses the cornerstone of technical innovation in all lines including medical sciences. Currently, there are shortages of professional scientists as well as technical supporting teams and facilities in the field of basic research of ophthalmology and visual science in China. Evaluation system and personnel policies are not supportive for innovative but high-risk-of-failure research projects. Discussion of reasons and possible solutions are given here to address these problems, aiming at promoting buildup of platforms hosting novel and important basic research in eye science in this country. PMID- 22943859 TI - [Focus on innovation in and translation of basic research in ophthalmology]. AB - Innovation is the soul of scientific research. Each of the clinical scientists should bear in mind about how to carry out innovative and translational research in clinical practice. Equipped with theories, principles, strategies and modern technologies, they would address disease-related scientific questions through basic research and solve clinical problems through translational research. Ultimately, all the efforts of the clinical scientists will benefit the patients. PMID- 22943860 TI - [Innovation and application are vital for translational research in ophthalmology]. AB - Although the resource devoted for scientific research increased substantially in recent years, the quality of our basic and clinical study still leaves much to be improved. Besides the shortcomings in administration of research funding, our researchers, as the entity of scientific work, should fully recognize that innovation and application are vital for basic and clinical research in ophthalmology. It is emphasized that the principles and methods in an innovative study, including comprehensive grasp for up-to-date information, proposal of a key project, collaboration of multi-disciplines, through design of a study, and acceleration of application in practice, should be followed in order to make new advances in our cause in ophthalmology. PMID- 22943861 TI - [The problems that should be noticed in choosing animal models with diabetic retinopathy]. AB - Animal models of diabetes mellitus (DM) are vital for research on pathogenesis and pharmaceutical therapy of diabetic retinopathy (DR). At present, diabetic animal models include chemicals or dietary-induced models, transgenic or gene knockout mice, and spontaneous mice, etc. Among these models, rat model induced by streptozotocin is simple and imminent with high repeatability, which made it the most popular one. However, no available diabetic model could reproduce all vascular and neural pathological changes observed in human non-proliferative and proliferative DR. It is also known that not all DM models could lead to DR. In addition, features and severity of retinopathy in the model depend on animal kinds, animal lifespan, time course of the disease and induction methods. Therefore, researchers should consider characteristics and limitations of different models while choosing suitable DM model based on research objectives and resources. It is particularly emphasized that the results from animal models do not always fit human conditions. PMID- 22943862 TI - [The protective effects on the function and structure of retinae in diabetic rats by intravitreal injection of cyclosporin A]. AB - OBJECTIVE: To investigate the electrophysiological and morphological changes of retinae after intravitreal injection of cyclosporin A (CsA) in experimental diabetic rats. METHODS: Experimental study. SD diabetic mellitus (DM) rat models were induced with intraperitoneal injection of streptozotocin. The rats were divided into four groups, with 9 rats in each group:the normal control (group CON), the diabetic rats with or without CsA intravitreal injection respectively (group DM + CsA and group DM), and the diabetic rats with dimethyl sulfoxide (DMSO) intravitreal injection (group DM + DMSO). The intravitreal injection of CsA or contrast solution was performed 4 weeks after the modeling. The retinal function of rats was examined by electroretinogram (ERG) 48 hours after the intravitreal injection. All rats were sacrificed and the structural changes of retina were observed by optical and transmission electron microscope. The datas of ERG including amplitudes and latencies of a-wave and b-wave were analyzed by One-way ANOVA and Bonferroni post hoc test. RESULTS: There was difference in ERG b-wave among the 4 groups under different stimuli light intensity (F = 14.760 - 28.890, all P value < 0.01). And there was difference in ERG a-wave among the 4 groups when the stimuli light intensity >= -0.35 log cd*s*m(-2) (F = 12.510, 15.500, both P value < 0.01). Comparing to the group CON (ERG a-wave: 82.43 +/- 26.68, ERG b-wave: 208.40 +/- 51.20), the ERG a-wave and b-wave amplitudes of group DM (ERG a-wave: 39.71 +/- 7.61, ERG b-wave: 92.20 +/- 24.42) and group DM + DMSO (ERG a-wave: 37.63 +/- 17.25, ERG b-wave: 93.11 +/- 22.50)(t = 5.448 - 7.872, all P value < 0.05), and the ERG b-wave of group DM + CsA (160.10 +/- 43.39) (t = 3.299, P < 0.05) were declined in dark adaptation, while the ERG a wave (63.91 +/- 20.32) of group DM +/- CsA had no difference (P > 0.05). The a wave and b-wave amplitudes of group DM + CsA were significantly increased compared to the other two groups in dark adaptation (t = 3.203 - 4.759, both P < 0.05). Under optical microscope, group DM, DM + DMSO and DM + CsA had outer nuclear layer (ONL) disorder. Under transmission electron microscope, there were ultrastructure changes of the three groups. Furthermore, the ONL disorder and ultrastructure changes of group DM + CsA were less severe than the other two groups. CONCLUSIONS: Functional and morphological changes are evident in the early stages in DM rats. Intravitreal injection with CsA shows protective effects on the nerve function in DM retina. PMID- 22943863 TI - [The effect of AQP4 gene on the activation of retinal glial cells in chronic high intraocular pressure mice]. AB - OBJECTIVES: To investigate whether aquaporin 4 (AQP4) gene can affect the activation of glial cells and cause the injury of retina of chronic high intraocular pressure mice models, and to discuss its possible mechanism. METHODS: Experimental study. The chronic high intraocular pressure models were established by burning the scleral venous of the right eye, which as the experiment group, and the left eye without any treatment as the control group. The intraocular pressure (IOP) was measured by rebound tonometer. Selected each of the successful model of chronic high intraocular pressure male AQP4 knockout mice (AQP-/-) and their wild-type (WT) male mice 40, divided the two type of mice into five groups after scleral venous burn according to the time of establishing models (24 h, 3 d, 1 w, 2 w, 4 w after scleral venous burn), 8 mouse in each group. And then producing the paraffin sections of mouse eye. Immunohistochemical staining methods was used to observe the expression of the glial fibrillary acid protein (GFAP) in retina glial cells, and observe the expression of the AQP4 in the retina of the WT mouse. Image was acquired under the fluorescence microscopy. The intraocular pressure was analyzed by t-test. RESULTS: After scleral venous burn (24 h, 3 d, 1 w, 2 w, 4 w), there were significant difference (t = 6.66 - 18.08, all P value < 0.05) in the IOP of the AQP4-/- mice (11.30 +/- 1.59, 11.20 +/- 1.15, 10.60 +/- 1.53, 10.75 +/- 1.45, 10.45 +/- 1.39) and WT mice (11.50 +/- 2.56, 11.25 +/- 1.65, 10.75 +/- 1.33, 10.60 +/- 1.33, 10.40 +/- 1.19) between the experimental groups and control groups (6.60 +/- 0.94, 6.35 +/- 0.99, 6.55 +/- 0.94, 6.45 +/- 0.99, 6.50 +/- 0.94 and 6.60 +/- 1.05, 6.50 +/- 0.89, 6.40 +/- 1.09, 6.30 +/- 1.13, 6.50 +/- 1.05). Since 24 hours after the scleral venous burn, the expression of GAFP of the two type mice began to increase and reached to peak at 1 week after burning. This peak of WT mice was more obvious than that of AQP4-/- mice. The concentration of GAFP began to decrease at 2 weeks after burning and reached to bottom at 4 weeks later. To the WT mice, the expression of AQP4 was remarkable higher in experimental group than that in control group at 1 week after the scleral venous burn. The expression of AQP4 was related to the expression of GAFP in high intraocular pressure of WT mice at 1 w, 2 w, and 4 w after the scleral venous burn. CONCLUSIONS: The chronic high intraocular pressure models can be established successfully by burning the scleral venous. AQP4 gene can affect the activation of the glial cells in chronic high intraocular pressure mice and lead to the injury of retina. PMID- 22943864 TI - [Study on the differentially expressed microRNA of human retinal microvascular endothelial cells in high glucose environment by microRNA gene chip]. AB - OBJECTIVES: To explore the differentially expressed microRNA (miRNA) of human retinal microvascular endothelial cell (HRCEC) in hyperglycemic environment by miRNA gene chip, then adopt bioinformatics methods to forecast target genes of part differentially expressed miRNA. METHODS: Experimental study. HRCEC were cultured. Took the 3-4 generation growth good cells and divided the cells into three groups: (1) normal control group: DMEM medium with 25 mmol/L glucose; (2) high glucose group: conditioned medium with 90 mmol/L glucose; (3) mannitol high permeability control group: conditioned medium with 65 mmol/L mannitol and 25 mmol/L glucose. Each group cells were cultured in the above conditions for five days, then used in situ cell death detection kit for apoptosis detection; the total RNA was isolated and examined; the differentially expressed miRNA were detected by miRNA gene chip, part results of miRNA array were verified by real time quantitate polymerase chain reaction (PCR), potential miRNA targets were analyzed by bioinformatics methods. RESULTS: Observed apoptotic HRCEC by fluorescence microscope: the nucleus of normal control group and mannitol control group were dyed by DAPI and appeared blue fluorescence, but hadn't apoptosis fluorescent signals; the nucleus of high glucose group also appeared blue fluorescence, and had green apoptosis fluorescent signals. Quality testing of total RNA: with spectrophotometer measurement, the ratio of absorbance of total RNA in normal control group at A(260)/A(280) nm was 1.99, at A(260)/A(230) was 2.05;total RNA of high glucose group at A(260)/A(280) was 1.98, at A(260)/A(230) was 2.26. The results of formaldehyde degeneration agarose gel electrophoresis showed that the electrophoresis strips were clear and complete, indicated that the total RNA had better quality and high purity. Compared with normal control group, 49 miRNAs were found to be differentially expressed in high glucose group (fold change > 2 and fold change < 0.5), including 31 up-regulated miRNAs and 18 down-regulated miRNAs. The results of real-time quantity PCR revealed that hsa miR-320c and hsa-miR-29a(*) were up-regulated in high glucose group, which were consistence with the miRNA gene chip. Furthermore, the target genes prediction of two above miRNAs were involved many growth factors and proteins. CONCLUSION: miRNA are differently expressed in HRCEC under hyperglycemic conditions. PMID- 22943865 TI - [Possible mechanism of endothelial progenitor cells in the development of rat choroidal neovascularization]. AB - OBJECTIVE: To investigate the role and possible mechanism of endothelial progenitor cell (EPC) in the development of choroidal neovascularization (CNV). METHODS: Experimental study. Twenty-four BN rats were divided into 3 groups.One eye of each animal was induced by laser photocoagulation with 532 nm laser and the contralateral eye was taken as control. Three, seven and fourteen days after photocoagulation the formation of CNV was observed by histopathological study and the recruitment of EPC and the possible pro-angiogenic growth factors released by EPC during the development of CNV were examined by multi-labeled immunofluorescence staining. The difference among the 3 groups was analyzed by ANOVA and the comparison between any 2 groups was further checked by LSD-t test. RESULTS: Both the histopathological study and the immunofluorescence staining indicated that within the laser lesions proliferated and migrated cells grew into the subretinal space through the broken Bruch membrane 3 days after photocoagulation, 7 days after photocoagulation lumen-like structures were observed and CNV became stable until 14 days after photocoagulation. No EPC was observed in the normal retina whereas EPC were recruited into the laser lesions 3 days after photocoagulation, comprising (79.29 +/- 11.27)% of the total endothelial cell population within CNV. At 7-day EPC constituted new vessels within CNV area and the proportion decreased to (47.13 +/- 5.78)%. Then its number decreased dramatically 14 days after photocoagulation contributing to (10.83 +/- 2.79)% of the endothelial cells in CNV. The differences either among the 3 groups (F = 104.623, P < 0.05) or between any 2 groups (P < 0.05) were statistically significant. Moreover, triple labelled immunofluorescence staining showed that the EPC within CNV area could also secret pro-angiogenic factors such as vascular endothelial growth factor, IL-10, bFGF and MMP9. CONCLUSION: EPC involves in the development of CNV not only through participating in the formation of new vessels within the CNV area but also through secreting pro angiogenic factors. PMID- 22943866 TI - [Purification and characterization of adult optic nerve head astrocytes]. AB - OBJECTIVE: To establish a method of purifying and characterizing adult astrocytes from optic nerve head (ONH). METHODS: Experimental study. The lamina cribrosa tissue from ONH of human eye was isolated under anatomic microscopy, and then 4 to 6 little explants were incubated in each culture plate containing culture medium DMEM/F12. After 8 to 10 weeks, the cells were removed by digesting cells with 0.25% trypsogen. Selective astrocyte culture medium is subsequently used. After two passages, astrocytes were identified by the observation of cell morphology and immunofluorescent staining of GFAP and NCAM. RESULTS: After 2 to 3 weeks of explants planting, cells showed an obvious migration procession by crawling in succession from the verge of the explants and rapidly splitting. Most cells displayed a flat star shape or polygon after digested with trypsogen. Several cells are long fusiformis. Almost all cells presented a flat star shape and simultaneously expressed GFAP and NCAM when the cells cultured with selective astrocyte culture medium. CONCLUSIONS: Cultured human ONH astrocytes can be obtained by precisely separating lamina cribrosa and placing the explants on the margin of culture medium, a method that promotes cell adherence. Using selective astrocyte culture medium is very effective and convenient in purifying primary astrocytes. PMID- 22943867 TI - [Promoting effects of CYR61 on proliferation, migration and tube formation of choroid-retinal endothelial cells]. AB - OBJECTIVE: To observe the effects of CYR61 (cysteine-rich 61; CCN1) on the proliferation, migration and tube formation of choroid-retinal endothelial cells (RF-6A cell line). METHODS: Experimental study. RF-6A cells were cultured and treated with CYR61 at different concentrations. Effects of CYR61 on cell proliferation, migration and angiogenesis were observed by MTT assay, transwell assay and tube formation assay. RESULTS: When different concentrations of CYR61 (0, 5, 10, 100 and 500 ug/L) were used to treat RF-6A cells for 72 h, A(490) nm value of the MTT assay was changed dose-dependently (0.511, 0.522, 0.532, 0.597, 0.765 and 0.818), and the difference between different dosage groups was statistically significant (F = 318.828, P < 0.05). When RF-6A cells were treated with 400 ug/L CYR61 for different time periods (0, 12, 24, 48 and 72 h), A(490) nm value increased with the extension of treatment time (0.533, 0.598, 0.643, 0.695 and 0.756), and the difference was statistically significant (F = 42.910, P < 0.05). In transwell assay, migrated cells in cells treated with different concentrations of CYR61 (40, 200, 400 ug/L and 400 ug/L + 25 mg/Lanti-CYR61 antibody), 80 ug/L VEGF, and negative control groups were 66.83 +/- 3.87, 77.83 +/- 4.26, 96.83 +/- 3.49, 70.67 +/- 3.83, 98.33 +/- 3.14 and 62.00 +/- 7.62 per high-power field, respectively. RF-6A cell migration capacity increased with increased concentration of CYR61 (F = 46.987, P < 0.05). In tube formation assay, numbers of tube in different concentrations of CYR61 (40, 200, 400 ug/L, 400 ug/L + 25 mg/L anti-CYR61 antibody), 80 ug/L VEGF and negative control groups were 34.33 +/- 2.50, 60.67 +/- 3.72, 88.17 +/- 2.93, 51.17 +/- 2.14, 90.83 +/- 3.49 and 31.83 +/- 3.31 per field. RF-6A cell tube formation capacity increased with increased concentration of CYR61 (F = 355.224, P < 0.05). There were equal effects between 400 ug/L CYR61 and 80 ug/L VEGF. Anti-CYR61 antibody could inhibit cell migration and tube formation promoted by CYR61. CONCLUSIONS: CYR61 can promote proliferation, migration and tube formation of choroid-retinal endothelial cells in vitro. CYR61 are likely to be involved in the pathogenesis of retinal neovascularization. PMID- 22943868 TI - [Retinoblastoma regression patterns and results following chemo reduction and adjuvant therapy]. AB - OBJECTIVE: To evaluate retinoblastoma regression patterns following chemo reduction and adjuvant therapy. METHODS: Retrospective case series. 122 tumors of 47 eyes of 37 patients following chemo reduction and adjuvant therapy between January 2005 and June 2009 in the Eye & ENT hospital of Fudan University. Twenty seven patients are male, and 10 patients are female. The average age was 22 months. The combined therapy included chemo reduction using vincristine, etoposide, and carboplatin (VEC) combined with local cryotherapy and/or transpupillary thermotherapy (TTT). The average follow-up duration was 32 months ranging from 12 to 60 months. Regression patterns included type 0 (no remnant), type 1 (calcified remnant), type 2 (noncalcified remnant), type 3 (partially calcified remnant), and type 4 (flat scar). Wilcoxon rank sum test was used to test the difference of tumor number between the patients with family history and those without family history. Chi-square test was used to test the difference between the tumor thickness, tumor location and regression patterns. Multivariate logistic regression analysis was used to test the correlation between the regression patterns and age, sex, tumor thickness, tumor location and family history. Statistical significance was assigned at P < 0.05. RESULTS: Forty-seven eyes according to the International Intraocular Retinoblastoma Classification, 20 eyes (42.6%) were group A, 13 eyes (27.6%) group B, 6 eyes (12.8%) group C, 8 eyes (17.0%) group D. Of 122 tumors, the average number of tumors per eye was 2.6. Retinoblastoma regressions were type 0 (n = 3), type 1 (n = 15), type 2 (n = 8), type 3 (n = 25), and type 4 (n = 71). Tumor thickness and tumor location were related to regression patterns. Tumors with an initial thickness of 2 mm or less regressed most often to type 4, and those thicker than 8 mm regressed to type 1 or type 3. Tumors with greater distance from the foveola regressed most often to type 4. The factors predictive of regression pattern type 1 included tumor thickness larger than 8 mm (Z = 3.02, P = 0.003). The factors predictive of regression pattern type 3 included older age, tumor thickness larger than 8 mm and location not in the equator to ora serrata region (Z = 3.98, 2.23, 3.60; P = 0.000, 0.025, 0.000). The factors predictive of regression pattern type 4 included familial hereditary pattern, tumor thickness smaller than 2 mm and location in the equator to ora serrata region. (Z = 4.37, 3.42, 2.42; P = 0.000, 0.000, 0.021). 12 tumors recurred, 9 tumors were type 3 and 3 tumors were type 4. 8 eyes developed 15 new tumors. 5 patients developed new tumors were all younger patients and had familial hereditary history. The average period of recurrence of main tumors and development of new tumors was six months after the end of chemo reduction. CONCLUSIONS: Following chemo reduction, type 3 and type 4 regression patterns were most common. Smaller tumors were usually seen in type 4, and bigger tumors were usually seen in type 1 or type 3. Tumor recurrence was usually found following regression pattern type 3 or type 4. Younger patients and patients with familial hereditary history trend to develop new tumors. Patients accept chemo reduction and adjuvant therapy need close follow-up. PMID- 22943869 TI - [Changes of ophthalmic blood flow in obstructive sleep apnea-hypopnea syndrome]. AB - OBJECTIVE: To observe the ophthalmic artery (OA), central retinal artery (CRA) and posterior ciliary artery (PCA) blood flow and the changes of eye vascular auto-regulation in patients with obstructive sleep apnea-hypopnea syndrome (OSAS). METHODS: It was a case-control study. Fifteen health overweight male adult (as normal control) and 42 patients with OSAS were randomly selected from examination center and sleep detection center, respectively. The OSAS patients were divided into mild (14 patients) and moderate and severe (28 patients) groups based on the apnea-hypopnea index (AHI). All subjects filled the sleep questionnaire and carried out polysomnogram monitoring all night for at least 7 hours. Fasting peripheral venous blood was collected at 7 AM on next day. The end tidal CO(2) (ETCO(2)), intraocular pressure and color doppler sonography were examined next day to record the data in the inspection process before and after Mueller maneuver. Doppler ultrasound measurement of ocular blood flow diameter and blood flow velocity values were described in the median (max, min) and compared with Kruskal-Wallis test. And then two groups were compared with Bonferroni t test. Ocular blood flow velocity of patients with OSAS and PSG monitoring indicators were analyzed using partial correlation analysis. RESULTS: OA inner diameter in moderate and severe OSAS group [0.08 (0.15, 0.06) cm] was lower than that in healthy control [0.15 (0.26, 0.11) cm] and the difference was statistically significant (P = 0.000). PCA inner diameter in moderate and severe OSAS group [0.10 (0.13, 0.07) cm] were higher than that in healthy controls [0.05 (0.09, 0.04) cm]. CRA peak systolic velocity (PSV) in moderate and severe OSAS group [16.50 (19.40, 13.10) cm/s] was greater than that in healthy controls [11.30 (16.70, 8.20) cm/s]. The differences between these two groups were statistically significant (PCA inner diameter: P = 0.000, CRA-PSV: P = 0.001). The difference of CRA end diastolic velocity (EDV) between the moderate and severe group [8.90 (9.90, 5.10) cm/s], mild group [7.00 (8.30, 4.50) cm/s] and healthy control group [5.50 (7.40, 3.40) cm/s] was statistically significant (chi(2) = 14.45, P < 0.05). PCA-PSV [32.50 (43.10, 19.10) cm/s] and PCA-EDV [12.80 (15.20, 5.70) cm/s] in the moderate and severe group were higher than those in healthy control group [22.60 (32.20, 12.40) cm/s] and [7.20 (11.20, 3.90) cm/s], as well as those in the mild group [24.00 (30.70, 13.30) cm/s] and [8.00 (9.90, 3.90) cm/s]. These differences were statistically significant (PCA PSV: P = 0.000, 0.002; PCA-EDV: P = 0.000, 0.001). The diameter of OA and PCA correlated negatively with ETCO(2) (r = -0.41, -0.34; P < 0.05); CRA-PSV was correlated with SaO2 min (r = -0.37, P < 0.05). CRA-EDV was correlated with ETCO(2) and SaO2 mean (r = 0.57, -0.39; P < 0.05). PCA-PSV was correlated with SaO2 min and MAI (r = -0.34, 0.56; P < 0.05). PCA-EDV was correlated SaO2 min and MAI (r = -0.29, 0.61; P < 0.05). CONCLUSIONS: The diameter and blood flow of OA, PCA and CRA change in OSAS patients. Compared with non-OSAS patients, the autoregulation function of PCA and CRA is weakened in OSAS patients. PMID- 22943870 TI - [Measurement of canaliculus with ultrasound biomicroscopy]. AB - OBJECTIVE: To study biometric measurements of normal canaliculus in vivo with ultrasound biomicroscope. METHODS: Cross-sectional study. Eighty volunteers of normal lacrimal duct (80 eyes), including 40 men (40 eyes), 40 women (40 eyes), aged from 18 to 82 years old (average 41 years old). Eighty volunteers were divided into three stages, one eye of each volunteer was detected and measured with ultrasound biomicroscope in the goggle state and the imaging characteristics of canalicular ultrasound biomicroscopy were obtained. The length of the vertical canaliculus, the distal, middle, proximal anteroposterior diameter of the vertical canaliculus, the distal, middle, proximal anteroposterior diameter and vertical diameter of the horizontal canaliculus were measured. According to elliptical area formula S = piab (a = 1/2 anteroposterior diameter, b = 1/2 vertical diameter)the distal, middle, proximal transverse erea of the horizontal canaliculus were caculated. The differences among age groups and those among distal, middle, proximal measurements were compared by One-way ANOVA analysis. The measurements of canaliculus between male and female were analyzed using t test. RESULTS: Eighty volunteers (80 eyes) participated in the study, 6 eyes were failed to be imaged, the success rate was 92.5% (74/80). The length of vertical canaliculus of superior canaliculus were (2.10 +/- 0.12) mm, of inferior canaliculus were (2.08 +/- 0.10) mm. The proximal, middle, distal anteroposterior diameter of the vertical part of superior canaliculus respectively were (0.24 +/- 0.05) mm, (0.28 +/- 0.05) mm, (0.33 +/- 0.04) mm (F = 16.315, P = 0.000), of inferior canaliculus were (0.23 +/- 0.04) mm, (0.28 +/- 0.06) mm, (0.32 +/- 0.05) mm (F = 17.570, P = 0.000). The proximal, middle, distal transverse erea of the horizontal part of superior canaliculus respect were (0.77 +/- 0.13) mm(2), (0.62 +/- 0.13) mm(2), (0.48 +/- 0.11) mm(2) (F = 22.970, P = 0.000), of inferior canaliculus were (0.79 +/- 0.11) mm(2), (0.63 +/- 0.08) mm(2), (0.48 +/- 0.09) mm(2) (F = 21.45, P = 0.000). There was no significant difference of the canaliculus measurements between male and female (t = 0.105 - 0.487, P > 0.05). No significant differences were found among age groups (F = 0.142 - 3.954, P > 0.05). CONCLUSION: It is practicable to measure the normal canaliculus in vivo with UBM. PMID- 22943871 TI - [The latest advance of the relationship between autophagy and diabetic retinopathy]. AB - As a serious complication of diabetes mellitus, diabetic retinopathy (DR) is one of the major causes of blindness, and its prevalence has been increasing worldwide. Therefore, there is an urgent need to figure out the mechanism of DR and identify an effective therapeutic target to prevent it. Autophagy is a major catabolic pathway involved in degrading and recycling damaged organelles and macromolecules to maintain intracellular homeostasis. The study of autophagy in mammalian systems is advancing rapidly and has revealed that it is involved in the pathogenesis of various metabolic and age-related diseases. The role of autophagy in such diseases as tumors, diabetic nephropathy (DN), age-related macular degeneration (AMD), etc, is currently under intense investigation. And there's a close relationship between autophagy and DR related factors as well including nutrient stress, oxidative stress, hypoxia, endoplasmic reticulum stress, and so on. PMID- 22943872 TI - [Paraneoplastic retinopathy]. AB - Paraneoplastic retinopathy (PR) mainly includes cancer-associated retinopathy (CAR) and melanoma-associated retinopathy (MAR). Emerging evidences indicate that PR is mediated by immune cross-reaction between circulating antibodies originally generated against remote tumor with antigens expressed on retinal neurons. It is believed that CAR is a consequence of the autoantibodies against the photoreceptors and MAR is the autoantibodies against the retinal ON-bipolar cells. Recoverin autoantibody in serum is closely related to the pathogenesis of CAR, and the inactivation of TRPM1 channel plays a key role in dysfunction of ON bipolar cells in MAR. PR is characterized by visual dysfunctions, including decreased vision, night blindness, shimmering or flickering, and abnormalities of symbolic electroretinogram appearances. Based on the history of tumors, ophthalmic symptoms, and existence of circulating antibodies, it is easy to make a diagnosis of PR. Immunosuppressants and glucocorticoids may improve the visual dysfunctions in PR subjects. PMID- 22943873 TI - [Advances in near work-induced transient myopia]. AB - The possible mechanism of myopia remains controversial while gene and environment are two generally acknowledged factors underlie the development of human myopia. Near work which is a primary, environmentally based factor in the development and progression of permanent myopia (PM) may take effect via near work-induced transient myopia (NITM). In this review, the definition, measuring procedure and relative evaluation parameters of NITM as well as its characteristics, methods for reducing NITM and its possible mechanisms reported in the literature will be summarized. PMID- 22943874 TI - [Research status of photodynamic therapy for corneal neovascularization]. AB - Pathological corneal neovascularization is an important reason of visual impairment. Research outcomes showed that angiogenesis mechanism is similar in all the tissues of the body and photodynamic therapy demonstrate a useful effect in blocking tumor and choroidal neovascularization. This method is currently being tried for the treatment of corneal neovascularization. This paper will review the research status of photodynamic therapy in corneal neovascularization using various photosensitizers. PMID- 22943875 TI - Allergic contact stomatitis to dodecyl gallate? A review of the relevance of positive patch test results to gallates. AB - Gallic acid esters or gallates are antioxidants used as preservatives in food and cosmetics. Few cases of gallates causing allergic contact dermatitis (ACD) have been reported in the literature. We present a case report of a 42-year-old beauty therapist who presented with a swollen tongue. Patch testing was positive to dodecyl gallate, commonly reported as being present in edible oil and oily foods such as margarine. Our patient avoided foods presumed to contain gallates and at the 6-week review reported a substantial improvement in her tongue symptoms. We reviewed our database and found 16 (7%) definitely or possibly relevant reactions to dodecyl gallate, seven (15%) definitely or possibly relevant reactions to propyl gallate and six (3%) definitely or possibly relevant reactions to octyl gallate. Most reactions were attributed to margarine, moisturising cream and lipstick. These products are often mentioned in the literature as containing gallates; however, ingredient labelling and discussions with manufacturers made it difficult to establish whether they are currently present in foods. Ascertaining relevance for these reactions is not always possible. PMID- 22943877 TI - Five-year trends in mortality indices among gynecological cancer patients in Canada. AB - OBJECTIVE: To estimate and compare the five-year trends in excess mortality rate, net probability of death, and crude probability of death for patients diagnosed with epithelial invasive gynecological cancers in Canada. We compared these trends among ovarian, uterine, and cervical cancers. METHODS: A flexible parametric model was used to estimate the three mortality indices for gynecological cancers. We incorporated age group, type of cancer, and year of diagnosis in the model to estimate these indices over a five-year period after diagnosis. RESULTS: In total, 39,681 women who were diagnosed with epithelial invasive gynecological cancers were included in this analysis with a mean age of 57.9 (SD=15.1) years at diagnosis. Approximately 30% of patients were younger than 50 years old at diagnosis and 45% were between 50 and 69 years old. Ovarian cancer had the worst prognosis among the gynecological cancers based on all three mortality indices. CONCLUSIONS: The three mortality indices provide a clear insight in understanding the elements of mortality in population-based cancer studies where the underlying cause of death is not correctly identified, the accuracy of death certificates varies overtime and among countries, and death tends to be a multi-factorial event. PMID- 22943878 TI - FOXM1 promotes tumor cell invasion and correlates with poor prognosis in early stage cervical cancer. AB - OBJECTIVE: The forkhead box M1 (FOXM1) transcription factor plays crucial roles in regulating the proliferation, differentiation, and transformation of cells. Overexpression of FOXM1 is associated with a variety of aggressive solid carcinomas, including cervical cancer. However, the precise role and molecular mechanism responsible for the aggressive action of FOXM1 in cervical cancer remain unclear. This study investigated the cellular and molecular aggressive function of FOXM1 in cervical cancer. METHODS: The FOXM1 gene and protein expression profiles were determined by quantitative polymerase chain reaction, Western blotting and immunohistochemical staining, and other cellular and molecular approaches including gene transfection, short hairpin RNA interference (RNAi), and wound-healing, migration, and invasion assays. RESULTS: FOXM1 expression was significantly up-regulated at both mRNA and protein levels in early-stage cervical cancer, compared to cervical intraepithelial neoplasia and normal cervical tissues. High levels of FOXM1 expression were significantly associated with aggression in cervical cancer, and were an independent prognostic factor for poor survival in early-stage cervical cancer patients. Moreover, enforced expression of FOXM1 increased migration and invasion of cancer cells, whereas RNAi-mediated knockdown of FOXM1 had the opposite effect. In addition, up regulation of FOXM1 increased the expression of matrix metalloproteinase-2 (MMP 2) and MMP-9 in vitro and in vivo, and activated the Akt/glycogen synthase kinase 3beta/Snail pathway, resulting in the promotion of migration and invasion of cervical cancer cells. CONCLUSIONS: These results suggest that FOXM1 up regulation is associated with poor prognosis in early-stage cervical cancer, and therefore it may act as a prognostic marker and a new potential target for cervical cancer treatment. PMID- 22943879 TI - A phase I study with an expanded cohort to assess feasibility of intravenous docetaxel, intraperitoneal carboplatin and intraperitoneal paclitaxel in patients with previously untreated ovarian, fallopian tube or primary peritoneal carcinoma: a Gynecologic Oncology Group study. AB - OBJECTIVE: To define the maximum tolerated dose (MTD) and assess the feasibility of intravenous (IV) docetaxel, intraperitoneal (IP) carboplatin and IP paclitaxel in women with stage II-IV untreated ovarian, fallopian tube or primary peritoneal carcinoma. METHODS: Patients received docetaxel (55-75 mg/m(2)) IV and carboplatin (AUC 5-7) IP on day 1 and paclitaxel 60 mg/m(2) IP on day 8. A standard 3+3 design was used in the dose escalation phase. A 2-stage group sequential design with 20 patients at the MTD was used in the feasibility phase. RESULTS: The MTD determined during the dose escalation phase was day 1 docetaxel 75 mg/m(2) IV, carboplatin AUC 6 IP and day 8 IP paclitaxel 60 mg/m(2). Forty-six patients were enrolled in the feasibility portion at this dose level. Six were unevaluable. Fifteen evaluable patients had dose-limiting toxicities (DLTs) within the first four cycles. These DLTs were prolonged neutropenia (2), neutropenic fever (7), grade 4 thrombocytopenia (1), grade 4 dehydration (1), grade 3 infection (2), grade 3 oral mucositis (1) and pulmonary embolism (1). CONCLUSIONS: Docetaxel 75 mg/m(2) IV, carboplatin AUC 6 IP administered on day 1, and paclitaxel 60 mg/m(2) IP administered on day 8, is the MTD when considering one cycle of treatment but was not feasible over four cycles due to bone marrow toxicity. We recommend reduction of carboplatin to AUC 5 should this regimen be considered for treatment in women with newly diagnosed advanced ovarian cancer. PMID- 22943880 TI - Bilateral ultrastaging of sentinel lymph node in cervical cancer: Lowering the false-negative rate and improving the detection of micrometastasis. AB - OBJECTIVE: To evaluate the sensitivity of sentinel node (SN) ultrastaging and to define parameters that may reduce the overall false-negative rate in women with early-stage cervical cancer. METHODS: We analyzed data from a large retrospective multicenter cohort group with FIGO stages IA-IIB cervical cancer in whom at least one SN was identified and systematic pelvic lymphadenectomy was uniformly performed. All who were SN negative by initial evaluation were subjected to ultrastaging. RESULTS: In all, 645 patients were evaluable. SN were detected bilaterally in 72% of cases and unilaterally in 28%. Patients with optimal bilateral SN detection were significantly more likely to have any metastasis detected (33.3% vs. 19.2%; P<0.001) as well as micrometastasis detected in their SN (39.6% vs. 11.4%). SN ultrastaging resulted in a low overall false-negative rate of 2.8% (whole group) and an even lower false-negative rate of 1.3% for patients with optimal bilateral mapping. Patients with false-negative SN after ultrastaging had a higher prevalence of LVSI and more frequent unilateral SN detection. Sensitivity of SN ultrastaging was 91% (95% CI: 86%-95%) for the whole group and 97% (95% CI: 91%-99%) in the subgroup with bilateral SN detection. CONCLUSION: These data confirm previous observations that optimal bilateral SN detection substantially decreases the false negative rate of SN ultrastaging and increases detection of micrometastasis. In patients with bilateral SN detection, the sensitivity of SN ultrastaging is not reduced in more advanced stages of the disease. SN mapping and ultrastaging should become standard practice in the surgical management of early-stage cervical cancer. PMID- 22943881 TI - Psychological outcomes of familial ovarian cancer screening: no evidence of long term harm. AB - OBJECTIVES: Ovarian cancer screening for women at increased genetic risk in the UK involves 4-monthly CA125 tests and annual ultrasound, with further tests prompted by an abnormal result. The study evaluated the longer-term psychological and behavioural effects of frequent ovarian screening. METHODS: Women completed T1 questionnaires before their first routine 4-monthly CA125 test, and T2 follow up questionnaires one week after their result. Women with abnormal results completed a further questionnaire one week after return to routine screening (T3 primary end-point). T4 questionnaires were sent at nine months. Measures included cancer distress, general anxiety/depression, reassurance, and withdrawal from screening. RESULTS: A total 1999 (62%) of 3224 women completed T1 questionnaires. T2 questionnaires were completed by 1384/1609 participants (86%): 1217 (89%) with normal results and 167/242 (69%) with abnormal results. T3 questionnaires were completed by 141/163 (87%) women, with 912/1173 (78%) completing T4 questionnaires. Analysis of covariance indicated that, compared to women with normal results, women with abnormal results reported moderate cancer distress (F = 27.47, p <= .001, eta(2) = 0.02) one week after their abnormal result and were significantly more likely to withdraw from screening (OR = 4.38, p <= .001). These effects were not apparent at T3 or T4. The effect of screening result on general anxiety/depression or overall reassurance was not significant. CONCLUSIONS: Women participating in frequent ovarian screening who are recalled for an abnormal result may experience transient cancer-specific distress, which may prompt reconsideration of risk management options. Health professionals and policy makers may be reassured that frequent familial ovarian screening does not cause sustained psychological harm. PMID- 22943882 TI - Local transplantation of ex vivo expanded bone marrow-derived CD34-positive cells accelerates fracture healing. AB - Transplantation of bone marrow (BM) CD34(+) cells, an endothelial/hematopoietic progenitor-enriched cell population, has shown therapeutic efficiency in the treatment of ischemic diseases enhancing neovascularization. However, the number of CD34(+) cells obtained from bone marrow is not sufficient for routine clinical application. To overcome this issue, we developed a more efficient and clinically applicable CD34(+) cell expansion method. Seven-day ex vivo expansion culture of BM CD34(+) cells with a cocktail of five growth factors containing VEGF, SCF, IL-6, Flt-3 ligand, and TPO resulted in reproducible more than 20-fold increase in cell number. The favorable effect of the local transplantation of culture expanded (cEx)-BM CD34(+) cells on rat unhealing fractures was equivalent or higher than that of nonexpanded (fresh) BM CD34(+) cells exhibiting sufficient therapeutic outcome with frequent vasculogenic/osteogenic differentiation of transplanted cEx-BM CD34(+) cells and fresh BM CD34(+) cells as well as intrinsic enhancement of angiogenesis/osteogenesis at the treated fracture sites. Specifically, cEx-BM CD34(+) cell treatment demonstrated the best blood flow recovery at fracture sites compared with the nonexpanded BM CD34(+) cells. In vitro, cEx-BM CD34(+) cells showed higher colony/tube-forming capacity than nonexpanded BM CD34(+) cells. Both cells demonstrated differentiation potential into osteoblasts. Since fresh BM CD34(+) cells can be easily collected from fracture sites at the time of primary operation and stored for future use, autologous cEx-BM CD34(+) cell transplantation would be not only a simple but also a promising therapeutic strategy for unhealing fractures in the field of orthopedic trauma surgery. PMID- 22943884 TI - Life-long accumulation of 137Cs and 40K in the vertebral column of a cow. AB - We have investigated the accumulation of (137)Cs and (40)K in all the tissues and organs of an adult slaughtered Austrian "mountain pasture cow". In this paper we present measured (137)Cs- and (40)K-activity concentrations in different tissues of the vertebral bodies, in their other bony components and in all the vertebrae forming the vertebral column. Data are also given for activity concentrations of adherent tissues, and for activities of both the components and the whole vertebral column. The dairy cow was born in a highly contaminated region of Styria, Austria, at the time of the radioactive fallout following the Chernobyl accident. Both radionuclides were incorporated during life-long ingestion and their accumulation in all the vertebrae up to the day of slaughtering was determined by high-purity germanium detectors. Our results show considerable variations of (137)Cs- and (40)K-activity concentrations in the components of a certain vertebra, within vertebrae of a particular region, and between vertebrae of different regions of the vertebral column. Particularly, the courses of (137)Cs- and (40)K-activity concentrations in trabecular bone, cortical bone and intervertebral discs of thoracic vertebral bodies are subdivided by a strong drop into two sections. Mean values of (137)Cs-concentration in vertebral bodies of these subsections vary by a factor 4. Compared with corresponding quantities for the skeleton, total mass, as well as total (137)Cs- and (40)K-activities of the whole vertebral column came to 14%, and approximately 38% for each (137)Cs and (40)K, respectively. PMID- 22943883 TI - Chlamydia muridarum enters a viable but non-infectious state in amoxicillin treated BALB/c mice. AB - In culture, exposure to penicillin and other stressors induce chlamydiae to enter a non-infectious but viable state termed persistence. Chlamydiae may reenter their normal developmental cycle after stressor removal. Though aberrant RB similar to those present in culture models of persistence have been observed within infected tissues, the existence of persistent chlamydiae has not been definitively demonstrated in vivo. As a result, the role of persistent organisms in pathogenesis is undefined. In order to establish an experimentally tractable model of in vivo persistence, Chlamydia muridarum vaginally-infected mice were gavaged with either water or amoxicillin (amox). Vaginal swabs were collected for chlamydial titration and RNA isolated for quantification of pre-16s rRNA. Uterine tissue was analyzed by transmission electron microscopy (TEM). Although amox treatment reduced vaginal shedding by >99%, C. muridarum pre-16s rRNA accumulation was unchanged by treatment. These data indicate that the amox exposed organisms were viable but not infectious. Furthermore, TEM analyses demonstrated that inclusions in amox-treated animals contained primarily large, aberrant RB, but those observed in untreated control animals were normal. Collectively, these data suggest that amoxicillin treatment induces C. muridarum to enter the persistent state in vivo. This model also represents the first experimentally tractable animal model of chlamydial persistence. PMID- 22943885 TI - Novel multimodality endoscopic closure of postoperative esophageal fistula. AB - INTRODUCTION: Esophageal fistula following esophagectomy is associated with significant morbidity and mortality. PRESENTATION OF CASE: We present the case of a 71-year-old man who underwent salvage Ivor-Lewis esophagectomy, following definitive chemoradiotherapy 1 year previously. On postoperative day 9 the patient complained of chest pain, and a CT scan demonstrated extravasation of oral contrast from the gastric conduit into the right chest. A right chest drain and fully covered esophageal stent were placed at this time. Despite these measures, after 8 weeks, the esophageal fistula persisted. Ultimately, fistula closure was achieved using an interventional radiology-guided, endoscopically placed over-the-scope clip (OTSC). The patient had no further complications and was well at 3 months follow-up. DISCUSSION: The case reported herein describes this novel, combined-modality approach to esophageal fistula closure. CONCLUSION: This case report demonstrates a novel, minimally invasive, multidisciplinary approach to the closure of a post-esophagectomy anastamotic leak. PMID- 22943886 TI - Formation and stability of interpenetrating polymer network hydrogels consisting of fibrin and hyaluronic acid for tissue engineering. AB - Fibrin gel is widely used as a tissue engineering scaffold. However, it has poor mechanical properties, which often result in rapid contraction and degradation of the scaffold. An interpenetrating polymer network (IPN) hydrogel composed of fibrin and hyaluronic acid-tyramine (HA-Tyr) was developed to improve the mechanical properties. The fibrin network was formed by cleaving fibrinogen with thrombin, producing fibrin monomers that rapidly polymerize. The HA network was formed through the coupling of tyramine moieties using horseradish peroxidase (HRP) and hydrogen peroxide (H2O2). The degree of crosslinking of the HA-Tyr network can be tuned by varying the H2O2 concentration, producing IPN hydrogels with different storage moduli (G'). While fibrin gels were completely degraded in the presence of plasmin and contracted when embedded with cells, the shape of the IPN hydrogels was maintained due to structural support by the HA-Tyr networks. Cell proliferation and capillary formation occurred in IPN hydrogels and were found to decrease with increasing G' of the hydrogels. The results suggest that fibrin-HA-Tyr IPN hydrogels are a potential alternative to fibrin gels as scaffolds for tissue engineering applications that require shape stability. PMID- 22943887 TI - Daptomycin as supportive treatment option in patients developing mediastinitis after open cardiac surgery. AB - BACKGROUND: Mediastinitis is a severe complication after cardiac surgery. While improvement of prophylaxis and of medical and surgical therapy has reduced its incidence, the treatment of mediastinitis continues to be a challenging problem. Within this study, we report the successful use of daptomycin as supportive therapy in patients developing mediastinitis after open cardiac surgery. METHODS: The records of 21 consecutive patients who developed mediastinitis after cardiac surgery were retrospectively reviewed. After diagnosis, all patients received surgical debridement and antibiotic therapy with daptomycin. All patients were followed up to death or discharge. RESULTS: Clinical improvement after combined surgical and antibiotic therapy with daptomycin was found in 90.5% of the patients. The median time until clinical improvement occurred was 5 [4/6] days. Daptomycin was well-tolerated and no major adverse events during therapy were observed observed. CONCLUSIONS: This study provides new and helpful information regarding the beneficial use of daptomycin as supportive treatment option in patients developing mediastinitis after cardiac surgery. PMID- 22943888 TI - Suffering caused by care--patients' experiences from hospital settings. AB - Suffering and well-being are significant aspects of human existence; in particular, suffering and well-being are important aspects of patients' experiences following diseases. Increased knowledge about existential dimensions of illness and healthcare experiences may be needed in order to improve care and reduce unnecessary suffering. Therefore, the aim of this paper is to illuminate the phenomenon of suffering experienced in relation to healthcare needs among patients in hospital settings in Sweden. In this study, we used a reflective lifeworld approach. The data were analysed with a focus on meanings. The results describe the essential meaning of the phenomenon of suffering in relation to healthcare needs. The patients were suffering during care-giving when they felt distrusted or mistreated and when their perspective on illness and health was overlooked. Suffering was found to arise due to healthcare actions that neglected a holistic and patient-centred approach to care. Unfortunately, healthcare experiences that cause patients to suffer seem to be something one needs to endure without being critical. The phenomenon can be described as having four constituents: to be mistreated; to struggle for one's healthcare needs and autonomy; to feel powerless; and to feel fragmented and objectified. The study concludes that there are problems associated with patients experiencing suffering at the hands of healthcare providers, even if this suffering may not have been caused deliberately to the patient. Consequently, conscious improvements are needed to lessen the suffering caused by care-giving, as are strategies that promote more patient-centred care and patient participation. PMID- 22943890 TI - [Open source genomics: a new tool for countermeasuring emerging and remerging infectious diseases]. PMID- 22943891 TI - [Evolution, problems and recommendations on non-communicable diseases control and prevention system in China]. PMID- 22943889 TI - Patient decision making in the face of conflicting medication information. AB - When patients consult more than one source of information about their medications, they may encounter conflicting information. Although conflicting information has been associated with negative outcomes, including worse medication adherence, little is known about how patients make health decisions when they receive conflicting information. The objective of this study was to explore the decision making strategies that individuals with arthritis use when they receive conflicting medication information. Qualitative telephone interviews were conducted with 20 men and women with arthritis. Interview vignettes posed scenarios involving conflicting information from different sources (e.g., doctor, pharmacist, and relative), and respondents were asked how they would respond to the situation. Data analysis involved inductive coding to identify emergent themes and deductive contextualization to make meaning from the emergent themes. In response to conflicting medication information, patients used rules of thumb, trial and error, weighed benefits and risks, and sought more information, especially from a doctor. Patients relied heavily on trial and error when there was no conflicting information involved in the vignette. In contrast, patients used rules of thumb as a unique response to conflicting information. These findings increase our understanding of what patients do when they receive conflicting medication information. Given that patient exposure to conflicting information is likely to increase alongside the proliferation of medication information on the Internet, patients may benefit from assistance in identifying the most appropriate decision strategies for dealing with conflicting information, including information about best information sources. PMID- 22943892 TI - [Spatial-temporal transmission models of infectious disease: rule exploration and decision support]. PMID- 22943893 TI - [Status of knowledge and behavior of drug use among residents in 5 provinces in China in 2011]. AB - OBJECTIVE: To understand the status of knowledge and behavior of drug use among urban and rural residents in 5 provinces in China to suggest priority intervention strategies and measures for drug use health education. METHODS: From March to May of 2011, 6159 urban and rural residents were selected from Beijing, Liaoning, Zhejiang, Yunnan, Shaanxi provinces by the multistage stratified sampling method and were investigated by the questionnaires on drug use knowledge and behavior. RESULTS: The residents' average awareness rate for 11 pieces of basic drug use information was 48.3% (32,750/67,749). The residents' average awareness rate in the rural (40.3%, 9189/22 792) was lower than that in metropolitan (51.9%, 11 483/22 110) and small and middle-sized cities (52.9%, 12,078/22,847) and the differences had statistical significance (chi2=889.30, P<0.01). Overall, 77.0% (4742/6159) of residents purchased drug according to the doctors' prescription; 36.9% (2271/6159) of residents bought by their experiences; 33.3% (2049/6159) of residents did not know whether they had bought faked drugs; 32.7% (2016/6159) of residents did not read instructions carefully before using drug; 83.4% (5134/6159) of residents stored drugs in their house and only 29.2% (1798/6159) of residents would check up expired drugs regularly; 59.6% (3673/6159) of residents changed drug by themselves after suspected adverse reaction of drugs. CONCLUSION: Chinese urban and rural residents' knowledge level of drug use is inadequate and drug use behaviors are not optimistic. Drug use health education should be enhanced among urban and rural residents. PMID- 22943894 TI - [Survey on ticks and detection of new bunyavirus in some vect in the endemic areas of fever, thrombocytopenia and leukopenia syndrome (FTLS) in Henan province]. AB - OBJECTIVE: To investigate the distribution, species, seasonal fluctuation of ticks and detect new bunyavirus in some hematophagus in the endemic areas of fever thrombocytopenia and leukopenia syndrome (FTLS) in Henan province. METHODS: From March to December 2011, the free ticks were collected manually with white cloth from the grassland and the parasitic ticks were collected from the host skin by hand searching in Xinyang and Jiyuan. The density and seasonal fluctuation of ticks were analyzed after classification of the specimen. The hematophagus were collected including gadfly (38 in 16 groups), cattle lice (224 in 16 groups), mosquitoes (238 in 17 groups) and ticks (825 in 77 groups), then RNA of new bunyavirus were detected by RT-PCR. RESULTS: A total of 12 388 ticks were collected in Xinyang and Jiyuan, consisting of 2 families, 5 geniuses and 6 species. In Xinyang city, 622 ticks were identified, consisting of 2 families, 3 geniuses and 3 species, including 2 (0.32%) Ornithodoros lahorensis, 451 (72.51%) Haemaphysalis longicornis and 117 (18.81%) Boophilus microplus. In Jiyuan city, 11 766 ticks were identified, consisting of 1 family, 4 geniuses and 5 species, including 7718 (65.60%) Haemaphysalis longicornis, 164 (1.39%) H.anatolicum anatolicum and 710 (6.03%) other ticks such as H. detritum, Boophilus microplus and Rhipicephalus sanguineus. Haemaphysalis longicornis were found in both districts as the predominant species in Henan province. Ticks were active from March to October. The average density was 160 per person hour and the peak was from May to July with density 278, 209 and 542 per person hour respectively. The results was positive in RNA detection of new bunyavirus in 11 groups of tick and 3 groups of gadfly by RT-PCR. The results were negative in all other hematophagus. CONCLUSION: Ornithodoros lahorensis, Haemaphysalis longicornis, Boophilus microplus, H.anatolicum anatolicum, Rhipicephalus sanguineus and H. detritum were found in Henan province. Haemaphysalis longicornis was the predominant species. The density of ticks varied with the seasons. The detection of new bunyavirus by PCR was positive in some ticks and gadflies. PMID- 22943895 TI - [Analysis of the genetic differences in the nucleoprotein between rabies virus and its vaccine strains in Guizhou province from year 2005 to 2010]. AB - OBJECTIVE: This study was to explore the differences in the nucleoprotein gene between rabies virus (RABV) and its vaccine strains in Guizhou province from year 2005 to 2010. METHODS: Samples from 4 rabies patients and cerebral tissue samples of 28 rabies infected dogs were collected from different districts in Guizhou province between year 2005 and 2010. Direct Immunofluorescence Assay (DFA) and RT nested PCR assay were applied to detect the overall length of N gene sequence. Meanwhile, based on the comparison between the homology and phylogenetic tree, the differences in N gene sequence between the prevalent RABV and the RABV vaccine strains collected from NCBI database in these years. RESULTS: According to DFA and RT-nested PCR assay, the antigen and nucleic acid of the 21 dogs and 4 human samples were both confirmed positive; whose full length of N gene sequences were both 1353 bp. The homological analysis showed that the 25 strains of RABV virus and the RABV type I virus stored by GenBank database shared a high homology in N gene nucleotide and amino acid sequences, which were 89%-100% and 98%-100%, respectively. Besides, the homology between the 25 strains of RABV virus and its vaccines in nucleotide and amino acid sequences were separately 86%-95% and 96% 100%. The N gene of vaccines for livestock shared the highest homology with HEP Flury strain in the nucleotide and amino acid, which were 88%-89% and 98%-99%, respectively. The vaccines for human use showed its greatest homology with the CTN strain in nucleotide (86%-100%) and amino acid (96%-100%). The phylogenetic tree analysis indicated that the 25 strains of RABV virus, RABV type I virus and the CTN vaccine strains constituted one individual cluster, which was least different from the CTN vaccine for human use. CONCLUSION: The prevalent RABV virus, the vaccine HEP-Flury for livestock and the vaccine CTN for human use were found to be highly similar in N gene expression in Guizhou province from 2005 to 2010. PMID- 22943896 TI - [Study of immunogenicity after primary vaccination by different sequential program of inactivated poliovirus vaccine and oral poliovirus vaccine]. AB - OBJECTIVE: To evaluate immunogenicity after primary vaccination by different sequential program of inactivated poliovirus vaccine (IPV) and oral poliovirus vaccine (OPV). METHODS: Children of 2 months old (60-89 days) selected in Beijing were assigned to 4 groups, 1 dose IPV plus 2 doses OPV (I-O-O, 122 children), 2 doses IPV plus 1 dose OPV(I-I-O, 103 children), 3 doses IPV (I-I-I, 114 children), and 3 doses OPV (O-O-O, 106 children), and were vaccinated at the age of 2, 3, 4 months. Polio neutralizing antibody titers against poliovirus types 1, 2, and 3 were tested and protective rates were calculated before the 1st dose, after the last dose, and after the 1st and 2nd dose of IPV. RESULTS: After the primary immunization, geometric mean titers (GMT) of polio neutralizing antibody titers against poliovirus types 1, 2, and 3 were 788.32, 738.42 and 631.17 in O-O O group, 212.02, 262.30 and 537.52 in I-I-I group, 940.35, 929.72 and 940.35 in I O-O group and 901.09, 1102.68 and 1110.12 in I-I-O group (F values were 47.71, 53.84, and 9.81 respectively, all P values<0.01). The protective rate of three types among each group was 98.1% (104/106)-100.0% and the difference was not statistically significant (P>0.05). After the 1(st) dose of IPV, the GMT were 18.88, 37.77, 24.64 and the protective rate was 82.6% (122/138)-96.4% (133/138); after the 2nd dose of IPV, GMT were 177.03, 168.25, 321.86 and the protective rate was 99.1% (108/109)-100.0% (109/109) in antibody types 1, 2 and 3, respectively. CONCLUSION: GMT of polio neutralizing antibody titers against poliovirus is higher after vaccination by sequential program of IPV and OPV than that by IPV or OPV 3-doses program. High level of protective rate after 2 doses of IPV in I-I-O group may lead to better protection from vaccine associated paralytic poliomyelitis (VAPP). Sequential program of IPV and OPV can be used to maintain high level of herd immunity and to prevent VAPP, and the I-I-O sequential program should be the first choice. PMID- 22943897 TI - [Quality of life and its influencing factors of people living with HIV or AIDS in Beijing]. AB - OBJECTIVE: To assess the quality of life of people living with HIV or AIDS (PLWHA) and to identify influencing factors. METHODS: During September to December 2010, by a convenience sampling, a questionnaire survey was undertaken in 310 PLWHA living in Beijing, which included the general questionnaires, SF-36 for assessing quality of life and Berger-HIV stigma scale. T test and multivariable linear regression model were used to analyze the results. RESULTS: For the subjects investigated, the age was (32.87+/-8.76) years old. Homosexual behavior was the main dissemination (84.52%, 262/310). The results of SF-36 questionnaire were: the summary score 66.75+/-15.70; physical function 93.00+/ 9.49, role physical 66.53+/-40.26, bodily pain 73.88+/-22.63, general health 50.06+/-22.75, vitality 61.11+/-19.67, social function 69.50+/-24.24, role emotional 59.68+/-42.38, mental health 60.63+/-19.81. Except physical functioning, the scores of every scale were lower than general persons (P<0.05). Multivariable linear regression analysis showed that the stronger stigma, the lower the summary score (standardized coefficients (beta')=-0.38), role physical (beta'=-0.21), bodily pain (beta'=-0.13), general health (beta'=-0.33), vitality (beta'=-0.31), social function (beta'=-0.34), role emotional (beta'=-0.31), mental health (beta'=-0.47) (all P values<0.05). The higher expend on treating HIV, the lower the summary score (beta'=-0.17), physical function (beta'=-0.28), role physical (beta'=-0.15), bodily pain (beta'=-0.19), general health (beta'= 0.15), social function (beta'=-0.11), role emotional (beta'=-0.16) (all P values<0.05). Who having work got higher score in the summary score (beta'=0.13), physical function (beta'=0.13), role physical (beta'=0.12), bodily pain (beta'=0.12), vitality (beta'=0.13), social function (beta'=0.12), role emotional (beta'=0.12) than others (all P values<0.05). CONCLUSION: The quality of PLWHA's life was low. High stigma feeling, high expend on treating HIV, having a job were the main influencing factors of quality of life in PLWHA. PMID- 22943898 TI - [Survey of HIV drug resistance threshold in Zhejiang province from 2009 to 2011]. AB - OBJECTIVE: To survey the prevalence of drug resistant HIV in Zhejiang province in 2009-2011. METHODS: WHO truncated sequential sampling technique was adopted annually by using 63, 62 and 57 samples of newly diagnosed as HIV positive and aged 16-25 years in Hangzhou, Ningbo and Wenzhou from 2009 to 2011, respectively. RNA was prepared and HIV pol region was amplified by RT-PCR and nested PCR. Pol genetic mutation associated with drug resistance was analyzed. RESULTS: The success rates for sequence acquisition of the survey were 82.5% (52/63), 95.2% (59/62) and 94.7% (54/57) from year 2009 to 2011, respectively, and the main subtype was CRF01_AE (68.5% (37/54)-71.2% (37/52)). A total of 4 surveillance drug-resistance mutation (SDRMs), 2 SDRMs and 2 SDRMs were found by analyzing the 47 sequences each year, sampled from year 2009 to 2010, respectively, indicating that the prevalence of drug resistant HIV stains was moderate in 2009, and low for the next two years (2010-2011). A total of 8 individuals with drug resistant HIV stains found in this study were all infected by sexual transmission, especially in homosexual transmission (6 cases), and the main subtype was CRF01_AE (7 cases). SDRMs for protease inhibitor (PI), nucleotide HIV-reverse transcriptase inhibitor (NRTI) and non-NRTI (NNRTI) (L90M, T215S and Y188L) were all found in one case. CONCLUSION: The prevalence of drug resistant HIV stains in major areas with AIDS epidemic in Zhejiang province was low in 2009-2011. PMID- 22943899 TI - [Spatial heterogeneity of pulmonary tuberculosis by G statistics in Zhejiang province in 2006]. AB - OBJECTIVE: To investigate the spatial distribution characteristics of pulmonary tuberculosis in Zhejinag province in 2006 by G statistics, so as to find out the hotspot of occurrence of pulmonary tuberculosis in Zhejiang province and provide evidence for control and prevention on pulmonary tuberculosis. METHODS: The data of pulmonary tuberculosis cases in 90 counties (districts) in Zhejiang province in 2006 were obtained from the tuberculosis surveillance system. Based on the same county field in digital maps and pulmonary tuberculosis incidence database, digital map of Zhejiang province was interrelated with the database of Zhejiang province pulmonary tuberculosis incidence to establish Zhejiang geographic information system database. General and local G statistics were developed to test for spatial heterogeneity by ArcGIS 9.2 software. RESULTS: A total of 43 467 cases of pulmonary tuberculosis were reported in Zhejiang province in 2006, and the reported incidence was 88.74/100,000.G statistics indicated that there were high occurrence of pulmonary tuberculosis (Getis-Ord Gi=0.0764, P<0.05). Local Getis-Ord Gi statistics analysis showed that there were statistically significant hotspots in Yuhuan county, Leqing city, Pingyang county, Dongtou county, Yongjia county, Ruian city and Ouhai, Longwan, Lucheng district in Wenzhou city, other areas were intergradational zone with Z(Gi) value fell in -1.96 to 1.96. CONCLUSION: Pulmonary tuberculosis in Zhejiang province present unrandomly distributed and geographically clustered. PMID- 22943900 TI - [Correlation between interleukin-28B genetic polymorphisms and primary hepatocellular carcinoma]. AB - OBJECTIVE: To explore the correlation between single nucleotide polymorphisms (SNPs) of interleukin-28B (IL-28B) gene and the susceptibility to primary hepatocellular carcinoma (HCC). METHODS: A total of 300 histologically confirmed HCC cases (from November 2001 to April 2010) and 310 healthy controls with no history of chronic hepatitis B or hepatocellular carcinoma (2009-2010) were selected from a hospital in Guilin and a hospital in Beijing for this case control study.139 HCC patients in the case group had complete clinical tracking data. All the subjects were Han Chinese, with no age or gender restrictions.2 ml peripheral blood samples were drawn from each subject with informed consent. SNP of rs12972991, rs4803223, rs8099917 and rs12979860 four loci in IL-28B gene were analyzed by matrix-assisted laser desorption/ionization time of flight mass spectrometry (MALDI-TOF). RESULTS: The frequencies of C allele at rs12972991, G allele at rs8099917 and G allele at rs4803223 were 6.7% (40/598), 7.9% (47/598) and 10.0% (59/588) respectively in case group; all higher than the corresponding frequencies in control group, separately 2.9% (18/618), 4.1% (25/616) and 3.6% (21/608). The differences were statistically significant (chi2=9.542, 7.858, 20.736, P values all<0.05). The above alleles could increase the risk of HCC, and the OR (95%CI) values were separately 1.67 (1.13-2.46), 1.49 (1.08-2.06) and 2.91 (1.79-4.72). The genotype frequencies of AC+CC at rs12972991, GT+GG at rs8099917, GA+GG at rs4803223 were 13.0% (39/299), 14.7% (44/299) and 19.0% (56/296) respectively in case group; while the frequencies were lower in control group, separately 5.8% (18/309), 8.1% (25/308) and 6.6% (20/304). The differences were statistically significant (chi2=9.319, 6.557, 20.948, P values all<0.05). These genotypes may increase the risk of HCC, and the adjusted OR (95%CI) values were 2.24 (1.31-3.83), 1.81 (1.14-2.88) and 2.90 (1.78-4.70), respectively. The stratified analysis of the clinical data indicated that the frequency of genotype GA+GG at rs4803223 was 50.0% (13/26) in patients of tumor thrombosis in portal vein (TTPV), higher than the frequency of genotype AA (21.1%, 23/109). The difference was statistically significant (chi2=8.965, P=0.003). CONCLUSION: The results suggested that IL-28B gene polymorphisms was correlated to the susceptibility to HCC in Chinese Han ethnic population. Among them, GA + GG genotype at rs4803223 could increase the risk of TTPV in HCC patients. PMID- 22943901 TI - [Correlation between tag single nucleotide polymorphisms of microRNA regulatory genes and the genetic susceptibility of primary liver cancer]. AB - OBJECTIVE: This study aimed to understand the correlation between tag single nucleotide polymorphisms (tSNP) of microRNA regulatory genes and the gentic susceptibility of primary liver cancer. METHODS: 1:1 case-control study was applied in this research. A total of 532 primary liver cancer patients in 2 teaching hospitals in Zhengzhou city were enrolled as case group.532 healthy individuals were enrolled as control group. The subjects were surveyed by a face to-face interview and 5 ml of peripheral venous blood were collected. Candidate tSNP were screened from DICER1, RAN and GEMIN4 gene, respectively. PCR-RFLP or Allele specific PCR was applied for genotyping of the subjects. Conditional logistic regression model and Multifactor-Dimensionality Reduction method were applied for analyzing the correlation between tSNP of above genes and gentic susceptibility of primary liver cancer. The gene-environment interaction was also analyzed. RESULTS: The frequencies of genotype CC, CT, TT in rs14035 locus were 67.29% (358/532), 28.20% (150/532), 4.51% (24/532) in case group, and 70.30% (374/532), 28.20% (150/532), 1.50% (8/532) in control group, respectively (chi2=8.35, P<0.05). The frequencies of genotype GG, GA, AA in rs1045491 locus were 71.05% (378/532), 26.69% (142/532), 2.26% (12/532) in case group, and 80.45% (428/532), 18.42% (98/532), 1.13% (6/532) in control group, respectively (chi2=13.17, P<0.01); the frequencies of genetype GG, GT, TT in rs2291778 locus were 53.38% (284/532), 40.23% (214/532), 6.39% (34/532) in case group, and were 25.94% (138/532), 63.91% (340/532), 10.15% (54/532) in control group (chi2=83.71, P<0.01). TT genotype in rs14035 locus (OR=2.54, 95%CI: 1.19-6.32) and GA genetype in rs1045491 locus (OR=1.74, 95%CI: 1.08-2.66) were susceptible genotype of primary liver cancer, whereas GT (OR=0.52, 95%CI: 0.43-0.75) and TT genotype (OR=0.62, 95%CI: 0.46-0.86) in rs2291778 locus were protective genotype. Haplotype analysis showed that haplotype 3 (AACTGGGT) (OR=1.42, 95%CI: 1.10-1.82) and haplotype 5 (AGCCAGCC) increased the risk of occurrence of primary liver cancer (OR=1.36, 95%CI: 1.02-1.80), whereas haplotype 2 (AACTATCC) (OR=0.69, 95%CI: 0.52-0.91) and haplotype 6 (AACTGTGT)(OR=0.61, 95%CI: 0.45-0.81) decreased the risk. Subjects exposed to allele A of rs1045491, allele T of rs14035 and HBV infection intend to be the high risk population of primary liver cancer (OR = 3.72, 95%CI: 2.38 - 5.56). CONCLUSION: Genotypes of TT in rs14035 locus, and GA in rs1045491 locus may be susceptible genotypes of liver cancer carcinogenesis. T allele in rs2291778 locus is a non-susceptible allele of primary liver cancer. Combined effects of multigene alleles and multi-locus genotype may have a synergistic role in the carcinogenesis of liver cancer. PMID- 22943902 TI - [Correlation between polymorphism of sex hormone binding globulin and occurrence of hepatocellular carcinoma]. AB - OBJECTIVE: This study aims to investigate the correlation between polymorphism of sex hormone-binding globulin (SHBG) Asp327Asn (rs6259) locus and occurrence of hepatocellular carcinoma (HCC). METHODS: 621 cases with HCC and 621 cancer-free controls from two hospitals of Guangxi were recruited from January, 2007 to June, 2010. Single nucleotide polymorphisms (SNP) of SHBG Asp327Asn were detected by ABI7500 Fast Real-Time fluorescence quantitative PCR. Multivariate unconditional logistic regression was applied to analyze risk of HCC among different genotypes carriers and their interaction with the exposure factors. The Kaplan-Meier survival analysis was used to detect the relationship between onset age of HCC and genotypes. RESULTS: The frequencies of Asp/Asp, Asp/Asn and Asn/Asn genotype in case group were 86.31% (536/621), 12.40% (77/621) and 1.29% (8/621), respectively; while those in control group were 81.00% (503/621), 17.39% (108/621) and 1.61% (10/621), respectively. Significant difference in the genotype frequencies distribution was found between case and control groups (chi2=6.465, P<0.05). Compared with those harboring Asp/Asp genotype, multivariate logistic regression analysis revealed that the HCC risk of Asn/Asn+Asp/Asn genotype carriers was significantly decreased (adjusted OR=0.63, 95%CI: 0.40-0.98). Interaction analysis showed that there was interaction between the polymorphisms and two exposure factors, drinking (adjusted OR=3.45, 95%CI: 1.74-6.83) and HBV infection (adjusted OR=40.77, 95%CI: 21.60-76.97). Among those male patients with history of drinking, survival analysis indicated that the mean age of onset of individuals harboring Asp/Asp genotypes ((47.99+/-0.75) years old) was 6 years earlier than those with Asn/Asn or Asp/Asn genotypes ((53.68+/ 2.07) years-old) (chi2=6.91, P<0.01). CONCLUSION: Polymorphism of SHBG (Asp327Asn) may be associated with both the risk of HCC occurrence and onset age of HCC. PMID- 22943903 TI - [Study on the status and related socio-psychological factors of maternal depression among high-risk pregnancy women in Harbin city]. AB - OBJECTIVE: This study aimed to investigate the depression status among high-risk pregnancy women, and to analyze its relevant social and psychological factors. METHODS: A total of 42 high-risk pregnancy women and 40 normal pregnancy women in a teaching hospital in Harbin city were followed up at time points of 32 - 36 weeks pregnancy, one week before labor, one week postpartum, and six weeks postpartum, respectively. During follow-up, the basic situation, social psychosocial factors of pregnancy women were collected and the depression of pregnancy women was measured by self-designed questionnaire and self-rating depression scale. The Edinburgh Postnatal Depression Scale (EPDS) was applied at timepoint of one week postpartum. Single factor analysis and the unconditional multivariate logistic regression were applied for analyzing the on the related social-psychosocial factors among high-risk pregnancy women. RESULTS: The age of high-risk pregnancy women was (31.0+/-5.6), and the age of normal pregnancy women was (30.5+/-3.8) (t=0.169, P>0.05). The results showed that the depression rate in high-risk pregnancy women was 45.2% (19/42), which was 25.0% (10/40) in normal pregnancy women, the difference was significant (chi2=3.671, P=0.045). The depression rates at different time points were 30.9% (13/42), 42.9% (18/42), 23.8% (10/42), 26.2% (11/42) in high-risk pregnancy women respectively, and 25.0% (10/40), 15.0% (6/40), 20.0% (8/40), 17.5% (7/40) in the control group respectively, the difference of the depression rates among groups at one week before labor was significant (chi2=7.680, P<0.01), the difference among groups at 32-36 weeks pregnancy (chi2=0.133, P=0.80), at one week postpartum (chi2=0.174, P=0.79) and at six weeks postpartum (chi2=0.903, P=0.43) were not significant. At one week postpartum and six weeks postpartum periods, the EPDS depression rate were 12.5% (4/32), 30.4% (7/23) in case group respectively, 8.3% (3/36), 22.9% (8/35) in control group respectively, the difference were not significant (chi2=0.319, 0.416, P=0.573, 0.519). There were significantly associations between the depression mood of one week before labor and the depressive symptoms of six weeks postpartum in both groups (r=0.824, 0.677, both P values were <0.05). The risk factors for maternal depression among high-risk pregnancy women were not ready for production (OR=2.73, P<0.01) and fearing of childbirth safety (OR=2.89, P<0.01). CONCLUSION: The depression date of high-risk pregnancy was high, especially at the time point one week before labor. Risk factors of maternal depression among high-risk pregnancy were "not ready for production" and "fear of childbirth safety". PMID- 22943904 TI - [Birth defects among children aged 0-4 in Chongqing in 2010]. AB - OBJECTIVE: To learn the prevalence of birth defects in Chongqing. METHODS: A total of 6579 children aged 0 - 4 were chosen by multistage cluster sampling method in central economic districts of Chongqing. A total of 32 kinds of birth defects were selected. All the birth defects, except for the visible congenital malformation, must be diagnosed by the hospital in county. And municipal experts would make a consultation for those that couldn't be diagnosed at the level of county. Investigators trained strictly made a body examination and inquired medical history from May to September in 2010. RESULTS: A total of 6541 subjects, aged from 0 to 4, were recruited in the present study, and 216 of them were born with birth defects. The total prevalence was 33.480/00 (95%CI: 29.090/00 37.870/00). There were 25 kinds of birth defects in total, the first five were hernia (20.150/00), congenital heart disease (2.170/00), polydactylism (2.020/00), cryptorchid (1.860/00) and funnel chest (1.860/00). The prevalence among boys was 52.990/00 (178/3359), higher than girls 12.290/00 (38/3092) (chi2=82.42, P<0.05). The prevalence in each group aged 0, 1, 2, 3, 4 were 39.300/00 (36/916), 38.790/00 (41/1057), 36.460/00 (56/1536), 28.380/00 (47/1656), 27.990/00 (36/1286), respectively. There were no statistical differences in each group (chi2=4.83, P=0.31). The prevalence in countryside was 40.170/00 (136/3386), higher than that in town 26.180/00 (80/3065) (chi2=9.83, P<0.05). CONCLUSION: The rate of birth defects in Chongqing was moderate, and boys and kids in rural areas had a higher prevalence rate than their counterparts. PMID- 22943905 TI - [Immunogenicities and comparison of DNA vaccines encoding pol genes derived from B'/C and A/E recombinant HIV-1 strains]. AB - OBJECTIVE: To construct and compare the immunogenicities of DNA vaccines expressing pol genes derived from B'/C and A/E recombinant subtypes of HIV-1 in China. METHODS: Two DNA vaccines were constructed by inserting the codon optimized pol genes derived from B'/C and A/E subtypes of HIV-1 into mammalian expression vector pSV1.0. In vitro expression efficiencies of the two DNA vaccines were determined by Western blotting and their immunogenicities were compared by i.m. immunizing female BALB/c mice. After immunization, mice splenocytes were isolated sterilely and IFN-gamma based enzyme linked immunospot assay (ELISPOT) was employed to read out the specific T cell immunity. RESULTS: The constructed DNA vaccines were validated by restriction enzyme digestion and DNA sequencing. Western blotting result showed both of the two DNA vaccines could be expressed at appreciable levels in vitro. Under the stimulation of Consensus B Pol peptide pools, specific T cell frequency elicited by pSVAE-Pol was (636+/ 178) SFCs/10(6) splenocytes; specific T cell frequency elicited by pSVCN-Pol was (468+/-265)SFCs/10(6) splenocytes (P=0.412). Under the stimulation of HIV-1 AE2f Pol peptide pools, specific T cell frequency elicited by pSVAE-Pol was (1378+/ 611) SFCs/10(6) splenocytes; specific T cell frequency elicited by pSVCN-Pol was (713+/-61) SFCs/10(6) splenocytes (P=0.134). Further analysis suggested pSVAE-Pol induced specific T cell responses mainly focused on Pol 1 peptide pool, while, in addition to induce Pol 1 specific T cell responses, pSVCN-Pol could also elicit T cell responses against consensus B Pol 2 peptide pool. CONCLUSION: Although pSVAE Pol was more immunogenic, pSVCN-Pol could induce T cell responses against broader epitope spectrum. Rational vaccine design may need combine them together. PMID- 22943906 TI - [Immunotoxicologic assessment of genetically modified drought-resistant wheat T349 with GmDREB1]. AB - OBJECTIVE: To assess the immunotoxicologic effects of genetically modified drought resistant wheat T349 with GmDREB1 gene. METHODS: A total of 250 female BALB/c mice (6-8 week-old, weight 18-22 g) were divided into five large groups (50 mice for each large group) by body weight randomly. In each large group, the mice were divided into five groups (10 mice for each group) by body weight randomly, which were set as negative control group, common wheat group, parental wheat group, genetically modified wheat group and cyclophosphamide positive control group, respectively. Mice in negative control and positive control group were fed with feedstuff AIN-93G, mice in common wheat group, non-genetically modified parental wheat group and genetically modified wheat group were fed with feedstuffs added corresponding wheat (proportion up to 76%) for 30 days, then body weight, organ coefficient of spleen and thymus, peripheral blood lymphocytes phenotyping, serum cytokine, serum immunoglobulin, antibody plaque-forming cell (PFC), serum 50% hemolytic value (HC50), mitogen-induced splenocyte proliferation, delayed-type hypersensitivity (DTH) reaction and phagocytic activities of phagocytes were detected respectively. RESULTS: After 30 days raise, among negative control group, common wheat group, non-genetically modified parental wheat group, genetically modified wheat group and cyclophosphamide positive control group, mice body weight were (21.0+/-0.3), (20.4+/-0.7), (21.1+/ 1.0), (21.1+/-1.0), (19.4+/-1.0) g, respectively (F=7.47, P<0.01); organ coefficient of spleen were (0.407+/-0.047)%, (0.390+/-0.028)%, (0.402+/-0.042)%, (0.421+/-0.041)%, (0.304+/-0.048)%, respectively (F=12.41, P<0.01); organ coefficient of thymus were (0.234+/-0.032)%, (0.246+/-0.028)%, (0.249+/-0.040)%, (0.234+/-0.034)%, (0.185+/-0.039)%, respectively (F=5.58, P<0.01); the percentage of T cell in peripheral blood were (70.43+/-4.44)%, (68.33+/-5.37)%, (73.04+/ 2.68)%, (74.42+/-2.86)%, (90.42+/-1.66)%, respectively (F=57.51, P<0.01); the percentage of B cell were (13.89+/-3.19)%, (15.34+/-4.84)%, (13.06+/-4.22)%, (12.93+/-2.36)%, (3.01+/-0.96)%, respectively (F=12.79, P<0.01); the percentage of Th cell were (55.87+/-3.80)%, (55.24+/-4.60)%, (57.92+/-3.70)%, (59.57+/ 2.54)%, (77.37+/-2.31)%, respectively (F=68.58, P<0.01);the Th/Ts ratio were 4.16+/-0.29, 4.73+/-0.96, 4.19+/-0.78, 4.52+/-0.40, 6.34+/-0.73, respectively (F=17.57, P<0.01);the serum IgG were (1046.38+/-210.67), (1065.49+/-297.22), (1517.73+/-299.52), (1576.67+/-241.92), (1155.88+/-167.05) ug/ml, respectively (F=10.53, P<0.01); the serum IgM were (333.83+/-18.97), (327.73+/-27.72), (367.47+/-27.18), (363.42+/-46.14), (278.71+/-24.42) ug/ml, respectively (F=12.11, P<0.01); the serum IgA were (51.69+/-10.10), (42.40 +/- 8.35), (32.11+/ 4.22), (37.12+/-4.90), (41.45+/-8.89) ug/ml, respectively (F=8.25, P<0.01); the PFC were (29.2+/-14.6), (28.0+/-20.0), (34.8+/-30.9), (33.2+/-25.1), (4.8+/-5.3) per 10(6) splenocyte, respectively (F=3.33, P<0.05); the HC50 were 82.3+/-6.5, 79.7+/-4.6, 75.8+/-4.1, 74.9+/-3.6, 70.8+/-2.1, respectively (F=9.99, P<0.01);the LPS-induced splenocyte proliferation were 0.21+/-0.10, 0.21+/-0.14, 0.26+/-0.12, 0.25+/-0.14, 0.07+/-0.06, respectively (F=4.18, P<0.05). CONCLUSION: The genetically modified drought-resistant wheat T349 was substantially equivalent to parental wheat in the effects on immune organs and immunologic functions of mice, and it didn't show immunotoxicity. PMID- 22943907 TI - [The determination of phthalic acid esters in edible vegetable oils by gas chromatography-mass spectrometry]. AB - OBJECTIVE: We aimed to establish a quantified method for the 17 phthalate acid esters (PAE) in edible vegetable oil by gas chromatography-mass spectrometry (GC MS) with the pretreatment of acetonitrile extraction and silica/N-(n propyl)ethylenediamine (silica/PSA) mixed solid phase extraction column and evaluated the PAE of 25 edible oil samples from supermarkets in Hangzhou city. METHODS: The internal standard solution (D4-DEHP) was added in edible vegetable oil sample. The analytes were extracted by acetonitrile with 1 min vortex, and centrifuged at 3050*g for 5 min. The supernatant was then cleaned with silica/PSA column, and eluted with acetonitrile. The elution was dried with N2 flow at 50 degrees C and diluted to 1.0 ml with hexane. Then, 17 PAE were tested by GC-MS and quantified with internal standards. The repeatability and sensitivity of the assay were evaluated. PAE were then determined in 25 plastic buckets of edible vegetable oil from supermarkets in Hangzhou city. RESULTS: By the quantification of internal standard of D4-DEHP, a good linearity range of related 17 PAE was observed. The correlation coefficient was 0.994-1.000 and the standard lowest quantified level was 0.05-0.15 ug/ml. The spiking recoveries of 17 PAE were 78.3% 108.9% with the RSD of 4.3%-12.1% (n=6). The method detection limits were 0.1-0.2 mg/kg. In 25 plastic buckets of edible vegetable oil from Hangzhou, DMP, DEP, DIBP, DBP and DEHP were detected at the range of <0.1-1.8 mg/kg and the detection rates were 12% (3/25), 24% (6/25), 100% (25/25), 96% (24/25) and 100% (25/25), respectively. Other 12 PAE was not detected. For DBP with the level of <0.1 to 1.3 mg/kg, the results of 16% (4/25) samples exceeded the regular migrating limit of 0.3 mg/kg. For DEHP of <0.2-1.8 mg/kg, the data of 12% (3/25) samples were beyond the regular migrating limit of 1.5 mg/kg. CONCLUSION: The pretreatment by silica/PSA mixed solid phase extraction column can satisfy the PAE determination requirements in edible vegetable oils. The DMP, DIBP, DEP, DBP and DEHP were detected from the survey of 25 edible oil samples in Hangzhou city. PMID- 22943908 TI - Altered neurochemical profile in the McGill-R-Thy1-APP rat model of Alzheimer's disease: a longitudinal in vivo 1 H MRS study. AB - We investigated metabolite levels during the progression of pathology in McGill-R Thy1-APP rats, a transgenic animal model of Alzheimer's disease, and in healthy age-matched controls. Rats were subjected to in vivo (1) H magnetic resonance spectroscopy (MRS) of the dorsal hippocampus at age 3, 9 and 12 months and of frontal cortex at 9 and 12 months. At 3 months, a stage in which only Abeta oligomers are present, lower glutamate, myo-inositol and total choline content were apparent in McGill-R-Thy1-APP rats. At age 9 months, lower levels of glutamate, GABA, N-acetylaspartate and total choline and elevated myo-inositol and taurine were found in dorsal hippocampus, whereas lower levels of glutamate, GABA, glutamine and N-acetylaspartate were found in frontal cortex. At age 12 months, only the taurine level was significantly different in dorsal hippocampus, whereas taurine, myo-inositol, N-acetylaspartate and total creatine levels were significantly higher in frontal cortex. McGill-R-Thy1-APP rats did not show the same changes in metabolite levels with age as displayed in the controls, and overall, prominent and complex metabolite differences were evident in this transgenic rat model of Alzheimer's disease. The findings also demonstrate that in vivo (1) H MRS is a powerful tool to investigate disease-related metabolite changes in the brain. PMID- 22943909 TI - [Strengthening analysis and application of cancer registration data in China]. PMID- 22943910 TI - [Trend analysis and prediction of cancer incidence in China]. AB - OBJECTIVE: Based on the national cancer incidence database from 1998 to 2007, to analyze the cancer incidence trend and predict the cancer burden between 2008 and 2015. METHODS: We picked up the cancer incidence data of 40 cancer registry sites from National Central Cancer Registry Database between 1998 and 2007. In total, 1 109 594 cancer cases were registered, covering 446 734 668 person-year. The separate incidence by district and gender were calculated, and the standardized incidence rate was calculated by world's population age structure. The incidence trend between the 10 years was analyzed by JoinPoint software, as well as the age percentage-changes (APC). Age-Period-Cohort Bayesian Model was applied to fit the cancer incidence data stratified by age, district and gender. The cancer incidence between 2008 and 2015 was then predicted. RESULTS: During the period of 1998 - 2007, in urban areas, the male cancer incidence rate was 277.61/100 000 (472 307/170 131 309), with the age standardized rate (ASR) at 202.05/100 000; while the female cancer incidence rate was 236.35/100 000 (389 586/164 830 893), with the ASR at 159.15/100 000; in rural areas, the male and female cancer incidence rates were separately 272.23/100 000 (153 478/56 377 236) and 170.09/100 000 (94 223/55 395 230), with the corresponding ASR at 244.34/100 000 and 137.90/100 000. Crude incidence rate in urban men increased from 247.00/100 000 (27 758/11 237 967) in 1998 to 305.76/100 000 (68 953/22 551 353) in 2007; while it increased from 207.37/100 000 (22 476/10 838 355) to 263.20/100 000 (58 055/22 057 787) among urban women. The crude incidence rate in rural men increased from 232.33/100 000 (10 045/4 323 628) to 303.65/100 000 (23 313/7 677 484) and it increased from 139.03/100 000 (5836/4 197 806) to 197.40/100 000 (14 850/7 522 690) among rural women. After age adjustment, the urban male APC value (95%CI) was 0.5% (-0.2% - 1.3%), showed no significantly statistical difference. However, the urban female APC value (95%CI), rural male APC value (95%CI) and rural female APC value (95%CI) were separately 1.7% (1.3% - 2.0%), 1.8% (0.9% - 2.6%) and 2.8% (1.8% - 3.7%), all showed an obvious uptrend. The outcome of Age Period-Cohort Bayesian model predicted that by year 2015, the incidence cancer rate in urban areas will reach 309.13/100 000 (1.140 million new cases) among males and 303.79/100 000 (1.046 million new cases) among females; while in rural areas the rate will reach 288.66/100 000 (1.019 million new cases) among males and 222.59/100 000 (0.734 million new cases) among females. CONCLUSION: The cancer incidence has increased annually; the uptrend in rural areas was more obvious than it in urban areas; the uptrend in females was more obvious than it in males. It is predicted that the annual incidence will continue to increase in the next years, and effective control programs should be carried out immediately. PMID- 22943911 TI - [Analysis and prediction of liver cancer incidence in China]. AB - OBJECTIVE: Based on the cancer registry data during 1998 - 2007, to analyze the incidence of liver cancer in China and predict the trend of incidence of liver cancer between 2008 and 2015. METHODS: Liver cancer incidence data from cancer registry between 1998 and 2007 was collected, including a total of 115 417 cases, covering 446 734 668 person-year. We calculated the annual incidence rate of liver cancer by gender and area. Age-standardized rate (ASR) was calculated by the world's population age structure. JoinPoint software was applied to analyze the incidence trend and calculate annual percent change (APC). Age-Period-Cohort Bayesian Model was used to fit the incidence trend and predict the incidence trend between 2008 and 2015. RESULTS: From 1998 to 2007, according to the data from cancer registry, the liver cancer incidence was 25.84/100 000 (115 417/446 734 668), with the ASR at 18.82/100 000. In urban areas, the male incidence was 34.30/100 000 (58 353/170 131 309), with ASR at 24.99/100 000; while the female incidence was 12.33/100 000 (20 324/164 830 893), with ASR at 7.99/100 000. In rural areas, the male incidence was 48.56/100 000 (27 378/56 377 236), with ASR at 42.27/100 000; while the female incidence was 16.90/100 000 (9362/55 395 230), with ASR at 13.52/100 000. During the decade, in urban areas, the APC of male and female liver cancer incidence rates were separately 1.1% and -0.5%, with ASR at 0.5% and -1.9%; while in rural areas, the APC of male and female liver cancer incidence rates were separately 3.7% and 3.1%, with ASR at 1.9% and 1.3%. Age Period-Cohort Bayesian Model predicted that in urban areas, the male and female incidence of liver cancer in 2015 would reach 30.73/100 000 (113 279 cases) and 10.44/100 000 (35 978 cases), with ASR at 23.70/100 000 and 7.21/100 000, respectively; while in rural areas, the incidence rates would increase to 51.67/100 000 (182 382 cases) and 15.03/100 000 (49 580 cases), with ASR at 39.80/100 000 and 10.45/100 000, respectively. CONCLUSION: The incidence of liver cancer will increase between 2008 and 2015, but its ASR will decrease slightly. In the near future, the number of new liver cancer cases will keep increasing. Liver cancer is still the dominant cancer and one key point for cancer prevention and control in China. PMID- 22943912 TI - [Analysis and prediction of esophageal cancer incidence trend in China]. AB - OBJECTIVE: Based on the registered esophageal cancer data from 1998 to 2007, to analyze the incidence of esophageal cancer during the period and then to predict its trend between year 2008 and 2015. METHODS: The incidence data of esophageal cancer between 1998 and 2007 were sorted from National Cancer Registry Database. Data from forty selected registries were qualified and recruited in the study, including 86 427 cases in total, covering 446 734 668 person years. Crude incidence rates were calculated by area and gender. The standardized incidence rate was adjusted by World Segi's population composition. JoinPoint software was applied to analyze the 10 years' incidence trend and calculated the annual percentage change, while Age-Period-Cohort Bayesian Model was used to fit the data and predict the incidence between 2008 and 2015. RESULTS: Between 1998 and 2007, the crude incidence rates among males and females in urban areas were separately 16.58/100 000 (28 207/170 131 309) and 7.14/100 000 (11 761/164 830 893), with standardized rates at 12.06/100 000 and 4.55/100 000, respectively. In rural areas, the crude incidence rates and the standardized rates were separately 51.98/100 000 (29 303/56 377 236) and 47.18/100 000 among males, and 30.97/100 000 (17 156/55 395 230) and 25.30/100 000 among females. During the ten years, the crude incidence trend of esophageal cancer among urban females decreased from 10.29/100 000 (1115/10 838 355) in 1998 to 6.29/100 000 (1387/22 057 787) in 2007. However, the crude incidence rate among rural males increased from 47.69/100 000 (2062/4 323 628) to 54.80/100 000 (4207/7 677 484) in the same period. And the rate among rural females and urban males did not change obviously. After adjusting population structure, in urban areas, the male incidence rate decreased by 2.1% annually and female incidence rate dropped by 7.5% annually. In rural areas, the female incidence rate fell by 1.3% annually, while the male incidence rate remained the same without significant changes. The prediction model estimated that there would be 134 474 new esophageal cancer cases diagnosed in year 2015, including 104 400 males and 30 074 females, while 52 506 cases came from urban areas and the other 81 968 cases were from rural areas. CONCLUSION: The esophageal cancer incidence showed a downtrend, especially among urban females. By year 2015, the threat of esophageal cancer will be alleviated. PMID- 22943913 TI - [Analysis and prediction of colorectal cancer incidence trend in China]. AB - OBJECTIVE: Based on the data from National Cancer Registry between 1998 and 2007, to analyze the colorectal cancer incidence trend in China, and further to predict its incidence between 2008 and 2015. METHODS: We picked up the incidence data of 111 281 cases of colorectal cancer in total from National Central Cancer Registry Database between 1998 and 2007, covering 446 734 668 person-year. The annual incidence rate of colorectal cancer both by area and gender were calculated; while the age standardized rate (ASR) was standardized by world's population age structure. The incidence trend was analyzed and the annual percentage change (APC) was calculated by JoinPoint software. Age-Period-Cohort Bayesian Model was applied to fit the colorectal cancer incidence trend in China between 1998 and 2007; and further to predict its incidence between 2008 and 2015. RESULTS: From 1998 to 2007, the colorectal cancer registered incidence was 24.91/100 000 (111 281/446 734 668), with the ASR at 17.67/100 000. The incidence in male population was 26.50/100 000 (60 015/226 508 545), with ASR at 19.90/100 000; and the incidence in female was 23.28/100 000 (51 266/220 226 123), with ASR at 15.73/100 000. In urban area, the male incidence rose from 23.29/100 000 (2617/11 237 967) in 1998 to 37.84/100 000 (8534/22 551 353) in 2007; while the female incidence increased from 21.75/100 000 (2357/10 838 355) to 31.34/100 000 (6913/22 057 787). And in rural areas, the male and female incidences rose from 10.36/100 000 (448/4 323 628) and 8.86/100 000 (372/4 197 806) in 1998 to 16.80/100 000 (1290/7 677 484) and 13.00/100 000 (978/7 522 690) in 2007 respectively. In this decade, the colorectal cancer incidence has increased both in urban and rural areas. In urban area, the male APC value was 5.5% and the female APC value was 4.0%; while in rural area, the male and female APC values were 6.0% and 4.3% respectively. After adjusted by age structure, the uptrend became gently; with the urban male and urban female APC values separately increased by 3.7%, 2.5% and 2.3%. The rural male APC value rocketed up by 8.4% after its inflection point in 2004. The Bayesian model predicted that the male and female colorectal cancer incidences would separately reach 33.92/100 000 (125 thousand cases) and 27.13/100 000 (93 thousand cases) in urban areas; and 13.61/100 000 (48 thousand cases) and 13.68/100 000 (45 thousand cases) in rural areas by year 2015. CONCLUSION: The colorectal cancer incidence in China has been increasing annually; and it will continue to rise in the next years. PMID- 22943914 TI - [The analysis of the active follow-up study of registered cancer patients between 2002 and 2005 in urban areas of Beijing]. AB - OBJECTIVE: To evaluate the results of the active follow-up among registered cancer patients in 2002 - 2005 in urban areas of Beijing. METHODS: A number of 63 997 cancer patients diagnosed during 2002 - 2005 were selected from the surveillance database of Beijing Office for Cancer Prevention and Control. By matching the identity information of the patients with the death surveillance database built by the vital statistic department in Beijing, 29 223 patients were confirmed to be alive.1149 cases were removed from the study due to lack of exact key variables, such as address and telephone numbers. 28 074 patients were, at last, included in the active follow-up study. The investigators and the inspectors, who accepted standard training program, investigated each patient's status of census register and survival condition by phone calling, household interview and visits at local police station or residential committee. The loss ratio of follow-up and the constituent ratio of the withdrawal reasons were calculated. RESULTS: Among the 28 074 patients selected in active follow-up, 21 696 patients were followed successfully; 1453 of whom didn't have the census register of Beijing, which accounted for 6.70%. Out of the other 20 243 Beijing residents, 4715 patients (23.29%) were already dead and 84.22% (3971/4715) of them replenished the failure to report by passive follow-up. Among all the 4715 dead cases, 4405 (93.43%) patients were died from cancer. The follow-up study helped to replenish the vital statistics in different districts, the ratio ranged from 4.87% and 8.85%. 6378 patients were withdrawn from the study. The loss ratio was 22.72% (6378/28 074), and the total loss ratio was 12.03% ((6378 + 1149)/(63 997 - 1453)). Of these withdrawal cases, 3041 (47.68%) were lost to follow-up in that the investigators can't find the patients or the relatives of the patients according to the registered phone number or address information. The other reasons included: the patients removed to other areas (1199 cases, 18.80%), the patients and their family members were temporarily not at home (127 cases, 1.99%), the patients and their family members rejected to answer the interview (292 cases, 4.58%), and other reasons (1719 cases, 26.95%). CONCLUSION: The method of active follow-up towards registered cancer patients can replenish the missing information which could not be collected from passive follow-up procedure; and therefore effectively improve the quality of data in cancer registration. PMID- 22943915 TI - [The levels and distribution of the serum lipids in Chinese adults, 2010]. AB - OBJECTIVE: To study the levels of blood lipid among Chinese adults in 2010 and analyze the epidemiological features. METHODS: Fasting serum levels of total cholesterol (TC), triglyceride (TG), high density lipoprotein-cholesterol (HDL-C) and low density lipoprotein-cholesterol (LDL-C) were determined for 90 395 subjects aged 18 and over who were selected by multi stage cluster random sampling method from 162 surveillance sites of 31 provinces of China mainland in 2010. After complex weighting, the differences of levels of serum total TC, TG, HDL-C and LDL-C were analyzed in different age, gender and geographic regions. RESULTS: After complex weighting, the levels of serum TC in Chinese adults was (4.04 +/- 1.08) mmol/L, with (3.86 +/- 1.03), (4.29 +/- 1.11) and (4.33 +/- 1.09) mmol/L in the groups of 18 - 44, 45 - 59 and over 60 years old (F = 177.56, P < 0.01), respectively. The level of serum TC was (4.06 +/- 1.09) mmol/L and (4.03 +/- 1.07) mmol/L in males and females (F = 2.38, P > 0.05), respectively; (4.08 +/- 1.13) mmol/L and (4.03 +/- 1.06) mmol/L in urban and rural areas (F = 0.51, P > 0.05), respectively, and (4.13 +/- 1.11), (4.03 +/- 1.01) and (3.93 +/- 1.11) mmol/L in areas of east, middle and west respectively (F = 2.56, P > 0.05). The levels of serum TG was (1.33 +/- 1.28) mmol/L, with(1.26 +/- 1.24), (1.48 +/- 1.46) and (1.35 +/- 1.05) mmol/L in the groups of 18 - 44, 45 - 59 and over 60 years old (F = 85.98, P < 0.01), respectively. The level of serum TG was (1.45 +/ 1.48) mmol/L and (1.21 +/- 1.01) mmol/L in males and females (F = 172.01, P < 0.01), respectively, (1.34 +/- 1.26) mmol/L and (1.33 +/- 1.28) mmol/L in urban and rural areas (F = 0.16, P > 0.05), respectively, and(1.30 +/- 1.25), (1.35 +/- 1.23) and (1.35 +/- 1.36) mmol/L in areas of east, middle and west (F = 0.69, P > 0.05) respectively. The levels of serum HDL-C was (1.11 +/- 0.31) mmol/L, with (1.09 +/- 0.30), (1.13 +/- 0.33) and (1.14 +/- 0.33) mmol/L in the groups of 18 - 44, 45 - 59 and over 60 years old (F = 27.81, P < 0.01), respectively. The level of serum HDL-C was (1.08 +/- 0.32) mmol/L and (1.14 +/- 0.30) mmol/L in males and females (F = 178.66, P < 0.01), respectively, (1.11 +/- 0.31) mmol/L and (1.11 +/ 0.32) mmol/L in urban and rural areas (F = 0.09, P > 0.05), respectively, and (1.12 +/- 0.32), (1.12 +/- 0.31) and (1.09 +/- 0.32) mmol/L in areas of east, middle and west (F = 1.06, P > 0.05) respectively. The levels of serum LDL-C was (2.27 +/- 0.78) mmol/L, with (2.15 +/- 0.74), (2.42 +/- 0.80) and (2.46 +/- 0.81) mmol/L in the groups of 18 - 44, 45 - 59 and over 60 years old (F = 129.84, P < 0.01), respectively. The level of serum LDL-C was (2.30 +/- 0.78) mmol/L and (2.24 +/- 0.78) mmol/L in males and females (F = 25.06, P < 0.01), respectively, (2.33 +/- 0.82) mmol/L and (2.24 +/- 0.76) mmol/L in urban and rural areas (F = 3.48, P > 0.05), respectively, and (2.35 +/- 0.80), (2.25 +/- 0.74) and (2.17 +/- 0.77) mmol/L in areas of east, middle and west (F = 4.58, P < 0.05) respectively. CONCLUSION: The levels of serum lipid of middle aged male, female after menopause and people living in eastern region were higher than other Chinese adults. Effective measures should be taken earlier to control serum lipid levels. PMID- 22943916 TI - [Investigation on the perception of risk level of heat wave and its related factors in Guangdong province]. AB - OBJECTIVE: To investigate the risk perception of heat wave, and further explore its related factors in Guangdong province. METHODS: A total of 2183 adults were selected by a multi-stage sampling method in Guangdong province. Each subject was interviewed in their home with a structured questionnaire by a well trained investigator from September to November, 2010. The questionnaire contained socio demographic characteristics, heat wave related knowledge, risk perception of heat wave, etc. Chi-square test and multivariate logistic regression were employed in this study. RESULTS: The average age of total 2183 participants was (39.31 +/- 14.16) years, among which 53.37% (1165/2183) were males, and 48.74% (1064/2183) were selected from urban. About 38.11% (832/2183) of participants heard about heat wave, and 38.52% (841/2183) of subjects thought the heat wave had higher impact on their health (risk perception score of heat wave >= 5 points). About 81.91% (1788/2183) of all participants thought the weather in most recent years was hotter than several years ago. Among these people, 30.48% (545/1788) thought the main reason of weather becoming hotter was due to emission of carbon dioxide, and 26.51% (474/1788) thought it was due to air pollution. Results from the multivariate logistic regression showed that the risk perception score of heat wave were higher in subjects with higher education (OR = 2.16, 95%CI: 1.41 - 3.30), from urban(OR = 1.37, 95%CI: 1.10 - 1.72), with higher score of trust(OR = 1.08, 95%CI: 1.01 - 1.14) and participants with higher score of heat wave related knowledge (OR = 1.39, 95%CI: 1.27 - 1.52). Furthermore, compared to hierarchist, egalitarian (OR = 1.73, 95%CI: 1.30 - 2.29), individualist (OR = 1.93, 95%CI: 1.41 - 2.65) and fatalist (OR = 1.80, 95%CI: 1.41 - 2.29) also had higher risk perception score of heat wave. CONCLUSION: There is a lack of knowledge and risk perception to heat wave among the residents in Guangdong province. Risk perception of heat wave was higher in people who were from urban, had higher level of trust on government, experts and media, had higher health-related knowledge score, and non-hierarchists. PMID- 22943917 TI - [The epidemiological characteristics and correlated factors of daily hassles for thermal power plant workers]. AB - OBJECTIVE: This study aimed to investigate the epidemiological characteristics and correlated factors of daily hassles among thermal power plant workers. METHODS: A mass screening of daily hassles and correlated factors was conducted on 498 workers from a thermal power plant in Zhengzhou in July, 2008. The questionnaires included Daily Hassles Questionnaires, Work Roles Questionnaires, Job Content Questionnaires (Chinese version), Effort-Reward Imbalance (Chinese version), Work Locus of Control Scale and Type A Behavior Scale, with content covering demographic characters and occupational stress correlated factors among subjects. The daily hassles was divided into lower level and higher level according to scores, and the epidemiological characteristics and correlated factors of daily hassles were analyzed. RESULTS: A total of 446 qualified questionnaires were obtained, effective response rate was 89.6% (446/498). For respondents, the age was (36.96 +/- 6.49) years old, working length of the current job was (12.05 +/- 7.54) years, the daily hassles scores was (9.01 +/- 2.50), and the prevalence rate of the higher level of daily hassles was 34.1% (152/446). The multiple non-conditional logistic regression analysis showed 5-14 years' working length of current job (OR = 0.451, 95%CI: 0.225 - 0.904), average income > 3000 yuan(OR = 0.372, 95%CI: 0.202 - 0.684), reward (OR = 0.557, 95%CI: 0.325 - 0.954) and coping strategy (OR = 0.552, 95%CI: 0.330 - 0.925) were negatively correlated with daily hassles, and shift-work (OR = 1.887, 95%CI: 1.108 - 3.215), effort (OR = 2.053, 95%CI: 1.198 - 3.519), psychological demand (OR = 1.797, 95%CI: 1.049 - 3.078), negative affectivity (OR = 3.421, 95%CI: 2.065 - 5.668) were positively correlated with daily hassles. CONCLUSION: The prevalence rate of the higher level of daily hassles was considerable high for thermal power plant workers. Its negative correlated factors included 5 - 14 years' working length of the current job, average income > 3000 yuan, reward and coping strategy and its positive corelated factors included shift-work, effort, psychological demand and negative affectivity. PMID- 22943918 TI - [Prevalence of hepatitis B in Chaoyang district, Beijing in 2010]. AB - OBJECTIVE: To study the prevalence of hepatitis B infections and carrier status among general population in Chaoyang district, Beijing in 2010. METHODS: From May to December 2010, 14 491 subjects over 12 months old were selected by multistage random cluster sampling method from residents in Chaoyang district, Beijing. Five millilitre venous blood specimens were collected from these subjects to test hepatitis B virus antigens and antibodies. Status of hepatitis B infections were analyzed in different age, sex and registered permanent residence groups. RESULTS: The overall positive rate of surface antigen (HBsAg) was 2.66% (383/14 410). The lowest rate of 0.56% (9/1603) was found in the 1 to 14 years old group and the 35 to 44 years old group had the highest rate of 4.27% (92/2154). The rate in subjects younger than 24 years old was 1.03% (31/2986). The overall positive rate of surface antibody (anti-HBs) was 40.21% (5798/14 421). The highest positive rate of anti-HBs (80.59%, 407/505) was found in the 1 to 4 years old group. The overall positive rate of core antibody (anti-HBc) was 30.26% (4364/14 424). The overall hepatitis B virus infection rate was 30.32% (4364/14 393). For male and female groups, the positive rates of HBsAg were 2.93% (179/6108) and 2.44% (202/8287) respectively (chi2 = 3.32, P > 0.05); anti-HBs were 41.93% (2563/6113) and 38.96% (3231/8293) respectively (chi2 = 12.88, P < 0.01); and anti-HBc were 31.39% (1919/6114) and 29.39% (2438/8295) respectively (chi2 = 6.65, P = 0.01). For local residents group and mobile population group, the positive rates of HBsAg were 2.46% (283/11 510) and 3.60% (98/2719) respectively (chi2 = 11.08, P < 0.01); anti-HBs were 37.11% (4293/11 568) and 53.07% (1445/2723) respectively (chi2 = 233.51, P < 0.01); and anti-HBc were 30.83% (3567/11 570), and 28.41% (774/2724) respectively (chi2 = 6.08, P < 0.05). CONCLUSION: The positive rate of HBsAg in population younger than 24 years old has reached a relatively low level. The mobile population has significantly higher positive rate of HBsAg than local residents, indicating the need for enhancing prevention and control measures for hepatitis B for the mobile population and local residents over 25 years old. PMID- 22943919 TI - [The sexual behavior characteristics and STD infection status of women who have sex with women in Beijing]. AB - OBJECTIVE: To study sexual behavioral characteristics, infection status of HIV and sexually transmitted infections (STDs) among women who have sex with women (WSW) in Beijing. METHODS: A total of 150 WSWs were recruited by snowball sampling in several main types of activity sites of WSW (including NGOs, salons, bars, etc.) in Beijing during September 2010 to April 2011. Information on demographic factors, sexual behavioral characteristics, infection status of STDs, and use of medical care were collected by questionnaire investigation. Serum samples, vaginal and cervical swabs were taken for each subject to test HIV, hepatitis B (HBV), hepatitis C (HCV), syphilis, herpes simplex virus (HSV), neisseria gonorrhoeae, chlamydia trachoma, bacterial vaginosis, trichomonas vaginalis and mycotic vaginitis. RESULTS: The age range of the subjects was from 19 to 46 years old. Approximately 82.67% (124/150) of them aged 20 to 29 years old, and 54.00% (81/150) were unmarried. Approximately 76.67% (115/150) had an education level of college degree or above, and 70.67% (106/150) were migrants. Approximately 66.66% (100/150) of the subjects considered themselves as homosexual, 28.00% (42/150) as bisexual. The age at first homosexual sex ranged from 11 to 30 years old. The median of number of female sex partners in last 1 year was 1, and 33.78% (50/148) of the subjects had 2 or more female sex partners. Approximately 20.27% (30/148) of the subjects applied sex instruments, of which 66.67% (20/30) never or seldom used condoms. Hand-clitoris and hand vagina contacts were the main types of woman-to-woman sex, accounting for 91.22% (135/148). 12.00% (18/150) of the subjects had sex with men during last year. Among them, 50.00% (9/18) used condoms at last heterosexual sex, and 66.67% (12/18) never or seldom used condoms at last heterosexual sex in past 1 year. One subject provided paid sex service for men, and used condoms every time. In the past one year, 45.33% (68/150) of the subjects had symptoms of STDs, but only 36.76% (25/68) of them sought medical care. The infection rate of STDs was 34.67% (52/150). The infection rates of NG and GV were both 16.11% (24/149), and those of mycotic vaginitis, chlamydia trachoma, and TV were 8.72% (13/149), 4.03% (6/149), and 0.67% (1/150), respectively. The numbers of subjects tested positive for HBV, HCV, and syphilis were all 1. No subjects were found HIV positive or HSV 2 positive. CONCLUSION: Multiple sexual partners and heterosexual sex behavior were common among WSW in Beijing. More than 1/3 of the subjects were infected with STD. PMID- 22943920 TI - [Epidemiological studies on close contacts of smear-positive tuberculosis patients in Shijiazhuang city from 2007 to 2008]. AB - OBJECTIVE: To analyze the incidence of tuberculosis (TB) in people who were in close contact with smear-positive TB patients. METHODS: A total of 19 159 subjects, including 17 334 family members and 1825 classmates of patients, in close contact with 6653 smear-positive TB patients in Shijiazhuang city from 2007 to 2008 were observed. All the classmates were tested by purified protein derivative (PPD) test and symptom screening, and all family members were screened by symptoms. All these subjects were trained with knowledge related to TB. The ones with positive PPD test and suspected TB symptoms were further examined by chest X-ray and sputum smear microscopy, and those without any symptom were followed up monthly throughout a two year period and were examined at any time if symptoms occurred. RESULTS: A total of 281 patients with pulmonary TB were diagnosed in 2 years, including 176 family members and 105 classmates in all close contacts. The smear-positive incidences were 1466.67/100 000. The incidences for 14 - 25 years old group and more than 75 years old group were 2907.18/100 000 (83/2855) and 2650.96/100 000 (18/679), which were higher than those for other groups. Two higher incidences were related to close contact time periods of 6 months (929.07/100 000, 178/19 159) and 13 - 18 months (369.12/100 000, 70/18 964). Three highest incidences were observed in the roommates (11 384.62/100 000, 37/325), classmates (4533.33/100 000, 68/1500) and couples (1624.17/100 000, 86/5295). CONCLUSION: Closer contact with smear-positive patients with TB may result in the higher chance of TB. Close contact for 6 months or 13 to 18 months caused more patients, and the 14 - 25 years old group and more than 75 years old group had higher incidences of TB. PMID- 22943921 TI - [Effects of theanine on monoamine neurotransmitters and related genes in cerebral ischemia-reperfusion injury rats]. AB - OBJECTIVE: To study the effects of theanine on dopamine (DA), 5-hydroxy tryptamine (5-TH) and glutamate receptor 2 (GluR2) mRNA, phospholipase-gamma1 (PLC-gamma1) mRNA in cerebral ischemia-reperfusion injury rats and explore the mechanism of protective effects of theanine on the induced brain injury by ischemia-reperfusion in rats. METHODS: According to random number table, a total of 56 sprague-dawley rats in SPF grade about six-week old and 100 - 120 grams weighting were divided into five groups according to the body weight levels: model group (n = 12), sham-operation group (n = 8), low theanine group (10 mg/kg), middle theanine group (30 mg/kg) and high theanine group (90 mg/kg). There were 12 rats in each of the theanine group. The rats in model group and sham-operation groups were given distilled water, and the rats in theanine groups were given corresponding theanine solution intragastrically for fifteen days. Then the cerebral ischemia-reperfusion injury was established by middle cerebral artery occlusion (MCAO). The score of neurological behavior was evaluated at the 3rd and 24th hours after reperfusion. Rats were sacrificed at 24 hours after reperfusion, the concentrations of DA, 5-HT and theanine in rats brain following ischemia-reperfusion were determined. At the same time, we determined the levels of reactive oxygen species (ROS) and activities of catalase (CAT) in mitochondria of brain. The expressions of GluR2 mRNA and PLC-gamma1 mRNA in rat brain were examined by reverse transcription polymerase chain reaction (RT-PCR) technique. RESULTS: The score of neurological behavior of rats in model group, theanine-low, middle, high dose groups at the 3rd hour was 6.000 +/- 0.926, 4.100 +/- 0.738, 3.444 +/- 0.726 and 2.250 +/- 0.886 respectively (F = 29.70, P < 0.01), and the score at the 24th hour in these groups was 6.625 +/- 0.916, 5.000 +/- 0.817, 3.667 +/- 0.707 and 2.625 +/- 0.916 respectively(F = 34.68, P < 0.01). The concentration of DA in model group, theanine-low, middle, high dose groups and sham-operation group was (10.26 +/- 1.12), (12.48 +/- 1.09), (14.55 +/- 0.94), (15.97 +/- 0.92) and (11.98 +/- 0.63) ug/g respectively (F = 43.76, P < 0.01). The concentration of 5-HT in these groups was (1.091 +/- 0.160), (0.818 +/- 0.101), (0.571 +/- 0.050), (0.453 +/- 0.111) and (0.863 +/- 0.063) ug/g respectively (F = 48.68, P < 0.01). The level of ROS was (3.072 +/- 0.503), (1.331 +/- 0.268), (1.295 +/- 0.061), (0.804 +/- 0.200) and (2.158 +/- 0.218) U*min-1*mg-1 (F = 80.82, P < 0.01) respectively and the activities of CAT in these groups were (4.880 +/- 1.121), (8.405 +/- 1.356), (9.535 +/- 2.511), (15.090 +/- 4.054) and (21.260 +/- 6.054) U/g respectively (F = 28.58, P < 0.01). The expressions of GluR2 mRNA were 0.842 +/- 0.020, 1.063 +/- 0.100, 1.170 +/- 0.152, 1.254 +/- 0.131 and 1.012 +/- 0.056 respectively (F = 9.23, P < 0.01). The expressions of PLC-gamma1 mRNA in these groups were 0.737 +/- 0.090, 0.887 +/- 0.045, 0.963 +/- 0.025, 0.991 +/- 0.049 and 0.867 +/- 0.079 respectively(F = 10.24, P < 0.01). CONCLUSION: Theanine has a protective effect on the induced brain injury by ischemia-reperfusion in rats, which might be associated with its interaction with monoamine neurotransmitters and up-regulating the expressions of GluR2 mRNA and PLC-gamma1 mRNA. PMID- 22943922 TI - [Impact of specimen collection and storage consumable products on trace element quantitative analysis]. AB - OBJECTIVE: This study aimed to explore the impact of specimen collection and storage consumable products on trace element quantitative analysis. METHODS: Devices and consumable products of different brands used in specimen collection or storage were selected and treated separately as below:urine collection and storage tubes (Brand A, B, C and D, 2 samples for each brand) were treated with 1% of HNO(3) volume fraction for 2 - 4 h; blood taking device (Brand O, P and Q, 3 samples for each brand) were used for ultra-pure water samples collecting as simulation of blood sampling;dust sampling filters (Brand X, Y and Z, 2 samples for each brand) were cold digested by nitric acid for 12 h, followed by microwave digestion. Then cadmium, cobalt, chromium, copper, iron, manganese, molybdenum, nickel, lead, selenium, stannum, titanium, vanadium and zinc concentrations in the solutions obtained during the course of collect or storage were quantified by inductively coupled plasma mass spectrometer. RESULTS: For the urine collection and storage consumable products, background values of elements were described as mean of parellel samples. The consentration of 14 quantified elements were relatively low for 5 ml cryogenic vials (brand B) with background values range of 0.001 - 0.350 ng/ml. The background values of copper of 50 ml centrifuge tubes (brand A), chromium of 5 ml cryogenic vials (brand C) and zinc of 1.5 ml centrifuge tubes (brand D) were relatively high, which were 1.900, 1.095 and 1.368 ng/ml, respectively. Background values of elements in blood sampling devices were described as x(-) +/- s. Background values of chromium for brand O, P and Q were (0.120 +/- 0.017), (0.337 +/- 0.093) and (0.360 +/- 0.035) ng/ml; for copper were (0.050 +/- 0.001), (0.017 +/- 0.012) and (0.103 +/- 0.015) ng/ml; for lead were (0.057 +/- 0.072), (0.183 +/- 0.118) and (0.347 +/- 0.006) ng/ml; for titanium were (7.883 +/- 0.145), (8.863 +/- 0.190) and (8.613 +/- 0.274) ng/ml; zinc were (2.240 +/- 0.573), (42.140 +/- 22.756) and (8.850 +/- 3.670) ng/ml. There were statistically differences of background values for chromium, copper, lead, titanium and zinc among the above three brands of blood sampling devices (all P values < 0.05). For air sampling filters, background values of elements were described as mean of parellel samples. Background values of chromium and nickel of sampling filters (brand X) were lowest, which were 17.000 and 15.400 ng per piece, respectively; while background values for other elements were relatively high, the quantification of cadmium, cobalt, copper, iron, manganese, molybdenum, lead, selenium, stannum, titanium, vanadium and zinc were 0.250, 0.550, 48.500, 690.000, 25.500, 0.900, 6.500, 10.550, 7.950, 10.500, 0.850, 370.000 ng per piece, respectively. Background values of chromium and nickel of sampling filters (brand Z) were highest, which were 171.000 and 29.850 ng per piece. CONCLUSION: Background values of trace elements varied among products of different brands, and the most noticable differences were found in chromium, manganese, nickel, lead, stannum and zinc. PMID- 22943923 TI - [The establishment and application of the method with virus concentration and detection in drinking water]. AB - OBJECTIVE: This study aimed to construct an effective method to concentrate and detect virus in drinking water, and human adenovirus pollution status in actual water samples was monitored by constructed method. METHODS: The concentration efficient of NanoCeram filter for the first concentration with source water and drinking water and the concentration efficient of the different concentrations of PEG 8000 for the second concentration were assessed by spiking f2 bacteriophage into water samples. The standard of human adenovirus for real-time PCR was constructed by T-A clone. The plasmid obtained was identified through sequence analyzing and consistency check comparing to target gene fragment was conducted by using blast algorithm. Then, real-time PCR was constructed to quantify the concentration of human adenovirus using the plasmid as standard. Water samples were concentrated by using NanoCeram filter on the spot and then concentrated for the second time by PEG/NaCl in 2011. The DNA of concentrated samples were extracted for the quantification of human adenovirus in real-time PCR subsequently to monitor the pollution of human adenovirus in water. RESULTS: For the first concentration by NanoCeram filter, the recovery rates were (51.63 +/- 26.60)% in source water and (50.27 +/- 14.35)% in treated water, respectively. For the second concentration, the highest recovery rate was reached to (90.09 +/- 10.50)% at the concentration of 0.13 kg/L of PEG 8000. The sequence identity score of standard of adenovirus for real time PCR and adenovirus gene was 99%, implying that it can be successfully used to quantification with human adenovirus. The levels of human adenovirus in the water samples sampled in 2011 ranged from 4.13*103 to 2.20*106 copies/L in source water, while range from 5.57*102 to 7.52*105 copies/L in treated water and the removal efficiency range was (75.49 +/- 11.71)%. CONCLUSION: NanoCeram filers combined with PEG/NaCl was an effective method to concentrate virus in aquatic environment. There was a large number of human adenovirus in source water, and it is not sufficient to remove them thoroughly through conventional water treatment processes. PMID- 22943924 TI - Pharmacokinetics and tolerability of anagrelide hydrochloride in young (18 - 50 years) and elderly (>= 65 years) patients with essential thrombocythemia. AB - OBJECTIVE: To ascertain the role of patient age as an influencing factor in the pharmacokinetics of anagrelide and to clarify whether different dosing is required in young (18 - 50 years) vs. elderly (>= 65 years) patients with essential thrombocythemia (ET). METHOD: This Phase II, multicenter, open-label study compared the pharmacokinetics, pharmacodynamics and tolerability of anagrelide and its active metabolite, 3-hydroxy-anagrelide, in young and elderly patients with ET. Three days prior to pharmacokinetic assessment, patients divided their normal daily anagrelide into a structured twice-daily dosing (BID) schedule. Serial blood samples were obtained for pharmacokinetic and pharmacodynamic analysis over a 12-h dosing interval. Anagrelide and 3-hydroxy anagrelide plasma concentrations were normalized to a common dose (1 mg BID) to control for dosing differences between patients. Patients were monitored routinely for adverse events (AEs) and vital signs. RESULTS: A total of 24 patients (12 young; 12 elderly) completed the study. The dose-normalized anagrelide maximum observed plasma concentration (Cmax) and area under the plasma concentration vs. time curve over one dosing interval (AUCtau), were higher in elderly patients compared with young patients (Cmax: 3.63 vs. 2.66 ng/ml; p = 0.09, AUCtau: 10.3 vs. 6.4 ng*h/ml; p = 0.01). In contrast, the dose-normalized 3 hydroxy-anagrelide Cmax and AUCtau were lower in the elderly patients when compared with young patients (Cmax: 4.19 vs. 7.26 ng/ml; p = 0.02, AUCtau: 17.4 vs. 27.6 ng*h/ml; p = 0.03). No significant difference was observed in the geometric mean terminal half-life (t1/2) of anagrelide in elderly and young patients (1.4 vs. 1.3 h, respectively; p = 0.38), whereas the geometric mean t1/2 of 3-hydroxy-anagrelide was significantly longer in the elderly patients compared with the young patients (3.5 vs. 2.7 h, respectively; p = 0.01). There were no significant differences in platelet count or vital signs between the age groups. Anagrelide was well tolerated; there were no serious AEs or AEs that led to withdrawal from the study. CONCLUSIONS: To conclude, the differences observed in anagrelide and 3-hydroxy-anagrelide pharmacokinetics do not justify using a different dosing regimen in young vs. elderly patients with ET. PMID- 22943925 TI - Prediction of distribution volume of vancomycin in critically ill patients using extravascular lung water and pulmonary vascular permeability indices. AB - OBJECTIVE: Alterations in distribution volume affect the concentrations of hydrophilic drugs in plasma and tissues at the time of initial therapy. When the distribution volume of hydrophilic antimicrobials is increased in critically ill patients with a serious infection, antimicrobial concentrations are reduced, which may adversely affect the efficacy of antimicrobial therapy. A transpulmonary thermodilution technique system (PiCCO) enables measurements of pulmonary vascular permeability index (PVPI) and extravascular lung water index (EVLWI), which are related to pulmonary edema and pulmonary vascular permeability, respectively. In addition, those indices may also be related to the distribution volume of hydrophilic antimicrobials. The aim of this study was to investigate the relationships of PVPI and EVLWI with the distribution volume of vancomycin (Vss), as well as to establish a method for estimating Vss for planning an appropriate initial dose for individual patients. METHODS: Seven patients were administered vancomycin intravenously and underwent extended hemodynamic monitoring with the PiCCO system in the intensive care unit (ICU) from April 2009 to March 2011. Vss was calculated using the Bayesian method, and the relationships of PVPI and EVLWI with Vss were investigated. RESULTS: The relationship between Vss/actual body weight (ABW) and median EVLWI on days when blood levels were measured was significant (r = 0.900, p = 0.0057), whereas the relationship between Vss/ABW and PVPI was not significant (r = 0.649, p = 0.1112). CONCLUSION: EVLWI determined by the PiCCO system is useful to predict Vss and should lead to more effective vancomycin therapy for critically ill patients at the initial stage. PMID- 22943926 TI - Single-dose and multi-dose delivery systems for intranasal fentanyl spray are bioequivalent as demonstrated in a replicate pharmacokinetic study. AB - BACKGROUND: Intranasal fentanyl spray (INFS, Instanyl(r)) was developed to treat cancer patients with Breakthrough Pain (BTP). INFS is delivered via a multi-dose delivery system (MDS) that is available in various dose strengths. The aim of this study was to demonstrate the pharmacokinetic bioequivalence of INFS single dose delivery system (SDS) in relation to the currently marketed MDS device. METHODS: In a randomized, single-center, single-dose, open label, comparative, four-period, two-sequence, replicate cross-over study, 48 healthy subjects (24 male and 24 female, mean age of 28.1 years, mean bodyweight 69.8 kg) received 200 MUg/100 MUl fentanyl administered via SDS and via MDS in one of two alternating treatment sequences. Naltrexone was given to all subjects to prevent potential fentanyl adverse drug reactions. Blood samples were frequently taken up to 72 hours post INFS administration and analyzed by liquid chromatography with tandem mass spectrometric detection. Primary pharmacokinetic parameters were area under the curve extrapolated to infinity (AUC0-infinity) and peak plasma concentration (Cmax). Statistical analyses of the primary pharmacokinetic parameters were performed using a linear mixed effect model applied to the natural log transformed data. RESULTS: Healthy subjects showed very similar plasma concentration over time profiles for both delivery systems. The mean fentanyl Cmax and AUC0-infinity values for SDS and MDS were 948 pg/ml, 949 pg/ml and 4,439 pg*h/ml, 4,489 pg*h/ml. respectively. Point estimates (and 90% confidence intervals) for AUC and Cmax were 0.97 (0.93 - 1.02) and 1.00 (0.92 - 1.09) and therefore in the bioequivalence range of 0.80 - 1.25. CONCLUSIONS: Results of this study show that SDS and MDS met the pre-defined regulatory criteria for bioequivalence. Safety profiles were consistent between both devices and no safety concerns were identified with INFS administered in combination with oral naltrexone. PMID- 22943927 TI - Effects of 90-day hypolipidemic treatment on insulin resistance, adipokines and proinflammatory cytokines in patients with mixed hyperlipidemia and impaired fasting glucose. AB - OBJECTIVE: Concerns regarding worsening insulin sensitivity associated with statin treatment have recently emerged. Therefore the aim of this study was to assess and compare the effects of 90-day monotherapies with fenofibrate and atorvastatin, as well as combined therapy, on fasting plasma glucose, insulin resistance index, adipokines (leptin, resistin, adiponectin) and levels of proinflammatory cytokines (TNF-alpha, IL-6) in patients with impaired fasting glucose (IFG) and mixed hyperlipidemia. MATERIALS AND METHODS: 67 patients were randomly assigned to four treatment arms: monotherapy with atorvastatin, monotherapy with fenofibrate, combined therapy (fenofibrate and torvastatin) or therapeutic lifestyle change. The study lasted for 90 days. All participants received counseling regarding proper diet and physical activity. RESULTS: Compared to the control subjects, prediabetic patients exhibited elevated plasma levels of leptin, resistin, TNF-alpha and IL-6, and a lower plasma level of adiponectin. All therapeutic interventions resulted in significant alterations in the lipid profile. Insulin resistance index (HOMA-IR) was reduced after treatment with fenofibrate. The effect of atorvastatin on insulin resistance was comparable to therapeutic lifestyle change alone. Therapy with hypolipidemic drugs caused increases in adiponectin levels and decreases in leptin and resistin. An additive effect of the combined treatment on plasma IL-6 level was also observed. CONCLUSIONS: Fenofibrate-based treatment was associated with improved insulin sensitivity. Atorvastatin did not cause a deterioration in insulin sensitivity. Hypolipidemic therapies resulted in significant changes in the proinflammatory cytokine network as well as in adipokine levels. At the end of the study the measured parameters nearly resembled those of the healthy subjects. PMID- 22943928 TI - Drug interactions between micafungin at high doses and cyclosporine A in febrile neutropenia patients after allogeneic hematopoietic stem cell transplantation. AB - OBJECTIVES: The aim of this study was to assess the drug interaction between high doses of micafungin and cyclosporine A (CyA) in allo-HSCT patients. METHODS: We assigned 15 patients to Groups 1, 2, or 3. We investigated the serial changes in the blood concentration/dose (C/dose) of intravenous CyA during micafungin coadministration in 5 patients during the switch from the prophylactic dose (150 mg/body) to the therapeutic dose (300 mg/body) of micafungin (Group 1), and compared each of the 5 patients in Group 1 with those who continued to receive the prophylactic doses of 150 mg or 50 mg/body of micafungin (Groups 2 and 3). We collected blood samples from patients in Group 1 receiving CyA at 0 h (C0) and (C3) 3 h on the 7th day after allo-HSCT, and on the 3rd and 10th days after escalation of the dose of micafungin to 300 mg. RESULTS: In Group 1, no significant difference was observed between C0/dose (2.11 +/- 0.14) and C3/dose ratios of CyA (11.1 +/- 5.34, p > 0.05) under 150 mg; the C0/dose and C3/dose ratios of CyA were 2.40 +/- 0.60 and 10.8 +/- 4.72 on the 3rd day and 2.23 +/- 0.41 and 11.8 +/- 3.06 on the 10th day, respectively, after dose escalation of micafungin to 300 mg. No significant differences were observed in those ratios between Groups 1 and 2 and between Groups 1 and 3. CONCLUSION: Thus, high dose of micafungin seems to be safe and does not significantly interact with CyA in allo HSCT. PMID- 22943929 TI - A case of hyperprolactinemia, probably induced by eletriptan. AB - A 25-year-old woman with a severe migraine begins to use a migraine specific agent, eletriptan (40 mg/d). One month later, she had oligomenorrhea and galactorrhea. We ruled out all causes of hyperprolactinemia. To our knowledge, this is the first published postmarketing case report of eletriptan- induced hyperprolactinemia, presented as oligomenorrhea and galactorrhea in a patient. The Naranjo probability scale indicates a probable relationship between hyperprolactinemia and eletriptan therapy. PMID- 22943930 TI - Efficacy and tolerability of diphenyl-dimethyl-dicarboxylate plus garlic oil in patients with chronic hepatitis. AB - OBJECTIVE: To investigate the hepatoprotective effect, safety and tolerability of oral preparation comprising dimethyl-4,4'-dimethoxy-5,6,5',6'-dimethylene dioxybiphenyl-2,2'-dicarboxylate (DDB) plus garlic oil (GO) in chronic hepatitis patients. METHODS: In this double-blind, placebo-controlled clinical trial conducted for 6 weeks with 1-week follow-up, a total of 88 patients with histologically confirmed chronic hepatitis and persistently elevated levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were enrolled and randomly assigned to one of 4 treatment groups: placebo (Group A) and 3 escalating dose groups (2, 3, or 6 study drug capsules a day) (Groups B - D). Each study drug capsule contains 25 mg DDB plus 50 mg GO. Efficacy was assessed by monitoring changes in the circulating activities of ALT and AST as surrogate markers for liver injury. Safety and tolerability were assessed based on the evaluation of clinically adverse events and laboratory test results. RESULTS: Of 88 patients, 83 took at least one dose of study drug and 79 completed the study without any protocol violation. The majority of patients (81/83, 98%) had been infected with HBV. The proportions of patients whose ALT levels returned to normal ranges at Week 6, a primary outcome, were significantly different among 4 groups: 16% (3/19), 41% (9/22), 52% (11/21), and 88% (15/17) in Groups A, B, C, and D, respectively (p < 0.001). The proportions were significantly higher in Groups C (p = 0.022) and D (p < 0.001) but not in Group B compared to Group A. Interestingly, the proportion of Group D was higher than that of Group C (p = 0.034), suggesting a dose-response effect of DDB plus GO on the decrease of ALT levels. The mean ALT levels started to decrease from Week 1 in patients treated with DDB plus GO, whereas no decrease was seen in placebo group. The mean AST levels had a decreasing trend in all doses of DDB plus GO groups. Notably, patients treated with 6 capsules of DDB plus GO daily exhibited the statistically significant decrease in AST levels from Week 3. However, there was no difference in the proportions of patients with the AST decrease to normal ranges after 6 week therapy among 4 groups. The effects of DDB plus GO on decreases in ALT and AST levels lasted until 1 week after completion of treatment. Additionally, the ratios of ALT to AST gradually decreased in patients treated with DDB plus GO over time, suggesting higher degrees of reduction in ALT than in AST in those groups. No clinically meaningful adverse events and laboratory abnormalities were observed during the study period. CONCLUSIONS: The 6-week treatment of DDB plus GO lowered serum aminotransferase activities in patients with chronic hepatitis induced by HBV and/or HCV and was well tolerated. For the treatment of viral hepatitis patients, the optimal dose of this preparation was 3 to 6 capsules per day. PMID- 22943931 TI - Tolerability, pharmacokinetics, and pharmacodynamics of the glucokinase activator AZD1656, after single ascending doses in healthy subjects during euglycemic clamp. AB - OBJECTIVES: AZD1656 is a novel glucokinase activator with a postulated dual mechanism of action by activating glucokinase in both the pancreas and the liver, and with the potential to deliver effective glucose-lowering in Type 2 diabetes mellitus. Here, we present the tolerability, pharmacokinetics and pharmacodynamics of AZD1656 in two single-blind, randomized, placebo-controlled studies, one with Western and the other with Japanese healthy adult male subjects. METHODS: Both studies evaluated oral single ascending doses of AZD1656 of up to 180 mg, administered during euglycemic clamp conditions to explore a wide dose range without risking hypoglycemia. Safety, pharmacokinetics and effects on serum insulin and glucose infusion rate were assessed. A population pharmacokinetics analysis was also conducted. RESULTS: AZD1656 was well tolerated in single doses up to 180 mg in both populations. AZD1656 was rapidly absorbed, and a dose-proportional increase in total exposure was observed for AZD1656 and the equipotent metabolite, AZD5658. Taking differences in body weight into account, there were no differences in pharmacokinetic parameters between Western and Japanese subjects. A dose-dependent blood glucose lowering effect was indirectly demonstrated by the increased glucose infusion rate required to maintain euglycemia, which was of similar magnitude in both populations. Dose dependent increases in insulin secretion were also observed. CONCLUSIONS: No safety concerns were raised. AZD1656 displayed uncomplicated pharmacokinetics and dose-dependent pharmacodynamics effects were observed. The results suggest no ethnic differences in AZD1656 tolerability, pharmacokinetics or pharmacodynamics. PMID- 22943932 TI - Pharmacokinetics of single and repeated oral doses prucalopride in healthy Chinese volunteers. AB - AIM: This study investigated the pharmacokinetics of prucalopride in Chinese healthy volunteers. METHODS: This single-center, open-label study was conducted in 14 healthy males and 14 healthy females, aged 18 - 45 years. Fasted subjects received a single dose of 2 mg prucalopride, and after a 7-day wash-out period, they received the same dose once-daily for 7 days at fasted condition. Serial blood samples were taken at predefined time-points to measure plasma concentrations of prucalopride during the single-dose and multi-dose period. Daily evaluations were made on defecation frequency and stool consistency. Safety assessments were performed throughout the study. RESULTS: After oral administration, prucalopride reached the peak plasma level (Cmax) of 4.92 +/- 0.78 ng/ml with a median time to Cmax (tmax) of 2 hours and resulted in an area under concentration-time curve (AUC0-infinity) of 89.3 +/- 15.82 h*ng/ml. Steady state was attained 3 days after repeated dosing, when Cmax was 8.09 +/- 1.21 ng/ml and AUC0-24h was 103.6 +/- 14.35 h*ng/ml. Pharmacokinetic profiles were similar between genders except males had a slightly lower exposure level. Marked increase of defecation frequencies and predominance of "watery" or "loose" stools were seen after a single dose. The responses during multi-dose period were less remarkable and returned to baseline in 3 days. CONCLUSION: The pharmacokinetics of prucalopride 2 mg oral dose in Chinese healthy volunteers are similar to those observed in Caucasians. Compared to females, males exhibited a slightly lower exposure of prucalopride but similar changes of bowel habits were observed in both genders suggesting the inter-gender pharmacokinetic differences are not clinically relevant. PMID- 22943933 TI - Single dose pharmacokinetics and absolute bioavailability of mirabegron, a beta3 adrenoceptor agonist for treatment of overactive bladder. AB - BACKGROUND AND OBJECTIVES: Mirabegron is a potent and selective beta3 adrenoceptor agonist in development for treatment of overactive bladder. METHODS: Mirabegron pharmacokinetics after single intravenous (i.v.) and oral doses, absolute bioavailability (F), dose proportionality, sex differences and tolerability were assessed in 2 single-dose, open-label, randomized, parallel group, cross-over studies in healthy men (exploratory Study 1, n = 12) and men and women (Study 2, n = 91). RESULTS: After oral dosing (25 - 150 mg), peak plasma concentrations were attained after ~ 4 h. Mean half-life was around 40 h for both routes of administration. Volume of distribution at steady state was 1,670 l and total clearance was around 57 l/h for i.v. dosing. Mirabegron pharmacokinetics were linear after i.v. dosing (7.5 - 50 mg), but exposure increased more than proportionally after oral dosing due to increased F (29% for 25 mg to 45% at 150 mg). About 20% of the (absorbed) dose was excreted unchanged into urine. Area under the curve (AUC) was 27% and 64% higher in females than males after i.v. and oral dosing respectively; differences were mostly attributed to body weight, and for oral dosing, also to F. CONCLUSIONS: Mirabegron pharmacokinetics were linear after i.v. dosing (7.5 - 50 mg), but increased more than proportionally after oral dosing (25 - 150 mg) as a result of increased F. Sex differences in exposure could be explained by body weight and for oral dosing, also by F. Mirabegron was in general well tolerated up to the highest doses studied, 50 mg i.v. and 150 mg oral. PMID- 22943935 TI - [Transformation of the development of medicine and liver surgery in China]. PMID- 22943934 TI - Cardiac stem cell therapy: stemness or commitment? AB - Cardiac stem cell therapy to promote engraftment of de novo beating cardiac muscle cells in cardiomyopathies could potentially improve clinical outcomes for many patients with congestive heart failure. Clinical trials carried out over the last decade for cardiac regeneration have revealed inadequacy of current approaches in cell therapy. Chief among them is the choice of stem cells to achieve the desired outcomes. Initial enthusiasm of adult bone marrow stems cells for myocyte regeneration has largely been relegated to paracrine-driven, donor cell-independent, endogenous cardiac repair. However, true functional restoration in heart failure is likely to require considerable myocyte replacement. In order to match stem cell application to various clinical scenarios, we review the necessity to preprime stem cells towards cardiac fate before myocardial transplantation and if these differentiated stem cells could confer added advantage over current choice of undifferentiated stem cells. We explore differentiation ability of various stem cells to cardiac progenitors/cardiomyocytes and compare their applicability in providing targeted recovery in light of current clinical challenges of cell therapy. PMID- 22943936 TI - [Surgical procedure option for large hepatocellular carcinoma]. PMID- 22943937 TI - [The application of hepatectomy occlusion technology]. PMID- 22943938 TI - [Technique for hepatic veins in liver surgery]. PMID- 22943939 TI - [Hepatic vein occlusion with Satinsky clamp in hepatectomy for complicated liver tumor]. AB - OBJECTIVE: To investigate the application of an improved method of hepatic vein occlusion with Satinsky clamp when resecting the liver tumor involving second hepatic portal. METHODS: From January 2003 to December 2010, there were totally 330 patients with liver tumor admitted, who underwent liver resection with Pringle maneuver plus hepatic vein occlusion with Satinsky clamp. Data regarding the intra-operative and post-operative course of the patients were analyzed. There were 245 male and 85 female patients, with a mean age of (50 +/- 11) years. The diameter of tumor was (9 +/- 6) cm. Among the 330 patients, there were 271 patients with viral hepatitis B, 215 patients with liver cirrhosis; 321 patients were in Child class A of liver function and 9 in class B. Pringle maneuver plus hepatic vein occlusion with Satinsky clamp was used to occlude the blood flow in the liver resection. The liver transection was performed with clamp-crushing technique. RESULTS: Hepatic vein occlusion with Satinsky clamp was successful in all 330 patients. The operation time was (132 +/- 29) minutes, while (7 +/- 3) minutes for dissecting hepatic vein and (22 +/- 7) minutes for inflow blood occlusion. The blood loss in operation was (480 +/- 265) ml, with 20% of patients receiving blood transfusion. No patient had large hemorrhage and air embolism due to hepatic vein laceration. No patient died in the perioperative period. The complications included 31 patients of pleural effusion, 14 patients of seroperitoneum, 10 patients of biliary fistula, 2 patients of massive blood loss during liver resection and 2 patients of re-bleeding after operation. CONCLUSION: The method of hepatic vein occlusion with Satinsky clamp was safe and effective. PMID- 22943940 TI - [Radiofrequency-assisted anterior approach right hepatectomy for hepatocellular carcinoma]. AB - OBJECTIVE: To investigate the safety and efficacy of radiofrequency-assisted anterior approach right hepatectomy for hepatocellular carcinoma (HCC). METHODS: The clinic data of 12 HCC patients who underwent radiofrequency-assisted anterior approach right hepatectomy from January 2010 to July 2011 was analyzed retrospectively. Surgical techniques and treatment response were retrospectively reviewed. All the 12 patients were male, aging from 38 to 57 years with a mean of (48 +/- 6) years. Ten of the 12 patients were infected with hepatitis B virus. A retrohepatic tunnel anterior to the surface of the inferior vena cava (IVC) was developed. The liver was hanged away from the IVC and radiofrequency was carried out along the Cantline's line. Scalpel was used to cut off the liver parenchyma along the middle of the ablated area until the parenchyma was fully resected. After short hepatic veins and the right hepatic vein were ligated, ligaments of right liver were fully isolated and right liver was resected. The t test was performed between 2 groups. RESULTS: The surgical time was 165 to 295 minutes, with a mean of (230 +/- 55) minutes. The bleeding was 150 to 1500 ml, with a mean of (516 +/- 378) ml, which was better than those of anterior approach right hepatectomy ((1291 +/- 1159) ml) and classical right hepatectomy ((2129 +/- 2012) ml; t = 1.236, 3.265; P < 0.05). The postoperative hospital stay was 8 - 19 days, with a mean of (12 +/- 4) days. There were no medical complications and no postoperative death. All patients were cured and discharged. CONCLUSIONS: Radiofrequency-assisted anterior approach right hepatectomy for HCC is safe and effective and could effectively decrease intra-operative bleeding and shorten surgical time. PMID- 22943941 TI - [Prognosis after hepatectomy for primary liver cancer of segment 7 or 8]. AB - OBJECTIVE: To investigate the results of surgical treatment for primary liver cancer of segment VII or VIII. METHODS: The clinical data of 149 patients with primary liver cancer who underwent hepatectomy between January 2005 and December 2010 was retrospectively analyzed. There were 120 male and 29 female patients, aging from 19 to 75 years with a mean of 53.1 years. Among 149 patients, tumors were located at segment VII, VIII or several segments containing VII or VIII (VII/VIII group) in 53 patients, located at other segments (non-VII/VIII group) in 96 patients. The results of surgical treatment for VII/VIII group and non VII/VIII group were compared by using t test, chi(2) test, Kaplan-Meier survival analysis and Cox proportion hazard regression analysis. RESULTS: Right liver lobe was turned over completely in VII/VIII group, hepatic lobe which tumor was located at was not or partly turned over in non-VII/VIII group. Compared with non VII/VIII group, VII/VIII group had longer operative time ((215 +/- 68) min vs. (123 +/- 36) min, t = 2.860, P = 0.01). No significant difference was found for tumor size, tumor number, tumor encapsulation, microvascular invasion, Edmondson grade, pTNM stage, intraoperative blood loss, blood transfusion rate, R0 resection rate and postoperative complication rate between two groups. The cumulative 1-, 3-, and 5-year overall survival rates were 74.6%, 42.3%, 15.4% respectively, in VII/VIII group, and 89.3%, 63.0%, 40.4% respectively, in non VII/VIII group (chi(2) = 13.501, P = 0.000). Univariate and multivariate analysis of prognostic factors indicated that tumor location (tumor was located at segment VII or VIII) had unfavorable prognostic influence on overall survival (chi(2) = 10.329, P = 0.001; HR = 1.693, 95%CI: 1.232 - 2.694, P = 0.013). CONCLUSION: The results of surgical treatment for primary liver cancer located at segment VII or VIII are worse than that located at other segments. PMID- 22943942 TI - [Application of persistent methylene blue dyeing method for anatomic hepatectomy of hepatocellular carcinoma with bile duct tumor thrombi]. AB - OBJECTIVE: To evaluate the role of anatomic hepatectomy of hepatocellular carcinoma with bile duct tumor thrombi by application of persistent methylene blue dyeing method. METHODS: From January 2009 to February 2011, 11 hepatocellular carcinoma patients with bile duct tumor thrombi underwent anatomic hepatectomy with removal of the biliary tumor thrombus. There were 10 male and 1 female patients. The average age was 49 years (ranging from 31 to 67 years). The initial symptom of 9 out of the 11 patients was jaundice. After anatomy and ligation of Glissonean pedicle of pre-resection segment, methylene blue was injected into its far-end portal vein in order to dye the segment. RESULTS: Persistent methylene blue dyeing method was successful in all patients. Primary foci were found in all patients. Hepatectomy were performed, including 4 patients of segmentectomy, 3 patients of subsegmentectomy, 2 patients of hemihepatectomy, and 2 patients of hepatic sectionectomy. The mean operation time and blood loss was 137 minutes and 246 ml respectively. Severe complications such as liver function failure and sub-diaphragm abscess was avoided in all patients. No perioperative death. Post-operation radiotherapy was performed on 2 patients . Over a mean follow-up time of 14.6 months, liver cancer recurrence occurred in 2 patients, abdomen seeding metastasis in 1 patient, bile duct tumor thrombi recurrence in 1 case, and 2 patients died. CONCLUSIONS: Anatomic hepatectomy of hepatocellular carcinoma with bile duct tumor thrombi by application of persistent methylene blue dyeing method can make resection more precise and improve curative effect. PMID- 22943943 TI - [Novel surgery for refractory mixed constipation: analysis of the technical notes and outcome to Jinling procedure]. AB - OBJECTIVE: To discuss a new surgical strategy: Jinling procedure (subtotal colectomy combined with modified Duhamel procedure), of which the indications, technical notes and outcomes were analyzed. METHODS: The 590 patients with refractory slow-transit constipation associated with outlet obstruction was strictly included between February 2000 and December 2011. The patients included 103 males and 487 females. Their age were 14-75 years (average 42 +/- 13). The 412 patients received laparoscopic-assistant Jinling procedure, and 178 patients with open Jinling procedure. The pre- and post-operation data were collected. The follow up rate were 100%, 98.1%, 95.8% and 92.7% at 3, 6, 12 and 24 months. RESULTS: There was no surgery-related death. Mean hospital day was (12 +/- 9) days. Most complications were managed conservatively without significant events. The common complications after surgery were adhesive intestinal obstruction (9.2%), anastomosis bleeding (8.1%) and anastomosis leakage (2.9%). The gastrointestinal quality of life index score was 72 +/- 9 preoperatively and increased to 68 +/- 11, 99 +/- 6, 105 +/- 9, 106 +/- 9 at 3, 6, 12 and 24 month follow-up, respectively (t = 62.1, -25.1, -126.5, -143.2, P < 0.01). The Wexner constipation scale was 21.9 +/- 4.5 preoperatively and decreased to 9.6 +/- 2.4, 5.9 +/- 2.1, 4.6 +/- 1.9, 4.5 +/- 1.8 at 3, 6, 12 and 24 month follow-up, respectively (t = 48.6, 61.8, 58.2, 45.9, P < 0.01). The satisfactory rate was 77.5%, 92.1%, 93.0% and 94.1% at 3, 6, 12, and 24 month follow-up. CONCLUSIONS: Jinling procedure provides a good surgical option for refractory slow-transit constipation associated with outlet obstruction. PMID- 22943944 TI - [Clinic predictors of efficacy and adverse events of sorafenib therapy for advanced hepatocellular carcinoma patients]. AB - OBJECTIVE: To investigate the clinic predictors of efficacy and adverse events of sorafenib in treating with advanced hepatocellular carcinoma (HCC) patients. METHODS: From December 2008 to October 2011, 54 patients received sorafenib for unresectable or metastatic HCC. There were 46 male and 8 female patients. The mean age was 48.7 years (ranging from 21 to 77 years). Patients received sorafenib orally 400 mg twice daily on a continuous dosing schedule with 6 weeks counting as a single cycle. Tumor response was assessed according to the Response Evaluation Criteria in Solid Tumor and toxicity grading was performed using the National Cancer Institute Common Toxicity Criteria version 3.0. The relationship between different clinic variable factors and curative effects of sorafenib was analyzed by using Cox proportion hazard regression analysis. RESULTS: HCC was etiological related to HBV in 52 patients (96.3%). Following sorafenib therapy, 2 patients (3.7%) achieved a partial response and 24 patients (44.4%) achieved stable disease, with a disease control rate of 48.1%. The median time to progression (TTP) was 3.8 months. Multivariate analysis showed that greater Child and Eastern Cooperative Oncology Group (ECOG) grade were independent predictors of shorter TTP (HR = 1.361, 95%CI: 1.081 - 12.665, P = 0.041; HR = 1.449, 95%CI: 1.151 - 12.305, P = 0.032). The common adverse events were hand-foot syndrome (64.8%), alopecia (46.3%), and diarrhea (44.4%). CONCLUSIONS: Single-agent sorafenib demonstrates good efficacy and acceptable tolerability in treating advanced HCC. The presents of Child class A and ECOG performance grade 0 predict better response to sorafenib in advanced HCC patients. PMID- 22943945 TI - [Risk factors of thoracic curve decompensation after anterior selective fusion in adolescent idiopathic scoliosis with major thoracolumbar or lumbar curve]. AB - OBJECTIVES: To investigate the incidence of thoracic curve decompensation or proximal adding-on phenomenon after anterior selective fusion of thoracolumbar or lumbar curve in Lenke type 5 adolescent idiopathic scoliosis (AIS), and to identify its risk factors. METHODS: From June 2001 to December 2008, 130 Lenke type 5 AIS patients with a Cobb angle of 40 degrees - 73 degrees treated with anterior selective thoracolumbar or lumbar fusion, and with a minimum 2-year postoperative regular follow-up were recruited in this study. The average age, Cobb angle and Risser sign of all patients was 14.8 +/- 1.6 years, 46 degrees +/ 6 degrees of major thoracolumbar or lumbar curve (TL or L), 25 degrees +/- 7 degrees of proximal thoracic curve and 0-5, respectively. The patients were grouped according to the relationship between the upper instrumented vertebrae (UIV) and the upper end vertebrae (UEV), the patients' Risser sign and the relationship between UIV and C(7) plumb line (C(7)PL). The radiographic data of the patients were compared between patients with and without proximal adding-on by using t test, and the incidence of proximal adding-on was analyzed in terms of determination of UIV and Risser sign to identify the risk factors of this phenomenon by using Fisher's exact test. RESULTS: Eleven patients were identified with proximal adding-on, thus the incidence of it was 8.5%. At last follow-up postoperatively, the average Cobb angle of TL or L and proximal thoracic curve was 9 degrees +/- 4 degrees and 11 degrees +/- 5 degrees , respectively. Moreover, the incidence of adding-on in Rissex sign grade 0 to 1 (3/8) was higher than that of grade 2 to 3 (12.1%) and grade 4 to 5 (4.5%). In addition, the incidence of adding-on in UIV lower than UEV group (20.6%) was obviously higher than that of UIV higher than or equal to UEV group (4.2%). The incidence of adding-on for patients with C(7)PL falls away from UIV (19.5%) were obviously higher than that of patients with C(7)PL falls between the pedicle and lateral margin of UIV (3.6%) and between bilateral pedicles of UIV (3.0%). Each group showed significant difference for the incidence of adding-on by Fisher's exact test (P < 0.05). CONCLUSIONS: There exists the risk of proximal thoracic curve decompensation, with a not low rate, after anterior selective fusion for major TL or L curve AIS. The determination of UIV relative to UEV and the skeletal maturity of the patient are the two factors closely associated with the presence of such a phenomenon. PMID- 22943946 TI - [Ewing's sarcoma of the pelvis: treatment results of 31 patients]. AB - OBJECTIVE: To define oncologic and functional outcomes of multidisciplinary treatment methods combined chemotherapy, surgery and radiotherapy, patients with Ewing's sarcoma of the pelvis who were treated at our center were analyzed. METHODS: Thirty-one patients with Ewing's sarcoma of the pelvis were eligible for this analysis. Primary lung metastases occurred in ten patients who were classified as stage III according to the system of Musculoskeletal Tumor Society (MSTS). All the patients received multidisciplinary treatment methods combined chemotherapy, surgery and radiotherapy. Twenty-eight patients underwent limb sparing surgery, three patients underwent hemipelvectomy. The complications, including radiation or surgery-related complications and mechanical failures were recorded, besides the functional results were evaluated according to the MSTS 93 criteria. Kaplan-Meier survival analysis and Cox multivariate analysis were used as statistical methods. RESULTS: The 5-year overall survival (OS) rate for all the patients was 42.3%. The 5-year OS for patients with small tumor (< 10 cm) had a significant better prognosis than patients with large tumor (>= 10 cm, 58.2% vs. 26.0%, chi(2) = 4.382, P < 0.05). The 5-year OS for patients with surgical stage IIb was significantly better than for those with surgical stage III (50.2% vs. 30.3%, chi(2) = 4.521, P < 0.05). The 5-year OS for patients with wide or radical surgery had a better prognosis than patients with marginal, intralesional surgery or no surgery (60.0% vs. 29.4%, chi(2) = 4.851, P < 0.05). In multivariate analysis, surgical stage III (RR = 2.480, 95%CI: 0.857 - 7.173) and resection margin (RR = 2.576, 95%CI: 0.474 - 14.011) were independent prognostic factors. The mean MSTS 93 score for all the patients was 63.3%. The complication rate in patients treated with surgery was 29.0% (9/31). CONCLUSIONS: Patients with Ewing'sarcoma of the pelvis can benefit from multidisciplinary treatment in terms of improved survival, acceptable functional results and reasonable complications. Surgical staging and resection margin are independent prognostic factors. PMID- 22943947 TI - [Distinguish reasons for the variety of intraoperative transcranial magnetic motor evoked potential: the anaesthesia or the operative injury]. AB - OBJECTIVE: To find a way to discriminate operative reason from anaesthesia reason for the changes of intraoperative transcranial magnetic motor evoked potentials (MEPs). METHODS: In 26 patients under Etomidate/Fentanyl anesthesia from February 2001 to June 2004, MEPs elicited by transcranial magnetic stimulation were recorded from tibialis anterior muscles, simultaneously bispectral index (BIS) and train-of-four stimulation (TOF) were used to monitor the anesthesia depth and neuromuscular blockade respectively. MEP, BIS and measurements of TOF at different anesthesia depth and muscular relaxation were recorded synchronously, statistical analysis of this data set was done in order to find the inherent relationship between these variables. RESULTS: Under anesthesia, MEP amplitude was always positively correlated with the corresponding BIS and TOF value. A regression equation could be built, with which the MEP amplitude could be reckoned based on realtime BIS and T(1)/T(c). In case of spinal cord injury, the measured amplitude value would significantly deviate from predicted one, which suggested that the change of MEP was because of the operation, but not the anaesthesia or neuromuscular blockade. Each patient had his or her own regression equation, which was different from each other. CONCLUSIONS: The establishment of regression equation from MEPs, BIS and TOF is very useful to distinguish reasons of the changes of transcranial magnetic MEPs during surgery, and with this technique, the intraoperative MEP monitoring should be more reliable and practicable. PMID- 22943948 TI - [Risk factors in carotid angioplasty and stenting for extracranial carotid stenosis of elderly patients]. AB - OBJECTIVES: To evaluate the risk factors and safety of carotid angioplasty and stenting(CAS) for extracranial carotid stenosis in elderly patients and summarize CAS on the indication of elderly patients and the prevention of complications. METHODS: The population characteristics, clinical features and vascular data of 60 elderly patients (>= 75 years) treated between June 2001 and December 2010 were retrospectively analyzed. There were 57 male and 3 female. The median age of the patients was 78.8 years (range, 75 - 93 years ). The mean case history was 2.5 months with a range of 1 to 6 months. To summarize the prognosis of CAS according to the reduction of stenosis, NIHSS score, the incidence of early postoperative, 30 days adverse events and the follow-up status. Using chi(2) test as the statistical method. RESULTS: The mean stenosis was reduced from 81% +/- 17% preoperative to 18% +/- 9% postoperative. NIHSS score was reduced from preoperative 22 +/- 8 to postoperative 10 +/- 4. The average follow-up period was 1.5 years (range from 3 months to 3 years), and the results showed no procedure related death occurred. Ipsilateral stroke occurred in 1 case (1.7%) and restenosis (>= 50%) occurred in 2 patients (3.3%). Diabetes (chi(2) = 23.96, P < 0.01)and cardiac insufficiency (chi(2) = 6.446, P < 0.05)had a respectively significant impact on the incidence of early postoperative complications. CONCLUSIONS: CAS can be effective in restoring carotid artery stenosis of elderly patients and preventing the occurrence of stroke. The elderly, diabetes, cardiac insufficiency are more likely to increase the postoperative risk of adverse events. PMID- 22943949 TI - [Docetaxel plus prednisone versus mitoxantrone plus prednisone as first-line chemotherapy for metastatic hormone-refractory prostate cancer: long-term effects and safety]. AB - OBJECTIVE: To compare docetaxel plus prednisone with mitoxantrone plus prednisone as first-line chemotherapy for metastatic hormone-refractory prostate cancer (mHRPC). METHODS: From January 2007 through August 2010, 62 patients with mHRPC received 5 mg of prednisone twice daily were randomly assigned to receive mitoxantrone 12 mg/m2 every three weeks (group A) or 75 mg/m2 every three weeks (group B). The cycles of each regimen were less than 10 times. The primary end point was overall survival. The secondary end points were the prostate-specific antigen (PSA) response rate, the duration of PSA response and the objective tumor response rate (ORR). All the t test, chi2 test and Fisher's exact test were performed between 2 groups. RESULTS: Thirty-one patients enrolled in group A received a median 4 cycles of regimen (range 1 - 10), whereas 30 patients enrolled in group B received a median of 7 cycles of regimen (range 2 - 10). There were 45.2% patients in group A and 70.0% in group B had PSA response (chi2 = 3.85, P < 0.05). The duration time of PSA response was 121 days (range 20-323 days) in group A and 168 days (range 42 - 447 days) in group B, respectively. The ORR was 15.0(3/20) in group A and 10.3% (3/29) in group B, respectively. The median survival was 511 days (95%CI: 357 - 665 days) in group A and 833 days (95%CI: 634 - 1032 days) in group B, respectively (chi2 = 4.20, P = 0.040). The incidence of thrombocytopenia in group A was higher than group B (chi2 = 5.60, P = 0.018); the incidences of nausea and vomiting (chi2 = 4.32, P = 0.038), diarrhea (P = 0.024), fatigue (chi2 = 5.90, P = 0.015), and alopecia (chi2 = 5.42, P = 0.020) in group B were higher than group A. CONCLUSION: Docetaxel plus prednisone can lead to superior overall survival and PSA response rate in patients with mHRPC. PMID- 22943950 TI - [Experimental study of angiography using vascular interventional robot-2(VIR-2)]. AB - OBJECTIVE: To verify the feasibility and safety of new vascular interventional robot system used in vascular interventional procedures. METHODS: Vascular interventional robot type-2 (VIR-2) included master-slave parts of body propulsion system, image navigation systems and force feedback system, the catheter movement could achieve under automatic control and navigation, force feedback was integrated real-time, followed by in vitro pre-test in vascular model and cerebral angiography in dog. Surgeon controlled vascular interventional robot remotely, the catheter was inserted into the intended target, the catheter positioning error and the operation time would be evaluated. RESULTS: In vitro pre-test and animal experiment went well; the catheter can enter any branch of vascular. Catheter positioning error was less than 1 mm. The angiography operation in animal was carried out smoothly without complication; the success rate of the operation was 100% and the entire experiment took 26 and 30 minutes, efficiency was slightly improved compared with the VIR-1, and the time what staff exposed to the DSA machine was 0 minute. The resistance of force sensor can be displayed to the operator to provide a security guarantee for the operation. No surgical complications. CONCLUSIONS: VIR-2 is safe and feasible, and can achieve the catheter remote operation and angiography; the master-slave system meets the characteristics of traditional procedure. The three-dimensional image can guide the operation more smoothly; force feedback device provides remote real-time haptic information to provide security for the operation. PMID- 22943951 TI - [Ablation of segmental glissonian pedicle by ultrasound-guided radiofrequency in precision liver resection in a porcine model]. AB - OBJECTIVE: To demonstrate the ablation of segmental glissonian pedicle by ultrasound-guided radiofrequency in precision liver resection in porcine model. METHODS: The study was carried out on 6 Bama miniature pigs. Coagulative desiccation of the vessels feeding the segment to be resected was induced by introduction of a "cooled-tip" radiofrequency electrode under intraoperative ultrasound guidance at the level of the vessels. Then, an area of marked discoloration on the surface of the liver became obvious. Liver parenchymal transection followed without any form of hepatic inflow occlusion. Three segments (segment 3, 5, and 6) were resected on each pig. The criteria studied the local and general tolerance, the change of blood flow parameters of each segmental arterial and portal branches, and the microscopic appearance of the segmental arterial, portal and biliary tract branches. Using t test as the statistical methods. RESULTS: Postoperative mortality and morbidity were 0 and all serum parameters had normalized by 14 days. Demarcation area was obtained in 15 segments. The flow rate of the resected segmental portal branches was 0 cm/s after radiofrequency and the value of the arterial branches was (28 +/- 18) cm/s which was significantly lower than pre-radiofrequency, which were (10.2 +/- 3.0) cm/s and (60 +/- 17) cm/s (t = 14.439, 5.502; P = 0.000). There was no significant difference in the flow rate of the remnant segmental arterial and portal branches among pre-radiofrequency, post-radiofrequency and 14 days after operation. On microscopic observation, the mean ablated length of segmental portal, arterial and biliary tract branches were (1.6 +/- 0.4) cm, (1.2 +/- 0.4) cm, and (1.7 +/- 0.3) cm respectively. CONCLUSIONS: The ablation of the segmental glissonian pedicle by ultrasound-guided radiofrequency is quick, safe and effective. The probe needs to be away from vessels feeding segments 1.5 cm at least to avoid thermal injuries. PMID- 22943952 TI - [Expression of transgelin-2 and clinical significance in colorectal cancer]. AB - OBJECTIVES: To investigate the relationship between the expression of transgelin 2 and the clinicopathological factors of colorectal carcinoma and evaluate the value of transgelin-2 in prognostic assessment of the colorectal cancer patients. METHODS: Using tissue microarray and immunohistochemical methods, we examined transgelin-2 of 120 colorectal cancer patients received surgical treatment from September 2002 to April 2004, including 74 male and 46 female, age from 26 to 89 years. Analyzed the relationship between transgelin-2 and both the clinicopathological features and prognosis of the colorectal cancer by using chi2 test and Kaplan-Meier survival analysis. Cox proportion hazard regression analysis was used to study the independent prognostic factors. RESULTS: The positive rate of transgelin-2 expression was 69.2% in colorectal carcinoma. The transgelin-2 expression correlated with differentiation degree (chi2 = 5.420), lymph nodes metastasis (chi2 = 45.577), distant metastasis (chi2 = 12.009), and TNM staging (chi2 = 47.577). The survival time was (39 +/- 5) months in patients with positive expression of the transgelin-2, while (59 +/- 3) months in patients with negative expression. The patient's survival time was statistically correlated with the transgelin-2 expression (P = 0.003). Distant metastasis (RR = 8.318, 95%CI: 4.119 - 16.790), lymph nodes metastasis (RR = 2.794, 95%CI: 1.246 - 6.263) and transgelin-2 expression (RR = 1.834, 95%CI: 1.118- 2.973) were independent prognostic factors in patients with colorectal cancer (P < 0.05). CONCLUSIONS: The expression of transgelin-2 is correlated with clinicopathological features and prognosis in colorectal cancer, may be the potential marker of metastasis and the prognosis of colorectal cancer patients. PMID- 22943953 TI - [Percutaneous pelvic fracture stabilization using CT-based 3D navigation software combined with targeting mechanical arm: a cadaver model trial]. AB - OBJECTIVES: To investigate a new targeting mechanical arm for CT-based navigated percutaneous fixation of pelvic fractures, and to evaluate the safety and efficiency of the procedures. METHODS: Using CT-based 3D navigation software combined with targeting mechanical arm, percutaneous insertion of pelvic models (3 dry human cadaver pelvic skeletons and 5 plastic Sybone pelvic models) were performed, 8 pelvic models allowed percutaneous cannulated screw insertion of both S-I joint (2 S-I screws placement for each side, total 32 screws in this experiment) and both superior ramus (1 ramus medullary screw placement for each side, total 16 screws in this experiment). Percutaneous insertion of pelvic models (4 dry human cadaver pelvic skeletons and 4 plastic Sybone pelvic models, 1 S-I screws and 1 ramus medullary scre placement for each side, 32 screws in this experiment) were performed using fluoro-navigation system (Stryker, USA). Time necessary for every screw insertion were recorded. Accuracy of screw placement was assessed using C-arm imaging and direct eyes inspecting. The time and accuracy of the two methods were compared. RESULTS: The time required for the CT-based 3D navigation procedure (3.6 +/- 1.2) min was significantly less than using the targeting mechanical arm compared to drilling freehand with navigation (9.1 +/- 0.8) min (t = 2.50, P < 0.01). There was no significant difference in accuracy between the two methods. CONCLUSION: CT-based 3D navigation software combined with targeting mechanical arm should be potential to apply percutaneous sacroiliac screwing for pelvic fractures with more accurate and more reliable. PMID- 22943954 TI - [Preliminary histological and biomechanical study about the timing of surgical repair for acute rotator cuff tears in rabbits]. AB - OBJECTIVES: To establish the animal model of acute rotator cuff tear in rabbits, and study the effect of timing of surgical repair on healing of tendon-bone interface, formation and distribution of collagens in the supraspinatus tendon insertion and biomechanical properties of supraspinatus. METHODS: Supraspinatus tenotomy was performed in the right shoulder of 90 skeletally matured male New Zealand white rabbits to establish the animal model of acute rotator cuff tear. The rabbits were randomly divided into 3 groups : group of early repair, repaired at 1 week after tenotomy; group of late repair, repaired at 4 weeks after tenotomy; and group without repair, used as control. At 2 weeks, 4 weeks and 8 weeks after repair, healing of tendon-bone interface was observed by HE staining. Collagens were observed by Sirius Red F 3B (SR) in saturated carbazotic acid staining. The areas of type I and III collagens were measured by using imaging analysis software and the ratio of type I and III collagens were calculated. Failure loads of supraspinatus on both sides were measured. The percentage of failure loads of the surgical side was calculated and contralateral supraspinatus were uninjured. RESULTS: There was no obvious fatty infiltration and muscle atrophy in supraspinatus in all groups. At 8 weeks, the formation of a new enthesis of supraspinatus in groups of early and late repair were observed. In groups of early and late repair, the ratio of areas of type I and III collagens at 8 weeks (2.02 +/- 0.77 and 2.06 +/- 0.58) was larger than that at 2 weeks (1.10 +/- 0.24 and 1.14 +/- 0.50, t = 3.082, 3.655, P < 0.01). At 2, 4 and 8 weeks, the percentages of failure loads of the surgical side and uninjured contralateral supraspinatus in group of early repair(38% +/- 11%, 66% +/- 7%, 89% +/- 4%) and group of late repair (41% +/- 16%, 63% +/- 7%, 89% +/- 9%) were both higher than that in group without repair (14% +/- 6%, 32% +/- 4%, 56% +/- 12%); the differences were all statistically significant (group of early repair: t = 3.311, 8.549, 5.719; group of late repair: t = 3.713, 8.063, 6.044; P < 0.01). The percentage of failure loads of the surgical side and uninjured contralateral supraspinatus at 8 weeks was higher than those at 4 weeks (t = 3.878 - 4.613, P < 0.01) and 2 weeks (t = 7.158 - 10.024, P < 0.01) in all groups. CONCLUSIONS: Surgical repair within 4 weeks of acute rotator cuff tear lead to formation of a new enthesis of supraspinatus, improvement of both ratio of type I collagen in the supraspinatus tendon insertion and biomechanical properties of supraspinatus. PMID- 22943955 TI - Induction of functional mesenchymal stem cells from rabbit embryonic stem cells by exposure to severe hypoxic conditions. AB - Embryonic stem cells (ESCs) have the potential to be used as an unlimited cell source for cell transplantation therapy, as well as for studying mechanisms of disease and early mammalian development. However, applications involving ESCs have been limited by the lack of reliable differentiation methods in many cases. Mesenchymal stem cells (MSCs) have also emerged as a promising cell source, but as suggested in recent studies, these cells display limited potential for proliferation and differentiation, thereby limiting their usefulness in the clinic and in the laboratory. Unfortunately, effective methods for induction of MSCs from pluripotent stem cells have not been established, and the development of such methods remains a major challenge facing stem cell biologists. Oxygen concentration is one of the most important factors regulating tissue development. It has profound effects on cell metabolism and physiology and can strongly influence stem cell fate. Here we demonstrate that severelow O(2) concentrations (1%) can function as a selective pressure for removing undifferentiated pluripotent cells during the induction of MSCs from rabbit ESCs (rESCs) and that MSCs induced under severe hypoxic conditions function as normal MSCs; that is, they repopulate after cloning, express specific markers (vimentin, CD29, CD90, CD105, and CD140a) and differentiate into adipocytes, osteoblasts, and chondrocytes. Furthermore, we demonstrate that these cells can contribute to cartilage regeneration in an in vivo rabbit model for joint cartilage injury. These results support the notion that exposing ESCs to severe hypoxic conditions during differentiation can be used as a strategy for the preparation of functional MSCs from ESCs. PMID- 22943956 TI - Giant cell glioblastoma with unique bilateral cerebellopontine angle localization considered as extraaxial tumor growth in a patient with neurofibromatosis Type 1. AB - Giant cell glioblastoma multiforme (GCGBM) is a rare variant of glioblastoma, occurring predominantly in the cerebral hemispheres. Its infratentorial localization has been documented occasionally, while GCGBM in the cerebellopontine angle (CPA) region has not been described so far. We report a case of GCGBM presenting primarily as an extraaxial bilateral CPA tumor in a 29 year-old woman with neurofibromatosis Type 1 (NF1). The patient died shortly after surgery of the right CPA tumor. Postmortem study of the brain revealed large tumor masses, located in the CPA bilaterally, encasing the brainstem base and cisternal portions of the cranial nerves. Tumor masses were demarcated from the brainstem and cerebellum and covered by leptomeninges. Microscopically, a slight subpial tumor seeding from the leptomeninges into the brain parenchyma was observed in the right CPA region. The tumor showed highly pleomorphic, giant and multinucleated cells, densely cellular sheets of poorly differentiated cells and pseudopalisading necroses. Tumor cells were positive for GFAP, S-100 protein, and p53 and negative for neuronal antigens. The MIB-1 labeling index was very high in densely cellular areas. To our knowledge this is the second report of GCGBM in an NF1 patient and the first reported case of GCGBM presenting as an extraaxial leptomeningeal lesion with bilateral CPA localization, which might be considered as primary leptomeningeal gliomatosis. PMID- 22943957 TI - External granular cell layer bobbling: a distinct histomorphological feature of the developing human cerebellum. AB - INTRODUCTION: The external granular layer (EGL) of the developing human cerebellum is detectable until an age of ~ 1 year. It has been described as a thin, evenly calibrated layer of germinal cells. We have repeatedly observed a distinct discontinuous bobbled configuration of the EGL (external granular layer bobbling = EGLB) in human infantile autopsy brains. AIM, MATERIALS AND METHODS: We investigated 106 human fetal and infantile postmortem brains (range of gestational week at birth: 14 - term; range of postpartal age: 0 - 500 days) for presence of EGLB and correlated it with gestational/postpartal age, gender, developmental stage of cerebellar cortex, medical history and neuropathological findings. RESULTS: EGLB was detectable in 38/106 (35.8%) cases. EGLB presents as focal series of uniform knob-like protrusions of the EGL. In the notches between individual knobs, capillaries penetrate from the primitive leptomeningeal vascular plexus into the molecular layer. We found EGLB predominantly in depths of fissures of cerebellar hemispheres, vermis and/or tonsils. Presence of EGLB was statistically significantly more common in liveborn cases who died after gestational week 25 and cases with higher maturity grade of the cerebellar cortex, respectively. There was no gender difference. EGLB was not associated with medical history or neuropathological findings. CONCLUSIONS: EGLB is a distinct histomorphological feature of the developing cerebellum, which is predominantly found in infants. Our data indicate that EGLB is a physiological phenomenon occuring during cerebellar development at a certain gestational age, although we cannot exclude that it represents an artifact related to tissue fixation. In any case, recognition of this recurring feature is relevant for the practicing neuropathologist and should not be interpreted as a cerebellar migration disorder. PMID- 22943958 TI - The birth of oligodendrocytes in the anatomical and neuropathological literature: the seminal contribution of Pio del Rio-Hortega. 1921. AB - Comment on: del Rio-Hortega P. Glia with very few processes (oligodendroglia). Clin Neuropathol. 2012; 31: 440-459, originally published in Archivos de Neurobiologia. 1921; 2: 16-43 and del Rio-Hortega P. Are the glia with very few processes homologous with Schwann cells? Clin Neuropathol. 2012; 31: 460-462, originally published in Bol de la Soc Esp de Biol. 1922; X: 25-28. PMID- 22943960 TI - Pregnancy-specific anxiety: which women are highest and what are the alcohol related risks? AB - In a national US sample of pregnant women (n=311), we investigated the question of who becomes highly anxious about pregnancy by examining putative sociodemographic, pregnancy- and mental health-related predictors of pregnancy anxiety. We also assessed the contribution of pregnancy anxiety to the risk of significant alcohol consumption during pregnancy. English-speaking pregnant women aged 18+years were recruited online. Results indicated that sociodemographic factors (younger age, white, unmarried, lower education, lower household income, no previous children), feelings about current pregnancy (unwanted), and general anxiety (higher general and state anxiety) predicted higher pregnancy-related anxiety, whereas age, religiosity, number of weeks pregnant, unplanned pregnancy, and maternal depressive symptoms did not. Pregnancy anxiety was the single strongest predictor of alcohol drinking risk during pregnancy (p<.001, ?R(2)=.10) a relationship that held after controlling for other significant predictors. Pregnancy anxiety also represented the strongest predictor of screening positively for drinking risk during pregnancy at the total T-ACE (an alcohol risk screener for pregnancy) level of 3+ (odds ratio 95% CI=1.61-4.14, p<.001), though not at the level of 2+ (odds ratio 95% CI=0.98-1.68, p=.07). We discuss implications for the link between maternal mental health and birth/ child outcomes. PMID- 22943961 TI - Predictive validity of the Motivation To Stop Scale (MTSS): a single-item measure of motivation to stop smoking. AB - BACKGROUND: Many different measures of motivation to stop smoking exist but it would be desirable to have a brief version that is standard for use in population surveys and for evaluations of interventions to promote cessation. The aim of this study was to assess the predictive validity and accuracy of the single-item Motivation To Stop Scale (MTSS). METHODS: This study is part of the "Smoking Toolkit Study;" a monthly survey of representative samples of the English population. We used data from 2483 respondents to the surveys from November 2008 to January 2011, who were smokers, used the MTSS, and were followed up 6 months later to provide information on quit attempts since baseline. The MTSS consists of one item with seven response categories ranging from 1 (lowest) to level 7 (highest level of motivation to stop smoking). RESULTS: A total of 692 smokers (27.9% (95% CI=26.1-29.6)) made an attempt to quit smoking between baseline and 6 month follow-up. The odds of quit attempts increased linearly with increasing level of motivation at baseline (p<0.001) and were 6.8 (95% CI=4.7-9.9) times higher for the highest level of motivation compared with the lowest. The accuracy of the MTSS for discriminating between smokers who did and did not attempt to quit was ROC(AUC)=0.67 (95% CI=0.65-0.70). CONCLUSIONS: The MTSS provides strong and accurate prediction of quit attempts and is a candidate for a standard single item measure of motivation to stop smoking. Further research should assess the external validity of this measure in different smoking populations. PMID- 22943959 TI - Psychiatric disorder co-morbidity and correlates in an ethnically diverse sample of obese patients with binge eating disorder in primary care settings. AB - OBJECTIVE: To examine DSM-IV lifetime/current psychiatric disorder co-morbidity and correlates in ethnically-diverse obese patients with binge eating disorder (BED) seeking treatment for obesity and binge eating in primary care. METHOD: A consecutive series of 142 participants (43% Caucasian, 37% African-American, 13% Hispanic-American, and 7% "other" ethnicity) were evaluated with semi-structured interviews. RESULTS: 67% of BED patients had at least one additional lifetime psychiatric disorder, with mood (49%), anxiety (41%), and substance-use (22%) disorders most common. In terms of current co-morbidity, 37% had at least one other psychiatric disorder, with anxiety (27%) and mood (17%) most common. Few gender differences were observed but psychiatric co-morbidity rates differed across ethnic/racial groups with larger differences for current diagnoses. African-American and Hispanic groups were more than twice as likely as the Caucasian group to have additional current psychiatric disorders, mood disorders, and anxiety disorders. Psychiatric co-morbidity was associated with greater eating-disorder psychopathology and poorer functioning, but not with binge-eating or BMI. CONCLUSION: Our study presents new findings suggesting that among obese BED patients in primary care, ethnic/racial minority groups are more likely than Caucasian groups to present with psychiatric co-morbidity. Within BED, psychiatric co-morbidity shows few gender differences but is associated with greater eating-disorder psychopathology and poorer functioning. PMID- 22943963 TI - How the origin of fresh household waste affects its ability to be biodegraded: an assessment using basic tools and its application to the city of Kara in Togo. AB - Waste biodegradation has been largely investigated in the literature by using conventional tests like the BMP test and the respirometric test, whereas only few studies deal with the use of leaching tests in combination with biological activity measurements. Consequently, this study used an improved leaching test to evaluate the biodegradability of two deposits of fresh household waste from the city of Kara in Togo. The first deposit came from households in neighborhoods located in the outskirts of the city and the second consisted of fresh waste, mainly composed of business waste and household waste, collected in the urban center and aimed at being deposited in the landfill. A physicochemical characterization of the two deposits completed the leaching test. The biological activity was monitored by measuring O(2) consumption and CO(2) production. pH, DOC/OM, VFA/DOC ratios and the SUVA index was measured in the leaching juice to assess both the state of degradation of the waste in the deposits and the ability of the organic matter to be mobilized quickly and to be easily assimilated by microorganisms. The biodegradability of waste from the city of Kara correlated with their origin even though the physical characteristics of the two deposits studied differed greatly. PMID- 22943966 TI - [Epidemiologic picture of one-year-pediatric anesthesia in France]. AB - INTRODUCTION: Nowadays, the epidemiological data on French pediatric anesthesia is limited. The purpose of this study was to perform an "epidemiological picture" of this activity. MATERIAL AND METHOD: From the national Program Information System Medicalization, we have identified the institutions of France performing more than 50 anesthesia by year in children under 15 years in 2008 and noted the demographic data, types of institutions, hospital stay and surgeries. RESULTS: Seven hundred and eighty-nine thousands and two hundred anesthetic procedures have performed during 648,018 hospital stays in 929 institutions. A percentage of 68.4% of children were between 3 and 15 years old, 26.7% between 1 and 3 years, 4.1% between 1 year and 1 month and 0.8% less than one month, including 62% of boys and 38% of girls. A percentage of 53.6% of hospital stays were realized in private institutions, 20.9% in University Hospitals (UH), and 20.4% in General hospitals (GH), mainly in day-case surgery (60%), 15.2% in stay of 24h and 24.8% in full hospital stay (FHS). The main surgeries were ENT (29%), digestive (21%), orthopedic (14%), urology (12%) and plastics (9%). Children less than 1 year old were managed by University Hospital and during FHS. Older children were managed in private institution and during day-case surgery. CONCLUSION: Over 50% of stays with anesthesia were performed in private institution and during day-case surgery. Controversially, the management of children younger than 1 year was mainly in University Hospital. PMID- 22943965 TI - Characterising the uncommon corticobasal syndrome presentation of sporadic Creutzfeldt-Jakob disease. AB - BACKGROUND: Corticobasal syndrome (CBS), which encompasses cortical sensory loss, alien limb, bradykinesia, rigidity, limb apraxia and dystonia, is the classic presentation of corticobasal degeneration (CBD). It may occur in other neurodegenerative disorders including sporadic Creutzfeldt-Jakob disease (sCJD). Current CBD diagnostic criteria outline features of CBS but fail to distinguish CBD from other causative pathologies. OBJECTIVES: To characterise the CBS presentation of sCJD (sCJD-CBS) in the context of existing CBD diagnostic criteria. METHOD: Data of two new cases of sCJD-CBS and seven patients identified from the Australian National Creutzfeldt-Jakob Disease Registry database was reviewed. Additional data from 11 published cases was incorporated to illustrate the natural history of sCJD-CBS. Comparison was made with pathologically diagnosed CBD cases with ante-mortem CBS presentation (CBD-CBS). RESULTS: sCJD CBS accounts for 1.8% of all Australian sCJD cases. Compared to CBD-CBS, disease progression is more rapid in sCJD-CBS (median time to diagnosis 48 vs.1.5 months, p < 0.001; and disease duration until death 68 vs. 5 months, p < 0.001). Although no clinical features separate the two, alien limb and myoclonus tend to occur early in sCJD-CBS following initial 'sensory' disturbance in the affected limb. Consistent with sCJD, distinctive diffusion weighted imaging (DWI) abnormalities on magnetic resonance imaging may also occur in sCJD-CBS. CONCLUSION: sCJD should be suspected in patients presenting with CBS when clinical progression is rapid and accompanied by DWI abnormalities, even without cerebrospinal fluid 14-3-3 protein detection and electroencephalographic periodic sharp wave complexes. We propose the addition of rapid (<12 months) progression to akinetic-mutism or death and DWI abnormalities as exclusions in future CBD diagnostic criteria. PMID- 22943967 TI - [Fresh whole blood transfusion for war surgery: the experience of the Kabul French combat support hospital from 2006 to 2009]. AB - OBJECTIVE: The specificities of military medicine have led to the maintenance of fresh whole blood (FWB) transfusion. STUDY DESIGN: The aim of our study was to evaluate this practice at the French military hospital in Kabul between 2006 2009. PATIENTS AND METHODS: During our study period, 19 FWB transfusions were performed and the data from 15 FWB transfusions could be analyzed. We studied the number of units by recipient, the characteristics of recipients, the results of blood tests performed after transfusion, the incidents in donors and recipients, the period for obtaining a unit of FWB and mortality of recipients. RESULTS: A total of 66 units of FWB were transfused in 15 patients. The median number of FWB units transfused was three per patient. Thirteen out of 15 (87%) were combat related casualties. All units were tested before transfusion for HIV with rapid diagnostic tests. Every blood samples of donors were negative for pathogens screened at the French Blood Service. No incident in donors and in recipients was reported. The average time between collection and transfusion was 140+/ 197minutes (median 43min). Mortality in recipients was 27% (n=4). CONCLUSION: In our study, the FWB transfusion was not associated with incidents. Nonetheless, this practice should be used only for exceptional situations like military conflicts where risks of FWB are lower than the absence of transfusion. PMID- 22943968 TI - [Arsenic self-poisoning: a case report]. PMID- 22943970 TI - Evaluation of the pharmacokinetics, food effect, pharmacodynamics, and tolerability of DA-1229, a dipeptidyl peptidase IV inhibitor, in healthy volunteers: first-in-human study. AB - BACKGROUND: Inhibitors of dipeptidyl peptidase (DPP) IV are a class of oral hypoglycemic agents that increase glucagon-like peptide-1 (GLP-1) levels by inhibiting its degradation. OBJECTIVE: This study evaluated the pharmacokinetics, pharmacodynamics, and tolerability of DA-1229, which is a newly developed DPP IV inhibitor. This study was planned as part of a product development project at the request of the Korean regulatory agency. METHODS: A 7 parallel arm dose escalation study was conducted in healthy Korean male volunteers. A single oral dose of DA-1229 or placebo was given to 10 subjects (8 active + 2 placebo) in each dose group of 1.25, 2.5, 5, 10, 20, 40, or 60 mg. To assess the effects of food, the subjects in the 10-mg dose group received a single dose of DA-1229 10 mg after a high-fat meal, crossing over from the administration of DA-1229 under a fasting state, after a 7-day washout period. Serial blood samples were collected up to 120 hours after drug administration for pharmacokinetic analysis and the assessment of DPP IV activity, and blood samples were collected up to 2 hours after each meal until the next morning of drug administration to evaluate active GLP-1, glucose, and insulin levels. RESULTS: Seventy-two subjects, aged 20 to 39 years and weighing 52.1 to 79.8 kg, participated in this study. Twenty-one adverse events were reported; all were mild, and all subjects recovered spontaneously. DA-1229 reached a peak at 3.0 to 5.5 hours after a single oral dose and the concentrations declined, with a terminal t(1/2) from 32.5 to 39.8 hours. The %CV of C(max) and AUC(0-last) ranged from 11.1% to 54.6%. Dose proportional pharmacokinetics were confirmed within the dose range by using a linear regression analysis, and the 95% CIs of the slope of the log-transformed C(max) and AUC(0-last) included 1.0. The pharmacokinetics of DA-1229 were unchanged by food. The degree of DPP IV inhibition was dependent on the dose, and groups receiving >=10 mg exhibited >80% DPP IV inhibition for >24 hours. The %CV of the time of the last quantifiable concentration ranged from 4.6% to 15.2%. C(max) of active GLP-1 was achieved at 30 minutes after meal intake. The active GLP-1 levels were enhanced in groups receiving >=5 mg. There were no changes in the glucose and insulin levels after DA-1229 administration. CONCLUSIONS: DA-1229 was well tolerated within the dose range of 1.25 to 60 mg. DA-1229 pharmacokinetics suggested dose proportionality, and dose-dependent DPP IV inhibition was exhibited. ClinicalTrials.gov identifier: NCT00961025. PMID- 22943971 TI - Assessment of antidiabetogenic potential of fermented soybean extracts in streptozotocin-induced diabetic rat. AB - Most of the available drugs for the treatment of diabetes mellitus (DM) produce detrimental side effects, which has prompted an ongoing search for plant with the antidiabetic potential. The present study investigated the effect of soybean extracts fermented with Bacillus subtilis MORI, fermented soybean extracts (BTD 1) was investigated in streptozotocin (STZ)-induced diabetic rats. The possible effects of BTD-1 against hyperglycemia and free radical-mediated oxidative stress was investigated by assaying the plasma glucose level and the activity of enzymatic antioxidants, such as superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), catalase (CAT), and malondialdehyde (MDA). A significant increase in the levels of both plasma glucose and reactive oxygen species (ROS) was observed in the diabetic rats when compared to normal control group. After administration of BTD-1 (500 and 1000 mg/kg/day), the elevated plasma glucose level was significantly reduced while the plasma insulin level and the activities of SOD, GSH-Px, CAT and MDA were significantly increased. The results suggest that administration of BTD-1 can inhibit hyperglycemia and free radical-mediated oxidative stress. The administration of BTD-1 also inhibited the contractile response by norepinephrine (10(-10)-10(-5) M) in the presence of endothelium, and caused significant relaxation by carbachol (10(-8)-10(-5) M) in rat aorta. These findings indicate that BTD-1 improves vascular functions on STZ-induced diabetic rats. Therefore, subchronic administration of BTD-1 could prevent the functional changes in vascular reactivity in STZ-induced diabetic rats. The collective findings support that administration of BTD-1 may prevent some diabetes-related changes in vascular reactivity directly and/or indirectly due to its hypoglycaemic effect and inhibition of production of ROS. PMID- 22943972 TI - Combined treatment with capsaicin and resveratrol enhances neuroprotection against glutamate-induced toxicity in mouse cerebral cortical neurons. AB - Capsaicin and resveratrol as natural products have a variety of beneficial effects. However, capsaicin is also a neurotoxic agent, rendering its effect on the nervous system confusing. The aim of this study was to investigate whether capsaicin and/or resveratrol have a protective effect against glutamate (Glu) induced neurotoxicity. After exposure to glutamate for 15 min, cerebral cortical neurons of ICR mouse fetuses on embryonic days 15-16 were post-treated with capsaicin and/or resveratrol for 24 h. Glu induced a significant reduction in cell viability, but the cell viability increased significantly with capsaicin or resveratrol treatment and further was highest in the neurons co-treated with both phytochemicals. Glu-induced reactive oxygen species generation and apoptotic neuronal death also significantly decreased by a combined treatment with both phytochemicals. Due to Glu insults, the reduced mRNA levels of cytoplasmic glutathione peroxidase, copper/zinc and manganese superoxide dismutases, and Bcl x(L) and the overexpressed mRNA levels of interleukin-1beta and tumor necrosis factor-alpha were significantly restored by post-treatment of capsaicin and/or resveratrol. These findings indicate that capsaicin and resveratrol are neuroprotective against Glu-induced toxicity and that the combined treatment of both phytochemicals can enhance the neuroprotection, suggesting a useful therapeutic application in the treatment of neurodegenerative disorders. PMID- 22943969 TI - Effects of application durations and heat on the pharmacokinetic properties of drug delivered by a lidocaine/tetracaine patch: a randomized, open-label, controlled study in healthy volunteers. AB - BACKGROUND: The lidocaine/tetracaine heated patch is typically applied to the skin for 20 to 30 minutes to provide local dermal analgesia prior to venous access or minor dermatologic procedures. The potential exists for the use of multiple heated patches for longer application times, but the pharmacokinetic properties and tolerability of these multiple and/or longer applications have not been assessed. OBJECTIVE: The aim of this study was to assess the effects of heat and application time on the pharmacokinetic properties and tolerability of the patch after the application of 4 lidocaine/tetracaine (70/70 mg) heated patches applied at the same time in healthy volunteers for up to 12 hours. METHODS: In this randomized, open-labeled, controlled study, healthy subjects underwent 4 treatment periods (2-, 4-, or 12-hour application of 4 heated patches, or 4-hour application of 4 unheated patches), each separated by a 1-week washout period. RESULTS: Twelve subjects were enrolled (8 women, 4 men; mean age, 31.8 years; mean body mass index, 24.1 kg/m(2)). No tetracaine was detected in the plasma of any subject. Plasma concentrations of lidocaine increased rapidly during the first 2 hours of application in each heated-patch group, and with mean (SD) C(max) values of 18.2 (5.1), 25.7 (5.9), and 30.3 (8.1) ng/mL in the 2-, 4-, and 12-hour groups, respectively. Estimates of application time-normalized AUC(0-t) were not significantly different between the 2- and 4-hour applications of the heated patches, but were 25% lower during the 12-hour application time, suggesting continued but diminished drug delivery between 4 and 12 hours. Compared with subjects who received the unheated patch, those who received the heated patch had plasma lidocaine concentrations 5- and 3-fold higher after 30 and 60 minutes, respectively. Fifteen mild to moderate adverse events (AEs) were reported in 7 subjects, and none of the subjects discontinued the study due to treatment-related AEs. CONCLUSION: The heated patch continuously delivered drug for up to 12 hours and was generally well tolerated in these healthy subjects. ClinicalTrials.gov identifier: NCT01602757. PMID- 22943973 TI - Mangosteen xanthones mitigate ovalbumin-induced airway inflammation in a mouse model of asthma. AB - alpha- and gamma-Mangostin, which are the major xanthones purified from a Mangosteen, Garcinia mangostana Linn., exhibit a wide range of anticancer, antioxidant, and anti-inflammatory activities. Here, we assessed their therapeutic effects in a mouse model of ovalbumin (OVA)-induced allergic asthma. Animals were treated with alpha- and gamma-mangostins orally for 3 days at doses of 10 and 30 mg/kg daily, 1h before the OVA challenge. Administration of alpha- and gamma-mangostins significantly reduced the major pathophysiological features of allergic asthma, including inflammatory cell recruitment into the airway, airway hyperresponsiveness (AHR), and increased levels of Th2 cytokines. In addition, alpha- and gamma-mangostins attenuated the increases in phosphoinositide 3-kinase (PI3K) activity, phosphorylation of Akt, and NF-kappaB in nuclear protein extracts after OVA challenge. In conclusion, alpha- and gamma mangostin may have therapeutic potential for the treatment of allergic asthma. PMID- 22943974 TI - Prolonged consumption of flaxseed flour increases the 17beta-estradiol hormone without causing adverse effects on the histomorphology of Wistar rats' penis. AB - Consumption of foods rich in phytoestrogens such as flaxseed has increased due to its chemoprotective effects, especially those related to the cardiovascular system. The flaxseed has components that can interfere with development of male reproductive system. This study aims to investigate the possible effects of prolonged consumption of flaxseed flour on hormonal and histomorphologic penis parameters of adult Wistar rats. Rat dams were divided into two groups during lactation period: the control group that was fed with diet based on casein and the flaxseed group that was fed with diet based on casein containing 25% of flaxseed . At weaning, 10 male offspring from each group continued to receive the experimental diets until 250 days old. Rats fed with diet containing flaxseed showed increased concentrations of 17beta-estradiol (p=0.01) but no changes in testosterone concentrations. With regard to histomorphometric analysis of the penis, supplemented rats had lower values for the total area of the corpus spongiosum (p=0.01). All other analyzed parameters wer e similar as the control. Results showed that the use of flaxseed flour did not cause adverse effects on the penis morphology but increases the 17beta-estradiol hormone, when consumed in integral form for a prolonged period. PMID- 22943975 TI - [How to change behaviors without dying in the attempt: more favorable environments and less health education]. PMID- 22943976 TI - [Information needs and internet use in patients with breast cancer in Spain]. AB - OBJECTIVE: To analyze information needs and search strategies among women with breast cancer in Spain. An additional aim was to explore how the internet, as a source of health information, influences the autonomy and active management of this disease among patients. The research was conducted in 2010 and 2011. METHOD: This study forms part of a broader qualitative study that focuses on describing patients' experiences of breast cancer and the trajectory of the disease, with the aim of creating a platform of integrated information resources for patients, relatives and healthcare professionals (PyDEsalud: http://www.pydesalud.com). We carried out 41 in-depth, semi-structured interviews with breast cancer patients in different stage of the disease, who were aged between 32 and 69 years. The interviewees' were selected by intentional sampling, which included 15 Spanish regions. The field work was carried out from June to August, 2010. The interviews were recorded on videotape or audio. Based on patients' narratives of their disease, a thematic-inductive analysis was performed of the information gathered. RESULTS: The findings show the importance of the internet as a source of health information. Moreover, the internet is a resource that is able to promote the empowerment process among patients and, consequently, to aid improvement in disease management. CONCLUSIONS: Users need access to web sites with high quality health information, adapted to their needs and objectives. PMID- 22943977 TI - [Prevalence of smoking among drivers of private vehicles]. AB - OBJECTIVE: To determine the prevalence of smoking among drivers of private vehicles in the city of Lleida (Spain). METHODS: A random sample of 1600 cars passing through six intersections regulated by traffic lights were selected. The variables were age, sex, smoking driver, adult passengers, intersection (urban/interurban), day (working day/weekend), hour (morning/evening) and simultaneous smokers. We calculated the prevalence of smoking drivers and the corresponding odds ratios (ORs), adjusted for the potential confounding variables, as well as their 95% confidence intervals (95% CI). RESULTS: The prevalence was 6.0% (95% CI: 4.9-7.3) and was higher in men (6.4%), in the group aged 41 to 60 years (6.9%), and in unaccompanied drivers (6.5%). The probability of the driver smoking increased if there was a smoking passenger (aOR=10.8; 95% CI: 3.6-32.5). The frequency of smoking drivers was higher on working days (aOR=1.7; 95% CI: 1.0-2.8) and in the morning (aOR=1.6; 95% CI: 1.0-2.4). CONCLUSIONS: The prevalence of smoking drivers can be considered dangerously high. We recommend avoiding smoking while driving. PMID- 22943978 TI - [Cholera in the province of Valencia (Spain) by judicial district in the 19th Century]. PMID- 22943980 TI - Bovine mature adipocytes readily return to a proliferative state. AB - The dynamics of human and animal adipogenesis has been defined using several traditional cell systems including stromal vascular cells and adipocyte-related cell lines. But a relatively new cell system using progeny cells stemming from the dedifferentiation of purified cultures of mature adipocytes may be used for studying the development and biology of adipocytes. In this research, we show that isolated (and purified) mature adipocytes derived from Wagyu cattle dedifferentiate into progeny cells, and that these spindle-shaped, proliferative competent daughter cells possess ability to proliferate. We outline the optimum cell culture system and offer precautionary thoughts for effective mature adipocyte culture. Collectively, this represents a novel cell model which may provide new insights into cell development, physiology and use as a model for animal production/composition, tissue engineering and disease treatment. PMID- 22943979 TI - Covalent inhibition of recombinant human carboxylesterase 1 and 2 and monoacylglycerol lipase by the carbamates JZL184 and URB597. AB - Carboxylesterase type 1 (CES1) and CES2 are serine hydrolases located in the liver and small intestine. CES1 and CES2 actively participate in the metabolism of several pharmaceuticals. Recently, carbamate compounds were developed to inhibit members of the serine hydrolase family via covalent modification of the active site serine. URB597 and JZL184 inhibit fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), respectively; however, carboxylesterases in liver have been identified as a major off-target. We report the kinetic rate constants for inhibition of human recombinant CES1 and CES2 by URB597 and JZL184. Bimolecular rate constants (k(inact)/K(i)) for inhibition of CES1 by JZL184 and URB597 were similar [3.9 (+/-0.2) * 10(3) M(-1) s(-1) and 4.5 (+/-1.3) * 10(3) M( 1) s(-1), respectively]. However, k(inact)/K(i) for inhibition of CES2 by JZL184 and URB597 were significantly different [2.3 (+/-1.3) * 10(2) M(-1) s(-1) and 3.9 (+/-1.0) * 10(3) M(-1) s(-1), respectively]. Rates of inhibition of CES1 and CES2 by URB597 were similar; however, CES1 and MAGL were more potently inhibited by JZL184 than CES2. We also determined kinetic constants for spontaneous reactivation of CES1 carbamoylated by either JZL184 or URB597 and CES1 diethylphosphorylated by paraoxon. The reactivation rate was significantly slower (4.5*) for CES1 inhibited by JZL184 than CES1 inhibited by URB597. Half-life of reactivation for CES1 carbamoylated by JZL184 was 49 +/- 15 h, which is faster than carboxylesterase turnover in HepG2 cells. Together, the results define the kinetics of inhibition for a class of drugs that target hydrolytic enzymes involved in drug and lipid metabolism. PMID- 22943983 TI - [Consideration on the treatment of cervical ossification of the posterior longitudinal ligament]. PMID- 22943981 TI - Utility of a partner communication scale and a personal meaning scale in newly diagnosed HIV-infected persons. AB - No studies to our knowledge have examined the Lepore Social Constraint Scale or Fife Constructed Meaning Scale in recently diagnosed HIV-infected persons. Twenty four participants in a prospective observational cohort completed the social constraint measure, and 47 completed the constructed-meaning scale at either 3 or 9 months after diagnosis. Participants completed a 4-week visual analogue scale to assess adherence to antiretroviral therapy, and validated depression and self efficacy scales. Spearman correlation coefficients compared measures. In cross sectional analyses, participants with higher social-constraint scores had lower constructed meaning and adherence. Higher social constraint correlated negatively with self-efficacy and positively with depression. Higher constructed-meaning scores did not correlate with adherence but correlated positively with self efficacy and negatively with depression. The quality of HIV-infected individuals' discussions of HIV with their partners and positive constructed meaning were associated with better mental health and could be targets for improving medication adherence. PMID- 22943984 TI - [To focus on the diagnosis and treatment of ossification of posterior longitudinal ligament of cervical spine]. PMID- 22943982 TI - The impact of neuropsychological performance on everyday functioning between older and younger adults with and without HIV. AB - In this cross-sectional study, a community-based sample of 162 younger and older adults with and without HIV was compared on neuropsychological and everyday functioning measures. In the HIV sample, the relationship between cognition, everyday functioning, and HIV biomarkers was also examined. A battery of cognitive tests was completed along with two laboratory measures of everyday functioning and one measure of HIV medication adherence. Main effects for age and HIV were found on several neuropsychological measures and on the Timed Instrumental Activities of Daily Living test; those who were older or who had HIV exhibited poorer performance. Although age-by-HIV interactions were not observed, older adults with HIV as a group performed worse on eight out of the nine neuropsychological and everyday functioning measures. Few of these neuropsychological and everyday measures were related to HIV biomarkers (e.g., CD4+ T cell count). Implications for nursing practice and research are posited. PMID- 22943986 TI - [Cervical ossification of the posterior longitudinal ligament and it's surgical intervention]. PMID- 22943985 TI - [Surgical options of cervical posterior longitudinal ligament ossification]. PMID- 22943987 TI - [Use sagittal reconstruction CT for making decisions regarding the surgical strategy for cervical ossification of the posterior longitudinal ligament]. AB - OBJECTIVE: Use sagittal reconstruction CT to verify the surgical strategy for cervical ossification of the posterior longitudinal ligament (OPLL). METHODS: A retrospective study of 161 patients (106 males and 55 females) who had undergone surgery for OPLL from July 2007 to November 2010 was performed. The mean age at surgery was 54.5 years (range from 26 to 77 years). The mean follow-up period was 28 months (12 - 54 months). There were 40 patients accept anterior approach surgeries (anterior group) which include 14 cases of anterior cervical corpectomy and fusion and 26 cases of anterior cervical discectomy and fusion. There were 120 patients accept posterior approach surgeries (posterior group) which was spinous process-splitting laminoplasty for cervical myelopathy using coralline hydroxyapatite. One patient accepted combined anterior and posterior approach. According to the sagittal reconstruction CT, the main reason for spinal cord compression was cervical disc herniation in anterior group, and OPLL in posterior group. The level of spinal cord compression was 1 to 2 levels in anterior group, and 1 to 5 levels in posterior group with a major of 2 to 4 levels. As the classification of OPLL, segmental type and circumscribed type were major of segmental type in anterior group and all of the four types were in posterior group, the distribution of each type was average. The patients of posterior group were classified into two groups according to the modified K-line classification, and clinical results were compared between the two groups. The modified K-line was defined as a line that connects the midpoints of the spinal canal at C(2) and C(7) on sagittal CT myelography. Compression to the spinal cord did not exceed the K-line in the modified K-line(+) group and did exceed it in the modified K line(-) group. Clinical data were compared using t-test or chi(2) test. Correlation analysis was used to determine the relationships of C(2)-C(7) angulation between sagittal reconstruction CT and neutral position X-ray. RESULTS: The patient of anterior group had better recovery rate of the JOA score (72% +/- 27%) than the posterior group (59% +/- 35%) at the latest follow-up (t = 2.238, P = 0.027). In posterior group, the patients of modified K-line(+) group had better recovery rate of the JOA score (63% +/- 37%) than the K-line(-) group (49% +/- 30%) at the latest follow up (t = 2.150, P = 0.034). The C(2)-C(7) angulation on sagittal reconstruction CT was 11 degrees +/- 9 degrees which has significantly correlated with the C(2)-C(7) angulation on neutral position X-ray which was 10 degrees +/- 10 degrees (r = 0.947, P < 0.01). CONCLUSIONS: Considering the selection of surgical approach, it should be combined with the main clinical diagnosis for spinal cord compression, the level of compression, the classification of OPLL and the kyphotic alignment of the cervical spine. The modified K-line is a simple and practical tool for making decisions regarding the surgical strategy for cervical OPLL patients. PMID- 22943988 TI - [Surgical options and clinical outcomes of cervical ossification of the posterior longitudinal ligament]. AB - OBJECTIVE: To discuss the options and clinical outcomes of surgical treatment of cervical ossification of the posterior longitudinal ligament (OPLL). METHODS: From January 2006 to December 2010, 63 patients of cervical OPLL treated surgically by same team were retrospectively analyzed. There were 49 males, 14 females, with a mean age of 56.2 years (from 38 to 76 years). The duration of symptoms ranged from 2 months to 20 years (mean 3.2 years). The ossified ligament was classified via sagittal and coronal images on CT scan. The cervical curvature was measured. Choice of surgical methods was determined according to the type of ossified ligament and cervical curvature. All complications occurred was recorded. The Japanese Orthopedic Association (JOA) scoring system was used to evaluate the neurological status. The severity of cervical pain was assessed with visual analogue scale (VAS) method. The results of preoperative, postoperative and follow-up were statistically compared with student t test. RESULTS: The JOA scores of 35 patients performed with anterior approach improved from 9.8 +/- 2.3 preoperatively to 11.7 +/- 2.1 at final follow-up (t = 3.28, P < 0.05). The VAS sore was significantly decreased at final follow-up compared with preoperative (t = 3.15, P < 0.05). While the JOA scores improved from 10.4 +/- 2.7 preoperatively to 12.5 +/- 2.3 at final follow-up (t = 3.81, P < 0.05) in 12 patients with laminectomy and from 9.7 +/- 2.5 to 11.6 +/- 2.6 in 14 patients with laminoplasty (t = 3.56, P < 0.05). The VAS score either in laminectomy or in laminoplasty has not significantly difference between preoperative, 3 month postoperative and final follow-up (P > 0.05). Two patients underwent a combined anterior-posterior approach procedure. Complications in patients included 1 patient of postoperative neurologic deterioration and 2 cases of cerebrospinal fluid leakage in patients with anterior approach, and 2 cases of C(5) nerve palsy in patients with laminectomy. CONCLUSIONS: Surgical options of cervical OPLL should be determined by detailed study of type and range of ossified ligament, as well as the cervical curvature of patients. Good neurological function can be expected in case of appropriate choosing the method for treating the cervical OPLL. PMID- 22943989 TI - [Analysis of axial symptoms after indirect decompression for ossification of the posterior longitudinal ligament of the cervical spine]. AB - OBJECTIVE: To study the etiology and clinical significance of axial symptoms after posterior operative procedures for ossification of the posterior longitudinal ligament (OPLL). METHODS: From February 2005 to February 2010, 76 patients with OPLL treated were retrospectively experienced. There were 34 male and 42 female with average of 52.1 years (range from 37 to 74 years), the average duration of the disease was 32.1 months (range from 11 to 56 months). Nineteen patients underwent traditional laminectomy in group A, 33 patients received open door laminoplasty in group B and 24 patients underwent lateral mass screw fixation in group C. All patients underwent X-ray examination pre- and post operative, computed tomography were used for diagnosis of OPLL, the recovery rate was calculated using pre- and postoperative Japanese Orthopedic Association (JOA) scores for each patient. Pre- and postoperative cervical curvature index and axial symptoms were measured and compared. chi(2) test and SNK test were used as statistical methods. RESULTS: All patients were followed up for 14 - 35 months, average (21 +/- 5) months. Loss of cervical curvature index was 4.2% +/- 1.7% in group A, 2.9% +/- 2.2% in group B and 2.3% +/- 1.9% in group C. The difference was significant in loss of cervical curvature indice between group A and B (q = 2.94, P < 0.01), group A and C (q = 4.23, P < 0.01). The average JOA recovery rate was 58.3% for group A, 64.3% for group B and 66.7% for group C. There was no significant difference in JOA recovery rate among the three groups (P > 0.05). The rate of early evident axial symptoms was 7/19 in group A, 30.3% in group B and 33.3% in group C and the difference was not statistically significant (P > 0.05). The incidence of late evident axial symptoms was 5/19 in group A, 12.1% in group B and 8.3% in group C, the difference was not significant between group B and C (chi(2) = 13.762, P < 0.01), but of statistical difference between group A and B(chi(2) = 6.368, P < 0.01), group A and C (chi(2) = 11.481, P < 0.01). No kyphotic deformity in the group A, no "Close Door" phenomenon in group B and no internal failure in group C. CONCLUSION: The incidence of early axial symptoms are of no significant difference among the three groups, but late axial symptoms are higher in the laminectomy than other groups, which may be associated with loss of cervical lordosis. PMID- 22943990 TI - [Reoperation to the ossification of the posterior longitudinal ligament]. AB - OBJECTIVE: To discuss surgical approaches of ossification of the posterior longitudinal ligament (OPLL) of cervical spine. METHODS: Between June 2005 to July 2010, 36 patients with OPLL of cervical spine were reoperated. There were 23 male, 13 female, age from 39 to 72 years (mean 57 years). The time of the first operation to the reoperation were 4 months to 24 years, an average of 3.9 years. Among 20 patients underwent anterior corpectomy and fusion (ACD) at first operation, 14 cases combined stenosis of cervical spinal canal, 10 cases were insufficient decompression of OPLL, 5 cases injured of cervical spinal cord during the first operation, 1 case was adjacent disc herniation. Among 14 cases underwent expensive open-door laminoplasty (ELAP) at first operation, 6 cases were insufficient decompression of OPLL, 4 cases were inadequate decompressed segment, 2 cases were cervical segmental kyphosis, 2 cases were progression of OPLL combined with disc herniation. Among 2 cases underwent combined approach at first operation, 1 case was insufficient decompression of OPLL, the other was adjacent disc herniation. Their pre- and post-operative X-ray, CT and MRI were analyzed. The complications of reoperation were recorded. RESULT: There were 30 patients followed-up, with a period of 1.5 - 4.0 years, average 1.8 years. With 36 patients, none had deterioration, 2 patients had no recovery post-reoperation, 34 patients had 31.2% Japanese Orthopedic Association score improve rate. Among 22 cases underwent ELAP at second operation, 3 cases had postoperative segmental palsy. Among 14 cases underwent ACD at second operation, 3 cases had intraoperative dural defects. CONCLUSION: Surgical strategy for OPLL of cervical spine should consider the type of OPLL and stenosis of cervical spinal canal. PMID- 22943991 TI - [Surgical management and outcome of solid-pseudopapillary tumor of pancreas: a series of 58 cases]. AB - OBJECTIVE: To study the surgical management of solid-pseudopapillary tumor of the pancreas (SPTP) and its characteristics of outcome. METHODS: Fifty-eight patients with SPTP of the pancreas admitted from January 2001 to December 2010 were retrospectively analyzed. There were 7 male and 51 female patients, with an average age of 30 years (ranging 9 to 70 years). Most patients were symptomatic before admission; the most common symptom was abdominal pain. Of the 58 patients, 21 patients underwent pancreaticoduodenectomy, 30 patients underwent distal pancreatectomy, 6 patients underwent central pancreatectomy, 1 patient underwent simple tumor enucleation, and 1 patients underwent duodenum-preserving pancreatic head resection. RESULTS: The average length of stay in hospital was 23.8 days (ranging 12 to 64 days). Thirteen patients (22.4%) developed postoperative complications, including grade A postoperative pancreatic fistula of 8 cases, gastrointestinal tract bleeding of 1 case, pleural effusion of 2 cases, wound infection and fat liquefaction of 2 cases. Two patients underwent reoperation due to gastrointestinal tract bleeding or wound infection. There was no hospital death. Forty-four patients were followed-up for 7 to 136 months with an average of 41 months. All the 44 patients were alive, while 8 patients developed dyspepsia and 4 patients developed diabetes mellitus. There were no tumor recurrences or metastasis. CONCLUSIONS: SPTP is found primarily in young women. Excellent prognosis would be achieved with surgical resection. PMID- 22943992 TI - [Value of self-expanding metallic stent for obstructing left-sided colon cancer or rectal cancer]. AB - OBJECTIVE: To investigate the therapeutic value of self-expanding metallic stent (SEMS) for resectable obstructing left-sided colon cancer or rectal cancer. METHODS: Clinical data of 73 patients who had acute obstruction due to left-sided colon cancer or rectal cancer during May 2007 to January 2012 were retrospectively analyzed. The patients were divided into 2 groups: SEMS group (34 cases) underwent surgical resection after insertion of SEMS; emergency surgery group (39 cases) underwent emergency operation. The 2 group patients were compared for the incidence of primary anastomosis, stoma rate, laparoscopic surgery rate, mortality, postoperative morbidity, ICU admission rate, length of ICU stay, hospital stay, and hospitalization costs. RESULTS: The incidence of primary anastomosis in SEMS group was significantly higher than that in emergency surgery group (97.1% vs. 56.4%, chi(2) = 16.256, P < 0.001), and the protective stoma rate and permanent stoma rate in SEMS group were both lower than those in emergency surgery group (33.3% vs. 86.3%, 2.9% vs. 43.6%, chi(2) value were 14.972 and 16.156, both P < 0.001). Patients in SEMS group underwent significantly more laparoscopic surgery than in emergency surgery group (47.1% vs. 0, chi(2) = 23.505, P < 0.001). There were no significant difference in postoperative mortality (2.9% vs. 10.3%, P = 0.364). The postoperative morbidity in SEMS group was significantly lower than that in emergency surgery group (35.3% vs. 66.7%, P = 0.007). Incisional infection was the most common complication in both groups, and the incidence of which seemed to be more higher in emergency surgery group (17.6% vs. 38.5%, chi(2) = 3.840, P = 0.050). There was a lower ICU admission rate in SEMS group (24.2% vs. 53.9%, chi(2) = 6.972, P = 0.008), and the mean length of ICU stay and hospital stay were both shorter in SEMS group ((69.5 +/- 7.4) hours vs. (114.3 +/- 10.9) hours, t = -20.23, P < 0.001; (19.6 +/ 4.8) days vs. (23.4 +/- 6.2) days, t = -2.90, P = 0.005). The cost of hospitalization was less in SEMS group (45 383 +/- 15 648 vs. 61 485 +/- 20 380, t = -3.74, P < 0.001). CONCLUSIONS: SEMS can effectively relieve the large intestinal obstruction caused by left-sided colon cancer or rectal cancer, and change the traditional emergency surgery into a selective surgery with better outcomes. SEMS appears to be a valuable technique for resectable obstructing left sided colorectal cancer. PMID- 22943993 TI - [Hand-assisted laparoscopic surgery in radical resection of rectal cancer]. AB - OBJECTIVE: To investigate the application experience and clinical effects of hand assisted laparoscopic radical resection for rectal cancer. METHODS: The clinical data of 156 patients with rectal cancer treated with hand-assisted laparoscopic surgery between August 2009 and April 2011 were analyzed retrospectively. RESULTS: The operative procedures of 156 patients were completed successfully and 1 case was converted to laparotomy (0.6%). The mean operation time was (125 +/- 35) minutes; the mean intraoperative blood loss was (118 +/- 60) ml; the mean time of bowel function recovery was (60 +/- 8) hours; the median postoperative hospital stay was (9.5 +/- 2.2) days. The mean number of lymph nodes dissection was (14 +/- 5). Five patients (3.2%) had postoperative complications. All the patients were followed up. There had been no local recurrence or trocar site implantation metastasis. CONCLUSION: Hand-assisted laparoscopic surgery approach for the curative resection of rectal cancer is safe and effective and has broad prospects in clinical application. PMID- 22943994 TI - [Predictors of level V lymphatic metastasis in papillary thyroid carcinoma]. AB - OBJECTIVE: To study the predictors of level V metastasis in papillary thyroid carcinoma (PTC). METHODS: The clinic data of 122 patients with PTC who underwent therapeutic lateral neck dissection between March 2004 and November 2010 was analyzed retrospectively. There were 31 male and 91 female patients. The median age at diagnosis was 38.5 years (ranging from 8 to 87 years). All the patients had undergone unilateral or bilateral lymph node dissection (II-VI or I-VI). Univariate analysis and multivariate analysis were performed using chi(2) test and binary Logistic regression test, respectively. RESULT: The level V metastases was significantly associated with capsular invasion, extrathyroidal extension, preoperative distant metastasis, the size of primary, ipsilateral level IV lymph node metastasis and simultaneous metastases to ipsilateral level II, III and IV (chi(2) = 4.223 - 13.748, P < 0.05). Age, sex, tumor-multifocal, pTNM, central lymph node metastases ipsilateral level II lymph node metastases and ipsilateral level III lymph node metastases were not found to be associated with level V metastases (chi(2) = 0.882 - 3.167, P > 0.05). In multivariate analysis, extrathyroidal extension (OR = 8.32, 95%CI: 2.44 - 28.3, P = 0.001) and simultaneous metastases to ipsilateral level II, III and IV (OR = 7.81, 95%CI: 2.11 - 28.8, P = 0.002) were independent predictors of level V metastasis. CONCLUSIONS: Extrathyroidal extension, simultaneous metastases to ipsilateral level II, III and IV are risk factors for level V lymph nodes metastases in PTC. Dissection of level V lymph nodes should be considered for PTC patients with extrathyroidal extension and simultaneous metastases to ipsilateral level II, III and IV. PMID- 22943995 TI - [Early and midterm results of covered Cheatham-Platinum stent for treatment of aortic coarctation: a report of 9 cases]. AB - OBJECTIVE: To evaluate the early and midterm results of covered Cheatham-Platinum (CP) stent for treatment of aortic coarctation (CoA) in adolescents and adults. METHODS: From January 2007 to June 2011, 9 consecutive cases of CoA underwent covered CP stent implantation. There were 4 male and 5 female patients, aging from 13 to 44 years with a mean of (24 +/- 11) years. The covered CP stent and balloon-in-balloon catheter were selected according to digital subtraction angiography measurements. The covered CP stents were expanded to appropriate diameter by inflation of the inner balloon and outer balloon successively. The systolic pressure gradient across the stenosis and narrowest degree of the stenotic vessels were compared before and after the procedure. RESULTS: After the procedure, the systolic pressure gradient across the stenosis decreased from (66 +/- 21) mmHg to (9 +/- 4) mmHg (1 mmHg = 0.133 kPa, t = 9.13, P = 0.000) and the narrowest degree of CoA decreased from 79% +/- 12% to 17 +/- 4% (t = 16.65, P = 0.000). During a mean follow-up of (33 +/- 22) months (ranging 4 to 54 months), no intrastent restenosis were found and systolic pressure gradient from upper to low extremity was not more than 15 mmHg in each case. CONCLUSIONS: Covered CP stent implantation is safe and effective for treatment of CoA in adolescents and adults. The early and midterm results are encouraging, but long term results require further follow-up and observation. PMID- 22943996 TI - [Influence of pulmonary function after combined thoracoscopic and laparoscopic esophagectomy for the treatment of esophageal carcinoma]. AB - OBJECTIVES: To investigate the influence of combined thoracoscopic and laparoscopic esophagectomy for early postoperative pulmonary function, and to study the relative factors for postoperative pulmonary complications. METHODS: From September 2009 to December 2010, 61 patients with esophageal cancer had undergone esophagectomy surgery, of which 32 patients had undergone combined thoracoscopic and laparoscopic esophagectomy (CTLE group), and 29 patients had undergone open three-field esophagectomy (open group). Pulmonary function, including forced vital capacity (FVC), forced expiratory volume in 1 second (FEV(1)) were measured on the 1(th) preoperative day, 5(th) and 10(th) postoperative day, and arterial blood gas analyses were performed during the same period. Meanwhile, pain scores and other potentially relevant factors were recorded as well. RESULTS: Preoperative pulmonary function and arterial blood gas analysis, including FEV(1)%, FVC%, PaO2 in two groups had no significant difference (t = -1.608 to 0.709, P = 0.113 to 0.481). On the 10(th) postoperative day, FEV(1)%, FVC%, PaO2, and SaO2 of two groups were significantly different (FEV(1)%: 77% +/- 17% vs. 53% +/- 13%, t = 6.241, P = 0.000; FVC%: 78% +/- 13% vs. 57% +/- 16%, t = 5.549, P = 0.000; PaO2: (87 +/- 9) mmHg vs. (79 +/- 14) mmHg, t = 2.477, P = 0.017; SaO2: 96% +/- 3% vs. 94% +/- 2%, t = 2.313, P = 0.024; 1 mmHg = 0.133 kPa). Pain score of CTLE group was lower than open group, and the scores of two groups had significant difference before the 5(th) day after surgery (t = -4.398 to -1.815, P = 0.000 to 0.049). Postoperative pulmonary complications of CTLE group was lower than open group (6/32 vs. 12/29, chi(2) = 3.745, P = 0.049). CONCLUSIONS: Combined thoracoscopic and laparoscopic esophagectomy has advantages on early postoperative pulmonary function. It can relatively reduce the incidence of pulmonary complications after surgery. PMID- 22943997 TI - [Repair of posterior mitral valve prolapsed: comparative study of three different approaches]. AB - OBJECTIVE: To compared outcomes of robotic mitral valve repair with those of standard sternotomy, and right anterolateral thoracotomy. METHOD: From August 2010 to July 2011, 70 patients with degenerative mitral valve disease and posterior leaflet prolapsed scheduled for elective isolated mitral valve repair were prospectively nonrandomized to undergo mitral valve operation by standard sternotomy (n = 30), right anterolateral thoracotomy (n = 30), or a robotic approach (n = 10). There were 49 male and 21 female patients, aging from 16 to 70 years with a mean of 53.4 years. Outcomes of the three groups were compared. RESULTS: Mitral valve repair was achieved in all patients except 1 patient in the standard group. There were no in-hospital deaths. The median operation time [(300 +/- 41) min, (184 +/- 20) min and (169 +/- 22) min, F = 112.5, P < 0.01], cardiopulmonary bypass time [(139 +/- 26) min, (82 +/- 20) min and (69 +/- 23) min, F = 36.8, P < 0.01], aortic cross-clamping time [(93 +/- 23) min, (47 +/- 10) min and (38 +/- 8) min, F = 75.0, P < 0.01] were longer for robotic than standard sternotomy and right anterolateral thoracotomy. The robotic group had shortest time of mechanical ventilation time [(4.9 +/- 2.1) h, (5.3 +/- 4.5) h and (14.1 +/- 10.2) h, F = 13.2, P < 0.01], ICU time [(15.1 +/- 2.1) h, (16.4 +/- 5.4) h and (28.7 +/- 16.1) h, F = 11.6, P < 0.01], postoperative hospital stay time [(4.6 +/- 1.0) d, (5.7 +/- 1.7) d and (8.8 +/- 5.1) d, F = 8.0, P < 0.01] with the lowest of drainage [(192 +/- 200) ml, (215 +/- 163) ml and (405 +/- 239) ml, F = 7.1, P < 0.01] and ratio of the patients needed blood transfusion (0, 20.0% and 66.7%, chi(2) = 22.7, P < 0.01). Patients were followed up 6 to 17 months, with 100% completed. No patients died during follow-ups, and no moderate or more mitral regurgitation was observed. The robotic group had the shortest time of return to normal activities compared with the other two groups [(2.4 +/- 0.7) weeks, (4.2 +/- 1.2) weeks and (8.2 +/- 1.8) weeks, F = 83.0, P < 0.01]. CONCLUSION: This study shows mitral valve repair via the right anterolateral thoracotomy and a robotic approach is safe and feasible, with good cosmetic results and rapid postoperative recovery, and is worthy of clinical selective application. PMID- 22943998 TI - [Analysis of clinical characteristics of renal oncocytoma: 26 cases report]. AB - OBJECTIVES: To investigate the diagnosis, therapy and prognosis of renal oncocytoma. METHODS: The data of 26 patients of renal oncocytoma in the department of urology of the Peking University First Hospital from 1999 to 2010 were collected. Retrospective analysis of renal oncocytoma clinical characteristics of patients including pathological characteristics and long term follow-up, treatment methods, and prognosis was undergone. RESULTS: The mean age of these patients was (55 +/- 14) years, mean tumor size was (4.1 +/- 1.3) cm, corresponding to a mean tumor volume of (24.0 +/- 21.1) cm(3). All of these cases were unilocular unilateral. All of these 26 patients received surgical treatment, 5 cases accepted partial nephrectomy while the other cases accepted radical nephrectomy. After a median follow-up time was (47 +/- 34) months (range 4 - 144 months) for 25 patients who had been followed up, there was no disease recurrence, progression or death attributed to oncocytoma. CONCLUSIONS: Renal oncocytoma is an uncommon tumor. It exhibits numerous features which are characteristic but not necessarily unique.Preoperative renal mass biopsy is the only way for pre-nephrectomy histologic diagnosis of oncocytoma. PMID- 22943999 TI - [The role of oxide stress during the pathogenesis of chronic pancreatic injuries induced by chronic high-fat diets in rat]. AB - OBJECTIVE: To provide more detailed information on the roles of lipid peroxidation in the pathogenesis of chronic pancreatic injuries in a pre-clinical rat model. METHODS: Totally 72 rats were divided into 6 groups (12 in each group) Rats in 5 experimental groups (n = 12) were fed with a high-fat diet (1% cholesterol, 10% lard, 0.3% sodium tauroglycocholate, 87.3% standard rodent chow as the control group) for 2, 4, 6, 10 and 16 weeks, respectively. Morphological studies in the pancreas tissue samples from rats were investigated by using various histological methods. Pancreatic stellate cells (PSCs) were identified by immunohistochemical staining for Desmin and alpha-smooth muscle actin (alpha SMA). The expression of the lipid peroxidation was detected by immunostaining for 4-hydroxy-2-nonenal (4-HNE) and thromboxane A2 receptor (TxA2r). The co localization of alpha-SMA and 4-HNE or alpha-SMA and TxA2r in PSCs was also analyzed in this study. RESULTS: Pancreatic cells with positive staining for Desmin and alpha-SMA in HFD rats were distributed in a more extensive way when compared to that in the control group. The levels of pancreatic 4-HNE and TxA2r were increased in rats from HFD groups significantly. The co-localization of 4 HNE and TxA2r were also found within activated PSCs in both of groups. CONCLUSION: The results showed that a chronic HFD feeding may increase the lipid peroxidation process and collagen synthesis through a critical signaling pathway of activated PSCs following pancreatic injuries in rats. PMID- 22944000 TI - [The influence of oxygen partial pressure change and vascularization of rabbit wound through negative pressure wound therapy]. AB - OBJECTIVE: To investigate the effect of vacuum sealing drainage (VSD) on variation of oxygen partial pressure (PtO2) and vascularization. METHODS: The 12 cases of rabbit's wound models were undergoing the VSD (vacuum group, n = 6) or conventional therapy (conventional group, n = 6). Variation of PtO2 was measured by oxygen partial pressure admeasuring apparatus, expression of hypoxia inducible factor 1alpha (HIF-1alpha) mRNA was measured by real-time fluorescent quantitative PCR, content of vascular endothelial growth factor (VEGF) was measured by ELISA after tissue homogenate in 7 days. Vascular endothelial cell (VEC) and new blood capillary (NBC) of hematoxylin-eosin slice of tissue were counted by using light microscope. RESULTS: Average value of PtO2 of vacuum group was significant lower than conventional group (t = -99.780 to -5.305, P < 0.01). Expression of HIF-1alpha (30 minutes, 1, 6, 12 hours were 3.11 +/- 0.07, 3.68 +/- 0.26, 4.16 +/- 0.13 and 3.91 +/- 0.26 respectively) and content of VEGF (30 minutes, 1, 6, 12 hours were 103.3 +/- 2.4, 134.2 +/- 9.0, 167.8 +/- 3.8 and 232.1 +/- 9.5 respectively) of vacuum group were increased after 30 minutes and significant lower than conventional group (t = 13.038 - 80.208, P < 0.01), and both of them were reduced after 24 hours (P < 0.05). Counting numbers of VEC (2.47 +/- 0.45 to 4.70 +/- 0.38) and NBC (1.33 +/- 0.49 to 4.33 +/- 0.68) of vacuum group were increased at the same time-point and significant higher than conventional group (t = -0.670 to 16.500, P < 0.05). CONCLUSIONS: PtO2 of wound surface could be reduced significantly by VSD. Expression of HIF-1alpha and content of VEGF were increased by VSD for enhancing differentiated state of VEC and construction of NBC, which were better for vascularization and wound healing. PMID- 22944001 TI - [Effect of aloe polysaccharides pretreatment on the cerebral inflammatory response and lipid peroxidation in severe hemorrhagic shock rats first entering high altitude]. AB - OBJECTIVE: To investigate the effect of aloe polysaccharides pretreatment on the cerebral inflammatory response and lipid peroxidation in severe hemorrhagic shock rats first entering high altitude. METHODS: Forty healthy male SD rats weighing 250-300 g were randomly divided into 5 groups (n = 8 each): sham group, shock group, AP group was further divided into 3 subgroups (AP1 0.75 mg/kg; AP2 1.50 mg/kg; AP3 3.00 mg/kg). The different doses AP were given iv respectively at 30 min before hemorrhagic shock. The mean blood pressure (MAP) was maintained at (35 +/- 5) mmHg (1 mmHg = 0.133 kPa) for 60 minutes. The animals were killed at 2 hours after resuscitation. Blood samples were obtained from femoral artery for detecting tumor necrosis factor alpha (TNF-alpha), IL-6 and IL-10 concentrations; the frontal and parietal lobes brain and the hippocampus were separated from brain tissues on the ice for detecting superoxide dismutase (SOD) activity and myeloperoxidase (MPO) activity, malondialdehyde (MDA) concentration, brain Wet dry weight ratio (W/D). RESULTS: Compared with sham group, hemorrhagic shock significantly increased serum TNF-alpha ((76 +/- 11) ng/L), IL-6 ((1303 +/- 141) ng/L) and IL-10 concentrations ((95 +/- 14) ng/L), MPO activity ((20.72 +/- 2.28)*10(-2) U/g) and MDA concentration ((80 +/- 13) nmol/mgprot) in the brain tissue and brain W/D (6.21 +/- 0.18) (t = 6.928 - 14.565, P < 0.05), while SOD activity ((56 +/- 11) U/mgprot) decreased significantly (t = -5.374, P < 0.05). There were no significant difference between shock and AP1 groups. AP2 group significantly inhibited hemorrhagic shock-induced increase serum TNF-alpha ((54 +/- 12) ng/L), IL-6 ((846 +/- 78) ng/L) and IL-10 concentrations ((66 +/- 11) ng/L), MPO activity ((13.13 +/- 1.23)*10(-2) U/g) and MDA concentration ((56 +/- 9) nmol/mgprot) in the brain tissue and brain W/D (5.71 +/- 0.18) (t = -6.905 - 3.357, P < 0.05), while SOD activity ((86 +/- 12) U/mgprot) increased significantly compared to shock group (t = 4.240, P < 0.05). There were no significant difference between AP2 and AP3 groups. CONCLUSION: AP pretreatment can attenuate the cerebral ischemia and reperfusion injury in severe traumatic hemorrhagic rats first entering high altitude through inhibiting systemic inflammatory response and leukocyte aggregation and lipid peroxidation in the brain. PMID- 22944002 TI - The combined effect of subthalamic nuclei deep brain stimulation and L-dopa increases emotion recognition in Parkinson's disease. AB - Deep brain stimulation of the subthalamic nucleus (DBS) is a widely used surgical technique to suppress motor symptoms in Parkinson's disease (PD), and as such improves patients' quality of life. However, DBS may produce emotional disorders such as a reduced ability to recognize emotional facial expressions (EFE). Previous studies have not considered the fact that DBS and l-dopa medication can have differential, common, or complementary consequences on EFE processing. A thorough way of investigating the effect of DBS and l-dopa medication in greater detail is to compare patients' performances after surgery, with the two therapies either being administered ('on') or not administered ('off'). We therefore used a four-condition (l-dopa 'on'/DBS 'on', l-dopa 'on'/DBS 'off', l-dopa 'off'/DBS 'on', and l-dopa 'off'/DBS 'off') EFE recognition paradigm and compared implanted PD patients to healthy controls. The results confirmed those of previous studies, yielding a significant impairment in the detection of some facial expressions relative to controls. Disgust recognition was impaired when patients were 'off' l dopa and 'on' DBS, and fear recognition impaired when 'off' of both therapies. More interestingly, the combined effect of both DBS and l-dopa administration seems much more beneficial for EFE recognition than the separate administration of each individual therapy. We discuss the implications of these findings in the light of the inverted U curve function that describes the differential effects of dopamine level on the right orbitofrontal cortex (OFC). We propose that, while l dopa could "overdose" in dopamine the ventral stream of the OFC, DBS would compensate for this over-activation by decreasing OFC activity, thereby restoring the necessary OFC-amygdala interaction. Another finding is that, when collapsing over all treatment conditions, PD patients recognized more neutral faces than the matched controls, a result that concurs with embodiment theories. PMID- 22944003 TI - Implicit emotional processing in peripheral vision: behavioral and neural evidence. AB - Emotional facial expressions (EFE) are efficiently processed when both attention and gaze are focused on them. However, what kind of processing persists when EFE are neither the target of attention nor of gaze remains largely unknown. Consequently, in this experiment we investigated whether the implicit processing of faces displayed in far periphery could still be modulated by their emotional expression. Happy, fearful and neutral faces appeared randomly for 300 ms at four peripheral locations of a panoramic screen (15 and 30 degrees in the right and left visual fields). Reaction times and electrophysiological responses were recorded from 32 participants who had to categorize these faces according to their gender. A decrease of behavioral performance was specifically found for happy and fearful faces, probably because emotional content was automatically processed and interfered with information necessary to the task. A spatio temporal principal component analysis of electrophysiological data confirmed an enhancement of early activity in occipito-temporal areas for emotional faces in comparison with neutral ones. Overall, these data show an implicit processing of EFE despite the strong decrease of visual performance with eccentricity. Therefore, the present research suggests that EFE could be automatically detected in peripheral vision, confirming the abilities of humans to process emotional saliency in very impoverished conditions of vision. PMID- 22944004 TI - Normal imaging in patients with cerebral palsy: what does it tell us? AB - OBJECTIVE: To identify distinctive clinical features characterizing children with cerebral palsy (CP) and normal-appearing magnetic resonance imaging (MRI) findings. STUDY DESIGN: Using a population-based CP registry, the Registre de la Paralysie Cerebrale au Quebec (Quebec Cerebral Palsy Registry), various antenatal, perinatal, and postnatal predictor variables, as well as current phenotype, were compared in patients with normal-appearing MRI findings and those with abnormal MRI findings. RESULTS: Of the 213 patients evaluated, 126 (60%) had MRI imaging results available and were included in our analysis. Of these 126 patients, 90 (71%; 51 males, 39 females) had abnormal findings and 36 (29%; 17 males and 19 females) had normal-appearing findings. Compared with other CP variants, normal-appearing MRI was more prevalent (P = .001) in dyskinetic CP (72.7%; 8 of 11) and less prevalent (P = .002) in spastic hemiplegic CP (10%; 4 of 40). There were no significant differences between the 2 groups (P > .05) in terms of the prevalence of perinatal or postnatal clinical features or clinical outcomes. Furthermore, 42% (15 of 36) of the children with normal-appearing MRI exhibited a high degree of functional disability (Gross Motor Functional Classification System IV-V), compared with 33% (30 of 90) with abnormal MRI. CONCLUSION: No clinical features, except a higher prevalence of dyskinetic CP, was identified in the children with normal-appearing MRI. More refined imaging techniques may be needed to evaluate patients with normal-appearing MRI findings. Furthermore, genetic or functional, rather than gross structural lesions, may underlie the pathophysiology of CP in this cohort. Finally, the high proportion of substantial functional disability underscores the importance of continuous follow-up even in the absence of early structural abnormalities on imaging. PMID- 22944005 TI - Th17 cell frequency in peripheral blood from children with allergic asthma correlates with the level of asthma control. AB - Here we show that the frequency of T(H)17 cells (CD3(+)CD4(+)CD161(+)CCR6(+) lymphocytes) is increased in peripheral blood of children with allergic asthma. Moreover, we found a significant relationship between the frequency of T(H)17 cells and level of asthma control, with reduced asthma control correlated with a higher proportion of T(H)17 cells. PMID- 22944006 TI - On-line sample concentration and determination of cationic alkaloids in human plasma by micelle to solvent stacking in capillary zone electrophoresis. AB - A sensitive method for the determination of three cationic alkaloids (berberine, palmatine and jatrorrhizine) from human plasma samples was developed by micelle to solvent stacking (MSS) in capillary zone electrophoresis (CZE). In MSS, the sample preconcentration mainly relies on the reversal in the effective electrophoretic mobility of the analytes at the boundary zone between the sample and CZE background solution (BGS). Under the optimized conditions, the sensitivity enhancement factors achieved in terms of corrected peak area were in the range from 47 to 53 for the alkaloids. The limits of detection (LODs) (S/N=3) for berberine, palmatine and jatrorrhizine were 0.01, 0.01 and 0.02MUg/mL, respectively. The intraday (n=6) and interday repeatabilities (n=12) expressed as the relative standard deviations (RSDs) were less than 6.9% in terms of peak height and less than 7.3% in terms of corrected peak area, respectively. The recoveries of the method for the three alkaloids were in the range of 95.9-101.5% with peak height as the quantitative signal, and 92.6-103.6% with corrected peak area as the quantitative signal, respectively. The MSS-CZE method proved to be suitable for the analysis of the alkaloids in human plasma samples. PMID- 22944007 TI - Fermentation characteristics of resistant starch from maize prepared by the enzymatic method in vitro. AB - To investigate the fermentation characteristics of resistant starch prepared by hydrolysing maize starch with alpha-amylase and pullulanase, fresh faecal extracts from healthy humans and infants were used as a fermentation model of human intestines in vitro. The RS was fermented for a certain period of time under the simulated condition of the large intestines (anaerobic and 37 degrees C). The concentration of short-chain fatty acids in the fermented product as determined by gas chromatography was used as an index to characterise the fermentation effect. The results showed that the concentration of short-chain fatty acids, especially butyric acid, in the fermented product gradually increased with increased fermentation time and RS content. However, the concentration of short-chain fatty acids in the fermented product from healthy infant faecal extracts, especially butyric acid, was much higher than that from healthy adult faecal extracts. It suggested that the model of RS-produced acids was affected by the fermentation extract source, i.e., by the existence of microbial flora. The production model of acids demonstrated that maize RS prepared by the enzymatic method can be a promising ingredient of functional foods. PMID- 22944009 TI - Extratemporal surface EEG features do not preclude successful surgical outcomes in drug-resistant epilepsy patients with unitemporal MRI lesions. AB - Of 47 patients with onset of intractable partial seizures and temporal lobe MRI lesions, subjected to presurgical evaluation and temporal lobe surgery, we identified eight (mean age: 24 years; range: 7-52 years) demonstrating surface interictal and/or ictal EEG features suggestive of an extratemporal localisation. All eight patients underwent surgery aiming to predominantly resect the lesion, without extending to the extratemporal region. The patients were prospectively followed (mean follow-up duration: 38 months; range: 12-66 months) and all achieved excellent postoperative seizure control. Extratemporal surface interictal/ictal EEG features were more often encountered in tumoural and focal cortical dysplasia cases, compared with medial temporal sclerosis cases, and were most frequently localised over frontopolar and suprasylvian-pericentral locations. We postulate that propagation of interictal/ictal activity from the epileptogenic region of the temporal lobe to extratemporal neocortical areas, perhaps utilising the temporal pole and insula as intermediary nodes of a common epileptogenic network, accounts for the presence of our cohort's discordant lesion and EEG features. PMID- 22944010 TI - Anesthesia-based evaluation of outcomes of lower-extremity vascular bypass procedures. AB - BACKGROUND: This report examines the effects of regional versus general anesthesia for infrainguinal bypass procedures performed in the treatment of critical limb ischemia (CLI). METHODS: Nonemergent infrainguinal bypass procedures for CLI (defined as rest pain or tissue loss) were identified using the 2005 to 2008 American College of Surgeons National Surgical Quality Improvement Program database using International Classification of Disease, ninth edition, and Current Procedure Terminology codes. Patients were classified according to National Surgical Quality Improvement Program data as receiving either general anesthesia or regional anesthesia. The regional anesthesia group included those specified as having regional, spinal, or epidural anesthesia. Demographic, medical, risk factor, operative, and outcomes data were abstracted for the study sample. Individual outcomes were evaluated according to the following morbidity categories: wound, pulmonary, venous thromboembolic, genitourinary, cardiovascular, and operative. Length of stay, total morbidity, and mortality were also evaluated. Associations between anesthesia types and outcomes were evaluated using linear or logistic regression. RESULTS: A total of 5,462 inpatient hospital visits involving infrainguinal bypasses for CLI were identified. Mean patient age was 69 +/- 12 years; 69% were Caucasian; and 39% were female. In all, 4,768 procedures were performed using general anesthesia and 694 with regional anesthesia. Patients receiving general anesthesia were younger and significantly more likely to have a history of smoking, previous lower extremity bypass, previous amputation, previous stroke, and a history of a bleeding diathesis including the use of warfarin. Patients receiving regional anesthesia had a higher prevalence of chronic obstructive pulmonary disease. Tibial-level bypasses were performed in 51% of procedures, whereas 49% of procedures were popliteal-level bypasses. Cases performed using general anesthesia demonstrated a higher rate of resident involvement, need for blood transfusion, and operative time. There was no difference in the rate of popliteal level and infrapopliteal-level bypasses between groups. Infrapopliteal bypass procedures performed using general anesthesia were more likely to involve prosthetic grafts and composite vein. Mortality occurred in 157 patients (3%). The overall morbidity rate was 37%. Mean and median lengths of stay were 7.5 days (+/- 8.1) and 6.0 days (Q1: 4.0, Q3: 8.0), respectively. Multivariate analyses demonstrated no significant differences by anesthesia type in the incidence of morbidity, mortality, or length of stay. CONCLUSION: These results provide no evidence to support the systematic avoidance of general anesthesia for lower extremity bypass procedures. These data suggest that anesthetic choice should be governed by local expertise and practice patterns. PMID- 22944011 TI - [In Process Citation]. PMID- 22944012 TI - [The extraction of a lower incisor in orthodontics: indications, planning of the treatment and clinical handling in different malocclusions]. AB - The extraction of a lower incisor has been a therapeutic approach considered controversial in orthodontics over the last decades and, therefore, supported by some authors and questioned by others. In recent years, different publications have attempted to provide with substantial and structured information that could help to perform this atypical form of therapy in selected cases with a prospective good result. The purpose of this article is to summarise the available information, providing an order and structure to the diagnostic features that could support the indication and use of this treatment alternative, including the quantification of those parameters that can be measured in the decision-making process. Finally, to set up a clear and meaningful clinical frame that could be used by the orthodontist as a reference line in daily practice. Four case reports will be used in order to illustrate the indication of this treatment modality in different malocclusions. PMID- 22944013 TI - [Improvement of mini-implant stability in orthodontics]. AB - Orthodontists are continuing to increase the use of mini-implants as a source of skeletal anchorage. However, the relatively high 16.4% rate of their failures remains a problem. An analysis of articles in the literature on the loss of mini implants shows that larger size anchorage screws and plates inserted in the anterior and median regions of the hard palate are highly stable and, accordingly, contribute to a high rate of optimum orthodontic outcomes. It is the reliability of the mini-implant/skeletal structure couple that is the principal factor in this success. With mini-implants whose heads possess internal threads, orthodontists can attach different types of stable, screwed-in abutments. And with long plates with specifically designed perforations splinting two mini implants together, orthodontists can further increase the stability of this artificial anchorage. By employing a system with pre-fabricated components orthodontists can quickly create skeletal anchorage adaptable to the mechanics of different techniques. PMID- 22944008 TI - Herpes keratitis. AB - Herpes simplex virus-1 (HSV-1) infects the majority of the world's population. These infections are often asymptomatic, but ocular HSV-1 infections cause multiple pathologies with perhaps the most destructive being herpes stromal keratitis (HSK). HSK lesions, which are immunoinflammatory in nature, can recur throughout life and often cause progressive corneal scaring resulting in visual impairment. Current treatment involves broad local immunosuppression with topical steroids along with antiviral coverage. Unfortunately, the immunopathologic mechanisms defined in animal models of HSK have not yet translated into improved therapy. Herein, we review the clinical epidemiology and pathology of the disease and summarize the large amount of basic research regarding the immunopathology of HSK. We examine the role of the innate and adaptive immune system in the clearance of virus and the destruction of the normal corneal architecture that is typical of HSK. Our goal is to define current knowledge of the pathogenic mechanisms and recurrent nature of HSK and identify areas that require further study. PMID- 22944014 TI - [Dental pulp stem cells: characteristics, cryopreservation and therapeutic potentialities]. AB - Stem cells discovery and their potential have led to the emergence of new forms of therapy with the development of bio-engineering cell and tissue methods underlying future medicine. The availability of stem cells and their preservation thus become an issue for everyone's health. Among the different sources of stem cells, those in the dental pulp have the advantage of being pluripotent, they can be cryopreserved and stored for long periods without losing their multiplication and differentiation capacities and finally they are easily accessible. The wisdom or natal teeth extracted for medical reasons are an opportunity for everyone to preserve stem cells for an autologous use. Biobanks authorized and specialized in the preparation and storage of pulp stem cells provide access to autologous regenerative medicine of tomorrow. PMID- 22944015 TI - [Search of a cephalometric reference line]. AB - The variability of cephalometric reference lines is examined in this article with regard to typology, natural orientation of the head, orientation by the vestibular system, and anatomy. It appears that these lines have orientations that vary with individual subjects, that is, a line is not the same in a specific person as it is in a theoretical model that is based on average values. It follows from this that the deviation observed between a patient's measurement and the average could just as well reflect variations in the reference lines as it does of those of the structures being studied. Such a measurement cannot, accordingly, serve as the basis for a morphological diagnosis. To deal with this problem, we propose another cephalometric reference system that presents, for orthognathic diagnosis, many advantages over the traditional system but, itself, remains imperfect. PMID- 22944016 TI - [Total alloplastic temporomandibular joint reconstruction combined with orthodontic treatment in a patient with idiopathic condylar resorption]. AB - This case report describes the successful treatment of an adult patient with skeletal Class II open-bite malocclusion secondary to idiopathic condylar resorption. Total alloplastic joint reconstruction and counterclockwise rotation of the maxillomandibular complex combined with orthodontic treatment provided a satisfying outcome with maximum functional and esthetic improvement. PMID- 22944017 TI - Getting streetwise: a metaphor for empowering nurses for evidence-based practice. PMID- 22944018 TI - An investigation of the basic education of Japanese nurses: comparison of competency with European nurses. AB - BACKGROUND: A few studies have compared nursing education systems of Japan and Europe, particularly focusing on competency. OBJECTIVE: We evaluated the competency of registered Japanese nurses by comparing it with that of European nurses; the implications of evaluation for the education of nurses are discussed. DESIGN AND PARTICIPANTS: Subjects were 468 European graduate nurses and 100 Japanese nurses. Study used data from the Graduates in Knowledge Society (REFLEX) survey in Europe and the Japanese language version of REFLEX (2006) used in a survey of Japanese nurses. METHODS: The questionnaire referred to the survey items of REFLEX modified for use in Japan. Items common to the Japanese and European surveys were (1) The importance placed on university course elements while at university (2) Nineteen items of competency: for the abilities acquired in the present job ('Acquired skills') and those considered necessary to perform the job ('Required abilities on the job') (3) Usefulness of subject matter taught at university to the current job RESULTS: (1) The important course elements in Europe were 'Internship, work placement' and 'Lecture' while those in Japan were 'Theories and paradigms' and 'Lecture'. (2) The mean values for 'Acquired skills' were 5.06 for Europe and 3.73 for Japan and those for 'Required abilities on the job' were 4.86 for Europe and 5.16 for Japan. In Europe, no significant gap was observed between the above two scores, but in Japan, a big gap was found, particularly in relation to 'Ability to assert your authority'. (3) In terms of the usefulness of university-learned nursing education, Japan scored significantly lower on all five items. CONCLUSIONS: The content of basic university education for nursing is directly linked to the workplace in Europe but not in Japan. A comparison of competencies shows that in Japan, self evaluation scores are low and expectations are high. PMID- 22944019 TI - Facilitated family presence at resuscitation: effectiveness of a nursing student toolkit. AB - BACKGROUND: Facilitated family presence at resuscitation is endorsed by multiple nursing and specialty practice organizations. Implementation of this practice is not universal so there is a need to increase familiarity and competence with facilitated family presence at resuscitation during this significant life event. One strategy to promote this practice is to use a nursing student toolkit for pre licensure and graduate nursing students. The toolkit includes short video simulations of facilitated family presence at resuscitation, a PowerPoint presentation of evidence-based practice, and questions to facilitate guided discussion. METHODS: This study tested the effectiveness of this toolkit in increasing nursing students' knowledge, perceptions, and confidence in facilitated family presence at resuscitation. Nursing students from five universities in the United States completed the Family Presence Risk-Benefit Scale, Family Presence Self-Confidence Scale, and a knowledge test before and after the intervention. RESULTS: Implementing the facilitated family presence at resuscitation toolkit significantly increased nursing students' knowledge, perceptions, and confidence related to facilitated family presence at resuscitation (p<.001). The effect size was large for knowledge (d=.90) and perceptions (d=1.04) and moderate for confidence (d=.51). CONCLUSIONS: The facilitated family presence at resuscitation toolkit used in this study had a positive impact on students' knowledge, perception of benefits and risks, and self-confidence in facilitated family presence at resuscitation. The toolkit provides students a structured opportunity to consider the presence of family members at resuscitation prior to encountering this situation in clinical practice. PMID- 22944020 TI - Systematic review of induced pluripotent stem cell technology as a potential clinical therapy for spinal cord injury. AB - Transplantation therapies aimed at repairing neurodegenerative and neuropathological conditions of the central nervous system (CNS) have utilized and tested a variety of cell candidates, each with its own unique set of advantages and disadvantages. The use and popularity of each cell type is guided by a number of factors including the nature of the experimental model, neuroprotection capacity, the ability to promote plasticity and guided axonal growth, and the cells' myelination capability. The promise of stem cells, with their reported ability to give rise to neuronal lineages to replace lost endogenous cells and myelin, integrate into host tissue, restore functional connectivity, and provide trophic support to enhance and direct intrinsic regenerative ability, has been seen as a most encouraging step forward. The advent of the induced pluripotent stem cell (iPSC), which represents the ability to "reprogram" somatic cells into a pluripotent state, hails the arrival of a new cell transplantation candidate for potential clinical application in therapies designed to promote repair and/or regeneration of the CNS. Since the initial development of iPSC technology, these cells have been extensively characterized in vitro and in a number of pathological conditions and were originally reported to be equivalent to embryonic stem cells (ESCs). This review highlights emerging evidence that suggests iPSCs are not necessarily indistinguishable from ESCs and may occupy a different "state" of pluripotency with differences in gene expression, methylation patterns, and genomic aberrations, which may reflect incomplete reprogramming and may therefore impact on the regenerative potential of these donor cells in therapies. It also highlights the limitations of current technologies used to generate these cells. Moreover, we provide a systematic review of the state of play with regard to the use of iPSCs in the treatment of neurodegenerative and neuropathological conditions. The importance of balancing the promise of this transplantation candidate in the light of these emerging properties is crucial as the potential application in the clinical setting approaches. The first of three sections in this review discusses (A) the pathophysiology of spinal cord injury (SCI) and how stem cell therapies can positively alter the pathology in experimental SCI. Part B summarizes (i) the available technologies to deliver transgenes to generate iPSCs and (ii) recent data comparing iPSCs to ESCs in terms of characteristics and molecular composition. Lastly, in (C) we evaluate iPSC-based therapies as a candidate to treat SCI on the basis of their neurite induction capability compared to embryonic stem cells and provide a summary of available in vivo data of iPSCs used in SCI and other disease models. PMID- 22944021 TI - Development of an integrated electrochemical system for in vitro yeast viability testing. AB - This work describes the development and testing of a microfabricated sensor for rapid cell growth monitoring, especially focused on yeast quality assessment for wine applications. The device consists of a NMOS ISFET sensor with Si(3)N(4) gate, able to indirectly monitor extracellular metabolism through pH variation of the medium, and a solid-state reference electrode implemented with PVC membranes doped with lipophilic salts (tetrabutylammonium-tetrabutylborate (TBA-TBB) and Potassium tetrakis(4-chlorphenyl)borate (KTClpB)). The use of a solid state reference electrode enables the implementation of a large number of cell assays in parallel, without the need of external conventional reference electrodes. Microbial growth testing has been performed both in standard culture conditions and on chip at different concentrations of ethanol in order to carry out a commonly used screening of wine yeast strains. Cell growth tests can be performed in few hours, providing a fast, sensitive and low cost analysis with respect to the conventional procedures. PMID- 22944022 TI - Mussel adhesive protein-based whole cell array biosensor for detection of organophosphorus compounds. AB - A whole cell array biosensor for the efficient detection of neurotoxic organophosphate compounds (OPs) was developed through the immobilization of recombinant Escherichia coli cells containing periplasmic-expressing organophosphorus hydrolase (OPH) onto the surface of a 96-well microplate using mussel adhesive protein (MAP) as a microbial cell-immobilizing linker. Both the paraoxon-hydrolyzing activity and fluorescence microscopy analyses demonstrated that the use of MAP in a whole cell biosensor increased the cell-immobilizing efficiency and enhanced the stability of immobilized cells compared to a simple physical adsorption-based whole cell system. Scanning electron microscopic analyses also showed that the E. coli cells were effectively immobilized on the MAP-coated surface without any pretreatment steps. The whole cell array biosensor system, prepared using optimal MAP coating (50 MUg/cm(2)) and cell loading (4 OD(600)), detected paraoxon levels as low as 5 MUM with high reproducibility, and its quantitative detection range was ~5-320 MUM. The MAP-based whole cell array biosensor showed a good long-term stability for 28 day with 80% retained activity and a reusability of up to 20 times. In addition, paraoxon in tap water was also successfully detected without a reduction in sensitivity. Our results indicate that the proposed MAP-based whole cell array system could be used as a potential platform for a stable and reusable whole cell biosensor. PMID- 22944023 TI - Label-free detection of DNA hybridization using transistors based on CVD grown graphene. AB - The high transconductance and low noise of graphene-based field-effect transistors based on large-area monolayer graphene produced by chemical vapor deposition are used for label-free electrical detection of DNA hybridization. The gate materials, buffer concentration and surface condition of graphene have been optimized to achieve the DNA detection sensitivity as low as 1 pM (10(-12) M), which is more sensitive than the existing report based on few-layer graphene. The graphene films obtained using conventional PMMA-assisted transfer technique exhibits PMMA residues, which degrade the sensing performance of graphene. We have demonstrated that the sensing performance of the graphene samples prepared by gold-transfer is largely enhanced (by 125%). PMID- 22944024 TI - A new strategy based on aptasensor to time-resolved fluorescence assay for adenosine deaminase activity. AB - Quantitative protein bioanalysis in complex biological fluids presents considerable challenges in biological studies and medical diagnosis. The major obstacles are the background signals from the biological fluids and sensors themselves. Because the europium ion (Eu (III)) has the much longer fluorescence lifetime (1 ms) than that of the background (5 ns), time-resolved method can be widely used to eliminate the biological background. So, we report here an aptamer based sensor (aptasensor) for time-resolved fluorescence assay of adenosine deaminase (ADA). This aptasensor employs two oligonucleotides labeled with DIG and biotin, respectively. The DNA1 (an oligonucleotide modified with biotin) is immobilized at a streptavidin-modified plate surface via the biotin-avidin bridge, and the DIG which is modified on the DNA2 serves as an affinity tag for the Eu(3+) labeled anti-DIG (Eu-anti-DIG) binding. If the adenosine is binding with DNA1, it will make the DNA1 in the closed state with a close-packed tight structure, which forbids the DNA2 approaching. And if the ADA is added into the mixture, the DNA1 unbends, because of the adenosine is transformed to inosine catalyzed by the ADA. Then DNA2 could hybridize with DNA1. Accordingly, the DIG finds Eu-anti-DIG and the Eu-anti-DIG will give a remarkable fluorescent signal. The detection limit of the aptasensor can be lowered to 2 UL(-1), which can meet the clinical requirement of ADA cutoff value (4 UL(-1)). Moreover, we were able to detect ADA in human serum quantitatively. Combined with time-resolved based measurements and aptasensor, this strategy holds great potential in protein analysis. PMID- 22944026 TI - [Hybrid interventional procedure: the trend of interventional and intraluminal vascular therapy]. PMID- 22944025 TI - Recommendations for genetic testing of inherited eye diseases: report of the American Academy of Ophthalmology task force on genetic testing. AB - Genetic testing can make a very positive impact on individuals and families affected with inherited eye disease in a number of ways. When properly performed, interpreted, and acted on, genetic tests can improve the accuracy of diagnoses and prognoses, can improve the accuracy of genetic counseling, can reduce the risk of disease occurrence or recurrence in families at risk, and can facilitate the development and delivery of mechanism-specific care. However, like all medical interventions, genetic testing has some specific risks that vary from patient to patient. For example, the results of a genetic test can affect a patient's plans to have children, can create a sense of anxiety or guilt, and can even perturb a patient's relationships with other family members. For these reasons, skilled counseling should be provided to all individuals who undergo genetic testing to maximize the benefits and minimize the risks associated with each test. PMID- 22944027 TI - [The new treatment strategies of regional lymph nodes in tumor patients: eliminate metastatic lymph nodes, protect normal lymph nodes, observe suspicious lymph nodes]. PMID- 22944028 TI - [Transradial approach for transcatheter selective superior mesenteric artery urokinase infusion therapy in patients with acute extensive portal and superior mesenteric vein thrombosis]. AB - OBJECTIVE: To evaluate the feasibility and efficacy of urokinase infusion therapy via a transradial approach for transcatheter superior mesenteric artery (SMA) in patients with acute extensive portal and superior mesenteric venous thrombosis. METHODS: During a period of 8 years, 47 patients with acute extensive thrombosis of portal vein (PV) and superior mesenteric veins (SMV) received urokinase infusion therapy by transcatheter selective SMA via radial artery. Their mean age was 44 +/- 13 years (range: 19 - 65). Through radial sheath, a 5F catheter was placed into SMA and subsequently the infusion of urokinase was given for 5 - 11 days (mean: 7.1 +/- 2.5). Adequate anticoagulation was initiated during treatment, throughout hospitalization and post-discharge. Follow-up contrast enhanced computed tomography (CT) was performed in each patient every 3 days and before the removal of infusion catheter. Termination of urokinase infusion therapy was decided on the basis of clinical and radiographic findings. RESULTS: Technical success was achieved in all patients. Two patients had worsening abdominal pain, developed the signs of peritonitis at 24 hours after interventional treatment and underwent eventual laparotomy with the resection of necrotic bowel. Substantial clinical improvement was observed in 45 (95.7%) of them after the procedure. Minor complications at the radial puncture site were observed in 7 patients (14.9%) and infusion therapy continued. Follow-up CT scans at pre-discharge demonstrated a nearly complete disappearance of PV-SMV thrombosis in 29 patients (64.4%) and partial recanalization of PV-SMV thrombosis in 16 patients (35.6%). They were discharged at 9 - 20 days (mean: 12 +/- 6) post admission. The mean post-discharge duration of follow-up was 48 +/- 20 months. Recurrent episodes of PV and SMV thrombosis were observed in 2 (4.4%) patients at 6 months and 5 years respectively post-discharge and they were treated successfully with urokinase infusion. CONCLUSION: The transcatheter SMA urokinase infusion therapy via a transradial approach for plus anticoagulation is both safe and effective for the management of patients with acute extensive PV-SMV thrombosis. PMID- 22944029 TI - [Predictive value of serum beta 2-microglobulin level for recurrent stenosis or occlusion in patients with lower limb ischemia undergoing percutaneous transluminal angioplasty]. AB - OBJECTIVE: To evaluate the predictive value of serum beta 2-microglobulin level for recurrent stenosis or occlusion in patient undergoing percutaneous transluminal angioplasty (PTA) for lower limb ischemia. METHODS: Between March 2009 and October 2010, 81 patients were admitted with a diagnosis of lower limb ischemia. Among them, 54 patients had a mean age of 64 +/- 12 years. The baseline characteristics, stenting and post-procedure events were collected. And the serum level of beta 2-microglobulin was measured by dynamic timing nephelometry assay. Recurrent stenosis or occlusions were confirmed with color Doppler ultrasonography or CTA imaging. Cox regression univariate analysis was performed with variables with P value < 0.20 to investigate the independent predictors of recurrent stenosis or occlusions. Receiver-operating characteristics curves (ROC) were constructed to evaluate the sensitivity and specificity of this model. RESULTS: The baseline characteristics were evenly distributed in two groups. Twenty-three patients (42.5%) were found to have recurrent stenosis or occlusions. The cumulative primary patency was 85%, 69% and 34%at Month 6, 12 and 24 respectively. The serum levels of beta 2-microglobulin decreased during a follow-up period of 3 months and then increased gradually in patients with recurrent stenosis or occlusion. Cox regression analysis identified the serum level of beta 2-microglobulin as an independent predictor of recurrent stenosis or occlusion (Odds Ratio = 1.459, 95%CI 1.199 - 1.777, P = 0.000). The area under the curve (AUC) of the serum level of beta 2-microglobulin was 0.952 for recurrent stenosis or occlusion. And the sensitivity was 95.7% and the specificity 77.4% on a cut-off value 3.2 mg/L. CONCLUSION: With a cut-off value 3.2 mg/L, the serum level of beta 2-microglobulin may be useful for the prediction of recurrent stenosis or occlusion in patients after lower limb PTA. PMID- 22944030 TI - [Diagnosis and treatment of carotid-cavernous fistula: analysis of 28 patients]. AB - OBJECTIVE: To evaluate the feasibility and efficacy of endovascular treatment for different types of carotid cavernous fistula (CCF) via the approach of internal carotid artery (ICA) or inferior petrosal sinus (IPS). METHODS: From April 2005 to June 2010, 28 CCF patients underwent endovascular treatment at our institution. There were 13 males and 15 females with a mean age of 39 years (range: 21 - 71). According to the Barrow's classification, they were classified into type A (n = 21), type B (n = 2) and type D (n = 5). Patients of type A underwent detachable balloon embolization of ipsilateral cavernous sinus or stent graft placement via the ICA approach. Patients of types B and D received detachable coil plus n-BCA (n-butyl-2-cyanoacrylate) embolization of ipsilateral cavernous sinus via the IPS approach. The technical results, complications and therapeutic outcomes were reviewed. RESULTS: Detachable balloons (number: 1 - 4) were used in 16 patients of type A. Angiography at immediate postembolization showed a complete occlusion of fistula in 15 patients and a small residual fistula (< 20%) in 1 patient. Five patients of type A received stent-graft placement. One stent was placed in 4 patients and 2 stents in 1 patient. Complete fistula closures with preserved ICA were documented on immediate angiogram in 3 patients whereas a large residual flow (> 50%) persisted in 1. The fistula was completely occluded after 3 detachable balloons were deployed in affected cavernous sinus through a gap between stent and vascular wall. Both fistula and ICA were occluded in 1 patient after stenting. No cerebral infarction was observed due to the adequate collateral blood flow from contralateral ICA. Complete closures of affected cavernous sinus were achieved in 6 patients of types B and D while residual flow (< 50%) persisted in 1. The number of detachable coils for each embolization ranged from 3 to 8 (mean: 6.0). The volume of n-BCA mixture varied from 1.0 to 2.1 ml (mean: 1.3). The mean duration of n BCA injection was 65 s (range: 45 - 90). Clinical symptoms were completely relieved in 26 patients. During the mean follow-up period of 30 months (range: 12 - 60), no recurrence of clinical symptoms was observed. No thrombosis or stenosis was found in the lumina of stents. CONCLUSION: Detachable balloon embolization is the preferential treatment for direct CCF. Detachable coil plus n-BCA embolization of cavernous sinus via the IPS approach is an efficient and safe treatment for indirect CCF. PMID- 22944031 TI - [Analysis of CX32 gene mutation and related clinical features in Chinese Han Charcot-Marie-Tooth families]. AB - OBJECTIVE: To analyze the mutation of CX32 gene and related clinical features in Chinese Han patients with Charcot-Marie-Tooth (CMT) disease. METHODS: Thirty-four CMT families, from 2004 to 2011 at Departments of Neurology, Xiangya Hospital, Third Xiangya Hospital and National Key Laboratory of Medical Genetics, were selected for CX32 mutation screening after the exclusion of the PMP22 duplication and male-to-male transmission. Mutation analysis was carried out by polymerase chain reaction (PCR) plus direct sequencing. Analyses of clinical, electrophysiological and pathological features in 11 patients from 6 CMTX1 families were performed by 2 neurologists. RESULTS: Five CX32 gene mutations were detected in 6 CMT families: c.37G > A, c.65G > A, c.246C > G, c.256A > G and c.533A > G. Among them, c.246C > G and c.533A > G were firstly reported. The clinical manifestations included progressive distal muscle atrophy and weakness, areflexia, sensory abnormalities and pes vacus. Nerve conduction velocity ranged from 21.7 to 49.3 m/s. Both demyelination and axonal degeneration were detected in nerve biopsy. CONCLUSIONS: CMT1X has a frequency of around 9% in our study. The male patients tend to have more serious clinical features and their electrophysiological and pathological changes are intermediate. CX32 mutation analysis helps to confirm the genetic diagnosis of CMT so as to provide genetic counseling and reproductive guidance and elucidate its pathogenesis. PMID- 22944033 TI - [Value of nasal bone and serological screening for the detection of fetal chromosomal disorders in second trimester]. AB - OBJECTIVE: To assess the value of fetal chromosomal abnormality screening by a maternal serum test plus fetal nasal bone length in second trimester (parallel test). METHODS: From January 2009 to December 2010, fetal nasal bone was measured at 19 - 22 weeks gestation in 6173 unselected cases. Karyotyping was performed in cases with a high risk for maternal serum test and/or abnormal fetal nasal bone length. All cases were followed-up postnatally. RESULTS: Nasal bone was assessed successfully in 5607 cases (90.83%). Normally it is increases with gestational age. The detection rate of chromosomal abnormality was 69.64% by maternal serum test, 79.76% by maternal serum test plus hypoplastic nasal bone and 83.93% by maternal serum test plus shortened nasal bone. CONCLUSION: Fetal nasal bone hypoplasia is closely correlated with chromosomal abnormality. And sonographic evaluation of nasal bone may be a useful tool for screening chromosomal abnormality. The combination of maternal serum test and fetal nasal bone length will boost the detection rate of chromosomal abnormality. PMID- 22944032 TI - [Implementation of VarioGuide in stereotactic brain biopsy: a preliminary experience]. AB - OBJECTIVE: To evaluate the clinical value of VarioGuide in stereotactic brain biopsy. METHODS: Fifteen patients with brain lesions underwent frameless stereotactic brain biopsy guided by VarioGuide and multimodal neuronavigation. Intraoperative magnetic resonance imaging (iMRI) was used to confirm the accuracy of biopsy. And the VarioGuide-related adverse events, operative duration, surgical outcomes and postoperative complications were recorded respectively. RESULTS: In all patients, VarioGuide and multimodal neuronavigation were successfully integrated into the biopsy procedure. No VarioGuide-related adverse events were reported. The mean operative duration was (65 +/- 8) min. The biopsy accuracy was confirmed by iMRI in all cases. And the postoperative histological diagnostic rate was 100%. No mortality and morbidity occurred postoperatively. CONCLUSION: The combined approach of VarioGuide and multimodal neuronavigation is accurate, safe and efficient. It may improve the histological diagnostic rate without postoperative neurological deficits in stereotactic brain biopsy. PMID- 22944034 TI - [Clinical efficacies of skipping two-level transpedicular wedge osteotomy for correction of severe kyphosis in ankylosing spondylitis]. AB - OBJECTIVE: To explore the clinical efficacies of skipping two-level transpedicular wedge osteotomy in the correction of severe kyphotic deformity in ankylosing spondylitis (AS). METHODS: From January 2003 to December 2009, a total of 38 consecutive patients with AS and severe kyphosis (chin-brow vertical angle (CBVA) or global thoraco-lumbar kyphosis angle (TLKA) over 70 degrees ) undergoing skipping two-level transpedicular wedge osteotomy at the Department of Orthopedics of Chinese PLA General Hospital were reviewed retrospectively. There were 32 males and 6 females with an average age of 38.0 years (range: 22 - 65). The preoperative parameters of TLKA, T11-L2 kyphotic angle, L1-S1 lordosis angle, sagittal imbalance and CBVA were obtained from the total spine radiography or computed tomography and clinical lateral photograph. According to the characteristic curves and normal spinal alignment, their profiles of osteotomy location and angle were determined and confirmed by computer simulations. Improvement in postoperative parameters was observed and treatment satisfaction evaluated RESULTS: The average operating duration was 309 minutes and the average volume of blood loss was 2050 ml. The parameters of TLKA, T11-L2 kyphotic angle and L1-S1 lordosis angle improved from 101.0 degrees +/- 21.3 degrees , 45.2 degrees +/- 13.6 degrees , -28.2 degrees +/- 23.3 degrees at preoperation to 26.0 degrees +/- 12.1 degrees , 2.8 degrees +/- 11.6 degrees , 28.9 degrees +/ 13.3 degrees postoperation respectively (P < 0.01). CBVA improved from 79.4 degrees +/- 15.9 degrees to 13.6 degrees +/- 10.9 degrees (P < 0.01). The sagittal imbalance distance improved from (49 +/- 13) to (15 +/- 7) cm (P < 0.01). All patients could walk with orthophoria and lie horizontally postoperatively. The average follow-up was 32 months (range: 24 ~ 78 months). Fusion of osteotomy was achieved in all patients and there was no event of loss of correction or implant failure. The SRS-22 average score improved from 1.8 to 4.2. CONCLUSION: For severe kyphosis in AS, skipping two-level transpedicular wedge osteotomy is a satisfactory and reliable approach for the correction of kyphotic deformity and it may improve appearance and function significantly. PMID- 22944035 TI - [Correlation of adult spinal sagittal imbalance and life quality]. AB - OBJECTIVE: To evaluate the correlation of spinal sagittal imbalance and life quality. METHODS: Radiographic analysis for 48 consecutive symptomatic patients with spinal sagittal imbalance was performed with posteroanterior and lateral standing radiographs. There were 12 males and 36 females with an average age of (66.2 +/- 8.5) yrs. The measurement parameters included C7PL, thoracic kyphosis (TK), thoracolumbar kyphosis (TLK), lumbar lordosis (LL), pelvic tilt (PT), pelvic incidence (PI) and sacral slope (SS). Life quality was assessed with SF-36 questionnaire. Pearman's method was employed to analyze the correlation. RESULTS: Mean C7PL was (44.7 +/- 22.5) mm, TK (26.1 +/- 13.1) degrees , TLK (11.9 +/- 10.3) degrees , LL (23.5 +/- 18.2) degrees , PT (32.1 +/- 13.4) degrees , PI (57.4 +/- 10.9) degrees and SS (22.5 +/- 11.5) degrees . C7PL had a significant correlation with physical functioning (r = -0.428, P < 0.01) and general health (r = -0.428, P < 0.01). PI had a significant correlation with bodily pain (r = 0.374, P < 0.01), vitality (r = -0.303, P < 0.01), social functioning (r = 0.309, P < 0.01) and role emotional (r = -0.429, P < 0.05). TK had a significant correlation with physical functioning (r = -0.292, P < 0.05) and general health (r = -0.389, P < 0.01). LL had a significant correlation with physical functioning (r = 0.428, P < 0.01), general health (r = 0.340, P < 0.05) and vitality (r = 0.373, P < 0.01). PT had significant correlation with vitality (r = -0.385, P < 0.01) and social functioning (r = -0.417, P < 0.05). No significant correlation existed between TLK, SS and SF-36 categories. CONCLUSION: C7PL, TK, LL, PI and PT are significant parameters correlating with quality of life. PI is the most important one affecting bodily pain. TK, LL and C7PL are the main parameters affecting general health. PI, PT and LL affect vitality the most. Correcting these parameters while treating sagittal imbalance is important for a better life quality. PMID- 22944036 TI - [Subintimal angioplasty for chronic arterial occlusive disease: a systematic review]. AB - OBJECTIVE: To evaluate the clinical effectiveness of subintimal angioplasty in treating chronic arterial occlusive disease of lower extremity. METHODS: Eligible studies concerning treatment by subintimal angioplasty in patients with arterial occlusive disease of lower extremity were identified from electronic database, cross-reference search and relative articles. The study quality and data extraction of all relevant articles were assessed by three independent reviewers. The study endpoints were technical success, primary patency, limb salvage, and complications. RESULTS: A total of 352 studies were selected for comprehensive review. Fourteen studies including a total of 2350 patients matched the selection criteria. According to whether selective using of re-entry catheter were used or not, the technical success rates were 96.4% and 87% (P < 0.01). Limb salvage rate was 90.5% and 81.5% at 6 and 12 months respectively. Depending on whether preoperative use of anti-platelet drug, primary patency rate was 91% and 68.5% at 6 months respectively (P < 0.01). The complication rate was 8.25% without serious complications. CONCLUSION: This Meta-analysis suggests that subintimal angioplasty is a safe and effective method in treating chronic arterial occlusive disease of lower extremity with high technical success rate and limb salvage, and low serious complications. Selective using of re-entry devices and preoperative anti-platelet drug can improve the technical success rate and primary patency rate significantly. Despite the high rate of technical and clinical success of the procedure, randomized contrast trials and long-term follow-up results are required to confirm the efficacy of these results. PMID- 22944037 TI - [Operative treatment of displaced intra-calcaneal fractures]. AB - OBJECTIVE: To explore the clinical efficacies of displaced intra-calcaneal fractures with operative treatment. METHODS: From January 2005 to December 2010, 103 calcaneal patients (92 males, 11 females) were recruited. The mean age was 45.8 years old (range: 23 - 65). All received operative treatment. They included left calcaneal fractures (n = 51), right calcaneal fractures (n = 40) and bilateral calcaneal fractures (n = 12). All patients were of closed fractures. According to the Sanders classification, there were type II (n = 15), type III (n = 75) and type IV (n = 13). A modified lateral approach with profiled plate fixation was adopted for all. Partial weight-bearing occurred at 6 weeks and full weight-bearing at 12 weeks. Function assessment was made with the American Orthopedic Foot and Ankle Society ankle-hindfoot scale (AOFAS). RESULTS: The mean follow-up period was 18 months (range: 6 - 30) and the mean healing duration 12 weeks (range: 8 - 15). Two cases had incision dehiscence. After the removal of plate, the skin healed. Eight cases were associated with subtalus arthritis and painful walking. Three cases of caved calcaneal surface appeared after weight bearing. According to the AOFAS foot score, the outcomes were excellent (n = 83), good (n = 13), fair (n = 5) and poor (n = 2). And the excellent and good rate was 93.2%. CONCLUSION: With a modified lateral approach, displaced intra-calcaneal fracture may be treated with a satisfactory clinical efficacy.But an orthopedic surgeon should master skillful surgical techniques. PMID- 22944038 TI - [Application of intraoperative contrast-enhanced ultrasound in different pathological grades of glioma]. AB - OBJECTIVE: To explore the feasibility and value of intra-operative contrast enhanced ultrasound in different pathological grades of glioma. METHODS: A total of 46 patients with glioma were selected to undergo the contrast-enhanced ultrasound. They were divided into 3 groups according to their pathological grades. RESULTS: All 46 tumors were hyperechoic after examinations and the borders became much more distinct. Different level of tumors had their representative ultrasonic findings. CONCLUSIONS: Intraoperative contrast-enhanced ultrasound is quite useful for determining the position and border of tumors. And it is also excellent in detecting the residual tumor tissues post-operatively. And it can improve the resection accuracy and operative precision, especially for Grade IV glioma with internal necrosis, cyst and surrounding brain edema. PMID- 22944039 TI - [Involvement characteristics and influencing factors of anxiety and depression in patients after percutaneous coronary intervention]. AB - OBJECTIVE: To explore the involvement characteristics and influencing factors of anxiety and depression in patients after percutaneous coronary intervention (PCI). METHODS: A total of 396 patients undergoing PCI were investigated between January 2009 and December 2010. All of them completed the Hospital Anxiety and Depression Scale (HADS) before discharge and at 12 months post-PCI. We evaluated the involvement characteristics and used Logistic regression to analyze the influencing factors of mood changes. RESULTS: The relevant factors of post-PCI anxiety were gender (P = 0.003), age (P = 0.004) and acute myocardial infarction (P = 0.009) while depression was associated with acute myocardial infarction (P < 0.001). A 12-month follow-up study showed that anxiety remained stable in 76.3% of patients while depression in 79.5%. Multi-factor analysis showed that factors of presence of adverse cardiovascular events (OR: 1.323, 95%CI: 1.026 - 1.705, P = 0.031), Seattle angina score (OR: 0.870, 95%CI: 0.772 - 0.981, P = 0.023) and anxiety scores at pre-discharge (OR: 1.228, 95%CI: 1.053 - 1.432, P = 0.009) were correlated with the deterioration degree of depression. And the factor associated with the deterioration of depression was the scores before discharge (OR: 1.287, 95%CI: 1.072 ~ 1.545, P = 0.007). CONCLUSION: The levels of anxiety and depression remain stable in the majority of PCI patients at Month 12 post-PCI. Perioperative communication and effective control of postoperative cardiovascular events may ease a patient's negative emotions and improve their living quality. PMID- 22944040 TI - Serum asymmetric dimethylarginine, apelin, and tumor necrosis factor-alpha levels in non-obese women with polycystic ovary syndrome. AB - Polycystic ovary syndrome (PCOS) is associated with multiple risk factors for cardiovascular disease (CVD), including insulin resistance, type 2 diabetes mellitus, obesity, hypertension, and dyslipidemia. In addition, hyperandrogenism may contribute to the pathogenesis of CVD, independent of obesity and insulin resistance. We investigated serum levels of asymmetric dimethylarginine (ADMA), apelin, and tumor necrosis factor (TNF)-alpha as CVD risk markers and their relationship with hyperandrogenism in non-obese women with PCOS. In this study were included 82 non-obese women with PCOS and 33 controls. Women with PCOS were further divided into two groups: women with hyperandrogenism (HA-PCOS, n=37) and those without hyperandrogenism (NA-PCOS, n=45). Serum ADMA, apelin, and TNF-alpha levels were compared among the three groups and their relationship with hyperandrogenism was evaluated. Serum ADMA levels were significantly higher in the HA-PCOS group than in the NA-PCOS and control groups (0.45 +/- 0.09 vs. 0.38 +/- 0.08 vs. 0.40 +/- 0.07; P<0.0005). Serum TNF-alpha levels were significantly higher among women with PCOS compared with controls (2.91 +/- 1.25 vs. 1.74 +/- 0.77; P<0.001) and in the HA-PCOS group compared with the NA-PCOS group (3.21 +/- 1.24 vs. 2.60 +/- 1.24; P<0.0001). Both PCOS groups had significantly lower serum apelin levels compared with controls (1.31 +/- 0.54 vs. 1.16 +/- 0.34 vs. 2.78 +/ 1.10; P<0.0001). ADMA and TNF-alpha were positively correlated with total testosterone (r=0.219, P=0.022; r=0.332, P<0.001, respectively) and free androgen index (r=0.287, P=0.002; r=0.289, P=0.002, respectively), whereas apelin was negatively correlated with these parameters (r=-0.362, P<0.001; r=-0.251, P=0.008). These findings may indicate that non-obese women with PCOS are at an increased risk for CVD, which is further aggravated by hyperandrogenism. PMID- 22944041 TI - Carbon source and cell density-dependent regulation of type III secretion system gene expression in Pseudomonas syringae pathovar tomato DC3000. AB - Pseudomonas syringae utilizes a type III secretion system (T3SS) encoded by the hrp/hrc genes to translocate virulence proteins called effectors into plant cells. To ensure that the T3SS functions at appropriate times during infection, hrp/hrc and effector gene expression is modulated by environmental conditions and a complex network of transcription factors. The sigma factor HrpL activates hrp/hrc and effector genes, while sigma(54) and enhancer binding proteins HrpR and HrpS regulate hrpL. To better understand how environmental conditions control the T3SS regulatory cascade in P. syringae pathovar tomato strain DC3000, we tested the effects of various growth media and carbon sources on expression of the hrpRS operon, hrpL, and the effector avrPto. Fructose optimally induced hrpRS expression, while most other carbon sources had only mild stimulatory effects. In contrast, hrpL and avrPto were highly induced by several sugars and organic acids, yet expression decreased as cultures reached higher cell densities. This cell density-dependent regulation was not due to alteration of the pH of the medium, although involvement of a quorum sensing signal was also not apparent. Our findings may explain conflicting results from previous studies and additionally indicate that culture conditions should be considered carefully when examining T3SS gene expression. PMID- 22944042 TI - The genetics of selective serotonin reuptake inhibitors. AB - Selective serotonin reuptake inhibitors (SSRIs) are among the most widely prescribed drugs in psychiatry. Based on the fact that SSRIs increase extracellular monoamine levels in the brain, the monoamine hypothesis of depression was introduced, postulating that depression is associated with too low serotonin, dopamine and noradrenaline levels. However, several lines of evidence indicate that this hypothesis is too simplistic and that depression and the efficacy of SSRIs are dependent on neuroplastic changes mediated by changes in gene expression. Because a coherent view on global gene expression is lacking, we aim to provide an overview of the effects of SSRI treatment on the final targets of 5-HT receptor signal transduction pathways, namely the transcriptional regulation of genes. We address gene polymorphisms in humans that affect SSRI efficacy, as well as in vitro studies employing human-derived cells. We also discuss the molecular targets affected by SSRIs in animal models, both in vivo and in vitro. We conclude that serotonin transporter gene variation in humans affects the efficacy and side-effects of SSRIs, whereas SSRIs generally do not affect serotonin transporter gene expression in animals. Instead, SSRIs alter mRNA levels of genes encoding serotonin receptors, components of non-serotonergic neurotransmitter systems, neurotrophic factors, hypothalamic hormones and inflammatory factors. So far little is known about the epigenetic and age dependent molecular effects of SSRIs, which might give more insights in the working mechanism(s) of SSRIs. PMID- 22944043 TI - Guest editor's introduction--antibody engineering. PMID- 22944044 TI - Advanced glycation end products-induced reactive oxygen species generation is partly through NF-kappa B activation in human aortic endothelial cells. AB - Tumor necrosis factor (TNF)-alpha and reactive oxygen species (ROS) are involved in the endothelial dysfunction and the progression of atherosclerosis. In the pathogenesis of diabetic micro- and macro-vascular complications, advanced glycation end products (AGEs) and their receptor signaling are thought to play pivotal roles. We have studied the interaction among AGEs, TNF-alpha and ROS production using human aortic endothelial cells (HAoEC), and elucidated the significance of transcription factor NF-kappaB in that interaction. Concentration of TNF-alpha as well as 8-hydroxy-2'-deoxyguanosine (8-OHdG), an indicator of ROS generation, in the culture medium was significantly elevated 24 h after treatment with glycolaldehyde-derived AGE3. Antioxidant TEMPOL almost completely inhibited AGE3-induced TNF-alpha secretion, whereas NF-kappaB inhibitor PDTC partly suppressed AGE3-induced 8-OHdG production. Since NF-kappaB, which induces TNF alpha expression is activated by ROS and TNF-alpha itself, AGE3-induced ROS generation is partly through NF-kappaB activation and subsequent TNF-alpha production in these cells. Our findings suggest that sustained activation of NF kappaB might be crucial for endothelial dysfunction in diabetes, and that inhibition of local NF-kappaB and/or TNF-alpha action could be one of therapeutic strategies for vascular complications. PMID- 22944045 TI - A dose response study to assess effects after dietary administration of diisononyl phthalate (DINP) in gestation and lactation on male rat sexual development. AB - Male rat sexual development was evaluated after dietary administration of 0, 760, 3800, 11,400 ppm diisononyl phthalate (DiNP) and 7600 ppm dibutyl phthalate (DBP) from gestation day (GD) 12 to postnatal day (PND) 14. Maternal weight was reduced on GD 20, PND 2 and 14 at 11,400 ppm DiNP. Pup weight was reduced on PND 2 and 14 at 11,400 and 3800 ppm DiNP. DBP induced multinucleated germ cells (MNGs) and Leydig cell aggregates (LCAs) in PND 2 testes. 7600 ppm DBP reduced anogenital distance (AGD) on PND 2 and 14, and increased nipple retention and reproductive tract malformations on PND 49. DiNP induced MNGs (3800 ppm) and LCAs (11,400 ppm) on PND 2, and reduced AGD (11,400 ppm) on PND 14. DiNP did not alter AGD, nipple retention or reproductive tract malformations on PND 49. Global endpoint analysis showed no evidence of a rat "phthalate syndrome" on PND 49 with DiNP administration. PMID- 22944046 TI - The chromosome 15q14 locus for bipolar disorder and schizophrenia: is C15orf53 a major candidate gene? AB - Bipolar disorder (BD) and schizophrenia are complexly inherited and highly heritable disorders with currently unknown etiologies. Recently, two independent genome-wide association studies for BD identified a small region on chromosome 15q14-15.1, pointing to a locus close to the gene C15orf53. Previously, this genomic region was also found to co-segregate with periodic catatonia (SCZD10, OMIM %605419), an unsystematic schizophrenia according to Leonhard's classification, in several multiplex families, thus pointing to overlapping etiologies of both conditions. A susceptibility locus on chromosome 15q14-15.1 was narrowed down to a 4.38 Mb region in these affected families followed by mutation and segregation analyses of C15orf53. Association analysis of individuals affected by BD and/or SCZD10 (n = 274) and controls (n = 230) and expression analyses in distinct post-mortem human limbic brain tissues were conducted. C15orf53 revealed no mutations in our SCZD10 family members, but segregation of two common haplotypes was found. No association of identified haplotypes was found in our case-control samples. Gene expression could be demonstrated for immune-system-derived cells but not for the post-mortem human limbic brain tissue. Our results indicate that C15orf53 is probably neither causative for the etiology of BD nor for SCZD10 in our samples. PMID- 22944047 TI - [Understanding the non-use of long-lasting impregnated nets (LLINs) in Niger]. AB - In Niger, malaria is the leading cause of mortality and morbidity among pregnant women and children under 5 years. To decrease these rates, the country initiated a prevention policy of free distribution of long-lasting impregnated nets (LLINs). However, improved physical access to this preventive tool has not led to its regular use in households. A nationally representative quantitative and qualitative survey sought to document the reasons for non-use. The results show that the possession of a LLIN is quite low and confirm the low utilization rate, with significant differences by region. Cultural beliefs are not the main barriers to the use of LLINs in Niger. Knowledge and social, technical, environmental and economic dimensions were all more decisive. These results suggest that while improving awareness and communication is important for changing behavior, it cannot alone remove certain socioeconomic barriers and improve LLIN use. PMID- 22944048 TI - Consolidation and concentration in the German hospital market: the two sides of the coin. AB - In many countries, policy makers try to increase quality and efficiency in the hospital sector by fostering competition. The German hospital market is a good example of this approach and the challenges that come with it. We focus on market concentration which is both a result of and a potential threat to more competition. This study gives a detailed account of health reform in the German hospital sector and illustrates international experience with regard to market concentration. For the first time, concentration measures are consistently calculated at hospital system level. To make the results exploitable for comparative studies, this approach is described in detail. Patient flows are analyzed using data from the German hospital census, which is augmented with external data such as an indicator for the structures of urban and rural development. Our findings indicate that just some years after hospital competition was intensified, more than one third of German hospitals are located in strongly concentrated markets. Rural areas are especially prone to this development. If system membership is not accounted for, concentration is considerably underestimated. Policy makers are strongly advised to take precautions against excessive market concentration before promoting competition, as once consolidated, structures are difficult to unbundle. PMID- 22944051 TI - [Correct understanding of the status of targeted drugs in the treatment of pulmonary arterial hypertension]. PMID- 22944049 TI - PRAME expression in head and neck cancer correlates with markers of poor prognosis and might help in selecting candidates for retinoid chemoprevention in pre-malignant lesions. AB - OBJECTIVES: PRAME (Preferentially Expressed Antigen in Melanoma) is a tumor associated antigen recognized by immunocytes, and it induces cytotoxic T cell mediated responses in melanoma. PRAME expression in tumors interferes with retinoic acid receptor (RAR) signaling thus promoting tumor progression. Here, we study PRAME expression in head and neck squamous cell carcinoma (HNSCC) to determine its potential clinical significance. MATERIALS AND METHODS: PRAME expression in HNSCC was evaluated by immunohistochemistry in tissue microarrays of primary tumors (n=53), metastatic lymph nodes (n=8) and normal oral mucosa (n=11). Biopsies of dysplastic oral lesions (n=12) were also examined. PRAME expression levels in tissues were correlated with markers of poor prognosis in HNSCC. PRAME mRNA in HNSCC cell lines and in normal immortalized human keratinocytes (HaCaT cell line) was measured by qRT-PCR, and the protein expression by flow cytometry and western blots. RESULTS: PRAME was expressed in HNSCC cell lines and HNSCC lesions. PRAME expression in dysplastic mucosa was variable. No or only weak expression was found in normal cells or tissues. PRAME expression levels significantly correlated with the tumor grade, size, nodal involvement and the clinical status of HNSCC patients. CONCLUSIONS: Elevated PRAME expression associates with clinicopathologic markers of poor outcome in HNSCC and might identify potential candidates with pre-cancerous lesions for chemoprevention with retinoids. PMID- 22944050 TI - N-acetylcysteine (NAC) inhibits cell growth by mediating the EGFR/Akt/HMG box containing protein 1 (HBP1) signaling pathway in invasive oral cancer. AB - OBJECTIVES: Overexpression of the epidermal growth factor (EGF) receptor (EGFR) gene in the squamous cell carcinomas of the head and neck (SCCHN) is often associated with inauspicious prognosis and poor survival. N-acetylcysteine (NAC), a compound from some vegetables and allium species, appears anti-tumorigenesis, but the underlying mechanism is unclear. The objective of this study is to investigate the role of NAC in EGFR-overexpressing oral cancer. MATERIALS AND METHODS: Both HSC-3 and SCC-4 human tongue squamous carcinoma cell lines and an HSC-3 xenograft mouse model were used to test the anti-growth efficacy of NAC in vitro and in vivo, respectively. RESULTS: NAC treatment suppressed cell growth, with concomitantly increased expression of HMG box-containing protein 1 (HBP1), a transcription suppressor, and decreased EGFR/Akt activation, in EGFR overexpressing HSC-3 oral cancer cells. HBP1 knockdown attenuated the growth arrest and apoptosis induced by NAC. Lastly, NAC and AG1478, an EGFR inhibitor, additively suppressed colony formation in HSC-3 cells. CONCLUSION: Taken together, our data indicate that NAC exerts its growth-inhibitory function through modulating EGFR/Akt signaling and HBP1 expression in EGFR-overexpressing oral cancer. PMID- 22944052 TI - [Effects of PPARD-87T > C and interactions with single nucleotide polymorphisms in PPARA and PPARG on abdominal obesity]. AB - OBJECTIVE: To examine the main effect of 10 single nucleotide polymorphisms (SNPs) in contribution to abdominal obesity and study whether there is an interaction in the 10 SNPs in the cause of abdominal obesity. METHODS: A total of 820 subjects were randomly selected and no individual was related. Individual polymorphism and interactions were available for analyses. RESULTS: C allele carrier (CC + TC) was significantly higher than that of TT genotype (OR (95%CI) = 0.68 (0.52 - 0.90), P = 0.005). A 5-dimension gene-to-gene interaction model existed among rs135539, rs2016520, rs10865710, rs1805192 and rs709158 on the incidences of abdominal obesity. CONCLUSIONS: The C allele in rs2016520 is significantly associated with a lower rate of abdominal obesity. And there is an interaction among rs2016520, rs135539, rs10865710, rs1805192 and rs709158 on the incidences of abdominal obesity. PMID- 22944053 TI - [Efficacy of tianmaixiaoke tablets in the treatment of newly diagnosed type 2 diabetes mellitus in China]. AB - OBJECTIVE: To explore the efficacy and influencing factors of chromium picolinate (tianmaixiaoke tablet) in the treatment of newly diagnosed type 2 diabetes mellitus in China. METHODS: A total of 84 outpatients with newly diagnosed type 2 diabetes mellitus visiting 4 hospitals in Beijing were randomly divided into two equal groups: study group receiving tianmaixiaoke tablet 240 mg bid for 24 weeks (n = 42) and control group sitagliptin 100 mg qd for 24 weeks (n = 42). The levels of fasting plasma glucose (FPG), plasma glucose 2 h after meal (PG2 h) and glycated hemoglobin (HbA1c) were detected before and 24 weeks after treatment. The serum levels of chromium and insulin were detected. RESULTS: Study was completed in 76 patients. The serum level of chromium was significantly lower in the diabetes group than in the normal group at baseline ((56 +/- 28) ug/L vs (112 +/- 21) ug/L, P = 0.00). At 24 weeks after treatment, the levels of HbA1c, FPG and PG2 h decreased while the serum level of chromium increased significantly in both groups. There were 11 patients with changed HbA1c from baseline (DeltaHbA1c) >= 1% in the study group. At 24 weeks after treatment, HbA1c decreased by 1.61% (from 8.38% +/- 0.72% to 6.77% +/- 0.62%) and serum level of chromium increased by 35.14 ug/L in the DeltaHbA1c >= 1% group with a low baseline serum level of chromium ((36.2 +/- 18.0) ug/L). Both study group and control group were divided into three subgroups according to baseline serum level of chromium. DeltaHbA1c reduced with the increase in baseline serum level of chromium in study group, while in control group, DeltaHbA1c was unrelated with baseline serum level of chromium. At 24 weeks after treatment, insulin resistance index (HOMA-IR) reduced, beta cell function index (HOMA-beta) and insulinogenic index (IGI) increased in both groups. Multiple linear regression showed that the variables significantly associated with DeltaHbA1c were baseline HbA1c and the baseline serum level of chromium. CONCLUSIONS: Chromium is commonly deficient in the newly diagnosed type 2 diabetics in China. HbA1c decreases and serum chromium increases significantly after chromium supplementation in the patients with a low baseline serum level of chromium. PMID- 22944054 TI - [Efficacy analysis of third-generation plus platinum doublets in the first-line chemotherapy of advanced non-small cell lung cancer]. AB - OBJECTIVE: To compare the chemotherapeutic efficacies of third-generation plus platinum doublets in advanced non-small cell lung cancer (NSCLC) patients. METHODS: A total of 1112 patients were diagnosed as advanced NSCLC at Chinese Academy of Medical Science and Cancer Hospital from January 2005 to August 2009. Their clinical efficacies and regimen compositions were retrospectively analyzed. All calculations were performed by SPSS 17.0. RESULTS: Differences in objective response rate (ORR) existed among four third-generation agents (paclitaxel, gemcitabine, vinorelbine and docetaxel) plus platinum doublets. Their ORRs were 35.6%, 35.4%, 25.9% and 37.4% respectively (chi(2) = 16.331, P = 0.001). And vinorelbine doublets had the lowest ORR (all P < 0.01). The ORRs of cisplatin and carboplatin doublets were 35.2% and 33.5% respectively. There was no difference in ORR among them (chi(2) = 0.352, P = 0.569). Subgroup analysis showed that the ORRs of four third generation plus platinum doublets were 34.8%, 35.3%, 23.2% and 37.1% in non-agers. And the vinorelbine doublets performed the worst. In the patients with squamous-cell lung cancer, the ORRs of paclitaxel and gemcitabine doublets were 45.5% and 28.4% respectively. And the paclitaxel doublets had the better performance (chi(2) = 5.250, P = 0.026). When combined with carboplatin, the ORRs of four doublets were 36.2%, 16.7%, 15.4% and 32.0% respectively. And the paclitaxel regimen was more effective than the gemcitabine and vinorelbine regimens (P = 0.018 and P = 0.034). The influences of subsequent therapy were nullified when the progression-free survival (PFS) was analyzed. The PFSs of these doublets were (3.67 +/- 0.19), (2.95 +/- 0.18), (3.05 +/- 0.36) and (3.40 +/- 0.37) months respectively. There was no difference among them. Pairwise comparisons showed that the mean PFS of patients on paclitaxel doublets was longer than those on gemcitabine doublets. And their PFSs were (3.67 +/- 0.19) and (2.95 +/- 0.18) months respectively (chi(2) = 7.037, P = 0.008). The PFSs of cisplatin and carboplatin doublets were (3.05 +/- 0.14) and (3.65 +/- 0.20) months respectively. The patients on carboplatin doublets had a longer PFS than that of those on cisplatin doublets (chi(2) = 6.012, P = 0.014). CONCLUSIONS: No difference exist in ORRs among different third-generation plus platinum doublets. But as the first-line treatment of advanced NSCLC, carboplatin doublets is superior to cisplatin doublets in terms of PFS. PMID- 22944055 TI - [Simplified surgical procedure of stented elephant trunk fenestration in acute Stanford type A aortic dissection]. AB - OBJECTIVE: To study the technical feasibility of simplified total arch replacement via stented elephant trunk fenestration in the treatment of acute Stanford type A aortic dissection. METHODS: A total of 42 consecutive patients with acute type A aortic dissection underwent total aortic arch replacement plus fenestrate stented elephant trunk implantation under hypothermic cardiopulmonary bypass and bilateral antegrade cerebral perfusion between August 2008 to February 2011. The aortic arch was accessed longitudinally. Transection of aortic arch was performed between left common carotid artery and left subclavian artery. A stented elephant trunk was inserted in descending aorta. Then the reconstruction of left subclavian artery was made by fenestration in stented elephant trunk. Finally 3-branched graft was used to complete the reconstruction of aortic arch. RESULTS: Operations were performed successfully. The mean cardiopulmonary bypass (CPB) time was (156 +/- 42) min, mean aortic cross-clamp time (91 +/- 18) min, mean circulatory arrest time (20 +/- 5) min and mean antegrade cerebral perfusion (ACP) time (33 +/- 7) min. No postoperative death occurred. The incidence of temporary neurological dysfunction was 4.8% (2/42). They underwent neither re exploration for postoperative hemorrhage nor hoarseness due to recurrent nerve palsy. Left radial arterial pulses were palpable in all of them. None had sensory deficit and dyskinesia of left arm. All their angiographic findings showed complete patency of left subclavian artery. There was neither space nor blood flow around the stented elephant trunk. The false lumen of descending aorta around elephant trunk closed and obliterated in all cases. CONCLUSIONS: The above mentioned technique of modified total aortic arch replacement provides a distinct operative field and may achieve simple but reliable anastomosis with less bleeding. Thus aortic arch replacement becomes easier and more effective. PMID- 22944056 TI - [Detection of antibodies to cyclic citrullinated peptides and its clinical significance in patients with chronic hepatitis B virus infection]. AB - OBJECTIVE: To detect the presence of antibodies to cyclic citrullinated peptides (anti-CCP) in patients with chronic hepatitis B virus (HBV) infection and evaluate its potential clinical significance. METHODS: Serum samples of 280 patients with chronic HBV infection and 40 healthy controls were collected from May 2011 to October 2011 and tested for anti-CCP and IgM-rheumatoid factor (RF). Anti-CCP was detected by ELISA and RF by immunonephelometry. All of 280 patients with chronic HBV infection were divided into 3 groups according to joint symptoms: asymptomatic group, HBV-associated arthropathy group and HBV concomitant RA group. Meanwhile, according to liver disease, they were divided into 3 groups: carrier group, chronic hepatitis group and cirrhosis group. RESULTS: The positive rates of anti-CCP and RF were 5.7% and 13.9% in patients with chronic HBV infection respectively. Anti-CCP was detected in 3 of 265 non-RA (1.1%) and 13 of 15 RA patients (86.7%). And RF were detected in 27 of 265 non-RA (10.2%) and 12 of 15 RA patients (80.0%). Twelve of 15 RA patients were positive for both anti-CCP and RF. The specificity of anti-CCP for RA was 98.9% in chronic HBV infection while the specificity of RF 89.8% (P < 0.01). Compared with the positive detection rates of anti-CCP and RF among liver disease subgroups, no significant difference existed between the subgroups. The levels of anti-CCP and RF in HBV concomitant RA group were statistically higher than those in asymptomatic group, HBV-associated arthropathy group and healthy controls (all P < 0.01). The level of RF in patients with HBV-associated arthropathy group was higher than that in asymptomatic group (U = 6017, P < 0.05). CONCLUSION: It is better to detect anti-CCP than RF to discriminate non-RA from concomitant RA in patients with chronic HBV infection. PMID- 22944057 TI - [Expression and significance of trefoil factor 1 protein and serum pepsinogen in benign and malignant gastric ulcers]. AB - OBJECTIVE: To explore the clinical significance of trefoil factor 1 (TFF1) protein expression and serum pepsinogen (PG) concentration in benign and malignant gastric ulcers. METHODS: The TFF1 protein expression was evaluated by immunohistochemistry in biopsies of gastric mucosa from 18 normal controls, 25 patients with gastric ulcer and 13 patients with ulcerative gastric cancer at our hospital during January to June 2011. The serum concentrations of PGI and PGII were detected by enzyme-linked immunosorbent assay (ELISA) and PG/PGII (PGR) was subsequently calculated. RESULTS: The expression of TFF1 protein increased significantly in ulcerative and peripheral gastric mucosa and peripheral mucosa of gastric cancers versus that in normal controls and the ulcerocancer group (3.04% +/- 0.20%, 3.00% +/- 0.20%, 3.23% +/- 0.26% vs 1.67% +/- 0.18%, 0.46% +/- 0.18%, all P < 0.01). The elevated expression of TFF1 increased the risk of gastric ulcer (OR: 1.365, 95%CI: 1.065 - 1.749, P = 0.014) while the down regulation of TFF1 significantly increased the risk of ulcerocancer (OR: 3.067, 95%CI: 1.391 - 6.757, P = 0.005). The serum levels of PGI and PGII in gastric ulcer group were significantly higher than that in normal control and ulcerocancer group ((150 +/- 27), (28 +/- 9) vs (121 +/- 22), (17 +/- 7), (79 +/- 12), (20 +/- 5) ug/L,all P < 0.01). The PGI level and PGR decreased significantly in the ulcerocancer group versus normal control (both P < 0.01). But there was no statistical difference in PGII (P > 0.05). Receiver operating characteristic curve analysis revealed that PGI and PGR were valuable for the diagnosis of malignant gastric cancer with an area under curve of 0.975 and 0.914 respectively. CONCLUSIONS: The expression of TFF1 protein increases in gastric ulcer but decreases in gastric ulcerocancer. The elevated serum levels of PGI and PGII indicate benign ulcer while a marked decline of serum PG I and PGR serves as a risk signal of malignant gastric ulcer. The evaluation of expression profiles of TFF1 protein and PGs is helpful for the differentiation of benign gastric ulcer from malignant ulcerocancer. PMID- 22944058 TI - [Clinical characteristics of ischemic bowel disease in young and middle-aged patients]. AB - OBJECTIVE: To explore the clinical characteristics of ischemic bowel disease (IBD) in young and middle-aged patients (aged under 65 years old). METHODS: A total of 33 young and middle-aged IBD patients from January 1997 to July 2011 at Department of Gastroenterology, Renmin Hospital of Wuhan University were studied retrospectively. RESULTS: Among them, 4 patients underwent surgical procedures while 29 patients received conservative medical management. All became cured after correct treatment. The disease with a nighttime onset took up 36.4% (12/33). Among them, 21.2% (7/33) took oral contraceptives previously. Patients with no specific pre-existing condition accounted for 39.4% (13/33). Abdominal pain and hematochezia were the chief complaints of all patients. The laboratory findings were non-specific. The radiographic examination remained a major diagnostic tool. And 51.5% (17/33) patients had typical colonoscopic manifestations. CONCLUSION: More attention should be paid to young and middle aged patients with classic abdominal pain, hematochezia and a lack of baseline cardiovascular disease. PMID- 22944059 TI - [Risk factors of contrast-induced nephropathy in patients after coronary artery intervention]. AB - OBJECTIVE: To explore the risk factors of contrast-induced nephropathy (CIN) in patients after coronary artery intervention. METHODS: A total of 637 patients undergoing diagnostic coronary angiography or percutaneous coronary intervention were enrolled. They were divided into the CIN and non-CIN groups according to the changes in serum creatinine levels within 48 hours after coronary artery intervention. Then the relevant risk factors of CIN were analyzed. RESULTS: Among them, CIN occurred in 49 patients with an incidence of 7.7%. The patients with diabetes and renal insufficiency had higher incidence of CIN at 15.5% and 22.5% respectively. Logistic regression analysis showed that the risk factors of CIN included advanced age, smoking, diabetes, renal insufficiency, hypercholesterolemia and hyperuricemia. CONCLUSION: For the patients of coronary artery intervention, the major risk factors of CIN are advanced age, diabetes and renal insufficiency. PMID- 22944060 TI - [Effects of domestic rosuvastatin on coronary plaque in patients with mild-to moderate coronary artery stenosis as evaluated by virtual histology-intravascular ultrasound]. AB - OBJECTIVE: To evaluate the effects of domestic rosuvastatin tablets on coronary plaque in the patients with mild-to-moderate coronary artery stenosis through virtual histology-intravascular ultrasound (VH-IVUS). METHODS: Eighty-three patients with mild-to-moderate coronary artery stenosis of acute coronary syndrome (ACS) were enrolled and randomized into test group (domestic rosuvastatin, 10 mg/day, n = 42) or control group (CRESTOR, 10 mg/day, n = 41). The serum lipid levels, diameter stenosis (DS) on quantitative coronary angiography (QCA), MLA (minimal lumen area), plaque burden and component of target lesion on VH-IVUS were evaluated at baseline and at 6-month follow-up. RESULTS: After 6 months, the levels of total cholesterol (TC), low density lipoprotein cholesterol (LDL-C) and triglyceride (TG) significantly decreased while the high density lipoprotein cholesterol (HDL-C) level significantly increased in two groups(P < 0.05). VH-IVUS analysis showed that the proportion of necrotic core significantly decreased (domestic rosuvastatin: 14.8% +/- 7.0% vs 22.6% +/- 7.5%, P < 0.05, crestor: 14.9% +/- 7.1% vs 23.1% +/- 7.7%, P < 0.05) and the proportion of fibrous tissue significantly increased (domestic rosuvastatin: 51.5% +/- 9.9% vs 44.5% +/- 9.7%, P < 0.05, crestor: 51.4% +/- 10.1% vs 44.3% +/- 9.8%, P < 0.05) in two groups. There were no significant changes in DS, plaque burden, MLA or the proportion of dense calcium and fibro fatty tissue of target lesion in two groups (P > 0.05). And no significant differences existed in serum lipid levels, DS, MLA, plaque burden and component between two group(P > 0.05). CONCLUSION: The 6-month treatment of rosuvastatin may stabilize the atherosclerosis plaque and prevent its progression in patients with mild-to-moderate coronary artery stenosis. PMID- 22944061 TI - [Clinicopathological analysis of aggressive angiomyxoma]. AB - OBJECTIVE: To explore the clinicopathological characteristics of aggressive angiomyxoma (AAM) so as to boost the level of diagnosis and treatment. METHODS: Seven cases of aggressive angiomyxoma were studied with light microscope and immunohistochemistry. Antibody of Vimentin, Desmin, CD34, smooth muscle actin (SMA), estrogen receptor (ER), progesterone receptor (PR), androgen receptor (AR), S-100, p53 and Ki67 were used. RESULTS: There were 3 males and 4 females with an average age of 43.1 years. Three patients had urinary compressive complaints while others were symptom-free. All underwent surgical resection. Three patients were recurrent after operation. The tumor was generally nodular and its cut surface appeared jelly-like. Histologically, on myxoid stroma background, it was composed of a mixture of spindle and stellar cells without atypical cell and mitosis. There were various-sized vessels with thin to thick walls. The scattered muscle-like cells had a perivascular distribution. Immunohistochemistry showed that tumor cells were positive for Vimentin(+)7/7, Desmin(+)7/7, CD34(+)3/7, SMA(+)2/7, ER(+)6/7, p53(+)4/7, Ki67(+) 1% - 8% and negative for PR, AR and S-100. CONCLUSIONS: As a rare soft tissue tumor, AAM extremely rare in males. Owing to its local invasion and high recurrence, extensive resection and long-term follow-up are necessary. PMID- 22944062 TI - [Diagnosis and treatment of focal nodular hyperplasia of liver]. AB - OBJECTIVE: To explore the diagnosis and treatment of focal nodular hyperplasia (FNH) of liver. METHODS: The clinical data were retrospectively analyzed for 26 cases with confirmed FNH of liver from January 2006 to July 2011. Enhanced computed tomography and magnetic resonance imaging were performed. RESULTS: Among them, 22 cases underwent surgical resection, including left hemihepatectomy (n = 4), left lateral lobe hepatectomy (n = 5) and partial hepatectomy (n = 13). The pathological diagnosis was FNH. Most tumors were of soft texture. The gross surface was brown or yellow-brown in color. Central scar and radiating fibrous septas were spotted in some cases. There was no recurrence during a follow-up period of 4 months to 5 years. Serial observations were conducted for 4 cases with a follow-up period of 2 - 4 years. No growth was observed. CONCLUSIONS: Enhanced CT and MRI are important diagnostic tools. The confirmed cases may be followed up. Surgical resection is effective with an excellent prognosis. PMID- 22944063 TI - [Transurethral vapor enucleation and resection of prostate with TURis button electrode]. AB - OBJECTIVE: To describe an efficient and effective method of using Olympus TURis button plasma vaporization electrode plus loop electrode for transurethral vapor enucleation and resection of prostate. METHODS: Between July 2011 and October 2011, the investigators performed transurethral vapor enucleation and resection of prostate using Olympus TURis button plasma vaporization electrode plus loop electrode in 16 consecutive patients at our institution. The parameters of prostate weight, International Prostate Symptom Score (IPSS), quality of life (QOL), operative duration, blood loss volume, catheterization period, duration of hospitalization, perioperative complications and the weight of enucleated tissue were evaluated. IPSS and QOL were recorded during the follow-up. RESULTS: No patient had significant blood loss or signs of transurethral resection syndrome. The mean patient age was 67.3 +/- 8.1 years. Mean preoperative prostate weight was 49 +/- 24 g (range: 19 - 91) and mean resected tissue weight 36 +/- 16 g (range: 10 - 50). Serious complications were not observed. Operative duration was 116 +/- 31 minutes, mean catheter time 4.9 +/- 1.8 days and the duration of hospitalization was 16.6 +/- 5.5 days. Transurethral vapor enucleation and resection of prostate induced significant, pronounced, immediate and lasting improvement in IPSS (15.6 +/- 6.8 vs 6.7 +/- 2.4, P < 0.01) and QOL (3.4 +/- 1.4 vs 1.6 +/- 0.6, P < 0.01). CONCLUSION: Transurethral vapor enucleation and resection of prostate with Olympus TURis plasma button electrode is a safe, effective and thorough surgical method in the treatment of benign prostatic hyperplasia. PMID- 22944064 TI - [Status of endothelial progenitor cell in murine model of Kawasaki disease]. AB - OBJECTIVE: To assess whether the occurrence of coronary artery lesion was correlated with the changes of endothelial progenitor cell (EPC) number and function in murine model of Kawasaki disease (KD). METHODS: Lactobacillus casei cell wall extract (LCWE) was prepared and then C57BL/6 mice received a single intraperitoneal injection of LCWE for inducing KD. Twenty-four mice were categorized randomly into 3 groups: KD model group at Day 14 post-injection, KD model group at Day 56 post-injection and control group with an intraperitoneal injection of phosphate buffered solution (n = 8 each). The number of circulating EPC was defined as CD34(+)Flk-1(+)CD45(-) from mice. Meanwhile, bone marrow mononuclear cells were cultured in vitro to expand EPC for functional analysis. After 7 days of culturing, EPC were inoculated onto culture plate and thiazolyl blue assay was used to measure the absorbance value by enzyme labeling instrument to evaluate the proliferation. The adhesion of EPC was performed by replating cells on fibronectin coated dishes and then counting the number of adherent cells. The migration of EPC was assayed by Transwell. RESULTS: Focal inflammatory infiltrate was evident in coronary artery trunk and a series of branches at Day 14 post-injection. The inflammatory cell infiltrate consisted of mononuclear lymphocytes. The number of circulating EPC were significantly lower in the Day 14 LCWE-treating murine model versus the controls (0.017% +/- 0.008% vs 0.028% +/- 0.007%, P < 0.01). Disruption of elastin was consistently observed at Day 56 post injection. And there was no apparent recovery in number of EPC (0.016% +/- 0.007%, P < 0.01). When bone marrow mononuclear cells were cultured in vitro, the colony-forming ability of EPC decreased in the KD model group at Day 14 post injection versus the controls. Test of proliferating ability showed that the absorbance was 0.39 +/- 0.11 in MTT experiment and decreased than the controls (0.61 +/- 0.14, P < 0.01). Adhesion and migration were also down-regulated versus the controls ((3.1 +/- 0.6) and (3.2 +/- 0.6) vs (6.4 +/- 1.2) and (6.2 +/- 0.5) cells/HPF, both P < 0.01). In the KD model group at Day 56 post-injection, the colony-forming ability of EPC was not recovered significantly. Proliferation ability, adhesion and migration were still decreased compared to the controls (0.38 +/- 0.09, (3.12 +/- 0.56) cells/HPF and (3.29 +/- 0.63) cells/HPF, all P < 0.01). CONCLUSION: The occurrence of coronary artery lesion may be correlated with the down-regulation of EPC number and function in murine model of KD. PMID- 22944065 TI - [Changes of gamma-amino butyric acid and electrophysiology inferior colliculus after noise exposure in guinea pig]. AB - OBJECTIVE: To explore the changes of inferior collicular (IC) neurons after noise exposure cochlea injury in guinea pig to elucidate the encoding mechanism of pure tones, observe the changes of IC gamma-amino butyric acid (GABA) after cochlear damage by acoustic trauma and understand the possible mechanism of symptoms such as noise-induced tinnitus, hyperacusis and loudness recruitment. METHODS: The responses of IC neurons to pure tone stimuli were observed in guinea pig at Day 1 and Days 11-21 after cochlear damage induced by noise exposure. And the IC neurons of normal guinea pig were assigned as the controls. Reverse transcription polymerase chain reaction (RT-PCR) was used to measure the concentrations of GABA(A) and GABA(B) receptors. RESULTS: (1) The types of frequency reaction area (FRA) in the experiment group were the same as those in the control group (V shape 84.8%, W-shape 8.9%, N-shape 6.3%). But the percentages of types were markedly different at Day 1 (V-shape 63.9%, W-shape 18.1%, N-shape, 18.1%) and Days 11-21 (V-shape 84.2%, W-shape 12.3%, N-shape 3.5%) after noise exposure. (2) After noise exposure, there was a marked fault in characteristic frequency (CF) and depth function map corresponding to 4 kHz (noise frequency). The rake ratio of CF and depth linear function map in the experiment group was lower than that of the control group. The control group, Day 1 and Days 11-21 after noise exposure, the rake ratios were 6.6, 5.8, 5.2 respectively. (3) GABA(A)/GABA(B) receptors decreased markedly at Days 1, 11 and 21 post-exposure compared to normal controls. And the values increased gradually with the prolonged time after exposure. The above findings conformed to the changes of electrophysiology of IC. CONCLUSIONS: After acoustic trauma, the responses of IC neurons to pure tone stimuli change with the elongation of time. It may be explained by the changes of IC GABA receptors after noise exposure. PMID- 22944066 TI - [A murine model of human primary hepatic lymphoma constructed by surgical orthotopic implantation of histologically intact human tumor tissue and in vivo continuous orthotopic passage]. AB - OBJECTIVE: To establish a nude murine model of human primary hepatic lymphoma (PHL) with surgical orthotopic implantation of histologically intact human tumor tissue and in vivo continuous orthotopic passage. METHODS: Histologically intact lymphoma tissues harvested intraoperatively from a PHL patient were orthotopically transplanted into liver parenchyma of nude mice and in vivo continuous orthotopic passage in nude mice was used to develop a nude murine model mimicking the biological characteristics of PHL patients. Histopathology (light microscopy and immunohistochemistry), serological test, karyotypic analysis and flow cytometry were used to explore the tumorigenicity, invasion and metastasis. RESULTS: An orthotopic nude murine model of PHL, named HLBL-0102, was successfully developed. Histopathology of transplanted tumors showed primary hepatic lymphoma (diffuse large B cell) stained positive for CD20, CD79a and MUM1. Serological test in tumor-bearing mice indicated that alpha-fetal protein (AFP) was negative and hepatitis B surface antigen (HBsAg) positive. The serum level of lactate dehydrogenase (LDH) was elevated to an average of ((1223 +/- 258) vs (124 +/- 54) U/L, P < 0.01). The chromosomal number of transplanted tumors was between 55 and 59. The DNA index (DI) of 1.7 +/- 0.2 indicated heteroploid. So far HLBL-0102 model has been passed for 42 generations in nude mice. A total of 320 nude mice were used for transplantation. The growth rate and resuscitation rate of liquid nitrogen cryopreservation of transplanted tumors were both 100%. The transplanted tumors grew invasively in the liver of nude mice and destroyed adjacent liver tissues and bile ducts, veins and arteries of portal area. There was no involvement of other tissues, organs and distal lymph nodes. CONCLUSION: An orthotopically transplanted model has been successfully established for human primary hepatic lymphoma in nude mice. PMID- 22944068 TI - Suppression of collagen Q expression in the extrajunctional regions of rat fast muscles is encoded in their stem cells (satellite cells). AB - In rat fast muscles, collagen Q (ColQ) expression is restricted to the neuromuscular junctions. In contrast, it is high also extrajunctionally in the slow soleus muscles. Fast muscles activated by chronic low-frequency electrical stimulation, similar to neural activation of the soleus muscles, did not increase their extrajunctional expression of ColQ. We assumed that the myogenic stem cells (satellite cells) in fast and slow muscles were intrinsically different in regard to the capacity that they convey to their respective muscle fibers to increase the extrajunctional ColQ expression upon innervation. ColQ mRNA levels were determined by quantitative real-time PCR. Extensive neural suppression of the extrajunctional ColQ expression in regenerating fast muscles during maturation is a very slow process requiring 30-60 days. If the immature regenerating fast EDL muscles were indirectly or directly electrically stimulated immediately after innervation by chronic low-frequency impulse pattern for 8 days, no significant increase of the extrajunctional ColQ mRNA levels was observed in stimulated regenerates in comparison to non-stimulated ones. In contrast, the extrajunctional ColQ mRNA levels in the regenerates of the soleus muscles, trans innervated by the EDL nerve at the time of muscle injury, increased 4- to 5-fold after 8 days of the same chronic low-frequency electrical stimulation in comparison to those in the stimulated EDL regenerates. Since both fast and slow muscles completely regenerated only from their own myogenic stem cells and were innervated by the same nerve and later activated by the same tonic pattern of impulses, these results demonstrated that the mechanism causing incapacity of regenerating fast muscles to increase their extrajunctional ColQ expression upon tonic activation is encoded in their satellite cells, which in this respect differ from those in the slow muscles. PMID- 22944067 TI - The clinical significance of inflammatory cytokines in primary cell culture in endometrial carcinoma. AB - Endometrial cancer is the most common malignancy of the female genital tract, and the incidence and mortality rates from this disease are increasing. Although endometrial carcinoma has been regarded as a tissue-specific disease mediated by female sex steroid pathways, considerable evidence implicates a role for an inflammatory response in the development and propagation of endometrial cancer. We hypothesized that if specific patterns of cytokine expression were found to be predictive of adverse outcome, then selective receptor targeting may be a therapeutic option. This study was therefore undertaken to determine the relationship between cytokine production in primary cell culture and clinical outcome in endometrial adenocarcinoma. Fresh endometrial tissues were fractionated into epithelial and stromal fractions and cultured. After 6-7 days, supernatants were collected and cells enumerated. Batched aliquots were assayed using ELISA kits specific for CSF-1, GMCSF, G-CSF, TNF-alpha, IL-6, IL-8, and VEGF. Data were compared using ANOVA, Fisher's exact, and log rank tests. Increased epithelial VEGF production was observed more often in tumors with Type 2 variants (p = 0.039) and when GPR30 receptor expression was high (p = 0.038). Although increased stromal VEGF production was detected more often in grade 3 endometrioid tumors (p = 0.050), when EGFR expression was high (p = 0.003), and/or when ER/PR expression was low (p = 0.048), VEGF production did not correlated with overall survival (OS). Increased epithelial CSF-1 and TNF-alpha production, respectively, were observed more often in tumors with deep myometrial invasion (p = 0.014) and advanced stage (p = 0.018). Increased CSF-1 (89.5% vs. 42.9%, p = 0.032), TNF-alpha (88.9% vs. 42.9%, p = 0.032, and IL-6 (92.3% vs. 61.5%, p = 0.052) also correlated with low OS. In Cox multivariate models, CSF-1 was an independent predictor of low survival when stratified by grade (p = 0.046) and histology (p = 0.050), and TNF-alpha, when stratified by histology (p = 0.037). In this study, high CSF-1, TNF-alpha, and IL-6 production rates identified patients at greatest risk for death, and may signify patients likely to benefit from receptor-specific therapy. PMID- 22944069 TI - Lithium treatment induces proteasomal degradation of over-expressed acetylcholinesterase (AChE-S) and inhibit GSK3beta. AB - Lithium is one of the most widely used mood-stabilizing agents for the treatment of bipolar disorder. Lithium is also a potent inhibitor of glycogen synthase kinase-3beta (GSK3beta) activity, which is linked to Alzheimer's disease (AD). In experiments with cultured HEK293T cells, we show here that GSK3beta stabilizes synaptic acetylcholinesterase (AChE-S), a critical component of AD development. Cells treated with lithium exhibited rapid proteasomal degradation of AChE-S. Furthermore treatment of the cells with MG132, an inhibitor of the 26S proteasome, prevented the destabilizing effect of lithium on AChE-S. Taken together, these findings suggest that regulation of AChE-S protein stability may be an important biological target of lithium therapy. PMID- 22944071 TI - Can preload-reducing therapy prevent disease progression in arrhythmogenic right ventricular cardiomyopathy? Experimental evidence and concept for a clinical trial. AB - Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited cardiomyopathy and a leading cause of sudden cardiac death in a young population. ARVC is especially common in young athletes. Mutations in different desmosomal genes have been identified causing dysfunctional cell-cell contacts. Reduced myocardial expression of plakoglobin in cell-cell contact complexes appears to associate with disease manifestation in patients harbouring mutations within other cell-cell contact genes. Experimental data suggest that preload reduction may be a simple and effective intervention to prevent disease progression and ventricular arrhythmias in ARVC. This review discusses the potential effects of this innovative approach and describes the design of the first controlled trial of preload-reducing therapy in patients with ARVC. PMID- 22944072 TI - Occurrence of epsilon-proteobacterial species in rabbits (Oryctolagus cuniculus) reared in intensive and rural farms. AB - In order to investigate the occurrence of Campylobacter, Helicobacter and Arcobacter species in caecal contents of rabbits reared in intensive and rural farms, a total of 87 samples from animals belonging to 29 farms were analysed by both cultural and PCR analyses. PCR analysis directly from faecal samples detected 100% positive samples for Campylobacter genus, 3.4% for Helicobacter genus and none for Arcobacter genus. 83 out of 87 animals (95.4%) and all the 29 farms were positive for Campylobacter cuniculorum as also determined by cultural examination. Campylobacter coli and Campylobacter jejuni were isolated only from three animals reared in two rural farms. No Helicobacter and Arcobacter species were isolated. To evaluate a possible genetic variability, one strain of C. cuniculorum from each farm was analysed by Pulsed Field Gel Electrophoresis (PFGE) and Amplified Fragment Length Polymorphism (AFLP). Genotyping revealed that C. cuniculorum population is heterogeneous among the different sources and no dominant clone has spread in the investigated farms. This survey highlighted a high presence of C. cuniculorum with a high rate of intestinal colonization, low presence of C. jejuni-coli, Helicobacter spp. and any Arcobacter spp. in farmed rabbits. PMID- 22944073 TI - Comparative evaluation of novel African swine fever virus (ASF) antibody detection techniques derived from specific ASF viral genotypes with the OIE internationally prescribed serological tests. AB - The presence of antibodies against African swine fever (ASF), a complex fatal notifiable OIE disease of swine, is always indicative of previous infection, since there is no vaccine that is currently used in the field. The early appearance and subsequent long-term persistence of antibodies combined with cost effectiveness make antibody detection techniques essential in control programmes. Recent reports appear to indicate that the serological tests recommended by the OIE for ASF monitoring are much less effective in East and Southern Africa where viral genetic and antigenic diversity is the greatest. We report herein an extensive analysis including more than 1000 field and experimental infection sera, in which the OIE recommended tests are compared with antigen-specific ELISAs and immuno-peroxidase staining of cells (IPT). The antibody detection results generated using new antigen-specific tests, developed in this study, which are based on production of antigen fractions generated by infection and virus purification from COS-1 cells, showed strong concordance with the OIE tests. We therefore conclude that the lack of success is not attributable to antigenic polymorphism and may be related to the specific characteristics of the local breeds African pigs. PMID- 22944074 TI - High frequency PMN-PT single crystal focusing transducer fabricated by a mechanical dimpling technique. AB - High frequency (~30MHz and ~80MHz) focusing ultrasound transducers were fabricated using a PMN-0.28PT single crystal by a mechanical dimpling technique. The dimpled single crystal was used as an active element for the focusing transducer. Compared with a plane transducer, the focusing transducer fabricated with a dimpled active element exhibits much broader bandwidth and higher sensitivity. Besides, a high quality image can be obtained by the 30MHz focusing transducer, in which the -6dB axial and lateral resolution is 27MUm and 139MUm, respectively. These results prove that the dimpling technique is capable to fabricate the high frequency focusing transducers with excellent performance for imaging applications. PMID- 22944075 TI - Modification of the hand-held Vscan ultrasound and verification of its performance for transvaginal applications. AB - PURPOSE: The purpose of this work was to validate a new clinical obstetrics and gynecology (OB-GYN) application for a hand-held ultrasound (US) device. We modified the smallest hand-held device on the market and tested the system for transvaginal (TV) use. This device was originally conceived for abdominal scanning only. METHODS: The validation involved 80 successive patients examined by the same operator: 25 obstetric and 55 gynecologic cases. US examination was performed transvaginally with two US systems: the hand-held Vscan (General Electrics; GE Vingmed Ultrasound; Norway) for which an intravaginal gadget TTGP 2010(r) (Troyano transvaginal gadget probe) was designed, and the Voluson 730 Expert (multifrequency transvaginal ultrasound of 3-9MHz; GE Healthcare, Milwaukee, WI, USA). We performed the same measurements with both US systems in order to confirm whether or not their diagnostic capability was similar. Quantitative difference in measurements between the systems was assessed, as well as the overall diagnostic detection rate and suitability for telemedicine. RESULTS: Regarding lesion visibility with Vscan, optimal distance was 8-16cm depending on the examination type, and the total detection rate was 98.7%. The exception was an ovarian endometrioma, diagnosed as a follicular cyst using the hand-held device. Assessment of reproducibility in 180 measurements showed that the measurements obtained with Vscan were 0.3-0.4cm lower than those obtained with the high resolution US device (Voluson 730 Expert). Nevertheless, Pearson's correlation coefficient was high for biparietal diameter (0.72) and gynecological (GYN) (0.99) measurements, and for overall correlation (0.997). Image transport on USB and SD-flash cards proved convenient for telemedicine. CONCLUSIONS: A novel TV application of a hand-held US device is demonstrated for OB-GYN. Heart, abdominal and obstetrics presets of the Vscan together with color-Doppler enable a detection capability comparable to that of a high-definition US device. The lower values of the measurements obtained by the hand-held device (by 0.3-0.4cm) must be taken into account, although they have no effect on its diagnostic capability. PMID- 22944076 TI - Neural dynamics of image representation in the primary visual cortex. AB - Horizontal connections in the primary visual cortex have been hypothesized to play a number of computational roles: association field for contour completion, surface interpolation, surround suppression, and saliency computation. Here, we argue that horizontal connections might also serve a critical role for computing the appropriate codes for image representation. That the early visual cortex or V1 explicitly represents the image we perceive has been a common assumption in computational theories of efficient coding (Olshausen and Field (1996)), yet such a framework for understanding the circuitry in V1 has not been seriously entertained in the neurophysiological community. In fact, a number of recent fMRI and neurophysiological studies cast doubt on the neural validity of such an isomorphic representation (Cornelissen et al., 2006; von der Heydt et al., 2003). In this study, we investigated, neurophysiologically, how V1 neurons respond to uniform color surfaces and show that spiking activities of neurons can be decomposed into three components: a bottom-up feedforward input, an articulation of color tuning and a contextual modulation signal that is inversely proportional to the distance away from the bounding contrast border. We demonstrate through computational simulations that the behaviors of a model for image representation are consistent with many aspects of our neural observations. We conclude that the hypothesis of isomorphic representation of images in V1 remains viable and this hypothesis suggests an additional new interpretation of the functional roles of horizontal connections in the primary visual cortex. PMID- 22944077 TI - Healing rates and subscapularis fatty infiltration after lesser tuberosity osteotomy versus subscapularis peel for exposure during shoulder arthroplasty. AB - BACKGROUND: Controversy exists regarding the optimal technique of subscapularis mobilization during shoulder arthroplasty. The purpose of this study was to compare healing rates and subscapularis fatty infiltration in patients undergoing a lesser tuberosity osteotomy (LTO) versus subscapularis peel for exposure during shoulder arthroplasty. MATERIALS AND METHODS: Eighty-seven patients, with a mean age of 67.8 +/- 10.9 years, undergoing shoulder arthroplasty, were randomized to receive either an LTO (n = 43) or peel (n = 44). Computed tomography scans were conducted preoperatively and at 12 months postoperatively. Outcome variables included healing rates and subscapularis Goutallier fatty infiltration grade, as well as subscapularis strength and Western Ontario Osteoarthritis of the Shoulder Index and American Shoulder and Elbow Surgeons outcome scores. RESULTS: Computed tomography imaging was available in 91% (n = 79) of the cohort. The healing rates for the peel (100%) and for the LTO (95%) did not differ significantly (P = .493). Preoperatively, the mean fatty infiltration grade for the peel (mean, 0.53) was not significantly different (P = .925) from the LTO (mean, 0.54). Postoperatively, the Goutallier mean fatty infiltration grade for the peel (mean, 0.95) did not differ significantly (P = .803) from the LTO (mean, 0.9). A significant increase in subscapularis fatty infiltration grade occurred postoperatively from the preoperative status (peel, P = .003; LTO, P = .0002). No statistically significant associations were observed between postoperative fatty infiltration grades and subscapularis strength, Western Ontario Osteoarthritis of the Shoulder Index scores, or American Shoulder and Elbow Surgeons scores. DISCUSSION: No statistically significant differences were observed in the healing rates or subscapularis fatty infiltration grades between the peel and the LTO. This trial does not show any clear difference in radiologic and clinical outcomes of one subscapularis management technique over the other. PMID- 22944078 TI - Development of a primer-probe energy transfer based real-time PCR for the detection of Swine influenza virus. AB - Swine influenza virus (SIV) causes a contagious and requiring official notification disease of pigs and humans. In this study, a real-time reverse transcription-polymerase chain reaction (RT-PCR) assay based on primer-probe energy transfer (PriProET) for the detection of SIV RNA was developed. The assay uses matrix gene-specific primers and an Oregon Green-labeled fluorescent probe and was employed for the detection of SIV in clinical samples to identify outbreaks and to monitor the prevalence of disease. The PriProET technology was used to obtain a probe melting profile for confirmation of the specific product amplification. The assay is specific for influenza virus with a sensitivity of detection limit of approximately 10 copies of RNA by PCR. Based on serial dilutions of SIV, the detection limit of the assay was approximately 0.003 TCID(50)/ml for H1N1 A/Swine/Poland/KPR9/2004 virus. The PriProET RT-PCR was suitable for the detection of SIV RNA isolated directly from clinical samples. The assay detected SIV RNA in pre-clinical swab samples as early as 2 days post infection (dpi). The PriProET RT-PCR assay is an alternative to the existing diagnostic assays and could have enhanced applicability for clinical diagnosis. PMID- 22944079 TI - Detection and quantification of a radiation-associated mitochondrial DNA deletion by a nested real-time PCR in human peripheral lymphocytes. AB - In this study we implemented a new assay using a nested real-time polymerase chain reaction (PCR) to detect radiation-induced common deletion (CD) in mitochondrial DNA (mtDNA) of human peripheral lymphocytes. A standard curve for real-time PCR was established by applying a plasmid DNA containing human normal mtDNA or mutated mtDNA. Human peripheral lymphocyte DNA was amplified and quantified by real-time PCR using primer sets for total damaged or mutated mtDNA, plus probes labeled with the fluorescent dyes. The first-round PCR generated multiple products were used as the template for a second-round PCR. We herein describe a nested real-time PCR assay capable of quantifying mtDNA bearing the CD in human peripheral lymphocytes following exposure (in vitro) to (137)Cs gamma rays in a dose range of 0.5 up to 5Gy. The reproducibility of this assay was evident for both unirradiated and irradiated samples by examining human blood lymphocytes from 14 donors. This technique was sensitive enough to detect deletions in mtDNA at low dose levels, as low as 0.5Gy, and higher levels of CD mtDNA were evident at higher doses (>=1Gy), however, there was no consistent dose response relationship. PMID- 22944080 TI - Multiple synchronous early gastric cancers: high-risk group and proper management. AB - BACKGROUND: Multiple early gastric cancers (MEGCs) may be easily missed on preoperative gastroscopy because the lesions are predominantly small and flat. This may increase the risks of gastric remnant lesions and recurrence. We aimed to define high-risk group of MEGC and suggest proper management of missed lesion after partial gastrectomy. METHODS: A total of 117 patients with MEGCs and 2182 with solitary EGC who underwent gastrectomy between 2008 and 2010 were retrospectively analyzed to determine their clinicopathologic characteristics. We also assessed their family history, the presence of Helicobacter pylori infection, and of precancerous lesions; and the results of microsatellite instability and immunohistochemical staining of the primary (largest) lesion for p53, human epidermal growth factor receptor [HER1], and HER2 were also reviewed. RESULTS: MEGCs occurred more frequently in elderly males and in patients with adenoma, atrophic gastritis, or a family history of gastric cancer. These patients had more favorable pathologic findings, including less deep invasion, better differentiation, more intestinal type, and less frequent lymphovascular/perineural invasion than patients with solitary EGCs. The mean size of MEGCs was smaller (2.44 cm vs 3.36 cm) but there was no difference in the number of metastatic lymph nodes. Most accessory lesions were confined to the mucosal layer, with their average diameter was 1.82 cm. CONCLUSIONS: A careful preoperative gastroscopy should be performed in patients at high risk of MEGCs and more cautious postoperative endoscopic surveillance of the remnant stomach is required. For missed foci on remnant stomach, endoscopic resection can be a good option if it meets the criteria. PMID- 22944081 TI - Lung transplantation in patients 70 years old or older: have outcomes changed after implementation of the lung allocation score? AB - OBJECTIVE: The objective of the present study was to evaluate whether the outcomes of lung transplantation in patients aged 70 years or older have changed after implementation of the lung allocation score in May 2005. METHODS: Patients aged 70 years or older undergoing primary lung transplantation from 1995 to 2009 were identified from the United Network for Organ Sharing registry. The primary stratification was the pre-lung allocation score era versus lung allocation score era. Risk-adjusted multivariate Cox regression and Kaplan-Meier analyses were conducted to evaluate the effect of age 70 years or older on 1-year post transplant mortality compared with a reference cohort of patients aged 60 to 69 years. RESULTS: Of the overall 15,726 adult lung transplantation patients in the study period, 225 (1.4%) were 70 years old or older and 4634 (29.5%) were 60 to 69 years old. The patients aged 70 years or older were a larger cohort of overall lung transplantation patients in the lung allocation score era compared with before the lung allocation score era (3.1% vs 0.3%, P < .001). In the risk adjusted Cox analysis, age 70 years or older was a significant risk factor for 1 year post-lung transplantation mortality in the pre-lung allocation score era (hazard ratio, 2.00; 95% confidence interval, 1.10-3.62, P = .02) but not in the lung allocation score era (hazard ratio, 1.02; 95% confidence interval, 0.71 1.46; P = .92). Similarly, Kaplan-Meier 1-year survival was significantly reduced in patients 70 years old or older versus 60 to 69 years old in the pre-lung allocation score era (56.7% vs 76.3%, P = .006) but not in the lung allocation score era (79.0% vs 80.0%, P = .72). CONCLUSIONS: Recipients aged 70 years or older were a larger proportion of overall lung transplantation patients after implementation of the lung allocation score. Although associated with significantly increased post-lung transplantation mortality in the pre-lung allocation score era, age 70 years or older is currently associated with outcomes comparable to those of patients aged 60 to 69 years. Therefore, age 70 years or older should not serve as an absolute contraindication to lung transplantation in the lung allocation score era. PMID- 22944083 TI - Fetal cardiac intervention: improved results of fetal cardiac bypass in immature fetuses using the TinyPump device. AB - OBJECTIVE: Fetal cardiac surgery is a potential innovative treatment for certain congenital heart defects that have significant mortality and morbidity in utero or after birth, but it has been limited by placental dysfunction after fetal cardiac bypass. We have used the TinyPump device for fetal cardiac bypass in sheep fetuses at 90 to 110 days gestation. METHODS: Ten mixed-breed pregnant ewes were used over a period of 6 months, and 10 fetuses were placed on bypass for 30 minutes. Five fetuses with a mean gestational age of 104 +/- 4.5 days and mean weight of 1.4 +/- 0.4 kg were placed on bypass using the TinyPump device, and 5 fetuses with a mean gestational age of 119 +/- 4.5 days and mean weight of 3.4 +/ 0.4 kg were placed on bypass using the roller head pump. The fetuses were monitored for up to 3 hours after bypass or until earlier demise. RESULTS: Progressive respiratory and metabolic acidosis developed in all fetuses. The TinyPump group had a lower gestational age and weight compared with the roller head pump group. However, the rate of postbypass deterioration in the TinyPump group, as measured with blood gases, was noted to be significantly slower compared with the roller head pump group. CONCLUSIONS: We demonstrate the feasibility of the TinyPump device for fetal cardiac bypass in a fetal sheep model. The TinyPump group showed improved results compared with the roller head group despite more immature fetuses. The TinyPump device seems to be a promising device for future studies of fetal cardiac bypass in immature fetal sheep and in primates. PMID- 22944085 TI - Mild-to-moderate functional tricuspid regurgitation in patients undergoing mitral valve surgery. AB - OBJECTIVE: The decision to repair mild-to-moderate functional tricuspid regurgitation (TR) during mitral valve surgery remains controversial. We evaluated the effects of tricuspid valve (TV) repair for functional mild-to moderate TR during mitral valve surgery. METHODS: We enrolled 959 patients with mild-to-moderate functional TR who underwent mitral valve surgery with (repair group n = 431) or without (control group n = 528) concomitant TV repair from January 1994 to September 2010. RESULTS: There were no significant differences in early mortality or major morbidity rates. Median follow-up was 64.8 months (range, 0.03-203.6 months). After adjustment for baseline characteristics using a propensity score adjustment model, the repair group had similar risks for TV reoperation (hazard ratio [HR], 0.46; 95% confidence interval [CI], 0.10-2.07; P = .31); congestive heart failure (HR, 1.12; 95% CI, 0.37-3.36; P = .84); death (HR, 1.41; 95% CI, 0.82-2.42; P = .22); and the composite of death, TV reoperation, and congestive heart failure (HR, 1.24; 95% CI, 0.76-2.03; P = .39) compared with the control group. On multivariate Cox-regression analysis, old age, atrial fibrillation without a Maze procedure, diabetes mellitus, chronic renal failure, poor left ventricular ejection fraction, and redo surgery emerged as significant independent risk factors for the composite outcome of death, TV reoperation, and congestive heart failure. CONCLUSIONS: Early or late clinical benefits of concomitant TV repair for mild-to-moderate TR during mitral valve surgery were uncertain through a long-term follow-up of 959 patients. Several preoperative factors and the performance of Maze procedure for AF seem to be more important than TV repair in overall clinical outcomes. PMID- 22944082 TI - Robot-aided thoracoscopic thymectomy for early-stage thymoma: a multicenter European study. AB - OBJECTIVE: Minimally invasive thymectomy for stage I to stage II thymoma has been suggested in recent years and considered technically feasible. However, because of the lack of data on long-term results, controversies still exist on surgical access indication. We sought to evaluate the results after robot-assisted thoracoscopic thymectomy in early-stage thymoma. METHODS: Data were collected from 4 European centers. Between 2002 and 2011, 79 patients (38 men and 41 women; median age, 57 years) with early-stage thymoma were operated by left-sided (82.4%), right-sided (12.6%), or bilateral (5%) robotic thoracoscopic approach. Forty-five patients (57%) had associated myasthenia gravis. RESULTS: Average operative time was 155 minutes (range, 70-320 minutes). One patient needed open conversion, in 1 patient a standard thoracoscopy was performed after robotic system breakdown, and in 5 patients an additional access was required. No vascular and nervous injuries were recorded, and no perioperative mortality occurred. Ten patients (12.7%) had postoperative complications. Median hospital stay was 3 days (range, 2-15 days). Median diameter of tumor resected was 3 cm (range, 1-12 cm), and Masaoka stage was stage I in 30 patients (38%) and stage II in 49 patients (62%). At a median follow-up of 40 months, 74 patients were alive and 5 had died (4 patients from nonthymoma-related causes and 1 from a diffuse intrathoracic recurrence), with a 5-year survival rate of 90%. CONCLUSIONS: Our data indicate that robot-enhanced thoracoscopic thymectomy for early-stage thymoma is a technically sound and safe procedure with a low complication rate and a short hospital stay. Oncologic outcome seems good, but a longer follow-up is needed to consider this as a standard approach definitively. PMID- 22944086 TI - Discussion. PMID- 22944084 TI - Ex vivo rehabilitation of non-heart-beating donor lungs in preclinical porcine model: delayed perfusion results in superior lung function. AB - OBJECTIVES: Ex vivo lung perfusion (EVLP) is a promising modality for the evaluation and treatment of marginal donor lungs. The optimal timing of EVLP initiation and the potential for rehabilitation of donor lungs with extended warm ischemic times is unknown. The present study compared the efficacy of different treatment strategies for uncontrolled non-heart-beating donor lungs. METHODS: Mature swine underwent hypoxic arrest, followed by 60 minutes of no-touch warm ischemia. The lungs were harvested and flushed with 4 degrees C Perfadex. Three groups (n = 5/group) were stratified according to the preservation method: cold static preservation (CSP; 4 hours of 4 degrees C storage), immediate EVLP (I EVLP: 4 hours EVLP at 37 degrees C), and delayed EVLP (D-EVLP; 4 hours of CSP followed by 4 hours of EVLP). The EVLP groups were perfused with Steen solution supplemented with heparin, methylprednisolone, cefazolin, and an adenosine 2A receptor agonist. The lungs then underwent allotransplantation and 4 hours of recipient reperfusion before allograft assessment for resultant ischemia reperfusion injury. RESULTS: The donor blood oxygenation (partial pressure of oxygen/fraction of inspired oxygen ratio) before death was not different between the groups. The oxygenation after transplantation was significantly greater in the D-EVLP group than in the I-EVLP or CSP groups. The mean airway pressure, pulmonary artery pressure, and expression of interleukin-8, interleukin-1beta, and tumor necrosis factor-alpha were all significantly reduced in the D-EVLP group. Post-transplant oxygenation exceeded the acceptable clinical levels only in the D-EVLP group. CONCLUSIONS: Uncontrolled non-heart-beating donor lungs with extended warm ischemia can be reconditioned for successful transplantation. The combination of CSP and EVLP in the D-EVLP group was necessary to obtain optimal post-transplant function. This finding, if confirmed clinically, will allow expanded use of nonheart-beating donor lungs. PMID- 22944087 TI - Discussion. PMID- 22944088 TI - Increased plasma homocysteine predicts arrhythmia recurrence after minimally invasive epicardial ablation for nonvalvular atrial fibrillation. AB - OBJECTIVE: Minimally invasive epicardial ablation via right minithoracotomy is an emerging option for patients with drug-refractory nonvalvular atrial fibrillation. To guide the development of rational treatment algorithms, factors predisposing to recurrence of arrhythmia need to be quantified and eventually treated. We addressed the association of the plasma levels of homocysteine and the recurrence of atrial fibrillation after minimally invasive ablation. METHODS: We obtained peripheral blood samples from 104 patients at follow-up after arrhythmia surgery; the homocysteine concentration was expressed as micromoles per liter. Prospective follow-up was conducted through electrocardiogram Holter monitoring (average 18.5 +/- 5.8 months). Stratified analysis (high vs low homocysteine) was based on the cutoff value for the last quartile of homocysteine concentration (16 MUmol/L). Time-to-event and diagnostic performance analyses were performed. RESULTS: The rate of freedom from atrial fibrillation was 89.4% at the end of follow-up. Elevated circulating homocysteine level, persistent type of atrial fibrillation, and increased left atrial dimension independently predicted the recurrence of atrial fibrillation during the follow-up (adjusted Cox regression). Patients with a high homocysteine level were more likely to have atrial fibrillation recurrence (stratified Kaplan-Meier, P < .001). The cutoff value for elevated homocysteine (16 MUmol/L) yielded a good diagnostic performance in the prediction of atrial fibrillation recurrence (area under the receiver operating characteristic curve, 0.807). CONCLUSIONS: The homocysteine level measured during the follow-up reliably predicts the risk of recurrence after epicardial ablation of nonvalvular atrial fibrillation via minithoracotomy. Specific treatments to reduce plasma homocysteine could be considered in the future in these patients. PMID- 22944090 TI - A simplified technique for pulmonary artery aneurysm repair in a lung transplant recipient with right ventricular outflow tract obstruction. PMID- 22944089 TI - Experience with the first 50 ex vivo lung perfusions in clinical transplantation. AB - OBJECTIVE: Normothermic ex vivo lung perfusion is a novel method to evaluate and improve the function of injured donor lungs. We reviewed our experience with 50 consecutive transplants after ex vivo lung perfusion. METHODS: A retrospective study using prospectively collected data was performed. High-risk brain death donor lungs (defined as Pao(2)/Fio(2) <300 mm Hg or lungs with radiographic or clinical findings of pulmonary edema) and lungs from cardiac death donors were subjected to 4 to 6 hours of ex vivo lung perfusion. Lungs that achieved stable airway and vascular pressures and Pao(2)/Fio(2) greater than 400 mm Hg during ex vivo lung perfusion were transplanted. The primary end point was the incidence of primary graft dysfunction grade 3 at 72 hours after transplantation. End points were compared with lung transplants not treated with ex vivo lung perfusion (controls). RESULTS: A total of 317 lung transplants were performed during the study period (39 months). Fifty-eight ex vivo lung perfusion procedures were performed, resulting in 50 transplants (86% use). Of these, 22 were from cardiac death donors and 28 were from brain death donors. The mean donor Pao(2)/Fio(2) was 334 mm Hg in the ex vivo lung perfusion group and 452 mm Hg in the control group (P = .0001). The incidence of primary graft dysfunction grade 3 at 72 hours was 2% in the ex vivo lung perfusion group and 8.5% in the control group (P = .14). One patient (2%) in the ex vivo lung perfusion group and 7 patients (2.7%) in the control group required extracorporeal lung support for primary graft dysfunction (P = 1.00). The median time to extubation, intensive care unit stay, and hospital length of stay were 2, 4, and 20 days, respectively, in the ex vivo lung perfusion group and 2, 4, and 23 days, respectively, in the control group (P > .05). Thirty-day mortality (4% in the ex vivo lung perfusion group and 3.5% in the control group, P = 1.00) and 1-year survival (87% in the ex vivo lung perfusion group and 86% in the control group, P = 1.00) were similar in both groups. CONCLUSIONS: Transplantation of high-risk donor lungs after 4 to 6 hours of ex vivo lung perfusion is safe, and outcomes are similar to those of conventional transplants. Ex vivo lung perfusion improved our center use of donor lungs, accounting for 20% of our current lung transplant activity. PMID- 22944091 TI - Assessment of cardiovascular function by combining clinical data with a computational model of the cardiovascular system. AB - OBJECTIVE: A sufficient understanding of patients' cardiovascular status is necessary for doctors to make the best decisions with regard to the treatment of cardiovascular disease; however, it is often not available because of the limitation of clinical measurements. The objective of this study was to examine whether cardiovascular function can be assessed quantitatively and for specific patients by combining clinical data with a computational model of the cardiovascular system. METHODS: Seven consecutive patients undergoing off-pump coronary artery bypass grafting were enrolled in this study. The clinical data were collected both during the preoperative diagnosis and during the operation. Sensitivity analysis was performed to select the major model parameters most relevant to the measured data. The major model parameters were then estimated through a data-fitting procedure, enabling a patient-specific quantitative assessment of various aspects of cardiovascular function. RESULTS: The results revealed the prevalence of left ventricular diastolic dysfunction in the patients, although the severity of dysfunction exhibits significant interpatient variability (the estimated left ventricular passive elastance varies from 194% to 540% of its reference value). Moreover, 4 of the 7 patients studied had impaired left ventricular systolic function. CONCLUSIONS: The current study demonstrates the feasibility of assessing cardiovascular function quantitatively by combining clinical data with a cardiovascular model. In particular, the assessment utilizes the measurements already in use or available in clinical settings, enhancing the clinical potential of the proposed method. PMID- 22944092 TI - Lung transplantation on cardiopulmonary support: venoarterial extracorporeal membrane oxygenation outperformed cardiopulmonary bypass. AB - OBJECTIVES: Patients requiring extracorporeal cardiorespiratory support during lung transplantation can be treated with conventional cardiopulmonary bypass (CPB) or venoarterial extracorporeal membrane oxygenation (ECMO). In a retrospective analysis, we compared the postoperative course and outcomes of patients treated using these approaches. METHODS: Between August 2008 and September 2011, 92 consecutive patients underwent lung transplantation with extracorporeal support (CPB group, n = 46; and, since February 2010, ECMO group, n = 46) at our institution. We evaluated survival, secondary organ failure, bleeding complications, and the need for blood and platelet transfusions in these 2 patient populations. RESULTS: Intraoperatively, the CPB group required more packed red blood cell transfusions (12 +/- 11 vs 7 +/- 9 U; P = .01) and platelet concentrates (2.5 +/- 1.6 vs 1.5 +/- 1 U; P < .01) than the ECMO group. In hospital mortality (39% vs 13%; P = .004), the need for hemodialysis (48% vs 13%; P < .01), and new postoperative ECMO support (26% vs 4%; P < .01) were greater in the CPB group than in the ECMO group, respectively. After propensity score analysis, multivariate analysis identified retransplantation (odds ratio, 7; 95% confidence interval, 1-43; P = .034) and transplantation with CPB support (odds ratio, 4.9; 95% confidence interval, 1.2-20; P = .026) as independent risk factors for in-hospital mortality. The survival rate at 3, 9, and 12 months was 70%, 59%, and 56% in the CPB group and 87%, 81%, and 81% in the ECMO group (P = .004). CONCLUSIONS: Intraoperative ECMO allows for better periprocedural management and reduced postoperative complications and confers a survival benefit compared with CPB, mainly because of lower in-hospital mortality. It is now the standard of care in our lung transplantation program. PMID- 22944094 TI - Discussion. PMID- 22944093 TI - An open randomized controlled trial of median sternotomy versus anterolateral left thoracotomy on morbidity and health care resource use in patients having off pump coronary artery bypass surgery: the Sternotomy Versus Thoracotomy (STET) trial. AB - OBJECTIVE: Our objective was to compare off-pump coronary artery bypass surgery carried out via a left anterolateral thoracotomy (ThoraCAB) or via a conventional median sternotomy (OPCAB). BACKGROUND: Recent advances in minimally invasive cardiac surgery have extended the technique to allow complete surgical revascularization on the beating heart via thoracotomy. METHODS: Patients undergoing nonemergency primary surgery were enrolled between February 2007 and September 2009 at 2 centers. The primary outcome was the time from surgery to fitness for hospital discharge as defined by objective criteria. RESULTS: A total of 93 patients were randomized to off-pump coronary artery bypass surgery via a median sternotomy (OPCAB) and 91 to off-pump coronary artery bypass surgery via a left anterolateral thoracotomy (ThoraCAB). The surgery was longer for patients in the ThoraCAB group (median, 4.1 vs 3.3 hours) and there were fewer with more than 3 grafts (2% vs 17%). The median time from surgery to fitness for discharge was 6 days (interquartile range, 4-7) in the ThoraCAB group versus 5 days (interquartile range, 4-7) in the OPCAB group (P = .53). The intubation time was shorter, by on average 65 minutes, in the ThoraCAB group (P = .017), although the time in intensive care was similar (P = .91). Pain scores were similar (P = .97), but more analgesia was required in the ThoraCAB group (median duration, 38.8 vs 35.5 hours, P < .001; tramadol use, 66% vs 49%, P = .024). ThoraCAB was associated with significantly worse lung function at discharge (average difference, -0.25 L, P = .01) but quality of life scores at 3 and 12 months were similar (P = .52). The average total cost was 10% higher with ThoraCAB (P = .007). CONCLUSIONS: ThoraCAB resulted in no overall clinical benefit relative to OPCAB. PMID- 22944095 TI - Ten-year outcomes of patients randomized to surgery, angioplasty, or medical treatment for stable multivessel coronary disease: effect of age in the Medicine, Angioplasty, or Surgery Study II trial. AB - OBJECTIVE: With progressive aging, coronary artery disease has been diagnosed at more advanced ages. Although patients aged 65 years or more have been referred to surgical or percutaneous coronary interventions, the best option for coronary artery disease treatment remains uncertain. The current study compared the 3 treatment options for coronary artery disease in patients aged 65 years or more and analyzed the impact of age in treatment options. METHODS: Patients were separated according to age: 65 years or more (n = 200) and less than 65 years (n = 411). All patients were followed for 10 years. The rates of overall mortality, acute myocardial infarction, and new revascularizations were analyzed. RESULTS: Of 200 patients aged 65 years or more, 68 were randomized to medical therapy, 68 were randomized to percutaneous coronary intervention, and 64 were randomized to coronary artery bypass grafting. At 10 years, overall survival was 63% (medical therapy), 69% (percutaneous coronary intervention), and 66% (coronary artery bypass grafting) (P = .93). The survival free of combined events was 43% (medical therapy), 38% (percutaneous coronary intervention ), and 66% (coronary artery bypass grafting) (P = .007). The survival free of myocardial infarction was 82% (medical therapy), 77% (percutaneous coronary intervention), and 90% (coronary artery bypass grafting) (P = .17), and survival free of new revascularizations was 59% (medical therapy), 58% (percutaneous coronary intervention ), and 91% (coronary artery bypass grafting) (P = .0003). When the 2 age groups were compared, survival free of myocardial infarction for patients treated by percutaneous coronary intervention was 77% (older patients) and 92% (younger patients) (P = .004). CONCLUSIONS: In this analysis, treatment options for patients aged 65 years or more who have coronary artery disease yield similar overall survival. However, coronary artery bypass grafting was associated with fewer coronary events, and percutaneous coronary intervention was associated with a higher incidence of myocardial infarction. PMID- 22944096 TI - NKG2D blockade facilitates diabetes prevention by antigen-specific Tregs in a virus-induced model of diabetes. AB - It is thought that viral infections might jeopardize regulatory T cell therapy in type 1 diabetes. Viral infections can lead to surface expression of ligands for the activating NKG2D receptor, such as retinoic acid early transcript 1 (Rae-1), whose expression on beta-cells recruits NKG2D(+) autoreactive CD8(+) T cells. Both in men and mice, autoreactive cytotoxic T cells express NKG2D. We showed that NKG2D expression increased on CD4(+) and CD8(+) T cells during virus-induced diabetes development in the rat insulin promotor (RIP) Lymphocytic Choriomeningitis Virus (LCMV) model. Combination treatment with anti-NKG2D and antigen-specific regulatory T cells (Treg), at doses inefficacious in mono treatment, synergized to prevent diabetes in 75% of the virus-infected RIP-LCMV mice. Nevertheless, NKG2D blockade alone failed to reverse recent-onset diabetes in non-obese diabetic (NOD) mice, despite downregulation of NKG2D on NK cells in the blood and CD8(+) T cells in the spleen and pancreatic lymph nodes. Our data suggest that blocking the interaction of NKG2D with it ligands is insufficient to protect against diabetes when a strong inflammatory process actively drives NKG2D upregulation, but should be considered to help maintaining Treg functionality during ongoing pancreatic inflammation. PMID- 22944097 TI - Current treatment practices for essential thrombocythemia: survey results from European hematologists/oncologists. AB - Physicians from nine European countries were asked to complete a survey, which was conducted in two waves (Wave II, October 2009; Wave III, May 2010), based on their current treatment practices for essential thrombocythemia (ET). The aim of the study was to gain insight into physicians' criteria for treatment initiation and reasons for switching from one therapy option to another. The majority of patients receiving first-line cytoreductive therapy for ET were treated with hydroxycarbamide (HC; 63 and 71% in Waves II and III, respectively), while the majority of patients on second-line therapy received anagrelide (51 and 60% in Waves II and III, respectively). Efficacy was the main factor cited for switching therapies (cited by 47 and 58% of physicians in Waves II and III, respectively). Further studies are needed to determine whether current practices used by physicians for the treatment of ET are consistent with consensus guidelines. PMID- 22944098 TI - Cytotoxic effect of arsenic trioxide on acute promyelocytic leukemia cells through suppression of NFkbeta-dependent induction of hTERT due to down regulation of Pin1 transcription. AB - Acute promyelocytic leukemia (APL) is characterized by specific t(15;17), distinct morphologic picture, and clinical coagulopathy that contributes to the morbidity and mortality of the disease. This study was purposed to dissect the molecular mechanisms underlying telomerase-dependent arsenic trioxide (ATO) induced cytotoxic and anti-proliferative effects in NB4 cells. ATO exposure was associated with transcriptional repression of Pin1, survivin, c-Myc, hTERT, and PinX1 along with an expressive enhancement in p73 mRNA level. Moreover, ATO treatment suppressed cell growth, viability and metabolic activity, exerted apoptosis, hindered telomerase activity, shortened telomere length, and dampened NF-kappaB activation. On aggregate, these issues indicate that ATO might preempt cell growth and proliferation in NB4 cells through suppression of Pin1-mediated NF-kappaB-dependent stimulation of telomerase and survivin. PMID- 22944099 TI - Risk factors for and prognosis of hemorrhagic cystitis after allogeneic stem cell transplantation: retrospective analysis in a single institution. AB - Hemorrhagic cystitis (HC) is a major complication after allogeneic stem cell transplantation (allo-SCT) and can be life threatening. To analyze risk factors and prognosis, we retrospectively reviewed 249 cases receiving allo-SCT in our institution. Median age was 47 years (13-72 years). Disease status at SCT was progressive in 73 cases. Conditioning was myeloablative (MAC) in 146 cases. Acute graft-versus-host disease (aGVHD) grade II-IV treated with prednisolone occurred in 82 cases, and cytomegalovirus (CMV) was reactivated in 91 cases. HC was reported in 47 cases at a median of 35 days (7-469 days) after SCT, and 34 (72.3%) cases recovered after a median of 19.5 days (2-252 days). In univariate analysis, the identified risk factors for HC included age over 45 years, progressive disease status, MAC, aGVHD treated with prednisolone, and CMV reactivation. In multivariate analysis, older age, MAC, and CMV remained independent predictors (hazard ratios: 2.35, 3.50, and 2.87). In patients with severe HC, percentage recovery was lower (3 in 13 cases; 23.1%) and the median duration was longer (54 days) than in those with moderate HC (31 in 36 cases; 86.1%, 17 days, P < 0.01). Treatment-related mortality was also higher (59.1%, P = 0.03) and overall survival was poorer (16.7%, P < 0.01) at 1 year after SCT. Prospective studies should be started considering prophylactic antiviral administration in high-risk patients such as those identified in this study. PMID- 22944100 TI - Homing and engraftment of bone marrow cells derived from different donors in a murine model of sensitization. AB - Sensitized recipients are at a high risk of graft rejection in hematopoietic stem cell transplantation. To explore the trace of donor cells, we tried to explore homing and engraftment of bone marrow cells (BMCs) derived from different donors in a murine model of sensitization. Sensitized BALB/c mice were used as transplanted recipients, which received BMCs derived from C57BL/6 or BALB/c donors after lethal irradiation. The homing study showed that the donor cells decreased along with time in recipients of the C57BL/6 donor group, but the donor cells increased along with time in recipients of the BALB/c donor group. For the engraftment assay, all the sensitized recipients transplanted with BMCs derived from C57BL/6 donors died after lethal irradiation. In contrast, all the recipients transplanted with BMCs derived from BALB/c donors got long-term survival. Our results suggest that it is crucial to have human leukocyte antigen identical donors for sensitized recipients during hematopoietic stem cell transplantation. PMID- 22944101 TI - Platelet distribution width as an indicator of microvascular complications in type 2 diabetic patients. PMID- 22944102 TI - The concept of early labour in the experience of maternity in twentieth century Britain. AB - OBJECTIVE: This paper explores perceptions of time and experience in midwifery with particular reference to the concept of early labour. Health professionals and lay people are used to describing labour in terms of 'stages' which correspond to agreed notions of progress based on physiological features. However the understanding of labour which underpins them is not a static entity but is a product of a particular era and set of circumstances which are primarily socially rather than biologically mediated. DESIGN: The research uses a historical methodology to describe understanding of, and strategies around, the management of early labour. It includes a variety of source material, including midwifery and obstetric textbooks, midwifery casebooks, books of advice to women and the oral testimony of midwives and mothers. SETTING: Twentieth century Britain. The twentieth century was a period of significant philosophical and concrete change in maternity in Britain, with occupational hegemony developing around both midwifery and obstetrics, and with the concomitant institutionalisation of labour and birth. PARTICIPANTS: Mothers, midwives and doctors. FINDINGS: The evidence suggests that during the first half of the twentieth century early labour was not seen as a discrete period within the first stage of labour with specific features or associated issues. Instead it was a private and individual experience, which rarely involved the presence of either doctors or midwives. Women, and those around them, made the decision about what early labour meant and how they should respond to it. The development of divisions in labour and notions of what constituted 'normality' or 'abnormality' as regards the length of each stage, based on time and clinical features, developed as the setting for labour and birth moved from home to hospital in the second half of the twentieth century. Labour became more described and more proscribed, with a rash of textbooks aimed at both midwives and doctors, and with the growing visibility of the entire process of labour through the use of technological surveillance and through the fact that women labouring on a hospital bed were observable in a way that women labouring at home were not. KEY CONCLUSIONS AND IMPLICATIONS: To look for historical strategies around the management of entities such as early labour is to assume, ahistorically, that similar beliefs and issues existed in an earlier period, and that there perhaps existed strategies for management which could profitably be rediscovered for use in current maternity care. The evidence suggests that such divisions were not described or managed features of labour before the second half of the twentieth century. The use of history does, however, give insights into breaks and continuities in beliefs and practice over time, and demonstrates that beliefs about stages of labour and their management are, like other aspects of maternity, multi-faceted and complex in both origin and effect. PMID- 22944103 TI - Factors associated with maternal intrapartum transfers from a freestanding birth centre in Sao Paulo, Brazil: a case control study. AB - OBJECTIVES: to identify factors associated with maternal intrapartum transfer from a freestanding birth centre to hospital. DESIGN: case-control study with retrospective data collection. PARTICIPANTS AND SETTINGS: cases included all 111 women transferred from a freestanding birth centre in Sao Paulo to the referral hospital, from March 2002 to December 2009. The controls were 456 women who gave birth in the birth centre during the same period who were not transferred, randomly selected with four controls for each case. METHODS: data were obtained from maternal records. Factors associated with maternal intrapartum transfers were initially analysed using a chi(2) test of association. Variables with p<0.20 were then included in multivariate analyses. A multiple logistic regression model was built using stepwise forward selection; variables which reached statistical significance at p<0.05 were considered to be independently associated with maternal transfer. FINDINGS: during the study data collection period, 111 (4%) of 2,736 women admitted to the centre were transferred intrapartum. Variables identified as independently associated factors for intrapartum transfer included nulliparity (OR 5.1, 95% CI 2.7-9.8), maternal age >=35 years (OR 5.4, 95% CI 2.1 13.4), not having a partner (OR 2.8, 95% CI 1.5-5.3), cervical dilation <=3 cm on admission to the birth centre (OR 1.9, 95% CI 1.1-3.2) and between 5 and 12 antenatal appointments at the birth centre (OR 3.8, 95% CI 1.9-7.5). In contrast, a low correlation between fundal height and pregnancy gestation (OR 0.3, 95% CI 0.2-0.6) appeared to be protective against transfer. CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: identifying factors associated with maternal intrapartum transfer could support decision making by women considering options for place of birth, and support the content of appropriate information about criteria for admission to a birth centre. Findings add to the evidence base to support identification of women in early labour who may experience later complications and could support timely implementation of appropriate interventions associated with reducing transfer rates. PMID- 22944105 TI - Antidepressant and anxiolytic effects of amentoflavone isolated from Cnestis ferruginea in mice. AB - The root decoction of Cnestis ferruginea (CF) Vahl DC (Connaraceae) is used in traditional African medicine in the management of psychiatric disorders. This study presents the antidepressant and anxiolytic effects of amentoflavone (CF-2) isolated from the root extract of C. ferruginea. The antidepressant effect was studied using the forced swimming (FST) and tail suspension tests (TST) while the hole-board, elevated plus maze (EPM) and light/dark tests were used to evaluate the anxiolytic effect. Acute treatment with CF extract and amentoflavone significantly (p<0.001) reduced the duration of immobility in FST and TST with peak effects observed at 100 and 50mg/kg respectively in comparison to control treated. Antidepressant effects of CF and amentoflavone were significantly higher (p<0.05) when compared to imipramine in FST but comparable to the fluoxetine treated group in TST. The pretreatment of mice with metergoline (4mg/kg, i.p., a 5-HT2 receptor antagonist), prazosin (62.5MUg/kg, i.p., an alpha1-adrenoceptor antagonist), and yohimbine (1mg/kg, i.p., an alpha2-adrenoceptor antagonist), but not sulpiride (50mg/kg, i.p., a dopamine D2 receptor antagonist), cyproheptadine (3mg/kg, i.p., a 5-HT2 receptor antagonist), atropine (1mg/kg, i.p., a muscarinic receptor antagonist) 15mins before the administration of amentoflavone (50mg/kg; p.o.) significantly prevented its antiimmobility effect in the FST. CF extract and CF-2 significantly (p<0.05) attenuated anxiety by increasing the number of head-dips in the hole-board test, the time spent on the open arms in the EPM, and the exploration of the light chamber in the light/dark test. Pretreatment with flumazenil (3mg/kg, i.p., ionotropic GABA receptor antagonist) 15min before oral administration of amentoflavone (25mg/kg) significantly reduced the time spent in the open arms in EPM. It is concluded from the results obtained that amentoflavone produces its antidepressant effect through interaction with 5-HT2 receptor and alpha1-, and alpha2-adrenoceptors while the anxiolytic effect involved the ionotropic GABA receptor. PMID- 22944106 TI - Involvement of nitric oxide in pioglitazone memory improvement in morphine induced memory impaired mice. AB - INTRODUCTION: Pioglitazone, a PPAR-gamma agonist, which is clinically used in treating diabetic patients, has been recently reported to have crucial roles in improving cognition and memory performance. Since the mechanisms involved in the neuroprotective effect of pioglitazone are not entirely understood, the current study was designed to investigate the possible interaction of pioglitazone with morphine in memory-impaired mice and the probable role of nitric oxide (NO) in this effect. MATERIALS AND METHODS: All the experiments were performed in passive avoidance and Y-maze paradigms. To induce memory impairment, mice were administered morphine (1, 3 and 10mg/kg, s.c.) immediately before the training trial. Pioglitazone (20, 40 and 80mg/kg, p.o.) was gavaged 2h prior to the training trial. Further, an NO synthase inhibitor, L-NAME (10mg/kg, i.p.), or an inducible NO synthase inhibitor, aminoguanidine (100mg/kg, i.p.) was administered 30 min before the training trial to determine the possible involvement of NO in the restorative effect of pioglitazone. RESULTS: 1) Morphine dose dependently impaired the acquisition of spatial memory and passive avoidance task. 2) Treatment with pioglitazone significantly improved the memory performance in morphine-treated mice in both tests. 3) In the passive avoidance task, L-NAME, but not aminoguanidine, altered the effect of pioglitazone on morphine-induced memory impairment. 4) In Y-maze discrimination, the memory improving effect of pioglitazone was reversed by both NO synthase inhibitors, L-NAME and aminoguanidine. DISCUSSION: Our results demonstrate that the pioglitazone improving effect on the morphine-induced impairment of memory acquisition is at least in part through the NO pathway. It is suggested that in short term spatial recognition memory, both inducible and constitutive NO synthases are involved, but in the long term fear memory, only the constitutive NO synthases indicated a prominent role in the anti-amnestic effect of pioglitazone on morphine-induced memory impairment. PMID- 22944107 TI - Lateral diffusion of bilayer lipids measured via (31)P CODEX NMR. AB - We have employed (31)P CODEX (centre-band-only-detection-of-exchange) NMR to measure lateral diffusion coefficients of phospholipids in unilamellar lipid bilayer vesicles consisting of 1-palmitoyl-2-oleoyl-phosphatidylcholine (POPC), alone or in mixtures with 30 mol% 1-palmitoyl-2-oleoyl-phosphatidylglycerol (POPG) or cholesterol (CHOL). The lateral diffusion coefficients of POPC and POPG were extracted from experimental CODEX signal decays as a function of increasing mixing time, after accounting for the vesicle's size and size distribution, as determined via dynamic light scattering, and the viscosity of the vesicular suspension, as determined via (1)H pulsed field gradient NMR. Lateral diffusion coefficients for POPC and POPG determined in this fashion fell in the range 1.0 3.2 * 10(-12) m(2) s(-1) at 10 degrees C, depending on the vesicular composition, in good agreement with accepted values. Thus, two advantages of (31)P CODEX NMR for phospholipid lateral diffusion measurements are demonstrated: no labelling of the molecule of interest is necessary, and multiple lateral diffusion coefficients can be measured simultaneously. It is expected that this approach will prove particularly useful in diagnosing heterogeneities in lateral diffusion behaviours, such as might be expected for specific lipid-lipid or lipid protein interactions, and thermotropic or electrostatically induced phase inhomogeneities. PMID- 22944108 TI - Distinct innate immune responses in human macrophages and endothelial cells infected with shrew-borne hantaviruses. AB - Although hantaviruses have been previously considered as rodent-borne pathogens, recent studies demonstrate genetically distinct hantaviruses in evolutionarily distant non-rodent reservoirs, including shrews, moles and bats. The immunological responses to these newfound hantaviruses in humans are unknown. We compared the innate immune responses to Imjin virus (MJNV) and Thottapalayam virus (TPMV), two shrew-borne hantaviruses, with that toward two rodent-borne hantaviruses, pathogenic Hantann virus (HTNV) and nonpathogenic Prospect Hill virus (PHV). Infection of human macrophages and endothelial cells with either HTNV or MJNV triggered productive viral replication and up-regulation of anti viral responsive gene expression from day 1 to day 3 postinfection, compared with PHV and TPMV. Furthermore, HTNV, MJNV and TPMV infection led to prolonged increased production of pro-inflammatory cytokines from days 3 to 7 postinfection. By contrast, PHV infection failed to induce pro-inflammatory responses. Distinct patterns of innate immune activation caused by MJNV suggest that it might be pathogenic to humans. PMID- 22944109 TI - Serine 192 in the tiny RS repeat of the adenoviral L4-33K splicing enhancer protein is essential for function and reorganization of the protein to the periphery of viral replication centers. AB - The adenovirus L4-33K protein is a key regulator involved in the temporal shift from early to late pattern of mRNA expression from the adenovirus major late transcription unit. L4-33K is a virus-encoded alternative splicing factor, which enhances processing of 3' splice sites with a weak sequence context. Here we show that L4-33K expressed from a plasmid is localized at the nuclear margin of uninfected cells. During an infection L4-33K is relocalized to the periphery of E2A-72K containing viral replication centers. We also show that serine 192 in the tiny RS repeat of the conserved carboxy-terminus of L4-33K, which is critical for the splicing enhancer function of L4-33K, is necessary for the nuclear localization and redistribution of the protein to viral replication sites. Collectively, our results show a good correlation between the activity of L4-33K as a splicing enhancer protein and its localization to the periphery of viral replication centers. PMID- 22944110 TI - Vaccinia virions deficient in transcription enzymes lack a nucleocapsid. AB - The poxvirus virion contains an inner tubular nucleocapsid structure. The nucleocapsid is apparently labile to conventional electron microscopy fixation procedures and has therefore been largely ignored for decades. Advancements in electron microscopy sample preparation, notably high pressure freezing, better preserve the nucleocapsid structure. Using high pressure freezing and electron microscopy, we have compared the virion structures of wt virus and mutant viruses known to be deficient in packaging of viral transcription enzymes. We show that the mutant viruses lack a defined nucleocapsid. These results support the hypothesis that the nucleocapsid contains the viral DNA genome complexed with viral transcription enzymes and structural proteins. The studies open the door to further investigation of the composition and ultrastructure of the poxvirus nucleocapsid. PMID- 22944111 TI - Selection of variant viruses during replication and transmission of H7N1 viruses in chickens and turkeys. AB - The influence of different glycosylation patterns of the haemagglutinin glycoprotein of H7N1 avian influenza viruses on virus replication in vivo was examined. Experimental infection of chickens and turkeys was carried out with H7N1 avian influenza viruses with alternative sites of glycosylation in the haemagglutinin and infected birds were sampled daily by swabbing the buccal and cloacal cavities. cDNAs of the HA1 coding region of the HA gene were prepared from the swabs and cloned into plasmids. Sequencing multiple plasmids made from individual swabs taken over the period of virus shedding showed that viruses with specific patterns of glycosylation near the receptor binding site were stable when birds were infected with a single variant, but when presented with a mixed population of viruses encoding differing patterns of glycosylation a specific variant was rapidly selected in the infected host. PMID- 22944116 TI - Polycystic ovary syndrome in patients with epilepsy: a study in 102 Chinese women. AB - PURPOSE: The incidence of polycystic ovary syndrome (PCOS) increases in women with epilepsy (WWE), which appears to vary with ethnicity. This study was conducted to determine the incidence and risk factors of PCOS in Chinese WWE. METHODS: The study was carried out in 102 of 139 Chinese WWE at reproductive ages, with 32 receiving valproic acid (VPA), 40 receiving other antiepileptic drugs (AEDs), and 30 without AEDs therapy. PCOS was defined as having 2 or more of the following components: polycystic ovaries, hyperandrogenism, and amenorrhoea or oligomenorrhoea (a/oligomenorrhoea). RESULTS: One or more isolated components of PCOS were found in 56 (54.9%) patients, with 29 (28.4%) having polycystic ovaries, 20 (19.6%) with a/oligomenorrhea, 7 (6.9%) with hyperandrogenism, and 13 (12.7%) with defined PCOS. Their average age at the start of seizure was 13.8+/-6.5 years, younger than that of patients without these disorders (16.9+/-8.6 years, p<0.05). VPA therapy increased the incidence of PCOS (11/32, 34.4%), in addition to increased blood levels of testosterone and luteinizing hormone (LH) as well as LH to FSH (follicle-stimulating hormone) ratio. No significant relationship was found between the incidence of PCOS and the type, duration, or frequency of seizures in these WWE. CONCLUSION: There is an increased incidence of PCOS in Chinese WWE at reproductive ages, by more than 2 times of that in the general population. Risk factors include seizures starting at a young age and VPA therapy. PMID- 22944117 TI - Ago-allosteric modulators of human glucagon-like peptide 2 receptor. AB - Glucagon-like peptide 2 (GLP-2) is an intestinotropic peptide that binds to GLP-2 receptor (GLP-2R), a class-B G protein-coupled receptor (GPCR). Few synthetic agonists have been reported so far for class-B GPCRs. Here, we report the first scaffold compounds of ago-allosteric modulators for human GLP-2R, derived from methyl 2-{[(2Z)-2-(2,5-dichlorothiophen-3-yl)-2 (hydroxyimino)ethyl]sulfanyl}benzoate (compound 1). PMID- 22944118 TI - Imidazopyridazinones as novel PDE7 inhibitors: SAR and in vivo studies in Parkinson's disease model. AB - The synthesis and structure-activity relationship studies of a series of compounds from imidazopyridazinone scaffold as PDE7 inhibitors are disclosed. Potent analogs such as compounds 7 (31nM), 8 (27nM), and 9 (12nM) were identified. The PDE selectivity and pharmacokinetic profile of compounds 7, 8 and 9 are also disclosed. The adequate CNS penetration of compound 7 in mice allowed it to be tested in the MPTP induced PD model and haloperidol induced catalepsy model to probe the differential pharmacology of PDE7 in the striatal pathway. PMID- 22944119 TI - Comparison of the cytotoxic effects of enantiopure PPAPs, including nemorosone and clusianone. AB - The synthesis of an unnatural polyprenylated acylphloroglucinol (PPAP), regioisomeric with nemorosone and clusianone, has been accomplished. The separated enantiomers of this new PPAP, along with those of nemorosone and clusianone, have been screened for activity against HeLa (cervix carcinoma), MIA PaCa-2 (pancreatic carcinoma), and MCF7 (mamma carcinoma) cancer cell lines. All of the isomers examined gave surprisingly similar results in the screens. PMID- 22944120 TI - Radiosynthesis and in vivo tumor uptake of 2-deoxy-2-[(18)F]fluoro-myo-inositol. AB - Inositols play an important role in membrane lipid metabolism and mitogenic signaling of most cancer cells. There is paucity of data on the distribution of radiolabelled inositols. Based on work previously carried out on 1-deoxy-1 [(18)F]fluoro-scyllo-inositol ([(18)F]2), we began a program of work to label myo inositol (2-deoxy-2-[(18)F]fluoro-myo-inositol, [(18)F]1), the most abundant inositol in cells. Fluorination of a triflate precursor 4 afforded the desired [(18)F]1 following deprotection with a radiochemical yield of 8% n.d.c. [(18)F]1 showed higher uptake in vivo in a human breast cancer xenograft model, MDA-MB 231, compared to [(18)F]2. Thus, we have developed a new inositol radiotracer that could have utility for studying inositol uptake in tumors. PMID- 22944121 TI - New derivatives of 11-methyl-6-[2-(dimethylamino)ethyl]-6H-indolo[2,3-b]quinoline as cytotoxic DNA topoisomerase II inhibitors. AB - Novel indolo[2,3-b]quinoline derivatives substituted at N-6 and C-2 or C-9 positions with (dimethylamino)ethyl chains linked to heteroaromatic core by ether, amide or amine bonds, were manufactured and evaluated in vitro for their cytotoxic activity against several cell lines of different origin including multidrug resistant sublines and tested for their ability to influence the cell cycle and inhibit topoisomerase II activity. It was found, that all compounds show cytotoxic activity against cell lines tested, including multidrug resistant LoVo/DX, MES-SA/DX5 and HL-60 sublines. The tested compounds induce the G(2)M phase cell cycle arrest in Jurkat cells, and inhibit topoisomerase II activity. PMID- 22944122 TI - [We should make the correct choice of anterior surgical approaches of degenerative cervical spondylosis]. PMID- 22944123 TI - [Therapeutic complications of posterior vertebral column resection for spinal tumors]. AB - OBJECTIVE: To summarize and analyze the complications of posterior vertebral column resection in the treatment of spinal tumors. METHODS: The complications of 31 patients were recorded and categorized into primary and secondary complications. Many factors such as segment, bleeding volume and surgical duration were reviewed. The SPSS 12.0 software was used to analyze the relations between the complications and these factors retrospectively. RESULTS: Two primary and 30 secondary complications were identified. A definite relation existed between the delayed removal of endotracheal intubation and bleeding volume. And a definite relation existed also between transient thrombocytopenia and operative duration. There was no relation between prosthetic subsidence and various factors (including follow-up period). CONCLUSION: Most complications are secondary and have basically no effect on the recovery of patients. And prevention are feasible in most cases. So a thorough plan should be devised to prevent the occurrences of potential complications, especially primary ones. For any occurrence, active treatment should be offered to improve the surgical safety. PMID- 22944125 TI - [Experimental study of constructing vertebral canal on rabbit model with bone marrow mesenchymal stem cells]. AB - OBJECTIVE: To construct the artificial lamina of vertebral arch with bone marrow mesenchymal stem cells transplanted in collagen sponge on a rabbit model and observe the growth of new bone. METHODS: To draw out the bone marrow blood from the femur of 2 weeks old rabbit and get the bone marrow mesenchymal stem cells by centrifugal and adhesive effect. To induce the MSCs to osteoblasts and transplant the induced cells in collagen sponge to construct the tissue engineering bone. To divide 48 rabbits into 3 groups randomly, namely group A, group B and group C. All of the rabbits are taken laminectomy in L6, and to group B and C, collagen sponge and tissue engineering bone are implanted in the operation area respectively. The artificial lamina of vertebral arch is determined qualitatively and quantitatively by methods including imageology and histomorphometry. RESULTS: The artificial lamina of vertebral arch is successfully constructed 4 weeks after operation in group C, CT examination at 4 weeks shows that new lamina of vertebral arch is formed, and the vertebral canal is intact. CONCLUSIONS: The artificial lamina of vertebral arch can be constructed successfully with the usage of tissue engineering bone transplanted bone marrow mesenchymal stem cells. PMID- 22944124 TI - [A model of acute compression spinal cord injury by a mini-invasive expandable balloon in goats]. AB - OBJECTIVE: To establish a reproducible and manipulable model of acute spinal cord compression injury in large mammals so as to provide a technical and experimental platform for the repair and reconstruction of spinal cord injury (SCI). METHODS: A total of 15 adult male goats, weighting 35 - 45 kg, were selected. After intravenous anesthesia, a model of acute spinal cord compression injury was established with the balloon of kyphoplasty through mini-open laminotomy. The animals were divided into 4 groups, i.e. 3 in group A and 4 each in groups B, C and D. Goats in group A received mini-open laminotomy without insertion of balloon. In group B, balloons were surgically positioned within the T10-T11 spinal canal but not inflated. The spinal cords of goats in group C were partially compressed by inflating the balloon to approximately 30% of anterior/posterior diameter of vertebral canal. In group D, the balloon was inflated to occupy approximately 90% of canal on a lateral view. X-ray and thin section computed tomography (CT) scans were used to determine the balloon location. CT scans were also used to calculate the magnitude of balloon inflation and the degree of spinal cord compression within vertebral canal. Improved Tarlov motor function grade test and somatosensory evoked potentials (SSEP) were employed to evaluate the goat neurofunction 24 hours before and 7 days after surgery. RESULTS: Dye volumes of 0, 1.26 +/- 0.18 and 2.82 +/- 0.20 ml were injected into the balloon to produce spinal occupancies of 0%, 33% +/- 2% and 89% +/- 4% on X-ray and CT scan. There was a significant dose response for the different levels of injury, with reduced conduction of somatosensory evoked potentials and impaired mobility 7 days after injury. CONCLUSION: A model of acute spinal cord injury by a tunable compression with a mini-invasive balloon in goats is a useful experiment model of spinal cord injury. It may simulate the clinical situations of acute SCI. PMID- 22944126 TI - [Clinical and imaging features of adult anoxic-ischemic encephalopathy after cardiopulmonary resuscitation]. AB - OBJECTIVE: To explore the clinical and imaging features of anoxic-ischemic encephalopathy (AIE) patients after cardiopulmonary resuscitation. METHODS: A total of 28 qualified AIE patients during the last decade from Xiangya Hospital, Central South University were recruited and analyzed retrospectively. RESULTS: The symptoms of status epilepticus, acute posthypoxic myoclonus, Lance-Adams syndrome, subarachnoid hemorrhage and cognitive deficits were observed. The abnormal findings of magnetic resonance imaging (MRI) or computed tomography (CT), involving neocortex, basal ganglia and para-ventricular white matter, were also recorded. During the early phase of disease, swollen cortex was present on MRI/CT. However, encephalatrophy appeared during the late phase. The more severe symptoms were observed, the more foci were present on MRI/CT. CONCLUSION: The etiologies of AIE patients are heterogeneous after cardiopulmonary resuscitation. The clinical symptoms and imaging studies are of prognostic significance. PMID- 22944127 TI - [A survey of 20 inherited protein C deficiencies in the patients with venous thromboembolism]. AB - OBJECTIVE: To investigate the incidence of inherited protein C deficiency in the patients with venous thromboembolism (VTE). METHODS: From Apr. of 2010 to Apr. of 2011, 106 patients with VTE totally from Renji hospital were surveyed by a series of laboratory tests including clinical biochemistry tests, coagulation factors activities and anticoagulation factors activities. PROC gene mutations were screened by PCR-direct sequencing in the 20 patients with decreased PC activity. RESULTS: Among the 20 patients with decreased PC activity, the median activity of factor II, V, VII, VIII, IX, X, XI, XII were 97.0%, 199.9%, 105.5%, 254.7%, 106.4%, 150.4%, 123.1%, 89.9%, respectively.6 PROC gene mutations were found in 11 patients. Six patients have the same point mutation (c.565C > T), the other five mutations were c.508G > T, c.524G > A, c.1174G > A, c.1157T > C, c.577 579del. All of the six mutations were heterozygous, while the c.508G > T, c.524G > A and c.1157T > C were novel in the world. CONCLUSIONS: In this study, we found that PC deficiency is the major inherited risk factor of VTE. The most common PROC mutation identified in this study was heterozygous c.565C > T missense mutation., c.508G > T, c.524G > A and c.1157T > C were novel PROC mutation. The activities of factor V and VIII were elevated dramatically among VTE patients, which may be correlated to the disease. PMID- 22944128 TI - [Association between the synovial expression of cyclic citrullinated peptide and susceptibility variants of HLA-DRB1 shared epitope alleles and PADI 4 gene single nucleotide polymorphisms in patients with rheumatoid arthritis]. AB - OBJECTIVE: To analyze the association between the synovial expression of cyclic citrullinated peptide (CCP) and susceptibility variants of HLA-DRB1 shared epitope (SE) alleles and/or peptidylarginine deiminase 4 (PADI4) gene single nucleotide polymorphisms (SNP) in patients with rheumatoid arthritis (RA). METHODS: From October 2008 to December 2011, 53 RA patients and 42 controls were enrolled. The expression of CCP in RA synovial tissues was detected by immunohistochemical assay with 6*His tagged anti-CCP single chain fragment V (ScFv) antibodies generated by pHEN2 phagemid recombinant antibodies display system. PADI4 SNP was genotyped by reverse transcription cDNA sequencing and heterozygote was DNA haplotype was mapped by TA clone sequencing. HLA-DRB1 SE alleles were analyzed by sequence specific primer-polymerase chain reaction (SSP PCR). RESULTS: The prevalence of synovial CCP expression was significantly different between RA group and the control (76.9% and 11.4% respectively, P < 0.01). The frequencies of 2 SNPs (PADI4_89 G+ and PADI4_104 T+) varied significantly between the groups(P < 0.05). Compared with the major haplotypes, only these two minor alleles were associated with the increased RA susceptibility (OR = 3.67 and 2.53, P < 0.05). SE+ alleles was strongly associated with RA susceptibility (OR = 5.57, P < 0.01). The synovial expression of CCP in RA was strongly associated with SE+ alleles, only 2 minor SNPs (PADI4_89 G+ and PADI4_104T+) and the combination. Serum anti-CCP titers were significantly associated with SE+ alleles, PADI4_104T+, SE+/PADI4_89 G+ and SE+/PADI4_104T+ haplotype. CONCLUSION: The synovial expression of CCP and the generation of anti CCP antibodies are strongly associated with SE alleles and/or certain PADI4 gene SNP in RA. PMID- 22944129 TI - [Old and new staging of endometrial carcinoma]. AB - OBJECTIVE: To explore the rationality and clinical significance for the old and new surgical-pathological staging in endometrial carcinoma. METHODS: The clinical profiles and prognostic particulars were analyzed retrospectively in 92 cases of endometrial carcinoma from June 2005 to June 2011 at Xiaoshan Hospital. And the old and new surgical-pathological staging methods were applied to observe their rationality and treatment prognosis. RESULTS: There was 72.8% (67/92) for clinical stage I in the old surgical-pathological staging while 7.6% (7/92) for clinical stage II and 19.7% (18/92) for clinical stage III. There was 85.9% (79/92) for clinical stage I in the new surgical-pathological staging, 3.3% (3/92) for clinical stage IIand 10.7% (10/92) for clinical stage III. The detection rate of cancer cell was 8.7% (8/92) in peritoneal fluid. The positive rate of pelvic lymph node was 12.9% (11/85). A period of survival rates were compared among P > 0.05 after 3 years and 5 years of IA, IB and IIA. There was no statistical significance; there were statistical significance between IB and IC periods (P < 0.05). The survival of deep myometrial invasion was significantly shorter than that of superficial muscle layer. The positive rate of abdominal aortic lymph node was 3.8% (1/26). Six patients with positive lymph nodes died postoperatively of cancer within 4 to 28 months. CONCLUSION: The new surgical pathological staging is more objective, practical, simple and convenient than its old counterpart. Deep myometrial infiltration and positive lymph node are important prognostic factors of endometrial carcinoma. The positive rate of lymph node remains low in early low-risk endometrial carcinoma and routine excision of lymph node is of little significance. PMID- 22944130 TI - [Phase II study of radiotherapy plus erlotinib for elder patients with esophageal carcinoma]. AB - OBJECTIVE: To evaluate the safety and efficacy of radiation plus erlotinib in patients with esophageal cancer older than 70 years. METHODS: Radiotherapy was prescribed at a daily fraction of 2.0 Gy up to a total dose of 60 Gy over 6 weeks. Concurrent erlotinib was administrated at a dose of 150 mg daily at days 1 42. Acute toxicities were assessed by the criteria of Radiation Therapy Oncology Group (RTOG) and National Cancer Institute (NCI). The results were analyzed by the software SPSS 17.0. RESULTS: A total of 33 patients were enrolled. The median survival time was 16.3 +/- 8.6 months (95%CI 0.0 - 33.3) and the 1-and 2-year overall survival rates were 66.3% and 49.7% respectively. The media progression free survival was 16.7 +/- 7.1 months (95%CI 2.9 - 30.5) and the 1- and 2-year local control rates 73.3% and 54.9% respectively. Most toxicities were of grade 1 2 and manageable. CONCLUSION: The combined regimen of radiation and erlotinib is effective and safe in elder patients aged > 70 years with esophageal cancer. However the results of our study should be confirmed in randomized controlled trials of a larger sample size. PMID- 22944131 TI - [Short-term clinical efficacies of esophageal carcinoma treated surgically by Ivor-Lewis approach]. AB - OBJECTIVE: To explore the short-term clinical efficacies of treating esophageal carcinoma surgically by Ivor-Lewis approach so as to summarize the characteristics of lymph node metastasis of esophageal cancer and evaluate the safety and effectiveness of surgical treatment of middle and lower esophagus. METHODS: Our hospital started the Ivor-Lewis approach of esophageal cancer from 2005. During the period of 2007 - 2010, a total of 404 patients underwent the Ivor-Lewis approach for esophageal cancer. And the AJCC software was used for the probability statistical analysis. RESULTS: None of them died. But 89/101 patients (22.0%) had the occurrences of postoperative complications. And while still within the original stage of T1, tumor probably metastasized. CONCLUSION: Esophageal cancer has an early tendency of metastasis. Based upon the anatomic locations of metastatic lymph nodes, it is better to predict the prognosis of patients. Thus the combined regimen of Ivor-Lewis surgery plus two-field lymphadenectomy is both safe and efficacious for esophageal carcinoma in the middle and lower segments. PMID- 22944132 TI - [Small interfering RNA in silencing cox-2 expression enhances radiosensitivity of esophageal cancer EC9706 cell]. AB - OBJECTIVE: To explore the effects of small interfering RNA (siRNA) specific to cox-2 gene on the radiosensitivity of esophageal cancer cell EC9706. METHODS: The siRNA vector was established for cox-2 gene and then induced into esophageal cancer cell EC9706 by lipofectamine. G418 screening yielded stably transfected cells. After the irradiation of 0, 2 and 4 Gy, the cellular expression levels of cox-2, matrix metalloproteinase-2 (MMP2), Bax and Bcl-2 were detected by reverse transcriptase-polymerase chain reaction (RT-PCR) and those of cox-2 protein, AKT protein and phosphorylation AKT protein (pAKT) by Western blot. Cell apoptosis was examined by flow cytometer. Invasion of cells was detected by invasive assay in vitro. The invasive and metastatic capacities of cancer cells were assessed by invasion assay in vitro. Proliferative potential was quantified by clone-forming assay. RESULTS: The sequencing result confirmed that siRNA vector pRNA-U6 for cox 2 gene was established. The results of 1-sinCox214, RT-PCR and Western blot showed that cox-2 gene expression of transfected EC9706 cell was silenced efficiently. After the irradiation of 0, 2 and 4 Gy, the expressions of MMP2, Bcl 2 mRNA, AKT protein and pAKT in silencing cox-2 gene expression significantly decreased. There was an inverse correlation with irradiation dose. The Bax mRNA expression evidently increased directly with irradiation dose; the apoptotic rate in cox-2 silencing groups was evidently higher than the control groups. And the difference was significant (P < 0.01); invasion cells in vitro in Cox-2 silencing groups evidently decreased with significant difference (P < 0.01). The colony formation rate of cells decreased obviously in cox-2 silencing groups after the irradiation of 0, 1, 2, 4, 6, 8 and 10 Gy (P < 0.01). CONCLUSIONS: Small interference RNA in silencing cox-2 gene expression can enhance significantly the radiosensitivity of esophageal cancer EC9706 cells. And the mechanism may be related with MMP2, Bax, Bcl-2, AKT protein and pAKT protein. PMID- 22944133 TI - [Preparation and in vivo-in vitro evaluation of compound nanoparticles loaded with epirubicin hydrochloride and gadopentetate meglumine]. AB - OBJECTIVE: To prepare and characterize the compound Epirubicin hydrochloride and Gadopentetate meglumine (Gd-DTPA) nanoparticles, and evaluate its properties from rabbits in vivo and in vitro. METHODS: The compound Epirubicin hydrochloride and Gd-DTPA nanoparticles were prepared by double emulsion-solvent evaporation method. The main effective factors were orthogonal designed. The characteristics such as drug entrapment efficiency, drug loading, and drug utilization were assayed in vitro. MR imaging effect of the VX2 rabbit hepatoma model were observed after injecting the drug-loaded nanoparticles through the hepatic artery intubation in vivo. RESULTS: The drug encapsulation efficiency of the nanoparticles, drug loading and drug utilization were 33.8% +/- 3.4%, 0.225% +/- 0.052%, and 69.6% +/- 4.3% under the optimized prescription, respectively. The mean size of the nanoparticles was 180.6 nm, the drug release continued in 48 h with good MR imaging effect. CONCLUSIONS: Compound Epirubicin hydrochloride and Gd-DTPA Nanoparticles were in simply preparation and showed sustained drug release properties. These novel nanoparticles with detecting function could develop of epirubicin hydrochloride targeted therapy of liver cancer. PMID- 22944134 TI - [Promoting of angiogenesis and osteogenesis in radial critical bone defect regions of rabbits with nano-hydroxyapatite/collagen/PLA scaffolds plus endothelial progenitor cells]. AB - OBJECTIVE: To explore the roles of nano-hydroxyapatite/collagen/PLA (nHAC/PLA) plus endothelial progenitor cells (EPCs) in repairing segmental bone defects of rabbit radius and enhancing angiogenesis and new bone formation. METHODS: EPCs isolated from New Zealand white rabbit bone marrow were cultured, identified and seeded into nHAC/PLA scaffolds. And the growth of EPCs in scaffolds was observed under scanning electron microscopy (SEM). Thirty-six were randomly divided into 3 groups to establish segmental bone defect models in radii. Two groups were implanted with EPCs/scaffolds constructs (group A, n = 16) and scaffolds alone (group B, n = 16) respectively. The remaining four rabbits were used as negative control (group C) and nothing was implanted. Animals were sacrificed at different timepoints and radii harvested to undergo radiological examination, histological examination and microvessle density test. RESULTS: These cells isolated from bone marrow were confirmed as EPCs. SEM showed that EPCs attached to the nHAC/PLA scaffolds, grew and proliferated well. Animal experiments revealed that radiological scores (5w: 2.25 +/- 0.50 vs 1.00 +/- 0.00; 10w: 2.75 +/- 0.50 vs 1.75 +/- 0.50; 15w: 4.25 +/- 0.50 vs 3.0 +/- 0.0; each P < 0.05), percentage of new bone formation area in bone defect regions (5w: 29.0% +/- 3.5% vs 8.1% +/- 0.8%; 10w: 63.4% +/- 5.5% vs 16.6% +/- 1.3%; 15w: 96.0% +/- 4.3% vs 34.0% +/- 6.6%; each P < 0.05) and microvessel density (2w: 13.5 +/- 0.9 vs 4.3 +/- 1.0; 5w:9.8 +/- 0.7 vs 4.8 +/- 0.3; 10w: 7.0 +/- 0.4 vs 4.5 +/- 0.4; each P < 0.05) in group A were significantly higher than those in group B. No new bone formation occurred in group C. CONCLUSION: The composite structure of EPCs-nHAC/PLA can enhance angiogenesis and new bone formation in segmental bone defects in rabbit radii. It may become a potential candidate of promoting revascularization of tissue engineering bone and repairing large bone defects. PMID- 22944135 TI - [Effects of three different treatments on atherosclerosis and adipose in rats]. AB - OBJECTIVE: To explore the effects of three different treatments, including probucol plus aspirin (PS), lovastatin plus aspirin (AS) and probucol, lovastatin plus aspirin (PAS) on atherosclerotic plaque and adipose. METHODS: A total of 31 SD rats with established atherosclerosis were randomly divided into control group (n = 7), high-fat group (n = 4), PS group (n = 8), AS group (n = 5) and PAS group (n = 7). The PS group rats were lavaged with probucol (104.4 mg*kg(-1)*d(-1)) and aspirin 10.4 mg*kg(-1)*d(-1)), AS group ones aspirin (10.4 mg*kg(-1)*d(-1)) and lovastatin (2.1 mg*kg(-1)*d(-1)) and PAS group ones probucol (104.4 mg*kg(-1)*d( 1)), aspirin (10.4 mg*kg(-1)*d(-1)) and lovastatin (2.1 mg*kg(-1)*d(-1)) for 8 weeks. At the same time, the control group received an equal volume of saline. Finally the plaque stability and adipose function of treatment groups were evaluated by the changes of body weight, serum parameters, adipose weights and pathological specimens. RESULTS: Body weights in PS and PAS groups significantly increased than those in AS group (251 g +/- 5 g and 247 g +/- 7 g vs 220 g +/- 6 g, P < 0.01). The serum levels of low density lipoprotein cholesterol (LDL), glucose (Glu), total cholesterol (TC) and high density lipoprotein cholesterol (HDL) were significantly better in PS and PAS groups than those in AS group (P < 0.01). The level of tumor necrosis factor-alpha (TNF-alpha) was lower in PAS group than that in high-fat group (27 +/- 21 vs 100 +/- 34 pg/ml, P < 0.05). The stability level of atherosclerotic plaque was more in PAS group than those in PS and AS groups by oil red staining in aorta, oil red staining in different organs and hematoxylin and eosin staining in different aortal parts. CONCLUSION: Atherosclerosis improves more pronouncedly in PS and PAS groups than that in AS group. Through an analysis of the changes of fat-related indicators, adipose factor may play an important role in atherosclerotic treatment. PMID- 22944136 TI - [Preparation of HPV18 E7 peptide plus CpG vaccine and its immunologic effects in vitro]. AB - OBJECTIVE: To screen and prepare the vaccine of human papillomavirus (HPV) 18 E7 peptide target at human leukocyte antigen (HLA)-A2 plus CpG through SYFPEITHI. METHODS: (1) The SYFPEITHI database was employed for predicting and screening of HPV18 E7 HLA-A2 restricted T cell epitopes.(2) The peripheral blood and tumor tissue sample of HLA-A2 positive and HPV18 positive/negative patients were collected and randomly divided into 7 groups, i.e. E7PA + CpG, E7PB + CpG, E7PC + CpG, E7PD + CpG, CpG, IR-T + CpG and control groups respectively. T cell proliferation was detected by thiazolyl blue tetrazolium bromide (MTT) assay at different timepoints. Lactate dehydrogenase delivery method (LDH) was used to test the cytolytic t lymphocyte (CTL) activity of peripheral blood mononuclear cell (PBMC) in different ratios of effect and target (E:T). And the level of activity T cells was evaluated by interferon gamma (IFN-gamma)-related enzyme linked immuno-spot assay (ELISPOT). RESULTS: (1) Four peptides named E7PA, E7PB, E7PC and E7PD were obtained separately with high levels of affinity and specificity. (2) During continuous observations after vaccination, the E7PA + CpG group had the most pronounced proliferation rate. When E:T = 100:1, the E7PA + CpG group had more powerful CTL effect than the control group with statistic significance (P < 0.00). E:T was concentration-dependent. Except for IR-T + CpG, all other groups had great difference than control group with statistic significance (P < 0.05) but no significant difference between the groups. The levels of IFN-gamma spot-forming T cells were higher in the E7PA + CpG group than the control group with statistic significance (P < 0.01). In terms of specificity, E7PA + CpG in the HPV18 positive group could induce the proliferation of IFN-gamma-secreting T cells. And there was statistical difference with the control group (P < 0.05). CONCLUSION: Screening the HPV18 E7 peptide target at HLA-A2 plus CpG as the candidate targets by SYFPEITHI may active specific immunological cellular responses to HPV18 positive disease. PMID- 22944137 TI - Profound retrograde but absence of anterograde amnesia for cued place learning in rats with hippocampal lesions. AB - Previous studies in our lab have shown that slight modifications in the spatial reference memory procedure can overcome the deficit in spatial learning typically observed in rats with hippocampal damage. However, it is unknown if memory acquired under such training circumstances is spared after hippocampal lesions. With this aim a four-arm plus-shaped maze and a spatial reference memory paradigm were used, in which the goal arm was doubly marked: by an intramaze cue (a piece of sandpaper positioned on the floor of the arm) and by the extramaze constellation of stimuli around the maze. Experiment 1 replicated previous findings showing that hippocampally damaged rats can learn a place response just as well as the controls when the intramaze cue is present during the training, but they are unable to do so in the absence of the intramaze signal. When the learning procedure was doubly signaled, a transfer test performed 24h after the end of acquisition demonstrated that lesioned rats showed perfect memory for the goal arm when the intramaze cue was removed. Experiment 2 investigated the effect of hippocampal damage 1 day after the learning. Results showed that regardless of the training procedure employed (with or without the intramaze cue), hippocampal lesions produced a profound retrograde amnesia. Thus, although the absence of anterograde amnesia suggests that structures other that the hippocampus can take charge of the acquisition, the presence of retrograde amnesia indicates the critical role of the normal hippocampus in the long-term formation of allocentric information. PMID- 22944138 TI - Intrauterine growth restriction modifies the normal gene expression in kidney from rabbit fetuses. AB - The aim of this work was to study the effect of intrauterine growth restriction (IUGR) on fetal kidneys. The IUGR was induced by uteroplacental vessels ligature in a model of pregnant rabbit. We centralized the study in the gene expression of essential proteins for fetal kidney development and kidney protection against hypoxia, osmotic stress, and kidney injury. The gene expression of HIF-1alpha, NFAT5, IL-1beta, NGAL, and ATM were studied by qRT-PCR and Western blot in kidneys from control and IUGR fetuses. Experimental IUGR fetuses were significantly smaller than the control animals (39 vs. 48 g, p<0.05). The number of glomeruli was decreased in IUGR kidneys, without morphological alterations. IUGR increased the gene expression of HIF-1alpha, NFAT5, IL-1beta, NGAL, and ATM (p<0.05) in kidneys of fetuses undergoing IUGR, suggesting that fetal blood flow restriction produce alterations in gene expression in fetal kidneys. PMID- 22944139 TI - Corepressors (NCoR and SMRT) as well as coactivators are recruited to positively regulated 1alpha,25-dihydroxyvitamin D3-responsive genes. AB - Transcription factors require coactivators and corepressors to modulate transcription in mammalian cells. The vitamin D receptor (VDR) utilizes coactivators and corepressors to gain tight control over the activity of a diverse set of genes that can regulate calcium transport, slow proliferation and promote immune responses. We have recently established the VDR/RXR cistrome in human colon cancer cells and have linked these binding sites to the genes that are regulated by 1alpha,25-dihydroxyvitamin D3 (1,25(OH)2D3). In additional studies described herein, we demonstrate that the coactivators SRC1, CBP and MED1 are recruited to upregulated genes to facilitate transcription as expected. SRC1 was the most highly correlated to VDR/RXR binding (50%). However, we also found that corepressor molecules such as NCoR and SMRT were present along with SRC1, CBP or MED1 at these 1,25(OH)2D3 activated gene enhancers. Interestingly, genome wide NCoR binding mimicked VDR binding by increasing its association with VDR binding in response to 1,25(OH)2D3 treatment. Overall, these data indicate a complex role for corepressor and coactivator complexes in the activation or active repression of 1,25(OH)2D3 responsive genes. This article is part of a Special Issue entitled 'Vitamin D Workshop'. PMID- 22944140 TI - Determination of steroid metabolome as a possible tool for laboratory diagnosis of schizophrenia. AB - Metabolomic studies represent a promising tool for early diagnosis of schizophrenia. The aim of this study was to find differences in the steroid spectrum in patients and controls, and to assess the diagnosis of schizophrenia by building a predictive model based on steroid data. Thirty-nine serum steroids (22 neuroactive steroids and their metabolites and 17 polar conjugates) representing steroid metabolome were measured by gas chromatography-mass spectrometry in 22 drug-naive (first episode) schizophrenia patients (13 men and 9 women) before and after six-month treatment with atypical antipsychotics. The results were compared to the data from healthy subjects (22 males, 25 females). In summary the following significant differences were found: (1) In both sexes higher levels of pregnenolone sulfate and sulfated 5alpha- as well as 5beta saturated metabolites of C21-steroids in progesterone metabolic pathway were found in patients, pointing to decreased activity of sulfatase. (2) In a few instances decreased levels of the respective 5alpha-metabolites of C21 steroids were found in patients. (3) As C19 steroids concern, in both sexes there were considerably lowered levels of 5beta-reduced metabolites in patients. On the other hand, with only a few exceptions, the treatment did not significantly influence most steroid levels. Further, to assess the relationships between schizophrenia status and steroid levels and to build the predictive model of schizophrenia, multivariate regression with reduction of dimensionality (the method of orthogonal projections to latent structures, OPLS) was applied. Irrespective of the small number of patients, use of this model enabled us to state the diagnosis of schizophrenia with almost 100% sensitivity. Our findings suggest that the assessment of steroid levels may become a valid and accurate laboratory test in psychiatry. A limitation of our study is the absence of subjects with a diagnosis other than schizophrenia, so we cannot conclude whether the results are specific for schizophrenia. On the other hand, steroid metabolome model may be used as a diagnostic tool for further studies. PMID- 22944141 TI - A retrospective evaluation of submandibular gland involvement in oral cavity cancers: a case for gland preservation. AB - The key factor mitigating against prognosis in head and neck cancer is nodal metastasis and its management. Neck dissection has been known to play an integral part in this type of cancer management. Submandibular gland preservation during neck dissection and post radiotherapy, have been known to improve subjective symptoms of xerostomia. The authors retrospectively surveyed the involvement of submandibular gland involvement in oral cancer with a view to confirm oncologic safety of submandibular gland preservation, as a first step in a quest to manage radiation induced xerostomia by submandibular gland transfer. The medical and pathological records of oral cancer patients who underwent surgical treatment at the authors' centre were reviewed retrospectively. 194 patients were included in the study. 229 submandibular glands were excised from the same number of neck dissections. 3 (1.3%) submandibular glands were involved with malignancies microscopically. The mode of involvement was by direct infiltration. In conclusion, no metastasis to submandibular gland was observed. This may suggest the oncologic safety of submandibular gland preservation and transfer. PMID- 22944142 TI - Of bugs and joints: the relationship between infection and joints. AB - The association between microbes and joints has existed since antiquity, and remains complex. Diagnosis is often times difficult to determine despite highly suspicious clinical characteristics for the presence of an underlying infection. Over the several past decades, considerable advances have occurred in diagnostic methodologies and therapy. However, the morbidity and mortality of septic arthritis remains high. Great advances have occurred in the diagnosis, pathogenesis, and therapeutic management of reactive arthritis, and there is evidence that when the responsible microorganism is Chlamydia trachomathis, complete remission and cure is possible. Emergent infections, especially viral, has been recognized, i.e. HIV, hepatitis C, and most recently Chikengunya virus, and in the case of HIV associated articular manifestations, the introduction of HAART has resulted in a decrease in the incidence and development of newer complications such as the immune reconstitution syndrome. The infectious etiology of rheumatoid arthritis is being strongly considered once again, and the exciting association with periodontal disease is at the forefront of intense research. The gut microbiota is also being investigated and new and most interesting data is being gathered of the potential role of commensal gut organisms and the pathogenesis of rheumatoid arthritis. PMID- 22944143 TI - Analysis of a competitive prey-predator system with a prey refuge. AB - Gauss's competitive exclusive principle states that two competing species having analogous environment cannot usually occupy the same space at a time but in order to exploit their common environment in a different manner, they can co-exist only when they are active in different times. On the other hand, several studies on predators in various natural and laboratory situations have shown that competitive coexistence can result from predation in a way by resisting any one prey species from becoming sufficiently abundant to outcompete other species such that the predator makes the coexistence possible. It has also been shown that the use of refuges by a fraction of the prey population exerts a stabilizing effect in the interacting population dynamics. Further, the field surveys in the Sundarban mangrove ecosystem reveal that two detritivorous fishes, viz. Liza parsia and Liza tade (prey population) coexist in nature with the presence of the predator fish population, viz. Lates calcarifer by using refuges. In view of such observations in mind, a three-component model consisting of two prey and one predator population is considered in the present investigation with the inclusion of Holling type-II response function incorporating a constant proportion of prey refuge. The essential mathematical features of the present model have been analyzed thoroughly in terms of the local and the global stability and the bifurcations arising in some selected situations as well. The threshold values for some parameters indicating the feasibility and the stability conditions of some equilibria are also determined. The ranges of the significant parameters under which the system admits a Hopf bifurcation are investigated. The explicit formulae for determining the stability, direction and other properties of bifurcating periodic solutions are also derived with the use of both the normal form and the central manifold theory. Numerical illustrations are performed finally in order to validate the applicability of the model under consideration. PMID- 22944144 TI - Impact of visceral pleural invasion on the survival of patients with non-small cell lung cancer. AB - BACKGROUND: In this study, we investigated visceral pleural invasion (VPI) as a poor prognostic factor in patients with non-small cell lung cancer (NSCLC) according to the 7th edition of the TNM classification. METHODS: Between January 2000 and December 2007, 886 consecutive patients with pathological T1a-T2b NSCLC underwent complete resection with systematic lymph node dissection in Tokyo Medical University. We statistically analyzed the association between VPI and clinicopathologic factors, or clinical outcomes. RESULTS: The 5-year overall survival (OS) rates of the pl0, pl1, and pl2 patients were 80.8%, 63.7%, and 49.6%, respectively, with significant differences between pl0 and pl1 (p=0.002), pl1 and pl2 (p=0.03). Thus, the pl1 and pl2 patient groups were defined as patients with VPI. VPI was found to be a significant independent prognostic factor by multivariate survival analysis (p=0.0002). In patients with tumors <=3 cm, especially with tumors <=2 cm, VPI was significantly associated with an increased rate of lymph node metastasis, compared with non-VPI (p=0.0003 and p=0.015, respectively). Analysis of the OS of patients stratified by tumor size (<=3 cm, 3.1-5 cm, 5.1-7 cm) and VPI status showed that in any nodal status, patients with 3.1-5 cm/VPI tumors had significantly worse survival than patients with <=3 cm/VPI tumors (p=0.019) and patients with 3.1-5 cm/non-VPI tumors (p=0.001). On the other hand, there was no significant difference in the OS between patients with 3.1-5 cm/VPI tumors and patients with 5.1-7 cm tumors regardless of lymph node metastasis (T2b tumors). Similar relationships were observed among these groups with N0 disease. CONCLUSION: We identified the presence of VPI as an independent poor prognostic factor in patients with NSCLC of <=7 cm. Tumors 3.1-5cm with VPI should be upstaged to T2b tumors in the future in the TNM classification of the Union of International Cancer Control staging system. In addition, the surgical strategy involving more extensive lymph node dissection for patients with <=3 cm/VPI tumors, especially <=2 cm/VPI, is warranted owing to more frequent lymph node metastasis. PMID- 22944145 TI - Diagnostic values of urine CYFRA21-1, NMP22, UBC, and FDP for the detection of bladder cancer. AB - BACKGROUND: We compared the diagnostic utilities of CYFRA 21-1, nuclear matrix protein-22 (NMP22), urinary bladder cancer antigen (UBC), and fibrin/fibrinogen degradation products (FDP) for detecting urinary bladder cancer. METHODS: We assayed CYFRA 21-1, NMP22, UBC and FDP from urine samples for 250 subjects. Among them, 54 were diagnosed as bladder cancer, and the remaining 196, which consisted of healthy individuals and patients with hematuria, inflammation/infection, or benign prostate hyperplasia, were assigned to the control group. RESULTS: Urinary levels of all 4 markers were higher in the bladder cancer group than the control group. The areas under the receiver operating characteristic curves (ROC-AUCs) of CYFRA 21-1, NMP22, UBC and FDP, corrected with urine creatinine concentrations, were 0.90, 0.89, 0.80 and 0.77, respectively, for discriminating bladder cancer from controls. The ROC-AUCs for the combinations of the markers were not significantly higher than those with CYFRA 21-1 or NMP22. NMP22 was the only independent variable for predicting bladder cancer among the four markers in the multivariate analysis. CONCLUSIONS: All 4 tumor biomarkers exhibited diagnostic utility for predicting bladder cancer. Among them, CYFRA 21-1 and NMP22 were the most effective at predicting bladder cancer. PMID- 22944146 TI - Medicalisation or customisation? Sleep, enterprise and enhancement in the 24/7 society. AB - This paper extends and problematises recent sociological research on the medicalisation of sleep, focussing on trends and transformations in the prospective 'customisation' of sleep in the 24/7 society. What exactly does customisation mean in this context; how does it relate to the medicalisation of sleep; and how salient or significant are these trends to date in the 24/7 society? These are the key questions this paper seeks to address, taking workplace napping and wakefulness promoting drugs amongst the 'healthy' as our comparative case studies. Both we argue, despite their apparent differences and embryonic status to date, provide alternative routes to broadly similar ends. Namely they customise our sleep patterns and practices to fit around the escalating temporal demands of daily life, thereby helping remedy the increasing misalignment between biological and social time. Each, moreover, seeks to improve or optimise safety, productivity and performance in late modern society, where alertness is prized, sleepiness is problematised and vigilance is valorised. The paper concludes with some further reflections on these matters, including relations between the biomedicalisation and the customisation of sleep and a research agenda on the biopolitics of sleep and wakefulness. PMID- 22944147 TI - The weather-stains of care: interpreting the meaning of bad weather for front line health care workers in rural long-term care. AB - This paper addresses the gap in health services and policy research about the implications of everyday weather for health care work. Building on previous research on the weather-related challenges of caregiving in homes and communities, it examines the experiences of 'seasonal bad weather' for health care workers in long-term care institutions. It features a hermeneutic phenomenology analysis of six transcripts from interviews with nurses and personal support workers from a qualitative study of institutional long-term care work in rural Canada. Focussing on van Manen's existential themes of lived experience (body, relations, space, time), the analysis reveals important contradictions between the lived experiences of health care workers coping with bad weather and long-term care policies and practices that mitigate weather related risk and vulnerability. The findings contribute to the growing concern for rural health issues particularly the neglected experiences of rural health providers and, in doing so, offer insight into the recent call for greater attention to the geographies of health care work. PMID- 22944148 TI - Protein profile in vascular wall of atherosclerotic mice analyzed ex vivo using FT-IR spectroscopy. AB - The structure of proteins in a tissue can undergo changes on account of disease state such as diabetes or atherosclerosis. In this work the protein profile in atherosclerotic tissue is monitored by FT-IR imaging coupled with Hierarchical Cluster Analysis (HCA). Additionally, a model for prediction of secondary structure of proteins content based on amide I and II range is used to show the distribution of analyzed proteins. A new protein class emerged in atherosclerotic tissue in the region of the plaque and additionally the plaque was found to be strongly mixed with smooth muscle cell. The calculated secondary structure contents of proteins in atherosclerotic tissue in comparison to healthy tissue showed an increase of structures related to beta-sheet (E and T) and a decrease of helical (H) and unassigned arrangements. PMID- 22944149 TI - Study on the interaction of triadimenol with calf thymus DNA by multispectroscopic methods and molecular modeling. AB - The binding mechanism of triadimenol (NOL) to calf thymus DNA (ctDNA) in physiological buffer (pH 7.4) was investigated by multispectroscopic methods including UV-vis absorption, fluorescence, circular dichroism (CD), Fourier transform infrared (FT-IR), and nuclear magnetic resonance ((1)H NMR) spectroscopy, coupled with viscosity measurements and atomic force microscopy (AFM) technique. The results suggested that NOL interacted with ctDNA by intercalation mode. CD and AFM assays showed that NOL can damage the base stacking of ctDNA and result in regional cleavage of the two DNA strands. FT-IR and (1)H NMR spectra coupled with molecular docking revealed that a specific binding mainly exists between NOL and G-C base pairs of the ctDNA where two hydrogen bonds form. Moreover, the association constants of NOL with DNA at three different temperatures were determined to be in the 10(3) L mol(-1) range. The calculated thermodynamic parameters suggested that the binding of NOL to ctDNA was driven mainly by hydrogen bond and van der Waals. PMID- 22944150 TI - Text4Diet: a randomized controlled study using text messaging for weight loss behaviors. AB - OBJECTIVE: Text-messaging shows promise as a health intervention. This randomized controlled trial evaluated a daily text-messaging weight loss intervention. METHODS: Overweight and obese adults (n=170) in California were randomized to receive daily interactive and personally weight-relevant text-messages or monthly e-newsletters. Participants were measured at baseline, 6 and 12 months. Group differences were assessed in weight loss. Relation of text-messaging adherence to weight loss and change in pedometer steps was examined. RESULTS: There were no group differences in weight loss over 6 (1.53 lb vs 3.72 lb) or 12 months (2.27 lb vs 3.64 lb; control vs intervention). Text-messaging adherence was moderately strong (60-69%). Participants with greater adherence lost more weight at 6 (p=.039) and 12 months (p=.023) than those who were less adherent. Intervention participants' steps increased almost 3000 steps/day over time (p<.05), and higher step counts were associated with greater weight loss (p<.05). Text-messaging satisfaction was moderate to high, and pedometer-related satisfaction was associated with greater weight loss (p<.05). CONCLUSIONS: Although text-messaging had no effect on weight, adherence was associated with improvement in weight related behaviors and weight outcomes. Text-messages could be a useful adjunct to weight loss treatments. PMID- 22944151 TI - Association between lifetime stress and obesity in Canadians. AB - BACKGROUND: Obesity has been linked to stress, but there is lack of strong evidence from general populations. METHODS: The analysis was based on data from 112,716 Canadians aged 18 years or more who participated in a national survey conducted in 2007-2008. A questionnaire covered the information on self-perceived lifetime stress, height, and weight. Logistic regression analysis was used to determine the association between chronic stress and obesity. RESULTS: The crude prevalence of obesity was 18.1% for men and 16.0% for women. A small proportion (3.7%) of the participants reported being extremely stressed most days in their lives and 19.1% reported being quite a bit stressed, and the proportions of stress were slightly higher in women than in men. Overall, those who reported being extremely stressed (adjusted OR: 1.23, 95% CI: 1.13, 1.35) or those who reported being quite a bit stressed (adjusted OR: 1.08, 95% CI: 1.02, 1.15) had an increased risk of obesity compared with who were not at all stressed. The adjusted odds ratio was 1.44 (95% CI: 1.13, 1.35) for women who were extremely stressed compared with women who were not at all stressed. CONCLUSION: Lifetime stress was associated with an increased risk of obesity especially in women. PMID- 22944152 TI - [Multicenter clinical registries: chance for development of clinical research and clinical expertise]. PMID- 22944153 TI - [Unrelated umbilical cord blood transplantation with TBI/Ara-c/CY non-ATG conditioning regimen for adults with hematologic malignancies]. AB - OBJECTIVE: To retrospectively analyze the curative efficacy of umbilical cord blood transplantation (UCBT) with improved myeloablative conditioning regimen (total body irradiation (TBI)/cytosine arabinoside (Ara-c)/cyclophosphamide (CY) without antithymocyte globulin (ATG)) in adult patients with hematological malignancies. METHODS: Forty consecutive adult patients with hematological malignancies received improved myeloablative unrelated CBT at a single center from September 2006 to May 2011. Their average age was (23 +/- 6) years and the average weight (58 +/- 9) kg. Thirty-five (87.5%) patients were high-risk and 15 (37.5%) at the advanced disease status at pre-transplantation. They received 1 (n = 23) or 2 (n = 17) cord blood units. Seventy-five percent of them were transplanted with 1/2-human leukocyte antigen mismatched unit. The conditioning regimen consisted of 12 Gy TBI, granulocyte colony-stimulating factor (G-CSF) plus Ara-c and CY without ATG. All patients received a combination of cyclosporine (CsA) and mycophenolate mofetil (MMF) for the prophylaxis of graft versus-host disease (GVHD). RESULTS: For the entire group of patients, the average cell doses infused were (4.1 +/- 1.1)*107 total nucleated cells/kg and (2.4 +/- 1.0)*105 CD34(+) cells/kg. All patients acquired engraftment with an implantation rate of 100%. The average time of absolute neutrophil count (ANC) >= 0.5*109/L was (20 +/- 5) days and the average time of platelet >= 20*109/L was(38 +/- 12) days. Acute GVHD occurred in 23 patients (57.5%) and 4 (10.0%) were of grade III-IV. Chronic GVHD occurred in 22.9% (8/35) evaluable patients. Relapse occurred in 12.5% (5/40) patients. During a median follow-up period of 19.8 (range 4.6 - 55.0) months, the transplantation-related mortality was 15.0% (6/40) within 100 days and 35.0% (14/40) within 1 year. The main causes of mortality were pneumonia and severe acute GVHD. Two-year overall survival (OS) or disease free survival was 58.8% and 58.8%, respectively. Two-year OS for patients with advanced or complete remission disease was 48.6% and 63.8%, respectively. CONCLUSIONS: The TBI/Ara-c/CY myeloablative conditioning regimen is well tolerated and capable of establishing sustained donor cell engraftment and decreasing the risks of transplant-related death in adults with hematologic malignancies. For the high-risk and advanced patients, it may reduce the occurrences of relapse and chronic GVHD. PMID- 22944154 TI - [Research of regulative factors on CD8(+)HLA-DR(+) effector T cells in severe aplastic anemia]. AB - OBJECTIVE: To explore the regulative factors on CD8(+)HLA-DR(+) T cells in the patients with severe aplastic anemia (SAA) and examine the roles of these cells in the immunopathogenesis of SAA. METHODS: CD8(+)HLA-DR(+) T cells were sorted from bone marrow mononuclear cells of 13 SAA patients from July 2011 to March 2012 by magnetic activated cell sorting system and were divided into 3 groups: interleukin 2 (IL-2) group (0, 0.1, 1, 10, 100 and 1000 U/ml), cyclosporine A (CsA) group (addition of 400 ng/ml CsA in each IL-2-containing well),receptor antagonist group (addition of IL-2 receptor antagonist 8 ug/ml in each IL-2 containing well). Then cell proliferation rate was evaluated by MTT assay after a 72-hour culturing. Bone marrow mononuclear cells of the SAA patients were divided into CsA group, IL-2 group and control group and cultured for 18 hours and another 4 hours following the dosing of phorbol ester. The expression of tumor necrosis factor beta (TNF-beta) in CD8(+)HLA-DR(+) T cells was analyzed by flow cytometry. RESULTS: The cell proliferations of IL-2 wells at the concentrations of 10, 100 and 1000 U/L (0.36 +/- 0.12, 0.41 +/- 0.12, 0.46 +/- 0.14) were significantly higher than those of the control wells (0.23 +/- 0.11), CsA group (0.18 +/- 0.05, 0.19 +/- 0.00, 0.20 +/- 0.04) and receptor antagonist group (0.18 +/- 0.05, 0.17 +/- 0.04, 0.18 +/- 0.03, all P < 0.05). No statistic difference existed between CsA and receptor antagonist groups (P > 0.05). The expressions of TNF-beta of CD8(+)HLA-DR(+)T cells of the IL-2 group were higher than those of the control group (64% +/- 25% vs 46% +/- 22%) whereas the CsA group (27% +/- 20%) were lower than those of the control group (both P < 0.05). CONCLUSIONS: IL 2 can significantly stimulate the proliferation of CD8(+)HLA-DR(+) T cells and accelerate the in vitro secretion of TNF-beta in SAA patients. The proliferation may be inhibited by CsA and receptor antagonist. And the expression of TNF-beta is suppressed significantly by CsA. PMID- 22944155 TI - [Role of canonical Wnt signaling transduction pathway in the pathogenesis of pelvic organ prolapse]. AB - OBJECTIVE: To explore the effects of canonical Wnt signaling transduction pathway on the proliferation and secretion of fibroblasts of uterosacral ligament so as to elucidate the pathogenic mechanism of pelvic organ prolapse (POP). METHODS: Five patients with grade >=SH POP and five with other benign gynecologic disorders as control were recruited. Specimens were taken from uterosacral ligaments and fibroblasts were cultured and purified. After the confirmation of cultured fibroblasts by immunohistochemical staining, their growth and proliferation activity were detected by thiazolyl blue tetrazolium bromide (MTT) assay and the expressions of matrix metal proteinase-2 (MMP-2), Wnt16, FZD5 and beta-catenin by Western blot. RESULTS: (1) Over 90% of the cultured cells were fibroblasts of vimentin positive and keratin negative. (2) The growth and proliferation activity of fibroblasts were significantly lower in the POP group than those in the control group (P<0.01). (3) The levels of MMP-2 and FZD5 in the POP group were significantly higher than those in the control group (P<0.05 and P<0.01 respectively) while those of Wnt16 and beta-catenin were significantly lower than the control group (both P<0.05). CONCLUSIONS: Canonical Wnt16 signaling transduction pathway becomes inhibited in the fibroblasts of POP patients resulting in lower growth and proliferation activity and reduced secretion of collagen. Elevated MMP-2 contributes to the increased degradation of collagen. And MMP-2 and Wnt16 signaling transduction pathway may be important factors for the changes of collagen state in pelvic organ support structures leading ot POP. PMID- 22944156 TI - [Diagnosis and surgery of anomalous origin of the left coronary artery from the pulmonary artery in children]. AB - OBJECTIVE: To explore the clinical features, diagnosis and management of anomalous origin of the left coronary artery from the pulmonary artery (ALCAPA) in children. METHODS: The clinical manifestations, examinations, diagnostic modalities and treatments of children identified as ALCAPA at Beijing Anzhen Hospital from September 1993 to September 2011 were retrospectively reviewed. RESULTS: A total of 27 children were recruited. There were 16 males and 11 females with an age range of 1 month to 13 years. Among them, 19 patients had an onset age of <= 1 years. The initial symptoms were acute heart failure (n = 15), pneumonia (n = 7) and cardiac dilation with murmur (n = 5). The pre-admission misdiagnoses included endocardial fibroelastosis (EFE) (n = 13), dilated cardiomyopathy (DCM) (n = 4) and mitral severe regurgitation (n = 2). The definite diagnosis was established on the basis of electrocardiography (ECG), echocardiography and 64-slice computed tomography or angiography. Twenty-six cases underwent immediate surgery after an accurate diagnosis, including left coronary artery (LCA) ligation (n = 1), LCA ligation plus coronary artery bypass grafting (n = 1), Takeuchi operation (n = 7) and LCA reimplantation (n = 17). Six died postoperatively. And 20 cases were routinely followed up with symptoms, signs, ECG and echocardiography for 3-192 months. The outpatient visits were at Months 3, 6 and 12 post-operation and then annual check-ups by returning to hospital, telephone, letters and other forms. The cohort had no overt symptoms and left ventricular ejection fraction returned to normal range. No complications occurred after LCA reimplantation. CONCLUSIONS: As a rare congenital heart anomaly, ALCAPA may be definitely diagnosed with clinical features and serial diagnostic methods. It can be treated with several types of cardiac surgery. Coronary reimplantation is the technique of choice for surgical correction of ALCAPA due to its excellent prognosis. PMID- 22944157 TI - [Phase II clinical trial of docetaxel, platinum and S-1 for advanced gastric cancer]. AB - OBJECTIVE: To evaluate the efficacy and safety profile and to explore the role of docetaxel, S-1 plus cisplatin (DCS) or oxaliplatin (DOS) in the treatment of advanced gastric cancer. METHODS: A total of 45 patients with advanced gastric cancer were recruited. They received DCS or DOS at the discretion of investigators. Docetaxel was given intravenously at the dose of 60 mg/m2 at d1, S 1 60 mg*m-2*d-1 or 80 - 120 mg/d according to individual patient's area of body surface orally from d1 to d14 and cisplatin 30 mg/m2 at d1, d2 or oxaliplatin 111 - 127 (median: 117) mg/m 2at d2. Each cycle was for 21 days. RESULTS: Forty-three patients received >= 1 complete cycle of DCS/DOS with a median cycle number of 5(range: 1 - 8). Among 42 patients evaluated for efficacy, the outcomes were partial response (n = 28), stable disease (n = 9) and progression (n = 5). The response rate was 66.7%. Progression-free survival (PFS) of 32 patients on chemotherapy alone was 7.1 months and the median overall survival (OS) was not reached. The most common grade 3/4 adverse effects included neutropenia (46.5%), thrombocytopenia (9.3%), vomiting (9.3%), nausea (7.0%) and diarrhea (4.7%). Ten of fourteen patients with advanced unresectable gastric cancer without clinically detectable distant metastases underwent surgical resection after a median of 4 (2 6) cycles of DCS or DOS and 9 (64.3%) had R0 resection. CONCLUSIONS: DCS/DOS is effective for advanced gastric cancer and in the setting of neoadjuvant chemotherapy. And the toxicities of DCS/DOS are manageable. PMID- 22944158 TI - [Effect and risk factors of pitavastatin on high sensitivity C-reactive protein in patients with hypercholesterolemia: a multilevel models analysis]. AB - OBJECTIVE: To evaluate the effect of pitavastatin on high sensitivity C-reactive protein (hsCRP) in patients with hypercholesterolemia, and determine risk factors for the effect. METHODS: This study was a 12-week, multicenter, open-label, without parallel-group comparison, phase IV clinical trail. RESULTS: There were 330 subjects in the per protocol set. Contrast to the baseline, the average levels of hsCRP in all of subjects and the group without a history of receiving previous statin medication at week 12 post-treatment decreased respectively 26.4% (1.20 mg/L vs 1.68 mg/L) and 27.5% (1.21 mg/L vs 1.97 mg/L, all P < 0.05). The results of multilevel models indicated that the average levels of hsCRP reduced with the passage of treatment time, the time-varying rate of per-visit was 0.97 mg/L (95% confidence interval 0.96 - 0.98). Controlled individual background covariates, the model predicted that pulse pressure and white blood cell count on the baseline had the significant positive effects on hsCRP (P < 0.01). CONCLUSIONS: Pitavastatin decreases hsCRP in patients with hypercholesterolemia. The main risk factors for the effect are pulse pressure and white blood cell count on the baseline. PMID- 22944159 TI - [Incidence and risk factors of amputation among inpatients with diabetic foot]. AB - OBJECTIVE: To evaluate the incidence and risk factors of lower extremity amputation among inpatients with diabetic foot. METHODS: For this retrospective study, a total of 685 inpatients with diabetic foot (Wagner grade 1-5) admitted at a multi-disciplinary Diabetic Foot Care Center, West China Hospital, Sichuan University during January 1, 2005 and June 30, 2011. The data of each patient including clinical information, laboratory results and final outcome were collected and analyzed. They were divided into non-amputated and amputated groups. And the latter included minor and major amputation groups according to amputation site. RESULTS: The overall amputation rate was 11.4% in diabetic foot inpatients. The incidences of minor amputation and major amputation were 5.4% and 6.0% respectively. 17.9% of amputated patients experienced a second amputation. The amputated patients had a longer hospitalized stay, higher counts of white blood cells and neutrophils, greater HbA1c and lower serum levels of hemoglobin and albumin than the non-amputation patients (P < 0.05). The prevalence of diabetic peripheral neuropathy was significantly higher in the amputation group than that in the non-amputation group (P < 0.05). However, no difference existed between the minor and major amputation groups (P > 0.05). Ankle brachial index (ABI) in the amputation group was significantly lower than that in the non amputation group (0.41 +/- 0.25 vs 0.91 +/- 0.36, P < 0.01). Minor and major amputation inpatients had similar ABI (0.43 +/- 0.24 vs 0.39 +/- 0.26, P = 0.087). Ordinal regression showed that HbA1c (P = 0.015), ABI (P = 0.016), history of amputation (P < 0.01) and Wagner grade of diabetic foot (P < 0.01) were the independent risk factors of amputation. CONCLUSIONS: Diabetic foot inpatients have a higher rate of lower extremity amputation. The risk factors of amputation include HbA1c, ABI, history of amputation and Wagner grade of diabetic foot. And diabetic peripheral neuropathy, ischemia of lower limbs (especially peripheral arterial diseases below knees), infection and nutritional state are closely associated with amputation of diabetic foot inpatients. PMID- 22944160 TI - [Serum level of 25(OH)D and its relevant influencing factors in patients on maintenance hemodialysis]. AB - OBJECTIVE: To explore the serum level of 25(OH)D and its relevant influencing factors in patients on maintenance hemodialysis. METHODS: The serum level of 25(OH)D was detected by electrochemiluminescence. A total of 162 patients on maintenance hemodialysis were divided into 3 groups according to the serum level of 25(OH)D: vitamin D deficiency: 25(OH)D <= 15 ug/L, vitamin D insufficiency: 25(OH)D <= 30 ug/L and vitamin D normal: 25(OH)D > 30 ug/L. Age, gender, relevant biochemical indices, high sensitivity C-reactive protein (hsCRP) and HOMA-IR were compared among there groups. The associations between 25(OH)D and the influencing factors of its levels were analyzed by Pearson's correlation. The independent factors correlated with the level of 25(OH)D were estimated by multiple linear regression. RESULTS: The average level of 25(OH)D was 10.3 (range: 4.0 - 43.5) ug/L and the prevalence of 25(OH)D insufficiency and deficiency 88.9% (144/162). Significant differences existed in age, cholesterol (CHOL), low density lipoprotein (LDL), lipoprotein(a) (LP(a)), creatinine (Cr), lg(hsCRP), lg(reductase inhibitor) (lg(RI)) and lg(vitamin D) (lg(VitD)) between three groups (all P < 0.05). Pearson's correlation analyses revealed that the serum levels of albumin (ALB), Cr and Ca(2+) were correlated positively with lg(VitD) while those of white blood cell, CHOL, LDL, Lp(a), age, RI and hsCRP were correlated negatively with VitD. Multiple linear regression analyses demonstrated that hsCRP, RI, LDL and age were the independent influencing factors of the serum levels of 25(OH)D. CONCLUSIONS: The prevalence of 25(OH)D insufficiency and deficiency is high. And microinflammation and insulin resistance are closely correlated with the insufficiency and deficiency of 25(OH)D. The independent influencing factors of serum 25(OH)D are hsCRP, RI, LDL and age. PMID- 22944161 TI - [Treatment and prognosis of patients with duodenal gastrointestinal stromal tumors]. AB - OBJECTIVE: To evaluate the clinical characteristics and survival factors of patients with duodenal gastrointestinal stromal tumors (GIST). METHODS: The clinical data of 41 patients with duodenal GIST were analyzed retrospectively at Cancer Hospital and Institute, Chinese Academy of Medical Sciences from June 1996 to August 2011. Kaplan-Meier method was used to calculate the recurrence-free survival rate and the Cox proportional hazard regression model employed for the recurrence-free survival analysis. RESULTS: The lesions of duodenal GIST were predominantly located in the descending (n = 26, 63.4%) and transverse portions (n = 10, 24.4%). Most duodenal GIST presented commonly with upper gastrointestinal bleeding (n = 18, 43.9%) and 12 cases (29.3%) were incidentally detected by physical examinations. Eight patients underwent pancreatoduodenectomy and 27 limited resection. The tumor size varied from 0.6 cm to 30.0 cm (mean: 8.4 cm). The recurrence-free survival rates analyzed by Kaplan-Meier method at 1, 2 and 5-year were 94.1%, 77.5% and 65.0% respectively. The results of Cox proportional hazards regression model indicated that the patients with >10/50 HP mitotic count showed a worse recurrence-free survival than those with <= 10/50 HP (HR = 3.7, 95%CI 1.0 - 13.7, P = 0.049). After adjusting other confounding factors, mitotic activity was one significant prognostic factor of recurrence (P = 0.024). There was no significant association between the risk of recurrence and other prognostic factors, including diagnostic age, tumor size, type of operation and the risk of aggressive behaviors (all P > 0.05). CONCLUSIONS: Mitotic activity is one prognostic factor of duodenal GIST. And R(0) resection should be regarded as an optional treatment for duodenal GIST. PMID- 22944162 TI - [Effect of peritoneal fibrosis induced by transforming growth factor-beta 1 on the adhesion of gastric cancer cell]. AB - OBJECTIVE: To elucidate the effect of transforming growth factor-beta 1 (TGF beta1) on peritoneal fibrosis and the regulation of gastric cancer adhering to mesothelial cells. METHODS: The peritoneal mesothelial cell line of HMrSV5 was used to determine the role of TGF-beta1 in the regulation of gastric cancer cell adhering to mesothelial cells. And the mRNA and protein expressions of collagen III and fibronectin were detected by adhesion assay, Western blot, immunofluorescent staining and reverse transcription-polymerase chain reaction (RT-PCR). RESULTS: (1) The treatment of 5 ng/ml TGF-beta1 could induce the expressions of collagen III and fibronectin in mesothelial cells at 24, 48 and 72 h (P < 0.01). (2) As compared with the controls, the percentages of adhered HGC 27 and HSC-39 gastric cancer cells significantly increased under the treatment of TGF-beta1 for 24 and 72 h. The increased adhesion percentages of HGC-27 were 65% +/- 5% and 124% +/- 11% (P < 0.05) while those of HSC-39 85% +/- 9% and 146% +/- 17% respectively (P < 0.05). (3) Arginyl-glycyl-aspartic acid (RGD) (knockdown of minimal sites for cell-binding domain of extracellular matrix) decreased the number of cancer cells adhering to mesothelial cells under the stimulation of TGF beta1. And the decreased adhesion percentage of HGC-27 was 65% +/- 8% (P < 0.05). CONCLUSIONS: TGF-beta1 significantly stimulates the expressions of collagen III and fibronectin in mesothelial cells. And it is associated with the increased adhesion of gastric cancer cell and offers a favorable environment for the dissemination of gastric cancer. PMID- 22944163 TI - [Inhibition of lipopolysaccharide-induced myeloid-derived suppressor cells in the proliferation of spleen T lymphocytes]. AB - OBJECTIVE: To explore the effects of lipopolysaccharide (LPS)-induced myeloid derived suppressor cells (MDSCs) on the proliferation of spleen T lymphocytes. METHODS: BALB/c mice were randomly divided into two groups: LPS group and normal control group. They were injected intraperitoneally with LPS and normal saline solution respectively. MDSCs were separated with CD11b immunomagnetic beads from the spleen extract of mice. The morphological characteristics of MDCSs were observed by Wright-Giemsa staining and the characteristic molecules on cell surface identified by flow cytometry. And the effects of MDSCs on the in vitro proliferation of T cells were determined by methyl-thiazolyl-tetrazolium bromide (MTT). RESULTS: The proportion of MDSCs in the spleen of the LPS group was much more than that of the normal control group (27.4% +/- 6.6% vs 5.1% +/- 3.8%; t = 5.06, P = 0.007). CD11b(+)Gr-1(+)MDSCs could be separated by CD11b immunomagnetic beads from the spleen of mice injected with LPS at a high purity of 84.0% +/- 4.2%. MTT method showed that the proliferation of T cells decreased significantly after a co-cultivation with CD11b(+)MDSCs versus the control group. And it was positively correlated with the number of MDSCs (F = 46.26, P = 0.000). CONCLUSIONS: A high purity of LPS-induced myeloid-derived suppressor cells may be separated with CD11b immunomagnetic beads. And it has dose-dependent inhibitory effects on the proliferation of the spleen T lymphocytes. PMID- 22944164 TI - [Effect of endoplasmic reticulum stress in brain injury following chronic intermittent hypoxia in weanling rat]. AB - OBJECTIVE: To explore the role of endoplasmic reticulum stress in brain injury following chronic intermittent hypoxia (CIH) in weanling rats. METHODS: A total of 48 male healthy Sprague-Dawley rats (3-4-week-old, 80-100 g) were randomly divided into 4 groups: 2-week-CIH (2IH) group, 4-week-CIH (4IH) group, 2-week control (2C) group and 4-week-control (4C) group. The morphologic changes were observed by hematoxylin-eosin (HE) staining and cell apoptosis detected by terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling assay. Then hippocampus and prefrontal cortices were collected for transcription and expression analysis of glucose regulated protein 78 (GRP78) by reverse transcription (RT)-PCR and Western blotting respectively. And the expressions of Caspase-12 mRNA and Caspase-12 protein in prefrontal cortex were analyzed by RT PCR and immunohistochemistry. RESULTS: The neuronal apoptosis in hippocampus and prefrontal cortices in CIH exposed groups were more pronounced than those of the control groups (all P < 0.01), especially in the 4IH group (hippocampus: 8.78% +/ 0.71% vs 3.26% +/- 0.45%, cortices: 6.02% +/- 0.32% vs 2.91% +/- 0.29%). The expression levels of GRP78 mRNA (hippocampus: 0.424 +/- 0.033 vs 0.326 +/- 0.013 and 0.444 +/- 0.028 vs 0.310 +/- 0.015, cortices: 0.514 +/- 0.038 vs 0.430 +/- 0.017 and 0.524 +/- 0.038 vs 0.439 +/- 0.033) and GRP78 protein in hippocampus and prefrontal cortices (hippocampus: 0.221 +/- 0.032 vs 0.178 +/- 0.014 and 0.241 +/- 0.019 vs 0.170 +/- 0.013, cortices: 0.307 +/- 0.012 vs 0.226 +/- 0.022 and 0.311 +/- 0.023 vs 0.225 +/- 0.025), and the expression levels of Caspase-12 mRNA (0.396 +/- 0.004 vs 0.323 +/- 0.014, 0.417 +/- 0.011 vs 0.313 +/- 0.011) and Caspase-12 protein (0.334 +/- 0.035 vs 0.197 +/- 0.023, 0.368 +/- 0.079 vs 0.215 +/- 0.024) in prefrontal cortex in the IH groups all were more than those in the 2C and 4C groups (all P < 0.05). CONCLUSIONS: Chronic intermittent hypoxia can up regulate the GRP78 transcription and expression in brain regions associated with learning and memory. This may induce the endoplasmic reticulum stress and activate the Caspase-12 mediated apoptosis signaling pathway. In the end, neuronal apoptosis occurs. All these factors may play an important role in the impairment of learning memory during the exposure of growing rats to chronic intermittent hypoxia. PMID- 22944165 TI - [Atorvastatin inhibits the H2O2-induced apoptosis of human vascular endothelial cells through a down-regulation of cleaved caspase-9/caspase-3]. AB - OBJECTIVE: To investigate the effect and potential mechanism of atorvastatin against H2O2-induced apoptosis of human umbilical vein endothelial cells (ECV 304). METHODS: ECV-304 cells were pretreated with different concentrations of atorvastatin (0.1, 1 and 10 umol/L) for 2 h, followed by an exposure to 100 umol/L H2O2 for 18 h. Cellular morphology was observed under fluorescence microscope. Cellular viability and apoptosis were evaluated by methyl thiazolyl tetrazolium (MTT) and flow cytometry. Finally the expressions of cleaved caspase 3 and caspase-9 were measured by Western blot. RESULTS: H2O2 treatment caused an obvious apoptosis of ECV-304 cells and significantly decreased the cellular viability as characterized by a high percentage (50.71%) of apoptotic cells. Atorvastatin pretreatment inhibit cellular apoptosis induced by H2O2 (39.45%, 20.53% and 7.83%). Western blot assay showed that H2O2 treatment caused a high expression of cleaved caspase-3 and caspase-9 while atorvastatin pretreatment obviously inhibited the expression in a dose-dependent manner. CONCLUSIONS: Atorvastatin inhibits the H2O2-induced apoptosis of ECV-304 cells in a dose dependent manner. This effect may be associated with the down-regulation of cleaved caspase-9/caspase-3. PMID- 22944166 TI - [Experiences of establishing an abdominal heart transplantation model in rats]. AB - OBJECTIVE: To review the experiences and key factors of establishing an abdominal cardiac transplantation model in rats at National Institutes of Health Clinical Center. METHODS: Dark Agouti rats served as donor while Brown Norway rats as recipient. Cardiac transplantations were performed with a modified version of heterotopic cardiac transplantation. Proficiency was defined as 20 consecutive operations with < 15% mortality and no significant major co-morbidities. RESULTS: We performed 10 donor harvest-alone operations and 70 transplantations to reach the proficiency level. The survival rate of the last 20 consecutive surgeries was 95%. The mean total operative duration was 55 min and mean ischemic time of donor hearts 35 min. CONCLUSION: To ensure a consistently high operative success rate, a surgeon must not only be proficient in micro-surgical skills, but also closely follow the standardized training procedures and strictly observe the animal care and use guidelines. PMID- 22944167 TI - [Effects of hyaluronic acid on biomechanic performance of porcine acellular dermal matrix plus thin skin autograft after transplantation]. AB - OBJECTIVE: To explore the effects of hyaluronic acid (HA) on biomechanical properties for porcine acellular dermal matrix (PADM) plus thin skin autograft after transplantation. METHODS: The dorsa of 10 Japanese white rabbits were symmetrically divided into four areas of A-D by random grouping. Full-thickness skin defects were created in Groups A-C while Group D was blank with normal skin. Operations were performed in Group A: implant with HA + PADM + thin skin autografts, Group B: implant with PADM + thin skin autografts and Group C: skin autografts group. Histological examination of specimen was performed at Day 56 postoperatively. And the biomechanical properties such as relaxation and stress strain properties of grafts were recorded. RESULTS: The structure of PADM was found to be basically intact by hematoxylin and eosin E dyeing in Groups A and B. In Group A, dense fiber structure could be observed. Lots of regularly arranged collagenous fibers and new blood capillaries were grown into the dermal matrix with sparsely distributed inflammatory cells. In Group B, acellular dermal matrix became clustered with a small amount of invaded fibroblasts. And there was a high expression of inflammatory cells. The biomechanic performances of transplanted skin were: Group A's curve was mostly close to that of Group D's, Group B's curve was the most further from that of Group D's (P = 0.001) and Group C's curve stayed between Groups A and B. Under the same strain, the stress of Groups A-D was (87 +/- 8), (115 +/- 9), (63 +/- 7) and (81 +/- 4) kPa respectively. No significant difference of stress existed between these two groups (P = 0.838). There was significant difference of stress between Groups B/C and D (P = 0.001 and P = 0.009). CONCLUSION: Topical hyaluronic acid may be used to enhance the biomechanics performances of transplanted skin. PMID- 22944168 TI - Effects of repeated injection of kisspeptin-10 on the initiation of egg-laying in juvenile quail. AB - The kisspeptin (Kp) signaling pathway plays an essential role in the onset of reproduction in mammals. To investigate the effects of Kp on the initiation of egg laying in birds, juvenile female quail were given daily intraperitoneal injections of 300MUl saline (control, Con), or 10nmol (low dosage, L) or 100nmol (high dosage, H) kisspeptin-10 (Kp-10) dissolved in 300MUl saline for 3 weeks. The ratio of egg laying of quail in the L and H groups was notably increased compared to that of the Con group (P<0.01), which paralleled earlier ovarian growth and increases in circulating estrogen (E(2)) concentrations. In the hypothalamus, gonadotropin-releasing hormone-I (GnRH-I) mRNA expression was markedly up-regulated, whereas the level of gonadotropin-inhibiting hormone mRNA was down-regulated by high-dose Kp-10 (P<0.05). In the pituitary gland, expression of GnRH receptor type II, but not type I mRNA was significantly up regulated by high-dose Kp-10 administration (P<0.05). Moreover, compared with the Con group, follicle-stimulating hormone (FSH) gene expression in the pituitary was significantly decreased in the L and H groups (P<0.05), whereas luteinizing hormone (LH) mRNA expression was significantly increased in the H, but not the L group (P<0.05). These results indicate that repeated peripheral Kp-10 injections can advance the sexual maturation of female quail by regulating the activities of the hypothalamus-pituitary-gonadal axis. PMID- 22944169 TI - Transcriptomic changes in the bovine conceptus between the blastocyst stage and initiation of implantation. AB - Conceptus-maternal communication is vital for the successful establishment and maintenance of pregnancy, yet relatively little information exists for many of the mechanisms and the nature of the conceptus signals responsible for this cross talk. Sub-optimal communication, resulting from impairment of conceptus development and/or from abnormal uterine receptivity, contributes to a high incidence of embryonic mortality. Therefore, detailed examination of the mechanisms regulating both pre- and peri-implantation conceptus development are necessary to fully understand the factors regulating successful post-hatching development, pregnancy recognition and implantation signaling. Despite significant progress in understanding of the temporal changes in the transcriptome of the uterine endometrium, there is only a rudimentary knowledge of the genes and pathways governing growth and development of the cattle conceptus. Furthermore, although there are a large number of studies describing gene expression profiles in bovine embryos focused mainly during the earlier preimplantation stages (up to and including Day 7), very little information exists for the post-hatching embryo and elongating conceptus. This period of development is arguably more important as a significant proportion of all embryonic loss occurs between Days 8 and 16 of pregnancy in cattle, corresponding to the time of hatching of the blastocyst from the zona pellucida and its subsequent elongation coincident with the time of maternal recognition of pregnancy. Given that this is a critical period in development leading up to maternal recognition and establishment of pregnancy, the identification of key genes and pathways regulating these crucial developmental events is essential. PMID- 22944170 TI - Development of an untargeted metabolomics method for the analysis of human faecal samples using Cryptosporidium-infected samples. AB - Faecal metabolite profiling, though in its infancy, allows for investigation of complex metabolic interactions between gastrointestinal infections or diseases and host health. In the present study, we describe a faecal metabolite extraction method for untargeted gas chromatography-mass spectrometry (GC-MS) analysis using Cryptosporidium positive and negative human faecal samples. The extraction method takes into account the varying faecal consistencies and quantities received for clinical diagnosis. Optimisation was carried out using different extraction solvents and on three different faecal quantities to determine the minimum amount of faecal sample required. The method was validated by untargeted GC-MS analysis on 8 Cryptosporidium positive and 8 Cryptosporidium negative human faecal samples, extracted using the optimised conditions. The method showed good extraction reproducibility with a relative standard deviation of 9.14%. Multivariate analysis of the GC-MS generated dataset showed distinct differences between profiles of Cryptosporidium positive and Cryptosporidium negative samples. The most notable differences included changes in amino acid, nitrogen and energy metabolism, demonstrating the association of infection with Cryptosporidium and altered permeability of the small intestine. PMID- 22944171 TI - Flexor digitorum superficialis opposition tendon transfer improves hand function in children with Charcot-Marie-Tooth disease: case series. AB - Charcot-Marie-Tooth disease limits hand function. Tendon transfer has not been reported in pediatric CMT. We report two severely affected children following long finger flexor digitorum superficialis opposition tendon transfer. Improvement was noted in palmar abduction, (30 degrees /40 degrees ), opposition, (thumb to all digits), and acquisition of pincer, palmar, and lateral pinch with measureable force (1 lb). Dexterity testing improved on the 9 Hole Peg Test (1.03 s/77 s, 22 s) and Functional Dexterity Test (13 s/33 s, 88 s). Functional improvements were observed in self feeding, clothing management, and play. These cases support flexor digitorum superficialis opposition tendon transfer surgery to improve hand function in children with CMT. PMID- 22944172 TI - Outlier detection for patient monitoring and alerting. AB - We develop and evaluate a data-driven approach for detecting unusual (anomalous) patient-management decisions using past patient cases stored in electronic health records (EHRs). Our hypothesis is that a patient-management decision that is unusual with respect to past patient care may be due to an error and that it is worthwhile to generate an alert if such a decision is encountered. We evaluate this hypothesis using data obtained from EHRs of 4486 post-cardiac surgical patients and a subset of 222 alerts generated from the data. We base the evaluation on the opinions of a panel of experts. The results of the study support our hypothesis that the outlier-based alerting can lead to promising true alert rates. We observed true alert rates that ranged from 25% to 66% for a variety of patient-management actions, with 66% corresponding to the strongest outliers. PMID- 22944174 TI - Delayed enhancement on cardiac magnetic resonance imaging is a poor prognostic factor in patients with cardiac sarcoidosis. AB - BACKGROUND: Predictors of ventricular arrhythmias (VA) in patients with cardiac sarcoidosis (CS) remain unclear. METHODS AND RESULTS: We examined 61 consecutive CS patients who were admitted to our hospital from April 2002 to March 2012 with a mean follow-up period of 45 +/- 31 months for the relationship between delayed enhancement on cardiac magnetic resonance imaging (DE-MRI) and VA or a composite endpoint, including VA, heart failure hospitalization, and cardiovascular mortality. Although there was no significant difference in baseline clinical characteristics between patients with VA and those without it, the former group was characterized as compared with the latter by lower left ventricular (LV) ejection fraction (p<0.05), larger LV systolic/diastolic dimensions (both p<0.05), and a significant association with DE-MRI (p<0.05). Furthermore, the patients with DE-MRI (n=26), as compared with those without it (n=11), had a significantly higher composite endpoint event rate (41% vs. 0%, p<0.05) and a trend toward higher VA (29% vs. 0%, p=0.12). Univariate analysis also showed that impaired LV systolic function was significantly associated with composite events on follow-up. CONCLUSIONS: These results indicate that the presence of DE-MRI is a significant predictor of VA events and poor outcome in CS patients. PMID- 22944173 TI - A screen for inducers of p21(waf1/cip1) identifies HIF prolyl hydroxylase inhibitors as neuroprotective agents with antitumor properties. AB - Preventing neuronal death is a priority for treating neurological diseases. However, therapies that inhibit pathological neuron loss could promote tumorigenesis by preventing the physiological death of cancerous cells. To avert this, we targeted the transcriptional upregulation of p21(waf1/cip1) (p21), an endogenous tumor suppressor with neuroprotective and pro-regenerative activity. We identified potential p21 indcuers by screening a FDA-approved drug and natural product small molecule library against hippocampal HT22 cells stably expressing a luciferase reporter driven by the proximal 60bp of the p21 promoter, and tested them for neuroprotection from glutathione depletion mediated oxidative stress, and cytotoxicity to cancer cell lines (DLD-1, Neuro-2A, SH-SY5Y, NGP, CHLA15, CHP212, and SK-N-SH) in vitro. Of the p21 inducers identified, only ciclopirox, a hypoxia-inducible factor prolyl-4-hydroxylase (HIF-PHD) inhibitor, simultaneously protected neurons from glutathione depletion and decreased cancer cell proliferation at concentrations that were not basally toxic to neurons. We found that other structurally distinct HIF-PHD inhibitors (desferrioxamine, 3,4 dihydroxybenzoate, and dimethyloxalyl glycine) also protected neurons at concentrations that killed cancer cells. HIF-PHD inhibitors stabilize HIF transcription factors, mediating genetic adaptation to hypoxia. While augmenting HIF stability is believed to promote tumorigenesis, we found that chronic HIF-PHD inhibition killed cancer cells, suggesting a protumorigenic role for these enzymes. Moreover, our findings suggest that PHD inhibitors can be used to treat neurological disease without significant concern for cell-autonomous tumor promotion. PMID- 22944175 TI - Sediment-seawater solute flux in a polluted New Zealand estuary. AB - We investigated the sediment-seawater solute flux at five sites in the polluted Avon-Heathcote Estuary, New Zealand, to provide a point of comparison for future studies of the effects of the closure of a major wastewater outfall into the estuary. Sediments collected in winters 2007 and 2008, and summer 2008, ranked consistently in organic matter content. Microelectrode profiling and sediment core incubations revealed (1) a dominant role of microphytes in regulating solute flux causing significant differences in the dark and light sediment O2 consumption (R(d), R(l)), total sediment O2 utilisation (TOU(d), TOU(l)), and inorganic nutrient flux, (2) consistent ranking of sites in solute flux, and (3) a clear solute-flux signature of the wastewater effluent. Sediment near the wastewater outfall exhibited the highest absolute R and TOU(,) the lowest ratio R(l)/R(d,) the highest dark efflux of dissolved reactive phosphorus and ammonium, and the highest dark and light uptake of nitrate+nitrite. PMID- 22944176 TI - Ragworm fatty acid profiles reveals habitat and trophic interactions with halophytes and with mercury. AB - The present study aimed to assess if ragworm fatty acids (FA) profiles could be used to discriminate their spatial distribution in an historically mercury contaminated estuarine environment, i.e., if it was possible to differentiate ragworms present in salt marsh sediments surrounding plant roots and rhizomes (rhizosediment) from adjacent unvegetated sediment. Additionally, we also tried to determine if ragworms differed in mercury content and if these values could also be used to identify the habitat they occur in. Results show that, within the same area, ragworms can be distinguished using FA profiles and that in halophyte rhizosediment ragworms display more than twice the levels of alpha-linolenic acid (18:3n-3). The ratio cis-vaccenic/oleic acids (18:1n-7/18:ln-9) in ragworms suggests higher carnivory in unvegetated sediments. Our study indicates that ragworm FA profiles can be used to identify their habitat, their trophic interaction with halophytes and reveal a spatially contrasting feeding behaviour, which also reflects mercury accumulation. PMID- 22944177 TI - [To improve the diagnosis and treatment of caesarean scar pregnancy, and to reduce the damage to women reproduction--the understanding of " consensus on the diagnosis and treatment of caesarean scar pregnancy "]. PMID- 22944178 TI - [Secular trends of cesarean delivery and cesarean delivery on maternal request among primiparous women with singleton pregnancy in Southern and Northern China during 1993-2010]. AB - OBJECTIVE: To explore the secular trends of cesarean delivery and cesarean delivery on maternal request (CDMR) among primiparous women with singleton pregnancy in Southern and Northern China. METHODS: The Perinatal Healthcare Surveillance System was established in 26 counties/cities of 3 Chinese provinces since 1993. A total of 1 317 774 primiparous women with singleton pregnancy were monitored through the system during the 1993 - 2010 period. Chi-square tests were performed to assess the linear trends in the prevalence of cesarean delivery and CDMR. RESULTS: During the 18-year period, 496 054 cesarean deliveries and 129 219 CDMRs were identified. The prevalence rates of cesarean delivery and CDMR were 37.6% and 10.0% respectively. CDMR accounted for 26.0% of all cesarean births. The prevalence of cesarean delivery increased from 29.4% during the 1993 - 1995 period to 58.7% during the 2006 - 2010 in Southern urban area, from 18.2% to 58.3% in Southern rural area and from 4.3% to 49.5% in Northern rural area. The prevalence of CDMR increased by 34 folds from 0.6% during the 1993 - 1995 period to 21.3% during the 2006 - 2010 period in Southern urban area, by 40 folds from 0.6% to 24.4% in Southern rural area and by 44 folds from 0.6% to 27.3% in Northern rural area. The proportions of CDMR in all cesarean deliveries significantly increased in all three regions. Women aged over 30 years, overweight and well-educated were more likely to experience a cesarean delivery including CDMR. CONCLUSION: The Chinese prevalence rates of cesarean delivery and CDMR increased dramatically during the 1993 - 2010 period and ranked the highest in the world by 2010. And CDMR became a non-negligible component in all cesarean sections. PMID- 22944179 TI - [Influences of high-field intraoperative magnetic resonance imaging on the extent of resection in low-grade gliomas]. AB - OBJECTIVE: To evaluate the influences of high-field intraoperative magnetic resonance imaging (iMRI) on the extent of resection (EoR) in low-grade gliomas. METHODS: Fifty-nine patients with low-grade gliomas underwent microsurgeries under the guidance of high-field iMRI and functional neuro-navigation. The rates of gross total removal and EoR were recorded after initial and final iMRI scans and neurological performances were evaluated peri-operatively and at follow-up. RESULTS: iMRI and functional neuronavigation were successfully performed in all patients. Initial iMRI found that the rates of gross total removal were misestimated in 21 cases (35.6%). In 17 cases (28.8%), initial iMRI revealed resectable residual tumors and further resection achieved gross total removal in 8 cases (13.6%). iMRI boosted the level of EoR from 90% +/- 15% to 94% +/- 12% (P < 0.001) in all cases and from 78% +/- 17% to 91% +/- 12% in 17 cases undergoing further tumor resections. At 3-month follow-up, 2 cases (3.4%) developed neurological deficits. CONCLUSION: The combination of iMRI and functional neuronavigation helped maximize safe tumor resection in low-grade gliomas. PMID- 22944180 TI - [Neurologic complications in children with enterovirus 71-infected hand-foot mouth disease : clinical features, MRI findings and follow-up study]. AB - OBJECTIVE: To explore the clinical and magnetic resonance imaging (MRI) characteristics and the follow-up outcomes of neurologic complications in children with enterovirus 71-infected hand-foot-mouth disease. METHODS: The clinical and MRI manifestations and follow-up outcomes in 35 children, at Second Affiliated Hospital, Wenzhou Medical College from August 2008 to November 2010, hospitalized with neurologic complications of enterovirus 71-infected hand-foot mouth disease were retrospectively analyzed. RESULTS: Six children with aseptic meningitis presented the clinical symptoms and signs of meningitis. Five of them showed subdural effusion and ventriculomegaly, or both on MRI. At follow-ups, neurologic sequel could not be found. Among 24 cases with brainstem encephalitis, there were myoclonic jerks and tremor, ataxia, or both (grade I disease, n = 12), myoclonus and cranial-nerve involvement (grade II disease, n = 4), and cardiopulmonary failure after brain-stem infection (grade III disease, n = 8). In patients with brainstem encephalitis, lesions were predominantly located at the posterior portions of medulla and pons with hypointensity on T1WI and hyperintensity on T2WI. Cerebellar dentate nucleus, caudate nucleus and lenticular nucleus could also be involved. At follow-ups, the patients with mild symptoms had no neurologic sequel and the lesions within brain stem became small or vanished in most cases. While in the majority of serious patients, neurologic sequel could be found and the lesions located at brain stem became encephalomalacia. Fourteen cases with acute flaccid paralysis presented acute limb myasthenia with tendon reflex and muscular tension decreased. On spinal MRI, the lesions predominantly involved anterior horn regions of spinal cord with hypointensity on T1WI and hyperintensity on T2WI. Most patients improved their muscle strength and most lesions of spinal cord became smaller or vanished during follow-ups. CONCLUSION: MRI is the most effective modality of diagnosis and follow-up for neurologic complications in children with enterovirus 71-infected hand-foot-mouth disease. On MRI, the lesions mainly involve the anterior horn of spinal cord, medulla oblongata and pons. At follow-ups, most patients have no neurologic sequel and the visualized lesions will be absorbed after active treatment. PMID- 22944181 TI - [Repair of rotator cuff tear by allogenic cortical bone anchor with suture bridge]. AB - OBJECTIVE: To evaluate the repair of rotator cuff tear by allogenic cortical bone anchors with the technique of suture bridge. METHODS: A total of 18 patients with rotator cuff tear were recruited during the period of June 2006 to June 2009. There were 7 males and 11 females with an average age of 45.2 years old (range: 34 - 65). The locations included left shoulder (n = 11) and right shoulder (n = 7). Rotator cuff tear was repaired by allogenic cortical bone anchors with the technique of suture bridge under arthroscopy. The efficacy was evaluated by University of California Los Angeles (UCLA) standard score. RESULTS: The average follow-up period was 17.6 months (range: 12 - 36). The excellent rate of treatment was 100%. All rotator cuff tears were healed. Only 2 cases had minor pain and there was no limitation of joint activity. The bone anchor fully integrated with the subject area at Month 3 post-operation. CONCLUSION: The advantages of repairing rotator cuff tear by allograft cortical bone anchors with the technique of suture bridge includes minimal trauma, a large tendon bone area, firm fixation and a low cost. It is a better approach of repairing rotator cuff tear. PMID- 22944182 TI - [Short fusion and long fusion for degenerative lumbar scoliosis with lumbar stenosis]. AB - OBJECTIVE: To explore the indications, surgical techniques and prognostic factors of short fusion versus long fusion for elder patients with degenerative lumbar scoliosis. METHODS: Thirty-eight patients undergoing different kinds of surgical procedures for lumbar spinal scoliosis between June 2005 and October 2010 were recruited for this retrospective study. The mean patient age at surgery was 64.2 years (range: 61 - 75). The short fusion group included 13 patients and the long fusion group 25 patients. RESULTS: There were a variety of treatment methods of degenerative scoliosis based on the symptomatology and radiological measurements of scoliosis and stenosis. Thirty-eight patients were followed up for an average of 37 months. The number of fused levels was 2.8 +/- 0.7 segments in the short fusion group versus 5.1 +/- 1.4 in the long fusion group. The average preoperative Cobb angle was 18.6 degrees (range: 12 - 27) in the short fusion group versus 33.5 degrees (range: 3 - 42) in the long fusion group. The correction of Cobb angle averaged 40% in the short fusion group versus 67% in the long fusion group. Clinical symptoms and functional tolerance for daily activities improved postoperatively. Radiographic evaluations showed reduced deformity on the frontal and sagittal planes. There were no infections, pseudoarthrosis, instrument-related failures or reoperations. CONCLUSIONS: Long segment fusion is superior to its short segment counterpart in correcting scoliotic curvature and coronal imbalance and improving rotational subluxation of apical vertebra. Careful perioperative preparation is essential in the treatment of elder patients with lumbar spinal scoliosis. PMID- 22944183 TI - [Effects of cochlear implantation on ipsilateral tinnitus]. AB - OBJECTIVE: Cochlear implantation is the current standard of care in patients with significant sensorineural hearing loss. The purpose of this study was to assess the effects of cochlear implantation on ipsilateral tinnitus. METHODS: With standard assessment table and standard testing program, 48 postlingual hearing impaired adults aged 18 - 62 years (mean age at implantation: 35.0) were operated at 5 clinical centers from June 2009 to March 2010. There were 23 males (47.9%) and 25 females (52.1%). We evaluated the pre- and post-implantation degrees of tinnitus, performed free sound field audiometry and scored speech perception during different periods. Secondary analyses were conducted to examine the correlation between the effects of implantation on tinnitus and hearing or speech perception rehabilitation. RESULTS: Before implantation, there were 16 cases with ipsilateral tinnitus and 32 cases without tinnitus. After implantation, among 16 cases, the outcomes were recovery (n = 6), tinnitus suppression (n = 1) and no change in symptoms (n = 9). The total effective rate was 43.8%. Among another 32 cases without preoperative tinnitus, 2 cases developed tinnitus after implantation. The effects of cochlear implantation on tinnitus were negatively correlated with the course of tinnitus. There was no more correlation with other factors. CONCLUSION: Cochlear implants have significant therapeutic effects on tinnitus in 43.8% of implant users. Better efficacies are correlated with a shorter course of tinnitus. However, tinnitus suppression using electrical stimulation via cochlear implantation for deafness needs to be further evaluated. PMID- 22944184 TI - [Outcome prediction of single-period CO(2) laser therapy for vulvar condylomata acuminate]. AB - OBJECTIVE: To evaluate the outcome of CO(2) laser treatment as primary therapy for vulvar condylomata acuminate and examine the risk factors and prediction model of single-period CO(2) laser treatment. METHODS: Between March 2009 and December 2010, a multicenter prospective study was conducted at three 3A hospitals of China (Peking Union Medical College Hospital, Zhejiang Women's Health Hospital & Tongji Hospital). All enrolled patients of vulvar condylomata acuminata received CO(2) laser vaporization as the primary therapy and had return visits at 1, 3 and 6 months individually after treatment. Therapeutic recurrence and side effects were recorded. Logistic regression was used to analyze the associations between demographic or clinical characteristics and the outcome of single-period CO(2) laser treatment and a prediction model was established subsequently. The optimal cutoff value of model was evaluated by area under the receiver operating characteristic curve (AUC ROC). RESULTS: A total of 160 patients completed a 6-month follow-up with a loss rate of 9.1% (16/176). And 131 patients (82%) were cured after the single-period CO(2) laser therapy with a total recovery rate of 94% (150/160). Side effects occurred in 50 (31%) patients with a complete self-recovery within 6 months. The most common side effects were local ulceration, pain and edema. No severe side effect was present. Large area of lesion (>8 cm(2)), vagina involved and unemployment were associated with the failure of single-period treatment while pain symptom was a protective factor of effectiveness. Age, marital status, symptom-free and vaginal involvement were not related with outcome. A prediction model was established as follows: Logit (P(0)) = -1.511+1.573X(1)+1.679X(2)+3.254X(3)-1.685X(4) (X(1)-X(4) representing area of lesion > 8 cm(2), vaginal involvement, unemployment and pain symptom respectively). The optimal cutoff value of P(0) was 0.35 with AUC ROC of 0.816 (P < 0.01). The sensitivity, specificity, positive predictive value and negative predictive value of model were 58.6%, 91.6%, 60.7% and 90.9% respectively. CONCLUSION: CO(2) laser is effective and safe therapy for vulvar condylomata acuminata. A prediction model has been proposed to predict the outcome of single period CO(2) laser therapy in initially diagnosed patients. It may guide clinical decision-making. PMID- 22944185 TI - [Surgical outcome and prognostic factors in focal cortical dysplasia with intractable epilepsy]. AB - OBJECTIVE: To analyze surgical outcome and relevant surgical parameters including resection extent of epileptogenic zone,pathological subtype, brain MRS and MRI results in FCD with intractable epilepsy. METHODS: We retrospectively analyzed surgical outcomes of 35 patients with intractable epilepsy related to focal cortical dysplasia, accepted surgery in the first affiliated hospital of Fujian Medical University from January 2008 to January 2010, with 12-36 months of postoperative follow-up. The relevance between complete resection, pathological subtype, MRS and MRI result and surgical outcome were statistically evaluated. RESULTS: 22 patients (66.7%) were Engel class I, 5 patients (14.3%) were class II, 6 patients (17.2%) were class III, 2 patients (5.8%) were class IV. Complete resection of epileptogenic zone (P < 0.05), FCD type I (P < 0.05) correlated significantly with favorable surgical outcome. Other factors such as MRI results, abnormal NAA/CHO + Cr ratio on the contralateral side of epileptogenic zone, as well as MRS-accurate lateralization did not influence outcome. CONCLUSION: Overall, the surgical outcome of FCD is favorable. Complete resection, FCD type I correlates significantly with favorable surgical outcome. PMID- 22944186 TI - [Meliorated surgical procedure of Winograd for recurrent onychocryptosis]. AB - OBJECTIVE: To explore the improvement of surgical procedure in recurrent onychocryptosis and evaluate its efficacy. METHODS: The meliorated procedure was designed based on the Winograd surgical protocol. A total of 145 cases of recurrent onychocryptosis were recruited into this retrospective study. The recurrence rate and the difference between recurrent duration and follow-up period were analyzed statistically. RESULTS: In this series, onychocryptosis was categorized into type I (n = 86), type II (n = 19) and type III (n = 40) respectively. The average follow-up period was 28.72 +/- 9.58 months. No recurrent case was found. The outcomes were significant in both statistical analysis and clinical aspects. CONCLUSION: This modified surgical procedure is effective in the treatment of recurrent onychocryptosis. PMID- 22944187 TI - [Expression of alpha(5) subunit of extrasynaptic GABA(A) receptor in insular kindled rats]. AB - OBJECTIVE: To explore the expression of alpha(5) subunit of extrasynaptic GABA(A) receptor in insular electrical kindled rats and analyze its significance. METHODS: A total of 96 male Sprague-Dawley rats were divided randomly into kindled, sham-operated and control groups (n = 32). And each group was further divided into 2 sub-groups at different time points. Kindled group: insular electrical kindled via chronic electrical stimulation; Sham-operated group: electrode implantation without electrical stimulation; CONTROL GROUP: no operation at all. The number of hippocampal neurons was detected by Nissl staining; the mRNA of alpha(5) subunit of hippocampus by quantitative-polymerase chain reaction (q-PCR); the expression of alpha(5) subunit of hippocampus by immunohistochemistry. RESULTS: No significant difference existed in the number of hippocampal neurons between epileptic and normal rats (P > 0.05). The mRNA levels of alpha(5) subunit of hippocampus in the sham-operated and control groups were much higher than that of the kindled group at Day 1 and 7 post-sacrificing (P < 0.01). And the hippocampal expressions of alpha(5) subunit were much more in the sham-operated and control groups than that of the kindled group at Day 1 and 7 post-sacrificing (P < 0.01). CONCLUSION: The hippocampal expression of alpha(5) subunit decreases markedly in insular epilepsy. And alpha(5) subunit may play an important role in the occurrence and development of insular epilepsy. PMID- 22944188 TI - [Protective effect of breviscapine on human hepatocytes under hypoxia/re oxygenation and its possible mechanism]. AB - OBJECTIVE: To explore the protective effect of breviscapine on human hepatocytes (L-02) under hypoxia/re-oxygenation (H/R) and elucidate its possible mechanism. METHODS: A in vitro model of H/R was employed to mimic H/R injury of graft organ. L-02 cells were randomly divided into 3 groups: control, H/R and breviscapine treatment (pre-treated with breviscapine and H/R). After a 10 h hypoxic culturing under 1% O(2), 94% N(2) and 5% CO(2), L-02 cells received oxygen for 1, 2, 4, 8, 16 and 24 h respectively. MICA mRNA and protein levels were detected by quantitative real-time polymerase chain reaction (PCR) and Western blot. And the activity of natural killer (NK) cell cytotoxicity for L-02 was measured by lactate dehydrogenase (LDH) release assay. After blocking I/R treatment with NKG2D antibody, the activity of NK cell cytotoxicity for L-02 was detected. RESULTS: After 10 h hypoxia, MICA mRNA and protein levels significantly increased from 1 h, stayed up-regulated until 8 h and then went back to normal level after reoxygenation versus the control group. The activity of NK cell cytotoxicity for L-02 under the treatment of H/R increased markedly from 1 h post-reoxygenation and stayed up-regulated from 1 h to 8 h versus the control group. After hypoxia, L-02 cells were blocked with NKG2D antibody and the NK cell cytotoxicity for L-02 significantly decreased versus the I/R group. The administration of breviscapine significantly lowered the mRNA and protein levels of MICA in L-02 under I/R and then significantly decreased the NK cell cytotoxicity. CONCLUSION: The process of I/R may mediate the NK cell cytotoxicity activity toward to L-02 by inducing a strong increase of MICA at mRNA and protein levels in L-02 cells. And the administration of Breviscapine significantly reduces the NK cell cytotoxicity for L-02 under I/R through the down-regulated expression of MICA. PMID- 22944189 TI - The Spanish pictogram on medicines and driving: The population's comprehension of and attitudes towards its use on medication packaging. AB - The Spanish pictogram on medicines and driving is legally binding since 2011. We have evaluated patients' comprehension, change in driving frequency and the perceived usefulness, information, comprehensibility, and simplicity of this pictogram on 1385 Spaniards users of the National Health Service (pharmacies, primary care and hospital centres). Most, 85.7%, correctly related the symbol with the possible effects of the medicine on driving and the 83.9% of the drivers would reduce the frequency with which they drive when prescribed a medicine with such pictogram. The pictogram was found, in a 10-point Likert, useful (8.3+/ 1.7), informative (7.7+/-1.9), comprehensible (7.8+/-1.9) and simple (7.8+/-1.9). The Spanish pictogram on medicines and driving is understood by the great majority of those interviewed; is well considered by the users of the National Health Service; and offers good prospects for reinforce the awareness of health care professionals and patients on the effects of medicines on driving. PMID- 22944190 TI - How to initiate lithium therapy: a systematic review of dose estimation and level prediction methods. AB - BACKGROUND: Throughout the past decades, several methods have been developed to achieve therapeutic lithium blood levels as quick and safe as possible. The present study will systematically review the methods developed and studied for lithium dose estimation or level prediction at the initiation of therapy. METHODS: A systematic computerized Medline search was performed for papers published in English, French or Dutch between 1966 and April 2012 describing or studying methods for dosing lithium or predicting the lithium level on a certain dosage. References of relevant articles were screened for additional papers. RESULTS: Of 273 unique references retrieved, 65 met the inclusion criteria. Apart from the empirical titration method, 38 predictive methods for initiating lithium were identified. These methods can be classified into two categories: the a priori predictive methods, and the test-dose predictive methods requiring the administration of a test dose of lithium prior to starting treatment. LIMITATIONS: The methodological strength was not taken into account for a study to be included in the review. CONCLUSIONS: The most important distinction between the empirical titration method and the predictive methods appears to be the shorter time the latter need to achieve the targeted lithium level. The vast majority of predictive methods, however, show inconsistent or poor results or have not been replicated since their initial description. The empirical titration method, although not extensively studied, appears to be a time-honored method that can be recommended for use in daily clinical practice. PMID- 22944191 TI - The prognostic role of perceived criticism, medication adherence and family knowledge in bipolar disorders. AB - BACKGROUND: In schizophrenia, high levels of critical comments by significant others are associated with early relapse, especially if medication adherence is sub-optimal. Levels of criticism may be influenced by family knowledge about both the disorder and its treatment. No study has explored whether this combination factors influence outcome in adults with bipolar disorders. METHODS: Medication adherence was assessed in 81 individuals with bipolar disorder of whom 75 rated perceived criticism by an identified 'significant other' as well as their own perceived sensitivity. 33 (of the 75) had a close family member who agreed to completed an assessment of their knowledge and understanding of bipolar disorders. Psychiatric admissions were then recorded prospectively over 12 months. RESULTS: Perceived criticism and medication adherence were significant predictors of admission. In the patient-family member dyads (n=33), the odds ratio (OR) for admission was 3.3 (95% confidence intervals 1.3-8.6) in individuals with low levels of medication adherence, high perceived criticism, and a family member with poor knowledge and understanding. LIMITATIONS: The small sub-sample of patient-family member dyads means those findings require replication. Sensitivity to criticism by professional caregivers may not equate to that by relatives. CONCLUSIONS: Perceived criticism may be a simple but robust clinical predictor of relapse in mood disorders. High levels of perceived criticism, poor understanding of bipolar disorder by a significant other, and sub optimal treatment adherence are risk factors for hospitalization in adults with bipolar disorders that are potentially modifiable through the use of strategic psychosocial interventions. PMID- 22944192 TI - Towards a general, population-level understanding of eco-evolutionary change. AB - Most population-level studies of eco-evolutionary dynamics assume that evolutionary change occurs in response to ecological change and vice versa. However, a growing number of papers report simultaneous ecological and evolutionary change, suggesting that the eco-evolutionary consequences of environmental change for populations can only be fully understood through the simultaneous analysis of statistics used to describe both ecological and evolutionary dynamics. Here we argue that integral projection models (IPM), and matrix approximations of them, provide a powerful approach to integrate population ecology, life history theory, and evolution. We discuss key questions in population biology that can be examined using these models, the answers to which are essential for a general, population-level understanding of eco evolutionary change. PMID- 22944194 TI - The evolutionary consequences of indirect effects. AB - Indirect effects occur when the effect of one species on another is mediated by a third species or through other links in the ecosystem. Indirect interactions are widespread in nature with effects on the properties of populations, communities, and ecosystems. Despite their far-reaching ecological relevance, the evolutionary importance of indirect effects has only recently garnered attention. Here I highlight recent research illustrating significant evolutionary consequences of indirect effects. These studies span field and laboratory studies as well as terrestrial and aquatic ecosystems. I argue that these results provide a blueprint that future research can utilize to evaluate the link between the ecological community and evolution and, thereby, improve the predictive power of evolution in a natural setting. PMID- 22944195 TI - Eif4a3 is required for accurate splicing of the Xenopus laevis ryanodine receptor pre-mRNA. AB - The Exon Junction Complex (EJC) plays a critical role in multiple posttranscriptional events, including RNA subcellular localization, nonsense mediated decay (NMD), and translation. We previously reported that knockdown of the EJC core component Eukaryotic initiation factor 4a3 (Eif4a3) results in full body paralysis of embryos of the frog, Xenopus laevis. Here, we explore the cellular and molecular mechanisms underlying this phenotype. We find that cultured muscle cells derived from Eif4a3 morphants do not contract, and fail to undergo calcium-dependent calcium release in response to electrical stimulation or treatment with caffeine. We show that ryr (ryanodine receptor) transcripts are incorrectly spliced in Eif4a3 morphants, and demonstrate that inhibition of Xenopus Ryr function similarly results in embryonic paralysis. These results suggest that the EJC mediates muscle cell function via regulation of pre-mRNA splicing during early vertebrate embryogenesis. PMID- 22944196 TI - Loss of SPINK1 expression is associated with unfavorable outcomes in urothelial carcinoma of the bladder after radical cystectomy. AB - BACKGROUND: We assessed the association of serine protease inhibitor Kazal type I (SPINK1) expression with clinicopathologic outcomes in urothelial carcinoma of the bladder (UCB) patients treated with radical cystectomy (RC). MATERIALS AND METHODS: Tissue microarrays comprising 438 consecutive UCB patients treated with RC between 1988 and 2003 and 62 cases of normal urothelium controls were evaluated for SPINK1 protein expression by immunohistochemistry (IHC). Semiquantitative evaluation was performed by 2 pathologists blinded to clinical outcomes (loss of expression: <50% cells or intensity 0-2). RESULTS: In normal urothelium, SPINK1 expression was noted in umbrella cells of 32 of 62 controls (52%); 254 RC patients (57.9%) exhibited loss of SPINK1 expression. Loss of SPINK1 expression was significantly associated with higher pathologic stages (P = 0.002) and presence of lymph node metastasis (P = 0.04). At a median follow-up of 130 months (IQR: 98.4), loss of SPINK1 expression was associated with an increased risk of disease recurrence (P = 0.02) and cancer-specific mortality (P = 0.03). On multivariable analysis that adjusted for the effects of standard clinicopathologic parameters, SPINK1 was not an independent predictor of disease recurrence (P = 0.09) or cancer-specific mortality (P = 0.12). CONCLUSIONS: Over half of UCB patients treated with RC exhibit loss of SPINK1 expression. Loss of SPINK1 correlates with features of biologically aggressive UCB. Although SPINK1 expression did not have independent prognostic value in RC patients, it may serve as a biomarker for tumor staging and may be useful as an adjunct in clinical decision-making. PMID- 22944197 TI - Changes in histone deacetylase (HDAC) expression patterns and activity of HDAC inhibitors in urothelial cancers. AB - OBJECTIVE: To determine histone deacetylase (HDAC) isoenzyme expression patterns in urothelial cancer tissues and cell lines and investigate their potential to predict the efficacy of the HDAC inhibitor vorinostat. MATERIALS AND METHODS: Expression of HDAC mRNAs was determined by quantitative RT-PCR in 18 urothelial cancer cell lines (UCC), normal uroepithelial controls (NUC), 24 urothelial cancer tissues, and 12 benign controls. Results were compared with published microarray data. Effects of pan-HDAC inhibitor vorinostat and on UCCs were determined by viability and apoptosis assays, cell cycle analysis, and measurements of p21(CIP1), thymidylate synthase (TS), and EZH2. In addition, protein expression levels of HDACs were investigated in UCCs. RESULTS: Prominent changes in UCCs were HDAC2 and/or HDAC8 up-regulation in 11 of 18 cell lines and decreased expression of HDAC4, HDAC5, and/or HDAC7 mRNA in 15 of 18 cell lines. In cancer tissues, HDAC8 was likewise significantly up-regulated (P = 0.002), whereas HDAC2 up-regulation was detected only in a subset of tumors (9/24, P = 0.085). Overexpression of HDAC2 and HDAC8 mRNA did not correspond with the protein level. Vorinostat induced G2/M arrest, an increase in the sub-G1 fraction, up-regulation of p21, and down-regulation of TS in all UCC. Effects on EZH2 and PARP cleavage as well as activation of caspase 3/7 differed between cell lines. Associations between the overall sensitivity to the pan-HDACi vorinostat and overexpression of HDAC2 and HDAC8 mRNA were not observed. CONCLUSIONS: In urothelial cancer, up-regulation of HDAC2 and HDAC8 and down-regulation of HDAC4, HDAC5, and HDAC7 mRNA are common findings. The treatment effect of the pan-HDAC inhibitor vorinostat was variable in UCCs and up-regulation of HDAC2 and HDAC8 was not predictive for treatment response. Whether selective targeting of HDAC2, HDAC8, or other HDACs deregulated in urothelial cancer (e.g., HDAC4, HDAC5, and HDAC7) result in a more consistent treatment response needs further investigation. PMID- 22944198 TI - Antioxidant and immunomodulatory activities of polysaccharides from the roots of Sanguisorba officinalis. AB - The roots of Sanguisorba officinalis are used in traditional Chinese medicine for the treatment of diseases such as inflammation and internal haemorrhage. Several scientific investigations involving extraction and pharmacological studies of terpenoids and triterpenoid glycosides from this herb have been carried out. However, little is known regarding the immunomodulatory and antioxidant properties of polysaccharides from S. officinalis. Hence the polysaccharides from this herb have been investigated here. The hot water extract of S. officinalis has been fractionated using size-exclusion chromatography to obtain four polysaccharide fractions designated as SOP-1, SOP-2, SOP-3 and SOP-4. The range of molecular masses of these fractions were from 280 Da to 2000 kDa, and their sugar compositions consisted mainly of fructose, glucose, xylose, arabinose, and rhamnose. The antioxidant activities of the crude polysaccharide fractions were evaluated in a biological assay using Saccharomyces cerevisiae, whereas the radical scavenging activity was measured using the 2,2-diphenyl-1-picrylhydrazyl (DPPH) method. Analysis of the immunomodulatory activities of these polysaccharide fractions were measured by using mouse macrophages. Most of the polysaccharide fractions have stimulated the production of nitric oxide and tumour necrosis factor-alpha (TNF-alpha), and also displayed antioxidant activities. These results suggest that the roots of S. officinalis are likely to have therapeutic value for the treatment of cancer. PMID- 22944200 TI - Partial characterization and flocculating behavior of an exopolysaccharide produced in nutrient-poor medium by a facultative oligotroph Klebsiella sp. PB12. AB - A facultative oligotrophic strain from the water sample of River Mahananda, Siliguri India was selected for its property to produce exopolysaccharide (EPS) in nutrient-poor (oligotrophic) medium. Viability assay of the strain was performed in sterile liquid LB, R2A, river water and diluted (10(-3)) LB at 30 degrees C and pH 7 to understand oligotrophy. The selected strain was identified by 16S rRNA gene sequencing and designated as Klebsiella sp. PB12. Phylogenetic analysis showed its closest relationship with Klebsiella variicola ATCC BAA 830(T). Purification of EPS was performed by ethanol precipitation, dialysis and freeze-drying. Chemical analysis revealed that purified EPS was mainly composed of 72.32% (w/w) neutral sugar and 14.12% (w/w) uronic acids. Fourier transform infrared (FT-IR) spectroscopy indicated the presence of hydroxyl, carboxylic and methoxyl functional groups. The optimal dosages for flocculation of activated carbon suspension were 17 mg/l EPS and 4 mM CaCl(2). EPS showed flocculating rate of above 80% over a wide range of pH (pH 3-10) whereas, more than 90% rate was noted in the temperature range (10-50 degrees C) tested in presence of CaCl(2). Moreover, EPS showed characteristic emulsifying activity with toluene (66.6%), n hexadecane (65%), olive oil (63.3%) and kerosene (50%). The apparent molecular weight of the EPS was ~2 * 10(5) Da. PMID- 22944199 TI - Wnt signaling in myogenesis. AB - The formation of skeletal muscle is a tightly regulated process that is critically modulated by Wnt signaling. Myogenesis is dependent on the precise and dynamic integration of multiple Wnt signals allowing self-renewal and progression of muscle precursors in the myogenic lineage. Dysregulation of Wnt signaling can lead to severe developmental defects and perturbation of muscle homeostasis. Recent work has revealed novel roles for the non-canonical planar cell polarity (PCP) and AKT/mTOR pathways in mediating the effects of Wnt on skeletal muscle. In this review, we discuss the role of Wnt signaling in myogenesis and in regulating the homeostasis of adult muscle. PMID- 22944201 TI - Process engineering studies to investigate the effect of temperature and pH on kinetic parameters of alkaline protease production. AB - An in depth process engineering study on the effect of temperature and pH on kinetic parameters of alkaline protease production by Bacillus licheniformis NCIM 2042 using starch as substrate has been reported. PMID- 22944202 TI - Escherichia coli contamination and health aspects of soil and tomatoes (Solanum lycopersicum L.) subsurface drip irrigated with on-site treated domestic wastewater. AB - Faecal contamination of soil and tomatoes irrigated by sprinkler as well as surface and subsurface drip irrigation with treated domestic wastewater were compared in 2007 and 2008 at experimental sites in Crete and Italy. Wastewater was treated by Membrane Bio Reactor (MBR) technology, gravel filtration or UV treatment before used for irrigation. Irrigation water, soil and tomato samples were collected during two cropping seasons and enumerated for the faecal indicator bacterium Escherichia coli and helminth eggs. The study found elevated levels of E. coli in irrigation water (mean: Italy 1753 cell forming unit (cfu) per 100 ml and Crete 488 cfu per 100 ml) and low concentrations of E. coli in soil (mean: Italy 95 cfu g(-1) and Crete 33 cfu g(-1)). Only two out of 84 tomato samples in Crete contained E. coli (mean: 2700 cfu g(-1)) while tomatoes from Italy were free of E. coli. No helminth eggs were found in the irrigation water or on the tomatoes from Crete. Two tomato samples out of 36 from Italy were contaminated by helminth eggs (mean: 0.18 eggs g(-1)) and had been irrigated with treated wastewater and tap water, respectively. Pulsed Field Gel Electrophoresis DNA fingerprints of E. coli collected during 2008 showed no identical pattern between water and soil isolates which indicates contribution from other environmental sources with E. coli, e.g. wildlife. A quantitative microbial risk assessment (QMRA) model with Monte Carlo simulations adopted by the World Health Organization (WHO) found the use of tap water and treated wastewater to be associated with risks that exceed permissible limits as proposed by the WHO (1.0 * 10(-3) disease risk per person per year) for the accidental ingestion of irrigated soil by farmers (Crete: 0.67 pppy and Italy: 1.0 pppy). The QMRA found that the consumption of tomatoes in Italy was deemed to be safe while permissible limits were exceeded in Crete (1.0 pppy). Overall the quality of tomatoes was safe for human consumption since the disease risk found on Crete was based on only two contaminated tomato samples. It is a fundamental limitation of the WHO QMRA model that it is not based on actual pathogen numbers, but rather on numbers of E. coli converted to estimated pathogen numbers, since it is widely accepted that there is poor correlation between E. coli and viral and parasite pathogens. Our findings also stress the importance of the external environment, typically wildlife, as sources of faecal contamination. PMID- 22944203 TI - Characterization of natural organic matter treated by iron oxide nanoparticle incorporated ceramic membrane-ozonation process. AB - In this study, changes in the physical and structural properties of natural organic matter (NOM) were observed during hybrid ceramic membrane processes that combined ozonation with ultrafiltration ceramic membrane (CM) or with a reactive ceramic membrane (RM), namely, an iron oxide nanoparticles (IONs) incorporated CM. NOM from feed water and NOM from permeate treated with hybrid ceramic membrane processes were analyzed by employing several NOM characterization techniques. Specific ultraviolet absorbance (SUVA), high-performance size exclusion chromatography (HPSEC) and fractionation analyses showed that the hybrid ceramic membrane process effectively removed and transformed relatively high contents of aromatic, high molecular weight and hydrophobic NOM fractions. Fourier transform infrared spectroscopy (FTIR) and 3-dimensional excitation emission matrix (EEM) fluorescence spectroscopy revealed that this process caused a significant decrease of the aromaticity of humic-like structures and an increase in electron withdrawing groups. The highest removal efficiency (46%) of hydroxyl radical probe compound (i.e., para-Chlorobenzoic acid (pCBA)) in RM ozonation process compared with that in CM without ozonation process (8%) revealed the hydroxyl radical formation by the surface-catalyzed reaction between ozone and IONs on the surface of RM. In addition, experimental results on flux decline showed that fouling of RM-ozonation process (15%) was reduced compared with that of CM without ozonation process (30%). These results indicated that the RM-ozonation process enhanced the destruction of NOM and reduced the fouling by generating hydroxyl radicals from the catalytic ozonation in the RM-ozonation process. PMID- 22944205 TI - Efficient expression and purification of tag-free Epstein-Barr virus EBNA1 protein in Escherichia coli by auto-induction. AB - Epstein-Barr nuclear antigen 1 (EBNA1) is the essential Epstein-Barr virus (EBV) protein at the interface between the EBV genome and the host chromatin. It is EBNA1's task to guarantee replication and segregation of the multicopy closed circular viral genome in infected cells. While EBNA1's functions are relatively well understood, little is known about the molecular mechanisms of EBNA1 mediating chromatin tethering and DNA replication. To characterize those, purified EBNA1 would be a very useful tool in many different biochemical assays. For long, it was not possible to overexpress sufficient quantities of EBNA1 in Escherichia coli (E. coli) due to its rare codon usage, especially in the N terminal part of the protein. Recently, some groups succeeded in purifying EBNA1 from bacteria using advanced inducible E. coli cells [1-3]. However, all purification procedures ended in a His-tagged version of EBNA1, which might influence EBNA1's function in biological assays. Therefore, we inserted a tobacco etch virus (TEV)-cleavage site between the N-terminal His-tag and the following open reading frame of EBNA1. Using sequential Ni-NTA and gel filtration columns and TEV protease-mediated cleavage upon autoinduction, we were able to purify functional EBNA1 protein featuring just a single additional, artificial N terminal glycine residue. Following our simple and fast purification scheme we were able to synthesize 2mg of highly pure EBNA1 protein per liter culture. PMID- 22944204 TI - Cloning, expression, and purification of a recombinant Tat-HA-NR2B9c peptide. AB - To design a peptide disrupting the interaction between N-methyl-d-aspartate receptors-2B (NR2B) and postsynaptic density protein-95 (PSD-95), a gene fragment encoding a chimeric peptide was constructed using polymerase chain reaction and ligated into a novel expression vector for recombinant expression in a T7 RNA polymerase-based expression system. The chimeric peptide contained a fragment of the cell membrane transduction domain of the human immunodeficiency virus type1 (HIV-1) Tat, a influenza virus hemagglutinin (HA) epitope-tag, and the C-terminal 9 amino acids of NR2B (NR2B9c). We named the chimeric peptide Tat-HA-NR2B9c. The expression plasmid contained a gene fragment encoding the Tat-HA-NR2B9c was ligated to the C-terminal fragment of l-asparaginase (AnsB-C) via a unique acid labile Asp-Pro linker. The recombinant fusion protein was expressed in inclusion body in Escherichia coli under isopropyl beta-d-1-thiogalactopyranoside (IPTG) and purified by washing with 2M urea, solubilizing in 4M urea, and then ethanol precipitation. The target chimeric peptide Tat-HA-NR2B9c was released from the fusion partner following acid hydrolysis and purified by isoelectric point precipitation and ultrafiltration. SDS-PAGE analysis and MALDI-TOF-MS analysis showed that the purified Tat-HA-NR2B9c was highly homogeneous. Furthermore, we investigated the effects of Tat-HA-NR2B9c on ischemia-induced cerebral injury in the rats subjected to middle cerebral artery occlusion (MCAO) and reperfusion, and found that the peptide reduced infarct size and improved neurological functions. PMID- 22944206 TI - The cytosolic and extracellular proteomes of Actinoplanes sp. SE50/110 led to the identification of gene products involved in acarbose metabolism. AB - The pseudotetrasaccharide acarbose is a medically relevant secondary metabolite produced by strains of the genera Actinoplanes and Streptomyces. In this study gene products involved in acarbose metabolism were identified by analyzing the cytosolic and extracellular proteome of Actinoplanes sp. SE50/110 cultures grown in a high-maltose minimal medium. The analysis by 2D protein gel electrophoresis of cytosolic proteins of Actinoplanes sp. SE50/110 resulted in 318 protein spots and 162 identified proteins. Nine of those were acarbose cluster proteins (Acb proteins), namely AcbB, AcbD, AcbE, AcbK, AcbL, AcbN, AcbR, AcbV and AcbZ. The analysis of proteins in the extracellular space of Actinoplanes sp. SE50/110 cultures resulted in about 100 protein spots and 22 identified proteins. The identifications included the three acarbose gene cluster proteins AcbD, AcbE and AcbZ. After their identification, proteins were classified into functional groups. The dominant functional groups were the carbohydrate binding, carbohydrate cleavage and carbohydrate transport proteins. The other functional groups included protein cleavage, amino acid degradation, nucleic acid cleavage and a number of functionally uncharacterized proteins. In addition, signal peptide structures of extracellularly found proteins were analyzed. Of the 22 detected proteins 19 contained signal peptides, while 2 had N-terminal transmembrane helices explaining their localization. The only protein having neither of them was enolase. Under the conditions applied, the secretome of Actinoplanes sp. SE50/110 was dominated by seven proteins involved in carbohydrate metabolism (PulA, AcbE, AcbD, MalE, AglE, CbpA and Cgt). Of special interest were the identified extracellular pullulanase PulA and the two solute binding proteins MalE and AglE. The identifications suggest that Actinoplanes sp. SE50/110 has two maltose/maltodextrin import systems. We postulate the identified MalEFG transport system of Actinoplanes sp. SE50/100 as the missing acarbose metabolite importer and present a model of acarbose metabolism that is extended by the newly identified gene products. PMID- 22944208 TI - Evidence-based practice: for better or worse. PMID- 22944207 TI - Thermorecovery of cyanobacterial fatty acids at elevated temperatures. AB - We have developed a genetic system we call "thermorecovery" that allows us to lyse cyanobacterial cultures and hydrolyze membrane lipids to release free fatty acids (FFAs), a biofuel precursor. The system uses thermostable lipases encoded by genes from thermophilic organisms that have been transferred into the cyanobacterial genome and can be synthesized by turning off CO(2) availability and subsequently activated by increasing the concentrated culture temperature. When synthesized in FFA-producing strains, the lipase Fnl from Fervidobacterium nodosum Rt17-B1 released the most FFA. Of the seven candidate lipases investigated, Fnl-synthesizing strains yielded 42.7+/-1.5 mg/l FFA at 47 degrees C. We also determined that the optimal production conditions for SD338, the Synechocystis strain synthesizing Fnl, was to keep the cell concentrates at 46 degrees C for two days after a one-day CO(2) limitation pretreatment of the culture. A 4-l continuous semi-batch production experiment with SD338 showed that daily harvested cultures (1l) released an average of 43.9+/-6.6 mg fatty acid and this productivity lasted for at least 20 days without significant decline. This improved thermorecovery process can be used in conjunction with other means to genetically engineer cyanobacteria to produce biofuels or biofuel precursors as the final step in recovery of membrane lipids. PMID- 22944209 TI - Evidence for diazinon-mediated inhibition of cis-permethrin metabolism and its effects on reproductive toxicity in adult male mice. AB - The potential toxicity resulting from combinatorial effects of organophosphorus and pyrethroid insecticides are not completely known. We evaluated male reproductive toxicity in mice co-exposed to diazinon and cis-permethrin. Nine week-old male Sv/129 mice were exposed to diazinon (10 MUmol/kg/day) or cis permethrin (90 MUmol/kg/day) alone or in combination (100 MUmol/kg/day), or vehicle (corn oil), for 6 weeks. Diazinon and the diazinon-permethrin mixture inhibited plasma and liver carboxylesterase activities. In the mixture group, urinary excretion of cis-permethrin metabolite 3-phenoxybenzoic acid decreased along with increased plasma and testicular concentrations of cis-permethrin, while excretion of diazinon metabolites, diethylphosphate and diethylthiophosphate, did not change, versus mice exposed to each chemical alone, which suggested that inhibition of carboxylesterase decreased the metabolic capacity to cis-permethrin. Though the co-exposure decreased testosterone biosynthesis, increased degenerate germ cells in seminiferous tubule and sperm morphological abnormalities versus controls more clearly than exposure to cis permethrin alone, the expected potentiation of toxicity was not evident. PMID- 22944210 TI - De-novo mutations and genetic variation in the SCN1A gene in Malaysian patients with generalized epilepsy with febrile seizures plus (GEFS+). AB - Generalized epilepsy with febrile seizures plus (GEFS+) comprises a group of clinically and genetically heterogeneous epilepsy syndrome. Here, we provide the first report of clinical presentation and mutational analysis of SCN1A gene in 36 Malaysian GEFS+ patients. Mutational analysis of SCN1A gene revealed twenty seven sequence variants (missense mutation and silent polymorphism also intronic polymorphism), as well as 2 novel de-novo mutations were found in our patients at coding regions, c.5197A>G (N1733D) and c.4748A>G (H1583R). Our findings provide potential genetic insights into the pathogenesis of GEFS+ in Malaysian populations concerning the SCN1A gene mutations. PMID- 22944211 TI - [Prognosis of the hematologic patients admitted to an Intensive Care Unit]. PMID- 22944212 TI - Evaluation of a novel training package among frontline maternal, newborn, and child health workers in South Sudan. AB - OBJECTIVE: To develop, implement, and evaluate an evidence-based Maternal, Newborn, and Child Survival (MNCS) package for frontline health workers (FHWs) in South Sudan. METHODS: A multimodal needs assessment was conducted to develop a best-evidence package comprised of targeted training, pictorial checklists, and reusable equipment and commodities. Implementation utilized a training-of trainers model. Program effectiveness was assessed through knowledge assessments, objective structured clinical examinations (OSCEs), focus groups, and questionnaires. RESULTS: A total of 72 trainers and 708 FHWs were trained in 7 South Sudan states. Trainer knowledge assessments improved significantly: from 62.7% to 92.0% (P<0.001). Mean FHW scores on maternal OSCEs were 21.1% pre training, 83.4% post-training, and 61.5% 2-3 months after training (P<0.001). Corresponding mean newborn OSCE scores were 41.6%, 89.8%, and 45.7% (P<0.001). Questionnaires revealed high levels of use, satisfaction, and confidence. FHWs reported an average of 3.0 referrals (range, 0-20) to healthcare facilities during the 2-3 months following training, and 78.3% of FHWs were more likely to refer patients. Seven focus groups showed high satisfaction with trainings, commodities, and checklists, with few barriers. CONCLUSION: The MNCS package has led to improved FHW knowledge, skills, and referral. A novel package of training, checklists, and equipment can be successfully implemented in resource-limited settings and enhance links between community-based providers and healthcare facilities. PMID- 22944213 TI - Contraceptive counseling in Turkey after induced abortion. AB - OBJECTIVE: To determine the effectiveness of post-abortion contraceptive counseling to women with unwanted pregnancy and to investigate use of modern contraceptive methods among Turkish women. METHODS: A prospective case-control study was conducted at 3 Turkish centers between March 23, 2008, and January 10, 2011. A total of 333 women enrolled in the study were divided into 2 groups. Women in group 1 (n=140) presented with unwanted pregnancy requiring induced abortion whereas women in group 2 (n=193) had requested contraception counseling. RESULTS: The use of coitus interruptus or condoms was significantly more frequent in group 1 than in group 2 (P<0.001). No statistically significant differences were detected between the 2 groups in their use of oral contraceptives, intrauterine devices, injection methods, calendar methods, and other methods. The education level attained by women in group 1 was lower than that of women in group 2 (P=0.041). CONCLUSION: Increased effort is required to ensure that sufficient education about family planning is provided to Turkish women for the prevention of unwanted pregnancies and induced abortions. PMID- 22944214 TI - Correlation of first-trimester fetal crown-rump length with outcome of pregnancy and birth weight. AB - OBJECTIVE: To examine the association of crown-rump length (CRL) in the first trimester with low birth weight and adverse pregnancy outcome. METHODS: In a prospective cross-sectional study, CRL was measured in 876 healthy pregnant women undergoing ultrasound evaluation between 9 and 14 weeks of gestation. Birth weight and pregnancy outcomes were analyzed for the 544 participants who met the study criteria. RESULTS: Low (<2500 g) and high (>4000 g) birth weights were correlated with the difference between actual and expected CRL expressed in days of gestation, but no correlation was found between the difference between actual and expected CRL and premature delivery. Low birth weight (P=0.005) and abortion (P=0.03) were also correlated with the difference between actual and expected CRL. CONCLUSION: Routinely measuring CRL during the first trimester to detect CRLs shorter than expected for gestational age could be useful to obstetricians. Anticipating a low birth weight and being warned about the possibility of abortion would enable them to manage prenatal care and delivery more appropriately. PMID- 22944215 TI - State obligations to implement African abortion laws: employing human rights in a changing legal landscape. AB - Women in the African region are overburdened with unsafe abortion. Abortion regimes that fail to translate any given abortion rights into tangible access are partly to blame. Historically, African abortion laws have been highly restrictive. However, the post-independence era has witnessed a change toward liberalizing abortion law, even if incremental for many jurisdictions. Furthermore, Article 14 of the Protocol to the African Charter on Human and Peoples' Rights on the Rights of Women in Africa has significantly augmented the regional trend toward liberalization by recognizing abortion as a human right in given circumstances. However, states are failing to implement abortion laws. The jurisprudence that is emerging from the European Court of Human Rights and United Nations treaty bodies is a tool that can be used to render African governments accountable for failure to implement domestic abortion laws. PMID- 22944216 TI - Expert stakeholder attitudes and support for alternative water sources in a groundwater depleted region. AB - The main objectives of this research were to quantify the risks/benefits and impacts of alternative water sources (AWSs) as perceived by expert stakeholders and to evaluate the overall support for multiple AWSs by expert stakeholders. The St. Johns River (SJR) basin, FL, USA was chosen as a case study for AWSs because it is a fresh groundwater depleted region and there are ongoing activities related to water supply planning. Expert stakeholders included federal, state, and local governments, public utilities, consulting engineering and industry, and environmental and social non-governmental organizations. AWSs under consideration in the SJR basin include surface water, desalination, water reclamation, and water conservation. A two-phase research approach was followed that focused on expert stakeholders. First, an elicitation study was used to identify salient beliefs about AWSs. Open-ended questions were asked about the risks/benefits of AWSs in terms of the three pillars of sustainability: ecological, economic, and human health impacts. Second, an online survey was constructed using beliefs identified during the elicitation study. The online survey was used to quantify attitudes toward and overall support for AWSs. The salient beliefs of expert stakeholders were dominated by the ecological pillar of sustainability. The support of expert stakeholders for AWSs, from least favorable to most favorable, was surface water withdrawals 2 folds whereas miR-193a-5p was down-regulated. In particular, the level of miR-155 increased by 5.78 folds in AF patients versus healthy controls (9.42 +/- 4.74 vs 1.63 +/- 0.65). Furthermore, computational prediction identified CACNA1C encoding Cav1.2 as a direct target of miR-155. In the meantime, the construction of reporter plasmids and reporter assays showed that miR-155 repressed the Luciferase activity of 3' untranslated regions of CACNA1C. CONCLUSION: In LAA sample of nonvalvular AF, there is an expression of AF-related miRNAs including miR-155. And it reveals a potential link between the regulation of Cav1.2 and miR-155 in electric remodeling of AF. PMID- 22944231 TI - [Characteristics of real-life glucose profiles monitored by continuous glucose monitoring system in persons with normal glucose tolerance]. AB - OBJECTIVE: To decipher the characteristics of real-life glucose profiles in normal glucose tolerance (NGT) persons by continuous glucose monitoring system (CGMS). METHODS: Forty NGT subjects confirmed by oral glucose tolerance test (OGTT) completed a 3-day period of glucose monitoring via CGMS. RESULTS: The values of 24 h mean blood glucose (MBG), standard deviation of MBG (SDBG), mean amplitude of glycemic excursions (MAGE), largest amplitude of glycemic excursions (LAGE) and means of daily differences (MODD) were 6.0 +/- 0.7, 0.9 +/- 0.1, 1.9 +/- 0.8, 2.9 +/- 1.4 and 1.1 +/- 0.1 mmol/L respectively. Two of them experienced asymptomatic hypoglycemia defined as glucose concentration < 2.8 mmol/L. And 72.5% (29/40) subjects reached glucose concentrations > 7.8 mmol/L for 5.2 +/- 4.6 hours. In addition to higher glucose concentration (FPG: 5.0 +/- 0.4 vs 4.8 +/- 0.3 mmol/L, MBG: 6.4 +/- 0.7 vs 5.7 +/- 0.5 mmol/L), the subjects with glucose concentrations > 7.8 mmol/L showed more dramatic glucose excursion represented by higher SDBG (1.1 +/- 0.3 vs 0.6 +/- 0.2 mmol/L), MAGE (2.3 +/- 1.1 vs 1.1 +/- 0.3 mmol/L), LAGE (3.3 +/- 1.2 vs 2.0 +/- 1.0 mmol/L) and MODD (1.2 +/ 0.4 vs 0.9 +/- 0.3 mmol/L) versus those with glucose concentrations within 7.8 mmol/L. CONCLUSION: CGMS provides more detailed information of real-life glucose profiles in NGT subjects. And 72.5% NGT subjects in the present study spent a considerable amount of time at pre-diabetic or even diabetic glucose levels characterized by more predominant glucose excursion. PMID- 22944232 TI - [Differences of urodynamic tests between patients of detrusor hyperactivity with impaired contractility with and without bladder outlet obstruction and effect of anticholinergic medications in these patients]. AB - OBJECTIVE: To explore the differences of urodynamic parameters and lower urinary symptoms between detrusor hyperactivity with impaired contractility (DHIC) patients and DHIC patients with bladder outlet obstruction (BOO) and evaluate the effects and risks of anticholinergic medications in these patients. METHODS: A retrospective analysis was performed in 56 DHIC patients at our hospital between February 2000 to February 2011. Among them, 19 patients were complicated with BOO. Urodynamic studies were conducted and lower urinary symptoms assessed in all patients. Then the urodynamic parameters and lower urinary symptoms scores were compared between the DHIC and DHIC plus BOO patients. Among them, 27 received anticholinergic medications and there were 11 BOO patients. After 2-month anticholinergic medications, the differences of lower urinary symptom score were analyzed and anticholinergic-induced retention was also investigated. RESULTS: As compared with the DHIC patients, the DHIC plus BOO patients had a higher post voiding residual urine (70 (23 - 106) vs 20 (10 - 81) ml, P = 0.02), higher total international prognostic scoring system (IPSS) score (25.6 +/- 3.9 vs 22.1 +/- 4.1, P = 0.00) and higher total voiding symptom score (15.3 +/- 2.9 vs 11.8 +/- 3.3, P = 0.00). After 2-month anticholinergic medications, the IPSS score of DHIC plus BOO patients decreased from 25.7 +/- 4.6 to 23.6 +/- 4.9 (P = 0.01), 2/11 patients developed urinary retention. The IPSS scores of DHIC patients decreased from 22.8 +/- 4.7 to 21.4 +/- 4.6 (P = 0.01) and none had urinary retention. CONCLUSIONS: The DHIC plus BOO patients have more aggravated bladder empting and more severe lower urinary symptoms especially during voiding phase. Anticholinergic medications may alleviate the lower urinary symptoms in DHIC and DHIC plus BOO patients. But anticholinergic-induced retention is common among the DHIC plus BOO patients. PMID- 22944233 TI - [Initial exploration of epididymal sperm nuclear maturity in obstructive azoospermia patients]. AB - OBJECTIVE: To ascertain the epididymal sperm nuclear maturity in obstructive azoospermia (OA) patients. METHODS: A total of 81 infertile males from andriatry clinic of Renji hospital were selected, including 32 OA patients (OA group) and 49 asthenospermia patients (asthenospermia group). Another 32 fertile males were recruited for the control group. All semen samples of the asthenospermia and control groups underwent computer aided semen analysis (CASA). For the OA group, sperm specimens were collected by percutaneous epididymal sperm aspiration (PESA) and semen analyses completed by manual method. Further acridine orange test and aniline blue stain assay were performed. The results were processed with SPSS 15.0. RESULTS: No statistically significant differences existed in semen volume and sperm density between the asthenospermia and control groups (both P > 0.05). The OA group was significantly lower than the control group in sperm density (P < 0.01). The asthenospermia and OA groups were also significantly lower than the control group in sperm motility (both P < 0.01). As to the percentage of grade a + b sperm, the asthenospermia group was also significantly lower than the control group (P < 0.01). Compared with the control group (81% +/- 9%, 85% +/- 8%), the negative rate of acridine orange test and aniline blue assay of OA (57% +/- 20%, 64% +/- 20%) and asthenospermia group (62% +/- 19%, 67% +/- 15%) were statistically lower (all P < 0.05). CONCLUSIONS: The sperm nuclear maturity is lower in the asthenospermia and OA groups than that in the control group. Male fertility should be further improved. PMID- 22944234 TI - [Analysis of potential risk factors for early postoperative pulmonary infection after pediatric living donor liver transplantation]. AB - OBJECTIVE: To analyze the potential risk factors of early (<= 30 days) postoperative pulmonary infection after pediatric living donor liver transplantation (LDLT) and explore the feasible preventive and therapeutic measures. METHODS: Without preoperative respiratory disease, the clinical data of 36 cases undergoing LDLT at Children's Hospital of Chongqing Medical University between June 2006 and December 2009 were analyzed retrospectively so as to evaluate the incidence, prognosis and risk factors of early postoperative pulmonary infection. Univariate analysis was performed to determine the relative risk factors for postoperative pneumonia. And significant factors (P < 0.05) were then used for multivariate Logistic regression analysis. RESULTS: Twenty-four recipients suffered from early postoperative pulmonary infection at an incidence of 67% (24/36). The mortality rate in the pediatric patients who developed pulmonary infection was 17% (4/24). In univariate analysis, age <= 1 year, high Child-Pugh scores, hemoglobin < 90 g/L, congenital heart disease, mechanical ventilation > 12 hours, intraoperative transfusion > 150 ml/kg and indwelling gastric tube > 3 days were of statistical significance (all P < 0.05). Multivariate Logistic regression analysis showed age <= 1 year, intraoperative transfusion > 150 ml/kg and indwelling gastric tube > 3 days were independent risk factors for post-LDLT pneumonia (all P < 0.05). CONCLUSIONS: Pulmonary infection is an important factor of decreasing the survival rate during the early postoperative stage. To reduce the incidence of postoperative pulmonary infection and guarantee a successful transplantation, should improve the preoperative physical condition, restrict intraoperative fluid infusion with stable hemodynamics and strengthen gastric tube management. PMID- 22944235 TI - [Risk factors of Clostridium difficile-associated diarrhea in children]. AB - OBJECTIVE: To explore the risk factors of Clostridium difficile-associated diarrhea (CDAD) in children. METHODS: From December 2010 to March 2011, the hospitalized diarrheal patients under 18 years old at Beijing Children's Hospital were tested for Clostridium difficile. The CDAD(+) patients were selected and their fecal specimens were PCR-positive for tcdA and (or) tcdB genes. And the patients with healthcare facility-associated-CDAD (HCFA-CDAD) were selected from the group of CDAD(+). The CDAD patients were selected and their fecal specimens were PCR-negative for tcdA and (or) tcdB genes. And the 1:3 matched controls per case were selected from those hospitalized patients without diarrhea at the same department with similar diseases during the same period. The potential predictors of CDAD included age, gender, co-morbidities, prior hospitalization, the administration of C. difficile-active antibiotics during prior 24 hours, recent (< 1 month) exposure to antibiotics or acid-blocking medications or nonsteroidal anti-inflammatory drug (NSAID), C-reactive protein (CRP) and white blood cell (WBC), etc. Multivariate Logistic regression models were created to identify the independent predictors of CDAD. RESULTS: Among 93 PCR tests, 35 were positive in fecal samples. There were HCFA-CDAD (n = 30) and CDAD(-) (n = 58). Thirty-five CDAD(+) hospitalized patients were compared with 105 controls. According to multivariate analyses, the predictors of CDAD included prior hospitalization (P < 0.01, OR = 0.002), CRP(P = 0.008, OR = 3.465), NSAID (P = 0.015, OR = 13.950) and WBC (P = 0.003, OR = 8.063). CONCLUSION: The administration of NSAID, elevated CRP and abnormal WBC are significantly associated with CDAD. PMID- 22944236 TI - [Necessity of routine nasogastric decompression after gastrectomy for gastric cancer: a meta-analysis]. AB - OBJECTIVE: To evaluate the necessity of routine nasogastric decompression after radical gastrectomy for gastric cancer with systematic review and Meta-analysis. METHODS: The literature databases prior to September 2011 were extensively searched to retrieve the randomized controlled trials (RCT) with a relevance of study goal. The inclusion and exclusion criteria were formulated. After quality evaluation, the data were extracted. The Cochrane collaboration RevMan 5.1 version software was used for Meta-analysis. RESULTS: Seven RCT studies fulfilled the inclusion criteria for Meta-analysis. The total sample size of these studies was 871 cases. Those without a nasogastric tube routinely inserted experienced a marginal earlier time to flatus [weighted mean difference (WMD) = 0.10 days, 95% confidence interval (CI) 0.00 - 0.30, P = 0.05], a significant earlier time to oral diet [WMD = 0.43 days, 95%CI 0.25 - 0.61, P < 0.01], a significant shorter hospital stay [WMD = 0.60 days, 95%CI 0.15 - 1.18, P = 0.01) and a marginal decrease in pulmonary complications [relative risk (RR) = 1.30, 95%CI 1.00 - 1.68, P = 0.05)]. The postoperative rates of anastomotic leakage, morbidity and mortality were similar between two groups. CONCLUSION: Except for severe vomiting or abdominal distension, nasogastric tubes should not be used routinely in gastric cancer patients undergoing radical surgery. PMID- 22944237 TI - [Effects of breast cancer cells stably overexpressing RSK4 on growth of transplanted human breast cancer in severe combined immunodeficiency mice]. AB - OBJECTIVE: To construct a breast cancer cell line MD-MB-231 stably overexpressing RSK4 gene and study its in vivo effects on tumor tumorigenesis. METHODS: The MD MB-231 cells were transfected with pcDNA3.1/Neo and pcDNA3.1/Neo-RSK4 by lipofectamin transfection respectively. The stable expression of RSK4 (MR11 and MR12) and control vector (MN10 and MN11) were inoculated into severe combined immunodeficiency (SCID) mice subcutis to establish a model of human breast cancer in SCID mice. The xenograft tumor growth, invasion and metastasis were observed after 6 - 10 weeks. RESULTS: The stable cell lines MR11, MR12 and MN10, MN11 were screened successfully. We constructed the human breast cancer transplanted model and dissected SCID mice. After 6 weeks, SCID mice subcutis of the MN10/MN11 group yielded 10/10 metastatic tumors versus 6/10 and 7/10 in the MR11/MR12 group respectively. MR11 and MR12 showed much smaller tumor sizes and significantly reduced tumor volume and weight versus MN10 and MN11 (P < 0.001). In the control group, visceral metastasis developed in 80% (8/10) of mice while in metastasis developed in 40% (4/10) of mice injected with RSK4-overexpressing MDA-MB-231 cells. Histological examination of hematoxylin and eosin-stained paraffin sections of lungs revealed numerous metastases in mice injected with vector control cells whereas RSK4-overexpressing cells showed markedly decreased metastatic lesions. CONCLUSION: Transplanted human breast cancer in SCID mice closely correlates with the disease course of clinical tumor patients. Overexpression of RSK4 can inhibit tumor growth of transplanted human breast cancer in SCID mice. PMID- 22944238 TI - [Effects and mechanisms of combined suppression of epidermal growth factor receptor and hedgehog signaling on proliferation in pancreatic cancer cells]. AB - OBJECTIVE: To explore the synergistic effects on proliferation and apoptosis by targeted suppression of epidermal growth factor receptor (EGFR) in combination with blockade of Hedgehog signaling pathways in pancreatic cancer cells and examine the synergistic mechanism of Hedgehog and EGFR signaling pathways. METHODS: The sequences of RNA interference targeting EGFR gene were designed, synthesized and cloned into the pFU-GW-RNAi vector. And a stable transfection cell line was obtained by transfecting the human Panc-1 cells with lentivirus. The expressions of Shh and Gli1 were tested by real-time polymerase chain reaction (PCR). The antiproliferative effect was examined by the assays of colony formation and methyl thiazolyl tetrazolium (MTT). Fluorescence activated cell sorter (FACS) was applied to assay the apoptotic rate in all experimental groups. Western blot was applied to detect the phosphorylation levels of ERK and AKT.In vivo nude mice tumorigenicity model was used to test the effect of growth inhibition. RESULTS: The RNAi technology with lentivirus could restrain the expression of EGFR gene. After the blocking of EGFR and Hedgehog signaling pathways by RNAi silencing, the chemosensitivity to cyclopamine significantly increased in human pancreatic cancer cells. The half-inhibitory concentration (IC 50) of cyclopamine declined from (2.978 +/- 0.336) to (1.698 +/- 0.057) umol/L (P < 0.05). The prophase apoptotic rate of co-treated group was as high as 38.75% and it was significantly higher than the RNAi silencing EGFR (17.65%) and control groups (3.02%) (P < 0.05). The results of tumor xenografts assay showed that the tumor volume of co-treated group (394.8 +/- 87.5 mm(3)) was significantly lower than that of simple EGFR RNAi (594.7 +/- 86.1 mm(3)) and single cyclopamine treated group (771.3 +/- 82.9 mm(3)); the combination treatment could also produce obviously synergistic antiproliferative effect in colony formation assays. After RNAi silencing EGFR, the phosphorylation levels of ERK and AKT decreased significantly versus the control group. Further reduction was obtained with the combined use of cyclopamine in the co-treated group. CONCLUSION: The blocking of EGFR and Hedgehog signaling pathways by RNAi silencing may further inhibit cell proliferation and increase apoptosis in vivo and in vitro in human pancreatic cancer cells. The synergism of Hh and EGFR signaling pathways may be correlated with the phosphorylation levels of ERK and AKT. PMID- 22944239 TI - [Effects of atorvastatin and CoQ(10) on myocardial energy metabolism in rabbits with hypercholesterolemia]. AB - OBJECTIVE: To explore the interventional effects of atorvastatin and CoQ(10) on myocardial energy metabolism in rabbits with hypercholesterolemia. METHODS: Forty male New Zealand white rabbits were randomly divided into 5 groups: i.e. normal control, high cholesterol, statin, coenzyme Q(10) 1 and coenzyme Q(10) 2. After feeding for 6 weeks, the fasting blood samples were collected through ear marginal vein and the serum level of total cholesterol was determined. Myocardium was sampled for ultrastructures by electron microscopy; high-performance liquid chromatography (HPLC) was used to measure myocardial mitochondria adenosine triphosphate (ATP) and coenzyme CoQ(10). Ultraviolet spectrophotometry was used to measure the activities of mitochondrial complexes II and IV. RESULTS: In high cholesterol group, myocardial fibers were arrayed disorderly with partial rupture and dissolution. There was mitochondrial swelling with disorderly and fuzzy cristae. As compared with the controls, the activities of mitochondrial respiratory chain complexes II and IV declined (5.39 +/- 0.53 vs 12.95 +/- 0.99, 1.89 +/- 0.26 vs 6.65 +/- 0.95, P < 0.01), the contents of mitochondrial ATP and CoQ(10) decreased (0.17 +/- 0.05 vs 0.44 +/- 0.06, 0.09 +/- 0.02 vs 0.25 +/- 0.04, P < 0.01); for statin group versus high cholesterol group, the activities of mitochondrial respiratory chain complexes II and IV increased (9.12 +/- 1.19 vs 5.39 +/- 0.53, 4.61 +/- 0.52 vs 1.89 +/- 0.26, P < 0.01); the content differences of mitochondrial ATP and CoQ(10) were statistically insignificant. For CoQ(10) 1 group versus statin group, the differences of respiratory chain complexes II and IV were statistically insignificant; the contents of mitochondria ATP and CoQ(10) increased (0.35 +/- 0.03 vs 0.16 +/- 0.04, 0.17 +/- 0.02 vs 0.07 +/- 0.02, P < 0.01). For coenzyme Q(10) 2 group versus coenzyme Q(10) 1 group, none of the indices was statistically significant. CONCLUSION: High cholesterol can cause myocardial ultrastructural changes and impaired mitochondrial energy metabolism. Atorvastatin reduces the myocardial structural damage and the combination of atorvastatin and CoQ(10) may further improve the myocardial mitochondrial energy metabolism. PMID- 22944240 TI - [Establishment and evaluation of acute pulmonary thromboembolism model in minipig]. AB - OBJECTIVE: To establish and evaluate an acute pulmonary embolism (APTE) model by selective thromboembolism of lower left pulmonary artery in minipig. METHODS: Through intervention technique, a guiding catheter was inserted via femoral vein into pulmonary artery. And quantitative autologous venous thrombus was injected into the selected lower left pulmonary arteries in 8 minipigs. Thus the intended APTE model was established by selective thromboembolism of lower left pulmonary artery. Hemodynamic parameters were monitored. And computed tomography (CT) and macroscopic dissection were performed to evaluate the minipig APTE model. RESULTS: The measurements of mean pulmonary artery pressure (MPAP, mm Hg, 1 mm Hg = 0.133 kPa) and pulmonary capillary wedge pressure (PCWP, mm Hg) immediately increased significantly after thromboembolism versus the baseline values (MPAP: 42.0 +/- 3.4 vs 20.2 +/- 3.0, PCWP: 8 +/- 2 vs 4 +/- 3, both P < 0.05) and stayed at a higher level during the following 2 h. No significant difference existed between the value of cardiac output (CO) at 2 h post-thromboembolism and its baseline counterpart. Moreover, systemic arterial pressure (SAP, mm Hg) and heart rate (HR, beats/min) significantly increased after embolism versus the baseline values (SAP: 102 +/- 12 vs 80 +/- 7, HR: 119 +/- 22 vs 86 +/- 14, P = 0.008). Pulmonary arteriography, CT scan and gross anatomy all demonstrated that the selected lower left pulmonary arteries was successfully embolized. CONCLUSION: The establishment of APTE model by selective thromboembolism of lower left pulmonary artery is feasible, well-controlled and stable in minipigs. PMID- 22944241 TI - [The role of cellular retinol-binding protein-1 on pulmonary structural remodeling after rat myocardial infarction]. AB - OBJECTIVES: To observe the expression of cellular retinol-binding protein-1 (CRBP 1) in pulmonary tissues after rat myocardial infarction (MI) and uncover the role of CRBP-1 on the pulmonary structural remodeling. METHODS: MI was produced in male Wistar rats by left coronary ligation. Rats were sacrificed to obtain the lung at the 3(rd), 6(th), 15(th), 30(th), and 45(th) day after operation. After weighted, the rat lungs were fixed in 4% formalin and embedded in paraffin. Sections were cut and stained with hematoxylin and eosin (HE), Masson's trichrome (MT), rabbit anti-CRBP-1 antibody. RESULTS: Thirty-nine Wistar rats survived and developed MI. Pulmonary tissue sections with HE and MT staining showed a remarkable lung structural remodeling. The content of pulmonary tissue collagen at the 30(rd) was higher than in the sham group (8.4% +/- 3.6 vs 4.5% +/- 2.6, P < 0.001). CRBP-1 expression was detected on the alveolar septa at the 3(rd) day after operation, and peaked at the 15(th) day (43.8 +/- 7.4). Then the CRBP-1 expression decreased, and arrived at the level of the 3(rd) day. CONCLUSIONS: We demonstrate that CRBP-1 is expressed temporal on the alveolar septa after rat MI. It indicates a potential relationship between CRBP-1 and lung structure remodeling process after MI. PMID- 22944242 TI - Response to Jarrell and Albers: the name says it all. PMID- 22944243 TI - Unseen players shape benthic competition on coral reefs. AB - Recent work has shown that hydrophilic and hydrophobic organic matter (OM) from algae disrupts the function of the coral holobiont and promotes the invasion of opportunistic pathogens, leading to coral morbidity and mortality. Here we refer to these dynamics as the (3)DAM [dissolved organic matter (DOM), direct contact, disease, algae and microbes] model. There is considerable complexity in coral algae interactions; turf algae and macroalgae promote heterotrophic microbial overgrowth of coral, macroalgae also directly harm the corals via hydrophobic OM, whereas crustose coralline algae generally encourage benign microbial communities. In addition, complex flow patterns transport OM and pathogens from algae to downstream corals, and direct algal contact enhances their delivery. These invisible players (microbes, viruses, and OM) are important drivers of coral reefs because they have non-linear responses to disturbances and are the first to change in response to perturbations, providing near real-time trajectories for a coral reef, a vital metric for conservation and restoration. PMID- 22944244 TI - Beyond growth: novel functions for bacterial cell wall hydrolases. AB - The peptidoglycan cell wall maintains turgor pressure and cell shape of most bacteria. Cell wall hydrolases are essential, together with synthases, for growth and daughter cell separation. Recent work in diverse organisms has uncovered new cell wall hydrolases that act autonomously or on neighboring cells to modulate invasion of prey cells, cell shape, innate immune detection, intercellular communication, and competitor lysis. The hydrolases involved in these processes catalyze the cleavage of bonds throughout the sugar and peptide moities of peptidoglycan. Phenotypes associated with these diverse hydrolases reveal new functions of the bacterial cell wall beyond growth and division. PMID- 22944246 TI - Comparison of antigen detection and quantitative PCR in the detection of chlamydial infection in koalas (Phascolarctos cinereus). AB - The gold standard method for detecting chlamydial infection in domestic and wild animals is PCR, but the technique is not suited to testing animals in the field when a rapid diagnosis is frequently required. The objective of this study was to compare the results of a commercially available enzyme immunoassay test for Chlamydia against a quantitative Chlamydia pecorum-specific PCR performed on swabs collected from the conjunctival sac, nasal cavity and urogenital sinuses of naturally infected koalas (Phascolarctos cinereus). The level of agreement for positive results between the two assays was low (43.2%). The immunoassay detection cut-off was determined as approximately 400 C. pecorum copies, indicating that the test was sufficiently sensitive to be used for the rapid diagnosis of active chlamydial infections. PMID- 22944245 TI - Tricks an IRES uses to enslave ribosomes. AB - In eukaryotes, mRNAs are primarily translated through a cap-dependent mechanism whereby initiation factors recruit the 40S ribosomal subunit to a cap structure at the 5' end of the mRNA. However, some viral and cellular messages initiate protein synthesis without a cap. They use a structured RNA element termed an internal ribosome entry site (IRES) to recruit the 40S ribosomal subunit. IRESs were discovered over 20 years ago, but only recently have studies using a model IRES from dicistroviruses expanded our understanding of how a 3D RNA structure can capture and manipulate the ribosome to initiate translation. PMID- 22944247 TI - A case of childhood stiff-person syndrome with striatal lesions: a possible entity distinct from the classical adult form. AB - Parainfectious or autoimmune striatal lesions have been repeatedly described in children. We report a 7-year-old girl with painful muscle spasms, leading to the diagnosis of childhood stiff-person syndrome (SPS). Striatal lesions were demonstrated by diffusion-weighted magnetic resonance imaging (MRI) and single photon emission computed tomography but not by conventional MRI. Autoantibodies against glutamic acid decarboxylase (GAD) were absent. Steroid pulse therapy and high-dose intravenous immunoglobulin resolved all the symptoms with slight sequelae. Childhood SPS may be characterized by absent anti-GAD antibodies and a transient benign clinical course, and it may have a pathomechanism distinct from that in adult SPS. PMID- 22944248 TI - Longitudinal neurodevelopmental evolution in children with severe non-progressive encephalopathy. AB - AIM: The aim of this study was to evaluate the longitudinal neurodevelopmental evolution in children with severe non-progressive encephalopathy. METHODS: Between 1984 and 2005, 17 patients diagnosed with severe non-progressive encephalopathy under the care of the Institute Provvida Madre underwent neurodevelopmental evaluation on an annual basis for at least five consecutive years using the Munich Functional Developmental Diagnostics (MFDD). The severity of each patient's encephalopathy was assessed using the Capacity Profile (CAP). Longitudinal development trends were assessed by means of linear regression analysis, while the degree of discontinuity of the development trajectories was quantified using the Mean Absolute Deviation from Perfect Linear Development (MADPLD). Spearman's rank correlation coefficient and the Mann-Whitney test have been used to investigate the statistical significance of the relationships among the various parameters. RESULTS: We found that patients with severe non progressive encephalopathy showed, on average, a linear maturation of 1.5 2.5months per year, irrespective of the neurodevelopmental area considered. Nevertheless, we also discovered that the development trajectories could be discontinuous. Indeed, a given child can show no development sign at all for many years and then suddenly encounter a "development jump", especially in the active language and autonomy areas. However, the long-term development linearity hypothesis seemed to hold true in our study. We also found evidences suggesting that faster development in a given domain could be linked to faster development in other domains, that higher discontinuity in a given area could be associated with higher discontinuity in other areas and that higher degrees of discontinuity could be related to lower developmental evolutions. CONCLUSIONS: The main findings of this study are important for physicians to form prognoses, counsel effectively and appropriately target therapeutic interventions. In this perspective, there is a strong need to collect long-term repeated follow-up data concerning this group of infants in order to reinforce the findings presented. In fact, these results should be considered as a starting point for further research because they are based on a limited number of patients and more data are needed to confirm the findings. PMID- 22944249 TI - Interferon-alpha, -beta and -gamma induce CXCL11 secretion in human thyrocytes: modulation by peroxisome proliferator-activated receptor gamma agonists. AB - It has been previously shown IFN-alpha, -beta, -gamma and TNF-alpha (synergically with IFNs) dose-dependently induce the release of CXCL9 and CXCL10 chemokines by thyroid follicular cells, suggesting that this process may be related, at least in part, to the appearance of thyroid dysfunction during IFNs therapy. No study has evaluated the effect of IFN-alpha and -beta on CXCL11 chemokine production in thyrocytes. The aims of this study were: (a) to test the effect of IFN-alpha, beta and -gamma on the secretion of the Th1 chemokine CXCL11, in primary cultures of human thyroid follicular cells; (b) to assess the effect of PPAR-gamma activation on CXCL11 secretion. In primary cultures of human thyroid follicular cells, CXCL11 was undetectable in the supernatant. IFN-gamma, -alpha and -beta dose dependently induced CXCL11 release. TNF-alpha alone had no effect. The combination of each of the IFNs with TNF-alpha had a significant synergistic effect on CXCL11 secretion. Treatment of primary cultures of human thyroid follicular cells with rosiglitazone dose dependently inhibited the IFNs stimulated CXCL11 release. Compared with IFN-alpha and -beta, IFN-gamma was the most potent stimulus of CXCL11 secretion. In conclusion, we first show that IFN alpha, -beta and -gamma and TNF-alpha (synergically with IFNs) dose-dependently induce the release of CXCL11 by primary cultures of human thyroid follicular cells, suggesting that this process may be related to the appearance of thyroid dysfunction during IFNs therapy. Furthermore, PPAR-gamma activation partially inhibits this process. PMID- 22944250 TI - 1,25-Dihydroxyvitamin D3 curtails the inflammatory and T cell stimulatory capacity of macrophages through an IL-10-dependent mechanism. AB - The vitamin D receptor (VDR) is a hormone nuclear receptor regulating bone and calcium homeostasis. Studies revealing the expression of VDR on immune cells point toward a role for VDR-dependent signaling pathways in immunity. Here we verified the ability of the natural VDR ligand, 1,25-dihydroxyvitamin D(3) (1,25(OH)(2)D(3)) to interfere in inflammatory and T cell stimulatory capacity of macrophages, in particular within a chronic inflammatory disease features of experimental type 1 diabetes (T1D). We demonstrated that VDR is constitutively expressed in macrophages and both the levels of VDR and its downstream targets, are clearly induced by 1,25(OH)(2)D(3). In control mice, macrophage programming with 1,25(OH)(2)D(3) partially abrogated the activation-provoked expression of IL 12p40, TNFalpha and iNOS as well as the effector T cell-recruiting chemokines, CXCL9, CXCL10 and CXCL11. Targeting VDR signaling in macrophages counteracted their T-cell stimulatory ability despite essentially unaltered expression of antigen-presenting and costimulatory molecules. Furthermore, even in non-obese diabetic (NOD) mice, where macrophages/monocytes featured a heightened responsiveness toward danger signals and a superior T cell stimulatory capacity, 1,25(OH)(2)D(3) successfully curtailed these basic macrophage-mediated functions. Interestingly, the inhibitory action of the active compound was associated with an IL-10-dependent mechanism since 1,25(OH)(2)D(3)-treatment of IL-10-deficient macrophages failed to reproduce the characteristic repression on inflammatory mediators or T cell proliferation. Combined, these results highlight the possible therapeutic applicability of this natural immunomodulator, due to its ability to counteract macrophage inflammatory and T cell-activating pathways. PMID- 22944252 TI - New technologies: only a snapshot, but look how far we have come! PMID- 22944251 TI - Quantitative and phenotypic analysis of mesenchymal stromal cell graft survival and recognition by microglia and astrocytes in mouse brain. AB - Although cell transplantation is increasingly suggested to be beneficial for the treatment of various neurodegenerative diseases, the therapeutic application of such intervention is currently hindered by the limited knowledge regarding central nervous system (CNS) transplantation immunology. In this study, we aimed to investigate the early post transplantation innate immune events following grafting of autologous mesenchymal stromal cells (MSC) in the CNS of immune competent mice. First, the survival of grafted Luciferase/eGFP-expressing MSC (MSC-Luc/eGFP) was demonstrated to be stable from on day 3 post implantation using in vivo bioluminescence imaging (BLI), which was further confirmed by quantitative histological analysis of MSC-Luc/eGFP graft survival. Additional histological analyses at week 1 and week 2 post grafting revealed the appearance of (i) graft-surrounding/-invading Iba1+ microglia and (ii) graft-surrounding GFAP+ astrocytes, as compared to day 0 post grafting. While the density of graft surrounding astrocytes and microglia did not change between week 1 and week 2 post grafting, the density of graft-invading microglia significantly decreased between week 1 and week 2 post implantation. However, despite the observed decrease in microglial density within the graft site, additional phenotypic analysis of graft-invading microglia, based on CD11b- and MHCII-expression, revealed >50% of graft-invading microglia at week 2 post implantation to display an activated status. Although microglial expression of CD11b and MHCII is already suggestive for a pro-inflammatory M1-oriented phenotype, the latter was further confirmed by: (i) the expression of NOS2 by microglia within the graft site, and (ii) the absence of arginase 1-expression, an enzyme known to suppress NO activity in M2-oriented microglia, on graft-surrounding and -invading microglia. In summary, we here provide a detailed phenotypic analysis of post transplantation innate immune events in the CNS of mice, and warrant that such intervention is associated with an M1-oriented microglia response and severe astrogliosis. PMID- 22944253 TI - Established and novel imaging biomarkers for assessing response to therapy in hepatocellular carcinoma. AB - The management of hepatocellular carcinoma (HCC) is evolving because of recently introduced novel therapeutic approaches. There is growing recognition that optimal outcome requires choosing treatment tailored to suit each individual patient, necessitating an early and accurate assessment of tumor response to therapy. The established and adapted image biomarkers based on size for tumor burden measurement continues to be applied to HCC as size measurement can easily be used in any clinical practice. However, in the setting of novel targeted therapies and liver directed treatments, simple tumor anatomical changes can be less informative and usually appear later than biological changes. Therefore the importance of image biomarkers such as tumor viability measurement, functional perfusion and diffusion imaging for response assessment is increasingly being recognized. Although promising, these imaging biomarkers have not gone through all the required steps of standardization and validation. In this review, we discuss various established, evolving and emerging imaging biomarkers and the criteria of response evaluation and their challenges in HCC. PMID- 22944254 TI - Bioelectrochemical recovery of ammonia-copper(II) complexes from wastewater using a dual chamber microbial fuel cell. AB - The cathodic reduction of complex-state copper(II) was investigated in a dual chamber microbial fuel cell (MFC). The inner resistance of MFC system could be reduced in the presence of ionizing NH(4)(+), however, mass transfer was hindered at higher ammonia concentration. Thermodynamic and electrochemical analyses indicated that the processes of complex dissociation and copper reduction were governed by the ratio of T[Cu]:T[NH(3)] and the pH of solution. The reduction of Cu(NH(3))(4)(2+) could be achieved via two possible pathways: (1) releasing Cu(2+) from Cu(NH(3))(4)(2+), then reducing Cu(2+) to Cu or Cu(2)O and (2) Cu(NH(3))(4)(2+) accepting an electron and forming Cu(NH(3))(2)(+), and depositing as Cu or Cu(2)O consequently. At initial concentration of 350 mg T[Cu] L(-1), copper removal efficiency of 96% was obtained at pH=9.0 within 12 h (with ?Cu/?COD=1.24), 84% was obtained at pH=3.0 within 8 h (with ?Cu/?COD=1.72). Cu(NH(3))(4)(2+) was reduced as polyhedral deposits on the cathode. PMID- 22944255 TI - Arsenite transporters expression in rice (Oryza sativa L.) associated with arbuscular mycorrhizal fungi (AMF) colonization under different levels of arsenite stress. AB - As a silicon hyperaccumulator, lowland rice takes up higher levels of As than many other plants due to silicic acid and arsenite sharing the same transporters (Lsi1 and Lsi2). Glomus intraradices (AH01) was inoculated to rice under different arsenite concentrations (0, 2 and 8 MUM) in order to investigate the interactions between arbuscular mycorrhizal fungus and rice on the accumulation of arsenite. The relative mRNA expressions of Lsi1 and Lsi2 resulted in a down regulating trend in mycorrhizal plants. Under 2 MUM arsenite treatments, Lsi1 and Lsi2 were significantly decreased, by 0.7-fold (P<0.05) and 0.5-fold (P<0.01), respectively, in mycorrhizal plants when compared with non-mycorrhizal plants. This led to the decrease of arsenite uptake per unit of root dry mass. No organic As species were detected in both roots and shoots. The As(III)/As(V) ratios indicated that mycorrhizal plants immobilized most of the arsenite proportion in the roots and prevented its translocation from the roots to the shoots. PMID- 22944256 TI - Assessing the impact and social perception of self-regulated music stimulation with patients with Alzheimer's disease. AB - We assessed the impact and social rating of an active and a passive music condition implemented with six patients with Alzheimer's disease. In the active condition, the patients used a simple hand response and a microswitch to self regulate music stimulation inputs. In the passive condition, music stimulation was automatically presented throughout the sessions. Active and passive stimulation sessions were preceded and followed by control (non-stimulation) sessions. The active condition sessions showed an increase in the patients' indices of positive participation (e.g., singing or music-related movements, and smiles) greater than that observed in the passive condition sessions for five of the six patients. Positive intervention effects could also spread to the post intervention sessions. Social raters (42 care and rehabilitation staff members working with persons with multiple disabilities) favored the active condition on a six-item questionnaire dealing with, among others, conditions' suitability, respect of patients' dignity and independence, and practicality. The implications of the findings as to the plausibility/desirability of an active stimulation condition were discussed. PMID- 22944257 TI - Assessment of the relationship between diagnoses of ASD and caregiver symptom endorsement in adults diagnosed with intellectual disability. AB - Individuals diagnosed with an intellectual disability (ID) share overlapping traits with those diagnosed with both ID and an Autism Spectrum Disorder (ASD). Therefore, the purpose of this study was to determine if caregivers' reports of symptoms of ASD are of value (i.e., when comparing them to clinical diagnoses of ASD) and to determine which symptoms of ASD best differentiate those with ASD from those with ID only. It was hypothesized that a subset of items would emerge using the Autism Spectrum Disorders-Diagnostic for Adults (ASD-DA) which would differentiate the two groups utilize in this study. One hundred eighty-six adults diagnosed with ID with and without diagnosis of ASD were assessed for core symptoms and other behavioral differences using the ASD-DA. Most of the individuals in the ID group (n = 93) and the ID plus ASD group (n = 93) were in the profound range of ID. The items which were most likely to distinguish individuals with ASD were in socialization domain. Furthermore, adults with ASD were more likely to be male and to be non-verbal. PMID- 22944258 TI - Reaching to throw compared to reaching to place: a comparison across individuals with and without Developmental Coordination Disorder. AB - When picking up an object, adults show a longer deceleration phase when the onward action has a greater precision requirement. Tailoring action in this way is thought to need forward modelling in order to predict the consequences of movement. Some evidence suggests that young children also tailor reaching in this way; however, how this skill develops in children with Developmental Coordination Disorder (DCD) is unknown. The current study compared the kinematics of reaching to an object when the onward intention was: to place the object on a target (either with high or low precision requirements), to throw the object or to lift the object vertically. Movements of both adults (N = 18) and children (N = 24) with DCD and their age-matched controls were recorded. The typically developing adults discriminated across all action types, the adults with DCD and the typically developing children only across the actions to place and throw and the children with DCD only between the actions to lift and throw. The results demonstrate developmental progression towards fine tuning the planning of reaching in relation to onward intentions. Both adults and children with DCD are able to plan movement using inverse models but this skill is not yet fully developed in early adulthood. PMID- 22944259 TI - Adolescents with intellectual disability have reduced postural balance and muscle performance in trunk and lower limbs compared to peers without intellectual disability. AB - For adolescent people with ID, falls are more common compared to peers without ID. However, postural balance among this group is not thoroughly investigated. The aim of this study was to compare balance and muscle performance among adolescents aged between 16 and 20 years with a mild to moderate intellectual disability (ID) to age-matched adolescents without ID. A secondary purpose was to investigate the influence of vision, strength, height and Body Mass Index (BMI) on balance. A group of 100 adolescents with ID and a control group of 155 adolescents without ID were investigated with five balance tests and three strength tests: timed up and go test, one leg stance, dynamic one leg stance, modified functional reach test, force platform test, counter movement jump, sit ups, and Biering-Sorensen trunk extensor endurance test. The results showed that adolescents with an ID in general had significantly lower scores in the balance and muscle performance tests. The group with ID did not have a more visually dominated postural control compared to the group without ID. Height, BMI or muscle performance had no strong correlations with balance performance. It appears as if measures to improve balance and strength are required already at a young age for people with an ID. PMID- 22944260 TI - Dibenzofuran induces oxidative stress, disruption of trans-mitochondrial membrane potential (DeltaPsim) and G1 arrest in human hepatoma cell line. AB - Dioxins are a class of extremely toxic environmentally persistent pollutant, comprised of halogenated dibenzo-p-dioxins, dibenzofurans and biphenyls. Despite significant human exposure via multiple routes, very little is known about toxicity induced by dibenzofuran (DF). Current study shed lights on the potential toxicity mechanism of DF using human hepatoma cell line (HepG2). It was observed that the exposure to DF potentiate oxidative stress, apoptosis and necrosis at 10MUM within 8h in HepG2 cells. Interestingly, when we pre-incubated the cells with alpha-NF (1nM) for 12h, an aromatic hydrocarbon receptor antagonist, the IC(50) of DF increased by 14 folds indicating the cytoprotective ability of alpha NF from DF induced toxicity. Furthermore, three additional metabolites were observed while studying the metabolic profile of DF in HepG2 cells with and without pre-incubation with alpha-NF using chromatography-mass spectroscopy (GC MS). Of these, two metabolites were characterized as dihydroxylated derivative of DF and third metabolite was characterized as quinone derivative of DF. By flow cytometry and confocal laser microscopy analysis we followed the ROS formation after DF (10MUM) exposure for 3h. Significantly low ROS was generated in cells which were pre-incubated with alpha-NF than cells which were not pre-incubated with alpha-NF underlining the importance of metabolism in DF toxicity. The same pattern of protection was consistent while measuring mitochondrial membrane potential (MMP), i.e., less MMP dip was observed in 'with alpha-NF pre-incubated and DF (10MUM) exposed cells' than 'without alpha-NF pre-incubated but DF exposed cells'. In cell cycle studies, it was confirmed that cell population of HepG2 at G1 stage progressively increased in number (~74%) within 24h. Thus, DF and its metabolites induce significantly higher cytotoxicity after metabolism in HepG2 cells than its parent compound (DF) by ROS formation, MMP dip and impaired cell cycle. PMID- 22944261 TI - Serum amyloid A uptake by feline peripheral macrophages. AB - Serum amyloid A (SAA) is one of the major acute phase proteins in cats and humans. SAA concentrations increase in response to the inflammatory status and secondary amyloid A amyloidosis has been documented in cats. In order to control the SAA concentration, it is important to clarify how the SAA protein is metabolized. Although the details of SAA metabolism in the body remain unknown, human and murine research indicates that macrophages play a key role in SAA uptake. The objectives of this study were to demonstrate SAA uptake by feline macrophages and to evaluate the effects of lipopolysaccharide (LPS) and dexamethasone (Dex) on SAA uptake. The concentration of recombinant feline SAA added to a feline macrophage culture was decreased in a time-dependent manner and was significantly reduced after a 24-h incubation, as demonstrated by enzyme linked immunosorbent assay (ELISA). SAA uptake into feline peripheral macrophages was demonstrated by immunofluorescence microscopy. Pretreatment to macrophages with LPS did not affect this decrease in the SAA concentration, but this was significantly blocked by Dex pretreatment. In conclusion, SAA was incorporated by feline macrophages and pretreatment with Dex inhibited SAA uptake by macrophages in this study. Further investigation is needed to determine the molecules that influence SAA uptake by macrophages and the effect of clinical glucocorticoid usage on the SAA concentration in cats. PMID- 22944262 TI - Antioxidant and osteogenic properties of anodically oxidized titanium. AB - Cells adhering onto implant surfaces are subjected to oxidative stress during wound healing processes. Although titanium and its alloys are among the most frequently used biomaterials in orthopedic and dental implants, titanium surfaces do not have antioxidant properties, and cells grown on these surfaces can show permanent oxidative stress. The present study assessed the antioxidant property and osteogenic properties of titanium samples with or without oxidation treatments. A thick rutile TiO2 film was observed on thermally oxidized titanium surfaces, while amorphous anatase TiO2 formed on anodically oxidized titanium surfaces prepared by discharging in 1 M Na2HPO4. A resistance to the depletion of reduced glutathione in adherent osteoblasts, which correlates with antioxidant behavior, occurred on anodically oxidized titanium. Enhanced osteogenic gene expressions and nano-biomechanical properties of mineralized tissue were achieved on anodically oxidized titanium, in comparison with thermally oxidized or untreated titanium. Thus, anodic oxidation by discharging in electrolyte is expected to be a useful surface modification for titanium implants. PMID- 22944264 TI - Not just fear and sadness: meta-analytic evidence of pervasive emotion recognition deficits for facial and vocal expressions in psychopathy. AB - The present meta-analysis aimed to clarify whether deficits in emotion recognition in psychopathy are restricted to certain emotions and modalities or whether they are more pervasive. We also attempted to assess the influence of other important variables: age, and the affective factor of psychopathy. A systematic search of electronic databases and a subsequent manual search identified 26 studies that included 29 experiments (N = 1376) involving six emotion categories (anger, disgust, fear, happiness, sadness, surprise) across three modalities (facial, vocal, postural). Meta-analyses found evidence of pervasive impairments across modalities (facial and vocal) with significant deficits evident for several emotions (i.e., not only fear and sadness) in both adults and children/adolescents. These results are consistent with recent theorizing that the amygdala, which is believed to be dysfunctional in psychopathy, has a broad role in emotion processing. We discuss limitations of the available data that restrict the ability of meta-analysis to consider the influence of age and separate the sub-factors of psychopathy, highlighting important directions for future research. PMID- 22944265 TI - [The clinical choice of CT angiogram and ventilation-perfusion scintigraphy in pulmonary embolism diagnosis]. PMID- 22944263 TI - Targeting C/EBP homologous protein with siRNA attenuates cerebral vasospasm after experimental subarachnoid hemorrhage. AB - Endothelial apoptosis plays a major role in the development of cerebral vascular spasm after subarachnoid hemorrhage (SAH). C/EBP homologous protein (CHOP) orchestrates apoptosis in a variety of cell types in response to endoplasmic reticulum (ER) stress, implicated in the brain injury after SAH. However, the role of CHOP in the mechanism of cerebral vasospasm (CVS) after SAH remains unexplored. The aim of this study was to evaluate the effect of CHOP silencing on endothelial apoptosis and CVS following subarachnoid hemorrhage in the rat. The study was conducted on 65 rats and employed endovascular perforation model of SAH. CHOP siRNAs were injected 24 h prior to the hemorrhage. At 72 h after SAH brains with basilar arteries (BA) were collected from euthanized rats for laboratory investigations. Triple fluorescence stain revealed expression of CHOP in cerebral vascular endothelia after SAH. Marked reduction of CHOP protein and the reduction of its downstream signaling effectors, bim and caspase-3, were found in BA with Western blot analysis. CHOP silencing reduced number of apoptotic endothelial cells in BA, and increased BA diameter after SAH. The amelioration of CVS was associated with reduced neuronal injury in cerebral tissues. In conclusion, CHOP siRNA treatment can effectively combat apoptotic mechanisms of cerebral vasospasm set in motion by subarachnoid bleeding. PMID- 22944266 TI - [Ageing related changes of insulin secretion and insulin sensitivity among normal glucose tolerance individuals in China]. AB - OBJECTIVE: To explore the aging-related changes of insulin secretion and insulin sensitivity among normal glucose tolerance (NGT) individuals in China. METHODS: A total of 34 293 individuals were recruited. All of them were described as NGT by 75 g oral glucose tolerance test (75 g OGTT) according to the diagnostic criterion of WHO, 1999. HOMA-beta, DeltaI(30)/DeltaG(30), InsAuc30/GluAuc30, InsAuc120/GluAuc120 were calculated to estimate insulin secretion; HOMA-IR and Matsuda index measured to estimate insulin sensitivity; Disposition index: DI(30) and DI(120) were used to estimate beta-cell function. RESULTS: HOMA-beta, DeltaI(30)/DeltaG(30), InsAuc30/GluAuc30 and InsAuc120/GluAuc120 were all lower in the elder group then the younger group (P trend < 0.05). The mean HOMA-beta dropped from 192 +/- 16 (20 - 29 years) to 115 +/- 7 (70 or elder) among men and from 162 +/- 8 (20 - 29 years) to 120 +/- 12 (70 or elder) among women. The mean DeltaI(30)/DeltaG(30) dropped from 20.0 +/- 2.0 (20 - 29 years) to 8.6 +/- 0.6 (70 or elder) among men and from 22.4 +/- 1.6 (20 - 29 years) to 12.5 +/- 1.7 (70 or elder) among women. The above index were negatively correlated with age in univariate linear regression (P < 0.05), the results among men and overall still existed after adjusted for BMI and waist circumference in multivariate linear regression, while the relation between HOMA-beta and age disappeared among women. Matsuda Index was positively correlated with age (beta = 0.02, P = 0.001) and HOMA-IR were negatively correlated with age (beta = -0.01, P = 0.001) among men even after adjusted for BMI and waist circumference and the above correlation between Matsuda Index/HOMA-IR and ageing was not significant until adjusted for BMI and waist circumference in multivariate linear regression. Among women HOMA IR (beta = -0.01, P = 0.000), Matsuda index (beta = 0.03, P = 0.000). DI(30) and DI(120) were negatively correlated with age in both univariate and multivariate linear regression. CONCLUSIONS: The basal, postchallenge insulin secretion and postchallenge islet compensatory function decreases with ageing, while insulin sensitivity does not deteriorate with ageing and its related change of body composition and weight gain. PMID- 22944267 TI - [Expression and clinical significance of Sema4C in esophageal cancer, gastric cancer and rectal cancer]. AB - OBJECTIVE: To explore the expression and clinical significance of signal protein Sema4C in esophageal cancer, gastric cancer and rectal cancer. METHODS: Fifty esophageal cancer, 75 gastric cancer, 50 rectal cancer and 20 corresponding normal mucous membrane specimens, collected during the period of January 2008 to December 2010, were detected with streptavidin-peroxidase immunohistochemistry to detect the expression levels of Sema4C. And the relationships of the Sema4C expression with clinicopathological data was analyzed. RESULTS: The expression levels of Sema4C in three kinds of cancers were significantly higher than the corresponding normal mucous membranes (80.0% (n = 40) vs 20.0% (n = 4), 77.3% (n = 58) vs 25.0% (n = 5), 80.0% (n = 40) vs 15.0% (n = 3), all P = 0.000). Furthermore, the percentage of Sema4C positive cells was significantly higher in carcinoma nests of tumors with lymphatic metastasis than those without (90.3% (n = 28) vs 63.2% (n = 12), 85.0% (n = 51) vs 46.7% (n = 7), 92.0% (n = 23) vs 68.0% (n = 17), P = 0.049, 0.005, 0.034). However, no significant correlations were found between the Sema4C expression with gender, age, location of tumors, types of cancer cells, cell differentiation, tumor size, depth of invasion or tumor stage (all P > 0.05). CONCLUSION: There is a high expression of Sema4C in esophageal cancer, gastric cancer and rectal cancer. And it is strongly correlated with lymphatic metastasis. Thus Sema4C may play critical roles in the invasion and lymphatic metastasis of esophageal cancer, gastric cancer and rectal cancer. PMID- 22944268 TI - [A cross-sectional survey of crab intolerance positive rate and its determinants in healthy medical examination population in Beijing]. AB - OBJECTIVE: To explore the positive rate of crab intolerance and its related factors in a healthy physical examination population in Beijing, China. METHODS: A cross-sectional survey was carried out from August 1, 2008 to July 30, 2009. It recruited a total of 12 765 adults with crab intolerance at Health Sciences Center, Chinese PLA General Hospital. The epidemiological data were entered into computer by two persons and organized by Epidata3.0. Non-conditional Logistic regression model was used to calculate the values of odd ratio (OR) and 95%CI. Statistic analysis was performed by SPSS 13.0. RESULTS: The incidence rate of crab intolerance was 24.5% (3128/12 765) and increased with age. Grades of crab intolerance were associated with age and gender and there was a linear correlation tendency (P < 0.05). Incidence rate of crab intolerance in females (27.5%, 1077/3912) was higher than that of males (23.2%, 2051/8853). Multiple regression analysis showed that crab intolerance was correlated with age, gender, body mass index and helicobacter infections(all P < 0.05). In comparison with age group < 40 years old, the values of OR (95%CI) of age groups 41 - 50, 51 - 60 and > 60 years old were 1.224 (1.095 - 1.368), 1.616 (1.431 - 1.827) and 2.177 (1.799 - 2.634) respectively. In comparison with males, the OR (95%CI) of females was 1.286 (1.174 - 1.408). The OR (95%CI) of Helicobacter pylori infections was 1.303(1.201 - 1.413). In comparison with normal weighters, the OR (95%CI) of obese subjects was 1.154 (1.026 - 1.298). CONCLUSIONS: Crab intolerance may be correlated with age, gender, Helicobacter pylori infections and body mass index. Health education should be targeted at its characteristics. PMID- 22944269 TI - [Effects of smoke on clinical prognosis of patients with acute ST-segment elevation myocardial infarction]. AB - OBJECTIVE: To explore the effects of smoke on the clinical prognosis of patients with acute ST-segment elevation myocardial infarction (ASTEMI). METHODS: A total of 1213 consecutive ASTEMI patients were admitted into 20 hospitals in Liaoning province between May 2009 and May 2010. They were stratified into smoke (n = 588) and non-smoke (n = 625) groups. Basic demographic profiles, treatment data and clinical outcomes were compared between two groups. The primary endpoint was cardiac death and the secondary endpoints included non-fatal myocardial infarction, stroke and revascularization. Cox proportional hazard analyses were performed. RESULTS: The proportion of percutaneous coronary intervention (PCI) in the smoke group was significantly higher than that in the non-smoke group (40.8% vs 22.1%, P < 0.001). During the follow-up period, the medication rate was significantly higher in the smoke group than that in the non-smoke group (aspirin: 75.3% vs 62.2%, P < 0.001; clopidogrel: 40.5% vs 32.2%, P = 0.003; beta receptor blockade: 45.4% vs 36.0%, P = 0.001; angiotensin-converting-enzyme inhibitor/angiotensin II receptor blocker (ACEI/ARB): 38.3% vs 32.2%, P = 0.026; statins: 57.3% vs 44.2%, P < 0.001). During the follow-up period, the rate of cardiac death was lower in the smoke group than that in the non-smoke group (10.2% vs 24.2%, P < 0.001). No significant differences existed between two groups. During the follow-up period, the rate of cardiac death was significantly correlated with smoke (HR 2.777, 95%CI 1.113 - 6.928, P = 0.029), PCI (HR 0.208, 95%CI 0.062 - 0.700, P = 0.011), age (HR 1.049, 95%CI 1.005 - 1.095, P = 0.028), aspirin (HR 0.165, 95%CI 0.061 - 0.446, P < 0.001) and statins (HR 0.382, 95%CI 0.317 - 0.462, P < 0.001). CONCLUSION: Among the ASTEMI patients, the rate of cardiac death is significantly lower in the smoke group than that in the non smoke group. And it is significantly correlated with such independent risk factors as smoke, PCI, age, aspirin and statins. PMID- 22944270 TI - [Relationship between methylation status of promoter and expression of XAF1 gene in papillary thyroid carcinoma]. AB - OBJECTIVE: To explore the relationship between methylation status of XAF1 (X linked inhibitor of apoptosis protein associated factor-1) gene promoter and its protein expression in papillary thyroid carcinoma (PTC). METHODS: Methylation specific polymerase chain reaction (MSP) and immunohistochemical substance P (SP) technique were used to detect the methylation status of XAF1 gene promoter and its protein expression in 70 PTC cases and their matched adjacent non-cancerous epithelium (NCE). RESULTS: In NCE, there was no promoter methylation of XAF1 gene while the rate was 35.7% (25/70) in PTC (chi(2) = 27.206, P < 0.01). And it was correlated with tumor TNM stage, pathological grade and lymph node metastasis (P < 0.05). The positive rates of XAF1 protein expression in NCE and PTC were 100% (70/70) and 55.7% (39/70) respectively. And there was significant difference (chi(2) = 36.458, P < 0.01). In PTC, the positive rates of XAF1 protein expression in Grades I and II were 67.5% (27/40) and 40.0% (12/30) respectively. And they were 35.7% (10/28) and 69.0% (29/42) in the lymph node metastasis and non-metastasis groups respectively. And there were significant differences between two groups (P < 0.05). Futhermore, there was distinct correlation between methylation of XAF1 gene promoter and its protein expression (chi(2) = 8.864, P < 0.01). CONCLUSION: Methylation of promoter may be one of the important inactivating factors of XAF1 gene. And it plays an important role in the carcinogenesis and progression of PTC. PMID- 22944271 TI - [Normal values and influencing factors of fractional exhaled nitric oxide for Chinese healthy adults]. AB - OBJECTIVE: To evaluate the normal values of fractional exhaled nitric oxide (FENO) for Chinese adults. METHODS: A total of 200 non-smoking and healthy Chinese adults were recruited according to the inclusion and exclusion criteria. They received lung function and allergen skin prick tests at the Outpatient Department of China-Japan Friendship Hospital from February to August 2011. There were 100 males and 100 females. FENO test was performed according to the standard procedures of American Thoracic Society/European Respiratory Society (ATS/ERS) recommendation. The FENO levels of healthy non-smokers were tested by the NIOXMINO analyzer. All variables, such as age, gender, height, weight, forced expiratory volume at 1 second (FEV(1))% predicted and FEV(1)/FVC, were included for multiple regression analyses. RESULTS: The FENO level of healthy non-smokers was (14.2 +/- 5.6)*10(-9) mol/L with the 95% normal range of (3.2 - 25.2)*10(-9) mol/L. The value of FENO was significantly higher in males than females ((15.6 +/ 5.5) vs (12.9 +/- 5.4)*10(-9) mol/L, t = 3.48, P = 0.001). The FENO level of the subjects aged 60 - 80 years was (15.7 +/- 5.4)*10(-9) mol/L and it was higher than those aged 18 - 60 years ((13.8 +/- 5.6)*10(-9) mol/L, t = 2.04, P = 0.040). Multiple regression analysis showed that gender was an independent influencing factor of FENO level. CONCLUSIONS: The FENO level of non-smoking and healthy Chinese adults is similar with that of the westerners. Gender is an independent influencing factor of FENO level. PMID- 22944272 TI - [Survey of pertussis infection in infants aged under 3 months with persistent cough]. AB - OBJECTIVE: To explore the prevalence of pertussis in hospitalized infants aged under 3 months with persistent cough. METHODS: The nasopharyngeal secretions and serum samples were collected from hospitalized infants aged under 3 months with cough for over 2 weeks from January 2011 to January 2012. The samples of nasopharyngeal secretion were suctioned and collected. Multiplex PCR assay was employed to identify Bordetella pertussis (B. pertussis) and enzyme-linked immunosorbent assay used to detect antibody to pertussis toxin (PT-IgG). Total bacterial DNA was exacted from nasopharyngeal secretion and two-target IS481/PT of B. pertussis was detected by PCR. RESULTS: Fifty-nine infants (32 boys and 27 girls) were enrolled. None of them was pre-immunized with diphtheria-pertussis tetanus vaccine. Seventeen infants (28.8%) were B. Pertussis positive. Among 17 cases, 3 infants under 1 month, 4 infants 1 -2 months, and 10 infants 2 - 3 months. Three infants had household contacts with persistent cough and their serum antibodies to pertussis toxin were positive. Sixteen infants with pertussis had the paroxysms of frequent and rapid coughs while another 5 with pertussis had long inspiratory effort accompanied by a high-pitched "whoop" at the end of paroxysms. Seven infants with pertussis had conjunctiva bleeding, a special sign of pertussis. Ten infants had lymphocytosis with a predominant elevation of lymphocytes. CONCLUSIONS: B. pertussis is an important pathogen for the infants under 3 months with persistent cough. Multiplex PCR may be used to identify B. pertussis with a high sensitivity. The unrecognized close family members of the infants with pertussis are probably an important source of infection. PMID- 22944273 TI - [Case-control study on the correlation of bladder cancer incidence and occupational factors]. AB - OBJECTIVE: To explore the relationship between occupational factors and the incidence of bladder cancer. METHODS: The present research was based on a hospital-based case-control study. The cases were frequency matched. The non conditional Logistic regression was used to calculate the odds ratio (OR) of each occupation. RESULTS: The OR of business and administration professionals, male electricians and electronic workers were 3.88 and 7.40; the OR of janitors and helpers was 0.21; the OR of handcrafted and printing clerks was 0.71, but there was no significant difference. CONCLUSION: Business and administration professionals, male electricians and electronic workers tend to have bladder cancer. The occupation of janitors and helpers has a protective effect on bladder cancer while the occupation of printing clerks shows no statistical significance on bladder cancer. PMID- 22944274 TI - [High-dose tirofiban in patients with acute ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention]. AB - OBJECTIVE: To evaluate the clinical outcomes of high-dose tirofiban in patients with ST-elevation myocardial infarction (ASTEMI) undergoing primary percutaneous coronary intervention (PCI). METHODS: A total of 104 consecutive ASTEMI patients undergoing primary PCI were enrolled from January 2010 to February 2011. They were randomized into the high-dose tirofiban group (n = 52) and the normal-dose tirofiban group (n = 52). We measured the sumST-segment resolution of ECG post PCI respectively and left ventricular ejective fraction (LVEF) at Day 90 post PCI. RESULTS: After PCI, the sumST-segment resolution of ECG of the high-dose tirofiban group significantly improved than that of the normal-dose tirofiban group (38% +/- 12% vs 34% +/- 13%, P < 0.05). Before PCI, LVEF of two groups is 50.2% +/- 1.4% vs 49.6% +/- 1.1% (P > 0.05), but at day 90 post-PCI, LVEF had significant difference between two groups (60.1% +/- 1.1% vs 56.0% +/- 1.2%, P < 0.05). The rates of major and moderate hemorrhage did not differ significantly between two groups. CONCLUSION: High-dose tirofiban improves myocardial reperfusion and clinical outcome. It re-emphasizes the importance of further platelet aggregation inhibition in ASTEMI patients undergoing primary PCI. PMID- 22944275 TI - [Follow-up of pediatric inflammatory bowel disease]. AB - OBJECTIVE: To analyze the clinical characteristics and prognosis of pediatric inflammatory bowel disease (IBD) through a long-term follow-up so as to improve the diagnosis and management of IBD in children. METHODS: Seventy-three IBD patients admitted into our hospital from May 2000 to September 2010 were re evaluated with the uniform diagnostic criteria proposed by the 2010 consensus diagnostic criteria for pediatric IBD. All patients were followed up by questionnaire, telephone and face-to-face interview. RESULTS: Among them, 56 cases (76.7%) (ulcerative colitis (UC): n = 34, Crohn's disease (CD): n = 22) were available for follow-up study. Among 34 UC cases, 13 cases had their diagnosis confirmed and 21 cases were diagnosed as probable UC. Meanwhile, among 22 CD cases, 14 and 8 had definite and probable diagnoses respectively. At diagnosis, 46.9% (15/32) of UC patients had extensive colitis, 40.6% (13/32) left sided colitis while 72.7% (16/22) of CD patients with had ileocolonic. And 28 cases (82.4%) of UC patients and 20 cases (90.9%) of CD patients fulfilled the criteria for moderate to severe grade. Among 56 IBD cases, there was no death for CD, but 5 died for UC (14.7%). In the remaining 29 UC and 22 CD patients, 16 cases (55.2%) and 15 cases (68.2%) stayed symptom-free (P > 0.05). Moreover, 8 cases (27.6%) of UC and 3 cases (13.6%) of CD patients belonged to chronic relapsing type while 16 cases (55.2%) of UC and 15 cases (68.2%) of CD patients were of chronic persistent type. The physical activities of most IBD patients (n = 49) were unrestricted. The surgical rate for IBD was 19.6% (n = 11), 8.8% for UC (n = 3) and 36.4% for CD (n = 8) (P < 0.05). The incidences of surgical complications such as intestinal obstruction, intestinal perforation and hemorrhage of gastrointestinal tract were 7.1% (n = 4), 7.1% (n = 4) and 1.8% (n = 1). And it was more common in the CD group. CONCLUSIONS: Most IBD patients belong to chronic persistent type and then chronic relapsing type. Their physical activities are unrestricted. The surgical rate for CD is significantly higher than UC. And surgical complications such as intestinal obstruction, intestinal perforation and hemorrhage of gastrointestinal tract occur more frequently in the CD group. PMID- 22944276 TI - [Role of neuregulin-1beta in airway hypersecretion induced by in interleukin 1beta]. AB - OBJECTIVE: To explore the role of neuregulin 1beta (NRG-1beta) in airway hypersecretion induced by interleukin (IL)-1beta. METHODS: After stimulating the airway epithelial cell line HBE16 with IL-1beta, the expressions of NRG-1beta mRNA and mucin (MUC) 5AC mRNA were detected by reverse transcription-polymerase chain reaction (RT-PCR), the proteins of NRG-1beta and MUC5AC measured by enzyme linked immunosorbent assay (ELISA) and phosphorylated erythroblastic leukemia viral oncogene homolog (ErbB)1-4 detected by Western blot. The cells were pre treated with antibodies of ErbB1-4, inhibitors of p38 mitogen-activated protein kinase (MAPK), ERK1/2, mitogen- and stress-activated protein kinase (MSK)1 and antibody of cAMP-response element-binding protein (CREB). After the addition of stimulant NRG-1beta, MUC5AC was measured by ELISA. RESULTS: IL-1beta could increase markedly the levels of NRG-1beta mRNA and MUC5AC mRNA and also the proteins of NRG-1beta and MUC5AC in a dose-dependent fashion. NRG-1beta at concentrations of 1, 10, 100, 200 nmol/L increased the expression of MUC5AC (0.328 +/- 0.055, 0.364 +/- 0.086, 0.650 +/- 0.134, 0.586 +/- 0.068) versus the control group (0.227 +/- 0.019). And the results had statistical significances (P < 0.05). The expressions of phosphorylated ErbB2 and ErbB3 stimulated by NRG 1beta were positive while those of phosphorylated ErbB1 and ErbB 4 negative. After a pretreatment of antibodies of ErbB2, ErbB3, inhibitors of p38MAPK, ERK1/2, MSK1 and antibody of CREB and a stimulation of NRG-1beta, the expression of MUC5AC decreased (0.221 +/- 0.033, 0.238 +/- 0.044, 0.386 +/- 0.021, 0.352 +/- 0.022, 0.294 +/- 0.017, 0.252 +/- 0.019) versus the NRG-1beta group (0.650 +/- 0.134). And the results had statistical significances (P < 0.05). CONCLUSION: IL 1beta may cause airway hypersecretion probably through the combination of NRG 1beta with ErbB2 and ErbB3 heterodimers and the activation of MAPK/MSK1/CREB signal conduction. PMID- 22944277 TI - [Inhibition of elicitation of allergic contact dermatitis by topical use of Z-VAD FMK, a broad caspase inhibitor: experiment in mice]. AB - OBJECTIVE: To explore the effects of N-benzyloxycarbonyl-Val-Ala-Asp fluoromethylketone (Z-VAD-FMK), a broad caspase inhibitor, on the elicitation of murine allergic contact dermatitis (ACD) and examine the effects on T lymphocytes. METHODS: 1-fluoro-2,4-dinitrobenzene (DNFB) was used to establish the classical murine model of ACD. Different concentrations of Z-VAD-FMK were applied before ear provocation. Several parameters were detected, including ear swelling degree, weight differences and thickness of ear tissue under microscope between 2 ears. Enzyme-linked immunosorbent assay (ELISA) was used to detect the levels of Th1 cytokines (INF-gamma and IL-2) in ear tissues. Real-time reverse transcription-polymerase chain reaction (RT-PCR) was used to detect their levels of mRNA and the results were shown as "copies relative to one million housekeeping genes". Local lymph node assay (LLNA) was conducted. Bromodeoxyuridine-flow cytometry was used to detect the proliferation of T lymphocytes in local lymph node and flow cytometry to detect the activation of T lymphocytes. RESULTS: The right ear swelling degree, weight differences and thickness between two ears in the 1.25 mmol/L Z-VAD-FMK group were (12.6 +/- 1.2)*10(-2) mm, (3.1 +/- 0.2) mg, and (12.1 +/- 1.1)*10(-2) mm respectively. And they were all significantly lower than those of the negative control group((17.4 +/- 1.6)*10(-2) mm, (4.2 +/- 0.3) mg, (16.7 +/- 1.5)*10(-2) mm;q = 3.25, 2.98, 3.12, all P < 0.05). The levels of INF-gamma and IL-2 in the ear skin lesions of 1.25 mmol/L Z-VAD-FMK group were (856 +/- 45) and (167 +/- 12) pg/ml respectively and they were both significantly lower than those of the negative control group ((1180 +/- 58) and (225 +/- 16) pg/ml; q = 3.11, 3.14, both P < 0.05). The mRNA levels of the above two cytokines were 152 +/- 12 and 96 +/- 8 respectively and they were both significantly lower than those of the negative control group (220 +/- 15 and 156 +/- 11;q = 3.15, 3.42, both P < 0.05). In LLNA, the mean intensity of BrdU in T lymphocytes of 1.25 mmol/L Z-VAD-FMK-treated group was significantly weaker than that of the negative control group (185 +/- 15 vs 298 +/- 21, q = 3.02, P < 0.05). The percent of activation markers-positive T lymphocytes of the Z-VAD-FMK group were 7.8% +/- 0.7%, 9.8% +/- 0.8% and 31.2% +/- 2.8% respectively and they were all significantly lower than those of the negative control group (10.5% +/- 1.0%, 14.5% +/- 1.1%, 46.5% +/- 3.2%, q = 3.16, 3.52, 3.11, all P < 0.05). CONCLUSION: Topical use of Z-VAD-FMK prior to ear provocation can suppress the proliferation and activation of T lymphocytes in both skin tissues and local lymph nodes and thus result in the inhibitory effect of allergic contact dermatitis. PMID- 22944278 TI - [Curcumin inhibits iron overload-induced hepatocytic apoptosis and nuclear factor kappaB activity]. AB - OBJECTIVE: Iron is an essential micronutrient for human beings but its overload induces various diseases of liver, the main body storage site for iron, such as liver fibrosis. Curcumin is a natural polyphenol derived from turmeric and has been used widely. Its pharmacological action has attracted great attention in recent years. The apoptosis of rat cultured hepatocytes was induced by FeNTA (ferric nitrilotriacetate)-induced Iron overload. The present study was to examine the effect of curcumin at low concentrations on FeNTA-induced apoptosis of hepatocytes and elucidate the underlying mechanisms. METHODS: After the incubation of hepatocytes with 100 umol/L FeNTA in the presence or absence of 1 - 10 ummol/L of curcumin, a series of analyses were performed, including the analyses of hepatocytic apoptosis, the expressions of proteins relating with the regulations of cell apoptosis, caspase-3 activity, the production of reactive oxygen species (ROS) and nuclear factor NF-kappaB activity. RESULTS: Curcumin reduced the FeNTA-induced hepatocytic apoptosis by 46.65% and significantly down regulated the protein levels of Bcl-2 and Bcl-XL. In contrast, it had no effect on the protein levels of Bax and Bad. The curcumin treatment reduced FeNTA-caused production of ROS and caspase-3 activity by 45.01% and 59.71% respectively. And the NF-kappaB activity was also inhibited. CONCLUSION: Curcumin at low concentrations reduces iron overload-caused hepatocytic apoptosis and NF-kappaB activity, the key regulatory transcription factor for the inflammation-related gene expression in cultured hepatocyte. PMID- 22944279 TI - [Research and animal experiment of a remote-control locating device under the radiographic guidance for percutaneous nephrolithotomy]. AB - OBJECTIVE: To introduce an independently developed remote-control locating device under the radiographic guidance for percutaneous nephrolithotomy (PCNL) and conduct small-scale animal experiment to test its application effect. METHODS: Five experimental minipigs were selected. And an animal model of nephrolithotomy was established by implanting stones from outside the body. This locating device for PCNL was used to locate before puncture under the radiographic guidance and then begin puncturing to the target stone following the located angle. RESULTS: Four pigs achieved single puncture after localization. During the puncture process, no obvious hemorrhage occurred. The average time from starting locating to finishing puncture was 20.7 min, the average time of locating 15.6 min and the average time of puncture 5.1 min. CONCLUSIONS: This remote-control type of locating device can improve the accuracy and safety of puncture and minimize the radioactive exposure to operators. Thus it has an excellent perspective of further development and clinical application. PMID- 22944280 TI - Extracellular miRNAs: the mystery of their origin and function. AB - Mature miRNAs are 19-24 nucleotide noncoding RNAs that post-transcriptionally regulate gene expression in living cells by mediating targeted hydrolysis and translation inhibition of mRNAs. In recent years, miRNAs have been detected in a variety of biological fluids as extracellular nuclease-resistant entities. Importantly, extracellular circulating miRNAs are aberrantly expressed in blood plasma or serum during the course of many diseases, including cancer, and are promising noninvasive biomarkers. However, the biological function of extracellular miRNAs remains questionable. In this article, we summarise the current theories regarding extracellular miRNA origin and function, and suggest that these miRNAs are mostly byproducts of cellular activity. Nevertheless, some extracellular miRNA species might also carry cell-cell signaling function. PMID- 22944282 TI - Genes encoding cytoplasmic intermediate filament proteins of vertebrates revisited: identification of a cytoplasmic intermediate filament protein in the sea anemone Nematostella. AB - The cytoskeleton is crucial in determining cell architecture, division, motility, transport processes and in local control of signal transduction. Relatives of actin and tubulin are expressed in all phyla, underlining the fundamental importance of conserved cytoskeletal functions. Intermediate filament proteins have evolved in parallel with tissue diversity in the animal kingdom, likely from the demand to adapt one class of cytoskeletal proteins to cell type-restricted functions. Up to now, the evolutionary origin of cytoplasmic intermediate filament proteins remains unknown. Using a known gene encoding a cytoplasmic intermediate filament protein from the hemichordate Saccoglossus kowalevskii, we have identified the first corresponding gene in the sea anemone Nematostella, tentatively named cytovec. Our data reveal a relationship of cytovec with Hydra vulgaris nematocilins A and B that also lack a CAAX box. In light of additional recent findings, our data show that cytoplasmic intermediate filament genes are present in the common ancestor of Cnidaria and Bilateria. PMID- 22944281 TI - Gatekeepers of chromatin: Small metabolites elicit big changes in gene expression. AB - Eukaryotes are constantly fine-tuning their gene expression programs in response to the demands of the environment and the availability of nutrients. Such dynamic regulation of the genome necessitates versatile chromatin architecture. Rapid changes in transcript levels are brought about via a wide range of post translational modifications of the histone proteins that control chromatin structure. Many enzymes responsible for these modifications have been identified and they require various metabolic cofactors or substrates for their activity. Herein, we highlight recent developments that have begun to reveal particular cellular metabolites that might in fact be underappreciated regulators of gene expression through their ability to modulate particular histone modifications. PMID- 22944283 TI - The calcineurin dependent transcription factor TacA is involved in development and the stress response of Dictyostelium discoideum. AB - Calcineurin is an important signalling protein in a plethora of Ca(2+)-regulated cellular processes. In contrast to what is known about the function of calcineurin in various organisms, information on calcineurin substrates is still limited. Here we describe the identification and characterisation of the transcription factor activated by calcineurin (TacA) in the model organism Dictyostelium discoideum. TacA is a putative zinc-finger transcription factor orthologue of yeast Crz1. In resting unstimulated cells the protein is located in the cytosol and translocates to the nucleus in a calcineurin-dependent manner after Ca(2+)-stimulation. Nuclear export of TacA is partially dependent on GskA, the Dictyostelium orthologue of mammalian GSK3. The expression of tacA is developmentally regulated with its kinetics roughly paralleling calcineurin regulation. Silencing of tacA via RNAi leads to developmental defects and dysregulation of developmentally regulated and Ca(2+)-regulated marker genes. Additionally, TacA is involved in the stress response of D. discoideum during development in a separate pathway to the well-known stress response in Dictyostelium via STATc. Finally we provide evidence that TacA is not only an orthologue of yeast Crz1 but also functionally related to mammalian NFAT. PMID- 22944284 TI - Validation of the Spanish version of the questionnaire Practice Environment Scale of the Nursing Work Index. AB - BACKGROUND: The importance of the practice environment in the provision of care and its relation with patient outcomes and nurse-reported outcomes, support the need to have an instrument to measure such practice environment. OBJECTIVE: To evaluate the validity and reliability of the Spanish version of the Practice Environment Scale of the Nursing Work Index (PES-NWI), determining the content validity, test-retest reliability, internal consistency and construct validity. DESIGN: A cross-sectional survey of bedside care nurses undertaken in 2009 in medical, surgical and critical care wards of 33 Spanish National Health Service hospitals with more than 150 beds. METHODS: The validation process followed the internationally recognized guidelines about psychometric properties of instruments: translation and back-translation, content validity, test-retest reliability, internal consistency and construct validity. Other study variables included, like nurses' intention to leave and job satisfaction. RESULTS: The Intraclass Correlation Coefficient (ICC) for an overall score on the 31 item questionnaire was 0.87 (CI 95%: 0.85-0.89). Cronbach's alpha was 0.90 (CI 95%: 0.87-0.93). The weighted Kappa Index obtained for each of the items ranges from 0.24 (CI 95%: 0.22-0.26) to 0.51 (CI 95%: 0.49-0.53). The Content Validity Index score ranges from 0.5 for the item "Opportunities for advancement" to 1. Five of the terms attain this maximum level of agreement: "Active staff development or continuing education programs for nurses", "Enough registered nurses on staff to provide quality patient care", "Enough staff to get the work done", "Management that listens and responds to employee concerns" and "Collaboration between nurses and physicians". CONCLUSIONS: The validation process indicates that the Spanish version of the PES-NWI is valid and reliable in its current version and it can be used to measure the practice environment of Spanish nurses working in clinical practice in hospitals of the Spanish NHS. PMID- 22944285 TI - Nurses' and managers' perceptions of continuing professional development for older and younger nurses: a focus group study. AB - BACKGROUND: Continuing professional development of nurses is increasingly necessary to keep abreast of rapid changes in nursing care. Concurrently, the nursing workforce is growing older. Therefore, future strategies for continuing professional development should be directed at both younger and older nurses. Although there is some evidence that various personal, organisational and social factors result in lower participation of older workers in development activities, age-related differences in continuing professional development among nurses remain under-explored. OBJECTIVE: This study explored nurses' and their managers' perceptions of the differences in continuing professional development between younger and older nurses. DESIGN: A qualitative study using focus groups. The interviews were analysed using a thematic analysis strategy. SETTINGS: A large academic hospital in the Netherlands. PARTICIPANTS: 22 nurses in three age groups (20-34 years, 35-49 years and 50-65 years) and 10 nurse managers participated in four focus groups. RESULTS: Six themes regarding differences in continuing professional development for younger and older nurses emerged from the data: (1) level of focus, (2) creating possibilities to leave the bedside, (3) ambitious young nurses, (4) same resources, different requirements, (5) ceiling in courses for older nurses, and (6) social status and self esteem. Overall, participants seemed to conceptualise continuing professional development along three dimensions: purpose, level of formality of learning activities, and scope of development. CONCLUSIONS: The findings suggest that participants perceive differences in continuing professional development between younger and older nurses. Its purpose and the contributing learning activities are considered to change during the lifespan. When developing strategies for continuing professional development, the requirements and needs of different age groups need to be taken into account. Whether the scope of professional development is confined to "keeping up to date" or used more broad, including "expansion of skills and knowledge" seems to relate more to nurses' attitudes towards work than to their age. PMID- 22944286 TI - Pharmacokinetic and dynamic study of levofloxacin and rifampicin in bone and joint infections. AB - OBJECTIVE: We studied the pharmacokinetic and pharmacodynamic parameters of levofloxacin and rifampicin in bone and joint infections. The optimal dose regimen of these two antibiotics has not been documented yet. PATIENTS AND METHOD: We performed plasma dosage for each antibiotic in patients with a bone and joint infection requiring treatment with a levofloxacin and rifampicin combination. We then computed the 6 hours post dose area under the concentration time curve (AUC(0-6h)), the peak plasma concentration (Cmax), the area under the inhibitory concentration curve (AUIC), and the peak-to-minimum-inhibitory concentration ratio (Cmax/MIC). The pharmacodynamic results were then compared to the published thresholds of effectiveness. The doses used were levofloxacin 500 mg bid and rifampicin 20mg/kg per day. RESULTS: The plasma of 17 patients was dosed. The average AUC(0-6h) for levofloxacin was 46.59 mg.h/l, the average Cmax 10.7 mg/l, the average AUIC 932, and the average Cmax/MIC 107.5. The averages for rifampicin were 42.2mg.h/l, 11.8 mg/l, 11,125 and 1514. Given that bone concentration of levofloxacin is 30% that of the plasma concentration, that concentration was divided by three to estimate bone concentration. CONCLUSION: The optimal thresholds of pharmacodynamic effectiveness were obtained for most patients with levofloxacin at 500 mg bid. Additional studies are still required to determine the optimal rifampicin dose. PMID- 22944287 TI - Structural congenital brain disease in congenital heart disease: results from a fetal MRI program. AB - OBJECTIVE: To identify the type and incidence of fetal brain pathology in fetuses with a prenatal diagnosis of congenital heart disease (CHD). PATIENTS AND METHODS: 67 pregnant women underwent a fetal MR-examinations between 20 and 38 gestational weeks. MR was done on a 1.5 T superconducting system. The type of cardiac malformation was defined by fetal echocardiography. Fetuses with a chromosomal abnormality or an extracardiac anomaly were excluded. RESULTS: Fetal MRI scans in the final study cohort (53 fetuses) yielded normal results in 32 fetuses and a brain abnormality in 21 fetuses. Congenital brain disease (CBD) was found in 39% of the final study cohort of fetuses with CHD. MRI findings were classified into malformations, acquired lesions and widening of the ventricles and/or outer CSF spaces (malformations: 7 fetuses, acquired lesions: 5 fetuses, changes in CSF spaces: 9 fetuses). Asymmetry of the ventricles was the most common finding in the CSF group. CONCLUSIONS: Our data suggest that fetal MRI can be used to characterize structural CBD in CHD. Advanced MRI techniques such as diffusion tensor imaging and proton spectroscopy are tools that, in the future, will certainly shed light on the spectrum of structural and functional CBDs that are associated with CHD. PMID- 22944288 TI - Serum adiponectin, resistin, leptin concentration and central adiposity parameters in Barrett's esophagus patients with and without intestinal metaplasia in comparison to healthy controls and patients with GERD. AB - BACKGROUND/AIMS: Central obesity is a risk factor for GERD, Barrett's esophagus and esophageal adeno-carcinoma. Recent studies have suggested that adipocytokines are the possible link between adiposity and Barrett's carcinogenesis. To determine the adiponectin, resistin and leptin concentration as well as the central adiposity parameters in BE patients with and without intestinal metaplasia (IM) in comparison to GERD and healthy controls. METHODOLOGY: Total of 77 patients (30 patients with GERD, 26 BE with IM and 21 BE without IM) and 30 healthy controls were investigated for the central obesity parameters. Serum levels of adipocytokines were measured with ELISA. RESULTS: The serum concentration of adiponectin was significantly lower in BE compared to those in GERD and to controls (p<0.001). Levels of leptin was slightly higher in BE than in GERD and controls (NS). Level of resistin was significantly higher in GERD compared to both control and BE patients (p<0.001). Waist circumference, WHR and WTR were significantly higher in BE patients compared to GERD (p<0.001) and to control group (p<0.001). CONCLUSIONS: Features of central obesity rather than BMI are associated with BE development. Adipokines may be important at the early step of BE development, before the IM occurrence. PMID- 22944289 TI - The safety and utility of pancreatic duct stents in the emergency ERCP of acute biliary pancreatitis but difficult sphincterotomy. AB - BACKGROUND/AIMS: The aims of this study were to assess the feasibility and safety of emergency ERCP and pancreatic duct (PD) stenting in acute biliary pancreatitis (ABP) patients in whom biliary endoscopic sphincterotomy proved difficult, and to compare the clinical outcome of those patients having emergency ERCP without pancreatic stent. METHODOLOGY: One hundred and ninety-one consecutive patients with ABP were included in this study. Patients were randomly assigned to either the stent group (n=78) or the no-stent group (n=113). In the stent group, 3-5Fr,5 7cm-long pancreatic stent insertion was initially applied and removed endoscopically 1-2 weeks post-ER-CP. All patients were hospitalized for medical therapy and were followed-up. RESULTS: Mean age, initial symptom-to-ERCP times, Glasgow severity scores and peak amylase and CRP levels at initial presentation were not significantly different in the stent group vs. the no-stent group, and the selective biliary cannulation was achieved in 80% of the stent group and in 94% of the no-stent group (p=0.15). More importantly, the complication rate was significantly lower in the stent group (7.7% vs. 31.9%). There was no difference in mortality between the two groups statistically(1.3% vs. 3.5%). CONCLUSIONS: Pancreatic duct stent-ing is a safe and effective procedure that may afford sufficient PD decompression to reverse the process of ABP, show better outcomes as compared to no-stent group. It is recommended to reduce the incidence of the complication in the emergency ERCP of ABP but difficult sphincterotomy. However, further prospective trials are needed. PMID- 22944290 TI - Ethics in dermatology: toward a new paradigm. AB - Medical ethics have evolved over time, and ethical responsibilities have often been shared by priests, the governing classes, and physicians. The emergence of scientific medicine led to the separation of functions, yet physicians have nonetheless continued to enjoy an extraordinary degree of moral authority and great social privilege. From this starting point, professional medical ethics developed as a specific moral system based on special rights and duties (paternalism and medical confidentiality). Various historical events brought this longstanding situation to a point of crisis toward the middle of the 20th century, and for several decades since, medical ethics have been based on freedom of choice for the patient with regard to decisions about his or her own body and health. Recent developments have created a new, still poorly defined model that takes into consideration such matters as euthanasia, abortion, provision of information on the benefits and harm of treatments, the sharing of therapeutic decision-making with the patient and/or family members, the choice of public or private medical providers, therapeutic guidelines, and the extension of the scope of practice to include preventive measures and cosmetic procedures. What is needed now is a new ethical system for plural societies that harbor different religions, beliefs and lifestyles, but that is also rational, universal and subject to ongoing revision-a system always striving for scientific, technical and moral excellence. Such an ethical system would have to be taught in medical schools, as it would need to bear fruit beyond mere good intentions. PMID- 22944291 TI - Analysis of the surgical activity in the Dermatology Department of Fuenlabrada University Hospital, Madrid, Spain, between 2005 and 2010: determination of the standard operating times. AB - OBJECTIVES: To analyze the characteristics of the dermatologic surgery lists and to compare different indicators of surgical productivity. MATERIALS AND METHODS: This was a retrospective, descriptive study of the routine surgical activity undertaken in the Dermatology Department of Fuenlabrada University Hospital, Madrid, Spain, between January 2005 and December 2010. Data about the procedures performed and about the surgical lists were analyzed and an analysis was made of operating room occupancy. Surgical productivity was analyzed using standard operating times (SOTs) and surgical scheduling adequacy values (SA1 and SA2). Variables were recorded as relative frequencies. Covariance and the Pearson linear correlation index were used for comparisons. RESULTS: The study period included a total of 11,481 surgical sessions, of which 71% were minor surgery and the remainder were major outpatient surgery. A mean of 9.7 operations were performed in each session and the overall operating room occupancy was 71.9%. Four SOT descriptors (minor surgery, multiple minor skin lesions, nail surgery, and malignant tumors with primary closure) were sufficient to classify 86.7% of the operations performed. The operating room down-time was 0.15 SOT (9minutes) in 91.3% of operations. The mean SA1 index was 1.20. Overall surgical productivity measured using the SA2 index was 96.46%. The Pearson correlation showed a statistically significant relationship between the increase in the number of patients per surgical session, the reduction in operating room occupancy, and the increase in SA2 operating room productivity. CONCLUSIONS: The application of SOT descriptors enables us to quantify the complexity of the operations included in the surgical waiting list and to obtain indicators for the evaluation of surgical activity, improving efficiency in surgical time management. PMID- 22944293 TI - Clinicopathologic significance and function of mammalian target of rapamycin activation in esophageal squamous cell carcinoma. AB - Mammalian target of rapamycin (mTOR) has emerged as a key regulator of cell metabolism, growth, and proliferation. Despite the increasing significance of mTOR signaling in cancer cell cycle and proliferation, the clinical significance of activated mTOR in esophageal squamous cell carcinoma and its role in esophageal cancer cell proliferation and invasion remain unclear. Here, we show that both high levels of phosphorylated-mTOR and an increased ratio of phosphorylated-mTOR/mTOR (ratio >=0.2) were significantly associated with shortened disease-specific survival in 165 patients with esophageal squamous cell carcinoma in univariate analysis (P = .047 for phosphorylated-mTOR, P = .021 for phosphorylated-mTOR/mTOR); phosphorylated-mTOR and phosphorylated-mTOR/mTOR remained independent prognostic factors after adjusting for age, TNM stage, chemotherapy, and radiation therapy in multivariate analysis (hazard ratio, 1.67, P = .025 for phosphorylated-mTOR; hazard ratio, 1.95, P = .006 for phosphorylated mTOR/mTOR). Moreover, down-regulation of mTOR or mTOR complex components led to attenuation of proliferation, migration, and invasion of esophageal squamous cell carcinoma cell lines through suppression of cyclin D1 expression. Collectively, our findings suggest that phosphorylated-mTOR and the ratio of phosphorylated mTOR/mTOR are closely linked to tumor progression and represent independent prognostic factors in esophageal squamous cell carcinoma, thereby providing a potential therapeutic target for this malignancy. PMID- 22944295 TI - Expression of stem-cell markers OCT-4 and CD133: important prognostic factors in papillary renal cell carcinoma. AB - Except for tumor stage and histologic subtype, the prognostic factors of papillary renal cell carcinoma remain controversial. To the best of our knowledge, the prognostic significance of the expression of stem cell markers, OCT-4 and CD133, has not yet been studied in papillary renal cell carcinoma. Expressions of OCT-4 and CD133 were examined immunohistochemically in a tissue microarray construct generated from 119 cases of papillary renal cell carcinoma, collected from November 1996 to December 2008, and then the results were correlated with the clinicopathologic findings. OCT-4 was expressed at the nuclei of tumor cells in 26 cases (22%). The high expression of OCT-4 with a cut-off value of 12.5%, was associated with frequent microscopic lymphovascular invasion and poor disease-specific survival. CD133 was expressed in the apicolateral cell membrane of tumor cells in 21 cases (17.8%) with a cut-off value of 5%. The CD133 expression was correlated with small tumor size and lack of microscopic lymphovascular invasion, and it tended to be associated with a low Fuhrman nuclear grade and prolonged disease-specific survival. On multivariate analysis, tumor stage, histologic subtype, and OCT-4 expression, but not CD133 expression, were independent prognostic factors for disease-specific survival. OCT-4 expressing and CD133-nonexpressing papillary renal cell carcinoma showed the shortest disease-specific survival. These results showed that the expression of stem cell markers, OCT-4 and CD133, may serve, respectively, as a poor and favorable prognostic marker, in papillary renal cell carcinoma. PMID- 22944294 TI - Composite mantle cell lymphoma and chronic lymphocytic leukemia/small lymphocytic lymphoma: a clinicopathologic and molecular study. AB - Mantle cell lymphoma (MCL) and chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) share many features and both arise from CD5+ B-cells; their distinction is critical as MCL is a more aggressive neoplasm. Rarely, cases of composite MCL and CLL/SLL have been reported. Little is known about the nature of these cases and, in particular, the clonal relationship of the 2 lymphomas. Eleven composite MCL and CLL/SLL cases were identified. The clinical, morphologic and immunophenotypic features of the MCL and CLL/SLL were characterized. IGH (immunoglobulin heavy chain) gene analysis was performed on microdissected MCL and CLL/SLL components to assess their clonal relationship. Ten patients had lymphadenopathy, and 7 patients had bone marrow involvement. The MCL component had the following growth patterns: in situ (n = 1), mantle zone (n = 3), nodular and diffuse (n = 3), diffuse (n = 3), and interstitial in the bone marrow (the only patient without lymphadenopathy) (n = 1); 6 MCLs had blastoid or pleomorphic and 5 small lymphocytic features. The CLL/SLL component was nodular (n = 9) or diffuse (n = 2). All MCL were CD5(+) and cyclin D1(+) with t(11;14) translocation. All CLL/SLL were CD5(+), CD23(+) and negative for cyclin D1 or t(11;14). IGH gene analysis showed that the MCL and CLL/SLL components displayed different sized fragments, indicating that the MCL and CLL/SLL are likely derived from different neoplastic B-cell clones. The lack of a clonal relationship between the MCL and CLL/SLL components suggests that MCL and CLL/SLL components represent distinct disease processes and do not share a common progenitor B-cell. PMID- 22944296 TI - Epithelial and cartilaginous differentiation in clear cell chondrosarcoma. AB - Clear cell chondrosarcoma is a rare cartilaginous bone tumor, and little is known about its pathology. We investigated the immunohistochemical expression profiles of cytokeratins (CAM5.2, AE1/AE3, CK7, CK8, CK18, and CK20), epithelial membrane antigen, SRY (sex-determining region Y)-box 9, type II collagen, runt-related transcription factor 2, and osteocalcin in clear cell chondrosarcoma and compared them with those in chondroblastoma, conventional chondrosarcoma, and osteosarcoma. Of 5 cases of clear cell chondrosarcoma, 3 demonstrated positive staining for AE1/AE3 and some form of cytokeratin in the clear cell component. Of the 5 cases, 4 strongly expressed SRY (sex-determining region Y)-box 9 in the clear cell component but weakly expressed it in the cartilaginous component. Of the 5 cases of clear cell chondrosarcoma, 3 expressed runt-related transcription factor 2 in both the clear cell and cartilaginous components, but no expression of osteocalcin was detected. In chondroblastoma, 8 of 13 cases expressed AE1/AE3, and other cytokeratins, such as CK7 (4/13), CK8 (6/13), CK18 (8/13), and CK20 (3/13), demonstrated a similar staining extensity pattern between the cellular and cartilaginous components. Clear cell chondrosarcoma and chondroblastoma have similar immunohistochemical features in that they both express epithelial and chondrogenetic markers. On the other hand, tumor cells of clear cell chondrosarcoma have no osteoblastic immunohistochemical expression in comparison with chondroblastoma. PMID- 22944297 TI - A colorful future of quantitative pathology: validation of Vectra technology using chromogenic multiplexed immunohistochemistry and prostate tissue microarrays. AB - The Vectra platform (Caliper Life Sciences, Hopkinton, MA) is an advanced multispectral imaging system for biomarker quantitation in tissue microarray or intact tissue sections. This is the first study to validate its reliability for quantitating spatially overlapping biomarkers using chromogenic multiplexed immunohistochemistry on prostate tissue microarrays. Two tissue microarray cohorts (an outcome tissue microarray and a progression tissue microarray) were used. The outcome tissue microarray cohort consists of 462 duplicate cores with more than 5-year outcome information. The progression tissue microarray cohort consists of 384 duplicate cores from different disease (stage) groups. The tissue microarray slides were stained with different combinations of antibodies (anti androgen receptor, anti-E-cadherin, anti-erythroblastosis virus E26 oncogene related gene product, and anti-alpha-methylacyl-CoA racemase). Three outcome tissue microarrays were stained with androgen receptor + erythroblastosis virus E26 oncogene-related gene + E-cadherin (outcome tissue microarray 1), androgen receptor + E-cadherin (outcome tissue microarray 2), and erythroblastosis virus E26 oncogene-related gene + E-cadherin (outcome tissue microarray 3), respectively. One progression tissue microarray section was stained with E cadherin and alpha-methylacyl-CoA racemase; tissue microarray slides were then scanned with the Vectra platform. Biomarker expression analysis was performed with Vectra software-Nuance 3.0.0, and inForm 1.2. IBM SPSS Statistics 19 was used for statistical and correlation analysis (SPSS, Chicago, IL). Close concordance was found between the triple- and double-immunostaining assays used for quantitating spatially overlapping biomarkers androgen receptor and erythroblastosis virus E26 oncogene-related gene using outcome tissue microarrays (r = 0.897 for androgen receptor and 0.613 for erythroblastosis virus E26 oncogene-related gene, respectively). alpha-Methylacyl-CoA racemase and E cadherin expression levels measured in progression tissue microarray were consistent with previously published data by other groups. In conclusion, Vectra technology is reliable for objective and high-throughput biomarker quantitation and colocalization study using chromogenic multiplexed immunohistochemistry. PMID- 22944298 TI - Central nervous system involvement in systemic lupus erythematosus: Overview on classification criteria. AB - Central nervous system (CNS) involvement is one of the major causes of morbidity and mortality in systemic lupus erythematosus (SLE) patients. Clinical manifestations can involve both the central and peripheral nervous systems, and they must be differentiated from infections, metabolic complications, and drug induced toxicity. Recognition and treatment of CNS involvement continues to represent a major diagnostic challenge. In this Review, we sought to summarise the current insights on the various aspects of neuropsychiatric SLE with special emphasis on the terminology and classification criteria needed to correctly attribute the particular event to SLE. PMID- 22944299 TI - Tregitope update: mechanism of action parallels IVIg. AB - In the course of screening immunoglobulin G (IgG) sequences for T cell epitopes, we identified novel Treg epitope peptides, now called Tregitopes, contained in the highly conserved framework regions of Fab and Fc. Tregitopes may provide one explanation for the expansion and stimulation of Treg cells following intravenous immunoglobulin (IVIg) therapy. Their distinguishing characteristics include in silico signatures that suggest high-affinity binding to multiple human HLA class II DR and conservation across IgG isotypes and mammalian species with only minor amino acid modifications. Tregitopes induce expansion of CD4(+)/CD25(hi)/FoxP3(+) T cells and suppress immune responses to co-incubated antigens in vitro. By comparing the human IgG Tregitopes (hTregitopes 167 and 289, located in the IgG CH1 and CH2 domains) and Fab to murine sequences, we identified class II restricted murine Tregitope homologs (mTregitopes). In vivo, mTregitopes suppress inflammation and reproducibly induce Tregs to expand. In vitro studies suggest that the Tregitope mechanism of action is to induce Tregs to respond, leading to production of regulatory signals, followed by modulation of dendritic cell phenotype. The identification of Treg epitopes in IgG suggests that additional Tregitopes may also be present in other autologous proteins; methods for identifying and validating such peptides are described here. The discovery of Tregitopes in IgG and other autologous proteins may lead to the development of new insights as to the role of Tregs in autoimmune diseases. PMID- 22944300 TI - A high throughput platform for understanding the influence of excipients on physical and chemical stability. AB - The present study puts forward a miniaturized high-throughput platform to understand influence of excipient selection and processing on the stability of a given drug compound. Four model drugs (sodium naproxen, theophylline, amlodipine besylate and nitrofurantoin) and ten different excipients were selected. Binary physical mixtures of drug and excipient were transferred to a 96-well plate followed by addition of water to simulate aqueous granulation environment. The plate was subjected for XRPD measurements followed by drying and subsequent XRPD and HPLC measurements of the dried samples. Excipients with different water sorbing potential were found to influence distinctly on the phase transformation behaviour of each drug. Moreover, the amount of water addition was also a critical factor affecting phase transformation behaviour. HPLC analysis revealed one of the drug:excipient pairs with a tendency for chemical degradation. The proposed high-throughput platform can be used during early drug development to simulate typical processing induced stress in a small scale and to understand possible phase transformation behaviour and influence of excipients on this. PMID- 22944301 TI - Blood-pool multifunctional nanoparticles formed by temperature-induced phase transition for cancer-targeting therapy and molecular imaging. AB - Multifunctional nanoparticles (NPs) were prepared based on temperature-induced phase transition in a molten mixture of Lipiodol((r)), Tween 80, paclitaxel (PTX), and Pluronic F-68, wherein the Lipiodol((r))/Tween 80 mixture is used as a solubilizer for PTX, and Pluronic F-68 is used for the stabilization of the molten mixture. The morphology and size distribution of optimized multifunctional NPs were observed using transmittance electron microscopy (TEM) and a particle size analyzer. In the optical imaging of tumor-bearing mice using a near-infrared fluorescence (NIRF) imaging system, the multifunctional NPs were evaluated in terms of a time-dependent excretion profile, in vivo biodistribution and tumor targeting capability compared to free fluorescence dye. In addition, the prolonged circulation of multifunctional NPs was confirmed by enhancement of the blood-pool in live animals using a micro-CT imaging system, because iodine containing Lipiodol((r)) has an X-ray enhancement property. Finally, the anti tumor efficacy of multifunctional NPs was monitored by injecting the multifunctional NPs into the tail veins of tumor-bearing mice. The multifunctional NPs showed excellent tumor targetability and anti-tumor efficacy in tumor-bearing mice, caused by the enhanced permeation and retention (EPR) effect. PMID- 22944302 TI - Multiple administration of PEG-coated liposomal oxaliplatin enhances its therapeutic efficacy: a possible mechanism and the potential for clinical application. AB - We previously developed a PEG-coated cationic liposome that enabled dual targeting delivery of oxaliplatin (l-OHP) to both tumor endothelial cells and tumor cells in a solid tumor. The targeted liposomal l-OHP formulation consequently elicited potent antitumor efficacy in a murine solid tumor model after 3 sequential injections. However, the probable mechanism(s) for this enhanced antitumor activity has not been fully elucidated. In the present study, therefore, the changes in tumor microenvironment induced by sequential administration of liposomal l-OHP were investigated, with emphasis on its impact to the intratumoral localization of the subsequently injected dose. In addition, the potential for anti-PEG IgM production upon repeated administration of liposomal l-OHP-containing PEGylated lipid was clearly revealed. Two sequential injections of liposomal l-OHP induced superior apoptotic activity in tumor tissue and thus resulted in broader intratumor distribution of the subsequent test dose of PEG-coated cationic liposomes, compared with a single injection of liposomal l OHP. In addition, it was confirmed that repeated administration of liposomal l OHP did not induce a significant anti-PEG IgM response, indicating that l-OHP encapsulated in PEG-coated liposomes was efficient in abrogating the ABC phenomenon. These results suggest that sequential treatment strategies with liposomal cytotoxic agents might be superior to mono-treatment strategies in achieving alterations in the tumor microenvironment and maintaining/restoring the pharmacokinetics of the formulation, and, therefore, would result in substantial therapeutic efficacy. PMID- 22944303 TI - AFM study of hydrophilicity on acetaminophen crystals. AB - Pharmaceutical powder processing is notoriously subject to unpredictable jamming, sticking and charging disturbances. To unveil the material science underlying these effects, we use atomic force microscopy (AFM) on a common pharmaceutical, acetaminophen (APAP). Specifically, we study surface adhesion and morphology as a function of relative humidity (RH) for monoclinic acetaminophen, using both plain AFM tips and tips functionalized to be hydrophobic or hydrophilic. Results indicate that the (001) crystal face exhibits significantly higher adhesion (surface potential) than the other crystal faces. For all the faces clear peaks in adhesion occur at 50-60% RH when they are examined using hydrophilic tips. The surface morphology of some facets showed a strong dependence on RH while others showed little or no significant change. In particular, the morphology of the (1 10) faces developed large terraces at high humidity, possibly due to deliquescence followed by recrystallization. These results confirm the hypothesis that different crystal facets exhibit distinct surface potentials and morphology that change with environmental exposure. The work suggests that future studies of powder behaviors would benefit from a more detailed modeling of crystal surface contact mechanics. PMID- 22944305 TI - Development of ligustrazine-loaded lipid emulsion: formulation optimization, characterization and biodistribution. AB - Ligustrazine is a traditional Chinese medicine used to treat various cardiovascular and neurovascular complications. However, this compound exhibits rapid first-pass metabolism, a short biological half-life, low stability and potential vascular irritation that restrict its use for long-term therapy. The use of a lipid emulsion as a carrier for intravenous administration of ligustrazine might provide sustained and prolonged release, thereby reducing the frequency of administration and improving patient compliance. The main purpose of our study was to develop a highly stable and sterile optimal formulation of a ligustrazine lipid emulsion (LLE) and to evaluate its pharmacokinetic behavior and tissue distribution in rats. The final optimal formulation consisted of soybean oil (12.0%), oleic acid (0.6%), lecithin (1.0%), poloxamer 188 (0.6%) and glycerol (2.25%). The average particle size, polydispersity index (PDI), zeta potential and pH of the final product were 215.0+/-2.5 nm, 0.076+/-0.033, -40.4+/ 5.3 mV and 7.25+/-0.05, respectively. The LLE was stable for at least three months at room temperature. In vitro drug release studies of the LLE suggested a sustained release profile, which was further confirmed by in vivo pharmacokinetic studies in rats. The area under the drug concentration-time curve from 0 h to 10 h (AUC(0-10h)) for LLE was increased by 1.6-fold compared with that of the commercially available ligustrazine injection (LI), suggesting enhanced bioavailability from the lipid-based emulsion. Furthermore, a tissue distribution study showed significant improvement in the distribution pattern of ligustrazine with a higher AUC(0-180 min) observed in all tissues for LLE than for LI. In conclusion, LLE, with excellent stability, improved pharmacokinetics and tissue distribution, demonstrates great potential for the delivery of ligustrazine for clinical applications. PMID- 22944304 TI - Polymeric micelles and alternative nanonized delivery vehicles for poorly soluble drugs. AB - Poorly soluble drugs often encounter low bioavailability and erratic absorption patterns in the clinical setting. Due to the rising number of compounds having solubility issues, finding ways to enhance the solubility of drugs is one of the major challenges in the pharmaceutical industry today. Polymeric micelles, which form upon self-assembly of amphiphilic macromolecules, can act as solubilizing agents for delivery of poorly soluble drugs. This manuscript examines the fundamentals of polymeric micelles through reviews of representative literature and demonstrates possible applications through recent examples of clinical trial developments. In particular, the potential of polymeric micelles for delivery of poorly water-soluble drugs, especially in the areas of oral delivery and in cancer therapy, is discussed. Key considerations in utilizing polymeric micelles' advantages and overcoming potential disadvantages have been highlighted. Lastly, other possible strategies related to particle size reduction for enhancing solubilization of poorly water-soluble drugs are introduced. PMID- 22944306 TI - Quality by design: impact of formulation variables and their interactions on quality attributes of a lyophilized monoclonal antibody. AB - The purpose of this study was to use QbD approaches to evaluate the effect of several variables and their interactions on quality of a challenging model murine IgG3kappa monoclonal antibody (mAb), and then to obtain an optimized formulation with predefined quality target product profile. This antibody was chosen because it has a propensity to precipitate and thus represents a challenge condition for formulation development. Preliminary experiments were conducted to rule out incompatible buffer systems for the mAb product quality. A fractional factorial experimental design was then applied to screen the effects of buffer type, pH and excipients such as sucrose, sodium chloride (NaCl), lactic acid and Polysorbate 20 on glass transition temperature ( [Formula: see text] ), monoclonal antibody concentration (A(280)), presence of aggregation, unfolding transition temperature (T(m)) of the lyophilized product, and particle size of the reconstituted product. A Box-Behnken experimental design was subsequently applied to study the main, interaction, and quadratic effects of these variables on the responses. Pareto ranking analyses showed that the three most important factors affecting the selected responses for this particular antibody were pH, NaCl, and Polysorbate 20. The presence of curvature in the variables' effects on responses indicated interactions. Based on the constraints set on the responses, a design space was identified for this mAb and confirmed with experiments at three different levels of the variables within the design space. The model indicated a combination of high pH (8) and NaCl (50mM) levels, and a low Polysorbate 20 (0.008 mM) level at which an optimal formulation of the mAb could be achieved. Moisture contents and other analytical procedures such as size exclusion chromatography, protein A analysis and SDS-PAGE of the pre-lyophilized and final reconstituted lyophilized products indicated an intact protein structure with minimal aggregation after formulation and lyophilization. In conclusion, experimental design approach was effective in identifying optimal concentrations of excipients and pH for this challenging monoclonal antibody formulation. PMID- 22944307 TI - Weighted twin support vector machines with local information and its application. AB - A Twin Support Vector Machine (TWSVM), as a variant of a Multisurface Proximal Support Vector Machine via Generalized Eigenvalues (GEPSVM), attempts to improve the generalization of GEPSVM, whose solution follows from solving two quadratic programming problems (QPPs), each of which is smaller than in a standard SVM. Unfortunately, the two QPPs still lead to rather high computational costs. Moreover, although TWSVM has better classification performance than GEPSVM, a major disadvantage is it fails to exploit the underlying correlation or similarity information between any pair of data points with the same labels that may be important for classification performance as much as possible. To mitigate the above deficiencies, in this paper, we propose a novel nonparallel plane classifier, called Weighted Twin Support Vector Machines with Local Information (WLTSVM). WLTSVM mines as much underlying similarity information within samples as possible. This method not only retains the superior characteristics of TWSVM, but also has its additional advantages: (1) comparable or better classification accuracy compared to SVM, GEPSVM and TWSVM; (2) taking motivation from standard SVM, the concept of support vectors is retained; (3) more efficient than TWSVM in terms of computational costs; and (4) only one penalty parameter is considered as opposed to two in TWSVM. Finally, experiments on both simulated and real problems confirm the effectiveness of our method. PMID- 22944308 TI - Four-year follow-up of the rehabilitation of a mandibular arch with a cementable zirconia-reinforced fixed dental prosthesis: a clinical report. AB - Implant-supported prostheses have been used extensively to rehabilitate completely edentulous arches. Although combinations of different restorative materials have reportedly been used to fabricate such prostheses, a metal framework is usually chosen for acrylic resin reinforcement. However, cost and the frequent need to section and solder to attain a passive framework fit are disadvantages for using metal. Zirconia has been used widely in restorative dentistry as an alternative to metal. This clinical report describes the fabrication of a zirconia-reinforced cementable fixed dental prosthesis with a 4 year follow-up. PMID- 22944309 TI - The fabrication of a CAD/CAM ceramic crown to fit an existing partial removable dental prosthesis: a clinical report. AB - The application of computer-aided design/computer-assisted manufacturing (CAD/CAM) technology to fabricate a retrofit ceramic surveyed crown to an existing partial removable dental prosthesis (PRDP) is described. The fabrication of a surveyed crown by using CAD/CAM technology enables precise and easy replication of the shape and contours as well as the rest seat of the existing abutment tooth, ensuring excellent adaptation to the existing PRDP framework with minimal adjustment. PMID- 22944310 TI - The effect of fiber post presence and restorative technique on the biomechanical behavior of endodontically treated maxillary incisors: an in vitro study. AB - STATEMENT OF PROBLEM: Unresolved controversy exists concerning the best technique for restoring endodontically treated teeth. Prefabricated posts have been recommended with some debate as a method of restoring pulpless teeth before placement of the final restoration. PURPOSE: The purpose of this in vitro study was to evaluate the effect on the strain, fracture resistance, and fracture mode of endodontically treated human incisors of 4 types of restorations with or without glass fiber posts after thermal cycling. MATERIAL AND METHODS: Ninety human maxillary central incisors were selected and divided into 1 control group and 8 treatment groups (n=10). The teeth were endodontically treated and received 2 large Class III preparations simulating coronal destruction. The teeth were then restored with or without glass fiber posts and by using 4 restorative techniques: direct composite resin, direct composite veneer, feldspathic ceramic veneer, or a feldspathic ceramic crown. After artificial aging by thermal cycling, the incisors were loaded at a 135-degree angle, and the strain was measured by using strain gauges placed on the facial and proximal root surfaces. Specimens were subsequently loaded to the point of fracture. Strain and fracture resistance results were analyzed by a 1-way and 2-way ANOVA, followed by the Tukey HSD and Dunnett tests (alpha=.05). RESULTS: One-way analyses showed that the control group and the direct composite resin restoration with and without post groups presented significantly higher fracture resistance values (P<.001). Two-way analyses showed no significant differences for the post system. Proximal strain values were higher in the control and composite resin groups and lower in the feldspathic ceramic groups. CONCLUSIONS: The presence of glass fiber posts did not increase the fracture resistance of endodontically treated incisors. Conservative composite resin restorations showed higher fracture resistance values. PMID- 22944311 TI - Evaluation of fiber post-supported restorations under simulated occlusal loading. AB - STATEMENT OF PROBLEM: There is a lack of information comparing the effect of a rigid versus flexible post on the marginal seal of post-and-core supported crowns subjected to long-term repeated loading. PURPOSE: The purpose of this study was to examine the leakage pattern of complete coverage restorations retained with either a metal or fiber-reinforced resin post under simulated occlusal loads. MATERIAL AND METHODS: Thirty-six maxillary central incisors were endodontically treated and provided with a post-and-core supported crown. One group was restored with a fiber-post (EasyPost Lux) and another was restored with a metal post (Parapost) (n=12). Both groups were loaded for 120,000 cycles to 70 N while immersed in a dye solution. A control group (n=12), similarly restored with a fiber post but not loaded, was also included. All teeth were transversely sectioned serially from the tooth-core interface towards the apex. Digital photographs were made to determine the extent of leakage on the buccal, mesial, palatal, and distal aspects along the depth of the post. A nonparametric Kruskal Wallis test was used to determine any difference between groups (alpha=.05). RESULTS: Dye penetration occurred in all stress-cycled specimens and was more extensive on the palatal than other aspects. The fiber-post group cyclically stressed to 70 N showed a significantly greater amount of leakage than the control or the Parapost group (P<.05). CONCLUSIONS: In in vitro testing, the rigidity of the post influenced the seal of post-and-core-supported crowns at the palatal margin. PMID- 22944312 TI - Qualitative and quantitative three-dimensional accuracy of a single tooth captured by elastomeric impression materials: an in vitro study. AB - STATEMENT OF PROBLEM: The accuracy of impressions has been described in 1 or 2 dimensions, whereas it is most desirable to evaluate the accuracy of impressions spatially, in 3 dimensions. PURPOSE: The purpose of this study was to demonstrate the accuracy and reproducibility of a 3-dimensional (3-D) approach to assessing impression preciseness and to quantitatively comparing the occlusal correctness of gypsum dies made with different impression materials. MATERIAL AND METHODS: By using an aluminum replica of a maxillary molar, single-step dual viscosity impressions were made with 1 polyether/vinyl polysiloxane hybrid material (Identium), 1 vinyl polysiloxane (Panasil), and 1 polyether (Impregum) (n=5). Corresponding dies were made of Type IV gypsum and were optically digitized and aligned to the virtual reference of the aluminum tooth. Accuracy was analyzed by computing mean quadratic deviations between the virtual reference and the gypsum dies, while deviations of the dies among one another determined the reproducibility of the method. The virtual reference was adapted to create 15 occlusal contact points. The percentage of contact points deviating within a +/ 10 um tolerance limit (PDP(10) = Percentage of Deviating Points within +/-10 um Tolerance) was set as the index for assessing occlusal accuracy. Visual results for the difference from the reference tooth were displayed with colors, whereas mean deviation values as well as mean PDP(10) differences were analyzed with a 1 way ANOVA and Scheffe post hoc comparisons (alpha=.05). RESULTS: Objective characterization of accuracy showed smooth axial surfaces to be undersized, whereas occlusal surfaces were accurate or enlarged when compared to the original tooth. The accuracy of the gypsum replicas ranged between 3 and 6 um, while reproducibility results varied from 2 to 4 um. Mean (SD) PDP(10)-values were: Panasil 91% (+/-11), Identium 77% (+/-4) and Impregum 29% (+/-3). One-way ANOVA detected significant differences among the subjected impression materials (P<.001). CONCLUSIONS: The accuracy and reproducibility of impressions were determined by 3-D analysis. Results were presented as color images and the newly developed PDP(10)-index was successfully used to quantify spatial dimensions for complex occlusal anatomy. Impression materials with high PDP(10)-values were shown to reproduce occlusal dimensions the most accurately. PMID- 22944313 TI - Microleakage of different sealing materials in access holes of internal connection implant systems. AB - STATEMENT OF PROBLEM: Current implant systems cannot completely prevent microleakage from the access holes of screw-retained implant prostheses, which may constitute risks to the clinical success of the implants. PURPOSE: The purpose of this study was to evaluate the levels of microleakage through the access holes of screw-retained implant prostheses sealed with different materials. MATERIAL AND METHODS: An implant with an internal hexagonal configuration was connected to a temporary abutment with an acrylic resin crown. The apical 6.5 mm of the access hole was filled with 1 of the following materials: cotton pellet, silicone sealing material, vinyl polysiloxane, or gutta percha. The remaining coronal 3 mm was sealed with composite resin. Cyclic loading with 21 N at 1 Hz was applied 16,000 times to the specimens in 0.5% basic fuchsin solution according to the long axis of the tooth. Basic fuchsin dye which penetrated into the internal wall of the abutment through the access hole was dissolved with methyl alcohol. Then the absorbance was measured by a spectrophotometer at 540 nm to evaluate the degree of microleakage. The results were statistically analyzed with 1-way ANOVA and the Tukey HSD test. RESULTS: From greatest to least, the levels of microleakage were in the following order: cotton pellet, silicone sealing material, vinyl polysiloxane, and gutta-percha. The microleakage associated with gutta-percha was not significantly different from that of vinyl polysiloxane. CONCLUSIONS: When sealing the access holes of screw-retained implant prostheses, gutta-percha or vinyl polysiloxane would help reduce microleakage. PMID- 22944314 TI - Accuracy of three different types of stereolithographic surgical guide in implant placement: an in vitro study. AB - STATEMENT OF PROBLEM: Precise treatment planning before implant surgery is necessary to identify vital structures and to ensure a predictable restorative outcome. PURPOSE: The purpose of this study was to compare the accuracy of implant placement by using 3 different types of surgical guide: bone-supported, tooth-supported, and mucosa-supported. MATERIAL AND METHODS: Thirty acrylic resin mandibles were fabricated with stereolithography (SLA) based on data from the cone beam computerized tomography (CBCT) scan of an edentulous patient. Ten of the mandibles were modified digitally before fabrication with the addition of 4 teeth, and 10 of the mandibles were modified after fabrication with soft acrylic resin to simulate mucosa. Each acrylic resin mandible had 5 implants virtually planned in a 3-D software program. A total of 150 implants were planned and placed by using SLA guides. Presurgical and postsurgical CBCT scans were superimposed to compare the virtual implant placement with the actual implant placement. For statistical analyses, a linear mixed models approach and t-test with the 2-sided alpha level set at .016 were used. All reported P values were adjusted by the Dunn-Sidak method to control the Type I error rate across multiple pairwise comparisons. RESULTS: The mean angular deviation of the long axis between the planned and placed implants was 2.2 +/-1.2 degrees; the mean deviations in linear distance between the planned and placed implants were 1.18 +/-0.42 mm at the implant neck and 1.44 +/-0.67 mm at the implant apex for all 150 implants. After the superimposition procedure, the angular deviation of the placed implants was 2.26 +/-1.30 degrees with the tooth-supported, 2.17 +/-1.02 degrees with the bone-supported, and 2.29 +/-1.28 degrees with the mucosa supported SLA guide. The mean deviations in linear distance between the planned and placed implants at the neck and apex were 1.00 +/-0.33 mm and 1.15 +/-0.42 mm for the tooth-supported guides; 1.08 +/-0.33 mm and 1.53 +/-0.90 mm for the bone supported guides; and 1.47 +/-0.43 mm and 1.65 +/-0.48 mm for the mucosa supported SLA surgical guides. CONCLUSIONS: The results of this study show that stereolithographic surgical guides may be reliable in implant placement and that: 1) there was no statistically significant difference among the 3 types of guide when comparing angular deviation and 2) mucosa-supported guides were less accurate than both tooth-supported and bone-supported guides for linear deviation at the implant neck and apex. PMID- 22944315 TI - Delayed linear dimensional changes of five high strength gypsum products used for the fabrication of definitive casts. AB - STATEMENT OF PROBLEM: Prolonged storage of definitive casts made from Type IV and Type V gypsum products, especially in an environment of increased temperature and low humidity, may result in contraction. PURPOSE: The purpose of this study was to evaluate the linear dimensional changes of 5 different high strength stones after exposing them to 2 different storage conditions over a period of 3 weeks. MATERIAL AND METHODS: Three Type IV dental stones (Fujirock, Vel-Mix, Suprastone) and 2 Type V dental stones (Hard Rock, Jade Stone) were tested in this study. A circular conical stainless steel die with a diameter of 66 mm and a height of 10 mm was made. Two V-shaped grooves, 38 mm apart, were scribed on the surface of the die for the purposes of measurement. A conical stainless steel ring with a bottom inner diameter of 68 mm and a top inner diameter of 65 mm was also fabricated to fit precisely around the stainless steel die. The dental stone was mixed with water under vacuum and poured under vibration onto the stainless steel die, which was surrounded by the ring. The specimens (n=20) were separated from the stainless steel die 1 hour after pouring. Half of these specimens (control) were stored in a room at 22 +/-1 degrees C with relative humidity of 50 +/-5%, while the rest of the specimens were placed in a temperature regulating incubator at 40 +/-1 degrees C and relative humidity of <20%. The linear dimensional changes were recorded at designated time intervals with a traveling microscope over a 3 week period. Collected data were subjected to a 2-way repeated-measures analysis of variance (ANOVA) (alpha=.05). RESULTS: The highest expansion values for the specimens in the control group were recorded between 72 and 96 hours. A contraction was noticed thereafter for all specimens, in both groups. No difference in the measurements was registered between the second and third week. ANOVA revealed significant differences (P<.001) among different Type IV and V dental stone products, time, and storage conditions. CONCLUSIONS: The highest expansion values for all specimens in the control group were recorded between 72 and 96 hours. The highest expansion values for all specimens in the experimental group were recorded at 24 hours. For all specimens, contraction was noticed up to the 2-week measurements. All factors examined (dental stone, time, storage condition) significantly affected the linear dimensional changes. PMID- 22944316 TI - A technique for fabricating a definitive immediate implant-supported prosthesis for the edentulous mandible. AB - A technique for fabricating a definitive immediate fixed implant-supported prosthesis to rehabilitate the edentulous mandible is described. Temporary abutments were used first as impression copings, later modified to achieve parallelism, and finally incorporated in the definitive framework. The metal framework was fabricated with holes for the abutments and connected to the abutments with composite resin cement intraorally to obtain passive fit. This technique reduced the number of steps, thereby decreasing insertion time of the definitive prosthesis to 2 days. PMID- 22944317 TI - A straightforward modification of an immediate surgical obturator bulb. PMID- 22944318 TI - Emesis in diabetes mellitus. AB - It is estimated that 20-40% of patients with diabetes, particularly those with prolonged duration of type 1 diabetes mellitus with other complications develop gastroparesis .We present in a picture quiz format the interesting case of an elderly lady presenting with diabetic gastroparesis in a tertiary care hospital in India. PMID- 22944319 TI - Beta-adrenergic receptor activation primes microglia cytokine production. AB - Exaggerated pro-inflammatory cytokine production by primed microglia is thought to mediate pathology during stress, aging, and neurodegeneration. Recently, it was demonstrated that beta-adrenergic receptor (beta-AR) antagonism prevents priming of microglia in mice exposed to chronic stress. To determine if beta-AR stimulation is sufficient to prime microglia, rats were intra cerebroventricularly administered isoproterenol (beta-AR agonist) or vehicle and 24 h later hippocampal microglia were placed in culture with media or LPS. Prior isoproterenol treatment significantly enhanced IL-1beta and IL-6, but not TNF alpha production following LPS stimulation. These data suggest that central beta AR stimulation is sufficient to prime microglia cytokine responses. PMID- 22944320 TI - Therapeutic effects of anti-Delta1 mAb on Theiler's murine encephalomyelitis virus-induced demyelinating disease. AB - We examined the role of Notch ligand Delta-like 1 (Delta1) in the development of Theiler's murine encephalomyelitis virus (TMEV)-induced demyelinating disease (TMEV-IDD). Blocking of Delta1 by anti-Delta1 monoclonal antibody (mAb) in the effector phase significantly suppressed the disease development of TMEV-IDD both clinically and histologically. The number of infiltrating inflammatory mononuclear cells in the spinal cords was also decreased in mice treated with anti-Delta1 mAb at the effector phase. Flow cytometric analysis of cytokine staining revealed that IFN-gamma- or IL-4-producing CD4(+) splenocytes were significantly decreased in mice treated with anti-Delta1 mAb in the spleens, whereas IL-10-producing CD4(+) splenocytes were increased. Furthermore, IFN-gamma , TNF-alpha-, IL-4-, or IL-10-producing CD4(+) cells were decreased in spinal cords, and IL-17-producing CD4(+) cells were increased. These data suggest that Delta1 may play important roles in the development of TMEV-IDD and that antibodies to Delta1 could be used as a novel therapeutic treatment of demyelinating diseases such as human multiple sclerosis. PMID- 22944321 TI - Sweet potato calmodulin SPCAM is involved in salt stress-mediated leaf senescence, H2O2 elevation and senescence-associated gene expression. AB - The sweet potato calmodulin gene, SPCAM, was previously cloned and shown to participate in ethephon-mediated leaf senescence, H2O2 elevation and senescence associated gene expression. In this report, an association of SPCAM with NaCl stress is reported. Expression of SPCAM was significantly enhanced by NaCl on days 1 and 2 after salt treatment in a dose-dependent manner and drastically decreased again on the third day. Starting on day 6, salt stress also remarkably promoted leaf senescence, H2O2 elevation and senescence-associated gene expression in a dose-dependent manner. These salt stress-mediated effects were strongly inhibited by chlorpromazine, a calmodulin inhibitor, and the chlorpromazine-induced repression could be reversed by exogenous application of purified calmodulin fusion protein. These data suggest an involvement of calmodulin in salt stress-mediated leaf senescence, H2O2 elevation and senescence associated gene expression in sweet potato. Exogenous application of SPCAM fusion protein alone, however, did not significantly accelerate leaf senescence and senescence-associated gene expression, but only showed a slight effect 12 days after treatment. These data suggest that additional components are involved in salt stress-mediated leaf senescence in sweet potato, possibly induced by and coordinated with SPCAM. In conclusion, the sweet potato calmodulin gene is NaCl inducible and participates in salt stress-mediated leaf senescence, H2O2 elevation and senescence-associated gene expression. PMID- 22944322 TI - [Geriatrics creates a coherent response to the elderly patient with complex disease]. PMID- 22944323 TI - [The good guidance conversation shall promote learning]. PMID- 22944324 TI - [Learning-enhancing evaluation practice in post-graduate medicine]. AB - The article addresses the issue of evaluation in clinical supervisor interviews, and how learning outcomes can be increased in this setting. Based on a literature review the article demonstrates that a learning-enhancing evaluation is a context bound process that needs to take emotional, social and operational aspects in account, in order to be successful. The article contributes to an understanding of how to promote a learning-enhancing evaluation practice in post-graduate medicine in the Danish medical training. PMID- 22944325 TI - [Various methods for monitoring cardiac output in intensive care patients]. AB - This article presents a mini medical technology evaluation of three less invasive monitoring techniques for monitoring cardiac output, CardioQ, ECOM and PiCCO, with focus on validation, usability and costs in intensive care. In conclusion, when identifying patients with low cardiac output, we suggest starting with simple screening tools (e.g. CardioQ or central venous O2 saturation), and when in doubt, upgrade to better validated, yet more time-consuming techniques (e.g. PiCCO using thermodilution). Also consults should be made to other intensive care units in terms of the practical implementation of the monitors. PMID- 22944326 TI - [Bowel anastomoses can be safely performed using a suturing technique with a single layer instead of two layers]. AB - A recent Cochrane review has shown that bowel anastomoses can be safely performed using a suturing technique with a single layer of sutures rather than a double layer technique. In Denmark, however, relatively few departments use the single layer method as a standard technique. In this paper we discuss the review and recommend that all surgical departments in Denmark use the single layer technique for bowel anastomoses, since it is safe, fast and easy to learn for surgeons in training. PMID- 22944327 TI - [Journalistic narrative can complement health professional understanding in rehabilitation]. AB - Narrative journalism was used to convey subjective patient perspectives in a study of multidisciplinary rehabilitation of six people with amyotrophic lateral sclerosis. Narratives brought out complementary issues and compensated for loss of speech. A majority of health professionals assessed the narratives as relevant and useful for their professional duties. We suggest that when dealing with rehabilitation in chronic cases demanding palliation, a narrative method should be incorporated in order to complement health disciplines in the field. PMID- 22944328 TI - [Necrotizing tonsillitis and renal vein thrombosis due to acute myeloid leukaemia]. AB - A 37-year-old woman was admitted to hospital with severe tonsillitis with unilateral necrotizing tonsillitis. She suddenly got fever, malaise, difficulties swallowing, pain in the throat and deterioration despite four days of penicillin treatment. During hospitalisation, she experienced abdominal pain, and blood tests showed pancytopenia. She was transferred to a haematological department, where a bone marrow biopsy showed acute myeloid leukaemia. Subsequently, an abdominal computed tomography with intravenous contrast revealed bilateral renal vein thrombosis, probably because of coagulopathy due to leukaemia. PMID- 22944329 TI - [Toxic shock syndrome developed after scalding with water]. AB - Toxic shock syndrome (TSS) is a potentially lethal condition most often caused by Staphylococcus aureus. The diagnostic criteria for TSS are high fever, hypotension, rash, desquamation 1-2 weeks after onset of illness, and involvement of three or more organ systems. Most patients are young menstruating women, and most burn patients with TSS are children. A 66-year-old woman was scalded with water and developed TSS four days later. She was admitted to an intensive care unit where she received adequate treatment. She was discharged after 15 days in hospital. PMID- 22944330 TI - [Hyoid bone tumour]. PMID- 22944331 TI - Prediction and monitoring of treatment effect using T1-weighted dynamic contrast enhanced magnetic resonance imaging in colorectal liver metastases: potential of whole tumour ROI and selective ROI analysis. AB - PURPOSE: To evaluate dynamic contrast-enhanced magnetic resonance imaging (DCE MRI) for prediction and early monitoring of treatment in colorectal liver metastases. MATERIALS AND METHODS: Ten patients were included. Baseline and follow-up DCE-MRI examinations were evaluated by whole tumour and selected ROI placements calculating Kep-values. Selective ROIs, concentric-like and hot spot, were drawn on early arterial phase images. Monitoring of treatment was performed comparing RECIST1.1 criteria with whole tumour and selected ROI placement. To evaluate treatment effect between responders and non-responders, independent samples t-test was used on Kep-values. RESULTS: In each patient largest lesion was evaluated totalling 10 target lesions. At baseline, for whole tumour ROI placements mean Kep-values in responders were significantly higher than mean Kep values in non-responders (t=7.481, p<0.001). Selective ROI placement comparison of mean Kep-values at baseline and after 6 weeks of treatment (first follow-up measurement) showed significant decrease in responding patients (t=4.706, p=0.003) whereas increase in Kep-values in non-responding patients was not statistically significant. CONCLUSION: This preliminary study shows that baseline Kep for whole tumour ROI is a predictor for treatment outcome. Decrease of Kep using selective ROIs allows early identification of response after 6 weeks of treatment. PMID- 22944332 TI - Design and synthesis of EGFR dimerization inhibitors and evaluation of their potential in the treatment of psoriasis. AB - Hit compounds from in silico screening for inhibitors of the EGFR dimerization process were evaluated for their anti-proliferative (CCD-1106 keratinocytes) and anti-oxidant (TBA assay) activity and their effect on EGFR dimerization (BS(3) chemical crosslinking assay). 7-Benzyl-8-{N'-[1-(3-ethoxy-4-hydroxyphenyl)meth (Z)-ylidene]hydrazino}-1,3-dimethylxanthine 2a (127 MUM) leads to 37% inhibition of p-EGFR dimerization in the CCD-1106 cell line and also inhibits phosphorylation of proteins in the MAPK/ERK pathway, ERK 1/2 and p-38. Based on this initial data, 2a was selected for further study and was evaluated for its anti-proliferative activity in a range of keratinocyte (CCD-1106, HaCaT and NHEK) and monocyte (ThP1 and U937) cell lines. Xanthine 2a is pro-apoptotic in HaCaT keratinocytes, as shown by electron microscopy, caspase 3/7, and annexin V FITC/PI flow cytometric assays. It is significantly less cytotoxic than the established antipsoriatic agent dithranol 14, as determined by MTT and LDH release assays, and thus has potential as a lead compound for the treatment of psoriasis. PMID- 22944333 TI - Synthesis and biological evaluation of novel homochiral carbocyclic nucleosides from 1-amino-2-indanols. AB - New chiral purinyl and 8-azapurinyl carbanucleoside derivatives based on indanol were synthesized from commercial available (1S,2S)-trans-1-amino-2-indanol and (1R,2R)-trans-1-amino-2-indanol using a linear methodology. The antiviral activity and cytotoxicity of these compounds were evaluated against herpes simplex virus type 1 (HSV-1) in Vero cells, bovine viral diarrhea virus (BVDV) in Mardin-Darby bovine kidney (MDBK) cells and hepatitis B virus (HBV) in HepG2 2.2.15 cell line. Three compounds, showed an inhibition of the HBsAg levels similar to reference drug lamivudine. One chloropurinyl nucleoside, derived from the cis-1-amino-2-indanol, was cytotoxic on MDBK cells and it could be a lead for developing anticancer agents. PMID- 22944334 TI - Synthesis and evaluation of novel heteroaromatic substrates of GABA aminotransferase. AB - Two principal neurotransmitters are involved in the regulation of mammalian neuronal activity, namely, gamma-aminobutyric acid (GABA), an inhibitory neurotransmitter, and L-glutamic acid, an excitatory neurotransmitter. Low GABA levels in the brain have been implicated in epilepsy and several other neurological diseases. Because of GABA's poor ability to cross the blood-brain barrier (BBB), a successful strategy to raise brain GABA concentrations is the use of a compound that does cross the BBB and inhibits or inactivates GABA aminotransferase (GABA-AT), the enzyme responsible for GABA catabolism. Vigabatrin, a mechanism-based inactivator of GABA-AT, is currently a successful therapeutic for epilepsy, but has harmful side effects, leaving a need for improved GABA-AT inactivators. Here, we report the synthesis and evaluation of a series of heteroaromatic GABA analogues as substrates of GABA-AT, which will be used as the basis for the design of novel enzyme inactivators. PMID- 22944335 TI - O-Hydroxyl- or o-amino benzylamine-tacrine hybrids: multifunctional biometals chelators, antioxidants, and inhibitors of cholinesterase activity and amyloid beta aggregation. AB - In an effort to identify novel multifunctional drug candidates for the treatment of Alzheimer's disease (AD), a series of hybrid molecules were synthesised by reacting N-(aminoalkyl)tacrine with salicylic aldehyde or derivatives of 2 aminobenzaldehyde. These compounds were then evaluated as multifunctional anti Alzheimer's disease agents. All of the hybrids are potential biometal chelators, and in addition, most of them were better antioxidants and inhibitors of cholinesterases and amyloid-beta (Abeta) aggregation than the lead compound tacrine. Compound 7c has the potential to be a candidate for AD therapy: it is a much better inhibitor of acetylcholinesterase (AChE) than tacrine (IC(50): 0.55 nM vs 109 nM), has good biometal chelation ability, is able to inhibit Abeta aggregation and has moderate antioxidant activity (1.22 Trolox equivalents). PMID- 22944336 TI - The cumulative load of depressive illness is associated with cognitive function in the remitted state of unipolar depressive disorder. AB - OBJECTIVE: To investigate whether the cumulative number, duration and subtypes (severity and presence of psychotic features) of previous episodes of depression in patients with unipolar depressive disorder in a remitted state are associated with decreased global cognitive function. METHODS: Via the Danish registers individuals between 40 and 80 years of age were identified: (1) patients with a diagnosis of unipolar disorder at their first discharge from a psychiatric hospital in the period 1994 to 2002, and (2) gender and age matched control individuals. The participants were assessed with the Cambridge Cognitive Examination (CAMCOG), which provides a composite measure of global cognitive function. RESULTS: A total of 88 patients and 50 controls accepted our invitation to participate, fulfilled the selection criteria and were included in the study. The cumulative duration of depressive episodes was associated with a decreased CAMCOG score adjusted for age, gender, education, premorbid IQ and residual depressive symptoms (B=-0.14, 95% C.I. (-0.26, -0.02), R(2)adj=0.31, P=.02). Significant associations were also found between CAMCOG score and the cumulative duration and total number of depressive episodes with psychotic features, respectively. CONCLUSION: Our findings suggest that cognitive dysfunction is associated with the cumulative duration of depressive episodes, and that, in particular, depressive episodes with psychotic features in the course of illness may be a significant predictor of future impairment of cognitive function. PMID- 22944337 TI - Reduced thalamic volume in men with antisocial personality disorder or schizophrenia and a history of serious violence and childhood abuse. AB - OBJECTIVE: Violent behaviour has been associated with presence of certain mental disorders, most notably antisocial personality disorder (ASPD) and schizophrenia, childhood abuse, and multiple brain abnormalities. This study examined for the first time, to the authors' knowledge, the role of psychosocial deprivation (PSD), including childhood physical and sexual abuse, in structural brain volumes of violent individuals with ASPD or schizophrenia. METHODS: Fifty-six men (26 with ASPD or schizophrenia and a history of serious violence, 30 non-violent) underwent magnetic resonance imaging and were assessed on PSD. Stereological volumetric brain ratings were examined for group differences and their association with PSD ratings. PSD-brain associations were examined further using voxel-based-morphometry. RESULTS: The findings revealed: reduced thalamic volume in psychosocially-deprived violent individuals, relative to non-deprived violent individuals and healthy controls; negative association between thalamic volume and abuse ratings (physical and sexual) in violent individuals; and trend-level negative associations between PSD and hippocampal and prefrontal volumes in non violent individuals. The voxel-based-morphometry analysis detected a negative association between PSD and localised grey matter volumes in the left inferior frontal region across all individuals, and additionally in the left middle frontal and precentral gyri in non-violent individuals. CONCLUSIONS: Violent mentally-disordered individuals with PSD, relative to those with no or minimal PSD, suffer from an additional brain deficit, i.e., reduced thalamic volume; this may affect sensory information processing, and have implications for management, of these individuals. PSD may have a stronger relationship with volumetric loss of stress-linked regions, namely the frontal cortex, in non-violent individuals. PMID- 22944338 TI - Peer and family influence in eating disorders: a meta-analysis. AB - OBJECTIVE: The aim of the present study was to undertake a systematic review using meta-analysis procedures to assess the relationships between eating disorders and peer and family influence and to evaluate whether gender plays a moderator role in that relationship. METHOD: PsycINFO, Medline, Web of Science, EPSCO and Embase databases from 1980 to 2010 were searched in June and October 2010. Hand searching of relevant reference sections was also undertaken. RESULTS: It was possible to obtain 83 effect sizes from the 25 studies selected. Results showed that both peers and family influence dieting behavior, body dissatisfaction and bulimic symptoms in adolescent girls and boys. Furthermore, the analyses of the moderator variables showed that the variability of the effect sizes found was, in some cases, explained by gender, influence type and the country of the sample. DISCUSSION AND CONCLUSION: These results highlight how daily social interactions can influence unhealthy eating practices in adolescent girls and boys, and suggest that weight-related issues of parents and peers can be transmitted to adolescents. PMID- 22944339 TI - Childhood adversity and psychosis: examining whether the association is due to genetic confounding using a monozygotic twin differences approach. AB - PURPOSE: To test whether the association between childhood adversity and positive and negative psychotic experiences is due to genetic confounding. METHOD: Childhood adversity and psychotic experiences were assessed in an ongoing sample of 226 twins from the general population. A monozygotic (MZ) twin differences approach was used to assess possible genetic confounding. RESULTS: In the whole sample, childhood adversity was significantly associated with positive (beta=45; SE=0.16; P=0.008) and negative psychotic experiences (beta=0.77; SE=0.18; P<0.01). Within-pair MZ twin differences in exposure to childhood adversity were significantly associated with differences in positive (beta=71; SE=0.29; P=0.016) and negative psychotic experiences (beta=98; SE=0.38; P=0.014) in a subsample of 85 MZ twin pairs. CONCLUSIONS: Individuals exposed to childhood adversity are more likely to report psychotic experiences. Furthermore, our findings indicate that this association is not due to genetic confounding. PMID- 22944340 TI - Cognitive behavioral therapy for depression in patients with temporal lobe epilepsy. PMID- 22944341 TI - Clinical significance of MMP-7 and PTEN expression in colorectal cancer. AB - BACKGROUND/AIMS: The aim of this study was to investigate the expression of MMP-7 and PTEN protein in colorectal cancer and explore its correlation with clinicopathological parameters. METHODOLOGY: In colorectal cancer tissue samples (n=48) and normal rectal tissue samples (n=23), the expression of MMP-7 and PTEN was detected by immunohistochemistry. Using medical records, the relationship of MMP-7 and PTEN expression with clinicopathological parameters was analyzed. RESULTS: Compared to normal rectal tissue, MMP-7 expression was significantly higher in all grades of colorectal cancer. In contrast, PTEN expression was significantly lower than levels in normal rectal tissue. There was significant negative correlation between MMP-7 and PTEN expression in colorectal cancer (r= 0.403, p>0.05). MMP-7 and PTEN expression in colorectal cancer samples was correlated with differentiation, lymph node metastasis, serosa infiltration, and Duke's stage (p<0.05) but not with gender, age, or tumor size (p>0.05). CONCLUSIONS: Reduced PTEN expression and MMP-7 over-expression may play important roles in the pathogenesis of colorectal cancer. Combined detection may provide prognostic benefit towards colorectal cancer. PMID- 22944342 TI - Laparoscopic Roux-en-Y gastric bypass vs. laparoscopic sleeve gastrectomy for morbid obesity and diabetes mellitus: a meta-analysis of sixteen recent studies. AB - BACKGROUND/AIMS: Bariatric surgery has become the best option for the treatment for morbid obesity. It is not only a weight-reducing surgery but also a metabolic surgery. This study examined the short-term results undergoing LRYGB and LSG of bariatric surgery. METHODOLOGY: Studies and relevant literatures regarding the formation of LRYGB vs. LSG for morbid obesity or diabetes were searched through PubMed and Embase. The resolution of diabetes mellitus, resolution of hypertension and excess weight loss (EWL) in 12 months by LRYGB or LSG were pooled and compared using a meta-analysis. The odd ratios and mean differences were calculated with 95% confidence intervals to evaluate the influence of LRYGB. RESULTS: Sixteen recent studies including 2758 patients in total were included in this meta-analysis. These studies demonstrated that compared with LSG, LRYGB had the better effect in resolving diabetes mellitus and excess weight loss at 12 months, had a similar effect in resolving hypertension (pooled OR of 2.46 (95% CI: 1.48-4.09, p<0.00001), pooled OR of 0.81 (95% CI: 0.57-1.16, p>0.005), pooled mean difference of 8.27 (95% CI: 6.89-9.66, p<0.00001), respectively). CONCLUSIONS: In bariatric surgery, LRYGB is a more effective and reliable treatment for morbid obesity and for surgical treatment of poorly controlled T2DM. More large, prospective, controlled, randomized trials should be conducted to further compare the efficacy and safety of this approach. PMID- 22944343 TI - Chronic hepatic viral infection could be a protective factor for colorectal cancer liver metastases: analysis in a single institute. AB - BACKGROUND/AIMS: We tested the hypothesis that chronic hepatic virus infection could reduce the occurrence of colorectal cancer liver metastases (CLM) and investigated CLM patients' survival prolonged in positive viral infection. METHODOLOGY: 2868 colorectal cancer patients were divided into positive-infection and non-infection groups. Clinical variables, incidence of liver metastases and survival between the groups were respectively analyzed. RESULTS: The incidence of liver metastases in the positive group was much lower than in the control group, but other type distant metastasis was similar in the two groups. Infected group 5 year overall survival (OS) was better than the negative group. Meanwhile, CLM patients in the former group showed longer survival time than the control group (26 months vs. 20 months, p<0.001). CONCLUSIONS: Chronic hepatic viral infection could reduce the occurrence of CLM and improves the survival time of colorectal cancer. It could be a protective factor for CLM patients. PMID- 22944345 TI - Coordinate transformation between shoulder kinematic descriptions in the Holzbaur et al. model and ISB sequence. AB - Holzbaur et al. (2005) proposed a comprehensive 3-D biomechanical upper extremity model. Since then, this model has been adopted by many other studies for kinetic and kinematic analysis of the shoulder joint. Because of the 3-D anatomical structure, three angles are necessary to define or describe shoulder kinematics. In the Holzbaur et al. model, the three angles are shoulder elevation, elevation angle, and shoulder rotation. The computational implementation of the elevation angle degree of freedom is considered in a different way than described in the recommendation of the International Society of Biomechanics (ISB). This paper presents an analysis of the transformation between the coordinates of the shoulder kinematic defined in the Holzbaur et al. upper extremity model and those defined by the ISB. The results of this study could be used for comparing the coordinates between the different descriptions of the shoulder kinematics. PMID- 22944344 TI - In vivo passive mechanical properties of skeletal muscle improve with massage like loading following eccentric exercise. AB - A quasi-linear viscoelasticity (QLV) model was used to study passive time dependent responses of skeletal muscle to repeated massage-like compressive loading (MLL) following damaging eccentric exercise. Six skeletally mature rabbits were surgically instrumented with bilateral peroneal nerve cuffs for stimulation of the hindlimb tibialis anterior (TA) muscles. Following the eccentric exercise, rabbits were randomly assigned to a four-day MLL protocol mimicking deep effleurage (0.5 Hz, 10 N for 15 min or for 30 min). The contralateral hindlimb served as the exercised, no-MLL control for both MLL conditions. Viscoelastic properties of the muscle pre-exercise, post-exercise on Day 1, and pre- and post-MLL Day 1 through Day 4 were determined with ramp-and hold tests. The instantaneous elastic response (AG(0)) increased following exercise (p<0.05) and decreased due to both the 15 min and 30 min four-day MLL protocols (p<0.05). Post-four days of MLL the normalized AG(0) decreased from post-exercise (Day 1, 248.5%) to the post-MLL (Day 4, 98.5%) (p<0.05), compared to the no-MLL group (Day 4, 222.0%) (p<0.05). Exercise and four-day MLL showed no acute or cumulative effects on the fast and slow relaxation coefficients (p>0.05). This is the first experimental evidence of the effect of both acute (daily) and cumulative changes in viscoelastic properties of intensely exercised muscle due to ex vivo MLL. It provides a starting point for correlating passive muscle properties with mechanical effects of manual therapies, and may shed light on design and optimization of massage protocols. PMID- 22944346 TI - Nerve injury induces the expression of syndecan-1 heparan sulfate proteoglycan in peripheral motor neurons. AB - Heparan sulfate proteoglycans play important roles in embryogenesis, including the development of the central nervous system. However, their function in nerve regeneration is not yet understood. We previously reported that nerve injury induces the expression of heparan sulfate glycosaminoglycans and syndecan-1, a heparan sulfate proteoglycan, in injured hypoglossal motor neurons. In this study, we examined the expression of syndecan family members, including syndecan 1, in injured hypoglossal motor neurons after hypoglossal nerve axotomy. We could not detect any changes in expression after axotomy, except for syndecan-1. The expression of syndecan-1 was markedly increased on post-operative day 7. Syndecan 1 was localized not only in the cell bodies of hypoglossal motor neurons, but also in the injured hypoglossal nerve, and it accumulated in the terminals of regenerating fibers. Similarly, facial nerve axotomy and vagus nerve axotomy induced the expression of syndecan-1 in the facial nucleus, dorsal nucleus of vagus and ambiguous nucleus, respectively. However, sciatic nerve axotomy induced very little syndecan-1 expression in injured spinal motor neurons. These results suggest that syndecan-1 may have a crucial role in the survival of injured motor neurons and in nerve regeneration after injury. Our observations also reveal the diversity of peripheral motor neurons. PMID- 22944348 TI - Intergroup cannibalism in the European Early Pleistocene: the range expansion and imbalance of power hypotheses. AB - In this paper, we compare cannibalism in chimpanzees, modern humans, and in archaeological cases with cannibalism inferred from evidence from the Early Pleistocene assemblage of level TD6 of Gran Dolina (Sierra de Atapuerca, Spain). The cannibalism documented in level TD6 mainly involves the consumption of infants and other immature individuals. The human induced modifications on Homo antecessor and deer remains suggest that butchering processes were similar for both taxa, and the remains were discarded on the living floor in the same way. This finding implies that a group of hominins that used the Gran Dolina cave periodically hunted and consumed individuals from another group. However, the age distribution of the cannibalized hominins in the TD6 assemblage is not consistent with that from other cases of exo-cannibalism by human/hominin groups. Instead, it is similar to the age profiles seen in cannibalism associated with intergroup aggression in chimpanzees. For this reason, we use an analogy with chimpanzees to propose that the TD6 hominins mounted low-risk attacks on members of other groups to defend access to resources within their own territories and to try and expand their territories at the expense of neighboring groups. PMID- 22944347 TI - Impulsivity and drugs of abuse: a juice-reinforced operant procedure for determining within-session delay discounting functions in rhesus monkeys. AB - INTRODUCTION: Impulsivity is a behavioral trait that is thought to contribute to a variety of disorders, including drug abuse. Efficient, sensitive procedures are needed for studying drug effects on impulsivity (e.g., delay discounting) in nonhumans. METHODS: Three monkeys responded under an operant choice procedure whereby responses on one lever resulted in immediate delivery of 0.15 ml of juice [Hawaiian Punch(r)] and responses on another lever resulted in delivery of 0.75 ml of juice, either immediately or after a delay (3.75-40 s). The delay to the larger reinforcer increased within-session across discrete blocks allowing for generation of delay-discounting functions within sessions. RESULTS: Without delay, monkeys chose the larger reinforcer nearly exclusively. With increasing delay, monkeys progressively switched their choice from the larger to the smaller reinforcer in a delay-dependent manner. In 2 monkeys, acute administration of morphine (0.1 and 0.32 mg/kg) or ketamine (0.1 and 0.32 mg/kg) but not diazepam (0.1-1.0 mg/kg) dose-dependently shifted the delay-discounting functions to the left, indicating increased discounting. In one monkey, daily morphine treatment (0.32 mg/kg/day, 3-hour pretreatment) produced a rapid, sustained leftward shift in the delay-discounting function; the curve returned to the pre-drug position 6 days after discontinuation of treatment. DISCUSSION: This delay discounting procedure is sensitive to both behavioral and pharmacological manipulations and appears to be particularly sensitive to chronic drug treatment and drug withdrawal. Given the importance of drug dependence and withdrawal in the initiation, maintenance of, and relapse to drug taking, this procedure should be useful to study one aspect of this process. PMID- 22944349 TI - Opioids for the treatment of chronic noncancer pain. AB - Increasingly, opioids are used to treat chronic noncancer pain. While opioids are well recognized for their effectiveness in treating acute pain, the evidence supporting the benefits for the treatment of chronic pain is less well established. Improvement of both pain and function should be considered goals of therapy. Patients with chronic pain have a higher incidence of preexisting psychological disorders. Adverse effects of opioid therapy include dependence, overdose, and withdrawal. Risk factors for poor outcomes with opioid therapy are identified, and include preexisting mental illness and dose prescribed. Recommended strategies to more safely use opioids are discussed, including tools for identifying high-risk patients. The evidence supporting the use of treatment agreements and urine drug testing to reduce the effects of adverse outcomes is limited. PMID- 22944350 TI - Modern medicine and the Garden of Eden. PMID- 22944351 TI - Genotypic variation in sulfur assimilation and metabolism of onion (Allium cepa L.) III. Characterization of sulfite reductase. AB - Genomic and cDNA sequences corresponding to a ferredoxin-sulfite reductase (SiR) have been cloned from bulb onion (Allium cepa L.) and the expression of the gene and activity of the enzyme characterized with respect to sulfur (S) supply. Cloning, mapping and expression studies revealed that onion has a single functional SiR gene and also expresses an unprocessed pseudogene (phi-SiR). Northern and qPCR analysis revealed differences in expression pattern between the SiR gene and the pseudogene. Western analysis using antibodies raised to a recombinant SiR revealed that the enzyme is present in chloroplasts and phylogenetic analysis has shown that the onion protein groups with lower eudicots. In hydroponically-grown plants, levels of SiR transcripts were significantly higher in the roots of S-sufficient when compared with S-deficient plants of the pungent cultivar 'W202A' but not the less pungent cultivar 'Texas Grano'. In these same treatments, a higher level of enzyme activity was observed in the S-sufficient treatment in leaves of both cultivars before and after bulbing. In a factorial field trial with and without sulfur fertilization, a statistically significant increase in SiR activity was observed in the leaves of the pungent cultivar 'Kojak' in response to added S but not in the less pungent cultivar 'Encore'. PMID- 22944352 TI - Benzoxazinoids from Scoparia dulcis (sweet broomweed) with antiproliferative activity against the DU-145 human prostate cancer cell line. AB - Sweet broomweed (Scoparia dulcis) is an edible perennial medicinal herb widely distributed in tropical and subtropical regions of Asia, Africa, and the Americas. Four compounds, (2R)-7-methoxy-2H-1,4-benzoxazin-3(4H)-one 2-O-beta galactopyranoside [(2R)-HMBOA-2-O-Gal], 3,6-dimethoxy-benzoxazolin-2(3H)-one (3,6 M2BOA), 3-hydroxy-6-methoxy-2-benzoxazolinone (3-OH-MBOA), and scutellarein 7-O beta-glucuronamide, along with eight known compounds, including two 7-methoxy-1,4 benzoxazin-3(2H)-one 3-O-hexopyranosides [(2R)-HMBOA-2-O-Glc and (2R)-HDMBOA-2-O Glc], 6-methoxy-benzoxazolin-2(3H)-one (MBOA), acteoside, sodium scutellarin, p coumaric acid, and two monosaccharides (fructose and glucose), were isolated from the aqueous extract of S. dulcis. Antiproliferative activities of the six benzoxazinoid compounds against the DU-145 human prostate cancer cell line were assayed, and one of these displayed an IC50 of 65.8 MUg/mL. PMID- 22944353 TI - Demonstration of DSI-semen--A novel DNA methylation-based forensic semen identification assay. AB - Determining whether the source tissue of biological material is semen is important in confirming sexual assaults, which account for a considerable percentage of crime cases. The gold standard for confirming the presence of semen is microscopic identification of sperm cells, however, this method is labor intensive and operator-dependent. Protein-based immunologic assays, such as PSA, are highly sensitive and relatively fast, but suffer from low specificity in some situations. In addition, proteins are less stable than DNA under most environmental insults. Recently, forensic tissue identification advanced with the development of several approaches based on mRNA and miRNA for identification of various body fluids. Herein is described DNA source identifier (DSI)-semen, a DNA based assay that determines whether the source tissue of a sample is semen based on detection of semen-specific methylation patterns in five genomic loci. The assay is comprised of a simple single tube biochemical procedure, similar to DNA profiling, followed by automatic software analysis, yielding the identification (semen/non-semen) accompanied by a statistical confidence level. Three additional internal control loci are used to ascertain the reliability of the results. The assay, which aims to replace microscopic examination, can easily be integrated by forensic laboratories and is automatable. The kit was tested on 135 samples of semen, saliva, venous blood, menstrual blood, urine, and vaginal swabs and the identification of semen vs. non-semen was correct in all cases. In order to test the assay's applicability in "real-life" situations, 33 actual casework samples from the forensic biological lab of the Israeli police were analyzed, and the results were compared with microscopic examination performed by Israeli police personnel. There was complete concordance between both analyses except for one sample, in which the assay identified semen whereas no sperm was seen in the microscope. This sample likely represents true semen because sperm cells were detected from an adjacent sample from the same garment, therefore in this case the assay appears to be more sensitive than the microscopic examination. These results demonstrate that this assay is a bona fide confirmatory test for semen. PMID- 22944354 TI - Effects of an opioid on respiratory movements and expiratory activity in humans during isoflurane anaesthesia. AB - Opioids increase abdominal muscle activity during anaesthesia. We proposed that opioid activity during anaesthesia would change chest wall size and movement, and contribute to ventilation. Using an optical system to measure chest wall volume, we studied 10 patients during isoflurane anaesthesia, first under the influence of an opioid and then after reversal with naloxone. Measurements were made during quiet breathing and with carbon dioxide stimulation. Airway occlusion pressure was measured to assess inspiratory and expiratory muscle activity. Chest wall volume decreased with the onset of spontaneous breathing, and decreased further when breathing was stimulated by carbon dioxide. Reversal of opioid activity increased chest wall volume. Breathing movements were predominantly abdominal. Opioid action affected the timing and amplitude of breathing but the pattern of abdominal movement was not affected. Since opioids augment abdominal muscle action during expiration, the unchanged pattern of movement can be attributed to both diaphragm and abdominal activity displacing the abdominal wall reciprocally, in the inspiratory and expiratory phases of the respiratory cycle, respectively. PMID- 22944355 TI - Determination of cellular uptake and intracellular levels of Cenersen (Aezea((r)), EL625), a p53 antisense oligonucleotide in acute myeloid leukemia cells. AB - TP53 encodes for tumor protein p53. The suppression of p53 protein results in interruption of DNA repair mechanisms in dividing malignant cells thereby increasing the DNA damage and activating p53-independent mechanisms of apoptosis. This ultimately may translate into enhanced cytotoxic effects of standard chemotherapy. Based on this rationale, Cenersen, a phosphorothioate oligonucleotide antisense to p53-mRNA was synthesized and tested in clinical trials for patients with acute myeloid leukemia (AML). An important component of Cenersen clinical development is to develop a sensitive and specific method to quantify plasma and intracellular levels of Cenersen in different biologic matrices in order to determine tissue and intracellular distribution of the parent compound and its metabolites. Ultimately, this will allow us to determine pharmacokinetic and pharmacodynamic relationship for dose-effect correlation and design effective regimen to be rapidly translate into the clinic. An ELISA-based assay was adapted for assay development and validation of Cenersen in mouse plasma and cell lysate. Cellular uptake of Cenersen was studied in MV4-11 and KASUMI-1 AML cell lines. Real-time RT-PCR was used to measure P53-mRNA expression changes in treated cells. The assay had a limit of quantification of 35pmol/L in mouse plasma. Within-day and between-day precision of <15% and accuracy nearly 100% were observed in a linear range of 10-2000pmol/L (R(2)=0.99) in AML cell lysate. The selectivity of this assay examined as cross-reactivity with its 3'N 1, 3'N-2-metabolites, was 16.8% and 0.4%, respectively, and with its mismatch and the scramble oligonucleotides was 0.06% and 0.4%, respectively. Cenersen was stable in mouse plasma up to 8h at 37 degrees C. When exposed to 0.1-1MUmol/L Cenersen, MV4-11 and KASUMI-1 cells showed intracellular concentration in the range of 9.97-45.34nmol/mg protein and 0.1-2.1nmol/mg protein, respectively. Successful downregulation of p53-mRNA expression was observed in Cenersen treated cells. This ELISA-based assay was applicable to plasma and intracellular concentration measurement of Cenersen. Assessment of achievable concentration of Cenersen in different biologic matrices will be useful to elucidate the biological and clinical activity of this promising drug and define its recommended dose in future clinical trials. PMID- 22944356 TI - Determination of emodin in L-02 cells and cell culture media with liquid chromatography-mass spectrometry: application to a cellular toxicokinetic study. AB - The emodin-involved hepatotoxicity has been gaining increasing attention. The purpose of the present study was to evaluate the cytotoxicity of emodin on cultured human liver cells (L-02) and predict the possible relation between its cytotoxicity and cellular toxicokinetics. Cell viability and cell damage were assessed by Cell Counting Kit-8 (CCK-8) assay and phase-contrast microscopy, respectively. Cytotoxicity tests demonstrated a concentration- and time-dependent toxic effect of emodin on L-02 cells. Furthermore, emodin at concentration of 30MUM led to a significant apoptosis in a time-dependent manner supported by the morphological changes of drug-treated cells. In addition, to elucidate the toxicokinetic characteristics of emodin, a highly sensitive and selective liquid chromatography-mass spectrometry (LC-MS) method was employed and validated for detecting the dynamic alteration of emodin in cells and cell culture media. The proposed method appeared to be suitable for the analysis of emodin with desirable linearity (r(2)>0.99), and satisfying precision being less than 8.7%. The range of recoveries of this method was 90.2-101.9%. The preliminary cellular toxicokinetic study revealed a time-dependent intracellular accumulation of emodin, which was consistent with its in vitro toxic effects. These findings confirmed the cytotoxicity of emodin against L-02 cells and displayed the cytotoxic manner of emodin in terms of its cellular uptake and accumulation in L 02 cells. PMID- 22944357 TI - Analysis of synthetic cannabinoids in herbal blends by means of nano-liquid chromatography. AB - In this study, a rapid and simultaneous separation of 12 synthetic cannabinoids and Delta(9)-tetrahydrocannabinol (Delta(9)-THC) in herbal blends was obtained by means of nano-liquid chromatography (nano-LC). The nano-LC experiments were performed in a 100MUm i.d. capillary column packed with Cogent((r)) bidentate C(18) silica particles for 25.0cm. All compounds were resolved using an isocratic elution mode in less than 30min. A mobile phase containing ACN/MeOH/H(2)O/formic acid 69/5/25/1 (v/v/v/v) was employed for the chromatographic separation. The developed analytical method was validated in terms of precision, linearity, sensitivity and accuracy. Under optimal nano-LC-UV conditions, the resulting RSD percentages for intra-day and inter-day repeatability, related to retention time and peak area, were below 2.98 and 6.40%, respectively. Limits of detection and quantification were 0.2 and 0.5MUg/mL, respectively, for all the studied compounds. Linearity was assessed in the concentration range of interest for all analytes with determination coefficients r(2)>=0.9975. The method was then applied to the determination of synthetic cannabinoids in herbal blends. Quantitative analyses of the cannabimimetic compounds in six products showed that there was a wide difference in the concentration of the studied compounds among different products. Further, the nano-LC system was coupled with a mass spectrometer measuring the MS and MS-MS spectra to unequivocally identify the cannabinoids present in smoking mixtures. PMID- 22944358 TI - Rice consumption contributes to low level methylmercury exposure in southern China. AB - Fish consumption is considered as the primary pathway of human methylmercury (MeHg) exposure. However, recent studies highlighted that, rice, rather than fish, is the main route of human MeHg exposure in Guizhou, inland China. China is considered as the largest anthropogenic source of mercury (Hg) emission in the world, which has led to serious environmental Hg pollution. But there are no comprehensive studies regarding this environmental health problem to evaluate human Hg exposure and associated health effects. This study aimed to estimate daily MeHg intake and health risk in 7 provinces in southern China, and to assess the relative contribution from rice and fish consumption. The average levels of total mercury (THg) and MeHg in rice samples were generally low at 10.1 ng.g-1 and 2.47 ng.g-1, respectively. But a total of 36 rice samples (12.7%) had THg concentration exceeding the national limit (20 ng.g-1). Generally, rural population had significantly higher Probable Daily Intakes (PDIs) of MeHg than urban population from rice consumption and its relative contribution to MeHg exposure increased significantly from coastal to inland area. The averages of PDIs of MeHg were 0.020 MUg.kg-1.d-1 and 0.028 MUg.kg-1.d-1 for urban and rural population in southern China, respectively. Despite the serious environmental Hg pollutions in China, the general population in southern China had low risk of MeHg exposure. But rice is an important route of human MeHg exposure in southern China, especially for the rural population in inland area. The findings indicate that rice consumption should be considered when evaluating MeHg exposure in rice eating population in southern China. PMID- 22944359 TI - Propranolol for infantile haemangioma: striking effect in the first weeks. AB - OBJECTIVE: Discuss effect and dynamics of propranolol (PR) treatment in infantile haemangioma (IH) of head and neck in children during follow-up. METHODS: Between 2010 and 2011, 22 children with head and neck infantile haemangioma (IH) treated by PR were recruited into the study. In a retrospective chart review clinical data were analyzed at 5 consecutive, different check-up time from 1 week to 12-14 months. Effectiveness of PR treatment was assessed by a symptom score method. RESULTS: In the whole series a significant regression was observed in 13 patients (59%) in the first week of the therapy. Further five patients showed this time a marked, two mild improvements, and two children did not respond initially to the PR therapy. In one of them (case #8) later on a mild improvement could be seen too. At the second check-up (1 month after initiating PR therapy) 50% of children showed definitive improvement compared to the first visit. Difference between first and second check-ups was significant, and between the 4th and 5th visits the improvement showed the lowest rate. Comparison of IH regression between the 2nd and the 5th check-ups resulted in a p value a little larger than 0.05. There was not significant correlation between the initial IH severity and the treatment effectiveness at the follow-ups (p>0.05). No significant differences were found in treatment effectiveness concerning the IH localizations, too. CONCLUSION: PR treatment is highly effective in children with IHs. The most striking effect is seen at the first week of treatment; later improvement is much slower, sometimes with periods of stagnations. The cause of this is probably the spectacular early effect of vasoconstriction, though other impacts of PR to the individual molecular markers of IH seemed to be less impressive clinically. However, treatment should be continued for at least 6 months because early cessation can cause a relapse. PMID- 22944360 TI - Comparison between tracheal foreign body and bronchial foreign body: a review of 1,007 cases. AB - OBJECTIVE: To determine the differences between tracheal foreign body aspiration and bronchial foreign body aspiration. METHODS: This retrospective study includes 1007 patients with the diagnosis of foreign body aspiration according to rigid bronchoscopy. Patients were divided into two groups: tracheal and bronchial foreign body groups. Age, sex, clinical presentation, pre-operative radiographic findings, rigid bronchoscopy findings, types of foreign body, and the complications of each group were observed and analyzed. RESULTS: Out of 989 study patients, there were 146 patients (14.5%) in the tracheal foreign body group and 843 patients (83.7%) in the bronchial foreign body group. Eighteen patients with FBs located in the larynx and presenting with multiple FBs located in the tracheal and bronchial regions were excluded from this study. The majority of the patients were under the age of three for both groups. The male to female ratio was significantly higher in the bronchial foreign body group (P<0.001). More patients in the bronchial foreign body group were misdiagnosed upon first clinical visit (P=0.001), referred from another hospital (P<0.05), or had delayed diagnosis (P<0.05). The most prominent symptom in both groups was cough, followed by decreased breath sounds, wheezing, and dyspnea. More patients in the bronchial foreign body group experienced decreased breath sounds (P<0.001), while more patients in the tracheal foreign body group experienced dyspnea (P<0.05). Chest fluoroscopy abnormalities were observed at a higher frequency in the bronchial foreign body group (P<0.001). Lateral neck X-ray results showed higher frequencies of abnormalities in the tracheal foreign body patients. Out of 30 patients in the tracheal foreign body group received a CT scan, 27 had abnormal scan results, while all 253 patients in the bronchial foreign body subgroup had abnormal results. The majority of foreign bodies were organic materials and were removed by rigid bronchoscopy at the first clinical session in 96.6% of tracheal foreign body cases and 96.0% of bronchial foreign body cases (P=0.727). Major complications, including one death, were observed only in the bronchial foreign body group. CONCLUSIONS: The nature of tracheal foreign body aspiration is different from bronchial aspiration. Clinical presentation and pre-operative radiographic findings are helpful for diagnosis. The clinician should understand the differences between tracheal and bronchial FB cases and provide the appropriate management when either is presented. PMID- 22944361 TI - Nosocomial vs community-acquired pandemic influenza A (H1N1) 2009: a nested case control study. AB - BACKGROUND: The characteristics of nosocomial influenza in children are not well described. AIM: To compare the characteristics of nosocomial and community acquired pandemic influenza A (H1N1) 2009 (pH1N1) in Australian children. METHODS: In a nested case-control study, the clinical and epidemiological features of nosocomial vs community-acquired pH1N1 were compared among hospitalized children aged <15 years in six paediatric hospitals in Australia between 1 June and 30 September 2009. FINDINGS: Of 506 hospitalized children with pH1N1, 47 (9.3%) were of nosocomial origin. These 47 cases were compared with 141 gender- and age-matched controls. Cases had a significantly higher proportion of underlying medical conditions compared with controls (81% vs 42%, P < 0.001), and were more likely to be exposed to household smokers (36% vs 20%, P = 0.02). Fewer children with nosocomial influenza presented with classical symptoms of influenza, including subjective fever and lethargy. A higher proportion of children with nosocomial influenza received treatment with oseltamivir (77% vs 43%, P < 0.001), and they required a longer stay in hospital following the onset of influenza (mean 8.5 days vs 4.5 days, P = 0.006). Three children (2%) in the community-acquired group died of pH1N1, but there were no deaths in the nosocomial group. CONCLUSION: This study shows that children with pre-existing diseases and those who are exposed to household smokers are more susceptible to nosocomial pH1N1. They may have 'occult presentation' of influenza, but their course of illness is not markedly different from that of children with community acquired influenza. PMID- 22944362 TI - Using a PDSA cycle of improvement to increase preparedness for, and management of, norovirus in NHS Scotland. AB - BACKGROUND: The 2009-2010 norovirus season was reported anecdotally by infection prevention and control teams (IPCTs) to be one of the worst seasons in Scotland. At its peak, Health Protection Scotland's (HPS) weekly point prevalence identified that 53 wards were closed. AIM: To develop an annual cycle of learning lessons and improving systems to reduce the impact and incidence of norovirus outbreaks in Scotland. METHODS: An analysis of two end-of-year norovirus season evaluations (2009-2010 and 2010-2011) by IPCTs in Scotland using a national Plan, Do, Study, Act (PDSA) model. FINDINGS: The first evaluation (2009-2010) identified that IPCTs responded well when outbreaks were reported, but were not optimally prepared for the season. In addition, IPCTs had little data to describe their particular problems in detail. HPS planned for the 2010-2011 season with tools to optimize preparedness and norovirus management. The second evaluation (2010-2011) identified much more proactive responses to both preparedness and norovirus management. CONCLUSION: This national PDSA cycle has led to system improvements designed to reduce the incidence and impact of norovirus in NHS Scotland. The incidence of norovirus was reduced in the 2011-2012 season; however, confounding from the variation in circulating viruses makes it difficult to measure any effect of the system improvements. As noroviruses challenge the health service every year, mainly in winter months, the end-of-season evaluations can be used to improve planning for subsequent seasons to share and demonstrate good practice. As more years of data become available for analysis, the impact of system improvements will become measurable. PMID- 22944363 TI - Bortezomib and TRAIL: a perfect match for apoptotic elimination of tumour cells? AB - Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) is a cytokine that selectively eradicates tumour cells via specific cell surface receptors and is intensively explored for use as a novel anticancer approach. To enhance the efficacy of TRAIL receptor agonists the proteasome inhibitor bortezomib is one of the most potent sensitizers. Here we review the main mechanisms underlying bortezomib-dependent TRAIL sensitization, including stimulation of apoptosis by increasing expression of TRAIL receptors, reduction of cFLIP and enhancement of caspase 8 activation, and modulation of Bcl-2 family proteins and inhibitor of apoptosis proteins (IAPs). Concomitantly, pro-survival signals are suppressed such as elicited by NF-kappaB and Akt. The different preclinical tumour models explored with this combination, including primary tumour (stem) cells, stroma co culture and mice models, are discussed, as well as possible hurdles for clinical activity. Collectively, anticipating a solid rationale for bortezomib-TRAIL combination and very promising preclinical results, its clinical activity remains to be demonstrated. PMID- 22944364 TI - Assessing research activity on priority interventions for non-communicable disease prevention in low- and middle-income countries: a bibliometric analysis. AB - INTRODUCTION: Action is urgently needed to curb the rising rates of non communicable diseases (NCDs) in low- and middle-income countries (LMICs) and reduce the resulting social and economic burdens. There is global evidence about the most cost-effective interventions for addressing the main NCD risk factors such as tobacco use, unhealthy diets, physical inactivity, and alcohol misuse. However, it is unknown how much research is focused on informing the local adoption and implementation of these interventions. OBJECTIVE: To assess the degree of research activity on NCD priority interventions in LMICs by using bibliometric analysis to quantify the number of relevant peer-reviewed scientific publications. METHODS: A multidisciplinary, multi-lingual journal database was searched for articles on NCD priority interventions. The interventions examined emphasise population-wide, policy, regulation, and legislation approaches. The publication timeframe searched was the year 2000-2011. Of the 11,211 articles yielded, 525 met the inclusion criteria. RESULTS: Over the 12-year period, the number of articles published increased overall but differed substantially between regions: Latin America & Caribbean had the highest (127) and Middle East & North Africa had the lowest (11). Of the risk factor groups, 'tobacco control' led in publications, with 'healthy diets and physical activity' and 'reducing harmful alcohol use' in second and third place. Though half the publications had a first author from a high-income country institutional affiliation, developing country authorship had increased in recent years. CONCLUSIONS: While rising global attention to NCDs has likely produced an increase in peer-reviewed publications on NCDs in LMICs, publication rates directly related to cost-effective interventions are still very low, suggesting either limited local research activity or limited opportunities for LMIC researchers to publish on these issues. More research is needed on high-priority interventions and research funders should re-examine if intervention research is enough of a funding priority. PMID- 22944365 TI - Strengthening standardised interpretation of verbal autopsy data: the new InterVA 4 tool. AB - BACKGROUND: Verbal autopsy (VA) is the only available approach for determining the cause of many deaths, where routine certification is not in place. Therefore, it is important to use standards and methods for VA that maximise efficiency, consistency and comparability. The World Health Organization (WHO) has led the development of the 2012 WHO VA instrument as a new standard, intended both as a research tool and for routine registration of deaths. OBJECTIVE: A new public domain probabilistic model for interpreting VA data, InterVA-4, is described, which builds on previous versions and is aligned with the 2012 WHO VA instrument. DESIGN: The new model has been designed to use the VA input indicators defined in the 2012 WHO VA instrument and to deliver causes of death compatible with the International Classification of Diseases version 10 (ICD-10) categorised into 62 groups as defined in the 2012 WHO VA instrument. In addition, known shortcomings of previous InterVA models have been addressed in this revision, as well as integrating other work on maternal and perinatal deaths. RESULTS: The InterVA-4 model is presented here to facilitate its widespread use and to enable further field evaluation to take place. Results from a demonstration dataset from Agincourt, South Africa, show continuity of interpretation between InterVA-3 and InterVA-4, as well as differences reflecting specific issues addressed in the design and development of InterVA-4. CONCLUSIONS: InterVA-4 is made freely available as a new standard model for interpreting VA data into causes of death. It can be used for determining cause of death both in research settings and for routine registration. Further validation opportunities will be explored. These developments in cause of death registration are likely to substantially increase the global coverage of cause-specific mortality data. PMID- 22944366 TI - A plant cell-based system that predicts abeta42 misfolding: potential as a drug discovery tool for Alzheimer's disease. AB - Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by the accumulation of amyloid beta (Abeta) peptides and the failure of mechanisms to clear toxic aggregates. The Abeta42 peptide is considered to be a causative factor that underlies the pathophysiology of AD, in part due to its propensity for misfolding and aggregation; the small oligomers that result represent toxic species. Thus agents that prevent Abeta42 misfolding/aggregation or, alternatively improve Abeta42 oligomer clearance, may have significant therapeutic value. We have developed the basis for a drug screening system based on transgenic plant cells that express Abeta42 fusion proteins to serve as the reliable indicators of the general conformational status of Abeta42. Within cells of transgenic tobacco and Nicotiana benthamiana, misfolding of Abeta42 causes the misfolding of a GFP fusion partner, and consequently there is a loss of fluorescence associated with the native GFP protein. In a similar fusion consisting of Abeta42 linked to hygromycin phosphotransferase II (Hpt II), a hygromycin-resistance marker, misfolding of Abeta42 leads to a misfolded Hpt II, and consequently the transgenic cells are unable to grow on media containing hygromycin. Importantly, substitution of the 'aggregation-prone' Abeta42 with a missense mutant of Abeta42 (F19S/L34F) that is not prone to misfolding/aggregation, 'rescues' both fusion partners. Several 'positive control' chemicals that represent inhibitors of Abeta42 aggregation, including curcumin, epigallocatechin-3-gallate (EGCG), and resveratrol show efficacy in preventing the Abeta42-fusion proteins from misfolding/aggregating in the transgenic plant cells. We discuss the potential of the two fusion protein systems to serve as the basis for an inexpensive, selective, and efficient screening system in which a plant cell can fluoresce or survive only in the presence of drug candidates that are able to prevent Abeta42 misfolding/aggregation. PMID- 22944367 TI - Mutation spectrum in the French cohort of galactosemic patients and structural simulation of 27 novel missense variations. AB - BACKGROUND: Classic galactosemia refers to galactose-1-phosphate uridyltransferase (GALT) deficiency and is characterized by long-term complications of unknown mechanism and high allelic heterogeneity of GALT gene. AIM: To report molecular characterization of GALT variations in 210 French families, to analyze the structural effects of novel missense variations and to assess informativity of structural data in predicting outcome. METHODS: Sequencing of exons and intron-exon junctions of GALT gene was completed in unsolved cases by analysis of a long range PCR product. Structural consequences of novel missense variations were predicted using a homology model of GALT protein and a semi-automated analysis which integrates simulation of variations, structural analyses and two web servers dedicated to identify mutation-induced change of protein stability. RESULTS: Forty four novel variations were identified, among them 27 nucleotide substitutions. In silico modeling of these missense variations showed that 12 variations are predicted to impair subunit interactions and/or active site conformation and that 23 variations modify H-bond or salt-bridge networks. Twenty variations decrease the global stability of the protein. Five variations had apparently no structural effect. CONCLUSION: Our results expand the mutation spectrum in GALT gene and the list of GALT variations analyzed at the structural level, providing new data to assess the pathophysiology of galactosemia. PMID- 22944368 TI - Volumetric and topographic differences in hippocampal subdivisions in borderline personality and bipolar disorders. AB - Hippocampal abnormalities may be implicated in the pathophysiology of mental disorders with affective symptoms such as borderline personality disorder (BPD) and bipolar disorder (BD). We aimed to investigate hippocampal morphology in BPD and BD patients, compared to 1:1 age- and sex-matched healthy controls (HC) using a three-dimensional mapping method. Manual tracing of the hippocampi on magnetic resonance imaging (MRI) images was performed on 26 patients with BPD (age: 38+/ 11; sex (f): 16 (61%)) and 15 with BD (age: 44+/-9; sex (f): 5 (33%)) and their age- and sex-matched HC (for BPD: n=26; age: 38+/-11; sex (f): 16 (61%); for BD: n=15; age: 44+/-9; sex (f): 5 (33%)). Compared to their reference groups, BPD patients showed smaller hippocampal volume bilaterally. The BD group showed significantly smaller right hippocampal volumes. In the surface maps, alterations were localized to different hippocampal sectors for the two groups: the CA1 regions and subiculum, bilaterally, in BPD, and the right dentate gyrus in the BD group. These differences persisted after controlling for alcohol and substance abuse. BPD and BD groups may exhibit distinct patterns of volumetric MRI changes in hippocampal subdivisions that might be related to the clinical phenomenology of each disorder. PMID- 22944369 TI - Amygdala responses to masked and low spatial frequency fearful faces: a preliminary fMRI study in panic disorder. AB - Previous studies have demonstrated amygdala activation in response to fearful faces even if presented below the threshold of conscious visual perception. It has also been proposed that subcortical regions are selectively sensitive to low spatial frequency (LSF) information. However, chronic hyperarousal may reduce amygdala activation in panic disorder (PD). Our aim was to establish whether the amygdala is engaged by masked and LSF fearful faces in PD as compared to healthy subjects. Neutral faces were used as the mask stimulus. Thirteen PD patients (seven females, six males; mean age=29.1 (S.D: 5.9)) and 15 healthy volunteers (seven females, eight males; mean age=27.9 (S.D. 4.5)) underwent two passive viewing tasks during a 3T functional magnetic resonance imaging (fMRI) as follows: 1) presentation of faces with fearful versus neutral expressions (17ms) using a backward masking procedure and 2) presentation of the same faces whose spatial frequency contents had been manipulated by low-pass filtering. Level of awareness was confirmed by a forced choice fear-detection task. Whereas controls showed bilateral activation to fearful masked faces versus neutral faces, patients failed to show activation within the amygdala. LSF stimuli did not elicit amygdala response in either group, contrary to the view that LSF information plays a crucial role in the processing of facial expressions in the amygdala. Findings suggest maladaptive amygdala responses to potentially threatening visual stimuli in PD patients. PMID- 22944371 TI - Effective weight control and normalization of metabolic parameters after laparoscopic sleeve gastrectomy: a single center experience. AB - BACKGROUND/AIMS: Obesity is one of the most serious public health problems. Laparoscopic sleeve gastrectomy (LSG), a type of bariatric surgery, is emerging as the new promising therapy for the treatment of morbid obesity. METHODOLOGY: In the present study we aimed to assess the effects of LSG on body weight and other obesity related pathological conditions. RESULTS: A total of 19 obese subjects underwent LSG surgery. All patients underwent complete evaluation including anthropometric/clinical parameters and laboratory tests. Hypertension (HT), diabetes mellitus (DM), body mass index (BMI), and hyperlipidemia were significantly reduced after LSG. CONCLUSIONS: Results of this study demonstrate that LSG induces stable weight loss and resolution of obesity-associated comorbidities. PMID- 22944372 TI - Diagnosis and impact of hilar lymph node micrometastases on the outcome of resected colorectal liver metastasis. AB - BACKGROUND/AIMS: Liver resection is the only curative therapy for metastatic colorectal cancer. However, recurrence occurs in the majority of the cases. Hilar lymph node metastases occur with a high frequency but the methodology for its detection and the impact on the outcome of patients undergoing hepatectomy is still unknown. METHODOLOGY: Twenty-six patients submitted to partial liver resection and systematic lymphadenectomy were studied prospectively. Lymph nodes considered negative by hematoxylin and eosin (H&E) staining were analyzed by serial sectioning and immunohistochemistry (IHC) with anti-human pancytokeratin antibody AE1/AE3. Recurrence-free and overall survivals were compared among LN groups. RESULTS: The mean number of dissected lymph nodes were 6.3 per patient. H&E showed microscopic involvement of LN in 2 patients and 3 patients had metastases identified only by IHC. The median follow-up was 39.3 months. Sixteen patients (61.5%) recurred after liver resection and although no statistical difference in survival was demonstrated there was a trend towards shorter recurrence-free survival among microscopic positive LN. CONCLUSIONS: Microscopic LN metastases may have impact in the outcome of patients submitted to curative hepatectomy. A better definition of micrometastases to LN is warranted, as though the potential benefit of hilar lymphadenectomy and chemotherapy selection by hilar lymph node status. PMID- 22944373 TI - The effect of octreotide treatment on patients with pancreatic cancer who undergo endoscopic retrograde cholangiopancreatography (ERCP) with pancreatic duct stent placement. AB - BACKGROUND/AIMS: To investigate the effect of octreotide treatment on patients with pancreatic cancer who undergo endoscopic retrograde cholangiopancreatography (ERCP) with pancreatic duct stent placement for malignant biliary obstruction. METHODOLOGY: Patients (n=99) hospitalized from Jan 2006 to Dec 2011 were included in this study. All the patients were diagnosed with pancreatic cancer (obstructive jaundice). The patients were randomly divided into the octreotide treated group and the control group. Both groups underwent ERCP with pancreatic duct stent placement for malignant biliary obstruction. The patients' quality of life was evaluated by the symptoms of nausea, vomiting, abdominal pain, diarrhea and anorexia. Overall quality of life, liver function and survival time were compared between these two groups. RESULTS: Quality of life and liver function improved more in the octreotide group than the control group. In addition, the survival time was significantly longer in the octreotide group than in the control group (12.3 months vs. 7.3 months) (p<0.05). CONCLUSIONS: Octreotide therapy is beneficial in patients with pancreatic cancer who undergo ERCP with pancreatic duct stent placement for malignant biliary obstruction. PMID- 22944374 TI - Systematic review of the safety of living liver donors. AB - BACKGROUND/AIMS: Since the first living liver transplantation, the procedure has become routine with an excellent outcome and the shortage of organs for recipients has generated enthusiasm for living donor liver transplantation. One of the major challenges is the safety of the donor after donation. Here, we try to evaluate the overall safety of living donors. METHODOLOGY: This review examines the donor's complications by using the Clavien score system, observes the changes of the laboratory test including the liver and kidney functions and the blood routine, meanwhile the quality of life after operation is also investigated. RESULTS: The safety of living donors included complications, changes in laboratory examinations and the quality of the mental and physical health, and work after donation. The complication rate of the living liver donor ranges from 9.4% to 67%, and the most common complication are biliary complications, ranges from 11.1%-82.3%, if donors' liver function is damaged in the first week there is slow recovery, the qualities of life is mostly unaffected. CONCLUSION: Donation is a safe procedure for the donor and valuable for the recipient. PMID- 22944375 TI - Feasibility and safety of laparoscopic hydatid surgery: a systematic review. AB - BACKGROUND/AIMS: Eccinococal disease is an important problem in regions such as Turkey, where tapeworms are endemic. Surgery is the main key to successful treatment. Among the various techniques, laparoscopy has recently come to be preferred over the commonly used open technique. The aim of this review was to evaluate the feasibility, safety and potential benefits of laparoscopic hydatid surgery. METHODOLOGY: Three independent investigators conducted comprehensive research using PubMed, MEDLINE, Embase and the Cochrane library. Language was restricted to English; reference lists were searched manually. RESULTS: Tweny-two retrospective studies were selected for review, none of which were randomized controlled trials. It was found that the laparocopic approach was attempted in 666 patients. The overall conversion rate to laparotomy was 4% (27/666) with a recurrence rate of hydatid disease of 1.6% (11/666). Average length of hospital stay was 4.7 (1-30) days. CONCLUSIONS: Based on this meta-analsysis, evidence confirms that the laparoscopic surgical technique is feasable and safe. Good randomized controlled trials are lacking. PMID- 22944376 TI - Perioperative cimetidine administration improves systematic immune response and tumor infiltrating lymphocytes in patients with colorectal cancer. AB - BACKGROUND/AIMS: Cimetidine has been shown to play an important role in the treatment of cancer and the regulation of the immune system. Therefore, we aimed to observe the effects of cimetidine on the systematic immune response in the perioperative period. METHODOLOGY: Sixty patients with colorectal cancer were enrolled from Jan 2005 to Dec 2005 from Taizhou Hospital. The patients were administrated with cimetidine (0.8 g.d-1 or 1.2 g.d-1) or saline from the day of admission to the 10th POD. Venous blood sample was collected and the T-, B- and NK-lymphocyte subsets were determined by flow cytometry. The specimens were subjected to tumor-infiltrating lymphocytes (TILs) response examination. RESULTS: The levels of CD3 and CD4 T-lymphocytes were increased significantly in both low and high dose cimetidine groups 10 days after operation. The number of CD19 B cells was also elevated by cimetidine. However, no significant changes were observed in the CD8, CD4/CD8 value. TIL responses in the cimetidine groups were also enhanced significantly. CONCLUSIONS: Cimetidine can alleviate systematic immunosuppression and improve the local immune function of the colorectal cancer patients in the perioperative period. PMID- 22944377 TI - The orthogeriatrics model of care: systematic review of predictors of institutionalization and mortality in post-hip fracture patients and evidence for interventions. AB - Hip fracture is a common serious complication of osteoporosis, which is associated with high morbidity and mortality. In nursing home residents, incidence rates of hip fractures are at least twice to three times higher than in community-dwellers of the same age and sex. Older adults with hip fracture have a 5- to 8-fold increased risk for all-cause mortality and much higher risk of institutionalization. Therefore, interventions to prevent institutionalization, prevent a second fracture in institutionalized patients, and decrease mortality after a hip fracture are highly needed. The orthogeriatrics model of care is a shared-care approach to patients after suffering a hip fracture. This program, which has been studied in models run by geriatricians with the assistance of a multidisciplinary team, includes a comprehensive medical and nursing admission assessment focusing on the patient's premorbid function, cognition, comorbidities, and risks is followed by a comprehensive care plan design. This systematic review describes and analyzes the interrelation between hip fracture and nursing home placement taking into consideration those evidence-based interventions to prevent later complications and future institutionalization. PMID- 22944378 TI - Increased expression of Toll-like receptor 3 in decidual natural killer cells of patients with unexplained recurrent spontaneous miscarriage. AB - OBJECTIVE: To investigate whether the expression of Toll-like receptor 3 (TLR3) in decidual natural killer (dNK) cells plays a role in the pathogenesis of unexplained recurrent spontaneous miscarriage (URSM). STUDY DESIGN: NK cells were isolated from human decidual tissue through magnetic cell sorting and analyzed for phenotypes through flow cytometry. TLR3 expression in dNK cells was detected by quantitative reverse-transcriptase polymerase chain reaction and western blotting. The cytotoxicity of dNK was detected using a lactate dehydrogenase release test. RESULTS: The CD56(+) dNK percentages varied between 85% and 96%. The expression of TLR3 mRNA and protein in dNK cells of URSM patients was statistically significantly higher than that in control women (p=0.005 and p=0.01, respectively). Meanwhile, the mean cytotoxicity percentage of freshly isolated dNK cells from the patients was significantly higher than that from normal controls (31.24 +/- 7.46% vs. 16.20 +/- 6.03%; p=0.03). CONCLUSION: The expression of TLR3 in dNK cells is abnormally higher in URSM patients, which indicates that TLR3 expression may be critical to the activation of dNK cells infiltrating the maternal-fetal interface and account for the loss of immune tolerance. PMID- 22944379 TI - Cerebellar hemangioblastoma as the cause of maternal obstructive hydrocephalus during the third trimester. PMID- 22944380 TI - Risk factors and adverse pregnancy outcomes among births affected by velamentous umbilical cord insertion: a retrospective population-based register study. AB - OBJECTIVE: To identify risk factors associated with velamentous cord insertion (VCI) and to evaluate the association between adverse pregnancy outcomes and VCI in singleton pregnancies. STUDY DESIGN: The total population of women (n=26,849) with singleton pregnancies delivered in Kuopio University Hospital during the study period between 2000 and 2011 was reviewed. Risk factors and the risk of adverse pregnancy outcomes (admission to a neonatal unit, fetal death, preterm delivery, low birth weight (LBW< 2500 g), the infant being small for its gestation age (SGA), low Apgar scores (<7) at 1 and 5 min and fetal venous pH<7.15) were evaluated separately among women with and without VCI by means of logistic regression analyses. RESULTS: The incidence of VCI among women with singleton pregnancies was 2.4% (n=633 of 26,849). Independent risk factors for VCI were nulliparity, obesity, fertility problems, placenta previa and maternal smoking. VCI was associated with a 1.38-, 2.01-, 3.93- and 1.39-fold increased risk of admission to a neonatal unit, preterm delivery (<37 gestation weeks), LBW and SGA, respectively compared to pregnancies involving normal cord insertion. Of the women with VCI, 15.3% underwent non-elective cesarean section compared to 8.3% (p <= 0.001) of women without VCI. CONCLUSIONS: The results suggest that the incidence of VCI increases along with an increase in fertility problems and maternal obesity. VCI is a moderate risk condition increasing the risks of prematurity and impaired fetal growth. PMID- 22944381 TI - Complications of synthetic slings used in female stress urinary incontinence and applicability of the new IUGA-ICS classification. AB - OBJECTIVES: To analyze different complications of synthetic suburethral slings, and to apply the new "IUGA-ICS classification of complications directly related to the insertion of prosthesis (meshes, implants, tapes) and grafts in female pelvic floor surgery" to the list of complications, check its applicability, and give suggestions regarding possible improvements. STUDY DESIGN: This study is an analysis of complications of synthetic suburethral slings. Data on type of complication, time interval between the insertion of the prosthesis and the onset of symptoms of complication, type and nature of prosthesis, and management process were documented. Additional descriptions of the sling position in relation to lower urinary tract, shrinkage or prominence of the prosthesis, and intra-operative nature of the prosthetic material were collected for analysis. RESULTS: From the year 2003 to 2010, 376 women with complications of synthetic suburethral slings were managed surgically and the data were analyzed. Overactive bladder (OAB) at 54%, lower urinary tract obstruction (48%), vaginal exposure (19%), and pain (14%) were the most frequent complications. Infection, fistulae, urinary tract penetration, and groin/thigh pain were other complications. The new IUGA-ICS classification could be applied to most of the types of complications, a notable exception being de novo development of overactive bladder. Also category 4B of IUGA-ICS classifications encompasses a wide clinical variety of complications and may need reconsideration. CONCLUSION: De novo OAB seems to be the commonest complication of synthetic suburethral slings, followed by obstruction, vaginal exposure, and long term pain. The new IUGA-ICS classification on complications has good general applicability; some minor changes may be useful in the future. PMID- 22944382 TI - Automated method for determination of olive oil phenols and metabolites in human plasma and application in intervention studies. AB - The interest for olive oil phenols (OOPs) is a growing trend thanks to their contribution to prevent or improve diseases associated to oxidative damage. OOPs ingested in the diet are found at low concentrations in blood either as free forms (e.g. hydroxytyrosol, tyrosol, vanillin, ferulic acid, coumaric acid) or conjugated as sulfate and glucuronide derivatives. Therefore, the identification/quantitation of OOPs in plasma to study their biological effects and elucidate their metabolism requires selective and sensitive methods. The present research describes the development, validation and application of an automated method based on on-line coupling of solid-phase extraction and liquid chromatography-tandem mass spectrometry (SPE-LC-MS/MS) for quantitation of conjugated and free OOPs in human plasma. This approach minimizes sample handling thus reducing analyte losses and degradation by contact with the atmosphere-and increases analysis throughput, which is crucial in intervention studies dealing with cohorts formed by numerous individuals. The fundamental of the approach is the retention of OOPs and metabolites in an SPE anionic cartridge with subsequent on-line elution to an LC-MS/MS system. Quantitative analysis of OOPs (relative quantitation for conjugated OOPs) was carried out by selected reaction monitoring mode that reported relative limits of detection and quantitation between 0.02 0.28 ng/mL (16.6-232 pg on-column) and 0.05-0.83 ng/mL (41.5-689 pg on-column), respectively. The accuracy of the method, estimated as recovery factor, ranged from 84.2 to 99.4%, and precision, expressed as relative standard deviation, was below 3.8%. The resulting method has been applied to the determination of OOPs and metabolites in plasma samples from individuals who ingested a breakfast prepared with virgin olive oil. The proposed method has an excellent potential for high-throughput use in both clinical and research laboratories. PMID- 22944383 TI - Ruggedness testing and validation of a practical analytical method for >100 veterinary drug residues in bovine muscle by ultrahigh performance liquid chromatography-tandem mass spectrometry. AB - In this study, optimization, extension, and validation of a streamlined, qualitative and quantitative multiclass, multiresidue method was conducted to monitor >100 veterinary drug residues in meat using ultrahigh-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS). Optimization centered on extensive ruggedness evaluation of the method. Various clean-up sorbents were tested and the amount of co-extractives were weighed, matrix effects were measured using post-column infusion of representative analytes, the effect of extract dilution before injecting was studied, and analyte recoveries and reproducibilities were determined. In order to extend our previous method, more drug analytes were added that possessed a wider range of chemical properties, and a re-appraisal of different types of C18 in dispersive solid-phase extraction clean-up and mobile phases in UHPLC-MS/MS was done. Ultimately, end-capped C18 and post-column infusion of ammonium formate as an ionization enhancer for the late-eluting anthelmintics were found to give improved qualitative results for greater analytical scope. A multi-day, multi-analyst validation demonstrated that the final method is suitable for screening of 113 analytes, identifying 98 and quantifying (recoveries between 70-120% and RSD<25%) 87 out of the 127 tested drugs at or below US regulatory tolerance levels in bovine muscle. PMID- 22944384 TI - Capillary electrophoretic system of ribonucleic acid molecules. AB - Over the past two decades, capillary electrophoresis (CE) has been the subject of extensive development and progress in various DNA based sieving electrophoresis applications, namely Sanger sequencing, forensic short tandem repeat (STR) analysis, clinical genotype screening (SNP), and phylogenetic fingerprinting. Yet, this trend has not been emulated in the RNA field. This review will highlight the development and key analysis parameters of RNA electrophoresis by CE and provide possible explanations for the low research interest in this area. PMID- 22944385 TI - 1-Hexyl-3-methyl imidazolium tetrafluoroborate: an efficient column enhancer for the separation of basic drugs by reversed-phase liquid chromatography. AB - Ionic liquids are dual modifiers composed by a large anion and a large cation, which interact with both the hydrophobic alkyl-bonded phase and the anionic residual silanols in C18 columns. The deactivation of the silanol groups has important implications on the chromatographic analysis of basic drugs, being the improvement of peak profiles and shorter retention times the most noticeable features. However, other characteristics as selectivity or resolution are not usually considered, or are only examined for selected chromatographic conditions. In this work, the effect of the addition of the ionic liquid 1-hexyl-3-methyl imidazolium tetrafluoroborate to acetonitrile-water mixtures in a wide range of concentrations, using three C18 columns (Zorbax SB-C18, Nucleosil and Spherisorb) was studied for the separation of a group of beta-adrenolytic drugs. The extremely poor chromatographic performance was highly improved in the presence of the ionic liquid, giving rise to shorter analysis times, smaller consumption of acetonitrile, significantly narrower and more symmetric peaks, and high resolution. The improvement was especially noteworthy for the Spherisorb column, which yielded the poorest results in the absence of additive. PMID- 22944387 TI - The International Physical Activity Questionnaire-long form overestimates self reported physical activity of Brazilian adults. AB - OBJECTIVE: To explore issues associated with measuring physical activity using the International Physical Activity Questionnaire (IPAQ)-long form in adults living in a mid-sized Brazilian city. METHODS: A stratified random sampling procedure was used to select a representative sample of adults living in Rio Claro. This yielded 1572 participants who were interviewed using the IPAQ-long form. The data were analysed using standard statistical procedures. RESULTS: Overall, 83% of men and 89% of women reported at least 150 min of combined moderate and/or vigorous physical activity per week. Reliable values of leisure and transportation-related physical activity were observed for both males and females. With regard to the household and work-related physical activity domains, both males and females reported unusually high levels of participation. CONCLUSION: The IPAQ-long form appears to overestimate levels of physical activity for both males and females, suggesting that the instrument has problems in measuring levels of physical activity in Brazilian adults. Accordingly, caution is warranted before using IPAQ data to support public policy decisions related to physical activity. PMID- 22944386 TI - Contribution of the frontal eye field to gaze shifts in the head-unrestrained rhesus monkey: neuronal activity. AB - The frontal eye field (FEF) has a strong influence on saccadic eye movements with the head restrained. With the head unrestrained, eye saccades combine with head movements to produce large gaze shifts, and microstimulation of the FEF evokes both eye and head movements. To test whether the dorsomedial FEF provides commands for the entire gaze shift or its separate eye and head components, we recorded extracellular single-unit activity in monkeys trained to make large head unrestrained gaze shifts. We recorded 80 units active during gaze shifts, and closely examined 26 of these that discharged a burst of action potentials that preceded horizontal gaze movements. These units were movement or visuomovement related and most exhibited open movement fields with respect to amplitude. To reveal the relations of burst parameters to gaze, eye, and/or head movement metrics, we used behavioral dissociations of gaze, eye, and head movements and linear regression analyses. The burst number of spikes (NOS) was strongly correlated with movement amplitude and burst temporal parameters were strongly correlated with movement temporal metrics for eight gaze-related burst neurons and five saccade-related burst neurons. For the remaining 13 neurons, the NOS was strongly correlated with the head movement amplitude, but burst temporal parameters were most strongly correlated with eye movement temporal metrics (head eye-related burst neurons, HEBNs). These results suggest that FEF units do not encode a command for the unified gaze shift only; instead, different units may carry signals related to the overall gaze shift or its eye and/or head components. Moreover, the HEBNs exhibit bursts whose magnitude and timing may encode a head displacement signal and a signal that influences the timing of the eye saccade, thereby serving as a mechanism for coordinating the eye and head movements of a gaze shift. PMID- 22944389 TI - Informed consent for inguinal herniorrhaphy and cholecystectomy: describing how patients make decisions to have surgery. AB - BACKGROUND: We describe how patients perceive the process of informed consent and its influence on decision making for elective surgery. METHODS: A cohort of 38 patients documented consent for cholecystectomy or inguinal herniorrhaphy using the Veterans Affair's computer-based tool for documenting informed consent for clinical treatment. Participants completed semistructured telephone interviews exploring their attitudes about informed consent, iMed, and the decision-making process. We used qualitative methods to code and analyze the data. RESULTS: Sixty nine percent of patients decided to have surgery before meeting their surgeon, and 47% stated that the surgeon did not influence their decision. Although the surgeon was an important source of information for most patients (81%), patients frequently described using information gathered before meeting the surgeon, such as other health care providers (81%) or family members (58%). Most (68%) patients perceived iMed as a legal formality with little influence on decision making. CONCLUSIONS: Future research should examine whether patient decision making regarding elective surgery becomes better informed if nonsurgeon clinicians connect patients to educational resources such as iMed closer to the time of initial diagnosis and before meeting the surgeon. PMID- 22944390 TI - Identifying risk factors for surgical site infections in mastectomy patients using the National Surgical Quality Improvement Program database. AB - BACKGROUND: The Centers for Disease Control and Prevention reported that surgical site infections (SSIs) create a significant hospital burden. To date, few multi institutional studies have been performed to evaluate the risk factors for SSIs in mastectomy patients. METHODS: By using the American College of Surgeons' National Surgical Quality Improvement Program database, all patients undergoing mastectomy from 2005 to 2009 were identified. The outcome was to determine the incidence rate and identify significant independent risk factors of SSIs. RESULTS: The incidence of SSI was 2.3% (891 of 38,739; 95% confidence interval, 2.2%-2.5%) in patients undergoing mastectomy without reconstruction. Significant (P < .05) risk factors for SSI included a body mass index greater than 25, American Society of Anesthesiology classification of 3 or higher, diabetes mellitus, surgical time of 2 hours or longer (75th percentile), and current smoking status. CONCLUSIONS: Before this study, there was wide variation in the incidence rate of surgical site infections in this patient population. This was a large-scale study to address these inconsistencies. PMID- 22944391 TI - Effects of dexamethasone and pheniramine hydrogen maleate on stress response in patients undergoing elective laparoscopic cholecystectomy. AB - BACKGROUND: Laparoscopic cholecystectomy (LC) still leads to significant postoperative nausea and vomiting (PONV) and pain. Our aim was to evaluate the efficacy of dexamethasone or pheniramine hydrogen maleate, either alone or combined, in reducing the stress response and symptoms after LC. METHODS: Patients were randomly assigned to 1 of 4 groups, each consisting of 20 patients: control, dexamethasone (8 mg/2 mL), pheniramine hydrogen maleate (45.5 mg/2 mL), and the combined group. The drugs were given before anesthesia induction. RESULTS: C-reactive protein levels (CRP) and visual analog scale (VAS) scores were significantly less in the dexamethasone (P = .003) and combined groups (P < .001). Both dexamethasone (P < .001) and pheniramine hydrogen maleate (P = .005) significantly reduced PONV. CONCLUSIONS: Dexamethasone significantly reduced postoperative pain and the systemic acute-phase response, whereas these effects were only partially attained with pheniramine hydrogen maleate. Both dexamethasone and pheniramine hydrogen maleate significantly reduced PONV. An additive effect seemed to occur if these drugs were used in combination. PMID- 22944392 TI - Immediate passive motion versus immobilization after endoscopic supraspinatus tendon repair: a prospective randomized study. AB - INTRODUCTION: Rehabilitation programs after rotator cuff repair should allow recovery of shoulder function without preventing tendon healing. The aim of this randomized prospective study was to compare the clinical results after two types of postoperative management: immediate passive motion versus immobilization. PATIENTS AND METHODS: We followed 100 patients, mean age 55 years old, who underwent arthroscopic repair of a non-retracted supraspinatus tear. Patients were randomized to receive postoperative management of immediate passive motion or strict immobilization for 6 weeks. A clinical evaluation was performed in 92 patients, and CT arthrography in 82. Mean follow-up was 15 months. RESULTS: The mean preoperative Constant score improved significantly from 46.1 points to 73.9 at the final follow-up. The rate of intact cuffs was 58.5%. Functional results were statistically better after immediate passive motion with a mean passive external rotation of 58.7 degrees at the final follow-up versus 49.1 degrees after immobilization (P=0.011), a passive anterior elevation of 172.4 degrees versus 163.3 degrees (P=0.094) respectively, a Constant score of 77.6 points versus 69.7 (P=0.045) respectively, and a lower rate of adhesive capsulitis and complex regional pain syndrome. Results for healing seemed to be slightly better with immobilization, but this was not statistically significant: the cuff had a normal appearance in 35.9% of cases after immobilization compared to 25.6% after passive motion, an image of intratendinous addition was found in 25.6% versus 30.2%, punctiform leaks in 23.1% versus 20.9%, and recurrent tears in 15.4% versus 23.3% respectively. DISCUSSION: The rehabilitation program that results in better tendon healing by preventing postoperative stiffness has not yet been identified. Our results suggest that early passive motion should be authorized: the functional results were better with no significant difference in healing. PMID- 22944393 TI - Shoulder hemiarthroplasty: outcomes and long-term survival analysis according to etiology. AB - BACKGROUND: The indications for hemiarthroplasty in glenohumeral joint diseases remain controversial and depend mainly on the original underlying diagnosis. Our objective was to investigate the influence of the primitive aetiology on long term prosthesis survival and on the Constant-Murley score. MATERIALS AND METHODS: We studied 272 shoulders with the following diagnoses: fracture sequelae (n=73), primary osteoarthritis (n=67), cuff tear arthropathy (n=43), avascular necrosis (n=40), rheumatoid arthritis (n=31), and other (n=18). Of the 272 shoulders, 139 were evaluated after at least 8 years (mean follow-up, 134 months). In all, 30 prostheses required removal. Functional status was evaluated using the Constant Murley score and survival rate using the Kaplan-Meier method with prosthesis removal or conversion to total arthroplasty as the endpoint. RESULTS: Ten-year prosthesis survival was 88.13% overall, 100% in the rheumatoid arthritis group, 94.9% in the avascular necrosis group, 94.2% in the primary osteoarthritis group, 81.5% in the cuff tear arthropathy group, and 76.8% in the fracture sequelae (P=0.05). The mean Constant-Murley score after 8 years or more was 70.1 in avascular necrosis, 60.7 in primary osteoarthritis, 57.7 in fracture sequelae, 55.3 in rheumatoid arthritis, and 46.2 in cuff tear arthropathy (P=0.0006). The complication rate with the initial population as the denominator was 24.7% in fracture sequelae, 18.6% in cuff tear arthropathy, 15% in avascular necrosis, 8.9% in primary osteoarthritis, and 3.2% in rheumatoid arthritis. CONCLUSIONS: The best indication for shoulder hemiarthroplasty is avascular necrosis and the worst indications are cuff tear and post-traumatic fracture sequellae. Rheumatoid arthritis and primary glenohumeral osteoarthritis are good indications in patients younger than 50 years of age. LEVEL OF EVIDENCE: Level IV, retrospective study. PMID- 22944395 TI - Anticancer polysaccharides from natural resources: a review of recent research. AB - Taking into account the rising trend of the incidence of cancers of various organs, effective therapies are urgently needed to control human malignancies. However, almost all of the chemotherapy drugs currently on the market cause serious side effects. Fortunately, several previous studies have shown that some non-toxic biological macromolecules, including polysaccharides and polysaccharide protein complexes, possess anti-cancer activities or can increase the efficacy of conventional chemotherapy drugs. Based on these encouraging observations, a great deal of effort has been focused on discovering anti-cancer polysaccharides and complexes for the development of effective therapeutics for various human cancers. This review focuses on the advancements in the anti-cancer efficacy of various natural polysaccharides and polysaccharide complexes in the past 5 years. Most polysaccharides were tested using model systems, while several involved clinical trials. PMID- 22944394 TI - Stability of early-stage amyloid-beta(1-42) aggregation species. AB - Accumulation of aggregated amyloid-beta protein (Abeta) is an important feature of Alzheimer's disease. There is significant interest in understanding the initial steps of Abeta aggregation due to the recent focus on soluble Abeta oligomers. In vitro studies of Abeta aggregation have been aided by the use of conformation-specific antibodies which recognize shape rather than sequence. One of these, OC antiserum, recognizes certain elements of fibrillar Abeta across a broad range of sizes. We have observed the presence of these fibrillar elements at very early stages of Abeta incubation. Using a dot blot assay, OC-reactivity was found in size exclusion chromatography (SEC)-purified Abeta(1-42) monomer fractions immediately after isolation (early-stage). The OC-reactivity was not initially observed in the same fractions for Abeta(1-40) or the aggregation restricted Abeta(1-42) L34P but was detected within 1-2weeks of incubation. Stability studies demonstrated that early-stage OC-positive Abeta(1-42) aggregates were resistant to 4M urea or guanidine hydrochloride but sensitive to 1% sodium dodecyl sulfate (SDS). Interestingly, the sensitivity to SDS diminished over time upon incubation of the SEC-purified Abeta(1-42) solution at 4 degrees C. Within 6-8days the OC-positive Abeta42 aggregates were resistant to SDS denaturation. The progression to, and development of, SDS resistance for Abeta(1 42) occurred prior to thioflavin T fluorescence. In contrast, Abeta(1-40) aggregates formed after 6days of incubation were sensitive to both urea and SDS. These findings reveal information on some of the earliest events in Abeta aggregation and suggest that it may be possible to target early-stage aggregates before they develop significant stability. PMID- 22944396 TI - Studies on the characteristic and activity of low-molecular fragments from zymosan. AB - Zymosan was hydrolysed with HCl and fractionated by ultrafiltration and dialysis to obtain water-soluble fragments A, B and C. Physical and chemical analyses showed that these fractions are composed primarily of glucose and have molecular weights of 8 kDa, 5 kDa and 2 kDa, respectively. A glycosidic linkage analysis indicated that they are mainly composed of beta-1,3-glucans. Fragment A, which has the highest molecular weight, contains approximately 30% beta-1,6-linked glucans, but fragment C is almost entirely composed of linear beta-1,3-glucan chains. The anti-chronic atrophic gastritis activity experiments showed that fragment A has significant activity, the activity of zymosan is quite low and the activities of fragments B and C are in between those of fragment A and zymosan. PMID- 22944397 TI - Bromide-free oxidizing system for carboxylic moiety formation in cellulose chain. AB - NHPI (N-hydroxyphthalimide) was used to mediate the oxidation of cellulose fibers in the absence of sodium bromide, as traditionally was used in this kind of transformations, solely using sodium hypochlorite (NaOCl) as the primary oxidant. Avoiding the use of NaBr is highly desired from both environmental and corrosion concerns. The non-persistent PINO (phthalimide-N-oxy) radical, the key species in the oxidation reaction, has been in situ generated from NHPI and copper (II) chloride. The reaction was performed at room temperature at pH=10.5. The carboxylic moiety formation was evidenced by FTIR and X-ray photoelectronic spectroscopy (XPS) and the content of the negatively charged groups determined by potentiometric titration. The changes appeared in crystallinity were evidenced by X-ray diffraction technique. PMID- 22944398 TI - Ultrasound-assisted adsorption of anionic nanoscale pigment on cationised cotton fabrics. AB - Application of pigments in textile coloring has many advantages such as less water and energy consumption, less effluent load and higher efficiency, so the pigments are perfect alternatives to dyes for eco-friendly coloring. In this work, a stable anionic nanoscale pigment suspension was prepared using a polymeric dispersant to color the cationised cotton with the exhaust method. Meanwhile, ultrasound was carried out during the adsorption to evaluate the ultrasonic influences on the uptake of pigment, adsorption efficiency and final product quality. The uptake of pigment is found to be higher with ultrasonic method than that with conventional technique because of the good dispersing capacity of ultrasound to pigment particles. Besides, it is found that nanoscale pigment has higher adsorption rate when using ultrasonic method because the ultrasound promotes the diffusion of pigment through the fiber-liquid boundary layer. Lastly, the color difference (DeltaE) reveals the nanoscale pigment can be deposited on cotton surface more uniformly under ultrasonic condition, improving the product quality obviously. PMID- 22944399 TI - Dextran and gelatin based photocrosslinkable tissue adhesive. AB - A two-component tissue adhesive based on biocompatible and bio-degradable polymers (oxidized urethane dextran (Dex-U-AD) and gelatin) was prepared and photocrosslinked under the ultraviolet (UV) irradiation. The adhesive could adhere to surface of gelatin, which simulated the human tissue steadily. The structures of above Dex-U-AD were characterized by FTIR, (1)H NMR spectroscopy and XRD. The adhesion property of result products was evaluated by lap-shear test. The maximum adhesion strength could reach to 4.16+/-0.72 MPa which was significantly higher than that of fibrin glue. The photopolymerization process of Dex-U-AD/gelatin was monitored by real time infrared spectroscopy (RTIR). It took less than 5 min to complete the curing process. The cytotoxicity of Dex-U AD/gelatin also was evaluated which indicated that Dex-U-AD/gelatin gels were nontoxic to L929 cell. The relationship between all the above-mentioned properties and degree of oxidization of Dex-U-AD was assessed. The obtained products have the potential to serve as tissue adhesive in the future. PMID- 22944400 TI - Starch/polyaniline nanocomposite for enhanced removal of reactive dyes from synthetic effluent. AB - Starch/polyaniline nanocomposite was synthesized by chemical oxidative polymerization of aniline and was subsequently analyzed for dye removal from aqueous solution. Batch experiment results showed that nanocomposite removed 99% of Reactive Black 5, 98% of Reactive Violet 4, and decolorized 87% of dye bath effluent. The Toth isotherm model better described single component equilibrium adsorption, whereas the modified Freundlich model showed satisfactory fit for dye bath. In kinetic modeling, single system followed pseudo-second-order and dye bath followed the modified pseudo-first-order model. Fourier transform infrared spectroscopy pattern of the nanocomposite showed the participation of aromatic, amino, hydroxyl, and carboxyl groups. The results indicate that starch/polyaniline nanocomposite can be used as an effective adsorbent for removal of dyes from textile effluents. PMID- 22944401 TI - Electrospun poly(lactic acid)/chitosan core-shell structure nanofibers from homogeneous solution. AB - The core-shell structure nanofibers of poly(lactic acid)/chitosan with different weight ratios were successfully electrospun from homogeneous solution. The preparation process was more simple and effective than double-needle electrospinning. The nanofibers were obtained with chitosan in shell while poly(lactic acid) in core attributing to phase separation, which were characterized by scanning electron microscopy (SEM), transmission electron microscopy (TEM), X-ray diffraction (XRD) and energy dispersive spectrometer (EDS). The electrospun nanofibrous membrane was evaluated in vitro by using mouse fibroblasts (L929) as reference cell lines. Cell culture results indicated that these materials were good in promoting cell growth and attachment, thus they could be used for tissue engineering and wound healing dressing. PMID- 22944402 TI - Films of starch and poly(butylene adipate co-terephthalate) added of soybean oil (SO) and Tween 80. AB - Starch extruded in the presence of a plasticizer results in a material called thermoplastic starch (TPS). TPS mixed with poly(butylene adipate co terephthalate) (PBAT), soybean oil (SO), and surfactant may result in films with improved mechanical properties due to greater hydrophobicity and compatibility among the polymers. This study characterized films produced from blends containing 65% TPS and 35% PBAT with SO added as compatibilizer. The Tween 80 was added to prevention of phase separation. The elongation and resistance were greater in the films with SO. The infrared spectra confirmed an increase in ester groups bonded to the PBAT and the presence of groups bonded to the starch ring, indicating TPS-SO and PBAT-SO interactions. The micrographs suggest that the films with SO were more homogenous. Thus, SO is considered to be a good compatibilizer for blends of TPS and PBAT. PMID- 22944403 TI - Imaging of the GI tract by QDs loaded heparin-deoxycholic acid (DOCA) nanoparticles. AB - This study presents an approach to deliver non invasive, near-IR imaging agent using oral delivery system. Low molecular weight heparin (LMWH)-deoxycholic acid (DOCA)/(LHD) nanoparticles formed by a self-assembly method was prepared to evaluate their physicochemical properties and oral absorption in vitro and in vivo. Near-IR QDs were prepared and loaded into LHD nanoparticles for imaging of the gastro-intestinal (GI) tract absorption. Q-LHD nanoparticles were almost spherical in shape with diameters of 194-217 nm. The size and fluorescent intensity of the Q-LHD nanoparticles were stable in 10% FBS solution and retained their fluorescent even after 5 days of incubation. Cell viability of Q-LHD nanoparticles maintained in the range of 80-95% for 24h incubation. No damage was found in tissues or organs during animal experiments. The in vivo oral absorption of Q-LHD was observed in SKH1 mice for 3h under different doses. From the results, we confirmed that Q-LHD was absorbed mostly into the ileum of small intestine containing intestinal bile acid transporter as observed in TEM and molecular imaging system. Our designed nanoparticles could be administered orally for bio-imaging and studying the bio-distribution of drug. PMID- 22944404 TI - Electrosprayed polyelectrolyte complexes between mucoadhesive N,N,N, trimethylchitosan-homocysteine thiolactone and alginate/carrageenan for camptothecin delivery. AB - Novel hydrogel polyelectrolyte complexes (PECs) between the N,N,N, trimethylchitosan-homocysteine thiolactone (TM-HT-chitosan) and two anionic polymers were investigated. The particles of pure thiolated chitosan and its PECs with alginate and carrageenan were fabricated using the electrospray ionization technique. The hydrogel PEC particles were characterized by scanning electron microscopy, dynamic light scattering, Fourier transform infrared microscopy, thermogravimetric analysis, encapsulation efficiency (EE), mucoadhesive property and in vitro drug release behavior. TM-HT-chitosan/alginate particles could be loaded with camptothecin (CPT), employed as a model anti-cancer drug, at an over 70% EE, and revealed both a reduced burst effect and a prolonged release of CPT over 3 days. The resultant TM-HT-chitosan/alginate PEC particles displayed a 5.60 , 1.86- and 1.55-fold stronger mucoadhesive property compared to that of the unmodified chitosan/alginate PEC at pH 1.2, 4.0 and 6.4, respectively, and this was not affected by the CPT loading level. PMID- 22944405 TI - Effect of gamma-irradiation on pasting and emulsification properties of octenyl succinylated rice starches. AB - Octenylsuccinylated (OS) starches from waxy rice or high-amylose rice (28.1% amylose) (DS 0.023 and 0.025, respectively) were gamma-irradiated at 10, 30, or 50 kGy and their pasting and thermal properties, crystallinity, and emulsification property were examined. When the OS starches were irradiated, the degrees of substitution gradually decreased as irradiation dose increased. A significant decrease in pasting viscosity was observed with an increase in irradiation dose, indicating the presence of chain degradation induced by the radiation. The melting temperature and enthalpy determined by differential scanning calorimetry increased slightly by irradiating at 10 or 30 kGy. Little change in crystallinity was observed in the X-ray diffraction analysis for the OS high-amylose rice starch regardless of irradiation doses, whereas a decrease in crystallinity was observed with the OS waxy starch irradiated at 50 kGy. Chain degradation induced by irradiation occurred mainly in the amorphous regions, but some loss of crystallinity occurred when the irradiation was excessive. The OS starches showed greater emulsion capacity and stability than the native counterparts due to their amphipathic nature. The irradiation further improved the emulsification properties of OS starches. The irradiation at 10 kGy was optimal, and treating at higher doses decreased the emulsion capacity and stability of the OS starches. PMID- 22944406 TI - Preparation and characterization of novel oxidized cellulose acetate methyl esters. AB - In this paper, we report the preparation of oxidized cellulose acetate methyl esters (OCAM) from OCA (OC14A: carboxylic acid content 10.6% (w/w), degree of acetyl group substitution: 1.89; OC21A: carboxylic acid content 15.7% (w/w), degree of acetyl group substitution: 1.70) by treatment with methanol at room temperature using 4-dimethylaminopyridine (DMAP) as a catalyst and dicyclohexylcarbodiimide (DCC) as a coupling agent. The new polymers were characterized by Fourier-transform infrared (FT-IR) and (1)H and (13)C nuclear magnetic resonance spectroscopies, carboxylic acid content determination, moisture sorption isotherms, intrinsic viscosity, and powder X-ray diffractometry. The new polymers are amorphous powders. It is practically insoluble in water but show solubility in a range of organic solvents. PMID- 22944407 TI - In vitro evaluation of an RGD-functionalized chitosan derivative for enhanced cell adhesion. AB - Tissue repair is a spontaneous process that is initiated on wounding. However, if this complex mechanism is impaired or not sufficient the use of biomaterials might increase the chance of successful healing. In this view, an RGD functionalized polymer was developed to promote dermal healing. A water-soluble chitosan derivative, carboxymethyl-trimethylchitosan (CM-TM-chitosan) was synthesized and GRGDS-moieties were grafted to the backbone at a concentration of 59 nmol/mg polymer to increase cell-biomaterial interaction. Tested in vitro with cultured human dermal fibroblasts, the developed polymer showed good biocompatibility and the initial adhesion was increased by 3-5 times due to the GRGDS-moieties. Moreover, cell spreading was specific to the interaction with GRGDS, giving a 12-fold increase of cells showing a fully spread morphology within 30 min. Overall, CM-TM-chitosan conjugated with GRGDS-peptides may prove useful as a biomaterial in wound healing. PMID- 22944408 TI - A new route for chitosan immobilization onto polyethylene surface. AB - Low-density polyethylene (LDPE) belongs to commodity polymer materials applied in biomedical applications due to its favorable mechanical and chemical properties. The main disadvantage of LDPE in biomedical applications is low resistance to bacterial infections. An antibacterial modification of LDPE appears to be a solution to this problem. In this paper, the chitosan and chitosan/pectin multilayer was immobilized via polyacrylic acid (PAA) brushes grafted on the LDPE surface. The grafting was initiated by a low-temperature plasma treatment of the LDPE surface. Surface and adhesive properties of the samples prepared were investigated by surface analysis techniques. An antibacterial effect was confirmed by inhibition zone measurements of Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus). The chitosan treatment of LDPE led to the highest and most clear inhibition zones (35 mm(2) for E. coli and 275 mm(2) for S. aureus). PMID- 22944409 TI - beta-Chitin nanofibrils for self-sustaining hydrogels preparation via hydrothermal treatment. AB - A transparent nanofibril suspension could be readily obtained by treating purified squid pen powder in water with ultrasonic irradiation. The obtained suspension is consisted of beta-chitin nanofibrils (CNF) with 3-10 nm in width and several micrometers in length. The degree of acetylation (DA) of CNF was found to be 84% which is about 10% lower than that of untreated sample. The CNF suspension could be transformed into a durable 3-D hydrogels (CH) by simply heating to 180 degrees C for 1-4 h in an autoclave. Hydrophobic interaction between CNF was believed to play the major role for CNF self-assembling into hydrogels, since the as-prepared chitin hydrogels readily dissolved in a typical chaotropic solution (8 M urea) under room temperature. The hydrothermal duration and CNF concentration (0.3-2% (w/v)) strongly affected the physical properties of CH. The suspension of 1% (w/v) CNF treated with 4 h, 180 degrees C hydrothermal heating generated a CH with 99.3% water content, CNF with 87% crystallinity and an mechanical strength of 0.7 N breaking force. PMID- 22944411 TI - Graft copolymerization of acrylic acid to cassava starch--evaluation of the influences of process parameters by an experimental design method. AB - The graft copolymerization of cassava starch with acrylic acid was investigated using a free radical initiator system (Fe(2+)/H(2)O(2) redox system) in water. A comprehensive understanding of the important variables and their interaction has been obtained by applying an experimental design method. In this approach, two ('high' and 'low') values of selected variables are considered. Important result parameters are add-on and the grafting efficiency. Out of eight reaction variables, it was found that only temperature, starch concentration and the starch to monomer ratio have a pronounced influence on these response parameters. Moderate reaction temperature (40 degrees C) and high starch concentration (10%) give relatively good results of add-on and grafting efficiency. A low starch to monomer ratio favors add-on but decreases grafting efficiency. These findings can be used to optimize the production of cassava starch-acrylate copolymers and to gain insight in the process-product property interactions, for various applications. PMID- 22944410 TI - One-pot synthesis of chitosan-g-(PEO-PLLA-PEO) via "click" chemistry and "SET NRC" reaction. AB - For the development of biocompatible and degradable biomaterials, a kind of well defined graft copolymer consisting of chitosan back-bone and amphiphilic PEO-PLLA PEO branch chains was synthesized by Cu(0) catalyzed one-pot strategy combining "click" chemistry and single electron transfer-nitroxide radical coupling (SET NRC) reaction. First, the precursors of 6-azide-N-phthaloyl-chitosan, TEMPO-PEO alkyne and mPEO-PLLA-Br were designed and produced. Then, the one-pot coupling reactions between these precursors were performed in the presence of nanosized Cu and PMDETA. The efficiencies of the coupling reactions were greater than 90% determined by the FTIR and ESR spectra. The structure of graft copolymer with 43% of the grafting ratio was confirmed by the spectral analysis. This work provided a route to prepare chitosan graft copolymer. PMID- 22944412 TI - The effect of NaCl on the rheological properties of suspension containing spray dried starch nanoparticles. AB - The effect of NaCl on the rheological properties of suspensions containing spray dried starch nanoparticles produced through high pressure homogenization and emulsion cross-linking technique was studied. Rheological properties such as continuous shear viscosity, viscoelasticity and creep-recovery were measured. NaCl (5-20%, w/w) was found to lower viscosity quite significantly (p<0.05), enhance the heat stability and weaken their gelling behavior compared to starch only suspension. NaCl reduced both the storage and loss moduli of suspension within the frequency range (0.1-10 rads/s) studied. However, NaCl brought higher speed of reduction on the storage modulus than on the loss modulus, which resulted into large increase in loss angle. The creep-recovery behavior of suspension was affected by NaCl and the recovery rate was highest (86%) at 15% NaCl. The Cross, the Power law and the Burger's models followed the experimental viscosity, storage and loss moduli, and creep-recovery data well with R(2)>0.97. PMID- 22944413 TI - Rapid synthesis of antimicrobial paper under microwave irradiation. AB - The silver-nanoparticle (AgNP) containing paper was successfully prepared. The AgNP is deposited by the in situ reduction of silver nitrate on the acrylamide grafted bagasse paper sheets in the presence of citrate molecules as stabilizing agent. In the present paper, grafting of acrylamide onto bagasse paper sheets using potassium persulfate was carried out under the influence of microwave radiations (MWR). The modified paper sheets were characterized by Fourier transform infrared spectroscopy (FTIR), UV-spectroscopy, and scanning electron microscopy (SEM). Antimicrobial activities of the prepared paper sheets were also investigated against G+ve bacterium Staphylococcus aureus, G-ve bacterium Pseudomomas aeruginosa, and yeast Candida albicans, which are model microorganisms for testing bactericidal properties. The AgNP containing paper sheets exhibited antibacterial activity. PMID- 22944414 TI - Synthesis, characterization and evaluation of thiolated tamarind seed polysaccharide as a mucoadhesive polymer. AB - In the present study, thiol-functionalization of tamarind seed polysaccharide was carried out by esterification with thioglycolic acid. Thiol-functionalization was confirmed by SH stretch in Fourier-transformed infra-red spectra at 2586 cm(-1). It was found to possess 104.5 mM of thiol groups per gram. The results of differential scanning calorimetry and X-ray diffraction study indicate increase in crystallinity. Polymer compacts of thiolated tamarind seed polysaccharide required 6.85-fold greater force to detach from the mucin coated membrane than that of tamarind seed polysaccharide. Comparative evaluation of Carbopol-based metronidazole gels containing thiolated tamarind seed polysaccharide with gels containing tamarind seed polysaccharide for mucoadhesive strength using chicken ileum by modified balance method revealed higher mucoadhesion of gels containing thiolated tamarind seed polysaccharide. Further, the gels containing tamarind seed polysaccharide and thiolated tamarind seed polysaccharide released the drug by Fickian-diffusion following the first-order and Higuchi's-square root release kinetics, respectively. PMID- 22944415 TI - Physical, chemical and mechanical properties of pehuen cellulosic husk and its pehuen-starch based composites. AB - Pehuen cellulosic husk was characterized and employed as reinforcement for composite materials. In this research, thermoplastic pehuen starch (TPS) and TPS/poly(lactic acid) (PLA)/polyvinyl alcohol (PVA) composites, reinforced with 5 and 10% of pehuen husk, were prepared by melt-blending. Comparative samples of pehuen TPS and TPS/PLA/PVA blend were also studied. Physical, thermal, structural and mechanical properties of composites were evaluated. Pehuen husk mainly consists of cellulose (50 wt%), hemicellulose (30 wt%) and lignin (14 wt%). In respect to lipids, this husk has only a 0.6 wt%. Its surface is smooth and damage free and it is decomposed above 325 degrees C. The incorporation of pehuen husk improved considerably the thermal stability and mechanical properties of the studied composites, mainly in TPS composites. Their thermal stability enhances since biofiber hinders the "out-diffusion" of volatile molecules from the polymer matrix, while mechanical properties could raise due to the natural affinity between husk and starch in the pehuen seed. PMID- 22944416 TI - One pot synthesis of polypyrrole silver nanocomposite on cotton fabrics for multifunctional property. AB - Polymer-silver nanocomposites modified cotton fabrics were prepared by in situ chemical oxidative polymerization using pyrrole and silver nitrate. In a redox reaction between pyrrole and silver nitrate, silver ions oxidize the pyrrole monomer and get reduced. This reduced silver as nanoparticles deposited on/into the polypyrrole/cotton matrix layer and the interaction between silver and polypyrrole was by adsorption or electrostatic interaction. The structure and composite formation on cotton fiber was investigated using SEM, FT-IR, XPS and XRD. The results showed that a strong interaction existing between silver nanoparticles with polypyrrole/cotton matrix. FT-IR studies clearly indicated that the interaction between polypyrrole (-N-H) and cellulose (>C-OH) was by hydrogen bonding. It is observed that the conductivity of the composite coated fabrics has been increased by the incorporation of silver nanoparticles. In the synthesized composites, silver content plays an important role in the conductivity and antimicrobial activity rate of the fabrics against gram positive Staphylococcus aureus and gram negative Escherichia coli bacteria. PMID- 22944417 TI - Cereal beta-glucan quantification with calcofluor-application to cell culture supernatants. AB - The specific binding of the fluorescent dye calcofluor to cereal beta-glucan results in increased fluorescence intensity of the formed complex and is in use for the quantification of beta-glucan above a critical molecular weight (MW) by flow injection analysis. In this study, this method was applied in a fast and easy batch mode. In order to emphasize the spectral information of the emission spectra of the calcofluor/beta-glucan complexes, derivative signals were calculated. A linear relationship was found between the amplitude of the second derivative signals and the beta-glucan concentration between 0.1 and 0.4 MUg/mL. The low detection limit of this new method (0.045 MUg/mL) enabled its use to study the transport of cereal beta-glucans over differentiated Caco-2 cell monolayers. Additionally, the method was applied to quantify beta-glucan in arabinoxylan samples, which correlated well with data by an enzyme based method. PMID- 22944418 TI - Biomimetic growth of hydroxyapatite on phosphorylated electrospun cellulose nanofibers. AB - In biomimicking the formation of collagen fiber/hydroxyapatite (HAp) in natural bone, electrospun cellulose nanofiber (CelluNF)/HAp composites were synthesized in simulated body fluid (SBF). Their morphology and structure were characterized by SEM, TEM, XRD and XPS. CelluNFs showed low bioactivity in inducing the growth of HAp. In order to improve this ability, CelluNFs were slightly phosphorylated with a degree of substitution of phosphate group of 0.28. The modified CelluNFs were highly effective in guiding the HAp growth along the fibers. The HAp crystal size in the composites was ca. 24 nm, and the lattice spacing of (211) plane was 2.83 A. It was found that the HAps in the composites were calcium deficient. The CelluNF/HAp composites are highly porous materials with micro-, meso-, and macro pores. A mechanism for the HAp growth on CelluNFs was presented. Such CelluNF/HAp composites can be potentially useful in the field of bone tissue engineering. PMID- 22944419 TI - Electric field induced phase separation on electrospinning polyelectrolyte based core-shell nanofibers. AB - In the present study, we report a facile method to fabricate polyelectrolyte based core-shell nanofibers with the assistance of the high gradient electric potential between the tip of capillary and the collector. The core-shell structure and the composition of each layer have been supported by TEM and XPS studies. The effect of the electric field on the phase separation was considered to be the major factor. An electric field experiment was introduced to elucidate the influence of electric field on the phase separation process. It was assumed the polyelectrolyte based core-shell nanofibers membrane could be applied in wound care and tissue engineering. PMID- 22944420 TI - Preparation and characterization of gelatinized granular starches from aqueous ethanol treatments. AB - In order to modify the properties of native starch granules, the formation of gelatinized granular forms (GGS) from normal, waxy, and high amylose maize, as well as potato and tapioca starches was investigated by treating granules with aqueous ethanol at varying starch:water:ethanol ratios and then heating in a rotary evaporator to remove ethanol. The modified starches were characterized using bright field, polarized and electron microscopy. Short/long range molecular order and enthalpic transitions on heating were also studied using infrared spectroscopy, X-ray diffractometry and differential scanning calorimetry respectively. A diffuse birefringence pattern without Maltese cross was observed for most GGS samples. Treatment with aqueous ethanol resulted in starch-specific changes in the surface of granules, most noticeably swelling and disintegration in waxy maize, surface wrinkling in normal maize and tapioca, swelling and opening-up in potato starches, and swelling and bursting in high amylose maize. The ratio of ethanol to water at which original granular order was disrupted also varied with starch type. GGS had less short range molecular order than native granules as inferred by comparing 1047/1022 wave number ratio from infrared spectroscopy. Similarly, A- and B-type diffraction reflections were either reduced or completely lost with evolution of V-type patterns in GGS. PMID- 22944421 TI - Effect of gelatinization and additives on morphology and thermal behavior of corn starch/PVA blend films. AB - The blend films of ungelatinized and gelatinized starch/polyvinyl alcohol (PVA) were prepared with a solution casting method by the introduction of additives (glycerol/urea) or not. The phase morphologies and thermal behaviors of the blends were carefully analyzed. A droplet phase was observed in the blends containing ungelatinized starch and a laminated phase was observed in the blends containing gelatinized starch. For both ungelatinized and gelatinized starch/PVA blends, the melting temperature (T(m)) (210-230 degrees C) of PVA was detected, and the T(m) of gelatinized starch/PVA blends was higher than that of the ungelatinized starch/PVA blends. Blend films containing 16.8 wt% of glycerol or urea exhibited a decreased T(m). The introduction of additives (glycerol or urea) reduced the decomposition onset temperature of the blend films. These various morphologies and thermal behaviors could be attributed to the different hydrogen bonding interaction characteristics between starch and polyvinyl alcohol at different conditions. PMID- 22944422 TI - Mechanical and barrier properties of nanocrystalline cellulose reinforced chitosan based nanocomposite films. AB - Nanocrystalline cellulose (NCC) reinforced chitosan-based biodegradable films were prepared by solution casting. The NCC content in the films was varied from 1 to 10% (dry wt. basis). It was found that the tensile strength (TS) of the nanocomposite films with 5% (w/w) NCC content was optimum with an improvement of 26% compared to the control chitosan films. Incorporation of NCC also significantly improved barrier properties. Water vapor permeability (WVP) of the chitosan/NCC films was decreased by 27% for the optimum 5% (w/w) NCC content. Swelling studies revealed a decrease in water uptake of the NCC-reinforced chitosan films. Analyses of thermal properties showed no significant effect of NCC whereas X-ray diffraction studies confirmed the appearance of crystalline peaks in the nanocomposite films. Surface morphology of the films was investigated by scanning electron microscopy and it was found that NCC was dispersed homogenously into chitosan matrix. PMID- 22944423 TI - Homogeneous isolation of nanocellulose from sugarcane bagasse by high pressure homogenization. AB - Nanocellulose from sugarcane bagasse was isolated by high pressure homogenization in a homogeneous media. Pretreatment with an ionic liquid (1-butyl-3 methylimidazolium chloride ([Bmim]Cl)) was initially involved to dissolve the bagasse cellulose. Subsequently, the homogeneous solution was passed through a high pressure homogenizer without any clogging. The nanocellulose was obtained at 80 MPa for 30 cycles with recovery of 90% under the optimum refining condition. Nanocellulose had been characterized by Fourier transformed infrared spectra, X ray diffraction, thermogravimetric analysis, rheological measurements and transmission electron microscopy. The results showed that nanocellulose was 10-20 nm in diameter, and presented lower thermal stability and crystallinity than the original cellulose. The developed nanocellulose would be a very versatile renewable material. PMID- 22944424 TI - Preparation, characterization and properties of aminoethyl chitin hydrogels. AB - Aminoethyl chitins (AEC) with different amino contents were synthesized from chitin and 2-chlorethylamine hydrochloride, and the AEC hydrogels were prepared by crosslinking with glutaraldehyde. The microstructures, swelling behaviors and antibacterial activities of the hydrogels were investigated. The results of Fourier transform infrared spectroscopy (FTIR), (1)H nuclear magnetic resonance ((1)H NMR) spectrum and scanning electron microscopy (SEM) showed that the hydrogels were prepared by forming the Schiff base from AEC and glutaraldehyde. The aminoethyl chitin hydrogels were sensitive to acidic environment. The swelling ratio changed with the amino content of AEC, declined with the increase of the crosslinking agent concentration and increased with the increase of the AEC concentration. In addition, the antibacterial results of the hydrogels against Staphylococcus aureus (S. aureus) indicated that the hydrogels had good antibacterial activities, and the antibacterial properties were affected by the amino content of AEC and the crosslinking agent concentration. PMID- 22944425 TI - 'Green' crosslinking of native starches with malonic acid and their properties. AB - Starch is a highly hydrophilic biomaterial with weak mechanical properties rendering it useless for commercial applications. A fully 'green' water based process is presented to crosslink corn (cereal) and potato (tuber) starch to enhance mechanical properties as well as lower hydrophilicity. In addition, malonic acid, a green, plant based water soluble and relatively inexpensive polycarboxylic acid, was used as the crosslinker. The reactivity of potato starch toward esterification and crosslinking was found to be higher than that of corn starch owing to the inherent differences in the granule morphology and internal structure of the two starches. It was observed that potato starch granules had a higher degree of substitution (DS) of 0.19 than corn starch granules (DS=0.1) under similar reaction conditions. Chemical, thermal and mechanical test results confirmed the crosslinking as well as reduced moisture sensitivity. PMID- 22944426 TI - Radiation effects on microcrystalline cellulose in 1-butyl-3-methylimidazolium chloride ionic liquid. AB - The radiation processing of cellulose in ionic liquids (ILs) demands a comprehensive knowledge of radiation effects on cellulose in ILs. Herein, gamma radiation-induced degradation kinetics of microcrystalline cellulose (MCC) in 1 butyl-3-methylimidazolium chloride ([Bmim]Cl) was studied by viscometry. The intrinsic viscosity of MCC in [Bmim]Cl decreased slightly with increasing dose; while chemical structure and crystalline state of cellulose has no obvious change up to 300 kGy. The radiation degradation rate constant (k) of MCC in [Bmim]Cl was 2.60*10(-7)/kGy, lower than that of solid cellulose, but higher than that in N methylmorpholine-N-oxide (NMMO) solvent. Furthermore, k value decreased to 1.12*10(-7)/kGy in dimethyl sulfoxide (DMSO)/[Bmim]Cl system due to the free radicals scavenging of DMSO. The radicals generated during irradiation play main role in the radiation degradation of MCC in [Bmim]Cl. This work provides a new way to control the average molecular weight of cellulose by radiation-induced degradation of cellulose in ILs. PMID- 22944427 TI - Preparation of pH- and ionic-strength responsive biodegradable fumaric acid crosslinked carboxymethyl cellulose. AB - A novel biodegradable sodium carboxymethyl cellulose (NaCMC)-based hydrogel was synthesized by using fumaric acid (FA) as a crosslinking agent at various ratios. Hydrogels (CMCF) were characterized using Fourier transform infrared spectroscopy (FTIR), thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), X-ray diffraction analysis (XRD), scanning electron microscopy (SEM), and atomic force microscopy (AFM). Swelling behaviors of hydrogels were investigated in distilled water, various salt, and pH solutions. The FTIR results indicated the crosslinking between carboxyl groups of FA with hydroxyl group of NaCMC through ester formation. AFM analyses showed that roughness of hydrogel surface decreased with increasing crosslinker concentration. The swelling capacity decreased with an increase in charge of the metal cation (Al(3+)4)-linked Glcp (residue A), (1->6)-linked Galp (residue B), (1->2,6)-linked Glcp (residue C), (1 >5)-linked Araf (residue D), and non-reducing terminal (1->)-linked Glcp (residue E). The protective effect of S-CPPA1 on kidney ischemia/reperfusion (I/R) injury was also evaluated. Blood urea nitrogen (BUN), creatinine and TNF-alpha levels, as well as lactate dehydrogenase (LDH) and alanine transaminase (AST) activities were elevated in the I/R group as compared to the sham group. On the other hand, S-CPPA1 treatment reversed all these biochemical indices, as well as histopathological alterations, which were induced by I/R. The findings imply that S-CPPA1 plays a causal role in the protection against I/R-induced renal injury and its renoprotective effect is probably mediated by inhibiting the proinflammatory cytokine TNF-alpha release. PMID- 22944442 TI - Molecular and rheological characterization of carrageenan solutions extracted from Kappaphycus alvarezii. AB - This study evaluates and relates the molecular and rheological characteristics of native carrageenan obtained from Kappaphycus alvarezii seaweed. Native carrageenan was extracted by a differentiated methodology by atomization drying process, which reduces the time for obtaining carrageenan dry powder and minimizes costs and environmental damages. Rheological properties of native carrageenan were compared with a commercial carrageenan grade. Molecular properties were performed by SAXS and GPC analysis and the rheological properties by DMTA and stress relaxation tests. Molecular analysis proved a folded and compact molecular structure and indicated the presence of chains with different molecular weights for native carrageenan. The results obtained showed that the helix-coil transition occurs at temperature about 50 degrees C. The native and commercial grade carrageenan presented the characteristic of viscoelastic materials and their gel properties show a higher contribution from solid elastic component, and the initial force (F(0)) was higher in commercial carrageenan than native one. PMID- 22944443 TI - Biodegradable polymer based encapsulation of neem oil nanoemulsion for controlled release of Aza-A. AB - Azadirachtin a biological compound found in neem have medicinal and pesticidal properties. The present work reports on the encapsulation of neem oil nanoemulsion using sodium alginate (Na-Alg) by cross linking with glutaraldehyde. Starch and polyethylene glycol (PEG) were used as coating agents for smooth surface of beads. The SEM images showed beads exhibited nearly spherical shape. Swelling of the polymeric beads reduced with coating which in turn decreased the rate of release of Aza-A. Starch coated encapsulation of neem oil nanoemulsion was found to be effective when compared to PEG coated encapsulation of neem oil nanoemulsion. The release rate of neem Aza-A from the beads into an aqueous environment was analyzed by UV-visible spectrophotometer (214 nm). The encapsulated neem oil nanoemulsion have the potential for controlled release of Aza-A. Neem oil nanoemulsion encapsulated beads coated with PEG was found to be toxic in lymphocyte cells. PMID- 22944444 TI - Nanocrystalline cellulose (NCC) reinforced alginate based biodegradable nanocomposite film. AB - Nanocrystalline cellulose (NCC) reinforced alginate-based nanocomposite film was prepared by solution casting. The NCC content in the matrix was varied from 1 to 8% ((w/w) % dry matrix). It was found that the nanocomposite reinforced with 5 wt% NCC content exhibits the highest tensile strength which was increased by 37% compared to the control. Incorporation of NCC also significantly improved water vapor permeability (WVP) of the nanocomposite showing a 31% decrease due to 5 wt% NCC loading. Molecular interactions between alginate and NCC were supported by Fourier Transform Infrared Spectroscopy. The X-ray diffraction studies also confirmed the appearance of crystalline peaks due to the presence of NCC inside the films. Thermal stability of alginate-based nanocomposite films was improved after incorporation of NCC. PMID- 22944445 TI - Adsorption of rutin with a novel beta-cyclodextrin polymer adsorbent: thermodynamic and kinetic study. AB - The adsorption properties toward rutin of a cyclodextrin polymer adsorbent CroCD TuC 3 have been studied. The adsorption capacity is reduced as temperature and pH of solution rises, but increases with the increase of solvent polarity. Compared with SephadexTM G-15 dextran gel beads, CroCD-TuC 3 shows dramatically higher isosteric enthalpy due to a significant contribution of rutin/beta-cyclodextrin inclusion complex formation in CroCD-TuC 3 skeleton. A highlight in our study is that the pore diffusion model has been employed to describe the mass transfer inside the adsorbent pores. It reveals that the diffusion inside the pores is the rate-restricting step in the whole adsorption process. The effective pore diffusivity of rutin in CroCD-TuC 3 calculated is much lower than the diffusivity in diluted solution. The pore diffusion model is an available tool to investigate the profile of mass transfer inside the pores, and provides an effective method to describe adsorption kinetics. PMID- 22944446 TI - Theoretical study on the mechanisms of cellulose dissolution and precipitation in the phosphoric acid-acetone process. AB - Phosphoric acid-acetone fractionation was applied to pretreat lignocellulose for production of cellulosic ethanol. Cellulose solubility properties in H(2)O, H(3)PO(4) and CH(3)COCH(3) were simulated. Atomic geometry and electronic properties were computed using density functional theory with local-density approximation. H(3)PO(4) molecule is adsorbed between two cellulose segments, forming four hydrogen bonds with E(B) of -1.61 eV. Density of state for cellulose in H(3)PO(4)-cellulose system delocalizes without obvious peak. E(gap) of 4.46 eV is much smaller than that in other systems. Molecular dynamics simulation indicates that fragments of double glucose rings separate in the cellulose H(3)PO(4) interaction system. Icy CH(3)COCH(3) addition leads to re-gathering of separated fragments. Reaction energy of cellulose in three solvents is around 3.5 eV, implying that cellulose is chemically stable. Moreover, theoretical results correspond to the experiments we have performed, showing that cellulose dissolves in H(3)PO(4), flocculates after CH(3)COCH(3) addition, and finally becomes more liable to be hydrolyzed into glucoses. PMID- 22944447 TI - (1->2) and (1->6)-linked beta-D-galactofuranan of microalga Myrmecia biatorellae, symbiotic partner of Lobaria linita. AB - A structural study of the cell wall polysaccharides of Myrmecia biatorellae, the symbiotic algal partner of the lichenized fungus Lobaria linita was carried out. It produced a rhamnogalactofuranan, with a (1->6)-beta-D-galactofuranose in the main-chain, substituted at O-2 by single units of beta-D-Galf, alpha-L-Rhap or by side chains of 2-O-linked beta-D-Galf units. The structure of the polysaccharide was established by chemical and NMR spectroscopic analysis, and is new among natural polysaccharides. Moreover, in a preliminary study, this polysaccharide increased the lethality of mice submitted to polymicrobial sepsis induced by cecal ligation and puncture, probably due to the presence of galactofuranose, which have been shown to be highy immunogenic in mammals. PMID- 22944448 TI - Wound-dressing materials with antibacterial activity from electrospun polyurethane-dextran nanofiber mats containing ciprofloxacin HCl. AB - Dextran is a versatile biomacromolecule for preparing electrospun nanofibrous membranes by blending with either water-soluble bioactive agents or hydrophobic biodegradable polymers for biomedical applications. In this study, an antibacterial electrospun scaffold was prepared by electrospinning of a solution composed of dextran, polyurethane (PU) and ciprofloxacin HCl (CipHCl) drug. The obtained nanofiber mats have good morphology. The mats were characterized by various analytical techniques. The interaction parameters between fibroblasts and the PU-dextran and PU-dextran-drug scaffolds such as viability, proliferation, and attachment were investigated. The results indicated that the cells interacted favorably with the scaffolds especially the drug-containing one. Moreover, the composite mat showed good bactericidal activity against both of Gram-positive and Gram-negative bacteria. Overall, our results conclude that the introduced scaffold might be an ideal biomaterial for wound dressing applications. PMID- 22944449 TI - Development of low methoxy amidated pectin-based mucoadhesive patches for buccal delivery of triclosan: effect of cyclodextrin complexation. AB - A novel mucoadhesive buccal patch formulation of triclosan (TR), a broad spectrum antibacterial agent, was developed using low methoxy amidated pectin (AMP). The integrity of AMP matrix was improved by addition of 20% (w/w) Carbopol (CAR). The efficiency of beta-cyclodextrin-epichlorohydrin polymer (EPIbetaCD) and anionic carboxymethylated beta-cyclodextrin-epichlorohydrin polymer (CMEPIbetaCD) in optimization of TR solubility and release from such a matrix was investigated and confronted to that of parent beta-cyclodextrin (betaCD). Loading of TR/betaCD co ground complex into AMP/CAR matrix resulted in a biphasic release profile which was sensitive upon the hydration degree of the matrix, due to lower solubilizing efficiency of betaCD, while the drug release from patches loaded with TR/EPIbetaCD complex was significantly faster with a constant release rate. Microbiological studies evidenced faster onset and more pronounced antibacterial action of TR/EPIbetaCD loaded patches, clearly demonstrating their good therapeutic potential in eradication of Streptococcus mutans, a cariogenic bacteria, from the oral cavity. PMID- 22944450 TI - Chemical characteristic of an anticoagulant-active sulfated polysaccharide from Enteromorpha clathrata. AB - A sulfated polysaccharide FEP from marine green alga Enteromorpha clathrata was extracted with hot water and further purified by ion-exchange and size-exclusion chromatography. Results of chemical and spectroscopic analyses showed that FEP was a high arabinose-containing sulfated polysaccharide with sulfate ester of 31.0%, and its average molecular weight was about 511kDa. The backbone of FEP was mainly composed of (1->4)-linked beta-L-arabinopyranose residues with partially sulfate groups at the C-3 position. In vitro anticoagulant assay indicated that FEP effectively prolonged the activated partial thromboplastin time and thrombin time. The investigation demonstrated that FEP was a novel sulfated polysaccharide with different chemical characteristics from other sulfated polysaccharides from marine algae, and could be a potential source of anticoagulant. PMID- 22944451 TI - Conjugation of alpha-amylase with dextran for enhanced stability: process details, kinetics and structural analysis. AB - The influence of enzyme polysaccharide interaction on enzyme stability and activity was elucidated by covalently binding dextran to a model enzyme, alpha amylase. The conjugation process was optimized with respect to concentration of oxidizing agent, pH of enzyme solution, ratio of dextran to enzyme concentration, temperature and time of conjugate formation, and was found to affect the stability of alpha-amylase. alpha-Amylase conjugated under optimized conditions showed 5% loss of activity but with enhanced thermal and pH stability. Lower inactivation rate constant of conjugated alpha-amylase within the temperature range of 60-80 degrees C implied its better stability. Activation energy for denaturation of alpha-amylase increased by 8.81 kJ/mol on conjugation with dextran. Analysis of secondary structure of alpha-amylase after covalent binding with dextran showed helix to turn conversion without loss of functional properties of alpha-amylase. Covalent bonding was found to be mandatory for the formation of conjugate. PMID- 22944452 TI - Synthesis of methylcellulose-silver nanocomposite and investigation of mechanical and antimicrobial properties. AB - In this paper we reported preparation of methylcellulose-silver nanocomposite films by mixing of aqueous solution of methylcellulose with silver nitrate followed by casting. The silver nanoparticles were generated in methylcellulose matrix through reduction and stabilization by methylcellulose. The surface plasmon band at 412 nm indicated the formation of Ag nanoparticles. The MC-Ag nanocomposite films were characterized by X-ray diffraction (XRD), transmission electron microscopy (TEM) and Fourier transform infrared (FTIR). The X-ray diffraction analysis of synthesized MC-Ag nanocomposite films revealed that metallic silver was present in face centered cubic crystal structure. Average crystallite size of silver nanocrystal was 22.7 nm. The FTIR peaks of as synthesized MC-Ag nanocomposite fully designated the strong interaction between Ag nanoparticles and MC matrix. Nano-sized silver modified methylcellulose showed enhanced mechanical properties i.e. the introduction of Ag leading to both strengthening and toughening of MC matrix. The methylcellulose-silver nanocomposite films offered excellent antimicrobial activity against various microorganisms. PMID- 22944453 TI - Rapid exfoliation of rectorite in quaternized carboxymethyl chitosan. AB - Exfoliated quaternized carboxymethyl chitosan/rectorite (QCMC/REC) nanocomposite was prepared via microwave irradiation method for 70 min, which was performed in only water without any additional plasticizer. XRD, TEM, AFM, SEM and FTIR results revealed that when the mass ratio of QCMC to REC was no less than 4:1, the silicate layers of REC were completely exfoliated in QCMC matrix and were homogenous with QCMC, the surface of QCMC/REC nanobiocomposite was very smooth; two types of interactions of hydrogen bond and electrostatic attraction existed in the QCMC/REC nanobiocomposite. Thermal analysis indicated that QCMC/REC nanobiocomposite had higher thermal stability than only QCMC. Therefore, the microwave irradiation method appears to be a promising tool for preparing exfoliated biopolymer/layered silicate nanocomposites at a mild condition. PMID- 22944454 TI - An asymmetric and slightly dimerized structure for the tetanus toxoid protein used in glycoconjugate vaccines. AB - Tetanus toxoid protein has been characterized with regard oligomeric state and hydrodynamic (low-resolution) shape, important parameters with regard its use in glycoconjugate vaccines. From sedimentation velocity and sedimentation equilibrium analysis in the analytical ultracentrifuge tetanus toxoid protein is shown to be mostly monomeric in solution (~86%) with approximately 14% dimer. The relative proportions do not appear to change significantly with concentration, suggesting the two components are not in reversible equilibrium. Hydrodynamic solution conformation studies based on high precision viscometry, combined with sedimentation data show the protein to be slightly extended conformation in solution with an aspect ratio ~3. The asymmetric structure presents a greater surface area for conjugation with polysaccharide than a more globular structure, underpinning its popular choice as a conjugation protein for glycoconjugate vaccines. PMID- 22944455 TI - Can selected patients with newly diagnosed pulmonary embolism be safely treated without hospitalization? A systematic review. AB - STUDY OBJECTIVE: Omitting inpatient therapy for emergency department patients with newly diagnosed pulmonary embolism occurs infrequently in the United States. We seek to describe the safety of initial outpatient management of these patients and their demographics, comorbidities, risk stratification, treatment, and outcomes. METHODS: We identified studies from searches of MEDLINE, EMBASE, and other databases from inception through March 22, 2012. We supplemented this with a search of conference proceedings and consultation with experts. We selected prospective studies of adults with acute, symptomatic, objectively confirmed pulmonary embolism who were discharged home without hospitalization. All contributing studies explicitly defined inclusion and exclusion criteria plus objectively confirmed outcome measures: recurrent thromboembolism, major hemorrhage, and mortality. Two investigators independently identified eligible studies and extracted data. We used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) criteria to assess study quality. RESULTS: From 2,286 screened titles/abstracts, we selected 8 studies with a total of 777 patients. Seven observational studies were rated low in quality. The one randomized controlled trial was higher in quality, used stricter inclusion criteria, and found that 90-day outcomes for outpatient management were not inferior to inpatient care. Among the 7 studies that reported 90-day outcome measures, the overall incidence of venous thromboembolic-related and hemorrhage related mortality was very low: 0 of 741 (upper 95% confidence limit 0.62%). CONCLUSION: The data on exclusive outpatient management of acute symptomatic pulmonary embolism are limited, but the existing evidence supports the feasibility and safety of this approach in carefully selected low-risk patients. PMID- 22944456 TI - Reversible differentiation of pro- and anti-inflammatory macrophages. AB - Macrophages (Mphi) represent dynamic cell populations that develop according to the nature of environmental signals. It has been demonstrated that human Mphi can be polarized in vitro into pro-inflammatory (Mphi1) and anti-inflammatory cells (Mphi2) by the lineage-determining factors GM-CSF and M-CSF, respectively. Here we show that polarized Mphi1 and Mphi2 are not an end stage of differentiation but are able to reversibly undergo functional re-differentiation into anti inflammatory and pro-inflammatory Mphi. GM-CSF-driven Mphi1 exposed to M-CSF for an additional 6 days obtained a Mphi2-like phenotype, inhibited the production of pro-inflammatory cytokine IL-6 and TNF-alpha, and exhibited a reduced T cell stimulatory capacity. Vice versa, Mphi2 exposed to GM-CSF exhibited a Mphi1-like phenotype with significant lower production of anti-inflammatory cytokine IL-10 and a higher T cell stimulatory activity, and a decreased capacity for phagocytosis of early apoptotic cells. Our data suggest that polarized macrophages are flexible in modulating their immune functions upon environmental changes, i.e., steady-state versus inflammatory conditions. These observations are important for our understanding of the regulatory role of macrophages in tissue homeostasis and disease pathogenesis. PMID- 22944457 TI - Manipulating mIgD-expressing B cells with anti-migis-delta monoclonal antibodies. AB - Surface IgD and IgM doubly positive cells comprise the major population of B cells in the human immune system. The heavy chain of membrane-bound IgD (mdelta) differs from that of IgD (delta) in that mdelta contains a C-terminal membrane anchor peptide. Our group previously proposed that the N-terminal extracellular segment of 27 aa residues of the membrane-anchor peptide of mdelta, referred to as the mIg isotype-specific-delta (migis-delta) segment, may provide a unique antigenic site for isotype-specific targeting of mIgD(+) B cells. Here we report the preparation of mouse mAbs specific for human migis-delta. The mAbs bound to human migis-delta-containing recombinant proteins in an ELISA and to mIgD expressing transfectants of a CHO cell line as analyzed by flow cytometry. MAb 20E6, which binds to an epitope toward the N-terminal of human migis-delta, could stain human B cell line MC116, which expressed mIgD and mIgM. MC116 cells could be induced to undergo apoptosis by treatment with 20E6 in the presence of a second crosslinking antibody. Chimeric 20E6 caused antibody-dependent cellular cytotoxicity of MC116 cells in the presence of human PBMCs as the source of effector cells. In cultures of PBMCs, 20E6 down-regulated the population of mIgD(+) B cells. The production of human IgM by transplanted MC116 cells in NOD SCID (NOD.CB17-Prkdc(scid)/IcrCrlBltw) mice could be suppressed by 20E6. These results encourage further investigation of the potential of anti-migis-delta mAbs to control mIgD(+) B cells, when such a manipulation may alleviate a disease state. PMID- 22944459 TI - Gonadal sex differentiation, development up to sexual maturity and steroidogenesis in the skipper frog, Euphlyctis cyanophlyctis. AB - Gonadal sex differentiation, development up to sexual maturity and steroidogenesis were studied in the Indian skipper frog, Euphlyctis cyanophlyctis. In stage 25 tadpoles, gonads contained a few yolk laden germ cells and somatic cells. Ovarian differentiation occurred at stage 27 with the initiation of meiosis. Interestingly, meiosis preceded the formation of a central lumen that was discernible at stage 28. Folliculogenesis in the developing ovary was observed at stage 29. Vitellogenesis was observed in the 3 months old frogs and the females attained sexual maturity around 4 months. Testicular differentiation occurred indirectly through an ovarian phase. In some animals, from stage 37 onwards, oocyte degeneration was observed that was completed around metamorphic climax. Concurrently, large numbers of mesonephric cells were invading the gonads. Around metamorphosis, reorganization of the germ and somatic cells into testicular cords was observed. Following metamorphosis, the formation of seminiferous tubules was observed in the 2 weeks old males. Meiosis in the developing testes was observed in 1.5 months old males. In 3 months old males, the testes contained all stages spermatogenesis including spermatozoa. Steroidogenesis in the developing gonads was studied by immunohistochemical localization of 3beta-HSD enzyme. At stage 26, a few immunoreactive cells were seen in the kidneys (interrenal cells). However, during and after differentiation, gonads failed to show positive immunoreaction. In the developing ovary at stage 37, follicular cells surrounding the oocytes were positive for 3beta-HSD immunoreactivity. In the ovaries of 3 months old females, follicular cells surrounding the vitellogenic oocytes and stromal cells were positive for 3beta-HSD immunoreaction. E. cyanophlyctis exhibits undifferentiated type of gonadal differentiation, in which gonadal differentiation precedes steroidogenesis. PMID- 22944458 TI - Characterization of Escherichia coli urinary tract infection isolates in remote northern Saskatchewan communities: the Northern Antibiotic Resistance Partnership. AB - Antimicrobial resistance is a growing concern especially in many remote northern communities of Canada where antimicrobials are liberally used. In this study, 1418 Escherichia coli urinary tract infection (UTI) isolates, obtained over a 2.5 year period (October 2005-March 2008), from 3 remote northern sites in Saskatchewan, Canada, were identified. Antimicrobial susceptibility testing of the first 544 clinically significant isolates revealed high prevalence of resistance to trimethoprim-sulfamethoxazole (TMP-SXT) (30.7%). Pulsed-field gel electrophoresis (PFGE) of 165 TMP-SXT-resistant isolates revealed a heterogeneous population. Multilocus sequence typing identified 7 STs from 9 identified PFGE clusters, which included separate PFGE clusters of fluoroquinolone-resistant and susceptible ST131 isolates. The majority of TMP-SXT-resistant isolates (85.5%) were found to carry class 1 integrons, and plasmids from 62 (81%) of 77 representative isolates were successfully transformed into E. coli DH10B. Overall, ampicillin was the most common plasmid-encoded resistance phenotype transferred with TMP-SXT at 60% (37/62). Further characterization of 52 plasmids by restriction fragment length polymorphism and replicon typing revealed the presence of many plasmid lineages, suggesting that the elevated rates of TMP-SXT resistance in these communities are most likely attributed to the horizontal transfer of class 1 integrons. Results from this study emphasize the importance of continued surveillance of remote northern communities in order to optimize the efficacy of empiric UTI treatment. PMID- 22944460 TI - Inflammation and neurodegeneration: the story 'retolled'. AB - Toll-like receptors (TLRs) play a crucial role in innate immunity by recognizing conserved motifs predominantly found in microorganisms. Increasing evidence supports a role for TLRs in sterile inflammation as observed in neurodegenerative disorders. This includes work suggesting a contribution for these receptors to the pathophysiology of Alzheimer's disease (AD), Parkinson's disease (PD), and related disorders. In this review, the potential role of TLRs in the context of protein aggregation, neuronal degeneration, and genetic risk factors is addressed. In particular, we discuss the evidence derived from experimental models of both AD and PD which suggests that activation of TLRs can have beneficial and detrimental effects on pathological features such as protein aggregation and neuronal death. A deeper understanding of these dichotomous observations could be used for therapeutic benefit. PMID- 22944461 TI - Inflammatory cytokine profiles during Cyclosporin treatment for immunoglobulin resistant Kawasaki disease. AB - BACKGROUND: Kawasaki disease (KD) is an acute systemic vasculitis occurring in medium-sized arteries, especially coronary arteries. Patients with KD who fail to respond to standard therapy with intravenous immunoglobulin (IVIG) face a higher risk of developing coronary artery lesions. Cyclosporin A (CsA) is one treatment option for IVIG-resistant KD. However, the mechanism of its suppression of inflammation in patients with KD remains unknown. METHODS AND RESULTS: We analyzed time-line profiles of multiple inflammatory cytokines in sera of 19 patients treated with CsA (4 mg/kg/day, p.o., 14 days) after additional IVIG. Trough concentration of CsA in blood was maintained between 60 and 200 ng/ml. We examined serum samples before, on day 7, and at the end (day 14) of CsA treatment. Assays were conducted using a Milliplex kit(r). Fourteen patients responded to CsA and became afebrile within 5 days (Responders), although five patients were regarded as Non-responders. Serum transitional levels of IL-6 (p<0.001), sIL-2R (p<0.001), sTNFRII (p<0.001), and G-CSF (p<0.001) reflect disease severity. In Non-responders, average levels of IL-6 at day 7 (43.5 vs. 13.8 pg/ml, p<0.001) and average levels of sIL-2R at day 14 (21.3 vs. 3.31 pg/ml, p=0.014) were significantly higher than those in Responders. CONCLUSION: CsA treatment effectively reduced the persisting serum inflammatory cytokines in most of the IVIG-resistant KD patients. Soluble IL-2R suppression implies a mechanism explaining the effects of CsA. PMID- 22944463 TI - Temporal alteration of serum G-CSF and VEGF levels in perinatal asphyxia treated with head cooling. AB - OBJECTIVE: Granulocyte-colony stimulating factor (G-CSF) and vascular endothelial growth factor (VEGF) are thought to be associated with the pathophysiology of perinatal asphyxia. To clarify any such association, we analyzed the serum levels in neonates with perinatal asphyxia treated with head cooling. STUDY DESIGN: Temporal alterations of serum G-CSF and VEGF levels were measured within 24h of birth in five neonatal cases of severe asphyxia treated with head cooling, five neonatal cases without head cooling, and four healthy neonatal cases. RESULTS: G CSF in sera markedly increased and sustained in severely asphyxiated neonates treated with head cooling, while VEGF decreased and remained low. CONCLUSION: G CSF and VEGF levels in sera might be associated with an early phase of brain protection after birth in severe asphyxia treated with head cooling. PMID- 22944464 TI - Effect of (18)F-fluorodeoxyglucose positron emission tomography/computed tomography-guided management of suspected recurrent papillary thyroid carcinoma: long-term follow-up with tumour marker responses. AB - AIMS: To investigate the use of recombinant human thyroid-stimulating hormone stimulated co-registered (18)F-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) for detecting suspected recurrent papillary thyroid carcinoma among patients with rising tumour markers but negative whole-body iodine-131 scans. Tumour marker responses to (18)F-FDG PET/CT guided therapy were also measured for these patients. MATERIALS AND METHODS: A prospectively gathered (18)F-FDG PET/CT database and patient charts were reviewed. Patients having previously undergone total thyroidectomy and ablative iodine-131 therapy for papillary carcinoma before (18)F-FDG PET/CT were analysed. RESULTS: Nineteen patients formed the study population: 12 women and seven men, median age 49 years, with elevated thyroglobulin (n = 15), elevated anti thyroglobulin antibody (n = 4); the median follow-up was 46 months, range 27-56 months. Sixteen patients (84%) had a positive PET/CT scan (15 with disease confined to the head and neck and one with distant disease), whereas three patients (16%) had a negative scan. Eleven of the 15 patients with disease confined to the head and neck underwent potentially curative salvage therapy: surgery (n = 7), external beam radiotherapy (n = 2) or both (n = 2). All patients undergoing surgery had histological confirmation of malignancy. At a median follow-up of 50 months for these 11 patients, eight had detectable tumour markers at levels below pre-scan values, two had levels above, and one patient had an undetectable level. All three patients with negative PET/CT scans were placed on surveillance. At a median follow-up of 45 months for these three patients, two had tumour marker levels below pre-scan values and one had an undetectable level. CONCLUSIONS: Recombinant human thyroid-stimulating hormone-stimulated (18)F-FDG PET/CT detected recurrent disease in most patients. Although subsequent treatment of (18)F-FDG PET/CT-detected disease reduced tumour marker levels in most patients, markers remained detectable, suggesting that not all residual or metastatic disease had been identified, which compromised salvage therapy. This is the largest and most mature study to date reporting tumour marker responses to PET- or PET/CT-guided therapy in this setting. PMID- 22944462 TI - Microbial cell components induced tolerance to flagellin-stimulated inflammation through Toll-like receptor pathways in intestinal epithelial cells. AB - In the intestine, bacterial components activate innate responses that protect the host. We hypothesize that bacterial components reduce Interleukin-8 (IL-8) production in intestinal epithelial cells stimulated by flagellin via the Toll like receptor (TLR) signaling pathway. Caco-2 cells were pretreated with various doses of lipopolysaccharide (LPS), lipoteichoic acid (LTA), or low-dose flagellin (LDFL) for 24h. Cells were then treated with flagellin (FL) 500 ng/ml (HDFL) for another 48 h. IL-8 production was measured in the cell culture medium by ELISA. Eighty-four genes in the TLR pathway were evaluated by RT Profiler PCR Array. Pathway Studio 8.0 software was used for altered pathway analysis. HDFL induced IL-8 production by 19-fold (p<0.01). Pretreatment with LDFL at 20, 10 or 1 ng/ml reduced HDFL-induced IL-8 production by 61%, 52% and 40%, respectively (p<0.05). LPS at 50 MUg/ml decreased HDFL-induced IL-8 production by 38% (p<0.05). HDFL up regulated CXCL10, IL1B, IL-8, IRAK2, NF-kappaB1 and I-kappaB (all p<0.05). Pathway Studio analysis showed that HDFL induced cell processes including inflammation, cell death and apoptosis. Pretreatment with LDFL at 10 ng/ml down regulated FADD, FOS, MAP4K4, MyD88, TLR2, TLR3 and TNFERSF1A compared to HDFL (all p<0.05). These down-regulated genes are integral for numerous cell functions including inflammatory response, cell death, apoptosis and infection. These results demonstrate that LPS and LDFL provoke tolerance to HDFL-induced IL-8 production. This tolerance effect was accompanied by a complex interaction of multiple genes related to inflammatory as well as other responses in the TLR pathway rather than a single gene alteration. PMID- 22944465 TI - Clinical outcomes of PD patients having bilateral STN DBS using high-field interventional MR-imaging for lead placement. AB - OBJECTIVE: Recently, an iMRI-guided technique for implanting DBS electrodes without MER was developed at our center. Here we report the clinical outcomes of PD patients undergoing STN DBS surgery using this surgical approach. METHODS: Consecutive PD patients undergoing bilateral STN DBS using this method were prospectively studied. Severity of PD was determined using the UPDRS scores, Hoehn and Yahr staging score, stand-sit-walk testing, and the dyskinesia rating scale. The primary outcome measure was the change in UPDRS III off medication score at 6 months. DBS stimulation parameters, adverse events, levodopa equivalent daily dose (LEDD), and DBS lead locations were also recorded. Seventeen advanced PD patients (9M/8F) were enrolled from 2007 to 2009. RESULTS: The mean UPDRS III off medication score improved from 44.5 to 22.5 (49.4%) at 6 months (p=0.001). Other secondary outcome measures (UPDRS II, III on medication, and IV) significantly improved as well (p<0.01). LEDD decreased by an average of 24.7% (p=0.003). Average stimulation parameters were: 2.9V, 66.4MUs, 154Hz. CONCLUSION: This pilot study demonstrates that STN DBS leads placed using the iMRI-guided method results in significantly improved outcomes in PD symptoms, and these outcomes are similar to what has been reported using traditional frame based, MER-guided stereotactic methods. PMID- 22944466 TI - Prognostic factors in patients with primary brainstem hemorrhage. AB - OBJECTIVE: Primary brainstem hemorrhage (PBH) frequently causes severe disturbances of consciousness, papillary abnormalities, as well as respiratory and motor disturbances. The prognosis has been reported to be highly dependent on the clinical severity at presentation and the presence of certain radiological markers. However, the number of PBH patients enrolled in previous reports tended to be small, and precise statistical analyses were also lacking. The aim of this study was to analyze the impact of clinical or radiologic parameters on the outcome of patients with PBH. METHODS: We retrospectively reviewed 212 consecutive patients with PBH and analyzed the impact of the clinical or radiological parameters on the outcome of patients with PBH. RESULTS: Of the 212 patients, 134 (63.2%) were male and 78 (36.8%) were female, with an age range of 17-97 years (mean, 60.3 years). The median admission GCS score was 4. The outcomes included a good recovery in 13 patients (6.1%), moderate disability in 27 (12.7%), severe disability in 27 (12.7%), a vegetative state in 23 (10.8%), and death in 122 (57.5%). A multivariate analysis demonstrated bilateral hematoma extension, a GCS score <=8, the presence of hydrocephalus, gender, and the hematoma volume to all be significantly associated with the 3-month mortality, while the GCS score <=8, the presence of a pupillary abnormality, and the hematoma volume were found to be associated with the 3-month poor outcome. CONCLUSION: The identification of these factors is therefore considered to be useful for managing patients with PBH. PMID- 22944467 TI - Harvey Cushing's early management of hydrocephalus: an historical picture of the conundrum of hydrocephalus until modern shunts after WWII. AB - PURPOSE: Throughout his early career, Cushing proposed a variety of methods for temporary and permanent drainage and diversion of CSF in his patients, and acknowledged that certain techniques were more suited to particular subsets of hydrocephalus. METHODS: Following IRB approval, and through the courtesy of the Alan Mason Chesney Archives, the surgical records of the Johns Hopkins Hospital, from 1896 to 1912, were reviewed. Patients operated upon by Harvey Cushing were selected for further analysis. Within this cohort, we recovered all available records for a single patient with hydrocephalus and spina bifida, who was treated with a ventriculosubgaleal shunt prior to repair of the spina bifida. RESULTS: A 3 month-old infant presented with hydrocephalus associated with spina bifida. Cushing performed serial lumbar and ventricular punctures. Following this, Cushing took the patient to the operating room for placement of a ventriculosubgaleal shunt. The patient subsequently underwent excision of the myelomeningocele sac, with post-operative mortality due to unspecified causes. CONCLUSIONS: Cushing's publications document a preference for translumbar peritoneal drainage in patients with congenital hydrocephalus, particularly those with spina bifida. Although the placement of ventriculosubgaleal shunts has become an accepted practice for contemporary neurosurgeons, this case illustrates the challenges that early neurosurgeons faced in developing operative approaches for the treatment of congenital hydrocephalus. PMID- 22944468 TI - Amelioration of chronic neuropathic pain and motor deficit following removal of lumbar vertebroplasty intradural cement. PMID- 22944469 TI - Vertebral artery hypoplasia in posterior circulation cerebral ischemia. PMID- 22944470 TI - Review of vertebral artery fenestration and novel extracranial fenestration. PMID- 22944471 TI - Effects of inhaled nano-TiO2 aerosols showing two distinct agglomeration states on rat lungs. AB - Nano-aerosols composed of large agglomerates (LA) (>100nm) are more likely to promote pulmonary clearance via macrophages phagocytosis. Small agglomerates (SA) (<100nm) seem to escape this first defense mechanism and are more likely to interact directly with biological material. These different mechanisms can influence pulmonary toxicity. This hypothesis was evaluated by comparing the relative pulmonary toxicity induced by aerosolized nano-TiO(2) showing two different agglomeration states: SA (<100nm) and LA (>100nm) at mass concentrations of 2 or 7mg/m(3). Groups of Fisher 344 male rats were nose-only exposed for 6h. The median number aerodynamic diameters were 30 and 185nm at 2mg/m(3), and 31 and 194nm at 7mg/m(3). We found in rat's bronchoalveolar lavage fluids (BALF) a significant 2.1-fold increase in the number of neutrophils (p<0.05) in the group exposed to the 7mg/m(3) LA nano-aerosol suggesting a mild inflammatory response. Rats exposed to the 7mg/m(3) SA nano-aerosol showed a 1.8 fold increase in LDH activity and 8-isoprostane concentration in BALF, providing evidence for cytotoxic and oxidative stress effects. Our results indicate that biological responses to nanoparticles (NP) might depend on the dimension and concentration of NP agglomerates. PMID- 22944472 TI - Multiparametric immunotoxicity screening in mice during early drug development. AB - Evaluation of potential adverse effects on the immune system should be incorporated into drug development prior to phase III clinical trials. In addition to standard toxicity results, T-dependent antibody response (TDAR) assays are widely used to evidence impaired immune function. The present study was aimed at validating a multiparametric screening approach in mice to investigate exaggerated pharmacologic or unintended immunosuppressive effects in early drug development. Male CD1 mice injected with a single IV dose of 2mg KLH displayed a robust anti-KLH IgM response that peaked on day +5. Anti-KLH IgM response, standard haematology parameters, and thymus/spleen weight and histology were examined in mice treated once daily for 4 days with cyclophosphamide (CY; 5 20mg/kg/day), cyclosporine (CS; 10-90mg/kg/day), dexamethasone (DX; 5 20mg/kg/day), prednisolone (PR; 3-30mg/kg/day) or chlorpromazine (CZ; 10 30mg/kg/day). CY and CS decreased anti-KLH IgM response at all dose levels. CY induced a marked decrease in WBC count and thymus/spleen weight with histological changes in both lymphoid organs. CS mainly decreased thymus weight (highest dose), which was associated with lymphoid depletion, without relevant effects on haematology parameters. Neither DX nor PR nor CZ induced significant changes in anti-KLH IgM response. DX and PR decreased lymphocyte counts and thymus/spleen weight, and induced histological changes in both lymphoid organs. CZ (higher doses) decreased lymphocyte count and thymus weight, and induced consistent histological changes in the thymus. This multiparametric study was able to detect 5 human drugs with variable immunosuppressive potency and thus may prove to be a useful early screening tool for predicting drug immunotoxicity. PMID- 22944473 TI - Synthetically engineered chitosan-based materials and their sorption properties with methylene blue in aqueous solution. AB - Chitosan (CS) and poly(acrylic acid) (PAA) were crosslinked by an ionic gelation method to form super absorbent polymers (SAPs). CS and PAA form amide bonds between the amino and carboxyl groups. The CS-PAA copolymers were synthetically engineered by varying the feed ratios of the prepolymer units. The copolymer materials possess tunable sorption and mucoadhesive properties with a backbone structure resembling proteinaceous materials. The sorption properties of the copolymers toward methylene blue (MB) in aqueous solution were studied using UV Vis spectrophotometry at ambient pH and 295 K. The copolymers showed markedly varied interactions with MB, from physisorption- to chemisorption-like behavior, in accordance with their composition, surface area, and pore structure characteristics. The sorption isotherms were evaluated with the Sips model to provide estimates of the sorption properties. The sorbent surface area (271 and 943 m(2)/g) and the sorption capacity (Q(m)=1.03 and 3.59 mmol/g) were estimated for the CS-PAA copolymer/MB systems in aqueous solution. PMID- 22944474 TI - Magnetic titania-silica composite-polypyrrole core-shell spheres and their high sensitivity toward hydrogen peroxide as electrochemical sensor. AB - A novel core-shell sphere with controlled shell thickness was synthesized by in situ chemical oxidative polymerization of pyrrole on FTS (Fe(2)O(3)/TiO(2)/SiO(2) composite) surface. The dual porosity of 2-3 nm and 40-50 nm in FTS core particle provides the hybrids with a high surface area to volume ratio, which enormously facilitates the molecule diffusion process. Furthermore, the porous FTS particle encapsulate Fe(2)O(3) and TiO(2) leading to its synergetic interaction with the PPy coating based on FTIR analysis. The unique structure and composition of the hybrid spheres result in new sensing property that is not available from their single counterparts. Cyclic voltammetry results demonstrate that the spheres with appropriate concentration of PPy exhibit enhanced electrocatalytic activity toward the reduction of H(2)O(2) in 0.1 M phosphate buffer solution. The sensing performance tests show that the hybrids possess good linear response in wide H(2)O(2) concentration range (10-4000 MUM) and high sensitivity to H(2)O(2) (0.653 AM(-1) cm(-2)) at room temperature. The formation mechanism of the spheres was proposed based on the fact that the FTS core was coated firstly by a smooth PPy layer and then PPy nanoparticles. The work reported here provides an alternative concept for preparation of functional materials with new nanostructures and properties. PMID- 22944475 TI - Multifunctional covalently stabilized vesicles acting simultaneously as the template of gold nanoparticle cluster and the nanocarrier of guest molecules. AB - The terminal hydroxyl groups of amphiphilic multiarm star copolymers with a hydrophilic hyperbranched polyethylenimine (PEI) core and hydrophobic poly(epsilon-caprolactone) (PCL) arms were partially or completely transformed into the radical-crosslinkable methacrylate (MA) groups (PEI-b-PCL-MA). The resulting PEI-b-PCL-MA polymers with 100% MA substitution self-assembled in water into simple vesicles, whereas those with partial MA substitution aggregated into complex vesicles. These structures could be proved by transmission electron microscopy and dynamic light scattering only after crosslinking the intra vesicular MA groups that generated the covalently stabilized vesicles (CSVs). The obtained CSVs could be used as host for the formation of gold nanoparticle (AuNP) cluster, and the AuNP clusters stabilized by the CSVs were stable under a wider range of CSV/AuNP feed ratio than those stabilized by the uncrosslinked precursors. The diameter of AuNPs in the clusters was in the range of 4-6 nm, and the distance of adjacent AuNPs could be modulated through altering the feed ratio of CSV/AuNP. The color of the solutions of AuNPs with CSV could be tuned from brown to red, purple, even blue. The composites of CSV and AuNPs could be further used as nanocarriers to accommodate hydrophobic guest of pyrene, and a higher amount of AuNPs in the nanocarriers led to a lower encapsulation capacity for pyrene guests. PMID- 22944476 TI - Preparation and sorption studies of polyester microsphere copolymers containing beta-cyclodextrin. AB - Polyester copolymer sorbent materials that incorporate beta-Cyclodextrin (beta CD) were prepared using water-in-oil (w/o) micro-emulsion conditions at variable beta-CD: cross linker mole ratios; where the cross linker units were sebacoyl chloride (SCl) and terephthaloyl chloride (TCl). The copolymers were characterized using TGA, nitrogen adsorption, and NMR/IR spectroscopy. The dye based sorption properties of the copolymers with p-nitrophenol (PNP) in aqueous solution were evaluated at pH 4.6 and 295 K using UV-Vis spectrophotometry. The uptake of PNP varied from 0.221 to 0.352 mmol/g, according to the nature of the cross linker and the copolymer mole ratio. The sorption capacity of SCl-based copolymers exceed that for TCl-based copolymers, and correlate with the relative swelling properties and hydrated surface areas of the sorbent frameworks. (1)H NMR spectroscopy of copolymers with low levels of linker content (i.e. SCl or TCl) indicate dual sorption sites for PNP (i.e. beta-CD inclusion sites and non inclusion (interstitial) linker domains). The existence of dual sorption sites is similarly concluded for copolymers containing higher levels of cross linker. Inclusion complexes are firstly formed between PNP and the beta-CD inclusion sites of the copolymer; thereafter, PNP is adsorbed onto the linker domains of the copolymer sorbent framework. PMID- 22944477 TI - Phase control and its mechanism of CuInS2 nanoparticles. AB - CuInS(2) nanoparticles (NPs) usually take chalcopyrite-(CP) structure. Recently, CuInS(2) NPs with pseudo-wurtzite (WZ) structure, which is thermodynamically less favored, have been synthesized. However, the formation mechanism of this metastable-phase has not been understood yet. In this report, the key issue of phase selectivity of CuInS(2) (CIS) NPs has been investigated using various metal sources and ligands. Experimental results suggested that the crystalline structure and morphology of CIS NPs were decided by the stability of indium ligand complex; the active ligand reduces the precipitation rate of In(2)S(3), resulting in pre-generation of Cu(2)S seed NPs. Crystallographic analogy and superionic conductivity of Cu(2)S remind us that the formation of WZ CIS NPs is attributed to the pre-generation of Cu(2)S seed NPs and the following cation exchange reaction. In order to confirm this hypothesis, Cu(2-)(x)S seed NPs with various structures have been annealed in indium-ligand solution. This experiment revealed that the crystalline structure of CIS NP was determined by that of pre generation Cu(2-)(x)S NPs. Our results provide the important information for the phase control and synthesis of ternary chalcogenide NPs with a novel crystalline structure. PMID- 22944478 TI - Reactive capture of gold nanoparticles by strongly physisorbed monolayers on graphite. AB - Anthracene Diels Alder adducts (DAa) bearing two long side chains (H (CH(2))(22)O(CH(2))(6)OCH(2)-) at the 1- and 5-positions form self-assembled monolayers (SAMs) at the phenyloctane-highly oriented pyrolytic graphite (HOPG) interface. The long DAa side chains promote strong physisorption of the monolayer to HOPG and maintain the monolayer morphology upon rinsing or incubation in ethanol and air-drying of the substrate. Incorporating a carboxylic acid group on the DAa core enables capture of 1-4 nm diameter gold nanoparticles (AuNPs) provided (i) the monolayer containing DAa-carboxylic acids is treated with Cu(2+) ions and (ii) the organic coating on the AuNP contains carboxylic acids (11 mercaptoundecanoic acid, MUA-AuNP). AuNP capture by the monolayer proceeds with formation of Cu(2+)-carboxylate coordination complexes. The captured AuNP appear as mono- and multi-layered clusters at high coverage on HOPG. The surface density of the captured AuNPs can be adjusted from AuNP multi-layers to isolated AuNPs by varying incubation times, MUA-AuNP concentration, the number density of carboxylic acids in the monolayer, the number of MUA per AuNP, and post incubation treatments. PMID- 22944480 TI - Utility of colposcopy in a phase 2 portion of a microbicide clinical trial of BufferGel and 0.5% PRO 2000 Gel. AB - BACKGROUND: The majority of new HIV infections are acquired through heterosexual transmission. There is urgent need for prevention methods to compliment behavior change and condom use. Topical microbicide represent a potential strategy for reduction of HIV transmission in women. METHODS: Monthly Colposcopy evaluations were performed during pelvic examinations among 299 women enrolled in the Phase 2 portion of HPTN 035 study at four sites (1 in USA, 3 in Southern Africa). This was a phase 2/2b, multisite, randomized, and controlled clinical trial with four arms: BufferGel, 0.5% PRO2000 Gel, placebo gel and no gel. At two of the sites, pelvic examinations were conducted by the use of naked eye without colposcopy. RESULTS: A colposcopy finding of any kind was detected in 48% of participants at baseline compared to 40% at 3 months (p =0.04). The lower rates were also observed in vaginal discharge (22% at baseline, 16% at 3 months, p=0.06), erythema (15% at baseline, 8% at 3 months, p=0.004). The trend towards significance at p=0.05 disappear when utilizing stringent statistical significance levels. A pelvic finding of any kind was detected in 71% of colposcopy participants compared to 41% of participants who had naked eye examination only conducted at two sites that performed both colposcopy and naked eye without colposcopy. Use of colposcopy yielded significantly higher rates of participants with deep epithelial disruption, erythema and ecchymosis. We observed no cases of incident Chlamydia, Gonorrhea, or Syphilis during the three month follow up. There were 2 cases of incident HIV during 3-month study period neither of which was associated with any abnormal colposcopy evaluation findings. CONCLUSION: No safety signals were observed in the 4 study arms, allowing seamless transition from phase 2 to 2b. Colposcopy utility in microbicide clinical trials has minimal value given high rates of background noise findings of no relevant clinical significance. PMID- 22944479 TI - HIV treatment and care in resource-constrained environments: challenges for the next decade. AB - Many successes have been achieved in HIV care in low- and middle-income countries (LMIC): increased number of HIV-infected individuals receiving antiretroviral treatment (ART), wide decentralization, reduction in morbidity and mortality and accessibility to cheapest drugs. However, these successes should not hide existing failures and difficulties. In this paper, we underline several key challenges. First, ensure long-term financing, increase available resources, in order to meet the increasing needs, and redistribute the overall budget in a concerted way amongst donors. Second, increase ART coverage and treat the many eligible patients who have not yet started ART. Competition amongst countries is expected to become a strong driving force in encouraging the least efficient to join better performing countries. Third, decrease early mortality on ART, by improving access to prevention, case-finding and treatment of tuberculosis and invasive bacterial diseases and by getting people to start ART much earlier. Fourth, move on from WHO 2006 to WHO 2010 guidelines. Raising the cut-off point for starting ART to 350 CD4/mm(3) needs changing paradigm, adopting opt-out approach, facilitating pro-active testing, facilitating task shifting and increasing staff recruitments. Phasing out stavudine needs acting for a drastic reduction in the costs of other drugs. Scaling up routine viral load needs a mobilization for lower prices of reagents and equipments, as well as efforts in relation to point-of-care automation and to maintenance. The latter is a key step to boost the utilization of second-line regimens, which are currently dramatically under prescribed. Finally, other challenges are to reduce lost-to follow-up rates; manage lifelong treatment and care for long-term morbidity, including drug toxicity, residual AIDS and HIV-non-AIDS morbidity and aging related morbidity; and be able to face unforeseen events such as socio-political and military crisis. An old African proverb states that the growth of a deep rooted tree cannot be stopped. Our tree is well rooted in existing field experience and is, therefore, expected to grow. In order for us to let it grow, long-term cost-effectiveness approach and life-saving evidence-based programming should replace short-term budgeting approach. PMID- 22944481 TI - Cerebral amyloid angiopathy impact on endothelium. AB - Cerebral amyloid angiopathy (CAA) is an age-associated disease characterized by amyloid deposition in cerebral and meningeal vessel walls. CAA is detected in the majority of the individuals with dementia and also in a large number of non demented elderly individuals. In addition, CAA is strongly associated with Alzheimer's disease (AD) pathology. Mechanical consequences including intra cerebral or subarachnoid hemorrhage remains CAA most feared complication, but only a small fraction of CAA results in severe bleeding. On the hand the non mechanical consequences in cerebrovascular regulation are prevalent and may be even more deleterious. Studies of animal models have provided strong evidence linking the vasoactive Abeta 1-40, the main species found in CAA, to disturbances in endothelial-dependent factors, disrupting cerebrovascular regulation Here, we aimed to review experimental findings regarding the non-mechanical consequences of CAA for cerebrovascular regulation and discuss the implications of these results to clinical practice. PMID- 22944482 TI - Serum cathelicidin level is associated with viral etiology and severity of bronchiolitis. PMID- 22944483 TI - Inhibition of Pim1 kinase prevents peanut allergy by enhancing Runx3 expression and suppressing T(H)2 and T(H)17 T-cell differentiation. AB - BACKGROUND: The provirus integration site for Moloney murine leukemia virus (Pim) 1 kinase is an oncogenic serine/threonine kinase implicated in cytokine-induced cell signaling, whereas Runt-related transcription factor (Runx) has been implicated in the regulation of T-cell differentiation. The interaction of Pim1 kinase and Runx3 in the pathogenesis of peanut allergy has not been defined. OBJECTIVES: We sought to determine the effects of Pim1 kinase modulation on Runx3 expression and T(H)2 and T(H)17 cell function in an experimental model of peanut allergy. METHODS: A Pim1 kinase inhibitor was administered to peanut-sensitized and challenged wild-type and Runx3(+/-) mice. Symptoms, intestinal inflammation, and Pim1 kinase and Runx3 mRNA expression and protein levels were assessed. The effects of Pim1 kinase inhibition on T(H)1, T(H)2, and T(H)17 differentiation in vivo and in vitro were also determined. RESULTS: Peanut sensitization and challenge resulted in accumulation of inflammatory cells and goblet cell metaplasia and increased levels of Pim1 kinase and T(H)2 and T(H)17 cytokine production but decreased levels of Runx3 mRNA and protein in the small intestines of wild-type mice. All of these findings were normalized with Pim1 kinase inhibition. In sensitized and challenged Runx3(+/-) mice, inhibition of Pim1 kinase had less effect on the development of the full spectrum of intestinal allergic responses. In vitro inhibition of Pim1 kinase attenuated T(H)2 and T(H)17 cell differentiation and expansion while maintaining Runx3 expression in T cell cultures from wild-type mice; these effects were reduced in T-cell cultures from Runx3(+/-) mice. CONCLUSION: These data support a novel regulatory axis involving Pim1 kinase and Runx3 in the control of food-induced allergic reactions through the regulation of T(H)2 and T(H)17 differentiation. PMID- 22944485 TI - [Managing digital medical imaging projects in healthcare services: lessons learned]. AB - Medical imaging is one of the most important diagnostic instruments in clinical practice. The technological development of digital medical imaging has enabled healthcare services to undertake large scale projects that require the participation and collaboration of many professionals of varied backgrounds and interests as well as substantial investments in infrastructures. Rather than focusing on systems for dealing with digital medical images, this article deals with the management of projects for implementing these systems, reviewing various organizational, technological, and human factors that are critical to ensure the success of these projects and to guarantee the compatibility and integration of digital medical imaging systems with other health information systems. To this end, the author relates several lessons learned from a review of the literature and the author's own experience in the technical coordination of digital medical imaging projects. PMID- 22944486 TI - Visualizing disaster attitudes resulting from terrorist activities. AB - The purpose of this study was to analyze people's attitudes to disasters by investigating how people feel, behave and think during disasters. We focused on disasters induced by humans, such as terrorist attacks. Two types of textual information were collected - from Internet blogs and from research papers. The analysis enabled forecasting of attitudes for the design of proactive disaster advisory scheme. Text was analyzed using a text mining tool, Leximancer. The outcome of this analysis revealed core themes and concepts in the text concerning people's attitudes. The themes and concepts were sorted into three broad categories: Affect, Behaviour, and Cognition (ABC), and the data was visualized in semantic maps. The maps reveal several knowledge pathways of ABC for developing attitudinal ontologies, which describe the relations between affect, behaviour and cognition, and the sequence in which they develop. Clearly, terrorist attacks induced trauma and people became highly vulnerable. PMID- 22944484 TI - Peanut allergy diagnoses among children residing in Olmsted County, Minnesota. AB - BACKGROUND: Peanut allergy is a major health concern, particularly in developed countries. Research indicates that as many as 2% of children are allergic to peanuts, which represents a 3-fold increase in diagnoses over the past 2 decades. OBJECTIVE: This population-based descriptive study used the Rochester Epidemiology Project to estimate the prevalence in 2007 and annual incidence rates of peanut allergy diagnoses from 1999 to 2007 among children residing in Olmsted County, Minnesota. METHODS: Residents of Olmsted County from January 1, 1999, through December 31, 2007, who received medical care at a Rochester Epidemiology Project facility and provided research authorization were eligible for the study. A medical chart review of 547 potential diagnoses resulted in 244 prevalent and 170 incident cases. Annual rates, crude and adjusted for age and sex, were standardized with the use of the indirect method to the Olmsted County population data in 1999. Incidence rate ratios were estimated with Poisson regression. RESULTS: The prevalence in 2007 was 0.65%. Female children were less likely to be diagnosed than male children (incidence rate ratio = 0.18; 95% CI, 0.07-0.48). Children aged birth to 2 years were significantly more likely to be diagnosed than older children aged 3-17 years (incidence rate ratio = 0.001; 95% CI, 0.0004-0.004). A significant 3-fold increasing trend was observed in diagnoses over time from 2.05 cases per 10,000 children in 1999 to 6.88 cases per 10,000 in 2007. CONCLUSIONS: Peanut allergies are an increasing concern in Olmsted County, Minnesota, as indicated by a 3-fold increase in diagnoses from 2.05 per 10,000 children in 1999 to 6.88 per 10,000 children in 2007. PMID- 22944487 TI - Using fluorescence excitation-emission matrix spectroscopy to monitor the conversion of organic matter during anaerobic co-digestion of cattle dung and duck manure. AB - In this study, the removal of volatile solids (VSs) and soluble chemical oxygen demand (SCOD) by co-digesting cattle dung (CD) and duck manure (DM) was determined and compared with the reduction achieved with CD or DM digestion alone. Moreover, fluorescence excitation-emission matrix spectroscopy was utilised to characterise the conversion mechanisms of organic nitrogen. It was found that the co-digestion provided 71% VS reduction compared with 58% for CD and 61% for DM. The amounts of COD removed were 28%, 23% and 31% for CD, DM and the mixture, respectively. Tyrosine-like/fulvic-like fluorescence intensity (FI) ratios increased during the initial 15days of co-digestion and were associated with an increase in total nitrogen in the supernatant. After 15days, CD and DM exhibited a lower tryptophan-like/fulvic-like FI ratio (0.8-1.6), whereas the co digestion remained stable at a high level (3.0-3.6), rendering an improved microbial population and biochemical activity. PMID- 22944488 TI - Novel magnetic cross-linked enzyme aggregates (magnetic CLEAs) of alpha amylase. AB - Novel magnetic cross-linked enzyme aggregates of alpha amylase were prepared by chemical cross-linking of enzyme aggregates with amino functionalized magnetite nanoparticles which can be separated from reaction mixture using magnetic field. Of the initially applied alpha amylase activity 100% was recovered in magnetic CLEAs, whereas only 45% was recovered in CLEAs due to the low content of Lys residues in alpha amylase. Scanning electron microscopy analysis showed that CLEAs and magnetic CLEAs were spherical structures. The CLEAs and magnetic CLEAs displayed a shift in optimal pH towards the acidic side, whereas optimal temperature of magnetic CLEAs was improved compared to free enzyme and CLEAs. Although V(max) of enzyme in CLEAs and magnetic CLEAs did not change, substrate affinity of the enzyme increased. The magnetic CLEAs also enhanced the thermal stability and storage stability. Moreover, the magnetic CLEAs retained 100% initial activity even after 6 cycles of reuse. PMID- 22944489 TI - Resistance and resilience of removal efficiency and bacterial community structure of gas biofilters exposed to repeated shock loads. AB - Since full-scale biofilters are often operated under fluctuating conditions, it is critical to understand their response to transient states. Four pilot-scale biofilters treating a composting gas mixture and undergoing repeated substrate pulses of increasing intensity were studied. A systematic approach was proposed to quantify the resistance and resilience capacity of their removal efficiency, which enabled to distinguish between recalcitrant (ammonia, DMDS, ketones) and easily degradable (esters and aldehyde) compounds. The threshold of disturbing shock intensity and the influence of disturbance history depended on the contaminant considered. The spatial and temporal distribution of the bacterial community structure in response to the perturbation regime was analysed by Denaturing Gradient Gel Electrophoresis (DGGE). Even if the substrate-pulses acted as a driving force for some community characteristics (community stratification), the structure-function relationships were trickier to evidence: the distributions of resistance and composition were only partially coupled, with contradictory results depending on the contaminant considered. PMID- 22944490 TI - Hydrogen production from steam reforming of acetic acid over Cu-Zn supported calcium aluminate. AB - Hydrogen can be produced by catalytic steam reforming (CSR) of biomass-derived oil. Typically bio oil contains 12-14% acetic acid; therefore, this acid was chosen as model compound for reforming of biooil with the help of a Cu-Zn/Ca-Al catalyst for high yield of H(2) with low CH(4) and CO content. Calcium aluminate support was prepared by solid-solid reaction at 1350 degrees C. X-ray diffraction indicates 12CaO.7Al(2)O(3) as major, CaA(l4)O(7) and Ca(5)A(l6)O(14) as minor phases. Cu and Zn were loaded onto the support by wet-impregnation at 10 and 1wt.%, respectively. The catalysts were characterized by Brunauer-Emmett-Teller (BET), Scanning Electron Microscopy (SEM) and Transmission Electron Microscopy TEM and the surface area for both support and Cu-Zn were 10.5 and 5.8m(2)/g, respectively. CSR was carried out in a tubular fixed bed reactor (I.D.=19mm) at temperatures between 600 and 800 degrees C with 3-g loadings and (H(2)O/acetic acid) wt. ratio of 9:1. Significantly high (80%) yield of hydrogen was obtained over Cu-Zn/Ca-Al catalyst, as incorporation of Zn enhanced the H(2) yield by reducing deactivation of the catalyst. The coke formation on the support (Ca 12/Al-7) surface was negligible due to the presence of excess oxygen in the 12CaO.7Al(2)O(3) phase. PMID- 22944491 TI - Role of extracellular polymeric substances (EPSs) in membrane fouling of membrane bioreactor coupled with worm reactor. AB - This study focused on the effect of worm reactor on the fouling behaviors of extracellular polymeric substances (EPSs) in the MBR coupled with Static Sequencing Batch Worm Reactor (SSBWR-MBR). The filtration tests showed that the C EPS (EPS in Control-MBR) and S-EPS (EPS in SSBWR-MBR) resulted in 76% and 67% of flux decrement, respectively. On both fouling layers, the preferential accumulation was protein, but the adsorption efficiency for protein in C-EPS was 20% higher than that in S-EPS. In comparison with the membrane fouled by C-EPS, the bio-volume of protein on the membrane fouled by S-EPS reduced 33%, and the protein porosity increased 20%. Meanwhile, the S-EPS approaching the membrane had to overcome*2.4 stronger repulsive interaction energy than C-EPS, and the membrane fouled by S-EPS exhibited relatively smoother compared to that fouled by C-EPS. As a result, the fouling potential of S-EPS was lower than that of C-EPS. PMID- 22944492 TI - Distribution and genetic diversity of functional microorganisms in different CANON reactors. AB - Completely autotrophic nitrogen removal over nitrite (CANON) has been regarded as an efficient and economical process for nitrogen removal from wastewater. The distribution and genetic diversity of the functional microorganisms in five lab scale CANON reactors have been investigated by using some molecular biology methods. Nitrosomonas-like aerobic ammonium oxidizing bacteria (AerAOB) and Candidatus Brocadia-related anaerobic ammonium oxidizing bacteria (AnAOB) were detected as predominant functional microbes in the five reactors while Nitrobacter-like nitrite oxidizing bacteria (NOB) existed only in the systems operated at ambient temperature. Communities of AerAOB and AnAOB were almost similar among the five reactors while the distribution of the functional microbes was either scattered or densely packed. Meanwhile, this study has demonstrated the feasibility of starting up CANON by inoculating conventional activated sludge in low ammonium content at ambient temperature. PMID- 22944493 TI - Combustion characteristics of Malaysian oil palm biomass, sub-bituminous coal and their respective blends via thermogravimetric analysis (TGA). AB - The combustion characteristics of Malaysia oil palm biomass (palm kernel shell (PKS), palm mesocarp fibre (PMF) and empty fruit bunches (EFB)), sub-bituminous coal (Mukah Balingian) and coal/biomass blends via thermogravimetric analysis (TGA) were investigated. Six weight ratios of coal/biomass blends were prepared and oxidised under dynamic conditions from temperature 25 to 1100 degrees C at four heating rates. The thermogravimetric analysis demonstrated that the EFB and PKS evolved additional peak besides drying, devolatilisation and char oxidation steps during combustion. Ignition and burn out temperatures of blends were improved in comparison to coal. No interactions were observed between the coal and biomass during combustion. The apparent activation energy during this process was evaluated using iso-conversional model free kinetics which resulted in highest activation energy during combustion of PKS followed by PMF, EFB and MB coal. Blending oil palm biomass with coal reduces the apparent activation energy value. PMID- 22944494 TI - Identification and quantification of key microbial trophic groups of methanogenic glucose degradation in an anaerobic digester sludge. AB - We investigated the major phylogenetic groups and population size of glucose-, propionate-, and acetate-degrading bacteria in the glucose-degrading anaerobic digester sludge by stable-isotope probing analysis of 16S rRNA (RNA-SIP) with [(13)C(6)]glucose followed by time course analysis of microautoradiography combined with fluorescent in situ hybridization (MAR-FISH) with [U-(14)C]glucose. The results indicated that glucose was predominately degraded to CH(4) and CO(2) by glucose-degrading Propionibacterium and Olsenella that are belonging to the phylum Actinobacteria, propionate-degrading Smithella and Syntrophobacter, and acetate-degrading Methanosaeta and Synergistes group 4 in this anaerobic sludge. The population size of propionate degraders was the smallest among three trophic groups and the specific degradation rate of propionate was also low. The specific degradation rate of acetate was low even though their population size was comparable to the glucose degraders. These results could explain why the degradation of propionate and acetate was the rate-limiting step in methanogenic glucose degradation. PMID- 22944495 TI - Green tea drinking and risk of pancreatic cancer: a large-scale, population-based case-control study in urban Shanghai. AB - BACKGROUND: Little is known about the etiology of pancreatic cancer. Epidemiological studies on tea consumption and pancreatic cancer risk have been inconclusive. The purpose of the present study was to investigate the association between green tea drinking and the risk of pancreatic cancer in urban Shanghai, China. METHODS: In this population-based case-control study conducted in urban Shanghai, 908 cases of pancreatic cancer and 1067 healthy controls were recruited. Information on tea drinking, including type of tea, amount of tea consumption, temperature of tea, and the duration of regular tea drinking, were collected via interview questionnaire. RESULTS: We examined the association of multiple tea drinking habits with the risk of pancreatic cancer. In women, regular green tea drinking was associated with 32% reduction of pancreatic cancer risk (OR 0.68, 95% CI 0.48-0.96), compared to those who did not drink tea regularly. Increased consumption and longer duration of tea drinking were both associated with reduced pancreatic cancer risk in women. Among regular tea drinkers, lower temperature of tea was associated with reduced risk of pancreatic cancer in both men and women, independent of amount or duration of tea drinking. CONCLUSIONS: Habits of green tea drinking, including regular drinking, amount of consumption, persistence of the habit, and tea temperature, may lower pancreatic cancer risk. PMID- 22944496 TI - Saving eyes, millions at a time. PMID- 22944497 TI - Ultrasound biometry vs. IOL Master. PMID- 22944498 TI - Vitamin E and prostate cancer. PMID- 22944499 TI - Capillary hemangioma treatment. PMID- 22944500 TI - Acronyms in ophthalmology. PMID- 22944502 TI - Endophthalmitis due to IOL solution. PMID- 22944503 TI - Myopia and open angle glaucoma. PMID- 22944504 TI - Optic disc crescent and tilt. PMID- 22944507 TI - VEGF trap for macular edema. PMID- 22944508 TI - Persistent fetal vasculature. PMID- 22944510 TI - Pulmonary and heart rate responses to wearing N95 filtering facepiece respirators. AB - BACKGROUND: Filtering facepiece respirators are the most common respirator worn by US health care and industrial workers, yet little is known on the physiologic impact of wearing this protective equipment. METHODS: Twenty young, healthy subjects exercised on a treadmill at a low-moderate (5.6 km/h) work rate while wearing 4 different models of N95 filtering facepiece respirators for 1 hour each, 2 models of which were equipped with exhalation valves, while being monitored for physiologic variables. RESULTS: Compared with controls, respirator use was associated with mean 1 hour increases in heart rate (range, 5.7-10.6 beats per minute, P < .001), respiratory rate (range, 1.4-2.4 breaths per minute, P < .05), and transcutaneous carbon dioxide (range, 1.7-3.0 mm Hg, P < .001). No significant differences in oxygen saturation between controls and respirators were noted (P > .05). CONCLUSION: The pulmonary and heart rate responses to wearing a filtering facepiece respirator for 1 hour at a low-moderate work rate are relatively small and should generally be well tolerated by healthy persons. PMID- 22944511 TI - Medication discrepancy and potentially inappropriate medication in older Chinese American home-care patients after hospital discharge. AB - BACKGROUND: Studies of potential medication problems among older adults have focused on English-speaking populations in a single health care setting or a single potential medication problem. No previous studies investigated potential inappropriate medications (PIMs) and medication discrepancies (MDs) among older Chinese Americans during care transitions from hospital discharge to home care. OBJECTIVE: The aims of this study were to examine, in older Chinese Americans, the prevalence of both PIMs and MDs; the relationship between PIMs and MDs; and the patient and hospitalization characteristics associated with them during care transitions from hospital discharge to home care. METHODS: This cross-sectional study was conducted with a sample of older Chinese Americans from a large certified nonprofit home-care agency in New York City from June 2010 to July 2011. PIMs were identified by using 2002 diagnosis-independent Beers criteria. MDs were identified by comparing the differences between hospital discharge medication order and home-care admission medication order. Prevalence of PIMs and MDs and their relationship was determined. Logistic regression examined the relationship between hospitalization and patient characteristics with PIMs and MDs. RESULTS: The sample consisted of 82 older Chinese-American home-care patients. Twenty (24.3%) study participants were prescribed at least one PIM at hospital discharge. Fifty-one (67.1%) study participants experienced at least one MD. A positive correlation was found between the occurrence of PIMs and MDs (r = 0.22; P = 0.05). Number of medications was the only significant factor associated with both PIMs and MDs. In addition, older age and more hospitalization days were associated with PIMs. CONCLUSIONS: The evident prevalence of PIMs and MDs supports the practice of evaluating the appropriateness of medications while reconciling inconsistencies in medication regimens. The number of medications was the only factor associated with both PIMs and MDs, underscoring the need to address polypharmacy as a multifaceted threat to patient health. PMID- 22944512 TI - Within-event learning in rats with lesions of the basolateral amygdala. AB - Rats with neurotoxic lesions of the basolateral amygdala were trained in procedures designed to assess the formation of within-event, taste-odor associations. In Experiments 1 and 2 the animals were given initial exposure to a taste-odor compound; the value of the taste was then modified, and the consequent change in responding to the odor was taken to indicate that an odor-taste association had been formed. In Experiment 1 the value of the taste (saline) was enhanced by means of salt-depletion procedure; in Experiment 2 the taste was devalued by aversive conditioning. In neither procedure did lesioned animals differ from sham-operated controls. Experiment 3 confirmed, however, that taste potentiation of odor aversion learning (an effect thought to depend on the formation of a taste-odor association) is abolished by the lesion. Implications for the view that the amygdala is necessary for sensory-sensory associations between events in different modalities are considered. PMID- 22944513 TI - Working memory performance in young adults is associated to the AATn polymorphism of the CNR1 gene. AB - Working memory (WM) depends on several neural networks and neurochemical systems. One of them is the endocannabinoid (eCB) system, which CB1 receptor (CB1R) is widely distributed all over the brain. The stimulation of CB1R by agonists reduces WM efficiency. The CNR1 human gene (6q14-15) encodes the CB1R. AATn polymorphism of the CNR1 gene has been related to psychiatric disorders, and to procedural learning and attention in healthy subjects. The aim of this exploratory research was to test whether AATn polymorphism of the CNR1 is related to the WM performance, by measuring n-back task. Mexican healthy young adults (n = 94) performed the WM n-back task. One of the most frequent AATn allele in our sample was the AAT12. We formed three groups, as a function of the AATn genotype: AAT <= 12/AAT<=12, AAT <= 12/AAT > 12 and AAT > 12/AAT > 12, and their accuracy on the n-back task was compared. WM accuracy differed among genotypes (P=0.03): AAT <= 12/AAT<=12 group had a higher performance than the AAT > 12/AAT > 12 group (statistical power: 0.65, f(2) = 0.20, P<0.05). These results suggest that the fewer AATn repeats of the CNR1 gene, the better WM performance, and sustain the idea that eCB system participates in the modulation of the human brain network involved in WM. PMID- 22944515 TI - The influence of exercise on prefrontal cortex activity and cognitive performance during a simulated space flight to Mars (MARS500). AB - With respect to the plans of national and internationals space agencies to send people to Mars or Moon, long-term isolation studies are performed to learn about the psycho-physiological and psycho-social limitations of such missions. From June 3rd 2010 to November 4th 2011 six participants lived under totally isolated and confined conditions in the MARS500 habitat located in Moscow. Despite the possibility to mimic the condition of space travel, this study allowed for experimental conditions under very reliable and traceable conditions. As exercise is widely discussed to have a positive impact on neuro-cognitive performance, this study aimed to test the effect of different exercise protocol (endurance/strength orientated) on brain cortical activity and cognitive performance. Brain cortical activity was recorded using a 16 channel EEG before and after exercise across the 520 days of confinement. Cognitive performance was assessed using three commercially available brain games. Following the theory of transient hypofrontality, results show a significant decrease of frontal brain cortical activity after exercise (p<.05) which was most expressed after endurance orientated protocols. Cognitive performance was improved following running sessions on an active treadmill (p<.05). Results let us assume that not exercise per se acts as a neuro-enhancer. It is more likely that a general defocusing caused by an immersion into exercise is necessary to improve cognitive performance. PMID- 22944514 TI - Social deficits in the AY-9944 mouse model of atypical absence epilepsy. AB - Atypical absence epilepsy (AAE) showing slow spike-and-wave discharges (SWD) is characterized by severely abnormal cognition and neurodevelopmental or neurological outcomes in humans. However, despite the severe behavioral outcomes in AAE, the relationship between AAE and social-behavioral dysfunctions has not defined well, either experimentally or in patients with AAE. Experimentally, AAE can be produced by administering AY-9944 (AY), a cholesterol biosynthesis inhibitor. In this study, we characterized social behavior in the AY mouse model of AAE. AAE in the mouse was induced by repeated postnatal administration of AY every 6 days from postnatal day (P) 2 to P20. AY-treated mice exhibited spontaneous, recurrent, and synchronous SWD (4-5 Hz) in electroencephalographic recordings. AY-treated mice performed tasks involving sociability/social novelty preference, social interaction with a juvenile conspecific, observational fear, and resident-intruder aggression. They showed behavioral dysfunction in social interactions with a juvenile conspecific and sociability/social novelty preference tasks. They also exhibited reduced social fear learning in observational fear conditioning. Interestingly, they showed increased levels of offensive behaviors in a resident-intruder task. However, AY-treated mice displayed normal levels of anxiety in light/dark transition and the elevated plus maze tasks, and showed slightly increased locomotor activity in an open-field task. These results demonstrate social dysfunction in the AY-induced AAE model. Our study of social behavior can also provide valuable information about Lennox Gastaut syndrome, in which AAE is a component. Thus, our findings may help to understand behavioral pathogenesis or characteristics of patients with AAE. PMID- 22944516 TI - Constructing the habituome for phenotype-driven zebrafish research. AB - Intra-session habituation to novelty reflects spatial working memory (related to exploration and cognition), and is observed in various species, including zebrafish (Danio rerio). With the growing understanding of complex zebrafish behaviors, the extent to which they habituate remains unclear. Here we perform a large-scale characterization of zebrafish novelty-evoked (novel tank and open field) behaviors, to establish their grouping based on intra-session habituation and sensitivity to anxiolytic or anxiogenic manipulations. We also assess multiple behaviors in high- and low-anxiety sub-cohorts of a large heterogeneous zebrafish population, comparing their habituation profiles. Overall, our analyses demonstrate that anxiety responsivity and the ability to habituate show little correlation for multiple zebrafish behaviors, suggesting that they most likely represent distinct behavioral phenomena in novel environments. Using these data, we also present the habituome--a new conceptual approach to study affective and cognitive responses in zebrafish by examining a big set of their habituation phenotypes. Given marked similarity in animal novelty exploration, this approach may also be used to construct habituomes in other model organisms, including rodents and humans. PMID- 22944518 TI - [Multifocal clear cell meningioma in the sacral and lumbar spine. Case report and literature review]. AB - Clear cell meningioma is a rare morphological form of meningioma. This case report describes a very rare case of multifocal clear cell meningioma in the sacral and lumbar spine. The patient was a 20-year-old female who presented back pain. Magnetic resonance imaging (MRI) revealed a large tumour at L4 to S2 level associated with two, smaller, satellite tumours at the lumbar level. An intra extradural tumour was surgically removed and the pathological diagnosis of clear cell meningioma was confirmed. Both satellite lesions were also resected and their histopathological diagnosis was the same. Therefore, clear cell meningioma should be considered in young patients with suggested meningioma in the lumbar spine, as well as the possibility of multifocal origin and postoperative recurrence. PMID- 22944517 TI - Acute genistein treatment mimics the effects of estradiol by enhancing place learning and impairing response learning in young adult female rats. AB - Endogenous estrogens have bidirectional effects on learning and memory, enhancing or impairing cognition depending on many variables, including the task and the memory systems that are engaged. Moderate increases in estradiol enhance hippocampus-sensitive place learning, yet impair response learning that taps dorsal striatal function. This memory modulation likely occurs via activation of estrogen receptors, resulting in altered neural function. Supplements containing estrogenic compounds from plants are widely consumed despite limited information about their effects on brain function, including learning and memory. Phytoestrogens can enter the brain and signal through estrogen receptors to affect cognition. Enhancements in spatial memory and impairments in executive function have been found following treatment with soy phytoestrogens, but no tests of actions on striatum-sensitive tasks have been made to date. The present study compared the effects of acute exposure to the isoflavone genistein with the effects of estradiol on performance in place and response learning tasks. Long Evans rats were ovariectomized, treated with 17beta-estradiol benzoate, genistein containing sucrose pellets, or vehicle (oil or plain sucrose pellets) for 2 days prior to behavioral training. Compared to vehicle controls, estradiol treatment enhanced place learning at a low (4.5 MUg/kg) but not high dose (45 MUg/kg), indicating an inverted pattern of spatial memory facilitation. Treatment with 4.4 mg of genistein over 2 days also significantly enhanced place learning over vehicle controls. For the response task, treatment with estradiol impaired learning at both low and high doses; likewise, genistein treatment impaired response learning compared to rats receiving vehicle. Overall, genistein was found to mimic estradiol-induced shifts in place and response learning, facilitating hippocampus-sensitive learning and slowing striatum-sensitive learning. These results suggest signaling through estrogen receptor beta and membrane-associated estrogen receptors in learning enhancements and impairments given the preferential binding of genistein to the ERbeta subtype and affinity for GPER. PMID- 22944519 TI - Comparison of segmental wall motion abnormalities on echocardiography in patients with anteroseptal versus extensive anterior wall ST-segment elevation myocardial infarction. AB - OBJECTIVE: Acute anteroseptal ST-segment elevation (STE) myocardial infarction (AS-STEMI), defined as STE limited to leads V1 to V3, has historically been associated with a smaller infarct size than extensive anterior STEMI (EA-STEMI), in which STE extends to leads V4 to V6. We compared the differences in global and regional wall motion by transthoracic echocardiography between patients with AS STEMI and EA-STEMI. METHODS: Patients who presented with anterior STEMI and underwent primary percutaneous coronary intervention between January 2008 and March 2011 were included. For each subject, a transthoracic echocardiogram that was performed within 24 hours of admission was interpreted by an independent investigator blinded to the patient's electrocardiographic data. RESULTS: Of the 65 subjects who met our inclusion criteria, 30 had AS-STEMI and 35 had EA-STEMI. No differences were observed between groups in baseline characteristics or the mean number of hypokinetic, akinetic, and dyskinetic segments. Apical inferior segment dysfunction occurred more often in patients with EA-STEMI than in patients with AS-ASTEMI (71.4% vs 43.3%; P=.04). Distribution and extent of wall motion abnormalities were similar between patients with AS-STEMI and those with EA-STEMI. CONCLUSION: The term AS-STEMI may be misleading, as it implies that only the anteroseptal segments are involved. We show that regional dysfunction in patients with AS-STEMI extends beyond the anteroseptal region. PMID- 22944520 TI - Prevalence and predictors of severe autonomic failure in patients with insulin dependent type 2 diabetes mellitus and coronary artery disease: pilot study. AB - BACKGROUND: Presence of severe autonomic failure (SAF), defined as coincidence of abnormal heart rate turbulence and abnormal deceleration capacity, identifies a group of patients with very poor prognosis among post-infarction patients with diabetes mellitus. However, factors contributing to development of SAF are entirely unknown. Here, we aimed to identify clinical, biochemical, and hemodynamic factors predicting SAF in a consecutive cohort of diabetic patients with coronary artery disease (CAD). METHODS: Between January 2010 and July 2011, we prospectively enrolled 97 patients with insulin-dependent type 2 diabetes mellitus and stable CAD in sinus rhythm. Heart rate turbulence (as marker of autonomic reflex activity) and deceleration capacity (as marker of autonomic tonic activity) were calculated from 24-hour Holter recordings. Uni- and multivariable logistic regression analysis included duration of diabetes mellitus, diabetic neuropathy, retinopathy, nephropathy, level of HbA(1c), left ventricular ejection fraction (LVEF), brain natriuretic peptide, presence of multivessel disease, and history of myocardial infarction. RESULTS: Ten (10.3%) of the 97 patients exhibited signs of SAF. Patients with SAF were characterized by longer duration of diabetes (25 years vs 15 years), higher prevalence of diabetic neuropathy (70% vs. 36%), retinopathy (80% vs 45%) and nephropathy (90% vs 55%), significantly higher levels of HbA(1c) (9.0% vs 7.4%; P = .002) and a lower LVEF (30% vs.55%; P = .001). On multivariable analysis, LVEF <= 35% and HbA(1c) >8% were the only factors which were independently associated with SAF (odds ratios of 23.1 [95% CI, 1.8-287.0]; P = .015 and 6.6 [1.1-40.1]; P = .043). DISCUSSION: In patients with insulin-dependent type 2 diabetes mellitus and CAD, presence of SAF correlates with both glycemic control and diabetic complications. Impaired LVEF and increased level of HbA(1c) were independently associated with SAF. PMID- 22944521 TI - Valerian extract characterized by high valerenic acid and low acetoxy valerenic acid contents demonstrates anxiolytic activity. AB - Valerian is one of the most commonly used herbal remedies for the treatment of insomnia and anxiety. Valerian extracts allosterically modulate GABAA receptors, an action related to valerenic acid, which is one of the active compounds determined from pharmacological studies. Derivatives of valerenic acid, i.e. acetoxy valerenic acid or hydroxy valerenic acid, do not allosterically modulate GABAA receptors, but they bind to identical binding sites. Therefore, the question arises whether they might interfere with the effects of valerenic acid. Two valerian extracts were tested in the elevated plus maze test and the tail suspension test for anxiolytic and antidepressive activity, respectively. Reference substances were diazepam (1.0mg/kg) and imipramine (30mg/kg). The extracts were standardized to the identical total amounts of the acids (0.1; 0.5; 1.0 and 2.0mg/kg), i.e. valerenic and acetoxy valerenic acid, but the ratio between the acids was different (12:1 and 1:1.5). The extract with the ratio 12:1 prolonged the time spent on the open arm significantly when 0.5mg/kg was applied. Of the other extract, with the ratio 1:1.5, four times that amount was required (2.0mg/kg). Both of the tested extracts did not show any antidepressive effect, rather the other way around, the extract with the ratio 1:1.5 prolonged the immobility phase. However, since the core body temperature was reduced by the 1.0 and 2.0mg/kg extract dose, the prolongation may be related to the temperature phenomenon and is not indicative of a specific depressive action. In conclusion, the anxiolytic activity of the valerian extract seems rather related to valerenic acid and, moreover, standardization with respect to the total amount of valerenic acids, i.e. valerenic acid together with acetoxy valerenic acid, is misleading. PMID- 22944522 TI - The effect of walking poles on the knee adduction moment in patients with varus gonarthrosis. AB - OBJECTIVES: (1) Test the hypothesis that walking poles decrease the external knee adduction moment during gait in patients with varus gonarthrosis, and (2) explore potential mechanisms. DESIGN: Thirty-four patients with medial compartment knee osteoarthritis (OA) and varus alignment underwent three dimensional (3D) gait analysis with and without using walking poles. Conditions were randomized and walking speed was maintained +/-5% of the self-selected speed of the initial condition. The pole held in the hand of the unaffected side was instrumented with a compression load cell. RESULTS: Student's t tests for paired samples indicated small but statistically significant increases (P < 0.001) in knee adduction moment (calculated from inverse dynamics) for its first peak, second peak and angular impulse when using the poles; mean increases (95% confidence interval - CI) were 0.17%BW*Ht (0.08, 0.27), 0.17%BW*Ht (0.04, 0.30) and 0.15%BW*Ht*s (0.09, 0.22), respectively. There was a decrease (P = 0.015) in vertical ground reaction force (-0.02 BW (-0.04, -0.01)), yet increase (P < 0.001) in its frontal plane lever arm about the knee (0.30 cm (0.15, 0.44)), at the time of the first peak knee adduction moment. Pole force in the vertical direction was inversely related (r = -0.34, P = 0.05) to the increase in first peak adduction moment. CONCLUSION: Although results are variable among patients, and may be related to individual technique, these overall findings suggest that walking poles do not decrease knee adduction moments, and therefore likely do not decrease medial compartment loads, in patients with varus gonarthrosis. Decreases in knee joint loading should not be used as rationale for walking pole use in these patients. PMID- 22944523 TI - Pain in patients with equal radiographic grades of osteoarthritis in both knees: the value of gray scale ultrasound. AB - OBJECTIVES: To investigate the association of ultrasound (US) features with pain and the functional scores in patients with equal radiographic grades of osteoarthritis (OA) in both knees. METHODS: Fifty-six consecutive patients with knee OA: 85 symptomatic knees (81 knees with medial pain) and 27 asymptomatic knees, and 10 healthy patients without knee OA as a control were enrolled. US was done by two ultrasonographers blinded to patient diagnoses. US features were semiquantitatively scored (0-3) when appropriate. RESULTS: In the OA group, common US findings were marginal osteophyte, suprapatellar synovitis, suprapatellar effusion (SPE), medial meniscus protrusion, medial compartment synovitis (MCS), lateral compartment synovitis, and Baker's cyst. Only SPE and MCS were significantly associated with knee pain. Visual analog pain scale (VAS) scores on motion were positively linearly associated with SPE and MCS (P < 0.01). Only MCS was degree-dependently associated with VAS scores at rest, the Western Ontario and McMaster Universities pain subscale, and the presence of medial knee pain (P < 0.01) after adjustments for age, gender, body mass index (BMI), radiographic grade, and other US features. In the control group, no US features were associated with knee pain. CONCLUSIONS: US inflammation features, including SPE and MCS, were positively linearly associated with knee pain in motion. MCS was also degree-dependently associated with pain at rest and the presence of medial knee pain. These findings show that synovitis was one important predictive factor of pain. Further studies to confirm the association of US features and pain are warranted. PMID- 22944524 TI - Bone marrow lesions in knee osteoarthritis change in 6-12 weeks. AB - OBJECTIVES: Knee osteoarthritis (OA) is thought to be a slowly evolving disease with glacial changes in cartilage morphology necessitating trials of potential treatments lasting 1-2 years with evidence that over 6 months change in cartilage is not detectable. In contrast to cartilage, bone has the capacity to adapt rapidly, such as after fracture. We tested whether bone marrow lesions (BMLs) change in volume in 6 and 12 weeks, suggesting they may provide evidence of short term fluctuations of joint damage. METHODS: In 62 patients with patellofemoral knee OA (mean age 55.7 years, 59.7% women, mean BMI 31.0), we obtained baseline, 6 and 12 week knee MRIs with contrast enhancement. Of those with BMLs at baseline, we assessed BML volume on the axial proton density fat saturated (FS) images and postcontrast sagittal T1 weighted FS images. We manually segmented BML volumes, testing repeatability of BML volumes in knees remeasured. Using the standard deviation of the difference between repeated measurements to calculate Bland-Altman Limits of Agreement, we determined how much BML volume change represented a change greater than due to chance. RESULTS: Fifty-two patients had BMLs at baseline. Test-retest reliability for BML volume was high (ICC 0.89, 95% CI 0.80-0.97). All knees showed at least some change in BML volume by 6 and 12 weeks. On the axial view at 6 weeks, 20/49 (40.8%) knees showed BML volume changes greater than the limits of agreement with similar results at 12 weeks. BML changes were evenly divided among knees with enlarging and shrinking BMLs. 63.3% of the knees had more than 50% change in BML volume at either 6 or 12 weeks on the axial view and 48.7% on the sagittal view. CONCLUSIONS: Knee BML volumes change in several weeks in many persons with knee OA. To the extent that they could be regarded as treatment targets, trials testing BML effects could avoid the usual prolonged structure modification trials. PMID- 22944525 TI - Measurement properties of performance-based measures to assess physical function in hip and knee osteoarthritis: a systematic review. AB - OBJECTIVES: To systematically review the measurement properties of performance based measures to assess physical function in people with hip and/or knee osteoarthritis (OA). METHODS: Electronic searches were performed in MEDLINE, CINAHL, Embase, and PsycINFO up to the end of June 2012. Two reviewers independently rated measurement properties using the consensus-based standards for the selection of health status measurement instrument (COSMIN). "Best evidence synthesis" was made using COSMIN outcomes and the quality of findings. RESULTS: Twenty-four out of 1792 publications were eligible for inclusion. Twenty one performance-based measures were evaluated including 15 single-activity measures and six multi-activity measures. Measurement properties evaluated included internal consistency (three measures), reliability (16 measures), measurement error (14 measures), validity (nine measures), responsiveness (12 measures) and interpretability (three measures). A positive rating was given to only 16% of possible measurement ratings. Evidence for the majority of measurement properties of tests reported in the review has yet to be determined. On balance of the limited evidence, the 40 m self-paced test was the best rated walk test, the 30 s-chair stand test and timed up and go test were the best rated sit to stand tests, and the Stratford battery, Physical Activity Restrictions and Functional Assessment System were the best rated multi-activity measures. CONCLUSION: Further good quality research investigating measurement properties of performance measures, including responsiveness and interpretability in people with hip and/or knee OA, is needed. Consensus on which combination of measures will best assess physical function in people with hip/and or knee OA is urgently required. PMID- 22944526 TI - Development of a simplified Chinese version of the Hip Disability and Osteoarthritis Outcome Score (HOOS): cross-cultural adaptation and psychometric evaluation. PMID- 22944528 TI - Cell lineage tracing techniques for the study of brain development and regeneration. AB - Characterization of the means by which cells are generated and organized to make an organ as complex as the brain is a formidable task. Understanding how adult stem cells give rise to progeny that integrate into the existing structures during regeneration or in response to injury is equally challenging. Lineage tracing techniques are essential to studying cell behaviors such as proliferation, migration and differentiation, since they allow stem or precursor cells to be marked and their descendants followed and characterized over time. Here, we describe some of the key lineage tracing techniques available to date, highlighting advantages and drawbacks and focusing on their application in neural fate mapping. The more traditional methods are now joined by exciting new approaches to provide a vast array of tools at the disposal of neurobiologists. PMID- 22944527 TI - Serum non-coding RNAs as biomarkers for osteoarthritis progression after ACL injury. AB - OBJECTIVE: The aim of this study was to examine serum non-coding RNAs as potential biomarkers for cartilage damage associated with anterior cruciate ligament (ACL) injury. METHODS: Serum was obtained from 80 patients 1 year after surgery for ACL injury and 60 normal donors without overt skeletal injury. Total serum RNA was isolated, small non-coding RNAs profiled by TaqMan array MicroRNA (miRNA) analysis and individual small RNA assays performed by quantitative TaqMan RT-PCR (qPCR). Semi-quantitative magnetic resonance imaging (MRI) analysis was performed using Whole Organ Magnetic Resonance Knee Score (WORMS) scoring for analysis of cartilage damage. RESULTS: Initial TaqMan array miRNA profiling showed an increased serum concentration of a small nucleolar RNA (snoRNA), U48, in five patients with cartilage damage compared with that in five patients without cartilage damage and six normal donors. Independent qPCR analysis of snoRNAs in serum from all patients and normal donors showed a strong association between the serum level of another snoRNA, U38, and cartilage damage in ACL injury patients and together with snoRNA, U48, clear distinction between ACL injury patients and normal donors. CONCLUSION: SnoRNAs U38 and U48 are significantly elevated in the serum of patients developing cartilage damage at 1 year after ACL injury. Serum levels of U38 have the potential to facilitate early diagnosis of patients with cartilage damage after ACL injury. This study suggests serum non-coding RNAs may serve as novel noninvasive biomarkers for the detection and assessment of cartilage damage after ACL injury. PMID- 22944529 TI - Changes in N400 topography following intensive speech language therapy for individuals with aphasia. AB - Our goal was to characterize the effects of intensive aphasia therapy on the N400, an electrophysiological index of lexical-semantic processing. Immediately before and after 4 weeks of intensive speech-language therapy, people with aphasia performed a task in which they had to determine whether spoken words were a 'match' or a 'mismatch' to pictures of objects. Pre-therapy, people with aphasia exhibited an N400 mismatch effect that started over right hemisphere electrodes. Post-therapy, gains were seen in clinical measures of language ability, and the onset of the N400 was left-lateralized. No changes in the scalp distribution of the N400 were observed in healthy controls tested twice over the same 4 week interval. Since the distribution of the N400 after aphasia therapy differed from that of healthy controls, we conclude that it reflects the engagement of compensatory neural mechanisms for language processing rather than a return to a "normal" pattern of brain activation. PMID- 22944530 TI - The role of the anterior cingulate cortex in choices based on reward value and reward contingency. AB - Although several studies have emphasized the role of the anterior cingulate cortex (ACC) in associating actions with reward value, its role in guiding choices on the basis of changes in reward value has not been assessed. Accordingly, we compared rhesus monkeys with ACC lesions and controls on object- and action-based reinforcer devaluation tasks. Monkeys were required to associate an object or an action with one of two reward outcomes, and we assessed the monkey's shift in choices of objects or actions after changes in the value of 1 outcome. No group differences emerged on either task. For comparison, we tested the same monkeys on their ability to make choices guided by reward contingency in object- and action-based reversal learning tasks. Monkeys with ACC lesions were impaired in using rewarded trials to sustain the selection of the correct object during object reversal learning. They were also impaired in using errors to guide choices in action reversal learning. These data indicate that the role of the ACC is not restricted to linking specific actions with reward outcomes, as previously reported. Instead, the data suggest a more general role for the ACC in using information about reward and nonreward to sustain effective choice behavior. PMID- 22944532 TI - 225Ac and 223Ra production via 800 MeV proton irradiation of natural thorium targets. AB - Cross sections for the formation of (225,227)Ac, (223,225)Ra, and (227)Th via the proton bombardment of natural thorium targets were measured at a nominal proton energy of 800 MeV. No earlier experimental cross section data for the production of (223,225)Ra, (227)Ac and (227)Th by this method were found in the literature. A comparison of theoretical predictions with the experimental data shows agreement within a factor of two. Results indicate that accelerator-based production of (225)Ac and (223)Ra is a viable production method. PMID- 22944531 TI - Morphology and physiology of excitatory neurons in layer 6b of the somatosensory rat barrel cortex. AB - Neocortical lamina 6B (L6B) is a largely unexplored layer with a very heterogeneous cellular composition. To date, only little is known about L6B neurons on a systematic and quantitative basis. We investigated the morphological and electrophysiological properties of excitatory L6B neurons in the rat somatosensory barrel cortex using whole-cell patch-clamp recordings and simultaneous biocytin fillings. Subsequent histological processing and computer assisted 3D reconstructions provided the basis for a classification of excitatory L6B neurons according to their structural and functional characteristics. Three distinct clusters of excitatory L6B neurons were identified: (C1) pyramidal neurons with an apical dendrite pointing towards the pial surface, (C2) neurons with a prominent, "apical"-like dendrite not oriented towards the pia, and (C3) multipolar spiny neurons without any preferential dendritic orientation. The second group could be further subdivided into three categories termed inverted, "tangentially" oriented and "horizontally" oriented neurons. Furthermore, based on the axonal domain two subcategories of L6B pyramidal cells were identified that had either a more barrel-column confined or an extended axonal field. The classification of excitatory L6B neurons provided here may serve as a basis for future studies on the structure, function, and synaptic connectivity of L6B neurons. PMID- 22944533 TI - Study of structure of calcium phosphate materials by means of electron spin resonance. AB - Structure of gamma-irradiated calcium phosphates synthesized in different conditions was studied by means of ESR. It has been shown that amorphous and nanocrystalline calcium phosphates have qualitatively different ESR spectra. The new paramagnetic center in hydroxyapatite (HA) has been found. It consists of four protons of water molecules located in the parallelogram vertexes and the free electron formed in HA by gamma-irradiation. This center is thermally stable up to 300 degrees C, when the water molecules release from the HA crystal lattice. PMID- 22944534 TI - Water-equivalent one-dimensional scintillating fiber-optic dosimeter for measuring therapeutic photon beam. AB - In this study, we fabricated a one-dimensional scintillating fiber-optic dosimeter, which consists of 9 scintillating fiber-optic dosimeters, septa, and PMMA blocks for measuring surface and percentage depth doses of a therapeutic photon beam. Each dosimeter embedded in the 1-D scintillating fiber-optic dosimeter is composed of square type organic scintillators and plastic optical fibers. Also black PVC films are used as septa to minimize cross-talk between the scintillating fiber-optic dosimeters. To construct a dosimeter system, a 1-D scintillating fiber-optic dosimeter and a CMOS image sensor were combined with 20 m-length plastic optical fibers. Using the dosimeter system, we measured surface and percentage depth doses of 6 and 15 MV photon beams and compared the results with those of EBT films and an ionization chamber. PMID- 22944535 TI - The effects of 3 different compression methods on intrathoracic pressure in a swine model of ventricular fibrillation. AB - OBJECTIVE: The aim of this study was to provide a realistic comparison of 3 different extracorporeal compression methods during cardiopulmonary resuscitation on intrathoracic pressure (ITP), hemodynamics, and oxygen metabolism in a swine model of ventricular fibrillation (VF). METHODS: Eight minutes after the development of VF, pigs were subjected to 3 different extracorporeal compression methods: traditional artificial manual compression, mechanical compression using an AutoPulse apparatus, or manual sucker. Heart rhythm was assessed by electrocardiography after 5 cycles of extracorporeal compression. If VF still occurred, electrical defibrillation was performed. After defibrillation, an additional 5 cycles of extracorporeal compression were performed. Resuscitation was considered to have failed if the above procedure was continued for 30 minutes without return of spontaneous circulation. Hemodynamics and ITP waveforms were monitored continuously. Oxygen metabolism indices were measured, and success rates were compared among the groups. RESULTS: Manual compression showed advantages over both of the other methods in terms of maximal ITP and fluctuation amplitude, hemodynamic and oxygen dynamic changes, convenience of administration, and duration of treatment. Survival rates and cerebral performance category scores for the manual compression group were significantly higher than that for the other groups. CONCLUSIONS: Mechanical compression cannot replace traditional artificial manual compression, which remains the preferred method for cardiopulmonary resuscitation. PMID- 22944536 TI - Anterior-posterior compression pelvic fracture increases the probability of requirement of bilateral embolization. AB - INTRODUCTION: Transarterial embolization has become an effective method in the management of pelvic fracture-related retroperitoneal hemorrhage. However, the selection of bilateral embolization or selective unilateral embolization remains controversial. The anterior-posterior compression (APC) pelvic fracture creates a complete diastasis of the anterior pelvis, which might be associated with bilateral sacroiliac joint injuries and further bilateral arterial injuries. In the current study, we evaluated the correlation between APC pelvic fracture and the need for bilateral internal iliac artery (IIA) embolization. METHODS: During the 78-month investigational period, patients who received either unilateral or bilateral IIA embolization over the injured site, as determined by angiographic findings, were enrolled. The patients with bilateral contrast extravasation (CE) revealed by angiography were compared with the patients with unilateral CE revealed by angiography. Among the patients with only unilateral positive findings (CE or hematoma formation) on computed tomographic scanning, the characteristics and risk factors of patients who required bilateral IIA embolization were analyzed. The patients with postembolization hemorrhage who had received repeat transarterial embolization were also identified and discussed. RESULTS: Seventy patients were enrolled in the current study. The rate of APC pelvic fracture among patients who received bilateral IIA embolization was 66.7% (18/27), which was significantly higher than the rate among patients who received unilateral IIA embolization (30.2%; 3/43) (P = .006). Of the patients with only unilateral positive findings on computed tomographic scanning, 21.6% (11/51) underwent bilateral IIA embolization because of bilateral CE revealed by angiography. There were also more patients with APC pelvic fracture in this group. CONCLUSION: In the management of APC pelvic fracture, more attention should be paid to the higher probability of bilateral hemorrhage. Bilateral IIA embolization should be considered in patients with APC pelvic fracture. PMID- 22944537 TI - Splenic infarction at high altitude secondary to sickle cell trait. PMID- 22944538 TI - Presence of crystals is not an evidence of absence of infection. AB - Acute monoarthritis is one of the most common rheumatologic presentations. However, it is clinically difficult to distinguish between an inflamed joint due to crystal-induced arthritis and an inflamed joint due to septic arthritis. Arthrocentesis and synovial fluid analysis are used to differentiate between these 2 conditions. The presence of crystals and positive synovial fluid culture confirm the diagnosis of crystal-induced arthritis and septic arthritis, respectively. Although uncommon, these 2 arthritides can coexist, and presence of crystal does not exclude bacterial arthritis. We reported a case of 85-year-old woman whose synovial fluid contained crystals and was initially diagnosed with crystal-induced arthritis. However, her joint fluid culture subsequently grew Staphylococcus aureus, and she was treated with arthroscopic debridement and antibiotics. PMID- 22944539 TI - Prospective evaluation of the use of the thrombolysis in myocardial infarction score as a risk stratification tool for chest pain patients admitted to an ED observation unit. AB - BACKGROUND: The Thrombolysis in Myocardial Infarction (TIMI) score has shown use in predicting 30-day and 1-year outcomes in emergency department (ED) patients with potential acute coronary syndrome. Few studies have evaluated the TIMI score in risk stratifying patients selected for the ED observation Unit (EDOU). Risk stratification of patients in this group could identify those at risk for significant cardiac events. Our goal was to evaluate TIMI use for risk stratification in this population and compare outcomes among differing scores. METHODS: A prospective observational study with 30-day telephone follow-up for a 12 month period. Baseline data, outcomes related to EDOU stay, admission, and 30 day outcomes were recorded. TIMI scores were calculated for each patient placed in EDOU. TIMI score was not utilized in the decision to place patients in observation. RESULTS: N = 552. Composite outcomes recorded were myocardial infarction, revascularization, or death either during the EDOU stay, inpatient admission, or the 30-day follow-up. Eighteen composite outcomes were recorded: stent (12 patients), coronary artery bypass graft (3 patients), myocardial infarction and stent (2 patients), and myocardial infarction, and coronary artery bypass graft (1 patient). Distribution by TIMI score was: 0 (102 patients), 1 (196), 2 (142), 3 (72), 4 (27), and 5 (5). Risk of composite outcome increased by score: 0 (1%), 1 (2.6%), 2 (2.1%), 3 (6.9%), 4 (11.1%), and 5 (20%). Those with an intermediate risk score (3-5) were also more likely to require admission (15.4% vs 9.8%, P = .048). CONCLUSION: The TIMI risk score may serve as an effective risk stratification tool among chest pain patients selected for EDOU placement. Patients with intermediate-risk by TIMI may be considered for inpatient admission and/or more aggressive evaluation and therapy. PMID- 22944540 TI - Point-of-care ultrasound diagnosis and treatment of posterior shoulder dislocation. AB - Acute traumatic posterior shoulder dislocations are rare. The diagnosis is often missed or delayed, as radiologic abnormalities can be subtle. We report a case of a 37-year-old man who presented to the emergency department with severe right shoulder pain and inability to move his arm after a motor vehicle collision. Based on examination, he was initially thought to have an anterior dislocation; however, point-of-care (POC) ultrasound clearly demonstrated a posterior shoulder dislocation. Real-time ultrasound-guided intra-articular local anesthetic injection facilitated closed reduction in the emergency department without procedural sedation, and POC ultrasound confirmed successful reduction at the bedside after the procedure. This case demonstrates that POC ultrasound can be a useful diagnostic tool in the rapid assessment and treatment for patients with suspected posterior shoulder dislocation. PMID- 22944541 TI - Acute complications of tattooing presenting in the ED. AB - Permanent decorative tattooing involves the introduction of exogenous pigments and/or dyes into the dermis to produce the permanent design. Despite improved hygiene in the tattoo parlors of Western countries, this procedure still carries risk. Various complications may occur right after tattooing, from benign complications such as transient limb edema, palpable lymph nodes, and contact eczema, to more severe ones such as the inoculation of virulent microorganisms into the dermis, potentially life-threatening cellulitis, and necrotizing fasciitis or cutaneous vasculitis. This review focuses specifically on the complications that occur within the first month of tattooing that emergency physicians may have to manage. PMID- 22944543 TI - Stress-induced transient midventricular ballooning: a new variant of broken heart syndrome. PMID- 22944544 TI - Bradykinin-mediated angioedema: factors prompting ED visits. AB - OBJECTIVE: Bradykinin-mediated angioedema (AE) is characterized by periodic subcutaneous or submucosal swelling, with the absence of urticaria and itching. It affects the face and extremities. Attacks of abdominal pain and obstruction of the upper airways are the hallmarks of disease severity. The aim of this study was to determine the factors prompting patients to turn up at the hospital emergency department (ED) in the event of an attack. METHODS: This was a retrospective review of attacks experienced by all patients with bradykinin mediated AE (hereditary, acquired, or drug-induced) who visited our ED between January 2002 and March 2011. Characteristics of attacks prompting ED visits and attacks when patients stayed at home were compared using logistic regression with generalized estimating equations to take into account the correlation between multiple attacks from the same patient. RESULTS: A total of 55 patients were included, of whom 39 had hereditary AE; 13, drug-induced AE; and 3, acquired C1 inhibitor deficiency. The median follow-up was 32 months (interquartile range, 10 99 months). The attack was severe in 324 (58%) of 559 cases. Thirty-two patients (58%) visited the ED for a total of 75 attacks. First attack and laryngeal edema were significantly associated with more frequent ED visits (odds ratio, 5.28 [95% confidence interval, 2.42-11.5] and 4.83 [1.54-15.5], respectively]. C1 inhibitor concentrate and icatibant treatment was significantly more often administered in the ED than at home (odds ratio, 4.9 [2.43-9.88] and 8.25 [2.4-28.3], respectively). CONCLUSIONS: First attack of bradykinin AE and swelling of the larynx were significantly associated with visits to the ED. PMID- 22944545 TI - Ventricular fibrillation caused by coronary artery spasm during mild therapeutic hypothermia after resuscitation. PMID- 22944546 TI - Flash pulmonary edema and renal artery stenosis: pickering syndrome. PMID- 22944547 TI - Jejunojejunal intussusception after Roux-en-Y gastric bypass. PMID- 22944548 TI - Carbon monoxide poisoning-induced compartment syndrome: is it really a novel phenomenon? PMID- 22944549 TI - Urgent apheresis combined with insulin infusion in hypertriglyceridemia-induced acute pancreatitis. PMID- 22944550 TI - Head position angles to open the upper airway differ less with the head positioned on a support. AB - INTRODUCTION: The aim of the study was to assess the effects of positioning the head on a support on "head position angles" to optimally open the upper airway during bag-valve mask ventilation. METHODS: We ventilated the lungs of anesthetized adults with a bag-valve mask and the head positioned with (n = 30) or without a support (n = 30). In both groups, head position angles and ventilation parameters were measured with the head positioned in (1) neutral position, (2) in a position deemed optimal for ventilation by the investigator, and (3) in maximal extension. RESULTS: Between groups ("head with/without a support") and between head positions within each group, head position angles and ventilation parameters differed (P < .0001, respectively). However, head position angles and ventilation parameters between head positions differed less "with a support" (P < .001), and ventilation parameters improved with a support compared with the head-without-a-support group (P < .001). CONCLUSIONS: In the head-with-a support group, when compared with the head-without-a-support group, head position angles differed less, indicating a decreased potential for failure during bag valve mask ventilation with the head on a support. Moreover, in the head-with-a support group, ventilation parameters differed less between head positions, and ventilation improved. These findings suggest a potential benefit of positioning the head on a support during bag-valve mask ventilation. PMID- 22944551 TI - Nonfatal tramadol overdose may cause false-positive phencyclidine on Emit-II assay. PMID- 22944552 TI - C-reactive protein as predictor of bacterial infection among patients with an influenza-like illness. AB - OBJECTIVE: During the influenza season patients are labeled as having an influenza-like illness (ILI) which may be either a viral or bacterial infection. We hypothesize that C-reactive protein (CRP) levels among patients with ILI diagnosed with a bacterial infection will be higher than patients diagnosed with an influenza or another viral infection. METHODS: We enrolled a convenience sample of adults with ILI presenting to an urban academic emergency department from October to March during the 2008 to 2011 influenza seasons. Subjects had nasal aspirates for viral testing, and serum CRP. Bacterial infection was determined by positive blood cultures, radiographic evidence of pneumonia, or a discharge diagnosis of bacterial infection. Receiver operating characteristic curve, analysis of variance, and Student t test were used to analyze results. RESULTS: Over 3 influenza seasons there were 131 total patients analyzed (48 influenza infection, 42 other viral infection and 41 bacterial infection). CRP values were 25.65 mg/L (95% CI, 18.88-32.41) for influenza, 18.73 mg/L (95% CI, 12.97-24.49) for viral and 135.96 mg/L (95% CI, 99.38-172.54) for bacterial. There was a significant difference between the bacterial group, and both the influenza and other viral infection groups (P < .001). The receiver operating characteristic curve for CRP as a determinant of bacterial infection had an area under the curve of 0.978, whereby a CRP value of <20 had a sensitivity of 100% and >80 had a specificity of 100%. CONCLUSION: C-reactive protein is both a sensitive and specific marker for bacterial infection in patients presenting with ILI during the influenza season. PMID- 22944553 TI - Use of the sonographic diameter of optic nerve sheath to estimate intracranial pressure. AB - BACKGROUND AND AIMS: An increase in the intracranial pressure (ICP) might aggravate patient outcomes by inducing neurologic injuries. In patients with increased ICP the optic nerve sheath diameter (ONSD) increases due to its close association with the flow of cerebrospinal fluid. The present study was an attempt to evaluate the efficacy of sonographic ONSD in estimating ICP of patients who are candidates for lumbar puncture (LP). MATERIALS AND METHODS: In this descriptive prospective study, the ONSD was measured before LP using an ultrasonography in 50 nontraumatized patients who were candidates for LP due to varies diagnoses. Immediately after the sonography, the ICP of each patient was measured by LP. Correlation tests were used to evaluate the relationship between ICP and the sonographic diameter of the optic nerve sheath. Receiver operating characteristic curve was used to find the optimal cut-off point in order to diagnose ICP values higher than 20 cm H(2)O. RESULTS: The means of the ONSD were 5.17 +/- 1.01 and 5.19 +/- 1.06 mm on the left and right sides, respectively (P = .552). The mean ONSD for the patients with increased ICP and normal individuals were 6.66 +/- 0.58 and 4.60 +/- 0.41 mm, respectively (P < .001). This mean was significantly correlated with ICP values (P < .05; r = 0.88). The ONSD of greater than 5.5 mm predicted an ICP of >=20 cm H(2)O with sensitivity and specificity of 100% (95% CI, 100-100) (P < .001). CONCLUSION: The sonographic diameter of the optic nerve sheath might be considered a strong and accurate predicting factor for increased intracranial pressure. PMID- 22944554 TI - Early antidote use associated with noninvasive ventilation in prehospital treatment of methadone intoxication. PMID- 22944555 TI - Comparison of ketamine-low-dose midozolam with midazolam-fentanyl for orthopedic emergencies: a double-blind randomized trial. AB - OBJECTIVE: Most of the fractures and dislocations are reduced in the emergency setting. Many drugs are available for procedural sedation and analgesia in the emergency department (ED); however, the adverse effects are still a common problem. The aim of our study was to compare the 2 drug combinations. METHOD: We performed a prospective, randomized, double-blinded, placebo-controlled trial of patients presenting to the ED after a traumatic event and required urgent reduction either for a fracture or dislocation. Patients were randomized to midazolam-fentanyl (MF) group or ketamine-low-dose midazolam (KM) group. Hypoxia, duration of hypoxia, need for oxygen, time to onset of sedation, recovery time, pain scores during reduction, and sedation depth were set as primary outcome measures and were recorded. RESULTS: A total of 498 patients who presented to ED with extremity injury and required closed reduction were assessed; 130 of them were approached for eligibility and 69 patients were excluded. The remaining 61 patients were randomized to either KM group (n = 31) or MF group (n = 30). Hypoxia and duration of hypoxia were significantly lower in the KM group compared with the MF group. Patients in the KM group reported significantly lower pain scores during reduction; however, adverse effects were higher compared with MF group. CONCLUSION: Both drug combinations can be effectively used for procedural sedation and analgesia; however, with lower risk for hypoxia and lower pain scores, KM combination stands as a reasonable choice for orthopedic interventions in the emergency unit. PMID- 22944556 TI - Lateral canal benign paroxysmal positional vertigo and decompression illness. PMID- 22944557 TI - Rectus sheath hematoma: clinical examination is the key. PMID- 22944558 TI - Implications of early and accurate imaging for suspected transient ischemic attack. PMID- 22944559 TI - Secondary acute myelogenous leukemia (AML) with trisomy 10 and del(9q) following precursor B-cell acute lymphoblastic leukemia (ALL) with a hyperdiploid karyotype. AB - Acute myelogenous leukemia (AML) secondary to acute lymphoblastic leukemia (ALL) in children is uncommon and usually occurs within 10 years of completing therapy for ALL. A variety of recurrent cytogenetic abnormalities have been described, suggesting significant biological heterogeneity. We report a case of highly refractory secondary AML with trisomy 10 and del(9q) occurring in an adolescent female 12 years after she was treated successfully for precursor B-cell ALL with chemotherapy only. PMID- 22944560 TI - Myelodysplastic syndrome with a t(2;11)(p21;q23-24) and translocation breakpoint close to miR-125b-1. AB - The upregulation of oncogenes and the formation of fusion genes are commonly observed in hematological malignancies with recurring balanced translocations. However, in some malignancies exhibiting balanced chromosomal rearrangements, neither oncogene deregulation nor generation of fusion genes appears to be involved, suggesting that other mechanisms are at play. In the rare myelodysplastic syndrome (MDS) containing a t(2;11)(p21;q23-24) translocation, breakpoints near a microRNA locus, miR-125b-1, in 11q24 have been suggested to be pathogenetically involved. Here we report the detailed mapping and sequencing of the breakpoint located only 2 kilobases from miR-125b-1 in an MDS patient with a t(2;11)(p21;q23-24). PMID- 22944562 TI - H-Y antigen in kidney transplant: does gender matter? PMID- 22944561 TI - Case of polycythemia vera concurrent with FIP1L1-PDGFRA-positive myeloproliferative neoplasm with eosinophilia. AB - We report an unusual case of a symptomatic patient who initially had high hemoglobin and low serum erythropoietin levels, fitting a clinical diagnosis of polycythemia vera. However, after treatment with hydroxyurea and serial phlebotomies had been started, the patient developed hypereosinophilia, fitting the category of a myeloproliferative neoplasm with eosinophilia associated with the FIP1L1-PDGFRA gene fusion, as confirmed by molecular analysis. We discuss the clinical presentation, evolution, response to treatment, and pathogenetic implications of this case. PMID- 22944563 TI - Editor's commentary. PMID- 22944564 TI - Vascular surgery in China. PMID- 22944565 TI - Transfemoral intraluminal graft implantation for abdominal aortic aneurysms, 1991: two decades later. PMID- 22944566 TI - Female and elderly abdominal aortic aneurysm patients more commonly have concurrent thoracic aortic aneurysm. AB - BACKGROUND: A recent report unexpectedly revealed that one-fourth of abdominal aortic aneurysm (AAA) patients also have an aneurysm in the thoracic aorta (TAA). It remains to be investigated which AAA patients have a higher risk of also developing TAAs. The aim of this study was to identify possible differences in the risk factor profile in AAA patients with or without a TAA. METHODS: All AAA patients attending an outpatient clinic and investigated using an abdominal and thoracic computed tomography scan were included (n = 354). Image analysis and hospital chart review were conducted. The association between comorbidity and TAA was estimated by logistic regression and odds ratios (ORs) with 95% confidence intervals (CIs). Gender-specific and neutral criteria were used. Validation of excluded patients was performed. RESULTS: Ninety-four (27%) of 354 AAA patients had a concurrent descending TAA (AAA/TAA). AAA/TAA patients were older than AAA patients (76 vs. 73 years). More women were identified in the AAA/TAA group (39% vs. 16%, P < 0.001). In the univariate logistic regression model, female gender (OR: 3.3, 95% CI: 1.9-5.6), hypertension (OR: 1.8, 95% CI: 1.1-3.0), and age (70 79 years-OR: 2.4, 95% CI: 1.3-4.6; 80-89 years-OR: 3.0, 95% CI: 1.5-6.0) were associated with concurrent TAA. In the multivariate model, only female gender and age were associated with TAA. CONCLUSIONS: AAA patients, in general, should be offered examination of the thoracic aorta, and special attention needs to be paid to female AAA patients and AAA patients at high age, if the AAA patient is considered operable. Surveillance of AAA patients must improve to enhance identification of the large group of patients who have developed, or will develop, TAAs. Future strategies will, of course, address pathophysiological aspects of aneurysmal development in the thoracic and infrarenal aorta. PMID- 22944567 TI - Significance of combining distal filter protection and a guiding catheter with temporary balloon occlusion for carotid artery stenting: clinical results and evaluation of debris capture. AB - BACKGROUND: Carotid artery stenting (CAS) with distal filter protection allows for continuous cerebral perfusion. However, this procedure has been reported to be associated with a greater risk of debris migrating into the cerebral arteries. To improve the extent of debris capture, we used a guiding catheter with temporary balloon occlusion and temporary aspiration from the common carotid artery. METHODS: Eighty-one stenoses were treated with CAS using distal filter protection; simple distal filter protection (conventional group, n = 50) or distal filter protection with temporary proximal flow control and blood aspiration was performed using a 9-F guiding catheter with a temporary balloon occlusion positioned at the common carotid artery (proximal occlusion group, n = 31). Clinical outcomes, rates of capturing visible debris, and new ischemic signals on diffusion-weighted magnetic resonance imaging (DWI) were evaluated. RESULTS: Events involving procedure-related emboli causing neurological deficits occurred in 6.0% (3/50) and 3.2% (1/31) of patients in the conventional and proximal occlusion groups, respectively (P = 1.0). The rates of visible debris capture by using the distal filter were 64.0% (32/50) and 29.0% (9/31) in the convention and proximal occlusion groups, respectively, being significantly lower in the proximal occlusion group (P < 0.01). New ischemic signals on DWI were detected in 44.0% (22/50) and 12.9% (4/31) of cases in the conventional and proximal occlusion groups, respectively, being significantly lower in the proximal occlusion group (P < 0.01). CONCLUSIONS: Combining distal filter protection and a guiding catheter with temporary balloon occlusion in CAS significantly reduced visible debris captured by the distal filter and occurrence of small postprocedural cerebral infarctions detected by DWI. PMID- 22944568 TI - Common femoral artery endarterectomy for lower-extremity ischemia: evaluating the need for additional distal limb revascularization. AB - BACKGROUND: The role of common femoral artery endarterectomy (CFE) and the need for distal revascularization is challenging in certain clinical scenarios. For some patients with claudication or rest pain CFE alone may suffice, however, some surgeons advocated that in-line flow must be re-established in patients with major tissue loss for wound healing purposes. The decision when to perform CFE with or without distal revascularization is sometimes difficult. The objective of this study was to evaluate the outcomes of common femoral artery endarterectomy (CFE) to define predictive factors for additional distal revascularization. METHODS: Retrospective review of 262 consecutive CFEs in 230 patients with lower extremity ischemia between 1997 and 2008. Patients were divided into two groups: group A (n = 169; CFE alone) and group B (n = 93; CFE + distal revascularization). Concomitant iliac intervention was included only if performed by endovascular approach. Patients were analyzed by Rutherford category (RC) and TransAtlantic InterSociety Consensus (TASC) II classification. Primary end points were mortality, patency, reintervention, and limb salvage. RESULTS: Demographics, preoperative Society for Vascular Surgery score assessment, and TASC II classification did not differ between groups. Mean follow-up was 75 months (range: 1-128 months). Technical success was obtained in all patients. RC (3 +/- 1.2 vs. 5 +/- 1.4; P = 0.001), diabetes (33% vs. 52%; P = 0.005), mean operative time (+154 minutes; P < 0.001), and length of hospital stay (+1.7 days; P = 0.03) were higher in group B. Reintervention rates were higher in group B than group A (12% vs. 3%; P = 0.015). For patients with RC 5/TASC D lesions and patients with RC 6 regardless of TASC, initial distal revascularization (group B) was associated with fewer reinterventions or major amputations (29%) than CFE alone (67%) (P = 0.002). The cumulative 5-year primary patencies for groups A and group B were 96% and 92%, respectively. Secondary patency was 100% at both time points. Limb salvage was also lower in patients with RC 5 and 6 (P = 0.01; P = 0.02). Overall survival was 93% at 1 year and 77% at 5 years. Independent predictors for distal revascularization were RC 5 or 6 (P < 0.001), TASC D lesions (P < 0.0001), diabetes (P = 0.04), and being on anticoagulation (P = 0.003). There was no difference in survival between the two groups for RC 1 to 5 (P = 0.2), but for patients with RC 6, survival was improved in group B (39% vs. 67%; P = 0.9). CONCLUSION: CFE alone is sufficient for patients with lower-extremity ischemia who present with life-limiting claudication regardless of TASC lesion and for those with RC 5 and TASC lesions A to C. Patients with RC 5 and TASC D lesions and those with major tissue loss (RC 6) regardless of TASC lesion are better served with additional distal revascularization to improve limb salvage, reintervention, and survival rates. PMID- 22944569 TI - Late follow-up of saphenofemoral junction ligation combined with ultrasound guided foam sclerotherapy in patients with venous ulcers. AB - BACKGROUND: Venous ulcers are a frequent complication of venous disease, and a variety of healing methods have been proposed for these lesions. The objective of this study was to provide late follow-up data for a group of patients with venous ulcers who presented with advanced chronic venous insufficiency and were treated with saphenofemoral junction ligation combined with ultrasound-guided foam sclerotherapy. METHODS: This was a prospective study of 35 patients. Patients were classified as CEAP6 and were followed during a 45- to 68-month period. The following variables were assessed: wound healing, ultrasound findings, and venous clinical severity scores. RESULTS: The following ultrasound findings were observed: total and partial recanalization in 19 patients (treatment failure) and occlusion in 13 patients (treatment success). Two patients were lost to follow up, and one patient died. Ulcers healed between 30 and 70 days and remained closed for a mean period of 48 months (Kaplan-Meyer method). The analysis of clinical severity scores (pain, edema, pigmentation, lipodermatosclerosis, and inflammation) revealed significant improvement when comparing pre- and post treatment results. CONCLUSION: Our preliminary findings suggest that saphenofemoral junction ligation combined with ultrasound-guided foam sclerotherapy is a feasible and simple palliative treatment method for this group of patients. PMID- 22944570 TI - High glucose-induced dysfunction of endothelial cells can be restored by HoxA9EC. AB - BACKGROUND: High glucose (HG)-induced endothelial dysfunction is a common pathologic process of vascular disease in patients with diabetes. HoxA9EC is a transcriptional regulator of genes involved in the stabilization of endothelial function. We sought to elucidate the effect of HG on HoxA9EC expression in human umbilical venous endothelial cells (HUVECs), and the potential role of HoxA9EC in antagonizing HG-induced endothelial dysfunction. METHODS: HUVECs treated with HoxA9EC transfection were cultured in media with HG, and those treated either by HG or HoxA9EC knockdown were incubated without HG. These cells were then subjected to experiments including mRNA expression analysis for eNOS, VEGFR-2, and HoxA9EC by quantitative RT-PCR; protein level analysis for eNOS, VEGFR-2, and HoxA9EC by Western blot; detection of nitric oxide (NO) concentration; and migration assay. RESULTS: Expression levels of eNOS, VEGFR-2, and HoxA9EC, as well as cell migration and NO concentration, decreased rapidly in HUVECs with HoxA9EC knockdown or under HG conditions. Overexpression of HoxA9EC significantly repaired expression of eNOS and VEGFR-2, cell migration, and NO release of endothelial cells under HG conditions. CONCLUSIONS: Inhibition of HoxA9EC induced by HG contributed to endothelial cell dysfunction, which could be rescued by augmentation of HoxA9EC under HG conditions. PMID- 22944571 TI - Endovascular chimney technique of aortic arch pathologies: a systematic review. AB - BACKGROUND: The aim of this review was to determine the safety and efficacy of endovascular chimney technique for aortic arch pathologies by performing a systematic and pooled analysis of the relevant literature. METHODS: Electronic searches were performed in database Medline between 1994 and 2011 to identify studies on endovascular chimney technique for aortic arch pathology. The extracted variables and outcomes were synthesized through pooled analyses. RESULTS: Eight articles with 51 patients who underwent endovascular chimney technique for aortic arch pathologies met the inclusion criteria. Chimney grafts were deployed in innominate (n = 11), left common carotid (n = 32), and left subclavian (n = 12) arteries. Single-stent chimney in the deployed artery was used in 37 patients, whereas double-stent chimney was utilized in 14 patients. The overall technical success rate was 90.2%. The overall perioperative mortality and morbidity were 5.9% and 13.7%, respectively. The stroke rate was 7.8%, and the fatal stroke rate accounted for 50%. The rates of primary early endoleaks and type-Ia endoleaks were 21.6% and 11.8%, respectively. The overall late mortality and morbidity were 4.4% and 15.5%, respectively. Of 5 late endoleaks, no secondary type-Ia endoleak occurred. No studies had adequate follow-up to reliably evaluate the long-time durability. CONCLUSIONS: Endovascular chimney technique is technically feasible with the high initial technical success rate and relatively favorable rates of perioperative outcomes for aortic arch pathologies. However, further establishment of the role of endovascular chimney necessitates the accumulation of more cases and comparative study with other management as well as prolonged follow-up. PMID- 22944572 TI - Modification of the sandwich technique to preserve flow in the hypogastric artery after endovascular repair of aortoiliac aneurysmal disease: our initial experience with two cases. AB - BACKGROUND: To describe modification of the sandwich technique to preserve flow in the hypogastric artery after endovascular repair of aortoiliac aneurysmal disease in patients with challenging anatomy. METHODS AND RESULTS: The sandwich technique has been proposed as an option in patients with aortoiliac aneurysmal disease, in whom standard iliac branch device may not be technically feasible. We feel that even with the sandwich technique, there are issues with adequately treating these aneurysms in patients with short common iliac arteries with critical landing zones and in those with narrow-caliber external iliac arteries. We describe our experience with two patients we operated on using a modification of the originally described technique and their follow-up. CONCLUSIONS: The modification of the sandwich technique is a promising alternative technique that would be useful in situations where standard endovascular grafts cannot be used in patients with challenging anatomy. PMID- 22944573 TI - Chronic contained abdominal aortic aneurysm rupture after suprarenal fixation fatigue fracture. AB - Chronic contained rupture (CCR) of an abdominal aortic aneurysm is a rare condition, and differential diagnosis might be difficult. We present a clinical case of a hemodynamically stable octogenarian who presented with intermittent pain in the left lower abdomen. The patient had a history of diverticulitis, and 6 years ago, he had undergone endovascular abdominal aortic aneurysm repair (EVAR) with a Talent bifurcated prosthesis. Additionally, 20 days before his admission to our hospital, he had undergone a secondary iliac limb extension for treatment of post-EVAR rupture. On admission, abdominal plain radiography identified suprarenal fixation fracture as a possible reason for CCR, but computed tomographic angiography failed to confirm any endoleak or "active" bleeding and rupture. The patient received medication treatment for possible diverticulitis and was kept under close monitoring for suspected failure of recently performed secondary endovascular procedure and CCR. A day later, the abdominal pain symptoms worsened, and a new computed tomographic angiography confirmed the suspected CCR. The patient was treated successfully by "open" repair using a Y prosthesis. To our knowledge, this is the first reported case of post-EVAR CCR due to suprarenal fixation fatigue fracture. Lifelong post-EVAR follow-up with high level of both clinical and imaging diagnostic accuracy is essential for the early recognition and proper treatment of EVAR pitfalls. PMID- 22944574 TI - Primary aortoduodenal fistula supplied by type II endoleak. AB - Aortoenteric fistulas are a rare but potentially lethal condition. Here we present an unusual case of a fistula between the excluded portion of an infrarenal aneurysm repaired by stent-grafting and the duodenum. The fistula was supplied by a type II endoleak. The patient was successfully treated by extra anatomic bypass grafting and removal of the aneurysm sac and the stent-graft. PMID- 22944575 TI - Endovascular strategy for recanalization of long-segment central vein occlusion with concomitant arteriovenous fistula creation. AB - Recanalization of long-segment central vein flush occlusion in hemodialysis patients has been advocated in lieu of central vein bypass and thoracotomy to restore arteriovenous access availability. We report a challenging case of complex central venous flush occlusion in a 50-year-old woman on hemodialysis who presented with right arm and facial swelling. A concise step-by-step description of endovascular strategy with retrograde and antegrade balloon angioplasty techniques for central vein recanalization with concomitant arteriovenous fistula creation is provided. PMID- 22944576 TI - Carotid-brachial bypass and simultaneous radiocephalic fistula for a patient on hemodialysis. AB - Patients undergoing long-term hemodialysis often suffer from obliterative arterial disease, which may lead to hand ischemia and/or access failure. We present the case of a 54-year-old female patient with multiple failures in obtaining vascular access. Computed tomography angiogram revealed a long occlusion of the axillary artery. Vein mapping through duplex scanning demonstrated a suitable cephalic vein in the left forearm. A left carotid brachial bypass was performed with simultaneous radiocephalic arteriovenous fistula formation. Immediate results were excellent, and the postoperative course was uneventful. To our knowledge, this is the first report of such a combined approach. PMID- 22944577 TI - Ruptured abdominal aortic aneurysm with left-sided inferior vena cava. AB - We present a case of ruptured abdominal aortic aneurysm with left-sided inferior vena cava. An 82-year-old man was admitted to our hospital with a sudden onset of severe abdominal pain and loss of consciousness. Computed tomography revealed rupture of an infrarenal abdominal aortic aneurysm and a left-sided inferior vena cava. At surgery, the inferior vena cava was found to cross anteriorly over the abdominal aorta at the usual level of the renal vein. Graft replacement was successfully performed, with careful mobilization and retraction of the inferior vena cava. The patient had an uneventful postoperative course without any deterioration of renal function. PMID- 22944578 TI - Leiomyosarcoma of the deep femoral vein. A rare cause of venous obstruction in lower limbs and an alternative diagnosis to chronic venous thrombus. AB - Primary venous leiomyosarcoma of the extremities is an uncommon, but aggressive, tumoral entity with a high rate of local recurrence and early hematogenous metastasis. In the present article, we report a case of leiomyosarcoma of the vena profunda femoris. This pathology causes deep venous thrombosis-like symptoms. No improvement in lower limb status and a significant and progressive increase in the diameter of the vein as seen using ultrasonography could indicate tumor disease. Particular care must be taken to avoid biopsies due to the possible dissemination. We must complete the medical study with imaging techniques, and the tumor must be removed as soon as possible for histopathological diagnosis. After a follow-up of 12 months, there was no evidence of local or metastatic recurrence in our patient. PMID- 22944579 TI - Endovascular treatment of bronchial artery aneurysm with aortic stent-graft placement and coil embolization. AB - Bronchial artery aneurysm (BAA) represents a rare, but dangerous, pathology because its rupture can cause a life-threatening hemorrhage; opportune treatment is mandatory when a definite diagnosis is obtained. There are several reports of endovascular treatment of BAA with transcatheter arterial embolization and only few cases treated with aortic stent-graft exclusion. We report a case of mediastinal BAA close to thoracic aorta treated with a combined approach of stent graft occlusion of the inflow and coil embolization of the outflow arteries. PMID- 22944580 TI - Spontaneous rupture of autogenous saphenous vein graft in bypass surgery for peripheral arterial disease possibly associated with collagen disease. AB - We encountered two cases of spontaneous rupture of a saphenous vein bypass graft for lower-leg peripheral arterial disease possibly associated with collagen disease. Rupture occurred 5 and 14 days postoperatively. Neither case had any signs of infection, graft degeneration, or evident injury, but both were associated with collagen disease diagnosed at another hospital. We believe that an association with collagen disease might have contributed to vein wall fragility in the present cases. PMID- 22944581 TI - Reduced proliferation and excess astrogenesis of Pax6 heterozygous neural stem/progenitor cells. AB - Neural stem/progenitor cells (NSPCs) are generated in early embryonic brains and maintained to produce neurons and glial cells in the central nervous system throughout the lifespan. A transcription factor Pax6 is a pivotal player in various neurodevelopmental processes. Previously, we have shown that Pax6 heterozygous rodents have defects in hippocampal neurogenesis and production of olfactory bulb interneurons. However, characters of NSPCs derived from Pax6 heterozygous rodents have not been studied in vitro. Here we examined the maintenance/proliferation and differentiation of Pax6 heterozygous mutant (rSey(2)/+) rat NSPCs in the neurosphere culture system. We found that the proliferative activity of NSPCs derived from rSey(2)/+ rats was reduced after serial passages. We also observed an excess astrogenesis in serially passaged NSPCs from rSey(2)/+ rats. These results show that Pax6 is essential for maintaining NSPCs and determining their differentiation fates. PMID- 22944582 TI - Uranium quantification in semen by inductively coupled plasma mass spectrometry. AB - In this study we report uranium analysis for human semen samples. Uranium quantification was performed by inductively coupled plasma mass spectrometry. No additives, such as chymotrypsin or bovine serum albumin, were used for semen liquefaction, as they showed significant uranium content. For method validation we spiked 2g aliquots of pooled control semen at three different levels of uranium: low at 5 pg/g, medium at 50 pg/g, and high at 1000 pg/g. The detection limit was determined to be 0.8 pg/g uranium in human semen. The data reproduced within 1.4-7% RSD and spike recoveries were 97-100%. The uranium level of the unspiked, pooled control semen was 2.9 pg/g of semen (n=10). In addition six semen samples from a cohort of Veterans exposed to depleted uranium (DU) in the 1991 Gulf War were analyzed with no knowledge of their exposure history. Uranium levels in the Veterans' semen samples ranged from undetectable (<0.8 pg/g) to 3350 pg/g. This wide concentration range for uranium in semen is consistent with known differences in current DU body burdens in these individuals, some of whom have retained embedded DU fragments. PMID- 22944583 TI - Boron enhances strength and alters mineral composition of bone in rabbits fed a high energy diet. AB - An experiment was performed to determine whether boron had a beneficial effect on bone strength and composition in rabbits with apparent adiposity induced by a high energy diet. Sixty female New Zealand rabbits, aged 8 months, were randomly divided into five groups with the following treatments for seven months: control 1, fed alfalfa hay only (5.91 MJ/kg); control 2, high energy diet (11.76 MJ and 3.88 mg boron/kg); B10, high energy diet+10 mg/kg body weight boron gavage/96 h; B30, high energy diet+30 mg/kg body weight boron gavage/96 h; B50, high energy diet+50mg/kg body weight boron gavage/96 h. Bone boron concentrations were lowest in rabbits fed the high energy diet without boron supplementation, which suggested an inferior boron status. Femur maximum breaking force was highest in the B50 rabbits. Tibia compression strength was highest in B30 and B50 rabbits. All boron treatments significantly increased calcium and magnesium concentrations, and the B30 and B50 treatments increased the phosphorus concentration in tibia of rabbits fed the high energy diet. The B30 treatment significantly increased calcium, phosphorus and magnesium concentrations in femur of rabbits fed the high energy diet. Principal component analysis of the tibia minerals showed that the three boron treatments formed a separate cluster from controls. Discriminant analysis suggested that the concentrations of the minerals in femur could predict boron treatment. The findings indicate boron has beneficial effects on bone strength and mineral composition in rabbits fed a high energy diet. PMID- 22944584 TI - Short-term mercury exposure on Na(+)/K(+)-ATPase activity and ionoregulation in gill and brain of an Indian major carp, Cirrhinus mrigala. AB - Recently mercury pollution has been increased considerably in aquatic resources throughout the world and it is a growing global concern. In this study, the 96 h LC50 value of waterborne mercuric chloride for Cirrhinus mrigala was found to be 0.34 mg/L (with 95% confidence limits). Fingerlings of C. mrigala were exposed to 0.068 and 0.034 mg/L of mercuric chloride for 96 h to assess the Na(+)/K(+) ATPase activity and ionoregulation (Na(+), K(+) and Cl(-)) in gill and brain. Results showed that Na(+)/K(+)-ATPase activity and ionic levels (Na(+), K(+) and Cl(-)) in gill and brain of fish exposed to different concentrations of mercuric chloride were found to be significantly (p<0.05) decreased throughout the study period. Mercury inactivates many enzymes by attaching to sulfur atoms in which the enzyme Na(+)/K(+)-ATPase is highly sensitive to mercury. The inhibition of gill and brain Na(+)/K(+)-ATPase activity might have resulted from the physicochemical alteration of the membrane due to mercury toxicity. Moreover, inhibition of Na(+)/K(+)-ATPase may affect the ion transport and osmoregulatory function by blocking the transport of substances across the membrane by active transport. The present study indicates that the alterations in these parameters can be used in environmental biomonitoring of mercury contamination in aquatic ecosystem. PMID- 22944585 TI - Alterations in kidney tissue following zinc supplementation to STZ-induced diabetic rats. AB - Diabetes mellitus is a chronic disease characterized by anomalies forming in carbohydrate, lipid, protein metabolisms and the incidence of this disease varies widely throughout the world. Zinc is an important element which is essential for life and is present in nature. In this study, the animals were divided into four groups. These groups were named as untreated; zinc sulfate; streptozotocin (STZ); STZ and zinc sulfate. STZ (65 mg/kg) was dissolved in a freshly prepared 0.01 M pH 4.5 citrate buffer and given with intraperitoneal injection in a single dose. Zinc sulfate (100mg/kg) was dissolved in distilled water and given to the animals by gavage at a daily dose for 60 days. The rats were sacrificed under ether anesthesia. This study was aimed to investigate histological and biochemical changes of zinc supplementation on the kidney tissue in STZ-induced diabetic rats. In the current study, histological and histochemical observations showed that the occurred degenerative changes decreased after giving zinc in the kidney tissue of diabetic group. Kidney glutathione (GSH) levels decreased and lipid peroxidation (LPO), nonenzymatic glycosylation (NEG), urea and creatinine levels increased in diabetic rats. GSH levels increased, while LPO, NEG, urea and creatinine levels decreased in the kidney with administration of zinc to diabetic rats. As a result, we observed curative effects of zinc given to diabetic rats. We can say that zinc may be an important antioxidant for the treatment of secondary complications of diabetes in kidney tissue. PMID- 22944586 TI - Effect of CoCl(2) treatment on major and trace elements metabolism and protein concentration in mice. AB - Cobalt (Co) is a transition metal and an essential trace element, required for vitamin B(12) biosynthesis, enzyme activation and other biological processes, but toxic in high concentrations. There is lack of data for the effect of long-term Co(II) treatment on the concentrations of other trace elements. We estimate the influence of cobalt chloride (CoCl(2)) on the relative content of different metals in mouse plasma using two-jet arc plasmatron atomic emission and on the total protein content. On average, the content of different elements in the plasma of 2-month-old balb/c mice (control group) decreased in the order: Ca>Mg>Si>Fe>Zn>Cu>=Al>=B. The treatment of mice for 60 days with CoCl(2) (daily dose 125 mg/kg) did not appreciably change the relative content of Ca, Cu, and Zn, while a 2.4-fold statistically significant decrease in the content of B and significant increase in the content of Mg (1.4-fold), Al and Fe (2.0-fold) and Si (3.2-fold) was found. A detectable amount of Mo was observed only for two control mice, while the plasma of 9 out of 16 mice of the treated group contained this metal. The administration of Co made its concentration detectable in the plasma of all mice of the treated group, but the relative content varied significantly. The treatment led to a 2.2-fold decrease in the concentration of the total plasma protein. Chronic exposure to CoCl(2) affects homeostasis as well as the concentrations and metabolism of other essential elements, probably due to competition of Co ions for similar binding sites within cells, altered signal transduction and protein biosynthesis. Long-term treatment also leads to significant weight changes and reduces the total protein concentration. The data may be useful for an understanding of Co toxicity, its effect on the concentration of other metal ions and different physiological processes. PMID- 22944587 TI - The Hippo pathway--from top to bottom and everything in between. PMID- 22944588 TI - Total thiol redox status as a potent biomarker of PAH-mediated effects on mussels. AB - This laboratory study describes phenanthrene (Ph) and/or anthracene (An) ability to alter the total thiol redox status (TRS), via depletion of protein free thiols (PSH) and glutathione (GSH) levels, in gills of mussel Mytilus galloprovincialis, after a short-term (7 days) exposure period to each contaminant (at a final concentration of 0.1 mg L(-1)) or in a mixture (ration 1:1, at a final concentration of 0.2 mg L(-1)). A number of observable changes, like lysosomal membrane impairment (as detected via the neutral red retention time assay, primarily performed in haemocytes), enhancement of lipid peroxidation byproducts, increased nuclear abnormalities, inhibition of AChE and ALP activity, as well as a significant depletion of PSH and GSH were detected in gills of exposed mussels, in any case. Significant relationships occurred among TRS parameters with each change/stress indices measured in tissues of mussels, could reinforce the use of PSH as a potent biomarker. PMID- 22944589 TI - [Can a publicly-funded health system be built with economic assets?]. PMID- 22944590 TI - [Nurse knowledge on the prevention of nosocomial infections]. PMID- 22944591 TI - Alumina supported carbon composite material with exceptionally high defluoridation property from eggshell waste. AB - A new alumina supported carbon composite material called "Eggshell Composite" (EC) was synthesized from eggshell waste as calcium source for selective fluoride adsorption from water. The effect of various synthesis parameters like eggshell (ES): Eggshell membrane (ESM) ratio, aluminium loading, mixing time and calcinations temperature to optimize the synthesis conditions for selective fluoride removal has been studied. It was observed that the synthesis parameters have significant influence on development of EC and in turn on fluoride removal capacity. EC synthesized was characterized for elemental composition, morphology, functionality and textural properties. Results showed that EC obtained from eggshell modified with alumina precursor is more selective and efficient for fluoride removal. Langmuir and Freundlich isotherm were used to obtain ultimate fluoride removal capacity. The calcium and alumina species in EC shows synergistic effect in fluoride adsorption process. Fluoride sorption studies were carried out in synthetic, groundwater and wastewater. EC proved to be a potential, indigenous and economic adsorbent for fluoride removal. PMID- 22944592 TI - Chromatin regulators in mammalian epidermis. AB - One fundamental aspect of biological sciences is to understand how different cell fates are established during development and how cellular identity is maintained in adulthood. The molecular root of these processes is the interaction of chromatin modifications with epigenetic regulators and tissue-specific transcription factors. The concerted activities among them robustly define lineage specification, but also allow a degree of lineage flexibility required for tissue homeostasis and repair. The epidermis is emerging as an ideal model system to characterize the functional roles of epigenetic mechanisms that orchestrate organogenesis and adult tissue homeostasis. Here we summarize and discuss emerging roles of chromatin and epigenetic complexes in the mammalian epidermis. PMID- 22944593 TI - Toxicity of terpenes on fibroblast cells compared to their hemolytic potential and increase in erythrocyte membrane fluidity. AB - Terpenes are considered potent skin permeation enhancers with low toxicity. Electron paramagnetic resonance (EPR) spectroscopy of the spin label 5-doxyl stearic acid (5-DSA) was used to monitor the effect of sesquiterpene nerolidol and various monoterpenes on membrane fluidity in erythrocyte and fibroblast cells. In addition, the hemolytic levels and cytotoxic effects on cultured fibroblast cells were also measured to investigate possible relationships between the cellular irritation potentials of terpenes and the ability to modify membrane fluidity. All terpenes increased cell membrane fluidity with no significant differences between the monoterpenes, but the effect of sesquiterpene was significantly greater than that of the monoterpenes. The IC(50) values for the terpenes in the cytotoxicity assay indicated that 1,8-cineole showed lower cytotoxicity and alpha-terpineol and nerolidol showed higher cytotoxicity. The correlation between the hemolytic effect and the IC(50) values for fibroblast viability was low (R=0.61); however, in both tests, nerolidol was among the most aggressive of terpenes and 1,8-cineole was among the least aggressive. Obtaining information concerning the toxicity and potency of terpenes could aid in the design of topical formulations optimized to facilitate drug absorption for the treatment of many skin diseases. PMID- 22944594 TI - [Hamartoma of the palate: case report and review of literature]. AB - INTRODUCTION: A hamartoma is a benign tumor-like malformation, often taking the form of vascular malformation such as hemangiomas and lymphangiomas; hamartoma composed of other tissue types are much rarer in the oral cavity, exceptionally reported in the palate. We report herein a new case of palatal hamartoma. Our aim is to describe the epidemiological, clinico-pathologic and therapeutic features of this lesion. OBSERVATION: A 53-years-old woman had a painless mass located on the right hard palate, measuring 2*1.5 cm of diameter, the mass was elastic with a smooth surface. On imaging, this mass was well-circumscribed, homogenous with moderate enhancement and thinning of the bone. A surgical excision was performed. Histological examination showed an ill-defined mass composed of hyperplasic salivary gland, nerve fibers, blood vessels and adipose tissue. According to these findings, the palatal lesion was interpreted as hamartoma. CONCLUSION: The palatal hamartoma can mimic clinically a malign neoplasm; its diagnosis is histological. Its treatment is essentially surgical. The prognosis is usually favorable without recurrence. PMID- 22944595 TI - Assessing fidelity of treatment delivery in group and individual 12-step facilitation. AB - Twelve step facilitation (TSF) is an emerging, empirically supported treatment, the study of which will be strengthened by rigorous fidelity assessment. This report describes the development, reliability and concurrent validity of the Twelve Step Facilitation Adherence Competence Empathy Scale (TSF ACES), a comprehensive fidelity rating scale for group and individual TSF treatment developed for the National Drug Abuse Treatment Clinical Trials Network study, Stimulant Abuser Groups to Engage in 12-Step. Independent raters used TSF ACES to rate treatment delivery fidelity of 966 (97% of total) TSF group and individual sessions. TSF ACES summary measures assessed therapist treatment adherence, competence, proscribed behaviors, empathy and overall session performance. TSF ACES showed fair to good overall reliability; weighted kappa coefficients for 59 co-rated sessions ranged from .31 to 1.00, with a mean of .69. Reliability ratings for session summary measures were good to excellent (.69-.91). Internal consistency for the instrument was variable (.47-.71). Relationships of the TSF ACES summary measures with each other, as well as relationships of the summary measures with a measure of therapeutic alliance provided support for concurrent and convergent validity. Implications and future directions for the use of TSF ACES in clinical trials and community treatment implementation are discussed. PMID- 22944596 TI - Early pacing-induced systolic dyssynchrony is a strong predictor of left ventricular adverse remodeling: analysis from the Pacing to Avoid Cardiac Enlargement (PACE) trial. AB - BACKGROUND: Right ventricular apical (RVA) pacing is associated with adverse left ventricular (LV) remodeling and biventricular (BiV) pacing may prevent it although the mechanisms remain unclear. The current study aimed to assess the role of early pacing-induced systolic dyssynchrony (DYS) to predict adverse LV remodeling. METHODS: Patients with standard pacing indications and normal LV ejection fraction were randomized either to BiV (n=89) or RVA pacing (n=88). Pacing-induced DYS, defined as the standard deviation of the time to peak systolic velocity (Dyssynchrony Index) >33 ms in a 12-segmental model of LV, was measured by tissue Doppler echocardiography at 1 month. RESULTS: At 1 month, 59 patients (33%) had DYS which was more prevalent in RVA than BiV pacing group (52% vs. 15%, chi(2)=28.3, p<0.001), though Dyssynchrony Index was similar at baseline (30 +/- 14 vs. 26 +/- 11 ms, p=0.06). At 12 months, those developing DYS had significantly lower LV ejection fraction (55.1 +/- 9.7 vs. 62.2 +/- 7.9%, p<0.001) and larger LV end-systolic volume (35.3 +/- 14.3 vs. 27.0 +/- 10.4 ml, p<0.001) when compared to those without DYS. Reduction of ejection fraction >= 5% occurred in 67% (39 out of 58) of patients with DYS, but only in 18% (21 out of 115) in those without DYS (chi(2)=40.8, p<0.001). Both DYS at 1 month (odds ratio [OR]: 4.725, p=0.001) and RVA pacing (OR: 3.427, p=0.009) were independent predictors for reduction of ejection fraction at 12 months. CONCLUSION: Early pacing-induced DYS is a significant predictor of LV adverse remodeling and the observed benefit of BiV pacing may be related to the prevention of DYS. CLINICAL TRIAL REGISTRATION: Centre for Clinical Trials number, CUHK_CCT00037 (URL: http://www.cct.cuhk.edu.hk/Registry/publictrialrecord.aspx?trialid=CUHK_CCT00037) PMID- 22944597 TI - Expression of the antiapoptotic protein BAG3 is a feature of pancreatic adenocarcinoma and its overexpression is associated with poorer survival. AB - Pancreatic ductal adenocarcinoma (PDAC) is one of the most deadly cancers, being the fourth leading cause of cancer-related deaths. Long-term survival reaching 15% is achieved in less than 5% of patients who undergo surgery, and median survival is only 6 months in those with inoperable lesions. A deeper understanding of PDAC biologic characteristics as well as novel prognostic markers are therefore required to improve outcomes. Herein we report that BAG3, a protein with recognized anti-apoptotic activity, was expressed in 346 PDACs analyzed, but was not expressed in the surrounding nonneoplastic tissue. In a cohort of 66 patients who underwent radical resection (R0), survival was significantly shorter in patients with high BAG3 expression (median, 12 months) than in those with low BAG3 expression (median, 23 months) (P = 0.001). Furthermore, we report that BAG3 expression in PDAC-derived cell lines protects from apoptosis and confers resistance to gemcitabine, offering a partial explanation for the survival data. Our results indicate that BAG3 has a relevant role in PDAC biology, and suggest that BAG3 expression level might be a potential marker for prediction of patient outcome. PMID- 22944598 TI - Proteomic profiling of paraffin-embedded samples identifies metaplasia-specific and early-stage gastric cancer biomarkers. AB - Early diagnosis and curative resection are the predominant factors associated with increased survival in patients with gastric cancer. However, most gastric cancer cases are still diagnosed at later stages. Since most pathologic specimens are archived as FFPE samples, the ability to use them to generate expression profiles can greatly improve cancer biomarker discovery. We sought to uncover new biomarkers for stomach preneoplastic metaplasias and neoplastic lesions by generating proteome profiles using FFPE samples. We combined peptide isoelectric focusing and liquid chromatography-tandem mass spectrometry analysis to generate proteomic profiles from FFPE samples of intestinal-type gastric cancer, metaplasia, and normal mucosa. The expression patterns of selected proteins were analyzed by immunostaining first in single tissue sections from normal stomach, metaplasia, and gastric cancer and later in larger tissue array cohorts. We detected 60 proteins up-regulated and 87 proteins down-regulated during the progression from normal mucosa to metaplasia to gastric cancer. Two of the up regulated proteins, LTF and DMBT1, were validated as specific markers for spasmolytic polypeptide-expressing metaplasia and intestinal metaplasia, respectively. In cancers, significantly lower levels of DMBT1 or LTF correlated with more advanced disease and worse prognosis. Thus, proteomic profiling using FFPE samples has led to the identification of two novel markers for stomach metaplasias and gastric cancer prognosis. PMID- 22944599 TI - On the etiology of type 1 diabetes: a new animal model signifying a decisive role for bacteria eliciting an adverse innate immunity response. AB - The cause of type 1 diabetes (T1D) remains unknown; however, a decisive role for environmental factors is recognized. The increased incidence of T1D during the last decades, as well as regional differences, is paralleled by differences in the intestinal bacterial flora. A new animal model was established to test the hypothesis that bacteria entering the pancreatic ductal system could trigger beta cell destruction and to provide new insights to the immunopathology of the disease. Obtained findings were compared with those present in two patients dying at onset of T1D. Different bacterial species, present in the human duodenum, instilled into the ductal system of the pancreas in healthy rats rapidly induced cellular infiltration, consisting of mainly neutrophil polymorphonuclear cells and monocytes/macrophages, centered around the pancreatic ducts. Also, the islets of Langerhans attracted polymorphonuclear cells, possibly via release of IL-6, IL 8, and monocyte chemotactic protein 1. Small bleedings or large dilatations of the capillaries were frequently found within the islets, and several beta-cells had severe hydropic degeneration (ie, swollen cytoplasm) but with preserved nuclei. A novel rat model for the initial events in T1D is presented, revealing marked similarities with the morphologic findings obtained in patients dying at onset of T1D and signifying a decisive role for bacteria in eliciting an adverse innate immunity response. The present findings support the hypothesis that T1D is an organ-specific inflammatory disease. PMID- 22944600 TI - Tumor cell vasculogenic mimicry: from controversy to therapeutic promise. AB - In 1999, The American Journal of Pathology published an article entitled "Vascular channel formation by human melanoma cells in vivo and in vitro: vasculogenic mimicry," by Maniotis and colleagues, which ignited a spirited debate for several years and earned distinction as a citation classic. Tumor cell vasculogenic mimicry (VM) refers to the plasticity of aggressive cancer cells forming de novo vascular networks, which thereby contribute to perfusion of rapidly growing tumors, transporting fluid from leaky vessels, and/or connecting with the constitutional endothelial-lined vasculature. The tumor cells capable of VM share a plastic, transendothelial phenotype, which may be induced by hypoxia. Since VM was introduced as a novel paradigm for melanoma tumor perfusion, many studies have contributed new findings illuminating the underlying molecular pathways supporting VM in a variety of tumors, including carcinomas, sarcomas, glioblastomas, astrocytomas, and melanomas. Facilitating the functional plasticity of tumor cell VM are key proteins associated with vascular, stem cell, and hypoxia-related signaling pathways, each deserving serious consideration as potential therapeutic targets and diagnostic indicators of the aggressive, metastatic phenotype. PMID- 22944601 TI - Selective stabilization of HIF-1alpha in renal tubular cells by 2-oxoglutarate analogues. AB - The role of proximal versus distal tubular injury in the pathogenesis of acute kidney injury (AKI) is debatable. Inhibition of prolyl hydroxylases that regulate the degradation of hypoxia-inducible transcription factors (HIFs) is a promising therapeutic approach to optimize energy preservation under hypoxia and has successfully been applied to protect kidney structure and function in AKI models. Presently used prolyl hydroxylase inhibitors are lipophilic 2-oxoglutarate analogues (2OGAs) that are widely taken up in cells of most organs. Given the selective expression of organic anion transporters (OATs) in renal proximal tubular cells, we hypothesized that hydrophilic 2OGAs can specifically target proximal tubular cells. We found that cellular hydrophilic 2OGAs uptake depended on OATs and largely confined to the kidney, where it resulted in activation of HIF target genes only in proximal tubular cells. When applied in ischemia reperfusion experiments, systemically active 2OGA preserved kidney structure and function, but OAT1-transported 2OGA was not protective, suggesting that HIF stabilization in distal tubular rather than proximal tubular cells and/or nontubular cells mediates protective effects. This study provides proof of concept for selective drug targeting of proximal tubular cells on the basis of specific transporters, gives insights into the role of different nephron segments in AKI pathophysiology, and may offer options for long-term HIF stabilization in proximal tubules without confounding effects of erythropoietin induction in peritubular cells and unwarranted extrarenal effects. PMID- 22944602 TI - Role of the phosphatidylinositol 3-kinase and extracellular signal-regulated kinase pathways in the neuroprotective effects of cilnidipine against hypoxia in a primary culture of cortical neurons. AB - Cilnidipine, a calcium channel blocker, has been reported to have neuroprotective effects. We investigated whether cilnidipine could protect neurons from hypoxia and explored the role of the phosphatidylinositol 3-kinase (PI3K) and extracellular signal-related kinase (ERK) pathways in the neuroprotective effect of cilnidipine. The viability of a primary culture of cortical neurons injured by hypoxia, measured by trypan blue staining and lactate dehydrogenase (LDH) assay, was dramatically restored by cilnidipine treatment. TUNEL and DAPI staining showed that cilnidipine significantly reduced apoptotic cell death induced by hypoxia. Free radical stress and calcium influx induced by hypoxia were markedly decreased by treatment with cilnidipine. Survival signaling proteins associated with the PI3K and ERK pathways were significantly increased while death signaling proteins were markedly decreased in the primary culture of cortical neurons simultaneously exposed to cilnidipine and hypoxia when compared with the neurons exposed only to hypoxia. These neuroprotective effects of cilnidipine were blocked by treatment with a PI3K inhibitor or an ERK inhibitor. These results show that cilnidipine protects primary cultured cortical neurons from hypoxia by reducing free radical stress, calcium influx, and death-related signaling proteins and by increasing survival-related proteins associated with the PI3K and ERK pathways, and that activation of those pathways plays an important role in the neuroprotective effects of cilnidipine against hypoxia. These findings suggest that cilnidipine has neuroprotective effects against hypoxia through various mechanisms, as well as a blood pressure-lowering effect, which might help to prevent ischemic stroke and reduce neuronal injury caused by ischemic stroke. PMID- 22944603 TI - Functional expression of carnitine/organic cation transporter OCTN1 in mouse brain neurons: possible involvement in neuronal differentiation. AB - The aim of the present study is to clarify the functional expression and physiological role in brain neurons of carnitine/organic cation transporter OCTN1/SLC22A4, which accepts the naturally occurring antioxidant ergothioneine (ERGO) as a substrate in vivo. After intracerebroventricular administration, the distribution of [(3)H]ERGO in several brain regions of octn1(-/-) mice was much lower than that in wild-type mice, whereas extracellular marker [(14)C]mannitol exhibited similar distribution in the two strains. The [(3)H]ERGO distribution in wild-type mice was well correlated with the amount of ERGO derived from food intake and the OCTN1 mRNA level in each brain region. Immunohistochemical analysis revealed colocalization of OCTN1 with neuronal cell markers microtubule associated protein 2 (MAP2) and betaIII-tubulin in mouse brain and primary cultured cortical neurons, respectively. Moreover, cultured cortical neurons exhibited time-dependent and saturable uptake of [(3)H]ERGO. These results demonstrate that OCTN1 is functionally expressed in brain neurons. The addition of ERGO simultaneously with serum to culture medium of cortical neurons attenuated mRNA and protein expressions of MAP2, betaIII-tubulin and synapse formation marker synapsin I, and induced those of sex determining region Y-box 2 (Sox2), which is required to maintain the properties of undifferentiated neural stem cells. In neuronal model Neuro2a cells, knockdown of OCTN1 by siRNA reduced the uptake of [(3)H]ERGO with concomitant up-regulation of oxidative stress marker HO-1 and Sox2, and down-regulation of neurite outgrowth marker GAP43. Interestingly, the siRNA knockdown decreased the number of differentiated Neuro2a cells showing long neurites, but increased the total number of cells. Thus, OCTN1 is involved in cellular differentiation, but inhibits their proliferation, possibly via the regulation of cellular oxidative stress. This is the first evidence that OCTN1 plays a role in neuronal differentiation and proliferation, which are required for brain development. PMID- 22944604 TI - Non-invasive ventilation in immunosuppressed patients with pneumonia and extrapulmonary sepsis. AB - PURPOSE: International guidelines recommend the use of noninvasive ventilation in immunocompromised patients with acute respiratory failure (ARF). We analyzed failure rates and risk factors for NIV failure in immunocompromised patients. METHODS: We retrospectively analyzed 120 immunodeficient patients treated with NIV in our medical ICU from 2005 to 2011. We compared the clinical course and NIV failure rates. Furthermore, we compared patients with secondary respiratory failure due to those with Systemic Inflammatory Response Syndrome (SIRS) of other than pulmonary origin to those with primary pulmonary infiltrations. RESULTS: Regression analyses revealed high APACHE II score (p < 0.01), need for catecholamines (p < 0.05) and low paO(2)/FIO(2) ratio (p < 0.05) as risk factors for NIV failure. Regarding the underlying diseases, we could not find differences in NIV duration (p = 0.07) and outcome (p = 0.44). 59.2% suffered from ARF due to lung infiltrations whereas 40.8% had secondary ARF caused by sepsis of extrapulmonary origin. Patients with lung infiltrations had a longer stay on ICU (16.3 vs 13.2 days; p = 0.047) and showed a trend toward longer NIV duration (87 +/- 102 h vs 65.6 +/- 97.8 h; p = 0.056). The SIRS patients compared to pneumonia patients showed a trend toward higher serum creatinine (1.63 mg/dL to 1.51 mg/dL; p = 0.059), a higher rate of renal failure (p < 0.01), higher APACHE II score (30.6-25.7, p < 0.01) and more frequently needed catecholamines (p < 0.01). NIV failure rate (overall 55%) was not different. CONCLUSIONS: Almost 50% of the immunocompromised patients treated with NIV did not require intubation independent of the etiology of ARF. High APACHE II scores and severity of oxygenation failure were associated with NIV failure. PMID- 22944605 TI - Peer influence and selection processes in adolescent smoking behavior: a comparative study. AB - INTRODUCTION: Adolescent smoking studies find evidence of active peer influence and selection processes. However, studies have shown that these processes operate differently depending on context. This study uses SIENA to model coevolutionary processes between smoking and changes in friendship ties, comparing two high schools in which data were collected in identical fashion to explore influence and selection mechanisms with respect to current smoking, and smoking levels. METHODS: This is a longitudinal survey with 2 waves of data. In-home surveys were conducted with students from 2 large high schools in the United States: a West Coast school, and a Midwestern school. Participants were consented students in 10th and 11th grades at the first wave of data collection. The primary measures were self-reported smoking behavior and friendship nominations. RESULTS: There is evidence of influence and selection in both schools for adolescents' smoking status (1 = any smoking) and for level of smoking. CONCLUSIONS: These models reflect great similarities in influence and selection processes across schools for different smoking behaviors. However, smoking prevalence may impact the exact mechanisms by which influence and selection operate. Researchers should consider smoking interventions with independent modules addressing different selection and influence processes, implemented based on contextual factors such as the prevalence of smoking. PMID- 22944606 TI - Increased variability of bone tissue mineral density resulting from estrogen deficiency influences creep behavior in a rat vertebral body. AB - Progressive vertebral deformation increases the fracture risk of a vertebral body in the postmenopausal patient. Many studies have observed that bone can demonstrate creep behavior, defined as continued time-dependent deformation even when mechanical loading is held constant. Creep is a characteristic of viscoelastic behavior, which is common in biological materials. We hypothesized that estrogen deficiency-dependent alteration of the mineral distribution of bone at the tissue level could influence the progressive postmenopausal vertebral deformity that is observed as the creep response at the organ level. The objective of this study was thus to examine whether the creep behavior of vertebral bone is changed by estrogen deficiency, and to determine which bone property parameters are responsible for the creep response of vertebral bone at physiological loading levels using an ovariectomized (OVX) rat model. Correlations of creep parameters with bone mineral density (BMD), tissue mineral density (TMD) and architectural parameters of both OVX and sham surgery vertebral bone were tested. As the vertebral creep was not fully recovered during the post creep unloading period, there was substantial residual displacement for both the sham and OVX groups. A strong positive correlation between loading creep and residual displacement was found (r=0.868, p<0.001). Of the various parameters studied, TMD variability was the parameter that best predicted the creep behavior of the OVX group (p<0.038). The current results indicated that creep caused progressive, permanent reduction in vertebral height for both the sham and OVX groups. In addition, estrogen deficiency-induced active bone remodeling increased variability of trabecular TMD in the OVX group. Taken together, these results suggest that increased variability of trabecular TMD resulting from high bone turnover influences creep behavior of the OVX vertebrae. PMID- 22944608 TI - STIM1 and Orai1 mediate thrombin-induced Ca(2+) influx in rat cortical astrocytes. AB - In astrocytes, thrombin leads to cytoplasmic Ca(2+) elevations modulating a variety of cytoprotective and cytotoxic responses. Astrocytes respond to thrombin stimulation with a biphasic Ca(2+) increase generated by an interplay between ER Ca(2+) release and store-operated Ca(2+) entry (SOCE). In many cell types, STIM1 and Orai1 have been demonstrated to be central components of SOCE. STIM1 senses the ER-Ca(2+) depletion and binds Orai1 to activate Ca(2+) influx. Here we used immunocytochemistry, overexpression and siRNA assays to investigate the role of STIM1 and Orai1 in the thrombin-induced Ca(2+) response in primary cultures of rat cortical astrocytes. We found that STIM1 and Orai1 are endogenously expressed in cortical astrocytes and distribute accordingly with other mammalian cells. Importantly, native and overexpressed STIM1 reorganized in puncta under thrombin stimulation and this reorganization was reversible. In addition, the overexpression of STIM1 and Orai1 increased by twofold the Ca(2+) influx evoked by thrombin, while knockdown of endogenous STIM1 and Orai1 significantly decreased this Ca(2+) influx. These results indicate that STIM1 and Orai1 underlie an important fraction of the Ca(2+) response that astrocytes exhibit in the presence of thrombin. Thrombin stimulation in astrocytes leads to ER-Ca(2+) release which causes STIM1 reorganization allowing the activation of Orai1 and the subsequent Ca(2+) influx. PMID- 22944607 TI - Body size and pubertal development explain ethnic differences in structural geometry at the femur in Asian, Hispanic, and white early adolescent girls living in the U.S. AB - Variation in structural geometry is present in adulthood, but when this variation arises and what influences this variation prior to adulthood remains poorly understood. Ethnicity is commonly the focus of research of skeletal integrity and appears to explain some of the variation in quantification of bone tissue. However, why ethnicity explains variation in skeletal integrity is unclear. METHODS: Here we examine predictors of bone cross sectional area (CSA) and section modulus (Z), measured using dual-energy X-ray absorptiometry (DXA) and the Advanced Hip Analysis (AHA) program at the narrow neck of the femur in adolescent (9-14 years) girls (n=479) living in the United States who were classified as Asian, Hispanic, or white if the subject was 75% of a given group based on parental reported ethnicity. Protocols for measuring height and weight follow standardized procedures. Total body lean mass (LM) and total body fat mass (FM) were quantified in kilograms using DXA. Total dietary and total dairy calcium intakes from the previous month were estimated by the use of an electronic semi-quantitative food frequency questionnaire (eFFQ). Physical activity was estimated for the previous year by a validated self-administered modifiable activity questionnaire for adolescents with energy expenditure calculated from the metabolic equivalent (MET) values from the Compendium of Physical Activities. Multiple regression models were developed to predict CSA and Z. RESULTS: Age, time from menarche, total body lean mass (LM), total body fat mass (FM), height, total calcium, and total dairy calcium all shared a significant (p<0.05), positive relationship with CSA. Age, time from menarche, LM, FM, and height shared significant (p<0.05), positive relationships with Z. For both CSA and Z, LM was the most important covariate. Physical activity was not a significant predictor of geometry at the femoral neck (p>=0.339), even after removing LM as a covariate. After adjusting for covariates, ethnicity was not a significant predictor in regression models for CSA and Z. CONCLUSION: Variability in bone geometry at the narrow neck of the femur is best explained by body size and pubertal maturation. After controlling for these covariates there were no differences in bone geometry between ethnic groups. PMID- 22944609 TI - High-content multiplexed tissue imaging and quantification for cancer drug discovery. AB - Targeting multiple hallmarks of cancer with drug combinations may provide unique opportunities for cancer therapeutics; however, phenotypic quantification is necessary to understand in vivo mechanisms of action of each drug alone or in combination. Immunohistochemistry (IHC) can quantify phenotypic changes, but traditional methods are not amenable for high-throughput drug discovery. In this article, we describe a high-content method to quantify changes in tumor angiogenesis, vascular normalization, hypoxia, tumor cell proliferation, and apoptosis using IHC. This method to quantify tumor model phenotypes can be useful for cancer drug discovery by increasing the understanding of: (i) tumor models used in efficacy studies, (ii) changes occurring during the growth of the tumor, and (iii) novel mechanisms of actions of cancer therapeutics. PMID- 22944610 TI - Pharmaceutical treatment patterns for patients with a diagnosis related to chronic pain initiating a slow-release strong opioid treatment in Sweden. AB - Slow-release strong opioids (SRSO) are indicated in patients with severe chronic pain. Side effects, lack of efficacy and risk of dependency limit their use in clinical practice. The aim of this study was to explore prescription patterns of SRSO in Swedish real-world data on patients with a diagnosis related to chronic pain (DRCP). Patient-level data were extracted from the national prescriptions register and a regional register with diagnosis codes. The prescription sequences, switches, co-medications, and strengths over time were analyzed for cancer and noncancer patients. Of 840,000 patients with a DRCP, 16,257 initiated treatment with an SRSO in 2007 to 2008. They were 71 years old on average; 60% were female and 34% had cancer. The most common first prescription was oxycodone (54%) followed by fentanyl (19%), buprenorphine (14%), and morphine (13%). 63% refilled their prescription within 6 months, and 12% switched to another SRSO, most commonly fentanyl. After 3 years, 51% of cancer and 27% of noncancer patients still being in contact with health care remained on any SRSO. Of noncancer patients, 35% had a psychiatric co-medication (SSRI or benzodiazepine). In conclusion, fewer patients remain on SRSO in the long-term in clinical practice than reported in previous clinical trials. Oxycodone is the most common first SRSO prescription and one-third of patients get a prescription indicating psychiatric comorbidity. Our interpretation of these findings are that there is need for better treatment options for these patients, and that more effort is needed to improve treatment guidelines and to ascertain that these guidelines are followed. PMID- 22944611 TI - Recording odor-evoked response potentials at the human olfactory epithelium. AB - Electro-olfactogram (EOG) represents the sum of generator potentials of olfactory receptor neurons in response to an olfactory stimulus. Although this measurement technique has been used extensively in animal research, its use in human olfaction research has been relatively limited. To understand the promises and limitations of this technique, this review provides an overview of the olfactory epithelium structure and function, and summarizes EOG characteristics and conventions. It describes methodological pitfalls and their possible solutions, artifacts, and questions of debate in the field. In summary, EOG measurements provide a rare opportunity of recording neuronal input from the peripheral olfactory system, while simultaneously obtaining psychophysical responses in awake humans. PMID- 22944612 TI - Effect of acute stress on taste perception: in relation with baseline anxiety level and body weight. AB - We aimed to determine the effect of acute stress on taste perception and its modulation in relation to body weight and baseline anxiety in this study. The anxiety of the participants, randomly allocated to stress (n = 35) or control (n = 16) groups, was assessed by State Trait Anxiety Inventory. Stroop color-word interference and cold pressor tests were applied as stress protocol. Glucose and salt taste detection thresholds were evaluated before and after the stress protocol in the stress group and corresponding times in the control group. Stress protocol increased heart rate and blood pressure as an indicator of stress system activation. Following stress glucose and salt thresholds decreased in the stress group, unchanged in the control group. Prestress salt thresholds were positively and decrements in salt thresholds were negatively correlated with trait anxiety scores of participants. The state anxiety levels of stress group positively correlated with the decrease in glucose thresholds. Waist-to-hip ratio was negatively correlated with prestress salt thresholds of the subjects. Our results revealed that thresholds for sweet and salty tastes are modulated during stressful conditions. Our data also demonstrated a relationship between taste perception and baseline anxiety levels of healthy individuals, which may be important to understand the appetite alterations in individuals under stressful conditions. PMID- 22944613 TI - The molecular receptive range of a lactone receptor in Anopheles gambiae. AB - In an environment filled with a complex spectrum of chemical stimuli, insects rely on the specificity of odorant receptors (ORs) to discern odorants of ecological importance. In nature, cyclic esters, or lactones, represent a common class of semiochemicals that exhibit a range of diversity through ring size and substituents, as well as stereochemistry. We have used heterologous expression to explore the lactone sensitivity of AgOr48, an odorant-sensitive OR from the principal malaria vector mosquito, Anopheles gambiae. Voltage clamp and calcium imaging experiments revealed that AgOr48 is particularly sensitive to changes in the size of the lactone ring and in the length of the carbon chain substituent. In addition, the two enantiomers of a strong agonist, delta-decalactone, elicited significantly different potency values, implicating AgOr48 as an enantioselective odorant receptor. Investigation of the molecular receptive range of this lactone receptor may contribute to a greater understanding of ligand-OR interactions and provide insight into the chemical ecology of An. gambiae. PMID- 22944614 TI - Assessment of the interoceptive effects of alcohol in rats using short-term training procedures. AB - In the present study, we sought to determine whether the interoceptive effects of alcohol (1 g/kg, IG) could be assessed using a Pavlovian discrimination method, in which the alcohol drug state sets the occasion for which an environmental stimulus (e.g., light) will be followed by a sucrose reward. This procedure takes advantage of a naturally occurring behavior (i.e., food-seeking) which can be trained rapidly prior to the initiation of discrimination training. Given that the interoceptive effects of alcohol are routinely assessed using operant drug discrimination methods, another group of rats was trained using standard two lever operant drug discrimination procedures in an effort to compare the Pavlovian procedure to a known behavioral benchmark. The results from this work show that, in addition to operant discrimination procedures, a Pavlovian discrimination task can be used to evaluate the interoceptive effects of alcohol. In addition to the brief behavioral sucrose access training (3 days) required prior to the initiation of the Pavlovian discrimination, the alcohol discrimination was acquired relatively rapidly (i.e., 8 training sessions), shortening the overall duration of the experiment. These features of the Pavlovian procedure make it a valuable method by which to assess the interoceptive effects of alcohol if a short experimental time frame is required, such as assessing the interoceptive effects of alcohol during a brief developmental window (e.g., adolescence) or determining the effects of a pretreatment (i.e., chronic stress, chronic drug pretreatment) on the acquisition of the alcohol discrimination. As such, this initial characterization confirms the feasibility of using this Pavlovian discrimination training method as an additional tool by which to assess the interoceptive effects of alcohol, as there may be experimental situations that necessitate short term discrimination training. PMID- 22944615 TI - Acute and chronic ethanol intake: effects on spatial and non-spatial memory in rats. AB - Abusive alcohol consumption produces neuronal damage and biochemical alterations in the mammal brain followed by cognitive disturbances. In this work rats receiving chronic and acute alcohol intake were evaluated in a spontaneous delayed non-matching to sample/position test. Chronic alcohol-treated rats had free access to an aqueous ethanol solution as the only available liquid source from the postnatal day 21 to the end of experiment (postnatal day 90). Acute alcoholic animals received an injection of 2 g/kg ethanol solution once per week. Subjects were evaluated in two tests (object recognition and spatial recognition) based on the spontaneous delayed non-matching to sample or to position paradigm using delays of 1 min, 15 min and 60 min. Results showed that chronic and acute alcohol intake impairs the rats' performance in both tests. Moreover, chronic alcohol-treated rats were more altered than acute treated animals in both tasks. Our results support the idea that chronic and acute alcohol administration during postnatal development caused widespread brain damage resulting in behavioral disturbances and learning disabilities. PMID- 22944616 TI - The Wasp System: an open source environment for managing and analyzing genomic data. AB - The challenges associated with the management, analysis and interpretation of assays based on massively-parallel sequencing (MPS) are both individually complex and numerous. We describe what we believe to be the appropriate solution, one that represents a departure from traditional computational biology approaches. The Wasp System is an open source, distributed package written in Spring/J2EE that creates a foundation for development of an end-to-end solution for MPS-based experiments or clinical tests. Recognizing that one group will be unable to solve these challenges in isolation, we describe a nurtured open source development model that will allow the software to be collectively used, shared and developed. The ultimate goal is to emulate resources such as the Virtual Observatory of the astrophysics community, enabling computationally-inexpert scientists and clinicians to explore and interpret their MPS data. Here we describe the current implementation and development of the Wasp System and the roadmap for its community development. PMID- 22944617 TI - Novel protein scaffolds as emerging therapeutic proteins: from discovery to clinical proof-of-concept. AB - Recent advances in combinatorial protein engineering have made it possible to develop immunoglobulin (Ig)-based and non-Ig protein scaffolds that can potentially substitute for most whole antibody-associated properties and currently translate into biologicals with drug-like properties. During the past 10 years, the most validated scaffolds have reached the clinical development phase and, recently, one of them [Kalbitor((r)) (Dyax)] has made it to the market, making these alternative scaffold proteins viable drug candidates in a post-antibody landscape. Interestingly, several scaffolds include an immune active component as part of their therapeutic mode of action, which yielded spectacular clinical efficacy in some hematological malignancies. Here, we review the most recent clinical advances and analyze their benefits for patients. PMID- 22944618 TI - [Geriatrics now]. PMID- 22944619 TI - [Markers of prodromal Alzheimer's disease]. AB - The diagnosis of Alzheimer's disease has long been considered a diagnosis of probability, as the definitive diagnosis can only be established by histopathological examination. However, the development of in-vivo biomarkers, considered a reflection of physiopathological processes, has changed our view of the disease. New criteria have recently been proposed that integrate such biomarkers as found in the cerebrospinal fluid (CSF) using new diagnostic tools such as magnetic resonance imaging (MRI), brain scintigraphy, FDG-positron emission tomography (PET) and PET amyloid ligand uptake studies. The value of these new criteria for the diagnosis of prodromal Alzheimer's disease and the prospect of disease-modifying drugs are also discussed. PMID- 22944620 TI - [Apathy neural bases in neurodegenerative disorders]. AB - Apathy is widely recognized as a lack of motivation, which expresses through the cognitive, behavioral and emotional dimensions of living. It is described within several neuropsychiatric syndromes such as degenerative disorder and is associated with poorer outcomes. In order to better understand the underpinnings of apathy and to develop specific treatment strategies, much research has been conducted to define its neural bases. In the present review, perfusion, metabolic, pathologic and functional results of apathy neural bases in Alzheimer's and Parkinson's diseases are displayed. Methods and strategies to control for confounding factors such as depression, cognitive impairments and other behavioral disorders are described. Results are not strictly identical between disorders and even within disorders. Variation of methods employed on assessment tools and control for confounding factors such as cognitive disorders, depression, other behavioral disorders and medical treatment is thought to be the main reason for this discrepancy. However, it seems that the inferior prefrontal cortex, especially the orbitofrontal cortex, the lateral prefrontal cortex and the anterior cingulate are of particular interest. The second part of the review discusses the literature in these three areas in conditional learning essentially via the reward characteristic encoding, auto-initiated and perseverance behaviors and emotional experience and its regulation. PMID- 22944621 TI - Gene of the month: BRAF. PMID- 22944622 TI - Management of myelofibrosis: a survey of current practice in the United Kingdom. AB - AIMS: To investigate the experience of clinicians in the management of patients with myelofibrosis, current treatment options and their utility. METHODS: We used an internet-based survey RESULTS: Of 105 respondents (mostly consultants), 79% identified bothersome symptoms as the most common issue to be addressed, while for 19%, lack of efficacy of treatment fell into this category. The survey found that a wide variety of treatments are employed but with poor perceived efficacy. CONCLUSIONS: This is the first UK based assessment of management of myelofibrosis. Perspectives may evolve with the inception of novel therapeutics in this field , but clinical guidelines for effective management currently recommend a wide variety of agents and suggest a limited likely success rate. PMID- 22944623 TI - Cortactin is associated with tumour progression and poor prognosis in prostate cancer and SIRT2 other than HADC6 may work as facilitator in situ. AB - OBJECTIVE: Cortactin acts as a prominent substrate of histone deacetylases (HDACs) and plays important roles in tumour progression in several human cancers. However, the clinical significance of its expression in human prostate cancer (PCa) has not been determined. We aimed to identify the potential role of cortactin expression in tumour progression and prognosis in PCa and the association with HDACs. METHODS: 256 foci with distinctive lesions in 110 prostate specimens were collected to identify the status of among cortactin, SIRT2, histone deacetylase 6 (HDAC6) by immunohistochemistry and its relationship with clinicopathological and follow-up data were analysed. RESULTS: The results showed that cortactin expression was significantly higher (79.1%), and SIRT2 expression was lower (37.3%) in PCa foci, when it was compared with high-grade prostatic intraepithelial neoplasia foci and benign foci, respectively. HDAC6 expression was low and had no statistical significance in PCa. High intensity of cortactin staining was significantly and independently associated with a high prostate-specific antigen (PSA) level, high Gleason score, clinical stage progression and shortened survival time in patients with PCa. High intensity of SIRT2 staining was significantly and independently associated with a high PSA level, old age, high Gleason score and clinical stage progression. Multivariable Cox regression analysis showed cortactin expression was a significant prognostic factor for survival of patients with PCa (beta, 0.736; 95% CI 1.371 to 3.181; p=0.001). CONCLUSIONS: The results suggested that cortactin seems to be a satisfactory marker to predict tumour progression and survival in cases of PCa. And it may be SIRT2 rather than HADAC6 is responsible for tumour occurrence and the progression of PCa. PMID- 22944624 TI - Arrhythmogenic right ventricular cardiomyopathy: severe structural alterations are associated with inflammation. AB - AIM: Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC) is a rare cardiomyopathy associated with sudden cardiac death. It is characterised by a progressive right ventricle (RV) fibrofatty replacement, although biventricular replacement (BV) is also common. Inflammation believed to be a key player in disease progression and outcome. Our study investigates the relationship between the presence of inflammatory infiltrates in myocardium and the severity of structural heart alterations in ARVC. METHODS: Our study included eight control and 36 ARVC postmortem human heart samples. We performed macroscopic assessment and microscopic analysis for different inflammatory cell types. RESULTS: Fibrofatty replacement of RV was present in all our cases. Thirteen cases showed sole RV involvement (36.11%). Of these, only one showed inflammatory infiltrates (7.69%). Sixteen cases showed severe ARVC phenotypic forms characterised by BV involvement and right auricular (RA) fatty accumulation plus RV dilation (44.44%); eight of them also showed inflammatory infiltrates (50%). Immunohistochemical studies revealed ventricular multifocal inflammatory infiltrates, showing seven T-lymphocytes as the main infiltrate cell types. CONCLUSIONS: The presence of inflammatory infiltrates in ventricular myocardium of ARVC samples is associated with severe structural heart changes, indicating that an inflammatory process may be a modulator of severity in ARVC. PMID- 22944625 TI - Reappraisal of immunohistochemical profiling of special histological types of breast carcinomas: a study of 121 cases of eight different subtypes. AB - Histological special types (HST) account for about 25% of breast cancers, and correspond to at least 17 pathological entities. However, their molecular characteristics remain to be determined. The purpose of the present study is to apply the recently used immunohistochemical profiling of HST breast carcinomas (BC), as a surrogate for the molecular subtyping, what could be relevant for therapeutic purposes. One hundred and twenty-one cases were included. Immunohistochemical study was performed on paraffin sections, including markers for oestrogen, progesterone and androgen receptors, keratin 5, HER2/neu, epithelial growth factor receptor, p63 protein, P-cadherin, and Ki-67. Tubular (16 cases), mucinous (27) and papillary (9) types were all categorised as luminal like A and B. The medullary (21) and metaplastic (10) types corresponded largely to the basal-like tumours (85.7% and 90%, respectively). Cases of the micropapillary type (8) were luminal A (3/8), luminal B (4/8) and HER2 overexpressing (1/8), whereas the apocrine carcinomas (24) presented a heterogeneous profile. The proliferation rate (Ki-67) varied among the types, being the medullary carcinoma subtype with higher proliferation. Comparing the current data with those based on molecular studies, there was good agreement in the classification of the tubular, mucinous and papillary types. Only a partial concordance was achieved for the other types, which may be due to sampling, and to the relatively low frequency of such cases. The present work supports the clinical usage of immunohistochemistry as a surrogate to molecular classification of special types of BC. PMID- 22944626 TI - Measuring bovine viral diarrhea virus vaccine response: using a commercially available ELISA as a surrogate for serum neutralization assays. AB - Genetic selection in livestock offers the opportunity to improve bovine viral diarrhea virus (BVDV) vaccine response, but first we must define how vaccine response should be measured. For measuring humoral vaccine response, serum neutralization (SN) measures antibodies that can neutralize BVDV, but relative to enzyme-linked immunosorbent assay (ELISA) is time consuming, technically demanding, and expensive. The ELISA, however, measures total BVDV-specific antibodies, regardless of whether the antibodies can neutralize BVDV. Our objective was to test whether a commercially available BVDV antibody ELISA could be used as a surrogate (or indicator trait) for neutralizing antibodies as measured by SN. Angus and Angus-cross calves (n=193) from two South Dakota research herds were vaccinated for BVDV-1 and BVDV-2. Sera and plasma samples (n=406) were collected from these calves at the time of vaccination and post vaccination (20-72 days post-vaccination). The BVDV-specific antibody concentration was measured on each serum and plasma sample by (1) a commercially available total antibody ELISA, (2) BVDV-1 SN, and (3) BVDV-2 SN. Correlation between the ELISA and SN tests was estimated with a Spearman correlation coefficient. Higher BVDV ELISA sample-to-positive (S/P) ratios were positively correlated with higher BVDV-1 (rho=0.809) and BVDV-2 (rho=0.638) SN titers (P<0.0001), although the relationship was weaker when SN titers were <1:64. Higher BVDV-1 SN titers were also positively correlated with higher BVDV-2 SN titers (rho=0.708; P<0.0001). The correlation between ELISA S/P ratios and SN titers was lower when calves were <=2 months of age (rho=0.344-0.566). Our results suggest that increased ELISA S/P ratios were associated with higher SN titers. We conclude that this BVDV antibody ELISA can be used as a surrogate for BVDV-1 and -2 SN titers when investigating genetic determinants of vaccine response, as long as samples are collected at 2 months of age or older. PMID- 22944627 TI - HLA-DR specific monoclonal antibodies block lymphoproliferative response to measles vaccine in vitro: a pilot study. AB - Humoral and cell-mediated immune responses are important in protection against measles. Non-response to vaccination has been associated with specific HLA-DR and HLA-DQ alleles; however, little is known about the relative importance of these alleles in the cellular immune response induced by measles virus vaccine. To investigate the role of HLA-DR/DQ class II restriction, a small pilot study was conducted. Lymphoproliferation assays using class II DR and DQ-specific monoclonal antibodies (MoAb) were performed at one week and two weeks post immunization with MMRII vaccine. The mean stimulation index (SI) was 4.4 and 5.3 at one and two weeks with reductions in SI of 47.6% and 70.2%, respectively, following the addition of DR-specific MoAb (p<0.001). These results clearly show that a significant proportion of the cell-mediated immune response to measles virus vaccine, as measured by SI, is HLA-DR restricted. PMID- 22944628 TI - Strain impact on equine herpesvirus type 1 (EHV-1) abortion models: viral loads in fetal and placental tissues and foals. AB - Equine herpesvirus-1 (EHV-1) continues to cause both sporadic and epidemic abortions despite extensive vaccination. Lack of progress in the development of protective vaccines may be hindered by the lack of equine abortion models that employ contemporary EHV-1 strains. The objective of our experiments was to compare a contemporary EHV-1 strain with a previously described challenge strain, and to quantify EHV-1 loads in various maternal and fetal tissues. Infection experiments were performed in two groups of 7 pregnant pony mares at 270-290 days of gestation with a contemporary EHV-1 strain (University of Findlay 2003 isolate - OH03) or an EHV-1 strain isolated over 30 years ago, and previously described in abortion models (Ab4). All mares in both groups exhibited nasal viral shedding and viremia. Infection with OH03 resulted in 1/7 abortion and infection with Ab4 resulted in 5/7 abortions. In the OH03 challenge, placentas of foals delivered at term showed little detectable virus, while the aborted fetus expressed high levels of virus infection in the spleen and liver, lower levels in the lung and thymus, and lowest levels in the chorioallantois. After Ab4 challenge, high viral loads were detected in fetal and placental tissues in abortions. In the two normal deliveries, the chorioallantois contained virus levels comparable with the chorioallantois of aborted foals and both foals shed EHV-1 starting on day 4 of life, but were clinically healthy. Our results demonstrate the continued importance of strain selection for abortion models, and this study is the first report of viral load quantification using contemporary methods. Extremely high EHV-1 loads in decidua from abortions illustrate the infection risk posed to other horses. PMID- 22944629 TI - Distinguishing vaccine efficacy and effectiveness. AB - BACKGROUND: Mathematical models of disease transmission and vaccination typically assume that protective vaccine efficacy (i.e. the relative reduction in the transmission rate among vaccinated individuals) is equivalent to direct effectiveness of vaccine. This assumption has not been evaluated. METHODS: We used dynamic epidemiological models of influenza and measles vaccines to evaluate the common measures of vaccine effectiveness in terms of both the protection of individuals and disease control within populations. We determined how vaccine mediated reductions in attack rates translate into vaccine efficacy as well as into the common population measures of 'direct', 'indirect', 'total', and 'overall' effects of vaccination with examples of compartmental models of influenza and measles vaccination. RESULTS: We found that the typical parameterization of vaccine efficacy using direct effectiveness of vaccine can lead to the underestimation of the impact of vaccine. Such underestimation occurs when the vaccine is assumed to offer partial protection to every vaccinated person, and becomes worse when the level of vaccine coverage is low. Nevertheless, estimates of 'total', 'indirect' and 'overall' effectiveness increase with vaccination coverage in the population. Furthermore, we show how the measures of vaccine efficacy and vaccine effectiveness can be correctly calculated. CONCLUSIONS: Typical parameterization of vaccine efficacy in mathematical models may underestimate the actual protective effect of the vaccine, resulting in discordance between the actual effects of vaccination at the population level and predictions made by models. This work shows how models can be correctly parameterized from clinical trial data. PMID- 22944630 TI - Comparative proteome and transcriptome analyses of wild-type and live vaccine strains of Salmonella enterica serovar Gallinarum. AB - Salmonella enterica serovar Gallinarum causes fowl typhoid in chickens and is of economic importance to the chicken industry. A serovar Gallinarum live vaccine strain 9R (SG 9R) has been used to control fowl typhoid in many areas where the disease is endemic. Because the attenuation mechanism of SG 9R was not defined, there has been continued concern about reversion to virulence. In this study, we examined the molecular characteristics, which might provide better insight into attenuation of SG 9R, by comparing its proteome and transcriptome with those of two wild-type strains (287/91 and 06Q110). Proteins present in wild-type strains but absent in SG 9R were identified by two-dimensional gel electrophoresis and MALDI-TOF MS. Genes up- or down-regulated in SG 9R compared to wild-type strains were identified using an expression array. The proteome analysis identified nine proteins absent in SG 9R of which one protein had relevance to virulence. The transcriptome analysis revealed 24 up-regulated and 97 down-regulated genes in SG 9R. Approximately one-half of down-regulated genes (42 genes) were associated with virulence mechanisms. This finding suggests that attenuation of SG 9R may be associated with a combination of impaired virulence factors and thus reversion to virulence would not be caused by any single mutation event. PMID- 22944654 TI - N-acetylcysteine as a potentially useful medication to prevent conversion to schizophrenia in at-risk individuals. AB - Schizophrenia is a chronic and often severe psychotic disorder. Its causes include imbalances in mediators involved in neuroplasticity, apoptosis, cell resilience and dendritic arborization. Among these mediators, oxidative species are particularly relevant for the pathophysiology of the disease, and this is the rationale for experimental use of antioxidant medications, such as N acetylcysteine (NAC). Onset of schizophrenia is usually preceded by a period of subtle and unspecific symptoms, the prodrome, in which preventive interventions could delay or even stop the progression to full-blown psychosis. In this article, we propose that NAC could be a useful medication to prevent evolution of schizophrenia in individuals at risk for psychosis. PMID- 22944656 TI - Effect of tenofovir, an antiretroviral drug, on hepatic and renal functional indices of Wistar rats: protective role of vitamin E. AB - BACKGROUND: Tenofovir (TFR) is a nucleotide reverse transcriptase inhibitor with activity against human immunodeficiency virus. We studied the effect of TFR administered to Wistar rats on hepatic and renal function markers and the possible modulatory role of vitamin E (Vit E). METHODS: The study consists of four groups of six rats each. The first group served as control, the second group received TFR at 50 mg/kg/day for 4 weeks, third group received TFR and Vit E, and the last group received Vit E alone. RESULTS: TFR administration caused a significant (p<0.05) increase in the levels of serum urea, creatinine, urinary glucose, and protein by 65%, 51%, 88%, and 79%, respectively, relative to controls. This was followed by a significant (p<0.05) reduction in creatinine clearance of TFR-treated rats. There were no significant differences (p>0.05) in the activities of serum aminotransferases, gamma-glutamyltransferase, and alkaline phosphatase in TRF-treated rats relative to controls. TFR administration caused a marked elevation of malondialdehyde (MDA; index of lipid peroxidation) in the animals. Specifically, serum, hepatic, and renal MDA levels increased by 75%, 90%, and 102%, respectively. TRF-treated rats had significantly (p<0.05) reduced activities of renal catalase, glutathione-S-transferase, and superoxide dismutase. Supplementation of Vit E ameliorated TFR-induced effects by decreasing the levels of MDA and enhancing the activities of renal antioxidative enzymes. The biochemical data were supported by histopathological findings from the slides. CONCLUSIONS: TFR increased oxidative stress and altered kidney function markers in the rats, whereas supplementation of Vit E attenuated these effects. PMID- 22944657 TI - Chronic administration of the antiretroviral nevirapine increases body weight, food, and water intake in albino Wistar rats. AB - BACKGROUND: Nevirapine (NVP) is an antiretroviral medication that prevents human immunodeficiency virus (HIV) cells from multiplying in the blood. This study was undertaken to investigate the effect of chronic administration of NVP on body weight, food, and water intake using apparently healthy albino Wistar rats. METHODS: Twenty adult albino Wistar rats (50-125 g body weight) were used for the study. Rats in the control group (n=10) were fed normal rodent chow, whereas the NVP group (n=10) were fed by gavage NVP (0.4 mg/kg body weight) two times daily (07.00 h and 18.00 h) in addition to normal rodent chow for 12 weeks. All animals were allowed free access to clean drinking water. RESULTS: Results showed that the mean daily food and water intake in the NVP group were significantly higher (p<0.001) when compared with the control group, respectively. The mean change in body weight in the NVP group was significantly higher (p<0.001) than the control group. CONCLUSIONS: These results suggest that chronic administration of NVP may increase body weight in rats, probably due to its stimulatory effects on food and water intake. PMID- 22944660 TI - Zinc networks: the cell-specific compartmentalization of zinc for specialized functions. AB - Zinc (Zn2+) is the most abundant trace element in cells and is essential for a vast number of catalytic, structural, and regulatory processes. Mounting evidence indicates that like calcium (Ca2+), intracellular Zn2+ pools are redistributed for specific cellular functions. This occurs through the regulation of 24 Zn2+ transporters whose localization and expression is tissue and cell specific. We propose that the complement and regulation of Zn2+ transporters expressed within a given cell type reflects the function of the cell itself and comprises a 'Zn2+ network.' Importantly, increasing information implicates perturbations in the Zn2+ network with metabolic consequences and disease. Herein, we discuss our current understanding of Zn2+ transporters from the perspective of a Zn2+ network in four specific tissues with unique Zn2+ requirements (mammary gland, prostate, pancreas, and brain). Delineating the entire Zn2+ transporting network within the context of unique cellular Zn2+ needs is important in identifying critical gaps in our knowledge and improving our understanding of the consequences of Zn2+ dysregulation in human health and disease. PMID- 22944653 TI - Cocaine-induced adaptations in metabotropic inhibitory signaling in the mesocorticolimbic system. AB - The addictive properties of psychostimulants such as cocaine are rooted in their ability to activate the mesocorticolimbic dopamine (DA) system. This system consists primarily of dopaminergic projections arising from the ventral tegmental area (VTA) and projecting to the limbic and cortical brain regions, such as the nucleus accumbens (NAc) and prefrontal cortex (PFC). While the basic anatomy and functional relevance of the mesocorticolimbic DA system is relatively well established, a key challenge remaining in addiction research is to understand where and how molecular adaptations and corresponding changes in function of this system facilitate a pathological desire to seek and take drugs. Several lines of evidence indicate that inhibitory signaling, particularly signaling mediated by the Gi/o class of heterotrimeric GTP-binding proteins (G proteins), plays a key role in the acute and persistent effects of drugs of abuse. Moreover, recent evidence argues that these signaling pathways are targets of drug-induced adaptations. In this review we discuss inhibitory signaling pathways involving DA and the inhibitory neurotransmitter GABA in two brain regions - the VTA and PFC - that are central to the effects of acute and repeated cocaine exposure and represent sites of adaptations linked to addiction-related behaviors including sensitization, craving, and relapse. PMID- 22944661 TI - Cyclophilin involvement in the replication of hepatitis C virus and other viruses. AB - In recent months, there has been a wealth of promising clinical data suggesting that a more effective treatment regimen, and potentially a cure, for hepatitis C virus (HCV) infection is close at hand. Leading this push are direct-acting antivirals (DAAs), currently comprising inhibitors that target the HCV protease NS3, the viral polymerase NS5B, and the non-structural protein NS5A. In combination with one another, along with the traditional standard-of-care ribavirin and PEGylated-IFNalpha, these compounds have proven to afford tremendous efficacy to treatment-naive patients, as well as to prior non responders. Nevertheless, by targeting viral components, the possibility of selecting for breakthrough and treatment-resistant virus strains remains a concern. Host-targeting antivirals are a distinct class of anti-HCV compounds that is emerging as a complementary set of tools to combat the disease. Cyclophilin (Cyp) inhibitors are one such group in this category. In contrast to DAAs, Cyp inhibitors target a host protein, CypA, and have also demonstrated remarkable antiviral efficiency in clinical trials, without the generation of viral escape mutants. This review serves to summarize the current literature on Cyps and their relation to the HCV viral life cycle, as well as other viruses. PMID- 22944659 TI - Mitophagy: mechanisms, pathophysiological roles, and analysis. AB - Abstract Mitochondria are essential organelles that regulate cellular energy homeostasis and cell death. The removal of damaged mitochondria through autophagy, a process called mitophagy, is thus critical for maintaining proper cellular functions. Indeed, mitophagy has been recently proposed to play critical roles in terminal differentiation of red blood cells, paternal mitochondrial degradation, neurodegenerative diseases, and ischemia or drug-induced tissue injury. Removal of damaged mitochondria through autophagy requires two steps: induction of general autophagy and priming of damaged mitochondria for selective autophagic recognition. Recent progress in mitophagy studies reveals that mitochondrial priming is mediated either by the Pink1-Parkin signaling pathway or the mitophagic receptors Nix and Bnip3. In this review, we summarize our current knowledge on the mechanisms of mitophagy. We also discuss the pathophysiological roles of mitophagy and current assays used to monitor mitophagy. PMID- 22944663 TI - Platelet function and thymosin beta4. AB - Thymosin beta4 (Tbeta4) is a small, low-molecular-weight peptide ubiquitously expressed in all cells and extracellular fluids. It is a major actin sequestering protein present in the cells. In addition to this, Tbeta4 has also been shown to be involved in endothelial cell migration, angiogenesis, corneal wound healing, and stem cell differentiation. It is also released by platelets after activation. The amount of Tbeta4 increases at sites of injury and thus suggests an important role of this biopeptide in wound healing. Herein, we provide an overview of the role of Tbeta4 in thrombosis and platelet aggregation. PMID- 22944664 TI - Exportin t and Exportin 5: tRNA and miRNA biogenesis - and beyond. AB - Abstract The biogenesis of most eukaryotic kinds of RNA requires nuclear export, which is mediated by a variety of specific nuclear transport receptors. The nuclear export receptors Exportin-t (Exp-t) and Exportin 5 (Exp5), and their homologues, are involved in the export of transfer RNA to the cytoplasm. Exp5 is further involved in additional nucleocytoplasmic transport pathways, which include nuclear export of microRNA precursors (pre-miRNAs) and pre-60S ribosomal subunits. Inactivation of Exp5 results in nuclear accumulation of pre-miRNAs and perturbation of gene expression, and its mutation was recently found in malignant diseases. Here, we compare the cellular function of Exp5 and Exp-t with focus on Exp5 substrates and its role in diseases. PMID- 22944662 TI - TDP-43 in central nervous system development and function: clues to TDP-43 associated neurodegeneration. AB - From the earliest stages of embryogenesis and throughout life, transcriptional regulation is carefully orchestrated in order to generate, shape, and reshape the central nervous system (CNS). TAR DNA-binding protein 43 (TDP-43) is identified as a regulator of essential transcriptional events in the CNS. Evidence for its importance comes from the identification of TDP-43 protein aggregates and genetic mutations in patients with amyotrophic lateral sclerosis and frontotemporal lobar degeneration. Efforts are being made to learn more about the biological function of TDP-43 and gain a better understanding of its role in neurodegeneration. TDP 43 RNA targets and protein interactions have now been identified, and in vivo evidence shows that TDP-43 is essential in CNS development and function. This review will highlight aspects of these findings. PMID- 22944665 TI - Biological and molecular analysis of the pathogenic variant C3 of potato spindle tuber viroid (PSTVd) evolved during adaptation to chamomile (Matricaria chamomilla). AB - Viroid-caused pathogenesis is a specific process dependent on viroid and host genotype(s), and may involve viroid-specific small RNAs (vsRNAs). We describe a new PSTVd variant C3, evolved through sequence adaptation to the host chamomile (Matricaria chamomilla) after biolistic inoculation with PSTVd-KF440-2, which causes extraordinary strong ('lethal') symptoms. The deletion of a single adenine A in the oligoA stretch of the pathogenicity (P) domain appears characteristic of PSTVd-C3. The pathogenicity and the vsRNA pool of PSTVd-C3 were compared to those of lethal variant PSTVd-AS1, from which PSTVd-C3 differs by five mutations located in the P domain. Both lethal viroid variants showed higher stability and lower variation in analyzed vsRNA pools than the mild PSTVd-QFA. PSTVd-C3 and AS1 caused similar symptoms on chamomile, tomato, and Nicotiana benthamiana, and exhibited similar but species-specific distributions of selected vsRNAs as quantified using TaqMan probes. Both lethal PSTVd variants block biosynthesis of lignin in roots of cultured chamomile and tomato. Four 'expression markers' (TCP3, CIPK, VSF-1, and VPE) were selected from a tomato EST library to quantify their expression upon viroid infection; these markers were strongly downregulated in tomato leaf blades infected by PSTVd-C3- and -AS1 but not by PSTVd-QFA. PMID- 22944666 TI - Heterologous production and functional and thermodynamic characterization of cation diffusion facilitator (CDF) transporters of mesophilic and hyperthermophilic origin. AB - The members of the cation diffusion facilitator (CDF) family transport heavy metal ions and play an important function in zinc ion homeostasis of the cell. A recent structure of an Escherichia coli CDF transporter protein YiiP has revealed its dimeric nature and autoregulatory zinc transport mechanism. Here, we report the cloning and heterologous production of four different CDF transporters, two each from the pathogenic mesophilic bacterium Salmonella typhimurium and from the hyperthermophilic bacterium Aquifex aeolicus, in E. coli host cells. STM0758 of S. typhimurium was able to restore resistance to zinc ions when tested by complementation assays in the zinc-sensitive GG48 strain. Furthermore, copurification of bicistronically produced STM0758 and cross-linking experiments with the purified protein have revealed its possible oligomeric nature. The interaction between heavy metal ions and Aq_2073 of A. aeolicus was investigated by titration calorimetry. The entropy-driven, high-affinity binding of two Cd2+ and two Zn2+ per protein monomer with Kd values of around 100 nm and 1 MUm, respectively, was observed. In addition, at least one more Zn2+ can be bound per monomer with low affinity. This low-affinity site is likely to possess a functional role contributing to Zn2+ transport across membranes. PMID- 22944667 TI - Functional characterization of the Mycobacterium tuberculosis zinc metallopeptidase Zmp1 and identification of potential substrates. AB - Zinc metallopeptidases of bacterial pathogens are widely distributed virulence factors and represent promising pharmacological targets. In this work, we have characterized Zmp1, a zinc metallopeptidase identified as a virulence factor of Mycobacterium tuberculosis and belonging to the neprilysin (NEP; M13) family, whose X-ray structure has been recently solved. Interestingly, this enzyme shows an optimum activity toward a fluorogenic substrate at moderately acidic pH values (i.e., 6.3), which corresponds to those reported for the Mtb phagosome where this enzyme should exert its pathological activity. Substrate specificity of Zmp1 was investigated by screening a peptide library. Several sequences derived from biologically relevant proteins were identified as possible substrates, including the neuropeptides bradykinin, neurotensin, and neuropeptide FF. Further, subsequences of other small bioactive peptides were found among most frequently cleaved sites, e.g., apelin-13 and substance P. We determined the specific cleavage site within neuropeptides by mass spectrometry, observing that hydrophobic amino acids, mainly phenylalanine and isoleucine, are overrepresented at position P1'. In addition, the enzymatic mechanism of Zmp1 toward these neuropeptides has been characterized, displaying some differences with respect to the synthetic fluorogenic substrate and indicating that the enzyme adapts its enzymatic action to different substrates. PMID- 22944668 TI - Antimicrobial activity of human islet amyloid polypeptides: an insight into amyloid peptides' connection with antimicrobial peptides. AB - Human islet amyloid polypeptide (hIAPP) shows an antimicrobial activity towards two types of clinically relevant bacteria. The potency of hIAPP varies with its aggregation states. Circular dichroism was employed to determine the interaction between hIAPP and bacteria lipid membrane mimic. The antimicrobial activity of each aggregate species is associated with their ability to induce membrane disruption. Our findings provide new evidence revealing the antimicrobial activity of amyloid peptide, which suggest a possible connection between amyloid peptides and antimicrobial peptides. PMID- 22944669 TI - Necroptosis modulated by autophagy is a predominant form of melanoma cell death induced by sanguilutine. AB - We show that the plant quaternary benzo[c]phenanthridine alkaloid sanguilutine (SL) is a strong inducer of caspase-independent non-apoptotic death in human melanoma cells. Necrostatin-1, a specific inhibitor of necroptosis, completely reversed the cytotoxic effect of SL, suggesting that necroptosis was a predominant type of cell death induced by SL in these cells. In addition, we showed that SL can trigger an autophagic response, as confirmed by GFP-LC3 puncta formation and LC3-II accumulation. Interestingly, we observed a significant decrease in the viability of melanoma cells treated with combination of autophagy inhibitors (3-methyladenine, bafilomycin-A1 and LY294002) and SL. Our results further indicated that autophagy may serve as a pro-survival mechanism, delaying the induction of necroptosis in melanoma cells. The ability of SL to induce caspase-independent non-apoptotic cell death (necroptosis) suggests its possible therapeutic potential in the treatment of apoptosis-resistant melanoma tumours. Furthermore, SL might serve as a useful tool for studying the mechanisms of necroptosis and autophagy induction and the interplay between these two processes. PMID- 22944670 TI - Highlight: dolce vita--a sample from European glycobiology. PMID- 22944673 TI - Protein O-glycosylation analysis. AB - This review provides an overview on the methods available for analysis of O glycosylation. Three major themes are addressed: analysis of released O-glycans including different O-glycan liberation, derivatization, and detection methods; analysis of formerly O-glycosylated peptides yielding information on O-glycan attachment sites; analysis of O-glycopeptides, representing by far the most informative but also most challenging approach for O-glycan analysis. Although there are various techniques available for the identification of O-linked oligosaccharides, the focus here is on MS fragmentation techniques such as collision-induced fragmentation, electron capture dissociation, and electron transfer dissociation. Finally, the O-glycan analytical challenges that need to be met will be discussed. PMID- 22944671 TI - Complicated N-linked glycans in simple organisms. AB - Although countless genomes have now been sequenced, the glycomes of the vast majority of eukaryotes still present a series of unmapped frontiers. However, strides are being made in a few groups of invertebrate and unicellular organisms as regards their N-glycans and N-glycosylation pathways. Thereby, the traditional classification of glycan structures inevitably approaches its boundaries. Indeed, the glycomes of these organisms are rich in surprises, including a multitude of modifications of the core regions of N-glycans and unusual antennae. From the actually rather limited glycomic information we have, it is nevertheless obvious that the biotechnological, developmental and immunological relevance of these modifications, especially in insect cell lines, model organisms and parasites means that deciphering unusual glycomes is of more than just academic interest. PMID- 22944672 TI - Methylation--an uncommon modification of glycans. AB - A methyl (Me) group on a sugar residue is a rarely reported event. Until now, this type of modification has been found in the animal kingdom only in worms and molluscs, whereas it is more frequently present in some species of bacteria, fungi, algae and plants, but not in mammals. The monosaccharides involved as well as the positions of the Me groups on the sugar vary with species. Methylation appears to play a role in some recognition events, but details are still unknown. This review summarises the current knowledge on methylation of sugars in all types of organism. PMID- 22944674 TI - A sensitive gel-based global O-glycomics approach reveals high levels of mannosyl glycans in the high mass region of the mouse brain proteome. AB - We developed a gel-based global O-glycomics method applicable for highly complex protein mixtures entrapped in discontinuous gradient gel layers. The protocol is based on in-gel proteolysis with pronase followed by (glyco)peptide elution and off-gel reductive beta-elimination. The protocol offers robust performance with sensitivity in the low picomolar range, is compatible with gel-based proteomics, and shows superior performance in global applications in comparison with workflows eliminating glycans in-gel or from electroblotted glycoproteins. By applying this method, we analyzed the O-glycome of human myoblasts and of the mouse brain O-glycoproteome. After semipreparative separation of mouse brain proteins by one-dimensional SDS gel electrophoresis, the O-glycans from proteins in different mass ranges were characterized with a focus on O-mannose-based glycans. The relative proportion of the latter, which generally represent a rare modification, increases to comparatively high levels in the mouse brain proteome in dependence of increasing protein masses. PMID- 22944675 TI - Glycan profiles of the 27 N-glycosylation sites of the HIV envelope protein CN54gp140. AB - Hope rests on the envelope proteins of human immunodeficiency virus (HIV) as protective vaccines and thus their antibody binding sites are of prime interest. 2G12 and other human antibodies bind to a cluster of oligomannose N-glycans. Owing to the extreme number and density of N-glycosylation sites gp160 and its recombinant form gp140 represent challenging tasks for site-specific glycosylation analysis. We have conducted a glycosylation analysis of CN54gp140 by liquid chromatography-electrospray ionization-mass spectrometry (LC-ESI-MS) using an ion trap as well as a Q-TOF instrument and standard software for glycopeptide identification. First, a deglycosylated sample of the protease digest served to locate the elution positions of peptides covering all of the 27 potential N-glycosylation sites. Then, the assignments of the similarly eluting glycopeptides were verified by collision-induced decay MS/MS experiments with elevated fragmentation energy. The acquisition of site-specific glycan profiles was facilitated by the use of buffered eluent, which rounds up all glycoforms of a peptide into one peak. Calculation of the molecular mass drawn on the weighted averages of the glycans at each site led to the actual mass of gp140 of approximately 120 kDa. PMID- 22944676 TI - The analysis of N-glycans of cell membrane proteins from human hematopoietic cell lines reveals distinctions in their pattern. AB - Human cell lines are often different in their features and present variations in the glycosylation patterns of cell membrane proteins. Protein glycosylation is the most common posttranslational modification and plays a particular role in functionality and bioactivity. The key approach of this study is the comparative analysis of five hematopoietic cell lines for their N-glycosylation pattern. The N-glycans of membrane proteins were elucidated by matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF-MS) and MALDI TOF/TOF-MS analyses. Furthermore, the expression of a set of glycosyltransferases was determined via RT-PCR. The B-lymphoma BJA-B and promyelocytic HL-60 cell lines distinguish in levels and linkages of glycan-bound sialic acids. Furthermore, subclones of BJA-B and HL-60 cells, which completely lack UDP-N acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE), the key enzyme of sialic acid biosynthesis, contained almost no sialylated N-glycans. Compared to wild-type cells, the GNE-deficient cells presented a similar cell surface N glycosylation pattern in terms of antennarity and fucosylation. The Jurkat T-cell line revealed only partially sialylated N-glycans. Additionally, the different hematopoietic cell lines vary in their level of bisecting GlcNAcylation and antennary fucosylation with the quantities of bisecting N-acetylglucosamine (GlcNAc) and core fucose coinciding with the expression of GnT-III and FucT-VIII. Of note is the occurrence of N-acetyllactosamine (LacNAc) extensions on tetraantennary structures in GNE-deficient cell lines. PMID- 22944677 TI - The structure of the extracellular teichoic acids from the allergy-protective bacterium Lactococcus lactis G121. AB - The Gram-positive bacterium Lactococcus lactis G121 is a farm isolate that protects mice from ovalbumin-induced asthma. To understand the molecular mechanisms of such allergy-protective properties, the isolation and characterization of cell envelope constituents is crucial. Here, structural analyses of the extracellular teichoic acid (EC TA) from L. lactis G121 are presented. Extraction with 0.9% saline afforded a crude TA fraction. Consecutive size exclusion chromatography on Biogel P60 and P10 matrix was performed to purify the sample. Chemical component analyses, high-resolution electrospray ionization Fourier-transformed ion cyclotron mass spectrometry, and nuclear magnetic resonance spectroscopy were conducted for structural elucidation. The EC TA was a poly(glycosylglycerol phosphate) molecule with a repeating unit of -6) [beta-D-Glcp-(1->3)-][alpha-D-GlcpNAc-(1->4)-]alpha-D-GalpNAc-(1->3)-beta-D GlcpNAc-(1->2)-glycerol-(1-P-). PMID- 22944678 TI - Aminoquinolines as fluorescent labels for hydrophilic interaction liquid chromatography of oligosaccharides. AB - In this study, we investigated the potential of four different aminoquinoline (AQ) compounds as fluorescent labels for glycan analysis using hydrophilic interaction liquid chromatography (HILIC) and fluorescence detection (FLD). We confirmed the optimal excitation and emission wavelengths of 3-AQ and 6-AQ conjugated to glycan standards using three-dimensional fluorescent spectral scanning. The optimal excitation and emission wavelengths for 6-AQ were confirmed at lambda(ex)=355 nm and lambda(em)=440 nm. We concluded that the optimal wavelengths for 3-AQ were lambda(ex)=355 nm and lambda(em)=420 nm, which differed considerably from the wavelengths applied in previous reports. HILIC-FLD chromatograms using experimentally determined wavelengths were similar to 2 aminobenzamide controls, but the peak capacity and resolution differed significantly when published 3-AQ lambda(ex/em) values were applied. Furthermore, we found that 5-AQ and 8-AQ labeled maltohexaose did not display any fluorescent properties when used as a carbohydrate tag for HPLC analysis. Finally, we applied experimentally determined wavelengths to 3-AQ labeled N-glycans released from human IgG to illustrate changes in retention time as well as to demonstrate that AQ labeling is applicable to complex sample analysis via exoglycosidase sequencing. PMID- 22944679 TI - Fungal alpha-arabinofuranosidases of glycosyl hydrolase families 51 and 54 show a dual arabinofuranosyl- and galactofuranosyl-hydrolyzing activity. AB - Aspergillus niger possesses a galactofuranosidase activity, however, the corresponding enzyme or gene encoding this enzyme has never been identified. As evidence is mounting that enzymes exist with affinity for both arabinofuranose and galactofuranose, we investigated the possibility that alpha-L arabinofuranosidases, encoded by the abfA and abfB genes, are responsible for the galactofuranosidase activity of A. niger. Characterization of the recombinant AbfA and AbfB proteins revealed that both enzymes do not only hydrolyze p nitrophenyl-alpha-L-arabinofuranoside (pNp-alpha-Araf) but are also capable of hydrolyzing p-nitrophenyl-beta-D-galactofuranoside (pNp-beta-Galf). Molecular modeling of the AbfB protein with pNp-beta-Galf confirmed the possibility for AbfB to interact with this substrate, similarly as with pNp-alpha-Araf. We also show that galactomannan, a cell wall compound of A. niger, containing beta-linked terminal and internal galactofuranosyl moieties, can be degraded by an enzyme activity that is present in the supernatant of inulin-grown A. niger. Interestingly, purified AbfA and AbfB did not show this hydrolyzing activity toward A. nigergalactomannan. In summary, our studies demonstrate that AbfA and AbfB, alpha-L-arabinofuranosidases from different families, both contain a galactofuranose (Galf)-hydrolyzing activity. In addition, our data support the presence of a Galf-hydrolase activity expressed by A. niger that is capable of degrading fungal galactomannan. PMID- 22944680 TI - Glycoengineering the N-acyl side chain of sialic acid of human erythropoietin affects its resistance to sialidase. AB - During the last years, the use of therapeutic glycoproteins has increased strikingly. Glycosylation of recombinant glycoproteins is of major importance in biotechnology, as the glycan composition of recombinant glycoproteins impacts their pharmacological properties. The terminal position of N-linked complex glycans in mammals is typically occupied by sialic acid. The presence of sialic acid is crucial for functionality and affects the half-life of glycoproteins. However, glycoproteins in the bloodstream become desialylated over time and are recognized by the asialoglycoprotein receptors via the exposed galactose and targeted for degradation. Non-natural sialic acid precursors can be used to engineer the glycosylation side chains by biochemically introducing new non natural terminal sialic acids. Previously, we demonstrated that the physiological precursor of sialic acid (i.e., N-acetylmannosamine) can be substituted by the non-natural precursors N-propanoylmannosamine (ManNProp) or N pentanoylmannosamine (ManNPent) by their simple application to the cell culture medium. Here, we analyzed the glycosylation of erythropoietin (EPO). By feeding cells with ManNProp or ManNPent, we were able to incorporate N-propanoyl or N pentanoyl sialic acid in significant amounts into EPO. Using a degradation assay with sialidase, we observed a higher resistance of EPO to sialidase after incorporation of N-propanoyl or N-pentanoyl sialic acid. PMID- 22944681 TI - Shiga toxin glycosphingolipid receptor expression and toxin susceptibility of human pancreatic ductal adenocarcinomas of differing origin and differentiation. AB - Shiga toxins (Stxs) are composed of an enzymatically active A subunit (StxA) and a pentameric B subunit (StxB) that preferentially binds to the glycosphingolipid (GSL) globo?xadtriaosylceramide (Gb3Cer/CD77) and to a reduced extent to globotetraosylceramide (Gb4Cer). The identification of Gb3Cer as a tumor associated GSL in human pancreatic cancer prompted us to investigate the expression of Gb3Cer and Gb4Cer in 15 human pancreatic ductal adenocarcinoma cell lines derived from primary tumors and liver, ascites, and lymph node metastases. Thin-layer chromatography overlay assays revealed the occurrence of Gb3Cer in all and of Gb4Cer in the majority of cell lines, which largely correlated with transcriptional expression analysis of Gb3Cer and Gb4Cer synthases. Prominent Gb3Cer and Gb4Cer lipoform heterogeneity was based on ceramides carrying predominantly C16:0 and C24:0/C24:1 fatty acids. Stx2-mediated cell injury ranged from extremely high sensitivity (CD(50) of 0.94 pg/ml) to high refractiveness (CD(50) of 5.8 MUg/ml) and to virtual resistance portrayed by non-determinable CD(50) values even at the highest Stx2 concentration (10 MUg/ml) applied. Importantly, Stx2-mediated cytotoxicity did not correlate with Gb3Cer expression (the preferential Stx receptor), suggesting that the GSL receptor content does not primarily determine cell sensitivity and that other, yet to be delineated, cellular factors might influence the responsiveness of cancer cells. PMID- 22944682 TI - Structural determinants of the eosinophil cationic protein antimicrobial activity. AB - Antimicrobial RNases are small cationic proteins belonging to the vertebrate RNase A superfamily and endowed with a wide range of antipathogen activities. Vertebrate RNases, while sharing the active site architecture, are found to display a variety of noncatalytical biological properties, providing an excellent example of multitask proteins. The antibacterial activity of distant related RNases suggested that the family evolved from an ancestral host-defence function. The review provides a structural insight into antimicrobial RNases, taking as a reference the human RNase 3, also named eosinophil cationic protein (ECP). A particular high binding affinity against bacterial wall structures mediates the protein action. In particular, the interaction with the lipopolysaccharides at the Gram-negative outer membrane correlates with the protein antimicrobial and specific cell agglutinating activity. Although a direct mechanical action at the bacteria wall seems to be sufficient to trigger bacterial death, a potential intracellular target cannot be discarded. Indeed, the cationic clusters at the protein surface may serve both to interact with nucleic acids and cell surface heterosaccharides. Sequence determinants for ECP activity were screened by prediction tools, proteolysis and peptide synthesis. Docking results are complementing the structural analysis to delineate the protein anchoring sites for anionic targets of biological significance. PMID- 22944683 TI - Anticancer peptide NK-2 targets cell surface sulphated glycans rather than sialic acids. AB - Some antimicrobial peptides have emerged as potential anticancer agents. In contrast to chemotherapeutics, they act primarily by physical disruption of the cancer cell membrane. Selective targeting of these cationic peptides still remains elusive. We focus on the interaction of alpha-helical peptides NK-2, cathelicidin LL32, and melittin with PC-3 prostate cancer cells, and we provide strong evidence that, amongst the anionic glycans covering the cell surface, sulphated carbohydrates rather than sialic acids are the preferred interaction sites of the peptides. To test the significance of cell surface carbohydrates, a glycan microarray screen with fluorescently labelled peptides has been performed. Amongst 465 mammalian glycan structures on the chip, more than 20 different sulphated glycans were detected as the preferred binding partners of the peptide NK-2. The amount of peptide bound to sialic acid containing oligosaccharides was close to background level. These findings were consistent with microcalorimetric experiments revealing high and low binding enthalpies of peptides to sulphated carbohydrates and to sialic acid, respectively. Enzymatic desialylation of PC-3 cells did not affect peptide-mediated changes in cell metabolism, cell membrane permeabilisation, killing rate, and kinetics. Finally, the cytotoxicity of all peptides could be drastically impaired through the competitive inhibition by chondroitin sulphate, but not by sialic acid and sialylated fetuin. PMID- 22944685 TI - Highlight: the universe of proteolytic networks and mechanisms. PMID- 22944684 TI - Extracellular aspartic protease SAP2 of Candida albicans yeast cleaves human kininogens and releases proinflammatory peptides, Met-Lys-bradykinin and des Arg(9)-Met-Lys-bradykinin. AB - Bradykinin-related peptides, universal mediators of inflammation collectively referred to as the kinins, are often produced in excessive amounts during microbial infections. We have recently shown that the yeast Candida albicans, the major fungal pathogen to humans, can exploit two mechanisms to enhance kinin levels at the sites of candidial infection, one depending on adsorption and activation of the endogenous kinin-generating system of the host on the fungal cell wall and the other relying on cleavage of kinin precursors, the kininogens, by pathogen-secreted proteases. This work aimed at assigning this kininogenase activity to the major secreted aspartic protease of C. albicans (SAP2). The purified SAP2 was shown to cleave human kininogens, preferably the low molecular mass form (LK) and optimally in an acidic environment (pH 3.5-4.0), and to produce two kinins, Met-Lys-bradykinin and its derivative, [Hydroxyproline(3)] Met-Lys-bradykinin, both of which are capable of interacting with cellular bradykinin receptors of the B2 subtype. Additionally, albeit with a lower yield, des-Arg(9)-Met-Lys-bradykinin, an effective agonist of B1-subtype receptors, was released. The pathophysiological potential of these kinins and des-Arg-kinin was also proven by presenting their ability to stimulate human promonocytic cells U937 to release proinflammatory interleukin 1beta (IL-1beta) and IL-6. PMID- 22944686 TI - Current and prospective applications of non-proteinogenic amino acids in profiling of proteases substrate specificity. AB - Proteases recognize their endogenous substrates based largely on a sequence of proteinogenic amino acids that surrounds the cleavage site. Currently, several methods are available to determine protease substrate specificity based on approaches employing proteinogenic amino acids. The knowledge about the specificity of proteases can be significantly extended by application of structurally diverse families of non-proteinogenic amino acids. From a chemical point of view, this information may be used to design specific substrates, inhibitors, or activity-based probes, while biological functions of proteases, such as posttranslational modifications can also be investigated. In this review, we discuss current and prospective technologies for application of non proteinogenic amino acids in protease substrate specificity profiling. PMID- 22944687 TI - Understanding the substrate specificity of conventional calpains. AB - Calpains are intracellular Ca(2+)-dependent Cys proteases that play important roles in a wide range of biological phenomena via the limited proteolysis of their substrates. Genetic defects in calpain genes cause lethality and/or functional deficits in many organisms, including humans. Despite their biological importance, the mechanisms underlying the action of calpains, particularly of their substrate specificities, remain largely unknown. Studies show that certain sequence preferences influence calpain substrate recognition, and some properties of amino acids have been related successfully to substrate specificity and to the calpains' 3D structure. The full spectrum of this substrate specificity, however, has not been clarified using standard sequence analysis algorithms, e.g., the position-specific scoring-matrix method. More advanced bioinformatics techniques were used recently to identify the substrate specificities of calpains and to develop a predictor for calpain cleavage sites, demonstrating the potential of combining empirical data acquisition and machine learning. This review discusses the calpains' substrate specificities, introducing the benefits of bioinformatics applications. In conclusion, machine learning has led to the development of useful predictors for calpain cleavage sites, although the accuracy of the predictions still needs improvement. Machine learning has also elucidated information about the properties of calpains' substrate specificities, including a preference for sequences over secondary structures and the existence of a substrate specificity difference between two similar conventional calpains, which has never been indicated biochemically. PMID- 22944689 TI - An ensemble view of thrombin allostery. AB - Thrombin is the central protease of the coagulation cascade. Its activity is tightly regulated to ensure rapid blood clotting while preventing uncontrolled thrombosis. Thrombin interacts with multiple substrates and cofactors and is critically involved in both pro- and anticoagulant pathways of the coagulation network. Its allosteric regulation, especially by the monovalent cation Na(+), has been the focus of research for more than 30 years. It is believed that thrombin can adopt an anticoagulant ('slow') conformation and, after Na(+) binding, a structurally distinct procoagulant ('fast') state. In the past few years, however, the general view of allostery has evolved from one of rigid structural changes towards thermodynamic ensembles of conformational states. With this background, the view of the allosteric regulation of thrombin has also changed. The static view of the two-state model has been dismissed in favor of a more dynamic view of thrombin allostery. Herein, we review recent data that demonstrate that apo-thrombin is zymogen-like and exists as an ensemble of conformations. Furthermore, we describe how ligand binding to thrombin allosterically stabilizes conformations on the continuum from zymogen to protease. PMID- 22944690 TI - Processive proteolysis by gamma-secretase and the mechanism of Alzheimer's disease. AB - gamma-Secretase is a membrane-embedded protease complex with presenilin as the catalytic component. Cleavage within the transmembrane domain of the amyloid beta protein precursor (APP) by gamma-secretase produces the C-terminus of the amyloid beta-peptide (Abeta), a proteolytic product prone to aggregation and strongly linked to Alzheimer's disease (AD). Presenilin mutations are associated with early-onset AD, but their pathogenic mechanisms are unclear. One hypothesis is that these mutations cause AD through a toxic gain of function, changing gamma secretase activity to increase the proportion of 42-residue Abeta over the more soluble 40-residue form. A competing hypothesis is that the mutations cause AD through a loss of function, by reducing gamma-secretase activity. However, gamma secretase apparently has two types of activities, an endoproteolytic function that first cuts APP to generate a 48/49-residue form of Abeta, and a carboxypeptidase activity that processively trims these longer Abeta intermediates approximately every three residues to form shorter, secreted forms. Recent studies suggest a resolution of the gain-of-function vs. loss-of-function debate: presenilin mutations may increase the proportion of longer, more aggregation-prone Abeta by specifically decreasing the trimming activity of gamma secretase. That is, the reduction of this particular proteolytic function of presenilin, not its endoproteolytic activity, may lead to the neurotoxic gain of function. PMID- 22944688 TI - Protease-dependent mechanisms of complement evasion by bacterial pathogens. AB - The human immune system has evolved a variety of mechanisms for the primary task of neutralizing and eliminating microbial intruders. As the first line of defense, the complement system is responsible for rapid recognition and opsonization of bacteria, presentation to phagocytes and bacterial cell killing by direct lysis. All successful human pathogens have mechanisms of circumventing the antibacterial activity of the complement system and escaping this stage of the immune response. One of the ways in which pathogens achieve this is the deployment of proteases. Based on the increasing number of recent publications in this area, it appears that proteolytic inactivation of the antibacterial activities of the complement system is a common strategy of avoiding targeting by this arm of host innate immune defense. In this review, we focus on those bacteria that deploy proteases capable of degrading complement system components into non-functional fragments, thus impairing complement-dependent antibacterial activity and facilitating pathogen survival inside the host. PMID- 22944691 TI - TMPRSS4 is a type II transmembrane serine protease involved in cancer and viral infections. AB - Proteolytic enzymes are involved in almost all biological processes reflecting their importance in health and disease. The human genome contains nearly 600 protease-encoding genes forming more than 2% of the total human proteome. The serine proteases, with about 180 members, built the oldest and second largest family of human proteases. Ten years ago, a novel serine protease family named the type II transmembrane family (TTSP) was identified. This minireview summarizes the up-to-date knowledge about the still growing TTSPs, particularly focusing on the pathophysiological functions of the family member type II transmembrane serine protease (TMPRSS) 4. Recent studies provided important data on TMPRSS4 activity associated with the spreading of influenza viruses, mediated by the cleavage of hemagglutinin. Progression and metastatic potential of several cancers is concordant with an increased expression of TMPRSS4, though being a possible diagnostic marker. However, to benefit from TMPRSS4 as a therapeutic target, more data concerning its physiological relevance are needed, as done by a specific morpholino knockdown in zebrafish embryos. PMID- 22944692 TI - A catalogue of putative HIV-1 protease host cell substrates. AB - Processing of human immunodeficiency virus (HIV) proteins by the HIV-1 protease is essential for HIV infectivity. In addition, several studies have revealed cleavage of human proteins by this viral protease during infection; however, no large-scale HIV-1 protease degradomics study has yet been performed. To identify putative host substrates in an unbiased manner and on a proteome-wide scale, we used positional proteomics to identify peptides reporting protein processing by the HIV-1 protease, and a catalogue of over 120 cellular HIV-1 protease substrates processed in vitro was generated. This catalogue includes previously reported substrates as well as recently described interaction partners of HIV-1 proteins. Cleavage site alignments revealed a specificity profile in good correlation with previous studies, even though the ELLE consensus motif was not cleaved efficiently when incorporated into peptide substrates due to subsite cooperativity. Our results are further discussed in the context of HIV-1 infection and the complex substrate recognition by the viral protease. PMID- 22944693 TI - Identification of protease exosite-interacting peptides that enhance substrate cleavage kinetics. AB - Many peptidases are thought to require non-active site interaction surfaces, or exosites, to recognize and cleave physiological substrates with high specificity and catalytic efficiency. However, the existence and function of protease exosites remain obscure owing to a lack of effective methods to identify and characterize exosite-interacting substrates. To address this need, we modified the cellular libraries of peptide substrates (CLiPS) methodology to enable the discovery of exosite-interacting peptide ligands. Invariant cleavage motifs recognized by the active sites of thrombin and caspase-7 were displayed on the outer surface of bacteria adjacent to a candidate exosite-interacting peptide. Exosite peptide libraries were then screened for ligands that accelerate cleavage of the active site recognition motif using two-color flow cytometry. Exosite CLiPS (eCLiPS) identified exosite-binding peptides for thrombin that were highly similar to a critical exosite interaction motif in the thrombin substrate, protease-activated receptor 1. Protease activity probes incorporating exosite binding peptides were cleaved ten-fold faster than substrates without exosite ligands, increasing their sensitivity to thrombin activity in vitro. For comparison, screening with caspase-7 yielded peptides that modestly enhanced (two fold) substrate cleavage rates. The eCLiPS method provides a new tool to profile the ligand specificity of protease exosites and to develop improved substrates. PMID- 22944694 TI - A plant Kunitz-type inhibitor mimics bradykinin-induced cytosolic calcium increase and intestinal smooth muscle contraction. AB - BbKI is a kallikrein inhibitor with a reactive site sequence similar to that of kinins, the vasoactive peptides inserted in kininogen moieties. This structural similarity probably contributes to the strong interaction with plasma kallikrein, the enzyme that releases, from high-molecular weight kininogen (HMWK), the proinflammatory peptide bradykinin, which acts on B(2) receptors (B(2)R). BbKI was examined on smooth muscle contraction and Ca(2+) mobilization, in which the kallikrein-kinin system is involved. Contrary to expectations, BbKI (1.8 MUm) increased [Ca(2+)](c) and contraction, as observed with BK (2.0 MUm). Not blocked by B(1) receptors (B(1)R), the BbKI agonistic effect was blocked by the B(2)R antagonist, HOE-140 (6 MUm), and the involvement of B(2)R was confirmed in B(2)R knockout mice intestine. The same tissue response was obtained using a synthetic peptide derived from the BbKI reactive site structure, more resistant than BK to angiotensin I-converting enzyme (ACE) hydrolysis. Depending on the concentration, BbKI has a dual effect. At a low concentration, BbKI acts as a potent kallikrein inhibitor; however, due to the similarity to BK, in high concentrations, BbKI greatly increases Ca(2+) release from internal storages, as a consequence of its interaction with B(2)R. Therefore, the antagonistic and agonistic effects of BbKI may be considered in conditions of B(2)R involvement. PMID- 22944695 TI - Characterisation and metabolism of astroglia-rich primary cultures from cathepsin K-deficient mice. AB - Cathepsin K is important for the brain, because its deficiency in mice is associated with a marked decrease in differentiated astrocytes and changes in neuronal patterning in the hippocampus as well as with learning and memory deficits. As cathepsin K activity is most prominent in hippocampal regions of wild type animals, we hypothesised alterations in astrocyte-mediated support of neurons as a potential mechanism underlying the impaired brain functions in cathepsin K-deficient mice. To address this hypothesis, we have generated and characterised astroglia-rich primary cell cultures from cathepsin K-deficient and wild type mice and compared these cultures for possible changes in metabolic support functions and cell composition. Interestingly, cells expressing the oligodendrocytic markers myelin-associated glycoprotein and myelin basic protein were more frequent in astroglia-rich cultures from cathepsin K-deficient mice. However, cell cultures from both genotypes were morphologically comparable and similar with respect to glucose metabolism. In addition, specific glutathione content, glutathione export and gamma-glutamyl-transpeptidase activity remained unchanged, whereas the specific activities of glutathione reductase and glutathione-S-transferase were increased by around 50% in cathepsin K-deficient cultures. Thus, lack of cathepsin K in astroglia-rich cultures appears not to affect metabolic supply functions of astrocytes but to facilitate the maturation of oligodendrocytes. PMID- 22944697 TI - Synthesis and biological actions of diphosphoinositol phosphates (inositol pyrophosphates), regulators of cell homeostasis. AB - Diphosphoinositol phosphates are a subclass of inositol phosphates possessing one or two high energy diphosphate groups instead of phosphoester substituents of the myo-inositol. Here we describe the enzymes responsible for their synthesis and degradation and how these may be regulated. Formation of diphosphoinositol phosphates in yeast and mammals is driven by an increase of the cellular energy charge, a lack of inorganic phosphate, and in mammals by osmotic or heat stress and in some cases by receptor mediated signaling. Known cellular actions are an improvement of the cell homeostasis by a reduction of the energy charge, increased phosphate uptake, improvement of mitochondrial performance, and an increase of insulin secretion in mammals. The underlying molecular mechanisms of action are far from being clarified but an increasing body of knowledge about molecular details has highlighted their complex participation in many cellular systems and metabolic processes. PMID- 22944696 TI - Disruption of gingipain oligomerization into non-covalent cell-surface attached complexes. AB - RgpA and Kgp gingipains are non-covalent complexes of endoprotease catalytic and hemagglutinin-adhesin domains on the surface of Porphyromonas gingivalis. A motif conserved in each domain has been suggested to function as an oligomerization motif. We tested this hypothesis by mutating motif residues to hexahistidine or insertion of hexahistidine tag to disrupt the motif within the Kgp catalytic domain. All modifications led to the secretion of entire Kgp activity into the growth media, predominantly in a form without functional His-tag. This confirmed the role of the conserved motif in correct posttranslational proteolytic processing and assembly of the multidomain complexes. PMID- 22944698 TI - Redox Biology on the rise. AB - Redox reactions are at the heart of bioenergetics, yet their biological role is not restricted to metabolism. One specific focus of contemporary Redox Biology is the study of how the folding, stability, activity, and interactivity of proteins are subject to redox control. Key questions pertain to the chemical nature of physiological redox changes and their exact location inside the cell, the nature and distribution of protein redox modifications, and their meaning for cellular physiology. In recent years, Redox Biology has developed novel methodological directions, for example, the proteomic profiling of protein redox modifications and the noninvasive monitoring of redox processes in vivo. These and other approaches allow asking new questions for which the answers are almost completely unknown. To stimulate exchange of technical knowledge and the appreciation of Redox Biology in general, the German Society for Biochemistry and Molecular Biology (GBM) recently founded a Study Group for Redox Biology. PMID- 22944700 TI - Insights into the modulation of optimum pH by a single histidine residue in arginine deiminase from Pseudomonas aeruginosa. AB - Arginine deiminase (ADI) is a potential antitumor agent for the arginine deprivation treatment of L-arginine auxotrophic tumors. The optimum pH of ADI varies significantly, yet little is known about the origin of this variety. Here, Pseudomonas aeruginosa ADI (PaADI), an enzyme that functions only at acidic pH, was utilized as the model system. The results of UV-pH titration imply that the nucleophilic Cys406 thiol group is protonated in the resting state. The H405R single mutation resulted in an altered pH optimum (from pH 5.5 to 6.5), an increased k(cat) (from 9.8 s(-1) to 101.7 s(-1) at pH 6.5), and a shifted pH rate dependence (ascending limb pK(a) from 3.6 to 4.4). Other mutants were constructed to investigate the effects of hydrogen bonding, charge distribution, and hydrophobicity on the properties of the enzyme. The pH optima of His405 mutants were all shifted to a relatively neutral pH except for the H405E mutant. The results of kinetic characterizations and molecular dynamic simulations revealed that the active site hydrogen bonding network involving Asp280 and His405 plays an important role in controlling the dependence of PaADI activity on pH. Moreover, the H405R variant showed increased cytotoxicity towards arginine auxotrophic cancer cell lines. PMID- 22944699 TI - Adipose triglyceride lipase in immune response, inflammation, and atherosclerosis. AB - Consistent with its central importance in lipid and energy homeostasis, lipolysis occurs in essentially all tissues and cell types, including macrophages. The hydrolytic cleavage of triacylglycerol by adipose triglyceride lipase (ATGL) generates non-esterified fatty acids, which are subsequently used as essential precursors for lipid and membrane synthesis, mediators in cell signaling processes or as energy substrate in mitochondria. This review summarizes the current knowledge concerning the consequences of ATGL deficiency in macrophages with particular emphasis on macrophage (dys)-function, apoptosis, and atherosclerosis. PMID- 22944714 TI - Cluster-localized sparse logistic regression for SNP data. AB - The task of analyzing high-dimensional single nucleotide polymorphism (SNP) data in a case-control design using multivariable techniques has only recently been tackled. While many available approaches investigate only main effects in a high dimensional setting, we propose a more flexible technique, cluster-localized regression (CLR), based on localized logistic regression models, that allows different SNPs to have an effect for different groups of individuals. Separate multivariable regression models are fitted for the different groups of individuals by incorporating weights into componentwise boosting, which provides simultaneous variable selection, hence sparse fits. For model fitting, these groups of individuals are identified using a clustering approach, where each group may be defined via different SNPs. This allows for representing complex interaction patterns, such as compositional epistasis, that might not be detected by a single main effects model. In a simulation study, the CLR approach results in improved prediction performance, compared to the main effects approach, and identification of important SNPs in several scenarios. Improved prediction performance is also obtained for an application example considering urinary bladder cancer. Some of the identified SNPs are predictive for all individuals, while others are only relevant for a specific group. Together with the sets of SNPs that define the groups, potential interaction patterns are uncovered. PMID- 22944715 TI - A preliminary study of the mechanism of hypoglycaemic activity of Nauclea latifolia leaf ethanolic extract. AB - The aim of this study was to determine the possible underlying mechanism of the hypoglycaemic activity of the ethanolic extract of Nauclea latifolia leaves in rats. The extract, glibenclamide or water was administered orally in a glucose, sucrose and maltose tolerance tests. In addition, the effect of the extract on alpha-glucosidase enzymes was also studied. The ethanolic extract at 200mg/kg body weight inhibited the increase in glucose level after both oral and intraperitoneal glucose loads as did glibenclamide. The extract also dose dependently inhibited both maltase and sucrase activities in vitro but not in vivo. The hypoglycaemic effect of N. latifolia leaf ethanolic extract thus appears to be most probably exerted through a mechanism similar to that of glibenclamide which is related to increased insulin release from pancreatic beta cells. PMID- 22944716 TI - Glucose metabolism and diabetogenic gene expression analysis of chloroform fraction of Andrographis paniculata (Nees) whole herb in diabetic albino mice. AB - Exposure of rampant higher glucose level in diabetic condition could lead earlier and late diabetic complication eventually caused malign effect in body organs. The aim of the present work was to analyze the anti-diabetic potential of chloroform fraction of ethanol extract of Andrographis paniculata (AP) and diabetes laden gene expression alteration. In streptozotocin (60 mg/kg bw, i.p.) induced Type 2 diabetes albino mice, two weeks consecutive repeated dose treatment of chloroform fraction of AP at dose of 200 mg/kg, orally was evaluated for antidiabetic screening. Fasting blood glucose, oral glucose tolerance, serum lipid profile, tissues glycogen content, glucose 6-phosphatase and hexokinase enzymes level in liver, in vitro and in vivo insulin estimation were measured on last day of treatment. Subsequently presence of responsible phytoconstituents for respective activity was observed by HPLC. In diabetic mice, the fraction reduced the level of harmful cholesterol, while increased the favorable cholesterol significantly. Biochemical enzymes like glycogen, glucose-6-phosphatase and hexokinase were evaluated in body tissues. Apart from this in vitro, in vivo insulin estimation and diabetogenic gene expression analysis like GK, PEPCK, G 6pase, Glut-4, AR, PPAR-alpha,gamma and TNF-alpha were evaluated using RT-PCR technique. Antidiabetic screening of fraction of AP at molecular level revealed significant antidiabetic activity. PMID- 22944717 TI - Flavonoids purified from parsley inhibit human blood platelet aggregation and adhesion to collagen under flow. AB - INTRODUCTION: Blood platelets are directly involved in both haemostatic and pathologic thrombotic processes, through their adhesion, secretion and aggregation. In this study, we investigated the effect of genins (aglycone flavonoids without sugar group) isolated from parsley (Petroselinum crispum) leaves in vitro on human platelet aggregation and adhesion to a collagen-coated surface under physiologic flow conditions. MATERIALS AND METHODS: The aggregation and adhesion studies were monitored after pre-incubation of platelets with genins. RESULTS: Genins inhibited dose dependently aggregation induced by thrombin, ADP and collagen. The strongest effect was observed in collagen induced aggregation (IC50 = 0.08 +/- 0.01 mg/ml). The HPLC identification of genins compounds revealed the presence of keampferol, apigenin and other not identified compounds. The aggregation tests showed that these compounds have anti aggregating activity. In addition, adhesion of human platelets to collagen was greatly decreased (over 75 %) by genins (0.3 mg/ml). While the mechanism by which genins act is unclear, we suggest that these compounds may interfere with a multiple target step in the haemostasis process. CONCLUSION: These results show that genins isolated from parsley has a potent antiplatelet activity. It may be an important source of beneficial antiplatelet compounds that decrease thrombosis and cardiovascular diseases. PMID- 22944718 TI - Potentiation of etoposide and temozolomide cytotoxicity by curcumin and turmeric forceTM in brain tumor cell lines. AB - We have investigated on the potentiation of etoposide (ETP) and temozolomide (TMZ) cytotoxicity in U-87MG glioblastoma and D283 medulloblastoma cell lines by curcumin (CUR) and turmeric force (TF), a nutraceutical formulation of turmeric, with the objective of assessing the potential for their adjuvant use in brain tumor chemotherapy. While U-87MG cell line was generally resistant to TMZ, IC50 values for CUR and TF were 37.33 and 30.75 ug/ml, respectively. TF is the only agent that demonstrated efficacy at the IC90 level. When CUR or TF was combined with ETP and TMZ, increased chemotherapeutic efficiency in the U-87MG cells was observed. TF is highly cytotoxic to D283 Med cell line compared to curcumin with an IC50 value of 1.55 ug/ml. Although both CUR and TF potentiated ETP and TMZ cytotoxicity, TF is more efficient than CUR in both U-87MG and D283 Med cell lines. Treatment of U-87MG cells with the triple combination of TMZ+ETP+TF induced a high percentage of apoptotic cells. Potential mechanisms that may explain evidence of synergy include down regulation of p10 and p53 mRNAs and increase in BAX/Bcl-2 mRNA ratio. These pre-clinical results suggest that TF may be useful as an adjuvant with ETP and TMZ for brain tumor chemotherapy. PMID- 22944719 TI - Evaluation of antiulcer potential of Mimusops hexandra in experimental gastro duodenal ulcers. AB - The study was aimed to investigate antiulcer effects of acetone extract and its different fractions Mimusops hexandra against experimental gastro-duodenal ulcers. 80% acetone extract of stem bark of Mimusops hexandra (Extract A, p.o.) and its different fractions namely diethyl ether (Extract A1, p.o.), ethyl acetate (Extract A2, p.o.) and aqueous (Extract A3, p.o.) were tested for the presence of preliminary phytoconstituents and were screened for their antiulcer potential in experimental animals using ethanol-HCl and aspirin-induced gastric damage at the dose of 500 mg kg-1p.o. Extract A2 being the most active fraction amongst all the fractions tested was also studied at different doses to find its ED50. Further, to establish the mechanism of action, Extract A2 was also tested for its effects in acetic acid-induced gastric ulcer models and cysteamine induced duodenal ulcer. The effect was compared with cimetidine. Flavonoids (quercetin), procyanidins, saponins and triterpenoids were found to be present in bark. Oral administration of Extract A2 inhibited formation of gastric lesions induced by aspirin in a dose dependent manner. Elevated level of lipid peroxidation due to ethanol-HCl and aspirin induced gastric damage was significantly (p<0.05) reduced by the treatment with Extract A2. Further, Extract A2 at the dose of 100 mg kg-1 (p.o.) reduced extent of acetic acid induced gastric ulcer in experimental animals. Moreover, protection afforded by Extract A2 against cysteamine-induced duodenal lesions was evident from dose dependent decrease in ulcer index (p<0.05), score for intensity (p<0.05) and total lesion area (p<0.05), when compared with the control group. The antiulcer activity shown by Extract A2 in experimental gastro-duodenal ulcer could be attributed to decrease in gastric acid secretory activity along with strengthening of mucosal defensive mechanisms. PMID- 22944720 TI - The microalga Spirulina platensis presents anti-inflammatory action as well as hypoglycemic and hypolipidemic properties in diabetic rats. AB - Spirulina platensis (Spi) is a microalga presenting high contents of proteins, gamma-linolenic acid, vitamins and minerals, and showing many biological activities. It is a promising drug for the treatment of diseases including diabetes. The objectives of this work were to study Spi effects on alloxan induced diabetic rats, and associate this to its anti-inflammatory activity. The treatment with Spi (25, 50 or 100 mg/kg, p.o.) started 48 h after the alloxan injection, continuing for 5 or 10 days. Biochemical parameters were measured in sera of treated and untreated animals. The anti-inflammatory activity of Spi was assessed by the formalin test and carrageenan-induced paw edema in mice. Immunostainings for TNF-alpha were carried out in the carrageenan-induced paw edema in rats, before and after the Spi treatment, and its effect on the release of myeloperoxidase from human neutrophils was also determined. Spi decreased glycemia as well as triglyceride and total cholesterol levels of diabetic rats. Levels of urea and creatinine were also reduced, while liver transaminases were unaltered. Spi also decreased dose-dependently the 1st (neurogenic) and mainly the 2nd phase (inflammatory) of the formalin test, as well as the carrageenan induced paw edema in mice. The anti-inflammatory effect of Spi was further confirmed by decreases in TNF-alpha immunostaining in the inflamed paw and in the myeloperoxidase release from human neutrophils. The results showed that the anti diabetic effect of S. platensis is already manifested after a 5-day treatment. Additionally, considering the relationship between diabetes and inflammation, the microalga anti-inflammatory action may also be involved. PMID- 22944721 TI - Evaluating treatment effectiveness in patient subgroups: a comparison of propensity score methods with an automated matching approach. AB - Propensity score (Pscore) matching and inverse probability of treatment weighting (IPTW) can remove bias due to observed confounders, if the Pscore is correctly specified. Genetic Matching (GenMatch) matches on the Pscore and individual covariates using an automated search algorithm to balance covariates. This paper compares common ways of implementing Pscore matching and IPTW, with Genmatch for balancing time-constant baseline covariates}. The methods are considered when estimates of treatment effectiveness are required for patient subgroups, and the treatment allocation process differs by subgroup. We apply these methods in a prospective cohort study that estimates the effectiveness of Drotrecogin alfa activated, for subgroups of patients with severe sepsis. In a simulation study we compare the methods when the Pscore is correctly specified, and then misspecified by ignoring the subgroup-specific treatment allocation. The simulations also consider poor overlap in baseline covariates, and different sample sizes. In the case study, GenMatch reports better covariate balance than IPTW or Pscore matching. In the simulations with correctly specified Pscores, good overlap and reasonable sample sizes, all methods report minimal bias. When the Pscore is misspecified, GenMatch reports the least imbalance and bias. With small sample sizes, IPTW is the most efficient approach, but all methods report relatively high bias of treatment effects. This study shows that overall GenMatch achieves the best covariate balance for each subgroup, and is more robust to Pscore misspecification than common alternative Pscore approaches. PMID- 22944722 TI - Estimation and asymptotic theory for transition probabilities in Markov renewal multi-state models. AB - In this paper we discuss estimation of transition probabilities for semi-Markov multi-state models. Non-parametric and semi-parametric estimators of the transition probabilities for a large class of models (forward going models) are proposed. Large sample theory is derived using the functional delta method and the use of resampling is proposed to derive confidence bands for the transition probabilities. The last part of the paper concerns the presentation of the main ideas of the R implementation of the proposed estimators, and data from a renal replacement study are used to illustrate the behavior of the estimators proposed. PMID- 22944723 TI - Instruments and bounds for causal effects under the monotonic selection assumption. AB - Abstract Noncompliance with assigned treatment is an important problem of randomized clinical trials. In this situation, the structural mean model (SMM) approach focuses on the average treatment effect among patients actually treated (ATT). In contrast, the principal stratification (PS) approach addresses the effect on a certain subgroup defined by latent compliance behavior. While these approaches target different causal effects, the estimators have the same form as the classical instrumental variable estimator, under the assumption of no effect modification (NEM) and monotonic selection. In this article, we clarify the relation between SMM and PS under the monotonic selection assumption. Specifically, we translate the NEM assumption for the SMM estimator into the words of the PS approach. Then, we propose a new bound for the ATT by making a possibly more plausible assumption than the NEM assumption based on the PS approach. Furthermore, we extend these results to the average treatment effect for the entire population. The proposed bounds are illustrated with applications to a real clinical trial data. Although our assumption cannot be empirically verified, the proposed bounds can be considerably tighter than those previously proposed. PMID- 22944724 TI - Epidemiology and resistance of Achromobacter xylosoxidans from cystic fibrosis patients in Dijon, Burgundy: first French data. AB - BACKGROUND: Achromobacter xylosoxidans is an emerging pathogen in cystic fibrosis (CF) patients recognised as causal agent of inflammation. The prevalence of infection or colonisation is variable among CF centres. We report here the first epidemiological data about A. xylosoxidans in a French CF centre: Dijon, Burgundy. METHODS: All isolates recovered from the patients affiliated with our centre in 2010 since their first visit were included. Antimicrobial susceptibility was determined by disk diffusion method and E-test. Molecular epidemiology was performed by Pulsed Field Gel Electrophoresis (PFGE) and compared with repetitive sequence-based PCR (rep-PCR, DiversiLab(r)). We also sequenced the constitutive bla-oxa-114 gene. RESULTS: Out of 120 patients, 21 (17.5%) had at least one positive culture with A. xylosoxidans since they started to receive routine care in our CF centre (447 isolates). Median age at first positive culture was 16 years (range 3-34 years). Most patients were colonised by their own strain, cross-contamination was very rare. We observed two cases of intra-family spread. DiversiLab(r) is a useful tool as efficient as PFGE to compare isolates recovered simultaneously from different patients when an outbreak is suspected. However, PFGE remains the reference method for long-term survey of chronically colonised patients. We detected new OXA-114 variants and the new oxacillinase OXA-243 (88% amino acid identity with OXA-114). Acquired resistance to ciprofloxacin, ceftazidime and carbapenems was frequent. In 2010, 7 patients harboured strains resistant to ceftazidime, 6 patients strains with decreased susceptibility to carbapenems (especially meropenem) and 12 patients strains resistant to ciprofloxacin. CONCLUSIONS: In our centre, the high prevalence of colonisation is not due to cross-contamination. Our main concern is the high rate of antimicrobial resistance. PMID- 22944725 TI - Pseudomonas aeruginosa serology and risk for re-isolation in the EPIC trial. AB - BACKGROUND: The prognostic value of Pseudomonas aeruginosa serology for antibiotic therapy in cystic fibrosis patients is not well understood. METHODS: Using five antigens from two ELISAs, we assessed whether positive serology in CF patients participating in the multi-center Early Pseudomonas Infection in Children (EPIC) trial would predict treatment failure, time to pulmonary exacerbation and risk for recurrent P. aeruginosa isolation post eradication. RESULTS: Baseline positive P. aeruginosa serology was not significantly associated with failure of initial P. aeruginosa eradication measured at week 10 (adjusted for baseline culture) but seropositivity to the antigens alkaline protease and exotoxin A was significantly associated with increased risk for recurrent P. aeruginosa isolation during the 60 week post eradication follow-up period (p=0.003 and p=0.001 respectively). There was no association between baseline seropositivity and time to pulmonary exacerbation. CONCLUSION: P. aeruginosa serology may complement culture results in clinicians' efforts to successfully monitor recurrence of early P. aeruginosa in CF patients. PMID- 22944727 TI - Cardiovascular anatomy and cardiac function in the air-breathing swamp eel (Monopterus albus). AB - Monopterus albus, a swamp eel inhabiting the freshwaters of South East Asia, relies on an extensive vascularisation of the buccal cavity, pharynx and anterior oesophagus for gas exchange, while the gills are much reduced. In the present study we describe the macro-circulation in the cephalic region and the vascularisation of the buccal cavity of M. albus using vascular fillings and micro-computed tomography (MUCT). We also show that M. albus has the capacity to use the buccal cavity for aquatic gas exchange, being able to maintain normal arterial blood gas composition, blood pressure, heart rate and cardiac output throughout 10h of forced submergence. M. albus therefore can be characterised as a facultative air-breather. Because M. albus aestivates for many months in moist mud during the dry season we characterised in vivo cardiovascular function during exposure to anoxia as well as the effects of anoxia on in vitro contractility of strip preparations from atria and ventricle. Both studies revealed a low anoxia tolerance, rendering it unlikely that M. albus can survive prolonged exposure to anoxia. PMID- 22944726 TI - Cadherins in collective cell migration of mesenchymal cells. AB - Immunity, embryogenesis and tissue repair rely heavily on cell migration. Cells can be seen migrating as individuals or large groups. In the latter case, collectiveness emerges via cell-cell interactions. In migratory epithelial cell sheets, classic Cadherins are critical to maintain tissue integrity, to promote coordination and establish cell polarity. However, recent evidence indicates that mesenchymal cells, migrating in streams such as neural crest or cancer cells, also exhibit collective migration. Here we will explore the idea that Cadherins play an essential role during collective migration of mesenchymal cells. PMID- 22944729 TI - Speeding up the solar water disinfection process (SODIS) against Cryptosporidium parvum by using 2.5l static solar reactors fitted with compound parabolic concentrators (CPCs). AB - Water samples of 0, 5, and 100 nephelometric turbidity units (NTU) spiked with Cryptosporidium parvum oocysts were exposed to natural sunlight in 2.5l static borosilicate solar reactors fitted with two different compound parabolic concentrators (CPCs), CPC1 and CPC1.89, with concentration factors of the solar radiation of 1 and 1.89, respectively. The global oocyst viability was calculated by the evaluation of the inclusion/exclusion of the fluorogenic vital dye propidium iodide and the spontaneous excystation. Thus, the initial global oocyst viability of the C. parvum isolate used was 95.3 +/- 1.6%. Using the solar reactors fitted with CPC1, the global viability of oocysts after 12h of exposure was zero in the most turbid water samples (100 NTU) and almost zero in the other water samples (0.3 +/- 0.0% for 0 NTU and 0.5 +/- 0.2% for 5 NTU). Employing the solar reactors fitted with CPC1.89, after 10h exposure, the global oocyst viability was zero in the non-turbid water samples (0 NTU), and it was almost zero in the 5 NTU water samples after 8h of exposure (0.5 +/- 0.5%). In the most turbid water samples (100 NTU), the global viability was 1.9 +/- 0.6% after 10 and 12h of exposure. In conclusion, the use of these 2.5l static solar reactors fitted with CPCs significantly improved the efficacy of the SODIS technique as these systems shorten the exposure times to solar radiation, and also minimize the negative effects of turbidity. This technology therefore represents a good alternative method for improving the microbiological quality of household drinking water in developing countries. PMID- 22944728 TI - Age-related decrease in cerebrovascular-derived neuroprotective proteins: effect of acetaminophen. AB - As the population ages, the need for effective methods to maintain brain function in older adults is increasingly pressing. Vascular disease and neurodegenerative disorders commonly co-occur in older persons. Cerebrovascular products contribute to the neuronal milieu and have important consequences for neuronal viability. In this regard vascular derived neuroprotective proteins, Such as vascular endothelial growth factor (VEGF), pigment epithelium-derived factor (PEDF), and pituitary adenylate cyclase activating peptide (PACAP) are important for maintaining neuronal viability, especially in the face of injury and disease. The objective of this study is to measure and compare levels of VEGF, PEDF and PACAP released from isolated brain microvessels of Fischer 344 rats at 6, 12, 18, and 24 months of age. Addition of acetaminophen to isolated brain microvessels is employed to determine whether this drug affects vascular expression of these neuroprotective proteins. Experiments on cultured brain endothelial cells are performed to explore the mechanisms/mediators that regulate the effect of acetaminophen on endothelial cells. The data indicate cerebrovascular expression of VEGF, PEDF and PACAP significantly decreases with age. The age-associated decrease in VEGF and PEDF is ameliorated by addition of acetaminophen to isolated brain microvessels. Also, release of VEGF, PEDF, and PACAP from cultured brain endothelial cells decreases with exposure to the oxidant stressor menadione. Acetaminophen treatment upregulates VEGF, PEDF and PACAP in brain endothelial cells exposed to oxidative stress. The effect of acetaminophen on cultured endothelial cells is in part inhibited by the selective thrombin inhibitor hirudin. The results of this study suggest that acetaminophen may be a useful agent for preserving cerebrovascular function. If a low dose of acetaminophen can counteract the decrease in vascular-derived neurotrophic factors evoked by age and oxidative stress, this drug might be useful for improving brain function in the elderly. PMID- 22944730 TI - Diamond GERD diagnosis studies: clinical feelings are good, but are measurements using a PPI test better? PMID- 22944731 TI - Unfolding the plot of obscure gastrointestinal bleeding: excellent or elementary? PMID- 22944732 TI - Follow-up of patients with celiac disease. PMID- 22944734 TI - Interconfigurational 5d -> 4f luminescence of Ce3+ and Pr3+ in Ca9Lu(PO4)7. AB - Ca(9)Lu(PO(4))(7):Ce (3+) and Ca (9)Lu (PO (4))(7):Pr (3+) polycrystalline materials were synthesized by solid state reaction at high temperature. The materials were characterized by powder x-ray diffraction (XRPD). The luminescence spectroscopy and the excited state dynamics of these compounds were investigated upon excitation with UV/VUV synchrotron radiation. Both materials showed efficient and fast 5d-4f emission upon direct VUV excitation into the 5d levels but only Ca(9)Lu(PO(4))(7):Ce (3+) revealed luminescence upon excitation across the bandgap. The decay kinetics of the 5d-4f emission upon VUV intra-center excitation is characterized by a decay time of 29 ns for Ce (3+) and 17 ns for Pr (3+) with no significant build-up after the excitation pulse. For the both compounds, no significant temperature dependence of the 5d-4f emission lifetime was observed within the range 8-300 K. PMID- 22944733 TI - Association between depressive symptoms and incidence of Crohn's disease and ulcerative colitis: results from the Nurses' Health Study. AB - BACKGROUND & AIMS: Depression and psychosocial stress are believed to contribute to the pathogenesis of Crohn's disease (CD) and ulcerative colitis (UC). Although many mechanisms have been proposed to link these disorders, few prospective studies have examined the relationship between depressed mood and incidence of CD or UC. METHODS: We analyzed data from 152,461 women (aged 29-72 years) enrolled since 1992-1993 in the Nurses' Health Study cohorts I and II. Self-reported depressive symptoms were assessed by using the Mental Health Index (MHI)-5, a validated 5-item subscale of the 36-item Short-Form health survey, which is designed to estimate psychological distress on the basis of scores that range from 0 to 100. Self-reported CD and UC were confirmed through blinded record review by 2 gastroenterologists. Cox proportional hazards models were used to associate recent (within 4 years) and baseline MHI-5 scores with risk for CD or UC, adjusting for other risk factors. RESULTS: During 1,787,070 person-years of follow-up, we documented 170 cases of CD and 203 cases of UC. Compared with women with recent MHI-5 scores of 86-100, women with recent depressive symptoms (MHI-5 scores <52) had an increased risk of CD (multivariate-adjusted hazard ratio [HR], 2.39; 95% confidence interval [CI], 1.40-3.98; P trend = .001). Baseline depressive symptoms, assessed from the baseline MHI-5 score, were also associated with CD, although with a lower HR (1.62; 95% CI, 0.94-2.77). Recent (HR, 1.14; 95% CI, 0.68-1.92) and baseline depressive symptoms were not associated with increased risk of UC (HR, 1.07; 95% CI, 0.63-1.83). CONCLUSIONS: On the basis of data from the Nurses' Health Study, depressive symptoms increase the risk for CD, but not UC, among women. Psychological factors might therefore contribute to development of CD. Further studies are needed to determine the mechanisms of this association. PMID- 22944735 TI - Microbiological quality and potential public health risks of export meat from springbok (Antidorcas marsupialis) in Namibia. AB - To assess the microbiological quality and safety of export game meat; i) a total of 80 pooled meat samples for aerobic plate count (APC) and Enterobacteriaceae ii) water used in harvesting and processing for microbiological quality and iii) meat and rectal contents for Salmonella spp. and Shiga toxin Escherichia coli (STEC) were evaluated in 2009 and 2010. No differences (p>0.05) in the APCs were observed between the years, but the mean Enterobacteriaceae count for 2009 was 1.33 +/- 0.69 log(10)cfu/cm(2) compared to 2.93 +/- 1.50 log(10)cfu/cm(2) for 2010. Insignificant Heterotrophic Plate Count (HPC) levels were detected in 9/23 field water samples, while fecal bacterial (coliforms, Clostridium perfringens and enterococci) were absent in all samples. No Salmonella spp. was isolated and all E. coli isolates from meat were negative for STEC virulence genes (stx1, stx2, eae and hlyA), suggesting a negligible role by springbok in the epidemiology of STEC and Salmonella. PMID- 22944736 TI - Pancreatic polypeptide and peptide YY3-36 induce Ca2+ signaling in nodose ganglion neurons. AB - Peripheral injection of pancreatic polypeptide (PP) and peptide YY(3-36) (PYY(3 36)), the hormones released in response to meals, reduce food intake, in which the rank order of the potency is PP>PYY(3-36). These anorectic effects are abolished in abdominal vagotomized rats, suggesting that PP and PYY(3-36) induce anorexia via vagal afferent nerves. However, it is not clear whether PP and PYY(3 36) directly act on vagal afferent neurons. In this study, we examined the effects of PP and PYY(3-36) on cytosolic Ca(2+) concentration ([Ca(2+)](i)) in isolated nodose ganglion neurons of the mouse vagal afferent nerves. At 10(-11)M, PP but not PYY(3-36) recruited a significant population of nodose ganglion neurons into [Ca(2+)](i) increases. PP at 10(-11) to 10(-7) and PYY(3-36) at 10( 10) to 10(-7)M increased [Ca(2+)](i) in a concentration-dependent manner. At submaximal to maximal concentrations of 10(-10) and 10(-8)M, PP increased [Ca(2+)](i) in approximately twice greater population of nodose ganglion neurons than PYY(3-36). Furthermore, the majority of PP-responsive neurons also exhibited [Ca(2+)](i) responses to cholecystokinin-8, a hormone known to induce satiety through activating nodose ganglion neurons. The results demonstrate that PP and PYY(3-36) directly activate nodose ganglion neurons and suggest that the marked effect of PP on cholecystokinin-8-responsive nodose ganglion neurons could be linked to the regulation of feeding. PMID- 22944737 TI - Study of the molecularly imprinted polymers for selective binding of the mono substituted sulfonylurea herbicides. AB - A new molecularly imprinted polymer (MIP) was synthesized for the selective extraction of mono-substituted sulfonylurea herbicides, with monosulfuron as the template and acrylamide as the functional monomer. The recognition property and affinity of the MIP for monosulfuron and its analog, monosulfuron-ester, were evaluated by equilibrium adsorption and a chromatographic study. Computer modeling, including simulated annealing and semi-empirical quantum calculation, was employed to study the recognition mechanism. The computer modeling demonstrated that monosulfuron can form multiple hydrogen bonds with methacrylic acid and acrylamide, whereas monosulfuron-ester cannot form a stable complex with these two functional monomers, which aligns with the results of the rebinding experiment. The selectivity study further demonstrated that binding sites in the MIP interact with the hydrogen in the acylamino group of mono-substituted sulfonylurea. A comparison experiment also showed that monosulfuron-imprinted MIP offers better selectivity for monosulfuron-ester than the commercial C18 high performance liquid chromatography stationary phase material. PMID- 22944738 TI - Introduction to special issue. PMID- 22944739 TI - Milestones in blindness prevention in India. PMID- 22944740 TI - A model initiative. PMID- 22944741 TI - Best practice eye care models. AB - Since the launching of Global Initiative, VISION 2020 "the Right to Sight" many innovative, practical and unique comprehensive eye care services provision models have evolved targeting the underserved populations in different parts of the World. At places the rapid assessment of the burden of eye diseases in confined areas or utilizing the key informants for identification of eye diseases in the communities are promoted for better planning and evidence based advocacy for getting / allocation of resources for eye care. Similarly for detection and management of diabetes related blindness, retinopathy of prematurity and avoidable blindness at primary level, the major obstacles are confronted in reaching to them in a cost effective manner and then management of the identified patients accordingly. In this regard, the concept of tele-ophthalmology model sounds to be the best solution. Whereas other models on comprehensive eye care services provision have been emphasizing on surgical output through innovative scales of economy that generate income for the program and ensure its sustainability, while guaranteeing treatment of the poorest of the poor. PMID- 22944742 TI - The economic burden of blindness in Pakistan: a socio-economic and policy imperative for poverty reduction strategies. AB - State and nonstate health programs in developing countries are often influenced by priorities that are defined in the Millennium Development Goals (MDGs). In the wake of recessionary pressures, policy makers in the health sector are often seen to divert significant budgets to some specific health programs and make only token allocations for other health problems that are important but do not fall under the traditional MDG box of health priorities. This paper illustrates the economic argument for investment in one such program: The eye health program and employs a country case study of Pakistan to demonstrate that there are significant economic gains that are being foregone by not addressing the needs of the blind in poverty reduction strategies. By applying appropriate growth and discounting factors and using the average wage rate, the paper estimates the total productivity gains that are realizable over a period of 10 years if the blind population in Pakistan is rehabilitated and their carers released to participate in the mainstream economic activity. Our findings indicate that significant productivity gains accumulated over 10 years, range from Rs. 61 billion (US$ 709 million) to Rs. 421 billion (US$ 4.9 billion) depending upon whether the entire blind population or only those affected by a specific cause are rehabilitated. The per annum productivity gains of rehabilitating the entire blind population represents 0.74% of the current gross domestic product of Pakistan, which is higher than the total public spending on health. In order to reap these benefits, the subsequent absorption of the rehabilitated blind and their carers into mainstream economic activity is as important as their effective rehabilitation. PMID- 22944743 TI - Training of an ophthalmologist in concepts and practice of community eye health. AB - Training in community eye health (CEH; public health applied to ophthalmology) complements clinical ophthalmology knowledge and enhances the physician's ability to meet the needs at the individual and community level in the context of VISION 2020. The upcoming version of the ophthalmological residency curriculum that was developed by the International Council of Ophthalmology (ICO) includes a new, specific section on CEH. It has basic, standard, advanced and very advanced levels of goals (the last one is exclusively for fellows/master students), and provides a public health approach to the main causes of blindness and low vision. The number of individuals aged >=60 years is increasing twice as fast as the number of ophthalmologists, and as this age group is more likely to become blind/visually impaired, accessibility to eye care in the near future might be suboptimal even in wealthier countries. In order to achieve VISION 2020 goals, it is necessary to train more ophthalmologists and other eye care workers. However, the adoption of CEH component of the ICO curriculum for ophthalmology residents will enable them to meet local needs for eye care. PMID- 22944745 TI - Advocacy for eye care. AB - The effectiveness of eye care service delivery is often dependant on how the different stakeholders are aligned. These stakeholders range from the ministries of health who have the capacity to grant government subsidies for eye care, down to the primary healthcare workers who can be enrolled to screen for basic eye diseases. Advocacy is a tool that can help service providers draw the attention of key stakeholders to a particular area of concern. By enlisting the support, endorsement and participation of a wider circle of players, advocacy can help to improve the penetration and effectiveness of the services provided. There are several factors in the external environmental that influence the eye care services - such as the availability of trained manpower, supply of eye care consumables, government rules and regulations. There are several instances where successful advocacy has helped to create an enabling environment for eye care service delivery. Providing eye care services in developing countries requires the support - either for direct patient care or for support services such as producing trained manpower or for research and dissemination. Such support, in the form of financial or other resources, can be garnered through advocacy. PMID- 22944744 TI - Social inequalities in blindness and visual impairment: a review of social determinants. AB - Health inequities are related to social determinants based on gender, socioeconomic status, ethnicity, race, living in a specific geographic region, or having a specific health condition. Such inequities were reviewed for blindness and visual impairment by searching for studies on the subject in PubMed from 2000 to 2011 in the English and Spanish languages. The goal of this article is to provide a current review in understanding how inequities based specifically on the aforementioned social determinants on health influence the prevalence of visual impairment and blindness. With regards to gender inequality, women have a higher prevalence of visual impairment and blindness, which cannot be only reasoned based on age or access to service. Socioeconomic status measured as higher income, higher educational status, or non-manual occupational social class was inversely associated with prevalence of blindness or visual impairment. Ethnicity and race were associated with visual impairment and blindness, although there is general confusion over this socioeconomic position determinant. Geographic inequalities and visual impairment were related to income (of the region, nation or continent), living in a rural area, and an association with socioeconomic and political context was suggested. While inequalities related to blindness and visual impairment have rarely been specifically addressed in research, there is still evidence of the association of social determinants and prevalence of blindness and visual impairment. Additional research should be done on the associations with intermediary determinants and socioeconomic and political context. PMID- 22944746 TI - The accomplishments of the global initiative VISION 2020: The Right to Sight and the focus for the next 8 years of the campaign. AB - In the first 12 years of VISION 2020 sound programmatic approaches have been developed that are capable of delivering equitable eye health services to even the most remote and impoverished communities. A body of evidence around the economic arguments for investment in eye health has been developed that has fuelled successful advocacy work resulting in supportive high level policy statements. More than a 100 national plans to achieve the elimination of avoidable blindness have been developed and some notable contributions made from the corporate and government sectors to resource eye health programs. Good progress has been made to control infectious blinding diseases and at the very least there is anecdotal evidence to suggest that the global increase in the prevalence of blindness and visual impairment has been reversed in recent years, despite the ever increasing and more elderly global population. However if we are to achieve the goal of VISION 2020 we require a considerable scaling up of current efforts-this will depend on our future success in two key areas: i) Successful advocacy and engagement at individual country level to secure significantly enhanced national government commitment to financing their own VISION 2020 plans.ii) A new approach to VISION 2020 thinking that integrates eye health into health system development and develops new partnerships with wider health development initiatives. PMID- 22944747 TI - Future trends in global blindness. AB - The objective of this review is to discuss the available data on the prevalence and causes of global blindness, and some of the associated trends and limitations seen. A literature search was conducted using the terms "global AND blindness" and "global AND vision AND impairment", resulting in seven appropriate articles for this review. Since 1990 the estimate of global prevalence of blindness has gradually decreased when considering the best corrected visual acuity definition: 0.71% in 1990, 0.59% in 2002, and 0.55% in 2010, corresponding to a 0.73% reduction per year over the 2002-2010 period. Significant limitations were found in the comparability between the global estimates in prevalence or causes of blindness or visual impairment. These limitations arise from various factors such as uncertainties about the true cause of the impairment, the use of different definitions and methods, and the absence of data from a number of geographical areas, leading to various extrapolation methods, which in turn seriously limit comparability. Seminal to this discussion on limitations in the comparability of studies and data, is that blindness has historically been defined using best corrected visual acuity. PMID- 22944748 TI - Integrated model of primary and secondary eye care for underserved rural areas: the L V Prasad Eye Institute experience. AB - Blindness is a major global public health problem and recent estimates from World Health Organization (WHO) showed that in India there were 62 million visually impaired, of whom 8 million are blind. The Andhra Pradesh Eye Disease Study (APEDS) provided a comprehensive estimate for prevalence and causes of blindness for the state of Andhra Pradesh (AP). It also highlighted that uptake of services was also an issue, predominantly among lower socio-economic groups, women, and rural populations. On the basis of this analysis, L V Prasad Eye Institute (LVPEI) developed a pyramidal model of eye care delivery. This article describes the LVPEI eye care delivery model. The article discusses infrastructure development, human resource development, and service delivery (including prevention and promotion) in the context of primary and secondary care service delivery in rural areas. The article also alludes to opportunities for research at these levels of service delivery and the amenability of the evidence generated at these levels of the LVPEI eye health pyramid for advocacy and policy planning. In addition, management issues related to the sustainability of service delivery in rural areas are discussed. The article highlights the key factors required for the success of the LVPEI rural service delivery model and discusses challenges that need to be overcome to replicate the model. The article concludes by noting the potential to convert these challenges into opportunities by integrating certain aspects of the existing healthcare system into the model. Examples include screening of diabetes and diabetic retinopathy in order to promote higher community participation. The results of such integration can serve as evidence for advocacy and policy. PMID- 22944749 TI - The role of optometrists in India: an integral part of an eye health team. AB - India has a proud tradition of blindness prevention, being the first country in the world to implement a blindness control programme which focused on a model to address blinding eye disease. However, with 133 million people blind or vision impaired due to the lack of an eye examination and provision of an appropriate pair of spectacles, it is imperative to establish a cadre of eye care professionals to work in conjunction with ophthalmologists to deliver comprehensive eye care. The integration of highly educated four year trained optometrists into primary health services is a practical means of correcting refractive error and detecting ocular disease, enabling co-managed care between ophthalmologists and optometrists. At present, the training of optometrists varies from two year trained ophthalmic assistants/optometrists or refractionists to four year degree trained optometrists. The profession of optometry in India is not regulated, integrated into the health care system or recognised by the majority of people in India as provider of comprehensive eye care services. In the last two years, the profession of optometry in India is beginning to take the necessary steps to gain recognition and regulation to become an independent primary health care profession. The formation of the Indian Optometry Federation as the single peak body of optometry in India and the soon to be established Optometry Council of India are key organisations working towards the development and regulation of optometry. PMID- 22944750 TI - What the comprehensive economics of blindness and visual impairment can help us understand. AB - Since the year 2000, the amount written about the economics of blindness and visual impairment has increased substantially. In some cases, the studies listed under this heading are calculations of the costs related to vision impairment and blindness at a national or global level; in other cases the studies examine the cost-effectiveness of strategies to prevent or modify visual impairment or blindness that are intended to be applied as a guide to treatment recommendations and coverage decisions. In each case the references are just examples of many that could be cited. These important studies have helped advocates, policy makers, practitioners, educators, and others interested in eye and vision health to understand the magnitude of the impact that visual impairment and blindness have on the world, regions, nations, and individuals and the tradeoffs that need to be made to limit the impact. However, these studies only begin to tap into the insights that economic logic might offer to those interested in this field. This paper presents multiple case studies that demonstrate that the economics of blindness and visual impairment encompasses much more than simply measures of the burden of the condition. Case studies demonstrating the usefulness of economic insight include analysis of the prevention of conditions that lead to impairment, decisions about refractive error and presbyopia, decisions about disease and injury treatment, decisions about behavior among those with uncorrectable impairment, and decisions about how to regulate the market all have important economic inputs. PMID- 22944751 TI - Millennium development goals and eye health. AB - In September 2000, world leaders made a commitment to build a more equitable, prosperous and safer world by 2015 and launched the Millennium Development Goals (MDGs). In the previous year, the World Health Organization and the International Agency for the Prevention of Blindness in partnership launched the global initiative to eliminate avoidable blindness by the year 2020-VISION 2020 the Right to Sight. It has focused on the prevention of a disability-blindness and recognized a health issue-sight as a human right. Both global initiatives have made considerable progress with synergy especially on MDG 1-the reduction of poverty and the reduction in numbers of the blind. A review of the MDGs has identified the need to address disparities within and between countries, quality, and disability. Noncommunicable diseases are emerging as a challenge to the MDGs and Vision 2020:0 the Right to Sight. For the future, up to and beyond 2015, there will be need for both initiatives to continue to work in synergy to address present and emerging challenges. PMID- 22944752 TI - Rapid assessment methods in eye care: an overview. AB - Reliable information is required for the planning and management of eye care services. While classical research methods provide reliable estimates, they are prohibitively expensive and resource intensive. Rapid assessment (RA) methods are indispensable tools in situations where data are needed quickly and where time- or cost-related factors prohibit the use of classical epidemiological surveys. These methods have been developed and field tested, and can be applied across almost the entire gamut of health care. The 1990s witnessed the emergence of RA methods in eye care for cataract, onchocerciasis, and trachoma and, more recently, the main causes of avoidable blindness and visual impairment. The important features of RA methods include the use of local resources, simplified sampling methodology, and a simple examination protocol/data collection method that can be performed by locally available personnel. The analysis is quick and easy to interpret. The entire process is inexpensive, so the survey may be repeated once every 5-10 years to assess the changing trends in disease burden. RA survey methods are typically linked with an intervention. This article provides an overview of the RA methods commonly used in eye care, and emphasizes the selection of appropriate methods based on the local need and context. PMID- 22944753 TI - Turning the tide of corneal blindness. AB - Corneal diseases represent the second leading cause of blindness in most developing world countries. Worldwide, major investments in public health infrastructure and primary eye care services have built a strong foundation for preventing future corneal blindness. However, there are an estimated 4.9 million bilaterally corneal blind persons worldwide who could potentially have their sight restored through corneal transplantation. Traditionally, barriers to increased corneal transplantation have been daunting, with limited tissue availability and lack of trained corneal surgeons making widespread keratoplasty services cost prohibitive and logistically unfeasible. The ascendancy of cataract surgical rates and more robust eye care infrastructure of several Asian and African countries now provide a solid base from which to dramatically expand corneal transplantation rates. India emerges as a clear global priority as it has the world's largest corneal blind population and strong infrastructural readiness to rapidly scale its keratoplasty numbers. Technological modernization of the eye bank infrastructure must follow suit. Two key factors are the development of professional eye bank managers and the establishment of Hospital Cornea Recovery Programs. Recent adaptation of these modern eye banking models in India have led to corresponding high growth rates in the procurement of transplantable tissues, improved utilization rates, operating efficiency realization, and increased financial sustainability. The widespread adaptation of lamellar keratoplasty techniques also holds promise to improve corneal transplant success rates. The global ophthalmic community is now poised to scale up widespread access to corneal transplantation to meet the needs of the millions who are currently blind. PMID- 22944754 TI - The worldwide epidemic of diabetic retinopathy. AB - Diabetic retinopathy (DR), a major microvascular complication of diabetes, has a significant impact on the world's health systems. Globally, the number of people with DR will grow from 126.6 million in 2010 to 191.0 million by 2030, and we estimate that the number with vision-threatening diabetic retinopathy (VTDR) will increase from 37.3 million to 56.3 million, if prompt action is not taken. Despite growing evidence documenting the effectiveness of routine DR screening and early treatment, DR frequently leads to poor visual functioning and represents the leading cause of blindness in working-age populations. DR has been neglected in health-care research and planning in many low-income countries, where access to trained eye-care professionals and tertiary eye-care services may be inadequate. Demand for, as well as, supply of services may be a problem. Rates of compliance with diabetes medications and annual eye examinations may be low, the reasons for which are multifactorial. Innovative and comprehensive approaches are needed to reduce the risk of vision loss by prompt diagnosis and early treatment of VTDR. PMID- 22944755 TI - Uncorrected refractive errors. AB - Global estimates indicate that more than 2.3 billion people in the world suffer from poor vision due to refractive error; of which 670 million people are considered visually impaired because they do not have access to corrective treatment. Refractive errors, if uncorrected, results in an impaired quality of life for millions of people worldwide, irrespective of their age, sex and ethnicity. Over the past decade, a series of studies using a survey methodology, referred to as Refractive Error Study in Children (RESC), were performed in populations with different ethnic origins and cultural settings. These studies confirmed that the prevalence of uncorrected refractive errors is considerably high for children in low-and-middle-income countries. Furthermore, uncorrected refractive error has been noted to have extensive social and economic impacts, such as limiting educational and employment opportunities of economically active persons, healthy individuals and communities. The key public health challenges presented by uncorrected refractive errors, the leading cause of vision impairment across the world, require urgent attention. To address these issues, it is critical to focus on the development of human resources and sustainable methods of service delivery. This paper discusses three core pillars to addressing the challenges posed by uncorrected refractive errors: Human Resource (HR) Development, Service Development and Social Entrepreneurship. PMID- 22944756 TI - Elimination of avoidable blindness due to cataract: where do we prioritize and how should we monitor this decade? AB - BACKGROUND: In the final push toward the elimination of avoidable blindness, cataract occupies a position of eminence for the success of the Right to Sight initiative. AIMS: Review existing situation and assess what monitoring indicators may be useful to chart progress towards attaining the goals of Vision 2020. SETTINGS AND DESIGN: Review of published papers from low and middle income countries since 2000. MATERIALS AND METHODS: Published population-based data on prevalence of cataract blindness/visual impairment were accessed and prevalence of cataract blindness/visual impairment computed, where not reported. Data on prevalence of cataract blindness, cataract surgical coverage at different visual acuity cut offs, surgical outcomes, and prevalence of cataract surgery were analyzed. Scatter plots were used to look at relationships of some variables, with Human Development Index (HDI) rank. Available data on Cataract Surgical Rate (CSR) was plotted against prevalence of cataract surgery reported from surveys. RESULTS: Worse HDI Ranks were associated with higher prevalence of cataract blindness. Most studies showed that a significant proportion of the blind were covered by surgery, while a fifth showed that a significant proportion, were operated before they went blind. A good visual outcome after surgery was positively correlated with higher surgical coverage. CSR was positively correlated with cataract surgical coverage. CONCLUSIONS: Cataract surgical coverage is increasing in most countries at vision <3/60 and visual outcomes after cataract surgery are improving. Establishing population-based surveillance of cataract surgical need and performance is a strong monitoring tool and will help program planners immensely. PMID- 22944757 TI - Glaucoma in developing countries. AB - OBJECTIVE: To describe the background and strategy required for the prevention of blindness from glaucoma in developing countries. MATERIALS AND METHODS: Extrapolation of existing data and experience in eye care delivery and teaching models in an unequally developed country (India) are used to make recommendations. RESULTS: Parameters like population attributable risk percentage indicate that glaucoma is a public health problem but lack of simple diagnostic techniques and therapeutic interventions are barriers to any effective plan. Case detection rather than population-based screening is the recommended strategy for detection. Population awareness of the disease is low and most patients attending eye clinics do not receive a routine comprehensive eye examination that is required to detect glaucoma (and other potentially blinding eye diseases). Such a routine is not taught or practiced by the majority of training institutions either. Angle closure can be detected clinically and relatively simple interventions (including well performed cataract surgery) can prevent blindness from this condition. The strategy for open angle glaucoma should focus on those with established functional loss. Outcomes of this proposed strategy are not yet available. CONCLUSIONS: Glaucoma cannot be managed in isolation. The objective should be to detect and manage all potential causes of blindness and prevention of blindness from glaucoma should be integrated into existing programs. The original pyramidal model of eye care delivery incorporates this principle and provides an initial starting point. The routine of comprehensive eye examination in every clinic and its teaching (and use) in residency programs is mandatory for the detection and management of potentially preventable blinding pathology from any cause, including glaucoma. Programs for detection of glaucoma should not be initiated unless adequate facilities for diagnosis and surgical intervention are in place and their monitoring requires reporting of functional outcomes rather than number of operations performed. PMID- 22944758 TI - Eye conditions and blindness in children: priorities for research, programs, and policy with a focus on childhood cataract. AB - The major causes of blindness in children encompass intrauterine and acquired infectious diseases, teratogens and developmental and molecular genetics, nutritional factors, the consequences of preterm birth, and tumors. A multidisciplinary approach is therefore needed. In terms of the major avoidable causes (i.e., those that can be prevented or treated) the available evidence shows that these vary in importance from country to country, as well as over time. This is because the underlying causes closely reflect socioeconomic development and the social determinants of health, as well as the provision of preventive and therapeutic programs and services from the community through to tertiary levels of care. The control of blindness in children therefore requires not only strategies that reflect the local epidemiology and the needs and priorities of communities, but also a well functioning, accessible health system which operates within an enabling and conducive policy environment. In this article we use cataract in children as an example and make the case for health financing systems that do not lead to 'catastrophic health expenditure' for affected families, and the integration of eye health for children into those elements of the health system that work closely with mothers and their children. PMID- 22944759 TI - Critical issues in implementing low vision care in the Asia-Pacific region. AB - Two-thirds of the world's population with low vision resides in the Asia-Pacific region. Provision of comprehensive low vision services is important to improve vision-related quality of life (QoL) for people with this condition. This review outlines the critical issues and challenges facing the provision of low vision services in the Asia-Pacific region. The review offers possible strategies to tackle these issues and challenges facing service providers and policy makers in lieu of Vision 2020 strategies in this area. Pertinent findings from the global survey of low vision services and extensive ground work conducted in the region are used; in addition, a discussion on the availability of services, human resources and training, and funding and the future sustainability of low vision care will be covered. In summary, current issues and challenges facing the region are the lack of specific evidence-based data, access, appropriate equipment and facilities, human resources, funding, and sustainability. These issues are inextricably interlinked and thus cannot be addressed in isolation. The solutions proposed cover all areas of the VISION 2020 strategy that include service delivery, human resources, infrastructure and equipment, advocacy and partnership; and include provision of comprehensive care via vertical and horizontal integration; strengthening primary level care in the community; providing formal and informal training to enable task shifting and capacity building; and promoting strong government and private sector partnership to achieve long-term service financial sustainability. PMID- 22944760 TI - Vision-related research priorities and how to finance them. AB - A number of organizations have employed a consultative process with the vision community to engage relevant parties in identifying needs and opportunities for vision research. The National Eye Institute in the US and the European Commission are currently undergoing consultation to develop priorities for vision research. Once these priorities have been established, the challenge will be to identify the resources to advance these research agendas. Success rates for Federal funding for research have decreased recently in the USA, UK, and Australia. Researchers should consider various potential funding sources for their research. The universal consideration for funding is that the reason for funding should align with the mission of the funding organization. In addition to Federal research organizations that fund investigator-initiated research, other potential funding sources include nongovernmental organizations, for-profit companies, individual philanthropy, and service organizations. In addition to aligning with organizational funding priorities, researchers need to consider turn-around time and total funds available including whether an organization will cover institutional indirect costs. Websites are useful tools to find information about organizations that fund research, including grant deadlines. Collaboration is encouraged. PMID- 22944761 TI - The challenges in improving outcome of cataract surgery in low and middle income countries. AB - Cataract is the leading cause of blindness globally and surgery is the only known measure to deal with it effectively. Providing high quality cataract surgical services is critical if patients with cataract are to have their sight restored. A key focus of surgery is the outcome of the procedure. In cataract surgery this is measured predominantly, using visual acuity. Population- and hospital-based studies have revealed that the visual outcome of cataract surgery in many low and middle income settings is frequently sub-optimal, often failing to reach the recommended standards set by the World Health Organization (WHO). Another way of measuring outcome of cataract surgery is to ask patients for their views on whether surgery has changed the functioning of their eyes and their quality of life. There are different tools available to capture patient views and now, these patient-reported outcomes are becoming more widely used. This paper discusses the visual outcome of cataract surgery and frames the outcome of surgery within the context of the surgical service, suggesting that the process and outcome of care cannot be separated. It also discusses the components of patient-reported outcome tools and describes some available tools in more detail. Finally, it describes a hierarchy of challenges that need to be addressed before a high quality cataract surgical service can be achieved. PMID- 22944762 TI - Applying principles of health system strengthening to eye care. AB - Understanding health systems have now become the priority focus of researchers and policy makers, who have progressively moved away from a project-centred perspectives. The new tendency is to facilitate a convergence between health system developers and disease-specific programme managers in terms of both thinking and action, and to reconcile both approaches: one focusing on integrated health systems and improving the health status of the population and the other aiming at improving access to health care. Eye care interventions particularly in developing countries have generally been vertically implemented (e.g. trachoma, cataract surgeries) often with parallel organizational structures or specialised disease specific services. With the emergence of health system strengthening in health strategies and in the service delivery of interventions there is a need to clarify and examine inputs in terms governance, financing and management. This present paper aims to clarify key concepts in health system strengthening and describe the various components of the framework as applied in eye care interventions. PMID- 22944763 TI - The global cost of eliminating avoidable blindness. AB - AIMS: To complete an initial estimate of the global cost of eliminating avoidable blindness, including the investment required to build ongoing primary and secondary health care systems, as well as to eliminate the 'backlog' of avoidable blindness. This analysis also seeks to understand and articulate where key data limitations lie. MATERIALS AND METHODS: Data were collected in line with a global estimation approach, including separate costing frameworks for the primary and secondary care sectors, and the treatment of backlog. RESULTS: The global direct health cost to eliminate avoidable blindness over a 10-year period from 2011 to 2020 is estimated at $632 billion per year (2009 US$). As countries already spend $592 billion per annum on eye health, this represents additional investment of $397.8 billion over 10 years, which is $40 billion per year or $5.80 per person for each year between 2010 and 2020. This is concentrated in high-income nations, which require 68% of the investment but comprise 16% of the world's inhabitants. For all other regions, the additional investment required is $127 billion. CONCLUSIONS: This costing estimate has identified that low- and middle-income countries require less than half the additional investment compared with high income nations. Low- and middle-income countries comprise the greater investment proportion in secondary care whereas high-income countries require the majority of investment into the primary sector. However, there is a need to improve sector data. Investment in better data will have positive flow-on effects for the eye health sector. PMID- 22944764 TI - Causes, epidemiology, and long-term outcome of traumatic cataracts in children in rural India. AB - PURPOSE: To describe preoperative factors, long-term (>3 years) postoperative outcome and cost of traumatic cataracts in children in predominantly rural districts of western India. Subjects : Eighty-two traumatic cataracts in 81 children in a pediatric ophthalmology department of a tertiary eye-care center. MATERIALS AND METHODS: Traumatic cataracts operated in 2004-2008 were reexamined prospectively in 2010-2011 using standardized technique. Cause and type of trauma, demographic factors, surgical intervention, complications, and visual acuity was recorded. STATISTICAL ANALYSIS: Data analysis done by using SPSS (Statistical package for social sciences) version 17.0 We have used Chi-square test, Fisher's exact test, paired t-test to find the association between the final vision and various parameters at 5% level of significance; binary logistic regression was performed for visual outcome >=6/18 and >=6/60. RESULTS: The children were examined in a 3-7 year follow-up (4.35 +/- 1.54). Average age at time of surgery was 10.4 +/- 4.43 years (1.03 to 18). Fifty (61.7%) were boys. Forty (48.8%) were blunt and 32 (39%) were sharp trauma. The most common cause was wooden stick 23 (28.0%) and sharp thorn 14 (17.1%). Delay between trauma and presentation to hospital ranged from same day to 12 years after the injury with median of 4 days. The mean preoperative visual acuity by decimal notation was 0.059 +/- 0.073 and mean postoperative visual acuity was 0.483 +/- 0.417 (P < 0.001). Thirty-eight (46.3%) had best corrected visual acuity (BCVA) >=6/18 and 51 (62.2%) had BCVA >= 6/60. In univariable analysis, visual outcome (>=6/18) depended on type of surgery (P = 0.002), gender (P = 0.028), and type of injury (P = 0.07)-sharp trauma and open globe injury had poorer outcomes; but not on age of child, preoperative vision, and type of surgeon. On multivariable binary logistic regression, only gender was significant variable. Of the 82 eyes, 18 (22%) needed more than one surgery. The parents spent an average of Rs. 2250 ($45) for the surgery and 55 (66.4%) were from lower socio-economic class. CONCLUSION: The postoperative visual outcomes varied and less than half achieved >= 6/18. PMID- 22944765 TI - Key factors determining success of primary eye care through vision centres in rural India: patients' perspectives. AB - AIM: This paper intends to discuss the patients' perspective on the determinants of primary eye care services from vision centers (VC) in rural India. MATERIALS AND METHODS: A retrospective study design and interview method was used on 127 randomly selected patients who accessed the 4 VCs in 2007. Factor analyses and linear regression models were used to predict the associations with patient satisfaction. RESULTS: The three factors derived from factor analyses were: (1) vision technician (VT), (2)-location of VC, and (3)-access to VC; explaining 60% of the variance in total patients' satisfaction with VC. The first model (R2 : 0.61; F 1,124=144.36, P <0.001), indicated that respondents who had 'difficulty to travel to the place of VC' and those who can afford to pay had less satisfaction with VT services. The second model (R2 =0.18; F 1,124=29.5, P <0.001) explained that respondents' difficulty to identify the building of VC had decreased patients' satisfaction and the third model (R2 =0.36; F 1,124=45.6, P <0.001) indicated that those who had to travel<5 km to the VC and had 0.38 units of increased satisfaction level with the services of VC. CONCLUSION: A good VT can enhance patient satisfaction. However, patient expectations are not only confined to the provider but also other factors such as ability to pay and convenient transportation that helps patients reach the location of the VC with ease. PMID- 22944767 TI - Mathematical model of electrotaxis in osteoblastic cells. AB - Electrotaxis is the cell migration in the presence of an electric field (EF). This migration is parallel to the EF vector and overrides chemical migration cues. In this paper we introduce a mathematical model for the electrotaxis in osteoblastic cells. The model is evaluated using different EF strengths and different configurations of both electrical and chemical stimuli. Accordingly, we found that the cell migration speed is described as the combination of an electrical and a chemical term. Cell migration is faster when both stimuli orient cell migration towards the same direction. In contrast, a reduced speed is obtained when the EF vector is opposed to the direction of the chemical stimulus. Numerical relations were obtained to quantify the cell migration speed at each configuration. Additional calculations for the cell colonization of a substrate also show mediation of the EF strength. Therefore, the term electro osteoconduction is introduced to account the electrically induced cell colonization. Since numerical results compare favorably with experimental evidence, the model is suitable to be extended to other types of cells, and to numerically explore the influence of EF during wound healing. PMID- 22944766 TI - Changing trends in the prevalence of blindness and visual impairment in a rural district of India: systematic observations over a decade. AB - Context : Globally, limited data are available on changing trends of blindness from a single region. Aims : To report the changing trends in the prevalence of blindness, visual impairment (VI), and visual outcomes of cataract surgery in a rural district of Andhra Pradesh, India, over period of one decade. Settings and Design : Rural setting; cross-sectional study. Materials and Methods : Using a validated Rapid Assessment of Cataract Surgical Services (RACSS) method, population-based, cross-sectional survey was done in a rural district in the state of Andhra Pradesh, India. Two-stage sampling procedure was used to select participants >=50 years of age. Further, a comparative analysis was done with participants >=50 years from the previously concluded Andhra Pradesh Eye Disease Study (APEDS) study, who belonged to the same district. Statistical Analysis : Done using 11 th version of Stata. Results : Using RACSS, 2160/2300 (93.9%) participants were examined as compared with the APEDS dataset (n=521). Age and sex adjusted prevalence of blindness in RACSS and APEDS was 8% (95% CI, 6.9-9.1%) and 11% (95% CI, 8.3-13.7%), while that of VI was 13.6% (95% CI, 12.2-15.1%) and 40.3% (95% CI, 36.1-44.5%), respectively. Cataract was the major cause of blindness in both the studies. There was a significant reduction in blindness following cataract surgery as observed through RACSS (17.3%; 95% CI, 13.5-21.8%) compared with APEDS (34%; 95% CI, 20.9-49.3%). Conclusion : There was a significant reduction in prevalence of blindness and VI in this rural district of India over a decade. PMID- 22944769 TI - Nanocrystalline iron oxide synthesised within Hierarchical Porous Silica prepared by nanoemulsion templating. AB - PIC (Phase Inversion Composition) O-W nanoemulsions was used as a template for the synthesis of Hierarchical Porous Silica (HPS), and the oil phase of the nanoemulsion was used as a nanoreactor for the preparation of magnetic gamma Fe(2)O(3) nanoparticles, confined within the silica matrix. PMID- 22944768 TI - IGHV gene features and MYD88 L265P mutation separate the three marginal zone lymphoma entities and Waldenstrom macroglobulinemia/lymphoplasmacytic lymphomas. AB - To clarify the relationships between marginal zone lymphomas (MZLs) and Waldenstrom macroglobulinemia/lymphoplasmacytic lymphomas (WM/LPLs), immunoglobulin heavy chain variable gene (IGHV) features were analyzed and the occurrence of MYD88 L265P mutations was identified in a series of 123 patients: 53 MZLs from the spleen (SMZLs), 11 from lymph nodes (NMZLs), 28 mucosa associated lymphatic tissue (MALT) lymphomas and 31 WM/LPLs. SMZLs were characterized by overrepresentation of IGHV1-2 gene rearrangements with a canonical motif, without selection pressure and with long CDR3 segments. NMZLs had increased frequencies of IGHV3 genes. The IGHV gene was unmutated in most cases, often with long CDR3 segments. MALT lymphomas were usually associated with a mutated IGHV gene, but with the absence of selection pressure. WM/LPLs were associated with an IGHV3-23 overrepresentation and high IGHV mutation rate, with features of selection pressure and short CDR3 segments. MYD88 L265P mutations were almost restricted exclusively to WM/LPL patients. Taken all diagnoses together, all patients with MYD88 L265P mutations had an immunoglobulin M peak and almost all patients except one had bone marrow infiltration. These results demonstrate that the history of antigen exposure of the four entities studied was different and MYD88 L265P was specifically associated with WM/LPLs. WM/LPL may thus be functionally associated with constitutive nuclear factor-kappaB activation. PMID- 22944770 TI - Preventive effects of conjugated linoleic acid on obesity by improved physical activity in nescient basic helix-loop-helix 2 knockout mice during growth period. AB - The purpose of this study was to evaluate whether conjugated linoleic acid (CLA) exposure during the developmental period increases voluntary activity, which would influence obesity outcome later in life. The effects of dietary supplementation of 0.5% CLA in a high fat diet were evaluated in nescient basic helix-loop-helix 2 (Nhlh2) knock-out (N2KO) mice, which is a unique animal model representing inactivity-induced obesity in a pre-obese condition. Male wild type and N2KO mice were fed either control or CLA (0.5%) diet for 8 weeks. As expected, control diet fed N2KO animals showed greater body weight with decreased physical activity in the late stage of the experimental period compared with wild type control. Dietary CLA significantly decreased body weight and adipose depots in both wild type and N2KO mice, and the body weights of both genotypes fed CLA were similar during the experimental period. CLA exposure during the developmental period significantly improved the impairment of physical activity in N2KO mice, but the wild type did not show any effect of CLA. In both genotypes, CLA significantly reduced serum triglycerides levels and down regulated the mRNA expressions of CCAAT/enhancer binding protein alpha (C/EBPalpha) and leptin in white adipose tissue. These findings suggest that early CLA exposure could prevent obesity with improved voluntary physical activity in N2KO mice. PMID- 22944771 TI - Genetic characterisation and molecular epidemiology of Ascaris spp. from humans and pigs in Brazil. AB - The molecular epidemiology of Ascaris spp. of human and pig origin has been studied as a means to assess the potential of pigs as reservoirs for human ascariasis. In this study, human (H) and pig (P) Ascaris spp. haplotypes from two Brazilian regions were characterised based on two mitochondrial genes, nad1 and cox1. The results show six haplotypes of the cox1 gene, with two haplotypes (H9P9 and P3) corresponding to haplotypes previously characterised in China. Because P3 was found in humans in this study, it was designated as H14P3. Furthermore, five new Ascaris spp. nad1 haplotypes from humans (H12-H16) and five from pigs (P16 P20) were observed, with one being highly frequent and present in both hosts, here designated as H12P17. Phylogenetic and network analysis demonstrated that the molecular epidemiology of Ascaris spp. in Brazil is driven by the globally distributed haplotypes cox1 H14P3 and nad1 H12P17. In conclusion, in this study genetic characterisation of Ascaris spp. showed that humans and pigs share common haplotypes that are also present in two widely separated geographical regions of Brazil. PMID- 22944772 TI - Discovery of N6-phenyl-1H-pyrazolo[3,4-d]pyrimidine-3,6-diamine derivatives as novel CK1 inhibitors using common-feature pharmacophore model based virtual screening and hit-to-lead optimization. AB - Aberrant activation of casein kinase 1 (CK1) has been demonstrated to be implicated in the pathogenesis of cancer and various central nervous system disorders. Discovery of CK1 inhibitors has thus attracted much attention in recent years. In this account, we describe the discovery of N6-phenyl-1H pyrazolo[3,4-d]pyrimidine-3,6-diamine derivatives as novel CK1 inhibitors. An optimal common-feature pharmacophore hypothesis, termed Hypo2, was firstly generated, followed by virtual screening using Hypo2 against several chemical databases. One of the best hit compounds, N6-(4-chlorophenyl)-1H-pyrazolo[3,4 d]pyrimidine-3,6-diamine, was chosen for the subsequent hit-to-lead optimization under the guide of Hypo2, which led to the discovery of a new lead compound (1-(3 (3-amino-1H-pyrazolo[3,4-d]pyrimidin-6-ylamino)phenyl)-3-(3-chloro-4 fluorophenyl)urea) that potently inhibits CK1 with an IC(50) value of 78 nM. PMID- 22944798 TI - An automated approach to analyze microstructural remodeling from confocal microscopies of ventricular myocytes from diseased hearts. PMID- 22944866 TI - Informatics competencies for healthcare professionals: the Technology Informatics Guiding Education Reform (TIGER) Initiative model. AB - A growing awareness exists that informatics competencies are essential skills for healthcare professionals today, yet the development of these competencies lags behind the need. The Technology Informatics Guiding Education Reform (TIGER) Initiative represents a comprehensive, interdisciplinary effort that is well suited to the integration of informatics into education, practice, administration, and research environments. This article briefly discusses the background and significance of the TIGER Initiative and why it may be used as a model to instill informatics among the healthcare professionals globally. PMID- 22944867 TI - European Best Practice Guidelines for Quality Assurance, Provision and Use of Genome-based Information and Technologies: the 2012 Declaration of Rome. PMID- 22944870 TI - Directed differentiation of embryonic P19 cells and neural stem cells into neural lineage on conducting PEDOT-PEG and ITO glass substrates. AB - Differentiation of pluripotent and lineage restricted stem cells such as neural stem cells (NSCs) was studied on conducting substrates of various nature without perturbation of the genome with exogenous genetic material or chemical stimuli. Primary mouse adult neural stem cells (NSCs) and P19 pluripotent embryonal (P19 EC) carcinoma cells were used. Expression levels of neuronal markers beta-III tubulin and neurofilament were evaluated by immunochemistry and flow cytometry. It was shown that the ability of the substrate to induce differentiation directly correlated with its conductivity. Conducting substrates (conducting oxides or doped pi-conjugated organic polymers) with different morphology, structure, and conductivity mechanisms all promoted differentiation of NSC and P19 cells into neuronal lineage to a similar degree without use of additional factors such as poly-L-ornithine coating or retinoic acid, as verified by their morphology and upregulation of the neuronal markers but not astrocyte marker GFAP. However, substrates with low conductance below ca. 10(-4) S cm(-2) did not show this ability. Morphology of differentiating cells was visualized by atomic force microscopy. NSCs cells increased beta-III-tubulin expression by 95% and P19 cells by over 30%. Our results suggest that the substrate conductivity is a key factor governing the cell fate. Differentiation of P19 cells into neuronal lineage on conducting substrates was attributed to downregualtion of Akt signaling pathway and increase in expression of dual oxidase 1 (DUOX 1). PMID- 22944871 TI - Fulminant subacute sclerosing panencephalitis in an individual with a perinatally acquired human immunodeficiency virus infection. AB - BACKGROUND Case reports of subacute sclerosing panencephalitis (SSPE) in individuals with human immunodeficiency virus (HIV) infection are scarce, and the natural history is unclear. To our knowledge, a fulminant presentation has not yet been described. OBJECTIVE To describe a case of fulminant SSPE in an individual with a perinatally acquired HIV infection. DESIGN Case report and literature review. SETTING Christian Medical College Hospital, Vellore, India. PATIENT A 17-year-old boy with a perinatally acquired HIV infection. RESULTS The patient presented with subacute-onset cognitive decline and myoclonic jerks with rapid deterioration of health (the patient died within 12 weeks of onset). The findings from magnetic resonance imaging and electroencephalography and the cerebrospinal fluid and serum measles antibody titers were suggestive of SSPE. The fulminant presentation in this case needs to be noted. CONCLUSIONS Along with the better life expectancy of HIV-infected individuals, there may be an increase in the incidence of SSPE in this population. Fulminant SSPE may be added to the spectrum of measles-associated neurological disorders in HIV. PMID- 22944872 TI - Effect of nonpayment for hospital-acquired, catheter-associated urinary tract infection: a statewide analysis. AB - BACKGROUND: Most (59% to 86%) hospital-acquired urinary tract infections (UTIs) are catheter-associated urinary tract infections (CAUTIs). As of 2008, claims data are used to deny payment for certain hospital-acquired conditions, including CAUTIs, and publicly report hospital performance. OBJECTIVE: To examine rates of UTIs in adults that are coded in claims data as hospital-acquired and catheter associated events and evaluate how often nonpayment for CAUTI lowers hospital payment. DESIGN: Before-and-after study of all-payer cross-sectional claims data. SETTING: 96 nonfederal acute care Michigan hospitals. PATIENTS: Nonobstetric adults discharged in 2007 (n = 767 531) and 2009 (n = 781 343). MEASUREMENTS: Hospital rates of UTIs (categorized as catheter-associated or hospital-acquired) and frequency of reduced payment for hospital-acquired CAUTIs. RESULTS: Hospitals frequently requested payment for non-CAUTIs as secondary diagnoses: 10.0% (95% CI, 9.5% to 10.5%) of discharges in 2007 and 10.3% (CI, 9.8% to 10.9%) in 2009. Hospital rates of CAUTI were very low: 0.09% (CI, 0.06% to 0.12%) in 2007 and 0.14% (CI, 0.11% to 0.17%) in 2009. In 2009, 2.6% (CI, 1.6% to 3.6%) of hospital acquired UTIs were described as CAUTIs. Nonpayment for hospital-acquired CAUTIs reduced payment for 25 of 781 343 (0.003%) hospitalizations in 2009. LIMITATIONS: Data are from only 1 state and involved only 1 year before and after nonpayment for complications. Hospital prevention practices were not examined. CONCLUSION: Catheter-associated UTI rates determined by claims data seem to be inaccurate and are much lower than expected from epidemiologic surveillance data. The financial impact of current nonpayment policy for hospital-acquired CAUTI is low. Claims data are currently not valid data sets for comparing hospital-acquired CAUTI rates for the purpose of public reporting or imposing financial incentives or penalties. PRIMARY FUNDING SOURCE: Blue Cross Blue Shield of Michigan Foundation. PMID- 22944873 TI - The immune reconstitution inflammatory syndrome after antiretroviral therapy initiation in patients with tuberculosis: findings from the SAPiT trial. AB - BACKGROUND: Concerns about the immune reconstitution inflammatory syndrome (IRIS) remain a barrier to antiretroviral therapy (ART) initiation during antituberculosis treatment in co-infected patients. OBJECTIVE: To assess IRIS incidence, severity, and outcomes relative to the timing of ART initiation in patients with HIV-related tuberculosis. DESIGN: Randomized, open-label clinical trial. (ClinicalTrials.gov registration number: NCT00398996) SETTING: An outpatient clinic in Durban, South Africa. PATIENTS: 642 patients co-infected with HIV and tuberculosis. MEASUREMENTS: In a secondary analysis of the SAPiT (Starting Antiretroviral Therapy at Three Points in Tuberculosis) trial, IRIS was assessed in patients randomly assigned to initiate ART within 4 weeks of tuberculosis treatment initiation (early integrated treatment group), within 4 weeks of completion of the intensive phase of tuberculosis treatment (late integrated treatment group), or within 4 weeks after tuberculosis therapy completion (sequential treatment group). The syndrome was defined as new-onset or worsening symptoms, signs, or radiographic manifestations temporally related to treatment initiation, accompanied by a treatment response. Severity of IRIS, hospitalization, and time to resolution were monitored. RESULTS: Incidence of IRIS was 19.5 (n = 43), 7.5 (n = 18), and 8.1 (n = 19) per 100 person-years in the early integrated, late integrated, and sequential treatment groups, respectively. Among patients with a baseline CD4+ count less than 0.050 * 109 cells/L, IRIS incidence was 45.5, 9.7, and 19.7 per 100 person-years in the early integrated, late integrated, and sequential treatment groups, respectively. Incidence of IRIS was higher in the early integrated treatment group than in the late integrated (incidence rate ratio, 2.6 [95% CI, 1.5 to 4.8]; P < 0.001) or sequential (incidence rate ratio, 2.4 [CI, 1.4 to 4.4]; P < 0.001) treatment groups. More severe IRIS cases occurred in the early integrated treatment group than in the other 2 groups (35% vs. 19%; P = 0.179), and patients in the early integrated treatment group had significantly higher hospitalization rates (42% vs. 14%; P = 0.007) and longer time to resolution (70.5 vs. 29.0 days; P = 0.001) than patients in the other 2 groups. LIMITATIONS: It was not possible to assess IRIS in more patients in the sequential treatment group (n = 74) than in the late integrated (n = 50) and early integrated (n = 32) treatment groups because of loss to follow-up, withdrawal, or death within 6 months of scheduled ART initiation. This study did not assess IRIS risk in nonambulatory patients or in those with extrapulmonary and smear-negative tuberculosis. CONCLUSION: Initiation of ART in early stages of tuberculosis treatment resulted in significantly higher IRIS rates, longer time to resolution, and more severe cases of IRIS requiring hospitalization. These findings are particularly relevant to patients initiating ART with a CD4+ count less than 0.050 * 109 cells/L, given the increased survival benefit of early ART initiation in this group. PRIMARY FUNDING SOURCE: Comprehensive International Program of Research on AIDS. PMID- 22944876 TI - The importance of accurate data in quality-of-care measurement. PMID- 22944875 TI - Are organic foods safer or healthier than conventional alternatives?: a systematic review. AB - BACKGROUND: The health benefits of organic foods are unclear. PURPOSE: To review evidence comparing the health effects of organic and conventional foods. DATA SOURCES: MEDLINE (January 1966 to May 2011), EMBASE, CAB Direct, Agricola, TOXNET, Cochrane Library (January 1966 to May 2009), and bibliographies of retrieved articles. STUDY SELECTION: English-language reports of comparisons of organically and conventionally grown food or of populations consuming these foods. DATA EXTRACTION: 2 independent investigators extracted data on methods, health outcomes, and nutrient and contaminant levels. DATA SYNTHESIS: 17 studies in humans and 223 studies of nutrient and contaminant levels in foods met inclusion criteria. Only 3 of the human studies examined clinical outcomes, finding no significant differences between populations by food type for allergic outcomes (eczema, wheeze, atopic sensitization) or symptomatic Campylobacter infection. Two studies reported significantly lower urinary pesticide levels among children consuming organic versus conventional diets, but studies of biomarker and nutrient levels in serum, urine, breast milk, and semen in adults did not identify clinically meaningful differences. All estimates of differences in nutrient and contaminant levels in foods were highly heterogeneous except for the estimate for phosphorus; phosphorus levels were significantly higher than in conventional produce, although this difference is not clinically significant. The risk for contamination with detectable pesticide residues was lower among organic than conventional produce (risk difference, 30% [CI, -37% to -23%]), but differences in risk for exceeding maximum allowed limits were small. Escherichia coli contamination risk did not differ between organic and conventional produce. Bacterial contamination of retail chicken and pork was common but unrelated to farming method. However, the risk for isolating bacteria resistant to 3 or more antibiotics was higher in conventional than in organic chicken and pork (risk difference, 33% [CI, 21% to 45%]). LIMITATION: Studies were heterogeneous and limited in number, and publication bias may be present. CONCLUSION: The published literature lacks strong evidence that organic foods are significantly more nutritious than conventional foods. Consumption of organic foods may reduce exposure to pesticide residues and antibiotic-resistant bacteria. PRIMARY FUNDING SOURCE: None. PMID- 22944877 TI - Knot. PMID- 22944879 TI - Dose response to vitamin D supplementation in postmenopausal women. PMID- 22944874 TI - U.S. trends in antiretroviral therapy use, HIV RNA plasma viral loads, and CD4 T lymphocyte cell counts among HIV-infected persons, 2000 to 2008. AB - BACKGROUND: The U.S. National HIV/AIDS Strategy targets for 2015 include "increasing access to care and improving health outcomes for persons living with HIV in the United States" (PLWH-US). OBJECTIVE: To demonstrate the utility of the NA-ACCORD (North American AIDS Cohort Collaboration on Research and Design) for monitoring trends in the HIV epidemic in the United States and to present trends in HIV treatment and related health outcomes. DESIGN: Trends from annual cross sectional analyses comparing patients from pooled, multicenter, prospective, clinical HIV cohort studies with PLWH-US, as reported to national surveillance systems in 40 states. SETTING: U.S. HIV outpatient clinics. PATIENTS: HIV infected adults with 1 or more HIV RNA plasma viral load (HIV VL) or CD4 T lymphocyte (CD4) cell count measured in any calendar year from 1 January 2000 to 31 December 2008. MEASUREMENTS: Annual rates of antiretroviral therapy use, HIV VL, and CD4 cell count at death. RESULTS: 45 529 HIV-infected persons received care in an NA-ACCORD-participating U.S. clinical cohort from 2000 to 2008. In 2008, the 26 030 NA-ACCORD participants in care and the 655 966 PLWH-US had qualitatively similar demographic characteristics. From 2000 to 2008, the proportion of participants prescribed highly active antiretroviral therapy increased by 9 percentage points to 83% (P < 0.001), whereas the proportion with suppressed HIV VL (<=2.7 log10 copies/mL) increased by 26 percentage points to 72% (P < 0.001). Median CD4 cell count at death more than tripled to 0.209 * 109 cells/L (P < 0.001). LIMITATION: The usual limitations of observational data apply. CONCLUSION: The NA-ACCORD is the largest cohort of HIV-infected adults in clinical care in the United States that is demographically similar to PLWH-US in 2008. From 2000 to 2008, increases were observed in the percentage of prescribed HAART, the percentage who achieved a suppressed HIV VL, and the median CD4 cell count at death. PRIMARY FUNDING SOURCE: National Institutes of Health; Centers for Disease Control and Prevention; Canadian Institutes of Health Research; Canadian HIV Trials Network; and the government of British Columbia, Canada. PMID- 22944881 TI - Antivirals for treatment of influenza. PMID- 22944882 TI - Antivirals for treatment of influenza. PMID- 22944884 TI - Diabetes mellitus and the Moyamoya syndrome. PMID- 22944886 TI - In the clinic. Pharyngitis. PMID- 22944887 TI - Site occupancy and magnetic properties of pyrochlore-structured AgOs2O6. AB - AgOs(2)O(6) prepared from ion-exchanged superconducting beta-pyrochlore KOs(2)O(6) has been shown to be non-superconducting. Synchrotron x-ray structure refinement suggests that AgOs(2)O(6) has the Ag ion mostly occupying the low symmetry 32e site in the [Formula: see text] space group of proper occupancy, which is different from the original major occupancy at the high-symmetry 8b site for KOs(2)O(6), and similar to non-superconducting Na(1.4)Os(2)O(6).H(2)O. Magnetic susceptibility measurements found no magnetic ordering down to ~1.7 K. The trace amount of isolated spins suggests that the Ag could be neutral and lead to a pure Os(6+) valence state of zero spin in the newly prepared AgOs(2)O(6). PMID- 22944888 TI - [Removal of foreign bodies]. PMID- 22944889 TI - [Foreign bodies in ENT medicine]. AB - A foreign body (Latin: corpus alienum) is any object originating outside the body. Of all specialties, otolaryngology covers the greatest number of natural body orifices, making foreign bodies a common diagnosis. Foreign bodies of the ear canal and nose often occur in children and are easily accessible during physical examination. Foreign bodies of the oral cavity and oropharynx are also easily removed. Esophageal and tracheobronchial foreign bodies are common in children and the elderly. A number of rigid and flexible endoscopic techniques are available for foreign body removal. In Germany, flexible endoscopy is six times more common than rigid endoscopy. Both methods are highly effective, and each has its advantages in certain situations. Rigid endoscopy is still a key in otolaryngology and can be used in case of failure of flexible techniques. It is therefore important for otolaryngologists to be proficient in both techniques. PMID- 22944890 TI - [Ingestion of foreign bodies in the gastrointestinal tract of children and adolescents]. AB - The diagnosis of foreign bodies in the gastrointestinal (G-I) tract can sometimes be difficult. Esophageal foreign bodies are dangerous and should be extracted as soon as possible whereas foreign bodies in the stomach usually pass through the GI-tract without complications. Exceptions are large, sharp or potentially toxic foreign bodies, such as button batteries or magnetic foreign bodies. Extraction by flexible endoscopy with the patient under deep sedation has proven to be effective, relatively minimally invasive and safe. Complications, such as ulcers, fistulas and perforations occur in 13% of patients and are strongly correlated to the localization in the esophagus. PMID- 22944891 TI - [Bronchial foreign bodies]. AB - Coughing, wheezing, dyspnea and recurrent pneumonia can be signs of foreign body aspiration. About 80% of all foreign body aspirations occur in children, especially in infants between 1 and 3 years of age. Although most foreign bodies are found in the bronchi they are especially dangerous in the larynx or trachea. Foreign body aspiration is less common in adults, being confirmed in only about 1 2 of every 1,000 bronchoscopies. The most common foreign bodies are foods particles. Bronchoscopy is the method of choice for foreign body removal. PMID- 22944892 TI - [Foreign bodies in the upper gastrointestinal tract]. AB - Foreign bodies in the upper GI tract are an important medical problem and cause about 5% of emergency endoscopies. Endoscopic removal is the method of the choice and is successful in 99% of cases. Nevertheless, endoscopic removal is not necessary in every case because most foreign bodies can pass through the digestive tract and be evacuated in the natural way. An immediate emergency endoscopy is indicated for foreign bodies in the esophagus with signs of obstruction, which is present in more than 75% of cases, because the risk of complications increases with retention time. The endoscopist has myriad possibilities for finding the best and safest way to extract the foreign body. PMID- 22944893 TI - [Evidence-based medicine, health-related quality of life, and outcomes research: utility and necessity of validated survey instruments]. PMID- 22944894 TI - [Two formulas for exact calculation of hearing loss for numbers]. AB - BACKGROUND: In Germany assessment of hearing loss for numbers is used to calculate the percentage hearing loss from speech audiometry and for plausibility checking with pure tone thresholds. It is common practice to take a graphical reading from the speech audiogram to determine the hearing loss for numbers. This study searches for a mathematical formula for the exact calculation of the hearing loss for numbers from the intelligibility values measured. METHODS: With analytical methods on the basis of the standard curve following DIN 45626-1, two simple formulas for the calculation of the hearing loss for numbers were developed. RESULTS: The hearing loss for numbers a(1) is calculated as a(1)=p(1)+(50-v(1)) (p(2)-p(1))/(v(2)-v(1))-18,4 for two available measured values and as a(1)=p(1)-0,13 v(1)-11,9 if only one measured value is used, with v(i )being number intelligibility in percent at the level p(i) in decibels (dB) of measurement number i. Number intelligibility of all inserted pairs of values must be between 30% and 70% because the standard curve of DIN 45626-1 runs approximately linearly only in this range. The calculated value for the hearing loss for numbers is subsequently mathematically rounded up to 5 dB as well as for the conventional graphically determined value. CONCLUSIONS: With the presented formulas the hearing loss for numbers can be calculated exactly from the measured values of the Freiburg number test especially in matters of expertise if the conventional graphical determination of this value does not seem to be unambiguous. PMID- 22944895 TI - [A 2-year-old child falls on its face]. AB - Foreign bodies in the face are often not discovered at first sight. If there is reasonable suspicion caused by anamnesis or by clinical examination of a facial foreign body, a CT scan should be done. However, consideration should be given to wooden foreign bodies, which may appear different depending on the water content and are therefore often misinterpreted. Wooden foreign bodies should be extracted immediately to avoid severe complications. After surgery, regular controls of the wound should be carried out to immediately recognize and treat infection of the lesion. PMID- 22944896 TI - [Vestibular schwannoma: Part I: epidemiology and diagnostics]. AB - Vestibular schwannoma is with 80% the most frequent of all tumors of the cerebellopontine angle. Usually, this benign, neuroectodermal, mostly unilateral occurring tumor is called acoustic neuroma, although it develops from the Schwann cells of the nerve sheath of the eighth cranial nerve. The tumor is localized in the meatus acusticus internus in the majority of cases. The most common initial symptom is a unilateral or, at least, asymmetric hearing loss. Other symptoms may include tinnitus and feeling of insecurity or vertigo, but adjacent cranial nerves may also be affected. Besides clinical and apparatus-based (neuro )otological diagnostics, MRI imaging has established itself as the gold standard with a sensitivity and specificity of up to 100%. PMID- 22944897 TI - Gamma-knife-based stereotactic radiosurgery for medium- and large-sized posterior uveal melanoma. AB - BACKGROUND: This study investigated the use of gamma-knife-based stereotactic radiosurgery (GKRS) for medium- and large-sized posterior uveal melanoma treatment. METHODS: We assessed 50 eyes from 50 consecutive patients with uveal melanoma who were treated with GKRS. All tumors met the criteria for medium- and large-sized uveal melanomas. Patients underwent a single session treatment under local anesthesia; the prescribed radiation dose at the tumor periphery was standardized to 30 Gy at the 50 % isodose field for all patients. The main outcomes were local tumor control, eye retention, and survival rates. RESULTS: The median follow-up time was 40 months (16-78 months). The baseline mean tumor diameter was 10.3 mm (7.1-15.7 mm) and the apical tumor height was 8.7 mm (4.1 16.8 mm). After treatment, the mean tumor diameter was 8.7 mm (5.5-12.0 mm) and the tumor height was 6.2 mm (0.5-11.2 mm). Changes in both tumor height and diameter were statistically significant (p < 0.001). The tumor control rate was 90 %, and the eye retention rate was 82 %. A total of nine patients (18 %) developed metastasis, and seven (14 %) died due to metastasis during follow-up. Cataracts (34 %) and radiation maculopathy (30 %) were the most frequent complications, and 14 % of patients developed neovascular glaucoma. Visual acuity (VA) decreased significantly after treatment (p < 0.0001). CONCLUSION: Treatment using low doses of GKRS, (30 Gy) is an eye-sparing outpatient option for patients with medium- or large-sized posterior uveal melanomas who are not eligible for brachytherapy or particle therapy. Complications, particularly impaired VA, should be taken into consideration. PMID- 22944899 TI - Knowledge of state-level abortion laws and policies among front-line staff at facilities providing abortion services. AB - OBJECTIVE: To determine the accuracy of information regarding state-level abortion laws and policies received by a simulated patient from front-line staff at facilities providing abortion services. METHODS: U.S. states were ranked by restrictiveness of access to abortion, and a simulated patient made calls to the five most and six least restrictive states. Three scripts were used to simulate the following three patients: a 17-year-old minor, a married woman, and a woman at 15 weeks of gestation. Each facility was called three times. Accuracy of the information provided was assessed using a list of laws published monthly by the Guttmacher Institute. RESULTS: Of 138 calls, 72 (52.2%) were made to least restrictive states, and 66 (47.8%) were made to most restrictive states. Information provided by front-line staff was generally excellent, with over 90% accuracy regarding spousal and parental involvement, presence of, and length of mandatory waiting periods. Most inaccuracies were owing to responses of "I don't know." Despite providing highly accurate information regarding the existence of parental involvement laws, only 55.6% of front-line staff members in states with parental involvement laws informed the simulated minor patient of her right to a judicial bypass. CONCLUSION: Information regarding state abortion laws and policies provided by front-line staff members at facilities that provide abortion services is highly accurate, with the exception of judicial bypass for parental involvement. Resources should be developed for reproductive health care providers and their staff to ensure that all information provided to patients is accurate and comprehensive. PMID- 22944900 TI - Attempts at weight loss in U.S. women with and without a history of gestational diabetes mellitus. AB - BACKGROUND AND OBJECTIVE: Gestational diabetes mellitus (GDM) is a risk factor for type 2 diabetes. Relatively modest weight loss can delay or prevent the onset of type 2 diabetes. The objective of this study was to determine, using a nationally representative survey, whether among women without diabetes, those with a history of GDM (hGDM) were more likely than those without hGDM to be currently attempting weight loss. METHODS: This study used data from the 2003 Behavioral Risk Factor Surveillance System, a national, population-based, random sample telephone survey. Women aged 18 to 44 years without diabetes who answered questions related to current weight loss activity were included in the analysis. The primary outcome was currently attempting weight loss. Logistic regression was used to analyze the association between hGDM and currently attempting weight loss. RESULTS: We included 53,608 women without diabetes: 1,260 (2%) with hGDM, and 52,348 (98%) without hGDM. Among women with hGDM, 53% were currently attempting weight loss compared with 47% of women without hGDM. Overall, after adjusting for age, race/ethnicity, education, marital status, and medical insurance, compared with women without hGDM, those with hGDM had 20% higher odds of currently attempting weight loss (95% confidence interval [CI], 0.97-1.49); however, among obese women (body mass index >= 30 kg/m(2)), compared with women without hGDM, those with hGDM had 46% lower odds of currently attempting weight loss (95% CI, 0.35-0.82). CONCLUSIONS: Obese women with hGDM are less likely to be currently attempting weight loss compared with those without hGDM. Effective interventions for obese women with hGDM are needed. PMID- 22944902 TI - Health inequalities among older adults in Spain: the importance of gender, the socioeconomic development of the region of residence, and social support. AB - BACKGROUND: This study analyzes health inequalities among older adults in Spain by adopting a conceptual framework that globally considers two dimensions of health determinants (gender and the socioeconomic development of the region of residence) and the mediating influence of social support, taking into account individual socioeconomic position. METHODS: Data came from the 2006 Spanish National Health Interview Survey. A subsample of people aged 65 to 85 years with no paid work living in two socioeconomically developed regions situated in the north of Spain and in two less developed ones situated in the south was selected. The health outcomes analyzed were self-rated health status and poor mental health status. Multiple logistic regression models were fitted and covariates (age, socioeconomic position, household type, and social support) were added in subsequent steps. FINDINGS: Self-rated health status among older adults was poorer in the less socioeconomically developed regions, but especially among women, whereas the poorest mental health status was found in one of the most socioeconomically developed regions, especially for men. Social support was an important determinant of health status, regardless of the socioeconomic development of the region. Gender inequalities in health did not differ by regional socioeconomic development with one exception regarding poor self-rated health. CONCLUSION: These results show the importance of implementing stronger gender equity policies, as well as reducing socioeconomic inequalities among regions and strengthen social support among older adults. PMID- 22944901 TI - Reproductive and other health outcomes in Iraq and Afghanistan women veterans using VA health care: association with mental health diagnoses. AB - BACKGROUND: An increasing number of women serve in the military and are exposed to trauma during service that can lead to mental health problems. Understanding how these mental health problems affect reproductive and physical health outcomes will inform interventions to improve care for women veterans. METHODS: We analyzed national Department of Veterans Affairs (VA) data from women Iraq and Afghanistan veterans who were new users of VA healthcare from October 7, 2001, through December 31, 2010 (n = 71,504). We used ICD-9 codes to categorize veterans into five groups by mental health diagnoses (MH Dx): Those with no MH Dx, posttraumatic stress disorder (PTSD), depression, comorbid PTSD and depression, and a MH Dx other than PTSD and depression. We determined the association between mental health category and reproductive and other physical health outcomes defined by ICD-9 codes. Categories included sexually transmitted infections, other infections (e.g., urinary tract infections), pain-related conditions (e.g., dysmenorrhea and dsypareunia), and other conditions (e.g., polycystic ovarian syndrome, infertility, sexual dysfunction). Models were adjusted for sociodemographic and military service factors. RESULTS: There were 31,481 patients (44%) who received at least one mental health diagnosis. Women veterans with any mental health diagnosis had significantly higher prevalences of nearly all categories of reproductive and physical disease diagnoses (p < .0001 for adjusted prevalences). There was a trend of increasing prevalence of disease outcomes in women with PTSD, depression, and comorbid PTSD and depression (p for trend <.0001 for all outcomes). CONCLUSIONS: Iraq and Afghanistan women veterans with mental health diagnoses had significantly greater prevalences of several important reproductive and physical health diagnoses. These results provide support for VA initiatives to address mental and physical health concerns and improve comprehensive care for women veterans. PMID- 22944903 TI - Factors that contribute or impede the physical health recovery of women exposed to intimate partner violence: a longitudinal study. AB - BACKGROUND: Several cross-sectional studies have demonstrated the negative impact that intimate partner violence (IPV) has on the physical health of women. However, longitudinal studies are needed to establish the time course of this effect. This study assessed the physical health course of female IPV victims and established the factors that enhance or impede their recovery. METHODS: Women (n = 91) who participated in a previous cross-sectional study (T-1) and were either victims of physical/psychological IPV (n = 33) or psychological IPV (n = 23) were evaluated 3 years later (T-2). A control group of women (n = 35) was included for comparison. Structured interviews provided information regarding IPV characteristics, physical health, and lifestyle. FINDINGS: Physical symptoms decreased over time for both groups of abused women. Factors that contributed to this improvement were perception of social support and the cessation of physical IPV. Factors that impaired recovery included cohabitation with the aggressor, victimization experiences at T-2, negative perceptions of life events, and continuing psychological IPV. CONCLUSIONS: This study shows that physical health improvement is possible in female victims of IPV, but that continuing psychological IPV hinders recovery. Additional longitudinal studies are needed to investigate the factors that best predict health recovery in female IPV victims to design effective intervention programs. PMID- 22944904 TI - The "Latina epidemiologic paradox": contrasting patterns of adverse birth outcomes in U.S.-born and foreign-born Latinas. AB - BACKGROUND: The "Latina epidemiologic paradox" postulates that despite socioeconomic disadvantages, Latina mothers have a lower risk for delivering low birth weight (LBW) babies than non-Latina Whites. However, these patterns may be changing over time and may differ depending on the mother's birthplace and legal status in the United States. This study investigates differences in risk for three birth outcomes among Whites, U.S.-born Latinas, and foreign-born Latinas. METHODS: We undertook a cross-sectional study of rates of LBW, preterm, and small for-gestational-age (SGA) births among 196,617 women delivering live, singleton births in Utah from 2004 to 2007. Each group was compared using logistic regression. RESULTS: U.S.-born Latinas had a similar or greater risk for all three outcomes when compared with Whites. Foreign-born Latinas had lower risk for preterm birth (odds ratio [OR], 0.85; 95% confidence interval [CI], 0.80-0.90) compared with Whites, but not for LBW and SGA; foreign-born Latinas had a lower risk for LBW (OR, 0.82; 95% CI, 0.74-0.92), preterm birth (OR, 0.81; 95% CI, 0.74 0.89), and SGA (OR, 0.91; 95% CI, 0.83-0.99) compared with U.S.-born Latinas. Among foreign-born Latinas only, there was no difference in risk between documented (i.e., those who had a legal social security number) and undocumented women for LBW, preterm birth, or SGA. CONCLUSIONS: These data support the existence of a variation of the "Latina paradox" among Latinas according to birthplace, where U.S.-born Latinas do not experience better birth outcomes than Whites, but foreign-born Latinas experience better birth outcomes for several endpoints compared with U.S.-born Latinas. Prevention efforts may prove more effective by considering the different composition of risk factors among foreign- and U.S.-born Latina populations. PMID- 22944905 TI - Kinetics and thermodynamics of phenotype: unwinding and rewinding the nucleosome. AB - Chromatin "remodeling" is widely accepted as the mechanism that permits access to DNA by the transcription machinery. To date, however, there has been no experimental measurement of the changes in the kinetics and thermodynamics of the DNA-histone octamer association that are required to remodel chromatin so that transcription may occur. Here, we present the results of optical tweezer measurements that compare the kinetic and thermodynamic properties of nucleosomes composed of unmodified histones with those of nucleosomes that contain a mutant histone H4 (H4-R45H), which has been shown to allow SWI/SNF remodeling factor independent transcription from the yeast HO promoter in vivo. Our measurements, carried out in a force-clamp mode, determine the force-dependent unwinding and rewinding rates of the nucleosome inner turn. At each force studied, nucleosomes containing H4-R45H unwind more rapidly and rewind more slowly than nucleosomes containing unmodified H4, indicating that the latter are the more stable. Extrapolation to forces at which the winding and unwinding rates are equal determines the absolute free energy of the nucleosome inner turn to be -32k(B)T for nucleosomes containing unmodified H4 and -27k(B)T for nucleosomes containing H4-R45H. Thus, the "loosening" or "remodeling" caused by this point mutation, which is demonstrated to be sufficient to allow transcriptional machinery access to the HO promoter (in the absence of other remodeling factors), is 5k(B)T. The correlation between the free energy of the nucleosome inner turn and the sin (SWI/SNF-independent) transcription suggests that, beyond partial unwinding, complete histone unwinding may play a role in transcriptional activation. PMID- 22944906 TI - Epinephrine infusion in the evaluation of unexplained cardiac arrest and familial sudden death: from the cardiac arrest survivors with preserved Ejection Fraction Registry. AB - BACKGROUND: Epinephrine infusion may unmask latent genetic conditions associated with cardiac arrest, including long-QT syndrome and catecholaminergic polymorphic ventricular tachycardia (VT). METHODS AND RESULTS: Patients with unexplained cardiac arrest (normal left ventricular function and QT interval) and selected family members from the Cardiac Arrest Survivors with Preserved Ejection Fraction Registry (CASPER) registry underwent epinephrine challenge at doses of 0.05, 0.10, and 0.20 MUg/kg per minute. A test was considered positive for long-QT syndrome if the absolute QT interval prolonged by >= 30 ms at 0.10 MUg/kg per minute and borderline if QT prolongation was 1 to 29 ms. Catecholaminergic polymorphic VT was diagnosed if epinephrine provoked >= 3 beats of polymorphic or bidirectional VT and borderline if polymorphic couplets, premature ventricular contractions, or nonsustained monomorphic VT was induced. Epinephrine infusion was performed in 170 patients (age, 42 +/- 16 years; 49% men), including 98 patients with unexplained cardiac arrest. Testing was positive for long-QT syndrome in 31 patients (18%) and borderline in 24 patients (14%). Exercise testing provoked an abnormal QT response in 42% of tested patients with a positive epinephrine response. Testing for catecholaminergic polymorphic VT was positive in 7% and borderline in 5%. Targeted genetic testing of abnormal patients was positive in 17% of long-QT syndrome patients and 13% of catecholaminergic polymorphic VT patients. CONCLUSIONS: Epinephrine challenge provoked abnormalities in a substantial proportion of patients, most commonly a prolonged QT interval. Exercise and genetic testing replicated the diagnosis suggested by the epinephrine response in a small proportion of patients. Epinephrine infusion combined with exercise testing and targeted genetic testing is recommended in the workup of suspected familial sudden death syndromes. Clinical Trial Registration- URL: http://www.clinicaltrials.gov. Unique identifier: NCT00292032. PMID- 22944907 TI - Effects of poly-victimization on self-esteem and post-traumatic stress symptoms in Spanish adolescents. AB - This study aims to provide evidence concerning the effects of experiencing multiple forms of victimization (poly-victimization) on self-esteem and post traumatic stress symptoms in Spanish adolescents. A total of 722 adolescents were recruited from seven secondary schools in Catalonia, Spain. The Rosenberg Self Esteem Scale, the Youth Self Report and the Juvenile Victimization Questionnaire were employed to assess self-esteem, post-traumatic stress symptoms and victimization, respectively. Participants were divided into three groups (non victim, victim and poly-victim groups) according to the total number of different kinds of victimization experienced. Results showed that 88.4 % of adolescents had been exposed to at least one kind of victimization. Poly-victimization was associated with a higher number of post-traumatic stress symptoms in both boys and girls. Also, self-liking was significantly lower in the poly-victim group, whereas self-competence was equivalent across the three victimization groups. Girls were approximately twice as likely to report child maltreatment (OR = 1.92) and sexual victimization (OR = 2.41) as boys. In conclusion, the present study adds evidence on the importance of taking account of the full burden of victimizations suffered when studying victimization correlates. Also, it highlights the importance of prevention policies to focus particularly on preserving adolescents' sense of social worth. PMID- 22944908 TI - To adhere or not, and what we can do to help. AB - Two factors predict treatment outcome, how effective the treatment is and whether the patient takes or follows the treatment plan. As clinicians or scientists, we strive to develop newer and more effective treatments, both pharmacological and non-pharmacological to improve treatment outcome in our patient population. Adherence is the single most modifiable factor associated with treatment outcome, yet how often is the issue of adherence addressed in clinical consultations? The best treatment is rendered useless if not adhered to. Initial adherence rates are low and get worse with time, but methodological difficulties in studies make it difficult to determine both the clinical implication of suboptimal adherence and successful strategies. Further research should apply more rigour to the area of definition and measurement, be sufficiently powered and long term, and measure possible confounders, to allow for an understanding on the link and impact between adherence and clinical outcome. This article reviews some of the main issues with regard to adherence and cost implications of suboptimal adherence and suggests future directions. PMID- 22944910 TI - alpha-Synuclein elevation in human neurodegenerative diseases: experimental, pathogenetic, and therapeutic implications. AB - The discovery of alpha-synuclein has had profound implications concerning our understanding of Parkinson's disease (PD) and other neurodegenerative disorders characterized by alpha-synuclein accumulation. In fact, as compared with pre alpha-synuclein times, a "new" PD can now be described as a whole-body disease in which a progressive spreading of alpha-synuclein pathology underlies a wide spectrum of motor as well as nonmotor clinical manifestations. Not only is alpha synuclein accumulation a pathological hallmark of human alpha-synucleinopathies but increased protein levels are sufficient to trigger neurodegenerative processes. alpha-Synuclein elevations could also be a mechanism by which disease risk factors (e.g., aging) increase neuronal vulnerability to degeneration. An important corollary to the role of enhanced alpha-synuclein in PD pathogenesis is the possibility of developing alpha-synuclein-based biomarkers and new therapeutics aimed at suppressing alpha-synuclein expression. The use of in vitro and in vivo experimental models, including transgenic mice overexpressing alpha synuclein and animals with viral vector-mediated alpha-synuclein transduction, has helped clarify pathogenetic mechanisms and therapeutic strategies involving alpha-synuclein. These models are not devoid of significant limitations, however. Therefore, further pursuit of new clues on the cause and treatment of PD in this post-alpha-synuclein era would benefit substantially from the development of improved research paradigms of alpha-synuclein elevation. PMID- 22944913 TI - Bone marrow stromal cells from aged male rats have delayed mineralization and reduced response to mechanical stimulation through nitric oxide and ERK1/2 signaling during osteogenic differentiation. AB - Bone marrow stromal cells (MSCs) are a source of osteoblast precursors that can be recruited during bone remodeling or injury, both important processes in aging populations. With advancing age, alterations in bone structure and mineralization are often associated with an increase in osteoporosis and fracture risk. Changes in the number of osteoprogenitor cells and their osteogenic potential may occur with advancing age; however few studies have considered the influence of mechanical conditions. Here, we investigated the ability of bone MSCs from mature and aged rats to differentiate into osteoblasts and to respond to short and long periods of mechanical stimulation through signaling by ERK1/2, nitric oxide (NO), and prostaglandin E(2) (PGE(2)) during differentiation. Mineralization was delayed and reduced, but extracellular matrix production appeared less affected by increased age. Differentiating MSCs from aged animals had a decreased response to short and long periods of mechanical stimulation through ERK1/2 signaling, and to long periods of mechanical loading through NO signaling early and late during differentiation. Increases in relative PGE(2) signaling were higher in MSCs from aged animals, which could compensate for reduced ERK1/2 and NO signaling. The decreased mineralization may decrease the ability of cells from aged animals to respond to mechanical stimulation through ERK1/2 and NO signaling, with increased impairment over differentiation time. Decreasing the delay in mineralization of MSCs from aging animals might improve their ability to respond to mechanical stimulation during bone remodeling and injury, suggesting therapies for bone fragility diseases and tissue engineering treatments in elderly populations. PMID- 22944912 TI - A calcium-dependent interaction between calmodulin and the calponin homology domain of human IQGAP1. AB - IQGAPs are cytoskeletal scaffolding proteins which collect information from a variety of signalling pathways and pass it on to the microfilaments and microtubules. There is a well-characterised interaction between IQGAP and calmodulin through a series of IQ-motifs towards the middle of the primary sequence. However, it has been shown previously that the calponin homology domain (CHD), located at the N-terminus of the protein, can also interact weakly with calmodulin. Using a recombinant fragment of human IQGAP1 which encompasses the CHD, we have demonstrated that the CHD undergoes a calcium ion-dependent interaction with calmodulin. The CHD can also displace the hydrophobic fluorescent probe 1-anilinonaphthalene-8-sulphonate from calcium-calmodulin, suggesting that the interaction involves non-polar residues on the surface of calmodulin. Molecular modelling identified a possible site on the CHD for calmodulin interaction. The physiological significance of this interaction remains to be discovered. PMID- 22944914 TI - Mature proteins derived from Epstein-Barr virus fail to feed into the MHC class I antigenic pool. AB - The immediate presentation of peptide epitopes on MHC class I (MHC I) after antigen expression has led to the concept that MHC I ligands are mostly derived from defective ribosomal products (DRiPs), a subset of newly synthesized proteins that are rapidly degraded by the proteasome. Whether and to what extent mature proteins contribute to the antigenic pool, however, has remained elusive. Here, we developed a conditional antigen expression system that allows studying antigen presentation from mature proteins by inducing their rapid proteasomal degradation in the absence of further antigen synthesis. Target cells in which expression of two Epstein-Barr virus (EBV) antigens was induced were rapidly recognized by antigen-specific CD8(+) T cells in a time- and dosage-dependent manner, demonstrating that antigen presentation was linked to antigen synthesis. By contrast, T cells failed to recognize target cells containing large amounts of mature protein even after induction of their rapid proteasomal degradation. Thus, the presentation of these antigens proved to be strictly dependent on protein synthesis whereas mature proteins failed to furnish the antigenic pool. These results have implications for the design of immunotherapeutic strategies that aim at targeting proteins with increased half-lives and are hence overexpressed in tumors. PMID- 22944911 TI - Regulation of neural stem cell differentiation by transcription factors HNF4-1 and MAZ-1. AB - Neural stem cells (NSCs) are promising candidates for a variety of neurological diseases due to their ability to differentiate into neurons, astrocytes, and oligodentrocytes. During this process, Rho GTPases are heavily involved in neuritogenesis, axon formation and dendritic development, due to their effects on the cytoskeleton through downstream effectors. The activities of Rho GTPases are controlled by Rho-GDP dissociation inhibitors (Rho-GDIs). As shown in our previous study, these are also involved in the differentiation of NSCs; however, little is known about the underlying regulatory mechanism. Here, we describe how the transcription factors hepatic nuclear factor (HNF4-1) and myc-associated zinc finger protein (MAZ-1) regulate the expression of Rho-GDIgamma in the stimulation of NSC differentiation. Using a transfection of cis-element double-stranded oligodeoxynucleotides (ODNs) strategy, referred to as "decoy" ODNs, we examined the effects of HNF4-1 and MAZ-1 on NSC differentiation in the NSC line C17.2. Our results show that HNF4-1 and MAZ-1 decoy ODNs significantly knock down Rho GDIgamma gene transcription, leading to NSC differentiation towards neurons. We observed that HNF4-1 and MAZ-1 decoy ODNs are able enter to the cell nucleolus and specifically bind to their target transcription factors. Furthermore, the expression of Rho-GDIgamma-mediated genes was identified, suggesting that the regulatory mechanism for the differentiation of NSCs is triggered by the transcription factors MAZ-1 and HNF4-1. These findings indicate that HNF4-1 and MAZ-1 regulate the expression of Rho-GDIgamma and contribute to the differentiation of NSCs. Our findings provide a new perspective within regulatory mechanism research during differentiation of NSCs, especially the clinical application of transcription factor decoys in vivo, suggesting potential therapeutic strategies for neurodegenerative disease. PMID- 22944915 TI - Lighting-up of the dye malachite green with mercury(II)-DNA and its application for fluorescence turn-off detection of cysteine and glutathione. AB - This work describes a novel strategy for the highly sensitive and selective detection of cysteine (Cys) and glutathione (GSH) based on the Hg(2+)-AGRO100 malachite green (MG) complex system. The dye MG, which has a very low quantum yield in aqueous solution by itself, can bind with the thymine-rich DNA AGRO100 in the presence of Hg(2+) ions to generate a striking fluorescence intensity enhancement of 1000-fold. As sulfur-containing amino acids, Cys and GSH effectively sequester Hg(2+) ions from the Hg(2+)-AGRO100-MG complex structure to switch the 'lit-up' chemosensor to the 'off' state (about a 50-fold fluorescence intensity decrease), thus providing a facile, but effective, method to probe for Cys/GSH. The fluorescence titration, UV absorption, CD, and Raman spectra provide some insight into the structural and chemical basis for the enhancement effect. The formation of the Hg(2+)-AGRO100-MG complex significantly affects the electronic structure and conformation of the MG molecule by leading to an extended pi system, which is the likely origin of the observed striking fluorescence intensity enhancement. Notably, the proposed sensing platform exhibits exquisite selectivity and sensitivity toward Cys/GSH with limits of detection of 5 nM for Cys and 10 nM for GSH, respectively. Furthermore, the straightforward assay design avoids labeling of the probe, uses only commercially available materials, and still displays comparable sensitivity and excellent selectivity. PMID- 22945016 TI - Theory of the interplay between the superconductivity and the blocked antiferromagnetic order in A(y)Fe(2-x)Se2. AB - Based on an effective two-orbital tight-binding model, we examine the possible superconducting states in iron-vacancy-ordered A(y)Fe(2-x)Se(2). In the presence of ordered vacancies and blocked antiferromagnetic order, it is shown that the emergent SC pairing is the nodeless next-nearest-neighbor (NNN)-pairing due to the dominant antiferromagnetic (AFM) interaction between the inter-block NNN sites. In particular, we show that due to the ordered vacancies and the associated blocked AFM order, the interplay between the superconducting and AFM states results in three distinct states in the phase diagram as doping is varied. The divergent experimental observations can be accounted for by considering the different charge carrier concentrations in their respective compounds. PMID- 22945018 TI - Rational engineering of Candida antarctica lipase B for selective monoacylation of diols. AB - The enzyme Candida antarctica lipase B was subjected to site directed mutagenesis suggested by molecular modelling. The selectivity for the enzyme increased towards a range of diols over their corresponding monoesters as an effect of the mutations. PMID- 22945017 TI - The long-term outcomes of pediatric pleural empyema: a prospective study. AB - OBJECTIVE: To describe the long-term outcomes of pediatric pleural empyema. DESIGN: Prospective observational study from October 2008 to October 2011. SETTING: Tertiary care children's hospital. PARTICIPANTS: Children with pleural empyema (loculations and/or septations identified on radiologic imaging or frank pus on thoracentesis). MAIN OUTCOME MEASURES: Children were seen 1, 6, and 12 months postdischarge. Outcome measures included symptoms and signs of respiratory disease, child and parental impact, radiographic resolution, spirometry, and health-related quality of life (Pediatric Quality of Life Inventory score). Analysis was based on the last observation carried forward for missing data. RESULTS: Eighty-two of 88 patients (93%) eligible were recruited. Fifty-four percent were male and mean (SD) age was 4.5 (3.4) years. Outcome data was obtained in 100% at 1 month, 90% at 6 months, and 72% at 1 year. Seventy-one percent had effusions occupying a quarter or more of the hemithorax and 62% of effusions were drained. Fever, cough, parental work loss, child school loss, radiographic abnormalities, and abnormal spirometry results were common in the first month and then declined. By the last observation, 2% of patients had abnormal radiographs (aside from pleural thickening), 6% had mild obstruction on spirometry, and Pediatric Quality of Life Inventory scores were better than for children with asthma (P < .001). Patients with abnormal outcomes in 1 measure had normal outcomes in all other clinical measures. CONCLUSIONS: Clinically important phenomena persist in the short-term, but virtually all children with pleural empyema have no long-term sequelae. PMID- 22945019 TI - Synthesis and antitubercular activity evaluation of novel unsymmetrical cyclohexane-1,2-diamine derivatives. AB - A library of unsymmetrical cyclohexane-1,2-diamine derivatives were synthesized and evaluated for their activity against Mycobacterium tuberculosis H37Rv in vitro. Out of the 46 compounds synthesized, eight compounds (11h, 13a, 13e, 13f, 14a, 14c, 14d, and 15d) were found to be active at or below 6.25 uM concentration, with negligible toxicity to human red blood cells at a concentration much higher than the MIC(99) . Compound 13a was the best active compound showing inhibition at 3.125-6.25 uM, and was found to be non-hemolytic up to 500 ug/mL concentration. PMID- 22944909 TI - Mouse models of polyglutamine diseases in therapeutic approaches: review and data table. Part II. AB - Mouse models of human diseases are created both to understand the pathogenesis of the disorders and to find successful therapies for them. This work is the second part in a series of reviews of mouse models of polyglutamine (polyQ) hereditary disorders and focuses on in vivo experimental therapeutic approaches. Like part I of the polyQ mouse model review, this work is supplemented with a table that contains data from experimental studies of therapeutic approaches in polyQ mouse models. The aim of this review was to characterize the benefits and outcomes of various therapeutic strategies in mouse models. We examine whether the therapeutic strategies are specific to a single disease or are applicable to more than one polyQ disorder in mouse models. In addition, we discuss the suitability of mouse models in therapeutic approaches. Although the majority of therapeutic studies were performed in mouse models of Huntington disease, similar strategies were also used in other disease models. PMID- 22945020 TI - Closure of scalp and forehead defects using external tissue expander. AB - OBJECTIVE: To describe the novel use of an external tissue expander in the reconstruction of scalp and forehead defects. METHODS: A prospective review was performed on 7 patients who underwent extirpation of head and neck malignant neoplasms resulting in scalp and forehead defects. Reconstruction was performed using an external tissue expander device. Patient clinical factors, defect size, and photographs were collected. RESULTS: Seven patients had large scalp and forehead defects ranging in greatest dimension from 5.0 *4.0 to 8.0 *7.0 cm. The external tissue expander was in place for 6 to 14 days, reducing the defect sizes by 50% to 99%. At the time of device removal, primary closure was achieved in 5 patients. One patient required bilateral advancement rotation flaps, and 1 patient healed by second intention. One patient with a history of scalp irradiation and diabetes had partial skin loss after device removal and required reconstruction with a latissimus dorsi myocutaneous free flap. There were no other postoperative complications, wound breakdown, or device failures. CONCLUSION: External tissue expansion is a safe and effective technique for closing large scalp and forehead defects that would otherwise require skin grafting or free flap reconstruction. PMID- 22945021 TI - Aza-BODIPY derivatives: enhanced quantum yields of triplet excited states and the generation of singlet oxygen and their role as facile sustainable photooxygenation catalysts. AB - A new series of aza-BODIPY derivatives (4 a-4 c, 5 a,c, and 6 b,c) were synthesized and their excited-state properties, such as their triplet excited state and the yield of singlet-oxygen generation, were tuned by substituting with heavy atoms, such as bromine and iodine. The effect of substitution has been studied in detail by varying the position of halogenation. The core-substituted dyes showed high yields of the triplet excited state and high efficiencies of singlet-oxygen generation when compared to the peripheral-substituted systems. The dye 6 c, which was substituted with six iodine atoms on the core and peripheral phenyl ring, showed the highest quantum yields of the triplet excited state (Phi(T) =0.86) and of the efficiency of singlet-oxygen generation (Phi(Delta) =0.80). Interestingly, these dyes were highly efficient as photooxygenation catalysts under artificial light, as well as under normal sunlight conditions. The uniqueness of these aza-BODIPY systems is that they are stable under irradiation conditions, possess strong red-light absorption (620-680 nm), exhibit high yields of singlet-oxygen generation, and act as efficient and sustainable catalysts for photooxygenation reactions. PMID- 22945023 TI - Regio- and stereoselective oxidative phenol coupling in Aspergillus niger. AB - Piecing it together: Aspergillus niger produces kotanin by dimerization of the monomeric, polyketide-synthase-derived (PKS) 7-demethylsiderin. A combined approach, comprising bioinformatics and gene-deletion experiments, identified the biosynthetic cluster responsible for kotanin production. Homology modeling and substrate docking provide a rationale for the regio- and stereoselective phenol coupling reaction. PMID- 22945022 TI - Noninvasive assessment of magnetic nanoparticle-cancer cell interactions. AB - The success of magnetic nanoparticle (mNP)-based diagnostic and therapeutic techniques is dependent upon how the mNP are distributed in vivo. The potential efficacy and timing of a given magnetic nanoparticle treatment or diagnostic test is largely determined by the number of nanoparticles in each tissue and microscopic compartment: e.g., in the intravascular and extravascular spaces, in the interstitial space, cell surface and in cell cytoplasm. Techniques for monitoring these cell-level interactions generally require the harvesting and destruction of tissues or cells at each time point of interest. We present a method (magnetic spectroscopy of Brownian motion, MSB) for longitudinally monitoring nanoparticle binding to cell surface proteins and uptake by cancer cells in vitro using the harmonics of the magnetization produced by the nanoparticles. These harmonics can be measured rapidly and noninvasively without the need for nanoparticle modifications and without damaging the cells. We demonstrate sensitivity of this harmonic signal to the nanoparticles' microenvironment and use this technique to monitor the nanoparticle binding activities of different cell lines. PMID- 22945025 TI - Simple synthesis of modafinil derivatives and their anti-inflammatory activity. AB - Simple synthesis of modafinil derivatives and their biological activity are described. The key synthetic strategies involve substitution and coupling reactions. We determined the anti-inflammatory effects of modafinil derivatives in cultured BV2 cells by measuring the inhibition of nitrite production and expression of iNOS and COX-2 after LPS stimulation. It was found that for sulfide analogues introduction of aliphatic groups on the amide part (compounds 11a-d) resulted in lower anti-inflammatory activity compared with cyclic or aromatic moieties (compounds 11e-k). However, for the sulfoxide analogues, introduction of aliphatic moieties (compounds 12a-d) showed higher anti-inflammatory activity than cyclic or aromatic fragments (compounds 12e-k) in BV-2 microglia cells. PMID- 22945024 TI - Prevalence of esophageal atresia among 18 international birth defects surveillance programs. AB - BACKGROUND: The prevalence of esophageal atresia (EA) has been shown to vary across different geographical settings. Investigation of geographical differences may provide an insight into the underlying etiology of EA. METHODS: The study population comprised infants diagnosed with EA during 1998 to 2007 from 18 of the 46 birth defects surveillance programs, members of the International Clearinghouse for Birth Defects Surveillance and Research. Total prevalence per 10,000 births for EA was defined as the total number of cases in live births, stillbirths, and elective termination of pregnancy for fetal anomaly (ETOPFA) divided by the total number of all births in the population. RESULTS: Among the participating programs, a total of 2943 cases of EA were diagnosed with an average prevalence of 2.44 (95% confidence interval [CI], 2.35-2.53) per 10,000 births, ranging between 1.77 and 3.68 per 10,000 births. Of all infants diagnosed with EA, 2761 (93.8%) were live births, 82 (2.8%) stillbirths, 89 (3.0%) ETOPFA, and 11 (0.4%) had unknown outcomes. The majority of cases (2020, 68.6%), had a reported EA with fistula, 749 (25.5%) were without fistula, and 174 (5.9%) were registered with an unspecified code. CONCLUSIONS: On average, EA affected 1 in 4099 births (95% CI, 1 in 3954-4251 births) with prevalence varying across different geographical settings, but relatively consistent over time and comparable between surveillance programs. Findings suggest that differences in the prevalence observed among programs are likely to be attributable to variability in population ethnic compositions or issues in reporting or registration procedures of EA, rather than a real risk occurrence difference. Birth Defects Research (Part A), 2012. PMID- 22945026 TI - Fumigant antifungal activity of Myrtaceae essential oils and constituents from Leptospermum petersonii against three Aspergillus species. AB - Commercial plant essential oils obtained from 11 Myrtaceae plant species were tested for their fumigant antifungal activity against Aspergillus ochraceus, A. flavus, and A. niger. Essential oils extracted from Leptospermum petersonii at air concentrations of 56 * 10(-3) mg/mL and 28 * 10(-3) mg/mL completely inhibited the growth of the three Aspergillus species. However, at an air concentration of 14 * 10(-3) mg/mL, inhibition rates of L. petersonii essential oils were reduced to 20.2% and 18.8% in the case of A. flavus and A. niger, respectively. The other Myrtaceae essential oils (56 * 10(-3) mg/mL) only weakly inhibited the fungi or had no detectable affect. Gas chromatography-mass spectrometry analysis identified 16 compounds in L. petersonii essential oil. The antifungal activity of the identified compounds was tested individually by using standard or synthesized compounds. Of these, neral and geranial inhibited growth by 100%, at an air concentration of 56 * 10(-3) mg/mL, whereas the activity of citronellol was somewhat lover (80%). The other compounds exhibited only moderate or weak antifungal activity. The antifungal activities of blends of constituents identified in L. petersonii oil indicated that neral and geranial were the major contributors to the fumigant and antifungal activities. PMID- 22945027 TI - Structural characterization and identification of major constituents in Jitai tablets by high-performance liquid chromatography/diode-array detection coupled with electrospray ionization tandem mass spectrometry. AB - In the present study a universally applicable HPLC-DAD/ESI-MS/MS method was developed for carrying out the comprehensive characterization of Jitai tablets (JTT). Based on the ESI-MS(n) fragmentation patterns of the reference standards, a total of 101 components were identified or tentatively characterized by comparing their retention times, UV and MS spectra with those of reference standards or through the matching of empirical information with those of published components in the in-house library. The characteristic fragmentation pattern of alkaloids, phenolic acids, tanshinones, flavonoid glycosides, cyanogenic glycosides, ginsenosides, 2-(2-phenylethyl) chromones, phthalides and gingerol-related compounds were tentatively elucidated using structurally relevant product ions. It was observed that neutral losses of C(9)H(10)O(3) and C(9)H(8)O(2) were the characteristic product ions of scopola alkaloids. Neutral fragment mandelonitrile was the characteristic ion of cyanogenic glycosides. To our knowledge, tropylium ion and C(4)H(2)O unit were the characteristic ions of 2 (2-phenylethyl) chromone, which resulted from the Retro-Diels-Alder (RDA) cleavage of the C ring. The results indicated that the developed analysis method could be employed as a rapid, effective technique for structural characterization of chemical constituents in TCM. This work is expected to provide comprehensive information for the quality evaluation and pharmacokinetic studies of JTT. PMID- 22945028 TI - Steroidal and phenolic glycosides from the bulbs of Lilium pumilum DC and their potential Na+/K+ ATPase inhibitory activity. AB - A new steroidal saponin, named pumilum A (1), and a new phenolic glycoside, threo 1-(4'-hydroxy-2'-methoxyphenyl)-2-(2",4"-dihydroxyphenyl)-1,3-propanediol-4'-O beta-D-glucopyranoside (7) were isolated from the methanolic extract of the bulbs of Lilium pumilum DC, along with five known steroidal saponins. Their chemical structures were elucidated on the basis of detailed spectroscopic analysis, including 1D and 2D NMR techniques and chemical methods. In addition, the inhibitory activity of all the isolates on Na(+)/K(+) ATPase was evaluated. PMID- 22945029 TI - Promising therapeutics with natural bioactive compounds for improving learning and memory--a review of randomized trials. AB - Cognitive disorders can be associated with brain trauma, neurodegenerative disease or as a part of physiological aging. Aging in humans is generally associated with deterioration of cognitive performance and, in particular, learning and memory. Different therapeutic approaches are available to treat cognitive impairment during physiological aging and neurodegenerative or psychiatric disorders. Traditional herbal medicine and numerous plants, either directly as supplements or indirectly in the form of food, improve brain functions including memory and attention. More than a hundred herbal medicinal plants have been traditionally used for learning and memory improvement, but only a few have been tested in randomized clinical trials. Here, we will enumerate those medicinal plants that show positive effects on various cognitive functions in learning and memory clinical trials. Moreover, besides natural products that show promising effects in clinical trials, we briefly discuss medicinal plants that have promising experimental data or initial clinical data and might have potential to reach a clinical trial in the near future. PMID- 22945030 TI - Activator-free olefin oligomerization and isomerization reactions catalyzed by an air- and water-tolerant Wacker oxidation intermediate. AB - A bench-stable, hydroxy-bridged alpha-diimine-Pd dimer can self-activate to an olefin oligomerization and isomerization catalyst in the presence of substrate. A cationic Pd-hydride is generated principally through a Wacker oxidation of olefin to ketone, and with C(4+) olefins, lesser amounts of allylic C-H activation, beta-H transfer, and release of diene products are observed. PMID- 22945031 TI - Ideal cardiovascular health in adolescence is associated with reduced risks of hypertension, metabolic syndrome and high cholesterol in adulthood. PMID- 22945032 TI - The serotonin transporter gene-linked polymorphic region (5-HTTLPR) and cortisol stress reactivity: a meta-analysis. AB - Recent meta-analyses have stimulated an active debate on whether the serotonin transporter gene-linked polymorphic region (5-HTTLPR) is associated with an elevated vulnerability to psychiatric diseases upon exposure to environmental adversity. As a potential mechanism explaining genotype-dependent differences in stress sensitivity, altered stress-induced activation of the hypothalamus pituitary-adrenal (HPA) axis has been investigated in several experimental studies, with most of these studies comprising small samples. We evaluated the association of 5-HTTLPR genotype and cortisol reactivity to acute psychosocial stress by applying a meta-analytical technique based on eleven relevant data sets (total N=1686), which were identified through a systematic literature search up to October 2011. This meta-analysis indicates a small (d=0.27), but significant association between 5-HTTLPR genotype and HPA-axis reactivity to acute psychosocial stress with homozygous carriers of the S allele displaying increased cortisol reactivity compared with individuals with the S/L and L/L genotype. The latter association was not further moderated by participants' age, sex or the type of stressor. Formal testing revealed no evidence for a substantial selection or publication bias. Our meta-analytical results are consistent with a wide variety of experimental studies indicating a significant association between 5 HTTLPR genotype and intermediate phenotypes related to stress sensitivity. Future studies are needed to clarify the consistency of this effect and to further explore whether altered HPA-axis stress reactivity reflects a potential biological mechanism conveying an elevated risk for the development of stress related disorders in S allele carriers. PMID- 22945033 TI - Structure and energetics changes during hydrogenation of 4H-SiC{0001} surfaces: a DFT study. AB - The changes in the atomic and electronic structure of Si- and C-terminated hexagonal SiC{0001} surfaces resulting from on-surface and subsurface hydrogen adsorption have been studied within the density functional theory framework. Hydrogen coverages ranging from a submonolayer to one monolayer were considered. Our results show that a monolayer of adsorbed H almost completely suppresses the relaxation of the SiC surface atomic layers. On both terminations H binds strongly to the surface and the binding is about 2 eV stronger in on-surface sites than subsurface. Hydrogen binding to the C-terminated surface varies very little with coverage and is distinctly stronger than to the Si-terminated surface. PMID- 22945034 TI - Long-term outcomes in children with pleural empyema. PMID- 22945035 TI - Chemical and biological sensors based on metal oxide nanostructures. AB - Unique and fascinating features of metal oxide nanostructures (MONs) have attracted considerable attention in recent years because without much effort, the MONs can be grown in many different nanoscale forms, thus allowing various novel devices of chemical and biological sensing to be fabricated. To improve the sensors performance by tailoring the properties of MONs through engineering of morphology, particle size, effective surface area, functionality, adsorption capability and electron-transfer properties have been extensively explored. This feature article collates the various MONs and their potential applications in the chemical and biological sensors for clinical and non-clinical applications. PMID- 22945138 TI - Effective algorithm for high-channel-count multichannel fiber Bragg grating designs. AB - We present an efficient approach to design a high-channel-count multichannel fiber Bragg grating by assigning optimal sets of delay coefficients and constant phases to the corresponding channel responses. Based on approximate Fourier transform, the delay coefficients are chosen to separate all the single-channel gratings into several groups spatially in the grating structure, and the constant phases in each group are optimized to minimize the maximum index modulation to be approximately the square root of the maximum of the number of the channels in all groups times larger than that of the one-channel grating. Design examples demonstrate that the proposed method has advantages of low index modulation, low algorithmic complexity, and suitability for multichannel fiber Bragg grating designs with either identical or nonidentical spectral responses. PMID- 22945136 TI - Single-cell analysis of the dynamics and functional outcomes of interactions between human natural killer cells and target cells. AB - Natural killer (NK) cells are a subset of innate immune lymphocytes that interrogate potential target cells and rapidly respond by lysing them or secreting inflammatory immunomodulators. Productive interactions between NK cells and targets such as tumor cells or virally infected cells are critical for immunological control of malignancies and infections. For individual NK cells, however, the relationship between the characteristics of these cell-cell interactions, cytolysis, and secretory activity is not well understood. Here, we used arrays of subnanoliter wells (nanowells) to monitor individual NK cell target cell interactions and quantify the resulting cytolytic and secretory responses. We show that NK cells operate independently when lysing a single target cell and that lysis is most probable during an NK cell's first encounter with a target. Furthermore, we demonstrate that the secretion of interferon-gamma (IFN-gamma) occurs most often among NK cells that become the least motile upon contacting a target cell but is largely independent of cytolysis. Our findings demonstrate that integrated analysis of the cell-cell interaction parameters, cytolytic activity, and secretory activity of single NK cells can reveal new insights into how these complex functions are related within individual cells. PMID- 22945139 TI - Reconfigurable 1*2 wavelength selective switch using high birefringence nematic liquid crystals. AB - A reconfigurable 1*2 wavelength selective switch, based on a Lyot filter and high birefringence nematic liquid crystals, is proposed. Simulations and experimental results of a reconfigurable switch are reported. Insertion losses from 3.4 dB and rejection ratios up to 15 dB are obtained in a two input channel system at 560 and 621 nm. Control voltages of 0 to 3 V(RMS) are used. PMID- 22945140 TI - Performance of imaging systems analyzed with two-dimensional target. AB - We have recently shown [Appl. Opt.51, 2739 (2012)] that performance analysis of optical imaging systems based on results obtained with classic one-dimensional (1D) resolution targets (such as the U.S. Air Force resolution target) are significantly different than those obtained with a newly proposed two-dimensional (2D) target. We hereby provide experimental evidence and show how the new 2D template can be used to correctly characterize optical imaging systems in terms of resolution and contrast. In particular, we apply the consequences of these observations to the optimal design of some 2D barcode structures. PMID- 22945141 TI - Back-focal-plane position detection with extended linear range for photonic force microscopy. AB - In photonic force microscopes, the position detection with high temporal and spatial resolution is usually implemented by a quadrant position detector placed in the back focal plane of a condenser. An objective with high numerical aperture (NA) for the optical trap has also been used to focus a detection beam. In that case the displacement of the probe at a fixed position of the detector produces a unique and linear response only in a restricted region of the probe displacement, usually several hundred nanometers. There are specific experiments where the absolute position of the probe is a relevant measure together with the probe position relative the optical trap focus. In our scheme we introduce the detection beam into the condenser with low NA through a pinhole with tunable size. This combination permits us to create a wide detection spot and to achieve the linear range of several micrometers by the probe position detection without reducing the trapping force. PMID- 22945142 TI - Time-domain diffuse optical tomography processing by using the Mellin-Laplace transform. AB - We investigate the use of the Mellin-Laplace transform for reconstructing optical parameters from time-resolved optical tomography in diffusive media. We present here its definition, its mathematical properties, and its sensitivity to variations of optical properties. The method was validated on two-dimensional reconstructions from simulation in the reflection geometry. We conclude that reconstructions based on the Mellin-Laplace transform are more robust to noise than the methods using first moments. PMID- 22945143 TI - Highly precise micro-retroreflector array fabricated by the LIGA process and its application as tapped delay line filter. AB - We report on the fabrication of a one-dimensional micro-retroreflector array with a pitch of 100 MUm. The array was fabricated by x-ray lithography and the lithographie, galvanik und abformung (LIGA) process in a 1 mm thick poly(methyl methacrylate) (PMMA) layer and subsequently covered with Au. The area of the array is 1 mm*10 mm. The high precision of the LIGA-based fabrication process allows one to use the element in spectrometers. Here, it is suggested to apply it to the implementation of a transversal filter for femtosecond pulses. We present a theoretical description of the performance of the retroreflector array as a filtering device and show experimental results. PMID- 22945144 TI - Comparison of probability density functions for analyzing irradiance statistics due to atmospheric turbulence. AB - A large number of model probability density functions (PDFs) are used to analyze atmospheric scintillation statistics. We have analyzed scintillation data from two different experimental setups covering a range of scintillation strengths to determine which candidate model PDFs best describe the experimental data. The PDFs were fitted to the experimental data using the method of least squares. The root-mean-squared fitting error was used to monitor the goodness of fit. The results of the fitting were found to depend strongly on the scintillation strength. We find that the log normally modulated Rician and the log normal PDFs are the best fit to the experimental data over the range of scintillation strengths encountered. PMID- 22945145 TI - Infrared spectral responsivity scale realization and validations. AB - An InSb working standard radiometer, first calibrated at the National Institute of Standards and Technology (NIST) in 1999 against a cryogenic bolometer, was recently calibrated against a newly developed low-noise-equivalent-power pyroelectric transfer standard detector. The pyroelectric transfer standard, which can operate at the output of a monochromator, holds the newly realized NIST spectral power responsivity scale between 1.7 and 14 MUm with an uncertainty of 1% (k=2). The InSb working standard was also measured at the National Physical Laboratory (NPL) of the United Kingdom in 1999. The less than 2% spectral power responsivity disagreements obtained on the InSb working standard (both from the 1999 NIST and NPL comparison and also against the pyroelectric standard) validate the three independently realized power responsivity scales and verify the long term stability of the InSb working standard. The InSb working standard was also used in irradiance measurement mode to validate the previously determined spectral irradiance responsivity of four narrowband InSb radiometers that were applied to calibrate IR target simulators. The uncertainty of the present spectral irradiance responsivity scale held by the InSb working standard is 2.5% (k=2) in the 2 to 5.2 MUm wavelength range. PMID- 22945146 TI - Sensing of formaldehyde using a distributed feedback interband cascade laser emitting around 3493 nm. AB - We have demonstrated sensing of formaldehyde (H(2)CO) using a room-temperature distributed feedback interband cascade laser (ICL) emitting around 3493 nm. The ICL has been characterized and proved to be very suitable for tunable laser spectroscopy (TLS). The H(2)CO TLS spectra were recorded in direct absorption mode and showed excellent agreement with the Pacific Northwest National Laboratory database. The measurements reported here were taken from a series of measurements of a mixture of H(2)CO in air obtained by vaporizing a solution also containing methanol and formic acid. We obtained a resolution limit better than 1 ppm * m assuming a relative absorption of 10(-3). PMID- 22945147 TI - Liquid-crystal-display-based touchable light field three-dimensional display using display-capture mapping calibration. AB - An approach to achieving a light field three-dimensional (3D) display with a large viewing angular range based on spliced multi-LCDs is investigated. The light field reconstruction principle, LCD-based hardware configuration, and diffuser characteristics are analyzed. A point-to-point mapping calibration method is proposed to improve imaging performance, by using an image sensor to capture the coordinate distributions of the images on the LCD panel, projected onto the display space. By measuring the coordinate distributions, calibration is implemented considering both imaging aberration and geometrical inaccuracy of the whole system. The LCD-based experiment demonstrates that this method can achieve not only fast and precise calibration but also easy scalability, flexible depth, and angular range. A touchable floating 3D scene with correct occlusion, high image resolution, and a large continuous viewing angular range can be observed. PMID- 22945148 TI - Modeling of micro cat's eye retroreflectors using a matrix-based three dimensional ray tracing technique. AB - In this paper we develop a three-dimensional (3D) ray tracing tool based on the ABCD ray transfer matrices. With symmetric optical components and under paraxial approximation, two sets of 2*2 ABCD matrices, each for a two-dimensional subspace, can be used to describe the 3D ray propagation completely. Compared to commercial ray-tracing software packages, our tool requires no tedious drawing, and the results for various conditions, such as different device dimensions and incident angles, can be easily obtained by simply changing the parameter values used for the calculation. We have employed this matrix-based 3D ray tracing tool to model cat's eye retroreflectors. The cat's eye performance, including the retroreflection efficiency, acceptance angle (i.e., field of view), and beam divergence and deviation, is fully studied. The application of this 3D ray tracing technique can be further extended to other optical components. PMID- 22945149 TI - Improved resolution three-dimensional integral imaging using optimized irregular lens-array structure. AB - A rigorous approach is proposed to improve the resolution of integral imaging (InI) by finding the appropriate form of irregularity in the arrangement of the InI lenslets. The improvement of the resolution is achieved through redistribution of the sampling points in a uniform manner. The optimization process for finding the optimum pattern of the lens-array irregularity is carried out by minimizing a cost function, whose mathematical closed-form expression is provided. The minimization of the proposed cost function ensures the uniform distribution of sampling points and thus improves the resolution within the desired depth of field (DOF) and field of view (FOV). A set of standard resolution charts is used to demonstrate the improvement of the quality of the three-dimensional (3D) images obtained by using the optimized irregular lens array. It is shown that the overall level of the lateral and depth resolutions is improved at the same time. PMID- 22945150 TI - Design, fabrication, and evaluation of a multilevel spiral-phase Fresnel zone plate for optical trapping. AB - A compact optics configuration for the generation of donut beams for trapping atoms at the micrometer scale using a multilevel spiral-phase Fresnel zone plate (FZP) and a semiconductor laser is proposed. A FZP is designed and a multilevel spiral phase is integrated into it. A spiral-phase FZP with a radius of 1 mm and with more than 1300 half-period zones is designed with multiple angular levels for integer and fractional topological charges, and the device is fabricated using electron-beam lithography direct writing. The performance of the device is evaluated, and the generation of symmetric and asymmetric donut beams is successfully demonstrated. PMID- 22945151 TI - Dynamic range and sensitivity requirements of satellite ocean color sensors: learning from the past. AB - Sensor design and mission planning for satellite ocean color measurements requires careful consideration of the signal dynamic range and sensitivity (specifically here signal-to-noise ratio or SNR) so that small changes of ocean properties (e.g., surface chlorophyll-a concentrations or Chl) can be quantified while most measurements are not saturated. Past and current sensors used different signal levels, formats, and conventions to specify these critical parameters, making it difficult to make cross-sensor comparisons or to establish standards for future sensor design. The goal of this study is to quantify these parameters under uniform conditions for widely used past and current sensors in order to provide a reference for the design of future ocean color radiometers. Using measurements from the Moderate Resolution Imaging Spectroradiometer onboard the Aqua satellite (MODISA) under various solar zenith angles (SZAs), typical (L(typical)) and maximum (L(max)) at-sensor radiances from the visible to the shortwave IR were determined. The L(typical) values at an SZA of 45 degrees were used as constraints to calculate SNRs of 10 multiband sensors at the same L(typical) radiance input and 2 hyperspectral sensors at a similar radiance input. The calculations were based on clear-water scenes with an objective method of selecting pixels with minimal cross-pixel variations to assure target homogeneity. Among the widely used ocean color sensors that have routine global coverage, MODISA ocean bands (1 km) showed 2-4 times higher SNRs than the Sea viewing Wide Field-of-view Sensor (SeaWiFS) (1 km) and comparable SNRs to the Medium Resolution Imaging Spectrometer (MERIS)-RR (reduced resolution, 1.2 km), leading to different levels of precision in the retrieved Chl data product. MERIS FR (full resolution, 300 m) showed SNRs lower than MODISA and MERIS-RR with the gain in spatial resolution. SNRs of all MODISA ocean bands and SeaWiFS bands (except the SeaWiFS near-IR bands) exceeded those from prelaunch sensor specifications after adjusting the input radiance to L(typical). The tabulated L(typical), L(max), and SNRs of the various multiband and hyperspectral sensors under the same or similar radiance input provide references to compare sensor performance in product precision and to help design future missions such as the Geostationary Coastal and Air Pollution Events (GEO-CAPE) mission and the Pre Aerosol-Clouds-Ecosystems (PACE) mission currently being planned by the U.S. National Aeronautics and Space Administration (NASA). PMID- 22945152 TI - Gas phase temperature measurements in the liquid and particle regime of a flame spray pyrolysis process using O2-based pure rotational coherent anti-Stokes Raman scattering. AB - For the production of oxide nanoparticles at a commercial scale, flame spray processes are frequently used where mostly oxygen is fed to the flame if high combustion temperatures and thus small primary particle sizes are desired. To improve the understanding of these complex processes in situ, noninvasive optical measurement techniques were applied to characterize the extremely turbulent and unsteady combustion field at those positions where the particles are formed from precursor containing organic solvent droplets. This particle-forming regime was identified by laser-induced breakdown detection. The gas phase temperatures in the surrounding of droplets and particles were measured with O(2)-based pure rotational coherent anti-Stokes Raman scattering (CARS). Pure rotational CARS measurements benefit from a polarization filtering technique that is essential in particle and droplet environments for acquiring CARS spectra suitable for temperature fitting. Due to different signal disturbing processes only the minority of the collected signals could be used for temperature evaluation. The selection of these suitable signals is one of the major problems to be solved for a reliable evaluation process. Applying these filtering and signal selection steps temperature measurements have successfully been conducted. Time-resolved, single-pulse measurements exhibit temperatures between near-room and combustion temperatures due to the strongly fluctuating and flickering behavior of the particle-generating flame. The mean flame temperatures determined from the single pulse data are decreasing with increasing particle concentrations. They indicate the dissipation of large amounts of energy from the surrounding gas phase in the presence of particles. PMID- 22945153 TI - Interference-based optical image encryption using three-dimensional phase retrieval. AB - In recent years, optical image encryption has attracted more and more attention in information security due to its unique advantages, such as parallel processing and multiple-parameter characteristics. In this paper, we propose a new method using three-dimensional (3D) processing strategy for interference-based optical image encryption. The plaintext is considered as a series of particles distributed in 3D space, and any one sectional extraction cannot render information about the plaintext during image decryption. In addition, the silhouette problem in the conventional interference-based optical encryption method is effectively suppressed, and the proposed optical cryptosystem can achieve higher security compared with the previous work. A numerical experiment is conducted to demonstrate the feasibility and effectiveness of the proposed method. PMID- 22945154 TI - Frequency stabilization of internal-mirror He-Ne lasers by air cooling. AB - Instead of the traditional heating method, the cavity length of an internal mirror He-Ne laser is controlled by air cooling which is implemented by a mini cooling fan. The responsive property of the cooling fan and the thermal expansion of the internal-mirror laser tube are investigated. According to these investigations, a controlling system is designed to drive the cooling fan controlling the cavity length of the laser. Then the frequency is stabilized by comparing the light intensities of two operating longitudinal modes. The results of beating with an iodine stabilized He-Ne laser show that a relative uncertainty (Deltaf/f-) of 4.3*10(-9) in 5 months, a frequency fluctuation of <1.4 MHz, and an Allan deviation of 6*10(-11) (tau=10,000 s) in 20 h are obtained. PMID- 22945155 TI - Small-scale self-focusing in a tapered optical beam. AB - The analysis of Bespalov and Talanov concerning small scale self-focusing or filamentation effects for plane waves is generalized to a tapered beam case in this paper. A model of nonlinear phase and amplitude perturbations different from Siegman's is suggested. The previous conclusion that self-focusing is very ineffectual for strongly tapered, both divergent and convergent, beams in optical Kerr media as compared to small-scale self-focusing in plane waves is found to be inappropriate. Moreover, the different conditions of phase matching in cases of cylindrical and spherical waves are explicated, which could throw some light on the issue. PMID- 22945156 TI - Using near infrared measurement of water content as a cue for detecting biological materials. AB - This paper uses the spectral characteristics of water as a cue to detect biological materials in a scene. The spectra of a wide variety of materials were measured; most of the biological materials showed a spectral feature corresponding to the absorption peak of water at 962 nm. A machine vision system that used two narrowband near infrared light sources and a conventional CCD camera is described. The ability of the system to detect biological material is demonstrated in a series of examples. Water content is not an infallible indicator that a material is biological-wet inanimate surfaces will give a false positive, and some tissues are surrounded by highly scattering, impermeable layers that conceal internal water. Nonetheless, in this paper, we will show that many tissues do give a strong response to this feature and dry, nonbiological materials do not. PMID- 22945157 TI - Measurement of air refractive index fluctuation based on interferometry with two different reference cavity lengths. AB - A measurement method based on interferometry with two different reference cavity lengths is presented and applied in air refractive index measurement in which the two cavity lengths and a laser wavelength are combined to generate two wavelength equivalents of cavity. Corresponding calculation equations are derived, and the optical path configuration is designed, which is inspired by the traditional synthetic wavelength method. Theoretical analyses indicate that the measurement uncertainty of the determined index of refraction is about 2.3*10(-8), which is mainly affected by the length precision of the long vacuum cavity and the ellipticity of polarization components of the dual-frequency laser, and the range of nonambiguity is 3.0*10(-5), which is decided by the length difference of the two cavities. Experiment results show that the accuracy of air refractive index measurement is better than 5.0*10(-8) when the laboratory conditions changes slowly. The merit of the presented method is that the classical refractometry can be also used without evacuation of the gas cavity during the experiment. Furthermore, the application of the traditional synthetic wavelength method may be extended by using the wavelength equivalents of cavity, any value of which can be easily acquired by changing cavity length rather than using actual wavelengths whose number is limited. PMID- 22945158 TI - Removing baseline flame's spectrum by using advanced recovering spectrum techniques. AB - In this paper, a novel automated algorithm to estimate and remove the continuous baseline from measured flame spectra is proposed. The algorithm estimates the continuous background based on previous information obtained from a learning database of continuous flame spectra. Then, the discontinuous flame emission is calculated by subtracting the estimated continuous baseline from the measured spectrum. The key issue subtending the learning database is that the continuous flame emissions are predominant in the sooty regions, in absence of discontinuous radiation. The proposed algorithm was tested using natural gas and bio-oil flames spectra at different combustion conditions, and the goodness-of-fit coefficient (GFC) quality metric was used to quantify the performance in the estimation process. Additionally, the commonly used first derivative method (FDM) for baseline removing was applied to the same testing spectra in order to compare and to evaluate the proposed technique. The achieved results show that the proposed method is a very attractive tool for designing advanced combustion monitoring strategies of discontinuous emissions. PMID- 22945159 TI - Two-axis solar tracking accomplished through small lateral translations. AB - High-concentration solar-power optics require precise two-axis tracking. The planar micro-optic solar concentrator uses a lenslet array over a planar waveguide with small reflective facets at the focal point of each lenslet to couple incident light into the waveguide. The concentrator can use conventional tracking, tilting the entire assembly, but the system geometry also allows tracking by small lateral translation of the lenslet relative to the waveguide. Here, we experimentally demonstrate such microtracking with the existing concentrator optics and present optimized optical designs for systems with higher efficiency and angle range. PMID- 22945160 TI - Generation of optical vortices in spun multihelicoidal optical fibers. AB - We have theoretically studied long-period spun l-helicoidal fibers and their ability to generate singular beams from regular ones. On the basis of perturbation theory in the presence of degeneracy, applied to the scalar waveguide equation, we obtained the structure of coupled modes of such fibers and their spectra. It is shown that the coupled modes consist of the fields, which taken separately bear topological charges that differ by l units. We have numerically studied the process of the passage of a Gaussian beam through such a fiber and demonstrated that long-period l-helicoidal fibers have the ability to change-in a certain wavelength range-the topological charge of the incoming Gaussian beam by l units, generating in this way charge-l optical vortex. PMID- 22945161 TI - Temperature-insensitive polarimetric vibration sensor based on HiBi microstructured optical fiber. AB - A new type of highly birefringent microstructured optical fiber has been tested for vibration measurements using a polarimetric technique. This technique takes advantage of the stress-induced phase shift between the two orthogonally polarized fiber eigenmodes. Comparison of three different fiber types shows that standard single-mode fibers do not provide stable measurements and that conventional polarization-maintaining fibers lead to a significant cross sensitivity to temperature. However, for highly birefringent microstructured fibers specifically designed to provide a temperature-independent birefringence, our experiments show repeatable vibration measurements over a frequency range extending from 50 Hz to 1 kHz that are unaffected by temperature variations (up to 120 degrees C). PMID- 22945162 TI - Direct multiangle solution for poorly stratified atmospheres. AB - The direct multiangle solution is considered, which allows improving the scanning lidar-data-inversion accuracy when the requirement of the horizontally stratified atmosphere is poorly met. The signal measured at zenith or close to zenith is used as a core source for extracting optical characteristics of the atmospheric aerosol loading. The multiangle signals are used as auxiliary data to extract the vertical transmittance profile from the zenith signal. Details of the retrieval methodology are considered that eliminate, or at least soften, some specific ambiguities in the multiangle measurements in horizontally heterogeneous atmospheres. Simulated and experimental elastic lidar data are presented that illustrate the essentials of the data-processing technique. Finally, the prospects of the utilization of high-spectral-resolution lidar in the multiangle mode are discussed. PMID- 22945163 TI - Atmospheric turbulence effects measured along horizontal-path optical retro reflector links. AB - The scintillation measured over close-to-ground retro-reflector links can be substantially enhanced due to the correlations experienced by both the direct and reflected echo beams. Experiments were carried out at China Lake, California, over a variety of ranges. The emphasis in this paper is on presenting the data from the 1.1 km retro-reflecting link that was operated for four consecutive days. The dependence of the measured irradiance flux variance on the solar fluence and on the temperature gradient above the ground is presented. The data are consistent with scintillation minima near sunrise and sunset, rising rapidly during the day and saturating at irradiance flux variances of ~10. Measured irradiance probability distributions of the retro-reflected beam are compared with standard probability density functions. The ratio of the irradiance flux variances on the retro-reflected to the direct, single-pass case is investigated with two data sets, one from a monostatic system and the other using an off-axis receiver system. PMID- 22945164 TI - Radiative properties of dense nanofluids. AB - The radiative properties of dense nanofluids are investigated. For nanofluids, scattering and absorbing of electromagnetic waves by nanoparticles, as well as light absorption by the matrix/fluid in which the nanoparticles are suspended, should be considered. We compare five models for predicting apparent radiative properties of nanoparticulate media and evaluate their applicability. Using spectral absorption and scattering coefficients predicted by different models, we compute the apparent transmittance of a nanofluid layer, including multiple reflecting interfaces bounding the layer, and compare the model predictions with experimental results from the literature. Finally, we propose a new method to calculate the spectral radiative properties of dense nanofluids that shows quantitatively good agreement with the experimental results. PMID- 22945165 TI - Development of an ice crystal scattering database for the global change observation mission/second generation global imager satellite mission: investigating the refractive index grid system and potential retrieval error. AB - Computing time and retrieval error of the effective particle radius are important considerations when developing an ice crystal scattering database to be used in radiative transfer simulation and satellite remote sensing retrieval. Therefore, the light scattering database should be optimized based on the specifications of the satellite sensor. In this study, the grid system of the complex refractive index in the 1.6 MUm (SW3) channel of the Global Change Observation Mission/Second Generation Global Imager satellite sensor is investigated for optimizing the ice crystal scattering database. This grid system is separated into twelve patterns according to the step size of the real and imaginary parts of the refractive index. Specifically, the LIght Scattering solver Applicable to particles of arbitrary Shape/Geometrical-Optics Approximation technique is used to simulate the scattering of light by randomly oriented large hexagonal ice crystals. The difference of radiance with different step size of the refractive index is calculated from the developed light scattering database using the radiative transfer (R-STAR) solver. The results indicated that the step size of the real part is a significant factor in difference of radiance. PMID- 22945166 TI - Residual-stress relaxation and densification in CO2-laser-induced long-period fiber gratings. AB - The first concurrent measurements of the three-dimensional refractive-index and residual-stress distributions in a CO(2)-laser-irradiated fiber are presented. A Corning SMF-28 fiber was exposed from one side to focused pulses with durations of 100-500 ms. The cross-sectional form of the index modulation is asymmetric with changes concentrated on the side of the fiber facing the exposure. The longitudinal form is Gaussian-like with a wide top and extends approximately 100 MUm from the center of the exposure. Relaxation of frozen-in viscoelasticity results in a maximum index modulation of 5*10(-4) on the side of the fiber facing the exposure with mechanical stress relaxation contributing changes of less than 1*10(-4). PMID- 22945167 TI - Femtosecond laser-induced damage of HfO2/SiO2 mirror with different stack structure. AB - Laser-induced damage of the "standard" (lambda/4 stack structure) and "modified" (reduced standing-wave field) HfO(2)/SiO(2) mirrors were investigated by a commercial 800 nm Ti:sapphire laser system. Three kinds of pulse duration of 50 fs, 105 fs, and 135 fs were chosen. The results show that the single-shot damage threshold of the "modified" mirror was about 14%-23% higher compared to that of the "standard" mirror. A model based on the rate equation for free electron generation was adopted to explain the threshold results. It took in account the transient changes in the dielectric function of material during the laser pulse. The simulated threshold agreed with the experimental very well. Besides, for two kinds of mirror, typical breakdown craters for both the single-shots and multi shots damage tests reveal striking distinct characteristics. Interestingly, the multi-shots damage crater with zigzag-like edge was observed only on the "standard" mirror. These phenomena were illustrated reasonably by the distribution features of the electric field intensity within the mirrors. PMID- 22945168 TI - Improving optical measurement uncertainty with combined multitool metrology using a Bayesian approach. AB - Recently, there has been significant research investigating new optical technologies for dimensional metrology of features 22 nm in critical dimension and smaller. When modeling optical measurements, a library of curves is assembled through the simulation of a multidimensional parameter space. A nonlinear regression routine described in this paper is then used to identify an optimum set of parameters that yields the closest experiment-to-theory agreement. However, parametric correlation, measurement noise, and model inaccuracy all lead to measurement uncertainty in the fitting process for optical critical dimension measurements. To improve the optical measurements, other techniques such as atomic force microscopy and scanning electronic microscopy can also be used to provide supplemental a priori information. In this paper, a Bayesian statistical approach is proposed to allow the combination of different measurement techniques that are based on different physical measurements. The effect of this hybrid metrology approach will be shown to reduce the uncertainties of the parameter estimators. PMID- 22945169 TI - Horizontal lidar measurements for the proof of spontaneous Rayleigh-Brillouin scattering in the atmosphere. AB - Several atmospheric lidar techniques rely on the exact knowledge of the spectral line shape of molecular scattered light in air, which, however, has not been accurately measured in real atmosphere up to now. In this paper we report on the investigation of spontaneous Rayleigh-Brillouin scattering within the atmosphere, utilizing horizontal lidar measurements (lambda=355 nm, theta=180 degrees ) performed from the mountain observatory Schneefernerhaus (2650 m), located below Germany's highest mountain, the Zugspitze. These lidar measurements give proof of the effect of Brillouin scattering within the atmosphere for the first time to our knowledge. The measurements confirm that the Tenti S6 model can be used to adequately describe spontaneous Rayleigh-Brillouin spectra of light scattered in air under real atmospheric conditions. The presented results are of relevance for spectrally resolving lidars like those deployed on the Atmospheric Dynamics Mission Aeolus (ADM-Aeolus) andthe Earth Clouds, Aerosols, and Radiation Explorer Mission (EarthCARE). PMID- 22945170 TI - Improved inversion procedure for particle size distribution determination by photon correlation spectroscopy. AB - We propose a minimum variation of solution method to determine the optimal regularization parameter for singular value decomposition for obtaining the initial distribution for a Chahine iterative algorithm used to determine the particle size distribution from photon correlation spectroscopy data. We impose a nonnegativity constraint to make the initial distribution more realistic. The minimum variation of solution is a single constraint method and we show that a better regularization parameter may be obtained by increasing the discrimination between adjacent values. We developed the S-R curve method as a means of determining the modest iterative solution from the Chahine algorithm. The S-R curve method requires a smoothing operator. We have used simulated data to verify our new method and applied it to real data. Both simulated and experimental data show that the method works well and that the first derivative smoothing operator in the S-R curve gives the best results. PMID- 22945171 TI - Revisiting twin-core fiber sensors for high-temperature measurements. AB - A twin-core fiber Michelson interferometer is evaluated as a high-temperature sensor. Although linear and reproducible operation up to 300 degrees C is obtained, at higher temperatures (700 degrees C) the refractive index shifts plastically and hysteresis is observed, rendering an untreated sensor head unusable. The shift is shown to be greatly reduced by an annealing process of the fiber for 10 h at 900 degrees C, with which the linear response is preserved. PMID- 22945172 TI - Development of a high spectral resolution lidar based on confocal Fabry-Perot spectral filters. AB - The high spectral resolution lidar (HSRL) instrument described in this paper utilizes the fundamental and second-harmonic output from an injection seeded Nd:YAG laser as the laser transmitter. The light scattered in the atmosphere is collected using a commercial Schmidt-Cassegrain telescope with the optical receiver train first splitting the fundamental and second-harmonic return signal with the fundament light monitored using an avalanche photodiode. The second harmonic return signal is mode matched into a tunable confocal Fabry-Perot (CFP) interferometer with a free spectral range of 7.5 GHz and a finesse of 50.7 (312) at 532 nm (1064 nm) placed in the optical receiver for spectrally filtering the molecular and aerosol return signals. The light transmitted through the CFP is used to monitor the aerosol return signal while the light reflected from the CFP is used to monitor the molecular return signal. Data collected with the HSRL are presented and inversion results are compared to a co-located solar radiometer, demonstrating the successful operation of the instrument. The CFP-based filtering technique successfully employed by this HSRL instrument is easily portable to other arbitrary wavelengths, thus allowing for the future development of multiwavelength HSRL instruments. PMID- 22945173 TI - Light-trapping design of graphene transparent electrodes for efficient thin-film silicon solar cells. AB - In this paper, the performance of solar cells with graphene transparent electrodes is compared with cells using conventional indium tin oxide (ITO) electrodes, and it is demonstrated the optical absorption of solar cells with bare graphene structure is worse than that of bare ITO structure because of the higher refractive index of graphene. To enhance the light trapping of graphene based thin-film solar cells, a simple two-layer SiO(2)/SiC structure is proposed as antireflection coatings deposited on top of graphene transparent electrodes, and the thickness of each layer is optimized by differential evolution in order to enhance the optical absorption of a-Si:H thin-film solar cells to the greatest degree. The optimization results demonstrate the optimal SiO(2)/SiC/graphene structure can obtain 37.30% enhancement with respect to bare ITO structure, which has obviously exceeded the light-trapping enhancement of 34.15% for the optimal SiO(2)/SiC/ITO structure. Therefore, with the aid of the light-trapping structure, the graphene films are a very promising indium-free transparent electrode substitute for the conventional ITO electrode for use in cost-efficient thin-film silicon solar cells. PMID- 22945174 TI - Finger vein verification system based on sparse representation. AB - Finger vein verification is a promising biometric pattern for personal identification in terms of security and convenience. The recognition performance of this technology heavily relies on the quality of finger vein images and on the recognition algorithm. To achieve efficient recognition performance, a special finger vein imaging device is developed, and a finger vein recognition method based on sparse representation is proposed. The motivation for the proposed method is that finger vein images exhibit a sparse property. In the proposed system, the regions of interest (ROIs) in the finger vein images are segmented and enhanced. Sparse representation and sparsity preserving projection on ROIs are performed to obtain the features. Finally, the features are measured for recognition. An equal error rate of 0.017% was achieved based on the finger vein image database, which contains images that were captured by using the near-IR imaging device that was developed in this study. The experimental results demonstrate that the proposed method is faster and more robust than previous methods. PMID- 22945175 TI - Tunable acousto-optic spectral imager for atmospheric composition measurements in the visible spectral domain. AB - We describe a new spectral imaging instrument using a TeO(2) acousto-optical tunable filter (AOTF) operating in the visible domain (450-900 nm). It allows for fast (~1 second), monochromatic (FWHM ranges from 0.6 nm at 450 nm to 3.5 nm at 800 nm) picture acquisition with good spatial resolution. This instrument was designed as a breadboard of the visible channel of a new satellite-borne atmospheric limb spectral imager, named the Atmospheric Limb Tracker for the Investigation of the Upcoming Stratosphere (ALTIUS), that is currently being developed. We tested its remote sensing capabilities by observing the dense, turbulent plume exhausted by a waste incinerator stack at two wavelengths sensitive to NO(2). An average value of 6.0+/-0.4*10(17) molecules cm(-2) has been obtained for the NO(2) slant column density within the plume, close to the stack outlet. Although this result was obtained with a rather low accuracy, it demonstrates the potential of spectral imaging by using AOTFs in remote sensing. PMID- 22945176 TI - Hybrid wavefront sensor for the fast detection of wavefront disturbances. AB - Strongly aberrated wavefronts lead to inaccuracies and nonlinearities in holography-based modal wavefront sensing (HMWS). In this contribution, a low resolution Shack-Hartmann sensor (LRSHS) is incorporated into HMWS via a compact holographic design to extend the dynamic range of HMWS. A static binary-phase computer-generated hologram is employed to generate the desired patterns for Shack-Hartmann sensing and HMWS. The low-order aberration modes dominating the wavefront error are first sensed with the LRSHS and corrected by the wavefront modulator. The system then switches to HMWS to obtain better sensor sensitivity and accuracy. Simulated as well as experimental results are shown for validating the proposed method. PMID- 22945177 TI - Applied Optics 2000-2005. PMID- 22945178 TI - Clare College - the view of one medical doctor. AB - This short Paper presents Clare College Cambridge, its history and its Medical and other Traditions to the participants in this symposium. PMID- 22945179 TI - Predictability of levels of physical and mental health in adults and adolescents: a 2 years longitudinal study. AB - BACKGROUND: Comparative study at two years between adults and adolescents aimed at identifying the social, family, personality traits and health locus of control factors influencing physical and mental health, consumption of medications, and frequency of medical consultations. METHOD: Twenty participants (10 adults and 10 adolescents) were included in a two years long longitudinal study. At baseline, participants' age, gender, family composition, net income, chronic treatments, family dynamics (Family Adaptation and Cohesion Scale), Multidimensional Health Locus of Control, and personality (NEO Personality Inventory) were recorded. Every six months their state of mental and physical health (12 Survey Factors and Hamilton Depression Scale), consumption of medications and number of medical consultations were reassessed. RESULTS: Age has a deleterious effect not only on physical health (r=-0.628*) but also on the frequency of depressive symptoms (r=0.576*). Adults are protected against the above effect by the number of people living in the same household (r=-0.588*). The ideal family or couple is more important than the actual family or couple. The higher these ideals, the healthier the adults (r=0.738*), and the less teenagers go to the doctors (r= 0.648*). Among adults, independence from others is correlated with good mental health (r=-0.829**) and among teens, ability to manage their wishes is positively correlated with good mental health (r=0.718**). CONCLUSION: Although different mechanisms determine adolescents and adults' levels of health, other common mechanisms involved include age and the need for love. The older we grow, the more our health tends to deteriorate; the more we dream of love, the more it improves. The differences depend on the place that is left to others. Among teenagers, the first factor pertains to how well they manage their own desires; among adults, what matters most is independence from others. PMID- 22945180 TI - The current perspective of neuromodulation techniques in the treatment of alcohol addiction: a systematic review. AB - BACKGROUND: Alcohol dependency can be considered as a chronic mental disorder characterized by frequent relapses even when treated with appropriate medical or psychotherapeutic interventions. Here, the efficacy of different neuromodulation techniques in alcohol addiction, such as transcranial direct current stimulation (tDCS), repetitive transcranial magnetic stimulation (rTMS), deep brain stimulation (DBS), vagal nerve stimulation (VNS) and electroconvulsive therapy (ECT) is critically evaluated. METHODS: A broad literature search on electronic databases such as NCBI PubMed, the Web of Knowledge, the Cochrane Library was conducted. Additionally, we searched recent handbooks on neuromodulation and/or addiction. RESULTS: Studies investigating these neuromodulation techniques in alcohol addiction remain to date rather limited and especially tDCS and rTMS applications have been investigated. Overall, the clinical effects seem modest. The use of VNS and ECT has yet to be investigated in alcohol dependent patients. CONCLUSIONS: Neuromodulation techniques have only recently been subject to investigation in alcohol addiction and methodological differences between the few studies restrict clear-cut conclusions. Nevertheless, the scarce results encourage further investigation in alcohol addiction. PMID- 22945181 TI - Unexplained syncopes: what place is there for the liaison psychiatry? Analysis of the first year of the Interdisciplinary Centre of Unexplained Faintness and Syncopes. AB - INTRODUCTION: The diagnostic process of syncopes remains an important and complex issue. In spite of everything, it is estimated that 20 to 30% of syncopes remain unexplained. The diagnosis of psychogenic syncope is estimated at 5.5% to 14% of syncopes. A systematic psychiatric evaluation of unexplained syncopes would be strongly recommended. We present here the original care by the "Centre Interdisciplinaire des Malaises Inexpliques et des Syncopes (Interdisciplinary Centre of Unexplained Faintness and Syncopes.)" set up by the neurology and cardiology departments associated with the ENT department. We describe the place liaison psychiatry has been able to define and its field of action. SUBJECT AND METHODS: After a year of operation, and on the basis of structured interviews with the "Mini International Neuropsychiatric Interview" and on a review of records, we assessed the recruitment in terms of psychiatric monitoring as well as the associated psychiatric diagnoses in patients who consulted for an unexplained syncope. RESULTS: Of the 91 patients who have consulted the Interdisciplinary Centre of Unexplained Faintness and Syncopes in 2009, 24% have been directed towards a psychiatric evaluation. Among these, 68% suffered from an anxiety disorder, 27% from a major depressive disorder and 22% from a substance related disorder. DISCUSSION: We assess the interesting conditions that the Interdisciplinary Centre of Unexplained Faintness and Syncopes proposes for a liaison psychiatry activity. We note the interest in easier access to psychiatric care for a group that would not have spontaneously approached the Centre. CONCLUSION: Other measures of quality of care indices are still to be developed. PMID- 22945182 TI - An approach to the diagnosis and treatment of patients with bipolar spectrum mood disorders, identifying temperaments. AB - Disorders of the bipolar spectrum (including sub-threshold forms) are very common, more so than is normally considered: these pathologies are often underestimated, not diagnosed or badly treated. In this article we describe a method hereby a patient with bipolar disorder is evaluated clinically, having regard to establishing the patient's underlying temperament. PMID- 22945183 TI - Rationale for clinical interventions in prodromal psychosis. Are such interventions safe? AB - We compare the reported side effects of medication from the trials of prodromal psychosis treatment. We note that the side effects of antipsychotics are those described in the usual pharmacology of these substances and that the severity of side effects are dependent on dosage, with more side effects at higher doses. We report on the search for alternative compounds for the treatment of prodromal psychosis. Omega fatty acids and Cognitive Behavioural Therapy are certainly good adjuvant treatments for suspected prodromal psychosis. With further evidence they may be considered appropriate to use as monotherapy, particularly in the early prodrome. Treatment of prodromal psychosis continues to present a number of risks; therefore the decision to treat ultimately must depend on the symptoms presented by the individual. PMID- 22945184 TI - Psychosis risk syndrome: is it worth the risk? AB - The American Psychiatric Association is considering listing the 'Psychosis Risk Syndrome' as a diagnosis in its own right in the DSM-5. This decision recognises the paradigm shift in clinical psychiatry to a model of early intervention. However, this decision has aroused much discussion. The controversy which has arisen around this proposal reflects the difficulties in implementing the early intervention paradigm. Here we review the different opinions which have been expressed regarding this issue and consider whether this is the appropriate time to include 'Psychosis Risk Syndrome' as an independently listed psychiatric diagnosis. PMID- 22945185 TI - Cognitive correlates in panic disorder as related to impulsivity - preliminary report. AB - BACKGROUND: Impulsivity is the neurophysiologically based inability to confirm behaviour to its context or consequences. Overimpulsiveness characterizes many mental disorders and poses an important clinical dilemma. Although the relationship between mood disorders and impulsivity has been well studied the relationship between anxiety and impulsivity is controversial and not well explored. Some studies hypothesise that patients with the diagnosis of panic disorders are characterised by higher levels of impulsivity as a trait as compared to healthy individuals. The aim of this study was to assess cognitive correlates in panic disorder as related to impulsivity measures. MATERIAL AND METHODS: Within the preliminary studies four patients diagnosed with panic disorder (DSM-IV-TR) were studied. The severity measure was the Panic and Agoraphobia Scale. The experimental group comprised of psychotropic drug naive patients. Impulsiveness was evaluated with the Barrat Impulsiveness Scale - 11th version (BIS-11). To asses cognitive functions we used CANTAB (Cambridge Neuropsychological Test Automated Battery). RESULTS: BIS-11 scores observed in the group of psychotropic drug naive patients with panic disorder were higher than the adjusted average for the population and correlated with the number of mistakes in CANTAB (Spatial Working Memory Test); rs=0.949; p=0.0513. CONCLUSIONS: The preliminary findings indicate a correlation between impulsivity and cognitive deficits in panic disorder in psychotropic drug naive patients. PMID- 22945186 TI - Mood disorders in epilepsy - diagnostic and methodological considerations. AB - BACKGROUND: Mood disorders are common in people with epilepsy (PWE) with prevalence rates ranging from 11% to 62%. The variation in epidemiological data results probably from the diversity of methodologies employed and selection of the populations across the studies. Moreover, the symptomathology of mood disorders in epilepsy is often atypical, intermittent and pleomorphic and fails to meet DSM-IV-TR categories. Several studies suggested the existence of distinct interictal dysphoric disorder (IDD) in patients with epilepsy. The majority of research studies in mood disorders in epilepsy were based on screening instruments in the diagnosis of mood disorders in PWE. However, the results in validity and reliability in detecting major depression in epilepsy using self report inventories of mood symptoms is vague. The aim of this study was to review studies on mood disorders in epilepsy with particular focus on diagnostic methods. SUBJECTS AND METHODS: The focus of this Review was on patient studies on mood disorders in epilepsy (2000-2012). We searched PubMed using the following search terms (effective date: 20th May 2012): (epilepsy (Title/Abstract) OR seizure (Title/Abstract)) AND depression (Title/Abstract) OR Dysthymia OR mania OR bipolar disorder OR affective disorder OR Interictal Dysphoric Disorder OR AND (humans (MeSH Terms) AND English (lang) AND (2000/01/01(PDAT): 2012/04/31(PDAT)). RESULTS: Depression is the most frequent comorbid psychiatric disorder in epilepsy. Recent studies pointed out that bipolar disorders are not rare in epilepsy. Most of the research in PWE did not rely on standardized psychiatric measures and only about 18% of studies were based on diagnostic psychiatric interviews (mainly MINI and SCID-I). Mood disorders in epilepsy excluding the ictal or periictal symptoms can be categorized using standardized measures. CONCLUSIONS: Common self-report depression measures may be used to screen for depression in clinical settings. The use of screening instruments in epilepsy must be followed by structured psychiatric interviews designed to establish a DSM IV-TR diagnoses. Standardized psychiatric interview procedures based on DSM criteria like SCID-I or MINI provide a comprehensive way to diagnose mood disorders in patients with epilepsy. PMID- 22945187 TI - The efficacy of Cognitive-Behavioural Therapy (CBT) as related to sleep quality and hyperarousal level in the treatment of primary insomnia. AB - BACKGROUND: Primary insomnia (PI) is a common sleep disorder affecting diurnal functioning. It may contribute to the development of several comorbidities such as major depression or arterial hypertension. It affects about 7% of the adult population. Pharmacotherapy remains the most common treatment for insomnia. However, many studies suggest CBT may be a supreme therapeutic approach resulting in a better long-term outcome. The aim of the study was to determine the efficacy of a CBT-protocol in the treatment of PI by means of sleep onset latency and the number of awakenings during night parameters along with sleep quality and the level of psychophysiological hyperarousal. The secondary outcomes were focused on CBT efficacy as determined by the predisposition to insomnia as related to higher vulnerability to stress (measured with FIRST) MATERIAL AND METHODS: Twenty six individuals from a tertiary reference sleep disorders outpatients' clinic (22 women; mean age 41.4; 4 men; mean age 42.5) with primary insomnia (DSM-IV-TR) were included in the study. The exclusion covered other primary sleep disorders, secondary insomnia (psychiatric illness, unstable somatic illness, shift work), substance abuse/dependence, high results in HADS-M scale (score above 11). The participants were scored with HADS-M, Ford Insomnia Response to Stress Test (FIRST) at the beginning of the study. The Athens Insomnia Scale (AIS), Hyperarousal Scale, Leeds Sleep Questionnaire (LSEQ) were applied at the beginning, at the end and three months after the end of the study. The participants were also examined by 7 days actigraphic records before and after treatment. During the course of the treatment patients completed a Sleep Diary (SD). The CBT program employed was based on the Perlis protocol. Standard individual sessions of 50 minutes were provided on a weekly basis for 8-10 weeks by a board certified CBT therapist. After 3 months a follow-up session was scheduled. RESULTS: The significant improvement as related to the CBT treatment was present in the measures of sleep onset latency (67.2 vs. 23.4 min.; p<0.000), numbers of awakenings during night (2 vs. 0.4; p<0.000) and sleep efficiency (77.3 vs. 91%; p<0.000) - data from SD, quality of falling asleep (3.2 vs. 6; p<0.000), quality of sleep (3.3 vs. 5.8; p<0.000) and quality of morning awakening (3.2 vs. 6; p<0.000) - data from LSEQ. The improvement reached the significance level in the measure of psychophysiological arousal (52.3 vs. 42.4; p<0.000) and AIS (15.7vs. 6.8; p<0.000). No significant differences were identified between actigraphic records (light/dark ratio) before and after CBT. FIRST scores allocating patients to high and low stress vulnerability groups were non-contributory to the observed treatment efficacy. CONCLUSION: CBT is an effective treatment in primary insomnia. No relationship between CBT efficacy and predisposition to insomnia as determined by higher vulnerability to stress was identified. PMID- 22945188 TI - Psychopharmacological treatment and psychoeducational management in bipolar disease. AB - In bipolar disorder there is a deterioration of concomitant diseases, a marked deterioration in the quality of life, an increased difficulty of personal relationships, both in the family and the workplace, and an increased vulnerability and inability to deal with stress. Here we describe how pharmacotherapy can be combined with psychotherapy and psycho-education to improve recovery of a patient with bipolar disorder. PMID- 22945189 TI - Bipolar disorder and stress. AB - The management of stress in a group of patients with Bipolar II Disorder is described. The use of psychotherapy and psycho-education has been shown to reduce the number of relapses and improve the quality of life of these patients. PMID- 22945190 TI - Single nucleotide polymorphisms and suicidal behaviour. AB - The World Health Organization estimates that almost one million deaths each year are attributable to suicide, and suicide attempt is close to 10 times more common than suicide completion. Suicidal behaviour has multiple causes that are broadly divided into proximal stressors or triggers and predisposition such as genetic. It is also known that single nucleotide polymorphisms (SNPs) occur throughout a human DNA influencing the structure, quantity and the function of proteins and other molecules. Abnormalities of the serotonergic system were observed in suicide victims. Beside 5-HT1A and other serotonin receptors most studied are the serotonin transporter 5' functional promoter variant, and monoamine oxidase A and the tryptophan-hydroxylase 1 and 2 (TPH) polymorphisms. It seems that especially genes regulating serotoninergic system and neuronal systems involved in stress response are associated with suicidal behaviour. Most genetic studies on suicidal behaviour have considered a small set of functional polymorphisms relevant mostly to monoaminergic neurotransmission. However, genes involved in regulation of other factors such as brain-derived neurotropic factor seems to be even more relevant for further research. PMID- 22945191 TI - Religious content of hallucinations in paranoid schizophrenia. AB - BACKGROUND: Different environmental factors are thought to be responsible for 15 20% of schizophrenia pathogenesis. Religion has long been considered a major force in human life, regardless of economic, social or political affiliation. How the perception of religion has changed over time, especially in the context of mental illness, was the focal point of this long-term comparative study. SUBJECTS AND METHODS: A random selection of 100 case histories from the years 1932, 1952, 1972 and 1992 was selected. By reviewing the subject history and medical notes, information on the presence of religious hallucinations and/or delusions were collected and grouped. RESULTS: Religious topics were demonstrated in 46.8% of the test population. Whereas there was a clear diversity of religious-themed delusions, "God", "Christ", "Mary", "Satan/devil" and "hell" all figured prominently across all reviewed years. There is a progressive decrease in the number of religious topics in paranoid schizophrenia. The transfer of holiness from historical saints onto a subject was observed. Evil dominates over good in productive symptoms in paranoid schizophrenia. The phenomenon of apocalyptic subjects in paranoid hallucinations and delusions increased after the Second World War. CONCLUSION: Religious topics of hallucinations and delusions change over time and relate to objective historical events and reflect changes in religiosity in society. PMID- 22945192 TI - An exploration of how film portrays psychopathology: the animated documentary film Waltz with Bashir, the depiction of PTSD and cultural perceptions. AB - With the inauguration of the UK's first ever Medical Film festival MedFest in 2011 there has been resurgence in the interest of the association between psychiatry and film. The festival in 2012 was titled "HealthScreen": Understanding Illness through Film and its aim, according to the founder Dr Kamran Ahmed, was, 'To stimulate debate of the social, political and ethical implications of portrayals of health and illness on our screens' (1). Waltz with Bashir is a 2008 Israeli animated documentary film written and directed by Ari Folman. It portrays the protagonist (Folman) in search of his lost memories of his experience as a soldier in the 1982 Lebanon War and his attempt to both decipher them and reconcile himself with them. 2012 marks the 30th year commemoration of the Sabra and Shatilla tragedies. Waltz with Bashir vividly depicts the massacres of Palestinians in the Sabra and Shatilla refugee camps in Beirut through the lens of an ex-IDF serviceman and the harrowing effects that PTSD has on him. Waltz with Bashir was nominated for an Academy Award for Best Foreign Language Film however despite the popularity of the film and much critical acclaim it is officially banned in Lebanon. The authors are mindful of the devastating effects that the atrocities have had on the mental health of all those who were involved, the Lebanese, Palestinians and also the Israelis. The purpose of this presentation is to explore how the film Waltz with Bashir portrays PTSD and how it has influenced cultural perceptions. PMID- 22945193 TI - Depression, pathological dependence, and risky behaviour in adolescence. AB - During adolescence, there is an increased chance of increased incidence of depression and the development of addictive/dependent behaviours such as pathological gambling, excessive Internet use and compulsive shopping, Here we present a psychoeducational approach in the schools of Pescara and Penne to identify and treat these problems. PMID- 22945194 TI - Inter-regional variations in suicide rates. AB - Suicidal behaviour is a significant public health problem. Suicide alone represents the 10th leading cause of death worldwide. Suicide is a complex phenomenon and may be the result of an interaction of biological, psychological and socioeconomic factors. Although there are many differences in suicide rates between different countries in the world, some studies reported huge differences of suicide rates between different regions within the same country as well. The studies that investigated the regional differences in suicide rates were gathered in the present article. The studies revealed that depression frequently remained unidentified and thus untreated and could contribute to high regional suicide rates. It could be speculated that access to services, which increases the possibility of diagnosis and treatment of mental disorders, could have an impact on regional suicide rates. Thus the availability of services may be relevant in explaining geographical variations in suicide incidence. Many studies reported that suicide was a major public health issue of particular concern among rural populations, which experienced a consistently higher suicide rate than urban areas considering the availability of psychiatric services, was typically less available in rural regions. As suggested in some studies, it seems that socioeconomic factors outweighed climatic factors in explaining regional differences in the suicide rate but further research is needed. PMID- 22945196 TI - Depression and suicidality in modern life. AB - This paper describes the relationship between depression and the difficulties experienced in the postmodern world for human beings who must reconcile their consciousness of their own death and the feelings of powerlessness in the face of inevitable consequences. Depression and suicide are closely linked, and the consequences in terms of philosophy and psychology are described. PMID- 22945195 TI - Diagnosis of mental illness in primary and secondary care with a focus on bipolar disorder. AB - INTRODUCTION: While most of the management of mental health in the UK is conducted in primary care, the diagnosis by GPs has been shown to deficient in some areas. Bipolar disorder in particular is known to under-diagnosed but there is confusion as to whether this is due to poor recognition or conversion from unipolar depression SUBJECTS AND METHODS: In April and May 2012 an audit was conducted in secondary psychiatric services in Bedford, UK among 146 representative patients and 112 bipolar patients, examining the course of their illness and diagnosis RESULTS: Bipolar disorder is under-diagnosed in the community and in secondary care. First manic or hypomanic symptoms usually follow first depressive symptoms by several years (MU=7.3, sigma=7.9). A diagnosis of bipolar also commonly follows manic or hypomanic symptoms by years (MU=7.6, sigma=8.3). DISCUSSION: Both psychiatrists and GPs under-diagnose bipolar, but this study shows it may be due to two factors: poor recognition by doctors and conversion from major depressive disorder. CONCLUSION: GPs and psychiatrists must be more aware of the under-diagnosis of bipolar and its tendency to convert from pure depressive symptoms. PMID- 22945197 TI - The differences between typical and atypical antipsychotics: the effects on neurogenesis. AB - Recently, the pharmacological division between typical and atypical antipsychotics has been called into question. New evidence, however, continues to emerge showing differences between these two classes of drugs. Hence typical and atypical antipsychotics are clearly different classes of drugs, as evidenced by their actions, mechanisms, effects and side effects. The most recently investigated field in which both classes of drugs have opposing effects is neuron survival and neurogenesis. Schizophrenia has been found to be a disease of progressive reductions in grey matter, and the more lost, the worse the outcome. Medication naive patients have lowered levels of neurotrophins e.g. NT-3, NGF BDNF. The antipsychotic drugs alter the levels of these neurotrophins. Haloperidol, of the typical antipsychotics, causes neuron apoptosis by a free radical induced mechanism, involving Bcl-XS, P53, cytochrome c translocation and caspase 3 activation. Haloperidol also lowers BDNF levels, reducing neuroprotection in the brain to enable haloperidol's toxic effects. Atypical drugs have opposing effects. They increase levels of BDNF, improve cell survival and enhance neurogenesis. Atypical drugs can also prevent or reverse the effects of haloperidol induced toxicity. The mechanism involves the inverse agonism of 5HT receptors, particularly those of the 2A subset, but the situation is considerably more complicated. PMID- 22945198 TI - Bipolar and unipolar depression. AB - Since Kraepelin grouped affective disorders under the title of 'manic-depressive insanity', there has been controversy over whether the bipolar and unipolar entities within this are distinct affective disorders or whether they are merely two ends of an affective continuum. In order to bring some clarity and goal-posts to this argument, we define the criteria that must be fulfilled by diseases in order to be considered as part of a spectrum. We analyse bipolar disorder and major depressive disorder with respect to these criteria and find the model fits in many respects but fails to account for either the poor correlation in severity of manic and depressive symptoms or for the apparent discontinuity in the distribution of familial mania. A one-dimensional spectrum is thus too simple and a two-dimensional approach is required; this also fits much better with our current understanding of the genetic picture. PMID- 22945199 TI - Childrens mental health and civil society in the Gaza strip. AB - The Gaza Strip, with a population of 1.7 million, over half of whom are under 18 years old, has existed in a state of ongoing conflict and containment for years, most notably since its closure in 2007. There is much concern for the mental health of the vast young generation who have little memory of other circumstances of existence, and even less exposure to the outside world. Their society forms the site of direct conflict and social destruction pertaining to untreated stress among the adults. However, leaving the social realm for the institutional for mental health treatment carries strong taboo, especially for adults. Civil society expert organisations offering a range of mental health work primarily pertaining to childrens social development can bypass some of this taboo and can also intervene at their schools and in their families, and may be most strategically located as social rather than institutional actors. Empowering the youth and seeking to strengthen Gazan society through them and for them causes some friction with the local government. However, despite the cultural and political challenges of mental health treatment for children within the Gaza Strip, the wider fact remains that however treated and psychosocially rehabilitated, society is predictably the site of renewed trauma in the short term and foreseeable future, enmeshing the mental health of its future generation inseparably with the international politics it inhabits. PMID- 22945200 TI - Case report of a patient with bipolar disorder - migraines and epilepsy. AB - Bipolar disorder; migraines and epilepsy are three prevalent conditions, of which little is understood about their pathophysiological processes. Co-morbidities often present between two of these conditions, but it is uncommon for all three to co-exist in a patient. Here, we present a middle-aged gentleman, seen in the outpatient department of a district general hospital in England, who suffers from severe effects of all three disorders, with no other medical history. Clinical difficulties have arisen in the diagnosis and treatment of his bipolar disorder. Management of his depressive episodes with simple selective serotonin reuptake inhibitors and mood stabilisers were either ineffective, or precipitated complicating adverse effects. Persistent use of citalopram is likely to have triggered bipolar disorder, whilst quetiapine induced seizures. The clinical problems presented question the possibility that bipolar disorder; migraines and epilepsy may fall on the same spectrum of disorders. This could contribute towards the complexities in treating his conditions. Further insight into their link and interactions would facilitate diagnoses of these conditions, as well as improve treatment strategies when they are presented co-morbidly. PMID- 22945201 TI - Involvement of genetic factors in bipolar disorders: current status. AB - Bipolar disorder, also known as manic-depressive illness, is a brain disorder that causes unusual shifts in mood, energy, activity levels, and the ability to carry out day-to-day tasks. The involvement of genetic factors has been evaluated through twin, family, linkage and association studies but specific genes that contribute to the illness remain unclear. This study gives an overview of available literature. PMID- 22945202 TI - The Kraepelinian dichotomy in terms of suicidal behaviour. AB - The Kraepelinian dichotomy sees schizophrenia and bipolar disorder as two distinctly separate diseases each with its own pathogenesis and disease process. This study looks at the difference between patients with schizophrenia and bipolar disorder in terms of suicidal behaviour. Both schizophrenia and bipolar disorder have been identified as significant risk factors for suicide, while bipolar and major depressive disorder appear to be the greatest diagnostic indicators. This study also aims to look at any differences in suicidal behaviour between the two major classes of bipolar disorder (bipolar I and bipolar II) to possibly determine how distinct these two conditions are in this respect. As expected, this study found that patients with a diagnosis of bipolar disorder were significantly more likely (OR=4.79) to have a history of suicidal behaviour than patients with a diagnosis of schizophrenia. Neither bipolar I nor bipolar II patients were significantly more likely to have a history of suicidal behaviour. However, this study yielded a weak association between bipolar II patients and suicidal behaviour (OR=1.83) compared to bipolar I patients, which may have been more significant under different circumstances such as a greater sample size. PMID- 22945203 TI - Analysis of multi-instrumental assessment of eating disorders: comparison between Anorexia and Bulimia. AB - INTRODUCTION: The origin and course of eating disorders constitute a multifactorial etiopathology. This is why it is important to consider the psychological, developmental, biological and socio - cultural evaluation of each patient. The Diagnostic and Statistical Manual DSM IV - TR (APA, 1994) distinguishes two main eating disorders: Anorexia Nervosa and Bulimia Nervosa. Together with them are described a broad and heterogeneous category (EDNOS) of "atypical eating disorders," that is a clinically significant eating disorder, but that does not meet all the diagnostic criteria for Anorexia Nervosa or Bulimia Nervosa. The aim of this pilot study was to analyze the differences detectable in anorexic and bulimic patients in relation to several factors of mental functioning, particularly with respect to the presence of distinctive characteristics and symptoms and the associated substrate personality. METHOD: 20 patients with eating disorders who have a residential rehabilitation program, all women, 10 diagnosed with AN aged between 18 years and 31 years, including (5 Restrictive and 5 with Purging) and 10 diagnosed with BN aged between 19 years and 31 years (including 5 with Purging). RESULTS: The pictures of AN and BN can be placed within a continuum of symptoms that distinguishes them exclusively for the presence or absence of bulimic episodes; also the symptom of bulaemia can be considered a most important aspect in the distinction between anorexia and bulimia as all other aspects of mental functioning appear to be similar in almost direct measurement, and finally some food pathological events are associated with personality characteristics, Axis I symptoms and quality of life, linked to specific types of global functioning. DISCUSSION: Some symptoms may have different functions depending on the patient's personality style: a patient may develop a symptom of anorexia because it is competitive and a perfectionist, another as a form of self-punishment or as a strategy to regulate the feeling of being out of control, another again as a phenotypic expression of an underlying mood disorder, in the same way the purging may represent a reaction for a patient who is emotionally dysregulated or a measure of weight control which is more deliberate for a patient who is highly controlled perfectionist. CONCLUSION: There is a need to look at eating disorders within a global view of mental functioning, these conditions may be considered "diagnostic trans', ie disturbances traveling along a continuum, and are therefore characterized by a "diagnostic migration." PMID- 22945204 TI - Impact of family and school environment on the development of social anxiety disorder: a questionnaire study. AB - BACKGROUND: Social anxiety disorder (SAD) is a very common condition, although its prevalence is believed to be underestimated. The affected subjects often have trouble to search for support. The onset occurs mainly in early adolescence. The aim of this paper was to evaluate the impact of school and family background on the development of SAD. SUBJECTS AND METHODS: Our survey, available on a popular social network site, was divided into 4 parts: 1) demographic data (gender, age, site of residence), 2) genetic and organic background (comorbid mental disorders, addictions), 3) situation at school and in the family environment during adolescence, 4) the part designed to define the group that may suffer from SAD with the use of the Mini-Social Phobia Inventory (Mini-SPIN). RESULTS: 226 people were recruited. The age range was 16-61, with the average of 25,8. 71% of the respondents lived in cities with a population of more than 100 000. Male to female ratio was 3:1. According to Mini-SPIN 26,5% of the interviewees might suffer from SAD (28.2% of women and 21.4% of men). Our study showed, that both family and school environment factors have an influence on the development of SAD. It was shown that the especially important risk factors are bad relations with peers and being an object of derision at school. CONCLUSION: The percentage of network community users that are likely to suffer from SAD, significantly exceeds the clinical data. Both family and school environment factors were shown to be risk factors for the development of this disorder. PMID- 22945205 TI - The effect of psychiatric condition and medication on the prevalence of diabetes in a psychiatric out-patient clinic: an audit. AB - BACKGROUND: A diagnosis of schizophrenia, as well as the use of atypical antipsychotic medications, have previously been linked with a higher prevalence of diabetes. METHODS: 670 patients from a single out-patient clinic were analysed (Chi-square) to determine if diagnosis or antipsychotic treatment had an effect on the prevalence of diabetes. The overall rate of diabetes was also compared to the national average. RESULTS: No significant effects of antipsychotic class or diagnosis were found on prevalence, and the prevalence was not significantly different to the national average. INTERPRETATION: This work may point to a need to carry out a systematic assessment of these patients for Metabolic Syndrome or diabetes as a thorough review/screen for these patients. PMID- 22945206 TI - Impact of psychotherapy and antidepressive treatment on cognitive functions in patients treated for depression. AB - BACKGROUND: Depressive disorders are often treated with the use of antidepressants and with psychotherapy at the same time. According to the literature these two types of treatment may exert a certain influence on brain functioning. The aim of this study was to evaluate the effectiveness of different forms of therapeutic methods on the improvement of cognitive functions. SUBJECTS AND METHODS: 60 patients participated in the study. They were divided into 3 groups treated with pharmacotherapy, psychotherapy or both, respectively. The neuropsychological changes observed as a results of the application of these methods was assessed with the Vienna Test System (VTS). The patients recruited to the study were treated at the psychotherapeutic subdivision of a psychiatric ward. Inclusion in the study was restricted to individuals with a diagnosis of recurrent depressive disorder. RESULTS: The improvement in psychological tests measuring short-term memory and attention was present on average after 8 weeks of treatment and was most prominent in patients treated with both forms of therapy. CONCLUSIONS: The interpretation of the achieved results must be cautious because of the relatively small groups participating in the study. Further research is necessary to analyze the impact of different therapeutic forms used in the treatment of depression on cognitive processes. PMID- 22945207 TI - Eating disorders in Silesian schools - pilot study. AB - BACKGROUND: Modern media have a huge impact on eating habits, which result in pathologies among young people, especially females. Fashion models have become a pattern for ordinary women, however the difference in a mean weight between these two groups is increasing. The aim of the study was to assess the correlation between school students' results in EAT-26 self-report questionnaire and their daily diet behavior and to analyze the occurrence of eating disorders among students in schools of the region of Silesia in Poland. SUBJECTS AND METHODS: Our survey was based on the EAT-26 (Eating Attitude Test) and Behavioral Four Questions Test. 150 questionnaires were given to students of Secondary Schools, 116 were filled out correctly. The interviewed group consisted of 85 girls and 31 boys. Average age was 17.24+/-1.18. All of the data were analyzed statistically. RESULTS: Average BMI was 21,06; half of the recruited subjects had correct BMI whereas over 40% of them presented underweight. Within 116 responses from the EAT 26 nearly 93% belonged to the group with a small risk of the development of future eating disorders. Nevertheless, over 6% of the survey participants were in the group at high risk. In the Behavioral Four Questions Test 10% participants turned out to be in the compulsive overeating group, other ones in the group of a probable development of anorexia (7%) or bulimia nervosa (3%). CONCLUSIONS: There is a strong correlation between particular daily activities and the score achieved in EAT-26, however there is no significant correlation between the calculated BMI and EAT-26 results. Specific socio-cultural factors are faced by public services. They refer both to health promotion programs and the organization of spare time spent by teenagers outside schools. PMID- 22945208 TI - Suicidal attempts among Emergency Department patients: one-year of clinical experience. AB - INTRODUCTION: Suicidal ideation and attempts account for a significant number of Emergency Department visits and represent a major public and mental health problem. Suicide and suicide attempts are a major cause of death and morbidity worldwide. SUBJECTS AND METHODS: 111 suicide attempters (81 F (73%), 30 M (27%)) were consequently recruited in the Emergency Department of the Santa Maria della Misericordia, Perugia, Italy between June 2011 and June 2012. Patients were assessed and demographic and clinical data were collected in clinical records. Data analysis was conducted using SPSS software. Chi-square test and logistic regression were used as appropriate. A p-value <0.05 was considered statistically significant. RESULTS: Females attempt suicide 3 times more frequently than males and generally use a non-violent suicide attempt method. In our sample unmarried status is the most represented and the most common diagnosis is major depressive disorder, followed by borderline personality disorder. Suicide attempts are more frequent in January. CONCLUSION: It is of crucial importance to conduct a suicide risk assessment when subjects are admitted to an ED given that the strongest known predictor for future suicide is attempted suicide. PMID- 22945209 TI - The continuum between Bipolar Disorder and Borderline Personality Disorder. AB - INTRODUCTION: Several studies have been carried out regarding the possible overlap between Bipolar Disorder and borderline personality disorder. Up to now, it is not possible to provide a definitive picture. In fact, there is currently significant debate about the relationship between Borderline Personality Disorder and Bipolar Disorder. METHODS: MEDLINE searches were performed to identify the latest studies of these disorders, considering psychodynamic aspects. DISCUSSION: Bipolar disorder and borderline personality disorder share common clinical features, namely affective instability and impulsivity which however differ in quality. Consequently, to better understand these aspects, it is necessary to trace the stages of childhood psychological development. CONCLUSIONS: It has been claimed that Bipolar Disorder Type II can be divided into two subtypes: one stable and functional between episodes and one unstable between episodes which is related to Borderline Personality Disorder. However, better diagnostic theories, psychiatrist's empathy and patience remain the essential tool to understand and to face human suffering. PMID- 22945210 TI - Aggression in the work environment of physiotherapists. AB - BACKGROUND: Aggression in the medical environment can take on different forms. It can be inflicted both by patients and workmates and may also cause a rise of aggressive behavior performed by the physiotherapists themselves. The aim of the study was to evaluate possible danger that may occur in the working environment of physiotherapists as well as to assess the correlation between such factors as the length of professional experience and exposure to the aggression inflicted by patients and workmates in the workplace with the level of aggression occurring within the professional group of physiotherapists. SUBJECTS AND METHODS: The study was conducted among 50 physiotherapists from Opole and the Silesian Voivodships in Poland. Two types of questionnaires were used: the author's own questionnaire, assessing exposure of the physiotherapists to aggression in the workplace, and the Buss-Perry Aggression Questionnaire. The results were analyzed with the Statistica 8.0 application. RESULTS: 60% of participants suffered from patients' verbal aggression, 8% from physical aggression and 26% from the patients' emotional self-aggression at least twice a month. The study showed a minor correlation between the duration of the length of professional experience and the level of hostility (r=0.2; p>0.05). There is a considerable impact of negative emotions present in relations with workmates at the workplace causing mainly increase of general aggression among physiotherapists and hostility. Similarly, negative emotions that may appear in relations between psychiatrists and patients show a positive correlation with the level of general aggression developed by doctors. CONCLUSIONS: It can be observed that there is a huge impact of the impulsive behaviour and attitude (presented both by patients and workmates in the workplaces) on the appearance of aggressive actions by physiotherapists (especially anger and hostility). Further research in this field is needed. PMID- 22945211 TI - Increased interleukin-6 and tumor necrosis factor alpha in first episode schizophrenia patients versus healthy controls. AB - BACKGROUND: Inflammatory immune processes have been clearly implicated in the etiopathology of schizophrenia. There are, however, only limited data dealing with immune parameters in the first episode patients with schizophrenia and the course of these parameters during treatment. SUBJECTS AND METHODS: The presented study compared plasma levels of interleukin (IL)-6, IL-8, IL-10 and TNF-alpha in 25 patients with the first episode of schizophrenia with the minimal exposition of antipsychotics before and after treatment and with age and sex matched group of healthy volunteers. Changes in plasma cytokine levels were investigated after 4 weeks of treatment in relationship with the therapeutic outcome. RESULTS: Our results show significantly increased plasma levels of IL-6 (p<=0.001) and TNF alpha (p<=0.001) in patients at the admission in comparison with healthy volunteers. After 4 weeks of the treatment the PANSS score decreased (p<=0.001), concurrently the plasma level of IL-6 decreased and TNF-alpha did not show any decrease after treatment. The patients' posttreatment and healthy control group comparison showed higher plasma levels of TNF-alpha (p=0.008) and marginally elevated plasma level of IL-6 (p=0.046) in the posttreatment group. Plasma levels of IL-8 and IL-10 did not show any significant differences. CONCLUSIONS: Our study validated the presence of the proinflammatory state in the first episode of schizophrenia. IL-6 may be considered as a state marker for acute exacerbations and TNF-alpha may be a trait marker of schizophrenia. PMID- 22945212 TI - The mental illness spectrum. AB - There exists a growing argument in favour of a more dimensional approach to the diagnosis and treatment of psychiatric patients. This encompasses first the idea of a spectrum of symptoms correlating to severity within a single disorder, and secondly, the idea of spectra of different disorders sharing overlapping collections of symptoms. Here we consider the issue in light of specific clinical examples we have observed, which support the idea of a 'mental illness spectrum', both with symptoms within a single disorder, and between different mental disorders. PMID- 22945213 TI - Reasons for the choice to specialize in psychiatry - a retrospective study. AB - BACKGROUND: Providing the mental health service is one of the main tasks of every state. Its implementation obviously depends on the number of professionally active psychiatrists. The aim of the study was to analyze the motives in the choice of the specialization in psychiatry from the perspective of physicians practitioners. SUBJECTS AND METHODS: An original questionnaire, containing 22 questions, was implemented. The study group was created by recruiting 132 psychiatrists participating in the International Scientific-Training Conference in Wisla, Poland in 2011. The obtained results were analyzed statistically. RESULTS: The majority of the respondents decided to become psychiatrists during their university studies (43.61%) and just after their studies (37.59%). Only 9.02% knew before starting university, which field of medicine to select, and 8.27% were originally practitioners in a different medical specialization. The factors having the greatest influence on making the decision were: self-esteem (58.64%), practical classes in college and the experience of special types of work with a patient (the percentage for both factors was 33.83%). Prestige (3%) and media influence (3.76%) seem to be the least important factors. 81% of respondents admitted that it was their own independent decision. In the group of those who were influenced by others, the strongest source of advice was the opinion of a partner (4.51%), while the opinion of the family and a well-known specialist in the field turned out to be much less important (the percentage for both factors was 1.5%). 94.73% participants said that they would choose the same specialization once again. CONCLUSIONS: Public perception of psychiatry is still not satisfactory and may have little impact on the popularity of this specialization. The form of teaching at universities is important in the selection process of the specialization. The results of our questionnaire may be a helpful tool to improve the image of psychiatry as an attractive path of professional career, and become an essential argument during the discussion about current problems in psychiatry. PMID- 22945214 TI - Different dimensions of aggression occurring in the work environment of psychiatrists. AB - BACKGROUND: The term "aggression" refers to forceful behavior, action, or attitude that is expressed physically, verbally, or symbolically. Aggression in the medical environment can have different forms. The interactions between psychiatrists and patients may be one of the reasons for the appearance of symptoms of aggression in the behaviour of the physicians. The main aim of the study was to evaluate different aspects of aggression among psychiatric professionals. SUBJECT AND METHODS: The study was conducted among 132 psychiatrists (97 women and 34 men) from all over Poland. The average age was 43.1+/-9.48, the average professional experience was 15.76+/-10.09 years. Authors' original questionnaire and Buss-Perry Aggression Questionnaire were used to evaluate different aspects of aggression. RESULTS: The study showed a correlation between the length of professional experience and the level of verbal aggression (p=0.022) as well as with the level of hostility (p<0.05) presented by psychiatrists. Negative emotions appear in relations with workmates and causes the increase of general aggression among psychiatrists. These negative emotions are also present in relations with patients. The exposure to verbal aggression inflicted by patients causes the increase of verbal aggression, anger and hostility among psychiatrists. CONCLUSIONS: Significant occurrence of general aggression among psychiatrists caused by difficult relations with co-workers and patients suggests the importance and necessity of providing appropriate support for this professional group in their work environment. PMID- 22945215 TI - The brain derived neurotrophic factor and influences of stress in depression. AB - Brain derived neurotrophic factor (BDNF) is a member of the neurotrophin family and is widely expressed throughout the central nervous system (CNS). BDNF is involved in proliferation, differentiation, survival and death of neuronal and non-neuronal cells in the developing and adult CNS. The BDNF hypothesis of depression postulates that a reduction in BDNF is directly involved in the pathophysiology of depression, whilst anti-depressant mediated restoration of BDNF is responsible for the alleviation of the depressive state. This hypothesis is drawn from several studies implicating BDNF in depression and has received considerable support, which will be reviewed in this paper. This review will also discuss the implications of the functional Val66Met polymorphism of the gene encoding BDNF, which may reduce BDNF expression particularly when exposed to stress and thus may play a critical role in the pathogenesis of depression. PMID- 22945216 TI - Recovery in schizophrenia: focus on neurocognitive functioning. AB - Recovery encompasses symptom remission and functional elements such as cognition, social functioning and quality of life. Personal recovery is also important in illness management to help the person stay on track with treatment and focus on activities unrelated to taking medication that maintain mental health. In the present study we aimed to identify neurocognitive functioning in two clinically stable groups of patients with personal recovery and non-recovered patients. The results showered generalized cognitive deficits in both groups while the non recovery group was more impaired in verbal and visual memory, acoustic and tactile gnosis and neurodynamics and executing functioning. Interestingly the recovery group demonstrated lack of programming of actions and sufficient error monitoring and self-correction whereas the non-recovery group was significantly more impaired in all executive domains. The obtained results could be beneficial in identifying a target for psychosocial treatments and specifically cognitive remediation for patients with schizophrenia to facilitate the process of recovery. PMID- 22945217 TI - Bedrich Smetana - art and disease. AB - In this article we discuss what we can discover about Bedrich Smetana's illness and its effect on his art. PMID- 22945218 TI - The relationship between depression and cognitive deficits. AB - In the last years cognitive impairment in depression has been widely reported. It is clear that cognitive symptoms persist after remission of psychopathological symptoms but little is known about the pathophysiological events linking depression and cognitive impairment. Novel biological, structural and functional neuroimaging techniques have allowed a better definition of this relation. Depression and cognitive dysfunction share a common neuropathological platform in cortical and sub-cortical brain areas implicated in emotional and cognitive processing which may be under the control of genetic and environmental factors. PMID- 22945220 TI - Factors influencing French medical students towards a career in psychiatry. AB - BACKGROUND: There is a need to increase the recruitment to psychiatry in France. Our aim in this study was to compare factors influencing career choice between French medical students considering and not considering psychiatry as a specialty. SUBJECTS AND METHODS: Quantitative cross-sectional online survey on 145 French students in their last year of medical school. RESULTS: 22.7% of our sample considered choosing a career in psychiatry. A preference for a career in psychiatry was associated with more frequent history of personal/familial mental illness, higher ratings of psychiatric teaching, more weeks of compulsory psychiatry teaching and placement, during which students had more often met patients in recovery and been asked their opinion on patients. Students considering psychiatry as a career also emphasized more the need for a good work life balance, and presented better attitudes toward psychiatry. CONCLUSIONS: Improving opportunities of interactions between students and psychiatrists or psychiatric patients might help to improve recruitment in psychiatry. PMID- 22945219 TI - Coexisting bipolar disorder and cognitive impairment - case report. AB - OBJECTIVE: The objective of our study was to show how the cognitive impairment caused by bipolar disorder influenced on the patient's life quality. RESULTS: Our case report shows that there exists the dependence between the deterioration of the cognitive impairment caused by the bipolar disorder and increasing level of the patient's quality of life. CONCLUSION: The result of our investigation is consistent with a number of other studies connected with cognitive functioning in patient with bipolar disease. PMID- 22945221 TI - Do atypical antipsychotics promote neurogenesis as a class effect? AB - It has been reported that some atypical antipsychotics promote neurogenesis in the hippocampus and possibly in the frontal cortex. Atypical antipsychotics are a heterogeneous group of drugs. Hence the question arises as to whether neurogenesis is a class effect which relates to them all. We here present a literature search which we have carried out to establish this. PMID- 22945222 TI - Epigenetics and migration - considerations based on the incidence of psychosis in South Asians in Luton, England. AB - A higher rate of psychosis has been observed in immigrant populations as compared to the indigenous populations of the UK. Specifically, second generation immigrants (born in the UK) have been noted to have the highest risk. This phenomenon has been attributed to a number of genetic and social factors such as problems with acculturation. Previous studies in Luton, Bedfordshire have shown that the Bangladeshi community experience the highest rate of psychosis above all other ethnic minorities in this area. Here, we consider the lasting epigenetic impact of the stressor of migration and discuss the implications for further work and treatment. PMID- 22945223 TI - Bipolar II Disorder and Borderline Personality Disorder - co-morbidity or spectrum? AB - We assess the number of patients who we have on the Database of a Community Mental Health Team in the UK who have Bipolar Disorder and Borderline Personality Disorder. We report how many of these have been seen as having both disorders. Hence we discuss the issue as to whether Borderline Personality disorder is to be placed within the bipolar spectrum. We note the difficulties regarding the use of phenomenology alone to decide this problem, and we note the similarities in genetics, neuroimaging observations and neurobiological mechanisms among the following conditions; Bipolar Disorder, Unipolar Depression, Post-traumatic Stress Disorder, and Borderline Personality Disorder. Ethiologies such as Trauma, Abuse, Childhood adversity and exposure to War appear to influence all these conditions via epigenetic mechanisms. Hence we argue that for a spectrum to be proposed, conditions in the spectrum need to be underpinned by similar or common Neuroimaging and neurobiological mechanisms.On this basis, it may be reasonable to include Borderline Personality Disorder within a broadly described bipolar spectrum. New details of the common Neurobiological mechanisms continue to emerge. PMID- 22945224 TI - Differing approaches to experimental therapeutics: are we a world apart? PMID- 22945227 TI - Treatment of chemotherapy-refractory cancer in the advanced therapy access program. PMID- 22945228 TI - Athletes' use of unproven stem cell therapies: adding to inappropriate media hype? PMID- 22945229 TI - A CRISPR approach to gene targeting. PMID- 22945230 TI - All for one, one for all: new combinatorial RNAi therapies combat hepatitis C virus evolution. PMID- 22945232 TI - Campylobacter spp. recovered from the Upper Oconee River Watershed, Georgia in a 4-year study. AB - Waterways should be considered in the migration routes of Campylobacter, and the genus has been isolated from several water sources. Inferences on migration routes can be made from tracking genetic types in populations found in specific habitats and testing how they are linked to other types. Water samples were taken over a 4-year period from waterways in the Upper Oconee River Watershed, Georgia, to recover isolates of thermophilic Campylobacter. The isolates were typed by multilocus sequence typing (MLST) and analyzed to determine the overall diversity of Campylobacter in that environment. Forty-seven independent isolates were recovered from 560 samples (8.4 %). Two (~4 %) isolates were Campylobacter coli, three (~6 %) isolates were putatively identified as Campylobacter lari, and the remaining 42 (~90 %) were Campylobacter jejuni. The C. jejuni and C. coli isolates were typed by the Oxford MLST scheme. Thirty sequence types (STs) were identified including 13 STs that were not found before in the MLST database, including 24 novel alleles. Of the 17 previously described STs, 10 have been isolated from humans, 6 from environmental water, and 6 from wild birds (five types from multiple sources). Seven sites had multiple positive samples, and on two occasions, the same ST was isolated at the same site. The most common type was STST61 with four isolates, and the most common clonal complex was CC179 with nine isolates. CC179 has been commonly associated with environmental water. Although some Campylobacter STs that were found in the Oconee River engage in widespread migration, most are tightly associated with or unique to environmental water sources. PMID- 22945233 TI - Microbial community diversity in the gut of the South American termite Cornitermes cumulans (Isoptera: Termitidae). AB - Termites inhabit tropical and subtropical areas where they contribute to structure and composition of soils by efficiently degrading biomass with aid of resident gut microbiota. In this study, culture-independent molecular analysis was performed based on bacterial and archaeal 16S rRNA clone libraries to describe the gut microbial communities within Cornitermes cumulans, a South American litter-feeding termite. Our data reveal extensive bacterial diversity, mainly composed of organisms from the phyla Spirochaetes, Bacteroidetes, Firmicutes, Actinobacteria, and Fibrobacteres. In contrast, a low diversity of archaeal 16S rRNA sequences was found, comprising mainly members of the Crenarchaeota phylum. The diversity of archaeal methanogens was further analyzed by sequencing clones from a library for the mcrA gene, which encodes the enzyme methyl coenzyme reductase, responsible for catalyzing the last step in methane production, methane being an important greenhouse gas. The mcrA sequences were diverse and divided phylogenetically into three clades related to uncultured environmental archaea and methanogens found in different termite species. C. cumulans is a litter-feeding, mound-building termite considered a keystone species in natural ecosystems and also a pest in agriculture. Here, we describe the archaeal and bacterial communities within this termite, revealing for the first time its intriguing microbiota. PMID- 22945234 TI - Improved bioavailability of a water-insoluble drug by inhalation of drug containing maltosyl-beta-cyclodextrin microspheres using a four-fluid nozzle spray drier. AB - We previously developed a unique four-fluid nozzle spray drier that can produce water-soluble microspheres containing water-insoluble drug nanoparticles in one step without any common solvent between the water-insoluble drug and water soluble carrier. In the present study, we focused on maltosyl-beta-cyclodextrin (malt-beta-CD) as a new water-soluble carrier and it was investigated whether drug/malt-beta-CD microspheres could improve the bioavailability compared with our previously reported drug/mannitol (MAN) microspheres. The physicochemical properties of bare drug microparticles (ONO-2921, a model water-insoluble drug), drug/MAN microspheres, and drug/malt-beta-CD microspheres were evaluated. In vitro aerosol performance, in vitro dissolution rate, and the blood concentration profiles after intratracheal administration were compared between these formulations. The mean diameter of both drug/MAN and drug/malt-beta-CD microspheres was approximately 3-5 MUm and both exhibited high aerosol performance (>20% in stages 2-7), but drug/malt-beta-CD microspheres had superior release properties. Drug/malt-beta-CD microspheres dissolved in an aqueous phase within 2 min, while drug/MAN microspheres failed to dissolve in 30 min. Inhalation of drug/malt-beta-CD microspheres enhanced the area under the curve of the blood concentration curve by 15.9-fold than that of bare drug microparticles and by 6.1-fold than that of drug/MAN microspheres. Absolute bioavailability (pulmonary/intravenous route) of drug/malt-beta-CD microspheres was also much higher (42%) than that of drug/MAN microspheres (6.9%). These results indicate that drug/malt-beta-CD microspheres prepared by our four-fluid nozzle spray drier can improve drug solubility and pulmonary delivery. PMID- 22945236 TI - Structural investigations of Ge5As(x)Se(95-x) and Ge15As(x)Se(85-x) glasses using x-ray diffraction and extended x-ray fine structure spectroscopy. AB - The structure of Ge(5)As(x)Se(95-x) (x = 10, 20, 30, 38 at.%) and Ge(15)As(x)Se(85-x) (x = 10, 25, 34 at.%) glasses has been investigated by high energy x-ray diffraction and extended x-ray absorption fine structure measurements. The experimental datasets have been modelled using the reverse Monte Carlo simulation technique. The model atomic configurations have been analysed in detail. It has been found that the homonuclear Ge-Ge, As-As, Se-Se and heteronuclear Ge-As bonds play an important role in the structure formation of the Ge-As-Se glasses. The total number of these bonds decreases quite slowly with the mean coordination number similarly to the nonlinear refractive index. PMID- 22945235 TI - A ketogenic diet did not prevent effects on the ectonucleotidases pathway promoted by lithium-pilocarpine-induced status epilepticus in rat hippocampus. AB - A Ketogenic Diet (KD) mimics the anticonvulsant effects of fasting, which are known to suppress seizures. The purinergic system has been investigated in the matter of epilepsy development, especially the nucleoside adenosine, which has been considered a natural brain anticonvulsant. During epileptic seizures, extracellular adenosine concentration rises rapidly to micromolar levels. Adenosine can exert its anticonvulsant functions, after its release by nucleoside bidirectional transport, or by production through the sequential catabolism of ATP by ectonucleotidases, such as E-NTPDases (ectonucleoside triphosphate diphosphohydrolases) and ecto-5'-nucleotidase. Here, we have investigated the effect of a ketogenic diet on the nucleotide hydrolysis and NTPDases expression in the lithium-pilocarpine (Li-Pilo) model of epilepsy. For the induction of Status Epileticus (SE), 21-day-old female Wistar rats received an i.p. injection of lithium chloride (127 mg/kg) and 18-19 h later an i.p. injection of pilocarpine hydrochloride (60 mg/kg). The control groups received an injection of saline. After induction of SE, the control and Li-Pilo groups received standard or ketogenic diets for 6 weeks. The lithium-pilocarpine exposure affected the ATP (a decrease of between 8 % and 16 %) and ADP (an increase of between 18 % and 22 %) hydrolysis in both groups whereas the diet did not impact the nucleotide hydrolysis. NTPDase2 and 3 mRNA expressions decreased in the Li-Pilo group (41 % and 42 %). This data highlights the participation of the purinergic system in the pathophysiology of this model of epilepsy, since nucleotide hydrolysis and NTPDase expressions were altered by Li-Pilo exposure, with no significant effects of the ketogenic diet. However, the interaction between purinergic signaling and a ketogenic diet on epilepsy still needs to be better elucidated. PMID- 22945237 TI - The maternal embryonic leucine zipper kinase (MELK) is upregulated in high-grade prostate cancer. AB - Loss of cell cycle control is a prerequisite for cancer onset and progression. In prostate cancer, increased activity of cell cycle genes has been associated with prognostic parameters such as biochemical relapse and survival. The identification of novel oncogenic and druggable targets in patient subgroups with poor prognosis may help to develop targeted therapy approaches. We analyzed prostate cancer and corresponding benign tissues (n = 98) using microarrays. The comparison of high- and low-grade tumors (Gleason score >= 4 + 3 vs. <= 3 + 4) revealed 144 differentially expressed genes (p < 0.05). Out of these, 15 genes were involved in the cell cycle process. The gene maternal embryonic leucine zipper kinase (MELK) was identified to be highly correlated with cell cycle genes like UBE2C, TOP2A, CCNB2, and AURKB. Increased MELK gene expression in high-risk prostate cancer was validated by qPCR in an independent patient cohort (p < 0.005, n = 79). Immunohistochemistry analysis using a tissue microarray (n = 94) revealed increased MELK protein expression in prostate cancer tissues of high Gleason scores. RNAi-based inhibition of MELK in PC3 and LNCaP cells suggested putative function in chromatin modification, embryonic development and cell migration. The concerted inhibition of MELK and other cell cycle targets by the antibiotic siomycin A strongly impaired cell viability of prostate cancer cells, and may point to a novel therapy approach for a subset of high-risk prostate cancer patients. PMID- 22945238 TI - Cell-intrinsic mechanism involving Siglec-5 associated with divergent outcomes of HIV-1 infection in human and chimpanzee CD4 T cells. AB - Human and chimpanzee CD4+ T cells differ markedly in expression of the inhibitory receptor Siglec-5, which contributes towards differential responses to activating stimuli. While CD4+ T cells from both species are equally susceptible to HIV-1 infection, chimpanzee cells survive better, suggesting a cell-intrinsic difference. We hypothesized that Siglec-5 expression protects T cells from activation-induced and HIV-1-induced cell death. Transduction of human CEM T cells with Siglec-5 decreased cell responses to stimulation. Following HIV-1 infection, a higher percentage of Siglec-5-positive cells survived, suggesting relative resistance to virus-induced cell death. Consistent with this, we observed an increase in percentage of Siglec-5-positive cells surviving in mixed infected cultures. Siglec-5-transduced cells also showed decreased expression of apoptosis-related proteins following infection and reduced susceptibility to Fas mediated cell death. Similar Siglec-5-dependent differences were seen when comparing infection outcomes in primary CD4+ T cells from humans and chimpanzees. A protective effect of Siglec-5 was further supported by observing greater proportions of circulating CD4+ T cells expressing Siglec-5 in acutely infected HIV-1 patients, compared to controls. Taken together, our results suggest that Siglec-5 expression protects T cells from HIV-1- and apoptosis-induced cell death and contributes to the different outcomes of HIV-1 infection in humans and chimpanzees. PMID- 22945239 TI - Competition of zinc ion for the [2Fe-2S] cluster binding site in the diabetes drug target protein mitoNEET. AB - Human mitochondrial protein mitoNEET is a novel target of type II diabetes drug pioglitazone, and contains a redox active [2Fe-2S] cluster that is hosted by a unique ligand arrangement of three cysteine and one histidine residues. Here we report that zinc ion can compete for the [2Fe-2S] cluster binding site in human mitoNEET and potentially modulate the physiological function of mitoNEET. When recombinant mitoNEET is expressed in Escherichia coli cells grown in M9 minimal media, purified mitoNEET contains very little or no iron-sulfur clusters. Addition of exogenous iron or zinc ion in the media produces mitoNEET bound with a [2Fe-2S] cluster or zinc, respectively. Mutations of the amino acid residues that hosting the [2Fe-2S] cluster in mitoNEET diminish the zinc binding activity, indicating that zinc ion and the [2Fe-2S] cluster may share the same binding site in mitoNEET. Finally, excess zinc ion effectively inhibits the [2Fe-2S] cluster assembly in mitoNEET in E. coli cells, suggesting that zinc ion may impede the function of mitoNEET by blocking the [2Fe-2S] cluster assembly in the protein. PMID- 22945241 TI - How to do the double orifice valve technique to treat tricuspid valve incompetence. AB - A straightforward tricuspid valve repair technique is illustrated here, which may be employed either for functional (normal valve with dilated annulus) or for primary or organic (Ebstein's anomaly, leaflet retraction/tethering and chordal malposition/tethering, with annular dilatation) tricuspid valve incompetence and for moderate and severe degrees of incompetence, without any residual regurgitation or reoperation. The basic principle is to reduce the distance between the coapting leaflets in a manner in which the most mobile leaflet, which is usually the anterior, could coapt to the opposite leaflet, by creating two orifices, ensuring valve competence. Additionally, it reduces annular dilatation and lessens tricuspid valve leaflet tethering, thereby stabilizing the annulus and increasing leaflet coaptation. PMID- 22945240 TI - (1)H-MR spectroscopy for analysis of cardiac lipid and creatine metabolism. AB - Magnetic resonance spectroscopy (MRS) is the only non-invasive, non-radiation based technique for investigating the metabolism of living tissue. MRS of protons (1H-MRS), which provides the highest sensitivity of all MR-visible nuclei, is a method capable of detecting and quantifying specific cardiac biomolecules, such as lipids and creatine in normal and diseased hearts in both animal models and humans. This can be used to study mechanisms of heart failure development in a longitudinal manner, for example, the potential contribution of myocardial lipid accumulation in the context of ageing and obesity. Similarly, quantifying creatine levels provides insight into the energy storage and buffering capacity in the heart. Creatine depletion is consistently observed in heart failure independent of aetiology, but its contribution to pathophysiology remains a matter of debate. These and other questions can in theory be answered with cardiac MRS, but fundamental technical challenges have limited its use. The metabolites studied with MRS are much lower concentration than water protons, requiring methods to suppress the dominant water signal and resulting in larger voxel sizes and longer scan times compared to MRI. However, recent technical advances in MR hardware and software have facilitated the application of 1H-MRS in humans and animal models of heart disease as detailed in this review. PMID- 22945242 TI - Huge aneurysm of the ascending aorta in a patient with adult-type Pompe's disease: histological findings mimicking fibrillinopathy. AB - Adult-type Pompe's disease (glycogen storage disease type II) has rarely been shown to present with dilatative arteriopathy, suggesting potential smooth muscle involvement in addition to lysosomal glycogen deposits usually restricted to skeletal muscle tissue. We report the case of a middle-aged man under enzyme replacement therapy presenting with an exceedingly large thoracic aortic aneurysm. Surprisingly, the histological work-up of resected aortic tissue revealed changes mimicking those observed in patients with classic connective tissue diseases. Enzyme replacement therapy, in addition to musculoskeletal and pulmonary treatment for patients with Pompe's disease, may prolong survival and lead to patients presenting with vascular alterations that may pose surgical and potential diagnostic challenges in the future. PMID- 22945249 TI - The causes, treatment, and outcome of acute heart failure in 1006 Africans from 9 countries. AB - BACKGROUND: Acute heart failure (AHF) in sub-Saharan Africa has not been well characterized. Therefore, we sought to describe the characteristics, treatment, and outcomes of patients admitted with AHF in sub-Saharan Africa. METHODS: The Sub-Saharan Africa Survey of Heart Failure (THESUS-HF) was a prospective, multicenter, observational survey of patients with AHF admitted to 12 university hospitals in 9 countries. Among patients presenting with AHF, we determined the causes, treatment, and outcomes during 6 months of follow-up. RESULTS: From July 1, 2007, to June 30, 2010, we enrolled 1006 patients presenting with AHF. Mean (SD) age was 52.3 (18.3) years, 511 (50.8%) were women, and the predominant race was black African (984 of 999 [98.5%]). Mean (SD) left ventricular ejection fraction was 39.5% (16.5%). Heart failure was most commonly due to hypertension (n = 453 [45.4%]) and rheumatic heart disease (n = 143 [14.3%]). Ischemic heart disease (n = 77 [7.7%]) was not a common cause of AHF. Concurrent renal dysfunction (estimated glomerular filtration rate, <30 mL/min/173 m(2)), diabetes mellitus, anemia (hemoglobin level, <10 g/dL), and atrial fibrillation were found in 73 (7.7%), 114 (11.4%), 147 (15.2%), and 184 cases (18.3%), respectively; 65 of 500 patients undergoing testing (13.0%) were seropositive for the human immunodeficiency virus. The median hospital stay was 7 days (interquartile range, 5-10), with an in-hospital mortality of 4.2%. Estimated 180-day mortality was 17.8% (95% CI, 15.4%-20.6%). Most patients were treated with renin-angiotensin system blockers but not beta-blockers at discharge. Hydralazine hydrochloride and nitrates were rarely used. CONCLUSIONS: In African patients, AHF has a predominantly nonischemic cause, most commonly hypertension. The condition occurs in middle-aged adults, equally in men and women, and is associated with high mortality. The outcome is similar to that observed in non-African AHF registries, suggesting that AHF has a dire prognosis globally, regardless of the cause. PMID- 22945251 TI - Metal nanoparticle catalysts decorated with metal oxide clusters. AB - Au nanoparticles decorated with mononuclear Ti-oxo units dispersed in silica clusters were formed by activating Au nanoparticles (~2 nm) stabilized with Ti- and amine-functionalized siloxane oligomers. These Au nanoparticles were active catalysts for selective oxidation of propane to acetone, and the activity increased with increasing Ti density. PMID- 22945253 TI - Science and politics: picking a winner. PMID- 22945250 TI - Food consumption and screen-based sedentary behaviors in European adolescents: the HELENA study. AB - OBJECTIVE: To examine the association between time spent on different sedentary behaviors and consumption of certain food and beverage groups in a sample of European adolescents. DESIGN: Data from the Healthy Lifestyle in Europe by Nutrition in Adolescence Cross-sectional Study. SETTING: Eight survey centers (Athens, Dortmund, Ghent, Lille, Rome, Stockholm, Vienna, and Zaragoza). PARTICIPANTS: A total of 2202 participants (45.5% boys) aged 121/2 to 171/2 years. MAIN OUTCOME MEASURES: Information on sedentary behaviors (weekdays and weekends) collected via a standardized self-reported questionnaire, including watching television, playing computer and video games, using the Internet for studying or recreation, and studying. Food and beverage consumption data of selected groups were obtained using 2 nonconsecutive 24-hour recalls. RESULTS: Boys reporting more than 4 h/d of watching television, playing computer games, and using the Internet for recreation were more likely to consume sweetened beverages (weekends) (odds ratio [OR], 1.83 [95% CI, 1.21-2.75]; 1.99 [1.31 3.01]; and 1.73 [1.03-2.91], respectively), and less likely to consume fruit (weekdays) (0.39 [0.21-0.72], 0.37 [0.18-0.77], and 0.39 [0.19-0.78], respectively) than those who spent less than 2 h/d. Girls spending more time per day watching television and playing computer or video games (weekdays) and playing computer games or surfing the Internet for recreation (weekends) were more likely to drink sweetened beverages (OR, 1.89 [95% CI, 1.21-2.94]; 1.57 [1.00-2.46]; 2.14 [1.16-3.97]; and 2.30 [1.24-4.28], respectively) and less likely to consume fruit (weekdays) (0.43 [0.23-0.80], 0.40 [0.19-0.83], 0.37 [0.14-0.94], and 0.42 [0.20-0.85], respectively) than those who spent less than 2 h/d. CONCLUSION: Increased television viewing and computer and Internet use during adolescence is associated with higher odds of consumption of sweetened beverages and lower odds of fruit consumption. PMID- 22945252 TI - MODULATING CO-STIMULATION DURING ANTIGEN PRESENTATION TO ENHANCE CANCER IMMUNOTHERAPY. AB - One of the key roles of the immune system is the identification of potentially dangerous pathogens or tumour cells, and raising a wide range of mechanisms to eliminate them from the organism. One of these mechanisms is activation and expansion of antigen-specific cytotoxic T cells, after recognition of antigenic peptides on the surface of antigen presenting cells such as dendritic cells (DCs). However, DCs also process and present autoantigens. Therefore, antigen presentation has to occur in the appropriate context to either trigger immune responses or establishing immunological tolerance. This is achieved by co stimulation of T cells during antigen presentation. Co-stimulation consists on the simultaneous binding of ligand-receptor molecules at the immunological synapse which will determine the type and extent of T cell responses. In addition, the type of cytokines/chemokines present during antigen presentation will influence the polarisation of T cell responses, whether they lead to tolerance, antibody responses or cytotoxicity. In this review, we will focus on approaches manipulating co-stimulation during antigen presentation, and the role of cytokine stimulation on effective T cell responses. More specifically, we will address the experimental strategies to interfere with negative co-stimulation such as that mediated by PD-L1 (Programmed cell death 1 ligand 1)/PD-1 (Programmed death 1) to enhance anti-tumour immunity. PMID- 22945255 TI - Visualizing global effects of the DNA damage response. AB - In a large-scale analysis, the effects of DNA damage on the levels and localization of almost every protein in an organism have now been tracked in living cells. It is shown that that although many proteins change their position or concentration, they rarely do both. PMID- 22945254 TI - Lineage conversion methodologies meet the reprogramming toolbox. AB - Lineage conversion has recently attracted increasing attention as a potential alternative to the directed differentiation of pluripotent cells to obtain cells of a given lineage. Different means allowing for cell identity switch have been reported. Lineage conversion relied initially on the discovery of specific transcription factors generally enriched and characteristic of the target cell, and their forced expression in cells of a different fate. This approach has been successful in various cases, from cells of the hematopoietic systems to neurons and cardiomyocytes. Furthermore, recent reports have suggested the possibility of establishing a general lineage conversion approach bypassing pluripotency. This requires a first phase of epigenetic erasure achieved by short overexpression of the factors used to reprogram cells to a pluripotent state (such as a combination of Sox2, Klf4, c-Myc and Oct4), followed by exposure to specific developmental cues. Here we present these different direct conversion methodologies and discuss their potential as alternatives to using induced pluripotent stem cells and differentiation protocols to generate cell populations of a given fate. PMID- 22945256 TI - A cellular sense of touch. AB - How cells sense and respond to physical forces is an area of intense investigation, which poses significant challenges for in vitro experiments and even greater obstacles for in vivo studies. Analyses of integrin complex dynamics in Drosophila melanogaster now provide evidence that altering mechanical force modulates the stability of integrin adhesion in vivo. PMID- 22945257 TI - Regulating intraflagellar transport. AB - Kinesin-2 motors mediate anterograde intraflagellar transport (IFT) of IFT particles from the ciliary base to its tip, where particles are remodelled before retrograde transport by dynein 2 motors. Bardet-Biedl syndrome (BBS) and IFT-A proteins are now implicated in regulation of IFT assembly at the ciliary base and tip. PMID- 22945258 TI - Bending membranes. AB - It is widely assumed that peripheral membrane proteins induce intracellular membrane curvature by the asymmetric insertion of a protein segment into the lipid bilayer, or by imposing shape by adhesion of a curved protein domain to the membrane surface. Two papers now provide convincing evidence challenging these views. The first shows that specific assembly of a clathrin protein scaffold, coupled to the membrane, seems to be the most prevalent mechanism for bending a lipid bilayer in a cell. The second reports that membrane crowding, driven by protein-protein interactions, can also drive membrane bending, even in the absence of any protein insertion into the bilayer. PMID- 22945264 TI - Pathway of cytotoxicity induced by folic acid modified selenium nanoparticles in MCF-7 cells. AB - Selenium nanoparticles (Se NPs) have been recognized as promising materials for biomedical applications. To prepare Se NPs which contained cancer targeting methods and to clarify the cellular localization and cytotoxicity mechanisms of these Se NPs against cancer cells, folic acid protected/modified selenium nanoparticles (FA-Se NPs) were first prepared by a one-step method. Some morphologic and spectroscopic methods were obtained to prove the successfully formation of FA-Se NPs while free folate competitive inhibition assay, microscope, and several biological methods were used to determine the in vitro uptake, subcellular localization, and cytotoxicity mechanism of FA-Se NPs in MCF 7 cells. The results indicated that the 70-nm FA-Se NPs were internalized by MCF 7 cells through folate receptor-mediated endocytosis and targeted to mitochondria located regions through endocytic vesicles transporting. Then, the FA-Se NPs entered into mitochondria; triggered the mitochondria-dependent apoptosis of MCF 7 cells which involved oxidative stress, Ca(2)+ stress changes, and mitochondrial dysfunction; and finally caused the damage of mitochondria. FA-Se NPs released from broken mitochondria were transported into nucleus and further into nucleolus which then induced MCF-7 cell cycle arrest. In addition, FA-Se NPs could induce cytoskeleton disorganization and induce MCF-7 cell membrane morphology alterations. These results collectively suggested that FA-Se NPs could be served as potential therapeutic agents and organelle-targeted drug carriers in cancer therapy. PMID- 22945265 TI - Production of influenza H1N1 vaccine from MDCK cells using a novel disposable packed-bed bioreactor. AB - A process for human influenza H1N1 virus vaccine production from Madin-Darby canine kidney (MDCK) cells using a novel packed-bed bioreactor is described in this report. The mini-bioreactor was used to study the relationship between cell density and glucose consumption rate and to optimize the infection parameters of the influenza H1N1 virus (A/New Caledonia/20/99). The MDCK cell culture and virus infection were then monitored in a disposable perfusion bioreactor (AmProtein Current Perfusion Bioreactor) with proportional-integral-derivative control of pH, dissolved O(2) (DO), agitation, and temperature. During 6 days of culture, the total cell number increased from 2.0 * 10(9) to 3.2 * 10(10) cells. The maximum virus titers of 768 hemagglutinin units/100 MUL and 7.8 * 10(7) 50 % tissue culture infectious doses/mL were obtained 3 days after infection. These results demonstrate that using a disposable perfusion bioreactor for large-scale cultivation of MDCK cells, which allows for the control of DO, pH, and other conditions, is a convenient and stable platform for industrial-scale production of influenza vaccines. PMID- 22945266 TI - Journal impact factor: holy grail? PMID- 22945263 TI - Spatiotemporal control of microRNA function using light-activated antagomirs. AB - MicroRNAs (miRNAs) are small non-coding RNAs that act as post-transcriptional gene regulators and have been shown to regulate many biological processes including embryonal development, cell differentiation, apoptosis, and proliferation. Variations in the expression of certain miRNAs have been linked to a wide range of human diseases - especially cancer - and the diversity of miRNA targets suggests that they are involved in various cellular networks. Several tools have been developed to control the function of individual miRNAs and have been applied to study their biogenesis, biological role, and therapeutic potential; however, common methods lack a precise level of control that allows for the study of miRNA function with high spatial and temporal resolution. Light activated miRNA antagomirs for mature miR-122 and miR-21 were developed through the site-specific installation of caging groups on the bases of selected nucleotides. Installation of caged nucleotides led to complete inhibition of the antagomir-miRNA hybridization and thus inactivation of antagomir function. The miRNA-inhibitory activity of the caged antagomirs was fully restored upon decaging through a brief UV irradiation. The synthesized antagomirs were applied to the photochemical regulation of miRNA function in mammalian cells. Moreover, spatial control over antagomir activity was obtained in mammalian cells through localized UV exposure. The presented approach enables the precise regulation of miRNA function and miRNA networks with unprecedented spatial and temporal resolution using UV irradiation and can be extended to any miRNA of interest. PMID- 22945267 TI - Interspecific chromosomal effects on agronomic traits in Gossypium hirsutum by AD analysis using intermated G. barbadense chromosome substitution lines. AB - The untapped potential of the beneficial alleles from Gossypium barbadense L. has not been well utilized in G. hirsutum L. (often referred to as Upland cotton) breeding programs. This is primarily due to genomic incompatibility and technical challenges associated with conventional methods of interspecific introgression. In this study, we used a hypoaneuploid-based chromosome substitution line as a means for systematically introgressing G. barbadense doubled-haploid line '3-79' germplasm into a common Upland genetic background, inbred 'Texas marker-1' ('TM 1'). We reported on the chromosomal effects, lint percentage, boll weight, seedcotton yield and lint yield in chromosome substitution CS-B (G. barbadense L.) lines. Using an additive-dominance genetic model, we studied the interaction of alleles located on two alien substituted chromosomes versus one alien substituted chromosome using a partial diallel mating design of selected CS-B lines (CS-B05sh, CS-B06, CS-B09, CS-B10, CS-B12, CS-B17 and CS-B18). Among these parents, CS-B09 and CS-B10 were reported for the first time. The donor parent 3 79, had the lowest additive effect for all of the agronomic traits. All of the CS B lines had significant additive effects with boll weight and lint percentage. CS B10 had the highest additive effects for lint percentage, and seedcotton and lint yield among all of the lines showing a transgressive genetic mode of inheritance for these traits. CS-B09 had greater additive genetic effects on lint yield, while CS-B06, CS-B10 and CS-B17 had superior additive genetic effects on both lint and seedcotton yield compared to TM-1 parent. The 3-79 line had the highest dominance effects for boll weight (0.513 g) and CS-B10 had the lowest dominance effect for boll weight (-0.702). Some major antagonistic genetic effects for the agronomic traits were present with most of the substituted chromosomes and chromosome arms, a finding suggested their recalcitrance to conventional breeding efforts. The results revealed that the substituted chromosomes and arms of 3-79 carried some cryptic beneficial alleles with potential to improve agronomic traits including yield, whose effects were masked at the whole genome level in 3 79. PMID- 22945268 TI - Genetic diversity analysis of elite European maize (Zea mays L.) inbred lines using AFLP, SSR, and SNP markers reveals ascertainment bias for a subset of SNPs. AB - Recent advances in high-throughput sequencing technologies have triggered a shift toward single-nucleotide polymorphism (SNP) markers. A systematic bias can be introduced if SNPs are ascertained in a small panel of genotypes and then used for characterizing a larger population (ascertainment bias). With the objective of evaluating a potential ascertainment bias of the Illumina MaizeSNP50 array with respect to elite European maize dent and flint inbred lines, we compared the genetic diversity among these materials based on 731 amplified fragment length polymorphisms (AFLPs), 186 simple sequence repeats (SSRs), 41,434 SNPs of the MaizeSNP50 array (SNP-A), and two subsets of it, i.e., 30,068 Panzea (SNP-P) and 11,366 Syngenta markers (SNP-S). We evaluated the bias effects on major allele frequency, allele number, gene diversity, modified Roger's distance (MRD), and on molecular variance (AMOVA). We revealed ascertainment bias in SNP-A, compared to AFLPs and SSRs. It affected especially European flint lines analyzed with markers (SNP-S) specifically developed to maximize differences among North American dent germplasm. The bias affected all genetic parameters, but did not substantially alter the relative distances between inbred lines within groups. For these reasons, we conclude that the SNP markers of the MaizeSNP50 array can be employed for breeding purposes in the investigated material. However, attention should be paid in case of comparisons between genotypes belonging to different heterotic groups. In this case, it is advisable to prefer a marker subset with potentially low ascertainment bias, like in our case the SNP-P marker set. PMID- 22945269 TI - Inter-unit variability in two ParvoMedics TrueOne 2400 automated metabolic gas analysis systems. AB - Knowing the inter-unit variability, especially the technological error, is important when using many physiological measurement systems, yet no such inter unit analysis has been undertaken on duplicate automated gas analysis systems. This study investigated the inter-unit performance of two identical ParvoMedics TrueOne 2400 automated gas analysis systems during a range of submaximal steady state exercises performed on an electromagnetic cycle ergometer. Fifteen adult males were tested on two separate days a rest, 30, 60, 90, and 120 Watts with the duplicate gas analysis units arranged (1) collaterally (2 min of steady-state expired gas was alternately passed through each system), and (2) simultaneously (identical steady-state expired gas was passed simultaneously through both systems). Total within-subject variation (biological + technological) was determined from the collateral tests, but the unique inter-unit variability (technological error between identical systems) was shown by the simultaneous tests. Absolute percentage errors (APE), coefficient of variations (CV), effect sizes and Bland-Altman analyses were undertaken on the metabolic data, including expired ventilation (V (E)), oxygen consumption (VO(2)) and carbon dioxide production (VCO(2)). The few statistically significant differences detected between the two duplicate systems were determined to have small or trivial effect sizes, and their magnitudes to be of little physiological importance. The total within-subject variations for VO(2), VCO(2) and V (E) each equated to a mean CV and mean APE value of ~4 and ~6 %, whilst the respective inter-unit technological errors equated to ~1.5 and ~2.1 %. The two ParvoMedics TrueOne 2400 systems demonstrated excellent inter-unit agreement. PMID- 22945270 TI - Detection of (1, 3)-beta-D-glucan in bronchoalveolar lavage and serum samples collected from immunocompromised hosts. AB - The incidence of invasive fungal infections (IFI) has increased in recent years, especially among immunocompromised hosts (ICH). In 2003, the Fungitell((r)) assay received FDA clearance for the presumptive diagnosis of IFI using serum and detects (1-3)-beta-D-glucan, which is a major cell wall component of certain fungi (e.g., Candida, Aspergillus, and Pneumocystis). The goal of the current study was to assess the performance of the assay on bronchoalveolar lavage (BAL) fluid and serum to identify IFI in ICH. Patients were classified as having proven, probable, possible, or no IFI according to the European Organization for Research and Treatment of Cancer/Mycoses Study Group (EORTC/MSG) guidelines. Among 109 patients for whom the results of Fungitell were compared to the EORTC/MSG criteria, Fungitell showed a low positive predictive value for the identification of IFI from both BAL (20.0%) and serum (26.7%). However, the negative predictive value of Fungitell was significantly higher for both sample types (BAL, 83.0%; serum, 84.8%). Interestingly, the results of Fungitell were positive in BAL and serum in 7/8 (87.5%) patients diagnosed with Pneumocystis pneumonia (PcP) by real-time, non-nested PCR. These data indicate that the Fungitell assay has a low positive predictive value for the diagnosis of IFI in ICH, regardless of the specimen type that is tested. However, testing of serum samples by Fungitell may permit a rapid and noninvasive initial screening approach in patients with presumed PcP. PMID- 22945271 TI - Intravenous iron treatment in pregnancy: comparison of high-dose ferric carboxymaltose vs. iron sucrose. AB - OBJECTIVE: Oral iron substitution has shown to be insufficient for treatment of severe iron deficiency anemia in pregnancy. Ferric carboxymaltose is a new intravenous (i.v.) iron formulation promising to be more effective and as safe as iron sucrose. We aimed to assess side effects and tolerance of ferric carboxymaltose compared to i.v. iron sucrose in pregnant women. METHODS: We performed a retrospective analysis of 206 pregnant women who were treated either with ferric carboxymaltose or iron sucrose for iron-deficiency anemia with intolerability to oral iron substitution, or insufficient hemoglobin increase after oral iron treatment, or need for rapid hemoglobin reconstitution. Primary endpoint was to evaluate the maternal safety and tolerability. Secondary endpoint was to assess efficacy of the treatment and exclude safety concerns for the fetus. RESULTS: The incidence of drug-related adverse events was low and mostly mild in both groups. Mild adverse events occurred in 7.8% for ferric carboxymaltose and in 10.7% for iron sucrose. The mean rise of hemoglobin value was 15.4 g/L for ferric carboxymaltose and 11.7 g/L for iron sucrose. CONCLUSION: Ferric carboxymaltose administration in pregnant women is well tolerated and is not associated with any relevant clinical safety concerns. Ferric carboxymaltose has a comparable safety profile to iron sucrose but offers the advantage of a much higher iron dosage at a time reducing the need for repeated applications and increasing patients' comfort. Ferric carboxymaltose is the drug of choice, if i.v. iron treatment becomes necessary in the second or third trimester of pregnancy. PMID- 22945272 TI - Trophoblastic progranulin expression is upregulated in cases of fetal growth restriction and preeclampsia. AB - AIMS: The expression of the anti-inflammatory glycoprotein progranulin and the hypoxia-induced transcription factor 1alpha (HIF-1alpha) in the villous trophoblast was compared between placentae from patients with preeclampsia (PE), fetal growth restriction (FGR), and normal controls. STUDY DESIGN: Matched pairs analysis of third trimester placentae specimens (mean gestational age 36+2) was performed by semiquantitative measurements of the immunohistochemical staining intensities for progranulin and HIF-1alpha expression (PE n=13, FGR n=9 and controls n=11). Further, placental progranulin mRNA expression was analyzed by qRT-PCR on term placentae (n=3 for each group). RESULTS: Compared to controls, villous trophoblast revealed a significantly higher expression of progranulin in cases of PE (P<0.05) and FGR (P<0.01). Similar results were shown for HIF-1alpha expression (P<0.01 for PE and <0.05 for FGR). The increase of the progranulin protein was not accompanied by an increase of the progranulin mRNA in term placentae. CONCLUSIONS: Increased expression of progranulin protein in villous trophoblast cells in cases of PE and FGR may result from disturbed placental development and, therefore, may be of pathogenetic importance. The increase was correlated to HIF-1alpha expression. Further evaluation of this potential mechanism of regulation is required. PMID- 22945273 TI - Can a customized standard for large for gestational age identify women at risk of operative delivery and shoulder dystocia? AB - OBJECTIVE: To determine whether a customized standard for large for gestational age (LGA) identifies undiagnosed women at risk of operative delivery and shoulder dystocia. METHODS: We previously generated customized standards from our institution. We compared the baseline maternal characteristics and neonatal outcomes between LGA and non-LGA births, which were classified by both population based and customized standards. The risk of operative delivery (vacuum delivery or emergent cesarean section) and shoulder dystocia was compared by logistic regression analysis in LGA pregnancies that were identified by a population-based birth weight standard and a customized standard after adjusting for maternal age, parity, body mass index, and neonatal gender. RESULTS: Multivariable analysis revealed that the pregnancies identified as LGA by a customized standard were associated with an increased risk of emergent cesarean section [odds ratio (OR), 4.09; 95% confidence interval (CI), 3.00-5.74] and shoulder dystocia (OR, 10.56; 95% CI, 5.52-20.19). However, there was no association between an increased risk of vacuum delivery (OR, 1.45; 95% CI, 0.92-2.30) and pregnancies identified as non-LGA, using both standards. In addition, customized LGA infants were at increased risk of admission to neonatal intensive care unit (OR 1.63; 95% CI, 1.09-2.43). CONCLUSION: A customized standard of LGA is useful in identifying previously unrecognized women at risk of emergent cesarean section and shoulder dystocia. PMID- 22945274 TI - Can discordance in CRL at the first trimester predict birth weight discordance in twin pregnancies? AB - OBJECTIVE: To examine the correlation between measurements of crown rump length (CRL), nuchal translucency (NT), and birth weight in dichorionic (DC) and monochorionic (MC) twin pregnancies. METHODS: A retrospective analysis was performed on all twin term pregnancies delivered between 2001 and 2007 at the McGill University Health Center. Data collected included maternal age, CRL and NT measurement, results of glucose challenge test, birth weight and length, gestational age at delivery, and fetal gender. RESULTS: The study population comprised 792 fetuses: 94 MC/DA and 698 DC/DA. Maternal age, gestational age at delivery, birth weight, and birth length were all significantly higher for the DC group. Male fetuses had significantly higher NT and higher birth weight than female fetuses. Discordance in CRL was found to correlate with discordance in birth weight in the entire study population (P<0.0001, R=0.25), in the DC twins (P<0.0001, R=0.275), but not in MC twins (R=0.10, P=0.33). CRL discordance above the 90th percentile (>12%) predicted 14/40 pregnancies with birth weight discordance above the 90th percentile (>24%) [P<0.001, LR=4.1 (2.6-6.2)]. CRL discordance above the 95th percentile (>16%) predicted 5/21 pregnancies with birth weight discordance above the 95th percentile (>30%) [P<0.001, LR=5.5 (2.6 10.4)]. NT discordance was correlated with CRL discordance (R=0.15, P<0.0001), but not with birth weight, regardless of chorionicity or gender. CONCLUSION: In twin pregnancies, CRL discordance in first trimester can predict discordance of more than 25% in neonatal birth weight. PMID- 22945275 TI - Fetal myocardial peak systolic strain before and after intrauterine red blood cell transfusion--a tissue Doppler imaging study. AB - OBJECTIVES: The purpose of this study is to evaluate the cardiac function in anemic fetuses by tissue Doppler imaging (TDI) measuring the myocardial peak systolic strain (PS) in fetuses before and after intrauterine transfusion (IUT) of red blood cells. METHODS: In our prospective clinical study in anemic fetuses, high-frame-rate TDI data files from a four-chamber view of fetal hearts pre- and post-IUT were analyzed. The biventricular PS parameters of the mid-segment of the ventricular walls [region of interest (ROI) 1 right ventricle, ROI 2 left ventricle] and the basal segment of the ventricular walls (ROI 3 tricuspid annulus, ROI 4 mitral annulus) were compared with the PS data of the normal controls. RESULTS: We analyzed the pre-/post-data sets from the 15 hearts of anemic fetuses and from the 17 controls. The threshold of statistical significance was set to P<=0.05. Compared with the controls, in anemic fetuses the left ventricular longitudinal myocardial PS (ROI 2, P=0.001) and PS in the basal segment of the right ventricle (ROI 3 P=0.009) was significantly increased (absolute amount). Compared with pre-IUT, post-IUT PS decreased significantly in both ventricles (ROI 1 P=0.025, ROI 2 P=0.02). Compared with the controls, post IUT left ventricular PS was still higher (absolute amount) (ROI 2, P=0.026; ROI 4, P=0.009). CONCLUSIONS: The increase in myocardial PS due to severe fetal anemia is partially normalized by IUT. In anemic fetuses, assessment of TDI fetal myocardial PS is feasible. PMID- 22945276 TI - Factors that affect the postnatal increase in superior mesenteric artery blood flow velocity in very low birth weight preterm infants. AB - OBJECTIVE: To identify factors related to the postnatal increase in superior mesenteric artery blood flow velocity (SMA BFV). STUDY DESIGN: SMA BFV was measured in 35 infants (birth weight 1047+/-246 g) on day of life (DOL) 1, 3, 5, 7 10 and 14. Latent curve modeling (LCM) was used to measure the longitudinal change in BFV for each subject, and the correlation between changes in BFV and baseline values. Non-parametric correlations were calculated between BFV and variables previously reported to be related to SMA BFV. RESULTS: There was significant variability in SMA BFV on DOL 1, a significant increase from DOL 1 14, and significant variability in the postnatal increase. Infants with higher enteral feeding volumes had greater increases, while infants receiving positive pressure ventilation or hyperalimentation had lower increases. CONCLUSIONS: Several clinical factors affect the postnatal increase in SMA BFV. The use of LCM is useful in longitudinal studies of very low birth weight (VLBW) infants, who are clinically and demographically heterogeneous. PMID- 22945277 TI - Central-peripheral temperature gradient: an early diagnostic sign of late-onset neonatal sepsis in very low birth weight infants. AB - AIMS: We assessed central-peripheral temperature gradient alteration for the diagnosis of late-onset neonatal sepsis and compared earliness detection of this sign with altered blood cell count and C-reactive protein. METHOD: Thirty-one preterm babies (<1500 g or <32 weeks) participated in an observational prospective study. Axillary (central) and sole (peripheral) temperatures were continuously monitored with a thermal probe (ThermoTracer; Drager Medical AGF & Co. KgaA, Lubeck, Germany) adjusting incubator air temperature for a thermal gradient <1.5 degrees C. Central-peripheral temperature alteration was defined as a thermal gradient >2 degrees C that could not be corrected with protocolized air temperature modifications. Proven (positive blood culture) sepsis and probable late-onset sepsis were recorded. RESULTS: Late-onset sepsis was diagnosed in 11 neonates (proven, 9; probable, 2). Thermal gradient alteration was present in 12 cases, in association with the onset of sepsis in 10 and concomitantly with a ductus arteriosus and stage 1 necrotizing enterocolitis in 2. Thermal gradient alteration had a sensitivity of 90.9% [95% confidence interval (CI), 62.3-98.4] and specificity of 90% (95% CI, 69.9-97.2%), and in 80% of cases, it occurred before abnormal laboratory findings. CONCLUSIONS: Central-peripheral temperature gradient monitoring is a feasible, non-invasive, and simple tool easily applicable in daily practice. An increase of >2 degrees C showed a high sensitivity and specificity for the diagnosis of late-onset sepsis. PMID- 22945278 TI - A practical method for reducing blindness due to retinopathy of prematurity in a developing country. AB - BACKGROUND: Retinopathy of prematurity (ROP) is a common cause of blindness in countries with rapidly developing systems of neonatal care. At present, detection and treatment programs are not widely available in many regions of middle- and low-income countries. SUBJECT POPULATION: Case series. METHODS: An analysis was undertaken to determine in which neonatal intensive care units (NICUs) in Peru babies blind from ROP had been cared for. Demographic and hospital information was gathered for children blind from ROP presenting before the age of 5 years. NICUs with a high likelihood of having ROP-blind children were offered training and equipment designed to improve neonatal care. RESULTS: Ninety-one children with ROP blindness were identified. Twenty-six percent were <1000 g at birth, and 17% had birth weights of >1500 g. Forty-six percent came from NICUs in Lima. Interventional workshops emphasizing neonatal care and oxygen administration have been conducted thus far in six of the 13 largest NICUs in Lima. The percentage of at-risk babies being examined has generally increased, whereas the percentage of babies requiring treatment decreased in three NICUs and increased slightly in two, and no preworkshop data were available in one. CONCLUSION: This report represents the initial results of an evidence-based approach to decreasing blindness from ROP in Peru. Workshops emphasizing neonatal care, especially targeting oxygen administration, provide methods for improving care of at-risk babies. PMID- 22945279 TI - Density functional simulations of Sb-rich GeSbTe phase change alloys. AB - We generated models of the amorphous phase of Sb-rich GeSbTe phase change alloys by quenching from the melt within density functional molecular dynamics. We considered the two compositions Ge(1)Sb(1)Te(1) and Ge(2)Sb(4)Te(5). Comparison with previous results on the most studied Ge(2)Sb(2)Te(5) allowed us to draw some conclusions on the dependence of the structural properties of the amorphous phase on the alloy composition. Vibrational and electronic properties were also scrutinized. Phonons at high frequencies above 200 cm(-1) are localized in tetrahedra around Ge atoms in Sb-rich compounds as well as in Ge(2)Sb(2)Te(5). All compounds are semiconducting in the amorphous phase, with a band gap in the range 0.7-1.0 eV. PMID- 22945280 TI - IL-18 upregulates the production of key regulators of osteoclastogenesis from fibroblast-like synoviocytes in rheumatoid arthritis. AB - Recent data have demonstrated the importance of IL-18 in the induction and perpetuation of chronic inflammation in experimental arthritis. The aim of the present study was to elucidate whether IL-18 has any indirect effects on osteoclastogenesis by regulating the production of molecules from fibroblast-like synoviocytes (FLS) in rheumatoid arthritis (RA). Human FLS were isolated from RA synovial tissue and cultured in vitro for three to five passages. The expression of IL-18 receptor was determined by RT-PCR. The levels of soluble receptor activator of nuclear factor kappaB ligand (RANKL), osteoprotegerin (OPG), macrophage colony-stimulating factor (M-CSF), and granulocyte-macrophage colony stimulating factor (GM-CSF) in culture supernatants were determined by ELISA. Membrane-bound RANKL expression was analyzed by flow cytometry. Both alpha and beta chains of IL-18 receptor were confirmed in cultured FLS. IL-18 upregulated membrane-bound RANKL expression and soluble RANKL production by FLS in both time- and dose-dependent manners. In addition, IL-18 enhanced production of M-CSF, GM CSF, and OPG from cultured FLS in a dose-dependent manner. IL-18 also increased the ratio of RANKL/OPG, suggesting that the net effect of IL-18 on FLS favors for the induction of osteoclast formation and bone resorption. In conclusion, IL-18 upregulates the production of key regulators of osteoclastogenesis from FLS in RA. PMID- 22945282 TI - Perfluorooctanoic acid and cardiovascular disease in US adults. AB - BACKGROUND: Cardiovascular disease (CVD) is a major public health problem. Identifying novel risk factors for CVD, including widely prevalent environmental exposures, is therefore important. Perfluorooctanoic acid (PFOA) is a manmade chemical used in the manufacture of common household consumer products. Biomonitoring surveys have shown that PFOA is detectable in the blood of more than 98% of the US population. Experimental animal studies suggest that an association between PFOA and CVD is plausible. However, this association in humans has not been previously examined. We therefore examined the independent relationship between serum PFOA levels and CVD outcomes in a representative sample of Americans. METHODS: We examined 1216 subjects (51.2% women) from the 1999-2003 National Health and Nutritional Examination Survey. Serum PFOA levels were examined in quartiles. The main outcomes of interest were self-reported CVD, including coronary heart disease and stroke, and objectively measured peripheral arterial disease (PAD), defined as an ankle-brachial blood pressure index of less than 0.9. RESULTS: We found that increasing serum PFOA levels are positively associated with CVD and PAD, independent of confounders such as age, sex, race/ethnicity, smoking status, body mass index, diabetes mellitus, hypertension, and serum cholesterol level. Compared with quartile 1 (reference) of PFOA level, the multivariable odds ratio (95% CI) among subjects in quartile 4 was 2.01 (1.12 3.60; P = .01 for trend) for CVD and 1.78 (1.03-3.08; P = .04 for trend) for PAD. CONCLUSION: Exposure to PFOA is associated with CVD and PAD, independent of traditional cardiovascular risk factors. PMID- 22945281 TI - Minocycline treatment and bone marrow mononuclear cell transplantation after endothelin-1 induced striatal ischemia. AB - We explored whether the modulation of microglia activation with minocycline is beneficial to the therapeutic actions of bone marrow mononuclear cells (BMMCs) transplanted after experimental stroke. Male Wistar adult rats were divided in four experimental groups: ischemic control saline treated (G1, N = 6), ischemic minocycline treated (G2, N = 5), ischemic BMMC treated (G3, N = 5), and ischemic minocycline/BMMC treated (G4, N = 6). There was a significant reduction in the number of ED1+ cells in G3 animals (51.31 +/- 2.41, P < 0.05), but this effect was more prominent following concomitant treatment with minocycline (G4 = 29.78 +/- 1.56). There was conspicuous neuronal preservation in the brains of G4 animals (87.97 +/- 4.27) compared with control group (G1 = 47.61 +/- 2.25, P < 0.05). The behavioral tests showed better functional recovery in animals of G2, G3, and G4, compared with G1 and baseline (P < 0.05). The results suggest that a proper modulation of microglia activity may contribute to a more permissive ischemic environment contributing to increased neuroprotection and functional recovery following striatal ischemia. PMID- 22945283 TI - A palladium-catalyzed reaction of aryl halides, potassium metabisulfite, and hydrazines. AB - Aryl N-aminosulfonamides could be easily produced via a palladium-catalyzed coupling of aryl halides, potassium metabisulfite, and hydrazines. Potassium metabisulfite is an excellent equivalent of sulfur dioxide in the reaction of palladium-catalyzed aminosulfonylation. PMID- 22945284 TI - Bullying involvement and autism spectrum disorders: prevalence and correlates of bullying involvement among adolescents with an autism spectrum disorder. AB - OBJECTIVES: To produce nationally representative estimates for rates of bullying involvement among adolescents with an autism spectrum disorder (ASD), to compare population estimates with adolescents who have other developmental disabilities, and to identify social ecological correlates of bullying involvement. DESIGN: Nationally representative surveys from 2001. SETTING: United States. PARTICIPANTS: Parents of adolescents with an ASD, principals of the schools they attended, and staff members most familiar with their school programs. MAIN EXPOSURE: Autism spectrum disorders. MAIN OUTCOME MEASURES: Parent report of victimization, perpetration, and victimization/perpetration within the past school year. RESULTS: The prevalence rates of bullying involvement for adolescents with an ASD were 46.3% for victimization, 14.8% for perpetration, and 8.9% for victimization/perpetration. Victimization was related to having a non Hispanic ethnicity, attention-deficit/hyperactivity disorder, lower social skills, some form of conversational ability, and more classes in general education. Correlates of perpetration included being white, having attention deficit/hyperactivity disorder, and getting together with friends at least once a week. Victimization/perpetration was associated with being white non-Hispanic, having attention-deficit/hyperactivity disorder, and getting together with friends at least once a week. CONCLUSIONS: School-based bullying interventions need to target the core deficits of ASD (conversational ability and social skills) and comorbid conditions (eg, attention-deficit/hyperactivity disorder). Future bullying interventions also need to address the higher rates of victimization that occur in general education settings by increasing social integration into protective peer groups and increasing the empathy and social skills of typically developing students toward their peers with an ASD. PMID- 22945286 TI - Surgery in a population-based cohort of Crohn's disease from Olmsted County, Minnesota (1970-2004). AB - OBJECTIVES: We sought to estimate the need for surgery in an American population based cohort of Crohn's disease. METHODS: The medical records of 310 incident cases of Crohn's disease from Olmsted County, Minnesota, diagnosed between 1970 and 2004, were reviewed through March 2009. Cumulative incidence was estimated using the Kaplan-Meier method, and associations between baseline factors and time to first event were assessed using proportional hazards regression and expressed as hazards ratios (HRs) with 95% confidence intervals. RESULTS: Median follow-up per patient was 12 years. One hundred and fifty-two patients underwent at least 1 major abdominal surgery, 65 had at least 2 surgeries, and 32 had at least 3 surgeries. The cumulative probability of major abdominal surgery was 38, 48, and 58% at 5, 10, and 20 years after diagnosis, respectively. Baseline factors significantly associated with time to major abdominal surgery were: ileocolonic (HR, 3.3), small bowel (HR, 3.4), and upper gastrointestinal (HR, 4.0) extent, relative to colonic alone; current cigarette smoking (HR, 1.7), male gender (HR, 1.6), penetrating disease behavior (HR, 2.7), and early corticosteroid use (HR=1.6). Major abdominal surgery rates remained stable, with 5-year cumulative probabilities in 1970-1974 and 2000-2004 of 37.5 and 35.1%, respectively. CONCLUSIONS: The cumulative probability of major abdominal surgery in this population-based cohort of Crohn's disease approached 60% after 20 years of disease, and many patients required second or third surgeries. Non-colonic disease extent, current smoking, male gender, penetrating disease behavior, and early steroid use were significantly associated with major abdominal surgery. PMID- 22945287 TI - Neural tube defects on the Texas-Mexico border: what we've learned in the 20 years since the Brownsville cluster. AB - We reviewed the published findings from the Texas Neural Tube Defect Project, a 6 year case-control study (1995-2000) of neural tube defects (NTDs) on the Texas Mexico border. In this review, we highlight what was learned about environmental, genetic, and nutritional factors (i.e., those related to the folate and other metabolic pathways) and the novel putative risk factors that emerged from this study of Mexican American women living on the Texas-Mexico border. Our investigations of the micronutrients and metabolic pathways involved confirmed the findings of other researchers that increased folate intake has a protective effect and that low serum B(12) , high serum homocysteine levels, and obesity independently contribute to risk. Studies of this population also have implicated hyperinsulinemia and low ferritin, metabolic risk factors, which require additional study to elucidate their physiologic mechanism. Environmental contaminants such as heavy metals, pesticides, and polychlorinated biphenyls (PCBs), which were of community concern, did little to explain NTD risk. Studies in this folic acid deficit-population also revealed several novel risk factors, namely, diarrhea, stress, fumonisins, and the combination of nitrosatable drug exposure with high nitrate/nitrite intake. In conclusion, the 23 studies among the Mexican American women living along the Texas-Mexico border have demonstrated the multifactorial nature of NTDs and that a population deficient in folic acid will be vulnerable to a variety of insults whether brought on by individual behaviors (e.g., obesity) or through the surrounding environment (e.g., fumonisins). Birth Defects Research (Part A), 2012. (c) 2012 Wiley Periodicals, Inc. PMID- 22945288 TI - BASHD-J-resolved-COSY: a new method for measuring proton-proton spin coupling constants of multiplet signals. AB - An effective pulse sequence for measuring H-H coupling constants, named BASHD-J resolved-COSY, has been developed. In the spin systems such as -CH(A) CH(B)(CH(3))-CH(C)-, a methine proton H(B) splits into a multiplet owing to several vicinal couplings, resulting in attenuation of its cross-peak intensity. Therefore, the measurements of (3)J(H-H) with respect to H(B) are generally difficult in the E-COSY-type experiments. With the aim of accurate measurements of (3)J(H-H) in such a spin system, we have developed a new pulse sequence, which selectively decouples the secondary methyl group. The proposed pulse sequence provides the simplified cross-peak patterns, which are suitable for reliable measurements of (3)J(H-H) in a complicated natural product. PMID- 22945285 TI - Thrombolytic evacuation of intracerebral and intraventricular hemorrhage. AB - Intracranial hemorrhage (ICH) accounts for 10-15 % of all strokes, however it causes 30-50 % of stroke related mortality, disability and cost. The prevalence increases with age with only two cases/100,000/year for age less than 40 years to almost 350 cases/100,000/year for age more than 80 years. Several trials of open surgical evacuation of ICH have failed to show clear benefit over medical management. However, some small trials of minimal invasive hematoma evacuation in combination with thrombolytics have shown encouraging results. Based on these findings larger clinical trials are being undertaken to optimize and define therapeutic benefit of minimally invasive surgery in combination with thrombolytic clearance of hematoma. In this article we will review some of the background of minimally invasive surgery and the use of thrombolytics in the setting of ICH and intraventricular hemorrhage (IVH) and will highlight the early findings of MISTIE and CLEAR trials for these two entities respectively. PMID- 22945289 TI - ZNF385B is characteristically expressed in germinal center B cells and involved in B-cell apoptosis. AB - We previously identified zinc finger (ZF) protein ZNF385B as a molecule specifically expressed in Burkitt's lymphoma (BL) among hematologic malignancies. Here, we investigated ZNF385B expression in healthy B cells in a variety of hematological tissues by RT-PCR and immunohistochemistry. ZNF385B expression was found to be limited to a subset of GC B cells, the healthy counterpart to BL B cells. To elucidate the function of ZNF385B in healthy B cells, we established a tetracycline-controlled protein-inducible system in B-cell lines and observed that ectopic expression of the longest transcript variant of ZNF385B, possessing four ZF domains, induced upregulation of PERP and FAS/CD95, a downstream target of p53, and activation of caspase, resulting in apoptosis induction. However, a ZNF385B deletion mutant with three ZF domains corresponding to shorter isoforms, did not induce upregulation; rather it inhibited apoptosis induced by CD20 cross linking and BCR stimulation. The direct binding of ZNF385B with p53 has suggested the involvement of ZNF385B in B-cell apoptosis via modulation of p53 transactivation; our data indicate that ZNF385B characteristically expressed in GC B cells has both proapoptotic and antiapoptotic activities depending on the type of isoform and should be a novel player in GC B-cell selection. PMID- 22945290 TI - Lipid profiling of cancerous and benign gallbladder tissues by 1H NMR spectroscopy. AB - Qualitative and quantitative (1) H NMR analysis of lipid extracts of gallbladder tissue in chronic cholecystitis (CC, benign) (n = 14), xanthogranulomatous cholecystitis (XGC, intermediate) (n = 9) and gallbladder cancer (GBC, malignant) (n = 8) was carried out to understand the mechanisms involved in the transformation of benign gallbladder tissue to intermediate and malignant tissue. The results revealed alterations in various tissue lipid components in gallbladder in CC, XGC and GBC. The difference in the nature of lipid components in benign and malignant disease may aid in the identification of the biological pathways involved in the etiopathogenesis of GBC. This is the first study on lipid profiling of gallbladder tissue by (1) H NMR spectroscopy, and has possible implications for the development of future diagnostic approaches. PMID- 22945291 TI - Neural correlates of motor imagery for elite archers. AB - Motor imagery is a mental rehearsal of simple or complex motor acts without overt body movement. It has been proposed that the association between performance and the mental rehearsal period that precedes the voluntary movement is an important point of difference between highly trained athletes and beginners. We compared the activation maps of elite archers and nonarchers during mental rehearsal of archery to test whether the neural correlates of elite archers were more focused and efficiently organised than those of nonarchers. Brain activation was measured using functional MRI in 18 right-handed elite archers and 18 right-handed nonarchers. During the active functional MRI imagery task, the participants were instructed to mentally rehearse their archery shooting from a first-person perspective. The active imagery condition was tested against the nonmotor imagery task as a control condition. The results showed that the premotor and supplementary motor areas, and the inferior frontal region, basal ganglia and cerebellum, were active in nonarchers, whereas elite archers showed activation primarily in the supplementary motor areas. In particular, our result of higher cerebellar activity in nonarchers indicates the increased participation of the cerebellum in nonarchers when learning an unfamiliar archery task. Therefore, the difference in cerebellar activation between archers and nonarchers provides evidence of the expertise effect in the mental rehearsal of archery. In conclusion, the relative economy in the cortical processes of elite archers could contribute to greater consistency in performing the specific challenge in which they are highly practised. PMID- 22945292 TI - Perfusion territory imaging of intracranial branching arteries - optimization of continuous artery-selective spin labeling (CASSL). AB - Continuous artery-selective spin labeling (CASSL) is based on a standard continuous arterial spin labeling sequence with adiabatic flow-driven inversion and an amplitude-modulated control experiment, and has been proposed recently as a new method for the noninvasive flow territory mapping of cerebral arteries. Spatial selectivity is achieved by the rotation of a tilted labeling plane about the axis of a selected artery, which restricts the tagging pulses to the same spatial position for the vessel of interest but, for any other adjacent and parallel artery, the locus of resonance will vary in time and saturates the blood at a certain distance to the labeling focus. In numerical simulations and in a volunteer study, the key labeling parameters of CASSL were investigated with the goal of increasing the spatial selectivity whilst maintaining sufficient labeling efficiency, in order to selectively label the blood in small intracranial arteries distal to the circle of Willis. The optimized labeling parameters were employed in vivo and adapted to different vascular geometries. The labeling of small intracranial branches of the anterior, middle and posterior cerebral arteries in close vicinity to other vessels yielded clearly delineated perfusion territories and demonstrated the method's capability for highly selective perfusion measurements. PMID- 22945293 TI - Increased blood oxygen level-dependent (BOLD) sensitivity in the mouse somatosensory cortex during electrical forepaw stimulation using a cryogenic radiofrequency probe. AB - Functional MRI (fMRI) based on the blood oxygen level-dependent (BOLD) contrast is widely used in preclinical neuroscience. The small dimensions of rodent brain place high demands on spatial resolution, and hence on the sensitivity of the fMRI experiment. This work investigates the performance of a 400-MHz cryogenic quadrature transceive radiofrequency probe (CryoProbe) with respect to the enhancement of the BOLD sensitivity. For this purpose, BOLD fMRI experiments were performed in mice during electrical forepaw stimulation using the CryoProbe and a conventional room temperature surface coil of comparable dimensions. Image signal to-noise ratio (SNR) and temporal SNR were evaluated as quality measures for individual images and for fMRI time series of images, resulting in gains (mean +/ standard deviation) with factors of 3.1 +/- 0.7 and 1.8 +/- 1.0 when comparing the CryoProbe and room temperature coil. The CryoProbe thermal shield temperature did not affect the noise characteristics, with temporal noise levels being 63 +/- 16% of the corresponding room temperature value. However, a significant effect on BOLD amplitudes was found, which was attributed to temperature-dependent baseline cerebral blood volumes. Defined local thermal conditions were found to be a critical parameter for achieving an optimal and reproducible fMRI signal. In summary, the CryoProbe represents an attractive alternative for the enhancement of image SNR, temporal SNR and BOLD sensitivity in mouse fMRI experiments. PMID- 22945294 TI - Synthesis of tetrahydropyridazines by a metal-carbene-directed enantioselective vinylogous N-H insertion/Lewis acid-catalyzed diastereoselective Mannich addition. AB - A versatile cascade of reactions, triggered by Rh(II)-catalyzed diazo decomposition followed by a vinylogous N-H insertion/Lewis acid catalyzed Mannich addition, that produces highly substituted 1,2,3,6-tetrahydropyridazines in up to 97 % ee with high yield and diastereocontrol has been developed. PMID- 22945295 TI - The role of tryptophan spatial arrangement for antimicrobial-derived, membrane active peptides adsorption and activity. AB - Herein we explored the role of topological distribution of aromatic amino acids in peptide-membrane interfacial interactions. The membrane activity of closely related peptides and their binding energy is sensitive to the positioning of minimum two tryptophans, and by the degree of flanking at the membrane interface mediated by aromatic amino acids. PMID- 22945297 TI - Synthesis and characterization of alkyl-imidazolium-based periodic mesoporous organosilicas: a versatile host for the immobilization of perruthenate (RuO4-) in the aerobic oxidation of alcohols. AB - The preparation and characterization of a set of periodic mesoporous organosilicas (PMOs) that contain different fractions of 1,3-bis(3 trimethoxysilylpropyl)imidazolium chloride (BTMSPI) groups uniformly distributed in the silica mesoporous framework is described. The mesoporous structure of the materials was characterized by powder X-ray diffraction, transmission electron microscopy, and N(2) adsorption-desorption analysis. The presence of propyl imidazolium groups in the silica framework of the materials was also characterized by solid-state NMR spectroscopy and diffuse-reflectance Fourier transform infrared spectroscopy. The effect of the BTMSPI concentration in the initial solutions on the structural properties (including morphology) of the final materials was also examined. The total organic content of the PMOs was measured by elemental analysis, whereas their thermal stability was determined by thermogravimetric analysis. Among the described materials, it was found that PMO with 10% imidazolium content is an effective host for the immobilization of perruthenate through an ion-exchange protocol. The resulting Ru@PI-10 was then employed as a recyclable catalyst in the highly efficient aerobic oxidation of various types of alcohols. PMID- 22945296 TI - [Guidelines for COPD prevention, diagnosis and treatment in Argentina]. AB - Since morbidity, mortality and socioeconomic costs from Chronic Obstructive Pulmonary Disease (COPD) are widely increasing, a group of respiratory medicine specialists was summoned by the AAMR to update basic knowledge on COPD and to issue recommendations for its prevention, diagnosis and treatment. The authors review the definition of COPD together with current knowledge on pathophysiology. Clinical presentation, functional evaluation and imaging are summarized. Early diagnosis through pulmonary function tests -mainly spirometry- and the role of smoking cessation are stressed. Smoking cessation strategies are described as well as pharmacological and non-pharmacological treatment. Long acting bronchodilators are considered the first pharmacological option for treatment due to its effectiveness and patient compliance. Inhaled corticosteroids are indicated in combination with long-acting bronchodilators in patients who present persistent airway obstruction associated with frequent exacerbations since they reduce their number although further studies are needed to confirm their cost/benefit. Annual influenza vaccination is recommended in all patients. In the non-pharmacological section, surgery for emphysema is suggested in very specific cases. Respiratory rehabilitation is a useful tool for patients with daily activities limitation. Long-term oxygen therapy at home improves survival in patients with severe chronic hypoxemia. Non-invasive home ventilation in chronic patients has limited indications in specific subgroups. Acute exacerbations should be aggressively treated with bronchodilators, oxygen, antibiotics, corticosteroids and eventually mechanical ventilation, as invasive as not invasive respiratory support. The importance of public education as well as of individual patients and their families is deemed essential in the prevention and treatment of the disease. PMID- 22945298 TI - Effects on insulin sensitivity and body composition of combination therapy with GH and IGF1 in GH deficient adults with type 2 diabetes. AB - OBJECTIVE: The aim of this trial was to evaluate the effect on insulin sensitivity and body composition of combination therapy with GH and IGF1 in adults with GH deficiency (GHD) and diabetes. DESIGN, PATIENTS AND METHODS: A 6 month randomised placebo-controlled pilot study. Fourteen adults with GHD and type 2 diabetes were included. All received rhGH (0.15 mg/day for 1 month and 0.3 mg/day for 5 months) and were randomised to rhIGF1 (15 MUg/kg per day for 1 month and 30 MUg/kg per day for 5 months) or placebo. Insulin sensitivity was evaluated with euglycaemic hyperinsulinaemic clamp and body composition by computed tomography of abdominal and thigh fat, as well as bioimpedance. RESULTS: Twelve patients completed the study. They were overweight and obese; at baseline, insulin sensitivity (M-value) was low. IGF1 and IGF1 SDS increased in both groups, with the highest increase in the GH and IGF1 group. Positive changes in M value by +1.4 mg/kg per min, in subcutaneous abdominal fat by -60.5 ml and in fat free mass by +4.4% were seen in the GH and IGF1 group. Corresponding values in the GH and placebo-treated group were -1.5 mg/kg per min, +23 ml and -0.04% respectively (P=0.02, P=0.04 and P=0.03 for delta values between groups). No safety issues occurred. CONCLUSIONS: Combined GH and IGF1 treatment resulted in positive, but rather small effects, and might be a treatment option in a few selected patients. PMID- 22945299 TI - Expression of the CD11c gene in subcutaneous adipose tissue is associated with cytokine level and insulin resistance in women with polycystic ovary syndrome. AB - OBJECTIVE: Alterations in the phenotypes of macrophages in adipose tissue play a key role in inflammation and insulin resistance (IR). The phenotypes of macrophages in subcutaneous adipose tissue (SAT) and the relationship between proinflammation markers and IR in women with polycystic ovary syndrome (PCOS) remain unclear. The objectives of this study are to characterize the gene expression of macrophage markers and cytokines in the SAT of PCOS women and to estimate their relationships with circulating levels of cytokines and IR. METHODS: The cross-sectional study involves 16 PCOS women and 18 normal control women. Cytokines and macrophage markers in the circulation and SAT were determined using ELISA, quantitative PCR, or immunofluorescence staining. IR was estimated using the homeostasis model assessment (HOMA-IR). RESULTS: The gene expression levels of CD11c along with TNF alpha and leptin in SAT remained significantly higher in PCOS women than in normal women (P<0.05). However, no significant differences were found in CD68 mRNA expression in SAT between women with and without PCOS (P>0.05). Furthermore, CD11c mRNA abundance provided a stronger contribution to models predicting serum levels of TNFalpha (sTNFalpha) than did CD68 mRNA abundance. Lastly, increased sTNFalpha was associated with increased HOMA-IR in PCOS women, and this association was independent of both overall and visceral adiposity. CONCLUSION: The high expression level of CD11c mRNA in SAT was proved to be an important feature in PCOS women. Furthermore, CD11c mRNA abundance made a stronger contribution to models predicting sTNFalpha in which existing proinflammatory properties might significantly contribute to the pathogenesis of IR in PCOS women. PMID- 22945300 TI - Multicentric reticulohistiocytosis. PMID- 22945301 TI - The soleus muscle: MRI, anatomic and histologic findings in cadavers with clinical correlation of strain injury distribution. AB - OBJECTIVE: The purpose of this study was to describe the normal anatomy of the soleus muscle using magnetic resonance (MR) imaging, anatomic dissection and histologic correlation in cadavers. The second objective of this study was to analyse the morphometry of the soleus muscle in normal volunteers. The final objective was to undertake a retrospective review of soleal strain injuries confirmed with MR imaging, with correlation made between the cadaveric anatomic findings and the MR imaging features. MATERIALS AND METHODS: Eleven fresh cadaveric legs were studied using a high resolution 3.0 T (T) MR imaging scanner to obtain images in the axial, coronal and sagittal planes. After imaging, six specimens were dissected and evaluated by histological analysis, with the remaining five specimens then frozen and cut into axial sections. The corresponding levels on the MR examination were then compared with the levels of anatomic sectioning. MR imaging was also used to examine the soleus muscle in both legs of 20 healthy volunteers. Finally, 55 clinical cases of soleus muscle strains diagnosed between October 2006 and January 2011 that had also previously undergone MR imaging were re-evaluated. The location of strain injury was reviewed and correlated with the anatomic information that had been revealed in the anatomic component of our study. RESULTS: Dissection of the soleus muscle revealed two proximal intramuscular aponeuroses (medial and lateral) that are formed as a direct continuation of the surrounding epimysium. From an anatomic, functional and pathologic perspective, these aponeuroses are considered in this study as intramuscular tendons, however they have been not previously described as such. These tendons penetrate deep into the muscle belly, from which the proximal muscle fibres of the soleus arise. Inferiorly, these muscle fibres insert onto a long distal central tendon that becomes confluent with the overlying distal tendon of gastrocnemius to form the Achilles tendon. Significant differences between the length of the central tendon on the right side (31.35 cm) and the left side (30.36 cm) were observed (p = .002), as well as the length of insertion of this tendon onto the Achilles tendon on the right side (7.19 cm) compared with the left (7.94 cm) (p = .02). The retrospective analysis identified five sites within the soleus where strains were distributed: musculotendinous junction sites (proximal medial strains accounting for 25.5% of all injuries, proximal lateral strains accounting for 12.7% and distal central tendon strains accounting for 18.2%) and myofascial sites (anterior strains accounting for 21.8% of all injuries and posterior strains accounting for 21.8%). Strains of the proximal medial musculotendinous junction were the most common of soleal muscle injuries, comprising 56.4% of all cases. CONCLUSION: Current information on the detailed anatomy of the soleus muscle in the anatomic and radiological literature is lacking. Knowledge of this anatomy accounts for the distribution of sports induced injuries within the soleus muscle-tendon unit and therefore assists in the accurate identification of these injuries, with possible prognostic benefit. PMID- 22945302 TI - Optimization of acoustic liposomes for improved in vitro and in vivo stability. AB - PURPOSE: Liposomes encapsulating perfluoropropane gas, termed acoustic liposomes (ALs), which can serve both for ultrasound (US) imaging and US-mediated gene delivery, have been reported. However, the echogenicity of ALs decreases within minutes in vivo due to gas diffusion and leakage, hindering time-consuming procedures such as contrast-enhanced 3D US imaging and raising the need for improvement of their stability. METHODS: The stability of ALs preparations incorporating increasing ratios of anionic / unsaturated phospholipids, polyethylene glycol (PEG)ylated phospholipid and cholesterol was investigated by measurement of their reflectivity over time using a high-frequency US imaging system, both in vitro and in vivo. RESULTS: The retention of echogenicity of ALs in vitro is enhanced with increasing molar ratios of PEGylated lipids. Addition of 10 molar percent of an anionic phospholipid resulted in a 31% longer half life, while cholesterol had the opposite effect. Assessment of the stability of an optimized composition showed a more than 2-fold increase of the detection half life in mice. CONCLUSIONS: Presence of a PEG coating not only serves to provide "stealth" properties in vivo, but also contributes to the retention of the encapsulated gas. The optimized ALs reported here can be used as a contrast agent for lengthier imaging procedures. PMID- 22945303 TI - Hospitalised hip fracture risk with rosiglitazone and pioglitazone use compared with other glucose-lowering drugs. AB - AIMS/HYPOTHESIS: Current drug labels for thiazolidinediones (TZDs) warn of increased fractures, predominantly for distal fractures in women. We examined whether exposure to TZDs affects hip fracture in women and men and compared the risk to that found with other drugs used in diabetes. METHODS: Using a nationwide database of prescriptions, hospital admissions and deaths in those with type 2 diabetes in Scotland we calculated TZD exposure among 206,672 individuals. Discrete-time failure analysis was used to model the effect of cumulative drug exposure on hip fracture during 1999-2008. RESULTS: There were 176 hip fractures among 37,479 exposed individuals. Hip fracture risk increased with cumulative exposure to TZD: OR per year of exposure 1.18 (95% CI 1.09, 1.28; p = 3 * 10( 5)), adjusted for age, sex and calendar month. Hip fracture increased with cumulative exposure in both men (OR 1.20; 95% CI 1.03, 1.41) and women (OR 1.18; 95% CI 1.07, 1.29) and risks were similar for pioglitazone (OR 1.18) and rosiglitazone (OR 1.16). The association was similar when adjusted for exposure to other drugs for diabetes and for other potential confounders. There was no association of hip fracture with cumulative exposure to sulfonylureas, metformin or insulin in this analysis. The 90-day mortality associated with hip fractures was similar in ever-users of TZD (15%) and in never-users (13%). CONCLUSIONS/INTERPRETATION: Hip fracture is a severe adverse effect with TZDs, affecting both sexes; labels should be changed to warn of this. The excess mortality is at least as much as expected from the reported association of pioglitazone with bladder cancer. PMID- 22945304 TI - TCF7L2 promotes beta cell regeneration in human and mouse pancreas. AB - AIMS/HYPOTHESIS: Diabetes is characterised by loss and dysfunction of the beta cell. A major goal of diabetes therapy is to promote the formation of new beta cells. Polymorphisms of T cell factor 7-like 2 (TCF7L2) are associated with type 2 diabetes, negatively regulating beta cell survival and function. Here, we provide evidence for a role of TCF7L2 in beta cell proliferation and regeneration. METHODS: Pancreatic sections from three mouse models (high-fat diet, exendin-4 and streptozotocin-treated mice) and from healthy individuals and patients with type 2 diabetes were used to investigate the association of beta cell regeneration and TCF7L2 levels. To analyse a direct effect of TCF7L2 on duct cell to beta cell conversion, TCF7L2 was overexpressed in isolated exocrine cells. RESULTS: TCF7L2 levels correlated with beta cell compensation during high fat diet feeding. TCF7L2 was increased together with pancreatic duct cell proliferation and differentiation. Small islet-like cell clusters (ICCs) that contained TCF7L2 originated in the vicinity of the ductal epithelium. In human isolated exocrine tissue, TCF7L2 overexpression induced proliferation of pancreatic duct cells and ICC formation next to duct cells, an effect dependent on the JAK2/STAT3 pathway. CONCLUSIONS/INTERPRETATION: The present study demonstrates that TCF7L2 overexpression fosters beta cell regeneration. Our findings imply correlation of TCF7L2 levels and new beta cell formation. PMID- 22945307 TI - Might hypovitaminosis D aggravate endothelial dysfunction-related increases in arterial stiffness seen in patients with hypertension and type 2 diabetes? PMID- 22945309 TI - Mossbauer study of the '11' iron-based superconductors parent compound Fe(1+x)Te. AB - (57)Fe Mossbauer spectroscopy was applied to investigate the superconductor parent compound Fe(1+x)Te for x = 0.06, 0.10, 0.14, 0.18 within the temperature range 4.2-300 K. A spin density wave (SDW) within the iron atoms occupying regular tetrahedral sites was observed, with the square root of the mean square amplitude at 4.2 K varying between 9.7 and 15.7 T with increasing x. Three additional magnetic spectral components appeared due to the interstitial iron distributed over available sites between the Fe-Te layers. The excess iron showed hyperfine fields at approximately 16, 21 and 49 T for three respective components at 4.2 K. The component with a large field of 49 T indicated the presence of isolated iron atoms with large localized magnetic moments in interstitial positions. Magnetic ordering of the interstitial iron disappeared in accordance with the fallout of the SDW with increasing temperature. PMID- 22945305 TI - Type 2 diabetes and cardiovascular disease in women. AB - Cardiovascular disease is the leading cause of death in both men and women. This is also true for patients with diabetes. In general, differences between the sexes are present in several areas, such as epidemiology, pathophysiology, diagnostics, treatment response and prognosis, as well as the way in which disease is experienced and expressed. Cardiovascular disease presents later in life in women, who are therefore more likely to suffer from comorbidities. However, this age-related difference is attenuated in women with diabetes, who suffer their first myocardial infarction at about the same age as men with diabetes. Diabetes mellitus increases the risk of cardiovascular disease by three to four times in women and two to three times in men, after adjusting for other risk factors. This paper describes the differences in cardiovascular disease in men and women and the special situation of women with type 2 diabetes when it comes to risk factors, symptoms and the setting of acute coronary syndromes. Furthermore, it highlights the importance of sex-specific analyses in clinical research to improve our knowledge of cardiovascular disease in women in general and in women with diabetes in particular. The importance of taking sex into account when treating women and men at risk of cardiovascular disease is discussed. PMID- 22945310 TI - Five questions for health economists. PMID- 22945311 TI - Palladium(II)-catalysed tandem cyclisation of electron-deficient aromatic enynes. AB - A novel palladium(II) catalysed tandem cyclisation of substituted 2-alkenylphenyl alkynones gives substituted 2-vinyl indenones and 6,5,6-fused tricyclic lactone skeletons (pyrones), in one-pot. Wagner-Meerwein-like rearrangements were observed which occur preferentially to conventional chloride-mediated chloropalladations of enynes. PMID- 22945312 TI - Perfluorooctanoic acid exposure and cardiovascular disease: potential role and preventive measures: comment on "Perfluorooctanoic acid and cardiovascular disease in US adults". PMID- 22945313 TI - ARABIDILLO gene homologues in basal land plants: species-specific gene duplication and likely functional redundancy. AB - ARABIDILLO proteins regulate multicellular root development in Arabidopsis thaliana. Conserved ARABIDILLO homologues are present throughout land plants, even in early-evolving plants that do not possess complex root architecture, suggesting that ARABIDILLO genes have additional functions. Here, we have cloned and characterised ARABIDILLO gene homologues from two early-evolving land plants, the bryophyte Physcomitrella patens and the lycophyte Selaginella moellendorffii. We show that two of the PHYSCODILLO genes (PHYSCODILLO1A and -1B) exist as a tail to-tail tandem array of two almost identical 12 kb sequences, while a third related gene (PHYSCODILLO2) is located elsewhere in the Physcomitrella genome. Physcomitrella possesses a very low percentage of tandemly arrayed genes compared with the later-evolving plants whose genomes have been sequenced to date. Thus, PHYSCODILLO1A and -1B genes represent a relatively unusual gene arrangement. PHYSCODILLO promoters are active largely in the haploid gametophyte, with additional activity at the foot of the sporophyte. The pattern of promoter activity is uniform in filamentous and leafy tissues, suggesting pleiotropic gene functions and likely functional redundancy: the latter possibility is confirmed by the lack of discernible phenotype in a physcodillo2 deletion mutant. Interestingly, the pattern of PHYSCODILLO promoter activity in female reproductive organs is strikingly similar to that of an Arabidopsis homologue, suggesting co-option of some PHYSCODILLO functions or regulation into both the sporophyte and gametophyte. In conclusion, our work identifies and characterises some of the earliest-evolving land plant ARABIDILLO homologues. We confirm that all land plant ARABIDILLO genes arose from a single common ancestor and suggest that PHYSCODILLO proteins have novel and pleiotropic functions, some of which may be conserved in later-evolving plants. PMID- 22945314 TI - Brachial plexus variations during the fetal period. AB - The brachial plexus is an important nervous system structure. It can be injured during the perinatal period and by postnatal damage. The goal of this study was to assess human fetal brachial plexus variability. A total of 220 brachial plexuses were surgically prepared from 110 human fetuses aged 14-32 weeks of fetal life (50 females and 60 males) ranging in CRL from 80 to 233 mm. The study incorporated the following methods: dissectional and anthropological, digital image acquisition, digital image processing using Image J and GIMP software, and statistical methods (Statistica 9.0). Symmetry and sexual dimorphism were examined. Anomalies of the brachial plexuses were observed in 117 (53.18 %) cases. No sexual dimorphism was found. It was observed that cord variations occurred more often on the left side. Division variants (33.64 %) occurred most often, but also cords (18.18 %) as well as root nerves and terminal ramifications (15.90 %) were found. Trunk anomalies were rare and occurred in only 5.45 % of plexuses. Three height types of median nerve roots in combination with the nerve were distinguished. In one-third of cases, median nerve root connections were found below the axillary fossa and even half in the proximal part of the humerus. In conclusion, the brachial plexus was characterized for anatomical structural variability. Most often division and cord variations were observed. Anomalies occurred regardless of sex or body side except for cord variants. Brachial plexus variation recognition is significant from the neurosurgical and traumatological point of view. PMID- 22945315 TI - Accelerated cell sheet detachment by copolymerizing hydrophilic PEG side chains into PNIPAm nanocomposite hydrogels. AB - One-end-connected short poly(ethylene glycol) (PEG) side chains were facilely introduced into the poly(N-isopropylacrylamide) (PNIPAm) nanocomposite hydrogel (NC gel) via in situ copolymerization of NIPAm monomer and PEG macromonomer in the aqueous suspension of hectorite clay Laponite XLS. The NC gels were characterized with Fourier transform infrared and x-ray photoelectron spectroscopy for the composition, DSC and transmittance for the phase separation temperature, dynamic mechanical spectra and swelling ratio for the interaction. Increasing the PEG content led to a small increase in the storage modulus and the lower critical solution temperature (LCST) of the copolymerized NC gels, and the LCST of the copolymerized NC gels was still below 37 degrees C. The L929 cell adhesion and proliferation on the surface of these NC gels were not suppressed by the incorporation of hydrophilic PEG side chains. By lowering temperature below the LCST, the cell sheet spontaneously detached from the copolymerized NC gels. The surface morphology and surface wettability of the NC gels were detected by atom force microscope and contact angle measurement. A rough and hydrophilic surface induced by a small amount of PEG side chains was found to be favorable to accelerate the cell sheet detachment, probably due to the enhanced water permeation into the gel-cell sheet interface. PMID- 22945316 TI - Antibiotics for irritable bowel syndrome: rationale and current evidence. AB - Irritable bowel syndrome (IBS) is the most common gastrointestinal condition effecting adults in developed countries worldwide. Over the last decade, evidence has emerged suggesting that gut bacteria play a role in the pathophysiology of IBS. While difficult to identify using noninvasive means, one of the most common attributable bacterial concepts in IBS is the small intestinal bacterial overgrowth hypothesis (SIBO). In this article, we review the different mechanisms by which gut flora and, specifically, SIBO may contribute to IBS and the evidence supporting the use of various antibiotic therapies in treating IBS. PMID- 22945321 TI - Picture of the month-quiz case. Infantile Fibrosarcoma. PMID- 22945317 TI - Maternal occupational exposure to polycyclic aromatic hydrocarbons and congenital heart defects among offspring in the national birth defects prevention study. AB - BACKGROUND: There is evidence in experimental model systems that exposure to polycyclic aromatic hydrocarbons (PAHs) results in congenital heart defects (CHDs); however, to our knowledge, this relationship has not been examined in humans. Therefore, we conducted a case-control study assessing the association between estimated maternal occupational exposure to PAHs and CHDs in offspring. METHODS: Data on CHD cases and control infants were obtained from the National Birth Defects Prevention Study for the period of 1997 to 2002. Exposure to PAHs was assigned by industrial hygienist consensus, based on self-reported maternal occupational histories from 1 month before conception through the third month of pregnancy. Logistic regression was used to evaluate the association between maternal occupational PAH exposure and specific CHD phenotypic subtypes among offspring. RESULTS: The prevalence of occupational PAH exposure was 4.0% in CHD case mothers (76/1907) and 3.6% in control mothers (104/2853). After adjusting for maternal age, race or ethnicity, education, smoking, folic acid supplementation, and study center, exposure was not associated with conotruncal defects (adjusted odds ratio [AOR], 0.98; 95% confidence interval [CI], 0.58 1.67), septal defects (AOR, 1.28; 95% CI, 0.86-1.90), or with any isolated CHD subtype. CONCLUSIONS: Our findings do not support an association between potential maternal occupational exposure to PAHs and various CHDs in a large, population-based study. For CHD phenotypic subtypes in which modest nonsignificant associations were observed, future investigations could be improved by studying populations with a higher prevalence of PAH exposure and by incorporating information on maternal and fetal genotypes related to PAH metabolism. Birth Defects Research (Part A), 2012. PMID- 22945322 TI - Picture of the month: diagnosis: infantile fibrosarcoma. PMID- 22945323 TI - More proof that home fortification is of value in children with iron deficiency anemia. PMID- 22945324 TI - Adolescent opioid abuse. PMID- 22945325 TI - Rapidly-moving insect muscle-powered microrobot and its chemical acceleration. AB - Insect dorsal vessel (DV) tissue seems well suited for microactuators due to its environmental robustness and low maintenance. We describe an insect muscle powered autonomous microrobot (iPAM) and its acceleration with a neuroactive chemical, crustacean cardioactive peptide (CCAP). The iPAM, consisting of a DV tissue and a frame, was designed on the basis of a finite element method simulation and fabricated. The iPAM moved autonomously by spontaneous contraction of the DV tissue at a significantly improved velocity compared to our previous model. The best-case iPAM moved faster than other reported microrobots powered by mammalian cardiomycytes. It moved forward with a small declination of 0.54 degrees during one contraction since the DV tissue not only shortened but also twisted. The iPAM frame should be designed by taking into account the innate contractile characteristic of DV tissue. The acceleration effect of CCAP on contracting frequency was evaluated using a micropillar array and was a maximum at 10(-6)M. The effect peaked 1 min after addition and remained for 2 min. CCAP addition at 10(-6)M accelerated the iPAM temporally and the velocity increased 8.1-fold. We view the DV tissue as one of the most promising materials for chemically regulatable microactuators. PMID- 22945326 TI - HDL cholesterol is not HDL--don't judge the book by its cover. AB - The concept that raising HDL-cholesterol level will uniformly translate into cardiovascular risk reduction has been challenged by genetic epidemiology studies and large-scale, randomized clinical trials. Studies suggest that we should go beyond HDL cholesterol, and consider emerging biomarkers of HDL concentration, composition, and functionality as surrogates for cardiovascular risk reduction. PMID- 22945327 TI - Imaging cerebral microemboli during TAVI. PMID- 22945328 TI - CT coronary angiography in low-risk, acute chest pain. AB - The ROMICAT-II trial shows that CT coronary angiography is safe and fast for the exclusion of clinically significant obstructive coronary artery disease in low risk patients with acute chest pain. Several issues and questions relating to the low prevalence of disease and the actual benefit to patients remain to be answered. PMID- 22945329 TI - The many faces of heart failure with preserved ejection fraction. AB - By definition, patients with heart failure and preserved ejection fraction are characterized by a normal or near-normal left ventricular ejection fraction, but marked heterogeneity in the extent of other cardiac structural and functional abnormalities exists. Improved appreciation of this diversity might provide insights into prognosis and therapeutic interventions. PMID- 22945331 TI - Combined MR, fluorescence and histology imaging strategy in a human breast tumor xenograft model. AB - Applications of molecular imaging in cancer and other diseases frequently require the combination of in vivo imaging modalities, such as MR and optical imaging, with ex vivo optical, fluorescence, histology and immunohistochemical imaging to investigate and relate molecular and biological processes to imaging parameters within the same region of interest. We have developed a multimodal image reconstruction and fusion framework that accurately combines in vivo MRI and MRSI, ex vivo brightfield and fluorescence microscopic imaging and ex vivo histology imaging. Ex vivo brightfield microscopic imaging was used as an intermediate modality to facilitate the ultimate link between ex vivo histology and in vivo MRI/MRSI. Tissue sectioning necessary for optical and histology imaging required the generation of a three-dimensional reconstruction module for two-dimensional ex vivo optical and histology imaging data. We developed an external fiducial marker-based three-dimensional reconstruction method, which was able to fuse optical brightfield and fluorescence with histology imaging data. The registration of the three-dimensional tumor shape was pursued to combine in vivo MRI/MRSI and ex vivo optical brightfield and fluorescence imaging data. This registration strategy was applied to in vivo MRI/MRSI, ex vivo optical brightfield/fluorescence and histology imaging datasets obtained from human breast tumor models. Three-dimensional human breast tumor datasets were successfully reconstructed and fused with this platform. PMID- 22945332 TI - Polyploidy road to therapy-induced cellular senescence and escape. AB - Therapy-induced cellular senescence (TCS), characterized by prolonged cell cycle arrest, is an in vivo response of human cancers to chemotherapy and radiation. Unfortunately, TCS is reversible for a subset of senescent cells, leading to cellular reproliferation and ultimately tumor progression. This invariable consequence of TCS recapitulates the clinical treatment experience of patients with advanced cancer. We report the findings of a clinicopathological study in patients with locally advanced non-small cell lung cancer demonstrating that marker of in vivo TCS following neoadjuvant therapy prognosticate adverse clinical outcome. In our efforts to elucidate key molecular pathways underlying TCS and cell cycle escape, we have previously shown that the deregulation of mitotic kinase Cdk1 and its downstream effectors are important mediators of survival and cell cycle reentry. We now report that aberrant expression of Cdk1 interferes with apoptosis and promotes the formation of polyploid senescent cells during TCS. These polyploid senescent cells represent important transition states through which escape preferentially occurs. The Cdk1 pathway is in part modulated differentially by p21 and p27 two members of the KIP cyclin-dependent kinase inhibitor family during TCS. Altogether, these studies underscore the importance of TCS in cancer therapeutics. PMID- 22945330 TI - The role of 3D wall motion tracking in heart failure. AB - Heart failure is a major health problem in developed countries and a growing one in developing countries. Cardiac remodeling in heart failure affects myocardial mechanics, which requires comprehensive evaluation in three dimensions. The novel technique of 3D wall motion tracking applies speckle tracking technology to full volume, 3D echocardiographic datasets. Quantification of conventional and novel left ventricular (LV) parameters including volumes, ejection fraction, global and regional 3D strain, endocardial area strain, twist, and dyssynchrony, and identification of the site of latest mechanical activation are feasible on the basis of a single acquisition of a full-volume dataset. Clinical applications of 3D wall motion tracking include the assessment of global and regional LV performance in ischemic and nonischemic heart diseases, evaluation of mechanics in cardiomyopathies and congenital heart disease, potential selection of patients for cardiac resynchronization therapy and prediction of their response, and detection of subclinical cardiac dysfunction in diseases with likelihood of progression to heart failure. Technological advances with improvement in spatial and temporal resolution of this novel imaging modality are expected. Although 3D wall motion tracking is still in its infancy, this method has begun to provide new insights into LV mechanics and has already found clinical applications. Future developments in 3D assessment of right ventricular and myocardial layer specific mechanics are awaited. PMID- 22945333 TI - Genetic encoding of a bicyclo[6.1.0]nonyne-charged amino acid enables fast cellular protein imaging by metal-free ligation. AB - Visualizing biomolecules by fluorescent tagging is a powerful method for studying their behaviour and function inside cells. We prepared and genetically encoded an unnatural amino acid (UAA) that features a bicyclononyne moiety. This UAA offered exceptional reactivity in strain-promoted azide-alkyne cycloadditions. Kinetic measurements revealed that the UAA reacted also remarkably fast in the inverse electron-demand Diels-Alder cycloaddition with tetrazine-conjugated dyes. Genetic encoding of the new UAA inside mammalian cells and its subsequent selective labeling at low dye concentrations demonstrate the usefulness of the new amino acid for future imaging studies. PMID- 22945334 TI - Barriers to implementing WHO's exclusive breastfeeding policy for women living with HIV in sub-Saharan Africa: an exploration of ideas, interests and institutions. AB - The vertical transmission of HIV occurs when an HIV-positive woman passes the virus to her baby during pregnancy, delivery or breastfeeding. The World Health Organization's (WHO) Guidelines on HIV and infant feeding 2010 recommends exclusive breastfeeding for HIV-positive mothers in resource-limited settings. Although evidence shows that following this strategy will dramatically reduce vertical transmission of HIV, full implementation of the WHO Guidelines has been severely limited in sub-Saharan Africa. This paper provides an analysis of the role of ideas, interests and institutions in establishing barriers to the effective implementation of these guidelines by reviewing efforts to implement prevention of vertical transmission programs in various sub-Saharan countries. Findings suggest that WHO Guidelines on preventing vertical transmission of HIV through exclusive breastfeeding in resource-limited settings are not being translated into action by governments and front-line workers because of a variety of structural and ideological barriers. Identifying and understanding the role played by ideas, interests and institutions is essential to overcoming barriers to guideline implementation. PMID- 22945335 TI - DC vaccine therapy combined concurrently with oral capecitabine in metastatic colorectal cancer patients. AB - BACKGROUND/AIMS: Patients with metastatic colorectal cancer cannot receive adequate therapy due to their general bad condition, which is at least one of the reasons resulting in poor prognosis. The aim of this study was to evaluate the efficacy and safety in the use of DC vaccine combined with oral Capecitabine therapy in patients with metastatic colorectal cancer; these two methods are commonly used in colorectal cancer separately as monotherapy. METHODOLOGY: All 17 patients received Capecitabine orally twice daily at 1,250 mg/m2. One cycle included two weeks of treatment followed by one week's rest. Concurrently, all patients received 1x107 tumor lysate-pulsed DC vaccinations both intradermally and intravenously every week for 3 times. RESULTS: There was an improvement in appetite in 14/17 cases and an increase of physical strength 15/17 cases. The serum CEA level was reduced and the phenotypes of peripheral blood T lymphocytes CD3+, CD8+ and CD56+ increased significantly in all patients; 4 out of the 17 patients were DTH positive and 14 patients were alive at the end of 6 months follow-up. No server toxicity was observed. CONCLUSIONS: Lymphopenia induced by Capecitabine then followed by DC vaccine is an effective way to generate anti tumor immune response to CRC. PMID- 22945336 TI - Tumor chemosensitivity is correlated with expression of multidrug resistance associated factors in variously differentiated gastric carcinoma tissues. AB - BACKGROUND/AIMS: To evaluate the relationship between chemosensitivities in vitro and expressions of multidrug resistance (MDR) associated factors in differentiated gastric carcinomas. METHODOLOGY: Gastric carcinomas tissues of varying degree of differentiation (65 cases) were collected and chemosensitivities to 5-FU, HCPT, PTX, L-OHP, CDDP and eADM were detected by sulphorhodamine B (SRB) assay, and expressions of P-gp, GST-pi, Topo IIalpha, p53, Bcl-2, Bax and Survivin were tested by immunohistochemical staining. RESULTS: Inhibition rates of 5-FU, L-OHP and CDDP for well differentiated tumors were lower than those of poorly differentiated tumors (p<0.05). Expressions of P gp, Bcl-2 and Survivin were higher in well differentiated than in poorly differentiated carcinomas (p<0.05); while expression of Topo IIalpha in well differentiated carcinomas was lower than in poorly differentiated carcinomas (p<0.05). The expression of MDR factors was different between well and poorly differentiated carcinomas. CONCLUSIONS: Different MDR characteristics were exhibited in well and poorly differentiated gastric carcinomas, which may be caused by different expressed MDR associated factors in these tissues. PMID- 22945337 TI - Early recurrence after curative resection in oligonodular hepatocellular carcinoma. AB - BACKGROUND/AIMS: Often patients experience an unexpected early recurrence after hepatectomy for multinodular HCC. We conducted this retrospective study to observe the recurrence rate within 1 year after hepatectomy for oligonodular HCC (2 or 3 nodules) and investigate the risk factors for early recurrence. METHODOLOGY: The study population consisted of 102 patients with 2 or 3 HCCs that received curative resection between January 2009 and December 2009. Clinicopathological data were collected and subjected to univariate and multivariate analysis. RESULTS: Forty-three (42.2%) patients were diagnosed as with recurrence within 1 year after hepatectomy. According to univariate analysis, the risk factors for early recurrence were alpha-fetoprotein (AFP) >200 ng/mL, microvascular involvement and lack of complete tumor capsule; microvascular involvement was an independent predictive factor for early recurrence by multivariate analysis (HR, 4.02; 95% CI, 1.42-11.39, p=0.009). CONCLUSIONS: There was a high rate of early recurrence for patients with oligonodular HCC (2 or 3 nodules) after hepatectomy. Microvascular involvement was an independent predictive factor for early recurrence, and adjuvant therapy, such as TACE, may be considered for those patients af PMID- 22945338 TI - Hot biopsy forceps vs. endoscopic ultrasonography in determining the depth of gastric epithelial neoplasia: a simple novel method to decide whether or not to perform endoscopic submucosal dissection. AB - BACKGROUND/AIMS: It is of vital importance to determine the depth of lesions to be treated by endoscopic submucosal dissection. This study aimed to compare the accuracy of using hot biopsy forceps method with endoscopic ultrasonography for determination of the depth of gastric epithelial neoplasia. METHODOLOGY: Hot biopsy forceps method and/or endoscopic ultrasonography were used to determine the depth of lesions in 27 patients. With hot biopsy forceps method, we assumed a lesion completely lifted up by a hot biopsy forceps to be confined to the mucosal layer, and one partly lifted up to be located beyond the mucosal layer. The accuracy of hot biopsy forceps method and endoscopic ultrasonography in determining the depth of lesions were compared. RESULTS: Of the 27 patients, 25 underwent endoscopic submucosal dissection and 2 underwent surgery. The total accuracy of hot biopsy forceps method in determining the depth of lesions was 92.6% and that of endoscopic ultrasonography was 81.8%. Overestimation of hot biopsy forceps method and endoscopic ultrasonography were 3.7% vs. 13.6%, respectively. The sensitivity and the specificity of hot biopsy forceps method were 95.5% and 80.0% and those of EUS were 83.3% and 75.0%. CONCLUSIONS: Hot biopsy forceps method has a trend towards higher accuracy and lower overestimation than endoscopic ultrasonography. PMID- 22945339 TI - Mechanism and efficacy of mobilization of granulocyte colony-stimulating factor in the treatment of chronic hepatic failure. AB - BACKGROUND/AIMS: To explore the efficacy of G-CSF mobilization in the treatment of chronic liver failure (CLF) and the mechanism of its action. METHODOLOGY: The proportions of cluster-of-differentiation (CD)-34+ cells and their receptor-CXCR4 were detected by flow cytometry in patients with different types of chronic HBV infection. The levels of chemokines and cytokines were measured by enzyme-linked immunosorbent assay. RESULTS: The proportion of CD34+ cells in patients with cirrhosis was significantly increased compared with the healthy controls (p<0.05) and was increased obviously after treatment by G-CSF mobilization (p<0.01). The expression levels of SDF-1, SCF and MMP-9 were significantly elevated in patients with chronic hepatitis B and liver cirrhosis (p<0.01). The expression levels of SCF and MMP-9 were significantly elevated after treatment with G-CSF (p<0.05). No significant differences were found in the levels of total bilirubin, albumin and prothrombin time between the treated and control groups; furthermore, no significant differences were observed in the cure and improvement rates between the two groups. CONCLUSIONS: The basal levels of stem cell mobilization in patients with liver cirrhosis might be associated with the repair of liver injury. G-CSF could promote hematopoietic stem cell mobilization through regulation of the expression levels of stem-cell-mobilization-related factors in patients with liver cirrhosis. No apparent effects of G-CSF therapy on both liver function and short-term prognosis in patients with liver cirrhosis were confirmed. PMID- 22945340 TI - Enantioselective synthesis and stereoselective ring opening of N-acylaziridines. AB - Kinetic resolution of N-acylaziridines by nucleophilic ring opening was achieved with (R)-BINOL as the chiral modifier under boron-catalyzed conditions (see scheme; Ar=3,5-dinitrophenyl). The consumed enantiomer of aziridine can be further converted to an enantioenriched 1,2-chloroamide with recovery of (R) BINOL. PMID- 22945343 TI - ST-segment elevation: alert the catheterization laboratory? PMID- 22945342 TI - Pathways from depressive symptoms to low social status. AB - This research examined two pathways through which depressive symptoms contribute to low social status (i.e., neglect and rejection) within the peer group over time: (a) depressive symptoms promote socially helpless behavior and consequent neglect by peers; and (b) depressive symptoms promote aggressive behavior and consequent rejection by peers. These pathways were investigated in independent samples of youth at two developmental stages: middle childhood (2nd-4th grade) and early adolescence (5th-7th grade). In both Study 1 (M age = 7.97, SD = 0.37; 338 girls, 298 boys) and Study 2 (M age = 11.74, SD = 0.68; 305 girls, 300 boys), youth and their teachers completed questionnaires at three waves. Multi-group comparison path analyses were conducted to examine sex differences in the models. Consistent with expectations, two pathways emerged through which depressive symptoms undermined subsequent social status. Support was not found for the reverse direction of effect nor for developmental or sex differences in the pathways with one exception: In early adolescence, neglect directly predicted depressive symptoms. These findings suggest specificity but also heterogeneity in the effects of depressive symptoms on social status, and identify behaviors that may be targeted for preventing the persistence of depression and its interpersonal consequences. PMID- 22945341 TI - A complex systems approach to Arabidopsis root stem-cell niche developmental mechanisms: from molecules, to networks, to morphogenesis. AB - Recent reports have shown that the molecular mechanisms involved in root stem cell niche development in Arabidopsis thaliana are complex and contain several feedback loops and non-additive interactions that need to be analyzed using computational and formal approaches. Complex systems cannot be understood in terms of the behavior of their isolated components, but they emerge as a consequence of largely non-linear interactions among their components. The study of complex systems has provided a useful approach for the exploration of system level characteristics and behaviors of the molecular networks involved in cell differentiation and morphogenesis during development. We analyzed the complex molecular networks underlying stem-cell niche patterning in the A. thaliana root in terms of some of the key dynamic traits of complex systems: self-organization, modularity and structural properties. We use these analyses to integrate the available root stem-cell niche molecular mechanisms data and postulate novel hypotheses, missing components and interactions and explain apparent contradictions in the literature. PMID- 22945344 TI - Health-related quality of life and depression in patients with dentofacial deformity. AB - INTRODUCTION: Patients with dentofacial deformities present difficulties at work and in social adaptation. At the same time, they often appear depressed, and as a consequence, the psychosocial aspects of surgery play an important role. The aim of this study was to investigate the effects that depression causes in the quality of life of patients with dentofacial deformity. MATERIAL AND METHODS: Filthy patients were recruited 1 year before undergoing orthognathic surgery and correlated oral and general health with the presence and absence of depression. In order to accomplish this, these patients received an adapted questionnaires of quality of life and Beck Depression Inventory to fill out. Fisher's test was applied, with a significance level of 5 %. Intercooled Stata version 9.0 was used to analyze data. RESULTS: Among the eight domains of quality of life, there were three associated with depression status: vitality (p < 0.001), social aspects (p = 0.011), and mental health (p = 0.008). DISCUSSION: There is growing interest in the impact of dentofacial deformity conditions on patients' quality of life. The scientific literature has discussed the social aspects of these deformities and showed that untreated patients had low self-esteem and suffered social restrictions before making the orthodontic and surgical treatments. This study concluded that the depression interferes significantly in vitality, social aspects of the individual, and mental health and, at the same time, emphasizes that the orthognathic surgery aims to not only restore esthetics and function to the patient but also improve the quality of life. PMID- 22945345 TI - Closure of anterior open bites with mandibular surgery: advantages and disadvantages of this approach. AB - INTRODUCTION: While closure of an anterior open bite with a mandibular procedure may predispose a surgical case to instability, there are instances where this type of treatment planning is indicated. METHODS AND MATERIALS: In this paper, the authors review the advantages and disadvantages of this approach and present three cases with varying degrees of success. Additionally, treatment strategies are presented for managing large advancements of the maxilla and mandible. RESULTS AND SUMMARY: Counterclockwise rotation of the mandible is a valuable tool that can be used in the treatment of patients with dentofacial deformities. PMID- 22945346 TI - Fabrication of positively charged poly(ethylene glycol)-diacrylate hydrogel as a bone tissue engineering scaffold. AB - To improve cell attachment and to understand the effects of positive charge on the behavior of osteoblasts, 2-(methacryloyloxy)ethyl-trimethylammonium chloride (MAETAC), a positively charged monomer, was incorporated into poly(ethylene glycol)-diacrylate (PEGDA) hydrogel. The physicochemical properties of the resultant polymers, including the degree of acrylation of PEGDA, pKa of MAETAC, swelling ratio, zeta potential, and protein adsorption were investigated. Meanwhile, osteoblast-like MC3T3-E1 cells were seeded on the hydrogel to evaluate the effect of the positive charge on the behavior of the cells, including attachment, proliferation, and differentiation. The results revealed that PEGDA was synthesized with 90 percent of acrylation and MAETAC had been successfully incorporated into PEGDA. The pKa value of MAETAC was 9.4 determined by acid-based titration. The electrically charged nature of modified hydrogels was confirmed by zeta potential. With increasing concentration of MAETAC, the swelling ratio of the hydrogel in deionized water increased, while the swelling ratio stayed constant in phosphate buffer solution. The protein adsorption of the hydrogel also increased with increasing concentration of MAETAC. The modification of positive charge not only enhanced the attachment and proliferation of osteoblast like MC3T3-E1 cells on the hydrogel, but also up-regulated alkaline phosphatase activity in the cells as well as gene expression of focal adhesion kinase and osteogenic markers, including collagen I, osteopontin, and osteocalcin. These findings indicate that the positively charged PEGDA may not only be a promising scaffold candidate for bone tissue engineering, but also a good platform to study the effect of positive charge on cell behavior due to the controllable charge density. PMID- 22945347 TI - Can the informant fluctuation composite score help in the diagnosis of synucleinopathies? A pragmatic study. PMID- 22945348 TI - Antipsychotic prescribing in dementia patients in care homes: proactive in-reach service improved quality of care. PMID- 22945350 TI - Comparative analyses of three legume species reveals conserved and unique root extracellular proteins. AB - Increasing evidence suggests that root extracellular proteins are involved in interactions between roots and their soil environment. In the present study, exudates released by 6-day-old roots of the three legume species white lupin (Lupinus albus), soybean (Glycine max), and cowpea (Vigna sinensis) were collected under axenic conditions, and their constitutively secreted proteomes were analyzed. Between 42 and 93 unique root extracellular proteins with 2 or more different peptide fragments per protein were identified by LC-MS/MS. Functional annotation of these proteins classified them into 14-16 different functional categories. Among those 14 homologous proteins were identified in at least two legume species. Among the unique proteins, 58 in white lupin, 85 in soybean, and 31 in cowpea were specific for each plant species, and many of them were classified in the same functional categories. Interestingly, in contrast to soybean and cowpea, two protein bands of approximately 16 and 30 kDa were present on the SDS-PAGE gel of white lupin. The identification of these bands revealed a class III chitinase and a thaumatin-like protein. Both belong to the class of pathogenesis-related proteins. The results imply that root extracellular proteins play important roles in the cross-talk between plant roots and the rhizosphere. PMID- 22945349 TI - Epithelial fusion during neural tube morphogenesis. AB - Adhesion and fusion of epithelial sheets marks the completion of many morphogenetic events during embryogenesis. Neural tube closure involves an epithelial fusion sequence in which the apposing neural folds adhere initially via cellular protrusions, proceed to a more stable union, and subsequently undergo remodeling of the epithelial structures to yield a separate neural tube roof plate and overlying nonneural ectoderm. Cellular protrusions comprise lamellipodia and filopodia, and studies in several different systems emphasize the critical role of RhoGTPases in their regulation. How epithelia establish initial adhesion is poorly understood but, in neurulation, may involve interactions between EphA receptors and their ephrinA ligands. Epithelial remodeling is spatially and temporally correlated with apoptosis in the dorsal neural tube midline, but experimental inhibition of this cell death does not prevent fusion and remodeling. A variety of molecular signaling systems have been implicated in the late events of morphogenesis, but genetic redundancy, for example among the integrins and laminins, makes identification of the critical players challenging. An improved understanding of epithelial fusion can provide insights into normal developmental processes and may also indicate the mode of origin of clinically important birth defects. PMID- 22945351 TI - PKR stirs up inflammasomes. AB - Inflammasomes are multiprotein complexes that detect and respond to foreign and endogenous danger signals by activating caspase-1; active caspase-1, in turn, matures the pro-inflammatory IL-1beta family cytokines by cleaving their pro forms into the biologically active cytokines. The upstream mechanisms leading to inflammasome activation, in particular for the NRLP3 inflammasome, remain poorly understood. Lu and colleagues identify a new function of Protein Kinase R (PKR) for activating the NLRP1, NLRP3, NLRC4 and AIM2 inflammasomes, thus identifying a potential new target for treating inflammasome-mediated diseases. PMID- 22945352 TI - Structural insights into SUN-KASH complexes across the nuclear envelope. AB - Linker of the nucleoskeleton and the cytoskeleton (LINC) complexes are composed of SUN and KASH domain-containing proteins and bridge the inner and outer membranes of the nuclear envelope. LINC complexes play critical roles in nuclear positioning, cell polarization and cellular stiffness. Previously, we reported the homotrimeric structure of human SUN2. We have now determined the crystal structure of the human SUN2-KASH complex. In the complex structure, the SUN domain homotrimer binds to three independent "hook"-like KASH peptides. The overall conformation of the SUN domain in the complex closely resembles the SUN domain in its apo state. A major conformational change involves the AA'-loop of KASH-bound SUN domain, which rearranges to form a mini beta-sheet that interacts with the KASH peptide. The PPPT motif of the KASH domain fits tightly into a hydrophobic pocket on the homotrimeric interface of the SUN domain, which we termed the BI-pocket. Moreover, two adjacent protomers of the SUN domain homotrimer sandwich the KASH domain by hydrophobic interaction and hydrogen bonding. Mutations of these binding sites disrupt or reduce the association between the SUN and KASH domains in vitro. In addition, transfection of wild type, but not mutant, SUN2 promotes cell migration in Ovcar-3 cells. These results provide a structural model of the LINC complex, which is essential for additional study of the physical and functional coupling between the cytoplasm and the nucleoplasm. PMID- 22945353 TI - Recognition of methylated DNA by TAL effectors. PMID- 22945354 TI - The double-edged sword of CRISPR-Cas systems. AB - A recent paper gives the details on how specific small RNAs can program a protein to cleave an undesired piece of DNA and to provide immunity to a microbial cell. PMID- 22945355 TI - AP2gamma regulates neural and epidermal development downstream of the BMP pathway at early stages of ectodermal patterning. AB - Bone morphogenetic protein (BMP) inhibits neural specification and induces epidermal differentiation during ectodermal patterning. However, the mechanism of this process is not well understood. Here we show that AP2gamma, a transcription factor activator protein (AP)-2 family member, is upregulated by BMP4 during neural differentiation of pluripotent stem cells. Knockdown of AP2gamma facilitates mouse embryonic stem cell (ESC) neural fate determination and impairs epidermal differentiation, whereas AP2gamma overexpression inhibits neural conversion and promotes epidermal commitment. In the early chick embryo, AP2gamma is expressed in the entire epiblast before HH stage 3 and gradually shifts to the putative epidermal ectoderm during HH stage 4. In the future neural plate AP2gamma inhibits excessive neural expansion and it also promotes epidermal development in the surface ectoderm. Moreover, AP2gamma knockdown in ESCs and chick embryos partially rescued the neural inhibition and epidermal induction effects of BMP4. Mechanistic studies showed that BMP4 directly regulates AP2gamma expression through Smad1 binding to the AP2gamma promoter. Taken together, we propose that during the early stages of ectodermal patterning in the chick embryo, AP2gamma acts downstream of the BMP pathway to restrict precocious neural expansion in the prospective neural plate and initiates epidermal differentiation in the future epidermal ectoderm. PMID- 22945356 TI - Coxsackievirus mutants that can bypass host factor PI4KIIIbeta and the need for high levels of PI4P lipids for replication. AB - RNA viruses can rapidly mutate and acquire resistance to drugs that directly target viral enzymes, which poses serious problems in a clinical context. Therefore, there is a growing interest in the development of antiviral drugs that target host factors critical for viral replication, since they are unlikely to mutate in response to therapy. We recently demonstrated that phosphatidylinositol 4-kinase IIIbeta (PI4KIIIbeta) and its product phosphatidylinositol-4-phosphate (PI4P) are essential for replication of enteroviruses, a group of medically important RNA viruses including poliovirus (PV), coxsackievirus, rhinovirus, and enterovirus 71. Here, we show that enviroxime and GW5074 decreased PI4P levels at the Golgi complex by directly inhibiting PI4KIIIbeta. Coxsackievirus mutants resistant to these inhibitors harbor single point mutations in the non-structural protein 3A. These 3A mutations did not confer compound-resistance by restoring the activity of PI4KIIIbeta in the presence of the compounds. Instead, replication of the mutant viruses no longer depended on PI4KIIIbeta, since their replication was insensitive to siRNA-mediated depletion of PI4KIIIbeta. The mutant viruses also did not rely on other isoforms of PI4K. Consistently, no high level of PI4P could be detected at the replication sites induced by the mutant viruses in the presence of the compounds. Collectively, these findings indicate that through specific single point mutations in 3A, CVB3 can bypass an essential host factor and lipid for its propagation, which is a new example of RNA viruses acquiring resistance against antiviral compounds, even when they directly target host factors. PMID- 22945358 TI - Microenvironment-mediated resistance to anticancer therapies. AB - Resistance to molecularly targeted therapies can result from genomic alterations in the tumor cells that reactivate oncogenic signaling. Less is known of tumor cell-extrinsic mechanisms of resistance to targeted therapies. Two recent studies have identified HGF as a soluble factor capable of mediating resistance to BRAF and HER2 inhibitors in a paracrine manner. These new findings suggest an important role for the tumor microenvironment in mediating resistance to molecularly targeted therapies. PMID- 22945357 TI - Activated mouse CD4(+)Foxp3(-) T cells facilitate melanoma metastasis via Qa-1 dependent suppression of NK-cell cytotoxicity. AB - The regulatory activities of mouse CD4(+)Foxp3(+) T cells on various immune cells, including NK cells, have been well documented. Under some conditions, conventional CD4(+)Foxp3(-) T cells in the periphery are able to acquire inhibitory function on other T cells, but their roles in controlling innate immune cells are poorly defined. As a potential cellular therapy for cancer, ex vivo activated CD4(+)Foxp3(-) effector T cells are often infused back in vivo to suppress tumor growth and metastasis. Whether such activated T cells could affect NK-cell control of tumorigenesis is unclear. In the present study, we found that mitogen-activated CD4(+)Foxp3(-) T cells exhibited potent suppressor function on NK-cell proliferation and cytotoxicity in vitro, and notably facilitated B16 melanoma metastasis in vivo. Suppression of NK cells by activated CD4(+)Foxp3(-) T cells is cell-cell contact dependent and is mediated by Qa-1:NKG2A interaction, as administration of antibodies blocking either Qa-1 or NKG2A could completely reverse this suppression, and significantly inhibited otherwise facilitated melanoma metastasis. Moreover, activated CD4(+)Foxp3(-) cells from Qa-1 knockout mice completely lost the suppressor activity on NK cells, and failed to facilitate melanoma metastasis when transferred in vivo. Taken together, our findings indicate that innate anti-tumor response is counter regulated by the activation of adaptive immunity, a phenomenon we term as "activation-induced inhibition". Thus, the regulatory role of activated CD4(+)Foxp3(-) T cells in NK cell activity must be taken into consideration in the future design of cancer therapies. PMID- 22945359 TI - A prospective study of autistic-like traits in unaffected siblings of probands with autism spectrum disorder. AB - CONTEXT: The presence of autistic-like traits in relatives of individuals with autism spectrum disorder (ASD) is well recognized, but, to our knowledge, the emergence of these traits early in development has not been studied. OBJECTIVE: To prospectively investigate the emergence of autistic-like traits in unaffected (no ASD diagnosis) infant siblings of probands diagnosed as having ASD. DESIGN: Two groups of children unaffected with ASD were assessed prospectively-siblings of probands diagnosed as having ASD (high risk [HR]) and control subjects with no family history of ASD (low risk [LR]). Scores on a measure of autistic-like traits at 12 months of age were used in a cluster analysis of the entire sample. SETTING: A prospective study of infant siblings of probands with ASD from 3 diagnostic centers in Canada. PARTICIPANTS: The study included 170 HR and 90 LR children, none of whom was diagnosed as having ASD at age 3 years. MAIN OUTCOME MEASURES: The Autism Observation Scale for Infants was used to measure autistic like traits and derive clusters at 12 months of age. Clusters were compared on ASD symptoms, cognitive abilities, and social-emotional difficulties at age 3 years. RESULTS: Two clusters were identified. Cluster 1 (n = 37; 14.2% of total sample) had significantly higher levels of autistic-like traits compared with cluster 2. Within cluster 1, 33 children came from the siblings (19.4% of HR group) and only 4 came from the control subjects (4.5% of LR group). At age 3 years, children from cluster 1 had more social-communication impairment (effect size > 0.70; P < .001), lower cognitive abilities (effect size = -0.59; P < .005), and more internalizing problems (effect size = 0.55; P = .01). Compared with control subjects, HR siblings had a relative risk of 4.3 (95% CI,1.6-11.9) for membership in cluster 1. CONCLUSIONS: Study findings suggest the emergence of autistic-like traits resembling a broader autism phenotype by 12 months of age in approximately 19% of HR siblings who did not meet ASD diagnostic criteria at age 3 years. PMID- 22945361 TI - Bone: proton-pump inhibitors and fractures. PMID- 22945362 TI - Endocrine disorders in pregnancy: excessive maternal weight increases risk of infant overgrowth. PMID- 22945360 TI - GLP-1 receptor agonists for individualized treatment of type 2 diabetes mellitus. AB - In healthy humans, the incretin glucagon-like peptide 1 (GLP-1) is secreted after eating and lowers glucose concentrations by augmenting insulin secretion and suppressing glucagon release. Additional effects of GLP-1 include retardation of gastric emptying, suppression of appetite and, potentially, inhibition of beta cell apoptosis. Native GLP-1 is degraded within ~2-3 min in the circulation; various GLP-1 receptor agonists have, therefore, been developed to provide prolonged in vivo actions. These GLP-1 receptor agonists can be categorized as either short-acting compounds, which provide short-lived receptor activation (such as exenatide and lixisenatide) or as long-acting compounds (for example albiglutide, dulaglutide, exenatide long-acting release, and liraglutide), which activate the GLP-1 receptor continuously at their recommended dose. The pharmacokinetic differences between these drugs lead to important differences in their pharmacodynamic profiles. The short-acting GLP-1 receptor agonists primarily lower postprandial blood glucose levels through inhibition of gastric emptying, whereas the long-acting compounds have a stronger effect on fasting glucose levels, which is mediated predominantly through their insulinotropic and glucagonostatic actions. The adverse effect profiles of these compounds also differ. The individual properties of the various GLP-1 receptor agonists might enable incretin-based treatment of type 2 diabetes mellitus to be tailored to the needs of each patient. PMID- 22945363 TI - Obesity: Screening for the evident in obesity. PMID- 22945364 TI - The Botrytis cinerea type III polyketide synthase shows unprecedented high catalytic efficiency toward long chain acyl-CoAs. AB - BPKS from Botrytis cinerea is a novel type III polyketide synthase that accepts C(4)-C(18) aliphatic acyl-CoAs and benzoyl-CoA as the starters to form pyrones, resorcylic acids and resorcinols through sequential condensation with malonyl CoA. The catalytic efficiency (k(cat)/K(m)) of BPKS was 2.8 * 10(5) s(-1) M(-1) for palmitoyl-CoA, the highest ever reported. Substrate docking analyses addressed the unique features of BPKS such as its high activity and high specificity toward long chain acyl-CoAs. PMID- 22945366 TI - Risk factors for mental disorder among university students in Australia: findings from a web-based cross-sectional survey. AB - PURPOSE: To identify variables associated with common mental disorders in an Australian university population. METHODS: We invited all Australia-based students from a large public university (N = 24,209) to participate in a web based student mental health survey. Outcome measures included the patient health questionnaire depression, anxiety, and eating disorders modules, and the alcohol use disorders identification test. Explanatory variables of interest included gender, age, year of study, degree type, financial means, parental education, domestic/international status, and sexual orientation. Multiple logistic regression analysis was used to estimate independent associations with the four outcomes. RESULTS: Complete responses were received from 6,044 students (25 %). Proportions reporting depression, anxiety, eating disorders, and harmful drinking were 8, 13, 14, and 8 %, respectively, while 30 % had at least one of these disorders. The groups with the highest rates of disorder were women, 25-34-year olds, students on low income, and homosexual or bisexual students. Parental education was not associated with disorder, nor was international/domestic status. CONCLUSION: This is the first study examining mental disorders in a population-based sample of university students in Australia. Given increasing student numbers and participation of students from lower socio-economic backgrounds, policy is urgently needed to promote better mental health in this population, to routinely identify vulnerable students, and to intervene early. Groups in particular need are women, students on low incomes, and homosexual or bisexual students. PMID- 22945367 TI - Predictors of outcomes for users of mental health rehabilitation services: a 5 year retrospective cohort study in inner London, UK. AB - OBJECTIVE: There have been few recent studies reporting on the outcomes for users of psychiatric rehabilitation services. This group has complex, longer-term mental health problems. We aimed to investigate 5-year outcomes for this group and identify factors associated with outcome. METHOD: Clinical outcome data on 141 users of a mental health rehabilitation service in inner London, UK, surveyed in 2005, were collected retrospectively 5 years later. Positive outcome was defined for those who were inpatients in 2005 as achieving and sustaining community discharge, and for those who were community patients, as progressing to and sustaining a less supported community placement. Negative outcome was defined as remaining in the same placement, moving to more supported placement or having a psychiatric admission. RESULTS: Over 5 years, 17 (12 %) people died, 50 (40 %) had a positive outcome, 33 (27 %) remained in a placement with a similar level of support and 41 (38 %) moved to a more supported placement and/or had a psychiatric admission. Thirteen (10 %) people moved to independent accommodation and sustained their tenancy successfully. Those with a record of non-adherence with medication during the 5 years were more likely to have a negative outcome (OR 8.60, 95 % CI 3.41 to 21.70). CONCLUSION: Adherence to medication is an important factor in facilitating successful community discharge for people with complex mental health problems who require psychiatric rehabilitation. PMID- 22945365 TI - A review of calibrated blood oxygenation level-dependent (BOLD) methods for the measurement of task-induced changes in brain oxygen metabolism. AB - The dynamics of the blood oxygenation level-dependent (BOLD) response are dependent on changes in cerebral blood flow, cerebral blood volume and the cerebral metabolic rate of oxygen consumption. Furthermore, the amplitude of the response is dependent on the baseline physiological state, defined by the haematocrit, oxygen extraction fraction and cerebral blood volume. As a result of this complex dependence, the accurate interpretation of BOLD data and robust intersubject comparisons when the baseline physiology is varied are difficult. The calibrated BOLD technique was developed to address these issues. However, the methodology is complex and its full promise has not yet been realised. In this review, the theoretical underpinnings of calibrated BOLD, and issues regarding this theory that are still to be resolved, are discussed. Important aspects of practical implementation are reviewed and reported applications of this methodology are presented. PMID- 22945368 TI - Impact of right ventricular endocardial trabeculae on volumes and function assessed by CMR in patients with tetralogy of Fallot. AB - The objective of this study was to assess the impact of right ventricular (RV) trabeculae and papillary muscles on measured volumes and function assessed by cardiovascular magnetic resonance imaging in patients with repaired tetralogy of Fallot. Sixty-five patients with repaired tetralogy of Fallot underwent routine cardiovascular magnetic resonance imaging. Endocardial and epicardial contours were drawn manually and included trabeculae and papillary muscles in the blood volume. Semi-automatic threshold-based segmentation software excluded these structures. Both methods were compared in terms of end-diastolic, end-systolic and stroke volume, ejection fraction and mass. Observer agreement was determined for all measures. Exclusion of trabeculae and papillary muscle in the RV blood volume decreased measured RV end-diastolic volume by 15 % (from 140 +/- 35 to 120 +/- 32 ml/m(2)) compared to inclusion, end-systolic volume by 21 % (from 74 +/- 23 to 59 +/- 20 ml/m(2)), stroke volume by 9 % (from 66 +/- 16 to 60 +/- 16 ml/m(2)) and relatively increased ejection fraction by 7 % (from 48 +/- 7 to 51 +/- 8 %) and end-diastolic mass by 79 % (from 28 +/- 7 to 51 +/- 10 g/m(2)), p < .01. Excluding trabeculae and papillary muscle resulted in an improved interobserver agreement of RV mass compared to including these structures (coefficient of agreement of 87 versus 78 %, p < .01). Trabeculae and papillary muscle significantly affect measured RV volumes, function and mass. Semi automatic threshold-based segmentation software can reliably exclude trabeculae and papillary muscles from the RV blood volume. PMID- 22945369 TI - Snail-dependent repression of the RhoGEF pebble is required for gastrulation consistency in Drosophila melanogaster. AB - The Rho GTP exchange factor, Pebble (Pbl), long recognised as an essential activator of Rho during cytokinesis, also regulates mesoderm migration at gastrulation. Like other cell cycle components, pbl expression patterns broadly correlate with proliferative tissue. Surprisingly, in spite of its role in the early mesoderm, pbl is downregulated in the presumptive mesoderm before ventral furrow formation. Here, we show that this mesoderm-specific repression of pbl is dependent on the transcriptional repressor Snail (Sna). pbl repression was lost in sna mutants but was unaffected when Sna was ectopically expressed, showing that Sna is necessary, but not sufficient, for pbl repression. Using DamID, the first intron of pbl was identified as a Sna-binding region. Nine sites with the Sna-binding consensus motif CAGGT[GA] were identified in this intron. Mutating these to TAGGC[GA] abolished the ventral repression of pbl. Surprisingly, Sna dependent repression of pbl was not essential for viability or fertility. Loss of repression did, however, increase the frequency of low-penetrance gastrulation defects. Consistent with this, expression of a pbl-GFP transgene in the presumptive mesoderm generated similar gastrulation defects. Finally, we show that a cluster of Snail-binding sites in the middle of the first intron of pbl orthologues is a conserved feature in the other 11 sequenced Drosophila species. We conclude that pbl levels are precisely regulated to ensure that there is enough protein available for its role in early mesoderm development but not so much as to inhibit the orderly progression of gastrulation. PMID- 22945370 TI - Mode-mode coupling theory of itinerant electron antiferromagnetism in superconducting state. AB - It has been considered since the first discovery of a high-T(c) cuprate that an antiferromagnetic (AF) state and a superconducting (SC) state are separated in it. However, it is very intriguing that the coexistence of the AF and SC states has recently been observed in HgBa(2)Ca(4)Cu(5)O(12+) (Hg-1245). Moreover, it is very novel that this coexistence of these two states appears if the SC-transition temperature T(c) is higher than the AF-transition temperature T(N). The mode-mode coupling theory can provide a clear elucidation of this novel phenomenon. A key point of this theory is that the AF susceptibility consists of the random-phase approximation (RPA) term and the mode-mode coupling one. The RPA term works to make a positive contribution to the emergence of the antiferromagnetic critical point (AF-CP). In contrast, the mode-mode coupling term works to make a negative contribution to the emergence of the AF-CP. However, the growth of the SC-gap function in the d(x(2)-y(2))-wave SC state works to suppress the negative contribution of the mode-mode coupling term to the emergence of the AF-CP. Moreover, the effect of SC fluctuations near the SC-transition temperature T(c) suppresses the mode-mode coupling term of the AF susceptibility that works to hinder the AF ordering. For these two reasons, there is a possibility that the d(x(2)-y(2))-wave SC state is likely to promote the emergence of the AF-CP. Namely, the appearance of the above-mentioned novel coexistence of the AF and SC states observed in Hg-1245 can be explained qualitatively on the basis of this idea. PMID- 22945371 TI - Regional differences in serotonin content in the nucleus of the solitary tract of male rats after hypovolemia produced by polyethylene glycol. AB - Serotonin (5-HT) has been implicated in centrally mediated compensatory responses to volume loss in rats. Accordingly, we hypothesized that slowly developing, non hypotensive hypovolemia increases serotonin in the hindbrain nucleus of the solitary tract (NTS). We produced volume loss in adult male rats by administering hyperoncotic polyethylene glycol (PEG) and then assessed 5-HT levels in the NTS using measurements of tissue 5-HT content or 5-HT immunohistochemistry. The results show selective increases of 5-HT in the caudal NTS after PEG treatment, but no change in the primary 5-HT metabolite, 5-HIAA. Moreover, the intensity of 5-HT immunolabeled fibers in the caudal NTS was increased after PEG treatment. These findings suggest that, after PEG-induced hypovolemia, 5-HT accumulates in neural elements in the caudal NTS. We propose that this accumulation is attributable to an initial release of 5-HT that then acts at presynaptic autoreceptors to inhibit subsequent 5-HT release. PMID- 22945373 TI - Metal-organic frameworks constructed from flexible V-shaped ligands: adjustment of the topology, interpenetration and porosity via a solvent system. AB - Three new metal-organic frameworks (MOFs) are designed by the assembly of flexible V-shaped ligands and paddle-wheel second building units (SBUs). The topology, interpenetration numbers and porosity of frameworks have been well controlled by a solvent system. PMID- 22945372 TI - Reproducibility of functional volume and activity concentration in 18F-FDG PET/CT of liver metastases in colorectal cancer. AB - PURPOSE: Several studies showed potential for monitoring response to systemic therapy in metastatic colorectal cancer patients with (18)F-fluorodeoxyglucose (FDG) positron emission tomography (PET). Before (18)F-FDG PET can be implemented for response evaluation the repeatability should be known. This study was performed to assess the magnitude of the changes in standardized uptake value (SUV), volume and total lesion glycolysis (TLG) in colorectal liver metastases and validate the biological basis of (18)F-FDG PET in colorectal liver metastases. METHODS: Twenty patients scheduled for liver metastasectomy underwent two (18)F-FDG PET scans within 1 week. Bland-Altman analysis was performed to assess repeatability of SUV(max), SUV(mean), volume and TLG. Tumours were delineated using an adaptive threshold method (PET(SBR)) and a semiautomatic fuzzy locally adaptive Bayesian (FLAB) delineation method. RESULTS: Coefficient of repeatability of SUV(max) and SUV(mean) were ~39 and ~31 %, respectively, independent of the delineation method used and image reconstruction parameters. However, repeatability was worse in recently treated patients. The FLAB delineation method improved the repeatability of the volume and TLG measurements compared to PET(SBR), from coefficients of repeatability of over 85 % to 45 % and 57 % for volume and TLG, respectively. Glucose transporter 1 (GLUT1) expression correlated to the SUV(mean). Vascularity (CD34 expression) and tumour hypoxia (carbonic anhydrase IX expression) did not correlate with (18)F-FDG PET parameters. CONCLUSION: In conclusion, repeatability of SUV(mean) and SUV(max) was mainly affected by preceding systemic therapy. The repeatability of tumour volume and TLG could be improved using more advanced and robust delineation approaches such as FLAB, which is recommended when (18)F-FDG PET is utilized for volume or TLG measurements. Improvement of repeatability of PET measurements, for instance by dynamic PET scanning protocols, is probably necessary to effectively use PET for early response monitoring. PMID- 22945375 TI - Transition-metal complexes of tetrylones [(CO)5W-E(PPh3)2] and tetrylenes [(CO)5W NHE] (E=C-Pb): a theoretical study. AB - Quantum chemical calculations at the BP86/TZVPP//BP86/SVP level are performed for the tetrylone complexes [W(CO)(5) -E(PPh(3))(2)] (W-1 E) and the tetrylene complexes [W(CO)(5)-NHE] (W-2 E) with E=C-Pb. The bonding is analyzed using charge and energy decomposition methods. The carbone ligand C(PPh(3) ) is bonded head-on to the metal in W-1 C, but the tetrylone ligands E(PPh(3))(2) are bonded side-on in the heavier homologues W-1 Si to W-1 Pb. The W-E bond dissociation energies (BDEs) increase from the lighter to the heavier homologues (W-1 C: D(e) =25.1 kcal mol(-1); W-1 Pb: D(e) =44.6 kcal mol(-1)). The W(CO)(5) <-C(PPh(3))(2) donation in W-1 C comes from the sigma lone-pair orbital of C(PPh(3))(2), whereas the W(CO)(5) <-E(PPh(3))(2) donation in the side-on bonded complexes with E=Si-Pb arises from the pi lone-pair orbital of E(PPh(3))(2) (the HOMO of the free ligand). The pi-HOMO energy level rises continuously for the heavier homologues, and the hybridization has greater p character, making the heavier tetrylones stronger donors than the lighter systems, because tetrylones have two lone-pair orbitals available for donation. Energy decomposition analysis (EDA) in conjunction with natural orbital for chemical valence (NOCV) suggests that the W E BDE trend in W-1 E comes from the increase in W(CO)(5) <-E(PPh(3))(2) donation and from stronger electrostatic attraction, and that the E(PPh(3))(2) ligands are strong sigma-donors and weak pi-donors. The NHE ligands in the W-2 E complexes are bonded end-on for E=C, Si, and Ge, but side-on for E=Sn and Pb. The W-E BDE trend is opposite to that of the W-1 E complexes. The NHE ligands are strong sigma-donors and weak pi-acceptors. The observed trend arises because the hybridization of the donor orbital at atom E in W-2 E has much greater s character than that in W-1 E, and even increases for heavier atoms, because the tetrylenes have only one lone-pair orbital available for donation. In addition, the W-E bonds of the heavier systems W-2 E are strongly polarized toward atom E, so the electrostatic attraction with the tungsten atom is weak. The BDEs calculated for the W-E bonds in W-1 E, W-2 E and the less bulky tetrylone complexes [W(CO)(5) -E(PH(3))(2)] (W-3 E) show that the effect of bulky ligands may obscure the intrinsic W-E bond strength. PMID- 22945374 TI - Inhibitors of vacuolar ATPase proton pumps inhibit human prostate cancer cell invasion and prostate-specific antigen expression and secretion. AB - Vacuolar ATPases (V-ATPases) comprise specialized and ubiquitously distributed pumps that acidify intracellular compartments and energize membranes. To gain new insights into the roles of V-ATPases in prostate cancer (PCa), we studied the effects of inhibiting V-ATPase pumps in androgen-dependent (LNCaP) and androgen independent (C4-2B) cells of a human PCa progression model. Treatment with nanomolar concentrations of the V-ATPase inhibitors bafilomycin A or concanamycin A reduced the in vitro invasion in both cell types by 80%, regardless that V ATPase was prominent at the plasma membrane of C4-2B cells and only traces were detected in the low-metastatic LNCaP parental cells. In both cell types, intracellular V-ATPase was excessive and co-localized with prostate-specific antigen (PSA) in the Golgi compartment. V-ATPase inhibitors reversibly excluded PSA from the Golgi and led to the accumulation of largely dispersed PSA-loaded vesicles of lysosomal composition. Inhibition of acridine orange staining and transferrin receptor recycling suggested defective endosomal and lysosomal acidification. The inhibitors, additionally, interfered with the AR-PSA axis under conditions that reduced invasion. Bafilomycin A significantly reduced steady-state and R1881-induced PSA mRNA expression and secretion in the LNCaP cells which are androgen-dependent, but not in the C4-2B cells which are androgen ablation-resistant. In the C4-2B cells, an increased susceptibility to V-ATPase inhibitors was detected after longer treatments, as proliferation was reduced and reversibility of bafilomycin-induced responses impaired. These findings make V ATPases attractive targets against early and advanced PCa tumors. PMID- 22945376 TI - Structural investigations on the anti-HIV G-quadruplex-forming oligonucleotide TGGGAG and its analogues: evidence for the presence of an A-tetrad. AB - Several anti-HIV aptamers adopt DNA quadruplex structures. Among these, "Hotoda's aptamer" (base sequence TGGGAG) was one of the first to be discovered. Although it has been the topic of some recent research, no detailed structural investigations have been reported. Here we report structural investigations on this aptamer and analogues with related sequences, by using UV, CD, and NMR spectroscopy as well as electrophoretic techniques. The addition of a 3'-end thymine has allowed us to obtain a single, investigable quadruplex structure. Data clearly point to the presence of an A-tetrad. Furthermore, the effects of the incorporation of an 8-methyl-2'-deoxyguanosine at the 5'-end of the G-run were investigated. PMID- 22945377 TI - Convergent solid-phase synthesis of N-glycopeptides facilitated by pseudoprolines at consensus-sequence Ser/Thr residues. PMID- 22945378 TI - Morphological differences of tissue characteristics between early, late, and very late restenosis lesions after first generation drug-eluting stent implantation: an optical coherence tomography study. AB - AIMS: Restenosis of drug-eluting stents (DESs) might be different from that of bare metal stent restenosis in diverse ways including mechanisms and time course; however, these have not been fully examined. To gain insight into the mechanisms and time course of DES restenosis, we evaluated the characteristics of restenotic lesions of first generation DES using optical coherence tomography (OCT). METHODS AND RESULTS: We compared the morphological characteristics of early in-stent restenosis (<1 year: E-ISR, n = 43), late ISR (1-3 years: L-ISR, n = 22), and very late ISR (>3 years: VL-ISR, n = 21). OCT qualitative restenotic tissue analysis included the assessment of tissue structure [homogeneous or four types of heterogeneous intima (thin-cap fibroatheroma (TCFA)-like, layered, patchy or speckled pattern)], the presence of the peri-strut low intensity area (PLIA), microvessels, disruption with cavity, and intraluminal material and was performed at every 1 mm slice of the entire stent length. In addition to a greater trend for heterogeneous intima at the later phase, TCFA-like pattern image, intra intima microvessels were increased from the early to the very late phase. On the other hand, the speckled pattern image was decreased from the early to the very late phase. CONCLUSION: The OCT morphological characteristics of DES restenotic tissue varied at different time-points. OCT images in early DES ISR might be associated with delayed arterial healing, and neoatherosclerosis might contribute to late catch-up phenomenon (L-ISR and VL-ISR) after DES implantation. PMID- 22945379 TI - Staphylococcus aureus Bacteriuria: Source, Clinical Relevance, and Management. AB - Staphylococcus aureus bacteriuria is a common condition with still largely undetermined clinical relevance. Although S. aureus bacteriuria can be secondary to bacteremia and systemic infection in some patients, it may predispose to bacteremia and invasive disease in others. Whereas most patients with S. aureus bacteriuria do not have symptomatic urinary tract infection, it is reportedly associated with endocarditis and other types of invasive diseases, thereby resulting in major morbidity and occasional mortality. This review summarizes and analyzes the results of previous reports of S. aureus bacteriuria and assesses the clinical relevance and management of this increasingly recognized entity. PMID- 22945380 TI - Breast cancer management and outcome according to surgeon's affiliation: a population-based comparison adjusted for patient's selection bias. AB - BACKGROUND: Studies have reported that breast cancer (BC) units could increase the quality of care but none has evaluated the efficacy of alternative options such as private BC networks, which is our study objective. PATIENTS AND METHODS: We included all 1404 BC patients operated in the public unit or the private network and recorded at the Geneva Cancer Registry between 2000 and 2005. We compared quality indicators of care between the public BC unit and the private BC network by logistic regression and evaluated the effect of surgeon's affiliation on BC-specific mortality by the Cox model adjusting for the propensity score. RESULTS: Both the groups had high care quality scores. For invasive cancer, histological assessment before surgery and axillary lymph node dissection when indicated were less frequent in the public sector (adjusted odds ratio (OR): 0.4, 95% confidence interval (CI) 0.3-0.7, and OR: 0.4, 95% CI 0.2-0.8, respectively), while radiation therapy after breast-conserving surgery was more frequent (OR: 2.5, 95% CI 1.4-4.8). Surgeon affiliation had no substantial effect on BC specific mortality (adjusted hazard ratio (HR): 0.8, 95% CI 0.5-1.4). CONCLUSIONS: This study suggests that private BC networks could be an alternative to public BC units with both structures presenting high quality indicators of BC care and similar BC-specific mortality. PMID- 22945381 TI - Conservative management of early-stage epithelial ovarian cancer: results of a large retrospective series. AB - BACKGROUND: To assess the long-term oncological outcome and the fertility of young women with early-stage epithelial ovarian cancer (ES/EOC) treated with fertility-sparing surgery (FSS). PATIENTS AND METHODS: All patients treated with FSS for ES/EOC in two Italian centers were considered for this analysis. Univariate and multivariate analyses were used to test demographic characteristics and clinical features for the association with overall survival (OS), recurrence-free survival (RFS) and fertility. RESULTS: From 1982 to 2010, 240 patients with malignant ES/EOC were treated with FSS in two tertiary centers in Italy. At a median follow-up of 9 years, 27 patients had relapsed (11%) and 11 (5%) had died of progressive disease. Multivariate analysis found only grade 3 negatively affected the prognosis of patients [hazard ratio (HR) for recurrence: 4.2, 95% confidence interval (CI): 1.5-11.7, P=0.0067; HR for death: 7.6, 95% CI: 2.0-29.3, P=0.0032]. Grade 3 was also significantly associated with extra-ovarian relapse (P=0.006). Of the 105 patients (45%) who tried to become pregnant, 84 (80%) were successful. CONCLUSIONS: Conservative treatment can be proposed to all young patients when tumor is limited to the ovaries, as ovarian recurrences can always be managed successfully. Patients with G3 tumors are more likely to have distant recurrences and should be closely monitored. PMID- 22945382 TI - Insight into the role of N,N-dimethylaminoethyl methacrylate (DMAEMA) conjugation onto poly(ethylenimine): cell viability and gene transfection studies. AB - In the present study, the effect of N,N-dimethylaminoethyl methacrylate (DMAEMA) conjugation onto branched poly(ethylenimine) (PEI) with different grafting degree was examined for gene delivery applications. The DMAEMA-grafted-PEI conjugates were characterized and complexed with plasmid DNA (pDNA) at various concentrations, and the physicochemical properties, cell viability, and in vitro transfection efficiency of the complexes were evaluated in HEK 293T cells. Computational techniques were used to analyze the interaction energies and possible binding modes between DNA and conjugates at different grafting degrees. The cytotoxicity analysis and in vitro transfection efficiency of the conjugate/pDNA complexes exhibited a beneficial effect of DMAEMA conjugation when compared to PEI alone. The computational results revealed that the DNA/vector interaction energy decreases with increasing grafting degree, which can be associated to an enhanced release of the pDNA from the carrier once inside cells. The results indicate the significance of DMAEMA conjugation onto PEI as a promising approach for gene delivery applications. PMID- 22945383 TI - Alginate hydrogel as a promising scaffold for dental-derived stem cells: an in vitro study. AB - The objectives of this study were to: (1) develop an injectable and biodegradable scaffold based on oxidized alginate microbeads encapsulating periodontal ligament (PDLSCs) and gingival mesenchymal stem cells (GMSCs); and (2) investigate the stem cell viability, and osteogenic differentiation of the stem cells in vitro. Stem cells were encapsulated using alginate hydrogel. The stem cell viability, proliferation and differentiation to adipogenic and osteogenic tissues were studied. To investigate the expression of both adipogenesis and ontogenesis related genes, the RNA was extracted and RT-PCR was performed. The degradation behavior of hydrogel based on oxidized sodium alginate with different degrees of oxidation was studied in PBS at 37 degrees C as a function of time by monitoring the changes in weight loss. The swelling kinetics of alginate hydrogel was also investigated. The results showed that alginate is a promising candidate as a non toxic scaffold for PDLSCs and GMSCs. It also has the ability to direct the differentiation of these stem cells to osteogenic and adipogenic tissues as compared to the control group in vitro. The encapsulated stem cells remained viable in vitro and both osteo-differentiated and adipo-differentiated after 4 weeks of culturing in the induction media. It was found that the degradation profile and swelling kinetics of alginate hydrogel strongly depends on the degree of oxidation showing its tunable chemistry and degradation rate. These findings demonstrate for the first time that immobilization of PDLSCs and GMSCs in the alginate microspheres provides a promising strategy for bone tissue engineering. PMID- 22945384 TI - Progress towards the synthesis of Urukthapelstatin A and two analogues. AB - We report our progress towards the synthesis of Urukthapelstatin A (Ustat A) and two analogues. Our retrosynthetic strategy involved the synthesis of three fragments: a tri-heteroaromatic moiety, a phenyl oxazole fragment, and a dipeptide. Described are the syntheses of three unique tri-heteroaromatic moieties. In addition, the corresponding linear precursors of Ustat A and two analogues are presented. PMID- 22945386 TI - Laparoscopic approach for simultaneous treatment of rectal cancer and synchronous liver metastases:indications and initial experience. AB - BACKGROUND/AIMS: Lapraoscopic era provided a new alternative for rectal cancer and synchronous liver metastases (RCLM). However, there is no established consensus for laparoscopy "first" for patients with RCLM, whose metastasis is confined to the liver. This study aimed to evaluate its indications for one-stage surgery in laparoscopy. METHODOLOGY: Sixteen patients with RCLM, who had undergone laparoscopic colorectal resection and simultaneous treatment for liver metastasis, were retrospectively reviewed. RESULTS: With concomitant laparoscopic colorectal resection, 6 patients received liver resection simultaneously; 10 patients underwent all sorts of down-staging managing including local ablation, right hepatic portal vein ligation and chemotherapy pumps implanted into hepatic artery for liver metastases. The colo-anal/rectal anastomoses were performed with a stapler or "pull-through" mode through the anus. Three patients underwent two stage liver resection following tumor down-staging. Median survival time was 22.3 months. CONCLUSIONS: Laparoscopy approach first for rectal cancer and synchronous liver metastasis is feasible in selected patients, and can provide curative resection or benefit "down-staging" treatment. Colon "pull-through" anastomosis is a potential method to avoid abdominal incision and decrease the risk of anastomotic leakage. It is worth investigating its advantages over traditional approaches with a prospective randomized controlled study. PMID- 22945385 TI - Does the cranial mesenchyme contribute to neural fold elevation during neurulation? AB - The central nervous system is derived from the neural plate, which undergoes a series of complex morphogenetic events resulting in formation of the neural tube in a process known as neurulation. The cellular behaviors driving neurulation in the cranial region involve forces generated by the neural tissue itself as well as the surrounding epithelium and mesenchyme. Of interest, the cranial mesenchyme underlying the neural plate undergoes stereotypical rearrangements hypothesized to drive elevation of the neural folds. As the neural folds rise, the hyaluronate rich extracellular matrix greatly expands resulting in increased space between individual cranial mesenchyme cells. Based on inhibitor studies, expansion of the extracellular matrix has been implicated in driving neural fold elevation; however, because the surrounding neural and epidermal ectoderm were also affected by inhibitor exposure, these studies are inconclusive. Similarly, treatment of neurulating embryos with teratogenic doses of retinoic acid results in altered organization of the cranial mesenchyme, but alterations in surrounding tissues are also observed. The strongest evidence for a critical role for the cranial mesenchyme in neural fold elevation comes from studies of genes expressed exclusively in the cranial mesenchyme that when mutated result in exencephaly associated with abnormal organization of the cranial mesenchyme. Twist is the best studied of these and is expressed in both the paraxial mesoderm and neural crest derived cranial mesenchyme. In this article, we review the evidence implicating the cranial mesenchyme in providing a driving force for neural fold elevation to evaluate whether there are sufficient data to support this hypothesis. PMID- 22945387 TI - Dendritic cells with CED-3 and CED-4 siRNA is effective in prolonging DC lifetime and suppresses tumor growth in gastric cancer. AB - BACKGROUND/AIMS: We investigated effects of CED-3 and CED-4-siRNA on prolonging dendritic cell life in vivo and in vitro. METHODOLOGY: The DCs were divided into three groups: pure-DC, siRNA and CED-3 and CED-4-siRNA. we performed anti apoptosis assays for DCs with flow cytometry. The assay for cytotoxicity assay was performed in vitro by a standard chromium assay at various effector/target ratios. Percent-specific lysis was calculated. We injected three kinds of DCs from tail vein every 3 days, we calculated tumor volume control rate and tumor weight control rate with formula. RESULTS: The DC percentages of apoptosis of CED 3 and CED-4 siRNA group were (12.09+/-1.14)%. Tumor-specific CTL activity showed 82.1% specific lysis for CED-3 and CED-4-siRNA DC group and 39.4% and 40.2% specific lysis for pure DC and siRNA DC group respectively. The lysis of CED-3 and CED-4-siRNA group was higher than the any other groups (p<0.05).The experiment of transplantation tumor in BALB/C mice showed that CED-3 and CED-4 siRNA DC can inhibit mice with tumors in volume and weight. CONCLUSIONS: We found that vaccination with CED-3 and CED-4-siRNA was capable of prolonging the survival of antigen-expressing DCs, and generated a strong therapeutic effect in the treatment of gastric cancer. PMID- 22945388 TI - Analysis of the mRNA expression levels of thymidylate synthase (TS), dihydropyrimidine dehydrogenase (DPD) and orotate phosphoribosyl transferase (OPRT) in liver metastases from colorectal cancer. AB - BACKGROUND/AIMS: We measured the mRNA expression levels of thymidylate synthase (TS), dihydropyrimidine dehydrogenase (DPD) and orotate phosphoribosyl transferase (OPRT) in liver metastases from colorectal cancer and retrospectively analyzed their association with other clinicopathological factors and the prognosis of these patients. METHODOLOGY: The study involved 55 patients of colorectal cancer with liver metastasis who underwent surgery at our department between February 1988 and April 2003. RESULTS: Analysis of the mRNA expression levels of each of the aforementioned enzymes in the liver metastases revealed no significant differences in the mRNA expression levels of the enzymes depending on the timing of development of the liver metastasis, histological type of the cancer, or the patient gender. In the analysis of the survival period, no association was observed between the survival prognosis and the mRNA expression level of DPD or OPRT in the liver metastases; on the other hand, the prognosis was better in the group showing low TS mRNA expression (median survival period: 3.77 years) than in the group showing high TS mRNA expression (median survival period: 2.39 years) (p=0.0134). CONCLUSIONS: These results suggest that the mRNA expression level of TS in the liver metastases in colorectal cancer patients is a useful prognostic indicator. PMID- 22945389 TI - The relief of existential suffering. AB - Advanced and progressive illnesses bring existential suffering to patients as an inevitable consequence of the disease and its treatment. Physicians need a typology of existential distress to aid its recognition and improved management. The major forms of existential challenge include (1) death anxiety, (2) loss and change, (3) freedom with choice or loss of control, (4) dignity of the self, (5) fundamental aloneness, (6) altered quality of relationships, (7) our search for meaning, and (8) mystery about what seems unknowable. An adaptive response to each challenge promotes equanimity, peace, and fulfillment while sustaining engagement with life, creativity, and joy. Physicians can do much to nurture courage and maintain each person's sense of meaning, value, and purpose. PMID- 22945391 TI - Separability between overall and internal motion: a protein folding problem. AB - The separability between overall and internal motions is evaluated over multiple folding trajectories of the villin headpiece subdomain. The analysis, which relies on the Prompers-Bruschweiler separability index, offers a potentially useful perspective on protein folding. The protein is considered folded in this study, not when it reaches some static target, but rather when it tumbles as a dynamically constrained object. The analysis also demonstrates how the separability index, when applied to protein folding simulations, can facilitate the analysis of NMR relaxation data. PMID- 22945392 TI - Treatment with the MEK inhibitor U0126 induces decreased hyperpolarized pyruvate to lactate conversion in breast, but not prostate, cancer cells. AB - Alterations in cell metabolism are increasingly being recognized as a hallmark of cancer and are being exploited for the development of diagnostic tools and targeted therapeutics. Recently, 13C MRS-detectable hyperpolarized pyruvate to lactate conversion has been validated in models as a noninvasive imaging method for the detection of tumors and treatment response, and has successfully passed phase I clinical trials. To date, response to treatment has been associated with a decrease in hyperpolarized lactate production. In this study, we monitored the effect of treatment with the mitogen-activated protein kinase (MEK) inhibitor U0126 in prostate and breast cancer cells. Following treatment, we observed a 31% decrease in the flux of hyperpolarized 13C label in treated MCF-7 breast cancer cells relative to controls. In contrast, and unexpectedly, the flux increased to 167% in treated PC3 prostate cancer cells. To mechanistically explain these observations, we investigated treatment-induced changes in the different factors known to affect the pyruvate to lactate conversion. NADH (nicotinamide adenine dinucleotide, reduced form) levels remained unchanged, whereas lactate dehydrogenase expression and activity, as well as intracellular lactate, increased in both cell lines, providing an explanation for the elevated hyperpolarized lactate observed in PC3 cells. The expression of MCT1, which mediates pyruvate transport, decreased in treated MCF-7, but not PC3, cells. This identifies pyruvate transport as rate limiting in U0126-treated MCF-7 cells and explains the decrease in hyperpolarized lactate observed in these cells following treatment. Our findings highlight the complexity of interactions between MEK and metabolism, and the need for mechanistic validation before hyperpolarized 13C MRS can be used to monitor treatment-induced molecular responses. PMID- 22945393 TI - To know or not to know the genomic sequence of a fetus. PMID- 22945395 TI - Comprehensive pre-implantation genetic screening: ethical reflection urgently needed. PMID- 22945396 TI - Development: reinforcing feedback. PMID- 22945394 TI - DNA methylation profiling in the clinic: applications and challenges. AB - Knowledge of epigenetic alterations in disease is rapidly increasing owing to the development of genome-wide techniques for their identification. The ever-growing number of genes that show epigenetic alterations in disease emphasizes the crucial role of these epigenetic alterations - particularly DNA methylation - for future diagnosis, prognosis and prediction of response to therapies. This Review focuses on epigenetic profiling, which has started to be of clinical value in cancer and may in the future be extended to other diseases, such as neurological and autoimmune disorders. PMID- 22945397 TI - Combination of online enzyme digestion with stable isotope labeling for high throughput quantitative proteome analysis. AB - Various enzyme reactors and online enzyme digestion strategies have been developed in recent years. These reactors greatly enhanced the detection sensitivity and proteome coverage in qualitative proteomics. However, these devices have higher rates of miscleavage in protein digestion. Therefore, we investigated the effect of online enzyme digestion on the quantification accuracy of quantitative proteomics using chemical or metabolic isotope labeling approaches. The incomplete digestion would introduce some unexpected variations in comparative quantification when the samples are digested and then chemically isotope labeled in different aliquots. Even when identical protein aliquots are processed on these devices using post-digestion chemical isotope labeling and the CVs of the ratios controlled to less than 50% in replicate analyses, about 10% of the quantified proteins have a ratio greater than two-fold, whereas in theory the ratio is 1:1. Interestingly, the incomplete digestion with enzyme reactor is not a problem when metabolic isotope labeling samples were processed because the proteins are isotopically labeled in vivo prior to their simultaneous digestion within the reactor. Our results also demonstrated that both high quantification accuracy and high proteome coverage can be achieved in comparative proteome quantification using online enzyme digestion even when a limited amount of metabolic isotope labeling samples is used (1683 proteins comparatively quantified from 10(5) Hela cells). PMID- 22945399 TI - [Orthopedic rheumatologic/infections]. PMID- 22945398 TI - [Standards of microbiological diagnostics of spondylodiscitis]. AB - In most cases spondylodiscitis is due to a monomicrobial infection caused by hematogenous dissemination of Staphylococcus aureus. There are, however, many other possible pathogens causing spondylodiscitis and the pathogen responsible can only be identified in approximately 50% of cases. This leads to delayed diagnosis and therapy and an increased morbidity and mortality rate. Failures in planning and performing material recovery are often the reason. As pathogen specific antimicrobial treatment according to the results of susceptibility testing is the main component of interdisciplinary therapy, all available methods for identification of the pathogen, such as blood cultures, intraoperative and computed tomography (CT) guided biopsies of inflammatory fluids and tissues as well as molecular biological methods should be performed to optimize antimicrobial therapy. PMID- 22945400 TI - Controlling surface enrichment in polymeric hole extraction layers to achieve high-efficiency organic photovoltaic cells. AB - Hole extraction in organic photovoltaic cells (OPVs) can be modulated by a surface-enriched layer formed on top of the conducting polymer-based hole extraction layer (HEL). This tunes the surface work function of the HEL to better align with the ionization potential of the polymeric photoactive layer. Results show noticeable improvement in device power conversion efficiencies (PCEs) in OPVs. We achieved a 6.1 % PCE from the OPV by optimizing the surface-enriched layer. PMID- 22945401 TI - The initiative for innovation in pediatric education: the next chapter. PMID- 22945402 TI - Attributable risks for childhood overweight: evidence for limited effectiveness of prevention. AB - OBJECTIVE: Calculation of attributable risks (ARs) of childhood overweight to estimate effectiveness of prevention strategies. METHODS: We used pooled data of 4 population-based German studies including 34240 children and adolescents aged 3 to 18 years to calculate the impact of familial, social, "early life", and lifestyle factors on overweight. ARs (joint for all determinants as well as partial risks) were calculated. RESULTS: The prevalence of childhood overweight was 13.4%. Successfully tackling all determinants can reduce overweight by 77.7% (ie, from 13.4% to 3.0%; = joint AR) with partial effects of treating parental overweight (42.5%); improving social status (14.3%); reducing media time to <1 hour per day (11.4%); and not smoking during pregnancy, low weight gain during pregnancy, and breastfeeding (together 9.5%), respectively. Improving all preventable risk factors (ie, early life factors and lifestyle) the effect is 9.2%. Media time has the strongest effect. CONCLUSIONS: The determinants identified explained 78% of the prevalence of overweight. Taking into account the partial ARs, the effectiveness of lifestyle interventions to prevent overweight in children is limited. Our data argue in favor of interventions aimed at families and social environments, with a major focus on promoting a lower screen time and computer use in children. PMID- 22945403 TI - Postnatal fish oil supplementation in high-risk infants to prevent allergy: randomized controlled trial. AB - BACKGROUND AND OBJECTIVE: Relative deficiency of dietary omega 3 polyunsaturated fatty acids (n-3 PUFA) has been implicated in the rising allergy prevalence in Westernized countries. Fish oil supplementation may provide an intervention strategy for primary allergy prevention. The objective of this study was to assess the effect of fish oil n-3 PUFA supplementation from birth to 6 months of age on infant allergic disease. METHODS: In a double-blind randomized controlled trial, 420 infants at high atopic risk received a daily supplement of fish oil containing 280 mg docosahexaenoic acid and 110 mg eicosapentaenoic acid or a control (olive oil), from birth to age 6 months. PUFA levels were measured in 6 month-old infants' erythrocytes and plasma and their mothers' breast milk. Eczema, food allergy, asthma and sensitization were assessed in 323 infants for whom clinical follow-up was completed at 12 months of age. RESULTS: At 6 months of age, infant docosahexaenoic acid and eicosapentaenoic acid levels were significantly higher (both P < .05) and erythrocyte arachidonic acid levels were lower (P = .003) in the fish oil group. Although n-3 PUFA levels at 6 months were associated with lower risk of eczema (P = .033) and recurrent wheeze (P = .027), the association with eczema was not significant after multiple comparisons and there was no effect of the intervention per se on the primary study outcomes. Specifically, between-group comparisons revealed no differences in the occurrence of allergic outcomes including sensitization, eczema, asthma, or food allergy. CONCLUSIONS: Postnatal fish oil supplementation improved infant n-3 status but did not prevent childhood allergic disease. PMID- 22945404 TI - A framework for elimination of perinatal transmission of HIV in the United States. AB - The availability of effective interventions to prevent mother-to-child HIV transmission and the significant reduction in the number of HIV-infected infants in the United States have led to the concept that elimination of mother-to-child HIV transmission (EMCT) is possible. Goals for elimination are presented. We also present a framework by which elimination efforts can be coordinated, beginning with comprehensive reproductive health care (including HIV testing) and real-time case-finding of pregnancies in HIV-infected women, and conducted through the following: facilitation of comprehensive clinical care and social services for women and infants; case review and community action; allowing continuous quality research in prevention and long-term follow-up of HIV-exposed infants; and thorough data reporting for HIV surveillance and EMCT evaluation. It is emphasized that EMCT will not be a one-time accomplishment but, rather, will require sustained effort as long as there are new HIV infections in women of childbearing age. PMID- 22945405 TI - Pediatric sleep disorders and special educational need at 8 years: a population based cohort study. AB - OBJECTIVES: To examine associations between sleep-disordered breathing (SDB) and behavioral sleep problems (BSPs) through 5 years of age and special educational need (SEN) at 8 years. METHODS: Parents in the Avon Longitudinal Study of Parents and Children reported on children's snoring, witnessed apnea, and mouth-breathing at 6, 18, 30, 42, and 57 months, from which SDB symptom trajectories, or clusters, were derived. BSPs were based on report of >= 5 of 7 sleep behaviors at each of the 18-, 30-, 42-, and 57-month questionnaires. Parent report of SEN (yes/no) at 8 years was available for 11049 children with SDB data and 11467 children with BSP data. Multivariable logistic regression models were used to predict SEN outcome by SDB cluster and by cumulative report of SEN. RESULTS: Controlling for 16 putative confounders, previous history of SDB and BSPs was significantly associated with an SEN. BSPs were associated with a 7% increased odds of SEN (95% confidence interval [CI] 1.01-1.15), for each ~1-year interval at which a BSP was reported. SDB, overall, was associated with a near 40% increased odds of SEN (95% CI 1.18-1.62). Children in the worst symptom cluster were 60% more likely to have an SEN (95% CI 1.23-2.08). CONCLUSIONS: In this population-based longitudinal study, history of either SDB or BSPs in the first 5 years of life was associated with increased likelihood of SEN at 8 years of age. Findings highlight the need for pediatric sleep disorder screening by early interventionists, early childhood educators, and health professionals. PMID- 22945406 TI - Tanner stage 4 breast development in adults: forensic implications. AB - BACKGROUND AND OBJECTIVE: Forensic testimony in alleged child pornography cases commonly asserts that Tanner stage (TS) 4 breast development, characterized by secondary mounding of the areola that is obliterated in TS 5, is evidence of age <18 years. Clinical experience does not support this notion, but there are no relevant studies. We sought to estimate how frequently TS 4 might be interpreted from nonclinical images by individual forensic experts. METHOD: Published images of 547 adult women were independently examined by the authors and classified as having TS 4 or TS 5 breast development. RESULTS: There was concordance among all 4 of the examiners for 17 of the images, agreement of 3 of the examiners on another 36 images, of 2 examiners on 39 images, and 53 images were designated TS 4 by only 1 examiner, for a total of 153 (26.5%) images that could have been considered by a single forensic expert to represent TS 4. CONCLUSIONS: A substantial number of adults have persistent TS 4 breast development. This observation, and the frequent difficulty distinguishing TS 4 from TS 5, even by adolescent development specialists, especially in nonclinical images, renders testimony based on this distinction invalid. Without clinical relevance for distinguishing these advanced stages of breast development, they should both be considered indicative of full maturation. Testimony based on this inappropriate test of maturity should no longer be allowed. PMID- 22945407 TI - Obesity and metabolic syndrome and functional and structural brain impairments in adolescence. AB - BACKGROUND: The prevalence of metabolic syndrome (MetS) parallels the rise in childhood obesity. MetS is associated with neurocognitive impairments in adults, but this is thought to be a long-term effect of poor metabolism. It would be important to ascertain whether these brain complications are also present among adolescents with MetS, a group without clinically manifest vascular disease and relatively short duration of poor metabolism. METHODS: Forty-nine adolescents with and 62 without MetS, matched on age, socioeconomic status, school grade, gender, and ethnicity, received endocrine, MRI, and neuropsychological evaluations. RESULTS: Adolescents with MetS showed significantly lower arithmetic, spelling, attention, and mental flexibility and a trend for lower overall intelligence. They also had, in a MetS-dose-related fashion, smaller hippocampal volumes, increased brain cerebrospinal fluid, and reductions of microstructural integrity in major white matter tracts. CONCLUSIONS: We document lower cognitive performance and reductions in brain structural integrity among adolescents with MetS, thus suggesting that even relatively short-term impairments in metabolism, in the absence of clinically manifest vascular disease, may give rise to brain complications. In view of these alarming results, it is plausible that obesity-associated metabolic disease, short of type 2 diabetes mellitus, may be mechanistically linked to lower the academic and professional potential of adolescents. Although obesity may not be enough to stir clinicians or even parents into action, these results in adolescents strongly argue for an early and comprehensive intervention. We propose that brain function be introduced among the parameters that need to be evaluated when considering early treatment of childhood obesity. PMID- 22945408 TI - Implementation of a central line maintenance care bundle in hospitalized pediatric oncology patients. AB - OBJECTIVE: To investigate whether a multidisciplinary, best-practice central line maintenance care bundle reduces central line-associated blood stream infection (CLABSI) rates in hospitalized pediatric oncology patients and to further delineate the epidemiology of CLABSIs in this population. METHODS: We performed a prospective, interrupted time series study of a best-practice bundle addressing all areas of central line care: reduction of entries, aseptic entries, and aseptic procedures when changing components. Based on a continuous quality improvement model, targeted interventions were instituted to improve compliance with each of the bundle elements. CLABSI rates and epidemiological data were collected for 10 months before and 24 months after implementation of the bundle and compared in a Poisson regression model. RESULTS: CLABSI rates decreased from 2.25 CLABSIs per 1000 central line days at baseline to 1.79 CLABSIs per 1000 central line days during the intervention period (incidence rate ratio [IRR]: 0.80, P = .58). Secondary analyses indicated CLABSI rates were reduced to 0.81 CLABSIs per 1000 central line days in the second 12 months of the intervention (IRR: 0.36, P = .091). Fifty-nine percent of infections resulted from Gram positive pathogens, 37% of patients with a CLABSI required central line removal, and patients with Hickman catheters were more likely to have a CLABSI than patients with Infusaports (IRR: 4.62, P = .02). CONCLUSIONS: A best-practice central line maintenance care bundle can be implemented in hospitalized pediatric oncology patients, although long ramp-up times may be necessary to reap maximal benefits. Further research is needed to determine if this CLABSI rate reduction can be sustained and spread. PMID- 22945409 TI - Communication during pediatric asthma visits and self-reported asthma medication adherence. AB - OBJECTIVE: Our objectives were to examine how certain aspects of provider-patient communication recommended by national asthma guidelines (ie, provider asking for child and caregiver input into the asthma treatment plan) were associated with child asthma medication adherence 1 month after an audio-taped medical visit. METHODS: Children ages 8 through 16 with mild, moderate, or severe persistent asthma and their caregivers were recruited at 5 pediatric practices in nonurban areas of North Carolina. All medical visits were audio-tape recorded. Children were interviewed 1 month after their medical visits, and both children and caregivers reported the child's control medication adherence. Generalized estimating equations were used to determine if communication during the medical visit was associated with medication adherence 1 month later. RESULTS: Children (n = 259) completed a home visit interview ~1 month after their audio-taped visit, and 216 of these children were taking an asthma control medication at the time of the home visit. Children reported an average control medication adherence for the past week of 72%, whereas caregivers reported the child's average control medication adherence for the past week was 85%. Child asthma management self efficacy was significantly associated with both child- and caregiver-reported control medication adherence. When providers asked for caregiver input into the asthma treatment plan, caregivers reported significantly higher child medication adherence 1 month later. CONCLUSIONS: Providers should ask for caregiver input into their child's asthma treatment plan because it may lead to better control medication adherence. PMID- 22945410 TI - Congenital fibrosarcoma and history of prenatal exposure to petroleum derivatives. AB - Congenital fibrosarcoma (CFS) is a rare fibrous tissue malignancy that usually presents in the first few years of life. It is unique among human sarcomas in that it has an excellent prognosis. We describe a temporal clustering of a number of cases of CFS and investigate the possible associated prenatal risk factors. The Pediatric Environmental History, a questionnaire developed in our clinic that is instrumental in determining environmental risk factors for tumor-related disease, was essential in documenting the presence or absence of risk factors considered as human carcinogens. We found a history of exposure to petroleum products in four cases of CFS that occurred at a greater than expected rate in a short time frame-an apparent cancer cluster. We call attention to the possibility that exposure to petroleum products raises the risk of developing CFS. While future studies should focus on systematic investigation of CFS and its underlying mechanisms, this report suggests the need for proactive measures to avoid exposure to solvents and petroleum products during pregnancy. PMID- 22945411 TI - Bottle-feeding and the Risk of Pyloric Stenosis. AB - OBJECTIVES: Bottle-feeding has been suggested to increase the risk of pyloric stenosis (PS). However, large population-based studies are needed. We examined the effect of bottle-feeding during the first 4 months after birth, by using detailed data about the timing of first exposure to bottle-feeding and extensive confounder information. METHODS: We performed a large population-based cohort study based on the Danish National Birth Cohort, which provided information on infants and feeding practice. Information about surgery for PS was obtained from the Danish National Patient Register. The association between bottle-feeding and the risk of PS was evaluated by hazard ratios (HRs) estimated in a Cox regression model, adjusting for possible confounders. RESULTS: Among 70148 singleton infants, 65 infants had surgery for PS, of which 29 were bottle-fed before PS diagnosis. The overall HR of PS for bottle-fed infants compared with not bottle fed infants was 4.62 (95% confidence interval [CI]: 2.78-7.65). Among bottle-fed infants, risk increases were similar for infants both breast and bottle-fed (HR: 3.36 [95% CI: 1.60-7.03]), formerly breastfed (HR: 5.38 [95% CI: 2.88-10.06]), and never breastfed (HR: 6.32 [95% CI: 2.45-16.26]) (P = .76). The increased risk of PS among bottle-fed infants was observed even after 30 days since first exposure to bottle-feeding and did not vary with age at first exposure to bottle feeding. CONCLUSIONS: Bottle-fed infants experienced a 4.6-fold higher risk of PS compared with infants who were not bottle-fed. The result adds to the evidence supporting the advantage of exclusive breastfeeding in the first months after birth. PMID- 22945412 TI - Cell therapy: a novel treatment approach for bronchopulmonary dysplasia. AB - Bronchopulmonary dysplasia (BPD) is a major cause of substantial lifelong morbidity in preterm infants. Despite a better understanding of the pathophysiology of BPD and significant research effort into its management, there remains today no effective treatment. Cell-based therapy is a novel approach that offers much promise in the prevention and treatment of BPD. Recent research supports a therapeutic role for cell transplantation in the management of a variety of acute and chronic adult and childhood lung diseases, with potential of such therapy to reduce inflammation and prevent acute lung injury. However, considerable uncertainties remain regarding cell therapies before they can be established as safe and effective clinical treatments for BPD. This review summarizes the current literature investigating cell therapies in lung disease, with particular focus on the various types of cells available and their specific properties in the context of a future therapy for BPD. PMID- 22945413 TI - EEG for predicting early neurodevelopment in preterm infants: an observational cohort study. AB - OBJECTIVE: To clarify the prognostic value of conventional EEG for the identification of preterm infants at risk for subsequent adverse neurodevelopment in the current perinatal care and medicine setting. METHODS: We studied 780 EEG records of 333 preterm infants born <34 weeks' gestation between 2002 and 2008. Serial EEG recordings were conducted during 3 time periods; at least once each within days 6 (first period), during days 7 to 19 (second period), and days 20 to 36 (third period). The presence and the grade of EEG background abnormalities were assessed according to an established classification system. Neurodevelopmental outcomes were assessed at a corrected age of 12 to 18 months. RESULTS: Of the 333 infants, 33 (10%) had developmental delay and 34 (10%) had cerebral palsy. The presence of EEG abnormalities was significantly predictive of developmental delay and cerebral palsy at all 3 time periods: the first period (n = 265; odds ratio [OR], 4.5; 95% confidence interval [CI], 2.2-9.4), the second period (n = 278; OR, 7.6; 95% CI, 3.6-16), and the third period (n = 237; OR, 5.9; 95% CI, 2.8-13). The grade of EEG abnormalities correlated with the incidence of developmental delay or cerebral palsy in all periods (P < .001). After controlling for other clinical variables, including severe brain injury, EEG abnormality in the second period was an independent predictor of developmental delay (OR, 3.2; 95% CI, 1.1-9.7) and cerebral palsy (OR, 6.8; 95% CI 2.0-23). CONCLUSIONS: EEG abnormalities within the first month of life significantly predict adverse neurodevelopment at a corrected age of 12 to 18 months in the current preterm survivor. PMID- 22945414 TI - Functioning of 7-year-old children born at 32 to 35 weeks' gestational age. AB - OBJECTIVE: To compare neuropsychological functions in moderately preterm (32-35 weeks' gestation) and full-term children at the age of 7 years and identify gender differences. METHODS: Community-based prospective cohort study of 248 moderately preterm children (138 boys) and 130 full-term children (58 boys). Neuropsychological tests included IQ, memory, attention, visual perception, motor skills, visuomotor skills, and parental report of executive functioning. RESULTS: The moderately preterm group performed significantly worse on total and performance IQ, visuospatial reasoning, attention control, inhibition, and executive functioning. No differences were found in verbal IQ, verbal memory, and visuomotor and motor skills. Preterm children were at higher risk for scores <10th percentile on intelligence, visuospatial reasoning (relative risk ratio both: 1.69 [95% confidence interval: 1.29-2.28]), and executive functioning problems (relative risk: 1.94 [95% confidence interval: 1.51-2.57]). Using gender specific norms, preterm boys performed significantly worse than full-term boys on visuospatial reasoning (P < .01); preterm girls performed significantly worse than full-term girls on visuospatial reasoning, intelligence, attention, and executive functioning (P < .05). CONCLUSIONS: Moderately preterm birth is associated with lower intelligence and poorer neuropsychological functioning at early school age. No differences in motor skills and verbal memory were found. Using gender-specific norms, our data suggest that moderately preterm boys catch up, whereas moderately preterm girls lag behind their peers on various neuropsychological functions by the age of 7 years. PMID- 22945415 TI - Preterm birth and congenital heart defects: a population-based study. AB - BACKGROUND AND OBJECTIVES: Preterm birth (PTB) and congenital heart defect (CHD) are 2 major causes of mortality and disability of perinatal origin. There are limited data on the relation between CHD and PTB. Our objective was to use population-based data to estimate the risk of PTB in newborns with CHD and to study specific associations between categories of CHD and PTB. METHODS: We used data from a population-based cohort study of CHD (EPIdemiologique sur le devenir des enfants porteurs de CARDiopathies congenitales study), including 2189 live births with CHD (excluding isolated atrial septal defects) born between 2005 and 2008. We categorized CHD by using an anatomic and clinical classification. Data from the French National Perinatal Survey of 2003 were used to compare PTB in the EPIdemiologique sur le devenir des enfants porteurs de CARDiopathies congenitales study to that of the general population. RESULTS: Of the newborns with CHD, 13.5% were preterm. The odds of PTB were twofold higher than for the general population (odds ratio 2.0, 95% confidence interval 1.6-2.5), essentially due to an increase in spontaneous PTB for newborns with CHD. The risk of PTB associated with CHD persisted after exclusion of chromosomal or other anomalies. There were significant variations in risk of PTB across the categories of CHD after adjustment for known risk factors of PTB and factors related to medical management of pregnancy and delivery. CONCLUSIONS: We found a higher risk of PTB in newborns with CHD, which was essentially due to spontaneous PTB. Risk of PTB varied for categories of CHD. Our finding may be helpful for generating hypotheses about the developmental links between CHD and PTB. PMID- 22945417 TI - The influence of social deprivation on bone donation: a 10 year retrospective study. AB - An audit identifying all surgical bone donors over a 10 year period was conducted. Postcodes were used to link data from the index of multiple deprivation (IMD) 2007 to give each donor a deprivation score. An audit from 2000 to 2010 of primary total hip replacement (THR) patients was also conducted, and similarly a deprivation score was identified for each patient. IMD scores are split into quintiles. A high IMD score indicates a high degree of social deprivation. Conversely low IMD scores indicate a more affluent community. The mean IMD 2007 score was 13.36 (95% CI 13.12-13.60). The national mean IMD score is 21.7 (CI 21.52-21.88). The difference is significant (p < 0.0001). The mean IMD 2007 score of primary THR patients identified in the arthroplasty database was 19.19 (CI 19.00-19.38). The difference between the mean arthroplasty score and the mean score of donors is significant (p < 0.0001). The donation rate increases as social deprivation decreases from quintile to quintile in both: the older patients (CI 1.08-1.14; p < 0.0001) and the general population (CI 1.20 1.25; p < 0.0001). Bone donors are substantially less deprived than their donor pool of THR patients. Donor rates are consistently lower in quintiles which are more deprived. PMID- 22945418 TI - Nanostructured silicon nitride thin films for label-free multicolor luminescent cell imaging. AB - The application of nanostructured luminescent silicon nitride (SiN(X)) thin films for label-free cell imaging is reported for the first time. Different strong local fields ensured by various molecules concentrated in various cell compartments can lead to the creation of preferential electronic conditions for radiative recombination of photogenerated charge carriers via a given electronic channel. Thus, highly contrasted multicolor luminescent cell imaging under one photon excitation becomes possible. The described label-free bio-imaging approach has good compatibility with fluorescence optical microscopy, and allows rapid and efficient cell imaging and cell line recognition. PMID- 22945416 TI - A randomized controlled trial of the tumor necrosis factor antagonist infliximab for treatment-resistant depression: the role of baseline inflammatory biomarkers. AB - CONTEXT: Increased concentrations of inflammatory biomarkers predict antidepressant nonresponse, and inflammatory cytokines can sabotage and circumvent the mechanisms of action of conventional antidepressants. OBJECTIVES: To determine whether inhibition of the inflammatory cytokine tumor necrosis factor (TNF) reduces depressive symptoms in patients with treatment-resistant depression and whether an increase in baseline plasma inflammatory biomarkers, including high-sensitivity C-reactive protein (hs-CRP), TNF, and its soluble receptors, predicts treatment response. DESIGN: Double-blind, placebo-controlled, randomized clinical trial. SETTING: Outpatient infusion center at Emory University in Atlanta, Georgia. PARTICIPANTS: A total of 60 medically stable outpatients with major depression who were either on a consistent antidepressant regimen (n = 37) or medication-free (n = 23) for 4 weeks or more and who were moderately resistant to treatment as determined by the Massachusetts General Hospital Staging method. INTERVENTIONS: Three infusions of the TNF antagonist infliximab (5 mg/kg) (n = 30) or placebo (n = 30) at baseline and weeks 2 and 6 of a 12-week trial. MAIN OUTCOME MEASURES: The 17-item Hamilton Scale for Depression (HAM-D) scores. RESULTS: No overall difference in change of HAM-D scores between treatment groups across time was found. However, there was a significant interaction between treatment, time, and log baseline hs-CRP concentration (P = .01), with change in HAM-D scores (baseline to week 12) favoring infliximab-treated patients at a baseline hs-CRP concentration greater than 5 mg/L and favoring placebo-treated patients at a baseline hs-CRP concentration of 5 mg/L or less. Exploratory analyses focusing on patients with a baseline hs-CRP concentration greater than 5 mg/L revealed a treatment response (>=50% reduction in HAM-D score at any point during treatment) of 62% (8 of 13 patients) in infliximab-treated patients vs 33% (3 of 9 patients) in placebo treated patients (P = .19). Baseline concentrations of TNF and its soluble receptors were significantly higher in infliximab-treated responders vs nonresponders (P < .05), and infliximab-treated responders exhibited significantly greater decreases in hs-CRP from baseline to week 12 compared with placebo-treated responders (P < .01). Dropouts and adverse events were limited and did not differ between groups. CONCLUSIONS: This proof-of-concept study suggests that TNF antagonism does not have generalized efficacy in treatment resistant depression but may improve depressive symptoms in patients with high baseline inflammatory biomarkers. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00463580. PMID- 22945420 TI - Oxygen evolution at functionalized carbon surfaces: a strategy for immobilization of molecular water oxidation catalysts. AB - A molecular Ru(II) water oxidation catalyst was immobilized on a conductive carbon surface through a covalent bond, and its activity was maintained at the same time. The method can be applied to other materials and may inspire development of artificial photosynthesis devices. PMID- 22945421 TI - The effect of a Pt impurity layer on the magnetocrystalline anisotropy of hexagonal close-packed Co: a first-principles study. AB - On the basis of the fully relativistic screened Korringa-Kohn-Rostoker method we investigate the variation in the magnetocrystalline anisotropy energy (MAE) of hexagonal close-packed cobalt with the addition of platinum impurities. In particular, we perform calculations on a bulk cobalt system in which one of the atomic layers contains a fractional, substitutional platinum impurity. Our calculations show that at small concentrations of platinum the MAE is reduced, while at larger concentrations the MAE is enhanced. This change in the MAE can be attributed to an interplay between on-site Pt MAE contributions and induced MAE contributions on the Co sites. The latter are subject to pronounced, long-ranged Friedel oscillations that can lead to significant size effects in the experimental determination of the MAE of nanosized samples. PMID- 22945419 TI - Retrieval of contextual memories increases activity-regulated cytoskeleton associated protein in the amygdala and hippocampus. AB - Activity-regulated cytoskeleton-associated protein (Arc) integrates information from multiple intracellular signaling cascades and, in turn, regulates cytoskeletal proteins involved in structural synaptic modifications. The purposes of the present study were: (1) to determine if the retrieval of contextual memories would induce Arc in hippocampal and amygdalar neurons; (2) use unbiased stereology at the ultrastructural level to quantify synapses contacting Arc labeled (Arc+) and unlabeled (Arc-) postsynaptic structures in brain regions in which the amount of Arc integrated density (ID) correlated strongly with the degree of amphetamine conditioned place preference (AMPH CPP). The retrieval of contextual memories increased the Arc ID in the dentate gyrus, cornu ammonis (CA)1, and CA3 fields of the hippocampus and the basolateral, lateral, and central nuclei of the amygdala but not the primary auditory cortex, a control region. Stereological quantification of Arc+ and Arc- synapses in the basolateral nucleus of the amygdala (BLA) was undertaken because the strongest relationship between the amount of Arc ID and AMPH CPP was observed in the BLA. The retrieval of contextual memories increased the number and density of asymmetric (presumed excitatory) synapses contacting Arc+ spines and dendrites of BLA neurons, symmetric (presumed inhibitory or modulatory) synapses contacting Arc+ dendrites of BLA neurons, and multisynaptic boutons contacting Arc+ postsynaptic structures. Thus, the retrieval of contextual memories increases Arc in the amygdala and hippocampus, an effect that could be important for approach behavior to a drug-associated context. PMID- 22945422 TI - Pancreatic neuroendocrine neoplasm: correlation between computed tomography enhancement patterns and prognostic factors of surgical and endoscopic ultrasound guided fine-needle aspiration biopsy specimens. AB - PURPOSE: To retrospectively determine whether enhancement patterns in the pancreatic and equilibrium phases of computed tomography (CT) for pancreatic neuroendocrine neoplasms are related to prognostic factors of surgical and endoscopic ultrasound-guided fine-needle aspiration biopsy specimens. METHODS: Twenty-five pancreatic neuroendocrine neoplasms in 22 patients underwent preoperative dynamic CT. Tumors were classified into two groups by enhancement patterns on preoperative CT. A washout pattern was defined as peak enhancement in the pancreatic phase with washout of at least 60 Hounsfield units in the equilibrium phase. Group 1 comprised tumors showing a washout pattern in more than half of tumor and Group 2 comprised tumors showing a washout pattern in less than half of the tumor. The Ki-67 index and the presence of vascular invasion were evaluated in surgical specimens. The Ki-67 index from biopsy specimens was compared with that from surgical specimens. RESULTS: There were 12 surgical specimens in Group 1 and 13 in Group 2. Group 2 showed significant correlations with larger Ki-67 indices (p < 0.05) and positive vascular invasion (p < 0.05). The Ki-67 index discrepancy between biopsy and surgical specimens of Group 2 was significantly greater than that of Group 1 (p < 0.05). CONCLUSIONS: Pancreatic neuroendocrine neoplasms in which less than half of the tumor showed a washout pattern were correlated with poor prognostic factors. Analysis of enhancement patterns may provide predictive information about whether endoscopic ultrasound guided fine-needle aspiration biopsy is reliable for the assessment of Ki-67 index. PMID- 22945424 TI - Metastable tetragonal Cu2Se hyperbranched structures: large-scale preparation and tunable electrical and optical response regulated by phase conversion. AB - Despite the promising applications of copper selenide nanoparticles, an in-depth elucidation of the inherent properties of tetragonal Cu(2)Se (beta-Cu(2)Se) has not been performed because of the lack of a facile synthesis on the nanoscale and an energy-intensive strategy is usually employed. In this work, a facile wet chemical strategy, employing HCOOH as reducing agent, has been developed to access single-crystalline metastable beta-Cu(2)Se hyperbranched architectures for the first time. The process avoids hazardous chemistry and high temperatures, and thus opens up a facile approach to the large-scale low-cost preparation of metastable beta-Cu(2)Se hyperbranched architectures. A possible growth mechanism to explain the formation of the beta-Cu(2)Se dendritic morphology has been proposed based on time-dependent shape evolution. Further investigations revealed that the metastable beta-Cu(2)Se can convert into the thermodynamically more stable cubic alpha-Cu(2-x)Se maintaining the dendritic morphology. An increase in electrical conductivity and a tunable optical response were observed under ambient conditions. This behavior can be explained by the oxidation of the surface of the beta-Cu(2)Se hyperbranched structures, ultimately leading to solid state phase conversion from beta-Cu(2)Se into superionic conductor alpha Cu(1.8)Se, which has potential applications in energy-related devices and sensors. PMID- 22945423 TI - Aberrant methylation of the PTCH1 gene promoter region in aberrant crypt foci. AB - Patched homolog 1 (PTCH1) is a known tumor suppressor that regulates the Hedgehog (Hh) pathway and has been implicated in tumorigenesis. The role of PTCH1 in colon carcinogenesis, however, is controversial. The aim of the present study was to investigate epigenetic modifications of PTCH1 in aberrant crypt foci (ACF), the earliest precursor lesion of colorectal cancer (CRC). Using laser-capture microdissection (LCM), a pure population of ACF epithelial cells was isolated and studied. The inherent protein expression levels of SHH, PTCH1, SMO and GLI1 were assessed by immunohistochemistry for 405 ACF, including 54 dysplastic ACF (d-ACF) and 351 non-dysplastic ACF (n-ACF). The mRNA levels and methylation status of PTCH1 were also determined in 54 d-ACF and 96 n-ACF. Our data showed that the expression of SHH, SMO and GLI1 was significantly up-regulated in d-ACF, compared to n-ACF. Also, the mRNA and protein levels of PTCH1 were lower in d-ACF than n ACF. Using MSP or MS-HRM, PTCH1 methylation was present in 64.8% (35/54) or 63.3% (34/54), respectively, of d-ACF and 19.8% (19/96) or 22.9% (11/48), respectively, of n-ACF. PTCH1 methylation was more frequent in d-ACF than n-ACF (p < 0.001) and was associated with PTCH1 mRNA levels (r = 0.358, p < 0.01). There was a statistically significant correlation between PTCH1 methylation status and the prevalence of colorectal neoplasms. In conclusion, this study suggests that aberrant methylation of the PTCH1 promoter may be an early, initiating event of colon carcinogenesis. PMID- 22945425 TI - Tackling sample-related artifacts in membrane FCS using parallel SAF and UAF detection. AB - The complex shape and plasticity of cells is an intricate issue for the measurement of molecular diffusion in plasma membranes by fluorescence correlation spectroscopy (FCS). An important precondition for accurate diffusion measurements is a sufficient flatness of the membrane over the considered region and the absence of non-membrane-bound fluorescence diffusion. A method is presented to identify axial motion components caused by a non-ideal geometry of the membrane based on simultaneous measurement of the fluorescence emitted above and below the critical angle of the specimen/glass interface. Thereby, two detection volumes are generated that are laterally coincident, but differ in their axial penetration of the specimen. The similarity between the intensity tracks of the supercritical angle fluorescence (SAF) and the undercritical angle fluorescence (UAF) strongly depends on the membrane flatness and intracellular fluorescence, and can help to avoid sample-related artifacts in the diffusion measurement. PMID- 22945426 TI - CheShift-2 resolves a local inconsistency between two X-ray crystal structures. AB - Since chemical shifts provide important and relatively accessible information about protein structure in solution, a Web server, CheShift-2, was developed for structure interrogation, based on a quantum mechanics database of (13)C( alpha ) chemical shifts. We report the application of CheShift-2 to a local inconsistency between two X-ray crystal structures (PDB IDs 1IKN and 1NFI) of the complex between the p65/p50 heterodimer of NFkappaB and its inhibitor IkappaBalpha. The availability of NMR resonance assignments that included the region of the inconsistency provided an opportunity for independent validation of the CheShift 2 server. Application of the server showed that the (13)C( alpha ) chemical shifts measured for the Gly270-Pro281 sequence close to the C-terminus of IkappaBalpha were unequivocally consistent with the backbone structure modeled in the 1IKN structure, and were inconsistent with the 1NFI structure. Previous NOE measurements had demonstrated that the position of a tryptophan ring in the region immediately N-terminal in this region was not consistent with either structure. Subsequent recalculation of the local structure in this region, based on the electron density of the deposited structure factors for 1IKN, confirmed that the local backbone structure was best modeled by 1IKN, but that the rotamer of Trp258 is consistent with the 1NFI structure, including the presence of a hydrogen bond between the ring NepsilonH of Trp258 and the backbone carbonyl group of Gln278. The consensus between all of these measures suggests that the CheShift-2 server operates well under circumstances in which backbone chemical shifts are available but where local plasticity may render X-ray structural data ambiguous. PMID- 22945427 TI - New amino acid residue type identification experiments valid for protonated and deuterated proteins. AB - Two experiments are presented that yield amino acid type identification of individual residues in a protein by editing the (1)H-(15)N correlations into four different 2D subspectra, each corresponding to a different amino acid type class, and that can be applied to deuterated proteins. One experiment provides information on the amino acid type of the residue preceding the detected amide (1)H-(15)N correlation, while the other gives information on the type of its own residue. Versions for protonated proteins are also presented, and in this case it is possible to classify the residues into six different classes. Both sequential and intraresidue experiments provide highly complementary information, greatly facilitating the assignment of protein resonances. The experiments will also assist in transferring the assignment of a protein to the spectra obtained under different experimental conditions (e.g. temperature, pH, presence of ligands, cofactors, etc.). PMID- 22945428 TI - Imaging assessment of penetrating injury of the neck and face. AB - BACKGROUND: Penetrating trauma of the neck and face is a frequent presentation to acute emergency, trauma and critical care units. There remains a steady incidence of both gunshot penetrating injury to the neck and face as well as non-missile penetrating injury-largely, but not solely, knife-related. Optimal imaging assessment of such injuries therefore remains an on-going requirement of the general and specialised radiologist. METHODS: The anatomy of the neck and face-in particular, vascular, pharyngo-oesophageal, laryngo-tracheal and neural anatomy demands a more specialised and selective management plan which incorporates specific imaging techniques. RESULTS: The current treatment protocol of injuries of the neck and face has seen a radical shift away from expectant surgical exploration in the management of such injuries, largely as a result of advances in the diagnostic capabilities of multi-detector computed tomography angiography (MDCTA), which is now the first-line imaging modality of choice in such cases. CONCLUSION: This review aims to highlight ballistic considerations, differing imaging modalities, including MDCTA, that might be utilised to assist in the accurate assessment of these injuries as well as the specific radiological features and patterns of specific organ-system injuries that should be considered and communicated to surgical and critical care teams. TEACHING POINTS : * MDCTA is the first-line imaging modality in penetrating trauma of the neck and, often, of the face * The inherent deformability of a bullet is a significant factor in its tissue-damaging capabilities * MDCTA can provide accurate assessment of visceral injury of the neck as well as vascular injury * Penetrating facial trauma warrants radiological assessment of key adjacent anatomical structures * In-driven fragments of native bone potentiate tissue damage in projectile penetrating facial trauma. PMID- 22945429 TI - Prevalence and clinical impact of Toxocara vitulorum in cattle and buffalo calves in northern Lao PDR. AB - This study was completed to determine the prevalence and distribution of Toxocara vitulorum infection in cattle and buffalo calves and investigate its clinical impact in northern Lao PDR (Peoples Democratic Republic). The results aim to assist decisions on disease control measures that can contribute to increasing cattle and buffalo productivity within smallholder farming systems in tropical areas. A prevalence survey for T. vitulorum in buffalo and cattle calves aged <3 months was conducted between September 2009 and June 2010 in five provinces of northern Lao PDR using a two-stage sampling technique to select 69 villages and 899 calves, with faecal samples collected and examined for T. vitulorum eggs at a local laboratory. At the time of sampling, data on calf morbidity and anthelmintic treatment was also collected. Factors potentially associated with infection and severity of infection were analyzed at univariable and multivariable levels, using T. vitulorum status (positive/negative) and on the positive calves only, faecal egg count levels as outcome variables. The estimated prevalence of T. vitulorum in northern Lao was 22.6 % (95 % confidence interval [CI], 0.17-0.28), and 76.8 % of villages had at least one positive calf. Province was the only significant (p < 0.05) variable investigated associated with calf infection status. Species (buffalo) was the only variable significantly (p < 0.05) associated with higher egg per gram of faeces levels among infected calves. Prevalence in calves aged 1-21 days, the reported prepatent period, was 17.5 % (CI 0.11-0.24). Treatment levels were very low (8.2 %) and if treatment occurred it was mostly unsuccessful. The high and wide spread infection of T. vitulorum in cattle and buffalo calves identified in this survey is likely to result in suboptimal cattle and buffalo productivity. Improved management of T. vitulorum infection in cattle and buffalo calves in northern Lao PDR is indicated to reduce potential negative production impacts and enable more efficient development of large ruminant livestock industry as a pathway from rural poverty for smallholder farmers in northern Lao PDR. In addition to quantifying this disease problem in calves, the conduct of this applied participatory research study provided an important opportunity to improve animal health services by increasing the parasite, large ruminant handling and research knowledge and capacity of government animal health staff and farmers. PMID- 22945430 TI - Effect of yeast supplementation on the growth performance of Malpura lambs. AB - Thirty-six Malpura lambs (age = 58 days; 8.9 kg BW) were equally divided into three groups (N = 12; six males and six females) to assess the effect of probiotics supplementation on growth, digestibility, rumen fermentation and carcass attributes. The lambs of the control group (CON) were not supplemented with probiotics, while test groups received either Saccharomyces cerevisiae (SC) or combination of S. cerevisiae and Lactobacillus sporogenes (SCLS) at 1.5 % of concentrate mixture. The lambs were fed ad libitum concentrate mixture and bajra (Pennisetum typhoides) straw in a cafeteria system until 180 days of age. Daily feed intake and weekly live weight changes were recorded. A metabolism trial was conducted on six lambs at 90 days. Rumen fermentation study was conducted at 105 days. At 6 months, all male lambs were slaughtered and carcass characteristics were recorded. Body weight and average daily gain (ADG) were similar among the three groups. The digestibilities of all the nutrients were also similar among the groups, except acid detergent fiber (ADF) digestibility, which was higher (P = 0.032) in SC and SCLS than the CON. The rumen fluid pH was higher (P = 0.04) in CON and SC group than SCLS at 0 h while NH(3)-N at 8 h sample was higher (P = 0.031) in SC and SCLS group than the control. Pre-slaughter weight, hot carcass weight and dressing yields were similar. ADF digestibility and rumen fermentation was improved in lambs by probiotic supplementation. However, carcass traits remained unchanged due to probiotics supplementation. PMID- 22945431 TI - An organic hydride transfer reaction of a ruthenium NAD model complex leading to carbon dioxide reduction. AB - Ruthenium will fix it: CO(2) undergoes reduction to HCO(2)(-) when placed over a solution of a ruthenium complex bearing an NADH model ligand 1 (black in right structural formula). The organic hydride transfer is triggered by the addition of benzoate anion, which rapidly forms a complex with 1, a complex that is a stronger reductant than 1. A photocatalytic variant of the reaction using triethanolamine as a sacrificial reagent has also been developed. PMID- 22945432 TI - How to implement monitoring tools for sedation, pain and delirium in the intensive care unit: an experimental cohort study. AB - PURPOSE: Systematic monitoring of sedation, pain and delirium in the ICU is of paramount importance in delivering adequate patient care. While the use of systematic monitoring instruments is widely agreed upon, these tools are infrequently implemented into daily ICU care. The aim of this study is to compare the effectiveness of two different training strategies (training according to the local standard vs. modified extended method) on the implementation rate of scoring instruments on the ICU. METHODS: In this experimental cohort study we analyzed the frequency of scoring on three surgical ICUs before and after training, and in a 1 year follow-up. A modified extended training included establishing a local support team helping to resolve immediate problems. In addition we evaluated the impact on patients' outcome. RESULTS: ICUs trained by the modified extended method showed increased documentation rates of all scores per patient and day. In a 1 year follow-up, increased scoring rates for all scores were maintained. Scoring rates with training according to the local standard training protocol did not increase significantly. Implementation of delirium and pain monitoring were associated with a decrease in mortality [odds ratio (OR) 0.451; 95 % confidence interval (CI): 0.22-0.924, and, respectively, OR 0.348; 95 % CI: 0.140-0.863]. Monitoring had no significant influence on ventilation time or ICU length of stay. CONCLUSIONS: A modified extended training strategy for ICU monitoring tools (sedation, pain, delirium) leads to higher intermediate and long-term implementation rates and is associated with improved patient outcome. However, these findings may have been biased by unmeasured confounders. PMID- 22945433 TI - Picture-object recognition in the tortoise Chelonoidis carbonaria. AB - To recognize that a picture is a representation of a real-life object is a cognitively demanding task. It requires an organism to mentally represent the concrete object (the picture) and abstract its relation to the item that it represents. This form of representational insight has been shown in a small number of mammal and bird species. However, it has not previously been studied in reptiles. This study examined picture-object recognition in the red-footed tortoise (Chelonoidis carbonaria). In Experiment 1, five red-footed tortoises were trained to distinguish between food and non-food objects using a two alternative forced choice procedure. After reaching criterion, they were presented with test trials in which the real objects were replaced with color photographs of those objects. There was no difference in performance between training and test trials, suggesting that the tortoises did see some correspondence between the real object and its photographic representation. Experiment 2 examined the nature of this correspondence by presenting the tortoises with a choice between the real food object and a photograph of it. The findings revealed that the tortoises confused the photograph with the real-life object. This suggests that they process real items and photographic representations of these items in the same way and, in this context, do not exhibit representational insight. PMID- 22945434 TI - Same/different discrimination by bumblebee colonies. AB - Bumblebees were exposed to a discrimination procedure in which reinforcement was contingent on choice of one of two spatial locations. The correct choice depended on whether a stimulus display contained two identical stimuli or two different stimuli. Some bees were trained with color stimuli and tested with line grating stimuli and others with the opposite arrangement. Four colonies of bumblebees produced more correct than incorrect choices to both identical and different stimuli during the transfer phase. This pattern of results is a signature of choices under control of an identity ("same/different") concept. The results therefore indicate the existence of an identity concept in bumblebees. PMID- 22945439 TI - Proteomic exploration of the impacts of pomegranate fruit juice on the global gene expression of prostate cancer cell. AB - Prostate cancer has been known to be the second highest cause of death in cancer among men. Pomegranate is rich in polyphenols with the potent antioxidant activity and inhibits cell proliferation, invasion, and promotes apoptosis in various cancer cells. This study demonstrated that pomegranate fruit juice could effectively hinder the proliferation of human prostate cancer DU145 cell. The results of apoptotic analyses implicated that fruit juice might trigger the apoptosis in DU145 cells via death receptor signaling and mitochondrial damage pathway. In this study, we exploited 2DE-based proteomics to compare nine pairs of the proteome maps collected from untreated and treated DU145 cells to identify the differentially expressed proteins. Comparative proteomics indicated that 11 proteins were deregulated in affected DU145 cells with three upregulated and eight downregulated proteins. These dys-regulated proteins participated in cytoskeletal functions, antiapoptosis, proteasome activity, NF-kappaB signaling, cancer cell proliferation, invasion, and angiogenesis. Western immunoblotting were implemented to confirm the deregulated proteins and the downstream signaling proteins. The analytical results of this study help to provide insight into the molecular mechanism of inducing prostate cancer cell apoptosis by pomegranate fruit juice and to develop a novel mechanism-based chemopreventive strategy for prostate cancer. PMID- 22945436 TI - Novel CCK-dependent vasorelaxing dipeptide, Arg-Phe, decreases blood pressure and food intake in rodents. AB - SCOPE: We found that a dipeptide, Arg-Phe (RF), had vasorelaxing activity in mesenteric artery isolated from spontaneously hypertensive rats (SHRs) (EC(50) = 580 nM). We then investigated its mechanism of action, and elucidated its physiological functions. METHODS AND RESULTS: Vasorelaxing activities of RF related peptides were tested. The retro-sequence dipeptide FR was inactive, suggesting that the RF sequence is important for a potent vasorelaxing effect. RA and AF were also inactive. RF-nh(2) had vasorelaxing activity, implying that the C-terminal amidation of RF is tolerated. Nitric oxide (NO) and prostaglandins (PGs) are known to be vasorelaxing factors; however, the vasorelaxing activity of RF was inhibited by neither N(G) -nitro-l-arginine methyl ester (l-NAME), an NO synthase inhibitor, nor indomethacin, a COX inhibitor. Interestingly, the activity was blocked by lorglumide, an antagonist of the cholecystokinin (CCK)(1) receptor; however, RF had no affinity for CCK receptors, suggesting that RF stimulates CCK release. Orally administered RF decreased blood pressure in SHRs, and this antihypertensive activity was also blocked by a CCK(1) antagonist. RF had CCK-like suppressive effects on food intake and gastrointestinal transit. RF increased intracellular Ca(2+) flux and CCK release in enteroendocrine STC-1 cells. CONCLUSION: A novel CCK-dependent vasorelaxing RF decreases both blood pressure and food intake. PMID- 22945440 TI - Oesophagus: String theory aids EoE monitoring. PMID- 22945442 TI - IBD: Could oral Janus kinase inhibitor be a new drug treatment for active ulcerative colitis? PMID- 22945441 TI - Agents that act luminally to treat diarrhoea and constipation. AB - Diarrhoea and constipation are common clinical complaints that negatively affect quality of life, reduce work productivity and lead to considerable health-care expenditure. A variety of therapies have been used to treat these conditions. Unlike drugs that require systemic absorption to exert their effects, luminally acting agents improve diarrhoea and constipation by altering intestinal and/or colonic motility, as well as mucosal absorption and secretion, through a variety of mechanisms. Examples of luminally acting agents for diarrhoea include peripherally acting opiate analogues, enkephalinase inhibitors, bile-acid binding agents, nonabsorbed antibiotics, probiotics, bismuth-containing compounds, berberine and agents with possible effects on intestinal secretion or permeability. Luminally acting drugs for constipation include bulking agents, surfactants, osmotics, stimulants, chloride-channel activators, probiotics, drugs that increase delivery of bile acids to the colon and natural therapies such as prunes and hemp seed extract. As the physiological effects of luminally acting drugs are largely confined to the gastrointestinal tract, these agents are unlikely to cause adverse effects outside of the gastrointestinal tract. PMID- 22945444 TI - Neurogastroenterology: New view of enteric nervous system development. PMID- 22945445 TI - Gut microbiota: Colorectal cancer-driven by inflammation and gut bacteria? PMID- 22945446 TI - Gut microbiota: Dietary and social modulation of gut microbiota in the elderly. PMID- 22945443 TI - The role of the gut microbiota in nutrition and health. AB - The microbial communities that colonize different regions of the human gut influence many aspects of health. In the healthy state, they contribute nutrients and energy to the host via the fermentation of nondigestible dietary components in the large intestine, and a balance is maintained with the host's metabolism and immune system. Negative consequences, however, can include acting as sources of inflammation and infection, involvement in gastrointestinal diseases, and possible contributions to diabetes mellitus and obesity. Major progress has been made in defining some of the dominant members of the microbial community in the healthy large intestine, and in identifying their roles in gut metabolism. Furthermore, it has become clear that diet can have a major influence on microbial community composition both in the short and long term, which should open up new possibilities for health manipulation via diet. Achieving better definition of those dominant commensal bacteria, community profiles and system characteristics that produce stable gut communities beneficial to health is important. The extent of interindividual variation in microbiota composition within the population has also become apparent, and probably influences individual responses to drug administration and dietary manipulation. This Review considers the complex interplay between the gut microbiota, diet and health. PMID- 22945447 TI - Synthesis of a new alkali metal-organic solvent intercalated iron selenide superconductor with Tc ~ 45 K. AB - We report on a new iron selenide superconductor with a T(c) onset of 45 K and the nominal composition Li(x)(C(5)H(5)N)(y)Fe(2-z)Se(2), synthesized via intercalation of dissolved alkaline metal in anhydrous pyridine at room temperature. This superconductor exhibits a broad transition, reaching zero resistance at 10 K. Magnetization measurements reveal a superconducting shielding fraction of approximately 30%. Analogous phases intercalated with Na, K and Rb were also synthesized and characterized. The superconducting transition temperature of Li(x)(C(5)H(5)N)(y)Fe(2-z)Se(2) is clearly enhanced in comparison to those of the known superconductors FeSe(0.98) (T(c) ~ 8 K) and A(x)Fe(2 y)Se(2) (T(c) ~ 27-32 K) and is in close agreement with critical temperatures recently reported for Li(x)(NH(3))(y)Fe(2-z)Se(2). Post-annealing of intercalated material (Li(x)(C(5)H(5)N)(y)Fe(2-z)Se(2)) at elevated temperatures drastically enlarges the c-parameter of the unit cell (~44%) and increases the superconducting shielding fraction to nearly 100%. Our findings indicate a new synthesis route leading to possibly even higher critical temperatures for materials in this class: by intercalation of organic compounds between Fe-Se layers. PMID- 22945449 TI - Biocatalyzed artificial photosynthesis by hydrogen-terminated silicon nanowires. PMID- 22945448 TI - Chiroptical spectra of tetrakis (+)-3-heptafluorobutylrylcamphorate Ln(III) complexes with an encapsulated alkali metal ion: solution structures as revealed by chiroptical spectra. AB - The preparation of tetrakis((+)-hfbc) lanthanide(III) complexes with an encapsulated alkali metal and ammonium ions M[Ln((+)-hfbc)(4)] (hereafter abbreviated as M-Ln : (+)-hfbc, (+)-heptafluorobutyrylcamphorate; M, ammonium or benzyl ammonium ions as well as alkali metal ions) was reported and discussed. The electronic circular dichroism (CD) spectra in the intraligand pi-pi* transition of M-Ln were examined in view of the solvent effect. Here, the concentration, alkali metal, and ammonium ion dependences are compared with the solid CD, (5)D(0)<-(7)F(0) (Eu(III)) excitation spectra, circularly polarized luminescence, and vibrational circular dichroism. It has been revealed that the dodecahedral eight coordinate DD-8-M-Ln complexes in crystals are equilibrated between the diastereoselectively formed square antiprism eight coordinate SAPR-8 M-Ln and [Ln((+)-hfbc)(3)] in EtOH and CH(3) CN solutions or between the SAPR-8-M Ln and DD-D(2d) (mmmm)-8-M-Ln complexes in CHCl(3) solution. The observed CD couplets are found to reflect the exciton CD couplets which are useful to determine the four-bladed SAPR-(llll) absolute configuration around the lanthanide(III) ion. PMID- 22945450 TI - Progression-free survival versus overall survival in ovarian cancer: where are we now? PMID- 22945451 TI - Physical activity and cancer. AB - Epidemiological evidence continues to accumulate on the benefits of physical activity in relation to cancer risk, progression and mortality. Recent studies suggest that sedentary behavior may independently affect cancer risk; they also focus on factors that may explain associations with physical activity, including cancer risk factors and whether associations exist for precancerous lesions. Despite enormous efforts to examine associations between physical activity and cancer, the literature is hindered by inconsistent assessment of physical activity across studies, and incomplete consideration of variation of effects across population subgroups (for example, defined by body size, age or sex) or tumors subgroups (organ location, receptor status, or molecular subtype), and whether other factors explain study results. Clearly, public health recommendations for appropriate changes in activity levels are needed; unfortunately, at this time, we have no exact physical activity prescription to give to the public. PMID- 22945453 TI - A mussel-inspired polydopamine coating as a versatile platform for the in situ synthesis of graphene-based nanocomposites. AB - A facile and universal approach to prepare graphene-based nanocomposites by in situ nucleation and growth of diverse noble metals, metal oxides and semiconducting nanoparticles on the surface of RGO is proposed. PMID- 22945452 TI - Surgical management of early cervical cancer: the shape of future studies. AB - Early cervical cancer, in particular in the presence of favorable pathologic risk factors, accounts for a very low incidence of parametrial involvement and lymph node metastasis. This means that a less radical surgery may be an oncologically safe treatment in selected cases, with the aim of preserving fertility and/or reducing morbidity without compromising survival. The extensiveness of surgery has decreased relatively in recent decades, the "modified" radical hysterectomy still being the current gold standard by most international guidelines. Vaginal (or abdominal) radical trachelectomy, simple hysterectomy, or cervical conization has been proposed in association with pelvic lymphadenectomy. Sentinel lymph node mapping may be an option to avoid a complete pelvic lymphadenectomy. Ongoing research efforts are especially being made in properly identifying the patient subset suitable for a conservative/less radical approach and prospectively confirming the oncological safety of the proposed clinical-pathological algorithms. PMID- 22945454 TI - Caregivers' perceptions of patients as reminders to improve hand hygiene. PMID- 22945455 TI - Length distribution of stiff, self-assembled polymers at thermal equilibrium. AB - We investigate the length distribution of self-assembled, long and stiff polymers at thermal equilibrium. Our analysis is based on calculating the partition functions of stiff polymers of variable lengths in the elastic regime. Our conclusion is that the length distribution of this self-assembled system follows closely the exponential distribution, except at the short length limit. We then discuss the implications of our results on the experimentally observed length distributions in amyloid fibrils. PMID- 22945456 TI - Diethylstilbestrol impairs the morphology and function of mouse gubernaculum testis in culture. AB - Diethylstilbestrol (DES) is a nonsteroidal synthetic estrogen widely used in estrogen therapy. In animal models, exposure to DES disrupts the outgrowth of the gubernacula, leading to testis maldescent. However, it remains unclear whether the effects of DES on gubernaculum are direct or indirect, and the underlying mechanisms are largely obscure. In this study, mouse gubernaculum testis cells were isolated and treated by DES, and cell morphology and function were examined. The results showed that DES changed the morphology and inhibited the proliferation of gubernacular cells. Furthermore, DES increased intracellular [Ca(2+)] and induced F-actin rearrangement and stress fiber formation in gubernaculum testis cells in a dose-dependent manner. Taken together, these data suggest that DES impairs the morphology and inhibits the proliferation and contractility of gubernaculum testis cells. The experimental model we established and our observations based on this model help provide new insight into the role of DES in the etiology of cryptorchidism. PMID- 22945458 TI - Introduction to Special Issue on Food Allergy. PMID- 22945459 TI - Smoke-induced microRNA and related proteome alterations. Modulation by chemopreventive agents. AB - Dysregulation of microRNAs (miRNAs) has important consequences on gene and protein expression since a single miRNA targets a number of genes simultaneously. This article provides a review of published data and ongoing studies regarding the effects of cigarette smoke (CS), either mainstream (MCS) or environmental (ECS), on the expression of miRNAs and related proteins. The results generated in mice, rats, and humans provided evidence that exposure to CS results in an intense dysregulation of miRNA expression in the respiratory tract, which is mainly oriented in the sense of downregulation. In parallel, there was an upregulation of proteins targeted by the downregulated miRNAs. These trends reflect an attempt to defend the respiratory tract by means of antioxidant mechanisms, detoxification of carcinogens, DNA repair, anti-inflammatory pathways, apoptosis, etc. However, a long-lasting exposure to CS causes irreversible miRNA alterations that activate carcinogenic mechanisms, such as modulation of oncogenes and oncosuppressor genes, cell proliferation, recruitment of undifferentiated stem cells, inflammation, inhibition of intercellular communications, angiogenesis, invasion, and metastasis. The miRNA alterations induced by CS in the lung of mice and rats are similar to those observed in the human respiratory tract. Since a number of miRNAs that are modulated by CS and/or chemopreventive agents are subjected to single nucleotide polymorphisms in humans, they can be evaluated according to toxicogenomic/pharmacogenomics approaches. A variety of cancer chemopreventive agents tested in our laboratory modulated both baseline and CS-related miRNA and proteome alterations, thus contributing to evaluate both safety and efficacy of dietary and pharmacological agents. PMID- 22945460 TI - Fluorescence quenching of gold nanoparticles integrating with a conformation switched hairpin oligonucleotide probe for microRNA detection. AB - We report a new strategy for microRNA analysis based on the fluorescence quenching of gold nanoparticles (AuNPs) integrating with a conformation-switched hairpin-structured oligonucleotide probe for improving selectivity. PMID- 22945457 TI - Obesity and hepatocellular carcinoma: targeting obesity-related inflammation for chemoprevention of liver carcinogenesis. AB - Obesity and related metabolic abnormalities, including a state of chronic inflammation, increase the risk of hepatocellular carcinoma (HCC). Adipose tissue constitutively expresses the proinflammatory cytokine tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6), which are important tumor promoters in inflammation-related carcinogenesis. Dysregulation of TNF-alpha and IL-6 is associated with the development of steatosis and inflammation within the liver. These cytokines also lie at the core of the association between obesity and insulin resistance, which is a key factor in the development of obesity-related HCC. Here we present a detailed review of the relationship between metabolic abnormalities and the development of HCC, focusing on the role played by inflammation. Drawing from our basic and clinical research, the present report also reviews evidence that targeting metabolic abnormalities, such as attenuation of chronic inflammation and improvement of insulin resistance by either pharmaceutical or nutritional intervention, may be an effective strategy in preventing the development of HCC in obese individuals. PMID- 22945461 TI - Genome-wide association study reveals a complex genetic architecture underpinning induced CYP3A4 enzyme activity. AB - Atypical cytochrome P450 3A4 (CYP3A4) enzyme activity-induced and inhibited-is thought to be the driver of numerous poor or adverse therapeutic responses to up to 50 % of all commonly prescribed drugs. We carried out a genome-wide association study to identify common genetic variants associated with variation in induced CYP3A4 activity. A total of 310 twins were included in this study. Each participant had already completed a 14 days course of St John's Wort to induce CYP3A4, which was quantified through the metabolic ratio of exogenous 3 hydroxyquinine to quinine. We failed to detect any genome-wide significant associations (P < 1 * 10(-8)) with variation in induced CYP3A4 activity although several genomic regions were highlighted which may play minor roles. We report the first GWAS of variation in induced CYP3A4 activity and our preliminary results indicate a complex genetic architecture underpinning induced CYP3A4 enzyme activity. PMID- 22945463 TI - Cyclometalated iridium(III)-polyamine complexes with intense and long-lived multicolor phosphorescence: synthesis, crystal structure, photophysical behavior, cellular uptake, and transfection properties. AB - A new class of phosphorescent cyclometalated iridium(III)-polyamine complexes [{Ir(N^C)(2)}(n)(bPEI)](PF(6))(n)(bPEI=branched poly(ethyleneimine), average M(w =25 kDa, n=15.6-27.4; HN^C=2-phenylpyridine Hppy (1a), 2-((1,1'-biphenyl)-4 yl)pyridine Hpppy (2a), 2-phenylquinoline Hpq (3a), 2-phenylbenzothiazole Hbt (4a), 2-(1-naphthyl)benzothiazole Hbsn (5a)) and [Ir(N^C)(2)(en)](PF(6)) (en=ethylenediamine; HN^C=Hppy (1b), Hpppy (2b), Hpq (3b), Hbt (4b), Hbsn (5b)) have been synthesized and characterized. The X-ray crystal structure of complex 5b was also determined. All of these complexes showed a reversible iridium(IV/III) oxidation couple at +1.01 to +1.26 V and a quasi-reversible ligand-based reduction couple at -1.54 to -2.08 V (versus SCE). Upon photoexcitation, the complexes displayed intense and long-lived green to orange red emission in fluid solutions at room temperature and in low-temperature glass. Lipophilicity measurements indicated that bPEI played a dominant role in the polar nature of complexes 1a-5a, thus rendering them very soluble in aqueous solutions. Inductively coupled plasma-mass spectrometry (ICP-MS) and confocal laser scanning microscopy (CLSM) data indicated that an energy-requiring process, such as endocytosis, was involved in the cellular uptake of all of the complexes. In addition, the cytotoxicity of the complexes toward human cervix epithelioid carcinoma (HeLa) and human embryonic kidney 293T (HEK293T) cell-lines has been evaluated by the 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyltetrazolium bromide (MTT) assay. The DNA-binding properties of complex 5a have been investigated by gel-retardation assays and the polyplexes that were formed from this complex with plasmid DNA (pDNA) were studied by zeta-potential measurements and particle-size estimation. Furthermore, complex 5a was grafted with poly(ethylene glycol) (PEG, average M(w)=2 kDa) to different extents, thereby yielding the phosphorescent copolymers PEG(12.3)-g-5a, PEG(25.4)-g-5a, and PEG(62.1)-g-5a. Interestingly, these copolymers showed enhanced transfection activity, as revealed by in vitro transfection experiments with tissue-culture-based luciferase assays. PMID- 22945462 TI - Predicting treatment response in social anxiety disorder from functional magnetic resonance imaging. AB - CONTEXT: Current behavioral measures poorly predict treatment outcome in social anxiety disorder (SAD). To our knowledge, this is the first study to examine neuroimaging-based treatment prediction in SAD. OBJECTIVE: To measure brain activation in patients with SAD as a biomarker to predict subsequent response to cognitive behavioral therapy (CBT). DESIGN: Functional magnetic resonance imaging (fMRI) data were collected prior to CBT intervention. Changes in clinical status were regressed on brain responses and tested for selectivity for social stimuli. SETTING: Patients were treated with protocol-based CBT at anxiety disorder programs at Boston University or Massachusetts General Hospital and underwent neuroimaging data collection at Massachusetts Institute of Technology. PATIENTS: Thirty-nine medication-free patients meeting DSM-IV criteria for the generalized subtype of SAD. INTERVENTIONS: Brain responses to angry vs neutral faces or emotional vs neutral scenes were examined with fMRI prior to initiation of CBT. MAIN OUTCOME MEASURES: Whole-brain regression analyses with differential fMRI responses for angry vs neutral faces and changes in Liebowitz Social Anxiety Scale score as the treatment outcome measure. RESULTS: Pretreatment responses significantly predicted subsequent treatment outcome of patients selectively for social stimuli and particularly in regions of higher-order visual cortex. Combining the brain measures with information on clinical severity accounted for more than 40% of the variance in treatment response and substantially exceeded predictions based on clinical measures at baseline. Prediction success was unaffected by testing for potential confounding factors such as depression severity at baseline. CONCLUSIONS: The results suggest that brain imaging can provide biomarkers that substantially improve predictions for the success of cognitive behavioral interventions and more generally suggest that such biomarkers may offer evidence-based, personalized medicine approaches for optimally selecting among treatment options for a patient. PMID- 22945464 TI - Transcriptome analyses of Bactericera cockerelli adults in response to "Candidatus Liberibacter solanacearum" infection. AB - The potato/tomato psyllid, Bactericera cockerelli (Sulc) is an economically important crop pest that not only causes damage through its feeding but also transmits the bacterium, "Candidatus Liberibacter solanacearum" (CLs), which causes zebra chip disease in potato. There is some information about the phenotypic effects of phytopathogenic bacteria on their insect vectors; however, there are no published reports of the molecular mechanisms underlying phytopathogenic bacteria-insect vector interaction. In order to investigate the effects of CLs infection on B. cockerelli, transcriptomic analyses of CLs infected and uninfected adult psyllids that were reared on potato were performed. De novo assembly of cDNA sequences generated 136,518 and 109,983 contigs for infected and uninfected insect libraries with an average contig length of 514 bp. BlastX analysis against the NCBI-nr database revealed that 33.33 % had significant matches. Gene ontology data illustrated that the majority of the expressed psyllid genes are involved in metabolic process, biological regulation, binding and catalytic activity. The psyllid transcriptome had an abundance of genes such as vitellogenin, heat shock protein, ejaculatory bulb-specific protein, ferritin, and cytochrome oxidase. Notably absent in the psyllid transcriptome were innate immunity genes induced in response to Gram-negative bacteria (IMD pathway). Several functionally diverse contigs related to symbiotic bacteria including the primary endosymbiont Carsonella ruddii, Wolbachia, and CLs in the psyllid transcriptome were identified. A total of 247 contigs showed differential expression in response to CLs infection including immune and stress related genes and vitellogenins. Expression analyses of selected psyllid genes were performed on psyllids that were exclusively reared on potato (host of the insects used for RNAseq) and psyllids exclusively reared on tomato (alternative host of psyllids). These genes showed similar expression patterns irrespective of the host plant on which the psyllids were reared, which suggests that host-plant association may not modulate expression of these genes. Our findings suggest that the impact of CLs on psyllid transcriptome was to a large extent on genes involved in metabolic processes and to a small extent on immune and stress response genes. This study is the first description of transcriptomic changes in an insect vector in response to infection with a naturally occurring bacterial plant pathogen. Data from this study provide new sequence and gene expression resources for functional genomics of potato psyllids. PMID- 22945466 TI - Enhancement of iodine-hydride interaction by substitution and cooperative effects in NCX-NCI-HMY complexes. AB - The NCX-NCI-HMY (X=H, Cl, Br, I, Li; M=Be, Mg; Y=H, Li, Na) trimers are investigated to find ways to enhance the iodine-hydride interaction. The interaction energy in the NCI-HMH dimer is -2.87 and -5.87 kcal mol(-1) for M=Be and Mg, respectively. When the free H atom in the NCI-HMH dimer is replaced with an alkali atom, the interaction energy is enhanced greatly. When NCX is added into this dimer, the interaction energy of the iodine-hydride interaction is increased by 9-45 % and its increased percentage follows the order X=Cl= 16. METHODS: All patients notified to NOAR from 1990-5 with symptom onset in 1990 were included. The former Norwich Health Authority population was the denominator. Age and sex specific IRs using 1987 and 2010 classification criteria were calculated at baseline visit, annually for the first 3 years and at 5 years. RESULTS: 260 patients were notified to NOAR with symptom onset in 1990 and without an alternative diagnosis. IRs applying the 2010 criteria at baseline were 54/100 000 for women and 25/100 000 for men. Age and sex-specific IRs using the 2010 classification criteria at baseline were similar to cumulative IRs applying the 1987 criteria up to 5 years. However, some patients only ever satisfied one set of criteria and a proportion of IA patients (20%) did not satisfy either criteria set over 5 years. CONCLUSIONS: The 2010 criteria classify similar numbers of patients as having RA at baseline, as the 1987 criteria would have taken up to 5 years to identify. PMID- 22945500 TI - Incidences of overall and site specific cancers in TNFalpha inhibitor treated patients with rheumatoid arthritis and other arthritides - a follow-up study from the DANBIO Registry. AB - OBJECTIVES: To investigate the incidence of cancer in arthritis patients treated with or without TNFalpha inhibitors (TNF-I). METHODS: Arthritis patients from the DANBIO database were followed-up for cancer in the Danish Cancer Registry during 2000-2008. RESULTS: Hazard ratio for cancer overall was 1.02 (95% confidence interval (CI) 0.80-1.30) in 3347 TNF-I-treated RA patients compared to non treated. Excess among TNF-I-treated was found for colon cancer (HR 3.52 (95%CI 1.11-11.15), whereas 6 and 0 ovarian cancer cases were observed in treated and non-treated patients, respectively. Compared to the general population, TNF-I treated RA patients had increased risk for cancer overall, cancer in lymphatic haematopoietic tissue and non-melanoma skin cancer, while non-RA patients had no increase in overall cancer risk. CONCLUSIONS: Our results suggest that TNF-I therapy in routine care is not associated with an overall excess of cancer in arthritis patients, but observed increased risks of colon and ovarian cancer need further investigation. PMID- 22945502 TI - Spin thermopower and thermoconductance in a ferromagnetic graphene nanoribbon. AB - The spin thermoelectric properties of a zigzag edged ferromagnetic (FM) graphene nanoribbon are studied theoretically by using the non-equilibrium Green's function method combined with the Landauer-Buttiker formula. By applying a temperature gradient along the ribbon, under closed boundary conditions, there is a spin voltage DeltaV(s) inside the terminal as the response to the temperature difference DeltaT between two terminals. Meanwhile, the heat current DeltaQ is accompanied from the 'hot' terminal to the 'cold' terminal. The spin thermopower S = DeltaV(s)/DeltaT and thermoconductance kappa = DeltaQ/DeltaT are obtained. When there is no magnetic field, S versus E(R) curves show peaks and valleys as a result of band selective transmission and Klein tunneling with E(R) being the on site energy of the right terminal. The results are in agreement with the semi classical Mott relation. When |E(R)| < M (M is the FM exchange split energy), kappa is infinitesimal because tunneling is prohibited by the band selective rule. While |E(R)| > M, the quantized value of kappa = pi2k2(B)T/3h appears. In the quantum Hall regime, because Klein tunneling is suppressed, S peaks are eliminated and the quantized value of kappa is much clearer. We also investigate how the thermoelectric properties are affected by temperature, FM exchange split energy and Anderson disorder. The results indicate that S and kappa are sensitive to disorder. S is suppressed for even small disorder strengths. For small disorder strengths, kappa is enhanced and for moderate disorder strengths, kappa shows quantized values. PMID- 22945503 TI - Self-buffering hybrid gold-polyoxometalate catalysts for the catalytic cyclization of acid-sensitive substrates. AB - Grafting of a gold complex to an organo-polyoxometalate delivers catalytically active bitopic hybrids. The gold end activates allenes, while the metal-oxide surface can capture protons (see scheme). The scope of the gold-catalyzed oxacyclization of allenols is expanded to highly sensitive tertiary benzylic alcohols. PMID- 22945501 TI - Clinical associations of the metabolic syndrome in systemic lupus erythematosus: data from an international inception cohort. AB - BACKGROUND: The metabolic syndrome (MetS) may contribute to increased cardiovascular risk in systemic lupus erythematosus (SLE). We aimed to examine the association of demographic factors, lupus phenotype and therapy exposure with the presence of MetS. METHODS: The Systemic Lupus International Collaborating Clinics Registry for Atherosclerosis inception cohort enrolled recently diagnosed (<15 months) SLE patients from 30 centres across 11 countries from 2000. Clinical, laboratory and therapeutic data were collected according to a standardised protocol. MetS was defined according to the 2009 consensus statement from the International Diabetes Federation. Univariate and backward stepwise multivariate logistic regression were used to assess the relationship of individual variables with MetS. RESULTS: We studied 1686 patients, of whom 1494 (86.6%) had sufficient data to determine their MetS status. The mean (SD) age at enrolment and disease duration was 35.2 years (13.4) and 24.1 weeks (18.0), respectively. MetS was present at the enrolment visit in 239 (16%). In backward stepwise multivariable regression analysis, higher daily average prednisolone dose (mg) (OR 1.02, 95% CI 1.00 to 1.03), older age (years) (OR 1.04, 95% CI 1.03 to 1.06), Korean (OR 6.33, 95% CI 3.68 to 10.86) and Hispanic (OR 6.2, 95% CI 3.78 to 10.12) ethnicity, current renal disease (OR 1.79, 95% CI 1.14 to 2.80) and immunosuppressant use (OR 1.81, 95% CI 1.18 to 2.78) were associated with MetS. CONCLUSIONS: Renal lupus, higher corticosteroid doses, Korean and Hispanic ethnicity are associated with MetS in SLE patients. Balancing disease control and minimising corticosteroid exposure should therefore be at the forefront of personalised treatment decisions in SLE patients. PMID- 22945505 TI - Within-person variability in high-sensitivity C-reactive protein. PMID- 22945504 TI - Calcium- and voltage-gated potassium (BK) channel activators in the 5beta cholanic acid-3alpha-ol analogue series with modifications in the lateral chain. AB - Large conductance, calcium- and voltage-gated potassium (BK) channels regulate various physiological processes and represent an attractive target for drug discovery. Numerous BK channel activators are available. However, these agents usually interact with the ubiquitously distributed channel-forming subunit and thus cannot selectively target a particular tissue. We performed a structure activity relationship study of lithocholic acid (LCA), a cholane that activates BK channels via the accessory BK beta1 subunit. The latter protein is highly abundant in smooth muscle but scarce in most other tissues. Modifications to the LCA lateral chain length and functional group yielded two novel smooth muscle BK channel activators in which the substituent at C24 has a small volume and a net negative charge. Our data provide detailed structural information that will be useful to advance a pharmacophore in search of beta1 subunit-selective BK channel activators. These compounds are expected to evoke smooth muscle relaxation, which would be beneficial in the pharmacotherapy of prevalent human disorders associated with increased smooth muscle contraction, such as systemic hypertension, cerebral or coronary vasospasm, bronchial asthma, bladder hyperactivity, and erectile dysfunction. PMID- 22945506 TI - Survival and dispersal of turf algae and macroalgae consumed by herbivorous coral reef fishes. AB - The mechanisms by which algae disperse across space on coral reefs are poorly known. We investigated the ability of four common Caribbean herbivorous fish species to disperse viable algal fragments through consumption of macroalgae and subsequent defecation. Fragments of all major algal taxa (Phaeophyta, Rhodophyta, and Chlorophyta) were found in 98.7 % of the fecal droppings of all fish species; however, the ability to survive gut passage and reattach to a substrate differed between algal taxa. While survival and reattachment approached zero for Phaeophyta and Chlorophyta, 76.4 % of the fragments belonging to the group Rhodophyta (mostly species in the order Gelidiaceae) survived gut passage, and were able to grow and reattach to the substrate by forming new rhizoids. Our results thus show that Gelidid algal species are dispersed by swimming herbivores. While the relative contribution of this mechanism to overall algal dispersal and recruitment in a wider ecological context remains unknown, our findings illustrate a previously undescribed mechanism of algal dispersal on coral reefs which is analogous to the dispersal of terrestrial plants, plant fragments, and seeds via herbivore ingestion and defecation. PMID- 22945507 TI - Colon cancer cells expressing cell surface GRP78 as a marker for reduced tumorigenicity. AB - BACKGROUND: The glucose regulated heat shock protein 78 (GRP78) is a central regulator of ER (endoplasmic reticulum) stress due to its pro-survival property. Up regulated GRP78 expression in tumor cells has been correlated with aggressive malignancies whereas some reports have predicted an improved prognosis. Over expression of GRP78 in the ER promotes its localization to the cell surface on several cell types including tumor cells. METHODS: In order to elucidate whether GRP78 receptor positive and negative tumor cells manifest different properties in colorectal cancer, we first artificially separated GRP78 positive and negative sub-populations from HM7 and HCT116 cell lines using anti GRP78 antibody coated magnetic beads. RESULTS: Only GRP78 negative cells were highly proliferative, induced significant growth in tumor size in nude mice and metastasized to the liver in a human metastatic colorectal carcinoma model in mice. In contrast, GRP78 positive cells manifested reduced proliferation, colony formation, tumor growth and liver metastases. The reduced tumorigenicity of GRP78 positive subpopulation was abrogated by silencing GRP78 expression using siRNA oligomers. In our efforts to induce cell surface GRP78, we subjected the cells to doxorubicin and taxol that increased significantly the percent of GRP78 positive population. Cells pre-incubated with doxorubicin exhibited reduced proliferation and tumor growth in mice. CONCLUSION: This study demonstrates the significance of cell surface GRP78 in colon cancer, which may be used as a marker for reduced tumorigenicity. PMID- 22945508 TI - Identification of a novel short peptide seal specific to CD59 and its effect on HeLa cell growth and apoptosis. AB - BACKGROUND: In the past, some small peptide ligands identified by phage display technologies have successfully been used in early cancer diagnostics and therapy. In the present study, a novel CD59-binding peptide was identified and its effect on HeLa cell growth and apoptosis was investigated. METHODS: A phage display library was screened yielding a novel short peptide, sp22, that specifically binds to CD59, a protein that shows altered expression in various diseases, including cancer. The effect of ectopic sp22 administration and exogenous sp22 expression on the growth and apoptosis of HeLa cells was assessed. For the latter, we constructed and transfected a sp22-pIRES vector into HeLa cells. RESULTS: Our results show that sp22 peptides can inhibit the level of CD59 mRNA expression, down-regulate Bcl-2 expression, increase Fas and caspase-3 expression, increase the level of cytolysis, and increase the apoptosis of HeLa cells. In contrast, sp22 peptides had no effect on normal human embryonic lung (HEL) cells exhibiting a relatively low CD59 expression level. Compared to untransfected HeLa cells, exogenously sp22 expressing HeLa cells showed a reduced CD59 expression, an increased complement-mediated lysis, a decreased cellular survival ratio, and an increase in apoptotic cells. CONCLUSION: The newly identified sp22 peptide can, in a dose-dependent manner, inhibit CD59 expression. Concomitantly, sp22 can increase complement-mediated lysis and apoptosis signals. This information may be instrumental for the design of novel therapeutic strategies. PMID- 22945509 TI - Molecular diagnosis of minimal residual disease in head and neck cancer patients. AB - AIM: Locoregional recurrences and distant metastases in adequately treated head and neck squamous cell carcinoma (HNSCC) patients have a dismal effect on survival. Tumor cells that escape histopathological detection might be the prime cause of this effect. We evaluated whether minimal residual cancer (MRC) in deep surgical margins and disseminated tumor cells (DTCs) in bone marrow aspirates are associated with clinicohistopathological parameters and outcome. METHODS: Submucosal samples of deep resection margins of 105 HNSCC patients with histopathologically tumor-free surgical margins were analysed for the presence of MRC using hLy-6D qRT-PCR. Bone-marrow aspirates of 76 of these patients were analysed for DTCs by immunocytochemical staining. Presence of molecular-positive deep surgical margins, presence of DTC in bone marrow aspirates, and clinicohistopathological parameters were tested for associations with survival parameters by univariate and multivariate analyses. RESULTS: In addition to lymph node stage, it appeared that vasoinvasive growth and particularly infiltrative growth pattern are significant predictors for locoregional recurrence (p = 0.041 and p = 0.006, respectively) and disease-free survival (p = 0.014 and p = 0.008, respectively). Remarkably, neither the presence of molecular-positive deep surgical margins nor that of DTC in bone marrow aspirates were significantly related to outcome. CONCLUSIONS: The presence of vasoinvasive and infiltrative growth in HNSCC tumor specimens are significant risk-factors for locoregional recurrence and disease-free survival. At present there seems no role for molecular analysis of deep surgical margins and bone marrow aspirates in predicting outcome with the methods used. PMID- 22945510 TI - RGD-peptide lunasin inhibits Akt-mediated NF-kappaB activation in human macrophages through interaction with the alphaVbeta3 integrin. AB - SCOPE: Cardiovascular disease is the leading cause of mortality in the United States and regulation of aberrant macrophage activity under inflammatory conditions is critical for its prevention. The objective was to determine the effect of lunasin on the inhibition of Akt-mediated activation of nuclear factor kappa B (NF-kappaB)-dependent markers of inflammation and to characterize the physical interaction of lunasin with the alphaVbeta3 integrin receptor in lipopolysaccharide (LPS)-induced human THP-1 macrophages. METHODS AND RESULTS: The effect of lunasin was evaluated in vitro in LPS-induced THP-1 human macrophages using immunoassays, co-immunoprecipitation (Co-IP), and fluorescence confocal microscopy. Lunasin (50 MUM) reduced cyclooxygenase-2, inducible nitric oxide synthase, and NO levels by 57.9, 64.5, and 76.2%, respectively, and inhibited the activation of phosphorylated Akt and NF-kappaB p65 by 59.5 and 74.5%, respectively. Lunasin (50 MUM) reduced exogenous release of prostaglandin E(2) and tumor necrosis factor-alpha by 92.5 and 94.9%, respectively. Vitronectin (10 MUg/mL), an integrin ligand, increased expression of proinflammatory markers, whereas lunasin (50 MUM) attenuated them. Co-IP of lunasin-treated cells confirmed direct interaction with alphaVbeta3 integrin and LC/MS/MS verified its identity. Lunasin was detected within intracellular vesicles and reduced total alphaVbeta3 intensity as observed by fluorescence microscopy. CONCLUSION: Lunasin inhibited alphaVbeta3 integrin-mediated proinflammatory markers and downregulated Akt-mediated NF-kappaB pathways through interaction with alphaVbeta3 integrin. PMID- 22945511 TI - Base-stabilized diborenes: selective generation and eta2 side-on coordination to silver(I). AB - (B)olefin complexes: Reductive coupling of designed monoborane precursors (see scheme; Dur=2,3,5,6-tetramethylphenyl) gives convenient access to N-heterocyclic carbene stabilized diborenes. The presence of B-B multiple bonds in the dark red diborenes is shown experimentally and theoretically. Reaction with AgCl afforded a Ag(I) species with an unprecedented, olefin-like eta(2) coordination mode. PMID- 22945512 TI - Inflection, canards and excitability threshold in neuronal models. AB - A technique is presented, based on the differential geometry of planar curves, to evaluate the excitability threshold of neuronal models. The aim is to determine regions of the phase plane where solutions to the model equations have zero local curvature, thereby defining a zero-curvature (inflection) set that discerns between sub-threshold and spiking electrical activity. This transition can arise through a Hopf bifurcation, via the so-called canard explosion that happens in an exponentially small parameter variation, and this is typical for a large class of planar neuronal models (FitzHugh-Nagumo, reduced Hodgkin-Huxley), namely, type II neurons (resonators). This transition can also correspond to the crossing of the stable manifold of a saddle equilibrium, in the case of type I neurons (integrators). We compute inflection sets and study how well they approximate the excitability threshold of these neuron models, that is, both in the canard and in the non-canard regime, using tools from invariant manifold theory and singularity theory. With the latter, we investigate the topological changes that inflection sets undergo upon parameter variation. Finally, we show that the concept of inflection set gives a good approximation of the threshold in both the so-called resonator and integrator neuronal cases. PMID- 22945513 TI - Lung carcinogenesis by tobacco smoke. AB - Cigarette smoke is a complex mixture of chemicals including multiple genotoxic lung carcinogens. The classic mechanisms of carcinogen metabolic activation to DNA adducts, leading to miscoding and mutations in critical growth control genes, applies to this mixture but some aspects are difficult to establish because of the complexity of the exposure. This article discusses certain features of this mechanism including the role of nicotine and its receptors; lung carcinogens, co carcinogens and related substances in cigarette smoke; structurally characterized DNA adducts in the lungs of smokers; the mutational consequences of DNA adduct formation in smokers' lungs; and biomarkers of nicotine and carcinogen uptake as related to lung cancer. While there are still uncertainties which may never be fully resolved, the general mechanisms by which cigarette smoking causes lung cancer are well understood and provide insights relevant to prevention of lung cancer, the number one cancer killer in the world, causing 1.37 million deaths per year. PMID- 22945516 TI - Plasmonic enhancement of a photocycloreversion reaction of a diarylethene derivative using individually dispersed silver nanoparticles. AB - The fabrication of silver nanoparticles covered with polymers with a well-defined core-shell structure and the quantitative evaluation of the plasmonic enhancement effect on a photochemical reaction in the vicinity of these silver nanoparticles individually dispersed in a medium are described. The photocycloreversion reaction of a diarylethene polymer in the vicinity of silver nanoparticles was enhanced by 2-6 times relative to the reaction without the nanoparticles. The promotion of the photocycloreversion reaction is due to enhancement of the electromagnetic field near the surface of the silver core. PMID- 22945514 TI - Self-administration of gamma-hydroxybutyric acid (GHB) precursors gamma butyrolactone (GBL) and 1,4-butanediol (1,4-BD) in baboons. AB - RATIONALE: Gamma-butyrolactone (GBL) and 1,4-butanediol (1,4-BD) are gamma hydroxybutyrate (GHB) pro-drugs and drugs of abuse. OBJECTIVE: Given the reports of abuse, and the ease at which GBL and 1,4-BD may be obtained, we investigated the reinforcing effects of GBL (n = 5) and 1,4-BD (n = 4) in baboons using IV self-administration procedures. METHODS: Sessions ran 24 h/day. Each injection was contingent upon completion of a fixed number (120 or 160) of lever responses. A 3-h timeout period followed each injection, limiting the total number of injections to eight per day. Self-administration was first established with cocaine (0.32 mg/kg/injection). GBL (10-130.0 mg/kg/injection), 1,4-BD (10-100 mg/kg/injection), or vehicle was substituted for cocaine for at least 15 days. Food pellets were available ad libitum 24 h/day and were contingent upon completion of ten lever responses. RESULTS: GBL (32-100 mg/kg/injection) maintained significantly greater numbers of injections when compared to vehicle in four of five baboons, and the mean rates of injection were high (more than six per day) in three baboons and moderate in the fourth baboon (four to six per day). 1,4-BD (78-130 mg/kg/injection) maintained significantly greater numbers of injections when compared to vehicle in only two out of four baboons, and mean rates were moderate to high in both baboons. Self-injection of these doses of GBL and 1,4-BD generally inhibited food-maintained responding. CONCLUSIONS: GBL and 1,4-BD have abuse liability. Given that GBL and 1,4-BD are self-administered, are easier to obtain than GHB, and are detected in seized samples, additional legal control measures of these GHB pro-drugs may be needed. PMID- 22945517 TI - Comparative analysis of the acoustic parameters of vowels in child and adult speech. PMID- 22945515 TI - Differential effects of dopamine transporter inhibitors in the rodent Iowa gambling task: relevance to mania. AB - RATIONALE: The Iowa Gambling Task (IGT) can be used to quantify impulsive and risky choice behaviors in psychiatric patients, e.g., bipolar disorder (BD) sufferers. Although developing treatments for these behaviors is important, few predictive animal models exist. Inhibition of the dopamine transporter (DAT) can model profiles of altered motor activity and exploration seen in patients with BD. The effect of DAT inhibition on impulsive choices related to BD has received limited study however. We used a rodent IGT to elucidate the effects of similarly acting drugs on risky choice behavior. OBJECTIVES: We hypothesized that (1) C57BL/6 mice could adopt the "safe" choice options in the IGT and (2) DAT inhibition would alter risk preference. METHODS: Mice were trained in the IGT to a stable risk-preference and then administered the norepinephrine/DAT inhibitor amphetamine, or the more selective DAT inhibitors modafinil or GBR12909. RESULTS: Mice developed a preference for the "safe" option, which was potentiated by amphetamine administration. GBR12909 or modafinil administration increased motor impulsivity, motivation significantly, and risk preference subtly. CONCLUSIONS: The rodent IGT can measure different impulse-related behaviors and differentiate similarly acting BD-related drugs. The contrasting effects of amphetamine and modafinil in mice are similar to effects in rats and humans in corresponding IGT tasks, supporting the translational validity of the task. GBR12909 and modafinil elicited similar behaviors in the IGT, likely through a shared mechanism. Future studies using a within-session IGT are warranted to confirm the suitability of DAT inhibitors to model risk-preference in BD. PMID- 22945518 TI - Homologous thalamic nuclei of the tectofugal visual system of reptiles and birds have different immunoreactivities towards calcium-binding proteins. PMID- 22945519 TI - Expression of toll-like receptors 4 in nerve plexuses of the rat duodenum, jejunum, and colon. PMID- 22945521 TI - Immunodetection of cistathionine beta-synthase and cistathionine gamma-liase in the walls of cerebral arteries in normo- and hypertensive rats. PMID- 22945520 TI - Changes in copper metabolism in rat liver after adrenalectomy. PMID- 22945523 TI - The effect of low temperature on wheat roots causes rapid changes in chloroplast ultrastructure in wheat leaves. PMID- 22945522 TI - Involvement of microtubules in the glutoxim regulation of Na(+) transport in the frog skin. PMID- 22945524 TI - Lipid content in the young-of-the-year sockeye salmon Oncorhynchus nerka during feeding migration (the Ozernaya River, Western Kamchatka). PMID- 22945525 TI - New evidence for the existence of pleistocene cave bears in Arctic Siberia. PMID- 22945526 TI - Expression of nucleostemin in proliferating and differentiating cells of the human retina during prenatal development. PMID- 22945527 TI - Oscillatory processes in the interaction of air-dry soils with water. PMID- 22945528 TI - Molecular phylogeny of the Dacnomys division (Rodentia, Muridae): the taxonomic positions of Saxatilomys and Leopoldamys. PMID- 22945529 TI - New data on the symbiosis of Ischyrocerus amphipods colonizing the eggs of the host species, red king crab. PMID- 22945530 TI - Fatty acids of tissues of rainbow trout Parasalmo mykiss (Walbaum, 1792) depending on season, age, and forage composition. PMID- 22945531 TI - Center of species diversity of Eurasian marmots (Marmota, Rodentia) in an epi platformal orogeny area. PMID- 22945532 TI - Differences in length, weight, and feeding characteristics of hatchery-reared juvenile black sea trout (Salmo trutta labrax pall.) from two spatial groups. PMID- 22945533 TI - On the mechanism of nanostructural organization of soil gels. PMID- 22945534 TI - Regulation of the transcription of plastid genes in plants by brassinosteroids. PMID- 22945535 TI - The ability to accumulate fat reserves during pregnancy inherited in the maternal line increases the viability and reproductive potential of daughters: an example of water voles Arvicola Amphibius. PMID- 22945536 TI - Lipolytic enzymes of microorganisms from permafrost cryopegs. PMID- 22945538 TI - Thalamocortical disconnection in the orbitofrontal region associated with cortical thinning in schizophrenia. AB - CONTEXT: Dysfunction of the thalamocortical pathway has been proposed as a putative underlying pathology of schizophrenia. Although the mechanisms involved remain unclear, postmortem studies suggest the involvement of altered neural projections from the thalamus to layers within the prefrontal cortex. OBJECTIVES: To investigate thalamocortical connectivity in schizophrenia and to examine its possible association with cortical thinning in vivo. DESIGN: Case-control cross sectional study. SETTING: Department of Psychiatry at Kyoto University Hospital, Japan. PATIENTS AND OTHER PARTICIPANTS: A total of 37 patients with schizophrenia and 36 age-, sex-, and education-matched healthy controls recruited from the local community underwent diffusion-weighted imaging and T1-weighted 3 dimensional magnetic resonance imaging. MAIN OUTCOME MEASURES: Probabilistic tractography was performed to investigate thalamocortical pathways. Group differences in mean fractional anisotropy (FA) values were examined in the entire thalamocortical pathway, the thalamolateral prefrontal pathway, the thalamomedial prefrontal pathway, and the thalamo-orbitofrontal pathway. Surface-based analysis was performed to investigate cortical thickness, and the correlation between FA values and cortical thickness was examined. RESULTS: The patient group exhibited reduced FA values within the right thalamo-orbitofrontal pathway (P < .05 for the 8 group comparisons of FA, Bonferroni correction). In the patient group only, the mean FA value for this pathway was positively correlated with thickness of the right frontal polar and lateral orbitofrontal cortices (P < .05, clusterwise correction). CONCLUSIONS: These results suggest that, in schizophrenia, regional thalamocortical white matter pathology is specifically associated with cortical pathology in regions where fibers connect. PMID- 22945537 TI - Serotonin receptor 1B genotype and hostility, anger and aggressive behavior through the lifespan: the Young Finns study. AB - The serotonin system has been shown to be involved in the regulation of hostility, anger, and aggressive behavior. Previous molecular genetic studies suggest that the serotonin receptor 1B (HTR1B) rs6296 genotype might have a particular role in these types of behaviors. We examined whether HTR1B is related to hostility, anger, and aggressive behavior phenotypes over a lifespan and whether it modifies the connection between childhood aggressive behavior and adulthood hostility and anger. The participants were 967 women and men from a large population based sample (The Young Finns Study) with a 27-year follow-up. Childhood aggressive behavior was reported by the mother twice when the participants were 3 to 12 years of age. Adulthood hostility and anger were self reported by the participants between ages 24 and 36. Childhood aggressive behavior predicted adulthood hostility over 27 years. HTR1B SNP rs6296 was associated with childhood aggressive behavior but not with adulthood anger or hostility. The HTR1B SNP rs6296 modified the association between childhood aggressive behavior and adulthood hostility. Aggressive behavior and hostility might form a life course pattern, and the HTR1B might contribute to a development of this pattern. PMID- 22945539 TI - Incremental treatments with laser therapy augments good behavioral outcome in the rabbit small clot embolic stroke model. AB - Transcranial near-infrared laser therapy (TLT) improves behavioral outcome in animal stroke models when applied as single treatment within the 24 h of the stroke onset. It is unknown if the multiple TLT treatments have an added beneficial effect. We aim to determine whether multiple irradiations with TLT would have further improvement in behavioral outcomes in the rabbit small clot embolic stroke model (RSCEM). Using the RSCEM, two and three TLT treatments (7.5 20 mW/cm(2)) were compared against single laser treatment alone (7.5-10.8 mW/cm(2)). Two sham irradiation groups were added for the control curves. The double treatment group received TLT at 3 and 5 h and the triple treatment group at 2, 3, and 4 h after embolization. Behavioral analysis was conducted 24 h after embolization using a dichotomized behavioral score. The determination of the effective clot amount (milligrams) that produces neurological deficits in 50 % of the rabbits (P 50) was used to compare TLT treatments with the sham. The P 50 for double treatment was 5.47 +/- 0.90, with n = 39; the corresponding P 50 value for a single treatment was 3.87 +/- 0.73, with n = 38; and the corresponding control curve was 3.25 +/- 0.4, n = 32. The P 50 for triple treatment was 5.91 +/- 0.49, with n = 23; the corresponding P 50 value for a single treatment was 3.09 +/- 0.59, with n = 15, and the corresponding control curve was 1.71 +/- 0.26, with n = 17. The triple treatment had 91 % improvement when compared with the single treatment and 245 % improvement when compared with the sham. The present study suggests that the additional TLT treatments provide further behavioral improvement when given during the acute ischemic stroke phase. PMID- 22945540 TI - Influence of CPAP treatment on airway and systemic inflammation in OSAS patients. AB - AIM: Obstructive sleep apnea syndrome (OSAS) is characterized by recurrent respiratory disorders in the upper airways during sleep. Although continuous positive airway pressure (CPAP) has been accepted to be the most effective treatment for OSAS, its role on inflammation remains debatable. In this study, our aim was to examine the influence of 3 months of CPAP treatment on tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), 8-isoprostane, and peroxynitrite levels in exhaled breathing condensates (EBC) and serum. METHODS: Thirty-five patients who were newly diagnosed as moderate or severe OSAS with full night polysomnography and used CPAP therapy regularly for 3 months were included in the study. Polysomnography, spirometric tests, fasting blood samples, and EBC were ascertained on entry into the study and after 3 months of treatment. All patients were assessed monthly for treatment adherence and side effects. RESULTS: We found that all polysomnographic parameters were normalized after CPAP therapy in the control polysomnogram. Also, all markers in EBC and nitrotyrosine and 8-isoprostane levels in serum were decreased significantly with CPAP treatment. Sedimentation rate, C-reactive protein, IL-6, and TNF-alpha remained unchanged in serum after treatment. We found that baseline nitrotyrosine levels were significantly correlated with apnea-hypopnea index, oxygen desaturation index, and percent time in SpO2 < 90 % (p < 0.01). CONCLUSIONS: CPAP therapy has primarily a relevant impact on airways, and nitrotyrosine levels correlated well with severity of OSAS. This treatment decreases both inflammation and oxidative stress levels in airways in OSAS patients. Also, this treatment helps to decrease systemic oxidative stress levels in serum. PMID- 22945541 TI - Stage-matched intervention for adherence to CPAP in patients with obstructive sleep apnea: a randomized controlled trial. AB - PURPOSE: The objective of the study was to evaluate the effectiveness of stage matched intervention on adherence to continuous positive airway pressure (CPAP) in patients with obstructive sleep apnea syndrome. METHODS: One hundred and ten Chinese patients with newly diagnosed obstructive sleep apnea syndrome were enrolled in this study. They were randomly assigned into stage-matched care (SMC) and standard care (SC) groups (55 patients in each group). Patients in the SMC group received stage-matched intervention at different stages of behavior changes, and the SC group received only routine care. The intervention was based on the health action process approach theory and included risk perception, outcome expectancy, and self-efficacy. Questionnaires included the Self-Efficacy Measure for Sleep Apnea, the Epworth Sleepiness Scale (ESS), and the Pittsburgh Sleep Quality Index (PSQI). Data were collected at baseline and 1 and 3 months after home CPAP treatment, and hours of CPAP usage was also recorded at 1 and 3 months of follow-up. RESULTS: At 1 month, CPAP usage was 5.59 +/- 0.56 h/night (mean +/- SD) vs 5.28 +/- 0.67 h/night in the SMC and SC groups, respectively (p = 0.016). At 3 months, CPAP usage was 5.65 +/- 0.50 vs 5.26 +/- 0.82 h/night in the SMC and SC groups, respectively (p = 0.006). Repeated ANOVA analysis demonstrated that risk perception, outcome expectancy, and self-efficacy in the SMC group were significantly higher than those of the SC group (p < 0.05). Moreover, the time * group interaction was significant for outcome expectancy and self-efficacy, indicating that the groups differed significantly in changes in outcome expectancy and self-efficacy over the three time points. There was a significant difference between the SMC and SC groups in terms of improvement in ESS (p < 0.001) and PSQI (p = 0.013) after 3 months of CPAP treatment. CONCLUSIONS: Stage-matched intervention could not only facilitate intention formation and enhance treatment self-efficacy but significantly improve CPAP adherence in OSA patients for the 3-month treatment. PMID- 22945542 TI - Velocity measurement accuracy in optical microhemodynamics: experiment and simulation. AB - Micro particle image velocimetry (uPIV) is a common method to assess flow behavior in blood microvessels in vitro as well as in vivo. The use of red blood cells (RBCs) as tracer particles, as generally considered in vivo, creates a large depth of correlation (DOC), even as large as the vessel itself, which decreases the accuracy of the method. The limitations of uPIV for blood flow measurements based on RBC tracking still have to be evaluated. In this study, in vitro and in silico models were used to understand the effect of the DOC on blood flow measurements using uPIV RBC tracer particles. We therefore employed a uPIV technique to assess blood flow in a 15 um radius glass tube with a high-speed CMOS camera. The tube was perfused with a sample of 40% hematocrit blood. The flow measured by a cross-correlating speckle tracking technique was compared to the flow rate of the pump. In addition, a three-dimensional mechanical RBC-flow model was used to simulate optical moving speckle at 20% and 40% hematocrits, in 15 and 20 um radius circular tubes, at different focus planes, flow rates and for various velocity profile shapes. The velocity profiles extracted from the simulated pictures were compared with good agreement with the corresponding velocity profiles implemented in the mechanical model. The flow rates from both the in vitro flow phantom and the mathematical model were accurately measured with less than 10% errors. Simulation results demonstrated that the hematocrit (paired t tests, p = 0.5) and the tube radius (p = 0.1) do not influence the precision of the measured flow rate, whereas the shape of the velocity profile (p < 0.001) and the location of the focus plane (p < 0.001) do, as indicated by measured errors ranging from 3% to 97%. In conclusion, the use of RBCs as tracer particles makes a large DOC and affects the image processing required to estimate the flow velocities. We found that the current uPIV method is acceptable to estimate the flow rate on the condition that the measurement takes place at the equatorial plane of the vessel. Otherwise, it is not an appropriate method to estimate the shape of the velocity profile. PMID- 22945543 TI - Epilepsy: Psychiatric adverse effects of levetiracetam linked to genetic variation in dopamine signalling. PMID- 22945545 TI - Motor neuron disease: inflammatory monocytes--a novel therapeutic target for ALS? PMID- 22945546 TI - Room temperature solid-state synthesis of a conductive polymer for applications in stable I2-free dye-sensitized solar cells. AB - A solid-state polymerizable monomer, 2,5-dibromo-3,4-propylenedioxythiophene (DBProDOT), was synthesized at 25 degrees C to produce a conducting polymer, poly(3,4-propylenedioxythiophene) (PProDOT). Crystallographic studies revealed a short interplane distance between DBProDOT molecules, which was responsible for polymerization at low temperature with a lower activation energy and higher exothermic reaction than 2,5-dibromo-3,4-ethylenedioxythiophene (DBEDOT) or its derivatives. Upon solid-state polymerization (SSP) of DBProDOT at 25 degrees C, PProDOT was obtained in a self-doped state with tribromide ions and an electrical conductivity of 0.05 S cm-1, which is considerably higher than that of chemically polymerized PProDOT (2*10-6 S cm-1). Solid-state 13C NMR spectroscopy and DFT calculations revealed polarons in PProDOT and a strong perturbation of carbon nuclei in thiophenes as a result of paramagnetic broadening. DBProDOT molecules deeply penetrated and polymerized to fill nanocrystalline TiO2 pores with PProDOT, which functioned as a hole-transporting material (HTM) for I2-free solid state dye-sensitized solar cells (ssDSSCs). With the introduction of an organized mesoporous TiO2 (OM-TiO2) layer, the energy conversion efficiency reached 3.5 % at 100 mW cm-2, which was quite stable up to at least 1500 h. The cell performance and stability was attributed to the high stability of PProDOT, with the high conductivity and improved interfacial contact of the electrode/HTM resulting in reduced interfacial resistance and enhanced electron lifetime. PMID- 22945547 TI - Vitamin D content of food and its contribution to vitamin D status: a brief overview and Australian focus. AB - There are only a few natural foods that contain nutritionally significant quantities of vitamin D. These include egg yolk, some fatty fish, and in much lower concentrations, meat. The published values of the vitamin D content of food are summarised here and their contribution to dietary vitamin D intake is discussed, with particular reference to Australia. Dietary vitamin D is unlikely to reach the level recommended by the US Institute of Medicine. It is therefore concluded that dietary vitamin D will only be a component of vitamin D supply, with UV exposure and/or oral supplements continuing to be the main sources of vitamin D to maintain adequate status. PMID- 22945544 TI - Treatment of hereditary optic neuropathies. AB - The hereditary optic neuropathies are inherited disorders in which optic nerve dysfunction is a prominent feature in the phenotypic expression of disease. Optic neuropathy may be primarily an isolated finding, such as in Leber hereditary optic neuropathy and dominant optic atrophy, or part of a multisystem disorder. The pathophysiological mechanisms underlying the hereditary optic neuropathies involve mitochondrial dysfunction owing to mutations in mitochondrial or nuclear DNA that encodes proteins essential to mitochondrial function. Effective treatments are limited, and current management includes therapies directed at enhancing mitochondrial function and preventing oxidative damage, as well as genetic counselling, and supportive and symptomatic measures. New therapies, including gene therapy, are emerging via animal models and human clinical trials. Leber hereditary optic neuropathy, in particular, provides a unique model for testing promising treatments owing to its characteristic sequential bilateral involvement and the accessibility of target tissue within the eye. Lessons learned from treatment of the hereditary optic neuropathies may have therapeutic implications for other disorders of presumed mitochondrial dysfunction. In this Review, the natural history of the common inherited optic neuropathies, the presumed pathogenesis of several of these disorders, and the literature to date regarding potential therapies are summarized. PMID- 22945548 TI - High levels of vulnerability and anticipated stigma reduce the impetus for tuberculosis diagnosis in Cape Town, South Africa. AB - Prolonged diagnostic and treatment delays, particularly in settings experiencing concomitant human immunodeficiency virus (HIV) and tuberculosis (TB) epidemics, undermine global TB control efforts. Current TB control policy in South Africa, as organized through the National TB Control Programme (NTP), relies on the voluntary presentation of TB suspects to local clinics for diagnosis, i.e. passive case finding (PCF). In 2005 a participatory study suggested that popular interpretation and perception of TB within eight South African township sites in and around Cape Town, all carrying a high burden of HIV and undiagnosed TB, undermine PCF. Both people's association of TB with dirt and squalor, and the anticipation of HIV-related stigma, combine to impede TB diagnosis. Respondents conveyed TB as unavoidable; this perception is expressed in the context of vulnerability where so much-including dirt-is largely beyond the control of local residents. The lack of control has a disempowering effect, reducing the drive for seeking treatment. In addition, low confidence in patient confidentiality and anticipated HIV-related stigma act as direct deterrents to TB diagnosis and treatment. In conclusion, we wish to draw attention to high levels of disease stigma and vulnerability, and how these undermine PCF. Public health interventions that wish to improve case detection should aim to: (1) emphasize how early treatment improves outcome and can curb ongoing transmission; (2) combat a sense of communal vulnerability to TB; (3) address anticipated HIV-TB stigma; and (4) improve the quality of care provided at local diagnostic services, addressing low levels of patient confidentiality. PMID- 22945549 TI - A mesostructured Y zeolite as a superior FCC catalyst--lab to refinery. AB - A mesostructured Y zeolite was prepared by a surfactant-templated process at the commercial scale and tested in a refinery, showing superior hydrothermal stability and catalytic cracking selectivity, which demonstrates, for the first time, the promising future of mesoporous zeolites in large scale industrial applications. PMID- 22945550 TI - Transition metal oxides for organic electronics: energetics, device physics and applications. AB - During the last few years, transition metal oxides (TMO) such as molybdenum tri oxide (MoO(3) ), vanadium pent-oxide (V(2) O(5) ) or tungsten tri-oxide (WO(3) ) have been extensively studied because of their exceptional electronic properties for charge injection and extraction in organic electronic devices. These unique properties have led to the performance enhancement of several types of devices and to a variety of novel applications. TMOs have been used to realize efficient and long-term stable p-type doping of wide band gap organic materials, charge generation junctions for stacked organic light emitting diodes (OLED), sputtering buffer layers for semi-transparent devices, and organic photovoltaic (OPV) cells with improved charge extraction, enhanced power conversion efficiency and substantially improved long term stability. Energetics in general play a key role in advancing device structure and performance in organic electronics; however, the literature provides a very inconsistent picture of the electronic structure of TMOs and the resulting interpretation of their role as functional constituents in organic electronics. With this review we intend to clarify some of the existing misconceptions. An overview of TMO-based device architectures ranging from transparent OLEDs to tandem OPV cells is also given. Various TMO film deposition methods are reviewed, addressing vacuum evaporation and recent approaches for solution-based processing. The specific properties of the resulting materials and their role as functional layers in organic devices are discussed. PMID- 22945551 TI - Hierarchical supramolecular spinning of nanofibers in a microfluidic channel: tuning nanostructures at a dynamic interface. AB - One of the fundamental problems in supramolecular chemistry, as well as in material sciences, is how to control the self-assembly of polymers on the nanometer scale and how to spontaneously organize them towards the macroscopic scale. To overcome this problem, inspired by the self-assembly systems in nature, which feature the dynamically controlled self-assembly of biopolymers, we have previously proposed a self-assembly system that uses a dynamic liquid/liquid interface with dimensions in the micrometer regime, thereby allowing polymers to self-assemble under precisely controlled nonequilibrium conditions. Herein, we further extend this system to the creation of hierarchical self-assembled architectures of polysaccharides. A natural polysaccharide, beta-1,3-glucan (SPG), and water were injected into opposite "legs" of microfluidic devices that had a Y-shape junction, so that two solvents would gradually mix in the down stem, thereby causing SPG to spontaneously self-assemble along the flow in a head to-tail fashion, mainly through hydrophobic interactions. In the initial stage, several SPG nanofibers would self-assemble at the Y-junction owing to the shearing force, thereby creating oligomers with a three-way junction point. This unique structure, which could not be created through conventional mixing procedures, has a divergent self-assembly capability. The dynamic flow allows the oligomers to interact continuously with SPG nanofibers that are fed into the Y junction, thus amplifying the nanostructure along the flow to form SPG networks. Consequently, we were able to create stable, centimeter-length macroscopic polysaccharide strands under the selected flow conditions, which implies that SPG nanofibers were assembled hierarchically in a supramolecular fashion in the dynamic flow. Microscopic observations, including SEM and AFM analysis, revealed the existence of clear hierarchical structures inside the obtained strand. The network structures self-assembled to form sub-micrometer-sized fibers. The long fibers further entangled with each other to give stable micrometer-sized fibers, which finally assembled to form the macroscopic strands, in which the final stabilities in the macroscopic regime were governed by that of the network structures in the nanometer regime. Thus, we have exploited this new supramolecular system to create hierarchical polymeric architectures under precisely controlled flow conditions, by combining the conventional supramolecular strategy with microfluidic science. PMID- 22945552 TI - Advances in targeting voltage-gated sodium channels with small molecules. AB - Blockade of voltage-gated sodium channels (VGSCs) has been used successfully in the clinic to enable control of pathological firing patterns that occur in conditions as diverse as chronic pain, epilepsy, and arrhythmias. Herein we review the state of the art in marketed sodium channel inhibitors, including a brief compendium of their binding sites and of the cellular and molecular biology of sodium channels. Despite the preferential action of this drug class toward over-excited cells, which significantly limits potential undesired side effects on other cells, the need to develop a second generation of sodium channel inhibitors to overcome their critical clinical shortcomings is apparent. Current approaches in drug discovery to deliver novel and truly innovative sodium channel inhibitors is next presented by surveying the most recent medicinal chemistry breakthroughs in the field of small molecules and developments in automated patch clamp platforms. Various strategies aimed at identifying small molecules that target either particular isoforms of sodium channels involved in specific diseases or anomalous sodium channel currents, irrespective of the isoform by which they have been generated, are critically discussed and revised. PMID- 22945553 TI - Laboratory variability and precise clinical decision making. PMID- 22945554 TI - Isolating stem cells in the inter-follicular epidermis employing synchrotron radiation-based Fourier-transform infrared microspectroscopy and focal plane array imaging. AB - Normal function and physiology of the epidermis is maintained by the regenerative capacity of this tissue via adult stem cells (SCs). However, definitive identifying markers for SCs remain elusive. Infrared (IR) spectroscopy exploits the ability of cellular biomolecules to absorb in the mid-IR region (lambda = 2.5 25 MUm), detecting vibrational transitions of chemical bonds. In this study, we exploited the cell's inherent biochemical composition to discriminate SCs of the inter-follicular skin epidermis based on IR-derived markers. Paraffin-embedded samples of human scalp skin (n = 4) were obtained, and 10-MUm thick sections were mounted for IR spectroscopy. Samples were interrogated in transmission mode using synchrotron radiation-based Fourier-transform IR (FTIR) microspectroscopy (15 * 15 MUm) and also imaged employing globar-source FTIR focal plane array (FPA) imaging (5.4 * 5.4 MUm). Dependent on the location of derived spectra, wavenumber absorbance/intensity relationships were examined using unsupervised principal component analysis. This approach showed clear separation and spectral differences dependent on cell type. Spectral biomarkers concurrently associated with segregation of SCs, transit-amplifying cells and terminally-differentiated cells of epidermis were primarily PO(2)(-) vibrational modes (1,225 and 1,080 cm( 1)), related to DNA conformational alterations. FPA imaging coupled with hierarchical cluster analysis also indicated the presence of specific basal layer cells potentially originating from the follicular bulge, suggested by co clustering of spectra. This study highlights PO (2) (-) vibrational modes as potential putative SC markers. PMID- 22945555 TI - Real-time determination of the activity of ATPase by use of a water-soluble polythiophene. AB - This contribution introduces a fluorescence assay for real-time determination of the activity of p97/VCP, a 540-kDa homo-hexameric enzyme, belonging to the AAA ATPase family. A fluorescent reporter "poly 1-(3-((4-methylthiophen-3 yl)oxy)propyl)quinuclidin-1-ium" (poly PTQ) is used to monitor the hydrolysis of ATP to ADP by p97/VCP. The proposed assay relies on the different strength of coordination of ATP and ADP to the polymer backbone. We used recovery of fluorescence intensity on addition of p97/VCP to a poly PTQ/ATP solution to determine the enzymatic activity. The kinetic data K (m) and V (max) were 0.30 mmol L(-1) ATP and 0.134 nmol ATP min(-1) MUg(-1) enzyme, respectively. The specificity of the assay was investigated by using an unhydrolyzable ATP analogue and sensitivity against p97 mutagenesis was further examined by detection of the activity of wild type and truncated p97/VCP. Our study demonstrates that determination of the real-time activity of p97/VCP is possible, because of the superior sensitivity and very fast optical response of poly PTQ. PMID- 22945556 TI - Structural stability-chromatographic retention relationship on exenatide diastereomer separation. AB - In this study, the relationship of the structural stability of peptide diastereomers in elution solvents and their retention behaviors in reversed-phase chromatography (RPC) was examined to provide guidance on the solvent selection for a better separation of peptide diastereomers. We investigated the chromatographic retention behaviors of exenatide, a peptide drug for the treatment of type II diabetes mellitus and its three diastereomers using RPC and implicit molecular dynamics (MD) simulation analysis. Three diastereomers involved in the single serine residue mutation of D-form at the 11th, 32nd, and 39th residues were investigated in this study. Results show that the order of the solution structural stability of exenatide and its diastereomers is consistent with their retention order by 36 % acetonitrile/water elution. The sample loading solvent also affects the retention behaviors of exenatide peptide diastereomers in RPC column. Furthermore, a larger solution conformation energy difference of the critical pair of exenatide and its diastereomer (D-Ser39) at the elution solvent of 32 % tetrahydrofuran/water were obtained by MD simulation, and baseline separation was proved experimentally. In summary, we demonstrated that the solution structural stability-chromatographic retention relationship could be a powerful tool for elution solvent selection in peptide chromatographic purification, especially valuable for the separation of critical pair of diastereomers. PMID- 22945557 TI - Evaluating the validity of spectral calibration models for quantitative analysis following signal preprocessing. AB - When paired with high-powered chemometric analysis, spectrometric methods offer great promise for the high-throughput analysis of complex systems. Effective classification or quantification often relies on signal preprocessing to reduce spectral interference and optimize the apparent performance of a calibration model. However, less frequently addressed by systematic research is the affect of preprocessing on the statistical accuracy of a calibration result. The present work demonstrates the effectiveness of two criteria for validating the performance of signal preprocessing in multivariate models in the important dimensions of bias and precision. To assess the extent of bias, we explore the applicability of the elliptic joint confidence region (EJCR) test and devise a new means to evaluate precision by a bias-corrected root mean square error of prediction. We show how these criteria can effectively gauge the success of signal pretreatments in suppressing spectral interference while providing a straightforward means to determine the optimal level of model complexity. This methodology offers a graphical diagnostic by which to visualize the consequences of pretreatment on complex multivariate models, enabling optimization with greater confidence. To demonstrate the application of the EJCR criterion in this context, we evaluate the validity of representative calibration models using standard pretreatment strategies on three spectral data sets. The results indicate that the proposed methodology facilitates the reliable optimization of a well-validated calibration model, thus improving the capability of spectrophotometric analysis. PMID- 22945558 TI - Separation mechanism of chiral impurities, ephedrine and pseudoephedrine, found in amphetamine-type substances using achiral modifiers in the gas phase. AB - A new mechanism is proposed that describes the gas-phase separation of chiral molecules found in amphetamine-type substances (ATS) by the use of high resolution ion mobility spectrometry (IMS). Straight-chain achiral alcohols of increasing carbon chain length, from methanol to n-octanol, are used as drift gas modifiers in IMS to highlight the mechanism proposed for gas-phase separations of these chiral molecules. The results suggest the possibility of using these achiral modifiers to separate the chiral molecules (R,S) and (S,R)-ephedrine and (S,S) and (R,R)-pseudoephedrine which contain an internal hydroxyl group at the first chiral center and an amino group at the other chiral center. Ionization was achieved with an electrospray source, the ions were introduced into an IMS with a resolving power of 80, and the resulting ion clusters were characterized with a coupled quadrupole mass spectrometer detector. A complementary computational study conducted at the density functional B3LYP/6-31g level of theory for the electronic structure of the analyte-modifier clusters was also performed, and showed either "bridged" or "independent" binding. The combined experimental and simulation data support the proposed mechanism for gas-phase chiral separations using achiral modifiers in the gas phase, thus enhancing the potential to conduct fast chiral separations with relative ease and efficiency. PMID- 22945559 TI - The Andreev states of a superconducting quantum dot: mean field versus exact numerical results. AB - We analyze the spectral density of a single level quantum dot coupled to superconducting leads focusing on the Andreev states appearing within the superconducting gap. We use two complementary approaches: the numerical renormalization group and the Hartree-Fock approximation. Our results show the existence of up to four bound states within the gap when the ground state is a spin doublet (pi phase). Furthermore the results demonstrate the reliability of the mean field description within this phase. This is understood from a complete correspondence that can be established between the exact and the mean field quasiparticle excitation spectrum within the gap. PMID- 22945560 TI - Ovarian cancer: biomarker proteomic diagnosis in progress. AB - Ovarian cancer lacks clear syndromes at an early stage and could result in serious problem in woman's health status. The current diagnostic approach relies on physical examination, ultrasound examination, and blood test for CA125. These approaches could not diagnose early stage ovarian cancer with high sensitivity and specificity. The present paper reviewed the efforts in screening the proteomic biomarkers for ovarian cancer. The sources of biomarkers were discussed. Then, the current techniques in proteomics were introduced. Finally, the biomarkers for ovarian cancer were summarized. PMID- 22945561 TI - acetylcholinesterase inhibitory potential and insecticidal activity of an endophytic Alternaria sp. from Ricinus communis. AB - Keeping in view the vast potential of endophytic fungi to produce bioactive molecules, this study aimed at isolating and screening endophytes for the production of acetylcholinesterase inhibitors. Fifty-four endophytic fungi were isolated from Ricinus communis and screened for their AChE inhibitory activity using Ellman's colorimetric assay method. Six isolates were found to possess AChE inhibitory activity with maximum inhibition of 78 % being evinced by culture Cas1 which was identified to be Alternaria sp. on the basis of molecular as well as microscopic methods. Optimization of inhibitor production was carried out using one factor at a time approach. Maximum production of inhibitor was obtained on potato dextrose broth after 10 days incubation. The IC(50) of the chloroform extract was observed to be 40 MUg/ml. The extract was purified on silica gel and eluted stepwise with a gradient of chloroform/methanol. The insecticidal potential of the extract was evaluated by feeding the larvae of Spodoptera litura on diet containing varying concentrations of the extract. It was observed that with increase in the concentration of the extract, mortality of the larvae increased. The culture has the potential of being exploited in medicine as well as a biocontrol agent. PMID- 22945562 TI - Prenatal exposure to maternal cigarette smoking, amygdala volume, and fat intake in adolescence. AB - CONTEXT: Prenatal exposure to maternal cigarette smoking is a well-established risk factor for obesity, but the underlying mechanisms are not known. Preference for fatty foods, regulated in part by the brain reward system, may contribute to the development of obesity. OBJECTIVE: To examine whether prenatal exposure to maternal cigarette smoking is associated with enhanced fat intake and risk for obesity, and whether these associations may be related to subtle structural variations in brain regions involved in reward processing. DESIGN: Cross sectional study of a population-based cohort. SETTING: The Saguenay Youth Study, Quebec, Canada. PARTICIPANTS: A total of 378 adolescents (aged 13 to 19 years; Tanner stage 4 and 5 of sexual maturation), half of whom were exposed prenatally to maternal cigarette smoking (mean [SD], 11.1 [6.8] cigarettes/d). MAIN OUTCOME MEASURES: Fat intake was assessed with a 24-hour food recall (percentage of energy intake consumed as fat). Body adiposity was measured with anthropometry and multifrequency bioimpedance. Volumes of key brain structures involved in reward processing, namely the amygdala, nucleus accumbens, and orbitofrontal cortex, were measured with magnetic resonance imaging. RESULTS: Exposed vs nonexposed subjects exhibited a higher total body fat (by approximately 1.7 kg; P = .009) and fat intake (by 2.7%; P = .001). They also exhibited a lower volume of the amygdala (by 95 mm3; P < .001) but not of the other 2 brain structures. Consistent with its possible role in limiting fat intake, amygdala volume correlated inversely with fat intake (r = -0.15; P = .006). CONCLUSIONS: Prenatal exposure to maternal cigarette smoking may promote obesity by enhancing dietary preference for fat, and this effect may be mediated in part through subtle structural variations in the amygdala. PMID- 22945563 TI - Discrete and extended supersandwich structures based on weak interactions between phosphorus and mercury. AB - Supersized mercury: Adducts with polymeric (left) or discrete supersandwich structures (right) form from mixtures of the trinuclear mercury complex [(o C(6)F(4)Hg)(3)] (A) with the triple-decker complex [(CpMo)(2)(MU-eta(6):eta(6) P(6))] (B) in the solid state. This arrangement arises from P...Hg interactions between opposing atoms of the P(6) units and the Hg(3) units (see picture; P purple, Hg-orange, F-green, Mo-red, C-gray). PMID- 22945564 TI - Chemical hazards in the organisation. AB - The use of hazardous chemicals in organisations represents a substantial risk to occupational health, safety and the environment (OHSE). Organisational directors and managers have a responsibility to provide and maintain organisational management systems that manage these risks. The risk management approach of establishing organisational considerations, identifying chemical hazards (health and environmental), assessing and controlling risks and evaluating management activities has become the de facto means of managing organisational hazards in general and may be satisfactorily applied to the management of chemicals in the organisation. The Globally Harmonized System for the Classification and Labelling of Chemicals (GHS) is now at the forefront of major regulatory issues facing the chemicals manufacturing industry and downstream users of chemicals. The GHS offers one system for the classification of all dangerous, toxic and environmental (ecotoxic) effects of chemicals. Organisations should develop occupational health, safety and environment (OHSE) management systems which contain programs and procedures that contain systems for inventory control, hazard communication, competency training, risk assessment and control, transport and storage, monitoring and health surveillance, chemical emergencies (including accident investigation), waste minimisation and disposal, record keeping and management system review. PMID- 22945565 TI - Toxicology of water. AB - To protect the quality of water from toxic pollutants for the health of humans and the environment, two approaches are generally applied in the field of toxicology to predict the effects of pollutants and to monitor the toxic pollutants in water. Here we provide our perspective on state-of-the-art methods to develop water quality criteria and the use of molecular techniques for monitoring water quality. Emphasized is the recent development and application of cell-based assays and small fish model in toxicology research of water. PMID- 22945566 TI - Perfluorinated compounds. AB - Perfluorinated compounds such as the perfluoroalkyl acids (PFAAs) and their derivatives are important man-made chemicals that have wide consumer and industrial applications. They are relatively contemporary chemicals, being in use only since the 1950s and until recently have been considered as biologically inactive. However, during the past decade, their global distribution, environmental persistence, presence in humans and wildlife, and adverse health effects in laboratory animals have come to light, generating scientific, regulatory, and public interest on an international scale. This chapter will provide a brief overview of recent advances in understanding environmental and human exposure, toxicology, and modes of action for this class of compounds in animal models, as well as a summary of epidemiological findings to date. PMID- 22945567 TI - Toxicologically relevant phthalates in food. AB - Various phthalates have been detected in a wide range of food products such as milk, dietary products, fat-enriched food, meat, fish, sea food, beverages, grains, and vegetables as well as in breast milk. Here we present an overview on toxicologically considerable phthalate levels in food reported in the literature. The most common phthalates detected are di-(2-ethylhexyl) phthalate (DEHP), di-n butyl phthalate (DnBP), and di-isobutyl phthalate (DiBP). Milk analyses demonstrate that background levels in unprocessed milk are usually low. However, during processing the phthalate contents may significantly increase due to migration from plastic materials in contact with food. Among dietary products fat enriched food such as cheese and cream were identified with highest levels of DEHP. Plasticized PVC from tubes, conveyor belts, or disposable gloves used in food processing is an important source for contamination of food, especially of fatty food. Paper and cardboard packaging made from recycled fibers are another important source of contamination. In addition, gaskets used in metal lids for glass jars have been identified as possible source for the contamination of foodstuffs with phthalates. The highest concentrations of DEHP reported (>900 mg kg(-1)) were detected in food of high fat content stored in such glass jars. Beyond classical food, DEHP and DnBP were identified in human breast milk samples as the main phthalate contaminants. Phthalate monoesters and some oxidative metabolites were also quantified in breast milk. PMID- 22945568 TI - Exposure to polycyclic aromatic hydrocarbons: bulky DNA adducts and cellular responses. AB - Environmental and dietary carcinogens such as polycyclic aromatic hydrocarbons (PAHs) have been intensively studied for decades. Although the genotoxicity of these compounds is well characterized (i.e., formation of bulky PAH-DNA adducts), molecular details on the DNA damage response triggered by PAHs in cells and tissues remain to be clarified. The conversion of hazardous PAHs into carcinogenic intermediates depends on enzyme-catalyzed biotransformation. Certain cytochrome P450-dependent monooxygenases (CYPs) play a pivotal role in PAH metabolism. In particular, CYP1A1 and 1B1 catalyze oxidation of PAHs toward primary epoxide species that can further be converted into multiple follow-up products, both nonenzymatically and enzymatically. Distinct functions between these major CYP enzymes have only been appreciated since transgenic animal models had been derived. Electrophilic PAH metabolites are capable of forming stable DNA adducts or to promote depurination at damaged nucleotide sites. During the following DNA replication cycle, bulky PAH-DNA adducts may be converted into mutations, thereby affecting hot spot sites in regulatory important genes such as Ras, p53, and others. Depending on the degree of DNA distortion and cell cycle progression, PAH-DNA adducts trigger nucleotide excision repair (NER) and various DNA damage responses that might include TP53-dependent apoptosis in certain cell types. In fact, cellular responses to bulky PAH-DNA damage are complex because distinct signaling branches such as ATM/ATR, NER, TP53, but also MAP kinases, interact and cooperate to determine the overall outcome to cellular injuries initiated by PAH-DNA adducts. Further, PAHs and other xenobiotics can also confer DNA damage via an alternative route of metabolic activation, which leads to the generation of PAH semiquinone radicals and reactive oxygen species (ROS). One electron oxidations mediated by peroxidases or other enzymes can result in PAH radical cations that mainly form unstable DNA adducts subjected to depurination. In addition, generation of ROS can also trigger multiple cellular signaling pathways not directly related to mutagenic or cytotoxic effects, including those mediated by NFkappaB, SAPK/JNK, and p38. In recent years, it became clear that PAHs may also be involved in inflammatory diseases, autoimmune disorders, or atherosclerosis. Further research is under way to better characterize the significance of such newly recognized systemic effects of PAHs and to reconsider risk assessment for human health. PMID- 22945570 TI - Toxicology of ambient particulate matter. AB - It is becoming increasingly clear that inhalation exposure to particulate matter (PM) can lead to or exacerbate various diseases, which are not limited to the lung but extend to the cardiovascular system and possibly other organs and tissues. Epidemiological studies have provided strong evidence for associations with chronic obstructive pulmonary disease (COPD), asthma, bronchitis and cardiovascular disease, while the evidence for a link with lung cancer is less strong. Novel research has provided first hints that exposure to PM might lead to diabetes and central nervous system (CNS) pathology. In the current review, an overview is presented of the toxicological basis for adverse health effects that have been linked to PM inhalation. Oxidative stress and inflammation are discussed as central processes driving adverse effects; in addition, profibrotic and allergic processes are implicated in PM-related diseases. Effects of PM on key cell types considered as regulators of inflammatory, fibrotic and allergic mechanisms are described. PMID- 22945571 TI - Nanomaterials: a challenge for toxicological risk assessment? AB - Nanotechnology has emerged as one of the central technologies in the twenty-first century. This judgment becomes apparent by considering the increasing numbers of people employed in this area; the numbers of patents, of scientific publications, of products on the market; and the amounts of money invested in R&D. Prospects originating from different fields of nanoapplication seem unlimited. However, nanotechnology certainly will not be able to meet all of the ambitious expectations communicated, yet has high potential to heavily affect our daily life in the years to come. This might occur in particular in the field of consumer products, for example, by introducing nanomaterials in cosmetics, textiles, or food contact materials. Another promising area is the application of nanotechnology in medicine fueling hopes to significantly improve diagnosis and treatment of all kinds of diseases. In addition, novel technologies applying nanomaterials are expected to be instrumental in waste remediation and in the production of efficient energy storage devices and thus may help to overcome world's energy problems or to revolutionize computer and data storage technologies. In this chapter, we will focus on nanomaterials. After a brief historic and general overview, current proposals of how to define nanomaterials will be summarized. Due to general limitations, there is still no single, internationally accepted definition of the term "nanomaterial." After elaborating on the status quo and the scope of nanoanalytics and its shortcomings, the current thinking about possible hazards resulting from nanoparticulate exposures, there will be an emphasis on the requirements to be fulfilled for appropriate health risk assessment and regulation of nanomaterials. With regard to reliable risk assessments, until now there is still the remaining issue to be resolved of whether or not specific challenges and unique features exist on the nanoscale that have to be tackled and distinctively addressed, given that they substantially differ from those encountered with microsized materials or regular chemicals. Based on the current knowledge, we finally provide a proposal on how risk assessment in the nanofield could be achieved and how it might look like in the near future. PMID- 22945572 TI - Immunotoxicology and its application in risk assessment. AB - Immunotoxicology is the study of undesired modulation of the immune system by extrinsic factors. Toxicological assessments have demonstrated that the immune system is a target following exposure to a diverse group of xenobiotics including ultraviolet radiation, chemical pollutants, therapeutics, and recreational drugs. There is a well-established cause and effect relationship between suppression of the immune response and reduced resistance to infections and certain types of neoplasia. In humans, mild-to-moderate suppression of the immune response is linked to reduced resistance to common community-acquired infections, whereas opportunistic infections, which are very rare in the general population, are common in individuals with severe suppression. Xenobiotic exposure may also result in unintended stimulation of immune function. Although a cause and effect relationship between unintended stimulation of the immune response and adverse consequences has yet to be established, evidence does suggest that hypersensitivity, autoimmunity, and pathological inflammation may be exacerbated in susceptible populations exposed to certain xenobiotics. Xenobiotics can act as allergens and elicit hypersensitivity responses, or they can modulate hypersensitivity responses to other allergens such as pollen or dust mite by acting as adjuvants, enhancing the development or expression of hypersensitivity. Allergic contact dermatitis, allergic rhinitis, and asthma are the most commonly encountered types of hypersensitivity reactions resulting from chemical exposure. The immunologic effectors and mechanisms involved in autoimmune reactions are the same as those associated with responses to foreign antigens; however, the reactions are directed against the host's own cells. Thus, chemicals that induce immune suppression, nonspecific immunostimulation, or hypersensitivity may also impact autoimmunity. Risk assessment for immunotoxicity should be performed using the same approaches and principles for other noncancer effects. However, since xenobiotics may have effects on more than one aspect of immune function, immunotoxicity data should be evaluated separately for evidence of suppression, stimulation, hypersensitivity, and autoimmunity. PMID- 22945569 TI - Heavy metal toxicity and the environment. AB - Heavy metals are naturally occurring elements that have a high atomic weight and a density at least five times greater than that of water. Their multiple industrial, domestic, agricultural, medical, and technological applications have led to their wide distribution in the environment, raising concerns over their potential effects on human health and the environment. Their toxicity depends on several factors including the dose, route of exposure, and chemical species, as well as the age, gender, genetics, and nutritional status of exposed individuals. Because of their high degree of toxicity, arsenic, cadmium, chromium, lead, and mercury rank among the priority metals that are of public health significance. These metallic elements are considered systemic toxicants that are known to induce multiple organ damage, even at lower levels of exposure. They are also classified as human carcinogens (known or probable) according to the US Environmental Protection Agency and the International Agency for Research on Cancer. This review provides an analysis of their environmental occurrence, production and use, potential for human exposure, and molecular mechanisms of toxicity, genotoxicity, and carcinogenicity. PMID- 22945573 TI - Chemical sensitization and allergotoxicology. AB - Chemical sensitization remains an important environmental and occupational health issue. A wide range of substances have been shown to possess the ability to induce skin sensitization or respiratory sensitization. As a consequence, there is a need to have appropriate methods to identify sensitizing agents. Although a considerable investment has been made in exploring opportunities to develop methods for hazard identification and characterization, there are, as yet, no validated nonanimal methods available. A state of the art of the different in vitro approaches to identify contact and respiratory capacity of chemicals is covered in this chapter. PMID- 22945575 TI - Interspecies uncertainty in molecular responses and toxicity of mixtures. AB - Most of the experimental toxicity testing data for chemicals are generated through the use of laboratory animals, namely, rodents such as rats and mice or other species. Interspecies extrapolation is needed to nullify the differences between species so as to use such data for human health/risk assessment. Thus, understanding of interspecies differences is important in extrapolating the laboratory results to humans and conducting human risk assessments based on current credible scientific knowledge. Major causes of interspecies differences in anatomy and physiology, toxicokinetics, injury repair, molecular receptors, and signal transduction pathways responsible for variations in responses to toxic chemicals are outlined. In the risk assessment process, uncertainty associated with data gaps in our knowledge is reflected by application of uncertainty factors for interspecies differences. Refinement of the risk assessment methods is the ultimate goal as we strive to realistically evaluate the impact of toxic chemicals on human populations. Using specific examples from current risk assessment practice, this chapter illustrates the integration of interspecies differences in evaluation of individual chemicals and chemical mixtures. PMID- 22945576 TI - Recent trends in statistical QSAR modeling of environmental chemical toxicity. AB - Quantitative cheminformatics approaches such as QSAR modeling find growing applications in chemical risk assessment. Traditional methods rely on the use of calculated chemical descriptors of molecules and relatively small training sets. However, in recent years, there is a trend toward the increased use of in vitro biological testing approaches to reduce both the length of experimental studies and the animal use for chemical risk assessment. Furthermore, there is also much greater emphasis on model validation using external datasets to enable the reliable use of computational models as part of regulatory decision making. In this chapter, recent trends emphasizing the need for both careful curation of experimental data prior to model development and rigorous model validation are investigated. Furthermore, recent approaches to chemical toxicity prediction that employ both chemical descriptors and in vitro screening data for developing novel hybrid chemical/biological models are being reviewed. Examples of respective application studies that employ novel workflows for model developments are described and recent important efforts by several academic, nonprofit, and industrial groups to start placing both data and, especially, models in the public domain are discussed. PMID- 22945577 TI - Chirality and its role in environmental toxicology. AB - The role of chirality is crucial in our lives as it affects various processes and phenomenon in the earth's ecosystem. The chiral pollutants are widely distributed in water, soil, sand, air, and biota. Most notorious chiral pollutants are pesticides, biphenyls, polychlorinated hydrocarbons, and some drug residues. Enantiomers of chiral xenobiotics have different toxicities, and, hence, determination of their enantioselective toxicities is essential by the environmental point of views. The toxicities of enantiomers of some chiral pollutants have been established. This chapter describes the origin, chemistry, and environmental aspects of chirality. Attempts have been made to discuss the distribution and toxicities of various chiral pollutants in the environment. PMID- 22945578 TI - Genetic variability in molecular responses to chemical exposure. AB - Individuals differ in their response to environmental exposures. In the following, we describe examples and paradigms of studying heritable differences in response to exposure-commonly known as "gene-environment interaction" or "ecogenetics"-and their relation to disease etiology and susceptibility. Our discussion is framed in three parts. In the first, we describe replicated examples of studies that have typified the field, single genetic variant, and exposure associations to disease. Second, we describe how studies have scaled up search for interaction using genome-wide measurement modalities, bioinformatics, and model organisms. Finally, we discuss a more comprehensive representation of chemical exposures as the "envirome" and how we may use the envirome to examine interplay between genetics and the environment. PMID- 22945579 TI - Biomarkers in toxicology and risk assessment. AB - Over the last 30 years, the field of biomarkers has greatly expanded as early and specific endpoints for monitoring cellular responses to various disease states and exposures to drugs and chemical agents. They have enjoyed some success as predictors of health outcomes for a number of clinical diseases, but the application to chemical exposure risk assessments has been more limited. Biomarkers may be classified into categories of markers of exposure, effect, and susceptibility. Currently, "omics" biomarkers (i.e., genomic, proteomic, and metabolomic/metabonomic) are the major classes of biomarkers under development. These markers represent a continuum of cellular responses to drug or chemical exposures and provide linkages to mechanisms of cell injury/cell death or carcinogenic transformation. On the other hand, translation and application of these biomarkers for risk assessment has been limited due to validation and interpretation issues that need to be addressed in order for these potentially extremely valuable endpoints to reach their full potential as predictive tools for public health. This short chapter will briefly review these three "omics" biomarker classes and examine some validation/translation aspects needed in order for them to reach their full potential and acceptance as valuable tools for application to risk assessment. PMID- 22945574 TI - Male reprotoxicity and endocrine disruption. AB - Mammalian reproductive tract development is a tightly regulated process that can be disrupted following exposure to drugs, toxicants, endocrine-disrupting chemicals (EDCs), or other compounds via alterations to gene and protein expression or epigenetic regulation. Indeed, the impacts of developmental exposure to certain toxicants may not be fully realized until puberty or adulthood when the reproductive tract becomes sexually mature and altered functionality is manifested. Exposures that occur later in life, once development is complete, can also disrupt the intricate hormonal and paracrine interactions responsible for adult functions, such as spermatogenesis. In this chapter, the biology and toxicology of the male reproductive tract is explored, proceeding through the various life stages including in utero development, puberty, adulthood, and senescence. Special attention is given to the discussion of EDCs, chemical mixtures, low-dose effects, transgenerational effects, and potential exposure-related causes of male reproductive tract cancers. PMID- 22945580 TI - A personalized life: biomarker monitoring from cradle to grave. AB - Considering the holy grail of future medical treatment being personalized medicines, biomarker research will become more and more the focus for attention not only to develop new medical treatment regimes, based on changes in biomarker patterns, but also for nutritional advice to guarantee a lifelong optimized health condition. The current review gives an outline of how personalized medicine can become established for actual medical treatment using new biomarker concepts. Starting from the development of biomarker research using mainly immunological techniques, the review gives an overview about biomarkers of prediction evolved and focuses on new methodology for the identification of biomarkers using hyphenated analytical techniques like metabolomics and lipidomics. The actual use of multivariate statistical methods in combination with metabolomics and lipidomics is discussed not only for medical treatment but also for precautionary risk identification in human biomonitoring studies. PMID- 22945581 TI - On the role of low-dose effects and epigenetics in toxicology. AB - For a long time, scientists considered genotoxic effects as the major issue concerning the influence of environmental chemicals on human health. Over the last decades, a new layer superimposed the genome, i.e., the epigenome, tremendously changing this point of view. The term "epigenetics" comprises stable alterations in gene expression potential arising from variations in DNA methylation and a variety of histone modifications, without changing the underlying DNA sequence. Recently, also gene silencing by small noncoding RNAs (ncRNAs), in particular by microRNAs, was included in the list of epigenetic mechanisms. Multiple studies in vivo as well as in vitro have shown that a multitude of different environmental factors are capable of changing the epigenetic pattern as well as miRNA expression in certain cell types, leading to aberrant gene expression profiles in cells and tissues. These changes may have extensive effects concerning the proper gene expression necessary in a specified cell type and can even lead into a state of disease. Especially the roles of epigenetic modifications and miRNA alterations in tumorigenesis have been a major focus in research over the last years. This chapter will give an overview on epigenetic features and on the spectrum of epigenetic changes observed after exposure against environmental chemicals and pollutants. PMID- 22945582 TI - Hormesis: improving predictions in the low-dose zone. AB - This chapter explores the historical foundations of hormesis, including the underlying reasons for its marginalization during most of the twentieth century and factors that are contributing to its resurgence and acceptance within the toxicological and pharmacological communities. Special consideration is given to the quantitative features of the hormetic dose response, as well as its capacity for generalization. Based on subsequent comparisons with other leading dose response models, the hormesis dose response consistently provides more accurate predictions in the below threshold zone. It is expected that the hormetic dose response will become progressively more useful to the fields of toxicology, pharmacology, risk assessment, and the life sciences in general, especially where low-dose effects are of interest. PMID- 22945583 TI - [Werner Selberg. 5 July 1913-9 August 2011]. PMID- 22945585 TI - The natural history of colorectal adenomas and early cancer. AB - Adenomas represent the morphological precursors of the vast majority of colorectal cancers: although every adenoma has the capacity of malignant evolution, most adenomas stabilize their progression or even regress. Pathological factors are predictive of the natural history of adenomas in terms of potential and time interval for becoming malignant. Regression of adenomas is histologically well established, but it is thought to be a dynamic process, with cycling phases of regression and growth. Colorectal carcinoma invading the submucosa but not the muscular layer represents the earliest form of clinically relevant colorectal cancer. Grade of differentiation of carcinoma, lymphovascular invasion, and state of the resection margin predict the risk of metastasis. Microstaging of invasive cancer together with tumuor budding allow the metastatic risk to be further stratified into minimal, low, and high. Two distinct profiles are identifiable in the natural history of cancerous adenomas: blocking the growth of early cancer and allowing its progression towards advanced cancer. Thus, biomarkers to distinguish between progressive and non-progressive pT1 neoplasia are needed. PMID- 22945586 TI - Revealing the absolute configuration of the CO and CN- ligands at the active site of a [NiFe] hydrogenase. AB - Combined molecular dynamics (MD) and quantum mechanical/molecular mechanical (QM/MM) calculations were performed on the crystal structure of the reduced membrane-bound [NiFe] hydrogenase (MBH) from Ralstonia eutropha to determine the absolute configuration of the CO and the two CN(-) ligands bound to the active site iron of the enzyme. For three models that include the CO ligand at different positions, often indistinguishable on the basis of the crystallographic data, we optimized the structures and calculated the ligand stretching frequencies. Comparison with the experimental IR data reveals that the CO ligand is in trans position to the substrate-binding site of the bimetallic [NiFe] cluster. PMID- 22945587 TI - Flexible electrode belt for EIT using nanofiber web dry electrodes. AB - Efficient connection of multiple electrodes to the body for impedance measurement and voltage monitoring applications is of critical importance to measurement quality and practicality. Electrical impedance tomography (EIT) experiments have generally required a cumbersome procedure to attach the multiple electrodes needed in EIT. Once placed, these electrodes must then maintain good contact with the skin during measurements that may last several hours. There is usually also the need to manage the wires that run between the electrodes and the EIT system. These problems become more severe as the number of electrodes increases, and may limit the practicality and portability of this imaging method. There have been several trials describing human-electrode interfaces using configurations such as electrode belts, helmets or rings. In this paper, we describe an electrode belt we developed for long-term EIT monitoring of human lung ventilation. The belt included 16 embossed electrodes that were designed to make good contact with the skin. The electrodes were fabricated using an Ag-plated PVDF nanofiber web and metallic threads. A large contact area and padding were used behind each electrode to improve subject comfort and reduce contact impedances. The electrodes were incorporated, equally spaced, into an elasticated fabric belt. We tested the electrode belt in conjunction with the KHU Mark1 multi-frequency EIT system, and demonstrate time-difference images of phantoms and human subjects during normal breathing and running. We found that the Ag-plated PVDF nanofiber web electrodes were suitable for long-term measurement because of their flexibility and durability. Moreover, the contact impedance and stability of the Ag-plated PVDF nanofiber web electrodes were found to be comparable to similarly tested Ag/AgCl electrodes. PMID- 22945589 TI - Experimental arthritis: JAK inhibition with tofacitinib curbs RANKL-induced joint damage. PMID- 22945588 TI - Antibody response against Betaferon(r) in immune tolerant mice: involvement of marginal zone B-cells and CD4+ T-cells and apparent lack of immunological memory. AB - PURPOSE: The immunological processes underlying immunogenicity of recombinant human therapeutics are poorly understood. Using an immune tolerant mouse model we previously demonstrated that aggregates are a major trigger of the antidrug antibody (ADA) response against recombinant human interferon beta (rhIFNbeta) products including Betaferon(r), and that immunological memory seems to be lacking after a rechallenge with non-aggregated rhIFNbeta. The apparent absence of immunological memory indicates a CD4+ T-cell independent (Tind) immune response underlying ADA formation against Betaferon(r). This hypothesis was tested. METHODS: Using the immune tolerant mouse model we first validated that rechallenge with highly aggregated rhIFNbeta (Betaferon(r)) does not lead to a subsequent fast increase in ADA titers, suggesting a lack of immunological memory. Next we assessed whether Betaferon(r) could act as Tind antigen by inactivation of marginal zone (MZ) B-cells during treatment. MZ B-cells are major effector cells involved in a Tind immune response. In a following experiment we depleted the mice from CD4+ T-cells to test their involvement in the ADA response against Betaferon(r). RESULTS: Inactivation of MZ B-cells at the start of Betaferon(r) treatment drastically lowered ADA levels, suggesting a Tind immune response. However, persistent depletion of CD4+ T-cells before and during Betaferon(r) treatment abolished the ADA response in almost all mice. CONCLUSION: The immune response against rhIFNbeta in immune tolerant mice is neither a T-cell independent nor a classical T-cell dependent immune response. Further studies are needed to confirm absence of immunological memory (cells). PMID- 22945590 TI - Connective tissue diseases: Role for STIM proteins in Sjogren's syndrome pathogenesis. PMID- 22945593 TI - The effect of switchable water additives on clay settling. AB - The recycling of process water from strip mining extractions is a very relevant task both industrially and environmentally. The sedimentation of fine tailings during such processes, however, can often require long periods of time and/or the addition of flocculants which make later water recycling difficult. We propose the use of switchable water additives as reversible flocculants for clay/water suspensions. Switchable water additives are compounds such as diamines that make it possible to reversibly control the ionic strength of an aqueous solution. Addition of CO(2) to such an aqueous solution causes the ionic strength to rise dramatically, and the change is reversed upon removal of the CO(2). These additives, while in the presence of CO(2), promote the aggregation of clay tailings, reduce settling times, and greatly increase the clarity of the liberated water. The removal of CO(2) from the liberated water regenerates a low ionic strength solution that does not promote clay aggregation and settling until CO(2) is added again. Such reversible behavior would be useful in applications such as oil sands separations in which the recycled water must not promote aggregation. When added to kaolinite and montmorillonite clay suspensions, switchable water provided process waters of lower turbidity than those additives from inorganic salts or by CO(2)-treatment alone. When recollected, the switchable water supernatant was shown to be recyclable over three cycles for enhanced settling of kaolinite. PMID- 22945595 TI - Anisotropic elasticity of DyScO3 substrates. AB - The full elastic tensor of orthorhombic dysprosium scandate (DyScO(3)) at room temperature was determined by resonant ultrasound spectroscopy (RUS). Measurements were performed on three 500 MUm thick substrates with orientations (110), (100) and (001) in the Pbnm (a < b < c) setting. For this purpose, a modification of the RUS method was developed, enabling simultaneous processing of the resonant spectra of several platelet-shaped samples with different crystallographic orientations. The obtained results are compared with ab initio calculations and with elastic constants of other rare-earth scandates, and are used for discussion of the in-plane elasticity of the (110)-oriented substrate. PMID- 22945591 TI - Uric acid as a danger signal in gout and its comorbidities. AB - Uric acid is a waste product of purine catabolism. This molecule comes to clinical attention when it nucleates to form crystals of monosodium urate (MSU) in joints or other tissues, and thereby causes the inflammatory disease of gout. Patients with gout frequently suffer from a number of comorbid conditions including hypertension, diabetes mellitus and cardiovascular disease. Why MSU crystals trigger inflammation and are associated with comorbidities of gout has been unclear, but recent studies provide new insights into these issues. Rather than simply being a waste product, uric acid could serve a pathophysiological role as a local alarm signal that alerts the immune system to cell injury and helps to trigger both innate and adaptive immune responses. The inflammatory component of these immune responses is caused when urate crystals trigger both inflammasome-dependent and independent pathways to generate the proinflammatory cytokine IL-1. The resulting bioactive IL-1 stimulates the inflammation of gout and might contribute to the development of other comorbidities. Surprisingly, the same mechanisms underlie the inflammatory response to a number of irritant particles, many of which also cause disease. These new insights help to explain the pathogenesis of gout and point to potential new therapeutic targets for this and other sterile inflammatory diseases. PMID- 22945596 TI - Packaging the fly genome: domains and dynamics. AB - Two independent genomic approaches have recently converged to provide insight into the domain organization of the Drosophila genome. Genome-wide mapping of chromosomal proteins and histone modifications has generated detailed maps of the Drosophila chromatin landscape and has led to the identification of a number of different chromatin states and their distribution in domains across the genome. A remarkably similar domain organization is derived from whole genome mapping of chromatin interactions that reveals the segmentation of the genome into structural domains. This review focuses on our current understanding of this domain architecture which provides a foundation for our understanding of the link between chromatin organization and the dynamic activity of the genome. PMID- 22945592 TI - The genetics of hyperuricaemia and gout. AB - Gout is a common and very painful inflammatory arthritis caused by hyperuricaemia. This review provides an update on the genetics of hyperuricaemia and gout, including findings from genome-wide association studies. Most of the genes that associated with serum uric acid levels or gout are involved in the renal urate-transport system. For example, the urate transporter genes SLC2A9, ABCG2 and SLC22A12 modulate serum uric acid levels and gout risk. The net balance between renal urate absorption and secretion is a major determinant of serum uric acid concentration and loss-of-function mutations in SLC2A9 and SLC22A12 cause hereditary hypouricaemia due to reduced urate absorption and unopposed urate secretion. However, the variance in serum uric acid explained by genetic variants is small and their clinical utility for gout risk prediction seems limited because serum uric acid levels effectively predict gout risk. Urate-associated genes and genetically determined serum uric acid levels were largely unassociated with cardiovascular-metabolic outcomes, challenging the hypothesis of a causal role of serum uric acid in the development of cardiovascular disease. Strong pharmacogenetic associations between HLA-B*5801 alleles and severe allopurinol hypersensitivity reactions were shown in Asian and European populations. Genetic testing for HLA-B*5801 alleles could be used to predict these potentially fatal adverse effects. PMID- 22945597 TI - Layer-by-layer self-assembly in the development of electrochemical energy conversion and storage devices from fuel cells to supercapacitors. AB - As one of the most effective synthesis tools, layer-by-layer (LbL) self-assembly technology can provide a strong non-covalent integration and accurate assembly between homo- or hetero-phase compounds or oppositely charged polyelectrolytes, resulting in highly-ordered nanoscale structures or patterns with excellent functionalities and activities. It has been widely used in the developments of novel materials and nanostructures or patterns from nanotechnologies to medical fields. However, the application of LbL self-assembly in the development of highly efficient electrocatalysts, specific functionalized membranes for proton exchange membrane fuel cells (PEMFCs) and electrode materials for supercapacitors is a relatively new phenomenon. In this review, the application of LbL self assembly in the development and synthesis of key materials of PEMFCs including polyelectrolyte multilayered proton-exchange membranes, methanol-blocking Nafion membranes, highly uniform and efficient Pt-based electrocatalysts, self-assembled polyelectrolyte functionalized carbon nanotubes (CNTs) and graphenes will be reviewed. The application of LbL self-assembly for the development of multilayer nanostructured materials for use in electrochemical supercapacitors will also be reviewed and discussed (250 references). PMID- 22945598 TI - Ultraviolet radiation-induced upregulation of antimicrobial proteins in health and disease. AB - This article reviews recent data on the expression, regulation and activation of antimicrobial peptides (AMP) in human skin, and considers their potential protective and pro-inflammatory roles following upregulation by ultraviolet radiation (UVR). Antimicrobial peptides are small peptides that are key components of the innate immune system, originally identified by their vital role in protecting the body-environment interface from infection. However, it has now become clear that AMP have more extensive actions, including the provision of pivotal links with the adaptive immune system. Moreover, aberrant AMP expression may contribute to immuno-modulated inflammatory dermatoses including psoriasis, eczema and the photoaggravated condition lupus erythematosus. Recent work has demonstrated the direct upregulation of AMP in healthy skin by cutaneous UVR exposure. This may serve to protect the skin from risks imposed by both the biophysical barrier-compromise and the immunosuppression that are attributable to UVR exposure. Furthermore, it is observed that UVR provokes upregulation of AMP in an atypical manner in the photosensitivity disorder polymorphic light eruption. Dysregulated UVR responses of these pro-inflammatory proteins may play a role in the pathogenesis of certain immune-mediated diseases caused or aggravated by sunlight. PMID- 22945599 TI - The evaluation of metastatic lymph node ratio staging system in gastric cancer. AB - BACKGROUND: To evaluate the prognostic value and staging accuracy of the metastatic lymph node ratio (rN) staging system for gastric cancer. METHODS: A total of 1,075 patients with gastric cancer who underwent curative surgery between 2000 and 2009 at our institute were analyzed. Lymph node status was assigned according to the American Joint Committee on Cancer (AJCC) pN system and rN system. Patients with >15 (group 1, n = 691) and <=15 lymph nodes (group 2, n = 384) retrieved were analyzed separately. RESULTS: The rN staging system was generated using 0.2 and 0.5 as the cutoff values of lymph node ratio and then compared with AJCC pN stages. A linear regression model revealed that the number of retrieved lymph nodes was related to the number of metastatic lymph nodes, but not with rN. After a median follow-up of 47.66 months, the 5-year survival rates of N0, N1, N2, and N3 patients of group 1 were significantly better than group 2, whereas the differences were not obvious in the rN classification. CONCLUSIONS: The rN category is a better prognostic tool than the AJCC pN category for gastric cancer patients after curative surgery regardless of the number of lymph node examined. PMID- 22945601 TI - Alignment of liquid crystals using a molecular layer with patterned molecular density. AB - The surface of self-constructed molecular density modulation (SDM) exhibits a wide range of liquid crystal alignment capabilities including planar, tilted, and homeotropic alignments, disclination-free uniform and heterogeneous alignments, and even spatially varying alignments through the single non-contact process. Alignment defects are eliminated by temporary lowering the frictional energy barrier via the open-boundary elastic stabilization (OES) treatment. PMID- 22945600 TI - Assessment of macular function of glaucomatous eyes by multifocal electroretinograms. AB - PURPOSE: To determine whether significant correlations existed between the morphological and functional parameters of the macular region of eyes with open angle glaucoma (OAG). METHODS: Forty eyes of 40 OAG patients were studied. The morphological parameters were obtained by optical coherence tomography (OCT), and the functional parameters were acquired by automated Humphrey Field Analyzer (HFA) and multifocal electroretinograms (mfERGs). All of the tests were performed within 6 months of each other. The retinal thickness was determined by OCT in the nine Early Treatment of Diabetic Retinopathy Study (ETDRS) sectors of the macula, the fovea, and the four quadrants of the inner and an outer ring. The amplitudes of the second-order kernel responses of the mfERGs in the central 5 degrees including the amplitude ratio of the nasal to temporal hemispheres (N/T amplitude ratio) were analyzed. The total mean deviation of the HFA corresponding to each OCT region was measured. The correlation between the different parameters was determined by coefficients of correlation and linear regression analyses. RESULTS: The N/T amplitude ratio of the second-order kernel responses of the mfERGs was significantly correlated with the retinal thickness in the inferior quadrant (r = -0.44; P = 0.004). There was a significant correlation between the N/T amplitude ratio and the threshold in the superior quadrant measured by the HFA Central 10-2 program (r = -0.40; P = 0.011) and also between the N/T amplitude ratio and the total deviation in the superior quadrant (r = -0.40; P = 0.010). There were significant correlations between the inferior retinal thickness and the average threshold and the TD in superior (r = 0.70, P < 0.001; r = 0.692, P < 0.001, respectively), nasal (r = 0.53, P < 0.001; r = 0.53, P < 0.001, respectively), and temporal (r = 0.46, P = 0.003; r = 0.44, P = 0.004, respectively) quadrants. CONCLUSIONS: Functional glaucomatous changes determined by mfERGs and perimetry are significantly correlated with the morphological changes determined by OCT. PMID- 22945603 TI - Regional HIV knowledge hubs: a new approach by the health sector to transform knowledge into practice. AB - This study aims to introduce the knowledge hub (KH) as an initiative to facilitate transformation of knowledge into practice and to highlight the activity and limitations with this new policy. The study was conducted through a review of articles; expert views in this field were sought for further information. Regional human immunodeficiency virus (HIV) KHs were developed by the World Health Organization and GTZ. A series of activities including capacity building, development of training models, technical assistance, and application of studies are provided through these hubs. However, financial limitations are the main obstacle in achieving these aims. This piece of work introduces these HIV hubs in order to help countries, particularly developing countries, provide the support needed to fight the progression of HIV. PMID- 22945602 TI - Identification of drugs inducing phospholipidosis by novel in vitro data. AB - Drug-induced phospholipidosis (PLD) is a lysosomal storage disorder characterized by the accumulation of phospholipids within the lysosome. This adverse drug effect can occur in various tissues and is suspected to impact cellular viability. Therefore, it is important to test chemical compounds for their potential to induce PLD during the drug design process. PLD has been reported to be a side effect of many commonly used drugs, especially those with cationic amphiphilic properties. To predict drug-induced PLD in silico, we established a high-throughput cell-culture-based method to quantitatively determine the induction of PLD by chemical compounds. Using this assay, we tested 297 drug-like compounds at two different concentrations (2.5 MUM and 5.0 MUM). We were able to identify 28 previously unknown PLD-inducing agents. Furthermore, our experimental results enabled the development of a binary classification model to predict PLD inducing agents based on their molecular properties. This random forest prediction system yields a bootstrapped validated accuracy of 86 %. PLD-inducing agents overlap with those that target similar biological processes; a high degree of concordance with PLD-inducing agents was identified for cationic amphiphilic compounds, small molecules that inhibit acid sphingomyelinase, compounds that cross the blood-brain barrier, and compounds that violate Lipinski's rule of five. Furthermore, we were able to show that PLD-inducing compounds applied in combination additively induce PLD. PMID- 22945604 TI - Dose-dependent absorption of chlorogenic acids in the small intestine assessed by coffee consumption in ileostomists. AB - SCOPE: Until now, the question of how the ingested doses of chlorogenic acids (CGA) from coffee influence their absorption and metabolism remains unresolved. To assess absorption in the small intestine, we performed a dose-response study with a randomized, double-blinded, crossover design with ileostomist subjects. METHODS AND RESULTS: After a polyphenol-free diet, the volunteers consumed, on three separate occasions, coffee with different total CGA contents (high 4525 MUmol; medium 2219 MUmol; low 1053 MUmol). CGA concentrations in plasma, ileal effluent, and urine were subsequently determined by HPLC-DAD-ESI-MS and -ESI MS/MS. The results show that the consumption of higher CGA concentrations leads to a faster ileal excretion. This corresponds to a renal excretion of 8.0 +/- 4.9% (high), 12.1 +/- 6.7% (medium), and 14.6 +/- 6.8% (low) of total CGA and metabolites. Glucuronidation of CGA became slightly greater with increasing dose. After enzyme treatment, the area under the curve (AUC)(0-8h) for CGA metabolites in plasma was 4412 +/- 751 nM * h(0-8) (-1) (high), 2394 +/- 637 nM * h(0-8) ( 1) (medium), 1782 +/- 731 nM * h(0-8) (-1) (low), respectively. Additionally, we were able to identify new metabolites of CGA in urine and ileal fluid. CONCLUSION: We conclude that the consumption of high CGA concentrations via coffee might influence the gastrointestinal transit time and consequently affect CGA absorption and metabolism. PMID- 22945605 TI - Using routinely collected growth data to assess a school-based obesity prevention strategy. AB - BACKGROUND: Studies of school-based anti-obesity interventions have yielded inconsistent results. Using growth screening data from a school administrative database, we re-evaluated an obesity prevention strategy that was previously reported to have a beneficial effect on weight status of a sample of students in grades 5-7. METHODS: Ten K-8 schools (five control and five intervention) participated in a 2-year cluster-randomized trial of a multi-component nutrition education intervention. We obtained student height and weight data for 6 consecutive school years and imputed missing baseline and follow-up measurements (53% and 55%, respectively) and defined the target population based on the intent to-treat principle. We analyzed changes in body mass index (BMI) Z-scores via mixed-effects linear regression and in the prevalence of overweight/obesity via conditional logistic regression. We also assessed incidence and remission of overweight/obesity and long-term effects. RESULTS: We analyzed data for 8186 (96%) K-8 students in the 10 schools (4511 in intervention; 3675 in control). From baseline to the end of the intervention period, mean increases in BMI Z score were 0.10 and 0.09 in the control and intervention groups, respectively (P=0.671). The prevalence of overweight/obesity increased by 3% in both groups (P=0.926). There was no significant intervention effect on the incidence or remission of overweight/obesity. Among 5469 students who attended study schools during both years of the intervention, there was no significant intervention effect. Furthermore, there was no long-term effect among students with up to 2 years of data beyond the end of the intervention. CONCLUSION: Using routinely collected data for the entire target population, we failed to confirm earlier findings of an intervention effect observed in a subset of students in grades 5 7. Volunteer bias in the prior evaluation and/or measurement error in the routinely collected data are potential reasons for the discrepant findings. PMID- 22945606 TI - Changes in BMI and waist circumference in Scottish adults: use of repeated cross sectional surveys to explore multiple age groups and birth-cohorts. AB - OBJECTIVE: To document changes in body mass index (BMI) and waist circumference (WC) over a 10-year period 1998-2008, in representative surveys of adults. SUBJECTS: Adults aged 18-72 in the Scottish Health Surveys conducted in 1998, 2003 and 2008 were divided, separately for men and women, into eleven 5-year age bands. 'Synthetic birth-cohorts' were created by dividing participants into thirteen 5-years-of-birth bands (n=20 423). Weight, height and WC were objectively measured by trained observers. RESULTS: SUBJECTS with data available on BMI/WC were 7743/6894 in 1998, 5838/4437 in 2003 and 4688/925 in 2008 with approximately equal gender distributions. Mean BMI and waist were both greater in successive surveys in both men and women. At most specific ages, people were consistently heavier in 2008 than in 1998 by about 1-1.5 BMI units, and WCs were greater by about 2-6 cm in men and 5-7 cm in women. Greater increases were seen at younger ages between 1998 and 2003 than between 2003 and 2008, however increases continued at older ages, particularly in waist. All birth-cohorts observed over the 10 years 1998-2008 showed increases in both BMI and waist, most marked in the younger groups. The 10-year increases in waist within birth-cohorts (mean 7.4 cm (8.1%) in men and 8.6 cm (10.9%) in women) were more striking than in BMI (mean 1.8 kg m(-2) (6.6%) in men and 1.5 kg m(-2) (6.4%) in women) were particularly steep in older women. CONCLUSION: People were heavier and fatter in 2003 than those of the same age in 1998, with less marked increases in WC between 2003 and 2008 than between 1998 and 2003. There were proportionally greater increases in WC than in BMI, especially in older women. This suggests a disproportionate increase in body fat, compared with muscle, particularly among older women. PMID- 22945607 TI - Overweight impairs efficacy of iron supplementation in iron-deficient South African children: a randomized controlled intervention. AB - BACKGROUND: Many countries in the nutrition transition have high rates of iron deficiency (ID) and overweight (OW). ID is more common in OW children; this may be due to adiposity-related inflammation reducing iron absorption. OBJECTIVE: We investigated whether weight status predicts response to oral iron supplementation in ID South African children. DESIGN: A placebo-controlled trial of oral iron supplementation (50 mg, 4 * weeks for 8.5 months) was done in ID 6- to 11-year old children (n=321); 28% were OW or obese. BMI-for-age z-scores (BAZ), hepcidin (in a sub-sample), hemoglobin, serum ferritin (SF), transferrin receptor (TfR), zinc protoporphyrin (ZnPP) and C-reactive protein (CRP) were measured; body iron was calculated from the SF to TfR ratio. RESULTS: At baseline, BAZ correlated with CRP (r=0.201, P<0.001) and CRP correlated with hepcidin (r=0.384, P<0.001). Normal weight children supplemented with iron had significantly lower TfR concentrations at endpoint than the OW children supplemented with iron and the children receiving placebo. Higher BAZ predicted higher TfR (beta=0.232, P<0.001) and lower body iron (beta=-0.090, P=0.016) at endpoint, and increased the odds ratio (OR) for remaining ID at endpoint in both the iron and placebo groups (iron: OR 2.31, 95% CI: 1.13, 4.73; placebo: OR 1.78, 95% CI: 1.09, 2.91). In the children supplemented with iron, baseline hepcidin and BAZ were significant predictors of endpoint TfR, with a trend towards a hepcidin * BAZ interaction (P=0.058). CONCLUSION: South African children with high BAZ have a two-fold higher risk of remaining ID after iron supplementation. This may be due to their higher hepcidin concentrations reducing iron absorption. Thus, the current surge in OW in rapidly developing countries may undercut efforts to control anemia in vulnerable groups. The trial is registered at clinicaltrials.gov as NCT01092377. PMID- 22945610 TI - Characterization of Zn-containing metal-organic frameworks by solid-state 67Zn NMR spectroscopy and computational modeling. AB - Metal-organic frameworks (MOFs) are an extremely important class of porous materials with many applications. The metal centers in many important MOFs are zinc cations. However, their Zn environments have not been characterized directly by (67)Zn solid-state NMR (SSNMR) spectroscopy. This is because (67)Zn (I=5/2) is unreceptive with many unfavorable NMR characteristics, leading to very low sensitivity. In this work, we report, for the first time, a (67)Zn natural abundance SSNMR spectroscopic study of several representative zeolitic imidazolate frameworks (ZIFs) and MOFs at an ultrahigh magnetic field of 21.1 T. Our work demonstrates that (67)Zn magic-angle spinning (MAS) NMR spectra are highly sensitive to the local Zn environment and can differentiate non-equivalent Zn sites. The (67)Zn NMR parameters can be predicted by theoretical calculations. Through the study of MOF-5 desolvation, we show that with the aid of computational modeling, (67)Zn NMR spectroscopy can provide valuable structural information on the MOF systems with structures that are not well described. Using ZIF-8 as an example, we further demonstrate that (67)Zn NMR spectroscopy is highly sensitive to the guest molecules present inside the cavities. Our work also shows that a combination of (67)Zn NMR data and molecular dynamics simulation can reveal detailed information on the distribution and the dynamics of the guest species. The present work establishes (67)Zn SSNMR spectroscopy as a new tool complementary to X-ray diffraction for solving outstanding structural problems and for determining the structures of many new MOFs yet to come. PMID- 22945609 TI - Modifiable environmental influences on body mass index shared by young adult brothers. AB - OBJECTIVES: Twin and adoption studies suggest that family environment has little, if any, influence on body mass index (BMI) in adulthood. We investigated the hypothesis that the differences in the years of birth between siblings influence their similarity in BMI at comparable ages, which would give evidence for a possibly modifiable influence of the environment shared by family members. METHODS: Swedish full-brother pairs (N=261 712) born between 1951 and 1983 were measured for BMI in conscription examination at 16-26 years (median: 18.2 years) of age and were divided into quartiles by the difference between their birth years (< 2.25 years, 2.25-3.33 years, 3.34-5.08 years and >5.08 years). Furthermore, 1961 dizygotic twin brother pairs from the same population representing brothers born at the same time were included. In addition, the log BMI of the younger brother was modeled as a linear function of the log BMI of the older brother. Subsequently, the significance of the interaction between birth year difference and the BMI of the older brother was tested. RESULTS: Intraclass correlation for BMI in dizygotic twin pairs was higher (0.431, 95% confidence interval (CI) 0.394-0.466) than the correlation for full-brothers in the first quartile of birth-year difference (0.376, CI 0.342-0.408). Among full-brothers, the BMI correlation decreased from 0.376 (CI 0.342-0.408) [corrected] in the first quartile to 0.338 (CI 0.331-0.345) in the last quartile. The regression analysis showed a statistically significant decrease in correlation with increasing birth-year difference (P<0.001). CONCLUSION: The influence on BMI in young men of the environment shared by dizygotic twin brothers is greater than between non-twin full-brothers, indicating important influences of concomitant exposure to the same early life environment before and/or after birth. Among non twin siblings there is a slight possibly modifiable influence as evidenced by declining correlations by increasing distance in years of birth. PMID- 22945608 TI - Sleep duration and disorders in pregnancy: implications for glucose metabolism and pregnancy outcomes. AB - Humans have an innate requirement for sleep that is intrinsically governed by circadian and endocrine systems. More recently, reduced sleep duration has gained significant attention for its possible contribution to metabolic dysfunction. Significant evidence suggests that reduced sleep duration may elevate the risk for impaired glucose functioning, insulin resistance and type 2 diabetes. However, to date, few studies have determined the implications of reduced sleep duration with regard to glucose control during pregnancy. With the high prevalence of overweight and obesity in women of reproductive age, the occurrence of gestational diabetes mellitus (GDM) is increasing. GDM results in elevated risk of maternal and fetal complications, as well as increased risk of type 2 diabetes postpartum. Infants born to women with GDM also carry a life-long risk of obesity and type 2 diabetes. The impact of reduced sleep on glucose management during pregnancy has not yet been fully assessed and a paucity of literature currently exits. Herein, we review the association between reduced sleep and impaired carbohydrate metabolism and propose how reduced sleep during pregnancy may result in further dysfunction of the carbohydrate axis. A particular focus will be given to sleep-disordered breathing, as well as GDM-complicated pregnancies. Putative mechanisms of action by which reduced sleep may adversely affect maternal and infant outcomes are also discussed. Finally, we will outline important research questions that need to be addressed. PMID- 22945611 TI - Roll aftereffects: influence of tilt and inter-stimulus interval. AB - A theme in sensory perception is that exposure to a stimulus causes perception of subsequent stimuli to be shifted in the opposite direction. Such phenomenon is known as aftereffect and has been extensively described in the visual system as well as recently described for the vestibular system during translation. It is known from aviation studies that after a maneuver in roll, pilots can experience a false perception of roll in the opposite direction. The magnitude and duration of this effect as well as the potential influence of the gravity vector have not previously been defined. In the current paper this roll aftereffect (RAE) is examined in response to whole-body roll about an earth-horizontal axis in eight healthy human subjects. The peak velocity of a 0.5-s-duration roll was varied based on previous responses to find the point where subjects perceived no motion. Without a preceding stimulus, the starting position (upright, 9 degrees left, or 9 degrees right) did not influence roll perception. The RAE was measured in a completely dark room using an adapting (first interval) stimulus consisting of 9 degrees of roll over 1.5 s (peak velocity, 12 degrees /s), delivered 0.5, 3, or 6 s prior to test (second interval) stimulus. A significant RAE was seen in all subjects. Half a second after the adapting stimulus, a test stimulus had to be on average 1.5 +/- 0.4 degrees /s in the opposite direction to be perceived as stationary. When the subject remained upright after the adapting stimulus, the RAE diminished with time, although it remained significantly larger at 3 and 6 s when the subject remained tilted after the adapting stimulus. These data demonstrate that roll perception can be influenced by small preceding stimuli and tilt causes a persistence of the RAE. PMID- 22945612 TI - [Joint replacement surgery of the wrist, the distal radioulnar joint, and the hand]. AB - This article gives an overview about arthroplasties at the wrist joint, the distal radioulnar joint, and the hand with special emphasis on joint replacement. PMID- 22945613 TI - [A case of nerve angiomatosis associated with neurofibromatosis type I]. AB - We present the case of a patient suffering from Neurofibromatosis type I (NF-1) with acute, very painful neuropathy of the right lower extremity. The preoperative electro neuro- physiological study showed an impaired function of the peroneal nerve. The MRI revealed an extended diffuse plexiform tumour of the sciatic nerve and at thigh level. Biopsies showed marked diffuse angiomatosis within the sciatic nerve.To our knowledge, this is the first description of an intraneural vascular malformation in NF-1.Treatment of such an entity is a challenge and must be individually defined. PMID- 22945616 TI - Albrecht Durer's melencolia I. PMID- 22945617 TI - Delayed white matter growth trajectory in young nonpsychotic siblings of patients with childhood-onset schizophrenia. AB - CONTEXT Nonpsychotic siblings of patients with childhood-onset schizophrenia (COS) share cortical gray matter abnormalities with their probands at an early age; these normalize by the time the siblings are aged 18 years, suggesting that the gray matter abnormalities in schizophrenia could be an age-specific endophenotype. Patients with COS also show significant white matter (WM) growth deficits, which have not yet been explored in nonpsychotic siblings. OBJECTIVE To study WM growth differences in nonpsychotic siblings of patients with COS. DESIGN Longitudinal (5-year) anatomic magnetic resonance imaging study mapping WM growth using a novel tensor-based morphometry analysis. SETTING National Institutes of Health Clinical Center, Bethesda, Maryland. PARTICIPANTS Forty-nine healthy siblings of patients with COS (mean [SD] age, 16.1 [5.3] years; 19 male, 30 female) and 57 healthy persons serving as controls (age, 16.9 [5.3] years; 29 male, 28 female). INTERVENTION Magnetic resonance imaging. MAIN OUTCOME MEASURE White matter growth rates. RESULTS We compared the WM growth rates in 3 age ranges. In the youngest age group (7 to <14 years), we found a significant difference in growth rates, with siblings of patients with COS showing slower WM growth rates in the parietal lobes of the brain than age-matched healthy controls (false discovery rate, q = 0.05; critical P = .001 in the bilateral parietal WM; a post hoc analysis identified growth rate differences only on the left side, critical P = .004). A growth rate difference was not detectable at older ages. In 3-dimensional maps, growth rates in the siblings even appeared to surpass those of healthy individuals at later ages, at least locally in the brain, but this effect did not survive a multiple comparisons correction. CONCLUSIONS In this first longitudinal study of nonpsychotic siblings of patients with COS, the siblings showed early WM growth deficits, which normalized with age. As reported before for gray matter, WM growth may also be an age-specific endophenotype that shows compensatory normalization with age. PMID- 22945618 TI - Influence of ZNF804a on brain structure volumes and symptom severity in individuals with schizophrenia. AB - CONTEXT The single-nucleotide polymorphism rs1344706 in the gene ZNF804a has been associated with schizophrenia and with quantitative phenotypic features, including brain structure volume and the core symptoms of schizophrenia. OBJECTIVE To evaluate associations of rs1344706 with brain structure and the core symptoms of schizophrenia. DESIGN Case-control analysis of covariance. SETTING University-based research hospital. PARTICIPANTS Volunteer sample of 335 individuals with schizophrenia spectrum disorders (306 with core schizophrenia) and 198 healthy volunteers. MAIN OUTCOME MEASURES Cerebral cortical gray matter and white matter (WM) volumes (total and frontal, parietal, temporal, and occipital lobes), lateral ventricular cerebrospinal fluid volume, and symptom severity from the Scale for the Assessment of Negative Symptoms and the Scale for the Assessment of Positive Symptoms divided into 3 domains: psychotic, negative, and disorganized. RESULTS The rs1344706 genotype produced significant main effects on total, frontal, and parietal lobe WM volumes (F = 3.98, P = .02; F = 4.95, P = .007; and F = 3.08, P = .05, respectively). In the schizophrenia group, rs1344706 produced significant simple effects on total (F = 3.93, P = .02) and frontal WM volumes (F = 7.16, P < .001) and on psychotic symptom severity (F = 6.07, P = .003); the pattern of effects was concordant with risk allele carriers having larger volumes and more severe symptoms of disease than nonrisk homozygotes. In the healthy volunteer group, risk allele homozygotes had increased total WM volume compared with nonrisk allele carriers (F = 4.61, P = .03), replicating a previously reported association. CONCLUSIONS A growing body of evidence suggests that the risk allele of rs1347706 is associated with a distinctive set of phenotypic features in healthy volunteers and individuals with schizophrenia. Our study supports this assertion by finding that specific genotypes of the polymorphism are associated with brain structure volumes in individuals with schizophrenia and healthy volunteers and with symptom severity in schizophrenia. PMID- 22945619 TI - Failure of neural responses to safety cues in schizophrenia. AB - CONTEXT Abnormalities in associative memory processes, such as Pavlovian fear conditioning and extinction, have been observed in schizophrenia. The retrieval of fear extinction memories (safety signals) may be particularly affected; although schizophrenic patients can extinguish conditioned fear, they show a deficit in retrieving fear extinction memories after a delay. The neurobiological basis of this abnormality is unknown, but clues have emerged from studies in rodents and humans demonstrating that the ventromedial prefrontal cortex (vmPFC) is a key mediator of extinction memory retrieval. OBJECTIVE To measure autonomic and neural responses during the acquisition and extinction of conditioned fear and the delayed recall of fear and extinction memories in patients with schizophrenia and healthy control participants. DESIGN Cross-sectional case control, functional magnetic resonance imaging study. SETTING Academic medical center. PARTICIPANTS Twenty schizophrenic patients and 17 healthy control participants demographically matched to the patient group. MAIN OUTCOME MEASURES Skin conductance and blood oxygen level-dependent responses. RESULTS During fear conditioning, schizophrenic patients showed blunted autonomic responses and abnormal blood oxygen level-dependent responses, relative to control participants, within the posterior cingulate gyrus, hippocampus, and other regions. Several of these abnormalities were linked to negative symptoms. During extinction learning, patients with schizophrenia and control participants showed comparable autonomic and neural responses. Twenty-four hours after the learning phases, the control subjects exhibited decreased fear and increased vmPFC responses in the extinction (safe) context as expected, indicating successful retention of the extinction memory. In contrast, the schizophrenic patients showed inappropriately elevated fear and poor vmPFC responses in the safe context. CONCLUSION Failure of extinction memory retrieval in schizophrenia is associated with vmPFC dysfunction. In future studies, abnormalities in fear learning and extinction recall may serve as quantitative phenotypes that can be linked to genetic, symptom, or outcome profiles in schizophrenia and those at risk for the disorder. PMID- 22945620 TI - Toward clinically useful neuroimaging in depression treatment: prognostic utility of subgenual cingulate activity for determining depression outcome in cognitive therapy across studies, scanners, and patient characteristics. AB - CONTEXT Among depressed individuals not receiving medication in controlled trials, 40% to 60% respond to cognitive therapy (CT). Multiple previous studies suggest that activity in the subgenual anterior cingulate cortex (sgACC; Brodmann area 25) predicts outcome in CT for depression, but these results have not been prospectively replicated. OBJECTIVE To examine whether sgACC activity is a reliable and robust prognostic outcome marker of CT for depression and whether sgACC activity changes in treatment. DESIGN Two inception cohorts underwent assessment with functional magnetic resonance imaging using different scanners on a task sensitive to sustained emotional information processing before and after 16 to 20 sessions of CT, along with a sample of control participants who underwent testing at comparable intervals. SETTING A hospital outpatient clinic. PATIENTS Forty-nine unmedicated depressed adults and 35 healthy controls. MAIN OUTCOME MEASURES Pretreatment sgACC activity in an a priori region in response to negative words was correlated with residual severity and used to classify response and remission. RESULTS As expected, in both samples, participants with the lowest pretreatment sustained sgACC reactivity in response to negative words displayed the most improvement after CT (R2 = 0.29, >75% correct classification of response, >70% correct classification of remission). Other a priori regions explained additional variance. Response/remission in cohort 2 was predicted based on thresholds from cohort 1. Subgenual anterior cingulate activity remained low for patients in remission after treatment. CONCLUSIONS Neuroimaging provides a quick, valid, and clinically applicable way of assessing neural systems associated with treatment response/remission. Subgenual anterior cingulate activity, in particular, may reflect processes that interfere with treatment (eg, emotion generation) in addition to its putative regulatory role; alternately, its absence may facilitate treatment response. PMID- 22945621 TI - Reduced structural connectivity of a major frontolimbic pathway in generalized anxiety disorder. AB - CONTEXT: Emotion regulation deficits figure prominently in generalized anxiety disorder (GAD) and in other anxiety and mood disorders. Research examining emotion regulation and top-down modulation has implicated reduced coupling of the amygdala with prefrontal cortex and anterior cingulate cortex, suggesting altered frontolimbic white matter connectivity in GAD. OBJECTIVES: To investigate structural connectivity between ventral prefrontal cortex or anterior cingulate cortex areas and the amygdala in GAD and to assess associations with functional connectivity between those areas. DESIGN: Participants underwent diffusion-tensor imaging and functional magnetic resonance imaging. SETTING: University magnetic resonance imaging facility. PARTICIPANTS: Forty-nine patients with GAD and 39 healthy volunteer control subjects, including a matched subset of 21 patients having GAD without comorbid Axis I diagnoses and 21 healthy volunteers matched for age, sex, and education. MAIN OUTCOME MEASURES: The mean fractional anisotropy values in the left and right uncinate fasciculus, as measured by tract based analysis for diffusion-tensor imaging data. RESULTS: Lower mean fractional anisotropy values in the bilateral uncinate fasciculus indicated reduced frontolimbic structural connectivity in patients with GAD. This reduction in uncinate fasciculus integrity was most pronounced for patients without comorbidity and was not observed in other white matter tracts. Across all participants, higher fractional anisotropy values were associated with more negative functional coupling between the pregenual anterior cingulate cortex and the amygdala during the anticipation of aversion. CONCLUSIONS: Reduced structural connectivity of a major frontolimbic pathway suggests a neural basis for emotion regulation deficits in GAD. The functional significance of these structural differences is underscored by decreased functional connectivity between the anterior cingulate cortex and the amygdala in individuals with reduced structural integrity of the uncinate fasciculus. PMID- 22945622 TI - Common and unique therapeutic mechanisms of stimulant and nonstimulant treatments for attention-deficit/hyperactivity disorder. AB - CONTEXT Attention-deficit/hyperactivity disorder (ADHD) is a highly prevalent and impairing psychiatric disorder that affects both children and adults. There are Food and Drug Administration-approved stimulant and nonstimulant medications for treating ADHD; however, little is known about the mechanisms by which these different treatments exert their therapeutic effects. OBJECTIVE To contrast changes in brain activation related to symptomatic improvement with use of the stimulant methylphenidate hydrochloride vs the nonstimulant atomoxetine hydrochloride. DESIGN Functional magnetic resonance imaging before and after 6 to 8 weeks of treatment with methylphenidate (n = 18) or atomoxetine (n = 18) using a parallel-groups design. SETTING Specialized ADHD clinical research program at Mount Sinai School of Medicine, New York, New York. PARTICIPANTS Thirty-six youth with ADHD (mean [SD] age, 11.2 [2.7] years; 27 boys) recruited from randomized clinical trials. MAIN OUTCOME MEASURES Changes in brain activation during a go/no go test of response inhibition and investigator-completed ratings on the ADHD Rating Scale-IV-Parent Version. RESULTS Treatment with methylphenidate vs atomoxetine was associated with comparable improvements in both response inhibition on the go/no-go test and mean (SD) improvements in ratings of ADHD symptoms (55% [30%] vs 57% [25%]). Improvement in ADHD symptoms was associated with common reductions in bilateral motor cortex activation for both treatments. Symptomatic improvement was also differentially related to gains in task-related activation for atomoxetine and reductions in activation for methylphenidate in the right inferior frontal gyrus, left anterior cingulate/supplementary motor area, and bilateral posterior cingulate cortex. These findings were not attributable to baseline differences in activation. CONCLUSIONS Treatment with methylphenidate and atomoxetine produces symptomatic improvement via both common and divergent neurophysiologic actions in frontoparietal regions that have been implicated in the pathophysiology of ADHD. These results represent a first step in delineating the neurobiological basis of differential response to stimulant and nonstimulant medications for ADHD. PMID- 22945623 TI - Randomized trial of long-acting sustained-release naltrexone implant vs oral naltrexone or placebo for preventing relapse to opioid dependence. AB - CONTEXT Sustained-release naltrexone implants may improve outcomes of nonagonist treatment of opioid addiction. OBJECTIVE To compare outcomes of naltrexone implants, oral naltrexone hydrochloride, and nonmedication treatment. DESIGN Six month double-blind, double-dummy, randomized trial. SETTING Addiction treatment programs in St Petersburg, Russia. PARTICIPANTS Three hundred six opioid-addicted patients recently undergoing detoxification. INTERVENTIONS Biweekly counseling and 1 of the following 3 treatments for 24 weeks: (1) 1000-mg naltrexone implant and oral placebo (NI+OP group; 102 patients); (2) placebo implant and 50-mg oral naltrexone hydrochloride (PI+ON group; 102 patients); or (3) placebo implant and oral placebo (PI+OP group; 102 patients). MAIN OUTCOME MEASURE Percentage of patients retained in treatment without relapse. RESULTS By month 6, 54 of 102 patients in the NI+OP group (52.9%) remained in treatment without relapse compared with 16 of 102 patients in the PI+ON group (15.7%) (survival analysis, log-rank test, P < .001) and 11 of 102 patients in the PI+OP group (10.8%) (P < .001). The PI+ON vs PI+OP comparison showed a nonsignificant trend favoring the PI+ON group (P = .07). Counting missing test results as positive, the proportion of urine screening tests yielding negative results for opiates was 63.6% (95% CI, 60%-66%) for the NI+OP group; 42.7% (40%-45%) for the PI+ON group; and 34.1% (32% 37%) for the PI+OP group (P < .001, Fisher exact test, compared with the NI+OP group). Twelve wound infections occurred among 244 implantations (4.9%) in the NI+OP group, 2 among 181 (1.1%) in the PI+ON group, and 1 among 148 (0.7%) in the PI+OP group (P = .02). All events were in the first 2 weeks after implantation and resolved with antibiotic therapy. Four local-site reactions (redness and swelling) occurred in the second month after implantation in the NI+OP group (P = .12), and all resolved with antiallergy medication treatment. Other nonlocal-site adverse effects were reported in 8 of 886 visits (0.9%) in the NI+OP group, 4 of 522 visits (0.8%) in the PI+ON group, and 3 of 394 visits (0.8%) in the PI+ON group; all resolved and none were serious. No evidence of increased deaths from overdose after naltrexone treatment ended was found. CONCLUSIONS The implant is more effective than oral naltrexone or placebo. More patients in the NI+OP than in the other groups develop wound infections or local irritation, but none are serious and all resolve with treatment. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00678418. PMID- 22945624 TI - Evaluating the potential role of pomegranate peel in aluminum-induced oxidative stress and histopathological alterations in brain of female rats. AB - Studies have shown that pomegranate, Punica granatum Linn. (Lythraceae), has remarkable biological and medicinal properties. However, the effects of pomegranate peel methanolic extract (PPME) on the aluminum-induced oxidative stress and histopathological change have not been reported yet. To determine the effect of PPME (200 mg/kg bwt) on the aluminum chloride (AlCl3; 34 mg/kg bwt) induced neurotoxicity, aluminum accumulation in brain and oxidant/antioxidant status were determined. The change of brain structure was investigated with hematoxylin and eosin, and anti-apoptosis effects of PPME were analyzed by immunohistochemistry. The present study showed an indication of carcinogenicity in the AlCl3-treated group representing an increase in tissue tumor markers such as tumor necrosis factor-alpha and angiogenin and inflammation by inducing an increase in prostaglandin E2 and prostaglandin F2alpha. PPME protected brain through decreasing the aluminum accumulation and stimulating antioxidant activities and anti-apoptotic proteins namely Bcl-2. Therefore, these results indicated that pomegranate peel methanolic extract could inhibit aluminum-induced oxidative stress and histopathological alternations in brain of female rats, and these effects may be related to anti-apoptotic and antioxidants activities. PMID- 22945625 TI - Accumulation and regulation effects from the metal mixture of Zn, Pb, and Cd in the tropical shrimp Penaeus vannamei. AB - Environmental metal pollution is one of the major problems faced by humankind. This type of pollution affects aquatic systems (estuaries, coastal lagoons, etc.), which are very dynamic systems, therefore making the study of the effects on the organisms that inhabit them an essential issue. In this study, the capacity of metal regulation by decapod crustacean Penaeus vannamei juveniles was determined. The effects of zinc, lead, and cadmium were tested individually and as a metal mixture exposure to determine possible synergism. The results showed that juvenile shrimps were capable of regulating zinc and lead, whereas cadmium was accumulated without any excretion, at least within the concentrations studied. It was also proved that under the estuarine conditions tested here, P. vannamei juveniles showed capacity to act as a bioindicator for cadmium. PMID- 22945626 TI - Dramatic genotypic difference in, and effect of genetic crossing on, tissue culture-induced mobility of retrotransposon Tos17 in rice. AB - KEY MESSAGE : We show for the first time that intraspecific crossing may impact mobility of the prominent endogenous retrotransposon Tos17 under tissue culture conditions in rice. Tos17, an endogenous copia retrotransposon of rice, is transpositionally active in tissue culture. To study whether there exists fundamental genotypic difference in the tissue culture-induced mobility of Tos17, and if so, whether the difference is under genetic and/or epigenetic control, we conducted this investigation. We show that dramatic difference in tissue culture induced Tos17 mobility exists among different rice pure-line cultivars sharing the same maternal parent: of the three lines studied that harbor Tos17, two showed mobilization of Tos17, which accrued in proportion to subculture duration, while the third line showed total quiescence (immobility) of the element and the fourth line did not contain the element. In reciprocal F1 hybrids between Tos17 mobile and -immobile (or absence) parental lines, immobility was dominant over mobility. In reciprocal F1 hybrids between both Tos17-mobile parental lines, an additive or synergistic effect on mobility of the element was noticed. In both types of reciprocal F1 hybrids, clear difference in the extent of Tos17 mobility was noted between crossing directions. Given that all lines share the same maternal parent, this observation indicates the existence of epigenetic parent-of origin effect. We conclude that the tissue culture-induced mobility of Tos17 in rice is under complex genetic and epigenetic control, which can be either enhanced or repressed by intraspecific genetic crossing. PMID- 22945627 TI - Hypertension as an emerging risk factor for acute heart failure in Africa: comment on "The causes, treatment, and outcome of acute heart failure in 1006 Africans from 9 countries". PMID- 22945629 TI - FOXO1 orchestrates the bone-suppressing function of gut-derived serotonin. AB - Serotonin is a critical regulator of bone mass, fulfilling different functions depending on its site of synthesis. Brain-derived serotonin promotes osteoblast proliferation, whereas duodenal-derived serotonin suppresses it. To understand the molecular mechanisms of duodenal-derived serotonin action on osteoblasts, we explored its transcriptional mediation in mice. We found that the transcription factor FOXO1 is a crucial determinant of the effects of duodenum-derived serotonin on bone formation We identified two key FOXO1 complexes in osteoblasts, one with the transcription factor cAMP-responsive element-binding protein 1 (CREB) and another with activating transcription factor 4 (ATF4). Under normal levels of circulating serotonin, the proliferative activity of FOXO1 was promoted by a balance between its interaction with CREB and ATF4. However, high circulating serotonin levels prevented the association of FOXO1 with CREB, resulting in suppressed osteoblast proliferation. These observations identify FOXO1 as the molecular node of an intricate transcriptional machinery that confers the signal of duodenal-derived serotonin to inhibit bone formation. PMID- 22945628 TI - Loss of tumor suppressor NF1 activates HSF1 to promote carcinogenesis. AB - Intrinsic stress response pathways are frequently mobilized within tumor cells. The mediators of these adaptive mechanisms and how they contribute to carcinogenesis remain poorly understood. A striking example is heat shock factor 1 (HSF1), master transcriptional regulator of the heat shock response. Surprisingly, we found that loss of the tumor suppressor gene neurofibromatosis type 1 (Nf1) increased HSF1 levels and triggered its activation in mouse embryonic fibroblasts. As a consequence, Nf1-/- cells acquired tolerance to proteotoxic stress. This activation of HSF1 depended on dysregulated MAPK signaling. HSF1, in turn, supported MAPK signaling. In mice, Hsf1 deficiency impeded NF1-associated carcinogenesis by attenuating oncogenic RAS/MAPK signaling. In cell lines from human malignant peripheral nerve sheath tumors (MPNSTs) driven by NF1 loss, HSF1 was overexpressed and activated, which was required for tumor cell viability. In surgical resections of human MPNSTs, HSF1 was overexpressed, translocated to the nucleus, and phosphorylated. These findings reveal a surprising biological consequence of NF1 deficiency: activation of HSF1 and ensuing addiction to this master regulator of the heat shock response. The loss of NF1 function engages an evolutionarily conserved cellular survival mechanism that ultimately impairs survival of the whole organism by facilitating carcinogenesis. PMID- 22945630 TI - SLC26A9-mediated chloride secretion prevents mucus obstruction in airway inflammation. AB - Asthma is a chronic condition with unknown pathogenesis, and recent evidence suggests that enhanced airway epithelial chloride (Cl-) secretion plays a role in the disease. However, the molecular mechanism underlying Cl- secretion and its relevance in asthma pathophysiology remain unknown. To determine the role of the solute carrier family 26, member 9 (SLC26A9) Cl- channel in asthma, we induced Th2-mediated inflammation via IL-13 treatment in wild-type and Slc26a9-deficient mice and compared the effects on airway ion transport, morphology, and mucus content. We found that IL-13 treatment increased Cl- secretion in the airways of wild-type but not Slc26a9-deficient mice. While IL-13-induced mucus overproduction was similar in both strains, treated Slc26a9-deficient mice exhibited airway mucus obstruction, which did not occur in wild-type controls. In a study involving healthy children and asthmatics, a polymorphism in the 3' UTR of SLC26A9 that reduced protein expression in vitro was associated with asthma. Our data demonstrate that the SLC26A9 Cl- channel is activated in airway inflammation and suggest that SLC26A9-mediated Cl- secretion is essential for preventing airway obstruction in allergic airway disease. These results indicate that SLC26A9 may serve as a therapeutic target for airway diseases associated with mucus plugging. PMID- 22945631 TI - Suppressing T cell motility induced by anti-CTLA-4 monotherapy improves antitumor effects. AB - A promising strategy for cancer immunotherapy is to disrupt key pathways regulating immune tolerance, such as cytotoxic T lymphocyte-associated protein 4 (CTLA-4). However, the determinants of response to anti-CTLA-4 mAb treatment remain incompletely understood. In murine models, anti-CTLA-4 mAbs alone fail to induce effective immune responses to poorly immunogenic tumors but are successful when combined with additional interventions, including local ionizing radiation (IR) therapy. We employed an established model based on control of a mouse carcinoma cell line to study endogenous tumor-infiltrating CD8+ T lymphocytes (TILs) following treatment with the anti-CTLA-4 mAb 9H10. Alone, 9H10 monotherapy reversed the arrest of TILs with carcinoma cells in vivo. In contrast, the combination of 9H10 and IR restored MHC class I-dependent arrest. After implantation, the carcinoma cells had reduced expression of retinoic acid early inducible-1 (RAE-1), a ligand for natural killer cell group 2D (NKG2D) receptor. We found that RAE-1 expression was induced by IR in vivo and that anti-NKG2D mAb blocked the TIL arrest induced by IR/9H10 combination therapy. These results demonstrate that anti-CTLA-4 mAb therapy induces motility of TIL and that NKG2D ligation offsets this effect to enhance TILs arrest and antitumor activity. PMID- 22945632 TI - SOX2 regulates the hypothalamic-pituitary axis at multiple levels. AB - Sex-determining region Y (SRY) box 2 (SOX2) haploinsufficiency causes a form of hypopituitarism in humans that is characterized by gonadotrophin deficiency known as hypogonadotrophic hypogonadism. Here, we conditionally deleted Sox2 in mice to investigate the pathogenesis of hypogonadotrophic hypogonadism. First, we found that absence of SOX2 in the developing Rathke pouch of conditional embryos led to severe anterior lobe hypoplasia with drastically reduced expression of the pituitary-specific transcription factor POU class 1 homeobox 1 (POU1F1) as well as severe disruption of somatotroph and thyrotroph differentiation. In contrast, corticotrophs, rostral-tip POU1F1-independent thyrotrophs, and, interestingly, lactotrophs and gonadotrophs were less affected. Second, we identified a requirement for SOX2 in normal proliferation of periluminal progenitors; in its absence, insufficient precursors were available to produce all cell lineages of the anterior pituitary. Differentiated cells derived from precursors exiting cell cycle at early stages, including corticotrophs, rostral-tip thyrotrophs, and gonadotrophs, were generated, while hormone-producing cells originating from late born precursors, such as somatotrophs and POU1F1-dependent thyrotrophs, were severely reduced. Finally, we found that 2 previously characterized patients with SOX2 haploinsufficiency and associated hypogonadotrophic hypogonadism had a measurable response to gonadotropin-releasing hormone (GnRH) stimulation, suggesting that it is not the absence of gonadotroph differentiation, but rather the deficient hypothalamic stimulation of gonadotrophs, that underlies typical hypogonadotrophic hypogonadism. PMID- 22945633 TI - IL-1 receptor antagonist ameliorates inflammasome-dependent alcoholic steatohepatitis in mice. AB - Alcoholic liver disease (ALD) is characterized by steatosis and upregulation of proinflammatory cytokines, including IL-1beta. IL-1beta, type I IL-1 receptor (IL 1R1), and IL-1 receptor antagonist (IL-1Ra) are all important regulators of the IL-1 signaling complex, which plays a role in inflammation. Furthermore, IL-1beta maturation is dependent on caspase-1 (Casp-1). Using IL-1Ra-treated mice as well as 3 mouse models deficient in regulators of IL-1beta activation (Casp-1 and ASC) or signaling (IL-1R1), we found that IL-1beta signaling is required for the development of alcohol-induced liver steatosis, inflammation, and injury. Increased IL-1beta was due to upregulation of Casp-1 activity and inflammasome activation. The pathogenic role of IL-1 signaling in ALD was attributable to the activation of the inflammasome in BM-derived Kupffer cells. Importantly, in vivo intervention with a recombinant IL-1Ra blocked IL-1 signaling and markedly attenuated alcohol-induced liver inflammation, steatosis, and damage. Furthermore, physiological doses of IL-1beta induced steatosis, increased the inflammatory and prosteatotic chemokine MCP-1 in hepatocytes, and augmented TLR4 dependent upregulation of inflammatory signaling in macrophages. In conclusion, we demonstrated that Casp-1-dependent upregulation of IL-1beta and signaling mediated by IL-1R1 are crucial in ALD pathogenesis. Our findings suggest a potential role of IL-1R1 inhibition in the treatment of ALD. PMID- 22945634 TI - HOXA9 promotes ovarian cancer growth by stimulating cancer-associated fibroblasts. AB - Epithelial ovarian cancers (EOCs) often exhibit morphologic features of embryonic Mullerian duct-derived tissue lineages and colonize peritoneal surfaces that overlie connective and adipose tissues. However, the mechanisms that enable EOC cells to readily adapt to the peritoneal environment are poorly understood. In this study, we show that expression of HOXA9, a Mullerian-patterning gene, is strongly associated with poor outcomes in patients with EOC and in mouse xenograft models of EOC. Whereas HOXA9 promoted EOC growth in vivo, HOXA9 did not stimulate autonomous tumor cell growth in vitro. On the other hand, expression of HOXA9 in EOC cells induced normal peritoneal fibroblasts to express markers of cancer-associated fibroblasts (CAFs) and to stimulate growth of EOC and endothelial cells. Similarly, expression of HOXA9 in EOC cells induced normal adipose- and bone marrow-derived mesenchymal stem cells (MSCs) to acquire features of CAFs. These effects of HOXA9 were due in substantial part to its transcriptional activation of the gene encoding TGF-beta2 that acted in a paracrine manner on peritoneal fibroblasts and MSCs to induce CXCL12, IL-6, and VEGF-A expression. These results indicate that HOXA9 expression in EOC cells promotes a microenvironment that is permissive for tumor growth. PMID- 22945637 TI - Three modes of proton transfer in one chromophore: photoinduced tautomerization in 2-(1H-pyrazol-5-yl)pyridines, their dimers and alcohol complexes. AB - Studies of 2-(1H-pyrazol-5-yl)pyridine (PPP) and its derivatives 2-(4-methyl-1H pyrazol-5-yl)pyridine (MPP) and 2-(3-bromo-1H-pyrazol-5-yl)pyridine (BPP) by stationary and time-resolved UV/Vis spectroscopic methods, and quantum chemical computations show that this class of compounds provides a rare example of molecules that exhibit three types of photoreactions: 1) excited-state intramolecular proton transfer (ESIPT) in the syn form of MPP, 2) excited-state intermolecular double-proton transfer (ESDPT) in the dimers of PPP in nonpolar media, as well as 3) solvent-assisted double-proton transfer in hydrogen-bonded 1:1 complexes of PPP and MPP with alcoholic partners. The excited-state processes are manifested by the appearance of a dual luminescence and a bimodal irreversible kinetic coupling of the two fluorescence bands. Ground-state syn anti equilibria are detected and discussed. The fraction of the higher-energy anti form varies for different derivatives and is strongly dependent on the solvent polarity and hydrogen-bond donor or acceptor abilities. PMID- 22945635 TI - The stem cell niche: tissue physiology at a single cell level. AB - Stem cells are the critical unit affecting tissue maintenance, regeneration, and repair, with particular relevance to the tissues with high cell turnover. Stem cell regulation accommodates the conflicting needs of prompt responsiveness to injury and long-term preservation through quiescence. They are, in essence, the fundamental unit by which a tissue handles changing physiologic needs throughout the lifetime of the organism. As such, they are the focal point of dynamic tissue function, and their governance is physiology expressed at a cellular and molecular level. Here, we discuss the multiple components representing the stem cell niche in hematopoiesis and argue for a unbiased mapping of the niche constituents under different conditions as the first step in developing systems physiology. PMID- 22945638 TI - Isotopic phonon effects in LaB6-LaB6 do not possess cubic symmetry and show a non random isotope distribution. AB - The isotopic phonon effects in LaB(6) are investigated on the Raman spectra of a series of high-quality single crystals with systematically varied contents of (10)B and (11)B isotopes. A detailed group theoretical analysis enlightens the correlation between distortions of the B(6) octahedra and the splitting or broadening of phonon modes. It is evident that LaB(6) does not have cubic symmetry as assumed so far. A further symmetry reduction of the B(6) octahedra occurs in isotopically mixed crystals. There, the distribution of isotopes is not random as commonly assumed; the probability of associating equal isotopes increases with their mass decreasing. PMID- 22945636 TI - Mechanisms of thyroid hormone action. AB - Our understanding of thyroid hormone action has been substantially altered by recent clinical observations of thyroid signaling defects in syndromes of hormone resistance and in a broad range of conditions, including profound mental retardation, obesity, metabolic disorders, and a number of cancers. The mechanism of thyroid hormone action has been informed by these clinical observations as well as by animal models and has influenced the way we view the role of local ligand availability; tissue and cell-specific thyroid hormone transporters, corepressors, and coactivators; thyroid hormone receptor (TR) isoform-specific action; and cross-talk in metabolic regulation and neural development. In some cases, our new understanding has already been translated into therapeutic strategies, especially for treating hyperlipidemia and obesity, and other drugs are in development to treat cardiac disease and cancer and to improve cognitive function. PMID- 22945639 TI - A conjunctive carboiodination: indenes by a double carbopalladation-reductive elimination domino process. AB - Something gained, nothing lost: A Pd(0)-catalyzed domino intermolecular/intramolecular process terminated by carbohalogenation is reported. In this reaction, two new C-C bonds, one new C-I bond and one five membered ring are formed in a single step, and all of the atoms in the starting materials are incorporated into the product. PMID- 22945640 TI - Recent advances in paramagnetic-TM-substituted polyoxometalates (TM = Mn, Fe, Co, Ni, Cu). AB - During the past decade, research into transition-metal-substituted polyoxometalate self-assembly has been greatly developed. This review summarizes the conventional solution syntheses and hydrothermal syntheses of novel substituted polyoxometalates based on the incorporation of paramagnetic transition metals Mn, Fe, Co, Ni, and Cu, with an emphasis on the variety of nuclearities and configurations of encapsulated transition metal cores and the rich architectures of overall polyoxometalates. PMID- 22945641 TI - beta-Catenin signaling regulates Foxa2 expression during endometrial hyperplasia formation. AB - The Wnt/beta-catenin signaling is essential for various organogenesis and is often implicated during tumorigenesis. Dysregulated beta-catenin signaling is associated with the formation of endometrial adenocarcinomas (EACs), which is considered as the common form of endometrial cancer in women. In the current study, we investigate the downstream target of Wnt/beta-catenin signaling in the uterine epithelia and the mechanism leading to the formation of endometrial hyperplasia. We report that conditional ablation and activation of beta-catenin in the uterine epithelia lead to aberrant epithelial structures and endometrial hyperplasia formation, respectively. We demonstrate that beta-catenin regulates Foxa2 with its candidate upstream region for the uterine epithelia. Furthermore, knockdown of Foxa2 leads to defects in cell cycle regulation, suggesting a possible function of Foxa2 in the control of cell proliferation. We also observe that beta-catenin and Foxa2 expression levels are augmented in the human specimens of complex atypical endometrial hyperplasia, which is considered to have a greater risk of progression to EACs. Thus, our study indicates that beta catenin regulates Foxa2 expression, and this interaction is possibly essential to control cell cycle progression during endometrial hyperplasia formation. Altogether, the augmented expression levels of beta-catenin and Foxa2 are essential features during the formation of endometrial hyperplasia. PMID- 22945643 TI - CDK8 regulates E2F1 transcriptional activity through S375 phosphorylation. AB - Activation of the Wnt/beta-catenin pathway is a critical step in the development of colorectal cancers. A key mediator of this activation is the recently described oncogene CDK8, which is amplified in a large number of colorectal tumors. CDK8 affects beta-catenin activation by interaction of the CDK8 submodule of the mediator complex with beta-catenin/TCF transcriptional complex, and by CDK8 interacting with and phosphorylating E2F1, which acts as a repressor of beta catenin/TCF transcriptional activity. The amino-acid residue in E2F1 that CDK8 phosphorylates and how this phosphorylation impacts E2F1 activity in general is not known. Here, we describe that CDK8 phosphorylates serine 375 in E2F1 both in vitro and in cells, and that phosphorylation of this residue is required for E2F1 interaction with CDK8, and that the phosphorylation is dependent on CDK8 kinase activity. The phosphorylation of S375 by CDK8 regulates E2F1 ability to repress transcription of beta-catenin/TCF-dependent genes, as well as activation of E2F1 dependent genes. This regulation is due to inactivation of E2F1 transcriptional activation, and not to the interference of E2F1's ability to bind to E2F1-binding sites in various promoters or to interact with DP1. PMID- 22945642 TI - The epigenetic regulator UHRF1 promotes ubiquitination-mediated degradation of the tumor-suppressor protein promyelocytic leukemia protein. AB - The promyelocytic leukemia (PML) protein is a tumor suppressor originally identified in acute promyelocytic leukemia and implicated in tumorigenesis in multiple forms of cancer. Here, we demonstrate that the PML protein undergoes ubiquitination-mediated degradation facilitated by an E3 ligase UHRF1 (ubiquitin like with PHD and RING finger domains 1), which is commonly upregulated in various human malignancies. Furthermore, UHRF1 negatively regulates PML protein accumulation in primary human umbilical vein endothelial cells (HUVECs), HEK 293 cells and cancer cells. Knockdown of UHRF1 upregulates whereas ectopic overexpression of UHRF1 downregulates protein abundance of endogenous or exogenous PML, doing so through its binding to the N-terminus of PML. Overexpression of wild-type UHRF1 shortens PML protein half-life and promotes PML polyubiquitination, whereas deletion of the RING domain or coexpression of the dominant-negative E2 ubiquitin-conjugating enzyme, E2D2, attenuates this modification to PML. Finally, knockdown of UHRF1 prolongs PML half-life and increases PML protein accumulation, yet inhibits cell migration and in vitro capillary tube formation, whereas co-knockdown of PML compromises this inhibitory effect. These findings suggest that UHRF1 promotes the turnover of PML protein, and thus targeting UHRF1 to restore PML-mediated tumor suppression represents a promising, novel, anticancer strategy. PMID- 22945644 TI - MAP kinase signaling and inhibition in melanoma. AB - The mitogen-activated protein kinase (MAPK) pathway is critical to oncogenic signaling in the majority of patients with malignant melanoma. Driver mutations in both NRAS and BRAF have important implications for prognosis and treatment. The development of inhibitors to mediators of the MAPK pathway, including those to CRAF, BRAF, and MEK, has led to major advances in the treatment of patients with melanoma. In particular, the selective BRAF inhibitor vemurafenib has been shown to improve overall survival in patients with tumors harboring BRAF mutations. However, the duration of benefit is limited in many patients and highlights the need for understanding the limitations of therapy in order to devise more effective strategies. MEK inhibitors have proven to particularly active in BRAF mutant melanomas also. Emerging knowledge about mechanisms of resistance as well as a more complete understanding of the biology of MAPK pathway signaling provides insight into rational combination regimens and sequences of molecularly targeted therapies. PMID- 22945645 TI - Increased replication initiation and conflicts with transcription underlie Cyclin E-induced replication stress. AB - It has become increasingly clear that oncogenes not only provide aberrant growth signals to cells but also cause DNA damage at replication forks (replication stress), which activate the ataxia telangiectasia mutated (ATM)/p53-dependent tumor barrier. Here we studied underlying mechanisms of oncogene-induced replication stress in cells overexpressing the oncogene Cyclin E. Cyclin E overexpression is associated with increased firing of replication origins, impaired replication fork progression and DNA damage that activates RAD51 mediated recombination. By inhibiting replication initiation factors, we show that Cyclin E-induced replication slowing and DNA damage is a consequence of excessive origin firing. A significant amount of Cyclin E-induced replication slowing is due to interference between replication and transcription, which also underlies the activation of homologous recombination. Our data suggest that Cyclin E-induced replication stress is caused by deregulation of replication initiation and increased interference between replication and transcription, which results in impaired replication fork progression and DNA damage triggering the tumor barrier or cancer-promoting mutations. PMID- 22945646 TI - Progeny of Lgr5-expressing hair follicle stem cell contributes to papillomavirus induced tumor development in epidermis. AB - Epidermal keratinocytes and hair follicle (HF) stem cells (SCs) expressing oncogenes are competent at developing squamous cell carcinomas (SCCs) in epidermis and HFs, respectively. To determine whether bulge and hair germ (HG) SCs from HF contribute to SCC generation at distant epidermis, the most frequent epidermal region where these lesions arise in human skin, we used a skin cancer mouse model expressing E6 and E7 oncoproteins from Human papillomavirus (HPV) 16 in SCs and basal keratinocytes. This previously described mouse model recapitulates the human skin papillomavirus-induced SCC pathology. We show that E6 and E7 expression promote the expansion of keratin 15 (K15)-expressing cells. These K15(+) aberrant cells exhibit some HGSC markers and diminished expression of Tcf3 and Sox9 hair SC specification genes, which are accumulated in HFs and mislocalized to interfollicular epidermis. Leucine-rich G-protein-coupled receptor 5 (Lgr5)-expressing SCs, localized in the bulge and HG, are the origin of the expanded K15(+) cell population. A large subset of the Lgr5(+) SC progeny, expressing K15 and P-cadherin, is aberrantly mobilized to the upper region of HFs and the epidermis, and accumulates at E6/E7-induced pre-neoplastic lesions and epidermal tumors. These findings indicate that aberrant accumulation of altered SCs in HFs and their subsequent migration to the epidermis contribute to HPV induced tumor development. PMID- 22945647 TI - C-terminal binding protein-2 regulates response of epithelial ovarian cancer cells to histone deacetylase inhibitors. AB - Ovarian cancer survival rates have stagnated in the last 20 years despite the development of novel chemotherapeutic agents. Modulators of gene expression, such as histone deacetylase (HDAC) inhibitors, are among the new agents being used in clinical trials. Predictors of sensitivity to chemotherapy have remained elusive. In this study, we show that the expression of the transcriptional corepressor C terminal binding protein-2 (CtBP2) is elevated in human ovarian tumors. Downregulation of CtBP2 expression in ovarian cancer cell lines using short hairpin RNA strategy suppressed the growth rate and migration of the resultant cancer cells. The knockdown cell lines also showed upregulation of HDAC activity and increased sensitivity to selected HDAC inhibitors. Conversely, forced expression of wild-type CtBP2 in the knockdown cell lines reversed HDAC activity and partially rescued cellular sensitivity to the HDAC inhibitors. We propose that CtBP2 is an ovarian cancer oncogene that regulates gene expression program by modulating HDAC activity. CtBP2 expression may be a surrogate indicator of cellular sensitivity to HDAC inhibitors. PMID- 22945648 TI - Epigenetic regulation of CD133/PROM1 expression in glioma stem cells by Sp1/myc and promoter methylation. AB - Tumor stem cells, postulated to be the source cells for malignancies, have been identified in several cancers using cell-surface expression of markers including CD133, a pentaspan membrane protein. CD133+ve cells form neurospheres, exhibit self-renewal and differentiation, and are tumorigenic. However, despite its association with stem cells, a causal relationship of CD133 to tumorigenesis remains to be defined. Hypothesizing that specific epigenetic and transcription factors implicated in driving the stem cell state may concurrently regulate CD133 expression in stem cells, we analyzed the structure and regulation of CD133 promoter in glioma stem cells and glioma cell lines. Initially, a minimal promoter region was identified by analyzing the activity of CD133 promoter-driven luciferase-expressing 5'-and 3'-deletion-constructs upstream of the transcription start site. This region contained a CpG island that was hypermethylated in CD133 ve glioma stem cells (GSC) and glioma cells but unmethylated in CD133+ve ones. Of several predicted TF-binding sites in this region, the role of tandem Sp1 (-242 and -221) and two Myc (-541 and -25)-binding sites were examined. Overexpression of Sp1 or Myc increased CD133 minimal promoter-driven luciferase activity and CD133 levels in GSC and in glioma cell line. Mithramycin, a Sp1 inhibitor, decreased minimal promoter activity and downregulated CD133 levels in GSC. Gel shift assays demonstrated direct binding of Sp1 to their predicted sites that was competitively inhibited by oligonucleotide-binding-site sequences and supershifted by anti-Sp1 confirming the interaction. Sp1 and Myc-antibody chromatin immunoprecipitation (ChIP) analysis in GSC showed enrichment of regions with Sp1 and Myc-binding sites. In CD133-ve cells, ChIP analysis showed binding of the methyl-DNA-binding proteins, MBD1, MBD2 and MeCP2 to the methylated CpG island and repression of transcription. These results demonstrate that Sp1 and Myc regulate CD133 transcription in GSC and that promoter methylation and methyl DNA-binding proteins cause repression of CD133 by excluding transcription-factor binding. PMID- 22945649 TI - AGR2 is a SMAD4-suppressible gene that modulates MUC1 levels and promotes the initiation and progression of pancreatic intraepithelial neoplasia. AB - The mechanisms controlling expression of the putative oncogene Anterior gradient 2 (AGR2) in pancreatic ductal adenocarcinoma (PDAC) are not well understood. We now show that AGR2 is a transforming growth factor-beta (TGF-beta)-responsive gene in human pancreatic cancer cells, whose downregulation is SMAD4 dependent. We also provide evidence supporting a role for AGR2 as an ER-chaperone for the cancer-associated mucin, MUC1. AGR2 is both sufficient and required for MUC1 expression in pancreatic cancer cells. Furthermore, AGR2 is coexpressed with MUC1 in mouse pancreatic intraepithelial neoplasia (mPanIN)-like lesions and in the cancer cells of four distinct genetically engineered mouse models of PDAC. We also show that Pdx1-Cre/LSL-Kras(G12D)/Smad4(lox/lox) mice heterozygous for Agr2 exhibit a delay in mPanIN initiation and progression to PDAC. It is proposed that loss of Smad4 may convert TGF-beta from a tumor suppressor to a tumor promoter by causing the upregulation of AGR2, which then leads to increased MUC1 expression, at which point both AGR2 and MUC1 facilitate mPanIN initiation and progression to PDAC. PMID- 22945650 TI - Interactions between wild-type and mutant Ras genes in lung and skin carcinogenesis. AB - Ras oncogenes (Hras, Kras and Nras) are important drivers of carcinogenesis. However, tumors with Ras mutations often show loss of the corresponding wild-type (WT) allele, suggesting that proto-oncogenic forms of Ras can function as a suppressor of carcinogenesis. In vitro studies also suggest that WT Ras proteins can suppress the tumorigenic properties of alternate mutant Ras family members, but in vivo evidence for these heterologous interactions is lacking. We have investigated the genetic interactions between different combinations of mutant and WT Ras alleles in vivo using carcinogen-induced lung and skin carcinogenesis in mice with targeted deletion of different Ras family members. The major suppressor effect of WT Kras is observed only in mutant Kras-driven lung carcinogenesis, where loss of one Kras allele led to increased tumor number and size. Deletion of one Hras allele dramatically reduced the number of skin papillomas with Hras mutations, consistent with Hras as the major target of mutation in these tumors. However, skin carcinoma numbers were very similar, suggesting that WT Hras functions as a suppressor of progression from papillomas to invasive squamous carcinomas. In the skin, the Kras proto-oncogene functions cooperatively with mutant Hras to promote papilloma development, although the effect is relatively small. In contrast, the Hras proto-oncogene attenuated the activity of mutant Kras in lung carcinogenesis. Interestingly, loss of Nras increased the number of mutant Kras-induced lung tumors, but decreased the number of mutant Hras-induced skin papillomas. These results show that the strongest suppressor effects of WT Ras are only seen in the context of mutation of the cognate Ras protein, and only relatively weak effects are detected on tumor development induced by mutations in alternative family members. The data also underscore the complex and context-dependent nature of interactions between proto oncogenic and oncogenic forms of different Ras family members during tumor development. PMID- 22945652 TI - Emerging roles for the pro-oncogenic anterior gradient-2 in cancer development. AB - Clinical studies have defined the core 'genetic blueprint' of a cancer cell, but this information does not necessarily predict the cancer phenotype. Signalling hubs that mediate such phenotype have been identified largely using OMICS platforms that measure dynamic molecular changes within the cancer cell landscape. The pro-oncogenic protein anterior gradient 2 (AGR2) is a case in point; AGR2 has been shown using a range of expression platforms to be involved in asthma, inflammatory bowel disease, cell transformation, cancer drug resistance and metastatic growth. AGR2 protein is also highly overexpressed in a diverse range of human cancers and can be secreted and detected in extracellular fluids, thus representing a compelling pro-oncogenic signalling intermediate in human cancer. AGR2 belongs to the protein disulphide isomerase family with all the key features of an endoplasmic reticulum-resident protein-this gives clues into how it might function as an oncoprotein through the regulation of protein folding, maturation and secretion that can drive metastatic cell growth. In this review, we will describe the known aspects of AGR2 molecular biology, including gene structure and regulation, emerging protein interaction networks and how its subcellular localization mediates its biological functions. We will finally review the cases of AGR2 expression in human cancers, the pathophysiological consequences of AGR2 overexpression, its potential role as a tumour biomarker that predicts the response to therapy and how the AGR2 pathway might form the basis for drug discovery programmes aimed at targeting protein folding/maturation pathways that mediate secretion and metastasis. PMID- 22945651 TI - Epigenetic screen identifies genotype-specific promoter DNA methylation and oncogenic potential of CHRNB4. AB - Genome-wide association studies have highlighted three major lung cancer susceptibility regions at 15q25.1, 5p15.33 and 6p21.33. To gain insight into the possible mechanistic relevance of the genes in these regions, we investigated the regulation of candidate susceptibility gene expression by epigenetic alterations in healthy and lung tumor tissues. For genes up or downregulated in lung tumors, the influence of genetic variants on DNA methylation was investigated and in vitro studies were performed. We analyzed 394 CpG units within 19 CpG islands in the susceptibility regions in a screening set of 34 patients. Significant findings were validated in an independent patient set (n=50) with available DNA and RNA. The most consistent overall DNA methylation difference between tumor and adjacent normal tissue on 15q25 was tumor hypomethylation in the promoter region of CHRNB4 with a median difference of 8% (P<0.001), which resulted in overexpression of the transcript in tumors (P<0.001). Confirming previous studies, we also found hypermethylation in CHRNA3 and telomerase reverse transcriptase (TERT) with significant expression changes. Decitabine treatment of H1299 cells resulted in reduced methylation levels in gene promoters, elevated transcript levels of CHRNB4 and CHRNA3, and a slight downregulation of TERT demonstrating epigenetic regulation of lung cancer cells. Single-nucleotide polymorphisms rs421629 on 5p15.33 and rs1948, rs660652, rs8040868 and rs2036527 on 15q25.1, previously identified as lung cancer risk or nicotine-addiction modifiers, were associated with tumor DNA methylation levels in the promoters of TERT and CHRNB4 (P<0.001), respectively, in two independent sample sets (n=82; n=150). In addition, CHRNB4 knockdown in two different cell lines (A549 and H1299) resulted in reduced proliferation (PA549<0.05;PH1299<0.001) and propensity to form colonies in H1299 cells. These results suggest epigenetic deregulation of nicotinic acetylcholine receptor subunit (nAChR) genes which in the case of CHRNB4 is strongly associated with genetic lung cancer susceptibility variants and a functional impact on tumorigenic potential. PMID- 22945654 TI - Stem cell transcription factor NANOG controls cell migration and invasion via dysregulation of E-cadherin and FoxJ1 and contributes to adverse clinical outcome in ovarian cancers. AB - Ovarian cancer is the most lethal of all gynecological malignancies, and the identification of novel prognostic and therapeutic targets for ovarian cancer is crucial. It is believed that only a small subset of cancer cells are endowed with stem cell properties, which are responsible for tumor growth, metastatic progression and recurrence. NANOG is one of the key transcription factors essential for maintaining self-renewal and pluripotency in stem cells. This study investigated the role of NANOG in ovarian carcinogenesis and showed overexpression of NANOG mRNA and protein in the nucleus of ovarian cancers compared with benign ovarian lesions. Increased nuclear NANOG expression was significantly associated with high-grade cancers, serous histological subtypes, reduced chemosensitivity, and poor overall and disease-free survival. Further analysis showed NANOG is an independent prognostic factor for overall and disease free survival. Moreover, NANOG was highly expressed in ovarian cancer cell lines with metastasis-associated property and in clinical samples of metastatic foci. Stable knockdown of NANOG impeded ovarian cancer cell proliferation, migration and invasion, which was accompanied by an increase in mRNA expression of E cadherin, caveolin-1, FOXO1, FOXO3a, FOXJ1 and FOXB1. Conversely, ectopic NANOG overexpression enhanced ovarian cancer cell migration and invasion along with decreased E-cadherin, caveolin-1, FOXO1, FOXO3a, FOXJ1 and FOXB1 mRNA expression. Importantly, we found Nanog-mediated cell migration and invasion involved its regulation of E-cadherin and FOXJ1. This is the first report revealing the association between NANOG expression and clinical outcome of patients with ovarian cancers, suggesting NANOG to be a potential prognostic marker and therapeutic molecular target in ovarian cancer. PMID- 22945653 TI - Profiling phospho-signaling networks in breast cancer using reverse-phase protein arrays. AB - Measuring the states of cell signaling pathways in tumor samples promises to advance the understanding of oncogenesis and identify response biomarkers. Here, we describe the use of Reverse Phase Protein Arrays (RPPAs or RPLAs) to profile signaling proteins in 56 breast cancers and matched normal tissue. In RPPAs, hundreds to thousands of lysates are arrayed in dense regular grids and each grid is probed with a different antibody (100 in the current work, of which 71 yielded strong signals with breast tissue). Although RPPA technology is quite widely used, measuring changes in phosphorylation reflective of protein activation remains challenging. Using repeat deposition and well-validated antibodies, we show that diverse patterns of phosphorylation can be monitored in tumor samples and changes mapped onto signaling networks in a coherent fashion. The patterns are consistent with biomarker-based classification of breast cancers and known mechanisms of oncogenesis. We explore in detail one tumor-associated pattern that involves changes in the abundance of the Axl receptor tyrosine kinase (RTK) and phosphorylation of the cMet RTK. Both cMet and Axl have been implicated in breast cancer, or in resistance to anticancer drugs, but the two RTKs are not known to be linked functionally. Protein depletion and overexpression studies in a 'triple negative' breast cell line reveal cross talk between Axl and cMet involving Axl mediated modification of cMet, a requirement for cMet in efficient and timely signal transduction by the Axl ligand Gas6 and the potential for the two receptors to interact physically. These findings have potential therapeutic implications, as they imply that bi-specific receptor inhibitors (for example, ATP-competitive small-kinase inhibitors such as GSK1363089, BMS-777607 or MP470) may be more efficacious than the mono-specific therapeutic antibodies currently in development (for example, Onartuzumab). PMID- 22945655 TI - Occurrences and potential risks of 16 fragrances in five German sewage treatment plants and their receiving waters. AB - Fragrances are used in a wide array of everyday products and enter the aquatic environment via wastewater. While several musk compounds have been studied in detail, little is known about the occurrence and fate of other fragrances. We selected 16 fragrance compounds and scrutinized their presence in Bavarian sewage treatment plants (STP) influents and effluents and discussed their ecological risks for the receiving surface waters. Moreover, we followed their concentrations along the path in one STP by corresponding time-related water sampling and derived the respective elimination rates in the purification process. Six fragrance substances (OTNE, HHCB, lilial, acetyl cedrene, menthol, and, in some grab samples, also methyl-dihydrojasmonate) could be detected in the effluents of the investigated sewage treatment plants. The other fragrances under scrutiny were only found in the inflow and were eliminated in the purification process. Only OTNE and HHCB were found in the receiving surface waters of the STP in congruent concentrations, which exceeded the preliminary derived environmental thresholds by a factor of 1.15 and 1.12, respectively, indicating potential risks. OTNE was also detected in similar concentration ranges as HHCB in muscles and livers of fish from surface waters and from ponds that are supplied with purified wastewater. The findings show that some fragrance compounds undergo high elimination rates, whereas others-not only musks-are present in receiving surface water and biota and may present a risk to local aquatic biota. Hence, our results suggest that the fate and potential effects of fragrance compounds in the aquatic environment deserve more attention. PMID- 22945656 TI - Kinetics of Remazol Black B adsorption onto carbon prepared from sugar beet pulp. AB - Dried sugar beet pulp, an agricultural solid waste, was used for the production of carbon. Carbonised beet pulp was tested in the adsorption of Remazol Black B dye, and adsorption studies with real textile wastewater were also performed. Batch kinetic studies showed that an equilibrium time of 180 min was needed for the adsorption. The maximum dye adsorption capacity was obtained as 80.0 mg g(-1) at the temperature of 25 degrees C at pH = 1.0. The Langmuir and Freundlich adsorption models were used for the mathematical description of the adsorption equilibrium, and it was reported that experimental data fitted very well to the Langmuir model. Mass transfer and kinetic models were applied to the experimental data to examine the mechanisms of adsorption and potential rate-controlling steps. It was found that both external mass transfer and intraparticle diffusion played an important role in the adsorption mechanisms of dye, and adsorption kinetics followed the pseudo-second-order type kinetic model. The thermodynamic analysis indicated that the sorption process was exothermic and spontaneous in nature. PMID- 22945657 TI - Effects of hydromorphology and riparian vegetation on the sediment quality of agricultural low-order streams: consequences for stream restoration. AB - Intensive agricultural land use imposes multiple pressures on streams. More specifically, the loading of streams with nutrient-enriched soil from surrounding crop fields may deteriorate the sediment quality. The current study aimed to find out whether stream restoration may be an effective tool to improve the sediment quality of agricultural headwater streams. We compared nine stream reaches representing different morphological types (forested meandering reaches vs. deforested channelized reaches) regarding sediment structure, sedimentary nutrient and organic matter concentrations, and benthic microbial respiration. Main differences among reach types were found in grain sizes. Meandering reaches featured larger mean grain sizes (50-70 MUm) and a thicker oxygenated surface layer (8 cm) than channelized reaches (40 MUm, 5 cm). Total phosphorous amounted for up to 1,500 MUg g(-1) DW at retentive channelized reaches and 850-1,050 MUg g(-1) DW at the others. While N-NH(4) accumulated in the sediments (60-180 MUg g( 1) DW), N-NO(3) concentrations were generally low (2-5 MUg g(-1) DW). Benthic respiration was high at all sites (10-20 g O(2) m(-2) day(-1)). Our study shows that both hydromorphology and bank vegetation may influence the sediment quality of agricultural streams, though effects are often small and spatially restricted. To increase the efficiency of stream restoration in agricultural landscapes, nutrient and sediment delivery to stream channels need to be minimized by mitigating soil erosion in the catchment. PMID- 22945659 TI - Responses of juvenile European flounder (Platichthys flesus) to multistress in the Vilaine estuary, during a 6-month survey. AB - Physiological and genetic responses of age 0+ Platichthys flesus were investigated in the eutrophicated and moderately contaminated Vilaine estuary, during a 6-month survey. The main objective of this study was to explore the biological responses of fishes during their juvenile period in an estuarine system in order to detect a possible selective pressure induced by the environmental stress. Our results showed a general convergence in physiological responses along the survey: an increase in genotoxicity was associated with an increase in mRNA expression of ATPase and betaine homocysteine methyltransferase. These results could suggest an increase of cellular damage, energetic request, and detoxification rate related to the growing exposure time to stress. Considering the aging of the cohort, the genetic characteristics of the Vilaine flounder cohort came closer to the one observed in a highly stressed system, the Seine estuary, suggesting a potential selective pressure mainly induced by the chemical stress. PMID- 22945660 TI - A review of membrane fouling in municipal secondary effluent reclamation. AB - Reclamation of municipal secondary effluent for non-potable purposes is considered vital in alleviating the demand for existing limited water supplies while helping to protect remaining water sources from being polluted. In recent decades, reverse osmosis and nanofiltration membrane technologies have become increasingly attractive for reclamation of municipal secondary effluent because they are highly efficient, easy to operate, and economical. However, membrane fouling is a major obstacle in the development of membrane technology in municipal secondary effluent reclamation. This paper reviews three types of membrane fouling in municipal secondary effluent reclamation, namely, effluent organic matter (EfOM) membrane fouling, microbial membrane fouling, and inorganic membrane fouling, as well as their correlation. Membrane fouling by EfOM and microbes are found to be severe, and they are significantly correlated. Most previous studies conducted laboratory-scale experiments of membrane fouling with model organic matters and bacteria, but these model organic matters and bacteria might still be unrepresentative. More studies on membrane fouling in municipal secondary effluent reclamation with actual wastewater are essential. PMID- 22945661 TI - [Editorial: Pharmazie in unserer Zeit 5/2012]. PMID- 22945662 TI - Beet juice-induced green fabrication of plasmonic AgCl/Ag nanoparticles. AB - A simple, green, and fast approach (complete within 5 min) was explored for the fabrication of hybrid AgCl/Ag plasmonic nanoparticles under microwave (MW) irradiation. In this method, beet juice served as a reducing reagent, which is an abundant sugar-rich agricultural produce. Interestingly, the obtained AgCl/Ag samples have a smaller size than the AgCl reaction precursor. This makes it an unusual top-down hydrothermal synthesis. The as-prepared material displayed good photocatalytic activity for the degradation of methyl orange (MO) dye. PMID- 22945663 TI - Studies of the solvatochromic emission properties of N-aroylurea derivatives II: influence of hydrogen-bonding interactions. AB - The solvatochromic emission properties of five naphthoylurea derivatives with different substitution patterns at the naphthoylurea functionality were investigated, with a particular focus on the influence of inter- and intramolecular H-bonding interactions. The bathochromic shifts of the emission maxima correlate well with the acceptor number or Catalan's acidity of the solvent (Deltalambda = 47-86 nm), indicating an excited species with a pronounced negative charge that is stabilized by H-bond donating (HBD) solvents. In media with restricted free volume the formation of the charged species is not favored, because the required conformational change to establish an intramolecular charge transfer (ICT) between the fluorophore and the acylurea substituent is hindered, and the emission mainly originates from the locally excited state. This relationship between the alignment of the naphthoyl carbonyl functionality relative to the naphthyl ring and the spectroscopic shift was confirmed by the comparison of the ground state conformation and the emission spectra of the naphthoylurea derivatives in the solid state. Time-resolved experiments revealed different excited entities, whose lifetimes are significantly influenced by the HBD properties and the temperature of the environment. With few exceptions the naphthoylurea derivatives exhibit only two emissive species in the nanosecond range. All experimental data point to conformational relaxation and solvent reorganization leading to the cis and trans isomers of one preferential conformer with respect to the acylurea unit. The structure of the preferred conformation is mainly determined by the possible inter- or intramolecular H-bonds and is therefore also strongly influenced by the HBD and H-bond accepting (HBA) properties of the polar solvents. As the NH groups of the acylurea functionality contribute mainly to the entire inter- and intramolecular H-bond arrangement the variation of the substitution pattern of the urea unit, specifically the presence and position of the NH groups, leads to derivatives with significantly different steady-state and time-resolved emission properties. PMID- 22945664 TI - Factors associated with perceived cognitive problems in children and adolescents with congenital heart disease. AB - The objective of the present study was to assess demographic and disease-specific factors associated with perceived cognitive problems in children and adolescents with heart disease. 246 children with congenital heart disease ages 8-18 years and their parents completed the Cognitive Problems Scale of the Pediatric Quality of Life Inventory Cardiac Module. The 5-item Cognitive Problems Scale assesses school-related cognitive problems including attention and memory from the perspective of the child and parent. Multiple linear regression analysis was conducted with demographic variables and disease-specific factors entered as independent variables and perceived cognitive problems as the dependent variable. Socioeconomic status (SES) and cardiac disease severity were significantly associated with parent proxy-reported cognitive problems (p < .05). None of the demographic or disease-specific variables were significantly associated with child self-reported cognitive problems. In conclusion, our data suggest that assessment of perceived cognitive problems in children and adolescents with greater disease severity and from lower SES homes may facilitate early identification of children who need formal evaluation and interventions to address cognitive impairments. PMID- 22945665 TI - Parental illness encouragement behavior among children with functional gastrointestinal disorders: a factor analysis with implications for research and clinical practice. AB - The objective of the current study was to assess the factor structure of the Illness Behavior Encouragement Scale (IBES) by Walker and Zeman (1992) among children with functional gastrointestinal disorders (FGIDs). Two hundred seventy nine children (63 % female), and 135 primary caregivers (90.8 % mothers), recruited from a large Midwestern children's hospital completed the IBES, a 12 item measure of parental behavior in response to abdominal pain episodes. Findings suggested the IBES possesses two conceptually distinct scales that are invariant across parent self- and child-report, and are consistent with previous factor analysis in a Dutch sample of children with headaches. Different types of parental behaviors exist that naturally cluster and diverge in reliable ways. Future research is warranted to determine if these different types of parental behavior may differentially influence illness outcomes among children with FGIDs. PMID- 22945666 TI - Musculoskeletal: what's different in children? Fell on wrist, now pain. PMID- 22945667 TI - Terminating marine methane bubbles by superhydrophobic sponges. AB - Marine methane bubbles are absorbed, steadily stored, and continuously transported based on the employment of superhydrophobic sponges. Antiwetting sponges are water-repellent in the atmosphere and absorb gas bubbles under water. Their capacity to store methane bubbles increases with enhanced submerged depth. Significantly, trapped methane bubbles can be continuously transported driven by differential pressure. PMID- 22945668 TI - [Imaging findings in complications of Meckel's Diverticulum -- a rare differential diagnosis in acute abdomen]. PMID- 22945679 TI - [The radiologist must survey the entire field of diagnostic imaging]. PMID- 22945682 TI - [Granting and revocation of billing approvals in radiology according to S 135 para 2 SGB V]. PMID- 22945685 TI - Delipidating effect of resveratrol metabolites in 3T3-L1 adipocytes. AB - SCOPE: Due to the low bioavailability of resveratrol, determining whether its metabolites exert any beneficial effect is an interesting issue. METHODS AND RESULTS: 3T3-L1 maturing pre-adipocytes were treated from day 0 to day 8 of differentiation and mature adipocytes for 24 h on day 12 with 1, 10, or 25 MUM of resveratrol or its metabolites. Triacylglycerols were assessed by spectrophotometry and gene expression by real time RT-PCR. Resveratrol, trans resveratrol-4'-O-glucuronide and trans-resveratrol-3-O-sulfate reduced triacylglycerol content in maturing pre-adipocytes at 25 MUM. In mature adipocytes, both resveratrol and its glucuronide metabolites, though not sulfate metabolite, reduced triacylglycerol content, although resveratrol was more effective than them. Resveratrol and the three metabolites reduced C/EBPbeta mRNA levels. Trans-resveratrol-3-O-sulfate also reduced C/EBP-alpha, peroxisome proliferator-activated receptor gamma (PPAR-gamma), and lipoprotein lipase (LPL) expression. In mature adipocytes, resveratrol increased ATGL, CPT-1, deacetylase sirtuin 1 (SIRT-1), and PGC1-alpha expression. Trans-resveratrol-3-O-glucuronide reduced mRNA levels of FASN and increased those of SIRT-1. Trans-resveratrol-4'-O glucuronide increased HSL and SIRT-1 mRNA levels. Trans-resveratrol-3-O-sulfate did not change gene expression. CONCLUSION: The present study shows for the first time the delipidating effect of (i) resveratrol metabolites in maturing pre adipocytes and (ii) glucuronide metabolites in mature adipocytes. This suggests that both resveratrol and resveratrol metabolites may be involved in the anti obesity effect of this polyphenol. PMID- 22945686 TI - Regional white matter hyperintensity volume, not hippocampal atrophy, predicts incident Alzheimer disease in the community. AB - BACKGROUND New-onset Alzheimer disease (AD) is often attributed to degenerative changes in the hippocampus. However, the contribution of regionally distributed small vessel cerebrovascular disease, visualized as white matter hyperintensities (WMHs) on magnetic resonance imaging, remains unclear. OBJECTIVE To determine whether regional WMHs and hippocampal volume predict incident AD in an epidemiological study. DESIGN A longitudinal community-based epidemiological study of older adults from northern Manhattan, New York. SETTING The Washington Heights/Inwood Columbia Aging Project. PARTICIPANTS Between 2005 and 2007, 717 participants without dementia received magnetic resonance imaging scans. A mean (SD) of 40.28 (9.77) months later, 503 returned for follow-up clinical examination and 46 met criteria for incident dementia (45 with AD). Regional WMHs and relative hippocampal volumes were derived. Three Cox proportional hazards models were run to predict incident dementia, controlling for relevant variables. The first included all WMH measurements; the second included relative hippocampal volume; and the third combined the 2 measurements. MAIN OUTCOME MEASURE Incident AD. RESULTS White matter hyperintensity volume in the parietal lobe predicted time to incident dementia (hazard ratio [HR] = 1.194; P = .03). Relative hippocampal volume did not predict incident dementia when considered alone (HR = 0.419; P = .77) or with the WMH measures included in the model (HR = 0.302; P = .70). Including hippocampal volume in the model did not notably alter the predictive utility of parietal lobe WMHs (HR = 1.197; P = .049). CONCLUSIONS The findings highlight the regional specificity of the association of WMHs with AD. It is not clear whether parietal WMHs solely represent a marker for cerebrovascular burden or point to distinct injury compared with other regions. Future work should elucidate pathogenic mechanisms linking WMHs and AD pathology. PMID- 22945687 TI - Synthesis of rhenium-centric reverse turn mimics. AB - Molecular scaffolds have been shown to facilitate and stabilise secondary structural turn elements, with a central core-arranging functionality in a defined three-dimensional orientation. In a peptide-based molecular imaging probe, this approach is of particular value as it would essentially "hide" a metal radioisotope within the ligand framework, making the labelling element a critical component of the receptor-bound structure. Starting from a 1,2 diaminoethane loaded 2-chlorotrityl resin, a versatile set of triamine ligand systems were synthesised by using solid-phase Fmoc-based peptide chemistry. The resultant resin-bound peptides then underwent amide reduction by treatment with borane-THF at 65 degrees C. This provided complete conversion to the corresponding polyamine entities in high purity for the majority of the amino acids utilised. The triamines were then coordinated on solid support by using [NEt(4)](2)[Re(CO)(3)(Br)(3)] followed by resin cleavage and HPLC purification, to give the desired rhenium coordinated species. We have shown that amino acid sequences can be assembled, reduced and coordinated on-resin, resulting in a versatile set of metal-ligand constructs. These studies could be expanded to generate libraries of turn-based peptidomimetics containing Re/Tc(I) organometallic scaffolds, with the intention of developing an improved approach for finding new diagnostic and therapeutic radiopharmaceutical entities. PMID- 22945688 TI - Pathophysiological mechanisms of carotid plaque vulnerability: impact on ischemic stroke. AB - Stroke is among the major causes of mortality and disabilities in the world. About 80 % of all strokes in the anterior circulation are ischemic and up to 20 % of all ischemic strokes are caused by extracranial atherosclerotic carotid artery stenosis. The prevalence of a cervical internal carotid artery stenosis increases with age and can be found in 6.9 % of the elderly population (>65 years). Atherosclerotic changes of the carotid vessel wall can lead to plaque vulnerability and may result in arterio-arterial embolism, which frequently underlie carotid-related cerebrovascular ischemic events. Carotid atherosclerosis is characterised by inflammation, extensive degradation of extracellular matrix components, neovascularization, and as recently recognised is also affected by epigenetic changes. These factors accelerate the progression of atherosclerosis towards vulnerable plaques and increase the risk of ischemic stroke. In this review, the main pathophysiological mechanisms leading to rupture-prone carotid artery plaques and successive ischemic stroke are considered. It is important to recognise the heterogeneity of atherosclerosis and that various pathophysiological processes dissected in this review are not acting individually, but rather in a complementary manner. The identification and careful integration of all relevant factors will be required for the development of future diagnostic and therapeutic strategies. PMID- 22945689 TI - Serum tumor necrosis factor-alpha and interleukin-10 levels as markers to predict outcome of patients with chronic lymphocytic leukemia in different risk groups defined by the IGHV mutation status. AB - Tumor necrosis factor (TNF)-alpha and interleukin (IL)-10 are cytokines involved in the balance between cell-mediated and humoral immunity. We investigated whether serum TNF-alpha and IL-10 levels have any impact on clinical outcome of patients with chronic lymphocytic leukemia (CLL). TNF-alpha and IL-10 levels were determined in the serum of 160 CLL patients at the time of diagnosis. The cytokine low-risk group consisted of patients with either TNF-alpha and IL-10 levels below their medians or those with only one elevated parameter. Both TNF alpha and IL-10 levels greater than or equal to their medians defined the cytokine high-risk group. The high-risk patients presented a shorter 3-year treatment-free survival (TFS) than low-risk subjects (15 vs. 69.6 %; p < 0.0001). The high-risk group (p = 0.0002) along with high leukocyte count (p < 0.0001) and unmutated immunoglobulin heavy-chain variable region genes (p < 0.0001) independently predict the risk of progression in patients with Rai stage 0-II. Furthermore, the high-risk group had an independent prognostic impact on shorter TFS both in patients with mutated (24.3 vs. 78.2 %; p < 0.0001) and unmutated (8.2 vs. 49 %; p = 0.004) immunoglobulin heavy-chain variable region genes (IGHV) as compared to the low-risk group. The estimated 5-year overall survival (OS) of high-risk patients was shorter than those in the low-risk group (83.3 vs. 97.1 %; p = 0.003). Multivariate analysis demonstrated the cytokine high-risk group (p = 0.02) followed by Rai stage III-IV (p = 0.048) to be independent factors predicting shorter OS. At diagnosis, TNF-alpha and IL-10 may predict the outcome of patients with CLL. PMID- 22945690 TI - Bone density and microarchitecture: relationship between hand, peripheral, and axial skeletal sites assessed by HR-pQCT and DXA in rheumatoid arthritis. AB - We assessed the relationship of bone density and microarchitecture between hand, peripheral, and axial skeletal sites using high-resolution peripheral quantitative computed tomography (HR-pQCT) and dual-energy X-ray absorptiometry (DXA) in patients with rheumatoid arthritis (RA) and which factors influence these parameters. This was a cross-sectional study of 100 female patients (53.4 +/- 9.3 years) with RA. HR-pQCT scans at distal radius and the second metacarpal head were performed to assess cortical and trabecular volumetric bone mineral density (vBMD) and microarchitecture. DXA scans at the hip, lumbar spine, and ultradistal radius were performed to assess areal BMD. There was significant correlation in vBMD and microarchitectural parameters between the second metacarpal head and distal radius (r = 0.201-0.628). Areal BMD at the axial skeleton was moderately associated with vBMD at the peripheral sites (r = 0.354 0.558). Factors related to disease severity/chronicity significantly correlated with vBMD and microarchitecture at the distal radius and the second metacarpal head. Factors related to disease activity were more likely to correlate with vBMD and microarchitecture at the second metacarpal head but not those at the distal radius. HR-pQCT is a promising technique that is capable of providing detailed quantitative assessment of disease-associated periarticular bone loss at both cortical and trabecular bone compartments in patients with RA. Future longitudinal studies will be needed to investigate whether assessment by HR-pQCT can be used as a marker of disease activity and a predictor of disease progression in RA. PMID- 22945691 TI - Hydrogen-bonding interactions and properties of energetic nitroamino[1,3,5]triazine-based guanidinium salts: DFT-D and QTAIM studies. AB - The intramolecular hydrogen-bonding interactions and properties of a series of nitroamino[1,3,5]triazine-based guanidinium salts were studied by using the dispersion-corrected density functional theory method (DFT-D). Results show that there are evident LP(N or O; LP = lone pair)->sigma*(N-H) orbital interactions related to O???H-N or N???H-N hydrogen bonds. Quantum theory of atoms in molecules (QTAIM) was applied to characterize the intramolecular hydrogen bonds. For the guanidinium salts studied, the intramolecular hydrogen bonds are associated with a seven- or eight-membered pseudo-ring. The guanylurea cation is more helpful for improving the thermal stabilities of the ionic salts than other guanidinium cations. The contributions of different substituents on the triazine ring to the thermal stability increase in the order of -NO(2)<-NF(2)<-N(3) ( ONO(2))<-NH(2). Energy decomposition analysis shows that the salts are stable owing to electrostatic and orbital interactions between the ions, whereas the dispersion energy has very small contributions. Moreover, the salts exhibit relatively high densities in the range of 1.62-1.89 g cm(-3). The detonation velocities and pressures lie in the range of 6.49-8.85 km s(-1) and 17.79-35.59 GPa, respectively, which makes most of them promising explosives. PMID- 22945692 TI - Attitudes to prenatal diagnosis and termination of pregnancy for 30 conditions among women in Saudi Arabia and the UK. AB - OBJECTIVE: The aim of this research was to compare attitudes between women from different cultural and/or religious backgrounds toward prenatal diagnosis (PND) and termination of pregnancy (TOP) for 30 different conditions. METHODS: A questionnaire examining parents' attitudes toward PND and TOP for 30 different conditions was completed by 100 Saudi, 222 UK-White, and 198 UK-Pakistani women. Comparison of overall attitudes with PND and TOP between groups was carried out, and a total score reflecting attitudes was obtained. RESULTS: In general, there were positive attitudes toward PND among the three groups surveyed. The attitudes of Saudi and UK-Pakistani women toward PND were more favorable than UK-White women. Overall, acceptance of TOP was lower than for PND. For the majority of conditions, acceptance of TOP was highest in Saudi women and lowest in UK Pakistani women. CONCLUSION: Attitudes toward TOP were significantly different between the three groups and may be influenced by cultural and/or religious factors. Availability of social services, genetic counseling, and rehabilitation centers may also influence attitude toward PND and TOP. PMID- 22945693 TI - Methylation levels of sodium-iodide symporter (NIS) promoter in benign and malignant thyroid tumors with reduced NIS expression. AB - DNA methylation regulates gene expression. Aberrant methylation plays an important role in human tumorigenesis. We have previously detected reduced NIS mRNA expression in thyroid tumors as compared to non-tumor tissues. Thus, in this study we investigated whether the methylation of the CpG-island located in the NIS gene promoter was associated with reduced mRNA expression in thyroid tumors. Methylation levels of 30 pairs of samples from 10 benign and 20 malignant thyroid tumors (T) along with matched non-tumor (NT) areas were determined by semiquantitative methylation specific-PCR. NIS methylation was detected in all samples. Methylation levels and frequencies did not differ between the groups and were not associated with BRAF mutational status. Highest methylation levels and frequencies were detected in the 5' region of the CpG-island decreasing toward the 3' end. Intraindividual analysis (T versus NT) showed high tumor methylation levels in 40 % of the samples in the benign group and 30 % in the malignant group, associated with low NIS mRNA expression. No quantitative correlation was detected between methylation levels and mRNA expression in any the groups. The results of this study showed that methylation of NIS promoter is a very frequent event in both benign and malignant tumors as well as in their surrounding tissues, and characterized a non-homogeneous methylation pattern along the CpG island. Therefore, further investigations involving other sites that may be implicated in methylation regulation of NIS expression are warranted. PMID- 22945694 TI - Association of the polymorphisms 292 C>T and 1304 G>A in the SLC38A4 gene with hyperglycaemia. AB - BACKGROUND: The SLC38A4 gene is related to system 'A' activity, which seems to be related to impaired gluconeogenesis. The objective of this study was to determine whether the 292 C>T and 1304 G>A polymorphisms of SLC38A4 gene are associated with hyperglycaemia in humans. METHODS: A total of 227 individuals were enrolled in a case-control study, in which hyperglycaemia was defined by plasma glucose levels >=95 mg/dL. Genotyping was carried out by using real-time polymerase chain reaction. RESULTS: The frequency of mutant alleles of SLC38A4 gene for single nucleotide polymorphism (SNP) 1304 G>A was 23.6% and 30.2% for SNP 292 C>T. The frequency of allele T for the SNP 292 C>T in the case and control groups did not show significant differences, whereas the frequency of allele A for the SNP 1304 G>A was significantly higher in the case group than in the control group (p = 0.04). In the logistic regression analysis, the SNP 1304 G>A [odds ratio (OR) 1.78; 95%CI 1.04-3.05, p = 0.03] but not SNP 292 C>T (OR 1.41; 95%CI 0.80-2.47, p = 0.23) showed a significant association with hyperglycaemia. After adjusting by body mass index, waist circumference and triglycerides, the SNP 1304 G>A remained significantly associated with hyperglycaemia (OR 2.13; 95%CI 1.18-3.83, p = 0.03). Pair wise linkage disequilibrium showed correlation (D' > 0.82) between 292 C>T and 1304 G>A SNPs. Haplotype association with hyperglycaemia also showed significant association between both homozygous mutant alleles (A/T) and hyperglycaemia (OR 1.68; 95%CI 1.01-2.79, p = 0.048). CONCLUSIONS: Our results suggest that mutant allele A for SNP 1304 G>A of SLC38A4 gene is associated with hyperglycaemia. PMID- 22945696 TI - Centralized mouse repositories. AB - Because the mouse is used so widely for biomedical research and the number of mouse models being generated is increasing rapidly, centralized repositories are essential if the valuable mouse strains and models that have been developed are to be securely preserved and fully exploited. Ensuring the ongoing availability of these mouse strains preserves the investment made in creating and characterizing them and creates a global resource of enormous value. The establishment of centralized mouse repositories around the world for distributing and archiving these resources has provided critical access to and preservation of these strains. This article describes the common and specialized activities provided by major mouse repositories around the world. PMID- 22945695 TI - Neutral sphingomyelinase 2 deficiency is associated with lung anomalies similar to emphysema. AB - Neutral sphingomyelinase 2 (nSMase2) upregulation was recently demonstrated to serve as a molecular link between smoke inhalation and emphysematous changes in lungs. Here we report that nSMase2 deficit impairs lung development in mice. We have shown previously that fragilitas ossium (fro) mice carry a mutation in the Smpd3 gene, rendering nSMase2 catalytically inactive. Analysis of lung phenotype revealed that fro mice have abnormally enlarged alveoli and increased compliance of the respiratory system, similar to morphological and functional manifestations of emphysema. Analysis of sphingolipid content in fro lungs revealed a decreased level of C14:0 ceramide but no significant alterations in the levels of sphingosine or sphingosine-1-phosphate. Altogether, our data suggest that nSMase2 activity and ceramide level are critical for lung development and function. Based on our data, ceramide can no longer be viewed as a lipid solely detrimental to lung function. PMID- 22945697 TI - The effect of implant design on the stress distribution in a three-unit implant supported distal cantilever fixed partial denture: a three-dimensional finite element analysis. AB - CONTEXT: Implant design influences the stress distribution in an implant supported distal cantilever fixed partial denture and supporting bone tissue. AIM: The purpose of this study was to investigate the effect of implant design on the stress distribution in the framework, implant, and surrounding bone, using a three-dimensional finite-element analysis. MATERIALS AND METHODS: A three dimensional finite-element model of a mandibular section of bone with implants placed in the first and second premolar region was created to support a distal cantilever fixed partial denture. A one-piece and two-piece implant and its suprastructure were simulated into wire frame models using Pro engineer (Pro E) program. Four models were created in this study. RESULTS: Comparative analysis of all models showed that the maximum stress overall was in the cervical portion of the secondary abutment. When used in combination, the maximum stress was when the two-piece implant was used as secondary abutment. The one-piece implant showed less stress compared to its counterpart when used as secondary abutment. The maximum stress distribution in the bone was around the neck region of the secondary implant. CONCLUSION: Within the limitations of this study, it can be concluded that stress distribution is better in a one-piece implant design when compared with the two-piece implant design, with stress concentration being more at the junction of the abutment and the implant fixture in the two-piece implant. When implants are used as abutments (either primary or secondary), irrespective of their position and design, the secondary implant shows the maximum amount of stresses. PMID- 22945698 TI - Comparison of def index with Nyvad's new caries diagnostic criteria among three to six years old children in a school at Bangalore city. AB - BACKGROUND: Dental caries is a multifactorial disease with varying clinical picture and its diagnostic criteria is complicated, when initial lesion is considered. Hence, there is a need for an index which measures cavitated, non cavitated, and initial lesion in dental caries. So, the purpose of this study was to compare the of def index with Nyvad's new diagnostic criteria. MATERIALS AND METHODS: A total of 249 school children in the age group of three to six years were selected for the study from Sajjan Rao School at Bangalore city. Children teeth were cleaned and dried with cotton rolls and chip blower. The dental caries examinations were conducted under standardized conditions using plane mouth mirrors and explorers with the help of artificial illumination. The diagnostic criteria used were deft and d, e, and f component of Nyvad's new caries diagnostic criteria. Mann Whitney 'U' test was used to compare the two indexes at five percent significant level. RESULTS: The mean value for deft was 2.48 and the mean for d, e, and f component of Nyvad's new caries diagnostic criteria was 3.18 which shows statistically significant difference with P value of <0.05. CONCLUSION: The result obtained by Nyvad's new caries diagnostic criteria produces values much higher than those with def caries index system. Hence, Nyvad's new caries diagnostic criteria can be used to diagnose dental caries at the initial stages, which in turn will reflect exact prevalence of caries. PMID- 22945699 TI - In vitro comparative evaluation of the effect of two different fiber reinforcements on the fracture toughness of provisional restorative resins. AB - BACKGROUND: Fracture of provisional fixed partial denture (FPD) may jeopardize the success of provisional prosthodontic treatment phase and cause patient discomfort. AIM: The aim of this study was to compare the fracture toughness of the Polymethyl Methacrylate (PMMA) resin and Bis-Acryl Composite (BAC) resin reinforced with the Polyethylene and Glass fibers. MATERIALS AND METHODS: Three groups (N=10) of each of the two materials were prepared for the fracture toughness test. Two groups had the different reinforcements and group without reinforcement served as the control. The mean fracture toughness (MPa.m1/2 ) was compared by One-way ANOVA, followed by the Scheffe analysis. Fracture toughness between fiber-reinforced PMMA and BAC resin was compared by the independent samples t test. RESULTS: For the controls, the fracture toughness for PMMA resin (0.91) was significantly lower than for the BAC resin (1.19). Glass fiber reinforcement produced significantly higher fracture toughness for both, PMMA (1.48) and BAC (1.82) resin, but the Polyethylene fibers did not (0.95 for PMMA and 1.23 for BAC resin). Among the reinforced groups, Silane impregnated Glass fibers showed highest fracture toughness for the BAC resin (1.82). CONCLUSION: Of two fiber reinforcement methods evaluated, Glass fiber reinforcement for the PMMA and BAC resin produced highest fracture toughness. CLINICAL IMPLICATIONS: On the basis of this in--vitro study, the use of Glass and Polyethylene fibers tested may be an effective way to reinforce resins used to fabricate fixed provisional restorations. PMID- 22945700 TI - Palateless custom bar supported overdenture: a treatment modality to treat patient with severe gag reflex. AB - OBJECTIVE: To suggest a custom bar supported overdenture treatment modality for prosthodontic management of patients with severe gag reflex. BACKGROUND: Some patients have a severe gag reflex and cannot tolerate conventional maxillary complete dentures with maximum palatal coverage and extensions of all borders. The condition further gets complicated in patients suffering from respiratory problems along with severe gag reflex. Severe gagging acts as a barrier to treat such patients with accepted clinical procedures and prevent patients from wearing the prosthesis. By saving some of the remaining natural teeth and fabricating, a horse shoe shape palateless simple tooth or bar supported overdenture can be successfully used for treating such patients. MATERIALS AND METHODS: The remaining maxillary right and left canines were prepared with the tapered round end diamond bur to receive copings of custom bar after intentional root canal treatment of same teeth. Impression was made with light body and putty of the polyvinyl siloxane elastomer with double step putty wash technique. Impression was poured with die stone. Wax pattern of copings with bar was fabricated with inlay wax which was invested and casted. After retrieving the bar, it was finished and its fit was evaluated. The coping-bar assembly was finally cemented with the glass ionomer cement. Palateless overdenture was fabricated by conventional technique used for the fabrication of complete denture. CONCLUSION: Palateless custom bar supported overdenture procedure can be successfully used for the management of patients with severe gag reflex with improved denture retention, stability, chewing efficiency and comfort of the patient. PMID- 22945701 TI - Evaluation of complete denture patients using graphoanalysis: a clinical study. AB - PURPOSE OF THE STUDY: The purpose was to analyze and classify behavioral pattern of complete denture patients and to identify difficult patients. MATERIALS AND METHODS: Fifty complete denture patients were randomly selected for the study. Their behavioral pattern was categorized using House classification as philosophic, indifferent, exacting and hysterical. The above behavioral classification was based on two methods namely interview and questionnaire and graphoanalysis. Accuracy of the above-mentioned two methods in predicting behavior of complete denture patients was statistically evaluated. RESULTS: On analyzing the data it was found that a significant correlation exists between handwriting pattern and behavior of an individual. Further it was noticed that chances of identifying difficult patients such as hysterical was more effective by employing graphoanalysis than questionnaire and interview method. CONCLUSION: Graphoanalysis in addition with properly structured interview and questionnaire is useful in evaluation of behavior of an individual especially for recognizing difficult patients. PMID- 22945702 TI - A comparison of the accuracy of patterns processed from an inlay casting wax, an auto-polymerized resin and a light-cured resin pattern material. AB - BACKGROUND: Traditionally, inlay casting waxes have been used to fabricate patterns for castings. Newer resin pattern materials offer greater rigidity and strength, allowing easier laboratory and intraoral adjustment without the fear of pattern damage. They also claim to possess a greater dimensional stability when compared to inlay wax. AIMS: This study attempted to determine and compare the marginal accuracy of patterns fabricated from an inlay casting wax, an autopolymerized pattern resin and a light polymerized pattern resin on storage off the die for varying time intervals. MATERIALS AND METHODS: Ten patterns each were fabricated from an inlay casting wax (GC Corp., Tokyo, Japan), an autopolymerized resin pattern material (Pattern resin, GC Corp, Tokyo, Japan) and a light-cured resin pattern material (Palavit GLC, Hereaus Kulzer GmbH, Germany). The completed patterns were stored off the die at room temperature. Marginal gaps were evaluated by reseating the patterns on their respective dies and observing it under a stereomicroscope at 1, 12, and 24 h intervals after pattern fabrication. RESULTS: The results revealed that the inlay wax showed a significantly greater marginal discrepancy at the 12 and 24 h intervals. The autopolymerized resin showed an initial (at 1 h) marginal discrepancy slightly greater than inlay wax, but showed a significantly less marginal gap (as compared to inlay wax) at the other two time intervals. The light-cured resin proved to be significantly more dimensionally stable, and showed minimal change during the storage period. CONCLUSION: The resin pattern materials studied, undergo a significantly less dimensional change than the inlay waxes on prolonged storage. They would possibly be a better alternative to inlay wax in situations requiring high precision or when delayed investment (more than 1 h) of patterns can be expected. PMID- 22945704 TI - A comparison of root surface instrumentation using manual, ultrasonic and rotary instruments: an in vitro study using scanning electron microscopy. AB - BACKGROUND: The commonly accepted idea concerning root planing is that excessive removal of cementum is not necessary for removal of endotoxins. The ideal instrument should enable the removal of all extraneous substances from the root surfaces, without causing any iatrogenic effects. AIM: To compare the remaining calculus, loss of tooth substance, and roughness of root surface after root planing with Gracey curette, ultrasonic instrument (Slimline insert FSI-SLI-10S), and DesmoClean rotary bur. MATERIALS AND METHODS: The efficiency of calculus removal, the amount of lost tooth substance, and root surface roughness resulting from the use of hand curette, ultrasonic instrument, and rotary bur on 36 extracted mandibular incisors were examined by SEM. We used three indices to measure the changes: Remaining calculus index (RCI), Loss of tooth substance index (LTSI), and Roughness loss of tooth substance index (RLTSI). Twelve samples were treated with each instrument. The time required for instrumentation was also noted. STATISTICAL ANALYSIS: Kruskal-Wallis ANOVA was used for multiple group comparisons and the Mann-Whitney test for group-wise comparisons. Analysis was carried out with SPSS software (version 13). RESULTS AND CONCLUSION: The RCI and LTSI showed nonsignificant differences between the three groups. RLTSI showed a significant difference between Slimline and hand curette as well as Slimline and Desmo-Clean. Slimline showed the least mean scores for RCI, LTSI, and RLTSI. Thus, even though the difference was not statistically significant, Slimline insert was shown to be better than the other methods as assessed by the indices scores and the instrumentation time. PMID- 22945703 TI - Evaluation of the remineralization potential of amorphous calcium phosphate and fluoride containing pit and fissure sealants using scanning electron microscopy. AB - AIM: To evaluate the remineralization potential of Amorphous Calcium Phosphate (ACP) and Fluoride containing pit and Fissure Sealants using Scanning Electron Microscopy. MATERIALS AND METHODS: Thirty maxillary first premolars were divided into three groups of ten each and were randomly selected for ACP containing (Aegis- Opaque White, Bosworth Co. Ltd.), Fluoride containing (Teethmate F1 Natural Clear, Kuraray Co. Ltd.), resin based (Concise- Opaque White, 3M ESPE Co. Ltd.) pit and fissure sealant applications. The Concise group served as a control. The teeth weresubjected to the pH-cycling regimen for a period of two weeks. After two weeks, the teeth were sectioned bucco-lingually into 4mm sections and were observed under Scanning Electron Microscope at 50X, 250X, 500X, 1000X and 1500X magnifications. The qualitative changes at the tooth surface and sealant interface were examined and presence of white zone at the interface was considered positive for remineralization. RESULTS: Both ACP containing (Aegis) and Fluoride containing (Teethmate F1) group showed white zone at the tooth surface-sealant interface. The resin based group (Concise) showed regular interface between the sealant and the tooth structure, but no clear cut white zone was observed. CONCLUSION: Both, Aegis and Teethmate F1 have the potential to remineralize. Release of Amorphous Calcium Phosphate molecules in Aegis group and formation of Fluoroapetite in Teethmate F1 group, were probably responsible for the remineralization. PMID- 22945705 TI - Comprehensive dental health care program at an orphanage in Nellore district of Andhra Pradesh. AB - BACKGROUND: Provision of oral health care in India, especially for the underprivileged is limited due to inadequate finances and manpower. Resources of dental colleges in such a scenario can be utilized to provide prevention oriented oral health care. AIM: To improve the oral health status of children at an institute in Nellore district of Andhra Pradesh, India, through prevention based comprehensive dental health care program (CDHP). DESIGN AND SETTING: A longitudinal institution based interventional study conducted among the primary grade children (n=162). MATERIALS AND METHODS: Baseline data collection included (i) basic demographic data (ii) body mass index (BMI) (iii) assessment of the dentition status and treatment needs according to WHO 1997 criteria. The CDHP included group based dental health education, professional oral prophylaxis, weekly (0.2%) sodium fluoride mouth rinse program, biannual application of topical fluoride (1.23% APF), pit and fissure sealants for all first permanent molars and provision of all necessary curative services. RESULTS: Mean treatment requirements per child decreased at 18 months. New caries lesions developed among four children. BMI of children with decay was seen to improve significantly after instituting the CDHP. CONCLUSION: CDHP is effective in overall improvement of general and oral health. In resource limited countries like India, such programs organized by dental schools can improve oral health. PMID- 22945707 TI - Comparison of sagittal and vertical dental changes during first phase of orthodontic treatment with MBT vs ROTH prescription. AB - OBJECTIVE: The present study was to evaluate and compare anchorage loss in sagittal, vertical dimension in incisal, molar segments and distal tipping of upper canine after first phase of orthodontic mechanotherapy utilizing MBT and ROTH philosophies. MATERIALS AND METHODS: Thirty patients with class I dentoalveolar malocclusion requiring extraction of all first premolars were randomly assigned into group I and group II. Set of two lateral cephalograms (T1) and (T2) were obtained with appliance in place and after sufficient leveling and aligning respectively. Linear measurements were recorded on the tracings using Pancherz analysis. A Wilcoxon t-test was use to assess the linear changes. RESULTS: In group I sample, upper and lower incisors retroclined during T1 - T2; by mean (SD) value of 2.267 (1.0032) mm, 2.4 (0.98) mm, respectively. Group II sample showed upper incisor proclination by -0.4 (1.404) and lower incisal retroclination by 0.06 (1.48). Upper and lower molars in group I remained stationary and group II upper and lower molars moved mesially by -1.133 (0.351) and -0.002 (0.005). In group I, upper and lower incisors extruded by -0.867 (0.611) and -0.67 (0.703), respectively, and group II the upper and lower incisors extruded by -0.9 (0.507) and -0.133 (0.639). Upper canine tipped distally during T1 - T2 in group I by -0.33 degrees (2.609) and group II there was a change in distal tip of upper canine by -3 degrees (3.184). CONCLUSION: Results from this random clinical trial showed that MBT technique effectively addressed perceived inadequacies of ROTH philosophy. PMID- 22945706 TI - A finite element thermal analysis of various dowel and core materials. AB - AIM: Thermal analysis of the temperature and stress distribution of parallel sided, threaded and non-threaded dowels and core materials under thermal loading within a maxillary central incisor using a three dimensional finite element study. MATERIALS AND METHODS: 3D models of endodontically treated maxillary central incisor with parallel sided, threaded and non- threaded post and core materials were simulated using the ANSYS software. Materials simulated were parallel sided cast gold post and core, parallel sided fibre reinforced composite (FRC) post and core, and parallel sided, threaded, prefabricated stainless steel post and amalgam core. Thermal loads simulating hot (60 degree C/ 333K) and cold (15 degree C/288K) liquid were applied for 15 seconds at the incisal edge. The temperature changes at the selected nodes were obtained on the various post and core materials, interface between post and dentin, interface between core and dentin, within the dentin and within the cement layer. RESULTS: Temperature and stress distribution pattern were represented in numerical and color coding and results interpreted. Thermal stresses arises as a result of temperature changes. A decreased temperature gradient of the metallic dowels and core (T1 hot - 0.002K, T3 hot - 1.071K, T1 cold -0.99K, T3 cold - 0K) were obtained than that of the FRC dowel and core of 1.982K(hot) and1.55K(cold) respectively due to the higher thermal conductivity of the metals. Higher thermal stress values of 3.567 Mpa(hot) and 3.092 Mpa(cold) respectively were obtained for the FRC dowels and higher stress values of 39.679 Mpa(hot) and 57.855 Mpa(cold) respectively were also obtained for the FRC cores. These values indicated that thermal stresses of the FRC dowel and core were greater than that of cast gold dowel and core and prefabricated stainless steel dowel and amalgam core due to its high coefficient of thermal expansion. Maximum stress values of the FRC dowel and core of 1.87 Mpa(hot) and 2.57 Mpa(cold) respectively were also generated in the cement layer, core and metal ceramic crown. The junction of the metal ceramic crown and dentin demonstrated the maximum stress. Higher thermal stress values of 59.162 +/- 10 Mpa were obtained in the restoration and the coronal portion of the dentin than the stress levels of .0039 +/- 10 Mpa in the supporting bone due to an increased thermal expansion. CONCLUSION: Non-metallic dowel and core materials such as fibre reinforced composite dowels (FRC) generate greater stress than metallic dowel and core materials. This emphasized the preferable use of the metallic dowel and core materials in the oral environment. PMID- 22945708 TI - Role of buccal corridor in smile esthetics and its correlation with underlying skeletal and dental structures. AB - PURPOSE: This study was designed to evaluate the buccal corridor in smile esthetics and to correlate it with underlying hard tissues. MATERIALS AND METHODS: Posed smiling frontal photographs, digital posterior-anterior (PA) cephalograms, and study models of 25 males and 25 females in age range of 18-25 years were taken. Photographs were evaluated for smile esthetics by eight orthodontists, eight plastic surgeons, eight beauticians and eight lay people to group them into three groups with least attractive, average and attractive smile and buccal corridor width was measured. Digital PA cephalograms were transferred on Nemo-tech software for frontal facial analysis. Intercanine and intermolar widths were measured on upper study model with the help of a digital calliper. RESULTS: The buccal corridor width was least in attractive smile group and maximum in least attractive smile group. The buccal corridor width had a negligible correlation with hard tissues and a mild to moderate inverse correlation with intercanine and intermolar widths within the groups. CONCLUSION: As the amount of buccal corridor display was increased, smiling images were scored less attractive by the evaluators. The buccal corridor is not influenced by underlying skeletal hard tissues but have mild to moderate inverse correlation with the intercanine and intermolar width. PMID- 22945709 TI - An evaluation of the effectiveness and predictability of transpositional flap vs connective tissue graft for coverage of Miller's class-I and class-II facial marginal tissue recession lesions: a clinical study. AB - BACKGROUND: There has been no study to date comparing the effectiveness and predictability of transpositional flap (TF) with that of the gold standard connective tissue graft (CTG) for root coverage. This study was performed during 2001-2002 at Government Dental College and Hospital, Mumbai India. OBJECTIVES: To evaluate the effectiveness and predictability of TF vs CTG for coverage of Miller's class I and class II facial marginal tissue recession defects. MATERIALS AND METHODS: Twenty cases fulfilling the selection criteria were identified and randomly allotted to two groups: group I (TF, 10 cases) and group II (CTG, 10 cases). Registered parameters included plaque index (PI), defect-specific plaque index (DPI), gingival index (GI), defect-specific gingival index (DGI), recession depth (RD), recession width (RW), probing depth (PD), attachment level (AL), width of keratinized tissue (KT), percentage defect coverage (DC), and percentage root coverage (RC). RESULTS: For group I: preoperative PI, DPI, GI, DGI, RD, PD, KT, and RC were 0.38 +/- 0.14, 1.1 +/- 0.57, 0.02 +/- 0.02, 0.36 +/- 0.29, 4.45 +/- 2.0, 1.5 +/- 0.71, 1.45 +/- 1.30, and 68.57 +/- 14.36, respectively; the corresponding postoperative values were 0.38 +/- 0.11, 0.36 +/- 0.29, 0.01 +/- 0.01, 0.10 +/- 0.16, 3.2 +/- 2.44, 1.1 +/- 0.32, 2.65 +/- 1.03, and 77.40 +/- 17.23. For group II the preoperative PI, DPI, GI, DGI, RD, PD, KT, and RC were 0.77 +/- 0.5, 1.53 +/- 0.63, 0.12 +/- 0.18, 0.59 +/- 0.62, 4.95 +/- 1.59, 1.9 +/- 0.74, 0.50 +/- 1.08, and 65.05 +/- 11.22, respectively, and the corresponding postoperative values were 0.49 +/- 0.32, 0.8 +/- 0.50, 0.03 +/- 0.53, 0.03 +/- 0.10, 0.90 +/- 0.88, 1.2 +/- 0.42, 4.4 +/- 1.07, and 93.65 +/- 6.18, respectively. CONCLUSION: The TF technique for coverage of single tooth buccal recession defects of Miller's class I and class II types in mandibular anterior teeth was neither effective nor predictable in defect coverage and defect elimination. PMID- 22945710 TI - Evaluation of the effect of bracket and archwire composition on frictional forces in the buccal segments. AB - AIM OF THE STUDY: The aim of this study was to consider friction in buccal segment attachments during overjet reduction by means of sliding mechanics. Friction was compared in Stainless Steel, Titanium and Cobalt Chromium brackets, using Stainless Steel and Beta Titanium wires. MATERIALS AND METHODS: This in vitro study comprised 18 samples (6 x 3 brackets of different materials-stainless steel, titanium and cobalt chromium). Each jig comprised of a buccal segment model of two premolar brackets and a molar tube simulating the upper posterior buccal segment. Each jig was coupled with the wire of 0.019 x 0.025 inch dimension and was tested with a Universal Testing Machine. Ligation was achieved using low friction elastomeric modules (Slide, Leone, Italy), a non-conventional elastomeric module. RESULTS: All three bracket systems showed significantly higher frictional forces for the beta titanium wire than for the stainless steel wire. When coupled with the stainless steel wire, the titanium bracket showed the least friction, followed by stainless steel and cobalt chromium brackets. When coupled with the beta titanium wire, the titanium brackets again showed the least friction; while the difference in frictional levels between the stainless steel and cobalt chromium brackets was not statistically significant. The titanium brackets showed the least friction among all the groups tested for both wires. CONCLUSION: Titanium bracket with Beta Titanium wires could and probably should be the alternative metal bracket used in the nickel sensitive patient. PMID- 22945711 TI - Effect of five brands of latex gloves on the setting time of polyvinyl siloxane putty impression materials. AB - Addition silicone impression materials have been used as impression material for more than 20 years. Although they are among the most expensive impression materials, they became popular during the past decade as they have excellent physical properties. Prevention of infection is an important aspect in dental treatment since dental professionals are routinely exposed to the wide variety of microorganisms present in saliva. Gloves are the most common protective measure used during dental treatment. The gloves are mostly made of latex. In this study, we examine how the setting time of three types polyvinyl putty materials were affected by the use of five different brands of latex gloves and one brand of vinyl gloves. Each material was first mixed without wearing gloves according to the manufacturer's instructions. After the stipulated mixing time, the setting time was measured using the Vicat needle. The setting time is measured from the time of mixing till the time that the needle does not produce any indentation on the surface of the material. The putty material was then mixed with gloved hands (using the five different brands of latex gloves in turn) and the setting time was measured. Then the material was mixed with washed gloved hands, and the setting time was measured again. Finally, the material was mixed with vinyl gloved hands and the setting time was measured. The following conclusions were drawn from the study: Reprosil and Express showed significant variation in the setting time with the latex gloved hands.There was no significant variation in the setting time when material was mixed with unwashed vs washed gloved hands.Vinyl gloves did not significantly affect the setting time of any of the putty impression materials. PMID- 22945712 TI - Apical stress distribution on maxillary central incisor during various orthodontic tooth movements by varying cemental and two different periodontal ligament thicknesses: a FEM study. AB - CONTEXT: During fixed orthodontic therapy, when the stress levels in the periodontal ligament (PDL) exceedsan optimum level, it could lead to root resorption. AIMS: To determine an apical stress incident on the maxillary central incisor during tooth movement with varying cemental and periodontal ligament thickness by Finite Element Method (FEM) modeling. SETTINGS AND DESIGN: A three dimensional finite element model of a maxillary central incisor along with enamel, dentin, cementum, PDL and alveolar bone was recreated using EZIDCOM and AUTOCAD software. ALTAIR Hyper mesh 7.0 version was used to create the Finite Element meshwork of the tooth. This virtual model was transferred to Finite Element Analysis software, ANSYS where different tooth movements were performed. MATERIALS AND METHODS: Cemental thickness at the root apex was varied from 200 MUm to 1000 MUm in increments of 200 MUm. PDL thickness was varied as 0.24 mm and 0.15 mm. Intrusive, Extrusive, Rotation and Tipping forces were delivered to determine an apical stress for each set of parameters. RESULTS: Results indicated that an apical stress induced in the cementum and PDL, increased with an increase in cementum and PDL thickness respectively. Apical stress induced in the cementum remained the same or decreased with an increase in the PDL thickness. Apical stress induced in the PDL decreased with an increase in the cementum thickness. CONCLUSION: The study concluded that the clinical delivery of an orthodontic forces will cause stress in the cementum and PDL. Hence, it is necessary to limit the orthodontic force to prevent root resorption. PMID- 22945713 TI - Shear bond strength of three self-adhesive resin cements to dentin. AB - CONTEXT: The result of the studies concerning the bonding of self-adhesive resin cements to dentin is controversial. AIMS: To assess in vitro shear bond strength (SBS) of three self-adhesive dual-cured resin cements to dentin compared to a currently used dual-cured resin cement, using SBS test. SETTINGS AND DESIGN: The extant study is an experimental in vitro one on extracted human third molars dentin. MATERIAL AND METHODS: 40 intact human third molars were selected and randomly divided into 4 groups of 10. Buccal dentin surfaces were exposed perpendicular to the long axis and prepared with SiC papers. A translucent plastic ring, was placed over the dentin surfaces. Group I (Control group): After 15 s of etching and application of Excite DSC Bond (Ex), Variolink II (Var II) resin cement was injected into the plastic ring and was light cured for 40 s. Group II: RelyX Unicem (RX) was injected into the plastic ring and after 30 s, was light cured for 40 s. Group III: Maxcem (Mc) was injected into the plastic ring and after 30 s, was light cured for 40 s. Group IV: Multilink Sprint (MS) was injected into the plastic ring and after 30 s, was light cured for 40 s. After thermal cycling, SBS were measured with a universal testing machine. STATISTICAL ANALYSIS USED: Statistical computations were conducted according to Student's t-test. RESULTS: The mean SBS and standard deviations (in parentheses) for groups I, II, III, and IV were 12.95 (2.64), 6.73 (0.79), 3.01 (0.90), 4.60 (0.75) MPa, respectively. Statistical analysis, revealed that: (1) the mean SBS of Var II were significantly higher than the other groups (P<0.05). (2) The mean SBS of Mc and MS were significantly lower than RX (P<0.05). (3) The mean SBS of Mc and MS did not show significant difference (P>0.05). CONCLUSION: Bond strength of three self-adhesive resin cements was significantly lower than the conventional total-etch resin cement. RX significantly performed better SBS than Mc and MS to dentin. PMID- 22945714 TI - The effect of calcium hydroxide placement on pH and calcium concentration in periapical environment: an in vitro study. AB - AIMS: Comparing the calcium concentration and pH levels of Ca(OH) 2 medicament placing in pulp chamber and root canal. MATERIALS AND METHODS: Ninety-nine extracted human mandibular second premolars were instrumented to size #40 k file. Nine teeth served as the control group and the remaining teeth were assigned into two groups. Group 1-Ca(OH) 2 was placed in the dried pulp chamber, while root canals remained wet with normal saline; group 2-Ca(OH) 2 was placed in dried root canals. In control group, canals remained wet without medication. Each group was divided into 3 sub-groups of 15 teeth in which pH and calcium concentration were measured in three intervals of 2 days, 1 week, and 2 weeks by pH meter and atomic absorption spectrometer system, respectively. Findings were assessed using Kruskal-Wallis and t-test. RESULTS: At 1 and 2 weeks, the calcium concentration had increased without being significantly different from Ca(OH) 2 placed either in the root canal or in the pulp chamber. Ca(OH) 2 placed in the pulp chamber or root canal provided similar pH values (P=0.362). CONCLUSIONS: Placing Ca(OH) 2 in pulp chamber is as effective as placing it in the root canal. PMID- 22945715 TI - The effect of air abrasion on the retention of metallic brackets bonded to fluorosed enamel surface. AB - BACKGROUND: Bonding brackets to fluorosed enamel remains a clinical challenge and bracket failure at the compromised enamel interface is common. OBJECTIVE: To check the effect of air abrasion on the retention of metallic brackets bonded to fluorosed enamel surface. MATERIALS AND METHODS: Sixty freshly extracted human premolar teeth having moderate to severe dental fluorosis as per Dean's criteria were collected and divided into three groups of 20 each. The groups were treated as follows: In group I, acid etching was followed by bonding with Transbond XT ; in group II, sandblasting and acid etching was followed by bonding with Transbond XT ; and in group III, sandblasting and acid etching was followed by bonding with Enlight LC . An Instron universal testing machine was used for determining the debonding force, and from this the shear bond strength was computed. The sample with highest shear bond strength from each group was selected for the scanning electron microscopy (SEM) study. The prepared specimens were examined under a JSM 840A scanning electron microscope (JEOL Ltd, Tokyo, Japan) operated at 20 kV. Photographs were taken at progressively higher magnifications of *50, *100, *500, and *1000 to view the enamel surface and the adhesive remaining on the enamel surface after debonding. The shear bond strengths of the groups were compared using the one-way ANOVA (analysis of variance) and Tukey post hoc test. The distribution of adhesive remnant index (ARI) score was compared using the Chi square test. RESULTS: The mean shear bond strength in group I was 10.36 MPa, with a standard deviation of 0.225. The corresponding values in group II and group III were 11.41 +/- 0.237 MPa and 11.39 +/- 0.201 Mpa, respectively. There was a statistically significant difference between the three groups in the mean shear bond strength values. CONCLUSION: Sandblasting followed by acid etching provides significantly higher bond strength values compared to acid etching alone, irrespective of the bonding material employed. PMID- 22945716 TI - Relationship of deciduous teeth emergence with physical growth. AB - INTRODUCTION: Tooth eruption, recognized as an aspect of human growth and development, could possibly be influenced by a number of factors. It may reflect the general body development. AIM: The aim of the present research is to investigate the relationship of deciduous teeth emergence with physical growth (weight/height indices). MATERIALS AND METHODS: A study was conducted among a sample of 1132 Egyptian infants whose ages range from 4 to 36 months. The sample was collected from some randomly selected health centers affiliated to the ministry of health where various socioeconomic strata from different geographic localities were recruited. The children visit there regularly for vaccination at definite ages. Weight and height were evaluated as factors that might have influence on the time of deciduous teeth emergence. RESULTS: The results showed a certain degree of correlation between the number of deciduous teeth emerged and the studied anthropometric measurements which differed by sex and age. CONCLUSION: All anthropometric parameters showed relationship with the number of teeth at different levels. Although weight showed influence on the number of teeth emerged, it was less significant than height. PMID- 22945717 TI - Assessment of convergence angle of full-coverage porcelain fused to metal crowns in clinical practice. AB - BACKGROUND: Full-coverage porcelain fused to metal crowns is commonly recommended for restoration of extensively damaged teeth. Ability of the dentist to adequately prepare teeth is fundamental to success and longevity of these restorations. AIMS: This study was designed to compare recommended convergence angle and taper values of tooth preparation with clinically practiced values and to assess the factors such as tooth position, operator experience, vitality, and restorative status on convergence angle of prepared teeth. SETTING AND DESIGN: It was a descriptive, cross-sectional study design and held at The Aga Khan University Hospital, Dental Section, for a period of 1 year. MATERIALS AND METHODS: A minimum of 197 crown preparation models of molar and premolar teeth prepared by residents and specialists were collected in order to achieve the objectives of the study on the basis of convenient sampling technique. STATISTICAL ANALYSIS: One sample t-test used to compare the mean practiced convergence angle values with its recommended values. Independent sample t-test and one-way ANOVA was used to see difference in the convergence angle values of the teeth prepared by different operators, tooth type, vitality status, and restorative status of teeth. RESULTS: Mean reported convergence angle and axial wall taper values were 23.7 degrees +/- 8.9 degrees and 11.3 degrees +/- 7.8 degrees , respectively, which is significantly greater (P<0.001) than the recommended values. Convergence angle values were greater for molars as compared to premolars. CONCLUSION: There was a considerable disparity between the convergent angles values recorded in this study and the recommended guidelines and are affected by tooth type, vitality, and restorative status of tooth. PMID- 22945718 TI - In vitro study of microleakage of different techniques of surface preparation used in pits and fissures. AB - OBJECTIVE: The purpose of this in vitro study was to evaluate the effect of different techniques of surface preparation on the microleakage of a sealant applied with traditional acid etching and self-etched bonding agent. STUDY DESIGN: A total of 60 extracted third molars were randomly assigned into six groups (n = 10/each). The occlusal surfaces were sealed with a sealant (Clinpro) after one of the following pretreatments: (1) phosphoric acid etching; (2) Prompt L-Pop; (3) laser + etching; (4) laser + Prompt L-Pop; (5) air abrasion + etching; (6) air abrasion + Prompt L-Pop. The specimens were immersed in a 0.5% basic fuchsin solution. Buccolingual cuts parallel to the long axis of the tooth were made. The surfaces were scored 0--2 for extent of microleakage using a microscope and the data were analyzed statistically. RESULTS: The poorest results were obtained with laser + Prompt L-Pop which showed a greater number of specimens with microleakage (80%). Air abrasion surface preparation + phosphoric acid etching showed less microleakage than the other groups (40%). Kruskal--Wallis and t-tests revealed no significant difference in microleakage between six groups. conclusion: The self-etching adhesive studied seems an attractive alternative to the acid-etch technique for sealant application in young children where simplifications in the clinical procedure are warranted. No significant difference was noted between the different types of enamel preparation before fissure sealant. PMID- 22945719 TI - Quantification of AgNOR expression in exfoliated oral mucosal cells of tobacco chewers with and without lesion. AB - BACKGROUND: Nucleolar organizer regions (NOR) are associated with proliferative activity and represent a diagnostic and prognostic marker. MATERIALS AND METHODS: Smears were taken from smokers, tobacco chewers, oral squamous cell carcinoma patients, and normal subjects and evaluated by 2 silver-staining nucleolar organizer region (AgNOR) counting methods: (1) mean number of AgNORs per nucleus (mAgNOR); and (2) percentage of nuclei with >3 and >5 AgNORs (pAgNOR). RESULTS: A statistically significant difference was observed between normal subjects, smokers, tobacco chewers, and oral cancer patients and between tobacco chewers with and without lesion. No significant difference was observed between tobacco chewers and smokers except in the percentage of >5 criteria. CONCLUSIONS: AgNOR enumeration using noninvasive methods, such as the cytobrush appears to be useful technique in distinguishing between normal mucosa, mucosa with and without lesions exposed to carcinogens, such as tobacco and frank oral carcinoma. PMID- 22945720 TI - Implant crest module: a review of biomechanical considerations. AB - The success of dental implants has long been established through various studies with a particular emphasis laid on an implant design. Crest module is that portion of a two-piece metal dental implant, designed to hold the prosthetic components in place and to create a transition zone to the load bearing implant body. Its design, position in relation to the alveolar crest, and an abutment implant interface makes us believe that, it has a major role in integration to both hard and soft tissues. Unfortunately, in most clinical conditions, early tissue breakdown leading to soft tissue and hard tissue loss begins at this region. Early crestal bone loss is usually highest during the first year after placement ranging from 0.9 to 1.6mm and averaged 0.05-0.13 mm in the subsequent years . Various hypotheses have been stated to reason it however, none has been proved convincingly. In light of this, various attempts have been made to overcome this undesirable bone loss, by varying an implant design, the position, surgical protocol, and the prosthetic options. Irrespective of an implant system and designs that are used, crestal bone loss of up to the first thread is often observed. The purpose of this review is to look into the various designs and treatment modalities, which have been introduced into the crest module of an implant body to achieve the best biomechanical and esthetic result. PMID- 22945721 TI - Hypoglossia Type 1A: report of a case and review of literature with focus on clinical investigations. AB - Hypoglossia is a rare entity which is reported sporadically. Hypoglossia has often occurred in an association with limb anomalies and, therefore, these cases have been grouped together as hypoglossia-hypodactylia within oromandibular limb hypogenesis syndromes. The literature on this condition is reviewed, and a case of hypoglossia has also been presented. An investigative protocol to aid in the treatment planning of a patient with hypoglossia has also been suggested. PMID- 22945722 TI - Epithelioid hemangioma (angiolymphoid hyperplasia with eosinophilia) in the oral mucosa. AB - Angiolymphoid hyperplasia with an eosinophilia (ALHE) is a rare benign entity whose etiology and pathogenesis is under debate. Clinically, it is characterised by cutaneous papules or nodules on the head and neck. Literature reveals very few cases of this entity in the oral mucosa. Here, we report a case of ALHE in a 25 year-old woman, who presented with a painless, 5mm x 5mm, sub mucosal erythematous nodule on left angle of mouth at lower lip. Histological examination of lip biopsy specimens revealed an increase in small vessels. The vascular walls consist of prominent endothelial cells with a histiocytoid appearance, which protruded into the lumen. Many eosinophils and lymphocytes were also seen around the vessels. The diagnosis of ALHE was made from the above findings. PMID- 22945723 TI - Anterolateral thigh free flap for the reconstruction of through and through defect of cheek following cancer ablation. AB - The anterolateral thigh flap is a highly versatile and reliable flap for use in the reconstruction of various soft-tissue defects of the head and neck. This flap has gained great popularity due to its versatility, ability for a two-team approach, and minimal donor site morbidity. However, it has not met the same enthusiasm in the armamentarium of Maxillofacial Surgeons due to its relative difficulty in perforator dissection, reported variations of the vascular anatomy, and the presumed increased thickness of the anterolateral thigh tissue. These obstacles may be overcome by increased surgical experience and by the ability to create a thinner suprafacial flap or thinning the flap after it has been obtained. We have described the versatility of this flap for the reconstruction of the through and through defect of cheek following cancer ablation along with difficulties in raising flap. PMID- 22945724 TI - An alternative treatment of occlusal wear: cast metal occlusal surface. AB - Acrylic resin denture teeth often exhibit rapid occlusal wear, which may lead to decrease in the chewing efficiency, loss of vertical dimension of occlusion, denture instability, temporomandibular joint disturbances, etc. There are various treatment options available like, use of highly cross linked acrylic teeth, amalgam or metal inserts on occlusal surface, use of composite, gold or metal occlusal surface, etc. Several articles have described methods to construct gold and metal occlusal surfaces, however, these methods are time-consuming, expensive and requires many cumbersome steps. These methods also requires the patient to be without the prosthesis for the time during which the laboratory procedures are performed. This article presents a quick, simple and relatively inexpensive procedure for construction of metal occlusal surfaces on complete dentures. PMID- 22945725 TI - A patient with Eagle syndrome: radiological and scintigraphic evaluation. AB - A 42-year-old man who had been having otalgia and facial and neck pain for 6 months presented for a routine dental examination. He had suffered two head traumas, the first 20 years ago and the second 4 years ago. A panoramic radiograph (PR) was taken as a screening film after the clinical examination. Bilateral styloid process elongation (SPE) was detected, and the patient was diagnosed as having Eagle syndrome. The styloid process (SP) length was 78 mm on the right and 74 mm on the left on multislice computed tomography (MSCT). Bone scan of the cranium showed normal uptake of radiotracer in the cranial bones and some little activity was detected as a silhouette in the localization of SPE in planar and SPECT images. To the best of our knowledge, this is the first case investigating SPE by bone scintigraphy in a patient with Eagle syndrome. PMID- 22945726 TI - Peripheral squamous odontogenic tumor. AB - A case of peripheral squamous odontogenic tumor is described in a 60-year-old female who presented with a sessile growth in the right posterior mandible. Radiographic examination revealed no evidence of a central lesion in bone. With the characteristic histopathological picture of benign-appearing islands of squamous epithelium scattered randomly against a background of mature fibrous connective tissue, the tumor was diagnosed as peripheral squamous odontogenic tumor (PSOT). The epithelial islands showed peripheral cuboidal or flattened cells, microcyst formation, individual cell keratinization, and keratin pearl formation. PMID- 22945727 TI - Treatment of division II malocclusion in young adult with Forsus fatigue resistant device. AB - The traditional technique for correcting class II malocclusion - involving the use of class II elastics and headgear - has been problematic due to its dependence on patient compliance. Functional orthopedic treatment seeks to correct malocclusions and harmonize the shape of the dental arch and orofacial functions. Removable functional appliances are normally very large in size, have unstable fixation, cause discomfort, exert pressure on the mucosa, reduce space for the tongue, cause difficulties in deglutition and speech, and very often affect esthetic appearance. With a fixed appliance like the Forsus fatigue resistant device (FRD), as the appliance is fixed, there is less dependence on patient compliance and the remaining growth after the pubertal growth spurt can be harbored effectively. The Forsus FRD is not as rigid as the previous fixed functional appliances and hence is comfortable for the patients. In this case report we describe a patient at the end of the growth stage who had mandibular retrognathia and was successfully treated with the Forsus FRD. PMID- 22945728 TI - Ethical guidelines on authorship. PMID- 22945729 TI - Oral health-related knowledge, attitude, and practices among 12-year-old schoolchildren studying in rural areas of Panchkula, India. AB - Oral health is fundamental to general health and well being. Schools can provide a supportive environment for promoting oral health. School policies and education on health-related matters are imperative for the attainment of good oral health and control of related risk behaviors. AIM: This study was conducted to assess oral health-related knowledge, attitude, and practices among 12-year-old schoolchildren studying in rural areas of Panchkula, India. The ultimate goal was to implement an oral health-promotion program in this area. MATERIALS AND METHODS: A total of 440 children (216 males and 224 females) from 12 schools were included in this study. All the participants were requested to complete a 13 question closed-ended questionnaire. The statistical significance of any difference between the two genders was determined using the Chi-square test. RESULTS: Only 25% of the participants said that they cleaned their teeth more than once in a day. Thirty-two percent did not clean their teeth daily. Over the preceding 1 year, 45.5% of the childern had had some problem with their teeth and/or gums, but only 35.9% visited the dentist. Among these children, 8.2% used tobacco in some form. Oral health-related knowledge of girls was significantly better than that of boys. CONCLUSION: Based upon the findings of the present study, the knowledge, attitude, and practices of the surveyed children with regard to oral health is poor. Hence, there is a need for regular oral health education of the children, as well as their parents and school teachers. PMID- 22945730 TI - 30 Years of dental research in Australia and India: a comparative analysis of published peer review literature. AB - BACKGROUND: A sustained program of research is an integral part of human-kind's efforts to improve oral health. In addition, dental research is a vital part of the development of a strong and prosperous dental education system and has been one of the three pillars of the higher education sector (Research, Education and Service) for a very long time. AIM: This study aims to examine the last 30 years of peer review published dental literature in both, Australia and India, and to define the trends in publication over that time. MATERIALS AND METHODS: This study used the Pubmed database using a set of core dental words for the years 1980 to 2009. Detailed analysis of the year-by-year rates of publication was done using Microsoft Excel. RESULTS: India is on a near exponential upward growth while Australia through the latter half of the last decade has been more stable in output. State-wise breakdown in both countries shows that the proportions are more consistent for Australia, but for India, a major number of publications can be traced to three states. CONCLUSION: It is expected that dental research in Australia will grow in the coming decade as the new dental schools embed their educational programs and mature to develop strong research profiles. However, India is becoming a significant force in the published peer review dental research literature, and is growing at a very rapid rate. PMID- 22945731 TI - Honeybee propolis extract in periodontal treatment: a clinical and microbiological study of propolis in periodontal treatment. AB - OBJECTIVE: This study was conducted to evaluate by clinical and microbiological parameters the effect of subgingival irrigation with propolis extract. MATERIALS AND METHODS: Twenty patients diagnosed with chronic periodontitis, each presenting three non-adjacent teeth with deep pockets, were selected. Subgingival plaque sampling and clinical recording (at baseline) and scaling and root planing was performed. Two weeks later the selected periodontal sites were submitted to one of the following treatments: Irrigation with a hydroalcoholic solution of propolis extract twice a week for 2 weeks (group A); irrigation with a placebo twice a week for 2 weeks (group B); or no additional treatment (group C). Clinical and microbiological data was collected at baseline and after 4, 6, and 8 weeks. RESULTS: A decrease in the total viable counts of anaerobic bacteria (P=.007), an increase in the proportion of sites with low levels (<=105 cfu/mL) of Porphyromonas gingivalis (P=.044), and an increase in the number of sites negative for bleeding on probing was observed in group A sites as compared to group B and C sites. CONCLUSION: Subgingival irrigation with propolis extract as an adjuvant to periodontal treatment was more effective than scaling and root planing as assessed by clinical and microbiological parameters. PMID- 22945732 TI - Perception of smile esthetics among Indian dental professionals and laypersons. AB - INTRODUCTION: Patients' perceptions and expectations regarding their appearance play a significant role in treatment planning. The purpose of this study was to compare the perceptions of orthodontists, general dentists, and laypersons regarding smile esthetics after symmetrical and asymmetrical alterations in anterior teeth and their supporting tissues. MATERIALS AND METHODS: Alterations were made in the crown length, crown width, midline diastema, and gingiva-to-lip relationship of the maxillary anterior teeth in the close-up photograph of a woman's smile. The attractiveness of the smile in the original image and in each of the modified images were assessed by orthodontists (n=40), dentists (n=40), and laypersons (n=40) and scored using a visual analog scale (VAS). The mean VAS scores were calculated for each photograph. ANOVA was used for comparisons between photographs and between groups. To determine threshold levels at which each group discriminated between esthetic and less esthetic dental features were determined by one-way ANOVA (F-test) followed by Newman-Keul's range test. RESULTS: Orthodontists were found to be more critical when evaluating smile images compared to general dentists and laypersons. Symmetrical or asymmetrical alterations in the mesio-distal width of the lateral incisor of up to 2 mm was not perceived as unesthetic by general dentists and laypersons. CONCLUSION: Laypersons are more accepting of minor variations in anterior tooth size and alignment than orthodontists. PMID- 22945733 TI - Effect of a combination of oral midazolam and low-dose ketamine on anxiety, pain, swelling, and comfort during and after surgical extractions of mandibular third molars. AB - PURPOSE: To assess the clinical efficacy of a combination of oral midazolam plus low-dose ketamine for reducing anxiety during surgery and in preventing postoperative pain and swelling after the surgical extraction of third molars. MATERIALS AND METHODS: Thirty patients requiring bilateral surgical extraction of mandibular third molars were included in this study. Prior to extraction of the tooth on the right side, a combination of oral midazolam and low-dose ketamine was given to the patient, while this protocol was not followed for extraction of the tooth on the left side. Anxiety levels were checked before surgery. The postoperative pain and swelling and patient's comfort with and without the premedication were compared. RESULTS: Facial swelling on the postoperative days was lower on the right side than on the left. Pain scores at 30 minutes and 24 hours after surgery were significantly higher on the left side. Also, anxiety during the surgery was less and comfort levels were higher postoperatively when the combination of oral midazolam plus low-dose ketamine was used. CONCLUSIONS: Premedication with midazolam plus low-dose ketamine prior to surgical extraction of third molars can provide the patient with a comfortable procedure and good postoperative analgesia, with less swelling and significantly less pain. PMID- 22945734 TI - Role of delayed light polymerization of a dual-cured composite base on marginal adaptation of class II posterior composite open-sandwich restoration. AB - OBJECTIVE: To determine the effect of delayed light polymerization of a dual cured composite base material on the marginal adaptation of class II composite restoration. MATERIALS AND METHODS: 35 extracted human molar teeth were used to prepare class II mesio-occlusal or disto-occlusal slot preparations with gingival margins at the CEJ. The teeth were restored using an open-sandwich technique with a 2mm base increment of dual-cured composite, and divided into 5 groups based on the mode of the polymerization of the dual-cured composite base: Group A - self cured after placement (5 mins), Group B - light-cured immediately after placement, Group C - light-cured 30 seconds after placement, Group D - light cured 60 seconds after placement, Group E - light-cured 120 seconds after placement. Then a top layer of a light-cured composite resin is placed to complete the restoration. The teeth were thermocycled and immersed in 1% aqueous solution of methylene blue for 24 hours. Sectioning of the teeth and scoring under stereomicroscope was done. Data will be statistically evaluated using the kruskal wallis 1-way ANOVA. RESULTS: Statistical analysis using kruskal wallis 1 way ANOVA showed that the dual-cured composite light polymerized 1 minute after placement exhibited the least microleakage. CONCLUSION: Delayed light polymerization of the dual-cured composite base reduced the microleakage in class II open-sandwich restorations. PMID- 22945735 TI - A survey on the use of techniques, materials in dental implantology practice. AB - PURPOSE: To present results of a survey on the status of an implantology amongst implant-practicing dentist across the world in 2009. MATERIALS AND METHODS: A questionnaire was sent to the members of EAO (European Association of Osseointegration), ICOI (International Congress of Osseointegrated Implants), ISOI (Indian Society of Oral Implantologists), Asian Academy of Osseointegration (AAO), Deutsche Gasellschaft Fur Orale Implantologie (DGOI), Philippines Implant Organization, Korean Society of Oral Implantologist, Japanese Association of OralIimplantologists, Chinese Dental Association, Pakistan Dental Association, asking for the personal (anonymous) background data and their implantology concepts. Specific questions dealt with level of recognition of implants, use of implants, superstructures, techniques followed, and materials used. RESULTS: A total of 1500 (63.6%) of the 2358 questionnaires were answered. Dental implants were the most preferred treatment modality for restoring the missing teeth. Threaded implants were the most preferred. Cement retained implant prosthesis was the most preferred restoration procedure. Dentists believe that the general dentist should practice dental implant treatment modality, preferably teamwork. Immediate loading was the much-accepted concept among the dentists of the developed nations. CONCLUSION: Dental implants were much accepted treatment modality for the replacement of missing teeth. Most the dentists follow the well documented technique and proven materials, which have been documented in the literature, an evidenced based practice, thus, delivering the best to their patients. Dentists from the developing nations agreed to have standardization in implants. PMID- 22945736 TI - Cryosurgery in the treatment of oro-facial lesions. AB - Cryosurgery is a therapeutical method that uses freezing to obtain a tissue inflammatory and/or a destructive response. It has been successfully used for many cutaneous conditions. Its use is increasing for several conditions in the oral cavity. The oral mucosa, because of its characteristics of humidity and smoothness, is an ideal site for this technique. It shows a very good esthetic result and it may be either the first choice or an alternative option to conventional surgery. This article strives to review the modus operandi of cryosurgical instruments, the various indications, limitations and advantages of cryosurgery in the treatment of oral lesions. PMID- 22945737 TI - Is radiographic appearance a reliable indicator for the absence or presence of pathology in impacted third molars? AB - In dental practice, impacted third molar teeth are a common finding. The dentists usually remove them if they are associated with some radiographic finding suggestive of a cyst or a tumor or if they cause pain or resorption of the adjacent teeth. It has been found that, in many cases, even the radiographically and clinically asymptomatic impacted mandibular third molars are associated with some pathology. This paper brings into the light two cases with clinically and radiographically normal impacted third molar teeth associated with dentigerous cyst, thus highlighting that the radiographic appearance is not a reliable indicator of the absence or presence of pathology associated with the impacted third molars. PMID- 22945738 TI - Early dental implant failure in patient associated with oral bisphosphonates. AB - Oral bisphosphonates are routinely prescribed to post menopausal women. These have shown to increase the risk of osteonecrosis. However, this action may be augmented by local factors. A case report is presented showing an early implant failure in a patient taking oral bisphosphonates. Two implants were placed in left maxillary incisor area. Central incisor was associated with a previous endodontic failure and extraction. Lateral incisor was avulsed 3 years back. After 4 weeks of an implant placement, necrotic bone was evident along with the failing implant in central incisor area. This case report emphasizes on the incidence and an increased risk of implant failure in patients taking oral bisphosphonates. PMID- 22945740 TI - Advanced microstructure of boron carbide. AB - The rhombohedral elementary cell of the complex boron carbide structure is composed of B(12) or B(11)C icosahedra and CBC, CBB or B?B (?, vacancy) linear arrangements, whose shares vary depending on the actual chemical compound. The evaluation of the IR phonon spectra of isotopically pure boron carbide yields the quantitative concentrations of these components within the homogeneity range. The structure formula of B(4.3)C at the carbon-rich limit of the homogeneity range is (B(11)C) (CBC)(0.91) (B?B)(0.09) (?, vacancy); and the actual structure formula of B(13)C(2) is (B(12))(0.5)(B(11)C)(0.5)(CBC)(0.65)(CBB)(0.16) (B?B)(0.19), and deviates fundamentally from (B(12))CBC, predicted by theory to be the energetically most favourable structure of boron carbide. In reality, it is the most distorted structure in the homogeneity range. The spectra of (nat)B(x)C make it evident that boron isotopes are not randomly distributed in the structure. However, doping with 2% silicon brings about a random distribution. PMID- 22945741 TI - The VCD method--a simple and reliable way to distinguish cage C and B atoms in (hetero)carborane structures determined crystallographically. AB - Replacing a boron vertex in a [B(n)H(n)](2-) cluster with a smaller atom, e.g. carbon, results in the distance from that atom to the polyhedral centroid being shorter. This forms the basis of a simple but very effective method of distinguishing between B and C atoms in (hetero)carboranes that have been studied crystallographically, the Vertex-to-Centroid Distance (VCD) method. Examples of well-characterised icosahedral and sub-icosahedral closo carboranes, nido carboranes, icosahedral metallacarboranes and supraicosahedral metallacarboranes are used to illustrate the generality of the VCD method. In this process a number of structures are identified in which the method suggests B/C disorder not previously recognised and some structures in which it appears that a cage C atom has been wrongly assigned. The largest sub-group of heterocarboranes is the family of 3,1,2-MC(2)B(9) compounds, and for these species consideration of Exopolyhedral Ligand Orientation (ELO) can sometimes be used to quickly suggest when a literature structure is suspect in terms of cage C atom positioning. The crystal structure of one such compound, 3,3-NO(3)-3-PPh(3)-3,1,2-closo RhC(2)B(9)H(11), has been redetermined and the correct location of the cage C atoms established. PMID- 22945743 TI - Effects of chronic baclofen use on active movement in an individual with a spinal cord injury. AB - STUDY DESIGN: Case report. OBJECTIVES: To describe a case of chronic use of oral baclofen in a patient with spinal cord injury limiting lower extremity movements. SETTING: Frazier Rehab Institute, Louisville, Kentucky and University of Louisville. REPORT: A 24-year-old male with a C5 AIS-B spinal cord injury received a neurophysiological examination pre and post cessation of the use of oral baclofen. The initial results revealed no motor activity below the level of the lesion during reinforcement maneuvers or active movements. Following discontinuance of baclofen, motor activity was detected in upper and lower extremity muscles during some tasks. Locomotor patterns during stepping on a treadmill with body weight support did not reveal excessive overactivity of the lower extremity muscles. The patient was also able to perform squats independently at 35-40% body weight support when standing on a treadmill. CONCLUSION: Baclofen is typically prescribed for the management of spasticity in individuals with spinal cord injury. The interaction of reduced spasticity on functional tasks is not well understood, raising an important limitation of neurological exams and classifications done under heavy dosages of medication. PMID- 22945744 TI - Kinematic characteristics of tenodesis grasp in C6 quadriplegia. AB - STUDY DESIGN: Descriptive control case study. OBJECTIVES: To analyze the kinematics of tenodesis grasp in participants with C6 quadriplegia and healthy control participants in a pointing task and two daily life tasks involving a whole hand grip (apple) or a lateral grip (floppy disk). SETTING: France. METHODS: Four complete participants with C6 quadriplegia were age matched with four healthy control participants. All participants were right-handed. The measured kinematic parameters were the movement time (MT), the peak velocity (PV), the time of PV (TPV) and the wrist angle in the sagittal plane at movement onset, at the TPV and at the movement end point. RESULTS: The participants with C6 quadriplegia had significantly longer MTs in both prehension tasks. No significant differences in TPV were found between the two groups. Unlike control participants, for both prehension tasks the wrist of participants with C6 quadriplegia was in a neutral position at movement onset, in flexion at the TPV, and in extension at the movement end point. CONCLUSION: Two main kinematic parameters characterize tenodesis grasp movements in C6 quadriplegics: wrist flexion during reaching and wrist extension during the grasping phase, and increased MT reflecting the time required to adjust the wrist's position to achieve the tenodesis grasp. These characteristics were observed for two different grips (whole hand and lateral grip). These results suggest sequential planning of reaching and tenodesis grasp, and should be taken into account for prehension rehabilitation in patients with quadriplegia. PMID- 22945739 TI - Age- and calorie restriction-related changes in rat brain mitochondrial DNA and TFAM binding. AB - Aging markedly affects mitochondrial biogenesis and functions particularly in tissues highly dependent on the organelle's bioenergetics capability such as the brain's frontal cortex. Calorie restriction (CR) diet is, so far, the only intervention able to delay or prevent the onset of several age-related alterations in different organisms. We determined the contents of mitochondrial transcription factor A (TFAM), mitochondrial DNA (mtDNA), and the 4.8-kb mtDNA deletion in the frontal cortex from young (6-month-old) and aged (26-month-old), ad libitum-fed (AL) and calorie-restricted (CR), rats. We found a 70 % increase in TFAM amount, a 25 % loss in mtDNA content, and a 35 % increase in the 4.8-kb deletion content in the aged AL animals with respect to the young rats. TFAM specific binding to six mtDNA regions was analyzed by mtDNA immunoprecipitation and semiquantitative polymerase chain reaction (PCR), showing a marked age related decrease. Quantitative real-time PCR at two subregions involved in mtDNA replication demonstrated, in aged AL rats, a remarkable decrease (60-70 %) of TFAM-bound mtDNA. The decreased TFAM binding is a novel finding that may explain the mtDNA loss in spite of the compensatory TFAM increased amount. In aged CR rats, TFAM amount increased and mtDNA content decreased with respect to young rats' values, but the extent of the changes was smaller than in aged AL rats. Attenuation of the age-related effects due to the diet in the CR animals was further evidenced by the unchanged content of the 4.8-kb deletion with respect to that of young animals and by the partial prevention of the age-related decrease in TFAM binding to mtDNA. PMID- 22945745 TI - Study on the safe range of shortening of the spinal cord in canine models. AB - STUDY DESIGN: Experimental dog model of spinal cord shortening. OBJECTIVES: To clarify the relationship between the amount of shortening of the spinal cord and the degree of injury it may induce, and to determine the safe range of the shortening. SETTING: Xi'an Jiaotong University, China. METHODS: Thirty adult dogs were randomly allocated to five groups. Dogs in Group A (sham operation control) underwent spondylectomy to have two-thirds of the thirteenth thoracic segment (T13) resected, without bone-to-bone contact of the adjacent vertebral bodies. Those in Group B, C, D and E had one-third, half, two-thirds and total of their T13 resected, respectively, with bone-to-bone contact. Somatosensory-evoked potentials (SEP) and spinal cord blood flow (SCBF) were detected. The histopathologic changes of spinal cord tissue were observed by hematoxylin and eosin stain and electron microscope. RESULTS: The shortening of the spinal cord < half of a vertebral segment height caused a reversible change of SEP. Whereas, the changes resulted from the shortening of more than two-thirds of a vertebral segment height did not return to the normal level. SCBF increased temporarily when the shortening was within two-thirds of a vertebral segment height; whereas, it decreased progressively when the length of the shortening was equal to one vertebral segment height. More serious hemorrhage occurred as the shortening increased. CONCLUSION: Shortening of half of a vertebral segment height will not induce spinal cord injury (SCI), while that between half and two-thirds of a vertebral segment may lead to incomplete SCI. PMID- 22945746 TI - Reliability of the electrical perceptual threshold and Semmes-Weinstein monofilament tests of cutaneous sensibility. AB - STUDY DESIGN: Prospective experimental. OBJECTIVES: To compare the reliability and repeatability of the electrical perceptual threshold (EPT) and Semmes Weinstein monofilament (SWM) tests for cutaneous sensibility. EPT and SWM tests have potential as quantitative and sensitive adjuncts to the American Spinal Injuries Association (ASIA) Impairment Scale (AIS) assessment of spinal cord injury (SCI). SETTING: London, UK. METHODS: EPT and SWM tests were carried out on 40 neurologically healthy individuals (20 male). One examiner carried out all the tests. Each individual was examined for EPT and SWM sensitivity at ASIA key points on four dermatomes (C4, T1, T6, L4) on both sides of the body. The tests were repeated after an interval of approximately 1 week. Intra-rater reliability was determined using intra-class correlation coefficients (ICC). Repeatability was determined using the method of Bland and Altman. RESULTS: There were no significant differences in the mean values of EPT or SWM between assessments for any dermatome. Significant difference in mean values for both EPT and SWM were observed between some dermatomes. ICC ranged from 0.67 to 0.81 for the EPT and from 0.46 to 0.61 for the SWM. Higher ICC for the EPT compared with the SWM was again revealed when male and female subjects were assessed separately. Correlation between EPT and SWM was weak or (largely) absent. CONCLUSION: EPT has better reliability than SWM in healthy subjects. However, as both tests have the potential to add sensitivity and resolution to the AIS assessment, a further comparison of their repeatability in SCI is warranted. PMID- 22945747 TI - Pain-related pharmacotherapy, healthcare resource use and costs in spinal cord injury patients prescribed pregabalin. AB - STUDY DESIGN: Retrospective database analysis. OBJECTIVES: To describe comorbidities, pain-related pharmacotherapy, healthcare resource use and costs among patients with spinal cord injury (SCI) newly prescribed pregabalin. SETTING: United Kingdom (UK). METHODS: Using The Health Improvement Network database, SCI patients newly prescribed (index event) pregabalin (N=72; average age 48 years; 53% female) were selected. Study measures were evaluated during both the 9-months pre-index and follow-up periods. RESULTS: Prevalent comorbidities included musculoskeletal disorders (51.4%), digestive disorders (23.6%) and urogenital disorders (20.8%). Opioids were the most frequently prescribed medications (pre-index, 58.3%; follow-up, 61.1%, P=not significant (NS)) followed by nonsteroidal anti-inflammatory drugs (43.1 and 45.8%, P=NS). Use of anti-epileptics (other than pregabalin) recommended for SCI neuropathic pain decreased (25.0 vs 12.5%, P=0.0290), whereas sedative/hypnotic use (18.1 vs 26.4%, P=0.034) increased during follow-up. Over 50% of patients had visits to specialists, and at least 1 in every 10 had laboratory/radiology-related visits. There were numerical decreases in proportions of patients with emergency room visits (22.2 vs 13.9%, P=NS) and hospitalizations (16.7 vs 12.5%, P=NS) during follow-up. Medication costs were higher during follow-up (median, L 561.4 vs L 889.5, P<0.0001). Costs of outpatient visits were similar during both study periods (L 1082.1 vs L 1066.1) as were total medical costs (L 1689.0 vs L 2169.4) when costs of pregabalin prescriptions were excluded. Inclusion of pregabalin costs resulted in higher (P<0.0001) total medical costs during follow-up. CONCLUSION: SCI patients had a high comorbidity, medication and healthcare resource use burden in clinical practice. Further research with larger sample sizes and more comprehensive data sources may serve to clarify study findings. PMID- 22945748 TI - International spinal cord injury musculoskeletal basic data set. AB - OBJECTIVES: To develop an International Spinal Cord Injury (SCI) Musculoskeletal Basic Data Set as part of the International SCI Data Sets to facilitate consistent collection and reporting of basic musculoskeletal findings in the SCI population. SETTING: International. METHODS: A first draft of an SCI Musculoskeletal Basic Data Set was developed by an international working group. This was reviewed by many different organizations, societies and individuals over 9 months. Revised versions were created successively. RESULTS: The final version of the International SCI Musculoskeletal Basic Data Set contains questions on neuro-musculoskeletal history before spinal cord lesion; presence of spasticity/spasms; treatment for spasticity within the last 4 weeks; fracture(s) since the spinal cord lesion; heterotopic ossification; contracture; the location of degenerative neuromuscular and skeletal changes due to overuse after SCI; SCI related neuromuscular scoliosis; the method(s) used to determine the presence of neuromuscular scoliosis; surgical treatment of the scoliosis; other musculoskeletal problems; if any of the musculoskeletal challenges above interfere with activities of daily living. Instructions for data collection and the data collection form are freely available on the International Spinal Cord Society (ISCoS) website (www.iscos.org.uk). CONCLUSION: The International SCI Musculoskeletal Basic Data Set will facilitate consistent collection and reporting of basic musculoskeletal findings in the SCI population. PMID- 22945749 TI - Transient ischemia induces massive nuclear accumulation of SUMO2/3-conjugated proteins in spinal cord neurons. AB - OBJECTIVES: The objective of this study is to determine whether transient spinal cord ischemia activates small ubiquitin-like modifier (SUMO1-3) conjugation, a post-translational protein modification that protects neurons from ischemia-like conditions. METHODS: Mice were subjected to 8-12 min of spinal cord ischemia and 3-24 h of recovery using a newly developed experimental model. To characterize the model, activation of stress response pathways induced after spinal cord ischemia, previously observed in other experimental models, was verified by western blot analysis. Levels and subcellular localization of SUMO-conjugated proteins in spinal cords were evaluated by western blot analysis and immunohistochemistry, respectively. RESULTS: Following transient spinal cord ischemia, stress responses were activated as indicated by increased phosphorylation of eukaryotic initiation factor 2 (eIF2alpha), extracellular signal-regulated kinases (ERK1/2) and Akt. SUMO1 conjugation was not altered, but a selective rise in levels of SUMO2/3-conjugated proteins occurred, peaking at 6 h reperfusion. The marked activation of SUMO2/3 conjugation was a neuronal response to ischemia, as indicated by co-localization with the neuronal marker NeuN, and was associated with nuclear accumulation of SUMO2/3-conjugated proteins. CONCLUSION: Our study suggests that spinal cord neurons respond to ischemic stress by activation of SUMO2/3 conjugation. Many of the identified SUMO target proteins are transcription factors and other nuclear proteins involved in gene expression and genome stability. It is therefore concluded that the post ischemic activation of SUMO2/3 conjugation may define the fate of neurons exposed to a transient interruption of blood supply, and that this pathway could be a therapeutic target to increase the resistance of spinal cord neurons to transient ischemia. PMID- 22945750 TI - Epidemiological features of traumatic spinal cord injury in Anhui Province, China. AB - STUDY DESIGN: A retrospective hospital-based study. OBJECTIVES: To describe the epidemiologic features of traumatic spinal cord injury (TSCI) in Anhui Province. SETTING: Two hospitals within Anhui Province, China. METHODS: We retrospectively reviewed the hospital records on all patients with TSCI, admitted between 1 January 2007 and 31 December 2010 (n=761). Variables included age, gender, occupation, neurological level, severity of injury, cause and treatment. RESULTS: Seven hundred and sixty-one cases of TSCI were identified. Five hundred and eighty eight were males (77.3%) and 173 were females (22.7%), with a mean age of 45 years (s.d.=13, range from 5 to 87). Fall from height was the leading cause of injury (52.6%), followed by transport (21.2%). The neurological lesion levels were cervical (46.3%), lumbosacral (33.3%) and thoracic (20.4%). CONCLUSION: Prevention strategies for TSCI should target 30-60 age group, males, farmers and fall from height. The results of this study will serve as a basis for further studies on TSCI. The prevention strategies and treatment should be designed according to the injury features. PMID- 22945752 TI - Amsterdam international. PMID- 22945751 TI - Cardiac surgery in Germany during 2011: a report on behalf of the German Society for Thoracic and Cardiovascular Surgery. AB - All cardiac surgical procedures performed in 78 German cardiac surgical units throughout the year 2011 are presented in this report, based on a voluntary registry which is organized by the German Society for Thoracic and Cardiovascular Surgery. In 2011, a total of 100,291 cardiac surgical procedures (implantable cardioverter defibrillator and pacemakers procedures excluded) have been collected in this registry. More than 13.4% of the patients were older than 80 years compared with 12.4% in 2010. Hospital mortality in 41,976 isolated coronary artery bypass graft procedures (14.7% off-pump) was 2.9%. In 26,972 isolated valve procedures (including 5,210 catheter-based procedures), an in-hospital mortality of 5.2% has been observed.This voluntary registry of the German Society for Thoracic and Cardiovascular Surgery will continue to be an important tool enabling quality control and illustrating current facts and the development of cardiac surgery in Germany. PMID- 22945753 TI - Wetting transitions in underwater oleophobic surface of brass. AB - An oil droplet in water can be in the Cassie state (with water and/or air trapped between the solid and oil) with a high contact angle (top left) or in the Wenzel state (top right). Depending on the roughness of the brass substrate, both states with high (bottom left) and low (bottom right) contact angle are observed. PMID- 22945754 TI - Towards alternatives to anodic water oxidation: basket-handle thiolate Fe(III) porphyrins for electrocatalytic hydrocarbon oxidation. AB - Selective electrocatalytic oxidation of hydrocarbons to alcohols, epoxides or other (higher value) oxygenates should in principal present a useful complementary anodic half-cell reaction to cathodic generation of fuels from water or CO(2) viz. an alternative to oxygen evolution. A series of new basket handle thiolate Fe(III) porphyrins have been synthesised and shown to mediate anodic oxidation of hydrocarbons, specifically adamantane hydroxylation and cyclooctene epoxidation. We compare yields obtained by electrochemical and chemical oxidation of the thiolate porphyrins and benchmark their behaviour against that of Fe(III) tetraphenyl porphyrin chloride and its tetrapentafluorophenyl analogue. PMID- 22945755 TI - Introduction to the symposium "Comparative proteomics of environmental and pollution stress". AB - The study of the proteome in response to environmental change is beginning to generate a number of new hypotheses about how organisms respond and adapt to a variety of stressors. The contributions to this symposium highlight how comparisons at the levels of species, populations, and tissues provide exciting new perspectives on the diversity of biochemical responses involved in the tolerance of stress. Despite limited genomic information, a number of studies of nonmodel organisms provide insights that are only accessible through a systems approach like proteomics. The realization that these systemic responses differ among closely related species, populations, and tissues illustrates the potential importance of the proteome to an organism's evolutionary response to a rapidly changing environment. Changes in an organism's proteome may occur as early as during the first stages of development and continue through acclimatization of the adult and adaptation of the following generations. A proteomic approach can also demonstrate how pollutants have systemic effects that may be counter intuitive to expectations, emphasizing how isolating a single mode of action for a pollutant, e.g., xeno-androgen, is often inadequate. To continue with the progress made, we need a critical evaluation of the experimental designs used in proteomics studies, a reevaluation of some of the statistical analyses, and new technical advances in order to identify a greater number of proteins. The contributions to the current symposium offer the novice a starting point for assessing the potential of proteomics to generate novel hypotheses about how organisms interact with their environment. PMID- 22945756 TI - When skeletons are geared for speed: the morphology, biomechanics, and energetics of rapid animal motion. AB - A skeleton amplifies the minute contractions of muscles to animate the body of an animal. The degree that a muscular contraction displaces an appendage is determined by the gearing provided by the joints of a skeleton. Species that move rapidly commonly possess joints with relatively high gears that produce a large output displacement. However, the speed of an appendage can depend on dynamics that obscure how this motion is influenced by the skeleton. The aim of this review is to resolve mechanical principles that govern the relationship between the gearing and speed of skeletal joints. Forward dynamic models of three rapid force-transmission systems were examined with simulations that varied the gearing of a joint. The leg of a locust, the raptorial appendage of a mantis shrimp, and the jaw of a toad are all driven by the conversion of stored elastic energy into kinetic energy. A locust achieves this conversion with high efficiency when it kicks and thereby applies nearly all stored energy into fast movement. This conversion is unaffected by differences in the leverage of the knee joint, as demonstrated by a maximum kicking speed that was found to be independent of gearing. In contrast, the mantis shrimp creates drag as it strikes toward a prey and thereby loses energy. As a consequence, high gears displace the raptorial appendage relatively far and yield slower motion than do low gears. The muscle that opens a toad's jaw also dissipates energy during ballistic capture of prey. This loss of energy is reduced when jaw opening occurs from the slower muscle contraction produced by a high gear within the jaw. Therefore, the speed of these lever systems is dictated by how gearing affects the efficiency of the conversion of potential energy into kinetic energy. In this way, the energetics of force transmission mediate the relationship between the gearing of a skeletal joint and the maximum speed of its motion. PMID- 22945757 TI - IPH-926 lobular breast cancer cells harbor a p53 mutant with temperature sensitive functional activity and allow for profiling of p53-responsive genes. AB - Profiling of p53-responsive genes has been carried out in different cellular models, most of which involved genetic modifications or cytotoxic stimulation. We report on the utilization of IPH-926 human lobular breast cancer cells for the profiling of p53-responsive genes using a novel approach without such modifications. We discovered that IPH-926 cells harbor a homozygous TP53 missense mutation encoding for a rare p53 mutant (E285K) with temperature-sensitive (ts) loss of function characteristics. This mutation had evolved as a late, secondary genetic event during the natural clonal evolution of the corresponding lobular carcinoma. In vitro temperature shifts reconstituted endogenous wild-type p53 activity in IPH-926, as evidenced by induction of p21(Waf1). Transcriptional alterations associated with restored p53 function were profiled using Affymetrix microarrays and a new strategy to gate out non-specific temperature effects. At the P=0.0005 significance level, 60 genes were differentially expressed following reconstitution of p53 activity. These genes included CDKN1A, MDM2 and PHLDA3, a recently described p53-inducible inhibitor of AKT. Similar transcriptional alterations were observed upon reconstitution of p53 activity in BT-474 cells, which also harbor ts-p53 E285K, and in ASPC1 cells transduced with ts-p53 A138V. Consistent with these models, low PHLDA3 expression was associated with nuclear p53 accumulation, indicative of deleterious TP53 mutations, in primary breast cancers. From a molecular point of view, IPH-926 thus provides a new tool to study transcriptional programs controlled by p53. From a tumor pathology perspective, IPH-926 also provides the first direct evidence of a p53-related clonal evolutionary pathway in lobular breast cancer progression. PMID- 22945758 TI - Brookite versus anatase TiO2 photocatalysts: phase transformations and photocatalytic activities. AB - Titanium dioxide nanoparticles consisting of pure anatase, anatase-rich, brookite rich, and pure brookite modifications were synthesized and characterized by X-ray diffraction, field emission-scanning electron microscopy and nitrogen adsorption. The phase transformations among the three modifications of TiO2 (anatase, brookite, and rutile) and the photocatalytic activities of these nanoparticles were investigated by heat treatment over the temperature range from 400 to 800 degrees C and by the photooxidation of methanol, respectively. Direct transformation of anatase and brookite to rutile was observed, while in the case of the anatase-brookite mixture, anatase transforms firstly to brookite and then to rutile. The photocatalytic activity measurements indicate that brookite nanoparticles exhibit higher photocatalytic activities than anatase, and a comparable activity to that of the anatase-rich nanoparticles. The phase transformations and photocatalytic results are discussed regarding their dependence on crystallite size, surface area, and phase composition. PMID- 22945759 TI - Differentiation of highly anisotropic TbIII and DyIII with 57Fe Mossbauer spectroscopy. AB - Using (57)Fe Mossbauer spectroscopy, three examples of coordination compounds with different topologies containing Fe(III) and Ln(III) ions (Dy(III) and Tb(III); see diagram; insets: clusters cores) were analyzed. In the same crystal field environment, Dy and Tb ions show different degrees of anisotropy, which can be qualitatively detected using an indirect method. PMID- 22945760 TI - Substitution Monotherapy With Levetiracetam vs Older Antiepileptic Drugs: A Randomized Comparative Trial. AB - OBJECTIVE To determine whether patients who fail their first antiepileptic drug (AED) have better neuropsychiatric and quality-of-life (QOL) outcomes if substituted to levetiracetam monotherapy compared with a second older AED. DESIGN Randomized comparative trial. Participants with partial epilepsy who had failed monotherapy with phenytoin sodium, carbamazepine, or valproate sodium were randomized to substitution monotherapy with levetiracetam or a different older AED. Assessments were performed at baseline, 3 months, and 12 months using questionnaires measuring neuropsychiatric, QOL, seizure control, AED adverse effects, and neurocognitive outcomes. SETTING Epilepsy service of a teaching hospital. PATIENTS Fifty-one patients were randomized to levetiracetam and 48 were randomized to a second older AED (25 to valproate and 23 to carbamazepine). MAIN OUTCOME MEASURES Proportions showing improvements in depression (on the Hospital Anxiety and Depression Scale) and QOL scores (on the 89-item Quality of Life in Epilepsy Inventory) at 3 months. RESULTS There were no differences between the groups in depression scores at 3 months (improvement in 17 of 43 patients [39.5%] in the levetiracetam group and 15 of 44 patients [34.1%] in the older AED group; P = .60), but a greater proportion of the older AED group improved on the 89-item Quality of Life in Epilepsy Inventory compared with the levetiracetam group (27 of 38 patients [71.1%] vs 21 of 43 patients [48.8%], respectively; P = .04). The QOL, anxiety, and AED adverse effects scores were improved in both groups at 3 and 12 months after randomization. CONCLUSIONS Substitution monotherapy in a patient experiencing ongoing seizures or tolerability issues is associated with sustained improvements in measures of QOL, psychiatric, and adverse events outcomes. Patients switched to levetiracetam do not have better outcomes than those switched to a second older AED. TRIAL REGISTRATION anzctr.org.au Identifier: ACTRN12606000102572. PMID- 22945761 TI - Relationships between changes in bone mineral density or bone turnover markers and vertebral fracture incidence in patients treated with bazedoxifene. AB - We analyzed the relationships between bone mineral density (BMD) or bone turnover marker (BTM) changes and vertebral fracture incidence in women treated with bazedoxifene using a post hoc analysis from a 3-year randomized, placebo controlled study evaluating the effect of bazedoxifene (20 or 40 mg) on fracture risk reduction. BMD was assessed at baseline and every 6 months for 3 years. Osteocalcin and C-telopeptide of type I collagen were assessed at baseline and at 3, 12, and 36 months. Vertebral fractures were assessed with a semiquantitative visual assessment. Data were available for 5,244 women, of whom 3,476 were treated with bazedoxifene. Using a logistic regression analysis and the classical Li approach, the proportion of fracture incidence explained by BMD change after 3 years of bazedoxifene treatment was 29 % for the total hip and 44 % for the femoral neck. The proportion of treatment explained by lumbar BMD change could not be quantified accurately because of the significant interaction between treatment and change in BMD. With the same model, the 12-month BTM changes explained up to 29 % of the fracture risk reduction observed with the two forms of bazedoxifene. In women treated with bazedoxifene, changes in femoral neck BMD, hip BMD, or BTMs explained a moderate proportion of the fracture risk reduction observed during the 3 years of follow-up. However, BMD or BTM changes cannot be recommended for individual monitoring of women treated with bazedoxifene. PMID- 22945762 TI - FcgammaRIIa requires lipid rafts, but not co-localization into rafts, for effector function. AB - OBJECTIVE: To determine if receptor localization into lipid rafts, or the lipid rafts themselves, are important for FcgammaRIIa effector functions. MATERIAL: Wild-type FcgammaRIIa or mutant FcgammaRIIa(C208A) that does not translocate to lipid rafts were transfected into Chinese hamster ovary (CHO) cells which have been shown to be reliable cells for studying FcgammaR function. TREATMENT: Cells were treated with buffer or methyl-beta-cyclodextrin (MbetaCD) to deplete cholesterol and dissolve the structure of lipid rafts. METHODS: To evaluate lipid raft association, transfected CHO cells were lysed and centrifuged over a sucrose gradient. Fractions were run on SDS-PAGE and blotted for FcgammaRIIa or sphingolipid GM1 to illustrate the lipid raft fractions. Lateral mobility of GFP tagged wild-type or mutant FcgammaRIIa was assessed using fluorescence recovery after photobleaching (FRAP) microscopy. Internalization of IgG-opsonized erythrocytes was assessed by fluorescence microscopy and uptake of heat aggregated IgG (haIgG) was measured using flow cytometry. RESULTS: We observed that FcgammaRIIa(C208A) did not localize into lipid rafts. However, the mutant FcgammaRIIa retained lateral mobility and effector function similar to wild-type FcgammaRIIa. However, mutant FcgammaRIIa function was abolished upon treatment with MbetaCD. CONCLUSIONS: Lipid rafts provide an essential component required for effector activities independent of receptor localization. PMID- 22945763 TI - Gold nanoparticles grown on ionic liquid-functionalized single-walled carbon nanotubes: new materials for photothermal therapy. AB - Gold nanoparticles were grown on single-walled carbon nanotubes (SWNTs) coated with a thiol-functionalized ionic liquid resulting in the formation of core-shell structures referred to as SWNT-IL-Au nanohybrid materials. The nanohybrid materials were characterized by high-resolution transmission electron microscopy (HR-TEM), Raman-, and UV/Vis absorption spectroscopy. The nanohybrid materials were found to enter lysosomes in HeLa cells and show negligible cytotoxicity. Interestingly, they have an enhanced NIR absorption that is effectively transferred into heat to cause localized hyperthermia, resulting in rapid cell death; overall, the material appears to have excellent properties for photothermal therapeutic applications. PMID- 22945764 TI - Synthesis and ECL performance of highly efficient bimetallic ruthenium tris bipyridyl complexes. AB - In order to find the ideal carbon chain linkage number n for achieving the highest ECL in bimetallic ruthenium tris-bipyridyl complexes, a series of novel complexes [(bpy)(2)Ru(bpy')(CH(2))(n)(bpy')Ru(bpy)(2)](4+) (, where bpy is 2,2' bipyridyl, n = 10, 12, 14) for a coreactant electrochemiluminescence (ECL) system have been synthesized. Their ECL properties at a Au electrode have been studied in 0.1 M phosphate buffer by using tripropylamine (TPrA), 2-(dibutylamino)ethanol (DBAE) and melamine as the coreactant, to compare with that of the previously reported bimetallic ruthenium analogous complex [(bpy)(2)Ru(bpy')(CH(2))(8)(bpy')Ru(bpy)(2)](4+). The results demonstrate that the ECL intensity depends largely on the length of the saturated carbon chain linkage number n. The highest ECL is reached when n = 10, suggesting that a synergistic effect on ECL enhancement co-exists between the two intramolecular linked ruthenium activating centers. Density functional theory (DFT) calculation demonstrated that the optimized bond distances between Ru and N(bpy') are the longest both in the ground and the excited triplet states in the case of n = 10, while those for Ru and N(bpy) are the shortest in the excited triplet states. All these factors may be responsible for the above mentioned results. This study provided a methodology to further improve and tune ECL efficiency by using bimetallic ruthenium complexes linked by a flexible saturated carbon chain. PMID- 22945766 TI - Glomerular expression of connexin 40 and connexin 43 in rat experimental glomerulonephritis. AB - BACKGROUND: Gap junctional intercellular communication is thought to play an important role in the maintenance of cell differentiation and homeostasis. Gap junctions connect glomerular mesangial cells to each other. In this study, we examined the glomerular expression of connexins (Cxs) 40 and 43 at both the protein and transcript levels in anti-Thy1.1 glomerulonephritis (GN). METHODS: Anti-Thy1.1 GN was induced by intravenous injection of anti-Thy1.1 monoclonal antibody 1-22-3. Cx protein expression was examined by immunofluorescence, immunoelectron microscopy, and Western blotting. Changes in mRNA levels were detected by real-time reverse transcriptase-polymerase chain reaction. RESULTS: Cx40 was detected in mesangial cells in normal rat glomeruli; its expression was reduced on days 3 and 7 and recovered to normal on day 14 following GN induction. Cx43 was detected in mesangial cells and podocytes in normal rat glomeruli, and its expression did not change during the disease course of GN. Expression of Cx40 and Cx43 was also detected in extraglomerular mesangial cells; this expression did not change during the disease course. Opposing patterns of expression between Cx40 and smooth muscle actin (SMA) were observed with double-immunofluorescence labeling. SMA is a differentiation marker of mesangial cells; it is often expressed during proliferation but not under physiological conditions. CONCLUSION: These results suggest that Cx40 expression in mesangial cells is related to mesangial cell regeneration. Thus, Cx expression regulation could be a therapeutic target for glomerular diseases. PMID- 22945767 TI - Clinical efficacy and safety of biodegradable polymer-based sirolimus-eluting stents in patients with diabetes mellitus insight from the 4-year results of the create study. AB - BACKGROUND: Diabetes mellitus is an independent predictor of adverse clinical events after drug-eluting stent implantation. OBJECTIVES: The objective of this study is to evaluate the long-term clinical efficacy and safety of biodegradable polymer-based sirolimus-eluting stents in diabetic versus non-diabetic patients. METHODS: A total of 2077 "all comers," including 440 (21.2%) diabetic patients and 1637 (78.8%) non-diabetic patients, were prospectively enrolled in the CREATE study at 59 centers in four countries. The recommended antiplatelet regimen was clopidogrel and aspirin for 6 months followed by chronic aspirin therapy. The primary outcome was the rate of major adverse cardiac events (MACE), defined as a composite of cardiac death, non-fatal myocardial infarction (MI), and target lesion revascularization (TLR). RESULTS: Diabetic patients had higher risks of all-cause death (8.2% vs. 3.4%, P < 0.001) and cardiac death (4.1% vs. 1.4%, P < 0.001) compared with non-diabetic patients at 4 years. The rates of non-fatal MI (0.2% vs. 0.9%, P = 0.218), TLR (2.0% vs. 2.8%, P = 0.357), MACE (5.9% vs. 4.4%, P = 0.227), and overall stent thrombosis (1.6% vs. 1.6%, P = 0.932) were not significantly different between diabetic and non-diabetic patients. A landmark analysis showed that prolonged clopidogrel therapy (>6 months) was not beneficial in reducing the cumulative hazards of MACE either in diabetic or non-diabetic patients (log rank P = 0.810). CONCLUSIONS: Biodegradable polymer-based sirolimus eluting stents for the treatment of diabetic patients had a similar clinical event rate at 4 years compared with non-diabetic patients, except for a higher mortality rate. PMID- 22945768 TI - Investigation of the possible protective role of gallic acid on paraoxanase and arylesterase activities in livers of rats with acute alcohol intoxication. AB - Gallic acid, a polyphenyl class natural product from gallnut and green tea, is known to be antioxidant, anti-inflammatory and radical scavenger. In this study, we aimed to investigate the possible protective effects of gallic acid on paraoxonase and arylesterase activities in liver exposed to acute alcohol intoxication. Paraoxonase and arylesterase activities in liver tissue and serum aspartate aminotransferase, alanine aminotransferase and lactate dehydrogenase levels were measured. Histological investigations were also made. In our study, we observed a significant increase of serum alanine aminotransferase, aspartate aminotransferase and lactate dehydrogenase activities, which are indicators of liver damage after acute ethanol consumption. Gallic acid therapy has significantly reduced the increase in these biomarkers, indicating a possible hepatoprotective effect of gallic acid. Ethanol consumption caused a significant decrease in liver paraoxonase activity (P < 0.001). Gallic acid treatment partly restored this decreased paraoxonase activity, which resulted from ethanol administration. A gallic acid dose of 100 mg/kg was observed as highest restoring effect for paraoxonase activity (P < 0.05). The activity of arylesterase was decreased in the ethanol group as compared with the control group, but this was not significant. However, 50 mg/kg of gallic acid treatment restored the loss of this activity due to ethanol exposure (P < 0.001). We observed that gallic acid ameliorates the liver damage caused by excessive alcohol consumption in a dose dependent way. Our results in this study showed that gallic acid might have a protective effect against alcoholic liver disease. PMID- 22945769 TI - Relationship between blood mercury levels and components of male song in Nelson's sparrows (Ammodramus nelsoni). AB - Mercury (Hg) adversely affects the health and behavior of exposed wildlife; however, behavioral effects remain largely unknown. Changes in avian singing behavior may affect a male's fitness because song reveals male quality and thus influences female mate choice and male territory-holding ability. Nelson's sparrows (Ammodramus nelsoni) live exclusively on salt marshes and risk high levels of Hg exposure and bioaccumulation. We recorded songs of male Nelson's sparrows at two locations with different Hg exposure to determine if total blood Hg concentration was related to song characteristics, as previously reported for other species. Males with higher blood Hg levels sang at higher maximum tonal frequency, but blood Hg and site location did not influence low tonal frequency and bout duration, contrary to predictions based on other species. Within the contaminated site, Hg levels were related to bouts per minute and gap duration, such that males at that site sang faster songs. Hg influences hormones and alters brain development, raising questions about specific effects on the brains and singing behavior of male Nelson's sparrows. PMID- 22945770 TI - Ibudilast, a phosphodiesterase inhibitor, in combination with low-dose aspirin potently inhibits guinea pig carotid artery thrombosis without extending bleeding time and causing gastric mucosal injury. AB - A combination of low-dose aspirin (ASA) and a phosphodiesterase inhibitor has been clinically tried for the secondary prevention of atherothrombotic diseases. The in vivo antithrombotic property of ibudilast (CAS 50847-11-5), a phosphodiesterase 4 (PDE4) inhibitor, was evaluated in a photochemically-induced guinea pig carotid artery thrombosis model in combination with low-dose ASA. The time required to decrease the carotid artery blood flow to the reading "zero" was defined as the time to occlusion (TTO) of the artery through thrombogenesis. Each independent use of ASA (300 mg/kg, p.o.) and ibudilast (3 and 10 mg/kg, p.o.) significantly prolonged the TTO, and ASA (300 mg/kg) significantly increased bleeding time (BT) and gastric mucosal injury. A selective PDE4 inhibitor rolipram (1 and 5 mg/kg, p.o.) tended to prolong the TTO without extending BT. ASA (100 mg/kg) plus ibudilast (3 mg/kg) and ASA (100 mg/kg) plus rolipram (5 mg/kg) markedly prolonged the TTO compared with each agent alone. Interestingly, ASA (100 mg/kg) plus ibudilast (3 mg/kg) caused a longer TTO than ASA (300 mg/kg) alone, without significant extension of BT and gastric mucosal injury as observed in ASA (300 mg/kg). These results indicate that the combination of low-dose ASA and ibudilast has a more potent antithrombotic effect than ASA alone without increasing bleeding tendency and gastric mucosal injury. The potent in vivo antithrombotic effect of this combination may be brought about by an action that is associated with PDE4 inhibition of ibudilast. PMID- 22945771 TI - The preventive oral supplementation of a selenium nanoparticle-enriched probiotic increases the immune response and lifespan of 4T1 breast cancer bearing mice. AB - The immunomodulatory effects of lactic acid bacteria have been demonstrated previously. In this study, a Lactobacillus plantarum strain was selected and enriched with selenium nanoparticles for use as a new immunomodulating agent in a breast cancer murine model. 30 female inbred BALB/c mice were equally divided into a test group and a control group. For 2 weeks prior to tumor induction, each mouse received a daily oral administration of 2.5*108 CFU/ml of L. plantarum enriched with selenium nanoparticles (SeNPs), and then 1*106 4T1 cells were injected subcutaneously. After tumor induction, daily SeNP administration was repeated for 3 cycles of 7 days on/3 days off. Immunological parameters such as levels of cytokines, NK cell activity, tumor growth, and mouse survival were evaluated. The production of the pro-inflammatory cytokines IFN-gamma, TNF-alpha, and IL-2 in spleen cell cultures was increased in test mice administered SeNP enriched L. plantarum. The test mice also showed significant increases in NK cell activity. The tumor volumes of treated mice were decreased and their survival rate notably increased when compared to mice that received L. plantarum alone or control mice. Administration of SeNP-enriched L. plantarum can induce an efficient immune response through the elevation of the pro-inflammatory cytokines IFN-gamma, TNF-alpha and IL-2 levels and increased NK cell activity. Therefore, this treatment may result in better cancer prognosis. PMID- 22945772 TI - A rare but specific subset of adult AML patients can be defined by the cytogenetically cryptic NUP98-NSD1 fusion gene. PMID- 22945773 TI - Single-nucleotide polymorphism rs1052501 associated with monoclonal gammopathy of undetermined significance and multiple myeloma. PMID- 22945774 TI - Improved flow cytometric detection of minimal residual disease in childhood acute lymphoblastic leukemia. AB - Most current treatment protocols for acute lymphoblastic leukemia (ALL) include minimal residual disease (MRD) diagnostics, generally based on PCR analysis of rearranged antigen receptor genes. Although flow cytometry (FCM) can be used for MRD detection as well, discordant FCM and PCR results are obtained in 5-20% of samples. We evaluated whether 6-color FCM, including additional markers and new marker combinations, improved the results. Bone marrow samples were obtained from 363 ALL patients at day 15, 33 and 78 and MRD was analyzed using 6-color (218 patients) or 4-color (145 patients) FCM in parallel to routine PCR-based MRD diagnostics. Compared with 4-color FCM, 6-color FCM significantly improved the concordance with PCR-based MRD data (88% versus 96%); particularly the specificity of the MRD analysis improved. However, PCR remained more sensitive at levels <0.01%. MRD-based risk groups were similar between 6-color FCM and PCR in 68% of patients, most discrepancies being medium risk by PCR and standard risk by FCM. Alternative interpretation of the PCR data, aimed at prevention of false positive MRD results, changed the risk group to standard risk in half (52%) of these discordant cases. In conclusion, 6-color FCM significantly improves MRD analysis in ALL but remains less sensitive than PCR-based MRD-diagnostics. PMID- 22945775 TI - Calling song signals and temporal preference functions in the cricket Teleogryllus leo. AB - The acoustic display of many cricket species consists of trains of pulses (chirps) with intermittent pauses. Here, we investigated the temporal cues that females of the cricket Teleogryllus leo used to detect a pulse and a chirp pattern on two different time scales. For both patterns, females accepted a wide range of combinations that covered the respective pulse and chirp parameters in the songs of males. In tests with a continuous series of pulses at different modulation frequencies, the transfer function of pattern discrimination was also determined. Females exhibited two ranges of high response scores indicating two temporal filters with an inhibitory interaction. For the modulation frequency of the pulse pattern, the peak of the preference function was rather sharply tuned and at a lower pulse rate than produced by males. These results show that the combined output of both filters did not increase selectivity, but rather enlarged the accepted range of signals. PMID- 22945776 TI - Magnetizing DNA and proteins using responsive surfactants. AB - DNA chains and their movement in solvent may now be controlled simply by surfactant binding and the switching "on" and "off" of a magnetic field adding a new paradigm to the study and control, condensation and manipulation of DNA (and other biomolecules). Such control is essential for biotechnological applications such as transfection and the regulation of gene suppression, as well as in materials science concerning soft molecular self-assemblies. PMID- 22945777 TI - Self autonomy and informed consent in clinical setup. AB - A human being having intelligentsia of good personality or in simpler terms a personage is in full control of his body by the international convention. This is called as self-autonomy. Therefore, self-autonomy of a patient should be respected in terms of medical treatment protocol also. Informed consent should be encouraged in all the disciplines of medicine as we are entering the era of patient as a consumer and doctor as a service provider. The rising literacy in our community is esteeming the self-respect in people. Therefore, all the procedures involving medical treatment, surgical operations, assisting reproductive technologies, treatment of mentally disabled persons, and treatment of children should have proper consent in terms of age, mental capacity, free will, and full disclosure. PMID- 22945778 TI - Effect of lidocaine gel on pain from copper IUD insertion: a randomized double blind controlled trial. AB - CONTEXT: Insertion pain or fear of it may make women hesitate to use the intrauterine device (IUD); a long-term, reversible, highly-effective contraception method. Further study has been recommended on the effects of lidocaine (xylocaine) gel on IUD insertion pain in the recent Cochran review. AIMS: To determine the effect of lidocaine gel on pain from TCu-380AIUD insertion. MATERIALS AND METHODS: At a health center in Tabriz, Iran, 96 women were allocated into 3 groups using block randomization with 6 and 9 block sizes considering allocation concealment. In 1 st group, lidocaine 2% gel and in the 2 nd , lubricant gel was placed in the cervical canal 1 minute before an IUD insertion, and the 3 rd group got no intervention. Immediately after IUD insertion, pain during the insertion was measured using 0-10 cm visual analogue scale. STATISTICAL ANALYSIS USED: Kruskal-Wallis and linear regression in SPSS-13 were used to identify effect of lidocaine gel on the pain. RESULTS: Overall, the mean pain score was 3.5 +/- 1.8. In univariate analysis, there was no significant difference in pain scores between the 3 groups. Also, results of linear regression model by controlling effect of the possible confounding showed no significant effect of lidocaine gel on the insertion pain. The mean pain score in the lidocaine group was 0.39 less than the no intervention group, but it was not significant (CI 95% of the difference: -1.3, 0.57). CONCLUSIONS: Use of 2% lidocaine gel into the cervical canal has no effect on reducing overall pain during IUD insertion. PMID- 22945779 TI - Sublingual misoprostol: a better choice for cervical priming before manual vacuum aspiration. AB - BACKGROUND: Misoprostol is effective for cervical priming before manual vacuum aspiration (MVA). Aim of study was to determine whether sublingual misoprostol with a shorter interval of 2 hours before MVA would be as effective as its standard vaginal administration. STUDY DESIGN: This randomized control trial included 82 women randomly assigned to receive 400 mcg of misoprostol, either sublingually or vaginally. MVA was performed 2 hours and 3 hours after in sublingual and vaginal group, respectively. RESULTS: Cervical dilatation of 8 mm was achieved within 2 hours in sublingual group. Mean time taken for procedure (14.4 +/- 5.3: sublingual group and 16.2 +/- 5.7: vaginal group), and blood loss was comparable (12.2 +/- 9.7 ml in sublingual group and 13.7 +/- 8.5 ml in vaginal group). CONCLUSION: 2 hour of cervical priming with 400 mcg of sublingual misoprostol before MVA was as good as 3 hours with vaginal administration of the same dose. PMID- 22945780 TI - Pharmacologic bronchodilation response to salbutamol in COPD patients. AB - BACKGROUND: Airway hyperresponsiveness (AHR) is the most characteristic feature of asthma, which is reported in COPD patients and smokers. Increased airway responsiveness to iota-agonists is also demonstrated in asthmatics as well as smokers. However, there is no report regarding AHR to iota-agonist drugs in COPD patients. Therefore, in this study pharmacologic bronchodilation response to salbutamol in COPD patients was examined. MATERIALS AND METHODS: The threshold concentrations of inhaled salbutamol required for a 20% change in forced expiratory flow in 1 sec (FEV 1 ) as PC 20 , or a 35% change in specific airway conductance (sGaw) as PC 35 was measured in 14 COPD patients and 14 normal subjects. RESULTS: Airway responsiveness to salbutamol in COPD patients (PC 20 = 14.14 +/- 1.62 and PC 35 = 9.70 +/- 1.48 mg/l) was significantly lower than normal subjects (PC 20 = 224.57 +/- 16.62 and PC 35 = 81.87 +/- 8.16 mg/l, P < 0.001 for both cases). The values of FEV 1 and sGaw in COPD patients (56.43 +/- 14.45 and 0.081 +/- 0.120 respectively) were significantly lower than those of normal subjects (104.07 +/- 5.72 and 0.194 +/- 0.041 respectively), (P < 0.001 for FEV 1 and P < 0.005 for sGaw). There was a significant correlation between FEV 1 with PC 20 salbutamol (r = 0.862, P < 0.001). The correlations between PC 20 and PC 35 was also statistically significant (r = 0.862, P < 0.001). CONCLUSION: These results showed increased airway responsiveness of most COPD patients to salbutamol which was highly correlated to airway caliber. PMID- 22945781 TI - Outcomes of respiratory diphtheria in a tertiary referral infectious disease hospital. AB - BACKGROUND: Diphtheria is a fatal disease and may cause serious complications if not recognized early and treated properly. OBJECTIVES: To study the epidemiology, clinical features, complications, and outcomes in respiratory diphtheria. MATERIALS AND METHODS: Diphtheria cases admitted in the infectious disease hospital, Beliaghata, Kolkata, India between January 2009 to January 2011 were evaluated in respect to demographic profile, immunization status, clinical features, complications, and outcomes. RESULTS: 200 diphtheria cases were studied. 150 (75%) patients had history of an adequate immunization, and 100 (50%) patients were from lower socio-economic groups. Common clinical features observed were throat pain in 148 (74%) cases and fever in 112 (56%) cases. Complications observed were myocarditis in 136 (68%) cases, neuropathy in 30 (15%) cases, and respiratory compromise in 14 (7%) cases. Death occurred in 5 (2.5%) patients. CONCLUSIONS: diphtheria is still a public health problem in many developing countries. Strict public health measures like an increased immunization coverage, improvement of socio-economic status, easy availability of anti-diphtheritic serum (ADS), early recognition and effective treatment-all may reduce the incidence and mortality. PMID- 22945782 TI - Nephroprotective role of salacia chinensis in diabetic CKD patients: a pilot study. AB - BACKGROUND: Present study aimed to study effect of Salacia Chinensis, a herbal drug, on stabilization of renal functions, and markers of endothelial dysfunction in diabetic chronic kidney disease (CKD) patients. MATERIALS AND METHODS: 30 stable diabetic CKD patients were randomized into 2 groups; group A and B of 15 patients each. Group A was given trial drug Salacia chinensis 1000 mg twice-daily while group B received placebo. Measures of renal function: Serum creatinine and creatinine clearance; markers of endothelial dysfunction: Interleukin-6 and serum Homocysteine, and lipid profile were measured at baseline and during follow-up period of 6 months. RESULTS: There was stabilization of renal function as measured by serum creatinine and creatinine clearance in patients who received Salacia Chinensis compared to placebo (P value < 0.05), suggesting that Salacia chinensis may retard the progression of chronic kidney disease. Similarly, there was significant decline in both serum homocysteine and IL-6 levels. [P value < 0.05 for both]. CONCLUSION: This pilot study showed a promising role for Salacia chinensis as a renoprotective drug, but further prospective studies involving large number of patients are needed to confirm this and also to delineate possible mechanisms. PMID- 22945783 TI - Acute ischemic stroke in aortic dissection: case report and review of literature. AB - The estimated incidence of aortic dissection ranges from 5 to 30 cases per million per year. Nearly 38% of cases are missed at an initial presentation due to the wide range of clinical symptoms. We report a survivor of an inadvertent thrombolysis in acute ischemic stroke, secondary to aortic dissection. PMID- 22945784 TI - Predictors of treatment outcome among Asian pathological gamblers (PGs): clinical, behavioural, demographic, and treatment process factors. AB - Research on predictors of treatment outcome among pathological gamblers (PGs) is inconclusive and dominated by studies from Western countries. Using a prospective longitudinal design, the current study examined demographic, clinical, behavioural and treatment programme predictors of gambling frequency at 3, 6 and 12-months, among PGs treated at an addiction clinic in Singapore. Measures included the Hospital anxiety and depression scale, gambling symptom assessment scale (GSAS), personal well-being index (PWI), treatment perception questionnaire and gambling readiness to change scale. Treatment response in relation to changes in symptom severity, personal wellbeing and abstinence were also assessed. Abstinence rates were 38.6, 46.0 and 44.4 % at 3, 6 and 12-months respectively. Significant reductions in gambling frequency, GSAS, and improvement in PWI were reported between baseline and subsequent outcome assessments, with the greatest change occurring in the initial three months. No demographic, clinical, behavioural or treatment programme variable consistently predicted outcome at all three assessments, though treatment satisfaction was the most frequent significant predictor. However, being unemployed, having larger than average debts, poor treatment satisfaction and attending fewer sessions at the later stages of treatment were associated with significantly poorer outcomes, up to 1 year after initiating treatment. These findings show promise for the effectiveness of a CBT-based treatment approach for the treatment of predominantly Chinese PGs. Clinical implications and suggestions for future research are discussed. Taken together, the findings suggest early treatment satisfaction is paramount in improving short-term outcomes, with baseline gambling behaviour and treatment intensity playing a more significant role in the longer term. PMID- 22945786 TI - Interaction-based feature selection and classification for high-dimensional biological data. AB - MOTIVATION: Epistasis or gene-gene interaction has gained increasing attention in studies of complex diseases. Its presence as an ubiquitous component of genetic architecture of common human diseases has been contemplated. However, the detection of gene-gene interaction is difficult due to combinatorial explosion. RESULTS: We present a novel feature selection method incorporating variable interaction. Three gene expression datasets are analyzed to illustrate our method, although it can also be applied to other types of high-dimensional data. The quality of variables selected is evaluated in two ways: first by classification error rates, then by functional relevance assessed using biological knowledge. We show that the classification error rates can be significantly reduced by considering interactions. Secondly, a sizable portion of genes identified by our method for breast cancer metastasis overlaps with those reported in gene-to-system breast cancer (G2SBC) database as disease associated and some of them have interesting biological implication. In summary, interaction based methods may lead to substantial gain in biological insights as well as more accurate prediction. PMID- 22945787 TI - Updating annotations with the distributed annotation system and the automated sequence annotation pipeline. AB - SUMMARY: The integration between BioDAS ProServer and Automated Sequence Annotation Pipeline (ASAP) provides an interface for querying diverse annotation sources, chaining and linking results, and standardizing the output using the Distributed Annotation System (DAS) protocol. This interface allows pipeline plans in ASAP to be integrated into any system using HTTP and also allows the information returned by ASAP to be included in the DAS registry for use in any DAS-aware system. Three example implementations have been developed: the first accesses TRANSFAC information to automatically create gene sets for the Coordinated Gene Activity in Pattern Sets (CoGAPS) algorithm; the second integrates annotations from multiple array platforms and provides unified annotations in an R environment; and the third wraps the UniProt database for integration with the SPICE DAS client. AVAILABILITY: Source code for ASAP 2.7 and the DAS 1.6 interface is available under the GNU public license. Proserver 2.20 is free software available from SourceForge. Scripts for installation and configuration on Linux are provided at our website: http://www.rits.onc.jhmi.edu/dbb/custom/A6/ PMID- 22945788 TI - Causal stability ranking. AB - Genotypic causes of a phenotypic trait are typically determined via randomized controlled intervention experiments. Such experiments are often prohibitive with respect to durations and costs, and informative prioritization of experiments is desirable. We therefore consider predicting stable rankings of genes (covariates), according to their total causal effects on a phenotype (response), from observational data. Since causal effects are generally non-identifiable from observational data only, we use a method that can infer lower bounds for the total causal effect under some assumptions. We validated our method, which we call Causal Stability Ranking (CStaR), in two situations. First, we performed knock-out experiments with Arabidopsis thaliana according to a predicted ranking based on observational gene expression data, using flowering time as phenotype of interest. Besides several known regulators of flowering time, we found almost half of the tested top ranking mutants to have a significantly changed flowering time. Second, we compared CStaR to established regression-based methods on a gene expression dataset of Saccharomyces cerevisiae. We found that CStaR outperforms these established methods. Our method allows for efficient design and prioritization of future intervention experiments, and due to its generality it can be used for a broad spectrum of applications. PMID- 22945789 TI - JEnsembl: a version-aware Java API to Ensembl data systems. AB - MOTIVATION: The Ensembl Project provides release-specific Perl APIs for efficient high-level programmatic access to data stored in various Ensembl database schema. Although Perl scripts are perfectly suited for processing large volumes of text based data, Perl is not ideal for developing large-scale software applications nor embedding in graphical interfaces. The provision of a novel Java API would facilitate type-safe, modular, object-orientated development of new Bioinformatics tools with which to access, analyse and visualize Ensembl data. RESULTS: The JEnsembl API implementation provides basic data retrieval and manipulation functionality from the Core, Compara and Variation databases for all species in Ensembl and EnsemblGenomes and is a platform for the development of a richer API to Ensembl datasources. The JEnsembl architecture uses a text-based configuration module to provide evolving, versioned mappings from database schema to code objects. A single installation of the JEnsembl API can therefore simultaneously and transparently connect to current and previous database instances (such as those in the public archive) thus facilitating better analysis repeatability and allowing 'through time' comparative analyses to be performed. AVAILABILITY: Project development, released code libraries, Maven repository and documentation are hosted at SourceForge (http://jensembl.sourceforge.net). PMID- 22945790 TI - beta-Iminoenamine-BF2 complexes: aggregation-induced emission and pronounced effects of aliphatic rings on radiationless deactivation. AB - The synthesis, photophysical, and electrochemical attributes of a novel class of boron difluorides containing an aromatic-fused alicyclic/hetero-alicyclic ring built on a beta-iminoenamine chromophoric backbone are reported. The compounds displayed large Stokes shifts (86-121 nm), and were emissive in the solid state. The quantum yields obtained in solution at room temperature were unusually lower by an order of magnitude compared to those in the solid state. Some of the tested compounds displayed aggregation-induced emission (AIE). Single crystal XRD analyses revealed a lack of interplanar pi-pi interactions, which are presumed to be absent owing to non-planarity of the alicyclic component in the molecule. For most of the studied compounds, time-dependent DFT (TD-DFT) calculations invariably reveal intramolecular charge transfer (pi-pi*) characteristics with the frontier orbitals concentrated on the boron-nitrogen heterocycle. The participation of boron and fluorine atoms was found to be negligible. PMID- 22945791 TI - Photoinduced reductive electron transfer in LNA:DNA hybrids: a compromise between conformation and base stacking. PMID- 22945793 TI - Magnesium calcium phosphate/beta-tricalcium phosphate incorporation into gelatin scaffold: an in vitro comparative study. AB - Gelatin scaffolds incorporating or not 50 wt% of magnesium calcium phosphate (MCP) or beta-tricalcium phosphate (betaTCP) were prepared and the in vitro osteogenic differentiation of rat bone marrow mesenchymal stem cells (MSCs) in the scaffolds was investigated. The pore sizes of the scaffolds were in the range 123.8 +/- 47.2-153 +/- 60.72 um in diameter, while the porosity was 33.3 +/- 2 44.9 +/- 3.4%. The compression modulus of the sponges was about 2.04-2.24 mPa. There was no significant difference among groups regarding the physical and mechanical properties. When seeded into the sponges by an agitation method, the MSCs were distributed throughout the scaffold. Higher MSC proliferation was observed for scaffolds incorporating minerals. Following the incubation of MSCs in scaffolds incorporating MCP, the alkaline phosphatase activity was significantly higher at weeks 2, 3 and 4 in comparison with other scaffolds; however, the osteocalcin levels of MSCs did not show significant differences among groups. These findings indicate that MSCs seeded in scaffolds incorporating MCP showed significantly superior biological results in terms of proliferation and osteogenic differentiation in comparison with other scaffold types. PMID- 22945794 TI - Incorporation of spin-5/2 chain into 2D network with conformational pure e,a-cis cyclohexane-1,4-dicarboxylato linker. AB - A two-dimensional coordination network, (2)(infinity)[Fe(III) (OH)(e,a-cis-1,4 chdc)] (1,4-chdc: cyclohexane-1,4-dicarboxylate), featuring one-dimensional iron(III)-hydroxy chains that are transversely bridged by 1,4-chdc in its pure e,a-cis conformation have been isolated. The magnetic study shows a typical spin 5/2 Heisenberg chain above 20 K, but canted antiferromagnetic ordering at lower temperatures. PMID- 22945792 TI - A probable clinically significant interaction between warfarin and cloxacillin: three case reports. AB - CASES: Three patients were admitted to the Imam Hospital, Tehran, Iran with a diagnosis of bacterial endocarditis. The patients had indications for valve replacement surgery and anticoagulant therapy. The administration of cloxacillin reduced the effect of warfarin, and subsequent increases in warfarin doses were unable to overcome this effect. CONCLUSION: A decrease in warfarin anticoagulation effects was detected in our three patients following cloxacillin therapy for infective endocarditis. Penicillinase-resistant penicillins remain essential antibiotics in the treatment of severe infections caused by Staphylococcus aureus due to their bactericidal activity, safety, and cost. Thus, in situations where anticoagulants are indicated in patients with infective endocarditis, it would be better to replace warfarin with low-molecular-weight or unfractionated heparin. PMID- 22945795 TI - Shared predispositions of parkinsonism and cancer: a population-based pedigree linked study. AB - OBJECTIVE To use a statewide population-based genealogic database to evaluate the relationship between Parkinson disease (PD) and cancer subtypes. DESIGN Using a computerized genealogy for the Utah pioneers and their descendants linked to a statewide cancer registry and statewide death certificates, we estimated relative risks for cancer in individuals with PD listed on their death certificate, and in their first-degree, second-degree, and third-degree relatives. SETTING Utah Cancer Registry. PARTICIPANTS Approximately 2.3 million individuals in the Utah genealogic resource, including death certificates of 2998 individuals with PD listed as a cause of death from 1904 to 2008 and information on 100 817 individuals with a cancer diagnosis in the Utah Cancer Registry. RESULTS Melanoma and prostate cancer were the only cancers observed in significant excess among PD cases; colorectal, lung, pancreas, and stomach cancers were observed in deficit. A significantly increased risk for prostate cancer was observed in the PD population as well as among their relatives. A reciprocal significantly increased risk for PD was also found in the 22 147 prostate cancer cases and their relatives. A significantly elevated risk for melanoma was found in the Utah PD population as well as in their relatives. A reciprocal significantly increased relative risk for PD was found in 7841 Utah melanoma cases and their relatives. CONCLUSIONS Our study identified a novel association between PD and prostate cancer, which extended to first-degree, second-degree, and third-degree relatives. We also confirmed the reported risk association for melanoma in patients with PD; we extended the finding to include a significantly increased risk in relatives. These results strongly support a genetic link. This conclusion is further strengthened by observation of the reciprocal relationship, an increased risk for PD in relatives of individuals with melanoma or prostate cancer. PMID- 22945796 TI - Solid-state photochemistry of crystalline pyrazolines: reliable generation and reactivity control of 1,3-biradicals and their potential for the green chemistry synthesis of substituted cyclopropanes. AB - To expand on the limited number of examples that exist in the literature for the solid-state photodenitrogenation of azoalkanes, a series of crystalline 7-alkyl 2,3,7-triazabicyclo[3.3.0]oct-2-ene-6,8-diones with varying 4,4-substituents were prepared. Their photochemical behavior in solution and in the solid state was dependent on the 4,4-substitution of the 1-pyrazoline ring, with unsubstituted pyrazoline giving a mixture of products both in solution and in the solid state. Diphenyl substituted pyrazolines denitrogenate spontaneously in solution but require light exposure to react quantitatively in the solid state. t-Butyl-phenyl substituted pyrazolines were shown to denitrogenate both chemo- and diastereoselectively in solution and in the solid state to yield a single product in quantitative yield. PMID- 22945797 TI - Does a photocatalytic synergy in an anatase-rutile TiO2 composite thin-film exist? AB - It has often been suggested that anatase-rutile mixtures/composites synergistically enhance photocatalysis. However, in the case of dense thin-films containing an intimate mix of both anatase and rutile phases, such an effect has not been observed. In synthesising combinatorial films with graded film thickness and phase, and applying established photocatalytic mapping methods, we were able to assess how dense thin-films of intimately mixed anatase-rutile mixtures affect photocatalytic performance. We found that no photocatalytic synergy between anatase-rutile composites (29<=rutile %<=83) within such dense thin-film systems exists. In fact, an increased presence of rutile caused the photocatalytic activity to fall. This was explained by the unfavourable energetics in the multiple electron transfers required between several neighbouring rutile and anatase sites for the photo-generated electron to reach the material's surface; encouraging the trapping of electrons within the bulk and increasing the likelihood of charge recombination. The decrease in photocatalytic activity was found to vary linearly with rutile component. PMID- 22945798 TI - Susceptibility of young and adult rats to the oral toxicity of titanium dioxide nanoparticles. AB - Titanium dioxide nanoparticles (TiO2 NPs) have potential applications as food additives, but concerns persist about their safety. Children are identified as having the highest exposure and may face the greatest health risks. However, the toxicological sensitivity of TiO2 NPs in different ages is not clear. Here, a comparative toxicity study of TiO2 NPs in 3-week (youth) and 8-week (adult) old Sprague-Dawley rats is reported following oral exposure at doses of 0, 10, 50, 200 mg kg(-1) body weight per day for 30 days. The organ mass and histology, blood biochemistry and redox state, intestinal function, and biodistribution of NPs are characterized. The results show that TiO2 NPs induce different toxic effects on young and adult rats. The liver edema, heart injuries and non-allergic mast cell activation in stomach tissues are found in young rats. On the other hand, only slight injury in the liver and kidney and decreased intestinal permeability and molybdenum contents are found in adult rats. Furthermore, TiO2 NP exposure can provoke reductive stress (i.e., increased reduced glutathione (GSH)/oxidized glutathione (GSSG) ratios) in plasmas through enhancing the glucose and GSH levels in young rats or reducing the glutathione peroxidase (GSH Px) acitivity and GSSG levels in adult rats. These results suggest that different ages may require different biomarkers for identifying and monitoring oral toxicity of nanoparticles. PMID- 22945799 TI - KIF1Bbeta transports dendritically localized mRNPs in neurons and is recruited to synapses in an activity-dependent manner. AB - KIF1Bbeta is a kinesin-like, microtubule-based molecular motor protein involved in anterograde axonal vesicular transport in vertebrate and invertebrate neurons. Certain KIF1Bbeta isoforms have been implicated in different forms of human neurodegenerative disease, with characterization of their functional integration and regulation in the context of synaptic signaling still ongoing. Here, we characterize human KIF1Bbeta (isoform NM015074), whose expression we show to be developmentally regulated and elevated in cortical areas of the CNS (including the motor cortex), in the hippocampus, and in spinal motor neurons. KIF1Bbeta localizes to the cell body, axon, and dendrites, overlapping with synaptic vesicle and postsynaptic-density structures. Correspondingly, in purified cortical synaptoneurosomes, KIF1Bbeta is enriched in both pre- and postsynaptic structures, forming detergent-resistant complexes. Interestingly, KIF1Bbeta forms RNA-protein complexes, containing the dendritically localized Arc and Calmodulin mRNAs, proteins previously shown to be part of RNA transport granules such as Puralpha, FMRP and FXR2P, and motor protein KIF3A, as well as Calmodulin. The interaction between KIF1Bbeta and Calmodulin is Ca(+2)-dependent and takes place through a domain mapped at the carboxy-terminal tail of the motor. Live imaging of cortical neurons reveals active movement by KIF1Bbeta at dendritic processes, suggesting that it mediates the transport of dendritically localized mRNAs. Finally, we show that synaptic recruitment of KIF1Bbeta is activity-dependent and increased by stimulation of metabotropic or ionotropic glutamate receptors. The activity-dependent synaptic recruitment of KIF1Bbeta, its interaction with Ca(2+) sensor Calmodulin, and its new role as a dendritic motor of ribonucleoprotein complexes provide a novel basis for understanding the concerted co-ordination of motor protein mobilization and synaptic signaling pathways. PMID- 22945802 TI - Modeling of long-term fatigue damage of soft tissue with stress softening and permanent set effects. AB - One of the major failure modes of bioprosthetic heart valves is non-calcific structural deterioration due to fatigue of the tissue leaflets. Experimental methods to characterize tissue fatigue properties are complex and time-consuming. A constitutive fatigue model that could be calibrated by isolated material tests would be ideal for investigating the effects of more complex loading conditions. However, there is a lack of tissue fatigue damage models in the literature. To address these limitations, in this study, a phenomenological constitutive model was developed to describe the stress softening and permanent set effects of tissue subjected to long-term cyclic loading. The model was used to capture characteristic uniaxial fatigue data for glutaraldehyde-treated bovine pericardium and was then implemented into finite element software. The simulated fatigue response agreed well with the experimental data and thus demonstrates feasibility of this approach. PMID- 22945801 TI - Ablation of cyclase-associated protein 2 (CAP2) leads to cardiomyopathy. AB - Cyclase-associated proteins are highly conserved proteins that have a role in the regulation of actin dynamics. Higher eukaryotes have two isoforms, CAP1 and CAP2. To study the in vivo function of CAP2, we generated mice in which the CAP2 gene was inactivated by a gene-trap approach. Mutant mice showed a decrease in body weight and had a decreased survival rate. Further, they developed a severe cardiac defect marked by dilated cardiomyopathy (DCM) associated with drastic reduction in basal heart rate and prolongations in atrial and ventricular conduction times. Moreover, CAP2-deficient myofibrils exhibited reduced cooperativity of calcium-regulated force development. At the microscopic level, we observed disarrayed sarcomeres with development of fibrosis. We analyzed CAP2's role in actin assembly and found that it sequesters G-actin and efficiently fragments filaments. This activity resides completely in its WASP homology domain. Thus CAP2 is an essential component of the myocardial sarcomere and is essential for physiological functioning of the cardiac system, and a deficiency leads to DCM and various cardiac defects. PMID- 22945803 TI - Monitoring of trace metals and pharmaceuticals as anthropogenic and socio economic indicators of urban and industrial impact on surface waters. AB - The research focuses on the monitoring of trace metals and pharmaceuticals as potential anthropogenic indicators of industrial and urban influences on surface water. This study includes analysis of tracers use for the indication of water pollution events and discussion of the detection method of these chemicals. The following criteria were proposed for the evaluation of indicators: specificity (physical chemical properties), variability (spatial and temporal), and practicality (capacity of the sampling and analytical techniques). The combination of grab and passive water sampling (i.e., diffusive gradient in the thin film and polar organic chemical integrated samplers) procedure was applied for the determination of dissolved and labile trace metals (Ag, Cd, Cr, Cu, Ni, Pb, and Zn) and pharmaceuticals (carbamazepine, diazepam, paracetamol, caffeine, diclofenac, and ketoprofen). Samples were analyzed using inductively coupled plasma mass spectrometry (MS; trace metals) and liquid chromatography-tandem MS electrospray ionization+/- (pharmaceuticals). Our results demonstrate the distinctive spatial and temporal patterns of trace elements distribution along an urban watercourse. Accordingly, two general groups of trace metals have been discriminated: "stable" (Cd and Cr) and "time varying" (Cu, Zn, Ni, and Pb). The relationship Cd >> Cu > Ag > Cr >= Zn was proposed as an anthropogenic signature of the industrial and urban activities pressuring the environment from point sources (municipal wastewaters) and the group Pb-Ni was discussed as a relevant fingerprint of the economic activity (industry and transport) mainly from non point sources (runoff, atmospheric depositions, etc.). Pharmaceuticals with contrasting hydro-chemical properties of molecules (water solubility, bioaccumulation, persistence during wastewater treatment processes) were discriminated on conservative, labile, and with combined properties in order to provide information on wastewater treatment plant efficiency, punctual events (e.g., accidents on sewage works, runoff), and uncontrolled discharges. Applying mass balance modeling, medicaments were described as relevant socio-economic indicators, which can give a picture of main social aspects of the region. PMID- 22945804 TI - Studying the kinetics of crystalline silicon nanoparticle lithiation with in situ transmission electron microscopy. AB - In situ transmission electron microscopy (TEM) is used to study the electrochemical lithiation of high-capacity crystalline Si nanoparticles for use in Li-ion battery anodes. The lithiation reaction slows down as it progresses into the particle interior, and analysis suggests that this behavior is due not to diffusion limitation but instead to the influence of mechanical stress on the driving force for reaction. PMID- 22945805 TI - Iatrogenic intracranial aneurysms in childhood: case-based update. AB - PURPOSE: Iatrogenic aneurysms are very rare in children. Characteristic clinical manifestations are variable and asymptomatic course is possible especially for fusiform dilatation of internal carotid artery. Even though radiological diagnosis is easy, the management of iatrogenic intracranial aneurysm is still a subject for discussion. METHODS: Fusiform dilatations of internal carotid artery were diagnosed on three pediatric patients during follow-up imaging after primary surgery for suprasellar-parasellar tumor. All patients were asymptomatic. Conservative treatment was proposed because the lesion did not show any progression in subsequent examinations. Patients are stable under conservative treatment. CONCLUSIONS: Iatrogenic aneurysm may have an unusual presentation and their therapy still remains unclear. Fusiform dilatation of internal carotid artery rarely causes symptoms and there is no published paper of subarachnoid bleeding. Treatment would be difficult, since the main arterial branches arise from the dilated carotid segment. Conservative treatment is a choice only if aneurysm has no progression or in case of spontaneous healing. Intervention should be performed only in case of progression or if the aneurysm becomes symptomatic. PMID- 22945800 TI - EMT-activating transcription factors in cancer: beyond EMT and tumor invasiveness. AB - Cancer is a complex multistep process involving genetic and epigenetic changes that eventually result in the activation of oncogenic pathways and/or inactivation of tumor suppressor signals. During cancer progression, cancer cells acquire a number of hallmarks that promote tumor growth and invasion. A crucial mechanism by which carcinoma cells enhance their invasive capacity is the dissolution of intercellular adhesions and the acquisition of a more motile mesenchymal phenotype as part of an epithelial-to-mesenchymal transition (EMT). Although many transcription factors can trigger it, the full molecular reprogramming occurring during an EMT is mainly orchestrated by three major groups of transcription factors: the ZEB, Snail and Twist families. Upregulated expression of these EMT-activating transcription factors (EMT-ATFs) promotes tumor invasiveness in cell lines and xenograft mice models and has been associated with poor clinical prognosis in human cancers. Evidence accumulated in the last few years indicates that EMT-ATFs also regulate an expanding set of cancer cell capabilities beyond tumor invasion. Thus, EMT-ATFs have been shown to cooperate in oncogenic transformation, regulate cancer cell stemness, override safeguard programs against cancer like apoptosis and senescence, determine resistance to chemotherapy and promote tumor angiogenesis. This article reviews the expanding portfolio of functions played by EMT-ATFs in cancer progression. PMID- 22945806 TI - Differentiation of innate type-2 effector cells. AB - Type-2 immune responses are the underlying cause of many allergic diseases and provide protection against parasitic infection. Effective type-2 immune responses are generated by type-2 helper CD4(+) T cells (Th2) as well as type-2 innate effector cells. While we have learned a great deal about how CD4(+) Th2 cells regulate their Th2 cytokine gene transcription, we still do not know how type-2 innate effector cells acquire their capacity to express Th2 cytokine genes. Furthermore, it remains poorly understood how Th2 cytokines regulate the differentiation of innate type-2 progenitor cells. In this review, we will focus on (1) the long distance interaction between the sites of allergic inflammation and the site of hematopoiesis in the bone marrow, (2) the characteristics of innate type-2 progenitors, and (3) the molecular mechanisms by which innate type 2 effector cells acquire the capacity to produce type-2 cytokines. PMID- 22945807 TI - TLR7 drives accumulation of ABCs and autoantibody production in autoimmune-prone mice. AB - Although autoantibodies are the hallmarks of most autoimmune diseases, the mechanisms by which autoreactive B cells are generated and accumulate are still poorly understood. Overexpression of Toll-like receptor 7 (TLR7) that recognizes single-stranded RNAs has been implicated in systemic lupus erythematosus (SLE), although the cellular mechanism by which this receptor drives the disease is unknown. We recently identified a population of CD11c(+) age-associated B cells (ABCs) which is driven by TLR7 signaling, secretes autoantibodies and appears in autoimmune-prone mice by the time of onset of autoimmunity. Mice lacking the Mer receptor develop autoantibodies and splenomegaly similar to other mouse models of SLE. Here, we show that Mer(-/-) mice that lack TLR7 fail to develop anti chromatin IgG antibodies, perhaps because they also fail to develop ABCs. Moreover, depletion of CD11c(+) ABCs from Mer(-/-) mice leads to rapid reduction in autoantibodies. Together, these data strongly suggest that ABCs and/or their descendants are the primary source of autoantibodies in Mer(-/-) mice and that TLR7 signaling is crucial for accumulation of ABCs and development of autoantibodies. These data demonstrate for the first time that TLR7, and not TLR9, is responsible for generation of anti-chromatin IgG antibodies in Mer(-/-) mice. PMID- 22945809 TI - Porcine model of intracoronary pulverization of stent struts by rotablation atherectomy. AB - OBJECTIVE: To evaluate the feasibility and safety of rotablation atherectomy in a suboptimally expanded stent. METHODS: Seven pigs underwent suboptimal stent expansion in the left anterior descending coronary. Pulverization of the stent struts was performed by rotablation atherectomy with two different burr sizes. Two types of control porcine models were used: pigs with fully expanded stents and pigs without stents. Continuous electrocardiogram readings as well as microscopic and radiologic analysis of cardiac tissue were performed. RESULTS: Rotablation atherectomy reduces the suboptimally expanded stent by (26.95 +/- 5.03)%. Ninety-five percent of the metal microparticles, imbedded in the suboptimally expanded stent group cardiac tissue, are less than 15 MUm. Transient vasospasm and ST segments elevations were observed during rotablation atherectomy, which returned to basal conditions at the end of the intervention. CONCLUSION: Our study demonstrated the feasibility and safety of using rotablation atherectomy to pulverize stent struts in a suboptimally expanded stent. PMID- 22945810 TI - The hydrogen bond of water from the perspective of soft X-ray spectroscopy. AB - Its importance for life and its unusual properties keep water within the focus of ongoing research; this focus especially applies to water in the liquid phase. Scientists agree that the hydrogen-bond network, which is formed by interactions between the water molecules, is key for understanding the anomalies of water. However, a better understanding of the structure of this network, as well as its dynamics, must yet be established. Soft X-ray spectroscopy allows the investigation of the local electronic structure of water by probing the occupied and unoccupied valence molecular orbitals. In this Focus Review, we present soft X-ray-based techniques, their development in terms of liquid spectroscopy, and recent studies on the hydrogen-bond network of liquid water. PMID- 22945808 TI - Division of labor during primary humoral immunity. AB - B lymphocytes are often considered a homogenous population. However, B cells in both mouse and humans are comprised of distinct subpopulations that differ in development, phenotype, function, and microenvironmental niches. Much of our understanding about how these different B-cells populations mount antibody responses has been derived from experimental findings in mouse models and based on the use of model antigens. These reductionist studies performed over decades have been invaluable in defining the parameters of the B-cell antibody response to different types of antigens. However, these antigens also are now known to differ in a significant manner from bona fide physiological pathogens, and precisely how these different B-cell subsets divide labor in the primary humoral immune defense of pathogens is less well understood. While there are no absolutes in this area, there are recurring themes that divide the roles of B-cell subsets to different arms of the antibody response. This review provides an overview of rules that govern the B-cell labor roles, exceptions that break these rules, and models that have been used to define them. PMID- 22945811 TI - Effect of SWL on renal hemodynamics: could a change in renal artery contraction relaxation responses be the cause? AB - The aim of this study was to reveal the effect of shock wave lithotripsy (SWL) on renal artery contraction-relaxation responses and the relation of this effect with renal hemodynamics. Twenty-four rabbits are divided into six different groups. The first two groups evaluated as the control groups. After isolating the kidneys, we applied phenylephrine (Ph) and acetylcholine (Ach) in the first group and sodium nitroprusside (SNP) and histamine (H) in the second group. In the third, fourth, fifth and sixth groups, 14.5 kV shock wave (SW) was focused on the left kidneys. We adjusted the number of shocks to a total of 500, 1,500, and 3,000 SW, in the third, fourth and fifth groups, respectively. After isolating the kidneys, Ph, Ach was given in groups 3, 4 and 5. In the sixth group, to get the SNP and the H responses, 3,000 shocks modality was utilized. Marked contractile responses were obtained by phenylephrine in the control group. In kidneys that were exposed to 500 shocks SWL procedures, a decrease in contractile responses and hence, in perfusion pressures in different concentrations of phenylephrine was noted. However, a notable change in relaxation responses occurred after 3,000-shock applications. No difference in relaxation responses to nitroprusside, a direct vasodilating agent, was observed in any group, compared to the control group. Another cause of deterioration of renal hemodynamics after SWL can be attributed to the reduction in renal artery contraction-relaxation responses that result in the vascular smooth muscle and endothelial damage. PMID- 22945812 TI - Health service use among the previously uninsured: is subsidized health insurance enough? AB - Although it has been shown that gaining Medicare coverage at age 65 years increases health service use among the uninsured, difficulty in changing habits or differences in the characteristics of previously uninsured compared with insured individuals may mean that the previously uninsured continue to use the healthcare system differently from others. This study uses Medicare claims data linked to two different surveys--the National Health Interview Survey and the Health and Retirement Study--to describe the relationship between insurance status before age 65 years and the use of Medicare-covered services beginning at age 65 years. Although we do not find statistically significant differences in Medicare expenditures or in the number of hospitalizations by previous insurance status, we do find that individuals who were uninsured before age 65 years continue to use the healthcare system differently from those who were privately insured. Specifically, they have 16% fewer visits to office-based physicians but make 18% and 43% more visits to hospital emergency and outpatient departments, respectively. A key question for the future may be why the previously uninsured seem to continue to use the healthcare system differently from the previously insured. This question may be important to consider as health coverage expansions are implemented. PMID- 22945814 TI - [New drug treatment possibilities in castration resistant prostate carcinoma]. PMID- 22945813 TI - Can a minimal intervention reduce secondhand smoke exposure among children with asthma from low income minority families? Results of a randomized trial. AB - We report on the results of a low-intensity behavioral intervention to reduce second hand smoke (SHS) exposure of children with asthma from low income minority households in Los Angeles, California. In this study, 242 child/adult dyads were randomized to a behavioral intervention (video, workbook, minimal counseling) or control condition (brochure). Main outcome measures included child's urine cotinine and parental reports of child's hours of SHS exposure and number of household cigarettes smoked. Implementation of household bans was also considered. No differences in outcomes were detected between intervention and control groups at follow-up. Limitations included high attrition and low rates of collection of objective measures (few children with urine cotinine samples). There continues to be a need for effective culturally and linguistically appropriate strategies that support reduction of household SHS exposure among children with asthma in low income, minority households. PMID- 22945815 TI - [Basics of emergency ultrasound]. AB - Focused ultrasound is a key methodology of critical care medicine. By referencing few ultrasound differential diagnosis, it is possible to identifying in real-time the reason of the critical state of a patient. Therefore typical focused ultrasound protocols were developed. The well known Focused Assessment with Sonography for trauma (FAST) was incorporated into the Advanced Trauma Life Support (ATLS) for shock room. Focused echocardiographic evaluation in life support (FEEL) has been designed to be conformed with the universal Advanced Life Support (ALS) algorithm and to identify treatable conditions such as acute right ventricular pressure overload in pulmonary embolism, hypovolemia, or pericardial effusion/tamponade. Using lung ultrasound one can differentiate pulmonary edema, pleural effusion or pneumothorax. PMID- 22945816 TI - [New aspects in sonography of the liver]. AB - Ultrasound-based technologies are competing more and more success-fully against computerized tomography and magnetic resonance based imaging procedures. This thanks to technological improvements as well as accumulating evidence, stemming from properly conducted controlled clinical studies. The reduced cost and radiation safety issues are additional arguments in its favor. This article reviews new developments in ultrasound medicine as applied to the liver. Emphasis lies on new data related to contrast-ultrasound (Sulphur Hexafluoride SonoVue(r)) which allows a dynamic analysis of liver perfusion and hence improved characterization of focal liver lesions, such as metastases of extrahepatic tumors, regenerative nodules in patients with liver cirrhosis, focal nodular hyperplasia, hepatocellular carcinoma, liver hemangioma, liver adenoma and or focal hypo-respectively hypersteatosis. This article also deals with important new techniques, which allow assessment of liver stiffness such as transient elastography (Fibroscan), ARFI (Acoustic Radiation Force Impulse) or real-time tissue elastography. These new techniques will help us to assess and quantify the levels of liver steatosis with more precision and permit accurate follow-up measurements. PMID- 22945817 TI - [Thyroid nodules - how to proceed?]. AB - Ultrasonic examination of the thyroid is essential in any diagnostic process on the thyroid. It helps to meet the challenge of identifying the few malignant among the thousands of benign nodules. Besides tumour infiltration in surrounding tissue and lymph node metastases - which may prove thyroid cancer - there are well-established criteria suggesting malignancy. A safe distinction between benign and malignant nodules however is not possible by ultrasound alone, nor can hormone producing adenoma be discriminated from inactive nodules. Scintigraphy is helpful in identifying autonomous adenoma but is of no use in assessing the risk of malignancy of thyroid nodules. Ultrasound guided thyroid fine needle aspiration (FNA) is a safe method to prove malignancy. In selected cases, ultrasound guided therapies like percutaneous ethanol instillation (PEI) is an effective treatment of autonomous thyroid ademona. PMID- 22945818 TI - [Comments on the EFSUMB non-liver Guidelines 2011]. AB - Recently the "EFSUMB guidelines and recommendations on the clinical practice of contrast enhanced ultrasound (CEUS): update 2012 on non-hepatic applications" have been published. In the following paper a short summary and comments on the guidelines are given. PMID- 22945819 TI - [Hip ultrasound screening in Mongolia: a Swiss Mongolian Pediatric Project]. AB - To defect incidence of development hip dysplasia by hip ultrasound and to determine efficacy of early treatment: a pilot study in Ulan Bator, Mongolia. Until recently, in Mongolia, early detection and treatment of DDH (developmental dysplasia of the hip) in the first months of life was not possible. A high prevalence as well as a large number of false positive cases indicate an important burden of disease. Since 2009, a project based on ultrasound method of Reinhard Graf is being run by a swiss-mongolian cooperation. A large study including more than 8000 newborns proved, that trained neonatologists are well able to run an ultrasound hip screening. DDH can be detected in the first days after birth and early treatment with a flexion - abduction splint could not only prevent dislocation, but also ensure the maturation process. PMID- 22945820 TI - [Diagnosis and management of suspected nephrolithiasis in a primary care setting]. AB - Based on the prevalence of asymptomatic kidney stones (5% in our general ward, in accordance with the literature) the value of abdominal ultrasonography in the clinical assessment of a suspected kidney-colic is discussed. The eminent importance of the stone-analysis is emphasized. In addition, the most common causes of kidney stone formation (low urine output, mechanical urinary obstruction in the renal pelvis, hypercalciuria, hyperoxaluria, insufficient urinary citric acid excretion, hyperuricosuria) are highlighted. The cardinal symptom of the urolithiasis is the presence of micro/macrohematuria (which is often absent - according to citations - in 20-80%!). Moreover, the differential diagnosis of acute flank pain, as neoplastic- or infectious diseases, reno vascular and extrarenal causes (retro-peritoneal and mesenteric vascular processes and rupture of abdominal aneurysms), gynecological problems (e.g. rotation/rupture of ovarian cysts, ectopic pregnancy), appendicitis, diverticulitis, and splenic abscess/infarction, as well as hepato pancreaticobiliary causes are discussed. Moreover, metabolic syndromes, e.g. the intermittant porphyria or infectious diseases (e.g, Fitz-Hugh-Curtis syndrome) and other rare pathologies (such as the "Mediterranean fever") may be at the origin of acute flank pains. A particular attention is given to possible diagnostic procedures in a primary care setting: in addition to medical history, clinical status and specific laboratory findings the value of diagnostic ultrasound, with special reference to the color-Doppler application, as the "twinkling artefact" from kidney stones and the "urinary-jet phenomenon" for the assessment of urinary outflow obstruction, is emphasized. In this context we point out that a lack of dilatation of the kidney pelvis never excludes a kidney colic, on the other hand, a dilatation of the kidney pelvis does not necessarily mean congestion! The conservative treatment strategies (avoidance of excessive drinking - an obstructed kidney protects itself - NSAID in combination with Tamsulosin, especially in case of prevesical urolithiasis) are discussed. The critical stone size (<=5 mm) and the absence of "red flags" (especially obstructive and inflammatory signs) allow a non-specialist medical outpatient treatment of acute nephro-and ureterolithiasis. The possible complications of the urolithiasis, especially the urosepsis and the (iatrogenic) fornix rupture are highlighted, as well as the formation of a renal abscess or hydronephrosis. A short look is given to the metaphylaxis of the urolithiasis and its "recurrence rate". PMID- 22945821 TI - [Ultrasound in the musculoskeletal system - possibilities and limits]. AB - Since the early 1990's, ultrasound through the development of high-resolution probes in the musculoskeletal system has become more and more important. The development of ultrasound technology has gone hand in hand with the development of know-how in different clinical fields, so that diagnostic ultrasound has now become an indispensable diagnostic tool in orthopedics/traumatology, rheumatology and neurology. The following article will arouse curiosity and interest in musculoskeletal ultrasound. PMID- 22945822 TI - [The dilemma of data flood - reducing costs and increasing quality control]. AB - Digitization is found everywhere in sonography. Printing of ultrasound images using the videoprinter with special paper will be done in single cases. The documentation of sonography procedures is more and more done by saving image sequences instead of still frames. Echocardiography is routinely recorded in between with so called R-R-loops. Doing contrast enhanced ultrasound recording of sequences is necessary to get a deep impression of the vascular structure of interest. Working with this data flood in daily practice a specialized software is required. Comparison in follow up of stored and recent images/sequences is very helpful. Nevertheless quality control of the ultrasound system and the transducers is simple and safe - using a phantom for detail resolution and general image quality the stored images/sequences are comparable over the life cycle of the system. The comparison in follow up is showing decreased image quality and transducer defects immediately. PMID- 22945823 TI - [Ultrasound in East Africa]. AB - Ultrasound is poorly established in East Africa because of missing finances and medical staff. The Foundation for medical know how transfer SmW installed in the last 3 years an ultrasound department in all District Hospitals in the South Province Mombasa in Kenya and was teaching the medical staff 2-3 times an year according the guidelines of SGUM and EFSUMB. The project is based on the idea that knowledge transfer is more efficient than money transfer. The project is supervised by public health studies. The first results show that non physicians are able to perform good quality ultrasound examinations. 75% of the obstetrical and 50% of the abdominal ultrasound examinations show therapy-relevant findings. Ultrasound is going to rise to the position of the most important imagine system in developing countries. PMID- 22945824 TI - ["Knobology" (important device settings)]. AB - The correct setting of the ultrasound equipment is a prerequisite for a high quality of the ultrasound examination. Both the B-mode ultrasonography, as well as the Doppler technique offer interesting alternative settings that are often inadequately used. This brief summary of basic settings should help the practicing clinicians in everyday life and motivate them to deal with the "knobs" of the ultrasound device. Good practical help will provided by the "Sonocave" an event regularly organized at the annual ultrasonic training Congress in Davos, where recognized experts will answer such "Knobology"-questions and demonstrate the appropriate settings also practically. PMID- 22945826 TI - [Nodule of uncertain origin in the right parotid gland with neuroendocrine carcinoma of the lung. Warthin tumor of the right parotid gland (cystadenolymphoma)]. PMID- 22945829 TI - Mass spectrometric description of novel oxymetholone and desoxymethyltestosterone metabolites identified in human urine and their importance for doping control. AB - The metabolism of two anabolic steroids - oxymetholone and desoxymethyltestosterone - was reinvestigated to identify new targets potentially valuable for the antidoping analysis. Excretion urine samples from the laboratory reference collection were used in this study. Following fractionation of the urinary extract by means of high performance liquid chromatography (HPLC), each fraction was subjected to gas chromatography-mass spectrometry (GC-MS) and gas chromatography-tandem mass spectrometry (GC-MS/MS) analysis after trimethylsilylation. About 20 metabolites were found for desoxymethyltestosterone and more than 40 for oxymetholone, with many of them being isomeric compounds. In addition to the well-known reduced and hydroxylated metabolites, 18-nor-17,17 dimethyl and 18-nor-17-hydroxymethyl-17-methyl steroids were also identified. Having evaluated all the metabolites in terms of how long they could be detected, we suggest that 18-nor-2xi,17beta-hydroxymethyl-17alpha-methyl-5alpha-androst-13 en-3alpha-ol is an important marker of oxymetholone abuse. In case of desoxymethyltestosterone, better detectability could be achieved if 18-nor-17,17 dimethyl-5alpha-androst-13-en-2xi,3alpha-diol is monitored. These novel metabolites could be detected using GC-MS/MS at least for 14 days after administration of these anabolic steroids compared to 5-7 days for previously reported metabolites. PMID- 22945830 TI - Tris(triazolo)benzene and its derivatives: high-density energetic materials. AB - High-performance explosives: Tris(triazolo)benzene was synthesized and converted to its trinitro and trichloro derivatives (see scheme; R=NO(2), Cl). The heats of formation of this "high-nitrogen" compounds were calculated and combined with experimentally determined densities to determine detonation pressures and velocities. They exhibit high density, good thermal stability, high heats of formation, and moderate to good detonation properties. PMID- 22945831 TI - Determination of L-trantinterol in rat plasma by using chiral liquid chromatography-tandem mass spectrometry. AB - A simple, sensitive, and rapid method for determination of L-trantinterol in rat plasma was developed for the first time by using LC coupled to MS/MS based on chiral stationary phase. A baseline separation of the enantiomers of trantinterol was achieved on a Chirobiotic V column, using a mixture of acetonitrile-methanol ammonia-acetic acid (80:20:0.01:0.02, v/v/v/v) as the mobile phase. The detection was performed on a triple-quadrupole tandem mass spectrometer by multiple reaction monitoring mode via ESI. The calibration curve was linear in concentration range from 0.270 to 108 ng/mL in plasma with the lower limit of quantification of 0.270 ng/mL. The intra- and interday precision (relative standard deviation) values were within 10.9% and the accuracy (relative error) was from 2.6 to 9.2% at all quality control levels. The method has been successfully applied to a study of L-trantinterol pharmacokinetics in rats. PMID- 22945832 TI - Influence of reported study design characteristics on intervention effect estimates from randomized, controlled trials. AB - Published evidence suggests that aspects of trial design lead to biased intervention effect estimates, but findings from different studies are inconsistent. This study combined data from 7 meta-epidemiologic studies and removed overlaps to derive a final data set of 234 unique meta-analyses containing 1973 trials. Outcome measures were classified as "mortality," "other objective," "or subjective," and Bayesian hierarchical models were used to estimate associations of trial characteristics with average bias and between trial heterogeneity. Intervention effect estimates seemed to be exaggerated in trials with inadequate or unclear (vs. adequate) random-sequence generation (ratio of odds ratios, 0.89 [95% credible interval {CrI}, 0.82 to 0.96]) and with inadequate or unclear (vs. adequate) allocation concealment (ratio of odds ratios, 0.93 [CrI, 0.87 to 0.99]). Lack of or unclear double-blinding (vs. double blinding) was associated with an average of 13% exaggeration of intervention effects (ratio of odds ratios, 0.87 [CrI, 0.79 to 0.96]), and between-trial heterogeneity was increased for such studies (SD increase in heterogeneity, 0.14 [CrI, 0.02 to 0.30]). For each characteristic, average bias and increases in between-trial heterogeneity were driven primarily by trials with subjective outcomes, with little evidence of bias in trials with objective and mortality outcomes. This study is limited by incomplete trial reporting, and findings may be confounded by other study design characteristics. Bias associated with study design characteristics may lead to exaggeration of intervention effect estimates and increases in between-trial heterogeneity in trials reporting subjectively assessed outcomes. PMID- 22945833 TI - Families with Parkinson disease and cancer. PMID- 22945835 TI - Enhanced photocurrents of photosystem I films on p-doped silicon. AB - Tuning the Fermi energy of silicon through doping leads to alignment of silicon bands with the redox active sites of photosystem I. Integrating photosystem I films with p-doped silicon results in the highest reported photocurrent enhancement for a biohybrid electrode based on photosystem I. PMID- 22945836 TI - Is the HO4- anion a key species in the aqueous-phase decomposition of ozone? AB - The role of the HO(4)(-) anion in atmospheric chemistry and biology is a matter of debate, because it can be formed from, or be in equilibrium with, key species such as O(3) + HO(-) or HO(2) + O(2) (-). The determination of the stability of HO(4)(-) in water therefore has the greatest relevance for better understanding the mechanism associated with oxidative cascades in aqueous solution. However, experiments are difficult to perform because of the short-lived character of this species, and in this work we have employed DFT, CCSD(T) complete basis set (CBS), MRCI/aug-cc-pVTZ, and combined quantum mechanics/molecular mechanics (QM/MM) calculations to investigate this topic. We show that the HO(4)(-) anion has a planar structure in the gas phase, with a very large HOO-OO bond length (1.823 A). In contrast, HO(4)(-) adopts a nonplanar configuration in aqueous solution, with huge geometrical changes (up to 0.232 A for the HOO-OO bond length) with a very small energy cost. The formation of the HO(4)(-) anion is predicted to be endergonic by 5.53+/-1.44 and 2.14+/-0.37 kcal mol(-1) with respect to the O(3) + HO(-) and HO(2) + O(2)(-) channels, respectively. Moreover, the combination of theoretical calculations with experimental free energies of solvation has allowed us to obtain accurate free energies for the main reactions involved in the aqueous decomposition of ozone. Thus, the oxygen transfer reaction (O(3) + OH(-) > HO(2) + O(2)(-)) is endergonic by 3.39+/-1.80 kcal mol(-1), the electron transfer process (O(3) + O(2)(-) -> O(3)(-) + O(2)) is exergonic by 31.53+/-1.05 kcal mol(-1), supporting the chain-carrier role of the superoxide ion, and the reaction O(3) + HO(2)(-) -> OH + O(2)(-) + O(2) is exergonic by 12.78+/-1.15 kcal mol(-1), which is consistent with the fact that the addition of small amounts of HO(2)(-) (through H(2)O(2)) accelerates ozone decomposition in water. The combination of our results with previously reported thermokinetic data provides some insights into the potentially important role of the HO(4)(-) anion as a key reaction intermediate. PMID- 22945834 TI - Wilson's disease: changes in methionine metabolism and inflammation affect global DNA methylation in early liver disease. AB - Hepatic methionine metabolism may play an essential role in regulating methylation status and liver injury in Wilson's disease (WD) through the inhibition of S-adenosylhomocysteine hydrolase (SAHH) by copper (Cu) and the consequent accumulation of S-adenosylhomocysteine (SAH). We studied the transcript levels of selected genes related to liver injury, levels of SAHH, SAH, DNA methyltransferases genes (Dnmt1, Dnmt3a, Dnmt3b), and global DNA methylation in the tx-j mouse (tx-j), an animal model of WD. Findings were compared to those in control C3H mice, and in response to Cu chelation by penicillamine (PCA) and dietary supplementation of the methyl donor betaine to modulate inflammatory and methylation status. Transcript levels of selected genes related to endoplasmic reticulum stress, lipid synthesis, and fatty acid oxidation were down-regulated at baseline in tx-j mice, further down-regulated in response to PCA, and showed little to no response to betaine. Hepatic Sahh transcript and protein levels were reduced in tx-j mice with consequent increase of SAH levels. Hepatic Cu accumulation was associated with inflammation, as indicated by histopathology and elevated serum alanine aminotransferase (ALT) and liver tumor necrosis factor alpha (Tnf-alpha) levels. Dnmt3b was down-regulated in tx-j mice together with global DNA hypomethylation. PCA treatment of tx-j mice reduced Tnf-alpha and ALT levels, betaine treatment increased S-adenosylmethionine and up-regulated Dnmt3b levels, and both treatments restored global DNA methylation levels. CONCLUSION: Reduced hepatic Sahh expression was associated with increased liver SAH levels in the tx-j model of WD, with consequent global DNA hypomethylation. Increased global DNA methylation was achieved by reducing inflammation by Cu chelation or by providing methyl groups. We propose that increased SAH levels and inflammation affect widespread epigenetic regulation of gene expression in WD. PMID- 22945837 TI - Laparoscopic pectopexy: a randomised comparative clinical trial of standard laparoscopic sacral colpo-cervicopexy to the new laparoscopic pectopexy. Short term postoperative results. AB - PURPOSE: Sacral colpopexy is a well established method of vaginal prolapse correction. Although it is capable of restoring the physiologic axis of the vagina, this method also bears some serious operative risks [1]. The aim of the study was to compare the laparoscopic sacral colpopexy with a laparoscopic bilateral fixation of the vagina/cervix to the iliopectineal ligaments via a PVDF mesh (pectopexy). METHODS: This part of a single-center randomized prospective clinical trial (Canadian Task Force Classification) compared the short-term operative outcome of laparoscopic sacropexy and pectopexy. We evaluated the operating time, blood loss, hospital stay duration, occurrence of major complications, episodes of constipation, urinary retention, de novo urinary incontinence, urinary tract infections, body mass index and postoperative Creactive protein values. The 1-year follow up examination will be carried out to evaluate the occurrence of relapse as well as late complications. Local symptoms and sexual activity will be evaluated using a German version of the ICIQ Vaginal Symptoms Questionnaire. RESULTS: We carried out 43 pectopexies and 40 sacropexies in conjunction with other laparoscopic and/or vaginal procedures, as indicated. No major complications occurred in both groups during the hospital stay. There were no significant differences in the body mass index, average age, hospital stay duration and occurrence of constipation. The average operating time (43.1 vs. 52.1 min) and blood loss (4.6 vs. 15.3 ml) were significantly lower in the pectopexy group (p < 0.001). CONCLUSION: Although laparoscopic pectopexy cannot yet be generally recommended as an alternative to sacropexy until the follow-up data is obtained, the new method can be considered in patients where the presacral preparation bears a higher risk of injury. PMID- 22945838 TI - The diagnostic and prognostic value of serum YKL-40 in endometrial cancer. AB - PURPOSE: To evaluate the diagnostic and prognostic value of serum YKL-40 in endometrial cancer (EC). METHODS: Serum YKL-40 levels were detected and compared in 34 of the 50 cases with EC before surgery, in 22 of the 34 with EC after surgery, in 30 cases with uterine myoma, and in 30 healthy women as normal controls. Receiver operating characteristics (ROC) curves were adopted for diagnosis and calculation of area under each ROC curve in EC. The progression free survival (PFS) and overall survival (OS) between YKL-40 positive and negative patients were compared in the follow-up. RESULTS: The mean pre-operative serum YKL-40 values were significantly higher than that in the uterine myoma cases and in the healthy women (P = 0.000). The mean post-operative serum YKL-40 in the 22 EC cases was significantly lower than pre-operative serum YKL-40 levels in these cases (P = 0.000). There were critical differences between the area under ROC curve for YKL-40 and CA125 (P = 0.053). The PFS and OS for the YKL-40 positive patients were significantly shorter than those for the YKL-40-negative patients. CONCLUSION: Preliminary investigations have shown that serum YKL-40 level may have a definite clinical value in the diagnosis and prognosis of EC. PMID- 22945840 TI - Use of areas under the receiver operating curve (AROCs) and some caveats. PMID- 22945839 TI - Tracheobronchoplasty in Japan. AB - More than a century has passed since the first tracheoplasty was successfully performed by Eiselsberg in 1896. In that time, tracheobronchoplasty has developed with the extension of operative indications. This review focuses on who contributed to the development of this operation in Japan, and in what ways, with comparisons to results for these operations in the West. The headings include "Pioneers and colleagues", "Symbols and taxonomy", "Surgical anatomy", "Surgical diseases", "Anesthesia", "Surgical techniques", "Results", and "The present state". Although effort has been made to acknowledge various opinions, the convictions expressed herein are my own. PMID- 22945841 TI - Kosovo-Serbs' experiences of seeking healthcare in a post-conflict and ethnically segregated health system. AB - OBJECTIVE: To examine the experiences of Kosovo-Serbs who seek healthcare in the formal Kosovo health system. METHODS: Eleven semi-structured interviews were carried out with Kosovo-Serbs who live in one of the following mono-ethnic enclaves: Gorazhdevc/Gorazdevac, Videje/Vidanje, Kline/Klina and Viti/Vitina. A phenomenological approach was used to collect and analyze data. RESULTS: The analysis shows the critical role of the depth of the relationship with Kosovo Albanian doctors in the Kosovo-Serbs' experience of seeking care in the formal sector. The patient-doctor relationship is the result of two processes longitudinal care and consultation experiences. Four elements, i.e., knowledge, trust, closeness and regard were identified as key aspects contributing to the depth of the relationship between Kosovo-Serb patients and Kosovo-Albanian doctors. CONCLUSIONS: Fear, anxiety and language differences are still important barriers to Kosovo-Serbs' access to formal health care. These barriers are partly overcome as interviewees establish and develop relationships to Kosovo-Albanian doctors based on reciprocal knowledge, trust, closeness, and regard. Hereby, Kosovo-Serb patients and Kosovo-Albanian doctors contribute to blur the lines the ethnically divided health system and transcend the legacy of war. PMID- 22945842 TI - Testing Skype as an interview method in epidemiologic research: response and feasibility. AB - INTRODUCTION: Despite its popularity, Skype has not been tested as a tool for epidemiologic research. We examined its feasibility in Germany. METHODS: A population-based sample of young adults was randomly invited to a Skype (n = 150) or a phone interview (n = 150). Response and duration of interviews were analysed to evaluate the feasibility of Skype interviews. RESULTS: Response was low and, with 10 % (95 % CI 5-15 %), even worse among Skype candidates, compared to 22 % (15-28 %) in the phone group. A third of the Skype group asked for being interviewed by phone. Median duration was 34.0 minutes for Skype interviews and 37.0 minutes for phone interviews. CONCLUSIONS: Skype is not yet a feasible tool for data collection in Germany. PMID- 22945843 TI - "Tendency to excuse" and patient satisfaction of those suffering with breast cancer. AB - OBJECTIVES: The purpose of this study was to analyse the extent to which breast cancer patients excuse inconveniences that occur during their hospitalisation, and how this "tendency to excuse" affects their satisfaction with the hospital stay. METHODS: Breast cancer patients undergoing treatment at one of 51 breast centres in North Rhine-Westphalia (Germany) in 2009 were asked to complete the Cologne Patient Questionnaire-Breast Cancer (CPQ-BC). For the analyses, the "tendency to excuse" scale was subdivided into three groups. Linear regressions were performed to investigate associations between the "tendency to excuse" and patient satisfaction. RESULTS: 88 % (3,950) of the patients completed the questionnaire. The results show that the inpatients excused inconsistencies to a moderate degree. The "excusers" and "non-excusers" showed greater satisfaction with hospital services than the "medium-excusers". CONCLUSIONS: The "tendency to excuse" scale could aid future data analysis of patient satisfaction surveys by identifying patients who are more likely to answer in an unbiased fashion. According to hospital survey outcomes, adjusting for the "tendency to excuse" scale however, does not lead to substantially different results when comparing health care providers. PMID- 22945844 TI - No causal effect of unemployment on smoking? A German panel study. AB - OBJECTIVES: This study analyses the effects of different unemployment durations on smoking behaviour in Germany by investigating smoking take-up, relapse, quitting and smoking intensity. METHODS: Longitudinal data from the German Socio Economic Panel from the years 1998, 2001, 2002, 2004, 2006, and 2008 were used to examine the effect of unemployment (52,940 observations from 17,028 respondents, aged 17-65 years). Unemployment duration was measured at 1-6, 7-12, 13-24, and 24+ months. Effects were estimated using zero-inflated negative binomial regressions and fixed effects logistic panel regressions. RESULTS: The zero inflated negative binomial regression models suggest that the likelihood of smoking increases with unemployment, while smoking intensity is not affected. However, fixed effects logistic regression models demonstrate that unemployment is neither a significant predictor for taking up smoking, relapsing, nor quitting. CONCLUSIONS: The results indicate that in Germany, there is no direct causal effect of unemployment on smoking behaviour. The observed relationship between smoking and unemployment appears to be driven by stable, unobserved differences between employed and unemployed respondents. PMID- 22945847 TI - Pulmonary function of individual lung lobes after complex living-donor lobar lung transplantation using inspiratory and expiratory three-dimensional computed tomographic volumetry. AB - A combination of inspiratory and expiratory three-dimensional computed tomographic volumetry provides useful information on pulmonary function and lung volume. We previously reported an early outcome of a patient undergoing living donor lobar lung transplantation with sparing of the bilateral native upper lobes. Long-term follow-up on such patients had not been reported, and therefore we herein, for the first time, reported the 2-year follow-up of the previously reported case. According to the inspiratory and expiratory three-dimensional computed tomographic volumetric data, we demonstrated that transplanted lower lobe grafts had been working efficiently and spared bilateral native upper lobes had not provided any adverse effects. PMID- 22945848 TI - Can pregnant women be safely placed on cardiopulmonary bypass? AB - A best evidence topic was written according to a structured protocol. The question addressed was whether cardiopulmonary bypass can be used safely with satisfactory maternal and foetal outcomes in pregnant patients undergoing cardiac surgery. A total of 679 papers were found using the reported searches of which 14 represented the best evidence to answer the clinical question. The authors, date, journal, study type, population, main outcome measures and results are tabulated. Reported measures were maternal and foetal mortality and complications, mode of delivery, cardiopulmonary bypass and aortic cross-clamp times, perfusate flow rate and temperature and maternal NYHA functional class. The most recent of the best evidence studies, a retrospective observational study of 21 pregnant patients reported early and late maternal mortalities of 4.8 and 14.3%, respectively, and a foetal mortality of 14.3%. Median cardiopulmonary bypass and aortic cross-clamp times were 53 and 35 min, respectively, and the median bypass temperature was 37 degrees C. Three larger retrospective reviews of the literature reported maternal mortality rates of 2.9-5.1% and foetal mortality rates of 19-29%. Mean cardiopulmonary bypass times ranged from 50.5 to 77.8 min. Another retrospective observational study reported maternal mortality of 13.3% and foetal mortality of 38.5%. Mean cardiopulmonary bypass and aortic cross-clamp times were 89.1 and 62.8 min, respectively, with a mean bypass temperature of 31.8 degrees C. A retrospective case series reported no maternal mortality and one case of foetal mortality. Median cardiopulmonary bypass and aortic cross clamp times were 101 and 88 min, respectively. Eight case reports described 10 patients undergoing cardiopulmonary bypass. There were no reports of maternal mortality and one report of foetal mortality. Mean cardiopulmonary bypass and aortic cross-clamp times were 105 and 50 min, respectively. We conclude that while the use of cardiopulmonary bypass during pregnancy poses a high risk for both the mother and the foetus, the use of high-flow, high-pressure, pulsatile, normothermic bypass and continuous foetal and uterine monitoring can allow cardiac surgery with the use of cardiopulmonary bypass to be performed with the greatest control of risk in the pregnant patient. PMID- 22945849 TI - Do endobronchial valves improve outcomes in patients with emphysema? AB - A best evidence topic in thoracic surgery was written according to a structured protocol. The question addressed was whether endobronchial valves improve outcomes in patients with severe emphysema. Eighty-seven papers were found using the reported search, of which seven represented the best evidence to answer the clinical question. The authors, journal, date and country of publication, patient group studied, study type, relevant outcomes and results of these papers are tabulated. Endobronchial Valve for Emphysema Palliation Trial demonstrated that endobronchial valve increased forced expiratory volume in one second by 4.3% (95% confidence interval 1.4-7.2) and decreased by 2.5% in the control group (95% confidence interval -5.4 to 0.4) at a 6-month interval. This benefit is more marked in patients who do not have collateral ventilation into the area of lung being isolated as mapped by bronchoscopic physiological mapping (Chartis) or by computed tomography imaging documenting intact fissures. This evidence is reflected in the Endobronchial Valve for Emphysema Palliation Trial. Patients treated with endobronchial valve with high heterogeneity and complete fissures had greater improvement in forced expiratory volume in one second at 6- and 12 month intervals. We conclude that endobronchial valve placement improves lung function, exercise capacity and quality of life in selected patients with emphysematous diseases. PMID- 22945845 TI - Interleukin-8 reduces post-surgical lymphedema formation by promoting lymphatic vessel regeneration. AB - Lymphedema is mainly caused by lymphatic obstruction and manifested as tissue swelling, often in the arms and legs. Lymphedema is one of the most common post surgical complications in breast cancer patients and presents a painful and disfiguring chronic illness that has few treatment options. Here, we evaluated the therapeutic potential of interleukin (IL)-8 in lymphatic regeneration independent of its pro-inflammatory activity. We found that IL-8 promoted proliferation, tube formation, and migration of lymphatic endothelial cells (LECs) without activating the VEGF signaling. Additionally, IL-8 suppressed the major cell cycle inhibitor CDKN1C/p57(KIP2) by downregulating its positive regulator PROX1, which is known as the master regulator of LEC-differentiation. Animal-based studies such as matrigel plug and cornea micropocket assays demonstrated potent efficacy of IL-8 in activating lymphangiogenesis in vivo. Moreover, we have generated a novel transgenic mouse model (K14-hIL8) that expresses human IL-8 in the skin and then crossed with lymphatic-specific fluorescent (Prox1-GFP) mouse. The resulting double transgenic mice showed that a stable expression of IL-8 could promote embryonic lymphangiogenesis. Moreover, an immunodeficient IL-8-expressing mouse line that was established by crossing K14 hIL8 mice with athymic nude mice displayed an enhanced tumor-associated lymphangiogenesis. Finally, when experimental lymphedema was introduced, K14-hIL8 mice showed an improved amelioration of lymphedema with an increased lymphatic regeneration. Together, we report that IL-8 can activate lymphangiogenesis in vitro and in vivo with a therapeutic efficacy in post-surgical lymphedema. PMID- 22945846 TI - Muscle-directed anti-Abeta single-chain antibody delivery via AAV1 reduces cerebral Abeta load in an Alzheimer's disease mouse model. AB - We previously reported that anti-amyloid-beta (Abeta) single-chain antibody (scFv59) brain delivery via recombinant adeno-associated virus (rAAV) was effective in reducing cerebral Abeta load in an Alzheimer's disease (AD) mouse model without inducing inflammation. Here, we investigated the prophylactic effects and mechanism of a muscle-directed gene therapy modality in an AD mouse model. We injected rAAV serotype 1 encoding scFv59 into the right thigh muscles of 3-month-old mice. Nine months later, high levels of scFv59 expression were confirmed in the thigh muscles by both immunoblotting and immunohistochemistry. As controls, model mice were similarly injected with rAAV1 encoding antihuman immunodeficiency virus Gag antibody (scFvGag). AAV1-mediated scFv59 gene delivery was effective in decreasing Abeta deposits in the brain. Compared with the scFvGag group, levels of Abeta in cerebrospinal fluid (CSF) decreased significantly while Abeta in serum tended to increase in the scFv59 group. AAV1 mediated scFv59 gene delivery may alter the equilibrium of Abeta between the blood and brain, resulting in an increased efflux of Abeta from the brain owing to antibody-mediated sequestration/clearance of peripheral Abeta. Our results suggest that muscle-directed scFv59 delivery via rAAV1 may be a prophylactic option for AD and that levels of CSF Abeta may be used to evaluate the efficacy of anti-Abeta immunotherapy. PMID- 22945850 TI - Enhanced high-rate performance of double-walled TiO2-B nanotubes as anodes in lithium-ion batteries. AB - Curled up: TiO(2)-B nanotubes with two curled layers are successfully prepared by a facile hydrothermal route and subsequent calcination. The two curled layers produce a thin wall, and thus the obtained double-walled structure results in short distances of electron and lithium-ion transport, thereby leading to an improved high-rate performance. PMID- 22945851 TI - An isobutyronitrile-induced bienzymatic system of Alcaligenes sp. MTCC 10674 and its application in the synthesis of alpha-hydroxyisobutyric acid. AB - Alcaligenes sp. MTCC 10674 was isolated as acetone cyanohydrin hydrolyzing bacterium from soil of orchid gardens of Himachal Pradesh. Acetone cyanohydrin hydrolyzing activity of this organism comprised nitrile hydratase and amidase activities. It exhibited higher substrate specificity towards aliphatic hydroxynitrile (acetone cyanohydrin) in comparison to arylaliphatic hydroxynitrile. Isobutyronitrile (40 mM) acted as a carbon source as well as inducer for growth of Alcaligenes sp. MTCC 10674 and expression of acetone cyanohydrin hydrolyzing activity. Optimization of culture condition using response surface methodology increased acetone cyanohydrin hydrolyzing activity by 1.3-fold, while inducer mediation approach increased the activity by 1.2-fold. The half life of this enzyme was 25 h at 15 degrees C. V max and K m value for acetone cyanohydrin hydrolyzing enzyme was 0.71 MUmol mg(-1) min(-1) and 14.3 mM, when acetone cyanohydrin was used as substrate. Acetone cyanohydrin hydrolyzing enzyme encountered product inhibition and IC50 and K i value were calculated to be 28 and 10.2 mM, respectively, when product alpha-hydroxyisobutyric acid was added in the reaction. Under optimized reaction conditions at 40 ml fed batch scale, 3 mg dcw ml (-) resting cells of Alcaligenes sp. MTCC 10674 fully converted 0.33 M acetone cyanohydrin into alpha-hydroxyisobutyric acid (1.02 g) in 6 h 40 min. The characterization of acetone cyanohydrins hydrolyzing activity revealed that it comprises bienzymatic nitrile hydrolyzing system, i.e. nitrile hydratase and amidase for the production of alpha-hydroxyisobutyric acid from acetone cyanohydrin and maximum 70 % yield is being reported for the first time. PMID- 22945853 TI - Fitness costs associated with insecticide resistance. AB - Insects are exposed to a variety of stress factors in their environment, and, in many cases for insect pests to agriculture, those factors include toxic chemical insecticides. Coping with the toxicity of insecticides can be costly and requires energy and resource allocation for adaptation and survival. Several behavioural, physiological and genetic mechanisms are used by insects to handle toxic insecticides, sometimes leading to resistance by constitutive overexpression of detoxification enzymes or inducing mutations in the target sites. Such actions are costly and may affect reproduction, impair dispersal ability and have several other effects on the insect's fitness. Fitness costs resulting from resistance to insecticides has been reported in many insects from different orders, and several examples are given in this mini-review. PMID- 22945854 TI - Essential and nonessential elements in nestling rooks Corvus frugilegus from eastern Poland with a special emphasis on their high cadmium contamination. AB - Concentration of minerals (sodium, potassium, calcium [Ca], magnesium, iron [Fe], copper, zinc [Zn], manganese [Mn], and cobalt) as well as toxic metals (cadmium [Cd], lead [Pb]) were determined in five tissues (liver, lung, kidney, muscle, and bone) of nestling rooks (Corvus frugilegus; 1 to 13 days old) found dead in seven breeding colonies in eastern Poland. Cd concentration in all analyzed tissues was in the narrow range of 17.0-17.2 mg/kg dry weight (dw) Cd, which in the light of the literature data indicates acute contamination by this toxic metal. Similarly, we found increased levels of Pb, which in all tissues ranged between 5.0 and 6.2 mg/kg dw. Results of multivariate general linear model (GLM) testing of the effect of three variables (tissue type, colony, and nestling age) on tissue concentrations of various metals showed significance for Fe, Cu, Zn, and Mn. Only concentrations of Ca, Fe, and Zn differed significantly between the analyzed tissues. GLM analysis did not show any statistically significant differences in tissue levels of minerals and both toxic metals among examined rookeries, which indicates the widespread presence of nonpoint Cd and Pb pollution linked to agricultural activity and similar levels of these inorganic contaminants on crop fields (feeding grounds) around breeding colonies. We concluded that high levels of both toxic metals, Cd and Pb, probably resulting from the diet of nestling rooks, are based mainly on a diet of ground-dwelling beetles gathered on crop fields. PMID- 22945855 TI - Trace elements in faeces of great tit nestlings in relation to breeding performance in coastal areas in central Portugal. AB - This long-term study (2003-2010) compared the breeding parameters of great tits living in a paper-and-pulp-industry area to those of great tits living in a rural area on the west coast of Portugal. We also measured the abundance of caterpillar biomass, an important food source and determinant of breeding success for tits. In 2009, we further analysed trace metal [arsenic (As), calcium (Ca), cadmium, copper, mercury (Hg), nickel, lead, selenium, and zinc] as well as Ca concentrations in excrement of 15-day-old great tit nestlings. Generally, for most trace metals, fecal concentrations were similar at both sites. Nonetheless, greater Hg levels and lower As levels were detected in the industrial area. Great tits laid more eggs and produced more fledglings in the industrial area than in the rural area. Caterpillar biomass was also greater in the industrial area, which likely explains the better breeding success. Our results suggest that there are no direct effects of emissions on the studied species. PMID- 22945856 TI - A review of tags anti-collision and localization protocols in RFID networks. AB - Radio Frequency IDentification (RFID) has allowed the realization of ubiquitous tracking and monitoring of physical objects wirelessly with minimum human interactions. It plays a key role in a wide range of applications including asset tracking, contactless payment, access control, transportation and logistics, and other industrial applications. On the other side, RFID systems face several technical challenges that need to be overcome in order to achieve their potential benefits; tags collisions and localization of tagged objects are two important challenges. Numerous anti-collision and localization protocols have been proposed to address these challenges. This paper reviews the state-of-art tags' anti collision and localization protocols, and provides a deep insight into technical issues of these protocols. The probabilistic and deterministic anti-collision protocols are critically studied and compared in terms of different parameters. We further review distance estimation, scene analysis, and proximity localization schemes and provide useful suggestions. We also introduce a new hybrid direction that utilizes power control to spatially partition the interrogation range of a reader for more efficient anti-collision and localization. Finally, we present the applications of RFID systems in healthcare sectors. PMID- 22945852 TI - Analytical glycobiology at high sensitivity: current approaches and directions. AB - This review summarizes the analytical advances made during the last several years in the structural and quantitative determinations of glycoproteins in complex biological mixtures. The main analytical techniques used in the fields of glycomics and glycoproteomics involve different modes of mass spectrometry and their combinations with capillary separation methods such as microcolumn liquid chromatography and capillary electrophoresis. The need for high-sensitivity measurements have been emphasized in the oligosaccharide profiling used in the field of biomarker discovery through MALDI mass spectrometry. High-sensitivity profiling of both glycans and glycopeptides from biological fluids and tissue extracts has been aided significantly through lectin preconcentration and the uses of affinity chromatography. PMID- 22945858 TI - Rebounding droplet-droplet collisions on superhydrophobic surfaces: from the phenomenon to droplet logic. AB - When water droplets impact each other while traveling on a superhydrophobic surface, we demonstrate that they are able to rebound like billiard balls. We present elementary Boolean logic operations and a flip-flop memory based on these rebounding water droplet collisions. Furthermore, bouncing or coalescence can be easily controlled by process parameters. Thus by the controlled coalescence of reactive droplets, here using the quenching of fluorescent metal nanoclusters as a model reaction, we also demonstrate an elementary operation for programmable chemistry. PMID- 22945857 TI - Cognitive functioning in allogeneic hematopoietic stem cell transplantation recipients and its medical correlates: a prospective multicenter study. AB - BACKGROUND: Owing to its neurotoxicity, allogeneic hematopoietic stem cell transplantation (HSCT) carries risks for cognitive impairment. In this multicenter study, we prospectively evaluated cognitive functioning and its medical and demographic correlates in patients undergoing allogeneic HSCT. METHODS: A total of 102 patients were consecutively assessed prior to (T0 ), 100 +/- 20 days (T1 ) after, and 12 +/- 1 months (T2 ) after HSCT (61% men, 41% acute myeloid leukemia). A comprehensive neuropsychological test battery was applied to evaluate attention, memory, executive function, and fine motor function, summing up into 14 test scores. RESULTS: Before and after HSCT, patients performed below test norms in up to 50% of the test scores. Patients were mostly impaired on word fluency (24%, T0 ), fine motor function, and verbal delayed recall (19% each, T2 ). Impairment on >= 1/5 cognitive domains occurred in 47% (T0 ) and 41% (T2 ) of the patients. Performance (mean z-scores) partially improved over time (i.e., visual span forward, verbal learning, and word fluency). However, from baseline to T2 , 16% of the patients showed reliable decline on >= 3/14 test scores (reliable change index method). For the majority of neuropsychological subtests, no associations with conditioning intensity, total body irradiation, graft-versus host disease, cyclosporine treatment, and length of hospital stay were found. Age and premorbid intelligence level were consistently associated with cognition. CONCLUSIONS: Below average cognitive performance is common in this patient group. In addition, a subgroup shows reliable cognitive decline after allogeneic HSCT. Healthcare professionals should be aware of these treatment-related cognitive side effects. PMID- 22945859 TI - Determination of cyflumetofen residue in water, soil, and fruits by modified quick, easy, cheap, effective, rugged, and safe method coupled to gas chromatography/tandem mass spectrometry. AB - A new, highly sensitive, and selective method was developed for the determination of the cyflumetofen residue in water, soil, and fruits by using gas chromatography quadruple mass spectrometry. The target compound was extracted using acetonitrile and then cleaned up using dispersive solid-phase extraction with primary and secondary amine and graphitized carbon black, and optionally by a freezing-out cleanup step. The matrix-matched standards gave satisfactory recoveries and relative standard deviation values in different matrices at three fortified levels (0.05, 0.5, and 1.0 mg kg(-1) ). The overall average recoveries for this method in water, soil, and all fruits matrix at three fortified levels ranged from 76.3 to 101.5% with relative standard deviations in the range of 1.2 11.8% (n = 5). The calculated limits of detection and quantification were typically below 0.005 and 0.015 MUg kg(-1), which were much lower than the maximum residue levels established by Japanese Positive List. This study provides a theoretical basis for China to draw up maximum residue level and analytical method for cyflumetofen acaricide in different fruits. PMID- 22945860 TI - Mitral valve plasty in an adult patient without a right superior vena cava. AB - Persistent left superior vena cava without a right superior vena cava is an extremely rare condition. We report the case of a 65-year-old woman with this condition who underwent mitral valve plasty. During cardiac catheterization, the asymptomatic patient with mitral valve prolapse syndrome was found to have a persistent left superior vena cava without a right superior vena cava. During mitral valve plasty, cardiopulmonary bypass was established using bicaval drainage through the persistent left superior vena cava and the right atrium. A cannula was inserted into the persistent left superior vena cava to provide a large surgical field in the left atrium. We selected a technique that involved direct insertion of an L-shaped cannula into the persistent left superior vena cava and obtained a clear view of the surgical field. Proper assessment of the right superior vena cava is necessary when a persistent left superior vena cava is suspected. PMID- 22945861 TI - Hydrogen bonds guide the short-lived 5'-deoxyadenosyl radical to the place of action. PMID- 22945862 TI - Echinimonas agarilytica gen. nov., sp. nov., a new gammaproteobacterium isolated from the sea urchin Strongylocentrotus intermedius. AB - A novel Gram-negative, facultatively anaerobic and motile bacterial strain, designated KMM 6351(T), was isolated from the sea urchin Strongylocentrotus intermedius and examined using a polyphasic taxonomic approach. A phylogenetic analysis based on 16S rRNA gene sequencing revealed that the strain formed a distinct phyletic line in the class Gammaproteobacteria and was most closely related to the genera Aliivibrio, Photobacterium and Vibrio. Strain KMM 6351(T) grows at 4-40 degrees C and with 0.5-12 % NaCl and decomposes aesculin, agar, gelatin, starch, chitin and DNA. The DNA G+C content of the strain was determined to be 46.1 mol%. The prevalent fatty acids were found to be C(16:0), C(18:1) omega7c, C(12:0) 3-OH and summed feature 3 (comprising C(16:1) omega7c and/or iso C(15:0) 2-OH fatty acids). The major polar lipids were determined to be diphosphatidylglycerol, phosphatidylglycerol, phosphatidylethanolamine and an unidentified aminolipid. The predominant ubiquinone was found to be Q-8. The results of the phenotypic, chemotaxonomic and genotypic analyses clearly indicated that the novel strain should be assigned to a new genus and species within the class gamma-Proteobacteria for which the name Echinimonas agarilytica gen. nov., sp. nov. is proposed. The type strain is KMM 6351(T) (=KCTC 22996(T) = LMG 25420(T)). PMID- 22945864 TI - Publication of descriptions of novel bacterial taxa in Antonie van Leeuwenhoek. PMID- 22945863 TI - Increased frequency of integrons and beta-lactamase-coding genes among extraintestinal Escherichia coli isolated with a 7-year interval. AB - We analyzed the level of antimicrobial resistance, and the presence of integrons and beta-lactamase-coding genes in 69 clinically relevant Escherichia coli strains originating from extraintestinal infections isolated in 1999-2001 and 2008-2010. Comparison of the two groups showed significant differences in drug resistance frequency, and the presence of integron and beta-lactamase-coding genes. The frequency of resistance to all antimicrobials beside imipenem, streptomycin, piperacillin/tazobactam, and sulfamethoxazole increased significantly, especially towards aminoglycosides, beta-lactams and fluoroquinolones. Similarly, we noticed an increase in the number of strains with integrons from 31.6 to 80.7 %. The presence of integrase genes was associated with elevated frequency of resistance to each antimicrobial tested besides imipenem, piperacillin/tazobactam and ceftazidime. The presence of integrons was also associated with multidrug resistance phenotype. The genetic content of integrons comprised genes determining resistance toward aminoglycosides, sulfonamides and trimethoprim. Moreover, we noticed a significant increase in the frequency of bla (CTX-M) beta-lactamases, with appearance of bla (CTX-M-15) variant and newer plasmid-encoded beta-lactamases like CMY-15 and DHA. The emergence of strains resistant to several classes of antimicrobials and carrying integrons, ESBL and AmpC beta-lactamase-coding genes may predict the spread of isolates with limited treatment options. PMID- 22945865 TI - The use of group sequential designs with common competing risks tests. AB - Clinical trials are often performed using a group sequential design in order to allow investigators to review the accumulating data sequentially and possibly terminate the trial early for efficacy or futility. Standard methods for comparing survival distributions have been shown under varying levels of generality to follow an independent increments structure. In the presence of competing risks, where the occurrence of one type of event precludes the occurrence of another type of event, researchers may be interested in inference on the cumulative incidence function, which describes the probability of experiencing a particular event by a given time. This manuscript shows that two commonly used tests for comparing cumulative incidence functions, a pointwise comparison at a single point, and Gray's test, also follow the independent increments structure when used in a group sequential setting. A simulation study confirms the theoretical derivations even for modest trial sample sizes. We used two examples of clinical trials in hematopoietic cell transplantation to illustrate the techniques. PMID- 22945866 TI - From containers to catalysts: supramolecular catalysis within cucurbiturils. AB - Cucurbiturils are a family of molecular container compounds with superior molecular recognition properties. The use of cucurbiturils for supramolecular catalysis is highlighted in this concept. Both photochemical reactions as well as thermal transformations are reviewed with an eye towards tailoring substrates for supramolecular catalysis mediated by cucurbiturils. PMID- 22945867 TI - Detecting reduced renal function in children: comparison of GFR-models and serum markers. AB - BACKGROUND: The aim of this study was to compare the ability of renal indicators [serum creatinine (SCr), cystatin C (SCysC)] and glomerular filtration rate (GFR) models to discriminate normal and reduced renal function. As a single cut-off level will always lead to false classifications, we propose using two cut-off levels, dividing renal function into normal or reduced, with an intermediate "gray zone" of indeterminable results. METHODS: Glomerular filtration rate was measured by plasma clearance of (51)Cr-EDTA (13.7-147.4 mL/min/1.73 m(2)) in 119 children (age range 2.3-14.9 years). Reduced renal function was defined as a GFR of <82 mL/min/1.73 m(2). SCr, SCysC, age-normalized creatinine (SCr-ratio), and eight published GFR-models were compared for their ability to correctly classify renal function as normal or reduced. Cut-off levels were determined so as to give 99 % certainty outside the gray zone. RESULTS: The multivariable GFR-models by Schwartz et al. (J Am Soc Nephrol 2009; 20:629-637) and Zappitelli et al. (Am J Kidney Dis 2006; 48:221-230) and two models by Andersen et al. [Am J Kidney Dis 2012; 59(1):50-57: body cell mass (BCM)-model and Weight-model] performed significantly better than all other variables (P < 0.01), with the BCM-model performing the best (P < 0.05). The SCr-based Schwartz formula and SCr-ratio both performed better than SCr and SCysC. CONCLUSIONS: Among the 119 children enrolled in this study and the renal indicators tested, the BCM-model had the best diagnostic performance in terms of screening for normal or reduced renal function, and the SCr-ratio was a superior diagnostic tool to both SCr and SCysC. PMID- 22945869 TI - N-alkylsulfonylimines as dipolarophiles in cycloaddition reactions. AB - First described in the late 1960s, N-alkylsulfonylimines are heterocumulenes that participate in reactions with a range of 1,3-dipoles to afford interesting 3-, 4 , 5-, and 6-membered heterocycles. The distribution of adducts obtained suggests that multistage, stepwise mechanistic pathways rather than a concerted process are in operation. PMID- 22945868 TI - Patterns of heterogeneous expression of pannexin 1 and pannexin 2 transcripts in the olfactory epithelium and olfactory bulb. AB - Pannexins form membrane channels that release biological signals to communicate with neighboring cells. Here, we report expression patterns of pannexin 1 (Panx1) and pannexin 2 (Panx2) in the olfactory epithelium and olfactory bulb of adult mice. In situ hybridization revealed that mRNAs for Panx1 and Panx2 were both expressed in the olfactory epithelium and olfactory bulb. Expression of Panx1 and Panx2 was mainly found in cell bodies below the sustentacular cell layer in the olfactory epithelium, indicating that Panx1 and Panx2 are expressed in mature and immature olfactory neurons, and basal cells. Expression of Panx2 was observed in sustentacular cells in a few locations of the olfactory epithelium. In the olfactory bulb, Panx1 and Panx2 were expressed in spatial patterns. Many mitral cells, tufted cells, periglomerular cells and granule cells were Panx1 and Panx2 positive. Mitral cells located at the dorsal and lateral portions of the olfactory bulb showed weak Panx1 expression compared with those in the medial side. However, the opposite was true for the distribution of Panx2 positive mitral cells. There were more Panx2 mRNA positive mitral cells and granule cells compared to those expressing Panx1. Our findings on pannexin expression in the olfactory system of adult mice raise the novel possibility that pannexins play a role in information processing in the olfactory system. Demonstration of expression patterns of pannexins in the olfactory system provides an anatomical basis for future functional studies. PMID- 22945870 TI - B cells and CD22 are dispensable for the immediate antiinflammatory activity of intravenous immunoglobulins in vivo. AB - Intravenous immunoglobulins (IVIgs) efficiently suppress a variety of autoimmune diseases. Over the past few years several potential mechanisms underlying this antiinflammatory activity have become apparent. Among these, terminal sialic acid residues in the sugar moiety of the immunoglobulin G constant fragment have been shown to be critical for the antiinflammatory activity of IVIgs in models of rheumatoid arthritis and immunothrombocytopenia (ITP). More recently, B cells and the sialic acid-binding protein CD22 were suggested to be involved in this IVIg dependent immunomodulatory pathway. To study whether B cells are directly involved in IVIg-mediated suppression of acute autoimmune diseases, we tested the activity of IVIgs in mice deficient in B cells or CD22. We show that neither B cells nor CD22 are critical for the immediate antiinflammatory activity of IVIgs in mouse models of rheumatoid arthritis and ITP. PMID- 22945871 TI - Spiders (Araneae) in the pesticide world: an ecotoxicological review. AB - Being one of the most abundant and species-rich groups of natural enemies occurring in all agroecosystems, spiders are variably affected by pesticide applications. Here, a review is given of research on spider ecotoxicology. More than 40 species of spiders and almost 130 pesticides (acaricides, insecticides, fungicides and herbicides) have been tested so far in the field or under laboratory conditions. Field studies show that the degree of population reduction following pesticide application is a function of a number of factors inherent to pesticides, crops and spider species (guilds). These studies also revealed indirect effects via habitat and prey disruption. Among laboratory studies, a number of papers have investigated only the direct lethal effect. A meta-analysis of these data reveals that spiders are mainly affected by acaricides and insecticides, particularly neurotoxic substances. Currently, ecotoxicological research on spiders is focused more on direct sublethal effects on a variety of behavioural traits (locomotion, predation, web-building, reproduction, development) and physiology. Yet a standardised approach to the evaluation of sublethal effects is lacking. A few studies have provided some evidence for hormesis in spiders. Future research should be more concentrated on sublethal effects and the estimation of long-term changes in spider populations as a result of pesticide treatment. PMID- 22945872 TI - Processing of food, body and emotional stimuli in anorexia nervosa: a systematic review and meta-analysis of functional magnetic resonance imaging studies. AB - The characteristics of the cognitive processing of food, body and emotional information in patients with anorexia nervosa (AN) are debatable. We reviewed functional magnetic resonance imaging studies to assess whether there were consistent neural basis and networks in the studies to date. Searching PubMed, Ovid, Web of Science, The Cochrane Library and Google Scholar between January 1980 and May 2012, we identified 17 relevant studies. Activation likelihood estimation was used to perform a quantitative meta-analysis of functional magnetic resonance imaging studies. For both food stimuli and body stimuli, AN patients showed increased hemodynamic response in the emotion-related regions (frontal, caudate, uncus, insula and temporal) and decreased activation in the parietal region. Although no robust brain activation has been found in response to emotional stimuli, emotion-related neural networks are involved in the processing of food and body stimuli among AN. It suggests that negative emotional arousal is related to cognitive processing bias of food and body stimuli in AN. PMID- 22945873 TI - Bromenium-catalysed tandem ring opening/cyclisation of vinylcyclopropanes and vinylcyclobutanes: a metal-free [3+2+1]/[4+2+1] cascade for the synthesis of chiral amidines and computational investigation. AB - We present a detailed study of a [3+2+1] cascade cyclisation of vinylcyclopropanes (VCP) catalysed by a bromenium species (Br(delta+)-X(delta-)) generated in situ, which results in the synthesis of chiral bicyclic amidines in a tandem one-pot operation. The formation of amidines involves the ring-opening of VCPs with Br-X, followed by a Ritter-type reaction with chloramine-T and a tandem cyclisation. The reaction has been further extended to vinylcyclobutane systems and involves a [4+2+1] cascade cyclisation with the same reagents. The versatility of the methodology has been demonstrated by careful choice of VCPs and VCBs to yield bicyclo[4.3.0]-, -[4.3.1]- and -[4.4.0]amidines in enantiomerically pure form. On the basis of the experimental observations and DFT calculations, a reasonable mechanism has been put forth to account for the formation of the products and the observed stereoselectivity. We propose the existence of a pi-stabilised homoallylic carbocation at the cyclopropane carbon as the reason for high stereoselectivity. DFT studies at B3LYP/6-311+G** and M06 2X/6-31+G* levels of theory in gas-phase calculations suggest the ring-opening of VCP is initiated at the pi-complex stage (between the double bond and Br-X). This can be clearly perceived from the solution-phase (acetonitrile) calculations using the polarisable continuum model (PCM) solvation model, from which the extent of the ring opening of VCP was found to be noticeably high. Studies also show that the formation of zero-bridge bicyclic amidines is favoured over other bridged bicyclic amidines. The energetics of competing reaction pathways is compared to explain the product selectivity. PMID- 22945874 TI - Rapid decrease of neonatal mortality in Turkey. AB - Our aim was to assess trends in neonatal mortality in 2009, evaluate advances in health policy, determine new goals to preserve a higher quality health service, and to prevent neonatal deaths. Data were gathered from the system of the General Directorate of Mother and Child and Family Planning. Maternal age, birth weight, gestational week, delivery at a health center, delivery by trained assistant, antenatal visits, and cause of death were evaluated. The neonatal mortality rate was 10/1,000 in Turkey in 2009, significantly better than rates of 26 in 1998, 17 in 2003, and 13 in 2008. The percentage of pregnant women making a minimum of four antenatal visits was around 80 %. Most deaths were attributable to prematurity and its complications, including 47.2 % of early neonatal mortality (ENM) and 36.1 % of late neonatal mortality (LNM). In ENM, the next-most common causes of death were congenital anomalies other than heart and genetic disorders (17.5 %), infections (6.5 %), asphyxia (6.1 %), and congenital heart disease (4.0 %), whereas in LNM, they were infections (19.9 %), congenital anomalies other than heart and genetic disorders (13.1 %), congenital heart disease (7.7 %), and asphyxia (3.8 %). Neonatal mortality in Turkey has declined within 8 years to level similar to that reached by Organisation for Economic Co-operation and Development countries over 30 years. Our findings show that each of the major causes of the neonatal death can be prevented by available interventions. Interventions to prevent prematurity, early diagnosis of congenital anomalies, and the prevention of infections would contribute to further reductions in neonatal mortality in Turkey. PMID- 22945875 TI - Induction of rapid apoptosis for class I MHC molecule-restricted CD8(+) HIV-1 gp160-specific murine activated CTLs by free antigenic peptide in vivo. AB - We have previously reported that the cytotoxic activity of murine CD8(+) CTLs specific for HIV-1 gp160 envelope protein was markedly inhibited in vitro by brief exposure to a free epitope peptide P18-I10 (aa: RGPGRAFVTI) using the epitope-specific CTL line (LINE-IIIB) or a clone (RT-1). We have also shown that recently stimulated P18-I10-specific murine CTLs rapidly fell into apoptosis in vitro after brief exposure to the free epitope peptide. In the present study, we examined whether similar inactivation or apoptosis of recently stimulated CTLs occurred in vivo by exposure to the free epitope peptide using TCR transgenic (Tg RT-1) mice expressing TCRalphabeta genes of CTL clone RT-1. When the Tg mice were inoculated with recombinant vaccinia virus expressing HIV-1-IIIB gp160 genes followed by injection of P18-I10 epitope peptide, apparent reduction in the number of CTLs determined by flow cytometry using H-2D(d)/P18-I10 pentamer was observed within a few hours after the injection. Most of the H-2D(d)/P18-I10 pentamer-stained cells were positive for Annexin V and apoptosis was confirmed by microscopic analyses. Moreover, when mice were pretreated with immunosuppressive agents, such as cyclosporin A and tacrolimus (FK506), induction of apoptosis by P18-I10 was significantly inhibited and CTL cytotoxicity was maintained. These results suggest that the rapid loss of virus-specific CD8(+) CTLs might occur in vivo through apoptosis in the early stages of viral infection when activated CTLs may encounter viral epitope(s) released from virus-infected cells attacked by CTLs and we can prevent the loss by pretreatment with immunosuppressive agents. PMID- 22945876 TI - A low-copy-number plasmid for retrieval of toxic genes from BACs and generation of conditional targeting constructs. AB - Bacterial Artificial Chromosome (BAC) clones are widely used for retrieving genomic DNA sequences for gene targeting. In this study, low-copy-number plasmids pBAC-FB, pBAC-FC, and pBAC-DE, which carry the F plasmid replicon, were generated from pBACe3.6. pBAC-FB was successfully used to retrieve a sequence of a BAC that was resistant to retrieval by a high-copy-number plasmid via lambda Red-mediated recombineering (gap-repair cloning). This plasmid was also used to retrieve two other genes from BAC, indicating its general usability retrieving genes from BAC. The retrieved genes were manipulated in generating targeting vectors for gene knockouts by recombineering. The functionality of the targeting vector was further validated in a targeting experiment with C57BL/6 embryonic stem cells. The low-copy-number plasmid pBAC-FB is a plasmid of choice to retrieve toxic DNA sequences from BACs and to manipulate them to generate gene-targeting constructs by recombineering. PMID- 22945877 TI - Liquid chromatographic separation and thermodynamic investigation of stereoisomers of darunavir on Chiralpak AD-H column. AB - Liquid chromatographic separation of stereoisomers of darunavir on Chiralpak AD H, a column containing the stationary phase coated with amylose tris(3,5 dimethylphenylcarbamate) as a chiral selector, was studied under normal-phase conditions at different temperatures between 20 and 50 degrees C. The effect of quality and quantity of different polar organic modifiers viz: methanol, ethanol, 1-propanol, and 2-propanol in the mobile phase as well as column temperature on retention, separation, and resolution was investigated and optimized. The optimum separation was accomplished using a mobile phase composed of n hexane/ethanol/diethyl amine (80:20:0.1 v/v/v) at 40 degrees C. Apparent thermodynamic parameters DeltaH(0) and DeltaS* were derived from the Van't Hoff plots (lnk' versus 1/T) and used to explain the strength of interactions between the stereoisomers and amylose tris(3,5-dimethylphenylcarbamate) coated chiral stationary phase. PMID- 22945878 TI - One-pot gold-catalyzed synthesis of azepino[1,2-a]indoles. AB - Indoles from scratch: A gold(I)/N-heterocyclic carbene complex (IPr=1,3 di(isopropylphenyl)imidazol-2-ylidene) was found to be particularly effective as a catalyst, enabling the one-pot synthesis of tricyclic azepinoindoles by an unprecedented cascade reaction. Readily available substrates, high chemoselectivity, good yields, and water as the only stoichiometric by-product are some of the main advantages of this method. PMID- 22945879 TI - Diverse models for the prediction of HIV integrase inhibitory activity of substituted quinolone carboxylic acids. AB - In the present study both classification and correlation techniques of diverse nature were successfully employed for the development of models for the prediction of human immunodeficiency virus (HIV) integrase inhibitory activity using a dataset comprising 50 analogs of quinolone carboxylic acid. The values of various molecular descriptors (MDs) for each analog in the dataset were computed using the MDS V-life science QSAR plus module. The values of other MDs which are not part of MDS V-life science were computed using an in-house computer program. A decision tree (DT) was constructed for the HIV integrase inhibitory activity to determine the importance of MDs. The DT learned the information from the input data with an accuracy of 98% and correctly predicted the cross-validated (10 fold) data with an accuracy of 96%. Three MDs, E-state contribution descriptor (SssOHE), molecular connectivity topochemical index ($?chi {}^{{?rm A}} $), and eccentric connectivity topochemical index ($?xi _{{?rm C}}^{{?rm C}} $), were used to develop the models using moving average analysis (MAA). The accuracy of classification of single descriptor based models using MAA was found to vary from a minimum of 96% to a maximum of 98%. The statistical significance of the models was assessed through specificity, sensitivity, overall accuracy, Mathew's correlation coefficient, and intercorrelation analysis. The widely used methods like multiple linear regression, partial least squares, and principal component regression were employed for development of correlation models. The models were generated on a training set of 36 molecules. The models had a correlation coefficient (r(2) ) of 0.86 to 0.92, significant cross validated correlation coefficient (q(2) ) of 0.79 to 0.85, F-test from 63.2 to 93.06, r(2) for external test set (pred_r(2) ) from 0.69, coefficient of correlation of predicted dataset (pred_ r(2) Se) of 0.77, and degree of freedom from 27 to 30. Alignment independent descriptors, SsOHE-index, SaaCHE index, SssCH2, and x log P were found to be the most important descriptors for the development of correlation models for the prediction of HIV integrase inhibitory activity. PMID- 22945880 TI - Understanding the genetic, demographical and/or ecological processes at play in invasions: lessons from the southern cattle tick Rhipicephalus microplus (Acari: Ixodidae). AB - The southern cattle tick, Rhipicephalus microplus, is the ixodid species causing the largest economic losses in tropical agrosystems because of its recurrent invasive success, explosive demography on bovine herds, vector competence for diverse pathogens and frequent development of acaricide resistance. Its ecology and the physiological bases of the acaricide resistances it developed, as well as alternative tick control measures, have been intensively studied for decades. By contrast, the tick population genetic structure and its remarkable ability to quickly adapt to new environments have not yet received much attention. We investigated such issues using population genetics analyses in the recently invaded island New Caledonia. In this paper we aim to describe some guidelines for acarologists willing to investigate the processes at play in Acari invasions. Particular emphasis is given to the accuracy of sampling designs and sampling scales for population genetics to be actually informative on the demographical processes of the species (i.e., its mating rules, the determinants of population limits, population sizes, the relationships between genetic exchanges and geographical distances and relevant ecological factors). PMID- 22945883 TI - One-step synthesis of graphitic nanoplatelets that are decorated with luminescent carbon nanoparticles as new optical-limiting materials. AB - Graphitic nanoplatelets (GNPs) and luminescent carbon nanoparticles (CNPs) are simultaneously synthesized by controlling the laser parameters and the size of the graphite flakes. Because luminescent CNPs are attached onto GNPs, a new carbon nanostructure is obtained. Compared with carbon black, GNPs, and luminescent CNPs alone, this nanostructure shows better optical-limiting (OL) effects. The OL mechanism of GNPs that are decorated with luminescent CNPs can mainly be attributed to nonlinear scattering. The role of luminescent CNPs is to promote the formation and growth of nonlinear scattering bubbles, thereby enhancing their optical-limiting effects. PMID- 22945882 TI - SAMITAL(r) improves chemo/radiotherapy-induced oral mucositis in patients with head and neck cancer: results of a randomized, placebo-controlled, single-blind Phase II study. AB - PURPOSE: This randomised, placebo-controlled single-blind trial investigated the safety and efficacy of SAMITAL(r), a formulation of highly standardised botanical extracts, in the treatment of chemo/radiotherapy-induced oral mucositis (OM) in patients with head and neck cancer. METHODS: Patients received SAMITAL(r) or placebo four times daily for up to 50 days during scheduled chemo/radiotherapy. Severity of OM was monitored according to a modified WHO severity scale, and pain and quality-of-life assessments were based on the effect of symptoms of OM on relevant daily activities, according to a visual analogue scale. RESULTS: Mean scores for the severity of OM were significantly (p < 0.05 versus baseline) reduced from day 31 until the end of treatment in patients treated with SAMITAL(r) (n = 20). No significant improvement was observed in the placebo group (n = 10). Pain reduction was significant from day 4 till end of treatment with SAMITAL(r) and from days 7 to 21 in placebo patients. SAMITAL(r) also significantly improved quality of life, as shown by improvements in scores for relevant daily activities including eating, drinking and sleeping. All SAMITAL(r) patients completed the treatment period, but no placebo recipients completed treatment. No severe adverse events were observed with SAMITAL(r), and systemic absorption of relevant active ingredients was undetectable. CONCLUSIONS: SAMITAL(r) significantly decreased the severity of chemo/radiotherapy-induced OM in patients with head and neck cancer, with no treatment-related adverse events. Pain relief lasted through the treatment period, and improvements in quality of life were reflected by the significant benefits of SAMITAL(r) on activities like drinking, eating and speaking. PMID- 22945884 TI - Central-atom size effects on the methyl torsions of Group XIV tetratolyls. AB - The Group XIV tetratolyl series X(C(6)H(4)-CH(3))(4) (X = C, Si, Ge, Sn, Pb) were studied by using inelastic neutron scattering to measure the low-energy phonon spectra to directly access the methyl-group torsional modes. The effect of increased molecular radius as a function of the size of the central atom was shown to have direct influence on the methyl dynamics, reinforced with the findings of molecular dynamics and contact surface calculations, based upon the solid-state structures. The torsional modes in the lightest analogue were found to be predominantly intramolecular: the Si and Ge analogues have a high degree of intermolecular methyl-methyl group interactions, whilst the heaviest analogues (Sn and Pb) showed pronounced intermolecular methyl interactions with the whole phonon bath of the lattice modes. PMID- 22945881 TI - Economic and social changes among distressed family caregivers of lung cancer patients. AB - PURPOSE: Although costs of lung cancer care have been documented, economic and social changes among lung cancer patients' family caregivers have yet to be fully examined. In addition, research has not focused on caregivers with greater need for support services. This study examined various economic and social changes among distressed family caregivers of lung cancer patients during the initial months of cancer care in the USA. METHODS: Lung cancer patients' primary family caregivers with significant anxiety or depressive symptoms were recruited from three medical centers within 12 weeks of the patient's new oncology visit. Caregivers (N = 83) reported demographic and medical information and caregiving burden at baseline. Seventy-four caregivers reported anxiety and depressive symptoms and economic and social changes 3 months later. RESULTS: Seventy-four percent of distressed caregivers experienced one or more adverse economic or social changes since the patient's illness. Common changes included caregivers' disengagement from most social and leisure activities (56%) and, among employed caregivers (n = 49), reduced hours of work (45%). In 18% of cases, a family member quit work or made another major lifestyle change due to caregiving. Additionally, 28% of caregivers reported losing the main source of family income, and 18% reported losing most or all of the family savings. Loss of the main source of family income and disengagement from most social and leisure activities predicted greater caregiver distress. CONCLUSIONS: Findings suggest that distressed caregivers of lung cancer patients experience high rates of adverse economic and social changes that warrant clinical and research attention. PMID- 22945885 TI - Virulence of Verticillium lecanii (Z.) against cereal aphids; does timing of infection affect the performance of parasitoids and predators? AB - BACKGROUND: Entomopathogenic fungi such as Verticillium lecanii (Z.) (Mycotal((r))) are used for pest control as an alternative to chemical control. In this study, the effect of V. lecanii on cereal aphids is assessed. In addition, an investigation is carried out to determine whether the use of V. lecanii affects the performance of two natural enemies of aphids, the predator Harmonia axyridis (P.) and the parasitoid Aphidius colemani (V.), in no-choice experiments under laboratory conditions. RESULTS: The number of Rhopalosiphum padi (L.) and Sitobion avenae (F.) killed was increased by increasing the concentration of V. lecanii. The timing of application of fungus to aphids affected the efficacy of other biocontrol agents, a parasitoid and a predator. Parasitation by A. colemani (V.) in both cereal aphids (S. avenae and R. padi) was not affected by V. lecanii when aphids were first treated with V. lecanii and then exposed to A. colemani. The emergence of adults from parasitised mummies was, however, lower in infected aphids than in uninfected aphids when the aphids were first exposed to the parasitoids and then treated with fungus. The female sex ratio in the emerging adults was lower in V. lecanii-treated aphids in both species. When aphids were first treated with V. lecanii, 72 h before predation, fewer aphids of both species were consumed by H. axyridis (P.). CONCLUSION: Use of entomopathogenic fungus as a biological control agent could be a complementary strategy in an integrated pest management programme against cereal aphids, but it can reduce the efficiency of other biocontrol agents (parasitoids and predators) when applied simultaneously. PMID- 22945886 TI - Rapid separation of beryllium and lanthanide derivatives by capillary gas chromatography. AB - Previous studies describe derivatization of metal ions followed by analysis using gas chromatography, usually on packed columns. In many of these studies, stable and volatile derivatives were formed using fluorinated beta-diketonate reagents. This paper extends previous work by investigating separations of the derivatives on small-diameter capillary gas chromatography columns and exploring on-fiber, solid-phase microextraction derivatization techniques for beryllium. The beta diketonate used for these studies was 1,1,1,2,2,6,6,7,7,7-decafluoro-3,5 heptanedione. Derivatization of lanthanides also required addition of a neutral donor, dibutyl sulfoxide, in addition to 1,1,1,2,2,6,6,7,7,7-decafluoro-3,5 heptanedione. Unoptimized separations on a 100-MUm i.d. capillary column proved capable of rapid separations (within 15 min) of lanthanide derivatives that are adjacent to one another in the periodic table. Full-scan mass spectra were obtained from derivatives containing 5 ng of each lanthanide. Studies also developed a simple on-fiber solid-phase microextraction derivatization of beryllium. Beryllium could be analyzed in the presence of other alkali earth elements (Ba(II) and Sr(II)) without interference. Extension of the general approach was demonstrated for several additional elements (i.e. Cu(II), Cr(III), and Ga(III)). PMID- 22945887 TI - Aqueous alkali-metal silicate anions containing fully condensed four-coordinate sites. AB - Conspicuous absence: (29)SiNMR studies show that highly condensed, four coordinate Si-containing anions are common in concentrated alkali-metal silicate solutions, but reveal no evidence for the existence of specialized zeolite building units. The results add to the mounting evidence that silicate polymerization simply proceeds through stepwise condensation of monosilicate tetrahedra. PMID- 22945888 TI - Successful laparoscopic division of a patent ductus venosus: report of a case. AB - Patent ductus venosus (PDV) is a rare condition of a congenital portosystemic shunt from the umbilical vein to the inferior vena cava. This report presents the case of an adult patient with PDV, who was successfully treated with laparoscopic shunt division. A 69-year-old male was referred with hepatic encephalopathy. Contrast-enhanced CT revealed a large connection between the left portal vein and the inferior vena cava, which was diagnosed as PDV. The safety of a shunt disconnection was confirmed using a temporary balloon occlusion test for the shunt, and the shunt division was performed laparoscopically. The shunt was carefully separated from the liver parenchyma with relative ease, and then divided using a vascular stapler. Portal flow was markedly increased after the operation, and the liver function of the patient improved over the 3-month period after surgery. Although careful interventional evaluation for portal flow is absolutely imperative prior to surgery, a minimally invasive laparoscopic approach can be safely used for treating PDV. PMID- 22945889 TI - Long-term outcomes of patients undergoing extracorporeal membrane oxygenation for refractory postcardiotomy cardiogenic shock. AB - PURPOSE: Postcardiotomy cardiogenic shock is still associated with a poor prognosis. We reviewed patients undergoing extracorporeal membrane oxygenation (ECMO) support for postcardiotomy cardiogenic shock and assessed their long-term outcomes. METHODS: The subjects were 47 patients who received ECMO support for cardiogenic shock after open heart surgery. We analyzed the long-term survival and risk factors for early or late death. RESULTS: Twenty-nine patients were weaned off ECMO support, but 15 of these patients died during their hospital stay. An independent predictor of mortality during ECMO support was incomplete sternum closure (OR 4.089, 95 % CL 1.003-16.67, p = 0.049) and a predictor of mortality after weaning off ECMO was more than 48 h of support (OR 8.975, 95 % CL 1.281-62.896, p = 0.027). Fourteen patients were discharged from hospital, but seven of these patients died during the follow-up period owing to cardiac events (n = 2) or non-cardiac causes (n = 5). The actuarial survival rates were 34.0 % at 30 days, 29.8 % at 1 year, and 17.6 % at 10 years. CONCLUSION: Although postcardiotomy cardiogenic shock requiring ECMO support is associated with high morbidity and mortality, the long-term survival rate is acceptable. PMID- 22945890 TI - Rapid construction of the [6-6-6-5] tetracyclic skeleton of the Daphniphyllum alkaloid daphenylline. AB - You can call me Al: A concise route for construction of the [6-6-6-5] tetracyclic skeleton of daphenylline, a structurally novel Daphniphyllum alkaloid, has been developed with full stereocontrol in only 8 steps from two known fragments. This approach features an intramolecular [3+2] cycloaddition of a 2-azaallyl anion with an alkene to form the cis-fused AC rings. PMID- 22945891 TI - Transcriptional networks that mediate signals from reproductive tissues to influence lifespan. AB - Aging and reproduction are two defining features of our life. Historically, research has focused on the well-documented decline in reproductive capacity that accompanies old age, especially with increasing maternal age in humans. However, recent experiments in model organisms such as worms, flies, and mice have shown that a dialogue in the opposite direction may be widely prevalent, and that signals from reproductive tissues have a significant effect on the rate of aging of organisms. This pathway has been described in considerable detail in the nematode Caenorhabditis elegans. Molecular genetic studies suggest that signals from the germline control a network of transcriptional regulators that function in the intestine to influence longevity. This network includes conserved, longevity-promoting Forkhead Box (FOX) family transcription factors such as DAF 16/FOXO and PHA-4/FOXA, nuclear hormone receptors, as well as a transcription elongation factor, TCER-1/TCERG1. Genomic and targeted molecular analyses have revealed that these transcription factors modulate autophagy, lipid metabolism, and possibly other cellular processes to increase the length of the animal's life. This review aims to provide an overview of the current knowledge on the genetic mechanism that underlies the reproductive control of aging with particular focus on the transcriptional regulators that constitute the main molecular players in this longevity pathway. PMID- 22945892 TI - A general palladium-catalyzed carbonylative synthesis of 2-alkylbenzoxazinones from 2-bromoanilines and acid anhydrides. AB - (C), its (O)K! An efficient palladium-catalyzed carbonylative synthesis of 2 alkylbenzoxazinones has been developed. By starting from 2-bromoanilines and acid anhydrides, the corresponding products were isolated in good yields. PMID- 22945893 TI - Low-energy selective capture of carbon dioxide by a pre-designed elastic single molecule trap. AB - Single-molecule trap: Easy activation of the water-stable metal-organic framework PCN-200 provides a new route to low-energy selective CO(2) capture through stimuli-responsive adsorption behavior. This elastic CO(2) trapping effect was confirmed by single-component and binary gas-adsorption isotherms and crystallographic determination. PMID- 22945894 TI - Nickel-catalyzed Kumada reaction of tosylalkanes with Grignard reagents to produce alkenes and modified arylketones. AB - Open a new door: The first example of alkene synthesis from alkyl electrophiles with Grignard reagents using the Kumada cross-coupling reaction strategy is reported. This method opens a new door for the Kumada cross-coupling reaction, allowing alkenes to be prepared from the reaction of tosylalkanes with Grignard reagents. PMID- 22945895 TI - Surgical unroofing of the optic canal and visual outcome in basal meningiomas. AB - BACKGROUND: To define from a series of surgically treated suprasellar, anterior clinoid, and sphenoid wing meningiomas, an unequivocal criterion for performing optic canal deroofing in patients with basal meningiomas with deteriorated vision. METHODS: One hundred-fifty consecutive patients with suprasellar and parasellar meningiomas (44 tuberculum sellae, 46 clinoidal, and 60 spheno orbital) who underwent surgery between 1988 and 2008 are retrospectively analyzed. The rate of preoperative visual deficit, the incidence of optic canal involvement, the related surgical management, and its influence on visual outcome are reviewed in all tumor localizations. RESULTS: All 44 patients with tuberculum sellae meningiomas had variable preoperative visual impairment. All were operated on by transcranial approach. Unroofing of the optic canal was performed in the two cases with intracanalar tumor extension. Postoperatively, the visual function improved in 27 patients (61.4 %) and was unchanged in 17 (25 %). Among 46 patients with clinoidal meningiomas, visual dysfunction was found in 30 (65.2 %). The first 32 patients were operated on by classical pterional approach, with selective opening of the optic canal in six cases (group A), whereas all the last 14 underwent routine anterior clinoidectomy and opening of the optic canal (group B). The visual function improved postoperatively in 17 among 30 patients (56.7 %), with a significantly higher rate in group B cases (80 % versus 45 %). Among 60 patients with spheno-orbital meningiomas, 36 (60 %) had visual dysfunction and 43 (71.6 %) involvement of the optic canal. The visual function improved in 18 cases (50 %), was unchanged in 13 (36 %), and worsened in 5 (14 %). Lateral tumors had the lowest rate of optic canal involvement and a 100 % rate of visual improvement; on the other hand, all orbital apex and diffuse tumors had concentric invasion of the optic canal with a 18.6 % rate of visual worsening. CONCLUSIONS: UOC seems to be a safe procedure not associated with immediate postoperative impairment of the vision. We recommend routine deroofing of the optic canal coupled with extradural anterior clinoidectomy in all clinoidal meningiomas in order to obtain early and complete exposure of both intradural and extradural segments of the optic nerve. For tuberculum sellae meningiomas, we advise to open the optic canal only in cases with intracanalar tumor extension. Finally, for spheno-orbital meningiomas, we recommend UOC through a cranio orbital approach in almost all cases, except for lateral meningiomas, where the involvement of the lateral wall of the optic canal is rare and may be successfully managed through a lateral orbitotomy without craniotomy. PMID- 22945896 TI - MR imaging findings of extraventricular neurocytoma: a series of ten patients confirmed by immunohistochemistry of IDH1 gene mutation. AB - BACKGROUND: Extraventricular neurocytomas (EVNs) are rare neuronal tumors included as neoplasms in the 2007 World Health Organization (WHO) classification of tumors of the CNS. Although a few case reports describing EVNs have been published, a systematic analysis of MR imaging findings of EVN has not been reported. Furthermore, imaging findings of IDH1 mutation-negative EVNs have not yet been reported. The aim of our study is to describe the MR imaging findings of IDH1 mutation-negative EVNs. METHODS: MR images of ten patients with pathologically confirmed IDH1 mutation-negative EVNs were retrospectively reviewed. Conventional MR imaging of ten EVNs were reviewed with emphasis on the location, signal intensities, patterns, and grades of enhancement as well as the presence/grade of peritumoral edema, intratumoral cyst, hemorrhage, and calcification. The study also reviewed the results of DWI (b = 1,000 s/mm(2), n = 7). RESULTS: Seven EVN cases were located in the cerebral hemisphere, and the remaining cases were in the cerebellum and thalamus. Of those in the cerebral hemisphere, five were cortically based tumors. The tumors showed no or mild peritumoral edema. Eight tumors were enhanced on the postcontrast T1WIs. An intratumoral cyst, hemorrhage, and calcification were detected in four, one, and two cases, respectively. On DWI, only one case showed a lower ADC value than the brain parenchyma. CONCLUSION: EVNs are usually cortically based infiltrative hemispheric tumors with contrast enhancement, higher ADC value, and sometimes small cystic component, but hardly show peritumoral edema or intratumoral hemorrhage. The differential diagnosis of these findings includes low-grade glioneuronal tumors and low-grade gliomas. PMID- 22945897 TI - Eight-year follow-up of a fibromuscular dysplasia patient with multiple fusiform aneurysms. PMID- 22945898 TI - Plastic relocation of motor cortex in a patient with LGG (low grade glioma) confirmed by NBS (navigated brain stimulation). AB - We report on a patient with LGG, in whom NBS mapping confirmed relocation of the primary motor cortex (M1) concurrent with multistage surgery. Comparing the NBS results at 18 months with the initial results revealed that the M1 representation had shifted from the precentral to the postcentral gyrus. The patient underwent a third surgical intervention. Intraoperative direct cortical stimulation (DCS) confirmed the shift of the M1. Plastic changes in M1 localization permitted complete tumour removal without neurological sequela. To our knowledge, this is the first report on a LGG patient where induced brain plasticity has been confirmed by NBS mapping. PMID- 22945899 TI - Endoscopic endonasal approach for pituitary adenomas. AB - BACKGROUND: Pituitary surgery is a continuous evolving specialty of neurosurgery, requiring precise anatomical knowledge, technical skills and integrated appreciation of the pathophysiology. METHODS: We herein detail the features of the endoscopic endonasal approach for the management of pituitary adenomas, as experienced at the Division of Neurosurgery of the Universita' degli Studi di Napoli "Federico II". CONCLUSIONS: The endoscopic endonasal technique brings advantages to the patient (less nasal traumatism, less post-op pain), to the surgeon (wider and closer view of the surgical target area, increase of the scientific activity, smoothing of interdisciplinary cooperation), and to the institution (shorter post-op hospital stay, and increase of the case load). PMID- 22945900 TI - Synthesis and properties of bisphosphole-bridged ladder oligophenylenes. AB - Ladder-type oligophenylenes (LOPP) with bridging heteroatoms are interesting systems as they offer novel electronic and photophysical properties on account of the rigid structural features, more efficient electron delocalization on the coplanar aromatic framework, and strong intermolecular interactions. LOPPs incorporating multiple phosphorous centers combine the excellent electronic properties of phospholes and rigidified conjugated framework of LOPPs, thus positioning themselves as an attractive class of organic semiconductors. To date, there still lacks an effective synthetic methodology towards LOPPs with multiple phosphorous bridges. Herein, we describe the synthesis and properties of a new class of bisphosphole-bridged ladder oligo(p-phenylene)s and the related phosphoxides. The synthesis of phospholes was achieved by a four-fold free radical phosphanylation reaction of a tetrabromo p-terphenylene or biphenyl thiophene. Sequential trapping of four highly reactive aryl radicals occurred effectively to give the desired phosphorous-containing ladder compound. The oxides of the phospholes are shown to be strong fluorophores that can be used as potential n-type building blocks for organic semiconducting materials. PMID- 22945901 TI - Synthesis and characterization of multiferrocenyl-substituted group 4 metallocene complexes. AB - The reaction of different metallocene fragments [Cp(2)M] (Cp=eta(5) cyclopentadienyl, M=Ti, Zr) with diferrocenylacetylene and 1,4-diferrocenylbuta 1,3-diyne is described. The titanocene complexes form the highly strained three- and five-membered ring systems [Cp(2)Ti(eta(2)-FcC(2)Fc)] (1) and [Cp(2)Ti(eta(4) FcC(4)Fc)](2) (Fc=[Fe(eta(5)-C(5)H(4))(eta(5)-C(5)H(5))]) by addition of the appropriate alkyne or diyne to Cp(2)Ti. Zirconocene precursors react with diferrocenyl- and ferrocenylphenylacetylene under C-C bond coupling to yield the metallacyclopentadienes [Cp(2)Zr(C(4)Fc(4))](3) and [Cp(2)Zr(C(4)Fc(2)Ph(2))](5), respectively. The exchange of the zirconocene unit in 3 by hydrogen atoms opens the route to the super-crowded ferrocenyl-substituted compound tetraferrocenylbutadiene (4). On the other hand, the reaction of 1,4 diferrocenylbuta-1,3-diyne with zirconocene complexes afforded a cleavage of the central C-C bond, and thus, dinuclear [{Cp(2)Zr(MU-eta(1):eta(2)-C=CFc)}(2)] (6) that consists of two zirconocene acetylide groups was formed. Most of the complexes were characterized by single-crystal X-ray crystallography, showing attractive multinuclear molecules. The redox properties of 3, 5, and 6 were studied by cyclic voltammetry. Upon oxidation to 3(n+), 5(n+), and 6(n+) (n=1-3), decomposition occured with in situ formation of new species. The follow-up products from 3 and 5 possess two or four reversible redox events pointing to butadiene-based molecules. However, the dinuclear complex 6 afforded ethynylferrocene under the measurement conditions. PMID- 22945902 TI - Freezing of ring-puckering molecular motion and giant dielectric anomalies in metal-organic perovskites. AB - Pucker up! Metal-organic perovskites containing azetidinium cations, [(CH(2))(3)NH(2)][M(HCOO)(3)] (M = Mn, Cu, Zn), all show a structural phase transition, coupled with the freezing of the ring-puckering molecular motion of azetidinium cations, and an extremely large dielectric anomaly near room temperature. Molecular dynamics simulations showed the freezing of ring-puckering motion of the four-membered-ring azetidinium cation near room temperature. PMID- 22945903 TI - Genome-wide computational identification of bicistronic mRNA in humans. AB - Mammalian bicistronic mRNA is a recently discovered mammalian gene structure. Several reported cases of mammalian bicistronic mRNA indicated that genes of this structure play roles in some important biological processes. However, a genome wide computational identification of bicistronic mRNA in mammalian genome, such as human genome, is still lacking. Here we used a comparative genomics approach to identify the frequency of human bicistronic mRNA. We then validated the result by using a new support vector machine (SVM) model. We identified 43 human bicistronic mRNAs in 30 distinct genes. Our literature analysis shows that our method recovered 100 % (6/6) of the previously known bicistronic mRNAs which had been experimentally confirmed by other groups. Our graph theory-based analysis and GO analysis indicated that human bicistronic mRNAs are prone to produce different yet closely functionally related proteins. In addition, we also described and analyzed three different mechanisms of ORF fusion. Our method of identifying bicistronic mRNAs in human genome provides a model for the computational identification of characteristic gene structures in mammalian genomes. We anticipate that our data will facilitate further molecular characterization and functional study of human bicistronic mRNA. PMID- 22945904 TI - eIF5A dimerizes not only in vitro but also in vivo and its molecular envelope is similar to the EF-P monomer. AB - The protein eukaryotic initiation factor 5A (eIF5A) is highly conserved among archaea and eukaryotes, but not in bacteria. Bacteria have the elongation factor P (EF-P), which is structurally and functionally related to eIF5A. eIF5A is essential for cell viability and the only protein known to contain the amino acid residue hypusine, formed by post-translational modification of a specific lysine residue. Although eIF5A was initially identified as a translation initiation factor, recent studies strongly support a function for eIF5A in the elongation step of translation. However, the mode of action of eIF5A is still unknown. Here, we analyzed the oligomeric state of yeast eIF5A. First, by using size-exclusion chromatography, we showed that this protein exists as a dimer in vitro, independent of the hypusine residue or electrostatic interactions. Protein protein interaction assays demonstrated that eIF5A can form oligomers in vitro and in vivo, in an RNA-dependent manner, but independent of the hypusine residue or the ribosome. Finally, small-angle X-ray scattering (SAXS) experiments confirmed that eIF5A behaves as a stable dimer in solution. Moreover, the molecular envelope determined from the SAXS data shows that the eIF5A dimer is L shaped and superimposable on the tRNA(Phe) tertiary structure, analogously to the EF-P monomer. PMID- 22945905 TI - A novel radiofluorinated agouti-related protein for tumor angiogenesis imaging. AB - A novel protein scaffold based on the cystine knot domain of the agouti-related protein (AgRP) has been used to engineer mutants that can bind to the alpha(v)beta(3) integrin receptor with high affinity and specificity. In the current study, an (18)F-labeled AgRP mutant (7C) was prepared and evaluated as a positron emission tomography (PET) probe for imaging tumor angiogenesis. AgRP-7C was synthesized by solid phase peptide synthesis and site-specifically conjugated with 4-nitrophenyl 2-(18/19)F-fluoropropionate ((18/19)F-NFP) to produce the fluorinated peptide, (18/19)F-FP-AgRP-7C. Competition binding assays were used to measure the relative affinities of AgRP-7C and (19)F-FP-AgRP-7C to human glioblastoma U87MG cells that overexpress alpha(v)beta(3) integrin. In addition, biodistribution, metabolic stability, and small animal PET imaging studies were conducted with (18)F-FP-AgRP-7C using U87MG tumor-bearing mice. Both AgRP-7C and (19)F-FP-AgRP-7C specifically competed with (125)I-echistatin for binding to U87MG cells with half maximal inhibitory concentration (IC(50)) values of 9.40 and 8.37 nM, respectively. Non-invasive small animal PET imaging revealed that (18)F-FP-AgRP-7C exhibited rapid and good tumor uptake (3.24 percentage injected dose per gram [% ID/g] at 0.5 h post injection [p.i.]). The probe was rapidly cleared from the blood and from most organs, resulting in excellent tumor-to normal tissue contrasts. Tumor uptake and rapid clearance were further confirmed with biodistribution studies. Furthermore, co-injection of (18)F-FP-AgRP-7C with a large molar excess of blocking peptide c(RGDyK) significantly inhibited tumor uptake in U87MG xenograft models, demonstrating the integrin-targeting specificity of the probe. Metabolite assays showed that the probe had high stability, making it suitable for in vivo applications. (18)F-FP-AgRP-7C exhibits promising in vivo properties such as rapid tumor targeting, good tumor uptake, and excellent tumor-to-normal tissue ratios, and warrants further investigation as a novel PET probe for imaging tumor angiogenesis. PMID- 22945907 TI - Learning about scale, measurement and community mobilisation: reflections on the implementation of the Avahan HIV/AIDS initiative in India. AB - Debates have raged in development for decades about the appropriateness of participatory approaches and the degree to which they can be managed, scaled and measured. The Avahan programme confronted these issues over the last 7 years and concludes that it is advantageous to manage scaled community mobilisation processes so that participation evolves and programming on the ground is shaped by what is learnt through implementation. The donor (Bill & Melinda Gates Foundation) and its partners determined a standard set of programme activities that were implemented programme-wide but evolved with input from communities on the ground. Difficulties faced in monitoring and measurement in Avahan may be characteristic of similar efforts to measure community mobilisation in a scaled programme, and ultimately these challenges informed methods that were useful. The approach the programme undertook for learning and changing, the activities it built into the HIV prevention programme, and its logic model and measurement tools, may be relevant in other public health settings seeking to integrate community mobilisation. PMID- 22945908 TI - Increasing the evidence base on the role of the community in response to HIV/AIDS. PMID- 22945906 TI - Peroxisome proliferator-activated receptor delta agonist attenuates nicotine suppression effect on human mesenchymal stem cell-derived osteogenesis and involves increased expression of heme oxygenase-1. AB - Smoking has long been associated with osteoporosis, decreased bone mineral density, increased risk of bone fracture, and increased health costs. Nicotine, the main component of cigarette smoke, has major negative effects on bone metabolism and skeletal remodeling in vivo. Although osteoblasts and osteoblast like cells have been used extensively to study the impact of nicotine, few studies have been performed on human mesenchymal stem cells (hMSCs). In this context, we examined the impact of nicotine on (a) hMSCs proliferation, (b) osteoblastic differentiation, (c) alkaline phosphatase (ALP) activity, and (d) expression of canonical genes during differentiation of hMSCs. MSCs isolated from human bone marrow were treated with different concentrations (0, 0.1, 1 and 10 MUM) of nicotine for 7 days. Nicotine caused a dose-dependent decrease in cell proliferation, decreased heme oxygenase-1 (HO-1) expression (p < 0.05) and attenuated osteogenesis (p < 0.05) in hMSCs (45 % reduction at day 14). In addition, nicotine caused a dose-dependent decrease in alizarin red staining for calcium and staining for ALP. Induction of HO-1 by peroxisome proliferator activated receptor delta agonist (GW0742) prevented the effect of nicotine. Nicotine caused a dose-dependent reduction in the expression of BMP-2, a well known marker for bone formation; however, this was prevented by GW0742 treatment. Therefore, induction of HO-1 prevents the deleterious effects of nicotine on osteogenesis in hMSC. This offers insight into both how nicotine affects bone remodeling and a therapeutic approach to prevent fracture and osteoporosis in smokers. PMID- 22945909 TI - Community mobilisation programme for female sex workers in coastal Andhra Pradesh, India: processes and their effects. AB - BACKGROUND: This paper describes the process of setting up community-based organisations (CBOs) of sex workers during the 5-year community mobilisation initiative of the Swagati project, an HIV prevention programme in nine coastal districts of Andhra Pradesh. METHOD: The Swagati project facilitated the formation of 11 CBOs through partnerships with local non-governmental organisations and meetings with groups of sex workers. Activities included peer led outreach, information campaigns, institution building through community committees and capacity building for organisational development. RESULTS: In 2010, a Community Ownership and Preparedness Index tool assessed the CBOs in terms of leadership, democratic governance, decision making and others qualities. All except two CBOs scored in the 'promising' category. One of these CBOs moved to promising stage by the year 2011 indicating good progress, considering how recently they were established. The Community Ownership and Preparedness Index assessments of organisational strengths showed wide variations among the CBOs, despite the essentially similar organisational steps taken by the Swagati programme. A Behavioural Tracking Survey (2010) of individual CBO members also showed district-level differences in sex workers' expressions of confidence in collective action, participation in organisational activities and other indicators. CONCLUSION: Mobilising marginalised populations such as sex workers to form CBOs is a complex process and can be affected by many influences, including the qualities of CBO leadership. Although the CBOs have not yet reached full 'maturity', they have made significant improvements in terms of collectivisation and its translation into collective action as reported by individual sex workers. PMID- 22945910 TI - In-vitro characteristics of cemented titanium femoral stems with a smooth surface finish. AB - BACKGROUND: In cemented total hip arthroplasty (THA), a polished tapered femoral stem with a design based on the taper-slip concept enables extremely reliable and durable fixation. In contrast, cemented femoral stems made from titanium alloys are not favored because of reports describing insufficient clinical outcomes. However, we have reported excellent clinical and radiological outcomes for cemented titanium stems made using the composite-beam concept. This study examines the characteristics of cemented titanium femoral stems with a smooth surface. METHODS: The bonding strength between titanium alloys with different surface finishes and bone cement was evaluated by use of push-out and detachment tests. Torsional stability tests were performed to evaluate the initiation and propagation of disruption of the fixation of cemented stems at the cement-implant interface. The wear resistance was investigated by use of wear-friction tests performed using a multidirectional pin-on-disc machine. The bone strain loaded on to the femoral cortex was measured by use of an implanted Sawbone and analyzed by use of the finite element method. RESULTS: The push-out and detachment tests revealed increasing cement adhesion strength with increasing degree of roughness of the metal surface. The torsional stability tests indicated that a load >1,000 N led to progressive debonding between the cement and the implant with a smooth surface finish. Interestingly, wear-friction tests revealed the wear rate for polished titanium surfaces was clearly higher than for smooth surfaces. In addition, the greater elasticity of titanium stems compared with cobalt-chromium stems transmitted the external load to the proximal side of the femur more effectively. CONCLUSIONS: The smooth surface finish of the stems is an important factor for the satisfactory clinical and radiological outcomes of cemented titanium femoral stems. The greater elasticity of a titanium stem effectively transmits the external load to the medial side of the femur. PMID- 22945911 TI - Adjacent segment disease following C3-C7 en block laminoplasty and long-term follow-up of surgical treatment by T1-T3 laminoplasty. PMID- 22945912 TI - Validity, reliability and responsiveness of the Japanese version of the Neck Disability Index. AB - BACKGROUND: The Neck Disability Index (NDI) is one of the most widely used questionnaires for neck pain. The purpose of this study was to validate the Japanese NDI. METHODS: We performed two surveys with an 8-week interval in 130 patients with neck pain, radiculopathy and myelopathy. We asked patients to answer two versions of the Japanese NDI: the original NDI, which had been completed by a forward-backward translation procedure, and the modified NDI, which has the phrase "because of neck pain" to the phase "because of neck pain or numbness in the arm." The other parameters examined were the strength of pain and numbness, the Japanese Orthopaedic Association Cervical Myelopathy Evaluation Questionnaire, the Hospital Anxiety and Depression Scale, and Short Form 36. Attending surgeons judged the symptom severity. Patients were asked to report the patient global impression of change (PGIC) at the second survey. The internal consistency, criterion-related and discriminative validity, and reliability were evaluated. RESULTS: The original NDI and the modified NDI were 26.9 +/- 17.1 and 29.9 +/- 15.5, respectively. The Cronbach alpha values of the original NDI and the modified NDI were 0.92 and 0.89, respectively. Both versions of the NDI had good to excellent correlative coefficients with the related domains. The modified NDI had a higher validity for numbness and mental health-related QOL. The symptom severity was significantly correlated with the modified NDI. The intraclass correlation coefficients of the two surveys of the modified and original NDI were comparable. The effect sizes of the modified and the original NDI were 0.64 and 0.55, respectively. Spearman's rho between the change of the NDI and the PGIC was 0.47 in the original NDI and 0.59 in the modified NDI. CONCLUSIONS: We demonstrated the validity, reliability and responsiveness of the Japanese NDI. The modified NDI was more strongly correlated with numbness and mental health related QOL. PMID- 22945913 TI - Patterns of antibiotic use in the community and challenges of antibiotic surveillance in a lower-middle-income country setting: a repeated cross-sectional study in Vellore, South India. AB - OBJECTIVES: There is considerable evidence linking antibiotic usage to bacterial resistance. Intervention strategies are needed to contain antibiotic use and thereby resistance. To plan appropriate strategies, it is imperative to undertake surveillance in the community to monitor antibiotic encounters and drivers of specific antibiotic misuse. Such surveillance is rarely in place in lower-middle income countries (LMICs). This study describes antibiotic patterns and challenges faced while developing such surveillance systems in an LMIC. PATIENTS AND METHODS: Surveillance of antibiotic encounters (prescriptions and dispensations) was carried out using a repeated cross-sectional design for 2 years in Vellore, south India. Every month, patients attending 30 health facilities (small hospitals, general practitioner clinics and pharmacy shops) were observed until 30 antibiotic encounters were attained in each. Antibiotic use was expressed as the percentage of encounters containing specific antibiotics and defined daily doses (DDDs)/100 patients. Bulk antibiotic sales data were also collected. RESULTS: Over 2 years, a total of 52,788 patients were observed and 21,600 antibiotic encounters (40.9%) were accrued. Fluoroquinolones and penicillins were widely used. Rural hospitals used co-trimoxazole more often and urban private hospitals used cephalosporins more often; 41.1% of antibiotic prescriptions were for respiratory infections. The main challenges in surveillance included issues regarding sampling, data collection, denominator calculation and sustainability. CONCLUSIONS: Patterns of antibiotic use varied across health facilities, suggesting that interventions should involve all types of health facilities. Although challenges were encountered, our study shows that it is possible to develop surveillance systems in LMICs and the data generated may be used to plan feasible interventions, assess impact and thereby contain resistance. PMID- 22945914 TI - Impact on hospital mortality of catheter removal and adequate antifungal therapy in Candida spp. bloodstream infections. AB - OBJECTIVES: We set out to identify the prognostic factors in adult patients with Candida spp. bloodstream infection, assessing the impact on in-hospital mortality of catheter removal and adequacy of antifungal therapy. METHODS: Patients with positive blood culture for Candida spp. and a central venous catheter in place at the time of candidaemia were included. Data collected included demographics, underlying diseases, severity of illness, clinical presentation, catheter withdrawal and adequacy of empirical therapy. RESULTS: We included 188 patients (mortality 36.7%). The mortality rate was 34.9% (23/66) in patients with early adequate antifungal treatment and 18.9% (7/37) in patients with early adequate antifungal therapy and catheter withdrawal in the first 48 h. The APACHE (Acute Physiology and Chronic Health Evaluation) II score on the day of candidaemia [adjusted hazard ratio (aHR) 1.12; 95% CI 1.06-1.17; P < 0.001] was associated with death whereas early adequate therapy (aHR 0.4; 95% CI 0.23-0.83; P = 0.012) and catheter withdrawal (aHR 0.34; 95% CI 0.16-0.70; P = 0.03) were protective factors. In primary candidaemia, mortality was 28% (14/50) in patients with adequate therapy and decreased to 17.7% (6/34) in patients with both interventions in the first 48 h. Catheter removal was a protective factor and adequacy of antifungal therapy in the first 48 h showed a strong tendency to protection against death (aHR 0.46; 95% CI 0.19-1.08; P = 0.07). In secondary non catheter-related candidaemia, only early adequate therapy was a protective factor for mortality. CONCLUSIONS: Delay in catheter withdrawal and in administration of adequate antifungal therapy was associated with increased mortality in candidaemic patients. Catheter management did not influence the prognosis of secondary non-catheter-related candidaemia. PMID- 22945915 TI - 3,4-dimethoxyphenyl bis-benzimidazole, a novel DNA topoisomerase inhibitor that preferentially targets Escherichia coli topoisomerase I. AB - OBJECTIVES: Antibiotic resistance in bacterial pathogens is a serious clinical problem. Novel targets are needed to combat increasing drug resistance in Escherichia coli. Our objective is to demonstrate that 2-(3,4-dimethoxyphenyl)-5 [5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2yl]-1H-benzimidazole (DMA) inhibits E. coli DNA topoisomerase I more strongly than human topoisomerase I. In addition, DMA is non-toxic to mammalian cells at antibiotic dosage level. METHODS: In the present study, we have established DMA as an antibacterial compound by determining MICs, post-antibiotic effects (PAEs) and MBCs for different standard as well as clinical strains of E. coli. We have described the differential catalytic inhibitory mechanism of bis-benzimidazole, DMA, for human and E. coli topoisomerase I and topoisomerase II by performing different assays, including relaxation assays, cleavage-religation assays, DNA unwinding assays, ethidium bromide displacement assays, decatenation assays and DNA gyrase supercoiling assays. RESULTS: DMA significantly inhibited bacterial growth at a very low concentration, but did not affect human cell viability at higher concentrations. Activity assays showed that it preferentially targeted E. coli topoisomerase I over human topoisomerase I, topoisomerase II and gyrase. Cleavage religation assays confirmed DMA as a poison inhibitor of E. coli topoisomerase I. This study illuminates new properties of DMA, which may be further modified to develop an efficient topoisomerase inhibitor that is selective towards bacterial topoisomerase I. CONCLUSIONS: This is the first report of a bis-benzimidazole acting as an E. coli topoisomerase I inhibitor. DMA is a safe, non-cytotoxic molecule to human cells at concentrations that are needed for antibacterial activity. PMID- 22945916 TI - Outbreak of OXA-48 carbapenemase-producing Klebsiella pneumoniae in Greece involving an ST11 clone. AB - OBJECTIVES: First detected in Enterobacteriaceae isolates in Turkey, the OXA-48 carbapenemase has gradually disseminated in the wider Mediterranean area and Europe. Despite reports from other European regions, until now no such isolates have been detected in Greece. We describe the characteristics of the first outbreak caused by OXA-48-producing Klebsiella pneumoniae in Greece. METHODS: From December 2011 to March 2012, 13 ertapenem-resistant K. pneumoniae isolates, which were positive by the modified Hodge test while remaining negative by phenotypic screening for metallo-beta-lactamase (MBL) and KPC production, were recovered from nine patients. Patient records were retrieved to access patterns of acquisition. Resistance genes were identified by PCR and sequencing. ompK35, ompK36 and the genetic environment of the bla(OXA-48) gene were investigated. Plasmid profiling, conjugation experiments, PFGE and multilocus sequence typing (MLST) were performed. RESULTS: All isolates harboured the bla(OXA-48) gene along with the bla(CTX-M-15) and bla(OXA-1) genes. The bla(OXA-48) gene was located on a self-transferable IncL/M-type plasmid of ~62 kb, which harboured no other resistance genes. IS1999 was located upstream of the bla(OXA-48) gene. Genetic disruptions of the ompK35 and ompK36 genes were not detected. The isolates belonged to a unique PFGE clone and MLST assigned them to sequence type ST11. All cases were characterized as hospital acquired and none of them was linked to immigration or history of travel in endemic areas. CONCLUSIONS: Carbapenem resistance due to MBL and KPC carbapenemases is currently on an endemic scale in Greece and this report highlights the wider undetected dissemination of yet another carbapenemase in this region. PMID- 22945917 TI - Activity of carbapenems with ME1071 (disodium 2,3-diethylmaleate) against Enterobacteriaceae and Acinetobacter spp. with carbapenemases, including NDM enzymes. AB - OBJECTIVES: ME1071 is a maleic acid that inhibits metallo-beta-lactamases (MBLs). We examined its ability to potentiate different carbapenems against MBL-producing Enterobacteriaceae in relation to its inhibition kinetics. METHODS: Enterobacteriaceae and Acinetobacter isolates with IMP, VIM and NDM MBLs were tested; bacteria with other types of carbapenem resistance were used as controls. Chequerboard titrations were performed by CLSI agar dilution, carbapenemases were cloned into pET-28a(+) and purified by column chromatography, and kinetic parameters were determined by spectrophotometry. RESULTS: The key findings were: (i) the MICs of carbapenems varied widely among isolates with the same carbapenemase, but those with the NDM types were generally the most resistant; (ii) biapenem was the carbapenem least compromised by all MBL types, owing to weaker kinetic efficiency (k(cat)/K(m)) for hydrolysis, contingent on lower affinity (higher K(m)); (iii) MBLs were the only carbapenemases inhibited by ME1071, confirming its specificity of action; and (iv) irrespective of the partner carbapenem, synergy with ME1071 was least for organisms with NDM MBLs and most for those with IMP types, correlating with ME1071 having weakest affinity (highest K(i)) for NDM-1 and strongest affinity for IMP-1. CONCLUSIONS: ME1071 reduced the MICs of carbapenems for bacteria with NDM-1 enzyme though synergy was weaker than for bacteria with IMP and VIM metallo-enzymes; this correlated with ME1071 having weaker affinity for NDM-1 than IMP-1 and VIM-2. As the weakest MBL substrate carbapenem, biapenem was the easiest to protect. PMID- 22945918 TI - In vitro and structural evaluation of PL-100 as a potential second-generation HIV 1 protease inhibitor. AB - OBJECTIVES: HIV-1 protease inhibitors (PIs) are key components of HIV therapy. PL 100 is a novel lysine sulphonamide that demonstrates potent antiviral activity against multiresistant HIV-1 strains as well as a higher genetic barrier for development of resistance mutations compared with first-generation PIs. In the present study, we compared the antiviral activity of PL-100 against HIV-1 subtype B with that of darunavir. METHODS: We used tissue culture experiments to evaluate the in vitro development of resistance to PL-100 and tested the antiviral activity of several clinically approved PIs against PL-100-selected resistant variants. Structural modelling was also used to compare the binding of PL-100 and darunavir to the HIV-1 protease (PR) enzyme. RESULTS: PL-100-resistant variants that emerged within 8-48 weeks showed low- to high-level resistance (3.5- to 21.6 fold) to PL-100, but commonly retained susceptibility to darunavir, which, in contrast, did not select for resistance mutations over a period of 40 weeks. Structural modelling demonstrated that binding of PL-100 was predominantly based on polar interactions and delocalized hydrophobic interactions through its diphenyl groups, while darunavir has numerous interactions with PR that include hydrogen bonding to PR backbone oxygens at amino acid positions A28, D29 and D30 via di-tetrahydrofuran (di-THF) groups. CONCLUSIONS: Hydrogen-bonding contacts and the di-THF group in darunavir, as well as the hydrophobic nature of PL-100, contribute to PI binding and a high genetic barrier for resistance. Redesigning the structure of PL-100 to include a di-THF group might improve it. PMID- 22945919 TI - Disruption of SIRPalpha signaling in macrophages eliminates human acute myeloid leukemia stem cells in xenografts. AB - Although tumor surveillance by T and B lymphocytes is well studied, the role of innate immune cells, in particular macrophages, is less clear. Moreover, the existence of subclonal genetic and functional diversity in some human cancers such as leukemia underscores the importance of defining tumor surveillance mechanisms that effectively target the disease-sustaining cancer stem cells in addition to bulk cells. In this study, we report that leukemia stem cell function in xenotransplant models of acute myeloid leukemia (AML) depends on SIRPalpha mediated inhibition of macrophages through engagement with its ligand CD47. We generated mice expressing SIRPalpha variants with differential ability to bind human CD47 and demonstrated that macrophage-mediated phagocytosis and clearance of AML stem cells depend on absent SIRPalpha signaling. We obtained independent confirmation of the genetic restriction observed in our mouse models by using SIRPalpha-Fc fusion protein to disrupt SIRPalpha-CD47 engagement. Treatment with SIRPalpha-Fc enhanced phagocytosis of AML cells by both mouse and human macrophages and impaired leukemic engraftment in mice. Importantly, SIRPalpha-Fc treatment did not significantly enhance phagocytosis of normal hematopoietic targets. These findings support the development of therapeutics that antagonize SIRPalpha signaling to enhance macrophage-mediated elimination of AML. PMID- 22945920 TI - TRAF-interacting protein (TRIP) negatively regulates IFN-beta production and antiviral response by promoting proteasomal degradation of TANK-binding kinase 1. AB - TANK-binding kinase 1 (TBK1) plays an essential role in Toll-like receptor (TLR)- and retinoic acid-inducible gene I (RIG-I)-mediated induction of type I interferon (IFN; IFN-alpha/beta) and host antiviral responses. How TBK1 activity is negatively regulated remains largely unknown. We report that TNF receptor associated factor (TRAF)-interacting protein (TRIP) promotes proteasomal degradation of TBK1 and inhibits TLR3/4- and RIG-I-induced IFN-beta signaling. TRIP knockdown resulted in augmented activation of IFN regulatory factor 3 (IRF3) and enhanced expression of IFN-beta in TLR3/4- and RIG-I-activated primary peritoneal macrophages, whereas overexpression of TRIP had opposite effects. Consistently, TRIP impaired Sendai virus (SeV) infection-induced IRF3 activation and IFN-beta production and promoted vesicular stomatitis virus (VSV) replication. As an E3 ubiquitin ligase, TRIP negatively regulated the cellular levels of TBK1 by directly binding to and promoting K48-linked polyubiquitination of TBK1. Therefore, we identified TRIP as a negative regulator in TLR3/4- and RIG I-triggered antiviral responses and suggested TRIP as a potential target for the intervention of diseases with uncontrolled IFN-beta production. PMID- 22945922 TI - The price of a drink: the potential of alcohol minimum unit pricing as a public health measure in the UK. AB - The UK has seen a dramatic increase in alcohol consumption and alcohol-related harm over the past 30 years. Alcohol taxation has long been considered a key method of controlling alcohol-related harm but a combination of factors has recently led to consideration of methods which affect the price of the cheapest alcohol as a means of improved targeting of alcohol control measures to curb the consumption of the heaviest drinkers. Although much of the evidence in favour of setting a minimum price of a unit of alcohol is based on complex econometric models rather than empirical data, all jurisdictions within the UK now intend to make selling alcohol below a set price illegal, which will provide a naturalistic experiment allowing assessment of the impact of minimum pricing. PMID- 22945921 TI - Reduced TCR signaling potential impairs negative selection but does not result in autoimmune disease. AB - Negative selection and regulatory T (T reg) cell development are two thymus dependent processes necessary for the enforcement of self-tolerance, and both require high-affinity interactions between the T cell receptor (TCR) and self ligands. However, it remains unclear if they are similarly impacted by alterations in TCR signaling potential. We generated a knock-in allele (6F) of the TCR zeta chain gene encoding a mutant protein lacking signaling capability whose expression is controlled by endogenous zeta regulatory sequences. Although negative selection was defective in 6F/6F mice, leading to the survival of autoreactive T cells, 6F/6F mice did not develop autoimmune disease. We found that 6F/6F mice generated increased numbers of thymus-derived T reg cells. We show that attenuation of TCR signaling potential selectively impacts downstream signaling responses and that this differential effect favors Foxp3 expression and T reg cell lineage commitment. These results identify a potential compensatory pathway for the enforcement of immune tolerance in response to defective negative selection caused by reduced TCR signaling capability. PMID- 22945923 TI - Long-term consequences of mild traumatic brain injury. AB - A debate has ensued about the long-term consequences of mild traumatic brain injury, the 'signature injury' of the Iraq and Afghanistan Wars. Most epidemiological studies have found that mild traumatic brain injury is unrelated to unspecific post-concussion symptoms based on self-reported symptoms. A longitudinal study, in this issue of the Journal, using objective tests has demonstrated that mild traumatic brain injury has limited lasting neuropsychological consequences. PMID- 22945924 TI - The role of the high-risk approach in suicide prevention. AB - Evidence favours the population approach over high-risk approaches to suicide prevention, but methodological problems may have obscured the contribution of the latter. This editorial uses the findings of a recent evaluation of a high-risk approach used in England to consider the role of high-risk interventions in national suicide prevention strategies. PMID- 22945925 TI - Where are the hypotheses when you need them? AB - Poor staff morale is a pressing problem in UK mental health services, especially for acute in-patient wards, community mental health teams and social workers. Instead of interpreting low morale using a demand-control-support model, it is suggested here that simply being honest about what should be expected of staff and stopping constant criticism and reorganisation might be more fruitful. PMID- 22945926 TI - Effect of exercise on depression severity in older people: systematic review and meta-analysis of randomised controlled trials. AB - BACKGROUND: The prevalence of depression in older people is high, treatment is inadequate, it creates a substantial burden and is a public health priority for which exercise has been proposed as a therapeutic strategy. AIMS: To estimate the effect of exercise on depressive symptoms among older people, and assess whether treatment effect varies depending on the depression criteria used to determine participant eligibility. METHOD: Systematic review and meta-analysis of randomised controlled trials of exercise for depression in older people. RESULTS: Nine trials met the inclusion criteria and seven were meta-analysed. Exercise was associated with significantly lower depression severity (standardised mean difference (SMD) = -0.34, 95% CI -0.52 to -0.17), irrespective of whether participant eligibility was determined by clinical diagnosis (SMD = -0.38, 95% CI -0.67 to -0.10) or symptom checklist (SMD = -0.34, 95% CI -0.62 to -0.06). Results remained significant in sensitivity analyses. CONCLUSIONS: Our findings suggest that, for older people who present with clinically meaningful symptoms of depression, prescribing structured exercise tailored to individual ability will reduce depression severity. PMID- 22945927 TI - Extrapyramidal side-effects and antipsychotics: are second-generation agents still indicated? PMID- 22945928 TI - Epidemiological challenges in systematic reviews. PMID- 22945929 TI - Gluteal muscle activity and patellofemoral pain syndrome: a systematic review. AB - OBJECTIVE: There is growing evidence to support the association of gluteal muscle strength deficits in individuals with patellofemoral pain syndrome (PFPS) and the effectiveness of gluteal strengthening when treating PFPS. In additiona, an impressive body of work evaluating gluteal electromyography (EMG) has recently emerged, further supporting the importance of gluteal muscle function in PFPS. This systematic review synthesises these EMG findings in order to better understand the role of gluteal muscle activity in the aetiology, presentation and management of PFPS. METHODS: MEDLINE, EMBASE, CINAHL, Web of Knowledge and Google Scholar databases were searched in September 2011 for prospective and case control studies evaluating the association of gluteal EMG with PFPS. Two independent reviewers assessed each paper for inclusion and quality. Means and SDs were extracted from each included study to allow effect size calculations and comparison of results. RESULTS: Ten case-control, but no prospective studies were identified. Moderate-to-strong evidence indicates gluteus medius (GMed) activity is delayed and of shorter duration during stair negotiation in PFPS sufferers. In addition, limited evidence indicates GMed activity is delayed and of shorter duration during running, and gluteus maximus (GMax) activity is increased during stair descent. CONCLUSIONS: Delayed and shorter duration of GMed EMG may indicate impaired ability to control frontal and transverse plane hip motion. Further research evaluating the value of gluteal muscle activity screening in identifying individuals most likely to develop PFPS, and the effectiveness of interventions targeting changes to gluteal muscle activation patterns is needed. PMID- 22945930 TI - Tannishtha Reya: classic pathways, new views on cancer. Interview by Caitlin Sedwick. PMID- 22945931 TI - Stuck in the middle: Rac, adhesion, and cytokinesis. AB - Rho family small GTPases (Rac, RhoA, and Cdc42) function at the core of cytokinesis, the physical division of one cell into two. In this issue, Bastos et al. (2012. J. Cell Biol. http://dx.doi.org/10.1083/jcb.201204107) identify a new role for Rac inhibition: to release cell adhesion at the division plane and allow efficient constriction of the contractile ring. They show that the GTPase activating protein, CYK4, suppresses equatorial cell substrate adhesion by inhibiting Rac and therefore its effectors ARFGEF7 and PAK1/2. PMID- 22945932 TI - Neutrophil extracellular traps: is immunity the second function of chromatin? AB - Neutrophil extracellular traps (NETs) are made of processed chromatin bound to granular and selected cytoplasmic proteins. NETs are released by white blood cells called neutrophils, maybe as a last resort, to control microbial infections. This release of chromatin is the result of a unique form of cell death, dubbed "NETosis." Here we review our understanding of how NETs are made, their function in infections and as danger signals, and their emerging importance in autoimmunity and coagulation. PMID- 22945933 TI - Six1 regulates stem cell repair potential and self-renewal during skeletal muscle regeneration. AB - Satellite cells (SCs) are stem cells that mediate skeletal muscle growth and regeneration. Here, we observe that adult quiescent SCs and their activated descendants expressed the homeodomain transcription factor Six1. Genetic disruption of Six1 specifically in adult SCs impaired myogenic cell differentiation, impaired myofiber repair during regeneration, and perturbed homeostasis of the stem cell niche, as indicated by an increase in SC self renewal. Six1 regulated the expression of the myogenic regulatory factors MyoD and Myogenin, but not Myf5, which suggests that Six1 acts on divergent genetic networks in the embryo and in the adult. Moreover, we demonstrate that Six1 regulates the extracellular signal-regulated kinase 1/2 (ERK1/2) pathway during regeneration via direct control of Dusp6 transcription. Muscles lacking Dusp6 were able to regenerate properly but showed a marked increase in SC number after regeneration. We conclude that Six1 homeoproteins act as a rheostat system to ensure proper regeneration of the tissue and replenishment of the stem cell pool during the events that follow skeletal muscle trauma. PMID- 22945934 TI - Human chromokinesins promote chromosome congression and spindle microtubule dynamics during mitosis. AB - Chromokinesins are microtubule plus end-directed motor proteins that bind to chromosome arms. In Xenopus egg cell-free extracts, Xkid and Xklp1 are essential for bipolar spindle formation but the functions of the human homologues, hKID (KIF22) and KIF4A, are poorly understood. By using RNAi-mediated protein knockdown in human cells, we find that only co-depletion delayed progression through mitosis in a Mad2-dependent manner. Depletion of hKID caused abnormal chromosome arm orientation, delayed chromosome congression, and sensitized cells to nocodazole. Knockdown of KIF4A increased the number and length of microtubules, altered kinetochore oscillations, and decreased kinetochore microtubule flux. These changes were associated with failures in establishing a tight metaphase plate and an increase in anaphase lagging chromosomes. Co depletion of both chromokinesins aggravated chromosome attachment failures, which led to mitotic arrest. Thus, hKID and KIF4A contribute independently to the rapid and correct attachment of chromosomes by controlling the positioning of chromosome arms and the dynamics of microtubules, respectively. PMID- 22945935 TI - CYK4 inhibits Rac1-dependent PAK1 and ARHGEF7 effector pathways during cytokinesis. AB - In mitosis, animal cells lose their adhesion to the surrounding surfaces and become rounded. During mitotic exit, they reestablish these adhesions and at the same time physically contract and divide. How these competing processes are spatially segregated at the cell cortex remains mysterious. To address this question, we define the specific effector pathways used by RhoA and Rac1 in mitotic cells. We demonstrate that the MKlp1-CYK4 centralspindlin complex is a guanosine triphosphatase-activating protein (GAP) for Rac1 and not RhoA and that CYK4 negatively regulated Rac1 activity at the cell equator in anaphase. Cells expressing a CYK4 GAP mutant had defects in cytokinesis and showed elevated staining for the cell adhesion marker vinculin. These defects could be rescued by depletion of ARHGEF7 and p21-activated kinase, Rac1-specific effector proteins required for cell adhesion. Based on these findings, we propose that CYK4 GAP activity is required during anaphase to inhibit Rac1-dependent effector pathways associated with control of cell spreading and adhesion. PMID- 22945936 TI - Polarity and asymmetry in the arrangement of dynein and related structures in the Chlamydomonas axoneme. AB - Understanding the molecular architecture of the flagellum is crucial to elucidate the bending mechanism produced by this complex organelle. The current known structure of the flagellum has not yet been fully correlated with the complex composition and localization of flagellar components. Using cryoelectron tomography and subtomogram averaging while distinguishing each one of the nine outer doublet microtubules, we systematically collected and reconstructed the three-dimensional structures in different regions of the Chlamydomonas flagellum. We visualized the radial and longitudinal differences in the flagellum. One doublet showed a distinct structure, whereas the other eight were similar but not identical to each other. In the proximal region, some dyneins were missing or replaced by minor dyneins, and outer-inner arm dynein links were variable among different microtubule doublets. These findings shed light on the intricate organization of Chlamydomonas flagella, provide clues to the mechanism that produces asymmetric flagellar beating, and pose a new challenge for the functional study of the flagella. PMID- 22945938 TI - Phylogeny and photosynthetic pathway distribution in Anticharis Endl. (Scrophulariaceae). AB - C(4) photosynthesis independently evolved >62 times, with the majority of origins within 16 dicot families. One origin occurs in the poorly studied genus Anticharis Endl. (Scrophulariaceae), which consists of ~10 species from arid regions of Africa and southwest Asia. Here, the photosynthetic pathway of 10 Anticharis species and one species from each of the sister genera Aptosimum and Peliostomum was identified using carbon isotope ratios (delta(13)C). The photosynthetic pathway was then mapped onto an internal transcribed spacer (ITS) phylogeny of Anticharis and its sister genera. Leaf anatomy was examined for nine Anticharis species and plants from Aptosimum and Peliostomum. Leaf ultrastructure, gas exchange, and enzyme distributions were assessed in Anticharis glandulosa collected in SE Iran. The results demonstrate that C(3) photosynthesis is the ancestral condition, with C(4) photosynthesis occurring in one clade containing four species. C(4) Anticharis species exhibit the atriplicoid type of C(4) leaf anatomy and the NAD-malic enzyme biochemical subtype. Six Anticharis species had C(3) or C(3)-C(4) delta(13)C values and branched at phylogenetic nodes that were sister to the C(4) clade. The rest of Anticharis species had enlarged bundle sheath cells, close vein spacing, and clusters of chloroplasts along the centripetal (inner) bundle sheath walls. These traits indicate that basal-branching Anticharis species are evolutionary intermediates between the C(3) and C(4) conditions. Anticharis appears to be an important new group in which to study the dynamics of C(4) evolution. PMID- 22945937 TI - Nodal signaling regulates endodermal cell motility and actin dynamics via Rac1 and Prex1. AB - Embryo morphogenesis is driven by dynamic cell behaviors, including migration, that are coordinated with fate specification and differentiation, but how such coordination is achieved remains poorly understood. During zebrafish gastrulation, endodermal cells sequentially exhibit first random, nonpersistent migration followed by oriented, persistent migration and finally collective migration. Using a novel transgenic line that labels the endodermal actin cytoskeleton, we found that these stage-dependent changes in migratory behavior correlated with changes in actin dynamics. The dynamic actin and random motility exhibited during early gastrulation were dependent on both Nodal and Rac1 signaling. We further identified the Rac-specific guanine nucleotide exchange factor Prex1 as a Nodal target and showed that it mediated Nodal-dependent random motility. Reducing Rac1 activity in endodermal cells caused them to bypass the random migration phase and aberrantly contribute to mesodermal tissues. Together, our results reveal a novel role for Nodal signaling in regulating actin dynamics and migration behavior, which are crucial for endodermal morphogenesis and cell fate decisions. PMID- 22945939 TI - Ethylene independent induction of lycopene biosynthesis in tomato fruits by jasmonates. AB - One of the main characteristics of tomato (Solanum lycopersicum) fruit ripening is a massive accumulation of carotenoids (mainly lycopene), which may contribute to the nutrient quality of tomato fruit and its role in chemoprevention. Previous studies have shown that ethylene (ET) plays a central role in promoting fruit ripening. In this study, the role of jasmonic acid (JA) in controlling lycopene accumulation in tomato fruits was analysed by measuring fruit lycopene content and the expression levels of lycopene biosynthetic genes in JA-deficient mutants (spr2 and def1) and a 35S::prosystemin transgenic line (35S::prosys) with increased JA levels and constitutive JA signalling. The lycopene content was significantly decreased in the fruits of spr2 and def1, but was enhanced in 35S::prosys fruits. Simultaneously, the expression of lycopene biosynthetic genes followed a similar trend. Lycopene synthesis in methyl jasmonate (MeJA) vapour treated fruits showed an inverted U-shaped dose response, which significantly enhanced the fruit lycopene content and restored lycopene accumulation in spr2 and def1 at a concentration of 0.5 uM. The results indicated that JA plays a positive role in lycopene biosynthesis. In addition, the role of ET in JA-induced lycopene accumulation was also examined. Ethylene production in tomato fruits was depressed in spr2 and def1 while it increased in 35S::prosys. However, the exogenous application of MeJA to Never ripe (Nr), the ET-insensitive mutant, significantly promoted lycopene accumulation, as well as the expression of lycopene biosynthetic genes. Based on these results, it is proposed that JA might function independently of ethylene to promote lycopene biosynthesis in tomato fruits. PMID- 22945940 TI - Atypical iron storage in marine brown algae: a multidisciplinary study of iron transport and storage in Ectocarpus siliculosus. AB - Iron is an essential element for all living organisms due to its ubiquitous role in redox and other enzymes, especially in the context of respiration and photosynthesis. The iron uptake and storage systems of terrestrial/higher plants are now reasonably well understood, with two basic strategies for iron uptake being distinguished: strategy I plants use a mechanism involving induction of Fe(III)-chelate reductase (ferrireductase) and Fe(II) transporter proteins, while strategy II plants utilize high-affinity, iron-specific, binding compounds called phytosiderophores. In contrast, little is known about the corresponding systems in marine, plant-like lineages, particularly those of multicellular algae (seaweeds). Herein the first study of the iron uptake and storage mechanisms in the brown alga Ectocarpus siliculosus is reported. Genomic data suggest that Ectocarpus may use a strategy I approach. Short-term radio-iron uptake studies verified that iron is taken up by Ectocarpus in a time- and concentration dependent manner consistent with an active transport process. Upon long-term exposure to (57)Fe, two metabolites have been identified using a combination of Mossbauer and X-ray absorption spectroscopies. These include an iron-sulphur cluster accounting for ~26% of the total intracellular iron pool and a second component with spectra typical of a polymeric (Fe(3+)O(6)) system with parameters similar to the amorphous phosphorus-rich mineral core of bacterial and plant ferritins. This iron metabolite accounts for ~74% of the cellular iron pool and suggests that Ectocarpus contains a non-ferritin but mineral-based iron storage pool. PMID- 22945941 TI - Metabolomics reveals simultaneous influences of plant defence system and fungal growth in Botrytis cinerea-infected Vitis vinifera cv. Chardonnay berries. AB - Botrytis cinerea is a fungal plant pathogen of grape berries, leading to economic and quality losses in wine production. The global metabolite changes induced by B. cinerea infection in grape have not been established to date, even though B. cinerea infection is known to cause significant changes in chemicals or metabolites. In order to better understand metabolic mechanisms linked to the infection process and to identify the metabolites associated with B. cinerea infection, (1)H NMR spectroscopy was used in global metabolite profiling and multivariate statistical analysis of berries from healthy and botrytized bunches. Pattern recognition methods, such as principal component analysis, revealed clear metabolic discriminations between healthy and botrytized berries of botrytized bunches and healthy berries of healthy bunches. Significantly high levels of proline, glutamate, arginine, and alanine, which are accumulated upon plant stress, were found in healthy and botrytized berries of botrytized bunches. Moreover, largely degraded phenylpropanoids, flavonoid compounds, and sucrose together with markedly produced glycerol, gluconic acid, and succinate, all being directly associated with B. cinerea growth, were only found in botrytized berries of botrytized bunches. This study reports that B. cinerea infection causes significant metabolic changes in grape berry and highlights that both the metabolic perturbations associated with the plant defence system and those directly derived from fungal pathogen growth should be considered to better understand the interaction between metabolic variation and biotic pathogen stress in plants. PMID- 22945942 TI - The characterization of transgenic tomato overexpressing gibberellin 20-oxidase reveals induction of parthenocarpic fruit growth, higher yield, and alteration of the gibberellin biosynthetic pathway. AB - Fruit-set and growth in tomato depend on the action of gibberellins (GAs). To evaluate the role of the GA biosynthetic enzyme GA 20-oxidase (GA20ox) in that process, the citrus gene CcGA20ox1 was overexpressed in tomato (Solanum lycopersicum L.) cv Micro-Tom. The transformed plants were taller, had non serrated leaves, and some flowers displayed a protruding stigma due to a longer style, thus preventing self-pollination, similar to GA(3)-treated plants. Flowering was delayed compared with wild-type (WT) plants. Both yield and number of fruits per plant, some of them seedless, were higher in the transgenic plants. The Brix index value of fruit juice was also higher due to elevated citric acid content, but not glucose or fructose content. When emasculated, 14-30% of ovaries from transgenic flowers developed parthenocarpically, whereas no parthenocarpy was found in emasculated WT flowers. The presence of early-13-hydroxylation and non-13-hydroxylation GA pathways was demonstrated in the shoot and fruit of Micro Tom, as well as in two tall tomato cultivars (Ailsa Craig and UC-82). The transgenic plants had altered GA profiles containing higher concentrations of GA(4), from the non-13-hydroxylation pathway, which is generally a minor active GA in tomato. The effect of GA(4) application in enhancing stem growth and parthenocarpic fruit development was proportional to dose, with the same activity as GA(1). The results support the contention that GA20ox overexpression diverts GA metabolism from the early-13-hydroxylation pathway to the non-13-hydroxylation pathway. This led to enhanced GA(4) synthesis and higher yield, although the increase in GA(4) content in the ovary was not sufficient to induce full parthenocarpy. PMID- 22945945 TI - GenScalpel: an application for sequence retrieval and extraction from the GenBank flatfile. AB - GenScalpel is a program designed for the retrieval and extraction of specified sequences from large-scale sequence sets in NCBI GenBank flatfile format. This routine task in bioinformatics analysis is a pressing need for laboratory biologists. Another objective of application development is to respond to the new form of the NCBI Nucleotide Sequence Database, which was updated in November 2011. In addition to a powerful sequence refinement application, GenScalpel provides convenient functions for web-based sequence downloading or multiple files batch processing. This note discusses major applications of the program and includes example data sets to demonstrate its performance. The program is written in PERL. GenScalpel, including installation packages for Windows and Linux systems as well as the accompanying documentation, are available free of charge at http://genscalpel.biosv.com/. PMID- 22945943 TI - PPR8522 encodes a chloroplast-targeted pentatricopeptide repeat protein necessary for maize embryogenesis and vegetative development. AB - The pentatricopeptide repeat (PPR) domain is an RNA binding domain allowing members of the PPR superfamily to participate in post-transcriptional processing of organellar RNA. Loss of PPR8522 from maize (Zea mays) confers an embryo specific (emb) phenotype. The emb8522 mutation was isolated in an active Mutator (Mu) population and co-segregation analysis revealed that it was tightly linked to a MuDR insertion in the first exon of PPR8522. Independent evidence that disruption of PPR8522 caused the emb phenotype was provided by fine mapping to a region of 116kb containing no other gene than PPR8522 and complementation of the emb8522 mutant by a PPR8522 cDNA. The deduced PPR8522 amino acid sequence of 832 amino acids contains 10 PPR repeats and a chloroplast target peptide, the function of which was experimentally demonstrated by transient expression in Nicotiana benthamiana. Whereas mutant endosperm is apparently normal, mutant embryos deviate from normal development as early as 3 days after pollination, are reduced in size, exhibit more or less severe morphological aberrations depending on the genetic background, and generally do not germinate. The emb8522 mutation is the first to associate the loss of a PPR gene with an embryo-lethal phenotype in maize. Analyses of mutant plantlets generated by embryo-rescue experiments indicate that emb8522 also affects vegetative plant growth and chloroplast development. The loss of chloroplast transcription dependent on plastid-encoded RNA polymerase is the likely cause for the lack of an organized thylakoid network and an albino, seedling-lethal phenotype. PMID- 22945944 TI - Down-regulation of the IbEXP1 gene enhanced storage root development in sweetpotato. AB - The role of an expansin gene (IbEXP1) in the formation of the storage root (SR) was investigated by expression pattern analysis and characterization of IbEXP1 antisense sweetpotato (Ipomoea batatas cv. Yulmi) plants in an attempt to elucidate the molecular mechanism underlying SR development in sweetpotato. The transcript level of IbEXP1 was high in the fibrous root (FR) and petiole at the FR stage, but decreased significantly at the young storage root (YSR) stage. IbEXP1-antisense plants cultured in vitro produced FRs which were both thicker and shorter than those of wild-type (WT) plants. Elongation growth of the epidermal cells was significantly reduced, and metaxylem and cambium cell proliferation was markedly enhanced in the FRs of IbEXP1-antisense plants, resulting in an earlier thickening growth in these plants relative to WT plants. There was a marked reduction in the lignification of the central stele of the FRs of the IbEXP1-antisense plants, suggesting that the FRs of the mutant plants possessed a higher potential than those of WT plants to develop into SRs. IbEXP1 antisense plants cultured in soil produced a larger number of SRs and, consequently, total SR weight per IbEXP1-antisense plant was greater than that per WT plant. These results demonstrate that SR development was accelerated in IbEXP1-antisense plants and suggest that IbEXP1 plays a negative role in the formation of SR by suppressing the proliferation of metaxylem and cambium cells to inhibit the initial thickening growth of SRs. IbEXP1 is the first sweetpotato gene whose role in SR development has been directly identified in soil-grown transgenic sweetpotato plants. PMID- 22945946 TI - Phylogeography reveals routes of colonization of the bark beetle Dendroctonus approximatus Dietz in Mexico. AB - We used mitochondrial DNA (mtDNA) sequence data and allele frequencies at eight microsatellite loci to examine the population genetic structure, estimate the divergence times of distinct lineages, and infer patterns associated with host colonization in populations of the bark beetle Dendroctonus approximatus in Mexico. Two haplotype groups were identified using mtDNA sequences in 71 individuals from 15 populations. The first group was distributed in the Sierra Madre Occidental (SMOc, Western Mexico), with some populations in the Faja Volcanica Transmexicana (Central Mexico), and the second was found in the Sierra Madre Oriental (SMOr, Eastern Mexico), with populations in the Sierra Madre del Sur (Southern Mexico). The estimated split between groups occurred in the late Pleistocene, around 0.195 Mya. Microsatellite allele frequencies revealed high genetic differentiation between pairwise populations, and genetic differentiation values indicated a genetic structure of isolation by distance. Both mtDNA sequence data and microsatellite allele frequencies indicated that D. approximatus had two independent colonization routes in Mexico, one through the SMOc and another along the SMOr. The widespread geographic distribution of D. approximatus in Mexico follows a model of population range expansion of two haplotype groups in which gene flow is restricted by the geographic separation between hosts imposed by physical barriers between populations. PMID- 22945947 TI - Variable changes in genome size associated with different polyploid events in Plantago (Plantaginaceae). AB - The genus Plantago (Plantaginaceae) in New Zealand comprises species that can be difficult to delimit and contains a wide range of ploidy levels from diploid to 16-ploid. To investigate whether there have been changes in genome size associated with polyploid events and whether pollen and guard cell size can be used as an initial guide to identify polyploids, we have used flow cytometry with propidium iodide as the stain to measure the genome size (DNA C-value) in a range of Plantago species with different ploidy levels. Light microscopy was used to measure pollen diameter and guard cell length in these plants to see whether these could be used for ploidy level identification. Large differences in C-value were observed between species but the extent of changes associated with different polyploid events was highly variable. Pollen diameter was correlated with C-value but not necessarily with ploidy level. Guard cell lengths were different between diploids and polyploids but not between the different polyploid species. The significance of the changes in genome size and its relationship to pollen and stomatal guard cell size is discussed. PMID- 22945949 TI - Constrictive pericarditis. PMID- 22945948 TI - Identification of retinol binding protein 1 promoter hypermethylation in isocitrate dehydrogenase 1 and 2 mutant gliomas. AB - BACKGROUND: Mutations in isocitrate dehydrogenase 1 (IDH1) and associated CpG island hypermethylation represent early events in the development of low-grade gliomas and secondary glioblastomas. To identify candidate tumor suppressor genes whose promoter methylation may contribute to gliomagenesis, we compared methylation profiles of IDH1 mutant (MUT) and IDH1 wild-type (WT) tumors using massively parallel reduced representation bisulfite sequencing. METHODS: Reduced representation bisulfite sequencing was performed on ten pathologically matched WT and MUT glioma samples and compared with data from a methylation-sensitive restriction enzyme technique and data from The Cancer Genome Atlas (TCGA). Methylation in the gene retinol-binding protein 1 (RBP1) was identified in IDH1 mutant tumors and further analyzed with primer-based bisulfite sequencing. Correlation between IDH1/IDH2 mutation status and RBP1 methylation was evaluated with Spearman correlation. Survival data were collected retrospectively and analyzed with Kaplan-Meier and Cox proportional hazards analysis. All statistical tests were two-sided. RESULTS: Methylome analysis identified coordinated CpG island hypermethylation in IDH1 MUT gliomas, consistent with previous reports. RBP1, important in retinoic acid metabolism, was found to be hypermethylated in 76 of 79 IDH1 MUT, 3 of 3 IDH2 MUT, and 0 of 116 IDH1/IDH2 WT tumors. IDH1/IDH2 mutation was highly correlated with RBP1 hypermethylation (n = 198; Spearman R = 0.94, 95% confidence interval = 0.92 to 0.95, P < .001). The Cancer Genome Atlas showed IDH1 MUT tumors (n = 23) to be RBP1-hypermethylated with decreased RBP1 expression compared with WT tumors (n = 124). Among patients with primary glioblastoma, patients with RBP1-unmethylated tumors (n = 102) had decreased median overall survival compared with patients with RBP1-methylated tumors (n = 22) (20.3 months vs 36.8 months, respectively; hazard ratio of death = 2.48, 95% confidence interval = 1.30 to 4.75, P = .006). CONCLUSION: RBP1 promoter hypermethylation is found in nearly all IDH1 and IDH2 mutant gliomas and is associated with improved patient survival. Because RBP1 is involved in retinoic acid synthesis, our results suggest that dysregulation of retinoic acid metabolism may contribute to glioma formation along the IDH1/IDH2-mutant pathway. PMID- 22945950 TI - Managing patients with multimorbidity: systematic review of interventions in primary care and community settings. AB - OBJECTIVE: To determine the effectiveness of interventions designed to improve outcomes in patients with multimorbidity in primary care and community settings. DESIGN: Systematic review. DATA SOURCES: Medline, Embase, CINAHL, CAB Health, Cochrane central register of controlled trials, the database of abstracts of reviews of effectiveness, and the Cochrane EPOC (effective practice and organisation of care) register (searches updated in April 2011). ELIGIBILITY CRITERIA: Randomised controlled trials, controlled clinical trials, controlled before and after studies, and interrupted time series analyses reporting on interventions to improve outcomes for people with multimorbidity in primary care and community settings. Multimorbidity was defined as two or more chronic conditions in the same individual. Outcomes included any validated measure of physical or mental health and psychosocial status, including quality of life outcomes, wellbeing, and measures of disability or functional status. Also included were measures of patient and provider behaviour, including drug adherence, utilisation of health services, acceptability of services, and costs. DATA SELECTION: Two reviewers independently assessed studies for eligibility, extracted data, and assessed study quality. As meta-analysis of results was not possible owing to heterogeneity in participants and interventions, a narrative synthesis of the results from the included studies was carried out. RESULTS: 10 studies examining a range of complex interventions totalling 3407 patients with multimorbidity were identified. All were randomised controlled trials with a low risk of bias. Two studies described interventions for patients with specific comorbidities. The remaining eight studies focused on multimorbidity, generally in older patients. Consideration of the impact of socioeconomic deprivation was minimal. All studies involved complex interventions with multiple components. In six of the 10 studies the predominant component was a change to the organisation of care delivery, usually through case management or enhanced multidisciplinary team work. In the remaining four studies, intervention components were predominantly patient oriented. Overall the results were mixed, with a trend towards improved prescribing and drug adherence. The results indicated that it is difficult to improve outcomes in this population but that interventions focusing on particular risk factors in comorbid conditions or functional difficulties in multimorbidity may be more effective. No economic analyses were included, although the improvements in prescribing and risk factor management in some studies could provide potentially important cost savings. CONCLUSIONS: Evidence on the care of patients with multimorbidity is limited, despite the prevalence of multimorbidity and its impact on patients and healthcare systems. Interventions to date have had mixed effects, although are likely to be more effective if targeted at risk factors or specific functional difficulties. A need exists to clearly identify patients with multimorbidity and to develop cost effective and specifically targeted interventions that can improve health outcomes. PMID- 22945951 TI - Managing patients with mental and physical multimorbidity. PMID- 22945953 TI - Is bioethics a bully? PMID- 22945952 TI - Use of relative and absolute effect measures in reporting health inequalities: structured review. AB - OBJECTIVE: To examine the frequency of reporting of absolute and relative effect measures in health inequalities research. DESIGN: Structured review of selected general medical and public health journals. DATA SOURCES: 344 articles published during 2009 in American Journal of Epidemiology, American Journal of Public Health, BMJ, Epidemiology, International Journal of Epidemiology, JAMA, Journal of Epidemiology and Community Health, The Lancet, The New England Journal of Medicine, and Social Science and Medicine. MAIN OUTCOME MEASURES: Frequency and proportion of studies reporting absolute effect measures, relative effect measures, or both in abstract and full text; availability of absolute risks in studies reporting only relative effect measures. RESULTS: 40% (138/344) of articles reported a measure of effect in the abstract; among these, 88% (122/138) reported only a relative measure, 9% (13/138) reported only an absolute measure, and 2% (3/138) reported both. 75% (258/344) of all articles reported only relative measures in the full text; among these, 46% (119/258) contained no information on absolute baseline risks that would facilitate calculation of absolute effect measures. 18% (61/344) of all articles reported only absolute measures in the full text, and 7% (25/344) reported both absolute and relative measures. These results were consistent across journals, exposures, and outcomes. CONCLUSIONS: Health inequalities are most commonly reported using only relative measures of effect, which may influence readers' judgments of the magnitude, direction, significance, and implications of reported health inequalities. PMID- 22945954 TI - Making a diagnosis in patients who present with vertigo. PMID- 22945955 TI - Fears of an influx of sex workers to major sporting events are unfounded. PMID- 22945956 TI - The eccentricities of osteopathy. PMID- 22945957 TI - UK population enjoys a healthier older age. PMID- 22945959 TI - Johnson & Johnson pays $181m for misleading marketing of risperidone. PMID- 22945958 TI - Repeated abortions increase the risk of premature and low birthweight births. PMID- 22945960 TI - Focus on ubiquitin in plant biology. PMID- 22945961 TI - Republicans call for changes in US healthcare and gun laws. PMID- 22945963 TI - Protocol Evaluating the effectiveness of a school-based group programme for parents of children at risk of ADHD: the 'PArents, Teachers and CHildren WORKing Together (PATCHWORK)' cluster RCT protocol. AB - INTRODUCTION: Early intervention for childhood behavioural problems may help improve health and educational outcomes in affected children and reduce the likelihood of developing additional difficulties. The National Institute for Health and Clinical Excellence guidelines for attention deficit/hyperactivity disorder (ADHD), a common childhood behavioural disorder, recommend a stepped care approach for the identification and management of these problems. Parents of children with high levels of hyperactivity and inattention may benefit from intervention programmes involving behavioural management and educational approaches. Such interventions may be further enhanced by providing training and feedback to teachers about the strategies discussed with parents. In relation to children with high levels of hyperactivity, impulsiveness and inattention, we aim to test the feasibility and effectiveness of a parenting programme (with and without an accompanying teacher session) in primary schools. METHODS AND ANALYSIS: This clustered (at the level of school) randomised controlled trial (RCT) focuses on children in their first four school years (ages 4-8 years) in the East Midlands area of England. Parents will complete a screening measure, the Strengths and Difficulties Questionnaire, to identify children with high levels of hyperactivity/inattention. Three approaches to reducing hyperactivity and attention problems will be compared: a group programme for parents (parent-only intervention); group programme for parents combined with feedback to teachers (combined intervention); and waiting list control (no intervention). Differences between arms on the short version of Conners' Parent and Teacher Rating Scales Revised will be compared and also used to inform the sample size required for a future definitive cluster RCT. A preliminary cost-effectiveness analysis will also be conducted. ETHICS AND DISSEMINATION: The outcomes of this study will inform policy makers about the feasibility, acceptability and effectiveness of delivering targeted behavioural interventions within a school setting. The study has received ethical approval from the University of Nottingham Medical School Ethics Committee. TRIAL REGISTRATION: ISRCTN87634685. PMID- 22945962 TI - Are complementary therapies and integrative care cost-effective? A systematic review of economic evaluations. AB - OBJECTIVE: A comprehensive systematic review of economic evaluations of complementary and integrative medicine (CIM) to establish the value of these therapies to health reform efforts. DATA SOURCES: PubMed, CINAHL, AMED, PsychInfo, Web of Science and EMBASE were searched from inception through 2010. In addition, bibliographies of found articles and reviews were searched, and key researchers were contacted. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Studies of CIM were identified using criteria based on those of the Cochrane complementary and alternative medicine group. All studies of CIM reporting economic outcomes were included. STUDY APPRAISAL METHODS: All recent (and likely most cost-relevant) full economic evaluations published 2001-2010 were subjected to several measures of quality. Detailed results of higher-quality studies are reported. RESULTS: A total of 338 economic evaluations of CIM were identified, of which 204, covering a wide variety of CIM for different populations, were published 2001-2010. A total of 114 of these were full economic evaluations. And 90% of these articles covered studies of single CIM therapies and only one compared usual care to usual care plus access to multiple licensed CIM practitioners. Of the recent full evaluations, 31 (27%) met five study quality criteria, and 22 of these also met the minimum criterion for study transferability ('generalisability'). Of the 56 comparisons made in the higher quality studies, 16 (29%) show a health improvement with cost savings for the CIM therapy versus usual care. Study quality of the cost-utility analyses (CUAs) of CIM was generally comparable to that seen in CUAs across all medicine according to several measures, and the quality of the cost-saving studies was slightly, but not significantly, lower than those showing cost increases (85% vs 88%, p=0.460). CONCLUSIONS: This comprehensive review identified many CIM economic evaluations missed by previous reviews and emerging evidence of cost-effectiveness and possible cost savings in at least a few clinical populations. Recommendations are made for future studies. PMID- 22945964 TI - Mapping motor representations in the human cerebellum. AB - The cerebellum is a major motor structure. However, in humans, its efferent topographical organization remains controversial and indirectly inferred from neuroimaging and animal studies. Even central questions such as 'Can we evoke limb movements by stimulating the cerebellar cortex?' have no clear answer. To address this issue, we electrically stimulated the posterior cerebellum of 20 human patients undergoing surgery for tumours located outside this structure (e.g. pineal gland, quadrigeminal plate). Stimulation, delivered at a 60-Hz frequency for 2 s, evoked focal (single-joint) ipsilateral movements. Different regions were associated with the production of head (vermal lobule VI), face/mouth (hemispheric lobule VI) and lower-limb (hemispheric lobules VIIb-IX) responses. Upper-limb representations were more widely distributed. They intermingled with face/mouth representations in the superior posterior cerebellum (hemispheric lobule VI) and lower-limb representations in the inferior posterior cerebellum (hemispheric lobules VIIb-IX). No intra- or inter-limb somatotopy was found in these areas. Functionally, upper-limb (face/mouth movements) and upper limb-lower limb postural coordinations are major elements of our motor repertoire. Representation of these pairs of segments in common regions might favour the production of integrated motor behaviours. The intermediate region of the posterior cerebellum (hemispheric lobule VII and vermal lobules VII-VIII) was mostly silent. Latency results in conjunction with previous electrophysiological evidence in animals suggest that electrically evoked motor responses were not mediated by a cortical route but rather by brainstem structures. The potential role of this descending efferent pathway for fine motor control is discussed. PMID- 22945965 TI - When is the time right for a Phase III clinical study in spinal cord injury (P = 0.05)? PMID- 22945966 TI - William Gowers: the never completed third edition of the 'Bible of Neurology'. AB - William Gowers' classic single-authored two-volume A manual of diseases of the nervous system appeared in a first edition in 1886 and 1888, and in a second edition in 1892 and 1893, with a third edition of Volume 1 in 1899. No third edition of Volume 2 ever appeared. However, in 1949 Critchley stated that he had seen part of a revision of this volume. Subsequent writers could not find this material, but it recently came to light at Gowers' old hospital at Queen Square, London. The present paper describes the rediscovered material, containing Gowers' handwritten alterations for a further edition of Volume 2, and substantial new material, at least in relation to nystagmus and myasthenia. Gowers' declining health, or a conflict between his planned new text and his contributions to the neurology segments (1899) of Allbutt's System of medicine, may explain why a third edition of Volume 2 of the Manual of diseases of the nervous system never appeared. PMID- 22945968 TI - On neural systems for speech and song in autism. PMID- 22945967 TI - Recognition memory is impaired in children after prolonged febrile seizures. AB - Children with a history of a prolonged febrile seizure show signs of acute hippocampal injury on magnetic resonance imaging. In addition, animal studies have shown that adult rats who suffered febrile seizures during development reveal memory impairments. Together, these lines of evidence suggest that memory impairments related to hippocampal injury may be evident in human children after prolonged febrile seizures. The current study addressed this question by investigating memory abilities in 26 children soon after a prolonged febrile seizure (median: 37.5 days) and compared their results to those of 37 normally developing children. Fifteen patients were reassessed at a mean of 12.5 months after their first assessment to determine the transiency of any observed effects. We used the visual paired comparison task to test memory abilities in our group, as this task does not depend on verbal abilities and also because successful performance on the task has been proven to depend on the presence of functional hippocampi. Our findings show that patients perform as well as controls in the absence of a delay between the learning phase and the memory test, suggesting that both groups are able to form representations of the presented stimulus. However, after a 5-min delay, patients' recognition memory is not different from chance, and comparison of patients and controls points to an accelerated forgetting rate in the prolonged febrile seizure group. The patients' performance was not related to the time elapsed from the acute event or the duration of the prolonged febrile seizure, suggesting that the observed effect is not a by product of the seizure itself or a delayed effect of medication administered to terminate the seizure. By contrast, performance was related to hippocampal size; participants with the smallest mean hippocampal volumes revealed the biggest drop in performance from the immediate to the delayed paradigm. At follow-up, children were still showing deficiencies in recognizing a face after a 5-min delay. Similarly, this suggests that the observed memory impairments are not a transient effect of the prolonged febrile seizures. This is the first report of such impairments in humans, and it is clinically significant given the links between mesial temporal sclerosis and prolonged febrile seizures. The persistence of these impairments a year onwards signals the potential benefits of intervention in these children who run the risk of developing episodic memory deficits in later childhood. PMID- 22945969 TI - Cardiovascular stability and unchanged muscle sympathetic activity during xenon anaesthesia: role of norepinephrine uptake inhibition. AB - BACKGROUND: Intraoperative hypotension is associated with increased risk of perioperative complications. The N-methyl-d-aspartate (NMDA) receptor (NMDA-R) antagonist xenon (Xe) induces general anaesthesia without impairment of cardiac output and vascular resistance. Mechanisms involved in cardiovascular stability have not been identified. METHODS: Muscle sympathetic activity (MSA) (microneurography), sympathetic baroreflex gain, norepinephrine (NE) plasma concentration (high-performance liquid chromatography), anaesthetic depth (Narcotrend((r)) EEG monitoring), and vital parameters were analysed in vivo during Xe mono-anaesthesia in human volunteers (n=8). In vitro, NE transporter (NET) expressing HEK293 cells and SH-SY5Y neuroblastoma cells were pre-treated with ketamine, MK-801, NMDA/glycine, or vehicle. Subsequently, cells were incubated with or without Xe (65%). NE uptake was measured by using a fluorescent NET substrate (n=4) or [(3)H]NE (n=6). RESULTS: In vivo, Xe anaesthesia increased mean (standard deviation) arterial pressure from 93 (4) to 107 (6) mm Hg and NE plasma concentration from 156 (55) to 292 (106) pg ml(-1), P<0.01. MSA and baroreflex gain were unaltered. In vitro, ketamine decreased NET activity (P<0.01) in NET-expressing HEK293 cells, while Xe, MK-801, and NMDA/glycine did not. Xe reduced uptake in SH-SY5Y cells expressing NET and NMDA-Rs (P<0.01). MK 801 (P<0.01) and ketamine (P<0.01) also reduced NET activity, but NMDA/glycine blocked the effect of Xe on [(3)H]NE uptake. CONCLUSIONS: In vivo, Xe anaesthesia does not alter sympathetic activity and baroreflex gain, despite increased mean arterial pressure. In vitro, Xe decreases the uptake of NE in neuronal cells by the inhibition of NET. This inhibition might be related to NMDA-R antagonism and explain increased NE concentrations at the synaptic cleft and in plasma, contributing to cardiovascular stability during Xe anaesthesia. PMID- 22945970 TI - Differential effects of cognitive inhibition and intelligence on creativity. AB - There are different conceptions about how cognitive inhibition is related to creativity. Creativity has either been associated with effective inhibition, or with disinhibition, or with an adaptive engagement of inhibition. In this study, we examined the relationship of cognitive inhibition, assessed by means of the random motor generation task, with different measures of creativity. We also analyzed whether this relation is mediated by intelligence. We generally found a positive correlation of inhibition and creativity measures. Moreover, latent variable analyses indicate that inhibition may primarily promote the fluency of ideas, whereas intelligence specifically promotes the originality of ideas. These findings support the notion that creative thought involves executive processes and may help to better understand the differential role of inhibition and intelligence in creativity. PMID- 22945971 TI - TRADITIONAL USES OF PLANTS OF COMMONLAND HABITATS IN WESTERN CHITWAN, NEPAL. AB - This paper is based on the flora data gathered from 138 common land plots as part of a multi-method longitudinal study of the reciprocal relations between population and environment in western Chitwan, Nepal. The paper also describes the uses and availability of different species drawing upon both field data and knowledge of indigenous and local residents in the study area. Land use in western Chitwan is changing rapidly and common land areas have been under much stress due to population increase, whereas the common land areas are valuable to local residents. Both indigenous and new migrant residents in this area use the available plant resources for different purposes which bring economic benefit to the households. Plant species provide valuable food, vegetable and medicinal products that maintain human health and general wellbeing of the household. These plants are also economically valuable to farmers with high quality forage value as well as useful for crop management (e.g., pesticide, compost, green manure). Moreover, some plant species are used as fish poison to harvest fish from rivers and streams. Likewise, the common land areas provide materials for use in house construction (e.g., thatch) and making tools with the potential and viable sites as communal grazing land. It is evident that access and utilization of common land resources are important for many households, especially those in remote and poor agricultural areas such as western Chitwan. PMID- 22945972 TI - The value of using a prenatal education planning model: application to an aboriginal community. AB - A conceptual model for planning adolescent prenatal programs was developed that anticipated future trends, was easily modifiable, and fostered community self direction (Loos & Morton, 1996). However, the model's reliability with diverse groups in atypical settings required testing. Validation of its reliability focused on adolescent Aboriginal women living in an isolated northern community. Use of the model helped identify modifications in program design, implementation, and evaluation to meet the ethno-cultural, socioeconomic, and age-related needs differences of this population, suggesting that this model is an effective tool for program development. PMID- 22945974 TI - Integrating Preparation for Parenting Into Childbirth Education: Part II-A Study. AB - This study was designed to test the effectiveness of using a broad conceptualization of childbirth education that includes parenting preparation in pregnancy. The goal is to assist in breaking cycles of dysfunction in families. At the core of this expanded model of childbirth education is the concept of prevention. The intervention described in Part I in the Journal of Perinatal Education 7(4), 26-33 provided parents with information and coping mechanisms by drawing parallels to traditionally learned coping skills for childbirth with techniques needed to cope in post-partum. This approach also encouraged prenatal parents to learn techniques for promoting attachment to their children before birth. The curriculum was tested by randomizing 48 couples to the expanded or traditional model of childbirth education. A pre- and post-Prenatal Parenting Scale was administered to both groups. Only the experimental group demonstrated improvement at the post-class administration. PMID- 22945975 TI - Sex and breastfeeding: an educational perspective. PMID- 22945973 TI - Physiological effects of infant exposure to environmental tobacco smoke: a passive observation study. AB - This study explored infant physiologic responses of exposure to environmental tobacco smoke (ETS) using a longitudinal passive observation study with a control group. Fifteen smoking and 15 non-smoking mothers were initially contacted in hospital maternity units, with home visits made when their infants were 2, 4, and 6 weeks old. Exposure to ETS was measured using infant urinary nicotine and cotinine levels. The physiologic effects of infant ETS exposure were measured by rectal temperature, pulse rate, respiratory rate, blood pressure, and oxygen saturation. The smoking mothers in this sample were poorer, had less education, and were less likely to be married than the mothers who did not smoke. At birth, the infants of smoking mothers had higher diastolic blood pressure than infants of non-smoking mothers (p < .008). Mothers who smoke cigarettes should be educated that maternal smoking behavior can affect an infant's cardiovascular function. Parents should also be counseled about the risks of smoking in close proximity and/or in an enclosed space with an infant, especially in a motor vehicle. PMID- 22945977 TI - Kay's Perinatal Krossword Puzzle. PMID- 22945976 TI - Maternal stress can affect fetal neurobehavioral functioning. PMID- 22945978 TI - Considerations of adoption. AB - A childbirth educator asks for advice relative to a married couple in her class who plans to give up their baby for adoption. PMID- 22945979 TI - "How many?". PMID- 22945980 TI - CDM ad. PMID- 22945981 TI - Web wisdom, birth or other life transitions, and the pursuit of happiness. AB - This perspective on "happiness as a way" rather than focusing on finding a path to happiness may be particularly relevant for new and expectant parents. PMID- 22945982 TI - Really teaching lamaze: putting ideas into action. AB - The column contains concrete suggestions for preparing women to tap into their inner wisdom for their inherent when giving birth. PMID- 22945983 TI - The nature of maternal postnatal pain. AB - This study identifies the location and intensity of pain in a sample of 75 women during the first 4 days postpartum. The emphasis on normal processes and shortened hospital stays may decrease attention to maternal postnatal pain. Individual women's variations of pain in both location and intensity from day to day suggest that the reality of postnatal pain needs to become a more important aspect of perinatal education and postnatal care. PMID- 22945984 TI - Interaction of factors related to lactation duration. AB - Perceived social support and interpersonal dependency were studied as potential factors associated with lactation duration based upon previous breastfeeding experience. Inexperienced breastfeeding mothers perceived more social support than experienced breastfeeding mothers did. Perceived social support was not significantly correlated with lactation duration. An ancillary finding was that women providing a combination of breast milk and human milk substitutes had significantly lower social self-confidence than did mothers providing breast milk exclusively. PMID- 22945985 TI - Cost analysis of prenatal care using the activity-based costing model: a pilot study. AB - The cost of prenatal care in a private nurse-midwifery practice was examined using the activity-based costing system. Findings suggest that the activities of the nurse-midwife (the health care provider) constitute the major cost driver of this practice and that the model of care and associated, time-related activities influence the cost. This pilot study information will be used in the development of a comparative study of prenatal care, client education, and self care. PMID- 22945986 TI - Managed care reimbursement: does it conflict with optimum care? AB - In response to a reader's question, Dr. Philipsen examines the possibilities of conflict of interest in various methods of physician reimbursement. PMID- 22945987 TI - Kay's Perinatal Krossword Puzzle. PMID- 22945988 TI - Breast milk from mothers who smoke and drink smells! PMID- 22945989 TI - The whole truth and nothing but the truth. PMID- 22945990 TI - Verse and vision. PMID- 22945991 TI - The versatility of the perinatal educator. AB - Perinatal educators can expand their role beyond that of childbirth preparation. One such role is the perinatal bereavement counselor. Having the courage to balance one's skills with one's intuitive impulses may greatly enrich carrying out this or any role. PMID- 22945992 TI - Really teaching lamaze: the power of pain. AB - In response to a reader's question, this column discusses the benefits and uses of pain to facilitate childbirth. Childbirth educators are urged to help women understand pain, so that they may work with pain and appreciate the role it plays in providing them with the inner wisdom to give birth. PMID- 22945993 TI - Perinatal Education and Grandparents: Creating an Interdependent Family Environment Part II: The Pilot Study. AB - This second of two articles presents a study of the grandparenting perinatal education program. The following aspects are featured: recruitment, the setting, the program's content, supporting material and teaching aids, and the program's organization. An evaluation of the program was conducted and is presented in the article. PMID- 22945994 TI - The experience of pregnancy: a hermeneutical/phenomenological study. AB - The aim of this study was to describe women's experience of pregnancy. The setting was the Alternative Birth Center at Sahlgrenska University Hospital in Goteborg, Sweden, from 1996 to 1997. Anonymous diaries were written by 12 women and analyzed using a hermeneutical/phenomenological approach. The essential structure and interpretation of women's experience of pregnancy can be expressed as "transition to the unknown," which includes three themes: (1) meeting one's life situation, (2) meeting something inevitable, and (3) preparing for the unknown.The essential structure and interpretation of women's experience of pregnancy can be expressed as "transition to the unknown" ... PMID- 22945995 TI - The needs of postbirth parents: an international, multisite study. AB - Health care reform has moved postbirth care into the community without assessment of how this may change parents' needs. Mother-father pairs (n = 117) in six sites in four countries were interviewed at 5 to 10 days postbirth and again between 6 and 8 weeks postbirth to determine their needs. Content analysis revealed both parents in all sites had a strong focus on self-needs throughout the postbirth period. Postpartum programs oriented solely to family-centered care may not meet the specific needs of contemporary parents. PMID- 22945996 TI - Making the most of your revista lamaze: culturally responsive teaching for Hispanic clients. AB - The traditional classroom in many Latin American countries does not overtly support an environment of discussion, reflection, and analysis-the foundation of a Lamaze education. Even when working with couples from cultures that reflect learning styles different from our own, it is possible for the childbirth educator to be faithful to the goals of Lamaze education by changing the way in which information is presented and by encouraging learner participation. By using Revista Lamaze, combined with culturally appropriate teaching techniques, a childbirth educator can successfully educate Hispanic couples without offending their culture. PMID- 22945997 TI - Some suggested cautions for pregnant women. AB - Researchers continue to find new ways to protect the fetus and newborn from hazards posed by the environment through infectious and chemical agents. Research indicates that for women infected with toxoplasmosis during pregnancy, antibiotic treatment reduces the incidence of harmful effects this infection can have on the fetus. In addition, researchers have concluded that women's breast milk can be a source of lead exposure in infants. Maternal use of calcium supplements, however, can decrease the risk of lead transfer by reducing the mobilization of skeletal mineral stores. PMID- 22945999 TI - Kay's Perinatal Krossword Puzzle JPE 8.3. PMID- 22945998 TI - Tax-saving tips for self-employed childbirth educators. AB - A self-employed childbirth educator asks for advice on how to reduce her end-of the-year tax payments. The answer includes some general advice and four specific suggestions that may help a small-business owner save money on taxes. PMID- 22946000 TI - This time I mean it. AB - An overworked childbirth educator tries to become more discerning about the tasks she volunteers to do. PMID- 22946002 TI - Verse and vision. PMID- 22946001 TI - A year on. PMID- 22946003 TI - The quest to promote ideal early parenting philosophy, skills, and education. AB - Prenates, babies, and children deserve wholesome parents and parenting, now. This is the time in which we are all living and growing. The quest for more optimal parenting will bring about more whole-loving beings. Our children and our planet deserve our best effort. Readers can contribute to coalition building towards that aim. PMID- 22946004 TI - Does lamaze "work"? AB - In answer to a reader's question, this column affirms that Lamaze preparation for birth is important and valuable. PMID- 22946005 TI - Quality perinatal nursing education through coteaching. AB - Collaboration in teaching can take different forms, including the model of coteaching. This educational strategy requires time, effort, commitment, and collaboration between partners in order to ensure an enhanced teaching and learning experience. Little has been written recently on the theory of coteaching. The literature does not address the subject of coteaching or team teaching from a combined theoretical and clinical perspective. Two professors in nursing sciences present their experience in coteaching over a 4-year period, covering a theoretical course and a clinical practicum at the basic baccalaureate level, as well as the supervision of clinical preceptors for this same practicum. They describe the conceptual, personal, and environmental conditions that enabled them to use this particular form of teaching at this point in their careers. They discuss how the concept works as well as the advantages and disadvantages from the perspective of professors, students, and preceptors. Recommendations are made for implementing such a strategy while minimizing the risks for the program, the teachers, the students, and the educational milieux. Their discussion may provide insight for programs that prepare childbirth educators. PMID- 22946006 TI - Implementing coteaching in childbirth education classes. AB - In response to the article "Innovative Service: Quality Perinatal Nursing Education Through Coteaching" [Journal of Perinatal Education, 8(4), 27-35], the author of this column conducts an interview with two Lamaze Certified Childbirth Educators who share their experiences as coteachers. PMID- 22946007 TI - Uncertainty exists in recommendations for reducing prenatal exposure to mercury. AB - The Environmnetal Working Group, Health Care Without Harm (1999) recommends that pregnant women avoid eating tuna, swordfish, or shark and that young children avoid eating more than one serving of tuna per week. Childbirth educators are in a unique position to educate women about the dangers of methylmercury exposure during pregnancy. PMID- 22946009 TI - Verse and vision. PMID- 22946008 TI - Kay's Perinatal Krossword Puzzle JPE 8.4. PMID- 22946010 TI - Maternal-infant attachment, naturally. AB - In answer to a reader's question about the necessity of prenatal sonograms, this column asserts that, unl there is a serious medical problem, mothers should depend less on technology and more on their natural abilities to foster the all important bond with their babies. PMID- 22946012 TI - Prevalence of zinc deficiency in 3-18 years old children in shiraz-iran. AB - BACKGROUND: Zinc is an essential trace element with a prominent role in human nutrition. Zinc deficiency has been linked to growth retardation, hypogonadism in males, and lack of sexual development in females. It ranges from 50% in sub Saharan Africa to 5% in high income countries. The aim of this study is to evaluate the prevalence of zinc deficiency in healthy children in Shiraz, southern Iran. METHODS: In this study, 902 children aged 3-18 years old were randomly sampled for serum zinc level. Age, sex, weight, height, BMI, stunting and wasting indices were also recorded. With atomic absorption spectrophotometry method, the serum level of zinc less than 70 ug/dL was considered as deficient. RESULTS: Mean serum level of zinc was 122.3+/-55 ug/dL. The prevalence of zinc deficiency was 7.9%. There was no relationship among serum zinc level and age, sex, height, weight or BMI, but mild wasting (weight for age) and mild stunting (height for age) were significantly more prevalent among zinc deficient children compared to children with normal or high level of zinc. CONCLUSION: Zinc deficiency in Shiraz is not as prevalent as other areas of Iran. It was significantly more frequent among stunted and wasted (malnourished) children. Difference in soil zinc level, recent wide prescription of zinc supplements by pediatricians and especial pattern of nutrition, considered as possible factors responsible for lower prevalence of zinc deficiency in Shiraz, deserve more investigations. PMID- 22946013 TI - Bone loss with multiple sclerosis: effect of glucocorticoid use and functional status. AB - BACKGROUND: Emerging data suggest a significantly increased prevalence of low bone mineral density (BMD) in men and women with multiple sclerosis (MS) compared to age matched controls. This study was performed to evaluate bone mineral mass in patients with MS in comparison to healthy age-and sex matched controls and to determine association of glucocorticoid use or ambulation ability with changing in bone mass in these individuals. METHODS: Eighty two patients with MS and 328 age-sex matched healthy controls participated in the study. The Kurtzke expanded disability status scale (EDSS) was used to evaluate disability and functional capacity. Bone mineral density was measured using Dual X-ray absorptiometry. Serum calcium, phosphorus and 25(OH) vitamin D levels were assessed. RESULTS: The MS patients had significantly lower BMD at the lumbar spines, neck and total femur compared to age-sex matched controls. EDSS scores were inversely correlated with total femur and spinal BMD. There was a negative correlation with cumulative steroid dose and BMD only for femoral neck. CONCLUSION: BMD was significantly lower in MS patients. Decreased ambulatory status and glucocorticoid usage were associated with low BMD in MS patients. These patients should be encouraged to increase mobility and to have protective measures to maintain bone mass. PMID- 22946014 TI - Relationship between Daily Physical Activity During Last Month of Pregnancy and Pregnancy Outcome. AB - BACKGROUND: Previous researchers have evaluated the influence of physical exercise or physical activity on pregnancy outcome, but the influence of daily physical activities in details including energy expenditure, biomechanical load and exercise before and during pregnancy have remained unclear. This study evaluates the relationship between daily physical activities as a biomechanical load and energy expenditure and physical exercise during household activities with birth weight, type of delivery and Apgar score. METHODS: The participants of this study were household, first parity women who referred to a prenatal care center in southern Iran. 132 volunteer women were eligible to be enrolled according to their general health and not having any absolute or relative limitation for participating in any kind of activity. Information about daily physical activity was collected through a personal interview using a structured questionnaire during two separate days of ninth month of pregnancy. Data on delivery were recorded from recorded documents of mothers in the hospital. RESULTS: There was no relationship between biomechanical and energy load and birth weight. There was a significant correlation between Apgar score and biomechanical and energy load. Infants of mothers who exercised before or during pregnancy had a significant higher weight than the non-exercise group. Apgar score indicated no significant difference among those having exercise and those without before and during pregnancy. There was no significant difference in the biomechanical load and energy expenditure in the two types of delivery. CONCLUSION: Daily activities in normal range do not induce any harmful effect on birth weight; increasing biomechanical load as a result of some maternal body postures that may be harmful for infant health at birth time. Physical exercise before and during pregnancy may have a positive effect on birth weight. PMID- 22946011 TI - Macrophage-mediated lymphangiogenesis: the emerging role of macrophages as lymphatic endothelial progenitors. AB - It is widely accepted that macrophages and other inflammatory cells support tumor progression and metastasis. During early stages of neoplastic development, tumor infiltrating macrophages (TAMs) mount an immune response against transformed cells. Frequently, however, cancer cells escape the immune surveillance, an event that is accompanied by macrophage transition from an anti-tumor to a pro tumorigenic type. The latter is characterized by high expression of factors that activate endothelial cells, suppress immune response, degrade extracellular matrix, and promote tumor growth. Cumulatively, these products of TAMs promote tumor expansion and growth of both blood and lymphatic vessels that facilitate metastatic spread. Breast cancers and other epithelial malignancies induce the formation of new lymphatic vessels (i.e., lymphangiogenesis) that leads to lymphatic and subsequently, to distant metastasis. Both experimental and clinical studies have shown that TAMs significantly promote tumor lymphangiogenesis through paracrine and cell autonomous modes. The paracrine effect consists of the expression of a variety of pro-lymphangiogenic factors that activate the preexisting lymphatic vessels. The evidence for cell-autonomous contribution is based on the observed tumor mobilization of macrophage-derived lymphatic endothelial cell progenitors (M-LECP) that integrate into lymphatic vessels prior to sprouting. This review will summarize the current knowledge of macrophage dependent growth of new lymphatic vessels with specific emphasis on an emerging role of macrophages as lymphatic endothelial cell progenitors (M-LECP). PMID- 22946015 TI - Simultaneous pattern visual evoked potential and pattern electroretinogram in strabismic and anisometropic amblyopia. AB - BACKGROUND: Amblyopia is a relatively common condition in which visual acuity through an eye is subnormal despite no overt pathology. Pattern visual evoked potential (PVEP) can detect any defect from optic nerve to occipital cortex and pattern electroretinogram (PERG) can detect retinal defects specially the ganglion layers. This study was performed to evaluate the cortical and retinal activity in strabismic and anisometropic amblyopia. METHODS: PVEP and PERG were recorded simultaneously in 40 amblyopes (20 strabismics and 20 anisometropics) and 20 normal control subjects. Normal subjects were age and sex matched with patients. RESULTS: The P(100) latency in PVEP was increased in both groups of patients but the P(100) amplitude was reduced only in anisometropic group. In PERG, the amplitude of P(50) was reduced in all patients with no significant change in latency. CONCLUSION: Beside reduced PVEP responses in strabismic and anisometropic amblyopia, the activity of retina reduced too. It is likely that retinal impulses can affect the development of visual system. PMID- 22946016 TI - Antinociceptive, anti-inflammatory and acute toxicity effects of juglans regia L. Leaves in mice. AB - BACKGROUND: Juglans regia leaves have been used in folk medicine to alleviate inflammatory diseases. This study investigates the antinociceptive, anti Inflammatory and acute toxicity effects of Juglans regia L. leaves in mice. METHODS: 351 Male and female albino mice were divided into negative (saline), positive (morphine or diclofenac) controls as well as test groups (n=6-8). The acute (intraperitoneally) toxicity was evaluated for 2 days. Antinociceptive activities were done using hot-plate and writhing tests. Anti-inflammatory effects were studied using xylene induced ear edema and cotton pellet tests. RESULTS: The LD50 values of J. regia aqueous and ethanolic extrats were 5.5 and 3.3 g/kg, respectively. The aqueous (2.87 and 1.64 g/kg) and ethanolic (2.044 and 1.17 g/kg) extracts showed antinociceptive activity in hot-plate test. The pretreatment of naloxone (2 mg/kg, s.c.) did not inhibit the extracts activities. The extracts exhibited antinociceptive activity in writhing test, which were not blocked by naloxone. In xylene test, both extracts showed anti-inflammatory activity in some doses. The extracts showed anti-inflammatory activity against the chronic inflammation. CONCLUSION: J. regia leaves demonstrated antinociceptive effect through non-opioid receptors and anti-inflammatory effect against acute and chronic inflammation. The extracts of J. regia could be considered as a promising analgesic and anti-inflammatory agents against diseases such as rheumatoid arthritis. PMID- 22946017 TI - Seroprevalence of HIV, HBV and HCV in Persons Referred to Hamadan Behavioral Counseling Center, West of Iran. AB - BACKGROUND: Human immunodeficiency virus (HIV), hepatitis B virus (HBV) and hepatitis C virus (HCV) are three important prevalent infections all over the world. The aim of this study was to determine seroprevalence of HIV, HBV and HCV infections and high risk behaviors in persons who referred to the behavioral counseling center of Hamadan, west of Iran. METHODS: This was a cross-sectional study which was done on 379 persons who referred to the behavioral counseling center of Hamadan. All persons after obtaining the informed consent were tested for serologic markers including HBs Ag, HCV-Ab and HIV-Ab by ELISA and western blot methods. RESULTS: Of the 379 persons, 71.5 % (271 cases) were male and 28.5% (108 cases) were female. HIV infection was reported in 4% (15) of persons. HBV and HCV infections were reported in 2.9% (11 cases) and 35.6% (135 cases), respectively. The most common high risk behaviors were injection drug user and history of prison with 52.5% (199 cases) and 40.4% (153 cases), respectively. CONCLUSION: According to the results, injection drug users and prisoners are at the highest risk for HCV, HIV and HBV infections. PMID- 22946018 TI - Chronic recurrent multifocal osteomyelitis: a case report. AB - Chronic recurrent multifocal osteomyelitis (CRMO) is a rare inflammatory bone disease. It is a diagnosis of exclusion based on the clinical, radiological and pathological criteria. The awareness of the corresponding feature can help avoid of unnecessary diagnostic procedures and prolonged antibiotic therapy. We present a case of 4.5 year old girl, diagnosed with CRMO who were followed for 6 months as a case of chronic bacterial osteomyelitis and received long course of antibiotic therapy. PMID- 22946019 TI - Initial presentation of acute lymphoblastic leukemia with osteoporosis and multiple spontaneous bone fractures. AB - Acute lymphoblastic leukemia (ALL) is the most common childhood malignancy. Skeletal abnormalities have been described in association with ALL including osteoprosis and bone fractures. Different factors including the disease itself or soluble products of malignant cells and treatment agents like cytotoxic drugs, methotroxate, corticosteroids and radiotherapy may be responsible for defective bone homeostasis in these patients. Orthopedic conditions and pain may be the first manifestation of acute leukemia and it is important for physicians to recognize the skeletal manifestation of acute childhood leukemia because of a delay in diagnosis has adverse effect on survival. We present a child with ALL that refer with multi bone fractures as a first manifestation of the disease. PMID- 22946020 TI - Neurotrophic corneal ulcer after topical tetracaine abuse: management guidelines. PMID- 22946021 TI - Assessment of Psychiatric Symptoms Using SCL-90-R among HIV/AIDS Individuals in Razavi Khorasan Province, Iran. PMID- 22946022 TI - Understanding of medical students' information needs in emergency cases: the implications for emergency management in teaching hospitals of iran. PMID- 22946023 TI - Pneumatosis intestinalis developing in association with Crohn's disease and mimicking gastrointestinal system perforation. PMID- 22946024 TI - Intrafamily transmission of HCV need to more discussion. PMID- 22946025 TI - PDE4 inhibitors have no effect on eotaxin expression in human primary bronchial epithelial cells. AB - The bronchial epithelium is a very important factor during the inflammatory response, it produces many key regulators involved in the pathophysiology of asthma and COPD. Local influx of eosinophils, basophils, Th2 lymphocytes and macrophages is the source of many cytotoxic proteins, cytokines and other mediators of inflammation. These cells are attracted by eotaxins (eotaxin 1/CCL11, eotaxin-2/CCL24, eotaxin-3/CCL26). Inhibitors of phosphodiesterase 4 (PDE4) are new anti-inflammatory drugs which cause cAMP accumulation in the cell and inhibit numerous stages of allergic inflammation. The aim of our study was to evaluate the influence of PDE4 inhibitors: rolipram and RO-20-1724 on the expression of eotaxins in human primary bronchial epithelial cells. Cells were preincubated with PDE4 inhibitors for 1 hour and then stimulated with IL-4 or IL 13 alone or in combination with TNF-alpha. After 48 hours, eotaxin protein level was measured by ELISA and mRNA level by real time PCR. These cells produce CCL24 and CCL26. PDE4 inhibitors increased CCL24 and CCL26 mRNA level irrespectively of the used stimulators. Rolipram and RO-20-1724 had no effect on eotaxin protein production in our experimental conditions. Thus PDE4 inhibitors have no effect on eotaxin protein expression in human primary bronchial epithelial cells. In vitro experiments should be performed using a primary cell model rather than immortalized lines. PMID- 22946026 TI - Vasostatin increases oxygenation of B16-F10 melanoma tumors and raises therapeutic efficacy of cyclophosphamide. AB - One of the preconditions of effective anticancer therapy is efficient transfer of the therapeutic agent (chemotherapeutic) to tumor cells. Fundamental barriers making drug delivery and action difficult include underoxygenation, elevated interstitial pressure, poor and abnormal tumor blood vascular network and acidic tumor milieu. In this study we aimed at developing an optimized scheme of administering a combination of an angiogenesis-inhibiting drug (vasostatin) and a chemotherapeutic (cyclophosphamide) in the therapeutic treatment of mice bearing experimental B16-F10 melanoma tumors. We report that the strongest tumor growth inhibition was observed in mice that received two, three or four vasostatin doses in combination with one injection of cyclophosphamide (i.e., V2 + CTX, V3 + CTX or V4 + CTX schemes). Double administration of vasostatin increases oxygenation of B16-F10 tumors. On the other hand, its five-fold administration lowers tumor oxygenation, breaks down tumor vascular network (increasing hypoxia) and leads in consequence to death of cancer cells and appearance of necrotic areas in the tumor. A decreased cyclophosphamide dose in combination with two doses of vasostatin (V2 + CTX scheme) inhibits tumor growth similarly to a larger dose of cyclophosphamide alone. PMID- 22946027 TI - Purification and characterization of a novel laccase from the mushroom Pleurotus nebrodensis. AB - A novel laccase with a molecular mass of 64 kDa and the N-terminal sequence AIGPDDTINF was isolated from fresh fruiting bodies of the mushroom Pleurotus nebrodensis. The purification protocol comprised ion exchange chromatography on DEAE-cellulose, CM-cellulose, and Q-Sepharose, and gel filtration on Superdex 75. The laccase was adsorbed on DEAE-cellulose and Q-Sepharose, but not on CM cellulose. It demonstrated an optimal temperature of 70 degrees C. The enzyme activity increased steadily over the temperature range 20 degrees C-70 degrees C. There was only a slight reduction in activity at 80 degrees C. However, all activity disappeared following exposure to 100 degrees C for 10 minutes. The enzyme activity changed only slightly over the pH range 3-5, with the optimum at pH 5, but underwent a precipitous decline when the pH was elevated to 6, and was undetectable at pH 8 and pH 9. PMID- 22946028 TI - In vitro production of M. * piperita not containing pulegone and menthofuran. AB - The essential oils (EOs) and static headspaces (HSs) of in vitro plantlets and callus of Mentha x piperita were characterized by GC-MS analysis. Leaves were used as explants to induce in vitro plant material. The EO yields of the in vitro biomass were much lower (0.1% v/w) than those of the parent plants (2% v/w). Many typical mint volatiles were emitted by the in vitro production, but the callus and in vitro plantelet EOs were characterized by the lack of both pulegone and menthofuran. This was an important difference between in vitro and in vivo plant material as huge amounts of pulegone and menthofuran may jeopardise the safety of mint essential oil. Regarding the other characteristic volatiles, menthone was present in reduced amounts (2%) in the in vitro plantlets and was not detected in the callus, even if it represented the main constituent of the stem and leaf EOs obtained from the cultivated mint (26% leaves; 33% stems). The M. piperita callus was characterized by menthol (9%) and menthone (2%), while the in vitro plantlet EO showed lower amounts of both these compounds in favour of piperitenone oxide (45%). Therefore, the established callus and in vitro plantlets showed peculiar aromatic profiles characterized by the lack of pulegone and menthofuran which have to be monitored in the mint oil for their toxicity. PMID- 22946030 TI - Preface. PMID- 22946029 TI - Certain protein transducing agents convert translocated proteins into cell killers. AB - The majority of proteins are unable to translocate into the cell interior. Hence for peptide- and protein-based therapeutics a direct intracytoplasmic delivery with the aid of transducing agents is an attractive approach. We wanted to deliver to the cell interior a putatively cytotoxic protein VPg. Protein transduction was achieved in vitro with three different commercial products. However, in our hands, delivery of various control proteins without known deleterious effects, as well as of protein VPg, always induced cell death. Finally, we used a novel transducing peptide Wr-T, which was not toxic to cultured cells, even in a quite large range of concentrations. Most importantly, control protein delivered to cells in culture did not display any toxicity while VPg protein exerted a strong cytotoxic effect. These data show that results obtained with cell-penetrating agents should be interpreted with caution. PMID- 22946031 TI - Nuclear magnetic resonance quantum information processing. AB - For the past decade, nuclear magnetic resonance (NMR) has been established as a main experimental technique for testing quantum protocols in small systems. This Theme Issue presents recent advances and major challenges of NMR quantum information possessing (QIP), including contributions by researchers from 10 different countries. In this introduction, after a short comment on NMR-QIP basics, we briefly anticipate the contents of this issue. PMID- 22946032 TI - Recent advances in nuclear magnetic resonance quantum information processing. AB - Quantum information processors have the potential to drastically change the way we communicate and process information. Nuclear magnetic resonance (NMR) has been one of the first experimental implementations of quantum information processing (QIP) and continues to be an excellent testbed to develop new QIP techniques. We review the recent progress made in NMR QIP, focusing on decoupling, pulse engineering and indirect nuclear control. These advances have enhanced the capabilities of NMR QIP, and have useful applications in both traditional NMR and other QIP architectures. PMID- 22946033 TI - Implementing quantum logic gates with gradient ascent pulse engineering: principles and practicalities. AB - We briefly describe the use of gradient ascent pulse engineering (GRAPE) pulses to implement quantum logic gates in nuclear magnetic resonance quantum computers, and discuss a range of simple extensions to the core technique. We then consider a range of difficulties that can arise in practical implementations of GRAPE sequences, reflecting non-idealities in the experimental systems used. PMID- 22946034 TI - Control aspects of quantum computing using pure and mixed states. AB - Steering quantum dynamics such that the target states solve classically hard problems is paramount to quantum simulation and computation. And beyond, quantum control is also essential to pave the way to quantum technologies. Here, important control techniques are reviewed and presented in a unified frame covering quantum computational gate synthesis and spectroscopic state transfer alike. We emphasize that it does not matter whether the quantum states of interest are pure or not. While pure states underly the design of quantum circuits, ensemble mixtures of quantum states can be exploited in a more recent class of algorithms: it is illustrated by characterizing the Jones polynomial in order to distinguish between different (classes of) knots. Further applications include Josephson elements, cavity grids, ion traps and nitrogen vacancy centres in scenarios of closed as well as open quantum systems. PMID- 22946035 TI - Geometric aspects of composite pulses. AB - Unitary operations acting on a quantum system must be robust against systematic errors in control parameters for reliable quantum computing. Composite pulse technique in nuclear magnetic resonance realizes such a robust operation by employing a sequence of possibly poor-quality pulses. In this study, we demonstrate that two kinds of composite pulses-one compensates for a pulse length error in a one-qubit system and the other compensates for a J-coupling error in a two-qubit system-have a vanishing dynamical phase and thereby can be seen as geometric quantum gates, which implement unitary gates by the holonomy associated with dynamics of cyclic vectors defined in the text. PMID- 22946036 TI - Solid-state multiple quantum NMR in quantum information processing: exactly solvable models. AB - Multiple quantum (MQ) NMR is an effective tool for the generation of a large cluster of correlated particles, which, in turn, represent a basis for quantum information processing devices. Studying the available exactly solvable models clarifies many aspects of the quantum information. In this study, we consider two exactly solvable models in the MQ NMR experiment: (i) the isolated system of two spin-1/2 particles (dimers) and (ii) the large system of equivalent spin-1/2 particles in a nanopore. The former model is used to describe the quantum correlations and their relations with the MQ NMR coherences, whereas the latter helps one to model the creation and decay of large clusters of correlated particles. PMID- 22946037 TI - Storage of quantum coherences as phase-labelled local polarization in solid-state nuclear magnetic resonance. AB - Nuclear spins are promising candidates for quantum information processing because their good isolation from the environment precludes the rapid loss of quantum coherence. Many strategies have been developed to further extend their decoherence times. Some of them make use of decoupling techniques based on the Carr-Purcell and Carr-Purcell-Meiboom-Gill pulse sequences. In many cases, when applied to inhomogeneous samples, they yield a magnetization decay much slower than that of the Hahn echo. However, we have proved that these decays cannot be associated with longer decoherence times, as coherences remain frozen. They result from coherences recovered after their storage as local polarization and thus they can be used as memories. We show here how this freezing of the coherent state, which can subsequently be recovered after times longer than the natural decoherence time of the system, can be generated in a controlled way with the use of field gradients. A similar behaviour of homogeneous samples in inhomogeneous fields is demonstrated. It is emphasized that the effects of inhomogeneities in solid-state nuclear magnetic resonance, independently of their origin, should not be disregarded, as they play a crucial role in multipulse sequences. PMID- 22946038 TI - Experimental study of quantum simulation for quantum chemistry with a nuclear magnetic resonance simulator. AB - Quantum computers have been proved to be able to mimic quantum systems efficiently in polynomial time. Quantum chemistry problems, such as static molecular energy calculations and dynamical chemical reaction simulations, become very intractable on classical computers with scaling up of the system. Therefore, quantum simulation is a feasible and effective approach to tackle quantum chemistry problems. Proof-of-principle experiments have been implemented on the calculation of the hydrogen molecular energies and one-dimensional chemical isomerization reaction dynamics using nuclear magnetic resonance systems. We conclude that quantum simulation will surpass classical computers for quantum chemistry in the near future. PMID- 22946039 TI - Robust dynamical decoupling. AB - Quantum computers, which process information encoded in quantum mechanical systems, hold the potential to solve some of the hardest computational problems. A substantial obstacle for the further development of quantum computers is the fact that the lifetime of quantum information is usually too short to allow practical computation. A promising method for increasing the lifetime, known as dynamical decoupling (DD), consists of applying a periodic series of inversion pulses to the quantum bits. In the present review, we give an overview of this technique and compare different pulse sequences proposed earlier. We show that pulse imperfections, which are always present in experimental implementations, limit the performance of DD. The loss of coherence due to the accumulation of pulse errors can even exceed the perturbation from the environment. This effect can be largely eliminated by a judicious design of pulses and sequences. The corresponding sequences are largely immune to pulse imperfections and provide an increase of the coherence time of the system by several orders of magnitude. PMID- 22946040 TI - Quantum information processing by nuclear magnetic resonance on quadrupolar nuclei. AB - Nuclear magnetic resonance is viewed as an important technique for the implementation of many quantum information algorithms and protocols. Although the most straightforward approach is to use the two-level system composed of spin 1/2 nuclei as qubits, quadrupolar nuclei, which possess a spin greater than 1/2, are being used as an alternative. In this study, we show some unique features of quadrupolar systems for quantum information processing, with an emphasis on the ability to execute efficient quantum state tomography (QST) using only global rotations of the spin system, whose performance is shown in detail. By preparing suitable states and implementing logical operations by numerically optimized pulses together with the QST method, we follow the stepwise execution of Grover's algorithm. We also review some work in the literature concerning the relaxation of pseudo-pure states in spin 3/2 systems as well as its modelling in both the Redfield and Kraus formalisms. These data are used to discuss differences in the behaviour of the quantum correlations observed for two-qubit systems implemented by spin 1/2 and quadrupolar spin 3/2 systems, also presented in the literature. The possibilities and advantages of using nuclear quadrupole resonance experiments for quantum information processing are also discussed. PMID- 22946041 TI - Controlling and exploiting phases in multi-spin systems using electron spin resonance and nuclear magnetic resonance. AB - The phase of a superposition state is a quintessential characteristic that differentiates a quantum bit of information from a classical one. This phase can be manipulated dynamically or geometrically, and can be exploited to sensitively estimate Hamiltonian parameters, perform faithful quantum state tomography and encode quantum information into multiple modes of an ensemble. Here we discuss the methods that we have employed to manipulate and exploit the phase information of single-, two-, multi-qubit and multi-mode spin systems. PMID- 22946042 TI - Classical to quantum in large-number limit. AB - We construct a quantumness witness following the work of Alicki & van Ryn (AvR). We reformulate the AvR test by defining it for quantum states rather than for observables. This allows us to identify the necessary quantities and resources to detect quantumness for any given system. The first quantity turns out to be the purity of the system. When applying the witness to a system with even moderate mixedness, the protocol is unable to reveal any quantumness. We then show that having many copies of the system leads the witness to reveal quantumness. This seems contrary to the Bohr correspondence, which asserts that, in the large number limit, quantum systems become classical, whereas the witness shows quantumness when several non-quantum systems, as determined by the witness, are considered together. However, the resources required to detect the quantumness increase dramatically with the number of systems. We apply the quantumness witness for systems that are highly mixed but in the large-number limit that resembles nuclear magnetic resonance (NMR) systems. We make several conclusions about detecting quantumness in NMR-like systems. PMID- 22946043 TI - On the quantumness of correlations in nuclear magnetic resonance. AB - Nuclear magnetic resonance (NMR) was successfully employed to test several protocols and ideas in quantum information science. In most of these implementations, the existence of entanglement was ruled out. This fact introduced concerns and questions about the quantum nature of such bench tests. In this paper, we address some issues related to the non-classical aspects of NMR systems. We discuss some experiments where the quantum aspects of this system are supported by quantum correlations of separable states. Such quantumness, beyond the entanglement-separability paradigm, is revealed via a departure between the quantum and the classical versions of information theory. In this scenario, the concept of quantum discord seems to play an important role. We also present an experimental implementation of an analogue of the single-photon Mach-Zehnder interferometer employing two nuclear spins to encode the interferometric paths. This experiment illustrates how non-classical correlations of separable states may be used to simulate quantum dynamics. The results obtained are completely equivalent to the optical scenario, where entanglement (between two field modes) may be present. PMID- 22946044 TI - Role of phosphodiesterases in the shaping of sub-plasma-membrane cAMP oscillations and pulsatile insulin secretion. AB - Specificity and versatility in cyclic AMP (cAMP) signalling are governed by the spatial localisation and temporal dynamics of the signal. Phosphodiesterases (PDEs) are important for shaping cAMP signals by hydrolyzing the nucleotide. In pancreatic beta-cells, glucose triggers sub-plasma-membrane cAMP oscillations, which are important for insulin secretion, but the mechanisms underlying the oscillations are poorly understood. Here, we investigated the role of different PDEs in the generation of cAMP oscillations by monitoring the concentration of cAMP in the sub-plasma-membrane space ([cAMP](pm)) with ratiometric evanescent wave microscopy in MIN6 cells or mouse pancreatic beta-cells expressing a fluorescent translocation biosensor. The general PDE inhibitor IBMX increased [cAMP](pm), and whereas oscillations were frequently observed at 50 uM IBMX, 300 uM-1 mM of the inhibitor caused a stable increase in [cAMP](pm). The [cAMP](pm) was nevertheless markedly suppressed by the adenylyl cyclase inhibitor 2',5' dideoxyadenosine, indicating IBMX-insensitive cAMP degradation. Among IBMX sensitive PDEs, PDE3 was most important for maintaining a low basal level of [cAMP](pm) in unstimulated cells. After glucose induction of [cAMP](pm) oscillations, inhibitors of PDE1, PDE3 and PDE4 inhibitors the average cAMP level, often without disturbing the [cAMP](pm) rhythmicity. Knockdown of the IBMX insensitive PDE8B by shRNA in MIN6 cells increased the basal level of [cAMP](pm) and prevented the [cAMP](pm)-lowering effect of 2',5'-dideoxyadenosine after exposure to IBMX. Moreover, PDE8B-knockdown cells showed reduced glucose-induced [cAMP](pm) oscillations and loss of the normal pulsatile pattern of insulin secretion. It is concluded that [cAMP](pm) oscillations in beta-cells are caused by periodic variations in cAMP generation, and that several PDEs, including PDE1, PDE3 and the IBMX-insensitive PDE8B, are required for shaping the sub-membrane cAMP signals and pulsatile insulin release. PMID- 22946045 TI - Karyopherin-independent spontaneous transport of amphiphilic proteins through the nuclear pore. AB - Highly selective nucleocytoplasmic molecular transport is critical to eukaryotic cells, which is illustrated by size-filtering diffusion and karyopherin-mediated passage mechanisms. However, a considerable number of large proteins without nuclear localization signals are localized to the nucleus. In this paper, we provide evidence for the spontaneous migration of large proteins in a karyopherin independent manner. Time-lapse observation of a nuclear transport assay revealed that several large molecules spontaneously and independently pass through the nuclear pore complex (NPC). The amphiphilic motifs were sufficient to overcome the selectivity barrier of the NPC. Furthermore, the amphiphilic property of these proteins enables altered local conformation in hydrophobic solutions so that elevated surface hydrophobicity facilitates passage through the nuclear pore. The molecular dynamics simulation revealed the conformational change of the amphiphilic structure that exposes the hydrophobic amino acid residues to the outer surface in a hydrophobic solution. These results contribute to the understanding of nucleocytoplasmic molecular sorting and the nature of the permeability barrier. PMID- 22946046 TI - Cingulin is dispensable for epithelial barrier function and tight junction structure, and plays a role in the control of claudin-2 expression and response to duodenal mucosa injury. AB - Cingulin (CGN) is a 140 kDa protein, which is localized to the cytoplasmic region of vertebrate tight junctions (TJ), and regulates gene expression and RhoA signaling in cultured cells. To investigate the function of CGN at the organism level, we generated CGN knockout (CGN(-/-)) mice by homologous recombination. CGN(-/-) mice are viable and fertile, and are born at the expected mendelian ratios. Immunohistochemistry, immunofluorescence, electron microscopy and permeability assays of epithelial tissues of CGN(-/-) mice show no cingulin labeling at junctions, a normal localization of TJ proteins, and normal TJ structure and barrier function. Microarray analysis of intestinal cells does not show significant changes in gene expression between CGN(-/-) and CGN(+/+) mice, whereas immunoblotting analysis shows a twofold increase in the levels of claudin 2 protein in the duodenum and the kidney of CGN(-/-) mice, compared to CGN(+/+) littermates. Furthermore, CGN(-/-) mice show an exacerbated response to the ulcerogenic action of cysteamine, whereas acute injury of the colon by dextran sodium sulfate elicits undistinguishable responses in CGN(-/-) and CGN(+/+) mice. We conclude that at the organism level cingulin is dispensable for the structure and barrier function of TJ, and is embedded in signaling networks that control the expression of claudin-2, and the mucosal response to acute injury in the duodenum. PMID- 22946047 TI - Focal adhesion disassembly is regulated by a RIAM to MEK-1 pathway. AB - Cell migration and invasion require regulated turnover of integrin-dependent adhesion complexes. Rap1-GTP-interacting adaptor molecule (RIAM) is an adaptor protein that mediates talin recruitment to the cell membrane, and whose depletion leads to defective melanoma cell migration and invasion. In this study, we investigated the potential involvement of RIAM in focal adhesion (FA) dynamics. RIAM-depleted melanoma and breast carcinoma cells displayed an increased number, size and stability of FAs, which accumulated centrally at the ventral cell surface, a phenotype caused by defective FA disassembly. Impairment in FA disassembly resulting from RIAM knockdown correlated with deficient integrin dependent mitogen-activated protein kinase kinase (MEK)-Erk1/2 activation and, importantly, overexpression of constitutively active MEK resulted in rescue of FA disassembly and recovery of cell invasion. Furthermore, RIAM-promoted Ras homologue gene family, member A (RhoA) activation following integrin engagement was needed for subsequent Erk1/2 activation. In addition, RhoA overexpression partially rescued the FA phenotype in RIAM-depleted cells, also suggesting a functional role for RhoA downstream of RIAM, but upstream of Erk1/2. RIAM knockdown also led to enhanced phosphorylation of paxillin Tyr118 and Tyr31. However, expression of phosphomimetic and nonphosphorylatable mutants at these paxillin residues indicated that paxillin hyperphosphorylation is a subsequent consequence of the blockade of FA disassembly, but does not cause the FA phenotype. RIAM depletion also weakened the association between FA proteins, suggesting that it has important adaptor roles in the correct assembly of adhesion complexes. Our data suggest that integrin-triggered, RIAM-dependent MEK activation represents a key feedback event required for efficient FA disassembly, which could help explain the role of RIAM in cell migration and invasion. PMID- 22946048 TI - Autocrine regulation of TGF-beta1-induced cell migration by exocytosis of ATP and activation of P2 receptors in human lung cancer cells. AB - TGF-beta1 plays a key role in cancer progression through induction of various biological effects, including cell migration. Extracellular nucleotides, such as ATP, released from cells play a role in signaling through activation of P2 receptors. We show here that exocytosis of ATP followed by activation of P2 receptors play a key role in TGF-beta1-induced actin remodeling associated with cell migration. Treatment with TGF-beta1 facilitated migration of human lung cancer A549 cells, which was blocked by pretreatment with ecto-nucleotidase and P2 receptor antagonists. ATP and P2 agonists facilitated cell migration. TGF beta1-induced actin remodeling, which contributes to cell migration, was also suppressed by pretreatment with ecto-nucleotidase and P2 receptor antagonists. Knockdown of P2X7 receptor suppressed TGF-beta1-induced migration and actin remodeling. These results indicate the involvement of TGF-beta1-induced ATP release in cell migration, at least in part, through activation of P2X7 receptors. TGF-beta1 caused release of ATP from A549 cells within 10 minutes. Both ATP-enriched vesicles and expression of a vesicular nucleotide transporter (VNUT) SLC17A9, which is responsible for exocytosis of ATP, were found in cytosol of A549 cells. TGF-beta1 failed to induce release of ATP from SLC17A9-knockdown cells. TGF-beta1-induced cell migration and actin remodeling were also decreased in SLC17A9-knockdown cells. These results suggest the importance of exocytosis of ATP in cell migration. We conclude that autocrine signaling through exocytosis of ATP and activation of P2 receptors is required for the amplification of TGF-beta1 induced migration of lung cancer cells. PMID- 22946049 TI - Visualization of the moment of mouse sperm-egg fusion and dynamic localization of IZUMO1. AB - Gene disruption experiments have proven that the acrosomal protein IZUMO1 is essential for sperm-egg fusion in the mouse. However, despite its predicted function, it is not expressed on the surface of ejaculated spermatozoa. Here, we report the dynamics of diffusion of IZUMO1 from the acrosomal membrane to the sperm surface at the time of the acrosome reaction, visualized using a fluorescent protein tag. IZUMO1 showed a tendency to localize in the equatorial segment of the sperm surface after the acrosome reaction. This region is considered to initiate fusion with the oolemma. The moment of sperm-egg fusion and the dynamic movements of proteins during fusion were also imaged live. Translocation of IZUMO1 during the fertilization process was clarified, and a fundamental mechanism in mammalian fertilization is postulated. PMID- 22946050 TI - Vimentin and the K-Ras-induced actin-binding protein control inositol-(1,4,5) trisphosphate receptor redistribution during MDCK cell differentiation. AB - Inositol-(1,4,5)-triphosphate receptors (InsP(3)Rs) are ligand-gated Ca(2+) channels that control Ca(2+) release from intracellular stores and play a central role in a wide range of cellular responses. In most epithelial cells, InsP(3)Rs are not uniformly distributed within the endoplasmic reticulum (ER) membrane, with the consequence that agonist stimulation results in compartmentalized Ca(2+) signals. Despite these observations, little is known about the mechanisms that regulate the intracellular localization of InsP(3)Rs. Here, we report that exogenously expressed InsP(3)R1-GFP and endogenous InsP(3)R3 interact with the K Ras-induced actin-binding protein (KRAP) in both differentiated and undifferentiated Madin-Darby canine kidney (MDCK) cells. KRAP mediates InsP(3)R clustering in confluent MDCK cells and functions as an adapter, linking InsP(3)Rs to vimentin intermediate filaments. Upon epithelial differentiation, KRAP and vimentin are both required for InsP(3)R accumulation at the periphery of MDCK cells. Finally, KRAP associates with vimentin in chicken B lymphocytes and with keratins in a breast cancer cell line devoid of vimentin. Collectively, our data suggest that intermediate filaments in conjunction with KRAP may govern the localization of InsP(3)Rs in a large number of cell types (including epithelial cells) and in various physiological or pathological contexts. PMID- 22946051 TI - Mutations in Cog7 affect Golgi structure, meiotic cytokinesis and sperm development during Drosophila spermatogenesis. AB - The conserved oligomeric Golgi (COG) complex plays essential roles in Golgi function, vesicle trafficking and glycosylation. Deletions in the human COG7 gene are associated with a rare multisystemic congenital disorder of glycosylation that causes mortality within the first year of life. In this paper, we characterise the Drosophila orthologue of COG7 (Cog7). Loss-of-function Cog7 mutants are viable but male sterile. The Cog7 gene product is enriched in the Golgi stacks and in Golgi-derived structures throughout spermatogenesis. Mutations in the Cog7 gene disrupt Golgi architecture and reduce the number of Golgi stacks in primary spermatocytes. During spermiogenesis, loss of the Cog7 protein impairs the assembly of the Golgi-derived acroblast in spermatids and affects axoneme architecture. Similar to the Cog5 homologue, four way stop (Fws), Cog7 enables furrow ingression during cytokinesis. We show that the recruitment of the small GTPase Rab11 and the phosphatidylinositol transfer protein Giotto (Gio) to the cleavage site requires a functioning wild-type Cog7 gene. In addition, Gio coimmunoprecipitates with Cog7 and with Rab11 in the testes. Our results altogether implicate Cog7 as an upstream component in a gio-Rab11 pathway controlling membrane addition during cytokinesis. PMID- 22946052 TI - The SH2-domain-containing inositol 5-phosphatase (SHIP) limits the motility of neutrophils and their recruitment to wounds in zebrafish. AB - Neutrophil recruitment to sites of injury or infection is essential for host defense, but it needs to be tightly regulated to prevent tissue damage. Phosphoinositide 3-kinase (PI3K), which generates the phosphatidylinositol (3,4,5)-trisphosphate [PI(3,4,5)P(3)], is necessary for neutrophil motility in vivo; however, the role of SH2-domain-containing 5-inositol phosphatase (SHIP) enzymes, which hydrolyze PI(3,4,5)P(3) to phosphatidylinositol 3,4-bisphosphate [PI(3,4)P(2)], is not well understood. Here we show that SHIP phosphatases limit neutrophil motility in live zebrafish. Using real-time imaging of bioprobes specific for PI(3,4,5)P(3) and PI(3,4)P(2) in neutrophils, we found that PI(3,4,5)P(3) and PI(3,4)P(2) accumulate at the leading edge while PI(3,4)P(2) also localizes to the trailing edge of migrating neutrophils in vivo. Depletion of SHIP phosphatases using morpholino oligonucleotides led to increased neutrophil 3D motility and neutrophil infiltration into wounds. The increase in neutrophil wound recruitment in SHIP morphants was rescued by treatment with low dose PI3Kgamma inhibitor, suggesting that SHIP limits neutrophil motility by modulating PI3K signaling. Moreover, overexpression of the SHIP phosphatase domain in neutrophils impaired neutrophil 3D migration. Taken together, our findings suggest that SHIP phosphatases control neutrophil inflammation by limiting neutrophil motility in vivo. PMID- 22946053 TI - Arsenite interferes with protein folding and triggers formation of protein aggregates in yeast. AB - Several metals and metalloids profoundly affect biological systems, but their impact on the proteome and mechanisms of toxicity are not fully understood. Here, we demonstrate that arsenite causes protein aggregation in Saccharomyces cerevisiae. Various molecular chaperones were found to be associated with arsenite-induced aggregates indicating that this metalloid promotes protein misfolding. Using in vivo and in vitro assays, we show that proteins in the process of synthesis/folding are particularly sensitive to arsenite-induced aggregation, that arsenite interferes with protein folding by acting on unfolded polypeptides, and that arsenite directly inhibits chaperone activity. Thus, folding inhibition contributes to arsenite toxicity in two ways: by aggregate formation and by chaperone inhibition. Importantly, arsenite-induced protein aggregates can act as seeds committing other, labile proteins to misfold and aggregate. Our findings describe a novel mechanism of toxicity that may explain the suggested role of this metalloid in the etiology and pathogenesis of protein folding disorders associated with arsenic poisoning. PMID- 22946054 TI - Oxygen sensing by the prolyl-4-hydroxylase PHD2 within the nuclear compartment and the influence of compartmentalisation on HIF-1 signalling. AB - Hypoxia-inducible factors (HIFs) regulate more than 200 genes involved in cellular adaptation to reduced oxygen availability. HIFs are heterodimeric transcription factors that consist of one of three HIF-alpha subunits and a HIF beta subunit. Under normoxic conditions the HIF-alpha subunit is hydroxylated by members of a family of prolyl-4-hydroxylase domain (PHD) proteins, PHD1, PHD2 and PHD3, resulting in recognition by von-Hippel-Lindau protein, ubiquitylation and proteasomal degradation. It has been suggested that PHD2 is the key regulator of HIF-1alpha stability in vivo. Previous studies on the intracellular distribution of PHD2 have provided evidence for a predominant cytoplasmic localisation but also nuclear activity of PHD2. Here, we investigated functional nuclear transport signals in PHD2 and identified amino acids 196-205 as having a crucial role in nuclear import, whereas amino acids 6-20 are important for nuclear export. Fluorescence resonance energy transfer (FRET) showed that an interaction between PHD2 and HIF-1alpha occurs in both the nuclear and cytoplasmic compartments. However, a PHD2 mutant that is restricted to the cytoplasm does not interact with HIF-1alpha and shows less prolyl hydroxylase activity for its target HIF-1alpha than wild-type PHD2 located in the nucleus. Here, we present a new model by which PHD2-mediated hydroxylation of HIF-1alpha predominantly occurs in the cell nucleus and is dependent on very dynamic subcellular trafficking of PHD2. PMID- 22946055 TI - NO-beta-catenin crosstalk modulates primitive streak formation prior to embryonic stem cell osteogenic differentiation. AB - Nitric oxide (NO) has been shown to play a crucial role in bone formation in vivo. We sought to determine the temporal effect of NO on murine embryonic stem cells (ESCs) under culture conditions that promote osteogenesis. Expression profiles of NO pathway members and osteoblast-specific markers were analyzed using appropriate assays. We found that NO was supportive of osteogenesis specifically during an early phase of in vitro development (days 3-5). Furthermore, ESCs stably overexpressing the inducible NO synthase showed accelerated and enhanced osteogenesis in vitro and in bone explant cultures. To determine the role of NO in early lineage commitment, a stage in ESC differentiation equivalent to primitive streak formation in vivo, ESCs were transfected with a T-brachyury-GFP reporter. Expression levels of T-brachyury and one of its upstream regulators, beta-catenin, the major effector in the canonical Wnt pathway, were responsive to NO levels in differentiating primitive streak like cells. Our results indicate that NO may be involved in early differentiation through regulation of beta-catenin and T-brachyury, controlling the specification of primitive-streak-like cells, which may continue through differentiation to later become osteoblasts. PMID- 22946056 TI - Division of the intermediate compartment at the onset of mitosis provides a mechanism for Golgi inheritance. AB - As mammalian cells prepare for mitosis, the Golgi ribbon is first unlinked into its constituent stacks and then transformed into spindle-associated, pleiomorphic membrane clusters in a process that remains enigmatic. Also, it remains unclear whether Golgi inheritance involves the incorporation of Golgi enzymes into a pool of coat protein I (COPI) vesicles, or their COPI-independent transfer to the endoplasmic reticulum (ER). Based on the observation that the intermediate compartment (IC) at the ER-Golgi boundary is connected to the centrosome, we examined its mitotic fate and possible role in Golgi breakdown. The use of multiple imaging techniques and markers revealed that the IC elements persist during the M phase, maintain their compositional and structural properties and remain associated with the mitotic spindle, forming circular arrays at the spindle poles. At G2/M transition, the movement of the pericentrosomal domain of the IC (pcIC) to the cell centre and its expansion coincide with the unlinking of the Golgi ribbon. At prophase, coupled to centrosome separation, the pcIC divides together with recycling endosomes, providing novel landmarks for mitotic entry. We provide evidence that the permanent IC elements function as way stations during the COPI-dependent dispersal of Golgi components at prometa- and metaphase, indicating that they correspond to the previously described Golgi clusters. In addition, they continue to communicate with the vesicular 'Golgi haze' and thus are likely to provide templates for Golgi reassembly. These results implicate the IC in mitotic Golgi inheritance, resulting in a model that integrates key features of the two previously proposed pathways. PMID- 22946058 TI - Acentrosomal spindle organization renders cancer cells dependent on the kinesin HSET. AB - Centrosomes represent the major microtubule organizing centers (MTOCs) of animal somatic cells and orchestrate bipolar spindle assembly during mitotic cell division. In meiotic cells, the kinesin HSET compensates for the lack of centrosomes by focusing acentrosomal MTOCs into two spindle poles. By clustering multiple centrosomes into two spindle poles, HSET also mediates bipolar mitosis in cancer cells with supernumerary centrosomes. However, although dispensable in non-transformed human cells, the role of HSET in cancer cells with two centrosomes has remained elusive. In this study, we demonstrate that HSET is required for proper spindle assembly, stable pole-focusing and survival of cancer cells irrespective of normal or supernumerary centrosome number. Strikingly, we detected pronounced acentrosomal MTOC structures in untreated mitotic cancer cells. While in most cancer cells these acentrosomal MTOCs were rapidly incorporated into the assembling bipolar spindle, some cells eventually established bipolar spindles with acentrosomal poles and free centrosomes. These observations demonstrate that acentrosomal MTOCs were functional and that both centrosomal and acentrosomal mechanisms were required for bipolar spindle organization. Our study shows that HSET is critical for clustering acentrosomal and centrosomal MTOCs during spindle formation in human cancer cells with two bona fide centrosomes. Furthermore, we show that in checkpoint-defective cancer cells, acentrosomal spindle formation and HSET-dependence are partially mediated by a constitutive activation of the DNA damage response. In summary, we propose that acentrosomal spindle assembly mechanisms are hyperactive in cancer cells and promote HSET, a key driver of acentrosomal spindle organization, as an attractive target for cancer therapy. PMID- 22946057 TI - Upon Wnt stimulation, Rac1 activation requires Rac1 and Vav2 binding to p120 catenin. AB - A role for Rac1 GTPase in canonical Wnt signaling has recently been demonstrated, showing that it is required for beta-catenin translocation to the nucleus. In this study, we investigated the mechanism of Rac1 stimulation by Wnt. Upregulation of Rac1 activity by Wnt3a temporally correlated with enhanced p120 catenin binding to Rac1 and Vav2. Vav2 and Rac1 association with p120-catenin was modulated by phosphorylation of this protein, which was stimulated upon serine/threonine phosphorylation by CK1 and inhibited by tyrosine phosphorylation by Src or Fyn. Acting on these two post-translational modifications, Wnt3a induced the release of p120-catenin from E-cadherin, enabled the interaction of p120-catenin with Vav2 and Rac1, and facilitated Rac1 activation by Vav2. Given that p120-catenin depletion disrupts gastrulation in Xenopus, we analyzed p120 catenin mutants for their ability to rescue this phenotype. In contrast to the wild-type protein or other controls, p120-catenin point mutants that were deficient in the release from E-cadherin or in Vav2 or Rac1 binding failed to rescue p120-catenin depletion. Collectively, these results indicate that binding of p120-catenin to Vav2 and Rac1 is required for the activation of this GTPase upon Wnt signaling. PMID- 22946059 TI - Anoctamins are a family of Ca2+-activated Cl- channels. AB - Anoctamin 1 (Ano1; TMEM16A) and anoctamin 2 (Ano2; TMEM16B) are novel Cl(-) channels transiently activated by an increase in intracellular Ca(2+). These channels are essential for epithelial Cl(-) secretion, smooth muscle peristalsis and olfactory signal transduction. They are central to inherited diseases and cancer and can act as heat sensors. Surprisingly, another member of this protein family, Ano6, operates as a Ca(2+)-activated phospholipid scramblase, and others were reported as intracellular proteins. It is therefore unclear whether anoctamins constitute a family of Ca(2+)-activated Cl(-) channels, or are proteins with heterogeneous functions. Using whole-cell patch clamping we demonstrate that Ano4-10 are all able to produce transient Ca(2+)-activated Cl(-) currents when expressed in HEK293 cells. Although some anoctamins (Ano1, 2, 4, 6, 7) were found to be well expressed in the plasma membrane, others (Ano8, 9, 10) show rather poor membrane expression and were mostly retained in the cytosol. The transient nature of the Cl(-) currents was demonstrated to be independent of intracellular Ca(2+) levels. We show that inactivation of Ano1 currents occurs in the continuous presence of elevated Ca(2+) concentrations, possibly by calmodulin dependent kinase. The present results demonstrate that anoctamins are a family of Ca(2+)-activated Cl(-) channels, which also induce permeability for cations. They may operate as Cl(-) channels located in the plasma membrane or in intracellular compartments. These results increase our understanding of the physiological significance of anoctamins and their role in disease. PMID- 22946061 TI - PINCH-1 promotes Bcl-2-dependent survival signalling and inhibits JNK-mediated apoptosis in the primitive endoderm. AB - The focal adhesion (FA) protein PINCH-1 is required for the survival of primitive endoderm (PrE) cells. How PINCH-1 regulates this fundamental process is not known. Here, we use embryoid bodies (EBs) and isolated EB-derived PrE cells to investigate the mechanisms by which PINCH-1 promotes PrE survival. We report that loss of PINCH-1 in PrE cells leads to a sustained activity of JNK and the pro apoptotic factor Bax. Mechanistically, the sustained JNK activation was due to diminished levels of the JNK inhibitory factor Ras suppressor protein-1 (RSU-1), whose stability was severely reduced upon loss of PINCH-1. Chemical inhibition of JNK attenuated apoptosis of PrE cells but failed to reduce Bax activity. The increased Bax activity was associated with reduced integrin signalling and diminished Bcl-2 levels, which were shown to inhibit Bax. Altogether our findings show that PINCH-1 is a pro-survival factor that prevents apoptosis of PrE cells by modulating two independent signalling pathways; PINCH-1 inhibits JNK-mediated apoptosis by stabilising the PINCH-1 binding protein RSU-1 and promotes Bcl-2 dependent pro-survival signalling downstream of integrins. PMID- 22946060 TI - Microdomains of muscarinic acetylcholine and Ins(1,4,5)P3 receptors create 'Ins(1,4,5)P3 junctions' and sites of Ca2+ wave initiation in smooth muscle. AB - Increases in cytosolic Ca(2+) concentration ([Ca(2+)](c)) mediated by inositol (1,4,5)-trisphosphate [Ins(1,4,5)P(3), hereafter InsP(3)] regulate activities that include division, contraction and cell death. InsP(3)-evoked Ca(2+) release often begins at a single site, then regeneratively propagates through the cell as a Ca(2+) wave. The Ca(2+) wave consistently begins at the same site on successive activations. Here, we address the mechanisms that determine the Ca(2+) wave initiation site in intestinal smooth muscle cells. Neither an increased sensitivity of InsP(3) receptors (InsP(3)R) to InsP(3) nor regional clustering of muscarinic receptors (mAChR3) or InsP(3)R1 explained the selection of an initiation site. However, examination of the overlap of mAChR3 and InsP(3)R1 localisation, by centre of mass analysis, revealed that there was a small percentage (~10%) of sites that showed colocalisation. Indeed, the extent of colocalisation was greatest at the Ca(2+) wave initiation site. The initiation site might arise from a selective delivery of InsP(3) from mAChR3 activity to particular InsP(3)Rs to generate faster local [Ca(2+)](c) increases at sites of colocalisation. In support of this hypothesis, a localised subthreshold 'priming' InsP(3) concentration applied rapidly, but at regions distant from the initiation site, shifted the wave to the site of the priming. Conversely, when the Ca(2+) rise at the initiation site was rapidly and selectively attenuated, the Ca(2+) wave again shifted and initiated at a new site. These results indicate that Ca(2+) waves initiate where there is a structural and functional coupling of mAChR3 and InsP(3)R1, which generates junctions in which InsP(3) acts as a highly localised signal by being rapidly and selectively delivered to InsP(3)R1. PMID- 22946063 TI - A practical issue. PMID- 22946064 TI - Commentary: risk prediction models for people with Type 2 diabetes. PMID- 22946062 TI - The SNF2 family ATPase LSH promotes phosphorylation of H2AX and efficient repair of DNA double-strand breaks in mammalian cells. AB - LSH, a protein related to the SNF2 family of chromatin-remodelling ATPases, is essential for the correct establishment of DNA methylation levels and patterns in plants and mammalian cells. However, some of the phenotypes resulting from LSH deficiency cannot be explained easily by defects in DNA methylation. Here we show that LSH-deficient mouse and human fibroblasts show reduced viability after exposure to ionizing radiation and repair DNA double-strand breaks less efficiently than wild-type cells. A more detailed characterisation of this phenotype revealed that, in the absence of LSH, the histone variant H2AX is not efficiently phosphorylated in response to DNA damage. This results in impaired recruitment of MDC1 and 53BP1 proteins to DNA double-strand breaks and compromises phosphorylation of checkpoint kinase CHK2. Furthermore, we demonstrate that the ability of LSH to hydrolyse ATP is necessary for efficient phosphorylation of H2AX at DNA double-strand breaks and successful repair of DNA damage. Taken together, our data reveal a previously unsuspected role of LSH ATPase in the maintenance of genome stability in mammalian somatic cells, which is independent of its function in de novo DNA methylation during development. PMID- 22946065 TI - New Zealand Diabetes Cohort Study cardiovascular risk score for people with Type 2 diabetes: validation in the PREDICT cohort. AB - INTRODUCTION: New Zealand (NZ) guidelines recommend treating people for cardiovascular disease (CVD) risk on the basis of five-year absolute risk using a NZ adaptation of the Framingham risk equation. A diabetes-specific Diabetes Cohort Study (DCS) CVD predictive risk model has been developed and validated using NZ Get Checked data. AIM: To revalidate the DCS model with an independent cohort of people routinely assessed using PREDICT, a web-based CVD risk assessment and management programme. METHODS: People with Type 2 diabetes without pre-existing CVD were identified amongst people who had a PREDICT risk assessment between 2002 and 2005. From this group we identified those with sufficient data to allow estimation of CVD risk with the DCS models. We compared the DCS models with the NZ Framingham risk equation in terms of discrimination, calibration, and reclassification implications. RESULTS: Of 3044 people in our study cohort, 1829 people had complete data and therefore had CVD risks calculated. Of this group, 12.8% (235) had a cardiovascular event during the five-year follow-up. The DCS models had better discrimination than the currently used equation, with C statistics being 0.68 for the two DCS models and 0.65 for the NZ Framingham model. DISCUSSION: The DCS models were superior to the NZ Framingham equation at discriminating people with diabetes who will have a cardiovascular event. The adoption of a DCS model would lead to a small increase in the number of people with diabetes who are treated with medication, but potentially more CVD events would be avoided. PMID- 22946066 TI - Early connections: effectiveness of a pre-call intervention to improve immunisation coverage and timeliness. AB - INTRODUCTION: Children who have missed or delayed immunisations are at greater risk of vaccine-preventable diseases and getting their first scheduled dose on time strongly predicts subsequent complete immunisation. Developing a relationship with an infant's parents and general practice staff soon after birth followed by a systematic approach can reduce the number of delayed first immunisations. AIM: To assess the effectiveness of a general practice-based pre call intervention to improve immunisation timeliness. METHODS: Clustered controlled trial of general practices in a large urban district randomised to either delivery of pre-call intervention to all babies at aged four weeks or usual care. RESULTS: Immunisation timeliness for infants receiving the primary series of immunisations among their nominated Auckland general practices was higher than expected at 98% for the six week event. The intervention was statistically but not clinically significant. Coverage was significantly lower among infants with no nominated practice which reduced overall coverage rate for the district. DISCUSSION: Pre-call letters with telephone follow-up are simple interventions to introduce into the practice management system and can be easily implemented as usual standard of care. Early identification of newborn infants, primary care engagement and effective systems including tracking of infants not enrolled in general practices has the greatest potential to improve immunisation coverage rates even further. PMID- 22946067 TI - PSA testing in general practice. AB - INTRODUCTION: In New Zealand, prostate-specific antigen (PSA) testing has increased significantly (275 000 tests/year). Controversy exists around PSA testing as part of an unorganised screening programme. AIM: To look at the use of PSA testing in a sample of general practices and investigate the reasons GPs undertake PSA testing. METHODS: Five Waikato general practices investigated looking at PSA laboratory tests of men >=40 years in 2010 compared against GP notes. Testing rates, reasons for testing, histology and referral/s were examined for different age groups. A questionnaire was sent to the GPs to determine their views on PSA testing. RESULTS: One in four men aged 40+ years had a PSA test in 2010. Of these men, 71% were asymptomatic. More than half of men tested aged 70+ years were asymptomatic. Ten percent of all PSA tests were elevated. Twenty-one of 23 prostate cancers were diagnosed following an elevated PSA test: more than 80% of these men had histories of prostate pathology or lower urinary tract symptoms. The questionnaire confirmed that GPs believe in the benefits of PSA screening and it also showed they had difficulty in providing patients with information about pros and cons of PSA testing. DISCUSSION: All GPs in this study tested asymptomatic men. GPs in this study value PSA screening and believe that it reduces mortality rates. However, although PSA tests were most frequently done on asymptomatic patients, the majority of patients subsequently diagnosed with prostate cancer had been tested because of symptoms or had previous prostate problems. PMID- 22946068 TI - The incidence of acute otitis media in New Zealand children under five years of age in the primary care setting. AB - INTRODUCTION: Acute otitis media (AOM) is a common childhood infection. Baseline data are required to evaluate potential changes in the epidemiology of AOM with new public health measures. AIM: To estimate the incidence of AOM in children under five years of age in primary care in New Zealand. METHODS: Using a cohort study design, consultation notes from 1 November 2008 to 31 October 2009 from 63 primary care facilities were analysed for new and recurrent episodes of AOM, complications, antimicrobial use and outcome. RESULTS: There were 19 146 children in the sample. The raw incidence of AOM was 273 per 1000 children (27.3%; 95% CI 216-330). Of the 3885 children, 2888 (74%) had one episode of AOM and 152 (4%) of these children developed recurrent AOM. Incidence declined with age. There was no difference in incidence between Maori, Pacific and 'Other' ethnicities. Antibiotics were used to treat 2653 (51%) AOM episodes and 113 (4.3%) of these children re-presented within three days of antibiotic therapy for persistent symptoms. Tympanic membrane perforation was the only complication noted, observed in 62 (1%) episodes. DISCUSSION: These data indicate that AOM is an important and frequent childhood infection in New Zealand. The show a significant decline in the use of antibiotics to manage AOM in concordance with accepted best practice. The complication rate of AOM is likely under-represented. This study enables future research into the effectiveness of current and future immunisations and changing management practices in New Zealand. PMID- 22946069 TI - Does the order of presentation and number of online resources affect the frequency of access by learners? AB - INTRODUCTION: Provision of web-based resources is a valuable addition to face-to face teaching in a blended learning environment. AIM: To understand how both order of presentation and number of online resources impacts on the frequency of access by learners in postgraduate vocational training in general practice. METHODS: Information was collected on how many times individual online resources were accessed. Data regarding access rates for 15 separate topics used in postgraduate general practice vocational training were aggregated. Analysis was on the basis of order of presentation where the mean of percentages of hits by order of presentation with standard deviations was calculated. RESULTS: The first four listed resources were accessed at a higher rate than the remainder of the resources. All resources after the first four were accessed at a relatively uniform low rate. DISCUSSION: It would appear that providing more than four resources per topic is associated with learner overload. The number of online resources to support face-to-face teaching should be limited to four. Resource material needs to be carefully considered in terms of how it adds educational value. The ability of resource material to present a different perspective on a topic and adherence to both curriculum and assessment objectives are important considerations. PMID- 22946070 TI - Addressing patient alcohol use: a view from general practice. AB - INTRODUCTION: General practitioners (GPs) have the potential to promote alcohol harm minimisation via discussion of alcohol use with patients, but knowledge of GPs' current practice and attitudes on this matter is limited. Our aim was to assess GPs' current practice and attitudes towards discussing alcohol use with their patients. METHODS: This qualitative study involved semi-structured, face-to face interviews with 19 GPs by a group of medical students in primary care practices in Wellington, New Zealand. FINDINGS: Despite agreement amongst GPs about the importance of their role in alcohol harm minimisation, alcohol was not often raised in patient consultations. GPs' usual practice included referral to drug and alcohol services and advice. GPs were also aware of national drinking guidelines and alcohol screening tools, but in practice these were rarely utilised. Key barriers to discussing alcohol use included its societal 'taboo' nature, time constraints, and perceptions of patient dishonesty. CONCLUSION: In this study there is a fundamental mismatch between the health community's expectations of GPs to discuss alcohol with patients and the reality. Potential solutions to the most commonly identified barriers include screening outside the GP consultation, incorporating screening tools into existing software used by GPs, exploring with GPs the social stigma associated with alcohol misuse, and framing alcohol misuse as a health issue. As it is unclear if these approaches will change GP practice, there remains scope for the development and pilot testing of potential solutions identified in this research, together with an assessment of their efficacy in reducing hazardous alcohol consumption. PMID- 22946071 TI - Factors influencing diagnostic decision-making. AB - INTRODUCTION: Identifying influences on diagnostic decisions is important because diagnostic errors often have far-reaching consequences for an individual's future within the workforce and their eligibility for Accident Compensation Corporation funded treatment. Most investigations of factors biasing decision making have used quantitative techniques rather than qualitative methods. AIM: To identify factors influencing GPs' diagnostic decision-making and to develop a valid questionnaire to determine the desirability and importance of each factor's influence. METHODS: Focus groups and the Delphi method were combined with Rasch analysis to identify factors influencing GPs' diagnostic decision-making and then examine the strength and stability of ratings of the factors' desirability and importance. RESULTS: Thirty-nine factors were identified. Factors demonstrating high stability but no consensus included the importance of evidence-based medicine, the potential ramifications of a diagnosis, and the desirability of medicolegal issues. Factors for which there was disagreement in the first Delphi round but consensus in the second round included the importance of patient advocacy/support groups and the desirability of examination findings. Rasch analysis indicated that the questionnaire was close to the model (88.6% and 86.2% of variance in the ratings of importance and desirability explained). DISCUSSION: Participants readily identified factors influencing GPs' diagnostic decision making. Their ratings did not appear to support a prescriptive model of medicine, yet two cornerstones of prescriptive medicine, clinical information and probability of disease, were rated as highly desirable and important. PMID- 22946072 TI - Maori cultural adaptation of a brief mental health intervention in primary care. AB - INTRODUCTION: There are no brief psychological mental health interventions designed specifically for Maori in a primary care setting. AIM: To adapt an existing cognitive behavioural therapy-based, guided self-management intervention for near-threshold mental health syndromes in primary care, for Maori, and to examine its acceptability and effectiveness. METHODS: Semi-structured interviews with primary care clinicians and Maori patients were conducted to inform adaptations to the intervention. Clinicians were then trained in intervention delivery. Patients were recruited if they self-identified as Maori, were aged 18 65 years, were experiencing stress or distress and scored <=35 on the Kessler-10 (K10) measure of global psychological distress. Patient and clinician satisfaction was measured through a questionnaire and semi-structured interviews. Post-intervention, patients' mental health status was measured at two weeks, six weeks and three months. RESULTS: Maori adaptations included increased emphasis on forming a relationship; spirituality; increased use of Maori language and changes to imagery in the self-management booklets. Nine of the 16 patients recruited into the study completed the intervention. Patients and clinicians rated the intervention favourably and provided positive feedback. Improvement was seen in patients' K10 scores using intention-to-treat rated global psychological distress following intervention. DISCUSSION: This study found that it was not difficult to adapt an existing approach and resources, and they were well received by both providers and Maori patients. Further research is required with a larger sample utilising a randomised controlled trial, to establish whether this approach is effective. PMID- 22946073 TI - The anatomical placement of body organs by Australian and New Zealand patients and health professionals in general practice. AB - INTRODUCTION: Understanding patients' awareness of the anatomical placement of their body organs is important for doctor-patient communication. AIM: To measure the correct anatomical placement of body organs by people from Australian and New Zealand general practices METHOD: A questionnaire survey containing drawings of 11 organs placed in different locations within each drawing. RESULTS: Among 1156 participants, there was no difference in the proportion of correct placement of 11 organs between Australian (51.7%) and New Zealand (49.6%) general practices. There was a positive correlation between the proportion of correctly placed organs and the age participants left school (p=0.012) and a negative correlation with the number of GP visits in the previous year (p=0.040). Participants from rural Australia were more likely to correctly place organs than urban participants (p=0.018). The mean proportion of organs correctly placed for doctors was 80.5%, nurses 66.5%, allied health 61.5%, health administrators 50.6% and the remaining consulting patients 51.3%. DISCUSSION: Patients from Australian and New Zealand general practice were poorly aware of the correct placement of organs. Health professionals were moderately better than patients at correct placement. PMID- 22946075 TI - Hearing loss among Pacific peoples. PMID- 22946074 TI - Evaluation of Tu Meke PHO's Wairua Tangata Programme: a primary mental health initiative for underserved communities. AB - BACKGROUND AND CONTEXT: New Zealand's primary mental health initiatives (PMHIs) have successfully filled a health service gap and shown good outcomes for many presenting with mild to moderate anxiety/depression in primary health care settings. Maori have higher rates of mental health disorders and complexity of social and mental health needs not matched by access to PMHIs. ASSESSMENT OF PROBLEM: The Wairua Tangata Programme (WTP), a Hawkes Bay PMHI, aimed to provide an integrated, flexible, holistic, tikanga Maori-based therapeutic service targeting underserved Maori, Pacific and Quintile 5 populations. External evaluation of the programme provided formative and outcome feedback. RESULTS: The WTP reported high engagement of Maori (particularly women), low non-attendance rates, good improvements in mental health assessment exit scores, strong stakeholder support and service user gratitude. GPs reported willingness to explore mental health issues in this high needs population. Challenges included engaging Pacific peoples and males and recruiting from scarce Maori, Pacific and male therapist workforces. STRATEGIES FOR IMPROVEMENT: Effectively meeting the target population's complex social and therapeutic needs required considerable programme flexibility, referral back into the programme and assistance with transitioning to other therapeutic or social support services. Referral criteria required adaptation to accommodate some sectors, especially youth. A group programme was developed specifically for males. LESSONS: A holistic PMHI programme delivered with considerable flexibility and a skilled, culturally fluent team working closely with primary care providers can successfully engage and benefit underserved Maori communities with complex social and mental health needs. Successful targeted programmes are integral to reducing mental health disparities. PMID- 22946076 TI - Colloidal silver. PMID- 22946077 TI - From ladder to platform: a new concept for pain management. AB - BACKGROUND: Pain remains one of the top five reasons for consultations in general practice, presenting either alone or as comorbidity. The World Health Organization (WHO) analgesic ladder proposed in 1986 has been the cornerstone of pain management, but is often inadequate in daily practice, especially when dealing with the diverse nature and etiology of various pain conditions. There is a need for a better concept which is universally applicable that acknowledges the value of, and need for, other domains of treatment for pain. OBJECTIVE: This article reviews the original ideas of the WHO analgesic ladder and proposes its extension to a platform model in the context of pain management. DISCUSSION: Pain affects both the physical and psychological wellbeing of patients and should not be treated with pharmacotherapy alone. The model of WHO analgesic ladder provides guidelines for choosing the analgesic agents, but has its limitations. Incorporating the latest paradigm of neuromatrix theory, both acute and chronic pain should be best managed with a broader perspective incorporating multimodal non-pharmacological and supportive treatments, illustrated by the concept of interacting domains on a broad platform as presented in this article. Different levels of pain severity and chronicity necessitate different analgesic platforms of management, and the clinician should move up or down the appropriate platform to explore the various treatment options as per the status and needs of the patient. PMID- 22946078 TI - Frequently asked questions on measurement of bone mineral densitometry. PMID- 22946079 TI - Malaysian GAD-7 less sensitive than reported. PMID- 22946080 TI - Low-level phenolic estrogen pollutants impair islet morphology and beta-cell function in isolated rat islets. AB - Phenolic estrogen pollutants, a class of typical endocrine-disrupting chemicals, have attracted public attention due to their estrogenic activities of imitating steroid hormone 17beta-estradiol (E(2)) effects. Exposure to these pollutants may disrupt insulin secretion and be a risk factor for type 2 diabetes. In this study, we investigated the direct effects of phenolic estrogen diethylstilbestrol (DES), octylphenol (OP), nonylphenol (NP), and bisphenol A (BPA) on rat pancreatic islets in vitro, whose estrogenic activities were DES>NP>OP>BPA. Isolated beta-cells were exposed to E(2), DES, OP, NP, or BPA (0, 0.1, 0.5, 2.5, 25, and 250 MUg/l) for 24 h. Parameters of insulin secretion, content, and morphology of beta-cells were measured. In the glucose-stimulated insulin secretion test, E(2) and DES increased insulin secretion in a dose-dependent manner in a 16.7 mM glucose condition. However, for BPA, NP, or OP with lower estrogenic activity, the relationship between the doses and insulin secretion was an inverted U-shape. Moreover, OP, NP, or BPA (25 MUg/l) impaired mitochondrial function in beta-cells and induced remarkable swelling of mitochondria with loss of distinct cristae structure within the membrane, which was accompanied by disruption of mRNA expression of genes playing a key role in beta-cell function (Glut2 (Slc2a2), Gck, Pdx1, Hnf1alpha, Rab27a, and Snap25), and mitochondrial function (Ucp2 and Ogdh). Therefore, these phenolic estrogens can disrupt islet morphology and beta-cell function, and mitochondrial dysfunction is suggested to play an important role in the impairment of beta-cell function. PMID- 22946081 TI - Discrimination of functional hepatocytes derived from mesenchymal stem cells using FTIR microspectroscopy. AB - Functional hepatocytes differentiated in vitro from mesenchymal stem cells (MSCs) need to be fully characterized before they could be applied as a therapy to treat liver disease. Here, we employed Fourier Transform Infrared (FTIR) microspectroscopy to investigate the characteristics of hepatocyte-like cells derived from rat bone marrow mesenchymal stem cells (rBM-MSCs) by detecting changes in macromolecular composition occurring during the hepatogenesis process. Partial Least Squares Discriminant Analysis (PLS-DA) enabled us to discriminate undifferentiated rBM-MSCs, and early, mid-stage and late stage rBM-MSCs derived hepatocytes by their characteristic FTIR "spectroscopic signatures". The predominant spectroscopic changes responsible for this discrimination were changes in FTIR absorbance bands at: 3012 cm(-1) (cis C[double bond, length as m dash]C stretch from unsaturated lipids), 2952 cm(-1) (nu(as)CH(3) from lipids), 2854 cm(-1) (nu(s)CH(2) from lipids) and 1722 cm(-1) (C[double bond, length as m dash]O stretching from lipids), which were associated with triglyceride and unsaturated fatty acid accumulation in the hepatocyte-like cells occurring during differentiation. Based on these findings, rBM-MSCs derived hepatocytes are characterized by high lipid content which facilitates a means of identifying hepatocytes from their stem cells progenitors by using FTIR microspectroscopy. Other complex changes in spectral bands assigned to proteins and nucleic acids were observed during hepatocyte differentiation indicating that mRNA translation was taking place producing proteins related to the formation of the new hepatocyte-like phenotype, which was corroborated by immunohistochemistry. The results show FTIR microspectroscopy combined with bioinformatic modeling constitutes a powerful new phenotypic-based methodology for monitoring and characterization of the process of stem cell differentiation leading to the formation of hepatocytes, providing complementary information to existing methodologies such as immunohistochemistry and gene analysis, but having advantages of being reagent-free and non-destructive of the sample. PMID- 22946082 TI - Ultrasonic-electrodeposition of hierarchical flower-like cobalt on petalage-like graphene hybrid microstructures for hydrazine sensing. AB - A facile, one-pot ultrasonic electrochemical method to synthesize hierarchical cobalt (Co)-nanoflowers on petalage-like graphene (GE) was developed. The hybrid microstructures were successfully evaluated as a new material for highly sensitive determination of hydrazine (N(2)H(4)). Scanning electron microscopic measurements displayed that the synthesized Co-GE exhibited a related hierarchical structure of a petalage-like GE homogeneous distribution as a matrix for the growth of smooth nanosheets-assembled Co nanoflowers. Co-GE was confirmed by energy dispersive X-ray spectrograms. Electrochemical methods were adopted to characterize the sensing properties of Co-GE towards the electrocatalytic oxidation of N(2)H(4) at 0.15 V in 0.1 M pH 7.0 sodium phosphate buffered saline. The sensor displayed a broad linearity of 0.25-370 MUM and 370 MUM to 2.2 mM with a relatively low detection limit of 0.1 MUM (S/N = 3) and a response time of less than 3 s. Furthermore, the sensor showed outstanding sensitivity and reproducibility. PMID- 22946083 TI - A clinic-based interdisciplinary intervention for mothers of children newly diagnosed with cancer: a pilot study. AB - OBJECTIVE: To determine the feasibility and acceptability of an interdisciplinary intervention for mothers of children newly diagnosed with cancer and to estimate effect sizes for the intervention in reducing distress. Management of illness uncertainty was a key framework for the intervention. METHODS: Mothers (N = 52) were randomly assigned to the intervention or a treatment as usual group, completing measures at baseline and follow-up time points. RESULTS: Mothers' satisfaction ratings were consistently high, and intervention implementation appeared feasible. Significant mean effects or trends in favor of the intervention group were found for pre-to-post change on measures of distress. Evidence of a preventative effect was also observed; mothers in the intervention group tended to improve or remain stable in their adjustment, whereas many parents in the treatment as usual group showed worsening outcomes. CONCLUSIONS: An interdisciplinary intervention targeting maternal illness uncertainty has clinical value within this sample. PMID- 22946084 TI - Reliability, validity, and measurement invariance of the German version of the physical activity enjoyment scale. AB - OBJECTIVE: The purpose of this work is to examine reliability, factorial- and criterion-related validity, and measurement invariance across age and gender of the Physical Activity Enjoyment Scale for children and adolescents in the German speaking population. METHODS: Confirmatory factor analysis was applied to questionnaire responses obtained from a cross-sectional sample (Study 1) of 250 girls and 254 boys and a longitudinal sample (Study 2) of 109 boys and 87 girls aged 9 to 17 years. RESULTS: Results indicated sufficient test-retest reliability (ICC = 0.76), internal consistency (alpha = 0.89), and criterion-related validity (r = 0.42 with a physical activity diary; r = 0.16 with accelerometry data). Confirmatory factor analyses partially supported the factorial validity and invariance. CONCLUSIONS: The German version of the Physical Activity Enjoyment Scale is sufficiently reliable and valid to be used for German-speaking children and adolescents. Further research examining the invariance over a longer period is warranted. PMID- 22946085 TI - Immobilization of pectinase from Leucoagaricus gongylophorus on magnetic particles. AB - Polygalacturonases (EC 3.2.1.15) hydrolyze the alpha-1,4-glycosidic linkages in polygalacturonic acid chains. The interest on specific inhibitors of pectinase and the versatility of magnetic support for enzyme immobilization endorsed the preparation of an immobilized enzyme reactor (IMER). This work presents the synthesis of CoFe(2)O(4) amino-derivatives, which was employed as the support for the immobilization of pectinases from Leucoagaricus gongylophorus. Amino functionalized CoFe(2)O(4) was obtained from glyceryl-derivatized CoFe(2)O(4) and was characterized by infrared spectroscopy and electronic microscopy. The immobilized enzyme maintained the same thermal, chemical and kinetic behaviour of the free enzyme (T(opt) 60 degrees C; pH(opt) 5.0; K(app)(M) = 0.5 mg min(-1); V(app)(M) ~ 5.0 MUmol min(-1) mL(-1)). The straightforward synthesis of CoFe(2)O(4) derivatives and the efficiency of immobilization offer wide perspectives for the use of the developed new IMER. PMID- 22946086 TI - A fluorescent chemosensor for detection of perchlorate ions in water. AB - 1-(4-Biphenyl)benzimidazolium based dipodal system acts as a highly selective fluorescent chemosensor for determination of perchlorate ions in aqueous buffer and in drinking water at concentrations lower than that permissible by EPA. (1)H NMR titration studies, Job's plot, X-ray crystal structure and theoretical studies reveal cavity based recognition. PMID- 22946087 TI - Vinorelbine inhibits angiogenesis and 95D migration via reducing hypoxic fibroblast stromal cell-derived factor 1 secretion. AB - Tumor stroma plays a prominent role in cancer progression. Fibroblasts constitute a majority of the stromal cells in tumor, and yet the functional contributions of these cells to tumor angiogenesis and invasion are poorly understood, especially the anticancer drug interference to these processes. To estimate the effects of vinorelbine (VNR) on fibroblast-associated tumor invasion and angiogenesis, we evaluated the response of 95D and human umbilical vein endothelial cell (HUVEC) migration, tube formation in vitro, as well as capillary formation of rat thoracic aorta rings to hypoxic MRC-5 conditioned medium (CM) by VNR pretreatment. Our results demonstrated that VNR significantly inhibited 95D and HUVEC migration and angiogenesis induced by hypoxic MRC-5 cells. We also showed that hypoxic MRC-5 CM (Hypo-CM) had a higher level of stromal cell-derived factor 1 (SDF-1) secretion, while Hypo-CM up-regulated the CXCR4 expression in HUVECs and 95Ds. This increased activity of SDF-1/CXCR4 paracrine was clearly attenuated by VNR pretreatment. It was further found that pretreating HUVECs and 95Ds with AMD3100, a CXCR4 antagonist, markedly reversed the Hypo-CM promoting cell migration and angiogenesis, while adding exogenous SDF-1 attenuated the inhibition effects of CM collected from VNR-pretreated hypoxic MRC-5 (Hypo-CMV). These data indicate that VNR indirectly decreased 95D migration and angiogenesis through its effect on hypoxic MRC-5, via impacting SDF-1/CXCR4 paracrine, suggesting that VNR could interrupt the influence of fibroblasts on HUVECs and 95Ds to exert an anticancer role. Therefore, fibroblasts should be taken into consideration when evaluating and developing anticancer drugs. PMID- 22946088 TI - Stearoyl-CoA desaturase activity modulates the activation of epidermal growth factor receptor in human lung cancer cells. AB - Stearoyl-CoA desaturase-1 (SCD1), the main enzyme that converts saturated fatty acids into monounsaturated fatty acids, is a key factor in the mechanisms of cancer cell proliferation, survival and tumorigenesis. Evidence indicates that SCD1 activity regulates these events in part by targeting the phosphatidylinositol-3 phosphate kinase/Akt and Ras/extracellular signal regulated kinase (ERK) pathways, but the molecular mechanisms remain unknown. We now show that in H460 lung cancer cells, the suppression of SCD activity with CVT 11127, a specific small molecule SCD inhibitor, impairs the ligand-induced phosphorylation of epidermal growth factor (EGF) receptor, causing the inactivation of its downstream targets Akt, ERK and mammalian target of rapamycin. Importantly, the mitogenic response to EGF was markedly defective in SCD-depleted cancer cells. The inactivation of EGF receptor (EGFR) promoted by SCD inhibition may be caused by perturbations in the lipid microenvironment surrounding the receptor, since we detected significant alterations in the lateral mobility of plasma lipid microdomains. Finally, incubation of lung cancer cells with SCD blockers potentiated the antigrowth effect of gefitinib, an EGFR inhibitor employed in cancer treatment. Altogether, our data indicate that SCD activity may control cancer cell metabolism, proliferation and survival by modulating the EGFR->Akt/ERK signaling platforms. Our studies also suggest a value for SCD inhibitors as novel pharmacological agents in lung cancer, one of the most common and lethal forms of cancer for which therapeutic options remain very limited. PMID- 22946090 TI - BAX gene over-expression via nucleofection to induce apoptosis in human lens epithelial cells. AB - Despite significant advances in cataract surgery techniques, posterior capsule opacification (PCO) remains a common complication. In PCO, remaining epithelial cells cloud the lens capsule and impair postoperative vision. This in vitro study was designed to investigate the potential of a gene-based approach, specifically over-expression of the proapoptotic BAX gene, to prevent PCO. Human lens epithelial cells (HLECs) were transfected by nucleofection with a plasmid encoding a fusion protein of green fluorescent protein and human BAX. The expression levels of BAX and its antiapoptotic counterpart BCL2 were determined by realtime reverse transcription polymerase chain reaction, Western blotting and immunofluorescence. BAX over-expression-induced cell death was analyzed by fluorescence-activated cell sorting using the Annexin V antibody. Fluorescence microscopy and transmission electron microscopy were used to assess changes in morphology and ultrastructure. Differential expression of the downstream apoptosis-related factor, caspase 3, was detected by Western blotting. Nucleofection efficiency was high (nearly 80%). BAX-transfected HLECs showed remarkably enhanced BAX gene expression and BAX:BCL2 ratio, but relatively little change in endogenous BCL2 expression. BAX over-expression also led to significant cytotoxicity, induction of apoptosis-related characteristics and activation of caspase 3. In conclusion, our results indicate that BAX gene over-expression can trigger cell death in HLECs via an apoptotic pathway. Thus, BAX may be a promising candidate for human gene therapy to treat PCO. PMID- 22946089 TI - Chronically inadequate sleep results in abnormal bone formation and abnormal bone marrow in rats. AB - Insufficient sleep over long durations of the lifespan is believed to adversely affect proper development and healthful aging, although how this might become manifested is unknown. In the present study, rats were repeatedly sleep restricted during 72 days to permit maladaptations to evolve, thereby permitting study. Densitometric and histomorphometric analyses were performed on harvested bone. In sleep-restricted rats, bone lined by osteoid was reduced 45-fold and osteoid thickness was decreased, compared with controls. This corresponded to a decrease in osteoblast number and activity. The percentage of bone lined by osteoclasts did not differ from that of controls. Plasma concentrations of an osteoclast marker (TRACP 5b) were increased in sleep-restricted rats, indicating increased bone resorption. The low amount of new bone formation without a reduction in bone resorption is diagnostic of osteopenia. Bone mineral density was decreased in femurs from sleep-restricted rats compared with controls, indicating osteoporosis. Red marrow in sleep-restricted rats contained only 37% of the fat and more than twice the number of megakaryocytes compared with that of the control rats. These findings in marrow suggest changed plasticity and increased hematopoiesis. Plasma concentrations of insulin-like growth factor-1, a known, major mediator of osteoblast differentiation and the proliferation of progenitor cells, was decreased by 30% in sleep-restricted rats. Taken together, these findings suggest that chronically inadequate sleep affects bone metabolism and bone marrow composition in ways that have implications for development, aging, bone healing and repair, and blood cell differentiation. PMID- 22946092 TI - Facile in situ characterization of gold nanoparticles on electrode surfaces by electrochemical techniques: average size, number density and morphology determination. AB - A fast and cheap in situ approach is presented for the characterization of gold nanoparticles from electrochemical experiments. The average size and number of nanoparticles deposited on a glassy carbon electrode are determined from the values of the total surface area and amount of gold obtained by lead underpotential deposition and by stripping of gold in hydrochloric acid solution, respectively. The morphology of the nanoparticle surface can also be analyzed from the "fingerprint" in lead deposition/stripping experiments. The method is tested through the study of gold nanoparticles deposited on a glassy carbon substrate by seed-mediated growth method which enables an easy control of the nanoparticle size. The procedure is also applied to the characterization of supplied gold nanoparticles. The results are in satisfactory agreement with those obtained via scanning electron microscopy. PMID- 22946091 TI - Carvedilol reduces the severity of atherosclerosis in apolipoprotein E-deficient mice via reducing superoxide production. AB - It has been shown that oxidative stress may play an important role in the development of atherosclerosis, and carvedilol has the capacity of reducing oxidative stress. Accordingly, we assessed the hypothesis that carvedilol may reduce the severity of atherosclerosis in apolipoprotein E (apoE)-deficient mice in addition to its hemodynamic effects. Atherosclerosis was induced in apoE deficient mice fed a high-fat diet containing 0.3% cholesterol. Mice were orally treated with propranolol (30 mg/kg/day), metoprolol (75 mg/kg/day) and carvedilol (10 mg/kg/day) over eight weeks (each group n = 7-9). Fatty streak plaque developed in apoE-deficient mice, and was suppressed in mice treated with all three drugs. The accumulation of macrophages and expression of CD4(+) and CD8(+) cells in the lesions were decreased by the treatment of the drugs, of which carvedilol was the most effective. In addition, carvedilol reduced superoxide production in aortic walls detected by ethidium staining. There were no significant changes in blood pressure among the study groups. The heart rates in the treated groups were decreased by 4%-12% compared with the control group, with carvedilol yielding the highest suppression of heart rate. The beta-blocker treatment did not significantly modify the serum lipid profiles. Carvedilol may suppress atherosclerosis via reducing superoxide production, in addition to the hemodynamic modifications in this animal model. PMID- 22946094 TI - Identification of a key intermediate in the asymmetric Appel process: one pot stereoselective synthesis of P-stereogenic phosphines and phosphine boranes from racemic phosphine oxides. AB - Sequential treatment of racemic phosphine oxides with oxalyl chloride and chiral non-racemic alcohol generates the same ratios of diastereomeric alkoxyphosphonium salts obtained in the corresponding asymmetric Appel process, strongly implicating the intermediate chlorophosphonium salt in the stereoselecting step. Subsequent reduction allows a novel synthesis of enantioenriched P-stereogenic phosphines-phosphine boranes. PMID- 22946093 TI - Light-triggered reversible assemblies of azobenzene-containing amphiphilic copolymer with beta-cyclodextrin-modified hollow mesoporous silica nanoparticles for controlled drug release. AB - Hollow mesoporous silica nanoparticles (HMSs) were modified by beta-cyclodextrin via a "click" reaction, an amphiphilic copolymer with a trans-azobenzene structure was then assembled onto beta-cyclodextrin to cover the surface of the HMSs. The prepared nanocomposites can release drugs in a "release-stop-release" manner by converting light irradiation. PMID- 22946095 TI - Age-related influence of vision and proprioception on Ia presynaptic inhibition in soleus muscle during upright stance. AB - This study investigated the modulation of Ia afferent input in young and elderly adults during quiet upright stance in normal and modified visual and proprioceptive conditions. The surface EMG of leg muscles, recruitment curve of the soleus (SOL) Hoffmann (H) reflex and presynaptic inhibition of Ia afferents from SOL, assessed with the D1 inhibition and single motor unit methods, were recorded when young and elderly adults stood with eyes open or closed on two surfaces (rigid vs. foam) placed over a force platform. The results showed that elderly adults had a longer path length for the centre of pressure and larger antero-posterior body sway across balance conditions (P < 0.05). Muscle EMG activities were greater in elderly compared with young adults (P < 0.05), whereas the H(max) expressed as a percentage of the H(max) was lower (P = 0.048) in elderly (38 +/- 16%) than young adults (58 +/- 16%). The conditioned H reflex/test H reflex ratio (D1 inhibition method) increased with eye closure and when standing on foam (P < 0.05), with greater increases for elderly adults (P = 0.019). These changes were accompanied by a reduced peak motor unit discharge probability when standing on rigid and foam surfaces (P 0.001), with a greater effect for elderly adults (P = 0.026). Based on these latter results, the increased conditioned H reflex/test H reflex ratio in similar sensory conditions is likely to reflect occlusion at the level of presynaptic inhibitory interneurones. Together, these findings indicate that elderly adults exhibit greater modulation of Ia presynaptic inhibition than young adults with variation in the sensory conditions during upright standing. PMID- 22946096 TI - Human standing is modified by an unconscious integration of congruent sensory and motor signals. AB - We investigate whether the muscle response evoked by an electrically induced vestibular perturbation during standing is related to congruent sensory and motor signals. A robotic platform that simulated the mechanics of a standing person was used to manipulate the relationship between the action of the calf muscles and the movement of the body. Subjects braced on top of the platform with the ankles sway referenced to its motion were required to balance its simulated body-like load by modulating ankle plantar-flexor torque. Here, afferent signals of body motion were congruent with the motor command to the calf muscles to balance the body. Stochastic vestibular stimulation (+/-4 mA, 0-25 Hz) applied during this task evoked a biphasic response in both soleus muscles that was similar to the response observed during standing for all subjects. When the body was rotated through the same motion experienced during the balancing task, a small muscle response was observed in only the right soleus and in only half of the subjects. However, the timing and shape of this response did not resemble the vestibular evoked response obtained during standing. When the balancing task was interspersed with periods of computer-controlled platform rotations that emulated the balancing motion so that subjects thought that they were constantly balancing the platform, coherence between the input vestibular stimulus and soleus electromyogram activity decreased significantly (P < 0.05) during the period when plantar-flexor activity did not affect the motion of the body. The decrease in coherence occurred at 175 ms after the transition to computer-controlled motion, which subjects did not detect until after 2247 ms (Confidence Interval 1801, 2693), and then only half of the time. Our results indicate that the response to an electrically induced vestibular perturbation is organised in the absence of conscious perception when sensory feedback is congruent with the underlying motor behaviour. PMID- 22946097 TI - Vestibular-mediated synaptic inputs and pathways to sympathetic preganglionic neurons in the neonatal mouse. AB - To assess when vestibulosympathetic projections become functional postnatally, and to establish a preparation in which vestibulosympathetic circuitry can be characterized more precisely, we used an optical approach to record VIIIth nerve evoked synaptic inputs to thoracic sympathetic preganglionic neurons (SPNs) in newborn mice. Stimulation of the VIIIth nerve was performed in an isolated brainstem-spinal cord preparation after retrogradely labelling with the fluorescent calcium indicator Calcium Green 1-conjugated dextran amine, the SPNs and the somatic motoneurons (MNs) in the thoracic (T) segments T2, 4, 6, 8, 10 and 12. Synaptically mediated calcium responses could be visualized and recorded in individual SPNs and MNs, and analysed with respect to latency, temporal pattern, magnitude and synaptic pharmacology. VIIIth nerve stimulation evoked responses in all SPNs and MNs investigated. The SPN responses had onset latencies from 90 to 200 ms, compared with much shorter latencies in MNs, and were completely abolished by mephenesin, a drug that preferentially reduces polysynaptic over monosynaptic transmission. Bicuculline and picrotoxin, but not strychnine, increased the magnitudes of the SPN responses without changing the onset latencies, suggesting a convergence of concomitant excitatory and inhibitory synaptic inputs. Lesions strategically placed to test the involvement of direct vestibulospinal pathways versus indirect pathways within the brainstem showed that vestibulosympathetic inputs in the neonate are mediated predominantly, if not exclusively, by the latter. Thus, already at birth, synaptic connections in the vestibulosympathetic reflex are functional and require the involvement of the ventrolateral medulla as in adult mammals. PMID- 22946098 TI - Endocannabinoids mediate the glucocorticoid-induced inhibition of excitatory synaptic transmission to dorsal raphe serotonin neurons. AB - Glucocorticoids play a critical role in the modulation of stress responses by controlling the function of the serotonin (5-HT) system. However, the precise effects of glucocorticoids on the excitability of dorsal raphe (DR) 5-HT neurons remain unknown. In this study, we investigated the effects of glucocorticoids on excitatory synaptic transmission to putative DR 5-HT neurons. We found that corticosterone or the synthetic glucocorticoid agonist dexamethasone rapidly suppressed glutamatergic synaptic transmission to DR 5-HT neurons by inhibiting glutamate release in the DR. This inhibitory effect was mimicked by membrane impermeable glucocorticoids, indicating the involvement of membrane-located corticosteroid receptors. The glucocorticoid-induced inhibition of glutamatergic transmission was mediated by the activation of postsynaptic G-protein-coupled receptors and signalled by retrograde endocannabinoid (eCB) messengers. Examination of the downstream mechanisms revealed that glucocorticoids enhance eCB signalling via an inhibition of cyclooxygenase-2. Together, these findings unravel a novel mechanism by which glucocorticoids control the excitability of DR 5-HT neurons and provide new insight into the rapid effects of stress hormones on the function of the 5-HT system. PMID- 22946099 TI - Sprint interval and endurance training are equally effective in increasing muscle microvascular density and eNOS content in sedentary males. AB - Sprint interval training (SIT) has been proposed as a time efficient alternative to endurance training (ET) for increasing skeletal muscle oxidative capacity and improving certain cardiovascular functions. In this study we sought to make the first comparisons of the structural and endothelial enzymatic changes in skeletal muscle microvessels in response to ET and SIT. Sixteen young sedentary males (age 21 +/- SEM 0.7 years, BMI 23.8 +/- SEM 0.7 kg m(-2)) were randomly assigned to 6 weeks of ET (40-60 min cycling at ~65% , 5 times per week) or SIT (4-6 Wingate tests, 3 times per week). Muscle biopsies were taken from the m. vastus lateralis before and following 60 min cycling at 65% to measure muscle microvascular endothelial eNOS content, eNOS serine(1177) phosphorylation, NOX2 content and capillarisation using quantitative immunofluorescence microscopy. Whole body insulin sensitivity, arterial stiffness and blood pressure were also assessed. ET and SIT increased skeletal muscle microvascular eNOS content (ET 14%; P < 0.05, SIT 36%; P < 0.05), with a significantly greater increase observed following SIT (P < 0.05). Sixty minutes of moderate intensity exercise increased eNOS ser(1177) phosphorylation in all instances (P < 0.05), but basal and post-exercise eNOS ser(1177) phosphorylation was lower following both training modes. All microscopy measures of skeletal muscle capillarisation (P < 0.05) were increased with SIT or ET, while neither endothelial nor sarcolemmal NOX2 was changed. Both training modes reduced aortic stiffness and increased whole body insulin sensitivity (P < 0.05). In conclusion, in sedentary males SIT and ET are effective in improving muscle microvascular density and eNOS protein content. PMID- 22946101 TI - Even highly correlated measures can add incrementally to predicting recidivism among sex offenders. AB - Criterion-referenced measures, such as those used in the assessment of crime and violence, prioritize predictive accuracy (discrimination) at the expense of construct validity. In this article, we compared the discrimination and incremental validity of three commonly used criterion-referenced measures for sex offenders (Rapid Risk Assessment for Sex Offence Recidivism [RRASOR], Static-99R, and Static-2002R). In a meta-analysis of 20 samples (n = 7,491), Static-99R and Static-2002R provided similar discrimination but outperformed the RRASOR in the prediction of sexual, violent, and any recidivism. Remarkably, despite large correlations between them (rs ranging from .70 to .92), these risk scales consistently added incremental validity to one another. The direction of the incremental effects, however, was not consistently positive. When controlling for the other measures, high scores on the RRASOR were associated with lower risk for violent and any recidivism. We also examined different methods of combining risk scales and found that the averaging approach produced better discrimination than choosing the highest score and produced better calibration than either choosing the lowest or highest risk score. The findings reinforce the importance of understanding the psychological content of criterion-referenced measures, even when the sole purpose is to predict a particular outcome and provide some direction concerning the best methods for combining risk scales. PMID- 22946100 TI - Low-fidelity GABA transmission within a dense excitatory network of the solitary tract nucleus. AB - Visceral primary afferents enter the CNS at the caudal solitary tract nucleus (NTS), and activate central pathways key to autonomic and homeostatic regulation. Excitatory transmission from primary solitary tract (ST)-afferents consists of multiple contacts originating from single axons that offer a remarkably high probability of glutamate release and high safety factor for ST afferent excitation. ST afferent activation sometimes triggers polysynaptic GABAergic circuits, which feedback onto second-order NTS neurons. Although inhibitory transmission is observed at second-order neurons, much less is known about the organization and mechanisms regulating GABA transmission. Here, we used a focal pipette to deliver minimal stimulus shocks near second-order NTS neurons in rat brainstem slices and directly activated single GABAergic axons. Most minimal focal shocks activated low jitter EPSCs from single axons with characteristics resembling ST afferents. Much less commonly (9% of sites), minimal focal shocks activated monosynaptic IPSCs at fixed latency (low jitter) that often failed (30%) and had no frequency-dependent facilitation or depression. These GABA release characteristics contrasted markedly to the unfailing, large amplitudes for glutamate released during ST-EPCSs recorded from the same neurons. Surprisingly, unitary GABAergic IPSCs were only weakly calcium dependent. In some neurons, strong focal shocks evoked compound IPSCs indicating convergent summation of multiple inhibitory axons. Our studies demonstrate that second-order NTS neurons receive GABAergic transmission from a diffuse network of inhibitory axons that rely on an intrinsically less reliable and substantially weaker release apparatus than ST excitation. Effective inhibition depends on co activation of convergent inputs to blunt excitatory drive. PMID- 22946102 TI - The detection of feigning using multiple PAI scale elevations: a new index. AB - Archival data were collected from 98 male inmates at a psychiatric inpatient unit to examine the utility of the Multiscale Feigning Index (MFI) as a proposed feigning index for the Personality Assessment Inventory (PAI). MFI was compared with existing PAI feigning indices, Malingering (MAL), Negative Impression Management (NIM), and Rogers Discriminant Function (RDF), using performance on the Structured Interview of Reported Symptoms (SIRS) as the feigning criterion. Regression analyses revealed that MFI was a stronger predictor of SIRS outcome than NIM, MAL, and RDF. In addition, NIM, MAL, and RDF did not add substantial incremental validity to MFI in predicting SIRS outcome. Receiver operating characteristic analyses revealed sensitivity of 68.89% and specificity of 94.34% at an MFI cutoff of more than 76, which compared favorably with the utility of NIM, MAL, and RDF. PMID- 22946103 TI - The convergent structure of DSM-5 personality trait facets and five-factor model trait domains. AB - The DSM-5 Personality and Personality Disorder Work Group have proposed diagnosing personality disorder based in part on 25 pathological traits. Initial research suggests that five factors explain the covariance among these traits and that these factors reflect the domains of the well-validated Five-Factor Model (FFM) of normative personality. This finding is important because it signifies the potential to apply normative trait research to personality disorder classification in the DSM-5. In this study, trait scale scores on the Personality Inventory for DSM-5 (PID-5) and domain scores from the FFM Rating Form (FFMRF) were subjected to a conjoint exploratory factor analysis (EFA) to test the higher order convergence of the DSM-5 pathological trait model and the FFM in a nonclinical sample (N = 808). Results indicate that the five higher-order factors of the conjoint EFA reflect the domains of the FFM. The authors briefly discuss implications of this correspondence between the normative FFM and the pathological PID-5. PMID- 22946105 TI - Civil commitment of sexually violent predators: the importance of diagnostics. PMID- 22946104 TI - Tumor cycling hypoxia induces chemoresistance in glioblastoma multiforme by upregulating the expression and function of ABCB1. AB - Tumor cycling hypoxia is now a well-recognized phenomenon in animal and human solid tumors. However, how tumor cycling hypoxia impacts chemotherapy is unclear. In the present study, we explored the impact and the mechanism of cycling hypoxia on tumor microenvironment-mediated chemoresistance. Hoechst 33342 staining and hypoxia-inducible factor-1 (HIF-1) activation labeling together with immunofluorescence imaging and fluorescence-activated cell sorting were used to isolate hypoxic tumor subpopulations from human glioblastoma xenografts. ABCB1 expression, P-glycoprotein function, and chemosensitivity in tumor cells derived from human glioblastoma xenografts or in vitro cycling hypoxic stress-treated glioblastoma cells were determined using Western blot analysis, drug accumulation and efflux assays, and MTT assay, respectively. ABCB1 expression and P glycoprotein function were upregulated under cycling hypoxia in glioblastoma cells concomitant with decreased responses to doxorubicin and BCNU. However, ABCB1 knockdown inhibited these effects. Moreover, immunofluorescence imaging and flow cytometric analysis for ABCB1, HIF-1 activation, and Hoechst 3342 in glioblastoma revealed highly localized ABCB1 expression predominantly in potentially cycling hypoxic areas with HIF-1 activation and blood perfusion in the solid tumor microenvironment. The cycling hypoxic tumor cells derived from glioblastoma xenografts exhibited higher ABCB1 expression, P-glycoprotein function, and chemoresistance, compared with chronic hypoxic and normoxic cells. Tumor-bearing mice that received YC-1, an HIF-1alpha inhibitor, exhibited suppressed tumor microenvironment-induced ABCB1 induction and enhanced survival rate in BCNU chemotherapy. Cycling hypoxia plays a vital role in tumor microenvironment-mediated chemoresistance through the HIF-1-dependent induction of ABCB1. HIF-1 blockade before and concurrent with chemotherapy could suppress cycling hypoxia-induced chemoresistance. PMID- 22946106 TI - Status compatibility and help-seeking behaviors among female intimate partner violence victims. AB - Given the far-reaching social, personal, and economic costs of crime and violence, as well as the lasting health effects, understanding how women respond to domestic violence and the types of help sought are critical in addressing intimate partner violence. We use a nationally representative dataset (Canadian General Social Survey, Personal Risk, 1999) to examine the help-seeking behaviors of female intimate partner violence victims (N = 250). Although victims of violent crime often do not call the police, many victims, particularly women who have been battered by their partner rely on family, friends, social service, and mental health interventions in dealing with the consequences of violent crime. We examine the role of income, education, and employment status in shaping women's decisions to seek help, and we treat these economic variables as symbolic and relative statuses as compared to male partners. Although family violence researchers have conceptualized the association between economic variables and the dynamics of intimate partner violence with respect to the structural dimensions of sociodemographic factors, feminist researchers connect economic power to family dynamics. Drawing on these literatures, we tap the power in marital and cohabiting relationships, rather than treating these variables as simply socioeconomic resources. Controlling for other relevant variables we estimate a series of multivariate models to examine the relationship between status compatibilities and help-seeking from both formal and informal sources. We find that status incompatibilities between partners that favor women increase the likelihood of seeking support in dealing with the impact of violence. PMID- 22946107 TI - Shifting policy responses to domestic violence in the Netherlands and Spain (1980 2009). AB - This article seeks to understand differences in the evolution of policies to combat domestic violence against women in the Netherlands and Spain. Although policy change is often viewed as incremental change toward more progressive policies, the two countries studied here reflect opposing dynamics. The Netherlands moved from being a pioneering country to one that gradually marginalized the policy issue, whereas Spain, in contrast, recently developed innovative and far-reaching policies after a long period of low to moderate state responses. The case study points to the central role of frame negotiation, left wing governments, and strong feminist mobilization. PMID- 22946108 TI - Married women's risk of STIs in developing countries: the role of intimate partner violence and partner's infection status. AB - Data for nationally representative samples of cohabiting couples in six developing countries show that intimate partner violence (IPV) increases the risk of self-reported sexually transmitted infections (STIs) for currently married women (ORs = 1.4-2.2) in all six countries, and that the strength of this relationship is not diminished by controls for proximate determinants such as husband's self-reported STI status and men's and women's higher-risk behaviors. The robustness of the IPV-STI relationship suggests the need to acknowledge IPV as an STI risk factor for women on par with other recognized risk factors such as multiple sexual partners and unprotected sexual intercourse. PMID- 22946109 TI - SVM annual meeting--June 2012 Minneapolis, MN, USA. PMID- 22946110 TI - Brachial artery occlusion in a young adult with an ACTA2 thoracic aortic aneurysm. AB - Mutations of the ACTA2 gene, which encodes the smooth muscle cell-specific isoform of alpha-actin protein, have recently been found to be among the most common genetic abnormalities observed in patients with familial thoracic aortic aneurysms/dissection (TAAD). Other reported vascular manifestations caused by these mutations include premature coronary artery disease and stroke. We report a young adult who presented with an acute brachial artery occlusion and was subsequently found to have aortopathy and an ACTA2 mutation. This expands the spectrum of vascular disease associated with ACTA2 mutation to include acute limb ischemia. PMID- 22946112 TI - The Neurology(r) podcast: 2007-2012: can you hear me now? PMID- 22946111 TI - Spirituality and well-being: focusing on what matters. PMID- 22946113 TI - Higher normal fasting plasma glucose is associated with hippocampal atrophy: The PATH Study. AB - OBJECTIVES: Substantial evidence showing an association between type 2 diabetes (T2D) and cerebral atrophy, cognitive impairment, and dementia is accumulating. However, relatively little is known about the subclinical effects of high plasma glucose levels within the normal range. The aim of this study was to investigate the association between plasma glucose levels and hippocampal and amygdalar atrophy in a sample of 266 cognitively healthy individuals free of T2D, aged 60 64 years, taking part in a longitudinal study of aging. METHODS: Fasting plasma glucose was assessed at wave 1. Hippocampal and amygdalar volumes were manually traced on 1.5 T MRI scans collected at wave 1 and at wave 2-4 years later. General linear model analyses were used to assess the relationship between plasma glucose and incident medial temporal lobe atrophy after controlling for a range of sociodemographic and health variables. RESULTS: Plasma glucose levels were found to be significantly associated with hippocampal and amygdalar atrophy and accounted for 6%-10% in volume change after controlling for age, sex, body mass index, hypertension, alcohol, and smoking. CONCLUSIONS: High plasma glucose levels within the normal range (<6.1 mmol/L) were associated with greater atrophy of structures relevant to aging and neurodegenerative processes, the hippocampus and amygdala. These findings suggest that even in the subclinical range and in the absence of diabetes, monitoring and management of plasma glucose levels could have an impact on cerebral health. If replicated, this finding may contribute to a reevaluation of the concept of normal blood glucose levels and the definition of diabetes. PMID- 22946114 TI - Giuseppe Ferrario and the epidemiology of apoplexy during the 19th century. AB - OBJECTIVE: To analyze the pioneering research of Giuseppe Ferrario (1802-1870) on the epidemiology of apoplexy. To our knowledge, his work might have been the first to systematically investigate the epidemiology of cerebrovascular accidents, with the aim of shedding light on the underlying causes. METHODS: A detailed analysis of the essay "Statistics of sudden deaths, more particularly of deaths from apoplexy, in the city and neighborhood of Milan, from 1750 to 1834," published by Ferrario in 1834. RESULTS: Ferrario conducted a large retrospective study on 13,360 people who died from apoplexy during an 84-year observational period. Analyzed data showed that these events were more frequent among men and during winter. Apoplexy was reported as mainly occurring at the age of 60; an increase in mortality was observed in young women aged between 21 and 30 years, probably due to an abuse of bloodletting. Ferrario introduced the term "hereditary apoplexy," being one of the first to hypothesize hereditary components in cerebrovascular diseases. He also tried to investigate the role of social conditions in the etiopathogenesis of these events, analyzing marital and employment status and suggesting to his colleagues that cultural and economic factors should be further examined. CONCLUSIONS: Giuseppe Ferrario may be considered as a pioneer of modern science and epidemiology and his work deserves consideration within the history of neurology and of neuroepidemiology. PMID- 22946115 TI - MRI and PET imaging discordance in neurosarcoidosis. PMID- 22946116 TI - Total daily physical activity and the risk of AD and cognitive decline in older adults. PMID- 22946117 TI - Alemtuzumab more effective than interferon beta-1a at 5-year follow-up of CAMMS223 clinical trial. PMID- 22946119 TI - Teaching NeuroImages: Atypical Wyburn-Mason syndrome. PMID- 22946120 TI - Teaching NeuroImages: CNS actinomycosis in an immunocompetent patient. PMID- 22946121 TI - Teaching NeuroImages: Syntelencephaly: Middle interhemispheric fusion. PMID- 22946122 TI - Nutritional status and lipid profile of young children in Brazil. AB - OBJECTIVE: To evaluate the nutritional status and lipid profile of young children from an urban Brazilian region. METHODS: Cross-sectional study involving a representative sample of 472 children aged 5-8 years from Jundiai city. The nutritional status was assessed by the body mass index for age. Total cholesterol and fractions (low-density lipoprotein cholesterol, high density lipoprotein cholesterol) and triglycerides concentrations were determined by automated enzymatic methods. The results were analyzed by the student t-test and Fisher exact test. RESULTS: Overweight/obesity was observed in 22% of the children and thinness in 3.2%. Girls presented a higher prevalence of overweight/obesity (24.0%) and lower levels of high-density lipoprotein cholesterol (22.8%) compared with boys (19.7% and 10.6%), respectively (p < 0.001). The prevalence of children with elevated and borderline total cholesterol was 32.8% and 26.7%, respectively, although 82.8% had desirable levels of high-density lipoprotein cholesterol. CONCLUSION: The prevalence of overweight/obesity and dyslipidaemia observed in these children is a matter of concern considering the age group evaluated. PMID- 22946123 TI - Racial disparities and avoidable infant mortality in a city of Southeastern Brazil, 2001-09. AB - This study aims to evaluate the quality of information about race/colour (black or white) in health information systems and to analyse the causes of infant mortality in the Brazilian List of Avoidable Causes of Death by race/colour in Belo Horizonte in 2001-09. Infant deaths and live births were obtained from the Brazilian Information Systems on Mortality and Live Births. After redistribution of missing data, infant mortality rate (IMR) was estimated for blacks and whites and was stratified by birth weight. Deaths were classified in avoidable, ill defined or non-avoidable causes. Regardless of birth weight, avoidable mortality rate was higher among black infants. Low quality of care during pregnancy and delivery was more likely among black women. Inadequate care of low-birth-weight black newborns also led to their increased risk of death. To reduce infant mortality and inequality, we must identify black infants as the most vulnerable group and increase the efficiency of health services in preventing avoidable deaths. PMID- 22946124 TI - Do findings differ across research design? The case of antidepressant use in pregnancy and malformations. AB - BACKGROUND: Many studies examining the teratogenic potential of antidepressants have been published. A variety of observational designs have been used with apparent conflicting results, although odds ratios were rarely >2. OBJECTIVES: To examine whether these apparent differences were associated with research methods such as model, comparison groups, data source, data collection procedures, definition of malformations, outcome ascertainment or management of confounders. METHODS: Medline and Embase were searched using terms: pregnancy, antidepressants, serotonin uptake inhibitors OR SSRI, AND embryonic structures OR congenital malformations OR fetal development for observational studies with original data. Data were analyzed using a structured approach and narrative review. Designs that were compared, included prospective cohort, retrospective cohort, and case-control studies. Rates of major malformations and cardiac malformations were combined by study type using random effects meta-analytic models. RESULTS: We identified 150 papers; 127 were rejected, 23 were analyzed: 9 prospective cohort, 8 retrospective cohort, and 6 case-control studies. Sample sizes were large (1,818 exposed in case-control and 16,824 in cohort studies), providing relatively robust findings. Overall Odds Ratios for major malformations ranged from 1.03-1.24 and 0.81-1.32 for cardiac malformations. No discrepancies among research designs were identified. CONCLUSIONS: Diverse observational models with differing strengths and weaknesses produced remarkably similar non significant results. Perceived conflicting results may be due to subsequent dissemination of results with attention given to small statistically differences with negligible clinical importance. Improved methods of knowledge transfer and translation are required to provide sound evidence-based information to assist in decision-making surrounding the use of antidepressants in pregnancy. PMID- 22946125 TI - ASTRO presidential nominees chart priorities for future. PMID- 22946127 TI - Cancer charities kindle Olympic spirit. PMID- 22946126 TI - Carcinogenicity of diesel-engine and gasoline-engine exhausts and some nitroarenes. PMID- 22946128 TI - Teaching case: Cowden syndrome and headache. PMID- 22946129 TI - Education. Can a new vision bring new life to biology class? PMID- 22946130 TI - U.S. elections. Scientists urge Obama, Romney to address key S&T issues. PMID- 22946131 TI - Raising the bar for safety in the handling of surgical specimens. PMID- 22946132 TI - Key OR design, construction changes proposed. PMID- 22946133 TI - Sleep apnea: identifying patients at risk in the ASC. PMID- 22946134 TI - [Obituary of Veronica Carstens--January 25, 2012]. PMID- 22946135 TI - [Society bulletins]. PMID- 22946136 TI - Biophysical pain model and TMD diagnosis. PMID- 22946137 TI - Cognitive behavioral therapy for anxiety and depression: possibilities and limitations of a transdiagnostic perspective. AB - In the last several years, a number of researchers have developed a transdiagnostic or unified group cognitive behavioral therapy (CBT) that is provided to a diagnostically heterogeneous group consisting of individuals with various anxiety disorders and/or depression. This article provides a review of recent developments within this transdiagnostic perspective to CBT. Three approaches to transdiagnostic CBT are considered that vary in their theoretical emphasis. At this time, the unified protocol for emotional disorders offers the most cogent theory-driven transdiagnostic treatment approach, although its efficacy has yet to be demonstrated. The advantages and challenges of transdiagnostic CBT are reviewed, and the article concludes with a proposal that future research on transdiagnostic CBT would be better served if viewed as complementary rather than antagonist to well-established manualized disorder specific CBT for the anxiety disorders and depression. PMID- 22946138 TI - Medicare and Medicaid programs; electronic health record incentive program--stage 2. Final rule. AB - This final rule specifies the Stage 2 criteria that eligible professionals (EPs), eligible hospitals, and critical access hospitals (CAHs) must meet in order to qualify for Medicare and/or Medicaid electronic health record (EHR) incentive payments. In addition, it specifies payment adjustments under Medicare for covered professional services and hospital services provided by EPs, eligible hospitals, and CAHs failing to demonstrate meaningful use of certified EHR technology (CEHRT) and other program participation requirements. This final rule revises certain Stage 1 criteria, as finalized in the July 28, 2010 final rule, as well as criteria that apply regardless of Stage. PMID- 22946139 TI - Health information technology: standards, implementation specifications, and certification criteria for electronic health record technology, 2014 edition; revisions to the permanent certification program for health information technology. Final rule. AB - With this final rule, the Secretary of Health and Human Services adopts certification criteria that establish the technical capabilities and specify the related standards and implementation specifications that Certified Electronic Health Record (EHR) Technology will need to include to, at a minimum, support the achievement of meaningful use by eligible professionals, eligible hospitals, and critical access hospitals under the Medicare and Medicaid EHR Incentive Programs beginning with the EHR reporting periods in fiscal year and calendar year 2014. This final rule also makes changes to the permanent certification program for health information technology, including changing the program's name to the ONC HIT Certification Program. PMID- 22946140 TI - Choosing the 'best' plan in a health insurance exchange: actuarial value tells only part of the story. AB - In the health insurance exchanges that will come online in 2014, consumers will be able to compare health plans with respect to actuarial value, or the percentage of health care costs that a plan would pay for a standard population. This analysis illustrates the out-of-pocket costs that might result from plans with various plan designs and actuarial values. We find that average out-of pocket expense declines as actuarial values rise, but two plans with similar actuarial values can produce very different outcomes for a given person. The overall affordability of a plan also will be influenced by age rating, income related premium subsidies, and out-of-pocket subsidies. Actuarial value is a useful starting point for selecting a plan, but it does not pinpoint which plan will produce the best overall value for a particular person. PMID- 22946141 TI - Better outcomes, lower costs: palliative care program reduces stress, costs of care for children with life-threatening conditions. AB - This policy brief examines the Partners for Children (PFC) program--California's public pediatric community-based palliative care benefit to children living with life-threatening conditions and their families. Preliminary analysis of administrative and survey data indicates that participation in the PFC program improves quality of life for the child and family. In addition, participation in the program resulted in a one-third reduction in the average number of days spent in the hospital. Shifting care from a hospital setting to in-home community-based care resulted in cost savings of $1,677 per child per month on average--an 11% decrease in spending on a traditionally high-cost population. As the three-year pilot program draws to an end, policymakers are considering the advisability of extending the program beyond the 11 counties that now participate. This policy brief provides recommendations that policymakers, families and advocates should consider to ensure sustainability and successful expansion of the program PMID- 22946142 TI - [The power of magnetism: magnet hospitals as models - also for the German speaking area?]. PMID- 22946143 TI - Common mental disorders. AB - Common mental disorders are a group of distress states manifesting with anxiety, depressive and unexplained somatic symptoms typically encountered in community and primary care settings. Risk factors for these disorders are mainly lower socio-economic status, psychological illnesses, poor reproductive health, gender disadvantage and physical ill-health. WHO has recommended that treatment of all these disorders should be based in primary care to be more effective and accessible to all the community people. The structure of mental health care in primary care is generally understood in terms of the "pathways to care" model and it plays a major role in countries like ours where community-based mental health services do not exist. Both the psychological and pharmacological therapies are found to be equally effective for treating these disorders. Integration of mental health into primary care can be considered as the stepping stone in the way forward to tackle the barriers and problems in effective management of common mental disorders in the community. The acute shortage of mental health professionals and the relatively low levels of awareness about mental disorders make it mandatory that primary health care should remain the single largest sector for mental health care in low and middle income countries like ours. PMID- 22946144 TI - A diagnosis missed for several years-Wegener's granulomatosis. AB - Wegener's granulomatosis is a form of systemic vasculitis of small to medium sized vessels and affects upper respiratory tract, lungs and kidneys along with various organs. It causes necrotizing granulomatous inflammation of the affected parts and presents with positive antineutrophil cytoplasmic antibodies in more severe forms. Being a systemic disease with the potential to affect any organ systems with a wide range of clinical presentations, it is associated with a risk of delay in diagnosis with resultant setback in institution of appropriate treatment. Confusion may arise due to an extent of histological similarity between Wegener's granulomatosis and the more prevalent tuberculosis, both causing granulomatous inflammation of the affected parts. Here, we present two cases of this rare disorder where the diagnosis was missed for several years in the beginning causing a delay in institution of specific therapy which led to the development of complications. PMID- 22946145 TI - [Health service research (22). Mental health and health service research on the youths in the IT society]. PMID- 22946146 TI - Infant feeding and obesity risk in the child. AB - Early nutrition in infancy may influence later child health outcomes including overweight through 'programming'. Systematic reviews suggest that breastfeeding is associated with a modest reduction in the risk of later overweight and obesity. This commentary explores some of these mechanisms behind this association. Generally breastfed infants are leaner than artificially (formula) fed infants and behavioural and hormonal mechanisms may explain this difference. The theory is that a high nutrient diet in infancy adversely programs the principal components of the metabolic syndrome in the child (body mass index, blood pressure and blood lipids) by promoting growth acceleration, whereas slower growth benefits later cardiovascular disease and its risk factors. Artificial feeding stimulates a higher postnatal growth velocity with the adiposity rebound occurring earlier in those children who have greater fatness later, whereas breastfeeding has been shown to promote slower growth. The adverse long-term effects of early growth acceleration emerge as fundamental in later overweight and obesity. The higher protein content of artificial baby milk compared to the lower protein content in breastmilk is responsible for the increased growth rate and adiposity during the influential period of infancy of formula-fed infants. Breastfeeding, on the other hand, has a protective effect on child overweight and obesity by inducing lower plasma insulin levels, thereby decreasing fat storage and preventing excessive early adipocyte development. Plausible biological mechanisms underlying the protective effect of breastfeeding against obesity are based on the unique composition of human milk and the metabolic and physiological responses to human milk. PMID- 22946147 TI - Human milk use in Australian hospitals, 1949-1985. AB - This paper will draw mainly on the experiences of fourteen women to explore the use of expressed human milk by hospitals in Australia from the postwar period through to 1985. The purpose is to provide a snapshot of common practices before the decline of human milk banking and other uses of expressed breastmilk in Australian hospitals, thus providing a source for future comparison against the more rigorous, uniform practices being instituted in the new milk banks of the early-21st century. The ten mothers included were a convenience sample drawn from the author's networks, with recruitment continuing till a range of hospital types and a majority of states were included. Three of the mothers also had experience as trainee midwives and midwives, and four midwives contributed their experiences as staff members, only. The hospitals ranged from large teaching hospitals to small private hospitals and were in metropolitan, regional and country locations. The practices included routine expression and expression for specific purposes, whether for the mother's own baby or to donate. Some hospitals pooled the donor milk for premature or sick babies. PMID- 22946148 TI - Breastfeeding--a framework for educating the primary care medical workforce. AB - OBJECTIVE: Breastfeeding is an important public health issue with an increase in infant and maternal morbidity and mortality for artificially-fed infants and their mothers. Doctors in primary care can influence mothers' infant feeding decisions, both positively and negatively, depending on the adequacy of their training. As there is no consistent approach to educating doctors in Australia at present, the development of a curriculum outline and educational strategies would be one step towards improving doctors' breastfeeding knowledge. APPROACH: Studies investigating the breastfeeding knowledge, attitudes and training opportunities of doctors in Australia were reviewed and information pertinent to breastfeeding training of doctors working in primary care obtained. This information, in conjunction with relevant literature, was used to define a breastfeeding knowledge base and identify broader educational strategies applicable for the training of doctors. CONCLUSION: Australian primary care doctors require further breastfeeding training to be able to provide optimum care for breastfeeding mothers and their infants. This paper formulates a breastfeeding education framework for the training of medical students, junior doctors, GP registrars and GPs. PMID- 22946149 TI - It's not the contents, it's the container: Australian parents' awareness and acceptance of infant and young child feeding recommendations. AB - Adherence to public health recommendations around infant and young child feeding is poor amongst Australian parents. This study aimed to investigate Australian parents' awareness and acceptance of public health recommendations about infant feeding. A cross-sectional design was used to survey a convenience sample of Australian parents. A total of 439 surveys were collected by intercept over 2 days from parents of children less than 5 years old, including those expecting a first baby, at the Pregnancy, Babies and Children (PBC) Expo held in Sydney in May 2008. Only 58.3% were aware of the WHO and NHMRC recommendation of 6 months exclusive breastfeeding. Fewer than 70% of respondents indicated that they thought breastfeeding should continue to 12 months or later, in accordance with the NHMRC guidelines, and only 12.3% thought breastfeeding should continue to 24 months or later, in accordance with WHO recommendations. This research suggests that awareness and acceptance of infant feeding recommendations in Australia is poor. PMID- 22946150 TI - Celebrating 30 years of breastfeeding review--in the beginning. PMID- 22946151 TI - Breastfeeding and thyroid disease: a literature review. PMID- 22946152 TI - Breastfeeding interventions that improve breastfeeding outcomes and Australian Breastfeeding Association services that support those interventions. PMID- 22946153 TI - Safe sleeping recommendations. PMID- 22946154 TI - [Regional heterogeneity of lake eutrophication effects in China]. AB - Although biomass of algae (Chl-a) were in variant levels between different lake regions in China under the same nutrients conditions, it demonstrated that efficiencies of TN/TP used by algae had regional differences. In order to clarify the differences, curve estimation in SPSS was used to analyze the linear relationship between Ig Chl-a and Ig TN/lg TP. The slopes of these linear equations were identified as the efficiencies of TN/TP used by algae. The slopes of linear equations from Mengxin Plateau, Yungui Plateau, Northeast Mountain Plain, lower reach of Yangtze River Plain and North Plain were 1.002, 0.817, 0.761, 0.545, 0.250, orderly. The efficiencies of TN used by algae ranged from the highest to the lowest were lower reach of Yangtze River Plain, Yungui Plateau, North Plain, Northeast Mountain-Plain, Mengxin Plateau, and the slopes of linear equations were 1.401, 1.058, 0.447, 0.239, 0. 099, respectively. Consequently, in Northeast Mountain-Plain, Mengxin Plateau the efficiencies of TP used by algae were higher than those of TN, and in Yangtze River Plain, Yungui Plateau, North Plain, the efficiencies of TN used by algae were higher than those of TP. On the other hand, in order to describe the effects of algae on transparency in different lakes, the relationships between Chl-a and SD were analyzed. The results showed that in Yungui Plateau the effect of algae on transparency was the most obvious as the variation of SD explained by Chl-a was the highest, and Northeast Mountain-Plain, Mengxin Plateau and North Plain followed. However, in lower reach of Yangtze River Plain, the relationship between Chl-a and SD was not significant. PMID- 22946155 TI - [Correlating landscape pattern with total nitrogen concentration using a location weighted sink-source landscape index in the Haihe River Basin, China]. AB - Understanding the effect of land cover pattern on nutrient losses is of great importance in management of water resources. The extensive application of mechanism models is limited in large-scale watersheds owing to the intensive data and calibration requirements. On the other hand, the traditional landscape indexes only take the areas and types of land cover into account, considering less about their topographic features and spatial patterns. We constructed a location-weighted landscape index (LWLI) based on the Lorenz curve, which plots the cumulative proportion of areas for sink and source landscapes respectively against cumulative proportion of their relative location to the outlet in a watershed, including relative elevation, distance and slope. We assessed the effect of land cover pattern on total nitrogen losses in the Haihe River. Firstly, 26 watersheds were derived from 1: 250 000 digital elevation model (DEM), and their "source" and "sink" landscape types were identified from Landsat TM images in 2007. The source" landscapes referred to the paddy land, dry land and residential area, correspondingly the "sink" landscapes referred to the forest and grassland. Secondly, LWLI was calculated according to the landscape types and spatial patterns for each watershed. Thirdly, we accessed the effect of land cover pattern on total nitrogen (TN) flux according to the value of LWLI, comparing with the area proportion of sink-source landscapes. The correlation coefficients were different in three parts of Haihe River, i. e., 0.86, 0.67 and 0.65 in the Yanshan Mts, Taihang Mts and lower Haihe River. The results showed strong correlations between TN and LWLI in contrast to the weak correlations between TN and area proportion of sink and source landscape types. This study indicates the spatial pattern of land cover is essential for accessing the nutrient losses, and the location-weighted landscape pattern analysis may be an alternate to existing water quality models, especially in large watershed scales. The sink-source index is sufficiently simple that it can be compared across watersheds and be easily interpreted, and potentially be used in landscape pattern optimal designing and planning. PMID- 22946156 TI - [Impact of the land-use change on the non-point source nitrogen load in Yunmeng Lake watershed]. AB - Take potable water sources in Linyi City Yunmeng Lake watershed as a case study, it obtains the nutrient export coefficient of land use by the export coefficient model and simulative rainfall experiment. On the basis of GIS and RS, it analyses the effect of the non-point source (NPS) pollution load because of the land-use change during the past 25 years. The result indicates that the TN increased from 3.77 x 10(3) t in 1986, to 4.45 x 10(3) t in 1995, to 5.5 x 10(3) t in 2010; As far as land-use type is concerned, the TN from farm-land increased year by year, the contribution rate is 80.11% in 1986, 82.60% in 1995 and 85.59% in 2010, the forestland and the grass-land load have a little change, but the contribution rate decreased gradually, the residential load increased by a large margin, however, the contribution rate is very little. As for the sub-basin, the higher the proportion of the farm-land is, the more the TN load increased. There is a significant positive correlation between the farm-land and the nitrogen (TN) load, so the farm-land is the sources of the nitrogen. Conversely, there are negative correlations between the forest-land, grass-land and the TN load; therefore, the forest-land and grass-land are the sinks of the nitrogen. Therefore, it can adjust the land-use structure to reduce and control the TN loss to water environmental pollution. PMID- 22946157 TI - [Residue characteristics and distributions of perfluorinated compounds in surface seawater along Shenzhen coastline]. AB - In order to explore the residue characteristics and distributions of 15 perfluorinated compounds (PFCs) in 18 surface seawater samples along Shenzhen coastline, high performance liquid chromatography-tandem mass spectrometry (HPLC MS/MS) combined with solid phase extraction enrichment was applied in this research. The results indicated that residue level of PFCs in coastal surface seawater samples was significantly affected by human activities. Sigma PFCs residue levels in surface seawater from Shenzhen west coast, which locates below the estuary of Pearl River and Donghao River, are much higher than those from the east coast, which has low development and sparse population (P<0.05). Under natural conditions, sigma PFCs residue levels in coastal surface seawater samples from Shenzhen Bays are higher than those out of bays. The major residue species in surface seawater samples along Shenzhen coast were medium- and short-chain PFCs, including perfluorooctane sulfonate (PFOS), perfluorooctanoic acid (PFOA), perfluorohexanoic acid and perfluoropentanoic acid. Their similar environmental behavior (P<0.05, P<0.01) is likely associated with the production process of PFCs-related products. Furthermore, cluster analysis results show that PFOS (R2 = 0.4092) level can be used as a representative parameter for evaluating PFCs contamination status in surface seawater along Shenzhen coast. PMID- 22946158 TI - [Distribution and potential ecological risk of polycyclic aromatic hydrocarbons in the sediments from typical electronics industrial zone]. AB - In order to investigate the polycyclic aromatic hydrocarbons (PAHs) contamination status in a river of a typical electrical equipment industrial area, Ronggui, Foshan, 8 sediments simples were collected. The results showed that 12 components of PAHs were detected in all sediment samples, and the other 4 components were also detected in different degree. The total 16 EPA priority PAHs contents in surface sediments varied from 343.5 microg x kg(-1) to 2 099 microg x kg(-1) (dry wt), with an average of 1215.9 microg x kg(-1), and no significant variation was found in vertical distribution. The 2 to 3 aromatic rings were the dominant PAHs, and they accounted for 50.69% to 82.5% of the total PAHs. Diagnostic ratios were used to identify the possible sources of PAHs, and the results indicated that PAHs were mainly pyrogenic origin. Sediments were polluted by PAHs heavily according to Maliszewska-Kordybach's standard, the very high risk level was also confirmed by the contamination factors assessment which was investigated by comparison with the background area (SO). The assessment by the method of sediment quality guidelines (SQGs) and relative contamination factor (RCF) demonstrated that adverse biological toxicity effect might occasionally happen in a few sampling sites, and the ecological risk components included acenaphthene (Ace), fluorine (Flu), and phenanthrene (Phe). PMID- 22946159 TI - [Residues and potential ecological risk assessment of metal in sediments from lower reaches and estuary of Pearl River]. AB - In order to investigate the heavy metal concentrations and their potential ecological risks in surface sediments of lower reaches and estuary of Pearl River, 21 bottom sediment samples were collected from lower reaches and estuary of Pearl River. Total contents of Cr, Mn, Fe, Co, Ni, Cu, Zn, As, Se, Cd, Sb, Pb and Hg in these samples were measured by the inductively coupled plasma mass spectrometry (ICP-MS) and the atomic fluorescence spectrometry (AFS) and using the index of geoaccumulation and the potential ecological risk index to evaluate the pollution degree of heavy metals in the sediments. Results indicated that the concentration of total Fe and total Mn were 41658.73 and 1104.73 mg x kg(-1) respectively and toxic trace metals, such as Cr, Co, Ni, Cu, Zn, As, Se, Cd, Sb, Pb and Hg were 86.62, 18.18, 54.10, 80.20, 543.60, 119.55, 4.28, 10.60, 20.26, 104.58 and 0.520 mg x kg(-1). The descending order of pollution degree of various metals is: Cd > As approximately Zn > Hg > Pb approximately Cu approximately Cr, while the single potential ecological risk followed the order: Cd > Hg > As > Cu > Pb > Zn > Cr. The pollution extent and potential ecological risk of Cd were the most serious among all heavy metals. The distribution pattern of Cd individual potential ecological risk indices is exactly the same as that of general potential ecological risk indices for all heavy metals. Clustering analysis indicates that the sampling stations may be classified into five groups which basically reflected the characteristics of the heavy metal contamination and sedimentation environments along the different river reaches in lower reaches and estuary of Pearl Rive. In general, the serious heavy metal pollution and the high potential ecological risk existed in three river reaches: Chengcun-Shawan, Chengcun-Shundegang and Waihai-Hutiaomen. The pollution degree and potential ecological risk are higher in related river reaches of Beijiang than that in other lower reaches and estuary of Pearl River. PMID- 22946160 TI - [Character and sources identification of heavy metals contamination in sediment from the core sediment in Nanshan Lake, the Zhalong wetland]. AB - NSH2 sediment core from Nanshan Lake in the south of Zhalong wetland was studied, which was a typical lake for both empolder and aquaculture. The vertical distributions of heavy metals (Hg, Cd, Pb, Cr, As, Mn, Ag, Cu, Co, Fe and Zn) were investigated. The method of principal component analysis (PCA) was adopted to apportion the sources of heavy metals, and particle size, combined with 210Pb(ex) dating data were used to indicate characteristics, sources and polluted history of heavy metals in lake sediments since 1829. The results showed that: 1) the trend of changes in accumulation in the sedimentation was rather slow in the earlier stage, then was fast in the middle stage, and finally slowed down again in the later stage. The history of elements pollution is correspondent with the production of human activities and policies of soil and water conservation of Nanshan Lake; 2) the contents of all elements varied smoothly before 1957, and which fluctuated slightly from 1957 to 1985. The contents of Hg, Cd and Ag increased obviously since 1985. The sources of heavy metals determined were mainly from sewage, the loss of fertilizers, and combustion of fuel such as coal and gasoline; 3) natural sources of the degradation of organic matter, rock weathering and erosion, as well as the source of industrial emissions, with the contributions of 50.14%, 19.90% and 10.32%, respectively. High potential risk of heavy metals existed in NSH2 sediment core. Hence, enough attention must be paid to the pollution control of lakes. Therefore, this study can provide basic data for help wetland ecological environment improvement in Zhalong wetland. PMID- 22946161 TI - [Distribution characteristics of phosphorus forms in surface sediments of the Shantou Bay in China]. AB - In order to know the horizontal distribution and seasonal variation characteristics of phosphorus species in surface sediment, the contents of different phosphorus species in the surface sediment sampling from Shantou Bay were determined by using the SMT sequential extraction method in September and November, 2008, and June, 2009. The contents of different phosphorus species basically showed an order of the low-water period, normal-water period and high water period from high to low, and horizontal distributions of phosphorus species showed a decrease trend as waves from the inner bay to the outer bay with the maximum appeared in Niutianyang. The main form of total phosphorus in sediment was inorganic phosphorus, which accounted for 94.06%, and the content of Ca-P was the highest in all inorganic phosphorus of the surface sediment in Shantou Bay, comprising 70.21%, followed by Ads-P, Fe-P and De-P. The correlation analysis among different phosphorus forms suggested that they had similar sources and they were affected by surface runoff and seasonal variation. OP, Fe-P and Ads-P were bioavailable phosphorus, which were controlled by sources and water oxidation reduction potential; while Ca-P and De-P were mainly influenced by biological processes and geological characteristics. PMID- 22946162 TI - [Microcosm experiments on the influence of different N/P ratios on phytoplankton community growth in the East China Sea]. AB - In the present study, a microcosm experiment was conducted in situ for 30 days, in order to investigate the effects of different N/P ratios (1N: 1P, 4N: 1P, 8N: 1P, 16N: 1P, 32N: 1P, 64N: 1P, 128N: 1P, and 256N: 1P) on phytoplankton community growth in the East China Sea. The results indicated that the species number, cell abundance, Chl-a content, specific growth rate as well as species composition of the phytoplankton community significantly varied with the N/P ratios. After 6 days of culture, the species number, cell abundance, Chl-a content and specific growth rate in the high N/P ratio groups were significantly higher than those in the low N/P ratio groups. After 30 days of culture, the cell abundance in the groups close to the Redfield ratio (8N: 1P, 16N: 1P, and 32N: 1P) was significantly higher than those in the other treatments. On the other hand, the phytoplankton community in all the treatments was observed a definite succession from diatoms to dinoflagellates during the present study. Nonetheless, the N/P ratios strongly affected the duration of dinoflagellate bloom as well as the dominated species: at the beginning of culture (0th day-12th day), the diatoms dominated the phytoplankton community; then the relative contribution of dinoflagellates to the total cell abundance exceeded diatoms in the 4N: 1P, 16N: 1P, and 32N: 1P groups on the 18th day. After that, the relative contribution of dinoflagellates exceeded diatoms ordinally in the other groups from the 24th day to 30th day. At the end of culture, the phytoplankton community was dominated by the dinoflagellates in all the groups except for the 8N: 1P, 16N: 1P, and 32N: 1P treatments. PMID- 22946163 TI - [Species composition and distribution characteristics of pelagic copepods in the Northern Sea of Fujian during withdraw of Zhe-Min coastal current]. AB - Based on oceanographic survey data in April 2009 in the north central Taiwan Strait, ecological characteristics such as species composition, individual density, dominant species and distribution were analyzed. The results were compared with the same area survey in spring 2007 for discuss the annual variety. The result shows that 48 pelagic copepods species have been recognized, and most of them belongs to Calanodia. The higher species number occurs in southern and eastern area. The average density of pelagic copepoda was 231.96 ind x m(-3). As to the horizontal distribution, the coast and northern areas are higher than those of eastern and southern areas of the density of pelagic copepods which are dependent on the dominant species Calanus sinicus and Euchaeta plana. The community structure of pelagic copepoda was same to the other survey result, which shows low biodiversity index with remarkable dominant species. Owing to the Zhe-Min coastal current effect, the higher density distribution is different in 2007 and 2009. As to the ecological character, all the copepoda in this paper belong to warm-water, warm-temperature and tropic oceanic groups. Warm-water and tropic oceanic groups are the dominant groups of the pelagic copepods composition. When it comes to density, warm-temperature group is the dominant. The relationship of species number, diversity index and abundance with the environment were also discussed in this paper. The result showed that the pelagic copepoda species number and diversity would increase with the temperature and salty increase. PMID- 22946164 TI - [PAHs concentrations in aquatic products and food safety evaluation in the coupled mangrove planting-aquaculture ecological system]. AB - In order to know about the PAHs concentration in aquatic products from mangrove planting-aquaculture ecological system and to make sure of food quality and food safety, HPLC was used to determine concentrations of 13 polycyclic aromatic hydrocarbons (PAHs) in the Tilapia mossambica, Mugil cephalu and Concha ostreae from coupled mangrove planting-aquaculture ponds, food safety in aquatic products was also evaluated. The 13 PAHs were Fluorene (Flu), Phenanthrene (Phe), Anthracene (Ant), Fluoranthene (Fla), Pyrene (Pyr), Benz[a] anthraces (BaA), Chrysene (Chr), Benzo[b] fluoranthene (BbF), Benzo[k] fluoranthene (BkF), Benzo[a] Pyrene (BaP), Dibenzo [a, h] anthercene (DahA), Benzo [g, h, i] perylene (BghiP) and Indeno [1,2,3-c, d] pyrene (InP). Concentrations of PAHs were the highest in Concha ostreae which were in the range of 89.79-98.49 microg x kg(-1) dry weight, while those were in the range of 25.97-34.64 microg x kg(-1) in Mugil cephalu and 12.31-14.41 microg x kg(-1) in Tilapia mossambica. The content of fat affected the levels of PAHs content in different aquatic products. The individual composition of PAHs was characterized by 3 rings in samples with the range of 41.58% - 83.35%. Comparing with other areas, PAHs pollution of aquatic products in the studied area was in the mild level. Values of the total BaP(eq) concentration ranged from 0.0689 microg x kg(-1) to 1.0373 microg x kg(-1), which were lower than the maximum level set by European Union. PMID- 22946165 TI - [Tissue distribution and bioconcentration factors of tetrabromobisphenol A in five fishes in Lake Chaohu]. AB - Tissue distribution and bioconcentration factors of tetrabromobisphenol A (TBBPA) in five economic fishes in Chaohu Lake were measured with SPE-HPLC. The results showed that, the average concentration of TBBPA was 4.70-11.20 ng x g(-1) (dry weight) in these fishes, in an order as White fish > Silver Carp > Bighead Carp > Common Carp > Longsnout Catfish. The highest concentration of TBBPA was found in the kidney, followed by liver and gill. The concentrations in fat and muscle were very low. Silver carp was really different from the other four fishes with the highest measured level in liver, followed by kidney and gills. In addition, the TBBPA concentration in tissues of the white fish showed positive correlation with the fish weight, especially in liver and kidney, but the trend is not significant in the back and belly tissues. The bioaccumulation factors of TBBPA for the 5 fishes were 9.56-22.64 based on the average concentration of TBBPA in water (0.52 microg x L(-1)) detected in this study, indicating insignificant bioconcentration effects of TBBPA on five fishes in Chaohu Lake. PMID- 22946166 TI - [Induction effects of pentachlorophenol on vitellogenin and p53 in Chinese rare minnow (Gobiocypris rarus)]. AB - Taking the Chinese rare minnow (Gobiocypris rarus) as the test animal, the studies were designed to investigate induction effects of pentachlorophenol (PCP) on vitellogenin (VTG) protein, VTG gene and tumor suppressor p53 gene in the liver of Gobiocypris rarus. The endocrine disrupting of PCP was evaluated by detecting VTG, and sensitive biomarkers of PCP were screened at both protein and mRNA levels. Gobiocypris rarus were exposed to PCP at 1.5, 15, 40, 80, 120, 150, 160 microg x L(-1) respectively, while setting blank, solvent control and 17alpha ethynylestradiol (EE2) as positive control. Using sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE), enzyme-linked immunosorbent assay (ELISA), VTG protein expression differences were detected in the liver of Gobiocypris rarus after exposure to PCP. Cloning the VTG and p53 gene new fragments of Gobiocypris rarus based on conserved regions, mRNA expression levels of VTG and p53 gene in the liver of Gobiocypris rarus were determined by quantitative real-time PCR assay after PCP treatment. The results showed that 40, 80, 120, 160 microg x L(-1) PCP induced the liver of male and female Gobiocypris rarus to produce VTG protein, and had a significant concentration effect. VTG and p53 mRNA levels significantly increased in the liver of Gobiocypris rarus after exposure to 1.5, 15, 150 microg x L(-1) PCP, and had remarkable concentration and time effects. The studies suggested that PCP had estrogenic effects, and VTG protein, VTG and p53 gene in the liver of Gobiocypris rarus could be used as candidate sensitive biomarkers for detecting PCP. PMID- 22946167 TI - [Effects of perfluorooctane sulfonate (PFOS) exposure on vitellogenin mRNA level in zebrafish (Brachydanio rerio)]. AB - To study the endocrine disrupting effects and action mechanism of environmental levels of perfluorooctane sulfonate (PFOS) on the aquatic species, the research for the effects of PFOS exposure on vitellogenin (VTG) mRNA level in livers of zebrafish (Brachydanio rerio) was conducted. Zebrafish were exposed to PFOS at four environmental low concentrations (0.1, 1, 10, 100 microg x L(-1)) for 21 days. Livers from male and female zebrafish were collected for RNA extraction, VTG1 and VTG3 mRNA levels were measured respectively using real-time polymerase chain reaction (RT-PCR). The results show that: 1) The VTG1 and VTG3 mRNA level in the livers of male zebrafish increased after PFOS exposure. The VTG1 mRNA level increased with a positive dose response pattern, with the maximum response at 100 microg x L(-1) PFOS exposure where a significant difference compared with the control was observed. The VTG3 mRNA level increased as an inverted U-shaped dose response pattern, indicated as hormesis effects, where significant differences compared with the control were observed at 10 and 100 microg x L(-1) PFOS exposure. 2) The VTG1 mRNA level in the livers of female zebrafish increased where a significant difference compared with the control was observed at 10 microg x L(-1) PFOS exposure, but the standard errors for mRNA level at 10 and 100 microg x L(-1) PFOS exposure were distinct. The VTG3 mRNA level in the livers of female zebrafish increased at 10 microg L(-1) PFOS exposure but had no significant difference compared with the control. Thus, it deduced that PFOS exposure could be active on the endocrine system of zebrafish with the oestrogenic simulation action mechanism, and the VTG1 and VTG3 mRNA level in the livers of zebrafish might be sensitive biomarkers for the endocrine disrupting effects evaluation after PFOS exposure, with different responding patterns related to the gene subtypes and sex. PMID- 22946168 TI - [Relationship between electron transfer capacity and fluorescence characteristics of dissolved organic matter]. AB - This study demonstrated the relationship between redox activity and fluorescence characteristics of different dissolved organic matter (DOM) employing a combined method of electrochemistry and fluorescence spectroscopy. Chronoamperometry was used to quantitatively evaluate the electron transfer capacity (ETC) of DOM. Data showed that the electron accepting capacity of DOM ranged from 635.6 micromol x (g x C)(-1) to 1049.3 micromol x (g x C)(-1), and the electron donating capacity ranged from 27.3 micromol x (g x C)(-1) to 42.3 micromol x (g x C)(-1). For all DOM tested, the cyclic voltammetries (CVs) showed an evident pair of redox peak with the redox potentials in the range from -731 mV to -996 mV (vs. Ag/AgCl), suggesting their electrochemical activity. Using the multi-potential steps method, the ETC was measured to be 232.1-897.2 micromol x (g x C)(-1) and the electron recycling rates (ERRs) were 36.7%-78.2%, indicating the electron transfer of DOM has a reversible character. Using fluorescence excitation emission spectroscopy (EEMs), the ERRs were found to be highly correlated with the fulvic-like fluorescence intensity of DOM with a correlation coefficient of 0. 92. This study can potentially provide a scientific base for understanding the roles of DOM in the elements cycles, pollutants degradation and biogeochemical cycles. PMID- 22946169 TI - [Characterization of the change in DOM during municipal secondary effluent treatment with magnetic ion exchange resin by 3DEEM]. AB - Magnetic ion exchange resin was a very good advanced treatment process to remove organic matter from municipal wastewater, and three-dimensional excitation emission matrix fluorescence spectroscopy was widely used to analyze the characterization of the change in DOM. The results showed that both two-stage treatment process and the rate variation of inflow affected the removal effects of DOC and UV254 obviously, and the removal rates were 25.5% - 53.5% and 27.6% - 52.2%. The concentrations of DOC and UV254 were 3.29 mg x L(-1) and 0.057 cm(-1) in T2 effluent respectively. The fluorescence intensities of aromatic protein and visible fulvic-like were high in municipal secondary effluent. MIEX made the fluorescence intensities of tryptophan protein, aromatic protein and humic-like fluorescence peaks decreasing 38.2%, 85.8% and 85.7% respectively from secondary effluent, and make humic-like and visible fulvic-like fluorescence peaks disappearing. The fluorescence peak of soluble microbial byproducts appeared. The negative correlations were strong between the declining rates of tryptophan-like fluorescence intensity and aromatic protein fluorescence intensity and the rates of inflow. 50 - 100 L x h(-1) flow rate influenced most for the removal rate of each DOC. The linear treatment effect was higher for tryptohan-like and aromatic protein DOM by MIEX (R2 = 0.8348), and the treatment effect was the highest for aromatic protein DOM by MIEX (alpha = 850.2). The correlation between UV fulvic like DOM and fluorescence intensity was worse than that between DOC and fluorescence intensity. PMID- 22946170 TI - [Reverse osmosis membrane fouling by humic acid using XDLVO approach: effect of calcium ions]. AB - Interfacial interactions involved in reverse osmosis (RO) membrane fouling by humic acid were quantitatively evaluated using the XDLVO (extended Derjaguin Landau-Verwey-Overbeek) approach. The role of each individual interfacial interaction during membrane fouling was elucidated with special emphasis devoted into the influence of Ca2+ under different solution pHs. The results showed that, regardless of the presence of Ca2+, van der Waals interaction favoring fouling contributed the most to the interfacial interactions at pH 3, whereas the polar interaction inhibiting fouling played a dominant role at pH 7 and pH 10. Electrostatic double layer interaction appeared to be the weakest in all cases, thus contributing the least to membrane fouling. It was the changing of polar interaction that gave rise to the influence of Ca2+ on membrane fouling, which turned out to be more significant at lower pH. Ca2+ would accelerate humic acid RO membrane fouling at most cases. Correlation analysis between interfacial free energy and fouling extent revealed that XDLVO approach could reasonably predict humic acid RO membrane fouling behaviors under different solution conditions. PMID- 22946171 TI - [Growth, removal of nitrogen and phosphorus, and lipid accumulation property of Scenedesmus sp. LX1 in aquaculture wastewater]. AB - Treating wastewater by high-lipid-content microalgae, which can couple with wastewater treatment and biodiesel production, has become a new research direction in the wastewater treatment field. A high-lipid-content freshwater microalgae, Scenedesmus sp. LX1 was studied concerning its growth, removal efficiencies of nitrogen and phosphorus, and lipid accumulation property while growing in aquaculture wastewater. Results showed that the specific growth rate, maximum population density and maximum population growth rate of Scenedesmus sp. LX1 were 0.44 d(-1), 7.46 x 10(6) cells x mL(-1) and 0.82 x 10(6) cells x (mL x d)(-1), respectively. At stationary phase of training, removal efficiencies of ammonia, nitrite, nitrate and phosphorus by Scenedesmus sp. LX1 were 95.5%, 96.3%, 85.8% and 98.8%, respectively. It's biomass [dry weight] was 0.38 g x L( 1), algae lipid content was up to 31.6%. In general, Scenedesmus sp. LX1 has larger advantage in aquaculture wastewater depuration and resource utilization respect, and it can be used as the preferred algae species for coupling process. PMID- 22946172 TI - [Iron chloride for simultaneous denitrification and chemical-biological flocculation process]. AB - The efficiency of iron chloride on simultaneous denitrification and chemical biological flocculation process was investigated through a lab-scale study. The results showed that: there were not significant differences in the denitrification rate, COD and NO3(-) -N removal efficiency between the control reactor and the denitrification reactor with the dosage of 20 mg x L(-1) Fe after 14 days' domestication. Meanwhile the TP removal efficiency was increased to over 80%. Though sludge concentration was increased by adding FeCl3, the settling performance wasn't change because the sludge density was increased and the particle size was reduced. The sludge settling volume (SV30) and specific resistance of filtration (SRF) after adding FeCl3 were only 22% and 1.5 x 10(12) m x kg(-1), which were lower than the values in the control reactor and benefit for sludge treatment. PMID- 22946173 TI - [Characteristic research of shortcut denitrification in synthetic ammonia industrial wastewater treatment process]. AB - Active sludge was from a pilot-scale synthetic ammonia industrial wastewater treatment plant with a strengthen anoxic-oxic (A/O) technology. The zero order kinetic model was suit for describing shortcut and complete denitrification process. Experimental results showed that shortcut denitrification could reduce 14.1% carbon source consumption and 55.7% denitrification time, respectively, comparing with complete denitrification. The maximum specific denitrification rate was 0.509 g x (g x d)(-1) with an initial NO2(-) -N concentration of 36.82 mg x L(-1) and pH 7.5. In the industrial practice, it must be avoided pH higher than 9.0 in anoxic zone for industrial treatment. Replication-selective denitrifying bacteria showed a strong adaptability to methanol and ethanol, but showed maladaptation to other small molecular and easily biodegradable organics, such as glucose and acetic acid. PMID- 22946174 TI - [Stability control of aerobic granules using an innovative reactor]. AB - Uncontrolled variation of diameter and density of aerobic granules frequently resulted in instability and thus brought about operation failure. An innovative reactor was therefore developed for the control of diameter and density of aerobic granules. There were two ways to select the sludge, one was the short settling time select the big and dense granules in the reactor, and the other was the hydro cyclone that washed out the big and compact granules preventing big and compact fourthly growth in the reactor. By these means, the diameter of granules could maintained in the range of 300-1 000 microm for a long time, consequently, the long term stability could be obtained. According to the kinetic analysis, it was found that the energy maintenance coefficient was 0.08-0.10, which was much higher than the conventional granular system (0.06), and the ratio of the COD used for maintenance to the influent was higher than the conventional one. Additionally, the removal efficiencies of COD and ammonia were 92% and 60%, respectively. PMID- 22946175 TI - [Description of the stability of granules using nongrowth-related parameters]. AB - Qualitative rather than quantitative method was available in the study of aerobic granular sludge. This work therefore investigated two systems, one was the conventional heterotrophic system without anaerobic mix period, the other was the phosphorous removal system with anaerobic period, and it was found that the latter was more stable from the point view of diameter, density and morphology. It was further found that the stability of granule was associated with the metabolic characteristics, i. e., the slow growth system showed more stability may be due to higher fraction of maintenance metabolic energy. In order to evidence that, different size of granule in the slow growth system was obtained for the metabolic character analysis. It was found that the maintenance coefficient m and the ratio of maintenance COD consumption ratio S(min)/COD(influent) was well correlated with the stability of granules. Consequently, it was proposed that these two parameters could be used for the quantitative description of the stability of granules. This study established a new method for the quantitative description of the stability of aerobic granules from the metabolic perspective, which improved the conventional qualitative methods in terms of morphology, diameter and density of granules. PMID- 22946176 TI - [Enhancement of anaerobic digestion of excess sludge by acid-alkali pretreatment]. AB - In order to enhance the efficiency of anaerobic digestion of excess sludge, acid alkali pretreatment method was studied. Three different pretreatment methods (alkali alone,acid-alkali, alkali-acid) were compared to investigate their impacts on hydrolysis and acidification of activated sludge. In addition, their influences on methane-producing in subsequent anaerobic digestion process were also studied. The results showed that the soluble chemical oxygen demand (SCOD) of alkaline treatment alone was about 16% higher than the combining of acid and alkali treatment, SCOD concentration increased to 5406.1 mg x L(-1) after 8 d pretreatment. After treated by acid (pH 4.0, 4 d) and alkali (pH 10.0, 4 d), the acetic acid production and its content in short-chain fatty acids (SCFAs) were higher than other pretreatment methods. And the acetic acid production (as COD/VSS) could reach 74.4 mg x g(-1), accounting for 60.5% of SCFAs. After acid alkali pretreatment, the C: N ratio of the sludge mixed liquor was about 25, and the C: P ratio was between 35-40, which was more favorable than C: N and C: P ratio of alkali alone and alkali-acid to subsequent anaerobic digestion. The control experiments showed that, after acid-alkali pretreatment, anaerobic digestion cumulative methane yield (CH4/VSS(in)) reached to 136.1 mL x g(-1) at 15 d, which was about 2.5-, 1.6-, and 1.7-fold of the blank (unpretreated), alkali alone pretreatment and alkali-acid pretreatment, respectively. After acid alkali pretreatment for 8 d and anaerobic digestion for 15 d, the removal efficiency of VSS was about 60.9%, and the sludge reduction effect was better than other pretreatments. It is obvious that the acid-alkali pretreatment method was more favorable to anaerobic digestion and sludge reduction. PMID- 22946177 TI - [Pilot validation of sludge concentration partition at small reflux ratio condition]. AB - Using sub-milliFiltration (SMF) module get the sludge of the system divide into high concentration part and low concentration part, in order to make the high concentration part retain activated sludge to strengthen removal rate of organics and the low concentration part meet the need of MBR. Discussing the sludge concentration partition effect under the conditions of small reflux ratio(R 0.5, 1.0, 1.5, 2.0), In addition, investigating the COD removal efficiency of the system with SMF Module, comparing the measured and theoretical value of the MLVSS at each small reflux ratio. Results show that: the method of sludge concentration partition at small reflux ratio condition is feasible, the MLSS of the low concentration part is below 9 g x L(-1) and the high concentration part is above 20 g x L(-1); average removal rate of COD is above 90%; measured value of the two part is related to theoretical value. PMID- 22946178 TI - [Influence of non-ionic surfactants on sludge dewaterability]. AB - The water content of dewatered sludge cake decreases to about 80% by current sludge dewatering technologies, which hardly satisfies the stricter standards of sludge disposal. In order to evaluate the effects of non-ionic surfactants on sludge dewaterability, two kinds of non-ionic surfactants (OPEO and APG) were studied by using two evaluation indexes, i. e. , specific resistance to filtration (SRF) and dewatering efficiency. Moreover, morphologies of conditioned sewage sludge and raw sludge were comparatively investigated. Results showed that non-ionic surfactants can decrease the particle size of sewage sludge floc and generate more homogenous and regular shape, and then improve the dewatering efficiency. APG has better effect on sewage sludge dewatering than OPEO. SRF of conditioned sludge with APG dosage of 0.05% DS decreased to 42% of SRF of raw sludge, and its dewatering efficiency was as high as 93%. Plate-frame pressure filter experiment demonstrated that, the water content of dewatered cake conditioned with APG dosage of 0.05% DS was lower by about 10% than that of dewatered cake without APG, and its dewatering efficiency reached 97%. Therefore, this research provides some reference for the application of APG in sludge dewatering. PMID- 22946179 TI - [Variation characteristics and influencing factors of air pollution index in China]. AB - Based on the daily air pollution index (API), primary pollutant, air quality level and status of 42 cities in China during 2001-2010, the characteristics of air quality were analyzed. The results showed that the atmosphere was significantly influenced by consumption of coal. The primary pollutant was PM10, and the air quality status was excellent (0 < API < 50), good (50 < API <100) and slightly polluted (100 < API < 150) in the majority. The air pollution status varied seasonally, which was the most serious in winter, and slightest in summer. The air quality was better and better in the observed period generally; The spatial distribution of urban air environment displayed a worsening trend from the south to the north and from the coasts to the inland; The local emission and natural dust transmission from the Northwest China was the main sources of urban air pollution; The air pollutants were impacted by the meteorological elements, and the air pollution index correlated linearly with precipitation, wind speed and temperature inversion; The distribution of weather conditions, which was affected by the terrain, also could influence the air quality; In addition, the human activities had both positive and negative functions on the urban air quality. PMID- 22946180 TI - [Characteristics of aerosol water-soluble inorganic ions in three types air pollution incidents of Nanjing City]. AB - In order to compare aerosol water-soluble inorganic species in different air pollution periods, samples of PM10, PM2.1, PM1.1 and the main water-soluble ions (NH4+, Mg2+, Ca2+, Na+, K+, NO2(-), F(-), NO3(-), Cl(-), SO4(2-)) were measured, which were from 3 air-pollution incidents (continued pollution in October 16-30 of 2009, sandstorm pollution in April 27-30 of 2010, and crop burning pollution in June 14 of 2010. The results show that aerosol pollution of 3 periods is serious. The lowest PM2.1/PM10 is only 0.27, which is from sandstorm pollution period, while the largest is 0. 7 from crop burning pollution period. In continued pollution periods, NO3(-) and SO4(2-) are the dominant ions, and the total anions account for an average of 18.62%, 32.92% and 33.53% of PM10, PM2.1 and PM1.1. Total water-soluble ions only account for 13.36%, 23.72% and 28.54% of PM10, PM2.1 and PM1.1 due to the insoluble species is increased in sandstorm pollution period. The mass concentration of Ca2+ in sandstorm pollution period is higher than the other two pollution periods, and which is mainly in coarse particles with diameter larger than 1 microm. All the ten water-soluble ions are much higher in crop burning pollution especially K+ which is the tracer from crop burning. The peak mass concentrations of NO3(-), SO4(2-) and NH4+ are in 0.43 0.65 microm. PMID- 22946181 TI - [Characterization of atmospheric PM2.5 in the suburb of Shenzhen]. AB - In this study, PM2.5 samples had been measured from the summer of 2009 to the winter of 2010 in a suburb of Shenzhen. The results indicated serious PM2.5 pollution in the suburb of Shenzhen. Seasonal and daily variations of water soluble ions were discussed. SO4(2-), NO3(-) and NH4+ were the most abundant ions in winter. In summer, the average contributions of Cl(-), Na+, K+, Ca2+ and Mg2+ increased significantly, while SO4(2-), NO3(-) and NH4+ decreased. Furthermore, Naphthalene, acenaphthylene, acenaphthene and benzo fluoranthene were the major PAHs in PM2.5. Ratio analysis and characteristic compounds analysis were also used to determine the possible sources of PM2.5 in the suburb of Shenzhen. PMID- 22946182 TI - [Analysis on oil fume particles in catering industry cooking emission]. AB - By measuring the particulate matter of oil fume which is over 10 microm or below 10 microm separately and using microradiography and Electrical Low Pressure Impactor (ELPI), it is found out the distributing characteristic of oil fume particles in catering industry cooking emission. The result shows that the diameter of the oil fume particles which was sedimentated in the kitchen is between 10-400 microm, the concentration peak value is between 10-100 microm. The diameter of oil fume aerosol is mostly smaller than 1 microm, while the concentration peak value is between 0.063-0.109 microm. In addition, the mass concentration peak value is between 6.560-9.990 microm. Through the analysis to the physical characteristics of oil fume from catering industry cooking emissions, the eigenvalue of the oil fume has been found and the feature matter for monitoring the oil fume has been discovered to provide a reasonable standard for controlling and monitoring the catering industry cooking emission. PMID- 22946183 TI - [Low-temperature catalytic reduction of NO over Fe-MnOx-CeO2/ZrO2 catalyst]. AB - Fe-MnOx-CeO2/ZrO2 catalysts were prepared through impregnation method with nanometer ZrO2 as a carrier and used in selective catalytic reduction of NO with NH3 at low temperature. Effects of active component ratio and loading of promoter on the catalyst activity were investigated. The catalysts were characterized by means of XRD, SEM, EDS and BET. The effects of temperature, SO2 and H2O on NO conversion were studied and the results showed that in the absence of SO2 and H2O, the catalyst of 8% Fe-10% MnOx-CeO2/ZrO2 had good activity and stability as well as the NOx removal efficiency reached 85.23% at 120 degrees C and 92.0% at 180 degrees C. The presence of SO2 and H2O results in the catalyst deactivated. Properties of the catalyst on different reaction stages were characterized by FT IR to study the inactivation mechanism of the catalyst. The results showed that the catalyst deactivation was due to the deposition of ammonium sulfate on the catalyst and the sulphation of the catalyst. PMID- 22946184 TI - [CO2 absorption and regeneration performance of a natural amino acid and its potassium salt]. AB - In order to decrease the solvent loss due to amine volatilization and oxidative degradation and reduce the risk of environmental pollution resulting from amine volatilization, amino acid salts with negligible volatility and better resistance to oxidative degradation may be considered as the alternative during the course of CO2 capture. So, experimental study on CO2 absorption and regeneration characteristics of L-arginine and potassium argininate (PA) was put forward in this study based on the CO2 absorption rate and heating regeneration rate at ambient pressure. And the influences of absorbent mass concentration, reaction temperature and absorption-regeneration cycles on CO2 absorption performance of L arginine and PA were also investigated, which were used to compare with the typical absorbents including monoethanolamine (MEA), diethanolamine (DEA) and triethanolamine (TEA). Results showed that among all the five absorbents, PA had the highest CO2 absorption rate of 24.5 x 10(-3) mol x (L x min)(-1) and CO2 loading capacity of 1.99 mol x mol(-1), which were 2.1% and 290.2% higher than MEA with the same mass concentration, respectively. The results also showed that CO2 absorption rate of PA and MEA at 40 degrees C was the highest compared to other temperatures. In addition, although CO2 loading of lean PA solution was slightly higher than that of MEA under the same regeneration conditions, 72.8% CO2 in the rich PA solution can be released, which is 19% higher than that of MEA. After three absorption-regeneration cycles, CO2 absorption capacity of 10% PA was found to be approximate 1.03 mol x mol(-1), which is 255.2% higher than MEA. Furthermore, L-arginine was found to have the stronger CO2 absorption capacity, and its CO2 absorption rate may be comparable to DEA with the same mass concentration. PMID- 22946185 TI - [Effects of tillage-cropping systems on methane and nitrous oxide emissions from agro-ecosystems in a purple paddy soil]. AB - Using the static opaque chamber method, a field experiment, located in the Key Field Station for Monitoring of Eco-Environment of Purple Soil of the Ministry of Agriculture of China in the farm of Southwest University (30 degrees 26'N, 106 degrees 26'E) in Chongqing, was conducted in situ for one year to study the effect of different tillage systems on CH4 and N2O emission from ago-ecosystems in a purple paddy soil. In this paper, four tillage treatments including conventional tillage with rice only system (CT), conventional tillage with rotation of rice and rape system (CTR), no-till and plain culture with rotation of rice and rape system (NTP) and no-till and ridge culture with rotation of rice and rape system (NTR) were selected as research objectives. The results showed that the annual CH4 and N2O emissions were mainly occurred in the rice growing period, and were about 77.6% and 55.0% of the total annual of them emitted from this period. The total annual CH4 under CT was higher than that of other treatments. The annual average flux of CH4[CH4, mg x (m2 x h)(-1)] order was CT (2.96 +/- 0.04) >NTR (1.83 +/- 0.21) >NTP (1.42 +/- 0.01) >CTR (0.96 +/- 0.09); the annual average flux of N2O[N2O, microg x (m2 x h)(-1)] order was CTR (123.6 +/- 47.1) > NTR (115.2 +/- 22.1) > NTP (100.5 +/- 25.8) > CT (81.3 +/- 13.5), and the total annual N2O under CTR was higher than that of CT. The global warming potentials (GWPs) of CH4 and N2O emissions under different tillage-cropping systems were assessed in an integrated way. The results showed that the integrated GWPs of CH4 and N2O emission were in the following sequence: CT > NTR > NTP > CTR, and CTR was the best treatment for decrease the integrated GWPs in this area. PMID- 22946186 TI - [Factors influencing ammonia volatilization in a winter wheat field with plastic film mulched ridges and unmulched furrows]. AB - The objective of this experiment was to quantify ammonia volatilization from a winter wheat field with plastic film mulched-ridges and unmulched-furrows (PMRF). The trial was conducted during the 2010-2011 winter wheat growing season at Yangling, Shaanxi Province. Ammonia volatilization from the soil was measured using the closed-chamber method. The results indicated that NH3 emission losses ranged between (1.66 +/- 0.3) and (3.28 +/- 0.51) kg x hm(-2) in the PMRF treatment. In comparison, the NH3 emission loss was (4.68 +/- 0.35) kg x ha(-1) in the conventional tillage treatment (i. e., smooth soil surface). The PMRF treatment reduced NH3 emissions by 29.8 to 63.8% compared with the conventional treatment. The NH3 emission losses were equivalent to 1.9% of the applied N in the conventional practice treatment. In contrast, the losses were equivalent to only 0.3% to 0.8% of the applied N in the PMRF treatment. Ammonia emissions were greatest during the first two weeks after sowing. Emissions before winter accounted for 82% of total NH3 emission in the conventional practice treatment, but only 49% to 61% of the total NH3 emission in the PMRF treatment. The soil NH4+ -N content and the soil moisture content had direct effects on NH3 emission before winter in the conventional treatment. In thePMRF treatment, the soil NH4+ N content had a direct effect on NH3 emission before winter, whereas soil surface temperature and soil moisture had indirect effects. Ammonia emissions after the greening stage were mainly influenced by the soil NH4+ -N content. Simulation results indicated that logarithmic functions best described cumulative NH3 emission in the PMRF + high N rate treatment and the conventional treatment. A linear function best described cumulative NH3 emission in the PMRF + low N rate treatment and the unfertilized treatment. In conclusion, the PMRF treatment can significantly reduce N losses from winter wheat fields by changing the spatial temporal dynamics of soil NH3 volatilization. PMID- 22946187 TI - [Effects of typical herbicides on soil respiration and N2O emissions from soil added with different nitrogen fertilizers]. AB - To investigate the effects of typical herbicides on soil respiration and N2O emissions from soil added with different nitrogen fertilizers, a laboratory incubation experiment was carried out using a modified gas chromatograph (Agilent 4890D) method. The results showed that with (NH4)2SO4 amendment, soil respiration and N2O emissions from the Atrazine and Paraquat treatments had no significant difference in comparison to the control (P > 0.05). Glyphosate significantly inhibited soil respiration by 21.5% (P < 0.05) and had no obvious influence on N2O emissions (P > 0.05). Tribenuron-methyl significantly promoted soil respiration with the increase of 14.3% (P < 0.05) and also had no obvious influence on N2O emissions (P > 0.05). Acetochlor significantly increased soil respiration and N2O emissions (P < 0.05) with the increase of 6.1% and 45.1%, respectively. With urea application, Atrazine and Acetochlor had no significant influence on soil respiration and N2O emissions (P > 0.05). Paraquat increased N2O emissions significantly (P < 0.05)with the increase of 43.5% and had no significant influence on soil respiration ( P > 0.05). Glyphosate significantly inhibited soil respiration by 17.5% (P < 0.05), and had no significant influence on N2O emissions (P > 0.05). Tribenuron-methyl enhanced soil respiration and N2O emissions significantly (P < 0.05), and its soil respiration and N2O emissions were 1.3 and 1.6 times higher than those from the control. Due to the complexity of effects of different herbicides on microbial physiological metabolism, long term in-situ studies need to be carried out to better understand the effect of various herbicides on greenhouse gas emissions. PMID- 22946188 TI - [Analysis of characteristics of dioxin contamination in the chlor-alkali site that uses graphite anode for production]. AB - In order to find out the characteristics of dioxin contamination, we sampled and analyzed the soil and groundwater on a chlor-alkali factory site that uses graphite anode for production. The results show that the toxic equivalent quantity (TEQ) of dioxins in soil samples exceeds the U. S. EPA region screening value (RSL), with the chlorine hydrogen processing workshop, the electric tank workshop, the asbestos stack area, the sewage treatment plant and the oil depot were affected. The dioxin concentration limit of the groundwater sample doesn't exceed the drinking water standard of China. Considering the fingerprints characteristics of dioxin-contaminated concentration, dioxin isomers content and TEQ, the priority pollutants for control on this site are 2,3,7,8-TCDF, 2,3,4,7,8 PeCDF, 1,2,3,4,7,8-HxCDF, OCDD and 2,3,7,8-TCDD. The results show that dioxin pollution is very serious in the chlor-alkali plant that uses graphite anode for production, and the environmental supervision is imperative. PMID- 22946189 TI - [Effect of flue gas desulfurization gypsum application on remediation of acidified forest soil]. AB - Effect of flue gas desulfurization gypsum (FGDG) application on remediation of a typical acidified forest soil was studied through field experiments at Tieshanping, Chongqing in southwest China for one year. To evaluate the effect and risk of FGDG application, pH value, major ions and heavy metal of soil water in different soil layers were observed dynamically, and heavy metal contained in soil and FGDG were measured. Results showed that Ca2+ and SO4(-2) concentration of soil water in FGDG plots increased with time, pH value was elevated slightly, and n(Ca)/n(Al) value of annual average increased from 2.16, 1.35 and 0.88 to 2.58, 1.52 and 1.12 compared with control plots. The concentration of As, Cu, Cr, Ni and Zn in soil water was not elevated significantly. However, slight enrichment of Cr, Ni and Zn in some upper soil layers was observed. Consequently, FGDG application can improve acidified forest soil, without obviously heavy metal increasing in soil water. However, risk for heavy metal enrichment still exists, which is need for further study. PMID- 22946190 TI - [Morphology of soil iron oxides and its correlation with soil-forming process and forming conditions in a karst mountain]. AB - The quantity and morphology of iron oxides are indicators of soil forming-process and forming conditions. In order to analyze the connection between soil iron oxides and soil forming conditions and degenerative process of karst ecosystem, we have chosen 14 soil profiles on the top and middle section of Jinfo Mountain, a typical karst slope in Chongqing, China. Morphology and contents of soil iron oxides were studied by using chemical selective extraction techniques. We draw conclusions: 1) total iron (Fe(t)) is mainly controlled by parent material and lithology. Significant difference of Fe(t) content exists between soils in Top Mountain (51.49 g x kg(-1), mean value from 5 profiles) and soils at the middle sector of North Slope (86.29 g x kg(-1), mean value of 9 profiles); 2) the results show low concentration of F(d) (29.16 g x kg(-1)) and low ratio of Fe(d) to Fe(t)(35.40%) in soil clay under conditions of high elevation and low temperature on Top Mountain. In contrast, the results indicate advanced weathering and soil-forming process at middle slope sites due to high temperature; this is supported by high mean values of Fe(d) (43.92 g x kg(-1)) and ratio of Fe(d)/Fe(t) in clay (60.41%); 3) long humid climatic setting and large numbers of soil organic matter on top of the mountain result in high activation degrees (F(o)/Fe(d)) and high complexation degrees (Fe(p)/Fe(d)); mean values of them are 73.51%, 17.21% respectively, which are higher than that of soils at middle slope sites (13.06%, 0.41%); 4) after degradation or deforestation of secondary forestland (pines massoniana among bushes) at middle section of the hillslope, soil free iron oxides (Fe(d)) and total iron oxides (Fe(t)) decrease as well as soil organic carbon and clay, because of progressively increasing of soil erosion. Average contents of Fe(t) and Fe(d) in clay from 2 shrub profiles are 98.25 g x kg(-1), 50.81 g x kg(-1) respectively. However, the four tillage soils we have studied reveal lower values of Fe(t) (84.52 g x kg(-1)) and Fe(d) in clay (47.86 g x kg(-1)). Soil iron oxides are reliable indicators to estimate degeneration of karst ecosystem and karst rock desertification. PMID- 22946191 TI - [Pb, Zn accumulation and nutrient uptake of 15 plant species grown in abandoned mine tailings]. AB - Vegetation restoration field test was carried out in the abandoned lead-zinc tailings for 3 years. The study showed that accumulation of lead (Pb), zinc (Zn) and nutrient uptake differed with plant species and organs, heavy metals, and planting time. Pb was mainly accumulated in tree roots, and its content distribution in tree organs was generally in the order of roots > leaves > stems. But Zn concentrations in leaves of several tree species were higher than those in roots and stems. Within the tested 15 species, Cercis Canadensis had the highest concentrations of Pb and Zn in roots (1 803 and 2120 mg x kg(-1), respectively). Rhus chinensis had the highest Pb concentration in stems and leaves (280 and 546 mg x kg(-1), respectively) and Zn concentration (1 507 mg x kg(-1)) in leaves. Zn concentration in stems and leaves of Salix matsudana (729 and 1 153 mg x kg(-1), respectively) were the highest. Among the tested 15 species, TF values for Pb of Liquidambar formosana, Medicago sativa, and for Zn of Salix matsudana, Rhus chinensis, Medicago sativa were higher than 1. BCF values for Pb were all lower than 0.17, while that for Zn were all lower than 0.44. The N contents in nitrogen fixing plants, P contents in Rhus typhina and Ailanthus altissima, and K content in Nerium indicum were significantly higher than those in other plants. With the increase of planting time, concentrations of heavy metal in plant body increased significantly; however the inverse trend were observed in nutritional element content. The species have higher metal accumulation capacity, such as Rhus chinensis, Salix matsudana and those nitrogen-fixing plants have higher tolerance to metal contamination and nutrient deficiency, such as Amorpha fruticosa, Medicago sativa, Lespedeza cuneata, and Alnus cremastogyne, they were suitable as the phytostabilizers in abandoned mine tailings. PMID- 22946192 TI - [Effect of Cr(VI) stress on growth of three herbaceous plants and their Cr uptake]. AB - In order to elucidate the toxic mechanisms of Trifolium repens, Festuca arundinacea and Medicago sativa under chromium [Cr (VI)] stress, provide a theoretic foundation for phytoremediation of Cr-contaminated soil, pot experiment was conducted to investigate the effects of Cr(VI) on plant growth, physiological characteristics, Cr accumulation and distribution in three herbaceous plants. Soil sample was treated by adding K2Cr2O7 with the Cr(VI) concentration of 0, 100, 200, 300 and 400 mg x kg(-1), respectively. The results indicated that the average tolerance indices of T. repens, F. arundinacea and M. sativa were 62.5, 48.3 and 36.33, respectively. Compared with control group, contents of chlorophyll, the activity of superoxide dismutase(SOD) and peroxidase (POD) were 57.14%, 51.51%, 35.76% and 63.27%, 52.96%, 41.36% in T. repens, and F. arundinacea, respectively, but M. sativa died in 400 mg x kg(-1) Cr(VI) treatment. The plant height, root length, dry mass of roots and shoots decreased under Cr(VI) stress in three herbaceous plants, and M. sativa > F. arundinacea > T. repens, however, the content of malonyldialdehyde (MDA) increased compared to the control, and the variation range of M. sativa was the highest, while T. repens was the smallest among them. The tolerance of Cr( VI) was T. repens > F. arundinacea > M. sativa. Cr mainly distributed in cell wall and then in the cytoplasm, and less distributed in the mitochondrion and chloroplast in leaves of three herbaceous plants, whereas the content of chlorophyll, MDA, the activity of SOD and POD correlated well with Cr accumulation in the mitochondrion and chloroplast. Cr concentration in the subcellular of leaves increased with the adding Cr(VI) concentration,and M. sativa > F. arundinacea > T. repens. In comparison with T. repens, F. arundinacea, Cr concentration in the leaves of M. sativa was the maximal, i.e. 51.44 mg x kg(-1), and the proportions in the mitochondrion (18.04%) and chloroplast (19.09%) were also higher in 300 mg x kg( 1) Cr(VI). The average accumulation factors of shoots/roots were 1.22/1.54, 1.16/1.44 and 1.26/1.62, while the average translocation factors were 0.78, 0.78 and 0.74 in T. repens, F. arundinacea and M. sativa, respectively. The results suggest that T. repens and F. arundinacea are promising for the phytoremediation of Cr-contaminated soil. PMID- 22946193 TI - [Bioaccumulation of heavy metals by the dominant plants growing in Huayuan manganese and lead/zinc mineland, Xiangxi]. AB - Heavy metal pollution is a major environmental problem of mine wasteland. Finding out the tolerant plants, which can adapt to the local climate and the soil conditions, is the premise of vegetation restoration. An extensive vegetation survey and sampling were conducted in Huayuan Mn and Pb/Zn mineland, 76 species belonging to 69 genera and 39 families were recorded. The main dominant species and their associated soils were determined for heavy metal concentrations. The results showed that soil Pb, Zn and Cd levels exceeded the threshold levels of Class II of China Environmental Quality Standard for Soils, which suggested minesoils might be polluted by the three elements. The main dominant plants can adapt to the unfavorable edaphic conditions of mineland and were tolerant to heavy metals. There were great variations of metal uptake and accumulation among different plant species. They were classified into three types according to the metal concentrations in the plant shoots and roots: the accumulator, e. g. Camellia oleifera and Dicranopteris dichotoma, absorbed a large amount of heavy metals by the roots and transported to the shoots, which can be used to clean up the soils containing light to moderate toxic metal concentration and with high value; the root compartment, e. g. Rubus tephrodes, R. corchorifolius, R. chroosepalus, Artemisia princeps and Pteridium aquilinum also absorbed a large amount of heavy metals but held in the roots; and the excluder, e. g. Miscanthus sinensis, Imperata cylindrica, Indocalamus tessellatus and Toddalia asiatica, absorbed less heavy metals than the accumulators. The root compartment and the excluder were more suitable for remediation of the mine wastelands with high heavy metal concentration, low-value and extensive area. PMID- 22946194 TI - [Effect of CO2 fertilization on residual concentration of cypermethrin in rhizosphere of C3 and C4 plant]. AB - In order to achieve sustainable economic and environmental development in China, CO2-emission reduction and phytoremediation of polluted soil must be resolved. According to the effect of biological carbon sequestration on rhizosphere microenvironment, we propose that phytoremediation of polluted soil can be enhanced by CO2 fertilization, and hope to provide information for resolving dilemma of CO2-emission reduction and phytoremediation technology. In this study, effects of CO2 fertilization on cypermethrin reduction in rhizosphere of C3-plant (bush bean) and C4-plant (maize) were investigated. Results showed that dry weight of shoot and root of bush bean (C3 plant) was increased by CO2 fertilization. Relative to ambient CO2, dry weight of root was increased by 54.3%, 31.9% and 30.0% in soil added with 0, 20 and 40 mg x kg(-1) cypermethrin respectively. Microbial biomass was increased by CO2 fertilization in rhizosphere soil added with 0 mg x kg(-1) cypermethrin, but negative effect was found in rhizosphere soil added with 20 and 40 mg x kg(-1) cypermethrin. CO2 fertilization slightly affected residual concentration of cypermethrin in rhizosphere soil added with 0 mg x kg(-1) cypermethrin, but significantly decreased residual concentration of cypermethrin as 24.0% and 16.9% in soil added with 20 and 40 mg x kg(-1) relative to ambient CO2. In maize plant, however, plant growth, microbial biomass and residual cypermethrin concentration in rhizosphere was slightly affected by CO2 fertilization, and even negative effect was observed. This study indicated that CO2 fertilization decreases the residual concentration of cypermethrin in rhizosphere of C3-plant, and it is possible to enhance phytoremediation of organic-polluted soil by C3-plant through CO2 fertilization. However, further study is needed for C4-plant. PMID- 22946195 TI - [Bioaugmented removal of pyridine and the microbial community dynamic analysis]. AB - The bioaugmented removal of pyridine was investigated through introducing immobilized Paracoccus sp. strain KT-5 capable of degrading pyridine into the lab scale sequencing batch reactor (SBR) inoculated with activated sludge. The terminal restriction fragment length polymorphisms (T-RFLP) was used to analyzed the microbial community dynamics of two reactors during the whole operation process. The experimental results indicated that the introduction of immobilized strain KT-5 into the SBR could speed up the start-up of reactor, compared to the non-bioaugmented SBR. When the initial concentration of pyridine varied from 195.6 mg x L(-1) to 586.8 mg x L(-1), the bioaugmented effect was not significant; however, when the initial concentration of pyridine was 782.4-2934 mg x L(-1), the bioaugmentation role in pyridine degradation was obvious. The analysis of T-RFLP indicated that the introduced immobilized strain KT-5, as a dominant strain, always existed in both free and immobilized biomass of the bioaugmented SBR. PMID- 22946196 TI - [Relationship between sewage treatment efficiency and bacterial community diversity in an A/O MBR]. AB - An Anoxic/Oxic Membrane Bioreactor (A/O MBR) was used to treat sewage. Five different working conditions were run to determine the optimal process parameters. Bacterial community structures in both anoxic and oxic tanks were analyzed using denaturing gradient gel electrophoresis (DGGE). The relationship between effluent water quality and bacterial community diversity was established. The experimental results indicated that, under the optimal parameters of hydraulic retention time (HRT) 12 h, sludge retention time (SRT) 10 d, reflux ratio of nitrified effluent 300%, and reflux ratio of sludge 100%, the A/O MBR removed COD, NH4+ -N, and TN effectively and stably with the average removal rates of 96.4%, 99.1% and 75.8%, respectively. The bacterial communities varied markedly in both anoxic and oxic tanks during the sewage treatment experiment. Under a same working condition, the communities in both tanks were often similar with a similarity of more than 50%. The community diversity of the anoxic tank fluctuated depending on different working conditions, while the diversity of the oxic tank increased steadily along with the operation time. A positive correlation between the bacterial community diversity of the anoxic tank and the denitrification efficiency of the A/O MBR was established. PMID- 22946197 TI - [Dynamic changes in functional genes for nitrogen bioremediation of petroleum contaminated soil cycle during]. AB - Microorganisms in nitrogen cycle serve as an important part of the ecological function of soil. The aim of this research was to monitor the abundance of nitrogen-fixing, denitrifying and nitrifying bacteria during bioaugmentation of petroleum-contaminated soil using real-time polymerase chain reaction (real-time PCR) of nifH, narG and amoA genes which encode the key enzymes in nitrogen fixation, nitrification and ammoniation respectively. Three different kinds of soils, which are petroleum-contaminated soil, normal soil, and remediated soil, were monitored. It was shown that the amounts of functional microorganisms in petroleum-contaminated soil were far less than those in normal soil, while the amounts in remediated soil and normal soil were comparable. Results of this experiment demonstrate that nitrogen circular functional bacteria are inhibited in petroleum-contaminated soil and can be recovered through bioremediation. Furthermore, copies of the three functional genes as well as total petroleum hydrocarbons (TPH) for soils with six different treatments were monitored. Among all treatments, the one, into which both E. cloacae as an inoculant and wheat straw as an additive were added, obtained the maximum copies of 2.68 x 10(6), 1.71 x 10(6) and 8.54 x 10(4) per gram dry soil for nifH, narG and amoA genes respectively, companying with the highest degradation rate (48% in 40 days) of TPH. The recovery of functional genes and removal of TPH were better in soil inoculated with E cloacae and C echinulata collectively than soil inoculated with E cloacae only. All above results suggest that the nitrogen circular functional genes could be applied to monitor and assess the bioremediation of petroleum contaminated soil. PMID- 22946198 TI - [Risk assessment of lead exposure from different intake pathways for children in Wuhan City]. AB - 70 sampling points were set in Wuhan City to collect soil, dust, air and food samples. According to the U. S. EPA recommended childhood lead exposure parameters, U. S. EPA human exposure risk assessment method was used to assess the potential health risk of different pathway exposures of children in Wuhan City to lead. The results of calculation show: Wuhan urban children's daily lead exposure is 1.20 x 10(-3) mg x (kg x d)(-1). The digestive tract is the main way for children's exposure to lead, with the exposure of 1.04 x 10(-3) mg x (kg x d)(-1), followed by the respiratory route and dermal absorption route, the exposures were 0.153 x 10(-3) mg x (kg x d)(-1) and 8.56 x 10(-7) mg x (kg x d)( 1) respectively. Pathways of the digestive tract, ingestion of soil or dust lead exposure accounted for 52.0% of the total exposure, through the digestive tract of soil or dust ingestion is the main route of exposure. Monte-Carlo method was used to simulate the pathway in the digestive tract, the amount of lead exposure through ingestion of soil was 2. 48 x 10(-2) mg x d(-1). The probability that exceeded the PTDI (Provisional Tolerable Daily Intake) specified by JECFA (The Joint FAO/WHO Expert Committee on Food Additives) was 2.1%. The results of the risk assessment indicate that lead exposure risks from the digestive tract, respiratory tract, skin absorption are less than the maximum acceptable risk level 5.0 x 10(-5) respectively and the risk associated with skin absorption of lead is less than the negligible risk level 1 x 10(-8). Application of Kriging interpolation method, Wuhan City children lead exposure value on spatial distribution were obtained, and Qingshan district and Jiangan district have a high level of children lead exposure. The aggregate risk index of Wuhan City children lead exposure was yield by using the indicator Kriging. PMID- 22946199 TI - [Implementation of a pretreatment device for an electronic nose]. AB - A pretreament device was implemented for removing the interference of humidity on the baseline signal response of sensors in an electronic nose, which was used for rapid detection and real-time monitoring of volatile chlorinated hydrocarbons (VCHs) pollution in soil. The desiccant material was optimized, and the humidity removal performance and adsorpiton of VCHs was studied. The pretreatment device was evaluated by both the electronic nose and gas chromatography (GC) for its applicability in monitoring the PCE concentration in the desorption gas during the soil ventilation process. The following results were obtained: 1) A desiccant tube with anhydrous calcium chloride followed by a halogenated hydrocarbon separation tube was the best device, with a humidity removal rate of over 99%, and the baseline values of each sensor in the electronic nose were close to that of the control. 2) The desiccant device described above could continuously remove almost all the humidity from air with 75% humidity within 90 min, and the humidity removal rate remained above 95% within 120 min, while little interference was observed on the baseline of each sensor. 3) Little adsorption was observed by the pretreatment device, the relative error being only 3% - 5% between the concentration of VCHs before and after the filtration by the pretreatment device. 4) When applied for monitoring the remediation progress in a soil ventilation process, 99% of humidity was removed within 120 min from air with humidity of over 98%, and the data determined with the electronic nose and GC fitted each other very well, with R2 > 0.99. From the above, the pretreatment device connected with the electronic nose was considered to be applicable for monitoring the soil remediation process. PMID- 22946200 TI - [Copper and cadmium toxicities to activated sludge investigated with ToxTell biosensor]. AB - Effects of different concentrations of Cu2+, Cu2+ and Cd2+ combined pollution on the removal performance of COD in activated sludge system were investigated, and the ToxTell biosensor with activated sludge was constructed to determine the toxicity of Cu2+, Cu2+ and Cd2+ combined pollution. The results showed that there was no significant impact on the activated sludge process when Cu2+ concentration was lower than 10 mg x L(-1), and the addition of Cd2+ enhanced the inhibition of COD removal, and the maximum inhibition efficiency of COD reached at about 1.5 h. With the increase of aeration time, the COD removal efficiency increased slowly again. The toxicity measurement with ToxTell biosensor was close to the biological effects (inhibition efficiencies of COD), which showed that the ToxTell biosensor could be used well in the early warming determination of Cu2+ and Cd2+ in the activated sludge process. PMID- 22946201 TI - [Matrix effect and control of immunoassay for environmental samples]. AB - Immunoassay provides very specific, highly sensitive, rapid, and cost-effective analyses for a variety of environmental contaminants. Since the immunoassay detects the environmental samples without pre-treatment, the interferences caused by various matrixes of environmental samples are a major problem, which can greatly affect the detection results. In this paper, based on the enzyme-linked immunosorbent assay (ELISA) for detection of Microcystin-LR (MC-LR), the effect of many kinds of matrixes on ELISA was systematically analyzed, and the corresponding method to control or eliminate the disbennifit effect was proposed. Finally, an integrated and packaged strategy-using the following buffer system as a diluent, i.e. 0.1 mol x L(-1) pH 7.4 PBS (10 x PBS) containing 1% BSA, 0.5% EDTA and 40 g x L(-1) sodium chloride-was given to control the overall matrix effects of environmental samples on ELISA detection. This strategy is also applicable to other kinds of immunoassays for environmental samples. PMID- 22946202 TI - [Study on vitrification of simulated medical wastes by thermal plasma]. AB - The simulated medical wastes with different feed compositions were vitrified in a thermal plasma reactor, the core of which was a DC double anode plasma torch. The purpose of this study was directed towards the mobility characteristics of heavy metals contained during the vitrification process, the leaching behavior of heavy metals in the vitrified slag and the effectiveness of vitrification were investigated. Results indicated that the morphology of vitrified slag was amorphous state which showed the mostly glassy slag of SiO2 and the microstructure of slag was very compact. This thermal plasma could be effectively utilized for encapsulation of heavy metal in wastes, as the vitrification ratio was between 68.5% - 89.4%. Toxicity characteristic leaching procedure results showed that the slag had an excellent resistance against leaching of heavy metal ions. Except that the leaching concentration of Cd was lower than the detecting limit, those of Ni, Cr, Zn, Cu and Pb were much lower than that specified in relevant national standards. These results indicate that, with the proper feed compositions, the thermal plasma disposition is an alternative technology with a highly efficiency to dispose medical wastes. PMID- 22946203 TI - [Study on the low temperature drying of components of municipal solid waste and its model analysis]. AB - The drying behaviors of four typical municipal solid waste (MSW) components (including waste paper, textile, pericarp and wood) were studied under low temperature. Effects of temperature on drying characteristic, thin layer drying models, effective moisture diffusion coefficient and activation energy were investigated in this paper. Experimental results showed that with increasing temperature, the drying rate increased, but the added value reduced gradually. Four mathematical models were used to simulate drying curves of MSW components. Modified Page model was found to give better predictions when moisture content was more than 25%. Based on the Fick's second law, the effective moisture diffusion coefficient for waste paper, textile, pericarp and wood were 8.24 x 10( 8)-23.67 x 10(-8), 7.73 x 10(-8)-12.56 x 10(-8), 3.57 x 10(-8)-14.18 x 10(-8) and 6.51 x 10(-8)-23.84 x 10(-8)m2 x s(-1). The activation energy determined through Arrhenius equation were 25.26, 10.75, 32.16 and 29.49 kJ x mol(-1), respectively. Carried on the similar dry experiments to practical MSW, It was found that Modified Page model was also suitable for simulating the drying process of practical MSW, its effective moisture diffusion coefficient and activation energy were 6.78 x 10(-8)-18.65 x 10(-8)m2 x s(-1) and 22.36 kJ x mol(-1), respectively. PMID- 22946204 TI - [Aerogenesis evolution of the anaerobic-semiaerobic bioreactor landfill]. AB - A novel bioreactor landfill, the anaerobic-semiaerobic bioreactor landfill (AN SABL), was devised by combining an anaerobic bioreactor landfill (ANBL) with a semi-aerobic aged refuse biofilter (SAARB). Meanwhile, relevant parameters such as gas production volume and rate, and gas constituents were investigated to provide a theoretical foundation for the collection, utilization and treatment of landfill gas. Results indicated that the gas production of the anaerobic units was inhibited in the AN-SABLs. The gas production rates in the ANBL2 unit and the ANBL3 unit were 49 L x kg(-1) and 39 L x kg(-1) respectively, which were only 94.2% and 75.0% of that in the ANBL1. However, the gas production in the anaerobic unit could be accelerated by increasing the recirculation frequency. The maximum methane content could reach up to 62.67%. Moreover, the gas production volume and velocity in the ANBL were much higher in summer than those in winter, and the gas production peak could be observed with a 12-hour cycle. Besides, the nitrification and the denitrification in the anaerobic units would be enhanced remarkably in the AN-SABLs. It resulted that the content of N2O, which fluctuated between 0.0017% and 4.0179%, was influenced obviously by the seasonal variation and the landfill types. Based on the mathematical model of aerogenesis, the cumulative gas volume of the ANBL increased logarithmically in the initial aerobic phase, then increased linearly in the anaerobic acid phase, and increased exponentially in the methane production of acid phase afterwards. PMID- 22946205 TI - [Performance of microbial fuel cells with Fe/C catalyst carbon felt air-cathode for treating landfill leachate]. AB - Ferric nitrate/activated carbon powder catalyst was obtained through impregnation and Fe/C catalyst was adsorbed on carbon felt as air cathode electrodes. Effects of activated carbon powder dosage and ferric nitrate concentration on electricity generation of MFC with landfill leachate as fuel were measured. Performances of cathodes obtained at different ferric nitrate concentrations were evaluated by cyclic voltammetry tests. The results showed that with the increase of activated carbon powder dosage or the iron nitrate concentration, MFC produce electrical properties showed a decreasing trend after the first rise. When the activated carbon powder dosage was 1 g and the iron nitrate concentration was 0.25 mol x L( 1), it was proved to be an optimum cell performance for 4199.8 mW x m(-3) output power and 465 omega apparent resistance. Under the optimal ratio rang between ferric nitrate and activated carbon powder, MFC apparent resistance decreased and the power density increased respectively with the increase of catalyst total dosage. The best produce electrical properties of MFC with Fe/C catalyst for 0.25 mol x L(-1) iron nitrate and 1 g activated carbon powder dosage was observed by cyclic voltammetry tests. The output power of MFC and the removal quantity increased with the concentration of inlet and the maximum values were respectively 5478.92 mW x m(-3) and 1505.2 mg x L(-1). the maximum removal rates of COD achieved at 89.1%. PMID- 22946206 TI - [Relationships between soil and rocky desertification in typical karst mountain area based on redundancy analysis]. AB - Redundancy analysis (RDA) was employed to reveal the relationships between soil and rocky desertification through vegetation investigation and analysis of soil samples collected in typical karst mountain area of southwest Guizhou Province. The results showed that except TP, TK and ACa, all other variables including SOC, TN, MBC, ROC, DOC, available nutrients and basal respiration showed significant downward trends during the rocky desertification process. RDA results showed significant correlations between different types of desertification and soil variables, described as non-degraded > potential desertification > light desertification > moderate desertification > severe desertification. Moreover, RDA showed that using SOC, TN, AN, and BD as soil indicators, 74.4% of the variance information on soil and rocky desertification could be explained. Furthermore, the results of correlation analysis showed that soil variables were significantly affected by surface vegetation. Considering the ecological function of the aboveground vegetation and the soil quality, Zanthoxylum would be a good choice for restoration of local vegetation in karst mountain area. PMID- 22946207 TI - [Energy consumption and GDP growth in Beijing: cointegration and causality analysis]. AB - In this paper, the Johansen cointegration technique and the vector error correction model (VECM) were used to examine the causal relationship between energy consumption (LEC) and gross domestic product (LGDP) for Beijing during the period of 1980 to 2008. Results indicated that LEC and LGDP for Beijing were related by one cointegrating vector and there was a long-run unidirectional causal relationship from GDP to energy consumption. The long-term and short-term elasticity from economy to energy consumption were 0.44 and 0.12 separately. Statistic analysis showed that from 1980 to 2008 every 1% growth in GDP annually would drive energy consumption increasing rate by 0.4% correspondently. And the effect imposed from economy to energy consumption was lagging. It showed that energy consumption was not a strong exogenous variable as to economy. The finding has significant implications from the point of view of energy conservation, emission reduction and economic development. PMID- 22946208 TI - SCOTUS decision yields opportunity, demands responsibility. PMID- 22946209 TI - A look inside the Vault. Oregon tech partnership delivers best-in-class healthcare data security. PMID- 22946210 TI - Positive patient identification begins at step one. Affordable, high-resolution, dedicated ID card image scanners allow medical practices to start positive patient identification (PPID) at the point of registration. PMID- 22946211 TI - Palm scanners enhance patient safety. Iowa's Broadlawns Medical Center integrated the biometric system with its registration process. PMID- 22946212 TI - A breath of fresh air. Mobile solutions increase accuracy for medical equipment and oxygen respiratory supplier. PMID- 22946213 TI - Is RTLS a tipping-point technology? Boost in efficiency gained by real-time capacity management provides significant ROI, better patient care. PMID- 22946214 TI - Four steps to successful mobile implementation. Best practices for integrating mobile technology into existing hospital workflows. PMID- 22946215 TI - Insights from the office for civil rights. An inside look at the results of the first random HIPAA compliance audits. PMID- 22946216 TI - [The hyperuricosuria in patients with high content of triglycerides: the combination of genetic and environmental factors and tactics of treatment]. AB - The increasing of uric acid level (hyperuricosuria) is regularly detected in blood during the examination of patient with such cardiovascular diseases as arterial hypertension, atherosclerosis, diabetes mellitus, metabolic syndrome and obesity. The hyperiricosuria and hypertriglyceridemia are two independent risk factors, especially for arterial hypertension. The higher level of uric acid combined with hyper-lipoproteinemia (phenotypes) IIa and IIb was noted in 65% of patients. In males, hyperiricosuria was detected more often than in females. In groups with higher content of uric acid, the significant difference between median and quartiles was determined concerning the indicators of height, body mass, triglycerides concentration, beta-lipoprotein fractions content, pre beta lipoprotein fractions content, apolipoprotein E in blood serum and apolipoprotein B=100 lipoproteins, but not both apolipoprotein C=III and apolipoprotein E in lipoproteins of high density. The increase of concentration of triglycerides and uric acid in blood is the outcome of disorder of metabolism of fat acids and nucleotides under surplus intake of substances with food. The fructose of sweet drinks can be considered as the source of fructose. The fructose is capable to increase the concentration of uric acid The catabolism of nucleotides is under regulatory impact of fructose: dicarboxylic derivatives can provoke increase of uric acid concentration. The treatment of patients with hyper-triglycerideimia, hyperiricosuria and hyperglycemia has to begin from decreasing of triglycerides concentration, dietotherapy and further if it is necessary, to apply the hypolipidemic therapy with fibrates. PMID- 22946217 TI - [The preanalytical stage of under measuring of concentration of catalytic activity of enzymes: the characteristics and tasks of standardization]. AB - The article explains the importance of standardization, the development and maintenance of rules and recommendations regulating the conditions and order of implementation of particular parts of preanalytical stage. The order of these conditions is noted including the rules stated and published in such normative documents as national standards GOST R 15 189-2009, GOST R 53079.4-2008, GOST R ISO 6710-209 and in the recommendations of foreign National societies ofclini-cal chemistry and laboratory medicine. These requirements concern all the analytes, enzymes included. The cited data have a practical significance for acquisition of reliable results in everyday functioning of laboratories. Enough to mention data concerning the anticoagulants influence on catalytic concentration of enzymes, the most often measured concentrations of alpha-amylase, lipase, amynotransferase, alkaline and acid phosphatase, creatine kinase, lactate dehydrogenase, choline esterase, hemolysis impact, the increased concentration of bilirubin and hyperlipemia in samples and significance of measurement of indices of serum and plasma as well. The possible mechanisms of impact of these interferents on the results of measurement of catalytic concentration of enzymes are discussed. PMID- 22946218 TI - [The alteration of concentration of essential microelements in blood plasma in children with chronic diseases of gastrointestinal tract and having different body mass]. AB - The article deals with the characteristics of alterations of mineral metabolism indicators in children of various age with chronic diseases ofgastrointestinal tract and having body mass of normal and different surplus degrees. The sample consisted of 127 children aged from 6 to 15 years with chronic gastroduodenitis, pancreatitis and cholecystitis. The concentration of bioelements in plasma was determined using the technique of mass spectrometry with inductively coupled plasma. The study established the increase of concentration of molybdenum 4.3 times, chrome--8.4 times and selenium--1.36 times. The revealed bioelemental misbalance impacts the overall health of children and course of disease and hence has to be accounted in case of application of treatment targeted to the correction of mineral metabolism. PMID- 22946219 TI - [The functional tests in clinical diagnostic laboratory: the detection of magnesium deficiency in the loading test]. AB - The article deals with the value and role of functional tests in practice of clinical diagnostic laboratories. The possibilities of evaluation of biological function of homeostasis according the changes of magnesium ions or calcium concentration in urine or blood hence reflecting the deficiency of these ions in vivo. The magnesium tolerant test is described It is demonstrated that it can be applied both in curative preventive institutions and ambulatories. In the examined group of patients, 78% had physiologic parameters of magnesium concentration, 17% suffered from hypermagnesiumuria and 5%--from hypermagnesiumuria. The magnesium deficiency of different degree was detected in 87% of patients. In the most part of patients with magnesium deficiency normomagnesiumuria was detected. Only in one case with normomagnesiumuria the magnesium deficiency was absent. In 30% of patients with magnesium deficiency the concentration of cation in day urine decreased up to 2.2 times after load dose. In absence of deficiency the monotony of cation's excretion was noted. Under the magnesium deficiency the character of process changed but velocity of excretion of magnesium after load probe slightly decreased relative to values before the load. The impact of alcohol under established magnesium deficiency results in increasing of velocity of excretion of this analyte. In patient with diabetes mellitus type II six months before the diagnosis of this disease the hidden deficiency of magnesium was detected. The magnesium deficiency was not detected after the antidiabetic treatment was applied The results permit to postulate the possibility of application oral load test with magnesium to assess the impact of various stress, physical, emotional and psychological factors. The detection of magnesium deficiency permit to broad the complex treatment, to accelerate and to enhance the results of treatment of diseases. Besides, the evaluation of patient's condition according the reaction of the organism to the probe with magnesium load is an essential element of personalized medicine. PMID- 22946220 TI - [The gas chromatography detection of fat acids in dry blood serum]. AB - The article discusses the development of gas chromatography method of detecting the composition of fat acids in dry blood serum. The comparative analysis of content of fat acids in freshly selected and dry serum. The stability of composition of fat acids in dry serum under its conservation during 2 months was examined. It is demonstrated that qualitative and quantitative compound of fat acids in fresh and dry serum is identical and continue to be unchanged during one month. PMID- 22946221 TI - [The proteins of fast phase of inflammation in prognosis of condition of newborn in case of pregnancy complicated by hydramnion and under the risk of intrauterine infection]. AB - The content of alpha-macroglobulin associated with pregnancy, alpha2 glycoprotein, alpha1-antitripsin, and lactolerrin in blood serum of pregnant women and umbilical serum under hydramnion and risk of development of intrauterine infection of fetus is investigated. It is demonstrated that in case ofpresence in blood of pregnant woman of G-antibodies to C. trachomatis under low titers (1:20, 1:40) the increase of levels of alpha-macroglobulin, alpha2 glycoprotein, al-antitripsin and especially of lactoferrin in serum of pregnant women testifies the high risk of presence of intrauterine infection of fetus and probability of birth of child with low values on Apgar scale. PMID- 22946222 TI - [The diagnostic significance of testing cerebral natriuretic propeptide in patients with hemorrhagic fever and renal syndrome]. AB - The study of content of cerebral natriuretic propeptide (NT-proBNP) in patients with hemorrhagic fever and renal syndrome was carried out considering severity degree, period of disease, presence of clinical roentgenological signs of lungs affection. It is demonstrated that in patients with mild and severe degree of disease the content of NT-proBNP is reliably higher than in the control group and gets its peak values in oliguric period The indices of NT-proBNP are reliably higher in patients with clinical roentgenological signs of lungs affection as compared with patients without such signs. The correlation analysis revealed direct dependence between the content of NT-proBNP and systolic blood pressure in pulmonary artery in in patients with hemorrhagic fever and renal syndrome of mild severity PMID- 22946223 TI - [The endogenic intoxication during the early post-operational period in patients with combined intraabdominal injury and massive loss of blood]. AB - The sample of 39 patients with combined intraabdominal injury and massive loss of blood are examined. The loss of blood consisted from 1.5 to 3.0. The assessment of endogenic intoxication was established according the indices of total and effective concentrations of albumin and mean molecular weight peptides. The endogenic intoxication coefficient (mean molecular weight peptides/effective concentration of albumin x 1000) was used. The application of endogenic intoxication coefficient permits to monitor more meaningfully the development of endogenic intoxication in victims against the background of treatment measures. The results are the pathogenic foundation of implementation of more intensive disintoxication activities in the complex therapy of this category of patients. PMID- 22946224 TI - [The assessment of processes of lipoperoxidation in adolescents with essential arterial hypertension using the integral indicator]. AB - The sample of 69 male adolescents aged of 14-17 years (46 of them with essential arterial hypertension) is examined. The control group included 23 adolescents. The intensity of oxidizing stress assessed according to the oxidizing stress coefficient. The calculation of coeffcient was based on testing in blood serum the content of products of peroxidation of lipids (substrates with double bonds, diene conjugate, malonic dialdehyde). The indices of antioxidant system (content of alpha-tocopherol, retinol, reduced glutathione and activity of superoxid dismutase) were used too. It is established that the oxidizing stress coefficient characterizes the degree of intensity of oxidizing process. PMID- 22946225 TI - [The subcellular organelles of peroxisome, realization of biologic functions of trophology, homeostasis, endoecology and functional bond with mitochondrion: the lecture]. AB - The biologic role of peroxisomes in cells is that the organelles in respect to fatty acids, lipids and substrates synthesized from acetate implement the same fimnctions as the lysosomes exercise to proteins and polypeptides. The biologic role of peroxisomes is to optimize in vivo the exogenous fatty acids in hepatocytes under the realization of biologic functions of trophology, homeostasis, endoecology. About 800 individual fatty acids can penetrate into organism with food. At that, no more than thirty of them undergo the metabolic transformation in vivo. The rest hundreds of fatty acids are aphysiologic and have to be oxidized into peroxisomes under isochronic activation of alpha-, beta- and omega-oxydases without ATP formation. If in peroxisomes are formed fatty acids that can oxidize mitochondrions by beta-oxidation then the proteins of cytosol transfer fatty acids from peroxisomes to mitochondrions. The mitochondrions oxidize fatty acids in the Krebs cycle to form ATP. The oxidation in peroxisomes concerns the fatty acids with odd numbers of carbon atoms, the transforms of unsaturated fatty acids, the very long chain fatty acids, the fatty acids with carbon atoms side-chains, the dicarboxylic fatty acids, the fatty acids with benzene or indole rings in carbon atoms chains. The peroxisomes oxidize the surplus amount of exogenous palmitic saturated fatty acid too. The peroxisomes implement the biologic.function of endoecology on autocrine level supporting the "purity" of cells cytosol and interact functionally with mitochondrions. In the intercellular medium of paracrine cells coens the fimctions of endoecology are realized by the Toll-similar receptors by the "our not our" principle concerning phospholipids, positional aphysiologic triglycerides and proteolipids. In the peroxisomes, under the simultaneous oxidation of very long chain fatty acids, the synthesis by primate cells is possible of some amount of essential unsaturated and polyene fatty acids. The limited formation by animal cells of glucose from fatty acids is possible in the sequence "acetoneacetol spirit-metilglyoxal-D-glucose. The mutations in primary structure of peroxisomes oxidases are the main in-herent pathology. PMID- 22946226 TI - [The reference values of indicators of total blood analysis of adult working population]. AB - The application in laboratory diagnostics of the hematologic analyzers of different class functioning on the basis of various methods of calculation and identification of blood cells condition the need of establishing the reference intervals for the blood picture parameters. In the documents GOSTK 53002-2008, S28-A3 (CLSI) of 2008 the regulations are proposed to establish the reference intervals with detailed description of data statistical analysis. The processing of blood pictures of 1453 healthy patients the reference intervals were established for the indicators of clinical blood analysis. The results saved in the laboratory data base and obtained using analyzer Sysmex XT-2000i (Sysmex Corporation, Japan) were analyzed. PMID- 22946227 TI - [The phenotype IFNy+cd69- of T-lymphocytes of umbilical blood associated with epidemiologically verified risk factors of atopy formation]. AB - The article deals with the determination of possible role of imbalance of lymphocytes TH1/TH2 at birth in pathogenesis of atopy development in children. The subpopulation compound of umbilical blood lymphocytes was examined on sampling of 153 newborns. The following prospective monitoring was applied during first year of life. It is established that the low content ofnonactivated mononuclears in umbilical blood producing gamma-interferon (IFNy+/CD69-) is associated with atopic family anamnesis (p = 0.006), residing of pregnant woman in town (in comparison with rural area, p = 0.02) and male gender of newborn in case of repeated labor (p = 0.008). This situation matches the epidemiologic verified risk factors of atopy formation in children. The contact of pregnant woman with domestic pets results in increasing of content of activated lymphocytes producing gamma-interferon (IFNy+/CD69-), p = 0.03. The decrease of content of nonactivated cells producing gamma-interferon (IFNy+/CD69-) is a strong and independent predictor of formation of atopic dermatitis in children of infancy age. The relative risk of formation of atopic dermatitis consisted 3.4 (1.19-9.69). PMID- 22946228 TI - [The development of diagnostics of herpes viral infections]. AB - The representatives of herpesviruses family (Herpesviridae--virus of herpes simplex and human cytomegalovirus) are largely widespread in human population. These herpesviruses bring on severe disorders of embryonic development up to fetal death, newborn diseases, neurologic disturbances, deafness, and blindness and in transplantation patients the severe internal organs affections and transplanted organs rejection. Both herpesviruses are able to affect the central nervous system and result in encephalitis with lethal outcome. The particular attention deserve the asymptomatic forms in case of which virus is excretee and can be transmitted both by horizontal line (sexual way included) and by vertical line (in the process of itrauterine development offtetus). The lacking of clear djfefrentiating clinical symtoms frequentyv observed under manifestations of herpesviruses infections brings another danger The comparison is made of fouur methods of detection of herpes simplex in urethra scrapes: the immunocytochemical method of detection of herpes simplex antigen in smears: the rapid cultural method; the immune-enzyme method of detection of herpes simplex antigen; the polymerase chain reaction. The results demonstrated that the rapid cultural method detected herpes simplex in infected samples on all stages of disease and in even more quantity at the stage of exacerbtion as compared with the polymerase chain reaction. The presented data testify the actuality of development of of laboratory diagnostics of herpesviruses injection to relevant diagnosis, determination of form and stage of disease, timely initiation of treatment and monitoring of therapy. PMID- 22946229 TI - [The mode of detection of microorganisms' sensitivity to disinfectants]. AB - The article presents the technique to evaluate the sensitivity of microorganisms causative agents of infections isolated from patients, carriers and environment to the disinfectants. The proposed technique gives a possibility to detect the condition of microorganism resistance to disinfectant and to evaluate the degree of its sensitivity. The evaluation of sensitivity specificity accuracy, positive and negative prognostic value, reproducibility of developed technique was made. PMID- 22946230 TI - Topics all important to healthcare providers and organizations who wish to improve patient safety and processes within their environments. PMID- 22946231 TI - Interpersonal factors affecting communication in clinical consultations: Canadian physicians' perspectives. AB - PURPOSE: This study seeks to determine how process and latent errors in the interpersonal, organizational, health system, and public health domains impact doctor/patient communication and patient safety. DESIGN/METHODOLOGY/APPROACH: There were 278 physicians from Manitoba, Canada who completed a self-report questionnaire during 2006. The largest specialty was family medicine, followed by internal medicine and pediatrics. Mean years of practice was 16, and 60 percent of the respondents were male. Respondents indicated the extent to which difficulties were encountered when communicating with patients. FINDINGS: The study finds that physicians had more difficulties with patients in the 0-20 year age bracket on 12 of the 18 communication statements. Psychiatry and pediatrics reported more difficulties with language interpreters. Pediatrics reported more difficulties with patients using culturally-based alternative medicine. Internal medicine had more difficulty with patients not appearing to trust or participate in treatment decisions. Patients in the 41-60 years age bracket had the highest mean for non-adherence to treatment plans, health maintenance and needed lifestyle change. The female physician-female patient dyad had fewer communication difficulties on all statements. RESEARCH LIMITATIONS/IMPLICATIONS: Further research should examine how family structure influences health-care delivery and health outcomes. Health care organizations can contribute to improving quality of care by seeking out and correcting sources of latent errors, and by supporting professional development and practice interventions. ORIGINALITY/VALUE: Few studies exist that have linked communication difficulties to adverse events. This study provides insight on sources of interpersonal errors in communication that directly impact the physician/patient relationship and which may represent threats to patient safety. PMID- 22946232 TI - Impact of a novel training experience on the development of a customer service culture in a large hospital trust. AB - PURPOSE: This study was designed with the intention of exploring the effectiveness of a novel approach to training health services workers to meet the aims of raising awareness of their customer care framework and encouraging a culture of customer service throughout their organisation. DESIGN/METHODOLOGY/APPROACH: The impact of the educational intervention was examined using a mixed methods approach involving pre- and post-workshop questionnaires and one-to-one, semi-structured interviews. FINDINGS: The paper finds that the approach adopted was effective in raising awareness of the customer care framework and in enhancing participant's self-efficacy in relation to the principles of customer care. Transference to the workplace was dependent on personality and departments having sufficient numbers of staff participating. RESEARCH LIMITATIONS/IMPLICATIONS: Time and resources for the project limited the follow-up interviews designed to explore if, and to what extent, the learning had had a lasting impact on participants and if it had enabled transference to the workplace. In addition, complications in releasing people from work in order to take part meant that a number of volunteers had to withdraw. This limits the range of data obtained. ORIGINALITY/VALUE: This paper describes a novel research informed approach to training, involving participants in high fidelity, error based simulations and in a research process which facilitated their repeated reflection on the learning. As a result the paper demonstrates large-scale training of customer care can effectively impact on practice. PMID- 22946233 TI - Implementation of a quality management system according to 9001 standard in a hospital in the home unit: changes and achievements. AB - PURPOSE: The purpose of this paper is to describe changes and results obtained after implementation of a quality management system (QMS) according to ISO standards in a Hospital in the Home (HIH) Unit. DESIGN/METHODOLOGY/APPROACH: The paper describes changes made and outcomes achieved. This took part in the HiH Unit, Clinico Hospital, Madrid, Spain, and looked at admissions, mean stay, patient satisfaction, adverse events, returns to hospital, no admitted referrals, complaints, compliance to protocols, equipment failures and resolution of urgent consultations. FINDINGS: In June 2008, HiH Unit, Clinico Hospital obtained ISO certification. The main results achieved are as follows. There was an increase in patients' satisfaction--in June 2008, assessment of the quality of care provided by staff was scored at 4.7 (on a scale of 1 to 5); in 2010 it has been scored at 4.96. Patient satisfaction rate has increased from 92 percent to 98.8 percent. No complaints from patients were received. Unscheduled returns to hospital have decreased from 7 percent to 3 percent. There were no medical equipment failures. External suppliers' performance has improved. Material and medication needed by staff was available when necessary. The number of admissions has increased. Compliance to protocols has reached 97 percent. Inappropriate referrals have decreased by 8 percent. Six medications-related incidents were detected; in two cases the incident was not due to an error. In the other four cases error could have been detected before reaching the patient. ORIGINALITY/VALUE: Implementations of an ISO quality management system allow improved quality of care and patient satisfaction in a HIH Unit. PMID- 22946234 TI - Therapeutic equivalent substitute that is new or unfamiliar to the chronic patient may result in medication error. AB - PURPOSE: The developing generic market has huge advantages of availability and affordability of therapy. The question of whether a therapeutic equivalent substitute under an unfamiliar name may cause confusion that leads to medical errors has not been sufficiently studied. This paper seeks to answer this question. DESIGN/METHODOLOGY/APPROACH: The study was triggered following sporadic reports according to which patients mistakenly consider therapeutic equivalents as unrelated medications rather than substitutes. Family physicians and pharmacists in one of eight districts of Clalit, Israel's largest healthcare provider were surveyed. The survey's questions recall episodes of medication uncertainty, confusion, misidentification, and medication mistakes associated with switching from one therapeutic equivalent to another. A total of 66 physicians and 63 pharmacists responded to the surveys (61 percent and 45 percent, respectively). FINDINGS: The results recall uncertainty, confusion, misidentification, and mainly cases of medication mistakes in which patients consumed both therapeutic equivalents simultaneously as was reported by 81 percent of physicians and 70 percent of pharmacists. RESEARCH LIMITATIONS/IMPLICATIONS: There are two limitations in this work, the first is the study type, which is recall survey; the second is the response rate which is not unusual among health care professionals. However, the high face-validity and the consistency of the findings in both physicians and pharmacists surveyed indicates high validity of the study conclusions. PRACTICAL IMPLICATIONS: A practical implication is unique medication error of consuming both therapeutic equivalents simultaneously. The authors wish to raise awareness of the potential of such error, which may be difficult to disclose as each of the therapeutic equivalents is apparently the intended medication but consuming them simultaneously results practically in doubling the intended dose. Given the forecast for generic market growth, awareness is not enough and worldwide regulatory cooperation should be made otherwise these types of medication errors will inevitably emerge. ORIGINALITY/VALUE: The study is original as a literature search revealed no studies evaluating potential medication mistakes attributed to a switch between therapeutic equivalents. PMID- 22946235 TI - Testing linen disinfection procedures in practice with phage-charged bioindicators. AB - PURPOSE: Disinfecting laundry processes are essential to avoid contamination of laundering machines and linen during commercial laundry reprocessing in the health care sector. Recently a bacteriophage-charged bioindicator has been developed using MS2 as surrogate virus for testing of low-temperature disinfecting laundry processing on efficacy against viruses related to practice. This paper therefore aims to investigate application of MS2-bioindicators in chemothermal processes under practical conditions (phase 2/step 2) and in practice (phase 3). DESIGN/METHODOLOGY/APPROACH: The experimental design was developed and modified according to the German Society for Hygiene and Microbiology (DGHM) Standard Methods for Testing Chemical Disinfection Processes. Tests under practical conditions were performed at 60 degrees C and 70 degrees C. Additional tests in tunnel washers were carried out at 60 degrees C and 70 degrees C. In all experiments validated disinfecting laundry processes, recommended for bactericidal and virucidal performance (categories A and B), were applied. FINDINGS: The results show a temperature-dependent gradual efficacy against the test virus MS2 up to reduction values of more than 8 log10-steps. Therefore MS2-bioindicators prove to be suitable as a tool to determine the performance of disinfection procedures against viruses in practice. ORIGINALITY/VALUE: Phage-charged bioindicators may be a tool to provide further insights into the reliability of antiviral laundry processes for health care quality management and for infection control. PMID- 22946236 TI - Uncovering the common ground in qualitative inquiry: combining quality improvement and phenomenology in clinical nursing research. AB - PURPOSE: The purpose of this paper is to describe the use of a common qualitative data set analysed with both a quality improvement tool to facilitate service improvement, and a rigorous research methodology to engage beginning nurse researchers in a mentored project. DESIGN/METHODOLOGY/APPROACH: A qualitative cohort study of the experience of hospitalisation across six diagnostic groups interrogated data from 104 patient and carer interviews using the Picker Dimensions of Experience and Heideggerian Phenomenology. FINDINGS: The paper reveals that well-conducted qualitative interviews can provide common ground for service improvement initiatives and rigorous research analysis. RESEARCH LIMITATIONS/IMPLICATIONS: The Picker Dimensions use simple coding methods that push findings towards utility, but at times are overly reductionist and exile any data not related to hospital services. Heideggerian phenomenology is training and resource intensive, but its exploration of the meaning of the illness experience provides a profound backdrop for the subsequent understanding of hospitalisation. PRACTICAL IMPLICATIONS: The access that qualitative data provides to the patient and family's perspective is becoming increasingly valued in processes of ongoing quality improvement, clinical redesign and evaluation for hospital accreditation. SOCIAL IMPLICATIONS: The intrinsic rewards of deep qualitative analysis for the staff involved are extraordinary. Clinicians were humbled by new understandings, which surprised them despite their long clinical experience. ORIGINALITY/VALUE: While quality improvement processes require training, ethics applications and data collection, the same framework can support rigorous qualitative research through use of the data as "common ground". The researchers experienced a tension, but eventually, a balance between the strengths and limitations of these combined modes of qualitative inquiry: PMID- 22946237 TI - Synthesising the QA literature. PMID- 22946238 TI - Competition rules and health care players: principles and consequences. AB - PURPOSE: Competition rules maximise consumer welfare by promoting efficient use of scarce resource and thus high output, low prices, high quality, varied services, innovation, production and distribution. European courts consider doctors and hospital staff as undertakings (any entity that performs economic activities), so that if they enter into agreements then they have to comply with competition rules. This paper's objective is to determine whether competition law, which applies to undertakings, can in fact be applied to different healthcare-sector players and whether specific rules are needed regarding competition between healthcare undertakings. DESIGN/METHODOLOGY/APPROACH: Data were selected from relevant European and national case law, European institution legal documents (such as regulations, guidelines and communications) and healthcare competition law literature, and then examined. FINDINGS: The paper finds that competition rules are applicable to healthcare players considering the consequences if competition rules are applied to the healthcare market. For market processes to result in the appropriate cost, quality and output, competition law must be proactive. In other words, quality must be fully factored into the competitive mix, allowing consumers to weigh healthcare price and non price characteristics. RESEARCH LIMITATIONS/IMPLICATIONS: Countries have different healthcare system and competition rules (although similar), competition rule impact is different for each country. Some healthcare systems are more regulated and there will be less opportunity for healthcare players to compete. PRACTICAL IMPLICATIONS: Efficiently applying competition law to healthcare players means that several challenges need facing, such as healthcare quality complexity and court scepticism. ORIGINALITY/VALUE: This article points out the challenges when competition law is applied to the healthcare sector and how these challenges are faced in certain countries such as The Netherlands. PMID- 22946239 TI - A critical study of quality parameters in health care establishment: developing an integrated quality model. AB - PURPOSE: The purpose of this article is to identify and critically analyze healthcare establishment (HCE) quality parameters described in the literature. It aims to propose an integrated quality model that includes technical quality and associated supportive quality parameters to achieve optimum patient satisfaction. DESIGN/METHODOLOGY/APPROACH: The authors use an extensive in-depth healthcare quality literature review, discerning gaps via a critical analysis in relation to their overall impact on patient management, while identifying an integrated quality model acceptable to hospital staff. FINDINGS: The article provides insights into contemporary HCE quality parameters by critically analyzing relevant literature. It also evolves and proposes an integrated HCE-quality model. RESEARCH LIMITATIONS/IMPLICATIONS: Owing to HCE confidentiality, especially regarding patient data, information cannot be accessed. PRACTICAL IMPLICATIONS: The integrated quality model parameters have practical utility for healthcare service managers. However, further studies may be required to refine and integrate newer parameters to ensure continuous quality improvement. ORIGINALITY/VALUE: This article adds a new perspective to understanding quality parameters and suggests an integrated quality model that has practical value for maintaining HCE service quality to benefit many stakeholders. PMID- 22946240 TI - Connecting the voices of users, caregivers and providers on service quality: a study of home-care services. AB - PURPOSE: This article aims to discuss the relevancy of different instruments used to gather information on homecare service quality from multiple stakeholders and the challenges encountered when trying to blend their views for prioritizing areas needing improvement. DESIGN/METHODOLOGY/APPROACH: The study centers on four homecare agencies: one public, one private for-profit and two not-for-profit services, implementing continuous quality improvement (CQI) programs. Various instruments were tested with random and convenience elderly service user, family caregiver and front-line worker samples. Instrument evaluation included operational effectiveness and agency manageability. FINDINGS: A qualitative approach, centered on small stakeholder samples, is fairly effective at assessing service quality, yet demands a strong commitment from agencies in personnel time and resources, as well as the necessary skills. Small-size, private homecare providers seem less-well equipped to handle comprehensive assessments without external support More importantly, assessments have to be done strategically, such that timing and work needed does not undermine program viability. PRACTICAL IMPLICATIONS: The approach and instruments tested have practical implications for decision makers and homecare organization managers interested in CQI. ORIGINALITY/VALUE: The article systematically evaluates quality assessment and priority-setting instruments applied to various stakeholders and homecare settings. PMID- 22946241 TI - Towards a balanced performance measurement system in a public health care organization. AB - PURPOSE: This article attempts to devise an integrated performance measurement framework to assess the Hong Kong Hospital Authority (HA) management system by harnessing previous performance measurement systems. DESIGN/METHODOLOGY/APPROACH: An integrated evaluative framework based on the balanced score card (BSC) was developed and applied using the case study method and longitudinal data to evaluate the HA's performance management system. FINDINGS: The authors unveil evolving HA performance indicators (P1). Despite the HA staffs explicit quality emphasis, cost control remains the primary focus in their performance measurements. RESEARCH LHNITATIONS/IMPLICATIONS: Data used in this study are from secondary sources, disclosed mostly by HA staff. PRACTICAL IMPLICATIONS: This study shows public sector staff often attach too much importance to cost control and easily measurable activities at the expense of quality and other less easily measurable attributes'. ORIGINALITY/VALUE: A balanced performance measurement system, linked to health targets, with a complementary budgeting process that supports pertinent resource allocation is yet to be implemented in Hong Kong's public hospitals. PMID- 22946242 TI - Long-term care physical environments--effect on medication errors. AB - PURPOSE: Few studies examine physical environmental factors and their effects on staff health, effectiveness, work errors and job satisfaction. To address this gap, this study aims to examine environmental features and their role in medication and nursing errors in long-term care facilities. DESIGN/METHODOLOGY/APPROACH: A mixed methodological strategy was used. Data were collected via focus groups, observing medication preparation and administration, and a nursing staff survey in four facilities. FINDINGS: The paper reveals that, during the medication preparation phase, physical design, such as medication room layout, is a major source of potential errors. During medication administration, social environment is more likely to contribute to errors. Interruptions, noise and staff shortages were particular problems. RESEARCH LIMITATIONS/IMPLICATIONS: The survey's relatively small sample size needs to be considered when interpreting the findings. Also, actual error data could not be included as existing records were incomplete. PRACTICAL IMPLICATIONS: The study offers several relatively low-cost recommendations to help staff reduce medication errors. Physical environmental factors are important when addressing measures to reduce errors. ORIGINALITY/VALUE: The findings of this study underscore the fact that the physical environment's influence on the possibility of medication errors is often neglected. This study contributes to the scarce empirical literature examining the relationship between physical design and patient safety. PMID- 22946243 TI - Improving medical personnel selection and appointment processes. AB - PURPOSE: This paper seeks to argue that processes for selecting and appointing medically qualified personnel in some healthcare organizations may be limited, especially those that emphasize qualifications rather than expanding the criteria to include practice scope, person-organization fit and capability to function within a healthcare team. DESIGN/METHODOLOGY/APPROACH: The paper is based on the authors' experiences and a literature review. FINDINGS: Selection based purely on academic merit, advanced clinical training, skills and professional achievements may not address other essential selection criteria. Medical personnel need to possess competencies such as ability to give high quality care and work constructively in a clinical team; communication skills; willingness to actively participate in quality and safety programs; teaching ability; management and leadership skills; and support institutional values and corporate aims. These attributes are often over-looked and cannot be assumed from academic merit and achievements. RESEARCH LIMITATIONS/IMPLICATIONS: The study's conclusions are based on the authors' experiences and literature review. Future studies may wish to examine selection technique efficacy and outcomes empirically. PRACTICAL IMPLICATIONS: Better medical personnel selection and appointment processes are likely to reduce unnecessary costs associated with poorly-made appointments, improve patient outcomes and may have a formative role encouraging medical personnel to take a broader view of their healthcare organization roles. ORIGINALITY/VALUE: The authors challenge selection panel members to consider non traditional with normal selection criteria for medical appointments. Nine recommendations for enhancing selection processes are provided. PMID- 22946244 TI - Using complaints to enhance quality improvement: developing an analytical tool. AB - PURPOSE: This study aims to construct an instrument for identifying certain attributes or capabilities that might enable healthcare staff to use complaints to improve service quality. DESIGN/METHODOLOGY/APPROACH: PubMed and ProQuest were searched, which in turn expanded access to other literature. Three paramount dimensions emerged for healthcare quality management systems: managerial, operational, and technical (MOT). FINDINGS: The paper reveals that the managerial dimension relates to quality improvement program infrastructure. It contains strategy, structure, leadership, people and culture. The operational dimension relates to implementation processes: organizational changes and barriers when using complaints to enhance quality. The technical dimension emphasizes the skills, techniques or information systems required to achieve successfully continuous quality improvement. RESEARCH LIMITATIONS/IMPLICATIONS: The MOT model was developed by drawing from the relevant literature. However, individuals have different training, interests and experiences and, therefore, there will be variance between researchers when generating the MOT model. PRACTICAL IMPLICATIONS: The MOT components can be the guidelines for examining whether patient complaints are used to improve service quality. However, the model needs testing and validating by conducting further research before becoming a theory. ORIGINALITY/VALUE: Empirical studies on patient complaints did not identify any analytical tool that could be used to explore how complaints can drive quality improvement. This study developed an instrument for identifying certain attributes or capabilities that might enable healthcare professionals to use complaints and improve service quality. PMID- 22946245 TI - In the wake of the Supreme Court's ruling on health care reform, hospitals and EDs still grapple with uncertainty, continued stress. AB - Even though the U.S. Supreme Court has upheld the bulk of President Obama's signature health care legislation, the Accountable Care Act (ACA), the prospects for full implementation of the law remain uncertain as political opponents still vow to strike down portions of the law at the earliest opportunity. Further, the high court's decision to leave the law's Medicaid expansion provisions up to the states leaves hospitals and EDs in a particularly precarious position as they will still face mandated cuts that the law's authors anticipated would be offset by Medicaid dollars. Experts recommend that ED administrators prepare for continued stress on their departments and get involved with shaping the way emergency medicine fits into ACOs and other emerging models of care. Some experts predict that EDs will see a flood of new patients when the Medicaid expansion provisions go into effect in 2014, but this trend may be tempered by the fact that newly insured patients will be able to seek care in other settings. The health reform transition is expected to be most difficult in states with large uninsured populations, and experts agree that a shortage of primary care physicians will drive ED volume in many communities. Hospitals and health care business interests are putting pressure on states to opt in to the ACA's Medicaid expansion provisions because it will make federal dollars available to cover 100% of the cost to cover newly insured Medicaid patients for three years, and 90% of the cost after that. PMID- 22946246 TI - Palliative care options can ease strain on EDs, improve care for patients with poor prognoses or difficult symptoms. AB - A new study suggests that for too many older patients, a trip to the ED leads to a hospital admission, where many of these patients spend their final hours. Instead, experts argue that many of these patients could be better served by palliative care options. Experts note that palliative care consultation teams and staff education on how to have "goals-of-care"discussions can help EDs deliver more responsive care to these patients while also reducing use of the ICU and other costly procedures. Investigators found that roughly half of 4,500 older patients who died while participating in the Health and Retirement study, made at least one ED visit in the last month of their life, and that three-quarters of these visits resulted in hospital admissions. More than two-thirds of the patients who were admitted to the hospital died there. Study participants who enrolled in hospice at least one month prior to their death were much less likely to visit the ED or to die in the hospital. PMID- 22946247 TI - ED flow facilitators make throughput center stage, achieve decreases in LWBS, LOS, and door-to-bed times. AB - With volume and the left-without-being-seen (LWBS) rate on the increase, Mercy Hospital in Springfield, MO, created a new ED flow facilitator position to take charge of throughput.The ED flow facilitator is a nurse who assigns patients to the east and west zones of the department, and also handles all ambulance calls. The approach has helped the ED bring the LWBS rate from 8% to the 3% to 5% range, and it has also made a dent in length-of-stay and door-to-bed times, but rising volume continues to be a challenge. When the flow facilitators were first implemented in late 2010, yearly volume in the ED was 93,000. This year the ED is on track to see 97,000 to 100,000 patients, which is still very high compared to other EDs. Good flow facilitators are nurses with supervisor potential who typically prefer to stay involved with nursing care. They need to be able to multi-task and handle high levels of stress. Hospital administrators note that patient flow patterns need to be under constant review in order to fashion solutions that make sense for the ED. PMID- 22946248 TI - The controversy over billing for EKG/rhythm strip interpretations in the ED. PMID- 22946249 TI - Standards governing ED patient flow, patient boarding are strengthened. AB - The Joint Commission has revised its standards regarding ED patient flow and patient boarding so that hospital leaders must establish measures, set goals, and take responsibility for resolving throughput challenges. Some experts applaud the change, noting that problems with ED crowding often require system-level solutions. Experts suggest that one way for hospitals to meet the new standards and drive improvement is to make patient-flow goals part of the hospital's Quality Assurance and Performance Improvement (QAPI) plan. Hospitals and EDs need to look at how they will address behavioral health patients who are waiting for transfer to another facility. Safety needs to be the key consideration. PMID- 22946250 TI - Six health care organizations sign on to participate in project aimed at curbing sepsis mortality. AB - Recognizing that sepsis is the leading cause of death in hospitalized patients and a huge drain on health care resources, The Joint Commission's Center for Transforming Health Care, is taking aim at the problem in a new project that is already underway. Six participating health care systems are working to develop a targeted solutions tool that Joint Commission members can use to reduce the incidence of sepsis in their own settings. Sepsis is difficult to identify because the signs and symptoms are often subtle, and they mirror the signs and symptoms of other conditions. Many EDs face logistics barriers that can hinder response times. For example, ED physicians in many systems no longer place central lines, a key component of care in serious sepsis cases. Screening tools used to identify sepsis in adults have no validity in children, making identification of sepsis in youngsters particularly difficult. PMID- 22946251 TI - Patient safety reporting systems: sustained quality improvement using a multidisciplinary team and "good catch" awards. AB - BACKGROUND: Since 1999, hospitals have made substantial commitments to health care quality and patient safety through individual initiatives of executive leadership involvement in quality, investments in safety culture, education and training for medical students and residents in quality and safety, the creation of patient safety committees, and implementation of patient safety reporting systems. At the Weinberg Surgical Suite at The Johns Hopkins Hospital (Baltimore), a 16-operating-room inpatient/outpatient cancer center, a patient safety reporting process was developed to maximize the usefulness of the reports and the long-term sustainability of quality improvements arising from them. METHODS: A six-phase framework was created incorporating UHC's Patient Safety Net (PSN): Identify, report, analyze, mitigate, reward, and follow up. Unique features of this process included a multidisciplinary team to review reports, mitigate hazards, educate and empower providers, recognize the identifying/reporting individuals or groups with "Good Catch" awards, and follow up to determine if quality improvements were sustained over time. RESULTS: Good Catch awards have been given in recognition of 29 patient safety hazards identified since 2008; in each of these cases, an initiative was developed to mitigate the original hazard. Twenty-five (86%) of the associated quality improvements have been sustained. Two Good Catch award-winning projects--vials of heparin with an unusually high concentration of the drug that posed a potential overdose hazard and a rapid infusion device that resisted practitioner control- are described in detail. CONCLUSION: A multidisciplinary team's analysis and mitigation of hazards identified in a patient safety reporting process entailed positive recognition with a Good Catch award, education of practitioners, and long-term follow-up. PMID- 22946252 TI - Is development of postoperative venous thromboembolism related to thromboprophylaxis use? A case-control study in the Veterans Health Administration. AB - BACKGROUND: Observational studies continue to report thromboprophylaxis underuse for postoperative pulmonary embolism/deep vein thrombosis (pPE/DVT) despite the long-standing existence of prevention guidelines. However, data are limited on whether thromboprophylaxis use differs between patients developing pPE/DVT versus those who do not or on why prophylaxis is withheld. METHODS: Administrative data (2002-2007) from 28 Veterans Health Administration hospitals were screened for discharges with (1) pPE/DVT as flagged by the Agency for Healthcare Research and Quality (AHRQ) Patient Safety Indicator software and (2) pharmacoprophylaxis recommended procedures, and the medical records were reviewed to ascertain true pPE/DVT cases. Controls were selected by matching cases by hospital, age, sex, diagnosis-related group, and predicted probability for developing pPE/DVT, and who underwent a pharmacoprophylaxis-recommended procedure. Records were assessed for "appropriate pharmacoprophylaxis use," defined primarily per American College of Chest Physicians (ACCP) guidelines, and reasons for anticoagulant nonuse. RESULTS: The 116 case-control pairs were similar in terms of demographics, surgery type, ACCP risk category, and appropriate pharmacoprophylaxis rates overall. Of the highest-risk patients, respective pharmacoprophylaxis rates among cases and controls were 88% versus 92% among hip/knee replacements and 31% versus 48% among cancer patients. Of the cases and controls who did not receive appropriate pharmacoprophylaxis, only about 25% had documented contraindications. Reviewers identified contraindications in 14% of cases and 9% of controls. CONCLUSIONS: Similarities in preventive pPE/DVT practice between cases and controls suggest that pPE/DVTs occur despite implementation of guideline-adherent practices. PMID- 22946253 TI - Integrating the home management plan of care for children with asthma into an electronic medical record. AB - BACKGROUND: Asthma exacerbation is one of the most common causes for pediatric hospitalization. One of the three Joint Commission quality measures--which has proven the most challenging--addresses the provision of a home management plan of care (HMPC) for discharge of pediatric inpatients with a primary diagnosis of asthma. A user-friendly electronic medical record (EMR)-generated HMPC was developed and implemented at Lucile Packard Children's Hospital (LPCH) Palo Alto, California, an HPMC needed to be completed before entry of an inpatient discharge order. METHODS: A cohort study using historical controls was conducted in 2010 2011. Patients were eligible to receive an HMPC if they were between the ages of 2 and 17 years old at discharge, had a length of stay < 120 days, were not enrolled in clinical trials, and had the primary discharge diagnosis of asthma. These patients were identified by the EMR if this diagnosis was listed in the diagnosis list or problem list or if the asthma admit/discharge order set was initiated. RESULTS: Compliance with the HMPC increased from 65.3% for the 39 months (April 1, 2007-June 30, 2010) before integration of the HMPC into EMR to 93.7% for the 18 months after integration (July 1, 2010, through December 31, 2011); p < .0001. Users of the EMR-integrated HMPC found it to be significantly easier to complete, less time-consuming, and less prone to potential errors or omission. CONCLUSION: Lessons learned at LPCH included the need for a continuous surveillance and improvement model, which resulted in several iterations of the HMPC; the importance of soliciting user input, which resulted in improvements in work flow; and consistent support from the quality management and information technology departments, which are crucial to eliminating barriers and facilitating improvement. PMID- 22946254 TI - Using root cause analysis to reduce falls with injury in community settings. AB - BACKGROUND: Falls are a common occurrence for older adults living in the community that may lead to physical injury and psychological harm. The US Department of Veterans Affairs National Center for Patient Safety (NCPS) database contains root cause analysis (RCA) reviews that identify falls resulting in injury in the community and subsequent action plans that may be helpful to prevent future falls. METHODS: A search of the NCPS-database identified RCA reviews where the patient (community-dwelling and long term care elders) fell in the community resulting in moderate to severe injury. Falls occurred in the home, community living center, outpatient clinic, recreational outing, outdoors, or in a vehicle. Thirty-six RCAs from October 2001 through August 2010 were included. Cases were coded on the basis of location of the fall, primary activity of the patient before/during the fall, root causes, action items, outcome measures, and effectiveness of each action. RESULTS: Sixty-seven root causes resulting in 59 actions were identified from the RCA reports. Falls most frequently occurred in the patient's home (41.7%). The most common activities the individual was engaged in during a fill included getting up from the bed or chair/wheelchair (22.2%), walking (22.2%), and transportation in a wheelchair van (14.8%). Although many actions yielded improved outcomes, the only action that was significantly associated with improvement was changes made to the environment (p = .028). setting activity CONCLUSIONS: The and surrounding fallsthat occur in the that occur in the community and that result in moderate to serious injury were identified along with the events' root causes. The extremely limited number of reports suggests that there may be missed opportunities to conduct an RCA for adverse events that occur among community-dwelling and long term care elders. PMID- 22946255 TI - Measuring administrators' and direct care workers' perceptions of the safety culture in assisted living facilities. AB - BACKGROUND: Further understanding of patient safety in health care is still needed. This is particularly evident in long term care settings, where relatively little information exists. Safety culture has emerged as a critical component of efforts to improve patient safety; it is strongly associated with iniatatives that influence patient safety and quality of care. The safety culture of a large sample of assisted living (AL) facilities was examined. METHODS: The Nursing Home Survey on Patient Safety Culture (NHPSC) was modified and used to examine safety culture. A random sample of AL settings from all 50 states was selected to participate. Respondents were AL administrators and direct care workers (DCWs) who completed the modified safety culture survey. The applied properties of the instrument are examined. A summary score for administrators and DCWs for each NHPSC item is also presented. These summary scores have a range from 0 to 100, with low scores representing a poor safety culture (and vice versa). RESULTS: Information was received from 572 administrators (response rate = 57%) and 3,620 DCWs (response rate = 51%). The scores, using the 0-100 scale, fell into the 48 72 range for administrators and the 40-68 range for DCWs. Many of the scores were similar to those previously found in nursing homes. CONCLUSIONS: AL is recognized as one of the fastest-growing institutional components of the long term care industry. The modified NHPSC performed well. Some areas of safety culture were perceived less favorably than in nursing homes. As such, some further attention to safety culture in AL is warranted. This study provides a first step toward assessing safety culture in this underexamined setting. PMID- 22946257 TI - Health information management 2025. PMID- 22946256 TI - Vision 2016 to Reality 2016: building a profession. PMID- 22946258 TI - Bootcamp and beyond: a research journey. PMID- 22946259 TI - The future is now: engaging the next generation of HIM professionals. PMID- 22946260 TI - Keeping education honest. PMID- 22946261 TI - All you need to build a better PPE. PMID- 22946262 TI - Climbing higher: bridging the gap to advanced degrees in HIM. PMID- 22946263 TI - How can we prevent TWD? PMID- 22946264 TI - A dozen safety plans laboratories may need. PMID- 22946265 TI - Inspection process best practices. PMID- 22946266 TI - What's new with arc flash standards. PMID- 22946267 TI - New wrinkles in hand protection. PMID- 22946268 TI - Farming should yield life, not take it away. PMID- 22946269 TI - Online training keeps things moving. PMID- 22946270 TI - Curbing forklift hazards. PMID- 22946271 TI - Don't let your job run you down. PMID- 22946272 TI - Leading indicators and influencers. PMID- 22946273 TI - The art of approaching persuasion. PMID- 22946274 TI - Under the gun to act, hospitals in Washington state put their hopes on seven "best practices" to curb non-emergent use of their EDs by Medicaid patients. AB - Hospitals in Washington state are under intense pressure by their state legislature to reduce the non-emergent use of EDs by Medicaid patients. As a result, emergency physicians and the Washington State Hospital Association have put together a plan involving the implementation of seven best practices aimed at educating patients about using the most appropriate setting for their care needs, electronically sharing information across ED sites so that narcotic-seeking patients can be easily identified, and expanding access to primary care resources. The hospitals have pledged to show progress by January of 2013 under the threat that legislators may move to limit the number of non-emergent ED visits that Medicaid patients can have. One aspect of the effort involves the creation of a Patient Review and Coordination Program, so that frequent ED utilizers can be identified and tracked wherever they present for care. The Washington State Hospital Association is meeting with each of the Medicaid plans in the state to encourage them to establish strong call centers and to reassess the scripting used so that patients are appropriately advised about where to seek care for their complaints. Lack of funding for mental health care in Washington state remains an obstacle, as an estimated 85% of high ED utilizers have concurrent mental illness. PMID- 22946275 TI - New Jersey effort lowers non-emergent utilization at two sites, but findings suggest more changes needed. PMID- 22946276 TI - Study: To minimize errors, rely on interpreters when caring for LEP patients in the ED. AB - A new study strongly suggests that it is important for EDs to rely on professional interpreters, rather than ad hoc interpreters or no interpreters at all, when caring for patients with limited English proficiency (LEP). The researchers examined health care encounters involving LEP patients at two pediatric EDs, and found that the encounters associated with professional interpreters were associated with far fewer errors of potential clinical consequence than the encounters associated with ad hoc interpreters or no interpreters. Experts say the most important first step in minimizing language based errors is to identify patients with LEP when they present for care. Professional interpreters are defined as having at least 100 hours of training. Researchers say that when evaluating interpreters, professional training is more valuable in terms of minimizing errors than experience on the job. Make sure that interpreters are available to LEP patients throughout the course of their ED visit as well as during any follow-up visits or telephone calls. PMID- 22946277 TI - For improved outcomes, connect first-episode schizophrenia patients to comprehensive care quickly. AB - For schizophrenia patients, early diagnosis and comprehensive treatment can improve outcomes, according to mental health experts. And the first opportunity to intervene often occurs in an emergency setting. To help ED staff connect these patients to appropriate care quickly, the ED at the University of Alabama at Birmingham Medical Center has opened the First Episode Schizophrenia Clinic, one of only a few such care settings in the country. While most EDs don't have this type of resource available, experts suggest staff would benefit from regular education about the signs and symptoms of the disease, and they urge ED administrators and clinicians to foster relationships with outside mental health providers so suspected schizophrenia patients can be transitioned to appropriate care quickly. Onset of schizophrenia most often occurs during the teenage years. Patients may present with depressive symptoms, or they may be acting odd or reclusive. Other potential causes, such as substance abuse or alcohol intoxication, need to be excluded before a definitive diagnosis of schizophrenia can be made. Experts advise ED clinicians to make sure they communicate effectively with outside mental health providers when making a patient referral. The mental health provider needs to understand what workups were completed in the ED, and what conditions the ED staff are concerned about. Patients often fail to report why they have been referred. PMID- 22946278 TI - Turner syndrome: strategies to improve care outcomes. Foreword. PMID- 22946279 TI - Ending the late diagnosis of Turner syndrome through a novel high-throughput assay. AB - Turner syndrome (TS) occurs when an X-chromosome is completely or partially deleted, or when X-chromosomal mosaicism is present. Girls with TS benefit from early diagnosis and treatment with growth hormone; however, many girls with TS are not detected until after 10 years of age resulting in delayed evaluation and treatment. To facilitate the detection of TS, we developed a high-throughput test for TS, based on a quantitative method of genotyping to detect X-chromosome abnormalities. This test utilizes pyrosequencing to quantitate relative allele strength (RAS) from single nucleotide polymorphisms (SNPs) using 18 informative SNP markers that span the X-chromosome and one marker for the detection of Y chromosome material. To determine the validity of this rapid test for TS detection, we undertook a large-scale study using DNA from 132 females without TS and 74 females with TS for whom karyotypes were available. TS was identified with 96.0% sensitivity and 97.0% specificity in this cohort. We also tested buccal swab DNA from a group of 72 females without TS and 69 females with TS. In this group, TS was identified with 97.1 sensitivity and 90.3% specificity. These results demonstrate the validity of a high-throughput, pyrosequencing based test for the accurate detection of TS, providing a potential alternative to karyotype testing. PMID- 22946280 TI - Turner syndrome strategies to improve care outcomes--cardiac evaluation using new imaging techniques. AB - Turner syndrome (TS) is at high risk for congenital heart diseases (CHD), aortic dilatation (AoDil) and dissection. New imaging techniques such as MRI have revealed the presence of vascular anomalies (VA) undetected at echo. MR angiography has shown a high prevalence of aortic and venous anomalies. The VA often coexist and interact to increase the risk of premature death in adulthood. AoDil and VA have been found also in asymptomatic individuals with no predisposing factors, but the prevalence is still unknown. We evaluated 100 TS subjects (15-35 yrs) with no aortic CHD at echocardiography with transthoracic MRA; 42 of them showed VA and 58 did not. Aortic diameters were indexed on BSA. At the sinuses of Valsalva a higher prevalence of AoDil was found in subjects with VA than without; 57% of them showed AoDil. The presence of VA (elongation of the transverse arch, bovine arch, left superior vena cava, PAPVD etc.) increased their relative risk of AoDil by more than 2 times. Excluding BSA influence, a severe phenotype influenced positively ascending AoDil. New imaging techniques enhance our ability to provide a prognosis for their adult age and in particular before they seek to become pregnant. PMID- 22946282 TI - Ovarian function and in vitro fertilization (IVF) in Turner syndrome. AB - Normal numbers of oocytes and ovarian follicles develop to the ovaries during the first half of the fetal life. The oocytes then start gradually disappearing. Abnormal meiotic division due to the lack of a paring X-chromosome has been suggested as the causative factor. A large proportion, 40-50% of Turner girls have at least some pubertal development, and about 10% may undergo menarche. Ovarian follicles have been found in some 40% of teenagers with Turner syndrome. Serum concentrations of antimullerian hormone (AMH) and follicle stimulation hormone (FSH), karyotype with mosaicism or structural chromosomal abnormalities, and spontaneous onset of pubertal development are positive prognostic signs for the presence of oocytes and ovarian function. Spontaneous pregnancies occur in some 2-10% of Turner women, a higher number than estimated earlier. This is probably due to failed identification of the syndrome among Turner women with ovarian function. Premature ovarian failure (POF) at some age can be expected in most of Turner women. FSH-stimulated oocyte retrieval and IVF can be carried out before predicted POF. Counseling not to postpone childbearing unnecessarily is advisable. Collected oocytes can be cryopreserved using vitrification, and stored until a pregnancy is desired. Large number of primordial oocytes within ovarian follicles can be stored in within superficial biopsied pieces of ovarian cortical tissue, for transplantation back to the ovary later on. Oocyte donation is an effective infertility treatment for Turner women who have undergone POF. Adequate hormonal replacement therapy (HRT) before IVF is necessary. Only one embryo at a time should be transferred particularly to these women in order to avoid pregnancy complications. Pregnancies in Turner syndrome women have high risks. Comprehensive health control including MRI of the aorta is recommended already before a planned pregnancy, and aorta has to be followed up by echography at least twice during the pregnancy to evaluate the risk of aortic dissection. Some 30% of Turner women develop hypertension during pregnancy, but this is also common among all oocyte donation pregnancies. PMID- 22946281 TI - Cognition and behavior in Turner syndrome: a brief review. AB - There is increasing evidence that Turner syndrome is associated with a distinct pattern of cognitive and neurophysiological characteristics. Typically this has been characterized by relative strengths in verbal skills, contrasting with relative weaknesses in arithmetic, visuospatial and executive function domains. Potential differences in social cognitive processing have also been identified. More recently, applications of neuroimaging techniques have further elucidated underlying differences in brain structure, function and connectivity in individuals with Turner syndrome. Ongoing research in this area is focused on establishing a unified mechanistic model incorporating genetic influences from the X chromosome, sex hormone contributions, neuroanatomical variation and differences in cognitive processes. This review broadly covers current understanding of how X-monosomy impacts neurocognitive phenotype both from the perspective of cognitive-behavioral and neuroimaging studies. Furthermore, relevant clinical aspects of identifying potential learning difficulties and providing anticipatory guidance for affected individuals with TS, are briefly discussed. PMID- 22946283 TI - Estrogen therapy in Turner syndrome: does the type, dose and mode of delivery matter? AB - The best type, dose and route of estrogen replacement in hypogonadal females has not been fully elucidated and is the subject of this brief review. When feminizing girls with different forms of hypogonadism micronized 17betaE2 should be considered the first choice as it is the most physiological and can be accurately measured in plasma. Most studies of the metabolic effects of the different routes have also used different types of estrogen making comparisons difficult. However, when using the same estradiol compound, 17betaE2 transdermal results in E2, E1 and bioestrogen concentrations closer to normal as compared to oral and achieves greater suppression of LH/FSH but similar IGF-I and lipid concentrations. Whether this translates into better body composition and metabolic outcomes in girls with hypogonadism is being actively investigated and data will soon be available. PMID- 22946284 TI - Growth hormone therapy in Turner syndrome. AB - Short stature is the single most common physical abnormality in Turner syndrome (TS) with adult stature averaging 20 cm shorter than that of the general population. Randomized, placebo-controlled studies to final adult height have proven that GH therapy is effective in increasing stature in TS. Recently, randomized, controlled studies have demonstrated that adjunctive therapies with low-dose estrogen or low-dose oxandrolone enhance stature further. These therapies may provide benefits beyond height augmentation. PMID- 22946285 TI - Trends in GH use in a Turner syndrome natural history study. AB - The present observations are derived from 273 girls and women aged 7-40 years participating in the National Institutes of Health natural history study of Turner syndrome (TS) in the interval 2001-2011. There was a higher percentage of GH use among individuals in the pediatric age group (7-17, n = 118, 83%) compared to young adult women with prior GH use (18-40, n = 155, 61%). The major factor in this divergence seems to be a trend toward earlier diagnosis of TS in the younger age group. We find a striking association between history of GH use and lower total body and abdominal fat mass in young adults with TS approximately one decade after discontinuation of GH treatment. The interpretation of this observation is limited by the fact that our study subjects were not randomly assigned to GH treatment. There may be a bias involving poor health care, childhood obesity, delayed diagnosis, absent GH treatment and persistent adult obesity. Further studies on the socioeconomic factors implicated in patterns of GH use and non-use for girls with TS are needed to illuminate this important issue. PMID- 22946286 TI - Genomic imprinting and Turner syndrome. AB - The term 'genomic imprinting' refers to selective repression of transcription from distinct chromosomal regions determined by their maternal or paternal inheritance. There are two potentially important aspects of imprinting that may manifest in individuals with X monosomy, or Turner syndrome (TS). Given that men are monosomic for Xm while women are mosaic for Xm:Xp, genomic imprinting of important X-linked genes should be associated with sexually dimorphic traits, e.g., social skills, regional fat deposition and adult height. Such X-imprinted traits are predicted to differ in Turner groups monosomic for Xm vs. Xp. We review relevant studies of psychosocial attributes, regional fat distribution and height in TS related to parent of origin for the single normal X chromosome. In addition, we review recent evidence that monosomy for the X chromosome per se, regardless of the parental origin, may disrupt the normal distribution of autosomal imprint patterns. This may contribute to a high rate of fetal loss in human monosomy via impaired placentation in the most severe cases, and to loss of paternal contribution to growth in the mildest manifestation. PMID- 22946287 TI - New roles of SHOX as regulator of target genes. AB - The homeobox gene SHOX encodes a transcription factor which is important for normal limb development. Approximately 5 to 10% of short patients exhibit a mutation or deletion in either the SHOX gene or its downstream enhancer regions. In humans, SHOX deficiency has been associated with various short stature syndromes as well as non-syndromic idiopathic short stature. A common feature of these syndromes is disproportionate short stature with a particular shortening of the forearms and lower legs. Madelung deformity, cubitus valgus, high-arched palate and muscular hypertrophy also differed markedly between patients with or without SHOX gene defects. A clinical trial in patients with SHOX deficiency and Turner syndrome demonstrated highly significant growth hormone-stimulated increases in height velocity and height SDS in both groups. Employing microarray analyses and cell culture experiments, a strong effect of SHOX on the expression of the natriuretic peptide BNP and the fibroblast growth factor receptor gene FGFR3 could be demonstrated. We found that BNP was positively regulated, while Fgfr3 was negatively regulated by SHOX. A regulation that occurs mainly in the mesomelic segments, a region where SHOX is known to be strongly expressed, offers a possible explanation for the phenotypes seen in patients with FGFR3 (e.g. achondroplasia) and SHOX defects (e.g. Leri-Weill dyschondrosteosis). PMID- 22946288 TI - Clinical care of adult Turner syndrome--new aspects. AB - Turner syndrome (TS) is characterized by numerous medical challenges during adolescence and adulthood. Puberty has to be induced in most cases, and female sex hormone replacement therapy (HRT) should continue during adult years. These issues are normally dealt with by the paediatrician, but once a TS female enters adulthood it is less clear who should be the primary care giver. Morbidity and mortality is increased, especially due to the risk of dissection of the aorta and other cardiovascular diseases, as well as the risk of type 2 diabetes, hypertension, osteoporosis, thyroid disease and other diseases. The proper dose of HRT with female sex steroids has not been established, and, likewise, benefits and/or drawbacks from HRT have not been thoroughly evaluated. The transition period from paediatric to adult care seems to be especially vulnerable and the proper framework for transition has not yet been established. Likewise, no framework is in place for continuous follow-up during adult years in many countries. Today, most treatment recommendations are based on expert opinion and are unfortunately not evidence based, although more areas, such as growth hormone and oxandrolone treatment for increasing height, are becoming well founded. Osteoporosis, diabetes, both type 1 and 2, hypothyroidism, obesity and a host of other endocrine diseases and conditions are seen more frequently in TS. Prevention, intervention and proper treatment is only just being recognized. Hypertension is frequent and can be a forerunner of cardiovascular disease. The description of adult life with TS has been broadened and medical, social and psychological aspects are being added at a compelling pace. Proper care during adulthood should be studied and a framework for care should be in place, since most morbidity potentially is amenable to intervention. In summary, TS is a condition associated with a number of diseases and conditions which need the attention of a multi-disciplinary team during adulthood. PMID- 22946289 TI - An outbreak of veno-occlusive disease of the liver, in Tahtay Koraro Woreda, Northwestern Tigray. PMID- 22946290 TI - An epidemiological study into the investigation of liver disease of unknown origin in a rural community of northern Ethiopia, 2005. AB - BACKGROUND: An outbreak of an unidentified cause of liver disease that claimed the lives of more than 45 people occurred in a rural community, in Northwestern Tigray. Despite the wider need for an urgent response there was no obvious explanation for the disease occurrence. OBJECTIVE: The aim of the study was to collect basic descriptive information and compare exposure status among case and control house-holds to better understand the illness and its pattern of occurrence so as to identify the sources, mode of transmission and possible cause of the illness. METHODS: The initial study principally involved combination of descriptive and analytic study designs. Combinations of quantitative and qualitative data were collected using semi-structured questionnaires. STUDY SUBJECTS: Samples of the affected and non-affected individuals of study village, key informants from various levels in the administrative system, and focus group discussions organized from both the affected and non-affected households of the study village were the subjects included for the study. RESULTS: The outbreak involved about 118 people, (78 males and 40 females) who were residents of the same village, in most, members of same family. More than half of the cases were under the age of 15 years. The outstanding clinical features were abdominal pain, rapidly filling ascites and hepatomegaly. The median duration of illness was six months (range; 1, 36 months). Of the 118 cases, 45 were deaths reported from the same community, during the period of illness with an estimated case fatality rate of 38%. Of the 45 deaths, 64.4% were children below 15 years of age. Qualitative information from both case and control communities showed difference in their water source. Eighty four percent of the dwellers in the affected village of Tsaeda Amba fetch water for their drink from an open shallow unprotected pond, Mai Habi-Tselam, Analysis of the data on exposure to the risk factor (case- control house-holds) revealed that users of the Habi-Tselam water source were almost 3 times more likely to develop the liver disease than those who used other water sources in the same village, OR = 3.14, 95% CI: 3.14 (3.12, 3.23). Age, nutritional status and long duration of exposure to an implicated source tended to influence the prognosis. CONCLUSION: The initial epidemiological investigations therefore gave an important insight as to the need to conduct further possible in-depth etiologic investigations, including clinical and toxicological studies, Study recommended an intermediary control measures including: banning the use of the implicated water source and provision of save and alternative potable water to the affected community. PMID- 22946291 TI - An outbreak of veno-occlusive liver disease in northern Ethiopia, clinical findings. AB - BACKGROUND: Following the emergence of an unidentified fatal disease in Tahtay Koraro, rural farmers' village in Tigray, northern Ethiopia since 2001, a team of experts from Addis Ababa University Medical Faculty was assigned in November 2005, to investigate the problem in the field. The team consisted of an Infectious disease specialist, a Gastroenterologist, an Epidemiologist, a Pathologist, and a Microbiologist. The team was also joined by a group of Tigray Regional Health Bureauprofessionals. OBJECTIVES: To investigate the nature of unidentified liver disease, identify possible cause(s) and recommend specific interventions/treatment in order to save lives and stop further spread of the disease. METHODS: Data were collected from Clinical history, clinical evaluation of the affected cases in the area, relevant laboratory investigations, and histopathologic studies. RESULTS: The team evaluated sixty one of patients in the field (37 males and 24 females) with mean age of 27 years. The disease affected both gender and all age groups. Duration of the illness ranged from 1 month to 3 years with a median of 6 months. The illness was reported to have started with abdominal cramp in 75%, febrile syndrome in 77%, and abdominal distention in 63% of the cases. This was usually followed by jaundice, bleeding tendencies, and edematous states mainly in the form of rapidly filling ascites. Majority of the patients had similarly sick family members and/or lost family member(s) due to the same illness. Moreover, laboratory, sonography, histopathological, and toxicological studies revealed VOLD due to Pyrrolizidine alkaloid (PA) toxicity as described in the other sections of the supplement. CONCLUSION: From a detailed clinical and epidemiological investigation as well as histopathological and toxicological analyses, the disease was found to be fatal toxic hepatitis (veno occlusive liver disease (VOLD). To our knowledge, this is the first report of VOLD from Ethiopia. PMID- 22946292 TI - An outbreak of liver disease in Tahtay Koraro Woreda, Tigray region of Ethiopia: a case-control study for the identification of the etiologic agent. AB - BACKGROUND: An outbreak of fatal liver disease of unidentified origin in Tahtay Koraro Woreda, Tigray Region was reported at the end of 2005. In response to this report, a team of investigators was deployed from the EHNRI to assess the situation in the affected area. OBJECTIVES: The objective of the trip was to investigate the probable etiological agent(s) for the stated health problem and to suggest possible means of containing the outbreak. METHOD: A case-control epidemiological method was employed in collecting information from the affected (case) area and a non-affected adjacent area (control) using structured questionnaire. Qualitative data was also collected through focus group discussion (FGD) at community as well as woreda level. Samples of biological and environmental nature were also collected from both case and control areas for a subsequent laboratory analysis in order to identify the causative agent of the outbreak. RESULT: The comparative analysis of the various variables and possible exposure factors between the two sites (case vs control village) revealed that both villages were similar in terms of their exposure to most of the suspected factors including exposure to chemicals, food storage and handling practices, and to the use of traditional herbal medicines or consumption of wild edible plants. However, it was observed that the residents in the affected site (over 96%) relied more on unprotected or protected well as a source of drinking water and other household purposes while most in the non-affected depended on fresh water from river or unprotected spring. This difference was significant, p = 0.000 (OR = 840, 95% CI = 50.1, 14095.7). CONCLUSION: Though several of the possible exposure factors to the epidemic appear to be similar for both the case and control villages, the water source they use for drinking and other household purposes differed markedly. It therefore seems plausible that the problem in the case area could be linked to this water source. PMID- 22946293 TI - Toxicity study and evaluation of biochemical markers towards the identification of the causative agent for an outbreak of liver disease in Tahtay Koraro Woreda, Tigray. AB - BACKGROUND: A team of experts of the Faculty of Medicine, Addis Ababa University reported the emergence of unidentified fatal liver disease in Tahtay Koraro Woreda, Tigray in the mid of December 2005. The EHNRI has been then instructed to investigate the possible etiological agent that are likely to be responsible in triggering the health problem and a field survey team consisting of experts were went to the affected area to investigate the situations surrounding the disease. OBJECTIVES: This investigation was conducted to determine the possible etiological agent(s) for the stated health problem in the affected village. METHOD: Acute toxicity study was performed on animal model for the various samples used in human consumption, which was followed by histopathological examination of the liver of the sacrificed laboratory animals. In order to facilitate the elucidation of the causative agent for the alleged health problem further tests for clinical markers and antigens were also performed on the serum collected from affected persons. RESULT: Neither death nor toxic symptoms manifestations were observed on laboratory animals when feeding the consumable samples for a period of two weeks, however histopathological examination of the liver of the sacrificed animals that were given the unprotected pond water and Tela samples from the affected village as a drink revealed severe hepatoic necrosis. Biochemical test results of the serum samples revealed raised level of some clinical markers that are highly significant for detecting liver abnormality of toxic origin. Serological test for surface antigen ruled out the possible causes of infectious origin such as viral hepatitis. CONCLUSION: The overall results confirmed that the causative agent for the outbreak of the liver disease was of toxic origin rather than due to infectious agent and this was found to be associated with consumption of contaminated water as well as Tela. PMID- 22946294 TI - Physico-chemical investigation of consumables and environmental samples to determine the causative agent of liver disease outbreak in Tahitay Koraro Woreda, Tigray. AB - BACKGROUND: The occurrence of liver disease out break of unknown origin and of a significant morbidity and mortality with a major symptom of abdominal dropsy was reported among the inhabitants of Tsaeda--Emba village, Tahtay Koraro woreda, Tigray during mid December, 2005. OBJECTIVES: The aim of this study was to assess if chemical intoxicants were the responsible agents for the outbreak in the affected locality. METHODS: The experimental approach towards the identification of the possible causative agent from the consumables and environmental samples collected from the affected village were determination of physico-chemical quality parameters and chemical analysis using instrumental and chromatographic techniques. RESULTS: The intoxicant was found to stem from the consumption of the water from the unprotected well in which pyrrolizidine containing plant, Ageratum sp, abundantly thrives. CONCLUSION: The water source was intimately linked to the outbreak of disease and, therefore, immediate intervention and preventive measures are called for. PMID- 22946295 TI - Veno-occlusive liver disease: a case report. AB - A case of veno-occlusive liver disease (VOLD) in a 12-years old Ethiopian boy is described The salient clinical features and gross and microscopic examination of biopsy material are reviewed. Veno-occlusive disease which occurs in the West Indies, East and West Africa, and India is an acute, subacute or chronic condition that affects the central and sublobular hepatic veins. In the West Indies (1) it is related to the consumption of bush tea made from plants that contain toxic pyrrolizidine alkaloids, such as Crotalaria and Senecio (2). Hepatotoxic compounds in Crotalaria, Senecio, Heliotropium and other composite plants can also enter the diet through the contamination of cereals with weed seeds. For example 28 of 67 patients died with veno-occlusive disease in central India after consuming a local cereal, gondli contaminated with the seeds of Crotalaria (3). Heliotropium Popovii has been implicated in outbreaks in villages in northwestern Afghanistan, with high mortality (4). The primary pathological change of hepatic veno-occlusive disease is sub-endothelial edema followed by intimal growth of connective tissue, with narrowing and occlusion of the central and sub-lobular hepatic veins. Atrophy or necrosis of liver cells, with consequent fibrosis leads to gross changes similar to those seen in cardiac cirrhosis, portal hypertension results. The present report, the first of it kind in Ethiopia describes a case of veno-occlusive liver disease in a 12-year old Ethiopian boy. PMID- 22946296 TI - [Role of plasminogen/plasmin in functional activity of blood cells]. AB - The article deals with the data concerning structural peculiarities of plasminogen/plasmin molecule, which define the specificity of intermolecular interactions and provide the variety of its biological functions. The main principles of the modern classification of plasminogen receptors and factors, which modulate their expression, have been presented. We have considered the mechanisms regulating both plasmin formation and activity on the surface of cells, fibrin and proteins of extracellular matrix. The data of previous investigators and our own results, concerning the influence of plasminogen/plasmin on platelet aggregation induced by different agonists, have been summarized. The participation of plasminogen/plasmin in atherogenesis and angiogenesis mediated by endotheliocyte receptors has been discussed. Special attention was given to plasminogen/plasmin proinflammatory function, which is realized by regulatory processes of activation, secretion, migration and apoptosis of monocytes and macrophages. PMID- 22946297 TI - [Stoichiometric model of folate-dependent metabolism of one-carbon units in human placenta]. AB - The work is dedicated to creation of the mathematical model of folate-dependent one-carbon unit metabolism (FOCM) and study of its function in human placenta under homocysteine load and the most common mutations in the genes of methylenetetrahydrofolate reductase (MTHFR) and cystathionine beta-synthase (CBS). In the model we have taken into account specific features of placental expression of genes that encode enzymes of FOCM. Using software tools Metatool and COBRAToolbox we have identified key metabolites, elementary modes and metabolic fluxes through different reactions of the system. It is shown that the most vulnerable links in the system are the folate cycle and synthesis of precursors of nucleic acids, inosine monophosphate and thymidyne monophosphates, which are changing in the broad range from significant inhibition to activation depending on the imposed conditions. The most stable links in the system are the reactions of glutathione and taurine synthesis. Simulation results coincide with the results obtained in similar experimental conditions. Under certain imposed conditions non-obvious relationships between the system links are revealed, and this becomes the basis for a purposeful test of predictions generated by the model. PMID- 22946298 TI - [Influence of chemically different antiviral substances on the expression of IFNalpha, PKR, OAS1a and RNAse L genes]. AB - The aim of the study was to determine the ability of several chemically different antiviral substances to induce the expression of interferon alpha(IFNalpha), PKR, OAS1a and RNAse L genes in the rat liver. The investigated substances included Amizon, Altabor and Proteflasid, which are already used in practical medicine, and 3',7-dimethylquercetin extracted from Proteflasid, the mixture of synthesized trimethyl- and tetramethylquercetin and Sialospecific lectin from persimmon, which are at the stage of preclinical trial and experimental research respectively. The content of corresponding mRNAs in total RNA was detected with the help of reverse transcription and polymerase chain reaction in real time. The results have shown that all investigated substances induce the expression of genes alpha, PKR, OAS RNAse L in specific manner. The combination of 3',7 dimethylquercetin + lectin from persimmon had the highest stimulating effect exceeding the effect of each component of the mixture and the influence of Heberon (recombinant IFNalpha2b) and PolyI-polyC as the standard inducers of IFNalpha and its target genes. The ability of all substances to specifically induce the expression of IFNa and its target genes, the absence of correlation between the levels of IFNalpha and its target genes expression as well as between target genes themselves indicate that the mechanism of antiviral activity of the investigated substances is connected not only with up-regulation of IFNalpha and potential IFNalpha mediated effects. PMID- 22946299 TI - Effect of short-term salt stress on oxidative stress markers and antioxidant enzymes activity in tocopherol-deficient Arabidopsis thaliana plants. AB - Changes of carotenoids and anthocyanins content, lipid peroxidation, and activity of antioxidant enzymes were studied in wild type and tocopherol-deficient lines vte1 and vte4 of Arabidopsis thaliana subjected to 200 mM NaCI during 24 h. The salt stress enhanced the intensity of lipid peroxidation to different extent in all three plant lines. Salt stress resulted in an increase of carotenoid content and activity of catalase, ascorbate peroxidase, guaiacol peroxidase and glutathione reductase in wild type and tocopherol-deficient vte1 mutant. However, the increase in anthocyanins concentration was observed in vte1 mutants only. In vte4 mutant, which contain gamma-tocopherol instead of alpha-tocopherol, the response to salt stress occurred via coordinative action of superoxide dismutase and enzymes of ascorbate-glutathione cycle, in particular, ascorbate peroxidase, glutathione reductase, dehydroascorbate reductase, and glutathione-S-transferase. It can be concluded, that salt stress was accompanied by oxidative stress in three studied lines, however different mechanisms involved in adaptation of wild type and tocopherol-deficient lines to salt stress. PMID- 22946300 TI - [Effect of N-stearoylethanolamine on the DNA fragmentation intensity in tumour and extratumoral tissues of the human adrenal cortex]. AB - The effect of different concentrations of N-stearoylethanolamine (NSE 18:0) on fragmentation of DNA in the tumoural and extratumour tissues of the adrenal glands in vitro was studied. In this work the following types of tissue were investigated: extratumoural tissue from patients with hormonally active tumours, benign tumour tissue (hormonally active and hormonally inactive), tissue of malignant tumours and hyperplasic tissue of the adrenal glands (Itsenko-Cushing disease). It has been established that the NSE increases the intensity of DNA fragmentation only in the tissue of hormonally inactive tumours. Benign hormonally active tumours, malignant tumours and hyperplastic tissue of the adrenal glands were resistant to the NSE. The possible mechanisms of resistance to the drug are discussed. PMID- 22946301 TI - [ATPase activity of rabbit skeletal muscles actomyosin complex under ultrasound effect]. AB - Influence of continuous and impulsive ultrasound 0.05; 0.2; 0.4; 0.7 and 1.0 W/cm2 on ATPase activity of rabbit skeletal muscle actomyosin has been investigated in this work. It has been shown that most changes of Mg2+, Ca(2+) ATPase activity are observed under 0.2 and 0.4 W/cm2 continuous ultrasound. K(+) ATPase activity is inhibited by continuous ultrasound of all intensities studied. Impulsive 2 and 10 ms ultrasound did not change the Mg2+,Ca(2+)-ATPase activity. While K(+)-activity is reliably changed only under impulsive 0.7 and 1.0 W/cm2 ultrasound that can be explained by the thermal effect. It has been determined, when studying the reconstructed actomyosin with sound troponin complex, that troponin complex is the most ultrasound sensitive constituent of actomyosin. PMID- 22946302 TI - [Protective effect of N-stearoylethanolamine in suspension and in nanocomposite complex in the organs of mice with the Lewis carcinoma under doxorubicin intoxication administration]. AB - The antioxidant effects of N-stearoylethanolamine (NSE) in the nanocomplex composition and in suspension are shown on the model of intoxication by doxorubicin in conditions of development of the Lewis carcinoma in the heart, kidneys and liver tissue and in the blood plasma of female mice. The NSE suspension reduces the level of urea in the blood plasma of mice with the Lewis carcinoma, which growth was revealed as a result of introduction of doxorubicin. Under introduction of nanocomplex the amount of urea remains at the level of that in the intact mice. In the blood plasma of mice with the Lewis carcinoma the NSE suspension and nanocomplex reduce activity of aspartate aminotransferase, the basic marker of necrosis of the heart tissue, growth of which was caused by the tumour development. Doxorubicinum increases activity of alanine aminotransferase, the marker of the liver lesion; introduction of NSE in the nanocomplex composition prevents the growth of the enzyme activity. N-stearoylethanolamine, both in the nanocomplex and in suspension, modulates activity of enzymes of antioxidantive protection of the heart, kidney and liver tissue of mice with the Lewis carcinoma. PMID- 22946303 TI - [Changes in content of glycolipids, sphingosine and cytokines in the rat brain with experimental edema]. AB - The study of the content of cerebrosides, gangliosides and their hydrolytic degradation product--sphingosine in the rat brain with experimental edema was carried out. In parallel, the cytokine profile of pro- and anti-inflammatory cytokines in the blood of rats with experimental cerebral edema was studied. The experiments indicated that a decrease of the total fraction of glycolipids and an increase of sphingosine content in the brain of rats with brain swelling were observed. The development of brain edema was accompanied by the increase in proinflammatory and decrease in anti-inflammatory cytokine content. PMID- 22946305 TI - [New approach in evaluating affinity of bivalent antibodies by the method of surface plasmon resonance. Theory]. AB - Theoretical aspects of the affinity evaluation for the interaction between bivalent receptors (or antibodies) and corresponding ligands (or antigens) are considered. It was shown that the ligand presence in the solution at the stage when the receptor dissociation occurs leads to the increase of the affinity evaluation accuracy. We demonstrated that the analysis of the dissociative curve of the receptor from the chip is not necessary for affinity determination; the analysis of associative curve is sufficient for this purpose. We also suggested a new approach for evaluating the affinity of bivalent receptors (or antibodies) when these reagents are present in the studied solution and the correspondent ligand (or antigen) is immobilized on the chip. PMID- 22946304 TI - [Estimation of ROS in the presence of biologically active substances by porous silicon fluorescence]. AB - The fluorescence spectra of the porous silicon modified by water solutions of biologically active materials and materials of biological origin are recorded as well as the fluorescence spectra of the porous silicon modified by lecithin monolayers grown on the surface of water solutions of the biologically active materials. The analysis of the obtained spectra made it possible to conclude on the effect of the studied materials on the content of ROS. PMID- 22946306 TI - [Laureates of the O. V. Palladin prize of NAS of Ukraine of 1977-1978]. PMID- 22946307 TI - [The dynamics of hormonal changes in female rats exposed to chronic stress and androgen excess during pubescence]. AB - The dynamics of blood plasma corticosterone, testosterone and androstenedione levels and their reaction to acute stress (30 min immobilization) in 35-, 40- and 45-day old female rats exposed to chronic stress (daily 30-min immobilization from 35th to 45th day of life) and/or to excess of exogenous androgens (implantation of capsules with testosterone to 33-day old animals) during pubescence was studied. Both control and experimental females in all age groups responded to acute stress by significant elevation of blood plasma corticosterone levels. At the end of the chronic stress session, the extent of adrenals activation in response to acute dosed stress was lowered in androgenized 45-day old females and increased gradually in stressed ones. After acute stress, the blood plasma testosterone level decreased in control 35-day old females and rose in androgenized females against 10-fold rising of basal hormonal level. In 40 day old control females as well as in androgenized ones exposed to chronic stress during 5 days, the acute dosed stress did not result in significant changes of blood plasma testosterone and elevated blood plasma androstenedione. Stressed 40 day old females with increased basal androstenedione secretion did not respond to acute stress by the hormone level changes while blood plasma testosterone declined significantly. At the end ofpubescence (on the 45th day of life), acute stress did not affect the blood plasma testosterone level in control and androgenized animals, while decreased it in stressed females and increased - in androgenized rats exposed to chronic stress against elevated basal level of the hormone. The conclusion is made about possible functional relationship between the changes in hormonal homeostasis during pubescence and development of reproductive system in mature animals. PMID- 22946308 TI - [Hematopoietic stem cells and immune status of subjects with different hypoxic tolerance]. AB - Intermittent hypoxia treatment (IHT) is gaining attention as a clinical modality due to its capacity to protect cells, tissues, organs, and the whole organism from more intense and/or sustained hypoxia, ischemia and other stresses, to enhance physical and mental capacity. Circulating hematopoietic stem and progenitor cells (HSPC) play an important role in immune response to hypoxia ensuring tissue reparation processes, formation of all types of blood cells etc. There exist considerable individual differences in the capability to mobilize HSPC. This study was designed to compare the effects of IHT on HSPC, various factors of natural resistance and main humoral and cellular components of adaptive immunity in peripheral blood of subjects with normal and reduced tolerance to hypoxic load. Ten healthy male volunteers (age 30,9 +/- 0,6 y.o.) participated in the study and were divided into two groups with reduced (RT, 5 subjects) and normal (NT, 5 subjects) hypoxic tolerance. Criterion for reduced hypoxic tolerance detection was the exceeding deviation of arterial blood pressure, minute ventilation, SaO2 and/or pathological changes in ECG during sustained hypoxia test (breathing with 10% oxygen, 10 min). All subjects were studied before and after a 14 day IHT program consisting of four 5 min bouts/d of breathing 10% O2, with intervening 5 min room air exposures. Immunofluorescence detected HSPCs as CD45+CD34+ cells in peripheral blood. Phagocytic and bactericidal activities of neutrophils, circulating immunoglobulins (IgM, IgG, IgA), immune complexes, complement, and cytokines (EPO, TNF-alpha, IL-4, IFN gamma) were measured. It was shown that NT subjects had higher hemoglobin and erythrocytes level, hematocrit and physical working capacity, but leukocytes, lymphocytes, CD8+-cells contents and level of IgA were lower than in RT. These differences were preserved after IHT course. CD45+34+cells content was the same in both groups before IHT, but RT subjects demonstrated twice decrease in HSPCs content after IHT as opposed to NT who did not show distinct reactions. A decrease in HSPCs is probably associated with the change of their migration capacity. However, it remains unclear whether there is an inhibition of HSPCs migration into circulation or an activation ofHSPCs escape from circulation. In both cases tissues could accumulate more HSPCs which in turn could enhance hematopoiesis and general regenerative potential. RT group also had lower complement, induced and reserve bactericidal activities of neutrophils which were significantly increased after IHT reaching the level of NT. The level of cytokines EPO, TNF-alpha and IFN-gamma did not differ in both groups before IHT but considerably reduced level of IL-4 was registered in RN patients. IHT sharply lowered pro-inflammatory cytokine TNF-alpha in both groups, significantly increased IL-4 in RT subjects; increasing behavior of IFN-gamma was observed in both groups. EPO was not affected considerably during the study. The findings support the potential for eventual application of IHT for immunotherapy, especially for patients with reduced hypoxic tolerance. PMID- 22946309 TI - [The condition of lipid peroxidation in mice and the effect of fullerene C60 during immune response]. AB - The aim of this study was to assess the influence of fullerene C60 on lipid peroxidation (POL) and antioxidant protection during the induction of the immune response to heteroantigen. Balb/c mice were immunized intraperitoneal (i.p.) with sheep erythrocytes for the primary immunization. Water dispersion of fullerene C60 was injected i.p. once at the dose 50 ng to mice on first, third and sixth days after immunization. During immune response, the increment ofmalonic dialdehide (MDA) was enhanced in liver, kidneys and heart tissues. Fullerene C60 induced POL during the latent phase of immune response, but inhibited this process during progression of immune response. Activities of superoxide dismutase (SOD) and catalase in liver and spleen tissues were induced after injection of fullerene C60 to intact mice. After immunization, high level of activity of antioxidant enzymes and low level of organs mass factor were determined. Injection of fullerene C60 reduced the activities of SOD and catalase in spleen tissues. The results of our study indicate that fullerene C60 can display positive effect on POL processes and antioxidant enzymes activity which is probably due to membrane's stabilization action or the ability of fullerene C60 to bind free radicals independently. PMID- 22946310 TI - [Immune response in mice following intrabrain injections of allogeneic spleen or brain cells]. AB - Cytotoxic activity of spleen lymphocytes and lymphatic knots was studied. Accumulation of anibodies in blood serum of recipient in response to intrabrain injection of the antigen was investigated. Cellular and humoral immune response of mice developed with the intrabrain injection ofalohenic cells. The data obtained suggest that there is no isolation of the brain, because antigen injection to the brain is able to induce the immune reaction. PMID- 22946311 TI - [Displacement of center of pressure on the support and changes of the joint angles of the lower extremity at squatting]. AB - The relationship between movements and their postural adjustments was studied on the basis of the relation between the displacement of center of pressure (CoP) on grand force platform in the anterior-posterior direction and angular changes in the ankle and hip joints during squat in six healthy individuals. It was shown that during the fixation of the joint angles at the squatting the ankle joint more flexed than the hip joint when the CoP shifted forward, while the back displacement of the CoP resulted in more prominent changing of angular joint at the hip joint than at the ankle joint. A linear relationship between the displacement ofCoP and the flexion angles more frequently observed at the ankle joint than at the hip, which may indicate that during squatting at the locked position of the joint angles the flexion of the ankle joint was determined mainly by the biomechanics of the skeleton,while in the hip joint biomechanical factors could largely combined with the central processes controlling posture. PMID- 22946312 TI - [Dosed normobaric hypoxia as a non-medication approach of stimulation of physiological regeneration of liver parenchyma]. AB - The investigation was devoted to studying the effects of different modes of dosed normobaric hypoxia on the changes in morphometric indexes of functional activity and physiological regeneration of liver parenchyma in young rats. It was shown, that in rats exposed to hypoxic gas mixture (10% O2), the amount of karyonucleus and binuclear hepatocytes, nucleocytoplasmic and nucleolar-nuclear correlation increased. The changes in these indexes appeared to be more intensive when dosed normobaric intermittent hypoxia was administered with alternation of deoxygenation and reoxygenation periods. We believe that dosed normobaric hypoxia increases the functional activity and physiological regeneration of liver parenchyma. PMID- 22946313 TI - [Dynamical electrical states of heterogeneous populations of ion channels in the membranes of excitable cells]. AB - In computer models, we studied instantaneous (time-varying) current-voltage relationships (iIVs) of populations of ion channels characteristic of the membrane of different type excitable cells, of which the responses to electrical stimuli essentially differ: giant squid axon (Hodgkin-Huxley model), cardiomyocyte, dendrites of CA3 hippocampal pyramidal neurons and Purkinje neurons of the cerebellum. The membrane potential was stepped from the rest level to a certain depolarization test level that was clamped for a certain time, and the total current was measured at different moments after the step onset. For each iIV zero-current points (potentials) were determined. A set of such points, which were situated on the limb of iIV positive slop and corresponded to the state of high membrane depolarization (excitation state, upstate) at different time moments, were used to characterize the dynamics of the excitation state in time. With these indicators the axon membrane was characterized by a single excitation state that rapidly occurred (0.25 ms) and was short-lasting (decayed from -45 to 40 mV during life-time of 5.5 ms). There were two such states of the membrane of cardiomyocyte. The first one was early, rapidly occurring and short living (rapidly relaxing). It occurred shortly after the depolarization start and lasted for 14.5 ms. The second one was late, slowly rising and long-lasting (occurred with a 7.5-ms delay, increased from 11 to 46 mV in 39 ms and then relaxed lasting for 623 ms in total). The dendritic membrane ofCA3 neurons had one long-lasting excitation state that occurred shortly after the depolarization shift, first rapidly relaxed during 3 ms from initial 30 mV level to -10 mV and then slowly, in 80 ms, stabilized at the level of -20 mV. In the Purkinje neuron membrane two short-lasting and one very long-lasting excitation states were revealed. The first state of very high (>100 mV) depolarization relaxed to 4 mV in 0.8 ms. Shortly before its vanishing, at 0.7 ms, the second short-lasting state emerged, which relaxed in 1 ms from -22 mV to -48 mV. At 1.8 ms a new excitation state emerged, which after a transient relaxation stabilized at -29.65 mV starting from 88 ms. Thus, iIVs allowed disclosing a fine organization of the states of electrical excitation of the membrane and revealing, in populations of ion channels of different content, existence of different number of the mentioned states, which differ from each other in occurrence time and life-time. PMID- 22946314 TI - [To the question of the heart rate fluctuations during submaximal workload]. AB - The effect of oscillatory decrease in the heart rate and hemoglobin oxygen saturation (SaO2) during the submaximal workload (bicycle ergometry test) was demonstrated in high-performance athletes and volunteers practicing healthy life style. The obtained parameters (heart rate, SaO2, amplitude of oscillation, and recovery time) were analyzed taking into account modern notions about the mechanisms of pO2 maintenance during activation of aerobic metabolism in high resistance organisms under extreme conditions. It is concluded that optimal functioning of cardio-respiratory system can be achieved only when its labile oscillatory parameters are synchronized at the various levels of functional hierarchy, which are maintained by the higher intensity ofredox reactions, improved utilization of oxidative destruction products, more intensive fluctuations of endogenous oxygen, and fine regulation of hemoproteins' role in the free radical reactions. This, in turn, promotes long-term adaptive activation reaction at the higher levels of reactivity. Further studies of the described oscillations could facilitate their use as the new functional diagnostic criteria for the estimation of reactivity and adaptive reserve mechanisms in sports and preventive medicine. PMID- 22946315 TI - [Kidney function in oncologic patients after cisplastin chemotherapy]. AB - During examination of kidney function under cisplastin chemotherapy in oncologic patients the nephrotoxicity of the drug have been shown during 24 hours after administration. We found that in 24 hours after injection ofcisplastin in the dose 50 mg/m2 of the surface of the body, the excretion of creatinine, sodium, potassium, osmotic active compounds and chlorides is increased more than two times, indicating for disorder in osmolality, volume and ionic regulation of kidney function. The determined peculiarities are consequences of kidney injuries, which are confirmed by an increase in erythrocyte- and leucocyteuria. We showed that alterations in homeostatic kidney function is due to damage of renal tubules. Our study necessitates a need for renal protection during the whole period of cisplastin chemotherapy. PMID- 22946316 TI - Effects of intermittent normobaric hypoxia on the state of the CNS and cerebral circulation in children with cerebral palsy. AB - We studied the effects of intermittent normobaric hypoxia (INH) on the processes of CNS functions and cerebral circulation recovery in children with cerebral palsy (CP). Altogether, 87 patients (from 8.5 months to 12 years) with CP were examined and received the course of treatment. Clinico-neurophysiological examination was performed before the treatment and immediately after termination of the therapeutic course. Patients were divided into two groups; age and sex distributions and clinical manifestations of CP were randomized. The comparison group was formed from 34 children who received the course of the generally accepted complex therapy (medicamental treatment, massage, Bobat-therapy, Vojta therapy at al).. The main group included 53 patients who, in addition to the same therapy, were exposed to INH using an individual apparatus for artificial mountain air, Borey-M, made in the Scientific Medico-Engineering Center NORT (Ukrainian National Academy of Sciences, Kyiv). Children of the main group were exposed to the dosed normobaric sanogenetic level hypoxia intermittently once per day. For this purpose, we used a normobaric gas hypoxic mixture (12% O2 + 88% N2). Each cycle included a 15-min-long episode of breathing with the gas mixture alternated by a 5-min-long episode of breathing an ambient atmospheric air. The number of hypoxic cycles was gradually increased (from one to three). The entire course of treatment included, on average, 10 sessions. After complex therapy the stable positive effects on the motor status were observed in 94% of patients of the main group (exposed to INH) and in 74% of patients of the comparison group (unexposed to INH). EEG examination showed that positive dynamics of spectral EEG components were in 70% of patients of the main group and in 56% of children of the comparison group. Doppler examination showed that brain hemodynamics was normalized in 85% of patients of the main group and in 59% of children of the comparison group. In the course of ophthalmoscopic examination, we found that the dynamics of indices of the state of the eye fundus were expressed more clearly in children of the main group than in patients of the comparison group (in 32 and 12% of patients, respectively). PMID- 22946317 TI - [Evaluation of biological effects and possible mechanisms of action of static magnetic field]. AB - Modern views on mechanisms of interaction between static magnetic field and cells or cellular structures are reviewed. An analysis of the data about possible biotropic effects of this factor was performed. The emphasis was put on the analysis of the studies in which moderate (0.1-1 T) static magnetic fields were used, because such fields are used for targeted delivery ofmagnetosensitive nanocomposites in development of new strategies in target therapy of patients with malignant neoplasms. Based on available data it was concluded that the primary cause of changes in cells after incubation in external static magnetic field is disruption of free radical metabolism and elevation of their concentration. Such disruption causes oxidative stress, and, as a result, damages ion channels, leading to changes in cell morphology and expression of different genes and proteins, and also changes in apoptosis and proliferation. PMID- 22946318 TI - [Poly(ADP-ribose) polymerase (PARP): physiological and pathological roles]. AB - PARPs are a large family of 18 enzymes found in most eukaryotes. PARP-1, the most abundant isoform, is activated by DNA breaks and catalyzes the post-translational modification of proteins. It forms polymers ofADP-ribose and attaches them to acceptor proteins, including histones, DNA repair proteins, transcription factors. PARP-1 is a key enzyme involved in a maintenance of genomic stability. Excessive activation of the enzyme has been shown to contribute to tissue injury and inflammatory disorders. PARP is a key mediator of cell death in oxidative stress, ischemia and DNA damage. It also promotes the activation ofproinflammatory gene expression. Inhibition of PARP-1 provides significant protection in animal models of cardiovascular, autoimmune and inflammatory diseases. PARP inhibitors have shown antitumor activity because they compromise ability of cancer cells to repair DNA. PARP-1 is a promising therapeutic target. PMID- 22946320 TI - [Allelic polymorphism of Pro582-->Ser HIF-1alpha to exercise-induced hypoxia adaptation]. AB - The features of the distribution of allelic variants Pro582-->Ser polymorphism in HIF-1alpha gene in groups of athletes involved in sports, with different types of compensatory mechanisms of adaptation to hypoxic stress were investigated. During the study 191 highly qualified athletes were examined. The control group included 260 subjects, not engaged in sports. The possibility of using this polymorphism as a molecular genetic marker of susceptibility to a variety of sports pursuits. The distribution of allelic variants of HIF-1alpha Pro582-->Ser polymorphism of the residents of Ukraine was investigated. Found that the Pro/Pro genotype contributes to endurance performance. It is shown that the 582Ser gene HIF-1alpha is a marker of predisposition to power sports. The result revealed that the frequency of Ser allele of HIF-1alpha (16% vs 7%, P=0.03) was significantly higher in the power-orientated athletes compared to endurance athletes. PMID- 22946319 TI - [Phase changes in energy metabolism during periodic hypoxia]. AB - Male Wistar rats were exposed to periodic hypobaric hypoxia (PHH), by "lifting" in barochamber at "altitude" 5600 m for 1 h every 3 days (6 seances). The dynamics of changes in oxygen consumption (VO2), and body temperature (Tm), as well as in HIF-1alpha and HIF-3alpha gene expression, and mitochondrial respiration in the ventricles of the heart was studied. On the basis of the data we identified four phases of the physiological changes. The first phase, hypometabolic (1-3 seances), is characterized by decrease in VO2 and Tm, induction of HIF-1alpha and HIF-3alpha with delayed transient stimulation of metabolism in response to each seance of hypoxia. In heart mitochondria, V3 and V4 are increased, but V3/V4 and ADP/O are reduced. During the second phase, transitional (3-4 seances), there is reorganization of metabolism and decrease its hypoxic reactivity. The third phase, hypermetabolic (4-5 seances), is characterized by intensification of metabolism and compensation of hypoxic disorders. The fourth phase (after 5 seance) - is a state of metabolic adaptation with normalization of VO2 and Tm, expression of HIF-1alpha and HIF-3alpha, mitochondrial respiration, increased NAD-dependent oxidation of carbohydrate and lipid substrates. Thus, during PHH consequent rebuilding of processes of oxygen transport, tissue respiration and thermogenesis occurs, mediated by induction of the HIF subunits. PMID- 22946321 TI - [Hypoxic preconditioning prevents the induction and activation of 5-lipoxygenase during ischemia and reperfusion of rat heart]. AB - Male Wistar rats were subjected to hypoxic preconditioning (10% O2 in nitrogen for 3 h). In 24 h heart were isolated and subjected to 30 min ischemia and 40 min reperfusion. Changes in expression of 5-lipoxygenase (5-LO) protein in rat heart ventricles, and in myocardial subcellular fractions were evaluated by Western blotting. It was found that hypoxic preconditioning attenuated reperfusion damage of cardiomyocytes with reducing the release of LDH by 27.6%. After ischemia and reperfusion, expression of 5-LO was 10.5-fold elevated in the left ventricle and 14.3-fold - in the right one. During ischemia and reperfusion occurred gradual translocation of 5-LO protein in nuclear subcellular compartment, more expressive in the left ventricle. Hypoxic preconditioning did not significant increase in 5 LO expression, but fully prevented its growth in the following ischemia reperfusion, and partly reduced protein translocation at reperfusion in the left ventricle. Thus, hypoxic preconditioning limits proinflammatory effects ofischemia and reperfusion in myocardium, preventing the increase in expression of 5-LO, and reducing the alteration of cardiomyocytes. PMID- 22946322 TI - [Factors determining the functional state of regulatory systems in athletes after return from altitude conditions]. AB - We have studied a group of athletes who compete in speedpower disciplines. The athletes spent a period of time at the altitude of 2100 meters and the state of their regulatory systems was measured on their return to normal conditions. We have shown that training at the altitude improves the functional state, shifts the vegetative balance towards the prevalence of vagus influences, and improves stamina. The positive effects remain as long as 25-26 days after return from the altitude. At the same time for sportsmen after training at the level of sea in a state of relative rest and central and sympathetic influences prevail at the functional loading. In addition, the factor of the unstable states also begins to play a certain role forming of reaction of organism on loading. PMID- 22946323 TI - [Research of influencing of ecological factors of Antarctic on capacity of human for adaptation]. AB - A purpose of work is a study of influencing of ecological factors of Antarctic on the physiological functions of human and development of technologies of increase of adaptation stability of organism. Antarctic influences of heliophysicals factors are studied on the organism of human. It is set that natural hertzian waves with a frequency spectrum identical of brain of human biorhythm, straight influence on electric activity as a reaction of synchronization. It is shown that the reactions of the system of circulation of blood of human in Antarctic are closely associated with the changes of barometric pressure and humidity, have hypoxical genesises and depend on polymorphism of gene of HIF-1alpha. It is shown that the study of negative influence on the organism of ecological factors in the conditions of absence of factors of technogenidc origin is instrumental in development of new technologies of prophylaxis of morbidity and saving of capacity of human as in extreme terms so in the conditions of the modem status of ecological surroundings. PMID- 22946324 TI - [Cardiohemodynamics and efficiency Frank-Starling mechanism in spontaneously hypertensive rats]. AB - We studied cardiohemodynamics and efficiency Frank-Starling mechanism in 6-month old spontaneously hypertensive rats (SHR) and age-matched Wistar rats, using pressure-volume (PV) conductance catheter system (Millar Instruments, Houston, TX) to evaluate systolic and diastolic function in vivo. Rats were anesthetized with urethane. Cardiohemodynamics analyzed using PVAN 3.6 (Millar Instruments). We found that systolic and diastolic function of the heart in spontaneously hypertensive rats were lower, than in controls. We have shown, inhibition of the efficiency Frank-Starling mechanism, increasing arterial stiffness in spontaneously hypertensive rats. It's shown, less efficiency heart work, with more energy and more oxygen consumption in spontaneously hypertensive rats, may be associated with increasing arterial stiffness and decrease functional reserve of the heart. PMID- 22946325 TI - [Laboratory rat selection for the trait "the absence of audiogenic seizure proneness"]. AB - The hybrids between Krushinsky-Molodkina (KM) inbred strain, selected for high predisposition to audiogenic epilepsy (AE), and Wistar rats non-prone to audiogenic seizure were the initial population for selection. Rats were selected for the trait "the absence of audiogenic seizure proneness". The creation of such strain in which the significant proportion of animals develop no AE in response to sound and share partly the genetic background of the KM strain is very important for the correct use of RV strain as the laboratory model of seizure states. As alleles which determine the AE proneness are recessive the selection for the "opposite" trait proceeds necessarily slow. PMID- 22946326 TI - [Genetic aspects of sexual behavior in malaria mosquitoes on the basis of specific acoustic signals at mating]. AB - Acoustic characteristics were studied in two species of the "Anopheles maculipennis" species complex, A. messeae and A. atroparvus. The species were found to clearly differ in sound frequencies, which was assumed to play a key role in species identification during mating in regions of their sympatric distribution. The sound spectrum in A. messeae was far more diverse than in A. atroparvus, which was associated with intraspecific inversion polymorphism of the former. Mosquitoes with the inversion combinations that were most common in populations of the central region of the A. messeae species area specifically differed in acoustic signal spectrum from each other. Hence, sound communication within the species was considered to be the main mechanism that is responsible for sexual partner selection and determines the chromosome associations observed earlier in individual karyotypes. Since males carrying different inversion combinations significantly differed in acoustic characteristics, females were assumed to play a main role in selecting the sexual partner. PMID- 22946327 TI - [Chromosome pairing in wheat-rye ABDR hybrids depends on the microsporogenesis pattern]. AB - The character of chromosome pairing in meiocytes was studied in F1 wheat-rye Triticum aestivum L. x Secale cereale L. (ABDR, 4x = 28) hybrids with three types of chromosome behavior: reductional, equational, and equational + reductional. A high variation of the frequencies of bivalents and ring univalents was observed in meiocytes with the reductional or equational + reductional type of chromosome behavior. The type of chromosome division was found to affect the bivalent and ring univalent frequencies. Chromosome pairing occurred in 10.28% of meiocytes with the reductional chromosome behavior, 0.93% of meiocytes with the equational chromosome behavior, and 10.81% of meiocytes with the equational + reductional chromosome behavior. On average, 0.13 bivalents per cell formed in meiocytes of the hybrid population. C-banding and genomic in situ hybridization (GISH) showed that both rye and wheat chromosomes produced ring univalents. The role of the Ph genes in regulating the bivalent formation in meiocytes with different types of chromosome behavior is discussed. PMID- 22946328 TI - [Characterization of the Bellevalia sarmatica (Georgi) woronow populations from Volgograd oblast using molecular genetic identification]. AB - DNA samples obtained from the populations of the Red Data Book species Bellevalia sarmatica (Georgi) Worovow from Volgograd oblast were examined using RAPD and AFLP analyses. DNA marking revealed considerable differences in the levels of interpopulation and intraspecific polymorphism of the Bellevalia. Furthermore, RAPD analysis, despite of lower levels of interpopulation polymorphism identified, made it possible to obtain clearer data on population subdivision upon statistical treatment of the results. The results of this study can be used in developing conservation strategies for maintenance of the species abundance and genetic diversity, as well as in elaborating the criteria for construction genetic collections. PMID- 22946329 TI - [Selective processes and adaptive evolution of the cytochrome b gene in salamanders of the genus Salamandrella]. AB - Sequence analysis of the cytochrome b gene fragment in the salamanders of the genus Salamandrella, Siberian salamander and Schrenk salamander was performed with the purpose to elucidate the effect of natural selection on the evolution of mitochondrial DNA (mtDNA) in these species. It was demonstrated that despite of notable influence of negative selection (expressed as very low dN/dS values), speciation and intraspecific divergence in salamanders was accompanied by the appearance of radical amino acid substitutions, caused by the influence of positive (directional) selection. To examine the evolutionary pattern of synonymous mtDNA sites, distribution of conservative and non-conservative substitutions was analyzed. The rates of conservative and non-conservative substitutions were nearly equal, pointing to neutrality of mutation process at synonymous mtDNA sites of salamanders. Analysis of conservative and non conservative synonymous substitution distributions in different parts of phylogenetic trees showed that the differences between the synonymous groups compared were statistically significant only in one phylogenetic group of Siberian salamander (haplogroup C) (P = 0.02). In the group of single substitutions, located at terminal phylogenetic branches of Siberian salamanders from group C, increased rate of conservative substitutions was observed. Based on these findings, it was suggested that selective processes could have an influence on the formation of the synonymous substitution profile in the Siberian salamander mtDNA fragment examined. PMID- 22946330 TI - Differentiation of four Indian aboriginal cattle populations revealed by STR markers. AB - Cattle are the most important livestock in India and play a pivotal role in agrarian economy. There are 34 recognized breeds of cattle and number of unexplored lesser known populations. The present study is a contribution towards determining genetic variation and understanding the relationship among four lesser known populations. A total of 194 unrelated DNA samples from three cattle populations of Orissa (Binjharpuri, Ghumsuri, Motu) and Hill cattle of Kumaun (Kumauni) were collected from respective breeding tracts. Genotyping was done with 23 bovine microsatellite markers as suggested by International Society for Animal Genetics (ISAG) and FAO (DAD-IS) on automated sequencer. The average observed heterozygosity in the four populations lie within the narrow range of 0.623 +/- 0.04 in Binjharpuri to 0.664 +/- 0.03 in Kumauni. Mean estimates of observed and expected heterozygosity over all loci and breeds were 0.651 +/- 0.02 and 0.720 +/- 0.01, respectively. In the overall population, the homozygote excess (F(IT)) of 0.132 +/- 0.03, was partly due to the genetic differentiation among breeds (F(ST) = 0.044 +/- 0.01) and, to a larger extent, to a significant homozygote excess within breeds (F(IS) = 0.094 +/- 0.03). The phylogenetic reconstruction from a UPGMA clustering based on Nei's Standard genetic distance yielded a tree with Binjharpuri and Ghumsuri on a single node and Motu and Kumauni on separate nodes. The most probable clustering detected by STRUCTURE in population was three. Binjharpuri and Ghumsuri animals were assigned to one cluster with high proportion of membership. PMID- 22946331 TI - [Phylogeography of Altai osmans (Oreoleuciscus sp., Cyprinidae, Pisces) based on sequence variation of the mitochondrial DNA cytochrome b gene]. AB - Representatives of the genus Oreoleuciscus (Altai osmans) from the water bodies of Western Mongolia were examined for sequence polymorphism of the mitochondrial DNA fragment containing the cytochrome b (Cyt-b) gene. A total of 17 sequence variants (haplotypes) were discovered, which formed two clusters, A and B, with nonoverlapping geographic localization. Cluster A included haplotypes of Altai osmans from the Valley of Lakes water bodies. Cluster B consisted of two subclusters, the first of which (B1) united sequence variants of the populations from Hollow of the Great Lakes and the lakes of the Great Altai Range. The second subcluster (B2) was formed by the haplotypes originating from the Hollow of the Lake Uvs, some isolated lakes of the Northwestern Khangay region, and the water bodies of the Arctic Ocean Basin (basins of Selenga and Orchon rivers). Based on the genetic divergence estimates and the radiation time of genetic geographic groups identified, the existence of three allopatric species of Altaic osmans in the genus Oreoleuciscus was substantiated. PMID- 22946332 TI - [Migration rates as inferred from the 2002 Russian census]. AB - Migration rates in the modern Russian population have been studied on the basis of the results of the 2002 census. The migration rate at the population level corresponding to a city or rural administrative district is m = 0.443. The migration rate for women (m(F) = 0.463) is 11% higher than for men (m(M) = 0.418); the migration rate for urban populations (m(U) = 0.459) is 15% higher than for rural populations (m(R) = 0.398). The geographic variation of migrations has been studied; the geographic distributions of the migration rates for rural, urban, male, and female populations are presented. Comparison of migrations in the rural population of Russia at two temporal cross-sections (1970 and 2002) has shown that the geographic structure of migrations has remained the same in many respects. The ecological factor has remained the main determinant of the migration geography, which is expressed in the relationship of the settled way of life with the forest-steppe and broad-leaved forest landscapes. PMID- 22946333 TI - [Gene pool of ethnic groups of the caucasus: results of integrated study of the Y chromosome and mitochondrial DNA and genome-wide data]. AB - Genetic diversity has been analyzed in 22 ethnic groups of the Caucasus on the basis of data on Y-chromosome and mitochondrial DNA (mtDNA) markers, as well as genome-wide data on autosomal single-nucleotide polymorphisms (SNPs). It has been found that the West Asian component is prevailing in all ethnic groups studied except for Nogays. This Near Eastern ancestral component has proved to be characteristic of Caucasian populations and almost entirely absent in their northern neighbors inhabiting the Eastern European Plain. Turkic-speaking populations, except Nogays, did not exhibit an increased proportion of Eastern Eurasian mtDNA or Y-chromosome haplogroups compared to some Abkhaz-Adyghe populations (Adygs and Kabardians). Genome-wide SNP analysis has also shown substantial differences of Nogays from all other Caucasian populations studied. However, the characteristic difference of Nogays from other populations of the Caucasus seems somewhat ambiguous in terms of the R1a1a-M17(M198) and R1b1b1-M73 haplogroups of the Y chromosome. The state of these haplogroups in Turkic speaking populations of the Caucasus requires further study. PMID- 22946334 TI - Genotoxic effects of tacrolimus on human lymphocyte cells. AB - We designed in vitro study to determine possible genotoxic effects oftacrolimus (FK-506), which is used as a potent immunosuppressive drug, by using sister chromatid exchange (SCEs), chromosome aberration (CAs), micronuclei tests (MN) and cell growth kinetics such as mitotic index (MI) and replication index (RI) in human lymphocytes. The cells were treated with 5, 25, 50, and 100 ng/mL concentrations of tacrolimus, for 24 h and 48 h treatment periods. Tacrolimus induced CA and MN frequency at all concentrations for 24 and 48 h In additon, it induced the SCE at the highest concantration for 24 h and at 25 and 100 ng/mL for 48 h. Tacrolimus decreased MI at all concentrations (except 5 ng/mL) for all treatment periods. It also inhibited the RI at 50 and 100 ng/mL concentrations for 24 h and at all concentrations for 48 h. Treatments given with tacrolimus result in the enhance of the different endpoints ofgenotoxicity, suggesting its mutagenic action on lymphocytes in vitro. PMID- 22946335 TI - [Prevalence of mutations BRCA1 5382insC, and CHEK2 1100delC in the population of Siberian region]. AB - Frequencies of the 538insC mutation in the BRCA1 gene and the 1100delC mutation in the CHEK2 gene were compared in the group of breast cancer patients and the large-scale sample, consisting of 7920 DNA specimens from healthy residents of the city of Novosibirsk. Higher frequencies of these mutations in the patient group compared to the control sample (1.95 versus 0.25% for BRCA1 5382insC, and 1.78 versus 0.40% for CHEK2 1100delC) were observed, pointing to their association with susceptibility to breast cancer (OR = = 7.86, 95% CI 3.51-17.30 and OR =4.46, 95% C1 2.04-9.49, respectively). PMID- 22946336 TI - [The DD2R gene expression level in the corpus allatum affects the fitness of female Drosophila melanogaster]. AB - The effect of tissue-specific suppression of the dopamine D2-like receptor gene (DD2R) in the corpus allatum (CA), the gland that synthesizes juvenile hormone (JH) on the Drosophila melanogaster resistance to heat stress has been studied. A decreased expression of the DD2R gene in the CA has been found to substantially decrease the heat stress resistance of adult transgenic female, but not male, D. melanogaster compared to the control group, this phenomenon being weakly pronounced in juvenile flies. The effect of DD2R activation on the D. melanogaster reproductive function has been estimated. It has been shown that treatment of D. melanogaster with a synthetic specific agonist of DD2R decreases the fertility, the effect being considerably stronger in adult flies than in juvenile ones. It is concluded that the change in the number of DD2Rs in CA or their activation decreases the fitness of Drosophila. PMID- 22946337 TI - Identification of a specific scar marker for detection of Tilletia foetida (Wall) Liro pathogen of wheat. AB - Common bunt is one of the most important destructive diseases of wheat worldwide and is a domestic quarantined disease in China. However, a rapid and efficient method to identify the corresponding pathogens is currently limited. The objective of the present study was to develop a diagnostic molecular marker specific towards Tilletia foetida (Wall) Liro, a causal agent of the bunt disease. One specific DNA fragment for T. foetida (286 bp in length) was amplified using an Amplified Fragment Length Polymorphism (AFLP) assay and, this fragment was cloned and sequenced. One pair of specific primers (SC(286-1)/SC(286 2)), which was designed according to the sequence, could specifically amplify the corresponding fragment in all of the T. foetida isolates employed from both the People's Republic of China and United States, whereas this fragment could not be amplified by the other fungal species tested. Therefore, a specific Sequence Characterized Amplified Region (SCAR) marker was developed. This SCAR marker could distinguish T. foetida from related pathogenic fungi efficiently and could be used for the early diagnosis of the common bunt of wheat in the field, and provide an efficient way for disease surveillance and disease forecasting in cereal crop. PMID- 22946338 TI - [Time-dependent changes in reproductive parameters of Kazakhstan Uighurs]. AB - Time-dependent changes in reproductive parameters were analyzed using data on 203 female Uighurs. A decrease was observed for the total fertility (3.77 vs. 6.50 in females 45-55 or 56 and more years of age, respectively), live birth (3.3 vs. 5.14), stillbirth (0.045 vs. 0.41), and voluntary abortion (0.29 vs. 0.59) rates. PMID- 22946339 TI - Anticancer agent xanthohumol inhibits IL-2 induced signaling pathways involved in T cell proliferation. AB - Xanthohumol (XN), a prenylated chalcone present in hops exhibits anti inflammatory, antioxidant and anticancer activity. In the present study we show that XN inhibits the proliferation of mouse lymphoma cells and IL-2 induced proliferation and cell cycle progression in mouse splenic T cells. The suppression of T cell proliferation by XN was due to the inhibition of IL-2 induced Janus kinase/signal transducers and activators of transcription (Jak/STAT) and extracellular signal-regulated kinase 1 and 2 (Erk1/2) signaling pathways. XN also inhibited proliferation-related cellular proteins such as c Myc, c-Fos and NF-kappaB and cyclin D1. Thus, understanding of IL-2 induced cell signaling pathways in normal T cells, which are constitutively turned on in T cell lymphomas may facilitate development of XN for the treatment of hematologic cancers. PMID- 22946341 TI - Are fragile sites "hot-spots": a causative factor in tumor biology. AB - Genomic integrity of the cancer cell is doubt-full because of fragility on chromosome. Fragile--sites are non-randomly distributed on human genome prone to form gaps or breaks at either pre/or metaphase chromosome arise when cells are exposed to a perturbation of DNA replication process. Cancer cells commonly show various form of "hot spots" including point mutation, chromosome copy number and translocation involving specific gene mutation but the genetic diversity of fragile sites are still not clear. The chromosomal fragile sites (rare & common fragile sites) make the cancer cells not only susceptible to genomic instability but also contribute the process of malignancy due to expansions of microsatellite CGG or AT rich minisatellite. Fragile sites have been implicated due to inter chromosomal amplification events by initiation breakage - fusion cycles. The mechanisms behind these changes give raise to new insight the cytogenetic manifestation of oncogenesis. Fragile sites loci are associated with activation of oncogenesis during cell--cycle analysis. However, these mutations at fragile sites loci might have play a causative or functional role in tumor biology. The topography organization and informatics complexity of the fragile sites remained unexplored due to lack of systematic approach towards molecular cloning of the fragile sites DNA sequences and specific models as not are under taken. The information regarding mode of inheritance of fragile sites are still lacking but the first degree relative specially young proband and maternal side having variable prevalence in different population could be uses as suitable marker for determining genetic predisposition to cancer. This comprehensive review of fragile sites in tumor biology probably helpful to explore to understand the molecular mechanism of carcinogenesis or tumorgenesis. PMID- 22946340 TI - Nox4 inhibition enhances the cytotoxicity of cisplatin in human renal cancer cells. AB - PURPOSE: Kidney cancer is notoriously chemo-resistant and abundantly expresses the Nox4 NADPH oxidase. To determine if Nox4 superoxide generation contributes to drug resistance, we assayed in vitro drug cytotoxicity following Nox4 shRNA silencing in human renal cancer cells. MATERIALS AND METHODS: Human conventional kidney cell lines, 786-0 and RCC4 expressing Nox4-specific shRNA or a non targeting, control shRNA were grown in serial dilutions of cisplatin, vincristine, doxorubicin, or etoposide. Cell viability curves were generated and the concentration required to kill 50% of the cells (IC50) calculated for each drug. Apopotosis was estimated by TUNEL assay. Quantitative RT-PCR and Western blots were used to confirm Nox4 silencing and evaluate expression of apoptotic pathway proteins. RESULTS: Silencing significantly lowered the IC50 for cisplatin, vincristine and etoposide, and promoted drug-induced apoptosis by TUNEL assay. Improved sensitivity to cisplatin was reproduced by Nox inhibiton with diphenyliodonium, whereas induction of intracellular superoxide by dithiothreitol superoxide enhanced chemo-resistance. RT-PCR and Western blot revealed decreased expression of anti-apoptotic Bcl-XL and Bcl-2 and increased expression of pro-apoptotic Bax following Nox4 knockdown. CONCLUSION: Nox4 contributes to RCC chemo-resistance through modulation of pro-apoptotic and anti apoptotic signaling, suggesting that Nox4 inhibition might enhance the efficacy of conventional cytotoxic drugs against RCC. PMID- 22946342 TI - Intra-arterial bevacizumab with blood brain barrier disruption in a glioblastoma xenograft model. AB - PURPOSE: In this study we investigated the treatment response and survival of intra-arterial (IA) compared to intra-peritoneal (IP) delivery of bevacizumab (BV) in a glioblastoma (GBM) xenograft mouse model. METHODS: 3x10(5) U87-Luc cells were stereotactically implanted into the cortex of 35 nude mice and grouped for treatment (n = 7 in each group): IP saline (group 1), single IP BV (group 2), biweekly IP BV for 3 weeks (group 3), single intra-arterial (IA) BV alone (group 4) and single IA BV with blood brain barrier disruption (BBBD) (group 5). Tumor growth was monitored every 3 to 4 days using bioluminescence imaging (BLI) and survival was analyzed by the Kaplan Meier method. Tumor tissue was analyzed using H&E staining and immunohistochemistry. RESULTS: Based on BLI, BV treated mice showed a delayed tumor growth over time compared to control. Kaplan Meier analysis demonstrated a median survival time of 28 days for group 1,31 days for group 2, 34 days for group 3, 36 days for group 4 and 36 days for group 5 (p < 0.0001). Mice treated with repeated IP BV (p = 0.003) or single IA BV with (p = 0.015) or without (p = 0.005) BBBD showed a significant survival benefit compared to single IP BV treated mice. Post mortem analysis revealed a histological pattern with a more discontinuous border between tumor and mouse brain in the repeated IP BV and single IA BV with or without BBBD treated mice compared to the sharply defined edges of single IP BV treated and control mice. CONCLUSIONS: In this study we showed a significant survival benefit of repeated IP BV and single IA BV with or without BBBD treated mice compared to single IP BV treated and control mice in a U87 xenograft model. PMID- 22946343 TI - D-Pinitol attenuates 7, 12 dimethylbenz [a] anthracene induced hazards through modulating protein bound carbohydrates, adenosine triphosphatases and lysosomal enzymes during experimental mammary carcinogenesis. AB - We have reported here that the ameliorative potentials of D-Pinitol during 7, 12 Dimethylbenz [a] anthracene induced experimental breast carcinogenesis. DMBA is a potent organ specific carcinogen which is widely employed to induce mammary carcinoma in rats. D-Pinitol a natural inositol has been reported to found in soybean with many biological functions. The female sprague dawley rats were subjected to carcinogen 7, 12-DMBA and the ameliorative potentials of dietary compound D-Pinitol was investigated with reference to cell surface glycoproteins, lysosomal enzymes and adenosine triphosphatases. Interestingly, administration of D-Pinitol was found to be significantly down regulated the breast tissue glycoproteins and lysosomal enzymes and in contrast the levels of adenosine triphosphatases were remarkably up regulated. Further, the biochemical changes were well reflected and evidenced in the histology of breast and liver tissues. Thus, it can be concluded from the present study that D-Pinitol efficiently attenuates the hazardous consequences of the environmental carcinogen 7,12-DMBA through modulating cell surface glycoproteins, membrane protective role both in lysosomal and ATPase compartment via its antioxidant nature which ultimately results in the findings of future innovative remedies for genotoxin mediated hazards. PMID- 22946345 TI - Nedaplatin and irinotecan for patients with recurrent small cell lung cancer. AB - BACKGROUND: No standard second-line combination chemotherapy has yet been established for patients with recurrent small cell lung cancer (RSCLC). METHODS: Patients with RSCLC were treated with nedaplatin (NP) at 50 mg/m2 and irinotecan (CPT) at 50 mg/m2 on days 1 and 8 every 4 weeks for four cycles. RESULTS: The clinical outcomes of 12 patients (9 male and 3 female; age range 48-76 years, median 62 years) were retrospectively analyzed. Seven of the patients showed sensitive relapse. Two patients had a performance status of 2. Nine of the patients were able to receive 4 to 6 courses of NP and CPT chemotherapy. Grade 3 or 4 anemia, neutropenia and thrombocytopenia occurred in 25.0%, 50.0% and 41.7% of patients, respectively. There were no grade 3 or 4 non-hematologic toxicities except for febrile neutropenia in 1 patient. There was no treatment-related death. Nine patients achieved PR, and the objective response rate was 75.0%. The median survival time was 11.1 months (range 4.8 to 31.3+ months) and the 1-year survival rate was 50.0%. CONCLUSION: NP and CPT in combination are effective and safe for patients with RSCLC. PMID- 22946344 TI - Inhibition of cell proliferation and induction of apoptosis by CDDO-Me in pancreatic cancer cells is ROS-dependent. AB - Oleanolic acid-derived synthetic triterpenoids are broad spectrum antiproliferative and antitumorigenic agents. In this study, we investigated the role of reactive oxygen species (ROS) in induction of apoptosis and inhibition of prosurvival Akt, NF-kappaB and mTOR signaling pro-teins by methyl-2-cyano-3,12 dioxooleana-1,9(11)-dien-28-oate (CDDO-Me) in pancreatic cancer cells. Micromolar concentrations of CDDO-Me inhibited proliferation and induced apoptosis in MiaPaCa-2 and Panc-1 pancreatic cancer cells. Treatment with CDDO-Me caused the generation of hydrogen peroxide and superoxide anion and pretreatment of cells with NADPH oxidase inhibitor diphylene iodonium (DPI) or respiratory chain complex 1 inhibitor rotenone prevented ROS generation. Pretreatment with N acetylcysteine (NAC) or overexpression of glutathione peroxidase (GPx) or superoxide dismutase-1 (SOD-1) blocked the antiproliferative effects of CDDO-Me. Likewise, NAC prevented the induction of apoptosis (annexin V-FITC binding and cleavage of PARP-1 and procaspases-3,-8 and -9) and reversed the loss of mitochondrial membrane potential and release of cytochrome c from mitochondria by CDDO-Me. CDDO-Me down-regulated p-Akt, p-mTOR and NF-kappaB (p65) but increased the activation of Erk1/2 and NAC blocked the modulation of these cell signaling proteins by CDDO-Me. Thus, the results of this study indicate that the antiproliferative and apoptosis inducing effects of CDDO-Me are mediated through a ROS-dependent mechanism and the role of ROS in modulation of signaling proteins by CDDO-Me warrants further investigation. PMID- 22946346 TI - Phase I/II study of oral erlotinib for treatment of relapsed/refractory glioblastoma multiforme and anaplastic astrocytoma. AB - We evaluated the safety and survival benefits of orally administered erlotinib monotherapy for patients with relapsed/refractory glioblastoma multiforme (GBM) or anaplastic astrocytoma (AA). A dose escalation schedule was administered with a starting dose of 150 mg/day for the first cycle (28 days), followed by 100 mg twice daily for 14 days, and 150 mg twice daily for another 14 days. Assuming no dose limiting toxicities were observed, dosage was maintained at 150 mg BID for 10 more cycles. Disease and tumor responses were assessed after every other cycle; toxicity assessments were conducted for a minimum of 10 weeks. Patients discontinued use of enzyme-inducing anticonvulsants (EIAED) and started non EIAEDs. Patients with previous erlotinib exposure were ineligible. Eleven patients were enrolled: 8 (73%) GBM; 3 (27%) AA. Adverse events limited study accrual, originally intended to accrue 43 patients. Nine patients (90%) experienced rash within the first 2 cycles: 7 (64%) within cycle 1; 6 (60%) reported diarrhea within the first 2 cycles. Median progress-free survival (PFS) and overall survival (OS) was 1.9 months and 6.9 months. All patients showed disease progression while on the drug. Despite the sample size, the toxicity of erlotinib supersedes any marginal benefit it as a monotherapy for relapsed/refractory GBM/AA. PMID- 22946347 TI - Role of carotid baroreflex and sympathetic responses in the push-pull effect: a simulation study. AB - BACKGROUND: The push-pull maneuver (PPM) can lead to loss of consciousness in pilots of high-performance aircraft. This paper presents a mathematical model for the simulation of carotid baroreflex function and sympathetic responses during PPM. METHODS: The previous model was first modified by incorporating a submodel of the carotid baroreflex and then validated by comparing the simulation results with experimental data. Then the role of the carotid baroreflex was evaluated by varying the time delay and gain of the baroreflex independently during PPM and control runs, and the influence of different PPM profiles on sympathetic efferent activities were predicted. RESULTS: Model outputs suggest that the effects of carotid baroreflex regulation with different time delays and gain factors on the push-pull effect (PPE) are almost the same as those on the control run. Meanwhile, simulation of sympathetic responses indicates that the frequency of spikes in the efferent sympathetic nerves increases with higher magnitude and longer duration of -Gz exposure, as well as with higher magnitude of +Gz exposure. However, the effect of changed sympathetic responses may be alleviated when transferred to baroreflex effectors. CONCLUSION: The simulation results support that the carotid baroreflex and sympathetic responses might have little specific influences on the PPE. It also suggests that the limited range of G alteration and transition rate should be considered when using tilting experiments to investigate sympathetic response to PPE. The limitation of the present model due to the lack of sufficient data on the contribution of different peripheral vascular beds and their myogenic response is discussed. PMID- 22946348 TI - Pilot expertise and hippocampal size: associations with longitudinal flight simulator performance. AB - BACKGROUND: Previous research suggests that the size of the hippocampus can vary in response to intensive training (e.g., during the acquisition of expert knowledge). However, the role of the hippocampus in maintenance of skilled performance is not well understood. The Stanford/Veterans Affairs Aviation MRI Study offers a unique opportunity to observe the interaction of brain structure and multiple levels of expertise on longitudinal flight simulator performance. METHODS: The current study examined the relationship between hippocampal volume and three levels of aviation expertise, defined by pilot proficiency ratings issued by the U.S. Federal Aviation Administration (11). At 3 annual time points, 60 pilots who varied in their level of aviation expertise (ages ranging from 45 to 69 yr) were tested. RESULTS: At baseline, higher expertise was associated with better flight simulator performance, but not with hippocampal volume. Longitudinally, there was an Expertise x Hippocampal volume interaction, in the direction that a larger hippocampus was associated with better performance at higher levels of expertise. DISCUSSION: These results are consistent with the notion that expertise in a cognitively demanding domain involves the interplay of acquired knowledge ('mental schemas') and basic hippocampal-dependent processes. PMID- 22946349 TI - CT examination of the pericardium and lungs in helicopter pilots exposed to vibration and noise. AB - INTRODUCTION: Helicopter pilots are exposed to whole body vibration and noise in their working environment. Some researchers have found that kinetic energy from both noise and vibration is believed to affect pericardial thickness and lead to pulmonary fibrosis, known as vibroacoustic disease. The aim of this project was to determine whether we could discover similar findings in a selection of helicopter pilots. METHODS: A case control study where 27 helicopter pilots were compared to an age-matched control group of typical office workers was conducted. High resolution CT scanning of the thorax was used as the diagnostic method. Two medical radiologists interpreted the images independently, blinded to whether the subjects were pilots or from the control group. RESULTS: There were no signs of pericardial thickening or significant lung fibrosis formations in either of the groups. The average pericardium thickness for the helicopter group was 1.38 mm, SD = 0.54 mm, and for the control group: 1.37 mm, SD = 0.33 mm. There was no significant correlation between pericardium thickness and flight hours or age. DISCUSSION: The average pericardial thickness values for the helicopter and the age-matched control groups were almost identical. The results are within normal limits and comparable to an American study where 21 normal individuals were measured to 1.2 mm +/- 0.8 mm in an average of 26 different points by using trans esophageal echocardiography. CONCLUSION: On the basis of the CT scans, our findings do not support the existence of vibroacoustic disease, where pericardial thickening is the most prominent sign. PMID- 22946350 TI - Asymptomatic brain lesions in pilots: a comparative study with non-flying personnel using brain MRI. AB - INTRODUCTION: As modern aircraft fly at higher altitudes with rapid velocity, pilots have been put in the environment with a possible increasing risk of brain injury and could sustain cumulative brain damage. However, very few studies have investigated brain lesions using MRI in asymptomatic pilots. We evaluated asymptomatic pilots for the presence of cerebral lesions using MRI. METHODS: Enrolled were 31 healthy pilots of the Republic of Korea Air Force (ROKAF) on active flight duty and 31 healthy nonflying ROKAF personnel with ages of or over 45. We checked for the presence of acute and/or chronic medical conditions, smoking habits, alcohol intake, blood pressure, blood tests including lipid panel, glucose, and liver panel, aircraft type, flight hours, flight altitude, and white matter hyperintensities (WMH) on brain MRI. RESULT: The mean age of both groups was 51.2 yr and the mean total flight hours of the pilots was 3025.0 h. There was no statistical difference between the pilots and non-flying personnel for WMH findings (54.8%/ vs. 32.3%). Of the factors related to flight, only the flying altitude (OR 1.005) was significantly related to the presence of WMH on multivariate analysis. Glucose levels and cholesterol levels were also related to WMH. DISCUSSION: Despite our negative results, there could be the possibility of cumulative brain damage in asymptomatic pilots considering the positive effect of altitude and the positive trend of pilots for the presence of WMH. Additional investigations are surely needed. PMID- 22946351 TI - Digestive functional symptoms among commercial pilots in relation to diet, insomnia, and lifestyle factors. AB - BACKGROUND: The aim of our study was to identify associations between digestive symptoms among pilots and diet, insomnia, and lifestyle factors. METHODS: A standardized questionnaire was mailed to all Stockholm pilots on duty in a Swedish airline company: 354 pilots and 564 office workers from the same company participated. Associations were analyzed by multiple logistic regressions with mutual adjustment. RESULTS: Of the pilots, 9.9% reported poor appetite, 15.2% heartburn, 12.4% diarrhea, 62.1% bloating, 9.3% constipation, and 14.4% epigastralgia. Pilots reported more bloating and poor appetite compared with office workers. The prevalence of insomnia was 70.6% among pilots and 63.1% among office workers. Among pilots, insomnia was related to poor appetite, heartburn, diarrhea, bloating, constipation, and epigastralgia. There were no associations between insomnia and digestive symptoms among office workers. Among pilots, higher body mass index (BMI) was related to heartburn and smokers more often suffered from constipation. Frequent milk consumption was associated with heartburn and less constipation; female pilots suffered from more constipation. The number of years as an active pilot was negatively associated with epigastralgia and bloating. CONCLUSION: Insomnia and some digestive symptoms were more common among pilots than office workers. In addition to insomnia, BMI, smoking, female gender, and milk consumption were associated with some digestive symptoms. The strong association between insomnia and digestive symptoms among pilots, but not among office workers, suggests a stress component related to this occupation. PMID- 22946353 TI - An emergency medical planning guide for commercial spaceflight events. AB - BACKGROUND: Commercial spaceflight events transporting paying passengers into space will begin to take place at various spaceports around the country within the next few years. Many spaceports are located in remote areas that are far from major hospitals and trauma centers. Spaceport medical directors should develop emergency medical plans (EMPs) to prepare for potential medical contingencies that may occur during commercial spaceflight events. The aim of this article is to guide spaceport medical directors in emergency medical planning for commercial spaceflight events. METHODS: This guide is based on our experience and a recently developed EMP for Spaceport America which incorporated a literature review of mass gathering medicine, existing planning guides for mass gathering events, and EMPs for analogous aerospace events. RESULTS: We propose a multipronged approach to emergency medical planning, consisting of event planning, medical reconnaissance, medical personnel, protocols, physical facility and hardware, and documentation. DISCUSSION: Medical directors should use this guide to develop an emergency medical plan tailored to the resources and constraints specific to their events. PMID- 22946352 TI - Low back pain: considerations for rotary-wing aircrew. AB - Low back pain remains a significant issue among helicopter aircrew. There is a considerable body of scientific literature devoted to the problem, including epidemiologic and experimental studies addressing prevalence, characteristics, primary etiology, and contributing factors. It is endemic and multinational, with a prevalence ranging from 50-92%. Archetypal pain begins with flight or within hours of flight, is mostly targeted in the low back/lumbar region and/or buttocks, is transient, and is commonly described as dull and achy. A minority develop chronic, persistent pain that is variously described with dissimilar characteristics. The pernicious effects of back pain or discomfort while piloting may affect flight performance and safety, including reduced operational effectiveness and lost duty time, occupational attrition, curtailed or cancelled missions, compromised emergency egress, and performance deficits during critical phases of flight. The majority of etiologic studies have focused on the pathophysical posture adopted by pilots for aircraft control and exposure to whole body vibration. With more evidence for the former, it remains likely that both, as well as other factors, may have a contributory and perhaps integrative or concerted role. Corrective and mitigation strategies have addressed lumbar support, seat and cockpit ergonomic redesign, and improved aircrew health. Flight surgeons should be familiar with this prevalent issue and future research must address longitudinal cohort studies with clear definitions, relevant and valid exposure data, dose-response detail, and control for contributing factors and confounders. PMID- 22946354 TI - Low-dose chest computed tomography as a screening tool: findings in 536 aircrews. AB - BACKGROUND: Plain chest radiographs and pulmonary function tests have been used for pulmonary screening for flight duties of aircrews of the Republic of Korea Air Force. However, the screening accuracy of plain chest radiographs is controversial. Chest CT imaging with low-dose protocol (LDCT) improves detection of intra-thoracic abnormalities compared to plain chest radiographs. The aim of this study was to assess the influence of LDCT on flight duties of aircrews and to investigate their radiologic findings. METHODS: From June 2009 to May 2011, the Aerospace Medical Center screened asymptomatic subjects 40 yr of age or older to evaluate intra-thoracic abnormalities using LDCT. The abnormal findings, including types and frequency, were recorded and the aircrew's flight duties were also recorded. RESULTS: This study included 536 subjects. No abnormal findings were found in 387 (72.2%) subjects. Abnormal findings related to pulmonary nodules were detected in 123 (23.00%) subjects. Air-trapping lesions were found in 33 (6.1%) subjects. One subject had a mediastinal tumor. Changes of flight duty were made in 26 (4.9%) subjects on the basis of LDCT findings. No subject was permanently disqualified for flight duty. CONCLUSIONS: Pulmonary screening with LDCT could detect many intra-thoracic abnormalities. LDCT was especially useful in the detection of bullae and bleb, and the flight duties of all subjects with bullae and bleb were changed. PMID- 22946355 TI - High altitude induced bilateral non-traumatic subdural hematoma. AB - BACKGROUND: Minor clinical complaints such as headache and drowsiness after a disco party with alcohol abuse may be an unlikely cause for neurological consultation, but, rarely, they may hide a challenging diagnosis. CASE REPORT: A young male patient admitted to our Neurosurgical Department for progressive headache showed a sudden clinical deterioration of consciousness; head CT scan was promptly obtained and thick bilateral subdural hematomas requiring urgent craniotomies and drainage were detected. While his anamnesis was surprisingly negative for head trauma, coagulopathies, or other common causes of subdural hematoma, he reported a curious history of 10-d onset of symptoms after a farewell disco party on a high-altitude location, almost 9000 ft (>2700 m) above mean sea level, followed by an intercontinental flight back to his seaside hometown. Following surgery the patient eventually experienced a rapid recovery from this frightening experience. DISCUSSION: Due to its uniqueness, the case is reported and the influence of possible provoking causes relevant in the pathogenesis of subdural hematomas is carefully outlined. PMID- 22946356 TI - An independent, objective calibration check for the reduced oxygen breathing device. AB - INTRODUCTION: Normobaric hypoxia, which does not entail an altitude chamber, but reduces the fraction of inspired oxygen (02) by diluting air with nitrogen, is finding increased use. The reduced oxygen breathing device (ROBD-2) is one of several commercial devices for generating such normobaric hypoxia. Reported here are results of a procedure to check the calibration of the ROBD-2 using methods that may be readily available in physiology and psychophysiology facilities. METHODS: The %O2 output by the ROBD-2 was measured concurrently in two ways for altitudes from mean sea level (MSL) to 34,000 ft above MSL at 2000-ft intervals five times over 2 d. One measurement method used was the one built into the ROBD 2, which reports the %O2 the device is delivering at the selected target altitude. The other method diverted a sample of the ROBD-2's output gas to the paramagnetic O2, sensor of a metabolic measuring system via its sampling line. The %O2, measured with the two techniques was compared using Bland-Altman statistical procedures. RESULTS: The two measurement methods produced %O2 readings differing by no more than 0.18% O2 from MSL to 34,000 ft (from 20.95 to about 4.40% oxygen, respectively), the full operating range of the device. Calculating altitude from the measured %O2 showed the ROBD-2 operated within its design error margins over its whole operational range. DISCUSSION: The purpose for which the ROBD-2 is used should determine whether the reliability of its output in normobaric equivalent altitude is adequate. Differences between devices and device stability over time and with use have yet to be assessed. Our assessment does not address the accuracy of the algorithm the ROBD-2 uses to provide an equivalent target altitude under normobaric conditions. PMID- 22946357 TI - Major depression and fitness to fly by different aviation authorities. AB - Safety issues are paramount in aviation and careful treatment protocols have been developed to ensure fitness to fly among aviators recovering from major depressive episodes (MDE). Aeromedical examiners (AMEs) do not necessarily treat depressive patients frequently, so they often consult psychiatrists; however, psychiatrists are rarely familiar with aviator treatment protocols. U.S., Canadian, and Australian regulations allow several choices among antidepressant drugs for flying pilots recovering from an MDE. Symptom stability times before the possible return to flying duties vary from 4 wk to 12 mo. So far European regulations have not allowed antidepressants, but the situation may change. PMID- 22946358 TI - Accuracy of physiological altitude simulation. PMID- 22946359 TI - CAMI tools and services for evaluating space weather. PMID- 22946360 TI - You're the flight surgeon. Prostate cancer. PMID- 22946361 TI - You're the flight surgeon. Acoustic neuroma. PMID- 22946362 TI - This month in aerospace medicine history. PMID- 22946363 TI - Physiologic evaluation of capture and anesthesia with medetomidine-zolazepam tiletamine in brown bears (Ursus arctos). AB - Physiologic variables during anesthesia with medetomidine-zolazepam-tiletamine were evaluated in 52 free-ranging brown bears (Ursus arctos) darted from a helicopter and in six captive brown bears darted at a zoo. During anesthesia, rectal temperature, respiratory rate, heart rate, and pulse oximetry derived hemoglobin oxygen saturation were recorded. Arterial blood samples were collected and immediately analyzed for evaluation of pulmonary gas exchange, acid-base status, and selected hematologic and plasma variables. At the end of anesthesia, atipamezole was administered intramuscularly at five times the medetomidine dose. Capture-induced hyperthermia and lactic acidemia were documented in free-ranging bears. Hypoxemia during anesthesia was documented in both free-ranging and captive bears. In free-ranging bears, rectal temperature, heart rate, lactate, hematocrit, and hemoglobin decreased significantly during anesthesia, whereas partial pressure of arterial carbon dioxide, pH, potassium, and glucose increased. Yearlings had a significantly higher heart rate, pH, base excess, bicarbonate, and glucose, and had a significantly lower rectal temperature, sodium, hematocrit, and hemoglobin when compared with subadult and adult brown bears. In conclusion, alterations in pulmonary gas exchange and acid-base status in brown bears during anesthesia with medetomidine-zolazepam-tiletamine with the doses and capture methods used in this study were identified. Oxygen supplementation is recommended to counteract hypoxemia during anesthesia. PMID- 22946364 TI - Cardiorespiratory effects of isoflurane anesthesia in crested caracaras (Caracara plancus). AB - To evaluate the cardiorespiratory changes induced by isoflurane (ISO) anesthesia in the crested caracara (Caracara plancus), eight crested caracaras that weighed 1.0 kg (range 0.9-1.1 kg) were the subjects for the study. The birds were anesthetized by face mask with ISO for brachial artery catheterization. After recovery, anesthesia was re-induced and maintained with ISO with spontaneous ventilation. Electrocardiography, direct systolic arterial blood pressure (SAP), diastolic arterial blood pressure (DAP), mean arterial blood pressure (MAP), respiratory rate (RR), end-tidal carbon dioxide (P(ET)CO2), and cloacal temperature (T degrees C) were measured before induction (baseline, under physical restraint) and after 5, 10, 15, 20, 25, 30, 35, and 40 min of ISO anesthesia. Arterial blood samples were collected for blood gas analysis at baseline, 10, 25, and 40 min. No cardiac arrhythmias were observed in the present study. RR, SAP, DAP, MAP, T degrees C and pH decreased from baseline values, whereas arterial partial pressures of oxygen and carbon dioxide, bicarbonate concentration, and P(ET)CO2 were significantly higher than baseline. Apnea was not observed in any bird. ISO anesthesia is suitable for use in healthy members of this species despite the moderate cardiovascular and respiratory depression produced. PMID- 22946365 TI - Biochemical variables in free-ranging white-tailed deer (Odocoileus virginianus) after chemical immobilization in clover traps or via ground-darting. AB - The objective of this prospective observational cohort study in free-ranging female white-tailed deer (Odocoileus virginianus) was to compare the physiologic effects of two methods of anesthetic drug administration: hand-injection in Clover traps and remote injection by dart after ground-stalking. Six trapped and 14 darted female deer were injected with a median (minimum, maximum) of 590 microg/kg butorphanol (401, 1070 microg/kg), plus 235 microg/kg medetomidine (160, 429 microg/kg) intramuscularly. In the trap, the deer struggled when approached and were restrained for injection. Darted deer sprinted away after injection. Once immobilized, deer were transported to a veterinary hospital where blood was collected and vital signs were measured on admission. Admission data from a subset of deer in which measurements were taken within 40 min of trapping (n = 6) or darting (n = 5) were analyzed. After salpingectomy under isoflurane and while still anesthetized, another blood sample was collected from all 20 deer. Body weight and immobilization drug doses were not different between groups. On admission, most deer from both groups were hypoxemic, although the darted deer were significantly more hypoxemic. The median rectal temperature in trapped deer was higher than in darted deer, and temperatures higher than 39 degrees C only occurred in trapped deer. The median heart rate in trapped deer was more than twice that in darted deer. Trapped deer had lower median pH and base excess; in trapped deer, the median plasma lactate concentration was more than fivefold higher than in darted deer. After surgery, the median serum creatine kinase concentration was nearly 10-fold higher in trapped deer, and the median cardiac troponin I concentration was higher in trapped deer but undetectable in 10 of 14 darted deer. The white-tailed deer immobilized by hand injection in Clover traps experienced more severe physiologic perturbations than deer remotely injected by dart after ground-stalking. These perturbations might be sufficient to cause myocardial damage. PMID- 22946366 TI - Serosurvey for selected viral agents in white rhinoceros (Ceratotherium simum) in Kruger National Park, 2007. AB - One hundred serum samples collected from free-ranging white rhinoceros (Ceratotherium simum) in Kruger National Park (KNP) during the 2007 capture season were selected for measurement of antibody levels to several different vector-borne viral agents. These infectious diseases were chosen to compare with an earlier serosurvey that had been conducted in KNP in rhinos during 1987-1997. Positive antibody titers were found against epizootic hemorrhagic disease (EHD) of deer (8%), Bluetongue (BT) (1%), and Rift Valley fever (RVF) (49%). However, none of the 100 animals tested had detected antibody levels to African horse sickness (AHS). These values were in sharp contrast to those measured in the 1987 1997 survey in KNP white rhinos (AHS 60%, EHD 30%, BT 37%, RVF 0%). Vector-borne viral infection prevalence in white rhinos in the same geographical location appears to vary over time and may be important for monitoring presence of pathogens in an ecosystem. PMID- 22946367 TI - Serum chemistry comparisons between captive and free-ranging giraffes (Giraffa camelopardalis). AB - Serum chemistry analyses were compared between captive and free-ranging giraffes (Giraffa camelopardalis) in an attempt to better understand some of the medical issues seen with captive giraffes. Illnesses, including peracute mortality, energy malnutrition, pancreatic disease, urolithiasis, hoof disease, and severe intestinal parasitism, may be related to zoo nutrition and management issues. Serum samples were collected from 20 captive giraffes at 10 United States institutions. Thirteen of the captive animal samples were collected from animals trained for blood collection; seven were banked samples obtained from a previous serum collection. These samples were compared with serum samples collected from 24 free-ranging giraffes in South Africa. Differences between captive and free ranging giraffes, males and females, and adults and subadults were analyzed by using a 2 x 2 x 2 factorial and Fisher's least significant difference for mean separation; when necessary variables were ranked and analyzed via analysis of variance. Potassium and bilirubin concentrations and alanine aminotransferase (ALT) activities were different between captive and free-ranging giraffes, but all fell within normal bovid reference ranges. The average glucose concentration was significantly elevated in free-ranging giraffes (161 mg/dl) compared with captive giraffes (113 mg/dl). All giraffes in this study had glucose concentrations higher than bovine (42-75 mg/ dl) and caprine (48-76 mg/dl) reference ranges. Differences were also seen in lipase, chloride, and magnesium though these findings are likely not clinically significant. There were no differences detected between sexes. Adults had higher concentrations of potassium, total protein, globulins, and chloride and higher gamma glutamyltransferase activities, whereas subadults had higher concentrations of phosphorus. Within the captive group, nonimmobilized animals had higher concentrations of total protein and globulins. Captive giraffe diets need further investigation to determine if the differences seen in this study, especially glucose and bilirubin concentrations and ALT activities, may result in some health problems often seen in captive giraffes. PMID- 22946368 TI - Resorptive tooth root lesions in the Malayan tapir (Tapirus indicus). AB - Facial abscessation and osteomyelitis due to dental disease is commonly seen in the Malayan tapir (Tapirus indicus), but little is known about the prevalence or etiology of these lesions. To determine the prevalence of dental ailments, 56 skulls and mandibles of deceased Malayan tapirs were visually and radiographically evaluated. Dental lesions were scored according to severity, and individuals were classified according to their age (juvenile/ young adult/adult) and origin (captive/free ranging). All of the lesions identified were of a resorptive nature. seemingly originating at the cementoenamel junction and burrowing towards the center of the tooth. Overall, 27% of the investigated skulls presented radiolucent dental lesions. The prevalence among captive animals was 52% (13/25), while only 6% (2/31) of the free-ranging tapirs had dental lesions. The second, third, and fourth premolars and first molar were the teeth most commonly affected, and the mandibular teeth were more often involved than the maxillary dentition. This study demonstrates a high prevalence of resorptive dental lesions in captive Malayan tapirs and provides a strong indication that age and captivity are significant risk factors in the development of these lesions. Dental disease, Malayan tapir, radiology, resorptive lesions, Tapirus indicus. PMID- 22946369 TI - A serologic survey of viral infections in captive ungulates in Turkish zoos. AB - Zoos and zoologic gardens make optimal environments for interspecies transmission of viral infections. There are seven zoos and several small zoologic collections in Turkey. This study aimed to determine the current status of viral infections in captive ungulates living in these environments. Blood samples were taken from 163 captive animals from two zoos. There were 39 Cameroon sheep (Ovis ammon f aries), 11 Barbary sheep (Ammotragus lervia), 57 pygmy goats (Capra hircus), 9 Angora goats (Capra hircus), 21 mountain goats (Capra aegagrus-aegagrus), 7 llamas (Lama glama), 8 Persian goitred gazelle (Gazella subgutturosa subgutturosa), 7 Caspian red deer (Cervus elaphus maral), 2 fallow deer (Dama dama), and 2 camels (Camelus dromedarius). Antibodies against bovine viral diarrhea virus (BVDV), bovine herpesvirus-1 (BHV-1), bovine adenoviruses (BAV-1 and -3), parainfluenzavirus 3 (PI-3), and bluetongue viruses (BTV-4 and -9) were investigated using the virus neutralization test, and malignant catarrhal fever (MCF) antibodies were screened by ELISA. All animals were negative for BVDV and BHV-1 antibodies. Seroprevalence of BAV-1, BAV-3, PI-3, BRSV, BT-4, BT-9, and MCF were detected as follows: 46.6%, 60.1%, 0.6%, 7.3%, 1.8%, 1.2%, and 51.6%, respectively. Seroprevalence of BAVs and MCF were more common than all other viruses (P < 0.0001). Ten sheep (37.0%), 48 goats (84.2), and 1 Ilama (14.2%) were the only species positive for MCF antibodies. Prevalence of BRSV and MCF antibodies were found to be significantly higher in goats than in sheep. BTV antibodies were detected both in Cameroon sheep and mountain goats and suggest that zoo animals are at risk for BTV in endemic regions. PMID- 22946370 TI - Cardiac assessment of African hedgehogs (Atelerix albiventris). AB - Cardiomyopathy is a common finding in captive African hedgehogs (Atelerix albiventris) at postmortem exam. To date, treatment attempts have been mostly empirical and unrewarding. The objective of this study was to determine reference cardiac values for captive African hedgehogs based on echocardiogram, electrocardiogram (ECG), and radiographs. Adult African hedgehogs with no clinical signs of cardiac disease (n = 13) were selected. Each animal was anesthetized with isoflurane via facemask and an echocardiogram, ECG, and radiographs were performed. Standard measurements were taken and the descriptive statistics performed. Values were comparable to limited data available in other hedgehog species and other similar-sized exotic species. Two animals were removed from consideration of reference values due to valvular defects that were considered significant. These data are the first establishing cardiac parameters in normal African hedgehogs using radiographic cardiac measurement, echocardiogram, and ECG. Evaluating animals with possible cardiomyopathy may allow for earlier diagnosis and more successful treatment. PMID- 22946371 TI - Coelomic implantation of satellite transmitters in the bar-tailed godwit (Limosa lapponica) and the bristle-thighed curlew (Numenius tahitiensis) using propofol, bupivacaine, and lidocaine. AB - Intravenous propofol was used as a general anesthetic with a 2:1 (mg:mg) adjunctive mixture of lidocaine and bupivacaine as local anesthetics infiltrated into the surgical sites for implantation of satellite transmitters into the right abdominal air sac of 39 female and 4 male bar-tailed godwits (Limosa lapponica baueri and Limosa lapponica menzbeiri and 11 female and 12 male bristle-thighed curlews (Numenius tahitiensis). The birds were captured on nesting grounds in Alaska, USA, and on overwintering areas in New Zealand and Australia from 2005 through 2008. As it was developed, the mass of the transmitter used changed yearly from a low of 22.4 +/- 0.2 g to a high of 27.1 +/- 0.2 g and weighed 25.1 +/- 0.2 g in the final year. The mean load ratios ranged from 5.2% to 7.7% for godwits and from 5.7% to 7.5% for curlews and exceeded 5% for all years, locations, and genders of both species. The maximum load ratio was 8.3% for a female bar-tailed godwit implanted in Australia in 2008. Three godwits and no curlews died during surgery. Most birds were hyperthermic upon induction but improved during surgery. Two godwits (one in New Zealand and one in Australia) could not stand upon release, likely due to capture myopathy. These birds failed to respond to treatment and were euthanized. The implanted transmitters were used to follow godwits through their southern and northern migrations, and curlews were followed on their southern migration. PMID- 22946372 TI - Vaccination of llamas, Llama glama, with an experimental killed encephalomyocarditis virus vaccine. AB - Encephalomyocarditis virus (EMCV) is a pandemic virus that has caused mortality in numerous captive wildlife species worldwide. An experimental killed vaccine was created from two EMCV isolates associated with zoo animal mortality in the southern United States. The vaccine was tested for safety and efficacy in eleven llamas (Llama glama). All animals received an initial vaccination and a second booster vaccination 4 wk later. Serum antibody responses were monitored at initial vaccination and at 4 wks, 8 wk, 6 mo, and 12 mo postvaccination. Eight of the 11 llamas vaccinated experienced at least a 4-fold increase in serum antibody titers to EMCV. Antibody titers of those eight animals remained elevated above prevaccination levels when measured at 12 mo. The experimental killed EMCV vaccine tested may be a useful tool to prevent EMCV infection in llamas when given in 2 doses 4 wk apart, and then revaccinated or with antibody levels monitored annually thereafter. PMID- 22946373 TI - Survival and morphologic changes of entodiniomorphid ciliate Troglodytella abrassarti in chimpanzee feces. AB - Entodiniomorphid ciliates occur in the hindgut of both captive and wild African great apes. These ciliates do not form cysts, and therefore they are more susceptible for degradation. This present study focused on the survival, quantification, and decomposition processes of Troglodytella abrassarti trophozoites in the feces of captive chimpanzees. Fecal samples were examined using wet mounts and the merthiolate-iodine-formaldehyde concentration method, and the number of ciliates was expressed as ciliates per gram, which did not differ when examined from three different samples of the same feces. Trophozoites of T. abrassarti survived 5-15 hr after defecation at 25 degrees C under aerobic conditions. Decomposition of trophozoites began immediately after defecation; however, most of the trophozoites had a compact shape and visible cilia. Trophozoites, although without cilia, can be detected in the feces 55-65 hr after defecation, although most of the trophozoites were fragmented. The total number of ciliates in the sample started to decrease 35-55 hr after defecation. The absence of entodiniomorphid ciliates in fecal samples could not be caused by delayed feces fixation; instead, the absence was due to low sensitivity of coproscopic techniques. However, because of quick morphologic changes of trophozoites, accurate identification of ciliates in older samples may be difficult or even impossible. PMID- 22946374 TI - Field anesthesia of wild ring-tailed lemurs (Lemur catta) using tiletamine zolazepam, medetomidine, and butorphanol. AB - Telazol has been commonly used for field anesthesia of wild lemurs, including ring-tailed lemurs (Lemur catta). Telazol alone provides good induction, but doesn't cause adequate muscle relaxation and sedation for collecting consistent somatic measurements and high-quality dental impressions that are sometimes needed. Variability in induction response has been seen between individuals that have received similar dosages, with young lemurs seeming to need more anesthetic than mature lemurs. This investigation evaluated Telazol induction in young (2.0 4.9 yr) and mature (> or = 5.0 yr) ring-tailed lemurs and compared postinduction supplementation with medetomidine or medetomidine-butorphanol. Forty-eight lemurs were anesthetized with Telazol administered via blow dart; then, 20 min after darting, they were supplemented via hand injection with either medetomidine (0.04 mg/ kg) or medetomidine-butorphanol (0.04 mg/kg and 0.2 mg/kg, respectively). The odds ratio for young lemurs to need more than one dart for induction, relative to mature lemurs, was 3.8, even though the initial dose of Telazol received by young lemurs (19 +/- 7 mg/kg) was significantly higher than the initial dose administered to mature lemurs (12 +/- 5 mg/kg). The total Telazol dosage was also significantly different between young lemurs (33 +/- 15 mg/kg) and mature lemurs (18 +/- 9 mg/kg). Both medetomidine and medetomidine-butorphanol provided good muscle relaxation and sedation for all procedures. Physiologic values were similar between the two protocols. Oxygen saturation by pulse oximetry was generally good, although there were a few SaO2 values < 90%. Recoveries were smooth, but long. Time to head up was correlated with total Telazol dosage in mature lemurs. In young lemurs, time to standing was correlated with Telazol induction dosage and time of last Telazol administration. Lemurs that received hand injections of Telazol took longer to recover than those that did not. Further refinements are needed to increase induction reliability and to decrease recovery time, particularly in young lemurs. PMID- 22946375 TI - Anticoagulant rodenticide exposure and toxicosis in four species of birds of prey presented to a wildlife clinic in Massachusetts, 2006-2010. AB - Mortalities among birds of prey from anticoagulant rodenticide (AR) toxicosis have been documented in several countries. Reports on extent of exposure within regions of the United States are limited. This study investigated AR exposure and toxicosis in four species of birds of prey (red-tailed hawks [Buteo jamaicensis], barred owls [Strix varia], eastern screech owls [Megascops asio] and great horned owls [Bubo virginianus]) presented to a wildlife clinic in Massachusetts. The aims of this study are to document the proportion of these four species that died or were euthanized due to their presenting injuries that had detectable amounts of ARs in liver tissue; to identify and quantify ARs present; to describe clinical, postmortem, and histopathologic signs of toxicosis; to evaluate potential sublethal effects of AR exposure; and to associate liver AR level with toxicosis. Birds included in the study were sampled without regard to signs of AR toxicosis. Postmortem examinations were conducted, and liver samples were analyzed for AR residues. Of 161 birds tested, 86% had AR residues in liver tissue. The second-generation AR (SGAR) brodifacoum was identified in 99% of positive birds. Mortality from AR toxicosis was diagnosed in 6% of birds. No indications of sublethal effects of exposure were found, and no association between liver brodifacoum level and signs of toxicosis was apparent. Given the high proportion of birds in this study exposed to ARs, specifically brodifacoum, continued monitoring is warranted as new U.S. Environmental Protection Agency regulations on the sale and use of SGARs are enacted. PMID- 22946376 TI - Vitamin A deficiency and hepatic retinol levels in sea otters, Enhydra lutris. AB - Vitamin A deficiency has rarely been reported in captive or free-ranging wildlife species. Necropsy findings in two captively housed southern sea otters (Enhydra lutris nereis) included irregular thickening of the calvaria characterized by diffuse hyperostoses on the internal surface. One animal also had moderate squamous metaplasia of the seromucinous glands of the nose. There was no measurable retinol in the liver of either sea otter. For comparison, hepatic retinol concentration was determined for 23 deceased free-ranging southern and northern (Enhydra lutris kenyoni) sea otters from California and Alaska. Free ranging otters were found to have similar hepatic retinol concentrations (316 +/- 245 mg/kg wet weight) regardless of their location and subspecies. All of these values were significantly higher than the levels in the affected animals. Consumption of a diet with very low vitamin A concentrations and noncompliance in daily supplementation are hypothesized as the causes of vitamin A deficiency in these two sea otters. PMID- 22946377 TI - Tolazoline-induced apnea in mule deer (Odocoileus hemionus). AB - Eighteen mule deer (Odocoileus hemionus) and six Columbia black-tailed deer (Odocoileus hemionus columbianus) were held in pens and repeatedly anesthetized from April 2004 through June 2005 as part of an external parasite study. Deer were anesthetized using a combination of Telazol and xylazine hydrochloride (HCL) administered intramuscularly. Tolazoline HCL was slowly administered at 4 mg/kg intravenously to reverse the effects of xylazine with good results. For 17 of the 19 mule deer anesthesias in the fall of 2004, a mean dose of 7.3 mg/kg of intravenous tolazoline (range 6.1-8.4 mg/kg) was given by mistake. This paper describes clinical signs of apnea, muscle tensing, and fasciculations immediately following intravenous administration of tolazoline HCL in mule deer (O. hemionus) at 1.5-3 times the recommended dose. Mean dose for black-tailed deer during this time was 8.1 mg/kg (range 5.5-12.4 mg/kg) with no clinical signs as seen in the mule deer. Based on these findings, intravenous tolazoline use in mule deer is recommended at < or = 4 mg/kg. PMID- 22946378 TI - Streptococcus phocae isolated from a spotted seal (Phoca largha) with pyometra in Alaska. AB - A spotted seal harvested by subsistence hunters in Kotzebue Sound, Alaska (USA), showed a grossly enlarged uterus and associated lymph nodes. Streptococcus phocae was isolated from the purulent uterine discharge. Histopathologic examination revealed inflammation that was limited to the uterine mucosa. Lymph nodes draining the affected organ were reactive but no evidence of active infection was found in the lymph nodes. This report is the first Streptococcus phocae isolated from spotted seals as well as the first report of pyometra as the main pathologic finding associated with this pathogen. Isolation of this pathogen from Alaska expands the reported range to arctic pinnipeds. Zoonotic potential remains unknown. PMID- 22946379 TI - Osteofluorosis in captive gerenuk (Litocranius walleri) and bongo (Tragelaphus eurycerus isaaci) antelope. AB - Multiple cases of lameness in gerenuk (Litocranius walleri) and bongo antelope (Tragelaphus eurycerus isaaci) associated with high levels of fluoride in a commercial feed are reported. Clinical pathology and histopathology findings are described and the response to treatment is documented. The case highlights the importance of quality control in feed management. PMID- 22946380 TI - Granulomatous meningoencephalitis due to toxoplasma gondii in a black-headed night monkey (Aotus nigriceps). AB - This report describes toxoplasmosis infection in a black-headed night monkey (Aotus nigriceps) from the Zoological Park of the Federal University of Mato Grosso, Brazil. The animal was submitted alive to the Veterinary Hospital of the Federal University of Mato Grosso presenting neurologic clinical signs. There were no improvements on the animal's clinical condition after treatment, so it was euthanized. At necropsy, the most significant gross lesions observed were hemorrhages diffusely scattered throughout the cerebral hemispheres. Histologic findings were characterized by nonsuppurative encephalitis and mild multifocal necrotizing nonsuppurative myocarditis. Groups of tachyzoites and cysts were observed surrounding the inflamed areas of cerebral parenchyma. Sections of the brain were submitted for immunohistochemistry examination for Toxoplasma gondii and Neospora caninum and also for polymerase chain reaction (PCR) to determine the presence of Toxoplasma gondii. The samples were positive for Toxoplasma gondii by PCR; however, cross reactivity was observed between Toxoplasma gondii and Neospora caninum antibodies. These findings were consistent with a toxoplasmosis infection in this animal. PMID- 22946381 TI - Metastatic malignant melanoma in a prehensile-tailed porcupine (Coendou prehensilis). AB - A 14-yr-old male, prehensile-tailed porcupine (Coendou prehensilis) presented for an ulcerated, bleeding lesion of the right flank. The wound presented similar to a bite wound and was treated with antibiotics. After 2 mo, the lesion had increased in size and was nonhealing, so surgical excision was elected. Histopathology diagnosed this lesion as a malignant melanoma with incomplete margins. Radiographs showed no evidence of pulmonary metastasis. At 6 mo, another skin lesion was removed and was diagnosed as malignant melanoma with clean surgical margins. At 8 mo, another four dermal masses were surgically excised and, again, these were melanomas that were completely excised. The animal was euthanized approximately 15 mo after initial presentation due to continued growth of dermal masses, dyspnea, and decreased appetite. Necropsy and histopathology revealed metastatic melanoma present in skin, kidneys, and lung. PMID- 22946382 TI - Serum vitamin A concentrations in captive sea otters (Enhydra lutris). AB - Individual dietary preferences and difficulty with animal training create challenges and nutritional concerns when evaluating a captive sea otter (Enhydra lutris) diet. The importance of vitamin A within the body reflects the necessity that it be ingested in adequate amounts to ensure optimal health. To compare levels of serum vitamin A concentrations from captive sea otters on daily oral vitamin A supplementation, serum samples from eight adult sea otters from three institutions were evaluated for serum vitamin A concentrations. The eight animals were fed a total of four different diets and received oral supplementation via three different methods. Multiple diet items were analyzed for vitamin A content and were found to have low to nondetectable levels of vitamin A. Oral vitamin A supplementation, as a slurry with dietary items, was shown to be effective and a mean serum concentration of approximately 170 +/- 51 microg/L was obtained for serum vitamin A concentrations in captive sea otters. Captive diets can be modified to increase vitamin A concentration and supplementation and, if accepted, can be used as a means to ensure adequate vitamin A intake. PMID- 22946383 TI - Virtopsy in a red kangaroo with oral osteomyelitis. AB - This report describes the use of computed tomography (CT) in a nondomestic species. Postmortem CT was performed on a red kangaroo (Macropus rufus) and a diagnosis of oral osteomyelitis was made. CT examination revealed bony remodeling of the right mandible, an intraosseous lesion of the right temporal bone, muscle necrosis around the right mandible, and the absence of the right, first, upper molar tooth. Cardiac and intrahepatic gas and a distended intestine due to postmortem gas accumulation were also seen. All the lesions identified with CT were also identified by conventional necropsy, except the cardiac and intrahepatic gases. Virtopsy may be a useful procedure for the noninvasive identification of cause of death and as a guide for necropsy in animals. PMID- 22946384 TI - Safety of florfenicol in the adult lobster (Homarus americanus). AB - Aerococcus viridans, the causative agent of the disease gaffkemia, was a major cause of mortality in lobsters (Homarus americanus) held in tidal impoundments during the 1970s and 1980s. Despite reports of an increase in the mortality of lobsters during impoundment, and the widespread prophylactic use of oxytetracycline against A. viridans, this bacterium has not been detected in active disease surveillance of the Maine postcapture lobster population. However, Photobacterium indicum may be an emerging opportunistic pathogen of stressed lobsters. An acute toxicity trial was conducted as a rapid screening procedure for the potential future use of the antibiotic florfenicol. Based on the results of this experiment, florfenicol appears to be well tolerated in adult H. americanus by intrapericardial injection at the 10-100 mg/kg dose. Oxytetracycline dihydrate is contraindicated by intrapericardial injection at the 10-100 mg/kg dose. PMID- 22946385 TI - Mammary carcinoma in a tiger (Panthera tigris): morphological and immunohistochemical study. AB - The histologic and immunohistochemical features of a case of mammary gland carcinoma are described in a 14-yr-old female tiger (Panthera tigris). Immunoreactivity to estrogen receptor (ER), progesterone receptor (PR), tumoral protein 53 (p53), vascular endothelial growth factor (VEGF), human epidermal growth factor receptor 2 (HER-2), and cyclooxigenase-2 (COX-2) was investigated. Neoplastic cells were negative for ER, PR, and p53 but showed positivity for VEGF, HER-2, and COX-2, both in the primary and the metastatic lesions. Histopathologic findings and immunohistochemistry results suggested that the malignant behavior of the reported case could be comparable with some aggressive cat mammary carcinomas. PMID- 22946386 TI - Molecular and serological detection of Babesia spp. in neotropical and exotic carnivores in Brazilian zoos. AB - Large and small piroplasms have been observed in the blood smears of various wild carnivores, but few studies utilizing molecular characterization have been done. The goal of this present study was to investigate the presence of Babesia sp. by molecular and serologic techniques in exotic and neotropical carnivores maintained in captivity at Brazilian zoos. Blood and sera samples were collected from 146 Brazilian wild felids, 21 exotic felids, 1 genet (Genetta tigrina), 3 European wolves (Canis lupus), and 94 Brazilian wild canids in Brazilian zoos in the Sao Paulo and Mato Grosso states and in the Federal District. A total of 53 wild felids (31.74%) and 10 wild canids (10.31%) were seropositive for Babesia canis by Indirect Fluorescent Antibody Test (IFAT). Antibodies were detected in ocelots, little-spotted cats, margays, pampas cats, jaguars, pumas, jaguarundis, crab-eating foxes, and bush dogs. Babesia sp. DNA, with high similarity to B. leo, was detected in one pampas cat and one genet. PMID- 22946387 TI - Intermediate syndrome of chlorpyriphos toxicity (Polaris) in a caracal (Caracal caracal). AB - A 5-yr-old spayed female caracal (Caracal caracal) was presented with complaints of acute onset of mental dullness, ataxia, and ventroflexion of 24-hr duration. The animal's garden territory was sprayed a day earlier with an organophosphate (OP) insecticide (chlorpyriphos-methyl). The caracal was treated for OP toxicosis and mildly improved. It was discharged a day later at the owner's request, although clinical signs did not resolve. During the following week, the caracal was confined to prevent further toxin exposure but did not improve and was presented 8 days later with similar clinical signs. Serum butyril-cholinesterase activity was markedly low. The relatively long interval from OP exposure, along with the duration of clinical signs, suggested an intermediate syndrome of OP toxicity. The caracal was treated symptomatically and progressively improved. It was discharged after 8 days of hospitalization and made full recovery 30 days later. This is the first report of OP toxicity in a caracal, suspected to progress to an intermediate syndrome of OP poisoning. PMID- 22946388 TI - Generalized amyloidosis in an Eastern Bongo (Tragelaphus eurycerus isaaci). AB - Amyloidosis has been described in a wide range of domestic and wild species and man. A 10-yr-old male Eastern (Mountain) Bongo (Tragelaphus eurycerus isaaci) was submitted for postmortem examination after a period of 24-hr malaise. Gross examination found evidence of biventricular cardiac hypertrophy, congestive heart failure, and focal pulmonary abscessation. Histologic changes in the heart were consistent with hypertrophic change. Amyloid deposits were found within the liver, kidney medulla, heart, adrenal cortex, and pituitary gland and were confirmed as reactive systemic amyloid (AA) by immunohistochemistry. The pulmonary abscessation was thought to be the stimulus for excessive serum amyloid associated protein production leading to the reactive systemic amyloidosis. Colloidal goiter was also identified as an incidental finding. PMID- 22946389 TI - Bronchial carcinoma in a red-shouldered hawk (Buteo lineatus). AB - Respiratory neoplasms are rare in birds. This report describes carcinoma of the bronchial epithelium in a red-shouldered hawk (Buteo lineatus) that presented with weakness and lethargy lasting 4 days that progressed to seizures. Grossly, the caudal air sac and coelomic cavity contained approximately 15 ml of dark brown cloudy fluid that displaced the intestines cranially. Nodular plaques were present on the viscera and air sacs. Microscopic examination of tissues revealed a mass that expanded the bronchial lumen and was composed of papillary proliferations of rows of small cuboidal epithelial cells that were small and uniform in size with a low mitotic index. Metastases were present on the surfaces of caudal air sac, kidney, and multifocal peritoneal surfaces of the coelomic cavity. Clinical signs were most likely the result of West Nile virus infection, which was confirmed by immunohistochemistry of brain tissue. PMID- 22946390 TI - First description of onychomycosis caused by Chrysosporium keratinophilum in captive Bennett's wallabies (Macropus rufogriseus rufogriseus). AB - Seven Bennett's wallabies (Macropus rufogriseus rufogriseus) presented within a period of several months with onychodystrophy, onychomadesis, and severe digital tumefaction. Histopathologic findings included a pseudocarcinomatous hyperplasia of the claw matrix surrounding a cavity filled with keratin and septate hyphae stained with periodic acid Schiff reagent. The fungal species Chrysosporium keratinophilum was identified on cultures. The wallabies were orally treated with ketoconazole (15 mg/kg s.i.d.) for 20 wk. Material and enclosures were cleaned and sprayed with 0.2% enilconazole solution once a month over a period of 4 mo. No improvement of advanced cases was observed, but no new case appeared for the next 6 mo. The positive mycological culture and the invasion of tissues on histopathologic examination suggested that the fungal species C. keratinophilum was implicated in this claw disease. This is the first report of onychomycosis caused by C. keratinophilum in animals. PMID- 22946391 TI - Pilot study of antimicrobial-resistant Escherichia coli in herring gulls (Larus argentatus) and wastewater in the northeastern United States. AB - Wildlife may be an important reservoir of antibiotic-resistant bacteria and resistance genes. In this pilot study, the prevalence and patterns of antimicrobial resistance in Escherichia coli cultured from wild herring gull (Larus argentatus) feces and human wastewater at Cape Cod, Massachusetts, USA, was compared. Antimicrobial susceptibility was tested using Kirby-Bauer disk diffusion with seven antimicrobial agents. A high proportion of antimicrobial agent-resistant E. coli isolates (59.2%) were detected in wastewater samples compared with a lower prevalence of 17.5% in gull feces. In addition, there was a large proportion of isolates with intermediate susceptibility (93.0%) in gull feces. Although similar resistance patterns and shared resistance genes suggest possible wastewater contamination of the local environment, the relatively low frequency of resistance and high prevalence of intermediate susceptibility detected in E. coli cultured from gull feces depict a complex model of antimicrobial resistance among E. coli strains of wildlife origin. PMID- 22946392 TI - Dispharynx nasuta (Nematoda:Acuariidae) infection causing proventricular lesions and death in three captive rosellas (Psittaciformes:Psittacidae). AB - Two adult male Crimson rosellas (Platycercus elegans) and an adult female eastern rosella (Platycercus eximius) were found dead in their cages in a private aviary in March 2009, April 2010, and February 2010, respectively, without premonitory signs. Their postmortem examination showed pectoral muscle atrophy and a distended proventriculus. The proventricular mucosal surface was covered with a gelatinous, whitish material, where a large number of nematode parasites identified as Dispharynx nasuta were present. A histologic examination revealed a hyperplastic mucosa, spirurid nematodes in the mucosal layer and inflammatory mononuclear cells in the lamina propria. This is the first report of a D. nasuta infection associated with proliferative proventriculitis and subsequent death in psittacine birds. PMID- 22946393 TI - Suspected anaphylaxis to leuprolide acetate depot in two elf owls (Micrathene whitneyi). AB - Two adult female elf owls (Micrathene whitneyi) were treated with leuprolide acetate depot injections to prevent egg laying. The birds were treated for several years without complications. Several years into the treatment regimen, both birds died immediately after receiving an injection of leuprolide acetate. Remaining drug was analyzed, revealing 95.7% potency. We suspect that either an immediate Type 1 hypersensitivity reaction occurred or a contaminant was present, resulting in the fatalities of these elf owls. No reports of anaphylaxis to leuprolide acetate in birds were identified in the literature. Clinicians should be aware of the possibility of anaphylaxis when administering this medication to avian patients. PMID- 22946394 TI - Guidelines for zoo and aquarium veterinary medical programs and veterinary hospitals. AB - These guidelines for veterinary medical care and veterinary hospitals are written to conform with the requirements of the Animal Welfare Act, which states that programs of disease prevention and parasite control, euthanasia, and adequate veterinary care shall be established and maintained under the supervision of a veterinarian. Ideally the zoo and aquarium should be providing the best possible veterinary medical care for the animals in their collections. Many of these animals are rare and endangered and the institutions should endeavor both to provide for the long term health and well being of these animals and to advance the field of non-domestic animal medicine. It is hoped that this publication will aid in this process. PMID- 22946395 TI - Hospice in a zoologic medicine setting. AB - Forty years ago, Dr. Elizabeth Kubler-Ross in her landmark book On death and dying observed "maybe at the end of our days, when we have worked and given, enjoyed ourselves and suffered, we are going back to the stage that we started out with and the circle of life is closed." Just as human life expectancy has steadily increased over the last 4 or 5 decades, animal life expectancy has increased, including that of zoologic species. With this has come a need for humans to openly and frankly deal with end-of-life issues for themselves and for their animals, including those in zoos. By necessity, zoos have been dealing with problems such as aggressive pain management and triage, and efforts to incorporate end-of-life care into zoologic medicine. But these efforts have yet to include formal acknowledgment that they are a basic form of hospice. Hospice for humans, and now for companion animals, includes much more than pain relief and geriatric care. This article reviews the concepts and basic practices of hospice and the closely related field of palliative care, their relatively recent application to companion animal care, potential applications to zoologic medicine, and the ways this could provide opportunities for personal growth of zoo visitors and staff, including veterinary staff. PMID- 22946396 TI - Hematology and clinical chemistry values of free-ranging basilisk lizards (Basiliscus plumifrons) in Costa Rica. AB - Twenty-three lizards were captured for this study, both males and females (12 males, 10 females, 1 undetermined), with a large range in body weights (40-286 g) appeared to be healthy based on activity level, physical examinations, and body condition scores. Heparinized blood samples from 20 free-ranging basilisk lizards (Basiliscus plumifrons) in Costa Rica were used for determining complete blood cell counts, plasma, and heparinized whole blood biochemical analysis. This information will serve as baseline reference data for future health assessment studies of free-ranging and captive basilisk lizards, as well as epidemiologic, conservation, and captive-breeding studies. A point-of-care analyzer was useful for this field study, and clinical chemistry values from heparinized whole blood samples were similar to values from plasma, which indicates that separation of plasma may not be necessary to process blood samples on site in remote areas. To the authors' knowledge, this is the first report of hematologic and plasma biochemical data from free-ranging B. plumnifrons. PMID- 22946397 TI - Chemical and surgical interventions to alleviate intraspecific aggression in male collared lemurs (Eulemur collaris). AB - To reduce male-male aggression in collared lemurs (Eulemur collaris) at Disney's Animal Kingdom, a clinical trial of leuprolide acetate (Depo-Lupron) injections through one breeding season (24 wk), followed by surgical castration after the breeding season was implemented. Daily behavioral observations to record occurrences of aggression were conducted before and during the injection period, as well as after castration. Fecal sample collection began 2 wk before the first injection and continued throughout the clinical trial to determine testosterone metabolite concentration. Samples were collected 3 times per week. Fecal collection and behavioral observation continued for 5 mo after castration. Fecal samples from 3 intact males from other institutions were obtained to compare testosterone values. While the lemurs were treated with Depo-Lupron, testosterone concentrations spiked immediately after injection, and then returned to pretreatment, nonbreeding-season levels after varying lengths of time. Analysis of the behavioral data indicated that aggression was not significantly reduced with Depo-Lupron treatment. However, after castration, contact aggression and wounding decreased to zero. Although the sample is small, this study presents the first documented data on the effects that chemical treatment with Depo-Lupron and surgical castration have upon hormone levels and aggressive behavior in eulemurs. PMID- 22946398 TI - Pinniped tuberculosis in Malayan tapirs (Tapirus indicus) and its transmission to other terrestrial mammals. AB - In the last 7 yr, three different species of terrestrial mammals were diagnosed with Mycobacterium pinnipedii either within one collection or through the introduction of an infected animal from another zoo. The affected species included the Malayan tapir (Tapirus indicus), Bactrian camel (Camelus bactrianus bactrianus), and crested porcupine (Hystrix cristata). In the first zoo, all of these were living in exhibits adjacent to a group of South American sea lions (Otariaflavescens) and were cared for by the same keeper. One infected tapir was transferred to a different zoo and transmitted M. pinnipedii infection to three other Malayan tapirs. The tapirs were tested with various diagnostic methods, including comparative intradermal tuberculin test, PCR and culture of sputum samples, Rapid Test (RT), and multiantigen print immunoassay (MAPIA). The M. pinnipedii infection was confirmed at postmortem examination in all animals. RT and MAPIA showed the diagnostic potential for rapid antemortem detection of this important zoonotic disease. PMID- 22946399 TI - Assessment of the quality of multi-institutional data for population-based epidemiological studies: a case study of atoxoplasmosis in Bali mynahs (Leucopsar rothschildi). AB - To evaluate the potential to conduct population-based epidemiologic studies using multi-institutional data, the quality of data extracted from the MedARKS system was evaluated with regard to atoxoplasmosis in Bali mynahs (Leucopsar rothschildi). Data extracted for 338 Bali mynahs from 34 institutions were analyzed for completeness, correctness, and consistency and subjectively analyzed for accessibility. Data completeness was ascertained by analysis of missing records, tests, and blank fields. Two hundred and sixty four records had animal enclosure information missing, nine records were missing from the parasitology module, and 85 records did not include tests or results. Data correctness was assessed by evaluation of unclear and inaccurate results. From 2,432 parasitology records, 81 tests (3.3%) were not definitive because of uninterpretable entries. Data consistency was assessed by comparing the problem list to positive tests in the parasitology module and listing of buffy coat smears in the clinical pathology module. Overall, six different terms with 28 values were used to denote "positive for Atoxoplasma sp.," and a substantial number of discrepancies were found between problem lists, parasitology modules, and test findings among these data records. In general, this study showed that the data contained in a computer patient record (CPR) system for zoos has great promise for population-level studies if specific areas are addressed, including 1) reduced reliance on free text data entry, 2) universal use of a standardized vocabulary, 3) use of methods to identify and track individual animals accurately and easily, 4) integration of data checks and maintenance methods, and 5) concerted use of "centralized" animal medical record information. PMID- 22946400 TI - Evaluation of an 18-micron filter for use in reptile blood transfusions using blood from American alligators (Alligator mississippiensis). AB - Blood transfusions are a common therapeutic procedure in small animal medicine and have been investigated in some exotic species but little information is available about their safety and efficacy in reptiles. In human pediatrics and small animal practice, the Hemo-Nate18-micro filter is used to prevent embolic clots and particulate waste from entering the recipient during a transfusion. The goal of this study was to determine the hemolytic effect of an 18-micro Hemo-Nate filter for whole blood cell transfusions in reptiles using the American alligator (Alligator mississippiensis) as a reptilian model. Results revealed no significant difference in free plasma hemoglobin between the unfiltered and filtered samples (P = 0.21). There was no difference in the prefiltration and postfiltration packed cell volume (PCV) (P = 0.41). Results suggest that an 18 micro Hemo-Nate filter does not cause hemolysis or decrease the PCV of small quantities of alligator blood. PMID- 22946401 TI - Bioencapsulation of metronidazole in adult brine shrimp (Artemia sp.). AB - A description of bioencapsulation of metronidazole in adult brine shrimp (Artemia) for 2.5 g/L, 5 g/L, and 10 g/L treatment baths is presented. Metronidazole was detected in adult brine shrimp tissue after enrichment periods of 15 min, 30 min, 1 hr, 2 hr, 4 hr, 8 hr, 12 hr, and 24 hr. The assays were performed using high performance liquid chromatography. There was a positive relationship in both dose and time. When evaluating percent uptake, all three baths demonstrated a similar pattern. All three bath concentrations had a high initial concentration that fell at 30 min and slowly began to increase through the end of the study. Survival of shrimp was not affected by bath concentration but decreased over time in all treatment baths comparatively. It can be concluded that metronidazole can be successfully bioencapsulated in adult Artemia. PMID- 22946402 TI - Evaluation of hematology and serum biochemistry of cold-stunned green sea turtles (Chelonia mydas) in North Carolina, U.S.A. AB - Hypothermia or cold-stunning is a condition in which the body temperature of an animal decreases below normal physiologic range and which has been linked to severe morbidity in sea turtles. Reports have focused on the physiologic changes caused by cold-stunning in Kemp's Ridley sea turtles (Lepidochelys kempii) and loggerhead sea turtles (Caretta caretta), but few have evaluated the green sea turtle (Chelonia mydas). This study evaluated hematologic and serum biochemical profiles of cold-stunned green sea turtles in North Carolina, USA. When compared with healthy, free-ranging juvenile green turtles from the same region, cold stunned turtles exhibited hypoglycemia, hypocalcemia (both total and ionized calcium), hyponatremia, hypokalemia, hypoproteinemia, hypoalbuminemia, hyperphosphatemia, and elevations in uric acid and blood urea nitrogen. These findings contrast with some previously reported changes in cold-stunned Kemp's Ridley and loggerhead sea turtles. These results emphasize the importance of basing therapeutic regimens on biochemical analyses in cold-stunned sea turtles. PMID- 22946403 TI - Removal of an intracoelomic hook via laparotomy in a sandbar shark (Carcharhinus plumbeus). AB - A twenty-one-year-old male sandbar shark (Carcharhinus plumbeus) demonstrated signs of chronic weight loss even though its appetite remained unchanged. In addition, the gradual development of a red, circular lesion on its ventral body was noted. After months without any significant changes, a ventral fistula appeared revealing the tip of a wire exposed within its center. The shark was immobilized via intramuscular remote injection through dartgun with etomidate; removed from its exhibit tank; and clinically examined with radiographic imaging, a cell blood count/serum chemistry evaluation, and the use of a metal detector along the body wall. A metallic hook was identified in the coelom about 10 cm cranial to the external fistula. The shark was transferred to an isolation pool for 1 mo. A second immobilization via immersion in eugenol was conducted in order to perform a celiotomy. The hook was located in a liver lobe and was surgically removed. After a prolonged recovery from anesthesia, the shark was released into its primary tank and recovered uneventfully, although some of the skin sutures sloughed prematurely. PMID- 22946404 TI - Clinical management of a western lowland gorilla (Gorilla gorilla gorilla) with a cardiac resynchronization therapy device. AB - A 24-yr-old, male western lowland gorilla (Gorilla gorilla gorilla) was diagnosed with congestive heart failure using transesophageal and transthoracic echocardiology. New York Heart Association (NYHA) Class III was assigned to the severity of the condition. Over 16 mo, this progressed to NYHA Class IV despite increasing medical therapy. Repeated evaluations suggested that implantation of a cardiac resynchronization therapy device with a defibrillator (CRT-D) could benefit this animal based on clinical signs and underlying evidence of dyssynchrony and suspected fibrotic myocardial disease. Surgical implantation of leads into the right atrium, right ventricle, and left ventricle was accomplished. The CRT-D device was placed under the thoracic pectoral muscles during an initial surgical procedure. Improvement in the gorilla's clinical condition after implantation of the CRT-D device was immediate and dramatic. Subsequent scanning of the device was accomplished through operant conditioning. The data from these device interrogations included stored and real-time cardiac data, which were used to minimize recognized environmental stressors and change device settings. Over 4 yr, case management was critical to successful device use in treatment of the clinical disease. This involved medications, training for device interrogation, exercise to increase activity and improve body condition, and phlebotomy attempts. Dietary management was necessary to manipulate caloric and sodium intake and encourage medication compliance. Cardiac resynchronization therapy device implantation, although requiring specialized equipment and surgical skill, appears to be a viable option for treatment of fibrosing cardiomyopathy with systolic dysfunction in gorillas refractory to medical management. In addition to treatment, this device provides cardiovascular data at rest that could allow for early diagnosis and treatment of gorillas with this and other cardiac conditions in the future. This describes the comprehensive medical, husbandry, and training techniques necessary to successfully manage this intense clinical case in conjunction with intracardiac device therapy. PMID- 22946405 TI - Isolation of Staphylococcus simulans from dermatitis in a captive African pygmy hedgehog. AB - Staphylococcus simulans, a coagulase-negative staphylococcal species, can cause several diseases in humans and animals. This report describes a case of dermatosis characterized by broad, well-circumscribed hyperkeratosis and alopecia on the back of a household pygmy hedgehog (Erinaceous albiventris). Quills and exudates were studied by microscopy. The microscopic examination of the exudates collected from the lesion revealed several leukocytes and numerous gram-positive cocci. An aerobic bacterial culture revealed overgrowth of the same gram-positive bacteria. The bacterium was identified as S. simulans by polymerase chain reaction amplification and direct sequencing targeted to the 16S ribosomal RNA gene. This report is the first to show that S. simulans could be related to the dermatitis of hedgehogs. PMID- 22946406 TI - Abomasal impaction in captive bongo (Tragelaphus eurycerus). AB - Fatal abomasal impaction, often combined with omasal impaction, was diagnosed in 11 bongo (Tragelaphus eurycerus) from five different zoologic collections in the United States between 1981 and 2009. Nine of 11 cases occurred in young females (10 mo-7 yr old) and typical clinical signs prior to diagnosis or death included partial or complete anorexia, dehydration, and scant fecal production. Although the clinical histories in several of the earlier cases are incomplete, clinical signs were known to begin shortly after an anesthetic event in five of 11 bongo (45%). Pedigree analysis indicates that affected bongo were descendants of multiple founders and not from a single family line, suggesting that the development of abomasal impaction is not a strictly inheritable trait. Treatment, when attempted, was variable and included abomasotomy and removal of impacted ingesta, drug therapy (prokinetic drugs, nonsteroidal anti-inflammatories, antimicrobials), fluid therapy, and administration of oral lubricants or intralesional stool softeners. Based on the outcomes in the cases presented here, the prognosis for bongo with abomasal impaction is considered poor to grave. PMID- 22946407 TI - Alternative therapeutic options for medical management of epilepsy in apes. AB - Phenobarbital has been the primary antiepileptic drug used in primates, but the dosage required for seizure control is frequently associated with significant side effects. Newer antiepileptic drugs and adjunctive therapies currently being used in human medicine provide additional options for treatment of nonhuman primates. This report describes different drug regimes used for control of epileptic seizures in apes at the Milwaukee County Zoo (Milwaukee, Wisconsin, U.S.A.), including the addition of acetazolamide to phenobarbital, levetiracetam, carbamazepine, and the use of extended cycle oral contraceptives to assist seizure control in female apes with catamenial epilepsy. PMID- 22946408 TI - Evaluation of parenteral drugs for anesthesia in the blue crab (Callinectes sapidus). AB - The objective of this study was to evaluate the efficacy and safety of several parenteral anesthetics in blue crabs (Callinectes sapidus). Thirty-one animals were administered one or more of the following drugs by injection into the hemolymph (i.v.) through an arthrodial membrane: etomidate, ketamine, lidocaine, pentobarbital, propofol, tiletamine-zolazepam, xylazine, and ketamine-xylazine. A subset of crabs received intracardiac ketamine. Etomidate had no effect. Lidocaine effects were ultrashort (<3 min). Pentobarbital had prolonged inductions (2 min) and often caused violent excitement and poor anesthesia. Propofol induced light anesthesia accompanied by distress and limb autotomy. Inductions with ketamine, xylazine, tiletamine-zolazepam, and ketamine-xylazine were usually fast (<60 sec). Their anesthetic effects were generally very short (5-10 min) but predictable, smooth, and with good muscle relaxation. The latter two protocols induced a deep plane of anesthesia more consistently but also more significant bradycardia. Intracardiac ketamine injection was fatal in four of five crabs. In conclusion, the anesthetic protocols were considered unsuitable for prolonged anesthesia. However, if very short-term anesthesia is desired, then tiletamine-zolazepam or ketamine-xylazine is recommended. Further studies are indicated to identify a safe anesthetic protocol of longer duration in C. sapidus as well as in other crab species. PMID- 22946409 TI - Bilateral ocular abnormalities in a wild stranded harp seal (Phoca groenlandica) suggestive of anterior segment dysgenesis and persistent hyperplastic primary vitreous. AB - A male yearling harp seal (Phoca groenlandica) stranded and was brought to Mystic Aquarium & Institute for Exploration's Seal Rescue and Rehabilitation Center. The seal presented with a bilateral pendular vertical nystagmus, negative menace response, and a positive palpebral response. Ophthalmological examination by slit lamp biomicroscopy revealed perilimbal corneal edema, excessive iridal surface structures, pupils that appeared to be shaped improperly (dyscoria), and suspected cataracts. Attempts to dilate the pupils with both dark-lighted conditions and repeated dosages of 10% phenylephrine and 1% atropine ophthalmic solution in each eye (OU) were unsuccessful. Ocular ultrasonography findings suggested bilateral cataracts with flattened anterior-posterior (A-P) diameter and possible persistent hyperplastic primary vitreous. It is possible that these structural congenital abnormalities could produce further ocular complications for this seal including uveitis, secondary glaucoma, retinal detachment, and/or vitreal hemorrhage in the future. This case demonstrates the importance of a thorough ophthalmological examination in stranded wild animals, especially if their symptoms appear neurological. PMID- 22946410 TI - Pancreatic atrophy due to zinc toxicosis in two African ostriches (Struthio camelus). AB - Two of three captive adult African ostriches exhibited inappetance and weakness. In spite of treatment, the two birds were euthanized because of lack of clinical improvement. Postmortem examination demonstrated exocrine pancreatic degeneration, necrosis, and atrophy. Grossly, one ostrich had a markedly diminished pancreatic mass. Histologically, there was massive pancreatic acinar (exocrine) atrophy, marked interstitial fibrosis, and tubular complex formation in one animal, and the second ostrich had active pancreatic acinar necrosis. Toxicologic testing revealed markedly elevated liver zinc levels in the first two birds, whereas the third ostrich had normal serum levels of zinc and continues without apparent disease. This form of zinc toxicosis, while previously reported in different avian species, has been only rarely described in ratites. PMID- 22946411 TI - Penicilliosis in an African grey parrot (Psittacus erithacus). AB - Penicillium mycosis, or penicilliosis, is rare in animals. This report describes the clinical signs and pathological, immunohistochemical, and biomolecular findings in a case of avian penicilliosis in a Congo African grey parrot. On gross necropsy, pyogranulomatous changes were identified in the lung, liver, and kidney. Histopathology demonstrated periodic acid Schiff-(PAS) and Grocott positive hyphae in these tissues. Immunohistochemistry confirmed the genus of the fungus and polymerase chain reaction (PCR) confirmed a high homology with Penicillium chrysogenum. PMID- 22946412 TI - Prevalence of Salmonella and Yersinia in free-living pied flycatchers (Ficedula hypoleuca) in central Spain. AB - Salmonella and Yersinia are important enteropathogens in poultry and can affect birds of all ages, including embryos. These food-borne zoonotic enteropathogens are of great economic and medical concern worldwide and are intensely studied in poultry. Information regarding the prevalence of these bacteria in wild birds is scarce and biased toward avian species ecologically linked to humans, which have often been incriminated as both reservoirs and disseminators of these enteropathogens. The prevalence of Salmonella and Yersinia recovered from both the feces and eggs in a population of female pied flycatchers (Ficedula hypoleuca) breeding in nest-boxes in central Spain was evaluated. Salmonella arizonae was recovered from the feces of one female but was not recovered from eggs. Yersinia was not detected in either the feces or eggs. These results may suggest that Salmonella and Yersinia may be uncommon in this population studied and may indicate that these birds are unlikely reservoirs of Salmonella and Yersinia. PMID- 22946413 TI - Surgical amputation of a digit and vacuum-assisted-closure (V.A.C.) management in a case of osteomyelitis and wound care in an eastern black rhinoceros (Diceros bicornis michaeli). AB - A 14-yr-old female eastern black rhinoceros (Diceros bicornis michaeli) presented with progressive suppurative osteomyelitis in her left hind lateral toe. beta Hemolytic Streptococcus sp. was isolated. The animal was treated with multiple systemic antibiotics, and topical wound cleansing. Repeated debridements and nail trimmings were performed for 5 mo prior to electing amputation. The toe was surgically amputated under general anesthesia between the first and second phalanges. Analgesia was diffused into the wound topically via a catheter and elastomeric pump. The open amputation site was covered with adherent drapes and a negative-pressure wound therapy device provided vacuum-assisted closure (V.A.C.) for 72 hr. Three months later this animal developed a deep dermal ulcer on the lateral aspect of the right hind limb, at the level of the stifle. Methicillin resistant Staphylococcus aureus was isolated. The wound was managed by initial daily lavage, followed by 1 mo of V.A.C. therapy, with 72 hr between dressing changes. Clinically, this therapy expedited the formation of healthy granulation tissue and overall healing was accelerated. The animal tolerated the machine and bandage changes well via operant conditioning. The use of negative-pressure wound therapy appeared to shorten time to resolution of slow-healing wounds in black rhinoceros. PMID- 22946414 TI - Chemotherapeutic treatment for leukemia in a bearded dragon (Pogona vitticeps). AB - A 4.5-yr-old, captive-bred, male bearded dragon (Pogona vitticeps) presented for lethargy, anorexia, and increased mucoid salivation with upper respiratory clicks. Diagnostics were declined and the bearded dragon was prescribed ceftazidime 20 mg/kg i.m. q 72 hr. The patient presented again 1 wk later with a marked monocytosis, heterophilia, and lymphocytosis, and a clinical diagnosis of chronic monocytic leukemia was made. Chemotherapy with cytosine arabinoside (100 mg/m2 over 48 hr i.v.) was initiated. Forty-four hours into the treatment the dragon became acutely unresponsive and died within 1 hr. Adverse effects as a result of i.v. cytosine arabinoside therapy were not identified despite previous reports suggestive that the drug induces renal failure. PMID- 22946415 TI - Occurrence and molecular diagnosis of Cryptosporidium serpentis in captive snakes in Sao Paulo, Brazil. AB - The present study aimed to determine whether Cryptosporidium oocysts were present in stools from captive snakes at Fundacao Parque Zoologico (Zoological Park Foundation) in Sao Paulo, Brazil. Two collections were performed; the first in July 2008 and the second in February 2009. Fecal samples were collected from 74 enclosures that housed 101 individuals of 23 snake species. The stool specimens collected from 16 out of the 74 enclosures (21.6%) contained Cryptosporidium spp. oocysts; all of them were confirmed as Cryptosporidium serpentis, using molecular techniques. Only in three (18.7%) out of the 16 enclosures with positive samples were there animals with clinical signs compatible with infection by C. serpentis, such as regurgitation and significant progressive weight loss. From the results, it was concluded that diagnostic examinations need to be performed periodically, even on clinically healthy animals, as a preventive measure. PMID- 22946416 TI - Nasal osteosarcoma and interstitial cell tumor in a Vancouver Island marmot (Marmota vancouverensis). AB - A 6-yr-old male Vancouver Island marmot (Marmota vancouverensis) presented for poor hibernation, weight loss, and symmetric trunk alopecia. An abdominal interstitial cell tumor was identified and surgically removed. Serum levels of estrogen were markedly elevated before surgery and decreased after tumor removal, indicating that the tumor had been functionally secretory. Nine months later, the marmot presented with respiratory stridor. A large boney nasal mass was identified radiographically and evaluated by computed tomography (CT) prior to surgical debulking. The marmot did not recover from anesthesia. Pathologic findings included a nasal osteosarcoma with lysis of the cribriform plate, and endocardial fibrosis with degenerative changes within the adjoining myocardium. This is the first known report of nasal osteosarcoma and interstitial tumor in a Vancouver Island marmot. PMID- 22946417 TI - Vaginal calculi in a juvenile harbor porpoise (Phocoena phocoena). AB - A large number of vaginal calculi were observed in a juvenile harbor porpoise (Phocoena phocoena) stranded on Whidbey Island, Washington. Vaginal calculi have been reported in other species, but not in harbor porpoises. Histologic examination of the urinary tract revealed mucosal hyperplasia most likely attributable to the calculi. The calculi were numerous (>30), composed completely of struvite (magnesium ammonium phosphate), and on culture yielded Enterococcus spp., a bacterium not usually associated with struvite urolith formation in domestic animals. The only other lesion of note was severe hepatic lipidosis, and its relationship to the development of the vaginal calculi is unknown. PMID- 22946418 TI - Systemic mucormycosis in a hooded seal (Cystophora cristata). AB - A 4-yr-old male captive hooded seal (Cystophora cristata), previously diagnosed as hypothyroid, died after a 3-wk period of lethargy and inappetance despite treatment that included intramuscular administration of antibiotics and multivitamins. Gross pathologic findings included extensive muscle necrosis over the left flank, an underlying necrotic iliac lymph node, two necrotic pulmonary masses and a necrotic bronchial lymph node. Routine cultures yielded a number of bacterial isolates and a heavy pure fungal growth from the necrotic iliac lymph node; wet preparations of which revealed sporangiophores typical of Mucor sp. Histopathology of necrotic muscle, pulmonary lesions and bronchial and iliac lymph nodes revealed necrosis with a marked pyogranulomatous and eosinophilic inflammatory cell infiltrate and fungal hyphae consistent with a Zygomycete species. This is believed to be the first report of systemic mucormycosis in a pinniped likely to have originated from an injection site reaction. PMID- 22946419 TI - Hemoplasmas in wild canids and felids in Brazil. AB - Hemotropic mycoplasmas, epicellular erythrocytic bacterial parasites lacking a cell wall, are the causative agents of infectious anemia in numerous mammalian species. The presence of hemotropic mycoplasmas in blood samples of neotropical and exotic wild canids and felids from Brazilian zoos were recorded using molecular techniques. Blood samples were collected from 146 Brazilian wild felids, 19 exotic felids, 3 European wolves (Canis lupus), and from 97 Brazilian wild canids from zoos in the Brazilian states of Sao Paulo and Mato Grosso and the Federal District. Using conventional polymerase chain reaction (PCR), this work found 22 (13%) wild felids positive to Candidatus Mycoplasma haemominutum [4 jaguars (Panthera onca); 3 pumas (Puma concolor); 10 ocelots (Leopardus pardalis); 2 jaguarondis (Puma yagouaroundi); and 3 little spotted cats (Leopardus tigrinus)]. Only one little spotted cat (Leopardus tigrinus) was positive to Mycoplasma haemofelis, and none was positive to Candidatus Mycoplasma turicensis. Two bush dogs (Speothos venaticus) were positive for a Mycoplasma sp. closely related to Candidatus Mycoplasma haematoparvum, and two European wolves were positive for a Mycoplasma sp. closely related to Candidatus Mycoplasma haemominutum. This is the first study regarding the molecular detection of hemotropic mycoplasmas in wild canids. PMID- 22946420 TI - Surgical resolution of an avulsion fracture of the peroneus tertius origin in a giraffe (Giraffa camelopardalis reticulata). AB - A 4-mo-old, 185-kg male giraffe (Giraffa camelopardalis reticulata) was presented due to stifle effusion and lameness of 3-wk duration. Radiographs revealed a fracture of the extensor fossa of the lateral trochlear ridge of the femur at the origin of the peroneus tertius. Under anesthesia, dysfunction of the reciprocal apparatus was documented by flexing the stifle while the tarsus remained extended. An avulsion fracture of the origin of the peroneus tertius and extensor digitorum longus muscle was diagnosed. An exploratory arthroscopy of the femorotibial joint was followed by arthrotomy to excise the large bone fragment from its soft tissue attachments. Because of the fractious temperament of the animal, postoperative care was restricted to stall rest for 3 mo, and no postoperative complications arose. Only a mild residual lameness remained by 6 mo after surgery. PMID- 22946421 TI - Cardiac tamponade in largemouth bass (Micropterus salmoides). AB - A public aquarium with a 4-mo history of occasional fish mortalities submitted for necropsy an adult female largemouth bass (Micropterus salmoides) that died unexpectedly. Gross necropsy revealed that the pericardial cavity was markedly distended with partially coagulated blood. Examination of the heart revealed multiple nodular masses in the area of the atrium and two small perforations on the surface of one of the nodular masses. Histopathologic exam of the atrium revealed severe fibrinonecrotic endocarditis and transmural myocarditis with intralesional bacteria. A pure culture of Edwardsiella tarda was obtained from culture of posterior kidney and spleen. An area of stagnant water that may serve as the source of E. tarda was identified, and steps to rectify this problem were taken. Low-level supersaturation was also a significant stressor; the source of the supersaturation was not identified. To our knowledge, this is the first report of cardiac tamponade in a largemouth bass. PMID- 22946422 TI - Natural Fasciola hepatica infection in nutria (Myocastor coypus) in Uruguay. AB - Fascioliasis, the zoonotic disease caused by the trematode Fasciola hepatica, is expanding worldwide, with a 17 million people at risk. Rodents, often recognized as a major source of zoonotic diseases, are affected by F. hepatica, with some species playing important roles in the disease epidemiology. The case reported here in a nutria or kiya (Myocastor coypus) is the first documented case of F. hepatica in this species in Uruguay. Parasitic burden and total egg production detected are markedly higher than reported previously for this species, confirming its potential role as an effective reservoir and disseminator of liver flukes. Although further research is needed, nutria should be considered when designing effective control programs for fascioliasis. PMID- 22946423 TI - Gastric spiruridiasis caused by Mastophorus muris in a captive population of striped possums (Dactylopsila trivirgata). AB - Striped possums (Dactylopsila trivirgata) are small arboreal marsupials for which limited medical information is known. Mastophorus muris is a gastric spirurid nematode of rodents that uses insects as intermediate hosts. Three cases of gastric spiruridiasis caused by M. muris in captive striped possums are reported for the first time. Diagnosis was made by the presence of adult nematodes in regurgitant and at necropsy. Low numbers of nematode ova shed intermittently in possum feces made evaluation of treatment success difficult. No histopathologic abnormalities were identified in one case. Control of M. muris in captive possum colonies may be achieved by interrupting the life cycle of the parasite. PMID- 22946424 TI - Baseline levels of trace metals in blood of captive Asian elephants (Elephas maximus). AB - Whole blood from 33 healthy captive Asian elephants (Elephas maximus) was analyzed for 12 trace elements: aluminum, chromium, manganese, cobalt, nickel, copper, zinc, arsenic, selenium, cadmium, mercury, and lead for the purpose of estimating preliminary baseline population parameters for these minerals. Metals were quantified by inductively coupled plasma mass spectroscopy. Baseline ranges for all animals and for all trace elements were comparable to normal concentrations reported in other species. This is the first report of normal trace element levels in the blood of captive elephants. PMID- 22946425 TI - The gap between cell and animal models: nanoparticle drug-delivery development and characterization using microtissue models. PMID- 22946426 TI - Inhaled gene therapy in lung cancer: "as for the future, our task is not to foresee it, but to enable it". PMID- 22946427 TI - Interview with Dr You Han Bae: ligand-mediated versus 'passive' targeting approaches in nanoparticle oncology research. PMID- 22946428 TI - Microneedles 2012. AB - The second international conference on Microneedles was held on 13-15 May 2012 in Cork, Republic of Ireland, following on from a successful first meeting at the Georgia Institute of Technology (GA, USA) in May 2010. The meeting showcased the latest international developments in microneedle technology and applications. The gathering provided a platform to facilitate interdisciplinary communications and new collaborations for delegates from academic, industrial and clinical backgrounds. The meeting opened with a half-day short course on microneedle technology and applications, followed by invited lectures and poster presentations over 2 days, divided into sessions such as 'Design and technology- solid and hollow microneedles', 'Vaccine delivery' and 'Drug delivery'. This conference report summarizes the keynote and invited speaker lectures from leaders in the field such as Mark Prausnitz (Georgia Institute of Technology) and Mark Kendall (University of Queensland, Australia). PMID- 22946429 TI - Dendritic nanoparticles: the next generation of nanocarriers? AB - Dendritic polymers have attracted a great deal of scientific interest due to their well-defined unique structure and capability to be multifunctionalized. Here we present a comprehensive overview of various dendrimer-based nanomaterials that are currently being investigated for therapeutic delivery and diagnostic applications. Through a critical review of the old and new dendritic designs, we highlight the advantages and disadvantages of these systems and their structure biological property relationships. This article also focuses on the major challenges facing the clinical translation of these nanomaterials and how these challenges are being (or should be) addressed, which will greatly benefit the overall progress of dendritic materials for theranostics. PMID- 22946431 TI - Peptide therapeutics: it's all in the delivery. AB - Recent work has demonstrated that the route of administration affects the pharmacokinetics and biological activity of peptides. For example, the physiological profile of insulin consists of basal and prandial components with a small-scale oscillatory element. Insulin is used more efficiently when the pharmacokinetic profile mimics features of physiological release. Noninvasive administration of insulin by oral, transdermal, nasal and pulmonary routes resembles the relatively sharp peak and short duration of exposure of prandial release. The route of administration per se, can affect the response by avoiding first-pass metabolism or perhaps altering the timing in which the peptide reaches different sets of receptors. GLP-I delivered by injection and inhalation produces different side effect profiles. Nonclinical studies on two potential treatments for obesity, oxyntomodulin and PYY 3-36, are also presented to illustrate the relationship between exposure and effect as functions of route of administration. PMID- 22946432 TI - Mesenchymal stem cells in drug/gene delivery: implications for cell therapy. AB - Stem cells have been therapeutically utilized in replacement of hematopoetic cells for decades. This is in contrast to the recent emergence of adult stem cells as, perhaps, safe and beneficial therapeutics for multiple diseases and disorders. In particular, mesenchymal stem cells (MSCs) are currently used in multiple human clinical trials. Although MSCs are ubiquitous, bone marrow, umbilical cord and adipose tissue are the sources where MSCs are isolated for research and clinical application. MSCs were thought to be mesodermal due to the initial reports showing their differentiation into specialized mesodermal cells such as chondrocytes. However, it now appears that MSCs might be neuroectodermal in origin. Thus far, there is no evidence of in vivo transformation of MSCs. However, it is too early to prove or disprove that MSCs can be transformed in vivo in clinical trials. MSCs display immunosuppressive properties when placed in a milieu of inflammatory mediators. This phenotype makes MSCs easily available for therapies as 'off-the-shelf cells. Additionally, MSCs express chemotactic receptors, thereby allowing them to migrate to sites of tissue injury. This latter property has proven useful in the embodiment of MSCs as cellular vehicles to deliver targeted therapeutics to precise regions. The MSCs would typically harbor a prodrug or ectopically express a therapeutic gene to be delivered at a targeted site. This approach has been utilized in a number of different indications requiring precise therapeutic delivery, specifically cancer, cardiovascular disorders and neurodegenerative diseases. Combined with their immune-privileged status, safe clinical profile and low tumorigenicity, MSCs offer vast potential to benefit patients with serious diseases, for which limited treatment options exist. PMID- 22946433 TI - Recent progress in the application of nanotechnology for prevention and treatment of human papillomavirus infection. AB - Human papillomavirus (HPV) causes benign and malignant infections of the anogenital tract. Cervical cancer, caused by high-risk HPV types 16, 18, 31, 33, 35, 45, 56 and 58, is the second most common cancer in women and the fifth most common cancer overall. Prevention and treatment of HPV infection may be revolutionized using nanotechnology tools such as vaccines based on virus-like particles and nanoscale drug-delivery systems. Advances in both virus-like particle design and noninvasive delivery of antiviral protein drugs, such as IFNalpha, may provide new opportunities to take on the challenge of global elimination of HPV infections. Biphasic vesicle cream formulation, representing a new class of dermal delivery system for protein drugs, is an alternative to injectable dosage form to deliver IFNalpha for the treatment of HPV infections, showing efficacy in low-grade squamous epithelical lesions of the cervix. PMID- 22946430 TI - Targeting malignant mitochondria with therapeutic peptides. AB - The current status of peptides that target the mitochondria in the context of cancer is the focus of this review. Chemotherapy and radiotherapy used to kill tumor cells are principally mediated by the process of apoptosis that is governed by the mitochondria. The failure of anticancer therapy often resides at the level of the mitochondria. Therefore, the mitochondrion is a key pharmacological target in cancer due to many of the differences that arise between malignant and healthy cells at the level of this ubiquitous organelle. Additionally, targeting the characteristics of malignant mitochondira often rely on disruption of protein- protein interactions that are not generally amenable to small molecules. We discuss anticancer peptides that intersect with pathological changes in the mitochondrion. PMID- 22946434 TI - In-situ molecular-level elucidation of organofluorine binding sites in a whole peat soil. AB - The chemical nature of xenobiotic binding sites in soils is of vital importance to environmental biogeochemistry. Interactions between xenobiotics and the naturally occurring organic constituents of soils are strongly correlated to environmental persistence, bioaccessibility, and ecotoxicity. Nevertheless, because of the complex structural and chemical heterogeneity of soils, studies of these interactions are most commonly performed indirectly, using correlative methods, fractionation, or chemical modification. Here we identify the organic components of an unmodified peat soil where some organofluorine xenobiotic compounds interact using direct molecular-level methods. Using (19)F->(1)H cross polarization magic angle spinning (CP-MAS) nuclear magnetic resonance (NMR) spectroscopy, the (19)F nuclei of organofluorine compounds are used to induce observable transverse magnetization in the (1)H nuclei of organic components of the soil with which they interact after sorption. The observed (19)F->(1)H CP-MAS spectra and dynamics are compared to those produced using model soil organic compounds, lignin and albumin. It is found that lignin-like components can account for the interactions observed in this soil for heptafluoronaphthol (HFNap) while protein structures can account for the interactions observed for perfluorooctanoic acid (PFOA). This study employs novel comprehensive multi-phase (CMP) NMR technology that permits the application of solution-, gel-, and solid state NMR experiments on intact soil samples in their swollen state. PMID- 22946435 TI - PNA FIT-probes for the dual color imaging of two viral mRNA targets in influenza H1N1 infected live cells. AB - Fluorogenic hybridization probes that allow RNA imaging provide information as to how the synthesis and transport of particular RNA molecules is orchestrated in living cells. In this study, we explored the peptide nucleic acid (PNA)-based FIT probes in the simultaneous imaging of two different viral mRNA molecules expressed during the replication cycle of the H1N1 influenza A virus. PNA FIT probes are non-nucleotidic, nonstructured probes and contain a single asymmetric cyanine dye which serves as a fluorescent base surrogate. The fluorochrome acts as a local intercalator probe and reports hybridization of target DNA/RNA by enhancement of fluorescence. Though multiplexed hybridization probes are expected to facilitate the analysis of RNA expression, there are no previous reports on the dual color imaging of two different viral mRNA targets. In this work, we developed a set of two differently colored PNA FIT-probes that allow the spectrally resolved imaging of mRNA coding for neuraminidase (NA) and matrix protein 1 (M1); proteins which execute distinct functions during the replication of the influenza A virus. The probes are characterized by a wide range of applicable hybridization temperatures. The same probe sequence enabled live-cell RNA imaging (at 37 degrees C) as well as real-time PCR measurements (at 60 degrees C annealing temperature). This facilitated a comprehensive analysis of RNA expression by quantitative (qPCR) and qualitative (imaging) means. Confocal laser scanning microscopy showed that the viral-RNA specific PNA FIT-probes neither stained noninfected cells nor cells infected by a control virus. The joint use of differently colored PNA FIT-probes in this feasibility study revealed significant differences in the expression pattern of influenza H1N1 mRNAs coding for NA or M1. These experiments provide evidence for the usefulness of PNA FIT-probes in investigations on the temporal and spatial progression of mRNA synthesis in living cells for two mRNA species. PMID- 22946436 TI - Engagement in philosophical dialogue facilitates children's reasoning about subjectivity. AB - Theories of learning have long emphasized the essential role of social factors in the development of early reasoning abilities. More recently, it has been proposed that the presentation of conflicting perspectives may facilitate young children's understanding of knowledge claims as potentially subjective-one of many possible representations of the world. This development in epistemological understanding has been proposed to be an important determinant of academic performance and is highly correlated with the ability to understand and produce sound argumentation in adolescents and adults. In a longitudinal study of children 7-8 years old, we assessed the effects of a 3-month philosophy class designed to engage children in dialogic interaction with peers. We examined the influence of this intervention on children's epistemological understanding and argumentation skills in 4 domains of knowledge: aesthetic, value, social, and physical. Participation in dialogic interaction in an elementary school classroom improved children's ability to construct their own and opposing arguments across domains and facilitated reasoning about the subjectivity of knowledge in the value domain. PMID- 22946437 TI - Social-cognitive processes in preschoolers' selective trust: three cultures compared. AB - Research on preschoolers' selective learning has mostly been conducted in English speaking countries. We compared the performance of Turkish preschoolers (who are exposed to a language with evidential markers), Chinese preschoolers (known to be advanced in executive skills), and English preschoolers on an extended selective trust task (N = 144). We also measured children's executive function skills and their ability to attribute false belief. Overall we found a Turkish (rather than a Chinese) advantage in selective trust and a relationship between selective trust and false belief (rather than executive function). This is the 1st evidence that exposure to a language that obliges speakers to state the sources of their knowledge may sensitize preschoolers to informant reliability. It is also the first demonstration of an association between false belief and selective trust. Together these findings suggest that effective selective learning may progress alongside children's developing capacity to assess the knowledge of others. PMID- 22946438 TI - The typical developmental trajectory of social and executive functions in late adolescence and early adulthood. AB - Executive functions and social cognition develop through childhood into adolescence and early adulthood and are important for adaptive goal-oriented behavior (Apperly, Samson, & Humphreys, 2009; Blakemore & Choudhury, 2006). These functions are attributed to frontal networks known to undergo protracted maturation into early adulthood (Barker, Andrade, Morton, Romanowski, & Bowles, 2010; Lebel, Walker, Leemans, Phillips, & Beaulieu, 2008), although social cognition functions are also associated with widely distributed networks. Previously, nonlinear development has been reported around puberty on an emotion match-to-sample task (McGivern, Andersen, Byrd, Mutter, & Reilly, 2002) and for IQ in midadolescence (Ramsden et al., 2011). However, there are currently little data on the typical development of social and executive functions in late adolescence and early adulthood. In a cross-sectional design, 98 participants completed tests of social cognition and executive function, Wechsler Abbreviated Scale of Intelligence (Wechsler, 1999), Positive and Negative Affect Schedule (Watson, Clark, & Tellegen, 1988), Hospital Anxiety and Depression Scale (Zigmond & Snaith, 1983), and measures of pubertal development and demographics at ages 17, 18, and 19. Nonlinear age differences for letter fluency and concept formation executive functions were found, with a trough in functional ability in 18-year-olds compared with other groups. There were no age group differences on social cognition measures. Gender accounted for differences on 1 scale of concept formation, 1 dynamic social interaction scale, and 2 empathy scales. The clinical, developmental, and educational implications of these findings are discussed. PMID- 22946439 TI - Matters of accuracy and conventionality: prior accuracy guides children's evaluations of others' actions. AB - Studies show that children trust previously reliable sources over previously unreliable ones (e.g., Koenig, Clement, & Harris, 2004). However, it is unclear from these studies whether children rely on accuracy or conventionality to determine the reliability and, ultimately, the trustworthiness of a particular source. In the current study, 3- and 4-year-olds were asked to endorse and imitate one of two actors performing an unfamiliar action, one actor who was unconventional but successful and one who was conventional but unsuccessful. These data demonstrated that children preferred endorsing and imitating the unconventional but successful actor. Results suggest that when the accuracy and conventionality of a source are put into conflict, children may give priority to accuracy over conventionality when estimating the source's reliability and, ultimately, when deciding who to trust. PMID- 22946440 TI - Formation of alpha-helical nanofibers by mixing beta-structured and alpha-helical coiled coil peptides. AB - The helical coiled coil is a well-studied folding motif that can be used for the design of nanometer-sized bioinspired fibrous structures with potential applications as functional materials. A two-component system of coiled coil based model peptides is investigated, which forms, under acidic conditions, uniform, hundreds of nanometers long, and ~2.6 nm thick trimeric alpha-helical fibers. In the absence of the other component and under the same solvent conditions, one model peptide forms beta-sheet-rich amyloid fibrils and the other forms stable trimeric alpha-helical coiled coils, respectively. These observations reveal that the complementary interactions driving helical folding are much stronger here than those promoting the intermolecular beta-sheet formation. The results of this study are important in the context of amyloid inhibition but also open up new avenues for the design of novel fibrous peptidic materials. PMID- 22946441 TI - Exploring electrochemical windows of room-temperature ionic liquids: a computational study. AB - Room-temperature ionic liquids (RTILs) are regarded as green solvents due to their low volatility, low flammability, and thermal stability. RTILs exhibit wide electrochemical windows, making them prime candidates as media for electrochemically driven reactions such as electro-catalysis and electro-plating for separations applications. Therefore, understanding the factors determining edges of the electrochemical window, the electrochemical stability of the RTILs, and the degradation products is crucial to improve the efficiency and applicability of these systems. We present here computational investigations of the electrochemical properties of a variety of RTILs covering a wide range of electrochemical windows. We proposed four different approaches with different degrees of approximation and computational cost from gas-phase calculations to full explicit solvation models. It was found that, whereas the simplest model has significant flaws in accuracy, implicit and explicit solvent models can be used to reliably predict experimental data. The general trend of electrochemical windows of the RTILs studied is well reproduced, showing that it increases in the order of imidazolium < ammonium < pyrrolidinium < phosphonium giving confidence to the methodology presented to use it in screening studies of ionic liquids. PMID- 22946442 TI - Baicalin protects human skin fibroblasts from ultraviolet A radiation-induced oxidative damage and apoptosis. AB - Reactive oxygen species (ROS) are an important factor in the development of skin photodamage after ultraviolet A (UVA) radiation. A flavonoid antioxidant, baicalin, can selectively neutralize super-oxide anion (O(2)(-)) while having no significant effect on (*)OH. Fibroblasts are a key component of skin dermis. In the present study, we investigated the protective effects of baicalin on human skin fibroblasts (HSFs) under UVA induced oxidative stress. Fluorescence microscopy and flow cytometry were used to assay the intracellular O(2)(-), NO, ROS concentrations and the mitochondrial membrane potential. Cell viability was determined using the Cell Counting Kit-8 (CCK-8). The concentrations of cellular MDA, SOD, GSH, T-AOC, and 8-oxo-dG were also measured. Cellular apoptosis was measured by flow cytometry and caspase-3 detection. The results revealed that UVA radiation could cause oxidative stress and apoptosis in HSFs. Interestingly, the use of baicalin after UVA radiation significantly reduced the level of intracellular O(2)(-), NO, and ROS, stabilized the mitochondrial membrane potential, and attenuated production of MDA and 8-oxo-dG. These efficiently enhanced the antioxidative defense system and protected the HSFs from subsequent oxidative stress damage and apoptosis. In other words, baicalin decreased the excessive generation of intracellular ROS and NO, and elevated the cellular antioxidative defense, which eventually mitigate the UVA-induced apoptosis. Based on our results, baicalin may have applications in the treatment of skin photodamage caused by UVA irradiation. PMID- 22946443 TI - Children apply principles of physical ownership to ideas. AB - Adults apply ownership not only to objects but also to ideas. But do people come to apply principles of ownership to ideas because of being taught about intellectual property and copyrights? Here, we investigate whether children apply rules from physical property ownership to ideas. Studies 1a and 1b show that children (6-8 years old) determine ownership of both objects and ideas based on who first establishes possession of the object or idea. Study 2 shows that children use another principle of object ownership, control of permission-an ability to restrict others' access to the entity in question-to determine idea ownership. In Study 3, we replicate these findings with different idea types. In Study 4, we determine that children will not apply ownership to every entity, demonstrating that they do not apply ownership to a common word. Taken together, these results suggest that, like adults, children as young as 6 years old apply rules from ownership not only to objects but to ideas as well. PMID- 22946444 TI - Diffusion-free mediator based miniature biofuel cell anode fabricated on a carbon MEMS electrode. AB - We report on the functionalization of a micropatterned carbon electrode fabricated using the carbon-MEMS process for its use as a miniature diffusion free glucose oxidase anode. Carbon-MEMS based electrodes offer precise manufacturing control on both the micro- and nanoscale and possess higher electron conductivity than redox hydrogels. However, the process involves pyrolysis in a reducing environment that renders the electrode surface less reactive and introduction of a high density of functional groups becomes challenging. Our functionalization strategy involves the electrochemical oxidation of amine linkers onto the electrode. This strategy works well with both aliphatic and aryl linkers and uses stable compounds. The anode is designed to operate through mediated electron transfer between 2,5-dihydroxybenzaldehyde (DHB) based redox mediator and glucose oxidase enzyme. The electrode was first functionalized with ethylene diamine (EDA) to serve as a linker for the redox mediator. The redox mediator was then grafted through reductive amination, and attachment was confirmed through cyclic voltammetry. The enzyme immobilization was carried out through either adsorption or attachment, and their efficiency was compared. For enzyme attachment, the DHB attached electrode was functionalized again through electro-oxidation of aminobenzoic acid (ABA) linker. The ABA functionalization resulted in reduction of the DHB redox current, perhaps due to increased steric hindrance on the electrode surface, but the mediator function was preserved. Enzyme attachment was then carried out through a coupling reaction between the free carboxyl group on the ABA linker and the amine side chains on the enzyme. The enzyme incubation for both adsorption and attachment was done either through a dry spotting method or wet spotting method. The dry spotting method calls for the evaporation of enzyme droplet to form a thin film before sealing the electrode environment, to increase the effective concentration of the enzyme on the electrode surface during incubation. The electrodes were finally protected with a gelatin based hydrogel film. The anode half-cell was tested using cyclic voltammetry in deoxygenated phosphate buffer saline solution pH 7.4 to minimize oxygen interference and to simulate the pH environment of the body. The electrodes that yielded the highest anodic current were prepared by enzyme attachment method with dry spotting incubation. A polarization response was generated for this anodic half-cell and exhibits operation close to maximum efficiency that is limited by the mass transport of glucose to the electrode. PMID- 22946445 TI - Infrared spectroscopy of the mass 31 cation: protonated formaldehyde vs methoxy. AB - Pulsed discharges containing methanol or ethanol produce ions having the nominal formula [C,H(3),O](+), i.e. m/z = 31. Similar ions resulting from electron impact ionization in mass spectrometers are long recognized to have either the CH(2)OH(+) protonated formaldehyde or CH(3)O(+) methoxy cation structures. The H(2)OCH(+) oxonio-methylene structure has also been suggested by computational chemistry. To investigate these structures, ions are expanded in a supersonic beam, mass-selected in a time-of-flight spectrometer, and studied with infrared laser photodissociation spectroscopy. Sharp bands in the O-H and C-H stretching and fingerprint regions are compared to computational predictions for the three isomeric structures and their vibrational spectra. Protonated formaldehyde is the most abundant isomer, but methoxy is also formed with significant abundance. The branching ratio of these two ion species varies with precursors and formation conditions. PMID- 22946446 TI - Cucurbituril slippage: cations as supramolecular lubricants. AB - The dethreading rate of a polyaminated axle flanked by two benzo-15-crown-5 stoppers from the cavity of Cucurbit[7]uril (CB[7]) was enhanced by up to 500 times in the presence of aqueous metallic and organic cations. Cations likely stabilize the highest energy transition state of the dethreading process by interacting with both crown ether and CB[7] units. PMID- 22946447 TI - Experimental-like affinity constants and enantioselectivity estimates from flexible docking. AB - Experimental-like affinity constants and enantioselectivity estimates, not predicted so far computationally, were obtained using a novel flexible modeling/docking combined strategy. The S- and R-warfarin-human serum albumin (HSA, site I) complexes were used as an interaction model. The process for a verified estimation includes the following: (i) ionized open chain forming at physiological pH (a recent focus); (ii) conformational search (molecular mechanics and Monte Carlo methods); (iii) rigid protein-flexible ligand docking (GlideXP) generating low energy paired S- and R-poses; (iv) graphical comparison against the X-ray crystal structure (unsatisfactory verification step); (v) quantum polarized ligand docking (insufficient verification step); (vi) induced fit docking (one pose satisfying the verification criterion; selection step); (vii) converting docking scores to affinity and enantioselectivity estimates (log K(S) = 5.43, log K(R) = 5.34, ES = K(S)/K(R) = 1.23) and numerical comparison against equivalent literature data from bioanalytical techniques (validation step); (viii) intermolecular forces explaining ES (hydrogen bonding and pi-pi interactions). PMID- 22946448 TI - Epiphora after radioactive iodine ablation for thyroid cancer. AB - BACKGROUND: Epiphora is a condition in which an overflow of tears occurs because of excessive lacrimal secretion or insufficient drainage of tears due to obstruction of the nasolacrimal system. This ophthalmic complication can be an intermediate to late sequela of radioactive iodine ((131)I) therapy in thyroid cancer patients. PATIENT FINDINGS: We present a case of a 23-year-old woman with complaints of bilateral excessive tearing 6 months after (131)I therapy for well differentiated thyroid cancer. She was diagnosed with epiphora secondary to nasolacrimal duct obstruction (NDO) and had bilateral endoscopic dacryocystorhinostomy, which resulted in complete resolution of her symptoms. SUMMARY: The sodium iodide symporter, present in cells of the lacrimal drainage system, is the potential mechanism by which (131)I therapy can cause inflammation, fibrosis, and ultimate obstruction of tear outflow. Risk factors such as (131)I dose, female sex, older age, and anatomical variations may also play a role in the obstruction. However, the precise pathophysiologic mechanisms remain incompletely understood. CONCLUSIONS: NDO is an under-recognized complication of (131)I therapy in thyroid cancer patients. Questions regarding eye symptoms should be an integral part of clinical follow-up in management of such patients so that effective intervention may be performed. PMID- 22946449 TI - The effect of octreotide, an analog of somatostatin, on bleomycin-induced interstitial pulmonary fibrosis in rats. AB - In this study, octreotide (OCT), a synthetic somatostatin analog, was tested for its beneficial effects in the prevention of interstitial pulmonary fibrosis (IPF) induced by bleomycin (BLM) in rats by histological examination and by evaluating tissue OH-proline levels. Thirty male Wistar rats were divided randomly into three groups: group I: intratracheal (i.t.) BLM (7.5 mg/kg, single dose) + saline solution [0.9% NaCl, subcutaneously (s.c.), once-daily for 7 days]; group II: i.t. BLM (7.5 mg/kg, single dose) + OCT acetate (82.5 ug/kg, s.c., once-daily for 7 days); and the control group. At the end of the 7 days, lung tissues were excised and examined by histopathological methods. Levels of tissue hydroxyproline (OH-proline) were determined. BLM administration resulted in prominent histopathologic findings, such as diffuse alveolar damage and interstitial pulmonary fibrosis, as well as a significant increase in OH-proline level, as compared to controls. OCT application explicitly attenuated the histopathologic changes to a significant extent. OCT decreased paranchymal fibrosis and structural deformities in BLM-induced lung fibrosis. These results suggest that OCT administration to rats with BLM-induced IPF has a protective effect. Further studies are necessary to reveal the molecular mechanism(s) of OCT induced protective effect. PMID- 22946450 TI - Design strategies for the sequence-based mimicry of side-chain display in protein beta-sheets by alpha/beta-peptides. AB - The sophistication of folding patterns and functions displayed by unnatural backbone oligomers has increased tremendously in recent years. Design strategies for the mimicry of tertiary structures seem within reach; however, a general method for the mimicry of sheet segments in the context of a folded protein is an unmet need preventing realization of this goal. Previous work has shown that 1->1 alpha->beta-residue substitutions at cross-strand positions in a hairpin-forming alpha-peptide sequence can generate an alpha/beta-peptide analogue that folds in aqueous conditions but with a change in side-chain display relative to the natural sequence; this change would prevent application of single beta-residue substitutions in a larger protein. Here, we evaluate four different substitution strategies based on replacement of alphaalpha dipeptide segments for the ability to retain both sheet folding encoded by a parent alpha-peptide sequence as well as nativelike side-chain display in the vicinity of the beta-residue insertion point. High-resolution structure determination and thermodynamic analysis of folding by multidimensional NMR suggest that three of the four designs examined are applicable to larger proteins. PMID- 22946451 TI - Episodes of apnea, desaturation and bradycardia and the development of necrotizing enterocolitis in preterm infants: a case-control study. AB - OBJECTIVE: To investigate for any association between episodes of apnea, desaturation and bradycardia and necrotizing enterocolitis (NEC). METHODS: Case control study in infants of gestational age < 30 weeks. For each NEC case we selected two controls. During the period from 2001 to 2007, data were extracted from the nurse's notes of the patient's medical records. A p < 0.05 was statistically significant. RESULTS: A total of 38 out of 394 infants had NEC (9.6%). There were no significant differences in baseline characteristics between the 2 groups, except for a lower proportion of infants who were receiving breast milk in the NEC group (p = 0.02). There was no difference in the overall number of apneas & bradycardias or severe episodes of desaturation & bradycardia between the 2 groups. CONCLUSION: No association between episodes of apnea, severe desaturations or bradycardia and development of NEC was observed in this preterm population. PMID- 22946452 TI - The benefits of giving a massage on the mental state of massage therapists: a randomized, controlled trial. AB - OBJECTIVES: The objective of this study was to determine whether giving a massage had an impact of the mental state of the massage therapist. DESIGN: The design of this study was a randomized, controlled, blinded study with two parallel groups. SETTINGS/LOCATION: This study was conducted at an accredited school of therapeutic massage in Dallas, Texas. SUBJECTS: The study comprised healthy female and male final-term massage students between ages 18 and 65 years. INTERVENTIONS: The participants were randomized into two groups: (1) the experimental group who gave a 1-hour Swedish massage to a massage client (Massage group), or (2) the control group who sat in a room doing normal, daily activities (Control group). Both these activities were a normal part of the daily routine for these massage students. OUTCOME MEASURES: The primary outcomes were the change in the Depression Anxiety and Stress Scale (DASS) scores pre- and postparticipation. RESULTS: Twenty-two (22) participants were randomized in this trial. The baseline characteristics were comparable between the two groups. A statistically significant advantage for the massage group was found relative to the control group in subjective anxiety (DASS Anxiety Subscale, p=0.014). There were no significant differences between the groups with regard to total DASS score (p=0.540), subjective depressive symptoms (DASS Depression Subscale, p=0.472) and subjective stress-related symptoms (DASS Stress Subscale, p=0.919). There were no adverse events reported by any participant. CONCLUSIONS: This study shows that massage therapists themselves may benefit from giving a therapeutic massage by experiencing less subjective anxiety following the giving of a massage. PMID- 22946453 TI - Changes in autonomic variables following two meditative states described in yoga texts. AB - OBJECTIVES: In ancient yoga texts there are two meditative states described. One is dharana, which requires focusing, the second is dhyana, during which there is no focusing, but an expansive mental state is reached. While an earlier study did show improved performance in an attention task after dharana, the autonomic changes during these two states have not been studied. METHODS: Autonomic and respiratory variables were assessed in 30 healthy male volunteers (group mean age +/- SD, 29.1 +/- 5.1 years) during four mental states described in traditional yoga texts. These four mental states are random thinking (cancalata), nonmeditative focusing (ekagrata), meditative focusing (dharana), and effortless meditation (dhyana). Assessments were made before (5 minutes), during (20 minutes), and after (5 minutes), each of the four states, on four separate days. RESULTS: During dhyana there was a significant increase in the skin resistance level (p<0.001; post hoc analysis following ANOVA, during compared to pre) and photo-plethysmogram amplitude (p<0.05), whereas there was a significant decrease in the heart rate (p<0.001) and breath rate (p<0.001). There was a significant decrease in the low frequency (LF) power (p<0.001) and increase in the high frequency (HF) power (p<0.001) in the frequency domain analysis of the heart rate variability (HRV) spectrum, on which HF power is associated with parasympathetic activity. There was also a significant increase in the NN50 count (the number of interval differences of successive NN intervals greater than 50 ms; p<0.001) and the pNN50 (the proportion derived by dividing NN50 by the total number of NN intervals; p<0.001) in time domain analysis of HRV, both indicative of parasympathetic activity. CONCLUSIONS: Maximum changes were seen in autonomic variables and breath rate during the state of effortless meditation (dhyana). The changes were all suggestive of reduced sympathetic activity and/or increased vagal modulation. During dharana there was an increase in skin resistance. The changes in HRV during ekagrata and cancalata were inconclusive. PMID- 22946454 TI - Longitudinal morphometric analysis of epiretinal membrane in patients with uveitis. AB - PURPOSE: To evaluate temporal changes of epiretinal membrane (ERM) in uveitis. METHODS: Six consecutive eyes with uveitis and ERM documented by spectral-domain optical coherence tomography (SD-OCT) in 6 +/- 1-month intervals during a 2-year follow-up (FU) period were included. Clinical information and SD-OCT data were noted at all FU visits. ERM thickness maps were created. The main outcome measures were BCVA, central subfield thickness (CST) and ERM thickness at baseline and FU visits. The correlation between ERM thickness and BCVA was analyzed. RESULTS: Intraocular inflammation was inactive during the study period. Mean ERM thickness at the fovea increased 2.3 um at 12-month and 2.4 um at 24 month FU (p < .05). The increase in foveal ERM thickness was associated with foveal structural changes (p = .03). Visual acuity did not change during the FU. CONCLUSION: In well-controlled intraocular inflammation, increase in the ERM thickness does not lead to loss of vision in a 2-year FU period. PMID- 22946455 TI - Hyperthermia impairs the executive function using the Attention Network Test. AB - PURPOSE: The primary aim of this study was to examine the effect of passive hyperthermia on the human attention system using the Attention Network Test (ANT), which has been used in both healthy controls and patients. Using target contrasts between conditions within a Flanker paradigm, the ANT can isolate three essential networks in the attention system: maintaining an alert state that is receptive to stimulus input and ready for responding; orienting, which involves selection of sensory input; and executive control, which monitors for and resolves conflict in responding or other aspects of cognitive processing. MATERIALS AND METHODS: The ANT was administered to 16 right-handed subjects in a heat stress condition (50 degrees C, 40% relative humidity) and a control condition (20 degrees C, 40% relative humidity), for 1 hour each. Reaction time (RT) and accuracy rate as well as mean body core temperature (T-core) and body weight loss were recorded. RESULTS: Compared to the control condition, T-cores significantly increased and body weight was not significantly reduced in the heat stress condition. Overall, there were non-significant group differences for RT and accuracy rate. Although significant changes in neither alerting nor orienting effects were modulated by the simulated hyperthermia, the executive control effect on RTs was significantly larger in the heat compared to the control condition. CONCLUSIONS: Passive hyperthermia impaired executive control function, whereas alerting and orienting effects were unaffected. PMID- 22946457 TI - Virtual Special Issue (VSI) on mechanisms of plant response to global atmospheric change. PMID- 22946460 TI - Anti-allergic potential of herbs and herbal natural products - activities and patents. AB - The increase of allergic diseases has accompanied the global population growth and the major challenge is to reduce morbidity. The currently available treatments present limitations regarding efficacy and safety. Hence, patients with chronic allergic conditions seek alternatives to achieve better control of symptoms. Many natural products have been identified as potential anti-allergic agents. In addition, plant formulations have demonstrated, in general, to be safe in clinical trials and demonstrate additional effects along with Western medicines such as synergism and modulation of the immune system. It is known that plants represent a source of new therapeutic agents and some of them have shown mechanisms of action similar to synthetic agents. However, in general, herbs and their combination are patented mainly by Asian countries to be used in food and drinks or cosmetics and dietary supplements and the anti-allergic mechanisms of action are not yet fully elucidated. In this review, we highlight relevant patent and studies with cultivated plants, plant formulations, and secondary metabolites that have been evaluated with respect to its anti-allergic potential. PMID- 22946458 TI - Which factors predict the behavior of ventricular extrasystoles in athletes over time? AB - Spontaneous behavior of ventricular extrasystoles (VE) was analysed. From a database containing 578 athletes with VE, 84 males and 11 females (29.9 +/- 18.1 years) having >= 100 VE or repetitive VE [ventricular couplets (VC) or ventricular tachycardias (VT)] at first 24-hour Holter electrocardiographic monitoring (24-h-HM) (baseline) and at least 1-year of follow-up (3.1 +/- 2.2 years) over the past 10 years were selected. The baseline was compared with the last 24-h-HM to establish DVE (VE reduction of at least 98%/24 h in the absence of VC or VT). SDVE was calculated as standard deviation of the number of VE on serial 24-h-HMs. DVE and SDVE were considered as dependent variables. Independent variables were: age, sex, type of sport, symptoms, baseline VE rate (BVE), baseline VC and VT, VE morphology, VE behavior during the baseline training session, disqualification from competitive sports, echocardiographic abnormalities. DVE occurred in 32 athletes (34%). SDVE varied from 0 to 12,658 VE/24 h (1916 +/- 2649.9). Disappearance of VE during the baseline training session (DVET) correlated to DVE (P = 0.0319). BVE directly correlated to SDVE (P = 0.0008). Athletes' VE are highly variable over time, their variability depending on BVE, and they not infrequently tend to disappear. The only useful variable for predicting DVE is DVET. PMID- 22946461 TI - Tipping points in adolescent adjustment: predicting social functioning from adolescents' conflict with parents and friends. AB - Despite widespread interest in examining the role of conflict for adolescent development, researchers only rarely have examined adolescents' experiences of conflict across relationships. The present study examined how adolescents' experiences of conflict with parents and friends were linked to their social functioning. Adolescents (n = 189) and their mothers and fathers participated in semistructured discussions about areas of parent-adolescent conflict in the laboratory. In addition, adolescents reported about conflict in their best friendships, and peers reported about adolescents' social acceptance and behavior in social settings. Parent-adolescent conflict was associated with peer-reported aggression and delinquency, and friendship conflict was associated with delinquency and prosocial behavior. In addition, significant Parent-Adolescent Conflict * Friend-Adolescent Conflict interactions revealed that parent adolescent conflict was associated with poor social functioning only when conflict with best friends was also high. The findings suggest that consideration of conflict across relationships may yield insight into the specific contexts in which conflict is associated with negative outcomes for adolescents. PMID- 22946462 TI - Do cold feet warn of trouble ahead? Premarital uncertainty and four-year marital outcomes. AB - Are the doubts that people feel before marriage signs of impending difficulties or normative experiences that can be safely ignored? To test these opposing views, we asked 464 recently married spouses whether they had ever been uncertain about getting married and then compared 4-year divorce rates and marital satisfaction trajectories among those partners with and without premarital doubts. Doubts were reported by at least one partner in two thirds of couples. Women with premarital doubts had significantly higher 4-year divorce rates, even when controlling for concurrent marital satisfaction, the difficulty of their engagement, history of parental divorce, premarital cohabitation, and neuroticism. Among intact couples, men's and women's doubts predicted less satisfied marital trajectories. Premarital doubts appear to be common but not benign, suggesting that valid precursors of marital distress are evident during couples' engagements. PMID- 22946463 TI - Physical activity and reduced risk of depression: results of a longitudinal study of Mexican adults. AB - OBJECTIVE: To evaluate the effect of physical activity (PA) on the risk of depression among Mexican adults over a 6-year follow-up period. METHOD: We evaluated longitudinal data from the Health Worker Cohort Study, which follows employees of the Mexican Institute for Social Security in Morelos State, Mexico, over time. Depressive symptoms and PA were assessed at baseline and at a follow up measurement 6 years later. The study population was free of depressive symptomatology at baseline, as assessed by the Center for Epidemiological Studies Depression Scale (CES-D). After 6 years, the CES-D was completed once again by the participants to estimate their risk of depression based on the different PA patterns they reported during the follow-up period. PA was estimated using a questionnaire that has been applied in similar longitudinal studies and has been validated in Spanish, with metabolic equivalents (METs) as the unit of measurement. We identified three PA patterns: highly active, moderately active, and inactive. The relative risk of depression (CES-D score >= 16 points) was estimated using multivariate logistical regression analysis according to the PA patterns at a follow-up measurement 6 years later. RESULTS: The incidence of depression after 6 years was higher among inactive participants (16.5%) than among those with an active PA pattern (10.6%). We found that more active PA patterns have an important protective effect against depression. The odds ratio (OR) for the more active PA patterns was 0.46, 95% confidence interval (CI) [0.25, 0.87], and for individuals with a moderately active PA pattern, the OR was 0.57, 95% CI [0.34, 0.93]. These ORs were obtained after adjusting for confounding variables and baseline PA levels. CONCLUSION: Our results indicate that PA may reduce risk of depression in Mexican adults. These findings have potential applications for depression prevention programs in target populations with similar social and cultural contexts. PMID- 22946456 TI - The role of the paracrine/autocrine mediator endothelin-1 in regulation of cardiac contractility and growth. AB - Endothelin-1 (ET-1) is a critical autocrine and paracrine regulator of cardiac physiology and pathology. Produced locally within the myocardium in response to diverse mechanical and neurohormonal stimuli, ET-1 acutely modulates cardiac contractility. During pathological cardiovascular conditions such as ischaemia, left ventricular hypertrophy and heart failure, myocyte expression and activity of the entire ET-1 system is enhanced, allowing the peptide to both initiate and maintain maladaptive cellular responses. Both the acute and chronic effects of ET 1 are dependent on the activation of intracellular signalling pathways, regulated by the inositol-trisphosphate and diacylglycerol produced upon activation of the ET(A) receptor. Subsequent stimulation of protein kinases C and D, calmodulin dependent kinase II, calcineurin and MAPKs modifies the systolic calcium transient, myofibril function and the activity of transcription factors that coordinate cellular remodelling. The precise nature of the cellular response to ET-1 is governed by the timing, localization and context of such signals, allowing the peptide to regulate both cardiomyocyte physiology and instigate disease. LINKED ARTICLES: This article is part of a themed section on Endothelin. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2013.168.issue-1. PMID- 22946464 TI - Effects of amine oxidases in allergic and histamine-mediated conditions. AB - This review provides an update on histamine, on diamine oxidase (DAO) and on their implications in allergy and various conditions or affections, such as food histaminosis, ischemia and inflammatory bowel diseases (IBD). The review also presents, in brief, patent coverage on therapies for allergy and IBD with the focus on histamine-related treatments. PMID- 22946465 TI - Neoadjuvant chemotherapy in 16 patients with locally advanced papillary thyroid carcinoma. AB - BACKGROUND: It is believed that chemotherapy (ChT) is ineffective in papillary thyroid carcinoma (PTC). The aim of our retrospective chart review was to find out if neoadjuvant ChT before thyroid surgery had any effect on the size of primary tumors in patients with PTC. METHODS: The study included 16 patients (13 women, 3 men; median age 63.5 years) with PTC, who were treated with neoadjuvant ChT from 1988 to 2005. Poorly differentiated PTC, classical PTC, a follicular variant of PTC, and a Hurthle cell variant of PTC were diagnosed in 5, 5, 3, and 3 cases, respectively. The mean tumor diameter was 9.67 cm. Seven patients had a pT4 tumor. Regional and distant metastases were detected in 10 and 7 patients, respectively. ChT consisted of vinblastine in 11 cases, vinblastine with adriamycin in 2 cases, and other schedules in 3 cases. Four patients were also treated with preoperative external irradiation. RESULTS: Altogether, 40 cycles of ChT were given. After ChT, the tumor size decreased in all 16 patients: by >50% in 7 (44%) patients and by <50% in 9 patients. R0, R1, and R2 resection was performed in 2, 10, and 4 cases, respectively. The median survival time of our patients was 88 months. Six patients are still alive; two died of causes not related to carcinoma, while eight patients died of PTC. CONCLUSIONS: Neoadjuvant ChT before thyroid surgery may be effective in patients with locally advanced PTC. After neoadjuvant ChT, in 44% of patients, the tumor size decreased by >50%. PMID- 22946466 TI - There is hardly any association between Helicobacter pylori infection and the severity of acute pancreatitis. PMID- 22946468 TI - Synthesis, structure, and magnetic studies of manganese-oxygen clusters of reduced coordination number, featuring an unchelated, 5-coordinate octanuclear manganese cluster with water-derived oxo ligands. AB - The synthesis of reduced coordination (less than 6), unchelated manganese oxygen cluster systems is described. Addition of phenols to Mn(NR(2))(2) (R = SiMe(3)) results in protolytic amide ligand replacement, and represents the primary entry into the described chemistry. Addition of PhOH to Mn(NR(2))(2) results in the formation of the heteroleptic dimer Mn(2)(MU-OPh)(2)(NR(2))(2)(THF)(2) (1). Usage of the sterically larger 2,6-diphenylphenol (Ph(2)C(6)H(3)OH) as the ligand source results in the formation of a 3-coordinate heteroleptic dimer without THF coordination, Mn(2)(MU-OC(6)H(3)Ph(2))(2)(NR(2))(2) (2). Attempts to generate 2 in the presence of THF or Et(2)O resulted in isolation of monomeric Mn(OC(6)H(3)Ph(2))(2)L(2) (3, L = THF, Et(2)O). Use of the sterically intermediate 2,4,6-trimethylphenol (MesOH) resulted in formation of the linear trinuclear cluster Mn(3)(MU-OMes)(4)(NR(2))(2)(THF)(2) (4). Reaction of Mn(NR(2))(2) with PhOH in the presence of water, or reaction of 1 with water, results in the formation of a 5-coordinate, unchelated Mn-O cluster, Mn(8)(MU(5) O)(2)(MU-OPh)(12)(THF)(6) (5). Preparation, structures, steric properties, and magnetic properties are presented. Notably, complex 5 exhibits a temperature dependent phase transition between a 4-spin paramagnetic system at low temperature, and an 8-spin paramagnetic system at room temperature. PMID- 22946467 TI - Internet survey of the influence of environmental factors on human health: environmental epidemiologic investigation using the web-based daily questionnaire for health. AB - With increasing Internet coverage, the use of a web-based survey for epidemiological study is a possibility. We performed an investigation in Japan in winter 2008 using the web-based daily questionnaire for health (WDQH). The WDQH is a web-based questionnaire survey formulated to obtain information about the daily physical condition of the general public on a real-time basis, in order to study correlations between changes in physical health and changes in environmental factors. Respondents were asked whether they felt ill and had specific symptoms including fever. We analysed the environmental factors along with the health conditions obtained from the WDQH. Four factors were found to influence health: minimum temperature, hours of sunlight, median humidity and weekday or holiday. The WDQH allowed a daily health survey in the general population in real time via the Internet. PMID- 22946469 TI - The impact of child-rearing status on perceptual and behavioural predictors of ambulatory blood pressure variation among working women. AB - BACKGROUND: Past studies have shown that diurnal blood pressure varies between working women with and without children. Understanding of how perceptual and behavioural factors affect this relationship is limited. AIM: The study aim was to evaluate whether perceptions and behaviours differentially influenced ambulatory blood pressure variation across changing daily environments between working women with and without children. SUBJECTS AND METHODS: Women (83 with children, 157 without) working as secretaries or technicians were studied. Anthropometric, demographic, questionnaire and ambulatory blood pressure data were collected. Principal component analysis was utilized to create perceptual and behavioural factors from questionnaire items. Sequential stepwise regression and MANCOVA analyses were used to model blood pressure variation. RESULTS: Diurnal levels and variation in ambulatory blood pressures were similar between women with and without children. Those with children were older, shorter, heavier; more ethnically diverse, had a smaller social support network, perceived less stress and difficulty on the job and reported a better balance between work and home responsibilities then women without children (all significant at p < 0.05). Perceptual and behavioural predictors of work, home and sleep blood pressures differed between the groups. CONCLUSION: There are significant differences in biological and behavioural predictors of ambulatory blood pressure between women with and without children. PMID- 22946470 TI - Infliximab therapy for a severe case of IgG4-related ocular adnexal disorder recalcitrant to corticosteroid treatment. PMID- 22946471 TI - Group B Streptococcus colonization and higher maternal IL-1beta concentrations are associated with early term births. AB - Association between maternal Group B Streptococcus (GBS) colonization diagnosed between 35 and 37 weeks of gestation and early term birth (between 37 and 39 weeks) and maternal-fetal inflammatory response associated with this condition were tested. In this cohort study of women delivering at term at Centennial Women's Hospital in Nashville, TN, GBS status and other clinical and demographic data were obtained from medical records. Exposed women were those testing positive for GBS (GBS positive [n = 490]) and the unexposed tested negative for GBS (GBS negative [n = 1,127]). To determine the inflammatory response associated with GBS, a cross sectional study, maternal and fetal plasma biomarkers (IL 1beta, IL-2, IL-6, IL-8, and TNF-alpha) were measured in the same cohort. T-tests and logistic regression determined association between GBS status, biomarker concentrations and early term birth. Gestational age was reduced to 271.1 (95% CI 270.4, 271.1) for cases compared to 274.7 (95% CI 274.4, 275.1) days for controls (p < 0.0001). The odds of early term birth was increased by threefold in cases (OR 3.28; 95% CI 2.60-4.15; p < 0.0001). The mean birth weight in cases (3285.3 g) (95% CI 3242.6, 3327.9) was lower than the controls, 3373.8 g (95% CI 3348.9, 3398.7) (p = 0.0004). Maternal IL-1beta was greater in cases (22.8 ng/ml; range 5.2-157.7 ng/ml) compared to controls (5.7; range 2.4-69.5 ng/ml; p < 0.0001). IL 1beta was higher in fetal plasma in cases vs. controls (20.33 vs. 8.18 ng/ml; p = 0.01). A 10 ng/ml increase in maternal IL-1beta was associated with increased risk for GBS infection (OR: 1.628, CI: 1.163-2.278; p = 0.0045). GBS colonization shortened gestational age at term and IL-1beta concentration in maternal plasma is an indicator of GBS status. PMID- 22946472 TI - Impact of hyperthermic isolated limb perfusion on tumour oxygenation in soft tissue sarcoma. AB - PURPOSE: Hyperthermic isolated limb perfusion (ILP) with recombinant tumour necrosis factor alpha (TNF) and melphalan contributes to limb-saving treatment in patients with locally advanced extremity soft tissue sarcoma (STS). This study was conducted to evaluate the dynamic changes of tumour oxygenation and temperature during ILP and their effects on treatment response. PATIENTS AND METHODS: Tumour oxygenation (pO(2)) and tumour temperature were measured by intratumourally placed O(2)-sensitive catheter electrodes in 34 patients who underwent ILP for locally advanced or recurrent STS. Tumour response to ILP was assessed by the fraction of tumour necrosis in the resection specimen. RESULTS: Mean tumour pO(2) prior to application of TNF and melphalan was 36 mm Hg (range: 2-116 mm Hg) and dropped significantly to 13 mm Hg (range: 0-67 mm Hg, p = 0.03) during ILP. Mean tumour tissue temperature increased from 34.4 degrees C (range 32.4-36.4) to 38.5 degrees C (range 34.1-40.4, p = 0.0001). The mean fraction of necrosis in the resection specimen was 65% (range 5-99). Only the tumour tissue temperature at the onset of ILP correlated with the extent of tumour necrosis (p = 0.01). CONCLUSION: ILP with TNF and melphalan induces severe oxygen deprivation in soft tissue sarcoma. However, changes in tumour oxygenation did not correlate with treatment response. PMID- 22946473 TI - Two-photon absorption-molecular structure investigation using a porphycene chromophore with potential in photodynamic therapy. AB - Porphycenes have been shown to exhibit many advantageous properties when it comes to the application of two-photon absorption (TPA), a technique with potential use in the area of photodynamic therapy (PDT). A computational study of structure reactivity relationships in the one- and two-photon absorption spectra of a series of 2,7,12,17-substituted porphycenes has been carried out using linear and quadratic density functional response theory. The focus has been on determining the effect on the spectra of electron donating and withdrawing substituents, the outcome of extending the conjugation lengths to these substituents, and the consequence of formation of metallo-porphycene complexes. In particular, we have looked at the use of TPA in order to improve the penetration depth of the therapeutic light dose, in terms of the position of the absorption maximum with respect to the optical window of tissue penetration, as well as the effect on the TPA cross section. The extent of conjugation was shown to be particularly crucial for increasing the TPA cross section, for both the electron withdrawing and donating substituents, while the inclusion of a metal in the center of the macrocycle was shown to benefit the absorption wavelength in terms of tissue penetration considerations. PMID- 22946474 TI - In vitro induction/inhibition of germinal vesicle breakdown (GVBD) in frog (Euphlyctis cyanophlyctis) oocytes by endocrine active compounds. AB - Oocyte maturation is transformation of oocytes into a fertilizable egg. This study examined the effects of four classes of chemicals: 1) acephate (organophosphate); 2) atrazine (herbicide); 3) cypermethrin and fenvalerate (synthetic pyrethroids); and 4) carbaryl (carbamate) on in vitro germinal vesicle breakdown (GVBD) of Euphlyctis cyanophlyctis oocytes. Follicles were isolated and defolliculated from surgically removed ovaries of E. cyanophlyctis and exposed to either progesterone (1 MUM/mL) or graded concentrations (1, 5, 10, 15, and 20 MUg/mL) of test chemicals. GVBD was evident by the presence of a white spot in the animal pole as well as the absence of germinal vesicles in sectioned heat fixed oocytes. Percent GVBD was scored every 4 hours until 24 hours. Progesterone induced 77-84% GVBD, compared to 29-33% in controls, at 24 hours. Acephate induced 46-67% GVBD, whereas atrazine elicited 58-77% of GVBD. In cypermethrin or carbaryl- or fenvalerate-exposed oocytes, GVBD was limited to 22-28, 17-29 and 18 24%, respectively. The study infers that some chemical contaminants in the aquatic system may interfere with GVBD in amphibians. Because oocyte maturation is a prerequisite for the production of fertilizable eggs, any alteration in this process potentially impairs the fecundity of females. PMID- 22946475 TI - Age-dependence of power spectral density and fractal dimension of bone mineralized matrix in atomic force microscope topography images: potential correlates of bone tissue age and bone fragility in female femoral neck trabeculae. AB - There is an increasing interest in bone nano-structure, the ultimate goal being to reveal the basis of age-related bone fragility. In this study, power spectral density (PSD) data and fractal dimensions of the mineralized bone matrix were extracted from atomic force microscope topography images of the femoral neck trabeculae. The aim was to evaluate age-dependent differences in the mineralized matrix of human bone and to consider whether these advanced nano-descriptors might be linked to decreased bone remodeling observed by some authors and age related decline in bone mechanical competence. The investigated bone specimens belonged to a group of young adult women (n = 5, age: 20-40 years) and a group of elderly women (n = 5, age: 70-95 years) without bone diseases. PSD graphs showed the roughness density distribution in relation to spatial frequency. In all cases, there was a fairly linear decrease in magnitude of the power spectra with increasing spatial frequencies. The PSD slope was steeper in elderly individuals (-2.374 vs. -2.066), suggesting the dominance of larger surface morphological features. Fractal dimension of the mineralized bone matrix showed a significant negative trend with advanced age, declining from 2.467 in young individuals to 2.313 in the elderly (r = 0.65, P = 0.04). Higher fractal dimension in young women reflects domination of smaller mineral grains, which is compatible with the more freshly remodeled structure. In contrast, the surface patterns in elderly individuals were indicative of older tissue age. Lower roughness and reduced structural complexity (decreased fractal dimension) of the interfibrillar bone matrix in the elderly suggest a decline in bone toughness, which explains why aged bone is more brittle and prone to fractures. PMID- 22946476 TI - Zwitterionic guanidine-based oligomers mimicking cell-penetrating peptides as a nontoxic alternative to cationic polymers to enhance the cellular uptake of micelles. AB - The aim of this work is to generate polymer micelles decorated with a synthetic version of cell-penetrating peptides, which are often rich in arginine with its positively charged guanidine group. A methacrylate-based monomer with guanidinium as functional groups was prepared using arginine (M-Arg) as a building block, resulting in a zwitterionic monomer. RAFT (reversible addition-fragmentation chain transfer) polymerization was employed to generate triblock copolymers with poly(methyl methacrylate)-block-poly(polyethylene glycol methyl ether methacrylate) as the first two blocks, which were subsequently chain extended with the guanidine-based monomer to generate micelles with guanidinium functional groups on the surface. To simulate the actual oligoarginine peptide, which only carries cationic charges, the carboxylate group of P(M-Arg) was methylated to convert the zwitterionic polymer into a cationic polymer P(Me-M-Arg). For comparison, micelles based on triblock copolymers with a third block with permanently cationic charges, poly(2-methacryolyloxy ethyl) trimethyl ammonium chloride (PTMA), was prepared. The hydrodynamic diameters of the micelles were approximately 30-40 nm based on DLS and TEM. A direct correlation between surface charge (zeta potential zeta) and cytotoxicity was observed. The micelles based on the zwitterionic P(M-Arg) were nontoxic (zeta = -10 mV at pH = 7), while the methylated version P(Me-M-Arg) with a high cationic charge (zeta = +35 mV at pH = 7) were observed to be toxic. The cellular uptake of the block copolymers by OVCAR-3 ovarian cancer cell lines was found to be relatively fast (about 35% in 3 min) reaching an equilibrium after approximately 30 min. Both micelles, with either P(M-Arg) or P(Me-M-Arg) on the surface, showed an enhanced uptake compared to micelles with P(PEGMEMA) as shell only. In fact, the percentage of uptake was similar, with the difference that cells incubated with micelles with P(M-Arg) (zwitterionic) stayed alive, while P(Me-M-Arg) (cationic) led to significant cell death. PMID- 22946477 TI - Gas-phase structures of Pb(2+)-cationized phenylalanine and glutamic acid determined by infrared multiple photon dissociation spectroscopy and computational chemistry. AB - Infrared multiple photon dissociation (IRMPD) spectroscopy in the 3200-3800 cm( 1) region was used to determine the gas-phase structures of bare and monohydrated [Pb(Phe-H)](+) and [Pb(Glu-H)](+). These experiments were supported by infrared spectra calculated at the B3LYP/6-31+G(d,p) level of theory as well as 298 K enthalpies and Gibbs energies determined using the MP2(full)/6 311++G(2d,2p)//B3LYP/6-31+G(d,p) method. The gas-phase structure of [Pb(Phe H)](+) has Pb(2+) bound in a tridentate fashion between Phe's amine nitrogen, one oxygen of the deprotonated carboxyl group, and the aromatic ring. The IRMPD spectrum of [Pb(Glu-H)](+) can be assigned to a structure where the side chain carboxyl group is deprotonated. The structure of [Pb(Phe-H)H(2)O](+) is simply the hydrated analogue of [Pb(Phe-H)](+) where water attaches to Pb(2+) in the same hemisphere as the ligated amino acid. The spectrum of [Pb(Glu-H)H(2)O](+) could not be assigned a unique structure. The IRMPD spectrum shows features attributed to symmetric and antisymmetric O-H stretching of water and a broad band characteristic of a hydrogen bonded O-H stretching vibration. These features can only be explained by the presence of at least two isomers and agree with the computational results that predict the four lowest energy structures to be within 6 kJ mol(-1) of one another. PMID- 22946478 TI - Editorial comment to Chromophobe renal cell carcinoma: a review of an uncommon entity. PMID- 22946479 TI - Molecular photoconductor with simultaneously photocontrollable localized spins. AB - UV irradiation reversibly switches a new insulating and nonmagnetic molecular crystal, BPY[Ni(dmit)(2)](2) (BPY = N,N'-ethylene-2,2'-bipyridinium; Ni(dmit)(2) = bis(1,3-dithiole-2-thione-4,5-dithiolato)nickelate(III)), into a magnetic conductor. This is possible because the bipyridyl derivative cations (BPY(2+)) trigger a photochemical redox reaction in the crystal to produce a change of ~10% in the filling of the Ni(dmit)(2) valence band, leaving localized spins on the BPY themselves. In the dark, almost all of the BPY molecules are closed-shell cations, and most of the Ni(dmit)(2) radical anions form spin-singlet pairs; thus, this material is a diamagnetic semiconductor. Under UV irradiation, a photocurrent is observed, which enhances the conductivity by 1 order of magnitude. Electron spin resonance measurements indicate that the UV irradiation reversibly generates carriers and localized spins on the Ni(dmit)(2) and the BPY, respectively. This high photoconductivity can be explained by charge transfer (CT) transitions between Ni(dmit)(2) and BPY in the UV region. In other words, the photoconduction and "photomagnetism" can be described as reversible optical control of the electronic states between an ionic salt (BPY(2+)/[Ni(dmit)(2)](-), nonmagnetic insulator) and a CT complex (BPY(2(1-delta)+)/[Ni(dmit)(2)]((1-delta) ) (delta ~ 0.1), magnetic conductor) in the solid state. PMID- 22946481 TI - ECG feature extraction using differentiation, Hilbert transform, variable threshold and slope reversal approach. AB - An accurate and reliable ECG feature extraction algorithm is presented in this paper. ECG samples are de-noised and its first derivative and Hilbert transform are computed. Sample having maximum amplitude in the transformed domain is found out and those samples having amplitudes within a lead wise specified threshold of that maximum are marked. In the original signal, where these marked samples undergo slope reversals are spotted as R-peak. On the left and right side of the R-peak, slope reversals are identified as Q and S peak, respectively. QRS onset offset points, T and P waves are also detected. ECG baseline modulation correction is done after detecting characteristics points. The algorithm offers a good level of Sensitivity, Positive Predictivity and accuracy of R peak detection. Each wave and segment duration and each peak height is measured. Measurement errors of extracted ECG features are calculated. The algorithm is implemented on MATLAB 7.1 environment. PMID- 22946480 TI - Appropriate BMI cut-off values for identification of metabolic risk factors: third national surveillance of risk factors of non-communicable diseases in Iran (SuRFNCD-2007). AB - AIM: To determine the appropriate threshold of body mass index (BMI) associated with increased risk of cardiovascular diseases in a large representative sample of an Iranian population. SUBJECTS AND METHODS: Data of third national surveillance of risk factors of non-communicable diseases (SuRFNCD-2007) were used in this study. Sensitivity, specificity, and shortest distance on the receiver-operating characteristic (ROC) curves were used to determine gender specific optimal cut-offs of BMI for cardiometabolic risk factors including elevated blood pressure, low high-density lipoprotein cholesterol, high triglycerides, high fasting plasma glucose and for >= 2 of the aforementioned risk factors. RESULTS: There was a continuous increase in the prevalence of cardiometabolic risk factors with increasing BMI (p < 0.001). At the BMI of 25-29 kg/m(2) men were at higher risk of cardiovascular diseases compared to women (p < 0.001). The appropriate BMI cut-offs ranged from 24.6-26.1 kg/m(2) for men and from 26.9-28.8 kg/m(2) for women. The optimal BMI cut-offs for identifying any two or more of those risk factors were 25.2 and 27.3 kg/m(2) in men and women, respectively. CONCLUSION: In men the appropriate BMI cut-offs are ~25 kg/m(2), while in women higher BMI values are associated with risk of cardiovascular diseases. PMID- 22946482 TI - Wet chemical functionalization of graphene. AB - The fullerenes, carbon nanotubes, and graphene have enriched the family of carbon allotropes over the last few decades. Synthetic carbon allotropes (SCAs) have attracted chemists, physicists, and materials scientists because of the sheer multitude of their aesthetically pleasing structures and, more so, because of their outstanding and often unprecedented properties. They consist of fully conjugated p-electron systems and are considered topologically confined objects in zero, one, or two dimensions. Among the SCAs, graphene shows the greatest potential for high-performance applications, in the field of nanoelectronics, for example. However, significant fundamental research is still required to develop graphene chemistry. Chemical functionalization of graphene will increase its dispersibility in solvents, improve its processing into new materials, and facilitate the combination of graphene's unprecedented properties with those of other compound classes. On the basis of our experience with fullerenes and carbon nanotubes, we have described a series of covalent and noncovalent approaches to generate graphene derivatives. Using water-soluble perylene surfactants, we could efficiently exfoliate graphite in water and prepare substantial amounts of single layer-graphene (SLG) and few-layer-graphene (FLG). At the same time, this approach leads to noncovalent graphene derivatives because it establishes efficient pi-pi-stacking interactions between graphene and the aromatic perylene chromophors supported by hydrophobic interactions. To gain efficient access to covalently functionalized graphene we employed graphite intercalation compounds (GICs), where positively charged metal cations are located between the negatively charged graphene sheets. The balanced combination of intercalation combined with repulsion driven by Coulombic interactions facilitated efficient exfoliation and wet chemical functionalization of the electronically activated graphene sheets via trapping with reactive electrophilic addends. For example, the treatment of reduced graphite with aryl diazonium salts with the elimination of N(2) led to the formation of arylated graphene. We obtained alkylated graphene via related trapping reactions with alkyl iodides. These new developments have opened the door for combining the unprecedented properties of graphene with those of other compound classes. We expect that further studies of the principles of graphene reactivity, improved characterization methods, and better synthetic control over graphene derivatives will lead to a whole series of new materials with highly specific functionalities and enormous potential for attractive applications. PMID- 22946483 TI - 2,4- vs 3,4-disubsituted pyrrole synthesis switched by copper and nickel catalysts. AB - A novel and efficient copper or nickel catalyzed highly selective denitrogenative annulation of vinyl azides with aryl acetaldehydes has been developed. 2,4- and 3,4-diaryl substituted pyrroles, which are difficult to synthesize by the reported methods, can be highly regioselectively prepared by this protocol simply switched by the selection of the transition metal catalysts. Compared with the reported acidic or basic conditions for polysubstituted pyrrole synthesis, the present reaction conditions are mild, neutral, and very simple without any additives. PMID- 22946484 TI - Increased cancer incidence in some gallstone diseases, and equivocal effect of cholecystectomy: a long-term analysis of cancer and mortality. AB - BACKGROUND: Our aim was to investigate cancer incidence and the cause of long term mortality in different gallstone diseases and conditions. STUDY DESIGN: The study population consisted of 2034 subjects: 224 persons diagnosed with asymptomatic gallstones in 1983, 254 patients who underwent cholecystectomy in 1983, and 513 patients with symptomatic uncomplicated gallstones (SGS, n = 337) or acute cholecystitis (AC, n = 176) between 1992 and 1994. One thousand and forty-three people who participated in a population study in 1983 were controls. RESULTS: An overall increased risk of cancer, as well as higher mortality, was found among persons with asymptomatic gallstones compared to controls (HR 1.46, 95% CI: 1.06-2.00 and HR 1.39, 95% CI: 1.08-1.78), whereas patients who underwent cholecystectomy in 1983 showed a slightly higher risk (not significant) for both cancer and death than controls. Among patients with SGS from 1992 to 1994 there was a significantly higher risk of contracting cancer in patients who had undergone surgery (HR = 2.56, 95% CI: 1.13-5.83). For patients with AC, there was no significant difference between surgically treated and non-surgically treated subjects, but there was a higher risk of cancer in all AC compared to SGS patients (HR 2.03, 95% CI: 1.20-3.43). Mortality did not differ significantly between surgically treated and non-surgically treated patients with SGS or AC. CONCLUSION: Gallstone patients had a greater risk than the general population for developing cancer, but this was dependent on the type of gallstone condition and treatment. The effect of cholecystectomy seemed dubious. PMID- 22946485 TI - Physiological, biochemical and molecular responses to a combination of drought and ozone in Medicago truncatula. AB - Drought and tropospheric ozone are escalating climate change problems that can co occur. In this study, we observed Medicago truncatula cultivar Jemalong that is sensitive to ozone and drought stress when applied singly, showed tolerance when subjected to a combined application of these stresses. Lowered stomatal conductance may be a vital tolerance mechanism to overcome combined ozone and drought. Sustained increases in both reduced ascorbate and glutathione in response to combined stress may play a role in lowering reactive oxygen species and nitric oxide toxicity. Transcriptome analysis indicated that genes associated with glucan metabolism, responses to temperature and light signalling may play a role in dampening ozone responses due to drought-induced stomatal closure during combined occurrence of these two stresses. Gene ontologies for jasmonic acid signalling and innate immunity were enriched among the 300 differentially expressed genes unique to combined stress. Differential expression of transcription factors associated with redox, defence signalling, jasmonate responses and chromatin modifications may be important for evoking novel gene networks during combined occurrence of drought and ozone. The alterations in redox milieu and distinct transcriptome changes in response to combined stress could aid in tweaking the metabolome and proteome to annul the detrimental effects of ozone and drought in Jemalong. PMID- 22946486 TI - Prevalence and clinical spectrum of nonsecretory medullary thyroid carcinoma in a series of 839 patients with sporadic medullary thyroid carcinoma. AB - BACKGROUND: Medullary thyroid carcinoma (MTC) is characterized by the synthesis and secretion of calcitonin (Ct). MTC without Ct secretion has been reported on rare occasions. The aim of this study was to analyze the prevalence and clinical spectrum of nonsecretory MTC in two tertiary centers that cared for 839 patients with sporadic MTC. METHODS: Clinical, biochemical, histological, and immunohistological findings, and somatic RET mutations were analyzed, and long term follow-up was documented. RESULTS: Seven patients with nonsecretory MTC were identified among 839 patients with sporadic MTC; thus, the prevalence rate of nonsecretory MTC was 0.83%. In these seven patients, Ct and carcinoembryonic antigen (CEA) levels were normal when MTC was initially diagnosed in the patients, despite advanced tumor stage. Ct and CEA levels remained undetectable in four patients; recurrence was indicated in one patient after 10 years of follow-up by routine anatomic imaging and increased CEA levels, and Ct levels became slightly elevated during follow-up, despite massive tumor load, in the remaining two patients. The diagnosis of MTC was confirmed by positive immunohistochemistry for Ct, CEA, and chromogranin A. A high Ki67 proliferation index (PI) (three patients) and a high proportion of RET 918-mutated cells (four patients), as well as poorly differentiated histology, were associated with aggressive biological behavior of the MTC. The prognosis for nonsecretory MTC varied between long-term survival (12.5 years) and rapid progression leading to death within 1.75 years after diagnosis. CONCLUSIONS: The prevalence of nonsecretory MTC was low (0.83% of patients with MTC). Diagnosis was often made at a clinically advanced tumor stage. The histological and immunohistological characteristics and the clinical course and prognosis of nonsecretory MTC are markedly heterogeneous. A high Ki-67 PI and a large proportion of cells with RET 918 mutations are associated with a poor prognosis. PMID- 22946488 TI - Controlling the electronic states and physical properties of MMX-type diplatinum iodide chain complexes via binary countercations. AB - MMX-type quasi-one-dimensional iodide-bridged dinuclear Pt complexes (MMX chains) with binary countercations show a new alternating charge-polarization + charge density-wave (ACP+CDW) electronic state and reversible switching of the electronic states and physical properties upon dehydration and rehydration process. By comparing several MMX chains with various binary countercations with previous chains, we found that the short backbone of the aliphatic diammonium ion was indispensable for realizing the ACP+CDW state because it induces a 2-fold periodicity along the chain axis via twisting of the ligands. Moreover, the reversibility of the changes in the structure and electrical conductivity upon dehydration and rehydration depend on the length of aliphatic diammonium ion. Short diammonium ions support a robust framework, which undergoes reversible structural changes. On the other hand, long and bent aliphatic diammonium ions weaken the framework, which causes partial degradation of the crystal and a decrease in the electrical conductivity when the structure changes. However, the decrease in the activation energy of the electrical conductivity after the dehydration process is independent of the robustness of the complex, indicating that the orbital overlap in MMX chains with binary countercations increases upon dehydration. Controllable electronic states and physical properties provide a platform for designing the multifunctional materials based on MMX chains. PMID- 22946487 TI - Inhibition of MDMA-induced increase in cortisol does not prevent acute impairment of verbal memory. AB - BACKGROUND: Ecstasy use is commonly linked with memory deficits in abstinent ecstasy users. Similar impairments are being found during ecstasy intoxication after single doses of +/- 3,4 metylenedioxymethamphetamine (MDMA). The concordance of memory impairments during intoxication and abstinence suggests a similar neuropharmacological mechanism underlying acute and chronic memory impairments. The mechanism underlying this impairment is to date not known. We hypothesized that cortisol might play an important role in this mechanism as cortisol, implicated in the regulation of memory performance, can be brought out of balance by stressors like MDMA. METHODS: In the present study, we aimed to block the MDMA-induced acute memory defect by giving participants a cortisol synthesis inhibitor (metyrapone) together with a single dose of MDMA. Seventeen polydrug MDMA users entered this placebo-controlled within subject study with four treatment conditions. The treatments consisted of MDMA (75 mg) and metyrapone (750 mg), alone and in combination, and double placebo. Pre-treatment with metyrapone or Placebo occurred 1 h prior to MDMA or Placebo administration. Memory performance was tested at peak drug concentrations by means of several memory tests. Cortisol levels were determined in blood and oral fluid; this served as a control measure to see whether manipulations were effective. RESULTS: Main findings indicated that whereas treatment with metyrapone blocked the expected MDMA-induced increase in cortisol levels in blood, it did not prevent the MDMA-induced memory deficit from happening. CONCLUSION: We therefore conclude that MDMA-induced increments in cortisol concentrations are not related to MDMA induced memory impairments. PMID- 22946489 TI - Amyloidosis of the orbit and adnexae. AB - PURPOSE: To present a series of patients with orbital and adnexal amyloidosis and illustrate the diversity of disease and the challenges of managing such cases. METHODS: Descriptive case series of ten patients with biopsy proven amyloidosis involving the orbit, conjunctiva and eyelids. The presentation, clinical findings and management are discussed for each case. RESULTS: All patients had some form of eyelid abnormality or malposition. Presenting complaints included ptosis, epiphora and ocular discomfort. Other clinical findings included conjunctival lesions and proptosis. The majority of patients had localised amyloidosis and one patient had systemic disease. Conservative management included lubrication and the use of bandage contact lenses. Surgical management included debulking, ptosis or other lid surgery. CONCLUSION: Amyloidosis can present to an Occuloplastic clinic in a wide variety of ways. Definitive diagnosis is based on the histopathological findings. Management is often challenging. Multi-disciplinary team involvement is critical in view of its systemic associations. PMID- 22946490 TI - Bipolar radiofrequency ablation with four electrodes: ex vivo liver experiments and finite element method analysis. Influence of inter-electrode distance on coagulation size and geometry. AB - PURPOSE: The aim of this study was to develop an electrode system with simple needle electrodes which would allow a reliable and predictable ablation zone with radiofrequency ablation (RFA). MATERIALS AND METHODS: In the first step, four parallel electrodes (active length 3 cm, diameter 1.8 mm) were inserted in ex vivo bovine liver. A power of 50 W was applied between two pairs of electrodes for 10 min or until current shut-off due to impedance rise. In the second step, the influence of changing inter-electrode distance on coagulation size and geometry was measured. In the third step, a finite element method (FEM) analysis of the experiment was performed to better understand the experimental findings. RESULTS: A bipolar four-electrode system with templates adjusting the inter electrode distance was successfully developed for ex vivo experiments. A complete and reliable coagulation zone of a 3 * 2 * 2-cm block was obtained most efficiently with an inter-electrode distance of 2 cm in 5.12 +/- 0.71 min. Above 2 cm, coagulation was incomplete due to a too low electric field, as demonstrated by the FEM analysis. CONCLUSIONS: The optimal inter-electrode distance of the present bipolar four-electrode system was 2 cm, allowing a reliable and predictable ablation zone in ex vivo liver. The FEM analysis correctly simulated and explained the findings in ex vivo liver. The experimental set-up may serve as a platform to gain more insight and to optimise the application of RFA by means of four or more simple needle electrodes. PMID- 22946491 TI - The usefulness of the multiple allergen simultaneous test-chemiluminescent as compared to the Phadia Immunocap IgE test panel system in children and adolescents. AB - Several patents of methods for diagnostic work-up of IgE-mediated disease have recently been acclaimed. The aim of the present study was to assess the diagnostic usefulness of the Multiple allergen simultaneous test-chemiluminescent assay (MAST CLA) as compared to the Phadia Immunocap (Phadia CAP) allergen specific IgE test panel system. The design was a prospective, observational study in which MAST CLA and Phadia CAP test panels were assessed in 105 children aged 1 to 17 years (46 girls and 59 boys) with a suspected diagnosis of rhinoconjunctivitis, asthma, eczema or food allergy. The MAST CLA screening panel included 23 and 13, the Phadia CAP 10 inhalant and 6 food allergens. The MAST CLA screening panel found 353 sensitizations which were not detected by Phadia CAP, 93 (26.3%) of which were class 3 or 4 results. The sensitizations gave clinically useful information in 7 patients (6.6%). As compared to the Phadia CAP the MAST CLA screening test panel adds little to the diagnostic work-up of IgE mediated disease in children and adolescents. PMID- 22946493 TI - Erwinia asparaginase in pediatric acute lymphoblastic leukemia. AB - INTRODUCTION: Asparaginase is a major a component of therapy for acute lymphoblastic leukemia (ALL) and has been used for over 40 years. Hypersensitivity reactions limit the use and efficacy of asparaginase products. However, Erwinia asparaginase gained the Food and Drug Administration (FDA) approval in November 2011, for use in patients with allergic reactions to Escherichia coli-derived asparaginase. AREAS COVERED: Erwinia asparaginase is an enzyme that hydrolyzes the amino acid asparagine. This review examines the properties of Erwinia asparaginase compared to the two other preparations of asparaginase available for use in the United States. Results of selected clinical trials involving Erwinia asparaginase, including the pivotal study resulting in FDA approval, are presented. EXPERT OPINION: Erwinia asparaginase is well tolerated, and it is effective in achieving asparaginase levels associated with efficacy in the treatment of ALL. With FDA approval of Erwinia asparagainse, oncologists now have an alternative for ALL patients who become hypersensitive to E. coli-derived asparaginase. Future studies will be needed to establish optimal dosing of Erwinia asparaginase (e.g., intravenous vs. intramuscular) and to better define the most appropriate indications for its use in patients previously treated with E. coli-derived asparaginase. PMID- 22946492 TI - Augmented telomerase activity and reduced telomere length in parthenium-induced contact dermatitis. AB - BACKGROUND: Parthenium dermatitis is a common chronic inflammatory disease with activated T lymphocytes that recognize the antigens, which leads to proliferation and differentiation. Telomeres and telomerase play an important role in the regulation of life span of the cell. Telomere length maintained by telomerase, are specialized repeats present at the end of chromosomes which protect it from degradation, end-to-end fusion and are important for integrity of chromosomes. OBJECTIVES: The aim of this study was to measure telomerase activity and telomere length in Peripheral blood mononuclear cell (PBMC), CD4(+) and CD8(+) T lymphocytes from parthenium dermatitis patients. METHODS: The study includes 50 patients of parthenium dermatitis confirmed by patch testing and 50 healthy controls. Telomerase activity was measured using the telomere repeat amplification protocol using PCR-ELISA kit. Telomere length was measured by using Telo TAGGG Telomere Length Assay Kit. RESULTS: Significantly elevated levels of telomerase activity was observed in PBMC, CD4(+) and CD8(+) T cells of parthenium dermatitis patients as compared with healthy controls. However, significantly reduced telomere length in PBMC, CD4(+) and CD8(+) T cells have been found in patients than healthy subjects, but there was no difference between CD4(+) and CD8(+) T cells in patients. CONCLUSION: This study might have provided insight into the role of telomerase in parthenium dermatitis that is characterized by the recruitment of T lymphocytes, which play an important role in this inflammatory disease. The augmented telomerase activity and reduced terminal restriction fragment length might be explored as a potential diagnostic/prognostic marker for parthenium dermatitis in future. PMID- 22946494 TI - Processing of surfactant templated nano-structured silica films using compressed carbon dioxide as interpreted from in situ fluorescence spectroscopy. AB - The local environment and dynamics of compressed carbon dioxide (CO(2)) penetration in surfactant templated silica film synthesis is interpreted from the in situ fluorescence emission spectra of pyrene (Py) and a modified pyrene probe. Pyrene emission in cetyltrimethylammonium bromide (CTAB) and cetylpyridinium bromide (CPB) templated silica films is monitored immediately after casting and during processing with gaseous and supercritical (sc) CO(2) (17-172 bar, 45 degrees C). The solvatochromic emission spectra of pyrene in CTAB templated films suggest CO(2) penetration in both the micelle interface and its interior. An anchored derivative of pyrene, 1-pyrenehexadecanoic acid (C(16)-pyr), is established for probing CPB films, where the pyrene moiety is preferentially oriented toward the micelle interior, thus limiting quenching by the pyridinium headgroup of CPB. CO(2) processing of CPB templated silica films results in an increase in the time scale for probe mobility, suggesting an increased time scale of silica condensation through CO(2) processing. The mobility of C(16)-pyr increases with pressure from gaseous to sc CO(2) processing and persists for over 5 h for sc CO(2) processing at 172 bar and 45 degrees C compared to about 25 min for the unprocessed film. The delivery of CO(2) soluble solutes to specific regions of surfactant templated mesoporous materials is examined via the nonradiative energy transfer (NRET) between pyrene and CO(2)-solubilized naphthalene. PMID- 22946495 TI - Reversible control over the valency of a nanoparticle-based supramolecular system. AB - The reversible "catch-and-release" of small molecules from the surface of monolayer-protected gold nanoparticles is described. The valency of the system (i.e., the number of molecules bound to the surface) can be controlled through the addition and removal of metal ions from the monolayer. Both the change in valency and the release rate of the molecules are strongly pH-dependent. The release rate can be regulated by altering the ratio of metal ions in the monolayer. PMID- 22946498 TI - Glycation of whey protein to provide steric hindrance against thermal aggregation. AB - Thermal processing is required for a variety of products and remains a problem for whey proteins that undergo denaturation and aggregation above the denaturation temperature. This causes challenges to maintain clarity and dispersibility of protein dispersions, particularly at acidity near the isoelectric point of the protein and increased ionic strength. This work reports for the first time that glycation of whey protein with a sufficient number of maltodextrins prevented protein aggregation before and after heating at 88 degrees C for 2 min at pH 3.0-7.0 and 0-150 mM NaCl or CaCl(2). The mechanism of maintaining protein dispersion clarity during heating was illustrated by several complementary analytical techniques that elucidated primary, secondary, and tertiary structures, as well as thermal denaturation and surface charge properties of glycated whey proteins. Steric hindrance was concluded to be the major mechanism responsible for transparent dispersions with protein structures smaller than 12 nm after heating. PMID- 22946496 TI - 3D geometric morphometric analysis of the proximal epiphysis of the hominoid humerus. AB - In this study we perform a three-dimensional geometric morphometric (3D GM) analysis of the proximal epiphysis of the humerus in extant great apes, including humans, in order to accurately describe the functional anatomical differences between these taxa. In addition, a fossil hominin specimen of Australopithecus afarensis was included in a multivariate GM analysis in order to test the potential of this methodological approach for making locomotor inferences from fossil remains. The results obtained show significant differences in proximal humeral morphology among the taxa studied, which had thus far largely remained unnoticed. Based on morphofunctional considerations, these anatomical differences can be correlated to differences in the locomotor repertoires of the taxa, thus confirming that the proximal humerus is suitable for constructing paleobiological inferences about locomotion. Modern humans display markedly divergent features, which set them apart from both the extant great apes and the fossil hominin A. afarensis. The morphology of the proximal epiphysis of the humerus of the latter more closely resembles that of the orangutans, thus suggesting that despite hindlimb adaptations to bipedalism, the forelimb of this taxon was still functionally involved in arboreal behaviors, such as climbing or suspension. PMID- 22946499 TI - Proline as chiral auxiliary for the economical asymmetric synthesis of ruthenium(II) polypyridyl complexes. AB - A straightforward method for the synthesis of virtually enantiomerically pure ruthenium(II) polypyridyl complexes [Ru(pp)(pp')(pp")](PF(6))(2), pp = bidentate polypyridyl has been developed. The synthesis draws from the readily available racemic starting material cis-[Ru(pp)(pp')Cl(2)] and the natural amino acids l- or d-proline and relies on a dynamic asymmetric transformation under thermodynamic control. PMID- 22946500 TI - Anastomosis of both posterior and anterior flaps or only anterior flaps in external dacryocystorhinostomy. AB - PURPOSE: To evaluate the outcomes of external dacryocystorhinostomy (DCR) by using two different patterns of flap anastomosis; one only with anterior flap anastomosis and the other with both anterior and posterior flap anastomosis. METHODS: One hundred and sixty-four patients were enrolled in the study. Patients were then randomly divided into two groups as follows: those who underwent DCR with both anterior and posterior flap anastomosis (Group 1) and those who underwent DCR with only anterior flap anastomosis (Group 2). Surgical success was defined as patient satisfaction, disappearance of epiphora and lacrimal patency up to 12 months after surgery. RESULTS: After 12 months, the DCR with both anterior and posterior flap anastomosis had a success rate of 89.8% (71/79), while the DCR with only anterior flap anastomosis had a success rate of 89.4% (76/85). There was no statistically significant difference between the two groups (p < 0.05). CONCLUSION: Anastomosis of posterior flaps does not seem to affect success rate of external DCR. Creating only the anterior anastomosis is technically simpler and does not seem to negatively influence the outcome of DCR surgery. PMID- 22946501 TI - Direct experimental evidence for dissociative photoionization of oxygen molecule via 2Sigma(u)(-) ionic "optical dark" state. AB - Direct experimental evidence for dissociative photoionization of oxygen molecule via the (2)Sigma(u)(-) ionic optical dark state is presented by an investigation using the method of threshold photoelectron-photoion coincidence (TPEPICO) velocity imaging. Besides vibrational progress of the B(2)Sigma(g)(-) state, several weak vibrational bands of the (2)Sigma(u)(-) ionic optical dark state are observed concomitantly in an excitation energy range of 20.2-21.1 eV. Only O(+) fragments are detected in the whole excitation energy range; therefore, all vibrational bands are completely predissociative. TPEPICO three-dimensional time sliced velocity images of O(+) fragments dissociated from vibrational state selected O(2)(+)((2)Sigma(u)(-),v(+)) ions are recorded. For the (2)Sigma(u)( )(v(+)=0-3) vibrational states, only the lowest dissociation channel of O(+)((4)S) + O((3)P) is observed. Once the photon energy is slightly increased to the (2)Sigma(u)(-)(v(+)=4) level, a new concentric doughnut appears in the image, indicating that the second dissociation channel of O(+)((4)S) + O((1)D) is identified indeed. With the aid of potential energy curves, the dissociative mechanism of O(2)(+) in the (2)Sigma(u)(-)(v(+)) state is proposed. PMID- 22946502 TI - Enantioselective approach to 13a-methylphenanthroindolizidine alkaloids. AB - The first enantioselective approach to 13a-methylphenanthroindolizidine alkaloids is reported, featuring an efficient stereoselective Seebach's alkylation and Pictet-Spengler cyclization. The proposed and other three most probable structures were ruled out, indicating hypoestestatin 1 needs further assignment. PMID- 22946503 TI - Differentiated thyroid carcinoma after iodine-131 metaiodobenzylguanidine treatment for neuroblastoma: assessment of causality. PMID- 22946504 TI - Temperature distribution analysis of tissue water vaporization during microwave ablation: experiments and simulations. AB - The temperature distribution in the region near a microwave antenna is a critical factor that affects the entire temperature field during microwave ablation of tissue. It is challenging to predict this distribution precisely, because the temperature in the near-antenna region varies greatly. The effects of water vaporisation and subsequent tissue carbonisation in an ex vivo porcine liver were therefore studied experimentally and in simulations. The enthalpy and high temperature specific absorption rate (SAR) of liver tissues were calculated and incorporated into the simulation process. The accuracy of predictions for near field temperatures in our simulations has reached the level where the average maximum error is less than 5 degrees C. In addition, a modified thermal model that accounts for water vaporisation and the change in the SAR distribution pattern is proposed and validated with experiment. The results from this study may be useful in the clinical practice of microwave ablation and can be applied to predict the temperature field in surgical planning. PMID- 22946505 TI - Evaluation effect of microwave irradiation on the amount of volatile compounds, monoterpenes and sesquiterpenoids from Thymus kotschyanus Boiss with four methods. AB - This article investigates the effect of microwaves on the amount of volatile compounds from Thymus kotschyanus Boiss with four methods, headspace single-drop microextraction, microwave-assisted headspace single-drop microextraction, microwave distillation extraction and hydrodistillation, for the analysis of essential oil. Solvent selection, solvent volume, microwave power, irradiation time and sample mass were optimised by simplex method. PMID- 22946506 TI - Development of a single-tube loop-mediated isothermal amplification assay for detection of four pathogens of bacterial meningitis. AB - Several loop-mediated isothermal amplification (LAMP) assays have been developed to detect common causative pathogens of bacterial meningitis (BM). However, no LAMP assay is reported to detect Streptococcus agalactiae and Streptococcus suis, which are also among common pathogens of BM. Moreover, it is laborious and expensive by performing multiple reactions for each sample to detect bacterial pathogen. Thus, we aimed to design and develop a single-tube LAMP assay capable of detecting multiple bacterial species, based on the nucleotide sequences of the 16S rRNA genes of the bacteria. The nucleotide sequences of the 16S rRNA genes of main pathogens involved in BM were aligned to identify conserved regions, which were further used to design broad range specific LAMP assay primers. We successfully designed a set of broad range specific LAMP assay primers for simultaneous detection of four species including Staphylococcus aureus, Streptococcus pneumoniae, S. suis and S. agalactiae. The broad range LAMP assay was highly specific without cross-reactivity with other bacteria including Haemophilus influenzae, Neisseria meningitidis and Escherichia coli. The sensitivity of our LAMP assay was 100-1000 times higher compared with the conventional PCR assay. The bacterial species could be identified after digestion of the LAMP products with restriction endonuclease DdeI and HaeIII. PMID- 22946507 TI - Pelvis feature extraction and classification of Cardiff body match rig base measurements for input into a knowledge-based system. AB - The purpose of this paper is to determine whether it is possible to use an automated measurement tool to clinically classify clients who are wheelchair users with severe musculoskeletal deformities, replacing the current process which relies upon clinical engineers with advanced knowledge and skills. Clients' body shapes were captured using the Cardiff Body Match (CBM) Rig developed by the Rehabilitation Engineering Unit (REU) at Rookwood Hospital in Cardiff. A bespoke feature extraction algorithm was developed that estimates the position of external landmarks on clients' pelvises so that useful measurements can be obtained. The outputs of the feature extraction algorithms were compared to CBM measurements where the positions of the client's pelvis landmarks were known. The results show that using the extracted features facilitated classification. Qualitative analysis showed that the estimated positions of the landmark points were close enough to their actual positions to be useful to clinicians undertaking clinical assessments. PMID- 22946508 TI - The International Menopause Study of Climate, Altitude, Temperature (IMS-CAT) and vasomotor symptoms. AB - OBJECTIVE: To examine the relationship between climate (including altitude, temperature, humidity and annual range of temperature) and experience of hot flushes and night sweats amongst Spanish-speaking mid-aged women living in five urban centers. METHODS: A total of 896 peri- and postmenopausal women from centers in Chile (Santiago de Chile), Ecuador (Guayaquil and Quito), Panama (Panama City) and Spain (Madrid) completed questionnaires eliciting information about sociodemographics, hot flushes (prevalence, frequency and problem-rating), health and lifestyle (body mass index, diet, exercise, alcohol use) and mood (Women's Health Questionnaire). RESULTS: There was a wide range of altitude and temperature in the participating centers. Of the sample, 58.5% (524/896) were currently experiencing vasomotor symptoms. Prevalence was associated with higher temperatures, while hot flushes were more frequent and problematic for women living in higher temperature and lower altitudes. Hot flush variables were not associated with seasonal variation in temperature. When health and lifestyle variables were included as covariates in regression analyses, prevalence was best predicted by age (younger), poor general health, more depressed mood and anxiety; hot flush frequency by anxiety, temperature, life satisfaction (lower), age (higher), regular strenuous exercise (more strenuous exercise more frequent), and a diet including regular hot spicy food intake. Hot flush problem-rating was best predicted by anxiety, life satisfaction, altitude (lower more problematic), any regular exercise (more exercise less problematic), and depressed mood. CONCLUSIONS: In this study of Spanish-speaking women, those living in countries with higher temperatures and lower altitudes reported more frequent and problematic hot flushes. PMID- 22946509 TI - A dynamic FRET reporter of gene expression improved by functional screening. AB - Here, we describe a reporter system that consists of a FRET biosensor and its corresponding aptamer. The FRET biosensor employs the synthetic aptamer binding peptide Rsg1.2 sandwiched between mutants of the Green Fluorescent Protein and undergoes FRET when binding its corresponding Rev Responsive Element (RRE) RNA aptamer. We developed a novel approach to engineer FRET biosensors by linker extension and screening to improve signal strength of the biosensor which we called VAmPIRe (Viral Aptamer binding Peptide based Indicator for RNA detection). We demonstrate that the system is quantitative, reversible and works with high specificity in vitro and in vivo in living bacteria and mammalian cells. Thus, VAmPIRe may become valuable for RNA localizations and as a dynamic RNA-based reporter for live cell imaging. Moreover, functional screening of large libraries as demonstrated here may become applicable to optimize some of the many FRET biosensors of cellular signaling. PMID- 22946510 TI - Total synthesis of incarvilleatone and incarviditone: insight into their biosynthetic pathways and structure determination. AB - A concise biomimetic total synthesis of incarvilleatone and incarviditone is achieved in one pot via the highly stereoselective hetero- and homodimerization of (+/-)-rengyolone, respectively. The structure of incarviditone is revised on the basis of spectroscopic and computational evidence. PMID- 22946512 TI - Critical issues on high-dose chemotherapy with autologous hematopoietic progenitor cell transplantation in breast cancer patients. AB - INTRODUCTION: High-dose chemotherapy (HDC) with autologous hematopoietic progenitor cell transplantation (AHPCT) for high-risk (HR) or metastatic breast cancer (MBC) is no longer an option. AREAS COVERED: An expert panel including medical oncologists and hematologists produce an opinion paper on the use of HDC and AHPCT in BC patients and they explain why they believe that; despite inconclusive results thus far, this treatment should have an ongoing role in breast cancer management under clinical trials. EXPERT OPINION: HDC with AHPCT has become a safe treatment modality and an advantage in disease-free survival has been observed in most of the studies with HDC, with the caveat that today, even a limited relapse-free survival and progression-free survival benefit is sufficient for the approval of new antineoplastic agents. Moreover, in HRBC, an overall survival benefit by HDC could be achieved in the HER2-ve and triple negative populations and, in this setting, HDC with AHPCT represents a therapeutic option that can be proposed to well-informed patients. In MBC, the HDC approach should be investigated further in selected patients with HER2-ve, chemosensitive disease. This paper is not intended to give any conclusion, but rather to open a debate on the value of HDC in HR and MBC. PMID- 22946511 TI - Receptor activity-modifying protein-dependent impairment of calcitonin receptor splice variant Delta(1-47)hCT((a)) function. AB - BACKGROUND AND PURPOSE: Alternative splicing expands proteome diversity to GPCRs. Distinct receptor variants have been identified for a secretin family GPCR, the calcitonin receptor (CTR). The possible functional contributions of these receptor variants are further altered by their potential interactions with receptor activity-modifying proteins (RAMPs). One variant of the human CTR lacks the first 47 residues at its N terminus [Delta(1-47)hCT((a)) ]. However, very little is known about the pharmacology of this variant or its ability to interact with RAMPs to form amylin receptors. EXPERIMENTAL APPROACH: Delta(1-47)hCT((a)) was characterized both with and without RAMPs in Cos7 and/or HEK293S cells. The receptor expression (ELISA assays) and function (cAMP and pERK1/2 assays) for up to six agonists and two antagonists were determined. KEY RESULTS: Despite lacking 47 residues at the N terminus, Delta(1-47)hCT((a)) was still able to express at the cell surface, but displayed a generalized reduction in peptide potency. Delta(1-47)hCT((a)) retained its ability to interact with RAMP1 and formed a functional amylin receptor; this also appeared to be the case with RAMP3. On the other hand, its interaction with RAMP2 and resultant amylin receptor was reduced to a greater extent. CONCLUSIONS AND IMPLICATIONS: Delta(1-47)hCT((a)) acts as a functional receptor at the cell surface. It exhibits altered receptor function, depending on whether it associates with a RAMP and which RAMP it interacts with. Therefore, the presence of this variant in tissues will potentially contribute to altered peptide binding and signalling, depending on the RAMP distribution in tissues. PMID- 22946513 TI - Kidney transplant outcomes are related to tacrolimus, mycophenolic acid and prednisolone exposure in the first week. AB - This study analysed associations between tacrolimus, mycophenolic acid (MPA) and prednisolone exposures on day 4 and month 1 post kidney transplant and clinical outcomes. Area under the concentration-time curve (AUC) for each drug was estimated using validated multiple regression-derived limited sampling strategies. Multivariate logistic regression was used to associate drug exposure with clinical outcomes. One hundred and twenty subjects were studied. Between subject variability in dose-adjusted exposure to each medication was high. Both day 4 tacrolimus and MPA exposures were independently predictive of delayed graft function (2.6 change in odds for a standard deviation (SD) increase in tacrolimus AUC(0-12) , P = 0.02; 0.23 change in odds for a SD increase in MPA AUC(0-12) , P = 0.02). Both day 4 MPA and total prednisolone exposures were independently predictive of rejection (0.20 change in odds for a SD increase in MPA AUC(0-12) , P = 0.04; 0.40 change in odds for a SD increase in total prednisolone AUC(0-6) , P = 0.03). Lowest tertile exposure to all three immunosuppressant medications imposed significantly higher odds of rejection [adjusted odds ratio 34.2 (95% CI 4.1, 284.4), P = 0.001]. This study highlights the importance of achieving early target exposure and suggests a potential role for individualized initial dosing or early therapeutic monitoring of all three immunosuppressive agents. PMID- 22946514 TI - Theoretical studies of chemical reactivity of metabolically activated forms of aromatic amines toward DNA. AB - The metabolism of aromatic and heteroaromatic amines (ArNH2) results in nitrenium ions (ArNH+) that modify nucleobases of DNA, primarily deoxyguanosine (dG), by forming dG-C8 adducts. The activated amine nitrogen in ArNH+ reacts with the C8 of dG, which gives rise to mutations in DNA. For the most mutagenic ArNH2, including the majority of known genotoxic carcinogens, the stability of ArNH+ is of intermediate magnitude. To understand the origin of this observation as well as the specificity of reactions of ArNH+ with guanines in DNA, we investigated the chemical reactivity of the metabolically activated forms of ArNH2, that is, ArNHOH and ArNHOAc, toward 9-methylguanine by DFT calculations. The chemical reactivity of these forms is determined by the rate constants of two consecutive reactions leading to cationic guanine intermediates. The formation of ArNH+ accelerates with resonance stabilization of ArNH+, whereas the formed ArNH+ reacts with guanine derivatives with the constant diffusion-limited rate until the reaction slows down when ArNH+ is about 20 kcal/mol more stable than PhNH+. At this point, ArNHOH and ArNHOAc show maximum reactivity. The lowest activation energy of the reaction of ArNH+ with 9-methylguanine corresponds to the charge transfer pi-stacked transition state (pi-TS) that leads to the direct formation of the C8 intermediate. The predicted activation barriers of this reaction match the observed absolute rate constants for a number of ArNH+. We demonstrate that the mutagenic potency of ArNH2 correlates with the rate of formation and the chemical reactivity of the metabolically activated forms toward the C8 atom of dG. On the basis of geometric consideration of the pi-TS complex made of genotoxic compounds with long aromatic systems, we propose that precovalent intercalation in DNA is not an essential step in the genotoxicity pathway of ArNH2. The mechanism-based reasoning suggests rational design strategies to avoid genotoxicity of ArNH2 primarily by preventing N-hydroxylation of ArNH2. PMID- 22946516 TI - Covalent electron transfer chemistry of graphene with diazonium salts. AB - Graphene is an atomically thin, two-dimensional allotrope of carbon with exceptionally high carrier mobilities, thermal conductivity, and mechanical strength. From a chemist's perspective, graphene can be regarded as a large polycyclic aromatic molecule and as a surface without a bulk contribution. Consequently, chemistries typically performed on organic molecules and surfaces have been used as starting points for the chemical functionalization of graphene. The motivations for chemical modification of graphene include changing its doping level, opening an electronic band gap, charge storage, chemical and biological sensing, making new composite materials, and the scale-up of solution-processable graphene. In this Account, we focus on graphene functionalization via electron transfer chemistries, in particular via reactions with aryl diazonium salts. Because electron transfer chemistries depend on the Fermi energy of graphene and the density of states of the reagents, the resulting reaction rate depends on the number of graphene layers, edge states, defects, atomic structure, and the electrostatic environment. We limit our Account to focus on pristine graphene over graphene oxide, because free electrons in the latter are already bound to oxygen-containing functionalities and the resulting chemistries are dominated by localized reactivity and defects. We describe the reaction mechanism of diazonium functionalization of graphene and show that the reaction conditions determine the relative degrees of chemisorption and physisorption, which allows for controlled modulation of the electronic properties of graphene. Finally we discuss different applications for graphene modified by this chemistry, including as an additive in polymer matrices, as biosensors when coupled with cells and biomolecules, and as catalysts when combined with nanoparticles. PMID- 22946515 TI - Acetate-bridged platinum(III) complexes derived from cisplatin. AB - Oxidation of the acetate-bridged half-lantern platinum(II) complex cis [Pt(II)(NH(3))(2)(MU-OAc)(2)Pt(II)(NH(3))(2)](NO(3))(2), [1](NO(3))(2), with iodobenzene dichloride or bromine generates the halide-capped platinum(III) species cis-[XPt(III)(NH(3))(2)(MU-OAc)(2)Pt(III)(NH(3))(2)X](NO(3))(2), where X is Cl in [2](NO(3))(2) or Br in [3](NO(3))(2), respectively. These three complexes, characterized structurally by X-ray crystallography, feature short (~2.6 A) Pt-Pt separations, consistent with formation of a formal metal-metal bond upon oxidation. Elongated axial Pt-X distances occur, reflecting the strong trans influence of the metal-metal bond. The three structures are compared to those of other known dinuclear platinum complexes. A combination of (1)H, (13)C, (14)N, and (195)Pt NMR spectroscopy was used to characterize [1](2+)-[3](2+) in solution. All resonances shift downfield upon oxidation of [1](2+) to [2](2+) and [3](2+). For the platinum(III) complexes, the (14)N and (195)Pt resonances exhibit decreased line widths by comparison to those of [1](2+). Density functional theory calculations suggest that the decrease in the (14)N line width arises from a diminished electric field gradient at the (14)N nuclei in the higher valent compounds. The oxidation of [1](NO(3))(2) with the alternative oxidizing agent bis(trifluoroacetoxy)iodobenzene affords the novel tetranuclear complex cis-[(O(2)CCF(3))Pt(III)(NH(3))(2)(MU-OAc)(2)Pt(III)(NH(3))(MU NH(2))](2)(NO(3))(4), [4](NO(3))(4), also characterized structurally by X-ray crystallography. In solution, this complex exists as a mixture of species, the identities of which are proposed. PMID- 22946517 TI - Introduction of 2011-2012 ASP President Armand M. Kuris. PMID- 22946518 TI - Correlation between posterior offset of femoral condyles and sagittal slope of the tibial plateau. AB - The aim of this study was to address, in normal knees, the variability of posterior offset of femoral condyles and tibial slope, and the presence of any correlation between the two that might be needed to achieve an adequate joint motion in flexion. Magnetic resonance images of normal knees of 80 subjects, 45 males and 35 females, with a mean age of 38.9 years, were analysed. Measurements were performed by two independent observers using an imaging visualization software. The tibial slope averaged 8 and 7.7 degrees , on the medial and lateral sides, respectively (P = 0.2); the mean posterior offset of femoral condyles was 27.4 and 25.2 mm on the two sides, respectively (P = 0.0001). The variation coefficient of the condylar offset and tibial slope was 11.5 and 38%, respectively. In the medial compartment, a significant correlation was found between the femoral condylar offset and the tibial slope, while the same was not observed in the lateral compartment of the knee. Magnetic resonance imaging allows the assessment of tibial slope and femoral condylar offset in the medial and lateral side separately, taking into account any difference between the two compartments. The sagittal tibial slope exhibits a greater variability compared with the posterior offset of femoral condyles. The correlation found, in the medial compartment, between the tibial slope and femoral condylar offset suggests that the reconstitution of the proper morphology of the posterior part of the knee joint may be necessary to obtain a full range of motion in flexion after total knee replacement. PMID- 22946519 TI - Effect of coffee combining green coffee bean constituents with typical roasting products on the Nrf2/ARE pathway in vitro and in vivo. AB - This study investigated Nrf2-activating properties of a coffee blend combining raw coffee bean constituents with 5-O-caffeoylquinic acid (CGA) as a lead component with typical roasting products such as N-methylpyridinium (NMP). In cell culture (HT29) the respective coffee extract (CN-CE) increased nuclear Nrf2 translocation and enhanced the transcription of ARE-dependent genes as exemplified for NAD(P)H:quinone oxidoreductase and glutathione-S-transferase (GST)A1, reflected in the protein level by an increase in GST enzyme activity. In a pilot human intervention study (29 healthy volunteers), daily consumption of 750 mL of CN-coffee for 4 weeks increased Nrf2 transcription in peripheral blood lymphocytes on average. However, the transcriptional response pattern of Nrf2/ARE dependent genes showed substantial interindividual variations. The presence of SNPs in the Nrf2-promoter, reported recently, as well as the detection of GSTT1*0 (null) genotypes in the study collective strengthens the hypothesis that coffee acts as a modulator of Nrf2-dependent gene response in humans, but genetic polymorphisms play an important role in the individual response pattern. PMID- 22946520 TI - Epidemiology of parainfluenza virus types 1, 2 and 3 infections based on virus isolation between 2002 and 2011 in Yamagata, Japan. AB - To clarify the epidemiology of viral acute respiratory infections (ARIs), 305 human parainfluenza virus types 1 (HPIV1), 154 HPIV2 and 574 HPIV3 strains were isolated from 16,962 nasopharyngeal swabs obtained between 2002 and 2011 at pediatric clinics in Yamagata, Japan. The total isolation frequency for HPIV1-3 was 6.1%. Unlike HPIV1 infections, HPIV3 showed clear seasonality with yearly outbreaks in the spring-summer season. HPIV2 tended to appear biannually in autumn-winter. Although no reliable techniques for the laboratory diagnosis of these infections have been established, the present results suggest that HPIV1-3 are an important causative agent of ARIs in children. PMID- 22946521 TI - The natural history of cognitive decline in Alzheimer's disease. AB - The study aim was to describe the temporal course of cognitive decline in Alzheimer's disease (AD). We selected 226 persons from 2 longitudinal clinical pathological studies who were cognitively healthy at baseline, followed at least 4 years (M = 10.2, SD = 3.5), and clinically diagnosed with AD at some point during follow-up. Each evaluation included a battery of 17 cognitive tests from which a previously established composite measure of global cognition was derived. In those who died, a uniform neuropathologic examination established the pathological diagnoses of Alzheimer's disease and other common conditions that impair cognition. Mixed-effects models with 2 change points were used to assess trajectories of cognitive decline. In the main analysis, there was no change in cognitive function until a mean of 7.5 years before dementia was diagnosed (95% confidence interval [CI]: -8.3, -6.7). The global cognitive measure declined a mean of 0.087-unit per year (95% CI: -0.099, -0.073) until a mean of 2.0 years before the diagnosis (95% CI: -2.2, -1.7) when it increased more than 4-fold to a mean loss of 0.370-unit per year (95% CI: -0.417, -0.334). Of 126 individuals who died and underwent autopsy, 101 (80%) met pathologic criteria for AD, of whom 67 had at least one other pathologic condition. Pathologic measures of AD and cerebral infarction were not strongly related to cognitive trajectories. The results indicate that cognitive decline in AD begins many years before dementia is diagnosed and accelerates during the course of the disease. PMID- 22946522 TI - Associations among fluid and crystallized cognition and daily stress processes in older adults. AB - The current study examined associations among fluid and crystallized cognition, and daily stress processes in older adults. Older adults (N = 107) completed measures of daily stressors and affect on six occasions over 2 weeks, as well as measures of fluid and crystallized cognition. Higher crystallized cognition was associated with a greater likelihood of exposure to daily stressors, including arguments and avoided arguments. Higher fluid cognition was associated with diminished emotional reactivity to daily stressors for negative but not positive affect. Discussion focuses on the roles of fluid and crystallized cognition for understanding daily stress processes, daily activity and lifestyle, and health. PMID- 22946524 TI - A diffusion model account of age differences in posterror slowing. AB - People generally slow down after they make an error, a phenomenon that is more pronounced for older individuals than it is for young individuals. Here, we examine the origin of this age-related difference in posterror slowing (PES) by applying the diffusion model to data from young and older participants performing a random dot motion task and a lexical decision task. Results show that the PES effects on response time and accuracy were qualitatively different for young and older participants. A diffusion model analysis revealed that following an error, older participants became more cautious, processed information less effectively, and spent more time on irrelevant processes. This pattern was evident in both the random dot motion task and the lexical decision task. For young participants, in contrast, the origin of the PES effect depended on the task that was performed: In the random dot motion task, the PES effect was due to time spent on irrelevant processes; in the lexical decision task, the PES effect was due to increased caution and decreased effectiveness in information processing. Overall, PES effects were much larger in the lexical decision task than in the random dot motion task. These findings indicate that PES originates from the interplay of different psychological processes whose contribution depends on both task settings and individual differences. PMID- 22946525 TI - The region of proximal learning heuristic and adult age differences in self regulated learning. AB - Younger, middle-aged, and older adults were asked to study 36 Chinese-English vocabulary pairs of different complexity levels from grids where presentation order was randomized and no information about item complexity was provided. Of interest was whether participants' item selection and study time allocation would initially favor simple items, as predicted by Metcalfe's (2002) region of proximal learning (RPL) model, or complex items, as suggested by the discrepancy reduction model (DRM; Nelson & Leonesio, 1988), when participants had to select items based on something other than similarity to English. Each age group gauged item complexity similarly and made a similar use of the RPL heuristic in initial selection and study behaviors. However, older adults were more likely to restudy and allocate more time to simpler items, suggesting that, at least for restudy, older adults particularly relied on the RPL heuristic. Results are discussed in terms of self-regulated learning models. PMID- 22946523 TI - Stress modulates reinforcement learning in younger and older adults. AB - Animal research and human neuroimaging studies indicate that stress increases dopamine levels in brain regions involved in reward processing, and stress also appears to increase the attractiveness of addictive drugs. The current study tested the hypothesis that stress increases reward salience, leading to more effective learning about positive than negative outcomes in a probabilistic selection task. Changes to dopamine pathways with age raise the question of whether stress effects on incentive-based learning differ by age. Thus, the present study also examined whether effects of stress on reinforcement learning differed for younger (age 18-34) and older participants (age 65-85). Cold pressor stress was administered to half of the participants in each age group, and salivary cortisol levels were used to confirm biophysiological response to cold stress. After the manipulation, participants completed a probabilistic learning task involving positive and negative feedback. In both younger and older adults, stress enhanced learning about cues that predicted positive outcomes. In addition, during the initial learning phase, stress diminished sensitivity to recent feedback across age groups. These results indicate that stress affects reinforcement learning in both younger and older adults and suggests that stress exerts different effects on specific components of reinforcement learning depending on their neural underpinnings. PMID- 22946526 TI - Identification of structural and electronic features for a series of MCH1R antagonists. AB - MCH1R antagonists have been used to treat several diseases, such as obesity, depression and anxiety. In this study, we have performed several pharmacophore based CoMFA studies for a series of 2,4,6 substituted quinolines as potent antagonists of MCH1R. Significant statistical results were obtained (q2 = 0.78, r2 = 0.99), indicating the high internal consistency of the 3D model generated, as well as its predictive power for untested compounds. The 3D model was externally validated employing a test set and the predicted biological values showed good agreement with experimental results. Important insights on the molecular interactions between the studied ligands and the MCH1R receptor, inferred from the 3D contour maps, were obtained and can be useful for the design of new structurally related analogs with improved binding affinity. PMID- 22946527 TI - Synthesis, p38 kinase inhibitory and anti-inflammatory activity of new substituted benzimidazole derivatives. AB - P38 mitogen activated protein kinases have been found to involve in the production and release of unwarranted levels of pro-inflammatory cytokines including TNFalpha and IL-1beta in numerous inflammatory diseases. A new series of molecules, 5-substituted benzoylamino-2-substituted phenylbezimidazoles has been synthesized from 4-nitro-1, 2- diaminobenzene. The synthesized compounds were characterized by FTIR, 1HNMR and Mass. The final compounds were screened for in vitro p38 kinase inhibitory and in vivo anti-inflammatory activity. Three compounds from the series demonstrated nearly 50% inhibition of p38 kinase in the in vitro screening method at 10 MUM concentration and two molecules exhibited greater than 75% inhibition of paw oedema volume during the first hour. The docking study of synthesized molecule revealed a new binding pose in ATP binding pocket. PMID- 22946528 TI - Synthesis and study the antimicrobial activity of novel 2-(1H-indol-3-yl)- N-(3, 4-diphenylthiazol-2(3H)-ylidene) ethanamine derivatives. AB - A series of novel 2-(1H-indol-3-yl)-N-(3, 4-diphenylthiazol-2(3H)-ylidene) ethanamine derivatives (5a-o) were synthesized by cyclization of corresponding 1 (2-(1H-indol-3-yl) ethyl)-3-phenylthiourea 3 with 2-bromoacetophenone. All synthesized compounds were evaluated for in vitro antibacterial activity using Gram-positive bacteria and Gram-negative bacteria. In vitro antifungal activity also determined against the five fungal species. Structures of the synthesized compounds were established by elemental analysis and spectral data. PMID- 22946529 TI - Parallel synthesis of "click" chalcones as antitubulin agents. AB - It has been shown that some chalcones are able to inhibit tubulin polymerization, giving cytotoxicity and destruction of tumoral vasculature. A library of 180 novel chalcone analogs has been synthesized via click chemistry and screened for their cytotoxicity and tubulin assembly inhibition. 10 out 180 click chalcones displayed low micromolar cytotoxicity but only compound Nf depicted antitubulin activity. While Nf displayed only micromolar potency this result shows click chalcones may be anti-tubulin agents and validate this strategy to search for novel active chemical entities. PMID- 22946530 TI - Computer aided discovery of potential anti-inflammatory (S)-naproxen analogs as COX-2 inhibitors. AB - A series of substituted 2-(6-methoxynapthalen-2-yl) propanoic acid (naproxen) analogs were synthesized. (S)- naproxen (1) was treated with thionyl chloride to yield acid chloride (2) which was then reacted with different heterocyclic moieties and aryl acids to yield the (S)-naproxen analogs (3a-k). All the compounds were screened for antiinflammatory activity using in vivo rat paw oedema model and most of the active ones were investigated for their ulcerogenic potential. In silico studies (molecular modeling and docking) were carried out to recognize the hypothetical binding motif of the title compounds with the cyclooxygenase isoenzymes (COX-1 and COX-2) employing Maestro (Version 9.1, Schrodinger, LLC.) software. 2-(1-(2(2-methoxynaphthalen-6-yl)propanoyl)-1H-indol 2-yl) acetic acid (3k) was found to be the most active compound amongst the series with inhibition of paw edema volume by 62.1%, in silico sitemap score of 0.40kcal/mol and ulcerogenic index as least as 1.19. PMID- 22946532 TI - Synthesis and antimalarial activity study of some new Mannich bases of 7-chloro-4 aminoquinoline. AB - New derivatives of 7-chloro-4-aminoquinoline Mannich base were prepared by selectively modifying the aliphatic diethyl amino function of isoquine with different aliphatic/aromatic heterocyclic primary amino moieties at Mannich side chain. The synthesized compounds were characterized by their analytical and spectral data, and screened for in-vitro antimalarial activity against a chloroquine-sensitive 3D7 strain of Plasmodium falciparum. All the compounds showed in-vitro antimalarial activity at the tested dose; which, however, was considerably less than that of the standard reference drug, chloroquine. Among synthesized compounds, compounds with cyclohexyl (2f), methyl (2c) substitutions showed better activity than compounds substituted with n-octyl (2a), propyl (2b), 3-aminopropyl (2d) and furan-2- ylmethyl (2e) moieties at aminomethyl side chain. The results clearly demonstrate that the compound substituted with saturated cycloalkyl moiety (cyclohexyl) exhibited to some extent increased activity as compared to the compound containing heterocyclic moiety (furan-2-ylmethyl), and compounds with short chain alkyl substitutions (methyl, propyl) were found to be more active than that of compounds with long chain alkyl substitution (n-octyl). PMID- 22946531 TI - Exploring the biological potential of urea derivatives against mPGES-1: a combination of quantum mechanics, pharmacophore modelling and QSAR analyses. AB - In the present molecular modelling study, recently discovered 36 selective urea derivatives were considered to develop pharmacophore based 3D-QSAR model coupled with quantum mechanics (QM) calculations to uncover the essential structural features of urea molecules for mPGES-1 inhibition. The 3D-QSAR model was selected on the basis of highest values of external predictability parameters i.e. Q2 (0.775) and Pearson-r (0.912). The model also showed the highest values of R2, 0.985; F-value, 306.3 and least SD, 0.147. The selected model was further validated for its external prediction power by calculating k, k' , R2 o and R'2 o. The contour maps generated against the selected QSAR model helped to interpret the important molecular sites of urea derivatives where the suitable structural modifications would help in better complementary fit to the active site of mPGES 1, in turn would improve the potency of newly designed molecules. PMID- 22946533 TI - Investigations towards new antidiabetic drugs from fungal endophytes associated with Salvadora oleoides Decne. AB - The nature has provided abundant natural resources which can be explored for their medicinal uses. The present study was undertaken to investigate the antidiabetic and hypolipidemic activity of various extract's fractions obtained from mycelia of seventeen endophytic fungi in different solvents (methanol, acetone and aqueous) isolated from Salvadora oleoides Decne (Salvadoraceae) in glucose loaded fasting and alloxan induced diabetic Wistar albino rats. Only four extracts namely; unidentified fungus (aqueous), Aspergillus sp.JPY2 (methanol), Aspergillus sp.JPY1 (methanol) and Phoma sp. (acetone) significantly reduced blood glucose levels as revealed by glucose tolerance test. It has been observed that in alloxan induced diabetic rats, the maximum reduction in blood glucose level was after 5 hours in the acute treatment experiment and on14th day in sub acute treatment at a dose of 250mg/kg of body weight (P<0.05). The reduction in blood glucose in long term treatment experiment was ranged from 11.3% to 28.04%, whereas standard drug tolbutamide reduced the blood glucose level up to 40%. In long term treatment, unidentified fungus (aqueous) extract showed significant improvement in parameters like body weight and lipid profile of alloxan induced diabetic rats. The gas chromatography mass spectrometer (GCMS) analysis of bioactive fraction (aqueous) of unidentified fungus and methanolic extract fraction of Aspergillus sp.JPY1 revealed that the main constituents were 2, 6-di tert-butyl-p-cresol and Phenol, 2, 6-bis (1, 1-dimethylethyl)-4-methyl respectively. The results have also suggested that the above four bioactive fractions have good margin of safety and did not show any lethal effects on the animals up to the doses of 1000mg/kg b.w. along with safe doses up to 500 MUg/ ml to human erythrocytes. PMID- 22946534 TI - Synthesis and biological activities of new halophenols. AB - A series of new halophenols were synthesized, and their structures were established on the basis of 1H, 13C NMR and mass spectral data. All of the prepared compounds were screened for their in vitro protein tyrosine kinase (PTK) and vascular smooth muscle cell (VSMC) proliferation inhibitory activity. Twelve halophenols showed significant PTK inhibitory activity, most of them exhibited stronger activities than that of genistein, a positive reference compound. Several halophenols also displayed moderate VSMC proliferation inhibitory activity, compound 8c showed higher activity than that of tetrandrine, a positive reference compound. The preliminary structure-activity relationships of these compounds were investigated and discussed. The results provided a foundation for the action mechanism study and further structure optimization of the halophenols. PMID- 22946535 TI - Synthesis, antifungal evaluation and molecular docking studies on 2- thioxoimidazolidin-4-one derivatives. AB - A series of 2-thioxoimidazolidin-4-one derivatives were synthesized and were characterized by IR, 1H NMR, 13C NMR, mass spectral data and elemental analysis. All compounds were tested for antifungal and antibacterial activity. Some of the compounds were found to exhibit promising antifungal activity. Molecular modeling investigations showed that the active compounds may interact at the active site of the fungal cytochrome P450- dependent sterol 14alpha- demethylase in the sterol biosynthesis pathway. PMID- 22946536 TI - 2012 ISBRA (International Society for Biomedical Research on Alcoholism) World Congress. September 8-12, 2012. Sapporo, Japan. PMID- 22946537 TI - Chemical constituents of the leaf of Alpinia mutica Roxb. AB - Hydrodistillation of the fresh leaves of Alpinia mutica afforded 0.005% colourless essential oil. GC and GC-MS analysis revealed the presence of 33 components accounting for 92.9% of the total oil, dominated by 20 sesquiterpenes (76.7%) and 10 monoterpenes (8.3%). The major constituent was found to be beta sesquiphellandrene which was 29.2% of the total oil. Soxhlet extraction, followed by repeated column chromatography of the dried leaves yielded two phenolic compounds, identified as 5,6-dehydrokawain and aniba dimer A, together with one amide assigned as auranamide. The structures of these compounds were determined by using spectroscopic analysis. Antibacterial screening of the essential oil, the crude and isolated compounds showed weak to moderate inhibitory activity. PMID- 22946539 TI - Structural and spectroscopic properties of water around small hydrophobic solutes. AB - We investigated the structural, dynamical and spectroscopic properties of water molecules around a solvated methane by means of Car-Parrinello molecular dynamics simulations. Despite their mobility, in the first shell, water molecules are dynamically displaced in a clathrate-like cage around the hydrophobic solute. No significant differences in water geometrical parameters, in molecular dipole moments or in hydrogen bonding properties, are observed between in-shell and out shell molecules, indicating that liquid water can accommodate a small hydrophobic solute without altering its structural properties. The calculated contribution of the first-shell water molecules to the infrared spectra does not show significant differences with respect the bulk signal once the effects of the missing polarization of second-shell molecules has been taken into account. Small fingerprints of the clathrate-like structure appear in the vibrational density of states in the libration and OH stretching regions. PMID- 22946541 TI - Metal migration processes in homo- and heterobimetallic bismuth(III)-lead(II) porphyrin complexes: emergence of allosteric Newton's cradle-like devices. AB - Metal ion migration in a bis-strapped porphyrin ligand with overhanging carboxylate groups has been investigated in solution. Two types of homobimetallic complexes are generated with Pb(II) and Bi(III) cations, which stand on both sides of the macrocycle: (i) a dissymmetric complex with one cation bound to the porphyrin N core and the other cation hung over the N core through bonding with a carboxylate of a strap; (ii) a C(2)-symmetric complex with both cations coordinated to the N core and to the carboxylate groups of the straps. Variable temperature NMR studies and 2D rotational Overhauser effect spectroscopy NMR experiments have shown that in the former dissymmetric complexes, the two cations undergo a coupled intramolecular migration resulting in exchange of their coordination modes. Such complexes constitute active states of Newton's cradle like devices (NCDs), with the ion migration rate depending on the lability of the metal-ligand interactions [Pb(II) faster than Bi(III) NCDs]. On the other hand, the C(2)-symmetric complexes constitute either an inactive state [with Pb(II)] or a resting state [with Bi(III)] of an NCD, since they correspond respectively to a precursor or an intermediate in the motion of the cations. The NCDs are under both allosteric and acid-base control: (i) with Pb(II), the addition of an allosteric effector such as an acetate anion to the medium allows the conversion of the symmetric form to the dissymmetric one, thus triggering the Newton's cradle-like motion of the cations; (ii) with Bi(III), a lifted state was converted to a resting one by the addition of protons and then restored by the addition of a base. As an extension to nondegenerate systems, a heterobimetallic Bi(III)-Pb(II) complex was selectively obtained, and it constitutes a frozen lifted state of a dissymmetric NCD. All of these homo- and hetero-NCDs could be successively formed by selective metal ion exchange. These unique findings open the way to novel tristable devices. PMID- 22946542 TI - "Whatever my mother wants": barriers to adequate pain management. AB - Opioids are the preferred medications to treat cancer pain; however, several barriers to cancer pain management exist, including those related to the patient, health care provider, and family caregiver. We describe one such situation in which a family member prevents the patient from receiving adequate pain management at the end of life despite interdepartmental and interdisciplinary efforts. This case highlights the importance of understanding and addressing fears regarding opioid use and implementing an integrated approach including oncologists and palliative care physicians, along with early referrals to palliative care. PMID- 22946543 TI - Fe20 cluster units based coordination polymer from in situ ligand conversion and trapping of an intermediate. AB - A coordination polymer based on an unprecedented Fe(20) core has been constructed by in situ ligand conversion, including trapping of an intermediate. PMID- 22946540 TI - Translational neuropharmacology: the use of human isolated gastrointestinal tissues. AB - Translational sciences increasingly emphasize the measurement of functions in native human tissues. However, such studies must confront variations in patient age, gender, genetic background and disease. Here, these are discussed with reference to neuromuscular and neurosecretory functions of the human gastrointestinal (GI) tract. Tissues are obtained after informed consent, in collaboration with surgeons (surgical techniques help minimize variables) and pathologists. Given the difficulties of directly recording from human myenteric neurones (embedded between muscle layers), enteric motor nerve functions are studied by measuring muscle contractions/relaxations evoked by electrical stimulation of intrinsic nerves; responses are regionally dependent, often involving cholinergic and nitrergic phenotypes. Enteric sensory functions can be studied by evoking the peristaltic reflex, involving enteric sensory and motor nerves, but this has rarely been achieved. As submucosal neurones are more accessible (after removing the mucosa), direct neuronal recordings are possible. Neurosecretory functions are studied by measuring changes in short-circuit current across the mucosa. For all experiments, basic questions must be addressed. Because tissues are from patients, what are the controls and the influence of disease? How long does it take before function fully recovers? What is the impact of age- and gender-related differences? What is the optimal sample size? Addressing these and other questions minimizes variability and raises the scientific credibility of human tissue research. Such studies also reduce animal use. Further, the many differences between animal and human GI functions also means that human tissue research must question the ethical validity of using strains of animals with unproved translational significance. PMID- 22946544 TI - High intensity focused ultrasound treatment for patients with advanced pancreatic cancer: a preliminary dosimetric analysis. AB - OBJECTIVE: To analyse the clinical dosimetry of high intensity focused ultrasound (HIFU) for the treatment of inoperable pancreatic cancer in humans. METHODS: 136 patients with advanced pancreatic cancer were treated with HIFU, including 89 male and 47 female patients. The median targeted volume (V(t)) was 31.1 cm(3) (range: 9.8-102.1). The median of the average ultrasound power (P(avg)) was 225 W (range: 117-399), and the median energy of the ultrasound (E(total)) was 278.3 kJ (range: 70.5-1195.2). Spearman rank correlation analysis for HIFU dosimetric analysis was conducted. RESULTS: There was a significant correlation between greyscale changes after HIFU ablation and HIFU dose intensity (DI), P(avg), and unit time (T(u)). However, no correlation was found between greyscale changes after HIFU ablation and gender, age, pancreatic cancer position, or depth of tumour. CONCLUSIONS: We preliminarily deem that dose intensity and sound power can act as good reference points for HIFU dosimetry in the treatment of pancreatic tumours using the Chongqing system. If there was no obvious change in the ultrasound-monitored image following HIFU treatment for pancreatic cancer, the P(avg) and DI should be no less than 260 W and 11 kJ/cm(3), respectively. PMID- 22946545 TI - Abatacept for systemic lupus erythematosus: the outlook. AB - Abatacept is a selective T-cell co-stimulation modulator that inhibits full T cell activation and subsequent antibody production by B cells. Despite the efficacy of abatacept in murine lupus, randomized controlled trials in human SLE do not reveal benefit of abatacept in non-renal and renal lupus. While problems in the study design and the primary efficacy end points may contribute to the negative results of these trials, post hoc analyses using alternative definitions for clinical response suggest the possibility that abatacept may have beneficial effects in active lupus arthritis and proliferative nephritis. Future clinical trials of abatacept should target on defined subsets of SLE patients, utilize multiple pre-defined outcomes based on experience from previous studies and determine the best timing of adding abatacept on a background of minimal immunosuppressive therapies. PMID- 22946547 TI - Gold-catalyzed cyclizations of (o-alkynyl)phenoxyacrylates with external nucleophiles: regio- and stereoselective synthesis of functionalized benzo[b]oxepines. AB - A catalytic approach to benzo[b]oxepines with high stereoselectivity by Au catalyzed cyclization of (o-alkynyl)phenoxyacrylates with various nucleophiles under mild reaction conditions has been developed. Notably, the use of vinyl ether instead of alcohol could afford the same benzoxepines. The reaction may proceed by Au-catalyzed oligomerization of vinyl ether to release the alcohol, which then reacts with (o-alkynyl)phenoxyacrylates to furnish the benzoxepines. PMID- 22946546 TI - Udenafil improves exercise capacity in patients with chronic obstructive pulmonary disease: a prospective study. AB - Pulmonary hypertension (PH) is a serious complication of chronic obstructive pulmonary disease (COPD), and there is no effective pharmacological treatment for COPD-associated PH. We evaluated the effect of udenafil, a phosphodiesterase-5 (PDE-5) inhibitor, on the exercise capacity of patients with severe COPD. Patients with severe and very severe COPD (forced expiratory volume in one second (FEV(1)) <50% of predicted) received udenafil (50 mg daily) for 8 weeks. A 6-min walk test (6MWT), lung function test, Doppler echocardiography, and Saint George's Respiratory Questionnaire (SGRQ) were completed before and after therapy. The primary outcome was a change in the 6-min walk distance (6MWD). Thirty-eight patients were screened for eligibility, and 23 completed the study. After 8 weeks of udenafil treatment, the mean 6MWD increased from 315 to 348 m (p = 0.02), and median PASP decreased from 36 to 30 mmHg (p = 0.02). There were no changes in the SGRQ score, Borg dyspnea score, or pulmonary function parameters. The PDE-5 inhibitor udenafil improved exercise capacity and decreased pulmonary artery pressure in patients with severe COPD. However, due to the small sample size, uncontrolled design and high dropout rate, the efficacy of udenafil in severe COPD needs to be confirmed in a large-scale randomized controlled study. This study was registered at ClinicalTrials.gov (number: NCT01364181). PMID- 22946548 TI - IL-8 release from human neutrophils cultured with pro-haptenic chemical sensitizers. AB - Cytokine release from dendritic cells in vitro is a useful marker to discriminate between sensitizing and irritant haptenic chemicals. Unfortunately, pro-haptens, which gain reactivity following metabolic/auto activation, yield negative results. To overcome this, we exposed human neutrophils and THP-1 cells to haptens/pro-haptens and measured IL-8 release. Haptenic compounds stimulated IL-8 release in neutrophils and THP-1 cells. In contrast, the pro-haptens eugenol, isoeugenol, and 2-aminophenol stimulated high levels of IL-8 release from neutrophils alone. Neutrophil cytokine release was reduced when glutathione was added. Cyp1A1/1B1/3A4 were not detectable in THP-1 cells or neutrophils; however, neutrophils expressed high levels of myeloperoxidase. PMID- 22946549 TI - Self-treating hypoglycaemia: a longitudinal qualitative investigation of the experiences and views of people with Type 1 diabetes. AB - AIMS: Despite improvements in insulin therapy, hypoglycaemia remains an inevitable part of life for many people with Type 1 diabetes. Little attention has been paid to how individuals self-treat hypoglycaemia and their likes and dislikes of clinically recommended treatments. We explored participants' experiences of self-treating hypoglycaemia after attending a structured education programme for people with Type 1 diabetes. Our aims were: to identify treatments that are acceptable to people with Type 1 diabetes; and to provide recommendations for promoting self-treatment in line with clinical guidelines. METHODS: Thirty adults with Type 1 diabetes were recruited from the Dose Adjustment for Normal Eating (DAFNE) programme in the UK. Study participants were interviewed post-course and 6 and 12 months later, enabling their experiences to be explored over time. RESULTS: Study participants described a poor knowledge of how to self-treat hypoglycaemia correctly pre-course. Post-course, individuals often struggled to adhere to clinically recommended guidelines because of: panic, disorientation, hunger sensations and consequent difficulties ingesting fixed quantities of fast-acting carbohydrate; use of sweets to manage hypoglycaemia; reversion to habituated practices when cognitive impairment as a result of hypoglycaemia supervened; difficulties ingesting dextrose tablets; and other people's anxieties about under-treatment. CONCLUSIONS: Historical experiences of hypoglycaemia and habituated practices can influence present self-treatment approaches. Professionals need to be aware of the range of difficulties individuals may experience restricting themselves to fixed quantities of fast acting carbohydrate to manage hypoglycaemia. There may be merit in developing a more acceptable range of treatments tailored to people's own preferences, circumstances and needs. PMID- 22946550 TI - Total synthesis of laetevirenol A. AB - The first complete synthesis of laetevirenol A was performed in nine steps via intramolecular Friedel-Crafts alkylation in a trans-selective manner. The key phenanthrene intermediate was synthesized by a one-pot Suzuki-Miyaura coupling and an aldol condensation cascade reaction. PMID- 22946551 TI - Electrochemiluminescence imaging-based high-throughput screening platform for electrocatalysts used in fuel cells. AB - High throughput screening is very important for accelerating the discovery of fuel cell catalysts. In this paper, a novel electrochemiluminescence (ECL, a technology changing electric current into light) imaging-based screening platform for electrocatalysts used in fuel cells has been developed. The ECL imaging-based screening platform consists of bipolar electrode array-bridged electrochemical (EC)/ECL twin cells, by which electrocatalytic reduction currents of O(2) can be imaged directly by ECL. The ECL imaging-based screening platform is simple in instrumentation, can image the "current-voltage" dependence directly, reversibly, and sensitively, and may enable the activities of electrocatalysts to be evaluated in a high-throughput way. The developed ECL imaging-based screening platform is envisioned to have promising applications in high throughput combinatorial screening of electrocatalysts for fuel cells. PMID- 22946552 TI - Neck lymph nodes in chronic autoimmune thyroiditis: the sonographic pattern. AB - BACKGROUND: Neck lymph nodes may be involved in the pathogenesis of chronic autoimmune thyroiditis (CAT). This study was undertaken to identify which of the sonographic features of cervical lymph nodes are readily applicable to patients affected by CAT compared to healthy control subjects. METHODS: We recruited 106 patients (92 females and 14 males) with CAT and 70 control subjects (53 females and 17 males) without clinical, biochemical, and ultrasonographic evidence of thyroid and neck diseases. We performed laboratory tests (thyrotropin, antithyroperoxidase antibodies, antithyroglobulin antibodies, and ultrasonography) to evaluate in each group: (i) thyroid function, autoimmunity, and morphology; (ii) number, topographic distribution (levels I-VI), and morphology of neck nodes (long-axis diameter; short-axis diameter; short axis/long-axis ratio; absence or presence of hilus). RESULTS: Total number of neck nodes with long-axis diameter >10 mm was significantly higher in the CAT group than in the control group (mean+/-standard deviation [SD]: 3.7+/-2.4 vs. 0.8+/-1.3; p<0.001) with significantly increased differences in levels II (1.4+/ 0.8 vs. 0.3+/-0.5; p<0.001), III (2+/-1.2 vs. 0.3+/-0.7; p<0.001), and IV (0.7+/ 0.7 vs. 0.07+/-0.2; p<0.001). More nodes with a hilus were found in the CAT group than in the control group (mean number of nodes+/-SD: 2.8+/-1.9 vs. 0.7+/-1.1; p<0.001). Short-axis diameter of level III (4.4+/-1 vs. 3.7+/-1.2 mm; p=0.002) and level IV nodes (3.9+/-1 vs. 3.1+/-0.5 mm p=0.030) was increased in CAT patients when compared with healthy controls. CONCLUSIONS: The present study is the first one aiming at a systematic description of the sonographic pattern of cervical lymph nodes in CAT. An increased number of benign hyperplastic neck nodes, especially in levels II-IV, appears to be a characteristic sonographic finding associated with CAT. PMID- 22946553 TI - Bias in favour of self-selected hypotheses is associated with delusion severity in schizophrenia. AB - INTRODUCTION: Delusions are typically characterised by idiosyncratic, self generated explanations used to interpret events, as opposed to the culturally normative interpretations. Thus, a bias in favour of one's own hypotheses may be a fundamental aspect of delusions. METHODS: We tested this possibility in the current study by comparing judgements of self-selected hypotheses to judgements of externally selected ones in a probabilistic reasoning task. This allowed us to equate self- and externally selected hypotheses in terms of objectively quantifiable supporting evidence. It is normal to be biased in favour of self selected hypotheses, but we expected this bias to be exacerbated in schizophrenia patients relative to healthy and psychiatric controls, and to be correlated with the severity of delusions in the schizophrenia sample. RESULTS: As expected, all groups showed the self-selection bias. Although this bias was not increased in schizophrenia patients relative to the control groups, it was significantly correlated with the severity of delusions in the schizophrenia sample. CONCLUSIONS: These results fit with an account holding that the hypersalience of an individual's own interpretations of events, relative to culturally normative interpretations, may manifest in a self-selection bias, contributing to the delusional state in schizophrenia. PMID- 22946554 TI - Sudden cardiac death in Brazil: study based on physicians' perceptions of the public health care system. AB - BACKGROUND: There are no available statistical data about sudden cardiac death in Brazil. Therefore, this study has been conducted to evaluate the incidence of sudden cardiac death in our population and its implications. METHODS: The research methodology was based on Thurstone's Law of Comparative Judgment, whose premise is that the more an A stimulus differs from a B stimulus, the greater will be the number of people who will perceive this difference. This technique allows an estimation of actual occurrences from subjective perceptions, when compared to official statistics. Data were collected through telephone interviews conducted with Primary and Secondary Care physicians of the Public Health Service in the Metropolitan Area of Sao Paulo (MASP). RESULTS: In the period from October 19, 2009, to October 28, 2009, 196 interviews were conducted. The incidence of 21,270 cases of sudden cardiac death per year was estimated by linear regression analysis of the physicians' responses and data from the Mortality Information System of the Brazilian Ministry of Health, with the following correlation and determination coefficients: r = 0.98 and r(2) = 0.95 (95% confidence interval 0.8 1.0, P < 0.05). The lack of waiting list for specialized care and socioadministrative problems were considered the main barriers to tertiary care access. CONCLUSIONS: The incidence of sudden cardiac death in the MASP is high, and it was estimated as being higher than all other causes of deaths; the extrapolation technique based on the physicians' perceptions was validated; and the most important bureaucratic barriers to patient referral to tertiary care have been identified. (PACE 2012; 35:1326-1331). PMID- 22946555 TI - Preparation of acetylated waxy, normal, and high-amylose maize starches with intermediate degrees of substitution in aqueous solution and their properties. AB - Acetylated waxy, normal, and high-amylose maize starches with intermediate degrees of substitution (DS) were prepared in aqueous solution with 20% (w/w) sodium hydroxide as a catalyst. The level of DS was in the order high-amylose maize starch > waxy maize starch > normal maize starch. Settling volume indicated that during the early reaction, normal maize starch swelled to a lesser extent compared with waxy and high-amylose maize starches. The settling volume of all three starches increased initially but decreased after long reaction time. Aggregation of granules was observed as DS increased. The A-type X-ray diffraction pattern of acetylated normal and waxy maize starches weakened as DS increased, whereas the diffraction peaks disappeared in acetylated high-amylose starch when DS was 0.95. Low DS promoted the swelling of the starches in water, but at high DS, the starches became more hydrophobic and the peak viscosity of acetylated starches decreased. PMID- 22946556 TI - Inferring animal population distributions from individual tracking data: theoretical insights and potential pitfalls. AB - Animal population-level phenomena are often inferred from large tracking data sets obtained from only a few individuals. Two key challenges are to understand how these two scales are related, and to identify the factors that influence the extent to which small samples consisting of a few individuals can predict spatial patterns at the population scale. We used a simple spatially explicit theoretical model to explore some of the factors that affect inferences made at the population level from individual tracking data. We adopted a 'mixtures of correlated random walks' approach to simulate two discrete movement modes with different step lengths and turning angles in a hypothetical ungulate population with contrasting population sizes and sampling intensities. Movement state was assumed to be influenced by habitat type (patch or matrix) and social cues. We explored the predictive power of a tracked population subsample by regressing the space-use map generated by a few randomly chosen individuals against the map generated by the entire population (the 'true' map) for different scenarios (e.g. random and clumped habitat distributions) and parameter values. We show that the predictive power of the tracking sample varies nonlinearly and often counter intuitively with factors such as habitat preference, the spatial context of the landscape and the importance of social interactions. We suggest that movement models coupled with individual tracking data can be used with Monte Carlo simulations to improve tracking studies by better understanding the links between detailed individual movement data and population distributions. PMID- 22946557 TI - Exploring the molecular mechanism of stabilization of the adhesion domains of human CD2 by N-glycosylation. AB - N-Glycosylation is one of the most common cotranslational and post-translational modifications occurring in protein biosynthesis and plays a critical role in protein folding and structural diversification. Molecular dynamics studies of two benchmark systems, the NH(2)-terminal human CD2 adhesion domain (HsCD2ad), and the NH(2)-terminal rat CD2 adhesion domain (RnCD2ad) were carried out to investigate the energetic and dynamic effect of N-glycosylation on protein's stability. Our study revealed that N-glycosylation of HsCD2ad at the type I beta bulge turn strengthens the relevant hydrogen bonds, in particular, the hydrogen bond between Asn(65)OD1-Thr(67)HG1. Dynamic cross correlation map analysis showed that nonglycosylated HsCD2ad has strong anticorrelated motions, whereas glycosylated HsCD2ad largely destroyed this anticorrelated motion. As a result, N glycosylation energetically and dynamically stabilizes HsCD2ad. In contrast, N glycosylation of RnCD2ad does not display observable effect on protein's stabilization. The current theoretical result is in excellent agreement with the recent thermodynamic experiment of Culyba et al. and indicates that enthalpy and entropy may both contribute to the stabilization of human CD2 by N-glycosylation. PMID- 22946558 TI - New polyhydroxylated steroid from the South China Sea gorgonian Anthogorgia caerulea. AB - One new polyhydroxylated steroid, caerulsteroid A (1), along with nine known analogues (2-10), was isolated from the gorgonian coral Anthogorgia caerulea collected from the South China Sea. The structure of the new compound was elucidated by 1-D and 2-D NMR, and mass spectrometry. The absolute configuration of 1 was assigned on the basis of the absolute configurations of the related congeners 2 and 3, which were determined by application of the modified Mosher's method. The isolated compounds were assayed for their cytotoxicity, antimicrobial activity and lethality towards brine shrimp Artemia salina. PMID- 22946560 TI - Lithium-stuffed diamond polytype Zn-Tt structures (Tt = Sn, Ge): the two lithium zinc-tetrelides Li3Zn2Sn4 and Li2ZnGe3. AB - In view of the search for alternative structures for Li ion battery materials and electron-poor framework semiconductors for thermoelectric applications, the systems Li-Zn-Tt with Tt = Ge or Sn were investigated. Li3Zn2Sn4 and Li2ZnGe3 were obtained by high-temperature syntheses from the elements. The crystal structures of both phases were determined with single-crystal X-ray diffraction methods and the electronic structure of Li3Zn2Sn4 was analyzed by means of DFT calculations (TB-LMTO-ASA). Both phases show diamond polytype analogous Zn-Tt networks with tetrahedrally four-coordinated Zn and Tt atoms. The new phase Li3Zn2Sn4 crystallizes in space group P6(3)/mmc (No. 194) with lattice parameters a = 4.528(1) A and c = 22.119(2) A. Zn and Sn atoms are fully ordered on three sites that constitute a 6H diamond polytype like network. Li2ZnGe3 is also described in space group P6(3)/mmc (No. 194) with lattice parameters a = 4.167(1) A and c = 6.754(1) A. The Zn-Ge substructure is a hexagonal diamond (2H polytype) like network. The existence of such a Ge-rich Li-Zn-Ge phase has already been reported, but a full structure determination has not yet been published. No indication for an ordering of Zn and Ge atoms on different sites could be deduced from the X-ray diffraction data. Band structure calculations for Li3Zn2Sn4 indicate that the phase is metallic, with the Fermi level at the flank of a pseudogap in the density of states curve. The topological analysis of the electron localization function (ELF) shows covalent Sn-Sn bonding and lone pair like valence basins for the Sn atoms. Concerning the appearance of the lone pair like ELF basins, a strong influence of the basis set for Li that is employed in the calculations is found. PMID- 22946559 TI - Resin-supported catalysts for CuAAC click reactions in aqueous or organic solvents. AB - The copper-catalyzed azide-alkyne cycloaddition click reaction is a valuable process for the synthesis of libraries of drug candidates, derivatized polymers and materials, and a wide variety of other functional molecules. In some circumstances, the removal of the copper catalyst is both necessary and inconvenient. We describe here two immobilized forms of a Cu-binding ligand that has been shown to accelerate triazole formation under many different conditions, using different resin supports that are appropriate for aqueous or organic solvents. Copper leaching from these resins was modest, allowing them to be reused in many reaction/filtration cycles without recharging with metal ion. The utility of this catalyst form was demonstrated in the convenient synthesis of 20 N-acetylgalactosamine derivatives for biological testing. PMID- 22946561 TI - Three-dimensional analysis of tooth movement after intrusion of a supraerupted molar using a mini-implant with partial-fixed orthodontic appliances. AB - OBJECTIVE: To evaluate three-dimensional (3D) positional changes of an intruded tooth, a neighboring tooth, and a tooth connected to a mini-implant following intrusion of a single supraerupted molar, using a mini-implant with partial-fixed orthodontic appliances. MATERIALS AND METHODS: The study consisted of 14 adult patients (two males and 12 females, mean age 41.9 years) with a supraerupted molar due to loss of an antagonist. Intrusion was performed using a mini-implant with a partial strap-up. The mean treatment time was 11.9 months, and the mean retention time was 23.3 months. To quantify the positional changes of the teeth, 3D models using a laser-based, dental scanning system and 3D software at pretreatment, posttreatment, and retention were oriented in a coordinate system and superimposed using nonmoved teeth as references. The changes on the x-, y-, and z-axes were measured at the tip of each cusp in the involved teeth. RESULTS: A supraerupted molar was intruded by a mean amount of 1.35 +/- 0.48 mm and was well maintained during the retention period. The overall change in the neighboring tooth was insignificant, although it showed opposite movement compared to the intruded tooth during the intrusion. The tooth connected to a mini-implant exhibited a secure anchorage. CONCLUSION: 3D analysis showed the detailed positional changes of each tooth, and the involved molars were well maintained after intrusion. PMID- 22946562 TI - Potent vasorelaxant activity of the TMEM16A inhibitor T16A(inh) -A01. AB - BACKGROUND AND PURPOSE: T16A(inh) -A01 is a recently identified inhibitor of the calcium-activated chloride channel TMEM16A. The aim of this study was to test the efficacy of T16A(inh) -A01 for inhibition of calcium-activated chloride channels in vascular smooth muscle and consequent effects on vascular tone. EXPERIMENTAL APPROACH: Single channel and whole cell patch clamp was performed on single smooth muscle cells from rabbit pulmonary artery and mouse thoracic aorta. Isometric tension studies were performed on mouse thoracic aorta and mesenteric artery as well as human abdominal visceral adipose artery. KEY RESULTS: In rabbit pulmonary artery myocytes T16A(inh) -A01 (1-30 MUM) inhibited single calcium (Ca(2+) )-activated chloride (Cl(-) ) channels and whole cell currents activated by 500 nM free Ca(2+) . Similar effects were observed for single Ca(2+) activated Cl(-) channels in mouse thoracic aorta, and in both cell types, channel activity was abolished by two antisera raised against TMEM16A but not by a bestrophin antibody. The TMEM16A potentiator, F(act) (10 MUM), increased single channel and whole cell Ca(2+) -activated Cl(-) currents in rabbit pulmonary arteries. In isometric tension studies, T16A(inh) -A01 relaxed mouse thoracic aorta pre-contracted with methoxamine with an IC(50) of 1.6 MUM and suppressed the methoxamine concentration-effect curve. T16A(inh) -A01 did not affect the maximal contraction produced by 60 mM KCl and the relaxant effect of 10 MUM T16A(inh) -A01 was not altered by incubation of mouse thoracic aorta in a cocktail of potassium (K(+) ) channel blockers. T16A(inh) -A01 (10 MUM) also relaxed human visceral adipose arteries by 88 +/- 3%. CONCLUSIONS AND IMPLICATIONS: T16A(inh) -A01 blocks calcium-activated chloride channels in vascular smooth muscle cells and relaxes murine and human blood vessels. PMID- 22946563 TI - Syntaxin 1 is required for DCC/Netrin-1-dependent chemoattraction of migrating neurons from the lower rhombic lip. AB - Directed cell migration and axonal guidance are essential steps in neural development that share many molecular mechanisms. The guidance of developing axons and migrating neurons is likely to depend on the precise control of plasmalemma turnover in selected regions of leading edges and growth cones, respectively. Previous results provided evidence of a signaling mechanism that couples chemotropic deleted in colorectal cancer (DCC)/Netrin-1 axonal guidance and exocytosis through Syntaxin1(Sytx1)/TI-VAMP SNARE proteins. Here we studied whether Netrin-1-dependent neuronal migration relies on a similar SNARE mechanism. We show that migrating neurons in the lower rhombic lip (LRL) express several SNARE proteins, and that DCC co-associates with Sytx1 and TI-VAMP in these cells. We also demonstrate that cleavage of Sytx1 by botulinum toxin C1 (BoNT/C1) abolishes Netrin-1-dependent chemoattraction of migrating neurons, and that interference of Sytx1 functions with shRNAs or Sytx1-dominant negatives disrupts Netrin-1-dependent chemoattraction of LRL neurons. These findings indicate that a Sytx1/DCC interaction is required for Netrin-1 guidance of migrating neurons, thereby highlighting a relationship between guidance signaling and SNARE proteins that regulate membrane turnover. PMID- 22946564 TI - Usefulness of combined treatment with continuous administration of tirapazamine and mild temperature hyperthermia in gamma-ray irradiation in terms of local tumour response and lung metastatic potential. AB - PURPOSE: To evaluate the usefulness of combined treatment with continuous administration of a hypoxic cytotoxin, tirapazamine (TPZ), and mild temperature hyperthermia (MTH) in gamma-ray irradiation in terms of local tumour response and lung metastatic potential, referring to the response of intratumour quiescent (Q) cells. MATERIALS AND METHODS: B16-BL6 melanoma tumour-bearing C57BL/6 mice were continuously given 5-bromo-2'-deoxyuridine (BrdU) to label all proliferating (P) cells. The tumour-bearing mice then received gamma-ray irradiation after a single intraperitoneal injection or 24 h continuous subcutaneous infusion of TPZ, either with or without MTH. Immediately after the irradiation, cells from some tumours were isolated and incubated with a cytokinesis blocker. The responses of the Q and total (= P + Q) cell populations were assessed based on the frequency of micronuclei using immunofluorescence staining for BrdU. In other tumour-bearing mice, 17 days after irradiation, macroscopic lung metastases were enumerated. RESULTS: Continuous administration elevated the sensitivity of both the total and Q cells, especially the total cells. MTH raised the sensitivity of Q cells more remarkably in both single and continuous administrations, probably because of more exposure to TPZ in intermediately hypoxic areas derived mainly from chronic hypoxia through MTH. With or without irradiation, TPZ, especially administered continuously and combined with MTH, decreased the number of lung metastases. CONCLUSION: The combination of continuous long-term administration of TPZ and MTH in gamma-ray irradiation was thought to be promising because of its potential to enhance local tumour response and repress lung metastatic potential. PMID- 22946565 TI - A diastereoselective cyclic imine cycloaddition strategy to access polyhydroxylated indolizidine skeleton: concise syntheses of (+)-/(-) lentiginosines and (-)-2-epi-steviamine. AB - We describe in this paper the development of a novel diastereoselective cyclic imine cycloaddition strategy to access the polyhydroxylated indolizidine skeleton and its application in the concise syntheses of (+)-/(-)-lentiginosines and (-)-2 epi-steviamine. PMID- 22946566 TI - Design, synthesis and characterization of N', N"-diaryl ureas as p38 kinase inhibitors. AB - Kinases have been known as important molecular targets for various diseases and p38 kinase is found to be vital target among all mitogen activated protein kinases for inflammatory diseases. P38 kinase inhibitors bearing urea scaffold have shown potent kinase inhibitory activity and also selectivity over other kinases. We present here the synthesis, p38 kinase inhibitory and anti inflammatory activities of compounds containing N', N"-diarylurea scaffold. Compound 7f demonstrated IC50 value of 1.09 MUM in p38 kinase assay and 79.41% inhibition of rat paw edema at the 2nd hour of carrageenan challenge. The molecular docking studies of synthesized compounds indicated some of the important hydrogen bonding interactions and also revealed the minor change in the binding pose when compared to BIRB796. PMID- 22946567 TI - Antioxidant activity of rooperol investigated through Cu (I and II) chelation ability and the hydrogen transfer mechanism: a DFT study. AB - Rooperol is a norlignan derivative with numerous biological activities including immunomodulatory, antitumor, anticonvulsant, antibacterial, and antioxidant activities. Its antioxidant activity has been studied by means of experimental techniques, which have shown that it has the ability to scavenge radical species, inhibit lipid peroxidation, and reduce transition metal ions. However, its ability to scavenge radical species and chelate transition metal ions has not been previously studied by means of quantum chemical methods. In this study, density functional theory (DFT) is utilized to investigate the conformational preferences of rooperol, the ability of rooperol to scavenge radical species, and the rooperol...Cu interaction mechanism, which might assist in understanding the antioxidant and prooxidant activities of rooperol. The study was performed in vacuo and in selected solvents. The results suggest that lowest-energy conformers of neutral rooperol are stabilized by two intramolecular hydrogen bonds, while the radical species of rooperol are stabilized by both intramolecular hydrogen bonds and spin delocalization of the unpaired electron. The results in different solvents show that the stability of the conformers of rooperol increases with the increase in the solvent polarity, while the stability of radical species decreases with increase in solvent polarity. The stability of the rooperol...Cu complexes depends on the site on which the Cu ion binds, while the binding strength depends on both the nature of the cation and the nature of the binding site. The inclusion of solvent effects using the polarizable continuum model shows that the rooperol...Cu interaction energies are highly overestimated in vacuo. Finally, the results suggest that the antioxidant activity shown by rooperol corresponds to its interaction with closed-shell transition metal ions, while its prooxidant activity is a result of its interaction with open-shell transition metal ions. PMID- 22946568 TI - Cobalt(III) porphyrin catalyzed aza-Diels-Alder reaction. AB - An efficient protocol for the aza-Diels-Alder reaction of electron-deficient 1,3 dienes with unactivated imines in the presence of a cationic cobalt(III) porphyrin complex was developed. The transformation proceeded smoothly to afford the desired piperidine scaffold within 2 h at ambient temperature. Highly chemoselective cycloaddition of imines with dienes in the presence of a variety of carbonyl compounds was also demonstrated. PMID- 22946571 TI - The importance of mortality. PMID- 22946569 TI - Mechanism of ion transport by fluorescent oligoester channels. AB - The synthesis and membrane activity of a suite of linear oligoesters containing a common diphenylacetylene unit core and differing in the hydroxyl terminus are reported. Active compounds formed high-conductance channels efficiently in both vesicle and planar bilayers, with one compound showing a very unusual slow loss of transport activity over a 20-30 min period. Steady-state and time-resolved fluorescence studies establish the rapid partition of active compounds to the bilayer and identify at least three types of membrane-associated species by their differing fluorescence lifetimes. The change in the distribution of species is correlated with the slow loss of activity. The results are interpreted in terms of an aggregate within a single bilayer leaflet that is nonetheless competent to transport ionic species through the bilayer. The properties of such structures, revealed by these compounds, appear to be consistent with commonly observed behaviors of other synthetic ion channels. PMID- 22946572 TI - End-of-life research: do we need to build proxy consent into all clinical trial protocols studying the terminal phase? PMID- 22946573 TI - Morphine as the first drug for the treatment of cancer pain. PMID- 22946574 TI - End-of-life enhancement: a novel introduction of medical students to palliative medicine. PMID- 22946575 TI - Confirmatory factor analysis of the burden interview of the caregivers of terminally ill home care clients. PMID- 22946576 TI - The Patient Dignity Inventory: applications in the oncology setting. AB - BACKGROUND: The Patient Dignity Inventory (PDI) is a novel 25-item psychometric instrument, designed to identify multiple sources of distress (physical, functional, psychosocial, existential, and spiritual) commonly seen in patients who are terminally ill. It was also designed to help guide psychosocial clinicians in their work with patients. While its validity and reliability have been studied within the context of palliative care, its utility in clinical settings has not as yet been examined. PURPOSE: The purpose of this study was to determine how psychosocial oncology professionals would use the PDI with within their practice and what utility it might have across the broad spectrum of cancer. METHODS: Between October 2008 and January 2009, psychosocial oncology clinicians from across Canada were invited to use the PDI to determine their impressions of this approach in identifying distress and informing their practice. RESULTS: Ninety participants used the PDI and submitted a total of 429 feedback questionnaires detailing their experience with individual patients. In 76% of instances, the PDI revealed one or more previously unreported concerns; in 81% of instances, clinicians reported that the PDI facilitated their work. While it was used in a wide range of circumstances, clinicians were more inclined to apply the PDI to patients engaged in active treatment or palliation, rather than those in remission, having recently relapsed, or newly diagnosed. Besides its utility in identifying distress, the PDI enabled clinicians to provide more targeted therapeutic responses to areas of patient concern. CONCLUSIONS: While this study suggests various clinical applications of the PDI, it also provides an ideal forerunner for research that will directly engage patients living with cancer. PMID- 22946577 TI - Suicide attempts in the terminally ill #210. PMID- 22946578 TI - Palliative care per rectum #257. PMID- 22946579 TI - Unconditional love. PMID- 22946580 TI - Three love stories. PMID- 22946581 TI - An unusual case of Ogilvie syndrome in a pediatric oncology patient receiving palliative care after failed treatment with neostigmine. AB - BACKGROUND: We present a case of severe refractory constipation in an adolescent oncology patient with widely metastatic clear cell osteosarcoma who was ultimately found to have Ogilvie syndrome, also known as acute colonic pseudo obstruction (ACPO). Ogilvie syndrome is characterized by dilatation of the large intestine in the absence of mechanical obstruction, usually occurring in adult patients with serious underlying medical conditions and rarely seen in children. It is likely that chronic narcotic use, abdominal metastasis, and a paraneoplastic process contributed to development of ACPO in this patient. DISCUSSION: This case highlights an infrequent, but important, gastrointestinal complication that can occur in pediatric patients with serious comorbid disease. Ogilvie syndrome should be included on the differential diagnosis list in pediatric patients with refractory constipation. Our case illustrates the progression of therapies, including surgical intervention that can be undertaken to treat this disorder in children and adults while providing important considerations for clinicians treating patients of any age with this unusual clinical complication. PMID- 22946584 TI - Lead(II)-catalyzed oxidation of guanine in solution studied with electrospray ionization mass spectrometry. AB - The oxidation of guanine was investigated in water/methanol solution both in the absence and in the presence of Pb(II) with a variable temperature reactor coupled to a tandem mass spectrometer that allowed signature ions of solution reagents and products to be monitored by electrospray ionization (ESI). Two different oxidizing agents were employed, one strong (peroxymonosulfuric acid) and one weaker (hydrogen peroxide). Peroxymonosulfuric acid was observed to oxidize guanine rapidly at room temperature, k(app) > 10(-2) s(-1), whether in the absence or in the presence of Pb(II), to produce spiroiminohydantoin. Guanine did not show measurable oxidation by hydrogen peroxide in the absence of Pb(II) at concentrations of H(2)O(2) up to 1 M at temperatures up to 333 K (k(app) < 3 * 10(-8) s(-1) at 298 K), but in the presence of Pb(II), it was observed to produce both 5-carboxamido-5-formamido-2-iminohydantoin (2-Ih) and imidazolone (Iz) in a ratio of 2.3 +/- 0.1 with a total rate enhancement of more than 4 * 10(3). The activation energy was measured to be 82 +/- 11 kJ mol(-1) and is more than 120 kJ mol(-1) lower than that for the uncatalyzed oxidation with hydrogen peroxide measured to be at least 208 +/- 26 kJ mol(-1). An activation energy of 113 +/- 9 kJ mol(-1) has been reported by Bruskov et al. (Nucleic Acids Res.2002, 30, 1354) for the heat-induced oxidation by hydrogen peroxide of guanine embedded as guanosine in DNA which leads to the production of 8-oxo-7,8-dihydro-guanine (8 oxo-Gua). The atomic lead dication lowers the activation energy by activating the hydrogen peroxide oxidant, possibly by O-O bond activation, and by directing the oxidation, possibly through coordination to the functional groups adjacent to the carbon C5: the C6 carbonyl group and the N7 nitrogen. The coupling of tandem mass spectrometry (MS(2)) with a simple variable temperature reactor by ESI proved to be very effective for measuring reaction kinetics and activation energies in solution. Signature ions of both reagents and products, as well as the catalyst, could be identified, and the data were acquired in real time. The technique should be suitable for exploring other chemical and biochemical reactions that occur on similar time scales (minutes to hours). PMID- 22946585 TI - Structure-based selectivity optimization of piperidine-pteridine derivatives as potent Leishmania pteridine reductase inhibitors. AB - The upregulation of pteridine reductase (PTR1) is a major contributor to antifolate drug resistance in Leishmania spp., as it provides a salvage pathway that bypasses dihydrofolate reductase (DHFR) inhibition. The structure-based optimization of the PTR1 inhibitor methyl-1-[4-(2,4-diaminopteridin-6 ylmethylamino)benzoyl]piperidine-4-carboxylate (1) led to the synthesis of a focused compound library which showed significantly improved selectivity for the parasite's folate-dependent enzyme. When used in combination with pyrimethamine, a DHFR inhibitor, a synergistic effect was observed for compound 5b. This work represents a step forward in the identification of effective antileishmania agents. PMID- 22946586 TI - Performance of homeostasis model assessment and serum high-sensitivity C-reactive protein for prediction of isolated post-load hyperglycaemia. AB - AIMS: To evaluate whether homeostasis model assessment and high-sensitivity C reactive protein improve the prediction of isolated post-load hyperglycaemia. METHODS: The subjects were 1458 adults without self-reported diabetes recruited between 2006 and 2010. Isolated post-load hyperglycaemia was defined as fasting plasma glucose < 7 mmol/l and 2-h post-load plasma glucose >= 11.1 mmol/l. Risk scores of isolated post-load hyperglycaemia were constructed by multivariate logistic regression. An independent group (n = 154) was enrolled from 2010 to 2011 to validate the models' performance. RESULTS: One hundred and twenty-three subjects (8.28%) were newly diagnosed as having diabetes mellitus. Among those with undiagnosed diabetes, 64 subjects (52%) had isolated post-load hyperglycaemia. Subjects with isolated post-load hyperglycaemia were older, more centrally obese and had higher blood pressure, HbA(1c), fasting plasma glucose, triglycerides, LDL cholesterol, high-sensitivity C-reactive protein and homeostasis model assessment of insulin resistance and lower homeostasis model assessment of beta-cell function than those without diabetes. The risk scores included age, gender, BMI, homeostasis model assessment, high-sensitivity C reactive protein and HbA(1c). The full model had high sensitivity (84%) and specificity (87%) and area under the receiver operating characteristic curve (0.91), with a cut-off point of 23.81; validation in an independent data set showed 88% sensitivity, 77% specificity and an area under curve of 0.89. CONCLUSIONS: Over half of those with undiagnosed diabetes had isolated post-load hyperglycaemia. Homeostasis model assessment and high-sensitivity C-reactive protein are useful to identify subjects with isolated post-load hyperglycaemia, with improved performance over fasting plasma glucose or HbA(1c) alone. PMID- 22946587 TI - A new sesquiterpene lactone from Sarcandra glabra. AB - A new eudesmanolide sesquiterpene, atractylenolide IV (1), together with seven known compounds were isolated from the 70% aqueous acetonic extract of the whole plant of Sarcandra glabra (Chloranthaceae). Their structures were established by spectral analysis, mainly UV, IR, HRESI-MS, 1D and 2D-NMR experiments (HSQC, HMBC and NOESY). Compounds 1-4 showed no remarkable cytotoxic activity against Hela, HCT-8 and MCF-7 cancer cell lines with IC50 > 50 ug mL(-1). PMID- 22946588 TI - Studies comparing the efficacy of constraint-induced movement therapy and bimanual training in children with unilateral cerebral palsy: a systematic review. AB - OBJECTIVE: To review studies comparing the efficacy of constraint-induced movement therapy (CIMT) and bimanual training (BIT) in improving the hemiplegic arm functioning and overall functional performance for children with unilateral cerebral palsy (CP). METHODS: Systematic searches of electronic databases, reference lists and journals identified seven studies that met pre-determined inclusion criteria. These studies were analysed in terms of participants, treatment activities and regime, outcome measures and results of intervention. RESULTS: Both CIMT and BIT produced similar improvements in the bimanual and unimanual capacities of the affected arm and overall functional performance. CONCLUSIONS: CIMT yields more improvements in the unimanual capacity of the impaired arm compared with BIT. A potential benefit of BIT is that participants may see more improvement in both bimanual performance and self-determined overall life goals. A combination of CIMT and BIT could be an option on improving arm function for children with unilateral CP in future. PMID- 22946590 TI - Editorial. Gendered age: cumulative disadvantage or advantage? PMID- 22946589 TI - Unusual cause of far-field atrial sensing by the ventricular lead of a dual chamber defibrillator. What is the mechanism? PMID- 22946591 TI - The effects of caregiving on women's self-assessed health status: an international comparison. AB - To compare the self-assessed health status (SAHS) of female caregivers of older adults across the United States (N = 1,496), China (N = 485), and the United Kingdom (N = 252), data from three data sets were analyzed to isolate significant predictors of SAHS using an adapted meta-analytic technique. Higher income and full-time employment were predictors of higher SAHS; chronic health condition and emotional strain predicted lower SAHS. Female gender was a predictor of lower SAHS. The health status of women was negatively impacted by the caregiving experience. National policies, such as those in the United Kingdom, may result in higher SAHS for women caregivers. PMID- 22946592 TI - Gender differences in discharge destination among older adults following traumatic brain injury. AB - Traumatic brain injury (TBI) is a leading cause of death and disability, and the highest in-patient admission rates are among older adults. We identified that gender independently influences discharge destination following TBI in older adults. In this cross-sectional study, we examined discharge destinations of patients admitted to acute care over a 4-year period, as captured by the Ontario Trauma Registry (n = 3,480). Following TBI, women were significantly more likely than men to be sent to long term care facilities rather than home settings (p < .05), controlling for age, injury severity, mechanism of injury, and comorbidities. PMID- 22946593 TI - "Being-in-the-world-of-care": the lived experiences of older people receiving community aged care packages in Queensland. AB - The lived experiences of older people living in Queensland who were receiving a Community Aged Care Package (CACP) were explored using Heidegger's interpretive hermeneutical phenomenological approach. A number of key themes were identified including the importance these older people placed on personal autonomy and the central significance of relationships. The comprehensive understanding developed revealed that the meanings of care experiences can significantly alter the older person's lived experiences and personal identity. This understanding can enhance the development of care practices that are more likely to support the older person's active participation in care and their own life choices. PMID- 22946594 TI - Women and stroke knowledge: influence of age, race, residence location, and marital status. AB - Worldwide, stroke is the second leading cause of death and leading cause of disability. Women experience over half of all strokes, 60% of stroke-related deaths, and a death rate of 11% versus 8.4% for men. To understand the delay in stroke recognition and treatment, a convenience sample of 97 midlife women living in southeast North Carolina completed the Stroke Recognition Questionnaire. Rural women, younger women (<49 years old), and participants with incomes under $35,601 had higher stroke symptom and risk factor knowledge scores. Educational interventions should target women over the age of 50, and should distinguish between symptoms of stroke versus heart attack. PMID- 22946595 TI - Improving women's cardiovascular health: a position statement from the International Council on Women's Health Issues. AB - Cardiovascular disease (CVD) is the number one killer of women worldwide, and it remains the primary cause of death and disability in both developed and developing countries. The International Council on Women's Health Issues is an international nonprofit association dedicated to the goals of promoting the health, health care, and the well-being of women. Based on the outcomes of a facilitated discussion at its 18th biannual meeting, delegates aim to raise awareness about the potent influence of gender-specific factors on the development, progression, and outcomes of CVD. Key recommendations for decreasing the burden of CVD are also discussed. PMID- 22946596 TI - Improvement of older women's sexuality through emancipatory education. AB - The purpose of this action research (AR) was to explore the ways in which sexuality is experienced daily and to improve the expression of older women's sexuality. The pedagogy of autonomy as proposed by the Brazilian educator Paulo Freire theoretically supported this AR, with the participation of six older adult women living in a rural setting in southwest Brazil. The older women's experiences regarding sexuality, their concerns, and their educational demands could be summarized through five phrases: the improvement of self-esteem as a way to promote sexuality; sexuality impaired by loneliness and lack of affection; men's sexual satisfaction seen as a woman's obligation; women's sexuality controlled by the society; and relinquishment of the companion to attend to the expectations of family members. Dialogical and participative educational approaches and continuous observation-participation strategies were performed to support the women's care and educational requirements. PMID- 22946597 TI - Prevalence and correlates of elder abuse among older women in rural and urban communities in South Western Nigeria. AB - Elderly women face the same health, economic, and social issues that all elderly people face, but often encounter more challenges compared with men and are more prone to abuse. Elder abuse has hitherto been uncharacterized among women in South Western Nigeria. A cross-sectional survey was conducted to describe the prevalence, patterns, and factors associated with elder abuse among elderly women in Nigeria. The abuse of elderly women is quite prevalent in the two communities studied, especially physical abuse. Positive predictors of elder abuse were urban dwelling, financial dependency, and a high level of educational attainment. Appropriate interventions should be targeted toward reducing the occurrence. PMID- 22946598 TI - Allosteric effects in binuclear homo- and heterometallic triple-stranded lanthanide podates. AB - This work illustrates a simple approach for deciphering and exploiting the various free energy contributions to the global complexation process leading to the binuclear triple-stranded podates [Ln(2)(L9)](6+) (Ln is a trivalent lanthanide). Despite the larger microscopic affinities exhibited by the binding sites for small Ln(3+), the stability constants measured for [Ln(2)(L9)](6+) decrease along the lanthanide series; a phenomenon which can be ascribed to the severe enthalpic penalty accompanying the intramolecular cyclization around small Ln(III), combined with increasing anticooperative allosteric interligand interactions. Altogether, the microscopic thermodynamic characteristics predict beta(1,1,1)(La,Lu,L9)/beta(1,1,1)(Lu,La,L9) = 145 for the ratio of the formation constants of the target heterobimetallic [LaLu(L9)](6+) and [LuLa(L9)](6+) microspecies, a value in line with the quantitative preparation (>90%) of [LaLu(L9)](6+) at millimolar concentrations. Preliminary NMR titrations indeed confirm the rare thermodynamic programming of a pure heterometallic f-f' complex. PMID- 22946600 TI - Use of an Australian quality of life tool in patients with COPD. AB - COPD is a leading chronic disease, increasing globally. Given this condition's irreversible and progressive nature, health-related quality of life (HRQOL) is increasingly a primary end-point in COPD management. We evaluated several HRQOL tools with a primary goals of (1) investigating how the generic Assessment Quality of Life (AQOL) functions compared to the Medical Outcomes Study 36-item Short Form Health Survey (SF36) and the St. Georges Respiratory Questionnaire (SGRQ); and (2) considering the extent to which clinical disease severity, as measured by the BODE index, predicts variation in HRQOL reports. METHODS: 134 consecutive patients entering a pulmonary rehabilitation program were recruited. Participants completed two generic measures of HRQOL (SF36 and AQOL) and one disease specific measure (SGRQ). The clinical severity of COPD was assessed using a composite global COPD severity score, BODE. RESULTS: Significant associations were demonstrated between AQOL and both the SF36 (r = .68) and SGRQ (r = -.60). BODE significantly predicted AQOL scores (R = -.31); mMRC (R = -.36) and 6MWD (R = .39) were stronger contributors to these predictions than were FEV(1) or BMI. CONCLUSIONS: This study establishes convergent validity between AQOL, and the SF36 and SGRQ in patients with COPD. For future studies wishing to examine HRQOL from a generic perspective, we have shown that during cross-sectional analyses AQOL performs similarly to the SF36. In addition we identified that the clinical severity of COPD, as assessed by BODE, significantly influences reports of quality of life made using AQOL. The components of BODE that most strongly contributed to predicting HRQOL were dsypnea and exercise tolerance. PMID- 22946601 TI - SonoKnife for ablation of neck tissue: in vivo verification of a computer layered medium model. AB - PURPOSE: This study aimed to determine which treatment parameters of the SonoKnife device can be used to safely and effectively perform non-invasive thermal ablation of subcutaneous tissue. METHODS: A three-dimensional computational layered medium model was constructed to simulate thermal ablation treatment of the SonoKnife device. The acoustic and thermal fields were calculated with the Fast Object-Oriented C++ Ultrasound-Simulator software and a finite difference code, respectively. Subcutaneous tissue was represented as layers of skin, fat and muscle. The simulations were conducted for ultrasound frequencies of 1 or 3.5 MHz. The thermal dose model was used to predict the size and location of the ablated regions. The computer simulations were verified by using the SonoKnife to perform subcutaneous ablations in the neck area of healthy pigs, in vivo. Triphenyltetrazolium chloride viability stain was used to differentiate viable tissue from ablated regions ex vivo. RESULTS: The simulations for the layered medium model suggest that operating the SonoKnife at frequency of 1 MHz is more effective and safer than 3.5 MHz providing skin cooling is applied prior to ablation. These predictions were in agreement with the results observed in the animal studies. The required sonication time for ablation increased from 50 to 300 s by using 1 MHz. CONCLUSION: Our modelling and animal studies suggest that 1 MHz with pretreatment skin cooling are the optimal settings to operate the SonoKnife to safely and effectively perform subcutaneous thermal ablation of porcine skin. More work is needed to optimise skin cooling and define the optimal sonication time. PMID- 22946602 TI - Influence of beet sugar, calcium lactate, and Staphylococcus xylosus (with nitrate reductase activity) on the chemical, microbiological, and sensorial properties of Persian uncured frankfurters. AB - This study investigated the effects of beet sugar (BS), calcium lactate (CL), and Staphylococcus xylosus (SX) on the general characteristics of uncured frankfurters. Minimum residual nitrite was observed in samples with a high level of BS and S. xylosus (8log(10) l0 viable cfu/g) after 2 mo. There was an increase in total aerobic counts in frankfurters after 4 wk. Samples containing higher BS and CL had no Clostridium perfringens at storage time. Histamine content was similar for all treatments except SX. No differences were observed in textural properties among the treatments. Water activity was decreased significantly in treatment CL1+BS2. The results indicated that samples treated with BS or CL had (P < 0.05) taste and sensory attributes considered appropriate by a tasting panel. PRACTICAL APPLICATIONS: Frankfurters are among the most popular meat products in many countries. Health problems (such as cancer) associated with the overconsumption of cured meat have led to searches for new, alternative methods of preservation. Hurdle technology (combinations of beet sugar, calcium lactate, and Staphylococcus xylosus in different concentrations) can be developed for frankfurter processing. Results of this research will be useful for meat manufacturers; however, any new process may affect the strategies chosen for marketing these products. PMID- 22946603 TI - IDegAsp: a novel soluble insulin analogs combination. AB - INTRODUCTION: Current rapid- and long-acting insulin analogs cannot maintain their individual pharmacokinetic profile when they are co-formulated. IDegAsp , a novel soluble combination was developed with rapid-acting insulin aspart and a new-generation ultra-long-acting insulin, insulin degludec and was anticipated to offer clinical advantage over available premixed insulin suspensions. AREAS COVERED: We reviewed published data regarding pharmacological characters, clinical efficacy, safety, and tolerability of IDegAsp. Literature was searched through the electronic medical databases (PubMed, EMBASE, and Web of Knowledge) up to June 2012. EXPERT OPINION: Preliminary clinical data indicate that IDegAsp is a safe, well-tolerated insulin combination and provides a similar overall glycemic control to current insulin preparations with a reduced risk of hypoglycemia. IDegAsp might be a promising treatment option for patients with type 2 diabetes who need to improve control of postprandial glucose excursions and fasting glucose levels. PMID- 22946604 TI - Synthesis and structural investigation of an "oxazinoquinolinespirohexadienone" that only exists as its long-wavelength ring-opened quinonimine isomer. AB - The spirocyclic oxazinoquinolinespirohexadienone (OSHD) "photochromes" are computationally predicted to be an attractive target as electron deficient analogues of the perimidinespirohexadienone (PSHD) photochromes, for eventual application as photochromic photooxidants. We have found the literature method for their preparation unsuitable and present an alternative synthesis. Unfortunately the product of this synthesis is the long wavelength (LW) ring opened quinonimine isomer of the OSHD. We have found this isomer does not close to the spirocyclic short wavelength isomer (SW) upon prolonged standing in the dark, unlike other PSHD photochromes. The structure of this long wavelength isomer was found by NMR and X-ray crystallography to be exclusively the quinolinone (keto) tautomer, though experimental cyclic voltammetry supported by our computational methodology indicates that the quinolinol (enol) tautomer (not detected by other means) may be accessible through a fast equilibrium lying far toward the keto tautomer. Computations also support the relative stability order of keto LW over enol LW over SW. PMID- 22946605 TI - Amelalpha8 subunit knockdown in the mushroom body vertical lobes impairs olfactory retrieval in the honeybee, Apis mellifera. AB - We studied the involvement of the alpha8 subunit of nicotinic acetylcholine receptors (nAChRs) in olfactory learning and memory in Apis mellifera. We have previously shown, by injecting different nicotinic antagonists into the bee brain, that pharmacologically different subtypes of nAChRs are important for honeybee memory -alpha-bungarotoxin-sensitive receptors are necessary for memory consolidation and mecamylamine-sensitive receptors are involved in retrieval processes. Here, we took advantage of the honeybee genome sequencing and the development of a small interfering RNA (siRNA) tool to focus on the role of the alpha8 subunit, which has been shown to be expressed in brain areas important for olfactory learning, such as the antennal lobes and mushroom bodies. We first demonstrated the efficacy of the siRNA tool by showing a decrease of the alpha8 protein level at 6 h after brain injection of alpha8 siRNA. We then tested the general role of this subunit in olfactory conditioning, using brain systemic or localized siRNA injections in the antennal lobes or the calyces and vertical lobes of the mushroom bodies. These injections were performed at either 6 h before the learning acquisition or 6 h before the memory test. The most prominent result was that 6-h pre-test injection of siRNA in the mushroom body vertical lobes impaired memory retrieval at 24 and 48 h post-training. This indicated the importance of cholinergic extrinsic neurons and nAChRs containing the alpha8 subunit for this process. PMID- 22946606 TI - Working well with a disability: health promotion as a means to employment. AB - PURPOSE/OBJECTIVE: The purpose of this study was to test the utility of the Working Well with a Disability health-promotion program with vocational rehabilitation (VR) clients. Health-promotion interventions have been shown to reduce limitation from secondary conditions, which can be a significant barrier to labor force participation among people with disabilities. The state and federal VR system represents a potential access point for delivery of health promotion activities. RESEARCH METHOD/DESIGN: A total of 297 VR clients participated in a randomized trial of the Working Well health promotion program. Control and intervention participants provided baseline and four waves of quarterly follow-up data. Data were analyzed with repeated-measures ANOVA. RESULTS: Intervention-group participants who attended over half of the Working Well sessions reported significantly lower rates of limitation from secondary conditions over the 1-year study span, F(1, 124) = 4.11, p = .004. Control-group participants also experienced significantly lower rates of limitation, but pre- to postdifferences were less dramatic, F(1, 308) = 4.19, p = .006. CONCLUSIONS/IMPLICATIONS: Overall, health data indicated that the Working Well program may be particularly helpful to VR clients with higher rates of secondary health conditions and may represent one strategy for overcoming barriers to employment. PMID- 22946607 TI - Reducing depression in stroke survivors and their informal caregivers: a randomized clinical trial of a Web-based intervention. AB - PURPOSE/OBJECTIVES: To develop and test the efficacy of a Web-based intervention for alleviating depression in male stroke survivors (SSs) and their spousal caregivers (CGs) that blends both peer and professional support. DESIGN AND METHODS: The research consisted of an intervention protocol evaluated by a focus group of rehabilitation professionals, a "think aloud" session conducted with female stroke CGs, and a usability test of the intervention's online features with 7 female stroke CGs. Efficacy of the final protocol was tested in a 2-group randomized clinical trial with a sample of 32 CG-SS dyads. The CGs in the intervention condition received an online group intervention. Intervention components were based on the Stress Process Model. Those CGs in a control condition received minimal support with individualized access to relevant online information. Measures of depression, as well as the secondary outcomes of mastery, self-esteem, and social support, were obtained from SSs and CGs at pretest, posttest, and 1-month later. RESULTS: At posttest and 1 month later, CGs in the intervention condition reported significantly lower depression than CGs in the control condition with baseline depression controlled. There was no significant effect on depression among SSs. Although no significant treatment effects for either SSs or CGs were found on the secondary outcomes, posttreatment changes on some constructs were significantly correlated with change in depression. CONCLUSIONS/IMPLICATIONS: CGs benefit from Web-based programs that help them better understand both their emotional needs and those of the SS. PMID- 22946608 TI - Cognitions, metacognitions, and chronic pain. AB - PURPOSE: Although the content of thoughts has received a considerable amount of attention in pain research, the importance of thought processes (metacognitions) has received less attention. METHOD: One hundred twenty-nine individuals with muscular dystrophy and chronic pain completed measures assessing metacognitions and frequency of both catastrophizing and pain control beliefs. RESULTS: Greater use of reappraisal and distraction metacognitions were associated with more perceived control over pain, whereas greater use of worry and punishment metacognitions were associated with more catastrophizing. CONCLUSIONS/IMPLICATIONS: The current findings indicate that metacognitions are associated with both pain control beliefs and catastrophizing and therefore may play an important role in the development or maintenance of pain-related cognitive content thought to influence patient functioning. Research is needed to determine whether treatments that encourage changes in both metacognitions and cognitive content are more effective than treatments that focus on cognitive content alone. PMID- 22946609 TI - Rasch analysis of the Hospital Anxiety and Depression Scale in spinal cord injury. AB - PURPOSE: The purpose of this study was to evaluate the psychometric properties of the Hospital Anxiety and Depression Scale (HADS), applied among persons with spinal cord injury (SCI), using Rasch analysis. METHODS: A cross-sectional multicenter study was conducted and the data of 102 people with SCI were analyzed. Rasch analyses were performed to assess dimensionality, overall and individual item fit, response scale structure, targeting, and differential item functioning. RESULTS: The anxiety and depression subscales showed unidimensionality, that is, model and item fit. The two subscales are reliable (r = .72, 0.82) in SCI. No disordered structure of the response scales or differential item functioning in age, gender, education, relationship status, level of spinal lesion were found. Stepwise deletion of the misfitting items did not produce a total score that fulfilled the statistical criteria for unidimensionality. CONCLUSIONS: The results of the Rasch analyses support the use of the anxiety and depression subscales among people with SCI. However, further research is needed to confirm these findings and examine sensitivity to change of the HADS in SCI, which would support its use in longitudinal observational and intervention studies. PMID- 22946610 TI - Influence of the social context on use of surgical-lengthening and group empowering coping strategies among people with dwarfism. AB - OBJECTIVE: To assess the role that social contextual factors exert on the way people with disproportionate short stature (dwarfism) cope with the negative consequences of discrimination. METHOD: Using multigroup structural equation modeling, we compare the coping process of people with dwarfism from Spain (N = 63) and the USA (N = 145), two countries that differ in the role played by organizations offering support to people with dwarfism. RESULTS: In Spain, where organizational support is recent, a coping approach aimed at achieving integration with the majority group through limb-lengthening surgery prevails; in the USA, where the long-standing organization of people with dwarfism encourages pride in being a "little person" and positive intragroup contact, a coping strategy based on empowering the minority group dominates. CONCLUSIONS: Both strategies, each in its own context, are effective at protecting psychological well-being from the negative consequences of stigmatization; however, they exert their positive effects through different processes. PMID- 22946611 TI - Trajectories of resilience, depression, and anxiety following spinal cord injury. AB - PURPOSE/OBJECTIVE: To investigate longitudinal trajectories of depression and anxiety symptoms following spinal cord injury (SCI) as well as the predictors of those trajectories. RESEARCH METHOD/DESIGN: A longitudinal study of 233 participants assessed at 4 time points: within 6 weeks, 3 months, 1 year, and 2 years from the point of injury. Data were analyzed using latent growth mixture modeling to determine the best-fitting model of depression and anxiety trajectories. Covariates assessed during hospitalization were explored as predictors of the trajectories. RESULTS: Analyses for depression and anxiety symptoms revealed 3 similar latent classes: a resilient pattern of stable low symptoms, a pattern of high symptoms followed by improvement (recovery), and delayed symptom elevations. A chronic high depression pattern also emerged but not a chronic high anxiety pattern. Analyses of predictors indicated that compared with other groups, resilient patients had fewer SCI-related quality of life problems, more challenge appraisals and fewer threat appraisals, greater acceptance and fighting spirit, and less coping through social reliance and behavioral disengagement. CONCLUSION/IMPLICATIONS: Overall, the majority of SCI patients demonstrated considerable psychological resilience. Models for depression and anxiety evidenced a pattern of elevated symptoms followed by improvement and a pattern of delayed symptoms. Chronic high depression was also observed but not chronic high anxiety. Analyses of predictors were consistent with the hypothesis that resilient individuals view major stressors as challenges to be accepted and met with active coping efforts. These results are comparable to other recent studies of major health stressors. PMID- 22946612 TI - Hope predicts positive functional role outcomes in acute rehabilitation populations. AB - PURPOSE/OBJECTIVE: The purpose of this study was to examine the association between facilitating psychological variables and functional rehabilitation outcomes following acute medical rehabilitation. RESEARCH METHOD/DESIGN: Using a longitudinal design and correlational and regression analyses, we studied 174 adults who were participating in inpatient rehabilitation for acute spinal cord dysfunction, stroke, amputation, or orthopedic surgery recovery. All participants completed the Hope Scale, Positive and Negative Affect Schedule, and Functional Independence Measure (FIM) during the first days of their inpatient stay, and then were contacted 3 months after discharge to complete the Craig Hospital Assessment and Reporting Technique (CHART) and FIM. RESULTS: Hope accounted for a statistically significant amount of the variance in the prediction of functional role participation at 3 months postdischarge (as measured by the CHART) above and beyond the variance accounted for by demographic and severity variables. In contrast, positive affect was not found to contribute to the prediction of functional role participation, and neither hope nor positive affect contributed to the prediction of functional skill level (FIM). CONCLUSIONS/IMPLICATIONS: The results indicate that positive psychological variables present during the rehabilitation stay, such as hopefulness, may contribute to the prediction of functional outcomes after discharge in rehabilitation populations. These findings suggest that incorporating interventions that enhance hope and build on the individual's psychological strengths may be useful to improve participation outcomes following acute medical rehabilitation. PMID- 22946613 TI - Age at injury and long-term behavior problems after traumatic brain injury in young children. AB - OBJECTIVE: This study examined the effects of age at injury on the persistence of behavior problems and social skill deficits in young children with complicated mild to severe traumatic brain injury (TBI). METHOD: A concurrent cohort/prospective research design was used with repeated assessments of children with TBI (n = 82) or Orthopedic Injury (OI) (n = 114). Parents completed the Child Behavior Checklist, the Behavior Rating Inventory of Executive Functions, and the Preschool and Kindergarten Behavior Scales or the Home and Community Social and Behavior Scales shortly after injury to assess preinjury functioning, and at an extended follow-up an average of 38 months postinjury. Generalized linear modeling was used to examine the relationship of age at injury to the maintenance of behavior problems, and logistic regression was used to examine the persistence of clinically significant behavior problems. RESULTS: At the extended follow-up, severe TBI was associated with significantly greater anxiety problems relative to the Group OI. With increasing time since injury, children who sustained a severe TBI at an earlier age had significantly higher levels of parent-reported symptoms of ADHD and anxiety than children who were older at injury. CONCLUSIONS: Findings suggest that longer-term treatment for behavior problems may be needed after severe TBI, particularly for those injured at an earlier age. PMID- 22946614 TI - The design and identification of brain penetrant inhibitors of phosphoinositide 3 kinase alpha. AB - Inhibition of phosphoinositide 3-kinase (PI3K) signaling through PI3Kalpha has received significant attention for its potential in cancer therapy. While the PI3K pathway is a well-established and widely pursued target for the treatment of many cancer types due to the high frequency of abnormal PI3K signaling, glioblastoma multiforme (GBM) is particularly relevant because the pathway is implicated in more than 80% of GBM cases. Herein, we report the identification of PI3K inhibitors designed to cross the blood-brain barrier (BBB) to engage their target where GBM tumors reside. We leveraged our historical experience with PI3K inhibitors to identify correlations between physicochemical properties and transporter efflux as well as metabolic stability to focus the selection of molecules for further study. PMID- 22946615 TI - Method for screening of bacterial strains biosynthesizing specific conjugated linoleic acid isomers. AB - A simple and accurate method for screening of bacterial strains with the ability to convert free linoleic acid into specific conjugated linoleic acid (CLA) isomers has been developed by combining the ultraviolet spectral scan and capillary electrophoresis analysis. The ultraviolet spectral scan was carried out for preliminary screening of bacterial strains with the capacity to biosynthesize CLA, and the absorption peak at 228-235 nm was used for assessing the possible production of CLA by bacteria. The capillary electrophoresis analysis was used as the follow-up confirmation to definitively conclude CLA production and the composition of CLA isomers. Linoleic acid at the concentration of 25 MUg/mL, which showed little inhibitory effect on the growth of bacteria, was used for initial screening of CLA-producing strains. The strains with the ability to produce specific CLA isomers can be selected quickly from a large number of bacteria by this high-throughput method. PMID- 22946616 TI - Stable Cu(II) and Cu(I) mononuclear intermediates in the assembly of the CuA center of Thermus thermophilus cytochrome oxidase. AB - CuA is a dinuclear mixed-valence center located in subunit 2 of the ba(3)-type cytochrome oxidase from Thermus thermophilus. The assembly of this site within the periplasmic membrane is believed to be mediated by the copper chaperones Sco and/or PCuAC, but the biological mechanisms are still poorly understood, thereby stimulating interest in the mechanisms of CuA formation from inorganic ions. The formulation of the CuA center as an electron-delocalized Cu(1.5)-Cu(1.5) system implicates both Cu(II) and Cu(I) states in the metalation process. In earlier work we showed that selenomethionine (SeM) substitution of the coordinated M160 residue provided a ligand-directed probe for studying the copper coordination environment via the Se XAS signal, which was particularly useful for interrogating the Cu(I) states where other spectroscopic probes are absent. In the present study we have investigated the formation of mixed-valence CuA and its M160SeM derivative by stopped-flow UV-vis, EPR, and XAS at both Cu and Se edges, while the formation of fully reduced di-Cu(I) CuA has been studied by XAS alone. Our results establish the presence of previously undetected mononuclear intermediates and show important differences from the metalation reactions of purple CuA azurin. XAS spectroscopy at Cu and Se edges has allowed us to extend mechanistic inferences to formation of the di-Cu(I) state which may be more relevant to biological CuA assembly. In particular, we find that T. thermophilus CuA assembles more rapidly than reported for other CuA systems and that the dominant intermediate along the pathway to mixed-valence is a new green species with lambda(max) = 460 nm. This intermediate has been isolated in a homogeneous state and shown to be a mononuclear Cu(II)-(His)(Cys)(2) species with no observable Cu(II)-(Met) interaction. Reduction with dithionite generates its Cu(I) homologue which is again mononuclear but now shows a strong interaction with the Met160 thioether. The results are discussed within the framework of the "coupled distortion" model for Cu(II) thiolates and their relevance to biological metalation reactions of the CuA center. PMID- 22946618 TI - CBCT assessment of alveolar buccal bone level after RME. AB - OBJECTIVE: To evaluate the maxillary alveolar buccal bone levels after expansion with banded and bonded expanders, using cone-beam computed tomography (CBCT). MATERIALS AND METHODS: The population sample consisted of 22 patients who required expansion during their comprehensive treatment; 10 patients (five males and five females) with a mean age of 13.5 years (CVMS 3) had bonded hygienic expanders, and 12 (six males and six females) with a mean age of 12.6 years (CVMS 3) had banded hyrax expanders. CBCT was taken both before (T1) and 6 months after last activation (T2). Measurements were made for buccal bone thickness (BT), buccal marginal bone level (MBL), and bone thickness level (BTL) at the right first molar (M(Rt)), left first molar (M(Lft)), right first premolar (PM(Rt)), and left first premolar (PM(Lft)). A mixed-design analysis of variance assessed differences between and within the groups. Post hoc t-tests were completed on significant analysis of variance results to determine where differences occurred. RESULTS: Analysis of variance revealed no significant differences between or within the two groups. BT significantly decreased horizontally following rapid maxillary expansion. The amount of bone lost was -0.59 mm M(Rt), -0.72 mm PM(Rt), -0.50 mm M(Lft), and -0.57 mm PM(Lft) (P < .003). CONCLUSIONS: There was no significant difference between or within the two groups. Buccal bone loss in the vertical dimension (MBL) only showed significance in the banded group for M(Rt) (0.63 mm) and PM(LFt) (0.37 mm) as evidenced by the paired t-test (P < .05). PMID- 22946617 TI - Computational assessment of drug-induced effects on the electrocardiogram: from ion channel to body surface potentials. AB - BACKGROUND AND PURPOSE: Understanding drug effects on the heart is key to safety pharmacology assessment and anti-arrhythmic therapy development. Here our goal is to demonstrate the ability of computational models to simulate the effect of drug action on the electrical activity of the heart, at the level of the ion-channel, cell, heart and ECG body surface potential. EXPERIMENTAL APPROACH: We use the state-of-the-art mathematical models governing the electrical activity of the heart. A drug model is introduced using an ion channel conductance block for the hERG and fast sodium channels, depending on the IC(50) value and the drug dose. We simulate the ECG measurements at the body surface and compare biomarkers under different drug actions. KEY RESULTS: Introducing a 50% hERG-channel current block results in 8% prolongation of the APD(90) and 6% QT interval prolongation, hERG block does not affect the QRS interval. Introducing 50% fast sodium current block prolongs the QRS and the QT intervals by 12% and 5% respectively, and delays activation times, whereas APD(90) is not affected. CONCLUSIONS AND IMPLICATIONS: Both potassium and sodium blocks prolong the QT interval, but the underlying mechanism is different: for potassium it is due to APD prolongation; while for sodium it is due to a reduction of electrical wave velocity. This study shows the applicability of in silico models for the investigation of drug effects on the heart, from the ion channel to the ECG-based biomarkers. PMID- 22946619 TI - Assembly of DNA curtains using hydrogen silsesquioxane as a barrier to lipid diffusion. AB - We have established a single-molecule imaging experimental platform called "DNA curtains" in which DNA molecules tethered to a lipid bilayer are organized into patterns at nanofabricated metallic barriers on the surface of a microfluidic sample chamber. This technology has wide applications for real-time single molecule imaging of protein-nucleic acid interactions. Here, we demonstrate that DNA curtains can also be made from hydrogen silsesquioxane (HSQ). HSQ offers important advantages over metallic barriers because it can be lithographically patterned directly onto fused silica slides without any requirement for further processing steps, thereby offering the potential for rapid prototype development and/or scale up for manufacturing. PMID- 22946620 TI - Total synthesis of (+)-aureol. AB - A total synthesis of the marine sponge meroterpenoid (+)-aureol has been achieved in 12 steps (6% overall yield) from (+)-sclareolide. Key steps of the synthesis include a biosynthetically inspired sequence of 1,2-hydride and methyl shifts, and a biomimetic cycloetherification reaction. PMID- 22946621 TI - Alendronate-conjugated amphiphilic hyperbranched polymer based on Boltorn H40 and poly(ethylene glycol) for bone-targeted drug delivery. AB - A novel type of alendronate(ALE)-conjugated amphiphilic hyperbranched copolymer based on a hydrophobic hyperbranched Boltorn H40 (H40) core with ALE targeting moiety and many hydrophilic poly(ethylene glycol) (PEG) arms was synthesized as a carrier for bone-targeted drug delivery. The star copolymer H40-star-PEG/ALE was characterized using nuclear magnetic resonance (NMR), Fourier transformed infrared spectroscopy (FTIR), and gel permeation chromatography (GPC) analysis. Benefiting from its highly branched structure, H40-star-PEG/ALE could form micelles in aqueous solution, which was confirmed by transmission electron microscopy (TEM) and dynamic light scattering (DLS) techniques. The cytotoxicity and hemolysis of the H40-star-PEG/ALE micelles were evaluated via methylthiazoletetrazolium (MTT) assay against NIH/3T3 normal cells and red blood cell (RBC) lysis assay, respectively. As a model anticancer drug, doxorubicin (DOX) was encapsulated into the H40-star-PEG/ALE micelles. The anticancer activity of DOX-loaded micelles was evaluated by MTT assay against an HN-6 human head and neck carcinoma cell line. The strong affinity of H40-star-PEG/ALE micelles to bone was confirmed by the hydroxyapatite (HA) binding assay. These results indicate that the H40-star-PEG/ALE micelles are highly promising bone targeted drug carriers for skeletal metastases. PMID- 22946623 TI - Values and love styles in Turkey and Great Britain: an intercultural and intracultural comparison. AB - Little previous research has examined the relationship between values and love styles, and none has done so across cultures or intracultural regions. This research was the first attempt to explore the correlation between individual level values and love styles, and examined both within- and between-cultural variations in love styles. In this study 224 participants from Turkey and Britain, from urban or rural locations, completed the Portrait Values Questionnaire and the Love Attitudes Scale measure of love styles. Pancultural analyses demonstrated significant correlations between certain value dimensions and love styles. In particular, agape (selfless love) was positively correlated with self-transcendence, ludus (game-playing love) was positively correlated with self-enhancement, and pragma (realistic love) was positively correlated with conservation. The inclusion of location and nationality and their interactions with values in the multiple regression analyses significantly increased the variance explained by values for five of the six love styles. Multivariate analyses indicated that ludus, storge, mania, and pragma were all significantly higher among Turkish respondents; pragma, mania, and agape all higher amongst rural respondents. Eros was highest among rural British respondents; storge, pragma, and agape highest among rural Turks. When these culture effects were explored, conservation significantly mediated the relationship between the groups of more conservative rural Turks (versus other participants) and both pragmatic and storgic love styles. Findings are discussed in the light of disparities in values and relationship styles within cultures, and the need to include both intracultural and intercultural variations in cross cultural research. PMID- 22946624 TI - Tuning structural topologies of three photoluminescent metal-organic frameworks via isomeric biphenyldicarboxylates. AB - Three new cadmium compounds, [Cd(2,4'-bpdc)(bib)(0.5)] (1; 2,4'-bpdc = biphenyl 2,4'-dicarboxylate and bib = 1,4-bis(2-methyl-imidazol-1-yl)butane), {[Cd(2)(3,4' bpdc)(2)(bib)(1.5)(H(2)O)](n).H(2)O}(n) (2; 3,4'-bpdc = biphenyl-3,4' dicarboxylate), and [Cd (4,4'-bpdc)(bib)] (3; 4,4'-bpdc = biphenyl-4,4' dicarboxylate), have been successfully synthesized by the assembly of Cd(2+) ions, bib ligands, and isomeric bpdc ligands, respectively. This paper presents a comparative study on the tuning of structural topologies using three isomers of biphenyldicarboxylates as bridging ligands. Compound 1 based on 2,4'-bpdc features a three-dimensional (3D) framework with 6-connected mab topology. Compound 2 based on 3,4'-bpdc is another 3D framework, but it possesses a rare 3 fold interpenetrating 4,6-connected fsh net, while compound 3 based on linear 4,4'-bpdc shows unusual 2D -> 3D parallel polycatenation of (4,4) layers. Furthermore, the luminescent properties of three compounds are investigated in the solid state. PMID- 22946625 TI - Stabilized metal nanoparticles from organometallic precursors for low temperature fuel cells. AB - In this work, a review of articles and patents related to the utilization of colloidal metal nanoparticles produced by the decomposition of organometallic precursors as supported electrocatalysts in different electrochemical reactions including hydrogen evolution reaction (HER), oxygen reduction reaction (ORR) and methanol oxidation reaction (MOR) is discussed. In the case of stabilized metal nanoparticles, the kind of functional group contained in the stabilizer as well as the metal/stabilizer ratio, to evaluate the effect of particle size on the electrochemical performance, were also debated. Potential applications and perspectives of these electrocatalysts in proton exchange membrane fuel cells (PEMFC) are contended with reference to the role played by the coordination compounds and costs. PMID- 22946626 TI - Carbon-supported palladium and ruthenium nanoparticles: application as catalysts in alcohol oxidation, cross-coupling and hydrogenation reactions. AB - In the last fifteen-years, the application of metal nanoparticles as catalysts in organic synthesis has received a renewed interest. Therefore, much attention is currently being paid to the synthesis of metal nanoparticles in order to achieve the control of their characteristics in terms of size, shape and surface chemistry. Besides this, the recyclability as well as the recovery from the reaction medium still remain the major drawbacks to widespread the use of nanoparticles in catalysis. To overcome these problems, the immobilization of metal nanoparticles on solid supports appears as a promising alternative. In that context, carbon materials offer several advantages as solid supports such as availability, relatively low cost, high mechanical strength, chemical stability, and a pore structure along with an attractive surface chemistry which allows easy modifications, such as its functionalization, to suit the nanoparticles immobilization needs. Among the transition metals Palladium and Ruthenium are widely employed as efficient catalysts in many reactions. Herein, the most recent advances, from recent papers and patents, in relation to the preparation of carbon-supported Pd or Ru nanoparticles systems as well as their application as catalysts in alcohol oxidation, cross-coupling or hydrogenation reactions, are reviewed. PMID- 22946627 TI - Application of nanofluids to microsphere generation using MEMS technology. AB - This paper provides a literature and patent review on the research and development work contributing to the current status of microsphere generation as an application of nanofluids for drug delivery. The polymer-based microsphere plays an important role to protect protein-based drugs and to deliver the drug to the desired sites. This review covers four microfluidic systems for microsphere generation: membrane emulsification with cross flow, T-junction, hydrodynamic flow focusing and chopper. A discussion on the current state of the arts of the microfluidic systems is addressed, and opportunities for future research are acknowledged. PMID- 22946628 TI - Nanostructured lipid carriers (NLCs) for drug delivery and targeting. AB - Nanostructured lipid carriers (NLCs) are drug-delivery systems composed of both solid and liquid lipids as a core matrix. It was shown that NLCs reveal some advantages for drug therapy over conventional carriers, including increased solubility, the ability to enhance storage stability, improved permeability and bioavailability, reduced adverse effect, prolonged half-life, and tissue-targeted delivery. NLCs have attracted increasing attention in recent years. This review describes recent developments in drug delivery using NLCs strategies. The structures, preparation techniques, and physicochemical characterization of NLCs are systematically elucidated in this review. The potential of NLCs to be used for different administration routes is highlighted. Special attention is paid to parenteral injection and topical delivery since these are the most common routes for investigating NLCs. Relevant issues for the introduction of NLCs to market, including pharmaceutical and cosmetic applications, are discussed. The related patents of NLCs for drug delivery are also reviewed. Finally, the future development and current obstacles needing to be resolved are elucidated. PMID- 22946629 TI - Effectiveness of screening for diabetes mellitus in dental health care. AB - AIMS: The aim of the present study was to test the effectiveness of opportunistic blood glucose screening in a cooperational framework between dental and primary health care. METHODS: Altogether, 1568 subjects, age 20-75 years, with no previous history of diabetes, who came for a regular dental examination, had their non-fasting blood glucose measured with a portable blood glucose meter. Subjects with a concentration of >= 6.7 mmol/l (121 mg dl(-1) ) were referred to their primary healthcare centre for follow-up. The outcome, a diagnosis of diabetes mellitus, was obtained from primary healthcare centre and hospital patient records, during 3 years after screening. RESULTS: Of the 155 (9.9%) subjects who screened positive, 139 (89.7%) came to their primary healthcare centre within the 3-year follow-up period and nine (5.8%) were diagnosed as having diabetes mellitus according to the World Health Organization criteria. Of the 1413 subjects who screened negative, 1137 (80.5%) came to the primary healthcare centre and eight (0.6%) were found to have diabetes mellitus. Screening sensitivity was 52.9%, specificity 90.6% and positive predictive value 5.8%. The number of subjects needed to screen to find one case of diabetes was 196. Delineating the study population to those 40- to 75-year-olds with a BMI >= 25 kg/m(2) , and 30-to 75-year-olds with a BMI >= 30 kg/m(2) , the numbers needed to screen was reduced to 96. CONCLUSIONS: Cooperation between dental and primary care for high blood glucose screening and follow-up appears to be a feasible method for early diagnosis of diabetes. PMID- 22946630 TI - Gender-specific correlates of complementary and alternative medicine use for knee osteoarthritis. AB - BACKGROUND: Knee osteoarthritis (OA) increases healthcare use and cost. Women have higher pain and lower quality of life measures compared to men even after accounting for differences in age, body mass index (BMI), and radiographic OA severity. Our objective was to describe gender-specific correlates of complementary and alternative medicine (CAM) use among persons with radiographically confirmed knee OA. METHODS: Using data from the Osteoarthritis Initiative, 2,679 women and men with radiographic tibiofemoral OA in at least one knee were identified. Treatment approaches were classified as current CAM therapy (alternative medical systems, mind-body interventions, manipulation and body based methods, energy therapies, and three types of biologically based therapies) or conventional medication use (over-the-counter or prescription). Gender specific multivariable logistic regression models identified sociodemographic and clinical/functional correlates of CAM use. RESULTS: CAM use, either alone (23.9% women, 21.9% men) or with conventional medications (27.3% women, 19.0% men), was common. Glucosamine use (27.2% women, 28.2% men) and chondroitin sulfate use (24.8% women; 25.7% men) did not differ by gender. Compared to men, women were more likely to report use of mind-body interventions (14.1% vs. 5.7%), topical agents (16.1% vs. 9.5%), and concurrent CAM strategies (18.0% vs. 9.9%). Higher quality of life measures and physical function indices in women were inversely associated with any therapy, and higher pain scores were positively associated with conventional medication use. History of hip replacement was a strong correlate of conventional medication use in women but not in men. CONCLUSIONS: Women were more likely than men to use CAM alone or concomitantly with conventional medications. PMID- 22946632 TI - A new antifeedant clerodane diterpenoid from Tinospora cordifolia. AB - Phytochemical investigation of the chloroform extract of Tinospora cordifolia yielded a new clerodane diterpenoid tincordin along with tinosporide, 8 hydroxytinosporide, columbin, 8-hydroxycolumbin and 10-hydroxycolumbin. The structure of the new compound was elucidated comprehensively using 1D and 2D NMR methods. All major clerodane diterpenoids isolated were tested for their efficacy as insect antifeedants against Earias vitella, Plutella xylostella and Spodoptera litura. PMID- 22946631 TI - Association of intimate partner violence and childhood sexual abuse with cancer related well-being in women. AB - BACKGROUND: Limited evidence suggests that intimate partner violence (IPV) may be associated with poorer cancer outcomes. We hypothesized that timing and type of IPV as well as childhood sexual abuse (CSA) may negatively affect depression, perceived stress, and cancer-related well-being. METHODS: This was a cross sectional study of women diagnosed with either breast, cervical, or colorectal cancer in the prior 12 months included in the Kentucky Cancer Registry. Consenting women were interviewed by phone (n=553). Multivariate analysis of covariance (MANCOVA) was used to determine the association between IPV (37% lifetime prevalence) and type, timing, and the range of correlated cancer-related well-being indicators, adjusting for confounding factors. RESULTS: IPV (p=0.002) and CSA (p=0.03) were associated with the six correlated well-being indicators. Specifically, lifetime and current IPV were associated with lower Functional Assessment of Cancer Therapy-Breast Cancer (FACT-B) (p=0.006) and Functional Assessment of Chronic Illness Therapy-Spiritual Well-being Scale (FACIT-SP) (p=0.03) scores, higher perceived stress at diagnosis (p=0.006), and depressive symptom scores at diagnosis (p<0.0001), whereas CSA was associated with lower FACT-B (p=0.02), increased number of comorbid conditions (p=0.03), and higher current stress levels (p=0.04). Current and past IPV, as well as psychologic abuse, were associated with poorer well-being among women with a recent cancer diagnosis. CONCLUSIONS: Our results provide evidence that both IPV and CSA negatively influence cancer-related well-being indicators. These data suggest that identification of lifetime IPV and other stressors may provide information that healthcare providers can use to best support and potentially improve the well-being of female cancer patients. PMID- 22946633 TI - Electronic states, potential energy surface, and theoretical spectroscopy of Be2H2. AB - The low-lying electronic states of Be(2)H(2) have been investigated using an ab initio methodology in order to explore the nature of the Be-Be bonding in this tetra-atomic molecule. The donation of two electrons from the antibonding molecular orbital mainly associated with Be(2) to orbitals mainly associated with the 1s of the H atoms is found to be responsible for the strong Be-Be bond in this tetra-atomic molecule compared with the Be(2) diatomic. In addition to the linear form, a cyclic isomer of Be(2)H(2) has been identified at about 1.47 eV above the linear structure. This structure results from an avoided crossing taking place above the lowest dissociation limit giving two BeH fragments. For the linear structure, a six dimensional potential energy surface has been generated and the rovibrational levels have been computed variationally. The fundamental modes obtained are found to be in well agreement with those detected experimentally. For Be(2)H(2) (Be(2)D(2)), the antisymmetric stretching mode nu(3) is computed at 2028.6 (1519.3) cm(-1). PMID- 22946634 TI - Sinularosides A and B, bioactive 9,11-secosteroidal glycosides from the South China Sea soft coral Sinularia humilis Ofwegen. AB - Two new 9,11-secosteroidal glycosides, namely, sinularosides A and B (1, 2), together with the known pregnene glycoside 3beta-(beta-xylopyranosyloxy)-5alpha pregna-20-ene (3), were isolated from the South China Sea soft coral Sinularia humilis Ofwegen. The structures of these compounds were elucidated by a combination of detailed spectroscopic analyses, chemical methods, and comparison with reported data. This is the first report of 9,11-secosteroidal glycosides from a soft coral and from nature. In in vitro bioassays, the new compounds exhibited potent antimicrobial activities and showed no growth inhibition activity against the tumor cells HepG2 and Caco-2. PMID- 22946635 TI - Synbiotic yogurt consumption by healthy adults and the elderly: the fate of bifidobacteria and LGG probiotic strain. AB - Synbiotic dietary supplements are used to modulate the intestinal microbiota in adults; however, studies regarding elderly people are limited. The aim of this work is to determine the effect of regular consumption of yogurt containing Lactobacillus rhamnosus GG (LGG) and the fructooligosaccharide (FOS) Actilight((r)) both in healthy adults and the elderly suffering from constipation. Yogurt was administered daily for 4 weeks; faecal samples were collected before starting, after 4-week administration and a 15-day wash out period, and analyzed for LGG and bifidobacteria counts. Constipation status in the elderly was recorded by a standardized questionnaire. Bifidobacteria did not increase in either groups; at the end of the intervention trial, LGG was detected in significantly different amount in the faeces of the elderly and adults, being higher in adults (95% vs. 30%). An increased evacuation number in the elderly was evidenced, probably due to the presence of FOS in yogurt. PMID- 22946636 TI - Clinical impact of an open-irrigated radiofrequency catheter with direct force measurement on atrial fibrillation ablation. AB - BACKGROUND: Electrode-tissue contact is crucial for adequate lesion formation in radiofrequency catheter ablation (RFCA). OBJECTIVE: We assessed the impact of direct catheter force measurement on acute procedural parameters during RFCA of atrial fibrillation (AF). METHODS: Fifty consecutive patients (28 male) with paroxysmal AF who underwent their first procedure of circumferential pulmonary vein (PV) isolation (PVI) were assigned to either RFCA using (1) a standard 3.5 mm open-irrigated-tip catheter or (2) a catheter with contact force measurement capabilities. Using the endpoint of PVI with entry and exit block, acute procedural parameters were assessed. RESULTS: Procedural data showed a remarkable decline in ablation time (radiofrequency time needed for PVI) from 50.5 +/- 15.9 to 39.0 +/- 11.0 minutes (P = 0.007) with a reduction in overall procedure duration from 185 +/- 46 to 154 +/- 39 minutes (P = 0.022). In parallel, the total energy delivered could be significantly reduced from 70,926 +/- 19,470 to 58,511 +/- 14,655 Ws (P = 0.019). The number of acute PV reconnections declined from 36% to 12% (P = 0.095). CONCLUSIONS: The use of contact force sensing technology is able to significantly reduce ablation and procedure times in PVI. In addition, energy delivery is substantially reduced by avoiding radiofrequency ablation in positions with insufficient surface contact. Procedural efficacy and safety of this new feature have to be evaluated in larger cohorts. PMID- 22946637 TI - Advances in use of functionalized carbon nanotubes for drug design and discovery. AB - INTRODUCTION: As a part of increasing interest in nanobiotechnology, nanoparticle based drug discovery as well as development and drug delivery constitute an important area in nanomedicine, and it is also driven by search for new drugs by the pharmaceutical industry. Nanomaterials for pharmaceutical application include carbon nanotubes (CNTs). AREAS COVERED: This article describes the properties of CNTs, both single-walled CNTs (SWCNTs) and multiwalled CNTs (MWCNTs) with relevance to drug discovery and development. Pharmacokinetics of CNTs as well as CNT-based drug delivery is discussed. The article also looks at how the scope for pharmaceutical applications of CNTs is broadened by conjugation with other molecules and presents the potential therapeutic applications. Finally, the toxicology of CNTs is considered with measures under investigation for reducing it. Literature on CNTs, from the past 5 years, was reviewed and selected publications relevant to drug discovery, development, and delivery were included in the bibliography. EXPERT OPINION: Carbon nanotubes combine more properties relevant to drug development and delivery than any other nanomaterial. Although a tremendous amount of basic research has been done on CNTs during the past decade, little of this is nearing translation into human applications. No CNT-based medicine has reached clinical trials. Nevertheless, CNT conjugation with other molecules has extended the horizons for their potential therapeutic applications. The most promising of these is PEGylation, which extends the survival of CNTs in circulation. Potential future applications of CNTs include combination of diagnostics and therapeutic drug delivery as well as a component of multimodal therapies for tissue regeneration. PMID- 22946638 TI - Classification of grape berries according to diameter and total soluble solids to study the effect of light and temperature on methoxypyrazine, glutathione, and hydroxycinnamate evolution during ripening of Sauvignon blanc (Vitis vinifera L.). AB - Grape berries were classified according to diameter and total soluble solids (TSS) to study the effect of light and temperature on methoxypyrazines (MPs), glutathione (GSH), and hydroxycinnamates (HCAs) during the ripening of Sauvignon blanc. The light exposure of the fruiting zone was modified within leaf and lateral removal at the phenological stage berry of peppercorn size and no removal (control). In comparison to the control, the concentration of 3-isobutyl-2 methoxypyrazine (IBMP) was below the limit of detection in leaf removal 2 weeks before harvest. Leaf removal had no significant influence on GSH and HCAs in the grape juice at harvest. Berry diameter significantly influenced the concentration of IBMP in the grape juice and did not influence the concentration of GSH and HCAs. At harvest, the concentrations of IBMP in grape juices of similar TSS in the control were 12.6 and 5.2 ng/L in 15.5 and 13.5 mm berry diameter classes, respectively. Furthermore, the study showed that berries of the same diameter were not at the same physiological ripening level (not the same TSS). PMID- 22946639 TI - Comparison of recording positions of physical activity in patients with severe COPD undergoing LTOT. AB - BACKGROUND: Accelerometry is increasingly used to assess physical activity (PA) in patients with chronic obstructive pulmonary disease (COPD). It is not known how the relationship of PA to clinical results depends on the position of the PA sensor. METHODS: We assessed the effect of monitor position by measuring lower extremity (ankle), upper extremity (wrist) and total body movement (hip) in 52 patients with severe COPD (mean [+/- SD] age, 62 +/- 10 years; FEV(1), 38 +/- 12% predicted) undergoing long-term oxygen therapy with and without walkers during a pulmonary rehabilitation (PR) program. Sensors were worn 8.5 +/- 3.1 days and data was compared to the BODE score and the 6-minute walk distance (6MWD) assessed at the beginning and end of the PR. RESULTS: Mean ankle PA was moderately related to the 6MWD, irrespective of patients being equipped with a walker or not (p < 0.05). Mean PA values were considerably lower in COPD patients with walker compared to patients without for all sensor positions. No significant association was observed between mean hip PA data and 6MWD; however, hip and ankle PA data were moderately related in walker-free and strongly related in walker patients (p < 0.01). In a multivariate regression model only ankle activity was significantly associated with the BODE score (p < 0.01). CONCLUSION: The sensor position had a significant impact on the association between PA recordings and the 6MWD in very severe COPD. In our setting, ankle measurement seemed to best reflect the clinical state of patients. PMID- 22946640 TI - Sugar and heavy atom effects of glycoconjugated chlorin palladium complex on photocytotoxicity. AB - Palladium(II) complexes of glycoconjugated porphyrin and pyrrolidine-fused chlorin were prepared to examine sugar and heavy atom effects on in vitro photocytotoxicity. Cellular uptake into HeLa cells was enhanced by introducing sugar units regardless of other features, such as the central ion (free base or palladium(II) ion) and the ring structure (porphyrin or chlorin). The palladium(II) complex of glycoconjugated pyrrolidine-fused chlorin (PdPC2) exerted an excellent degree of photocytotoxicity not only on HeLa cells, but also on metastatic B16-BL6 cells, weakly metastatic B16F1 cells, and metastatic 4T1 cells. However, free-base glycoconjugated pyrrolidine-fused chlorin (PC2) also exerted similar or much higher photocytotoxicity rather than PdPC2. Therefore, the palladium(II) ion did not improve the in vitro photocytotoxicity of PC2. The enhanced singlet oxygen generation of palladium(II) complexes (i.e., the heavy atom effect) was confirmed at least in O(2)-saturated D(2)O. In addition, the formation of hydrogen peroxide and hydroxyl radical were also detected in O(2) saturated phosphate buffered saline. However, the reactive oxygen species (ROS) generation efficiency, which is the product of the (relative) quantum yield of each ROS and the light absorbing ability, did not fit the trends of photocytotoxicity seen for the photosensitizers. In our glycoconjugated photosensitizers tested, the best indicator of the photocytotoxicity was found to be the light absorbing ability (namely, the oscillator strength in the wavelength region applied in the photocytotoxicity test). These results indicated that photochemical characteristics of glycoconjugated photosensitizers were notably susceptible to the microenvironment. The biological characteristics, such as the sugar effect, were a much more reliable approach to improving the photocytotoxicity of photosensitizers. PMID- 22946641 TI - Small molecular glucokinase activators: has another new anti-diabetic therapeutic lost favour? AB - Glucokinase activators (GKAs) represent one of the leading hopes for the next generation of type 2 diabetes (T2D) therapeutics, showing efficacy in reducing blood glucose and HbA1c levels in animal models of T2D and short-term human trials. While the hypoglycaemic risks of GCK activation in pancreatic beta-cells have long been appreciated, the hepatic effects of GKAs have generally been perceived to be without significant side effect. In this issue of the British Journal of Pharmacology, De Ceuninck et al. report that acute and chronic GKA treatment of normoglycaemic and hyperglycaemic rodent models results in significant accumulation of triglycerides in the liver. This suggests GKA mediated activation of hepatic glucose uptake and suppression of endogenous glucose production may come at a significant cost; namely, the development of hepatic steatosis. This raises important questions regarding the safety of GKAs and emphasizes that both plasma and hepatic lipid profiles should be carefully monitored in on-going and future studies of these molecules. LINKED ARTICLE: This article is a commentary on De Ceuninck et al., pp. 339-353 of this issue. To view this paper visit http://dx.doi.org/10.1111/j.1476-5381.2012.02184.x. PMID- 22946643 TI - Electrochemistry and electrogenerated chemiluminescence of pi-stacked poly(fluorenemethylene) oligomers. Multiple, interacting electron transfers. AB - The electrochemistry, spectroscopy, and electrogenerated chemiluminescence (ECL) of a series of pi-stacked poly(fluorenemethylene) oligomers (Fn, n = 1-6) were investigated. The pendant cofacially oriented fluorene moieties are essentially in contact with each other by Van der Waals interaction promoting electronic delocalization in these species. All six compounds give successive cyclic voltammetric one-electron (1e) oxidations in 1:1 acetonitrile/benzene (MeCN/Bz), and the multiple 1e transfer properties of all these compounds were confirmed by chronoamperometric experiments with an ultramicroelectrode and digital simulations. The potentials for oxidation of the successive 1e transfers can be explained in terms of electrostatic interactions among the fluorenes. The monomer (F1) shows one irreversible wave, while F2 shows two reversible 1e waves. F3 shows only two reversible 1e oxidation waves, which is consistent with the large energy to remove a third electron because of the greater electrostatic repulsion, so the third wave is shifted toward more positive potentials. Both F4 and F5 show three reversible 1e oxidation waves, while F6 shows four reversible 1e waves. The removal of the first electron from an oligomer becomes easier as n increases. The stability of the radical cations also increases with n. The removal of consecutive electrons from Fn can be correlated with the distance between fluorene moieties. No reduction peaks were observed except for some broad ones at ~-3.2 V vs SCE in THF, which is consitent with the wide highest occupied molecular orbital-lowest unoccupied molecular orbital gap in these compounds (absorbance at about 300 nm). No characteristic annihilation ECL signal was observed for these compounds in 1:1 MeCN/Bz mixed solvent. However, the ECL of F6 in the presence of the coreactant C(2)O(4)(2-) showed a long-wavelength ECL emission that was proposed to be electrolyzed byproduct from the radical cation. PMID- 22946642 TI - Synthesis and biological activity of ester- and amide-functionalized imidazolium salts and related water-soluble coinage metal N-heterocyclic carbene complexes. AB - N-Heterocyclic carbene (NHC) ligand precursors, namely, HIm(A)Cl [1,3-bis(2 ethoxy-2-oxoethyl)-1H-imidazol-3-ium chloride] and HIm(B)Cl {1,3-bis[2 (diethylamino)-2-oxoethyl]-1H-imidazol-3-ium chloride}, functionalized with hydrophilic groups on the imidazole rings have been synthesized and were used in the synthesis of corresponding carbene complexes of silver(I) and copper(I), {[Im(A)]AgCl}, {[Im(A)]CuCl}, and {[Im(B)](2)Ag}Cl. Related Au(I)NHC complexes {[Im(A)]AuCl} and {[Im(B)]AuCl} have been obtained by transmetalation using the silver carbene precursor. These compounds were characterized by several spectroscopic techniques including NMR and mass spectroscopy. HIm(B)Cl and the gold(I) complexes {[Im(A)]AuCl} and {[Im(B)]AuCl} were also characterized by X ray crystallography. The cytotoxic properties of the NHC complexes have been assessed in various human cancer cell lines, including cisplatin-sensitive and resistant cells. The silver(I) complex {[Im(B)](2)Ag}Cl was found to be the most active, with IC(50) values about 2-fold lower than those achieved with cisplatin in C13*-resistant cells. Growth-inhibitory effects evaluated in human nontransformed cells revealed a preferential cytotoxicity of {[Im(B)](2)Ag}Cl versus neoplastic cells. Gold(I) and silver(I) carbene complexes were also evaluated for their ability to in vitro inhibit the enzyme thioredoxin reductase (TrxR). The results of this investigation showing that TrxR appeared markedly inhibited by both gold(I) and silver(I) derivatives at nanomolar concentrations clearly point out this selenoenzyme as a protein target for silver(I) in addition to gold(I) complexes. PMID- 22946644 TI - Malawian secondary students' beliefs about intelligence. AB - Students who view intelligence as malleable tend to be more academically motivated and perform at higher levels than students who view it as a fixed trait. We examined the beliefs of students from Malawi because the culture and schooling process in this country is very different from some other areas of the world in which students' views of intelligence have already been studied. Our research questions were: (1) How do Malawian students define intelligence? (2) To what extent do Malawian students view intelligence as malleable? (3) Are Malawian students' definitions of intelligence and beliefs about the malleability of intelligence similar to those of students in more developed countries? We conducted a mixed methods study and surveyed 136 students attending a secondary school in Malawi using a 39-item questionnaire. Students responded to questions about their intelligence beliefs on open- and closed-ended items. Our results showed that Malawian students believe that an intelligent student exhibits a variety of behaviors, including studying, working hard, reading, performing well on exams and in class, answering and asking questions, paying attention, and demonstrating good behavior. Most students believe that intelligence is malleable and provided responses that indicated that students can become more intelligent through effort. When compared to the findings of other studies, the present results suggest that the Malawian students who remain in secondary school have definitions of intelligence and beliefs about the malleability of intelligence that are similar to those of students in more developed countries, such as the US and Germany. In fact, it appears that Malawian secondary students have even higher malleable beliefs than American and German students. Finally, some of the measures that have been found to produce scores that are reliable and valid in other populations do not produce scores that are as reliable when used with Malawian students. PMID- 22946645 TI - Combined quantum mechanics (TDDFT) and classical electrodynamics (Mie theory) methods for calculating surface enhanced Raman and hyper-Raman spectra. AB - Multiscale models that combine quantum mechanics and classical electrodynamics are presented, which allow for the evaluation of surface-enhanced Raman (SERS) and hyper-Raman scattering spectra (SEHRS) for both chemical (CHEM) and electrodynamic (EM) enhancement mechanisms. In these models, time-dependent density functional theory (TDDFT) for a system consisting of the adsorbed molecule and a metal cluster fragment of the metal particle is coupled to Mie theory for the metal particle, with the surface of the cluster being overlaid with the surface of the metal particle. In model A, the electromagnetic enhancement from plasmon-excitation of the metal particle is combined with the chemical enhancement associated with a static treatment of the molecule-metal structure to determine overall spectra. In model B, the frequency dependence of the Raman spectrum of the isolated molecule is combined with the enhancements determined in model A to refine the enhancement estimate. An equivalent theory at the level of model A is developed for hyper-Raman spectra calculations. Application to pyridine interacting with a 20 nm diameter silver sphere is presented, including comparisons with an earlier model (denoted G), which combines plasmon enhanced fields with gas-phase Raman (or hyper-Raman) spectra. The EM enhancement factor for spherical particles at 357 nm is found to be 10(4) and 10(6) for SERS and SEHRS, respectively. Including both chemical and electromagnetic mechanisms at the level of model A leads to enhancements on the order of 10(4) and 10(9) for SERS and SEHRS. PMID- 22946646 TI - Upregulation of iHsp70 by mild heat shock protects rabbit myogenic stem cells: involvement of JNK signalling and c-Jun. AB - iHsp70 [inducible Hsp70 (heat-shock protein 70)] family members (iHsp70, Hsp72 and Hsp70) are highly conserved proteins that act as molecular chaperones and promote cell survival during various forms of stress. Our data indicate that cultured adult rabbit myoblasts do not express iHsp70 under normal growth conditions, although increased expression was detectable 0.5-72 h following a 42 degrees C heat shock for 15-60 min. The intracellular iHsp70 level reached a maximum 8 h after onset of the heat shock, which correlated with its increased accumulation in nuclei. Inhibition of iHsp70 expression by quercetin showed that sustained activation of JNK (c-Jun N-terminal kinase) 2 and suppression of c-Jun phosphorylation were responsible for myoblast death after heat shock. The data also demonstrate that activation of transcription factor c-Jun depends mostly on JNK1, whereas JNK2 had higher affinity and was translocated to nuclei together with c-Jun. We have also shown that the JNK signalling pathway is an upstream effect of iHsp70 expression. These findings provide further in-depth understanding of the implication of the pro-survival signalling kinases JNK1 and JNK2 and their target, c-Jun, in expression of iHsp70 and regulation of myogenic stem cell survival and death mechanisms after heat shock. Mild heat shock before transplantation might be a way of improving myogenic stem cell survival. PMID- 22946648 TI - Markers of biological fitness as predictors of all-cause mortality. AB - INTRODUCTION: Within the Helsinki Birth Cohort, men who were tall when they were 7 years old lived for 5 years longer than men who were short. In the present analyses we examined two other influences known to be associated with lifespan: having children and educational attainment. We hypothesized that tall stature, the ability to have children, and high educational attainment reflect three aspects of biological fitness that are acquired during development. METHODS: We examined all-cause mortality in 6975 men and 6370 women born in Helsinki during 1934-1944, whose childhood growth, number of children, and educational attainment were recorded. RESULTS: In contrast to men, tall stature in childhood was not associated with longer lifespan among women. Men and women who had children lived for longer than those who had no children. Among women, having children was only associated with increased lifespan among those whose body mass index increased between 2 and 11 years. High educational attainment was associated with longer lifespan in both sexes. The trends of lower all-cause mortality with higher educational attainment were present in each socio-economic group. The men and women who had children, and attained upper tertiary education, lived for 16 years longer than those who had no children and only basic education. CONCLUSION: We suggest that the associations between having children, educational attainment, and lifespan reflect two different aspects of biological fitness that are acquired during early development. PMID- 22946647 TI - Melatonin influences proliferation and differentiation of rat dental papilla cells in vitro and dentine formation in vivo by altering mitochondrial activity. AB - Melatonin mediates a variety of biological processes ranging from the control of circadian rhythms to immune regulation. Melatonin also influences bone formation and osteointegration of dental implants. However, the effects of melatonin on dentine formation have not been examined. This study investigated the effects of melatonin on the proliferation and differentiation of rat dental papilla cells (rDPCs) in vitro and dentine formation in vivo. We found that melatonin (0, 10( 12) , 10(-10) ,10(-8) m) induced a dose-dependent reduction in rDPCs proliferation, increased alkaline phosphatase (ALP) activity, the expression of dentine sialoprotein (DSP), and mineralized matrix formation in vitro. In vivo melatonin (50 mg/kg, BW, i.p.) inhibited dentine formation. Melatonin (10(-8 ) m) suppressed the activity of complex I and IV in the basal medium (OS-) and enhanced the activity of complex I and complex IV in osteogenic medium (OS+). These results demonstrate that melatonin suppresses the proliferation and promotes differentiation of rDPCs, the mechanisms of which may be related to activity of mitochondrial complex I and complex IV. PMID- 22946649 TI - Characterization of endotoxin collected on California dairies using personal and area-based sampling methods. AB - Endotoxin, found in the cell wall of gram negative bacteria, is an important contributor to the biological activity of agriculture particulate matter (PM). We analyzed endotoxin in PM collected on 13 California dairies and from the breathing zone of 226 workers during the summer months of 2008. Two particle size fractions were measured: PM(2.5) and inhalable PM. Recombinant factor C assays were used to analyze biologically active endotoxin, while gas chromatography coupled with mass spectrometry in tandem was used to quantify total lipopolysaccharide. Biologically active endotoxin concentrations in the inhalable PM size fraction from area-based samples ranged from 11-2095 EU/m(3) and from 45 2061 EU/m(3) for personal samples. Total endotoxin in the inhalable PM size fraction ranged from 75-10,166 pmol/m(3) for area-based samples and 34-11,689 pmol/m(3) for personal samples. Area-based geometric mean concentrations for biologically active endotoxin and total endotoxin in PM(2.5) and inhalable PM size fractions were 3 EU/m(3), 149 EU/m(3), 60 pmol/m(3), and 515 pmol/m(3), respectively. Personal geometric mean concentrations in the inhalable PM size fraction were 334 EU/m(3), and 1178 pmol/m(3). Biologically active and total endotoxin concentration variation was best explained by meteorological data, wind speed, relative humidity, and dairy waste management practices. Differences in endotoxin concentration and composition were found across locations on the dairy. PMID- 22946650 TI - Mediterranean diet and bone mineral density in two age groups of women. AB - We hypothesized that adherence to the Mediterranean diet measured as a Mediterranean diet score (MDS) has a beneficial effect on bone mineral density (BMD). For the purposes of this study, a sample of healthy women from Southern Spain was chosen. Subjects were grouped into two major groups: a first group consisted of women of reproductive age (premenopausal, pre-M) and a second group consisted of postmenopausal women (pos-M). The consumption of vegetables and fruit was found to be significantly related to BMD in both groups of subjects studied. In the pre-M group, the lipid ratio was positively associated with BMD and in pos-M women nuts intake was also associated with BMD. After implementing the analysis of covariance analysis, significant linear trends between the MDS and BMD were observed in all subjects studied. Our results indicate that a varied diet based on Mediterranean diet patterns may be beneficial in the prevention of osteoporosis. PMID- 22946651 TI - Pentanidium-catalyzed enantioselective alpha-hydroxylation of oxindoles using molecular oxygen. AB - Pentanidium-catalyzed alpha-hydroxylation of 3-substituted-2-oxindoles using molecular oxygen has been developed with good yields and enantioselectivities. This reaction does not require an additional reductant such as triethyl phosphite, which was typically added to reduce the peroxide intermediate. The reaction was demonstrated to consist of two-steps: an enantioselective formation of hydroperoxide oxindole and a kinetic resolution of the hydroperoxide oxindole via reduction with enolates generated from the oxindoles. PMID- 22946652 TI - Electrocardiographic patterns during left ventricular epicardial pacing. AB - BACKGROUND: There is a paucity of data concerning the use of QRS morphology patterns for identifying pacing sites during left ventricle (LV)-only epicardial pacing in patients with a biventricular device. The objective of this study was to identify QRS patterns during LV-only pacing, and to establish their relationship with LV lead position. In addition, to validate the diagnostic performance of such electrocardiogram (ECG) patterns for predicting posterolateral versus anterior and apical versus nonapical LV pacing site. METHODS: The study retrospectively analyzed data from 376 cardiac resynchronization therapy device patients. Data analyzed included ECGs registered during LV-only VVI pacing, fluoroscopic projections, and lateral chest roentgenograms that documented postimplantation LV lead position. Phase one of the study involved categorization of the ECG patterns of the first 66 study cases. Phase two of the study examined the association between ECG pattern and different LV lead positions. RESULTS: As the LV epicardial pacing site became more anteroapical, the LV-only paced QRS complexes in the precordial leads became more negative. Three ECG patterns were identified (posterolateral, intermediate, and anteroapical), and their distribution was found to be associated with LV lead position (P < 0.001). The posterolateral ECG pattern was mostly observed in cases where the LV lead was in the posterolateral area (diagnostic accuracy of 89.1% for predicting a nonapical LV lead position). The anteroapical ECG pattern was associated with LV leads in anteroapical segments (specificity of 98.5%, accuracy of 89.1% for predicting an anteroapical pacing site). CONCLUSIONS: Posterolateral and anteroapical ECG patterns are highly predictive of LV lead position. PMID- 22946654 TI - Targeting T-cell migration in inflammatory bowel disease. AB - Crohn's disease and ulcerative colitis are chronic inflammatory disorders of the gastrointestinal tract and are collectively referred to as inflammatory bowel disease (IBD). IBD is a major cause of lifetime morbidity, has a severe impact on quality of life of patients (equivalent to that of rheumatoid arthritis, asthma, migraine or diabetes) and constitutes a substantial economic burden to the healthcare system. The introduction of anti-tumour necrosis factor (TNF) antibodies has dramatically improved the treatment of IBD, but approximately one third of patients are nonresponders and another 30-50% will eventually lose the therapeutic effect or become intolerant to these antibodies. Thus, there is an urgent and unmet need for new therapies. The aetiologies of the different forms of IBD have not been fully elucidated but there is strong evidence implicating T cells and T-cell migration to the gut in initiating and perpetuating the intestinal inflammatory process and tissue destruction. In recent years, progress in basic science has shed light on the mechanisms regulating T-cell migration to the gut and new therapeutics targeting these pathways have been developed. It is interesting that some of the factors directing the localization of T cells to the gut have been shown to be relatively organ specific, potentially enabling new T cell-targeted treatments to demonstrate improved safety whilst preserving therapeutic efficacy. Here, fundamental aspects of the gut immune system, the generation of tissue-tropic effector T cells and the mechanisms of T-cell trafficking to the gut mucosa will be reviewed. In addition, the role of these processes in IBD and how they have been exploited for the development of novel therapies for IBD will be discussed. PMID- 22946655 TI - Boron as a platform for new drug design. AB - INTRODUCTION: Boron lies on the borderline between metals and non-metals in the periodic table. As such, it possesses peculiarities which render it suitable for a variety of applications in chemistry, technology and medicine. However, boron's peculiarities have been exploited only partially so far. AREAS COVERED: In this review, the authors highlight selected areas of research which have witnessed new uses of boron compounds in recent times. The examples reported illustrate how difficulties in the synthesis and physicochemical characterization of boronated molecules, encountered in past years, can be overcome with positive effects in different fields. EXPERT OPINION: Many potentialities of boron-based systems reside in the peculiar properties of both boron atoms (the ability to replace carbon atoms, electron deficiency) and of boronated compounds (hydrophobicity, lipophilicity, versatile stereochemistry). Taken in conjunction, these properties can provide innovative drugs. The authors highlight the need to further investigate the assembly of boronated compounds, in terms of drug design, since the mechanisms required to obtain supramolecular structures may be unconventional compared with the more standard molecules used. Furthermore, the authors propose that computational methods are a valuable tool for assessing the role of multicenter, quasi-aromatic bonds and its peculiar geometries. PMID- 22946653 TI - Myofibroblast keratinocyte growth factor reduces tight junctional integrity and increases claudin-2 levels in polarized Caco-2 cells. AB - The colonic epithelium is composed of a polarized monolayer sheathed by a layer of pericryptal myofibroblasts (PCMFs). We mimicked these cellular compartments in vitro to assess the effects of paracrine-acting PCMF-derived factors on tight junction (TJ) integrity, as measured by transepithelial electrical resistance (TER). Coculture with 18Co PCMFs, or basolateral administration of 18Co conditioned medium, significantly reduced TER of polarized Caco-2 cells. Among candidate paracrine factors, only keratinocyte growth factor (KGF) reduced Caco-2 TER; basolateral KGF treatment led to time- and concentration-dependent increases in claudin-2 levels. We also demonstrate that amphiregulin (AREG), produced largely by Caco-2 cells, increased claudin-2 levels, leading to epidermal growth factor receptor-mediated TER reduction. We propose that colonic epithelial TJ integrity can be modulated by paracrine KGF and autocrine AREG through increased claudin-2 levels. KGF-regulated claudin-2 induction may have implications for inflammatory bowel disease, where both KGF and claudin-2 are upregulated. PMID- 22946656 TI - Supercritical carbon dioxide extraction of aromatic turmerone from Curcuma longa Linn. induces apoptosis through reactive oxygen species-triggered intrinsic and extrinsic pathways in human hepatocellular carcinoma HepG2 cells. AB - The mechanisms underlying the antiproliferative and antitumor activities of aromatic turmerone (ar-turmerone), a volatile turmeric oil isolated from Curcuma longa Linn., have been largely unknown. In this study, 86% pure ar-turmerone was extracted by supercritical carbon dioxide and liquid-solid chromatography and its potential effects and molecular mechanisms on cell proliferation studied in human hepatocellular carcinoma cell lines. Ar-turmerone exhibited significant antiproliferative activity, with 50% inhibitory concentrations of 64.8 +/- 7.1, 102.5 +/- 11.5, and 122.2 +/- 7.6 MUg/mL against HepG2, Huh-7, and Hep3B cells, respectively. Ar-turmerone-induced apoptosis, confirmed by increased annexin V binding and DNA fragmentation, was accompanied by reactive oxygen species (ROS) production, mitochondrial membrane potential dissipation, increased Bax and p53 up-regulated modulator of apoptosis (PUMA) levels, Bax mitochondrial translocation, cytochrome c release, Fas and death receptor 4 (DR4) augmentation, and caspase-3, -8, and -9 activation. Exposure to caspase inhibitors, Fas antagonistic antibody, DR4 antagonist, and furosemide (a blocker of Bax translocation) effectively abolished ar-turmerone-triggered apoptosis. Moreover, ar-turmerone stimulated c-Jun N-terminal kinase (JNK) and extracellular signal related kinase (ERK) phosphorylation and activation; treatment with JNK and ERK inhibitors markedly reduced PUMA, Bax, Fas, and DR4 levels and reduced apoptosis but not ROS generation. Furthermore, antioxidants attenuated ar-turmerone mediated ROS production; mitochondrial dysfunction; JNK and ERK activation; PUMA, Bax, Fas, and DR4 expression; and apoptosis. Taken together, these results suggest that ar-turmerone-induced apoptosis in HepG2 cells is through ROS mediated activation of ERK and JNK kinases and triggers both intrinsic and extrinsic caspase activation, leading to apoptosis. On the basis of these observations, ar-turmerone deserves further investigation as a natural anticancer and cancer-preventive agent. PMID- 22946658 TI - Tuning the functionality of a carbon nanofiber-Pt-RuO2 system from charge storage to electrocatalysis. AB - Chemical-functionalization-induced switching in the property of a hybrid system composed of a hollow carbon nanofiber (CNF) and Pt and RuO(2) nanoparticles from charge storage to electrocatalysis is presented. The results of this study show how important it is to have a clear understanding of the nature of surface functionalities in the processes involving dispersion of more than one component on various substrates including carbon nanomorphologies. When pristine CNF is used to decorate Pt and RuO(2) nanoparticles, random dispersion occurs on the CNF surface (C-PtRuO(2)). This results in mainly phase-separated nanoparticles rich in RuO(2) characteristics. In contrast to this, upon moving from the pristine CNF to those activated by a simple H(2)O(2) treatment to create oxygen-containing surface functional groups, a material rich in Pt features on the surface is obtained (F-PtRuO(2)). This is achieved because of the preferential adsorption of RuO(2) by the functionalized surface of CNF. A better affinity of the oxygen containing functional groups on CNF toward RuO(2) mobilizes relatively faster adsorption of this moiety, leading to a well-controlled segregation of Pt nanoparticles toward the surface. Further reorganization of Pt nanoparticles leads to the formation of a Pt nanosheet structure on the surface. The electrochemical properties of these materials are initially evaluated using cyclic voltammetric analysis. The cyclic voltammetric results indicate that C PtRuO(2) shows a charge storage property, a typical characteristic of hydrous RuO(2), whereas F-PtRuO(2) shows an oxygen reduction property, which is the characteristic feature of Pt. This clear switch in the behavior from charge storage to electrocatalysis is further confirmed by galvanostatic charge discharge and rotating-disk-electrode studies. PMID- 22946659 TI - Compact MCTDH wave functions for high-dimensional system-bath quantum dynamics. AB - We employ a simple multiconfiguration time-dependent Hartree (MCTDH) ansatz tailored to an effective-mode transformation of environmental variables that brings the bath into a linear chain form. In this form, important (primary) degrees of freedom can be easily identified and treated at a high correlation level, whereas secondary modes are left uncorrelated. The resulting approach scales linearly with the bath dimensions and allows us to easily access recurrence times much longer than usually possible, at a very small computational cost. Test calculations for model atom-surface problems show that the system dynamics is correctly reproduced in the relevant time window, and quantitative agreement is attained for energy relaxation and sticking, particularly in non Markovian environments. These results pave the way for tackling realistic system bath quantum dynamical problems on the picosecond scale. PMID- 22946657 TI - Receptor activity modifying proteins (RAMPs) interact with the VPAC2 receptor and CRF1 receptors and modulate their function. AB - BACKGROUND AND PURPOSE: Although it is established that the receptor activity modifying proteins (RAMPs) can interact with a number of GPCRs, little is known about the consequences of these interactions. Here the interaction of RAMPs with the glucagon-like peptide 1 receptor (GLP-1 receptor), the human vasoactive intestinal polypeptide/pituitary AC-activating peptide 2 receptor (VPAC(2)) and the type 1 corticotrophin releasing factor receptor (CRF(1)) has been examined. EXPERIMENTAL APPROACH: GPCRs were co-transfected with RAMPs in HEK 293S and CHO K1 cells. Cell surface expression of RAMPs and GPCRs was examined by ELISA. Where there was evidence for interactions, agonist-stimulated cAMP production, Ca(2+) mobilization and GTPgammaS binding to G(s), G(i), G(12) and G(q) were examined. The ability of CRF to stimulate adrenal corticotrophic hormone release in Ramp2(+/-) mice was assessed. KEY RESULTS: The GLP-1 receptor failed to enhance the cell surface expression of any RAMP. VPAC(2) enhanced the cell surface expression of all three RAMPs. CRF(1) enhanced the cell surface expression of RAMP2; the cell surface expression of CRF(1) was also increased. There was no effect on agonist-stimulated cAMP production. However, there was enhanced G protein coupling in a receptor and agonist-dependent manner. The CRF(1) : RAMP2 complex resulted in enhanced elevation of intracellular calcium to CRF and urocortin 1 but not sauvagine. In Ramp2(+/-) mice, there was a loss of responsiveness to CRF. CONCLUSIONS AND IMPLICATIONS: The VPAC(2) and CRF(1) receptors interact with RAMPs. This modulates G-protein coupling in an agonist specific manner. For CRF(1), coupling to RAMP2 may be of physiological significance. PMID- 22946660 TI - Effect of carnosine on erythrocyte deformability in diabetic rats. AB - It is known that oxidative stress plays an important role in the chronic complications of diabetes. Lipid peroxidation is one of the consequences of oxidative stress. Erythrocyte deformability abilities are reduced as a result of lipid peroxidation. Conversely, a decrease nitric oxide (NO) production seems to be responsible in endothelial dysfunction which occurs in diabetic vascular complications. Carnosine is a molecule with anti-oxidant properties. The aim of this study was to investigate erythrocyte deformability indices and the effects of carnosine on erythrocyte deformability in diabetes and to determine a possible relationship between carnosine and nitric oxide. Male Wistar albino rats were used in the study. Injections were administered to seven groups consisting of eight rats each. The groups were: Control, Carnosine, L-NAME (NG-nitro-L-arginine methyl ester), Diabetic, STZ (Streptozotocin) +Carnosine, STZ+L-NAME and STZ+Carnosine+L-NAME. In addition, glucose, insulin, MDA (Malondialdehyde) and NO levels were measured and erythrocyte deformability indices were calculated in all groups. Erythrocyte deformability indices and NO levels were decreased and MDA levels were found to be increased in diabetic group. It was also found that carnosine can significantly reverse erythrocyte deformability, reduce lipid peroxidation and increase NO levels in diabetes. It can be concluded that carnosine can recover from microvascular circulation problems by increasing erythrocyte deformability, can protect cells and tissues against lipid peroxidation and can be used as a multi-functional anti-oxidant in the treatment of diabetes mellitus to prevent the complications of diabetes. PMID- 22946661 TI - Quantitation of affinity, avidity, and binding kinetics of protein analytes with a dynamically switchable biosurface. AB - A label-free method for the analysis of interactions of proteins with surface tethered ligands is introduced. Short DNA levers are electrically actuated on microelectrodes by ac potentials, and their switching dynamics are measured in real-time by fluorescence energy transfer. Binding of proteins to ligands attached to the top of the DNA levers is detected by time-resolved measurements of the levers' dynamic motion. We demonstrate the quantitation of binding kinetics (k(on), k(off) rate constants), dissociation constants (K(D) in the pM regime), and the influence of competitive binders (EC(50) values). Moreover, the "switchSENSE" method reveals avidity effects and allows discriminating between analytes with one or more binding sites. In a comparative study, interactions of six hexa-histidine-tagged proteins with tris-nitrilotriacetic acid (NTA(3)) ligands are quantitated. Their binding kinetics and affinities are found to vary over up to 2 orders of magnitude, evidencing that the proteins' individual chemical environments significantly influence the His(6)-NTA(3) interaction. PMID- 22946662 TI - The race for survival in myelodysplastic syndromes. PMID- 22946663 TI - Clinical outcome of non-surgical treatment for primary small intestinal lymphoma diagnosed with double-balloon endoscopy. AB - Primary small intestinal lymphoma (PSIL) is often treated with surgical resection, and therefore response to non-surgical treatment is rarely known. We retrospectively analyzed the clinicopathological features of 19 patients with PSIL, who had been diagnosed by double-balloon endoscopy (DBE) and had not received surgical treatment. The immunohistological phenotypes of 18 patients were B-cell lymphomas. Five patients had tumors within the jejunum, nine within the ileum and five in multiple sites including the duodenum. Most cases were in the low or low-intermediate risk group of the International Prognostic Index score. Seventeen patients received chemotherapy, with an overall response rate of 82.4%. The estimated overall survival at 5 years was 72.2%. Response to initial chemotherapy and levels of hemoglobin (Hb) and albumin (Alb) were identified as favorable prognostic indicators. We conclude that PSIL can be effectively diagnosed by DBE and shows a good prognosis with chemotherapy alone. PMID- 22946664 TI - Vascular endothelial growth factor receptor-3 expression in mycosis fungoides. AB - Here, we have studied vascular endothelial growth factor receptor-3 (VEGFR-3) expression in mycosis fungoides (MF), the most common type of cutaneous T-cell lymphoma (CTCL). Immunohistochemistry revealed that in two-thirds of 34 patients, VEGFR-3 was expressed in situ by both tumor and stromal cells irrespective of the disease stage. The natural VEGFR-3 ligand, VEGF-C, partially protected malignant T-cell lines from growth inhibition by the histone deacetylase inhibitor, suberoylanilide hydroxamic acid (SAHA). Whereas the malignant T cells did not produce VEGF-C in vitro, its expression was induced during tumor formation in vivo in a xenograft mouse model of MF. In conclusion, malignant and stromal cells express high levels of VEGFR-3 in all stages of MF. Moreover, malignant T cells trigger enhanced VEGF-C expression in fibroblasts, suggesting that cross-talk between tumor and stromal cells plays a role in lymphangiogenesis and possibly disease progression. PMID- 22946665 TI - Role of interleukin-10 in the regulation of tumorigenicity of a T cell lymphoma. AB - Interleukin-10 (IL-10) is a cytokine that is produced by a variety of immune cells and is known to inhibit T helper cell type 1 (T(H)1) responses, which are essential to combat tumors. In the present study, we used LSA, a T cell lymphoma cell line that expresses IL-10, to study the role of this cytokine in its tumorigenesis. To this end, LSA cells were modified to overexpress IL-10 or to block its expression via Ret-off-IL-10 vector transfection. Interestingly, blocking IL-10 expression using Ret-off-IL-10 antisense inhibited the growth of LSA in syngeneic C57BL/6 mice. Also, overexpression of IL-10 in LSA cells using Ret-off-IL-10 sense significantly increased LSA tumorigenicity. Additionally, administration of antibodies against IL-10 significantly inhibited LSA tumor growth in vivo. Together, our data stress the importance of tumor-produced IL-10 in regulating the tumorigenicity of this T cell lymphoma, and suggest that antagonizing IL-10 expression in IL-10 secreting lymphomas may have significant potential in their treatment. PMID- 22946666 TI - The rs10757278 polymorphism of the 9p21.3 locus is associated with premature coronary artery disease in Polish patients. AB - Recently, genome-wide association studies have revealed a locus associated with coronary artery disease (CAD) and myocardial infarction, namely, 9p21.3. Its participation in the conditioning of the disease has been proven in many populations of European descent, but not yet in Slavs. Allelic variants of the rs10757278 polymorphism functionally affect the activity of the 9p21.3 locus; therefore, we conducted a study to determine whether the rs10757278 is associated with premature CAD in Polish patients. We studied 320 subjects aged 25-55 years, divided into two groups matched by sex and age: (1) patients with angiographically proven premature CAD (n=160), and (2) blood donors as a control group (n=160). The rs10757278 was genotyped using the method of fluorescently labeled allele-specific oligonucleotides. The frequency of the G allele was significantly higher in patients than in controls (58.2% vs. 42.8%, respectively, p=0.011) and was similar to the frequency of the GG homozygotes (30.6% vs. 17.5%, respectively, p=0.006). Both the GG homozygosity (odds ratio [OR]=2.08, 95% confidence interval [CI]: 1.19-3.66) as well as the G allele (OR=1.49, 95% CI: 1.08-2.07) have been associated with CAD in the analyzed population. These variants may be considered as risk factors, also in the Polish population. PMID- 22946667 TI - Fas, Fas Ligand, and vitamin D Receptor FokI gene polymorphisms in patients with type 1 diabetes mellitus in the Aegean region of Turkey. AB - OBJECTIVE: Several gene polymorphisms have been reported to be associated with the risk of developing type 1 diabetes. Among them, the human leukocyte antigen locus is the strongest genetic determinant. To identify additional genetic markers, we aimed to evaluate the relationship between the Fas, Fas ligand (FasL), and vitamin D receptor (VDR) FokI gene polymorphisms and the susceptibility to type 1 diabetes in the Aegean region of Turkey. MATERIALS AND METHODS: Eighty-five patients with type 1 diabetes and 80 healthy controls were included in this study. The Fas -670A/G, FasL -843C/T, and VDR FokI gene polymorphisms were evaluated using the polymerase chain reaction-restriction fragment length polymorphism method. RESULTS: The evaluation of the Fas genotype and the gene allele frequency did not show statistically significant differences between the patient and control group. Distribution of the FasL genotype differed significantly between patients and controls. The distribution of the VDR FokI genotype and allele frequencies differed significantly between the patients and controls. Individuals with type 1 diabetes presented less commonly with the FokI f allele. CONCLUSIONS: Our findings suggest that the FasL -843C/T and VDR FokI gene polymorphisms are associated with type 1 diabetes in the Agean region of Turkey; however, the Fas -670A/G gene polymorphism is not. PMID- 22946669 TI - Analysis of ingredient lists of commercially available gluten-free and gluten containing food products using the text mining technique. AB - Ingredients mentioned on the labels of commercially available packaged gluten free and similar gluten-containing food products were analyzed and compared, using the text mining technique. A total of 324 products' labels were analyzed for content (162 from gluten-free products), and ingredient diversity in gluten free products was 28% lower. Raw materials used as ingredients of gluten-free products were limited to five varieties: rice, cassava, corn, soy, and potato. Sugar was the most frequently mentioned ingredient on both types of products' labels. Salt and sodium also were among these ingredients. Presence of hydrocolloids, enzymes or raw materials of high nutritional content such as pseudocereals, suggested by academic studies as alternatives to improve nutritional and sensorial quality of gluten-free food products, was not identified in the present study. Nutritional quality of gluten-free diets and health of celiac patients may be compromised. PMID- 22946668 TI - Variations in the S and P regions of the hepatitis B virus genome under immunosuppression in vitro and in vivo. AB - To provide a basis for improved prevention and treatment of hepatitis B virus (HBV) re-infection after liver transplantation, variations in the S and P genes of HBV under immunosuppression in vitro and their association with patient prognosis were investigated. For the in vitro study, HepG2.2.15 hepatocellular carcinoma cells stably producing HBV particles were treated with the immunosuppressants methylprednisolone (MP) and tacrolimus (FK506) at doses found to be non-toxic by the methylthiazolyl tetrazolium (MTT) cell viability assay. MP dose-dependently inhibited HBV DNA expression in HepG2.2.15 cells, while FK506 did not, as determined by quantitative real-time PCR (qRT-PCR). By gene sequencing, both MP and FK506 were found to cause variations in HBV S, P, and S/P overlapping regions. MP- but not FK506-induced mutations were common in the glucocorticoid response element of the P region, while both immunosuppressants caused mutations outside the nucleoside analogue resistance sites. For the in vivo study, 14 patients with HBV-related end-stage liver disease re-infected after liver transplantation, and 20 cases without HBV re-infection as controls, were studied. Seventy-five percent of re-infected recipients showed multi-loci amino acid mutations at different sites besides lamivudine (LAM)-resistant loci in the P region, including in the glucocorticoid response element. Fifty percent of re-infected recipients had mutations in the "a" determinant region and flanking sequences. Re-infection was associated with negative serum hepatitis B immunoglobulin (HBIG), as measured by a microparticle capture enzyme immunoassay. Nucleotide mutations in the S region caused missense or synonymous mutations, which caused synonymous mutations in the overlapping P region. These results showed that effects of immunosuppressants on HBV genes in vitro were different from those in clinical recipients. Positive HBV DNA and gene mutations pre transplantation were factors affecting re-infection post-transplantation. Multiple mutations found in the P and S genes suggest that the formation of quasispecies contributes to HBV re-infection after liver transplantation. PMID- 22946670 TI - Shock anxiety among implantable cardioverter defibrillator recipients with recent tachyarrhythmia. AB - BACKGROUND: Shock anxiety has been documented irrespective of shock exposure in implantable cardioverter defibrillator (ICD) recipients. The presence of tachyarrhythmia may lead to an anticipation of receiving a shock and thereby give rise to shock anxiety. The aims were to assess: (1) the level of shock anxiety in a sample of ICD recipients, (2) the relationship between such anxiety and shock exposure, and (3) the relationship between recent tachyarrhythmia and shock anxiety. METHODS: ICD recipients (n = 167) completed the Florida Shock Anxiety Scale measure of shock anxiety. The recipients were divided into three groups: (1) Recipients with no documented tachyarrhythmia over the previous 12 months (n = 56), (2) recipients with documented tachyarrhythmia over the previous twelve months (n = 54), and (3) recipients with any history of shocks (n = 57). RESULTS: Of the recipients, 44% experienced some form of shock anxiety, whereas 15% reported general shock anxiety. Analyses of covariance revealed that recipients with recent tachyarrhythmia (F = 7.675 df = 9/100, P = 0.007) as well as recipients with a shock history (F = 9.976, df = 9/103, P = 0.002) reported higher levels of shock anxiety than recipients with no recent tachyarrhythmia. CONCLUSION: This study indicates that although a substantial proportion of the ICD recipients experienced some form of shock anxiety, only a relatively small proportion reported general shock anxiety. ICD recipients with recent tachyarrhythmia, in addition to recipients with shock history, appear to be at greater risk for development of shock anxiety. This implies that these recipients may profit from clinical-based strategies and interventions targeting shock anxiety. PMID- 22946671 TI - Method for estimation of protein isoelectric point. AB - Adsorption of sample protein to Eu(3+) chelate-labeled nanoparticles is the basis of the developed noncompetitive and homogeneous method for the estimation of the protein isoelectric point (pI). The lanthanide ion of the nanoparticle surface conjugated Eu(3+) chelate is dissociated at a low pH, therefore decreasing the luminescence signal. A nanoparticle-adsorbed sample protein prevents the dissociation of the chelate, leading to a high luminescence signal. The adsorption efficiency of the sample protein is reduced above the isoelectric point due to the decreased electrostatic attraction between the negatively charged protein and the negatively charged particle. Four proteins with isoelectric points ranging from ~5 to 9 were tested to show the performance of the method. These pI values measured with the developed method were close to the theoretical and experimental literature values. The method is sensitive and requires a low analyte concentration of submilligrams per liter, which is nearly 10000 times lower than the concentration required for the traditional isoelectric focusing. Moreover, the method is significantly faster and simpler than the existing methods, as a ready-to-go assay was prepared for the microtiter plate format. This mix-and-measure concept is a highly attractive alternative for routine laboratory work. PMID- 22946672 TI - Palladium-catalyzed borylation of aryl and heteroaryl halides utilizing tetrakis(dimethylamino)diboron: one step greener. AB - The palladium-catalyzed borylation of aryl and heteroaryl halides with a novel borylating agent, tetrakis(dimethylamino)diboron [(Me(2)N)(2)B-B(NMe(2))(2)], is reported. The method is complementary to the previously reported method utilizing bis-boronic acid (BBA) in that certain substrates perform better under one set of optimized reaction conditions than the other. Because tetrakis(dimethylamino)diboron is the synthetic precursor to both BBA and bis(pinacolato)diboron (B(2)Pin(2)), the new method represents a more atom economical and efficient approach to current borylation methods. PMID- 22946673 TI - Tolerability and use in co-administration of pregabalin in affective patients: a 6-month prospective naturalistic study. AB - OBJECTIVE: The aims of the present study were to investigate the main demographic and clinical characteristics, comorbidity patterns, use in association and tolerability of pregabalin in a sample of patients with affective disorders, and to compare demographic and clinical variables of the groups divided, according to the treatment pregabalin was associated with. METHODS: One hundred and fourteen consecutive outpatients, with anxiety and/or depressive disorders with or without comorbidity, were started on pregabalin, assessed and interviewed and their demographic data, associated therapy, tolerability and side effects collected over an observational period of 6 months. RESULTS: The most frequent primary diagnoses were mood disorders (49.1%) and generalized anxiety disorder (21.9%). The most commonly associated treatments were antidepressants (66.7%) and mood stabilizers (15.8%). The most frequent side effects were sedation (3.4%), dizziness (0.9%), nausea (0.9%), diarrhea (0.9%), cough (0.9%) and peripheral edema (0.9%). When patients were divided according to the co-treatments, subgroups differed in terms of prescription of benzodiazepines (chi(2) = 15.25, df = 6, p = 0.013, phi = 0.37), with the most frequent use of these molecules in patients co-treated with tricyclic antidepressants and minor use in the selective serotonin reuptake inhibitors group. CONCLUSIONS: Differences in the co administration of benzodiazepines might suggest a stronger anxiolytic effect when pregabalin is combined with specific psychotropic drugs (e.g., SSRIs). PMID- 22946674 TI - Mass spectrometric evidence of malonaldehyde and 4-hydroxynonenal adductions to radical-scavenging soy peptides. AB - Antioxidative peptides in food systems are potential targets of lipid oxidation generated reactive aldehydes, such as malonaldehyde (MDA) and 4-hydroxynonenal (HNE). In this study, covalent modifications on radical-scavenging peptides prepared from soy protein hydrolysate by MDA and HNE were characterized by liquid chromatography-electrospray ionization-mass spectrometry (LC-ESI-MS/MS). MS/MS analyses detected the formation of Schiff base type adducts of MDA on the side chain groups of lysine, histidine, arginine, glutamine, and asparagine residues as well as the N-termini of peptides. MDA also formed a fluorescent product with lysine residues. HNE adducted on lysine residues through Schiff base formation and on histidine, arginine, glutamine, and asparagine residues mainly through Michael addition. Despite the extensive MDA modification, peptide cross-linking by this potential mechanism was undetectable. PMID- 22946675 TI - The WOX13 homeobox gene promotes replum formation in the Arabidopsis thaliana fruit. AB - The Arabidopsis fruit forms a seedpod that develops from the fertilized gynoecium. It is mainly comprised of an ovary in which three distinct tissues can be differentiated: the valves, the valve margins and the replum. Separation of cells at the valve margin allows for the valves to detach from the replum and thus dispersal of the seeds. Valves and valve margins are located in lateral positions whereas the replum is positioned medially and retains meristematic properties resembling the shoot apical meristem (SAM). Members of the WUSCHEL related homeobox family have been involved in stem cell maintenance in the SAM, and within this family, we found that WOX13 is expressed mainly in meristematic tissues including the replum. We also show that wox13 loss-of-function mutations reduce replum size and enhance the phenotypes of mutants affected in the replum identity gene RPL. Conversely, misexpression of WOX13 produces, independently from BP and RPL, an oversized replum and valve defects that closely resemble those of mutants in JAG/FIL activity genes. Our results suggest that WOX13 promotes replum development by likely preventing the activity of the JAG/FIL genes in medial tissues. This regulation seems to play a role in establishing the gradient of JAG/FIL activity along the medio-lateral axis of the fruit critical for proper patterning. Our data have allowed us to incorporate the role of WOX13 into the regulatory network that orchestrates fruit patterning. PMID- 22946677 TI - Improved data normalization methods for reverse phase protein microarray analysis of complex biological samples. AB - Reverse phase protein microarrays (RPMA) are designed for quantitative, multiplexed analysis of proteins, and their posttranslational modified forms, from a limited amount of sample. To correct for sample to sample variability due to the number of cells in each lysate and the presence of extracellular proteins or red blood cells, a normalization method is required that is independent of these potentially confounding parameters. We adopted a gene microarray algorithm for use with RPMA to optimize the proteomic data normalization process and developed a systematic approach to RPMA processing and analysis, tailored to the study set. Our approach capitalizes on the gene microarray algorithms geNorm and NormFinder to identify the normalization parameter with the lowest variability across a proteomic sample set. Seven analytes (ssDNA, glyceraldehyde 3-phosphate dehydrogenase, alpha/beta-tubulin, mitochondrial ribosomal protein L11, ribosomal protein L13a, beta-actin, and total protein) were compared across sample sets including cell lines, tissues subjected to laser capture microdissection, and blood-contaminated tissues. We examined normalization parameters to correct for red blood cell content. We show that single-stranded DNA (ssDNA) is proportional to total non-red blood cell content and is a suitable RPMA normalization parameter. Simple modifications to RPMA processing allow flexibility in using ssDNA-or protein-based normalization molecules. PMID- 22946678 TI - Autophagy, mitochondria and 3-nitropropionic acid joined in the same model. AB - Huntington's disease (HD) is a neurodegenerative disorder caused by a mutation in the gene encoding the huntingtin protein. Although the precise mechanism by which neuronal degeneration occurs is still unclear, several elements are important to its development: (1) altered gene expression and protein synthesis, (2) mitochondrial damage and (3) improper regulation of the autophagy programme. In this issue of British Journal of Pharmacology, Galindo and co-workers provide the first evidence for a role of the mitochondrial permeability transition pore (mPTP) in mitochondrial fragmentation and autophagy activation. In a model of cell death induced by 3-nitropropionic acid (3-NP) in human neural cells, the authors describe clear functions for mPTP and Bax, but not the mitochondrial fusion/fission machinery, mitochondrial fragmentation and autophagy (mitophagy). This commentary summarises the significance of this relationship and suggests several points for future development. PMID- 22946679 TI - Platinum(II) complexes of cyclic triphosphenium ions: a 31P NMR spectroscopic and computational study. AB - The first transition metal complexes of cyclic triphosphenium ions have been unequivocally identified in solution by (31)P NMR spectroscopy. The ligands coordinate to platinum(II) via the central phosphorus atom, but only when at least one of the outer phosphorus atoms has non-aromatic substituents. Depending on the system, either trans- (the kinetic reaction product) and/or cis- (the thermodynamic reaction product) complexes are formed. The (1)J coupling constants between (195)Pt and the central phosphorus atom of the CTI (P(A)) are small for both cis- and trans-isomers, between 900 and 1300 Hz, whereas other phosphanes in these complexes derived from the platinum(II) starting material show normal (1)J(PtP) values. These results suggest a possible long P-Pt bond between the overall positively charged ligand and the platinum(II) cation. Calculations including predicted (31)P NMR shifts for the CTIs and their Pt(II) complexes largely support our experimental findings. PMID- 22946680 TI - Variable temperature rate studies for the reaction H3O(+) + (C2H2)2 measured with a coaxial molecular beam radio frequency ring electrode ion trap. AB - The independent molecule and ion temperature dependence of the rate coefficient for the H(3)O(+) and (C(2)H(2))(2) reaction producing C(2)H(5)O(+) are determined using a coaxial molecular beam radio frequency ring electrode ion trap (CoMB RET). The H(3)O(+) temperature is varied from 25 to 170 K, while the equilibrated C(2)H(2)/(C(2)H(2))(2) beam temperatures sampled are 160, 180, 200, and 220 K. The rate coefficient of the H(3)O(+) + (C(2)H(2))(2) reaction is determined to be 4.0 * 10(-10) * (T(react)/300)(-2.5) in the reaction temperature range of T(react) = 114-187 K. The H(3)O(+) and C(2)H(2) radiative association reaction is found to have a rate coefficient below 1 * 10(-13) cm(3).s(-1) at 187 K. This result is consistent with Herbst's experimental determination. PMID- 22946681 TI - Stable isotope-assisted metabolomics for network-wide metabolic pathway elucidation. AB - The combination of high-resolution LC-MS-based untargeted metabolomics with stable isotope tracing provides a global overview of the cellular fate of precursor metabolites. This methodology enables detection of putative metabolites from biological samples and simultaneous quantification of the pattern and extent of isotope labeling. Labeling of Trypanosoma brucei cell cultures with 50% uniformly (13)C-labeled glucose demonstrated incorporation of glucose-derived carbon into 187 of 588 putatively identified metabolites in diverse pathways including carbohydrate, nucleotide, lipid, and amino acid metabolism. Labeling patterns confirmed the metabolic pathways responsible for the biosynthesis of many detected metabolites, and labeling was detected in unexpected metabolites, including two higher sugar phosphates annotated as octulose phosphate and nonulose phosphate. This untargeted approach to stable isotope tracing facilitates the biochemical analysis of known pathways and yields rapid identification of previously unexplored areas of metabolism. PMID- 22946682 TI - Life-style and metformin for the prevention of endometrial pathology in postmenopausal women. AB - In western women, the endometrium is frequently exposed, even after menopause, to the endogenous hormonal stimulation. Such a stimulation increases the risk of pathologic conditions such as endometrial hyperplasia and type I (endometrioid) endometrial adenocarcinoma. Metabolic syndrome, obesity, insulin resistance and type II diabetes promote the endometrial stimulation, and are recognized risk factors for endometrial cancer. Furthermore, chronic hyperinsulinemia linked both to obesity and metabolic syndrome influences endometrial proliferation through direct and indirect actions. Intentional weight loss, calorie restriction and physical activity are associated with a reduced risk of the endometrial pathology. Biological mechanisms include reduction in insulin and sex steroid hormone levels. In addition to life-style modifications, the antidiabetic metformin may be proposed as preventive agent. Metformin reduces the metabolic syndrome, lowers insulin and testosterone levels in postmenopausal women, and it is a potent inhibitor of endometrial cancer cell proliferation. PMID- 22946683 TI - Antibiotics and antiseptics to prevent infection in cardiac rhythm management device implantation surgery. AB - BACKGROUND: Surgical site infections (SSIs) resulting from cardiac implantable electronic device (CIED) implantation cause significant morbidity and mortality, and are increasing at a disproportionately higher rate than the rate of CIED implantation. The prophylactic administration of antibiotics and antiseptics can reduce this infection rate. The objective of this systematic review and meta analysis was to determine whether the prophylactic administration of antibiotics and antiseptics in patients undergoing CIED implantation reduces the incidence of SSI in randomized controlled trials. We searched the Cochrane Wounds Group Specialized Register, the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2011, Issue 2), Ovid MEDLINE, Ovid EMBASE, and EBSCO CINAHL. No date or language restrictions were applied. METHODS: Two review authors independently screened papers for inclusion, assessed risk of bias, and extracted data using a data collection form. Data were pooled where appropriate. RESULTS: Fifteen studies (3,970 participants) were included in this review. For patients undergoing a CIED implant, perioperative systemic antibiotics (PSA) plus antiseptics delivered 1 hour before the procedure significantly reduced the incidence of SSI compared with no antibiotics (risk ratio [RR] 0.13; 95% confidence interval [CI] 0.05-0.36; P value < 0.00001). Furthermore, PSA plus antiseptics significantly reduced the incidence of postoperative infection compared to antibiotics delivered postoperatively (RR 0.14; 95% CI 0.03-0.60; P value 0.008). CONCLUSION: The evidence strongly suggests that antibiotic prophylaxis within 1 hour before CIED implantation is effective at reducing SSI. PMID- 22946684 TI - Emerging areas of focus for social work practitioners in end-of-life and palliative care. PMID- 22946685 TI - Notes for the new hospice social worker. PMID- 22946686 TI - Trauma that should have been avoided: it can happen to you! PMID- 22946687 TI - Public hospital palliative social work: addressing patient cultural diversity and psychosocial needs. AB - Through creative practice innovations and a wide range of professional competencies, social work has contributed substantively to the development of the palliative care field (Harper, 2011 ). As the field continues to grow and evolve, new opportunities are emerging to profile palliative social work in diverse health care settings. A statewide initiative to spread palliative care in California's public hospitals provided just such an opportunity. Palliative social workers from six public hospitals participating in the initiative formed a group to discuss palliative social work in this unique hospital setting. This article highlights the group's insights and experiences as they address the significant cultural diversity and psychosocial needs of public hospital patients receiving palliative care. PMID- 22946688 TI - Acculturation and attitudes of Latinos toward hospice. AB - The relationship between acculturation and attitudes of Latinos toward hospice was examined in a sample of 380 Latinos from southern New Jersey. A survey design, using self-administered questionnaires, including a bi-dimensional acculturation scale, examined attitudes toward hospice. The sample represented a cross-section of socioeconomic groups and various nationalities of Latinos. Findings revealed that education and income were significantly related to attitudes toward hospice but acculturation was not. Findings also revealed that more than one-half of participants were unfamiliar with the word "hospice" prior to the study. Respondents with higher incomes, higher levels of education, and who were older were more familiar and had more positive attitudes. Overall, despite respondents' limited knowledge of hospice, the majority would use it. These findings underscore the need to intensify hospice education in Latino communities taking into account Latinos' socioeconomic status. PMID- 22946689 TI - What their terms of living and dying might be: hospice social workers discuss Oregon's Death with Dignity Act. AB - This article presents data from a qualitative study of nine social work hospice practitioners and experts as they discuss Oregon's Death with Dignity Act. Three themes emerged from the analysis: (a) values regarding physician-assisted death; (b) agency policies about the option; and (c) the role of hospice social workers with physician-assisted death. Three states now allow terminally ill persons to obtain a lethal prescription if criteria are met. Two other states are actively considering and may pass similar legislation over time. Hospice social work practitioners work with patients and families as they consider this option and their voices reflect the complexities and nuances of these interactions. PMID- 22946690 TI - Causes of death among an urban homeless population considered by the medical examiner. AB - Those who are homeless face illness and death, however, live in places not conducive to provision of end-of-life care. Limited information exists on causes of death among this group of people. To characterize causes of death, data were requested from the Office of the Chief Medical Examiner for Alberta Justice, Canada, for people determined to be homeless in the period 2007-2009. One hundred and thirty-two deaths were reported. Most deaths that could be classified were attributed to drug and alcohol use/abuse and to natural causes. For many, end-of life circumstances may have been improved through provision of palliative care delivered in a hospice setting. PMID- 22946693 TI - Tuning the gate opening pressure of Metal-Organic Frameworks (MOFs) for the selective separation of hydrocarbons. AB - Separation of hydrocarbons is one of the most energy demanding processes. The need to develop materials for the selective adsorption of hydrocarbons, under reasonable conditions, is therefore of paramount importance. This work unveils unexpected hydrocarbon selectivity in a flexible Metal-Organic Framework (MOF), based on differences in their gate opening pressure. We show selectivity dependence on both chain length and specific framework-gas interaction. By combining Raman spectroscopy and theoretical van der Waals Density Functional (vdW-DF) calculations, the separation mechanisms governing this unexpected gate opening behavior are revealed. PMID- 22946694 TI - Reactivity of compound II: electronic structure analysis of methane hydroxylation by oxoiron(IV) porphyrin complexes. AB - The methane hydroxylation reaction by a Compound II (Cpd II) mimic PorFe(IV)=O and its hydrosulfide-ligated derivative [Por(SH)Fe(IV)=O](-) is investigated by density functional theory (DFT) calculations on the ground triplet and excited quintet spin-state surfaces. On each spin surface both the sigma- and pi-channels are explored. H-abstraction is invariably the rate-determining step. In the case of PorFe(IV)=O the H-abstraction reaction can proceed either through the classic pi-channel or through the nonclassical sigma-channel on the triplet surface, but only through the classic sigma-mechanism on the quintet surface. The barrier on the quintet sigma-pathway is much lower than on the triplet channels so the quintet surface cuts through the triplet surfaces and a two state reactivity (TSR) mechanism with crossover from the triplet to the quintet surface becomes a plausible scenario for C-H bond activation by PorFe(IV)=O. In the case of the hydrosulfide-ligated complex the H-abstraction follows a pi-mechanism on the triplet surface: the sigma* is too high in energy to make a sigma-attack of the substrate favorable. The sigma- and pi-channels are both feasible on the quintet surface. As the quintet surface lies above the triplet surface in the entrance channel of the oxidative process and is highly destabilized on both the sigma- and pi-pathways, the reaction can only proceed on the triplet surface. Insights into the electron transfer process accompanying the H-abstraction reaction are achieved through a detailed electronic structure analysis of the transition state species and the reactant complexes en route to the transition state. It is found that the electron transfer from the substrate sigma(CH) into the acceptor orbital of the catalyst, the Fe-O sigma* or pi*, occurs through a rather complex mechanism that is initiated by a two-orbital four-electron interaction between the sigma(CH) and the low-lying, oxygen-rich Fe-O sigma-bonding and/or Fe-O pi bonding orbitals of the catalyst. PMID- 22946695 TI - Novel pillar[5]arene-based dynamic polyrotaxanes interlocked by the quadruple hydrogen bonding ureidopyrimidinone motif. AB - Novel dynamic polyrotaxanes constructed from pillar[5]arenes as wheels and diamines as axles have been successfully synthesized in good yield using quadruple hydrogen bonding ureidopyrimidinone (UPy) motifs, which play a dual role as the end-capping and interlocking units. The present study is the first example of noncovalent bonded dynamic polyrotaxanes constructed by multiple hydrogen bonding interactions. PMID- 22946696 TI - Using the NHS sustainability framework to understand the activities and resource implications of Canadian nursing guideline early adopters. AB - AIMS AND OBJECTIVES: To examine the activities and resource implications for the initial cohort of healthcare organisations involved in the introduction of multiple nursing guidelines. BACKGROUND: The Best Practice Spotlight Organization initiative was launched in 2003 as part of the Registered Nurses' Association of Ontario's Best Practice Guidelines programme. While previous research has evaluated improvements in patient care and outcomes, there has been limited research from an organisational perspective on the activities conducted to introduce nursing guidelines. DESIGN: Secondary analysis of retrospective narrative data. METHODS: We conducted a content analysis of the 2004-2006 annual reports from the seven participating sites. We used both deductive and inductive approaches to categorise the guideline implementation activities and their resource implications. RESULTS: All sites reported implementing multiple guidelines (four to nine guidelines per site) and used a wide range of implementation activities that clearly addressed nine of the 10 NHS Sustainability dimensions. The dimension not reported was benefits beyond helping patients. All sites established steering committees that involved staff and senior leaders, reviewed selected guidelines and recommendations, reviewed existing policies and procedures and developed new policies and procedures, recruited champions or peer mentors, applied for additional external funding to support activities, developed relationships with external clinical partners, included guideline implementation in orientation, developed intra-agency web based and print communications for the project, and evaluated practice changes. For each of these activities, the sites reported expenditures and resource usage. CONCLUSIONS: The organisational processes used for the introduction of new nursing guidelines in Canada are remarkably consistent with factors identified by leaders and change agents in the UK who developed the NHS Sustainability Model. RELEVANCE TO CLINICAL PRACTICE: A multidimensional framework for sustainability is useful for planning successful guideline implementation across an organisation. Examples of specific activities and resource implications for organisational change are provided. PMID- 22946698 TI - A report from the publication office. PMID- 22946697 TI - Craniofacial and dental development in cardio-facio-cutaneous syndrome: the importance of Ras signaling homeostasis. AB - Cardio-facio-cutaneous syndrome (CFC) is a RASopathy that is characterized by craniofacial, dermatologic, gastrointestinal, ocular, cardiac, and neurologic anomalies. CFC is caused by activating mutations in the Ras/mitogen-activated protein kinase (MAPK) signaling pathway that is downstream of receptor tyrosine kinase (RTK) signaling. RTK signaling is known to play a central role in craniofacial and dental development, but to date, no studies have systematically examined individuals with CFC to define key craniofacial and dental features. To fill this critical gap in our knowledge, we evaluated the craniofacial and dental phenotype of a large cohort (n = 32) of CFC individuals who attended the 2009 and 2011 CFC International Family Conferences. We quantified common craniofacial features in CFC which include macrocephaly, bitemporal narrowing, convex facial profile, and hypoplastic supraorbital ridges. In addition, there is a characteristic dental phenotype in CFC syndrome that includes malocclusion with open bite, posterior crossbite, and a high-arched palate. This thorough evaluation of the craniofacial and dental phenotype in CFC individuals provides a step forward in our understanding of the role of RTK/MAPK signaling in human craniofacial development and will aid clinicians who treat patients with CFC. PMID- 22946699 TI - Effect of microfluidization on bioaccessibility of carotenoids from Chlorella ellipsoidea during simulated digestion. AB - This study focused on the bioaccessibility of carotenoids from Chlorella ellipsoidea using a simulated digestion model. To increase the bioaccessibility of carotenoids, C. ellipsoidea was pulverized by microfluidization at pressures up to 20000 psi. The microfluidization treatment significantly reduced mean microalga particle size from 2463 to 361 nm. The major carotenoid in C. ellipsoidea was zeaxanthin, with two minor carotenoids, antheraxanthin and beta carotene. After microfluidization, the zeaxanthin and beta-carotene contents in C. ellipsoidea were not changed in comparison to the untreated group, whereas the antheraxanthin content was significantly reduced. The bioaccessibility of carotenoids in untreated C. ellipsoidea was very low (zeaxanthin, 2.60%; beta carotene, 1.69%). Approximately 95% of total C. ellipsoidea carotenoids could not be released and micellized by simulated digestion. The microfluidized microalga (at 20000 psi) was 10 times more effective for zeaxanthin and beta-carotene micelle formation compared with untreated C. ellipsoidea, showing higher bioaccessibility of carotenoids (zeaxanthin, 32.60%; beta-carotene, 18.19%). These results indicate that microfluidization may be useful for disrupting C. ellipsoidea cell walls and improving zeaxanthin and beta-carotene bioaccessibility from C. ellipsoidea during the digestion process. PMID- 22946700 TI - Haemodynamic optimisation in lower limb arterial surgery: room for improvement? AB - BACKGROUND: Goal-directed therapy has been proposed to improve outcome in high risk surgery patients. The aim of this study was to investigate whether individualised goal-directed therapy targeting stroke volume and oxygen delivery could reduce the number of patients with post-operative complications and shorten hospital length of stay after open elective lower limb arterial surgery. METHODS: Forty patients scheduled for open elective lower limb arterial surgery were prospectively randomised. The LiDCOTMplus system was used for haemodynamic monitoring. In the intervention group, stroke volume index was optimised by administering 250 ml aliquots of colloid intraoperatively and during the first 6 h post-operatively. Following surgery, fluid optimisation was supplemented with dobutamine, if necessary, targeting an oxygen delivery index level >= 600 ml/min(/) m(2) in the intervention group. Central haemodynamic data were blinded in control patients. Patients were followed up after 30 days. RESULTS: In the intervention group, stroke volume index, and cardiac index were higher throughout the treatment period (45 +/- 10 vs. 41 +/- 10 ml/m(2), P < 0.001, and 3.19 +/- 0.73 vs. 2.77 +/- 0.76 l/min(/) m(2), P < 0.001, respectively) as well as post operative oxygen delivery index (527 +/- 120 vs. 431 +/- 130 ml/min(/) m(2), P < 0.001). In the same group, 5/20 patients had one or more complications vs. 11/20 in the control group (P = 0.05). After adjusting for pre-operative and intraoperative differences, the odds ratio for >= 1 complications was 0.18 (0.04 0.85) in the intervention group (P = 0.03). The median length of hospital stay did not differ between groups. CONCLUSION: Perioperative individualised goal directed therapy may reduce post-operative complications in open elective lower limb arterial surgery. PMID- 22946701 TI - Abnormal uterine bleeding and dysfunctional uterine bleeding in pediatric and adolescent gynecology. AB - Abnormal uterine bleeding (AUB), which is defined as excessively heavy, prolonged and/or frequent bleeding of uterine origin, is a frequent cause of visits to the Emergency Department and/or health care provider. While there are many etiologies of AUB, the one most likely among otherwise healthy adolescents is dysfunctional uterine bleeding (DUB), which is characterizing any AUB when all possible underlying pathologic causes have been previously excluded. The most common cause of DUB in adolescence is anovulation, which is very frequent in the first 2-3 post-menarchal years and is associated with immaturity of the hypothalamic - pituitary - ovarian axis. Management of AUB is based on the underlying etiology and the severity of the bleeding and primary goals are prevention of complications, such as anemia and reestablishment of regular cyclical bleeding, while the management of DUB can in part be directed by the amount of flow, the degree of associated anemia, as well as patient and family comfort with different treatment modalities. Treatment options for DUB are: combined oral contraceptives (COCs), progestogens, non steroidal anti inflammatory drugs (NSAIDs), tranexamic acid (anti-fibrinolytic), GnRH analogues, Danazol and Levonorgestrel releasing intra uterine system (LNG IUS). PMID- 22946702 TI - Si(6-n)C(n)H6 (n = 0-6) series: when do silabenzenes become planar and global minima? AB - In the current work we studied a structural transition from nonplanar three dimensional structures to planar benzene-like structures in the Si(6-n)C(n)H(6) (n = 0-6) series. We performed unbiased Coalescence-Kick global minimum and low lying isomers search for the Si(6)H(6), Si(5)CH(6), Si(4)C(2)H(6), Si(3)C(3)H(6), Si(2)C(4)H(6), and SiC(5)H(6) stoichiometries at the B3LYP/6-31G** level of theory. The lowest isomers were recalculated at the CCSD(T)/CBS//B3LYP/6-311++G** level of theory. It was shown that the pseudo-Jahn-Teller effect, which is responsible for the deformation of planar Si(6)H(6), Si(5)CH(6), and Si(4)C(2)H(6) structures, is suppressed at n = 3 (the planar structure of 1,3,5 trisilabenzene). We also showed that the 3D-2D transition, which occurs only at n = 5, is due to the aromaticity of monosilabenzene (SiC(5)H(6)) along with other factors, such as stronger C-C sigma bonds compared to weaker C-Si and Si-Si sigma bonds. PMID- 22946703 TI - Spiro-fused pyrrolidine, piperidine, and oxindole scaffolds from lactams. AB - Expedient routes to three classes of novel spiro-fused pyrrolidine, piperidine, and indoline heterocycle scaffolds are described. These three-dimensional frameworks, which conform to the "rule of three", are suitably protected to allow for site-selective manipulation and functionalization. Different modes of substrate control were explored, which allow for good to excellent levels of diastereoselectivity and dispense with the need for additional chiral reagents or catalysts. The concepts developed were applied in short, formal syntheses of (+/ )-coerulescine and (+/-)-horsfiline. PMID- 22946704 TI - Cryoablation for presumed atrioventricular nodal reentrant tachycardia in pediatric patients. AB - BACKGROUND: Little data exist on the outcomes of cryoablation for the treatment of presumptive atrioventricular nodal reentrant tachycardia (AVNRT) in a pediatric population. METHODS: We performed a retrospective chart review of patients undergoing cryoablation from January 2006 to October 2010 for presumed AVNRT at the Children's Hospital Colorado. Inclusion criteria were age <= 18, normal heart structure, no prior ablation procedures, documented narrow complex tachycardia, and no inducible tachycardia or other tachycardia mechanisms during electrophysiology study. RESULTS: Thirteen patients underwent cryoablation for presumed AVNRT. Cryoablation catheter tip size varied from 4 to 8 mm with a median of eight cryoablation lesions. Isoproterenol was utilized preablation in 54% and none postablation. Procedural endpoints, per written report, were loss of sustained slow pathway, change in Wenckebach cycle length, and no specific endpoint. Procedural endpoints, per measured data, were a decrease in patients exhibiting sustained slow pathway conduction. Maximum atrial-His (AH) interval with atrial overdrive pacing was reduced from 266 ms preablation to 167 ms postablation, p = 0.006. The number of patients with an AH jump was reduced from 6 to 2. After follow-up of 13.8 +/- 14.3 months, 23% (3/13) had documented tachycardia recurrence. No statistical significance was determined when comparing electrophysiology testing parameters pre- and postablation among the group with recurrence versus the group without recurrence. CONCLUSIONS: Cryoablation can be considered as a safe alternative to radiofrequency ablation for the treatment of presumed AVNRT among pediatric patients, albeit with a recurrence rate of 23%. PMID- 22946705 TI - Electrochemically active nitrogen-enriched nanocarbons with well-defined morphology synthesized by pyrolysis of self-assembled block copolymer. AB - Novel nanoporous nitrogen-enriched carbon materials were prepared through a simple carbonization procedure of well-defined block copolymer precursors containing the source of carbon, i.e., polyacrylonitrile (PAN), and a sacrificial block, i.e., poly(n-butyl acrylate) (PBA). The preparation of nitrogen-enriched nanocarbons with hierarchical pore structure was enabled by the high fidelity preservation of the initial phase-separated nanostructure between two polymer blocks upon carbonization. Supercapacitors fabricated from the prepared carbons exhibited unusually high capacitance per unit surface area (>30 MUF/cm(2)) which was attributed to the pseudocapacitance resulting from the high nitrogen content originating from the PAN precursor. Electrochemical availability of the nitrogen species was also evident from the results of oxygen reduction experiments. The hierarchical pore structure and the high nitrogen content in such materials make them particularly promising for use in supercapacitor and electrocatalyst applications. PMID- 22946706 TI - Salivary gland botulinum toxin injections for drooling in children with cerebral palsy and neurodevelopmental disability: a systematic review. AB - AIM: The aim of this paper was to systematically review the efficacy and safety of botulinum toxin (BoNT) injections to the salivary glands to treat drooling in children with cerebral palsy and neurodevelopmental disability. METHOD: A systematic search of The Cochrane Central Register of Controlled Trials, PubMed, CINAHL (Cumulative Index to Nursing and Allied Health Literature), EMBASE, and the Physiotherapy Evidence Database (PEDro) was conducted (up to 1 October 2011). Data sources included published randomized controlled trials (RCTs) and prospective studies. RESULTS: Sixteen studies met inclusion criteria. Three outcome measures support the effectiveness of BoNT for drooling. One RCT found an almost 30% reduction in the impact of drooling on patients' lives, as measured by the Drooling Impact Scale (mean difference -27.45; 95% confidence interval [CI] 35.28 to -19.62). There were sufficient data to pool results on one outcome measure, the Drooling Frequency and Severity Scale, which supports this result (mean difference -2.71; 95% CI -4.82 to -0.60; p<0.001). There was a significant reduction in the observed number of bibs required per day. The incidence of adverse events ranged from 2 to 41%, but was inconsistently reported. One trial was terminated early because of adverse events. INTERPRETATION: BoNT is an effective, temporary treatment for sialorrhoea in children with cerebral palsy. Benefits need to be weighed against the potential for serious adverse events. More studies are needed to address the safety of BoNT and to compare BoNT with other treatment options for drooling. PMID- 22946707 TI - Combination of aripiprazole with mood stabilizers for the treatment of bipolar disorder: from acute mania to long-term maintenance. AB - INTRODUCTION: Bipolar disorder is characterized by a complex set of symptoms, including recurrent manic, depressive or mixed episodes. Acute and long-term treatment of patients with bipolar disorder is mandatory to prevent symptom relapse and episode recurrences. Outcomes with monotherapy are often unsatisfactory in clinical practice, hence combinations of mood stabilizers and antipsychotics are widely utilized in patients showing no or partial response to, as well as intolerance to, monotherapies. This may offer a therapeutic advantage, however, the possibility of an increased incidence of side effects should be considered. AREAS COVERED: This paper reviews the current treatment guidelines for the treatment of bipolar disorder and examines the rationale behind the use of aripiprazole in combination with mood stabilizers for acute and long-term treatment of bipolar disorder. EXPERT OPINION: The combination of aripiprazole and mood stabilizers seems to offer an effective and relatively well-tolerated option for the treatment of acute mania and for the maintenance treatment of patients with bipolar I disorder. The combination presents a lower risk of metabolic side effects compared with other combination therapies, but increases the risk of extrapyramidal side effects with long-term treatment. The aripiprazole-valproate combination seems to be particularly promising in the treatment of patients with comorbidities such as anxiety and drug abuse, obsessive-compulsive disorder and bipolar disorder, as well as in mixed depressive disorder. Controlled trials are necessary in order to confirm these observations and to provide a useful insight for improving the use of drug combinations in bipolar patients. PMID- 22946708 TI - Shotgun lipidomics strategy for fast analysis of phospholipids in fisheries waste and its potential in species differentiation. AB - An efficient shotgun lipidomics strategy was established and optimized for fast phospholipid profiling of viscera from three fish species: Lateolabrax japonicas, Ctenopharyngodon idellus, and Carassius auratus. This strategy relies on direct infusion of total lipid extracts into a tandem mass spectrometer without additional separation of the individual molecular species. Four classes of phospholipids, including phosphatidylcholine (PC), phosphatidylethanolamine (PE), phosphatidylinositol (PI), and phosphatidylserine (PS), were analyzed, and at least 81 molecular species of phospholipids were identified, including 34 species of PC, 24 species of PE, 12 species of PS, and 11 species of PI, in both positive and negative-ion electrospray ionization mode. The results show that fish viscera, which are traditionally discarded as fisheries wastes, are nutritional in phospholipids with total contents of the four detected phospholipid classes ranging from 1.52 to 3.29 mg/g in the three tested fish species. Regardless of the tested fish species, PC and PE are the dominant phospholipid classes, followed by PI and PS. Furthermore, principal component analysis (PCA) was applied to normalize the relative amounts of the identified phospholipid species. The results demonstrate that PS 18:0/22:6, PI 18:0/20:4, and PI 18:0/20:5 were the main contributors of cumulative value and could be used as an indicator for fish species differentiation. This shotgun lipidomics method was >10 times faster than traditional methods, because no chromatographic separation was needed. The successful application of this strategy paves the way for full utilization of traditionally discarded fisheries wastes and provides an alternative means for fish species differentiation. PMID- 22946709 TI - Fertility drug use and risk of ovarian tumors: a debated clinical challenge. AB - Infertility itself increases the incidence of ovarian carcinoma, while the potential additional risk associated with the use of fertility drugs is still debated. In 1992, the cumulative analysis of 12 US case-control studies revealed that women who received ovulation-inducing drugs had approximately three-fold higher incidence of invasive ovarian carcinoma. Other investigations reported a lower increase of the risk of invasive carcinoma or borderline tumor of the ovary in women treated with these agents. Conversely, several other case-control or cohort studies failed to detect a significant correlation between fertility drug use and ovarian tumor risk in either parous or nulliparous women compared with untreated infertile women. Moreover neither the number of treatment cycles nor the type of drug used was associated with an increased risk in most studies. Incessant ovulation and excessive gonadotropin secretion have been long considered to play a major role in the development of ovarian carcinoma, and therefore fertility drugs, which raise the serum levels of gonadotropins and increase the chances of multiple ovulations, have been retained as a risk factor for this malignancy, However, the large majority of literature data as well as the new hypotheses on ovarian carcinogenesis appear to exclude a relevant impact of fertility drug use on the risk of ovarian tumors, and especially of high-grade invasive epithelial ovarian cancers. PMID- 22946710 TI - Cognitive function in patients with chronic pain treated with opioids: characteristics and associated factors. AB - BACKGROUND: The paucity of studies regarding cognitive function in patients with chronic pain, and growing evidence regarding the cognitive effects of pain and opioids on cognitive function prompted us to assess cognition via neuropsychological measurement in patients with chronic non-cancer pain treated with opioids. METHODS: In this cross-sectional study, 49 patients were assessed by Continuous Reaction Time, Finger Tapping, Digit Span, Trail Making Test-B and Mini-mental State Examination tests. Linear regressions were applied. RESULTS: Patients scored poorly in the Trail Making Test-B (mean = 107.6 s, SD = 61.0, cut off = 91 s); and adequately on all other tests. Several associations among independent variables and cognitive tests were observed. In the multiple regression analyses, the variables associated with statistically significant poor cognitive performance were female sex, higher age, lower annual income, lower schooling, anxiety, depression, tiredness, lower opioid dose, and more than 5 h of sleep the night before assessment (P < 0.05). CONCLUSIONS: Patients with chronic pain may have cognitive dysfunction related to some reversible factors, which can be optimized by therapeutic interventions. PMID- 22946711 TI - Clinical observations and outcome of ventricular tachycardia ablation in patients with left ventricular assist devices. AB - BACKGROUND: Ablation of ventricular tachycardia (VT) in patients with left ventricular assist devices (LVAD) is challenging and not well documented. This report describes our experience with endocardial VT ablation in six patients with an LVAD. METHODS: We retrospectively reviewed the clinical records of LVAD patients who underwent an ablation procedure for refractory VT. RESULTS: A total of eight ablation procedures were performed in six patients who, during the last 2 weeks before the ablation procedure, received a total of 101 appropriate shocks for VT. A closed aortic valve (n = 2) or aortic atheroma (n = 1) required a transseptal catheterization in three of six patients. The apical LVAD cannula served as a VT substrate in two of six patients. VT was eliminated in four patients and markedly reduced in two others. The latter two patients experienced a total of only four implantable cardioverter defibrillator (ICD) shocks during a follow-up of 130 and 493 days. Intravenous antiarrhythmic medications used in five of six patients before ablation were discontinued in all. The ablation procedures permitted hospital discharge in four of six patients. Five patients died during follow-up (228 +/- 207 days after the procedure). The cause of death was unrelated to cardiac arrhythmias. One patient is still alive 1,205 days after the procedure. CONCLUSION: Ablation of VT in LVAD patients is feasible and can result in a markedly decreased VT burden with a reduction of ICD shocks. The subsequent discontinuation of intravenous antiarrhythmic medications may facilitate hospital discharge. PMID- 22946712 TI - Theoretical study of atomic oxygen on gold surface by Huckel theory and DFT calculations. AB - It is fundamental to understand the behavior of atomic oxygen on gold surfaces so as to elucidate the mechanism of nano gold catalysts for low-temperature CO oxidation reactions since the atomic oxygen on gold system is an important intermediate involved in both the processes of O(2) dissociation and CO oxidation. We performed theoretical analysis of atomic oxygen adsorption on gold by using Huckel theory. It is found that formation of linear O-Au-O structure on Au surfaces greatly stabilizes the atomic oxygen adsorption due to stronger bond energy and bond order, which is confirmed subsequently by density functional theory (DFT) calculations. The linear O-Au-O structure may explain the surprising first order kinetics behavior of O(2) desorption from gold surfaces. This view of the linear O-Au-O structure as the natural adsorption status is quite different from the conventional view, which may lead to new understanding toward the reaction mechanism of low-temperature CO oxidation reaction on nano gold catalysts. PMID- 22946713 TI - Synthesis of enantiomerically enriched 3-amino-2-oxindoles through a palladium mediated asymmetric intramolecular arylation of alpha-ketimino amides. AB - A highly efficient and enantioselective synthesis of 3-amino-2-oxindoles through a palladium-catalyzed asymmetric intramolecular arylation of alpha-ketimino amides using (R)-DiFluorPhos as the coordinating ligand is reported. This report constitutes the first enantioselective palladium-catalyzed arylation of ketimines. PMID- 22946714 TI - Clinical benefits of ezetimibe use: is absence of proof, proof of absence? PMID- 22946715 TI - Introduction: The causes of epilepsy. PMID- 22946716 TI - Fever and fever-related epilepsies. AB - Febrile seizures are a common emergency faced by general pediatricians. They are mostly self-limiting, isolated events with no sequelae in later life. A minority are more complex. In the acute stage, there are a small number of underlying etiologies that are important to recognize in order to determine the prognosis accurately and to optimize management. There has been a long-standing debate about the relationship of early febrile seizures to the later development of epilepsy. It is now clear that this risk differs for simple and complex febrile seizures: complex febrile seizures may herald the presentation of a number of epilepsy syndromes of which febrile and illness-related seizures are part of the phenotype. This review examines the existing knowledge on febrile seizures and the various clinical phenotypes to which they are linked. PMID- 22946717 TI - Benign childhood focal epilepsies. AB - The idiopathic focal epilepsies comprise a group of syndromes characterized by focal-onset seizures for which there is no detectable structural brain abnormality and for which there is a proposed functional mechanism for the epilepsy and electroencephalography (EEG) abnormalities. This group includes benign rolandic epilepsy (BRE), benign epilepsy with occipital paroxysms (both early onset and late-onset types), idiopathic photosensitive occipital lobe epilepsy, and some less well-defined syndromes. The limits of the early onset idiopathic occipital epilepsy syndrome are not clear, and perhaps this entity represents part of a larger syndrome group of "autonomic" age-related epilepsies. The term "idiopathic" implies absence of a structural brain lesion and a genetic propensity to seizures. The term "benign" implies that the epileptic seizures are easily treated or require no treatment, show remission without sequelae with ultimate and definitive remission before adulthood, do not have severe or exceedingly disturbing seizures, and have no associated serious intellectual or behavioral disturbances. It may be that a syndrome is benign only when it can be recognized early with reasonable certainty, thereby avoiding unnecessary investigations, overtreatment, and lifestyle restrictions. Although BRE has such characteristic clinical and EEG features to make early recognition possible, this is less constantly so in the other focal idiopathic epilepsy syndromes, where the term "benign" may be inappropriate. Mild and selective neuropsychological impairment may occur even in those with typical syndromes but it is unclear whether such selective deficits outlast the active phase of epilepsy. Sometimes the clinical course may be complicated by obvious cognitive and language impairments. In such cases, the term benign is obviously inappropriate, even when seizures are rare. In most patients with the typical focal idiopathic epilepsy syndromes, medication is not necessary. PMID- 22946718 TI - Hippocampal sclerosis--origins and imaging. AB - The association between hippocampal sclerosis (HS) and epilepsy has been known for almost two centuries. For many years, HS was studied in postmortem series; however, since the mid-20th century, surgical specimens from temporal lobe resections have provided important new knowledge. HS is the most common pathology underlying drug-resistant mesial temporal lobe epilepsy (MTLE), a syndrome with a characteristic history and seizure semiology. In the early 1990 s, it was recognized that magnetic resonance imaging (MRI) could detect HS. The standard MRI protocol for temporal lobe abnormalities uses coronal slices perpendicular to the long axis of the hippocampus. The MRI features of HS include reduced hippocampal volume, increased signal intensity on T(2)-weighted imaging, and disturbed internal architecture. The histopathologic diagnosis of HS is usually straightforward, with neuronal loss and chronic fibrillary gliosis centered on the pyramidal cell layer. There are several patterns or subtypes of HS recognized from surgical series based on qualitative or quantified assessments of regional neuronal loss. The pathologic changes of HS include granule cell dispersion, mossy fiber sprouting, and alterations to interneurons. There may also be more extensive sclerosis of adjacent structures in the medial temporal lobe, including the amygdala and parahippocampal gyrus. Subtle cortical neuropathologies may accompany HS. The revised classification of dysplasias in epilepsy denotes these as focal cortical dysplasias type IIIa. Sometimes, HS occurs with a second lesion, either in the temporal lobe or extratemporal, most often ipsilateral to the HS. HS on preoperative MRI strongly predicts good seizure outcome following temporal lobe resection (TLR). If adequate MRI shows no structural correlate in patients with MTLE, functional imaging studies are valuable, especially if they are in agreement with ictal electroencephalography (EEG) findings. Focal hypometabolism on 18F-fluorodeoxyglucose-positron emission tomography (FDG-PET) ipsilateral to the symptomatic temporal lobe predicts a good surgical outcome; the added value of (11) C-Flumazenil-PET (FMZ-PET) and proton magnetic resonance spectroscopy (MRS) is less clear. Surgical methods have evolved, particularly resecting less tissue, aiming to preserve function without compromising seizure outcome. Around two thirds of patients operated for MTLE with HS obtain seizure freedom. However, the best surgical approach to optimize seizure outcome remains controversial. PMID- 22946719 TI - The outlook for adults with epileptic seizure(s) associated with cerebral cavernous malformations or arteriovenous malformations. AB - Cerebral cavernous malformations (CCMs) and arteriovenous malformations (AVMs) are common: their asymptomatic prevalence on brain magnetic resonance imaging (MRI) is 1 in 625 and 1 in 2,000, respectively. The risk of epileptic seizure(s) for people with AVMs and CCMs affects their domestic, social, and professional lives, and may influence their decisions about treatment. This article summarizes the seizure risks for people with AVMs and CCMs, gleaned from published original articles indexed in OVID Medline and Embase before 1 January 2012. In the absence of prior intracranial hemorrhage and nonhemorrhagic focal neurologic deficit, a population-based study in Scotland, United Kingdom, found that the 5-year risks of first seizure were 8% for AVM and 4% for CCM; presentation with intracranial hemorrhage or focal neurologic deficit raised this risk for AVM (23%) but not for CCM (6%). Features associated with the occurrence of epileptic seizures for CCM are lesion multiplicity and cortical CCM location, whereas for AVM the most consistently reported associations are younger age, temporal location, cortical involvement, and nidus diameter >3 cm. In the absence of prior intracranial hemorrhage and nonhemorrhagic focal neurologic deficit, the 5-year risk of developing epilepsy following a first seizure is 58% for AVM and 94% for CCM, though there is no difference in the chance of achieving 2-year seizure freedom in this time frame (45% AVM vs. 47% CCM). Observational case series describe encouraging differences in seizure frequency before and after AVM and CCM treatment, but the shortage of studies demonstrating dramatic effects in comparison to concurrent control groups justifies the need for more controlled studies, ideally with randomized treatment allocation when the benefits of AVM or CCM treatment are uncertain. PMID- 22946720 TI - Traumatic brain injury: risks of epilepsy and implications for medicolegal assessment. AB - Traumatic brain injury (TBI) is a potentially preventable cause of epilepsy. Increasing incidence among army personnel and the high incidence among children and young people raise concern. This article presents a review of selected studies dealing with the risks of TBI and the risk of posttraumatic epilepsy in humans. The incidence of persons admitted to hospital with TBI has decreased in developed countries in recent years. However, there is little change in TBI associated deaths, and the decrease in hospitalization may merely reflect that more people with head injury are cared for on an outpatient basis. It is clear that epilepsy is a frequent consequence of brain injury, even many years after the injury. However, several well-controlled studies have been unable to identify therapies that prevent the development of epilepsy after TBI. Posttraumatic epilepsy has significant implications for the affected individuals, family, and society. Despite several interventions used to prevent posttraumatic epilepsy, the only proven "intervention" to date is to prevent TBI from occurring. PMID- 22946721 TI - Alcohol and drugs in epilepsy: pathophysiology, presentation, possibilities, and prevention. AB - The potentially serious outcomes from ingestion of and dependence on toxins make this an important topic for epileptologists. We must be aware of the potential for harm from compounds that may be freely available, yet patients may try to conceal their use. Problematic compounds may cause seizures either acutely or on withdrawal: Their use may reduce effectiveness of antiepileptic drugs, or may simply promote and enhance chaotic lifestyles. Any or all of these factors may worsen seizure control or even directly cause seizures. This article highlights the pathophysiology behind provoked seizures, provides clues to diagnosis, and then outlines the steps that clinicians should take to reduce the deleterious effects of toxic compounds. PMID- 22946722 TI - Autoimmune and inflammatory epilepsies. AB - The role of immunity and inflammation in epilepsy have long been suggested by the anticonvulsant activity of steroids in some infancy and childhood epilepsies. The role of fever and infection in exacerbating seizures due to possible proinflammatory molecules, the increased frequency of seizures in systemic autoimmune diseases like systemic lupus erythematous, and, recently, the detection of autoantibodies in some unexplained epilepsies reinforced the causal place of immunity and inflammation in epilepsies with unknown etiology. In this article, we summarize epilepsies where clinical and biologic data strongly support the pathogenic role of autoantibodies (e.g., limbic encephalitides, N methyl-d-aspartate [NMDA] encephalitis) and epilepsies where immune-mediated inflammation occurs, but the full pathogenic cascade is either not clear (e.g., Rasmussen's encephalitis) or only strongly hypothesized (idiopathic hemiconvulsion-hemiplegia syndrome [IHHS] and fever-induced refractory epilepsy in school-aged children [FIRES]). We emphasize the electroclinical features that would help to diagnose these conditions, allowing early immunomodulating therapy. Finally, we raise some questions that remain unclear regarding diagnosis, mechanisms, and future therapies. PMID- 22946723 TI - Seizures and encephalitis: clinical features, management, and potential pathophysiologic mechanisms. AB - Encephalitis is an inflammation and swelling of the brain, which is often caused by a viral infection; it is an important cause of acute symptomatic seizures as well as subsequent epilepsy. Herein we describe the definition, epidemiology, and etiology of encephalitis as a cause of seizures. We then focus on encephalitis due to herpes simplex virus (the most common sporadic viral cause of encephalitis) and Japanese encephalitis virus (the most common epidemic viral cause). We also discuss the evidence for seizures occurring in the context of antibody-associated encephalitis, an increasingly important condition. Finally, we describe the acute and longer-term management of encephalitis-related seizures and their potential pathophysiologic mechanisms, concluding with the emerging etiologic role of human herpesvirus 6. PMID- 22946724 TI - How should we be searching for genes for common epilepsy? A critique and a prescription. AB - Despite enormous data collection and analysis efforts, the genetic influences on common epilepsies remain mostly unknown. We propose that reasons for the lack of progress can be traced to three factors: (1) A reluctance to consider fine grained phenotype definitions based on extensive and carefully collected clinical data; (2) the pursuit of genetic analysis methods that are popular but poorly conceived and are inadequate to the task of resolving the problems inherent in common disease studies; (3) preconceived ideas about the genetic mechanisms that cause epilepsy (which we have discussed elsewhere). We propose a paradigm for finding epilepsy-related loci and alleles that has proven successful in other common diseases. PMID- 22946725 TI - Complex single gene disorders and epilepsy. AB - Epilepsy is a heterogeneous group of disorders, often associated with significant comorbidity, such as intellectual disability and skin disorder. The genetic underpinnings of many epilepsies are still being elucidated, and we expect further advances over the coming 5 years, as genetic technology improves and prices fall for whole exome and whole genome sequencing. At present, there are several well-characterized complex epilepsies associated with single gene disorders; we review some of these here. They include well-recognized syndromes such as tuberous sclerosis complex, epilepsy associated with Rett syndrome, some of the progressive myoclonic epilepsies, and novel disorders such as epilepsy associated with mutations in the PCDH 19 gene. These disorders are important in informing genetic testing to confirm a diagnosis and to permit better understanding of the variability in phenotype-genotype correlation. PMID- 22946726 TI - Mitochondrial diseases and epilepsy. AB - The mitochondrial respiratory chain is the final common pathway for energy production. Defects affecting this pathway can give rise to disease that presents at any age and affects any tissue. However, irrespective of genetic defect, epilepsy is common and there is a significant risk of status epilepticus. This review summarizes our current understanding of the epilepsy that occurs in mitochondrial disease, focusing on three of the most common disorders: mitochondrial myopathy encephalopathy, lactic acidosis and stroke-like episodes (MELAS), myoclonus epilepsy and ragged-red fibers (MERRF), and polymerase gamma (POLG) related disease. In addition, we review the pathogenesis and possible treatment of these disorders. PMID- 22946727 TI - Surgical treatment of epilepsy associated with cortical dysplasia: 2012 update. AB - Cortical dysplasia is the most common etiology in children and the third most frequent finding in adults undergoing epilepsy neurosurgery. The new International League Against Epilepsy (ILAE) classification grades isolated cortical dysplasia into mild type I (cortical dyslamination), severe type II (dyslamination plus dysmorphic neurons and balloon cells), and dysplasia associated with other epileptogenic lesions (type III). Multilobar type II lesions present at an earlier age and with more severe epilepsy compared with focal type I abnormalities, often in the temporal lobe, and these findings are reflected in types and age of operations for cortical dysplasia. Presurgical evaluation of patients with epilepsy from cortical dysplasia can be challenging. Interictal and ictal scalp electroencephalography (EEG) accurately localizes cortical dysplasia with 50-66% accuracy. Structural magnetic resonance imaging (MRI) is negative in roughly 30% of cases, most often linked with mild type I cases. FDG-PET can be 80-90% accurate, but is not 100% sensitive. Chronic intracranial electrodes are used in about 50% of cases with cortical dysplasia, but often do not capture restricted ictal-onset zones. About 60% of patients with cortical dysplasia are seizure free after epilepsy neurosurgery, with much higher rates of becoming seizure free with complete (80%) compared with incomplete (20%) resections. The most common reason for incomplete resection is the risk of an unacceptable neurologic deficit. Future challenges include better tools in identifying subtle forms of type I cortical dysplasia, and development of adjunctive treatments from basic research for those undergoing incomplete resections. PMID- 22946728 TI - Provoked and reflex seizures: surprising or common? AB - Most patients with epilepsy report that seizures are sometimes, or exclusively, provoked by general internal precipitants (such as stress, fatigue, fever, sleep, and menstrual cycle) and by external precipitants (such as excess alcohol, heat, bathing, eating, reading, and flashing lights). Some patients describe very exotic and precise triggers, like tooth brushing or listening to a particular melody. Nevertheless, the most commonly noticed seizure increasers by far are stress, lack of sleep, and fatigue. Recognized reflex seizure triggers are usually sensory and visual, such as television, discotheques, and video games. Visually evoked seizures comprise 5% of the total of 6% reflex seizures. The distinction between provocative and reflex factors and seizures seems artificial, and in many patients, maybe all, there is a combination of these. It seems plausible that all of the above-mentioned factors can misbalance the actual brain network; at times, accumulation of factors leads then to primary generalized, partial, or secondarily generalized seizures. If the provoking factors are too exotic, patients may be sent to the psychiatrist. Conversely, if the seizure provoking fluctuating mechanisms include common habits and environmental factors, these may hardly be considered as provocative factors. Awareness of precipitating factors and its possible interactions might help us to unravel the pathophysiology of epilepsy and to change the notion that seizure occurrence is unpredictable. This article provides an overview of the epidemiology, classification, diagnosis, treatment, and especially similarities in the variety of provocative and reflex factors with resulting general hypotheses. PMID- 22946729 TI - Epileptic encephalopathies (including severe epilepsy syndromes). AB - Epileptic encephalopathies represent a group of devastating epileptic disorders that appear early in life and are characterized by pharmacoresistant generalized or focal seizures, persistent severe electroencephalography (EEG) abnormalities, and cognitive dysfunction or decline. The ictal and interictal epileptic discharges are age-specific and are the main etiologic factors causing cognitive deterioration. This is most obvious in the idiopathic group. In the symptomatic group, the most common causes are structural, congenital, or acquired and rarely some metabolic disorders. In certain cases, clinical and EEG abnormalities persist and may evolve from one type to another as the child grows older. Various factors trigger and sustain the underlying pathophysiologic process and the ongoing epileptic and epileptiform activity during the most critical periods of brain maturation, perpetuating their deleterious effect on the brain. Immune mediated mechanisms may have a role, suggested by certain encephalopathies responding to immune-modulating treatments and by the finding of various autoimmune antibodies. The chance of a better cognitive outcome improves with early diagnosis and treatment that is appropriate and effective. Current antiepileptic drugs are, in general, not effective: we urgently need new trials in this very special epileptic category. This article briefly reviews the most common epileptic encephalopathies and analyzes the most important clinical issues. PMID- 22946730 TI - Causes of status epilepticus. AB - Status epilepticus (SE) is the most extreme form of epilepsy. It describes a prolonged seizure that may occur in patients with previous epilepsy or in acute disorders of the central nervous system. It is one of the most common neurologic emergencies, with an incidence of up to 41 per 100,000 per year and an estimated mortality is 20%. The three major determinants of prognosis are the duration of SE, patient age, and the underlying cause. Common and easily recognized causes of SE include cerebrovascular disorders, brain trauma, infections, and low antiepileptic drug levels in patients with epilepsy. Less common causes present a clinical and diagnostic challenge, but are major determinants of prognosis. Among them, inflammatory causes and inborn errors of metabolism have gained wide interest; recent insights into these causes have contributed to a better understanding of the pathophysiology of SE and its appropriate treatment. This review focuses on the different etiologies of SE and emphasizes the importance of prompt recognition and treatment of the underlying causes. PMID- 22946731 TI - The frequency and nature of drug administration error during anaesthesia in a Chinese hospital. AB - BACKGROUND: Throughout the world, drug administration error remains a known and significant threat to patients undergoing anaesthesia. Estimates of the extent of the problem vary, but few are based on large prospectively collected datasets. Furthermore, little is known about whether differences in work culture are important in error rates. METHODS: A prospective incident monitoring study was conducted at a large tertiary hospital in China to estimate the frequency of drug administration error during anaesthesia. Anaesthetists were asked to return a study form anonymously for every anaesthetic, indicating whether or not a drug administration error had occurred, including incident details if affirmative. RESULTS: From 24,380 anaesthetics, 16,496 study forms were returned (67.7% response rate), reporting 179 errors. The frequency (95% confidence interval) of drug administration error was 0.73% (0.63% to 0.85%) based on total study anaesthetics and 1.09% (0.93% to 1.26%) based on total forms returned. The largest categories of error were omissions (27%), incorrect doses (23%) and substitutions (20%). Errors resulted in prolonged stay in recovery for 21 patients, transfer to the ICU for five and one case each of haemorrhagic shock and asthmatic attack. More respondents who were not fully rested reported inattention as a contributing factor to error (21%) than those who were fully rested (7%, P = 0.04). CONCLUSION: Our results are comparable with other international prospective estimates indicating that drug administration error is of concern in China as elsewhere. These results will form a baseline from which to detect the effects of countermeasures. PMID- 22946734 TI - Employment and drowsy driving: a survey of American workers. AB - Drowsy driving is a major public health problem in the United States. Employment characteristics affect sleep, yet little is known about relationships between employment variables and drowsy driving. This study examined employment correlates (specifically, hours worked per week and shift work) and rates of self reported drowsy driving, falling asleep while driving, and traffic crashes due to sleepiness in 1,000 employed adults who completed a telephone survey conducted by the National Sleep Foundation. Working > 40 hr per week and shift work were associated with increased risk for drowsy driving (ps <= .05). Odds ratios for falling asleep behind the wheel were higher in shift workers with symptoms of insomnia or excessive sleepiness relative to day workers and shift workers without sleep complaints (p <= .05). PMID- 22946733 TI - Perceived racial discrimination as an independent predictor of sleep disturbance and daytime fatigue. AB - Perceived discrimination is a potential cause of racial and ethnic disparities in health. Disturbed sleep may serve as a mechanism linking perceived racism with health consequences. This study investigates data from 7,148 adults from Michigan and Wisconsin who participated in the 2006 Behavioral Risk Factor Surveillance System. Hierarchical logistic regression analyses explored associations between perceived racial discrimination and self-reported sleep disturbance and daytime fatigue. Sleep disturbance and daytime fatigue were reported in 19% and 21% of the sample, respectively. Black/African American respondents (21%) report perceiving worse experiences, compared to people of other races, when seeking health care at higher rates than non-Hispanic White respondents (3%). Results from logistic regression models show that perceived racial discrimination is associated with increased risks of sleep disturbance (odds ratio [OR] = 2.62, p < .0001) and daytime fatigue (OR = 2.07, p < .0001). After adjustment for all covariates, perceived discrimination remains a significant predictor of sleep disturbance (OR = 1.60, p = .04). The interaction between perceived racism and race (Black/African American vs. non-Hispanic White) was nonsignificant. This population-based research adds to the growing body of data, suggesting that perceived racism may impact health via its influence on sleep-wake behaviors. PMID- 22946735 TI - Delayed bedtimes and obsessive-compulsive symptoms. AB - There is increasing recognition of an important interplay between psychiatric disorders and sleep. Clinical observations and several empirical studies have shown that later bedtimes are associated with obsessive-compulsive disorder (OCD). This study examined the relation of delayed bedtimes (DBs) and symptoms of OCD. Two hundred and sixty-six undergraduates completed a battery of questionnaires assessing sleep patterns, mood, and obsessive-compulsive (OC) symptoms. Results showed that participants with DBs reported increased rates of OC symptoms, as compared with non-DB participants. Further, this relation remained significant when controlling for negative affect. Additional work examining the interplay between sleep and OC symptoms is warranted. PMID- 22946736 TI - Clinical management of insomnia with brief behavioral treatment (BBTI). AB - Insomnia is a highly prevalent and debilitating sleep disorder. It is well documented that psychological treatments, including cognitive-behavioral therapy for insomnia (CBTI), are efficacious treatments, with effect sizes of comparable magnitude to that of pharmacologic treatment. However, a critical shortage of specialty-trained clinicians with experience in sleep medicine and cognitive behavioral therapy principles has limited the widespread dissemination of CBTI. A brief (four sessions; two of which may be phone sessions) treatment, titled "Brief Behavioral Treatment for Insomnia" (BBTI), was developed to address many of the barriers to widespread dissemination associated with standard CBTI. Specifically, BBTI has an explicit behavioral focus, is overtly linked to a physiological model of sleep regulation, and utilizes a hardcopy workbook that facilitates its concise delivery format and ease of training clinicians. BBTI has demonstrated efficacy in treating older adults with insomnia ( Buysse et al., 2011 ). This article describes the rationale for the development of BBTI, provides a session-by-session guide to the delivery of the treatment, and concludes with a discussion of contraindications, combined pharmacotherapy treatment, and future directions for the use of BBTI in diverse populations and utilizing different modalities of delivery. PMID- 22946739 TI - Thermogenic supplement use does not alter characteristics of sudden death in the young. AB - BACKGROUND: To evaluate supplement use, most notably ephedra, which has been temporally associated with sudden death. Animal models suggest increased myocardial irritability may predispose to primary arrhythmic death. METHODS: Clinical, pathological, and investigative records from the Office of the Armed Forces Medical Examiner's Cardiovascular Death Registry were reviewed. Forty eight cases of those with known supplement use were compared to 144 age-, gender , and socioeconomic-matched controls in a 1:3 case:control manner. RESULTS: Of the 48 sudden deaths temporally associated with supplement use, the mean age was 34.2 +/- 10.0 years and predominantly male (n = 44, 91.7%). The underlying cause of death was fatal atherosclerotic coronary disease in 18 (37.5%), sudden unexplained death in 16 (33.3%), and hypertrophic cardiomyopathy in six (12.5%). Compared with controls, there were no statistically significant differences in adjudicated cause of death. On autopsy, there were no differences in cardiac mass, ventricular wall thickness, or presence of atherosclerosis in those known to be taking identified supplements compared to a control population. In the subject >=35 years, and known to be taking supplements, there was a significant increase in causality of death as due to sudden unexplained death (relative risk = 5.1 [95% confidence interval, 1.4-18.7]). CONCLUSIONS: Active surveillance of mortality in an autopsy-derived series of young adults finds atherosclerotic coronary disease and idiopathic sudden death are common etiologies of death when taking supplements, but no cardiac structural or histologic mechanism to suggest different pathologic process than a matched control population. PMID- 22946740 TI - Regioselective catalytic hydroboration of propargylic species using Cu(I)-NHC complexes. AB - The catalytic regioselective hydroboration of propargylic alcohols and ethers was investigated using NHC-CuCl. We observe that different NHC-CuCl complexes catalyze hydroborations of propargylic substrates with opposite regioselectivity. A 6-NHC-CuCl complex provides alpha-selectivity whereas beta-selectivity is achieved using a 5-NHC-CuCl complex. The reaction tolerates a wide range of functional groups. PMID- 22946741 TI - Experimental determination of the high-temperature rate constant for the reaction of OH with sec-butanol. AB - The overall rate constant for the reaction of OH with sec-butanol [CH(3)CH(OH)CH(2)CH(3)] was determined from measurements of the near-first-order OH decay in shock-heated mixtures of tert-butylhydroperoxide (as a fast source of OH) with sec-butanol in excess. Three kinetic mechanisms from the literature describing sec-butanol combustion were used to examine the sensitivity of the rate constant determination to secondary kinetics. The overall rate constant determined can be described by the Arrhenius expression 6.97 * 10(-11) exp( 1550/T[K]) cm(3) molecule(-1) s(-1), valid over the temperature range of 888-1178 K. Uncertainty bounds of +/-30% were found to adequately account for the uncertainty in secondary kinetics. To our knowledge, the current data represent the first efforts toward an experimentally determined rate constant for the overall reaction of OH with sec-butanol at combustion-relevant temperatures. A rate constant predicted using a structure-activity relationship from the literature was compared to the current data and previous rate constant measurements for the title reaction at atmospheric-relevant temperatures. The structure-activity relationship was found to be unable to correctly predict the measured rate constant at all temperatures where experimental data exist. We found that the three-parameter fit of 4.95 * 10(-20)T(2.66) exp(+1123/T[K]) cm(3) molecule(-1) s(-1) better describes the overall rate constant for the reaction of OH with sec-butanol from 263 to 1178 K. PMID- 22946742 TI - Metal cocatalyzed tandem alkynylative cyclization reaction of in situ formed N iminoisoquinolinium ylides with bromoalkynes via C-H bond activation. AB - Silver triflate and copper(I) iodide cocatalyzed direct alkynylation and cyclization reaction of in situ formed N-iminoisoquinolinium ylides with bromoalkynes is described. The reaction proceeds efficiently through a combination of C-H activation and subsequent tandem reaction in one pot, leading to diverse H-pyrazolo[5,1-a]isoquinolines in good yields under mild reaction conditions. PMID- 22946743 TI - Gas permeability and thermal behavior of polypropylene films used for packaging minimally processed fresh-cut potatoes: a case study. AB - This work reports an experimental study on the permeability and thermal behavior of commercial polypropylene (PP) film used for fresh-cut potatoes packaging. The permeability was tested using oxygen, carbon dioxide, nitrogen, mix of these 3 gases, normally used for modified atmosphere packaging (MAP) and Air, to understand if it would be possible to extend the shelf life of this food product designed for the catering field in respect to the packaging behavior. The temperature influence on permeability data, from 5 to 40 degrees C, was analyzed, before and after 4, 8, 12, 15, and 20 d of food contact, pointing out the dependence between temperature and gas transmission rate (GTR), solubility (S), diffusion coefficient (D), and time lag (t(L)) parameters. The activation energies (E) of the permeation process were determined with the different gases used in the experiments. The thermal behavior of PP film was studied by differential scanning calorimetry (DSC) and thermogravimetric analysis (TG) to well understand its thermal stability. Fourier transformed-infrared with attenuated total reflectance (FT-IR/ATR) spectroscopy was also performed in order to study the influence of the food contact on the chemical characteristics of the polymer film. The results obtained were discussed and compared each other. Studied samples showed, for all investigated gases, an increase of gas permeability and S values at higher temperature. Heat resistance classification among the sample as it is and stored in modified atmospheres was made. Finally all performed experiments have showed good polymer stability for the shelf-life storage potatoes under study. PRACTICAL APPLICATION: Study of packaging material was performed in a range of temperature, which can simulate the service condition to assess the suitability of a commercial polymer film for modified atmosphere packaging of fresh-cut potatoes minimally processed designed for catering purpose. PMID- 22946746 TI - The argument of antidepressant drugs in the treatment of bipolar depression: mixed evidence or mixed states? AB - INTRODUCTION: The role of antidepressant drugs in acute and maintenance treatment of bipolar depression is a matter of debate that cannot be decided from the evidence available in the current literature. AREAS COVERED: This review includes two sections: in the first, important contributions from the current literature, emphasizing randomized controlled trials (RCTs) and meta-analysis, highlight current controversies and methodological issues; in the second, the impact of mixed depressive features in bipolar depression is evaluated from a psychopathological perspective. EXPERT OPINION: Methodological issues may complicate evaluation of the evidence from RCTs regarding antidepressants and mixed states. Moreover, nosological constructs may also contribute to the inconclusive findings, by introducing heterogeneity in patient selection and diagnosis. Acknowledging the impact of mixed features in the course of bipolar depression, essentially by the careful reading of classical Kraepelinian contributions, could enhance clinical management. This would in turn allow a more judicious use of antidepressants, ideally helping to shed some light on the much controversial 'antidepressant-related suicidality', and help to further clarify the reasons for the current literature discordance on this topic. PMID- 22946744 TI - An ideal observer analysis of visual working memory. AB - Limits in visual working memory (VWM) strongly constrain human performance across many tasks. However, the nature of these limits is not well understood. In this article we develop an ideal observer analysis of human VWM by deriving the expected behavior of an optimally performing but limited-capacity memory system. This analysis is framed around rate-distortion theory, a branch of information theory that provides optimal bounds on the accuracy of information transmission subject to a fixed information capacity. The result of the ideal observer analysis is a theoretical framework that provides a task-independent and quantitative definition of visual memory capacity and yields novel predictions regarding human performance. These predictions are subsequently evaluated and confirmed in 2 empirical studies. Further, the framework is general enough to allow the specification and testing of alternative models of visual memory (e.g., how capacity is distributed across multiple items). We demonstrate that a simple model developed on the basis of the ideal observer analysis-one that allows variability in the number of stored memory representations but does not assume the presence of a fixed item limit-provides an excellent account of the empirical data and further offers a principled reinterpretation of existing models of VWM. PMID- 22946747 TI - Fluid therapy in uncontrolled hemorrhage--what experimental models have taught us. AB - Intravenous fluid is life-saving in hypovolemic shock, but fluid sometimes aggravates the bleeding. During the past 25 years, animal models have helped our understanding of the mechanisms involved in this unexpected effect. A key issue is that vasoconstriction is insufficient to arrest the bleeding when damage is made to a major blood vessel. 'Uncontrolled hemorrhage' is rather stopped by a blood clot formed at the outside surface of the vessel, and the immature clot is sensitive to mechanical and chemical interactions. The mortality increases if rebleeding occurs. In the aortic tear model in swine, hemorrhage volume and the mortality increase from effective restoration of the arterial pressure. The mortality vs. amount of fluid curve is U-shaped with higher mortality at either end. Without any fluid at all, irreversible shock causes death provided the hemorrhage is sufficiently large. Crystalloid fluid administered in a 3 : 1 proportion to the amount of lost blood initiates serious rebleeding. Hypertonic saline 7.5% in 6% dextran 70 (HSD) also provokes rebleeding resulting in higher mortality in the recommended dosage of 4 ml/kg. Uncontrolled hemorrhage models in rats, except for the 'cut-tail' model, confirm the results from swine. To avoid rebleeding, fluid programs should not aim to fully restore the arterial pressure, blood flow rates, or blood volume. For a hemorrhage of 1000 ml, computer simulations show that deliberate hypovolemia (-300 ml) would be achieved by infusing 600-750 ml crystalloid fluid over 20-30 min or 100 ml of HSD over 10-20 min in an adult male. PMID- 22946749 TI - A new hemoglobin variant: Hb Izmir [beta86(F2)Ala->Val, GCC>GTC; HBB:c.260C>T]. AB - We report a new hemoglobin (Hb) variant [beta86(F2)Ala->Val; HBB:c.260C>T] that we have named Hb Izmir. We have identified Hb Izmir in a Turkish woman by ion exchange high performance liquid chromatography (HPLC) during a premarital screening program in the Aegean region of Turkey. The mother and sister of the proband also carried the same variant. Using direct sequencing, we have characterized this variant as resulting from a GCC>GTC replacement at codon 86 of the beta-globin chain, corresponding to an Ala->Val amino acid substitution. In the heterozygote, the level of Hb Izmir ranged from 41.38 to 45.6%. All heterozygotes had a Hb A(2) level of less than 3.5%. Total blood count values were normal and there were no other clinical findings. Although its clinical significance is thus far unclear, Hb Izmir may be important in hemoglobinopathy screening programs. PMID- 22946748 TI - Focal seizures with affective symptoms are a major feature of PCDH19 gene-related epilepsy. AB - PURPOSE: Mutations of the protocadherin19 gene (PCDH19) cause a female-related epilepsy of variable severity, with or without mental retardation and autistic features. Despite the increasing number of patients and mutations reported, the epilepsy phenotype associated with PCDH19 mutations is still unclear. We analyzed seizure semiology through ictal video-electroencephalography (EEG) recordings in a large series of patients. METHODS: We studied 35 patients with PCDH19 gene related epilepsy and analyzed clinical history and ictal video-EEG recordings obtained in 34 of them. KEY FINDINGS: Clusters of focal febrile and afebrile seizures had occurred in 34 patients, at a mean age of 10 months. The predominant and more consistent ictal sign was fearful screaming, occurring in 24 patients (70.5%); it was present since epilepsy onset in 12 and appeared later on, during the course in the remaining 12 patients. In infancy, fearful screaming mainly appeared within the context of seizures with prominent hypomotor semiology, whereas during follow-up it was associated with prominent early motor manifestations. In 16 patients, seizures were video-EEG recorded both at onset and during follow-up: in five patients (31%) seizure semiology remained identical, in 7 (44%) semiology varied and in four patients it was unclear whether ictal semiology changed with age. Three patients (9%) had both focal and generalized seizures, the latter consisting of absences and myoclonus. Ictal EEG during focal seizures showed a prominent involvement of the frontotemporal regions (22 patients). About 45% of patients had an alternating EEG pattern, with the ictal discharge migrating from one hemisphere to the contralateral during the same ictal event. Status epilepticus occurred in 30% of patients. Cognitive impairment occurred in 70%, ranging from mild (42%) to moderate (54%) and severe (4%); autistic features occurred in 28.5%. Direct sequencing detected 33 different heterozygous candidate mutations, 8 of which were novel. Mutations were missense substitutions (48.5%), premature termination (10 frameshift, 4 nonsense, and 2 splice-site mutations; 48.5%), and one in-frame deletion. Thirty candidate mutations (91%) were de novo. No specific genotype-phenotype correlation could be established, as missense and truncating mutations were associated with phenotypes of comparable severity. SIGNIFICANCE: Most patients with PCDH19 mutations exhibit a distinctive electroclinical pattern of focal seizures with affective symptoms, suggesting an epileptogenic dysfunction involving the frontotemporal limbic system. Awareness of this distinctive phenotype will likely enhance recognition of this disorder. PMID- 22946750 TI - A new germline VHL gene mutation in three patients with apparently sporadic pheochromocytoma. AB - CONTEXT: Germline mutations in four genes (RET, VHL, SDHB and SDHD) are detected in about 17% of patients with apparently sporadic pheochromocytoma. Thus, genetic screening of all patients with this disease is suggested for a rational diagnostic approach and management. OBJECTIVE: To report the clinical, biochemical and genetic analysis of three unrelated patients affected by pheochromocytoma. DESIGN AND PATIENTS: All the coding regions and exon-intron boundaries of RET, VHL, SDHB and SDHD genes were sequenced in three unrelated patients with intra-adrenal pheochromocytoma: a 17-year-old girl, a 15-year-old boy and a 73-year-old man. The family history of all three cases was negative for von Hippel-Lindau lesions or other types of endocrine tumours. Structural modelling of the VHL protein was then performed. RESULTS: We identified a novel germline VHL gene point mutation, a G to A nucleotide substitution in exon 3, leading to an aspartate to asparagine amino acid change in codon 197 (D197N). No mutations were found in RET, SDHB and SDHD genes. Structural modelling of the VHL protein suggests that the D197N mutation could have a functional role. CONCLUSIONS: Our study expands the number of VHL gene known mutations and indicates the usefulness of performing the genetic analysis in all patients with apparently sporadic pheochromocytoma. PMID- 22946751 TI - Computational study of the hydration of sulfuric acid dimers: implications for acid dissociation and aerosol formation. AB - We have investigated the thermodynamics of sulfuric acid dimer hydration using ab initio quantum mechanical methods. For (H(2)SO(4))(2)(H(2)O)(n) where n = 0-6, we employed high-level ab initio calculations to locate the most stable minima for each cluster size. The results presented herein yield a detailed understanding of the first deprotonation of sulfuric acid as a function of temperature for a system consisting of two sulfuric acid molecules and up to six waters. At 0 K, a cluster of two sulfuric acid molecules and one water remains undissociated. Addition of a second water begins the deprotonation of the first sulfuric acid leading to the di-ionic species (the bisulfate anion HSO(4)(-), the hydronium cation H(3)O(+), an undissociated sulfuric acid molecule, and a water). Upon the addition of a third water molecule, the second sulfuric acid molecule begins to dissociate. For the (H(2)SO(4))(2)(H(2)O)(3) cluster, the di-ionic cluster is a few kcal mol(-1) more stable than the neutral cluster, which is just slightly more stable than the tetra-ionic cluster (two bisulfate anions, two hydronium cations, and one water). With four water molecules, the tetra-ionic cluster, (HSO(4)(-))(2)(H(3)O(+))(2)(H(2)O)(2), becomes as favorable as the di-ionic cluster H(2)SO(4)(HSO(4)(-))(H(3)O(+))(H(2)O)(3) at 0 K. Increasing the temperature favors the undissociated clusters, and at room temperature we predict that the di-ionic species is slightly more favorable than the neutral cluster once three waters have been added to the cluster. The tetra-ionic species competes with the di-ionic species once five waters have been added to the cluster. The thermodynamics of stepwise hydration of sulfuric acid dimer is similar to that of the monomer; it is favorable up to n = 4-5 at 298 K. A much more thermodynamically favorable pathway forming sulfuric acid dimer hydrates is through the combination of sulfuric acid monomer hydrates, but the low concentration of sulfuric acid relative to water vapor at ambient conditions limits that process. PMID- 22946752 TI - Recombinant human c1 inhibitor (conestat alfa): in the treatment of angioedema attacks in hereditary angioedema. AB - Conestat alfa is a recombinant human C1 inhibitor used in the treatment of angioedema attacks in patients with hereditary angioedema (HAE). Patients with type I or II HAE have a deficiency in functional C1 inhibitor, which is an important regulator of complement and contact system activation. The therapeutic efficacy of conestat alfa in the treatment of angioedema attacks in patients with HAE was evaluated in two similar randomized, double-blind, placebo-controlled trials conducted in North America and Europe. The randomized controlled phases of both studies were closed after interim analyses provided compelling evidence of statistically significant positive efficacy findings and showed no apparent adverse safety findings. Results of the pooled analysis of the two trials showed that conestat alfa provided significantly faster initial relief of symptoms than placebo. The median time to the beginning of relief of symptoms (primary endpoint) was 66 minutes with conestat alfa 100 units/kg, 122 minutes with conestat alfa 50 units/kg, and 495 minutes with placebo. Conestat alfa was also statistically superior to placebo for the secondary endpoint of median time to minimal symptoms, with values of 266, 247, and 1210 minutes for the respective treatment groups. On the basis of data from open-label extension studies and integrated analyses of clinical trial data, conestat alfa has demonstrated efficacy in the treatment of repeated HAE attacks and in patients with potentially life-threatening HAE attacks with involvement of the upper airways. Conestat alfa was generally well tolerated in clinical trials, with the most frequently reported adverse event being headache. In the two randomized controlled trials, headache and vertigo were the only adverse events deemed to be related to study treatment. PMID- 22946753 TI - Vemurafenib: in unresectable or metastatic melanoma. AB - Vemurafenib is a first-in-class, small molecule BRAFV600E inhibitor. It is indicated in the US for the treatment of patients with unresectable or metastatic melanoma with the BRAFV600E mutation, and in the EU as monotherapy in adults with BRAFV600 mutation-positive unresectable or metastatic melanoma. Oral vemurafenib improved overall survival (OS) [co-primary endpoint] in patients with unresectable, previously untreated, BRAFV600E mutation-positive, stage IIIC or IV melanoma, according to the results of a randomized, open-label, multicenter, phase III trial (BRIM-3). With vemurafenib versus dacarbazine, the risk of death was significantly reduced by 63% in the interim OS analysis, and by 56%, 38%, and 30% in subsequent updated OS analyses. The median OS duration was 13.6 months in vemurafenib recipients and 9.7 months in dacarbazine recipients in the most recent OS analysis. In the phase III trial, progression-free survival (PFS) [co primary endpoint] was also significantly improved in vemurafenib versus dacarbazine recipients (median PFS of 5.3 vs 1.6 months), with a significant reduction in the risk of death or disease progression of 74% in the final PFS analysis. Vemurafenib was also associated with a high overall response rate in patients with previously treated, BRAFV600 mutation-positive, stage IV melanoma, according to the results of a noncomparative, multicenter, phase II trial. Patients had received at least one prior systemic treatment for advanced disease (excluding BRAF inhibitors other than sorafenib or MEK inhibitors). The overall response rate (primary endpoint) was 53% (complete response rate of 6% and partial response rate of 47%), with a median duration of response of 6.7 months, and a median OS duration of 15.9 months. Oral vemurafenib was generally well tolerated in patients with metastatic melanoma, with cutaneous adverse events among the most commonly occurring adverse events. Cutaneous squamous cell carcinoma and/or keratoacanthoma were reported in 18% of vemurafenib recipients in the BRIM-3 trial. PMID- 22946754 TI - Agalsidase alfa: a review of its use in the management of Fabry disease. AB - The enzyme replacement therapy agalsidase alfa (Replagal(r)) has an amino acid sequence identical to that of native alpha-galactosidase A; intravenous agalsidase alfa 0.2 mg/kg every other week is indicated for the long-term treatment of patients with confirmed Fabry disease. This article reviews the efficacy and tolerability of agalsidase alfa in patients with Fabry disease, as well as summarizing its pharmacologic properties. Agalsidase alfa had beneficial effects in adult men with Fabry disease, according to the results of two randomized, double-blind, placebo-controlled, 6-month trials (n = 15 and 26). For example, left ventricular mass index was reduced to a significantly greater extent with agalsidase alfa than with placebo. Although the change in myocardial globotriaosylceramide content (primary endpoint in one study) did not significantly differ between agalsidase alfa and placebo recipients, the change in the Brief Pain Inventory (BPI) 'pain at its worst' score (reflecting neuropathic pain while without pain medications; primary endpoint in the second study) was improved to a significantly greater extent with agalsidase alfa than with placebo. In addition, the change in creatinine clearance, but not inulin clearance, significantly favored agalsidase alfa versus placebo recipients. Abnormalities in functional cerebral blood flow and cerebrovascular responses were also reversed with agalsidase alfa therapy. In extensions of these placebo controlled trials, the reduction in left ventricular mass and improvements in BPI pain scores were maintained after longer-term agalsidase alfa therapy. The significant decline in estimated glomerular filtration rate (eGFR) seen after 48 months' agalsidase alfa treatment was mainly driven by a marked decline in eGFR seen in four patients with stage 3 chronic kidney disease at baseline (although the progression of decline appeared slower than that seen in historic controls); renal function appeared stable in patients with stage 1 or 2 chronic kidney disease. Certain benefits of agalsidase alfa became apparent with longer-term therapy. For example, a significant reduction in cold and warm detection thresholds and a significant improvement in sweat function were seen after 3 years' therapy. Final results from a head-to-head trial comparing the effects of agalsidase alfa and agalsidase beta at approved dosages are not yet available. The only available fully published study compared agalsidase alfa 0.2 mg/kg every other week with an off-label dosage of agalsidase beta 0.2 mg/kg every other week. This randomized, open-label, 24-month trial in adult men and women with Fabry disease generally found no significant differences in outcome between treatment arms. It should be noted that concerns were subsequently raised by the European Medicines Agency regarding the use of agalsidase beta at dosages other than the approved dosage of 1 mg/kg every other week. Preliminary results from an ongoing, randomized, open-label study suggest no differences in outcome between patients with Fabry disease receiving intravenous agalsidase alfa 0.2 mg/kg every other week and those receiving the approved regimen of agalsidase beta 1 mg/kg every other week. In three switching studies, no safety concerns were raised and disease stability was generally maintained following the switch from agalsidase beta 1 mg/kg every other week to agalsidase alfa 0.2 mg/kg every other week. Agalsidase alfa also demonstrated beneficial effects, including in women and pediatric patients, in noncomparative studies and in the Fabry Outcome Survey. Agalsidase alfa was generally well tolerated in patients with Fabry disease, with infusion reactions (e.g. rigors, pyrexia, flushing) being the most commonly occurring adverse event. IgG antibodies developed in ~24% of male patients with Fabry disease who received agalsidase alfa. After 12-54 months of treatment, 17% of agalsidase alfa recipients were still IgG antibody positive, with immunologic tolerance developing in 7% of agalsidase alfa recipients. No IgE antibodies have been detected in any patient receiving agalsidase alfa. No antibody formation was reported in women receiving agalsidase alfa in noncomparative studies. In conclusion, agalsidase alfa is an effective and well tolerated treatment option for use in patients with Fabry disease. PMID- 22946756 TI - Fast Pd- and Pd/Cu-catalyzed direct C-H arylation of cyclic nitrones. Application to the synthesis of enantiopure quaternary alpha-amino esters. AB - Cocatalysis by pivalic acid or copper bromide allows a very fast, clean, and high yielding palladium-catalyzed coupling of a large array of aryl, thienyl, and pyridyl halides with cyclic nitrones, including DMPO. The study of the reaction conditions, scope, and mechanism is presented. Applied to the chiral nitrone MiPNO, this transformation provides a straightforward access to enantiopure alpha methyl alpha-arylglycine esters. PMID- 22946755 TI - Numerical simulation of variable water diffusivity during drying of peeled and unpeeled tomato. AB - A mathematical model was formulated for the estimation, in conjunction with experimental measurements, of water diffusivity parameters during convective drying of peeled and unpeeled tomatoes. Fick's 2nd law of diffusion was solved numerically for a sphere, by explicit finite differences, considering shrinkage effect, variable diffusivity, and constant boundary conditions. Experiments were performed in a laboratory tunnel dryer. The equivalent radius of tomato decreased by 50% until the end of the process, which explains the necessity for shrinkage inclusion in the mass transfer model. The mean estimated diffusivities varied between 2.03 * 10(-10) and 15.1 * 10(-10) m(2)/s for peeled tomatoes and 0.59 * 10(-10) and 15.2 * 10(-10) m(2)/s for unpeeled tomatoes. The estimated water diffusivities and their variation with the tested drying temperatures (45, 55, and 65 degrees C) provide an insight of peeling effect during air-drying. Peeling was beneficial since yielded greater drying rates and shortened significantly drying times, thus saving energy during drying. In all the studied cases, good agreement was found between experimental and predicted drying curves (>= 0.99, mean relative deviation [MRD]<= 0.12, and root mean square error [RMSE]<= 0.03). In overall, the proposed methodology provides a reliable and easy estimation of temperature and moisture-dependent mass transfer properties and drying simulation of shrinkable food products such as tomato. PRACTICAL APPLICATION: Water diffusivity is a food property, difficult in estimation but essential in drying processing optimization. This property was estimated as a function of moisture content and drying temperature employing a numerical simulation procedure. The peeling effect was also studied and found beneficial for lower temperature drying (<55 degrees C) which is useful in the energy optimization of the drying process as well as the retention of the end-product quality. PMID- 22946758 TI - Haemophilia B: current pharmacotherapy and future directions. AB - INTRODUCTION: Hemophilia B is a rare hereditary hemorrhagic disorder characterized by deficiency of the clotting factor IX (FIX). Hemophilia B patients experience mild to severe bleeding complications according to the degree of FIX defect. Nowadays, the most challenging complication of individuals with hemophilia B is the development of alloantibodies, which render the standard replacement therapy with FIX concentrates ineffective, exposing them to a significantly increased morbidity and mortality. AREAS COVERED: This review summarizes the most important events leading to the development of the current FIX products available for the treatment of hemophilia B patients. In addition, it focuses on the more recent advances in the production of new FIX molecules aimed at improving the clinical management of such patients. EXPERT OPINION: Although the availability of plasma-derived FIX concentrates has greatly improved the clinical management of hemophilia B patients, the introduction of FIX products using recombinant DNA technology has represented the most significant therapeutic progress in hemophilia B therapy, ensuring an advanced level of safety. The development of rFIX products with extended half lives will further improve the therapeutic armamentarium for hemophilia B patients. PMID- 22946759 TI - Morphological transitions of droplets wetting rectangular domains. AB - We report the results of comprehensive experiments and numerical calculations of interfacial morphologies of water confined to the hydrophilic top face of rectangular posts of width W = 500 MUm and lengths between L = 5W and 30W. A continuous evolution of the interfacial shape from a homogeneous liquid filament to a bulged filament and back is observed during changes in the liquid volume. Above a certain threshold length of L* = 16.0W, the transition between the two morphologies is discontinuous and a bistability of interfacial shapes is observed in a certain interval of the reduced liquid volume V/W(3). PMID- 22946760 TI - Inhibition of hippocampal excitability by citalopram. AB - PURPOSE: Preclinical data have suggested that selective serotonin reuptake inhibitors (SSRIs) may have anticonvulsant properties, and some SSRIs are known to modulate ion channels in vitro. We screened citalopram, fluoxetine, and sertraline for anticonvulsant actions in mouse hippocampal slices, and studied the effects of citalopram on active membrane properties and repetitive action potential firing. METHODS: To enable testing of antiepileptic effects and target modulation in a single experimental system, we used the simplistic low Ca(2+) model, which is strongly dependent on the intrinsic excitability of CA1 pyramidal neurons. Field potentials and whole-cell currents were recorded from brain slices, and SSRIs were bath-applied. KEY FINDINGS: We found that citalopram, fluoxetine, and sertraline inhibited epileptiform activity recorded from area CA1. The effect of citalopram was more potent and less variable than that of fluoxetine and sertraline. The anticonvulsant action of citalopram was accompanied by marked slowing of action potential rise and decay, and robust inhibition of repetitive firing. This depression of membrane excitability appeared to be mediated in part by inhibition of a sustained potassium current. SIGNIFICANCE: These findings confirm that SSRIs can have anticonvulsant effects in the hippocampus, and further suggest that citalopram may exert these effects at least in part by inhibition of voltage-gated ion currents. PMID- 22946761 TI - The conjoint Rorschach comprehensive system: reliability and validity in clinical and nonclinical couples. AB - This article presents the comparison of 2 paired groups of satisfied (n = 22) and distressed (n = 22) couples using a conjoint version of the Rorschach Comprehensive System (CS; Exner, 2003). The aim of the study was to evaluate if the couples' verbalizations could be coded reliably using standard CS variables and if the 2 groups of protocols differed on several dimensions hypothesized to reflect relational dissatisfaction. The results showed good to excellent interrater reliability for the selected CS variables. Comparisons revealed expected moderate to large differences between the satisfied and distressed groups with regard to communication (R), some of the affective variables (DEPI%, Afr, SumV%, Col-Shading Blends%), and cognitive variables (X-%, WDA% Sum6%, WSum6%). Among variables connected with aggression, only AgPast% was moderately higher in the distressed group of couples. Overall, the results support the use of the Conjoint Rorschach Comprehensive System (ConRCS) in couples' assessments. PMID- 22946762 TI - Naloxone infusion and post-hysterectomy morphine consumption: a double-blind, placebo-controlled study. AB - BACKGROUND: The evidence that an infusion of a low dose of naloxone reduces post operative pain and opioid analgesic consumption is somewhat conflicting. Thus, the aim of the present study was to investigate the effect of an ultra-low dose of naloxone on patient-controlled morphine analgesia. METHODS: Ninety patients, 35-55 years old, scheduled for total abdominal hysterectomy, were enrolled in this prospective, randomized, double-blind and placebo-controlled study. Post operatively, they received either saline (n = 45) or naloxone (n = 45) for 24 h. A standard general anesthesia was administered in both groups. In the recovery room, patients received morphine by a patient-controlled analgesia device. An ultra-low dose of naloxone was infused intravenously at 0.25 MUg/kg/h for 24 h in the intervention group. Saline was infused in the control group. Following the surgery, morphine consumption, numeric rating score for pain intensity, nausea and vomiting, pruritus, and requests for antiemetic were recorded at baseline, 30 min, 1, 4, 8,16, 20, and 24 h following their discharge from recovery. RESULTS: Naloxone reduced morphine consumption over the first 24 post-operative hours significantly compared with the controls (saline) {19.5 [standard deviation (SD) 3.4] mg vs. 27.5 [SD 5.9] mg; P < 0.001}. The incidence and severity of nausea and vomiting was significantly reduced in the naloxone group. The incidence of pruritus and the pain scores at rest and activity were not significantly different. CONCLUSION: Following hysterectomy, an ultra-low dose of naloxone infusion proved to reduce morphine consumption as well as the incidence and severity of opioid-induced nausea and vomiting. PMID- 22946763 TI - Three-dimensional ordered macroporous (3DOM) composite for electrochemical study on acetylcholinesterase inhibition induced by endogenous neurotoxin. AB - In this paper, an electrochemical acetylcholinesterase (AChE) inhibition assay based on three-dimensional ordered macroporous (3DOM) composite was conducted. The 3DOM composite was first fabricated on the glassy carbon electrode by electropolymerization of aniline in the presence of ionic liquid (IL) on a sacrificial silica nanospheres template. After the silica nanospheres were etched, an IL-doped polyaniline (IL-PANI) film with 3DOM morphology was formed. Then, gold nanoparticles (AuNPs) were decorated on the IL-PANI film by electrodeposition. The immobilized AChE on the 3DOM composite displayed favorable affinity to substrate acetylthiocholine chloride (ATCh), and the 3DOM composite showed excellent electrocatalytic effect on thiocholine, the hydrolysis product of ATCh. The presence of IL and AuNPs could improve the sensitivity by accelerating the electron transfer. The designed AChE biosensor was successfully applied to evaluate the AChE inhibition induced by endogenous neurotoxin 1(R),2N dimethyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline [(R)-NMSal]. The results demonstrate that (R)-NMSal exerts a considerable effect on AChE activity, and the inhibition is reversible. The developed method offers a new approach for AChE inhibition assay, which is of great benefit in understanding the mechanism behind neurotoxin-induced neurodegenerative disorders. PMID- 22946764 TI - Rachycentron canadum (cobia) lectin promoted mitogenic response in mice BALB/c splenocytes. AB - The mitogenic lectins are invaluable tools to study the biochemical changes associated with lymphocyte activation and proliferation of various immune cells. Rachycentron canadum lectin (RcaL) was detected and purified from serum of cobia fish. The aim of this study was to evaluate the proliferative response and cytokine production in splenocytes of mice in vitro stimulated with RcaL lectin; Canavalia ensiformis lectin (Con A) was used as positive control. A high proliferation index was induced by RcaL in relation to control cells. Furthermore, RcaL induced higher IL-2 and IL-6 production in relation to control. The cell viability was 90% in splenocytes treated with RcaL lectin, but RcaL promoted significant late apoptosis after 24 and 48 h in relation to control. RcaL induced proliferative responses suggesting that this lectin can be used as a mitogenic agent in immunostimulatory assays. PMID- 22946765 TI - QSAR models for P-glycoprotein transport based on a highly consistent data set. AB - P-Glycoprotein (Pgp) is involved in the elimination and in the disposition of a significant portion of marketed drugs. So far, publicly available data sets used for modeling Pgp transport included compounds tested in different assays, different cell lines, and different protocols. In this work, we present a collection of 478 Efflux Ratios (ERs) in MDCK-MDR1 cell lines, and from this collection we define a data set of 187 compounds that were tested in the Borst derived MDCK-MDR1 cell lines. Of the 23 models resulting from the use of different descriptors, classification algorithms, and variable selection techniques, the 4 most accurate in external validation (~0.86) are based on VolSurf+ (VS+) descriptors. Two of these models are Naive Bayes (NB) classifiers using 4 descriptors that were selected through a new technique hereby first time extensively described. PMID- 22946766 TI - Time-resolved electron paramagnetic resonance and phosphorescence studies of the lowest excited triplet states of Rh(III) corrole complexes. AB - The lowest excited triplet (T(1)) pipi* states of gallium (Ga) and various rhodium (Rh) 5,10,15-trispentafluorophenyl corroles (Cors) were studied in the liquid crystal (LC) E-7 and in rigid glasses by time-resolved electron paramagnetic resonance (TR-EPR) spectroscopy. The triplet sublevel energies were experimentally determined by the alignment of the molecules in the LC and by magnetophotoselection in the glass. The sublevel scheme of GaCor was determined by calculating the zero field splitting (ZFS) parameters. Axial ligand effects and quantum chemical calculations were used for the sublevel assignment of RhCors. The anisotropic EPR parameters were used to determine the important higher excited states and the magnitudes of their spin-orbit coupling (SOC) contributions were evaluated. On the basis of these results and analyses, the EPR parameters and triplet lifetime were discussed for each RhCor complex. PMID- 22946767 TI - The evaluation of possible false positives with detergents when performing amylase serological testing on clothing. AB - For almost 40 years, detergent companies have been adding enzymes such as amylases to their products as an effective method of breaking down tough stains created by polysaccharides and proteins. The possibility that alpha-amylases present in common household laundry detergents may contribute to the positive detection of alpha-amylase on evidentiary samples during forensic presumptive screening procedures is a potential problem that has not yet been investigated. To determine whether alpha-amylase detection is possible following routine laundering, five different fabrics were laundered in a variety of detergents, and presumptive testing using RSID(TM)-Saliva and Phadebas((r)) Amylase Test was conducted. Our results demonstrate that clothing laundered in detergents known to contain enzymes does not retain any detectable levels of alpha-amylase following a typical wash cycle. We also show that, unlike laundered clothing, undiluted detergents do contain detectable levels of alpha-amylase; however, these findings were only observed using the Phadebas((r)) Amylase Test. PMID- 22946768 TI - Real-time telehealth for COPD self-management using SkypeTM. AB - The utility of real-time interactive voice and video telehealth for teaching pursed-lips breathing (PLB) in chronic obstructive pulmonary disease (COPD) is unknown. This was a pilot study to determine its feasibility and efficacy on the key variables of social support and dyspnea. A randomized control study design with repeated measures (baseline, 4 and 12 weeks) was used. All participants in the control and intervention groups received PLB instruction at baseline, but only the intervention group received one weekly PLB reinforcement session for 4 weeks via home computer and SkypeTM software. Outcome measures were Medical Outcomes Study Social Support Survey and dyspnea assessment (visual analogue scales for intensity and distress, modified Borg after six-minute walk distance, and Shortness of Breath Questionnaire for activity-associated dyspnea). A total of 22 participants with COPD (mean FEV(1)% predicted = 56) were randomized; 16 (9 telehealth, 7 control) completed the protocol. Intent-to-treat analysis at week 4, but not week 12, demonstrated significantly improved total social support (P = 0.02) and emotional/informational subscale (P = 0.03) scores. Dyspnea intensity decreased (P = 0.08) for the intervention group with a minimal clinical important difference of 10.4 units. Analysis of only participants who completed the protocol demonstrated a significant decrease in dyspnea intensity (P = < 0.01) for the intervention group at both week 4 and 12. Real-time telehealth is a feasible, innovative approach for PLB instruction in the home with outcomes of improved social support and decreased dyspnea. PMID- 22946769 TI - New anticoagulants for stroke prophylaxis in atrial fibrillation: assessing the impact on medication adherence. AB - Atrial fibrillation (AF), the most common sustained cardiac arrhythmia, is a potent risk factor for stroke and transient ischemic attack. Most patients with AF receive antithrombotic stroke prophylaxis, often in the form of a vitamin K antagonist, typically warfarin. Drug treatment with warfarin is associated with significant management issues, such as an unpredictable dose response necessitating dose adjustments, frequent laboratory monitoring, and multiple interactions with other medications, as well as foods. A new generation of novel anticoagulants has emerged that includes dabigatran etexilate, a direct thrombin inhibitor, and rivaroxaban and apixaban, both highly selective factor Xa inhibitors. These newer agents possess a highly predictable pharmacokinetic pharmacodynamic relationship, allowing for fixed dosing and no necessity for routine laboratory monitoring; additionally these agents have minimal drug interactions. Dabigatran etexilate and apixaban are both twice-daily medications, whereas rivaroxaban is administered once daily for stroke prophylaxis. The impact of dosing frequency on medication adherence with these agents has not been prospectively evaluated; however, the frequency of dosing intervals has been shown to affect medication adherence, which in turn may influence patient outcomes. PMID- 22946770 TI - Asymmetric synthesis of gem-difluoromethylenated dihydroxypyrrolizidines and indolizidines. AB - An asymmetric synthesis of gem-difluoromethylenated dihydroxypyrrolizidines and indolizidines is described. The fluoride-catalyzed nucleophilic addition of PhSCF(2)SiMe(3) (1) to chiral imides was achieved in satisfactory yields to provide mixtures of syn- and anti-isomers 6-9 with moderate to good diastereoselectivities. Reductive cleavage of the phenylsulfanyl group followed by intramolecular radical cyclization of the syn-isomers 6-9 occurred under refluxing conditions to afford the corresponding gem-difluoromethylenated 1 azabicyclic compounds 10-13 in moderate yields as a separable mixture of cis- and trans-isomers. The cis-isomers of compounds 10 and 12 and trans-13 were readily transformed to gem-difluoromethylenated dihydroxypyrrolizidines 20 and 27 and indolizidine 28, respectively, by reductive cleavage of the hydroxyl group and organometallic addition followed by hydrogenolysis. PMID- 22946771 TI - Fabrication and characterization of dendrimer-functionalized mesoporous hydroxyapatite. AB - A successful synthesis of mesostructured hydroxyapatite (HAp) using cetyltrimethylammonium bromide and poly(amido amine) dendrimer porogens has been reported. A comparative study of physicochemical properties has also been performed. The formation of a single-phase hydroxyapatite crystal in synthesized HAp particles with an aspect ratio of 2.3 was revealed. The formation of the mesostructural nature of HAp was proven with a specific surface area (56-63 m(2)/g) and a certain pore size (4.7-5.5 nm), although there were significant differences between particles from surfactant micelle and dendrimer porogens. In addition, the surface modification of mesoporous HAp particles was carried out using poly(amido amine) dendrimer. The content and thickness of the dendrimer coating on particle surfaces were highly dependent on the pH. At pH 9 or greater, the coating thickness corresponded to at least a double layer of dendrimer, but it decreased sharply with decreasing pH from 9 to 6, in agreement with the protonation of amine groups in the dendrimer, indicating the strong interaction of nonionic dendrimer with HAp. The developed dendrimer-functionalized mesoporous hydroxyapatite materials may be applicable in biocomposite material and/or bone tissue engineering. PMID- 22946772 TI - Current pharmacotherapy options for bulimia nervosa and binge eating disorder. AB - INTRODUCTION: Growing evidence indicates binge eating, defined as the consumption of an abnormally large amount of food accompanied by a sense of loss of control, is an important public health problem. Although psychotherapy may be effective, not all patients respond adequately. AREAS COVERED: This article provides an overview of bulimia nervosa (BN) and binge eating disorder (BED), the two conditions characterized by recurrent binge eating as a core feature, and reviews studies of specific medications in treating patients with BN or BED, focusing on randomized controlled trials (RCTs). EXPERT OPINION: Although the evidence base is small, growing data indicate pharmacotherapy may be helpful for some patients with BN or BED. Antidepressants, especially selective serotonin reuptake inhibitors (SSRIs), are modestly effective for reducing binge eating over the short term in BN and BED. SSRIs may be modestly effective in BN over the long term. Topiramate has consistently been shown to decrease binge eating in BED and BN, but side effects may limit its usefulness. Single RCTs suggest zonisamide and atomoxetine may be effective in BED. Combination therapy may be required for optimal outcomes. It is not yet known whether the binge eating of BN and BED respond similarly to pharmacotherapy. PMID- 22946773 TI - Therapeutic efficacy of melatonin in reducing retinal damage in an experimental model of early type 2 diabetes in rats. AB - Diabetic retinopathy (DR) is a leading cause of acquired blindness in adults, mostly affected by type 2 diabetes mellitus (T2DM). We have developed an experimental model of early T2DM in adult rats which mimics some features of human T2DM at its initial stages and provokes significant retinal alterations. The aim of this work was to analyze the effect of melatonin on retinal changes induced by the moderate metabolic derangement. For this purpose, adult male Wistar rats received a control diet or 30% sucrose in the drinking water. Three weeks after this treatment, animals were injected with vehicle or streptozotocin (STZ, 25 mg/kg). One day or 3 wk after vehicle or STZ injection, animals were subcutaneously implanted with a pellet of melatonin. Fasting and postprandial glycemia, and glucose, and insulin tolerance tests were analyzed. At 12 wk of treatment, animals which received a sucrose-enriched diet and STZ showed significant differences in metabolic tests, as compared with control groups. Melatonin, which did not affect glucose metabolism in control or diabetic rats, prevented the decrease in the electroretinogram a-wave, b-wave, and oscillatory potential amplitude, and the increase in retinal lipid peroxidation, NOS activity, TNFalpha, Muller cells glial fibrillary acidic protein, and vascular endothelial growth factor levels. In addition, melatonin prevented the decrease in retinal catalase activity. These results indicate that melatonin protected the retina from the alterations observed in an experimental model of DR associated with type 2 diabetes. PMID- 22946774 TI - A glimpse behind the mask: facets of narcissism and feelings of self-worth. AB - This study examined the connections that the facets of narcissism captured by the Narcissistic Personality Inventory (NPI; Raskin & Hall, 1979) and the Pathological Narcissism Inventory (PNI; Pincus et al., 2009) have with self esteem. This was accomplished by asking 372 participants to complete measures of narcissism and self-esteem level as well as daily diary measures concerning their state self-esteem and daily experiences. Our analyses found that the facets of narcissism differed in their associations with average level of self-esteem, fluctuations in state self-esteem over time, and self-esteem reactions following daily events. These results suggest that it is important to consider specific facets of narcissism when examining feelings of self-worth rather than relying on broader composite measures of narcissistic personality features. Implications of these results for our understanding of the dynamics of the narcissistic personality are discussed. PMID- 22946775 TI - LMA ProSeal(TM) vs. i-Gel(TM) in ventilated children: a randomised, crossover study using the size 2 mask. AB - BACKGROUND: The Laryngeal Mask Airway (LMA) ProSeal(TM) and the i-Gel(TM) are two extraglottic devices with either an inflatable cuff or a non-inflatable cuff. AIM: We test the hypothesis that oropharyngeal leak pressure and fiberoptic position of the airway tube differ between the size 2 LMA ProSeal(TM) and the i Gel(TM) in non-paralysed ventilated children. METHODS: Fifty-one children aged 1.5-6 years weighing 10-25 kg were studied using a crossover design. Anaesthesia was with remifentanil/propofol mixture. The LMA ProSeal(TM) and the i-Gel(TM) were inserted into each patient in random order. RESULTS: Oropharyngeal leak pressure for the LMA ProSeal(TM) and the i-Gel(TM) was similar at 22 (5) and 21 (5) cm H(2) O, respectively. Fiberoptic position of the airway tube for the LMA ProSeal(TM) and the i-Gel(TM) was similar, with the vocal cords visible from the distal airway tube in 94% and 96%, respectively. CONCLUSION: We conclude that oropharyngeal leak pressure and fiberoptic position of the airway tube are similar for the size 2 LMA ProSeal(TM) and i-Gel(TM) in non-paralysed ventilated children. PMID- 22946776 TI - Soluble CD163 is associated with body mass index and blood pressure in hypertensive obese Saudi patients. AB - BACKGROUND: The hallmark of vascular inflammation is the recruitment of circulating leucocytes, primarily monocytes, macrophages and T lymphocytes, into the vascular wall; however, the link between monocyte/macrophage activation and hypertension has not been established as yet. In this study, we determined how sCD163, a monocyte/macrophage soluble scavenger receptor and immunomodulator, relates to arterial blood pressure (BP) in hypertensive Saudi individuals. MATERIALS AND METHODS: A total of 90 (30 non-hypertensive obese, 30 hypertensive obese and 30 lean normotensive controls) adult Saudi subjects, aged 40-60 years, participated in this cross-sectional study. Serum fasting blood glucose, triglycerides, total cholesterol, HDL-cholesterol (HDL-C), LDL-cholesterol (LDL C), leptin, adiponectin, resistin, insulin, tumour necrosis factor-alpha (TNF alpha), PAI-1, angiotensin II, high-sensitivity C-reactive protein (hsCRP) and sCD163 were measured in all subjects studied. RESULTS: sCD163 concentrations were significantly increased in obese hypertensive patients compared to controls (P=0.016). Positive correlations between sCD163 and body mass index (BMI) (r=0.27, P=0.01), systolic BP (r=0.25, P=0.01), diastolic BP (r=0.33, P=0.001), LDL-C (r=0.21, P=0.04), TNF-alpha (r=0.23, P=0.02) and hsCRP (r=0.33, P=0.008) were observed. Positive correlations between sCD163 and diastolic BP (r=0.23, P=0.04) and LDL-C (r=0.22, P=0.03) remained significant after controlling for BMI. CONCLUSIONS: Taken together, these data demonstrate that the monocyte/macrophage activation-related sCD163 is positively associated with BMI and increased arterial BP with the elevation in diastolic BP being independent of the BMI. PMID- 22946778 TI - Screening for postpartum depression at pediatric visits. PMID- 22946777 TI - Extensive endoscopic image-guided sinus surgery decreases BPI-ANCA in patients with cystic fibrosis. AB - Antineutrophil cytoplasm autoantibodies (ANCA) directed against bactericidal/permeability-increasing protein (BPI) are common in patients with cystic fibrosis (CF), and serum levels are correlated with lung colonization by Pseudomonas aeruginosa and the severity of lung damage. The production of BPI ANCA may be due to the costimulation of BPI when mounting an immune response against P. aeruginosa. The effect of surgery aiming to eradicate bacteria and infected tissue on BPI-ANCA levels is sparsely described. A cohort of patients with CF were included: 53 patients having extensive image-guided sinus surgery (EIGSS) with topical postoperative antibiotic treatment, 131 non-operated controls and 36 who had double lung transplantation (LTX). In all 219 patients, serum samples before and after surgery or at similar intervals were analysed for IgG and IgA BPI-ANCA. The EIGSS group showed a highly significant decrease in both IgA and IgG BPI-ANCA levels compared with their own preoperative values and control group values (P < 0.001-0.02). The LTX patients also showed a highly significant decrease in both IgA and IgG BPI-ANCA levels (P < 0.001). EIGSS and LTX decrease IgA and IgG BPI-ANCA levels in patients with CF, indicating that extensive removal of infected tissue influences the pathogenic process of autoantibody production. The results shown herein are in favour of applying EIGSS in selected patients with CF and for using BPI-ANCA as a surrogate marker for guiding further therapeutic interventions. PMID- 22946783 TI - Excited state intramolecular proton transfer in electron-rich and electron-poor derivatives of 10-hydroxybenzo[h]quinoline. AB - Eight previously inaccessible derivatives of 10-hydroxybenzo[h]quinoline were prepared via a straightforward strategy comprising formation of the benzo[h]quinoline skeleton followed by C-H acetoxylation at position 10. The occurrence of excited state intramolecular proton transfer (ESIPT) was detected in all cases since emission was observed only from the excited keto-tautomer. Studies on derivatives bearing both electron-donating and electron-withdrawing groups adjacent to the pyridine ring allowed us to identify some design patterns giving rise to NIR emission and large Stokes shifts. For a derivative of 10 hydroxybenzo[c]acridine, emission at 745 nm was observed, one of the lowest energy fluorescence ever reported for ESIPT system. On the basis of time-resolved measurements, proton transfer was found to be extremely fast with time constants in the range (0.08-0.45 ps). PMID- 22946784 TI - Pushing the Ir-catalyzed C-H polyborylation of aromatic compounds to maximum capacity by exploiting reversibility. AB - Small amounts of base (e.g., 10% potassium t-butoxide or sodium methoxide) have been found to promote equilibration of the kinetically favored products from Ir catalyzed C-H polyborylations of aromatic compounds. In the presence of excess borylating agent, bis(pinacolato)diborane (B(2)pin(2)), repetitive deborylation/reborylations reposition the Bpin substituents until a pattern that accommodates the maximum number of Bpin substituents is achieved. A high-yield, one-step synthesis of 1,3,5,7,9-pentakis(Bpin)corannulene is reported that illustrates this useful extension of the Ir-catalyzed borylation reaction. PMID- 22946785 TI - Glutathione S-transferase (GST) M1, but not GSTT1, genotype influences plasma proteomic profiles in Caucasian and East Asian young adults. AB - Glutathione S-transferase (GST) M1 and T1 are major detoxifying enzymes that have been associated with a number of chronic diseases, but their effect on various physiological pathways remains unclear. We investigated the association between the common GSTM1 and GSTT1 genotypes and multiple disease-related high-abundance proteins of the plasma proteome in young Caucasian (n = 476) and East Asian (n = 352) adults. Overnight fasting blood samples were collected, and 54 high abundance plasma proteins from several physiological pathways were quantified by mass spectrometry-based multiple reaction monitoring (LC-MRM/MS). Subjects were genotyped for GSTM1 and GSTT1 deletion polymorphisms. Principal component analysis was used to identify proteomic profiles, and differences in individual protein concentrations between genotypes were assessed by ANCOVA. Among Caucasians, 19 proteins differed between GSTM1 genotypes (P < 0.05), with all protein concentrations being higher among the null genotypes. However, only complement C3 reached the Bonferroni-corrected significance threshold for multiple testing (P < 0.0009). Among East Asians, three proteins differed between GSTM1 genotypes (P < 0.05) with higher concentrations among the null genotypes, but none reached the Bonferroni level of significance. Protein concentrations did not differ between GSTT1 genotypes in either ethnicity. These findings suggest that GSTM1 may have novel physiological effects related to immunity and cardiometabolic disease. PMID- 22946787 TI - 3D multiscale segmentation and morphological analysis of X-ray microtomography from cold-sprayed coatings. AB - X-ray microtomography from cold-sprayed coatings brings a new insight on this deposition process. A noise-tolerant segmentation algorithm is introduced, based on the combination of two segmentations: a deterministic multiscale segmentation and a stochastic segmentation. The stochastic approach uses random Poisson lines as markers. Results on a X-ray microtomographic image of aluminium particles are presented and validated. PMID- 22946786 TI - Sustained wound healing activity of curcumin loaded oleic acid based polymeric bandage in a rat model. AB - Wound healing is an intricate multistage process that includes inflammation, cell proliferation, matrix deposition and remodeling phases. It is often associated with oxidative stress and consequent prolonged inflammation, resulting in impaired wound healing. Curcumin has been reported to improve wound healing in different animal models. In order to increase the efficacy of curcumin in the healing arena a curcumin loaded oleic acid based polymeric (COP) bandage was formulated. The in vivo wound healing potency was compared with void bandage and control (cotton gauze treatment) in a rat model. Biochemical parameters and histological analysis revealed increased wound reduction and enhanced cell proliferation in COP bandage treated groups due to its efficient free radical scavenging properties. Comparative acceleration in wound healing was due to early implementation of fibroblasts and its differentiation (increased level of alpha smooth muscle actin). Western blotting and semiquantitative PCR analysis clearly indicate that COP bandage can efficiently quench free radicals leading to reduced antioxidative enzyme activity. Further evidence at mRNA and protein level indicates that our system is potent enough to reduce the inflammatory response mediated by the NFkappaB pathway during wound healing. With this background, we anticipate that such a versatile approach may seed new arena for topical wound healing in the near future. PMID- 22946788 TI - Gymnothelignans A-O: conformation and absolute configuration analyses of lignans bearing tetrahydrofuran from Gymnotheca chinensis. AB - Fifteen new lignans, gymnothelignans A-O (1-15), bearing tetrahydrofuran with variable conformations belonging to three potentially related skeletons were isolated from Gymnotheca chinensis Decne. The structures were elucidated by means of detailed spectroscopic analysis. Absolute configurations were assigned using X-ray single-crystal diffraction and chemical transformations. Moreover, by the homology, compounds 1-11 and eupomatilones were confirmed to have uniform R configuration at C-5. However, a synthesized congener has long been mistaken as 5 epimer of eupomatilone-6. This work provides guidance for the absolute configuration establishment of the subeupomatilone family with trans-H-4-H-5 configuration. PMID- 22946789 TI - Cost-effectiveness analysis of therapies for chronic kidney disease patients on dialysis: a case for excluding dialysis costs. AB - In many jurisdictions, cost-effectiveness analysis (CEA) plays an important role in determining drug coverage and reimbursement and, therefore, has the potential to impact patient access. Health economic guidelines recommend the inclusion of future costs related to the intervention of interest within CEAs but provide little guidance regarding the definition of 'related'. In the case of CEAs of therapies that extend the lives of patients with chronic kidney disease (CKD) on dialysis but do not impact the need for or the intensity of dialysis, the determination of the relatedness of future dialysis costs to the therapy of interest is particularly ambiguous. The uncertainty as to whether dialysis costs are related or unrelated in these circumstances has led to inconsistencies in the conduct of CEAs for such products, with dialysis costs included in some analyses while excluded in others. Due to the magnitude of the cost of dialysis, whether or not dialysis costs are included in CEAs of such therapies has substantial implications for the results of such analyses, often meaning the difference between a therapy being deemed cost effective (in instances where dialysis costs are excluded) or not cost effective (in instances where dialysis costs are included). This paper explores the issues and implications surrounding the inclusion of dialysis costs in CEAs of therapies that extend the lives of dialysis patients but do not impact the need for dialysis. Relevant case studies clearly demonstrate that, regardless of the clinical benefits of a life-extending intervention for dialysis patients, and due to the high cost of dialysis, the inclusion of dialysis costs in the analysis essentially eliminates the possibility of obtaining a favourable cost-effectiveness ratio. This raises the significant risk that dialysis patients may be denied access to interventions that are cost effective in other populations due solely to the high background cost of dialysis itself. Finally, the paper presents a case for excluding dialysis costs in CEAs of therapies that extend the lives of patients receiving dialysis but do not impact the need for dialysis. The argument is founded on the following: (i) health economic guidelines imply that dialysis costs are unrelated to such therapies and therefore should not be included in CEAs of such therapies; (ii) the high cost and cost-effectiveness ratio associated with dialysis place an unreasonable and insurmountable barrier to demonstrating the cost effectiveness of such therapies, particularly since the decision to fund dialysis has already been made; and (iii) current clinical and reimbursement practices include the use of such therapies for patients with CKD receiving dialysis. We conclude that the exclusion of dialysis costs in such cases is methodologically correct given current health economic guidelines and is consistent with current practices regarding the treatment of dialysis patients. PMID- 22946790 TI - C-reactive protein, lung hyperinflation and heart rate variability in chronic obstructive pulmonary disease --a pilot study. AB - Chronic obstructive pulmonary disease (COPD) is associated to cardiovascular morbidity and mortality, and abnormalities of the autonomic nervous system have been described in subjects with severe disease. We studied heart rate variability (HRV) in COPD patients at rest and during the 6-minute Walk Test (6mWT) and the association with lung function impairment taking into account systemic inflammation. Thirty outpatients with stable COPD underwent lung function measurements, blood gas analysis, ECG Holter and transcutaneous pulse oximetry during 6mWT and then they were classified by BODE index. Also C-reactive protein (CRP) was measured. At rest, we observed a significant reduction of HRV for increasing BODE index. During the 6mWT, HRV tended to decrease in BODE 1 subjects whereas an increase was observed in BODE 2 and BODE 3-4 subjects. Subjects with elevated CRP values had a significant reduction in Standard Deviation of all normal RR intervals at rest (SDNN: p = 0.013), Total Power (TFA: p = 0.04) and Very Low Frequency band (VLF: p = 0.041). At rest, subjects with Inspiratory Capacity-to-Total Lung Capacity ratio (IC/TLC) < 36% had a significant reduced SDNN (p = 0.004), TFA (p = 0.001), VLF (p = 0.001), Low Frequency band (p = 0.007). During 6mWT, changes of HRV parameters were significantly related to airflow obstruction and static hyperinflation indices. At rest and during submaximal exercise, COPD patients with moderate and severe disease had an abnormal cardiac autonomic modulation which was related to both systemic inflammation and lung function impairment. PMID- 22946791 TI - High ionic liquid concentration-induced structural change of protein in aqueous solution: a case study of lysozyme. AB - The structural change of chicken egg white lysozyme in aqueous 1-butyl-3 methylimidazolium nitrate ([bmim][NO(3)]) solutions (0-24 M) has been investigated by optical spectroscopy and small-angle X-ray scattering (SAXS) methods. Fourier-transform infrared (FTIR) and circular dichroism (CD) spectra and SAXS profiles indicated that the addition of up to 6 M of [bmim][NO(3)] induces unfolding of lysozyme resulting from disruption of the alpha-helix by the NO(3)(-) ion. On the other hand, even with the addition of more than 10 M of [bmim][NO(3)], lysozyme aggregation is inhibited and the protein adopts a partially globular state (the secondary structure is partially refolded while the tertiary structure is disrupted). Observation of the structural features of the aqueous [bmim][NO(3)] solution by Raman OD stretching spectra indicated that bulk like water still remains at concentrations above 10 M and form an "aggregated water" (water pool) in the nanoheterogeneous structure consisting of a polar domain (the high charge-density region) and nonpolar areas (the alkyl-chain region) in the IL. At these concentrations (above 10 M), lysozyme is not sufficiently hydrated because of the reduced number of water molecules. Consequently lysozyme above 10 M assumes the partially globular state. We propose that the changes of the unique IL solution structure (nanoheterogeneous) between the lower and higher [bmim][NO(3)] concentrations strongly correlated to the differences in the protein stability of the present results. PMID- 22946792 TI - Electrochemical, high-resolution photoemission spectroscopy and vdW-DFT study of the thermal stability of benzenethiol and benzeneselenol monolayers on Au(111). AB - The preparation and thermal stability of benzenethiol and benzeneselenol self assembled monolayers (SAMs) grown on Au(111) have been investigated by electrochemical experiments and high-resolution photoemission spectroscopy. Both techniques confirm the formation of monolayers with high packing densities (theta = 0.27-0.29 ML) and good degrees of order in both cases. Despite many similarities between the two SAMs, the thermal desorption is distinctly different: whereas the benzenethiol SAM desorbs in a single steplike process, the desorption of the benzeneselenol SAM occurs with a much lower activation energy and involves the cleavage of some Se-C bonds and a change in molecular configuration from standing up to lying down. This behavior is explained by considering the different nature of the bonding of the headgroup with the metal surface and with the phenyl ring. Density functional theory calculations show that the breakage of the Se-C bond has a lower activation energy barrier than the breakage of the S-C bond. PMID- 22946793 TI - Ischemic injury promotes Keap1 nitration and disturbance of antioxidative responses in endothelial cells: a potential vasoprotective effect of melatonin. AB - Clinical epidemiology has indicated that the endothelial injury is a potential contributor to the pathogenesis of ischemic neurovascular damage. In this report, we assessed S-nitrosylation and nitration of Keap1 to identify downstream nitric oxide redox signaling targets into endothelial cells during ischemia. Here, oxygen-glucose deprivation (OGD) exposure initiates the nuclear import of Keap1 in endothelial cells, which interacted with nuclear-localized Nrf2, as demonstrated through co-immunoprecipitation and immunocytochemical assay. Paralleling the ischemia-induced nuclear import of Keap1, increased nitrotyrosine immunoreactivity in endothelial cells was also observed. Consistently, the addition of peroxynitrite provoked nuclear import of Keap1 and a concomitant Nrf2 nuclear import in the endothelial cells. Importantly, pharmacological inhibition of nitrosative stress by melatonin partially inhibited the OGD-induced constitutive nuclear import of Keap1 and subsequently disturbance of Nrf2/Keap1 signaling. Moreover, the effect of melatonin on nitration and S-nitrosylation of keap1 was examined in endothelial cells with 6 hr OGD exposure. Here, we demonstrated that OGD induced tyrosine nitration of Keap1, which was blocked by melatonin treatment, while there were no significant changes in S-nitrosylation of Keap1. The specific amino acid residues of Keap1 involved in tyrosine nitration were identified as Y473 by mass spectrometry. Moreover, the protective role of melatonin against damage to endothelial tight junction integrity was addressed by ZO-1 expression, paralleled with the restored heme oxygenase-1 levels during OGD. Together, our results emphasize that upon nitrosative stress, the protective effect of melatonin on endothelial cells is likely mediated at least in part by inhibition of ischemia-evoked protein nitration of Keap1, hence contributing to relieve the disturbance of Nrf2/Keap1 antioxidative signaling. PMID- 22946794 TI - Meta-analysis suggests choosy females get sexy sons more than "good genes". AB - Female preferences for specific male phenotypes have been documented across a wide range of animal taxa, including numerous species where males contribute only gametes to offspring production. Yet, selective pressures maintaining such preferences are among the major unknowns of evolutionary biology. Theoretical studies suggest that preferences can evolve if they confer genetic benefits in terms of increased attractiveness of sons ("Fisherian" models) or overall fitness of offspring ("good genes" models). These two types of models predict, respectively, that male attractiveness is heritable and genetically correlated with fitness. In this meta-analysis, we draw general conclusions from over two decades worth of empirical studies testing these predictions (90 studies on 55 species in total). We found evidence for heritability of male attractiveness. However, attractiveness showed no association with traits directly associated with fitness (life-history traits). Interestingly, it did show a positive correlation with physiological traits, which include immunocompetence and condition. In conclusion, our results support "Fisherian" models of preference evolution, while providing equivocal evidence for "good genes." We pinpoint research directions that should stimulate progress in our understanding of the evolution of female choice. PMID- 22946795 TI - Runaway sexual selection without genetic correlations: social environments and flexible mate choice initiate and enhance the Fisher process. AB - Female mating preferences are often flexible, reflecting the social environment in which they are expressed. Associated indirect genetic effects (IGEs) can affect the rate and direction of evolutionary change, but sexual selection models do not capture these dynamics. We incorporate IGEs into quantitative genetic models to explore how variation in social environments and mate choice flexibility influence Fisherian sexual selection. The importance of IGEs is that runaway sexual selection can occur in the absence of a genetic correlation between male traits and female preferences. Social influences can facilitate the initiation of the runaway process and increase the rate of trait elaboration. Incorporating costs to choice do not alter the main findings. Our model provides testable predictions: (1) genetic covariances between male traits and female preferences may not exist, (2) social flexibility in female choice will be common in populations experiencing strong sexual selection, (3) variation in social environments should be associated with rapid sexual trait divergence, and (4) secondary sexual traits will be more elaborate than previously predicted. Allowing feedback from the social environment resolves discrepancies between theoretical predictions and empirical data, such as why indirect selection on female preferences, theoretically weak, might be sufficient for preferences to become elaborated. PMID- 22946796 TI - Genetic conflicts, intrinsic male fertility, and ejaculate investment. AB - Few aspects of biology are linked to so many evolutionary conflicts as sperm production and fertilization. Segregation distortion and maternal inheritance of cytoplasmic genes, causing maladapted males, are common sources of variation in the competitive ability of sperm, leading males to vary in their intrinsic fertility. Here, I theoretically analyze the effect of such variation in male intrinsic fertility on ejaculate investment. The model reveals that with increasing variation in male fertility, males should overall spend less resources on their ejaculates. Furthermore, if males differing in intrinsic fertility are able to invest differently in sperm production, there are two contrasting outcomes. Typically, less fertile males should invest more. However, if female mating frequency is relatively low and differences between males relatively large, the most common male genotype should invest more. These results have important consequences both for the understanding of sperm competition strategies as well as for the evolution of female polyandry and female mating preferences. PMID- 22946797 TI - A new Bayesian method for fitting evolutionary models to comparative data with intraspecific variation. AB - Phylogenetic comparative methods that incorporate intraspecific variability are relatively new and, so far, not especially widely used in empirical studies. In the present short article we will describe a new Bayesian method for fitting evolutionary models to comparative data that incorporates intraspecific variability. This method differs from an existing likelihood-based approach in that it requires no a priori inference about species means and variances; rather it takes phenotypic values from individuals and a phylogenetic tree as input, and then samples species means and variances, along with the parameters of the evolutionary model, from their joint posterior probability distribution. One of the most novel and intriguing attributes of this approach is that jointly sampling the species means with the evolutionary model parameters means that the model and tree can influence our estimates of species mean trait values, not just the reverse. In the present implementation, we first apply this method to the most widely used evolutionary model for continuously valued phenotypic trait data (Brownian motion). However, the general approach has broad applicability, which we illustrate by also fitting the lambda model, another simple model for quantitative trait evolution on a phylogeny. We test our approach via simulation and by analyzing two empirical datasets obtained from the literature. Finally, we have implemented the methods described herein in a new function for the R statistical computing environment, and this function will be distributed as part of the 'phytools' R library. PMID- 22946798 TI - Chromosome number evolves independently of genome size in a clade with nonlocalized centromeres (Carex: Cyperaceae). AB - The effects of chromosome rearrangement on genome size are poorly understood. While chromosome duplications and deletions have predictable effects on genome size, chromosome fusion, fission, and translocation do not. In this study, we investigate genome size and chromosome number evolution in 87 species of Carex, one of the most species-rich genera of flowering plants and one that has undergone an exceptionally high rate of chromosome rearrangement. Using phylogenetic generalized least-squares regression, we find that the correlation between chromosome number and genome size in the genus grades from flat or weakly positive at fine phylogenetic scales to weakly negative at deeper phylogenetic scales. The rate of chromosome evolution exhibits a significant increase within a species-rich clade that arose approximately 5 million years ago. Genome size evolution, however, demonstrates a nearly constant rate across the entire tree. We hypothesize that this decoupling of genome size from chromosome number helps explain the high lability of chromosome number in the genus, as it reduces indirect selection on chromosome number. PMID- 22946799 TI - Large-scale candidate gene scan reveals the role of chemoreceptor genes in host plant specialization and speciation in the pea aphid. AB - Understanding the drivers of speciation is critical to interpreting patterns of biodiversity. The identification of the genetic changes underlying adaptation and reproductive isolation is necessary to link barriers to gene flow to the causal origins of divergence. Here, we present a novel approach to the genetics of speciation, which should complement the commonly used approaches of quantitative trait locus mapping and genome-wide scans for selection. We present a large-scale candidate gene approach by means of sequence capture, applied to identifying the genetic changes underlying reproductive isolation in the pea aphid, a model system for the study of ecological speciation. Targeted resequencing enabled us to scale up the candidate gene approach, specifically testing for the role of chemosensory gene families in host plant specialization. Screening for the signature of divergence under selection at 172 candidate and noncandidate loci, we revealed a handful of loci that show high levels of differentiation among host races, which almost all correspond to odorant and gustatory receptor genes. This study offers the first indication that some chemoreceptor genes, often tightly linked together in the genome, could play a key role in local adaptation and reproductive isolation in the pea aphid and potentially other phytophagous insects. Our approach opens a new route toward the functional genomics of ecological speciation. PMID- 22946800 TI - On the scent of standing variation for speciation: behavioral evidence for native sympatric host races of Rhagoletis pomonella (Diptera: Tephritidae) in the southern United States. AB - Standing variation can be critical for speciation. Here, we investigate the origins of fruit odor discrimination for Rhagoletis pomonella underlying the fly's sympatric shift in the northeastern United States from downy hawthorn (Crataegus mollis) to apple (Malus domestica). Because R. pomonella mate on host fruit, preferences for natal fruit volatiles generate prezygotic isolation. Apples emit volatiles that appear to be missing from gas chromatography/electroantennographic detection profiles for flies infesting downy hawthorns, raising the question of how R. pomonella evolved a preference for apple. In the southern United States, R. pomonella attacks several native hawthorns. Behaviorally active volatile blends for R. pomonella infesting southern hawthorns contain the missing apple volatiles, potentially explaining why downy hawthorn flies could have evolved to be sensitive to a blend of apple volatiles. Flight tunnel assays imply that southern hawthorn populations were not the antecedent of a preassembled apple race, as southern flies were not attracted to the apple volatile blend. Instead, behavioral evidence was found for southern host races on native hawthorns, complementing the story of the historical sympatric shift to introduced apple in the North and illustrating how R. pomonella may evolve novel combinations of agonist and antagonist responses to volatiles to use new fruit resources. PMID- 22946801 TI - Where are the wormy mice? A reexamination of hybrid parasitism in the European house mouse hybrid zone. AB - Wormy mice in a hybrid zone have been interpreted as evidence of low hybrid fitness, such that parasites contribute to species separation. However, because of its natural heterogeneity, observations of parasite load must be numerous with good field area coverage. We sampled 689 mice from 107 localities across the Bavaria-Bohemia region of the European house mouse hybrid zone and calculated their hybrid indices using 1401 diagnostic single nucleotide polymorphisms (SNPs). We tested whether hybrids have greater or lesser diversity and load of parasite helminths than additive expectations, performing load analyses on the four most common taxa. We found hybrids have significantly reduced diversity and load of each of the commonest helminths; rarer helminths further support reduced load. Although within-locality comparisons have little power, randomization tests show the repeated pattern is unlikely to be due to local parasite heterogeneity, and simulations show a patch of low parasite diversity is unlikely to fall by chance just so in the field area, such that it produces the observed effects. Our data therefore contradict the idea that helminths reduce hybrid fitness through increased load. We discuss a vicariant Red Queen model that implies immune genes tracking parasites will escape Dobzhansky-Muller incompatibilities, generating hybrid variants untargeted by parasites. PMID- 22946802 TI - The role of ecological constraint in driving the evolution of avian song frequency across a latitudinal gradient. AB - Just as features of the physical and biotic environment constrain evolution of ecological and morphological traits, they may also affect evolution of communication systems. Here we analyze constraints on rates of vocal evolution, using a large dataset of New World avian sister taxa. We show that species breeding in tropical forests sing at generally lower frequencies and across narrower bandwidths than species breeding in open habitats, or at high latitudes. We attribute these restrictions on birdsong frequency to the presence of high frequency insect noise and greater degradation of high-frequency sounds in tropical forests. We fit Ornstein-Uhlenbeck models to show that recent evolution of song frequency has been more greatly constrained in tropical forests than elsewhere, that is, songs have shown less tendency to diverge over time in tropical forests, consistent with inferred acoustic restrictions. In addition, we find that song frequency has evolved more rapidly overall at high latitudes in both forest and open habitats. Besides a larger available sound window, other factors contributing to more rapid divergence at high latitudes may include an overall increased intensity of sexual selection, occupation of more divergent habitats, and the presence of fewer competing species. PMID- 22946803 TI - Correlated evolution of beak morphology and song in the neotropical woodcreeper radiation. AB - Mating signals may diversify as a byproduct of morphological adaptation to different foraging niches, potentially driving speciation. Although many studies have focused on the direct influence of ecological and sexual selection on signal divergence, the role of indirect mechanisms remains poorly understood. Using phenotypic and molecular datasets, we explored the interplay between morphological and vocal evolution in an avian radiation characterized by dramatic beak variation, the Neotropical woodcreepers (Dendrocolaptinae). We found evidence of a trade-off between the rate of repetition of song syllables and frequency bandwidth: slow paced songs had either narrow or wide frequency bandwidths, and bandwidth decreased as song pace increased. This bounded phenotypic space for song structure supports the hypothesis that passerine birds face a motor constraint during song production. Diversification of acoustic characters within this bounded space was correlated with diversification of beak morphology. In particular, species with larger beaks produced slower songs with narrower frequency bandwidths, suggesting that ecological selection on beak morphology influences the diversification of woodcreeper songs. Because songs in turn mediate mate choice and species recognition in birds, these results indicate a broader role for ecology in avian diversification. PMID- 22946804 TI - Genetic divergence is decoupled from ecological diversification in the Hawaiian Nesosydne planthoppers. AB - Adaptive radiation involves ecological shifts coupled with isolation of gene pools. However, we know little about what drives the initial stages of divergence. We study a system in which ecological diversification is found within a chronologically well-defined geological matrix to provide insight into this enigmatic phase of radiation. We tested the hypothesis that a period of geographic isolation precedes ecological specialization in an adaptive radiation of host-specialized Hawaiian planthoppers. We examined population structure and history using mitochondrial and multiple independent microsatellite loci in a species whose geographic distribution on the island of Hawaii enabled us to observe the chronology of divergence in its very earliest stages. We found that genetic divergence is associated with geographic features but not different plant hosts and that divergence times are very recent and on the same timescales as the dynamic geology of the island. Our results suggest an important role for geography in the dynamics of the early stages of divergence. PMID- 22946805 TI - Colonization history and population genetics of the color-polymorphic Hawaiian happy-face spider Theridion grallator (Araneae, Theridiidae). AB - Past geological and climatological processes shape extant biodiversity. In the Hawaiian Islands, these processes have provided the physical environment for a number of extensive adaptive radiations. Yet, single species that occur throughout the islands provide some of the best cases for understanding how species respond to the shifting dynamics of the islands in the context of colonization history and associated demographic and adaptive shifts. Here, we focus on the Hawaiian happy-face spider, a single color-polymorphic species, and use mitochondrial and nuclear allozyme markers to examine (1) how the mosaic formation of the landscape has dictated population structure, and (2) how cycles of expansion and contraction of the habitat matrix have been associated with demographic shifts, including a "quantum shift" in the genetic basis of the color polymorphism. The results show a marked structure among populations consistent with the age progression of the islands. The finding of low genetic diversity at the youngest site coupled with the very high diversity of haplotypes on the slightly older substrates that are highly dissected by recent volcanism suggests that the mosaic structure of the landscape may play an important role in allowing differentiation of the adaptive color polymorphism. PMID- 22946806 TI - Species delimitation with ABC and other coalescent-based methods: a test of accuracy with simulations and an empirical example with lizards of the Liolaemus darwinii complex (Squamata: Liolaemidae). AB - Species delimitation is a major research focus in evolutionary biology because accurate species boundaries are a prerequisite for the study of speciation. New species delimitation methods (SDMs) can accommodate nonmonophyletic species and gene tree discordance as a result of incomplete lineage sorting via the coalescent model, but do not explicitly accommodate gene flow after divergence. Approximate Bayesian computation (ABC) can incorporate gene flow and estimate other relevant parameters of the speciation process while testing alternative species delimitation hypotheses. We evaluated the accuracy of BPP, SpeDeSTEM, and ABC for delimiting species using simulated data and applied these methods to empirical data from lizards of the Liolaemus darwinii complex. Overall, BPP was the most accurate, ABC showed an intermediate accuracy, and SpeDeSTEM was the least accurate under most simulated conditions. All three SDMs showed lower accuracy when speciation occurred despite gene flow, as found in previous studies, but ABC was the method with the smallest decrease in accuracy. All three SDMs consistently supported the distinctness of southern and northern lineages within L. darwinii. These SDMs based on genetic data should be complemented with novel SDMs based on morphological and ecological data to achieve truly integrative and statistically robust approaches to species discovery. PMID- 22946807 TI - Multilocus coalescence analyses support a mtDNA-based phylogeographic history for a widespread Palearctic passerine bird, Sitta europaea. AB - Our understanding of species phylogeography in much of the Palearctic is incomplete. In addition, many existing studies based solely on mitochondrial DNA (mtDNA) can provide a biased view of phylogeographic history because of the effects of lineage sorting, natural selection, or hybridization. We analyzed 13 introns to assess a mtDNA study of the Eurasian nuthatch (Sitta europaea) that suggested a seemingly contemporaneous origin of distinct taxa in the Caucasus, Europe, and Asia. Neutrality tests showed no evidence of selection on either the mtDNA or nuclear sequences. Most nuclear gene trees, except for Z-linked ones, did not recover the three lineages, which we attribute to recent splitting. Analyses of the 13 introns combined revealed the same three groups as did the mtDNA and suggested that nuthatches experienced a trichotomous (or two indistinguishable) split(s) 1-2 million years ago (Mya) and have remained isolated with trifling if not zero gene flow since then, and the Asian group increased in population size. This result demonstrates the usefulness of mtDNA in discovering phylogeographic patterns. The use of multiple nuclear loci facilitated detection of an introgressed individual and improved estimates of process parameters such as divergence time and population expansion. We recommend that phylogeographic studies should be based on both mtDNA and nuclear genes. PMID- 22946808 TI - Patterns of genetic variation in desiccation tolerance in embryos of the terrestrial-breeding frog, Pseudophryne guentheri. AB - Environmental change often requires evolutionary responses, and therefore understanding the genetic architecture of susceptible populations is essential for predicting their capacity to respond adaptively. However, quantitative genetic studies are rarely targeted at populations considered vulnerable to such environmental perturbations. Here, we assess the level of heritable variation in the ability of embryos to tolerate desiccation stress in Pseudophryne guentheri, a terrestrial-breeding frog that is currently experiencing a drying climate. We applied a North Carolina II breeding design to identify sources of genetic and environmental variance, and genotype-by-environment interactions (GEIs), underlying the expression of embryo survival, hatching times, hatchling mass, size, and shape. Our analysis revealed highly significant effects of water potential and maternal effects on all measured traits, while additive genetic effects were significant for hatchling shape, and nonadditive effects were observed for embryo survival. Interestingly, GEIs, including for some traits complex three-way sire-by-dam-by-environment interactions, were significant, indicating that progeny from certain male-female crosses were more tolerant to water stress than others. These findings suggest a limited capacity of P. guentheri to respond to a drying climate, but also reveal that the detrimental effects of nonviable male-female crosses (i.e., genetic incompatibility) can be masked in benign environments. PMID- 22946809 TI - Deficiency screening for genomic regions with effects on environmental sensitivity of the sensory bristles of Drosophila melanogaster. AB - Environmental canalization is defined as a reduction in the effect of external environmental perturbations on a phenotype, while phenotypic plasticity is defined as the production of different phenotypes in alternative environments. These terms describe different aspects of the same phenomenon, that is, the sensitivity of the phenotype to the environment. Genetic regulation of the environmental sensitivity has been a central topic in the field of evolutionary biology. In this study, we performed deficiency screening to detect genomic regions with effects on the environmental sensitivity of Drosophila melanogaster sensory bristles. We used a collection of isogenic deficiency strains established by the DrosDel Project for screening. We screened 423 genomic deficiencies that encompassed approximately 63.6% of the entire D. melanogaster genome. We identified 29 genomic deficiencies showing significant effects on environmental sensitivity, suggesting that multiple genomic regions may influence phenotypic variation. We also found significant correlations among the effects of deficiencies on environmental sensitivity for different bristle traits, suggesting that the same genetic mechanism can regulate environmental sensitivity of multiple traits. Current high-resolution mapping will facilitate the examination of individual candidate genes using mutations or RNAi approaches in future studies. PMID- 22946810 TI - Phenotypic plasticity facilitates mutational variance, genetic variance, and evolvability along the major axis of environmental variation. AB - Phenotypically plastic genotypes express different phenotypes in different environments, often in adaptive ways. The evolution of phenotypic plasticity creates developmental systems that are more flexible along the trait dimensions that are more plastic, and as a result, we hypothesize that such traits will express greater mutational variance, genetic variance, and evolvability. We develop an explicit gene network model with three components: some genes can receive environmental cues about the adult selective environment, some genes that interact repeatedly to determine each others' final state, and other factors that translate these final expression states into the phenotype. We show that the evolution of phenotypic plasticity is an important determinant of mutational patterns, genetic variance, and evolutionary potential of a population. Phenotypic plasticity tends to lead to populations with greater mutational variance, greater standing genetic variance, and, when the optimal phenotypes of two traits vary in concert, greater mutational and genetic correlations. However, plastic populations do not tend to respond much more rapidly to selection than do populations evolved in a static environment. We find that the quantitative genetic descriptions of traits created by explicit developmental network models are evolutionarily labile, with genetic correlations that change rapidly with shifts in the selection regime. PMID- 22946811 TI - Life-history evolution in guppies VIII: the demographics of density regulation in guppies (Poecilia reticulata). AB - In prior research, we found the way guppy life histories evolve in response to living in environments with a high or low risk of predation is consistent with life-history theory that assumes no density dependence. We later found that guppies from high-predation environments experience higher mortality rates than those from low-predation environments, but the increased risk was evenly distributed across all age/size classes. Life-history theory that assumes density independent population growth predicts that life histories will not evolve under such circumstances, yet we have shown with field introduction experiments that they do evolve. However, theory that incorporates density regulation predicts this pattern of mortality can result in the patterns of life-history evolution we had observed. Here we report on density manipulation experiments performed in populations of guppies from low-predation environments to ask whether natural populations normally experience density regulation and, if so, to characterize the short-term demographic changes that underlie density regulation. Our experiments reveal that these populations are density regulated. Decreased density resulted in higher juvenile growth, decreased juvenile mortality rates, and increased reproductive investment by adult females. Increased density causes reduced offspring size, decreased fat storage by adult females, and increased adult mortality. PMID- 22946812 TI - Predicting the response to simultaneous selection: genetic architecture and physiological constraints. AB - A great deal is known about the evolutionary significance of body size and development time. They are determined by the nonlinear interaction of three physiological traits: two hormonal events and growth rate (GR). In this study we investigate how the genetic architecture of the underlying three physiological traits affects the simultaneous response to selection on the two life-history traits in the hawkmoth Manduca sexta. The genetic architecture suggests that when the two life-history traits are both selected in the same direction (to increase or decrease) the response to selection is primarily determined by the hormonal mechanism. When the life-history traits are selected in opposite directions (one to increase and one to decrease) the response to selection is primarily determined by factors that affect the GR. To determine how the physiological traits affect the response to selection of the life-history traits, we simulated the predicted response to 10 generations of selection. A total of 83% of our predictions were supported by the simulation. The main components of this physiological framework also exist in unicellular organisms, vertebrates, and plants and can thus provide a robust framework for understanding how underlying physiology can determine the simultaneous evolution of life-history traits. PMID- 22946813 TI - Late paleozoic fusulinoidean gigantism driven by atmospheric hyperoxia. AB - Atmospheric hyperoxia, with pO(2) in excess of 30%, has long been hypothesized to account for late Paleozoic (360-250 million years ago) gigantism in numerous higher taxa. However, this hypothesis has not been evaluated statistically because comprehensive size data have not been compiled previously at sufficient temporal resolution to permit quantitative analysis. In this study, we test the hyperoxia-gigantism hypothesis by examining the fossil record of fusulinoidean foraminifers, a dramatic example of protistan gigantism with some individuals exceeding 10 cm in length and exceeding their relatives by six orders of magnitude in biovolume. We assembled and examined comprehensive regional and global, species-level datasets containing 270 and 1823 species, respectively. A statistical model of size evolution forced by atmospheric pO(2) is conclusively favored over alternative models based on random walks or a constant tendency toward size increase. Moreover, the ratios of volume to surface area in the largest fusulinoideans are consistent in magnitude and trend with a mathematical model based on oxygen transport limitation. We further validate the hyperoxia gigantism model through an examination of modern foraminiferal species living along a measured gradient in oxygen concentration. These findings provide the first quantitative confirmation of a direct connection between Paleozoic gigantism and atmospheric hyperoxia. PMID- 22946814 TI - On the reversibility of mandibular symphyseal fusion. AB - Experimental and comparative studies suggest that a major determinant of increased ossification of the mandibular symphysis is elevated masticatory stress related to a mechanically challenging diet. However, the morphology of this joint tracks variation in dietary properties in only some mammalian clades. Extant anthropoid primates are a notable exception: synostosis is ubiquitous in this speciose group, despite its great age and diverse array of feeding adaptations. One possible explanation for this pattern is that, once synostosis evolves, reversion to a lesser degree of fusion is unlikely or even constrained. If correct, this has important implications for functional and phylogenetic analyses of the mammalian feeding apparatus. To test this hypothesis, we generated a molecular tree for 76 vespertilionoid and noctilionoid chiropterans using Bayesian phylogenetic analysis and examined character evolution using parsimony and likelihood ancestral-state reconstructions along with the binary state speciation and extinction (BiSSE) model. Results indicate that reversals have occurred within Vespertilionoidea. In contrast, noctilionoids exhibit an anthropoid-like pattern, which suggests that more detailed comparisons of the functional and developmental bases for fusion in these bat clades may provide insight into why fusion is maintained in some lineages but not in others. Potential functional and developmental explanations for the lack of reversal are discussed. PMID- 22946815 TI - A test of the hypothesis that correlational selection generates genetic correlations. AB - Theory predicts that correlational selection on two traits will cause the major axis of the bivariate G matrix to orient itself in the same direction as the correlational selection gradient. Two testable predictions follow from this: for a given pair of traits, (1) the sign of correlational selection gradient should be the same as that of the genetic correlation, and (2) the correlational selection gradient should be positively correlated with the value of the genetic correlation. We test this hypothesis with a meta-analysis utilizing empirical estimates of correlational selection gradients and measures of the correlation between the two focal traits. Our results are consistent with both predictions and hence support the underlying hypothesis that correlational selection generates a genetic correlation between the two traits and hence orients the bivariate G matrix. PMID- 22946816 TI - Ergosterol biosynthesis: a fungal pathway for life on land? AB - Sterols, essential lipids of most eukaryotic cells, ensure important structural and signaling functions. The selection pressure that has led to different dominant sterols in the three eukaryotic kingdoms remains unknown. Here, we investigated the influence of the progression in the different steps of the ergosterol biosynthetic pathway (EBP) on the yeast resistance to transitions from aqueous to aerial media, typical perturbations of the higher fungi habitats. Five mutants of the EBP (ergDelta), accumulating different sterol intermediates in the EBP, and the wild-type (WT) strain were exposed to drying under atmospheric air or nitrogen and wetting. Results show that the progression in the EBP parallels an increase in the yeast resistance to air-drying with a maximal survival rate for the WT strain. When drying/wetting was performed under nitrogen, yeast survival was higher, particularly for the earlier mutants of the EBP. Thus, ergosterol, through its protective role against mechanical and oxidative stress, might have been selected by the pressure induced by drying/wetting cycles occurring in the fungi habitats. These results support the Bloch hypothesis, which postulates that the properties of sterols are gradually optimized for function along the biosynthetic pathway and provide a response to the enduring question "why ergosterol in fungi?". PMID- 22946817 TI - Unexpectedly many extinct hominins. AB - Recent studies indicate that Neanderthal and Denisova hominins may have been separate species, while debate continues on the status of Homo floresiensis. The decade-long debate between "splitters," who recognize over 20 hominin species, and "lumpers," who maintain that all these fossils belong to just a few lineages, illustrates that we do not know how many extinct hominin species to expect. Here, we present probability distributions for the number of speciation events and the number of contemporary species along a branch of a phylogeny. With estimates of hominin speciation and extincton rates, we then show that the expected total number of extinct hominin species is 8, but may be as high as 27. We also show that it is highly unlikely that three very recent species disappeared due to natural, background extinction. This may indicate that human-like remains are too easily considered distinct species. Otherwise, the evidence suggesting that Neanderthal and the Denisova hominin represent distinct species implies a recent wave of extinctions, ostensibly driven by the only survivor, H. sapiens. PMID- 22946818 TI - Parental genetic effects in a cavefish adaptive behavior explain disparity between nuclear and mitochondrial DNA. AB - Epigenetic parental genetic effects are important in many biological processes but their roles in the evolution of adaptive traits and their consequences in naturally evolving populations remain to be addressed. By comparing two divergent blind cave-dwelling cavefish populations with a sighted surface-dwelling population (surface fish) of the teleost Astyanax mexicanus, we report here that convergences in vibration attraction behavior (VAB), the lateral line sensory receptors underlying this behavior, and the feeding benefits of this behavior are controlled by parental genetic effects, either maternal or paternal inheritance. From behavioral studies and mathematical evolutionary simulations, we further demonstrate that disparity in nuclear and mitochondrial DNA in one of these cavefish populations that has hybridized with surface fish can be explained by paternal inheritance of VAB. The results suggest that parental genetic effects in adaptive behaviors may be important factors in biasing mitochondrial DNA inheritance in natural populations that are subject to introgression. PMID- 22946819 TI - Algae for biofuel: will the evolution of weeds limit the enterprise? AB - Algae hold promise as a source of biofuel. Yet, the manner in which algae are most efficiently propagated and harvested is different from that used in traditional agriculture. In theory, algae can be grown in continuous culture and harvested frequently to maintain high yields with a short turnaround time. However, the maintenance of the population in a state of continuous growth will likely impose selection for fast growth, possibly opposing the maintenance of lipid stores desirable for fuel. Any harvesting that removes a subset of the population and leaves the survivors to establish the next generation may quickly select traits that escape harvesting. An understanding of these problems should help identify methods for retarding the evolution and enhancing biofuel production. PMID- 22946821 TI - Identifying personality-related problems in living: the multi-context problems checklist. AB - The Multi-Context Problems Checklist (MCPC) is a new measure of personality related problems designed for a young adult population. Previously published problem checklists either have little supporting empirical documentation to support their validity or focus on specific kinds of difficulties in specific contexts (e.g., interpersonal, close relationships). The MCPC is a straightforward and easy-to-use instrument covering 6 domains of functioning, takes about 5 minutes to complete, and is intended for young adults ages 18 to 29. Psychometric data are presented in 3 studies. In Study 1, correlations with self- and observer ratings showed scores on the MCPC to be consensually valid, and associations with measures of well-being and personality provided evidence of construct validity. Study 2 added to these findings by identifying specific personality-related problems associated with each pole of each trait of the five factor model of personality, demonstrating moderate to high test-retest reliability of problem endorsements, and showing strong associations with measures of psychological distress. Study 3 indicated that the MCPC is sufficiently sensitive to capture more frequent problem reporting among individuals undergoing counseling. Problem-trait associations are related to a broader literature on global personality dimensions and psychosocial outcomes at the individual, interpersonal, and social and institutional levels. The MCPC deserves attention from both researchers and clinicians who are interested in assessing personality-related problems in living. PMID- 22946822 TI - Concomitant medication among persistent opioid users with chronic non-malignant pain. AB - BACKGROUND: Recent guidelines for opioid treatment of chronic non-malignant pain discourage co-medication with benzodiazepines and benzodiazepine-related hypnotics, whereas co-medication with non-opioid analgesics and co-analgesics may offer a beneficial opioid sparing effect, and is recommended. The aim of this study was to describe 1-year periodic prevalence of co-medication with benzodiazepines, benzodiazepine-related hypnotics, non-opioid analgesics, co analgesics and antidepressants in persistent opioid users with chronic non malignant pain. METHODS: The study is based on data from the Norwegian Prescription Database, covering all drugs dispensed to outpatients in 2008. Concomitant medication levels were compared between users in two definitions of persistent opioid use, all Norwegian adults dispensed opioids in 2008 and the Norwegian background population. RESULTS: Of the Norwegian adult population studied, 1.2% met the criteria of persistent opioid use based on prescription pattern and prescription level. Sixty percent of persistent opioid users were dispensed a benzodiazepine or benzodiazepine-related hypnotic in amounts indicating regular use, with 15% dispensed a high amount of both classes. Sixty two percent of persistent opioid users were dispensed one or more non-opioid analgesics, 47% an antidepressant and 33% were dispensed an antiepileptic drug. CONCLUSION: Approximately 60% of persistent opioid users also receive benzodiazepines or benzodiazepine-related hypnotics in amounts indicating regular use. This is in conflict with recent guidelines for the treatment of chronic non malignant pain and may indicate that these users are at an increased risk of developing problematic opioid use. PMID- 22946824 TI - Combination of gas-phase fractionation and MS3 acquisition modes for relative protein quantification with isobaric tagging. AB - Relative quantification of peptides and proteins with isobaric tags such as iTRAQ or TMT is commonly used in comparative quantitative proteomics based on tandem mass spectrometry (MS/MS). Nonetheless, isobaric tagging inherently suffers from the cofragmentation/interference phenomenon that may compromise the quality of the quantitative data. An MS(3) acquisition mode has been recently proposed to address this issue. Because of the additional ion isolation and fragmentation step, the MS(3) acquisition mode significantly alleviates this interference effect. However, MS(3) acquisition exhibits a lower sensitivity and a higher duty cycle, both of which reduce the number of identified and quantified proteins. In the present study, we evaluated the combination of gas-phase fractionation (GPF) and MS(3) acquisition modes to optimize both identification and quantification of tryptic peptides labeled with TMT using a hybrid ion trap-orbitrap (LTQ-OT) instrument. An interference model was used where TMT-labeled human plasma proteolytic digests were spiked with TMT-labeled E. coli proteolytic digests. When combined with GPF, the MS(3) acquisition mode was compared with MS(2) modes such as high-energy collision dissociation (HCD) and combined collision-induced dissociation (CID)/HCD. We demonstrated the benefit of using both GPF and MS(3) to analyze tryptic peptides labeled with TMT in terms of quantification precision and accuracy as well as proteome coverage. We further explored parameters such as the influence of automatic gain control and additional MS(3) scans. The TMT-GPF MS(3) workflow was shown to be a powerful alternative for quantitative proteomic studies that offers improved identification/quantification accuracy and enhanced proteome coverage without the need for extensive sample fractionation before MS analysis. PMID- 22946823 TI - Regulation of SOD2 in cancer by histone modifications and CpG methylation: closing the loop between redox biology and epigenetics. AB - SIGNIFICANCE: Manganese superoxide dismutase (SOD2), encoded by the nuclear gene SOD2, is a critical mitochondrial antioxidant enzyme whose activity has broad implications in health and disease. Thirty years ago, Oberley and Buettner elegantly folded SOD2 into cancer biology with the free radical theory of cancer, which was built on the observation that many human cancers had reduced SOD2 activity. In the original formulation, the loss of SOD2 in tumor cells produced a state of perpetual oxidative stress, which, in turn, drove genetic instability, leading to cancer development. RECENT ADVANCES: In the past two decades, research has established that SOD2 transcriptional activity is controlled, at least in part, via epigenetic mechanisms at different stages in the development of human cancer. These mechanisms, which include histone methylation, histone acetylation, and DNA methylation, are increasingly recognized as being aberrantly regulated in human cancer. Indeed, the epigenetic progenitor model proposed by Henikoff posits that epigenetic events are central governing agents of carcinogenesis. Important recent advances in epigenetics research have indicated that the loss of SOD activity itself may contribute to changes in epigenetic regulation, establishing a vicious cycle that drives further epigenetic instability. CRITICAL ISSUES: With these observations in mind, we propose an epigenetic revision to the free radical theory of cancer: that loss of SOD activity promotes epigenetic aberrancies, driving the epigenetic instability in tumor cells which produces broad phenotypic effects. FUTURE DIRECTIONS: The development of next-generation sequencing technologies and novel approaches in systems biology and bioinformatics promise to make testing this exciting model a reality in the near future. PMID- 22946825 TI - Synthesis and optical properties of phenylene-containing oligoacenes. AB - Synthesis of a new class of fully unsaturated ladder structures, phenylene containing oligoacenes (POAs), using 3,4-bis(methylene)cyclobutene as a building block for sequential Diels-Alder reactions is described. The geometric effects of strain and energetic cost of antiaromaticity can be observed via the optical and electrochemical properties of the reported compounds. The resulting shape persistant ladder structures contain neighboring chromophores that are partially electronically isolated from one another while still undergoing a reduction in the band gap of the material. PMID- 22946826 TI - An almost pragmatic trial for COPD screening. PMID- 22946827 TI - The responses of multiple cytokines following incubation of whole blood from TB patients, latently infected individuals and controls with the TB antigens ESAT-6, CFP-10 and TB7.7. AB - The development of clinically relevant biomarkers is important for diagnosing latent tuberculosis infection (LTBI) and active tuberculosis (TB) and predicting their prognoses. This study examined whether the responses of multiple cytokines can be used as a biomarker to distinguish the TB infection status and mycobacterial load. We analysed the responses of multiple cytokines (IFN-gamma, IL-2, IL-10, IL-13, IL-17 and TNF-alpha) in the supernatant from the QuantiFERON TB Gold In-Tube assay following stimulation of whole blood from the TB group (n = 32), LTBI group (n = 19) and healthy controls (n = 30) with TB antigens (ESAT-6, CFP-10 and TB7.7). The median responses of IFN-gamma, IL-2, IL-10 and IL-13 were higher in the LTBI and active TB groups than in the non-TB control group (IFN gamma, P < 0.001; IL-2, P < 0.001; IL-10, P = 0.012; IL-13, P < 0.001). The median IL-2/IFN-gamma ratio of the LTBI group was higher than that of the active TB group (P = 0.014) and differed significantly between patients with LTBI, patients with smear-negative TB and patients with smear-positive TB (P = 0.027). This difference was especially evident between the patients with LTBI and patients with smear-positive TB (P = 0.047). In conclusion, IFN-gamma, IL-2, IL 10 and IL-13 can serve as biomarkers for distinguishing TB infection. In addition, the IL-2/IFN-gamma ratio appears to be a biomarker for diagnosing LTBI and may be useful as a prognostic factor and for evaluating treatment responses. PMID- 22946828 TI - Total synthesis of (-)-sessilifoliamide J. AB - An efficient synthesis of the Stemona alkaloid (-)-sessilifoliamide J (1) in 12 steps and 7.7% overall yield from the known building block 8 is presented. The synthesis features the Corey lactonization reaction and a highly diastereoselective alpha-methylation reaction to build the spiro-lactone moiety. PMID- 22946829 TI - The role of multiscale roughness in the Lotus effect: is it essential for super hydrophobicity? AB - The role of multiscale (hierarchical) roughness in optimizing the structure of nonwettable (superhydrophobic) solid surfaces was theoretically studied for 2D systems of a drop on three different types of surface topographies with up to four roughness scales. The surface models considered here were sinusoidal, flat top pillars, and triadic Koch curves. Three criteria were used to compare between the various topographies and roughness scales. The first is the transition contact angle (CA) between the Wenzel (W) and Cassie-Baxter (CB) wetting states, above which the CB state is the thermodynamically stable one. The second is the solid-liquid (wetted) interfacial area, as an indicator for the ease of roll-off of a drop from the superhydrophobic surfaces. The third is the protrusion height that reflects the mechanical stability of the surface against breakage. The results indicate that multiscale roughness per se is not essential for superhydrophobicity; however, it mainly decreases the necessary protrusion height. Thus, multiscale roughness is beneficial for the Lotus effect mostly with regard to mechanical stability. The sinusoidal topography with three levels of roughness scales is best for nonwettability out of the topographies studied here. This observation may partially explain why Nature chose rounded-top protrusions, such as those on the Lotus leaf. The least useful topography is the flat-top pillars with three roughness scales. In the case of the triadic Koch topography, four roughness scales are required to have nonwettable surface. PMID- 22946830 TI - Letter to the editor: Charting the course forward: promising trends in health behavior theory application. PMID- 22946831 TI - The role of attitude functions, efficacy, anticipated emotions, and relationship status on college students' condom use intentions. AB - Conducted from the reasoned action perspective, previous research related to condom use generally included a limited number of variables and treated attitudes and self-efficacy as unidimensional constructs. Informed by attitude functions theory and health literature on condom use and anticipated emotions, this project aims to provide a more detailed understanding of college students' intentions to use condoms during sexual intercourse. Results show that relationship status moderated the relationships between several psychological variables and condom use intentions. For female college students negative anticipated emotions were a stronger predictor of condom use intentions for those in monogamous relationships for three months or longer than for those in other relationships or not in a relationship. On the other hand, subjective norms were a stronger predictor of intentions for those in other types of relationship or not in a relationship than for those in a monogamous relationship for three months or longer. For male participants, sexual sensation was a more important, negative predictor of condom use intentions among those in monogamous relationships for three months or longer (versus other relationship status or not in a relationship). Both theoretical and practical implications are discussed. PMID- 22946833 TI - SULT1A inhibition and how a migraine stops. PMID- 22946832 TI - Errata in "Triptan exposure during pregnancy and the risk of major congenital malformations and adverse pregnancy outcomes: results from the norwegian mother and child cohort study". PMID- 22946834 TI - Topiramate-valproate-induced encephalopathy in migraine. PMID- 22946835 TI - Emerging role of polymorphisms of the MTHFR gene in systemic carcinogenesis besides their role in migraines. PMID- 22946836 TI - In defense of butalbital. PMID- 22946837 TI - Bleeding in pregnancy caused by condyloma acuminatum of the cervix. PMID- 22946838 TI - Darwinian behavior in a cold, sporadically fed pool of ribonucleotides. AB - A testable, explicit origin for Darwinian behavior, feasible on a chaotic early Earth, would aid origins discussion. Here I show that a pool receiving unreliable supplies of unstable ribonucleotide precursors can recurrently fill this role. By using numerical integration, the differential equations governing a sporadically fed pool are solved, yielding quantitative constraints for the proliferation of molecules that also have a chemical phenotype. For example, templated triphosphate nucleotide joining is >10(4) too slow, suggesting that a group more reactive than pyrophosphate activated primordial nucleotides. However, measured literature rates are sufficient if the Initial Darwinian Ancestor (IDA) resembles a 5'-5' cofactor-like dinucleotide RNA, synthesized via activation with a phosphorimidazolide-like group. A sporadically fed pool offers unforeseen advantages; for example, the pool hosts a novel replicator which is predominantly unpaired, even though it replicates. Such free template is optimized for effective selection during its replication. Pool nucleotides are also subject to a broadly based selection that impels the population toward replication, effective selection, and Darwinian behavior. Such a primordial pool may have left detectable modern traces. A sporadically fed ribonucleotide pool also fits a recognizable early Earth environment, has recognizable modern descendants, and suits the early shape of the phylogenetic tree of Earthly life. Finally, analysis points to particular data now needed to refine the hypothesis. Accordingly, a kinetically explicit chemical hypothesis for a terran IDA can be justified, and informative experiments seem readily accessible. PMID- 22946839 TI - Highly selective and sensitive fluorescent paper sensor for nitroaromatic explosive detection. AB - Rapid, sensitive, and selective detection of explosives such as 2,4,6 trinitrotoluene (TNT) and 2,4,6-trinitrophenol (TNP), especially using a facile paper sensor, is in high demand for homeland security and public safety. Although many strategies have been successfully developed for the detection of TNT, it is not easy to differentiate the influence from TNP. Also, few methods were demonstrated for the selective detection of TNP. In this work, via a facile and versatile method, 8-hydroxyquinoline aluminum (Alq(3))-based bluish green fluorescent composite nanospheres were successfully synthesized through self assembly under vigorous stirring and ultrasonic treatment. These polymer-coated nanocomposites are not only water-stable but also highly luminescent. Based on the dramatic and selective fluorescence quenching of the nanocomposites via adding TNP into the aqueous solution, a sensitive and robust platform was developed for visual detection of TNP in the mixture of nitroaromatics including TNT, 2,4-dinitrotoluene (DNT), and nitrobenzene (NB). Meanwhile, the fluorescence intensity is proportional to the concentration of TNP in the range of 0.05-7.0 MUg/mL with the 3sigma limit of detection of 32.3 ng/mL. By handwriting or finger printing with TNP solution as ink on the filter paper soaked with the fluorescent nanocomposites, the bluish green fluorescence was instantly and dramatically quenched and the dark patterns were left on the paper. Therefore, a convenient and rapid paper sensor for TNP-selective detection was fabricated. PMID- 22946841 TI - Serum metabolic profiling study of hepatocellular carcinoma infected with hepatitis B or hepatitis C virus by using liquid chromatography-mass spectrometry. AB - The objective of the present study was to explore the common and specific metabolic alterations of hepatocellular carcinoma (HCC) infected with hepatitis B virus (HBV) or hepatitis C virus (HCV). Serum profiling data revealed that the two HCC groups shared a mainly similar metabolic profile, providing a basis for investigating their common tumor pathogenesis mechanism and early diagnosis biomarkers. Arachidonic acid as a pro-inflammatory precursor increased significantly in the HCC group compared to the cirrhosis and healthy control. And the lysophosphatidylcholines (lysoPCs) with polyunsaturated fatty acid acyl chain with potent anti-inflammatory activity significantly decreased in the HCC and cirrhosis groups compared to those in the healthy control group, which may partly contribute to maintaining chronic inflammation and benefit the initiation and progression of the malignant hepatic tumor. The decreased ratios of polyunsaturated lysoPCs to saturated lysoPCs in HCC groups compared to chronic liver diseases infected with HBV or HCV and healthy control further demonstrated that a malignant liver tumor exerts profound influences independent of virus infection. Especially, serum endocannabinoids anandamide (AEA) and palmitylethanolamide (PEA) were found significantly elevated in HCC groups compared to healthy control, and in HCC with HCV compared to corresponding chronic liver diseases. AEA, PEA, or their combination showed better sensitivity, specificity, and the area under the curve for distinguishing HCC from chronic liver diseases, showing they are potential biomarkers to distinguish the HCC from cirrhosis infected with HCV. PMID- 22946840 TI - Biocompatible polymeric nanoparticles degrade and release cargo in response to biologically relevant levels of hydrogen peroxide. AB - Oxidative stress is caused predominantly by accumulation of hydrogen peroxide and distinguishes inflamed tissue from healthy tissue. Hydrogen peroxide could potentially be useful as a stimulus for targeted drug delivery to diseased tissue. However, current polymeric systems are not sensitive to biologically relevant concentrations of H(2)O(2) (50-100 MUM). Here we report a new biocompatible polymeric capsule capable of undergoing backbone degradation and thus release upon exposure to such concentrations of hydrogen peroxide. Two polymeric structures were developed differing with respect to the linkage between the boronic ester group and the polymeric backbone: either direct (1) or via an ether linkage (2). Both polymers are stable in aqueous solution at normal pH, and exposure to peroxide induces the removal of the boronic ester protecting groups at physiological pH and temperature, revealing phenols along the backbone, which undergo quinone methide rearrangement to lead to polymer degradation. Considerably faster backbone degradation was observed for polymer 2 over polymer 1 by NMR and GPC. Nanoparticles were formulated from these novel materials to analyze their oxidation triggered release properties. While nanoparticles formulated from polymer 1 only released 50% of the reporter dye after exposure to 1 mM H(2)O(2) for 26 h, nanoparticles formulated from polymer 2 did so within 10 h and were able to release their cargo selectively in biologically relevant concentrations of H(2)O(2). Nanoparticles formulated from polymer 2 showed a 2 fold enhancement of release upon incubation with activated neutrophils, while controls showed a nonspecific response to ROS producing cells. These polymers represent a novel, biologically relevant, and biocompatible approach to biodegradable H(2)O(2)-triggered release systems that can degrade into small molecules, release their cargo, and should be easily cleared by the body. PMID- 22946842 TI - Antitumor activity and structure-activity relationship of diterpenoids with a dehydroabietyl skeleton. AB - A series of novel diterpenoids including imines, amides and ureas with a dehydroabietyl skeleton were screened to hepatocellular carcinoma (SMMC-7721), lung cancer (A-549), glioma (C-6) and breast carcinoma (MCF-7) tumor cells by MTT method. Their antitumor activity and structure activity relationship were analyzed. Several of the title compounds such as I-2, I-10, I-6 and I-5, possess noticeable antitumor activity against SMMC-7721, A-549, C-6 and MCF-7 tumor cells, with lowest IC(50) values of 6.65, 0.75, 0.81 and 10.65MUM, respectively. Based on the structure-activity relationship investigation, the three kinds of diterpenoids with a dehydroabietyl skeleton show high activity to SMMC-7721 cells. Imines derivatives exhibit broad spectrum and highly efficient activities to the selected four kinds of tumor cells. PMID- 22946844 TI - Growth mechanism and controlled synthesis of AB-stacked bilayer graphene on Cu-Ni alloy foils. AB - Strongly coupled bilayer graphene (i.e., AB stacked) grows particularly well on commercial "90-10" Cu-Ni alloy foil. However, the mechanism of growth of bilayer graphene on Cu-Ni alloy foils had not been discovered. Carbon isotope labeling (sequential dosing of (12)CH(4) and (13)CH(4)) and Raman spectroscopic mapping were used to study the growth process. It was learned that the mechanism of graphene growth on Cu-Ni alloy is by precipitation at the surface from carbon dissolved in the bulk of the alloy foil that diffuses to the surface. The growth parameters were varied to investigate their effect on graphene coverage and isotopic composition. It was found that higher temperature, longer exposure time, higher rate of bulk diffusion for (12)C vs(13)C, and slower cooling rate all produced higher graphene coverage on this type of Cu-Ni alloy foil. The isotopic composition of the graphene layer(s) could also be modified by adjusting the cooling rate. In addition, large-area, AB-stacked bilayer graphene transferrable onto Si/SiO(2) substrates was controllably synthesized. PMID- 22946845 TI - Low-cost synthesis and physical characterization of thieno[3,4-c]pyrrole-4,6 dione-based polymers. AB - The improved synthesis of thieno[3,4-c]pyrrole-4,6-dione (TPD) monomers, including Gewald thiophene ring formation, a Sandmeyer-type reaction, and neat condensation with an amine, is presented. This protocol enables faster, cheaper, and more efficient preparation of TPD units in comparison to traditional methods. Furthermore, a series of TPD homo- and pseudohomopolymers bearing various alkyl chains was synthesized via a direct heteroarylation polymerization (DHAP) procedure. UV-visible absorption and powder X-ray diffraction measurements revealed the relationship between the ratio of branched to linear alkyl chains and the optoelectronic properties of the polymers as well as their packing in the solid state. PMID- 22946843 TI - In vitro optimization of EtNBS-PDT against hypoxic tumor environments with a tiered, high-content, 3D model optical screening platform. AB - Hypoxia and acidosis are widely recognized as major contributors to the development of treatment resistant cancer. For patients with disseminated metastatic lesions, such as most women with ovarian cancer (OvCa), the progression to treatment resistant disease is almost always fatal. Numerous therapeutic approaches have been developed to eliminate treatment resistant carcinoma, including novel biologic, chemo, radiation, and photodynamic therapy (PDT) regimens. Recently, PDT using the cationic photosensitizer EtNBS was found to be highly effective against therapeutically unresponsive hypoxic and acidic OvCa cellular populations in vitro. To optimize this treatment regimen, we developed a tiered, high-content, image-based screening approach utilizing a biologically relevant OvCa 3D culture model to investigate a small library of side-chain modified EtNBS derivatives. The uptake, localization, and photocytotoxicity of these compounds on both the cellular and nodular levels were observed to be largely mediated by their respective ethyl side chain chemical alterations. In particular, EtNBS and its hydroxyl-terminated derivative (EtNBS OH) were found to have similar pharmacological parameters, such as their nodular localization patterns and uptake kinetics. Interestingly, these two molecules were found to induce dramatically different therapeutic outcomes: EtNBS was found to be more effective in killing the hypoxic, nodule core cells with superior selectivity, while EtNBS-OH was observed to trigger widespread structural degradation of nodules. This breakdown of the tumor architecture can improve the therapeutic outcome and is known to synergistically enhance the antitumor effects of front-line chemotherapeutic regimens. These results, which would not have been predicted or observed using traditional monolayer or in vivo animal screening techniques, demonstrate the powerful capabilities of 3D in vitro screening approaches for the selection and optimization of therapeutic agents for the targeted destruction of specific cellular subpopulations. PMID- 22946846 TI - The COPD pipeline XVIII. PMID- 22946847 TI - Retention prediction of peptide diastereomers in reversed-phase liquid chromatography assisted by molecular dynamics simulation. AB - In this study, we explored the relationship between the retention factors and structural flexibilities of peptide diastereomers in reversed-phase chromatography (RPC) based on thermodynamic interpretations. The RPC retention order of antimicrobial peptides, IL-K7F89 (H-ILPWKWKFFPWRR-NH(2)), and its four diastereomers were well correlated with the order of their conformation energies in elution solvent. In particular, when the composition of the sample loading solvent was altered, the retention order changed accordingly. The thermodynamic analysis revealed that the peptide adsorption was driven by adsorption enthalpy, but the retention order was dominated by adsorption entropy. To further understand the relationships between the retention factor and conformation energy, the intramolecular van der Waals energy of peptides and the ordered water molecules associated with peptides were analyzed by all-atom molecular dynamics (MD) simulation. The results showed that the flexible peptide with larger conformation energy had weaker intramolecular hydrophobic interaction and associated with more ordered water molecules. For this peptide diastereomer set, the elution difference is derived by the difference in adsorption entropy gain from repelling the ordered water molecules around the peptide. Consequently, we suggested that the separation of peptide diastereomers could be achieved by RPC, and the elution order could be predicted by their structural flexibilities. PMID- 22946848 TI - An empiric treatment for idiopathic oligozoospermia revisited: a 20-year investigative saga. AB - A series of studies aiming at introducing an effective treatment for idiopathic oligozoospermia was conducted in a step-wise fashion spanning over a 20-year period. The concept was that co-administration of an accessory gland-stimulating androgen, testosterone undecanoate (40 mg t.i.d.) and the FSH raising anti oestrogen tamoxifen citrate (10 mg b.i.d.) may improve sperm parameters. A prerequisite for such an effect was the demonstration that testosterone undecanoate had no suppressing action on pituitary-testicular axis. In this context, initial studies demonstrated no change in basal or stimulated gonadotrophin and testosterone secretion in short- or long-term protocols. Two subsequent trials with this combination showed a marked improvement of sperm parameters and pregnancy incidence, with a seasonal variation noted in response to treatment, this being higher during the cold seasons of autumn and winter. Regarding the mechanism of testosterone undecanoate's action, a recent study from our unit showed that its administration resulted in a marked rise of serum DHT levels. Because this steroid is an epididymal function promoter, it appears that its contribution in the combination is mediated mainly through its DHT raising effect. By and large, this empiric approach for the treatment of idiopathic oligozoospermia was satisfactorily documented after a 20-year investigative saga. PMID- 22946849 TI - Tocotrienol research: past into present. AB - The vitamin E family consists of eight isomers known as alpha-, beta-, gamma-, and delta-tocopherols and alpha-, beta-, gamma-, and delta-tocotrienols. Numerous studies focused on the health benefits of these isomers have been performed since the discovery of vitamin E in 1922. Recent discoveries on the potential therapeutic applications of tocotrienols have revolutionized vitamin E research. Nevertheless, despite the abundance of literature, only 1% of vitamin E research has been conducted on tocotrienols. Many new advances suggest that the use of tocotrienols for health improvement or therapeutic purposes is promising. Although the mechanisms of action of tocotrienols in certain disease conditions have been explored, more detailed investigations into the fundamentals of the health-promoting effects of these molecules must be elucidated before they can be recommended for health improvement or for the treatment or prevention of disease. Furthermore, many of the studies on the effects of tocotrienols have been carried out using cell lines and animal models. The effects in humans must be well established before tocotrienols are used as therapeutic agents in various disease conditions, hence the need for more evidence-based human clinical trials. PMID- 22946851 TI - Current evidence on the associations of breastfeeding, infant formula, and cow's milk introduction with type 1 diabetes mellitus: a systematic review. AB - Current evidence provides contradictory results in regards to the associations of breastfeeding or early introduction of cow's milk and formula with the development of type 1 diabetes (T1D). The aim of this systematic review was to evaluate the type of feeding, duration of breastfeeding, time of introduction of formula or cow's milk, and the potential impact on developing T1D. The literature search was conducted based on the standards outlined in the MOOSE Guidelines for Meta-Analyses and Systematic Reviews of Observational Studies and yielded a total of 161 studies, 28 of which were included in this review. Twenty seven of the included studies were case-control and one was a prospective cohort study. Eight of the studies indicated breastfeeding has a protective role against the development of T1D. Seven additional studies emphasized that a short period or absence of breastfeeding could be a risk factor for T1D development. The results of this systematic review indicate a short duration and/or a lack of breastfeeding may constitute a risk factor for the development of T1D later in life. PMID- 22946852 TI - Vitamin D: an overview of its role in skeletal muscle physiology in children and adolescents. AB - Many children may have insufficient serum concentrations of vitamin D, which could prevent optimal muscle development and function. Vitamin D deficiency in animal models results in negative effects on muscle fiber structure and calcium/phosphorus handling, suggesting an integral role of vitamin D in skeletal muscle function. While there is a dearth of data in humans, the available evidence demonstrates a positive association between vitamin D status and muscle function. This review focuses on the important role of vitamin D in muscle function in children and adolescents who live in North American regions where exposure to ultraviolet B radiation is limited and who are thus at increased risk for vitamin D insufficiency. The effects of vitamin D on muscle cell proliferation and differentiation, muscle fiber structure, and calcium and phosphorus handling are discussed. Moreover, the roles of vitamin D and the vitamin D receptor and their genomic and nongenomic actions in muscle function are explored in depth. Future research should aim to establish a vitamin D status consistent with optimal musculoskeletal development and function in young children. PMID- 22946853 TI - Diverse biological activities of dandelion. AB - Dandelion (Taraxacum officinale Weber) is a member of the Asteraceae (Compositae) family, native to Europe but widely distributed in the warmer temperate zones of the Northern Hemisphere. Dandelion and its parts are habitually consumed as plant foods in several areas of the world, where they are also employed in phytotherapy. Indeed, dandelion contains a wide array of phytochemicals whose biological activities are actively being explored in various areas of human health. In particular, emerging evidence suggests that dandelion and its constituents have antioxidant and anti-inflammatory activities that result in diverse biological effects. The present review provides a comprehensive analysis of the constituents of dandelion, an assessment of the pharmacological properties of dandelion, and a description of relevant studies that support the use of dandelion as a medicinal plant. PMID- 22946850 TI - Associations between flavonoids and cardiovascular disease incidence or mortality in European and US populations. AB - Twenty publications from twelve prospective cohorts have evaluated associations between flavonoid intakes and incidence or mortality from cardiovascular disease (CVD) among adults in Europe and the United States. The most common outcome was coronary heart disease mortality, and four of eight cohort studies reported significant inverse associations for at least one flavonoid class (multivariate adjusted p(trend) < 0.05). Three of seven cohorts reported that greater flavonoid intake was associated with lower risk of incident stroke. Comparisons among the studies were difficult because of variability in the flavonoid classes included, demographic characteristics of the populations, outcomes assessed, and length of follow-up. The most commonly examined flavonoid classes were flavonols and flavones combined (11 studies). Only one study examined all seven flavonoid classes. The flavonol and flavone classes were most strongly associated with lower coronary heart disease mortality. Evidence for protection from other flavonoid classes and CVD outcomes was more limited. The hypothesis that flavonoid intakes are associated with lower CVD incidence and mortality requires further study. PMID- 22946854 TI - Better newborn vitamin D status lowers RSV-associated bronchiolitis in infants. AB - Each year 1.5 million children under the age of 5 years die from pneumonia. In the United States, respiratory syncytial virus (RSV) is the number one cause of bronchiolitis and pneumonia in children under 1 year of age. Low serum 25(OH)D is associated with an increased risk of lower respiratory tract infections (LRTI). Two recent studies have provided important information concerning the association between cord blood 25(OH)D and subsequent risk of developing respiratory infection in very young children. These findings support the need in future studies to determine the extent to which an intervention to change the vitamin D status of mothers during pregnancy can reduce the risk of RSV-associated LRTI in their offspring. An answer to this question would have significant worldwide public health importance given the high prevalence of low vitamin D status worldwide and the high mortality burden accompanying infectious lung diseases in young children. PMID- 22946857 TI - The relationship of tobacco use with gambling problem severity and gambling treatment outcome. AB - This study sought to examine the impact of tobacco use on gambling treatment. Pathological gambling (PG) is a psychiatric condition associated with significant financial, emotional, and psychosocial consequences. Elevated rates of nicotine dependence have been associated with increased gambling severity and more frequent psychiatric problems. A total of 385 treatment-seeking pathological gamblers enrolled in one of 11 gambling treatment providers in Minnesota were assessed. Linear regression modeling was used to examine demographic and clinical variables at treatment entry and the relationship between those variables and the number of days gambled at a 6-month posttreatment. Logistic regression was utilized to assess predictors of treatment completion. Daily tobacco use was reported in 244 (63.4%) subjects. Tobacco users presented with significantly more severe gambling and mental health symptoms at treatment intake. Daily tobacco use, however, was not significantly associated with the number of days gambled or with treatment completion. Although tobacco users present with greater gambling problem severity, they had similar rates of treatment completion and treatment outcomes as nonusers. PMID- 22946856 TI - Through a glass darkly: some insights on change talk via magnetoencephalography. AB - Motivational interviewing (MI) is a directive, client-centered therapeutic method employed in the treatment of substance abuse, with strong evidence of effectiveness. To date, the sole mechanism of action in MI with any consistent empirical support is "change talk" (CT), which is generally defined as client within-session speech in support of a behavior change. "Sustain talk" (ST) incorporates speech in support of the status quo. MI maintains that during treatment, clients essentially talk themselves into change. Multiple studies have now supported this theory, linking within-session speech to substance use outcomes. Although a causal chain has been established linking therapist behavior, client CT, and substance use outcome, the neural substrate of CT has been largely uncharted. We addressed this gap by measuring neural responses to clients' own CT using magnetoencephalography (MEG), a noninvasive neuroimaging technique with excellent spatial and temporal resolution. Following a recorded MI session, MEG was used to measure brain activity while participants heard multiple repetitions of their CT and ST utterances from that session, intermingled and presented in a random order. Results suggest that CT processing occurs in a right hemisphere network that includes the inferior frontal gyrus, insula, and superior temporal cortex. These results support a representation of CT at the neural level, consistent with the role of these structures in self-perception. This suggests that during treatment sessions, clinicians who are able to evoke this special kind of language are tapping into neural circuitry that may be essential to behavior change. PMID- 22946858 TI - Examining the interactive effect of posttraumatic stress disorder, distress tolerance, and gender on residential substance use disorder treatment retention. AB - An extensive body of research has demonstrated that patients with a co-occurring posttraumatic stress disorder (PTSD) and substance use disorder (SUD) diagnosis are at high risk for a wide range of negative clinical outcomes, including treatment noncompletion. However, no studies to date have explored the effect of a PTSD-SUD diagnosis on residential SUD treatment completion, as well as potential moderators of this effect. Consequently, the goal of this study was to examine the interactive effect of a PTSD diagnosis, distress tolerance (DT), and gender on residential SUD treatment retention. Participants were 214 substance dependent patients consecutively admitted to a residential SUD treatment facility. Participants were administered diagnostic interviews, completed a laboratory-based measure of DT, and were followed throughout the course of treatment. Although no significant main effects were found, results did reveal a significant PTSD * gender * DT interaction. Post hoc analyses indicated that, among men, those with a current diagnosis of PTSD and low DT completed a significantly lower proportion of residential SUD treatment compared to all other groups. The implications of the study's findings for identifying ways to improve residential SUD treatment retention among patients with a PTSD-SUD diagnosis are discussed. PMID- 22946859 TI - The effect of state regulatory stringency on nursing home quality. AB - OBJECTIVE: To test the hypothesis that more stringent quality regulations contribute to better quality nursing home care and to assess their cost effectiveness. DATA SOURCES/SETTING: Primary and secondary data from all states and U.S. nursing homes between 2005 and 2006. STUDY DESIGN: We estimated seven models, regressing quality measures on the Harrington Regulation Stringency Index and control variables. To account for endogeneity between regulation and quality, we used instrumental variables techniques. Quality was measured by staffing hours by type per case-mix adjusted day, hotel expenditures, and risk-adjusted decline in activities of daily living, high-risk pressure sores, and urinary incontinence. DATA COLLECTION: All states' licensing and certification offices were surveyed to obtain data about deficiencies. Secondary data included the Minimum Data Set, Medicare Cost Reports, and the Economic Freedom Index. PRINCIPAL FINDINGS: Regulatory stringency was significantly associated with better quality for four of the seven measures studied. The cost-effectiveness for the activities-of-daily-living measure was estimated at about 72,000 in 2011/ Quality Adjusted Life Year. CONCLUSIONS: Quality regulations lead to better quality in nursing homes along some dimensions, but not all. Our estimates of cost-effectiveness suggest that increased regulatory stringency is in the ballpark of other acceptable cost-effective practices. PMID- 22946860 TI - Long-term reproductive outcome after hysteroscopic proximal tubal cannulation--an outcome analysis. AB - BACKGROUND: The optimal therapeutic method for proximal tubal obstruction (PTO) has yet to be defined. In addition, the reported successful recanalisation rate and reproductive outcome from hysteroscopic proximal tubal cannulation have been inconsistent. AIMS: To examine the morbidity and efficacy of laparoscopic hysteroscopic proximal tubal cannulation for treating PTO. MATERIAL AND METHODS: This was a retrospective study evaluating 70 infertile women with PTO who underwent laparoscopic-hysteroscopic proximal tubal cannulation in The Prince of Wales Hospital, a university-affiliated hospital, from January 2005 to December 2010. Demographical data and operative details were reviewed. Women were then contacted by phone and completed a structured questionnaire. Recanalisation rate, intra-operative complication, pregnancy rates and pregnancy outcomes were examined. RESULTS: Fifty women had successful proximal cannulation on at least one side of the tube, providing an overall successful recanalisation rate of 71.4% per woman and 67.0% per tube. The overall pregnancy rate after successful hysteroscopic proximal cannulation of at least one tube is 55%. The overall mean time to become pregnant from natural conception or via clomiphene induction after successful unilateral or bilateral hysteroscopic cannulation was 10.5 +/- 8.9 months. The procedure is associated with minimal morbidity. No prognostic factors were significantly associated with recanalisation and pregnancy rate. CONCLUSION: Laparoscopic-hysteroscopic cannulation for proximal obstruction is a procedure with minimal morbidity and a reasonable successful recanalisation rate. It should be considered as an alternative to in vitro fertilisation. PMID- 22946861 TI - Simultaneous radiotherapy and superficial hyperthermia for high-risk breast carcinoma: a randomised comparison of treatment sequelae in heated versus non heated sectors of the chest wall hyperthermia. AB - PURPOSE: In vitro data demonstrate that heat-induced radiosensitisation is maximised if hyperthermia and radiotherapy are given simultaneously, with the radiation fraction delivered midway through a hyperthermia session, rather than sequentially. The long-term normal tissue toxicity of full-dose simultaneous thermoradiotherapy is unknown. MATERIALS AND METHODS: Patients with locally advanced breast cancer (T3, T4 or more than three involved nodes or local recurrence), no prior radiotherapy, received between four and eight sessions of simultaneous thermoradiotherapy. Hyperthermia always included the primary tumour site. In addition an electively heated sector (EHS) was included. The EHS was randomised to either medial or lateral to the tumour site, with the other side an irradiated but unheated control. As per our usual practice, patients received surgery and/or chemotherapy prior to radiotherapy. Radiation doses were 46-50 Gy followed by a boost of <=16 Gy at 1.8-2 Gy per fraction. EHS and control sectors received the same dose. RESULTS: A total of 57 evaluable cases with average follow-up of 79 months experienced two local and two nodal recurrences. There was no significant difference in >=grade 2 toxicity for heated versus control sectors (LR chi(2 )= 0.78, p = 0.38) with no relationship between number of hyperthermia sessions and toxicity (LR chi(2 )= 2.90, p = 0.09). CONCLUSIONS: Simultaneous full-dose thermoradiotherapy for breast cancer is feasible and well tolerated, with no significant difference in late toxicity between electively heated and unheated control sectors. All patients had hyperthermia to the primary tumour site with excellent local control. PMID- 22946862 TI - Elemental labeling and isotope dilution analysis for the quantification of the peptide hepcidin-25 in serum samples by HPLC-ICP-MS. AB - Hepcidin-25 is a peptide-hormone that has been proposed as the key biomarker for the diagnosis and monitoring of iron disorders. Structurally, hepcidin-25 is a S rich peptide (with 8 cysteines and 1 methionine) that contains a metal binding motif in the N-terminus. That domain binds preferably Cu(II) ion forming a stable complex. Such selective binding can be used as mean to determine hepcidin-25 in biological fluids by highly sensitive Cu measurement. Thus, we use liquid chromatography coupled to inductively coupled plasma mass spectrometry (LC-ICP MS) to perform hepcidin-25 determination via Cu detection. For this purpose, the incubation conditions were optimized to address the complex formation and stability by electrospray-MS (ESI-q-TOF). It was found that Cu:hepcidin-25 complex is stable under physiological conditions and shows an equimolar stoichiometry (1:1). The collisional induced dissociation (CID) experiments confirmed the specific binding of Cu to the N-terminal motif. For Cu quantification, two isotope dilution strategies have been developed. The first one, including postcolumn addition of a (65)Cu spike and the second, by synthesizing the labeled (65)Cu:hepcidin-25 complex as tracer (species-specific). Both methods have been optimized and critically compared in real samples. The determination of hepcidin-25 in different serum samples from healthy individuals based on Cu monitoring showed a mean value of 21.6 ng mL(-1) which is in good agreement to previously published data. PMID- 22946863 TI - Rapid protein global fold determination using ultrasparse sampling, high-dynamic range artifact suppression, and time-shared NOESY. AB - In structural studies of large proteins by NMR, global fold determination plays an increasingly important role in providing a first look at a target's topology and reducing assignment ambiguity in NOESY spectra of fully protonated samples. In this work, we demonstrate the use of ultrasparse sampling, a new data processing algorithm, and a 4-D time-shared NOESY experiment (1) to collect all NOEs in (2)H/(13)C/(15)N-labeled protein samples with selectively protonated amide and ILV methyl groups at high resolution in only four days, and (2) to calculate global folds from this data using fully automated resonance assignment. The new algorithm, SCRUB, incorporates the CLEAN method for iterative artifact removal but applies an additional level of iteration, permitting real signals to be distinguished from noise and allowing nearly all artifacts generated by real signals to be eliminated. In simulations with 1.2% of the data required by Nyquist sampling, SCRUB achieves a dynamic range over 10000:1 (250* better artifact suppression than CLEAN) and completely quantitative reproduction of signal intensities, volumes, and line shapes. Applied to 4-D time-shared NOESY data, SCRUB processing dramatically reduces aliasing noise from strong diagonal signals, enabling the identification of weak NOE crosspeaks with intensities 100* less than those of diagonal signals. Nearly all of the expected peaks for interproton distances under 5 A were observed. The practical benefit of this method is demonstrated with structure calculations for 23 kDa and 29 kDa test proteins using the automated assignment protocol of CYANA, in which unassigned 4 D time-shared NOESY peak lists produce accurate and well-converged global fold ensembles, whereas 3-D peak lists either fail to converge or produce significantly less accurate folds. The approach presented here succeeds with an order of magnitude less sampling than required by alternative methods for processing sparse 4-D data. PMID- 22946864 TI - Evaluation of an educational programme for family members of patients living with heart failure: a randomised controlled trial. AB - AIMS AND OBJECTIVES: To evaluate the effect of a group-based multi-professional educational programme for family members of patients with chronic heart failure with regard to quality of life, depression and anxiety. The secondary aim was to investigate the impact of social support and sense of coherence on changes in quality of life, anxiety and depression during the period of the study. BACKGROUND: When a person is diagnosed with heart failure, the daily life of the family members is also affected. DESIGN: Randomised controlled trial. METHODS: A total of 128 family members were randomly assigned to participate in a multi professional educational programme or a control group. Analysis of variance and regression analysis were used. RESULTS: There were no significant differences in anxiety, depression or quality of life between the intervention group and control group. Adequacy of social network was the only independent variable that explained levels of anxiety and depression after 12 months beyond baseline levels of anxiety (p < 0.001, R(2) = 0.35) and depression (p = 0.021, R(2) = 0.37). Younger family members were found to have a higher quality of life (p < 0.01). CONCLUSION: Improved disease-related knowledge may need to be combined with other target variables to induce desired effects on depression, anxiety and quality of life of family members. Antecedents of depression and anxiety, such as sense of control, may need to be specifically targeted. Our results also suggest that intervention aimed at enhancing social support may be beneficial for family members. RELEVANCE TO CLINICAL PRACTICE: Anxiety and depression did not decrease nor did quality of life improve after the intervention. An educational programme for family members with a component specifically targeting anxiety, depression and quality of life warrants testing. Furthermore, it is important that health care providers understand the influence of social support on anxiety, depression and quality of life when interacting with family members. PMID- 22946865 TI - Use of antiplatelet therapy after percutaneous coronary intervention with bare metal stents and different types of drug-eluting stents. AB - Dual antiplatelet therapy (DAPT) with a thienopyridine and aspirin has been the standard of care post coronary stent implantation. DAPT has been shown to reduce the risk of stent thrombosis (ST) and complications of myocardial infarction and death after placement of a drug-eluting stent (DES) and bare-metal stent (BMS). This article reviews the available clinical efficacy and safety data of antiplatelet therapies. The aim of this review is to highlight not only the importance of antiplatelets in the prevention of early and late thrombosis but also emphasize the importance of newer more potent antiplatelet agents and their role in the setting of clopidogrel resistance. MEDLINE, and EMBASE were searched for studies related to the clinical efficacy and safety of antiplatelet therapy after DES and BMS placement using the terms dual antiplatelet therapy, thienopyridine, aspirin, clopidogrel, prasugrel, ticagrelor,elinogrel, bare-metal stents, drug-eluting stent, stent thrombosis and myocardial infarction. PMID- 22946866 TI - Neglected aspects of drug discovery--microbiological aspects. AB - Developing new, efficient drugs is a long and costly process. However, although a failure to establish new drugs can in part be related to lack of funding, often it is also associated with various deficiencies in current approaches to drug development. Chemical and genetic validation, in addition to estimating future drug resistance, are considered critical for predicting the therapeutic efficacy of a compound. However, such approaches, when employed to decide upon further investigation or rejection of a candidate drug, often ignore several factors. These are: (i) the possibility of successful treatment by rejected drugs - compounds used in the past that individually are no longer effective because of resistance but are useful in combination; (ii) synergy between drugs that are not necessarily directed against the pathogen; (iii) drugs that can attenuate immune or inflammatory responses and consequently can alleviate clinical symptoms that are caused by host responses against the pathogen. High-throughput screening (HTS) could be adapted to accommodate these categories but, ultimately, only in vivo assessment would reveal really significant therapeutic effects. One group of investigators is unlikely to be able to complete the development of a drug, from idea to a successful product. However, individual efforts might contribute and be significant for the advance towards drug applicability. PMID- 22946868 TI - Plasma pharmacokinetics of antimicrobial agents in critically ill patients. AB - Prompt optimal antimicrobial treatment in critically ill patients is mandatory and must be achieved not only in terms of spectrum of activity, but also in terms of exposure at the infection site. Plasma profile of antimicrobial agents may represent a valid surrogate marker of drug exposure and allow to identify the correct dosage for a given drug. However, in the critically ill patients the pharmacokinetic behavior of antimicrobials may be altered by some very peculiar pathophysiological conditions, so that dosages significantly different from those used in clinically stable patients or from those originally studied in healthy volunteers for regulatory purposes may often be needed in order to ensure optimal plasma drug exposure in such population. This is especially true for hydrophilic antimicrobials (aminoglycosides, beta-lactams, glycopeptides, lipopeptides, echinocandins, fluconazole, acyclovir, ganciclovir) whose volume of distribution and clearance may be significantly altered by these conditions. These aspects are particularly relevant in patients with severe sepsis or with septic shock for whom the time for being considered as a special population to be studied apart from the general population has probably come. From the healthcare system perspective, this means that individualization of antimicrobial therapy by means of a real time therapeutic drug monitoring coupled with clinical pharmacological advice should be considered an invaluable tool for optimizing antimicrobial therapy and for the containment of microbial resistance in this setting. PMID- 22946869 TI - Continuous infusion of antibiotics in critically ill patients. AB - Antibiotics are the most commonly used drugs in intensive care unit patients and their supply should be based on pharmacokinetic/pharmacodynamic rules. The changes that occur in septic patients who are critically ill may be responsible for subtherapeutic antibiotic concentrations leading to poorer clinical outcomes. Evolving in time the disturbed pathophysiology in severe sepsis (high cardiac output, glomerular hyperfiltration) and therapeutic interventions (e.g. haemodynamically active drugs, mechanical ventilation, renal replacement therapy) alters antibiotic pharmacokinetics mainly through an increase in the volume of distribution and altered drug clearance. The lack of new and efficacious drugs and increased bacterial resistance are current problems of contemporary antibiotic therapy. Although intermittent administration is a standard clinical practice, alternative methods of antibiotic administration are sought, which may potentialise effects and reduce toxicity as well as contribute to inhibition of bacterial resistance. A wide range of studies prove that the application of continuous infusion of time-dependent antibiotics (beta-lactams, glycopeptides) is more rational than standard intermittent administration. However, there are also studies which do not confirm the advantage of one method over the other. In spite of controversy the continuous administration of this group of antibiotics is common practice, because the results of both studies point to the higher efficacy of this method in critically ill patients. Authors reviewed the literature to determine whether any clinical benefits exist for administration of time-dependent antibiotics by continuous infusion. Definite specification of the clinical advantage of administration this way over standard dosage requires a large-scale multi-centre randomised controlled trial. PMID- 22946870 TI - Antimicrobial drug interactions in the critically ill patients. AB - Critically ill patients are typically polymedicated and therefore at a high risk for potential drug interactions. Clinical consequences of drugs interactions vary in severity from mild to lethal events. Since infection is an important issue in the Intensive Care Unit (ICU), a significant number of patients will receive an antimicrobial at some stage during their ICU admission. Therefore an adequate knowledge about possible interactions between antimicrobials and other drugs is necessary, since it may not only impact on the effectiveness of the antimicrobial but also in the incidence of drug adverse events. This review describes important drug interactions involving antimicrobials in the critically ill patient. PMID- 22946871 TI - Effects of renal replacement therapy on antimicrobial therapy. AB - Antimicrobial therapy in patients receiving renal replacement therapy (RRT) is challenging due to the varying pharmacokinetic profile of each drug-membrane technique combination. Renally excreted drugs are usually affected by RRT to a much higher extend than hepatically excreted drugs. However, highly protein bound drugs might be eliminated during RRTs regardless of their usual route of elimination through the formation of a protein membrane within the filter. Beta lactames pose a good example: most beta-lactames are excreted renally as unchanged drug. However, some betalactames, e.g. flucloxacillin or ceftriaxone adhere to the filter membrane due to their strong protein-drug interaction. Depending on the implemented RRT different administration regimens should be chosen. While beta-lactames may be administered three times daily as well as continuously during continuous RRT, they should be given only once after each hemodialysis session. Aminoglycosides on the other hand should best be given previous to HD to allow for high peak and low through concentrations due to their small therapeutic index and high toxicity. The current Recommendation for glycopeptides in hemodialysis is a post-HD administration. In both groups, aminoglycosides as well as glycopeptides drug monitoring is mandatory. For chinolones the standard dosing intervals should remain unchanged, however they require a significant reduction of the dose, with the exception of moxifloxacin which is excreted hepatically. Until now there are few publications guiding the clinician to the correct dosing schemes in RRT. This review aims to give dosage recommendations for a broad collection of currently used antimicrobial agents and should be applicable for all types of presently employed membranes. PMID- 22946872 TI - Methods to measure target site penetration of antibiotics in critically ill patients. AB - While several tools are necessary to repair a car, the engineer knows exactly which instrument he has to utilize at different parts of the broken machine. Likewise, depending on the information we are interested in, we have to choose different tools to investigate and consecutively understand the multiple aspects that are involved in pharmacokinetics of antimicrobial agents in critically ill patients. Some techniques, like blood sampling, microdialysis or positrons emission tomography (PET) will allow for obtaining continues concentration time profiles while others like bronchoalveolar lavage (BAL), biopsy or surgical tissue samples can only be used a limited number of times per subject. PET and methods based on tissue homogenization will deliver an average of the actual concentrations in intra - and extracellular compartments while investigations in isolated blood cells or microdialysis allow for more distinguished allocation of a concentration to a defined compartment. The present review aims at discussing the advantages and disadvantages of the various methods used for assessing pharmacokinetics in critically ill patients with regard to specific aspects of pharmacokinetic research and further reviews data of selected antibiotics as examples for applications of the individual techniques. PMID- 22946874 TI - TEMPO mixed SAMs: electrocatalytic efficiency versus surface coverage. AB - Electrocatalytic behavior of TEMPO derivative SAMs on gold has been studied in the presence of benzyl alcohol. The results demonstrate that interfacial activity of the SAMs can be enhanced by diluting the TEMPO moiety with an alkyl passive matrix. The absolute catalytic activity exhibits a maximum for an intermediate value of the surface coverage of catalytic centers. The most significant feature is the monotonic increase of the turnover (relative activity) until a limit value reached for low TEMPO surface concentrations. The electrocatalytic performances seem to be governed by a combination of two factors: the physical accessibility (by alcohol molecules in solution) and the regeneration (via the comproportionation of oxoammonium and hydroxylamine before electrochemical reoxidation) of the catalytic centers. PMID- 22946873 TI - Improving clinical outcomes for naltrexone as a management of problem alcohol use. AB - Despite being a relatively effective and safe treatment, the clinical management of alcohol abuse/dependence by oral naltrexone can be compromised due to the patient's non-compliance with daily use of this medication. Over the past decade an increasing body of research has suggested that the use of sustained release depot naltrexone preparations can overcome this issue and deliver improved clinical outcomes. However, at the same time, research findings from diverse areas of pharmacogenetics, neurobiology and behavioural psychology have also been converging to identify variables including genetic markers, patient psychosocial characteristics and drug use history differences, or clusters of these variables that play a major role in mediating the response of alcohol abuse/dependent persons to treatment by naltrexone. While this article does not attempt to review all available data pertaining to an individual alcohol dependent patient's response to treatment by naltrexone, it does identify relevant research areas and highlights the importance of data arising from them. The characterization of clinical markers, to identify those patients who are most likely to benefit from naltrexone and to tailor a more individual naltrexone treatment, will ultimately provide significant benefit to both patients and clinicians by optimizing treatment outcome. PMID- 22946875 TI - An in vivo evaluation of fit of zirconium-oxide based ceramic single crowns, generated with two CAD/CAM systems, in comparison to metal ceramic single crowns. AB - PURPOSE: The purpose of this study was to assess in vivo the marginal fit of single crowns produced using two CAD/CAM all-ceramic systems, in comparison to more traditional metal ceramic crowns. MATERIALS AND METHODS: Thirty vital, caries-free, and previously untreated teeth were chosen in five patients who needed extraction for implant placement and therefore were included in this study. In the control group (C), 10 regular metal ceramic crowns with porcelain occlusal surfaces were fabricated. In the other two groups (Z and E), CAD/CAM technology was used for the fabrication of 20 zirconium-oxide-based ceramic single crowns with two systems. All zirconia crowns were cemented with glass ionomer cement, always following the manufacturer's instructions. The same dentist carried out all clinical phases. The teeth were extracted 1 month later. Marginal gaps along vertical planes were measured for each crown, using a total of four landmarks for each tooth by means of a microscope at a magnification of 50*. On completion of microscopic evaluation, representative specimens from each group were prepared for ESEM evaluation. Mean and standard deviations of the four landmarks (mesial, distal, buccal, palatal) at each single crown were calculated for each group. Multivariate analysis of variance (MANOVA) was performed to determine whether the four landmarks, taken into consideration together, differed between groups. Two-way ANOVA was performed to study in detail, for each landmark, how the three systems used to produce the FPDs affected the gap measurements. Differences were considered to be significant at p < 0.05. RESULTS: MANOVA revealed no quantitative differences of the four landmarks, when taken into consideration together, between the three groups (p < 0.0001). Two-way ANOVA, performed at each landmark, revealed no quantitative differences between the three groups (p < 0.0001 for each landmark). CONCLUSIONS: Within the limitations of this study, it was concluded that the two zirconium-oxide-based ceramic CAD/CAM systems demonstrated a similar and acceptable marginal fit when compared to more traditional metal ceramic crowns. PMID- 22946876 TI - The intestinal absorption mechanism of gabapentin makes it appropriate for gastroretentive delivery. AB - Gabapentin is approved for the treatment of postherpetic neuralgia (PHN) and epilepsy. The pharmacokinetic (PK) properties of gabapentin, including absorption, distribution, metabolism, and excretion (ADME), were investigated during the development of Neurontin(r), an immediate-release (IR) formulation of gabapentin that is orally administered three-times daily. Recently, a gastroretentive (GR) once-daily formulation of gabapentin (Gralise(r)) has been developed and marketed for the treatment of PHN. This review focuses on the ADME properties of gabapentin and illustrates how GR delivery enhances its absorption compared with IR formulations and allows once-daily dosing with the evening meal for the treatment of PHN. It includes the following aspects: 1) the mechanism of gastroretention of gabapentin GR tablets, 2) in vitro dissolution profiles of the GR and IR formulations, 3) site of absorption of gabapentin in the human intestine, 4) studies of the mechanism of gabapentin absorption using intestinal tissue preparations, 5) human PK studies to examine the effects of dose and formulations on PK profiles and the bioavailability of gabapentin at therapeutically relevant doses, and 6) efficacy and safety of gastroretentive gabapentin in patients with PHN. The data reviewed support that GR delivery of gabapentin optimizes its absorption via a saturable uptake mechanism. The prolonged residence of the GR tablets in the stomach coupled with the gradual release of gabapentin attenuates saturation of the transporter, thus enhancing absorption and increasing bioavailability, especially at therapeutically relevant doses. The net result is a once-daily formulation of gabapentin that is well tolerated and efficacious for the treatment of PHN. PMID- 22946877 TI - Symmetry-constrained analysis of pulsed double electron-electron resonance (DEER) spectroscopy reveals the dynamic nature of the KcsA activation gate. AB - Distance determination from an echo intensity modulation obtained by pulsed double electron-electron resonance (DEER) experiment is a mathematically ill posed problem. Tikhonov regularization yields distance distributions that can be difficult to interpret, especially in a system with multiple discrete distance distributions. Here, we show that by using geometric fit constraints in symmetric homo-oligomeric protein systems, we were able to increase the accuracy of a model based fit solution based on a sum of Rice distributions. Our approach was validated on two different ion channels of known oligomeric states, KcsA (tetramer) and CorA (pentamer). Statistical analysis of the resulting fits was integrated within our method to help the experimenter evaluate the significance of a symmetry-constrained vs standard model distribution fit and to examine multidistance confidence regions. This approach was used to quantitatively evaluate the role of the C-terminal domain (CTD) on the flexibility and conformation of the activation gate of the K(+) channel KcsA. Our analysis reveals a significant increase in the dynamics of the inner bundle gate upon opening. Also, it explicitly demonstrates the degree to which the CTD restricts the motion of the lower gate at rest and during activation gating. PMID- 22946879 TI - An RNA aptamer-based microcantilever sensor to detect the inflammatory marker, mouse lipocalin-2. AB - Lipocalin-2 (Lcn2) is a biomarker for many inflammatory-based diseases, including acute kidney injury, cardiovascular stress, diabetes, and various cancers. Inflammatory transitions occur rapidly in kidney and cardiovascular disease, for which an in-line monitor could be beneficial. Microcantilever devices with aptamers as recognition elements can be effective and rapidly responsive sensors. Here, we have selected and characterized an RNA aptamer that specifically binds mouse Lcn2 (mLcn2) with a dissociation constant of 340 +/- 70 nM in solution and 38 +/- 22 nM when immobilized on a surface. The higher apparent affinity of the immobilized aptamer may result from its effective multivalency that decreases the off-rate. The aptamer competes with a catechol iron-siderophore, the natural ligand of mLcn2. This and the results of studies with mLcn2 mutants demonstrate that the aptamer binds to the siderophore binding pocket of the protein. A differential interferometer-based microcantilever sensor was developed with the aptamer as the recognition element in which the differential response between two adjacent cantilevers (a sensing/reference pair) is utilized to detect the binding between mLcn2 and the aptamer, ensuring that sensor response is independent of environmental influences, distance between sensing surface and detector and nonspecific binding. The system showed a detection limit of 4 nM. This novel microcantilever aptasensor has potential for development as an in-line monitoring system for mLcn2 in studies of animal models of acute diseases such as kidney and cardiac failure. PMID- 22946878 TI - Killing bacterial spores with blue light: when innate resistance meets the power of light. AB - This article is a highlight of the study by Maclean et al. in this issue of Photochemistry and Photobiology describing the sporicidal effects 405 nm visible light alone on endospores of the Clostridium and Bacillus genera. 1.73 kJ cm(-2) was capable of reducing endospore colony-forming units by up to 4-log(10). These findings have never been previously demonstrated and may be incorporated into decontamination methods that span medical, military and food preparatory applications. PMID- 22946880 TI - Thiopurine metabolite measurement leads to changes in management of inflammatory bowel disease. AB - BACKGROUND: The thiopurines azathioprine and 6-mercaptopurine are recommended for maintenance of remission in inflammatory bowel disease (IBD). Measurement of concentrations of the metabolites 6-thioguanine nucleotide and 6 methylmercaptopurine helps delineate interindividual variation in metabolism that may underlie variability in efficacy and toxicity. AIMS: We aimed to perform a retrospective observational study to determine the utility of thiopurine metabolite testing following its introduction into South Australia. METHODS: All patients having thiopurine metabolite tests done at Flinders Medical Centre between November 2008 and January 2010 were identified. Case notes of patients with testing done in the context of treatment for IBD were interrogated to determine the reason for testing, clinical context and outcome. RESULTS: One hundred and fifty-one patients were identified with thiopurine metabolite testing for IBD with 157 testing episodes. Eighty (51.0%) had testing done for flare or inefficacy, 18 (11.5%) for adverse effects, 5 (3.2%) for a combination of inefficacy and adverse effects, and 54 (34.4%) for routine or other reasons. Testing was followed by improved outcomes of increased efficacy, reduced toxicity or change to alternative therapy in 55.0% of the inefficacy/flare group, 27.8% of the suspected adverse reaction group, 60.0% of the combination group, and 13.0% of the routine/other group. Allopurinol was used as cotherapy in 16 patients and led to marked improvements in metabolite concentrations. CONCLUSIONS: Thiopurine metabolite testing has quickly become established in South Australia. When used for inefficacy or adverse effects, it often leads to improved outcomes. Prospective studies are needed to determine whether routine testing to guide dosing is of benefit. PMID- 22946881 TI - On the theoretical and empirical status of the matching law and matching theory. AB - The original and power function versions of the matching law and matching theory are mathematical accounts of continuous choice that have been applied to the behavior of many vertebrate species, including humans, and have become influential in a variety of disciplines, such as economics, behavioral pharmacology, and clinical science. Each version can be interpreted either from a response strength perspective or from a purely algebraic perspective. The point of departure of both versions of matching theory is the assertion that all behavior is choice governed by the matching law. This assertion permits sets of equations to be derived that constitute the 2 versions of the theory. Considerable experimental evidence leads to the conclusion that both interpretations of the original version of the matching law and theory are false and that both interpretations of the power function version of the law and theory are tenable. Specifically, the behavior of animal and human subjects conforms exactly to the mathematical forms required by the power function version of the law and theory, and the theoretical assumptions entailed by both interpretations of this version are supported by the empirical evidence. In addition, the theoretical interpretations of all but 1 of the parameters of the power function version's equations are consistent with available evidence. The one problematic parameter is interpreted as the rate at which unmeasured background resources are acquired. The theoretical interpretation of this parameter must be reconciled with observation in order to maintain matching theory's central assertion that all behavior is choice. PMID- 22946882 TI - Pd(OAc)2-catalyzed alkoxylation of arylnitriles via sp2 C-H bond activation using cyano as the directing group. AB - A Pd(OAc)(2)-catalyzed ortho-alkoxylation of arylnitrile was described. Using cyano as a directing group, the aromatic C-H bond can be functionalized efficiently to generate ortho-alkoxylated arylnitrile derivatives with moderate yields. The optimal reaction conditions were identified after examining various factors such as oxidant, solvent, and reaction temperature. The method was compatible to the arylnitriles with either electron-withdrawing or electron donating groups. PMID- 22946883 TI - What hospital inpatient services contributed the most to the 2001-2006 growth in the cost per case? AB - OBJECTIVE: To demonstrate a refined cost-estimation method that converts detailed charges for inpatient stays into costs at the department level to enable analyses that can unravel the sources of rapid growth in inpatient costs. DATA SOURCES: Healthcare Cost and Utilization Project State Inpatient Databases and Medicare Cost Reports for all community, nonrehabilitation hospitals in nine states that reported detailed charges in 2001 and 2006 (n = 10,280,416 discharges). STUDY DESIGN: We examined the cost per discharge across all discharges and five subgroups (medical, surgical, congestive heart failure, septicemia, and osteoarthritis). DATA COLLECTION/EXTRACTION METHODS: We created cost-to-charge ratios (CCRs) for 13 cost-center or department-level buckets using the Medicare Cost Reports. We mapped service-code-level charges to a CCR with an internally developed crosswalk to estimate costs at the service-code level. PRINCIPAL FINDINGS: Supplies and devices were leading contributors (24.2 percent) to the increase in mean cost per discharge across all discharges. Intensive care unit and room and board (semiprivate) charges also substantially contributed (17.6 percent and 11.3 percent, respectively). Imaging and other advanced technological services were not major contributors (4.9 percent). CONCLUSIONS: Payers and policy makers may want to explore hospital stay costs that are rapidly rising to better understand their increases and effectiveness. PMID- 22946884 TI - Smoking cessation and serious mental illness: a service evaluation of a drop-in stop smoking clinic on an acute in-patient unit. AB - AIMS AND OBJECTIVES: To evaluate the effect of a stop smoking clinic on the quit rates of patients admitted to an acute in-patient unit. BACKGROUND: The relationship between poor physical health and severe mental illness is well established. High rates of smoking appear to play an important causal role in the excess morbidity and mortality in this population. Stop smoking interventions for the general population are clinically effective and cost-effective. There is a small but promising evidence base for effective interventions to help people with a mental illness who wish to stop smoking but these have mostly been tested with community patients rather than acute in-patients. METHODS: A service evaluation of a drop-in stop smoking clinic on an acute mental health in-patient unit was conducted. Patients' smoking status was measured at baseline and four weeks after their quit date using patient self-report and an expired breath carbon monoxide reading. RESULTS: Over a six-month evaluation period, 46 patients set a quit date and 13 (28.3%) were abstinent at the four-week follow-up stage, verified by a carbon monoxide reading (chi(2) =33, df=1, sig p<0.0001). CONCLUSIONS: This small scale evaluation has shown a drop-in stop smoking intervention to be feasible, acceptable and associated with positive outcomes; further research with larger, more representative samples is required. RELEVANCE TO CLINICAL PRACTICE: Enforcing smoke-free legislation is a contentious issue on mental health in patient units, and there is a paucity of research to guide nursing practice in this area. An admission period in a smoke-free environment provides a crucial opportunity to offer smoking cessation treatment. With appropriate resources, expertise and support, it appears possible to apply smoking cessation interventions that are successful within the general population to mental health patients during an acute admission. PMID- 22946885 TI - The state of breastfeeding in a state. PMID- 22946886 TI - Breastfeeding social marketing: lessons learned from USDA's "Loving Support" campaign. AB - Social marketing involves the application of commercial marketing principles to advance the public good. Social marketing calls for much more than health communications campaigns. It involves four interrelated tasks: audience benefit, target behavior, essence (brand, relevance, positioning), and developing the "4Ps" (product, price, place, promotion) marketing mix. The ongoing U.S. Department of Agriculture "Loving Support Makes Breastfeeding Work" campaign was launched in 1997 based on social marketing principles to increase breastfeeding initiation rates and breastfeeding duration among Special Supplemental Nutrition Program for Women, Infants and Children (WIC) participants. Since then there have been improvements in breastfeeding duration in the country, and the majority of WIC women now initiate breastfeeding. Breastfeeding in public places is still not well accepted by society at large, and any and exclusive breastfeeding durations remain exceedingly low. Lessons learned from "Loving Support" and other campaigns indicate that it is important to design social marketing campaigns to target the influential societal forces (e.g., family and friends, healthcare providers, employers, formula industry, legislators) that affect women's decision and ability to breastfeed for the recommended amount of time. This will require formative research that applies the social-ecological model to different population segments, taking and identifying the right incentives to nudge more women to breastfeed for longer. Any new breastfeeding campaign needs to understand and take into account the information acquisition preferences of the target audiences. The vast majority of WIC women have mobile devices and are accessing social media. The Brazilian experience indicates that making breastfeeding the social norm can be done with a solid social marketing strategy. This is consistent with the recently released "Six Steps to Achieve Breastfeeding Goals for WIC Clinics," which identifies the need for exclusive breastfeeding to become the social norm at WIC clinics and strongly recommends for these clinics to adhere to the World Health Organization Code of Marketing of Breast-Milk Substitutes. PMID- 22946887 TI - The American Academy of Pediatrics and breastfeeding. PMID- 22946888 TI - Breastfeeding and the use of human milk: an analysis of the American Academy of Pediatrics 2012 Breastfeeding Policy Statement. PMID- 22946889 TI - Kelvin probe force microscopy in nonpolar liquids. AB - Work function changes of Au were measured by Kelvin probe force microscopy (KPFM) in the nonpolar liquid decane. As a proof of principle for the measurement in liquids, we investigated the work function change of an Au substrate upon hexadecanethiol chemisorption. To relate the measured contact potential difference (CPD) during the chemisorption of alkanethiols to a change of the work function, the influence of physisorbed decane must be taken into account. It is crucial that either the work function of the scanning probe microscope (SPM) tip or the sample surface remains constant throughout the reaction, since both contribute to the CPD. We describe two routes for determining the work function shift of Au coated with a monolayer of alkanethiols: In the first route, the SPM tips were taken as reference surfaces (constant tip work function). For this approach, we used Au(111) surfaces and kept the SPM tip ex situ during the adsorption process. In the second route, structured surfaces with reactive and inert parts were studied by KPFM (constant reference work function). For this route, we prepared nanometer sized Au structures by nanosphere lithography on SiO(x) substrates. Now, the SiO(x) served as the inert reference surface. The shifts in the work function after exposure to the hexadecanethiol (HDT) solution were determined to be DeltaPhi(Au+HDT,decane-Au,air) = -1.33 eV +/- 0.07 eV (route I) and DeltaPhi(Au+HDT,decane-Au,air) = -1.46 eV +/- 0.04 eV (route II). Both values are in excellent agreement with the work function shifts determined by ultraviolet photoemission spectroscopy (UPS) reported in literature. The presented procedures of measuring work function changes in decane open new ways to study local reactions at solid-liquid interfaces. PMID- 22946891 TI - Hyperemesis gravidarum and depression in pregnancy: is there an association? AB - OBJECTIVE: The aim of this study was to evaluate the impact of hyperemesis gravidarum (HG) and sociodemographic parameters on depression during pregnancy. STUDY DESIGN: Between September 2010 and September 2011, 200 consecutive women with HG were defined as the study group and 200 consecutive pregnant women without any signs and symptoms of HG, and matched for age, parity, and gestational age were defined as the control group. The Beck depression inventory II (BDI-II) questionnaire and sociodemographic questionnaire evaluating educational level, occupation, economic status, and obstetric history were given to all participants for self-completion. The forms were collected within 6 h of hospital admission. Groups were compared according to the presence of depression and predictors of depression were analyzed by regression analysis. RESULTS: Median BDI-II scores in study and control groups were 15 and 5, respectively. The difference was statistically significant (p < 0.001). In the HG group, 35.1% of patients had mild depression, 26.0% moderate, and 17.8% had severe depression, while only 5% of patients in the control group had mild depression and 95% had no depression. Multivariate analysis showed that HG, age and family relationship were related to depression during pregnancy. Moreover, depression risk was increased 76-fold in patients with HG (odds ratio = 76.000; 95% confidence interval: 36.840-156.788; p < 0.001). CONCLUSION: Depression risk is increased in patients with HG, therefore not only medical therapy of HG, but also psychiatric evaluation should be considered for these patients. PMID- 22946890 TI - Oral bioavailability of dabigatran etexilate (Pradaxa((r)) ) after co-medication with verapamil in healthy subjects. AB - AIM: To investigate the effect of the P-glycoprotein inhibitor verapamil on the pharmacokinetics and pharmacodynamics of dabigatran etexilate (DE). METHOD: In this two part multiple crossover trial in 40 healthy subjects, DE 150 mg was given alone or with verapamil at different doses, duration of treatment (single vs. multiple dosing), formulations, and timings (before, concurrently or after DE). Primary pharmacokinetic endpoints were determined from concentrations of total dabigatran (unconjugated plus conjugated). Pharmacodynamic endpoints were determined from clotting time. RESULTS: The greatest effect was observed with single dose verapamil 120 mg immediate release given 1 h before single dose DE. Geometric mean area under the plasma concentration curve [AUC(0,infinity)] and maximum analyte concentration in the plasma (Cmax ) were increased by 143% [90% confidence interval (CI) 91, 208] and 179% (90% CI 115, 262), respectively. The effect was reduced to a 71% and 91% increase in AUC and Cmax , respectively, when DE was administered with verapamil 240 mg extended release. After multiple verapamil dosing, DE AUC(0,infinity) and Cmax increases were 54% and 63%, respectively. However, DE given 2 h before verapamil increased DE AUC(0,infinity) and Cmax by <20%. With regard to clotting prolongation, the dabigatran plasma concentration-effect relationship was generally not affected by the co administration of verapamil. Concomitant administration of DE and verapamil did not reveal any unexpected safety findings. CONCLUSION: Verapamil increased DE bioavailability, likely due to inhibition of P-glycoprotein. Our results suggest that an interaction between verapamil and DE can be minimized if DE is administered 2 h prior to verapamil. PMID- 22946892 TI - Pharmaceutical kinetics and toxicological effects of nanosystems and nanomaterials for biomedical applications. PMID- 22946893 TI - Anti-inflammatory drugs and prediction of new structures by comparative analysis. AB - Nonsteroidal anti-inflammatory drugs (NSAIDs) are a group of agents important for their analgesic, anti-inflammatory, and antipyretic properties. This study presents several approaches to predict and elucidate new molecular structures of NSAIDs based on 36 known and proven anti-inflammatory compounds. Based on 36 known NSAIDs the mean value of Log P is found to be 3.338 (standard deviation= 1.237), mean value of polar surface area is 63.176 Angstroms2 (standard deviation = 20.951 A2), and the mean value of molecular weight is 292.665 (standard deviation = 55.627). Nine molecular properties are determined for these 36 NSAID agents, including Log P, number of -OH and -NHn, violations of Rule of 5, number of rotatable bonds, and number of oxygens and nitrogens. Statistical analysis of these nine molecular properties provides numerical parameters to conform to in the design of novel NSAID drug candidates. Multiple regression analysis is accomplished using these properties of 36 agents followed with examples of predicted molecular weight based on minimum and maximum property values. Hierarchical cluster analysis indicated that licofelone, tolfenamic acid, meclofenamic acid, droxicam, and aspirin are substantially distinct from all remaining NSAIDs. Analysis of similarity (ANOSIM) produced R = 0.4947, which indicates low to moderate level of dissimilarity between these 36 NSAIDs. Non hierarchical K-means cluster analysis separated the 36 NSAIDs into four groups having members of greatest similarity. Likewise, discriminant analysis divided the 36 agents into two groups indicating the greatest level of distinction (discrimination) based on nine properties. These two multivariate methods together provide investigators a means to compare and elucidate novel drug designs to 36 proven compounds and ascertain to which of those are most analogous in pharmacodynamics. In addition, artificial neural network modeling is demonstrated as an approach to predict numerous molecular properties of new drug designs that is based on neural training from 36 proven NSAIDs. Comprehensive and effective approaches are presented in this study for the design of new NSAID type agents which are so very important for inhibition of COX-2 and COX-1 isoenzymes. PMID- 22946894 TI - Anti-inflammatory effect of certain dihydroxy flavones and the mechanisms involved. AB - This study was designed to evaluate the anti-inflammatory action of four dihydroxy flavone derivatives; 3,3'- dihydroxy flavone, 5,6-dihydroxy flavone, 3,7-dihydroxy flavone and 6,3'-dihydroxy flavone and to further investigate the multiple cellular mechanisms underlying the anti-inflammatory effect of these compounds. The effect of dihydroxy flavones on acute inflammation was studied in rats employing carrageenan induced hind paw edema method. Further, the role of proinflammatory cytokines like TNF-alpha and IL-1beta, cyclooxygenases (COX-1 and COX-2), and free radicals in the action of flavone derivatives was investigated using in vitro assays. All the four dihydroxy flavone derivatives exhibited time and dose dependent inhibition of carrageenan induced paw edema. In addition, the investigated compounds inhibited both the isoforms of cyclooxygenase and cytokines in a concentration dependent manner and also suppressed the release of reactive oxygen species. The anti-inflammatory effect of dihydroxy flavones may be through mechanisms that involve an interaction with cyclooxygenases, cytokines and reactive oxygen species. PMID- 22946895 TI - Comparison of mandibular bone mineral densities in dentate and edentulous patients. AB - PURPOSE: In contemporary implant dentistry, bone mineral density (BMD) of the jaws is a patient-associated prognostic factor. The aim of this study was to compare the mandibular body BMD of dentate and edentulous patients using the dual energy X-ray absorptiometry (DXA) technique. MATERIALS AND METHODS: A total of 39 patients, 20 dentate and 19 edentulous, were included in this cross-sectional study. Mandibular body BMD was measured using the DXA technique. The variables were normally distributed; thus, the independent samples t-test was used for the determination of statistical significance between the dentate and edentulous groups (age, body mass index [BMI], DXA). Chi-square test was performed for identification of the gender differences between the groups. The Pearson correlation analysis was used to analyze the relationship between age, BMI, and mandibular body BMD. Note that p < 0.01 was accepted as the significance level. RESULTS: There was no statistically significant difference between the dentate and edentulous groups in matching variables (age, BMI, and gender) (p > 0.01). There was a statistically significant difference regarding the mandibular body BMD in the dentate and edentulous group (p < 0.01) controlling for age, gender, and BMI. The edentulous group patients had higher mandibular body BMD values (1.27 +/- 0.31 g/cm(2)) than those in the dentate group (0.94 +/- 0.22 g/cm(2)). CONCLUSION: Comparison of the mandibular body BMD revealed that dentate patients had less dense bone than the edentulous patients. Further investigations are needed to determine the BMD of the jaws in different regions and for different systemic conditions. PMID- 22946896 TI - Implicit misattribution of evaluative responses: contingency-unaware evaluative conditioning requires simultaneous stimulus presentations. AB - Recent research has shown that evaluative conditioning (EC) procedures can change attitudes without participants' awareness of the contingencies between conditioned and unconditioned stimuli (Hutter, Sweldens, Stahl, Unkelbach, & Klauer, 2012). We present a theoretical explanation and boundary condition for the emergence of unaware EC effects based on the implicit misattribution of evaluative responses from unconditioned to conditioned stimuli. We hypothesize that such misattribution is only possible when conditioned and unconditioned stimuli are perceived simultaneously. Therefore we manipulate the simultaneity of the stimulus presentations and apply a process dissociation procedure to distinguish contingency-aware from contingency-unaware EC effects. A multinomial model indicates that with sequential presentations, EC effects do not occur without contingency awareness. However, unaware EC effects do occur with simultaneous presentations. The findings support dual-process theories of learning. PMID- 22946897 TI - The power of movement: evidence for context-independent movement imitation. AB - Recent studies have shown that individuals often imitate the behavior of others. In these studies, the observed and imitated behaviors were always identical. The present research goes one step further and disentangles the imitation of movements from their behavioral contexts. On the basis of theories that the perception of behavior refers to the same mental representations as the execution, we found that imitation is not confined to the same class of behaviors but rather to the same class of movements that may be involved in different behaviors. Four studies demonstrated that watching an athlete lifting a barbell leads to an increase in participants' drink intake when drinking involved a similar movement (lifting a cup) but not when drinking did not involve a lifting movement (drinking through a tube). The effects were stronger for individuals high in perspective taking (Study 1) and for situations in which the perspective was manipulated to be similar to the observed actor's (Study 2). These findings demonstrate the power of movements in imitation processes, suggesting that shared goal representation is not necessary for imitating others' movements. PMID- 22946898 TI - Preventing motor skill failure through hemisphere-specific priming: cases from choking under pressure. AB - When well-learned motor skills fail, such as when elderly persons fall or when athletes "choke under pressure," it is assumed that attention is directed toward the execution of the action. Research findings suggest that this controlled execution and subsequent inferior performance depend on a dominant left hemispheric activation. In a series of 3 experiments, we tested whether increasing right-hemispheric activation by the use of hemisphere-specific priming extenuates motor skill failure. We compared the performances of a sample of experienced athletes in different sports (soccer, tae kwon do, and badminton) in a pressure-free situation with that performed under pressure. As expected, the hemisphere-specific priming extenuated a performance decrease after pressure induction when compared with a control condition. The results suggest that hemisphere-specific priming may prevent motor skill failure. It is argued that this hemispheric priming should be task dependent and can be understood as a functional regulation of the activation in the hemispheres. PMID- 22946899 TI - Quantum wave-packet dynamics in spin-coupled vibronic states. AB - Extending the Shin-Metiu two-electron Hamiltonian, we construct a new Hamiltonian with effective singlet-triplet couplings. The Born-Oppenheimer electronic potentials and couplings are obtained for different parameters, and the laser free dynamics is calculated with the full Hamiltonian and in the adiabatic limit. We compare the dynamics of the system using nuclear wave packets for different numbers of Born-Oppenheimer potentials and vibronic wave packets on a full 3 dimensional (two electron coordinates plus one nuclear coordinate) grid. Using strong fields, we show that it is possible to dynamically lock the spin state of the system by decoupling the singlet-triplet transition via a nonresonant dynamic Stark effect in the adiabatic limit. Although a similar spin-locking mechanism is observed in the dynamics of vibronic wave packets, multiphoton ionization cannot be neglected leading to the breakdown of the control scheme. PMID- 22946900 TI - The clinical utility of bivalirudin in patients with coronary artery disease. AB - Bivalirudin, a direct thrombin inhibitor, is an anticoagulant commonly used in invasive cardiology procedures. It has evolved from relative obscurity, as an anticoagulation option only utilized in rare instances of allergy or resistance to heparin products, to the now preferred antithrombotic anticoagulant in the cardiac catheterization laboratory. On the way to displacing unfractionated heparin as the preferred anticoagulant for percutaneous coronary intervention, multiple studies comparing bivalirudin with heparin have consistently shown equivalent ischemic efficacy endpoints (i.e. cardiovascular death, myocardial infarction, etc.), with significant reductions in bleeding. Bleeding has been directly linked to worse hospital outcomes in cardiac patient's undergoing invasive coronary artery revascularization procedures. More recent bivalirudin studies now demonstrate reductions in mortality, which has led to a paradigm shift to bivalirudin as the anticoagulant choice both in elective and emergent coronary procedures. We present the major studies that have brought bivalirudin to the forefront of coronary artery disease, specifically coronary interventional procedures. PMID- 22946901 TI - Cardiovascular complications of HIV infection and treatment. AB - With improved and highly active antiretroviral therapy (HAART) the average life span of HIV infected individuals has increased tremendously. HIV infections can now be managed with HAART for years making it a chronic disease much in line with others like diabetes or high blood pressure. However the increasing use of HAART therapy for HIV management has also revealed a growing concern for the side effects associated with this treatment regimen. The two groups of drugs currently at the forefront of HAART therapy namely Nucleoside Reverse Transcriptase inhibitors (NRTI) and Protease inhibitors (PI) are known to induce toxicities that lead to cardiovascular complications. While NRTIs are known to directly affect cardiac cells via their effect on mitochondria; the PIs have more indirect effects through alteration of lipid metabolism leading to dyslipidemia, a predisposing factor for atherosclerosis and heart disease. In this review, we provide a summary of the mechanism of cardiovascular complications that are associated with HIV infection as well as long term treatment with HAART. PMID- 22946902 TI - One-year audit of complaints made against a University Hospital Surgical Department. AB - BACKGROUND: There is relatively little in the medical literature relating to complaints about the healthcare process. The aim of this study was to report the frequency and content of patient complaints against a University Hospital Surgical Department. In particular, the study aimed to relate the number of complaints to the number of health-care episodes and to determine the frequency of patient safety incidents and subsequent medico-legal action. METHODS: Retrospective interrogation of a prospectively maintained Complaints Department database at a University Hospital for the calendar year 2009. RESULTS: Complaints relating to 360 aspects of the health-care journey in 113 patients were made. This translated into one complaint per 400 health-care episodes. Concerns about clinical care were cited in 31%, delays in the health-care process in 30%, communication issues in 19%, the institutional environment in 8% and poor discharge planning in 6%. Overall, 16 complaints (4%) were raised as patient safety incidents. Eighty-three per cent of complaints were addressed by a telephone conversation or a single letter response, 13% by a face-to-face meeting. Two per cent resulted in subsequent medico-legal action. CONCLUSIONS: Although perceived in a negative way by health-care professionals, only 1 in 400 health-care episodes resulted in a complaint. Only a small number related to patient safety incidents or resulted in medico-legal instructions. Attention should focus on developing effective strategies to improve patient satisfaction with all aspects of the patient journey. PMID- 22946903 TI - Molecular pharmacological approaches to effects of capsaicinoids and of classical antisecretory drugs on gastric basal acid secretion and on indomethacin-induced gastric mucosal damage in human healthy subjects (mini review). AB - BACKGROUND: Actions of various drugs have been tested on the gastric acid basal secretion and on the drug (Indomethacin)- induced gastric mucosal damage; however their physiological and pharmacological mechanisms have not been compared. AIMS: The effects of capsaicinoids, atropine, cimetidine, omeprazole, famotidine and ranitidine were studied on gastric basal acid output, whereas the gastric mucosal preventive effects of capsaicinoids (capsaicin), atropine and cimetidine were tested on the indomethacin-induced gastric mucosal microbleedings in human healthy subjects. Results were presented by molecular pharmacological method; affinity (pD) and intrinsic activity (alpha-values) were calculated. Intrinsic activity curves are based on comparison to atropine effect (alpha(atropine)= 1.00). For evaluation of physiological and pharmacological effects of compounds molar doses of pD(2) (necessary doses to produce 50% inhibition) and pA(2) (50% inhibion on intrinsic activity) were calculated from affinity and intrinsic activity curves. RESULTS: The pD(2) values for compounds were as follows: 5.88 for capsaicinoids, 5.40 for atropine , 2.23 for cimetidine, 3.33 for ranitidine, 3.77 for famotidine and 3.97 for omeprazole. alpha - value results for compounds were: 0.76 for capsaicinoids, and 1.00 for atropine, cimetidine, ranitidine, famotidine and omeprazole all equal to 1.00 on gastric acid basal secretion. The pD(2) values on indomethacin-induced gastric mucosal microbleeding were found as follows: 6.00 for capsaicinoids, 5.50 for atropine, and 3.50 for cimetidine, meanwhile alpha-values resulted 0.76 for capsaicinoids, 1.00 for atropine and cimetidine. CONCLUSIONS: Comparison classical antisecretory drugs acting on different pathways but in much more higher molar concentrations. The atropine and capsaicinoids act in about the same molar concentration which suggests a significant physiological role for capsaicin sensitive afferent nerves in the regulation of gastric basal acid secretion and in the prevention of chemically- induced gastric mucosal protection in human healthy subjects, suggesting a novel physiological pathway in regulation. These results clearly indicate the molecular pharmacological backgrounds of actions of classical antisecretory drugs and physiological role of capsaicin- sensitive afferent nerves in human healty subjects on the gastric basal secretion and on the prevention of drug-induced gastric mucosal damage. PMID- 22946904 TI - Neurodevelopmental outcome at 6 years of age after intrauterine laser therapy for twin-twin transfusion syndrome. AB - This study was undertaken to evaluate neurodevelopmental outcome of children at 6 years of age after intrauterine laser therapy for Twin-twin transfusion syndrome (TTTS). This is part of a longitudinal study in children after intrauterine laser therapy for TTTS; 190 of 254 (74.8%) children, previously investigated at a median age of 2 years 10 months, were re-evaluated at 6 years 5 months (range 4 years 11 months -10 years 4 months). Sixty-four patients were not examined due to loss of contact. The median gestational age at birth was 34 + 3 weeks. The study included a physical/neurological examination, a standardized neurodevelopmental test (Kaufman-ABC) and/or results from the national screening programme for children as well as questionnaires. Patients were grouped in three outcome categories: group I: normal examination and test result; group II: minor neurological deficiencies and normal test results; group III: major neurological deficiencies and/or test results below minus two standard deviations. The following results were obtained at 6 years 5 months (for comparison, results of the same patients at 2 years 10 months in brackets). Group I: 79.5% (84.2%); group II: 11.6% (8.9%); group III: 8.9% (6.8%). Twenty-one (11%) patients had a worse and 8 (4.2%) an improved classification at 6 years 5 months as compared to 2 years 10 months. Overall, the results with 6 years did not significantly differ from the results with 2 years. Neurodevelopmental outcome at 6 years 5 months was not statistically, significantly different from outcome at 2 years 10 months. PMID- 22946907 TI - Coping strategies of Ethiopian immigrants in Israel: association with PTSD and dissociation. AB - The aim of this study was to examine the relations between coping strategies, posttraumatic stress disorder (PTSD), and dissociation among Jewish Ethiopian refugees in Israel (following exposure to pre-, peri- and post-migration stressful events). METHOD: A random sample (N = 478) of three waves of refugees took part in the research (N = 165; N = 169; N = 144). Religiosity, coping strategies, stressful and traumatic events, pre- and peri- migration, post migration difficulties, posttraumatic symptoms, and dissociation were assessed. RESULTS: A significant relationship was found between PTSD symptoms and avoidance coping over and above immigration wave and traumatic events. Dissociation was positively associated with passivity and antisocial coping and negatively associated with social joining and level of religiosity, over and above immigration wave and traumatic events. The findings are discussed in the light of the coping strategies employed by Ethiopian refugees. PMID- 22946905 TI - The relationship between mental health diagnosis and treatment with second generation antipsychotics over time: a national study of U.S. Medicaid-enrolled children. AB - OBJECTIVE: To describe the relationship between mental health diagnosis and treatment with antipsychotics among U.S. Medicaid-enrolled children over time. DATA SOURCES/STUDY SETTING: Medicaid Analytic Extract (MAX) files for 50 states and the District of Columbia from 2002 to 2007. STUDY DESIGN: Repeated cross sectional design. Using logistic regression, outcomes of mental health diagnosis and filled prescriptions for antipsychotics were standardized across demographic and service use characteristics and reported as probabilities across age groups over time. DATA COLLECTION: Center for Medicaid Services data extracted by means of age, ICD-9 codes, service use intensity, and National Drug Classification codes. PRINCIPAL FINDINGS: Antipsychotic use increased by 62 percent, reaching 354,000 youth by 2007 (2.4 percent). Although youth with bipolar disorder, schizophrenia, and autism proportionally were more likely to receive antipsychotics, youth with attention deficit hyperactivity disorder (ADHD) and those with three or more mental health diagnoses were the largest consumers of antipsychotics over time; by 2007, youth with ADHD accounted for 50 percent of total antipsychotic use; 1 in 7 antipsychotic users were youth with ADHD as their only diagnosis. CONCLUSIONS: In the context of safety concerns, disproportionate antipsychotic use among youth with nonapproved indications illustrates the need for more generalized efficacy data in pediatric populations. PMID- 22946908 TI - Sulfation of buprenorphine, pentazocine, and naloxone by human cytosolic sulfotransferases. AB - Buprenorphine, pentazocine, and naloxone are opioid drugs used for the treatment of pain and opioid dependence or overdose. Sulfation as catalyzed by the cytosolic sulfotransferases (SULTs) is involved in the metabolism of a variety of xenobiotics including drug compounds. Sulfation of opioid drugs has not been well investigated. The current study was designed to examine the sulfation of three opioid drugs, buprenorphine, pentazocine, and naloxone, in HepG2 human hepatoma cells and to identify the human SULT(s) responsible for their sulfation. Analysis of the spent media of HepG2 cells, metabolically labeled with [(35)S]sulfate in the presence of each of the three opioid drugs, showed the generation and release of their [(35)S]sulfated derivatives. A systematic analysis using eleven known human SULTs revealed SULT1A3 and SULT2A1 as the major responsible SULTs for the sulfation of, respectively, pentazocine and buprenorphine; whereas three other SULTs, SULT1A1, SULT1A2, and SULT1C4, were capable of sulfating naloxone. Enzymatic assays using combinations of these opioid drugs as substrates showed significant inhibitory effects in the sulfation of buprenorphine and pentazocine by naloxone. Differential sulfating activities toward the three opioid drugs were detected in cytosol or S9 fractions of human lung, liver, kidney, and small intestine. Collectively, these results imply that sulfation may play a role in the metabolism of buprenorphine, pentazocine, and naloxone in vivo. PMID- 22946909 TI - Using mode and maximum values from the Numeric Rating Scale when evaluating postoperative pain management and recovery. AB - AIMS AND OBJECTIVES: To (1) examine the clinical applicability of compiled mode and maximum values from the Numeric Rating Scale (NRS) by comparing the correspondence between patient perceptions of pain and pain values from monitoring records, as well as (2) to study the relationship between mode and maximum values and self-assessed ability for early postoperative recovery. BACKGROUND: Documentation of pain remains a problem despite recommendations of quality improvements. To examine the correlation between patient perceptions and documented pain therefore becomes important. Few have studied how pain affects recovery. DESIGN: A quantitative cross-sectional design was used in which 157 postoperative patients answered a questionnaire on pain intensity and recovery. A parallel examination of pain in monitoring records was conducted. RESULTS: A total of 57% had a mode value calculated from records between 0 and 3 on postoperative day 1 and 69% on day 2. A maximum value between 4 and 10 was found in monitoring records for 73% on day 1 and for 67% on day 2. The correspondence between mode value from monitoring records and the patients' retrospective perceptions was 88% for NRS 0-3 and 92% between maximum value and NRS 4-10. The correlation between documented pain and retrospectively identified pain for mode value of the NRS in all (0-10) was rather weak (r = 0.37), while maximum value had a stronger correlation (r = 0.53). CONCLUSION: Mode and maximum values could be used as outcome measures when evaluating postoperative pain. Pain affects recovery negatively, but more research is needed to strengthen the evidence for the use and clarify the link between pain and recovery. RELEVANCE TO CLINICAL PRACTICE: International organisations emphasise the importance of improving pain assessment. Mode and maximum values are easy to compile for nurses and can, together with assessments of how experienced pain levels affect postoperative recovery, improve treatment of postoperative pain. PMID- 22946910 TI - Long-term stability of the Scientific and Standardization Committee Secondary Coagulation Standard (SSC Lot no. 3). PMID- 22946911 TI - Updates from the EBF DBS--microsampling consortium. PMID- 22946912 TI - The potential application of electromembrane extraction for the analysis of peptides in biological fluids. PMID- 22946914 TI - Error estimates on normal least squares linear regression with replicate injection of calibration standards. AB - BACKGROUND: In bioanalysis, including replicate injection of calibration standards, a normal least squares linear regression model can be generated from, A: the first injection dataset; B: the second injection dataset; C: averaged data from both injection datasets; and D: all data from both injections. Sample results, and their estimated confidence intervals, are expected to be different among these four models. RESULTS: Models C and D yield same slopes and intercepts, which are the mathematical means of respective values in models A and B. Relatively narrower confidence intervals on sample results are estimated in both models C and D as the former reduces the overall standard error of the curve and the latter increases the total number of calibration points and leads to a lower Student's t-value. CONCLUSION: Replicate injection of calibration standards provides added benefits for an analytical measurement on instrument sensitivity compensation and relatively improved precision of results. PMID- 22946915 TI - Validation of a bioanalytical method using capillary microsampling of 8 ul plasma samples: application to a toxicokinetic study in mice. AB - BACKGROUND: Capillary microsampling was recently introduced as a new technique for simplified collection and handling of small, exact volumes of liquid matrices. In this article, a bioanalytical method was developed and fully validated for 8 ul plasma samples and applied to a toxicology study in mice. RESULTS: The method was validated in the concentration range 0.06-30 uM. A procedure where 32 ul of blood was collected for preparation of 8 ul plasma was successfully implemented at the animal facility. All the results for the method and study validation met the requirements of a regulated assay. CONCLUSION: It is shown that 8 ul plasma microsamples can be sampled and analyzed with consistently excellent accuracy and precision. Capillary microsampling of plasma offers a possibility to combine ethical, scientific and economic benefits while still maintaining the advantage of having drug exposure data in plasma. PMID- 22946916 TI - Strategies to estimate and improve drug tolerance in anti-drug antibody assays. AB - BACKGROUND: Drug tolerance of anti-drug antibody (ADA) assays is becoming increasingly important due to the high number of newly emerging long-acting drugs. Methods to estimate and improve drug tolerance in ADA assays are needed. RESULTS: The relevance and precision of drug tolerance estimates in a bridging ELISA depended on characteristics and concentration of the surrogate control antibody together with assay cut point level. Stepwise and coincubation procedures were optimized for drug tolerance and sensitivity by adapting concentrations of reagents used for capture and detection of ADAs. In combination with acid treatment of samples, increase in drug tolerance of over 20-fold was achieved without losing sensitivity in two different assays. Acid treatment reduced drug interference observed in preclinical samples and prevented underestimation of ADA response. CONCLUSION: In a risk-based approach it may be possible to reliably predict in vivo drug tolerance using carefully chosen surrogate controls. General guidelines for development of drug-tolerant bridging ELISAs are presented. PMID- 22946917 TI - Overcoming soluble target interference in an anti-therapeutic antibody screening assay for an antibody-drug conjugate therapeutic. AB - BACKGROUND: The standard safety evaluation of biotherapeutics includes assessment of immunogenicity. Anti-therapeutic antibodies (ATA) can be detected in serum using immunoassays with a bridging format. However, these assays can be subject to interference. RESULTS: In the bridging ATA assay for 3A5 TDC, an antibody-drug conjugate that binds to the multimeric extracellular domain of MUC16 (CA125), soluble CA125 in the serum caused false-positive results by binding to the ATA assay reagents. This interaction was blocked by wheat germ agglutinin lectin as it binds to the glycans in CA125; thus, the specificity of the assay improved. CONCLUSION: The assay development and validation results showed that the addition of wheat germ agglutinin eliminates the interference from circulating CA125 without impacting the ability to detect ATA. PMID- 22946918 TI - Dried matrix on paper disks: the next generation DBS microsampling technique for managing the hematocrit effect in DBS analysis. AB - BACKGROUND: The hematocrit effect is a hurdle for successful introduction of the dried blood spot (DBS) in a regulated environment. Recently, attempts were taken to overcome the hematocrit effect by whole-cut DBS analysis. This paper presents the next-generation whole-cut DBS; dried matrix on paper disks (DMPD). RESULTS: DMPD eliminated the hematocrit effect and demonstrated better accuracy and precision than regular DBS with partial punching. Observed accuracy and precision were 6.0 and 2.3% for DMPD, respectively, and -10.4 and 17.1%, for DBS, respectively. CONCLUSION: The DMPD technique performed better than regular DBS by eliminating the hematocrit effect related blood volume bias. Although this effect was not observed with DMPD, a systematic error of 6.0% was detected and further technical development of DMPD could improve the performance. PMID- 22946919 TI - Application of DBS sampling in combination with LC-MS/MS for pharmacokinetic evaluation of a compound with species-specific blood-to-plasma partitioning. AB - BACKGROUND: Dried blood spot (DBS) sampling in combination with LC-MS/MS has been used increasingly in drug discovery for quantitative analysis to support pharmacokinetic (PK) studies. In this study, we assessed the effect of blood-to plasma (B:P) partitioning on the bioanalytical performance and PK data acquired by DBS for a compound AMG-1 with species and concentration-dependent B:P ratio. RESULTS: B:P partitioning did not adversely affect bioanalytical performance of DBS for AMG-1. For rat, (B:P ratio of 0.63), PK profiles from DBS and plasma methods were comparable. For dog, concentration-dependence of B:P ratio was observed both in vivo and in vitro. Additional studies demonstrated concentration dependence of the compound's unbound fraction in plasma, which may contribute to the concentration-dependence of the B:P ratio. CONCLUSION: DBS is a promising sampling technique for preclinical pharmacokinetic studies. For compounds with high B:P ratio, caution needs to be applied for data comparison and interpretation between matrices. PMID- 22946920 TI - Utilization of hydrophilic-interaction LC to minimize matrix effects caused by phospholipids. AB - BACKGROUND: In bioanalysis, phospholipids may affect the precision and accuracy of LC-MS/MS methods and compromise the quality of the results, especially when samples in complex biomatrices are extracted by protein precipitation techniques. RESULTS: It was found that the retentive behavior of both common pharmaceuticals and physiologically relevant phospholipids under bare silica hydrophilic interaction LC (HILIC) is more predictable than under reversed-phase conditions. In particular, the retention time of phospholipids was not significantly affected by varying the salt and acid modifiers in the mobile phases, but common pharmaceuticals can be shifted away from these phospholipid interferences through mobile phase modifiers. Several mass spectrometric techniques were applied to confirm this finding. CONCLUSION: HILIC chromatography is a valued tool in the development of robust bioanalytical assays with minimal and predictable phospholipid interferences. Furthermore, addition of a small amount of ion pairing additives can reliably move pharmaceutical compounds away from these suppressive regions. PMID- 22946921 TI - What is next for dried blood spots? AB - In the last several years, dried blood spot (DBS) sampling has re-emerged and attracted a great interest in the pharmaceutical industry as a microsampling technology for drug discovery and development studies. Although significant progress has been made to understand strengths and weaknesses of the technique, many organizations are still at the evaluation stage and experimental observations have resulted in more questions being raised as to whether there is a real future for this technology in pharmaceutical research, especially in support of pharmacokinetic studies. This article summarizes recently gained knowledge against the originally projected advantages of this technique, discusses some practical challenges that need to be overcome before DBS can be widely applied in drug development studies, and highlights some specific study types where DBS can be applied with a good benefit:risk ratio. The authors hope this article can stimulate further discussions about what are the next steps for DBS. PMID- 22946922 TI - Analysis of antithyroid drug residues in food animals. AB - In the late 1970s, concerns were raised regarding why antithyroid drugs were being administered to food animals to promote growth despite the fact that they had been implicated as being carcinogenic and teratogenic; the growth promotion process produced an inferior quality meat with increased water retention in the animal's gastrointestinal tract. An increased incidence of aplasia cutis (a characteristic scalp defect) in consumers in Spain was linked to an increased consumption of antithyroid-contaminated meat. Therefore, to protect human health, the EU banned the use of antithyroid drugs in food animal production in 1981. This article reviews the impact of this regulatory decision on the regulatory analysis of these compounds in foods of animal origin. It discusses the physiology of the thyroid gland, the chemistry of antithyroid drugs and critically evaluates the suitability of the analytical methods that have been developed and validated to support enforcement of the regulation. PMID- 22946923 TI - Control of protein-binding kinetics on synthetic polymer nanoparticles by tuning flexibility and inducing conformation changes of polymer chains. AB - Although a number of procedures to create synthetic polymer nanoparticles (NPs) with an intrinsic affinity to target biomacromolecules have been published, little has been reported on strategies to control the binding kinetics of target recognition. Here, we report an enzyme-mimic strategy to control binding/dissociation rate constants of NPs, which bind proteins through multipoint interactions, by taking advantage of the temperature-responsive coil globule phase transition of poly-N-isopropylacrylamide (PNIPAm)-based NPs. PNIPAm NPs with a "flexible" random-coil conformation had a faster binding rate than NPs with a "rigid" globule conformation; however, the dissociation rate constant remained unchanged, resulting in stronger affinity. The dissociation rate of the "flexible" NPs was decelerated by the "induced-fit"-type conformation change of polymers around the coil-globule phase transition temperature, resulting in the formation of the most stable NP-protein complexes. These results provide a guide for designing plastic antibodies with tailor-made binding kinetics and equilibrium constants. PMID- 22946924 TI - The learning mechanism underlying public information use in ninespine sticklebacks (Pungitius pungitius). AB - Elucidating the mechanisms by which animals learn from others is central to understanding the evolution of behavioral adaptations and the constraints that limit options when gathering information about the environment. Here we present findings from three experiments that investigated the psychological mechanisms underlying public-information use in ninespine sticklebacks (Pungitius pungitius). Using a prey patch choice assay we compared two candidate processes, local enhancement and stimulus enhancement. These experiments revealed (a) that fish only selected socially demonstrated prey patches via local enhancement, (b) that even in the absence of any confounding influence of local enhancement there was no evidence for stimulus enhancement in patch choice, and (c) sensitization rather than associative learning underlies the observed public information use. Our findings suggest that local and stimulus enhancement are distinct processes, and that local enhancement is not merely a subcategory of stimulus enhancement, as has previously been argued in the literature. We offer several reasons why learning via stimulus enhancement may not have arisen in ninespine sticklebacks, and speculate that the evolution of this learning mechanism may be favored by specific properties of social structure. PMID- 22946925 TI - Face and eye scanning in gorillas (Gorilla gorilla), orangutans (Pongo abelii), and humans (Homo sapiens): unique eye-viewing patterns in humans among hominids. AB - Because the faces and eyes of primates convey a rich array of social information, the way in which primates view faces and eyes reflects species-specific strategies for facial communication. How are humans and closely related species such as great apes similar and different in their viewing patterns for faces and eyes? Following previous studies comparing chimpanzees (Pan troglodytes) with humans (Homo sapiens), this study used the eye-tracking method to directly compare the patterns of face and eye scanning by humans, gorillas (Gorilla gorilla), and orangutans (Pongo abelii). Human and ape participants freely viewed pictures of whole bodies and full faces of conspecifics and allospecifics under the same experimental conditions. All species were strikingly similar in that they viewed predominantly faces and eyes. No particular difference was identified between gorillas and orangutans, and they also did not differ from the chimpanzees tested in previous studies. However, humans were somewhat different from apes, especially with respect to prolonged eye viewing. We also examined how species-specific facial morphologies, such as the male flange of orangutans and the black-white contrast of human eyes, affected viewing patterns. Whereas the male flange of orangutans affected viewing patterns, the color contrast of human eyes did not. Humans showed prolonged eye viewing independently of the eye color of presented faces, indicating that this pattern is internally driven rather than stimulus dependent. Overall, the results show general similarities among the species and also identify unique eye-viewing patterns in humans. PMID- 22946926 TI - Prey availability influences the ontogeny and timing of chemoreception-based prey shifting in the striped crayfish snake, Regina alleni. AB - Striped crayfish snakes (Regina alleni) undergo a dietary shift from dragonfly larvae to crayfish during ontogeny. Godley (1980) suggested that this shift is attributable to crayfish availability rather than an initial preference for dragonfly larvae. We experimentally tested this hypothesis by measuring the chemosensory response of newborn snakes to prey odors at 2 ages and also after they were fed on either dragonfly larvae or crayfish. The results show that R. alleni respond equally to dragonfly larvae, hard crayfish, and soft crayfish before feeding experience. We also show that the maintenance of this preference over fish and control stimuli is subsequently determined by the prey type encountered, through an unusual interaction. Snakes fed dragonfly larvae increased their chemosensory response to both dragonfly larvae and crayfish, whereas snakes fed crayfish increased their response only to crayfish. Our study demonstrates that innate chemosensory responses to prey can be modified by prey availability and that they do not necessarily result from maturation alone. Such plasticity has adaptive value to newborn animals that must fend for themselves from birth and respond to changing environmental conditions. PMID- 22946927 TI - ReQON: a Bioconductor package for recalibrating quality scores from next generation sequencing data. AB - BACKGROUND: Next-generation sequencing technologies have become important tools for genome-wide studies. However, the quality scores that are assigned to each base have been shown to be inaccurate. If the quality scores are used in downstream analyses, these inaccuracies can have a significant impact on the results. RESULTS: Here we present ReQON, a tool that recalibrates the base quality scores from an input BAM file of aligned sequencing data using logistic regression. ReQON also generates diagnostic plots showing the effectiveness of the recalibration. We show that ReQON produces quality scores that are both more accurate, in the sense that they more closely correspond to the probability of a sequencing error, and do a better job of discriminating between sequencing errors and non-errors than the original quality scores. We also compare ReQON to other available recalibration tools and show that ReQON is less biased and performs favorably in terms of quality score accuracy. CONCLUSION: ReQON is an open source software package, written in R and available through Bioconductor, for recalibrating base quality scores for next-generation sequencing data. ReQON produces a new BAM file with more accurate quality scores, which can improve the results of downstream analysis, and produces several diagnostic plots showing the effectiveness of the recalibration. PMID- 22946929 TI - 2-Deoxy-D-glucose and 6-aminonicotinamide-mediated Nrf2 down regulation leads to radiosensitization of malignant cells via abrogation of GSH-mediated defense. AB - Enhanced level of nuclear erythroid-related factor-2 (Nrf2) has been associated with cancer chemo/radioresistance. Therefore, the role of Nrf2 in radiosensitization of malignant cells induced by a combination of 2-deoxy-D Glucose (2-DG) and 6-aminonicotinamide (6-AN) was investigated. Two established human malignant cells lines namely KB (head and neck squamous carcinoma) and BMG 1 (cerebral glioma) were used. Following treatment with a combination of 2-DG (5 mM) and 6-AN (5 MUM), irradiated (2Gy) KB and BMG-1 cells were assessed for protein level of Nrf2, Keap1 and gamma-glutamylcysteine synthetase (gamma-GCS) by western blotting and mRNA expression of gamma-GCS, glutathione reductase (GR) and glutathione peroxidase (GPx1) by RT-PCR at 24 hours post treatment. A significant decrease in the level of Nrf2 with a concomitant increase in Keap1 was observed in both the irradiated malignant cells at 24 hours following treatment with combination (2-DG + 6-AN). Down regulation of gamma-GCS, GR and GPx1 at 24 hours following treatment with combination (2-DG + 6-AN) resulted in abrogation of glutathione (GSH)-mediated defense in both the irradiated malignant cells. Eventual accumulation of ROS led to radiosensitization of both the malignant cells. These results indicate that deregulated Nrf2-Keap1 signalling leads to the radiosensitization of malignant cells due to abrogated glutathione defense. Metabolic modification-mediated down regulation of Nfr2 and its downstream signalling may have a potential of improving tumour radiotherapy. PMID- 22946928 TI - Covalent attachment of heme to the protein moiety in an insect E75 nitric oxide sensor. AB - We have recombinantly expressed and purified the ligand binding domains (LBDs) of four insect nuclear receptors of the E75 family. The Drosophila melanogaster and Bombyx mori nuclear receptors were purified as ferric hemoproteins with Soret maxima at 424 nm, whereas their ferrous forms had a Soret maximum at 425 nm that responds to (*)NO and CO binding. In contrast, the purified LBD of Oncopeltus fasciatus displayed a Soret maximum at 415 nm for the ferric protein that shifted to 425 nm in its ferrous state. Binding of (*)NO to the heme moiety of the D. melanogaster and B. mori E75 LBD resulted in the appearance of a peak at 385 nm, whereas this peak appeared at 416 nm in the case of the O. fasciatus hemoprotein, resembling the behavior displayed by its human homologue, Rev-erbbeta. High performance liquid chromatography analysis revealed that, unlike the D. melanogaster and B. mori counterparts, the heme group of O. fasciatus is covalently attached to the protein through the side chains of two amino acids. The high degree of sequence homology with O. fasciatus E75 led us to clone and express the LBD of Blattella germanica, which established that its spectral properties closely resemble those of O. fasciatus and that it also has the heme group covalently bound to the protein. Hence, (*)NO/CO regulation of the transcriptional activity of these nuclear receptors might be differently controlled among various insect species. In addition, covalent heme binding provides strong evidence that at least some of these nuclear receptors function as diatomic gas sensors rather than heme sensors. Finally, our findings expand the classes of hemoproteins in which the heme group is normally covalently attached to the polypeptide chain. PMID- 22946931 TI - Spelling-stress regularity effects are intact in developmental dyslexia. AB - The current experiment investigated conflicting predictions regarding the effects of spelling-stress regularity on the lexical decision performance of skilled adult readers and adults with developmental dyslexia. In both reading groups, lexical decision responses were significantly faster and significantly more accurate when the orthographic structure of a word ending was a reliable as opposed to an unreliable predictor of lexical stress assignment. Furthermore, the magnitude of this spelling-stress regularity effect was found to be equivalent across reading groups. These findings are consistent with intact phoneme-level regularity effects also observed in dyslexia. The paper discusses how findings of intact spelling-sound regularity effects at both prosodic and phonemic levels, as well as other similar results, can be reconciled with the obvious difficulties that people with dyslexia experience in other domains of phonological processing. PMID- 22946930 TI - A 1-year randomized, double-blind, placebo-controlled study of intravenous ibandronate on bone loss following renal transplantation. AB - The clinical profile of ibandronate as add-on to calcitriol and calcium was studied in this double-blind, placebo-controlled trial of 129 renal transplant recipients with early stable renal function (<= 28 days posttransplantation, GFR >= 30 mL/min). Patients were randomized to receive i.v. ibandronate 3 mg or i.v. placebo every 3 months for 12 months on top of oral calcitriol 0.25 mcg/day and calcium 500 mg b.i.d. At baseline, 10 weeks and 12 months bone mineral density (BMD) and biochemical markers of bone turnover were measured. The primary endpoint, relative change in BMD for the lumbar spine from baseline to 12 months was not different, +1.5% for ibandronate versus +0.5% for placebo (p = 0.28). Ibandronate demonstrated a significant improvement of BMD in total femur, +1.3% versus -0.5% (p = 0.01) and in the ultradistal radius, +0.6% versus -1.9% (p = 0.039). Bone formation markers were reduced by ibandronate, whereas the bone resorption marker, NTX, was reduced in both groups. Calcium and calcitriol supplementation alone showed an excellent efficacy and safety profile, virtually maintaining BMD without any loss over 12 months after renal transplantation, whereas adding ibandronate significantly improved BMD in total femur and ultradistal radius, and also suppressed biomarkers of bone turnover. Ibandronate was also well tolerated. PMID- 22946933 TI - A mild and reliable method to label enveloped virus with quantum dots by copper free click chemistry. AB - Real-time tracking of the dynamic process of virus invasion is crucial to understanding the infection mechanism. For successful tracking, efficient labeling methods are indispensable. In this paper, we report a mild and reliable method for labeling viruses, especially with regard to easily disabled enveloped viruses. The copper-free click chemistry has been used to label enveloped viruses with quantum dots (QDs) by linking virions modified with azide to the QDs derived with dibenzocyclooctynes (DBCO). Both vaccinia virus (VACV) and avian influenza A virus (H9N2) can be specifically and rapidly labeled under mild conditions, with a labeling efficiency of more than 80%. The labeled virions were of intact infectivity, and their fluorescence was strong enough to realize single-virion tracking. Compared to previously reported methods, our method is less destructive, reliable, and universal, without specific requirements for the type and structure of viruses to be labeled, which has laid the foundation for long term dynamic visualization of virus infection process. PMID- 22946934 TI - Nasoalveolar molding with active columellar lengthening in severe bilateral cleft lip/palate: a clinical report. AB - Severe bilateral cleft-lip/palate patients are difficult to manage even if nasoalveolar molding therapy is advocated before surgical repair. A 5-day-old male infant with bilateral cleft-lip-palate was managed with the nasoalveolar molding technique. Periodic adjustments of the appliance were continued every week to mold the nasoalveolar complex into the desired shape for the 5 months of infancy. The cleft width of 12 mm on the right and 14 mm on the left side was completely reduced, and the absent columella was lengthened to 6 mm with the active molding appliance. The horizontal bar of the nasal stent of the appliance was modified by adding an additional 1 mm layer of resilient liner on the tissue surface to achieve rapid columellar lengthening. In severe bilateral cleft lip/palate cases, simple modifications in the appliance can achieve rapid results. PMID- 22946935 TI - Thrombolysis for acute ST elevation MI: nurse delivered decision support for community staff in remote areas. PMID- 22946936 TI - Guest editors' note for the special issue on the statistical considerations for the design and analysis of bridging and multiregional clinical trials. PMID- 22946937 TI - Ethnic sensitive or molecular sensitive beyond all regions being equal in multiregional clinical trials. AB - For decades, clinical trials have been the primary mechanism for medical products to enter the marketplace. Over more than a decade, globalization of medical product development via a multiregional clinical trial (MRCT) approach has generated greater enthusiasm because of tangible benefits in terms of cost and time for drug development. There are, however, many challenges including and not limited to design issues, statistical analysis methods, interpretation of extreme region performance, and in-process quality assurance issues. This article presents a number of examples to exemplify regional variability expected versus precision of treatment effect estimates that are generally impacted by the type of primary efficacy endpoint evaluated. We explore region-driven intrinsic and extrinsic ethnic factors for potential explanation of regional heterogeneity caused by differences in medical practice and / or disease etiology. Bayesian credible interval may be considered as a viable approach to assess the robustness of region-specific treatment effect. Ethnic-sensitive or molecular-sensitive region-driven designs may be explored to prospectively address the potential regional heterogeneity versus the potential predictiveness of causal genetic variants or molecular target biomarkers on treatment effect. PMID- 22946938 TI - Assessing dose-region profile of drug efficacy: a multiregional trial strategy. AB - In this article, we try to address the optimal dosing issue using a multiregional trial. In this trial, in addition to the treatment group using a globally promising dose of study drug, we have another treatment group using a lower dose treatment with which the drug also shows substantial treatment effect in some of the regions, and both treatment groups share the same placebo (control) group. The incorporation of an additional low-dose treatment group in the multiregional trial can provide the following advantages: (i) The multiregional trial can establish the whole treatment effect profile over different regions as well as drug doses; (ii) the multiregional trial allows for sharing drug efficacy information across different regions; and (iii) the use of a common placebo (control) group for the high- and low-dose treatment groups in the multiregional trial results in logistical convenience. We also examine the regional sample size allocation in the proposed multiregional trial for ensuring a desired power in a local region, using the Bayesian approach we proposed previously for analyzing the multiregional trial data. PMID- 22946939 TI - Statistical methods for bridging studies. AB - In 1998, the International Conference on Harmonization (ICH) published a guidance to facilitate the registration of medicines among ICH regions including the European Union, the United States, and Japan by recommending a framework for evaluating the impact of ethnic factors on a medicine's effect, such as its efficacy and safety at a particular dosage and dose regimen (ICH E5, 1998). The purpose of ICH E5 is not only to evaluate the ethnic factor influence on safety, efficacy, dosage, and dose regimen, but also more importantly to minimize duplication of clinical data and allow extrapolation of foreign clinical data to a new region. In this article, statistical methods for evaluation of bridging studies based on the concepts of consistency (Shih, 2001), reproducibility/generalizability (Shao and Chow, 2002), the weighted Z-tests for the design of bridging studies (Lan et al., 2005), and similarity between the new and original region based in terms of positive treatment effect (Hsiao et al., 2007) are studied. The relative merits and disadvantages of these methods are compared by several examples. PMID- 22946940 TI - A predictive Bayesian approach to the design and analysis of bridging studies. AB - Pharmaceutical product development culminates in confirmatory trials whose evidence for the product's efficacy and safety supports regulatory approval for marketing. Regulatory agencies in countries whose patients were not included in the confirmatory trials often require confirmation of efficacy and safety in their patient populations, which may be accomplished by carrying out bridging studies to establish consistency for local patients of the effects demonstrated by the original trials. This article describes and illustrates an approach for designing and analyzing bridging studies that fully incorporates the information provided by the original trials. The approach determines probability contours or regions of joint predictive intervals for treatment effect and response variability, or endpoints of treatment effect confidence intervals, that are functions of the findings from the original trials, the sample sizes for the bridging studies, and possible deviations from complete consistency with the original trials. The bridging studies are judged consistent with the original trials if their findings fall within the probability contours or regions. Regulatory considerations determine the region definitions and appropriate probability levels. Producer and consumer risks provide a way to assess alternative region and probability choices. [Supplemental materials are available for this article. Go to the Publisher's online edition of the Journal of Biopharmaceutical Statistics for the following free supplemental resource: Appendix 2: R code for Calculations.]. PMID- 22946941 TI - A Bayesian approach for inference from a bridging study with binary outcomes. AB - To address concerns that ethnic differences in any clinical trial may affect the performance of a treatment, separate clinical trials may be required for different regions. If a drug is approved in one region based on a bigger clinical trial, a bridging study with smaller size may be conducted in a new region to evaluate the similarity of the earlier clinical data to the new population. This article applies a Bayesian strategy to combine a bridging study with reference studies to assess treatment effect similarity for binary endpoints. The methods have been illustrated with a numerical example using Markov-chain Monte Carlo (MCMC) techniques. PMID- 22946942 TI - Weighted evidence approach of bridging study. AB - The ICH E5 Guidance facilitates the registration of medicine among ICH regions by recommending a framework for evaluating the impact of ethnic factors upon a medicine's effect. It further describes the use of bridging studies, when necessary, to allow extrapolation of foreign clinical data to a new region. Bridging studies are performed in a new region for medicines already approved in the original region. The conventional noninferiority criterion requires the treatment effect (adjusted for placebo) attained in the new region preserves a prespecified proportion of the treatment effect attained in the original region. Such a bridging criterion, however, is often impractical. Hsiao et al. (2007) proposed a Bayesian approach that borrows the strength of the original trial to establish the treatment effect in the bridging region through using a weighted prior distribution. The weight, however, is often difficult to prespecify. In this presentation, we consider the overall treatment effect by combining the weighted effects attained in the original and bridging regions. The maximum weight allowed to be placed on the estimate of bridging region in order to show a significant overall treatment effect represents the strength of the treatment effect in the bridging region. Regional approval will be evaluated either by comparing the weight estimate with the prespecified limit or by benefit-risk evaluation of the medicine. Sample size requirements for the approaches are derived. The simulation results of type I error rate and power for the proposed methods are given. An example illustrates the application of the proposed procedures. PMID- 22946943 TI - A note on two approaches of testing bridging evidence to a new region. AB - Bridging studies are performed in a new region for medicines already approved in the original region. In order to borrow the strength of the original trial to establish the treatment effect in the bridging region, Lan et al. (2005) proposed to use a weighted z-test approach to combine the test statistics of the same hypothesis for both the original and bridging regions for bridging study. Based on a similar concept, Tsou et al. (2012) proposed instead to test a hypothesis of the weighted treatment effects of the original and bridging regions. In this article, we explore the differences of the concept in hypothesis testing and perform a simulation study to examine the type I error rate and power of the two approaches. PMID- 22946944 TI - Multiregional clinical trials: Japanese perspective on drug development strategy and sample size for Japanese subjects. AB - Multiregional clinical trials including Japanese subjects are playing a key role in new drug development in Japan. In addition to the consideration of differences in intrinsic and extrinsic ethnic factors, deciding the sample size of Japanese subjects is an important issue when a multiregional clinical trial is intended to be used for Japanese submission. Accumulated experience suggests that there are several points to consider, such as the basic principles described in the guidance document, drug development strategy, trial phase, and disease background. The difficulty of interpreting the results of Japanese trials should also be considered. PMID- 22946945 TI - Qualitative consistency of treatment effects in multiregional clinical trials. AB - Consistency of treatment effects across different regions in multiregional clinical trials (MRCTs) has been an important question for the regulatory authorities. Many consistency definitions are proposed in literature. One of the definitions of consistency is expressed as qualitative consistency, whereas inconsistency is defined as qualitative treatment by region interaction. This article focuses on the qualitative consistency and extends Gail-Simon and Sasabuchi's one-sided multivariate likelihood ratio tests. Simulations are used to evaluate operating characteristics of these qualitative consistency assessment approaches. For a given number of regions, the guideline for setting significance level, and consistency cut-off are explored. PMID- 22946946 TI - Decision rules and associated sample size planning for regional approval utilizing multiregional clinical trials. AB - Multiregional clinical trials provide the potential to make safe and effective medical products simultaneously available to patients globally. As regulatory decisions are always made in a local context, this poses huge regulatory challenges. In this article we propose two conditional decision rules that can be used for medical product approval by local regulatory agencies based on the results of a multiregional clinical trial. We also illustrate sample size planning for such trials. PMID- 22946947 TI - Assessment of regional treatment effect in a multiregional clinical trial. AB - The 11th question-and-answer document (Q&A) for ICH E5 (1998) was published in 2006. This Q&A describes points to consider for evaluating the possibility of bridging among regions by a multiregional trial. The primary objective of a multiregional bridging trial is to show the overall efficacy of a drug in all participating regions while also evaluating the possibility of applying the overall trial results to each region. To apply the overall results to a specific region, it suggested that the results in that region should be consistent with the overall results. The Japanese Ministry of Health, Labor, and Welfare (MHLW) published the "Basic Principles on Global Clinical Trials" guidance document (2007) and proposed two methods to support the bridging claims. Due to the limited sample sizes allocated to the region, the regular interaction test for treatment by region is not practical. On the other hand, the sample size requirement for the Japanese region as described in Uyama et al. (2005) and Uesaka (2009) is to satisfy an 80% or greater power for the Japanese region, conditioning on the effect of the overall global trial. Quan et al. (2010) further extended the results to trials with various endpoints. Ko, Tsou, Liu and Hsiao (2010) focused on a specific region and established statistical criteria for consistency between the region of interest and overall results. The proposed method was based on the assumption that true effect size is uniform across regions. In this article, we propose to analyze a completed multiregional trial for any specific regional effect by controlling the type I error rate adjusted for the regional sample size and the planned power of the global trial. Accordingly, in order to attain the approval for a specific region, we propose to determine the sample size requirement for the specific regions using the overall power planned and a regional acceptable type I error rate. PMID- 22946948 TI - Design and evaluation of multiregional trials with heterogeneous treatment effect across regions. AB - To speed up drug development to allow faster access to medicines for patients globally, conducting multiregional trials incorporating subjects from many countries around the world under the same protocol may be desired. Several statistical methods have been proposed for the design and evaluation of multiregional trials. However, in most of the recent approaches for sample size determination in multiregional trials, a common treatment effect of the primary endpoint across regions is usually assumed. In practice, it might be expected that there is a difference in treatment effect due to regional difference (e.g., ethnic difference). In this article, a random effect model for heterogeneous treatment effect across regions is proposed for the design and evaluation of multiregional trials. We also address consideration of the determination of the number of subjects in a specific region to establish the consistency of treatment effects between the specific region and the entire group. PMID- 22946949 TI - Design and analysis issues of multiregional clinical trials with different regional primary endpoints. AB - One of the challenges of multiregional drug development program is to design and analyze a multiple regional clinical trial with the objective being to satisfy different regional requirements on primary endpoints. Considered in this article is a multiregional clinical trial (MRCT) designed to test for two primary endpoints. Data of a regular fixed-size well-controlled parallel arm trial are used to test for two null hypotheses in terms of two distinct yet correlated endpoints. The two hypotheses may be tested sequentially or simultaneously. Depending on the structure of the hypotheses to be tested and the understanding of type I error rate control, various scenarios of type I error rate adjustments may be applied. Furthermore, for the objective of getting approval from regional authorities for different primary endpoints, various sample size and power determinations may be applied. In this article, comparisons of different approaches are discussed systematically. PMID- 22946950 TI - Design and sample size considerations for simultaneous global drug development program. AB - Due to the potential impact of ethnic factors on clinical outcomes, the global registration of a new treatment is challenging. China and Japan often require local trials in addition to a multiregional clinical trial (MRCT) to support the efficacy and safety claim of the treatment. The impact of ethnic factors on the treatment effect has been intensively investigated and discussed from different perspectives. However, most current methods are focusing on the assessment of the consistency or similarity of the treatment effect between different ethnic groups in exploratory nature. In this article, we propose a new method for the design and sample size consideration for a simultaneous global drug development program (SGDDP) using weighted z-tests. In the proposed method, to test the efficacy of a new treatment for the targeted ethnic (TE) group, a weighted test that combines the information collected from both the TE group and the nontargeted ethnic (NTE) group is used. The influence of ethnic factors and local medical practice on the treatment effect is accounted for by down-weighting the information collected from NTE group in the combined test statistic. This design controls rigorously the overall false positive rate for the program at a given level. The sample sizes needed for the TE group in an SGDDP for three most commonly used efficacy endpoints, continuous, binary, and time-to-event, are then calculated. PMID- 22946951 TI - Practical and statistical considerations on simultaneous global drug development. PMID- 22946952 TI - Statistical considerations on design and analysis of bridging and multiregional clinical trials. PMID- 22946956 TI - Diagnosis and classification of factor XIII deficiencies. PMID- 22946958 TI - Facebook surveillance of former romantic partners: associations with postbreakup recovery and personal growth. AB - Previous research has found that continuing offline contact with an ex-romantic partner following a breakup may disrupt emotional recovery. The present study examined whether continuing online contact with an ex-partner through remaining Facebook friends and/or engaging in surveillance of the ex-partner's Facebook page inhibited postbreakup adjustment and growth above and beyond offline contact. Analysis of the data provided by 464 participants revealed that Facebook surveillance was associated with greater current distress over the breakup, more negative feelings, sexual desire, and longing for the ex-partner, and lower personal growth. Participants who remained Facebook friends with the ex-partner, relative to those who did not remain Facebook friends, reported less negative feelings, sexual desire, and longing for the former partner, but lower personal growth. All of these results emerged after controlling for offline contact, personality traits, and characteristics of the former relationship and breakup that tend to predict postbreakup adjustment. Overall, these findings suggest that exposure to an ex-partner through Facebook may obstruct the process of healing and moving on from a past relationship. PMID- 22946957 TI - Preventing compulsory admission to psychiatric inpatient care through psycho education and crisis focused monitoring. AB - BACKGROUND: The high number of involuntary placements of people with mental disorders in Switzerland and other European countries constitutes a major public health issue. In view of the ethical and personal relevance of compulsory admission for the patients concerned and given the far-reaching effects in terms of health care costs, innovative interventions to improve the current situation are much needed. A number of promising approaches to prevent involuntary placements have been proposed that target continuity of care by increasing self management skills of patients. However, the effectiveness of such interventions in terms of more robust criteria (e.g., admission rates) has not been sufficiently analysed in larger study samples. The current study aims to evaluate an intervention programme for patients at high risk of compulsory admission to psychiatric hospitals. Effectiveness will be assessed in terms of a reduced number of psychiatric hospitalisations and days of inpatient care in connection with involuntary psychiatric admissions as well as in terms of cost-containment in inpatient mental health care. The intervention furthermore intends to reduce the degree of patients' perceived coercion and to increase patient satisfaction, their quality of life and empowerment. METHODS/DESIGN: This paper describes the design of a randomised controlled intervention study conducted currently at four psychiatric hospitals in the Canton of Zurich. The intervention programme consists of individualised psycho-education focusing on behaviours prior to and during illness-related crisis, the distribution of a crisis card and, after inpatient admission, a 24-month preventive monitoring of individual risk factors for compulsory re-admission to hospital. All measures are provided by a mental health care worker who maintains permanent contact to the patient over the course of the study. In order to prove its effectiveness the intervention programme will be compared with standard care procedures (control group). 200 patients each will be assigned to the intervention group or to the control group. Detailed follow-up assessments of service use, psychopathology and patient perceptions are scheduled 12 and 24 months after discharge. DISCUSSION: Innovative interventions have to be established to prevent patients with mental disorders from undergoing the experience of compulsory admission and, with regard to society as a whole, to reduce the costs of health care (and detention). The current study will allow for a prospective analysis of the effectiveness of an intervention programme, providing insight into processes and factors that determine involuntary placement. PMID- 22946959 TI - Metabolic syndrome, its pathophysiology and the role of melatonin. AB - Metabolic syndrome (MetS) is characterised by symptoms of obesity, insulin resistance, hypertension, dyslipidemia and diabetes mellitus. The pathophysiological mechanisms involved in MetS are complex and involved dysregulation of many biochemical and physiological regulatory mechanisms of the body. Elevated levels of low density lipoproteins like VLDL, and LDL with reduction of HDL seen in patients with MetS contribute to atherogenic dyslipedemia. Melatonin has been suggested to be effective in improving MetS through its anti-hyperlipidemic action. Melatonin reduced both adiposity, and body weight in experimental animal studies and also attenuated weight gain and obesityinduced metabolic alterations and this effect of melatonin is attributed to its anti-oxidative effects. Melatonin administration has been shown to inhibit insulin release by acting through both MT1 and MT2 melatonin receptors present in pancreatic beta-cells. Melatonin also increased insulin sensitivity and glucose tolerance in animals fed with either high fat or high sucrose diet. Melatonin exerts most of its beneficial actions by acting through MT1 and MT2 melatonin receptors present in various tissues of the body and some of the metabolic actions of melatonin have been blocked by melatonin antagonist like luzindole. Ramelteon, the newly available melatonin agonist will also have more promising role in the control of MetS. The numbers of patents are available with regard to treatment of MetS. Drug related to antidepressant fluoxetine is used for treatment of MetS (US Patent No. 2008001400450). Anti-oxidants like S-adenosyl methionine, Vitamin E, and Vitamin C have been found beneficial in treating MetS (US Patent No. 8063024). Melatonin being a powerful Antioxidant will have a promising role in treating patients with metabolic syndrome. PMID- 22946961 TI - A red baby should not be taken too lightly. AB - AIM: To identify clinical and laboratory features that can drive the differential diagnosis of a primary immunodeficiency diseases in patients with ectodermal defects. METHODS: Analysis of selected teaching cases. RESULTS: We identified four exemplary cases that allowed to point out specific clues. CONCLUSIONS: A careful evaluation of immune and ectodermal signs is the key to the diagnosis. Therefore, a multidisciplinary approach can lead to diagnosis and to an appropriate treatment in most of the cases. PMID- 22946960 TI - Control of TMEM16A by INO-4995 and other inositolphosphates. AB - BACKGROUND AND PURPOSE: Ca(2+)-dependent Cl(-) secretion (CaCC) in airways and other tissues is due to activation of the Cl(-) channel TMEM16A (anoctamin 1). Earlier studies suggested that Ca(2+) -activated Cl(-) channels are regulated by membrane lipid inositol phosphates, and that 1-O-octyl-2-O-butyryl-myo-inositol 3,4,5,6-tetrakisphosphate octakis(propionoxymethyl) ester (INO-4995) augments CaCC. Here we examined whether TMEM16A is the target for INO-4995 and if the channel is regulated by inositol phosphates. EXPERIMENTAL APPROACH: The effects of INO-4995 on CaCC were examined in overexpressing HEK293, colonic and primary airway epithelial cells as well as Xenopus oocytes. We used patch clamping, double electrode voltage clamp and Ussing chamber techniques. KEY RESULTS: We found that INO-4995 directly activates a TMEM16A whole cell conductance of 6.1 +/ 0.9 nS pF(-1) in overexpressing cells. The tetrakisphosphates Ins(3,4,5,6)P(4) or Ins(1,3,4,5)P(4) and enzymes controlling levels of InsP(4) or PIP(2) and PIP(3) had no effects on the magnitude or kinetics of TMEM16A currents. In contrast in Xenopus oocytes, human airways and colonic cells, which all express TMEM16A endogenously, Cl(-) currents were not acutely activated by INO-4995. However incubation with INO-4995 augmented 1.6- to 4-fold TMEM16A-dependent Cl(-) currents activated by ionomycin or ATP, while intracellular Ca(2+) signals were not affected. The potentiating effect of INO-4995 on transient ATP-activated TMEM16A-currents in cystic fibrosis (CF) airways was twice of that observed in non-CF airways. CONCLUSIONS AND IMPLICATIONS: These data indicate that TMEM16A is the target for INO-4995, although the mode of action appears different for overexpressed and endogenous channels. INO-4995 may be useful for the treatment of CF lung disease. PMID- 22946962 TI - Cimetidine enhances delayed-type hypersensitivity responses and serum interleukin (IL)-2, -10, -12, and IL-17 levels after burn injury in an animal model. AB - The immunosuppression that occurs after burn injury causes an increase in susceptibility to infection. The aim was to investigate time-related alterations in various cytokines following thermal injury and to modulate cytokines by use of an immunomodulant, cimetidine. Male Balb/c mice were anesthetized and given a 10% total body surface area full-thickness burn by submerging in 90 degrees C water for 9 s. Time-dependent changes in delayed type hypersensitivity (DTH) and serum levels of the cytokines IL-2, IL-10, IL-12, IL-17 and TGFbeta were then assessed at various post-burn day (PBD) timepoints. Effects of 10 mg cimetidine/kg on DTH responses and cytokine levels were evaluated up to PBD 14. In comparison to healthy non-burned control mice, levels of IL-2 and IL-17 significantly decreased at PBD 3, 5, 10, and 14, those of IL-10 at PBD 1, 3, 5, and 10, and those of IL 12 at PBD 1, 3, 5, 10, and 14. Administration of cimetidine significantly augmented the levels of IL-2 (at PBD 3, 5, and 10), IL-10 (at PBD 1 and 5), IL-12 (at PBD 3, 5, 10, and 14), and IL-17 (at PBD 3 and 14) as compared to those in burned counterparts who did not receive drug. In comparison to healthy mice, biphasic alterations were observed regarding TGFbeta levels; values were significant decreased and increased at PBD 3 and PBD 14, respectively. Cimetidine significantly diminished the elevated TGFbeta levels at PBD 14. Cimetidine also significantly augmented DTH responses at PBD 5, 10, and 14 as compared to responses in non-drug-treated burned hosts. Taken together, the results here showed significant time-dependent changes in serum cytokines levels after burn injury and that cimetidine was able to significantly augment IL-2, IL-10, IL-12, and IL-17 levels as well as DTH responses that are normally suppressed following thermal trauma. PMID- 22946963 TI - Molecular cloning and characterization of peroxiredoxin 4 involved in protection against oxidative stress in the silkworm Bombyx mori. AB - Peroxiredoxins (Prxs) are a ubiquitous family of proteins that play important roles in insects in protection against oxidative stress through the detoxification of cellular peroxides. Here, we describe the cloning and characterization of a Prx4 cDNA of the silkworm Bombyx mori (BmPrx4). The BmPrx4 gene has an open reading frame of 744 bp encoding 248 amino acids and a conserved motif, VCP, involved in its presumed redox functions. The heterologously expressed proteins of the gene in Escherichia coli showed antioxidant activity, removed hydrogen peroxide and protected DnA. Western blotting analysis showed the presence of BmPrx4 in the haemolymph, suggesting that the protein is secretable. Moreover, BmPrx4 was expressed at all developmental stages. The expression level of BmPrx4 was relatively low during the feeding stage but high at the wandering stage. BmPrx4 was induced by quercetin or temperature stress. Immunohistochemical analysis revealed that BmPrx4 is present in the brain, neurones and olfactory organ of the head in silkworms. Overall, our results indicate that the expression profile of BmPrx4 correlates well with protection from oxidative damage. Our data provide clues for the development of control technology for agricultural and forestry pests as the silkworm is a representative of lepidopteran pests. PMID- 22946964 TI - Quantum chemical parametrization and spectroscopic characterization of the Frenkel exciton Hamiltonian for a J-aggregate forming perylene bisimide dye. AB - Quantum chemical and quantum dynamical calculations are performed for a bay substituted perylene bisimide dye up to its hexameric aggregate. The aggregate structure is determined by employing the self-consistent charge density functional tight-binding (SCC-DFTB) approach including dispersion corrections. It is characterized by a stabilization via two chains of hydrogen bonds facilitated by amide functionalities. Focusing on the central embedded dimer, the Coulomb coupling for this J-aggregate is determined by means of the time-dependent density functional theory (TDDFT) to be -514 cm(-1). Exciton vibrational coupling is treated within the shifted oscillator model from which five strongly coupled modes per monomer are selected for inclusion into a minimal dynamic model. Performing wave packet propagations for a model employing up to 7 electronic states and 30 vibrational modes using the multiconfiguration time-dependent Hartree method, aggregate absorption spectra are obtained and compared to experiment. PMID- 22946965 TI - Extradural haemorrhage: is there a role for endovascular treatment? AB - The middle meningeal artery (MMA) is the most proximal and largest branch of the internal maxillary artery (IMA). It courses superiorly to the foramen spinosum making a sharp right angle bend entering the skull. The MMA has frontal, parietal and petrosal branches, the frontal branch being identified by its anterior convex curve along the greater wing of sphenoid. Trauma and a resultant extradural haematoma (EDH) demands urgent neurosurgical intervention to prevent imminent foramen magnum herniation and rapid demise. The seriousness of EDHs cannot be overstated and is a clear neurosurgical emergency requiring immediate definitive management. Historically craniotomy is the gold standard. But recent advances propose angiography and subsequent embolization as an alternative to craniotomy. We employed embolization to manage EDHs in two cases whose original clinical presentation did not demand urgent surgery. We discuss their subsequent management focusing on treatment choices and the potential role of endovascular techniques. We describe an alternative diagnostic protocol and embolic agents using Onyx and coils. PMID- 22946966 TI - Single-dose antibiotic prophylaxis is effective enough in colorectal surgery. AB - BACKGROUND: The aim of this study was to investigate the hypothesis that prevention of surgical site infection (SSI) is equally effective when patients receive single-dose (SD) or three-dose antibiotic prophylaxis with second generation cephalosporin and metronidazole in elective colorectal surgery. METHODS: Ninety-three patients were enrolled from May 2009 to November 2010. The SD group received only one preoperative prophylactic intravenous dose and the three-dose or multiple-dose (MD) group received one preoperative prophylactic and two additional post-operative doses of second-generation cephalosporin and metronidazole. The incidence of infectious complications (SSI of the incision site and organ/space) was compared in the two groups. RESULTS: The overall post operative infection rate did not differ between the two groups (16.7% in the SD versus 13.3% in the MD, P = 0.653). The incidence of SSI of the incision site and organ/space also did not differ between the groups (6.3% (3/48) versus 4.4% (2/45), P = 0.700; 4.2% versus 6.7%, P = 0.593, respectively). The number of antibiotics administered was not an independent risk factor for SSIs in multivariable analysis. CONCLUSIONS: SD antibiotic prophylaxis with second generation cephalosporin and metronidazole is equivalent to a three-dose prophylaxis for preventing SSI in elective colorectal surgery. But further study would be needed to clarify this because of the small number of participants. PMID- 22946968 TI - Experienced donors, adverse events, and retention. PMID- 22946969 TI - Lessons learned from Trypanosoma cruzi test implementation. PMID- 22946970 TI - The effect of various platelet dosing strategies on transfusion costs. PMID- 22946971 TI - Transfusion medicine illustrated. Identification of blood draw error during trauma resuscitation. PMID- 22946973 TI - Erythropoietin provides a useful strategy for treating preoperative anemia in planned elective orthopedic surgery: an analysis of benefit in routine practice. PMID- 22946974 TI - Cord blood quality after vaginal and cesarean deliveries. PMID- 22946975 TI - Evaluation of iron status in volunteers and autologous blood donors: are there implications for an extended blood donation age? PMID- 22946976 TI - Allo- and autoanti-D in weak D types and in partial D. PMID- 22946977 TI - Anti-D alloimmunization propensity cannot be determined without information on D antigen exposure. PMID- 22946979 TI - The efficacy of gabapentin versus stabilization splint in management of sleep bruxism. AB - PURPOSE: This study aimed to determine if the use of gabapentin is more efficacious than a stabilization splint with regard to the intensity of masseter muscle contractions and/or sleep quality for patients experiencing sleep bruxism (SB). MATERIALS AND METHODS: Twenty patients with SB participated in this clinical study. They were randomly divided into two treatment groups: stabilization splint group (n = 10) and gabapentin group (n = 10). The first polysomnographic examination was performed before the beginning of the experiment for all the participants. At the end of a 2-month period of stabilization splint therapy or gabapentin usage, a second polysomnographic recording was made. RESULTS: Statistically significant reductions in the number of SB episodes per hour and per night, bruxism time index, total duration of SB episodes per night and number of SB episodes in stages NR I and NR II (p < 0.05) were observed in both groups after treatment. Both treatments significantly reduced the mean intensity of masseter muscle contractions during SB episodes. Moreover, the participants treated with gabapentin showed a significant improvement in total sleep time, slow wave sleep (stage III), and sleep efficiency (p < 0.05). CONCLUSIONS: Gabapentin could be an effective treatment modality in SBs, especially in those with poor sleep quality. PMID- 22946980 TI - Clinical validity of the counseling center assessment of psychological symptoms 62 (CCAPS-62): further evaluation and clinical applications. AB - Self-report instruments of psychological symptoms are increasingly used in counseling centers but rely on rigorous evaluation of their clinical validity. Three studies reported here (total N = 26,886) investigated the validity of the Counseling Center Assessment of Psychological Symptoms-62 (CCAPS-62; Locke et al., 2011) as an assessment and screening instrument. In Study 1, initial evidence regarding the concurrent validity of the CCAPS-62 was replicated and extended in a naturalistic clinical sample of clients from 16 counseling centers. Using this sample, convergent validity of the subscales was examined in counseling center clients, the range of sensitivity of the subscales was investigated using item-response theory, and the presence of 2nd-order factors was preliminarily examined. In Study 2, 7 of the 8 CCAPS-62 subscales statistically significantly differentiated between students in counseling and those who were not, using data collected from a large national survey, although most differences were small and the groups' distributions overlapped considerably. Cut scores based on the differences between these clinical and nonclinical populations showed limited utility due to overall similarities between these broadly defined groups. In Study 3, therapist-rated diagnoses collected from 5 university counseling centers were used to further examine the validity of subscale scores. In addition, cut points for diagnostic screening using receiver operating characteristic curves were evaluated. Overall, these studies support the use of the CCAPS-62 as an initial measure of psychological symptoms in college counseling settings, provide additional information about its psychometric performance, develop cut scores, and illustrate the potential for collaboration between practitioners and researchers on a large scale. PMID- 22946981 TI - Is the allegiance effect an epiphenomenon of true efficacy differences between treatments? a meta-analysis. AB - Many meta-analyses of comparative outcome studies found a substantial association of researcher allegiance (RA) and relative treatment effects. Therefore, RA is regarded as a biasing factor in comparative outcome research (RA bias hypothesis). However, the RA bias hypothesis has been criticized as causality might be reversed. That is, RA might be a reflection of true efficacy differences between treatments (true efficacy hypothesis). Consequently, the RA-outcome association would not be indicative of bias but an epiphenomenon of true efficacy differences. This meta-analysis tested the validity of the true efficacy hypothesis. This was done by controlling the RA-outcome association for true efficacy differences by restricting analysis to direct comparisons of treatments with equivalent efficacy. We included direct comparisons of different versions of trauma-focused therapy (TFT) in the treatment of posttraumatic stress disorder (PTSD). RA was measured from the research reports. Relative effect sizes for symptoms of PTSD were calculated. Random effects meta-regression was conducted. Twenty-nine comparisons of TFTs from 20 studies were identified. Initial heterogeneity among relative effect sizes was low. RA was a significant predictor of outcome and explained 12% of the variance in outcomes. The true efficacy hypothesis predicted the RA-outcome association to be zero; however, a substantial association was found. Thus, this study does not support the true efficacy hypothesis. Given findings from psychotherapy research and other fields that support a biasing influence of researcher preferences, RA should be regarded as a causal factor and conceptualized as a threat to the validity of conclusions from comparative outcome studies. PMID- 22946982 TI - The unfolding of the real relationship and the outcome of brief psychotherapy. AB - This study sought to assess the association of client- and therapist-rated real relationship with each other and with the outcome of brief psychotherapy. It also aimed to determine whether changes over time in perceptions of the real relationship and increasing convergence between clients' and therapists' ratings of the real relationship were associated with outcome. Forty-two clients and their therapists (n = 19) at 2 university counseling centers completed measures assessing the strength of their real relationship after every session of brief psychotherapy. They also completed an outcome measure at the end of treatment. Clients' ratings of the real relationship after the first session, first quarter of treatment, and after all sessions combined related to outcomes. Therapists' ratings of the real relationship at these time points did not relate to outcome. However, increases over time in therapists' ratings of real relationship strength, as well as increasing convergence with clients' ratings of the real relationship, did relate to outcome. Implications for future research and practice are discussed. PMID- 22946983 TI - Further development of the temporal model of control. AB - The temporal model of control (Frazier, Berman, & Steward, 2001) posits that different temporal aspects of control (i.e., past, present, and future) have markedly different relations with adjustment and need to be clearly distinguished from each other. The Perceived Control over Stressful Events Scale (PCOSES; Frazier, Keenan, et al., 2011) was recently developed to assess these different aspects of control and to advance understanding of the role of perceived control in adjustment to stressful life events. The goals of the 2 studies presented here were to expand the temporal model of control by developing a new subscale of the PCOSES and to gather additional evidence regarding the temporal model. In Study 1, we developed a new future likelihood subscale and found evidence for the internal consistency, test-retest reliability, and construct validity of its scores in a sample of undergraduate students (N = 201). In Study 2, we confirmed the 4-factor structure of the PCOSES with the new future likelihood subscale using confirmatory factor analysis in another sample of undergraduates (N = 1,084). Study 2 also provided additional evidence, consistent with the temporal model, that the PCOSES subscales were differentially related to distress and other forms of adjustment (e.g., physical health) and that present control and future likelihood were associated with less event-related distress after controlling for 4 known correlates of distress (e.g., social support). Implications for counseling psychology research and practice are discussed. PMID- 22946984 TI - Intuitive eating scale: an examination among early adolescents. AB - The Intuitive Eating Scale (IES; Tylka, 2006) initially was developed in a sample of college women to measure adaptive forms of eating, such as eating based on physiological rather than emotional cues. This study extends the work of Tylka (2006) and reports the psychometric evaluation of the IES in a sample of 515 middle-school boys and girls. Exploratory factor analysis identified 4 factors: Unconditional Permission to Eat, Eating for Physical Rather Than Emotional Reasons, Trust in Internal Hunger/Satiety Cues, and Awareness of Internal Hunger/Satiety Cues. These factors were confirmed in a separate sample and, with 4 items from the original scale dropped, the model fit the data well. Supporting its validity, IES scores were related inversely to body mass index, body dissatisfaction, negative affect, pressure for thinness, and internalization of the thin ideal, and positively to satisfaction with life and positive affect. The underlying structure of this measure appears valid for early adolescence, though it may be best defined by fewer items and one additional factor. PMID- 22946985 TI - Effects of malaria volunteer training on coverage and timeliness of diagnosis: a cluster randomized controlled trial in Myanmar. AB - BACKGROUND: The use of community volunteers is expected to improve access to accurate diagnosis and timely treatment of malaria, using rapid diagnostic test (RDT) and artemisinin-based combination therapy (ACT). However, empirical data from the field are still limited. The aim of this study was to assess whether training village volunteers on the use of Paracheck-Pf(r) RDT and ACT (artemether lumefantrine (AL)) for Plasmodium falciparum and presumptive treatment with chloroquine for Plasmodium vivax had an effect on the coverage of timely diagnosis and treatment and on mortality in malaria-endemic villages without health staff in Myanmar. METHODS: The study was designed as a cluster randomized controlled trial with a cross-sectional survey at baseline, a monthly visit for six months following the intervention (village volunteers trained and equipped with Paracheck-Pf(r)) and an endline survey at six months follow-up. Survey data were supplemented by the analysis of logbooks and field-based verbal autopsies. Villages with midwives (MW) in post were used as a third comparison group in the endline survey. Intention-to-treat analysis was used. RESULTS: Of 38 villages selected, 21 were randomly assigned to the intervention (two villages failed to participate) and 17 to the comparison group. The two groups had comparable baseline statistics. The blood tests provided by volunteers every month declined over time from 279 tests to 41 but not in MW group in 18 villages (from 326 to 180). In the endline survey, among interviewed subjects (268 intervention, 287 in comparison, 313 in MW), the coverage of RDT was low in all groups (14.9%, SE 2.4% in intervention; 5.7%, SE 1.7% in comparison; 21.4%, SE 2.6% in MW) although the intervention (OR 3.2, 95% CI 1.5-6.7) and MW (OR 5.4, 95% CI 2.6-11.0) were more likely to receive a blood test. Mean (SE) of blood tests after onset of fever in days was delayed (intervention 3.6 (0.3); comparison 4.8 (1.3); MW 3.2 (0.4)). Malaria mortality rates per 100,000 populations in a year were not significantly different (intervention 130 SE 37; comparison 119 SE 34; MW 50 SE 18). None of the dead cases had consulted volunteers. CONCLUSIONS: The results show that implementing volunteer programmes to improve the coverage of accurate and timely diagnosis with RDT and early treatment may be beneficial but the timeliness of detection and sustainability must be improved. PMID- 22946987 TI - The importance of hydrogen bonding to stereoselectivity and catalyst turnover in gold-catalyzed cyclization of monoallylic diols. AB - Density functional calculations and experiment were used to examine the mechanism, reactivity, and origin of chirality transfer in monophosphine Au catalyzed monoallylic diol cyclization reactions. The lowest energy pathway for cyclization involves a two-step sequence that begins with intramolecular C-O bond formation by anti-addition of the non-allylic hydroxyl group to the Au coordinated alkene followed by concerted hydrogen transfer/anti-elimination to liberate water. Concerted S(N)2'-type transition states were found to be significantly higher in energy. The two-step cyclization pathway is extremely facile due to hydrogen bonding between diol groups that induces nucleophilic attack on the alkene and then proton transfer between diol groups after C-O bond formation. Importantly, intramolecular proton transfer and elimination provides an extremely efficient avenue for catalyst regeneration from the Au-C sigma-bond intermediate, in contrast to other Au-catalyzed cyclization reactions where this intermediate severely restricts catalyst turnover. The origin of chirality transfer and the ensuing alkene stereochemistry is also the result of strong hydrogen-bonding interactions between diol groups. In the C-O bond-forming step, requisite hydrogen bonding biases the tethered nucleophilic moiety to adopt a chair-like conformation with substituents in either axial or equatorial positions, dictating the stereochemical outcome of the reaction. Since this hydrogen bonding is maintained throughout the course of the reaction, establishment of the resultant olefin geometry is also attributed to this templating effect. These computational conclusions are supported by experimental evidence employing bicyclic systems to probe the facial selectivity. PMID- 22946986 TI - Advantage of rapamycin over mycophenolate mofetil when used with tacrolimus for simultaneous pancreas kidney transplants: randomized, single-center trial at 10 years. AB - Simultaneous pancreas kidney transplantation (SPKT) is the treatment of choice for patients with type 1 diabetes and end-stage renal disease. Rapamycin and mycophenolate mofetil (MMF) have been used for maintenance immunosuppression with tacrolimus in SPKT; however, long-term outcomes are lacking. From September 2000 through December 2009, 170 SPKT recipients were enrolled in a randomized, prospective trial receiving Rapamycin (n = 84) or MMF (n = 86). All patients received dual induction therapy with thymoglobulin and daclizumab, and low-dose maintenance tacrolimus and corticosteroids. Compared to MMF, rates of freedom from first biopsy-proven acute kidney or pancreas rejection were superior for Rapamycin at year 1 (kidney: 100% vs. 88%; P = 0.001; pancreas: 99% vs. 92%; P = 0.04) and at year 10 (kidney: 88% vs. 71%, P = 0.01; pancreas: 99% vs. 89%, P = 0.01). The higher rates of rejection were associated with withholding MMF (vs. Rapamycin, p = 0.009), generally for gastrointestinal or bone marrow toxicity. There was no significant difference in creatinine, proteinuria, c-peptide, viral infections, lymphoproliferative disorders or posttransplant diabetes. HbA1C and lipid levels were normal in both groups, although higher in the Rapamycin arm. There were no significant differences in patient or allograft survival. In this 10-year SPKT study, Rapamycin in combination with tacrolimus was better tolerated and more effective than MMF. Overall, the patient and allograft survival were equivalent. PMID- 22946988 TI - Acceptability of early infant male circumcision among Chinese parents: strategy implications of HIV prevention for China. AB - BACKGROUND: Recent evidence has confirmed that circumcision can be performed as a preventive strategy for HIV and early infant male circumcision (EIMC) is regarded to be safer than circumcision in adulthood; however, limited data are available in the literature about EIMC in China. Therefore, the present study was designed to determine the willingness and attitudes of Chinese parents on newborn male circumcision so as to provide data for exploring the feasibility of implementing EIMC as an HIV prevention strategy in China. METHODS: Simple random sampling was used to draw participants from parents who had a newborn son delivered at Nanjing Maternity and Child Health Care Hospital, which is affiliated to Nanjing Medical University, between March and December 2010. A questionnaire was used to determine general medical knowledge or information about circumcision, attitudes about EIMC, and level of decision-making on circumcision for the newborn son. RESULTS: Data derived from 558 responses were analyzed and the ratio of respondents was 56.3% for fathers and 43.6% for mothers. Of the respondents, 34.4% agreed to circumcise their newborn son, and the level of agreement was 3.25 +/- 1.17 (range, 1-5 with "1" being "reluctantly agree" and "5" being "very strongly agree"). The major reason for EIMC was for health (44.8%), followed by doctor's advice (31.2%). The major reason not to agree to EIMC was concern about pain (50.5%), followed by the risk of the procedure (23.5%). CONCLUSION: The willingness and acceptability of EIMC in China is low and the parents of newborn sons are usually not very affirmative when making a decision on such a procedure, suggesting that significant effort will be needed if EIMC is to be implemented as an HIV prevention strategy for China. PMID- 22946990 TI - AAC assessment and clinical-decision making: the impact of experience. AB - People with complex communication needs often require a comprehensive augmentative and alternative communication (AAC) assessment to maximize participation in daily interactions. Assessment of AAC is a complex process and limited practice guidelines exist. The purpose of this qualitative study was to explore how 25 speech-language pathologists with varying levels of experience approach the AAC assessment process. Participants were classified as either (a) General Practice Speech-Language Pathologists (GPSLPs), (b) AAC Clinical Specialists (AAC-CS), or (c) AAC Research/Policy Specialists (AAC-RS). In-depth, semi-structured interviews were conducted to explore the participants' approach to AAC assessment. The results revealed that GPSLPs approach AAC assessment differently than the AAC-CS and AAC-RS; however, the Specialists reported a similar approach that may help guide the development of practice guidelines for AAC assessment. PMID- 22946989 TI - Considerations for the composition of visual scene displays: potential contributions of information from visual and cognitive sciences. AB - Aided augmentative and alternative (AAC) interventions have been demonstrated to facilitate a variety of communication outcomes in persons with intellectual disabilities. Most aided AAC systems rely on a visual modality. When the medium for communication is visual, it seems likely that the effectiveness of intervention depends in part on the effectiveness and efficiency with which the information presented in the display can be perceived, identified, and extracted by communicators and their partners. Understanding of visual-cognitive processing - that is, how a user attends, perceives, and makes sense of the visual information on the display - therefore seems critical to designing effective aided AAC interventions. In this Forum Note, we discuss characteristics of one particular type of aided AAC display, that is, Visual Scene Displays (VSDs) as they may relate to user visual and cognitive processing. We consider three specific ways in which bodies of knowledge drawn from the visual cognitive sciences may be relevant to the composition of VSDs, with the understanding the direct research with children with complex communication needs is necessary to verify or refute our speculations. PMID- 22946991 TI - Reading instruction for children who use AAC: considerations in the pursuit of generalizable results. AB - Our purpose was to review evidence-based literacy instruction for children with severe speech impairment (SSI) who communicate with AAC. This review focuses on three issues important to researchers in this area: participant heterogeneity, assessment and instruction tasks, and research design. We found eight articles that reported attempts to teach phonological awareness and individual-word reading to a total of 26 children with SSI who used AAC. We evaluated these studies based on reporting of participant characteristics, assessment and instruction modifications, and the strength of research designs. We conclude by highlighting the need for standard assessments that can be used across studies, discussing strategies for facilitating meta-analyses, and suggesting the creation of an online database for researchers to share results on literacy instruction for this population. PMID- 22946992 TI - Family impact of assistive technology scale: development of a measurement scale for parents of children with complex communication needs. AB - Young people use augmentative and alternative communication (AAC) systems to meet their everyday communication needs. However, the successful integration of an AAC system into a child's life requires strong commitment and continuous support from parents and other family members. This article describes the development and evaluation of the Family Impact of Assistive Technology Scale for AAC Systems - a parent-report questionnaire intended to detect the impact of AAC systems on the lives of children with complex communication needs and their families. The study involved 179 parents and clinical experts to test the content and face validities of the questionnaire, demonstrate its internal reliability and stability over time, and estimate its convergent construct validity when compared to a standardized measure of family impact. PMID- 22946993 TI - Intelligibility of children's speech in digitized speech. AB - The current investigation examined the intelligibility of digitized speech recorded from typically developing child speakers, ages 4, 5, 6, and 7 years, and reproduced on an augmentative and alternative communication (AAC) device with digitized speech output. The study used a between group design. Forty adults were asked to transcribe 120 words spoken by child speakers in one of the age groups, and presented on an AAC device with digitized speech output. The dependent variable was intelligibility (percent of words correctly identified) of the children's speech. Overall, the intelligibility of children's speech increases with the age of the child speaker. However, there was a lot of individual variation in the intelligibility of children's voices. There was no clear cut-off age, although the speech of some young children may not be sufficiently intelligible on an AAC device that uses digitized speech. Clinicians and parents choosing child speakers for AAC devices with digitized speech are cautioned to carefully consider the speakers used for recording digitized speech output and the characteristics of the speech of the individual speaker. Future research directions are discussed. PMID- 22946994 TI - Representation of potential communication items in medical settings: an intervention note. AB - Current augmentative and alternative communication (AAC) devices require individuals in medical settings to spell, locate symbols or phrases, or use non verbal communication to express health and personal information to family and medical staff. The purpose of this initial investigation was to examine the type (personal, family, staff, procedural, or health status), form or representation and frequency of items that could be used to represent communication content for people in inpatient rehabilitation settings. Results revealed that potential communication items within the personal or procedural categories were consistently represented in participants' rooms. Information related to medical staff was the least consistently represented and appeared to change frequently. The use of items to support the communication of patients with unmet communication needs is discussed. PMID- 22946995 TI - Prevalence of overconditioning in mature horses in southwest Virginia during the summer. AB - BACKGROUND: The prevalence of obesity in horses in the eastern United States is not well documented. OBJECTIVE: To determine body condition and risk factors for obesity in horses in Southwest Virginia during summer. ANIMALS: A sample of 300 mature (4-20 years old), light breed horses (140 mares, 151 geldings, and 9 stallions) from the VMRCVM Equine Field Service practice equine database. The horses were from 114 farms and 138 owners. METHODS: Horses were evaluated over a 60-day period in this cross-sectional, prospective study. A questionnaire was completed for each horse. Body condition score (BCS) was assigned using a scale of 1 (emaciated) to 9 (obese) by 2 independent scorers. Morphometric measurements included average neck circumference (ANC), girth, body length, and height at the withers. Horses were categorized based on BCS as underconditioned (BCS < 4), optimal condition (BCS 4-6), overconditioned (BCS 7), and obese condition (BCS 8 9). RESULTS: Five horses (1.7%) were underconditioned, 142 horses (47.3%) were optimally conditioned, 97 horses (32.3%) were overconditioned, and 56 (18.7%) were obese. Estimated body weight (EBW) (r = 0.14, P = .015), body mass index (BMI) (r = 0.46, P < .001), and neck circumference to height ratio (NCHR) (r = 0.50, P = .001) increased with increasing BCS. CONCLUSIONS AND CLINICAL IMPORTANCE: The prevalence of overconditioned and obese horses in this population was higher than reported in previous studies and indicates that obesity might be an emerging problem in horses. PMID- 22946996 TI - Only connect: the merger of BMC Pharmacology and BMC Clinical Pharmacology. AB - This editorial celebrates the launch of BMC Pharmacology and Toxicology within the BMC series of journals published by BioMed Central. The scope of the journal is interdisciplinary encompassing toxicology, experimental and clinical pharmacology including clinical trials. In this editorial we discuss the origins of this new journal and the ethos and policies under which it will operate. PMID- 22946998 TI - An expanded myeloid derived suppressor cell population does not play a role in gammaherpesvirus-exacerbated breast cancer metastases. AB - BACKGROUND: Mice latently infected with murine gammaherpesvirus 68 (HV-68) and transplanted with 4 T1 breast cancer cells developed exacerbated metastatic lesions when compared to controls. The mechanisms responsible for this viral exacerbated disease were not clear. The ability of HV-68 infection to induce S100A8 and S100A9 production and to expand a population of CD11b+Gr-1+ cells suggested that increased numbers, or activity, of viral-expanded myeloid derived suppressor cells (MDSCs) might contribute to HV-68-associated metastatic breast cancer in this model. We questioned whether mock or HV-68 infected mice with significant breast cancer might have differences in the number and/or activity of MDSCs. METHODS: Myeloid-derived macrophages and dendritic cells were isolated from normal mice and cultured in vitro with HV-68 to assess S100A8 and S100A9 mRNA and protein expression. In vivo studies were performed using groups of mice that were mock treated or infected with HV-68. After viral latency was established, 4 T1 breast cancer cells were transplanted in mice. When primary breast tumors were present mice were euthanized and cells isolated for phenotyping of myeloid cell populations using FACS, and for ex vivo analysis of suppressor activity. Serum from these animals was also collected to quantify S100A8 and S100A9 levels. RESULTS: In vitro studies demonstrated that direct exposure of myeloid cells to HV-68 did not induce increased expression of S100A8 or S100A9 mRNAs or secreted protein. HV-68 infected mice with metastatic breast cancer disease had no increases in S100A8/A9 levels and no significant increases in the numbers or activation of CD11b+Gr-1+MDSCs when compared to mock treated mice with breast cancer. CONCLUSIONS: Together these studies are consistent with the notion that expanded myeloid derived suppressor cells do not play a role in gammaherpesvirus-exacerbated breast cancer metastases. The mechanisms responsible for HV-68 induced exacerbation of metastatic breast cancer remain unclear. PMID- 22946999 TI - Shock tube studies on the decomposition of 2-butanol. AB - The thermal decomposition of 2-butanol have been studied at temperatures of 1045 1221 K and pressures of 1.5-6 bar using the single pulse shock tube technique. Dilute concentrations of 2-butanol have been decomposed in the presence of large quantities of a radical inhibitor. The mechanism for decomposition involves direct elimination of water producing cis- and trans-2-butene, and 1-butene, and C-C bond fission producing ethylene. Acetaldehyde, propionaldehyde, and propene were also observed in much smaller yields from C-C bond fission. The respective unimolecular rate expressions are as follows: k(C(3)H(6)(OH)CH(3) -> cis CH(3)CH?CHCH(3) + H(2)O) = 10(13.1 +/- 0.3) exp(-33414 +/- 755 K/T) s(-1); k(C(3)H(6)(OH)CH(3) -> trans-CH(3)CH?CHCH(3) + H(2)O) = 10(13.5 +/- 0.3) exp( 33820 +/- 755 K/T) s(-1); k(C(3)H(6)(OH)CH(3) -> CH(3)CH(2)CH?CH(2) + H(2)O) = 10(13.6 +/- 0.3) exp(-33002 +/- 755 K/T) s(-1); k(C(3)H(6)(OH)CH(3) -> C(2)H(5)(*) + (*)CH(OH)CH(3)) = 10(15.9 +/- 0.3) exp(-39252 +/- 755 K/T) s(-1). These rate expressions are compared with analogous reactions for primary and tertiary butanols. They form a basis for the prediction of those for related systems. Comparison with estimated values used in the simulation of butanol combustion is indicative of the uncertainties in the rate constants that are used in such models. The activation energy of 326 kJ/mol leads to a bond dissociation energy of the CH(OH)CH(3) radical (H-CH(OH)CH(3)) of 400 kJ/mol, in excellent agreement with earlier calculated results from theory and disagreement with the experimental results from iodination studies in the expected range. PMID- 22946997 TI - Extreme genetic diversity in the lizard Atlantolacerta andreanskyi (Werner, 1929): a montane cryptic species complex. AB - BACKGROUND: Atlantolacerta andreanskyi is an enigmatic lacertid lizard that, according to the most recent molecular analyses, belongs to the tribe Eremiadini, family Lacertidae. It is a mountain specialist, restricted to areas above 2400 m of the High Atlas Mountains of Morocco with apparently no connection between the different populations. In order to investigate its phylogeography, 92 specimens of A. andreanskyi were analyzed from eight different populations across the distribution range of the species for up to 1108 base pairs of mitochondrial DNA (12S, ND4 and flanking tRNA-His) and 2585 base pairs of nuclear DNA including five loci (PDC, ACM4, C-MOS, RAG1, MC1R). RESULTS: The results obtained with both concatenated and coalescent approaches and clustering methods, clearly show that all the populations analyzed present a very high level of genetic differentiation for the mitochondrial markers used and are also generally differentiated at the nuclear level. CONCLUSIONS: These results indicate that A. andreanskyi is an additional example of a montane species complex. PMID- 22947000 TI - What new immunotherapeutic techniques are currently being investigated for the treatment of melanoma? PMID- 22947001 TI - Cancer battlefield: six characters in search of an author. PMID- 22947003 TI - Conference scene: Immune signatures in the tumor and beyond. AB - Led by key opinion leaders in the field, the Cancer Immunotherapy Consortium of the Cancer Research Institute 2012 Scientific Colloquium included 179 participants who exchanged cutting-edge information on basic, clinical and translational cancer immunology and immunotherapy. The meeting revealed how rapidly this field is advancing. The keynote talk was given by Wolf H Fridman and it described the microenvironment of primary and metastatic human tumors. Participants interacted through oral presentations and panel discussions on topics that included host reactions in tumors, advances in imaging, monitoring therapeutic immune modulation, the benefit and risk of immunotherapy, and immune monitoring activities. In summary, the annual meeting gathered clinicians and scientists from academia, industry and regulatory agencies from around the globe to interact and exchange important scientific advances related to tumor immunobiology and cancer immunotherapy. PMID- 22947004 TI - Conference scene: taking the heat out of chaperokine function. AB - The field of heat-shock protein (HSP) research has been revitalized when extracellular HSPs were reported in the literature in the 1990s. Emerging findings suggest that HSPs can perform a wide variety of biological functions, more than their traditional role as molecular chaperones. With prominent speakers from various HSP fields, the 1(st) Heat Shock Protein - Multiple Roles in Inflammation, Vaccination and Homeostasis Conference covered topics on intracellular and extracellular HSPs along with the role of bacterial and self HSPs. This conference, organized by Euroscicon, brought together more than 20 delegates from industry and academia for a lively discussion of the current state of HSP research. PMID- 22947005 TI - Mechanisms of endogenous MHC class II presentation by tumor cells. AB - Evaluation of: Tsuji T, Matsuzaki J, Caballero OL et al. Heat shock protein 90 mediated peptide-selective presentation of cytosolic tumor antigen for direct recognition of tumors by CD4(+) T cells. J. Immunol. 188, 3851-3858 (2012). In this study, Tsuji and colleagues investigated how tumor antigen NY-ESO-1 was processed by melanoma cells and subsequently presented on HLA class II for the recognition of NY-ESO-1-specific CD4(+) T cells. Using a combination of specific inhibitors and RNAi techniques, they found that tumor cells utilize a novel peptide selective antigen presentation pathway that requires both proteasome and endosomal protease-dependent processing, as well as heat-shock protein 90 dependent chaperoning. This newly described tumor-specific, endogenous MHC class II antigen presentation could have an impact on both antitumor or protumor T-cell responses. PMID- 22947006 TI - The case for HER2/neu as a therapeutic target for gynecologic malignancies. AB - Evaluation of: Guzzo F, Bellone S, Buza N et al. HER2/neu as a potential target for immunotherapy in gynecological carcinosarcomas. Int. J. Gynecol. Pathol. 31, 211-221 (2012). Trastuzumab (Herceptin((r))) is a human monoclonal antibody that is US FDA-approved for the treatment of HER2/neu-overexpressing breast cancer and metastatic gastric cancer. HER2/neu expression has also been observed in other malignancies, notably in subsets of endometrial and ovarian cancers, raising the possibility that trastuzumab may be a viable treatment option in these settings. The current paper reveals that HER2/neu may also be expressed in gynecologic carcinosarcomas, which are rare but aggressive tumors with a high rate of resistance to chemotherapy. Cell lines derived from ovarian carcinosarcomas expressed HER2/neu and were sensitive to trastuzumab ADCC. By contrast, cell lines derived from uterine carcinosarcomas were HER2/neu-negative and insensitive to trastuzumab ADCC. These observations indicate that at least a subset of gynecologic carcinosarcoma patients may benefit from trastuzumab treatment. However, trastuzumab monotherapy typically has relatively low response rates, which in part may be related to impaired NK cell function in patients with advanced disease. Accordingly, treatments that boost NK cell activity may improve response rates to trastuzumab treatment, not only for gynecologic carcinosarcomas, but also for other HER2/neu-positive malignancies. PMID- 22947007 TI - Effects of alkaloid sinomenine on levels of IFN-gamma, IL-1beta, TNF-alpha and IL 6 in a rat renal allograft model. AB - AIMS: To evaluate the immunosuppressive efficacy of alkaloid sinomenine (SIN) and the synergistic effects in combination with cyclosporin A (CsA) in acute rejection after rat renal allograft. MATERIALS & METHODS: Animals were treated with saline in group 1, SIN (30 mg/kg/d) in group 2, CsA (2.5 mg/kg/d) in group 3 and SIN (30 mg/kg/d) + CsA(2.5 mg/kg/d) in group 4. Another 12 syngeneic renal transplantation animals were treated with saline as control. Survival time is observed. The levels of serum creatinine (Scr) and blood urea nitrogen (Bun) were detected; the secretion of IFN-gamma, IL-1beta, TNF-alpha and IL-6 were detected by ELISA. The kidneys were fixed to perform histological staining. RESULTS: The mean survival time was 8.00 +/- 2.10 days in group 1, 10.67 +/- 1.21 days in group 2, 11.00 +/- 1.41 days in group 3 and 19.67 +/- 2.80 days in group 4, while all the recipients survived more than 180 days in the control group. The 24-h urinary volume and urinary time of the other three groups were increased significantly compared with group 1. The levels of Scr and Bun, levels of IFN gamma, IL-1beta, TNF-alpha and IL-6 were significantly higher in group 1 than that in the other three groups; there were significant differences between group 4 and group 2 or 3. CONCLUSION: Our study showed that SIN had immunosupression effects in rat renal allograft models, it also had a synergistic effect in combination with CsA, which provided a new immunosuppressant for clinical application. PMID- 22947008 TI - Immunomodulating therapy in liver transplantation: principles and practice. AB - Liver transplantation has enjoyed dramatic success as a treatment option for patients suffering from chronic end-stage liver diseases. It also serves as a definitive treatment for certain genetic conditions such as familial amyloidosis and primary oxalosis, and as a potential curative therapy in selected cases of primary liver cancer. Currently, over 50,000 patients are alive with functioning liver transplants. Liver transplantation owes its success to advances in surgical technique, improvements in anesthesia and critical care, and advances in treatment of post-transplant complications including improved therapies for cytomegalovirus infections. But perhaps the most important advances in liver transplantation arise in the context of improvements in our understanding of the molecular biology of transplant immunology and the development of new agents that allow for manipulation of immunological signaling pathways. These improvements in immunosuppressive therapy have dramatically increased both graft and patient survival. PMID- 22947009 TI - Chemokine-based immunotherapy: delivery systems and combination therapies. AB - A major role of chemokines is to mediate leukocyte migration through interaction with G-protein-coupled receptors. Various delivery systems have been developed to utilize the chemokine properties for combating disease. Viral and mutant viral vectors expressing chemokines, genetically modified dendritic cells with chemokine or chemokine receptors, engineered chemokine-expressing tumor cells and pDNA encoding chemokines are among these methods. Another approach for inducing a targeted immune response is fusion of a targeting antibody or antibody fragment to a chemokine. In addition, chemokines induce more effective antitumor immunity when used as adjuvants. In this regard, chemokines are codelivered along with antigens or fused as a targeting unit with antigenic moieties. In this review, several chemokines with their role in inducing immune response against different diseases are discussed, with a major emphasis on cancer. PMID- 22947010 TI - Heat-shock proteins as endogenous ligands building a bridge between innate and adaptive immunity. AB - There has been growing evidence that heat-shock protein (HSP) functions as an endogenous immunomodulator for innate and adaptive immune responses. Since HSPs inherently act as chaperones within cells, passive release (e.g., by cell necrosis) and active release (including release by secretion in the form of an exosome) have been suggested as mechanisms of HSP release into the extracellular milieu. Such extracellular HSPs have been shown to be activators of innate immune responses through Toll-like receptors. However, it has also been suggested that HSPs augment the ability of associated innate ligands such as lipopolysaccharides to stimulate cytokine production and dendritic cell maturation. More interestingly, a recent study has demonstrated that innate immune responses elicited by danger signals were regulated spatiotemporally and that can be manipulated by HSPs, thereby controlling immune responses. We will discuss how spatiotemporal regulation of HSP-chaperoned molecules within antigen-presenting cells affects adaptive immunity via antigen cross-presentation and innate immune responses. Precise analysis of HSP biology should lead to the establishment of effective HSP-based immunotherapy. PMID- 22947011 TI - Allergen immunotherapy: how to balance the different views from pulmonologists and allergists? AB - Allergen immunotherapy (AIT) is the treatment characterizing the allergological approach to respiratory allergy. Unfortunately, most available data from the literature and current practice indicate that pulmonologists do no consider AIT when choosing the treatment strategy in patients with asthma. Indeed AIT, from its introduction in 1911 to nowadays, was unceasingly improved and has accumulated clear evidence on its effectiveness. Moreover, AIT has a characteristic not shared by drugs in the capacity to modify the natural history of asthma, due to its immunologic mechanisms of actions, and thus also works after the treatment withdrawal. This also makes AIT a clearly cost-effective treatment over time. It is surprising that pulmonologists, for whom asthma is a major disease to manage, do not consider AIT when choosing the optimal treatment in single patients. The insufficient information on AIT and the availability of allergen extracts with less than good quality are likely to be the most important factors influencing such an attitude. The current development of standardized, pharmaceutical-grade products for AIT seems capable of making allergen extracts comparable to drugs and to stimulate a rethinking of AIT's role in the treatment of asthma in pulmonologists. A reappraisal of the significance of the allergen specific bronchial challenge could represent a further factor suggesting AIT as a reliable option. PMID- 22947013 TI - Effect of temperature and cationic chain length on the physical properties of ammonium nitrate-based protic ionic liquids. AB - We report a systematic study of the effect of the cationic chain length and degree of hydrogen bonding on several equilibrium and transport properties of the first members of the alkylammonium nitrate protic ionic liquids (PILs) family (ethylammonium, propylammonium, and butylammonium nitrate) in the temperature range between 10 and 40 degrees C. These properties were observed by means of several experimental techniques, including density, surface tension, refractometry, viscosimetry, and conductimetry. The dilatation coefficients and compressibilities, as well as the Rao coefficients, were calculated, and an increase of these magnitudes with alkyl chain length was detected. Moreover, the surface entropies and enthalpies of the studied PILs were analyzed, and the temperature dependence of the surface tension was observed to be describable by means of a harmonic oscillator model with surface energies and critical temperatures that are increasing functions of the cationic chain length. Moreover, the refractive indexes were measured and the thermo-optic coefficient and Abbe numbers were calculated, and the contribution of the electrostrictive part seemed to dominate the temperature dependence of the electric polarization. The electric conductivity and the viscosity were measured and the influence of the degree of hydrogen bonding in the supercooled liquid region analyzed. Hysteresis loops were detected in freezing-melting cycles and the effect of the length of the alkyl chain of the cation on the size of the loop analyzed, showing that longer chains lead to a narrowing of the supercooled region. The temperature dependence of the conductivity was studied in the Vogel-Fulcher-Tamman (VFT) framework and the fragility indices, the effective activation energies, and the Vogel temperatures obtained. A high-temperature Arrhenius analysis was also performed, and the activation energies of conductivity and viscosity were calculated, showing that these transport processes are governed by two distinct mechanisms. The exponents of the fractional Walden rule for the different compounds were obtained. Finally, the ionicities and fragilities of the studied PILs were analyzed, proving that all the studied PILs are subionic and fragile liquids, with propylammonium nitrate showing the lowest fragility and the greater ionicity of all the studied compounds. PMID- 22947014 TI - The role of time preference in smoking cessation: a longitudinal analysis of data from the Household Income and Labour Dynamics of Australia survey, 2001-08. AB - AIMS: Time preference describes how consideration of future events may affect present-day behavioural decisions. The aim was to establish whether time preference predicts smoking cessation in a longitudinal analysis. DESIGN: Secondary analysis of data from the Household Income and Labour Dynamics of Australia survey. SETTING: Australian community. PARTICIPANTS: Members of the Household Income and Labour Dynamics of Australia survey panel, aged 15-64 years, who responded to at least four waves of data collection between 2001 and 2008, and reported any level of tobacco consumption at any wave. MEASUREMENTS: Smoking cessation was measured using a self-report questionnaire. Time preference was measured using self-reported time-period for financial planning. A range of socio demographic and smoking-related covariates were controlled for. FINDINGS: A total of 1817 individuals were included in the analysis, representing 7913 separate observations. After controlling for socio-demographic and smoking-related covariates, the hazard ratio of quitting in those with longer versus shorter-term time preference (95% confidence intervals) = 1.28 (1.02-1.59). CONCLUSIONS: Adult smokers with a longer-term time preference, who are more likely to consider future events when making present-day decisions, are more likely to quit smoking. PMID- 22947016 TI - Differential oxidative stress induction and lethality of rat embryos after maternal exposure to t-butyl hydroperoxide during postimplantation period. AB - In mammals, reactive oxygen species (ROS) are essential factors for cell proliferation, differentiation, and growth, notably during gestation, but are also potentially damaging agents. The present study describes the extent and pattern of oxidative stress (OS) induction in maternal milieu, placenta, and embryos of rats after in vivo exposure to sublethal doses of a well-known model prooxidant, such as t-butyl hydroperoxide (tbHP). tbHP administered (intraperitoneally) to pregnant rats on specific gestation days (GDs) (either GD(5-7) or GD(8-10)) at dosages of [one tenth the median lethal dose (LD(50)) and one fifth LD(50)/day) caused significant OS, as evident by enhancement of malondialdehyde (MDA) and ROS levels, depleted reduced glutathione levels and elevated protein carbonyl content in maternal liver and kidney. Further, tbHP treatment also caused significant oxidative impairments in placenta, whereas the weights were marginally increased. Further, tbHP treatment induced a higher incidence of embryonic lethality (4- to 6-fold higher than controls) and induced marked OS among GD(13) embryos, as evidenced by elevated MDA, ROS generation, altered redox status, and enzymatic antioxidant defenses, suggesting the vulnerability of embryos. Interestingly, incidence of embryonic mortality and degree of oxidative dysfunctions caused by tbHP treatment during GD(5-7) was relatively higher, compared with GD(8-10), suggesting differential susceptibility of embryos during the early postimplantation period. Based on these findings, it is hypothesized that critical windows during early gestation may account for the differential susceptibility of developing embryos to pro-oxidants and necessitate a better understanding of this embryonic response to pro-oxidant exposures. PMID- 22947017 TI - HELM: a hierarchical notation language for complex biomolecule structure representation. AB - When biological macromolecules are used as therapeutic agents, it is often necessary to introduce non-natural chemical modifications to improve their pharmaceutical properties. The final products are complex structures where entities such as proteins, peptides, oligonucleotides, and small molecule drugs may be covalently linked to each other, or may include chemically modified biological moieties. An accurate in silico representation of these complex structures is essential, as it forms the basis for their electronic registration, storage, analysis, and visualization. The size of these molecules (henceforth referred to as "biomolecules") often makes them too unwieldy and impractical to represent at the atomic level, while the presence of non-natural chemical modifications makes it impossible to represent them by sequence alone. Here we describe the Hierarchical Editing Language for Macromolecules ("HELM") and demonstrate its utility in the representation of structures such as antisense oligonucleotides, short interference RNAs, peptides, proteins, and antibody drug conjugates. PMID- 22947018 TI - Self-assembled monolayer-functionalized half-metallic manganite for molecular spintronics. AB - (La,Sr)MnO(3) manganite (LSMO) has emerged as the standard ferromagnetic electrode in organic spintronic devices due to its highly spin-polarized character and air stability. Whereas organic semiconductors and polymers have been mainly envisaged to propagate spin information, self-assembled monolayers (SAMs) have been overlooked and should be considered as promising materials for molecular engineering of spintronic devices. Surprisingly, up to now the first key step of SAM grafting protocols over LSMO surface thin films is still missing. We report the grafting of dodecyl (C12P) and octadecyl (C18P) phosphonic acids over the LSMO half-metallic oxide. Alkylphosphonic acids form ordered self assembled monolayers, with the phosphonic group coordinated to the surface and alkyl chains tilted from the surface vertical by 43 degrees (C12P) and 27 degrees (C18P). We have electrically characterized these SAMs in nanodevices and found that they act as tunnel barriers, opening the door toward the integration of alkylphosphonic acid//LSMO SAMs into future molecular/organic spintronic devices such as spin OLEDs. PMID- 22947020 TI - Abstracts of the AABB Annual Meeting and CTTXPO. Boston, Massachusetts, USA. October 6-9, 2012. PMID- 22947019 TI - BOROX catalysis: self-assembled amino-BOROX and imino-BOROX chiral Bronsted acids in a five component catalyst assembly/catalytic asymmetric aziridination. AB - A five-component catalyst assembly/aziridination reaction is described starting from an aldehyde, an amine, ethyl diazoacetate, B(OPh)(3), and a molecule of a vaulted biaryl ligand (VAPOL or VANOL). A remarkable level of chemo-selectivity was observed since, while 10 different products could have resulted from various reactions between the five components, an aziridine was formed in 85% yield and 98% ee and only two other products could be detected in 3% yield. Studies reveal that the first in a sequence of three reactions is an exceedingly rapid amine induced assembly of an amino-BOROX chiral Bronsted acid species from VAPOL and B(OPh)(3), which is followed by imine formation from the amine and aldehyde and the concomitant formation of an imino-BOROX chiral Bronsted acid and finally the reaction of the imine with ethyl diazoacetate mediated by the imino-BOROX catalyst to give aziridine-2-carboxylic esters with very high diastereo- and enantioselectivity. PMID- 22947024 TI - Construction of an implant-retained auricular prosthesis with the aid of contemporary digital technologies: a clinical report. AB - Implant-retained auricular prostheses are a successful treatment modality for children with microtia. They involve only minor surgical intervention of implant placement and result in an esthetically pleasing outcome. Integration of digital technologies (DT) in the prosthetic reconstruction process is a new approach toward enhancing outcomes. In this report we present a case of auricular prosthetic reconstruction following two implant placements in the right mastoid region. The ear prosthesis was constructed with the aid of various DTs. A structured light laser scanner was used to digitize the nondefect patient ear. The digitized 3D ear was then manipulated in specialist software, mirrored to reflect the opposing side, and a Rapid Prototyping (RP) machine (Z-Corp) was used to manufacture the soft tissue required. This RP-mirrored ear model allows very accurate reproduction to replicate missing soft tissue. A color Spectrometer was used to accurately reproduce skin tones. The use of these technologies is now routine practice at our unit. They enhance prosthetic outcomes and esthetics, save the prosthetist's time, and are digitally stored and subsequently readily available and reproducible. PMID- 22947025 TI - Immobilization of anti-aflatoxin B1 antibody by UV polymerization of aniline and aflatoxin B1 detection via electrochemical impedance spectroscopy. AB - In the study, we investigated the practicality of the UV polymerization of aniline for anti-aflatoxin B1 antibody immobilization, and utilization of the resulting biosensor in the impedimetric determination of aflatoxin B1. The anti aflatoxin B 1 antibody was physically immobilized on gold electrodes by UV polymerization of aniline at a fixed wavelength. The biosensor was based on specific interaction anti-aflatoxin B1 - aflatoxin B1 recognition and investigation of this recognition event by electrochemical impedance spectroscopy. A calibration curve was obtained in a linear detection range 1-20 ng/mL aflatoxin B1. Finally, the biosensor was applied to analysis of a real food sample. PMID- 22947026 TI - Ventilation distribution in rats: Part I--The effect of gas composition as measured with electrical impedance tomography. AB - The measurement of ventilation distribution is currently performed using inhaled tracer gases for multiple breath inhalation studies or imaging techniques to quantify spatial gas distribution. Most tracer gases used for these studies have properties different from that of air. The effect of gas density on regional ventilation distribution has not been studied. This study aimed to measure the effect of gas density on regional ventilation distribution. METHODS: Ventilation distribution was measured in seven rats using electrical impedance tomography (EIT) in supine, prone, left and right lateral positions while being mechanically ventilated with either air, heliox (30% oxygen, 70% helium) or sulfur hexafluoride (20% SF6, 20% oxygen, 60% air). The effect of gas density on regional ventilation distribution was assessed. RESULTS: Gas density did not impact on regional ventilation distribution. The non-dependent lung was better ventilated in all four body positions. Gas density had no further impact on regional filling characteristics. The filling characteristics followed an anatomical pattern with the anterior and left lung showing a greater impedance change during the initial phase of the inspiration. CONCLUSION: It was shown that gas density did not impact on convection dependent ventilation distribution in rats measured with EIT. PMID- 22947027 TI - Concurrent ivermectin and Solanum spp. toxicosis in a herd of horses. AB - BACKGROUND: Representatives from a herd of horses with acute onset of neurologic signs after administration of ivermectin presented for evaluation and treatment. OBJECTIVES: Describe clinical signs of horses intoxicated by ingestion of Solanum sp. and administered ivermectin. ANIMALS: Six of 11 affected unrelated horses presented for evaluation and treatment. The remaining 5 affected horses were treated at the farm. Four additional horses, housed separately, were unaffected. METHODS: Case series is presented. Serum ivermectin concentrations were evaluated in the 6 hospitalized horses. The remnants of the tubes of ivermectin paste were analyzed for ivermectin concentration. The hay fed to the affected horses was analyzed for the presence of toxic plants. RESULTS: Serum ivermectin concentrations were higher than expected, given the dosage of ivermectin administered. The ivermectin concentration remaining in the administration tubes did not exceed specifications. The hay was heavily contaminated by 2 Solanum species. All horses returned to normal neurologic function with supportive care. CONCLUSIONS AND CLINICAL IMPORTANCE: Horses might exhibit signs of ivermectin toxicity after appropriate dosing of the drug if they concurrently consume toxic plants of the Solanum family. PMID- 22947028 TI - Likelihood based observability analysis and confidence intervals for predictions of dynamic models. AB - BACKGROUND: Predicting a system's behavior based on a mathematical model is a primary task in Systems Biology. If the model parameters are estimated from experimental data, the parameter uncertainty has to be translated into confidence intervals for model predictions. For dynamic models of biochemical networks, the nonlinearity in combination with the large number of parameters hampers the calculation of prediction confidence intervals and renders classical approaches as hardly feasible. RESULTS: In this article reliable confidence intervals are calculated based on the prediction profile likelihood. Such prediction confidence intervals of the dynamic states can be utilized for a data-based observability analysis. The method is also applicable if there are non-identifiable parameters yielding to some insufficiently specified model predictions that can be interpreted as non-observability. Moreover, a validation profile likelihood is introduced that should be applied when noisy validation experiments are to be interpreted. CONCLUSIONS: The presented methodology allows the propagation of uncertainty from experimental to model predictions. Although presented in the context of ordinary differential equations, the concept is general and also applicable to other types of models. Matlab code which can be used as a template to implement the method is provided at http://www.fdmold.uni freiburg.de/~ckreutz/PPL. PMID- 22947030 TI - Serotonin immunoreactive interneurons in the brain of the Remipedia: new insights into the phylogenetic affinities of an enigmatic crustacean taxon. AB - BACKGROUND: Remipedia, a group of homonomously segmented, cave-dwelling, eyeless arthropods have been regarded as basal crustaceans in most early morphological and taxonomic studies. However, molecular sequence information together with the discovery of a highly differentiated brain led to a reconsideration of their phylogenetic position. Various conflicting hypotheses have been proposed including the claim for a basal position of Remipedia up to a close relationship with Malacostraca or Hexapoda. To provide new morphological characters that may allow phylogenetic insights, we have analyzed the architecture of the remipede brain in more detail using immunocytochemistry (serotonin, acetylated alpha tubulin, synapsin) combined with confocal laser-scanning microscopy and image reconstruction techniques. This approach allows for a comprehensive neuroanatomical comparison with other crustacean and hexapod taxa. RESULTS: The dominant structures of the brain are the deutocerebral olfactory neuropils, which are linked by the olfactory globular tracts to the protocerebral hemiellipsoid bodies. The olfactory globular tracts form a characteristic chiasm in the center of the brain. In Speleonectes tulumensis, each brain hemisphere contains about 120 serotonin immunoreactive neurons, which are distributed in distinct cell groups supplying fine, profusely branching neurites to 16 neuropilar domains. The olfactory neuropil comprises more than 300 spherical olfactory glomeruli arranged in sublobes. Eight serotonin immunoreactive neurons homogeneously innervate the olfactory glomeruli. In the protocerebrum, serotonin immunoreactivity revealed several structures, which, based on their position and connectivity resemble a central complex comprising a central body, a protocerebral bridge, W-, X-, Y-, Z tracts, and lateral accessory lobes. CONCLUSIONS: The brain of Remipedia shows several plesiomorphic features shared with other Mandibulata, such as deutocerebral olfactory neuropils with a glomerular organization, innervations by serotonin immunoreactive interneurons, and connections to protocerebral neuropils. Also, we provided tentative evidence for W-, X-, Y-, Z-tracts in the remipedian central complex like in the brain of Malacostraca, and Hexapoda. Furthermore, Remipedia display several synapomorphies with Malacostraca supporting a sister group relationship between both taxa. These homologies include a chiasm of the olfactory globular tract, which connects the olfactory neuropils with the lateral protocerebrum and the presence of hemiellipsoid bodies. Even though a growing number of molecular investigations unites Remipedia and Cephalocarida, our neuroanatomical comparison does not provide support for such a sister group relationship. PMID- 22947031 TI - Synthesis of silylene-bridged endohedral metallofullerene Lu3N@I(h)-C80. AB - Functionalization of endohedral metallofullerenes has been shown to differ depending on photochemical or thermal pathways. We report that Lu(3)N@I(h)-C(80) reacts with thermally generated bis(2,6-diethylphenyl)silylene with high selectivity and forms monosilylated derivative 1b. Unexpectedly, 1b undergoes photochemical conversion to afford isomer 1a under ambient light. These adducts were characterized using NMR, visible-near-IR spectroscopy, and matrix-assisted laser desorption ionization time-of-flight mass spectrometry. Single-crystal X ray structure determination of 1a reveals a rare example of an open 1,2-adduct at the [5,6]-ring junction of the I(h)-C(80) cage. The electrochemical study reveals that the redox potentials of 1a and 1b are shifted cathodically compared to those of pristine Lu(3)N@I(h)-C(80) and that monosilylation is effective to fine-tune the electronic properties of endohedral metallofullerenes as well as empty fullerenes. Density functional theory calculations were also performed, which provide a theoretical basis for the structures and the behavior of the encapsulated Lu(3)N cluster. PMID- 22947032 TI - Mygalomorph spider community of a natural reserve in a hilly system in central Argentina. AB - The diversity, abundance, spatial distribution, and phenology of the mygalomorph spider community in the "Ernesto Tornquist" Strict Nature Reserve were analyzed in this study. Located in southwestern Buenos Aires, Argentina, the Reserve is representative of the Ventania system, which is a sigmoidal mountain belt 180 km in length. This exceptional hilly ecosystem is home for many endemic species and rich native fauna and flora. Spider abundance was sampled monthly from October 2009 to October 2010 by hand capture and pitfall traps on grassland slopes. The species recorded in the study area were: Actinopus sp.1 (Actinopodidae); Grammostola vachoni and Plesiopelma longisternale (Theraphosidae); Acanthogonatus centralis (Nemesiidae); and Mecicobothrium thorelli (Mecicobothriidae). Grammostola vachoni and Acanthogonatus centralis were the dominant species in hand capture and pitfall traps, respectively. The seasonal variation, diversity, and abundance of the mygalomorph community are analyzed and discussed here. The Mygalomorphae of the Ventania system comprises an important group of sedentary and cryptozoic spiders that seem to be highly dependent on habitat type and environmental factors. PMID- 22947029 TI - The high burden of infant deaths in rural Burkina Faso: a prospective community based cohort study. AB - BACKGROUND: Infant mortality rates (IMR) remain high in many sub-Saharan African countries, especially in rural settings where access to health services may be limited. Studies in such communities can provide relevant data on the burden of and risk factors for infant death. We measured IMR and explored risk factors for infant death in a cohort of children born in Banfora Health District, a rural area in South-West Burkina Faso. METHODS: A prospective community-based cohort study was nested within the PROMISE-EBF trial (NCT00397150) in 24 villages of the study area. Maternal and infant baseline characteristics were collected at recruitment and after birth, respectively. Home visits were conducted at weeks 3, 6, 12, 24 and 52 after birth. Descriptive statistics were calculated using robust standard errors to account for cluster sampling. Cox multivariable regression was used to investigate potential risk factors for infant death. RESULTS: Among the 866 live born children included in the study there were 98 infant deaths, yielding an IMR of 113 per 1000 live births (95% CI: 89-143). Over 75% of infant deaths had occurred by 6 months of age and the post neonatal infant mortality rate was 67 per 1000 live births (95% CI: 51-88). Infections (35%) and preterm births complications (23%) were the most common probable causes of death by 6 months. Multivariable analyses identified maternal history of child death, polygyny, twin births and poor anthropometric z-scores at week-3 as factors associated with increased risk of infant death. CONCLUSIONS: We observed a very high IMR in a rural area of Burkina Faso, a country where 75% of the population lives in rural settings. Community-based health interventions targeting mothers and children at high risk are urgently needed to reduce the high burden of infant deaths in these areas. PMID- 22947033 TI - Twenty-year survivors of kidney transplantation. AB - There have been few studies of patients with renal allografts functioning for more than 20 years. We sought to identify clinical factors associated with ultra long-term (>20 year) renal allograft survival and to describe the clinical features of these patients. We performed a retrospective analysis of the Irish Renal Transplant Database and included 1174 transplants in 1002 patients. There were 255 (21.74%) patients with graft function for 20 years or more. Multivariate analysis identified recipient age (HR 1.01, CI 1.01-1.02), gender (male HR 1.25, CI 1.08-1.45), acute rejection (HR 1.26, CI 1.09-1.45) and transplant type (living related donor vs. deceased donor) (HR 0.52, CI 0.40-0.66) as significantly associated with long-term graft loss. Median serum creatinine was 115 MUmol/L. The 5-year graft survival in 20-year survivors was 74.7%. The mean age at death was 62.7 years (+/-10.6). The most common causes of death were cardiovascular disease and malignancy. The two major causes of graft loss were death (with function) and interstitial fibrosis/tubular atrophy. Comorbidities included skin cancer (36.1%), coronary heart disease (17.3%) and other malignancies (14.5%). This study identifies factors associated with long-term allograft survival and a high rate of morbidity and early mortality in long-term transplant recipients. PMID- 22947034 TI - Intercellular organelle trafficking by membranous nanotube connections: a possible new role in cellular rejuvenation? AB - Cells could make actin-based filopodial extensions that connect up with other cells. Such close-ended, actin-based filopodial bridges, or cytonemes, have been observed during developmental and pathological processes. On the other hand, tunneling nanotubes (TNTs) form conduits with open ends that allow transfer of cytoplasmic materials and organelles between cells. The past years have witnessed the description of TNTs in multiple cell types, with a range of interesting physiological and pathophysiological activities. Some hints of the molecular components that drive their formations are now emerging. Recent work has further suggested that TNTs could be important in regenerative transfer of large cellular components, including organelles such as mitochondria and lysosomes between senescing and younger cell types (at least for cells in culture). These findings have intriguing implications in cell biology and regenerative medicine. PMID- 22947035 TI - Bulk and single-molecule fluorescence studies of the saturation of the DNA double helix using YOYO-3 intercalator dye. AB - We report a thorough photophysical characterization of the interactions between double-stranded DNA (dsDNA) and the trimethine cyanine homodimer dye YOYO-3. The fluorescence emission of this dye is enhanced by intercalation within the DNA double helix. We have explored the saturation of the dsDNA by bound YOYO-3 at the single-molecule level by studying the single-pair Forster resonance energy transfer (FRET) from an energy donor, Alexa Fluor 488, tagged at the 5' end of the double helix and the energy acceptor, YOYO-3, bound to the same DNA molecule. The spontaneous binding of YOYO-3 gives rise to an effective distribution of different FRET efficiencies and, therefore, donor-acceptor (D-A) distances. These distributions reveal the existence of multiple states of YOYO-3. Steady-state and time-resolved fluorescence and circular dichroism confirmed the presence of a DNA bound aggregate of YOYO-3, conspicuous at high dye/base pair ratios. The spectral features of the aggregate suggest that it may have the structure of a parallel H aggregate. PMID- 22947036 TI - An interview with Philip Biggin, Section Editor for Computational, in silico and modelling studies. PMID- 22947037 TI - The benefits of interpopulation hybridization diminish with increasing divergence of small populations. AB - Interpopulation hybridization can increase the viability of small populations suffering from inbreeding and genetic drift, but it can also result in outbreeding depression. The outcome of hybridization can depend on various factors, including the level of genetic divergence between the populations, and the number of source populations. Furthermore, the effects of hybridization can change between generations following the hybridization. We studied the effects of population divergence (low vs. high level of divergence) and the number of source populations (two vs. four source populations) on the viability of hybrid populations using experimental Drosophila littoralis populations. Population viability was measured for seven generations after hybridization as proportion of populations facing extinction and as per capita offspring production. Hybrid populations established at the low level of population divergence were more viable than the inbred source populations and had higher offspring production than the large control population. The positive effects of hybridization lasted for the seven generations. In contrast, at the high level of divergence, the viability of the hybrid populations was not significantly different from the inbred source populations, and offspring production in the hybrid populations was lower than in the large control population. The number of source populations did not have a significant effect at either low or high level of population divergence. The study shows that the benefits of interpopulation hybridization may decrease with increasing divergence of the populations, even when the populations share identical environmental conditions. We discuss the possible genetic mechanisms explaining the results and address the implications for conservation of populations. PMID- 22947039 TI - Contribution of rubredoxin:oxygen oxidoreductases and hybrid cluster proteins of Desulfovibrio vulgaris Hildenborough to survival under oxygen and nitrite stress. AB - A genomic island (GEI) of the sulfate-reducing bacterium Desulfovibrio vulgaris Hildenborough, found to be able to migrate between two tRNA-Met loci of the genome, contains genes for rubredoxin:oxygen oxidoreductase-1 (roo1) and hybrid cluster protein-1 (hcp1) with additional copies for these genes (roo2 and hcp2) being found elsewhere on the chromosome. A suite of mutants was created in which roo2 and/or hcp2 and/or the GEI were either present or missing. The GEI and roo2 increased survival under microaerobic conditions and allowed growth in closer proximity to the air-water interface of soft agar tubes, two properties which appeared to be closely linked. When Hcp2(+) GEI(+) or Hcp2(-) GEI(+) cells, harbouring cytochrome c nitrite reductase (NrfHA) and growing on lactate and sulfate, were amended with 10 mM nitrite at mid-log phase (8-10 mM sulfide), all nitrite was reduced within 30 h with a rate of 3.0 mmol (g biomass)(-1) h(-1) after which sulfate reduction resumed. However, Hcp2(+) GEI(-) or Hcp2(-) GEI(-) cells were unable to use lactate, causing sulfide to be used as electron donor for nitrite reduction at a sixfold lower rate. Complementation studies indicated that hcp1, not roo1, enhanced the rate of nitrite reduction under these conditions. Hcp2 enhanced the rate of nitrite reduction when, in addition to lactate, hydrogen was also present as an electron donor. These results indicate a critical role of Hcps in alleviating nitrite stress in D. vulgaris Hildenborough by maintaining the integrity of electron transport chains from lactate or H(2) to NrfHA through removal of reactive nitrogen species. It thus appears that the GEI contributes considerably to the fitness of the organism, allowing improved growth in microaerobic environments found in sulfide-oxygen gradients and in environments, containing both sulfide and nitrite, through the action of Roo1 and Hcp1 respectively. PMID- 22947038 TI - 1-D and 2-D photonic crystals as optical methods for amplifying biomolecular recognition. AB - Label-free sensing strategies are an intensely studied and increasingly used alternative to signal amplification via fluorescent labels and enzymatic methods. This article discusses one class of optical sensors, termed "photonic crystals", that effectively amplify binding events (such as analyte capture) via strong light-matter interactions. PMID- 22947040 TI - Cationic copper(II) porphyrins intercalate into domains of double-stranded RNA. AB - A cationic, copper(II)-containing ligand, derived from bulky 5,10,15,20 tetrakis(N-methylpyridinium-4-yl)porphyrin, Cu(T4), and two sterically friendlier forms, [trans-5,15-di(N-methylpyridinium-4-yl)porphyrinato]copper(II), Cu(tD4), and [cis-5,10-di(N-methylpyridinium-4-yl)porphyrinato]copper(II), Cu(cD4), bind to DNA and RNA hosts. Six hairpin-forming RNA 18-mer sequences and two previously studied DNA analogues serve as convenient binding platforms of programmable base composition. A crystal structure shows that the copper center of Cu(tD4) is four coordinate, establishing compatibility with intercalative binding as well as susceptibility to solvent-induced emission quenching. From the hypochromic responses and the induced emission intensities obtained with all three porphyrins, it is clear that internalization into the RNA host occurs, irrespective of the base pair composition. Further analysis reveals that the porphyrins intercalate into the double-stranded stem domains. Subtle geometric and/or electronic aspects of the binding account for the signs of induced circular dichroic signals and splitting of the Soret band of Cu(tD4). PMID- 22947041 TI - The single nucleotide polymorphism CRTh2 rs533116 is associated with allergic asthma and increased expression of CRTh2. AB - BACKGROUND: CRTh2 (chemoattractant-receptor homologous molecule expressed on Th2 cells) is expressed by Th2 cells and other cells involved in allergic inflammation. Single nucleotide polymorphisms (SNPs) in CRTh2 (rs11571288, rs545659, rs634681) have been associated with various phenotypes of allergy in ethnically distinct populations. Here, we assessed the association between CRTh2 rs533116 and allergic asthma, expression of CRTh2 and Th2 cytokine production. METHODS: CRTh2 rs533116 was genotyped in an ethnically diverse population (n = 1282). The proportion of cells expressing CRTh2 was determined in peripheral blood from subjects with allergic airways disease and controls as well as with in vitro differentiated Th2 cells. Receptor function was assessed by stimulating Th2 cells with the CRTh2-specific agonist 13,14-dihydro-15-keto-PGD(2) (DK-PGD(2) ) and measuring IL-4 and IL-13 by intracellular staining and ELISA. RESULTS: CRTh2 rs533116 was associated with allergic asthma in White people (2.67 [1.09-6.55], P < 0.05), and expression of CRTh2 was higher in subjects with allergic airways disease compared to controls (P < 0.05). Among allergic individuals, the AA genotype was significantly associated with more eosinophils and higher expression of CRTh2 by both CD4(+) T cells and eosinophils (P < 0.05). In vitro, the AA genotype was associated with a higher proportion of CRTh2(+) cells during Th2 differentiation as well as more IL-4 and IL-13 expression following DK-PGD(2) stimulation (P < 0.05). CONCLUSIONS: These findings show an association between CRTh2 rs533116 and allergic asthma and suggest this may be mediated by elevated expression of CRTh2, leading to higher numbers of circulating eosinophils and Th2 cytokine production. PMID- 22947042 TI - Sudan dyes: are they dangerous for human health? AB - Azo and diazo compounds include Sudan dyes, which were widely used in industry. Although they are not permitted in food, they had been found contaminating different food products and their presence is investigated regularly (since 2003) in these products. Sudan III, as well as Sudan Black B, was included in different laboratory techniques for tissue ceroid and lipofucsin analysis and blood-cell staining. Also, Sudan Black B has been recently included in in vivo evaluations in human beings (through oral intake), and Sudan III is still allowed in cosmetics. These azo dyes were metabolized to possible carcinogenic colorless amines, both in the liver of mammalians and by the micro flora present in human skin and the gastrointestinal tract. Both human and laboratory animal cytochrome P450s (CYPs) were able to oxidize Sudan I, whereas Sudan III modified CYP activities. In vitro genotoxic effects were reported for Sudan I, and some DNA adducts formed through exposure to its metabolites were identified. Sudan I was also found to be carcinogenic in the rat, but not in the mouse. The aim of the present review is to put together the most relevant information concerning Sudan dye uses and toxicity to provide some tools for the identification of the risk they represent for human health. PMID- 22947043 TI - Optimizing predictive performance of CASE Ultra expert system models using the applicability domains of individual toxicity alerts. AB - Fragment based expert system models of toxicological end points are primarily comprised of a set of substructures that are statistically related to the toxic property in question. These special substructures are often referred to as toxicity alerts, toxicophores, or biophores. They are the main building blocks/classifying units of the model, and it is important to define the chemical structural space within which the alerts are expected to produce reliable predictions. Furthermore, defining an appropriate applicability domain is required as part of the OECD guidelines for the validation of quantitative structure-activity relationships (QSARs). In this respect, this paper describes a method to construct applicability domains for individual toxicity alerts that are part of the CASE Ultra expert system models. Defining applicability domain for individual alerts was necessary because each CASE Ultra model is comprised of multiple alerts, and different alerts of a model usually represent different toxicity mechanisms and cover different structural space; the use of an applicability domain for the overall model is often not adequate. The domain for each alert was constructed using a set of fragments that were found to be statistically related to the end point in question as opposed to using overall structural similarity or physicochemical properties. Use of the applicability domains in reducing false positive predictions is demonstrated. It is now possible to obtain ROC (receiver operating characteristic) profiles of CASE Ultra models by applying domain adherence cutoffs on the alerts identified in test chemicals. This helps in optimizing the performance of a model based on their true positive-false positive prediction trade-offs and reduce drastic effects on the predictive performance caused by the active/inactive ratio of the model's training set. None of the major currently available commercial expert systems for toxicity prediction offer the possibility to explore a model's full range of sensitivity-specificity spectrum, and therefore, the methodology developed in this study can be of benefit in improving the predictive ability of the alert based expert systems. PMID- 22947044 TI - Consecutive targetable smart nanoprobe for molecular recognition of cytoplasmic microRNA in metastatic breast cancer. AB - We report smart nanoprobe, hyaluronic acid (HA)-based nanocontainers containing miR-34a beacons (bHNCs), for the intracellular recognition of miR-34a levels in metastatic breast cancer cells, which is distinct from the imaging of biomarkers such of cell membrane receptors such as HER2. In this study, we demonstrate that a nanoscale vesicle that couples a targeting endocytic route, CD44, and a molecular imaging probe enables the efficient detection of specific miRNAs. Furthermore, bHNCs showed no cytotoxicity and high stability due to the anchored HA molecules on the surface of nanocontainers, and enables the targeted delivery of beacons via CD44 receptor-mediated endocytosis. In vitro and in vivo optical imaging using bHNCs also allow the measurement of miR-34a expression levels due to the selective recognition of the beacons released from the internalized bHNCs. We believe that the technique described herein can be further developed as a cancer diagnostic as well as a miRNA-based therapy of metastatic cancer. PMID- 22947045 TI - Analysis of carotid artery deformation in different head and neck positions for maxillofacial catheter navigation in advanced oral cancer treatment. AB - BACKGROUND: To improve the accuracy of catheter navigation, it is important to develop a method to predict shifts of carotid artery (CA) bifurcations caused by intraoperative deformation. An important factor affecting the accuracy of electromagnetic maxillofacial catheter navigation systems is CA deformations. We aimed to assess CA deformation in different head and neck positions. METHODS: Using two sets of computed tomography angiography (CTA) images of six patients, displacements of the skull (maxillofacial segments), C1-C4 cervical vertebrae, mandible (mandibular segment), and CA along with its branches were analyzed. Segmented rigid bones around CA were considered the main causes of CA deformation. After superimposition of maxillofacial segments, C1-C4 and mandible segments were superimposed separately for displacement measurements. Five bifurcation points (vA-vE) were assessed after extracting the CA centerline. A new standardized coordinate system, regardless of patient-specific scanning positions, was employed. It was created using the principal axes of inertia of the maxillofacial bone segments of patients. Position and orientation parameters were transferred to this coordinate system. CA deformation in different head and neck positions was assessed. RESULTS: Absolute shifts in the center of gravity in the bone models for different segments were C1, 1.02 +/- 0.9; C2, 2.18 +/- 1.81; C3, 4.25 +/- 3.85; C4, 5.90 +/- 5.14; and mandible, 1.75 +/- 2.76 mm. Shifts of CA bifurcations were vA, 5.52 +/- 4.12; vB, 4.02 +/- 3.27; vC, 4.39 +/- 2.42; vD, 4.48 +/- 1.88; and vE, 2.47 +/- 1.32. Displacements, position changes, and orientation changes of C1-C4 segments as well as the displacements of all CA bifurcation points were similar in individual patients. CONCLUSIONS: CA deformation was objectively proven as an important factor contributing to errors in maxillofacial navigation. Our study results suggest that small movements of the bones around CA can result in small CA deformations. Although patients' faces were not fixed properly during CT scanning, C1-C4 and vA-vE displacements were similar in individual patients. We proposed a novel method for accumulation of the displacement data, and this study indicated the importance of surrounding bone displacements in predicting CA bifurcation. PMID- 22947046 TI - Displacement of a deep brain stimulator lead during placement of an additional ipsilateral lead. AB - OBJECTIVE: The use of Deep Brain Stimulation (DBS) has been increasing. It follows the premise of neuromodulation in that it is reversible, as compared to previous lesioning procedures. MATERIALS AND METHODS: Complications with DBS are inherently low and range from short-term complications during surgery such as hemorrhage to long-term complications that include lead fractures and infection. Over time, the authors have experienced indications for additional lead placements or change in position of the lead on the ipsilateral side. There is the inherent possibility of direct contact between leads or the microelectrode. This can lead to malpositioning, displacement of a lead placed previously, and malfunctioning. RESULT: We report a case in which a lead placed previously becomes displaced during microelectrode recording on the ipsilateral side. CONCLUSION: This scenario was corrected and had no clinical or functional complication. Placement of an additional ipsilateral DBS lead can be a safe and effective treatment option. PMID- 22947047 TI - Venereal shedding of equid herpesvirus-1 (EHV-1) in naturally infected stallions. AB - BACKGROUND: Equid herpesvirus 1 (EHV-1) is a highly prevalent pathogen in horse populations worldwide. Oronasal infection represents the classic route of disease transmission. Venereal shedding of EHV-1 is not regarded relevant in terms of virus spreading, which is in contrast to the close relatives of EHV-1, bovine and suid alphaherpesvirus, for which artificial insemination is a well-documented and accepted means of virus spread. OBJECTIVES: Documentation of venereal EHV-1 shedding in 3 naturally infected stallions. ANIMALS: Three stallions were infected during an acute outbreak by an EHV-1 strain with the G(2254) /D(752) Pol genotype. METHODS: In this observational study, 12 semen samples from these 3 stallions were tested for EHV-1 to determine venereal shedding. EHV-1 was diagnosed by conventional PCR and paired serum neutralization tests in 42 horses. Semen samples were separated into sperm and seminal plasma fractions and tested for EHV-1 by conventional and quantitative PCR as well as virus isolation by cell culture. RESULTS: Acute EHV-1 infection was diagnosed on the premise. Five semen samples collected from 2 of the 3 stallions tested positive for EHV-1 by (q)PCR. On days 18 and 20 after onset of fever, the last positive samples were retrieved. All samples were positive in seminal plasma, only three in sperm fraction. Virus isolation attempts were unsuccessful. CONCLUSIONS AND CLINICAL IMPORTANCE: The data presented here document shedding of EHV-1 in semen of naturally infected stallions for close to 3 weeks, which seems not to be directly associated with spermatozoa. PMID- 22947048 TI - Resuscitation with polymerized human placenta hemoglobin attenuated hemorrhagic shock-induced lung injury. AB - This study was designed to investigate whether polymerized human placenta hemoglobin (PolyPHb) attenuated hemorrhagic shock-induced lung injury. A mean arterial pressure (MAP) of 30mmHg was maintained for 60 min. Then, all the rats were randomly resuscitated with hetastarch, whole blood, or PolyPHb. The result indicated that PolyPHb greatly improved the MAP and pulmonary function, and significantly reduced the release of inflammatory cytokines, histopathological changes, and pulmonary edema. Therefore, our findings suggest that PolyPHb could reduce pulmonary injury after hemorrhagic shock, and this effect was probably associated with the depressed inflammatory response. PMID- 22947049 TI - Stability indicating HPLC method for the simultaneous determination of moxifloxacin and prednisolone in pharmaceutical formulations. AB - BACKGROUND: A simple, specific, and fast stability indicating reverse phase liquid chromatographic method was established for instantaneous determination of moxifloxacin and prednisolone in bulk drugs and pharmaceutical formulations. RESULTS: Optimum chromatographic separations among the moxifloxacin, prednisolone and stress-induced degradation products were achieved within 10 minutes by use of BDS Hypersil C8 column (250 X 4.6 mm, 5 MUm) as stationary phase with mobile phase consisted of a mixture of phosphate buffer (18 mM) containing 0.1% (v/v) triethylamine, at pH 2.8 (adjusted with dilute phosphoric acid) and methanol (38:62 v/v) at a flow rate of 1.5 mL min-1. Detection was performed at 254 nm using diode array detector. The method was validated in accordance with ICH guidelines. Response was a linear function of concentrations over the range of 20 80 MUg mL-1 for moxifloxacin (r2 >= 0.998) and 40-160 MUg mL-1 for prednisolone (r2 >= 0.998). The method was resulted in good separation of both the analytes and degradation products with acceptable tailing and resolution. The peak purity index for both the analytes after all types of stress conditions was >= 0.9999 indicated a complete separation of both the analyte peaks from degradation products. The method can therefore, be regarded as stabilityindicating. CONCLUSIONS: The developed method can be applied successfully for simultaneous determination of moxifloxacin and prednisolone in pharmaceutical formulations and their stability studies. PMID- 22947051 TI - Pannexin1 and Pannexin3 exhibit distinct localization patterns in human skin appendages and are regulated during keratinocyte differentiation and carcinogenesis. AB - Having shown that Panx1 and Panx3 are expressed in the epidermis, we investigated their distribution in human skin adnexal structures and skin cancer. Both proteins were found in hair follicles, sebaceous and eccrine glands, as well as blood vessels. Panx1 was detected as punctate or diffuse intracellular labeling, while Panx3 was only observed as diffuse intracellular staining, suggesting different functions. We also identified the Panx3 immunoreactive ~70 kD species modulated during keratinocyte differentiation as Panx3. Since our data indicate that pannexins are regulated during keratinocyte differentiation, we assessed whether their levels are altered under circumstances in which keratinocyte differentiation is compromised. We found that Panx1 and Panx3 levels are highly reduced in human keratinocyte tumors, thus showing for the first time that both pannexins are dysregulated in human cancers. Altogether, these data suggest that Panx1 and Panx3 have distinct and unique functions within the skin in health and disease. PMID- 22947050 TI - Serpins in rice: protein sequence analysis, phylogeny and gene expression during development. AB - BACKGROUND: Most members of the serpin family of proteins are potent, irreversible inhibitors of specific serine or cysteine proteinases. Inhibitory serpins are distinguished from members of other families of proteinase inhibitors by their metastable structure and unique suicide-substrate mechanism. Animal serpins exert control over a remarkable diversity of physiological processes including blood coagulation, fibrinolysis, innate immunity and aspects of development. Relatively little is known about the complement of serpin genes in plant genomes and the biological functions of plant serpins. RESULTS: A structurally refined amino-acid sequence alignment of the 14 full-length serpins encoded in the genome of the japonica rice Oryza sativa cv. Nipponbare (a monocot) showed a diversity of reactive-centre sequences (which largely determine inhibitory specificity) and a low degree of identity with those of serpins in Arabidopsis (a eudicot). A new convenient and functionally informative nomenclature for plant serpins in which the reactive-centre sequence is incorporated into the serpin name was developed and applied to the rice serpins. A phylogenetic analysis of the rice serpins provided evidence for two main clades and a number of relatively recent gene duplications. Transcriptional analysis showed vastly different levels of basal expression among eight selected rice serpin genes in callus tissue, during seedling development, among vegetative tissues of mature plants and throughout seed development. The gene OsSRP-LRS (Os03g41419), encoding a putative orthologue of Arabidopsis AtSerpin1 (At1g47710), was expressed ubiquitously and at high levels. The second most highly expressed serpin gene was OsSRP-PLP (Os11g11500), encoding a non inhibitory serpin with a surprisingly well-conserved reactive-centre loop (RCL) sequence among putative orthologues in other grass species. CONCLUSIONS: The diversity of reactive-centre sequences among the putatively inhibitory serpins of rice point to a range of target proteases with different proteolytic specificities. Large differences in basal expression levels of the eight selected rice serpin genes during development further suggest a range of functions in regulation and in plant defence for the corresponding proteins. PMID- 22947052 TI - Self-propelled carbohydrate-sensitive microtransporters with built-in boronic acid recognition for isolating sugars and cells. AB - A new nanomotor-based target isolation strategy, based on a "built-in" recognition capability, is presented. The concept relies on a poly(3 aminophenylboronic acid) (PAPBA)/Ni/Pt microtube engine coupling the selective monosaccharide recognition of the boronic acid-based outer polymeric layer with the catalytic function of the inner platinum layer. The PAPBA-based microrocket is prepared by membrane-templated electropolymerization of 3-aminophenylboronic acid monomer. The resulting boronic acid-based microengine itself provides the target recognition without the need for additional external functionalization. "On-the-fly" binding and transport of yeast cells (containing sugar residues on their wall) and glucose are illustrated. The use of the recognition polymeric layer does not hinder the efficient propulsion of the microengine in aqueous and physiological media. Release of the captured yeast cells is triggered via a competitive sugar binding involving addition of fructose. No such capture and transport are observed in control experiments involving other cells or microengines. Selective isolation of monosaccharides is illustrated using polystyrene particles loaded with different sugars. Such self-propelled nanomachines with a built-in recognition capability hold considerable promise for diverse applications. PMID- 22947053 TI - Molecular dynamics simulations of the interactions of DMSO with DPPC and DOPC phospholipid membranes. AB - Molecular dynamics simulations have been used to investigate the effect of DMSO on 1,2-dipalmitoyl-sn-glycero-3-phosphatidylcholine (DPPC) and 1,2-dioleoyl-sn glycero-3-phosphocholine (DOPC) phospholipid bilayers. The concentration of DMSO was varied between 0 and 25.0 mol %. For both lipids, DMSO causes the membrane to expand in the plane of the membrane while thinning normal to that plane. Above a critical concentration, pores in the membrane form spontaneously, and if the concentration is increased further, then the bilayer structure is destroyed. Even at concentrations below those required to induce pores, DMSO readily diffuses across the bilayers. The free-energy profile associated with the diffusion of a DMSO molecules across the membrane has been calculated. The simulations suggest that the DOPC bilayer is more resistant to the deleterious effects of DMSO, both increasing the stability of the membranes and decreasing the rate at which DMSO diffuses across the membrane. In this way, the work highlights the importance of investigating the lipid composition of cell membranes when characterizing the effects of cryosolvents. PMID- 22947054 TI - Adapting enzyme-free DNA circuits to the detection of loop-mediated isothermal amplification reactions. AB - Loop-mediated isothermal amplification of DNA (LAMP) is a powerful isothermal nucleic acid amplification technique that can accumulate ~10(9) copies from less than 10 copies of input template within an hour or two. Unfortunately, while the amplification reactions are extremely powerful, the quantitative detection of LAMP products is still analytically difficult. In this article, to both improve the specificity of LAMP detection and to make direct readout of LAMP amplification simpler and much more reliable, we have developed a nonenzymatic nucleic acid circuit (catalyzed hairpin assembly, CHA) that can both amplify and integrate the specific sequence signals present in LAMP amplicons. Through a hairpin acceptor, one of the four loop products amplified from the LAMP is transduced to an active catalyst ssDNA which can in turn trigger a CHA reaction. After CHA detection, even less than 10 molecules/MUL model templates (M13mp18) can produce significant signal, and both nonspecific template and parasitic amplicons cannot bring interference at all. More importantly, to further enhance the specificity, we have designed a dual-CHA circuit that only gave positive responses in presence of two LAMP loops. The AND-GATE detector will act as a simultaneous, specific readout of the LAMP product, rather than of competing and parasitic amplicons. PMID- 22947055 TI - Virus adaptation to quantitative plant resistance: erosion or breakdown? AB - Adaptation of populations to new environments is frequently costly due to trade offs between life history traits, and consequently, parasites are expected to be locally adapted to sympatric hosts. Also, during adaptation to the host, an increase in parasite fitness could have direct consequences on its aggressiveness (i.e. the quantity of damages caused to the host by the virus). These two phenomena have been observed in the context of pathogen adaptation to host's qualitative and monogenic resistances. However, the ability of pathogens to adapt to quantitative polygenic plant resistances and the consequences of these potential adaptations on other pathogen life history traits remain to be evaluated. Potato virus Y and two pepper genotypes (one susceptible and one with quantitative resistance) were used, and experimental evolutions showed that adaptation to a quantitative resistance was possible and resulted in resistance breakdown. This adaptation was associated to a fitness cost on the susceptible cultivar, but had no consequence either in terms of aggressiveness, which could be explained by a high tolerance level, or in terms of aphid transmission efficiency. We concluded that quantitative resistances are not necessarily durable but management strategies mixing susceptible and resistant cultivars in space and/or in time should be useful to preserve their efficiency. PMID- 22947056 TI - The potential for selective pharmacological therapies through biased receptor signaling. AB - The discovery that not all agonists uniformly activate cellular signaling pathways (biased signaling) has greatly changed the drug discovery process for agonists and the strategy for treatment of disease with agonists. Technological advances have enabled complex receptor behaviors to be viewed independently and through these assays, the bias for an agonist can be quantified. It is predicted that therapeutic phenotypes will be linked, through translational studies, to quantified scales of bias to guide medicinal chemists in the drug discovery process. PMID- 22947057 TI - Progressive dyspnoea following the treatment of Mycobacterium abscessus infection in an individual with relapsing granulamatosis with polyangitis (Wegener's), complicated by hearing loss requiring cochlear implantation. AB - BACKGROUND: Granulomatosis with polyangitis (Wegener's) is a vasculitic disease predominantly affecting the lungs, skin, kidneys, ears, nose and throat. Mycobacterium abscessus is an uncommon rapidly growing mycobacterium causing sporadic lung disease. This is the first report of both GPA and Mycobacterium abscessus pulmonary disease reported in literature. CASE PRESENTATION: We present a case report of a 33 year old Caucasian man with relapsing disease complicated by pulmonary infection with Mycobacterium abscessus. He subsequently required bilateral cochlear implantation for progressive sensori-neural hearing loss. His M. abscessus was treated successfully with a prolonged course of antimicrobial therapy. His Granulomatosis with polyangitis (Wegener's) relapsed towards the end of antimicrobial therapy and required treatment. Shortly after completing his antimicrobial therapy and relapse, he developed progressive dyspnea due to pulmonary fibrosis. CONCLUSION: The potential causes of his progressive dyspnoea are discussed including the potential role of his underlying disease and treatment. PMID- 22947058 TI - Sulfur mustard causes oxidative stress and depletion of antioxidants in muscles, livers, and kidneys of Wistar rats. AB - Sulfur mustard (SM) is a chemical warfare agent with cytotoxic effect and a tight link to oxidative stress (OS). Depletion of antioxidants is considered as a cause of detrimental consequence and belongs to the important steps leading to cell death. The oxidative injury appearing after SM exposure is not well understood. Nevertheless, identification of the pathological processes would be a good opportunity to establish an efficient therapy. Here, we focused our effort on an estimation of reactive oxygen species homeostasis and apoptotic processes in Wistar rats exposed to 0-160 mg/kg of SM. We assayed antioxidant activity, thiobarbituric acid reactive substances, reduced glutathione/oxidized glutathione, metallothionein, glutathione reductase, glutathione peroxidase, glutathione S-transferase, caspase 3, and glucose in the livers, kidneys, and muscles of the animals. Significant OS, depletion of low-molecular-mass antioxidants, increase in caspase activity, and some other processes related to SM action were determined. Moreover, we infer a principal role of OS in the tested organs. PMID- 22947059 TI - Preformed and de novo donor specific antibodies in visceral transplantation: long term outcome with special reference to the liver. AB - Despite improvement in early outcome, rejection particularly chronic allograft enteropathy continues to be a major barrier to long-term visceral engraftment. The potential role of donor specific antibodies (DSA) was examined in 194 primary adult recipients. All underwent complement-dependent lymphocytotoxic crossmatch (CDC-XM) with pre- and posttransplant solid phase HLA-DSA assay in 156 (80%). Grafts were ABO-identical with random HLA-match. Liver was included in 71 (37%) allografts. Immunosuppression was tacrolimus-based with antilymphocyte recipient pretreatment in 150 (77%). CDC-XM was positive in 55 (28%). HLA-DSA was detectable before transplant in 49 (31%) recipients with 19 continuing to have circulating antibodies. Another 19 (18%) developed de novo DSA. Ninety percent of patients with preformed DSA harbored HLA Class-I whereas 74% of recipients with de novo antibodies had Class-II. Gender, age, ABO blood-type, cold ischemia, splenectomy and allograft type were significant DSA predictors. Preformed DSA significantly (p < 0.05) increased risk of acute rejection. Persistent and de novo HLA-DSA significantly (p < 0.001) increased risk of chronic rejection and associated graft loss. Inclusion of the liver was a significant predictor of better outcome (p = 0.004, HR = 0.347) with significant clearance of preformed antibodies (p = 0.04, OR = 56) and lower induction of de novo DSA (p = 0.07, OR = 24). Innovative multifaceted anti-DSA strategies are required to further improve long-term survival particularly of liver-free allografts. PMID- 22947060 TI - Does nature and persistence of substrate at a mesohabitat scale matter for Chironomidae assemblages? A study of two perennial mountain streams in Patagonia, Argentina. AB - Chironomid substrate-specific associations regarding the nature (organic inorganic) and stability (stable-unstable) of different habitats were investigated at two low order Patagonian streams, during high and low water periods. Nant y Fall and Glyn rivers were visited twice (October 2007 and March 2008) and seven different habitat types were identified. A total of 60 samples were collected using a Surber sampler (0.09 m(-2) and 250 um) and a set of 23 environmental descriptors including physicochemical parameters and different fractions of particulate organic matter were assessed. 35 Chironomidae taxa were recorded with Orthocladiinae (20), Chironominae (7), and Podonominae (4) being the most well-represented subfamilies. Paratrichocladius sp. 1, Parapsectrocladius sp. 2, Parametriocnemus sp. 1, Pseudochironomus sp., and Rheotanytarsus sp. were the most abundant taxa. According to the relative preference index, at least 14 taxa showed strong affinity for a particular substrate. The structurally complex macrophyte Myriophyllum quitense supported 11 taxa compared with only five taxa found on the less complex Isoetes savatieri. Generally, stable substrates (boulders, cobbles, and rooted plants) supported significantly higher chironomids richness, abundance, and diversity than unstable ones (gravel-sand). Canonical correspondence analysis revealed that detritus (leaves, seeds, and biomass), macrophyte biomass, and secondarily hydraulic variables had high explanatory power on chironomids species composition and structure. This work suggests that more complex substrates showing persistence in the temporal dimension supported a diverse array of chironomids, meaning that the maintenance of natural habitat heterogeneity is essential for the community. Land use practices having significant effects on ecological stream attributes such as increased turbidity, sediment deposition, and runoff patterns will alter assemblages. Understanding environmental associations of the Chironomidae assemblage at the habitat scale is significant for conservation purposes and for the management of low order streams in Patagonia. PMID- 22947062 TI - Report of the Subcommittee of Control of Anticoagulation on the determination of the anticoagulant effects of rivaroxaban. PMID- 22947061 TI - Superresolution microscopy for microbiology. AB - This review provides a practical introduction to superresolution microscopy from the perspective of microbiological research. Because of the small sizes of bacterial cells, superresolution methods are particularly powerful and suitable for revealing details of cellular structures that are not resolvable under conventional fluorescence light microscopy. Here we describe the methodological concepts behind three major categories of superresolution light microscopy: photoactivated localization microscopy (PALM) and stochastic optical reconstruction microscopy (STORM), structured illumination microscopy (SIM) and stimulated emission-depletion (STED) microscopy. We then present recent applications of each of these techniques to microbial systems, which have revealed novel conformations of cellular structures and described new properties of in vivo protein function and interactions. Finally, we discuss the unique issues related to implementing each of these superresolution techniques with bacterial specimens and suggest avenues for future development. The goal of this review is to provide the necessary technical background for interested microbiologists to choose the appropriate superresolution method for their biological systems, and to introduce the practical considerations required for designing and analysing superresolution imaging experiments. PMID- 22947063 TI - Structural rearrangements at physiological pH: nuclear magnetic resonance insights from the V210I human prion protein mutant. AB - A major focus in prion structural biology studies is unraveling the molecular mechanism leading to the structural conversion of PrP(C) to its pathological form, PrP(Sc). In our recent studies, we attempted to understand the early events of the conformational changes leading to PrP(Sc) using as investigative tools point mutations clustered in the open reading frame of the human PrP gene and linked to genetic forms of human prion diseases. In the work presented here, we investigate the effect of pH on the nuclear magnetic resonance (NMR) structure of recombinant human PrP (HuPrP) carrying the pathological V210I mutation responsible for familial Creutzfeldt-Jakob disease. The NMR structure of HuPrP(V210I) determined at pH 7.2 shows the same overall fold as the previously determined structure of HuPrP(V210I) at pH 5.5. It consists of a disordered N terminal tail (residues 90-124) and a globular C-terminal domain (residues 125 231) comprising three alpha-helices and a short antiparallel beta-sheet. Detailed comparison of three-dimensional structures of HuPrP(V210I) at pH 7.2 and 5.5 revealed significant local structural differences, with the most prominent pH related structural variations clustered in the alpha(2)-alpha(3) interhelical region, at the interface of the beta(1)-alpha(1) loop, in helices alpha(1) and alpha(3), and in the beta(2)-alpha(2) loop region. The detailed analysis of interactions among secondary structure elements suggests a higher degree of structural ordering of HuPrP(V210I) under neutral-pH conditions, thus implying that spontaneous misfolding of PrP(C) may occur under acidic-pH conditions in endosomal compartments. PMID- 22947065 TI - Design aspects of bright red emissive silver nanoclusters/DNA probes for microRNA detection. AB - The influence of the nucleic acid secondary structure on the fast (1 h) formation of bright red emissive silver nanoclusters (AgNCs) in a DNA sequence (DNA-12nt RED-160), designed for the detection of a microRNA sequence (RNA-miR160), was investigated. The findings show that especially the propensity for mismatch self dimer formation of the DNA probes can be a good indicator for the creation and stabilization of red emissive AgNCs. Also, the role of the thermal stability of the secondary DNA structures (mismatch self-dimer and hairpin monomers) and the observed AgNC red emission intensity were investigated. These findings can form the basis for a rationale to design new red emissive AgNC-based probes. As an example, a bright red emissive AgNC-based DNA probe was designed for RNA-miR172 detection. The latter opens the possibility to create a variety of AgNC-based DNA probes for the specific detection of plant and animal miRNAs. PMID- 22947064 TI - Transcutaneous immunotherapy via laser-generated micropores efficiently alleviates allergic asthma in Phl p 5-sensitized mice. AB - BACKGROUND: Specific immunotherapy via the subcutaneous or oral route is associated with local and, in some cases, systemic side effects and suffers from low patient compliance. Due to its unique immunological features, the skin represents a promising target tissue for effective and painless treatment of type I allergy. The current study was performed to compare the efficacy of transcutaneous immunotherapy via laser-generated micropores to subcutaneous injection. METHODS: BALB/c mice were sensitized by intraperitoneal injection of recombinant grass pollen allergen Phl p 5 together with alum. Subsequently, lung inflammation was induced by repeated intranasal challenge. During the treatment phase, adjuvant-free Phl p 5 was applied in solution to microporated skin or was subcutaneously injected. Lung function and cellular infiltration; Phl p 5 specific serum levels of IgG1, IgG2a, and IgE; and cytokine levels in bronchoalveolar lavage fluids as well as in supernatants of splenocyte cultures were assessed. RESULTS: Both therapeutic approaches reduced airway hyperresponsiveness and leukocyte infiltration into the lungs. Whereas subcutaneous immunotherapy induced a systemic increase in Th2-associated cytokine secretion, transcutaneous application revealed a general downregulation of Th1/Th2/Th17 responses. Successful therapy was associated with induction of IgG2a and an increase in FOXP3+ CD4+ T cells. CONCLUSIONS: Transcutaneous immunotherapy via laser microporation is equally efficient compared with conventional subcutaneous treatment but avoids therapy-associated boosting of systemic Th2 immunity. Immunotherapy via laser-microporated skin combines a painless application route with the high efficacy known from subcutaneous injections and therefore represents a promising alternative to established forms of immunotherapy. PMID- 22947067 TI - Socio-economic determinants of household out-of-pocket payments on healthcare in Pakistan. AB - BACKGROUND: Out-of-pocket (OOP) payment on healthcare is dominant mode of financing in developing countries. In Pakistan it is 67% of total expenditure on healthcare. Analysis of determinants of OOP health expenditure is a key aspect of equity in healthcare financing. It helps to formulate an effective health policy. Evidence on OOP in Pakistan is sparse. This paper attempts to fill this research gap. METHODS: We estimated determinants of OOP payments on healthcare in Pakistan. We used data sets of Pakistan Household Integrated Economic Survey (HIES) and Pakistan Standard of Living Measurement (PSLM) Survey for the year 2004-05. We developed a multiple regression model for the determinants of OOP payments using methods of Ordinary Least Square (OLS). We mainly used social, economic, demographic and health variables in our analysis. RESULTS: Median household OOP healthcare in the year 2004-05 was Pakistani Rupees (PKR) 2500 (US$ 41.99) in 2004-05. Household non-food expenditure was the single highest significant predictor of household OOP health expenditure. Household features like literate head and spouse, at least one obstetric delivery in last three years, unsafe water, unhygienic toilet and household belonging to Khyber Pukhtonkhwa (KPK) province were significant positive predictors of OOP payments. Households with male head, bricks used in housing construction, household with at least one child and no elderly, and head of household in a white collar profession were negative predictors of OOP payments. CONCLUSION: Our analysis confirms earlier findings that economic status and number of old aged members are significant positive predictors of OOP payments. This association can direct government to enhance allocations to healthcare and to include program focusing on non-communicable diseases. Our findings suggest further research to explore beneficiaries of government healthcare programs and determinants of high OOP payments by household residing in KPK province than other province. The interaction between white collar profession and their economic status in predicting OOP payments is also an area for further research. PMID- 22947066 TI - In vitro reconstruction of human junctional and sulcular epithelium. AB - BACKGROUND: The aim of this study was to develop and characterize standardized in vitro three-dimensional organotypic models of human junctional epithelium (JE) and sulcular epithelium (SE). METHODS: Organotypic models were constructed by growing human normal gingival keratinocytes on top of collagen matrices populated with gingival fibroblasts (GF) or periodontal ligament fibroblasts (PLF). Tissues obtained were harvested at different time points and assessed for epithelial morphology, proliferation (Ki67), expression of JE-specific markers (ODAM and FDC SP), cytokeratins (CK), transglutaminase, filaggrin, and basement membrane proteins (collagen IV and laminin1). RESULTS: The epithelial component in 3- and 5-day organotypics showed limited differentiation and expressed Ki-67, ODAM, FDC SP, CK 8, 13, 16, 19, and transglutaminase in a similar fashion to control JE samples. PLF supported better than GF expression of CK19 and suprabasal proliferation, although statistically significant only at day 5. Basement membrane proteins started to be deposited only from day 5. The rate of proliferating cells as well as the percentage of CK19-expressing cells decreased significantly in 7- and 9-day cultures. Day 7 organotypics presented higher number of epithelial cell layers, proliferating cells in suprabasal layers, and CK expression pattern similar to SE. CONCLUSION: Both time in culture and fibroblast type had impact on epithelial phenotype. Five-day cultures with PLF are suggested as JE models, 7-day cultures with PLF or GF as SE models, while 9 day cultures with GF as gingival epithelium (GE) models. Such standard, reproducible models represent useful tools to study periodontal bacteria-host interactions in vitro. PMID- 22947068 TI - Immune-stimulating potential of cell envelope proteins from Vibrio cholerae associated to chitosan microparticles: an in vitro study. AB - CONTEXT: Cholera is a severe diarrheal disease that remains an important cause of illness and death in many parts of the world. OBJECTIVE: This study has been designed to check the immune-stimulating potential of antigens in their native and associated form as chitosan microparticles in vitro. MATERIAL AND METHODS: Chitosan microparticles were prepared by the ionic gelation technique. The cell envelope proteins (CEPs) isolated from Vibrio cholerae were loaded as antigenic material. The prepared microparticles were characterized for their morphology, loading efficiency, particle size, and zeta potential. RESULTS: The average particle size of CEPs-loaded chitosan microparticles was 2.24 um and the zeta potential of loaded microparticles was less than blank microparticles. The in vitro release studies of CEPs from CEPs-loaded chitosan microparticles exhibited slow and extended release over a period of time. The higher release of cytokine profile, including interferon gamma (IFN-gamma), tumor necrosis factor alpha (TNF alpha), and interlukin-6 (IL-6), was observed for CEPs-loaded chitosan microparticles in comparison to CEPs as native antigen. DISCUSSION: The particle size of microparticles was within the range for phagocytosis by macropahges, which affects the immunogenicity. The decrease in zeta potential from blank to loaded microparticles further confirms the loading of antigen. The slow and extended release of CEPs provides continuous stimulus of antigen for a longer period of time. The cytokine profiling has shown the advantage of loaded microparticles over native antigen. CONCLUSION: The in vitro release studies and cytokine profiling strongly suggested that CEPs-associated chitosan microparticles could be a potential candidate for oral vaccination against Vibrio cholerae. PMID- 22947069 TI - Neurostimulation for the treatment of epilepsy: a review of current surgical interventions. AB - OBJECTIVES: Epilepsy continues to provide challenges to clinicians, as a significant proportion of patients continue to suffer from seizures despite medical and surgical treatments. Neurostimulation has emerged as a new treatment modality that has the potential to improve quality of life and occasionally be curative for patients with medically refractory epilepsy who are not surgical candidates. In order to continue to advance the frontier of this field, it is imperative to have a firm grasp of the current body of knowledge. METHODS: We performed a thorough review of the current literature regarding the three main modalities of vagus nerve stimulation, deep brain stimulation, and closed-loop stimulation (responsive neurostimulator [RNS]) for the treatment of refractory epilepsy. For each of these forms of treatment, we discuss the current understanding of the underlying mechanism of action, patient selection, outcomes to date, and associated side effects or adverse reactions. We also provide an overview of related ongoing clinical trials. RESULTS: A total of 189 sources from 1938 to 2012 pertaining to neuromodulation for the treatment of epilepsy were reviewed. Sources included review articles, clinical trials, case reports, conference proceedings, animal studies, and government data bases. CONCLUSIONS: This review shows us how neurostimulation provides us with yet another tool with which to treat the complex disease of medically refractory epilepsy. PMID- 22947070 TI - Salvage procedures in lower-extremity trauma in a child with hereditary motor and sensory neuropathy type I: a case report. AB - INTRODUCTION: Fractures of the lower extremity are a common type of childhood injury and many can be treated without surgery. Dislocated and open fractures are an indication for fracture stabilization via either intramedullary nailing or, in the case of complicated fractures, external fixation. But if complications are likely because of diseases and disabilities (for example, a neuropathy) that can complicate the post-operative procedure and rehabilitation, what options does one have? CASE PRESENTATION: We report a nine-year-old Caucasian girl who had hereditary motor and sensory neuropathy type I and who was admitted with a grade I open tibia fracture after a fall from a small height. Plain radiographs showed a dislocated tibia and fibula fracture. An open reduction with internal fixation with a compression plate osteosynthesis was performed, and soft tissue debridement combined with an external fixateur was undertaken. Three months later, she was re-admitted with localized swelling and signs of a local soft tissue infection in the middle of her tibia. Plain radiographs showed a non-union of the tibia fracture, and microbiological analysis confirmed a wound infection with cefuroxime-sensitive Staphylococcus aureus. Because of the non-union, the osteosynthesis was replaced with an Ilizarov external fixateur, and appropriate antibiotic therapy was initiated. Four months after the initial accident, the fracture was consolidated and we removed the external fixateur. CONCLUSIONS: If there is a pre-existing neuropathy and if disease makes it difficult for a child to follow all post-operative instructions, salvage procedures should be kept in mind in case of complications. There are multiple therapeutic options, including osteosynthesis, intramedullary nailing systems, cast therapy, or an external fixateur like the Ilizarov or Taylor spatial frame system. The initial use of an external fixateur such as an Ilizarov or Taylor spatial frame in patients with pre-existing neuropathies should be kept in mind as a possible treatment option in complicated fractures, especially in a child with pre-existing neurological or endocrine pathologies. PMID- 22947072 TI - Conducting an acute intense interval exercise session during the Ramadan fasting month: what is the optimal time of the day? AB - This study examines the effects of Ramadan fasting on performance during an intense exercise session performed at three different times of the day, i.e., 08:00, 18:00, and 21:00 h. The purpose was to determine the optimal time of the day to perform an acute high-intensity interval exercise during the Ramadan fasting month. After familiarization, nine trained athletes performed six 30-s Wingate anaerobic test (WAnT) cycle bouts followed by a time-to-exhaustion (T(exh)) cycle on six separate randomized and counterbalanced occasions. The three time-of-day nonfasting (control, CON) exercise sessions were performed before the Ramadan month, and the three corresponding time-of-day Ramadan fasting (RAM) exercise sessions were performed during the Ramadan month. Note that the 21:00 h session during Ramadan month was conducted in the nonfasted state after the breaking of the day's fast. Total work (TW) completed during the six WAnT bouts was significantly lower during RAM compared to CON for the 08:00 and 18:00 h (p < .017; effect size [d] = .55 [small] and .39 [small], respectively) sessions, but not for the 21:00 h (p = .03, d = .18 [trivial]) session. The T(exh) cycle duration was significantly shorter during RAM than CON in the 18:00 (p < .017, d = .93 [moderate]) session, but not in the 08:00 (p = .03, d = .57 [small]) and 21:00 h (p = .96, d = .02 [trivial]) sessions. In conclusion, Ramadan fasting had a small to moderate, negative impact on quality of performance during an acute high-intensity exercise session, particularly during the period of the daytime fast. The optimal time to conduct an acute high intensity exercise session during the Ramadan fasting month is in the evening, after the breaking of the day's fast. PMID- 22947073 TI - Symmetric and asymmetric Au-AgCdSe hybrid nanorods. AB - This paper describes a facile method for synthesis of Au-AgCdSe hybrid nanorods with controlled morphologies and spatial distributions. The synthesis involved deposition of Ag tips at the ends of Au nanorod seeds, followed by selenization of the Ag tips and overgrowth of CdSe on these sites. By simply manipulating the pH value of the system, the AgCdSe could selectively grow at one end, at both the ends or on the side surface of a Au nanorod, generating a mike-like, dumbbell like, or toothbrush-like hybrid nanorod, respectively. These three types of Au AgCdSe hybrid nanorods displayed distinct localized surface plasmon resonance and photoluminescence properties, demonstrating an effective pathway for maneuvering the optical properties of nanocrystals. PMID- 22947071 TI - Novel insights of structure-based modeling for RNA-targeted drug discovery. AB - Substantial progress in RNA biology highlights the importance of RNAs (e.g., microRNAs) in diseases and the potential of targeting RNAs for drug discovery. However, the lack of RNA-specific modeling techniques demands the development of new tools for RNA-targeted rational drug design. Herein, we implemented integrated approaches of accurate RNA modeling and virtual screening for RNA inhibitor discovery with the most comprehensive evaluation to date of five docking and 11 scoring methods. For the first time, statistical analysis was heavily employed to assess the significance of our predictions. We found that GOLD:GOLD Fitness and rDock:rDock_solv could accurately predict the RNA ligand poses, and ASP rescoring further improved the ranking of ligand binding poses. Due to the weak correlations (R(2) < 0.3) of existing scoring with experimental binding affinities, we implemented two new RNA-specific scoring functions, iMDLScore1 and iMDLScore2, and obtained better correlations with R(2) = 0.70 and 0.79, respectively. We also proposed a multistep virtual screening approach and demonstrated that rDock:rDock_solv together with iMDLScore2 rescoring obtained the best enrichment on the flexible RNA targets, whereas GOLD:GOLD Fitness combined with rDock_solv rescoring outperformed other methods for rigid RNAs. This study provided practical strategies for RNA modeling and offered new insights into RNA-small molecule interactions for drug discovery. PMID- 22947074 TI - A simplified sum-frequency vibrational imaging setup used for imaging lipid bilayer arrays. AB - Given the complexity of cell membranes, there is a need for an analytical technique which can explore the physical properties of lipid membranes in a high throughput and noninvasive manner. A simplified sum-frequency vibrational imaging (SFVI) setup has been developed and characterized using asymmetrically prepared 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC):1,2-distearoyl(d70)-sn-glycero 3-phosphocholine (DSPC-d(70)) lipid bilayer arrays. Exploiting the vibrational selectivity and inherent symmetry constraints of sum-frequency generation, SFVI was successfully used to probe the transition temperature of a patterned DSPC:DSPC-d(70) lipid bilayer array. SFVI was also used to study the phase behavior in a multicomponent micropatterned lipid bilayer array (MLBA) prepared using three different binary lipid mixtures (1,2-dioleoyl-sn-glycero-3 phosphocholine (DOPC):DSPC, DOPC:1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), and 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC:DSPC). This paper demonstrates that a simplified SFVI setup provides the necessary chemical imaging capabilities with the spatial resolution, sensitivity, and field of view required for exploring lipid membrane properties in a high-throughput array based assay. PMID- 22947076 TI - Beta-blocker use and COPD mortality: a systematic review and meta-analysis. AB - BACKGROUND: Despite the benefits of beta-blockers in patients with established or sub-clinical coronary artery disease, their use in patients with chronic obstructive pulmonary disease (COPD) has been controversial. Currently, no systematic review has examined the impact of beta-blockers on mortality in COPD. METHODS: We systematically searched electronic bibliographic databases including MEDLINE, EMBASE and Cochrane Library for clinical studies that examine the association between beta-blocker use and all cause mortality in patients with COPD. Risk ratios across studies were pooled using random effects models to estimate a pooled relative risk across studies. Publication bias was assessed using a funnel plot. RESULTS: Our search identified nine retrospective cohort studies that met the study inclusion criteria. The pooled relative risk of COPD related mortality secondary to beta-blocker use was 0.69 (95% CI: 0.62-0.78; I2=82%). CONCLUSION: The results of this review are consistent with a protective effect of beta-blockers with respect to all cause mortality. Due to the observational nature of the included studies, the possibility of confounding that may have affected these results cannot be excluded. The hypothesis that beta blocker therapy might be of benefit in COPD needs to be evaluated in randomised controlled trials. PMID- 22947075 TI - Time-course microarrays reveal early activation of the immune transcriptome and adipokine dysregulation leads to fibrosis in visceral adipose depots during diet induced obesity. AB - BACKGROUND: Visceral white adipose tissue (WAT) hypertrophy, adipokine production, inflammation and fibrosis are strongly associated with obesity, but the time-course of these changes in-vivo are not fully understood. Therefore, the aim of this study was to establish the time-course of changes in adipocyte morphology, adipokines and the global transcriptional landscape in visceral WAT during the development of diet-induced obesity. RESULTS: C57BL/6 J mice were fed a high-fat diet (HFD) or normal diet (ND) and sacrificed at 8 time-points over 24 weeks. Excessive fat accumulation was evident in visceral WAT depots (Epidydimal, Perirenal, Retroperitoneum, Mesentery) after 2-4 weeks. Fibrillar collagen accumulation was evident in epidydimal adipocytes at 24 weeks. Plasma adipokines, leptin, resistin and adipsin, increased early and time-dependently, while adiponectin decreased late after 20 weeks. Only plasma leptin and adiponectin levels were associated with their respective mRNA levels in visceral WAT. Time course microarrays revealed early and sustained activation of the immune transcriptome in epididymal and mesenteric depots. Up-regulated inflammatory genes included pro-inflammatory cytokines, chemokines (Tnf, Il1rn, Saa3, Emr1, Adam8, Itgam, Ccl2, 3, 4, 6, 7 and 9) and their upstream signalling pathway genes (multiple Toll-like receptors, Irf5 and Cd14). Early changes also occurred in fibrosis, extracellular matrix, collagen and cathepsin related-genes, but histological fibrosis was only visible in the later stages. CONCLUSIONS: In diet induced obesity, early activation of TLR-mediated inflammatory signalling cascades by CD antigen genes, leads to increased expression of pro-inflammatory cytokines and chemokines, resulting in chronic low-grade inflammation. Early changes in collagen genes may trigger the accumulation of ECM components, promoting fibrosis in the later stages of diet-induced obesity. New therapeutic approaches targeting visceral adipose tissue genes altered early by HFD feeding may help ameliorate the deleterious effects of diet-induced obesity. PMID- 22947077 TI - Kinetically controlled overgrowth of Ag or Au on Pd nanocrystal seeds: from hybrid dimers to nonconcentric and concentric bimetallic nanocrystals. AB - This article describes a systematic study of the nucleation and growth of Ag (and Au) on Pd nanocrystal seeds. By carefully controlling the reaction kinetics, the newly formed Ag atoms could be directed to selectively nucleate and then epitaxially grow on a specific number (ranging from one to six) of the six faces on a cubic Pd seed, leading to the formation of bimetallic nanocrystals with a variety of different structures. In addition to changing the injection rate of precursor, we also systematically investigated other reaction parameters including the capping agent, reductant, and reaction temperature. Our results suggest that the site-selective growth of Ag on cubic Pd seeds could be readily realized by optimizing these reaction parameters. On the basis of the positions of Pd seeds inside the bimetallic nanocrystals as revealed by TEM imaging and elemental mapping, we could identify the exact growth pathways and achieve a clear and thorough understanding of the mechanisms. We have successfully applied the same strategy based on kinetic control to cubic Pd seeds with different sizes and octahedral Pd seeds of one size to generate an array of novel bimetallic nanocrystals with well-controlled structures. With cubic Pd seeds as an example, we have also extended this strategy to the Pd-Au system. We believe this work will provide a promising route to the fabrication of bimetallic nanocrystals with novel structures and properties for applications in plasmonics, catalysis, and other areas. PMID- 22947078 TI - Exploring the relationship between safety culture and reported dispensing errors in a large sample of Swedish community pharmacies. AB - BACKGROUND: The potential for unsafe acts to result in harm to patients is constant risks to be managed in any health care delivery system including pharmacies. The number of reported errors is influenced by a various elements including safety culture. The aim of this study is to investigate a possible relationship between reported dispensing errors and safety culture, taking into account demographic and pharmacy variables, in Swedish community pharmacies. METHODS: A cross-sectional study was performed, encompassing 546 (62.8%) of the 870 Swedish community pharmacies. All staff in the pharmacies on December 1st, 2007 were included in the study. To assess safety culture domains in the pharmacies, the Safety Attitudes Questionnaire (SAQ) was used. Numbers of dispensed prescription items as well as dispensing errors for each pharmacy across the first half year of 2008 were summarised. Intercorrelations among a number of variables including SAQ survey domains, general properties of the pharmacy, demographic characteristics, and dispensing errors were calculated. A negative binomial regression model was used to further examine the relationship between the variables and dispensing errors. RESULTS: The first analysis demonstrated a number of significant correlations between reported dispensing errors and the variables examined. Negative correlations were found with SAQ domains Teamwork Climate, Safety Climate, Job Satisfaction as well as mean age and response rates. Positive relationships were demonstrated with Stress Recognition (SAQ), number of employees, educational diversity, birth country diversity, education country diversity and number of dispensed prescription items. Variables displaying a significant relationship to errors in this analysis were included in the regression analysis. When controlling for demographic variables, only Stress Recognition, mean age, educational diversity and number of dispensed prescription items and employees, were still associated with dispensing errors. CONCLUSION: This study replicated previous work linking safety to errors, but went one step further and controlled for a variety of variables. Controlling rendered the relationship between Safety Climate and dispensing insignificant, while the relationship to Stress Recognition remained significant. Variables such as age and education country diversity were found also to correlate with reporting behaviour. Further studies on the demographic variables might generate interesting results. PMID- 22947079 TI - Oral toxicity and pharmacokinetic studies of SHetA2, a new chemopreventive agent, in rats and dogs. AB - SHetA2 is a heteroarotinoid that has shown selective inhibition of cancer cell growth and an induction of apoptosis without activation of nuclear retinoic acid receptors. In the rat study, SHetA2 was administered in 1% aqueous methylcellulose/0.2% Tween 80 by oral gavage at 0, 100, 500, and 2,000 mg/kg/day for 28 days. The high-dose administration induced decreased activity in male rats, decreased body-weight gains and food consumption, and changes in organ weights. The major metabolite of SHetA2 in rat plasma was monohydroxy SHetA2, which was considerably higher than the parent compound after oral and intravenous administration. Pharmacokinetic analysis showed extremely low (<1%) systemic bioavailability of SHetA2 for all doses tested. The dose of 2,000 mg/kg/day was considered as the lowest observed adverse effect level. The no observed adverse effect level (NOAEL) was 500 mg/kg/day. In the dog study, no toxicity of SHetA2 in 30% aqueous Solutol((r)) HS 15 was observed in any tested dose groups (0, 100, 400, and 1,500 mg/kg/day). The major metabolite of SHetA2 in dog plasma was also monohydroxy SHetA2, which was equal to or lower than the parent compound after oral administration. SHetA2 levels in dog plasma were notably higher, when compared to levels in rat plasma. However, exposure was not dose proportional, as exemplified by a lack of proportional increase in maximum concentration or area under the plasma concentration-time curve with increasing dose. The NOAEL was not established and was considered to be above 1,500 mg/kg/day. PMID- 22947080 TI - Epidemiology in evolutionary time: the case of Wolbachia horizontal transmission between arthropod host species. AB - Wolbachia are bacterial endosymbionts that manipulate the reproduction of their arthropod hosts. Although theory suggests that infections are frequently lost within host species due to the evolution of resistance, Wolbachia infect a huge number of species worldwide. This apparent paradox suggests that horizontal transmission between host species has been a key factor in shaping the global Wolbachia pandemic. Because Wolbachia infections are thus acquired and lost like any other infection, we use a standard epidemiological model to analyse Wolbachia horizontal transmission dynamics over evolutionary time. Conceptually modifying the model, we apply it not to transmission between individuals but between species. Because, on evolutionary timescales, infections spread frequently between closely related species and occasionally over large phylogenetic distances, we represent the set of host species as a small-world network that satisfies both requirements. Our model reproduces the effect of basic epidemiological parameters, which demonstrates the validity of our approach. We find that the ratio between transmission rate and recovery rate is crucial for determining the proportion of infected species (incidence) and that, in a given host network, the incidence may still be increasing over evolutionary time. Our results also point to the importance of occasional transmission over long phylogenetic distances for the observed high incidence levels of Wolbachia. In conclusion, we are able to explain why Wolbachia are so abundant among arthropods, although selection for resistance within hosts often leads to infection loss. Furthermore, our unorthodox approach of using epidemiology in evolutionary time can be applied to all symbionts that use horizontal transmission to infect new hosts. PMID- 22947081 TI - Characterization of impurity doping and stress in Si/Ge and Ge/Si core-shell nanowires. AB - Core-shell nanowires (NWs) composed of silicon (Si) and germanium (Ge) are key structures for realizing high mobility transistor channels, since the site selective doping and band-offset in core-shell NWs separate the carrier transport region from the impurity doped region, resulting in the suppression of impurity scattering. Four different types of Si/Ge (i-Si/n-Ge, p-Si/i-Ge) and Ge/Si (n Ge/i-Si, i-Ge/p-Si) core-shell NWs structures were rationally grown. The surface morphology significantly depended on the types of the core-shell NWs. Raman and X ray diffraction (XRD) measurements clearly characterized the compressive and tensile stress in the core and shell regions. The observation of boron (B) and phosphorus (P) local vibrational peaks and the Fano effect clearly demonstrated that the B and P atoms are selectively doped into the shell and core regions and electrically activated in the substitutional sites, showing the success of site selective doping. PMID- 22947082 TI - Emissions from small-scale burns of simulated deployed U.S. military waste. AB - U.S. military forces have historically relied on open burning as an expedient method of volume reduction and treatment of solid waste during the conflicts in Afghanistan and Iraq. This study is the first effort to characterize a broad range of pollutants and their emission factors during the burning of military waste and the effects that recycling efforts, namely removing plastics, might have on emissions. Piles of simulated military waste were constructed, burned, and emissions sampled at the U.S. Environmental Protection Agency (EPA) Open Burn Testing Facility (OBTF), Research Triangle Park, NC. Three tests contained polyethylene terephthalate (PET #1 or PET) plastic water bottles and four did not. Emission factors for polycyclic aromatic hydrocarbons (PAHs), volatile organic compounds (VOCs), particulate matter (PM(10), PM(2.5)), polychlorinated and polybrominated dioxins/furans (PCDD/F and PBDD/F), and criteria pollutants were determined and are contained within. The average PCDD/F emission factors were 270 ng-toxic equivalency (TEQ) per kg carbon burned (ng-TEQ/kg Cb), ranging from 35 to 780 ng-TEQ/kg Cb. Limited testing suggests that targeted removal of plastic water bottles has no apparent effect on reducing pollutants and may even promote increased emissions. PMID- 22947083 TI - Ocular allergy: recognizing and diagnosing hypersensitivity disorders of the ocular surface. AB - Ocular allergy includes several clinically different conditions that can be considered as hypersensitivity disorders of the ocular surface. The classification of these conditions is complex, and their epidemiology has not been adequately studied because of the lack of unequivocal nomenclature. Ocular allergy symptoms are often, but not always, associated with other allergic manifestations, mostly rhinitis. However, specific ocular allergic diseases need to be recognized and managed by a team that includes both an ophthalmologist and an allergist. The diagnosis of ocular allergy is usually based on clinical history and signs and symptoms, with the support of in vivo and in vitro tests when the identification of the specific allergic sensitization is required for patient management. The aims of this Task Force Report are (i) to unify the nomenclature and classification of ocular allergy, by combining the ophthalmology and allergy Allergic Rhinitis and its Impact on Asthma criteria; (ii) to describe current methods of diagnosis; (iii) to summarize the therapeutic options for the management of ocular allergic inflammation. PMID- 22947084 TI - Probable disseminated Mycobacterium abscessus subspecies bolletii infection in a patient with idiopathic CD4+ T lymphocytopenia: a case report. AB - INTRODUCTION: Rapidly growing mycobacteria are opportunistic pathogens in patients with underlying risk factors. Mycobacterium abscessus subsp. bolletii is a newly recognized member of rapidly growing mycobacteria, isolated from respiratory tract and cutaneous infections. CASE PRESENTATION: We describe a case of chronic disseminated infection caused by M. abscessus subsp. bolletii in a 38 year-old Sri Lankan man with idiopathic CD4+ T lymphocytopenia. Idiopathic CD4+ T lymphocytopenia is a rare cause of immunodysfunction that, similar to human immunodeficiency virus infection, causes a depletion of CD4+ T lymphocytes. M. abscessus subsp. bolletii infection was diagnosed by culture isolation from two sputum samples. CONCLUSIONS: To the best of our knowledge this is the first report of M. abscessus subsp. bolletii disseminated infection in a patient affected by idiopathic CD4+ T lymphocytopenia. In contrast to previous reports, the isolate of M. abscessus subsp. bolletii presented intermediate resistance to clarithromycin and was susceptible to cefoxitin and imipenem. PMID- 22947085 TI - The neuroendocrine protein 7B2 is intrinsically disordered. AB - The small neuroendocrine protein 7B2 has been shown to be required for the productive maturation of proprotein convertase 2 (proPC2) to an active enzyme form; this action is accomplished via its ability to block aggregation of proPC2 into nonactivatable forms. Recent data show that 7B2 can also act as a postfolding chaperone to block the aggregation of a number of other proteins, for example, alpha-synuclein. To gain insight into the mechanism of action of 7B2 in blocking protein aggregation, we performed structural studies of this protein using gel filtration chromatography, intrinsic tryptophan fluorescence, 1-anilino 8-naphthalenesulfonate (ANS) binding, circular dichroism (CD), and nuclear magnetic resonance (NMR) spectroscopy. Gel filtration studies indicated that 7B2 exists as an extended monomer, eluting at a molecular mass higher than that expected for a globular protein of similar size. However, chemical cross-linking showed that 7B2 exhibits concentration-dependent oligomerization. CD experiments showed that both full-length 27 kDa 7B2 and the C-terminally truncated 21 kDa form lack appreciable secondary structure, although the longer protein exhibited more structural content than the latter, as demonstrated by intrinsic and ANS fluorescence studies. NMR spectra confirmed the lack of structure in native 7B2, but a disorder-to-order transition was observed upon incubation with one of its client proteins, alpha-synuclein. We conclude that 7B2 is a natively disordered protein whose function as an antiaggregant chaperone is likely facilitated by its lack of appreciable secondary structure and tendency to form oligomers. PMID- 22947086 TI - Prediction of therapy tumor-absorbed dose estimates in I-131 radioimmunotherapy using tracer data via a mixed-model fit to time activity. AB - BACKGROUND: For individualized treatment planning in radioimmunotherapy (RIT), correlations must be established between tracer-predicted and therapy-delivered absorbed doses. The focus of this work was to investigate this correlation for tumors. METHODS: The study analyzed 57 tumors in 19 follicular lymphoma patients treated with I-131 tositumomab and imaged with SPECT/CT multiple times after tracer and therapy administrations. Instead of the typical least-squares fit to a single tumor's measured time-activity data, estimation was accomplished via a biexponential mixed model in which the curves from multiple subjects were jointly estimated. The tumor-absorbed dose estimates were determined by patient-specific Monte Carlo calculation. RESULTS: The mixed model gave realistic tumor time activity fits that showed the expected uptake and clearance phases even with noisy data or missing time points. Correlation between tracer and therapy tumor residence times (r=0.98; p<0.0001) and correlation between tracer-predicted and therapy-delivered mean tumor-absorbed doses (r=0.86; p<0.0001) were very high. The predicted and delivered absorbed doses were within +/- 25% (or within +/- 75 cGy) for 80% of tumors. CONCLUSIONS: The mixed-model approach is feasible for fitting tumor time-activity data in RIT treatment planning when individual least squares fitting is not possible due to inadequate sampling points. The good correlation between predicted and delivered tumor doses demonstrates the potential of using a pretherapy tracer study for tumor dosimetry-based treatment planning in RIT. PMID- 22947087 TI - Early growth response protein-1 promoter-mediated synergistic antitumor effect of hTERTC27 gene therapy and 5-Flurorouracil on nasopharyngeal carcinoma. AB - hTERTC27 is a newly constructed polypeptide that can induce telomere dysfunction. To study the synergistic antitumor effects of the hTERTC27 polypeptide driven by the early growth response protein-1 (Egr-1) promoter and chemotherapeutic 5 flurorouracil (5-FU) on nasopharyngeal carcinoma, a series of in vitro and in vivo experiments were performed. The results showed that hTERTC27 expression was significantly increased up to 7.21-folds by the 5-FU-activated Egr-1 promoter in C666-1 cells. Overexpressed hTERTC27 made the cells more sensitive to 5-FU, and additionally, inhibited cell proliferation about 20.41%. Combinational therapy of overexpressed hTERTC27 driven by the 5-FU-activated Egr-1 promoter and 5-FU synergistically inhibited cell proliferation and promoted apoptosis of C666-1 cells for about 4.75-fold and 1.76-fold in comparison with a sole therapy of hTERTC27 or 5-FU in vitro. In vivo experiments showed that overexpressed hTERTC27 driven by 5-FU-activated Egr-1 promoter and 5-FU synergistically reduced tumor volume, tumor weight, and local infiltration, which may be relative to tumor cell apoptosis. These results suggest that combinational therapy of overexpressed hTERTC27, which is driven by the 5-FU-activated Egr-1 promoter, and 5-FU may provide a novel approach to treat nasopharyngeal cancer. PMID- 22947088 TI - Spectroscopic interaction of a coumarin derivative with bovine serum albumin. AB - The absorption and fluorescence spectra of the 7-diethylamino-4-methyl coumarin (DAMC) in ethanol-water (1:9 v/v) solution at varying pH values were investigated. The interaction between DAMC and bovine serum albumin (BSA) was investigated by fluorescence spectroscopy. The Stern-Volmer quenching constant, the quenching rate constant of the bimolecular reaction (kq), the binding constant, and number of binding sites are mentioned but not calculated in the paper. Moreover, in a preliminary pharmacological study, DAMC not only remarkably increased cellular apoptosis in a concentration-dependent manner but also clearly induced A549 cell cycle arrest. Thus, these coumarin derivatives merit investigation as novel potential antitumor agents with further structural modification to produce an optimal lead compound and elucidate the detailed pharmacological mechanism. PMID- 22947089 TI - Successful isolated intestinal transplantation in sensitized recipients with the use of virtual crossmatching. AB - We evaluated virtual crossmatching (VXM) for organ allocation and immunologic risk reduction in sensitized isolated intestinal transplantation recipients. All isolated intestine transplants performed at our institution from 2008 to 2011 were included in this study. Allograft allocation in sensitized recipients was based on the results of a VXM, in which the donor-specific antibody (DSA) was prospectively evaluated with the use of single-antigen assays. A total of 42 isolated intestine transplants (13 pediatric and 29 adult) were performed during this time period, with a median follow-up of 20 months (6-40 months). A sensitized (PRA >= 20%) group (n = 15) was compared to a control (PRA < 20%) group (n = 27) to evaluate the efficacy of VXM. With the use of VXM, 80% (12/15) of the sensitized patients were transplanted with a negative or weakly positive flow-cytometry crossmatch and 86.7% (13/15) with zero or only low-titer (<= 1:16) DSA. Outcomes were comparable between sensitized and control recipients, including 1-year freedom from rejection (53.3% and 66.7% respectively, p = 0.367), 1-year patient survival (73.3% and 88.9% respectively, p = 0.197) and 1 year graft survival (66.7% and 85.2% respectively, p = 0.167). In conclusion, a VXM strategy to optimize organ allocation enables sensitized patients to successfully undergo isolated intestinal transplantation with acceptable short term outcomes. PMID- 22947090 TI - Remote ischemic preconditioning reduces thrombus formation in the rat. PMID- 22947091 TI - Agrocybe aegerita polysaccharide combined with chemotherapy improves tumor necrosis factor-alpha and interferon-gamma levels in rat esophageal carcinoma. AB - Natural compounds have generated great interest as alternative treatments of diseases like cancer. Here, we investigated the anti-tumor mechanism of one such compound, Agrocybe aegerita polysaccharide, by assessing expression of tumor necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma) in rat esophageal carcinoma (EC). EC was induced in healthy Wistar rats by methyl-n-amyl nitrosamine. Subsequently, rats were administered cancer treatment daily for 4 weeks, as follows: the normal control group (the only group not treated with methyl-n-amyl nitrosamine) and model group received only distilled water; the chemotherapy group received tegafur treatment; and the combination group received tegafur combined with A. aegerita polysaccharide. In normal and combination groups, body weight increased gradually after each week of treatment (P < 0.05), while body weights did not change in model and chemotherapy groups. Using enzyme linked immunosorbent assay, we found serum TNF-alpha was lower in the combination group (31.56 +/- 7.20 pg/L) than either the model (46.24 +/- 8.52 pg/L) or chemotherapy (52.39 +/- 9.16 pg/L) group, and, while higher, was more similar to the normal controls (25.08 +/- 2.93 pg/L; P < 0.05), a finding that was confirmed by the immunohistochemistry of esophageal samples. In contrast, serum IFN-gamma was higher in the combination group (97.20 +/- 10.92 pg/L) than in either the model (76.11 +/- 11.92 pg/L) or chemotherapy (76.04 +/- 9.85 pg/L) group, but lower than in the normal group (117.56 +/- 10.88; P < 0.05), also confirmed by immunohistochemistry. Therefore, Agrocybe aegerita polysaccharide, when combined with chemotherapy, can regulate immune function in EC, potentially by modulating cytokine activity, specifically downregulation of TNF-alpha and upregulation of IFN-gamma. PMID- 22947093 TI - Stabilized TiN nanowire arrays for high-performance and flexible supercapacitors. AB - Metal nitrides have received increasing attention as electrode materials for high performance supercapacitors (SCs). However, most of them are suffered from poor cycling stability. Here we use TiN as an example to elucidate the mechanism causing the capacitance loss. X-ray photoelectron spectroscopy analyses revealed that the instability is due to the irreversible electrochemical oxidation of TiN during the charging/discharging process. Significantly, we demonstrate for the first time that TiN can be stabilized without sacrificing its electrochemical performance by using poly(vinyl alcohol) (PVA)/KOH gel as the electrolyte. The polymer electrolyte suppresses the oxidation reaction on electrode surface. Electrochemical studies showed that the TiN solid-state SCs exhibit extraordinary stability up to 15,000 cycles and achieved a high volumetric energy density of 0.05 mWh/cm(3). The capability of effectively stabilizing nitride materials could open up new opportunities in developing high-performance and flexible SCs. PMID- 22947092 TI - ALiBERO: evolving a team of complementary pocket conformations rather than a single leader. AB - Docking and virtual screening (VS) reach maximum potential when the receptor displays the structural changes needed for accurate ligand binding. Unfortunately, these conformational changes are often poorly represented in experimental structures or homology models, debilitating their docking performance. Recently, we have shown that receptors optimized with our LiBERO method (Ligand-guided Backbone Ensemble Receptor Optimization) were able to better discriminate active ligands from inactives in flexible-ligand VS docking experiments. The LiBERO method relies on the use of ligand information for selecting the best performing individual pockets from ensembles derived from normal-mode analysis or Monte Carlo. Here we present ALiBERO, a new computational tool that has expanded the pocket selection from single to multiple, allowing for automatic iteration of the sampling-selection procedure. The selection of pockets is performed by a dual method that uses exhaustive combinatorial search plus individual addition of pockets, selecting only those that maximize the discrimination of known actives compounds from decoys. The resulting optimized pockets showed increased VS performance when later used in much larger unrelated test sets consisting of biologically active and inactive ligands. In this paper we will describe the design and implementation of the algorithm, using as a reference the human estrogen receptor alpha. PMID- 22947095 TI - Multifunctionalized cantilever systems for electronic nose applications. AB - Multiple target detection using a cantilever is essential for biosensor, chemical sensor, and electronic nose systems. We report a novel microcantilever array chip that includes four microreaction chambers in a chip, which consequently contains four different functionalized surfaces for multitarget detection. For model tests, we designed microcantilever chips and demonstrated the ability of binding of 2,4-dinitrotoluene (DNT) targets onto four different surfaces. We used peptide receptors that are known to have highly selective binding. By simply using four microreaction chambers, we immobilized DNT specific peptide (HPNFSKYILHQRC; SP), DNT nonspecific peptide (TSMLLMSPKHQAC; NSP), and self-assembled monolayer (SAM) as well as a bare cantilever. After flowing DNT gases through the cantilever chip, we could monitor the four different binding signals simultaneously. The shifts in NSP provided information as a negative control because it contained information of temperature fluctuations and mechanical vibration from gas flow. By utilizing the differential signal of the SP and NSP, we acquired 7.5 Hz in resonant responses that corresponds with 160 part per billion (ppb) DNT concentration, showing the exact binding response by eliminating the inevitable thermal noise, vibration noise, as well as humidity effects on the peptide surface. PMID- 22947094 TI - Evaluation of two commercial and three home-made fixatives for the substitution of formalin: a formaldehyde-free laboratory is possible. AB - BACKGROUND: Formaldehyde (HCHO) is a gas (available as a 37% concentrated solution, stabilized with methanol). The 10% dilution (approximately 4% formaldehyde) has been used as a fixative since the end of the 19th century. Alternative fixatives are also commercially available or may be prepared in-house in laboratories. Statements by the IARC, along with other USA agencies (CalEPA, RoC/NTP) on the carcinogenicity of formaldehyde for humans renders its substitution in Pathology Departments necessary since the annual use of formalin may exceed 3,500 liters for a medium-large laboratory. To achieve a "formalin free laboratory" we tested straightforward-to-make fixatives along with registered reagents offered as formalin substitutes. METHODS: More than two hundreds specimens were fixed in parallel with in-laboratory made fixatives PAGA (Polyethylenglycol, ethyl Alcohol, Glycerol, Acetic acid), two zinc-based fixatives (ZBF, Z7), and commercially-available alternatives (RCL2 and CellBlock). Tissue micro arrays were used for morphological and immunohistochemical comparison. Extraction of RNA was carried out to evaluate preservation of nucleic acids. RESULTS: Differences compared to formalin fixation were evident in alcohol-based fixatives, mainly restricted to higher stain affinity and considerable tissue shrinkage. Conversely, nuclear detail was superior with these alcohol-based formulas compared to formalin or glyoxale-based recipes. RNA extraction was superior for Z7, PAGA and RCL2 with regard to concentration but relatively comparable regarding quality. CONCLUSIONS: Abolition of the human carcinogen formaldehyde from pathology laboratories is possible even in contexts whereby commercial alternatives to formalin are unavailable or are too expensive for routine use, and aspiration devices are lacking or not adequately serviced. The use of known formulations, possibly with simple and not noxious ("alimentary grade") constituents, comparable with registered proprietary products, may expand the search for the ideal fixative combining satisfactory morphology with improved preservation of nucleic acids and proteins as well as being easy and safe to dispose of. PMID- 22947096 TI - Purification, characterization, and investigation of in vitro inhibition by metals of paraoxonase from different sheep breeds. AB - Paraoxonase (PON) was purified and characterized from the Merino and Kivircik sheep's blood serums by a two-step procedure using ammonium sulphate precipitation and Sepharose-4B-L-tyrosine-1-napthylamine hydrophobic interaction chromatography for the first time. On SDS-polyacyrilamide gel electrophoresis, purified human serum paraoxonase yielded a single band of 66 kDa on SDS-PAGE. The KM and Vmax were 0.482 mM and 41.348 U/mL.dak for Merino PON enzyme, 0.153 mM and 70.289 U/mL.dak for Kivircik PON, respectively. The effect of Mn(2+) , Hg(2+) , Co(2+) , Cd(2+) , Ni(2+) and Cu(2+) heavy metals on purified Merino and Kivircik serum PON in vitro was determined. PMID- 22947097 TI - Association of Alanine Aminotransferase Levels (ALT) with the Hepatic Insulin Resistance Index (HIRI): a cross-sectional study. AB - BACKGROUND: The association between serum alanine aminotransferase (ALT) levels and hepatic insulin resistance (IR) has been evaluated with the hyperinsulinemic euglycemic clamp. However, there is no information about the association of ALT with the Hepatic Insulin Resistance Index (HIRI). The aim of this study was to evaluate the association between serum ALT levels and HIRI in subjects with differing degrees of impaired glucose metabolism. METHODS: This cross-sectional study included subjects that had an indication for testing for type 2 diabetes mellitus (T2DM) with an oral glucose tolerance test (OGTT). Clinical and biochemical evaluations were carried out including serum ALT level quantification. HIRI was calculated for each participant. Correlation analyses and lineal regression models were used to evaluate the association between ALT levels and HIRI. RESULTS: A total of 324 subjects (37.6% male) were included. The mean age was 40.4 +/- 14.3 years and the mean body mass index (BMI) was 32.0 +/- 7.3 kg/m2. Individuals were divided into 1 of 5 groups: without metabolic abnormalities (n = 113, 34.8%); with the metabolic syndrome (MetS, n = 179, 55.2%), impaired fasting glucose (IFG, n = 85, 26.2%); impaired glucose tolerance (IGT, n = 91, 28.0%), and T2DM (n = 23, 7.0%). The ALT (p < 0.001) and HOMA2-IR (p < 0.001) values progressively increased with HIRI quartiles, while ISI-Matsuda (p < 0.001) progressively decreased. After adjustment for sex, age, and BMI, we identified a significant correlation between HIRI and ALT in persons with the MetS (r = 0.22, p = 0.003), IFG (r = 0.33, p < 0.001), IGT (r = 0.37, p < 0.001), and T2DM (r = 0.72, p < 0.001). Lineal regression analysis adjusting for age, HDL C, TG and waist circumference (WC) showed an independent association between ALT and HIRI in subjects with the MetS (beta = 0.07, p = 0.01), IFG (beta = 0.10, p = 0.02), IGT (beta = 0.09, p = 0.007), and T2DM (beta = 0.31, p = 0.003). This association was not identified in subjects without metabolic abnormalities. CONCLUSIONS: ALT levels are independently associated with HIRI in subjects with the MetS, IFG, IGT, and T2DM. The ALT value in these subjects may be an indirect parameter to evaluate hepatic IR. PMID- 22947098 TI - Rearing the maize weevil, Sitophilus zeamais, on an artificial maize-cassava diet. AB - Dry artificial diet pellets prepared with maize, cassava chips, and amino acid supplements (lysine and methionine) were evaluated for mass culture of Sitophilus zeamais Motschulsky (Coleoptera: Curculionidae), a highly polyphagous pest of many stored grains. Evaluation was done in the laboratory at temperature 26 +/- 2 degrees C, 60-70% RH, 12:12 L:D photoperiod. The artificial diet was compounded from different proportions of maize (M) variety TZPB-SW-R, cassava (C) variety TMS-2110, and amino acid supplements, and was pelletized into 6 mm diameter pellets on which five pairs of one-day-old S. zeamais were bioassayed. The diet M(9)C(1) (90% M and 10% C) was the most suitable diet with comparatively shorter developmental period (34.8 days) and the highest F(1) emergence of progeny (145.4) compared to the control, M(10)C(0) (100% M and 0% C). PMID- 22947099 TI - Heterogeneous OH oxidation of motor oil particles causes selective depletion of branched and less cyclic hydrocarbons. AB - Motor oil serves as a useful model system for atmospheric oxidation of hydrocarbon mixtures typical of anthropogenic atmospheric particulate matter, but its complexity often prevents comprehensive chemical speciation. In this work we fully characterize this formerly "unresolved complex mixture" at the molecular level using recently developed soft ionization gas chromatography techniques. Nucleated motor oil particles are oxidized in a flow tube reactor to investigate the relative reaction rates of observed hydrocarbon classes: alkanes, cycloalkanes, bicycloalkanes, tricycloalkanes, and steranes. Oxidation of hydrocarbons in a complex aerosol is found to be efficient, with approximately three-quarters (0.72 +/- 0.06) of OH collisions yielding a reaction. Reaction rates of individual hydrocarbons are structurally dependent: compared to normal alkanes, reaction rates increased by 20-50% with branching, while rates decreased ~20% per nonaromatic ring present. These differences in rates are expected to alter particle composition as a function of oxidation, with depletion of branched and enrichment of cyclic hydrocarbons. Due to this expected shift toward ring opening reactions heterogeneous oxidation of the unreacted hydrocarbon mixture is less likely to proceed through fragmentation pathways in more oxidized particles. Based on the observed oxidation-induced changes in composition, isomer-resolved analysis has potential utility for determining the photochemical age of atmospheric particulate matter with respect to heterogeneous oxidation. PMID- 22947100 TI - Environmental and occupational exposure of metals and their role in male reproductive functions. AB - This review summarizes the effects of more than 20 metals that, research has indicated, may influence male reproductive health. Though males lack an apparent, easily measurable reproductive cycle, progress has been made in evaluating tests to identify chemical hazards and estimate reproductive health risks. Some agents discussed in this review are well known to have potential toxic effects on the male reproductive system, whereas some are not so well established in toxicology. This review attempts to cover most of the known toxicants and their effects on male fertility. The literature suggests a need for further research in those chemicals that are reactive and capable of covalent interactions in biological systems, as well as those defined as mutagens and/or carcinogens, to cause aneuploidy or other chromosomal aberrations, affect sperm motility in vitro, share hormonal activity or affect hormone action, and those that act directly or indirectly to affect the hypothalamo-pituitary-gonadal axis. PMID- 22947101 TI - Acute inflammatory demyelinating polyneuropathy after treatment with pegylated interferon alfa-2a in a patient with chronic hepatitis C virus infection: a case report. AB - INTRODUCTION: The combination of polyethylene glycol (PEG)ylated interferon (pegylated interferon) and ribavirin has been shown to be an effective treatment for chronic hepatitis C virus. In general, common side effects related to this combination therapy are mild and are well tolerated. However, peripheral neuropathy including demyelinating polyneuropathy related to PEG-interferon alpha2a (pegylated interferon alfa-2a) is extremely rare. In the literature, only one case of acute inflammatory demyelinating polyneuropathy related to PEG interferon alpha2a has been published previously. CASE PRESENTATION: To the best of our knowledge we present only the second case of acute inflammatory demyelinating polyneuropathy related to PEG-interferon alpha2a, occurring in a 63 year-old Caucasian man. He developed tingling, numbness, and weakness of his upper and lower extremities with acute neurological deficits after five weeks of a combination therapy with PEG-interferon alpha2a and ribavirin for chronic hepatitis C virus infection. His clinical course, neurological findings, and his electromyogram results were all consistent with acute inflammatory demyelinating polyneuropathy. Our patient recovered completely after interferon was stopped and symptomatic treatment and a further electromyogram showed a disappearance of neuropathy. Four weeks later, PEG-interferon alpha2a was reintroduced with a gradually increasing dose without any reappearance of neurological symptoms allowing hepatitis C seroconversion. CONCLUSIONS: Recognition of this rare yet possible presentation is important for early and accurate diagnosis and treatment. This case report also suggests that the reintroduction of PEGylated interferon in patients who had presented with acute inflammatory demyelinating polyneuropathy related to interferon alpha may be safe, but this must be confirmed by further studies. PMID- 22947102 TI - Microneedle pretreatment enhances the percutaneous permeation of hydrophilic compounds with high melting points. AB - BACKGROUND: Two commercially available microneedle rollers with a needle length of 200 MUm and 300 MUm were selected to examine the influence of microneedle pretreatment on the percutaneous permeation of four non-steroidal anti inflammatory drugs (diclofenac, ibuprofen, ketoprofen, paracetamol) with different physicochemical drug characteristics in Franz-type diffusion cells. Samples of the receptor fluids were taken at predefined times over 6 hours and were analysed by UV-VIS high-performance liquid-chromatography. Histological examinations after methylene blue application were additionally performed to gather information about barrier disruption. RESULTS: Despite no visible pores in the stratum corneum, the microneedle pretreatment resulted in a twofold (200 MUm) and threefold higher (300 MUm) flux through the pretreated skin samples compared to untreated skin samples for ibuprofen and ketoprofen (LogK(ow) > 3, melting point < 100 degrees C). The flux of the hydrophilic compounds diclofenac and paracetamol (logK(ow) < 1, melting point > 100 degrees C) increased their amount by four (200 MUm) to eight (300 MUm), respectively. CONCLUSION: Commercially available microneedle rollers with 200-300 MUm long needles enhance the drug delivery of topically applied non-steroidal anti-inflammatory drugs and represent a valuable tool for percutaneous permeation enhancement particularly for substances with poor permeability due to a hydrophilic nature and high melting points. PMID- 22947104 TI - A systematic review of the clinical performance of tooth-retained and implant retained double crown prostheses with a follow-up of >= 3 years. AB - PURPOSE: The objective of this review was to systematically screen the literature for data related to the survival and complication rates observed with dental or implant double crown abutments and removable prostheses under functional loading for at least 3 years. MATERIALS AND METHODS: A systematic review of the dental literature from January 1966 to December 2009 was performed in electronic databases (PubMed and Embase) as well as by an extensive hand search to investigate the clinical outcomes of double crown reconstructions. RESULTS: From the total of 2412 titles retrieved from the search, 65 were selected for full text review. Subsequently, 17 papers were included for data extraction. An estimation of the cumulative survival and complication rates was not feasible due to the lack of detailed information. Tooth survival rates for telescopic abutment teeth ranged from 82.5% to 96.5% after an observation period of 3.4 to 6 years, and for tooth-supported double crown retained dentures from 66.7% to 98.6% after an observation period of 6 to 10 years. The survival rates of implants were between 97.9% and 100% and for telescopic-retained removable dental prostheses with two mandibular implants, 100% after 3.0 and 10.4 years. The major biological complications affecting the tooth abutments were gingival inflammation, periodontal disease, and caries. The most frequent technical complications were loss of cementation and loss of facings. CONCLUSIONS: The main findings of this review are: (I) double crown tooth abutments and dentures demonstrated a wide range of survival rates. (II) Implant-supported mandibular overdentures demonstrated a favorable long-term prognosis. (III) A greater need for prosthetic maintenance is required for both tooth-supported and implant-supported reconstructions. (IV) Future areas of research would involve designing appropriate longitudinal studies for comparisons of survival and complication rates of different reconstruction designs. PMID- 22947103 TI - Using BAC transgenesis in zebrafish to identify regulatory sequences of the amyloid precursor protein gene in humans. AB - BACKGROUND: Non-coding DNA in and around the human Amyloid Precursor Protein (APP) gene that is central to Alzheimer's disease (AD) shares little sequence similarity with that of appb in zebrafish. Identifying DNA domains regulating expression of the gene in such situations becomes a challenge. Taking advantage of the zebrafish system that allows rapid functional analyses of gene regulatory sequences, we previously showed that two discontinuous DNA domains in zebrafish appb are important for expression of the gene in neurons: an enhancer in intron 1 and sequences 28-31 kb upstream of the gene. Here we identify the putative transcription factor binding sites responsible for this distal cis-acting regulation, and use that information to identify a regulatory region of the human APP gene. RESULTS: Functional analyses of intron 1 enhancer mutations in enhancer trap BACs expressed as transgenes in zebrafish identified putative binding sites of two known transcription factor proteins, E4BP4/ NFIL3 and Forkhead, to be required for expression of appb. A cluster of three E4BP4 sites at -31 kb is also shown to be essential for neuron-specific expression, suggesting that the dependence of expression on upstream sequences is mediated by these E4BP4 sites. E4BP4/ NFIL3 and XFD1 sites in the intron enhancer and E4BP4/ NFIL3 sites at -31 kb specifically and efficiently bind the corresponding zebrafish proteins in vitro. These sites are statistically over-represented in both the zebrafish appb and the human APP genes, although their locations are different. Remarkably, a cluster of four E4BP4 sites in intron 4 of human APP exists in actively transcribing chromatin in a human neuroblastoma cell-line, SHSY5Y, expressing APP as shown using chromatin immunoprecipitation (ChIP) experiments. Thus although the two genes share little sequence conservation, they appear to share the same regulatory logic and are regulated by a similar set of transcription factors. CONCLUSION: The results suggest that the clock-regulated and immune system modulator transcription factor E4BP4/ NFIL3 likely regulates the expression of both appb in zebrafish and APP in humans. It suggests potential human APP gene regulatory pathways, not on the basis of comparing DNA primary sequences with zebrafish appb but on the model of conservation of transcription factors. PMID- 22947106 TI - Circulating antimyenteric autoantibodies in Tunisian patients with idiopathic achalasia. AB - The physiopathology of idiopathic achalasia is still unknown. The description of circulating antimyenteric autoantibodies (CAA), directed against enteric neurons in sera of patients, suggests an autoimmune process. Recent data showed controversies according to the existence and the significance of CAA. The aims of this study were to investigate whether CAA are detected in Tunisian patients with idiopathic achalasia and to look for associated clinical or manometrical factors with CAA positivity. Twenty-seven patients with idiopathic achalasia and 57 healthy controls were prospectively studied. CAA were assessed by indirect immunofluorescence on intestinal monkey tissue sections. Western blot on primate cerebellum protein extract and dot technique with highly purified recombinant neuronal antigens (Hu, Ri, and Yo) were further used to analyze target antigens of CAA. CAA were significantly increased in achalasia patients compared with controls when considering nuclear or cytoplasmic fluorescence patterns. (33% vs. 12%, P = 0.03 and 48% vs. 23%, P = 0.001 respectively). By immunoblot analysis, CAA did not target neuronal antigens, however 52/53 and 49 kDa bands were consistently detected. CAA positivity was not correlated to specific clinical features. The results are along with previous studies demonstrating high CAA prevalence in achalasia patients. When reviewing technical protocols and interpretation criteria, several discrepancies which could explain controversies between studies were noted. PMID- 22947107 TI - Ultraviolet irradiation is an effective alternative to ozonation as a sea water treatment to prevent Kudoa neurophila (Myxozoa: Myxosporea) infection of striped trumpeter, Latris lineata (Forster). AB - Myxozoan parasites are known pathogens of cultured finfish. Kudoa neurophila n. comb. (Grossel, Dykova, Handlinger & Munday) has historically infected hatchery produced striped trumpeter, Latris lineata (Forster in Bloch and Schneider), a candidate species for seacage aquaculture in Australia. We examined the efficacy of four water treatment methods to prevent K. neurophila infection in post-larval (paperfish) and juvenile striped trumpeter. Treatments included dose-controlled ultraviolet irradiation [hydro-optic disinfection (HOD)], ozone with conventional UV (ozone), mechanical filtration at 25 MUm and then foam fractionation (primary filtration), and 50-MUm-filtered sea water (control). In post-larvae (initially 10.3 +/- 2.7 g, mean +/- SD, 259 days post-hatching, dph), the infection prevalence (PCR test) after 51 days was 93 +/- 12% in the control, 100 +/- 0% in primary filtration and 0 +/- 0% in both ozone and HOD. Likewise, in juveniles (initially 114 +/- 18 g, 428 dph), prevalence was 100 +/- 0% in the control and primary filtration treatments with no infection detected in ozone and HOD. Concurrently, there was a 50-100% reduction in heterotrophic bacteria and 100% reduction in presumptive Vibrio sp. in sea water HOD and ozone treatments. HOD with a dose of >=44 mJ cm(-2) UV was as effective as ozonation at >700 mV ORP for 10 min, in preventing K. neurophila infection. PMID- 22947105 TI - Platelet-derived CD154: ultrastructural localization and clinical correlation in organ transplantation. AB - CD154 is an immunostimulatory ligand for CD40 that markedly influences alloimmunity. Its presence in platelets suggests that its release and subsequent immune effects are driven by trauma and thus could be relevant following organ transplantation. However, the release of platelet derived CD154 and its consequences have not been investigated in a clinical transplant setting. To better characterize the relationship between platelet activation and CD154 release, we investigated CD154 release by platelets obtained from normal individuals, and patients with two genetic defects that influence platelet granule development. Using these unique patient populations and immune-electron microscopy, we confirmed that CD154 was an alpha granule and not a cell surface protein, and thereafter optimized the methods for its in vivo measurement in humans. We then investigated plasma CD154 levels in kidney and liver transplant recipients and found no evidence that CD154 levels fluctuated systemically as a result of kidney or liver transplant procedures. Paradoxically, we found that kidney transplant patients had significantly lower systemic CD154 levels during episodes of rejection. These data suggest that the immune effects of CD154 are likely mediated through local and not systemic mechanisms, and discourage the use of CD154 as a peripheral biomarker in organ transplantation. PMID- 22947108 TI - Cognitive behaviour therapy for menopausal hot flushes and night sweats: a qualitative analysis of women's experiences of group and self-help CBT. AB - BACKGROUND: There is a growing need for non-medical treatments for women experiencing problematic menopausal symptoms such as hot flushes and night sweats (HF/NS). A recent randomized control trial (RCT) (MENOS2) provides evidence of the effectiveness of Group CBT and Self-Help CBT for HF/NS. AIMS: This study examines MENOS 2 participants' experience of the CBT treatments. METHOD: Twenty women who had experienced CBT for HF/NS (10 Group CBT and 10 Self-Help CBT) were interviewed at the end of the trial to explore how they experienced the treatment and its effects. The interviews were analysed using interpretative phenomenological analysis. RESULTS: Women experienced both treatment formats as positive and helpful, increasing their ability to cope and their sense of control over HF/NS. Four super-ordinate themes were identified: making sense of symptom change, new ways of coping and regaining control, acknowledging and challenging the menopause taboo, and social interaction and support versus individual learning. CONCLUSIONS: These qualitative results are consistent with those of the main trial in that women found both CBT formats helpful in reducing the impact of HF/NS. However, the results also suggest possible mechanisms of change and provide useful information on women's responses to the different treatment components and formats. PMID- 22947109 TI - Plasmonic mode engineering with templated self-assembled nanoclusters. AB - Plasmonic nanoparticle assemblies are a materials platform in which optical modes, resonant frequencies, and near-field intensities can be specified by the number and position of nanoparticles in a cluster. A current challenge is to achieve clusters with higher yields and new types of shapes. In this Letter, we show that a broad range of plasmonic nanoshell nanoclusters can be assembled onto a lithographically defined elastomeric substrate with relatively high yields using templated assembly. We assemble and measure the optical properties of three cluster types: Fano-resonant heptamers, linear chains, and rings of nanoparticles. The yield of heptamer clusters is measured to be over 30%. The assembly of plasmonic nanoclusters on an elastomer paves the way for new classes of plasmonic nanocircuits and colloidal metamaterials that can be transfer printed onto various substrate media. PMID- 22947110 TI - Preface: Special 'retina' issue. PMID- 22947111 TI - Deposition of ordered layers of tetralactam macrocycles and ether rotaxanes on pyridine-terminated self-assembled monolayers on gold. AB - The deposition of tetralactam macrocycles and the corresponding benzyl ether rotaxanes on gold substrates is investigated for the first time exploiting metallo-supramolecular chemistry. Two pyridine-terminated self-assembled monolayers (SAMs) are developed that are used as well-ordered template layers. The two SAMs differ with respect to the rigidity of the terminal pyridines as shown by angle-resolved near-edge X-ray absorption fine structure (NEXAFS) spectroscopy. The template layers are then used for the metal-mediated self assembly of macrocylces and rotaxanes on solid supports. The SAM with the more rigid terminal pyridine shows a higher coverage with the macrocycles and is therefore preferable. Angle-resolved NEXAFS spectroscopy also shows the deposited supramolecules to be oriented preferentially upright. This order is only achieved for the macrocycles through the deposition on the more rigid SAM template, whereas rotaxanes form oriented layers on both SAMs. Time-of-flight secondary-ion mass spectrometry analysis was used to determine the deposition time required for the self-assembly process. PMID- 22947112 TI - Optical scattering artifacts observed in the development of multiplexed surface enhanced Raman spectroscopy nanotag immunoassays. AB - Here we describe scattering based signal suppression artifacts encountered while developing multiplex lateral flow (LF) immunoassay using surface enhanced Raman spectroscopy (SERS) "nanotags" as analyte labels. Using these SERS nanotags, we have produced a quantitative test for inflammation biomarkers that is transferable to the point of care (POC). The SERS assay shows similar performance when compared with a fluorescent nanoparticle POC test. Here, using cardiac and inflammation biomarkers, we highlight the need to carefully optimize the concentration of assay components when using SERS nanotags and a single-line multiplexing approach. We show that in certain circumstances the SERS signal may be suppressed, leading to a significant underestimation of the analyte concentrations. Using electron microscopy and optical spectroscopy, we demonstrate that the error in the measurement is associated with the light scattering properties of the nanotags. These findings will be applicable to other nanoparticle labels with high light scattering coefficients. Through careful modification of the assay to reduce the impact of light scattering, it is possible to produce quantitative assays, but potentially at the expense of multiplexing capability and assay sensitivity. PMID- 22947113 TI - Psychometric properties of the Sinhala version of the PedsQLTM 4.0 Generic Core Scales in early adolescents in Sri Lanka. AB - BACKGROUND: The concept Health related Quality of life (HRQOL) is increasingly recognized as an important health outcome measure in clinical and research fields. The present study attempted to evaluate the psychometric properties of the Sinhala version of the Pediatric Quality of Life InventoryTM 4.0 (PedsQLTM 4.0) Generic Core Scales among adolescents in Sri Lanka. METHODS: The original US PedsQLTM was translated into Sinhala and conceptually validated according to international guidelines. A cross-sectional study was conducted among 142 healthy school going adolescents (12-14 years), their parents (n = 120) and a group of adolescents with asthma who attended asthma clinics (n = 115). Reliability was assessed using Cronbach's alpha and validity by examining scale structure, exploring inter-scale correlations and comparing across known groups (healthy vs. chronically ill). RESULTS: The PedsQLTM Sinhala version was found to be acceptable with minimal missing responses. All scales demonstrated satisfactory reliability. Cronbach's alpha for the total scale scores was 0.85 for adolescent self-report while for the parent proxy-report for the healthy group it was 0.86. No floor effects were observed. Ceiling effects were noticed in self-report and parent proxy-report for the healthy group. Overall results of the multi trait scaling analysis confirmed the scale structure with 74% item-convergent validity, 88% item-discriminant validity and an overall scaling success of 72%. Moderate to high correlations were shown among the domains of teen self-report (Spearman rho = .37-.54) and between teen self-report and parent proxy-reports (Spearman rho = .41-.57). The PedsQLTM tool was able to discriminate between the quality of life in healthy adolescents and adolescents with asthma. CONCLUSION: The findings support the reliability and validity of the Sinhala version of the PedsQLTM 4.0 Generic Core Scales as a generic instrument to measure HRQOL among early adolescents in Sri Lanka in a population setting. PMID- 22947114 TI - The validity of the risk index for comparing the accident risk associated with different work schedules. AB - Although it is known that there is an association between working hours and occupational accidents, there are only few tools which allow for an assessment of the risk associated with different working time arrangements, none of them validated yet by independent samples. Promising tools like the risk index (RI), assessed via the fatigue and risk index calculator, thus need to be validated. Since analyses on the validity of the RI based on individual data found only moderate associations between the RI and the actual accident risk, the question arises, whether a validation based on grouped data yields more promising results. Thus, the validity of the RI was re-examined, using aggregated data, i.e. pooling several individuals into groups of respondents according to their RI-score and performing calculations on the group level in order to control for individual and random variation. The study sample (n=337) was derived from an Internet survey on working hours and health, which contained information on working hours over four weeks and on the occurrence of an occupational accident during the last 12 months. Two models of aggregation were used: a distribution based and a criterion based classification, resulting in four RI groups each. Accident rates for each group were calculated and compared via chi(2)-analyses and fitting trends to the data. Results show, for both models of aggregation, that the accident rate increased exponentially with an increasing RI. Risk was 3.7 times (distribution based aggregation) and 6.5 times (criterion based aggregation) higher in the highest compared to the lowest RI-groups. The exponential trend explained 92% (distribution based aggregation) and 98% (criterion based aggregation) of the variance, respectively. Analyses for homogeneous subgroups (e.g., service sector, and workers with high workload) showed similar trends. Thus the analyses based on aggregated data indicated a considerable and consistently higher validity of the RI than the earlier analyses based on individual data, irrespective of the model of aggregation. These results are quite promising although further analyses based on larger samples are needed to confirm these findings and in order to further develop the RI or similar indices. PMID- 22947115 TI - Miliary brain metastasis presenting with calcification in a patient with lung cancer: a case report. AB - INTRODUCTION: Miliary brain metastasis is an extremely rare form of brain metastasis which can present with atypical imaging findings. We report the case of a patient with miliary brain metastasis of lung cancer showing calcification in metastatic lesions. CASE PRESENTATION: A 68-year-old Japanese woman was diagnosed with lung adenocarcinoma. Brain computed tomography revealed multiple small calcified lesions in both cerebral hemispheres. Mutation of the epidermal growth factor receptor gene (exon 21, L858R) in lung cancer cells was detected, and treatment with gefitinib was initiated. A partial response was observed; however, the patient was readmitted to our hospital because of regrowth of the primary lesion and complaints of nausea, headache, and difficulty walking. Brain magnetic resonance imaging revealed scattered tiny nodules enhanced by gadolinium. A diagnosis of leptomeningeal carcinomatosis was made on the basis of cerebrospinal fluid cytology. The patient's general status worsened, and she died 356 days after the day of first medical examination. Upon autopsy, the brain was found to be edematous and swollen. Lung carcinoma cells were diffusely disseminated on the meningeal surface. Metastatic foci of small nodular form, accompanied by calcifications, were also found in the brain parenchyma. We diagnosed miliary metastasis of lung carcinoma. CONCLUSIONS: To the best of our knowledge, this is the third report of calcified miliary brain metastasis confirmed by autopsy. We describe calcified lesions that increased in size during the clinical course of nine months. Brain computed tomography findings that reveal multiple small calcified lesions in patients with malignancy should raise suspicion of miliary brain metastasis. PMID- 22947117 TI - The complete mitochondrial genome sequence of Triplophysa bleekeri (Teleostei, Balitoridae, Nemacheilinae). AB - The genus Triplophysa (plateau loach) is a highly diverse group in the family Balitoridae with 133 valid species, and they play an important role in zoogeographic study of the Qinghai-Tibet Plateau. In this study, we sequenced the complete mitochondrial genome of a Triplophysa species, Triplophysa bleekeri. Combined with the complete mitogenome sequences of other 10 balitorids, the phylogenetic position of T. bleekeri was estimated. The mitochondrial genome of T. bleekeri is similar to those of the typical vertebrates, 16,568 bp in length, including 13 protein-coding genes, 2 ribosomal RNA genes, 22 transfer RNA genes, and 1 non-coding control region (D-loop). In the D-loop region, two pair of motifs, "TACAT" and its reverted and complemented sequence "ATGTA", can be found in the domain of termination-associated sequence; six conserved sequences (CSB-F, CSB-E, CSB-D, and CSB I-III) can be identified by searching some conserved motifs. Phylogenetic analyses showed that the three Triplophysa species clustered together, with T. bleekeri sister to Triplophysa stoliczkai. The two genera Triplophysa and Barbatula formed a sister-group relationship, the genus Lefua located in the intermediate position, and the genus Schistura was in the basal position in the subfamily Nemacheilinae. Further investigations with more Triplophysa species included need to be performed to better understand the evolutionary history of this intriguing genus. PMID- 22947116 TI - Preserved local but disrupted contextual figure-ground influences in an individual with abnormal function of intermediate visual areas. AB - Visual perception depends not only on local stimulus features but also on their relationship to the surrounding stimulus context, as evident in both local and contextual influences on figure-ground segmentation. Intermediate visual areas may play a role in such contextual influences, as we tested here by examining LG, a rare case of developmental visual agnosia. LG has no evident abnormality of brain structure and functional neuroimaging showed relatively normal V1 function, but his intermediate visual areas (V2/V3) function abnormally. We found that contextual influences on figure-ground organization were selectively disrupted in LG, while local sources of figure-ground influences were preserved. Effects of object knowledge and familiarity on figure-ground organization were also significantly diminished. Our results suggest that the mechanisms mediating contextual and familiarity influences on figure-ground organization are dissociable from those mediating local influences on figure-ground assignment. The disruption of contextual processing in intermediate visual areas may play a role in the substantial object recognition difficulties experienced by LG. PMID- 22947119 TI - High productivity bioethanol fermentation by immobilized Saccharomyces bayanus onto carboxymethylcellulose-g- poly(N-vinyl-2-pyrrolidone) beads. AB - Crosslinked graft copolymers of CMC with N-vinyl-2-pyrrolidone (N-VP) were prepared in different grafting yields. Saccharomyces bayanus was immobilized in the graft copolymers of carboxymethylcellulose-g-poly(N-vinyl-2-pyrrolidone) (CMC g-PVP) for ethanol fermentation. The effects of grafting yield, initial glucose concentration, and crosslinker concentration on the yield of ethanol process was investigated. Ethanol production increased when percentage of N-vinyl-2 pyrrolidone in the graft copolymer was increased. The maximum concentration, productivity, and yield of ethanol were 98.78 g L (-1), 8.23 g L (-1) h (-1) and 0.494 g g (-1), respectively. Reusability of the immobilized yeasts was found that the materials can be used seven times without losing their activity. PMID- 22947118 TI - The effect of growth architecture on the induction and decay of bleomycin and X ray-induced bystander response and genomic instability in lung adenocarcinoma cells and blood lymphocytes. AB - PURPOSE: Cancer patients treated with radiomimetic drug bleomycin (BLM) have shown incidence of 7% second malignancy. Studies regarding BLM-induced genomic instability in bystander cells are scarce, and experiments with cells grown on three-dimensional (3D) cultures to mimic the in-vivo condition have never been attempted. MATERIALS AND METHODS: A549 and NCI-H23 (human lung adenocarcinoma) cells were grown as 3D cultures using Cytomatrix(TM), exposed to BLM or X radiation and co-cultured with their respective unexposed cells. The DNA damage in direct and bystander cells were assessed by the induction of micronuclei (MN) or phosphorylated serine-15 residue in protein 53 (p53(ser-15)), a reflection of DNA damage, and by up-regulation of protein 21 (p21Waf1). The persistence of DNA damage was measured using MN assay and fluorescence in situ hybridization (FISH) in cancer cells and human peripheral blood lymphocytes (PBL) respectively. RESULTS: BLM or X-irradiation induced DNA damage in both A549 and NCI-H23 cells and their respective bystander cells grown in 2D or 3D cultures. Further persistence of these damages in bystander PBL at delayed times indicated genomic instability in these cells. CONCLUSION: BLM-induced genomic instability in the progeny of bystander cells and their significance in therapy-induced second malignancy may not be eliminated completely. PMID- 22947120 TI - Cardiac computed tomography for valve disease. AB - Heart valve disease and coronary heart disease are very prevalent in the general population and often coincide in the same patient. Cardiac computed tomography (CT) makes it possible to noninvasively rule out coronary disease before valve surgery and to potentially avoid invasive heart catheterization in 66% to 75% of patients. The same imaging test provides abundant anatomic and functional information that complements the information from echocardiography, making it possible to characterize the etiology of the valve disease and its repercussions on the heart and aorta, as well as to quantify the severity of disease affecting the valves of the left side of the heart. In this article, we describe the anatomy of the heart valves and the technical requisites of cardiac CT for the study of the valves. We go on to explore the usefulness of CT in the preoperative study of the coronary arteries and in the morphological and functional characterization of valve disease, with special emphasis on the valves of the left side of the heart. PMID- 22947122 TI - Ten years' work on the World Organisation for Animal Health (OIE) Worldwide Animal Disease Notification System. AB - This article gives an overview of the World Organisation for Animal Health (OIE) Worldwide Animal Disease Notification System and highlights the major achievements during the past decade. It describes the different types of disease notification reports received and processed by the OIE. It also evaluates the three strategies implemented by the OIE in the recent years aimed at improving disease notification: introduction and use of a secure online notification system World Animal Health Information System (WAHIS) and its database interface World Animal Health Information Database (WAHID); implementation of active search and verification procedures for non-official information; and enhanced building of capacity for animal disease notification to the OIE by Members Countries. The improvements are evidenced by the increasing number of reports submitted on an annual basis and the reduction in submission time together with an improvement in the quality and quantity of the immediate notifications and follow-up reports, six-monthly and annual reports submitted by Veterinary Authorities. In the recent years, the OIE's notification system provides an early warning system more sensitive and global. Consequently, there is a greater knowledge of animal diseases' distribution worldwide. As a result, it is possible to ensure better prevention, more accurate risk assessment and evaluation by diminishing the spread of known or newly emerging pathogens. PMID- 22947123 TI - Molecular principles of parasitism. Preface. PMID- 22947124 TI - Comparative in vitro activities of daptomycin, vancomycin, teicoplanin and linezolid against resistant Gram-positive bacterial isolates from two large centres in western India. PMID- 22947121 TI - Tox-database.net: a curated resource for data describing chemical triggered in vitro cardiac ion channels inhibition. AB - BACKGROUND: Drugs safety issues are now recognized as being factors generating the most reasons for drug withdrawals at various levels of development and at the post-approval stage. Among them cardiotoxicity remains the main reason, despite the substantial effort put into in vitro and in vivo testing, with the main focus put on hERG channel inhibition as the hypothesized surrogate of drug proarrhythmic potency. The large interest in the IKr current has resulted in the development of predictive tools and informative databases describing a drug's susceptibility to interactions with the hERG channel, although there are no similar, publicly available sets of data describing other ionic currents driven by the human cardiomyocyte ionic channels, which are recognized as an overlooked drug safety target. DISCUSSION: The aim of this database development and publication was to provide a scientifically useful, easily usable and clearly verifiable set of information describing not only IKr (hERG), but also other human cardiomyocyte specific ionic channels inhibition data (IKs, INa, ICa). SUMMARY: The broad range of data (chemical space and in vitro settings) and the easy to use user interface makes tox-database.net a useful tool for interested scientists. DATABASE URL: http://tox-database.net. PMID- 22947125 TI - In vitro efficacy of the anticancer drug imatinib on Echinococcus multilocularis larvae. AB - The metacestode stage of Echinococcus multilocularis is the causative agent of alveolar echinococcosis (AE), a lethal zoonosis with very limited treatment options. Chemotherapy of AE currently employs benzimidazoles (BZs); however, these exert only a parasitostatic action in vivo and have to be given life-long. In the search for novel drug targets, we have concentrated on parasite signalling pathways. Here we report significant antiparasitic effects of imatinib, an ABL kinase inhibitor that is in clinical use to treat certain cancers. At concentrations of 25 MUM, imatinib was highly effective in killing Echinococcus stem cells, metacestode vesicles and protoscoleces in vitro. Moreover, already at concentrations as low as 10 MUM, imatinib significantly inhibited the formation of metacestode vesicles from parasite stem cells, inactivated 50% of vesicles after 7 days, and induced morphological alterations in the metacestode upon short term treatment. We also demonstrate that E. multilocularis larvae express enzymes with high homology to previously identified ABL-like kinases that act as imatinib targets in Schistosoma mansoni. In particular, amino acids known to mediate the binding of imatinib to target kinases are well conserved between human and Echinococcus ABL kinases. Taken together, these data demonstrate effective inactivation of Echinococcus larvae using imatinib concentrations that do not significantly affect cultivated human cells, indicating that imatinib might be a promising alternative to BZs in anti-AE chemotherapy. Furthermore, imatinib can also act as a lead substance for the identification of related compounds with higher antiparasitic activity, the identification of which will be facilitated by the Echinococcus ABL kinase sequences determined in this study. PMID- 22947126 TI - Comparison of whole-genome prediction models for traits with contrasting genetic architecture in a diversity panel of maize inbred lines. AB - BACKGROUND: There is increasing empirical evidence that whole-genome prediction (WGP) is a powerful tool for predicting line and hybrid performance in maize. However, there is a lack of knowledge about the sensitivity of WGP models towards the genetic architecture of the trait. Whereas previous studies exclusively focused on highly polygenic traits, important agronomic traits such as disease resistances, nutrifunctional or climate adaptational traits have a genetic architecture which is either much less complex or unknown. For such cases, information about model robustness and guidelines for model selection are lacking. Here, we compared five WGP models with different assumptions about the distribution of the underlying genetic effects. As contrasting model traits, we chose three highly polygenic agronomic traits and three metabolites each with a major QTL explaining 22 to 30% of the genetic variance in a panel of 289 diverse maize inbred lines genotyped with 56,110 SNPs. RESULTS: We found the five WGP models to be remarkable robust towards trait architecture with the largest differences in prediction accuracies ranging between 0.05 and 0.14 for the same trait, most likely as the result of the high level of linkage disequilibrium prevailing in elite maize germplasm. Whereas RR-BLUP performed best for the agronomic traits, it was inferior to LASSO or elastic net for the three metabolites. We found the approach of genome partitioning of genetic variance, first applied in human genetics, as useful in guiding the breeder which model to choose, if prior knowledge of the trait architecture is lacking. CONCLUSIONS: Our results suggest that in diverse germplasm of elite maize inbred lines with a high level of LD, WGP models differ only slightly in their accuracies, irrespective of the number and effects of QTL found in previous linkage or association mapping studies. However, small gains in prediction accuracies can be achieved if the WGP model is selected according to the genetic architecture of the trait. If the trait architecture is unknown e.g. for novel traits which only recently received attention in breeding, we suggest to inspect the distribution of the genetic variance explained by each chromosome for guiding model selection in WGP. PMID- 22947127 TI - Thermal processing as a means to prepare durable, submicron thickness ionomer films for study by transmission infrared spectroscopy. AB - A high temperature solution processing method was adapted to prepare durable, freestanding, submicrometer thickness films for transmission infrared spectroscopy studies of ionomer membrane. The materials retain structural integrity following cleaning and ion-exchange steps in boiling solutions, similar to a commercial fuel cell membrane. Unlike commercial membrane, which typically has thicknesses of >25 MUm, the structural properties of the submicrometer thickness materials can be probed in mid-infrared spectral measurements with the use of transmission sampling. Relative to the infrared attenuated total reflection (ATR) technique, transmission measurements can sample ionomer membrane materials more uniformly and suffer less distortion from optical effects. Spectra are reported for thermally processed Nafion and related perfluoroalkyl ionomer materials containing phosphonate and phosphinate moieties substituted for the sulfonate end group on the side chain. Band assignments for complex or unexpected features are aided by density functional theory (DFT) calculations. PMID- 22947128 TI - Advantages of positron emission tomography-computed tomography imaging in esophageal squamous cell carcinoma. AB - To explore the value of positron emission tomography-computed tomography (PET-CT) scan in esophageal squamous cell carcinoma (ESCC), we retrospectively summarize the results of PET-CT scan from 118 patients, with ESCC who underwent PET-CT scan in the different courses during treatment. Then, the results of PET-CT scan plus other conventional methods were analyzed to identify the value of PET-CT scan in diagnosis, staging, response evaluation, monitoring recurrence, and metastasis following treatment. It is suggested that PET-CT scan possess high value in diagnosis and gives more favorable indication in N and M staging. PET-CT scan should be translated into routine surveillance for postoperation follow up and is one of more helpful evaluators of response to chemoradiotherapy or chemotherapy. PMID- 22947129 TI - Toxicity of ricin toxin A chain in rats. AB - Ricin toxin A chain (RTA) is the cytotoxic component of the dimeric protein, ricin, one of the most potent and deadly plant toxins extracted from the seeds of Ricinus communis. RTA has been investigated as a potential candidate for cancer chemotherapy, in the form of immunotoxins, and as a method for depleting macrophages in vivo. The toxicity of RTA immunotoxins is mostly characterized by inflammation and necrosis and has been attributed to the RTA moiety of the conjugate. The present study was carried out to investigate the toxicity of intravenously (i.v.) administered RTA alone and to assess whether the observed tissue injuries are associated with increases in oxidative stress (OS) and inflammation. RTA (10 or 90 ug/kg body weight) was administered to animals i.v., and 5 or 24 hours later, liver, lungs, kidneys, and hearts were examined. RTA, at a dose of 90 ug/kg (i.v.), resulted in significant increases (P < 0.05) in an inflammatory response (i.e., increases in hepatic and lung myeloperoxidase activity) and increases in oxidant response (increases in lipid peroxidation and decreases in glutathione levels in hepatic and lung homogenates). These data suggest that i.v. administration of RTA resulted in organ injuries that were associated with inflammation and OS. PMID- 22947130 TI - Are Dutch patients willing to be seen by a physician assistant instead of a medical doctor? AB - BACKGROUND: The employment of physician assistants (PAs) is a strategy to improve access to care. Since the new millennium, a handful of countries have turned to PAs as a means to bridge the growing gap between the supply and demand of medical services. However, little is known about this new workforce entity from the patient's perspective. The objective of this study was to assess the willingness of Dutch patients to be treated by a PA or a medical doctor (MD) under various time constraints and semi-urgent medical scenarios. METHODS: A total of 450 Dutch adults were recruited to act as surrogate patients. A convenience sample was drawn from patients in a medical office waiting room in a general hospital awaiting their appointments. Each participant was screened to be naive as to what a PA and a nurse practitioner are and then read a definition of a PA and an MD. One of three medical scenarios was assigned to the participants in a patterned 1 2-3 strategy. Patients were required to make a trade-off decision of being seen after 1 hour by a PA or after 4 hours by a doctor. This forced-choice method continued with the same patient two more times with 30 minutes and 4 hours and another one of 2 hours versus 4 hours for the PA and MD, respectively. RESULTS: Surrogate patients chose the PA over the MD 96 % to 98 % of the time (depending on the scenario). No differences emerged when analysed by gender, age, or parenthood status. CONCLUSION: Willingness to be seen by a PA was tested a priori to determine whether surrogate Dutch patients would welcome this new health-care provider. The findings suggest that employing PAs, at least in concept, may be an acceptable strategy for improving access to care with this population. PMID- 22947131 TI - In vitro tests for aerosol deposition II: IVIVCs for different dry powder inhalers in normal adults. AB - BACKGROUND: A new in vitro test method for dry powder inhalers (DPIs) was recently found to be predictive of the published in vivo results for Budelin Novolizer. The present study was intended to assess the method's robustness by evaluating correlations between average drug deposition in vitro and in vivo from five different DPIs. METHODS: In vitro drug deposition from five marketed DPIs was assessed in a realistic physical airway model of a "medium" sized adult in an experimental setup that allowed deposition to be characterized regionally for carefully selected simulated air flow rate versus time profiles. The DPIs studied were Spiriva((r)) HandiHaler((r)), Relenza((r)) Diskhaler((r)), Salbutamol Easyhaler((r)), Pulmicort((r)) Turbuhaler((r)), and Foradil((r)) Aerolizer((r)). In vitro regional deposition results were compared with those reported in the literature in order to create in vitro-in vivo correlations (IVIVCs) for each inhaler. RESULTS: Mean percent total lung deposition (TLD +/- SD) in vitro for Spiriva HandiHaler, Relenza Diskhaler, Salbutamol Easyhaler, Pulmicort Turbuhaler, and Foradil Aerolizer were 17.3 +/- 1.2, 22.6 +/- 1.1, 29.0 +/- 1.1, 28.0 +/- 3.0, and 21.7 +/- 1.2, respectively. These results showed excellent agreement with reported in vivo values, with absolute prediction errors in TLD of <= 2% for all DPIs except Relenza Diskhaler. Similarly, in vitro mouth-throat and device deposition results were stoichiometrically comparable to those reported in vivo for all DPIs except Relenza Diskhaler and Turbuhaler. Inspection of the scintigraphy studies for Relenza Diskhaler and Turbohaler revealed possible problems with powder labeling and result interpretation in their in vivo clinical assessments. CONCLUSIONS: A characteristic physical airway model representing a medium-sized adult, when coupled to carefully chosen characteristic inhalation maneuvers used in the clinic, produced results that correlated with regional drug deposition estimates from scintigraphy across a group of different DPIs. PMID- 22947132 TI - Early duodenal adenocarcinoma resembling a submucosal tumor cured with endoscopic resection: a case report. AB - INTRODUCTION: Primary adenocarcinomas resembling submucosal tumors are rare in the gastrointestinal tract. Almost all the submucosal tumor-like adenocarcinomas previously reported invaded the submucosa or deeper. Therefore, submucosal tumor like lesions are usually treated by surgical resection, and those that arise in the duodenum have been treated by pancreaticoduodenectomy. CASE PRESENTATION: A 65-year-old Japanese man was diagnosed with a submucosal tumor-like adenocarcinoma in his duodenum. We considered it possible that the tumor invasion was limited to the mucosal or submucosal layers and could be removed by endoscopic resection. Tumor histopathology revealed a well-differentiated adenocarcinoma confined to the muscularis mucosae with no lymphovascular invasion. Complete resection of the carcinoma was achieved and there has been no recurrence three years after endoscopic resection. CONCLUSIONS: We suggest that submucosal tumor-like adenocarcinomas arising in nonampullary duodenal sites should be diagnosed carefully with a view to possible endoscopic resection. PMID- 22947133 TI - What leads to healthy ageing and longevity? PMID- 22947134 TI - High efficiency thin upgraded metallurgical-grade silicon solar cells on flexible substrates. AB - We present a thin film (<20 MUm) solar cell based on upgraded metallurgical-grade polycrystalline Si that utilizes silver nanoparticles atop silicon nanopillars created by block copolymer nanolithography to enhance light absorption and increase cell efficiency eta > 8%. In addition, the solar cells are flexible and semitransparent so as to reduce balance of systems costs and open new applications for conformable solar cell arrays on a variety of surfaces. Detailed studies on the optical and electrical properties of the resulting solar cells suggest that both antireflective and light-trapping mechanisms are key to the enhanced efficiency. PMID- 22947135 TI - Tumour characteristics, oncological and functional outcomes in patients aged >= 70 years undergoing radical prostatectomy. AB - Study Type - Therapy (case series) Level of Evidence 4 What's known on the subject? and What does the study add? The marked increase in life expectancy in recent years calls for reconsideration of the decision-making process for the treatment of prostate cancer, a condition particularly affecting the elderly. To date the general approach in elderly patients has tended to be more conservative, not least as it is generally thought that prostate cancer in these patients is less biologically aggressive. The present data showed that patients aged >=70 years had biologically more aggressive tumours significantly more often than those aged <70 years. Nevertheless, advanced age itself was not an independent predictor of survival after retropubic radical prostatectomy, whereas adverse prostate cancer features and severe comorbidities were. OBJECTIVE: To investigate the effect of advanced age (>=70 years) on prostate cancer characteristics, oncological and functional outcomes in patients undergoing retropubic radical prostatectomy (RP). PATIENTS AND METHODS: Between June 1997 and September 2009, 1636 patients underwent RP at one institution. Of these patients, 1225 were aged < 70 years and 411 >=70 years. Both groups were compared for prostate cancer characteristics, oncological and functional outcomes. Multivariate analyses were used to estimate the effect of advanced age on overall survival (OS), cancer specific survival (CSS), biochemical recurrence-free survival (BFS) and postoperative continence. RESULTS: The median (range) age of the patients aged >= 70 years was 72 (70-85) years and for those aged < 70 years was 64 (40-69) years (P < 0.001), respectively. The patients aged >= 70 years were assigned higher American Society of Anesthesiologists (ASA) classes (P < 0.001) reflecting a higher rate of severe comorbidities in this group. In the patients aged >= 70 years there were significantly more clinically palpable and pathologically non organ-confined tumours (P= 0.030 and P= 0.026, respectively), and higher biopsy and RP Gleason scores (P= 0.002 and P= 0.004, respectively). Accordingly, patients aged >= 70 years presented with a higher proportion of high-risk prostate cancer, although the difference was not significant (P= 0.060). There were no differences between the groups for preoperative prostate-specific antigen level (P= 0.898), rate of pelvic lymph node dissection (P= 0.231), pN+ (P= 0.526) and R+ status (P= 0.590). Kaplan-Meier curves showed a significantly lower 10 year OS (67 vs 82%; P= 0.017) and a trend towards a lower 10-year CSS (70 vs 83%; P= 0.057) in patients aged >= 70 years. However, on multivariate analysis advanced age was not an independent predictor of OS (P= 0.102) or CSS (P= 0.195), whereas pN+ status (both P < 0.001), RP Gleason scores 8-10 (both P < 0.001) and ASA classes 3-4 (P= 0.037 and P= 0.028, respectively) were. The 2-year postoperative continence rates was comparable between the groups (International Continence Society [ICS] male incontinence symptom score 2.10 vs 2.01; P= 0.984). In multivariate analysis it depended only on the preoperative ICSmale incontinence symptom score (P < 0.001) but not on advanced age (P= 0.341). CONCLUSIONS: Patients aged >= 70 years had biologically more aggressive and locally advanced tumours significantly more often than those aged < 70 years. However, advanced age itself was not an independent predictor of survival after RP. Rather, survival was associated with adverse prostate cancer features and severe comorbidities. Consequently, it seems unjustifiable to generally exclude elderly patients from RP, not least because surgery achieved excellent postoperative continence in this age group, too. PMID- 22947136 TI - Determination and comparison of two complete mitochondrial genomes of golden Chinese loach, Sinibotia superciliaris (Teleostei, Cypriniformes). AB - The golden Chinese loach, Sinibotia superciliaris (Gunther, 1892) is an endemic fish in China, which is only distributed in the main river and tributaries of the upper and middle Yangtze River. In this study, we sequenced two mitochondrial genomes simultaneously from two samples of S. superciliaris collected from two different locations. Both mitogenomes were 16,572 bp in length, showing a typical vertebrate mitogenome feature with 13 protein-coding genes, 22 transfer RNAs, 2 ribosomal RNAs, and 1 major non-coding control region (CR). Alignment and comparative analyses showed that the two mitogenome sequences possessed 22 mutation sites, all of which were transitions and mainly occurred in protein coding genes (13/22) and CR (7/22). Among the 13 mutation sites that occurred in protein-coding genes, three mutation sites occurred in the first codon position and the remaining 10 sites occurred in the third codon position. However, only one mutation that occurred in the first codon position resulted in non-synonymous substitution in COI gene. The molecular data presented in this study will contribute to further phylogenetic analyses for this group of fishes. PMID- 22947137 TI - Eosinophilic esophagitis: dilate or medicate? A cost analysis model of the choice of initial therapy. AB - Eosinophilic esophagitis (EoE) is an increasingly recognized clinical entity. The optimal initial treatment strategy in adults with EoE remains controversial. The aim of this study was to employ a decision analysis model to determine the less costly option between the two most commonly employed treatment strategies in EoE. We constructed a model for an index case of a patient with biopsy-proven EoE who continues to be symptomatic despite proton-pump inhibitor therapy. The following treatment strategies were included: (i) swallowed fluticasone inhaler (followed by esophagogastroduodenoscopy [EGD] with dilation if ineffective); and (ii) EGD with dilation (followed by swallowed fluticasone inhaler if ineffective). The time horizon was 1 year. The model focused on cost analysis of initial treatment strategies. The perspective of the healthcare payer was used. Sensitivity analyses were performed to assess the robustness of the model. For every patient whose symptoms improved or resolved with the strategy of fluticasone first followed by EGD, if necessary, it cost an average of $1078. Similarly, it cost an average of $1171 per patient if EGD with dilation was employed first. Sensitivity analyses indicated that initial treatment with fluticasone was the less costly strategy to improve dysphagia symptoms as long as the effectiveness of fluticasone remains at or above 0.62. Swallowed fluticasone inhaler (followed by EGD with dilation if necessary) is the more economical initial strategy when compared with EGD with dilation first. PMID- 22947138 TI - Stability of a formalin-inactivated Rift Valley fever vaccine: evaluation of a vaccination campaign for cattle in Mozambique. AB - In Africa and the Arabian Peninsula, outbreaks of Rift Valley fever (RVF) are characterized by abortions in gestating animals and high mortality rates among domestic ruminants. An immunization program using a formalin-inactivated vaccine was initiated in Mozambique in 2002 to control RVF in cattle. In this intervention, the vaccine must be transported for more than a week within the country before it can be administered to the animals, and it is practically impossible to maintain low storage temperatures during that time. Here, we evaluated the influence of transportation conditions on the efficacy of the vaccine. Sixty-three previously unvaccinated and RVF virus seronegative cattle were divided into four groups, which were given vaccine that had been stored for 1 week at 4 degrees C (n=9, group A), at 25 degrees C (n=8, group B), or alternating between 4 and 25 degrees C (n=8, group C), or under the temperature conditions ordinarily occurring during transportation within Mozambique (n=38, group D). The antibody responses induced were monitored for 6-9 months and in some animals up to 21 months. Two immunizations (3 weeks apart) with the formalin inactivated vaccine induced a long-lasting neutralizing antibody response that was still detectable up to 21 months later. The antibody titers in the animals did not differ significantly between the temperature-assigned vaccine groups A, B, and C, whereas they were significantly higher in group D. These results show that the formalin-inactivated RVF virus vaccine is stable, and, importantly, it is not adversely affected by the variation in temperature that ordinarily occurs during transport within Mozambique. PMID- 22947139 TI - Intranasal immunisation of mice against Streptococcus equi using positively charged nanoparticulate carrier systems. AB - In order to potentiate a strong immune response after mucosal vaccination with a low immunogenic S. equi enzymatic extract, two positively charged particulate delivery systems (liposomes and nanoparticles) were created. Positively surface charged particles were expected to efficiently bind to negatively charged cell membranes and facilitate antigen uptake. Phosphatidylcholine-cholesterol stearylamine liposomes encapsulating S. equi antigens were prepared and dimensionated to 0.22+/-0.01MUm with a polydispersity index <0.242, zeta potential of +12+/-4mV and an encapsulation efficiency of 13+/-3% (w/w). Chitosan nanoparticles were prepared by ionotropic gelation with sodium tripolyphosphate, presenting a particle size of 0.17+/-0.01MUm with polydispersity index <0.362, zeta potential of +23+/-8mV and an encapsulation efficiency of 53+/-6% (w/w). Both encapsulation methods were recognised as innocuous once antigens structure remained intact after incorporation as assessed by SDS-PAGE. Intranasal immunisation of mice with both formulations successfully elicited mucosal, humoral and cellular immune responses. Mucosal stimulation was confirmed by increased sIgA levels in the lungs, being the chitosan nanoparticles more successful in this achievement probably due to their different mucoadhesive properties. Both formulations share the ability to induce Th1-mediated immune responses characterised by IFN-gamma production and high IgG2a antibody titers as well as a Th2 immune response characterised mainly by IL-4 production and IgG1 antibodies. PMID- 22947140 TI - Induction of pulmonary mucosal immune responses with a protein vaccine targeted to the DEC-205/CD205 receptor. AB - It is of great interest to develop a pneumonic plague vaccine that would induce combined humoral and cellular immunity in the lung. Here we investigate a novel approach based on targeting of dendritic cells using the DEC-205/CD205 receptor (DEC) via the intranasal route as way to improve mucosal cellular immunity to the vaccine. Intranasal administration of Yersinia pestis LcrV (V) protein fused to anti-DEC antibody together with poly IC as an adjuvant induced high frequencies of IFN-gamma secreting CD4(+) T cells in the airway and lung as well as pulmonary IgG and IgA antibodies. Anti-DEC:LcrV was more efficient to induce IFN-gamma/TNF alpha/IL-2 secreting polyfunctional CD4(+) T cells when compared to non-targeted soluble protein vaccine. In addition, the intranasal route of immunization with anti-DEC:LcrV was associated with improved survival upon pulmonary challenge with the virulent CO92 Y. pestis. Taken together, these data indicate that targeting dendritic cells via the mucosal route is a potential new avenue for the development of a mucosal vaccine against pneumonic plague. PMID- 22947141 TI - Inactivated HSV-2 in MPL/alum adjuvant provides nearly complete protection against genital infection and shedding following long term challenge and rechallenge. AB - Herpes Simplex Virus Type 2 (HSV-2) infection can result in life-long recurrent genital disease, asymptomatic virus shedding, and transmission. No vaccine to date has shown significant protection clinically. Here, we used a mouse model of genital HSV-2 infection to test the efficacy of a vaccine consisting of whole, formalin-inactivated HSV-2 (FI-HSV2) formulated with monophosphoryl lipid A (MPL) and alum adjuvants. Vaccine components were administered alone or as a prime boost immunization together with DNA vaccines encoding a truncated glycoprotein D2 (gD2t) and two conserved HSV-2 genes necessary for virus replication, UL5 (DNA helicase) and UL30 (DNA polymerase). Our results show: (1) compared with mock immunized controls, mice immunized with FI-HSV2 plus MPL/alum consistently showed protection against disease burden and total viral shedding while the mice immunized with gD2t protein with MPL/alum did not; (2) protection against genital disease and viral replication correlated with the type of boost in a prime-boost immunization with little advantage afforded by a DNA prime; (3) intramuscular (i.m.) immunization with FI-HSV2 in MPL/Alhydrogel adjuvant provided nearly complete protection against vaginal HSV-2 shedding after a lethal intravaginal (i.vag.) short-term challenge and long-term rechallenge; (4) single formulation immunization with DNA vaccines, FI-HSV2, and MPL in an aluminum phosphate (Adju Phos) adjuvant did not increase protection relative to FI-HSV2/MPL/Adju-Phos alone; and (5) addition of MPL/alum to the FI-HSV2 was required for optimal protection against disease, viral replication, and latent virus load in the dorsal root ganglia (DRG). Most notably, an optimized vaccine formulation of FI HSV2 MPL/Alhydrogel given i.m. completely protected against detectable vaginal HSV-2 shedding in the majority of animals and HSV-2 latent DNA in the DRG of all animals. PMID- 22947142 TI - Microarray analysis revealing common and distinct functions of promyelocytic leukemia protein (PML) and tumor necrosis factor alpha (TNFalpha) signaling in endothelial cells. AB - BACKGROUND: Promyelocytic leukemia protein (PML) is a tumor suppressor that is highly expressed in endothelial cells nonetheless its role in endothelial cell biology remains elusive. Tumor necrosis factor alpha (TNFalpha) is an important cytokine associated with many inflammation-related diseases. We have previously demonstrated that TNFalpha induces PML protein accumulation. We hypothesized that PML may play a role in TNFalpha signaling pathway. To identify potential PML target genes and investigate the putative crosstalk between PML's function and TNFalpha signaling in endothelial cells, we carried out a microarray analysis in human primary umbilical endothelial cells (HUVECs). RESULTS: We found that PML and TNFalpha regulate common and distinct genes involved in a similar spectrum of biological processes, pathways and human diseases. More importantly, we found that PML is required for fine-tuning of TNFalpha-mediated immune and inflammatory responses. Furthermore, our data suggest that PML and TNFalpha synergistically regulate cell adhesion by engaging multiple molecular mechanisms. Our biological functional assays exemplified that adhesion of U937 human leukocytes to HUVECs is co-regulated by PML and TNFalpha signaling. CONCLUSIONS: Together, our study identified PML as an essential regulator of TNFalpha signaling by revealing the crosstalk between PML knockdown-mediated effects and TNFalpha-elicited signaling, thereby providing novel insights into TNFalpha signaling in endothelial cells. PMID- 22947143 TI - Ultra-short laser pulse generated by a microring resonator system for cancer cell treatment. AB - A microring resonator (MRRs) system incorporated with a add/drop filter is proposed in which ultra-short single, multi-temporal, and spatial optical soliton pulses are simulated and used to kill abnormal cells, tumors, and cancer. Chaotic signals are generated by a bright soliton pulse within a nonlinear MRRs system. Gold nanoparticles and ultra-short femtosecond/picosecond laser pulses' interaction holds great interest in laser nanomedicine. By using appropriate soliton input power and MRRs parameters, desired spatial and temporal signals can be generated over the spectrum. Results show that short temporal and spatial solitons pulse with FWHM = 712 fs and FWHM = 17.5 pm could be generated. The add/drop filter system is used to generate the high-capacity, ultra-short soliton pulses in the range of nanometer/second and picometer/second. PMID- 22947144 TI - Utilization pattern of traditional Chinese medicine for liver cancer patients in Taiwan. AB - BACKGROUND: Traditional Chinese Medicine (TCM) is one of the most popular complementary and alternative medicine modalities worldwide. In Chinese and East Asian societies, TCM plays an active role in the modern health care system and is even covered by the National Health Insurance Program of Taiwan. Liver cancer is the second most common cancer in Taiwan. This study aimed to analyze the TCM utilization patterns of patients with liver cancer from 1996-2007 using a population-based random sample of one million insured patients. METHODS: A cross sectional study was conducted using registration and claim data sets from 1996 to 2007 obtained from the Longitudinal Health Insurance Database 2005 (LHID2005). The outpatient datasets contained the encounter form-based dates of visit, three items from the International Classification of Diseases (Ninth Revision, Clinical Modification codes), the primary procedure (e.g., drug or diagnostic procedure), type of copayment, billed amount, and paid amount. Only ambulatory care was analyzed. RESULTS: A total of 6358 liver cancer patients utilized ambulatory care during the study period. Among them, 1240 (19.50%) availed of TCM outpatient services. The prevalence of TCM use fluctuated during the study period, with a peak of 25.11% in 2001. After multivariable adjustment, the likelihood of TCM users was lower in participants aged 70 years and older (odds ratio, OR = 0.79, 95% confidence interval, CI: 0.64-0.97), males (OR = 0.60, 95% CI: 0.52-0.68), residents of Taipei (OR = 0.75, 95% CI: 0.58-0.96) as well as farmers and fishermen (OR = 0.71, 95% CI: 0.54-0.94), but was higher in residents of central Taiwan (OR = 1.99, 95% CI: 1.56-2.54. Most biomedicine and TCM outpatient services were provided by private clinics, followed by private hospitals. The two most frequently recorded coexisting diseases for both biomedicine and TCM outpatient visits specifically for liver cancer were (1) chronic liver disease and cirrhosis, and (2) malignant neoplasm of the liver and hepatic bile duct. The mean fee per visit for biomedicine was much higher than that for TCM, and the average expenditure was NT$429.73 (US$13.25) per biomedicine visit and NT$301.93 (US$9.32) per TCM visit (US$1 = NT$32.4 in 2007). For outpatient visits specifically for liver cancer, the mean fee per visit for biomedicine was much higher than that for TCM. The average cost per visit was NT$1457.31 (US$44.98) for biomedicine and NT$1080.76 (US$33.36) for TCM. CONCLUSION: TCM was widely used by the patients with liver cancer, and the prevalence of TCM use remained stably high during the study period. The costs of insurance covering TCM were consistently lower than those covering biomedicine in patients with liver cancer. The findings of this study should be useful for health policy makers as well as researchers considering the integration of TCM and biomedicine. PMID- 22947145 TI - Dietary sources of five nutrients in ethnic groups represented in the Multiethnic Cohort. AB - Data are limited on how dietary sources of energy and nutrient intakes differ among ethnic groups in the USA. The objective of the present study was to characterise dietary sources of energy, total fat, saturated fat, protein, dietary fibre and added sugar for five ethnic groups. A validated quantitative FFQ was used to collect dietary data from 186,916 men and women aged 45-75 years who were living in Hawaii and Los Angeles between 1993 and 1996. Participants represented five ethnic groups: African-American; Japanese-American; Native Hawaiian; Latino; Caucasian. The top ten dietary sources of energy contributed 36.2-49.6% to total energy consumption, with rice and bread contributing the most (11.4-27.8%) across all ethnic-sex groups. Major dietary sources of total fat were chicken/turkey dishes and butter among most groups. Ice cream, ice milk or frozen yogurt contributed 4.6-6.2% to saturated fat intake across all ethnic-sex groups, except Latino-Mexico women. Chicken/turkey and bread were among the top dietary sources of protein (13.9-19.4%). The top two sources of dietary fibre were bread and cereals (18.1-22%) among all groups, except Latino-Mexico men. Regular sodas contributed the most to added sugar consumption. The present study provides, for the first time, data on the major dietary sources of energy, fat, saturated fat, protein, fibre and added sugar for these five ethnic groups in the USA. Such data are valuable for identifying target foods for nutritional intervention programmes and directing public health strategies aimed at reducing dietary risk factors for chronic disease. PMID- 22947146 TI - Sentinel site community surveillance of mortality and nutritional status in southwestern Central African Republic, 2010. AB - BACKGROUND: During 2010, a community-based, sentinel site prospective surveillance system measured mortality, acute malnutrition prevalence, and the coverage of a Medecins Sans Frontieres (MSF) intervention in four sous prefectures of Lobaye prefecture in southwestern Central African Republic. We describe this surveillance system and its evaluation. METHODS: Within 24 randomly selected sentinel sites, home visitors performed a census, weekly demographic surveillance of births, deaths, and in- or out-migration, and weekly anthropometry on a sample of children. We evaluated the system through various methods including capture-recapture analysis and repeat census. RESULTS: The system included 18,081 people at baseline. Over 32 weeks, the crude death rate was 1.0 (95% confidence interval [CI]: 0.8-1.2) deaths per 10,000 person-days (35 deaths per 1,000 person-years), with higher values during the rainy season. The under-5 death rate was approximately double. The prevalence of severe acute malnutrition (SAM) was 3.0% (95% CI: 2.3-4.0), almost half featuring kwashiorkor signs. The coverage of SAM treatment was 29.1%. The system detected >90% of deaths, and >90% of death reports appeared valid. However, demographic surveillance yielded discrepancies with the census and an implausible rate of population growth, while the predictive value of SAM classification was around 60%. DISCUSSION: We found evidence of a chronic health crisis in this remote region. MSF's intervention coverage improved progressively. Mortality data appeared valid, but inaccuracies in population denominators and anthropometric measurements were noted. Similar systems could be implemented in other remote settings and acute emergencies, but with certain technical improvements. PMID- 22947148 TI - Toolbox for healthy pets: program offers resources to help veterinarians promote preventive care. PMID- 22947149 TI - Veterinarians should stand against legislation that protects animal abusers in agriculture industry. PMID- 22947150 TI - What is your diagnosis? Intracranial parasitic migration. PMID- 22947151 TI - Theriogenology question of the month. Segmental aplasia of the uterine horn with mucometra. PMID- 22947152 TI - Pathology in practice. Granulomatous nephritis, lymphadenitis, and encephalitis with intralesional adult and larval H gingivalis. PMID- 22947153 TI - Pathology in practice. Transmissible venereal tumor located on the bulbus glandis and body of the penis. PMID- 22947154 TI - Rabies surveillance in the United States during 2011. AB - During 2011, 49 states and Puerto Rico reported 6,031 rabid animals and 6 human rabies cases to the CDC, representing a 1.9% decrease from the 6,153 rabid animals and 2 human cases reported in 2010. Approximately 92% of reported rabid animals were wildlife. Relative contributions by the major animal groups were as follows: 1,981 raccoons (32.8%), 1,627 skunks (27.0%), 1,380 bats (22.9%), 427 foxes (7.1%), 303 cats (5.0%), 65 cattle (1.1%), and 70 dogs (1.2%). Compared with 2010, there was a substantial increase in the number of rabid skunks reported. Six cases of rabies involving humans were reported from California, Massachusetts, New Jersey, New York, and South Carolina. Three cases reported from Massachusetts, New Jersey, and New York were determined to be a result of canine rabies virus variants acquired outside the United States. PMID- 22947155 TI - Control of terrestrial animal rabies in Anne Arundel County, Maryland, after oral vaccination of raccoons (1998-2007). AB - OBJECTIVE: To evaluate the effectiveness of an oral rabies vaccination (ORV) project conducted from 1998 through 2007 in Anne Arundel County, Md, for the control of rabies in terrestrial animals. DESIGN: Retrospective analysis of surveillance data (1997 through 2007). ANIMALS: Free-ranging raccoons (Procyon lotor) and other terrestrial mammals. PROCEDURES: Vaccinia-rabies glycoprotein recombinant virus oral rabies vaccine-bait units were distributed annually by aircraft and ground teams targeting free-ranging raccoons. Approximately 2 to 4 weeks following the vaccine-bait placement, raccoons were live trapped, sedated, processed, and then released. Serologic samples were tested for the presence of rabies virus-neutralizing antibodies (RVNAs). Bait acceptance was estimated by analysis of tetracycline biomarking of sampled teeth. Rabies incidence was determined by the passive identification of rabid terrestrial animals. RESULTS: The incidence of rabies in terrestrial animals decreased 92% between 1997 (the year prior to the start of the ORV project) and 2007. The mean RVNA prevalence across all years was 33% among trapped raccoons in areas baited with a fish meal polymer bait type, whereas the mean bait acceptance was 30%. Adult raccoons had a seropositivity rate twice that of juvenile raccoons, whereas the bait acceptance rate between adults and juveniles did not differ significantly. For areas baited with a coated sachet bait, adults and juveniles had the same seroprevalence. Juveniles had better seroprevalence when the annual campaign started in September and October, compared with August. CONCLUSIONS AND CLINICAL RELEVANCE: The ORV project contributed to a significant decrease in annual incidence of terrestrial animal rabies in Anne Arundel County, Md, during the 10-year project period. For fish meal polymer baits, juvenile raccoons accessed bait at the same rate as adult raccoons but had a significantly lower prevalence of RVNAs. For coated sachet baits, seroprevalence was the same in both age groups. The time of year the bait distribution occurred and the bait type used may be partial explanations for the difference in RVNA seroprevalence between adults and juvenile raccoons. PMID- 22947157 TI - Assessment of fracture healing after minimally invasive plate osteosynthesis or open reduction and internal fixation of coexisting radius and ulna fractures in dogs via ultrasonography and radiography. AB - OBJECTIVE: To evaluate fracture healing after minimally invasive plate osteosynthesis (MIPO) or open reduction and internal fixation (ORIF) of coexisting radius and ulna fractures in dogs via ultrasonography and radiography. DESIGN: Prospective cohort study. ANIMALS: 16 dogs with radius-ulna fractures that underwent MIPO (n = 9; 2 dogs were subsequently not included in the analyses because of incomplete follow-up information) or ORIF (7). PROCEDURES: Dogs in the 2 treatment groups were matched by age, body weight, and configuration of the fractures. Fracture healing was evaluated with ultrasonography, power Doppler ultrasonography, and radiography every 3 to 4 weeks until healing was complete; a semiquantitative score based on the number of Doppler signals was used to characterize neovascularization, and subjective B-mode ultrasonographic and radiographic scores were assigned to classify healing. RESULTS: Fractures in dogs that underwent MIPO healed in significantly less time than did fractures in dogs that underwent ORIF (mean +/- SD; 30 +/- 10.5 days and 64 +/- 10.1 days, respectively). Radiography revealed that fractures in dogs that underwent MIPO healed with significantly more callus formation than did fractures in dogs that underwent ORIF. Although Doppler ultrasonography revealed abundant vascularization in fractures that were healing following MIPO, no significant difference in neovascularization scores was found between groups. CONCLUSIONS AND CLINICAL RELEVANCE: For dogs with radius-ulna fractures, data indicated that bridging osteosynthesis combined with a minimally invasive approach contributed to rapid healing after MIPO. The MIPO technique may offer some clinical advantage over ORIF, given that complete radius-ulna fracture healing was achieved in a shorter time with MIPO. PMID- 22947158 TI - Effect of extradurally administered morphine on postoperative analgesia in dogs undergoing surgery for thoracolumbar intervertebral disk extrusion. AB - OBJECTIVE: To investigate the effect of intraoperative extradural morphine administration on postoperative analgesia in dogs undergoing thoracolumbar spinal surgery to treat disk extrusion. DESIGN: Prospective clinical trial. ANIMALS: 26 client-owned dogs undergoing thoracolumbar spinal surgery. PROCEDURES: Animals were randomly allocated to receive morphine (0.1 mg/kg [0.045 mg/lb], extradurally) or no treatment (control group). Following preanesthetic medication with methadone (0.25 mg/kg [0.11 mg/lb], IM), anesthesia was induced with propofol and maintained with isoflurane or sevoflurane in oxygen. Lidocaine and fentanyl were administered during surgery in both groups at fixed rates. In the morphine administration group, morphine was splashed over the dura mater immediately prior to wound closure. Postoperative analgesia was assessed for 48 hours by assessors unaware of group allocation, and methadone was administered as rescue analgesic. Demographic characteristics, urinary output, days of hospitalization, and perioperative use of analgesics were compared via a Mann Whitney U test. RESULTS: Demographic data were similar between groups. In the morphine administration group, 2 of 13 dogs required postoperative methadone, and in the control group, methadone was administered to 11 of 13 dogs. The total number of doses of methadone administered in the 48 hours after surgery was 28 in the control group and 3 in the morphine administration group. No adverse effects were recorded in any group. CONCLUSIONS AND CLINICAL RELEVANCE: Intraoperative extradural morphine administration was effective in reducing postoperative analgesic requirement. Dogs undergoing thoracolumbar spinal surgery benefited from topical administration of preservative-free morphine administered directly on the dura mater as part of analgesic management. PMID- 22947159 TI - Clinical and clinicopathologic abnormalities in young dogs with acquired and congenital portosystemic shunts: 93 cases (2003-2008). AB - OBJECTIVE: To determine whether clinical and clinicopathologic data could assist differentiation of congenital portosystemic shunts (CPSSs) from acquired portosystemic shunts (APSSs) in young dogs. DESIGN: Retrospective case series. ANIMALS: Dogs < 30 months of age with CPSSs (n = 62) or APSSs (31). PROCEDURES: Medical records from 3 referral centers identified 31 dogs with APSSs and 62 dogs with CPSSs diagnosed from July 2003 to July 2008. Signalment, clinical signs, physical examination, and clinicopathological data were recorded, and statistical analyses were performed to determine differences between groups. RESULTS: Univariable analysis showed APSS patients were older, heavier, and in poorer body condition, compared with CPSS patients. In CPSS patients, diarrhea was less prevalent, and neurologic signs were more prevalent. Ascites was more prevalent in APSS (Fisher exact test; OR, 50.2; 95% confidence interval [CI], 6.2 to 409.7), with no significant difference in albumin concentration between groups. The logistic regression model used to assess clinicopathological parameters showed lower Hct (OR, 1.42 * 10(-12); 95% CI, 1.42 * 10(-17) to 4.0 * 10(-6)), higher mean corpuscular volume (OR, 1.27; 95% CI, 1.08 to 1.50), and higher alanine aminotransferase concentrations (OR, 1.005; 95% CI, 1.001 to 1.009) were more likely in APSS patients. CONCLUSIONS AND CLINICAL RELEVANCE: Several clinicopathologic differences between dogs with congenital and acquired shunts were identified; however, assessed alone, these would be unlikely to enable differentiation between the 2 conditions. Awareness of the rarity of ascites in CPSS cases should prompt recognition of a likely diagnosis of APSS, allowing the veterinarian to target further diagnostics and counsel the owner appropriately. PMID- 22947160 TI - Use of a spiral rectal diaphragm technique to control anal sphincter incontinence in a cat. AB - CASE DESCRIPTION: A 10-year-old castrated male domestic shorthair cat was examined for a mass involving the right anal sac region. CLINICAL FINDINGS: The mass was diagnosed as a fibrosarcoma, and resulted in progressive tenesmus, requiring repeated resection. TREATMENT AND OUTCOME: Surgical removal of the fibrosarcoma was performed on 4 occasions, including complete resection of the anal sphincter muscles and portions of the rectum. A perineal urethrostomy was required during the third surgical procedure secondary to tumor invasion of the preputial tissues. To reduce involuntary loss of feces, the remaining rectal wall was rotated approximately 225 degrees prior to surgical closure during the second, third, and fourth surgical procedures. This procedure created a natural spiral diaphragm within the rectal lumen. The elastic spiral barrier reduced inadvertent fecal loss and facilitated fecal distention of the terminal portion of the colon, allowing the patient to anticipate the impending passage of feces and to use the litter tray on a daily basis. CLINICAL RELEVANCE: With complete loss of the terminal portion of the rectum and anal sphincter muscles, spiraling the rectum created a deformable threshold barrier to reduce excessive loss of stool secondary to fecal incontinence. On the basis of the positive outcome in this patient, this novel technique may be a useful option to consider for the treatment of cats with loss of anal sphincter function. PMID- 22947161 TI - Musculoskeletal Corynebacterium pseudotuberculosis infection in horses: 35 cases (1999-2009). AB - OBJECTIVE: To describe the clinical course and outcome in horses in which Corynebacterium pseudotuberculosis infections were associated with musculoskeletal disease and lameness. DESIGN: Retrospective case series. ANIMALS: 35 horses. PROCEDURES: Clinical and clinicopathologic data were collected from horses diagnosed with lameness associated with C pseudotuberculosis infection between 1999 and 2009. RESULTS: 32 (91.4%) horses had grade 4/5 lameness. Three (8.6%) horses had grade 5/5 lameness. Abscesses were diagnosed by clinical or ultrasonographic examination. Abscesses were located in the axillary or triceps region in 25 (71.4%) horses, the stifle region in 2 (5.7%), and the popliteal lymph node in 1 (2.9%). Diffuse lymphangitis was seen in 4 (11.4%) horses, osteomyelitis in 2 (5.7%) horses, and septic arthritis in 2 (5.7%) horses. Horses commonly had clinicopathologic abnormalities characterized by neutrophilia (96.4%), anemia (67.8%), hypoalbuminemia (66.6%), or hyperfibrinogenemia (42.8%). Treatment included surgical drainage of the abscess in 21 (60%) horses, performed under ultrasonography in 20 horses; anti-inflammatory medications in 34 (97.1 %) horses; and antimicrobials in 30 (85.7%) horses. CONCLUSIONS AND CLINICAL RELEVANCE: C pseudotuberculosis infection of the limbs in horses typically results in severe lameness but may have a favorable prognosis. The diagnosis may be challenging, and results of blood work consistent with inflammation are nonspecific, but anemia, hyperglobulinemia, and increased synergistic hemolysis inhibition titers are common. Ultrasonography may localize the lesions and facilitate surgical drainage to alleviate lameness. When C pseudotuberculosis musculoskeletal infection results in osteomyelitis or septic arthritis, the prognosis for survival is poor. PMID- 22947162 TI - Laparoscopic-assisted urinary bladder marsupialization in a goat that developed recurrent urethral obstruction following perineal urethrostomy. AB - CASE DESCRIPTION: A 5-year-old castrated male Nigerian Dwarf goat with recurrent urethral obstruction after perineal urethrostomy. CLINICAL FINDINGS: The wether goat was referred for evaluation of a perineal urethrostomy site; perineal urethrostomy had been performed 1.5 years earlier. The site was patent, but a moderate stricture was found just cranial to the perineal urethrostomy site. The goat had obstructed urine flow at the stricture site repeatedly in the previous few months. TREATMENT AND OUTCOME: Laparoscopically assisted urinary bladder marsupialization was recommended. The procedure was performed with the patient under general anesthesia in dorsal recumbency; food had been withheld for 36 hours prior to anesthesia. Ventral midline and left caudal paramedian portals were made for the laparoscopic camera and instruments. A larger incision in the right caudal paramedian portion of the abdomen was used to create the marsupialization stoma. Laparoscopic observation of anatomic structures within the abdomen was excellent. The goat recovered well from surgery and was discharged the day following surgery. Follow-up examinations were done every few months after surgery, and dermatitis of the abdominal skin secondary to urine scald was the only postoperative complication. At 9 months of follow-up, the goat continued to pass urine through the marsupialization site comfortably. CLINICAL RELEVANCE: In the goat of this report, laparoscopic urinary bladder marsupialization was a minimally invasive procedure with minimal signs of postoperative pain. The procedure was simple to perform and should be considered as an alternative to marsupialization via laparotomy. PMID- 22947163 TI - Assessment of on-screen measurements, magnification, and calibration in digital radiography. AB - OBJECTIVE: To compare calibration methods for digital radiography in terms of measurement accuracy and interobserver variability. DESIGN: Prospective study. SAMPLE: Digital radiographic images of a 155-mm-long Steinmann pin. PROCEDURES: Measurement of pin length on digital radiographs was determined with a 25.4-mm diameter calibration ball and commercially available software program via 3 calibration methods (ie, no calibration, autocalibration, and manual calibration). Digital radiographs of the calibration ball and pin were obtained with each placed at various vertical heights from the table (7 heights) and horizontal distances from the center of the beam (4 distances). Measurements of pin length on digital radiographs were made by 4 observers who were blinded to the orientation of the calibration ball and pin. RESULTS: Pin lengths obtained by each calibration method were significantly different from each other and from the true value. Manual calibration was the most accurate. There was no significant interobserver variability in measurements. There was no significant change in measurements when the calibration ball was moved horizontally, but pin length measurements changed significantly when the ball was moved vertically (away from the table) with an approximate magnification error of 1% per centimeter of distance between the calibration ball and pin. CONCLUSIONS AND CLINICAL RELEVANCE: For digital radiography, manual calibration is recommended to achieve the most accurate measurements. Ideally, the calibration ball should be placed at the same vertical height as the object to be measured; however, if this cannot be achieved, the magnification error can be expected to be approximately 1% per centimeter of distance. PMID- 22947164 TI - Priming of the Arabidopsis pattern-triggered immunity response upon infection by necrotrophic Pectobacterium carotovorum bacteria. AB - Boosted responsiveness of plant cells to stress at the onset of pathogen- or chemically induced resistance is called priming. The chemical beta-aminobutyric acid (BABA) enhances Arabidopsis thaliana resistance to hemibiotrophic bacteria through the priming of the salicylic acid (SA) defence response. Whether BABA increases Arabidopsis resistance to the necrotrophic bacterium Pectobacterium carotovorum ssp. carotovorum (Pcc) is not clear. In this work, we show that treatment with BABA protects Arabidopsis against the soft-rot pathogen Pcc. BABA did not prime the expression of the jasmonate/ethylene-responsive gene PLANT DEFENSIN 1.2 (PDF1.2), the up-regulation of which is usually associated with resistance to necrotrophic pathogens. Expression of the SA marker gene PATHOGENESIS RELATED 1 (PR1) on Pcc infection was primed by BABA treatment, but SA-defective mutants demonstrated a wild-type level of BABA-induced resistance against Pcc. BABA primed the expression of the pattern-triggered immunity (PTI) responsive genes FLG22-INDUCED RECEPTOR-LIKE KINASE 1 (FRK1), ARABIDOPSIS NON RACE SPECIFIC DISEASE RESISTANCE GENE (NDR1)/HAIRPIN-INDUCED GENE (HIN1)-LIKE 10 (NHL10) and CYTOCHROME P450, FAMILY 81 (CYP81F2) after inoculation with Pcc or after treatment with purified bacterial microbe-associated molecular patterns, such as flg22 or elf26. PTI-mediated callose deposition was also potentiated in BABA-treated Arabidopsis, and BABA boosted Arabidopsis stomatal immunity to Pcc. BABA treatment primed the PTI response in the SA-defective mutants SA induction deficient 2-1 (sid2-1) and phytoalexin deficient 4-1 (pad4-1). In addition, BABA priming was associated with open chromatin configurations in the promoter region of PTI marker genes. Our data indicate that BABA primes the PTI response upon necrotrophic bacterial infection and suggest a role for the PTI response in BABA induced resistance. PMID- 22947166 TI - Evolutionary principles and synthetic biology: avoiding a molecular tragedy of the commons with an engineered phage. AB - BACKGROUND: In prior work, adding a gene to phage T7 that degraded the host K1 capsule facilitated growth when plated on capsulated hosts. However, the transgenic protein (an endosialidase) is expressed as an exoenzyme, released from the cell at lysis but unattached to the phage particle. There is thus the possibility that the gene will be subject to a tragedy of the commons and be selected against, if the enzyme benefits other genomes. RESULTS: This evolutionary perspective was supported in short term experiments. The genome carrying the endosialidase gene was favored on a capsulated host if grown in physical isolation of control genomes (lacking the gene) but was selected against otherwise. CONCLUSIONS: These results challenge efforts to engineer phages with exoenzymes that degrade biofilm polymers. If biofilms do not facilitate spatially structured phage growth, the transgenic enzymes may be rapidly eliminated from the phage population after release in the environment, even if the transgene benefits overall phage growth on the biofilm. PMID- 22947167 TI - Graphene conductance uniformity mapping. AB - We demonstrate a combination of micro four-point probe (M4PP) and non-contact terahertz time-domain spectroscopy (THz-TDS) measurements for centimeter scale quantitative mapping of the sheet conductance of large area chemical vapor deposited graphene films. Dual configuration M4PP measurements, demonstrated on graphene for the first time, provide valuable statistical insight into the influence of microscale defects on the conductance, while THz-TDS has potential as a fast, non-contact metrology method for mapping of the spatially averaged nanoscopic conductance on wafer-scale graphene with scan times of less than a minute for a 4-in. wafer. The combination of M4PP and THz-TDS conductance measurements, supported by micro Raman spectroscopy and optical imaging, reveals that the film is electrically continuous on the nanoscopic scale with microscopic defects likely originating from the transfer process, dominating the microscale conductance of the investigated graphene film. PMID- 22947169 TI - Mitochondrial respiratory chain enzyme assay and DNA analysis in peripheral blood leukocytes for the etiological study of Chinese children with Leigh syndrome due to complex I deficiency. AB - Mitochondrial respiratory chain complex I enzyme deficiency is the most commonly seen mitochondrial respiratory chain disorder. Although screening and diagnostic methods are available overseas, clinically feasible diagnostic methods have not yet been established in China. In this study, four Chinese boys with Leigh syndrome due to complex I deficiency were diagnosed by mitochondrial respiratory chain enzyme assay and DNA analysis using peripheral blood leukocytes. Four patients were admitted at the age of 5-14 years because of unexplained progressive neuromuscular symptoms, including motor developmental delay or regression, weakness, and seizures. Their cranial magnetic resonance imaging revealed typical finding as Leigh syndrome. Peripheral leukocyte mitochondrial respiratory chain complex I activities were found decreased to 9.6-33.1 nmol/min/mg mitochondrial protein(control 44.0 +/- 5.4 nmol/min/mg). The ratios of complex I to citrate synthase activity were also decreased (8.9-19.8% in patients vs. control 48 +/- 11%). Three mtDNA mutations were identified from three out of four patients, supporting the diagnosis of complex I deficiency. Point mutations m.10191T>C in mitochondrial ND3 gene, m.13513G>A in ND5 gene and m.14,453G>A in ND6 gene were detected in three patients. PMID- 22947170 TI - Genome-wide identification of viral and host transcripts targeted by viral siRNAs in Vitis vinifera. AB - In plants, RNA silencing is a surveillance mechanism against invading viruses. It involves the production of virus-derived small interfering RNAs (vsiRNAs), which guide the RNA-induced silencing complex (RISC) to inactivate viruses. vsiRNAs may also promote the silencing of host mRNAs in a sequence-specific manner. In this work, vsiRNAs derived from two grapevine-infecting viruses (Grapevine fleck virus and Grapevine rupestris stem pitting-associated virus) were selected from cDNA libraries of short RNAs and were cross-referenced with the remnants of both cleaved host transcripts and viral RNAs from a degradome dataset. We identified dozens of host transcripts targeted by vsiRNAs. Among them, several encode putative proteins involved in ribosome biogenesis and in biotic and abiotic stresses. Moreover, we identified vsiRNAs which explain the cleavage sites in viral genomes. A consistent fraction of vsiRNAs did not apparently account for cleavage, suggesting that only a low percentage of vsiRNAs are involved in the antiviral response. PMID- 22947171 TI - Long-term persistency and costs associated with the use of iron chelation therapies in the treatment of Sickle cell disease within Medicaid programs. AB - OBJECTIVE: This retrospective study evaluated iron chelating therapy (ICT) discontinuation and costs in Sickle cell disease (SCD) Medicaid recipients using healthcare claims from 2006-2010. METHODS: Patients with >=1 SCD diagnosis claim, >=2 claims for deferoxamine (DFO) or deferosirox (DFX), and continuous enrollment >=6 months prior to and 18 months following ICT initiation were included. Outcomes included treatment discontinuation, persistence (i.e., refill gaps >=6 weeks), and total healthcare costs. RESULTS: The average age among 404 SCD patients meeting study inclusion criteria was 18.7 (+/-11.0) years, with 45.8% being males and 66.7% being Blacks. Switches or combinations from DFO at index occurred in 124 (74.7%) patients compared to 10 (4.2%) with DFX at index. The Cox regression model that assessed long-term medication persistence indicated a 1.30 times higher likelihood of treatment discontinuation with DFO compared to DFX (95% CI: 1.06-1.61). Some 19.7% of patient remained on DFX relative to 4.8% on DFO. Both inpatient and total costs were similar in DFX and DFO treatment groups. Following 1 year of treatment, 37.4% remained on DFX compared to 15.7% on DFO. Meaningful differences in treatment discontinuation between the two treatment groups did not occur until 220+ days during the study period. At 18-months, treatment discontinuation rates were high in both groups; 95% for DFO and 80% for DFX. CONCLUSION: This study of SCD Medicaid patients found more therapeutic switches from DFO to DFX and a higher medication persistency rate with DFX than DFO. The conclusions are limited by the study's retrospective nature, which depends on multivariate statistics to account for patient heterogeneity and risk factors. PMID- 22947172 TI - Dietary chia seed induced changes in hepatic transcription factors and their target lipogenic and oxidative enzyme activities in dyslipidaemic insulin resistant rats. AB - The present study analyses the effect of dietary chia seed rich in n-3 alpha linolenic acid on the mechanisms underlying dyslipidaemia and liver steatosis developed in rats fed a sucrose-rich diet (SRD) for either 3 weeks or 5 months. The key hepatic enzyme activities such as fatty acid synthase (FAS), acetyl-CoA carboxylase (ACC), glucose-6-phosphate dehydrogenase (G-6-PDH), carnitine palmitoyltransferase-1 (CPT-1) and fatty acid oxidase (FAO) involved in lipid metabolism and the protein mass levels of sterol regulatory element-binding protein-1 (SREBP-1) and PPARalpha were studied. (1) For 3 weeks, Wistar rats were fed either a SRD with 11 % of maize oil (MO) as dietary fat or a SRD in which chia seed replaced MO (SRD+Chia). (2) A second group of rats were fed a SRD for 3 months. Afterwards, half the rats continued with the SRD while for the other half, MO was replaced by chia for 2 months (SRD+Chia). In a control group, maize starch replaced sucrose. Liver TAG and the aforementioned parameters were analysed in all groups. The replacement of MO by chia in the SRD prevented (3 weeks) or improved/normalised (5 months) increases in dyslipidaemia, liver TAG, FAS, ACC and G-6-PDH activities, and increased FAO and CPT-1 activities. Protein levels of PPARalpha increased, and the increased mature form of SREBP-1 protein levels in the SRD was normalised by chia in both protocols (1 and 2). The present study provides new data regarding some key mechanisms related to the fate of hepatic fatty acid metabolism that seem to be involved in the effect of dietary chia seed in preventing and normalising/improving dyslipidaemia and liver steatosis in an insulin-resistant rat model. PMID- 22947173 TI - Investigation of L-type Ca(2+) current in the aganglionic bowel segment in Hirschsprung's disease. AB - BACKGROUND: Studies on animal models of Hirschsprung's disease (HD) suggest that L-type Ca(2+) channels are down-regulated in the aganglionic bowel segment, however, this has yet to be confirmed in HD patients. The objective of this study was to test the hypothesis that L-type Ca(2+) current density is decreased in smooth muscle cells (SMC) obtained from the aganglionic bowel segment of patients with HD in comparison with those from the ganglionic segment. METHODS: Smooth muscle cells were freshly isolated from colon samples obtained from HD patients undergoing pull-through surgery. L-type Ca(2+) currents were recorded using the perforated patch configuration of the whole cell voltage clamp technique and the expression levels of CACNA1C transcripts (which encode L-type Ca(2+) channels) in the ganglionic and aganglionic bowel segments were compared using real-time quantitative PCR. KEY RESULTS: All SMC displayed robust currents that had activation/inactivation kinetics typical of L-type Ca(2+) current, were inhibited by nifedipine and enhanced by the L-type Ca(2+) channel agonists FPL 64176 and Bay K 8644. Moreover, FPL 64176 activated currents were also inhibited by nifedipine. However, there was no significant difference in L-type Ca(2+) current density, CACNA1C subunit expression or sensitivity to the pharmacological agents noted above, between SMC isolated from the ganglionic and aganglionic regions of the HD colon. CONCLUSIONS & INFERENCES: In contrast to studies on genetic animal models of HD, L-type Ca(2+) currents are not down-regulated in the aganglionic bowel segment of HD patients and are therefore unlikely to account for the impaired colonic peristalsis observed in these patients. PMID- 22947174 TI - Tenascin-W is a better cancer biomarker than tenascin-C for most human solid tumors. AB - BACKGROUND: Tenascins are large glycoproteins found in the extracellular matrix of many embryonic and adult tissues. Tenascin-C is a well-studied biomarker known for its high overexpression in the stroma of most solid cancers. Tenascin-W, the least studied member of the family, is highly expressed in the stroma of colon and breast tumors and in gliomas, but not in the corresponding normal tissues. Other solid tumors have not been analyzed. The present study was undertaken to determine whether tenascin-W could serve as a cancer-specific extracellular matrix protein in a broad range of solid tumors. METHODS: We analyzed the expression of tenascin-W and tenascin-C by immunoblotting and by immunohistochemistry on multiple frozen tissue microarrays of carcinomas of the pancreas, kidney and lung as well as melanomas and compared them to healthy tissues. RESULTS: From all healthy adult organs tested, only liver and spleen showed detectable levels of tenascin-W, suggesting that tenascin-W is absent from most human adult organs under normal, non-pathological conditions. In contrast, tenascin-W was detectable in the majority of melanomas and their metastases, as well as in pancreas, kidney, and lung carcinomas. Comparing lung tumor samples and matching control tissues for each patient revealed a clear overexpression of tenascin-W in tumor tissues. Although the number of samples examined is too small to draw statistically significant conclusions, there seems to be a tendency for increased tenascin-W expression in higher grade tumors. Interestingly, in most tumor types, tenascin-W is also expressed in close proximity to blood vessels, as shown by CD31 co-staining of the samples. CONCLUSIONS: The present study extends the tumor biomarker potential of tenascin-W to a broad range of solid tumors and shows its accessibility from the blood stream for potential therapeutic strategies. PMID- 22947177 TI - Plasmonic manipulation of color and morphology of single silver nanospheres. AB - Optical control of size, shape, or orientation of a metal nanoparticle is important for development of nanoscale optical devices and elements of photonic circuits. Thus far, however, independent control of two or more parameters has not yet been achieved. Here we place a simple spherical Ag nanoparticle on TiO(2) with high refractive index and separate a plasmon mode localized at the Ag-TiO(2) interface from the other mode distributed over the nanoparticle. Selective excitation of each mode gives rise to a corresponding morphological change and selective suppression of the plasmon mode, resulting in multicolor changes of scattering light from orange to red, green, or a dark color. PMID- 22947175 TI - Comparative genomics of Brachyspira pilosicoli strains: genome rearrangements, reductions and correlation of genetic compliment with phenotypic diversity. AB - BACKGROUND: The anaerobic spirochaete Brachyspira pilosicoli causes enteric disease in avian, porcine and human hosts, amongst others. To date, the only available genome sequence of B. pilosicoli is that of strain 95/1000, a porcine isolate. In the first intra-species genome comparison within the Brachyspira genus, we report the whole genome sequence of B. pilosicoli B2904, an avian isolate, the incomplete genome sequence of B. pilosicoli WesB, a human isolate, and the comparisons with B. pilosicoli 95/1000. We also draw on incomplete genome sequences from three other Brachyspira species. Finally we report the first application of the high-throughput Biolog phenotype screening tool on the B. pilosicoli strains for detailed comparisons between genotype and phenotype. RESULTS: Feature and sequence genome comparisons revealed a high degree of similarity between the three B. pilosicoli strains, although the genomes of B2904 and WesB were larger than that of 95/1000 (~2,765, 2.890 and 2.596 Mb, respectively). Genome rearrangements were observed which correlated largely with the positions of mobile genetic elements. Through comparison of the B2904 and WesB genomes with the 95/1000 genome, features that we propose are non-essential due to their absence from 95/1000 include a peptidase, glycine reductase complex components and transposases. Novel bacteriophages were detected in the newly sequenced genomes, which appeared to have involvement in intra- and inter-species horizontal gene transfer. Phenotypic differences predicted from genome analysis, such as the lack of genes for glucuronate catabolism in 95/1000, were confirmed by phenotyping. CONCLUSIONS: The availability of multiple B. pilosicoli genome sequences has allowed us to demonstrate the substantial genomic variation that exists between these strains, and provides an insight into genetic events that are shaping the species. In addition, phenotype screening allowed determination of how genotypic differences translated to phenotype. Further application of such comparisons will improve understanding of the metabolic capabilities of Brachyspira species. PMID- 22947176 TI - Infection of human pericytes by HIV-1 disrupts the integrity of the blood-brain barrier. AB - Human immunodeficiency virus type 1 (HIV-1) infection of the central nervous system (CNS) affects cross-talk between the individual cell types of the neurovascular unit, which then contributes to disruption of the blood-brain barrier (BBB) and the development of neurological dysfunctions. Although the toxicity of HIV-1 on neurons, astrocytes and brain endothelial cells has been widely studied, there are no reports addressing the influence of HIV-1 on pericytes. Therefore, the purpose of this study was to evaluate whether or not pericytes can be infected with HIV-1 and how such an infection affects the barrier function of brain endothelial cells. Our results indicate that human brain pericytes express the major HIV-1 receptor CD4 and co-receptors CXCR4 and CCR5. We also determined that HIV-1 can replicate, although at a low level, in human brain pericytes as detected by HIV-1 p24 ELISA. Pericytes were susceptible to infection with both the X4-tropic NL4-3 and R5-tropic JR-CSF HIV-1 strains. Moreover, HIV-1 infection of pericytes resulted in compromised integrity of an in vitro model of the BBB. These findings indicate that human brain pericytes can be infected with HIV-1 and suggest that infected pericytes are involved in the progression of HIV-1-induced CNS damage. PMID- 22947178 TI - Macroporous PHEMA-based cryogel discs for bilirubin removal. AB - A novel N-methacryloyl-L-tryptophan methyl ester (MATrp) containing poly (hydroxyethyl methacrylate) cryogel (PHEMATrp) disc was prepared for removal of bilirubin (BR) out of human plasma. PHEMATrp cryogel disc was produced by bulk polymerization, with high gelation yield up to 92% and characterized by swelling tests, scanning electron microscopy (SEM), elemental analysis, Brunauer- Emmett Teller (BET) analysis, contact angle measurements and surface energy calculations. BR adsorption studies were performed in a batch system, and the maximum BR adsorption capacity was found as 22.2 mg/g cryogel disc. PMID- 22947179 TI - Analysis of 34 candidate genes in bupropion and placebo remission. AB - There is considerable variability in the rate of response and remission following treatment with antidepressant drugs or placebo in depression patients. No pharmacogenetic studies of bupropion response have been done. We investigated 532 tagging single nucleotide polymorphisms (SNPs) in 34 candidate genes for association with remission and response to either bupropion (n=319) or placebo (n=257) in patients with major depressive disorder. Analyses were performed using conditional logistic regression. Significant association (gene-wide correction) was observed for remission following treatment with bupropion for a SNP within the serotonin receptor 2A gene (HTR2A rs2770296, p(corrected)=0.02). Response to bupropion treatment was significantly associated with a SNP in the dopamine transporter gene (rs6347, p(corrected)=0.013). Among the patients who received placebo, marginal association for remission was observed between a SNP in HTR2A (rs2296972, p(corrected)=0.055) as well as in the serotonin transporter gene (5 HTT or SLC6A4 rs4251417, p(corrected)=0.050). Placebo response was associated with SNPs in the glucocorticoid receptor gene (NR3C1; rs1048261, p(corrected)=0.040) and monoamine oxidase A gene (MAOA; rs6609257, p corrected=0.046). Although the above observations were significant after gene wide corrections, none of these would be significant after a more conservative study-wide correction for multiple tests. These results suggest a possible role for HTR2A in remission to bupropion treatment. In accordance with bupropion pharmacology, dopamine transporter may play a role in response. The MAOA gene may be involved in placebo response. PMID- 22947180 TI - Assessment of solid phase microfiber extraction fibers for the monitoring of volatile organoarsinicals emitted from a plant-soil system. AB - Phytoremediation, the use of plants and microbes to clean up inorganic and organic pollutants, has shown great promise as an inexpensive and feasible form of remediation. More recently, studies have shown that some plants have an amazing capacity to volatilize contaminants and can be an effective remediation strategy if the chemicals released are non-toxic. Arsenic contamination and remediation has drawn great attention in the scientific community. However, its toxicity also varies depending on its form. We evaluated, optimized, and then utilized a solid phase microfiber extraction (SPME) head space sampling technique to characterize the organoarsinical emissions from rabbitfoot grass (Polypogon monspeliensis) in arsenic treated soils to determine if the potentially more toxic organic forms of arsenic (AsH3, AsH2CH3, AsH(CH3)2, and As(CH3)3) were being emitted from the plant-soil system. The SPME fiber that proved best fitted for this application was the DVB/CAR/PDMS fiber with a 45 min sampling period. We did detect and confirm the emissions of dimethylchloroarsine (AsCl(CH3)2) and pentamethylarsine (As(CH3)5). However, it was determined that the more toxic organic forms of arsenic were not released during phytovolatilization. PMID- 22947181 TI - Sonochemical fabrication of novel square-shaped F doped TiO2 nanocrystals with enhanced performance in photocatalytic degradation of phenol. AB - A sonochemical method was developed for the fabrication of novel square-shaped TiO(2) nanocrystals doped with different F contents. The prepared samples were characterized by some physicochemical characterizations like X-ray diffraction (XRD), N(2) physical adsorption, X-ray photoelectron spectroscopy (XPS), Fourier transform infrared spectrum (FT-IR), scanning electron microscopy (SEM), transmission electron microscopy (TEM), photoluminescence (PL) spectroscopy and UV-vis diffuse reflectance spectra (DRS). Phenol, as a hazardous chemical in water, was chosen to evaluate the photocatalytic degradation performance of the prepared TiO(2) nanocrystals under UV light irradiation. Results show that under ultrasonic irradiation conditions, F can easily be doped into TiO(2) and the obtained pure and F doped TiO(2) nanocrystals show mesoporous structures which were formed by the role of ultrasound-induced aggregation. Moreover, the doping of optimal content of F (1.3 mol%) gives 5.3 times increase in the phenol degradation rate. The high photocatalytic degradation activity of the doped TiO(2) could be attributed to the factor that F doping increases the surface hydroxyl groups over TiO(2) and effectively reduces the recombination rate of photo-generated electron/hole pairs, then producing more OH radicals to decompose the phenol molecules. PMID- 22947182 TI - Efficient removal of toluene and benzene in gas phase by the TiO2/Y-zeolite hybrid photocatalyst. AB - Efficient removal of toluene or benzene molecules thinly diffused in gas phase was achieved by using TiO(2)/Y-zeolite hybrid photocatalysts. TiO(2) of 10 wt% hybridized with a hydrophobic USY zeolite showed higher photocatalytic reactivity as compared to TiO(2) hybridized with hydrophilic H-Y or Na-Y zeolites. This phenomenon can be explained by the fact that the hydrophobic USY zeolite efficiently adsorbs the organic compounds and smoothly supplies them onto the TiO(2) photocatalyst surface. However, the toluene or benzene molecules, which are strongly trapped on the hydrophilic H(+) or Na(+) sites of zeolite, cannot diffuse onto the TiO(2) surfaces, resulting in lower photocatalytic reactivity. Although the adsorption capacity of the pure TiO(2) sample rapidly deteriorated, the TiO(2)/Y-zeolite hybrid system maintained a high adsorption efficiency to remove such aromatic compounds for a long period. PMID- 22947183 TI - Photocatalytic degradation of quinoline in aqueous TiO2 suspension. AB - Anatase TiO(2) nanoparticles with an average size of 16 nm were synthesized via a modified sol-gel method and were employed to degrade quinoline under UV irradiation (lambda=365 nm). The influence of reaction parameters such as TiO(2) dosage, initial quinoline concentration and pH was investigated. Under the optimized reaction condition, 91.5% photodegradation efficiency of quinoline was achieved. When the TiO(2) nanoparticles were reused for four times, the photodegradation efficiency was still as high as 90.6%. The analysis of the organic intermediates suggested that superoxide radical (O(2)) predominantly attacked the pyridine ring of quinoline leading to the formation of 2 aminobenzaldehyde, 2-quinolinone, 4-quinolinone; while the hydroxyl radical (OH) contributed much less by attacking benzene rings resulting in the formation of 5 hydroxyquinoline. The photocatalytic performance of the as-synthesized TiO(2) nanoparticles was comparable to the commercial P25. A tentative mechanism was postulated for the photodegradation of quinoline over TiO(2) nanoparticles. PMID- 22947184 TI - Study on soluble heavy metals with preconcentration by using a new modified oligosilsesquioxane sorbent. AB - In this work, a new modified oligosilsesquioxane was prepared, characterized and evaluated for its heavy metal adsorption characteristics from aqueous solution. The material was characterized using infrared spectroscopy, X-ray diffractometry, solid-state (29)Si and (13)C nuclear magnetic resonance. Batch and column experiments were conducted to investigate for Fe (III), Cr (III), Cu (II), Cd (II), Pb (II) and Ni (II) removal from dilute aqueous solution by sorption onto modified oligosilsesquioxane. The results obtained in the flow experiments, showed a recovery of ca. 100% of the metal ions adsorbed in a column packed with 2.0 g of nanomaterial, using 3 mL of 1.0 mol L(-1) HCl solution as eluent. The detection limits for Fe, Cr, Cu, Cd, Pb, and Ni were 0.26, 0.33, 0.38, 0.41, 0.47 and 0.55 MUg L(-1), respectively. The relative standard deviation values (n=12) were <4.82% for Fe, <4.12% for Cr, <3.79% for Cu, <3.03% for Cd, <4.02% for Pb and <2.65% for Ni. The proposed method was successfully applied to the analysis of environmental samples. PMID- 22947185 TI - Removal of chloride from MSWI fly ash. AB - The high levels of alkali chloride and soluble metal salts present in MSWI fly ash is worth noting for their impact on the environment. In addition, the recycling or reuse of fly ash has become an issue because of limited landfill space. The chloride content in fly ash limits its application as basis for construction materials. Water-soluble chlorides such as potassium chloride (KCl), sodium chloride (NaCl), and calcium chloride hydrate (CaCl(2) . 2H(2)O) in fly ash are easily washed away. However, calcium chloride hydroxide (Ca(OH)Cl) might not be easy to leach away at room temperature. The roasting and washing-flushing processes were applied to remove chloride content in this study. Additionally, air and CO(2) were introduced into the washing process to neutralize the hazardous nature of chlorides. In comparison with the water flushing process, the roasting process is more efficient in reducing the process of solid-liquid separation and drying for the reuse of Cl-removed fly ash particles. In several roasting experiments, the removal of chloride content from fly ash at 1050 degrees C for 3h showed the best results (83% chloride removal efficiency). At a solid to liquid ratio of 1:10 the water-flushing process can almost totally remove water-soluble chloride (97% chloride removal efficiency). Analyses of mineralogical change also prove the efficiency of the fly ash roasting and washing mechanisms for chloride removal. PMID- 22947186 TI - Factors secreted by mesenchymal stem cells and endothelial progenitor cells have complementary effects on angiogenesis in vitro. AB - Stem cell-based therapy for myocardial regeneration has reported several functional improvements that are attributed mostly to the paracrine effects stimulating angiogenesis and cell survival. This study was conducted to comparatively evaluate the potential of factors secreted by mesenchymal stem cells (MSCs) in normoxic and hypoxic conditions to promote tissue repair by sustaining endothelial cell (EC) adhesion and proliferation and conferring protection against apoptosis. To this aim, a conditioned medium (CM) was generated from MSCs after 24-h incubation in a serum-free normal or hypoxic environment. MSCs exhibited resistance to hypoxia, which induced increased secretion of vascular endothelial growth factor (VEGF) and decreased levels of other cytokines, including stromal-derived factor-1 (SDF). The CM derived from normal (nMSC-CM) and hypoxic cells (hypMSC-CM) induced similar protective effects on H9c2 cells in hypoxia. Minor differences were noticed in the potential of normal versus hypoxic CM to promote angiogenesis, which were likely connected to SDFalpha and VEGF levels: the nMSC-CM was more effective in stimulating EC migration, whereas the hypMSC-CM had an enhanced effect on EC adhesion. However, the factors secreted by MSCs in normoxic or hypoxic conditions supported adhesion, but not proliferation, of ECs in vitro, as revealed by impedance-based dynamic assessments. Surprisingly, factors secreted by other stem/progenitor cells, such as endothelial progenitor cells (EPCs), had complementary effects to the MSC-CM. Thus, the EPC-CM, in either a normal or hypoxic environment, supported EC proliferation, but did not sustain EC adhesion. Combined use of the MSC-CM and EPC-CM promoted both EC adhesion and proliferation, suggesting that the local angiogenesis at the site of ischemic injury might be better stimulated by simultaneous releasing of factors secreted by multiple stem/progenitor cell populations. PMID- 22947187 TI - Niosomes: novel sustained release nonionic stable vesicular systems--an overview. AB - Vesicular systems are novel means of delivering drug in controlled manner to enhance bioavailability and get therapeutic effect over a longer period of time. Niosomes are such hydrated vesicular systems containing nonionic surfactants along with cholesterol or other lipids delivering drug to targeted site which are non toxic, requiring less production cost, stable over a longer period of time in different conditions, so overcomes drawbacks of liposome. Present review describes history, all factors affecting niosome formulation, manufacturing conditions, characterization, stability, administration routes and also their comparison with liposome. This review also gives relevant information regarding various applications of niosomes in gene delivery, vaccine delivery, anticancer drug delivery, etc. PMID- 22947188 TI - Over-limiting currents and deionization "shocks" in current-induced polarization: local-equilibrium analysis. AB - The problem is considered theoretically of dynamics of current-induced concentration polarization of interfaces between ideally perm-selective and non ideally perm-selective ("leaky") ion-exchange media in binary electrolyte solutions under galvanostatic conditions and at negligible volume flow. In contrast to the previous studies, the analysis is systematically carried out in terms of local thermodynamic equilibrium in the approximation of local electric neutrality in virtual solution. For macroscopically homogeneous media, this enables one to obtain model-independent results in quadratures for the stationary state as well as an approximate scaling-form solution for the transient response to the step-wise increase in electric-current density. These results are formulated in terms of such phenomenological properties of the "leaky" medium as ion transport numbers, diffusion permeability to salt and specific chemical capacity. An easy-to-solve numerically 1D PDE is also formulated in the same terms. A systematic parametric study is carried out within the scope of fine-pore model of "leaky" medium in terms of such properties as volumetric concentration of fixed electric charges and diffusivities of ions of symmetrical electrolyte. While previous studies paid principal attention to the shape and propagation rate of the so-called deionization "shocks", we also consider in detail the time evolution of voltage drop and interface salt concentration. Our analysis confirms the previously predicted pattern of propagating deionization "shocks" within the "leaky" medium but also reveals several novel features. In particular, we demonstrate that the deionization-shock pattern is really pronounced only at intermediate ratios of fixed-charge concentration to the initial salt concentration and at quite high steady-state voltages where the model used in this and previous studies is applicable only at relatively early stages of concentration-polarization process. PMID- 22947190 TI - Prevalence of diabetes mellitus among the adult population in rural blocks of Haryana, India: a community-based study. AB - OBJECTIVE: The aim of this was to study the prevalence of diabetes in the rural adult population of Haryana, India. RESEARCH DESIGN AND METHODS: A total of 2606 adults aged >= 18 years were randomly selected from two rural blocks of Haryana State. Those without diabetes were subjected to a 75-gram oral glucose tolerance test. Demographic, socioeconomic, and anthropometric details along with blood pressure and physical activity were recorded, and their association with the prevalence of diabetes was studied. RESULTS: The prevalence of newly detected diabetes was 7.3%, whereas the overall prevalence of known and newly detected diabetes was 13.3%. Multiple logistic analysis showed a statistically significant association between the prevalence of diabetes and increasing age, waist-to-hip ratio (WHR), positive family history of diabetes, low level of physical activity, and systolic blood pressure. No significant association was observed with education level and socioeconomic status. CONCLUSIONS: The prevalence of diabetes is rising, even in the rural population of Haryana. A positive family history of diabetes, low physical activity, and high WHR are strong predictors of diabetes in tested adult rural population of Haryana. PMID- 22947189 TI - HLA-E expression in cervical adenocarcinomas: association with improved long-term survival. AB - BACKGROUND: Cervical cancer is the third most common cancer in women worldwide. The most common histopathological subtype is cervical squamous cell carcinoma (SCC, 75-80%), followed by adenocarcinoma (AC) and adenosquamous carcinoma (ASC; together 15-20%). Rising incidence rates of AC have been observed relative and absolute to SCC and evidence is accumulating that cervical AC is a distinct clinical entity. Cervical SCC, ASC, and AC are caused by a persistent infection with high-risk human papillomavirus (HPV) and failed control of the immune system plays a pivotal role in the carcinogenesis of all three histopathological subtypes. Human leukocyte antigen E (HLA-E), a non-classical HLA class Ib molecule, plays an important role in immune surveillance and immune escape of virally infected cells. In this study we investigated HLA-E expression in three well-defined cohorts of cervical AC, ASC, and SCC patients, and determined whether HLA-E expression was associated with histopathological parameters and patient survival. METHODS AND RESULTS: HLA-E expression was assessed by immunohistochemistry on formalin-fixed, paraffin-embedded tissue sections of 79 SCC, 38 ASC, and 75 AC patients. All patients included were International Federation of Gynaecology and Obstetrics stage I-II and underwent radical hysterectomy with lymphadenectomy as primary treatment. Significant differences between the histopathological subgroups were detected for age distribution, HPV positivity, HPV type distribution, tumour size, tumour infiltration depth, lymph vascular space invasion, and adjuvant radiotherapy. High expression of HLA-E was found in 107/192 (56%) cervical carcinomas, with significantly more overexpression in cervical AC compared to SCC and ASC (37/79 SCC, 18/38 ASC, and 52/75 AC; P = 0.010). High HLA-E expression in cervical AC was associated with favourable long term disease-specific and recurrence-free survival (P = 0.005 and P = 0.001, respectively). CONCLUSION: High expression of HLA-E occurred in the majority of all histopathological subtypes of cervical cancer; especially in cervical AC. High HLA-E expression in cervical AC was associated with improved patient survival. This study also highlights the importance of careful evaluation of cervical carcinomas to distinguish histopathological subtypes. In the future, insight into the biological behaviour and distinct molecular carcinogenetic processes of the AC, ASC, and SCC subtypes may contribute to the development of more tumour-specific treatment strategies. PMID- 22947191 TI - Involvement of FgERG4 in ergosterol biosynthesis, vegetative differentiation and virulence in Fusarium graminearum. AB - The ergosterol biosynthesis pathway is well understood in Saccharomyces cerevisiae, but currently little is known about the pathway in plant-pathogenic fungi. In this study, we characterized the Fusarium graminearum FgERG4 gene encoding sterol C-24 reductase, which catalyses the conversion of ergosta 5,7,22,24-tetraenol to ergosterol in the final step of ergosterol biosynthesis. The FgERG4 deletion mutant DeltaFgErg4-2 failed to synthesize ergosterol. The mutant exhibited a significant decrease in mycelial growth and conidiation, and produced abnormal conidia. In addition, the mutant showed increased sensitivity to metal cations and to various cell stresses. Surprisingly, mycelia of DeltaFgErg4-2 revealed increased resistance to cell wall-degrading enzymes. Fungicide sensitivity tests revealed that DeltaFgErg4-2 showed increased resistance to various sterol biosynthesis inhibitors (SBIs), which is consistent with the over-expression of SBI target genes in the mutant. DeltaFgErg4-2 was impaired dramatically in virulence, although it was able to successfully colonize flowering wheat head and tomato, which is in agreement with the observation that the mutant produces a significantly lower level of trichothecene mycotoxins than does the wild-type progenitor. All of these phenotypic defects of DeltaFgErg4-2 were complemented by the reintroduction of a full-length FgERG4 gene. In addition, FgERG4 partially rescued the defect of ergosterol biosynthesis in the Saccharomyces cerevisiae ERG4 deletion mutant. Taken together, the results of this study indicate that FgERG4 plays a crucial role in ergosterol biosynthesis, vegetative differentiation and virulence in the filamentous fungus F. graminearum. PMID- 22947192 TI - Right ventricular morphology and function in chronic obstructive pulmonary disease patients living at high altitude. AB - INTRODUCTION: Pulmonary vasculature is affected in patients with chronic pulmonary obstructive disease (COPD). As a result of increased pulmonary resistance, right ventricular morphology and function are altered in COPD patients. High altitude and related hypoxia causes pulmonary vasoconstriction, thereby affecting the right ventricle. We aimed to investigate the combined effects of COPD and altitude-related chronic hypoxia on right ventricular morphology and function. MATERIALS AND METHODS: Forty COPD patients living at high altitude (1768 m) and 41 COPD patients living at sea level were enrolled in the study. All participants were diagnosed as COPD by a pulmonary diseases specialist depending on symptoms, radiologic findings and pulmonary function test results. Detailed two-dimensional echocardiography was performed by a cardiologist at both study locations. RESULTS: Oxygen saturation and mean pulmonary artery pressure were higher in the high altitude group. Right ventricular end diastolic diameter, end systolic diameter, height and end systolic area were significantly higher in the high altitude group compared to the sea level group. Parameters of systolic function, including tricuspid annular systolic excursion, systolic velocity of tricuspid annulus and right ventricular isovolumic acceleration were similar between groups, while fractional area change was significantly higher in the sea level groups compared to the high altitude group. Indices of diastolic function and myocardial performance index were similar between groups. CONCLUSION: An increase in mean pulmonary artery pressure and right ventricular dimensions are observed in COPD patients living at high altitude. Despite this increase, systolic and diastolic functions of the right ventricle, as well as global right ventricular performance are similar in COPD patients living at high altitude and sea level. Altitude-related adaptation to chronic hypoxia could explain these findings. PMID- 22947193 TI - Should we monitor with bispectral index in all patients at high risk for seizures in the operating room? AB - We report the case of a patient with a cerebral aneurysm, located in the left middle cerebral artery. During the clipping of this aneurysm, the bispectral index (BIS) increased for no apparent reason. This was then interpreted as intraoperative non-convulsive status epilepticus. This clinical condition may have negative impact in the prognosis of the patient, so it is very important to be able to detect this conditions as early as possible. Measuring the BIS while the patient is anaesthetised could be useful in this situation, considering that an increase in values greater than 60, associated with acidosis and without any other peri-anaesthetic explanation, may provide evidence of a convulsive equivalent state, allowing appropriate action to be taken. PMID- 22947194 TI - Sugammadex reversal of rocuronium-induced neuromuscular blockade in two types of neuromuscular disorders: Myotonic dystrophy and spinal muscular atrophy. AB - Neuromuscular disorders like myotonic dystrophy (dystrophia myotonica or Steinert's disease) and spinal muscular atrophy are associated with perioperative complications related to muscle weakness. These patients have an increased sensitivity to non-depolarising neuromuscular blocking agents, which can lead to postoperative residual curarization (PORC) and its associated respiratory complications. Adequate reversal of neuromuscular blockade is essential to prevent this. Sugammadex is the first selective relaxant binding agent and it reverses rocuronium- and vecuronium-induced neuromuscular block. Two cases are reported in which the patients received sugammadex to reverse a rocuronium induced neuromuscular block. Reversal of the rocuronium-induced neuromuscular block (NMB) in both cases was fast, effective and without recurarization, and no safety concerns were observed. PMID- 22947196 TI - Differential patterns of muscle modification in women with episodic and chronic tension-type headache revealed using surface electromyographic analysis. AB - Tension-type headache (TTH) is a prototypical disorder in which muscular factors play a key role in the pathogenesis. This study was designed to understand muscular dysfunction in patients with episodic (ETTH) and chronic TTH (CTTH) using surface electromyography analysis (SEMG). Women with frequent ETTH (n = 14), CTTH (n = 14) and age-matched controls (n = 13) were recruited. SEMG data were recorded from the masseter, sternocleidomastoid, and upper trapezius muscles during maximum voluntary contraction and sustained voluntary isometric clenching, the neck flexion endurance test and shoulder elevation for 30s. The root mean square (RMS) and median frequency (MDF) of the SEMG signal were measured throughout the test. The fatigue index, which is the MDF slope during sustained muscle contraction, decreased significantly faster in the ETTH and CTTH groups compared with that in the control (p < 0.05). The mean absolute RMS and relative percentage values at the initial and final period during sustained isometric contraction decreased significantly in the CTTH group (p < 0.05). Furthermore, headache clinical parameters (frequency and duration) were negatively correlated with the amplitude values (p < 0.05). A different muscle firing pattern or some muscle modifications in patients with CTTH may reflect reorganization of the motor-control strategy. PMID- 22947195 TI - [Airway management algorithm in the obstetrics patient]. PMID- 22947197 TI - Pelvic instability and trunk and hip muscle recruitment patterns in patients with total hip arthroplasty. AB - Hip and lumbar spine disorders often coexist in patients with total hip arthroplasty (THA). The current study aimed to reveal pelvic motion pathology and altered trunk and hip muscle recruitment patterns relating to pelvic motion in patients with THA. Twenty-one women who underwent THA and 12 age-matched healthy women were recruited. Pelvic kinematics and muscle recruitment patterns (i.e., amplitude, activity balance, and onset timing) of the gluteus maximus, semitendinosus, multifidus, and erector spinae were collected during prone hip extension. Compared with healthy subjects, the patients showed increased pelvic motion, especially ventral rotation, decreased multifidus muscle activity relative to the hip extensors, and delayed onset of multifidus activity, despite reaction times and speeds of leg motion not being significantly different between the groups. Furthermore, while contributing factors associated with ventral pelvic rotation were not found, delayed onset of multifidus activity was detected as a factor related to the increased anterior tilt of the pelvis (r = 0.47, p < 0.05) in patients with THA. These results suggest that patients with THA have dysfunction of the stabilizer muscles of the lumbopelvic region along with increased pelvic motion. PMID- 22947198 TI - Mitotoxicity and bortezomib-induced chronic painful peripheral neuropathy. AB - Many of the most effective anti-cancer drugs induce a dose-limiting peripheral neuropathy that compromises therapy. Evidence from animal models of chemotherapy induced painful peripheral neuropathy produced by the taxane agent, paclitaxel, and the platinum-complex agent, oxaliplatin, indicate that they produce neuropathy via a common mechanism-a toxic effect on the mitochondria in primary afferent sensory neurons. Bortezomib is from the proteasome-inhibitor class of chemotherapeutics. It also produces a dose-limiting peripheral neuropathy, but its effects on neuronal mitochondria are unknown. To investigate this, we developed a model of bortezomib-induced painful peripheral neuropathy in the rat and assessed mitochondrial function (respiration and ATP production) in sciatic nerve samples harvested at two time points: day 7, which is three days after treatment and before pain appears, and day 35, which is one month post-treatment and the time of peak pain severity. We found significant deficits in Complex I mediated and Complex II-mediated respiration, and in ATP production at both time points. Prophylactic treatment with acetyl-L-carnitine, which has previously been shown to prevent paclitaxel- and oxaliplatin-induced mitochondrial dysfunction and pain, completely blocked bortezomib's effects on mitochondria and pain. These results suggest that mitotoxicity may be the core pathology for all chemotherapy induced peripheral neuropathy and that drugs that protect mitochondrial function may be useful chemotherapy adjuncts. PMID- 22947199 TI - Evidence for only oxygenative cleavage of aldehydes to alk(a/e)nes and formate by cyanobacterial aldehyde decarbonylases. AB - Cyanobacterial aldehyde decarbonylases (ADs) catalyze the conversion of C(n) fatty aldehydes to formate (HCO(2)(-)) and the corresponding C(n-1) alk(a/e)nes. Previous studies of the Nostoc punctiforme (Np) AD produced in Escherichia coli (Ec) showed that this apparently hydrolytic reaction is actually a cryptically redox oxygenation process, in which one O-atom is incorporated from O(2) into formate and a protein-based reducing system (NADPH, ferredoxin, and ferredoxin reductase; N/F/FR) provides all four electrons needed for the complete reduction of O(2). Two subsequent publications by Marsh and co-workers [ Das, et al. ( 2011 ) Angew. Chem. Int. Ed. 50 , 7148 - 7152 ; Eser, et al. ( 2011 ) Biochemistry 50 , 10743 - 10750 ] reported that their Ec expressed Np and Prochlorococcus marinus (Pm) AD preparations transform aldehydes to the same products more rapidly by an O(2)-independent, truly hydrolytic process, which they suggested proceeded by transient substrate reduction with obligatory participation by the reducing system (they used a chemical system, NADH and phenazine methosulfate; N/PMS). To resolve this discrepancy, we re examined our preparations of both AD orthologues by a combination of (i) activity assays in the presence and absence of O(2) and (ii) (18)O(2) and H(2)(18)O isotope-tracer experiments with direct mass-spectrometric detection of the HCO(2)(-) product. For multiple combinations of the AD orthologue (Np and Pm), reducing system (protein-based and chemical), and substrate (n-heptanal and n octadecanal), our preparations strictly require O(2) for activity and do not support detectable hydrolytic formate production, despite having catalytic activities similar to or greater than those reported by Marsh and co-workers. Our results, especially of the (18)O-tracer experiments, suggest that the activity observed by Marsh and co-workers could have arisen from contaminating O(2) in their assays. The definitive reaffirmation of the oxygenative nature of the reaction implies that the enzyme, initially designated as aldehyde decarbonylase when the C1-derived coproduct was thought to be carbon monoxide rather than formate, should be redesignated as aldehyde-deformylating oxygenase (ADO). PMID- 22947200 TI - The ethical decisions UK doctors make regarding advanced cancer patients at the end of life--the perceived (in) appropriateness of anticoagulation for venous thromboembolism: a qualitative study. AB - BACKGROUND: Cancer patients are at risk of developing blood clots in their veins venous thromboembolism (VTE) - which often takes the form of a pulmonary embolism or deep vein thrombosis. The risk increases with advanced disease. Evidence based treatment is low molecular weight heparin (LMWH) by daily subcutaneous injection. The aim of this research is to explore the barriers for doctors in the UK when diagnosing and treating advanced cancer patients with VTE. METHOD: Qualitative, in-depth interview study with 45 doctors (30 across Yorkshire, England and 15 across South Wales). Doctors were from three specialties: oncology, palliative medicine and general practice, with a mixture of senior and junior staff. Framework analysis was used. RESULTS: Doctors opinions as to whether LMWH treatment was ethically appropriate for patients who were symptomatic from VTE but at end of life existed on a shifting continuum, largely influenced by patient prognosis. A lack of immediate benefit coupled with the discomfort of a daily injection had influenced some doctors not to prescribe LMWH. The point at which LMWH injections should be stopped in patients at the end of life was ambiguous. Some perceived 'overcaution' in their own and other clinicians' treatment of patients. Viewpoints were divergent on whether dying of a PE was considered a "good way to go". The interventionalism and ethos of palliative medicine was discussed. CONCLUSIONS: Decisions are difficult for doctors to make regarding LMWH treatment for advanced cancer patients with VTE. Treatment for this patient group is bounded to the doctors own moral and ethical frameworks. PMID- 22947201 TI - Workshop Report: concepts and methods in the economics of nutrition--gateways to better economic evaluation of nutrition interventions. AB - Improving health through better nutrition of the population may contribute to enhanced efficiency and sustainability of healthcare systems. A recent expert meeting investigated in detail a number of methodological aspects related to the discipline of nutrition economics. The role of nutrition in health maintenance and in the prevention of non-communicable diseases is now generally recognised. However, the main scope of those seeking to contain healthcare expenditures tends to focus on the management of existing chronic diseases. Identifying additional relevant dimensions to measure and the context of use will become increasingly important in selecting and developing outcome measurements for nutrition interventions. The translation of nutrition-related research data into public health guidance raises the challenging issue of carrying out more pragmatic trials in many areas where these would generate the most useful evidence for health policy decision-making. Nutrition exemplifies all the types of interventions and policy which need evaluating across the health field. There is a need to start actively engaging key stakeholders in order to collect data and to widen health technology assessment approaches for achieving a policy shift from evidence-based medicine to evidence-based decision-making in the field of nutrition. PMID- 22947203 TI - An Arabidopsis class II formin, AtFH19, nucleates actin assembly, binds to the barbed end of actin filaments, and antagonizes the effect of AtFH1 on actin dynamics. AB - Formin is a major protein responsible for regulating the nucleation of actin filaments, and as such, it permits the cell to control where and when to assemble actin arrays. It is encoded by a multigene family comprising 21 members in Arabidopsis thaliana. The Arabidopsis formins can be separated into two phylogenetically-distinct classes: there are 11 class I formins and 10 class II formins. Significant questions remain unanswered regarding the molecular mechanism of actin nucleation and elongation stimulated by each formin isovariant, and how the different isovariants coordinate to regulate actin dynamics in cells. Here, we characterize a class II formin, AtFH19, biochemically. We found that AtFH19 retains all general properties of the formin family, including nucleation and barbed end capping activity. It can also generate actin filaments from a pool of actin monomers bound to profilin. However, both the nucleation and barbed end capping activities of AtFH19 are less efficient compared to those of another well-characterized formin, AtFH1. Interestingly, AtFH19 FH1FH2 competes with AtFH1 FH1FH2 in binding actin filament barbed ends, and inhibits the effect of AtFH1 FH1FH2 on actin. We thus propose a mechanism in which two quantitatively different formins coordinate to regulate actin dynamics by competing for actin filament barbed ends. PMID- 22947202 TI - Reversal of subcellular remodelling by losartan in heart failure due to myocardial infarction. AB - This study tested the reversal of subcellular remodelling in heart failure due to myocardial infarction (MI) upon treatment with losartan, an angiotensin II receptor antagonist. Twelve weeks after inducing MI, rats were treated with or without losartan (20 mg/kg; daily) for 8 weeks and assessed for cardiac function, cardiac remodelling, subcellular alterations and plasma catecholamines. Cardiac hypertrophy and lung congestion in 20 weeks MI-induced heart failure were associated with increases in plasma catecholamine levels. Haemodynamic examination revealed depressed cardiac function, whereas echocardiographic analysis showed impaired cardiac performance and marked increases in left ventricle wall thickness and chamber dilatation at 20 weeks of inducing MI. These changes in cardiac function, cardiac remodelling and plasma dopamine levels in heart failure were partially or fully reversed by losartan. Sarcoplasmic reticular (SR) Ca(2+)-pump activity and protein expression, protein and gene expression for phospholamban, as well as myofibrillar (MF) Ca(2+)-stimulated ATPase activity and alpha-myosin heavy chain mRNA levels were depressed, whereas beta-myosin heavy chain expression was increased in failing hearts; these alterations were partially reversed by losartan. Although SR Ca(2+)-release activity and mRNA levels for SR Ca(2+)-pump were decreased in failing heart, these changes were not reversed upon losartan treatment; no changes in mRNA levels for SR Ca(2+)-release channels were observed in untreated or treated heart failure. These results suggest that the partial improvement of cardiac performance in heart failure due to MI by losartan treatment is associated with partial reversal of cardiac remodelling as well as partial recovery of SR and MF functions. PMID- 22947204 TI - Quantum confinement-controlled exchange coupling in manganese(II)-doped CdSe two dimensional quantum well nanoribbons. AB - The impact of quantum confinement on the exchange interaction between charge carriers and magnetic dopants in semiconductor nanomaterials has been controversially discussed for more than a decade. We developed manganese-doped CdSe quantum well nanoribbons with a strong quantum confinement perpendicular to the c-axis, showing distinct heavy hole and light hole resonances up to 300 K. This allows a separate study of the s-d and the p-d exchange interactions all the way up to room temperature. Taking into account the optical selection rules and the statistical distribution of the nanoribbons orientation on the substrate, a remarkable change in particular of the s-d exchange constant with respect to bulk is indicated. Room-temperature studies revealed an unusually high effective g factor up to ~13 encouraging the implementation of the DMS quantum well nanoribbons for (room temperature) spintronic applications. PMID- 22947205 TI - Hidden yet visible: methodological challenges researching sexual health in Sudanese refugee communities. AB - Research addressing sensitive topics with people from small, minority, ethnic communities can present challenges that are difficult to address using conventional methods. This paper reports on the methodological approach used to explore sexual health knowledge, attitudes and beliefs among the Sudanese community in Queensland, Australia. The multiphase, mixed-method study involved young people 16 to 24 years of age participating in a written survey and semi structured interview and focus-group discussions with the broader Queensland Sudanese community members. Community collaboration, the key factor to the success of this research, optimised the development of a research environment that built trust and facilitated access and subsequent understanding. Research conducted in partnership with the target community can address methodological challenges and produce meaningful information when researching sensitive topics with small but 'highly-visible' populations. PMID- 22947206 TI - Loss of asymmetric spine synapses in prefrontal cortex of motor-asymptomatic, dopamine-depleted, cognitively impaired MPTP-treated monkeys. AB - Parkinson's disease is usually characterized as a movement disorder; however, cognitive abilities that are dependent on the prefrontal cortex decline at an early stage of the disease in most patients. The changes that underlie cognitive deficits in Parkinson's disease are not well understood. We hypothesize that reduced dopamine signalling in the prefrontal cortex in Parkinson's disease is a harbinger of detrimental synaptic changes in pyramidal neurons in the prefrontal cortex, whose function is necessary for normal cognition. Our previous data showed that monkeys exposed to the neurotoxin, 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP), but not exhibiting overt motor deficits (motor asymptomatic), displayed cognitive deficits in prefrontal cortex-dependent tasks. The present results demonstrate that motor-asymptomatic MPTP-treated monkeys have a reduced dopamine concentration and a substantially lower number (50%) of asymmetric (excitatory) spine synapses in layer II/III, but not layer V, of the dorsolateral prefrontal cortex, compared to controls. In contrast, neither dopamine concentration nor asymmetric synapse number was altered in the entorhinal cortex of MPTP-treated monkeys. Together, these findings suggest that the number of asymmetric spine synapses on dendrites in the prefrontal cortex is dopamine-dependent and that the loss of synapses may be a morphological substrate of the cognitive deficits induced by a reduction in dopamine neurotransmission in this region. PMID- 22947207 TI - Can the rural poor in India afford to treat non-communicable diseases. AB - OBJECTIVE: Non-communicable diseases (NCD) are on the increase in low-income countries, where healthcare costs are paid mostly out-of-pocket. We investigate the financial burden of NCD vs. communicable diseases (CD) among rural poor in India and assess whether they can afford to treat NCD. METHODS: We used data from two household surveys undertaken in 2009-2010 among 7389 rural poor households (39 205 individuals) in Odisha and Bihar. All persons from the sampled households, irrespective of age and gender, were included in the analysis. We classify self-reported illnesses as NCD, CD or 'other morbidities' following the WHO classification. RESULTS: Non-communicable diseases accounted for around 20% of the diseases in the month preceding the survey in Odisha and 30% in Bihar. The most prevalent NCD, representing the highest share in outpatient costs, were musculoskeletal, digestive and cardiovascular diseases. Cardiovascular and digestive problems also generated the highest inpatient costs. Women, older persons and less-poor households reported higher prevalence of NCD. Outpatient costs (consultations, medicines, laboratory tests and imaging) represented a bigger share of income for NCD than for CD. Patients with NCD were more likely to report a hospitalisation. CONCLUSION: Patients with NCD in rural poor settings in India pay considerably more than patients with CD. For NCD cases that are chronic, with recurring costs, this would be aggravated. The cost of NCD care consumes a big part of the per person share of household income, obliging patients with NCD to rely on informal intra-family cross-subsidisation. An alternative solution to finance NCD care for rural poor patients is needed. PMID- 22947209 TI - On the need to review carefully: commentary on Cardena and Marcusson-Clavertz: on the need to compare anomalous experience carefully. PMID- 22947208 TI - Physiology of deletion mutants in the anaerobic beta-myrcene degradation pathway in Castellaniella defragrans. AB - BACKGROUND: Monoterpenes present a large and versatile group of unsaturated hydrocarbons of plant origin with widespread use in the fragrance as well as food industry. The anaerobic beta-myrcene degradation pathway in Castellaniella defragrans strain 65Phen differs from well known aerobic, monooxygenase containing pathways. The initial enzyme linalool dehydratase-isomerase ldi/LDI catalyzes the hydration of beta-myrcene to (S)-(+)-linalool and its isomerization to geraniol. A high-affinity geraniol dehydrogenase geoA/GeDH and a geranial dehydrogenase geoB/GaDH contribute to the formation of geranic acid.A genetic system was for the first time applied for the betaproteobacterium to prove in vivo the relevance of the linalool dehydratase-isomerase and the geraniol dehydrogenase. In-frame deletion cassettes were introduced by conjugation and two homologous recombination events. RESULTS: Polar effects were absent in the in frame deletion mutants C. defragrans Deltaldi and C. defragrans DeltageoA. The physiological characterization of the strains demonstrated a requirement of the linalool dehydratase-isomerase for growth on acyclic monoterpenes, but not on cyclic monoterpenes. The deletion of geoA resulted in a phenotype with hampered growth rate on monoterpenes as sole carbon and energy source as well as reduced biomass yields. Enzyme assays revealed the presence of a second geraniol dehydrogenase. The deletion mutants were in trans complemented with the broad host range expression vector pBBR1MCS-4ldi and pBBR1MCS-2geoA, restoring in both cases the wild type phenotype. CONCLUSIONS: In-frame deletion mutants of genes in the anaerobic beta-myrcene degradation revealed novel insights in the in vivo function. The deletion of a high-affinity geraniol dehydrogenase hampered, but did not preclude growth on monoterpenes. A second geraniol dehydrogenase activity was present that contributes to the beta-myrcene degradation pathway. Growth on cyclic monoterpenes independent of the initial enzyme LDI suggests the presence of a second enzyme system activating unsaturated hydrocarbons. PMID- 22947210 TI - Outcome of aortoiliac, femoropopliteal and infrapopliteal endovascular interventions in lesions categorised by TASC classification. AB - AIM: To analyse lower limb angioplasty results using the defined anatomical classification of the Trans-Atlantic Inter-Society Consensus (TASC) in a training environment and to compare the results with published data. MATERIALS AND METHODS: Retrospective, consecutive data were collected for a period of 1 year for all patients undergoing lower limb endovascular interventions. The radiology information system and notes were used to obtain clinical data, and angiograms were reviewed in all cases. All cases were performed or supervised by five vascular interventional consultants assisted by fellows or registrars. Patient demographics, the indication for treatment, the TASC classification of the treated lesion, calcification, use of stent, technical success (residual stenosis <20% on completion angiography), and complications were assessed. RESULTS: Two hundred and sixty-two lesions were treated. Of the aortoiliac lesions (83), the overall primary technical success rate was 91.6% (TASC A and B: 96.7%, TASC C and D: 77.3%). Sixty-one lesions were stented and no complications recorded. Of the femoropopliteal lesions (n = 123), the overall primary technical success rate was 91.9% (TASC A and B: 98.7%, TASC C and D: 80.9%). There were four major and five minor complications in this group (five groin haematomas, two vessel ruptures, one retroperitoneal haematoma, and one distal embolization). Five patients were stented. In the infrapopliteal group (n = 56), the overall primary technical success rate was 91.1% (TASC A and B: 96.3%, TASC C and D: 86.2%). There was one complication (small retroperitoneal hematoma) and two stents were used. CONCLUSION: The results of the present study showed good technical success and low complication rates in lower limb endovascular interventions with variable operator expertise. The results are comparable to published data. Use of the TASC classification system is encouraged as it allows an objective assessment of severity and enables standardized comparison. PMID- 22947211 TI - Deficiencies in the transfer and availability of clinical trials evidence: a review of existing systems and standards. AB - BACKGROUND: Decisions concerning drug safety and efficacy are generally based on pivotal evidence provided by clinical trials. Unfortunately, finding the relevant clinical trials is difficult and their results are only available in text-based reports. Systematic reviews aim to provide a comprehensive overview of the evidence in a specific area, but may not provide the data required for decision making. METHODS: We review and analyze the existing information systems and standards for aggregate level clinical trials information from the perspective of systematic review and evidence-based decision making. RESULTS: The technology currently used has major shortcomings, which cause deficiencies in the transfer, traceability and availability of clinical trials information. Specifically, data available to decision makers is insufficiently structured, and consequently the decisions cannot be properly traced back to the underlying evidence. Regulatory submission, trial publication, trial registration, and systematic review produce unstructured datasets that are insufficient for supporting evidence-based decision making. CONCLUSIONS: The current situation is a hindrance to policy decision makers as it prevents fully transparent decision making and the development of more advanced decision support systems. Addressing the identified deficiencies would enable more efficient, informed, and transparent evidence based medical decision making. PMID- 22947213 TI - Why no feeding frenzy? Mechanisms of nutrient acquisition and utilization during infection by the rice blast fungus Magnaporthe oryzae. AB - Magnaporthe oryzae is a devastating pathogen of rice and wheat. It is a hemibiotroph that exhibits symptomless biotrophic growth for the first 4 to 5 days of infection of susceptible cultivars before becoming necrotrophic. Here, we review recent advances in our understanding of how M. oryzae is able to grow, acquire nutrients, and interact with the plant cell during infection. In particular, we describe direct mechanisms (such as the integration of carbon and nitrogen metabolism by trehalose-6-phosphate synthase 1) and indirect mechanisms (such as the suppression of host responses) that allow M. oryzae to utilize available host nutrient. We contrast the ability of M. oryzae to voraciously metabolize a wide range of carbon and nitrogen sources in vitro with the carefully orchestrated development it displays during the biotrophic phase of in planta growth and ask how the two observations can be reconciled. We also look at how nutrient acquisition and effector biology might be linked in order to facilitate rapid colonization of the plant host. PMID- 22947212 TI - Isoproterenol modulates matrix metalloproteinase-2 (MMP-2) and its tissue inhibitor-2 (TIMP-2) in rat parotid gland. AB - OBJECTIVE: Chronic isoproterenol treatment causes hypertrophy and hyperplasia of rodent salivary glands. Cell-extracellular matrix interactions play a critical role in salivary gland proliferation and matrix metalloproteinases (MMPs) are known to be involved in cell proliferation. The present study was undertaken to investigate the expression of MMP-2 and the tissue inhibitor metalloproteinase (TIMP)-2 in rat parotid gland following isoproterenol treatment. DESIGN: Female Wistar rats were daily treated with isoproterenol (25mg/kg body weight) for 0, 1, 3, and 7 days. Expression of parotid gland MMP-2 and its tissue inhibitor TIMP-2 was analysed by reverse transcription-polymerase chain reaction (RT-PCR) and immunohistochemistry. RESULTS: Our results suggest that isoproterenol modulates expression of MMP-2 and TIMP-2 mRNAs, as well as their protein expression levels in a time dependent-manner. Interestingly, at day 1 of treatment, MMP-2 and TIMP 2 expression were higher in comparison to untreated gland. At days 3 and 7, we can observe a gradual decrease of mRNA and protein levels of MMP-2 and TIMP-2. CONCLUSIONS: Our results suggest the presence of a isoproterenol-dependent modulation of extracellular matrix components. Such a modulation seems to be associated with beta-adrenergic agonist-induced hyperplasy, occurring during the first 24h of agonist treatment, and hypertrophy of the parotid gland. PMID- 22947214 TI - TALE1 from Xanthomonas axonopodis pv. manihotis acts as a transcriptional activator in plant cells and is important for pathogenicity in cassava plants. AB - Many plant-pathogenic bacteria suppress pathogen-associated molecular pattern (PAMP)-triggered immunity by injecting effector proteins into the host cytoplasm during infection through the type III secretion system (TTSS). This type III secretome plays an important role in bacterial pathogenicity in susceptible hosts. Xanthomonas axonopodis pv. manihotis (Xam), the causal agent of cassava bacterial blight, injects several effector proteins into the host cell, including TALE1(Xam) . This protein is a member of the Transcriptional Activator-Like effector (TALE) protein family, formerly known as the AvrBs3/PthA family. TALE1(Xam) has 13.5 tandem repeats of 34 amino acids each, as well as two nuclear localization signals and an acidic activation domain at the C-terminus. In this work, we demonstrate the importance of TALE1(Xam) in the pathogenicity of Xam. We use versions of the gene that lack different domains in the protein in structure-function studies to show that the eukaryotic domains at the 3' end are critical for pathogenicity. In addition, we demonstrate that, similar to the characterized TALE proteins from other Xanthomonas species, TALE1(Xam) acts as a transcriptional activator in plant cells. This is the first report of the identification of a TALE in Xam, and contributes to our understanding of the pathogenicity mechanisms employed by this bacterium to colonize and cause disease in cassava. PMID- 22947215 TI - Emerging nursing roles for late effects care for children and young adults with cancer. AB - INTRODUCTION: Annually around 3500 children and young adults are diagnosed with cancer in the UK. While five year childhood cancer survival rates are high, many will experience long-term health problems as a result of their illness and its treatment. Providing late effects services is vital for this group of patients. The skills and expertise needed for nurses working within these services has not been systematically clarified or agreed. PURPOSE OF THE RESEARCH: To identify and compare the views of managers and nurses on the ideal and existing role of nurses in the provision of late effects care. METHODS AND SAMPLE: Structured questionnaires were utilised to collect data in two phases. Phase 1 captured the views of 80 health service managers and clinicians on ideal roles; Phase 2 captured the perspectives of 36 nurses in existing roles. Questionnaires were distributed via children, teenage and young adult treatment centres across England, UK. The data were tabulated using descriptive statistics while differences were analysed using chi-squared tests. KEY RESULTS: The findings identified ideal and actual roles from the perspectives of managers and nurses. Differences were identified in a number of domains. The nurses' role was clinically and patient-care focused, containing fewer elements relating to service development, research or education. CONCLUSION: Our work has identified existing and ideal roles for nurses providing late effects services. This information has provided the foundation for the development of a nurse competence framework which has been ratified by the Royal College of Nursing, UK. PMID- 22947216 TI - Living into old age with the consequences of breast cancer. AB - PURPOSE OF THE RESEARCH: Breast cancer survival rates are improving with over 60% likely to live 20 years. As 30% diagnoses occur in women over 70 the prevalence of breast cancer survivors living into older age is increasing. The specific needs and experiences of this group have rarely been addressed. This study aimed to explore older women's experience of living with breast cancer alongside other health conditions, and to identify their information and support needs and preferences. METHODS AND SAMPLE: Data were collected from 28 semi-structured qualitative interviews and 2 focus groups (n = 14), with breast cancer survivors aged 70-90, and were analysed using thematic analysis. KEY RESULTS: These older breast cancer survivors experienced a range of long-term physical problems resulting from treatment, including poor cosmetic results and poor shoulder movements, and bras and prostheses were often unsuitable. Many were keen to preserve their body image ideal irrespective of age. Reconstruction was rarely discussed, but all would have liked this option. Older women wanted to be treated as individuals rather than uniformly as older people, with their personal physical and social needs (including co-morbidities) taken into account. They expressed a preference for information direct from health professionals. CONCLUSIONS: Many breast cancer survivors will live into advanced old age with permanent physical and emotional consequences of their treatment. Holistic and personalized assessment of needs becomes increasingly important with age, particularly with comorbidity. Effective rehabilitative care is important to reduce the impact of breast cancer into old age. PMID- 22947217 TI - Nano-TiO2 particles impair adhesion of airway epithelial cells to fibronectin. AB - Titanium dioxide engineered nanoparticles (nano-TiO(2)) are widely used in the manufacturing of a number of products. Due to their size (<100 nm), when inhaled they may be deposited in the distal lung regions and damage Clara cells. We investigated the mechanisms by which short-term (1-h) incubation of human airway Clara-like (H441) cells to nano-TiO(2) (6 nm in diameter) alters the ability of H441 cells to adhere to extracellular matrix. Our results show that 1h post incubation, there was a 3-fold increase of extracellular H(2)O(2), increased intracellular oxidative stress as demonstrated by 2',7' dichlorodihydrofluorescein diacetate (DCFH-DA) oxidation, and a 5-fold increase of phosphor-ERK1/2 as measured by Western blotting. These changes were accompanied by a 25% decrease of H441 adherence to fibronectin (p<0.05 compared to vehicle incubated H441 cells). Pretreatment with the ERK1/2 inhibitor U0126 for 3h, partially prevented this effect. In conclusion, short-term exposure of H441 cells to nano-TiO(2) appears to reduce adherence to fibronectin due to oxidative stress and activation of ERK1/2. PMID- 22947218 TI - Effects of postnatal environmental tobacco smoke on non-nutritive swallowing breathing coordination in newborn lambs. AB - While prenatal environmental tobacco smoke (ETS) exposure is a well-known risk factor for sudden infant death syndrome, the effect of postnatal ETS exposure is less clear. The objective of this study was to investigate the effect of postnatal ETS exposure on non-nutritive swallowing (NNS) and NNS-breathing coordination, which are crucial to prevent aspiration related-cardiorespiratory events. Eighteen newborn lambs (6 per group) were randomly exposed to either 10 cigarettes/day, 20 cigarettes/day or room air for 15 days. Lambs were instrumented for recording states of alertness, swallowing, electrocardiogram and breathing; recordings were performed in non-sedated lambs at the end of ETS exposure. Urinary cotinine/creatinine ratio confirmed relevant real-life exposure. Postnatal ETS exposure had no effect on NNS frequency but tended to decrease inspiratory NNS (p=0.07) during quiet sleep. No effect on respiratory or heart rate (p>0.6), apnea index (p=0.2) or sleep states (p=0.3) was observed. In conclusion, postnatal ETS exposure in lambs had only mild effects on NNS breathing coordination. PMID- 22947219 TI - Solution nuclear magnetic resonance structure and molecular dynamics simulations of a murine 18.5 kDa myelin basic protein segment (S72-S107) in association with dodecylphosphocholine micelles. AB - The 18.5 kDa myelin basic protein (MBP), the most abundant splice isoform in adult mammalian myelin, is a multifunctional, intrinsically disordered protein involved in the development and compaction of the myelin sheath in the central nervous system. A highly conserved central segment comprises a membrane-anchoring amphipathic alpha-helix followed by a proline-rich segment that represents a ligand for SH3 domain-containing proteins. Here, we have determined using solution nuclear magnetic resonance spectroscopy the structure of a 36-residue peptide fragment of MBP (murine 18.5 kDa residues S72-S107, denoted the alpha2 peptide) comprising these two structural motifs, in association with dodecylphosphocholine (DPC) micelles. The structure was calculated using CS ROSETTA (version 1.01) because the nuclear Overhauser effect restraints were insufficient for this protein. The experimental studies were complemented by molecular dynamics simulations of a corresponding 24-residue peptide fragment (murine 18.5 kDa residues E80-G103, denoted the MD-peptide), also in association with a DPC micelle in silico. The experimental and theoretical results agreed well with one another, despite the independence of the starting structures and analyses, both showing membrane association via the amphipathic alpha-helix, and a sharp bend in the vicinity of the Pro93 residue (murine 18.5 kDa sequence numbering). Overall, the conformations elucidated here show how the SH3 ligand is presented to the cytoplasm for interaction with SH3 domain-containing proteins such as Fyn and contribute to our understanding of myelin architecture at the molecular level. PMID- 22947220 TI - Gnathostoma spinigerum: immunodepression in experimental infected mice. AB - Mice were infected with 8- or 25-infective worms of advanced third stage Gnathostoma spinigerum larvae (L3) which were obtained from natural infected eels. On day 14, 60 and 200 post infections (PI), spleen cells of infected mice were tested for lymphoproliferative responses in vitro against the mitogen and specific L3 somatic antigen in order to clarify the cellular immune status of the host upon this nematode infection. Reduced responsiveness to Con A was observed in infected mice. These depressed responses were more pronounced in chronically infected mice (day 200, PI) than in day 14 and day 60, PI. There was no significant difference of lymphoproliferative response between groups of high (25 L3) and low (8 L3)-infective dose in the chronic readily stage. Regarding to the L3 somatic Ag stimulation, the depressed response was obviously detected in high dose and chronic infection. Our results demonstrated that in this G. spinigerum mouse system T-cell response is defective. The depression could be reversible and was associated with active infection because it was abolished by anthelmintic (ivermectin) treatment. This study shows the involvement of Th-2 response to this nematode in regulating T cell proliferation. PMID- 22947221 TI - Nonlinear vibration behavior of graphene resonators and their applications in sensitive mass detection. AB - Graphene has received significant attention due to its excellent mechanical properties, which has resulted in the emergence of graphene-based nano-electro mechanical system such as nanoresonators. The nonlinear vibration of a graphene resonator and its application to mass sensing (based on nonlinear oscillation) have been poorly studied, although a graphene resonator is able to easily reach the nonlinear vibration. In this work, we have studied the nonlinear vibration of a graphene resonator driven by a geometric nonlinear effect due to an edge clamped boundary condition using a continuum elastic model such as a plate model. We have shown that an in-plane tension can play a role in modulating the nonlinearity of a resonance for a graphene. It has been found that the detection sensitivity of a graphene resonator can be improved by using nonlinear vibration induced by an actuation force-driven geometric nonlinear effect. It is also shown that an in-plane tension can control the detection sensitivity of a graphene resonator that operates both harmonic and nonlinear oscillation regimes. Our study suggests the design principles of a graphene resonator as a mass sensor for developing a novel detection scheme using graphene-based nonlinear oscillators. PMID- 22947222 TI - Transcriptional regulation of plant secondary metabolism. AB - Plant secondary metabolites play critical roles in plant-environment interactions. They are synthesized in different organs or tissues at particular developmental stages, and in response to various environmental stimuli, both biotic and abiotic. Accordingly, corresponding genes are regulated at the transcriptional level by multiple transcription factors. Several families of transcription factors have been identified to participate in controlling the biosynthesis and accumulation of secondary metabolites. These regulators integrate internal (often developmental) and external signals, bind to corresponding cis-elements--which are often in the promoter regions--to activate or repress the expression of enzyme-coding genes, and some of them interact with other transcription factors to form a complex. In this review, we summarize recent research in these areas, with an emphasis on newly-identified transcription factors and their functions in metabolism regulation. PMID- 22947223 TI - Response to: who receives opioids for acute pain in emergency departments? Considering evidence, patient and provider preferences. PMID- 22947225 TI - Effects of fish oil supplementation on the fatty acid profile in erythrocyte membrane and plasma phospholipids of pregnant women and their offspring: a randomised controlled trial. AB - We aimed to investigate the effects of fish oil (FO) supplementation to pregnant women on the maternal and fetal fatty acid profile in plasma and erythrocyte phospholipids (PL) and to identify the best compartment for the assessment of fatty acid status. A multi-centre, double-blind, controlled trial was conducted. Healthy pregnant women from three European centres were randomly assigned to receive from week 20 of gestation until delivery a daily dietary supplement with either FO (500 mg DHA+150 mg EPA), 400 MUg 5-methyltetrahydrofolate, both or placebo. Fatty acids in plasma and erythrocyte PL were determined in maternal blood (week 20, week 30 of pregnancy and delivery) and in cord blood (delivery). FO supplementation increased DHA levels in maternal and cord plasma and erythrocyte PL. Higher percentage changes were observed in erythrocyte PL than in plasma PL. There were significant correlations between plasma and erythrocyte fatty acid levels in maternal and cord blood. Significant correlations between maternal and cord fatty acid levels at delivery in plasma and erythrocytes were also observed; however, correlation coefficients were higher for erythrocyte phophatidylethanolamine. FO supplementation increases maternal and fetal DHA status. Both plasma and erythrocytes appear to be suitable to evaluate the fatty acid status of mothers but erythrocytes seem to be a more reliable marker in neonates. PMID- 22947224 TI - Spinal cord injury causes bone loss through peroxisome proliferator-activated receptor-gamma and Wnt signalling. AB - It has long been recognized that spinal cord injury (SCI) leads to a loss of bone mineral. However, the mechanisms of bone loss after SCI remain poorly understood. The aim of this study was to investigate whether SCI causes a shift in skeletal balance between osteoblastogenesis and adipogenesis. Eighty male Sprague-Dawley rats at 6 weeks of age were randomly divided into two groups: sham-operated (SHAM) group and SCI group. The rats were killed after 3 weeks, 3 months and 6 months, and their femora, tibiae and humeri were collected for mesenchymal stem cells (MSCs) culture, bone mineral density (BMD) measurement, RNA analysis and Western Blot analysis. Osteogenic and adipogenic differentiation potential of MSCs from SCI rats and SHAM rats was evaluated. We found increased marrow adiposity in sublesional tibiae of SCI rats. SCI caused increased peroxisome proliferator-activated receptor-gamma (PPARgamma) expression and diminished Wnt signalling in sublesional tibiae. Interestingly, in MSCs from SCI rats treated with the PPARgamma inhibitor GW9662, the ratios of RANKL to OPG expression were significantly decreased. On the contrary, in MSCs from SCI rats treated with the PPARgamma ligand troglitazone, the ratios of RANKL to OPG expression in SCI rats were significantly increased. High expression of PPARgamma may lead to increased bone resorption through the RANKL/OPG axis after SCI. In addition, high expression also results in the suppression of osteogenesis and enhancement of adipogenesis in SCI rats. SCI causes a shift in skeletal balance between osteoblastogenesis and adipogenesis, thus leading to bone loss after SCI. PMID- 22947226 TI - Molecular epidemiology of cutaneous leishmaniasis and heterogeneity of Leishmania major strains in Iran. AB - OBJECTIVE: To determine the geographical distribution of Leishmania species causing cutaneous leishmaniasis (CL) and to study the genetic heterogeneity of Leishmania major isolates from different endemic areas of Iran. METHODS: A total of 341 isolates from lesions of patients living in 11 provinces of Iran were grown in culture medium and inoculated to BALB/c mice to detect possible visceralisation. The species were identified by isoenzyme analysis using a battery of six enzymes and kinetoplast (k) DNA-PCR technique. Genetic variation among L. major isolates was analysed by random amplified polymorphic DNA (RAPD) technique. RESULTS: Of the total 341 isolates, 283 isolates were L. major and 58 isolates were Leishmania tropica. In rural areas, the causative agent of CL was mainly L. major (95%L. major vs. 5%L. tropica), in urban areas it was L. tropica (65%L. tropica vs. 35%L. major). All isolates of L. major and 8.6% of L. tropica isolates showed visceralisation in BALB/c mice. There is considerable genetic diversity between L. major strains from different endemic areas and even between some isolates of the same endemic area. CONCLUSION: Leishmania major is the most frequent species in the endemic areas of CL in eleven provinces of Iran, and genetic diversity is a common feature of L. major in the country. PMID- 22947227 TI - Environmental impact assessment of chlorine in liquid crystal display glass (LCDG) based on material flow analysis. AB - Liquid crystal display glass (LCDG) may contain chlorine in trace amounts to attain some of its special properties. LCDG is primarily manufactured by glass companies, which then supply the electronic industry for utilization in the manufacture of items such as televisions, computer monitors, etc. In order to be seen as environmentally friendly, some electronic companies that utilize LCDG request that glass companies eliminate halogens such as chlorine from LCDG. The issue of halogens in products is often associated with dioxin-like problems. By using halogen-free LCDG in their manufacturing process, electronic companies aim to enhance their eco-friendly branding. Nevertheless, the real gains in terms of environmental improvement are yet to be assessed. In this study, we discussed the effectiveness of reducing or eliminating chlorine in electrical and electronic products on a scientific basis, by carrying out a quantitative assessment of cancer risk posed by potential emissions of dioxins when discarded LCDG is incinerated. The results indicate that the maximum increase of individual lifetime cancer risk is 3.2 * 10(-10). This level of cancer risk is negligible. Consequently, we suggest that there is no need to introduce stricter standards for chlorine content in LCDG, from the viewpoint of potential dioxin formation. PMID- 22947228 TI - Does organic farming reduce environmental impacts?--a meta-analysis of European research. AB - Organic farming practices have been promoted as, inter alia, reducing the environmental impacts of agriculture. This meta-analysis systematically analyses published studies that compare environmental impacts of organic and conventional farming in Europe. The results show that organic farming practices generally have positive impacts on the environment per unit of area, but not necessarily per product unit. Organic farms tend to have higher soil organic matter content and lower nutrient losses (nitrogen leaching, nitrous oxide emissions and ammonia emissions) per unit of field area. However, ammonia emissions, nitrogen leaching and nitrous oxide emissions per product unit were higher from organic systems. Organic systems had lower energy requirements, but higher land use, eutrophication potential and acidification potential per product unit. The variation within the results across different studies was wide due to differences in the systems compared and research methods used. The only impacts that were found to differ significantly between the systems were soil organic matter content, nitrogen leaching, nitrous oxide emissions per unit of field area, energy use and land use. Most of the studies that compared biodiversity in organic and conventional farming demonstrated lower environmental impacts from organic farming. The key challenges in conventional farming are to improve soil quality (by versatile crop rotations and additions of organic material), recycle nutrients and enhance and protect biodiversity. In organic farming, the main challenges are to improve the nutrient management and increase yields. In order to reduce the environmental impacts of farming in Europe, research efforts and policies should be targeted to developing farming systems that produce high yields with low negative environmental impacts drawing on techniques from both organic and conventional systems. PMID- 22947229 TI - Incidence and outcomes of pregnancy-associated cancer in Australia, 1994-2008: a population-based linkage study. AB - OBJECTIVE: To determine trends in pregnancy-associated cancer and associations between maternal cancer and pregnancy outcomes. DESIGN: Population-based cohort study. SETTING: New South Wales, Australia, 1994-2008. POPULATION: A total of 781 907 women and their 1 309 501 maternities. METHODS: Cancer and maternal information were obtained from linked cancer registry, birth and hospital records for the entire population. Generalised estimating equations with a logit link were used to examine associations between cancer risk factors and pregnancy outcomes. MAIN OUTCOME MEASURES: Incidence of pregnancy-associated cancer (diagnosis during pregnancy or within 12 months of delivery), maternal morbidities, preterm birth, and small- and large-for-gestational-age (LGA). RESULTS: A total of 1798 new cancer diagnoses were identified, including 499 during pregnancy and 1299 postpartum. From 1994 to 2007, the crude incidence rate of pregnancy-associated cancer increased from 112.3 to 191.5 per 100 000 maternities (P < 0.001), and only 14% of the increase was explained by increasing maternal age. Cancer diagnosis was more common than expected in women aged 15-44 years (observed-to-expected ratio 1.49; 95% CI 1.42-1.56). Cancers were predominantly melanoma (33.3%) and breast cancer (21.0%). Women with cancer diagnosed during pregnancy had high rates of labour induction (28.5%), caesarean section (40.0%) and planned preterm birth (19.7%). Novel findings included a cancer association with multiple pregnancies (adjusted odds ratio 1.52, 95% CI 1.13-2.05) and LGA (aOR 1.47, 95% CI 1.14-1.89). CONCLUSIONS: Pregnancy associated cancers have increased, and this increase is only partially explained by increasing maternal age. Pregnancy increases women's interaction with health services and the possibility for diagnosis, but may also influence tumour growth. PMID- 22947230 TI - A systematic review and analysis of long-term outcomes in attention deficit hyperactivity disorder: effects of treatment and non-treatment. AB - BACKGROUND: In childhood, attention deficit/hyperactivity disorder (ADHD) is characterized by age-inappropriate levels of inattentiveness/disorganization, hyperactivity/impulsiveness, or a combination thereof. Although the criteria for ADHD are well defined, the long-term consequences in adults and children need to be more comprehensively understood and quantified. We conducted a systematic review evaluating the long-term outcomes (defined as 2 years or more) of ADHD with the goal of identifying long-term outcomes and the impact that any treatment (pharmacological, non-pharmacological, or multimodal) has on ADHD long-term outcomes. METHODS: Studies were identified using predefined search criteria and 12 databases. Studies included were peer-reviewed, primary studies of ADHD long term outcomes published between January 1980 to December 2010. Inclusion was agreed on by two independent researchers on review of abstracts or full text. Published statistical comparison of outcome results were summarized as poorer than, similar to, or improved versus comparators, and quantified as percentage comparisons of these categories. RESULTS: Outcomes from 351 studies were grouped into 9 major categories: academic, antisocial behavior, driving, non-medicinal drug use/addictive behavior, obesity, occupation, services use, self-esteem, and social function outcomes. The following broad trends emerged: (1) without treatment, people with ADHD had poorer long-term outcomes in all categories compared with people without ADHD, and (2) treatment for ADHD improved long-term outcomes compared with untreated ADHD, although not usually to normal levels. Only English-language papers were searched and databases may have omitted relevant studies. CONCLUSIONS: This systematic review provides a synthesis of studies of ADHD long-term outcomes. Current treatments may reduce the negative impact that untreated ADHD has on life functioning, but does not usually 'normalize' the recipients. PMID- 22947232 TI - Usefulness of skin biopsies in the evaluation and management of patients with suspected small fiber neuropathy. AB - OBJECTIVE: To assess the usefulness of skin biopsy in the assessment of patients with suspeted small fiber neuropathy (SFN). METHODS: Retrospective chart review of patients with sensory symptoms or findings restricted to small nerve fibers and normal nerve conduction studies (NCS) seen in a subspecialty neuromuscular private practice. RESULTS: Assessments were made on 145 patients. Skin biopsy was abnormal in at least one site in 86 patients (59%). There was no significant difference between patients with normal or abnormal skin biopsies with respect to age, gender, or duration of symptoms. Compared to patients with normal skin biopsies, patients with confirmed SFN were significantly more likely to have pain and were more than twice as likely to respond to standard neuropathic pain medications. CONCLUSIONS: Skin biopsy is useful in the diagnosis and management of patients with otherwise unexplained sensory symptoms or findings. PMID- 22947231 TI - A dialogue-based Web application enhances personalized access to healthcare professionals--an intervention study. AB - BACKGROUND: In today's short stay hospital settings the contact time for patients is reduced. However, it seems to be more important for the patients that the healthcare professionals are easy to get in contact with during the whole course of treatment, and to have the opportunity to exchange information, as a basis for obtaining individualized information and support. Therefore, the aim was to explore the ability of a dialogue-based application to contribute to accessibility of the healthcare professionals and exchangeability of information. METHOD: An application for online written and asynchronous contacts was developed, implemented in clinical practice, and evaluated. The qualitative effect of the online contact was explored using a Web-based survey comprised of open-ended questions. RESULTS: Patients valued the online contacts and experienced feelings of partnership in dialogue, in a flexible and calm environment, which supported their ability to be active partners and feelings of freedom and security. CONCLUSION: The online asynchronous written environment can contribute to accessibility and exchangeability, and add new possibilities for dialogues from which the patients can benefit. The individualized information obtained via online contact empowers the patients. The Internet-based contacts are a way to differentiate and expand the possibilities for contacts outside the few scheduled face-to-face hospital contacts. PMID- 22947233 TI - Demographic and anthropometric factors affecting elbow range of motion in healthy adults. AB - BACKGROUND: To use elbow range of motion routinely as a diagnostic index, it is important to explain the normal variability among the population. Consequently, this study assessed the possible associations between age, sex, laterality, body mass index, joint laxity, level of physical activities, upper limb dimensions, and the elbow range of motion in flexion/extension. MATERIALS AND METHODS: Maximal flexion and extension were measured on the lateral radiographs of 102 elbows of 51 volunteers. The difference of range of motion regarding sex and laterality was assessed with Student t tests. The Pearson correlation coefficient was used to evaluate the relationship between elbow mobility and the other factors, and a stepwise multiple regression analysis was performed. RESULTS: Among the 51 volunteers, a correlation was found between flexion and body mass index, age, and midbrachial and forearm circumferences (r = -0.234 to -0.594). Age (r = 0.268) and hyperlaxity (r = -0.323) were the only factors associated with a change in elbow extension. No correlation was found between the level of physical activity or with the laterality and changes in elbow mobility. Finally, women presented with more flexion and total elbow range of motion than men. CONCLUSIONS: This study confirms the association between various demographic and anthropometric factors and elbow range of motion in healthy adults. Among these, the body mass index and forearm circumference are the most likely responsible for mobility variations among the population. PMID- 22947234 TI - Risk factors for development of heterotopic ossification of the elbow after fracture fixation. AB - BACKGROUND: Postoperative heterotopic ossification (HO) about the elbow may occur after surgical fixation of fractures and can contribute to dysfunction. Factors associated with HO formation after surgical fixation of elbow trauma are not well understood. METHODS: All patients who underwent surgery for elbow trauma at our institution from October 2001 through August 2010 were retrospectively reviewed. Patients with prior injury or deformity to the involved elbow were excluded. Demographic data; fracture type; surgical treatment; and presence, location, and size of HO were recorded. The Fisher exact test, chi(2) test, and multivariate logistic regression were used with an alpha value of .05 used for significance. RESULTS: A total of 159 patients were identified, with 89 (37 men and 52 women) meeting inclusion and exclusion criteria. The mean age was 54.4 years (range, 18 90 years), and the mean follow-up time was 180 days. Age, male gender, lateral collateral ligament repair, and dual-incision approach were not associated with increased ectopic bone formation. Distal humeral fractures were a significant predictor of heterotopic bone. In patients in whom HO ultimately developed, it was visible on radiographs obtained 2 weeks postoperatively in 86% of cases. CONCLUSION: This investigation found predictors for the development of HO after surgical fixation of intra-articular elbow fractures. Furthermore, HO went on to develop at the time of final follow-up in only 14% of patients without HO on radiographs obtained 2 weeks postoperatively. This may suggest that absence of HO on radiographs obtained 2 weeks postoperatively may predict a more favorable outcome. PMID- 22947235 TI - Diaphragm function after interscalene brachial plexus block: a double-blind, randomized comparison of 0.25% and 0.125% bupivacaine. AB - BACKGROUND: Interscalene brachial plexus block (ISBPB) provides excellent analgesia after rotator cuff surgery but is associated with diaphragm dysfunction. In this study, ISBPB with 20 mL of 0.125% or 0.25% bupivacaine were compared to assess the effect on diaphragm function, oxygen saturation, pain control, opioid requirements, and patient satisfaction. MATERIALS AND METHODS: In this prospective, randomized, double-blind study, 30 adults undergoing outpatient arthroscopic rotator cuff repair were enrolled to receive ultrasound-guided interscalene brachial plexus catheter placement with 20 mL of 0.125% (n = 15) or 0.25% bupivacaine (n = 15). Diaphragm function and oxygen saturation were assessed before ISBPB placement and on discharge from the postanesthesia care unit. Postoperative pain scores, opioid requirements, and patient satisfaction were compared. RESULTS: Diaphragm function and oxygen saturation were superior in the low concentration group. Absent or paradoxic motion of the diaphragm was present in 78% of the 0.25% group compared with 21% of patients in the 0.125% group (P = .008). Oxygen saturation decreased 4.3% in the 0.25% group compared with a decrease of 2.6% in the 0.125% group (P = .04). Pain scores averaged 1 of 10 in the 0.25% group and 0 of 10 in the 0.125% group (P = .02). Opioid requirements and patient satisfaction were not different between the two groups. CONCLUSIONS: In this randomized, double-blind comparison of ISBPB performed with 20 mL of 0.125% or 0.25% bupivacaine, diaphragm function and oxygen saturation were superior in patients treated with more dilute bupivacaine. Furthermore, there were no clinically significant differences in pain scores, and no statistically significant differences in opioid requirements and patient satisfaction. PMID- 22947236 TI - The Latarjet coracoid process transfer procedure: alterations in the neurovascular structures. AB - BACKGROUND: The Latarjet coracoid process transfer procedure is an established, reliable treatment for glenoid deficiency associated with recurrent anterior shoulder instability, but changes in neurovascular anatomy resulting from the procedure are a concern. The purpose of our cadaveric study was to identify changes in the neurovascular anatomy after a Latarjet procedure. MATERIALS AND METHODS: We obtained 4 paired, fresh-frozen cadaveric forequarters (8 shoulders) from the Maryland State Anatomy Board. In each shoulder, we preoperatively measured the distances from the midanterior glenoid rim to the musculocutaneous nerve, axillary nerve, and axillary artery in 2 directions (lateral to medial and superior to inferior) and with the arm in 2 positions (0 degrees abduction/neutral rotation; 30 degrees abduction/30 degrees external rotation), for a total of 12 measurements. We then created a standardized bony defect in the anterior-inferior glenoid, reconstructed it with the Latarjet procedure, and repeated the same measurements. Two examiners independently took each measurement twice. Inter-rater reliability was adequate, allowing pre-Latarjet measurements to be combined, averaged, and compared with combined and averaged post-Latarjet measurements by using paired Student t tests (significance, P <= .05). RESULTS: We found (1) significant differences in the location of the musculocutaneous nerve in the superior-to-inferior direction for both arm positions, (2) notably lax and consistently overlapping musculocutaneous and axillary nerves, and (3) an unchanged axillary artery location. CONCLUSIONS: The Latarjet procedure resulted in consistent and clinically significant alterations in the anatomic relationships of the musculocutaneous and axillary nerves, which may make them vulnerable to injury during revision surgery. PMID- 22947237 TI - Rim reconstruction with autogenous iliac crest for anterior glenoid deficiency: forty-three instability cases followed for 5-19 years. AB - BACKGROUND: The purpose of this study was to evaluate the long-term results of instability patients treated with iliac crest graft glenoid augmentation. MATERIALS AND METHODS: Retrospective study including 48 consecutive patients (40 male; mean age 25; range, 17-35). There were 20 primary and 28 revision cases. Three patients declined follow-up examination, and 5 lost to >5 years follow-up. Mean follow-up was 9.2 years (range, 5-19). Reconstruction comprised: iliac crest graft, interposition of the labrum on the burred surface of the graft and capsular re-tensioning. We measured the Oxford Shoulder Instability Score (OSIS) and assessed arthrotic changes and atrophy and fatty infiltration of the subscapularis. RESULTS: 8/43 had residual pain, 3/43 had a subjective sensation of instability, 1/43 had a re-dislocation and required re-intervention. The mean OSIS was 18.1 points (12-50) (n = 40). 1/40 developed postoperative subscapularis insufficiency. The mean subscapularis atrophy was 7.4% (37% atrophy to 27% hypertrophy). 2/40 had a relevant fatty infiltration of the SSC muscle stage III to stage IV. 19/40 had mild and 1/40 had a moderate arthrosis. Arthrosis progressed by 1 stage in 7 of 35 shoulders. The mean residual glenoid defect area was 4.0% (0-13.5) and the mean defect width was 8.3% (range, 0-19.2) (n = 40). CONCLUSION: Glenoid rim reconstruction with iliac crest graft was equally effective for patients with primary repair and for failed previous stabilization. It offered the advantage of an anatomic reconstruction with a comparatively good long-term preservation of the joint line. PMID- 22947238 TI - Comparison of computerized and paper versions of the Western Ontario Rotator Cuff (WORC) Index. AB - BACKGROUND: The Western Ontario Rotator Cuff Index (WORC) is commonly used in orthopedic research to assess the effect of a rotator cuff injury. Questions in the WORC are presented in a visual analog scale format, which requires patients to place a pencil mark along a 10-cm line indicating their responses. The purpose of our study was to determine if a computerized version of a visual analog scale requiring patients drag a cursor along a line was comparable to data collected using the standard paper version of the WORC. MATERIALS AND METHODS: Administration of the WORC was randomized, with the first version given in the waiting room before the office visit, and the second immediately after the office visit, to ensure the participant's shoulder function had not significantly changed. RESULTS: Thirty-five patients with rotator cuff injury completed the paper and computerized versions of the WORC. There was no significant difference in mean scores for the WORC between the paper (1040.3) and computerized versions (1021.2, P = .488). The intraclass correlation coefficient for the 2 versions was 0.94. Similarly, there were no significant differences in scores between the subset of scores within the WORC (Physical Activity, Work, Sports, Lifestyle, and Emotion, P > .05), and each subset was highly correlated (intraclass correlation coefficient >0.80). CONCLUSIONS: There was no significant difference in scores for the WORC index when administered in a computerized format vs a paper format. PMID- 22947239 TI - Plate versus intramedullary nail fixation in the treatment of humeral shaft fractures: an updated meta-analysis. AB - BACKGROUND: Regarding the treatment of humeral shaft fractures, the choice of plating or intramedullary nailing remains controversial. Previous randomized controlled trials and meta-analyses failed to draw a unanimous conclusion. To guide clinical decision making, we conducted an updated meta-analysis on the optimal treatment of humeral shaft fractures. METHODS: We identified eligible studies published from 1969 to July 2011 using the Cochrane Library; Cochrane Bone, Joint and Muscle Trauma Group; MEDLINE; Embase; OVID; and Google Scholar and manually searched the references of relevant studies. Randomized controlled trials that compared nailing and plating in the treatment of humeral shaft fractures were included. After the methodologic assessment, available data were extracted and statistically reviewed. The primary outcomes were nonunion, delayed union, postoperative infection, reoperation, and radial nerve palsy. The secondary outcomes were restriction of shoulder motion, shoulder impingement, iatrogenic fracture comminution, and implant failure. RESULTS: We included 10 studies comparing plating and nailing in patients with humeral shaft fractures, comprising 439 participants. Plating reduced the risk of shoulder impingement and shoulder restriction in comparison with nailing. Regarding reoperation risk, a secondary sensitivity analysis showed the finding favoring plating over nailing remained unstable. Otherwise, no significant differences were found in postoperative infection, nonunion, delayed union, radial nerve palsy, iatrogenic fracture comminution, and implant failure between groups. CONCLUSIONS: On the basis of current evidence, both plating and nailing can achieve a similar treatment effect on humeral shaft fractures, but plating may reduce the occurrence of shoulder problems. Randomized controlled trials with larger sample sizes using appropriate blinding methods are needed to confirm these findings. LEVEL OF EVIDENCE: Level II, Meta-analysis of prospective comparative trials. PMID- 22947241 TI - The impact of pricing and patent expiration on demand for pharmaceuticals: an examination of the use of broad-spectrum antimicrobials. AB - The aim of the analysis was to determine whether demand in Germany for specific antimicrobial agents is driven by prices that drop considerably when generic substitutes become available. A time-series approach was therefore carried out to explore price elasticities of demand for two different classes of broad-spectrum antimicrobials (fluoroquinolones and cephalosporins) using data on ambulatory antibiotics prescribed on the German statutory health insurance scheme and data on in-hospital antibiotic use in a German teaching hospital. In short, we attempted to explain demand for different antibiotics based on changes in price and hospital-wide morbidity. The data indicate that patent expiration is followed by substantial decreases in the price of antibiotics. In the outpatient sector, all antibiotics included in the analysis showed significant negative own-price elasticities of demand. However, in the hospital settings, significant own-price elasticities were only determined for some antibiotics, although price decreases were stronger than in the outpatient sector. We conclude that price dependence of demand for antimicrobials is present both in the ambulatory and the hospital setting. However, this is especially surprising in the hospital setting because price differences among the antibiotics observed are particularly small compared with the overall cost of hospitalisation. PMID- 22947240 TI - Motor control retraining exercises for shoulder impingement: effects on function, muscle activation, and biomechanics in young adults. AB - OBJECTIVE: Evidence for effective management of shoulder impingement is limited. The present study aimed to quantify the clinical, neurophysiological, and biomechanical effects of a scapular motor control retraining for young individuals with shoulder impingement signs. METHOD: Sixteen adults with shoulder impingement signs (mean age 22 +/- 1.6 years) underwent the intervention and 16 healthy participants (24.8 +/- 3.1years) provided reference data. Shoulder function and pain were assessed using the Shoulder Pain and Disability Index (SPADI) and other questionnaires. Electromyography (EMG) and 3-dimensional motion analysis was used to record muscle activation and kinematic data during arm elevation to 90 degrees and lowering in 3 planes. Patients were assessed pre and post a 10-week motor control based intervention, utilizing scapular orientation retraining. RESULTS: Pre-intervention, patients reported pain and reduced function compared to the healthy participants (SPADI in patients 20 +/- 9.2; healthy 0 +/- 0). Post-intervention, the SPADI scores reduced significantly (P < .001) by a mean of 10 points (+/-4). EMG showed delayed onset and early termination of serratus anterior and lower trapezius muscle activity pre intervention, which improved significantly post-intervention (P < .05). Pre intervention, patients exhibited on average 4.6-7.4 degrees less posterior tilt, which was significantly lower in 2 arm elevation planes (P < .05) than healthy participants. Post-intervention, upward rotation and posterior tilt increased significantly (P < .05) during 2 arm movements, approaching the healthy values. CONCLUSION: A 10-week motor control intervention for shoulder impingement increased function and reduced pain. Recovery mechanisms were indicated by changes in muscle recruitment and scapular kinematics. The efficacy of the intervention requires further examined in a randomized control trial. PMID- 22947242 TI - Timing-error-difference calibration of a two-dimensional array imaging system using the overlapping-subaperture algorithm. AB - Timing errors in the transmitting and receiving electronic channels of an imaging system can generate different transmission and reception phase-aberration profiles. To decide if these two profiles need to be measured separately, an overlapping-subaperture algorithm has been proposed in a previous paper to measure the difference between timing errors in transmitting and receiving channels connected to each element in a two-dimensional array. This algorithm has been used to calibrate a custom built imaging system with a curved linear two dimensional array, and the results are presented in this paper. The experimental results have demonstrated that the overlapping-subaperture algorithm is capable of calibrating the timing-error-difference profile of this imaging system with a standard deviation of only a few nanoseconds. Experimental results have also shown that the time-error-difference profile of this imaging system is smaller than one tenth of a wavelength and there is no need to measure the transmission and reception phase-aberration profiles separately. The derived average phase aberration profile using the near-field signal-redundancy algorithm can be used to correct phase aberrations for both transmission and reception. PMID- 22947244 TI - Increasing quinolone resistance and multidrug resistant isolates among Salmonella enterica in Hong Kong. AB - OBJECTIVES: To study the antimicrobial susceptibility and molecular epidemiology of Salmonella enterica isolates from 2005 to 2010 in Hong Kong. METHODS: S. enterica isolates from 2005 to 2010 in one of the hospital clusters were serotyped and studied their antimicrobial susceptibility by determining the minimal inhibitory concentration of 17 antimicrobial agents and their relatedness by pulsed-field gel electrophoresis (PFGE). RESULTS: A total of 60 S. enterica serovars were identified among the 963 strains of Salmonella from 2005 to 2010. Enteritidis (47.3%) and Typhimurium (17.2%) were the two most common serovars. Ciprofloxacin non-susceptibility increased significantly from 39.3% in 2005 to 63% in 2010 (p < 0.05) and the percentage of multidrug resistant strains increased from 17.8% in 2005 to 36.2% in 2010 (p < 0.05). However, resistance to the third generation cephalosporins (1.4%) remained low. More strains of S. Typhimurium than other Salmonella serovars were resistant to the antimicrobial agents tested than S. Enteritidis. PFGE analysis showed there were predominant clones of S. Enteritidis, S. Typhimurium and S. Stanley circulating in the community, and two outbreaks caused by S. Enteritidis and S. Virchow during the study period. CONCLUSIONS: The study showed both a worrying percentage of Salmonella strains resistant to quinolone and of multidrug resistant strains. PFGE identified two outbreaks in the study period. PMID- 22947245 TI - [Knowledge, attitudes and practices of general practitioners about asthma in the city of Ouagadougou]. AB - INTRODUCTION: In spite of a better understanding of the physiopathology of asthma and the existence of effective molecules, morbidity and mortality of asthma across the world are constantly increasing. International guidelines are not apparently applied. This study intended to assess the knowledge, attitudes and practices of general practitioners on asthma in Ouagadougou. METHODS: This was a cross-sectional anonymous self-administered questionnaire involving 93 General Practitioners practicing in Ouagadougou. RESULTS: The participation rate was 63.4% or 59 respondents. The majority of General Practitioners (88%).know the chronic nature of asthma and 61% of them had good knowledge of severe asthma signs. The post-exercise asthma and medication asthma were known respectively by 22% and 15% of General Practitioners. Knowledge of the technique of using pressurized metered dose inhalers was bad in 54% of General Practitioners. In intermittent asthma, 52.5% of General Practitioners prescribed steroids including 27% in oral form. Inhaled corticosteroids were associated with beta2-agonists by 34% of General Practitioners in persistent asthma. After initial treatment, 44% of study physicians routinely referred their patients to pulmonologists. Drug costs, lack of in-service training and lack of national guidelines were perceived as barriers by 56%, 66% and 44% of General Practitioners. CONCLUSION: The management of asthma is not optimal. The training of General Practitioners on the management of asthma is essential. PMID- 22947243 TI - Constitutive expression of transgenes encoding derivatives of the synthetic antimicrobial peptide BP100: impact on rice host plant fitness. AB - BACKGROUND: The Biopeptide BP100 is a synthetic and strongly cationic alpha helical undecapeptide with high, specific antibacterial activity against economically important plant-pathogenic bacteria, and very low toxicity. It was selected from a library of synthetic peptides, along with other peptides with activities against relevant bacterial and fungal species. Expression of the BP100 series of peptides in plants is of major interest to establish disease-resistant plants and facilitate molecular farming. Specific challenges were the small length, peptide degradation by plant proteases and toxicity to the host plant. Here we approached the expression of the BP100 peptide series in plants using BP100 as a proof-of-concept. RESULTS: Our design considered up to three tandemly arranged BP100 units and peptide accumulation in the endoplasmic reticulum (ER), analyzing five BP100 derivatives. The ER retention sequence did not reduce the antimicrobial activity of chemically synthesized BP100 derivatives, making this strategy possible. Transformation with sequences encoding BP100 derivatives (bp100der) was over ten-fold less efficient than that of the hygromycin phosphotransferase (hptII) transgene. The BP100 direct tandems did not show higher antimicrobial activity than BP100, and genetically modified (GM) plants constitutively expressing them were not viable. In contrast, inverted repeats of BP100, whether or not elongated with a portion of a natural antimicrobial peptide (AMP), had higher antimicrobial activity, and fertile GM rice lines constitutively expressing bp100der were produced. These GM lines had increased resistance to the pathogens Dickeya chrysanthemi and Fusarium verticillioides, and tolerance to oxidative stress, with agronomic performance comparable to untransformed lines. CONCLUSIONS: Constitutive expression of transgenes encoding short cationic alpha-helical synthetic peptides can have a strong negative impact on rice fitness. However, GM plants expressing, for example, BP100 based on inverted repeats, have adequate agronomic performance and resistant phenotypes as a result of a complex equilibrium between bp100der toxicity to plant cells, antimicrobial activity and transgene-derived plant stress response. It is likely that these results can be extended to other peptides with similar characteristics. PMID- 22947246 TI - The present status of anthelmintic resistance in gastrointestinal nematode infections of sheep in the northwest of Spain by in vivo and in vitro techniques. AB - The aim of this study was to update the anthelmintic resistance (AR) status in sheep flocks infected by gastrointestinal nematodes (GIN) by means of in vivo and in vitro methods in the northwest of Spain. With this objective, we studied the efficacy of benzimidazoles (BZs), imidazothiazoles (IMs) and macrocyclic lactones (MLs), between 2006 and 2011. The sampling area was the Autonomous Community of Castilla y Leon but the majority of the flocks were located in the province of Leon. When the mean of GIN eggs per gram (epg) in faeces in a flock was higher than 150, the in vivo Faecal Egg Count Reduction Test (FECRT) was carried out. According to this test, AR was present in 63.6% of flocks, independently of the anthelmintic used. Flocks were mainly resistant to levamisole (LEV) (59.0%), followed by ivermectin (IVM) (27.3%) and albendazole (13.6%). Multidrug resistance was also observed in 27.2% of the flocks, one of them being resistant to all anthelmintic families, including long-acting moxidectin. Comparing the evolution of AR in the last decade, between 1999 and 2011, the level of resistance to BZs and MLs was fairly constant throughout the time by means of the FECRT. However, the resistance to LEV increased significantly in only one decade since during the period 1999-2003 the percentage was 38.5%. The AR status was also measured by in vitro techniques in those flocks with an egg output lower than 150 epg. The prevalence of AR to BZs reached the 35.3% by Egg Hatch Assay. However, the level of resistance reported for LEV and IVM was 61.5% and 23.5%, respectively, by using the Larval Feeding Inhibition Assay, percentages very similar to those reported with the FECRT. PMID- 22947247 TI - Rapid identification and differentiation of Theileria sergenti and Theileria sinensis using a loop-mediated isothermal amplification (LAMP) assay. AB - The present study developed and validated a species-specific loop-mediated isothermal amplification (LAMP) assay for the rapid detection and discrimination of two benign bovine Theileria species -T. sergenti and T. sinensis. The LAMP assay is inexpensive and easy to perform and involves a rapid reaction-the amplification can be performed in 55 min or 50 min under isothermal conditions of 61 degrees C or 63 degrees C, respectively, by employing a set of four species specific primer mixtures. The results can be checked using agarose gels. The optimal assay conditions, under which the assay exhibited with no cross-reaction with other closely related tick-borne parasites (T. annulata, Babesia bovis, B. bigemina, B. major, B. ovata, B. U. sp., Anaplasma marginale) or between the two Theileria species of interest, was established. The assay is approximately 10 fold more sensitive than the conventional specific PCR assay. The LAMP assay was validated using DNA from 6 standard stocks in the laboratory and was evaluated for its diagnostic utility using blood samples collected from experimentally and naturally infection cattle or yaks in China. These findings indicate that this Theileria species-specific LAMP assay may have potential clinical applications for the detection and differentiation of two benign bovine Theileria species -T. sergenti and T. sinensis, especially in endemic countries. PMID- 22947248 TI - Rho-kinase mediates diphosphorylation of myosin regulatory light chain in cultured uterine, but not vascular smooth muscle cells. AB - Phosphorylation of myosin regulatory light chain (RLC) triggers contraction in smooth muscle myocytes. Dephosphorylation of phosphorylated RLC (pRLC) is mediated by myosin RLC phosphatase (MLCP), which is negatively regulated by rho associated kinase (ROK). We have compared basal and stimulated concentrations of pRLC in myocytes from human coronary artery (hVM), which has a tonic contractile pattern to myocytes from human uterus (hUM), which has a phasic contractile pattern. Our studies reveal fundamental differences between hVM and hUM regarding the mechanisms regulating phosphorylation RLC. Whereas hVM responded to stimulation by phosphorylation of RLC at S19, hUM responded by forming diphosphorylated RLC (at T18 and S19; ppRLC), which, compared to pRLC, causes two to threefold greater activation of myosin ATPase that provides energy to power the contraction. Importantly, the conversion of pRLC to ppRLC is mediated by ROK. In hUM, MLCP has high activity for ppRLC and this is inhibited by ROK through phosphorylation of the substrate targeting subunit (MYPT1) at T853. Inhibitors of ROK significantly reduce contractility in both hVM and hUM. We demonstrated that inhibition of ppRLC in phasic myocytes (hUM) is 100-fold more sensitive to ROK inhibitors than is pRLC in tonic myocytes (hVM). We speculate that these differences in phosphorylation of RLC might reflect evolution of different contractile patterns to perform distinct physiological functions. Furthermore, our data suggest that low concentrations of ROK inhibitors might inhibit uterine contractions with minimal effects on vascular tone, thus posing a novel strategy for prevention or treatment of conditions such as preterm birth. PMID- 22947249 TI - Immunoprotective effects of oral intake of heat-killed Lactobacillus pentosus strain b240 in elderly adults: a randomised, double-blind, placebo-controlled trial. AB - Oral intake of Lactobacillus pentosus strain b240 (b240) has been shown to enhance the secretion of salivary secretory IgA in elderly adults. However, its clinical benefits remain to be determined. We tested the hypothesis that b240 exerts a protective effect against the common cold in elderly adults. The design of the present study was a randomised, double-blind, placebo-controlled trial (RCT) with parallel three-group comparison. For this purpose, 300 eligible elderly adults were randomly allocated to one of three groups, namely a placebo, low-dose or high-dose b240 group. Participants in the low-dose and high-dose b240 groups were given tablets containing 2 * 10(9) or 2 * 10(10) cells, respectively, of heat-killed b240, while those in the placebo group were given tablets without b240. Each group consumed their respective tablets once daily for 20 weeks. The common cold was assessed on the basis of a diary. Change in quality of life was evaluated using the SF-36. Of the total participants, 280 completed the 20-week RCT. The accumulated incidence rate of the common cold was 47.3, 34.8 and 29.0 % for the placebo, low-dose b240 and high-dose b240 groups, respectively (P for trend = 0.012). Lower incidence rates were consistently observed throughout the experimental period in the b240 groups (log-rank test, P= 0.034). General health perception, as determined by the SF-36(r), dose-dependently increased in the b240 groups ( P <0.025). In conclusion, oral intake of b240 significantly reduced the incidence rate of the common cold in elderly adults, indicating that b240 might be useful in improving resistance against infection through mucosal immunity. PMID- 22947250 TI - Advances with vaccination against Neisseria meningitidis. AB - In the last decade, meningococcal serogroup C conjugate vaccination programs have been demonstrated to be hugely successful with a truly impressive public health impact. In sub-Saharan Africa, with the implementation of an affordable serogroup A conjugate vaccine, it is hoped that a similar public health impact will be demonstrated. Challenges still remain in the quest to develop and implement broadly protective vaccines against serogroup B disease. New, broad coverage vaccines against serogroup B are for the first time becoming available although little is known about their antibody persistence, effectiveness or effect on nasopharyngeal carriage. Enhanced surveillance following any potential vaccine introduction against serogroup B needs to be thoroughly implemented. The future now holds a distinct possibility, globally, for substantially decreasing meningococcal disease, regardless of infecting serogroup. PMID- 22947251 TI - Nuclear medicine technologists are able to accurately determine when a myocardial perfusion rest study is necessary. AB - BACKGROUND: In myocardial perfusion scintigraphy (MPS), typically a stress and a rest study is performed. If the stress study is considered normal, there is no need for a subsequent rest study. The aim of the study was to determine whether nuclear medicine technologists are able to assess the necessity of a rest study. METHODS: Gated MPS using a 2-day 99mTc protocol for 121 consecutive patients were studied. Visual interpretation by 3 physicians was used as gold standard for determining the need for a rest study based on the stress images. All nuclear medicine technologists performing MPS had to review 82 training cases of stress MPS images with comments regarding the need for rest studies, and thereafter a test consisting of 20 stress MPS images. After passing this test, the nuclear medicine technologists in charge of a stress MPS study assessed whether a rest study was needed or not or if he/she was uncertain and wanted to consult a physician. After that, the physician in charge interpreted the images and decided whether a rest study was required or not. RESULTS: The nuclear medicine technologists and the physicians in clinical routine agreed in 103 of the 107 cases (96%) for which the technologists felt certain regarding the need for a rest study. In the remaining 14 cases the technologists were uncertain, i.e. wanted to consult a physician. The agreement between the technologists and the physicians in clinical routine was very good, resulting in a kappa value of 0.92. There was no statistically significant difference in the evaluations made by technicians and physicians (P = 0.617). CONCLUSIONS: The nuclear medicine technologists were able to accurately determine whether a rest study was necessary. There was very good agreement between nuclear medicine technologists and physicians in the assessment of the need for a rest study. If the technologists can make this decision, the effectiveness of the nuclear medicine department will improve. PMID- 22947252 TI - Determination of carcinoembryonic antigen and cancer antigen (CA 15-3) in bitches with tumours on mammary gland: preliminary report. AB - The aim of this work was to determine levels of carcinoembryonic antigen (CEA) and cancer antigen (CA 15-3) in the blood serum of 45 bitches. A modified procedure was used to determine the CEA and CA 15-3 markers with the human kits using the radioimmunoassay method. Samples collected from extirpated tumour of mammary glands were histologically processed and classified as per WHO guidelines. The average age of animals with tumour was 10.00 +/- 2.2 years; for healthy bitches average age was 4.2 +/- 3.2 years. Values of CEA and CA 15-3 were considered positive, if they exceeded 0.23 ng mL(-1) and 7 IU mL(-1) , respectively. Average levels of CEA in the tumour group were 0.25 +/- 0.06 versus 0.20 +/- 0.03 in healthy bitches (P = 0.0001). The average CA 15-3 value in bitches with tumour was 8.58 +/- 1.27 versus 5.14 +/- 1.34 in healthy animals (P < 0.0001). PMID- 22947253 TI - TGFbeta signalling plays an important role in IL4-induced alternative activation of microglia. AB - BACKGROUND: Microglia are the resident immune cells of the central nervous system and are accepted to be involved in a variety of neurodegenerative diseases. Several studies have demonstrated that microglia, like peripheral macrophages, exhibit two entirely different functional activation states, referred to as classical (M1) and alternative (M2) activation. TGFbeta is one of the most important anti-inflammatory cytokines and its effect on inhibiting microglia or macrophage classical activation has been extensively studied. However, the role of TGFbeta during alternative activation of microglia has not been described yet. METHODS: To investigate the role of TGFbeta in IL4-induced microglia alternative activation, both, BV2 as well as primary microglia from new born C57BL/6 mice were used. Quantitative RT-PCR and western blots were performed to detect mRNA and protein levels of the alternative activation markers Arginase1 (Arg1) and Chitinase 3-like 3 (Ym1) after treatment with IL4, TGFbeta or both. Endogenous TGFbeta release after IL4 treatment was evaluated using the mink lung epithelial cell (MLEC) assay and a direct TGFbeta2 ELISA. TGFbeta receptor type I inhibitor and MAPK inhibitor were applied to address the involvement of TGFbeta signalling and MAPK signalling in IL4-induced alternative activation of microglia. RESULTS: TGFbeta enhances IL4-induced microglia alternative activation by strongly increasing the expression of Arg1 and Ym1. This synergistic effect on Arg1 induction is almost completely blocked by the application of the MAPK inhibitor, PD98059. Further, treatment of primary microglia with IL4 increased the expression and secretion of TGFbeta2, suggesting an involvement of endogenous TGFbeta in IL4-mediated microglia activation process. Moreover, IL4-mediated induction of Arg1 and Ym1 is impaired after blocking the TGFbeta receptor I indicating that IL4-induced microglia alternative activation is dependent on active TGFbeta signalling. Interestingly, treatment of primary microglia with TGFbeta alone results in up regulation of the IL4 receptor alpha, indicating that TGFbeta increases the sensitivity of microglia for IL4 signals. CONCLUSIONS: Taken together, our data reveal a new role for TGFbeta during IL4-induced alternative activation of microglia and consolidate the essential functions of TGFbeta as an anti-inflammatory molecule and immunoregulatory factor for microglia. PMID- 22947254 TI - Estimation methods with ordered exposure subject to measurement error and missingness in semi-ecological design. AB - BACKGROUND: In epidemiological studies, it is often not possible to measure accurately exposures of participants even if their response variable can be measured without error. When there are several groups of subjects, occupational epidemiologists employ group-based strategy (GBS) for exposure assessment to reduce bias due to measurement errors: individuals of a group/job within study sample are assigned commonly to the sample mean of exposure measurements from their group in evaluating the effect of exposure on the response. Therefore, exposure is estimated on an ecological level while health outcomes are ascertained for each subject. Such study design leads to negligible bias in risk estimates when group means are estimated from 'large' samples. However, in many cases, only a small number of observations are available to estimate the group means, and this causes bias in the observed exposure-disease association. Also, the analysis in a semi-ecological design may involve exposure data with the majority missing and the rest observed with measurement errors and complete response data collected with ascertainment. METHODS: In workplaces groups/jobs are naturally ordered and this could be incorporated in estimation procedure by constrained estimation methods together with the expectation and maximization (EM) algorithms for regression models having measurement error and missing values. Four methods were compared by a simulation study: naive complete-case analysis, GBS, the constrained GBS (CGBS), and the constrained expectation and maximization (CEM). We illustrated the methods in the analysis of decline in lung function due to exposures to carbon black. RESULTS: Naive and GBS approaches were shown to be inadequate when the number of exposure measurements is too small to accurately estimate group means. The CEM method appears to be best among them when within each exposure group at least a 'moderate' number of individuals have their exposures observed with error. However, compared with CEM, CGBS is easier to implement and has more desirable bias-reducing properties in the presence of substantial proportions of missing exposure data. CONCLUSION: The CGBS approach could be useful for estimating exposure-disease association in semi-ecological studies when the true group means are ordered and the number of measured exposures in each group is small. These findings have important implication for cost-effective design of semi-ecological studies because they enable investigators to more reliably estimate exposure-disease associations with smaller exposure measurement campaign than with the analytical methods that were historically employed. PMID- 22947255 TI - Conductive-diamond electrochemical oxidation of chlorpyrifos in wastewater and identification of its main degradation products by LC-TOFMS. AB - The electrochemical transformation of the organophosphorous insecticide chlorpyrifos (CPF) was investigated in wastewater. The oxidation of CPF was carried out in a single-compartment electrochemical flow cell working under batch operation mode, using diamond-based material as anode and stainless steel as cathode. In order to evaluate its persistence and degradation pathway, two different concentration levels (1.0 mg L(-1) and 0.1 mg L(-1)) were studied. Liquid chromatography/mass spectrometry was used for evaluation of the initial and electrolyzed solutions. The identification of CPF transformation products was performed by liquid chromatography-time of flight-mass spectrometry (LC-TOFMS). Results showed that CPF is completely removed at the end of treatment time. Analysis by LC-TOFMS allowed the identification of six degradation products (with Mw 154, 170, 197, 305 321 and 333). Three of the identified intermediates (Mw 170, 305 and 321) were completely removed at the end of electrolysis time. Interestingly, the formation of diethyl 3,5,6-trichloropyridin-2yl phosphate (chlorpyrifos oxon) and 3,5,6-trichloropyridin-2-ol was also found in previous reported degradation pathways using different degradation technologies. PMID- 22947256 TI - Mineralization and deflourization of 2,2,3,3-tetrafluoro-1-propanol (TFP) by UV/persulfate oxidation and sequential adsorption. AB - This work demonstrates the combination of UV/persulfate and adsorption processes for treating 2,2,3,3-tetrafluoro-1-propanol (TFP) wastewater. Under the optimum conditions, 20mM persulfate (S(2)O(8)(2-)), 254 nm UV-C, and pH 3, 99.7% of TOC removal from an initial TFP solution of 1.39 mM was achieved. The photolysis of persulfate (S(2)O(8)(2-)) by UV irradiation yielded the sulfate radical (SO(4)( )) with high activity, which mineralized most of the TFP in 2h. The released fluoride ions were then removed by using a waste iron oxide, BT-4 adsorbent. 20 g L(-1) BT-4 adsorbed 95% of the fluoride that was produced by mineralization of 1.39 mM TFP. The kinetics and isotherms of adsorption were examined to determine the fluoride removal efficiency of BT-4 which co-existed with the sulfate ions from the consumed sulfate radicals. Accordingly, the kinetics of adsorption was described by a pseudo-second-order rate model, while the adsorption isotherms were well fitted with the Langmuir model. BT-4 had a high adsorption capacity of 26.4 mg g(-1) (25 degrees C) in removing the fluoride from TFP mineralization, suggesting that the co-existing sulfate ions never significantly affected the fluoride removal efficiency. PMID- 22947257 TI - The medicalisation of health inequalities and the English NHS: the role of resource allocation. AB - Tackling health inequalities (HI) has become a key policy objective in England in recent years. Yet, despite the wide-ranging policy response of the 1997-2010 Labour Government, socio-economic variations in health continued to widen. In this paper, we seek to explore why. We propose that a meta-narrative has emerged in which the health problems facing England's most deprived areas, and the solution to those problems, have increasingly come to be linked to levels of National Health Service (NHS) funding. This has been, in part, a response to key shortcomings in previous rounds of resource allocation. The very significant sums of money allocated with respect to 'health inequalities' reflects and reinforces the belief that the NHS can and should play a central role in promoting health equity. This medicalisation of HI focuses attention on the role of individual risk factors that lend themselves to medical management, but effectively sidelines the macroprocesses of social inequality, legitimising the kind of society that neo-liberal government has produced in the United Kingdom - one in which health (like other assets) has become a matter of individual and not collective responsibility. PMID- 22947258 TI - Goal relevance and goal conduciveness appraisals lead to differential autonomic reactivity in emotional responding to performance feedback. AB - Using an appraisal framework, the present experiment tested the hypothesis that goal relevance and goal conduciveness have an interactive effect on emotional responding. We expected that elicitation of positive or negative emotions in response to events that are conducive or obstructive to attainment of one's goals depends on the level of goal relevance. To test this hypothesis, we presented 119 participants with positive (success) or negative (failure) performance feedback of high or low relevance in an achievement context. Feeling self-report showed effects of conduciveness, but no interaction with relevance. Physiological reactivity showed the predicted interaction effect on cardiac autonomic regulation (CAR), with higher CAR for high-relevance conducive than obstructive conditions. Moreover, mean arterial pressure (MAP) and skin conductance level (SCL) differed between conducive and obstructive conditions, and heart rate (HR) and SCL differed between relevance conditions. Implications for the plausibility and current empirical support of the interaction hypothesis are discussed. PMID- 22947259 TI - Is variety always the spice of life? PMID- 22947260 TI - Appropriate documentation of confirmation of endotracheal tube position and relationship to patient outcome from in-hospital cardiac arrest. AB - OBJECTIVES: To determine the rate of appropriate documentation of endotracheal tube (ET) position confirmation in the American Heart Association's Get With the Guidelines-Resuscitation (GWTG-R) and to determine whether outcomes of patients who experience in-hospital cardiac arrest differ in relation to documentation rate. DESIGN: Analysis of data from the GWTG-R, a prospective observational registry of in-hospital cardiac arrest and resuscitation. SETTING: Database containing clinical information from the 507 hospitals participating in the GWTG R. PATIENTS: Adults resuscitated after in-hospital cardiac arrest. MEASUREMENTS: The rate of appropriate documentation of ET position confirmation, defined as the use of capnography or an esophageal detector device (EDD); relationship between appropriate documentation of ET position confirmation and return of spontaneous circulation (ROSC) or survival to hospital discharge. Proportions with 95% CI are reported for prevalence data. Binary logistic regression was used to determine the relationship between appropriate documentation of ET position confirmation and outcome (ROSC, survival to hospital discharge). Adjusted and unadjusted odds ratios are reported. MAIN RESULTS: Of the 176,054 patients entered into the GWTG R database, 75,777 had an ET placed. For 13,263 (17.5%) of these patients, ET position confirmation was not documented in the chart. Auscultation alone was documented in 19,480 (25.7%) cases. Confirmation of ET position by capnography or EDD was documented in 43,034 (56.8%) cases. ROSC occurred in 39,063 (51.6%), and 13,474 (17.8%) survived to discharge. Patients whose ET position was confirmed by capnography or EDD were more likely to have ROSC (adjusted OR 1.229 [1.179, 1.282]) and to survive to hospital discharge (adjusted OR 1.093 [1.033, 1.157]). CONCLUSION: Documentation of ET position confirmation in patients who experience cardiac arrest is suboptimal. Appropriate documentation of ET position confirmation in the GWTG-R is associated with greater likelihood of ROSC and survival to hospital discharge. PMID- 22947261 TI - Chest compression-only cardiopulmonary resuscitation performed by lay rescuers for adult out-of-hospital cardiac arrest due to non-cardiac aetiologies. AB - OBJECTIVE: Bystander CPR improves survival in patients with out-of-hospital cardiac arrest (OHCA). For adult sudden collapse, bystander chest compression only CPR (COCPR) is recommended in some circumstances by the American Heart Association and European Resuscitation Council. However, adults who arrest from non-cardiac causes may also receive COCPR. Because rescue breathing may be more important for individuals suffering OHCA secondary to non-cardiac causes, COCPR is not recommended for these cases. We evaluated the relationship of lay rescuer COCPR and survival after OHCA from non-cardiac causes. METHODS: Analysis of a statewide Utstein-style registry of adult OHCA, during a large scale campaign endorsing COCPR for OHCA from presumed cardiac cause. The relationship between lay rescuer CPR (both conventional CPR and COCPR) and survival to hospital discharge was evaluated. RESULTS: Presumed non-cardiac aetiologies of OHCA accounted for 15% of all cases, and lay rescuer CPR was provided in 29% of these cases. Survival to hospital discharge occurred in 3.8% after conventional CPR, 2.7% after COCPR, and 4.0% after no CPR (p=0.85). The proportion of patients receiving COCPR was much lower in the cohort of OHCA from respiratory causes (8.3%) than for those with presumed cardiac OHCA (18.0%; p<0.001). CONCLUSIONS: In the setting of a campaign endorsing lay rescuer COCPR for cardiac OHCA, bystanders were less likely to perform COCPR on OHCA victims who might benefit from rescue breathing. PMID- 22947262 TI - The Constructor: a web application optimizing cloning strategies based on modules from the registry of standard biological parts. AB - Synthetic biology is an emerging field that combines molecular biology with engineering principles, which requires abstraction levels applied to a modular biological componentry. The Registry of Standard Biological Parts harbours such a repository of standardized parts, and thereby facilitates the combination of complex molecular modules to novel genetic circuits and devices. However, since finding the best parts for a pre-determined genetic design can be time consuming, we devised the Constructor, a web tool that recommends the smallest number of cloning steps for pre-designed circuits, and implements user-defined quality checks.We present the Constructor ( http://www.systemsbiology.nl/the_constructor) as a constructive web tool that simplifies the in silico assembly of pre-designed gene circuitries from standard parts, reducing both planning and subsequent cloning time. PMID- 22947263 TI - Association study between vitamin d receptor gene polymorphisms and patients with Parkinson disease in Chinese Han population. AB - Vitamin D and vitamin D receptor (VDR) have been postulated as environmental and genetic factors in neurodegenerative disorders including multiple sclerosis, Alzheimer disease, and recently Parkinson disease (PD). The purpose of this study is to explore the potential correlation between single nucleotide polymorphisms of the VDR gene (VDR) rs4334089 and rs731236 and PD. A total of 483 patients with PD and 498 age- and sex-matched controls were involved in this study. Genotypes were determined by using polymerase chain reaction-restriction fragment length polymorphism and DNA sequencing. There were no significant differences in the genotype and allele frequencies of VDR rs4334089 and rs731236 polymorphisms between the group of patients with PD and the control group in a Chinese Han population (for VDR rs4334089: OR 1.02, 95% CI: 0.85-1.23; for VDR rs731236: OR 1.13, 95% CI: 0.75-1.71). Similarly, there were still no differences when stratifying by age or by gender. These findings suggest that VDR gene is not a susceptibility gene for PD in our population. PMID- 22947264 TI - Conditional neural knockout of the adenosine A(2A) receptor and pharmacological A(2A) antagonism reduce pilocarpine-induced tremulous jaw movements: studies with a mouse model of parkinsonian tremor. AB - Tremulous jaw movements are rapid vertical deflections of the lower jaw that resemble chewing but are not directed at any particular stimulus. In rats, tremulous jaw movements can be induced by a number of conditions that parallel those seen in human parkinsonism, including dopamine depletion, dopamine antagonism, and cholinomimetic drugs. Moreover, tremulous jaw movements in rats can be attenuated using antiparkinsonian agents such as L-DOPA, dopamine agonists, muscarinic antagonists, and adenosine A(2A) antagonists. In the present studies, a mouse model of tremulous jaw movements was established to investigate the effects of adenosine A(2A) antagonism, and a conditional neuronal knockout of adenosine A(2A) receptors, on cholinomimetic-induced tremulous jaw movements. The muscarinic agonist pilocarpine significantly induced tremulous jaw movements in a dose-dependent manner (0.25-1.0mg/kg IP). These movements occurred largely in the 3-7.5 Hz local frequency range. Administration of the adenosine A(2A) antagonist MSX-3 (2.5-10.0 mg/kg IP) significantly attenuated pilocarpine-induced tremulous jaw movements. Furthermore, adenosine A(2A) receptor knockout mice showed a significant reduction in pilocarpine-induced tremulous jaw movements compared to littermate controls. These results demonstrate the feasibility of using the tremulous jaw movement model in mice, and indicate that adenosine A(2A) receptor antagonism and deletion are capable of reducing cholinomimetic-induced tremulous jaw movements in mice. Future studies should investigate the effects of additional genetic manipulations using the mouse tremulous jaw movement model. PMID- 22947265 TI - Supporting meningitis diagnosis amongst infants and children through the use of fuzzy cognitive mapping. AB - BACKGROUND: Meningitis is characterized by an inflammation of the meninges, or the membranes surrounding the brain and spinal cord. Early diagnosis and treatment is crucial for a positive outcome, yet identifying meningitis is a complex process involving an array of signs and symptoms and multiple causal factors which require novel solutions to support clinical decision-making. In this work, we explore the potential of fuzzy cognitive map to assist in the modeling of meningitis, as a support tool for physicians in the accurate diagnosis and treatment of the condition. METHODS: Fuzzy cognitive mapping (FCM) is a method for analysing and depicting human perception of a given system. FCM facilitates the development of a conceptual model which is not limited by exact values and measurements and thus is well suited to representing relatively unstructured knowledge and associations expressed in imprecise terms. A team of doctors (physicians), comprising four paediatricians, was formed to define the multifarious signs and symptoms associated with meningitis and to identify risk factors integral to its causality, as indicators used by clinicians to identify the presence or absence of meningitis in patients. The FCM model, consisting of 20 concept nodes, has been designed by the team of paediatricians in collaborative dialogue with the research team. RESULTS: The paediatricians were supplied with a form containing various input parameters to be completed at the time of diagnosing meningitis among infants and children. The paediatricians provided information on a total of 56 patient cases amongst children whose age ranged from 2 months to 7 years. The physicians' decision to diagnose meningitis was available for each individual case which was used as the outcome measure for evaluating the model. The FCM was trained using 40 cases with an accuracy of 95%, and later 16 test cases were used to analyze the accuracy and reliability of the model. The system produced the results with sensitivity of 83.3% and specificity of 80%. CONCLUSIONS: This work suggests that the application and development of a knowledge based system, using the formalization of FCMs for understanding the symptoms and causes of meningitis in children and infants, can provide a reliable front-end decision-making tool to better assist physicians. PMID- 22947266 TI - Characterization of the tissue-level Ca2+ signals in spontaneously contracting human myometrium. AB - In the labouring uterus, millions of myocytes forming the complex geometrical structure of myometrium contract in synchrony to increase intrauterine pressure, dilate the cervix and eventually expel the foetus through the birth canal. The mechanisms underlying the precise coordination of contractions in human myometrium are not completely understood. In the present study, we have characterized the spatio-temporal properties of tissue-level [Ca(2+)](i) transients in thin slices of intact human myometrium. We found that the waveform of [Ca(2+)](i) transients and isotonic contractions recorded from thin slices was similar to the waveform of isometric contractions recorded from the larger strips in traditional organ bath experiments, suggesting that the spatio-temporal information obtained from thin slices is representative of the whole tissue. By comparing the time course of [Ca(2+)](i) transients in individual cells to that recorded from the bundles of myocytes we found that the majority of myocytes produce rapidly propagating long-lasting [Ca(2+)](i) transients accompanied by contractions. We also found a small number of cells showing desynchronized [Ca(2+)](i) oscillations that did not trigger contractions. The [Ca(2+)](i) oscillations in these cells were insensitive to nifedipine, but readily inhibited by the T-type Ca(2+) channel inhibitor NNC55-0396. In conclusion, our data suggest that the spread of [Ca(2+)](i) signals in human myometrium is achieved via propagation of long-lasting action potentials. The propagation was fast when action potentials propagated along bundles of myocytes and slower when propagating between the bundles of uterine myocytes. PMID- 22947267 TI - Role of paediatric intensive care following adenotonsillectomy for severe obstructive sleep apnoea: criteria for elective admission. AB - AIMS: This study aimed to critically review our criteria for elective admission to the paediatric intensive care unit following adenotonsillectomy for obstructive sleep apnoea. MATERIALS AND METHODS: We reviewed 122 children electively admitted between 1997 and 2011. During this time, our criteria for admission evolved. RESULTS: In these 122 children, the respiratory disturbance index during rapid eye movement sleep ranged from 6 to 159 (mean, 83). Forty-one per cent of the children had a recognised co-morbidity. Nine children required extra intervention, i.e. in addition to re-positioning and/or supplemental oxygen. One child was an unplanned re-admission after discharge from the paediatric intensive care unit. Over the same period, five children required unplanned transfers into the paediatric intensive care unit following adenotonsillectomy for sleep-disordered breathing. CONCLUSION: Based upon these results, we describe our current criteria for elective admission to the paediatric intensive care unit following adenotonsillectomy for severe obstructive sleep apnoea. PMID- 22947268 TI - Seronegative anti-hepatitis C virus antibody in hemodialysis patients. PMID- 22947269 TI - Randomized controlled trial on cardiovascular risk management by practice nurses supported by self-monitoring in primary care. AB - BACKGROUND: Treatment goals for cardiovascular risk management are generally not achieved. Specialized practice nurses are increasingly facilitating the work of general practitioners and self-monitoring devices have been developed as counseling aid. The aim of this study was to compare standard treatment supported by self-monitoring with standard treatment without self-monitoring, both conducted by practice nurses, on cardiovascular risk and separate risk factors. METHODS: Men aged 50-75 years and women aged 55-75 years without a history of cardiovascular disease or diabetes, but with a SCORE 10-year risk of cardiovascular mortality >= 5% and at least one treatable risk factor (smoking, hypertension, lack of physical activity or overweight), were randomized into two groups. The control group received standard treatment according to guidelines, the intervention group additionally received pro-active counseling and self monitoring (pedometer, weighing scale and/ or blood pressure device). After one year treatment effect on 179 participants was analyzed. RESULTS: SCORE risk assessment decreased 1.6% (95% CI 1.0-2.2) for the control group and 1.8% (1.2 2.4) for the intervention group, difference between groups was .2% (-.6-1.1). Most risk factors tended to improve in both groups. The number of visits was higher and visits took more time in the intervention group (4.9 (SD2.2) vs. 2.6 (SD1.5) visits p< .001 and 27 (P25 -P75:20-33) vs. 23 (P25 -P75:19-30) minutes/visit p= .048). CONCLUSIONS: In both groups cardiovascular risk decreased significantly after one year of treatment by practice nurses. No additional effect of basing the pro-active counseling on self-monitoring was found, despite the extra time investment. TRIAL REGISTRATION: trialregister.nl NTR2188. PMID- 22947270 TI - Epidemiological, molecular and clinical features of enterovirus 109 infection in children and in adult stem cell transplant recipients. AB - BACKGROUND: A novel human enterovirus (HEV) type within the species HEV-C, named EV109, was discovered from cases of respiratory illness in Nicaragua in September 2010. The aim of this study, was to retrospectively examine the presence and the role of EV109 in respiratory samples from two patients populations; infants below the age of 2 years, hospitalized for acute respiratory diseases (ARDs) and adult hematopoietic stem cell transplantation recipients. RESULTS: A total of 1149 nasopharingeal aspirates were collected and tested for the presence of EV109 by reverse transcription-PCR (RT-PCR). In positive samples, the presence of the most common respiratory viruses was also assayed and clinical symptoms were evaluated. Samples from 2 of the 974 infants tested positive for EV109 RNA (0.2%) and belonged to patients with lower ARDs; co-infection with other viral pathogens under study was observed in both cases. In transplant recipients, one out of the 175 samples analyzed, from a patients with upper respiratory simptoms tested positive for HEV 109 in the absence of co-infecting viruses. Sequence analysis of amplified EV109 genomic regions, showed only a few nucleotide differences when compared with the Nicaraguan strains. CONCLUSIONS: Overall these results indicate that HEV109 variants have circulated and differentiated in different lineages worldwide. Although more cases and larger studies are needed, HEV109 infection may be associated to ARDs both in infants and in hematopoietic stem cell transplantation recipients. If these preliminary observations will be confirmed, improved molecular methods with a wider panel of potential pathogens will be useful for monitoring these categories of patients. PMID- 22947271 TI - Optimizing adjuvant treatment decisions for stage t2 rectal cancer based on mesorectal node size: a decision analysis. AB - RATIONALE AND OBJECTIVES: The aim of this study was to optimize treatment decisions for patients with suspected stage T2 rectal cancer on the basis of mesorectal lymph node size at magnetic resonance imaging. MATERIALS AND METHODS: A decision-analytic model was developed to predict outcomes for patients with stage T2 rectal cancer at magnetic resonance imaging. Node-positive patients were assumed to benefit from chemoradiation prior to surgery. Imperfect magnetic resonance imaging performance for primary cancer and mesorectal nodal staging was incorporated. Five triage strategies were considered for administering preoperative chemoradiation: treat all patients; treat for any mesorectal node >3, >5, and >7 mm in size; and treat no patients. If nodal metastases or unsuspected stage T3 disease went untreated preoperatively, postoperative chemoradiation was needed, resulting in poorer outcomes. For each strategy, rates of acute and long-term chemoradiation toxicity and of 5-year local recurrence were computed. Effects of input parameter uncertainty were evaluated in sensitivity analysis. RESULTS: The optimal strategy depended on the outcome prioritized. Acute and long-term chemoradiation toxicity rates were minimized by triaging only patients with nodes >7 mm to preoperative chemoradiation (18.9% and 10.8%, respectively). A treat-all strategy minimized the 5-year local recurrence rate (5.6%). A 7-mm nodal triage threshold increased the 5-year local recurrence rate to 8.0%; when no patients were treated preoperatively, the local recurrence rate was 10.1%. With improved primary tumor staging, all outcomes could be further optimized. CONCLUSIONS: Mesorectal nodal size thresholds for preoperative chemoradiation should depend on the outcome prioritized: higher size thresholds reduce chemoradiation toxicity but increase recurrence rates. Improvements in nodal staging will have greater impact if primary tumor staging can be improved. PMID- 22947272 TI - Matrix metalloproteinase-9 (MMP-9) and myeloperoxidase (MPO) levels in patients with nonobstructive coronary artery disease detected by coronary computed tomographic angiography. AB - RATIONALE AND OBJECTIVES: The aim of this study was to evaluate whether matrix metalloproteinase-9 (MMP-9) and myeloperoxidase (MPO) are elevated in patients with nonobstructive coronary artery disease. MATERIALS AND METHODS: Eighty-four patients with nonobstructive coronary artery disease (group A) and 90 patients with no coronary plaques (group B) were enrolled. MMP-9 and MPO levels were compared between the two groups. The relationships between these biomarkers and Framingham risk score were analyzed. Receiver-operating characteristic curves were used to evaluate the ability of these biomarkers to predict the presence of coronary artery plaques. RESULTS: The MMP-9 and MPO values in group A were significantly higher than in group B (P < .001). The levels of MMP-9 and MPO showed significant correlations with Framingham risk score (r = 0.796, P < .001, and r = 0.409, P < .001, respectively). The areas under the receiver-operating characteristic curves for MMP-9 and MPO were 0.80 (95% confidence interval, 0.74 0.87) and 0.74 (95% confidence interval, 0.66-0.81), respectively. CONCLUSIONS: Levels of MMP-9 and MPO are positively correlated with Framingham risk score. Additionally, in patients with nonobstructive coronary artery disease, elevated levels of MMP-9 and MPO may identify patients at risk for future myocardial infarction or sudden cardiac death. PMID- 22947273 TI - Reevaluating the sonographic criteria for acute appendicitis in children: a review of the literature and a retrospective analysis of 246 cases. AB - RATIONALE AND OBJECTIVES: There has been little rigorous evaluation of the sonographic criteria for acute appendicitis in children. Our clinical experience has called the traditional diagnostic criteria into question. We set out to review the literature, evaluate the most commonly applied diagnostic criteria for acute appendicitis, and identify those criteria that best predict the presence of disease. MATERIALS AND METHODS: A critical review of the literature concerning the sonographic diagnosis of acute appendicitis was performed. Based on diagnostic criteria identified in that review, two independent, blinded pediatric radiologists retrospectively reviewed 246 right lower quadrant ultrasound examinations in which the appendix was identified with attention to commonly described diagnostic criteria for acute appendicitis. Multivariate and classification and regression tree analysis were performed to identify criteria that predict appendicitis. RESULTS: In a multivariate analysis, inflammation of the periappendiceal fat is the only finding that statistically significantly predicts acute appendicitis (OR = 68.93, P < .0001). Other criteria such as diameter, noncompressibility, hyperemia, the presence of an appendicolith, and loss of stratification of the appendiceal wall do not independently predict appendicitis. CONCLUSION: Periappendiceal fat infiltration is the most important diagnostic criterion for acute appendicitis in children. Strict application of other criteria such as diameter should be avoided. PMID- 22947275 TI - Mass conserved elementary kinetics is sufficient for the existence of a non equilibrium steady state concentration. AB - Living systems are forced away from thermodynamic equilibrium by exchange of mass and energy with their environment. In order to model a biochemical reaction network in a non-equilibrium state one requires a mathematical formulation to mimic this forcing. We provide a general formulation to force an arbitrary large kinetic model in a manner that is still consistent with the existence of a non equilibrium steady state. We can guarantee the existence of a non-equilibrium steady state assuming only two conditions; that every reaction is mass balanced and that continuous kinetic reaction rate laws never lead to a negative molecule concentration. These conditions can be verified in polynomial time and are flexible enough to permit one to force a system away from equilibrium. With expository biochemical examples we show how reversible, mass balanced perpetual reaction(s), with thermodynamically infeasible kinetic parameters, can be used to perpetually force various kinetic models in a manner consistent with the existence of a steady state. Easily testable existence conditions are foundational for efforts to reliably compute non-equilibrium steady states in genome-scale biochemical kinetic models. PMID- 22947274 TI - Comparison of semi-automatic volumetric VX2 hepatic tumor segmentation from cone beam CT and multi-detector CT with histology in rabbit models. AB - RATIONALE AND OBJECTIVES: The purpose of this study was to compare tumor volume in a VX2 rabbit model as calculated using semiautomatic tumor segmentation from C arm cone-beam computed tomography (CBCT) and multidetector computed tomography (MDCT) to the actual tumor volume. MATERIALS AND METHODS: Twenty VX2 tumors in 20 adult male New Zealand rabbits (one tumor per rabbit) were imaged with CBCT (using an intra-arterial contrast medium injection) and MDCT (using an intravenous contrast injection). All tumor volumes were measured using semiautomatic three-dimensional volumetric segmentation software. The software uses a region-growing method using non-Euclidean radial basis functions. After imaging, the tumors were excised for pathologic volume measurement. The imaging based tumor volume measurements were compared to the pathologic volumes using linear regression, with Pearson's test, and correlated using Bland-Altman analysis. RESULTS: Average tumor volumes were 3.5 +/- 1.6 cm(3) (range, 1.4-7.2 cm(3)) on pathology, 3.8 +/- 1.6 cm(3) (range, 1.3-7.3 cm(3)) on CBCT, and 3.9 +/ 1.6 (range, 1.8-7.5 cm(3)) on MDCT (P < .001). A strong correlation between volumes on pathology and CBCT and also with MDCT was observed (Pearson's correlation coefficient = 0.993 and 0.996, P < .001, for CBCT and MDCT, respectively). Bland-Altman analysis showed that MDCT tended to overestimate tumor volume, and there was stronger agreement for tumor volume between CBCT and pathology than with MDCT, possibly because of the intra-arterial contrast injection. CONCLUSIONS: Tumor volume as measured using semiautomatic tumor segmentation software showed a strong correlation with the "real volume" measured on pathology. The segmentation software on CBCT and MDCT can be a useful tool for volumetric hepatic tumor assessment. PMID- 22947276 TI - Phenotype-genotype relation in Wagner's canalization model. AB - Theoretical works have shed light on the impact of natural selection in shaping phenotypes and genotypes. Wagner's canalization model (Wagner, 1996) is one of the well-established models which describe emergent properties of evolving gene networks. In this paper, we propose a deeper theoretical understanding of this well-studied model and we extend its conclusions by characterizing new emergent properties of evolving networks. We start with the review of the Wagner model and its applications to robustness of gene networks, gene duplication and evolution of sexual reproduction. Then, we perform a mathematical analysis to gain a better understanding of the model evolutionary dynamics. Doing so paves the way to study systematically the impact of mutation rates on compatibility of genotypes, variability of phenotypes and viability of offspring in evolving populations. Finally, we derive new observations concerning two emergent properties concerning evolved genomes robustness. First, we show that selecting for development towards a specific phenotype also contributes to enhance the stability of other alternative phenotypes which can be revealed under stress. Second, we find that this generalized canalization also renders gene networks more robust towards gene deletion, loss of interactions, perturbations of regulation activity and mutations. Therefore, not only evolution selects for individuals robust to types of perturbation they have faced in previous generations, but also robust to types of perturbations they have never experienced. PMID- 22947277 TI - An HIV infection model based on a vectored immunoprophylaxis experiment. AB - A medical experiment published in Nature has shown that humanized mice receiving the vectored immunoprophylaxis can be fully protected from HIV infection. In this paper, a mathematical model is proposed to investigate the viral dynamics under the effect of antibodies in the experiment. It is shown that the introduction of vectored immunoprophylaxis can induce the backward bifurcation and the ignorance of antibodies' loss due to their involvement with virus may result in the loss of backward bifurcation. By numerical simulations, it is found that the model also exhibits some other complicated dynamical behaviors. A subcritical Hopf bifurcation, a fold bifurcation of equilibria and a limit point bifurcation of limit cycles are detected, which induce five typical patterns of dynamical behaviors including the bistable phenomenon. PMID- 22947278 TI - The effects of sibling relationships on social adjustment among Japanese twins compared with singletons. AB - This study examined the link between sibling relationships and children's social adjustment by comparing twin siblings and siblings with different ages (singleton siblings}, and clarified the role of reciprocity in sibling relationships on children's social development. Mothers of 58 monozygotic twin pairs, 48 dizygotic twin pairs, and 86 singleton sibling pairs reported their children's sibling relationships and social adjustment.This study showed that the effects of sibling relationships on the prosocial behaviors and conduct problems of each child are stronger for twins than for singleton siblings. Moreover, positivity toward one's sibling increased peer problems only among monozygotic twins. The opposite tendency was present among dizygotic twins and singleton siblings. This study suggests the importance for children's social development of having many interactions with siblings and establishing reciprocity in sibling relationships. Moreover, our results suggest that the quality of sibling relationships among monozygotic twins may be different from those among dizygotic twins and singleton siblings. PMID- 22947279 TI - Angiogenic activity of subchondral bone during the progression of osteoarthritis in a rabbit anterior cruciate ligament transection model. AB - OBJECTIVE: To investigate the longitudinal angiogenic activity of subchondral bone and cartilage during the progression of osteoarthritis (OA) using a rabbit model of OA. MATERIALS AND METHODS: OA was surgically induced by anterior cruciate ligament transaction (ACLT) in left knee of 12 months old female New Zealand white rabbits (n = 33). Histological examination, immunohistochemistry, and angiogenic activity assay was done at 0, 2, 4, 6, 8, 12 weeks after ACLT. Histologic evaluation was performed with haematoxylin and eosin, safranin-O staining to assess the OA change of medial femoral condyle (MFC) and lateral femoral condyle (LFC). CD31 immunohistochemistry was performed to confirm the vascular invasion at osteochondral junction. A co-cultured tubule formation assay was conducted to evaluate angiogenic activity of the subchondral bone and cartilage of MFC and LFC as well as synovium. Association between histological changes, angiogenic activity, and vascular invasion were evaluated. RESULTS: OA changes increased in a time-dependent manner both in MFC and LFC. Angiogenic activity of subchondral bone showed a monomodal change during the OA progression, achieved a peak in the early to progressive stage and decreased to normal level in the late stage of OA. Surge of vascular invasion was observed following the increase of angiogenic activity in the progressive stage of OA. Angiogenic activity of cartilage did not change during the course of OA progression. CONCLUSION: Angiogenic activity of subchondral bone was elevated in the early to progressive stage of OA and vascular invasion into the osteochondral junction followed. PMID- 22947280 TI - Expression of microRNAs during chondrogenesis of human adipose-derived stem cells. AB - OBJECTIVES: MicroRNAs (miRNAs) play an important role in the regulation of chondrogenesis of mesenchymal stem cells, but their expression still remains unknown in human adipose-derived stem cells (hADSCs). In this study the miRNA expression profile during chondrogenic differentiation of hADSC and the potential mechanism whereby miRNAs may affect the process of chondrogenesis are considered. METHODS: hADSCs were isolated and cultured. The expression of chondrogenic proteins was detected using enzyme-linked immunosorbent assay (ELISA). miRNA expression profiles before and after chondrogenic induction were obtained using miRNA microarray essay and differently expressed miRNAs were primarily verified using quantitative real-time polymerase chain reaction (qRT-PCR). Putative targets of the miRNAs were predicted using online software programs MiRanda, TargetScan and miRBase. RESULTS: Twelve miRNAs were found to be differentially expressed pre- and post-chondrogenic induction by over a two-fold change, including eight up-regulated miRNAs (miR-193b, miR-199a-3p/hsa-miR-199b-3p, miR 455-3p, miR-210, miR-381, miR-92a, miR-320c, and miR-136), and four down regulated miRNAs (miR-490-5p, miR-4287, miR-BART8*, and miR-US25-1*). qRT-PCR analysis further confirmed these results. Predicted target genes of the differentially expressed miRNAs were based on the overlap of at least two online prediction algorithms, with the known functions of regulating chondrogenic differentiation, self-renewal, signal transduction and cell cycle control. CONCLUSIONS: In this study we have identified a group of miRNAs and their target genes, which may play important roles in regulating chondrogenic differentiation of hADSCs. Our results provide the basis for further investigation into the molecular mechanism of chondrogenesis in hADSCs and their differentiation for cartilage engineering. PMID- 22947281 TI - Droplet centrifugation, droplet DNA extraction, and rapid droplet thermocycling for simpler and faster PCR assay using wire-guided manipulations. AB - A computer numerical control (CNC) apparatus was used to perform droplet centrifugation, droplet DNA extraction, and rapid droplet thermocycling on a single superhydrophobic surface and a multi-chambered PCB heater. Droplets were manipulated using "wire-guided" method (a pipette tip was used in this study). This methodology can be easily adapted to existing commercial robotic pipetting system, while demonstrated added capabilities such as vibrational mixing, high speed centrifuging of droplets, simple DNA extraction utilizing the hydrophobicity difference between the tip and the superhydrophobic surface, and rapid thermocycling with a moving droplet, all with wire-guided droplet manipulations on a superhydrophobic surface and a multi-chambered PCB heater (i.e., not on a 96-well plate). Serial dilutions were demonstrated for diluting sample matrix. Centrifuging was demonstrated by rotating a 10 MUL droplet at 2300 round per minute, concentrating E. coli by more than 3-fold within 3 min. DNA extraction was demonstrated from E. coli sample utilizing the disposable pipette tip to cleverly attract the extracted DNA from the droplet residing on a superhydrophobic surface, which took less than 10 min. Following extraction, the 1500 bp sequence of Peptidase D from E. coli was amplified using rapid droplet thermocycling, which took 10 min for 30 cycles. The total assay time was 23 min, including droplet centrifugation, droplet DNA extraction and rapid droplet thermocycling. Evaporation from of 10 MUL droplets was not significant during these procedures, since the longest time exposure to air and the vibrations was less than 5 min (during DNA extraction). The results of these sequentially executed processes were analyzed using gel electrophoresis. Thus, this work demonstrates the adaptability of the system to replace many common laboratory tasks on a single platform (through re-programmability), in rapid succession (using droplets), and with a high level of accuracy and automation. PMID- 22947282 TI - Osteopontin as a two-sided mediator in acute neuroinflammation in rat models. AB - Osteopontin (OPN) plays an important role in the initiation of inflammation, affecting cell adhesion, chemotaxis, immune regulation, and protection against apoptosis, depending on its intracellular or extracellular localization. Although OPN in inflammation of the autoimmune central nervous system is proinflammatory, recent studies have shown that OPN during the induction stage of inflammation may also participate in neuroprotection and neurite growth. The present review examines the dual roles of OPN, specifically, its proinflammatory and subsequent neuroprotective roles, in acute neuroinflammation in rat models, including experimental autoimmune encephalomyelitis, brain injury, and autoimmune neuritis. All of these models are characterized by acute neuroinflammation, followed by remodeling of neural tissues. PMID- 22947284 TI - The perils of the least publishable unit. PMID- 22947283 TI - Immunolocalization and expression of small-conductance calcium-activated potassium channels in human myometrium. AB - Small-conductance calcium-activated potassium (SK3) channels have been detected in human myometrium and we have previously shown a functional role of SK channels in human myometrium in vitro. The aims of this study were to identify the precise localization of SK3 channels and to quantify SK3 mRNA expression in myometrium from pregnant and non-pregnant women. Myometrial biopsies were obtained from pregnant (n = 11) and non-pregnant (n = 11) women. The expression of SK3 channels was assessed using immunohistochemistry and SK3 mRNA was determined by qRT-PCR. In non-pregnant myometrium SK3 immunoreactivity was observed in CD34 positive (CD34(+)) interstitial Cajal-like cells (ICLC), now called telocytes. Although CD34(+) cells were also present in pregnant myometrium, they lacked SK3 immunoreactivity. Furthermore, the immunohistochemical results showed that SK3 expression in vascular endothelium was similar between the two groups. CD117 immunoreactivity was only detected in small round cells that resemble mast cells. Compared to non-pregnant myometrium we found significantly less SK3 mRNA in pregnant myometrium. We demonstrate that SK3 channels are localized solely in CD34(+) cells and not in smooth muscle cells, and that the molecular expression of SK3 channels is higher in non-pregnant compared to pregnant myometrium. On the basis of our previous study and the present findings, we propose that SK3 activators reduce contractility in human myometrium by modulating telocyte function. This is the first report to provide evidence for a possible role of SK3 channels in human uterine telocytes. PMID- 22947285 TI - Corneal collagen cross-linking for keratoconic cornea pretreated with PRK. PMID- 22947286 TI - Stability of epithelial thickness during 5 minutes immersion in 33 degrees C 0.9% saline using very high-frequency digital ultrasound. PMID- 22947287 TI - Comparison of long-term visual outcome and IOL position with a single-optic accommodating IOL After 5.5- or 6.0-mm Femtosecond laser capsulotomy. AB - PURPOSE: To evaluate the long-term visual outcome and intraocular (IOL) position parameters with a single-optic accommodating IOL after 5.5- or 6.0-mm femtosecond laser capsulotomy. METHODS: This prospective, randomized, pilot study comprised 17 eyes from 11 patients (7 men) with a mean age of 65.82+/-10.64 years (range: 51 to 79 years). All patients received a Crystalens AT-50AO (Bausch & Lomb) accommodating IOL after femtosecond laser refractive cataract surgery using either a 5.5-mm capsulotomy (5.5-mm group; 9 eyes) or 6.0-mm capsulotomy (6.0-mm group; 8 eyes). Near and distance visual acuities, manifest refraction spherical equivalent (MRSE), and IOL tilt and decentration were evaluated 1 year postoperatively. RESULTS: No significant differences were noted between groups for postoperative uncorrected distance visual acuity, uncorrected near visual acuity, distance-corrected near visual acuity, and MRSE. Vertical and horizontal tilt were significantly higher in the 6.0-mm group than in the 5.5-mm group (P=.014 and P=.015, respectively). No significant difference was observed between groups regarding IOL decentration. CONCLUSIONS: A 5.5-mm capsulotomy created with a femtosecond laser is associated with less IOL tilt and therefore may be superior to a 6.0-mm capsulotomy when implanting a single-optic accommodating IOL. PMID- 22947288 TI - Correction of undesirable pseudophakic refractive error with the Sulcoflex intraocular lens. AB - PURPOSE: To evaluate the visual outcomes, efficacy, predictability, and short term safety of implanting the Sulcoflex (Rayner Intraocular Lenses Ltd) intraocular lens (IOL) to correct residual pseudophakic errors. METHODS: Retrospective study of patients undergoing implantation of the Sulcoflex IOL. Uncorrected (UDVA) and corrected (CDVA) distance visual acuity and refractive outcomes were evaluated. Postoperative follow-up was at 1 week and 1, 3, 6, and 12 months. RESULTS: Fifteen eyes (13 patients) were evaluated. Mean follow-up was 20 months (range: 14 to 30 months). The Sulcoflex aspheric (653L) and toric (653T) IOLs were implanted in 3 and 12 eyes, respectively. Preoperatively, mean logMAR (Snellen) UDVA and CDVA were 0.44 (20/55) and 0.05 (20/22), respectively. At 3 months, all eyes achieved logMAR UDVA of 0.20 (20/32) or better, with 10 (67%) eyes achieving UDVA of 0 (20/20) or better. Preoperative mean spherical and astigmatic errors were 1.07+/-0.83 diopters (D) and -1.45+/-0.98 D, respectively. Preoperative mean spherical equivalent refraction was -0.54+/-1.11 (D). Postoperative mean sphere and astigmatism at 3 months were -0.25+/-0.38 D and 0.50+/-0.57 D, respectively. Postoperative mean spherical equivalent refraction at 3 months was -0.15+/-0.28 D. All patients were within 1.00 D of attempted correction, with 93% within 0.50 D. Linear regression analysis showed good correlation (R2=0.72) between attempted versus achieved spherical equivalent refractions. No significant intra- or postoperative complications occurred. CONCLUSIONS: Implantation of the Sulcoflex IOL was found to be an effective and predictable option for enhancing postoperative refractive results and reducing spectacle dependence for distance after surgery. The IOL was well tolerated in all eyes. PMID- 22947289 TI - Evaluating the speed of visual recovery following thin-flap LASIK with a femtosecond laser. AB - PURPOSE: To investigate the speed of visual recovery following myopic thin-flap LASIK with a femtosecond laser. METHODS: This pilot study prospectively evaluated 20 eyes from 10 patients who underwent bilateral simultaneous LASIK with the Femto LDV Crystal Line femtosecond laser (Ziemer Ophthalmic Systems AG) used to create a circular flap of 9.0-mm diameter and 110-MUm thickness followed by photoablation with the Allegretto Wave Eye-Q (WaveLight AG) excimer laser. Binocular and monocular uncorrected distance visual acuity (UDVA), monocular contrast sensitivity, and a patient questionnaire were evaluated during the first hours, 1 day, and 1 month postoperatively. RESULTS: For monocular UDVA, 100% of eyes were 20/40 at 1 hour and 100% were 20/25 at 4 hours. For binocular UDVA, all patients achieved 20/32 by 30 minutes and 20/20 by 4 hours. Low frequency contrast sensitivity returned to preoperative baseline by 1 hour (P=.73), and showed a statistically significant improvement over baseline by 4 hours (P=.01). High frequency monocular contrast sensitivity returned to preoperative baseline by 4 hours (P=.48), and showed a statistically significant improvement by 1 month (P=.04). At 2 and 4 hours, 50% and 100% of patients, respectively, indicated that they would feel comfortable driving. CONCLUSIONS: Visual recovery after thin-flap femtosecond LASIK is rapid, occurring within the first few hours after surgery. PMID- 22947290 TI - Effect of hinge position on corneal sensation and dry eye parameters after femtosecond laser-assisted LASIK. AB - PURPOSE: To evaluate the effect of superior- versus nasal-hinged flaps on corneal sensation and dry eye after femtosecond laser-assisted LASIK. METHODS: A total of 43 patients who had undergone bilateral femtosecond laser-assisted LASIK for myopia were evaluated in a prospective, nonrandomized, contralateral eye study to compare the difference between different hinges on corneal sensation and dry eye. Corneal esthesiometry, Schirmer basic tear secretion test (BST), tear break-up time (BUT), ocular surface stainings, and the Ocular Surface Disease Index (OSDI) questionnaire were used to evaluate corneal sensation and dry eye parameters preoperatively as well as at 1 week and 1, 3, and 6 months postoperatively. RESULTS: Corneal sensation decreased significantly in both groups 1 week after surgery (P<.05 in the nasal hinge group; P<.01 in the superior hinge group) and gradually recovered over the first 3 months. No significant change was noted in BUT after surgery in either group (P>.05). Significant increases were noted in BST values at 1 and 3 months (P<.05) and 6 months (P<.01) postoperatively in both groups. Corneal fluorescein staining increased significantly in both groups at 1 week (P<.01) and returned to baseline by 6 months. Conjunctival Rose Bengal staining decreased significantly by 6 months in the superior hinge group only (P<.05). The OSDI significantly increased 1 week after surgery (P<.01) and did not completely return to baseline by 6 months postoperatively in either group (P<.05). No significant differences were noted in any of the parameters between groups at any time point (P>.05). CONCLUSIONS: Hinge position had no significant effect on corneal sensation or dry eye parameters. Aggressive dry eye regimens are needed for patients with preoperative dry eye. PMID- 22947291 TI - Comparison of Tear cytokines and clinical outcomes between off-flap and on-flap epi-LASIK with mitomycin C. AB - PURPOSE: To compare tear cytokines and clinical outcomes between off-flap and on flap epi-LASIK eyes and explore the possible mechanism for the clinical differences. METHODS: This double-masked, randomized study enrolled 18 myopic patients who underwent off-flap epi-LASIK with mitomycin C (MMC) in 1 eye and on flap epi-LASIK with MMC in the contralateral eye. Tears were collected from each eye preoperatively and 2 hours, 1 day, and 5 days postoperatively. Concentrations of multiple tear cytokines were measured by a multiplex immunobead assay. Uncorrected distance visual acuity (UDVA), refraction, haze scores, pain scores, and percentage of corneal epithelial healing were evaluated. RESULTS: Compared with the on-flap group, the off-flap group had outcomes of better UDVA and higher percentages of epithelial healing at 5 days after surgery (P<.001) and lower levels of haze at 1 month after surgery (P=.049). Preoperatively, no significant differences were noted in the release rate of all tear cytokines between groups. At 2 hours postoperatively, the release rate of tear basic fibroblast growth factor (bFGF), platelet-derived growth factor-BB (PDGF-BB), interleukin-8 (IL-8), and tumor necrosis factor alpha (TNF-alpha) in the off-flap group were significantly lower than those in the on-flap group (P=.011, .017, .048, and .041, respectively). CONCLUSIONS: Off-flap epi-LASIK with MMC offers faster corneal epithelial healing and visual recovery, and temporary less haze than on flap epi-LASIK with MMC. The lower tear levels of bFGF, PDGF-BB, IL-8, and TNF alpha in the offflap group 2 hours after surgery may suggest a possible mechanism for the clinical differences. PMID- 22947292 TI - Initial surface temperature of PMMA plates used for daily laser calibration affects the predictability of corneal refractive surgery. AB - PURPOSE: To investigate the relevance of initial temperature of the polymethylmethacrylate (PMMA) plates used as a target for photoablation during calibration of excimer lasers performed in daily clinical routine. METHODS: An experimental argon fluoride excimer laser with a repetition rate of 1050 Hz, a radiant exposure of 500 mJ/cm2, and single pulse energy of 2.1 mJ was used for photoablation of PMMA plates. The initial plate temperature varied from 10.1 degrees C to 75.7 degrees C. The initial temperature was measured with an infrared camera and the central ablation depth of a myopic ablation of -9.00 diopters (D) with an optical zone of 6.5 mm was measured by means of a surface profiling system. RESULTS: The ablation depth increased linearly from 73.9 to 96.3 MUm within a temperature increase from 10.1 degrees C to 75.7 degrees C (increase rate of 0.3192 MUm/K). The linear correlation was found to be significant (P<.05) with a coefficient of determination of R2=0.95. Based on these results and assuming a standard room temperature of 20 degrees C, optimal plate temperature was calculated to be 15 degrees C to 25 degrees C to maintain an ablation within 0.25 D. CONCLUSIONS: The temperature of PMMA plates for clinical laser calibration should be controlled ideally within a range of approximately +/-5 degrees C, to avoid visually significant refractive error due to calibration error. Further experimental investigations are required to determine the influence of different initial corneal temperatures on the refractive outcome. PMID- 22947293 TI - Corneal changes in progressive keratoconus after cross-linking assessed by Scheimpflug camera. AB - PURPOSE: To evaluate corneal changes after corneal cross-linking (CXL) in progressive keratoconus with Scheimpflug imaging. METHODS: This prospective analysis included 40 eyes from 22 patients with progressive keratoconus. Corneal CXL was performed in 25 eyes (CXL group) and 15 fellow eyes served as controls (control group). Uncorrected (UDVA) and corrected distance visual acuity (CDVA), thinnest corneal thickness (ThCT), posterior elevation, and Holladay equivalent keratometry values (K1, K2) were determined with Pentacam (Oculus Optikgerate GmbH) before and 1 year after CXL. Area under the receiver operator characteristic (ROC) curve and multivariable general estimating equation models were used to determine the most sensitive parameters of corneal changes. RESULTS: Manifest sphere (-2.55+/-3.21 to -1.48+/-2.39 diopters [D], P=.02), UDVA (0.23+/ 0.25 to 0.31+/-0.25, P<.001), and CDVA (0.58+/-0.28 to 0.72+/-0.19, P=.019) improved significantly in the CXL group. Significant decreases were found in ThCT (472.53+/-33.18 to 440.53+/-38.67 MUm, P<.001), posterior elevation (68.33+/ 28.69 to 22.67+/-16.21, P<.001), and keratometry values (K1 [45.06+/-4.55 to 43.51+/-4.67 D, P<.001], K2 [48.39+/-5.41 to 46.71+/-5.67 D, P<.001]) in the CXL group. These parameters remained stable in controls (P>.05). According to ROC analysis, posterior elevation change was the most characteristic parameter of corneal change after CXL (area under the curve=0.99). General estimating equation model showed that CXL (P=.001) and initial ThCT (P=.007) were significant predictors of decrease in posterior elevation with a significant negative interaction of initial ThCT on CXL effect (P=.005). CONCLUSIONS: Posterior elevation is a sensitive parameter to monitor corneal remodeling after CXL. Corneal CXL showed augmented effect on corneal protrusion in eyes with thinner corneas. PMID- 22947294 TI - Accuracy of intraocular lens calculation with ray tracing. AB - PURPOSE: To quantify the current accuracy limits of ray tracing for intraocular lens (IOL) calculations, compare results for spherical vs aspheric IOLs, and determine the value of using crystalline lens thickness in IOL calculations. METHODS: Of 591 eyes, 363 eyes were implanted with spherical IOLs (320 SA60AT [Alcon Laboratories Inc] and 43 Y-60H [Hoya Corp]) and 228 eyes had aspheric, aberration-correcting IOLs (57 SN60WF [Alcon Laboratories Inc], 112 Tecnis ZCB00 [Abbott Medical Optics], 21 CTAsphina404 [Carl Zeiss Meditec], and 38 iMics1 [Hoya Corp]), all calculated with OKULIX ray tracing (Tedics), based on Lenstar (Haag-Streit) measurements of axial length, corneal radii, and position and thickness of the crystalline lens. The measure of accuracy was the prediction error, ie, the difference between calculated refraction and manifest refraction (spherical equivalent) 1 month after surgery calculated as mean absolute error (MAE). RESULTS: The prediction error with aspheric IOLs was lower than that with spherical IOLs (MAE 0.27 vs 0.36 D) and was lower for patients with corrected distance visual acuity (CDVA) ?1.0 compared to CDVA <1.0 (MAE 0.26 vs 0.38 D). For aspheric IOLs and CDVA ?1.0, MAE differed by a factor of two compared to spherical IOLs and CDVA <1.0 (MAE 0.21 vs 0.42 D). Taking the crystalline lens position and thickness into account improved the prediction error by ~9% overall (MAE 0.33 vs 0.36 D) and was most beneficial in patients with aspheric lenses and CDVA ?1.0 (MAE improved from 0.26 to 0.21 D). All differences between the investigated subgroups were statistically significant (P<.05). CONCLUSIONS: Ray tracing for IOL calculation is particularly beneficial with aspheric IOLs and in eyes with good (20/20 or better) postoperative visual acuity. PMID- 22947295 TI - Refractive and topographic errors in topography-guided ablation produced by epithelial compensation predicted by 3D Artemis VHF digital ultrasound stromal and epithelial thickness mapping. AB - PURPOSE: To describe and quantify the errors inherent to topography-guided ablation of irregular corneas due to natural epithelial thickness compensatory remodeling. METHODS: Artemis very high-frequency (VHF) digital ultrasound scanning (ArcScan Inc) was performed on a cornea that had undergone radial keratotomy with inferior and superior trapezoidal keratotomies, resulting 27 years later in high irregular astigmatism (+6.50 -8.00 * 101) and severe loss of corrected distance visual acuity (CDVA) to 20/50. The epithelial thickness profile was highly irregular, masking a significant proportion of the true stromal irregularity from front corneal surface topography, which would have resulted in significant inaccuracies had a topography-guided ablation been performed. The stromal ablation pattern of a transepithelial phototherapeutic keratectomy (PTK) ablation was modeled, which appeared logically to reduce the areas of abnormal stromal surface elevation and resembled a hyperopic astigmatic ablation of approximately 3.50 diopters of cylinder. Artemis-assisted transepithelial PTK was performed to target the stromal irregularity masked by epithelium. RESULTS: Artemis-assisted transepithelial PTK induced a refractive change similar to that predicted (+2.24 -3.97 * 120), demonstrating the refractive shift produced by the epithelium. The epithelial thickness profile became relatively regular and CDVA returned to 20/20-2. Two topography wavefront guided ablations were performed to correct the remaining topographic irregularity and refractive error, resulting in a near plano refraction, significantly lower higher order aberrations, and CDVA of 20/20+2. CONCLUSIONS: A knowledge of stromal surface shape and power shift produced by epithelial thickness profile alterations after corneal surgery has the potential of improving the efficacy and safety of custom corneal ablation. PMID- 22947296 TI - [Digestive tract perforations at Point G Teaching Hospital in Bamako, Mali]. AB - AIMS: To determine the most frequent causes of the digestive perforations and to evaluate the surgical procedures, the morbidity and mortality. PATIENTS AND METHODS: It was about a retrospective descriptive study, over 5 year's period in a visceral service of CHU du Point G, Bamako. Were included in the study all the patients operated for digestive perforation and hospitalized in the service of surgery "A". Were not included in the study patient operated not presenting a digestive perforation. Per operational etiologies of the perforations and their frequency were determined, as well as the morbidity and morbidity and mortality. RESULTS: Files of 202 patients were collected. The average age of the patients was 28.3 +/- 15.5 years with extremes of 6 and 71 years. The frequency of digestive perforations was higher in the age from 11 to 20 years (29.7%). The average time of consultation was of 7+/- 6 days. Abdominal pains, nauseas and vomiting, matter and gas stop (48.5%) were the most current functional signs. A "wood belly" abdomen was found in 72,3% of the cases. The radiography of abdomen without preparation found a diffuse greyness (64.7%), a pneumoperitoine (30.7%). A double antibiotic therapy was made in all the cases. A median laparotomy was practiced in 98,5%, and laparoscopy in 3 cases (1.5%). A single perforation was found among 172 patients (85,1%). Morbidity, all confused causes, was made of 30 cases of parietal suppurations (14.8%). Total mortality was 74%. According to aetiologies it was 10.3% in the typhic perforations, 4.6% in the appendicular perforations and 4.9% in the perforations of gastroduodenal ulcers. CONCLUSION: The most frequent aetiologies of digestive perforation in our context were the typhoid fever, acute appendicitis and the gastroduodenal ulcer. The resection - joining and peritoneal toilet were the most practised procedure. The main factor of bad outcome remains the diagnostic delay burdening morbidity and mortality. PMID- 22947298 TI - Gustav Killian: beyond his dehiscence. AB - For most doctors, Gustav Killian is best known for his eponymous pharyngeal dehiscence. Otorhinolaryngologists may also be familiar with his contributions to rhinology by way of his well-known incision and speculum. Few, however, will be aware of the true significance of his contributions to medicine. Killian was at the forefront of advances in ENT surgery at the turn of the twentieth century. From his early years to his revolutionary work on bronchoscopy and a narrowly missed Nobel Prize, this paper reviews the life and works of a most prolific and often overlooked surgical innovator. PMID- 22947297 TI - The tumorigenic liver fluke Opisthorchis viverrini--multiple pathways to cancer. AB - Liver fluke infection caused by Opisthorchis viverrini is a major public health problem in Thailand and adjacent countries. In addition to infection-associated morbidity, infection with O. viverrini and the related Clonorchis sinensis are unarguable risk factors for cholangiocarcinoma (CAA, bile-duct cancer). Here we review the pathogenesis of opisthorchiasis and the association between O. viverrini infection and bile-duct cancer, focusing on the molecular parallels between wound healing, chronic inflammation, and cancer development. We review a schema for human disease progression from fluke infection, chronic opisthorchiasis, advanced periductal fibrosis, and cholangiocarcinogenesis, and present a rationale for biomarker discovery to facilitate early intervention. We conclude by addressing post-genomic advances with a view to developing new control strategies to combat this infectious cancer. PMID- 22947299 TI - Specific guidelines for assessing and improving the methodological quality of economic evaluations of newborn screening. AB - BACKGROUND: Economic evaluation of newborn screening poses specific methodological challenges. Amongst others, these challenges refer to the use of quality adjusted life years (QALYs) in newborns, and which costs and outcomes need to be considered in a full evaluation of newborn screening programmes. Because of the increasing scale and scope of such programmes, a better understanding of the methods of high-quality economic evaluations may be crucial for both producers/authors and consumers/reviewers of newborn screening-related economic evaluations. The aim of this study was therefore to develop specific guidelines designed to assess and improve the methodological quality of economic evaluations in newborn screening. METHODS: To develop the guidelines, existing guidelines for assessing the quality of economic evaluations were identified through a literature search, and were reviewed and consolidated using a deductive iterative approach. In a subsequent test phase, these guidelines were applied to various economic evaluations which acted as case studies. RESULTS: The guidelines for assessing and improving the methodological quality of economic evaluations in newborn screening are organized into 11 categories: "bibliographic details", "study question and design", "modelling", "health outcomes", "costs", "discounting", "presentation of results", "sensitivity analyses", "discussion", "conclusions", and "commentary". CONCLUSIONS: The application of the guidelines highlights important issues regarding newborn screening-related economic evaluations, and underscores the need for such issues to be afforded greater consideration in future economic evaluations. The variety in methodological quality detected by this study reveals the need for specific guidelines on the appropriate methods for conducting sound economic evaluations in newborn screening. PMID- 22947300 TI - Discrepancy between effects of carbapenems and flomoxef in treating nosocomial hemodialysis access-related bacteremia secondary to extended spectrum beta lactamase producing Klebsiella pneumoniae in patients on maintenance hemodialysis. AB - BACKGROUND: Hemodialysis (HD) patients are susceptible to extended spectrum beta lactamase (ESBL)-producing bacterial infections. Because the optimal treatment and clinical significance of ESBL-producing Klebsiella pneumoniae (ESBL-Kp) HD access-related bacteremia remain unclear, we conducted this retrospective study to determine the clinical outcomes of patients treated with either flomoxef or a carbapenem. METHODS: The eligibility criterion was fistula or graft- or catheter- related ESBL-Kp bacteremia in patients on maintenance HD. The clinical characteristics and antibiotic management were analyzed. Outcome was determined by mortality resulting from bacteremia during the 14-day period after the first positive blood culture for flomoxef-susceptible ESBL-Kp. RESULTS: The 57 patients studied were predominantly elderly, malnourished, with a history of severe illnesses and broad-spectrum antibiotic use before the onset of bacteremia, and with severe septicemia as determined by the Pitt bacteremia score (PBS). The study population comprised 7 fistula, 8 graft, and 42 HD catheter-related bacteremia (CRB) cases, and the mortality rate was high (36/57, 63.2%) in these 57 patients. Of 42 patients with CRB, those in the deceased group (27/42, 64.3%) had significantly lower levels of serum albumin, longer prior hospital stay and duration of catheter-dependent HD, and higher PBS than patients in the survived group. Failure to receive effective antibiotics (flomoxef or a carbapenem) within 5 days after onset of bacteremia and treatment with flomoxef both significantly contributed to higher mortality. Multivariate analyses revealed that flomoxef use, PBS, and catheter-dependent HD >30 days were independently associated with increased mortality (OR, 3.52; 95% CI, 1.19-58.17, OR, 2.92; 95% CI, 1.36-6.26 and OR, 5.73; 95% CI, 1.21-63.2, respectively). CONCLUSIONS: Considering the high mortality rate, ESBL-Kp should be recognized as a possible pathogen in patients on maintenance HD at high risk of acquiring HD access infections associated with ESBL-producing bacteria. Carbapenems rather than flomoxef should be the therapy of choice in these critically vulnerable patients. PMID- 22947301 TI - Effect of preharvest anti-fungal compounds on Aspergillus steynii and A. carbonarius under fluctuating and extreme environmental conditions. AB - Ochratoxin A (OTA) has been found in pre-harvest and freshly harvested wheat. Spanish climatic conditions point to Aspergillus species as probably responsible for this OTA. In this study the effectiveness of 5 non-specific antifungal chemicals used on wheat fields (25.9% tebuconazole+60.0% N,N-capramide dimethyl; 12.70% tebuconazole+12.7% prothioconazole+59.5% N,N-amide dimethyldecane; 12.5% epoxiconazole; 12.5% tetraconazole; and 70% thiophanate methyl) and an extract from Equisetum arvense were investigated in vitro on wheat by recording growth (colony size, fungal growth and DNA concentration) and OTA production of two ochratoxigenic isolates of Aspergillus carbonarius and three of A. steynii, simulating current and extreme climatic conditions. Inoculated wheat was incubated under two alternating temperature cycles (20/30 degrees C and 25/35 degrees C) with photoperiod (14/10h lightness/darkness), and two moisture levels (40 and 25%). The Aspergillus species tested seemed to be able to persist in predicted future climatic conditions, in particular, A. steynii, a high OTA producer. Azoles were effective in controlling the growth of A. carbonarius and A. steynii, and this effectiveness may not be compromised by the increase in temperature and decrease of humidity. However, azoles are not useful for the prevention of OTA accumulation, which could be only reduced in A. carbonarius under non-extreme conditions. Although some adjustment will probably be required, further studies should be conducted in the field, since the antifungals used in this study are applied at flowering and not directly on the grain. Moreover, timing of antifungal application may need to be optimized. Finally, Equisetum extract showed promising results as an antifungal, however further work to adjust the applied concentrations is required. PMID- 22947302 TI - Preeclampsia: is it because of the asymptomatic, unrecognized renal scars caused by urinary tract infections in childhood that become symptomatic with pregnancy? AB - Preeclampsia is an important disease of pregnancy whose exact etiology is still unknown despite continuing developments in medicine. Although most commonly it is believed to be caused by a defective placentation, in this paper, we hypothesize that the primary underlying problem in the development of preeclampsia can be in kidneys in a greater proportion of cases than it is believed today. The increased intravascular volume and the increased work load of kidneys together with the resulting glomerular hypertrophy may precipitate nephrotic syndrome, which in this case is called "preeclampsia" in a previously affected kidney. Urinary tract infections in childhood leaving silent, unrecognized small scars in the kidneys may be the underlying renal cause which disrupts its silence with an increased work load of kidneys prominently occurring after the midtrimester. The histopathologic finding in kidneys with renal scars after childhood urinary tract infections and in preeclampsia is focal segmental glomerulosclerosis in the majority of cases and this similarity strengthens our hypothesis. PMID- 22947303 TI - Effects of an epidermal growth factor receptor-based cancer vaccine on wound healing and inflammation processes in murine experimental models. AB - Anti-epidermal growth factor receptor (EGFR) therapies have been proven clinically effective for a variety of epithelial tumours. Vaccination of mice with the extracellular domain (ECD) of autologous EGFR overcomes the tolerance to self-EGFR and has antimetastatic effect on EGFR+ tumour. Because EGF/EGFR signalling plays an important role in the inflammation stage of wound healing, the main objective of this study was to explore the possible role of murine (m) EGFR-ECD vaccine in the croton-oil-induced ear oedema and wound healing process in mice as autologous experimental models, mimicking the possible post-surgical wound complication in patients treated with human EGFR-ECD/VSSP vaccine. Mice were intramuscularly immunised four times; biweekly with the mEGFR-ECD/VSSP/Mont. Seven days later, an 8 mm diameter, full-thickness skin wound was created on the back of each animal. Immunisation induced a strong specific humoral response against the mEGFR-ECD protein and a DTH dose-response curve but interestingly, animals treated with mEGFR-ECD/VSSP/Mont had similar inflammatory and healing speed responses compared to control ones. These data suggest that application of mEGFR-ECD/VSSP vaccine as a therapeutic approach in cancer patients could not elicit a poor healing process after surgery. PMID- 22947304 TI - Endosomal sorting related protein CHMP2B is localized in Lewy bodies and glial cytoplasmic inclusions in alpha-synucleinopathy. AB - Charged multivesicular body protein 2B (CHMP2B) is a component of the endosomal sorting complex required for transport-III, which is involved in the degradation of proteins in the endocytic and autophagic pathways. Mutations in the CHMP2B gene cause frontotemporal dementia and amyotrophic lateral sclerosis characterized by accumulation of ubiquitinated protein aggregates. Recent studies have shown that autophagosomal proteins are present in alpha-synuclein aggregates in neurons and glial cells in Parkinson's disease (PD), dementia with Lewy bodies (DLB) and multiple system atrophy (MSA). We therefore immunohistochemically examined the brains of various neurodegenerative diseases using CHMP2B-specific antibody. CHMP2B immunoreactivity was present in intracytoplasmic and axonal Lewy bodies in PD and DLB as well as in neuronal and glial cytoplasmic inclusions in MSA. No CHMP2B immunoreactivity was found in a variety of other neuronal and glial inclusions in TDP-43 proteinopathy and tauopathy. These findings suggest that endosomal and autophagic pathway is associated with degradation or formation of alpha-synuclein aggregates in alpha-synucleinopathy. PMID- 22947305 TI - LTR point mutations in the Tax-responsive elements of HTLV-1 isolates from HIV/HTLV-1-coinfected patients. AB - BACKGROUND: In Virology Journal 2011, 8:535, Neto et al. described point mutations into Tax-responsive elements (TRE) of the LTR region of HTLV-1 isolates from asymptomatic carriers from Sao Paulo, Brazil, and hypothesized that the presence of the G232A mutation in the TRE-1 increase viral proliferation and consequently the proviral load (PvL), while the A184G mutation in the TRE-2 do not have such effect. FINDINGS: We performed the real-time PCR assay (pol) and sequenced LTR region of HTLV-1 isolates from 24 HIV/HTLV-1-coinfected patients without HTLV-1-associated diseases from the same geographic area. These sequences were classified as belonging to the transcontinental subgroup A of the Cosmopolitan subtype a. The frequency of G232A mutation (16/24, 66.7%) was high as much as 61.8% reported by Neto's in HTLV-1 asymptomatic carriers with high PvL. High frequency (13/24, 54.2%) of double mutations G232A and A184G was also detected in HIV/HTLV-1-coinfected patients. We did not quantify PvL, but comparative analyses of the cycle threshold (Ct) median values of the group of isolates presenting the mutated-types sequences (Ct 33.5, n = 16) versus the group of isolates with the wild-type sequences (Ct 32, n = 8) showed no statistical difference (p = 0.4220). CONCLUSION: The frequencies of mutated-type sequences in the TRE-1 and TRE-2 motifs were high in HIV/HTLV-1-coinfected patients from Sao Paulo, Brazil. If these LTR point mutations have predictive value for the development of HTLV-1-associated diseases or they correspond to the subtype of virus that circulate in this geographic area has to be determined. PMID- 22947306 TI - Alkaline cooking (nixtamalisation) and the reduction in the in vivo toxicity of fumonisin-contaminated corn in a rat feeding bioassay. AB - Nixtamalisation is a widely used food processing method in which whole kernel corn is cooked and steeped in alkaline water. It reduces the amount of fumonisin B1 (FB1) that can be detected after cooking. However, the fate of FB1 during nixtamalisation is not fully understood and potentially toxic reaction products, including matrix-associated "masked" FB1 forms that are not detected by routine analytical methods might remain in nixtamalised corn. To assess how nixtamalisation of whole kernel corn affects fumonisin toxicity, male rats were fed diets containing low, mid or high levels of uncooked (LU, MU, HU) or alkaline cooked (LC, MC, HC) FB1-contaminated corn for 3 weeks. The control diet contained uncontaminated corn only. Apoptotic kidney lesions of the type caused by FB1 were not found in the LC or MC groups. Lesions in the group fed HC were minimal and less severe than those found in the rats fed LU, MU or HU. Furthermore, significantly increased sphinganine and sphingosine concentrations indicative of FB1 exposure were found in the kidneys of the rats given LU, MU or HU. Concentrations were also elevated, but to a lesser extent, in rats fed HC, whereas sphinganine and sphingosine concentrations in rats given LC or MC did not differ from the control group. FB1 concentrations in the LC (0.08 mg kg(-1)), MC (0.13 mg kg(-1)) and HC (0.37 mg kg(-1)) diets were markedly reduced compared with their LU (1.8 mg kg(-1)), MU (3.5 mg kg(-1)) and HU (4.2 mg kg(-1)) counterparts as determined by HPLC (n = 1 analysis/diet). Taken together, the findings show that nixtamalisation is an effective cooking method for reducing the potential toxicity of FB1 contaminated corn. PMID- 22947307 TI - Activation of NMDA receptors reduces metabotropic glutamate receptor-induced long term depression in the nucleus accumbens via a CaMKII-dependent mechanism. AB - Glutamate is the major excitatory neurotransmitter in the brain and exerts its actions through two distinct types of receptors, ionotropic and metabotropic glutamate receptors (mGluR). Although functional interplay between ionotropic N methyl-d-aspartate receptors (NMDAR) and mGluR has been convincingly demonstrated in native and recombinant systems, the mechanism by which NMDAR activation leads to modulation of mGluR function has yet to be elucidated. Using whole-cell patch clamp recordings in mouse nucleus accumbens (NAc) slices, we found that tetanic stimulation (TS) of excitatory afferents with a naturally occurring frequency (10 min at 13 Hz) reliably induces a mGluR1/5-dependent long-term depression (mGluR1/5-LTD) of excitatory synaptic transmission. Blockade of NMDAR during but not after TS showed enhanced mGluR1/5-LTD induction, which is associated with its antagonism of TS-induced calcium/calmodulin-dependent protein kinase II (CaMKII) activation. The ability of NMDAR antagonists to promote mGluR1/5-LTD induction was mimicked by a selective CaMKII inhibitor KN-62. However, the induction of mGluR1/5-LTD by bath-applied agonist (S)-3,5-dihydrophenylglycine was not affected by NMDAR blockade. We also observed that NMDAR or CaMKII blockade during TS significantly blunted TS-induced increased serine/threonine phosphorylation of the scaffold protein Homer1b/c and resulted in an increased interaction of mGluR5 with the Homer1b/c. These results indicate that synaptically released glutamate during TS of excitatory afferents can activate both NMDAR and mGluR1/5 in NAc neurons concomitantly and that activation of NMDAR may stimulate CaMKII-mediated phosphorylation of Homer1b/c and impair the interaction between mGluR5 and Homer1b/c, thereby attenuating mGluR1/5-LTD induction. This study provides a novel molecular mechanism by which NMDAR could regulate mGluR5 function. PMID- 22947308 TI - Vertebral fracture assessment in acromegaly. PMID- 22947309 TI - Do Alzheimer-specific microstructural changes in mild cognitive impairment predict conversion? AB - Diffusion tensor imaging (DTI) is a magnetic resonance imaging (MRI) technique that provides information on the fiber architecture of the brain by measuring water diffusion. Prior work has shown that neuronal degeneration in Alzheimer's disease (AD) and mild cognitive impairment (MCI) alters this architecture. Since the conversion rate to AD is much higher for MCI patients than for normal healthy people, it is important to identify biomarkers with a predictive value on this conversion. In this study, we applied tract-based spatial statistics (TBSS) on datasets of 15 healthy controls, 15 AD patients, and 17 MCI patients. Of these MCI patients eight remained stable, whereas nine developed AD within the first 12 18 months of follow-up investigations. Analysis using TBSS combined with a maximum likelihood regression with random effects of the fornix, the corpus callosum, and the cingulum identified significant differences between these two types of MCI patients in fractional anisotropy (FA) and radial diffusivity (DR). Thus, DTI reveals Alzheimer-specific changes in those MCI subjects that later convert, although they were clinically identical to the other MCI-patients at the time the data were acquired. This finding could lead to early identification of AD and thereby aid early clinical intervention. PMID- 22947310 TI - Thinner cortex in the frontal lobes in mentally disordered offenders. AB - Antisocial and violent behaviour have been associated with both structural and functional brain abnormalities in the frontal and the temporal lobes. The aim of the present study was to assess cortical thickness in offenders undergoing forensic psychiatric assessments, one group with psychopathy (PSY, n=7) and one group with autism spectrum disorder (ASD, n=7) compared to each other as well as to a reference group consisting of healthy non-criminal subjects (RG, n=12). A second aim was to assess correlation between scores on a psychopathy checklist (PCL-SV) and cortical thickness. Magnetic resonance imaging (MRI) and surface based cortical segmentation were used to calculate cortical thickness. Analyses used both regions of interest and statistical maps. When the two groups of offenders were compared, there were no differences in cortical thickness, but the PSY group had thinner cortex in the temporal lobes and in the whole right hemisphere compared to RG. There were no differences in cortical thickness between the ASD group and RG. Across subjects there was a negative correlation between PCL-SV scores and cortical thickness in the temporal lobes and the whole right hemisphere. The findings indicate that thinner cortex in the temporal lobes is present in psychopathic offenders and that these regions are important for the expression of psychopathy. However, whether thinner temporal cortex is a cause or a consequence of the antisocial behaviour is still unknown. PMID- 22947311 TI - Decreased leftward bias of prefrontal activity in autism spectrum disorder revealed by functional near-infrared spectroscopy. AB - Hemodynamic responses in rostral prefrontal cortex (RoPFC) were measured by functional near-infrared spectroscopy. Although performance level was equal, autistic patients showed a decrease in leftward bias of the balance between right and left RoPFC activity when compared with typically developing children when anatomical imitation was contrasted with mirror-image imitation. PMID- 22947312 TI - Immobilized furanone derivatives as inhibitors for adhesion of bacteria on modified poly(styrene-co-maleic anhydride). AB - The ability of brominated furanones and other furanone compounds with 2(3H) and 2(5H) cores to inhibit bacterial adhesion of surfaces as well deactivate (destroy) them has been previously reported. The furanone derivatives 4-(2-(2 aminoethoxy)-2,5-dimethyl-3(2H)-furanone and 5-(2-(2-aminoethoxy)-ethoxy)methyl) 2(5H)-furanone were synthesized in our laboratory. These furanone derivatives were then covalently immobilized onto poly(styrene-co-maleic anhydride) (SMA) and electrospun to fabricate nonwoven nanofibrous mats with antimicrobial and cell adhesion inhibition properties. The electrospun nanofibrous mats were tested for their ability to inhibit cell attachment by strains of bacteria commonly found in water ( Klebsiella pneumoniae Xen 39, Staphylococcus aureus Xen 36, Escherichia coli Xen 14, Pseudomonas aeruginosa Xen 5, and Salmonella tymphimurium Xen 26). Proton nuclear magnetic resonance spectroscopy ((1)H NMR), electrospray mass spectroscopy (ES-MS), and attenuated total reflectance Fourier transform infrared spectroscopy (ATR-FTIR) were used to confirm the structures of the synthesized furanones as well as their successful immobilization on SMA. To ascertain that the immobilized furanone compounds do not leach into filtered water, samples of water, filtered through the nanofibrous mats were analyzed using gas chromatography coupled with mass spectroscopy (GC-MS). The morphology of the electrospun nanofibers was characterized using scanning electron microscopy (SEM). PMID- 22947313 TI - Fixed cervical count and the origin of the mammalian diaphragm. AB - Why is mammalian cervical count fixed across the historically long and ecologically broad mammalian radiation? Multiple lines of evidence, considered together, suggest a link between fixed cervical count and the muscularization of the diaphragm, a key innovation in mammalian history. We test this hypothesis by documenting the anteroposterior (AP) movement of the diaphragm, a lateral plate derivative, relative to that of the somitic thoracolumbar transition in unusually patterned mammals, by comparing the temporal occurrence of an osteological proxy for the diaphragm and fixed cervical counts in the fossil record, and by quantifying morphological differentiation within the mammalian cervical series. We then integrate these anatomical observations with details of diaphragm function and development to propose a sequence of innovations in mammalian evolution that could have led to fixed cervical count. We argue that the novel commitment of migratory muscle precursor cells (MMPs) of mid-cervical somites to a fate in the abaxial diaphragm defined these somites as a new and uniquely mammalian modular subunit. We further argue that the coordination of primaxial abaxial patterning constrained subsequent AP migration of the forelimb, thereby secondarily fixing cervical count. PMID- 22947314 TI - Acquisition of the paired fins: a view from the sequential evolution of the lateral plate mesoderm. AB - The origin of paired fins has long been a focus of both paleontologists and developmental biologists. Fossil records indicate that the first pair of fin-like structures emerged in the body wall of early vertebrates. However, extant agnathan lampreys and hagfishes lack paired fins, and thus it has been difficult to determine the developmental processes underlying the ancestral acquisition of paired fins in vertebrates. Fortunately, recent advances in our knowledge of the developmental mechanisms of the lateral plate mesoderm among different taxa have provided clues for understanding the evolutionary origin of vertebrate paired appendages. PMID- 22947315 TI - A merciful death for the "earliest bilaterian," Vernanimalcula. AB - Fossils described as Vernanimalcula guizhouena, from the nearly 600 million-year old Doushantuo Formation in South China, have been interpreted as the remains of bilaterian animals. As such they would represent the oldest putative record of bilaterian animals in Earth history, and they have been invoked in debate over this formative episode of early animal evolution. However, this interpretation is fallacious. We review the evidential basis of the biological interpretation of Vernanimalcula, concluding that the structures key to animal identity are effects of mineralization that do not represent biological tissues, and, furthermore, that it is not possible to derive its anatomical reconstruction on the basis of the available evidence. There is no evidential basis for interpreting Vernanimalcula as an animal, let alone a bilaterian. The conclusions of evolutionary studies that have relied upon the bilaterian interpretation of Vernanimalcula must be called into question. PMID- 22947316 TI - Heterochronic activation of VEGF signaling and the evolution of the skeleton in echinoderm pluteus larvae. AB - The evolution of the echinoderm larval skeleton was examined from the aspect of interactions between skeletogenic mesenchyme cells and surrounding epithelium. We focused on vascular endothelial growth factor (VEGF) signaling, which was reported to be essential for skeletogenesis in sea urchin larvae. Here, we examined the expression patterns of vegf and vegfr in starfish and brittle stars. During starfish embryogenesis, no expression of either vegfr or vegf was detected, which contrast with previous reports on the expression of starfish homologs of sea urchin skeletogenic genes, including Ets, Tbr, and Dri. In later stages, when adult skeletogenesis commenced, vegfr and vegf expression were upregulated in skeletogenic cells and in the adjacent epidermis, respectively. These expression patterns suggest that heterochronic activation of VEGF signaling is one of the key molecular evolutionary steps in the evolution of the larval skeleton. The absence of vegf or vegfr expression during early embryogenesis in starfish suggests that the evolution of the larval skeleton requires distinct evolutionary changes, both in mesoderm cells (activation of vegfr expression) and in epidermal cells (activation of vegf expression). In brittle stars, which have well-organized skeletons like the sea urchin, vegfr and vegf were expressed in the skeletogenic mesenchyme and the overlying epidermis, respectively, in the same manner as in sea urchins. Therefore, the distinct activation of vegfr and vegf may have occurred in two lineages, sea urchins and brittle stars. PMID- 22947317 TI - Ontogenetic modulation of branch size, shape, and biomechanics produces diversity across habitats in the Bursera simaruba clade of tropical trees. AB - Organismal size and shape inseparably interact with tissue biomechanical properties. It is therefore essential to understand how size, shape, and biomechanics interact in ontogeny to produce morphological diversity. We estimated within species branch length-diameter allometries and reconstructed the rates of ontogenetic change along the stem in mechanical properties across the simaruba clade in the tropical tree genus Bursera, measuring 376 segments from 97 branches in nine species in neotropical dry to rain forest. In general, species with stiffer materials had longer, thinner branches, which became stiffer more quickly in ontogeny than their counterparts with more flexible materials. We found a trend from short stature and flexible tissues to tall statures and stiff tissues across an environmental gradient of increasing water availability, likely reflecting a water storage-mechanical support tradeoff. Ontogenetic variation in size, shape, and mechanics results in diversity of habits, for example, rapid length extension, sluggish diameter expansion, and flexible tissues results in a liana, as in Bursera instabilis. Even species of similar habit exhibited notable changes in tissue mechanical properties with increasing size, illustrating the inseparable relationship between organismal proportions and their tissue mechanics in the ontogeny and evolution of morphological diversity. PMID- 22947318 TI - Hox gene expression in the harvestman Phalangium opilio reveals divergent patterning of the chelicerate opisthosoma. AB - Among chelicerates, Hox gene expression has only been investigated in representatives of two arachnid orders to date: Acari (mites and ticks) and Araneae (spiders). Limited data are available for the "primitive" arachnid orders, such as Scorpiones (scorpions) and Opiliones (harvestmen). Here, we present the first data on Hox gene expression in the harvestman Phalangium opilio. Ten Hox genes of this species were obtained from a de novo assembled developmental transcriptome using the Illumina GAII platform. All 10 genes are expressed in characteristic Hox-like expression patterns, and the expression of the anterior and central Hox genes is similar to those of other chelicerates. However, intriguingly, the three posteriormost genes-Ultrabithorax, abdominal-A, and Abdominal-B-share an identical anterior expression boundary in the second opisthosomal segment, and their expression domains extend through the opisthosoma to the posterior growth zone. The overlap in expression domains of the posterior Hox genes is correlated with the absence of opisthosomal organs posterior to the tubular tracheae, which occur on the second opisthosomal segment. Together with the staggered profile of posterior Hox genes in spiders, these data suggest the involvement of abdominal-A and Abdominal-B in the evolution of heteronomous patterning of the chelicerate opisthosoma, providing a mechanism that helps explain the morphological diversity of chelicerates. PMID- 22947319 TI - The Norwegian Twin Registry. AB - Norway has a long-standing tradition in twin research, but the data collected in several population-based twin studies were not coordinated centrally or easily accessible to the scientific community. In 2009, the Norwegian Twin Registry was established at the Norwegian Institute of Public Health (NIPH) in Oslo with the purpose of creating a single research resource for Norwegian twin data. As of today, the Norwegian Twin Registry contains 47,989 twins covering birth years 1895-1960 and 1967-1979; 31,440 of these twins consented to participate in health related research. In addition, DNA from approximately 4,800 of the twins is banked at the NIPH biobank and new studies are continually adding new data to the registry. The value of the Norwegian twin data is greatly enhanced by the linkage opportunities offered by Norway's many nationwide registries, spanning a broad array of medical, demographic, and socioeconomic information. PMID- 22947321 TI - [Drug eruptions in children in Cotonou, Benin]. AB - INTRODUCTION: The aim of this study was to investigate the epidemiological aspects of drug eruptions in children in hospital area in Cotonou. PATIENTS AND METHOD: A retrospective study was carried out in the Department of Dermatology of Cotonou (Benin) from 1998 to 2009. All cases of drug eruption occurred, during the study period, in children under 16 years old were selected for the study. The diagnosis of the drug eruption was based on clinical findings. The Identification of culprit drugs was based on the criteria as defined by the French Group of Pharmaco-vigilance. RESULTS: From 1998 to 2009, 232 cases of drug eruption were diagnosed in the Department of Dermatology. Of this, 35 cases occurred in children under 16 years old. The patient mean age was 6.6 years with a sex ratio of 0.94. 4 patients were HIV positive. The culprit drug was identified in 21 patients (60%): sulfonamides 52.38% (11/21 cases), penicillin 9.52% (2 cases), vaccine 9.52% (2 cases), acetaminophen 9.52% (2 cases), acetyl salicylic acid 4.76% (n = 1), quinine 4.76% (n = 1), phenobarbital 4.76% (n = 1) and ceftriaxone 4.76% (n = 1). The main clinical patterns were: fixed drug eruption 45.71% (16/35), maculopapular rash 17.14% (n = 6), Stevens-Johnson syndrome 17.14% (n=6), and urticaria 8.57% (n = 3), 1 case of toxic epidermal necrolysis was seen and one patient died. CONCLUSION: Skin reactions caused by drug intake are a rare disorder among children and fixed drug eruption is the main clinical presentation of the disease in Cotonou (Benin). PMID- 22947320 TI - Analysis of T-DNA alleles of flavonoid biosynthesis genes in Arabidopsis ecotype Columbia. AB - BACKGROUND: The flavonoid pathway is a long-standing and important tool for plant genetics, biochemistry, and molecular biology. Numerous flavonoid mutants have been identified in Arabidopsis over the past several decades in a variety of ecotypes. Here we present an analysis of Arabidopsis lines of ecotype Columbia carrying T-DNA insertions in genes encoding enzymes of the central flavonoid pathway. We also provide a comprehensive summary of various mutant alleles for these structural genes that have been described in the literature to date in a wide variety of ecotypes. FINDINGS: The confirmed knockout lines present easily scorable phenotypes due to altered pigmentation of the seed coat (or testa). Knockouts for seven alleles for six flavonoid biosynthetic genes were confirmed by PCR and characterized by UPLC for altered flavonol content. CONCLUSION: Seven mutant lines for six genes of the central flavonoid pathway were characterized in ecotype, Columbia. These lines represent a useful resource for integrating biochemical and physiological studies with genomic, transcriptomic, and proteomic data, much of which has been, and continues to be, generated in the Columbia background. PMID- 22947322 TI - Tacrolimus enhances the recovery of normal laryngeal muscle fibre distribution after reinnervation. AB - OBJECTIVES: To assess the recovery of various muscle fibre types in the posterior cricoarytenoid muscle after laryngeal reinnervation in the rat, and to determine the influence of tacrolimus on this process. METHODS: Four groups of rats underwent resection and anastomosis of the left vagus nerve, and were administered either tacrolimus at a low dose or an immunosuppressive dose, or cyclosporin A at a low dose or an immunosuppressive dose. A fifth group received surgery alone, and a sixth group received neither surgery nor drug treatment (healthy group). Muscles were removed for immunohistochemical analysis 45 days after surgery. RESULTS: There was no difference in the proportion of types 1, 2a and 2b muscle fibres, comparing the immunosuppressive tacrolimus group and the healthy group, whereas there were fewer type 1 fibres in the group receiving surgery alone, compared with the healthy group (7 vs 12.1 per cent, respectively; p = 0.0303). CONCLUSION: Tacrolimus enhanced the recovery of normal laryngeal muscle fibres after reinnervation in the rat, indicating a possible role in laryngeal transplantation. PMID- 22947323 TI - Endotoxins affect bioactivity of chitosan derivatives in cultures of bone marrow derived human mesenchymal stem cells. AB - Biomaterials research has been expanding over the last decade, in part to provide improved medical devices for the treatment of orthopedic tissue injuries. In the quest to provide the best performance combined with low cost for medical implants, an increasing number of non-chemists have entered the field of biomaterials research without the profound knowledge of chemistry needed to understand the complex interaction mechanisms and characteristics of natural substances. Likewise, non-biologists often lack understanding when it comes to the presence of the contaminating biota frequently found in natural substances. This lack of knowledge by researchers in the field, combined with sensitive in vitro cell-based assays, can lead to inaccurate evaluation of biomaterials. Hence, there should be both an active effort to assemble multi-disciplinary teams and a genuine concern for the possible effects of contamination on in vitro assays. Here, we show that the presence of bacterial endotoxins in chitosan derivatives can result in false-positive results, profoundly altering product performance in in vitro assays. False-positive results through uncritical use of natural substances in vitro can be avoided by proper endotoxin testing and careful evaluation of cytokine secretion patterns. PMID- 22947324 TI - Hydraulic permeability of multilayered collagen gel scaffolds under plastic compression-induced unidirectional fluid flow. AB - Under conditions of free fluid flow, highly hydrated fibrillar collagen gels expel fluid and undergo gravity driven consolidation (self-compression; SC). This process can be accelerated by the application of a compressive stress (plastic compression; PC) in order to generate dense collagen scaffolds for tissue engineering. To define the microstructural evolution of collagen gels under PC, this study applied a two-layer micromechanical model that was previously developed to measure hydraulic permeability (k) under SC. Radially confined PC resulted in unidirectional fluid flow through the gel and the formation of a dense lamella at the fluid expulsion boundary which was confirmed by confocal microscopy of collagen immunoreactivity. Gel mass loss due to PC and subsequent SC were measured and applied to Darcy's law to calculate the thickness of the lamella and hydrated layer, as well as their relative permeabilities. Increasing PC level resulted in a significant increase in mass loss fraction and lamellar thickness, while the thickness of the hydrated layer dramatically decreased. Permeability of lamella also decreased from 1.8*10(-15) to 1.0*10(-15) m(2) in response to an increase in PC level. Ongoing SC, following PC, resulted in a uniform decrease in mass loss and k with increasing PC level and as a function SC time. Experimental k data were in close agreement with those estimated by the Happel model. Calculation of average k values for various two-layer microstructures indicated that they each approached 10(-15)-10(-14) m(2) at equilibrium. In summary, the two-layer micromechanical model can be used to define the microstructure and permeability of multi-layered biomimetic scaffolds generated by PC. PMID- 22947325 TI - Enhanced endothelialization for developing artificial vascular networks with a natural vessel mimicking the luminal surface in scaffolds. AB - Large tissue regeneration remains problematic because of a lack of oxygen and nutrient supply. An attempt to meet the metabolic needs of cells has been made by preforming branched vascular networks within a scaffold to act as channels for mass transport. When constructing functional vascular networks with channel patency, emphasis should be placed on anti-thrombogenic surface issues. The aim of this study was to develop a rapid endothelialization method for creating an anti-thrombogenic surface mimicking the natural vessel wall in the artificial vascular networks. Shear stress preconditioning and scaffold surface modification were investigated as effective approaches for promoting biomaterial endothelialization. We found that a transient increase in shear stress at the appropriate time is key to enhancing endothelialization. Moreover, surface modification with bioactive materials such as collagen and recombinant mussel adhesive protein fused with arginine-glycine-aspartic acid peptide (MAP-RGD) showed a synergetic effect with shear stress preconditioning. Platelet adhesion tests demonstrated the anti-thrombogenic potential of MAP-RGD itself without endothelialization. The rapid endothelialization method established in this study can be easily applied to preformed artificial vascular networks in porous scaffolds. Development of artificial vascular networks with an anti-thrombogenic luminal surface will open up a new chapter in tissue engineering and regenerative medicine. PMID- 22947326 TI - Alginate-lanthanide microspheres for MRI-guided embolotherapy. AB - In cancer therapy, a promising treatment option to accomplish a high tumor-to normal-tissue ratio is endovascular intervention with microsized particles, such as embolotherapy. In this study, alginate microspheres (ams) were prepared with the JetCutter technique, which is based on cutting a sodium alginate solution jet stream into small droplets of uniform size which are then cross-linked with different lanthanides or iron-III, resulting in microspheres of a predefined size which can be visualized by magnetic resonance imaging (MRI). The microspheres were investigated for their size and morphology (light microscopy and scanning electron microscopy analysis), cation content and MRI properties. The lanthanide ams formulations, with a uniform size of 250 MUm and a cation content between 0.72-0.94%, showed promising results for MR imaging. This was further demonstrated for Ho(3+)-cross-linked alginate microspheres (Ho(3+)-ams), the most potent microsphere formulation with respect to MR visualization, allowing single sphere detection and detailed microsphere distribution examination. Intravascular infusion of Ho(3+)-ams by catherization of ex vivo rabbit and porcine liver tissue and assessment of the procedure with MRI clearly showed accumulation and subsequently embolization of the targeted vessels, allowing accurate monitoring of the microsphere biodistribution throughout the tissue. Therefore, the different alginate-lanthanide microsphere formulations developed in this study show great potential for utilization as image-guided embolotherapy agents. PMID- 22947327 TI - UMOD as a susceptibility gene for end-stage renal disease. AB - BACKGROUND: In recent genetic association studies, common variants including rs12917707 in the UMOD locus have shown strong evidence of association with eGFR, prevalent and incident chronic kidney disease and uromodulin urinary concentration in general population cohorts. The association of rs12917707 with end-stage renal disease (ESRD) in a recent case-control study was only nominally significant. METHODS: To investigate whether rs12917707 associates with ESRD, graft failure (GF) and urinary uromodulin levels in an independent cohort, we genotyped 1142 ESRD patients receiving a renal transplantation and 1184 kidney donors as controls. After transplantation, 1066 renal transplant recipients were followed up for GF. Urinary uromodulin concentration was measured at median [IQR] 4.2 [2.2-6.1] yrs after kidney transplantation. RESULTS: The rs12917707 minor allele showed association with lower risk of ESRD (OR 0.89 [0.76-1.03], p = 0.04) consistent in effect size and direction with the previous report (Boger et al, PLoS Genet 2011). Meta-analysis of these findings showed significant association of rs12917707 with ESRD (OR 0.91 [0.85-98], p = 0.008). In contrast, rs12917707 was not associated with incidence of GF. Urinary uromodulin concentration was lower in recipients-carriers of the donor rs12917707 minor allele as compared to non-carriers, again consistent with previous observations in general population cohorts. CONCLUSIONS: Our study thus corroborates earlier evidence and independently confirms the association between UMOD and ESRD. PMID- 22947329 TI - The journal of sexual medicine monthly mathematics. PMID- 22947328 TI - A cytotoxic cardenolide and a saponin from the rhizomes of Tupistra chinensis. AB - A new cardenolide tupichinolide (1) and a new steroidal saponin tupichinin A (2), together with seven known compounds, were isolated from the rhizomes of Tupistra chinensis. Their structures were established using spectroscopic analysis and chemical methods. Compound 1 was the first cardenolide isolated from Tupistra chinensis and exhibited potent cytotoxicity against five human cancer cell lines: HL-60, SMMC-7721, A-549, MCF-7 and SW480. PMID- 22947330 TI - Subcoronal rod penile prosthesis placement with scrotoplasty. PMID- 22947332 TI - Using financial incentives to increase initial uptake and completion of HPV vaccinations: protocol for a randomised controlled trial. AB - BACKGROUND: HPV vaccination reduces the risk of cervical cancer. Uptake however, of the 'catch-up' campaign in England for 17-18 year old girls is below the 80% NHS target. The aim of this randomized controlled trial is to assess the impact of financial incentives on (a) the uptake and completion of an HPV vaccination programme and (b) the quality of the decisions to undertake the vaccination. METHOD/DESIGN: One thousand (n = 1000) 16-18 year-old girls will be invited to participate in an HPV vaccination programme: Five-hundred (n = 500) will have received a previous invitation to get vaccinated but will have failed to do so (previous non-attenders) and 500 will not have previously received an invitation (first-time invitees). Girls will be randomly selected from eligible participants who are registered with a GP in areas covered by the Birmingham East and North (BEN) and Heart of Birmingham Primary Care Trusts. The two samples of girls will be randomised to receive either a standard vaccination invitation letter or an invitation letter including the offer of vouchers worth L45 for receiving three vaccinations. Girls will also complete a questionnaire to assess the quality of their decisions to be vaccinated. The primary outcome will be uptake of the 1st and 3rd vaccinations. The secondary outcome will be the quality of the decisions to undertake the vaccination, measured by assessing attitudes towards and knowledge of the HPV vaccination. DISCUSSION: The key results will be: a) the effectiveness of financial incentives in increasing uptake of the 1st and 3rd vaccinations; b) the role of participants' socio-economic status in the moderation of the impact of incentives on uptake; and c) the impact of incentives on the quality of decisions to undertake the HPV vaccinations. PMID- 22947333 TI - The effects of telbivudine in late pregnancy to prevent intrauterine transmission of the hepatitis B virus: a systematic review and meta-analysis. AB - Chronic hepatitis B virus (HBV) infection poses a serious public health problem in many parts of the world. Presently, even with proper joint immunoprophylaxis, approximately 10-15% of newborns from HBV carrier mothers suffer from HBV infection through intrauterine transmission. One of the risk factors is the level of maternal viraemia. Telbivudine is a synthetic thymidine nucleoside analogue with activity against HBV. A few studies have evaluated the efficacy of telbivudine in preventing intrauterine HBV infection during late pregnancy. So we conducted this meta-analysis to arrive at an evidence-based conclusion. We searched Medline/PubMed, EMBASE, Cochrane Library, Web of Knowledge and China Biological Medicine Database from January 1990 to December 2011. Relative risks (RR) of the seropositivity rates for hepatitis B surface antigen (HBsAg) and HBV DNA in newborns and infants were studied. Mean differences (MD) in maternal HBV DNA levels were reviewed. Finally two randomised controlled trials (RCTs) and four non-randomised controlled trials (NRCTs) were left for analysis which included 576 mothers in total, of whom 306 received telbivudine treatment and 270 did not receive any drug. All newborns received hepatitis B vaccine (HBVac) and hepatitis B immunoglobulin (HBIG) after birth. The seropositivity rate for HBsAg or HBV DNA was significantly lower in the telbivudine group, both at birth and at 6-12 months follow up. Meanwhile, maternal HBV DNA levels prior to delivery were significantly lower in the telbivudine group. In addition, the frequency of serum creatine kinase (CK) elevation was similar in the two groups. Our meta-analysis provides preliminary evidence that telbivudine application in late pregnancy is effective in the interruption of intrauterine HBV infection, with no significant adverse effects or complications. More high quality, well-designed, double blinded, randomised controlled and large size clinical trials are needed for further investigation and more convincing results in the future. PMID- 22947334 TI - Ubiquitin released in the plasma of whole blood during storage promotes mRNA expression of Th2 cytokines and Th2-inducing transcription factors. AB - Many biological molecules in the stored blood were involved in transfusion related immunomodulation. One important effect was the differentiation bias of immune cells to Th2 type. In this study, we observed the immune regulation of extracellular ubiquitin accummulated in the plasma of whole blood on the differentiation of T help cells in vitro using ELISA and quantitative fluorescence real-time PCR with the help of LPS stimulated human peripheral blood mononuclear cells. We found extracellular ubiquitin promoted Th2 cytokine IL-4 production and Th2-inducing transcription factor STAT6 expression, but inhibited Th1 cytokine IFN-gamma and Th1-inducing transcription factor T-bet, at the same time, proinflammation cytokine TNF-alpha was also inhibited. These findings probably contribute to the potent evidence that extracellular ubiquitin plays an indispensable role in the differentiation of T help cells which is crucial to the effects of transfusion-related immunomodulation. PMID- 22947337 TI - Predictors of a favourable socio-economic situation in middle age for Swedish conscripts with self-reported drug use. AB - BACKGROUND: Risk and protective factors for adverse outcomes among drug users in the general population have been identified. This study considers whether some of these factors predict favourable socio-economic situations in middle age. METHODS: A 37-year follow-up of 49,411 Swedish male conscripts 1969/70, born 1949 1951. Based on self-reports at conscription, 36,191 living subjects in 2006 were divided into users of certain dominant drugs (n=3946) and non-users (n=32,245). Individual data from conscription and national registers were linked. Using logistic bivariate and multivariate regression, odds ratios (ORs) for the categories of dominant-drug users, compared with non-users, were computed for outcomes in 1990 and in 2006: education >=12 years, being in work, and having a disposable income above the median. The ORs were calculated after considering familial, social and individual risk and protective factors, with separate analyses being performed for drug-use categories. RESULTS: Small changes were observed in the ORs for the outcomes in 1990 and 2006. After adjustment for protective and risk factors, users of the various dominant drugs had increased ORs with an education >=12 years but lower or non-significantly different from non-users for the other outcomes. The ORs decreased with severity of drug use. Among drug users, high intellectual ability, having a father from highest SES group, and communication with parents were among the factors that increased the probability of favourable socio-economic outcomes, especially when several protective factors were involved. CONCLUSIONS: Protective factors increase the probability of favourable outcomes, but least among individuals with severe drug use. PMID- 22947335 TI - The dual cyclooxygenase/5-lipoxygenase inhibitor licofelone attenuates p glycoprotein-mediated drug resistance in the injured spinal cord. AB - There are currently no proven effective treatments that can improve recovery of function in spinal cord injury (SCI) patients. Many therapeutic compounds have shown promise in pre-clinical studies, but clinical trials have been largely unsuccessful. P-glycoprotein (Pgp, Abcb1b) is a drug efflux transporter of the blood-spinal cord barrier that limits spinal cord penetration of blood-borne xenobiotics. Pathological Pgp upregulation in diseases such as cancer causes heightened resistance to a broad variety of therapeutic drugs. Importantly, several drugs that have been evaluated for the treatment of SCI, such as riluzole, are known substrates of Pgp. We therefore examined whether Pgp-mediated pharmacoresistance diminishes delivery of riluzole to the injured spinal cord. Following moderate contusion injury at T10 in male Sprague-Dawley rats, we observed a progressive, spatial spread of increased Pgp expression from 3 days to 10 months post-SCI. Spinal cord uptake of i.p.-delivered riluzole was significantly reduced following SCI in wild type but not Abcb1a-knockout rats, highlighting a critical role for Pgp in mediating drug resistance following SCI. Because inflammation can drive Pgp upregulation, we evaluated the ability of the new generation dual anti-inflammatory drug licofelone to promote spinal cord delivery of riluzole following SCI. We found that licofelone both reduced Pgp expression and enhanced riluzole bioavailability within the lesion site at 72 h post-SCI. This work highlights Pgp-mediated drug resistance as an important obstacle to therapeutic drug delivery for SCI, and suggests licofelone as a novel combinatorial treatment strategy to enhance therapeutic drug delivery to the injured spinal cord. PMID- 22947338 TI - Limited role of marital status in the impact of dermatological diseases on quality of life. AB - Health status, health services utilization and mortality differ by marital status for both sexes in most conditions, but little is known about dermatological diseases. We evaluated whether marital status is associated with the impact that dermatological diseases have on quality of life (QoL). Data from two surveys on dermatological outpatients were pooled. Marital status, sex, age, and educational level were analysed in relation to QoL (using the scales of the Skindex-29 questionnaire: emotions, symptoms, and functioning) and psychological well-being (using the GHQ-12 questionnaire). Data on 5,471 patients (59% females, 46% married) were obtained. Married patients in univariate analysis had lower mean values on the emotions scale and higher mean values in the symptoms scale of the Skindex-29 compared to singles. Statistically significant differences were identified only in men, for the emotions scale and for the GHQ-12. Females had significantly higher mean scores than males on each of the Skindex-29 scales and on the GHQ-12. Married patients had a lower disease impact on the emotions scale even if they suffered a higher impact on the symptoms scale. However, after multiple adjustment, gender seems to be more relevant than marital status in the evaluation of health status. PMID- 22947336 TI - Expression profile of telomere-associated genes in multiple myeloma. AB - To further contribute to the understanding of multiple myeloma, we have focused our research interests on the mechanisms by which tumour plasma cells have a higher survival rate than normal plasma cells. In this article, we study the expression profile of genes involved in the regulation and protection of telomere length, telomerase activity and apoptosis in samples from patients with monoclonal gammopathy of undetermined significance, smouldering multiple myeloma, multiple myeloma (MM) and plasma cell leukaemia (PCL), as well as several human myeloma cell lines (HMCLs). Using conventional cytogenetic and fluorescence in situ hybridization studies, we identified a high number of telomeric associations (TAs). Moreover, telomere length measurements by terminal restriction fragment (TRF) assay showed a shorter mean TRF peak value, with a consistent correlation with the number of TAs. Using gene expression arrays and quantitative PCR we identified the hTERT gene together with 16 other genes directly involved in telomere length maintenance: HSPA9, KRAS, RB1, members of the Small nucleolar ribonucleoproteins family, A/B subfamily of ubiquitously expressed heterogeneous nuclear ribonucleoproteins, and 14-3-3 family. The expression levels of these genes were even higher than those in human embryonic stem cells (hESCs) and induced pluripotent stem cells (iPSCs), which have unlimited proliferation capacity. In conclusion, the gene signature suggests that MM tumour cells are able to maintain stable short telomere lengths without exceeding the short critical length, allowing cell divisions to continue. We propose that this could be a mechanism contributing to MM tumour cells expansion in the bone marrow (BM). PMID- 22947339 TI - Treatment and prognosis of nasopharyngeal angiofibroma involving the eye and optic nerve. AB - OBJECTIVE: To discuss the minimally invasive treatment and prognosis of juvenile nasopharyngeal angiofibroma involving the eye and optic nerve. METHODS: Retrospective analysis of clinical data for 18 large juvenile nasopharyngeal angiofibromas, with reports of three typical cases. RESULTS: The tumour invaded the orbit, eye, optic nerve and optic chiasm in 18, 9, 8 and 5 patients, respectively. Twelve patients were cured after surgery, with the affected eye and vision essentially returning to normal. In six patients, tumour residue was found in the middle cranial fossa; two of these six did not return for follow up. Four patients underwent radiotherapy; all four regained placement of the eye in a normal or near-normal position. One of these four patients regained normal visual acuity, two experienced no improvement in visual acuity, and one became blind. CONCLUSION: In patients with this tumour, surgery may return the eye to the normal position and may restore visual acuity if the optic fundus, macula, retina and optic nerve are only mildly affected. Modern radiotherapy can treat the intracranial residue effectively. A combined approach via the antrum, infratemporal fossa and nasal cavity, using a Caldwell-Luc incision, provides minimally invasive surgical access. PMID- 22947340 TI - CMV-associated encephalitis and antineuronal autoantibodies--a case report. AB - BACKGROUND: Human cytomegalovirus (CMV) is an ubiquitous pathogen capable of modulating the host immune system. Immune dysfunction is common during CMV infection and includes autoimmune phenomena. Here we focus on a case of primary CMV infection associated with encephalopathy in a patient with a rudimentary spleen. We discuss diagnostic challenges and immunological aspects as well as the hypothesis that CMV may break tolerance and induce potentially encephalitogenic autoantibodies. CASE PRESENTATION: A 33-year-old woman was admitted with features of encephalitis, rapidly progressing into a catatonic state. The patient tested negative for presence of herpes simplex virus DNA in cerebrospinal fluid (CSF), and had elevated liver enzymes and hepatomegaly at computed tomography scan (CT) examination. CT scan and magnetic resonance imaging (MRI) showed only a rudimentary spleen. Initially, serum was negative for anti-CMV IgM, but borderline for anti-CMV IgG by enzyme-linked immunosorbent assay. However, a more sensitive assay resulted in a positive specific IgM Western blot profile and low IgG avidity, suggesting primary CMV infection. Further, CMV DNA was retrospectively detected in a CSF sample collected at admission. We also detected antineuronal autoantibodies, which stained GAD-positive neurons in the hippocampus. The patient was treated by a combination of prednisone, intravenous immunoglobulins (IVIg) and antivirals, which resulted in a dramatic amelioration of the patient's neurological status. One year after admission the patient exhibited a nearly complete recovery with mild deficits in attention and memory. CONCLUSIONS: A possible reason for the critical course of CMV infection could be the lack of a functional spleen in this patient, a condition previously associated with severe CMV infection. Prompt treatment with antiviral drugs, steroids and IVIg was most likely important for the positive outcome in this case and should be considered for similar cases of severe primary CMV infection associated with immunopathological phenomena. PMID- 22947341 TI - Isolation and functional analysis of the promoter of the amphioxus Hsp70a gene. AB - Amphioxus is a promising laboratorial model animal for studying the evolutionary and developmental mechanisms that appeared during the invertebrate-chordate to vertebrate transition. However, the main drawback for the use of amphioxus as a model organism is the lack of well-developed technical approaches. Conditional gene expression, as performed with thermal control, is a very useful strategy in gene function studies. To make this method possible in amphioxus studies, here we report the isolation and characterization of an amphioxus Hsp70 gene (Hsp70a) and its promoter in Chinese amphioxus (Branchiostoma belcheri). Hsp70a showed very low expression at normal temperatures but was robustly induced in animals upon heat shock. The basal cis-acting elements (CAAT and TATA), as well as four heat shock elements (HSEs), were found within the regulatory region (-1031 to -11 upstream from the start codon), but surprisingly most of the elements were located in the 5'UTR region (-252 to -10). Reporter constructs, including sequences from both the transcription start site (TSS) and ATG were tested for transient expression in EPC cells and microinjected zebrafish embryos. Results suggested that the 5'UTR region, which includes a TATA box at -92bp, a CAAT box at -152bp, and three HSE elements (-212 to -106), represents the core hsp promoter sequence of the B. belcheri Hsp70a gene. Therefore in this study we identified an effectively thermo-inducible promoter in amphioxus that could be used for the establishment of a conditional gene expression system in which the target gene can be regulated in a temporal- or tissue-specific way in amphioxus. PMID- 22947342 TI - Reducing salt intake for prevention of cardiovascular diseases in high-risk patients by advanced health education intervention (RESIP-CVD study), Northern Thailand: study protocol for a cluster randomized trial. AB - BACKGROUND: Decreasing salt consumption can prevent cardiovascular diseases (CVD). Practically, it is difficult to promote people's awareness of daily salt intake and to change their eating habits in terms of reducing salt intake for better cardiovascular health. Health education programs visualizing daily dietary salt content and intake may promote lifestyle changes in patients at high risk of cardiovascular diseases. METHODS/DESIGN: This is a cluster randomized trial. A total of 800 high-CVD-risk patients attending diabetes and hypertension clinics at health centers in Muang District, Chiang Rai province, Thailand, will be studied with informed consent. A health center recruiting 100 participants is a cluster, the unit of randomization. Eight clusters will be randomized into intervention and control arms and followed up for 1 year. Within the intervention clusters the following will be undertaken: (1) salt content in the daily diet will be measured and shown to study participants; (2) 24-hour salt intake will be estimated in overnight-collected urine and the results shown to the participants; (3) a dietician will assist small group health education classes in cooking meals with less salt. The primary outcome is blood pressure change at the 1-year follow up. Secondary outcomes at the 1-year follow-up are estimated 24-hoursalt intake, incidence of CVD events and CVD death. The intention-to-treat analysis will be followed.Blood pressure and estimated 24-hour salt intake will be compared between intervention and control groups at the cluster and individual level at the 1-year follow-up. Clinical CVD events and deaths will be analyzed by time event analysis. Retinal blood vessel calibers of CVD-risk patients will be assessed cross-sectionally. Behavioral change to reduce salt intake and the influencing factors will be determined by structured equation model (SEM). Multilevel regression analyses will be applied. Finally, the cost effectiveness of the intervention will be analyzed. DISCUSSION: This study is unique as it will recruit the individuals most vulnerable to CVD morbidity and mortality by applying the general Framingham CVD risk scoring system. Dietary salt reduction will be applied as a prioritized, community level intervention for the prevention of CVD in a developing country. TRIAL REGISTRATION: ISRCTN39416277. PMID- 22947343 TI - Methodology on the My World Survey (MWS): a unique window into the world of adolescents in Ireland. AB - BACKGROUND: Internationally, 75% of all mental health problems emerge before the age of 25 years, and adolescence represents a critical period that strongly influences the course of these problems. To date, there is limited research on the mental health of young people aged 12-25 years in Ireland. The My World Survey (MWS) national study provides data on risk and protective factors of mental health among 14 306 young people. The MWS was conducted in two phases: Phase 1 - MWS-Second Level (MWS-SL) with adolescents aged 12-19 years, and Phase 2 - MWS-Post Second Level among young adults aged 17-25 years. AIM: This article provides a comprehensive overview of the development of the MWS-SL study. Another aim is to identify key learning points when conducting research in the second level school system. METHODS: The MWS-SL study was conducted with 6085 adolescents aged 12-19 years in 72 second-level schools. The MWS consists of standardized reliable and valid measures that have been used internationally to assess a range of risk and protective factors associated with adolescent mental health. RESULTS: Schools recruited for the MWS-SL study represented quite well the national distribution of second-level schools based on gender composition, disadvantaged/non-disadvantaged status and geographic location. CONCLUSIONS: Key learning points when collecting survey data in schools include pilot testing of survey instruments; building relationships with key stakeholders to ensure buy-in for the study from schools; establishing rigorous data collection and processing protocols; and recognizing the value of online surveys. PMID- 22947344 TI - Efficacy and safety of subcutaneous allergen-specific immunotherapy with depigmented polymerized mite extract in atopic dermatitis. AB - BACKGROUND: Exposure to house dust mites (HDMs) aggravates the course of atopic dermatitis (AD) in patients sensitized to HDMs. OBJECTIVES: This study investigated the efficacy and safety of subcutaneous allergen-specific immunotherapy with the use of depigmented polymerized mite extract as an add-on therapy to basic (ie, topical and, as necessary, systemic) medication. METHODS: Patients (n = 168) were recruited in a randomized, double-blind, placebo controlled parallel group phase III study conducted in Germany (21 sites), in adult patients with AD aggravated by HDMs. The primary end points of the study were the assessments of the area under the curves of the total Severity Scoring Atopic Dermatitis (SCORAD) score and of the use of basic medication during the 18 month treatment period. Post hoc subgroup analyses were also performed. RESULTS: Overall efficacy analysis of the intention-to-treat and per-protocol study populations showed no statistically significant differences between the active treatment and placebo groups. However, the subgroup of patients with severe AD (SCORAD > 50) showed a statistically significant reduction of the median total SCORAD by 18% (P = .02) compared with placebo. The frequency of adverse reactions was similar in both groups, suggesting the safety of the active treatment. CONCLUSION: Although subcutaneous allergen-specific immunotherapy showed no statistically significant difference in the overall population of patients with AD, statistically significant reduction of the total SCORAD could be achieved in a subgroup of patients with severe AD. PMID- 22947345 TI - Parent report of physician diagnosis in pediatric food allergy. AB - BACKGROUND: Childhood food allergy is a serious health problem. However, little is known about the frequency and manner in which it is currently diagnosed. OBJECTIVE: To describe parent report of physician practices in the diagnosis of pediatric food allergy. METHODS: Data from children with food allergy were identified for analysis from a representative survey administered in US households with children from June 2009 to February 2010. Analyses were performed at the level of the allergy. Demographic characteristics, symptom prevalence, and diagnostic methods were calculated as weighted proportions. Adjusted models were estimated to examine the association of reaction history and allergenic food with odds of physician diagnosis and testing. RESULTS: Food allergies (n = 3,218) to 9 common allergens were reported among 2,355 children in a sample of 38,480. We found that 70.4% of reported food allergy was diagnosed by a physician. Among physician-diagnosed food allergy, 32.6% was not evaluated with diagnostic testing, 47.3% was assessed with a skin prick test, 39.9% with a serum specific IgE test, and 20.2% with an oral food challenge. Odds of physician diagnosis and testing were significantly higher for severe versus mild/moderate food allergy. Urticaria and angioedema were not reported as symptoms in 40.7% and 34.6% of severe food allergies, respectively. CONCLUSION: Thirty percent of parent reported food allergies in this study were not diagnosed by a physician. One in 5 physician-diagnosed allergies was evaluated with oral food challenge. Understanding parent report of practices in food allergy provides insight into ways in which to streamline the diagnosis and management of care. PMID- 22947347 TI - Long-term 3,5,3'-triiodothyroacetic acid therapy in a child with hyperthyroidism caused by thyroid hormone resistance: pharmacological study and therapeutic recommendations. AB - BACKGROUND: The effectiveness of short-term 3,5,3'-triiodothyroacetic acid (TRIAC) therapy for the treatment of hyperthyroidism caused by thyroid hormone resistance (RTH) has been documented. Here, we report a 3-year course of TRIAC therapy in an RTH boy, with a quantitative evaluation of the therapeutic effects and pharmacological study of TRIAC. PATIENT FINDINGS: The gene encoding the thyroid hormone receptor beta (THRB) of the patient carries a P453T mutation. During treatment with up to 3.0 mg TRIAC per day, reduction in the thyroid volume, resolution of supraventricular arrhythmia, and decrease in thyroid stimulating hormone (TSH) and free-thyroxine (FT4) levels were achieved. In addition, attention-deficit hyperactivity disorder (ADHD) symptoms improved, with a concomitant decline in the ADHD Rating Scale score. SUMMARY: A TRIAC pharmacokinetic study, conducted using triiodothyronine level as a surrogate for TRIAC level, demonstrated that TRIAC disappears from the circulation rapidly and has a shorter duration of TSH secretion inhibitory effect in the RTH patient compared to that in the control subject. Studies of TSH and FT4 levels over a period of 3 years indicated that the TRIAC effect is dose dependent. CONCLUSIONS: TRIAC was effective and safe in ameliorating the effects of hyperthyroidism and ADHD symptoms in a child with known genetic RTH. Further, it was demonstrated that TRIAC has a short half-life and functions dose dependently. PMID- 22947346 TI - Corticosteroid insensitivity of chemokine expression in airway smooth muscle of patients with severe asthma. AB - BACKGROUND: Patients with severe asthma are less responsive to the beneficial effects of corticosteroid therapy. OBJECTIVE: We investigated whether corticosteroid insensitivity was present in airway smooth muscle cells (ASMCs) of patients with severe asthma. METHODS: ASMCs cultured from bronchial biopsy specimens of nonasthmatic control subjects (n = 12) and patients with nonsevere (n = 10) or severe (n = 10) asthma were compared for the effect of dexamethasone on suppression of TNF-alpha- and IFN-gamma-induced CCL11 (eotaxin), CXCL8 (IL-8), and CX3CL1 (fractalkine) expression. The mechanisms of corticosteroid insensitivity are also determined. RESULTS: CCL11 release was higher in ASMCs of patients with nonsevere but not severe asthma and nonasthmatic control subjects; CXCL8 and CX3CL1 release were similar in all groups. In patients with severe asthma, dexamethasone caused less suppression of CCL11 and CXCL8 release induced by TNF-alpha. Dexamethasone potentiated TNF-alpha- and IFN-gamma-induced CX3CL1 release equally in all 3 groups. TNF-alpha-induced phosphorylated p38 mitogen activated protein kinase levels were increased in ASMCs from patients with severe asthma compared with those from patients with nonsevere asthma and nonasthmatic subjects, whereas TNF-alpha-induced phosphorylated c-Jun N-terminal kinase and phosphorylated extracellular signal-related kinase levels were increased in all asthmatic groups. A p38 inhibitor increased the inhibitory effect of dexamethasone. CONCLUSIONS: ASMCs of patients with severe asthma are corticosteroid insensitive; this might be secondary to heightened p38 mitogen activated protein kinase levels. PMID- 22947348 TI - Hypothyroidism and levothyroxine-responsive liver dysfunction in a patient with ring chromosome 18 syndrome. AB - BACKGROUND: Ring chromosome 18 [r18] is a rare constitutional chromosomal aberration syndrome, characterized by dysmorphic face, hypoactivity, short stature, and delayed development. Autoimmune thyroiditis and immunoglobulin (Ig) A deficiency are occasionally associated with chromosome-18 deletion syndromes. SUMMARY: Here, we report a 2-year-old male child with r(18) syndrome and a selective IgA deficiency (<1.6 mg/dL, reference range [rr]: 20-149), who developed hypothyroidism and liver dysfunction. Thyroid function tests (thyroid stimulating hormone [TSH]: 1031 MUIU/mL, rr 0.43-4.0; free triiodothyronine: 0.52 pg/mL, rr 2.37-4.65; free thyroxine: 0.11 ng/dL, rr 1.03-2.00) and positive thyroid antibodies (anti-TSH receptor 1.7 IU/L, cut-off index [coi]: <1.0, antithyroid peroxidase 171 IU/mL, coi <0.3, and antithyroglobulin 2.8 IU/mL, coi <0.3) indicated autoimmune hypothyroidism. Elevated levels of aspartate aminotransferase (AST, 240 IU/L, rr 17-39) and alanine aminotransferase (ALT, 315 IU/L, rr 4-23), but negative antibodies against LKM and mitochondrial M2, suggested no autoimmune hepatitis. Transaminase levels became normalized after he was given levothyroxine therapy to achieve the euthyroid state, but they repeatedly became elevated when levothyroxine was inadvertently discontinued (peak AST=409 IU/L; peak ALT=390 IU/L). A maintenance dose of levothyroxine has effectively maintained the euthyroid state and normalized liver function tests despite no immunosuppressive therapy. CONCLUSIONS: The r18 patient with autoimmune hypothyroidism and IgA deficiency suffered from idiopathic hepatitis. The liver dysfunction was associated with hypothyroidism that resolved with thyroid hormone treatment. While the former combination has been described, the latter has not. The reason for the development of hepatitis in association with hypothyroidism is unexplained. However, we postulate that it might be related, in ways that are not clear, to the deleted genes of r18. PMID- 22947349 TI - Asymptomatic thyrotropin-secreting pituitary macroadenoma in a 13-year-old girl: successful first-line treatment with somatostatin analogs. AB - BACKGROUND: Thyrotropin-secreting pituitary adenomas (TSHomas) are an extremely rare cause of hyperthyroidism. Up to now there are only few cases reported in the pediatric age range. Thefirst therapeutic option is surgical resection, whereas medical treatment with somatostatin analogs has been reported only in cases wherein surgery was unsuccessful. PATIENT FINDINGS: A 13-year-old girl was referred to our clinic for incidental finding of increased circulating free thyroid hormones in the presence of detectable TSH concentrations. She had no signs/symptoms of thyrotoxicosis. Resistance to thyroid hormone was excluded due to the lack of TSH response after thyrotropin-releasing hormone (TRH) stimulation test. Cerebral magnetic resonance imaging showed the presence of a large pituitary macroadenoma, with intra- and suprasellar extension. We decided to treat this patient with somatostatin analog as a first-line therapy because of high surgery risks due to the tumor dimensions. The response to medical treatment was excellent, with rapid and significant tumor shrinkage. No major side effects were reported. The patient developed central hypothyroidism that was corrected with L-thyroxine therapy. SUMMARY: We report the first pediatric case of TSHoma treated with somatostatin analog as a first-line therapy. The diagnosis was challenging because of the insidious and asymptomatic presentation of the tumor. CONCLUSIONS: We conclude that somatostatin analogs should be considered as first choice, bridge-to-surgery treatment in young patients, in order to reduce neurosurgical complications and prevent hypopituitarism during pubertal development. PMID- 22947350 TI - Clinical and pathologic features of "sporadic" papillary thyroid carcinoma registered in the years 2005 to 2008 in children and adolescents of Belarus. AB - BACKGROUND: A systematic analysis of the clinical and pathologic patterns of childhood "sporadic" thyroid carcinoma in Belarus, in the absence of the "Chernobyl radioactive iodine factor," has never been performed. The aim of this study was to establish the essential features of "sporadic" papillary thyroid carcinoma (PTC) in Belarusian children and adolescents, and the relationship of tumor pathology to extrathyroidal extension (ETE) and lymph node metastases. METHODS: This was a retrospective population-based study with assessment of histological samples of 119 cases of thyroid cancer in Belarusian children and adolescents of 0-18 years old registered during 2005-2008 years. Sporadic PTC was noted in 94 children who were not exposed to the Chernobyl radiation release. None of the 119 cases of thyroid were follicular thyroid cancer. RESULTS: The incidence rate of PTC was 1.13 per 100,000 persons. The median age at diagnosis was 15.1 years with fourfold predominance of diagnosis in female patients. Relapse was detected in 2% of cases with median follow-up of 4.2 years. Median tumor size was 12 mm. Three percent of the cases of PTC had multifocal growth. The classical variant of PTC was registered in 46% of the patients with thyroid cancer, the follicular variant of PTC was noted in 20% of the cases. The percent of rare types of PTC (tall cell and diffuse sclerosing) were equal to that for solid PTCs (13%, 12%, and 10%, respectively). Adolescents had a pure papillary carcinoma more often compared to children who represented tumors with mixed papillary/follicular patterns more frequently (p<0.05). Two-thirds of the patients with PTC had regional lymph node metastases. ETE was established in 39 of 74 patients in whom ETE could be assessed by morphology. Multivariate analysis showed that lymphatic invasion was the strongest independent factor associated with both ETE (p<0.0001) and lymph node metastases (p<0.0001). CONCLUSION: In 2005-2008, sporadic thyroid cancer in children of Belarus was represented by high prevalence of PTC and absence of follicular thyroid cancer. Sporadic cases of PTC in Belarus were characterized by smaller tumor size, a small number of cases with multifocal growth, an equal number of rare types and solid PTCs, a relatively high prevalence of pure papillary variant of PTC in adolescents, and a low frequency of early relapses. A high frequency of ETE and lymph node metastases was detected. The strongest morphologic factor associated with both of them was lymphatic invasion. PMID- 22947352 TI - Seasonal iodine deficiency in Latvian school children. PMID- 22947353 TI - Combined blockade of the renin system: an example of hormesis. PMID- 22947351 TI - Fortification of bread with iodized salt corrected iodine deficiency in school aged children, but not in their mothers: a national cross-sectional survey in Belgium. AB - BACKGROUND: In the years 1985-1998, it was noted that mild iodine deficiency (MID) was a public health problem in Belgium. Therefore, an agreement was signed in 2009 between the bakery sector and the Ministry of Health, to fortify bread with iodized salt. We tested the hypothesis that the iodine status of Belgian children improved after the introduction of bread fortified with iodized salt. Since the dietary habits of children and adults may differ, we also investigated whether the median urinary iodine concentration (UIC) among the children in this study reflected the iodine status of their mothers. METHODS: The study was cross sectional. In a van, equipped with an ultrasound device, the thyroid volumes (Tvol) of children were measured and household salt samples and urine samples were collected from the children and their mothers. From across Belgium, 60 schools were selected and 1541 children participated in the study. RESULTS: The median UIC in children was 113.1 and 84.4 MUg/L among their mothers. The median UIC among children was substantially greater compared to more than 10 years ago (80 MUg/L; p<0.001). The median UIC in school-aged children was lower in Wallonia than in Flanders (p<0.001) and was higher in boys than in girls (p<0.001). The percentage of children with goiter was 7.2%. Of the 904 salt samples received, 63.2% did not contain iodine. CONCLUSIONS: Fortification of bread with iodized salt corrected iodine deficiency in Belgian children, but not in their mothers. To provide these women with an adequate iodine intake, the use of both iodized salt in bread and iodized instead of noniodized household salt needs to increase. Our findings suggest that the median UIC in children may not be an adequate surrogate of adults' iodine status. Therefore, monitoring iodine status should not be limited to children, but should be extended to women of child-bearing age. PMID- 22947354 TI - Comparison of two noninvasive devices for measurement of central systolic blood pressure with invasive measurement during cardiac catheterization. AB - Recently, a new device for noninvasive assessment of central systolic blood pressure (cSBP) (BPro device with A-Pulse) was approved by the US Food and Drug Administration, but available data are limited. In 52 patients undergoing invasive elective cardiac evaluation, central hemodynamics were measured invasively. Immediately thereafter, radial artery waveforms were sampled by two noninvasive techniques, the BPro and, as a comparator, the SphygmoCor System. Then, central hemodynamics were measured invasively for a second time. The invasively recorded cSBP (137 +/- 27 mm Hg) did not differ with both noninvasively assessed cSBP by BPro (136 +/- 21 mm Hg, P = .627 vs invasive cSBP) and by SphygmoCor (136 +/- 23 mm Hg, P=.694 vs invasive cSBP) and correlated highly between invasively recorded and both noninvasively assessed cSBP. However, using Bland-Altman plots, spreading of compared data of both devices can be found (BPro: 0.87 +/- 13 mm Hg vs invasive cSBP; SphygmoCor: 0.77 +/- 14 mm Hg vs invasive cSBP). There was an excellent correlation of both noninvasive devices for the calculation of cSBP (r=0.961, P<.001). cSBP differed by only 0.1 +/- 6 mm Hg (P=.913) between the two noninvasive devices. Therefore, both noninvasive devices showed an accurate agreement in cSBP compared with invasively measured cSBP. PMID- 22947355 TI - The effects of aldosterone synthase inhibition on aldosterone and cortisol in patients with hypertension: a phase II, randomized, double-blind, placebo controlled, multicenter study. AB - Blockade of the renin-angiotensin-aldosterone system (RAAS) is an established method to lower blood pressure in patients with hypertension. Aldosterone, the end product of the RAAS cascade, acts by increasing salt reabsorption in the kidney and catecholamine release from the adrenal medulla. Currently available aldosterone inhibitors have the disadvantage of increasing circulating aldosterone and thus may lead to aldosterone breakthrough. Aldosterone synthase inhibition (ASI) is a novel approach to suppressing the RAAS. Due to homology between the enzymes responsible for aldosterone synthesis (CYP11B2) and cortisol synthesis (CYP11B1), the blockade of aldosterone synthesis may also suppress cortisol release. The authors evaluated the effect of the novel ASI LCI699 on the cortisol response to adrenocorticotropic hormone (ACTH) stimulation in patients with hypertension in order to find the maximally tolerated dose (MTD) in this patient population. Among the 63 patients evaluated, there was a dose- and time dependent effect of LCI699 on both aldosterone and ACTH-stimulated cortisol. Based on exposure-response analysis, the MTD was estimated to be 1.30 mg once daily with a 90% prediction interval of 0.88 mg once daily to 1.81 mg once daily. No patients required intervention for adrenal insufficiency. LCI699 was well tolerated with no serious adverse events. PMID- 22947356 TI - Blood pressure effects of combined beta-blocker and angiotensin-converting enzyme inhibitor therapy compared with the individual agents: a placebo-controlled study with nebivolol and lisinopril. AB - Blood pressure (BP) reductions when combining blockers of the renin-angiotensin system (RAS) and beta-blockers have generally not been shown to be greater than for individual agents, possibly because of overlapping mechanisms of action. The authors tested the additivity of the beta-blocker nebivolol, which has vasodilating activity, with the angiotensin-converting enzyme inhibitor lisinopril in patients with stage 2 diastolic hypertension. The BP effects of placebo (n=93), nebivolol 5 mg to 20 mg daily (n = 185), lisinopril 10 mg to 40 mg daily (n=189), and nebivolol 5 mg to 20 mg + lisinopril 10 mg to 40 mg (n=189) during 6 weeks of treatment were compared. The primary end point was change in diastolic BP (DBP). For the full cohort, baseline BP was 163.8/104.4 mm Hg, mean age was 49.2 years, 58% were men, 62% were white, and 34% were black. DBP fell by 17.2 +/- 10.2 mm Hg with the combination, greater than placebo (8.0 +/- 9.2, P<.0001), nebivolol (13.3 +/- 8.9, P=.0010), and lisinopril (12.0 +/- 9.8, P<.0001). For systolic BP, corresponding reductions were 19.2 +/- 19.8 mm Hg, 9.9 +/- 16.4 (P<.0001 vs combination), 14.4 +/- 14.1 (P=.0470), and 16.1 +/- 17.2 (P=.0704). Adverse event rates were similar in all groups. This study demonstrated the potential antihypertensive benefits of combining nebivolol with a RAS blocker. PMID- 22947357 TI - Central/Peripheral fat mass ratio is associated with increased risk of hypertension in HIV-infected patients. AB - The data on the risk of hypertension in human immunodeficiency virus (HIV) infected patients, particularly in those with lipodystrophy, are controversial. The authors assessed the impact of lipodystrophy on hypertension in a cohort of HIV-infected adults receiving combination antiretroviral therapy. This was a cross-sectional study in which lipodystrophy (clinically and fat mass ratio [FMR] defined), blood pressure, and body composition (dual-energy x-ray absorptiometry and computed tomography) were evaluated in 368 HIV adults. The prevalence of hypertension in HIV patients with or without clinically or FMR-defined lipodystrophy was similar (with clinical lipodystrophy 35.3% vs without 32.9%, not significant; with FMR lipodystrophy 41.7% vs without 32.2%, not significant). When HIV-infected patients were classified into 4 categories of fat distribution (based on the presence or absence of lipoatrophy and abdominal prominence), isolated lipoatrophy was not significantly associated with hypertension, but patients with isolated central fat accumulation and mixed forms of lipodystrophy had a significantly higher prevalence of hypertension. Hypertensive HIV patients had significantly higher total fat, central, and central/peripheral fat mass ratio than normotensive ones. After adjustment for age, sex, smoking, and body mass index, hypertension remains significantly associated with central/peripheral fat mass ratio (odds ratio, 1.258; 95% confidence interval, 1.008-1.569). Hypertension was not more prevalent in lipodystrophic HIV-infected patients, but was significantly associated with central/peripheral fat mass ratio. PMID- 22947358 TI - Comparative effectiveness analysis of amlodipine/renin-angiotensin system blocker combinations. AB - A comparative effectiveness analysis of antihypertensive therapy amlodipine (AML) and angiotensin receptor blocker (ARB) fixed- and loose-dose combinations (FDCs and LDCs) in achieving blood pressure (BP) reduction and Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure (JNC 7) goal attainment was made using retrospective electronic medical record (EMR) data. Treatment goal rates ranged from 35.0% for LDC AML/losartan to 45.7% for FDC AML/olmesartan (OM). FDC AML/OM achieved significantly greater reductions in systolic BP than FDC AML/benazepril (BEN), FDC AML/valsartan (VAL), and LDC AML/ARBs, respectively, and significantly greater reductions in diastolic BP than FDC AML/VAL and LDC therapy, respectively. Compared with patients treated with AML/OM, patients prescribed AML/VAL and LDC AML/ARB were significantly less likely to attain JNC 7 BP goal. Among subpopulations, AML/OM yielded higher rates of goal attainment among both African Americans and obese/overweight patients relative to AML/VAL and combined LDCs. Switchers from monotherapy with AML, OM, or VAL to AML/OM were significantly more likely to attain JNC 7 goals than those switching to AML/VAL or AML/BEN. PMID- 22947359 TI - Ambulatory blood pressure monitoring in patients with chronic kidney disease and resistant hypertension. AB - The role of ambulatory blood pressure (BP) monitoring (ABPM) has not been well studied in patients with chronic kidney disease and resistant hypertension. In a retrospective study of the outpatient chronic kidney disease population, 156 patients with chronic kidney disease and resistant hypertension who had 24-hour ABPM and clinic BP measurements were identified. Resistant hypertension was defined as uncontrolled clinic BP while taking >= 3 medications including a diuretic or controlled BP while taking >= 4 medications. Within the study group, ambulatory BP <130/80 mm Hg was found in 35.9% of all patients. Only 6.4% had both ambulatory and clinic BP <130/80 mm Hg. Prevalence of white-coat hypertension, masked hypertension, and sustained hypertension were 29.5%, 5.8%, and 58.3%, respectively. Compared with patients with sustained hypertension, more patients in the white-coat hypertension group had low nocturnal average systolic BP (defined as nocturnal average systolic BP <100 mm Hg) (17.4% vs 0%) and low 24 hour average diastolic BP (defined as 24-hour average diastolic BP <60 mm Hg) (52.2% vs 22%, P<.01). ABPM provides more reliable assessment of BP in patients with chronic kidney disease and resistant hypertension. PMID- 22947360 TI - Relationship of resistant hypertension and treatment outcomes with total arterial compliance in a predominantly African American hypertensive cohort. AB - Resistant hypertension (RH) affects 8% to 30% of hypertensive patients. Blood pressure (BP) reflects the interaction between vascular compliance, resistance to flow, intravascular volume, and cardiac contractility. The relationship of RH with total arterial compliance index (TACI) has not been adequately explored. The RH period prevalence (RH at baseline or follow-up) was determined in a hypertensive cohort (N=156) and compared across quartiles of TACI. Age- and sex adjusted systolic BP, diastolic BP, and antihypertensive therapeutic intensity score (TIS) were also determined at the time of first BP control. The cohort was 85.3% African American and 67.3% female. Median follow-up was 7 months. The prevalence of RH at baseline was 14.7% while the period prevalence was 43.6%. The period prevalence of RH by ascending quartile for TACI was 66%, 36.8%, 40%, and 30.8% (P=.008). The average BP and antihypertensive TIS at first BP control across TACI quartiles was 122.3/73.4 mm Hg (2.26), 120.7/72.5 mm Hg (1.88), 122.4/75.3 mm Hg (1.71), and 120.0/79.4 mm Hg (1.64) (P=.62, P=.03, P=.13). Low TACI was linked to higher RH prevalence and antihypertensive TIS at first attainment of goal BP according to the Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure. TACI provides prognostic information that is clinically and perhaps pathophysiologically relevant in RH. PMID- 22947361 TI - The comparative effectiveness of hydrochlorothiazide and chlorthalidone in an observational cohort of veterans. AB - Indirect evidence suggests that chlorthalidone may be more effective than hydrochlorothiazide (HCTZ), but direct comparisons are lacking. Using national Veterans Administrative pharmacy data from 2003 to 2008, the authors performed a retrospective cohort study examining the effectiveness of chlorthalidone and HCTZ among new thiazide users. For 1 year following the thiazide start, rates of persistence of thiazide use, adequacy of response (defined as the absence of additional new antihypertensive medications following thiazide initiation), and an overall composite of treatment effectiveness incorporating both outcomes were examined. In this cohort of >125,000 individuals, persistence of thiazide use was higher for HCTZ than chlorthalidone (72.0% vs 62.0%; P<.001), but among thiazide persistent users, more HCTZ users had additional antihypertensives added compared with chlorthalidone (76.4% vs 70.1%; P<.001). The overall composite treatment response (thiazide persistence and no antihypertensive additions) revealed a slight advantage for HCTZ over chlorthalidone (50.7% vs 47.4%; P=.002). These findings remained consistent after adjustment using multivariable logistic regression. This study provides real-world clinical data supporting a potential efficacy advantage of chlorthalidone among patients who tolerate the drug and remain persistent with treatment; however, strategies to optimize the way chlorthalidone is prescribed in clinical practice are necessary to increase its overall effectiveness relative to HCTZ. PMID- 22947362 TI - Acute and long-term hemodynamic effects of sesame oil consumption in hypertensive men. AB - The possible effects of sesame oil on hemodynamics are unknown. The aim of the study was to investigate the acute and long-term effects of sesame oil on hemodynamic responses in hypertensive men. The authors enrolled 30 hypertensive men in a two-phase study. In the first phase, patients consumed 35 g of either sesame oil or control oil. Central and peripheral blood pressure, pulse wave velocity, augmentation index (AI), C-reactive protein, tumor necrosis factor alpha, malonydealdehyde, and total antioxidant capacity (TAC) were assessed at fast and 2 hours postprandially. In the second phase, patients consumed 35 g of either sesame oil or control oil daily for 2 months. The above-mentioned parameters were assessed before and following 15, 30, and 60 days of oil consumption. Sesame oil decreased central and peripheral diastolic pressures 1 hour postprandially (P=.006). Fifteen days of sesame oil intake decreased peripheral systolic blood pressure (P=.016) and heart rate-corrected AI75 (P=.017) and increased TAC (P=.007). This is the first study to demonstrate a favorable acute and long-term effect of sesame oil on hemodynamics in hypertensive men. Further research is warranted to establish the potential protective role of sesame oil. PMID- 22947363 TI - Trends in hypertension prevalence, awareness, treatment, and control rates in Shandong Province of China. AB - The authors retrospectively examined data from 3 surveys on hypertension according to the 2010 Chinese Guidelines for the Management of Hypertension. These surveys were conducted in 1991, 1999, and 2007, and included 85,371 individuals 18 years and older who were living in Shandong Province, China. Age standardized prevalent hypertension increased from 15.6% in 1991 to 17.3% in 1999 and 32.7% in 2007 (both P<.0001). The ascending prevalence can be partially explained by increasing body weight. Among individuals with hypertension, awareness increased significantly from 27.8% in 1991 to 39.1% in 1999 and 49.2% in 2007. The proportion of pharmacologic treatment also considerably improved, with the estimate of 12.9%, 28.1%, and 43.3% in the 3 surveys, respectively. Hypertension control increased from 3.0% to 4.4% to 7.1% in the past 20 years. The upward trend in blood pressure control was mostly attributable to a rise among men and persons at middle age. This study suggests that the prevalence of hypertension increased in the Shandong population from 1991 to 2007. Although substantially improved, control rates were still unacceptably low. Comprehensive strategies are urgently required to put into practice for the management of hypertension in Shandong Province, China. PMID- 22947364 TI - The pleiotropic effects of phosphodiesterase 5 inhibitors on function and safety in patients with cardiovascular disease and hypertension. AB - Phosphodiesterase 5 (PDE-5) inhibitors are selective blockers of PDE-5, which catalyzes the hydrolysis of cyclic guanosine monophosphate (cGMP) to its corresponding monophosphates. cGMP is a potent vasodilator and nitric oxide donor. Since PDE-5 is widely distributed in the body, it was hypothesized that inhibition of its actions could lead to significant vasodilation, which could benefit patients with coronary artery disease. This hypothesis led to the development of PDE-5 inhibitors, the first being sildenafil citrate. Studies of sildenafil in patients with coronary artery disease demonstrated a modest cardiovascular effect but a potent action on penile erection in men, resulting in sildenafil becoming first-line treatment of erectile dysfunction. Two more PDE-5 inhibitors are now US Food and Drug Administration-approved (vardenafil and tadalafil) for the treatment of erectile dysfunction. Recent studies have demonstrated several beneficial pleiotropic cardiovascular effects of PDE-5 inhibitors in patients with erectile dysfunction and multiple comorbidities, including coronary artery disease, heart failure, hypertension, and diabetes mellitus. Treatment of these conditions with PDE-5 inhibitors has been very effective, safe, and well tolerated. Drug interactions have been minimal with the exception of nitrates, where coadministration may result in severe vasodilation and hypotension. These beneficial pleiotropic and safe cardiovascular effects of PDE-5 inhibitors will be discussed in this concise review. PMID- 22947366 TI - Hyponatremia and thiazides. PMID- 22947365 TI - Cardiac arrest in a patient with asthma: role of hemorrhagic pheochromocytoma discovered at autopsy. PMID- 22947367 TI - Improved heart rate dynamics in patients undergoing percutaneous renal denervation. PMID- 22947368 TI - Effect of hypokalemia on the clinical impact of hyponatremia. PMID- 22947369 TI - Growing old before growing rich: inequality in health service utilization among the mid-aged and elderly in Gansu and Zhejiang Provinces, China. AB - BACKGROUND: China's recent growth in income has been unequally distributed, resulting in an unusually rapid retreat from relative income equality, which has impacted negatively on health services access. There exists a significant gap between health care utilization in rural and urban areas and inequality in health care access due to differences in socioeconomic status is increasing. We investigate inequality in service utilization among the mid-aged and elderly, with a special attention of health insurance. METHODS: This paper measures the income-related inequality and horizontal inequity in inpatient and outpatient health care utilization among the mid-aged and elderly in two provinces of China. The data for this study come from the pilot survey of the China Health and Retirement Longitudinal Study in Gansu and Zhejiang. Concentration Index (CI) and its decomposition approach were deployed to reflect inequality degree and explore the source of these inequalities. RESULTS: There is a pro-rich inequality in the probability of receiving health service utilization in Gansu (CI outpatient = 0.067; CI inpatient = 0.011) and outpatient for Zhejiang (CI = 0.016), but a pro poor inequality in inpatient utilization in Zhejiang (CI = -0.090). All the Horizontal Inequity Indices (HI) are positive. Income was the dominant factor in health care utilization for out-patient in Gansu (40.3 percent) and Zhejiang (55.5 percent). The non-need factors' contribution to inequity in Gansu and Zhejiang outpatient care had the same pattern across the two provinces, with the factors evenly split between pro-rich and pro-poor biases. The insurance schemes were strongly pro-rich, except New Cooperative Medical Scheme (NCMS) in Zhejiang. CONCLUSIONS: For the middle-aged and elderly, there is a strong pro-rich inequality of health care utilization in both provinces. Income was the most important factor in outpatient care in both provinces, but access to inpatient care was driven by a mix of income, need and non-need factors that significantly differed across and within the two provinces. These differences were the result of different levels of health care provision, different out-of-pocket expenses for health care and different access to and coverage of health insurance for rural and urban families. To address health care utilization inequality, China will need to reduce the unequal distribution of income and expand the coverage of its health insurance schemes. PMID- 22947370 TI - Utilizing conformational changes for patterning thin films of recombinant spider silk proteins. AB - Recombinant spider silk proteins mimicking the properties of dragline silk proteins represent a class of materials that hold great potential for future high performance applications. Here we explore the self-assembly behavior of a recombinantly produced spider silk protein based on the dragline silk of the Araneus diadematus , eADF4 (C16), by selectively patterning its secondary structure using capillary transfer lithography and solvent-assisted microcontact molding. Two conformational transitions were observed, influenced by initial solvent composition: alpha-helix/random coil conformation to a more densely packed beta-sheet conformation (by casting from 1,1,1,3,3,3-hexafluoro-propanol) and moderate initial beta-sheet content to higher beta-sheet content (casting from formic acid). Furthermore, by using the solvent-assisted microcontact molding technique, we were able to achieve a submicrometer spatial resolution and reveal fine details of morphological and mechanical changes in patterned regions and at interfaces. PMID- 22947371 TI - An elegant technique for ex vivo imaging in experimental research-Optical coherence tomography (OCT). AB - Optical coherence tomography (OCT) is an elegant technology for imaging of tissues and organs and has been established for clinical use for around a decade. Thus, it is used in vivo but can also serve as a valuable ex vivo imaging tool in experimental research. Here, a brief overview is given with a focus on an ex vivo application of OCT. Image and video examples of freshly obtained murine lungs are included. The main advantage of OCT for ex vivo analysis is the non-contact, non invasive, and non-destructive fast acquisition of a three-dimensional data set with micrometer-resolution. PMID- 22947372 TI - Do communication training programs improve students' communication skills?--a follow-up study. AB - BACKGROUND: Although it is taken for granted that history-taking and communication skills are learnable, this learning process should be confirmed by rigorous studies, such as randomized pre- and post-comparisons. The purpose of this paper is to analyse whether a communication course measurably improves the communicative competence of third-year medical students at a German medical school and whether technical or emotional aspects of communication changed differently. METHOD: A sample of 32 randomly selected students performed an interview with a simulated patient before the communication course (pre intervention) and a second interview after the course (post-intervention), using the Calgary-Cambridge Observation Guide (CCOG) to assess history taking ability. RESULTS: On average, the students improved in all of the 28 items of the CCOG. The 6 more technically-orientated communication items improved on average from 3.4 for the first interview to 2.6 in the second interview (p < 0.0001), the 6 emotional items from 2.7 to 2.3 (p = 0.023). The overall score for women improved from 3.2 to 2.5 (p = 0.0019); male students improved from 3.0 to 2.7 (n.s.). The mean interview time significantly increased from the first to the second interview, but the increase in the interview duration and the change of the overall score for the students' communication skills were not correlated (Pearson's r = 0.03; n.s.). CONCLUSIONS: Our communication course measurably improved communication skills, especially for female students. These improvements did not depend predominantly on an extension of the interview time. Obviously, "technical" aspects of communication can be taught better than "emotional" communication skills. PMID- 22947373 TI - Heritability and whole genome linkage of pulse pressure in chinese twin pairs. AB - Elevated pulse pressure is associated with cardiovascular disorders and mortality in various populations. The genetic influence on pulse pressure has been confirmed by heritability estimates using related individuals.Recently, efforts have been made in mapping genes that are linked to the phenotype. We report results on our heritability and linkage study conducted on the Chinese population in mainland China where cardiovascular and cerebrovascular diseases are becoming the leading cause of death. A total of 630 pairs of middle-aged Chinese twins were collected for heritability analysis, from which 63 dizygotic twin pairs were randomly selected for genome-wide linkage analysis using Affymetrix 6.0 SNP array. Regression analysis reconfirmed the significant effects of age, sex, and BMI on pulse pressure. Comparison of twin models suggested the parsimonious AE model as the best model with a heritability estimate of 0.45.Genome-wide non parametric linkage analysis identified three significant linkage peaks on chromosome11 (lod score 4.06 at 30.5 eM), chromosome 12 (lod score 3. 97 at 100.7 eM), and chromosome 18 (lod score 4.01 at 70.7 eM) with the last two peaks closely overlapping with linkage peaks reported by two American studies. In addition, multiple regions with suggestive linkage were identified with many of them overlapping with published linkage regions. Our results provide both epidemiological and molecular genetic evidence for the genetic dissection of pulse pressure in the Chinese population, which could help in fine mapping and in characterizing genes that are involved in the regulation of pulse pressure. PMID- 22947375 TI - Commentary to 'Age does not impact risk for urethroplasty complications after tubularized incised plate repair of hypospadias in prepubertal boys'. PMID- 22947374 TI - Cellularity and structure of fresh human coronary thrombectomy specimens; presence of cells with markers of progenitor cells. AB - Acute coronary syndromes and acute myocardial infarctions are often related to plaque rupture and the formation of thrombi at the site of the rupture. We examined fresh coronary thrombectomy specimens from patients with acute coronary syndromes and assessed their structure and cellularity. The thrombectomy specimens consisted of platelets, erythrocytes and inflammatory cells. Several specimens contained multiple cholesterol crystals. Culture of thrombectomy specimens yielded cells growing in various patterns depending on the culture medium used. Culture in serum-free stem cell enrichment medium yielded cells with features of endothelial progenitor cells which survived in culture for a year. Immunohistochemical analysis of the thrombi revealed cells positive for CD34, cells positive for CD15 and cells positive for desmin in situ, whereas cultured cell from thrombi was desmin positive but pancytokeratin negative. Cells cultured in endothelial cell medium were von Willebrand factor positive. The content of coronary thrombectomy specimens is heterogeneous and consists of blood cells but also possibly cells from the vascular wall and cholesterol crystals. The culture of cells contained in the specimens yielded multiplying cells, some of which demonstrated features of haematopoietic progenitor cells and which differentiated into various cell-types. PMID- 22947376 TI - Effect of intratympanic dexamethasone, memantine and piracetam on cellular apoptosis due to cisplatin ototoxicity. AB - OBJECTIVE: This study aimed to contribute to the literature on the prevention and treatment of ototoxicity due to various drugs and chemicals. MATERIAL AND METHODS: This study compared the histological effects of intratympanic dexamethasone, memantine and piracetam on cellular apoptosis due to cisplatin ototoxicity, in 36 rats. RESULTS: Dexamethasone and memantine had significant effects on the stria vascularis, organ of Corti and spiral ganglion (p < 0.05). Although piracetam decreased the apoptosis rate, this effect was not statistically significant (p > 0.05). CONCLUSION: Dexamethasone and memantine were found superior to piracetam in reducing apoptosis due to cisplatin ototoxicity. Further studies of this subject are needed, incorporating electron microscopy and auditory brainstem response testing. PMID- 22947378 TI - Maternal and perinatal outcome in cases of fulminant viral hepatitis in late pregnancy. AB - OBJECTIVE: To investigate maternal and perinatal outcomes in cases of fulminant viral hepatitis in late pregnancy (FVHILP). METHODS: A multicenter retrospective study was conducted. The records of 40 patients with FVHILP were retrieved from 3 hospitals in China. To analyze the influence of mode of delivery on maternal and perinatal outcomes, women were allocated to the cesarean delivery group or the spontaneous vaginal delivery (SVD) group. To study the relationship between maternal outcome and perinatal outcome, patients were allocated to the maternal survival group or the non-survival group. RESULTS: There were no significant differences between the cesarean group and the SVD group in clinical manifestations or laboratory indices before delivery, or in fatality rate (P>0.05 for all), whereas there were significant differences in newborn weight, 1-minute Apgar score, and incidence of severe perinatal asphyxia between the maternal survival group and the non-survival group (P<0.05 for all). CONCLUSION: Maternal and perinatal outcomes in cases of FVHILP were not influenced by mode of delivery, whereas perinatal outcome significantly correlated with maternal outcome. PMID- 22947377 TI - Upregulation of the angiotensin-converting enzyme 2/angiotensin-(1-7)/Mas receptor axis in the heart and the kidney of growth hormone receptor knock-out mice. AB - OBJECTIVE: Growth hormone (GH) resistance leads to enhanced insulin sensitivity, decreased systolic blood pressure and increased lifespan. The aim of this study was to determine if there is a shift in the balance of the renin-angiotensin system (RAS) towards the ACE2/Ang-(1-7)/Mas receptor axis in the heart and the kidney of a model of GH resistance and retarded aging, the GH receptor knockout (GHR-/-) mouse. DESIGN: RAS components were evaluated in the heart and the kidney of GHR-/- and control mice by immunohistochemistry and Western blotting (n=12 for both groups). RESULTS: The immunostaining of Ang-(1-7) was increased in both the heart and the kidney of GHR-/- mice. These changes were concomitant with an increased immunostaining of the Mas receptor and ACE2 in both tissues. The immunostaining of AT1 receptor was reduced in heart and kidney of GHR-/- mice while that of AT2 receptor was increased in the heart and unaltered in the kidney. Ang II, ACE and angiotensinogen levels remained unaltered in the heart and the kidney of GH resistant mice. These results were confirmed by Western blotting and correlated with a significant increase in the abundance of the endothelial nitric oxide synthase in both tissues. CONCLUSIONS: The shift within the RAS towards an exacerbation of the ACE2/Ang-(1-7)/Mas receptor axis observed in GHR-/- mice could be related to a protective role in cardiac and renal function; and thus, possibly contribute to the decreased incidence of cardiovascular diseases displayed by this animal model of longevity. PMID- 22947379 TI - Brain physiology and the mind in the nineteenth century. AB - This article explores the integration of research and theory in nineteenth century neurophysiology. Four generalities combine to explain their integration. They are the core beliefs of the neurologists, the pervasive habit of perceiving mind when observing behavior, the criteria for the existence of mind, and mind as an efficient cause. These generalities help explain specific choices made by certain researchers to work within the traditional model of the nervous system, to reject materialism, and to find intelligence and voluntary behaviors in physiological systems. PMID- 22947380 TI - Monoamine theories of depression: historical impact on biomedical research. AB - Monoamine theories associate depression with reduced brain monoamine levels. These theories achieved broad popularity in the mid-1960s. The present article reviews the historical development of monoamine theories and their subsequent impact on biomedical research. Alleged divisions between West European and US researchers over competing versions of the theories are investigated using bibliometrics. Subsequently, the application of monoamine theories in the NIMH Collaborative Program on the Psychobiology of Depression is covered. The article argues that the impact of monoamine theories is best explained by the ability of researchers, governmental agencies, and pharmaceutical companies to invoke theories that advance various projects and agendas. PMID- 22947381 TI - Ivane Tarkhnishvili (Tarchanoff): a major Georgian figure from the Russian physiological school. AB - This article is dedicated to one of the outstanding scientists of the nineteenth century: Ivane Tarkhnishvili (Tarchanoff), a Russian physiologist of Georgian origin who graduated from the St. Petersburg Medico-Surgical Academy and worked under the supervision of the founder of Russian physiology, Ivan Sechenov. Among his numerous contributions was the discovery of the skin galvanic reflex; however, Tarkhnishvili's most significant contribution was the discovery of the influence of X-rays on the central nervous system, animal behavior, the heart and circulation, and embryonic development. Indeed, these works have given rise to a new field in science (radiobiology). PMID- 22947382 TI - Alcmaeon of Croton's observations on health, brain, mind, and soul. AB - Alcmaeon of Croton (sixth-fifth century BC), a pre-Socratic physician philosopher, introduced the concept that mind and soul are located in the brain. Alcmaeon made observations about seeing, hearing, tasting, and smelling and distinguished perception from understanding. Alcmaeon contributed two major ideas to natural sciences: (1) the brain is the seat of human intelligence, and (2) physicians should draw conclusions from empirical observations, an idea that implicitly rejects the alternative notion that science should depend on "divine revelation." Two thousand and five-hundred years later, these two insights remain true and guarantee Alcmaeon a place in the history of neuroscience. PMID- 22947383 TI - Neurognostics question. Richard Caton V. PMID- 22947384 TI - Neuroanniversary 2012. PMID- 22947387 TI - Ethnopharmacological survey of plants used against diabetes in Kisangani City (DR Congo). AB - ETHNOPHARMACOLOGICAL RELEVANCE: An ethnopharmacological survey was conducted in Kisangani City (Democratic Republic of Congo) in order to make an inventory of plant species used in folk medicine for the management of diabetes and their different modes of preparation. MATERIALS AND METHODS: Fifty-five traditional practitioners from different ethnic groups were interviewed about the plants they use against diabetes in folk medicine in Kisangani. All cited plants were collected and identified at the herbarium of the Faculty of Sciences, University of Kisangani. RESULTS: Thirty-one plant species were collected out of which phanerophytes predominate (18 species). Eighty-three percent of herbal remedies are prepared by aqueous decoction. Ninety-seven percents of recipes are administered to patients by oral route. All plant parts are used fresh with water as the sole solvent. Leaves are the most used parts and the treatment lasts one to two weeks. CONCLUSION: Herbal remedies used against diabetes in Kisangani City, DR Congo are widely administered as aqueous decoctions. Chemical and pharmacological studies of these preparations are in progress and might lead to interesting antidiabetic remedies. PMID- 22947388 TI - Arnica: a multivariate analysis of the botany and ethnopharmacology of a medicinal plant complex in the Iberian Peninsula and the Balearic Islands. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Medicinal plant complexes of different species sharing vernacular names, morphological and aromatic characteristics and uses are common in traditional medicine of different cultures. A quantitative methodology as a tool for ethnopharmacological studies is presented for systematically analyzing morphological and therapeutic features shared by several species integrating such complexes. AIM OF THE STUDY: The aim of this paper is to apply a novel methodology to determine whether complexes are homogeneous and species within the complexes are completely interchangeable or not. Moreover, to find out if those species giving the name to the complex are also those which provide a large number of complex descriptors. For this purpose we study the complex of medicinal plant species which share the vernacular name "Arnica" in the Iberian Peninsula and the Balearic Islands, through the systematic recording of past and current local therapeutic uses and administration forms, plant-parts and localities where the different species are used. Being a newly introduced name in the region, "Arnica" offers an interesting field to study the genesis and dynamics of ethnopharmacological categories and medicinal plant complexes. METHODS: A systematic review of the botanical, ethnobotanical and ethnopharmacological literature from 1895 to 2010 and of databases was performed in order to obtain information on the use of plants locally named as "Arnica" or with binomials that include the word "Arnica", in the Iberian Peninsula and the Balearic Islands. RESULTS: The "Arnica" complex includes 32 different plant species in the Iberian Peninsula, belonging to six families of Angiosperms, which partially share morphological characteristics and therapeutic properties. These are some of the most popular medicinal species of the Iberian Peninsula and are mainly used to treat inflammation, wounds, hematoma, and contusion. The vegetal materials are primarily macerated or decocted, and the methods of administration are plasters, washes, frictions or direct application of the plant. CONCLUSIONS: Medicinal plant complexes are frequent in ethnopharmacological contexts and require being clearly detected, and systematically studied. Plant species within each complex are only partly interchangeable because the sharing of characters, including medicinal uses, is low. "Arnica" medicinal plant complex is extremely dynamic in the Iberian Peninsula. In less than two hundred years up to 32 different plant species belonging to six different plant families became labeled "Arnica". Medical staff was extremely influential in the adoption of "Arnica" as a vernacular name between 1785 and 1864 in Spain and Portugal but not in the repertory of uses adopted for the plants within the complex. In terms of total descriptors shared in the complex, Arnica montana L. is less relevant than other three species, belonging to the Inuleae Cass. tribe, of the Asteraceae (Chiliadenus glutinosus (L.) Fourr., Inula montana L. and Dittrichia viscosa (L.) Greuter). Thus "Arnica" complex is labeled by three different Inuleae Cass. species and receives the name from a fourth Madieae Jeps. species (Arnica montana L.). PMID- 22947389 TI - The epidemiology of Clostridium perfringens type A on Ontario swine farms, with special reference to cpb2-positive isolates. AB - BACKGROUND: There is poor understanding of most aspects of Clostridium perfringens type A as a possible cause of neonatal diarrhea in piglets, and the prevalence and types of C. perfringens present on Ontario swine farms is unknown. To study the prevalence of fecal C. perfringens and selected toxin genes, 48 Ontario swine farms were visited between August 2010 and May 2011, and 354 fecal samples were collected from suckling pigs, lactating sows, weanling pigs, grower finisher pigs, and gestating sows, as well as from manure pits. The fecal samples were cultured quantitatively, and toxin genes were detected by real-time multiplex polymerase chain reaction (PCR). RESULTS: In mixed multivariable linear analysis, log(10) C. perfringens in fecal samples from suckling pigs were higher than that of weanling pigs, grower-finisher pigs, and manure pit samples (P <0.05). In mixed multivariable logistic analysis, the C. perfringens isolates recovered from lactating sows (OR = 0.069, P <0.001), gestating sows (OR = 0.020, P <0.001), grower-finishers (OR = 0.017, P <0.001), and manure pits (OR = 0.11, P <0.001) were less likely to be positive for the consensus beta2 toxin gene cpb2 compared to the isolates from suckling pigs. The prevalence of cpb2 in the isolates recovered from weanlings did not differ significantly from suckling pigs. C. perfringens isolates that were positive for cpb2 were more likely to carry the atypical cpb2 gene (atyp-cpb2) (OR = 19, P <0.001) compared to isolates that were negative for cpb2. Multivariable analysis did not identify farm factors affecting the presence of consensus cpb2 and atyp-cpb2 genes. CONCLUSIONS: This study provides baseline data on the prevalence of C. perfringens and associated toxin genes in healthy pigs at different stages of production on Ontario swine farms. The study suggests that if C. perfringens type A are involved in neonatal enteritis, there may be strains with specific characteristics that cannot be identified by the existing genotyping system. PMID- 22947390 TI - Comparison of first-episode and chronic patients diagnosed with schizophrenia: symptoms and childhood trauma. AB - AIM: There has been considerable interest in identifying and addressing the specific needs of early-episode patients diagnosed with schizophrenia in the hope that by addressing such needs early, chronic disabilities can be avoided. METHODS: One hundred twenty-eight early-episode and 571 chronic patients were compared on socio-demographic characteristics, clinical symptoms and history of childhood trauma. Symptoms were measured with the Positive and Negative Syndrome Scale (PANSS), and trauma with the short version of the Childhood Trauma Questionnaire. RESULTS: First-episode patients scored 9.3% higher than chronic patients on the PANSS positive symptom scale and 16.3% lower on the negative symptom scale. More first episode patients reported childhood sexual abuse (P = 0.033); however, fewer reported childhood emotional neglect (P = 0.01). Childhood trauma was associated with positive symptoms, specifically with hallucinations in first-episode patients (r = 0.174; P = 0.049). Moreover, fewer parents of first episode patients were living alone (P = 0.008). On multiple logistic regression, the first-episode patients were younger (odds ratio = 0.92), had higher PANSS positive symptom scores (odds ratio 1.04) and lower negative symptom scores (odds ratio 0.948 recalculate). CONCLUSIONS: More positive symptoms, fewer negative symptoms, less isolated parents and greater risk of childhood sexual abuse might warrant attention in first episode schizophrenia and perhaps should be a focus for the development of targeted interventions. PMID- 22947391 TI - BoB, a best-of-breed automated text de-identification system for VHA clinical documents. AB - OBJECTIVE: De-identification allows faster and more collaborative clinical research while protecting patient confidentiality. Clinical narrative de identification is a tedious process that can be alleviated by automated natural language processing methods. The goal of this research is the development of an automated text de-identification system for Veterans Health Administration (VHA) clinical documents. MATERIALS AND METHODS: We devised a novel stepwise hybrid approach designed to improve the current strategies used for text de identification. The proposed system is based on a previous study on the best de identification methods for VHA documents. This best-of-breed automated clinical text de-identification system (aka BoB) tackles the problem as two separate tasks: (1) maximize patient confidentiality by redacting as much protected health information (PHI) as possible; and (2) leave de-identified documents in a usable state preserving as much clinical information as possible. RESULTS: We evaluated BoB with a manually annotated corpus of a variety of VHA clinical notes, as well as with the 2006 i2b2 de-identification challenge corpus. We present evaluations at the instance- and token-level, with detailed results for BoB's main components. Moreover, an existing text de-identification system was also included in our evaluation. DISCUSSION: BoB's design efficiently takes advantage of the methods implemented in its pipeline, resulting in high sensitivity values (especially for sensitive PHI categories) and a limited number of false positives. CONCLUSIONS: Our system successfully addressed VHA clinical document de-identification, and its hybrid stepwise design demonstrates robustness and efficiency, prioritizing patient confidentiality while leaving most clinical information intact. PMID- 22947393 TI - The impact of foliar boron sprays on reproductive biology and seed quality of black gram. AB - An experiment was conducted under glass house condition to study the effect of foliar application of boron (B) on reproductive biology and seed quality of black gram (Vigna mungo). Black gram (V. mungo L. var. DPU-88-31) was grown under controlled sand culture condition at deficient and sufficient B levels. After 32 days of sowing B deficient plants were sprayed with three concentrations of B (0.05%, 0.1% and 0.2% borax) at three different stages of reproductive development, i.e. prior to flowering, initiation of bud formation and after bud formation. Deficient B supply decreased the anther and pollen size, pollen tube growth, pollen viability as well as stigmatic receptivity which were increased by foliar B application. Foliar spray at all the three concentrations and at all stages increased the yield parameters like number of pods, pod size and number of seeds formed per plant. Foliar B application also improved the seed yield and seed quality in terms of storage seed proteins (albumin, globulin, glutenin and prolamin) and carbohydrates (sugars and starch) in black gram. The foliar application of B in appropriate doses (particularly 0.1%) after bud formation made quantitative and qualitative improvement in seed yield of black gram by supplementing additional/critical B requirements for reproductive development. PMID- 22947392 TI - Sunitinib treatment does not improve blood supply but induces hypoxia in human melanoma xenografts. AB - BACKGROUND: Antiangiogenic agents that disrupt the vascular endothelial growth factor pathway have been demonstrated to normalize tumor vasculature and improve tumor oxygenation in some studies and to induce hypoxia in others. The aim of this preclinical study was to investigate the effect of sunitinib treatment on the morphology and function of tumor vasculature and on tumor oxygenation. METHODS: A-07-GFP and R-18-GFP human melanoma xenografts grown in dorsal window chambers were used as preclinical tumor models. Morphologic parameters of tumor vascular networks were assessed from high-resolution transillumination images, and tumor blood supply time was assessed from first-pass imaging movies recorded after a bolus of 155 kDa tetramethylrhodamine isothiocyanate-labeled dextran had been administered intravenously. Tumor hypoxia was assessed from immunohistochemical preparations of the imaged tissue by use of pimonidazole as a hypoxia marker. RESULTS: Sunitinib treatment reduced vessel densities, increased vessel segment lengths, did not affect blood supply times, and increased hypoxic area fractions. CONCLUSION: Sunitinib treatment did not improve vascular function but induced hypoxia in A-07-GFP and R-18-GFP tumors. PMID- 22947394 TI - Immobilization of Acetobacter sp. CCTCC M209061 for efficient asymmetric reduction of ketones and biocatalyst recycling. AB - BACKGROUND: The bacterium Acetobacter sp. CCTCC M209061 is a promising whole-cell biocatalyst with exclusive anti-Prelog stereoselectivity for the reduction of prochiral ketones that can be used to make valuable chiral alcohols such as (R)-4 (trimethylsilyl)-3-butyn-2-ol. Although it has promising catalytic properties, its stability and reusability are relatively poor compared to other biocatalysts. Hence, we explored various materials for immobilizing the active cells, in order to improve the operational stability of biocatalyst. RESULTS: It was found that Ca-alginate give the best immobilized biocatalyst, which was then coated with chitosan to further improve its mechanical strength and swelling-resistance properties. Conditions were optimized for formation of reusable immobilized beads which can be used for repeated batch asymmetric reduction of 4' chloroacetophenone. The optimized immobilized biocatalyst was very promising, with a specific activity of 85% that of the free-cell biocatalyst (34.66 MUmol/min/g dw of cells for immobilized catalyst vs 40.54 MUmol/min/g for free cells in the asymmetric reduction of 4'-chloroacetophenone). The immobilized cells showed better thermal stability, pH stability, solvent tolerance and storability compared with free cells. After 25 cycles reaction, the immobilized beads still retained >50% catalytic activity, which was 3.5 times higher than degree of retention of activity by free cells reused in a similar way. The cells could be recultured in the beads to regain full activity and perform a further 25 cycles of the reduction reaction. The external mass transfer resistances were negligible as deduced from Damkohler modulus Da < <1, and internal mass transfer restriction affected the reduction action but was not the principal rate controlling step according to effectiveness factors eta < 1 and Thiele modulus 0.3T (p.G158G) mutation was detected in two unrelated children of Jewish Bukharian origin. This mutation generates an abnormal splicing and early termination codon. A carrier frequency of 1:39 (5/196) was determined among unrelated healthy Bukharian Jews. Given the disease severity and allele frequency, a population screening for individuals of this ancestry is warranted in order to allow prenatal, or preimplantation diagnosis. PMID- 22947401 TI - The unusual appearance of a postmenopausal uterine cavity. PMID- 22947402 TI - Trippingly on the tongue. PMID- 22947403 TI - Stopping 24-hour work shifts in obstetrics: at Laval University, we did it! PMID- 22947404 TI - The association between influenza vaccine in pregnancy and adverse neonatal outcomes. AB - OBJECTIVE: To determine whether neonatal outcomes differ between women vaccinated during pregnancy and those not vaccinated. METHODS: Self-reported history of receipt of influenza vaccination during pregnancy was collected from women at the time of admission for obstetrical delivery at the IWK Health Centre in Halifax, Nova Scotia, beginning in April 2006. The cohort for this study included women who delivered a singleton infant prior to November 2009, reflecting the pre pandemic H1N1 vaccination period. Neonatal outcomes were compared using logistic regression between vaccinated and non-vaccinated women. RESULTS: Overall, 1957 of 9781 women (20%) included in the cohort received influenza vaccine during their pregnancy. The adjusted odds ratio and 95% confidence interval for a small for gestational age infant (lowest 10th percentile birth weight for gestational age and sex) was 0.80 (95% CI 0.65 to 0.95) for vaccinated women relative to non vaccinated women. The adjusted odds ratio for a low birth weight infant was 0.74 (95% CI 0.58 to 0.95). Rates of preterm birth and a composite indicator of adverse neonatal outcomes were lower among vaccinated women, but were not statistically significant. The effects of maternal vaccination on neonatal outcomes did not differ between high- and low-risk women. CONCLUSION: As evidence continues to mount in support of improved neonatal outcomes associated with receiving influenza vaccination during pregnancy, enhanced public health measures are necessary to encourage pregnant women to receive the influenza vaccine. PMID- 22947396 TI - Derailed estrogen signaling and breast cancer: an authentic couple. AB - Estrogen or 17beta-estradiol, a steroid hormone, plays a critical role in the development of mammary gland via acting through specific receptors. In particular, estrogen receptor-alpha (ERalpha) acts as a transcription factor and/or a signal transducer while participating in the development of mammary gland and breast cancer. Accumulating evidence suggests that the transcriptional activity of ERalpha is altered by the action of nuclear receptor coregulators and might be responsible, at least in part, for the development of breast cancer. In addition, this process is driven by various posttranslational modifications of ERalpha, implicating active participation of the upstream receptor modifying enzymes in breast cancer progression. Emerging studies suggest that the biological outcome of breast cancer cells is also influenced by the cross talk between microRNA and ERalpha signaling, as well as by breast cancer stem cells. Thus, multiple regulatory controls of ERalpha render mammary epithelium at risk for transformation upon deregulation of normal homeostasis. Given the importance that ERalpha signaling has in breast cancer development, here we will highlight how the activity of ERalpha is controlled by various regulators in a spatial and temporal manner, impacting the progression of the disease. We will also discuss the possible therapeutic value of ERalpha modulators as alternative drug targets to retard the progression of breast cancer. PMID- 22947405 TI - Maternal height and the risk of preterm birth and low birth weight: a systematic review and meta-analyses. AB - OBJECTIVE: Preterm birth (PTB) and low birth weight (LBW) are the leading causes of neonatal morbidity and mortality, but the effect of maternal height on these outcomes continues to be debated. Our objective was to determine the relationships between maternal height and PTB and LBW. DATA SOURCES: Medline and EMBASE were searched from their inceptions. STUDY SELECTION: Studies with a reference group that assessed the effect of maternal height on PTB (< 37 weeks) and LBW (< 2500 grams) in singletons were included. DATA EXTRACTION: Data were extracted independently by two reviewers. DATA SYNTHESIS: Fifty-six studies were included involving 333 505 women. In the cohort studies, the unadjusted risk of PTB in short-statured women was increased (relative risk [RR] 1.23; 95% CI 1.11 to 1.37), as was the unadjusted risk of LBW (RR 1.81; 95% CI 1.47 to 2.23), although not all of the studies with adjusted data found the same association. Maternal tall stature was not associated with PTB (unadjusted RR 0.97; 95% CI 0.82 to 1.14), although LBW was decreased (unadjusted RR 0.56; 95% CI 0.46 to 0.69), but not in the adjusted data. CONCLUSION: From our complete systematic review and meta-analyses, to our knowledge the first in this area, we conclude that short-statured women have higher unadjusted risks of PTB and LBW and tall women have approximately one half the unadjusted risk of LBW of women of reference height. PMID- 22947406 TI - Obstetric anal sphincter injuries: a survey of clinical practice among Canadian obstetricians. AB - OBJECTIVE: To describe the current practice, experience, and confidence of Canadian obstetricians in the management of obstetric anal sphincter injuries (OASIS) and to explore the need for national practice guidelines on this topic. METHODS: We conducted a cross-sectional, Internet-based survey between December 2010 and March 2011. The survey was initially tested among a sample population and then distributed electronically to 665 Canadian obstetricians. Data were analyzed descriptively. The main outcome measures were the self-reported confidence and experience of Canadian obstetricians in OASIS management and the frequency of performing specific OASIS management steps. RESULTS: The survey response rate was 28.7%. The majority of the respondents (95%) reported confidence in performing OASIS repairs. In the event of a perineal laceration, 47.9% of respondents routinely performed a rectal examination. Most OASIS repairs were performed in the delivery room (89.4%) under local anaesthesia (60.6%) when regional anaesthesia was not already present. If lacerated, the internal anal sphincter was repaired separately by 63.4% of respondents, and intraoperative antibiotics were ordered by 51.1% of respondents. Most (92%) reported the absence of a local protocol to guide OASIS repair. CONCLUSION: The confidence of Canadian obstetricians who participated in this survey in performing OASIS repairs was high. However, their experience in performing repairs and their use of management steps varied. The need for national guidelines and an increase in awareness is suggested. PMID- 22947407 TI - Efficacy and safety of tension-free vaginal tape compared with transobturator tape among obese women with stress urinary incontinence: a retrospective cohort study. AB - OBJECTIVE: To determine the efficacy and safety of tension-free vaginal tape (TVT) compared with transobturator tape (TOT) in obese women with stress urinary incontinence (SUI). METHODS: We performed a retrospective chart review of patients who underwent insertion of TVT or TOT for stress urinary incontinence between January 2003 and October 2009. Women were excluded if they had had previous surgery for SUI or had a diagnosis of intrinsic sphincter deficiency. RESULTS: One hundred eighty obese women (BMI > 30 kg/m2) with SUI and with follow up for at least one year were identified (90 had TVT and 90 had TOT). The rates of success on the objective criteria were 91% for the TVT group and 88% for the TOT group (P = 0.46) and 87% versus 80% (P = 0.23) on subjective assessment. CONCLUSION: Our retrospective cohort study demonstrated similar rates of cure for obese women with SUI who underwent insertion of TVT and TOT. PMID- 22947408 TI - The portrayal of Down syndrome in prenatal screening information pamphlets. AB - OBJECTIVE: To examine the information about Down syndrome (DS) provided to pregnant women in Canada through a content analysis of prenatal screening information pamphlets. METHODS: Prenatal screening information pamphlets were requested from Canadian prenatal testing centres. In total, 17 pamphlets were received (response rate = 65%). Statements presenting information descriptive of DS were identified from the pamphlets, and a content analysis was carried out. Specifically, each statement was analyzed with respect to both the content and the valence of the information presented on the basis of predetermined decision rules. To enhance reliability, four independent raters reviewed each statement, and any differences in coding were resolved through discussion. RESULTS: In total, 158 statements descriptive of DS were extracted from the pamphlets. The categorical analysis revealed that 91% of the extracted statements emphasized medical or clinical information about DS, whereas only 9% of the statements relayed information pertaining to psychosocial issues. The valence analysis revealed that nearly one half of the statements portrayed a negative message pertaining to DS, while only 2.4% of the statements conveyed a positive image of DS. CONCLUSION: The pamphlets provided to pregnant women do not appear to present a comprehensive, balanced portrayal of DS, which may serve to limit informed decision-making. PMID- 22947409 TI - Female sexual health consensus clinical guidelines. AB - OBJECTIVE: To establish national guidelines for the assessment of women's sexual health concerns and the provision of sexual heath care for women. EVIDENCE: Published literature was retrieved through searches of PubMed, CINAHL, and the Cochrane Library from May to October 2010, using appropriate controlled vocabulary (e.g., sexuality, "sexual dysfunction," "physiological," dyspareunia) and key words (e.g., sexual dysfunction, sex therapy, anorgasmia). Results were restricted, where possible, to systematic reviews, randomized control trials/controlled clinical trials, and observational studies. There were no language restrictions. Searches were updated on a regular basis and incorporated in the guideline to December 2010. Grey (unpublished) literature was identified through searching the websites of health technology assessment and health technology assessment-related agencies, clinical practice guideline collections, clinical trial registries, and national and international medical specialty societies. Each article was screened for relevance and the full text acquired if determined to be relevant. The evidence obtained was reviewed and evaluated by the members of the Expert Workgroup established by the Society of Obstetricians and Gynaecologists of Canada. VALUES: The quality of evidence was evaluated and recommendations made using the use of criteria described by the Canadian Task Force on Preventive Health Care (Table). PMID- 22947410 TI - Effect of improving the realism of simulated clinical judgement tasks on nurses' overconfidence and underconfidence: evidence from a comparative confidence calibration analysis. AB - BACKGROUND: Apparent overconfidence and underconfidence in clinicians making clinical judgements could be a feature of evaluative research designs that fail to accurately represent clinical environments. OBJECTIVES: To test the effect of improved realism of clinical judgement tasks on confidence calibration performance of nurses and student nurses. DESIGN: A comparative confidence calibration analysis. SETTINGS: The study was conducted in a large university of Northern England. METHODS: Ninety-seven participants rated their confidence - using a scale that ranged from 0 (no confidence) to 100 (totally confident) on dichotomous clinical judgements of critical event risk. The judgements were in response to 25 paper-based and 25 higher fidelity scenarios using a computerised patient simulator and clinical equipment. Scenarios, and judgement criteria of 'correctness', were generated from real patient cases. Using a series of calibration measures (calibration, resolution and over/underconfidence), participants' confidence was calibrated against the proportion of correct judgements. The calibration measures generated by the paper-based and high fidelity clinical simulation conditions were compared. RESULTS: Participants made significantly less accurate clinical judgements of risk in the high fidelity clinical simulations compared to the paper simulations (P=0.0002). They were significantly less confident in high fidelity clinical simulations than paper simulations (P=0.03). However, there was no significant difference of over/underconfidence for participants between the two simulated settings (P=0.06). Participants were no better calibrated in the high fidelity clinical simulations than paper simulations, P=0.85. Likewise, participants had no better ability of discriminating correct judgements from incorrect judgements as measured by the resolution statistic in high fidelity clinical simulations than paper simulations, P=0.76. CONCLUSIONS: Improving the realism of simulated judgement tasks led to reduced confidence and judgement accuracy in participants but did not alter confidence calibration. These findings suggest that judgemental miscalibration of confidence in nurses may be a systematic cognitive bias and that simply making scenarios more realistic may not be a sufficient condition for correction. PMID- 22947411 TI - Nationally placed liver allografts: the devil is in the details. PMID- 22947412 TI - Delphi approach to select rare diseases for a European representative survey. The BURQOL-RD study. AB - OBJECTIVES: The BURQOL-RD project is intended to develop a disease based model capable of quantifying the socio-economic burden and health-related quality of life for patients with rare diseases (RDs) and their caregivers in Europe. We described the methodology used to select a set of 10 RDs to be approached in a pilot study. METHODS: BURQOL-RD project includes 23 partners from 8 European countries: Spain, UK, France, Germany, Sweden, Italy, Hungary and Bulgaria. A two round Delphi panels in combination with Carroll diagram was used to generate consensus in the selection of the 10 RDs among the project participants. RESULTS: The two Delphi rounds yielded a prioritised list, to which the Carroll diagram was applied, taking into account three determinants: prevalence, availability of effective treatment and need for carer. The final set of RD to be studied was obtained: cystic fibrosis, Prader-Willi syndrome, haemophilia, duchenne muscular dystrophy, epidermolysis bullosa, fragile X syndrome, scleroderma, mucopolysaccharidosis, juvenile idiopathic arthritis and histiocytosis. CONCLUSIONS: This methodology permitted the generation of an equilibrated set of RDs for the pilot study of BURQOL-RD project. The model will be suitable for application in a wide range of RDs. PMID- 22947413 TI - Requirement for cardiac telemetry during intravenous phenytoin infusion: guideline fact or guideline fiction? AB - Guidelines recommend the use of cardiac telemetry when phenytoin is administered intravenously. Clinical areas where telemetry is available may not always be the most suitable place to monitor and treat these sick patients. We sought to clarify the evidence regarding the need for cardiac telemetry during intravenous infusion of phenytoin. PMID- 22947414 TI - Laboratory testing for heparin-induced thrombocytopenia: a conceptual framework and implications for diagnosis. PMID- 22947415 TI - Identification of the urinary metabolites of glionitrin A in rats using ultra performance liquid chromatography combined with quadrupole time-of-flight mass spectrometry. AB - Glionitrin A (GN A) is a new diketopiperazine disulfide with an aromatic nitro group, which is isolated from the coculture of an Aspergillus fumigatus fungal strain and a Sphingomonas bacterial strain. After intravenous administration of GN A in rats, 13 urinary metabolites of GN A were identified using ultra performance liquid chromatography/quadrupole time-of-flight mass spectroscopy (UPLC-QTOP-MS) analysis in conjunction with data processing programs such as MetaboLynxTM and MassFragnentTM. Reduction, nitro-reduction and hydration were the primary metabolic processes affecting GN A in vivo, followed by demethylation or oxidative deamination to alcohol, as well as cysteine, glycine, glucuronide or sulfate conjugation. The metabolite resulting from reduction was found to be a molecule with a dithiol group, and the metabolite made by nitro reduction was found to be an aromatic amine corresponding to GN A. Both of these products may have pharmacological or toxicological activity, which is valuable information in terms of using GN A as a lead compound. In addition, this work showed that UPLC QTOP-MS analysis coupled with efficient data processing programs is useful for rapid and reliable characterization of GN A metabolites in vivo. PMID- 22947416 TI - Aqueous normal phase liquid chromatography coupled with tandem time-of-flight quadrupole mass spectrometry for determination of zanamivir in human serum. AB - An aqueous normal phase (ANP) liquid chromatography coupled with a hybrid quadrupole time-of-flight mass spectrometry (ANP-LC-micrOTOFQ) method was used for the determination of zanamivir in human serum. Zanamivir was extracted with methanol from protein-precipitated human serum samples and further purified with SCX solid-phase extraction cartridges. Scherzo SM-C18, Agilent Zorbax SB-Aq, Cogent Diamond Hydride, Cogent Bidentate and Luna HILIC columns were compared and optimized for the retention and separation of zanamivir and the Luna HILIC and Diamond Hydride columns exhibited the best retention of zanamivir. The former provided a shorter retention time, a sharper peak and relatively high sensitivity, whereas the latter exhibited a longer retention time and less matrix interference. The analytical range of the calibration curve was between 5 and 1000 ng/mL. PMID- 22947417 TI - Cultural and social influences of negative illness appraisals in first-episode psychosis. AB - BACKGROUND: In the UK, there has been growing concern about the incidence and prognosis of psychosis in minority ethnic groups for a number of years. Negative self-appraisals after first-episode psychosis (FEP) are associated with post psychotic depression, poor functioning and suicidality. In carers, appraisals of loss and decreased control are linked with high expressed emotion and relapse; however, as yet there has been no investigation as to how ethnicity and culture relate to these negative appraisals in FEP. AIMS: The study aims to investigate the occurrence of negative illness appraisals, for example, loss and shame, in FEP within different ethnic and social-cultural groups. In addition, it aims to explore influence of insight, recovery style and carers' appraisals in the development of negative appraisals. METHODS: There were 67 patients and 46 carers who completed reliable and valid measures on beliefs about illness, insight and recovery style. Data on ethnicity and deprivation were also collected. RESULTS: Black patients experienced significantly less loss, lack of control and entrapment than White, Asian and mixed ethnicity patients, yet these were not explained by lower levels of insight or recovery style. Patient's and carer's appraisals were highly correlated. CONCLUSION: Black patients, in spite of higher incidence and poorer outcome in FEP, experienced less loss and shame. Possible explanations, including a protective aspect of alternative health belief models, are explored. This area provides much scope for further investigation. Strong relationships between patient and carer appraisals indicate that family interventions are essential to improved clinical outcomes. PMID- 22947418 TI - Real-time PCR assay for discrimination of Plasmodium ovale curtisi and Plasmodium ovale wallikeri in the Ivory Coast and in the Comoros Islands. AB - BACKGROUND: Plasmodium ovale is one of the five malaria species infecting humans. Recent data have shown that the name of this neglected species masks two distinct genotypes also called curtisi and wallikeri. Some authors show that these species could be sympatric. These two subspecies are not differentiated by microscopy techniques and malaria rapid diagnostic tests. This diagnostic defect is the result of low parasitaemia, antigenic polymorphism and absence of antibodies performance and requires the use of sequencing techniques. An accurate and easy discrimination detection method is necessary. METHODS: A new molecular assay was developed to easily identify the two genotypes of P. ovale. This tool allowed the study of 90 blood samples containing P. ovale, confirmed by molecular biology techniques, which were obtained from patients with imported malaria. RESULTS: The new marker was validated on well genotyped samples. The genotype of 90 P. ovale samples mainly imported from the Ivory Coast and the Comoros Islands was easily and quickly realized. The distribution of the two subspecies was described with a significant number of samples and showed that the two genotypes were present in the studied countries. CONCLUSION: This work confirms the presence of the two species in the same country for the first time, in the Ivory Coast and the Comoros Islands. A better genotyping of P. ovale types may improve a better characterization of the clinical pathophysiology for each. PMID- 22947419 TI - Progress in biophysics and molecular biology of the beating heart. PMID- 22947420 TI - Angiotensin converting enzyme 2 and atherosclerosis. AB - Angiotensin converting enzyme 2 (ACE2) is a homolog of angiotensin converting enzyme (ACE) which generates angiotensin II from angiotensin I. ACE, its product angiotensin II and the downstream angiotensin type I receptor are important components of the renin-angiotensin system (RAS). Angiotensin II, the most important component of the RAS, promotes the development of atherosclerosis. The identification of ACE2 in 2000 opened a new chapter of research on the regulation of the RAS. ACE2 degrades pro-atherosclerotic angiotensin II and generates anti atherosclerotic angiotensin 1-7. In this review, we explored the importance of ACE2 in protecting experimental animals from developing atherosclerosis and its involvement in human atherosclerosis. We also examined the published evidence assessing the importance of ACE2 in different cell types relevant to atherosclerosis and putative underlying cellular and molecular mechanisms linking ACE2 with protection from atherosclerosis. ACE2 shifts the balance from angiotensin II to angiotensin 1-7 inhibiting the progression of atherosclerosis in animal models. PMID- 22947421 TI - High throughput en face mapping of arterial permeability using tile scanning confocal microscopy. AB - Elevated uptake of plasma macromolecules by the arterial wall has been implicated in the initiation of atherosclerosis. Here we describe a new method for mapping such uptake in laboratory animals. Albumin was labelled with a fluorescent dye and administered intravenously. After 10 min, the aorta was fixed in situ, excised and opened. En face confocal microscopy employing a computer-controlled stage was used to obtain contiguous tiles, each consisting of a stack of images of fluorescence emission at different depths in the wall. To obtain two dimensional maps, intensities were summed in each column of voxels starting at the endothelial surface and extending 10 MUm into the wall. Variation in the sensitivity of the system with time and in all three spatial directions was assessed and corrected using calibration standards and model specimens. In immature rabbits, uptake around aorto-intercostal branches was greatest in an arrowhead-shaped region around the downstream half of each ostium, and at its lateral margins. Uptake around branches in mature rabbits was more uniform; it was highest upstream of the ostium. Patches and streaks of high uptake were also seen at non-branch locations in the descending thoracic aorta. Transport was more uniform around branches in mice, except for small regions of high uptake at the ostial rim and at the leading edge of an intimal cushion upstream of the ostium, where lesions develop. The technique provides accurate quantification in three dimensions over large areas; it has high throughput, sensitivity and resolution and is suitable for widespread use. PMID- 22947422 TI - Proximal junctional vertebral fracture-subluxation after adult spine deformity surgery. Does vertebral augmentation avoid this complication? A case report. AB - BACKGROUND: To report to the orthopedic community a case of vertebral fracture and adjacent vertebral subluxation through the upper instrumented vertebra after thoracolumbar fusion with augmentation of the cranial level. METHODS: This report reviewed the patient's medical record, her imaging studies and related literature. The possible factors contributing to this fracture are hypothesized. RESULTS: A 70-year-old woman underwent decompressive surgery and posterolateral fusion for adult lumbar scoliosis. We used pedicular screws from T10 to S1 and iliac screw at the right side, augmented with cement at T10, T11, L1, L5 and S1; and prophylactic vertebroplasty at T9 to avoid the "topping-off syndrome".Thirty days after discharge, without recognizable inciting trauma, the patient complained of pain in the lower thoracic area. The exam revealed overall neurological deficit below the level of fracture.CT scan and MRI demonstrated a T10 vertebral collapse and T9 vertebral subluxation with morphologic features of flexion-distraction fracture through the upper edge of the screw.At this point, the authors performed posterior decompression at T9 to T10 and extended posterolateral arthrodesis from T2 to T10.To our knowledge, this is an unreported fracture. CONCLUSIONS: Augmentation of the cranial level in a long thoracolumbar fusion has been developed to avoid the junctional kyphosis and compression fractures at that level. We alert the orthopedic community that this augmentation may lead to further and more severe fractures, although this opinion requires investigation for confirmation. PMID- 22947423 TI - Animal models to study aetiopathology of epilepsy: what are the features to model? AB - In order to understand the physiopathology of epilepsies and develop antiepileptic drugs, animal models have been developed. These models appear to be valuable predictors of treatment efficacy; however, several of the currently used models remain questionable and probably inappropriate for the search for new treatments, in particular for epilepsies that cannot be treated by current antiepileptic drugs. In the present review, we report the results of a recent survey conducted by neurologists in charge of an epilepsy programme based at different hospitals in France. The 36 experts were questioned, via the internet, on the most critical features of four prototypic forms of epilepsy (idiopathic generalised epilepsies with convulsive seizures, absence epilepsy, focal epilepsy associated with dysplasia, and focal epilepsy associated with hippocampal sclerosis) that should be taken into account with regards to the relevance of animal models of epilepsy. Their answers suggest that most current models for focal epilepsies associated with either dysplasia or hippocampal sclerosis do not address the most relevant features. The models currently used in mice and rats are discussed in light of the data obtained in our survey. PMID- 22947424 TI - Arachidonic acid and its COX1/2 metabolites inhibit interferon-gamma mediated induction of indoleamine-2,3 dioxygenase in THP-1 cells and human monocytes. AB - Using human acute monocytic leukaemic THP-1 cells and human primary monocytes, this study examined the ability of arachidonic acid (AA) to modulate the activity of the IFNgamma signalling cascade and its downstream effector indoleamine 2,3 dioxygenase (IDO). We established that AA inhibited IDO enzyme activity with an IC(50) of 20 MUM in THP-1 cells and 12 MUM in monocytes, and this was due to reduced expression of INDO1 mRNA and reduced level of IDO protein. Further mechanistic analysis revealed that AA interfered with the transcriptional function of the IFNgamma signalling pathway by reducing phosphorylation of signal transducer and activator of transcription (STAT1) on tyrosine 701. The importance of AA metabolism via the COX and LOX pathways was investigated using inhibitors. Indomethacin, but not nordihydroguaiaretic acid, prevented the AA-mediated inhibition of STAT1 phosphorylation and thereby IDO enzymatic activity in THP-1 cells and monocytes. This is the first study to demonstrate that AA inhibits the IFNgamma/STAT/IDO pathway, and this function is mediated by COX1/2 produced metabolites of AA. We now have evidence demonstrating that the AA metabolites, prostaglandins A(2) and D(2,) were highly inhibitory towards the IFNgamma pathway, while prostaglandin E(2) had no effect. Together, these results indicate that the fatty acid AA has the potential to modulate the immunosuppressive activity of IDO and may form the basis of novel inhibitory compounds. PMID- 22947425 TI - Histone deacetylases are required for amphibian tail and limb regeneration but not development. AB - Amphibians such as Xenopus laevis and Ambystoma mexicanum are capable of whole structure regeneration. However, transcriptional control over these events is not well understood. Here, we investigate the role of histone deacetylase (HDAC) enzymes in regeneration using HDAC inhibitors. The class I/II HDAC inhibitor valproic acid (VPA) inhibits tail regeneration in embryos of the anuran amphibian Xenopus laevis, confirming a recent report by others (Tseng et al., 2011). This inhibition correlates with a sixfold reduction in endogenous HDAC activity. VPA also inhibited tail regeneration in post-refractory stage Xenopus larvae and larvae of the urodele A. mexicanum (axolotl). Furthermore, Xenopus limb regeneration was also significantly impaired by post-amputation treatment with VPA, suggesting a general requirement for HDAC activity in the process of appendage regeneration in amphibians. The most potent inhibition of tail regeneration was observed following treatment with VPA during the wound healing, pre-blastema phase. A second HDAC inhibitor, sodium butyrate, was also shown to inhibit tail regeneration. While both VPA and sodium butyrate are reported to block sodium channel function as well as HDACs, regeneration was not inhibited by valpromide, an analogue of VPA that lacks HDAC inhibition but retains sodium channel blocking activity. Finally, although VPA is a known teratogen, we show that neither tailbud nor limb bud development are affected by exposure to this compound. We conclude that histone deacetylation is specifically required for the earliest events in appendage regeneration in amphibians, and suggest that this may act as a switch to trigger re-expression of developmental genes. PMID- 22947427 TI - Proinflammatory cytokines in serum and cerebrospinal fluid of CIDP patients. AB - INTRODUCTION: Little is known about the role of cytokines in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). Interleukin (IL)-12 and IL-15 are the major growth and differentiation factors for Th-1 cells and IL-17 is a marker of Th-17 cell expansion and activation, a high proinflammatory new subset of T cells that induce severe autoimmunity. PATIENTS AND METHODS: We measured by enzyme-like immunosorbent assay serum and cerebrospinal fluid (CSF) levels of IL 15, IL-12, and IL-17 in 24 patients with CIDP and 12 patients with other non inflammatory neurological disorders and serum levels in 16 healthy subjects. RESULTS: We found a positive association of CSF IL-12 (P = 0.012) with CIDP presence (P<0.001). CONCLUSIONS: Our findings suggest that IL-12 may be involved as potential marker of immune activation in CIDP. The increase in its levels in CSF may be a marker of initiation of Th-1 cell-mediated immunity. PMID- 22947426 TI - Efficacy and safety of maribavir dosed at 100 mg orally twice daily for the prevention of cytomegalovirus disease in liver transplant recipients: a randomized, double-blind, multicenter controlled trial. AB - Maribavir is an oral benzimidazole riboside with potent in vitro activity against cytomegalovirus (CMV), including some CMV strains resistant to ganciclovir. In a randomized, double-blind, multicenter trial, the efficacy and safety of prophylactic oral maribavir (100 mg twice daily) for prevention of CMV disease were compared with oral ganciclovir (1000 mg three times daily) in 303 CMV seronegative liver transplant recipients with CMV-seropositive donors (147 maribavir; 156 ganciclovir). Patients received study drug for up to 14 weeks and were monitored for CMV infection by blood surveillance tests and also for the development of CMV disease. The primary endpoint was Endpoint Committee (EC) confirmed CMV disease within 6 months of transplantation. In a modified intent-to treat analysis, the noninferiority of maribavir compared to oral ganciclovir for prevention of CMV disease was not established (12% with maribavir vs. 8% with ganciclovir: event rate difference of 0.041; 95% CI: -0.038, 0.119). Furthermore, significantly fewer ganciclovir patients had EC-confirmed CMV disease or CMV infection by pp65 antigenemia or CMV DNA PCR compared to maribavir patients at both 100 days (20% vs. 60%; p < 0.0001) and at 6 months (53% vs. 72%; p = 0.0053) after transplantation. Graft rejection, patient survival, and non-CMV infections were similar for maribavir and ganciclovir patients. Maribavir was well-tolerated and associated with fewer hematological adverse events than oral ganciclovir. At a dose of 100 mg twice daily, maribavir is safe but not adequate for prevention of CMV disease in liver transplant recipients at high risk for CMV disease. PMID- 22947428 TI - Valacyclovir in the treatment of acute retinal necrosis. AB - BACKGROUND: To report the outcome of oral valacyclovir as the sole antiviral therapy for patients with acute retinal necrosis (ARN). METHODS: This study reports a retrospective, interventional case series of nine consecutive patients with ten eyes with newly diagnosed ARN treated with oral valacyclovir as the sole antiviral agent. Eight patients received oral valacyclovir 2 g tid (Valtrex, GlaxoSmithKline) and one patient with impaired renal function received oral 1 g tid. The main outcome measures were response to treatment, time to initial response to treatment, time to complete resolution of retinitis, best corrected visual acuity (BCVA) at final follow-up, retinal detachment and development of recurrent or second eye disease. RESULTS: Retinitis resolved in ten of ten (100%) affected eyes. The median time to initial detectable response was seven days and the median time to complete resolution was 21 days. A final BCVA of 20/40 or better was achieved in 6/10 (60%) of eyes. 3/10 eyes (30%) developed a retinal detachment. No patients developed either disease reactivation or second eye involvement over the course of the study (mean follow up 31 weeks, range 7 to 104 weeks). CONCLUSIONS: Treatment with oral valacyclovir as the sole antiviral therapy resulted in complete resolution of retinitis. Final BCVA and retinal detachment rate were comparable with previously reported outcomes for intravenous acyclovir. PMID- 22947429 TI - An improved method of automatic colon segmentation for virtual colon unfolding. AB - The technique of virtual colon unfolding (VU) is a non-invasive procedure to detect polyps on the colon inner wall. Compared with conventional virtual colonoscopy, VU is faster and results in fewer uninspected regions. However, the performance of VU is more vulnerable to the quality of colon segmentation. In this paper, an improved colon segmentation method is proposed to enhance the performance of VU. The improved method is with the use of a novel post-processing scheme, which is composed of two parts: attain more accurate centerlines with the help of scalar complementary geodesic distance field and compensate gap-like artifacts based on local morphological information. We validated the improved method on twenty colon cases via two widely used VU techniques, the ray-casting technique and the conformal-mapping technique. Experimental results indicated that with the use of the improved method, the rates of correct response via ray casting and conformal-mapping techniques were respectively elevated by 14.9% and 13.1%, while the rates of false response were respectively reduced by 8.4% and 10.8%. PMID- 22947430 TI - Differentiating Entamoeba histolytica, Entamoeba dispar and Entamoeba moshkovskii using nested polymerase chain reaction (PCR) in rural communities in Malaysia. AB - BACKGROUND: In this study, a total of 426 human faecal samples were examined for the presence of Entamoeba histolytica, Entamoeba dispar, Entamoeba moshkovskii infection via a combination of microscopic examination and nested polymerase chain reaction (PCR) targeting 16S ribosomal RNA of Entamoeba species. METHODS: Faecal sample were collected from 426 participants in five rural villages in Peninsular Malaysia. The faecal samples were processed by direct wet smear and formalin ethyl acetate concentration technique followed by iodine staining and examined via microscopy for the presence of Entamoeba species and other intestinal parasites. Microscopically positive samples for Entamoeba species cysts were further characterized using a Nested Polymerase Chain Reaction (Nested PCR) targeting 16S-like ribosomal RNA gene. The data entry and analysis was carried out using the SPSS software (Statistical Package for the Social Sciences) program for Windows version 17 (SPSS, Chicago, IL, USA). RESULTS: Based on single faecal examination, overall prevalence of Entamoeba infection was 17.6% (75/426). Females (19.1%) were more commonly infected compared to males (15.9%). Comparison by age groups showed that adults (23.9%) had higher infection rates than children (15.3%). The PCR results showed that 52 out of 75 microscopy positive samples successfully generated species-specific amplicons. The infection with E. histolytica (75.0%; 39/52) was the most common, followed by E. dispar (30.8%; 18/52) and E. moshkovskii (5.8%; 3/52). Of these, 33 (63.5%) were shown to contain only E. histolytica, 10 (19.2%) contained E. dispar and 3 (5.8%) contained only E. moshkovskii. Mixed infection with E. histolytica and E. dispar was found in 6 (11.5%) samples. CONCLUSIONS: The present study essentially emphasized the benefit of molecular techniques in discriminating the pathogenic Entamoeba species from the non-pathogenic for accurate diagnosis and better management of amoebiasis. The presence of E. moshkovskii is of great public health concern as it was the first time it has been reported in Malaysia. PMID- 22947431 TI - Comparison of whole-body post mortem 3D CT and autopsy evaluation in accidental blunt force traumatic death using the abbreviated injury scale classification. AB - Although 3D CT imaging data are available on survivors of accidental blunt trauma, little similar data has been collected and classified on major injuries in victims of fatal injuries. This study compared the sensitivity of post mortem computed tomography (PMCT) with that of conventional autopsy for major trauma findings classified according to the trauma Abbreviated Injury Scale (AIS). Whole body 3D PMCT imaging data and full autopsy findings were analyzed on 21 victims of accidental blunt force trauma death. All major injuries were classified on the AIS scale with ratings from 3 (serious) to 6 (unsurvivable). Agreement between sensitivity of autopsy and PMCT for major injuries was determined. A total of 195 major injuries were detected (mean per fatality, 9.3; range, 1-14). Skeletal injuries by AIS grade included 37 grade 3, 45 grade 4, 12 grade 5, and 2 grade 6 major findings. Soft tissue injuries included 10 grade 3, 68 grade 4, 16 grade 5, and 5 grade 6 major findings. Of these, PMCT detected 165 (88 skeletal, 77 soft tissue), and autopsy detected 127 (59 skeletal, 68 soft tissue). PMCT agreed with autopsy in 86% and 76% of skeletal and soft tissue injuries, respectively. PMCT detected an additional 37 skeletal and 31 soft tissue injuries that were not identified at autopsy. Autopsy detected 8 skeletal and 22 soft tissue injuries that were not detected by PMCT. PMCT was more sensitive for skeletal (P=0.05) and head and neck region injury (P=0.043) detection. PMCT showed a trend for greater sensitivity than autopsy, but this did not reach statistical significance (P=0.083). 3D PMCT detected significantly more skeletal injuries than autopsy and a similar number of soft tissue injuries to autopsy and promises to be a sensitive tool for detection and classification of skeletal injuries in fatal blunt force accidental trauma. Use of the AIS scale allows standardized categorization and quantification of injuries that contribute to death in such cases and allows more objective comparison between autopsy and PMCT. PMID- 22947433 TI - Iptakalim ameliorates monocrotaline-induced pulmonary arterial hypertension in rats. AB - OBJECTIVES: We sought to investigate the experimental therapeutic effects and mechanisms of iptakalim, a new adenosine triphosphate (ATP)-sensitive potassium channel (K(ATP)) opener, on monocrotaline (MCT)-induced pulmonary arterial hypertension (PAH) and right heart ventricle remodeling in rats. METHODS: Rats were injected with a single dose (50 mg/kg, ip) of MCT and given iptakalim (1, 3, and 9 mg/kg.per d, orally [po]) or saline for 28 days. The hemodynamic and morphometric parameters were assessed. Tissue and plasma samples were collected for histological and molecular analysis. RESULTS: Treatment with iptakalim at daily oral doses of 1, 3, and 9 mg/kg from the day of MCT injection attenuated the high right ventricle systolic pressure (RVSP) and the increased weight ratio of right ventricle (RV) to left ventricle (LV) plus septum (S) (RV/(LV+S)), decreased heart rate (HR) and decreased mean arterial pressure (MAP), inhibited the RV myocardial tissue cell apoptosis, and the RV myocardial cell B-type natriuretic peptide (BNP) protein expression. Iptakalim also decreased the serum levels of nitric oxide (NO), endothelin 1 (ET-1), BNP, and the levels of NO, ET 1, and tumor necrosis factor-alpha (TNF-alpha) in the lung tissue. CONCLUSION: These results indicate that iptakalim prevents MCT-induced PAH and RV remodeling and its mechanisms are related to inhibiting the pathological increases in NO, ET 1, BNP, and TNF-alpha, and Iptakalim may be a promising candidate for the treatment of PAH. PMID- 22947432 TI - Prevalence of psychoactive substances, alcohol, illicit drugs, and medicines, in Spanish drivers: a roadside study. AB - Following population, geographic, road type and time criteria, Spain has carried out random, roadside controls of 3302 representative sample of Spanish drivers, including saliva analysis for 24 psychoactive substances and alcohol breath tests. The 81.4% of the drivers were male, with an average age of 34.8+/-11.8 (mean+/-SD). The 17% of the drivers were found to be positive to any of the substances analysed. The 6.6% of the drivers found positive to alcohol (>0.05 mg/l in breath), 11% were found positive to any illicit drug, and 2% were positive to one of the medicines analysed. Some drivers were positive in more than one substance. The most common illicit drugs among Spanish drivers were cannabis (7.7%), or cocaine (3.5%), either alone or combined with other substances. The most prevalent medicines were the benzodiazepines (1.6%). As a tendency, higher figures for positive cases were observed among males than in females (being statistically significant the differences for alcohol, cannabis and cocaine). Alcohol and cocaine positive cases were more frequently found among drivers of urban roads. Alcohol positive cases (alone, >0.05 mg/l), were more likely found as age increase (OR=1.02), those driving in urban roads (OR=2.13), and driving at any period than weekdays, while alcohol+drugs cases were more likely found among males (OR=2.819), those driving on urban road (OR=2.17) and driving at night periods. Finding a medicines positive case was more likely as elder the driver was (OR=1.05). There have been differences in the prevalence of positive cases of alcohol, cannabis and cocaine, in relation to the period of the week: in three cases the highest prevalence seen in night time. This study shows the high prevalence of psychoactive substances and alcohol in Spanish drivers, mainly illicit drugs (cannabis). This question requires a response from the authorities and from society, with an integral and multi-disciplinary approach that can heighten the population's awareness of the risks of driving under the influence of certain substances. PMID- 22947434 TI - Head orientation affects the intracranial pressure response resulting from shock wave loading in the rat. AB - Since an increasing number of returning military personnel are presenting with neurological manifestations of traumatic brain injury (TBI), there has been a great focus on the effects resulting from blast exposure. It is paramount to resolve the physical mechanism by which the critical stress is being inflicted on brain tissue from blast wave encounters with the head. This study quantitatively measured the effect of head orientation on intracranial pressure (ICP) of rats exposed to a shock wave. Furthermore, the study examined how skull maturity affects ICP response of animals exposed to shock waves at various orientations. Results showed a significant increase in ICP values in larger rats at any orientation. Furthermore, when side-ICP values were compared to the other orientations, the peak pressures were significantly lower suggesting a relation between ICP and orientation of the head due to geometry of the skull and location of sutures. This finding accentuates the importance of skull dynamics in explaining possible injury mechanisms during blast. Also, the rate of pressure change was measured and indicated that the rate was significantly higher when the top of the head was facing the shock front. The results confirm that the biomechanical response of the superior rat skull is distinctive compared to other areas of the skull, suggesting a skull flexure mechanism. These results not only present insights into the mechanism of brain injury, but also provide information which can be used for designing more effective protective head gear. PMID- 22947435 TI - Joint stabilisers or moment actuators: the role of knee joint muscles while weight-bearing. AB - Previous investigations have identified the roles of knee joint muscles in supporting external loads during non-weight-bearing tasks and found these to depend on moment arm orientation (MAO). However, during weight-bearing tasks ground reaction forces (GRF) are transferred up through the knee, subjecting it to large multi-directional forces and stability is dependent on articular geometry, loading, and muscle activation. The purpose of this study was to investigate activation strategies used by healthy individuals to generate and support highly controlled GRF during weight-bearing. Twenty healthy males (23.9+/ 1.9 yrs) stood with their foot in a boot fixed to a force platform. Subjects controlled an onscreen cursor by modulating normalised GRF and were required to produce 30% of their maximal force in 12 directions of the horizontal plane while maintaining 50% body weight on the test leg. Lower limb electromyography, kinematics and kinetics were recorded for each trial. Mean muscle activation was plotted in polar coordinates based on GRF orientation. Muscle activation symmetry was determined and when applicable, the mean direction of activation and muscle specificity index reported. The measured GRF were comparable to activities of daily living (0.48-0.58+/-0.17-0.19 N/kg in horizontal plane). Muscle activations were repeatable (ICCs: 0.78-0.98), however, only semitendinosus (ST) activation was indicated by its MAO. Considering the joint moments and activations patterns we therefore classified muscles as: (1) general joint stabilisers (vastus lateralis and medialis), (2) specific joint stabiliser (BF), and (3) moment actuators (ST and rectus femoris). General joint stabilisers were active in all load directions; specific stabilisers were active in directions opposite their MAO; moment actuators had higher specificities and activations corresponding to their MAO. We suggest the stabiliser muscles create a rigid mechanical linkage at the knee which allows the actuators of the hip and knee to modulate GRF. PMID- 22947440 TI - Vivid recollection of a past traumatic event: a rare manifestation of temporal lobe seizures. AB - Vivid recollection of a particular past memory is a rare ictal phenomenon in temporal lobe epilepsy. When the memory is traumatic, the presentation may mimic post-traumatic stress disorder (PTSD). We report a woman with temporal lobe epilepsy who was misdiagnosed with post-traumatic stress disorder for two years before she had a suspected generalised seizure; video-EEG monitoring confirmed that her episodes were epileptic. Adequate treatment with an antiepileptic medication resulted in total resolution of the episodes. PMID- 22947439 TI - Vitamin D and melanoma incidence and mortality. AB - The role of vitamin D (25-OH-D, or 25-hydroxyvitamin D) and its potential confounders in relationship to melanoma risk and mortality is discussed. The paradox that ultraviolet radiation (UVR) exposure is the major environmental risk factor for melanoma etiology as well as a major source of vitamin D might be explained by viewing vitamin D levels as the result of a healthy lifestyle rather than a cause of health. PMID- 22947441 TI - Mitral valve restoration using the No-React(R) MitroFixTM: a novel concept. AB - BACKGROUND: Mitral Valve Repair (MVRP) has been shown to be significantly superior to Mitral Valve Replacement (MVR). Since the majority of repairs involve the Posterior Mitral Leaflet (PML) and not the Anterior Mitral Leaflet (AML), the monocuspidalisation of the Mitral Valve (MV) can be achieved with a bio-posterior leaflet that imitates a closed PML. This approach may have the benefit of restoring the competence of the MV without reducing its effective orifice area. METHODS: We have used a new concept and device, the MitroFixTM, to correct MV regurgitation due to pathology of the PML. The device comes with functional sizers both of which have identical shape and size. This allows the surgeon to pre-test the success of the restoration. From December 2006 to October 2011, 51 MitroFixTM devices were implanted at three institutions. RESULTS: The mean age of the patients (32 males and 19 females) was 67.7 years. 37 of them were in NYHA class III or IV and all patients suffered from severe mitral valve regurgitation (MR). 31 patients underwent combined surgery. Successful implantation of the MitroFixTM device was performed in 51/53 patients.Mean cross-clamp time was 63.6 min (range: 29-118 min). Six patients had additional reconstructive procedures of the AML (chordae transfer, neo-chordae, triangular resection). At discharge, 33 patients showed no MR in the TTE and 17 patients exhibited trivial (I) or moderate (II) MR. The mean gradient was 4.0 mmHg and mean EOA was 2.52cm^2 (range: 1.5-4.0cm2). All patients were classified as being in NYHA class I or II. CONCLUSION: The MitroFixTM Mitral Valve Restoration Device is a new concept that offers an effective treatment of MR. The restoration of the mitral valve with the MitroFixTM device offers the advantage of preserving the AML and providing good coaptation with a prosthetic PML. Importantly, this preliminary evaluation indicates a mean effective orifice area ( EOA ) of 2.5cm2 in MV receiving a MitroFixTM device, witch is higher than EOA resulting from MVR or MVRP. The present study has also shown that severe regurgitation due to ischemic/rheumatic MR, endocarditis and complex prolapse of the PML are clear candidates for correction with the MitroFixTM. Larger studies and a longer follow up period are needed to validate these promising results. PMID- 22947442 TI - Specimen aspect ratio and light transmission in photoactive dental resins. AB - OBJECTIVES: To test the influence of specimen dimensions on light transmission and shrinkage strain properties of curing dental resins. MATERIALS AND METHODS: Photocurable resin specimens (Bis-GMA/TEGDMA) with aspect ratios (AR) of 2 (4mm*2mm); 4 (4mm*1mm and 8mm*2mm); 8 (8mm*1mm); 12 (AR: 12mm*1mm); and 24 (12mm*0.5mm) were light cured. Light transmission and shrinkage-strain data were recorded throughout, and upper and lower surface hardness measurements were performed following cure. RESULTS: Light transmission was significantly affected by the specimen aspect ratio even at similar thicknesses (p<0.05). By comparing light transmission through a negative control resin without photoinitiator, the lowest AR specimens showed a relative increase in transmission above 100% throughout curing, which was caused by specimen constraint. The extent of lower surface cure (as assessed by increasing hardness) was principally affected by cavity height and decreased for thicker specimens (p<0.05). Only the 2mm thick specimens showed a significantly greater lower to upper hardness ratio with increasing cavity diameter (p<0.05). The highest AR specimen showed the greatest lower to upper hardness percentage (p<0.05), and was expected since this AR was obtained by reducing the sample thickness to 0.5mm. Generally, total shrinkage strain increased and shrinkage strain per unit mass decreased with increasing AR. SIGNIFICANCE: Specimen constraint in low AR cavities may compromise light transmission as unexpected light intensity variations may occur for low configuration factors, which ultimately affect polymer conversion of light-cured resin-based restorations through depth. PMID- 22947443 TI - A pilot study of pulmonary rehabilitation and chest physiotherapy versus chest physiotherapy alone in bronchiectasis. AB - AIM: The aim of our study was to assess the efficacy of pulmonary rehabilitation in addition to regular chest physiotherapy in non cystic fibrosis bronchiectasis. METHODS: Thirty patients with clinically significant bronchiectasis and limited exercise tolerance were randomized into either the control group receiving chest physiotherapy (8 weeks) or into the intervention group, receiving pulmonary rehabilitation in addition to chest physiotherapy (8 weeks). Both groups were encouraged to maintain their exercise program and or chest physiotherapy, following completion of the study. RESULTS: End of training (8 weeks) No improvement in control group. In the intervention group, incremental shuttle walk test (ISWT) improved by 56.7 m (p = 0.03), endurance walk test (EWT) by 193.3 m (p = 0.01), Leicester Cough Questionnaire (LCQ) improved by 2.6 units (p < 0.001) and St. George's Respiratory Questionnaire (SGRQ) by 8 units (p < 0.001). At 20 weeks (12 weeks post end of training) No improvement in control group. In the intervention group, ISWT improved by 80 m (p = 0.04) and EWT by 247.5 m (p = 0.003). LCQ improved by 4.4 units (p < 0.001) and SGRQ by 4 units (p < 0.001). CONCLUSION: Pulmonary rehabilitation in addition to regular chest physiotherapy, improves exercise tolerance and health related quality of life in non cystic fibrosis bronchiectasis and the benefit was sustained at 12 weeks post end of pulmonary rehabilitation. Clinical trials regn no. NCT00868075. PMID- 22947445 TI - Hydrothermal pentose to furfural conversion and simultaneous extraction with SC CO2--kinetics and application to biomass hydrolysates. AB - This work explores hydrothermal d-xylose and hemicellulose to furfural conversion coupled with simultaneous furfural extraction by SC-CO(2) and the underlying reaction pathway. A maximum furfural yield of 68% was attained from d-xylose at 230 degrees C and 12MPa. Additionally missing kinetic data for l-arabinose to furfural conversion was provided, showing close similarity to d-xylose. Furfural yields from straw and brewery waste hydrolysates were significantly lower than those obtained from model compounds, indicating side reactions with other hydrolysate components. Simultaneous furfural extraction by SC-CO(2) significantly increased extraction yield in all cases. The results indicate that furfural reacts with intermediates of pentose dehydration. The proposed processing route can be well integrated into existing lignocellulose biorefinery concepts. PMID- 22947444 TI - Lower calcineurin inhibitor doses in older compared to younger kidney transplant recipients yield similar troughs. AB - The number of older adults undergoing kidney transplantation has increased, yet little is known about calcineurin inhibitor (CNI) metabolism in this group. We studied CNI troughs and doses to determine if there were age-related differences in metabolism and dose requirements. We studied 348 young (18-34 years), 1831 middle (35-64 years) and 374 older (65-84 years) adult kidney transplant recipients enrolled in a seven-center prospective study. Troughs were obtained from each patient 2*/week in weeks 1-8 and 2*/month in months 3-6. A multivariable linear-mixed model examined the effect of age on log dose and weight normalized troughs. Older recipients had higher normalized tacrolimus troughs than middle or young age adults despite receiving doses a median of 1-2 mg/day lower. Age and CYP3A5*1 genotype had the largest effect on tacrolimus troughs. Older recipients also had higher normalized cyclosporine troughs than middle or young adults despite receiving median doses 100 mg/day lower. After normalization for dose and weight, CNI troughs were more than 50% higher in older adults than young adults. These data support age-related changes in CNI metabolism. Further studies are needed to determine optimal dosing of CNIs in the elderly. PMID- 22947446 TI - Impact of steam explosion on biogas production from rape straw in relation to changes in chemical composition. AB - An 81day trial compared the cumulative production of methane from rape straw pre treated by steam explosion at 15 levels of severity. The final methane yields were similar. The temporal variation in production rate exhibited two peaks: maximum production occurred in the first peak at around 21days with heights that increased with severity; the height of the second peak reduced with severity and peaked between 32 and 36days. Changes in the straw composition were investigated using mid-infrared spectroscopy. These were also strongly related to the degree of severity, allowing good predictive models to be built of severity and subsequently the rate of methane production. The main spectral changes showed the degradation of cellulose and xylose-containing hemicelluloses and production of furfural-like components commonly associated with biomass pre-treatments. Only small changes to lignin were associated with increased methane generation suggesting a structural rather than chemical role in this process. PMID- 22947447 TI - Immobilization of pectinase and lipase on macroporous resin coated with chitosan for treatment of whitewater from papermaking. AB - Anionic residues and pitch deposits in whitewater negatively impact the operation of paper-forming equipment. In order to remove these substances, a macroporous resin based on a methyl acrylate matrix was synthesized and coated with chitosan of various molecular weights through glutaraldehyde cross-linking. Pectinase from Bacillus licheniformis and lipase from Thermomyces lanuginosus were immobilized on the resin coated with chitosan by a Schiff base reaction. The highest hydrolysis activities of the immobilized enzymes were achieved by using chitosan with 10*10(5)DaMW for coating and 0.0025% glutaraldehyde for cross-linking chitosan. The cationic demand and pitch deposits in whitewater were reduced by 58% and 74%, respectively, when treating whitewater with immobilized dual-enzymes for 15min at 55 degrees C and pH 7.5. This method is useful for treatment of whitewater in the papermaking industry. PMID- 22947448 TI - Synthesis, characterization and in vitro release behavior of carboxymethyl xanthan. AB - Carboxymethylation of xanthan gum was carried out by reacting xanthan gum with monochloroacetic acid in alkaline condition. FTIR spectroscopy confirmed the formation of carboxymethyl xanthan. DSC and XRD study revealed the crystalline nature of carboxymethyl xanthan. SEM images showed that carboxymethyl xanthan particles are globular in shape and smaller in size. Viscosity measurements also showed that the carboxymethyl xanthan is less viscous as compared to xanthan gum. Diclofenac sodium matrix tablets prepared using carboxymethyl xanthan revealed faster release of drug as compared with xanthan gum matrix. PMID- 22947449 TI - Biological study on carboxymethylated (1->3)-alpha-D-glucans from fruiting bodies of Ganoderma lucidum. AB - Water-insoluble, alkali-soluble polysaccharides (ASPs) were isolated from three fruiting bodies of the macromycete fungus Ganoderma lucidum. The structure of ASPs was determined using composition analysis, methylation analysis, Fourier transform infrared spectroscopy, and nuclear magnetic resonance spectroscopy. The analysis of the biological activity of the carboxymethylated (CM) (1->3)-alpha-D glucans was based on an assessment of their cytotoxic, mitochondrial metabolism modulating, and free radical scavenging effects against a tumor cell line (human cervical carcinoma HeLa), and two normal human cell lines (colon myofibroblasts CCD-18Co and epithelial cells CCD 841 CoTr). The chemical and spectroscopic investigations indicated that the ASPs from G. lucidum were (1->3)-alpha-D glucans. After carboxymethylation (1->3)-alpha-D-glucans were tested in the range of 25-250 MUg/mL concentrations. All the tested CM-(1->3)-alpha-D-glucans decreased the cellular metabolism of tumor and normal cells after 24h of incubation. The CM-(1->3)-alpha-D-glucans had no toxic effects on cervical carcinoma cells but reduced the viability of normal cells. The cytotoxic activity of the CM-(1->3)-alpha-D-glucans was concentration- and cell-type-dependent with normal cells more sensitive to their action than tumor cells. Generally, the CM (1->3)-alpha-D-glucans tested did not have a free radical scavenging effect. It was concluded that the carboxymethylated derivatives of (1->3)-alpha-D-glucans isolated from the G. lucidum fruiting bodies are biologically active and after further detailed studies may be regarded as a dietary or therapeutic supplements. PMID- 22947450 TI - Biosynthesis and characterization of polyhydroxyalkanoates by Pseudomonas guezennei from alkanoates and glucose. AB - The biosynthesis of medium chain length poly(3-hydroxyalkanoates) mcl PHAs by Pseudomonas guezennei using glucose, sodium octanoate, and 10-undecenoic acid as sole or mixed carbon sources was investigated. Chemical composition of polyesters was analyzed by GCMS and NMR. The copolyester produced by P. guezennei from glucose mainly consisted of 3-hydroxyoctanoate and 3-hydroxydecanoate, and the presence of 3-hydroxydodec-5-enoate was demonstrated. Using sodium octanoate as the sole nutrient, the microorganism produced a poly(3-hydroxyoctanoate) (PHO) polymer containing up to 94 mol% 3-hydroxyoctanoate. Biosynthesis of poly[(3 hydroxyoctanoate)-co-(3-hydroxyundecenoate)] (PHOU) copolymers bearing terminal reactive double bonds on its side chains with unsaturation degree ranging from 8.8% to 78.2% was obtained by tuning the ratio of sodium octanoate/10-undecenoic acid in the medium. Thermal analysis indicated semi-crystalline polymers with melting temperatures (T(m)) ranging from 46 to 55 degrees C, fusion enthalpy (DeltaH) comprised between 3 and 35 J/g and glass transition temperature (T(g)) from -36 to -44 degrees C, except for the highly amorphous 78.2% unsaturated PHOU with a low T(g) (-50 degrees C). Molecular weights determined by GPC ranged from 119000 and 530000 g/mol. The biosynthesis of natural polyesters with controlled ratio of vinyl-terminated side chains is of great interest for further chemical modifications. PMID- 22947451 TI - Chitosan-amylopectin/hydroxyapatite and chitosan-chondroitin sulphate/hydroxyapatite composite scaffolds for bone tissue engineering. AB - Over the past few decades, artificial graft materials for bone tissue engineering are gaining much importance. In this study, tri-component scaffolds of chitosan/natural hydroxyapatite with chondroitin sulfate (chitosan-CS/HAp) and amylopectin (chitosan-AP/HAp) have been developed for the first time via freeze drying method and were characterized physicochemically for bone grafting substitutes. Chemical interactions and dispersion of HAp, CS and AP in the chitosan matrix have been evaluated by various analytical techniques. The porosity and water uptake/retention ability of these composite scaffolds decreased whereas thermal stability increased when compared to the chitosan scaffold. The pore size of the chitosan/HAp, chitosan-CS/HAp and chitosan-AP/HAp scaffolds varied from 60 to 180 MUm, 60 to 400 MUm and 80 to 500 MUm, respectively. Cell proliferation, alkaline phosphatase activity and type-1 collagen production was evaluated in vitro using MG-63 cell line, which was observed to be higher in the composite scaffolds. Excellent interconnected porosity, controlled biodegradation and enhanced cell proliferation of the novel chitosan-CS/HAp and chitosan-AP/HAp scaffolds suggests that these scaffolds are promising biomaterials for bone tissue engineering. PMID- 22947452 TI - Effects of degree of carboxymethylation on physicochemical and biological properties of pachyman. AB - Polysaccharides (pachyman) extracted from Poria cocos sclerotium were chemically modified by carboxymethylation and the effects on the structural and biological properties of the polysaccharides were investigated as a function of the degree of carboxymethylation. The degree of substitution (DS) of five carboxymethylated pachyman, coded as CMP1/CMP2/CMP3/CMP4/CMP5, was determined to be 0.44-0.88. The structures were confirmed by FT-IR and their weight-average molecular masses (Mw) were obtained by SEC-LLS. Experimental results showed that derivatives were effective in anti-oxidation and bile acid binding in a dose dependent way. Furthermore, their water solubility and biological activities were improved with the increase of DS. Therefore, results proved that the carboxymethylation of pachyman effectively enhanced their potential biological properties. PMID- 22947454 TI - Calcium alginate/gum Arabic beads containing glibenclamide: development and in vitro characterization. AB - This work investigates the development, optimization and in vitro characterization of calcium alginate/gum Arabic beads by an ionotropic gelation method for prolonged sustained release of glibenclamide. The effects of amount of sodium alginate and gum Arabic as independent process variables on the drug encapsulation efficiency and drug release were optimized and analyzed based on central composite design and response surface methodology. Increment in drug encapsulation efficiency and decrease in drug release were found with the increase of both the amounts of sodium alginate and gum Arabic, used as polymer blend. These optimized beads showed high drug encapsulation efficiency (86.02+/ 2.97%), and suitable sustained drug release pattern over prolonged period (cumulative drug release after 7 h of 35.68+/-1.38%). The average size of these formulated dried beads containing glibenclamide ranged from 1.15+/-0.11 to 1.55+/ 0.19 mm. The in vitro dissolution of these beads showed prolonged sustained release of glibenclamide over 7 h, which followed first-order model (R(2)=0.9886 0.9985) with anomalous (non-Fickian) diffusion mechanism (release exponent, n=0.72-0.81). The swelling and degradation of the optimized beads were influenced by pH of test mediums. These beads were also characterized by SEM and FTIR spectroscopy for surface morphology and excipients-drug interaction analysis, respectively. These developed calcium alginate/gum Arabic beads containing glibenclamide could possibly be advantageous in terms of advanced patient compliance with reduced dosing interval. PMID- 22947453 TI - Cellular uptake of DNA-chitosan nanoparticles: the role of clathrin- and caveolae mediated pathways. AB - The success of gene therapy depends on efficient delivery of DNA and requires a vector. A promising non-viral vector is chitosan. We tailored chitosan to optimize it for transfection by synthesizing self-branched and trisaccharide substituted chitosan oligomers (SBTCO), which show superior transfection efficacy compared with linear chitosan (LCO). The aim of the work was to compare the cellular uptake and endocytic pathways of polyplexes formed by LCO and SBTCO. Both polyplexes were taken up by the majority of the cells, but the uptake of LCO was lower than SBTCO polyplexes. LCO polyplexes were internalized through both clathrin-dependent and clathrin-independent pathways, whereas SBTCO polyplexes were primarily taken up by clathrin-independent endocytosis. The different level of cellular uptake and the distinct endocytic pathways, may explain the difference in transfection efficacy. This was supported by the observation that photochemical internalization increased the transfection by LCO polyplexes considerably, whereas no effect on transfection was found for SBTCO polyplexes. PMID- 22947455 TI - Effect of temperature-cycled retrogradation on slow digestibility of waxy rice starch. AB - The temperature-cycled retrogradation conditions were optimized for producing slowly digestible starch (SDS) products in this study. The present data showed that the following conditions (temperature cycle, 4/25 degrees C; temperature cycled time, 14 d; temperature-cycled time interval, 24 h; and ratio of starch to water, 1:2) were available for increasing the SDS yield of the products. The maximum yield reached 54.5%, while the SDS products were prepared under the optimum conditions. The results also indicated that temperature-cycled retrogradation significantly increased the slow digestibility of the SDS products. This was probably attributed to many solid blocks remaining after the hydrolysis of the SDS products by the enzymes for 60 min and 120 min. The solid blocks may comprise of more imperfect crystallites and part of amorphous non digestible starch. These results suggest that the optimum conditions obtained are suited for preparing SDS products in food and pharmaceutical industries. PMID- 22947456 TI - [Pressure ulcers in the critical patient: detection of risk factors]. AB - INTRODUCTION: Patients admitted to intensive care units (ICU) are more vulnerable to the appearance of pressure ulcers. This is the reason why the highest rates of pressure ulcers (PU) incidence and prevalence are found in the ICU. This study has aimed to identify risk factors related to the appearance of PU in critically ill patients. PATIENTS AND METHOD: This was a prospective and observational study that included all patients admitted for more than 24 h from October 2009 to June 2010. Dependent variable: Appearance of PU. INDEPENDENT VARIABLES: APACHE II score, risk assessment score (EMINA), body mass index (BMI), support surface, nutrition, norepineprhine, sedation and care support devices. Data analyses: Kaplan-Meyer survival and Cox regression analysis. Significance p < 0.05. RESULTS: A total of 236 patients were included. A significant association was found to BMI>=30 (RR: 2.51), EMINA >10 (RR: 2.96), hyperproteic nutrition (RR: 0.946), turning (RR: 0.88), sedation (RR: 0.95), polyurethane nasogastric feeding tube (RR: 0.94), dynamic support surface (RR:0.88). Significant association of p < 0.1 for Norepinephrine (RR: 2.34). CONCLUSIONS: BMI>= 30, EMINA and norepinephrine are predictive factors of risk for PU development. Sedation days, dynamic support surfaces, hyperproteic nutrition, turning, and polyurethane nasogastric feeding tube were established as protective factors against PU. PMID- 22947457 TI - Evaluation of high mobility group box 1 protein as a presurgical diagnostic marker reflecting the severity of acute appendicitis. AB - OBJECTIVES: To validate the role of high mobility group box-1(HMGB1) in diagnosis of acute appendicitis (AA) with different pathological severity. METHODS: According to the pathologically diagnosis, 150 patients underwent appendectomies between Jan. 2007 and Dec, 2010 were divided into acute simple, acute suppurative and acute gangrenous appendicitis as group 1, 2 and 3, respectively. Each patient group contains 50 sex and age matched cases to make comparison with 50 healthy volunteers. The mRNA and protein expression levels of serum HMGB1 were determined by real-time quantitative PCR and enzyme linked immunosorbent assay (ELISA). Serum High-sensitivity C-reactive protein (hs-CRP) levels were determined by rate nephelometric immunoassay. RESULTS: In comparison with health volunteers, relative HMGB1 mRNA levels in group 1, 2 and 3 were significantly increased 3.05 +/- 0.51,8.33 +/- 0.75 and 13.74 +/- 1.09 folds, reflecting a tendency of augmented severity. In accordance, serum protein levels of HMGB1 were 10.97 +/- 1.64, 14.42 +/- 1.56 and 18.08 +/- 2.41 ng/ml in 3 patient groups, which are significantly higher than that of healthy volunteers' 5.47 +/- 0.73 ng/ml. hs-CRP levels were 12.85 +/- 3.41, 21.04 +/- 1.98 and 31.07 +/- 5.46 ng/ml in 3 patients groups compared with 2.06 +/- 0.77 ng/ml in controls. The concentrations of HMGB1 and hs-CRP were both positively correlated with disease severity. CONCLUSION: Serum HMGB1 constitutes as a valuable marker in diagnosis of AA. Positively correlated with hs-CRP level, mRNA and protein expression of HMGB1 to a certain extent reflected the severity of AA. PMID- 22947459 TI - [Neisseria meningitidis urethritis]. PMID- 22947458 TI - Malaria resistance genes are associated with the levels of IgG subclasses directed against Plasmodium falciparum blood-stage antigens in Burkina Faso. AB - BACKGROUND: HBB, IL4, IL12, TNF, LTA, NCR3 and FCGR2A polymorphisms have been associated with malaria resistance in humans, whereas cytophilic immunoglobulin G (IgG) antibodies are thought to play a critical role in immune protection against asexual blood stages of the parasite. Furthermore, HBB, IL4, TNF, and FCGR2A have been associated with both malaria resistance and IgG levels. This suggests that some malaria resistance genes influence the levels of IgG subclass antibodies. METHODS: In this study, the effect of HBB, IL4, IL12, TNF, LTA, NCR3 and FCGR2A polymorphisms on the levels of IgG responses against Plasmodium falciparum blood stage extract was investigated in 220 individuals living in Burkina Faso. The Pearson's correlation coefficient among IgG subclasses was determined. A family based approach was used to assess the association of polymorphisms with anti-P. falciparum IgG, IgG1, IgG2, IgG3 and IgG4 levels. RESULTS: After applying a multiple test correction, several polymorphisms were associated with IgG subclass or IgG levels. There was an association of i) haemoglobin C with IgG levels; ii) the FcgammaRIIa H/R131 with IgG2 and IgG3 levels; iii) TNF-863 with IgG3 levels; iv) TNF-857 with IgG levels; and, v) TNF1304 with IgG3, IgG4, and IgG levels. CONCLUSION: Taken together, the results support the hypothesis that some polymorphisms affect malaria resistance through their effect on the acquired immune response, and pave the way towards further comprehension of genetic control of an individual's humoral response against malaria. PMID- 22947460 TI - Isolation of Shiga toxin-producing Escherichia coli serogroups O26, O45, O103, O111, O121, and O145 from ground beef using modified rainbow agar and post immunomagnetic separation acid treatment. AB - It is estimated that at least 70% of human illnesses due to non-O157 Shiga toxin producing Escherichia coli (STEC) in the United States are caused by strains from the top six serogroups (O26, O45, O103, O111, O121, and O145). Procedures for isolating STEC from food products often use plating media that include antimicrobial supplements at concentrations that inhibit background microflora growth but can also inhibit target STEC growth. In this study, an agar medium with lower supplement concentrations, modified Rainbow agar (mRBA), was evaluated for recovery of STEC serogroups O26, O45, O103, O111, O121, and O145 from ground beef enrichments. A post-immunomagnetic separation (IMS) acid treatment step was additionally used to reduce background microflora and increase recovery of target STEC strains. Ground beef samples (325 g) were artificially contaminated with STEC and confounding organisms and enriched for 15 h. Recovery of the target STEC was attempted on the enrichments using IMS and plating onto mRBA and Rainbow agar (RBA). Additionally, acid treatment was performed on the post-IMS eluate followed by plating onto mRBA. Using the combination of mRBA and acid treatment, target STEC were isolated from 103 (85.8%) of 120 of the low-inoculated samples (1 to 5 CFU/325-g sample) compared with 68 (56.7%) of 120 using no acid treatment and plating onto RBA with higher levels of novobiocin and potassium tellurite. The combination of acid treatment and mRBA provides a significant improvement over the use of RBA for isolation of STEC serogroups O26, O45, O103, O111, O121, and O145 from raw ground beef. PMID- 22947461 TI - Detection and isolation of Yersinia pestis without fraction 1 antigen by monoclonal antibody in foods and water. AB - Most available immunoassays for Yersinia pestis are based on the detection of fraction 1 antigen (F1) when yersiniae are grown at 37 degrees C. A monoclonal antibody (MAb) was developed based on the detection of surface antigens that are not F1. F1-deficient Y. pestis cells were induced and used to immunize BALB/c mice from which MAb (immunoglobulin G1), which specifically recognizes Y. pestis, with or without F1, was obtained. This MAb (6B5) did not cross-react with enteric bacteria, including Yersinia enterocolitica. Enzyme-linked immunosorbent assay results revealed that MAb 6B5 is specific for Y. pestis, with the exception of a minor cross-reaction with Yersinia pseudotuberculosis. Western immunoblot analysis revealed that MAb 6B5 recognizes a Y. pestis outer membrane protein of ca. 30 kDa. Magnetic beads that were coated with MAb 6B5 were compared with beads coated with polyclonal antibody (PAb; rabbit) against Y. pestis for the isolation of Y. pestis in food and water samples by using a PATHATRIX cell concentration apparatus. Enrichment cultures of Y. pestis in different foods by using two different times (6 and 24 h) in brain heart infusion broth at 37 degrees C were evaluated. Results revealed MAb 6B5-coated magnetic beads were equivalent to magnetic beads coated with PAb against Y. pestis A1122 whole cells in concentrating Y. pestis for isolation, especially when samples were enriched for 6 h. However, the selectivity for Y. pestis of the magnetic beads coated with MAb 6B5 was greater than that coated with PAb. PMID- 22947462 TI - Comparison of individual, pooled, and composite fecal sampling methods for detection of Salmonella on U.S. dairy operations. AB - The objectives of this study were to estimate the prevalence of Salmonella for individual, pooled, and composite fecal samples and to compare culture results from each sample type for determining herd Salmonella infection status and identifying Salmonella serovar(s). During the U.S. Department of Agriculture National Animal Health Monitoring System Dairy 2007 study, data and samples were collected from dairy operations in 17 major dairy states. As part of the study, composite fecal samples (six per operation) were collected from cow areas, such as holding pens, alleyways, and lagoons, where manure accumulates. Fecal samples also were collected from individual cows (35 per operation), and fecal sample pools were created by combining samples from 5 cows (7 per operation). A total of 1,541 composite fecal samples were collected from 260 operations in 17 states, and 406 (26.3%) of these samples were culture positive for Salmonella. Among the 116 operations for which all three sample types were obtained, 41.4% (48 operations) were Salmonella culture positive based on individual samples, 39.7% (46 operations) were positive based on pooled samples, and 49.1% (57 operations) were positive based on composite fecal samples. Relative to individual samples, the sensitivity of composite fecal samples for determining herd infection status was 85.4% and the sensitivity of pooled fecal samples was 91.7%. On 33.6% of operations (39 of 116), Salmonella was cultured from all three fecal sample types (individual, pooled, and composite), and 20 (51.3%) of these operations had exactly the same serovar in all three sample types. Use of composite fecal samples is less costly and time-consuming than use of individual or pooled samples and provides similar results for detecting the presence and identifying serovars of Salmonella in dairy herds. Therefore, composite sampling may be an appropriate alternative to culture of individual samples when assessing Salmonella status in dairy herds. PMID- 22947463 TI - Direct real-time PCR with ethidium monoazide: a method for the rapid detection of viable Cronobacter sakazakii in powdered infant formula. AB - The goal of this study was to establish a rapid assay for the specific detection of viable Cronobacter sakazakii in powdered infant formula (PIF). Samples were subjected to treatment multiple times with ethidium monoazide with a concentration gradient (gEMA) prior to PCR to discriminate viable from dead C. sakazakii cells. To improve the current detection limits, we developed a new buffer for direct quantitative real-time PCR (DqPCR) without DNA isolation. Using 17 PIF samples, our rapid assay was compared with the new U.S. Food and Drug Administration (FDA) method published in the Bacteriological Analytical Manual in 2012. Although both the new FDA method and our rapid assay, which consists of DqPCR combined with gEMA (gEMA-DqPCR), produced negative results for all 17 PIF samples, 5 of the 17 PIFs were positive by DqPCR when they were not treated with EMA. Furthermore, for PIF samples artificially contaminated with viable C. sakazakii, gEMA-DqPCR successfully detected between 1 and 9 CFU of viable C. sakazakii in 300 g of PIF within 9 h, including a 6-h preincubation. Our results indicate that multiple EMA treatments are required to avoid false-positive results due to the contamination of commercial PIF with dead or injured C. sakazakii cells. Our rapid assay may also improve the sensitivity of the screening portion required by the new FDA method published in the Bacteriological Analytical Manual in 2012. PMID- 22947464 TI - Longitudinal dissemination of Salmonella enterica clonal groups through the slaughter process of Salmonella-positive pig batches. AB - This study was conducted to assess the dissemination of Salmonella clonal groups in slaughterhouses that received batches of Salmonella -positive pigs and used different routine processing procedures. Eight serial sampling sessions were conducted in three slaughterhouses (A, B, and C). Blood was collected randomly (n = 25) from each batch of pigs and processed for serology. Carcasses (n = 12) were identified and sampled after dehairing, after singeing, after evisceration, and before chilling. A section of cecum also was collected. Salmonella isolates were submitted to pulsed-field gel electrophoresis. The overall seroprevalence of Salmonella was 80.6% (316 of 392 samples), and cecal contents were positive for Salmonella in 23.8% (26 of 109) of the pigs sampled. Carcasses after dehairing had a significantly higher prevalence of Salmonella (P = 0.004) and the highest Salmonella levels (median = 0.26 log CFU/300 cm(2)). The singeing step significantly affected the Salmonella status of the carcasses (P = 0.001); however, the efficacy of singeing differed among slaughterhouses. In the prechilling step, 14.7% (16 of 109) of the carcasses were positive for Salmonella. Salmonella pulsotypes found on the prechill carcasses were also found in the lairage, in the cecal contents, and on carcasses after dehairing, suggesting that the main source of contamination was the slaughter process before singeing. Slaughterhouse C was the most likely (odds ration [OR] = 6.51) to have pigs carrying Salmonella in the gut, and slaughterhouse B was the most likely (OR = 14.66) to have contaminated carcasses at the prechilling step. These findings indicate that the procedures adopted in slaughterhouse B contributed to the spread of Salmonella strains. In contrast, in slaughterhouse C the Salmonella strains carried by the pigs or found in the lairage were not recovered from prechilled carcasses, validating the effectiveness of the slaughterhouse interventions. These results indicate that an effective slaughter process can help decrease the number of Salmonella-positive carcasses in slaughterhouses that receive Salmonella-positive pig batches. PMID- 22947465 TI - Effects of lactic acid and commercial chilling processes on survival of Salmonella, Yersinia enterocolitica, and Campylobacter coli in pork variety meats. AB - Current industry chilling practices with and without the application of 2% L lactic acid were compared for their effectiveness at reducing levels of Salmonella, Yersinia enterocolitica, and Campylobacter coli on pork variety meats. Pork variety meats (livers, intestines, hearts, and stomachs) were inoculated individually with one of the three pathogens and subjected to five different treatment combinations that included one or more of the following: water wash (25 degrees C), lactic acid spray (2%, 40 to 50 degrees C), chilling (4 degrees C), and freezing (-15 degrees C). Samples were analyzed before treatment, after each treatment step, and after 2, 4, and 6 months of frozen storage. Results showed that when a lactic acid spray was used in combination with water spray, immediate reductions were approximately 0.5 log CFU per sample of Salmonella, 0.8 log CFU per sample of Y. enterocolitica, and 1.1 log CFU per sample of C. coli. Chilling, both alone and in combination with spray treatments, had little effect on pathogens, while freezing resulted in additional 0.5-log CFU per sample reductions in levels of Salmonella and Y. enterocolitica, and an additional 1.0-log CFU per sample reduction in levels of C. coli. While reductions of at least 1 log CFU per sample were observed on variety meats treated with only a water wash and subsequently frozen, samples treated with lactic acid had greater additional reductions than those treated with only a water spray throughout frozen storage. The results of this study suggest that the use of lactic acid as a decontamination intervention, when used in combination with good manufacturing practices during processing, causes significant reductions in levels of Salmonella, Y. enterocolitica, and C. coli on pork variety meats. PMID- 22947466 TI - Antibiotic-resistant Enterococcus faecalis in abattoir pigs and plasmid colocalization and cotransfer of tet(M) and erm(B) genes. AB - This study was conducted to determine plasmid colocalization and transferability of both erm(B) and tet(M) genes in Enterococcus faecalis isolates from abattoir pigs in Canada. A total of 124 E. faecalis isolates from cecal contents of abattoir pigs were examined for antibiotic susceptibility. High percentages of resistance to macrolides and tetracyclines were found. Two predominant multiresistance patterns of E. faecalis were examined by PCR and sequencing for the presence of genes encoding antibiotic resistance. Various combinations of antibiotic resistance genes were detected; erm(B) and tet(M) were the most common genes. Plasmid profiling and hybridization revealed that both genes were colocated on a ~9-kb transferable plasmid in six strains with the two predominant multiresistant patterns. Plasmid colocalization and cotransfer of tet(M) and erm(B) genes in porcine E. faecalis isolates indicates that antibiotic coselection and transferability could occur via this single genetic element. To our knowledge, this is the first report on plasmid colocalization and transferability of erm(B) and tet(M) genes in E. faecalis on a mobile genetic element of ~9 kb. Physical linkage between important antibiotic resistance determinants in enterococci is of interest for predicting potential transfer to other bacterial genera. PMID- 22947467 TI - Filter-based pathogen enrichment technology for detection of multiple viable foodborne pathogens in 1 day. AB - Conventional foodborne pathogen assays currently used in the food industry often require long culture enrichments to increase pathogen levels so they can be detected. Even using sensitive real-time PCR assays, culture enrichment at least overnight is necessary especially for detection of pathogens with slow growth rates such as Listeria monocytogenes. To eliminate this cumbersome enrichment step and detect minute amounts of pathogens within 1 day, filter-based pathogen enrichment technology was developed utilizing a unique combination of glass fiber depth filter and porous filter aid materials to efficiently separate pathogens from food homogenates and avoid filter clogging by food particles. After pathogen immobilization in depth filters, only viable pathogens were selectively collected in a small volume of growth medium via microbial multiplication and migration; nonviable pathogens remained inside the filters. By assaying viable pathogens using real-time PCRs, multiple species of foodborne pathogens were detected, including L. monocytogenes, Salmonella enterica, and Escherichia coli O157:H7, at around 1 CFU/ml or 1 CFU/g in various food samples. This filter-based pathogen enrichment technology is a unique bacterial enrichment alternative to the conventional culture enrichment step and can significantly shorten the time necessary to obtain assay results. PMID- 22947468 TI - Inactivation of Listeria innocua, Salmonella Typhimurium, and Escherichia coli O157:H7 on surface and stem scar areas of tomatoes using in-package ozonation. AB - A novel in-package ozonation device was evaluated for its efficacy in inactivating three microorganisms (viz., Listeria innocua, attenuated Salmonella Typhimurium, and Escherichia coli O157:H7) on tomatoes and for its effect on fruit quality. The device produced ozone inside sealed film bags, reaching a concentration of 1,000 ppm within 1 min of activation. The three bacterial cultures were inoculated onto either the smooth surface or the stem scar areas of the tomatoes, which were then sealed in plastic film bags and subjected to in package ozonation. L. innocua on tomatoes was reduced to nondetectable levels within 40 s of treatment on the tomato surface, with inactivation of ca. 4 log CFU per fruit on the stem scar area. An increase in treatment time did not result in a proportional increase in bacterial reduction. For E. coli O157:H7 and Salmonella, there was little difference (<1 log) in the effectiveness of the system when comparing surface and scar-inoculated bacteria. Both bacteria were typically reduced by 2 to 3 log CFU per fruit after 2- to 3-min treatments. No negative effects on fruit color or texture were observed during a 22-day posttreatment storage study of ozone-treated tomatoes. These results suggest that the three bacteria responded differently to ozonation and that in-package ozonation may provide an alternative to chemical sanitizers commonly used by the industry. PMID- 22947469 TI - Effect of curing method and freeze-thawing on subsequent growth of Listeria monocytogenes on cold-smoked salmon. AB - The presence of the foodborne pathogen Listeria monocytogenes on cold-smoked salmon is a major concern for the seafood industry. Understanding processing and postprocessing handling factors that affect the ability of this pathogen to grow on cold-smoked salmon is critical for developing effective control strategies. In this study, we investigated the effect of curing method and freeze-thawing of cold-smoked salmon on (i) physicochemical properties and (ii) subsequent growth of genetically diverse strains of L. monocytogenes (inoculated after freeze thawing) and endogenous lactic acid bacteria. The majority of the measured physicochemical properties were unaffected by freezing and thawing. Overall, wet cured cold-smoked salmon had higher pH, water activity, and moisture, as well as lower fat, water-phase salt, and phenolic content compared with dry-cured cold smoked salmon. The curing method and freeze-thawing did not affect growth of endogenous lactic acid bacteria. Freeze-thawing cold-smoked salmon prior to inoculation led to pronounced growth of L. monocytogenes at 7 degrees C. The increase in cell density between days 0 and 30 was significantly (P = 0.0078) greater for cold-smoked salmon that was frozen and thawed prior to inoculation compared with nonfrozen cold-smoked salmon. On dry-cured, freeze-thawed cold smoked salmon, L. monocytogenes had a lag phase ranging from 3.7 +/- 0.1 to 11.2 +/- 1.4 days compared with salmon that was wet cured and freeze-thawed, on which L. monocytogenes began to grow within 24 h. Variation in growth among L. monocytogenes strains was also observed, indicating the significance of assessing multiple strains. Further efforts to understand the impact of processing and postprocessing handling steps of cold-smoked salmon on the growth of genetically diverse L. monocytogenes will contribute to improved challenge study designs and data. This, in turn, will likely lead to more reliable and unbiased risk assessments and control measures. PMID- 22947470 TI - Effects of nisin and lysozyme on growth inhibition and biofilm formation capacity of Staphylococcus aureus strains isolated from raw milk and cheese samples. AB - Effects of nisin and lysozyme on growth inhibition and biofilm formation capacity of 25 Staphylococcus aureus strains isolated from raw milk (13 strains) and cheese (12 strains) were studied. Nisin was tested at concentrations between 0.5 and 25 MUg/ml; the growth of all strains was inhibited at 25 MUg/ml, but the resistances of strains showed a great variation at lower nisin concentrations. In contrast, lysozyme tested at concentrations up to 5.0 mg/ml showed no inhibition on the growth of strains. Nisin used at the growth inhibitory concentration prevented the biofilm formation of strains, but strains continued biofilm formation at subinhibitory nisin concentrations. Lysozyme did not affect the biofilm formation of 19 of the strains, but it caused a considerable activation in the biofilm formation capacity of six strains. Twelve of the strains contained both biofilm-related protease genes (sspA, sspB, and aur) and active proteases; eight of these strains were nisin resistant. These results suggest a potential risk of S. aureus growth and biofilm formation when lysozyme is used in the biopreservation of dairy products. Nisin can be used to control growth and biofilm formation of foodborne S. aureus, unless resistance against this biopreservative develops. PMID- 22947471 TI - High pressure homogenization versus heat treatment: effect on survival, growth, and metabolism of dairy Leuconostoc strains. AB - The effect of high pressure homogenization (HPH) with respect to a traditional heat treatment on the inactivation, growth at 8 degrees C after treatments, and volatile profile of adventitious Leuconostoc strains isolated from Cremoso Argentino spoiled cheeses and ingredients used for their manufacture was evaluated. Most Leuconostoc strains revealed elevated resistance to HPH (eight passes, 100 MPa), especially when resuspended in skim milk. Heat treatment was more efficient than HPH in inactivating Leuconostoc cells at the three initial levels tested. The levels of alcohols and sulfur compounds increased during incubation at 8 degrees C in HPH-treated samples, while the highest amounts of aldehydes and ketones characterized were in heated samples. Leuconostoc cells resuspended in skim milk and subjected to one single-pass HPH treatment using an industrial-scale machine showed remarkable reductions in viable cell counts only when 300 and 400 MPa were applied. However, the cell counts of treated samples rose rapidly after only 5 days of storage at 8 degrees C. The Leuconostoc strains tested in this work were highly resistant to the inactivation treatments applied. Neither HPH nor heat treatment assured their total destruction, even though they were more sensitive to the thermal treatment. To enhance the inhibitory effect on Leuconostoc cells, HPH should be combined with a mild heat treatment, which in addition to efficient microbial inactivation, could allow maximal retention of the physicochemical properties of the product. PMID- 22947472 TI - Prevalence and fate of Bacillus cereus in African traditional cereal-based foods used as infant foods. AB - The objective of the present work was to estimate the prevalence of Bacillus cereus group species in traditional cereal-based lactic acid-fermented slurries and nonfermented flours used to prepare infant foods in an African context. High counts on mannitol-egg yolk-polymixin agar medium were determined for the fermented slurries (median, 4.5 * 10(4) CFU/ml of slurry) compared with the nonfermented flours, most of whose counts were lower than 10(-1) CFU/g. Virulence genes were characterized in 60 isolates from 26 traditional cereal-based foods in Ouagadougou (Burkina Faso). Seventy-two and 38 % of isolates were positive for the complete set of genes coding for hemolysin BL and nonhemolytic enterotoxin, respectively, suggesting a high enterotoxigenic potential for these foodborne isolates. No potentially emetic toxin-producing strains were detected. Because of the high counts found for fermented slurries, survival tests with vegetative cells inoculated in fermented slurries were performed, which showed that growth of B. cereus was inhibited. This result suggests that fermentation in traditional production units is presumably not adequately controlled, enabling growth during any unit operations before fermentation, or even during the fermentation step, when the process was poorly controlled. However, adding nisin (0.1 mg/ml) enabled a 5-log reduction in the B. cereus population in 5 h, suggesting that the use of nisin could be a way to upgrade the hygienic quality of this type of food. PMID- 22947473 TI - Validation of extrusion as a killing step for Enterococcus faecium in a balanced carbohydrate-protein meal by using a response surface design. AB - Outbreaks of salmonellosis and recalls of low-moisture foods including extruded products highlight the need for the food and feed industries to validate their extrusion processes to ensure the destruction of pathogenic microorganisms. Response surface methodology was employed to study the effect of moisture and temperature on inactivation by extrusion of Enterococcus faecium NRRL B-2354 in a carbohydrate-protein mix. A balanced carbohydrate-protein mix was formulated to different combinations of moisture contents, ranging from 24.9 to 31.1%, and each was inoculated with a pure culture of E. faecium to a final level of 5 log CFU/g. Each mix of various moistures was then extruded in a pilot scale extruder at different temperatures (ranging from 67.5 to 85 degrees C). After the extruder was allowed to equilibrate for 10 min, samples were collected in sterile bags, cooled in dry ice, and stored at 4 degrees C prior to analysis. E. faecium was enumerated with tryptic soy agar and membrane Enterococcus media, followed by incubation at 35 degrees C for 48 h. Each extrusion was repeated twice, with the central point of the design being repeated four times. From each extrusion, three subsamples were collected for microbial counts and moisture determination. Based on the results, the response surface model was y = 185.04 - 3.11X(1) - 4.23X(2) + 0.02X(1)(2) - 0.004X(1)X(2) + 0.08X(2)(2), with a good fit (R(2) = 0.92), which demonstrated the effects of moisture and temperature on the inactivation of E. faecium during extrusion. According to the response surface analysis, the greatest reduction of E. faecium for the inoculation levels studied here (about 5 log) in a carbohydrate-protein meal would occur at the temperature of 81.1 degrees C and moisture content of 28.1%. Other temperature and moisture combinations needed to achieve specific log reductions were plotted in a three dimensional response surface graph. PMID- 22947474 TI - Semicarbazide in selected bird's nest products. AB - Currently, a number of food producers use hypochlorite to bleach food and inhibit the growth of bacteria, preserving the food. Because the presence of high amounts of nitrogen could result in the formation of semicarbazide (SEM), the bleaching process could be one of the predominant sources of SEM in food. To investigate this, we selected instant bottled bird's nest as an example of a food that is bleached in its production. SEM was detected in 27 of 28 instant bottled bird's nest samples. The levels of SEM detected mostly fell in the range of 5 to 50 MUg/kg, which accounted for 75% of all samples measured. The SEM detected in the instant bottled bird's nest was found to have originated neither from the use of the antimicrobial agent nitrofurazone nor from azodicarbonamide, which is used as a blowing agent in gaskets used to seal the metal lid of the bottle. Instead, it could have originated from the bleaching process used in the preparation of the nests. Additionally, human exposure to SEM via consumption of instant bottled bird's nest for five subgroups of the population was estimated. Sensitivity analysis suggested that concentration of SEM in food is the most significant parameter governing human exposure via consumption of SEM-containing food. PMID- 22947475 TI - Companies' opinions and acceptance of global food safety initiative benchmarks after implementation. AB - International attention has been focused on minimizing costs that may unnecessarily raise food prices. One important aspect to consider is the redundant and overlapping costs of food safety audits. The Global Food Safety Initiative (GFSI) has devised benchmarked schemes based on existing international food safety standards for use as a unifying standard accepted by many retailers. The present study was conducted to evaluate the impact of the decision made by Walmart Stores (Bentonville, AR) to require their suppliers to become GFSI compliant. An online survey of 174 retail suppliers was conducted to assess food suppliers' opinions of this requirement and the benefits suppliers realized when they transitioned from their previous food safety systems. The most common reason for becoming GFSI compliant was to meet customers' requirements; thus, supplier implementation of the GFSI standards was not entirely voluntary. Other reasons given for compliance were enhancing food safety and remaining competitive. About 54 % of food processing plants using GFSI benchmarked schemes followed the guidelines of Safe Quality Food 2000 and 37 % followed those of the British Retail Consortium. At the supplier level, 58 % followed Safe Quality Food 2000 and 31 % followed the British Retail Consortium. Respondents reported that the certification process took about 10 months. The most common reason for selecting a certain GFSI benchmarked scheme was because it was widely accepted by customers (retailers). Four other common reasons were (i) the standard has a good reputation in the industry, (ii) the standard was recommended by others, (iii) the standard is most often used in the industry, and (iv) the standard was required by one of their customers. Most suppliers agreed that increased safety of their products was required to comply with GFSI benchmarked schemes. They also agreed that the GFSI required a more carefully documented food safety management system, which often required improved company food safety practices and increased employee training. Adoption of a GFSI benchmarked scheme resulted in fewer audits, i.e., one less per year. An educational opportunity exists to acquaint retailers and suppliers worldwide with the benefits of having an internationally recognized certification program such as that recognized by the GFSI. PMID- 22947476 TI - Application of hazard analysis and critical control point methodology and risk based grading to consumer food safety surveys. AB - Traditionally, consumer food safety survey responses have been classified as either "right" or "wrong" and food handling practices that are associated with high risk of infection have been treated in the same way as practices with lower risks. In this study, a risk-based method for consumer food safety surveys has been developed, and HACCP (hazard analysis and critical control point) methodology was used for selecting relevant questions. We conducted a nationally representative Web-based survey (n = 2,008), and to fit the self-reported answers we adjusted a risk-based grading system originally developed for observational studies. The results of the survey were analyzed both with the traditional "right" and "wrong" classification and with the risk-based grading system. The results using the two methods were very different. Only 5 of the 10 most frequent food handling violations were among the 10 practices associated with the highest risk. These 10 practices dealt with different aspects of heat treatment (lacking or insufficient), whereas the majority of the most frequent violations involved storing food at room temperature for too long. Use of the risk-based grading system for survey responses gave a more realistic picture of risks associated with domestic food handling practices. The method highlighted important violations and minor errors, which are performed by most people and are not associated with significant risk. Surveys built on a HACCP-based approach with risk-based grading will contribute to a better understanding of domestic food handling practices and will be of great value for targeted information and educational activities. PMID- 22947477 TI - Polyester cloth-based hybridization array system for identification of enterohemorrhagic Escherichia coli serogroups O26, O45, O103, O111, O121, O145, and O157. AB - A cloth-based hybridization array system (CHAS) was developed for the identification of foodborne colony isolates of seven priority enterohemorrhagic Escherichia coli (EHEC-7) serogroups targeted by U. S. food inspection programs. Gene sequences associated with intimin; Shiga-like toxins 1 and 2; and the antigenic markers O26, O45, O103, O111, O121, O145, and O157 were amplified in a multiplex PCR incorporating a digoxigenin label, and detected by hybridization of the PCR products with an array of specific oligonucleotide probes immobilized on a polyester cloth support, with subsequent immunoenzymatic assay of the captured amplicons. The EHEC-7 CHAS exhibited 100 % inclusivity and 100 % exclusivity characteristics with respect to detection of the various markers among 89 different E. coli strains, with various marker gene profiles and 15 different strains of non-E. coli bacteria. PMID- 22947478 TI - Virulence genes in isolates of Escherichia coli from samples of milk and feces from dairy cattle. AB - The aim of this work was to determine if Escherichia coli isolates carrying the virulence genes eae and eltB and exhibiting the Ehly phenotype are present in feces and milk samples from healthy dairy cattle on farms. Isolates from calves showed a statistically higher prevalence of eae and eltB compared with isolates from older animals. The other factors tested (stx(1), stx(2), and Ehly) were not statistically different between the two groups. Two isolates originating from calf feces were identified as serotype O157:H7; one of these isolates carried stx(1) and eae, the other stx(2) and eae. E. coli isolated from milk contained stx(1), stx(2), and eltB. The results show that feces or milk from healthy dairy cattle may contain E. coli pathotypes that express virulence genes, indicating that these materials have zoonotic potential. The results also reinforce the idea that host age can influence the dynamics of virulence genes in E. coli from cattle. PMID- 22947479 TI - Evaluation of lactic acid as an initial and secondary subprimal intervention for Escherichia coli O157:H7, non-O157 Shiga toxin-producing E. coli, and a nonpathogenic E. coli surrogate for E. coli O157:H7. AB - Lactic acid can reduce microbial contamination on beef carcass surfaces when used as a food safety intervention, but effectiveness when applied to the surface of chilled beef subprimal sections is not well documented. Studies characterizing bacterial reduction on subprimals after lactic acid treatment would be useful for validations of hazard analysis critical control point (HACCP) systems. The objective of this study was to validate initial use of lactic acid as a subprimal intervention during beef fabrication followed by a secondary application to vacuum-packaged product that was applied at industry operating parameters. Chilled beef subprimal sections (100 cm(2)) were either left uninoculated or were inoculated with 6 log CFU/cm(2) of a 5-strain mixture of Escherichia coli O157:H7, a 12-strain mixture of non-O157 Shiga toxin-producing E. coli (STEC), or a 5-strain mixture of nonpathogenic (biotype I) E. coli that are considered surrogates for E. coli O157:H7. Uninoculated and inoculated subprimal sections received only an initial or an initial and a second "rework" application of lactic acid in a custombuilt spray cabinet at 1 of 16 application parameters. After the initial spray, total inoculum counts were reduced from 6.0 log CFU/cm(2) to 3.6, 4.4, and 4.4 log CFU/cm(2) for the E. coli surrogates, E. coli O157:H7, and non-O157 STEC inoculation groups, respectively. After the second (rework) application, total inoculum counts were 2.6, 3.2, and 3.6 log CFU/cm(2) for the E. coli surrogates, E. coli O157:H7, and non-O157 STEC inoculation groups, respectively. Both the initial and secondary lactic acid treatments effectively reduced counts of pathogenic and nonpathogenic strains of E. coli and natural microflora on beef subprimals. These data will be useful to the meat industry as part of the HACCP validation process. PMID- 22947480 TI - Molecular characterization of antibiotic-resistant Salmonella isolates from retail meat from markets in Northern Vietnam. AB - A total of 118 Salmonella isolates were detected from 283 retail meat samples (135 pork and 148 chicken meat) purchased at retail markets in Northern Vietnam. Thirteen serovars, including Infantis, Anatum, Rissen, Reading, Emek, Typhimurium, Blockley, London, Newport, Derby, Weltevreden, Albany, and Hadar, were determined. Resistance to tetracycline (54.2%), sulfonamides (52.5%), streptomycin (41.5%), trimethoprim (36.4%), chloramphenicol (35.6%), and ampicillin (33.1%) was commonly seen in the Salmonella isolates. Fourteen [bla(TEM), bla(OXA-1), bla(PSE-1), aadA1, sul1, tetA, tetB, tetG, cmlA1, floR, dfrA1, dfrA12, aac(3)-IV, and aphA1-1AB ] of 17 resistance genes were detected from the isolates demonstrating resistance. Genes for plasmid-mediated quinolone resistance, such as qnrA, qnrB, qnrS, qepA, and acc(6')-1b-cr, were not detected in 23 quinoloneresistant isolates. The substitution TCC to TTC at codon 83 of gyrA was found in the 18 quinolone-resistant isolates. The data revealed that resistant Salmonella strains were widely distributed in Northern Vietnam via the food chain and that they might contain multiple genes specifying identical resistance phenotypes. Thus, further studies are necessary to clarify the mechanisms of antibiotic resistance in Salmonella strains and their spread in the livestock market. PMID- 22947481 TI - Multiple clusters of norovirus among shellfish consumers linked to symptomatic oyster harvesters. AB - We describe the investigation of a norovirus outbreak associated with raw oyster consumption affecting 36 people in British Columbia, Canada, in 2010. Several genotypes were found in oysters, including an exact sequence match to clinical samples in regions B and C of the norovirus genome (genogroup I genotype 4). Traceback implicated a single remotely located harvest site probably contaminated by ill shellfish workers during harvesting activities. This outbreak resulted in three recalls, one public advisory, and closure of the harvest site. PMID- 22947482 TI - Isotope dilution-gas chromatography/mass spectrometry method for the analysis of alkylphenols, bisphenol A, and estrogens in food crops. AB - A gas chromatography/mass spectrometry (GC/MS)-based isotope dilution technique was developed for determination of environmental estrogens in vegetables and fruits. The isotopically labeled standards of related environmental estrogens were used as the isotope dilution standards (IDS) to form the following analyte/surrogate pairings: octylphenol/(13)C6-4-n-nonylphenol, 4-n nonylphenol/(13)C6-4-n-nonylphenol, 4-nonylphenol/(13)C6-4-n-nonylphenol, bisphenol A/(13)C12-bisphenol A, estrone/(13)C6-estrone, 17-alpha estradiol/(13)C6-beta-estradiol, 17-beta-estradiol/(13)C6-beta-estradiol, 17 alpha-ethynylestradiol/(13)C2-17-alpha-ethynylestradiol, and estriol/D4-estriol. Plant samples were homogenized and extracted ultrasonically with acetone. Acid pretreatment greatly increased peak intensities for the analytes. Acid hydrolysis pretreatment was important for liberating conjugates of estrogenic contaminants in plant materials. Recoveries of the spiked analytes were greater than 90%. Method limits of detection (LOD) ranged from 0.01 to 0.20 MUg kg(-1) while limits of quantification (LOQ) ranged from 0.04 to 0.60 MUg kg(-1). Bisphenol, nonylphenol, and natural estrogens were detected in vegetable and fruit samples obtained from local markets, illustrating the feasibility of this method for determining trace estrogenic contaminants in vegetables and fruits. The method has significant environmental implications in terms of the simultaneous analysis of estrogenic contaminants in vegetables and fruit. PMID- 22947483 TI - The epiphytic microbiota of the globally widespread macroalga Cladophora glomerata (Chlorophyta, Cladophorales). AB - PREMISE OF THE STUDY: The filamentous chlorophyte Cladophora produces abundant nearshore populations in marine and freshwaters worldwide, often dominating periphyton communities and producing nuisance growths under eutrophic conditions. High surface area and environmental persistence foster such high functional and taxonomic diversity of epiphytic microfauna and microalgae that Cladophora has been labeled an ecological engineer. We tested the hypotheses that (1) Cladophora supports a structurally and functionally diverse epiphytic prokaryotic microbiota that influences materials cycling and (2) mutualistic host-microbe interactions occur. Because previous molecular sequencing-based analyses of the microbiota of C. glomerata found as western Lake Michigan beach drift had identified pathogenic associates such as Escherichia coli, we also asked if actively growing lentic C. glomerata harbors known pathogens. METHODS: We used 16S rRNA gene amplicon pyrosequencing to examine the microbiota of C. glomerata of Lake Mendota, Dane, Wisconsin, United States, during the growing season of 2011, at the genus- or species-level to infer functional phenotypes. We used correlative scanning electron and fluorescence microscopy to describe major prokaryotic morphotypes. KEY RESULTS: We found microscopic evidence for diverse bacterial morphotypes, and molecular evidence for ca. 100 distinct sequence types classifiable to genus at the 80% confidence level or species at the 96-97% level within nine bacterial phyla, but not E. coli or related human pathogens. CONCLUSIONS: We inferred that bacterial epiphytes of lentic C. glomerata have diverse functions in materials cycling, with traits that indicate the occurrence of mutualistic interactions with the algal host. PMID- 22947484 TI - Nitrogen enrichment differentially affects above- and belowground plant defense. AB - PREMISE OF THE STUDY: Human nitrogen (N) inputs to terrestrial ecosystems have greatly increased in recent years and may have important consequences for plant growth, reproduction, and defense. Although numerous studies have investigated the effects of nitrogen addition on plants, few have examined both above- and belowground responses within a range of predicted increase and apart from concomitant increases in other nutrients. * METHODS: We conducted a greenhouse experiment to study the consequences of increased nitrogen inputs, such as those from atmospheric N deposition, on plant performance, chemical defenses, and allocation tradeoffs for an invasive species, Linaria dalmatica. This plant produces iridoid glycosides, which are a group of terpenoid compounds. * KEY RESULTS: Soil nitrogen enrichment increased growth, reproduction, and whole-plant iridoid glycosides while decreasing some costs of defense. Interestingly, nitrogen addition had varying effects on defense allocation to above- and belowground tissues. Specifically, there was no change in iridoid glycoside concentrations of shoots, whereas concentrations decreased in flowers by ~35% and increased in roots by >400%. * CONCLUSIONS: Observed increases in plant performance and chemical defenses may have implications for the invasion potential of L. dalmatica. Moreover, our results highlight the importance of evaluating both above- and belowground plant defenses. In particular, findings presented here indicate that research focused on leaf-level defenses may not detect key allelochemical responses, including changes in plant resistance traits that could affect consumers (e.g., herbivores and pathogens) that specialize on different plant tissues as well as plant fitness and invasion success. PMID- 22947485 TI - Microsatellite markers developed for Utricularia reniformis (Lentibulariaceae). AB - PREMISE OF THE STUDY: Microsatellite markers were developed to study the genetic diversity and population structure of the carnivorous bladderwort Utricularia reniformis, which is endemic to the Atlantic Forest of southern and southeastern Brazil. Cross-species amplification was tested in U. gibba, U. neottioides, U. subulata, and Pinguicula benedicta. METHODS AND RESULTS: The U. reniformis genome was sequenced in a 454 GS FLX sequencer, and eight primer sets were developed based on the microsatellites identified from the reads. All loci are polymorphic, showing 1.6 to 4.8 alleles per population. Preliminary results show that primer sets are suitable for population-level studies. Cross-species amplification was successful in three other Utricularia species and one Pinguicula species. CONCLUSIONS: Markers developed in this study provide tools for analyses of intra- and interpopulation genetic diversity in Utricularia and Pinguicula. PMID- 22947487 TI - Animal models of drug-resistant epilepsy. AB - Several animal models are discussed in order to outline features of difficult-to treat or drug-resistant epilepsy. These models can be categorised as those which show a poor response to different antiepileptic drugs and those in which subgroups of drug-resistant animals are selected, based on interindividual differences. Non-responders to antiepileptic drugs have been described in the amygdala kindling model, as well as the chronic phase of post-status epilepticus models. Epileptic dogs which do not respond to standard antiepileptic drugs may serve as a translational model to provide a more clinical environment for drug testing. Drug resistance or a poor response to several antiepileptic drugs has been reported for the 6-Hz model, lamotrigine-pretreated kindled rats, pentylentetrazole-induced seizures in rats pre-exposed to pilocarpine, as well as following intrauterine exposure of rats to methylazoxymethanol. Using models to select non-responders is highly time-consuming and elaborate, limiting their use in routine drug-screening procedures. Current efforts to identify biomarkers of drug resistance may simplify the selection process, e.g. replacing several weeks of seizure monitoring by a single imaging scan. Moreover, further elucidation of mechanisms of resistance may help to design a series of ex vivo or in vitro screening procedures in order to evaluate whether a test compound is affected. PMID- 22947486 TI - Porosity and mechanically optimized PLGA based in situ hardening systems. AB - Goal of the present study was to develop and to characterize in situ-hardening, porous PLGA-based systems for their future application as bone grafting materials. Therefore, we investigated the precipitation behavior of formulations containing PLGA and a water-miscible solvent, DMSO, PEG 400, and NMP. To increase porosity, a pore forming agent (NaCMC) was added and to enhance mechanical properties of the system, an inorganic filler (alpha-TCP) was incorporated. The behavior upon contact with water and the influence of the prior addition of aqueous media on the morphology of the corresponding hardened implants were investigated. We proved cell-compatibility by live/dead assays for the hardened porous polymer/ceramic-composite scaffolds. The IsHS formulations can therefore be used to manufacture hardened scaffolds ex vivo by using molds with the desired shape and size. Cells were further successfully incorporated into the IsHS by precultivating the cells on the alpha-TCP-powder prior to their admixing to the formulation. However, cell viability could not be maintained due to toxicity of the tested solvents. But, the results demonstrate that in vivo cells should well penetrate, adhere, and proliferate in the hardened scaffolds. Consequently, we consider the in situ hardening system being an excellent candidate as a filling material for non-weight-bearing orthopedic indications, as the resulting properties of the hardened implant fulfill indication-specific needs like mechanical stability, elasticity, and porosity. PMID- 22947488 TI - Enteroscopy in paediatric Crohn's disease. AB - Small bowel evaluation is crucial in children with suspected inflammatory bowel disease to differentiate Crohn's disease from other enteropathies, in making therapeutic decisions and planning the follow-up. Endoscopic investigation of small bowel has historically been difficult due to the length and tortuosity of the organ itself. New technology, introduced over the past decade, allows minimally invasive and detailed endoscopic evaluation of the entire small bowel mucosa. While understudied in the paediatric population, literature is emerging supporting the use of these techniques in children. In this review we will provide an overview on the currently available technology, on its feasibility in paediatric age and on the available literature concerning the use of enteroscopy in paediatric Crohn's disease. PMID- 22947489 TI - Cell-mediated immune response during experimental acute infection with bovine viral diarrhoea virus: evaluation of blood parameters. AB - Acute infections with bovine viral diarrhoea virus (BVDV), a major pathogen of cattle, are often asymptomatic or produce only mild clinical symptoms. However, they may play an important role in the bovine respiratory disease complex by exerting a marked immunosuppressive effect, as a result of the death of the immunocompetent cell populations involved in controlling innate and adaptive immune responses, together with a marked reduction of both cytokine expression and co-stimulatory molecule synthesis. Although experimental research and field studies have shown that acute BVDV infection enhances susceptibility to secondary infection, the precise mechanism involved in BVDV-induced immunosuppression remains unclear. The present study is aimed at measuring a range of blood parameters in a single group of fourteen calves infected with non-cytopathic BVDV 1. Focus has been put on those related to the cell-mediated immune response just as leucocyte populations and lymphocyte subpopulations, serum concentrations of cytokines (IL-1beta, TNF-alpha, IFN-gamma, IL-12, IL-4 and IL-10) and acute phase proteins [haptoglobin, serum amyloid A (SAA), fibrinogen and albumin], as well as BVDV-specific antibodies and viremia. After non-cytopathic BVDV-1 infection, clinical signs intensity was never more than moderate coinciding with the presence of viremia and leucocyte and lymphocyte depletion. An early increase in TNF-alpha, IFN-gamma and IL-12 levels in contrast to IL-1beta was observed in line with a raise in haptoglobin and SAA levels on the latest days of the study. As regards IL-4 levels, no evidence was found of any changes. However, a slight increase in IL-10 was observed, matching up the TNF-alpha decline during the acute phase response. These findings would help to increase our knowledge of the immune mechanisms involved in acute infection with non-cytopathic BVDV-1 strains, suggesting the existence of a clear tendency towards a type 1 immune response, thereby enhancing resistance against viral infections. PMID- 22947490 TI - Does subtype matter? Assessing the effects of maltreatment on functioning in preadolescent youth in out-of-home care. AB - OBJECTIVES: Attempts to understand the effects of maltreatment subtypes on childhood functioning are complicated by the fact that children often experience multiple subtypes. This study assessed the effects of maltreatment subtypes on the cognitive, academic, and mental health functioning of preadolescent youth in out-of-home care using both "variable-centered" and "person-centered" statistical analytic approaches to modeling multiple subtypes of maltreatment. METHODS: Participants included 334 preadolescent youth (ages 9-11) placed in out-of-home care due to maltreatment. The occurrence and severity of maltreatment subtypes (physical abuse, sexual abuse, physical neglect, and supervisory neglect) were coded from child welfare records. The relationships between maltreatment subtypes and children's cognitive, academic, and mental health functioning were evaluated with the following approaches: (1) "Variable-centered" analytic methods: a. Regression approach: Multiple regression was used to estimate the effects of each maltreatment subtype (separate analyses for occurrence and severity), controlling for the other subtypes. b. Hierarchical approach: Contrast coding was used in regression analyses to estimate the effects of discrete maltreatment categories that were assigned based on a subtype occurrence hierarchy (sexual abuse > physical abuse > physical neglect > supervisory neglect). (2) "Person-centered" analytic method: Latent class analysis was used to group children with similar maltreatment severity profiles into discrete classes. The classes were then compared to determine if they differed in terms of their ability to predict functioning. RESULTS: The approaches identified similar relationships between maltreatment subtypes and children's functioning. The most consistent findings indicated that maltreated children who experienced physical or sexual abuse were at highest risk for caregiver-reported externalizing behavior problems, and those who experienced physical abuse and/or physical neglect were more likely to have higher levels of caregiver-reported internalizing problems. Children experiencing predominantly low severity supervisory neglect had relatively better functioning than other maltreated youth. CONCLUSIONS: Many of the maltreatment subtype differences identified within the maltreated sample in the current study are consistent with those from previous research comparing maltreated youth to non maltreated comparison groups. Results do not support combining supervisory and physical neglect. The "variable-centered" and "person-centered" analytic approaches produced complementary results. Advantages and disadvantages of each approach are discussed. PMID- 22947491 TI - Hong Kong domestic health spending: financial years 1989/90 to 2008/09. AB - This report presents the latest estimates of Hong Kong domestic health spending for financial years 1989/90 to 2008/09, cross-stratified and categorised by financing source, provider and function. Total expenditure on health (TEH) was HK$84,391 million in financial year 2008/09, which represents an increase of HK$5030 million or 6.3% over the preceding year. Amid the financial tsunami in late 2008, TEH grew faster relative to gross domestic product (GDP) leading to a marked increase as a percentage of GDP from 4.8% in 2007/08 to 5.1% in 2008/09. During the period 1989/90 to 2008/09, TEH per capita (at constant 2009 prices) grew at an average annual rate of 4.9%, which was faster than that of per capita GDP by 2.0 percentage points. 6.4% when compared with 2007/08, reaching HK$41 257 million and HK$43 134 million, respectively. Consequently, public and private shares of total health expenditure remained the same in the 2 years at 48.9% and 51.1%, respectively. Regarding private spending, the most important source of health financing was out-of-pocket payments by households (35.4% of TEH), followed by employer-provided group medical benefits (7.5%) and private insurance (6.4%). During the period, a growing number of households (mostly in middle to high-income groups) subscribed to pre-payment plans for financing health care. As such, private insurance has taken on an increasingly important role for financing private spending. Of the HK$84 391 million total health expenditure in 2008/09, current expenditure comprised HK$81 186 million (96.2%), whereas HK$3206 million (3.8%) was for capital expenses (ie investment in medical facilities). Analysed by health care function, services for curative care accounted for the largest share of total health spending (66.1%), which was made up of ambulatory services (32.8%), in-patient curative care (28.8%), day patient hospital services (3.9%) and home care (0.5%). Notwithstanding the small share of total spending for day patient hospital services, there was an increasing trend over the period 1989/90 to 2008/09, likely as a result of policy directives to shift the emphasis from inpatient to day patient care. 1989/90 to 46.8% in 2002/03 and then dropped slightly to 43.1% in 2007/08, which was primarily driven by reduced expenditure of Hospital Authority. Compared with the preceding year, expenditure on hospitals increased by HK$2935 million in 2008/09, whereas the corresponding increase for providers of ambulatory health care was only HK$919 million. As a result, the hospital share rebounded a little to 44.0% of total health spending, whereas that of providers of ambulatory health care dropped to 29.1%. Without taking into account capital expenses (ie investment in medical facilities), public current expenditure on health amounted to HK$39 301 million (48.4% of total current expenditure) in 2008/09 with the remaining HK$41 885 million made up from private sources. Public current expenditure was mostly incurred at hospitals (76.1%), whereas private current expenditure was mostly incurred at providers of ambulatory health care (48.9%). Although both public and private spending were mostly expended on personal health care services and goods (91.8% of total current spending), the patterns of distribution among functional categories differed. Public expenditure was targeted at in-patient care (51.8%) and substantially less on out-patient care (25.1%). In comparison, private spending was mostly concentrated on out-patient care (42.6%), whereas in-patient care (23.4%) and medical goods outside the patient care setting (22.5%) accounted for the majority of the remaining share. Compared to the Organisation for Economic Cooperation and Development countries, Hong Kong has devoted a relatively low percentage of GDP to health care in the last decade. As a share of total spending, public funding (either general government revenue or social security funds) in Hong Kong was also lower than that in most economies with comparable economic development and public revenue collection base. PMID- 22947492 TI - Vessel-specific rate of vasorelaxation is slower in diabetic rats. AB - The rate of adjustment of endothelium-dependent vasorelaxation was examined in the aorta, iliac and femoral arteries of eight control and eight diabetic rats with and without supplementation with vitamin C. Vessels were constricted using 10(-5) M phenylephrine (PE) and relaxed with 10(-4) M acetylcholine (ACh condition) or 10(-4) M ACh plus 10(-4) M vitamin C (ACh + vitamin C condition) in a myography system. Vasorelaxation was modelled as a mono-exponential function using a non-linear regression analysis. The adjustment (tau) of vasorelaxation was faster in control (6.6 +/- 3.2 s) compared to diabetic rats (8.4 +/- 3.4 s) (p < 0.05). The time-to-steady-state tended to be shorter in control (32.0 +/- 13.9 s) compared to diabetic rats (38.0 +/- 15.0 s) (p = 0.1). ACh + vitamin C did not speed the vasorelaxation response. The tau for vasorelaxation was shorter in the femoral (6.5 +/- 2.7 s) and iliac (6.8 +/- 2.5 s) compared to the aorta (9.2 +/- 4.2 s) (p < 0.05). The rate of vasorelaxation was greater in the femoral (3.2 +/- 1.4%.s(-1)) compared to the iliac (2.0 +/- 1.0%.s(-1)) and aorta (1.1 +/ 0.4%.s(-1)) in both groups and in the iliac compared to the aorta (p < 0.05) in the control group. In conclusion, the vasorelaxation response was vessel specific with a slower rate of adjustment in diabetic compared to control animals. PMID- 22947493 TI - Reprogramming and the mammalian germline: the Weismann barrier revisited. AB - The germline represents a unique cell type that can transmit genetic material to the next generation. During early embryonic development, somatic cells give rise to a small population of cells known as germ cells, which eventually differentiate into mature gametes. Germ cells undergo a process of removing and resetting relevant epigenetic information, mainly by DNA demethylation. This extensive epigenetic reprogramming leads to the conversion of germ cells into immortal cells that can pass on the genome to the next generation. In the absence of germline-specific reprogramming, germ cells would preserve the old, parental epigenetic memory, which would prevent the transfer of heritable information to the offspring. On the contrary, somatic cells cannot reset epigenetic information by preserving the full methylation pattern on imprinting genes. In this review, we focus on the capacity of germ cells and somatic cells (soma) to transfer genetic information to the next generation, and thus revisit the Weismann theory of heredity. PMID- 22947494 TI - Environmental control of cell size at division. AB - Tight coupling between cell growth and cell cycle progression allows cells to adjust their size to the demands of proliferation in varying nutrient environments. Target of rapamycin (TOR) signalling pathways co-ordinate cell growth with cell cycle progression in response to altered nutritional availability. To increase cell size the active TOR Complex 1 (TORC1) promotes cell growth to delay mitosis and cell division, whereas under limited nutrients TORC1 activity is decreased to reduce cell size. It remains unclear why cell size is subject to such tight control. Recent evidence suggests that in addition to modulating cell size, changes in nutrient availability also alter nuclear:cytoplasmic (N/C) ratios and may therefore compromise optimal cellular physiology. This could explain why cells increase their size when conditions are favourable, despite being competent to survive at a smaller size if necessary. PMID- 22947496 TI - Central and peripheral venous lines-associated blood stream infections in the critically ill surgical patients. AB - Critically ill surgical patients are always at increased risk of actual or potentially life-threatening health complications. Central/peripheral venous lines form a key part of their care. We review the current evidence on incidence of central and peripheral venous catheter-related bloodstream infections in critically ill surgical patients, and outline pathways for prevention and intervention. An extensive systematic electronic search was carried out on the relevant databases. Articles were considered suitable for inclusion if they investigated catheter colonisation and catheter-related bloodstream infection. Two independent reviewers engaged in selecting the appropriate articles in line with our protocol retrieved 8 articles published from 1999 to 2011. Outcomes on CVC colonisation and infections were investigated in six studies; four of which were prospective cohort studies, one prospective longitudinal study and one retrospective cohort study. Outcomes relating only to PICCs were reported in one prospective randomised trial. We identified only one study that compared CVC- and PICC-related complications in surgical intensive care units. Although our search protocol may not have yielded an exhaustive list we have identified a key deficiency in the literature, namely a paucity of studies investigating the incidence of CVC- and PICC-related bloodstream infection in exclusively critically ill surgical populations. In summary, the diverse definitions for the diagnosis of central and peripheral venous catheter-related bloodstream infections along with the vastly different sample size and extremely small PICC population size has, predictably, yielded inconsistent findings. Our current understanding is still limited; the studies we have identified do point us towards some tentative understanding that the CVC/PICC performance remains inconclusive. PMID- 22947495 TI - A three-state model of telomere control over human proliferative boundaries. AB - Intrinsic limits on cellular proliferation in human somatic tissue serves as a tumor suppressor mechanism by restricting cell growth in aged cells with accrued pre-cancerous mutations. This is accompanied by the potential cost of restricting regenerative capacity and contributing to cellular and organismal aging. Emerging data support a model where telomere erosion controls proliferative boundaries through the progressive change of telomere structure from a protected state, through two distinct states of telomere deprotection. In this model telomeres facilitate a controlled permanent cell cycle arrest with a stable diploid genome during differentiation and may serve as an epigenetic sensor of general stress in DNA metabolism processes. PMID- 22947497 TI - Ultrasound assisted the chemoselective 1,1-diacetate protection and deprotection of aldehydes catalyzed by poly(4-vinylpyridinium)hydrogen sulfate salt as a eco benign, efficient and reusable solid acid catalyst. AB - Poly(4-vinylpyridinium) hydrogen sulfate solid acid was found to be efficient catalyst for preparation of 1,1-diacetate using ultrasound irradiation at ambient temperature and neat condition. Deprotection of the resulting 1,1-diacetates were achieved using the same catalyst in methanol solvent under ultrasound irradiation at room temperature. This new method consistently has the advantage of excellent yields and short reaction times. Utilization of solvent free, simple reaction conditions, isolation, and purification makes this manipulation very interesting from an economic and environmental perspective. Further, the catalyst can be reused and recovered for several times. PMID- 22947498 TI - Low frequency ultrasound-assisted leaching of sewage sludge for toxic metal removal, dewatering and fertilizing properties preservation. AB - The aim of this research was to evaluate the efficiency of an ultrasonication process in combination with METIX-AC technology, a chemical process, for metal removal and dewatering ability, with preservation of fertilizing properties of sewage sludge. Waste activated sludge samples having a total solids concentration of 4 and 20 g L(-1), were enriched with Cu and Zn in order to exceed the limiting values recommended by Quebec regulation for sludge valorization. Ultrasonication was applied at low frequency (22 kHz) at specific energies ranging from 180 to 66,000 kJ kg(-1) of dry sludge. Ultrasound-assisted leaching rates and yields were similar to chemical leaching alone for Zn, whereas solubilisation was reduced for Cu, regardless the specific energy. Fertilizing properties preservation and dewatering ability were similar in ultrasound-assisted leaching, compared to chemical leaching alone. These trends were mainly attributed to the changes of metal speciation, particle size and morphology during ultrasonication, in addition to untreated sludge properties. PMID- 22947499 TI - Longitudinal patterns of poverty and health in early childhood: exploring the influence of concurrent, previous, and cumulative poverty on child health outcomes. AB - BACKGROUND: Although the links between poverty and health have often been studied , the dynamics of poverty and physical health in early childhood remain under investigated. In particular, it is not known whether the health of young children is affected differently from that of adults by patterns of poverty unique to them. METHODS: We examined patterns of health from 5 to 41 months of age as a function of concurrent, lagged, and chronic exposure to insufficient income. Using data from the first four rounds of the Quebec Longitudinal Study of Child Development, we performed multilevel logistic and multilevel Poisson regressions and latent growth curve analyses to explore associations between exposure to poverty and mother-reported asthma-like attacks, and maternal perception of health status controlling for neonatal, maternal, and environmental characteristics. RESULTS: The mean number of mother-reported asthma-like attacks significantly decreased as children aged. The likelihood of being perceived in a poorer health status also decreased across time. Concurrent poverty was associated with more mother-reported asthma-like attacks and with a higher risk of being perceived in poorer health status. One-period-lagged poverty was associated with more mother-reported asthma-like attacks and this remained significant after controlling for concurrent poverty. The number of mother reported asthma-like attacks was significantly higher among children in the chronic poverty class compared to those in the never-poor class, particularly at 17 and 29 months. Perceived health status at 5-months was significantly poorer among chronically poor children compared to never-poor children. CONCLUSION: Exposure to poverty negatively affects two major health indicators in early childhood - maternal perception of child health and mother-reported asthma-like attacks. Patterns of the effects vary according to timing and duration of poverty exposure. Further longitudinal research is warranted to disentangle time-specific from cumulative effects of poverty on child health. PMID- 22947500 TI - Evaluation of the Scandinavian guidelines for head injuries based on a consecutive series with computed tomography from a Norwegian university hospital. AB - BACKGROUND: This study prospectively assesses clinical characteristics and management of consecutive minimal, mild and moderate head injury patients referred for CT scans. Compliance with the Scandinavian head injury guidelines and possible reasons for non-compliance is explored. METHODS: From January 16th 2006 to January 15th 2007, 1325 computed tomography (CT) examinations due to minimal, mild or moderate head injury according to the Head Injury Severity Scale (HISS) were carried out at our University Hospital. When ordering a CT scan due to head trauma, physicians were asked to fill out a questionnaire. RESULTS: Guideline compliance was impossible to assess in 49.5% of all cases. This was due to non-assessable or missing key variables necessary in the decision making algorithm. One or more key variables for HISS classification were not assessable in 34.4% as it was unknown whether there had been loss of consciousness (LOC), duration of LOC was unknown or it was impossible to assess amnesia or focal neurologic deficits. Definite compliance with both CT and admittance recommendations in guidelines was seen in only 31.2%. In 54.2% of patients with minimal head injuries who underwent CT scans, imaging was not necessary according to guidelines. 59.1% of all patients were admitted to hospital, however only 23.7% of these were admitted because of the head-injury alone. Age < 4 years, possible medical cause of injuries, severe headache/nausea or vomiting and the presence of non-traumatic CT findings were independently associated with non assessable compliance with Scandinavian guidelines. Suspicion of influence of alcohol was inversely associated to non-compliance. CONCLUSIONS: Despite the prospective study design, guideline compliance was not assessable in nearly half of the patients. Patients with isolated head injuries and available and obtainable complete clinical information necessary for guideline-based decision making are not dominating in a head injury population. PMID- 22947502 TI - Simultaneous determination of amlodipine and bisoprolol in rat plasma by a liquid chromatography/tandem mass spectrometry method and its application in pharmacokinetic study. AB - A sensitive, specific liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was established for the quantitative determination of amlodipine and bisoprolol, using clenbuterol as the internal standard (IS). The analytes and IS were isolated from 100MUL plasma samples by a simple liquid-liquid extraction (LLE). Reverse-phase high performance liquid chromatography (RP-HPLC) separation was accomplished on a Diamonsil C(18) column (50mm*4.6mm, 5MUm) with a mobile phase composed of methanol-water-formic acid (75:25:0.01, v/v/v) at a flow rate of 0.3mL/min. The method had a chromatographic total run time of 3min. Multiple reacting monitoring (MRM) transitions of m/z [M+H](+) 409.1->237.9 (amlodipine), m/z [M+H](+) 326.2->116.0 (bisoprolol) and m/z [M+H](+) 277.0->203.0 (clenbuterol, IS) were used to quantify amlodipine, bisoprolol and IS, respectively. The method was sensitive with a lower limit of quantitation (LLOQ) of 0.2ng/mL for both amlodipine and bisoprolol, and the linear range was 0.2 50ng/mL for both amlodipine and bisoprolol (r(2)>0.9961). All the validation data, such as accuracy, precision and inter-day repeatability, were within the required limits. The method was successfully applied to pharmacokinetic studies of amlodipine and bisoprolol in Sprague-Dawley (SD) rats. PMID- 22947503 TI - Evaluation of fluorescence anisotropy to assess drug-lipid membrane partitioning. AB - PURPOSE: We evaluated fluorescence anisotropy measurements as an alternative technique to estimate drug-lipid membrane partitioning of fluorescent solutes. METHODS: The lipid bilayer partitioning of six drugs (logP in octanol/water between 2.6 and 5.4) was investigated by fluorescence anisotropy measurements with egg phosphatidylcholine liposomes at pH 7.4. Anisotropy was measured at about 5 and 50MUM drug and varying lipid concentrations between 3 and 700MUM. Fluorescence was corrected for light scattering and membrane affinities were estimated by non-linear regression analysis of the relative anisotropy as a function of lipid and solute concentrations. Liposome partitioning was in addition determined by equilibrium dialysis and potentiometric titration for comparison. RESULTS: Correction for light scattering by the liposomes was possible to some extent for two drugs. The estimated partition coefficients of three drugs were concentration-independent. For two drugs, membrane saturation was expected at the higher drug concentration. One drug showed significant differences between the parameters estimated at high and low drug concentrations, indicating measurement artifacts. Linear regression between the estimated logarithmic partition coefficients from anisotropy measurements and equilibrium dialysis revealed a slope of 1.05 and an intercept of 1.16 (n=5, r(2)=0.87). CONCLUSION: Anisotropy measurement with liposomes is hampered by light scattering and pH-dependent fluorescence properties of ionizable drugs. Taking these limitations into account, the technique may offer an alternative to established methods for the estimation of drug membrane partitioning, in particular when potentiometric titration or equilibrium dialysis are not applicable. PMID- 22947504 TI - Direct glutathione quantification in human blood by LC-MS/MS: comparison with HPLC with electrochemical detection. AB - Glutathione plays a central role in the defence against oxidative damage and in signaling pathways. Upon oxidation the reduced glutathione (GSH) is transformed to glutathione disulfide (GSSG). The concentration of GSH and GSSG in whole blood samples and their ratios is useful indicator of the oxidative stress status and/or disease risk. Here we describe a liquid-chromatographic method coupled with tandem mass spectrometry (LC-MS/MS) and we present the results of its comparison with a high-performance liquid-chromatographic method with electrochemical detection (HPLC-ECD). The method performed well in terms of validation parameters, i.e. linear range (0.01-50MUM for both GSH and GSSG), precision (intra- and inter-day coefficients of variation were less than 10% for both GSH and GSSG), accuracy (bias% varied between -2.1 and 7.9% for both analytes), quantification limits (LLOQs were 0.5MUM and 0.0625MUM for GSH and GSSG respectively). Furthermore the LC-MS/MS method showed a good agreement with the HPLC-ECD assay. However, major benefits of LC-MS/MS are the improved selectivity, precision and accuracy, the higher sensitivity and the unaltered capacity of detection with time in contrast to ECD. PMID- 22947505 TI - Directed synthesis of germanium oxide nanowires by vapor-liquid-solid oxidation. AB - We report on the directed synthesis of germanium oxide (GeO(x)) nanowires (NWs) by locally catalyzed thermal oxidation of aligned arrays of gold catalyst-tipped germanium NWs. During oxygen anneals conducted above the Au-Ge binary eutectic temperature (T > 361 degrees C), one-dimensional oxidation of as-grown Ge NWs occurs by diffusion of Ge through the Au-Ge catalyst droplet, in the presence of an oxygen containing ambient. Elongated GeO(x) wires grow from the liquid catalyst tip, consuming the adjoining Ge NWs as they grow. The oxide NWs' diameter is dictated by the catalyst diameter and their alignment generally parallels that of the growth direction of the initial Ge NWs. Growth rate comparisons reveal a substantial oxidation rate enhancement in the presence of the Au catalyst. Statistical analysis of GeO(x) nanowire growth by ex situ transmission electron microscopy and scanning electron microscopy suggests a transition from an initial, diameter-dependent kinetic regime, to diameter independent wire growth. This behavior suggests the existence of an incubation time for GeO(x) NW nucleation at the start of vapor-liquid-solid oxidation. PMID- 22947506 TI - Trophic status and metal bioaccumulation differences in multiple fish species exposed to coal ash-associated metals. AB - On December 22, 2008 a dike containing coal fly ash from the Tennessee Valley Authority Kingston Fossil Plant near Kingston Tennessee USA failed and resulted in the largest coal ash spill in U.S. history. Coal ash, a by-product of coal combustion, is known to contain multiple contaminants of concern, including arsenic and selenium. The purpose of this study was to investigate species differences in the bioaccumulation of arsenic and selenium and potential factors contributing to these differences (i.e., trophic dynamics and gut pH) in the vicinity of the Kingston coal ash spill. Elevated levels of arsenic and selenium were observed in various tissues of largemouth bass, white crappie, bluegill and redear sunfish from sites associated with the Kingston coal ash spill. Highest concentrations of selenium were found in redear sunfish with liver concentrations as high as 24.83mg/kg dry weight and ovary concentrations up to 10.40mg/kg dry weight at coal ash-associated sites. Investigations into the gut pH and trophic dynamics of redear sunfish and bluegill demonstrated a large difference in the gut physiology between these two species. Redear sunfish stomach and intestinal pH was found to be 1.1 and 0.16 pH units higher than in bluegill, respectively. In addition, fish from coal ash-associated sites showed enrichment differences ((15)N and (13)C) compared to no ash sites, indicating differences in food web dynamics between sites. These results imply the incorporation of coal ash associated compounds into local food webs and/or a shift in diet at ash sites compared to the no ash reference sites. Based on these results, further investigation into a broader food web at ash-associated sites is warranted. PMID- 22947507 TI - Toxicological responses in halophyte Suaeda salsa to mercury under environmentally relevant salinity. AB - Mercury is a highly risky heavy metal contaminant in intertidal zones in the Yellow River Delta (YRD). Suaeda salsa is a native halophyte in the YRD. In this work, we investigated the toxicological effects of mercury (20MUgL(-1)) in S. salsa under environmentally relevant salinity (500mM). The metabolic responses included the increased amino acids and decreased succinate, fructose, glucose, fumarate and ferulate in above-ground part of S. salsa exposed to mercury. The expression levels of INPS, CMO, BADH, CAT and GPx were elevated in above-ground part of S. salsa after combined Hg and salinity exposure. Increased activities of antioxidant enzymes including SOD, POD and CAT were uniquely observed in salinity treated samples. Our results indicated potential oxidative stresses and disturbances in protein bio-degradation and energy metabolism induced by mercury in S. salsa. Additionally, both synergistic and antagonistic effects were observed in S. salsa exposed to combined mercury and salinity. PMID- 22947508 TI - Estrogenic and anti-estrogenic activity of 23 commercial textile dyes. AB - The presence of dyes in wastewater effluent of textile industry is well documented. In contrast, the endocrine disrupting effects of these dyes and wastewater effluent have been poorly investigated. Herein, we studied twenty three commercial dyes, usually used in the textile industry, and extracts of blue jean textile wastewater samples were evaluated for their agonistic and antagonistic estrogen activity. Total estrogenic and anti-estrogenic activities were measured using the Yeast Estrogen Screen bioassay (YES) that evaluates estrogen receptor binding-dependent transcriptional and translational activities. The estrogenic potencies of the dyes and wastewater samples were evaluated by dose-response curves and compared to the dose-response curve of 17beta-estradiol (E2), the reference compound. The dose-dependent anti-estrogenic activities of the dyes and wastewater samples were normalized to the known antagonistic effect of 4-hydroxytamoxifen (4-OHT) on the induction of the lac Z reporter gene by E2. About half azo textile dyes have anti-estrogenic activity with the most active being Blue HFRL. Most azo dyes however have no or weak estrogenic activity. E2/dye or E2/waste water ER competitive binding assays show activity of Blue HFRL, benzopurpurine 4B, Everzol Navy Blue FBN, direct red 89 BNL 200% and waste water samples indicating a mechanism of action common to E2. Our results indicate that several textile dyes are potential endocrine disrupting agents. The presence of some of these dyes in textile industry wastewater may thus impact the aquatic ecosystem. PMID- 22947509 TI - [Pediatric global health: the challenge of moving from the intolerable to the improvable]. PMID- 22947510 TI - [Severe hepatic dysfunction due to endotoxemia secondary to central venous catheter bacterial colonisation]. PMID- 22947511 TI - Phase II trial of ixabepilone and carboplatin with or without bevacizumab in patients with previously untreated advanced non-small-cell lung cancer. AB - BACKGROUND: Epothilones, a new class of cytotoxic agents, have demonstrated activity in non-small-cell lung cancer (NSCLC). This phase II study examined ixabepilone/carboplatin (cohort A) and ixabepilone/carboplatin/bevacizumab (cohort B) as first-line therapy for patients with advanced NSCLC. METHOD: Patients were enrolled to either cohort A or B at physician discretion and when eligibility met. Eligible patients had newly diagnosed stage III/IV NSCLC, ECOG PS 0-1, adequate organ function, no active CNS metastases, and, in cohort B, bevacizumab treatment criteria. Both cohorts received ixabepilone 30 mg/m2 and carboplatin AUC=6 IV day 1 every 3-weeks for a maximum of 6 cycles. Patients assigned to cohort B also received bevacizumab 15 mg/kg IV day 1 of each cycle, and could continue single-agent bevacizumab for 6 additional cycles. RESULTS: Eighty-two patients (median age, 63 years; majority stage IV and former smokers) were enrolled from 11/08 to 10/09 (A-42, B-40) and received medians of 4 and 6 cycles, respectively. The ORRs were 29% and 50%. After median follow up of 17.5 months (A) and 15.7 months (B), median progression free survivals were A-5.3 months (95% CI 2.8-8.6) and B-6.7 months (95% CI 5.1-8.4), with median overall survivals of 9.3 months (95% CI 6.4-16.6) 13.2 months (95% CI 8.9-upper limit not reached), respectively. Grade 3/4 toxicity included: anemia (A-10%, B-27%), neutropenia (A-31%, B-48%), thrombocytopenia (A-19%, B-20%), fatigue (A-10%, B 23%), infection (A-5%, B-20%), and hypersensitivity reaction (A-2%, B-5%). There was one treatment-related death, due to hemoptysis in a cohort B patient with squamous histology. CONCLUSIONS: Ixabepilone can be safely combined with carboplatin in newly diagnosed patients with advanced NSCLC. The benefits of treatment appear consistent with those achieved with other modern platinum doublet regimens. The addition of bevacizumab increases toxicities, however, these are largely expected and reversible. The high ORR and OS observed in the bevacizumab-cohort are encouraging, but would require validation in a larger randomized trial of cohort A versus B. PMID- 22947512 TI - Brassica juncea nitric oxide synthase like activity is stimulated by PKC activators and calcium suggesting modulation by PKC-like kinase. AB - Nitric oxide (NO) is an important signaling molecule having varied physiological and regulatory roles in biological systems. The fact that nitric oxide synthase (NOS) is responsible for NO generation in animals, prompted major search for a similar enzyme in plants. Arginine dependent NOS like activity (BjNOSla) was detected in Brassica juncea seedlings using oxyhemoglobin and citrulline assays. BjNOSla showed 25% activation by NADPH (0.4 mM) and 40% by calcium (0.4 mM) but the activity was flavin mononucleotide (FMN), flavin dinucleotide (FAD) and calmodulin (CaM) independent. Pharmacological approach using mammalian NOS inhibitors, NBT (300 MUM) and l-NAME (5 mM), showed significant inhibition (100% and 67% respectively) supporting that the BjNOSla operates via the oxidative pathway. Most of the BjNOSla activity (80%) was confined to shoot while root showed only 20% activity. Localization studies by NADPH-diaphorase and DAF-2DA staining showed the presence of BjNOSla in guard cells. Kinetic analysis showed positive cooperativity with calcium as reflected by a decreased K(m) (~13%) and almost two fold increase in V(max). PMA (438 nM), a kinase activator, activated BjNOSla ~1.9 fold while its inactive analog 4alphaPDD was ineffective. Calcium and PMA activated the enzyme to ~3 folds. Interestingly, 1,2-DG6 (2.5 MUM) and PS (1 MUM) with calcium activated the enzyme activity to ~7 fold. A significant inhibition of BjNOSla by PKC inhibitors-staurosporine (~90%) and calphostin-C (~40%), further supports involvement of PKC-like kinase. The activity was also enhanced by abiotic stress conditions (7-46%). All these findings suggest that BjNOSla generates NO via oxidative pathway and is probably regulated by phosphorylation. PMID- 22947513 TI - Patient and physician preferences: impact on treatment effectiveness. AB - The greater reliability of randomised controlled trials (RCTs) over non randomised studies to objectively assess efficacy and/or safety of new therapeutic interventions is one of the main paradigms which sustains the evidence-based decision process in clinical practice. This assumption is primarily based on the hypothesis that randomisation, and particularly blinding procedure, drastically reduces the potential bias related to the preferences of patients and physicians. However, from non-randomised studies to double-blind, placebo-controlled RCTs, the preferences of patients and physicians can impact the evaluation of treatment effectiveness. Both internal validity and external validity of RCTs are impacted by various biases related to patient and physician preferences. Thus, influence of patient and physician expectations on trial outcomes might be much less trivial than expected, both in open-label and double blind, placebo-controlled, randomised trials. Accordingly, it might be interesting to systematically collect information about patient preferences before randomisation, using dedicated questionnaires, in order to be able to evaluate the impact of non-preferred allocation on trial results. PMID- 22947514 TI - A label-free electrochemical assay for methyltransferase activity detection based on the controllable assembly of single wall carbon nanotubes. AB - A sensitive label-free "signal-on" electrochemical approach for detection of methyltransferases (MTase) activity is developed based on the signal transduction and amplification of single wall carbon nanotubes (SWCNTs). In this method, the oligonucleotide I is first self-assembled on the electrode via Au-S bonding. After hybridization with its complement ssDNA (oligonucleotide II), duplex strand DNA (dsDNA) probes containing specific recognition sequence of Dam MTase and methylation-sensitive restriction endonuclease Dpn I is then formed on the electrode. In the presence of Dam MTase and Dpn I, the dsDNA probes are methylated and subsequently cleaved into two dsDNA fragments. After heating, the remained dsDNA fragments on the electrode melted into ssDNA fragments. Then the SWCNTs can be controllably assembled on the ssDNA fragments remained on the electrode, mediating efficient electron transfer between the electrode and electroactive species. It generates measurable current signal (eT ON), which is related to the concentration of the Dam MTase. The resulting change in electron transfer efficiency is readily measured by differential pulse voltammetry at Dam MTase concentrations as low as 0.04 U/mL. This method does not need electroactive molecules labeling on the methylation-responsive DNA probes. The linear response of the developed facile signal-on electrochemical sensing system for Dam MTase is in the range of 0.1-1.0 U/mL. In addition, such a SWCNTs based electrochemical assay also has the ability to screen inhibitors for Dam MTase. PMID- 22947515 TI - G-quadruplex DNA aptamers for zeatin recognizing. AB - Zeatins, a major type of cytokinin, are ubiquitous in higher plants, and involve in regulating a wide range of developmental processes. The development of highly specific ligands to zeatins would be very useful in plant biological research. Here we describe a group of oligonucleotide ligands (aptamers) generated against trans-zeatin. The optimized aptamers possess strong affinity to trans-zeatin and trans-zeatin riboside (Kd=3-5 MUM), and relatively weak affinity (Kd=27-30 MUM) to cis-zeatin and dihydrozeatin. These aptamers adopt a hairpin-G-quadruplex structure for binding to zeatin. A fluorescence turn-on aptasensor based on graphene oxide (GO) was developed for the recognition of zeatins. The specificity assay of this aptasensor shows good response to zeatins, and no response to the adenine derivatives (analog of zeatins) abundantly existing in biological samples. These results show the great potential of these aptamers in chemical analysis and biological investigation of zeatins. PMID- 22947516 TI - Electrochemical detection of hepatitis B and papilloma virus DNAs using SWCNT array coated with gold nanoparticles. AB - This study investigated electrochemical detection of human hepatitis B and papilloma viruses using electrochemical impedance spectroscopy technique. The sensor was fabricated by electrochemically depositing Au nanoparticles on the in situ prepared single walled carbon nanotube (SWCNTs) arrays, followed by the self assembly of single-stranded probe DNA on the SWCNTs/Au platform. The as-prepared electrochemical sensor could detect lower than 1 attomole complimentary hepatitis B single-stranded DNA (ssDNA), which corresponds to having 600 ssDNA molecules in a 1.0 mL sample. For a 1-base mismatched hepatitis B ssDNA, the experimental detection limit is 0.1 pmol. When being applied to detect 24-base papilloma virus ssDNA, the experimentally determined low detection limit is 1 attomole. In addition to the low detection limit, the SWCNTs/Au/ssDNA sensor also showed great stability, where after being kept in a refrigerator for a month at a temperature 4-8 degrees C its charge transfer resistance decreased by less than 1%. The sensor could be conveniently regenerated via dehybridization in hot water. Both aligned and random SWCNTs arrays have been investigated in this study and there was nearly no difference in the low limit in the detection of hepatitis B and papilloma viruses. This study illustrates that combining Au nanoparticles with the in situ fabricated SWCNTs array is a promising platform for ultrasensitive biosensing. PMID- 22947517 TI - NiO nanoparticle-based urea biosensor. AB - NiO nanoparticles (NiO-NPs) have been exploited successfully for the fabrication of a urea biosensor. A thin film of NiO nanoparticles deposited on an indium tin oxide (ITO) coated glass substrate serves as an efficient matrix for the immobilisation of urease (Ur), the specific enzyme for urea detection. The prepared bioelectrode (Ur/NiO-NP/ITO/glass) is utilised for urea sensing using cyclic voltammetry and UV-visible spectroscopy. NiO nanoparticles act as electro catalytic species that are based on the shuttling of electrons between Ni(2+) and Ni(3+) in the octahedral site and result in an enhanced electrochemical current response. The prepared bioelectrode (Ur/NiO-NPs/ITO/glass) exhibits a high sensitivity of 21.3 MUA/(mM (*) cm(2)) and a good linearity in a wide range (0.83 16.65 Mm) of urea concentrations with fast response time of 5s. The low value of the Michaelis-Menten constant (K(m)=0.34 mM) indicates the high affinity of Ur towards the analyte (urea). The high catalytic activity, along with the redox behaviour of NiO-NPs, makes it an efficient matrix for the realisation of a urea biosensor. PMID- 22947519 TI - Central nervous system damage due to acute paraquat poisoning: a neuroimaging study with 3.0 T MRI. AB - Paraquat (PQ) is an organic heterocyclic herbicide that is widely used throughout the world. Epidemiological and neuropathological studies have shown that chronic exposure to PQ increases the risk of Parkinson's disease. Patients with acute PQ poisoning show damage to the lungs, liver, and kidneys, and some also show symptoms of central nervous system (CNS) toxicity. However, few studies have focused on the acute neurotoxic changes caused by PQ. Dynamic pathological changes in the human brain cannot be explored in animal models. Thus, to elucidate the impact of acute PQ poisoning on the CNS, neuroimaging studies of poisoned victims, and especially survivors, should be performed. This study reports the first application of magnetic resonance imaging (MRI) techniques on patients with acute PQ poisoning, including survivors. We found significant abnormal signals in the brains of two patients during the acute post-poisoning phase. Using susceptibility weighted imaging (SWI), we documented changes in the corrected phase values for the extrapyramidal ganglia of survivors, and these values correlate with excessive iron deposition. Our diffusion tensor imaging (DTI) results were suggestive of microstructural changes in the extrapyramidal ganglia and hippocampus after PQ poisoning. These neuroimaging results provide an indirect demonstration that acute PQ neurotoxicity exerts a sustained effect during the acute and recovery stages of poisoning. PMID- 22947518 TI - Sex dimorphic behaviors as markers of neuroendocrine disruption by environmental chemicals: the case of chlorpyrifos. AB - The complexity of the neuroendocrine level of investigation requires the assessment of behavioral patterns that extend beyond the reproductive functions, which are age- and sex-specific in rodents, described by defined clusters of behavioral items regulated by genetic, hormonal, and epigenetic factors. The study of social behavior in laboratory rodents reveals sex-dimorphic effects of environmental chemicals that may be undetected either by a traditional neurotoxicological approach or referring to the classical definition of endocrine disrupting chemicals. Here we review data on the neurobehavioral effects of developmental exposure to the non-persistent organophosphorus insecticide chlorpyrifos, whose neurotoxic activity at low doses is currently a matter of concern for children's health. In mice exposed to chlorpyrifos in utero and/or in early development social/emotional responses are differently affected in the two sexes in parallel with sex-dependent interference on hypothalamic neuroendocrine pathways regulating social behaviors (vasopressin, oxytocin, and steroid regulated systems). Through the analysis of complex sex-dimorphic behavioral patterns we show that neurotoxic and endocrine disrupting activities of CPF overlap. This widely diffused organophosphorus pesticide might thus be considered as a neuroendocrine disruptor possibly representing a risk factor for sex-biased neurodevelopmental disorders in children. PMID- 22947521 TI - Review of the neurological manifestations of hepatitis E infection. AB - Hepatitis E (HEV) is a common infection worldwide and is an emerging disease in developed countries. The presence of extra-hepatic manifestation of HEV infection is important to bear in mind so that the diagnosis is not missed, since HEV is not routinely tested for in acute hepatitis due to perceived rarity of this infection outside of endemic countries. This article reviews the neurological presentations of acute and chronic HEV, and discusses the viral kinetics against symptomatology, and outcomes of specific treatment. Possible mechanisms of pathogenesis are considered. PMID- 22947522 TI - The epidemiologic burden of hepatitis C virus infection in Latin America . AB - Chronic infection with hepatitis C virus (HCV) is a major and growing public health concern worldwide, including in Latin America. With more efficacious therapies becoming available, decision-makers will require accurate estimates of disease prevalence to assess the potential impact of new treatments. However, few estimates of the epidemiologic burden, either overall or by country, are available for Latin America; and the potential impact of currently-available treatments on the epidemiologic burden of HCV in Latin America has not been assessed. To address this, we systematically reviewed twenty-five articles presenting population-based estimates of HCV prevalence from general population or blood donor samples, and supplemen- ted those with publically-available data, to estimate the total number of persons infected with HCV in Latin America at 7.8 million (2010). Of these, over 4.6 million would be expected to have genotype 1 chronic HCV, based on published data on the risk of progression to chronic disease and the HCV genotype distribution of Latin America. Finally, we calculated that between 1.6 and 2.3 million persons with genotype 1 chronic HCV would potentially benefit from current treatments, based on published estimates of genotype-specific treatment responsiveness. In conclusion, these estimates demonstrate the substantial present epidemiologic burden of HCV, and quantify the impending societal and clinical burden from untreated HCV in Latin America. PMID- 22947523 TI - Role of nitric oxide in liver regeneration. AB - The liver has a remarkable ability to regenerate in response to surgical removal or chemical insult. The mechanisms regulating regenerative processes are complex, and incompletely understood. A large number genes, which are not normally expressed in the quiescent liver, are activated. Immediately after partial hepatectomy (PH) (1-6 h), nitric oxide (NO) is synthesized by liver parenchymal and nonparenchymal cells from L-arginine, via induction of the inducible form of nitric oxide synthase (iNOS). NO is a highly reactive molecule, known to be involved in diverse biological processes in nearly all aspects of life. Liver regeneration is a major area within the field of NO research. Our review describes several processes that have been suggested to be modulated by the NO released following PH, including proliferation, apoptosis and angiogenesis in the remnant tissue. Because iNOS up regulation has such profound physiologic effects, its regulation is strictly controlled. The up regulation of iNOS after PH and the subsequent production of NO induce positive effects on the regulation of early stages of the regenerative process. However, overproduction (> 100%) can have detrimental effects, including apoptosis. Thus, the iNOS induction after PH is necessary, and enough to allow for the normal regenerative process. PMID- 22947524 TI - Serum cystatin C: a non-invasive marker of liver fibrosis or of current liver fibrogenesis in chronic hepatitis C? . AB - BACKGROUND: Serum levels of cystatin C, an endogenous inhibitor of cysteine proteases, provide an alternative method to creatinine-based criteria for measuring glomerular filtration rate. Preliminary data suggested that serum cystatin C levels parallel with the stage of liver fibrosis in chronic liver disorders. Our aim has been to evaluate the possible role of serum cystatin C as a marker of liver fibrosis in hepatitis C virus (HCV)-induced chronic liver disease. MATERIAL AND METHODS: 100 consecutive patients (56 men, mean age 51.2 +/ 9.5 yrs) with HCV-induced chronic liver disease, scheduled for their first liver biopsy and naive for antiviral therapy were included. Liver fibrosis was evaluated with the METAVIR score. Serum cystatin C and standard laboratory tests were measured simultaneously. Patients with ethanol abuse (> 50 g/day), HBV or HIV coinfection or plasma creatinine >= 1.20 mg/dL were excluded. In addition, a second group of 16 patients fulfilling the same requisites and diagnosed with HCV induced compensated cirrhosis by clinical evidence of portal hypertension was included. RESULTS: Serum cystatin C levels significantly increase from F0 to F2 fibrosis stages, remained stable in F3 and F4 stages and increased again in the group of non-biopsied compensated cirrhosis. Serum cystatin C levels were higher in patients with moderate-advanced necroinflammation in the liver biopsy. CONCLUSION: Serum cystatin C level may reflect current fibrogenic and necroinflammatory activities in chronic HCV-induced liver disease with normal renal function but can not be considered as a non-invasive marker of liver fibrosis. PMID- 22947525 TI - Clinical course and management of acute hepatitis A infection in adults. AB - BACKGROUND: Hepatitis A is the most common type of viral hepatitis in Mexico. The change of hepatitis A epidemiology in Mexico from high to intermediate endemicity leads to increasing susceptible adults for severe illness. OBJECTIVE: To describe the clinical characteristics and hospital outcome of adult patients with acute hepatitis A infection, and determine risk factor for mortality. MATERIAL AND METHODS: This is a retrospective observational, multicentre study in Mexico City and in Guatemala City. All inhospital patients were followed until discharge or death. Risk factors for death/acute liver failure were identified. RESULTS: Forty seven patients were analyzed, sixty percent were male, the prodrome phase was from 3 to 30 days. The three most common symptoms were fever, malaise and jaundice, with 87%, 74% and 62% respectively. The incidence of patients who were treated with antibiotics before hospital admission was up to 34%. Unnecessary imaging studies and out of guidelines drugs were used. Presence of encephalopathy, leukocytes > 19,000/mL, blood urea nitrogen > 36 mg/dL, creatinine > 2 mg/dL, albumin < 2.5 mg/dL and total bilirubin > 9.6 mg/dL, are predictors of mortality. Serum creatinine > 2 mg/dL has the best sensibility and specificity for predicting fulminant hepatitis/death. CONCLUSION: Acute hepatitis A infection in adults is associated some unnecessary diagnostic and therapeutic approach. Could be associated with fulminant hepatitis, and a creatinine value > 2 mg/dL is the best predictor for fulminant hepatitis and death. PMID- 22947526 TI - Natural history of hepatitis C virus infection in a cohort of asymptomatic post transfused subjects. AB - BACKGROUND & AIMS. Studies about the natural history of hepatitis C virus (HCV) infection report variable progression to cirrhosis depending on study design. Retrospective cross-sectional liver clinic studies overestimate the rate of fibrosis progression due to inclusion of patients with more severe disease leaving mild and asymptomatic patients underrepresented. We evaluated fibrosis progression in a group of "healthy" asymptomatic subjects, attending to a voluntary campaign for the detection of HCV infection. MATERIAL AND METHODS: A detection campaign was launched on subjects transfused before 1993. Of 1699 volunteers, 61(3.6%) had HCV infection. A liver biopsy was performed in 40 (65%). Assessed risk factors for liver fibrosis were: sex, body mass index, alcohol consumption (> 20 g/d - > 40g/d ), genotype, HLA-DRB1 alleles, present age, age at infection and duration of infection. RESULTS: 25 (62.5%) were women with a median age of 52.5 years. The median duration of infection was 21.5 years with a median age at infection of 27 years. As regards fibrosis, 25 (62.5%) had a Low Stage (F0-F1), 8 patients, 20%, had severe fibrosis, one patient (2.5%) had cirrhosis. Alcohol consumption was the only risk factor associated with fibrosis progression. CONCLUSIONS: The low progression to cirrhosis may be explained by the clinical characteristics of our population: asymptomatic middle-aged "healthy" subjects infected at young age. The progression to severe fibrosis was noticeable; hence a longer follow-up might demonstrate changes in this outcome. Significant alcohol consumption clearly worsens the natural history of HCV infection; this is no so evident for occasional or mild alcohol consumers. PMID- 22947527 TI - Decreased serum total T3 level in hepatitis B and C related cirrhosis by severity of liver damage. AB - OBJECTIVE: Thyroid hormones profile in patients with hepatic cirrhosis due to chronic HBV and HCV infections was evaluated in order to find any relationship between thyroid hormones and severity of liver damage. MATERIAL AND METHODS: Patients with the diagnosis of hepatic cirrhosis due to hepatitis B or C were screened for thyroid function status. Child-Pugh and model for end-stage liver disease (MELD) scores were calculated. Considering each thyroid function test, patients were divided into two groups with lower than normal and normal range of thyroid hormones, separately for each (for TSH, normal and upper than nor- mal). The correlation between thyroid function tests and severity of liver disease was taken into account. RESULTS: Number of patients with a T3 level lower than normal range (70-110 ng/dL) significantly increased along with Child-Pugh scores A, B and C. A negative correlation was found between Child-Pugh scores and total serum T3 level (r = -0.453, P < 0.001). Also a reverse correlation was observed between MELD score and T3 levels (r = -0.305, P = 0.14). CONCLUSION: In conclusion serum T3 concentration is a good index of hepatic function, decreasing by the severity of liver damage. PMID- 22947528 TI - Epidemiologic trends in HBV infections at a reference centre in Turkey: an 11 year retrospective analysis. AB - OBJECTIVE: To identify changes in hepatitis B epidemiology after the implementation of the nationwide vaccination program in Turkey, hepatitis B virus (HBV) and related tests performed over a period of 11 years (2000-2010) at a reference centre were retrospectively overviewed and statistically analysed for trends. RESULTS: Assay results for Hepatitis B surface antigen (HBsAg) and e antigen (HBeAg), Anti-HBs, Anti-HBe, Anti-HBc immunoglobulins and HBV DNA as well as aspartate aminotransferase (AST), alanine aminotransferase (ALT), gama glutamyl transpeptidase (GGT) and alkaline phosphatase (AP) levels, obtained via standardized commercial assays were included in the analysis. Overall, a stable anti-HBs incidence (43.6%) and male predominance in infected individuals were noted. Total Anti-HBc was detected in 43.3% of the Anti-HBs reactive population, demonstrating that the immunity against HBV has still been acquired through virus exposure. An intermediate HBsAg seroprevalence of 6.0% was observed with a significant decrease from 12.3% to 5.0% from 2000 to 2010. Anti-HBe positive infections were more frequent than those with HBe antigenemia (77.1% vs. 18.5%) with a notable increase from 2000 to 2003. HBV DNA was detected in 23.6-25.6% with serological markers of viral replication and was more prevalent in HBeAg positive individuals in parallel with AST, ALT and GGT levels. Evidence for horizontal transfer as the major transmission route was revealed with a reduction of childhood HBV infections, attributable to the ongoing vaccination efforts. PMID- 22947529 TI - Liver transplantation in the critically ill: donation after cardiac death compared to donation after brain death grafts. AB - Patients with end stage liver disease may become critically ill prior to LT requiring admission to the intensive care unit (ICU). The high acuity patients may be thought too ill to transplant; however, often LT is the only therapeutic option. Choosing the correct liver allograft for these patients is often difficult and it is imperative that the allograft work immediately. Donation after cardiac death (DCD) donors provide an important source of livers, however, DCD graft allocation remains a controversial topic, in critically ill patients. Between January 2003-December 2008, 1215 LTs were performed: 85 patients at the time of LT were in the ICU. Twelve patients received DCD grafts and 73 received donation after brain dead (DBD) grafts. After retransplant cases and multiorgan transplants were excluded, 8 recipients of DCD grafts and 42 recipients of DBD grafts were included in this study. Post-transplant outcomes of DCD and DBD liver grafts were compared. While there were differences in graft and survival between DCD and DBD groups at 4 month and 1 year time points, the differences did not reach statistical significance. The graft and patient survival rates were similar among the groups at 3-year time point. There is need for other large liver transplant programs to report their outcomes using liver grafts from DCD and DBD donors. We believe that the experience of the surgical, medical and critical care team is important for successfully using DCD grafts for critically ill patients. PMID- 22947530 TI - A clinical survey of bleeding, thrombosis, and blood product use in decompensated cirrhosis patients. AB - BACKGROUND: The relative incidence of bleeding and thrombotic events and the use of blood products in hospitalized cirrhosis patients have not been widely reported. We aimed to estimate the magnitude of bleeding events and venous thrombosis in consecutive hospitalized cirrhotic patients over a finite time period and to examine the amount and indications for blood product use in cirrhosis patients admitted to a tertiary care center. RESULTS: Among patients admitted with decompensated liver disease, 34 (40%) suffered bleeding events (about one-half non-variceal) and 6 patients (7%) suffered deep venous thrombosis. In the blood product survey, 168 patients were transfused with plasma or platelets during the survey inter- vals. Liver disease patients accounted for 7.7% of the total but disproportionately consumed 32.4% (46 of 142) of the units of plasma mostly administered as prophylaxis. In contrast, cirrhosis patients received only 7 of the 53 units of platelets transfused (13.2%) during the survey intervals. CONCLUSIONS: Coagulation issues constitute a common problem in patients with liver disease. Recent advances in laboratory testing have shown that stable cirrhosis patients are relatively hypercoagulable. The result of this prospective survey among decompensated (unstable) cirrhosis patients shows that, while DVT is not uncommon, bleeding (non-variceal in one half) remains the dominant clinical problem. This situation likely sustains the common practice of plasma infusion in these patients although its use is of unproven and questionable benefit. Better clinical tools are needed to refine clinical practice in this setting. PMID- 22947531 TI - Does the size of the needle influence the number of portal tracts obtained through percutaneous liver biopsy? AB - AIM: Liver biopsy (LB) is often essential for the diagnosis and staging of chronic viral hepatitis. The aim of our paper was to establish if the size of the biopsy needle influences the number of portal tracts obtained through LB. MATERIAL AND METHODS: We conducted a retrospective study on 596 echoassisted percutaneous LBs performed in the Department of Gastroenterology and Hepatology Timisoara during a 4 years period. We included only those biopsy results that had mentioned both the type of needle and the number of portal tracts. All LBs were echoassisted and performed with Menghini modified needles 1.4 and 1.6 mm in diameter (technique with two passages into the liver). The liver fragments were analyzed by a senior pathologist and Knodell score was used to describe necroinflammatory activity as well as fibrosis. We compared the number of portal tracts obtained with 1.4 vs. 1.6 Menghini needles. RESULTS: Type 1.4 mm Menghini needles were used for 80 LBs, while 1.6 mm type were used in 516 LBs. Liver fragments obtained with 1.6 mm Menghini needles had a significantly higher mean number of portal tracts as compared to those obtained with 1.4 needles (24.5 +/- 10.6 vs. 20.8 +/- 8.6, p = 0.003). CONCLUSION: The 1.6 mm Menghini needles provide better liver biopsy specimens, with higher number of portal tracts, as compared to 1.4 mm Menghini needles. PMID- 22947532 TI - Rapid diagnosis of spontaneous bacterial peritonitis using leukocyte esterase reagent strips in emergency department: uri-quick clini-10SG(r) vs. Multistix 10SG(r). AB - BACKGROUND AND AIM: Bacterial peritonitis (SBP) is the most frequent infection in patients with cirrhosis causing significant mortality. Delay in SBP diagnosis is a serious problem. The aim of this study was to evaluate the diagnostic yield of Uri-Quick Clini-10SG(r) vs. Multistix 10SG(r) reagent strips in an Emergency Department. MATERIAL AND METHODS: A prospective study of consecutive patients with ascites and paracentesis attending to Emergency Department from March 2005 to February 2007 was made. SBP was defined by >= 250 neutrophiles /mm3. The ascites obtained at bedside was immediately tested in a dry test tube with both the Uri-Quick Clini 10SG(r) and MultistixSG10(r). The Uri-Quick Clini 10SG(r) and Multistix SG10(r). Strips were considered positive at grade >= 3 (>= 125 leukocytes/mL). RESULTS: A total of 223 ascitic fluid samples were obtained. There were 49 episodes of SBP. Median age was 54 (range 18-87 year) years; 62.3% were female. The sensitivity, specificity, PPV, NPV, and 95% CI for Uri-Quick Clini 10SG(r) were 79.6 (64-87), 98.2 (94-99), 90.5 (78-96) and 93.9 (89-96), respectively. For MultistixSG10(r) the values were 77.5 (64-88), 97.7 (93-98), 90 (77.9-96.2), and 94 (89.4-96.6), respectively. CONCLUSION: The use of reagent strip is useful for SBP diagnosis in an emergency setting. The high PPV allow start antibiotic treatment. In areas without the resources to perform conventional ascites fluid analyses, these strips could be presently used. PMID- 22947533 TI - NAT2 genetic polymorphisms and anti-tuberculosis drug-induced hepatotoxicity in Chinese community population. AB - BACKGROUND: Anti-tuberculosis drug-induced hepatotoxicity (ATDH) is one of the most prevalent and serious adverse drug reactions in the course of anti tuberculosis (TB) treatment. Some researchers suggested that determination of N acetyltransferase 2 (NAT2) genotype may be clinically useful to identify patients at high risk of developing ATDH. AIM: To evaluate whether the NAT2 genotype could be as a predictor for ATDH in Chinese community TB population. MATERIAL AND METHODS: A total of 4304 community-based TB patients were followed up six to nine months prospectively. A nested case-control study was designed. Each ATDH case was 1:4 matched with controls by age (within 5 years old), gender, treatment history, disease severity and drug dosage. The polymorphisms of NAT2 were determined using polymerase chain reaction with restriction fragment length polymorphism. Conditional Logistic regression model was used to calculate odds ratio (OR) and 95% confidence interval (CI), as well as corresponding P-values. RESULTS: A total of 89 ATDH cases and 356 controls were included in this study. Allele frequency of NAT2*5, NAT2*6 and NAT2*7 in cases and controls were 4.5 and 3.2%, 25.3 and 26.5%, and 13.5 and 13.5%, respectively. Frequencies of genotypes and alleles of NAT2*5, NAT2*6 and NAT2*7 did not differ significantly between cases and controls. The OR of intermediate acetylator and slow acetylator compared with rapid acetylator was 1.040 (95%CI 0.616-1.758) and 0.990 (95%CI 0.509-1.925), respectively. The NAT2 haplotype distribution in cases was similar to controls. CONCLUSIONS: In conclusion, we did not find significant association between NAT2 genotype and ATDH in community-based Chinese population. It may be deficient to take NAT2 genotype as a predictor for ATDH in Chinese community TB patients. PMID- 22947534 TI - Inflammatory myofibroblastic tumor of the liver. AB - Hepatic inflammatory myofibroblastic tumors are uncommon low grade malignant neoplasms. They can be confused clinically and by imaging studies with abscess. PMID- 22947535 TI - Prolonged cholestasis triggered by hepatitis A virus infection and variants of the hepatocanalicular phospholipid and bile salt transporters. AB - Hepatitis A virus (HAV) infection resolves in most patients uneventfully within weeks from the onset of the disease. In rare cases, however, it may relapse or cause prolonged cholestasis. Here we present a case of a 36-year-old female patient who developed severe pruritus and jaundice three weeks after initially uncomplicated hepatitis A. A relapse of the infection was excluded. Since therapy with colestyramin, antihistaminics, naloxon and ursodeoxycholic acid (UDCA) did not improve symptoms, we decided to perform plasma absorption and to start rifampicin therapy. Under these measures, pruritus and jaundice, as well as serum bilirubin levels improved gradually and after four plasmapheresis sessions we were able to discharge the patient. Genetic testing showed the presence of two procholestatic polymorphisms, the c.3084 [GG] variant within the gene encoding the hepatocanalicular bile salt transporter ABCB11 and the c.711 [AT] variant of the phosphatidylcholine floppase ABCB4. We speculate that this compound ABCB4 ABCB11 genotype led to a severe intrahepatic cholestasis in the setting of HAV infection. In conclusion, our case suggests that polymorphisms within the hepatocanalicular transporters may contribute to a more pronounced course of HAV infection. Although dedicated studies in large cohorts of patients are needed to confirm this observation, we speculate that patients carrying procholestatic hepatobiliary transporter variants may benefit from vaccination against hepatitis A. PMID- 22947536 TI - Primary hepatic neuroendocrine tumour requiring live donor liver transplantation: case report and concise review. AB - Primary hepatic neuroendocrine tumours are rare tumours effecting relatively young patients. As metastatic neuroendocrine tumours to the liver are much more common, extensive investigations are crucial to exclude a primary tumour elsewhere. We report a case of a 27 year old woman who presented with fatigue, increased abdominal girth and feeling of early satiety and bloating. Extensive work up failed to show tumour at another primary site. Hepatic artery embolization showed no effect, so the patient underwent total hepatectomy and live-donor liver transplant. Grossly the tumour measured 27 cm. Microscopic examination showed bland, monomorphic cells growing in tubuloglandular and trabecular growth patterns. Cells were positive for neuroendocrine (synaptophysin, chromogranin, CD56) and epithelial markers (MOC31, CK7, CK19). Cytoplasmic dense neurosecretory vesicles were seen on ultrastructural examination. Based on the Ki-67 rate, mitotic count, lack of marked nuclear atypia and absence of necrosis, a diagnosis of primary neuroendocrine grade 2 was conferred. PMID- 22947537 TI - Primary hepatic amyloidosis: a mini literature review and five cases report. AB - Primary hepatic amyloidosis (PHA) is characterized by abnormal deposition of monoclonal immunoglobulin light chains (AL) in the liver. This rare condition is frequently undiagnosed or misdiagnosed and can be associated with poor prognosis. At present, the precise pathogenesis is not fully understood. Despite that hepatomegaly and elevated alkaline phosphatase (ALP) are present in most patients with PHA, no specific clinical markers have been identified. Staining of hepatic tissues with Congo Red is often regarded as the "gold standard". Pharmacological therapy should aim to rapidly reduce the supply of misfolded amyloidogenic AL. High-dose intravenous melphalan (HDM) and autologous stem cell transplantation (ASCT) appear to be the most appropriate therapy but controversies still exist. PMID- 22947539 TI - Silybin/Silymarin treatment in chronic hepatitis C. PMID- 22947538 TI - Shark liver oil: hidden dangers. PMID- 22947540 TI - The dopamine D2 receptor gene DRD2 and the nicotinic acetylcholine receptor gene CHRNA4 interact on striatal gray matter volume: evidence from a genetic imaging study. AB - Dopaminergic activity is modulated by acetylcholine with relevance for cognitive functioning, as shown by pharmacological work in a rodent model. In humans, the two transmitter systems' joint effort on cognition has been described on the molecular genetic level: DRD2 rs6277, a single nucleotide polymorphism (SNP) on the dopamine D2 receptor gene and CHRNA4 rs1044396, a SNP on the nicotinic acetylcholine receptor gene interact on visuo-spatial and phonological working memory. The present study uses structural MRI and voxel based morphometry to extend this behavioral work to an intermediate phenotype on the neural level. We found significantly reduced gray matter volume in the right putamen in carriers of the DRD2 C/C and CHRNA4 T/T groups. This genotype combination has previously proven to be beneficial for working memory capacity. Results are in line with the idea that the two genes jointly influence the gating signals from subcortical structures to the prefrontal cortex. PMID- 22947543 TI - Is a small muscle mass index really detrimental for insulin sensitivity in postmenopausal women of various body composition status? AB - OBJECTIVES: We sought to determine if a small muscle mass index (MMI) is actually detrimental for insulin sensitivity when studying a large group of postmenopausal women displaying various body composition statuses and when age and visceral fat mass (VFM) are taken into account. METHODS: A cross-sectional study was conducted in 99 healthy postmenopausal women with a BMI of 28+/-4 kg/m(2). Fat mass and total fat-free mass (FFM) were obtained from DXA and VFM and MMI were estimated respectively by the equation of Bertin and by: Total FFM (kg)/height (m)(2). Fasting plasma insulin and glucose were obtained to calculate QUICKI and HOMA as an insulin sensitivity index. RESULTS: Total MMI and VFM were both significantly inversely correlated with QUICKI and positively with HOMA even when adjusted for VFM. A stepwise linear regression confirmed Total MMI and VFM as independent predictors of HOMA and plasma insulin level. CONCLUSIONS: A small muscle mass might not be detrimental for the maintenance of insulin sensitivity and could even be beneficial in sedentary postmenopausal women. The impact of muscle mass loss on insulin sensitivity in older adults needs to be further investigated. PMID- 22947541 TI - Acute alcohol intoxication decreases glucose metabolism but increases acetate uptake in the human brain. AB - Alcohol intoxication results in marked reductions in brain glucose metabolism, which we hypothesized reflect not just its GABAergic enhancing effects but also the metabolism of acetate as an alternative brain energy source. To test this hypothesis we separately assessed the effects of alcohol intoxication on brain glucose and acetate metabolism using Positron Emission Tomography (PET). We found that alcohol intoxication significantly decreased whole brain glucose metabolism (measured with FDG) with the largest decrements in cerebellum and occipital cortex and the smallest in the thalamus. In contrast, alcohol intoxication caused a significant increase in [1-(11)C]acetate brain uptake (measured as standard uptake value, SUV), with the largest increases occurring in the cerebellum and the smallest in the thalamus. In heavy alcohol drinkers [1-(11)C]acetate brain uptake during alcohol challenge tended to be higher than in occasional drinkers (p<0.06) and the increases in [1-(11)C]acetate uptake in cerebellum with alcohol were positively associated with the reported amount of alcohol consumed (r=0.66, p<0.01). Our findings corroborate a reduction of brain glucose metabolism during intoxication and document an increase in brain acetate uptake. The opposite changes observed between regional brain metabolic decrements and regional increases in [1-(11)C]acetate uptake support the hypothesis that during alcohol intoxication the brain may rely on acetate as an alternative brain energy source and provides preliminary evidence that heavy alcohol exposures may facilitate the use of acetate as an energy substrate. These findings raise the question of the potential therapeutic benefits that increasing plasma acetate concentration (i.e. ketogenic diets) may have in alcoholics undergoing alcohol detoxification. PMID- 22947544 TI - Effect of exercise on bone structural traits, physical performance and body composition in breast cancer patients--a 12-month RCT. AB - In this 12-month RCT, we examined whether aerobic impact exercise training (3x/week) could facilitate breast cancer survivors' recovery by enhancing their bone structural strength, physical performance and body composition. After the adjuvant chemo- and/ or radiotherapy, 86 patients were randomly assigned into the training or control group. Structural bone traits were assessed with pQCT at the tibia and with DXA at the femoral neck. Agility (figure-8 running), jump force and power (force platform), grip strength and cardiovascular fitness (2-km walk test) were also assessed. Training effects on outcome variables were estimated by two-way factorial ANCOVA using the study group and menopausal status as fixed factors. Bone structural strength was better maintained among the trainees. At the femoral neck, there was a small but significant 2% training effect in the bone mass distribution (p=0.05). At the tibial diaphysis, slight 1% to 2% training effects (p=0.03) in total cross-sectional area and bone structural strength were observed (p=0.03) among the postmenopausal trainees. Also, 3% to 4% training effects were observed in the figure-8 running time (p=0.03) and grip strength (p=0.01). In conclusion, vigorous aerobic impact exercise training has potential to maintain bone structural strength and improve physical performance among breast cancer survivors. PMID- 22947545 TI - Whole body vibration exercise improves body balance and walking velocity in postmenopausal osteoporotic women treated with alendronate: Galileo and Alendronate Intervention Trail (GAIT). AB - A randomized controlled trial was conducted to determine the effect of 6 months of whole body vibration (WBV) exercise on physical function in postmenopausal osteoporotic women treated with alendronate. Fifty-two ambulatory postmenopausal women with osteoporosis (mean age: 74.2 years, range: 51-91 years) were randomly divided into two groups: an exercise group and a control group. A four-minute WBV exercise was performed two days per week only in the exercise group. No exercise was performed in the control group. All the women were treated with alendronate. After 6 months of the WBV exercise, the indices for flexibility, body balance, and walking velocity were significantly improved in the exercise group compared with the control group. The exercise was safe and well tolerated. The reductions in serum alkaline phosphatase and urinary cross-linked N-terminal telopeptides of type I collagen during the 6-month period were comparable between the two groups. The present study showed the benefit and safety of WBV exercise for improving physical function in postmenopausal osteoporotic women treated with alendronate. PMID- 22947546 TI - A comparison of the effect of two types of vibration exercise on the endocrine and musculoskeletal system. AB - BACKGROUND: Whole body vibration (WBV) is a novel training intervention but a comparison of different methods of WBV has rarely been performed. AIM: To compare the short and medium term effects of two regimens of WBV on endocrine status, muscle function and markers of bone turnover. PATIENTS AND METHODS: Over a period of 16 weeks, 10 men with a median age of 33 yrs (range, 29,49), were randomised to stand on the Galileo platform (GP) or Juvent1000 platform (JP) 3 times/wk. The total study duration was 16 weeks with measurements performed in a 4 week period of run-in, 8 weeks of WBV and a 4 week period of washout. These measurements included an assessment of anthropometry, body composition, muscle function and biochemical markers of endocrine status and bone turnover. To assess immediate effects of WBV, measurements were also performed at 60 mins before and 5, 30 and 60 mins after WBV. To assess immediate effects of WBV, measurements were also performed at 60 mins before and 5, 30 and 60 mins after WBV. RESULTS: GP at 22 Hz was associated with an immediate increase in serum GH, rising from 0.07 MUg/l (0.04,0.69) to 0.52 MUg/l (0.06,2.4) (p=0.06), 0.63 MUg/l (0.1,1.18) (p=0.03), 0.21 MUg/l (0.07,0.65) (p=0.2) at 5 mins, 20 mins and 60 mins after WBV, respectively. An immediate effect was also observed in median serum cortisol which reduced from 316 nmol/l (247,442) before WBV to 173 nmol/l (123,245) (p=0.01),165 nmol/l (139,276) (p=0.02) and 198 nmol/l (106,294) (p=0.04) at 5 mins, 20 mins and 60 mins after WBV, respectively. Median serum CTX reduced significantly after 8 weeks of WBV training in the GP group from 0.42 ng/ml (0.29,0.90) pre-WBV to 0.29 ng/ml (0.18,0.44) at the end of WBV training (p=0.03). Over the 8 weeks, there was a reduction in median serum cortisol in the GP group from 333 nmol/l (242,445) (pre-WBV) to 270 nmol/l (115,323) (WBV) (p=0.04). None of the changes observed in the JP group reached statistical significance. Neither group showed any significant effect on muscle function, IGF 1, testosterone, leptin, CRP, creatine kinase, insulin or other markers of bone turnover. CONCLUSION: WBV can stimulate GH secretion, reduce circulating cortisol and reduce bone resorption. These effects are independent of clear changes in muscle function and depend on the type of WBV that is administered. PMID- 22947547 TI - Peripheral QCT sector analysis reveals early exercise-induced increases in tibial bone mineral density. AB - OBJECTIVES: The purpose of this controlled trial was to determine whether subtle changes in mineralization and geometry of the tibia were evident following short term exercise interventions. METHODS: Fifty-seven female volunteers (age 20.1+/ 1.6) were randomized to one of four, 13-week training groups: sedentary control, resistance training, aerobic training, or combined aerobic-resistance. A pQCT image analysis software was developed and used to analyze images taken at sites 4%, 38% and 66% from the distal tibia at baseline and at completion of training. Parameters of bone mineral density, geometry and strength were determined for the entire scan cross-section and for each of six 60 degrees polar sectors. Repeated measures ANOVA and Fisher's LSD post hoc tests analyzed the effects of training over time. RESULTS: Trabecular density (TrDn) at the 4% site increased from 279.8+/-37.1 to 283.1+/-36.0 mg/cm(3) in the aerobic group, and from 285.1+/-24.6 to 287.5+/-22.9 mg/cm(3) in the combined group over the study period (P<=0.001). Regional sector analyses revealed that impact exercises resulted in localized changes to the medial aspect of the tibia. Small increases in total bone area were observed in the diaphysis (38% site) (P<0.05). CONCLUSIONS: Subtle, regional increases in trabecular density may be an early measurable manifestation of bone quality changes. PMID- 22947548 TI - Bisphosphonate therapy for painless fracture: change of HSAN 1 clinical course with biphosphonate and Vitamin D therapy. AB - Hereditary Sensory and Autonomic Neuropathies comprise a set of 5 rare neurologic conditions, little known to radiologists as the neurologic and skin abnormalities precede the radiographic changes by months or even years. We report a Caucasian patient with a clinical history of HSAN, most consistent with subtype 1, whose progressive, destructive bone changes of the foot were not only controlled but to a degree reversed by the administration of bisphosphonates (Alendronate ) and vitamin D (Colecalciferol). The authors believe that combined bisphosphonate and vitamin D therapy is the treatment of choice for progressive bony changes in HSAN1. This therapy may be beneficial in other neuropathic osteoarthropathies and possibly osteolytic bone disorders. PMID- 22947549 TI - Overview of pediatric bone problems and related osteoporosis. AB - Osteoporosis is a well-established clinical problem in adults. Osteoporosis in pediatrics, on the other hand, is a new and evolving area, with certain unique diagnostic and clinical challenges. Recently, there has been an increased awareness of osteoporosis in children, both as a primary problem due to genetic mutations and enzyme deficiencies, and as secondary to various diseases, medications, and lifestyle issues. In this review we discuss the common forms of osteoporosis, including candidate genes, mutations of which can lead to primary osteoporosis, the mechanisms involved in the pathogenesis of secondary bone loss, and possible ways of diagnosing, preventing, or treating these conditions. The purpose of the article is to provide a summary of our current knowledge of pediatric bone problems and to provide a basis for discussion of the most appropriate ways to detect, treat, or prevent such problems. PMID- 22947550 TI - First use of the RANKL antibody denosumab in osteogenesis imperfecta type VI. AB - Osteogenesis imperfecta (OI) is a genetically heterogeneous disease leading to bone fragility. OI-VI is an autosomal-recessive form caused by mutations in SERPINF1. There is experimental evidence suggesting that loss of functional SERPINF1 leads to an activation of osteoclasts via the RANK/RANKL pathway. Patients with OI-VI show a poor response to bisphosphonates. We report on four children with OI-VI who had shown continuously elevated urinary bone resorption markers during a previous treatment with bisphosphonates. We treated these children with the RANKL antibody denosumab to reduce bone resorption. INTERVENTION AND RESULTS: Denosumab (1 mg/kg body weight) was injected s.c. every 3 months. There were no severe side effects. Markers of bone resorption decreased to the normal range after each injection. N-terminal Propeptide of collagen 1 was measured in the serum during the first treatment cycle and decreased also. Urinary deoxypyridinoline/creatinine was monitored in a total of seven treatment cycles and indicated that bone resorption reached the pre-treatment level after 6 8 weeks. CONCLUSION: This was the first use of denosumab in children with OI-VI. Denosumab was well tolerated, and laboratory parameters provided evidence that the treatment reversibly reduced bone resorption. Therefore, denosumab may be a new therapeutic option for patients with OI-VI. PMID- 22947551 TI - A painless finger mass. PMID- 22947552 TI - Measures of central hyperexcitability in chronic whiplash associated disorder--a systematic review and meta-analysis. AB - OBJECTIVES: To synthesise the evidence for central hyperexcitability in Chronic WAD (whiplash associated disorders) with meta-analysis, and review test protocols. METHODS: Chronic WAD was compared to healthy controls. Studies were eligible if they used measures of central hyperexcitability with standardised procedure. Meta-analyses (where possible) were conducted. RESULTS: The search yielded 27 trials of good quality and 13 were suitable for meta-analyses. Individuals with chronic WAD showed heightened sensitivity to the following tests (p < 0.05): Pressure Pain Thresholds at Head/Neck/Upper Thoracic area (H/N/UT) (SMD (Standardised mean differences) -1.36, 95% CI (confidence intervals) -1.89 to -0.82), Upper Limb (UL) (-1.33, 95% CI -2.50 to -0.16), Lower Limb (LL) ( 1.01, 95% CI -1.70 to -0.33), flexor withdrawal (-0.73, 95% CI -1.11 to -0.35), Cold Pain Threshold at H/N/UT (0.91, 95% CI 0.66-1.17) and UL (0.66, 95% CI 0.37 0.94), Heat Pain Threshold at H/N/UT (-0.58, 95% CI -0.88 to -0.28), Electrocutaneous Stimulation at H/N/UT (-1.04, 95% CI -1.63 to -0.45) and LL ( 0.85, 95% CI -1.67 to -0.03), and elbow extension with the Brachial Plexus Provocation Test (SMD -0.55, 95% CI -0.76 to -0.35). DISCUSSION: There is compelling evidence for central hyperexcitability in chronic WAD. This should be considered in the management of chronic WAD. PMID- 22947555 TI - Health together: how community resources can enhance clinical practice. PMID- 22947554 TI - Diagnosis: shifting the ROC curve. PMID- 22947556 TI - Integrated care: final objective or fortuitous by-product? PMID- 22947557 TI - How do we identify and support maltreated children? PMID- 22947558 TI - Ruling out coronary heart disease in primary care: external validation of a clinical prediction rule. PMID- 22947559 TI - Scent of a patient: an underestimated role in clinical practice? PMID- 22947560 TI - Primary care of children: the unique role of GPs. PMID- 22947561 TI - Do English patients want continuity of care, and do they receive it? PMID- 22947562 TI - Communication in the 21st century. PMID- 22947563 TI - Burnout and empathy in primary care. PMID- 22947564 TI - Confirming death in general practice. PMID- 22947565 TI - Recording concerns about child maltreatment. PMID- 22947566 TI - The girl in the cupboard: oppression and suppression in a time of recession. PMID- 22947567 TI - Notes from the Olympic health centre. PMID- 22947568 TI - On your bike! PMID- 22947569 TI - First do no harm: giving the patient the single positive diagnosis that offers them the best outcome. PMID- 22947570 TI - The Leonardo Grant: an opportunity to undertake a Hippokrates Exchange Programme. PMID- 22947571 TI - Medical ethics debate: access to NHS resources. PMID- 22947575 TI - To be or not to be LGBT in primary health care: health care for lesbian, gay, bisexual, and transgender people. PMID- 22947576 TI - Improving recruitment to primary care trials: some lessons from the use of modern marketing techniques. PMID- 22947577 TI - Eosinophilic oesophagitis: a clinical update. PMID- 22947578 TI - The eagle is landing: Eagle syndrome--an important differential diagnosis. PMID- 22947579 TI - Variation in use of the 2-week referral pathway for suspected cancer: a cross sectional analysis. AB - BACKGROUND: A 2-Week Wait (2WW) referral pathway for earlier diagnosis of suspected cancer was introduced in England in 2000. Nevertheless, a significant proportion of patients with cancer are diagnosed by other routes (detection rate), only a small proportion of 2WW referrals have cancer (conversion rate) and there is considerable between-practice variation. AIM: This study examined use by practices of the 2WW referral in relation to all cancer diagnoses. DESIGN AND SETTING: A cross-sectional analysis of data extracted from the Cancer Waiting Times Database for all 2WW referrals in 2009 and for all patients receiving a first definitive treatment in the same year. METHOD: The age standardised referral ratio, conversion rate, and detection rate were calculated for all practices in England and the correlation coefficient for each pair of measures. The median detection rate was calculated for each decile of practices ranked by conversion rate and vice versa, performing nonparametric tests for trend in each case. RESULTS: Data for 8049 practices, 865 494 referrals, and 224 984 cancers were analysed. There were significant correlations between referral ratio and conversion rate (inverse) and detection rate (direct). There was also a direct correlation between conversion and detection rates. There was a significant trend in conversion rate for deciles of detection rate, and vice versa, with a marked difference between the lowest and higher deciles. CONCLUSION: There is a consistent relationship between 2WW referral conversion rate and detection rate that can be interpreted as representing quality of clinical practice. The 2WW referral rate should not be a measure of quality of clinical care. PMID- 22947580 TI - Clinical features of bladder cancer in primary care. AB - BACKGROUND: Bladder cancer accounts for over 150,000 deaths worldwide. No screening is available, so diagnosis depends on investigations of symptoms. Of these, only visible haematuria has been studied in primary care. AIM: To identify and quantify the features of bladder cancer in primary care. DESIGN AND SETTING: Case-control study, using electronic medical records from UK primary care. METHOD: Participants were 4915 patients aged >=40 years, diagnosed with bladder cancer January 2000 to December 2009, and 21,718 age, sex, and practice-matched controls, were selected from the General Practice Research Database, UK. All clinical features independently associated with bladder cancer using conditional logistic regression were identified, and their positive predictive values for bladder cancer, singly and in combination, were estimated. RESULTS: Cases consulted their GP more frequently than controls before diagnosis: median 15 consultations (interquartile range 9-22) versus 8 (4-15): P<0.001. Seven features were independently associated with bladder cancer: visible haematuria, odds ratio 34 (95% confidence interval [CI] = 29 to 41), dysuria 4.1 (95% CI = 3.4 to 5.0), urinary tract infection 2.2 (95% CI = 2.0 to 2.5), raised white blood cell count 2.1 (95% CI = 1.6 to 2.8), abdominal pain 2.0 (95% CI = 1.6 to 2.4), constipation 1.5 (95% CI = 1.2 to 1.9), raised inflammatory markers 1.5 (95% CI = 1.2 to 1.9), and raised creatinine 1.3 (95% CI = 1.2 to 1.4). The positive predictive value for visible haematuria in patients aged >=60 years was PPV of 2.6% (95% CI = 2.2 to 3.2). CONCLUSION: Visible haematuria is the commonest and most powerful predictor of bladder cancer in primary care, and warrants investigation. Most other previously reported features of bladder cancer were associated with the disease, but with low predictive values. There is a need for improved diagnostic methods, for those patients whose bladder cancer presents without visible haematuria. PMID- 22947581 TI - Developing a complex intervention to reduce time to presentation with symptoms of lung cancer. AB - BACKGROUND: Lung cancer is the commonest cause of cancer in Scotland and is usually advanced at diagnosis. Median time between symptom onset and consultation is 14 weeks, so an intervention to prompt earlier presentation could support earlier diagnosis and enable curative treatment in more cases. AIM: To develop and optimise an intervention to reduce the time between onset and first consultation with symptoms that might indicate lung cancer. DESIGN AND SETTING: Iterative development of complex healthcare intervention according to the MRC Framework conducted in Northeast Scotland. METHOD: The study produced a complex intervention to promote early presentation of lung cancer symptoms. An expert multidisciplinary group developed the first draft of the intervention based on theory and existing evidence. This was refined following focus groups with health professionals and high-risk patients. RESULTS: First draft intervention components included: information communicated persuasively, demonstrations of early consultation and its benefits, behaviour change techniques, and involvement of spouses/partners. Focus groups identified patient engagement, achieving behavioural change, and conflict at the patient-general practice interface as challenges and measures were incorporated to tackle these. Final intervention delivery included a detailed self-help manual and extended consultation with a trained research nurse at which specific action plans were devised. CONCLUSION: The study has developed an intervention that appeals to patients and health professionals and has theoretical potential for benefit. Now it requires evaluation. PMID- 22947582 TI - Developing a 'traffic light' test with potential for rational early diagnosis of liver fibrosis and cirrhosis in the community. AB - BACKGROUND: Liver disease develops silently and presents late, with often fatal complications. AIM: To develop a 'traffic light' test for liver disease suitable for community use that could enhance assessment of liver risk and allow rational referral of more severe disease to specialist care. DESIGN AND SETTING: Two cohorts from Southampton University Hospital Trust Liver Unit: model development and a validation cohort to evaluate prognosis. METHOD: A total of 1038 consecutive liver patients (inpatient and outpatient) (development n = 397, validation n = 641) for whom the relevant blood tests had been performed, were followed for a mean of 46 months (range 13-89 months). Blood tests for: hyaluronic acid (HA), procollagen-3 N-terminal peptide (P3NP), and platelet count were combined in a diagnostic algorithm to stage liver disease. RESULTS: A simple clinical rule combined: HA, P3NP, and platelet count into a 'traffic light' algorithm, grading the results red--high risk, amber--intermediate risk, and green--low risk. In the validation cohort, no green subjects died or developed varices or ascites (n = 202); in the amber group, 9/267 (3.3%) died, 0/267 developed varices, and 2/267 (0.7%) developed ascites; in the red group, 24/172 died (14%), 24/172 (14%) developed varices, and 20/172 developed (11.6%) ascites. Survival was reduced in red (P<0.001) and amber (P<0.012) groups compared with green. CONCLUSION: A simple blood test triages liver disease into three prognostic groups; used in the community, it could enhance the management of risk factors in primary care and rationalise secondary care referrals, including the many patients with fatty liver and relatively minor elevations in alanine transaminase. PMID- 22947583 TI - Early identification of palliative care patients in general practice: development of RADboud indicators for PAlliative Care Needs (RADPAC). AB - BACKGROUND: According to the World Health Organization (WHO) definition, palliative care should be initiated in an early phase and not be restricted to terminal care. In the literature, no validated tools predicting the optimal timing for initiating palliative care have been determined. AIM: The aim of this study was to systematically develop a tool for GPs with which they can identify patients with congestive heart failure (CHF), chronic obstructive pulmonary disease (COPD), and cancer respectively, who could benefit from proactive palliative care. DESIGN: A three-step procedure, including a literature review, focus group interviews with input from the multidisciplinary field of palliative healthcare professionals, and a modified Rand Delphi process with GPs. METHOD: The three-step procedure was used to develop sets of indicators for the early identification of CHF, COPD, and cancer patients who could benefit from palliative care. RESULTS: Three comprehensive sets of indicators were developed to support GPs in identifying patients with CHF, COPD, and cancer in need of palliative care. For CHF, seven indicators were found: for example, frequent hospital admissions. For COPD, six indicators were found: such as, Karnofsky score <=50%. For cancer, eight indicators were found: for example, worse prognosis of the primary tumour. CONCLUSION: The RADboud indicators for PAlliative Care Needs (RADPAC) is the first tool developed from a combination of scientific evidence and practice experience that can help GPs in the identification of patients with CHF, COPD, or cancer, in need of palliative care. Applying the RADPAC facilitates the start of proactive palliative care and aims to improve the quality of palliative care in general practice. PMID- 22947584 TI - Accuracy of symptoms, signs, and C-reactive protein for early chronic obstructive pulmonary disease. AB - BACKGROUND: Guidelines recommend detection of early chronic obstructive pulmonary disease (COPD), but evidence on the diagnostic work-up for COPD only concerns advanced and established COPD. AIM: To quantify the accuracy of symptoms and signs for early COPD, and the added value of C-reactive protein (CRP), in primary care patients presenting with cough. DESIGN AND SETTING: Cross-sectional diagnostic study of 73 primary care practices in the Netherlands. METHOD: Four hundred primary care patients (182 males, mean age 63 years) older than 50 years, presenting with persistent cough (>14 days) without established COPD participated, of whom 382 completed the study. They underwent a systematic diagnostic work-up of symptoms, signs, conventional laboratory CRP level, and hospital lung functions tests, including body plethysmography, and an expert panel decided whether COPD was present (reference test). The independent value of all items was estimated by multivariable logistic regression analysis. RESULTS: According to the expert panel, 118 patients had COPD (30%). Symptoms and signs with independent diagnostic value were age, sex, current smoking, smoking more than 20 pack-years, cardiovascular comorbidity, wheezing complaints, diminished breath sounds, and wheezing on auscultation. Combining these items resulted in an area under the receiver operating characteristic curve (ROC area) of 0.79 (95% confidence interval = 0.74 to 0.83) after internal validation. The proportion of subjects with elevated CRP was higher in those with early COPD, but CRP added no relevant diagnostic information above symptoms and signs. CONCLUSION: In subjects presenting with persistent cough, the CRP level has no added value for detection of early COPD. PMID- 22947585 TI - Delayed antibiotic prescribing and associated antibiotic consumption in adults with acute cough. AB - BACKGROUND: Delayed antibiotic prescribing is promoted as a strategy to reduce antibiotic consumption, but its use and its effect on antibiotic consumption in routine care is poorly described. AIM: To quantify delayed antibiotic prescribing in adults presenting in primary care with acute cough/lower respiratory tract infection (LRTI), duration of advised delay, consumption of delayed antibiotics, and factors associated with consumption. DESIGN AND SETTING: Prospective observational cohort in general practices in 14 primary care networks in 13 European countries. METHOD: GPs recorded clinical features and antibiotic prescribing for adults presenting with an acute infective illness with cough as the dominant symptom. Patients recorded their consumption of antibiotics from any source during the 28-day follow up. RESULTS: Two hundred and ten (6.3%) of 3368 patients with usable consultation data were prescribed delayed antibiotics. The median recommended delay period was 3 days. Seventy-five (44.4%) of the 169 with consumption data consumed the antibiotic course and a further 18 (10.7%) took another antibiotic during the study period. 50 (29.6%) started their delayed course on the day of prescription. Clinician diagnosis of upper respiratory tract/viral infection and clinician's perception of patient's wanting antibiotics were associated with less consumption of the delayed prescription. Patient's wanting antibiotics was associated with greater consumption. CONCLUSION: Delayed antibiotic prescribing was used infrequently for adults presenting in general practice with acute cough/LRTI. When used, the effect on antibiotic consumption was less than found in most trials. There are opportunities for standardising the intervention and promoting wider uptake. PMID- 22947586 TI - Domestic violence: knowledge, attitudes, and clinical practice of selected UK primary healthcare clinicians. AB - BACKGROUND: Domestic violence affects one in four women and has significant health consequences. Women experiencing abuse identify doctors and other health professionals as potential sources of support. Primary care clinicians agree that domestic violence is a healthcare issue but have been reluctant to ask women if they are experiencing abuse. AIM: To measure selected UK primary care clinicians' current levels of knowledge, attitudes, and clinical skills in this area. DESIGN AND SETTING: Prospective observational cohort in 48 general practices from Hackney in London and Bristol, UK. METHOD: Administration of the Physician Readiness to Manage Intimate Partner Violence Survey (PREMIS), comprising five sections: responder profile, background (perceived preparation and knowledge), actual knowledge, opinions, and practice issues. RESULTS: Two hundred and seventy two (59%) clinicians responded. Minimal previous domestic violence training was reported by participants. Clinicians only had basic knowledge about domestic violence but expressed a positive attitude towards engaging with women experiencing abuse. Many clinicians felt poorly prepared to ask relevant questions about domestic violence or to make appropriate referrals if abuse was disclosed. Forty per cent of participants never or seldom asked about abuse when a woman presented with injuries. Eighty per cent said that they did not have an adequate knowledge of local domestic violence resources. GPs were better prepared and more knowledgeable than practice nurses; they also identified a higher number of domestic violence cases. CONCLUSION: Primary care clinicians' attitudes towards women experiencing domestic violence are generally positive but they only have basic knowledge of the area. Both GPs and practice nurses need more comprehensive training on assessment and intervention, including the availability of local domestic violence services. PMID- 22947587 TI - An end to depression in primary care? PMID- 22947588 TI - A theoretical framework for multimorbidity: from complicated to chaotic. PMID- 22947589 TI - The short-term effects of vitamin D repletion on cholesterol: a randomized, placebo-controlled trial. AB - OBJECTIVE: Vitamin D deficiency is common and associated with dyslipidemia. However, it is unclear whether oral vitamin D supplementation improves the lipid profile. Therefore, we conducted a randomized, placebo-controlled trial to determine the short-term effects of vitamin D repletion on the lipid profile. METHODS AND RESULTS: One hundred fifty-one vitamin D-deficient (25-hydroxyvitamin D <20 ng/mL) adults with elevated risk for cardiovascular disease were randomized to receive either 50 000 IU of vitamin D3 weekly for 8 weeks or placebo. The primary outcome was the change in small low-density lipoprotein (LDL) particle number. Secondary outcomes included changes in other nuclear magnetic resonance based and chemical lipid fractions. Vitamin D failed to improve the lipid profile. Compared with the placebo, vitamin D repletion did not change small LDL particle number (mean change, +18 nmol/L; 95% CI [-80 to +116 nmol/L]; P=0.63). There were also no changes in the chemical lipid profile: total cholesterol (+5.8 mg/dL, 95% CI [-1.4 to +13.0 mg/dL], P=0.14); LDL cholesterol (+3.8 mg/dL, 95% CI [-2.5 to +10.2 mg/dL], P=0.13); high-density lipoprotein cholesterol (+0.4 mg/dL 95% CI [-1.6 to +2.6 mg/dL], P=0.71); and triglycerides (+7.9 mg/dL 95% CI [-6.5 to +22.3 mg/dL]). In the vitamin D repletion group, exploratory multivariate regression analysis demonstrates that changes in LDL cholesterol were positively correlated with the changes in serum calcium (P<0.001) and inversely with the changes in serum parathyroid hormone (P=0.02). CONCLUSIONS: In contrast to the association between low 25-hydroxyvitamin D levels and dyslipidemia, correcting vitamin D deficiency in the short-term does not improve the lipid profile. Repletion of 25-hydroxyvitamin D levels raised serum calcium levels and decreased serum parathyroid hormone levels. These expected physiological responses to vitamin D therapy were correlated with a significant increase in LDL cholesterol. Clinical Trial Registration- URL: http://www.clinicaltrials.gov. Unique identifier: NCT01008384. PMID- 22947590 TI - Cardiac troponin I levels and its relation to echocardiographic findings in infants of diabetic mothers. AB - BACKGROUND: Cardiomyopathy is noted in up to 40% of infants of diabetic mothers, and the exact mechanisms responsible for it are unknown. The aim of this study was to compare between infants of diabetic mothers (IDM) and infants of non- diabetic mothers (INDM) as regards cardiac troponin I (cTnI) levels (as a marker of cardiac dysfunction) and to examine the relationship between this marker and neonatal echocardiographic changes (cardiac structure and function). METHODS: A prospective, comparative study included eighty full term neonates during the first three days of life, during the period from April 2008 to June 2011. They were divided into 2 groups, group I: included 40 infants of diabetic mothers (IDMs)and group II: included 40 infants of non diabetic healthy mothers as a control group. RESULTS: 37.5% of the IDMs were large for gestational age and demonstrated a significantly lower blood glucose level than the control group (34.6 +/- 11.3mg/dl Vs 77.2 +/- 19.8 mg/dl respectively) , respiratory distress and cyanosis were the presenting signs in 67.5% of IDMs. Cardiac TnI on the second day of life increased significantly in infants of diabetic mothers in comparison to INDM (p < 0.006) . IDMs had a significant increase in left atrial thickness ( 11.5 +/- 1.8mm in IDM Vs 10.5 +/- 0.9mm in INDM P < 0.002*) and a significant increase in septal thickness (5.0 +/- 1.2mm in IDM Vs 4.0 +/- 0.5mm in INDM P < 0.001*). CTnI correlated positively with interventricular septum thickness (P-value = 0.002*). Cardiac TnI was significantly increased in IDMs with respiratory distress (P -value < 0.05). CONCLUSIONS: This study demonstrated a highly significant positive correlation between cTnI level on the second day of life and the left ventricular end diastolic diameter (LVED) and interventricular septum diameter (IVSD). Cardiac troponin I (cTnI) is a useful biochemical marker for monitoring myocardial injury in infants of diabetic mothers. An elevated cTnI concentration in infants of diabetic mothers with respiratory distress was a good predictor for hypertrophic cardiomyopathy and/or left ventricular dysfunction. PMID- 22947591 TI - CYP3A5 polymorphism effect on cyclosporine pharmacokinetics in living donor renal transplant recipients: analysis by population pharmacokinetics. AB - BACKGROUND: Cyclosporine is often used to prevent allograft rejection in renal transplant recipients. However, cyclosporine has a narrow therapeutic window and large variability in its pharmacokinetics. Individual characteristics and genetic polymorphisms can cause the variation. Hence, it is important to determine the cause(s) of the variation in cyclosporine pharmacokinetics. To our knowledge, this is the first reported population pharmacokinetic study of cyclosporine in living donor renal transplant recipients that considered the genetic polymorphism as a covariate. OBJECTIVE: To build a population pharmacokinetic model of cyclosporine in living donor renal transplant recipients and identify covariates including CYP3A5*3, ABCB1 genetic polymorphisms that affect cyclosporine pharmacokinetic parameters. METHODS: Clinical characteristics and cyclosporine concentration data for 69 patients who received cyclosporine-based immunosuppressive therapy after living donor renal transplantation were collected retrospectively for up to 400 postoperative days. CYP3A5*1/*3 and ABCB1C1236T, G2677T/A, C3435T geno-typing was performed. A population pharmacokinetic analysis was conducted using a NONMEM program. After building the final model, 1000 bootstrappings were performed to validate the final model. RESULTS: In total, 2034 blood samples were collected. A 1-compartment open model with first-order absorption and elimination was chosen to describe the pharmacokinetics of cyclosporine. A population pharmacokinetic analysis showed that postoperative days, sex, and CYP3A5 genotype significantly affected the pharmacokinetics of cyclosporine. The final estimate of mean clearance was 56 L/h, and the mean volume of distribution was 4650 L. The interindividual variability for these parameters was 22.98% and 51.48%, respectively. CONCLUSIONS: Using the present model to calculate the dose of cyclosporine with CYP3A5 genotyping can be possible for the patients whose cyclosporine concentration is not within the therapeutic range even with therapeutic drug monitoring. PMID- 22947592 TI - Effect of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers on risk of atrial fibrillation before coronary artery bypass grafting. AB - OBJECTIVE: To review the primary literature evaluating the effect preoperative use of angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) has on the risk of postoperative atrial fibrillation following coronary artery bypass grafting (CABG). DATA SOURCES: PubMed was searched from January 1, 2000, to May 17, 2012, using the MeSH terms coronary artery bypass, angiotensin-converting enzyme inhibitors, angiotensin receptor antagonists, and atrial fibrillation. Additional articles were identified from the reference lists of the articles identified in the PubMed search. STUDY SELECTION AND DATA EXTRACTION: Abstracts from the PubMed search were screened for relevance to the topic. Articles including information on the effect of ACE inhibitors or ARBs on postoperative atrial fibrillation following CABG were indentified for further review. Data extracted from these studies included patient baseline characteristics, outcome definitions, incidence of atrial fibrillation after CABG, and preoperative use of ACE inhibitors or ARBs. DATA SYNTHESIS: The PubMed search resulted in 6 articles, 4 of which were applicable to the clinical question. Four other articles were identified from the reference lists of the applicable studies, resulting in a literature review of 8 studies. These studies included patients undergoing CABG with or without valve procedures. Four studies included patients undergoing isolated CABG procedures; the remaining 4 included patients undergoing CABG with a valve procedure. Information on preoperative ACE inhibitor or ARB use was included in all studies. Two studies suggested a decreased risk of postoperative atrial fibrillation following CABG with preoperative ACE inhibitor or ARB therapy, 3 suggested an increased risk, and 3 found no effect on risk. CONCLUSIONS: The studies reviewed here had conflicting results. Randomized placebo-controlled trials are necessary to determine the risk for atrial fibrillation after CABG associated with preoperative use of ACE inhibitors and ARBs. The decision to continue or withhold the drugs is not evidence-based and should be based on a patient's other clinical characteristics. PMID- 22947593 TI - Vancomycin versus linezolid in the treatment of methicillin-resistant Staphylococcus aureus nosocomial pneumonia: implications of the ZEPHyR trial. AB - In 2003, a retrospective trial comparing linezolid versus vancomycin in the treatment of methicillin-resistant Staphylococcus aureus (MRSA) showed improved survival in the linezolid group. This led to the ZEPHyR (Linezolid in the Treatment of Subjects with Nosocomial Pneumonia Proven to Be Due to Methicillin Resistant Staphylococcus aureus) trial comparing linezolid versus vancomycin for MRSA pneumonia, which showed a benefit for linezolid with respect to clinical response but without a survival advantage. Limitations of the study included unbalanced treatment groups at baseline and number of patients excluded to reach the per-protocol group. Results of the ZEPHyR trial do not support routine use of linezolid for the treatment of MRSA pneumonia. PMID- 22947595 TI - Everolimus: a new treatment option for advanced pancreatic neuroendocrine tumors. AB - OBJECTIVE: To present the current clinical evidence on everolimus for use in pancreatic neuroendocrine tumors (pNET). DATA SOURCES: A literature search was performed using PubMed and MEDLINE (1946-March 2012). Search terms were everolimus, RAD001, mTOR inhibitor, and pancreatic neuroendocrine tumors. Abstracts from the American Society of Clinical Oncology 2000-2012 meetings and Food and Drug Administration (FDA) reviews were searched to obtain otherwise unpublished data. The national clinical trials registry was searched for current and future studies of everolimus in pNET. STUDY SELECTION AND DATA EXTRACTION: Clinical studies available in the English language describing the pharmacology, pharmacokinetics, clinical activity, and safety of everolimus in pNET were included. All peer-reviewed, clinically relevant publications were reviewed for inclusion. DATA SYNTHESIS: Everolimus is an oral mammalian target of rapamycin (mTOR) inhibitor approved by the FDA in May 2011 for the treatment of progressive, advanced pNET. Everolimus exerts its effect by inhibiting multiple downstream pathways of mTOR, which decreases cell proliferation, survival, and angiogenesis. Its pNET indication was based on the results of RADIANT-3, a Phase 3 trial demonstrating increased median progression-free survival (11 months) with everolimus 10 mg orally once daily compared to placebo (4.6 months). Everolimus was well tolerated in clinical trials. The most commonly reported adverse events included stomatitis, rash, diarrhea, fatigue, infections, nausea, and decreased appetite. Grade 3/4 events including anemia, thrombocytopenia, pneumonitis, and hyperglycemia occurred in approximately 5% of patients. CONCLUSIONS: Based on review of the available literature, everolimus is a safe and effective treatment option for patients with low- to intermediate-grade, unresectable or metastatic pNET that have progressed on prior therapies. Until results of head-to-head, randomized controlled trials are conducted to compare everolimus to other treatment options, it cannot be said whether everolimus is more efficacious or tolerable than other treatment options. PMID- 22947594 TI - An analysis of potentially prolactin-related adverse events and abnormal prolactin values in randomized clinical trials with paliperidone palmitate. AB - BACKGROUND: Paliperidone palmitate has been associated with serum prolactin elevations in some patients. However, few individuals with elevated prolactin levels (hyperprolactinemia) have symptomatic potentially prolactin-related adverse events (PPR-AEs). OBJECTIVE: To quantify rates of hyperprolactinemia in subjects treated with the newly marketed paliperidone palmitate long-acting injection (PP-LAI) in randomized clinical trials, summarize rates of PPR-AEs in those trials by sex and dose, and determine how many PPR-AEs required treatment. METHODS: Numbers and rates of investigator-reported hyperprolactinemia and PPR AEs were obtained from the sponsor's clinical trial database and have been included in regulatory filings. Results were tabulated for males, females, and overall, and by dose administered, using descriptive statistics. Those requiring treatment were described as well. RESULTS: There were 3173 subjects (61.4% males) exposed to PP-LAI in 10 clinical trials; 2831 (89.2%) patients had recorded prolactin levels, including 1759 males (90.3% of exposed males) and 1072 females (87.5% of exposed females). Overall, at any time, prolactin levels were elevated for 38.8% of the subjects (39.5% for males and 37.7% for females; p = 0.354 between sexes). However, there was no significant correlation between monthly dose and proportion of subjects with elevated prolactin levels (p = 0.109). There were 115 PPR-AEs in 107 patients (3.4%); 51 (44.3% of PPR-AEs) cases represented asymptomatic hyperprolactinemia. The remaining 64 symptomatic PPR-AEs affected 2.0% of the total number of subjects. Fifteen events in 13 participants (0.41% of patients or 4.7 events/1000 patients) required treatment. CONCLUSIONS: Clinicians should periodically assess patients on paliperidone palmitate for any PPR-AEs and carefully assess the benefits and risks when managing these effects. PMID- 22947596 TI - Improving the quality of surveys of physicians and medical groups: a research agenda. AB - Because health care providers have a central role in implementing guidelines, health care reform, and new standards of care and technologies, surveying them about their practices and perspectives is vital for health services and policy research. In November 2010, the National Cancer Institute convened a workshop to review and discuss current methodologies in designing and fielding large-scale surveys of physicians and medical groups. This report summarizes key issues and future directions for four topic areas addressed in the workshop: sample frames for surveying physicians and medical groups; points of contact and response modes; response incentives; and questionnaire design and burden. Recommendations were made for improving sample frame databases, optimizing mixed-mode surveys, and studying use of incentives with gatekeepers and in medical group settings. There is particular need for empirical assessment of factors that motivate or impede participation of physicians, other types of clinicians, and medical groups in survey research. PMID- 22947597 TI - Effect of routine probiotic, Lactobacillus reuteri DSM 17938, use on rates of necrotizing enterocolitis in neonates with birthweight < 1000 grams: a sequential analysis. AB - BACKGROUND: Necrotizing enterocolitis (NEC) is a disease in neonates, often resulting in death or serious medical or neurodevelopmental complications. The rate of NEC is highest in the smallest babies and many efforts have been tried to reduce the rate of NEC. In neonates born below 1500 grams, the rate of NEC has been significantly reduced with the use of various probiotics. This study examines the impact of routine use of a probiotic, Lactobacillus reuteri DSM 17938 (BioGaia(r)), on the rate of NEC in neonates at highest risk for developing NEC, those with birth weight <=1000 grams. METHODS: This is a retrospective cohort study comparing the rates of NEC in neonates with birth weight <= 1000 grams. The groups are separated into those neonates born from January 2004 to June 30, 2009, before introduction of L. reuteri , and neonates born July 2009 through April 2011 who received routine L. reuteri prophylaxis. The chart review study was approved by our institutional review board and exempted from informed consent.Neonates were excluded if they died or were transferred within the first week of life. The remainder were categorized as having no NEC, medical NEC, surgical NEC, or NEC associated death. Since no major changes occurred in our NICU practice in recent years, and the introduction of L. reuteri as routine prophylaxis was abrupt, we attributed the post-probiotic changes to the introduction of this new therapy. Rates of NEC were compared using Chi square analysis with Fisher exact t-test. RESULTS: Medical records for 311 neonates were reviewed, 232 before- and 79 after-introduction of L. reuteri prophylaxis. The incidence of NEC was significantly lower in the neonates who received L. reuteri (2 of 79 neonates [2.5%] versus 35 of 232 untreated neonates [15.1%]). Rates of late-onset gram-negative or fungal infections (22.8 versus 31%) were not statistically different between treated and untreated groups. No adverse events related to use of L reuteri were noted. CONCLUSIONS: Prophylactic initiation of L. reuteri as a probiotic for prevention of necrotizing enterocolitis resulted in a statistically significant benefit, with avoidance of 1 NEC case for every 8 patients given prophylaxis. PMID- 22947598 TI - Functionalization of carbon nanotubes by water plasma. AB - Multiwall carbon nanotubes grown by plasma enhanced chemical vapour deposition were functionalized by H(2)O plasma treatment. Through a controlled functionalization process of the carbon nanotubes (CNTs) we were able to modify and tune their chemical reactivity, expanding the range of potential applications in the field of energy and environment. In particular, different oxygen groups were attached to the surfaces of the nanotubes (e.g. carboxyl, hydroxyl and carbonyl), which changed their physicochemical properties. In order to optimize the main operational parameters of the H(2)O plasma treatment, pressure and power, a Box-Wilson experimental design was adopted. Analysis of the morphology, electrochemical properties and functional groups attached to the surfaces of the CNTs allowed us to determine which treatment conditions were suitable for different applications. After water plasma treatment the specific capacitance of the nanotubes increased from 23 up to 68 F g(-1) at a scan rate of 10 mV s(-1). PMID- 22947599 TI - Polyvalent immunoglobulin significantly attenuated the formation of IL-1beta in Escherichia coli-induced sepsis in pigs. AB - Evidence suggests that adjunctive treatment with intravenous immunoglobulin preparations enriched with IgA and IgM reduce mortality in sepsis. The mode of action of polyvalent immunoglobulin is complex, including neutralization of toxins and modulation of complement activation and cytokine formation toward an anti-inflammatory profile. In this study we explored the effect of Pentaglobin, containing IgG, IgA and IgM, on the initial inflammatory reaction as well as on hemodynamics, using a well characterized and standardized porcine model of sepsis. Anesthetized and mechanically ventilated pigs, mean weight 14.9 kg, were allocated into two groups of 8 animals, receiving either Pentaglobin or saline, before sepsis was induced by intravenous Escherichia coli infusion. Five negative controls received saline only. All animals were observed for 4 h under extensive invasive monitoring. Pentaglobin significantly (p < 0.05) attenuated IL-1beta formation by 38% at the end of the experiment, and markedly increased (p < 0.05) the formation of IL-10 at 60 min. TNF-alpha, IL-6, IL-8 and expression of the cell surface marker wCD11R3 were lower in the Pentaglobin group, but the differences were not significant. The serum concentration of LPS was three times higher in the Pentaglobin group (p < 0.005), indicating binding of LPS to Pentaglobin. Complementary in vitro experiments showed a higher binding affinity for IgM and IgA to LPS than for IgG. LPS-induced formation of IL-6 was significantly (p < 0.05) attenuated by Pentaglobin in an in vitro whole blood model. In conclusion, Pentaglobin decreased the key inflammasome IL-1beta molecule in an E. coli-model of pigs sepsis. PMID- 22947600 TI - Denosumab for the treatment of osteoporosis: a systematic literature review. AB - PURPOSE: To determine the efficacy and safety of denosumab in osteoporosis. METHODS: A systematic search was performed in MEDLINE, EMBASE, and The Cochrane Central Register of Controlled Trials (1950 to July 2010), meeting abstracts (2009-2010), trial registries, and reference lists. The selection criteria were as follows: (population) osteoporosis patients of any age; (intervention) treatment with denosumab; (outcome) efficacy and safety; (study design) randomized clinical trials (RCTs); no language restrictions. Two reviewers independently screened titles and abstracts and subsequently extracted data from the selected studies including quality items, and on outcomes of interest. A meta analysis was performed for safety issues. RESULTS: A total of 25 studies were included. Denosumab reduces the risk of new radiographic vertebral fracture in a 68% compared with placebo (p<0.001) and increases bone mineral density (BMD) at lumbar spine, total hip, and one-third radius more than alendronate and placebo. A single subcutaneous dose of denosumab resulted in a dose-dependent, rapid, profound, and sustained decrease bone turnover markers (BTMs). Denosumab was in general well tolerated. A meta-analysis has shown an increase in the incidence of urinary infections (p=0.012) and eczema (p<0.001) in the patients treated with denosumab. Meta-analysis of efficacy was complicated due to the study features. CONCLUSIONS: Denosumab given subcutaneously twice yearly is associated with a reduction in the risk of vertebral, nonvertebral, and hip fractures in women with osteoporosis. Denosumab is associated with greater and sustained increases in BMD and reductions in BTMs compared with placebo and/or alendronate and with a risk of urinary infections and eczema. PMID- 22947601 TI - Comparative genomics: a revolutionary tool for wine yeast strain development. AB - The application of Next Generation sequencing to comparative genomics is enabling in-depth characterization of genetic variation between wine yeast strains used in fermentation starter cultures. Knowledge from this work will be harnessed in strain development programs. As a result, winemakers will soon have at their disposal novel, improved yeast starter cultures displaying increased reliability and providing a means of tailoring wine sensory characteristics for new and ever changing markets. PMID- 22947602 TI - Plant genome-scale metabolic reconstruction and modelling. AB - Genome-scale metabolic reconstructions are used extensively in the study of microbial metabolism and have proven powerful tools to guide rational pathway design of industrial strains. Generation and curation of plant genome-scale metabolic models has proven far more challenging, not the least of which is our incomplete knowledge of compartmentation and organelle transporters in plants. Conversely, the potential value of modelling is far greater when exploring a complex, multi-organelle and multi-tissue metabolism. The first generation of plant genome-scale metabolic reconstructions have proven surprisingly functional and robust as well as capable of predicting many observed complex phenotypes. With further refinement, the application of these models promises to make important contributions to plant biology and metabolic engineering. PMID- 22947603 TI - [Quackery and doctors' response to it]. PMID- 22947604 TI - [Employment-related vocational rehabilitation and rehabilitation funds]. PMID- 22947605 TI - [A study of risk factors for cardiovascular disease among schizophrenic patients using the rehabilitation mental health services at Kleppur]. AB - BACKGROUND: Studies have shown that schizophrenic patients die on average 15-20 years earlier than the normal population, and that increased prevalance of cardiovascular risk factors plays a crucial role Schizophrenic patients are underdiagnosed and undertreated when it comes to diabetes, hypertension and dyslipidemia. The aim of this study was to investigate the prevalence of metabolic syndrome, obesity, hypertension, diabetes and dyslipidemia among schizophrenic patients in Iceland. METHODS: An observational study of 106 schizophrenic patients in Iceland during the period 2007-2009. The results were compared to age adjusted population based data. RESULTS: 106 patients participated, 86 men and 20 women. In all 57% were diagnosed with metabolic syndrome (p<0.0001) in comparison to 14.1% in the general population. In all 73% were smokers (21% in the general population) p<0.0001 and 23.6% had hypertension of which only 20% were treated with anti-hypertensive medication. The average systolic blood pressure was 134.8 mmHg <0.001. In all 15.1% had a fasting glucose over 7 mmol/l but only 38% were previously diagnosed with diabetes. The average BMI was 29.7 kg/m2 p=0.0007, 45.3% were obese (BMI >30 kg/m2). Only 32.1% had normal BMI, and 82.1% had waist circumference over the normal limits. CONCLUSION: The physical condition of Icelandic schizophrenic patients is poor and their risk for cardiovascular diseases is high. It is necessary to follow their weight, blood pressure, blood glucose and lipids more closely It is imperative to educate and enable the schizophrenic patient to live a healthier life. PMID- 22947606 TI - [Reliability, validity and responsiveness of the Icelandic version of the knee injury and osteoarthritis outcome score (KOOS)]. AB - PURPOSE: The KOOS self-report questionnaire (Knee injury and Osteoarthritis Outcome Score) has 5 sub-scales, assessing knee symptoms and function, and quality of life. It is widely used as it has been found to be a valid and reliable measure. The purpose of this study was to investigate the validity, reliability and responsiveness of the Icelandic translation of KOOS. METHODS: A total of 145 were recruited for the study and in addition to answering KOOS, knee pain was rated on a visual analog scale (VAS), perception of knee function during activities of daily living on a numerical rating scale, and some were tested with the timed up-and-go test (TUG). Reliability was assessed by observing ICC-values, internal consistency with Cronbach's alpha, and associations between KOOS subscales and other outcome measures with Pearson's correlation coefficient. A one-way ANOVA was used to assess differences between groups of participants with different levels of knee dysfunction. RESULTS: A significant change in all KOOS subscales was found in a group of individuals seeking treatment for their knee dysfunction (p<0.001), while no change was seen in a group reporting stable knee status (ICC-values ranging from 0.825 to 0.930). Cronbach's alpha ranged from 0.726 to 0.966 and significant correlations were found between all KOOS sub scales and other outcome measures (p<0.001). CONCLUSION: The results indicate that the Icelandic version of KOOS is a valid and reliable measure that may be used as an outcome measure assessing knee symptoms and function of individuals with knee symptoms and impaired knee function. PMID- 22947607 TI - [Choledochal cyst--case report]. AB - The clinical manifestation of a choledochal cyst is diverse and can mimic common diseases like gallstones, cholecystitis or pancreatitis. Initial diagnosis is often suspected after ultrasound of the biliary tract and confirmed with more specific studies as magnetic resonance cholangiopancreatography or endoscopic retrograde cholangiopancreatography. The risk of malignant transformation is well documented and the mainstay of therapy is excision of the choledochal cysts along with the gallbladder. Choledochal cysts are a rare phenomenon and only three cases were diagnosed in Iceland in the years 2000-2010. The following is a description of one of these cases along with an overview of the literature. PMID- 22947608 TI - [Case of the month: woman with hematuria and depressed mental status]. PMID- 22947609 TI - Mortality outcome of out-of-hours primary percutaneous coronary intervention in the current era. AB - AIMS: To assess the impact of the time of primary percutaneous coronary intervention (PPCI) on in-hospital and long-term all-cause mortality in ST segment elevation myocardial infarction (STEMI). METHODS AND RESULTS: The study retrospectively analyses the prospectively collected data on 2571 consecutive PPCI-treated STEMI patients between March 2008 and June 2011. Of these, 1036 patients (40.3%) underwent PPCI during a weekday between 08:00 and 18:00 (routine hours group) and 1535 patients (59.7%) underwent PPCI on a weekday between 18:00 and 08:00 or a weekend (out-of-hours group). Compared with the routine-hours group, the out-of-hours group had a lower mean age, fewer patients with previous angina, longer call-to-hospital time, and fewer multivessel PCI. The overall in hospital mortality rate was 4.5% with no significant difference [0.2%, 95% confidence interval (CI): -1.4 to 1.9%] between the routine-hours group (4.3%) and the out-of-hours group (4.6%) (adjusted odds ratio: 1.33, 95% CI: 0.73-2.40, P = 0.35). During a mean follow-up period of 560 days, 295 patients (11.5%) died, 12.2% in the routine-hours group and 11.0% in the out-of-hours group (difference of -0.1%, 95% CI: -0.4 to 0.2%). In the multiple Cox proportional hazards model, there was no difference in mortality between the two groups (adjusted hazard ratio: 1.09, 95% CI: 0.82-1.46, P = 0.57). Similarly, no increase in mortality was seen in patients who underwent PPCI later at night (22:00-06:00). CONCLUSION: This study of real-world, unselected STEMI patients demonstrates that in a large, well-staffed centre, PPCI outside routine-working hours is safe with no difference in outcome of in-hospital and long-term mortality compared with PPCI during routine-working hours. PMID- 22947610 TI - Evidence for obesity paradox in patients with acute coronary syndromes: a report from the Swedish Coronary Angiography and Angioplasty Registry. AB - AIMS: The obesity paradox refers to the epidemiological evidence that obesity compared with normal weight is associated with counter-intuitive improved health in a variety of disease conditions. The aim of this study was to investigate the relationship between body mass index (BMI) and mortality in patients with acute coronary syndromes (ACSs). METHODS AND RESULTS: We extracted data from the Swedish Coronary Angiography and Angioplasty Registry and identified 64 436 patients who underwent coronary angiography due to ACSs. In 54 419 (84.4%) patients, a significant coronary stenosis was identified, whereas 10 017 (15.6%) patients had no significant stenosis. Patients were divided into nine different BMI categories. The patients with significant stenosis were further subdivided according to treatment received such as medical therapy, percutaneous coronary intervention (PCI), or coronary artery by-pass grafting. Mortality for the different subgroups during a maximum of 3 years was compared using Cox proportional hazards regression with the lean BMI category (21.0 to <23.5 kg/m(2)) as the reference group. Regardless of angiographic findings [significant or no significant coronary artery disease (CAD)] and treatment decision, the underweight group (BMI <18.5 kg/m(2)) had the greatest risk for mortality. Medical therapy and PCI-treated patients with modest overweight (BMI category 26.5-<28 kg/m(2)) had the lowest risk of mortality [hazard ratio (HR) 0.52; 95% CI 0.34-0.80 and HR 0.64; 95% CI 0.50-0.81, respectively]. When studying BMI as a continuous variable in patients with significant CAD, the adjusted risk for mortality decreased with increasing BMI up to ~35 kg/m(2) and then increased. In patients with significant CAD undergoing coronary artery by-pass grafting and in patients with no significant CAD, there was no difference in mortality risk in the overweight groups compared with the normal weight group. CONCLUSION: In this large and unselected group of patients with ACSs, the relation between BMI and mortality was U-shaped, with the nadir among overweight or obese patients and underweight and normal-weight patients having the highest risk. These data strengthen the concept of the obesity paradox substantially. PMID- 22947611 TI - Does obesity make it better or worse: insights into cardiovascular illnesses. PMID- 22947613 TI - Right bundle branch block: prevalence, risk factors, and outcome in the general population: results from the Copenhagen City Heart Study. AB - AIMS: To determine the prevalence, predictors of newly acquired, and the prognostic value of right bundle branch block (RBBB) and incomplete RBBB (IRBBB) on a resting 12-lead electrocardiogram in men and women from the general population. METHODS AND RESULTS: We followed 18 441 participants included in the Copenhagen City Heart Study examined in 1976-2003 free from previous myocardial infarction (MI), chronic heart failure, and left bundle branch block through registry linkage until 2009 for all-cause mortality and cardiovascular outcomes. The prevalence of RBBB/IRBBB was higher in men (1.4%/4.7% in men vs. 0.5%/2.3% in women, P < 0.001). Significant predictors of newly acquired RBBB were male gender, increasing age, high systolic blood pressure, and presence of IRBBB, whereas predictors of newly acquired IRBBB were male gender, increasing age, and low BMI. Right bundle branch block was associated with significantly increased all-cause and cardiovascular mortality in both genders with age-adjusted hazard ratios (HR) of 1.31 [95% confidence interval (CI), 1.11-1.54] and 1.87 (95% CI, 1.48-2.36) in the gender pooled analysis with little attenuation after multiple adjustment. Right bundle branch block was associated with increased risk of MI with an HR of 1.67 (95% CI, 1.16-2.42) and pacemaker insertion with an HR of 2.17 (95% CI, 1.22-3.86), but not with chronic heart failure (HR 1.37; 95% CI, 0.96 1.94), atrial fibrillation (HR 1.10; 95% CI, 0.73-1.67), or chronic obstructive pulmonary disease (HR 0.99; 95% CI, 0.60-1.62). The presence of IRBBB was not associated with any adverse outcome. CONCLUSION: In this cohort study, RBBB and IRBBB were two to three times more common among men than women. Right bundle branch block was associated with increased cardiovascular risk and all-cause mortality, whereas IRBBB was not. Contrary to common perception, RBBB in asymptomatic individuals should alert clinicians to cardiovascular risk. PMID- 22947612 TI - The intriguing metabolically healthy but obese phenotype: cardiovascular prognosis and role of fitness. AB - AIMS: Current knowledge on the prognosis of metabolically healthy but obese phenotype is limited due to the exclusive use of the body mass index to define obesity and the lack of information on cardiorespiratory fitness. We aimed to test the following hypotheses: (i) metabolically healthy but obese individuals have a higher fitness level than their metabolically abnormal and obese peers; (ii) after accounting for fitness, metabolically healthy but obese phenotype is a benign condition, in terms of cardiovascular disease and mortality. METHODS AND RESULTS: Fitness was assessed by a maximal exercise test on a treadmill and body fat per cent (BF%) by hydrostatic weighing or skinfolds (obesity = BF% >= 25 or >= 30%, men or women, respectively) in 43 265 adults (24.3% women). Metabolically healthy was considered if meeting 0 or 1 of the criteria for metabolic syndrome. Metabolically healthy but obese participants (46% of the obese subsample) had a better fitness than metabolically abnormal obese participants (P < 0.001). When adjusting for fitness and other confounders, metabolically healthy but obese individuals had lower risk (30-50%, estimated by hazard ratios) of all-cause mortality, non-fatal and fatal cardiovascular disease, and cancer mortality than their metabolically unhealthy obese peers; while no significant differences were observed between metabolically healthy but obese and metabolically healthy normal fat participants. CONCLUSIONS: (i) Higher fitness should be considered a characteristic of metabolically healthy but obese phenotype. (ii) Once fitness is accounted for, the metabolically healthy but obese phenotype is a benign condition, with a better prognosis for mortality and morbidity than metabolically abnormal obese individuals. PMID- 22947614 TI - Roots, water, and nutrient acquisition: let's get physical. AB - Improved root water and nutrient acquisition can increase fertiliser use efficiency and is important for securing food production. Root nutrient acquisition includes proliferation, transporter function, exudation, symbioses, and the delivery of dissolved nutrients from the bulk soil to the root surface via mass flow and diffusion. The widespread adoption of simplified experimental systems has restricted consideration of the influence of soil symbiotic organisms and physical properties on root acquisition. The soil physical properties can directly influence root growth and explain some of the disparities obtained from different experimental systems. Turning this to an advantage, comparing results obtained with the same model plant Arabidopsis (Arabidopsis thaliana) in different systems, we can tease apart the specific effects of soil physical properties. PMID- 22947615 TI - Plant RNA chaperones in stress response. AB - Post-transcriptional regulation of RNA metabolism is a key regulatory process in diverse cellular processes, including the stress response of plants, during which a variety of RNA-binding proteins (RBPs) function as central regulators in cells. RNA chaperones are RBPs found in all living organisms and function by providing assistance to the correct folding of RNA molecules during RNA metabolism. Although our understanding of the role of RNA chaperones in plants is far less advanced than in bacteria, viruses, and animals, recent progress in functional characterization and determination of RNA chaperone activity of several RBPs has shed new light on the emerging roles of RNA chaperones during the stress response of plants. PMID- 22947616 TI - Evaluating airborne and ground based gamma spectrometry methods for detecting particulate radioactivity in the environment: a case study of Irish Sea beaches. AB - In several places, programmes are in place to locate and recover radioactive particles that have the potential to cause detrimental health effects in any member of the public who may encounter them. A model has been developed to evaluate the use of mobile gamma spectrometry systems within such programmes, with particular emphasis on large volume (16l) NaI(Tl) detectors mounted in low flying helicopters. This model uses a validated Monte Carlo code with assessment of local geochemistry and natural and anthropogenic background radiation concentrations and distributions. The results of the model, applied to the example of particles recovered from beaches in the vicinity of Sellafield, clearly show the ability of rapid airborne surveys conducted at 75 m ground clearance and 120 kph speeds to demonstrate the absence of sources greater than 5 MBq (137)Cs within large areas (10-20 km(2)h(-1)), and identify areas requiring further ground based investigation. Lowering ground clearance for airborne surveys to 15m whilst maintaining speeds covering 1-2 km(2) h(-1) can detect buried (137)Cs sources of 0.5MBq or greater activity. A survey design to detect 100 kBq (137)Cs sources at 10 cm depth has also been defined, requiring surveys at <15m ground clearance and <2 ms(-1) ground speed. The response of airborne systems to the Sellafield particles recovered to date has also been simulated, and the proportion of the existing radiocaesium background in the vicinity of the nuclear site has been established. Finally the rates of area coverage and sensitivities of both airborne and ground based approaches are compared, demonstrating the ability of airborne systems to increase the rate of particle recovery in a cost effective manner. The potential for equipment and methodological developments to improve performance are discussed. PMID- 22947617 TI - Diurnal/nocturnal concentrations and sources of particulate-bound PAHs, OPAHs and NPAHs at traffic and suburban sites in the region of Paris (France). AB - Particulate concentrations of polycyclic aromatic compounds (PACs) including, 17 polycyclic aromatic hydrocarbons (PAHs), 9 oxygenated PAHs (OPAHs) and 18 nitrated PAHs (NPAHs) were determined at traffic and suburban sites located in the region of Paris. A 12 h sampling basis time resolution was applied in order to study their diurnal and nocturnal variations. Observed concentrations were about 10 times higher at the traffic site for all compounds and were higher during the night-time for both sites (except for NPAHs at the traffic site). No significant differences in PAH and OPAH profiles were observed at both sites whereas, for NPAHs, 1-nitropyrene (diesel source) was the most abundant at the traffic site and 2+3-nitrofluoranthene (secondary formed by gas-phase reaction) was predominant at the suburban site. The study of the specific ratio 2 nitrofluoranthene/1-nitropyrene (2-NFlt/1-NP) showed a local formation of NPAHs in gaseous phase at the suburban site. A detailed analysis showed that atmospheric humidity and rainfalls modified differently PAH and NPAH profiles, in comparison to OPAH. A difference of the scale variability of water solubility between, light (MW<=228 g mol(-1)) and heavy compounds (MW>=273 g mol(-1)), could explain these observations. The specific study of the relationships between PACs and other measured pollutants highlighted that particle resuspension could constitute a significant source of PM on the traffic site. Even if NPAH formation seemed clearly evident at the suburban site during periods characterised by high O(3) and NO(2) concentration levels, results showed also that the primary and/or secondary origins of OPAHs and NPAHs were strongly dependent on the sampling site and on sampling conditions. Finally, we conclude that higher time sampling resolutions would be helpful in investigating the atmospheric chemistry and behaviours of PACs in correlation with the local meteorological variations and the daily cycle of human activities. PMID- 22947618 TI - A generic emission model to predict release of organic substances from materials in consumer goods. AB - Organic chemicals may be released when consumer goods are used, contributing to environmental and human levels of potentially hazardous chemicals. A generic model was developed to predict emissions of organic chemicals from various materials in consumer products. The model involved three modules, which each predict a key parameter needed to calculate the mass of individual chemicals emitted. Partition coefficients between a material and the surrounding air were predicted using Abraham solvation parameters, diffusion coefficients in materials were calculated using the Piringer equation, and convective mass transfer coefficients were evaluated by applying the Chilton-Colburn analogy. The calculated emission rates from predicted parameters were evaluated and agreed well with literature data. The release of plasticizers from vinyl flooring used in Sweden was calculated to demonstrate the utility of the generic model. The estimated emitted masses of di(2-ethylhexyl)phthalate (DEHP), di-iso nonylphthalate (DINP), and 1,2-cyclohexanedicarboxylic acid di-iso-nonyl ester (DINCH) in 2012 were 210 kg, 40 kg, and 3.6 kg respectively. Emissions from vinyl flooring were estimated for the period 1990 to 2035 and it was shown that the recent substitution of DEHP with DINP will help to reduce plasticizer emissions. Model calculations for alternative plasticizers revealed that DINCH would yield similar emissions to DINP, whereas use of diethyl hexyl-iso-sorbide or diethyl hexyl adipate would result in higher emissions. PMID- 22947619 TI - Selective filling of nanowells in nanowell arrays fabricated using polystyrene nanosphere lithography with cytochrome P450 enzymes. AB - This work describes an original and simple technique for protein immobilization into nanowells, fabricated using nanopatterned array fabrication methods, while ensuring the protein retains normal biological activity. Nanosphere lithography was used to fabricate a nanowell array with nanowells 100 nm in diameter with a periodicity of 500 nm. The base of the nanowells was gold and the surrounding material was silicon dioxide. The different surface chemistries of these materials were used to attach two different self-assembled monolayers (SAM) with different affinities for the protein used here, cytochrome P450 (P450). The nanowell SAM, a methyl terminated thiol, had high affinity for the P450. The surrounding SAM, a polyethylene glycol silane, displayed very little affinity toward the P450 isozyme CYP2C9, as demonstrated by x-ray photoelectron spectroscopy and surface plasmon resonance. The regularity of the nanopatterned array was examined by scanning electron microscopy and atomic force microscopy. P450-mediated metabolism experiments of known substrates demonstrated that the nanowell bound P450 enzyme exceeded its normal activity, as compared to P450 solutions, when bound to the methyl terminated self-assembled monolayer. The nanopatterned array chips bearing P450 display long term stability and give reproducible results making them potentially useful for high-throughput screening assays or as nanoelectrode arrays. PMID- 22947620 TI - Thermoelectric properties of porous multi-walled carbon nanotube/polyaniline core/shell nanocomposites. AB - Porous polyaniline (PANI)-coated multi-walled carbon nanotube (MWNT) core/shell nanohybrids were fabricated through in situ polymerization and subsequently assembled into macroscopic composites. N(2) adsorption/desorption analysis indicated that the volume of nanopores increased significantly, which could make a significant contribution to phonon scattering. Thermal annealing was also carried out to improve the Seebeck coefficient of the as-produced nanocomposites. The optimal sample showed electrical conductivity of 14.1 S cm(-1), a Seebeck coefficient of 79.8 MUV K(-1) and thermal conductivity of 0.27 W mK(-1), resulting in a highest figure of merit (ZT) of 0.01 at a very low loading of MWNTs (<1 wt%). These results will provide a potential direction to enhance thermoelectric performance of organic materials and also facilitate the application of organic materials in thermal energy harvesting or cooling. PMID- 22947622 TI - Disclaimer labels on fashion magazine advertisements: effects on social comparison and body dissatisfaction. AB - Recent proposals across a number of Western countries have suggested that idealised media images should carry some sort of disclaimer informing readers when these images have been digitally enhanced. The present studies aimed to experimentally investigate the impact on women's body dissatisfaction of the addition of such warning labels to fashion magazine advertisements. Participants were 120 and 114 female undergraduate students in Experiment 1 and Experiment 2 respectively. In both experiments, participants viewed fashion magazine advertisements with either no warning label, a generic warning label, or a specific more detailed warning label. In neither experiment was there a significant effect of type of label. However, state appearance comparison was found to predict change in body dissatisfaction irrespective of condition. Unexpectedly, trait appearance comparison moderated the effect of label on body dissatisfaction, such that for women high on trait appearance comparison, exposure to specific warning labels actually resulted in increased body dissatisfaction. In sum, the present results showed no benefit of warning labels in ameliorating the known negative effect of viewing thin-ideal media images, and even suggested that one form of warning (specific) might be harmful for some individuals. Accordingly, it was concluded that more extensive research is required to guide the most effective use of disclaimer labels. PMID- 22947621 TI - An annotated list of fish parasites (Isopoda, Copepoda, Monogenea, Digenea, Cestoda, Nematoda) collected from Snappers and Bream (Lutjanidae, Nemipteridae, Caesionidae) in New Caledonia confirms high parasite biodiversity on coral reef fish. AB - BACKGROUND: Coral reefs are areas of maximum biodiversity, but the parasites of coral reef fishes, and especially their species richness, are not well known. Over an 8-year period, parasites were collected from 24 species of Lutjanidae, Nemipteridae and Caesionidae off New Caledonia, South Pacific. RESULTS: Host parasite and parasite-host lists are provided, with a total of 207 host-parasite combinations and 58 parasite species identified at the species level, with 27 new host records. Results are presented for isopods, copepods, monogeneans, digeneans, cestodes and nematodes. When results are restricted to well-sampled reef fish species (sample size > 30), the number of host-parasite combinations is 20-25 per fish species, and the number of parasites identified at the species level is 9-13 per fish species. Lutjanids include reef-associated fish and deeper sea fish from the outer slopes of the coral reef: fish from both milieus were compared. Surprisingly, parasite biodiversity was higher in deeper sea fish than in reef fish (host-parasite combinations: 12.50 vs 10.13, number of species per fish 3.75 vs 3.00); however, we identified four biases which diminish the validity of this comparison. Finally, these results and previously published results allow us to propose a generalization of parasite biodiversity for four major families of reef-associated fishes (Lutjanidae, Nemipteridae, Serranidae and Lethrinidae): well-sampled fish have a mean of 20 host-parasite combinations per fish species, and the number of parasites identified at the species level is 10 per fish species. CONCLUSIONS: Since all precautions have been taken to minimize taxon numbers, it is safe to affirm than the number of fish parasites is at least ten times the number of fish species in coral reefs, for species of similar size or larger than the species in the four families studied; this is a major improvement to our estimate of biodiversity in coral reefs. Our results suggest that extinction of a coral reef fish species would eventually result in the coextinction of at least ten species of parasites. PMID- 22947623 TI - Effect of varying displays and room illuminance on caries diagnostic accuracy in digital dental radiographs. AB - In clinical practice, digital radiographs taken for caries diagnostics are viewed on varying types of displays and usually in relatively high ambient lighting (room illuminance) conditions. Our purpose was to assess the effect of room illuminance and varying display types on caries diagnostic accuracy in digital dental radiographs. Previous studies have shown that the diagnostic accuracy of caries detection is significantly better in reduced lighting conditions. Our hypothesis was that higher display luminance could compensate for this in higher ambient lighting conditions. Extracted human teeth with approximal surfaces clinically ranging from sound to demineralized were radiographed and evaluated by 3 observers who detected carious lesions on 3 different types of displays in 3 different room illuminance settings ranging from low illumination, i.e. what is recommended for diagnostic viewing, to higher illumination levels corresponding to those found in an average dental office. Sectioning and microscopy of the teeth validated the presence or absence of a carious lesion. Sensitivity, specificity and accuracy were calculated for each modality and observer. Differences were estimated by analyzing the binary data assuming the added effects of observer and modality in a generalized linear model. The observers obtained higher sensitivities in lower illuminance settings than in higher illuminance settings. However, this was related to a reduction in specificity, which meant that there was no significant difference in overall accuracy. Contrary to our hypothesis, there were no significant differences between the accuracy of different display types. Therefore, different displays and room illuminance levels did not affect the overall accuracy of radiographic caries detection. PMID- 22947624 TI - Precious cargo: regulation of sex-specific germ cell development in mice. AB - Although mammalian sex determination is normally specified genetically by an XX or XY chromosome complement, germ cells develop as sperm or oocytes in response to molecular cues provided by the gonadal somatic cells. In an ovary, germ cells enter meiosis during fetal life, thereby committing to oogenesis. In a testis, germ cells do not enter meiosis until after birth, at puberty. Recent findings indicate that, in mice, the sex-specific timing of entry into meiosis is governed by the balance between 2 secreted signalling molecules, retinoic acid (RA), which promotes entry into meiosis, and fibroblast growth factor 9 (FGF9), which counteracts RA. The combined action of these 2 molecular regulators provides a safety mechanism to guard against germ cell dysregulation that can lead to infertility or germ cell cancers. PMID- 22947625 TI - [Equipment in Landspitali University Hospital: compassion-professionalism-safety progress?[editorial]]. PMID- 22947626 TI - [Coronary bypass in Iceland[Editorial]]. PMID- 22947627 TI - [Outcome of myocardial revascularisation in Iceland]. AB - INTRODUCTION: In Iceland over 3500 coronary artery bypass operations have been performed, both On-Pump, using cardiopulmonary bypass and Off-Pump, surgery on a beating heart. The aim was to study their outcome. MATERIAL AND METHODS: This was a retrospective study on 720 consecutive patients who underwent surgical revascularisation at Landspitali-The National University Hospital of Iceland between 2002-2006; 513 On-Pump and 207 Off-Pump patients. Complications and operative mortality (<30 days) were compared between the groups and predictors of survival identified using multivariate analysis. RESULTS: The number of males was significantly higher in the On-Pump group, but other risk factors of coronary artery disease, including age and high body mass index, were comparable, as were the number of distal anastomoses and EuroSCORE. The Off-Pump procedure took 25 minutes longer on average and chest tube output was significantly increased, but the amount of transfusions administered was similar. The rate of minor complications was higher in the On-Pump group. Of the major complications, stroke rates were similar in both groups (2%) but the rate of reoperation for bleeding was higher in the On-Pump group. Mean length of hospital stay was one day longer for On-Pump patients but operative mortality was similar for both groups (4% vs. 3%, p=0.68) as was 5 year survival (92% in both groups). In multivariate analysis both EuroSCORE and age predicted outcome of operative mortality and long term survival but type of surgery (On-Pump vs. Off-Pump) was not a predictive variant. CONCLUSIONS: Outcome of myocardial revascularisation in Iceland is good as regards operative mortality and long term survival. This applies to both conventional On-Pump and Off-Pump procedures. PMID- 22947628 TI - [The usefullness of implantable loop recorders for evaluation of unexplained syncope and palpitations]. AB - OBJECTIVE: Syncope is a common complaint and determining the underlying cause can be difficult despite extensive evaluation. The purpose of this study was to evaluate the usefulness of an implantable loop recorder for patients with unexplained syncope and palpitations. MATERIAL AND METHODS: This was a retrospective analysis of 18 patients, five of whom still have the device implanted. All patients had undergone extensive evaluation for their symptoms before getting the loop recorder implanted and this was therefore a highly select group. RESULTS: Of the thirteen patients where use of the device was completed, the mean age was 65+/-20 years. The loop recorder was in use for a mean time of 20+/-13 months. Unexplained syncope, eleven of thirteen, was the most common indication. The other two received the loop recorder for unexplained palpitations. Four patients had sick sinus syndrome during monitoring, three had supraventricular tachycardia and one had ventricular tachycardia. Further three had typical symptoms but no arrhythmia was recorded and excluding that as a cause. Two patients had no symptoms the entire time they had the loop recorder. Of the five patients still with the device three had syncope as the indication for monitoring and two have the device as a means of evaluating the results of treatment for arrhythmia. CONCLUSION: This study on our initial experience with implantable loop recorders shows that these devices can be useful in the investigation of the causes of syncope and palpitations. PMID- 22947629 TI - [Cervicofascial subcutaneous emphysema and pneumomediastinum following routine restorative dentistry--two case reports]. AB - Although a well-known complication of dental treatment, cervicofacial subcutaneous emphysema is uncommon, especially with co-existing pneumomediastinum. This complication is usually attributed to high-speed air driven handpieces or air-water syringes. Pneumomediastinum is usually self limiting but potentially life threatening. We present two cases where both patients suffered from cervicofacial subcutaneous emphysema, one additionally having pneumomediastinum following routine restorative dentistry. PMID- 22947630 TI - [Results of immediate breast reconstructions at Landspitali-The National University Hospital of Iceland, in 2008-2010]. AB - INTRODUCTION: In late 2007, the availability of immediate breast reconstructions increased as a result of the establishment of an oncoplastic breast surgical service at Landspitali-The National University Hospital The aim of this study was to look at the rates and early complications of immediate breast reconstructions in our hospital in 2008-2010 and compare with the results from the UK National Mastectomy and Breast Reconstruction Audit (NMBRA). MATERIAL AND METHODS: This is a retrospective population-based study, including all women who had immediate breast reconstruction at Landspitali in 2008-2010. RESULTS: 319 mastectomies and 157 breast reconstructions were performed. Of these, 98 (62%) were immediate, (mean age 49, 29-69). The immediate breast reconstruction rate was therefore 31%, with a respective 55% for patients 50 years old or younger. In comparison, the rate was 5% in 2000-2005. Immediate reconstructions with an extended autologous latissimus dorsi flap were performed in 25 (26%) cases and implant based reconstructions in the remaining (n=73, 74%). Inpatient complications occurred in 12 (12%) patients and 5 needed reoperation (3 post-operative bleeding, 1 skin necrosis, 1 imminent LD-flap failure). Readmission due to complications after discharge occurred in 14 (14%), while 37 (38%) developed mild complications not requiring readmission. The results were comparable to NMBRA, although the rates of autologous flap reconstructions were significantly higher than in this study (63% vs. 26%). CONCLUSION: As a result of the establishment of an oncoplastic breast surgical service at Landspitali, the rates of immediate breast reconstruction have increased significantly (from 5% to 31%). The complication rates are low and similar to NMBRA. PMID- 22947631 TI - Long-term outcome of breast cancer patients treated with radiofrequency ablation. AB - BACKGROUND: Radiofrequency ablation (RFA) is considered to be the most promising non-surgical ablation technique for the treatment of small breast cancer. However, few data are available regarding long-term follow-up of patients treated with this modality. METHODS: Since 2005, we have performed RFA and sentinel lymph node (SLN) biopsy in 19 cases. Axillary lymph node dissection (ALND) was performed in patients with positive SLNs. From 24 to 202 days after RFA, the ablated tumour tissue was excised by mammotome biopsy and examined histologically or immunohistochemically with H&E staining, nicotinamide adenine dinucleotide (NADH)-diaphorase staining, and single-stranded (ss) DNA staining. All cases were followed-up after breast radiation and systemic therapies. RESULTS: Although complete response was histologically confirmed in only 8 cases, NADH-diaphorase and ssDNA staining did not demonstrate any viable tumour cells in the ablated lesions. At a mean follow-up of 60 months (follow-up range, 37-82 months), there were no cases of in-breast recurrence, although one patient died due to hepatic metastases. Cosmesis of the conserved breast was excellent or good in all of the cases, but a hard lump was persistent after RFA in half of the cases. CONCLUSIONS: The long-term outcome of patients treated with RFA is encouraging with regard to cosmesis and local control. Because a persisted lump may cause patient discomfort, anxiety and fear, however, further studies are needed to establish the optimal technique. Moreover, a prospective study will be required to determine the equivalency in local recurrence rates between the RFA therapy and conventional breast-conserving treatment. PMID- 22947632 TI - Sleep-wake state tradeoffs, impulsivity and life history theory. AB - Evolutionary ecological theory predicts that sleep-wake state tradeoffs may be related to local environmental conditions and should therefore correlate to alterations in behavioral life history strategies. It was predicted that firefighters who slept more and reported better quality sleep on average would exhibit lower impulsivity inclinations related to slower life history trajectories. UPPS impulsivity scores and self-reported sleep averages were analyzed and indicated a negative association between sleep variables and urgency and a positive association with premeditation. Perseverance, and in some cases premeditation, however, disclosed an unpredicted marginally significant positive association between increased and emergency nighttime waking-related sleep deprivation. Sensation seeking was not associated with sleep variables, but was strongly associated with number of biological children. This research contributes to understanding the implications of human sleep across ecological and behavioral contexts and implies further research is necessary for constructing evolutionarily oriented measures of impulsivity inclination and its meaning in the context of life history strategies. PMID- 22947633 TI - The lurking snake in the grass: interference of snake stimuli in visually taxing conditions. AB - Based on evolutionary considerations, it was hypothesized that humans have been shaped to easily spot snakes in visually cluttered scenes that might otherwise hide camouflaged snakes. This hypothesis was tested in a visual search experiment in which I assessed automatic attention capture to evolutionarily-relevant distractor stimuli (snakes), in comparison with another animal which is also feared but where this fear has a disputed evolutionary origin (spiders), and neutral stimuli (mushrooms). Sixty participants were engaged in a task that involved the detection of a target (a bird) among pictures of fruits. Unexpectedly, on some trials, a snake, a spider, or a mushroom replaced one of the fruits. The question of interest was whether the distracting stimuli slowed the reaction times for finding the target (the bird) to different degrees. Perceptual load of the task was manipulated by increments in the set size (6 or 12 items) on different trials. The findings showed that snake stimuli were processed preferentially, particularly under conditions where attentional resources were depleted, which reinforced the role of this evolutionarily relevant stimulus in accessing the visual system (Isbell, 2009). PMID- 22947635 TI - Kinship recognition by unrelated observers depends on implicit and explicit cognition. AB - Previous studies have shown that neutral observers are able to identify kinship in strangers by matching photographs of children with their parents. We asked whether this ability depended on implicit and/or explicit cognitive processes. Fifty unrelated male observers viewed triads of photographs (one woman in her early 20's and two older women) and had to select which of the two older women was the mother, and rate their confidence in their decision. Observers identified 62.5% of mother-daughter pairs correctly (p < .001). Signal detection analyses showed that confidence was related to accuracy (d' = .28) and observers could report the cues they utilized. However, those who failed to show a relationship between confidence and accuracy (d' <= 0) still performed significantly above chance, and both confidence and d' decreased over trials whereas accuracy did not. Results show that neutral observers spontaneously used both explicit and implicit cognitive processes in the task. Recognition of kinship by neutral observers may be a task which allows the interplay between explicit and implicit cognition for a system relevant to ancestral social environments to be observed in the laboratory. PMID- 22947636 TI - Human nonindependent mate choice: is model female attractiveness everything? AB - Following two decades of research on non-human animals, there has recently been increased interest in human nonindependent mate choice, namely the ways in which choosing women incorporate information about a man's past or present romantic partners ('model females') into their own assessment of the male. Experimental studies using static facial images have generally found that men receive higher desirability ratings from female raters when presented with attractive (compared to unattractive) model females. This phenomenon has a straightforward evolutionary explanation: the fact that female mate value is more dependent on physical attractiveness compared to male mate value. Furthermore, due to assortative mating for attractiveness, men who are paired with attractive women are more likely to be of high mate value themselves. Here, we also examine the possible relevance of model female cues other than attractiveness (personality and behavioral traits) by presenting video recordings of model females to a set of female raters. The results confirm that the model female's attractiveness is the primary cue. Contrary to some earlier findings in the human and nonhuman literature, we found no evidence that female raters prefer partners of slightly older model females. We conclude by suggesting some promising variations on the present experimental design. PMID- 22947637 TI - Shifts in color discrimination during early pregnancy. AB - The present study explores two hypotheses: a) women during early pregnancy should experience increased color discrimination ability, and b) women during early pregnancy should experience shifts in subjective preference away from images of foods that appear either unripe or spoiled. Both of these hypotheses derive from an adaptive view of pregnancy sickness that proposes the function of pregnancy sickness is to decrease the likelihood of ingestion of foods with toxins or teratogens. Changes to color discrimination could be part of a network of perceptual and physiological defenses (e.g., changes to olfaction, nausea, vomiting) that support such a function. Participants included 13 pregnant women and 18 non-pregnant women. Pregnant women scored significantly higher than non pregnant controls on the Farnsworth-Munsell (FM) 100 Hue Test, an objective test of color discrimination, although no difference was found between groups in preferences for food images at different stages of ripeness or spoilage. These results are the first indication that changes to color discrimination may occur during early pregnancy, and is consistent with the view that pregnancy sickness may function as an adaptive defense mechanism. PMID- 22947638 TI - A multi-informant longitudinal study on the relationship between aggression, peer victimization, and dating status in adolescence. AB - Adolescent peer-aggression has recently been considered from the evolutionary perspective of intrasexual competition for mates. We tested the hypothesis that peer-nominated physical aggression, indirect aggression, along with self-reported bullying behaviors at Time 1 would predict Time 2 dating status (one year later), and that Time 1 peer- and self-reported peer victimization would negatively predict Time 2 dating status. Participants were 310 adolescents who were in grades 6 through 9 (ages 11-14) at Time 1. Results showed that for both boys and girls, peer-nominated indirect aggression was predictive of dating one year later even when controlling for age, peer-rated attractiveness, and peer-perceived popularity, as well as initial dating status. For both sexes, self-reported peer victimization was negatively related to having a dating partner at Time 2. Findings are discussed within the framework of intrasexual competition. PMID- 22947639 TI - Different cues of personality and health from the face and gait of women. AB - Redundant cues for attractiveness in humans have been identified, but the idea of multiple systems displaying different socially-relevant traits has yet to be extensively examined. We compared the accuracy with which observers could identify socially-relevant information of female targets, both from static images of their faces, and from point-light displays of their gait. Perception of extraversion was at chance. However, agreeableness and sociosexuality were more accurately perceived from the face than gait, while physical health showed the opposite pattern. This double dissociation suggests different information can be carried in different modalities. In addition, partial correlation analyses suggested that even when both modalities allowed accurate trait identification, the information content was different. Our results demonstrate that cues of different socially-relevant traits are communicated more effectively through different modalities, and these modality-specific cues contain distinctive information, supporting a "multiple messages" hypothesis. PMID- 22947640 TI - Dominance-popularity status, behavior, and the emergence of sexual activity in young adolescents. AB - In this paper, we investigated the sexual activity levels of several subtypes of middle adolescents (age 14-15 years). The subtype profiles were based on dominance-popularity status and a range of behaviors associated with dominance and popularity. In addition, gender differences in behavioral profiles were examined among dominant-popular, sexually active young adolescents. Results showed that socially dominant and popular young adolescent boys who exhibited a highly aggressive profile were more sexually active than their low-status and non aggressive male peers; dominant-popular girls who were very attractive and gossips were more sexually active than their female peers. The results are discussed from an evolutionary psychological framework. PMID- 22947641 TI - Cues to personality and health in the facial appearance of chimpanzees (Pan troglodytes). AB - Humans (Homo sapiens) and chimpanzees (Pan troglodytes) can extract socially relevant information from the static, non-expressive faces of conspecifics. In humans, the face is a valid signal of both personality and health. Recent evidence shows that, like humans, chimpanzee faces also contain personality information, and that humans can accurately judge aspects of chimpanzee personality relating to extraversion from the face alone (Kramer, King, and Ward, 2011). These findings suggest the hypothesis that humans and chimpanzees share a system of personality and facial morphology for signaling socially-relevant traits from the face. We sought to test this hypothesis using a new group of chimpanzees. In two studies, we found that chimpanzee faces contained health information, as well as information of characteristics relating to extraversion, emotional stability, and agreeableness, using average judgments from pairs of individual photographs. In a third study, information relating to extraversion and health was also present in composite images of individual chimpanzees. We therefore replicate and extend previous findings using a new group of chimpanzees and demonstrate two methods for minimizing the variability associated with individual photographs. Our findings support the hypothesis that chimpanzees and humans share a personality signaling system. PMID- 22947643 TI - Birth weight predicts scores on the ADHD self-report scale and attitudes towards casual sex in college men: a short-term life history strategy? AB - Early development can have long-term effects on physiology and behavior. While severe disturbances predictably lead to dysfunction, recent work in humans and animals has led to a growing appreciation for the more subtle ways in which early conditions can modulate behavioral tendencies later in life. Life history theory predicts that early cues signaling a stressful or suboptimal environment might lead an organism to adopt a strategy favoring short-term gains and early reproduction. Fifty college men reported their birth weight, completed the Attention-Deficit/Hyperactivity Disorder (ADHD) Self-Report Scale, and answered a series of questions about their sexual history and attitudes towards short-term sexual encounters. Lower birth weights were associated with higher scores on the ADHD scale (r = -.352; p <= .05) and more favorable attitudes towards casual sex (r = -.456; p <= 0.001). There was a significant interaction between birth weight and casual sex favorability in predicting number of sexual partners (F1,46 = 4.994; p <= .05). This suggests that, although men who are smaller at birth may otherwise be at a disadvantage in reproductive terms, they may offset their reduced fitness by being more willing to engage in casual sex. PMID- 22947645 TI - Post-translational modifications induce significant yet not extreme changes to protein structure. AB - MOTIVATION: A number of studies of individual proteins have shown that post translational modifications (PTMs) are associated with structural rearrangements of their target proteins. Although such studies provide critical insights into the mechanics behind the dynamic regulation of protein function, they usually feature examples with relatively large conformational changes. However, with the steady growth of Protein Data Bank (PDB) and available PTM sites, it is now possible to more systematically characterize the role of PTMs as conformational switches. In this study, we ask (1) what is the expected extent of structural change upon PTM, (2) how often are those changes in fact substantial, (3) whether the structural impact is spatially localized or global and (4) whether different PTMs have different signatures. RESULTS: We exploit redundancy in PDB and, using root-mean-square deviation, study the conformational heterogeneity of groups of protein structures corresponding to identical sequences in their unmodified and modified forms. We primarily focus on the two most abundant PTMs in PDB, glycosylation and phosphorylation, but show that acetylation and methylation have similar tendencies. Our results provide evidence that PTMs induce conformational changes at both local and global level. However, the proportion of large changes is unexpectedly small; only 7% of glycosylated and 13% of phosphorylated proteins undergo global changes >2 A. Further analysis suggests that phosphorylation stabilizes protein structure by reducing global conformational heterogeneity by 25%. Overall, these results suggest a subtle but common role of allostery in the mechanisms through which PTMs affect regulatory and signaling pathways. CONTACT: predrag@indiana.edu. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 22947644 TI - Cross-cultural differences and similarities in proneness to shame: an adaptationist and ecological approach. AB - People vary in how easily they feel ashamed, that is, in their shame proneness. According to the information threat theory of shame, variation in shame proneness should, in part, be regulated by features of a person's social ecology. On this view, shame is an emotion program that evolved to mitigate the likelihood or costs of reputation-damaging information spreading to others. In social environments where there are fewer possibilities to form new relationships (i.e., low relational mobility), there are higher costs to damaging or losing existing ones. Therefore, shame proneness toward current relationship partners should increase as perceived relational mobility decreases. In contrast, individuals with whom one has little or no relationship history are easy to replace, and so shame-proneness towards them should not be modulated by relational mobility. We tested these predictions cross-culturally by measuring relational mobility and shame proneness towards friends and strangers in Japan, the United States, and the United Kingdom. Japanese subjects were more shame-prone than their British and American counterparts. Critically, lower relational mobility was associated with greater shame proneness towards friends (but not strangers), and this relationship partially mediated the cultural differences in shame proneness. Shame proneness appears tailored to respond to relevant features of one's social ecology. PMID- 22947646 TI - Pithecellobium dulce mediated extra-cellular green synthesis of larvicidal silver nanoparticles. AB - Present study reports a green chemistry approach for the biological synthesis of silver nanoparticles using the aqueous leaf extract of Pithecellobium dulce, which acts as a reducing and capping agent. It is observed that use of P. dulce leaf extract makes a fast, environmentally benign and convenient method for the synthesis of silver nanoparticles and can reduce silver ions into silver nanoparticles. Silver nanoparticles so prepared have been characterized by UV Vis, FT-IR, X-ray diffraction, atomic force microscopy and scanning electron microscope studies. Furthermore, these nanoparticles show effective larvicidal activity against Culex quinquefasciatus (LC(50)=21.56 mg/L and r(2)=0.995) due to high surface to volume ratio. PMID- 22947647 TI - Molecular dynamics of glycine ions in alanine doped TGS single crystal as probed by polarized laser Raman spectroscopy. AB - Polarized Raman spectra of pure and alanine doped tri-glycine sulfate (TGS) single crystals at 12 K in different scattering geometries are analyzed. Sub species modes due to three crystallographically distinguishable glycine ions G (I), G (II) and G (III) are assigned. It is observed that alanine doping does not change the crystalline field and acts as local perturbation only. The major changes due to doping are observed in the relative intensities of different modes; most of the modes associated with G (I) and SO(4)(2-) ions show reversal behavior in relative intensity at high doping concentration. The observed spectral changes are analyzed in terms of reorientation of G (I) ions with sub species modes of G (II)/ G (III) following the reorientation due to complex hydrogen bonding network. PMID- 22947648 TI - Thiophene-functionalized octupolar triindoles: synthesis and photophysical properties. AB - Two thiophene-functionalized octupolar triindole molecules were synthesized through Suzuki and Sonogashira cross-coupling reactions. Their photophysical and electrochemical properties were explored. The spectroscopic data demonstrate that triindole is an excellent rich electronic central donor for building octupolar optoelectronic molecules and possesses excellent luminescent properties. Thiophenylethynyl substituted triindole compound 3,8,13-tri(2-thiophenylethynyl) 5,10,15-tributyltriindole forms an intermolecular aggregation induced by pi-pi stacking from the rigid coplanar molecular scaffold. The redox curves and results of theoretical calculation imply that the two compounds have low ionization potential and low E(1/2 oxd), which may be originated from the high electronic density of both triindole and thiophene groups. PMID- 22947649 TI - Feasibility and benefits of second-line chemotherapy in advanced biliary tract cancer: a large retrospective study. AB - INTRODUCTION: First-line chemotherapy (CT1) is effective in advanced biliary tract cancer (ABTC). The benefits of second-line chemotherapy (CT2) are unclear. METHODS: We retrospectively studied all patients starting at least one line of chemotherapy for ABTC at our institution between 1991 and 2011. We analysed patient and chemotherapy characteristics in order to: (1) characterise patients eligible for CT2; (2) evaluate the efficacy of CT2. RESULTS: Three hundred and seventy-eight received CT1 and 96 (25%) patients received CT2. Primary tumour location was the gallbladder (29%), intraphepatic (20%), perihilar (16%), distal common bile duct (19%) and ampulla of Vater (14%). Ninety percent had a baseline performance status (PS) of 0-1 prior to CT1. Females (p=0.03), ages <= 60 years (p=0.001) and patients with progression free survival (PFS) >= 6 months following CT1 (p=0.01) were more likely to be offered CT2. Objective response rates and stable disease with CT2 were 9% and 34%, respectively. Median PFS and median overall survival (OS) from the beginning of CT2 were 2.8 and 7.5 months, respectively. Prognostic factors impacting PFS with CT2 were the regimen type (doublet versus monotherapy, p=0.001) and PS<2 (p<0.0001). CONCLUSIONS: Among patients with ABTC, 25% received CT2, typically younger patients and those with longer PFS following CT1. Disease control occurred in 43% of patients, and more often with a doublet than a single agent. However, clearly more effective therapies must be found. PMID- 22947650 TI - Morbidity and mortality associated with Clostridium difficile ribotype 078: a case-case study. AB - The morbidity and mortality associated with Clostridium difficile ribotype 078 were examined by comparison with other known outbreak strains. A healthcare interaction within eight weeks of a positive specimen significantly increased the likelihood of ribotype 078 compared with ribotype 027. Individuals with ribotype 078 also tended to come from community sources, have a hospital stay post specimen similar to ribotype 027 and a lower 30-day mortality, but these differences were not statistically significant. This study generates several hypotheses and a methodological platform to explore this unique profile. PMID- 22947652 TI - Polyarteritis nodosa in a 9-year-old boy. PMID- 22947651 TI - Longitudinal evaluation of sleep-disordered breathing in children with Prader Willi Syndrome during 2 years of growth hormone therapy. AB - OBJECTIVE: To review longitudinal polysomnography data to assess sleep-related disordered breathing (SRDB) before and up to 2 years after initiation of growth hormone (GH) therapy in children with Prader-Willi syndrome (PWS). STUDY DESIGN: This was a retrospective review of systematic polysomnography evaluations performed in children with PWS before and at 6 weeks, 6 months, 1 year, and 2 years after initiation of GH therapy. RESULTS: A total of 15 children with PWS were reviewed. At baseline, the median age was 3.7 years (range, 0.8-15.4 years), and the median body mass index percentile was 82.4 (range, 0-100). GH was discontinued in 2 of these 15 children owing to the occurrence of severe obstructive sleep apnea after 6 weeks of GH therapy. The remaining 13 children who were followed for up to 2 years on GH therapy demonstrated no statistically significant trends over time for any adverse sleep-related outcomes, specifically obstructive or central sleep apnea. CONCLUSION: In young children with PWS with known SRDB at baseline, the first few weeks after initiation of GH therapy may represent a vulnerable time for the development of significant SRDB. However, most children with PWS did not show significant changes in SRDB after 2 years of GH therapy. We conclude that long-term GH therapy appears to be safe after an initial period of increased risk in the context of SRDB in children with PWS. PMID- 22947653 TI - Intracranial hemorrhage and a white blood cell count of almost 1 million cells/MUL. PMID- 22947654 TI - Gestational age at birth and risk of autism spectrum disorders in Alberta, Canada. AB - OBJECTIVE: To examine the association between autism spectrum disorders (ASD) and each completed week of gestation using a graphical method of presenting results at all possible categorizations of gestational age (GA). STUDY DESIGN: The risk of ASD in a total of 218110 singleton live births with complete data from Alberta, Canada between 1998 and 2004 was examined through linkage to health insurance records. The relative risk of developing ASD according to the 21 dichotomizations of shorter gestation (GA <= 23 weeks vs >23 weeks to <= 43 weeks vs >43 weeks, in 1-week increments) was calculated using log-binomial regression and adjusted for fetal sex, socioeconomic status, and birth year. RESULTS: We observed a gradual increased risk of ASD with shorter gestation. Cutoffs only between 29 and 40 weeks clearly denoted an elevated risk of developing ASD compared with longer gestation, and the risk increased with earlier GA cutoff. The results were not affected by sex or measures of fetal growth. CONCLUSION: Our data confirm the role of shortened gestation in ASD risk. We warn against the use of prespecified or a data-driven GA cutoff, however; instead, we recommend systematically examining all plausible cutoffs for GA to avoid overstating the homogeneity of risk in children on either side of a given cutoff, as well as to increase the comparability of studies. PMID- 22947657 TI - Whole blood genome-wide gene expression profile in males after prolonged wakefulness and sleep recovery. AB - Although the specific functions of sleep have not been completely elucidated, the literature has suggested that sleep is essential for proper homeostasis. Sleep loss is associated with changes in behavioral, neurochemical, cellular, and metabolic function as well as impaired immune response. Using high-resolution microarrays we evaluated the gene expression profiles of healthy male volunteers who underwent 60 h of prolonged wakefulness (PW) followed by 12 h of sleep recovery (SR). Peripheral whole blood was collected at 8 am in the morning before the initiation of PW (Baseline), after the second night of PW, and one night after SR. We identified over 500 genes that were differentially expressed. Notably, these genes were related to DNA damage and repair and stress response, as well as diverse immune system responses, such as natural killer pathways including killer cell lectin-like receptors family, as well as granzymes and T cell receptors, which play important roles in host defense. These results support the idea that sleep loss can lead to alterations in molecular processes that result in perturbation of cellular immunity, induction of inflammatory responses, and homeostatic imbalance. Moreover, expression of multiple genes was downregulated following PW and upregulated after SR compared with PW, suggesting an attempt of the body to re-establish internal homeostasis. In silico validation of alterations in the expression of CETN3, DNAJC, and CEACAM genes confirmed previous findings related to the molecular effects of sleep deprivation. Thus, the present findings confirm that the effects of sleep loss are not restricted to the brain and can occur intensely in peripheral tissues. PMID- 22947660 TI - Situated peer coaching and unfolding cases in the fundamentals skills laboratory. AB - Using unfolding case studies and situated peer coaching for the Fundamentals Skills Laboratory provides students with individualized feedback and creates a realistic clinical learning experience. A quasi-experimental design with pre- and post-intervention data was used to evaluate changes in student ratings of the course. An instrument was used to examine students' self-ratings and student comments about each lab. We found that students' ratings of the lab remained high with the new method and self-evaluations of their performance were higher as the semester progressed. Students appreciated the personalized feedback associated with peer coaching and demonstrated strong motivation and self-regulation in learning. By participating in unfolding case studies with situated peer coaching, students focus on safety issues, practice collaborative communication, and critical thinking in addition to performing psychomotor skills. PMID- 22947655 TI - If the skull fits: magnetic resonance imaging and microcomputed tomography for combined analysis of brain and skull phenotypes in the mouse. AB - The mammalian brain and skull develop concurrently in a coordinated manner, consistently producing a brain and skull that fit tightly together. It is common that abnormalities in one are associated with related abnormalities in the other. However, this is not always the case. A complete characterization of the relationship between brain and skull phenotypes is necessary to understand the mechanisms that cause them to be coordinated or divergent and to provide perspective on the potential diagnostic or prognostic significance of brain and skull phenotypes. We demonstrate the combined use of magnetic resonance imaging and microcomputed tomography for analysis of brain and skull phenotypes in the mouse. Co-registration of brain and skull images allows comparison of the relationship between phenotypes in the brain and those in the skull. We observe a close fit between the brain and skull of two genetic mouse models that both show abnormal brain and skull phenotypes. Application of these three-dimensional image analyses in a broader range of mouse mutants will provide a map of the relationships between brain and skull phenotypes generally and allow characterization of patterns of similarities and differences. PMID- 22947656 TI - Fine-mapping diabetes-related traits, including insulin resistance, in heterogeneous stock rats. AB - Type 2 diabetes (T2D) is a disease of relative insulin deficiency resulting from both insulin resistance and beta cell failure. We have previously used heterogeneous stock (HS) rats to fine-map a locus for glucose tolerance. We show here that glucose intolerance in the founder strains of the HS colony is mediated by different mechanisms: insulin resistance in WKY and an insulin secretion defect in ACI, and we demonstrate a high degree of variability for measures of insulin resistance and insulin secretion in HS rats. As such, our goal was to use HS rats to fine-map several diabetes-related traits within a region on rat chromosome 1. We measured blood glucose and plasma insulin levels after a glucose tolerance test in 782 male HS rats. Using 97 SSLP markers, we genotyped a 68 Mb region on rat chromosome 1 previously implicated in glucose and insulin regulation. We used linkage disequilibrium mapping by mixed model regression with inferred descent to identify a region from 198.85 to 205.9 that contains one or more quantitative trait loci (QTL) for fasting insulin and a measure of insulin resistance, the quantitative insulin sensitivity check index. This region also encompasses loci identified for fasting glucose and Insulin_AUC (area under the curve). A separate <3 Mb QTL was identified for body weight. Using a novel penalized regression method we then estimated effects of alternative haplotype pairings under each locus. These studies highlight the utility of HS rats for fine-mapping genetic loci involved in the underlying causes of T2D. PMID- 22947661 TI - Evaluation of the use of simulation with student midwives in Zambia. AB - The largest health discrepancy in the world is maternal mortality with most deaths occurring around the labor, delivery and postpartum period. The presence of skilled birth attendants such as qualified midwives is a leading factor in averting death and disability. This study evaluated the use of simulation with midwifery students in Zambia using a pre and post test quasi experimental design measuring confidence, satisfaction with learning, and knowledge between students who experienced simulation and those who had traditional instruction. A total of 34 students participated in the study. There were no statistical differences between mean scores on knowledge or confidence measures. Students who participated in simulation were more satisfied with learning than those who did not (p = .03). This pilot study provided data on the process of implementing simulation with midwifery students in a low resourced setting and area's for improvement for it to be an effective teaching method. PMID- 22947663 TI - Phosphodiesterase 2 inhibitors promote axonal outgrowth in organotypic slice co cultures. AB - The development of appropriate models assessing the potential of substances for regeneration of neuronal circuits is of great importance. Here, we present procedures to analyze effects of substances on fiber outgrowth based on organotypic slice co-cultures of the nigrostriatal dopaminergic system in combination with biocytin tracing and tyrosine hydroxylase labeling and subsequent automated image quantification. Selected phosphodiesterase inhibitors (PDE-Is) were studied to identify their potential growth-promoting capacities. Immunohistochemical methods were used to visualize developing fibers in the border region between ventral tegmental area/substantia nigra co-cultivated with the striatum as well as the cellular expression of PDE2A and PDE10. The quantification shows a significant increase of fiber density in the border region induced by PDE2-Is (BAY60-7550; ND7001), comparable with the potential of the nerve growth factor and in contrast to PDE10-I (MP-10). Analysis of tyrosine hydroxylase-positive fibers indicated a significant increase after treatment with BAY60-7550 and nerve growth factor in relation to dimethyl sulfoxide. Additionally, a dose-dependent increase of intracellular cGMP levels in response to the applied PDE2-Is in PDE2-transfected HEK293 cells was found. In summary, our findings show that PDE2-Is are able to significantly promote axonal outgrowth in organotypic slice co-cultures, which are a suitable model to assess growth related effects in neuro(re)generation. PMID- 22947664 TI - Comparing the effects of dispersed Stone-Thrower-Wales defects and double vacancies on the thermal conductivity of graphene nanoribbons. AB - Classical molecular dynamics with the AIREBO potential is used to investigate and compare the thermal conductivity of both zigzag and armchair graphene nanoribbons possessing various densities of Stone-Thrower-Wales (STW) and double vacancy defects, within a temperature range of 100-600 K. Our results indicate that the presence of both kinds of defects can decrease the thermal conductivity by more than 80% as defect densities are increased to 10% coverage, with the decrease at high defect densities being significantly higher in zigzag compared with armchair nanoribbons. Variations of thermal conductivity in armchair nanoribbons were similar for both kinds of defects, whereas double vacancies in the zigzag nanoribbons led to more significant decreases in thermal conductivity than STW defects. The same trends are observed across the entire temperature range tested. PMID- 22947662 TI - Minimally invasive injectable short nanofibers of poly(glycerol sebacate) for cardiac tissue engineering. AB - Myocardial tissue lacks the ability to appreciably regenerate itself following myocardial infarction (MI) which ultimately results in heart failure. Current therapies can only retard the progression of disease and hence tissue engineering strategies are required to facilitate the engineering of a suitable biomaterial to repair MI. The aim of this study was to investigate the in vitro properties of an injectable biomaterial for the regeneration of infarcted myocardium. Fabrication of core/shell fibers was by co-axial electrospinning, with poly(glycerol sebacate) (PGS) as core material and poly-L-lactic acid (PLLA) as shell material. The PLLA was removed by treatment of the PGS/PLLA core/shell fibers with DCM:hexane (2:1) to obtain PGS short fibers. These PGS short fibers offer the advantage of providing a minimally invasive injectable technique for the regeneration of infarcted myocardium. The scaffolds were characterized by SEM, FTIR and contact angle and cell-scaffold interactions using cardiomyocytes. The results showed that the cardiac marker proteins actinin, troponin, myosin heavy chain and connexin 43 were expressed more on short PGS fibers compared to PLLA nanofibers. We hypothesized that the injection of cells along with short PGS fibers would increase cell transplant retention and survival within the infarct, compared to the standard cell injection system. PMID- 22947665 TI - Alzheimer's disease diagnostic criteria: practical applications. AB - Alzheimer's disease (AD) can be identified prior to the occurrence of dementia by using biomarkers. Three phases of AD are recognized: an asymptomatic biomarker positive phase, a phase with positive biomarkers and mild cognitive deficits, and a dementia phase. Codification of these phases was first accomplished in 2007 by an International Work Group (IWG) led by Bruno Dubois. The definitions relevant to the approach were further clarified in 2010. In 2011, the National Institute on Aging/Alzheimer's Association (NIA/AA) established three work groups to develop definitions and criteria for these three phases of AD. The criteria of the IWG and those of the NIA/AA have many similarities and important differences. The two sets of criteria concur in recognizing the onset of AD prior to dementia. The three phases of AD described in both sets of criteria embrace the same clinical entities but with different terminologies and emphases. IWG criteria emphasize a single clinico-biological approach that includes all symptomatic phases of AD and uses the same diagnostic framework across the spectrum of symptomatic disease; the NIA/AA criteria apply different diagnostic approaches to the three phases. Biomarkers are an integrated and required part of the IWG criteria and are optional in the NIA/AA approach. Both sets of criteria have substantial strengths, but new information demonstrates shortcomings that can be addressed in future revisions of the criteria. These new criteria have profound implications, including greatly increasing the number of people identified as suffering from AD and increasing the time that patients will spend with knowledge of the presence of the disease. PMID- 22947667 TI - Second-trimester uterine artery Doppler in the prediction of stillbirths. AB - OBJECTIVE: To examine the role of second-trimester uterine artery Doppler in the prediction of stillbirths. METHODS: Uterine artery pulsatility index (PI) was measured at 20-24 weeks' gestation in 65,819 singleton pregnancies. The PI was converted to multiples of median (MoM) and compared in live births and stillbirths. Regression analysis was used to determine the significance of association between log(10) uterine artery PI MoM and gestational age (GA) at delivery in cases of stillbirths. RESULTS: There were 306 (0.46%) stillbirths and in 159 (52.0%) of these there was pre-eclampsia (PE), placental abruption and/or birthweight below the 10th percentile (small for gestational age, SGA). In the stillbirths, the uterine artery PI MoM was significantly higher than in live births and was inversely associated with GA at delivery. The uterine artery PI MoM was above the 90th percentile in 80.6% of stillbirths with PE, abruption and/or SGA delivering at <32 weeks' gestation, in 41.9% at 33-36 weeks and in 34.3% at >=37 weeks, and the respective percentages for stillbirths without PE, abruption or SGA were 15.8, 25.0 and 12.4%. CONCLUSION: Second-trimester uterine artery PI is effective in identifying early stillbirths in association with PE, abruption or SGA but not late deaths in the absence of PE, abruption or SGA. PMID- 22947666 TI - Enamel pits in hamster molars, formed by a single high fluoride dose, are associated with a perturbation of transitional stage ameloblasts. AB - Excessive intake of fluoride (F) by young children results in the formation of enamel subsurface porosities and pits, called enamel fluorosis. In this study, we used a single high dose of F administered to hamster pups to determine the stage of ameloblasts most affected by F and whether pit formation was related to F related sub-ameloblastic cyst formation. Hamster pups received a single subcutaneous injection of either 20 mg or 40 mg NaF/kg body weight, were sacrificed 24 h later, and the number of cysts formed in the first molars were counted. Other pups were sacrificed 8 days after F injection, when the first molars had just erupted, to score for enamel defects. All F-injected pups formed enamel defects in the upper half of the cusps in a dose-dependent way. After injection of 20 mg NaF/kg, an average of 2.5 white spots per molar was found but no pits. At 40 mg NaF/kg, almost 4.5 spots per molar were counted as well as 2 pits per molar. The defects in erupted enamel were located in the upper half of the cusps, sites where cysts had formed at the transition stage of ameloblast differentiation. These results suggest that transitional ameloblasts, located between secretory- and maturation-stage ameloblasts, are most sensitive to the effects of a single high dose of F. F-induced cysts formed earlier at the pre secretory stage were not correlated to either white spots or enamel pits, suggesting that damaged ameloblasts overlying a F-induced cyst regenerate and continue to form enamel. PMID- 22947668 TI - Smiles as signals of lower status in football players and fashion models: evidence that smiles are associated with lower dominance and lower prestige. AB - Across four studies, the current paper demonstrates that smiles are associated with lower social status. Moreover, the association between smiles and lower status appears in the psychology of observers and generalizes across two forms of status: prestige and dominance. In the first study, faces of fashion models representing less prestigious apparel brands were found to be more similar to a canonical smile display than the faces of models representing more prestigious apparel brands. In a second study, after being experimentally primed with either high or low prestige fashion narratives, participants in the low prestige condition were more likely to perceive smiles in a series of photographs depicting smiling and non-smiling faces. A third study of football player photographs revealed that the faces of less dominant (smaller) football players were more similar to the canonical smile display than the faces of their physically larger counterparts. Using the same football player photographs, a fourth study found that smiling was a more reliable indicator of perceived status relevant personality traits than perceptions of the football players' physical sizes inferred from the photographs. PMID- 22947669 TI - What have you done for me lately? Friendship-selection in the shadow of the Dark Triad traits. AB - The current studies examined how the Dark Triad personality traits (i.e., Machiavellianism, narcissism, and psychopathy) facilitate the strategic structuring of an individual's social environment in terms of same- and opposite sex friends. In one study using normative questions (N = 267) and another using a budget-allocation task (N = 114), we found that the Dark Triad traits were associated with choosing friends for strategic purposes and to create a volatile environment. Narcissistic individuals reported relatively more reasons to form friendships, such as shared interests, makes me feel good, and intelligence. Women high in narcissism chose same-sex friends who were attractive and women high on Machiavellianism chose same-sex friends who have social status. Men high on psychopathy devalued traits associated with good social relationships in favor of friends who could facilitate their mating efforts and to offset risks incurred in their life history strategy. Results are discussed using the selection manipulation-evocation framework for explaining how personality traits interact with social environments and integrated with findings from evolutionary biology. PMID- 22947670 TI - Sex differences in relationship regret: the role of perceived mate characteristics. AB - The current set of studies examined regret involving action and inaction in the realm of romantic relationships by testing whether such regret is associated with the characteristics of one's mate. In study 1, 394 participants reported on a previous casual sexual encounter, and in study 2, 358 participants reported on a previous romantic relationship. In both, instances of actual engagement and instances of passing up opportunities were studied. Study 3 was experimental and elicited reactions to hypothetical scenarios from 201 participants. Regret reported by men in both study 1 and study 2 varied as a function of the perceived attractiveness of the participants' actual and potential mate. Regret reported by women in study 2 varied as a function of the perceived stinginess of the participant's mate and perceived wealth of the participants' potential mate. Study 3 found that sex differences in type of regret (with men regretting inaction more than women) occurred only when the mate presented in the scenario was described in ways consistent with mate preferences. Together these findings suggest that regret differs between the sexes in ways consistent with sex differences in mate preferences. PMID- 22947672 TI - From one extreme to the other: negative evaluation anxiety and disordered eating as candidates for the extreme female brain. AB - Simon Baron-Cohen pioneered the idea that different brain types evolved to process information in gender specific ways. Here we expand this approach to looking at eating disorders as a byproduct of the extreme female brain. The incidence of eating disorders is higher among females, and recent findings show that hormones may play a role in eating disorders. We present new evidence from four studies that both an empathizing bias and hyper-mentalizing (as measures of the extreme female brain; EFB) are related to disordered eating and negative evaluation anxiety in women. We also advance the novel hypothesis that concerns about animal welfare (a unique expression of the EFB) may account for the relationship between vegetarianism and eating disorders. PMID- 22947673 TI - A reproductive threat-based model of evolved sex differences in jealousy. AB - Although heterosexual women and men consistently demonstrate sex differences in jealousy, these differences disappear among lesbians and gay men as well as among heterosexual women and men contemplating same-sex infidelities (infidelities in which the partner and rival are the same sex). Synthesizing these past findings, the present paper offers a reproductive threat-based model of evolved sex differences in jealousy that predicts that the sexes will differ only when the jealous perceivers' reproductive outcomes are differentially at risk. This model is supported by data from a web-based study in which lesbians, gay men, bisexual women and men, and heterosexual women and men responded to a hypothetical infidelity scenario with the sex of the rival randomly determined. After reading the scenario, participants indicated which type of infidelity (sexual versus emotional) would cause greater distress. Consistent with predictions, heterosexual women and men showed a sex difference when contemplating opposite sex infidelities but not when contemplating same-sex infidelities, whereas lesbians and gay men showed no sex difference regardless of whether the infidelity was opposite-sex or same-sex. PMID- 22947674 TI - Sexual selection under parental choice: evidence from sixteen historical societies. AB - Asymmetrical fitness benefits between parents and offspring result in the ideal spouse not being the ideal in-law. This enables parents to attempt to control the mating behavior of their children, and when they succeed, parental choice becomes a primary sexual selection force. A number of studies indicate that parental choice is dominant in contemporary pre-industrial societies. This paper presents evidence from the historical record which indicates that parental choice was also dominant during the later stages of human evolution. More specifically, 40 variables have been coded for a sample of 16 historical societies. Consistent with the model of parental choice, it is found that mating is controlled by parents, male parents exercise more control over marriage arrangements than females, and more control is exercised over female than male offspring. Finally, the specific qualities that parents desire in an in-law and offspring desire in a spouse have also been identified. The implications of these findings are discussed. PMID- 22947675 TI - Adult learners in a novel environment use prestige-biased social learning. AB - Social learning (learning from others) is evolutionarily adaptive under a wide range of conditions and is a long-standing area of interest across the social and biological sciences. One social-learning mechanism derived from cultural evolutionary theory is prestige bias, which allows a learner in a novel environment to quickly and inexpensively gather information as to the potentially best teachers, thus maximizing his or her chances of acquiring adaptive behavior. Learners provide deference to high-status individuals in order to ingratiate themselves with, and gain extended exposure to, that individual. We examined prestige-biased social transmission in a laboratory experiment in which participants designed arrowheads and attempted to maximize hunting success, measured in caloric return. Our main findings are that (1) participants preferentially learned from prestigious models (defined as those models at whom others spent longer times looking), and (2) prestige information and success related information were used to the same degree, even though the former was less useful in this experiment than the latter. We also found that (3) participants were most likely to use social learning over individual (asocial) learning when they were performing poorly, in line with previous experiments, and (4) prestige information was not used more often following environmental shifts, contrary to predictions. These results support previous discussions of the key role that prestige-biased transmission plays in social learning. PMID- 22947677 TI - The impact of premature childbirth on parental bonding. AB - The development of an affectionate parent-infant bond is essential for a newborn infant's survival and development. However, from evolutionary theory it can be derived that parental bonding is not an automatic process, but dependent on infants' cues to reproductive potential and parents' access to resources. The purpose of the present study was to examine the process of bonding in a sample of Dutch mothers (n = 200) and fathers (n = 193) of full-term (n = 69), moderately premature (n = 68), and very premature infants (n = 63). During the first month postpartum parents completed the Pictorial Representation of Attachment Measure (PRAM) and Postpartum Bonding Questionnaire (PBQ). Longitudinal analyses revealed that mothers' PRAM scores decreased after moderately preterm delivery, whereas decreases in PRAM scores occurred in both parents after very preterm delivery. As lower PRAM scores represent stronger feelings of parent-infant connectedness, our findings suggest a higher degree of bonding after premature childbirth. Results of the PBQ analysis were in line with PRAM outcomes, as parents of preterm infants reported less bonding problems compared to parents of full-terms. These findings support the hypothesis that in affluent countries with adequate resources, bonding in parents of preterm infants on average may be higher than in parents of full-term infants. PMID- 22947678 TI - Redness enhances perceived aggression, dominance and attractiveness in men's faces. AB - In a range of non-human primate, bird and fish species, the intensity of red coloration in males is associated with social dominance, testosterone levels and mate selection. In humans too, skin redness is associated with health, but it is not known whether--as in non-human species--it is also associated with dominance and links to attractiveness have not been thoroughly investigated. Here we allow female participants to manipulate the CIELab a* value (red-green axis) of skin to maximize the perceived aggression, dominance and attractiveness of photographs of men's faces, and make two findings. First, participants increased a* (increasing redness) to enhance each attribute, suggesting that facial redness is perceived as conveying similar information about a male's qualities in humans as it does in non-human species. Second, there were significant differences between trial types: the highest levels of red were associated with aggression, an intermediate level with dominance, and the least with attractiveness. These differences may reflect a trade-off between the benefits of selecting a healthy, dominant partner and the negative consequences of aggression. PMID- 22947679 TI - Social exclusion and female mating behavior: rejected women show strategic enhancement of short-term mating interest. AB - Because cost asymmetries in sexual reproduction have historically enabled women to exchange sexual access for other resources, including social resources, we tested the possibility that social exclusion would lead women to display an elevated preference for short-term mating strategies in the service of reaffiliation. In Study 1, women were given false feedback to manipulate social inclusion or exclusion prior to indicating their endorsement of short and long term mating behaviors. Socially excluded women indicated greater interest in short-term mating and reduced interest in long-term mating. In Study 2, women wrote about a social inclusion, social exclusion, or control experience and then indicated their preference for different male body types. Women in the social exclusion condition preferred more muscular male partners--a pattern of preference typical of short-term mating--than women in the other conditions. Collectively, these results are consistent with a social exchange theory of women's sexual behavior following social exclusion. PMID- 22947680 TI - High and mighty: height increases authority in professional refereeing. AB - Throughout the animal kingdom, larger males are more likely to attain social dominance. Several lines of evidence suggest that this relationship extends to humans, as height is positively related to dominance, status and authority. We hypothesized that height is also a determinant of authority in professional refereeing. According to the International Football Association Board, FIFA, football ("soccer") referees have full authority to enforce the laws of the game and should use their body language to show authority and to help control the match. We show that height is indeed positively related to authority status: referees were taller than their assistants (who merely have an advisory role) in both a national (French League) and an international (World Cup 2010) tournament. Furthermore, using data from the German League, we found that height was positively associated with authoritative behavior. Taller referees were better able to maintain control of the game by giving fewer fouls, thereby increasing the "flow of the game". Referee height was also positively associated with perceived referee competence, as taller referees were assigned to matches in which the visiting team had a higher ranking. Thus, height appears to be positively related to authority in professional refereeing. PMID- 22947681 TI - Artificial natural selection: can supplemental feeding domesticate mosquitoes and control mosquito-borne diseases? AB - A new method is proposed for controlling mosquito-borne diseases. In particular, instead of trying to kill mosquitoes, we suggest provisioning them with food from artificial feeders. Because mosquito populations are frequently limited by ecological factors other than blood meals, such as the availability of egg-laying sites, feeding mosquitoes would not necessarily increase the total number of mosquitoes, but could reduce the number of human-drawn mosquito meals. Like mosquito traps, feeders could divert biting mosquitoes away from people by means of lures, but, after diversion, prevent subsequent human bites by satiating the mosquitoes instead of killing them. Mosquito feeders might reduce the problem of the evolution of resistance to control: in an ecology with mosquito feeders, which provide safe and abundant calories for adult female mosquitoes, there could be selection for preferring (rather than avoiding) feeders, which could eventually lead to a population of feeder-preferring mosquitoes. Artificial feeders also offer the chance to introduce novel elements into the mosquito diet, such as anti- malarial or other anti-parasitic agents. Feeders might directly reduce human bites and harnesses the power of natural selection by selectively favoring feeder-preferring (rather than trap-resistant) mosquitoes. PMID- 22947684 TI - Sexual imprinting on facial traits of opposite-sex parents in humans. AB - Positive sexual imprinting is a process by which individuals use the phenotype of their opposite-sex parent as a template for acquiring mates. Recent studies in humans have concluded that an imprinting-like mechanism influences human mate choice in facial traits. However, some of the previous studies have had methodological problems or flaws which might have invalidated or led to an overgeneralization of the original interpretation of their results. In this study, 70 heterosexual adults were used to test if their partners resembled facially their opposite-sex parent as the sexual imprinting hypothesis predicts. Judges assessed the subjective facial similarity between each participant's partner and their parent. We found that there was no perceived facial similarity between women's partners and their fathers. However, men tended to pair more often with women that were perceived as resembling the men's own mothers. In contrast to previous studies, the quality of the relationship between participants and their parents did not predict the level of facial resemblance between the participant's spouse and their parent. PMID- 22947685 TI - The prevalence and triage characteristics of patients presenting with infection to one tertiary referral hospital. AB - BACKGROUND: Globally, severe infection and or sepsis is a problem that is costing billions of dollars, using hundreds of hospital beds, and often results in patient death. Any infection can potentially develop a sepsis health trajectory if left unrecognised and unmanaged. METHODS: We conducted a 12 month retrospective descriptive exploratory study. Our research explored the prevalence and triage characteristics of patients presenting with infection to one tertiary referral hospital. Electronic medical records were reviewed to identify patients that had a primary diagnosis related to infection. RESULTS: The study identified that 16% (n=7756) of adult presentations had a discharge diagnosis related to infection. A significant difference (X(2)=297.83, df=4, p<=.001) in Triage Code allocation for the infection group was identified compared with the non-infection patient group. Thirty-nine percent (n=3027) of patients with infections were admitted to hospital. Of the patients (n=1930; 4%) admitted to a critical care area, 6% (n=122) had a primary diagnosis related to infection. Of the ED deaths (n=81), 12% (n=10) had a primary diagnosis related to infection. CONCLUSION: The study provides a detailed analysis of the prevalence and triage characteristics of patients with infection presenting to one ED. Further research is needed to identify strategies to improve the triage nurse's recognition of severe infection and consistency of urgency code allocation to prevent patient deterioration. PMID- 22947686 TI - Improving pain management of abdominal pain in children presenting to the paediatric emergency department: a pre-post interventional study. AB - BACKGROUND: In 2007, the Mater Children's Hospital Emergency Department participated in the Emergency Care Pain Management Initiative funded by the National Health and Medical Research Council National Institute of Clinical Studies (NHMRC-NICS). The findings of this NHMRC-NICS research across eleven paediatric emergency departments highlighted deficits in pain management of abdominal pain. Specifically pain assessment, timeliness of analgesia, and pain management guidelines were found to be lacking. METHODS: In response to the NICS report local practice was reviewed and a pilot research project undertaken to develop a clinical guideline for the pain management of abdominal pain in children presenting to the emergency department. The guideline was developed by an expert panel and trialled using a pre and post intervention design. RESULTS: The results demonstrated improved compliance to assessment and documentation of pain scores and assimilation of the best practice principles recommended in the guideline. CONCLUSIONS: This project raised local awareness in the pain management of abdominal pain and provides baseline information for future improvement. The guideline has been trialled in the clinical setting of paediatric emergency and has the potential to improve pain management practices in children presenting to the emergency department with abdominal pain. PMID- 22947687 TI - Managing people with mental health presentations in emergency departments--a service exploration of the issues surrounding responsiveness from a mental health care consumer and carer perspective. AB - Mainstreaming of mental health services (MHS) within the Australian medical system has generated a fundamental transformation in the way consumers and carers access emergency MHS. People present to the Emergency Department (ED) with many health issues which can often include the management of their mental illness, physical co morbidity, or substance use. This paper discusses the issues surrounding access to EDs for clients, families and staff in the context of presentations for mental health problems at a southern metropolitan hospital in Victoria. The pilot project utilised focus groups with mental health care consumers and carers to collaboratively focus on and document the mental health client's 'journey of care' in the ED. There is evidence to suggest from this project that the ED mental health client journey needs continuous improvement and evaluation. PMID- 22947688 TI - Beyond a clinical role: nurses were psychosocial supporters, coordinators and problem solvers in the Black Saturday and Victorian bushfires in 2009. AB - AIM: This research explores the roles of nurses that participated in the Black Saturday and Victorian bushfires in February 2009, including aspects that influence nurses' roles, such as prior education, training and availability of resources. BACKGROUND: It is acknowledged that nurses play an important role in disaster response and recovery. However, our understanding of nurses' roles is superficial and commonly based on descriptions of events in which specifics relating to the nurses' roles are embedded within other topics or issues. Similarly, aspects that support nurses in the disaster environment, including previous experience, education and the provision of resources, are not well understood. METHOD: Single, semi-structured telephone interviews were conducted with 11 volunteer nursing members of St John Ambulance Australia. These interviews were electronically recorded, transcribed verbatim and thematically analysed using a well-recognised human science approach. FINDINGS: The thematic analysis identified two broad themes: being prepared and having an expansive role. Participants indicated that they were educationally prepared and had adequate clinical experience. They outlined that they took many resources with them; however, they were used very little, as their role consisted of minimal clinical care. Additionally, nurses performed roles including a psychosocial supporter, a coordinator of care and resources, and problem solvers. CONCLUSIONS: The nurses' role in providing health care during and/or following a disaster is more than a clinical care role. This understanding should be applied to the development of education programs, competencies and policies, with a particular focus on contextualising the education to the realities of possible disastrous scenarios that incorporates elements of coordination, problem solving and psychosocial care within a national framework. Additionally, this awareness education should be used to inform nurses about the realities of working in disaster environments. PMID- 22947689 TI - Out-hospital donors after cardiac death in Madrid, Spain: a 5-year review. AB - OBJECTIVE: The Medical Emergencies Service of Madrid (Spain) (Servicio de Urgencias Medicas de Madrid), SUMMA112, forms part of an organ donor program involving patients who have suffered out-hospital cardiac arrest and fail to respond to advanced cardiopulmonary resuscitation maneuvers. Subjects meeting the inclusion criteria are moved to a transplant unit under sustained resuscitation maneuvering in order to harvest the organs. This paper presents compliance with the timelines of the program, the proportion of donors, the characteristics of donors and non-donors, and the number of organs obtained. MATERIAL: A retrospective descriptive study was made based on the review of case histories. The SPSS((c)) version 16.0 statistical package was used for data analysis. RESULTS: A total of 214 cases were recorded, of which 84% were males. The mean age was 40 years. The mean time to arrival on scene was 13 min and 34 s. The mean time to arrival in hospital was 88 min and 10 s. A total of 522 organs and tissues were harvested (250 kidneys, 33 livers, 123 corneas, 97 bone tissues and 19 lungs), corresponding to 3.2 organs/tissues per patient on average. A total of 21.7% of the patients were not valid. There were no differences between the valid and non-valid patients in terms of age and gender. The causes of non-donation included extracorporeal circuit failure (6.3%), family refusal (15.6%), patient refusal expressed in life (4.7%), legal denial (1.6%), biological causes (51.6%), and others (20.3%). Cardiac compressors were used in 85 cases, yielding 92 kidneys, 41 corneas, 30 bone tissues, 19 livers and 9 lungs, corresponding to 2.1 organs/tissues per patient on average. CONCLUSION: This program affords a very important number of organs for transplantation. Further studies are needed to assess the efficacy of mechanical cardiac compressor use in generating more organs. PMID- 22947690 TI - Practical use of the Glasgow Coma Scale; a comprehensive narrative review of GCS methodology. AB - OBJECTIVE: Narrative review of Glasgow Coma Scale (GCS) methodology. DESIGN: Narrative review of published papers describing methodological aspects of the GCS, from Premedline, Medline, EMBASE, CINAHL and Ovid Nursing databases from 1950 to May 2012. RESULTS: Examination of 18,851 references limited to descriptions of GCS development, pathophysiological correlations, examination techniques, complications or clinician agreement gave a final set of 33, which were summarised in this review. CONCLUSION: The GCS was designed for the objective measurement of level of consciousness, assessment of trend, and to facilitate accurate and valid communication between clinicians. Concerns have been raised about the potential for misleading levels of precision engendered by the use of the GCS, and the use of simpler scales suggested. This review discusses the GCS and conditions affecting calculation of domain and summary scores, and recommends a method of implementation and interpretation. PMID- 22947691 TI - Reverse transcription loop-mediated isothermal amplification for sensitive and rapid detection of Korean sacbrood virus. AB - Sacbrood virus (SBV) is one of the most serious honeybee viruses. The virus causes failure to pupate and death in both larvae and adult bees. Recently, the Korean sacbrood virus (KSBV) caused great losses in Korean honeybee (Apis cerana) colonies. Although KSBV shows high homology with SBV strains, it has unique motifs and causes different symptoms. Therefore, a simple, sensitive and specific method for detecting KSBV is needed urgently. In this study, a reverse transcription loop-mediated isothermal amplification (RT-LAMP) assay was developed for detecting KSBV using total RNA extracted from honeybees (A. cerana) infected with SBV. The LAMP and the polymerase chain reaction (PCR) methods were then compared for their ability to detect KSBV in clinical samples. The virus was detected in RT-LAMP reactions containing 10(3) copies of pBX-KSBV within 30min, which was comparable to RT-PCR. In addition, the LAMP was able to distinguish between KSBV and other closely-related SBV strains, indicating a high degree of specificity. This simple and sensitive RT-LAMP assay is a useful method for the rapid diagnosis of KSBV infection in honeybees. PMID- 22947692 TI - A reverse transcription loop-mediated isothermal amplification method for rapid detection of bovine viral diarrhea virus. AB - A reverse transcription loop-mediated isothermal amplification (RT-LAMP) assay was developed and optimized to detect bovine viral diarrhea viral (BVDV) RNA. The RT-LAMP assay is highly sensitive and able to detect 4.67*10(0)copies of BVDV RNA. Additionally, the RT-LAMP method is capable of detecting both genotypes of BVDV. No cross-reaction with other bovine viruses was observed. The ability of RT LAMP to detect BVDV RNA from bovine fecal swabs was also evaluated. Of the 88 fecal swabs, 38 were found to be positive by RT-LAMP assay, whereas 39 were positive by real-time RT-PCR. Taken together, the BVDV specific RT-LAMP method is highly specific and sensitive and can be used as a rapid and direct diagnostic assay for testing clinical samples. PMID- 22947693 TI - [Practical features of the pre-analytical phase of the BIOAMBIENT.ES biomonitoring study]. AB - The fieldwork of BIOAMBIENT.ES was developed from March 2009 to July 2010. BIOAMBIENT.ES is a human biomonitoring study of environmental pollutants performed in Spain at the national level. This article aims to show the tasks performed before starting the fieldwork to ensure the quality of the samples and consequently the quality of the results. A total of 1,936 whole blood, serum and first-morning urine samples and 604 hair samples were collected from workers who attended the annual occupational health examination in 38 centers in the Peninsula, Ceuta and the Canary Islands. Before the fieldwork was started, the optimal sampling material and sample shipment was identified and fieldworkers were trained in their tasks. Due to the planning and organization of the pre analytical phase, only 1% of the collected samples had to be rejected due to problem with spills, conservation, etc. In addition, the analyses conducted showed no pre-analytical interferences. PMID- 22947694 TI - Central dopaminergic activity influences metabolic parameters in healthy men. AB - BACKGROUND/AIMS: Central dopaminergic activity is probably linked to regulation of glucose and lipid metabolism and weight maintenance. The aim of our study was to evaluate the relationship between central dopaminergic activity measured using the apomorphine challenge test and metabolic parameters in healthy men. METHODS: Forty-two healthy men (average age 43.5 +/- 7.4 years, body mass index, BMI, 27.4 +/- 5.7) were examined anthropometrically and biochemically (glycemia, lipids, glycated hemoglobin). Central dopaminergic activity was assessed as the area under the curve (AUC) of prolactin (PRL) and growth hormone (GH) responses to the apomorphine challenge test after sublingual administration of apomorphine in a dose of 0.033 mg/kg. Insulin resistance was quantified by calculation of glucose disposal and metabolic clearance rate during a euglycemic hyperinsulinemic clamp on two insulin levels (1 and 10 mIU/kg/min). Linear regression was used for statistical analysis. RESULTS: Hormonal responses correlated negatively with age (for AUC/GH r = -0.33; p = 0.031) and BMI (AUC/GH r = -0.41; p = 0.007). After adjustment for age and BMI, a statistically significant negative correlations between AUC/PRL and total cholesterol (r = -0.41; p = 0.007), AUC/GH and HbA1c (r = -0.37; p = 0.016) and AUC/GH and HOMA (homeostasis model assessment; r = 0.345; p = 0.025) were observed. CONCLUSION: Central dopaminergic activity declines with age and BMI. Higher total cholesterol, glycated hemoglobin and insulin resistance parameters are connected with lower central dopamine tone. PMID- 22947695 TI - Comparative structural and electronic studies of hydrogen interaction with isolated versus ordered silicon nanoribbons grown on Ag(110). AB - We have investigated the geometry and electronic structure of two different types of self-aligned silicon nanoribbons (SiNRs), forming either isolated SiNRs or a self-assembled 5 * 2/5 * 4 grating on an Ag(110) substrate, by scanning tunnelling microscopy and high resolution x-ray photoelectron spectroscopy. At room temperature we further adsorb on these SiNRs either atomic or molecular hydrogen. The hydrogen absorption process and hydrogenation mechanism are similar for isolated or 5 * 2/5 * 4 ordered SiNRs and are not site selective; the main difference arises from the fact that the isolated SiNRs are more easily attacked and destroyed faster. In fact, atomic hydrogen strongly interacts with any Si atoms, modifying their structural and electronic properties, while molecular hydrogen has first to dissociate. Hydrogen finally etches the Si nanoribbons and their complete removal from the Ag(110) surface could eventually be expected. PMID- 22947696 TI - Towards a more complete standardization of mite allergen extracts. PMID- 22947697 TI - Pediatric abdominal CT scans: do it correctly. Better yet, don't do it at all. PMID- 22947698 TI - Association for Academic Surgery presidential address: Toward self-actualization in academic surgery. PMID- 22947699 TI - Osteopontin level correlates with acute cellular renal allograft rejection. AB - BACKGROUND: Osteopontin (OPN) is a potent proinflammatory cytokine that is upregulated in cell-mediated immunity and various inflammatory states of the kidney. However, the relationship between OPN levels plasma/urine and acute renal allograft rejection is still unknown. Therefore, we assessed the relationship between OPN levels in plasma/urine and acute cellular rejection post-renal transplantation. MATERIALS AND METHODS: Clinical data and biologic samples of renal transplant recipients were analyzed retrospectively. Patients with biopsy proved acute cellular rejection (ACR) (n = 22), protocol biopsy-proved non rejection (non-R) (n = 16), and living related donors as healthy control (HC) (n = 10) were involved in this study. OPN level in plasma and urine was detected using the human OPN enzyme-linked immunosorbent assay kit. Type and grade of ACR were diagnosed based on Banff' 03 classification criteria of renal allograft pathology. No prisoners or organs from prisoners were used in this study. RESULTS: Compared with non-R patients and HC, plasma and urine OPN levels in ACR patients were significantly increased (P < 0.05), whereas there was no significant difference between non-R patients and HC (P > 0.05). In ACR patients, plasma OPN level was positively correlated with Banff grading of acute rejection, and a cut-off value of 24.20 ng/mL was further demonstrated a good clinical value in receiver operation characteristic curve. CONCLUSIONS: The data obtained suggested that assessment of OPN levels in plasma and urine, especially in plasma, should be useful in predicting and evaluating the severity of ACR in renal transplant recipients. PMID- 22947700 TI - Metabolomic markers for intestinal ischemia in a mouse model. AB - BACKGROUND: Diagnosis of intestinal ischemia remains a clinical challenge. The aim of the present study was to use a metabolomic protocol to identify upregulated and downregulated small molecules (M(r) < 500) in the serum of mice with intestinal ischemia. Such molecules could have clinical utility when evaluated as biomarkers in human studies. METHODS: A mouse model for intestinal ischemia was established and validated using histology and serum tumor necrosis factor alpha concentrations. A second mouse model of peritoneal sepsis was used as a positive control. Serial serum samples were collected from these and from sham-operated animals. Sera were analyzed by gas chromatography-mass spectrometry for 40 small molecules as their trimethylsilyl and O-methyloxime derivatives. Peak areas were normalized against an internal standard and resultant peak area ratios subjected to multivariate data analysis using unsupervised principal components analysis and supervised orthogonal projection to latent structures discriminant analysis. Upregulated and downregulated serum molecules were identified from their correlation to the orthogonal projection to latent structures-discriminant analysis model. RESULTS: Three highly significantly upregulated (fold-change) serum molecules in intestinal ischemia were inorganic phosphate (2.4), urea (4.3), and threonic acid (2.9). Five highly significantly downregulated (fold-change) serum molecules were stearic acid (1.7), arabinose (2.7), xylose (1.6), glucose (1.4), and ribose (2.2). Lactic acid remained unchanged in intestinal ischemia. CONCLUSIONS: Distinct molecular changes are reported here for the first time in intestinal ischemia. They reveal impairments of gut microbiota metabolism, intestinal absorption, and renal function, together with increased oxidative stress. In contrast to other reports, lactic acid was not significantly changed. These molecular signatures may now be evaluated in clinical studies. PMID- 22947701 TI - Impact of electronic order management on the timeliness of antibiotic administration in critical care patients. AB - OBJECTIVE: To examine the effect of implementing electronic order management on the timely administration of antibiotics to critical-care patients. METHODS: We used a prospective pre-post design, collecting data on first-dose IV antibiotic orders before and after the implementation of an integrated electronic medication management system, which included computerized provider order entry (CPOE), pharmacy order processing and an electronic medication administration record (eMAR). The research was performed in a 24-bed adult medical/surgical ICU in a large, rural, tertiary medical center. Data on the time of ordering, pharmacy processing and administration were prospectively collected and time intervals for each stage and the overall process were calculated. RESULTS: The overall turnaround time from ordering to administration significantly decreased from a median of 100 min before order management implementation to a median of 64 min after implementation. The first part of the medication use process, i.e., from order entry to pharmacy processing, improved significantly whereas no change was observed in the phase from pharmacy processing to medication administration. DISCUSSION: The implementation of an electronic order-management system improved the timeliness of antibiotic administration to critical-care patients. Additional system changes are required to further decrease the turnaround time. PMID- 22947769 TI - Differences in surface marker expression and chondrogenic potential among various tissue-derived mesenchymal cells from elderly patients with osteoarthritis. AB - Mesenchymal stem cells (MSCs) are self-renewing, multipotent cells that could potentially be used to repair injured cartilage in diseases such as osteoarthritis (OA). In this study we used bone marrow, adipose tissue from articular and subcutaneous locations, and synovial fluid samples from 18 patients with knee OA to find a suitable alternative source for the isolation of MSCs with high chondrogenic potential. MSCs from all tissues analysed had a fibroblastic morphology, but their rates of proliferation varied. Subcutaneous fat-derived MSCs proliferated faster than bone marrow- and Hoffa's fat pad-derived MSCs, while synovial fluid-derived MSCs grew more slowly. CD36 and CD54 expression was similar across all groups of MSCs with several minor differences. High expression of these surface markers in subcutaneous fat-derived MSCs was correlated with poor differentiation into hyaline cartilage. Synovial fluid-derived MSCs presented a relatively small chondrogenic differentiation capacity while Hoffa's fat pad-derived MSCs had strong chondrogenic potential. In conclusion, MSCs from elderly patients with OA may still display significant chondrogenic potential, depending on their origin. PMID- 22947770 TI - Immobilization mechanisms of deoxyribonucleic acid (DNA) to hafnium dioxide (HfO2) surfaces for biosensing applications. AB - Immobilization of biomolecular probes to the sensing substrate is a critical step for biosensor fabrication. In this work we investigated the phosphate-dependent, oriented immobilization of DNA to hafnium dioxide surfaces for biosensing applications. Phosphate-dependent immobilization was confirmed on a wide range of hafnium oxide surfaces; however, a second interaction mode was observed on monoclinic hafnium dioxide. On the basis of previous materials studies on these films, DNA immobilization studies, and density functional theory (DFT) modeling, we propose that this secondary interaction is between the exposed nucleobases of single stranded DNA and the surface. The lattice spacing of monoclinic hafnium dioxide matches the base-to-base pitch of DNA. Monoclinic hafnium dioxide is advantageous for nanoelectronic applications, yet because of this secondary DNA immobilization mechanism, it could impede DNA hybridization or cause nonspecific surface intereactions. Nonetheless, DNA immobilization on polycrystalline and amorphous hafnium dioxide is predominately mediated by the terminal phosphate in an oriented manner which is desirable for biosensing applications. PMID- 22947771 TI - alpha-Tocopherol (vitamin E) stimulates cyclic AMP production in human peripheral mononuclear cells and alters immune function. AB - alpha-Tocopherol, the most biologically active member of the vitamin E family of fat soluble compounds, exhibits both antioxidant and anti-inflammatory properties. However, its mechanisms of action are not fully understood. Here, we show that, unlike other antioxidants, alpha-tocopherol stimulates the production of cyclic adenosine monophosphate (cAMP). Inhibitor studies demonstrate that the prostaglandin EP2 and EP4 receptors and adenylyl cyclases mediate the effects of alpha-tocopherol on cAMP production. Additionally, we show that alpha-tocopherol attenuates pro-inflammatory cytokine and chemokine production. This study provides novel evidence that alpha-tocopherol stimulates cAMP signaling, suggesting a mechanism of action for the immunomodulatory effects of vitamin E. PMID- 22947772 TI - Identification and characterization of a novel splice variant of rhesus macaque MHC IA. AB - Major histocompatibility complex class I (MHC I) molecules play a pivotal role in the immune recognition to intracellular pathogens. A number of important splice variants have already been characterized for these molecules in different species, suggesting their important roles in modulation of immune responses. In this study, we have identified and characterized a novel alternatively spliced form of rhesus macaque MHC IA (designated MHC IA-sv2) that lacks exons coding for the alpha2 and alpha3 domains. Despite lacking the alpha2 and alpha3 domains, MHC IA-sv2 is targeted to the cell surface, as a 23-kDa glycoprotein that is totally susceptible to endoglycosidase-H digestion and is reduced to 18kDa after deglycosylation with PNGase F. In contrast, the full-length MHC IA reaches the cell surface as a 43-kDa protein of form with complex-type N-glycosylation (endoglycosidase-H resistant). Moreover, we provide evidence here that MHC IA-sv2 can self-associate, forming homodimers, or associate with the fully mature MHC IA molecule, forming a heterodimeric structure in mammalian cells. These data demonstrate that the formation of heterodimers may have some functional implications in the fine tuning of MHC IA-mediated innate and adaptive immune responses. PMID- 22947773 TI - The use of a free vascularised fibula to reconstruct the radius following the resection of an osteosarcoma in a paediatric patient. AB - Osteosarcoma is the most common high grade bone malignancy in children and the surgical treatment traditionally involves amputation. In our case, a 6-year-old girl was diagnosed with an osteosarcoma of the left distal radius after presenting with forearm pain. After initially being offered an amputation, a second opinion was sought and a limb salvage procedure was offered using a free vascularised fibula bone flap. This resulted in limb preserving surgery which allowed the potential for growth with the maximal preservation of function. PMID- 22947775 TI - Predictors of how often and when people fall in love. AB - A leading theory of romantic love is that it functions to make one feel committed to one's beloved, as well as to signal this commitment to the beloved (Frank, 1988). Because women tend to be skeptical of men's commitment, this view entails that men may have evolved to fall in love first, in order to show their commitment to women. Using a sample of online participants of a broad range of ages, this study tested this sex difference and several related individual difference hypotheses concerning the ease of falling in love. There was mixed evidence for sex differences: only some measures indicated that men are generally more love-prone than are women. We also found that men were more prone to falling in love if they tended to overestimate women's sexual interest and highly valued physical attractiveness in potential partners. Women were more prone to falling in love if they had a stronger sex drive. These results provide modest support for the existence of sex differences in falling in love, as well as initial evidence for links between several individual difference variables and the propensity to fall in love. PMID- 22947778 TI - Altruistic behavior and cooperation: the role of intrinsic expectation when reputational information is incomplete. AB - Altruistic behavior is known to be conditional on the level of altruism of others. However, people often have no information, or incomplete information, about the altruistic reputation of others, for example when the reputation was obtained in a different social or economic context. As a consequence, they have to estimate the other's altruistic intentions. Using an economic game, we showed that without reputational information people have intrinsic expectations about the altruistic behavior of others, which largely explained their own altruistic behavior. This implies that when no information is available, intrinsic expectations can be as powerful a driver of altruistic behavior as actual knowledge about other people's reputation. Two strategies appeared to co-exist in our study population: participants who expected others to be altruistic and acted even more altruistically themselves, while other participants had low expected altruism scores and acted even less altruistically than they expected others to do. We also found evidence that generosity in economic games translates into benefits for other social contexts: a reputation of financial generosity increased the attractiveness of partners in a social cooperative game. This result implies that in situations with incomplete information, the fitness effects of indirect reciprocity are cumulative across different social contexts. PMID- 22947779 TI - Indirect peer aggression in adolescence and reproductive behavior. AB - Evolutionary psychologists have suggested that indirect aggression during adolescence is a strategy to compete with same-sex peer rivals for resources, status, and mating opportunities. We collected survey data on 143 young adults to determine retrospectively, the amount of indirect aggressive behavior they perpetrated and the amount of indirect victimization they experienced in middle school and high school. We also collected information about reproductive opportunities such as age at first sexual intercourse and number of lifetime sex partners to determine whether aggression or victimization could be used to predict measures of reproductive opportunity. We performed a principal components analysis to develop factors from 16 aggression and victimization variables. Results indicate that females who reported indirect aggression toward peers had earlier ages at first sexual intercourse and females who were more victimized in adolescence experienced later ages at first sexual intercourse. We discuss these results in terms of intrasexual competition and evolutionary theory. PMID- 22947780 TI - The role of human body movements in mate selection. AB - It is common scientific knowledge, that most of what we say within a conversation is not only expressed by the words' meaning alone, but also through our gestures, postures, and body movements. This non-verbal mode is possibly rooted firmly in our human evolutionary heritage, and as such, some scientists argue that it serves as a fundamental assessment and expression tool for our inner qualities. Studies of nonverbal communication have established that a universal, culture free, non-verbal sign system exists, that is available to all individuals for negotiating social encounters. Thus, it is not only the kind of gestures and expressions humans use in social communication, but also the way these movements are performed, as this seems to convey key information about an individual's quality. Dance, for example, is a special form of movement, which can be observed in human courtship displays. Recent research suggests that people are sensitive to the variation in dance movements, and that dance performance provides information about an individual's mate quality in terms of health and strength. This article reviews the role of body movement in human non-verbal communication, and highlights its significance in human mate preferences in order to promote future work in this research area within the evolutionary psychology framework. PMID- 22947781 TI - Maternal guilt. AB - The recent emphasis on humans as cooperative breeders invites new research on human family dynamics. In this paper we look at maternal guilt as a consequence of conditional maternal investment. Solicited texts written by Finnish mothers with under school-aged children in 2007 (n = 63) described maternal emotions perceived as difficult and forbidden. Content analysis of guilt-inducing situations showed that guilt arose from diverging interest and negotiations between the mother and child (i.e., classic parent- offspring conflict). Also cultural expectations of extensive and perpetual high-quality maternal investment or the "motherhood myth" induced guilt in mothers. We argue that guilt plays an important role in maternal-investment regulation. Maternal guilt is predicted to vary with social and cultural context but also to show universal characteristics due to parent-offspring conflict and allomaternal manipulation. Results are preliminary and intended to stimulate research into the mechanisms, gender differences and cultural variations of guilt and other social emotions in human parenting. PMID- 22947786 TI - Preachers who are not believers. AB - There are systemic features of contemporary Christianity that create an almost invisible class of non-believing clergy, ensnared in their ministries by a web of obligations, constraints, comforts, and community. Exemplars from five Protestant denominations, Southern Baptist, United Church of Christ, Presbyterian, Methodist and Church of Christ, were found and confidentially interviewed at length about their lives, religious education and indoctrination, aspirations, problems and ways of coping. The in-depth, qualitative interviews formed the basis for profiles of all five, together with general observations about their predicaments and how they got into them. The authors anticipate that the discussion generated on the Web (at On Faith, the Newsweek/Washington Post website on religion, http://newsweek.washingtonpost.com/onfaith//2010/03/disbelief_in_the_pulpit/all.h ml) and on other websites will facilitate a larger study that will enable the insights of this pilot study to be clarified, modified, and expanded. PMID- 22947787 TI - Zoonotic and non-zoonotic diseases in relation to human personality and societal values: support for the parasite-stress model. AB - The parasite-stress model of human sociality proposes that humans' ontogenetic experiences with infectious diseases as well as their evolutionary historical interactions with these diseases exert causal influences on human psychology and social behavior. This model has been supported by cross-national relationships between parasite prevalence and human personality traits, and between parasite prevalence and societal values. Importantly, the parasite-stress model emphasizes the causal role of non-zoonotic parasites (which have the capacity for human-to human transmission), rather than zoonotic parasites (which do not), but previous studies failed to distinguish between these conceptually distinct categories. The present investigation directly tested the differential predictive effects of zoonotic and non-zoonotic (both human-specific and multihost) parasite prevalence on personality traits and societal values. Supporting the parasite-stress model, cross-national differences in personality traits (unrestricted sexuality, extraversion, openness to experiences) and in societal values (individualism, collectivism, gender equality, democratization) are predicted specifically by non zoonotic parasite prevalence. PMID- 22947789 TI - Testosterone fluctuations in young men: the difference between interacting with like and not-like others. AB - The current study investigated young men's testosterone level changes as a result of interacting with other men. Male participants (n = 84) were led to believe that a group they would be interacting with was either similar to them or not similar. The interaction was then one of two types: the other group members were inclusive, or the others excluded the participant during the group interaction. Participants provided saliva samples before and after the interaction. Results suggest that interacting with highly similar men increases circulating testosterone whereas interacting with highly dissimilar men actually lowers testosterone. The nature of the interaction was less important than similarity. Considering that testosterone surges may relate to attempts to gain status within one's group, the results are interpreted as consistent with viewing hormonal changes as a mechanism to alter current behavioral propensities in ways that are likely to be most adaptive. Exploratory analyses suggest a methodologically interesting suppressor effect of the self-report items in predicting testosterone changes. PMID- 22947791 TI - Socio-demographic factors intensifying male mating competition exacerbate male mortality rates. AB - Sex differences in mortality rates stem from a complex set of genetic, physiological, psychological, and social causes whose influences and interconnections are best understood in an integrative evolutionary life history framework. Although there are multiple levels of mechanisms contributing to sex based disparities in mortality rates, the intensity of male mating competition in a population may have a crucial role in shaping the level of excess male mortality. The degree of variation and skew in male reproductive success may shape the intensity of male mating competition, leading to riskier behavioral and physiological strategies. This study examines three socio-demographic factors related to variation in human male reproductive success; polygyny, economic inequality, and the population ratio of reproductively viable men to women across nations with available data. The degrees of economic inequality and polygyny explained unique portions in the sex difference in mortality rates, these predictors accounted for 53% of the variance. The population ratio of reproductively viable men to women did not explain any additional variance. These results demonstrate the association between social conditions and health outcomes in modern nations, as well as the power of an evolutionary life history framework for understanding important social issues. PMID- 22947792 TI - Understanding of evolution may be improved by thinking about people. AB - The theory of evolution is poorly understood in the population at large, even by those with some science education. The recurrent misunderstandings can be partly attributed to failure to distinguish between processes which individual organisms undergo and those which populations undergo. They may be so pervasive because we usually explain evolutionary ideas with examples from non-human animals, and our everyday cognition about animals does not track individuals as distinct from the species to which they belong. By contrast, everyday cognition about other people tracks unique individuals as well as general properties of humans. In Study 1, I present experimental evidence that categorization by species occurs more strongly for non-human animals than for other people in 50 British university students. In Study 2, I show, in the same population, that framing evolutionary scenarios in terms of people produces fewer conceptual errors than when logically identical scenarios are framed terms of non-human animals. I conclude that public understanding of evolution might be improved if we began instruction by considering the organisms which are most familiar to us. PMID- 22947793 TI - Handgrip strength and socially dominant behavior in male adolescents. AB - Handgrip strength (HGS) is highly heritable and a good overall measure of strength and muscle function. Indicative of blood testosterone levels and fat free body mass, HGS is also highly sexually dimorphic. Recent psychological research shows that HGS is correlated with a number of social variables, but only in males. We conducted three studies to further investigate the relationship between HGS and measures of aggression and social competition among adolescents. Consistent with previous reports, correlations were almost exclusive to males, but this was only visible during late adolescence (i.e., high school). These findings support evolutionary hypotheses regarding grip strength in male-male competition and suggest that similar to measures of testosterone, HGS is a measure that is predictive of social behavior in older adolescent males. PMID- 22947794 TI - Does the brain consume additional glucose during self-control tasks? AB - A currently popular model of self-control posits that the exertion of self control relies on a resource, which is expended by acts of self-control, resulting in less of this resource being available for subsequent acts of self control. Recently, glucose has been proposed as the resource in question. For this model to be correct, it must be the case that A) performing a self-control task reduces glucose levels relative to a control task and B) performing a self control task reduces glucose relative to pre-task levels. Evidence from neurophysiology suggests that (A) is unlikely to be true, and the evidence surrounding (B) is mixed, and is unlikely to be true for subjects who have not recently fasted. From the standpoint of evolved function, glucose might better be thought of as an input to decision making systems rather than as a constraint on performance. PMID- 22947795 TI - The attention-getting capacity of whines and child-directed speech. AB - The current study tested the ability of whines and child-directed speech to attract the attention of listeners involved in a story repetition task. Twenty non-parents and 17 parents were presented with two dull stories, each playing to a separate ear, and asked to repeat one of the stories verbatim. The story that participants were instructed to ignore was interrupted occasionally with the reader whining and using child-directed speech. While repeating the passage, participants were monitored for Galvanic skin response, heart rate, and blood pressure. Based on 4 measures, participants tuned in more to whining, and to a lesser extent child-directed speech, than neutral speech segments that served as a control. Participants, regardless of gender or parental status, made more mistakes when presented with the whine or child-directed speech, they recalled hearing those vocalizations, they recognized more words from the whining segment than the neutral control segment, and they exhibited higher Galvanic skin response during the presence of whines and child- directed speech than neutral speech segments. Whines and child-directed speech appear to be integral members of a suite of vocalizations designed to get the attention of attachment partners by playing to an auditory sensitivity among humans. Whines in particular may serve the function of eliciting care at a time when caregivers switch from primarily mothers to greater care from other caregivers. PMID- 22947797 TI - Examining the acceptance of and resistance to evolutionary psychology. AB - The field of psychology remains a divided one. Several different sub-disciplines (e.g., developmental, cognitive, behaviorism, social, etc.) form what could be a unified scientific area. However, there is no widely accepted theory of unification. Charles Darwin once theorized that evolutionary theory would change the foundation of psychology; but over the years, evolutionary psychology has been met with hostile resistance from some of the prominent psychologists within the other sub-disciplines. Yet in recent years, all of the divided sub disciplines of psychology have been slowly implementing evolutionary principles into their literature and research. This slow integration of evolutionary psychology into the other sub-disciplines indicates the possibility of a unified psychology with evolution as its foundation. This paper briefly reviews the literature within each major sub-discipline of psychology to show their implementation of evolutionary psychological theories, indicating the possibility of evolutionary psychology becoming the unifying paradigm upon which the entire field of psychology can be based. A call for action to continue this process is also discussed. PMID- 22947799 TI - Remembering helpers and hinderers depends on behavioral intentions of the agent and psychopathic characteristics of the observer. AB - Individual differences in proneness towards granting benefits (i.e., helping) or imposing costs (i.e., hindering) may have led to processes that detect and remember people who are prone to help or hinder. We examined two factors that might influence such memory: the intentionality of the acts and individual differences in psychopathy characteristics. Participants viewed several videos of computer-animated agents that helped or hindered another agent, either intentionally or unintentionally. Afterward, participants had better memory for agents that acted intentionally. Additionally, participants with more psychopathic tendencies had enhanced memory for helpers, suggesting that certain individual characteristics might result in heightened memory for people who are prone to granting benefits. PMID- 22947800 TI - Exploring the evolved concept of NEWCOMER: experimental tests of a cognitive model. AB - Enduring human coalitions face the adaptive problem of integrating new members. Although newcomers can provide benefits (e.g., additional labor), newcomers can also create costs (e.g., by free riding). Due to the unique adaptive problems they pose, we hypothesize that the mind contains an evolved concept of NEWCOMER. We test the design of this concept experimentally and show that the activation of the NEWCOMER concept elicits a variety of anti-free rider responses (e.g., a decrease in trust) with adaptively-targeted exceptions (e.g., a minimal increase in exclusion sentiment). These results support the hypothesis that the mind contains specialized concepts for understanding, creating, and sustaining intergenerational coalitions. PMID- 22947803 TI - Understanding suicide terrorism: premature dismissal of the religious-belief hypothesis. AB - We comment on work by Ginges, Hansen, and Norenzayan (2009), in which they compare two hypotheses for predicting individual support for suicide terrorism: the religious-belief hypothesis and the coalitional-commitment hypothesis. Although we appreciate the evidence provided in support of the coalitional commitment hypothesis, we argue that their method of testing the religious-belief hypothesis is conceptually flawed, thus calling into question their conclusion that the religious-belief hypothesis has been disconfirmed. In addition to critiquing the methodology implemented by Ginges et al., we provide suggestions on how the religious-belief hypothesis may be properly tested. It is possible that the premature and unwarranted conclusions reached by Ginges et al. may deter researchers from examining the effect of specific religious beliefs on support for terrorism, and we hope that our comments can mitigate this possibility. PMID- 22947804 TI - Religious belief, coalitional commitment, and support for suicide attacks. PMID- 22947805 TI - Distinguishing between perceiver and wearer effects in clothing color-associated attributions. AB - Recent studies have noted positive effects of red clothing on success in competitive sports, perhaps arising from an evolutionary predisposition to associate the color red with dominance status. Red may also enhance judgments of women's attractiveness by men, perhaps through a similar association with fertility. Here we extend these studies by investigating attractiveness judgments of both sexes and by contrasting attributions based on six different colors. Furthermore, by photographing targets repeatedly in different colors, we could investigate whether color effects are due to influences on raters or clothing wearers, by either withholding from raters information about clothing color or holding it constant via digital manipulation, while retaining color-associated variation in wearer's expression and posture. When color cues were available, we found color-attractiveness associations when males were judged by either sex, or when males judged females, but not when females judged female images. Both red and black were associated with higher attractiveness judgments and had approximately equivalent effects. Importantly, we also detected significant clothing color-attractiveness associations even when clothing color was obscured from raters and when color was held constant by digital manipulation. These results suggest that clothing color has a psychological influence on wearers at least as much as on raters, and that this ultimately influences attractiveness judgments by others. Our results lend support for the idea that evolutionarily derived color associations can bias interpersonal judgments, although these are limited neither to effects on raters nor to the color red. PMID- 22947806 TI - Parent-offspring conflict over mating: the case of mating age. AB - Parents and offspring have asymmetrical preferences with respect to mate choice. So far, several areas of disagreement have been identified, including beauty, family background, and sexual strategies. This article proposes that mating age constitutes another area of conflict, as parents desire their children to initiate mating at a different age than the offspring desire it for themselves. More specifically, the hypothesis is tested that individuals prefer for their offspring to start having sexual relationships at a later age than they prefer for themselves to do so. Furthermore, it is hypothesized that individuals prefer to marry at a later age than they prefer their offspring to marry. Finally, the hypothesis is tested that parents prefer their daughters to marry at an earlier age and start sexual relationships later than their sons. Evidence from two independent studies employing 751 British parents provides support for all three hypotheses. PMID- 22947808 TI - Hooking up: gender differences, evolution, and pluralistic ignorance. AB - "Hooking-up"--engaging in no-strings-attached sexual behaviors with uncommitted partners--has become a norm on college campuses, and raises the potential for disease, unintended pregnancy, and physical and psychological trauma. The primacy of sex in the evolutionary process suggests that predictions derived from evolutionary theory may be a useful first step toward understanding these contemporary behaviors. This study assessed the hook-up behaviors and attitudes of 507 college students. As predicted by behavioral-evolutionary theory: men were more comfortable than women with all types of sexual behaviors; women correctly attributed higher comfort levels to men, but overestimated men's actual comfort levels; and men correctly attributed lower comfort levels to women, but still overestimated women's actual comfort levels. Both genders attributed higher comfort levels to same-gendered others, reinforcing a pluralistic ignorance effect that might contribute to the high frequency of hook-up behaviors in spite of the low comfort levels reported and suggesting that hooking up may be a modern form of intrasexual competition between females for potential mates. PMID- 22947807 TI - The Roman state and genetic pacification. AB - Over the last 10,000 years, the human genome has changed at an accelerating rate. The change seems to reflect adaptations to new social environments, including the rise of the State and its monopoly on violence. State societies punish young men who act violently on their own initiative. In contrast, non-State societies usually reward such behavior with success, including reproductive success. Thus, given the moderate to high heritability of male aggressiveness, the State tends to remove violent predispositions from the gene pool while favoring tendencies toward peacefulness and submission. This perspective is applied here to the Roman state, specifically its long-term effort to pacify the general population. By imperial times, this effort had succeeded so well that the Romans saw themselves as being inherently less violent than the "barbarians" beyond their borders. By creating a pacified and submissive population, the empire also became conducive to the spread of Christianity--a religion of peace and submission. In sum, the Roman state imposed a behavioral change that would over time alter the mix of genotypes, thus facilitating a subsequent ideological change. PMID- 22947809 TI - Sleeping in safe places: an experimental investigation of human sleeping place preferences from an evolutionary perspective. AB - Although humans spend a third of their life asleep, their choice of sleeping places has so far been little investigated both theoretically and empirically. We address this issue from the perspective of evolutionary psychology. Our basic assumption is that humans have an evolved preference for safe sleeping places, that is, those that promise protection against potential aggressors and nighttime predation. Several testable predictions were derived from this assumption concerning the preferred location of the bed in a sleeping room. Specifically, we predicted that people prefer sleeping places that allow them to view the entrances to the sleeping room (doors and windows) from a distance while remaining concealed from the entrances themselves. To test these hypotheses, 138 participants were asked to arrange a bed and other pieces of furniture on floor plans that were experimentally manipulated with respect to the direction in which the door opened and the presence of a window. In agreement with predictions, participants predominantly positioned the bed in a way that (a) allowed them to see the door, (b) was as distant as possible from the door, and (c) was on the side of the room toward which the door opened. In addition, the positioning of the bed was influenced as predicted by the presence of a window. PMID- 22947810 TI - Female scarcity reduces women's marital ages and increases variance in men's marital ages. AB - When women are scarce in a population relative to men, they have greater bargaining power in romantic relationships and thus may be able to secure male commitment at earlier ages. Male motivation for long-term relationship commitment may also be higher, in conjunction with the motivation to secure a prospective partner before another male retains her. However, men may also need to acquire greater social status and resources to be considered marriageable. This could increase the variance in male marital age, as well as the average male marital age. We calculated the Operational Sex Ratio, and means, medians, and standard deviations in marital ages for women and men for the 50 largest Metropolitan Statistical Areas in the United States with 2000 U.S Census data. As predicted, where women are scarce they marry earlier on average. However, there was no significant relationship with mean male marital ages. The variance in male marital age increased with higher female scarcity, contrasting with a non significant inverse trend for female marital age variation. These findings advance the understanding of the relationship between the OSR and marital patterns. We believe that these results are best accounted for by sex specific attributes of reproductive value and associated mate selection criteria, demonstrating the power of an evolutionary framework for understanding human relationships and demographic patterns. PMID- 22947811 TI - The evolutionary significance of Red Sox nation: sport fandom as a by-product of coalitional psychology. AB - Sport fandom has received considerable attention from social scientists, yet few have considered it from an evolutionary perspective. To redress this gap, we develop the hypothesis that team sports exhibit characteristics that activate mechanisms which evolved to facilitate the development of coalitions in the context of small-scale warfare. Based on this by-product hypothesis, we predicted a correlation between fandom and binding (i.e. group-relevant) concerns, especially loyalty. To test this prediction, we administered the Sport Spectator Identification Scale (SSI) and the Moral Foundations Questionnaire (MFQ) to 495 undergraduates. The MFQ measures three binding concerns, including loyalty, and two individualizing ones, harm and fairness. As predicted, fandom correlated significantly with loyalty (r = .27) and, within men, the two other binding concerns, authority (r =.22) and purity (r = .24). By contrast, fandom did not significantly correlate with harm or fairness. In addition, we predicted and found that men reported significantly higher levels of fandom (Cohen's d =.45) and loyalty (d = .27) than did women. In conclusion, this study presents data supporting the coalitional by-product hypothesis of fandom and should spur further research using fandom as a window into our evolved psychology. PMID- 22947812 TI - Correlated male preferences for femininity in female faces and voices. AB - Sexually dimorphic physical traits are important for mate choice and mate preference in many species, including humans. Several previous studies have observed that women's preferences for physical cues of male masculinity in different domains (e.g., visual and vocal) are correlated. These correlations demonstrate systematic, rather than arbitrary, variation in women's preferences for masculine men and are consistent with the proposal that sexually dimorphic cues in different domains reflect a common underlying aspect of male quality. Here we present evidence for a similar correlation between men's preferences for different cues of femininity in women; although men generally preferred feminized to masculinized versions of both women's faces and voices, the strength of men's preferences for feminized versions of female faces was positively and significantly correlated with the strength of their preferences for feminized versions of women's voices. In a second study, this correlation occurred when men judged women's attractiveness as long-term, but not short-term, mates, which is consistent with previous research. Collectively, these findings (1) present novel evidence for systematic variation in men's preferences for feminine women, (2) present converging evidence for concordant preferences for sexually dimorphic traits in different domains, and (3) complement findings of correlations between women's facial and vocal femininity. PMID- 22947813 TI - Altruism between romantic partners: biological offspring as a genetic bridge between altruist and recipient. AB - When the cost of altruism is low, individuals are more likely to help non-kin (i.e., friends and romantic partners) than kin. This trend is thought to reflect the fact that people tend to be emotionally closer with friends and romantic partners than kin. However, as the cost of altruism increases, altruistic preference shifts to kin. The present study highlights this phenomenon by examining altruism between siblings, romantic partners, romantic partners who have biological children together, and romantic partners who have adopted children together. Participants (n = 203) completed a questionnaire about altruism in low-, medium-, and high-cost situations. Participants gave more low cost help to their romantic partners (regardless of whether they had a child together) than their siblings. More medium-cost help was given to romantic partners who had a child (biological and adopted) than siblings and romantic partners without children. In the high-cost condition, the estimated altruistic tendencies were stronger toward siblings and romantic partners who have a biological child than toward romantic partners with no children and partners with adopted children. Participants also believed they were more altruistic than their siblings and romantic partners. PMID- 22947815 TI - The effect of life expectancy on aggression and generativity: a life history perspective. AB - Following a model that is inclusive of both dispositional and situational influences on life-history behaviors and attitudes, the effect of life expectancies on aggression and generativity was examined. Consistent with the hypotheses it was found that shorter life expectancies led to an increase in the desire to aggress and a decrease in the desire to engage in generative behaviors. The results are discussed in terms of how life history theory can be used to frame research on person-situation interactions. PMID- 22947816 TI - Regional differences in pathogen prevalence and defensive reactions to the "swine flu" outbreak among East Asians and Westerners. AB - Research has found that contagion-minimizing behavioral tendencies are amplified in pathogen-prevalent regions. We investigated whether reactions to the "swine flu" outbreak of 2009 were stronger among East Asians than Westerners, populations residing in regions that now enjoy comparable advances in healthcare but that are characterized by relatively high and low historical pathogen prevalence, respectively. In a survey, East Asians reported greater concerns about infection, especially from foreigners. Analyses of international air travel data around the time of the outbreak provided corroborating evidence: Immediately following the outbreak, airports in the Asia-Pacific region lost more international traffic relative to their Western counterparts, and East Asian airlines reported greater declines in international traffic compared to Western airlines. These differences are unlikely to reflect objective threat posed by swine flu (whose casualties were concentrated in the Americas); rather, they appear to reflect culturally adapted behavioral patterns forged and sustained by regionally variable levels of pathogen prevalence. PMID- 22947814 TI - The effect of mortality salience on women's judgments of male faces. AB - Previous research has shown that individuals who are reminded of their death exhibited a greater desire for offspring than those who were not reminded of their death. The present research investigated whether being reminded of mortality affects mate selection behaviors, such as facial preference judgments. Prior research has shown that women prefer more masculine faces when they are at the high versus low fertility phase of their menstrual cycles. We report an experiment in which women were tested either at their high or fertility phase. They were randomly assigned to either a mortality salience (MS) or control condition and then asked to judge faces ranging from extreme masculine to extreme feminine. The results showed that women's choice of the attractive male face was determined by an interaction between fertility phase and condition. In control conditions, high fertility phase women preferred a significantly more masculine face than women who were in a lower fertility phase of their menstrual cycles. In MS conditions, high fertility phase women preferred a significantly less masculine (i.e., more average) face than women who were in a low fertility phase. The results indicate that biological processes, such as fertility phase, involved in mate selection are sensitive to current environmental factors, such as death reminders. This sensitivity may serve as an adaptive compromise when choosing a mate in potentially adverse environmental conditions. PMID- 22947817 TI - Paternal care may influence perceptions of paternal resemblance. AB - Father-child resemblance is increasingly attracting attention from researchers interested in studying paternal investment. The current study sought to determine whether a quasi-experimental infant massage intervention would increase father's perceptions of resemblance. The study included a dozen fathers in each of two groups: the first received an intensive series of lessons on infant-father massage along with their infants, while the second group served as a neutral control. We failed to find significant correlations between paternal investment and resemblance, but we found that fathers who participated in the infant massage intervention reported significantly larger post-study ratings of resemblance and lower ratings of paternal stress. This suggests that the relationship between father-child resemblance and paternal investment may be bidirectional. PMID- 22947818 TI - Sexual dimorphism in stature (SDS), jealousy and mate retention. AB - Previous research has investigated the manner in which absolute height impacts on jealousy and mate retention. Although relative height is also important, little information exists about the potential influence of sexual dimorphism in stature (SDS) within established relationships. The current study investigated the relationship between SDS and the satisfaction, jealousy and mate retention behaviors reported by men and women. Heterosexual men (n = 98) and women (n = 102) completed a questionnaire. Men in high SDS relationships reported the lowest levels of cognitive and behavioral jealousy, although the impact of SDS on relationship satisfaction was less clear. SDS was not associated with the overall use of mate retention strategies; SDS did however affect the use of three specific strategies (vigilance, monopolization of time, love and care). SDS did not affect women's relationship satisfaction, jealousy (cognitive, behavioral, or emotional) or the use of mate retention strategies (with the exception of resource display). PMID- 22947819 TI - Strengths and weaknesses of McNamara's evolutionary psychological model of dreaming. AB - This article includes a brief overview of McNamara's (2004) evolutionary model of dreaming. The strengths and weaknesses of this model are then evaluated in terms of its consonance with measurable neurological and biological properties of dreaming, its fit within the tenets of evolutionary theories of dreams, and its alignment with evolutionary concepts of cooperation and spirituality. McNamara's model focuses primarily on dreaming that occurs during rapid eye movement (REM) sleep; therefore this article also focuses on REM dreaming. PMID- 22947820 TI - Pair-bonded humans conform to sexual stereotypes in web-based advertisements for extra-marital partners. AB - Partners advertisements provide advertisers with access to a large pool of prospective mates, and have proven useful in documenting sex differences in human mating preferences. We coded data from an Internet site (AshleyMadison.com) catering to advertisers engaged in existing pair-bonded relationships. While we predicted that pair-bonding may liberate advertisers from conforming to sexual stereotypes of male promiscuity and female choosiness, our results are uniformly consistent with those stereotypes. Our findings thus provide further evidence that human mating behavior is highly constrained by fundamental biological differences between males and females. PMID- 22947821 TI - A new viewpoint on the evolution of sexually dimorphic human faces. AB - Human faces show marked sexual shape dimorphism, and this affects their attractiveness. Humans also show marked height dimorphism, which means that men typically view women's faces from slightly above and women typically view men's faces from slightly below. We tested the idea that this perspective difference may be the evolutionary origin of the face shape dimorphism by having males and females rate the masculinity/femininity and attractiveness of male and female faces that had been manipulated in pitch (forward or backward tilt), simulating viewing the face from slightly above or below. As predicted, tilting female faces upwards decreased their perceived femininity and attractiveness, whereas tilting them downwards increased their perceived femininity and attractiveness. Male faces tilted up were judged to be more masculine, and tilted down judged to be less masculine. This suggests that sexual selection may have embodied this viewpoint difference into the actual facial proportions of men and women. PMID- 22947822 TI - Parents just don't understand: parent-offspring conflict over mate choice. AB - Previous research reveals that children and parents are not in complete agreement over which traits are most important for the mate of the child. Children tend to prefer traits that suggest genetic quality, whereas parents prefer characteristics that suggest high parental investment and cooperation with the ingroup. Using a sample of parents, mothers (n = 234) and fathers (n =240) the hypothesis was supported; parents perceived characteristics indicating a lack of genetic quality as being more unacceptable to the child, while characteristics indicating a lack of parental investment and cooperation with the ingroup were more unacceptable to themselves. Sex differences between mothers and fathers and sons and daughters were explored. PMID- 22947823 TI - Extending the the behavioral immune system to political psychology: are political conservatism and disgust sensitivity really related? AB - Previous research suggests that several individual and cultural level attitudes, cognitions, and societal structures may have evolved to mitigate the pathogen threats posed by intergroup interactions. It has been suggested that these anti pathogen defenses are at the root of conservative political ideology. Here, we test a hypothesis that political conservatism functions as a pathogen-avoidance strategy. Across three studies, we consistently find no relationship between sensitivity to pathogen disgust and multiple measures of political conservatism. These results are contrasted with theoretical perspectives suggesting a relationship between conservatism and pathogen avoidance, and with previous findings of a relationship between conservatism and disgust sensitivity. PMID- 22947824 TI - High religiosity and societal dysfunction in the United States during the first decade of the twenty-first century. AB - This study provides independent empirical evidence that bears upon the truth or falsity of recently formulated hypotheses regarding reciprocal relationships between levels of religiosity and societal dysfunction. Gregory S. Paul's findings, published in the Journal of Religion and Society (2005), Free Inquiry (2008), and Evolutionary Psychology (2009), have demonstrated that high degrees of theism are associated with high degrees of societal dysfunction among the prosperous democracies. Whereas his research employs numerous scatter diagrams and bivariate correlations involving measures of religiosity and societal dysfunction pertaining to 17 nation states, the current study's units of analysis are the 50 states and the District of Columbia. Additionally, the utilization of multiple regression analysis allows the detection of the effects of other potentially relevant explanatory variables, such as educational attainment, income level, and race. The findings are only minimally supportive of Paul's hypotheses regarding the contributions of high religiosity to societal dysfunction and to the effects of societal dysfunction upon religiosity. Simultaneously, the results of correlational and regression analyses attest to the more substantial explanatory power of the social inequality variables of education, income, and race. Accordingly, it is argued that "American Exceptionalism," when understood as referring to a society manifesting the coexistence of high levels of theism and high levels of societal dysfunction, is best explained by the United States' high degree of social inequality, compared with other modern industrialized democracies. PMID- 22947825 TI - On the adaptive origins and maladaptive consequences of human inbreeding: parasite prevalence, immune functioning, and consanguineous marriage. AB - We propose that consanguineous marriages arise adaptively in response to high parasite prevalence and function to maintain coadapted gene complexes and associated local adaptation that defend against local pathogens. Therefore, a greater prevalence of inbreeding by consanguineous marriage is expected in geographical regions that historically have had high levels of disease-causing parasites. Eventually such marriages may, under the contemporary high movement of people with modern transportation, jeopardize the immunity of those who practice inbreeding as this leads to an increased susceptibility to novel pathogens. Therefore, a greater frequency of inbreeding is expected to predict higher levels of contemporary mortality and morbidity from infectious diseases. This parasite model of human inbreeding was supported by an analysis involving 72 countries worldwide. We found that historically high levels of pathogen prevalence were related positively to the proportion of consanguineous marriages, and that a higher prevalence of such marriages was associated with higher contemporary mortality and morbidity due to pathogens. Our study addresses plausible alternative explanations. The results suggest that consanguineous marriage is an adaptive consequence of historical pathogen ecologies, but is maladaptive in contemporary disease ecologies. PMID- 22947827 TI - Rejection hurts: the effect of being dumped on subsequent mating efforts. AB - Many of the qualities that people seek in a long-term partner are not directly observable. As a consequence, information gathered through social learning may be important in partner assessment. Here, we tested the hypothesis that finding out potential partners were rejected by their last partner would negatively affect participants' desire to pursue a romantic relationship with them. Results support this hypothesis, and this effect was, as predicted, greater when the target was being evaluated for a potential long-term relationship compared to a sexual relationship. In a more exploratory vein, we tested the effect of the target having rejected their last partner and failing to disclose how their last relationship ended. These scenarios produced intriguing sex differences, such that men's ratings of women fell after learning she had rejected her last partner, but women's ratings of men increased after the same information was introduced. Failing to disclose information about a past relationship was unappealing to both men and women, though particularly so for women. PMID- 22947828 TI - Toward an integrative approach of cognitive neuroscientific and evolutionary psychological studies of art. AB - This paper examines explanations for human artistic behavior in two reductionist research programs, cognitive neuroscience and evolutionary psychology. Despite their different methodological outlooks, both approaches converge on an explanation of art production and appreciation as byproducts of normal perceptual and motivational cognitive skills that evolved in response to problems originally not related to art, such as the discrimination of salient visual stimuli and speech sounds. The explanatory power of this reductionist framework does not obviate the need for higher-level accounts of art from the humanities, such as aesthetics, art history or anthropology of art. PMID- 22947829 TI - The effects of control of resources on magnitudes of sex differences in human mate preferences. AB - We tested the hypothesis that magnitudes of sex differences in human mate preferences would be inversely related to control of resources. Specifically, we predicted that the ideal partner age, maximum and minimum partner ages tolerated and preferences for "physical attractiveness" over "good financial prospects" of female participants would approach parity with that of men with increasing control of resources. In a sample of 3770 participants recruited via an online survey, the magnitudes of sex differences in age preferences increased with resource control whereas the sex difference in preferences for "physical attractiveness" over "good financial prospects" disappeared when resource control was high. Results are inconsistent, and are discussed in the context of adaptive tradeoff and biosocial models of sex differences in human mate preferences. PMID- 22947830 TI - Indignation or insecurity: the influence of mate value on distress in response to infidelity. AB - Two studies examined the influence of mate value on responses to infidelity from an evolutionary perspective. Couples were recruited for Study 1, allowing an examination of both participants' self-perceived mate value and their partners' mate value on reactions to hypothetical scenarios describing an incidence of infidelity. As predicted, higher levels of perceived mate value were associated with greater levels of indignation while lower levels of mate value were associated with increased levels of insecurity and anxiety in response to infidelity. In Study 2, participants who had been the victim of infidelity in the past recounted their experiences and reported how they actually responded. Consistent with Study 1, higher levels of mate value were associated with greater levels of indignation in response to infidelity whereas lower levels of mate value were associated with greater levels of insecurity. Taken together, these two studies provide compelling support for the hypothesis that the nature of the distress experienced in response to infidelity is influenced by an individual's perceived mate value. PMID- 22947832 TI - Emotional faces capture spatial attention in 5-year-old children. AB - Emotional facial expressions are important social cues that convey salient affective information. Infants, younger children, and adults all appear to orient spatial attention to emotional faces with a particularly strong bias to fearful faces. Yet in young children it is unclear whether or not both happy and fearful faces extract attention. Given that the processing of emotional faces is believed by some to serve an evolutionarily adaptive purpose, attentional biases to both fearful and happy expressions would be expected in younger children. However, the extent to which this ability is present in young children and whether or not this ability is genetically mediated is untested. Therefore, the aims of the current study were to assess the spatial-attentional properties of emotional faces in young children, with a preliminary test of whether this effect was influenced by genetics. Five-year-old twin pairs performed a dot-probe task. The results suggest that children preferentially direct spatial attention to emotional faces, particularly right visual field faces. The results provide support for the notion that the direction of spatial attention to emotional faces serves an evolutionarily adaptive function and may be mediated by genetic mechanisms. PMID- 22947833 TI - Evidence for menstrual cycle shifts in women's preferences for masculinity: a response to Harris (in press) "Menstrual cycle and facial preferences reconsidered". AB - Over the last decade, a growing literature has shown that women in the fertile phase of the menstrual cycle demonstrate stronger preferences for men with masculine traits than they do when in the non-fertile phases of the cycle (see Gangestad and Thornhill, 2008 and Jones et al., 2008 for recent reviews). In a recent article, Harris (in press; Sex Roles) failed to replicate this increase in women's preferences for masculine faces when women are near ovulation. Harris represented her study as one of only three studies on the topic, and as the largest of the existing studies. There are, however, many more studies on menstrual cycle shifts in preferences for facial masculinity in the published literature, including one that is 2.5 times larger in size than the Harris study. In this article, we review the evidence for cyclic shifts in mate preferences and related behaviors and discuss weaknesses of Harris's methods. Considered as a whole, the evidence for menstrual cycle shifts in women's preferences and behaviors is compelling, despite the failure of replication reported by Harris. PMID- 22947835 TI - Sex differences in same-sex direct aggression and sociosexuality: the role of risky impulsivity. AB - Sex differences in same-sex direct aggression and sociosexuality are among the most robust in the literature. The present article evaluated the hypothesis that both can be explained by a sex difference in the willingness to take impulsive risks. Self-report data were gathered from 3,775 respondents (1,514 female) on same-sex aggression, sociosexuality, and risky impulsivity. Risky impulsivity was higher for men than for women (d = .34) and path analysis showed it to be a common cause of same-sex aggression and sociosexuality for both sexes. However, it did not completely mediate the sex differences in same-sex aggression and sociosexuality. The results suggest that same-sex aggression and sociosexual behavior share a common psychological mechanism, but that fully explaining sex differences in aggression requires a more sensitive assay of impulsive risk and a consideration of dyadic processes. PMID- 22947837 TI - Elevating dental hygiene scholarship in the future. PMID- 22947838 TI - Non-fluoride caries-preventive agents. PMID- 22947839 TI - Advancing our profession: are higher educational standards the answer? AB - PURPOSE: Educational models in health care professions have changed drastically since on-the-job training models. The purpose of this manuscript was to investigate how the professions of physical therapy, occupational therapy, physician assistant, nursing and respiratory therapy have advanced their educational models for entry into practice and to recommend how dental hygiene can integrate similar models to advance the profession. The recommendations are to create an accreditation council for dental hygiene education and to mandate articulation agreements for baccalaureate degree completion in developing and existing programs. Dental hygiene must continue on the path to advance our profession and glean lessons from other health professions. PMID- 22947840 TI - Interrelationship between pyogenic granuloma and peripheral ossifying fibroma: a case report. AB - PURPOSE: Pyogenic Granuloma (PG) is an inflammatory hyperplasia which is non neoplastic in nature. Because of the high incidence of oral PG, critical need exists for its proper diagnosis and treatment. Peripheral Ossifying Fibroma (POF) is a focal reactive overgrowth occurring in young adults. Though clinically similar to PG, it is important to differentiate the lesions based on the histopathological findings that facilitate the management of the lesion, which is diverse in nature when compared to PG. Proper treatment of such overgrowths and appropriate oral hygiene instructions shall ensure no recurrence of the lesion. There are very few case reports published depicting the recurrence of 1 lesion into another reactive overgrowth, and fewer case reports exists describing the interrelationship between these 2 lesions. Hence this case report depicts the interrelation between these 2 reactive fibrous overgrowths having different histomorphologic representation. Also, the importance of histopathologic diagnosis and a proper treatment plan is emphasized to prevent unnecessary distress to the patient regarding the severity of such lesions. An irregular gingival overgrowth occurring in the mandibular anterior region diagnosed histopathologically as PG in a 35 year old female is described. The lesion was excised. Furthermore, it recurred after a year in the same region and the histopathologic diagnosis of the lesion confirmed it as POF. The overgrowth was excised and thoroughly curetted. The case was followed up to 1 year without any signs of recurrence. PMID- 22947841 TI - Environmental tobacco smoke and periodontitis in U.S. non-smokers. AB - PURPOSE: The association of second hand smoke or environmental tobacco smoke (ETS) and periodontitis in non-smokers has not been confirmed using a biomarker of ETS exposure. To estimate periodontitis prevalence in non-smokers with detectable serum cotinine, and to investigate racial/ethnic and socioeconomic variation in ETS exposure in a representative sample of the U. S. adult population. Determining periodontitis risk indicators occurring with ETS appears to be a salient purpose as this study is the first of its kind to provide a link (a salivary biomarker) between second hand smoke and risk for periodontitis. METHODS: Data were collected from the 1999 to 2004 National Health and Nutrition Examination Survey (NHANES). Subjects were 3,137 adults who had smoked fewer than 100 cigarettes and had not used other forms of tobacco. ETS exposure was classified as negligible (cotinine concentrations below sex and race/ethnicity cut-points for smokers), moderate (cotinine 0.5-<1.5 MUg/mL) or high (cotinine >= 1.5 ng/mL). Periodontitis was classified according to the Centers for Disease Control and Prevention (CDC) and the American Academy of Periodontology (AAP) case definition for moderate-severe disease. Survey estimation procedures were used to estimate prevalence and odds ratios (OR) were from multivariable logistic regression models. RESULTS: ETS exposure was observed in 40.5% of subjects and 2.6% had periodontitis. ETS exposure was inversely associated with educational attainment and family income and was higher in non-Hispanic blacks than whites. After adjusting for age, sex and year of survey, adults with high ETS exposure (cotinine >= 1.5 ng/mL) had more than twice the odds of periodontitis as people with negligible exposure (OR=2.3, 95% confidence interval=1.3, 4.1). CONCLUSION: High ETS exposure was a risk indicator for periodontitis in lifetime non-smokers. PMID- 22947842 TI - Effect of scaling and root planing on erythrocyte count, hemoglobin and hematocrit in patients with chronic periodontal disease. AB - PURPOSE: Anemia of chronic disease, a cytokine-mediated anemia, is a frequent complication of many chronic inflammatory conditions. The present clinical trial was aimed to evaluate the effect of chronic periodontal disease on erythrocyte count, hemoglobin and hematocrit and the changes produced in these parameters after the provision of periodontal therapy. METHODS: 40 systemically healthy non smoker male subjects in the age group of 25 to 50 years suffering with chronic periodontal disease were selected and categorized into 2 groups. Group A was categorized as chronic generalized gingivitis, and Group B was categorized as chronic generalized periodontitis on the basis of clinical findings. The clinical parameters Gingival Index (GI), Probing Pock et Depth (PPD) and Relative Attachment Level (RAL) and laboratory blood investigations viz erythrocyte count (EC), hemoglobin (Hb), hematocrit (HCT) and red cell indices (MCV, MCH, MCHC) were recorded at baseline. Complete oral prophylaxis was performed for all patients. Patients were recalled after 3 weeks and 3 months. The clinical and hematological parameters were re-evaluated to analyze the changes after provision of phase I therapy. RESULTS: The mean values of EC, Hb and HCT were significantly lower in Group B in comparison to Group A, and showed a significantly greater increase at 3 months of observation. However, the values of MCV, MCH and MCHC showed a non significant change during the same observation period in both the groups. CONCLUSION: Lower values of EC, Hb and HCT in Group B showed that mild anemia is associated with chronic generalized periodontitis, which tends to improve after provision of periodontal therapy. Minimal changes in MCV, MCH and MCHC indicated that the lower values are not due to any vitamin and mineral deficiencies, but secondary to the chronic inflammatory changes associated with chronic periodontal disease. PMID- 22947843 TI - Effects of periodontal instrumentation on quality of life and illness in patients with chronic obstructive pulmonary disease: a pilot study. AB - PURPOSE: To assess if patients with chronic obstructive pulmonary disease (COPD) receiving periodontal debridement for treatment of chronic periodontitis with ultrasonic or hand instrumentation experienced changes in quality of life or incidents of illness following treatment or no treatment. METHODS: The study design was a 3 group, randomized, controlled pre- and post-test experimental pilot study. Volunteers with COPD and chronic periodontitis (n=30) were recruited from physician offices or fliers and randomly assigned to 1 of 3 groups. Of those, 2 groups had periodontal debridement using either magnetostrictive ultrasonic instrumentation (n=10) or hand instrumentation (n=10). A control group (n=10) received no treatment. Primary outcomes, quality of life and illness were measured by the St. George's Respiratory Questionnaire (SGRQ-A) and Illness Questionnaire, respectively. Subjects completed the questionnaires as pre-tests at baseline and as post-tests 4 weeks post-treatment/no treatment. Repeated measures ANOVA was used to compare groups on continuous variables (p <= 0.05) measured by SGRQ-A total scores and symptoms, activities and impacts subscales. Percentages, frequencies and cross tabulations were calculated for categorical data. RESULTS: SGRQ-A and Illness Questionnaire scores showed no significant differences between groups in quality of life or illness following periodontal debridement. Total SGRQ-A scores decreased slightly for all groups with no significant difference among groups (p=0.138) and no interaction (p=0.794). Cross tabulations showed no relationship between indicators of self-reported illness before and after treatment/no treatment. No adverse events were reported. CONCLUSION: Based on this small-scale study, it seems periodontal debridement for chronic periodontitis has no effect on quality of life and illness in patients with COPD, and it may be performed with ultrasonic or hand instruments without adverse events. PMID- 22947844 TI - Magnification loupes in U.S. entry-level dental hygiene programs--occupational health and safety. AB - PURPOSE: The purpose of this study was to determine policies and practices regarding magnification loupes among faculty and students in accredited dental hygiene programs as measured by a 31 item, self-designed questionnaire. In addition, the study compared policies among dental hygiene programs in 2 year versus 4 year programs in terms of requirements for the use of magnification loupes. METHODS: After institutional review board approval, a 31 item self designed questionnaire was emailed via Survey Monkey to 303 entry-level dental hygiene programs. An overall response rate of 75% was obtained. Data were analyzed using descriptive statistics and chi-square test of independence. RESULTS: Results reveal the vast majority of programs do not require loupes for faculty or students, with only 23% of responding schools requiring students to purchase loupes and 8% requiring faculty to use loupes. More dental hygiene programs require students to wear loupes than require faculty to wear loupes. No statistically significant differences (p-value=0.54) in program policies were found requiring the purchase of magnifying loupes by students, based on 2 year and 4 year dental hygiene educational programs. Odds ratio (1.25) give the odds of students purchasing loupes in a 2 year program as 25% higher than a 4 year program. Almost two thirds of respondents reported loupes instruction as a curriculum component, although most respondents spent 2 or less hours teaching in this area. Most programs (90%) do not plan to require students to purchase loupes in the future, although the majority believes proper use of loupes should be integrated in the curriculum. CONCLUSION: Most respondents see advantages to loupes, but clinical policies on loupes do not appear to correlate with beliefs. Educational programs in dental hygiene seem slow to adopt and require the use of loupes. Current clinical polices on loupes should be reviewed to ensure graduates experience the potential ergonomic benefits magnification brings to clinical practice during their education. PMID- 22947845 TI - Dental Team Experience (DTE): a five year experience. AB - PURPOSE: Several European countries have interprofessional training for health care professional students, including dental and dental hygiene students. However, very little training exists in the U.S. where dentists and dental hygienists are educated together. The 4th World Congress of Preventive Dentistry and the American Dental Education Association have stated that teamwork must be taught in the dental professions. In 2005, Eastern Washington University began an interdisciplinary team experience in which graduating dental hygiene, dental assisting and dental students worked in an interdisciplinary team providing care to the underserved. A new team was formed each year for the next 5 years. This paper addresses the establishment and outcomes of this interdisciplinary experience. PMID- 22947846 TI - Hygiene self-care of older adults in West Virginia: effects of gender. AB - PURPOSE: This study investigated whether oral hygiene self-care behavior differs between genders in older adults in Appalachia, a geographic area with significant oral health concerns. Identify ing the practices of older adults may provide valuable information for designing interventions and improving overall oral health outcomes. METHODS: As part of a larger, on-going study on cognition and oral health in later life in Appalachia, a sample of dentate, older adults without dementia aged 70 and above (n=245, 86 men and 159 women) received an oral assessment by either a dentist or dental hygienist. Psychometricians assessed cognition using a standardized battery of neuropsychological tests. They also administered the General Oral Health Assessment Index and conducted structured interviews concerning diet, oral hygiene practices, oral health, social support, income and years of education Results: Over 80% of women (n=128) and 52.3% of men (n=45) reported brushing their teeth twice daily. Multivariate logistic regression analysis was conducted, controlling for socioeconomic status, social support (i.e., frequency of contacting friends and relatives), general oral health assessment items, number of decayed, missing and filled surfaces, plaque index and having regular dental visits. The results showed that women reported more frequent tooth brushing than their male counterparts (OR=4.04, 95% CI:1.93,8.42). CONCLUSION: Older women in West Virginia had significantly better oral hygiene practices than older men, particularly regarding tooth brushing. Interventions are needed to improve older men's dental hygiene behaviors to improve overall oral health outcomes. PMID- 22947848 TI - Massachusetts dental public health program directors practice behaviors and perceptions of infection control. AB - PURPOSE: The objective of this exploratory study was to deter mine the current infection control practices used in Massachusetts dental public health programs and assess the perceived compliance and challenges with infection control standards as outlined in the 2003 Centers for Disease Control and Prevention (CDC) infection control guidelines. METHODS: A convenience sample of program directors of dental public health programs in Massachusetts (n=82) were invited to participate. The directors were identified through the Massachusetts Department of Public Health, Massachusetts League of Community Health Centers, local dental/dental hygiene schools and key stakeholders in dental public health. The electronic questionnaire-based survey consisted of 26 open/closed-ended and Likert scale questions. Statistical analysis included frequency distribution and factor analysis. RESULTS: The overall response rate was 43%. The majority of responders to the survey were from public health settings using fixed/mobile dental equipment (82.9%), compared to settings using portable equipment (17.1%). Perceived lapses in the guidelines were attributed to lack of finances (r=0.938), lack of personnel (r=0.874) and lack of space (r=0.763). The only significant correlation between the program directors perceived adherence to the CDC guidelines was having access to necessary supplies and equipment (r=0.914). Program directors indicated that the CDC guidelines are hard to apply (r=0.895) and guide lines specific to settings using portable equipment would be helpful (r=0.925). CONCLUSION: Within the limitations of the sample size and response rate, directors from public health settings using both fixed/mobile and portable equipment reported being able to apply the current 2003 CDC infection control guidelines with few compliance challenges. However, respondents indicated that the guidelines were hard to apply and that infection control guidelines for settings using portable equipment would be useful. PMID- 22947847 TI - Vital tooth whitening effects on oral health-related quality of life in older adults. AB - PURPOSE: The purpose of this study was to determine if vital tooth whitening affects oral health-related quality of life (OHRQOL) in adults age 50 years and older, and if tooth whitening causes increased participation in social activities. METHODS: Using a 2 group, single blind, randomized, pre-test, multiple post-test design, 62 participants were enrolled. The experimental group used a whitening product twice daily for 3 weeks. The control group used no whitening products. The Oral Health Impact Profile (OHIP) served as the pre- and post-test measure. The OHIP measures OHRQOL on 7 subscales: functional factors, psychological disabilities, psychological discomforts, physical disabilities, social disabilities, handicaps and physical pain. Additional questions measured the subjects' social activities at baseline, 3 weeks and 3 months. Data from 53 participants, who completed the study, were analyzed using paired t-tests and ANOVA at p=0.05. RESULTS: Statistical significance was observed for the OHIP physical pain subscale (p=0.0029) and the handicap subscale (p=0.05). Pre- to post-test means of the physical pain subscale increased in the experimental group (4.84 to 7.10), suggesting a lower OHRQOL, most likely related to tooth sensitivity experienced by the experimental group. Means from pre- to post-test of the handicap subscale (1.96 to 1.19) reveal that the experimental group reported an improved OHRQOL and felt they were more willing to work. Repeated measures ANOVA and Tukey's post-hoc tests revealed that the experimental group reported significantly less (p=0.04) social activities at the 3 month post-test (3.92 to 3.45). No statistically significant between-group differences were observed in the overall OHIP score for functional factors, psychological disabilities, psychological discomforts, physical disabilities and social disabilities. CONCLUSION: Results indicate that vital tooth whitening does not improve overall OHRQOL in older adults. PMID- 22947849 TI - Metabolic regulation, mitochondria and the life-prolonging effect of rapamycin: a mini-review. AB - The fungicide rapamycin increases lifespan in eukaryotes by interfering with the activity of a serine/threonine kinase called TOR (target of rapamycin). TOR complex 1 (TORC1) is an essential integrator of cellular nutrient cues, growth signals and cellular metabolism. Here, we review major components of TORC1, its downstream effectors and lifespan studies in various organisms involving these signaling components. In particular, we focus on the role of rapamycin in mitochondrial biogenesis, in metabolic regulation and in the control of reactive oxygen species production. PMID- 22947850 TI - Fractional excretion of uric acid as a predictor for saline responsiveness in long-term kidney transplant patients. AB - BACKGROUND/AIMS: Subclinical hypovolemia may contribute to allograft dysfunction in long-term kidney transplant (KT) patients. In order to predict responsiveness to saline hydration, indices for tubular transport were investigated. METHODS: Fifty-four clinically euvolemic long-term KT patients with recently aggravated azotemia were given intravenous hydration as follows: 0.9% saline 5 ml/kg over 1 h, followed by 0.9% saline 1 ml/kg/h over 12 h and 1 liter of 0.45% saline over the next 24 h. Serum and urine data were collected and analyzed to assess responses. RESULTS: In all patients, saline hydration relieved azotemia, as shown by blood urea nitrogen (46.9 +/- 17.2 vs. 39.3 +/- 15.4 mg/dl; p < 0.01) and serum creatinine levels (2.9 +/- 1.1 vs. 2.5 +/- 1.1 mg/dl; p < 0.01) on day 0 versus day 2. In 38 patients, serum creatinine did not increase in the following month (70% responders). Compared with the nonresponders, the responders had a higher urine-to-plasma creatinine ratio and lower fractional excretion of sodium, uric acid and urea at admission. Multivariate logistic regression analysis revealed that responsiveness to saline hydration was independently associated with lower fractional excretion of uric acid. CONCLUSION: Subclinical hypovolemia should be considered in long-term KT patients with azotemia of unexplainable causes. Fractional excretion of uric acid may predict responsiveness to saline hydration. PMID- 22947851 TI - 3,4,5-tricaffeoylquinic Acid inhibits the lipopolysaccharide-stimulated production of inflammatory mediators in keratinocytes. AB - BACKGROUND AND PURPOSE: Microbial product lipopolysaccharide (LPS) has been shown to be involved in the pathogenesis of inflammatory skin diseases. Caffeoyl derivatives have demonstrated anti-inflammatory and antioxidant effects. However, the effect of 3,4,5-tricaffeoylquinic acid (3,4,5-triCQA) on the production of microbial product-induced inflammatory mediators in keratinocytes has not yet been studied. EXPERIMENTAL APPROACH: Using human keratinocytes, we investigated the effect of 3,4,5-triCQA on the LPS-stimulated production of inflammatory mediators in relation to the nuclear factor (NF)-KB, Akt and ERK pathways. RESULTS: 3,4,5-triCQA inhibited the LPS-induced expression of Toll-like receptor 4, and the production of cytokines and chemokines in keratinocytes. 3,4,5-triCQA, Bay 11-7085, AKt inhibitor and ERK inhibitor each attenuated the LPS-induced production of inflammatory mediators by inhibiting the NF-KB, Akt and ERK pathways. CONCLUSIONS AND IMPLICATIONS: 3,4,5-triCQA may attenuate the LPS stimulated production of inflammatory mediators in keratinocytes by suppressing the Toll-like receptor 4 expression-mediated activation of the Akt, ERK and NF-KB pathways. 3,4,5-triCQA may exert a preventive effect against microbial product induced inflammatory skin diseases. PMID- 22947852 TI - Voltage-driven ring confinement in a graphene sheet: assessing conditions for bound state solutions. AB - We have systematically studied the single-particle states in quantum rings produced by a set of concentric circular gates over a graphene sheet placed on a substrate. The resulting potential profiles and the interaction between the graphene layer and the substrate are considered within the Dirac Hamiltonian in the framework of the envelope function approximation. Our simulations allow microscopic mapping of the character of the electron and hole quasi-particle solutions according to the applied voltage. General conditions to control and operate the bound state solutions are described as functions of external and controllable parameters that will determine the optical properties ranging from metallic to semiconductor phases. Contrasting behaviors are obtained when comparing the results for repulsive and attractive voltages as well as for variation of the relative strength of the graphene-substrate coupling parameter. PMID- 22947853 TI - Delayed protein synthesis reduces the correlation between mRNA and protein fluctuations. AB - Recent experimental results indicate that, in single Escherichia coli cells, the fluctuations in mRNA level are uncorrelated with those of protein. However, a basic two-stage model for prokaryotic gene expression suggests that there ought to be a degree of correlation between the two. Therefore, it is important to investigate realistic modifications of the basic model that have the potential to reduce the theoretical level of the correlation. In this work, we focus on translational and reporter maturation delay, reporting that its introduction into the two-stage model reduces the cross correlation between instantaneous mRNA and protein levels. Our results indicate that the experimentally observed sample correlation coefficient between mRNA and protein levels may increase if the protein measurements are shifted back in time by the value of the delay. PMID- 22947854 TI - Atomic force microscopy stiffness tomography on living Arabidopsis thaliana cells reveals the mechanical properties of surface and deep cell-wall layers during growth. AB - Cell-wall mechanical properties play a key role in the growth and the protection of plants. However, little is known about genuine wall mechanical properties and their growth-related dynamics at subcellular resolution and in living cells. Here, we used atomic force microscopy (AFM) stiffness tomography to explore stiffness distribution in the cell wall of suspension-cultured Arabidopsis thaliana as a model of primary, growing cell wall. For the first time that we know of, this new imaging technique was performed on living single cells of a higher plant, permitting monitoring of the stiffness distribution in cell-wall layers as a function of the depth and its evolution during the different growth phases. The mechanical measurements were correlated with changes in the composition of the cell wall, which were revealed by Fourier-transform infrared (FTIR) spectroscopy. In the beginning and end of cell growth, the average stiffness of the cell wall was low and the wall was mechanically homogenous, whereas in the exponential growth phase, the average wall stiffness increased, with increasing heterogeneity. In this phase, the difference between the superficial and deep wall stiffness was highest. FTIR spectra revealed a relative increase in the polysaccharide/lignin content. PMID- 22947855 TI - A method for spatially resolved local intracellular mechanochemical sensing and organelle manipulation. AB - Because both the chemical and mechanical properties of living cells play crucial functional roles, there is a strong need for biophysical methods to address these properties simultaneously. Here we present a novel (to our knowledge) approach to measure local intracellular micromechanical and chemical properties using a hybrid magnetic chemical biosensor. We coupled a fluorescent dye, which serves as a chemical sensor, to a magnetic particle that is used for measurement of the viscoelastic environment by studying the response of the particle to magnetic force pulses. As a demonstration of the potential of this approach, we applied the method to study the process of phagocytosis, wherein cytoskeletal reorganization occurs in parallel with acidification of the phagosome. During this process, we measured the shear modulus and viscosity of the phagosomal environment concurrently with the phagosomal pH. We found that it is possible to manipulate phagocytosis by stalling the centripetal movement of the phagosome using magnetic force. Our results suggest that preventing centripetal phagosomal transport delays the onset of acidification. To our knowledge, this is the first report of manipulation of intracellular phagosomal transport without interfering with the underlying motor proteins or cytoskeletal network through biochemical methods. PMID- 22947856 TI - Atomic force microscopy reveals important differences in axonal resistance to injury. AB - Axonal degeneration after traumatic brain injury and nerve compression is considered a common underlying cause of temporary as well as permanent disability. Because a proper functioning of neural network requires phase coherence of all components, even subtle changes in circuitry may lead to network failure. However, it is still not possible to determine which axons will recover or degenerate after injury. Several groups have studied the pressure threshold for axonal injury within a nerve, but difficulty accessing the injured region; insufficient imaging methods and the extremely small dimensions involved have prevented the evaluation of the response of individual axons to injury. We combined microfluidics with atomic force microscopy and in vivo imaging to estimate the threshold force required to 1), uncouple axonal transport without impairing axonal survival, and 2), compromise axonal survival in both individual and bundled axons. We found that rat hippocampal axons completely recover axonal transport with no detectable axonal loss when compressed with pressures up to 65 +/- 30 Pa for 10 min, while dorsal root ganglia axons can resist to pressures up to 540 +/- 220 Pa. We investigated the reasons for the differential susceptibility of hippocampal and DRG axons to mechanical injury and estimated the elasticity of live axons. We found that dorsal root ganglia axons have a 20% lower elastic modulus than hippocampal axons. Our results emphasize the importance of the integrity of the axonal cytoskeleton in deciding the axonal fate after damage and open up new avenues to improve injury diagnosis and to identify ways to protect axons. PMID- 22947857 TI - Distinct kinetic and molecular requirements govern CD44 binding to hyaluronan versus fibrin(ogen). AB - CD44 is a multifunctional glycoprotein that binds to hyaluronan and fibrin(ogen). Alternative splicing is responsible for the generation of numerous different isoforms, the smallest of which is CD44s. Insertion of variant exons into the extracellular membrane proximal region generates the variant isoforms (CD44v). Here, we used force spectroscopy to delineate the biophysical and molecular requirements of CD44-HA and CD44-fibrin(ogen) interactions at the single-molecule level. CD44v-HA and CD44s-HA single bonds exhibit similar kinetic and micromechanical properties because the HA-binding motif on CD44 is common to all of the isoforms. Although this is the primary binding site, O- and N-linked glycans and sulfation also contribute to the tensile strength of the CD44-HA bond. The CD44s-fibrin pair has a lower unstressed dissociation rate and a higher tensile strength than CD44s-fibrinogen but is weaker than the CD44-HA bond. In contrast to CD44-HA binding, the molecular interaction between CD44 and fibrin(ogen) is predominantly mediated by the chondroitin sulfate and dermatan sulfate on CD44. Blocking sulfation on CD44s modestly decreases the tensile strength of CD44s-fibrin(ogen) binding, which is in stark contrast to CD44v fibrin interaction. Collectively, the results obtained by force spectroscopy in conjunction with biochemical interventions enable us to delineate the biophysical parameters and molecular constituents of CD44 binding to hyaluronan and fibrin(ogen). PMID- 22947858 TI - Crowding effects on the formation and maintenance of nuclear bodies: insights from molecular-dynamics simulations of simple spherical model particles. AB - The physics of structure formation and maintenance of nuclear bodies (NBs), such as nucleoli, Cajal bodies, promyelocytic leukemia bodies, and speckles, in a crowded nuclear environment remains largely unknown. We investigate the role of macromolecular crowding in the formation and maintenance of NBs using computer simulations of a simple spherical model, called Lennard-Jones (LJ) particles. LJ particles form a one-phase, dilute fluid when the intermolecular interaction is weaker than a critical value, above which they phase separate and form a condensed domain. We find that when volume-exclusive crowders exist in significant concentrations, domain formation is induced even for weaker intermolecular interactions, and the effect is more pronounced with increasing crowder concentration. Simulation results show that a previous experimental finding that promyelocytic leukemia bodies disappear in the less-crowded condition and reassemble in the normal crowded condition can be interpreted as a consequence of the increased intermolecular interactions between NB proteins due to crowding. Based on further analysis of the simulation results, we discuss the acceleration of macromolecular associations that occur within NBs, and the delay of diffusive transport of macromolecules within and out of NBs when the crowder concentration increases. This study suggests that in a polydisperse nuclear environment that is enriched with a variety of macromolecules, macromolecular crowding not only plays an important role in the formation and maintenance of NBs, but also may perform some regulatory functions in response to alterations in the crowding conditions. PMID- 22947859 TI - Multi-ion distributions in the cytoplasmic domain of inward rectifier potassium channels. AB - Inward rectifier potassium (Kir) channels act as cellular diodes, allowing unrestricted flow of potassium (K(+)) into the cell while preventing currents of large magnitude in the outward direction. The rectification mechanism by which this occurs involves a coupling between K(+) and intracellular blockers-magnesium (Mg(2+)) or polyamines-that simultaneously occupy the permeation pathway. In addition to the transmembrane pore, Kirs possess a large cytoplasmic domain (CD) that provides a favorable electronegative environment for cations. Electrophysiological experiments have shown that the CD is a key regulator of both conductance and rectification. In this study, we calculate and compare averaged equilibrium probability densities of K(+) and Cl(-) in open-pore models of the CDs of a weak (Kir1.1-ROMK) and a strong (Kir2.1-IRK) rectifier through explicit-solvent molecular-dynamics simulations in ~1 M KCl. The CD of both channels concentrates K(+) ions greater than threefold inside the cytoplasmic pore while IRK shows an additional K(+) accumulation region near the cytoplasmic entrance. Simulations carried out with Mg(2+) or spermine (SPM(4+)) show that these ions interact with pore-lining residues, shielding the surface charge and reducing K(+) in both channels. The results also show that SPM(4+) behaves differently inside these two channels. Although SPM(4+) remains inside the CD of ROMK, it diffuses around the entire volume of the pore. In contrast, this polyatomic cation finds long-lived conformational states inside the IRK pore, interacting with residues E224, D259, and E299. The strong rectifier CD is also capable of sequestering an additional SPM(4+) at the cytoplasmic entrance near a cluster of negative residues D249, D274, E275, and D276. Although understanding the actual mechanism of rectification blockade will require high-resolution structural information of the blocked state, these simulations provide insight into how sequence variation in the CD can affect the multi-ion distributions that underlie the mechanisms of conduction, rectification affinity, and kinetics. PMID- 22947860 TI - Structure changes upon deprotonation of the proton release group in the bacteriorhodopsin photocycle. AB - In the photocycle of bacteriorhodopsin at pH 7, a proton is ejected to the extracellular medium during the protonation of Asp-85 upon formation of the M intermediate. The group that releases the ejected proton does not become reprotonated until the prephotolysis state is restored from the N and O intermediates. In contrast, at acidic pH, this proton release group remains protonated to the end of the cycle. Time-resolved Fourier transform infrared measurements obtained at pH 5 and 7 were fitted to obtain spectra of kinetic intermediates, from which the spectra of M and N/O versus unphotolyzed state were calculated. Vibrational features that appear in both M and N/O spectra at pH 7, but not at pH 5, are attributable to deprotonation from the proton release group and resulting structural alterations. Our results agree with the earlier conclusion that this group is a protonated internal water cluster, and provide a stronger experimental basis for this assignment. A decrease in local polarity at the N-C bond of the side chain of Lys-216 resulting from deprotonation of this water cluster may be responsible for the increase in the proton affinity of Asp 85 through M and N/O, which is crucial for maintaining the directionality of proton pumping. PMID- 22947862 TI - Quantitative analysis of amyloid-integrated biofilms formed by uropathogenic Escherichia coli at the air-liquid interface. AB - Bacterial biofilms are complex multicellular assemblies, characterized by a heterogeneous extracellular polymeric matrix, that have emerged as hallmarks of persistent infectious diseases. New approaches and quantitative data are needed to elucidate the composition and architecture of biofilms, and such data need to be correlated with mechanical and physicochemical properties that relate to function. We performed a panel of interfacial rheological measurements during biofilm formation at the air-liquid interface by the Escherichia coli strain UTI89, which is noted for its importance in studies of urinary tract infection and for its assembly of functional amyloid fibers termed curli. Brewster-angle microscopy and measurements of the surface elasticity (G(s)') and stress-strain response provided sensitive and quantitative parameters that revealed distinct stages during bacterial colonization, aggregation, and eventual formation of a pellicle at the air-liquid interface. Pellicles that formed under conditions that upregulate curli production exhibited an increase in strength and viscoelastic properties as well as a greater ability to recover from stress-strain perturbation. The results suggest that curli, as hydrophobic extracellular amyloid fibers, enhance the strength, viscoelasticity, and resistance to strain of E. coli biofilms formed at the air-liquid interface. PMID- 22947861 TI - Binding of beta-amyloid (1-42) peptide to negatively charged phospholipid membranes in the liquid-ordered state: modeling and experimental studies. AB - To explore the initial stages of amyloid beta peptide (Abeta42) deposition on membranes, we have studied the interaction of Abeta42 in the monomeric form with lipid monolayers and with bilayers in either the liquid-disordered or the liquid ordered (L(o)) state, containing negatively charged phospholipids. Molecular dynamics (MD) simulations of the system have been performed, as well as experimental measurements. For bilayers in the L(o) state, in the absence of the negatively charged lipids, interaction is weak and it cannot be detected by isothermal calorimetry. However, in the presence of phosphatidic acid, or of cardiolipin, interaction is detected by different methods and in all cases interaction is strongest with lower (2.5-5 mol%) than higher (10-20 mol%) proportions of negatively charged phospholipids. Liquid-disordered bilayers consistently allowed a higher Abeta42 binding than L(o) ones. Thioflavin T assays and infrared spectroscopy confirmed a higher proportion of beta-sheet formation under conditions when higher peptide binding was measured. The experimental results were supported by MD simulations. We used 100 ns MD to examine interactions between Abeta42 and three different 512 lipid bilayers consisting of palmitoylsphingomyelin, dimyristoyl phosphatidic acid, and cholesterol in three different proportions. MD pictures are different for the low- and high-charge bilayers, in the former case the peptide is bound through many contact points to the bilayer, whereas for the bilayer containing 20 mol% anionic phospholipid only a small fragment of the peptide appears to be bound. The MD results indicate that the binding and fibril formation on the membrane surface depends on the composition of the bilayer, and is the result of a subtle balance of many inter- and intramolecular interactions between the Abeta42 and membrane. PMID- 22947863 TI - Reorientation and dimerization of the membrane-bound antimicrobial peptide PGLa from microsecond all-atom MD simulations. AB - The membrane-active antimicrobial peptide PGLa from Xenopus laevis is known from solid-state (2)H-, (15)N-, and (19)F-NMR spectroscopy to occupy two distinct alpha-helical surface adsorbed states in membranes: a surface-bound S-state with a tilt angle of ~95 degrees at low peptide/lipid molar ratio (P/L = 1:200), and an obliquely tilted T-state with a tilt angle of 127 degrees at higher peptide concentration (P/L = 1:50). Using a rapid molecular-dynamics insertion protocol in combination with microsecond-scale simulation, we have characterized the structure of both states in detail. As expected, the amphiphilic peptide resides horizontally on the membrane surface in a monomeric form at a low P/L, whereas the T-state is seen in the simulations to be a symmetric antiparallel dimer, with close contacts between small glycine and alanine residues at the interface. The computed tilt angles and azimuthal rotations, as well as the quadrupolar splittings predicted from the simulations agree with the experimental NMR data. The simulations reveal many structural details previously inaccessible, such as the immersion depth of the peptide in the membrane and the packing of the dimerization interface. The study highlights the ability and limitations of current state-of-the-art multimicrosecond all-atom simulations of membrane-active peptides to complement experimental data from solid-state NMR. PMID- 22947864 TI - The dynamics of Bax channel formation: influence of ionic strength. AB - Mitochondrial outer membrane permeabilization (MOMP) is a complex multistep process. Studies of MOMP in vivo are limited by the stochastic variability of MOMP between cells and rapid completion of IMS protein release within single cells. In vitro models have provided useful insights into MOMP. We have investigated the dynamics of Bax-mediated MOMP in isolated mitochondria using ionic strength as a tool to control the rate of MOMP. We find that Bax can induce both transient permeabilization, detected by protein release, and more substantial long-lasting permeabilization, measured by the rate of oxidation of added cytochrome c. We found that higher ionic strength causes Bax to form small channels quickly but the expansion of these early channels is impeded. This inhibitory effect of ionic strength is independent of tBid. Channels formed under low ionic strength are not destabilized by raising the ionic strength. Increase in ionic strength also increases the ability of Bcl-xL to inhibit Bax-mediated MOMP. Ionic strength does not affect Bax insertion into mitochondria. Thus, ionic strength influences the assembly of Bax molecules already in membrane into channels. Ionic strength can be used as an effective biophysical tool to study Bax-mediated channel formation. PMID- 22947865 TI - Measuring molecular motor forces in vivo: implications for tug-of-war models of bidirectional transport. AB - Molecular motor proteins use the energy released from ATP hydrolysis to generate force and haul cargoes along cytoskeletal filaments. Thus, measuring the force motors generate amounts to directly probing their function. We report on optical trapping methodology capable of making precise in vivo stall-force measurements of individual cargoes hauled by molecular motors in their native environment. Despite routine measurement of motor forces in vitro, performing and calibrating such measurements in vivo has been challenging. We describe the methodology recently developed to overcome these difficulties, and used to measure stall forces of both kinesin-1 and cytoplasmic dynein-driven lipid droplets in Drosophila embryos. Critically, by measuring the cargo dynamics in the optical trap, we find that there is memory: it is more likely for a cargo to resume motion in the same direction-rather than reverse direction-after the motors transporting it detach from the microtubule under the force of the optical trap. This suggests that only motors of one polarity are active on the cargo at any instant in time and is not consistent with the tug-of-war models of bidirectional transport where both polarity motors can bind the microtubules at all times. We further use the optical trap to measure in vivo the detachment rates from microtubules of kinesin-1 and dynein-driven lipid droplets. Unlike what is commonly assumed, we find that dynein's but not kinesin's detachment time in vivo increases with opposing load. This suggests that dynein's interaction with microtubules behaves like a catch bond. PMID- 22947867 TI - QUAFIT: a novel method for the quaternary structure determination from small angle scattering data. AB - The new QUAFIT method for determining the quaternary structure of biological macromolecular assemblies by analyzing x-ray or neutron small-angle scattering data is presented. The method is based on the idea that asymmetric monomers, formed by rigid domains of known atomic structure possibly connected by flexible linkers of known sequence, are assembled according to a point-group symmetry combined with a screw axis. Scattering amplitudes of domains and linkers are determined by means of a spherical harmonics expansion and combined to get the form factor of the assembly. To avoid any overlap among domains, the contact distance between two asymmetric domains is determined as a function of their orientation by a new algorithm, based on Stone's Invariants expansion. To account for continuity and compactness of the whole assembly, an anisotropic Lennard Jones potential among domains, written in terms of the contact distances, is included in the merit function. QUAFIT allows for the simultaneous presence of oligomerization intermediates as well as of monomers distributed over multiple conformations. QUAFIT has been tested by studying the structure of a high molecular weight protein, the hemocyanin from Octopus vulgaris, under solution conditions that stabilize the decameric form or induce dissociation into monomers, respectively. Results are in very good agreement with the structural model derived from electron microscopy observations. PMID- 22947866 TI - Mechanical coupling between myosin molecules causes differences between ensemble and single-molecule measurements. AB - In contracting muscle, individual myosin molecules function as part of a large ensemble, hydrolyzing ATP to power the relative sliding of actin filaments. The technological advances that have enabled direct observation and manipulation of single molecules, including recent experiments that have explored myosin's force dependent properties, provide detailed insight into the kinetics of myosin's mechanochemical interaction with actin. However, it has been difficult to reconcile these single-molecule observations with the behavior of myosin in an ensemble. Here, using a combination of simulations and theory, we show that the kinetic mechanism derived from single-molecule experiments describes ensemble behavior; but the connection between single molecule and ensemble is complex. In particular, even in the absence of external force, internal forces generated between myosin molecules in a large ensemble accelerate ADP release and increase how far actin moves during a single myosin attachment. These myosin-induced changes in strong binding lifetime and attachment distance cause measurable properties, such as actin speed in the motility assay, to vary depending on the number of myosin molecules interacting with an actin filament. This ensemble-size effect challenges the simple detachment limited model of motility, because even when motility speed is limited by ADP release, increasing attachment rate can increase motility speed. PMID- 22947868 TI - Normal and reversed supramolecular chirality of insulin fibrils probed by vibrational circular dichroism at the protofilament level of fibril structure. AB - Fibrils are beta-sheet-rich aggregates that are generally composed of several protofibrils and may adopt variable morphologies, such as twisted ribbons or flat like sheets. This polymorphism is observed for many different amyloid associated proteins and polypeptides. In a previous study we proposed the existence of another level of amyloid polymorphism, namely, that associated with fibril supramolecular chirality. Two chiral polymorphs of insulin, which can be controllably grown by means of small pH variations, exhibit opposite signs of vibrational circular dichroism (VCD) spectra. Herein, using atomic force microscopy (AFM) and scanning electron microscopy (SEM), we demonstrate that indeed VCD supramolecular chirality is correlated not only by the apparent fibril handedness but also by the sense of supramolecular chirality from a deeper level of chiral organization at the protofilament level of fibril structure. Our microscopic examination indicates that normal VCD fibrils have a left-handed twist, whereas reversed VCD fibrils are flat-like aggregates with no obvious helical twist as imaged by atomic force microscopy or scanning electron microscopy. A scheme is proposed consistent with observed data that features a dynamic equilibrium controlled by pH at the protofilament level between left- and right-twist fibril structures with distinctly different aggregation pathways for left- and right-twisted protofilaments. PMID- 22947869 TI - Lipid loading of human vascular smooth muscle cells induces changes in tropoelastin protein levels and physical structure. AB - Aggregated low-density lipoprotein (agLDL), one of the main LDL modifications in the arterial intima, contributes to massive intracellular cholesteryl ester (CE) accumulation in human vascular smooth muscle cells (VSMC), which are major producers of elastin in the vascular wall. Our aim was to analyze the levels, physical structure, and molecular mobility of tropoelastin produced by agLDL loaded human VSMC (agLDL-VSMC) versus that produced by control VSMC. Western blot analysis demonstrated that agLDL reduced VSMC-tropoelastin protein levels by increasing its degradation rate. Moreover, our results demonstrated increased levels of precursor and mature forms of cathepsin S in agLDL-VSMC. Fourier transform infrared analysis revealed modifications in the secondary structures of tropoelastin produced by lipid-loaded VSMCs. Thermal and dielectric analyses showed that agLDL-VSMC tropoelastin has decreased glass transition temperatures and distinct chain dynamics that, in addition to a loss of thermal stability, lead to strong changes in its mechanical properties. In conclusion, agLDL lipid loading of human vascular cells leads to an increase in cathepsin S production concomitantly with a decrease in cellular tropoelastin protein levels and dramatic changes in secreted tropoelastin physical structure. Therefore, VSMC lipid loading likely determines alterations in the mechanical properties of the vascular wall and plays a crucial role in elastin loss during atherosclerosis. PMID- 22947870 TI - Calmodulin binds a highly extended HIV-1 MA protein that refolds upon its release. AB - Calmodulin (CaM) expression is upregulated upon HIV-1 infection and interacts with proteins involved in viral processing, including the multifunctional HIV-1 MA protein. We present here the results of studies utilizing small-angle neutron scattering with contrast variation that, when considered in the light of earlier fluorescence and NMR data, show CaM binds MA in an extended open-clamp conformation via interactions with two tryptophans that are widely spaced in sequence and space. The interaction requires a disruption of the MA tertiary fold such that MA becomes highly extended in a long snakelike conformation. The CaM-MA interface is extensive, covering ~70% of the length of the MA such that regions known to be important in MA interactions with critical binding partners would be impacted. The CaM conformation is semiextended and as such is distinct from the classical CaM-collapse about short alpha-helical targets. NMR data show that upon dissociation of the CaM-MA complex, either by the removal of Ca(2+) or increasing ionic strength, MA reforms its native tertiary contacts. Thus, we observe a high level of structural plasticity in MA that may facilitate regulation of its activities via intracellular Ca(2+)-signaling during viral processing. PMID- 22947871 TI - Binding of Congo red to amyloid protofibrils of the Alzheimer Abeta(9-40) peptide probed by molecular dynamics simulations. AB - Congo red (CR) is a commonly used histological amyloid dye and a weak amyloid inhibitor. There is currently no experimentally available structure of CR bound to an amyloid fibril and the binding modes, and the mechanisms governing its inhibitory and optical properties are poorly understood. In this work, we present the first, to our knowledge, atomistically detailed picture of CR binding to protofibrils of the Alzheimer Abeta(9-40) peptide. We identify three major binding modes, with the primary mode residing in the grooves formed by the beta sheets, and observe a restriction of the torsional rotation of the CR molecule upon binding. Our simulations reveal a novel, to our knowledge, electrostatic steering mechanism that plays an important role in the initial recognition and binding of CR to the positively charged surface residues of the fibril. Our simulations provide new, to our knowledge, insights into the striking spectrophotometric and inhibitory properties of CR. In particular, we show that birefringence upon CR binding is due to the anisotropic orientation of the CR dipoles resulting from the spatial ordering of these molecules in the grooves along the fibril axis. The fluorescent enhancement of the bound CR, in turn, is associated with the torsional restriction of this molecule upon binding. PMID- 22947872 TI - Chaperone-like effect of the linker on the isolated C-terminal domain of rabbit muscle creatine kinase. AB - Intramolecular chaperones (IMCs), which are specific domains/segments encoded in the primary structure of proteins, exhibit chaperone-like activity against the aggregation of the other domains in the same molecule. In this research, we found that the truncation of the linker greatly promoted the thermal aggregation of the isolated C-terminal domain (CTD) of rabbit muscle creatine kinase (RMCK). Either the existence of the linker covalently linked to CTD or the supply of the synthetic linker peptide additionally could successfully protect the CTD of RMCK against aggregation in a concentration-dependent manner. Truncated fragments of the linker also behaved as a chaperone-like effect with lower efficiency, revealing the importance of its C-terminal half in the IMC function of the linker. The aggregation sites in the CTD of RMCK were identified by molecular dynamics simulations. Mutational analysis of the three key hydrophobic residues resulted in opposing effects on the thermal aggregation between the CTD with intact or partial linker, confirming the role of linker as a lid to protect the hydrophobic residues against exposure to solvent. These observations suggested that the linkers in multidomain proteins could act as IMCs to facilitate the correct folding of the aggregation-prone domains. Furthermore, the intactness of the IMC linker after proteolysis modulates the production of off-pathway aggregates, which may be important to the onset of some diseases caused by the toxic effects of aggregated proteolytic fragments. PMID- 22947873 TI - Self-assembly of thin plates from micrococcal nuclease-digested chromatin of metaphase chromosomes. AB - The three-dimensional organization of the enormously long DNA molecules packaged within metaphase chromosomes has been one of the most elusive problems in structural biology. Chromosomal DNA is associated with histones and different structural models consider that the resulting long chromatin fibers are folded forming loops or more irregular three-dimensional networks. Here, we report that fragments of chromatin fibers obtained from human metaphase chromosomes digested with micrococcal nuclease associate spontaneously forming multilaminar platelike structures. These self-assembled structures are identical to the thin plates found previously in partially denatured chromosomes. Under metaphase ionic conditions, the fragments that are initially folded forming the typical 30-nm chromatin fibers are untwisted and incorporated into growing plates. Large plates can be self-assembled from very short chromatin fragments, indicating that metaphase chromatin has a high tendency to generate plates even when there are many discontinuities in the DNA chain. Self-assembly at 37 degrees C favors the formation of thick plates having many layers. All these results demonstrate conclusively that metaphase chromatin has the intrinsic capacity to self-organize as a multilayered planar structure. A chromosome structure consistent of many stacked layers of planar chromatin avoids random entanglement of DNA, and gives compactness and a high physical consistency to chromatids. PMID- 22947874 TI - Role of beta-hairpin formation in aggregation: the self-assembly of the amyloid beta(25-35) peptide. AB - The amyloid-beta(25-35) peptide plays a key role in the etiology of Alzheimer's disease due to its extreme toxicity even in the absence of aging. Because of its high tendency to aggregate and its low solubility in water, the structure of this peptide is still unknown. In this work, we sought to understand the early stages of aggregation of the amyloid-beta(25-35) peptide by conducting simulations of oligomers ranging from monomers to tetramers. Our simulations show that although the monomer preferentially adopts a beta-hairpin conformation, larger aggregates have extended structures, and a clear transition from compact beta-hairpin conformations to extended beta-strand structures occurs between dimers and trimers. Even though beta-hairpins are not present in the final architecture of the fibril, our simulations indicate that they play a critical role in fibril growth. Our simulations also show that beta-sheet structures are stabilized when a beta-hairpin is present at the edge of the sheet. The binding of the hairpin to the sheet leads to a subsequent destabilization of the hairpin, with part of the hairpin backbone dangling in solution. This free section of the peptide can then recruit an extra monomer from solution, leading to further sheet extension. Our simulations indicate that the peptide must possess sufficient conformational flexibility to switch between a hairpin and an extended conformation in order for beta-sheet extension to occur, and offer a rationalization for the experimental observation that overstabilizing a hairpin conformation in the monomeric state (for example, through chemical cross-linking) significantly hampers the fibrillization process. PMID- 22947876 TI - Smoothing of the GB1 hairpin folding landscape by interfacial confinement. AB - We study the effects of confinement between planar walls on the folding thermodynamics of a beta-hairpin, using large-scale replica-exchange molecular dynamics simulations with an all-atom model and explicit solvent. We find that the folding free-energy landscape of this peptide observed in bulk is significantly modified when the peptide is confined between the walls. Most notably, the propensity of the peptide to form a misfolded state observed in the bulk solution becomes negligible under confinement. The absence of the misfolded state under confinement can be explained by an increased tendency of hydrophobic aromatic side chains to stay near the walls, because the misfolded state is characterized by a nonnative arrangement of aromatic side chains. These results from a simple confinement model may provide clues about the role of chaperonin confinement in smoothing folding landscapes by avoiding trapped intermediates. PMID- 22947875 TI - Rapid calculation of protein pKa values using Rosetta. AB - We developed a Rosetta-based Monte Carlo method to calculate the pK(a) values of protein residues that commonly exhibit variable protonation states (Asp, Glu, Lys, His, and Tyr). We tested the technique by calculating pK(a) values for 264 residues from 34 proteins. The standard Rosetta score function, which is independent of any environmental conditions, failed to capture pK(a) shifts. After incorporating a Coulomb electrostatic potential and optimizing the solvation reference energies for pK(a) calculations, we employed a method that allowed side-chain flexibility and achieved a root mean-square deviation (RMSD) of 0.83 from experimental values (0.68 after discounting 11 predictions with an error over 2 pH units). Additional degrees of side-chain conformational freedom for the proximal residues facilitated the capture of charge-charge interactions in a few cases, resulting in an overall RMSD of 0.85 pH units. The addition of backbone flexibility increased the overall RMSD to 0.93 pH units but improved relative pK(a) predictions for proximal catalytic residues. The method also captures large pK(a) shifts of lysine and some glutamate point mutations in staphylococcal nuclease. Thus, a simple and fast method based on the Rosetta score function and limited conformational sampling produces pK(a) values that will be useful when rapid estimation is essential, such as in docking, design, and folding. PMID- 22947877 TI - High density waves of the bacterium Pseudomonas aeruginosa in propagating swarms result in efficient colonization of surfaces. AB - This work describes a new, to our knowledge, strategy of efficient colonization and community development where bacteria substantially alter their physical environment. Many bacteria move in groups, in a mode described as swarming, to colonize surfaces and form biofilms to survive external stresses, including exposure to antibiotics. One such bacterium is Pseudomonas aeruginosa, which is an opportunistic pathogen responsible for both acute and persistent infections in susceptible individuals, as exampled by those for burn victims and people with cystic fibrosis. Pseudomonas aeruginosa often, but not always, forms branched tendril patterns during swarming; this phenomena occurs only when bacteria produce rhamnolipid, which is regulated by population-dependent signaling called quorum sensing. The experimental results of this work show that P. aeruginosa cells propagate as high density waves that move symmetrically as rings within swarms toward the extending tendrils. Biologically justified cell-based multiscale model simulations suggest a mechanism of wave propagation as well as a branched tendril formation at the edge of the population that depends upon competition between the changing viscosity of the bacterial liquid suspension and the liquid film boundary expansion caused by Marangoni forces. Therefore, P. aeruginosa efficiently colonizes surfaces by controlling the physical forces responsible for expansion of thin liquid film and by propagating toward the tendril tips. The model predictions of wave speed and swarm expansion rate as well as cell alignment in tendrils were confirmed experimentally. The study results suggest that P. aeruginosa responds to environmental cues on a very short timescale by actively exploiting local physical phenomena to develop communities and efficiently colonize new surfaces. PMID- 22947878 TI - pH wave-front propagation in the urea-urease reaction. AB - The urease-catalyzed hydrolysis of urea displays feedback that results in a switch from acid (pH ~3) to base (pH ~9) after a controllable period of time (from 10 to >5000 s). Here we show that the spatially distributed reaction can support pH wave fronts propagating with a speed of the order of 0.1-1 mm min(-1). The experimental results were reproduced qualitatively in reaction-diffusion simulations including a Michaelis-Menten expression for the urease reaction with a bell-shaped rate-pH dependence. However, this model fails to predict that at lower enzyme concentrations, the unstirred reaction does not always support fronts when the well-stirred reaction still rapidly switches to high pH. PMID- 22947879 TI - Bayesian approach to MSD-based analysis of particle motion in live cells. AB - Quantitative tracking of particle motion using live-cell imaging is a powerful approach to understanding the mechanism of transport of biological molecules, organelles, and cells. However, inferring complex stochastic motion models from single-particle trajectories in an objective manner is nontrivial due to noise from sampling limitations and biological heterogeneity. Here, we present a systematic Bayesian approach to multiple-hypothesis testing of a general set of competing motion models based on particle mean-square displacements that automatically classifies particle motion, properly accounting for sampling limitations and correlated noise while appropriately penalizing model complexity according to Occam's Razor to avoid over-fitting. We test the procedure rigorously using simulated trajectories for which the underlying physical process is known, demonstrating that it chooses the simplest physical model that explains the observed data. Further, we show that computed model probabilities provide a reliability test for the downstream biological interpretation of associated parameter values. We subsequently illustrate the broad utility of the approach by applying it to disparate biological systems including experimental particle trajectories from chromosomes, kinetochores, and membrane receptors undergoing a variety of complex motions. This automated and objective Bayesian framework easily scales to large numbers of particle trajectories, making it ideal for classifying the complex motion of large numbers of single molecules and cells from high-throughput screens, as well as single-cell-, tissue-, and organism level studies. PMID- 22947880 TI - Tuning the voltage-sensor motion with a single residue. AB - The Ciona intestinalis voltage-sensitive phosphatase (Ci-VSP) represents the first discovered member of enzymes regulated by a voltage-sensor domain (VSD) related to the VSD found in voltage-gated ion channels. Although the VSD operation in Ci-VSP exhibits original voltage dependence and kinetics compared to ion channels, it has been poorly investigated. Here, we show that the kinetics and voltage dependence of VSD movement in Ci-VSP can be tuned over 2 orders of magnitude and shifted over 120 mV, respectively, by the size of a conserved isoleucine (I126) in the S1 segment, thus indicating the importance of this residue in Ci-VSP activation. Mutations of the conserved Phe in the S2 segment (F161) do not significantly perturb the voltage dependence of the VSD movement, suggesting a unique voltage sensing mechanism in Ci-VSP. PMID- 22947881 TI - Group treatment for depression in mothers of young children compared to standard individual therapy. AB - BACKGROUND: Studies on specific psychotherapy for depressed mothers of small children are rare. The aim of the present study was to investigate the effectiveness of a newly developed cognitive-behavioral group intervention for depressed mothers compared to standard individual therapy. SAMPLING AND METHODS: In a naturalistic design, 31 mothers suffering from depressive disorders with children aged <=4 years who had consecutively been admitted to our specialized clinic for mentally ill mothers were assigned to the group treatment, and the following 21 were admitted to the control group receiving standard individual therapy. The group treatment consisted of 12 group sessions and 1 couple session and was administered to five consecutive groups. Participants completed interviews and questionnaires - the Beck Depression Inventory and the Symptom Checklist- 90-R - before and 3 months after therapy. RESULTS: The treatment group and the control group showed a significant improvement in their depression, with no significant differences between the two treatment strategies. The women in group therapy, however, required fewer antidepressants, and group treatment was observed to be more effective in reducing anger and hostility. CONCLUSION: This form of group treatment for depressed women in early motherhood may have some important advantages over individual therapy; effects were small, however, and should be replicated in a further study. PMID- 22947882 TI - Improving healthy eating in families with a toddler at risk for overweight: a cluster randomized controlled trial. AB - OBJECTIVE: To ascertain whether a parent education program based on Satter's division of responsibility in feeding children (DOR) is effective in enhancing parent/child feeding interactions for children with an overweight/obese parent. The primary hypothesis was that the intervention would decrease parental pressure to eat. METHODS: Sixty-two families with a child between 2 and 4 years with at least 1 overweight/obese parent were randomly allocated using a cluster design to either the DOR intervention or a control group. The control group focused on increasing family consumption of healthy foods and activity levels and enhancing child sleep duration. The primary outcome was parent pressure on their child to eat. RESULTS: The DOR intervention was superior to the control group in reducing the pressure to eat. Two moderators of pressure to eat were found: disinhibition of eating and hunger. The parents in the DOR group, irrespective of disinhibition levels, lowered the pressure to eat, whereas those in the control group with low disinhibition increased the pressure to eat. There were similar findings for hunger. Gender moderated restrictive feeding with DOR parents lowering restriction more than parents of the control group in girls only. CONCLUSION: The DOR intervention was more effective in reducing the parent pressure to eat and food restriction (in girls only) than the control group. PMID- 22947883 TI - Ethical challenges in the care of children and families affected by life-limiting neuromuscular diseases. AB - OBJECTIVE: We sought to understand how neuromuscular clinicians respond to the ethical challenges that arise in caring for children with life-limiting neuromuscular diseases. METHODS: We conducted a national survey of interdisciplinary professionals who care for children with Duchenne Muscular Dystrophy and Spinal Muscular Atrophy Type-1 to document their knowledge, attitudes, beliefs and reported practices with regard to prominent ethical challenges, and their suggestions for ethics interventions that would assist them in improving clinical practice. RESULTS: 157 participants completed paper or electronic surveys for an overall participation rate of 24%. A significant minority of respondents were either unaware of or chose not to adopt relevant ethical guidelines, and reported experiencing crises of conscience in the care of their patients. In response to 8 ethical dilemmas, there was variability in how often respondents encountered them, their comfort in addressing them, and their reported practices, including only 24% who have requested ethics consultation. CONCLUSION: Training of interdisciplinary clinicians is needed to improve their adoption of relevant ethical guidelines, cultivate greater awareness of diverse attitudes regarding the ethical permissibility of different treatment options and the utility of ethics consultation, and foster greater confidence and competence in responding to ethical challenges that arise in pediatric neuromuscular practice. PMID- 22947885 TI - Stimulants to enhance academic achievement. AB - In a survey from a large urban community, a significant number of students in elite middle schools and high schools report using stimulants as grade enhancers. Falsifying symptoms of attention-deficit hyperactivity disorder at the time of a doctor visit is a frequently used method to obtain a prescription for a stimulant. There is a role for pediatricians to prevent this abuse of medication. PMID- 22947884 TI - Infant communication and subsequent language development in children from low income families: the role of early cognitive stimulation. AB - OBJECTIVES: To explore the relationship between early cognitive stimulation in the home, 6-month infant communication, and 24-month toddler language in a low socioeconomic status sample. METHODS: Longitudinal analyses of mother-child dyads participating in larger study of early child development were performed. Dyads enrolled postpartum in an urban public hospital. Cognitive stimulation in the home at 6 months was assessed using StimQ-lnfant, including provision of toys, shared reading, teaching, and verbal responsivity. Early infant communication was assessed at 6 months including the following: (1) Emotion and eye gaze (Communication and Symbolic Behavior Scale DP-CSBS DP), (2) Communicative bids (CSBS DP), and (3) Expression of emotion (Short Temperament Scale for Infants). Toddler language was assessed at 24 months using the Preschool Language Scale-4, including the following: (1) expressive language and (2) auditory comprehension. RESULTS: Three hundred twenty families were assessed. In structural equation models, cognitive stimulation in the home was strongly associated with early infant communication (beta = 0.63, p <.0001) and was predictive of 24-month language (beta = 0.20, p <.05). The effect of early cognitive stimulation on 24 month language was mediated through early impacts on infant communication (Indirect beta = 0.28, p =.001). Reading, teaching, availability of learning materials, and other reciprocal verbal interactions were all related directly to infant communication and indirectly to language outcomes. CONCLUSIONS: The impact of early cognitive stimulation on toddler language is manifested through early associations with infant communication. Pediatric primary care providers should promote cognitive stimulation beginning in early infancy and support the expansion and dissemination of intervention programs such as Reach Out and Read and the Video Interaction Project. PMID- 22947886 TI - Growth--and documentation-deficits: where to start in helping families. AB - REFERENCE: Pedro is a 2-year 7-month-old boy who was presented for the first time after a visit to a local emergency room (ER) for diarrhea. At the time of his birth, his undocumented mother, Clara, was 20 years old, uninsured, and with limited English proficiency living approximately 400 miles south of our practice in a different state. Although she had been brought to the United States as a child, she had never finished high school. Pedro was born what mother thought was full-term at his parent's home, where a lay midwife assisted during the delivery. Pedro was not brought to a medical facility at birth; therefore, neither medical nor legal documentation of his birth in the United States, or elsewhere, existed.After enduring 4 years of ongoing verbal and physical abuse, Clara fled to her maternal aunt in our community. The child's initial exposure to medical care was during the emergency visit, which ended up in referral to us. The ED physician suggested that the child visit a primary care physician, but establishment of pediatric care was not made until months later. The child received his first vaccines and immediately was referred to the Growth and Nutrition clinic due to mild wasting and stunting based on Waterlow criteria.Pedro speaks both English and Spanish and has no 2-word combinations and a 50-word combined vocabulary in English and Spanish. In addition, a complete blood count was consistent with iron deficiency anemia, but both sickle cell and G6PD screening are negative.The nutritionist from the specialty clinic obtained a detailed history including overall appetite, feeding skills, meal plans, and eating environment noting that the child was a competent finger feeder. The family's meals were distributed throughout the day as a meal at home and a shared fast food meal while accompanying mother, as she worked as a hair stylist 6 days per week. In addition, the diet is supplemented by rice water mixed with sugar and ground carrots throughout the day.Where would you head next? PMID- 22947887 TI - Development of the insight scale for affective disorders (ISAD): modification from the scale to assess unawareness of mental disorder. AB - BACKGROUND: Research on insight in patients with mood disorders has grown in recent years. Several instruments to assess insight have been used, but most of them have been specifically designed for psychosis and may not appear relevant to mood disorders. The aim of the present study is to develop a short, multidimensional, reliable and valid scale to measure insight in patients with mood disorders, based on the Amador's Scale to Assess Unawareness of Mental Disorders (SUMD). METHOD: A Delphi method was used to facilitate expert participation and ensure face and content validity. The SUMD structure and items were used as a reference in the scale development. A new scale with 17 items was obtained. Internal consistency, test-retest and inter-rater reliability and validity were studied in a sample of 76 outpatients with a DSM-IV diagnosis of major depression or bipolar disorder (type I or II). RESULTS: Internal consistency of the general items was moderate, and high for the symptoms awareness subscale. Scores on ISAD correlated with other measures of insight and with some clinical measures, thus supporting its validity. LIMITATIONS: The majority of the sample came from community services. Future studies should use inpatients or patients with severe symptoms to broaden the range of responses. Moreover, the rating of insight and other measures by the same clinician might introduce a methodological bias. CONCLUSION: The ISAD, with a multidimensional approach, appears as a short, reliable and valid measure of insight in mood disorders. Expert consensus ensures its face and content validity. PMID- 22947888 TI - Response to commentaries on 'beyond belief'. AB - A set of commentaries on Cromby (2012) are considered with respect to three themes: the relations between feeling and thinking, between theory and empirical research, and between health beliefs and beliefs in religion/spirituality. Clarifications of key issues are suggested, and the difference between health and other beliefs is briefly illustrated with reference to beliefs associated with smoking tobacco. PMID- 22947889 TI - Beyond belief. AB - Psychology, including health psychology, frequently invokes the concept of belief but almost never defines it. Drawing upon scholarship associated with the 'affective turn', this article argues that belief might usefully be understood as a structure of socialized feeling, contingently allied to discursive practices and positions. This conceptualization is explained, and its implications for health psychology discussed with respect to research on religiosity and spirituality and debates about the value of social cognition models such as the theory of planned behaviour. PMID- 22947890 TI - Developmental contexts and sense of coherence in adolescence: a systematic review. AB - The salutogenic model has led to revolutionary changes in the study of health. In recent years, a large amount of research has been carried out on the relationship between sense of coherence and health, but relatively little is known about sense of coherence in adolescence. This study is a systematic review of the studies that looked at sense of coherence in adolescent samples. Valuable information is provided regarding the characteristics of the samples, the reliability of the sense of coherence scale versions, the influence of demographic variables and how family, school, peers and neighbourhood impact sense of coherence development. Furthermore, future directions for the study of sense of coherence in adolescence are provided. PMID- 22947892 TI - Paediatric life-limiting conditions: coping and adjustment in siblings. AB - A total of 31 siblings, aged between 5 and 16 years, of children with a life limiting condition, participated in a longitudinal, mixed method study. Data collection included standardised psychometric measures and visual and participatory qualitative methods. Emotional functioning and perceptions of self worth were normative on standardised measures. Qualitative data indicated distinct psychosocial strategies that appeared to underpin functioning, positioning themselves as adults within the family, adopting a role of 'social glue' in key relationships and thereby diminishing their own needs, and compartmentalising home and school life. Some strategies appeared adaptive in the short term but may be limiting in the longer term. The implications for professionals working to support families are discussed. PMID- 22947893 TI - Asthma and its relation to smoking behavior and cessation motives among adult daily smokers. AB - Despite the negative effects of smoking on lung functioning and overall health, smoking is more prevalent among individuals with asthma compared to those without asthma. The purpose of this study was to examine the predictive ability of asthma diagnosis in terms of smoking behavior and reasons for quitting. Participants were 251 regular daily smokers: 125 smokers with self-reported, physician diagnosed asthma and 126 smokers without asthma. Asthma diagnosis significantly predicted age of regular smoking onset, number of quit attempts, and reasons for quitting related to self-control suggesting that smokers with asthma may have more difficulty quitting and unique reasons for quitting. PMID- 22947894 TI - Kinetics and docking studies of two potential new inhibitors of the nucleoside hydrolase from Leishmania donovani. AB - In this study the recombinant enzyme nucleoside hydrolase of Leishmania donovani (rLdNH) was expressed in Escherichia coli in connection with maltose binding protein (MBP). The rLdNH-MBP showed efficient a significant in vitro activity with inosine as substrate. From the coupled reaction with xanthine oxidase (XO) it was possible to determine the kinetic constants of rLdNH-MBP as K(M) (434 +/- 109 MUM) and V(max) (0.20 +/- 0.02 MUM). In addition, two nucleoside analogs (compounds 1 and 2) were tested as prototypes of rLdNH inhibitors. These compounds presented high affinity for the enzyme with K(i) values of 1.6 +/- 0.2 and 17.0 +/- 2.1 MUM, respectively, as well as 271 and 26 folds higher than the affinity constant found for inosine. We also determined the type of enzyme inhibition, using double-reciprocal plot for these two compounds and the results confirmed a competitive inhibition. Additional docking studies showed the binding manner of compounds 1 and 2 inside the active site of LdNH revealing the essential residues for an effective inhibition. These results confirm that compounds 1 and 2 are strong rLdNH-MBP inhibitors. PMID- 22947895 TI - Acquisition of oral intake in severely dysphagic patients with acute stroke: a single-center, observational study involving a database of 4972 consecutive stroke patients. AB - OBJECTIVE: A single-center, observational study was performed to identify the predictors for oral intake 3 months after onset in stroke patients with severe dysphagia. METHODS: Of 4972 consecutive acute stroke patients, 723 could not eat orally on day 10. Three months after onset, a questionnaire was sent to all patients. Those who survived and replied to the questionnaire were divided into 2 groups, and the clinical factors that predicted their acquisition of oral intake were analyzed. RESULTS: Of the 586 dysphagic patients who responded, 141 (24.2%) achieved oral intake after 3 months. On logistic-regression model analysis, age <= 80 years, hyperlipidemia, non-cardioembolic stroke, modified Rankin Scale score 0 before onset, and National Institutes of Health Stroke Scale (NIHSS) score were independently related to oral intake 3 months after onset. From two different model analyses, NIHSS score <= 17 on day 10 (OR 3.58, 95% CI, 2.35 5.54) was found to be a stronger predictor for oral intake than NIHSS score <= 17 on admission (OR 2.17, 95% CI, 1.40-3.39). CONCLUSION: In severely dysphagic acute stroke patients, functional independence at baseline, younger age, absence of hyperlipidemia, non-cardioembolic stroke, and a milder NIHSS score on day 10 are useful predictors of the resumption of oral intake. PMID- 22947896 TI - The role of CSF biomarkers in the diagnostic work-up of mixed vascular degenerative dementia. AB - Low average specificity levels of 48% for clinical diagnosis of possible Alzheimer's disease (AD) reflect the overlap of clinical profiles between AD and non-AD dementias. Should diagnostic errors occur, they most likely involve one of the other primary dementias, mixed pathologies that include a vascular component, or uncertainties that are associated with early diagnosis. Vascular dementia (VaD) is overdiagnosed when a routine brain MRI or CT scan is used in the context of standard clinical diagnostic criteria, meanwhile denying significant neurodegenerative co-pathology. A promising approach for increasing diagnostic accuracy is the use of biochemical markers (biomarkers) that are present in the cerebrospinal fluid (CSF). The CSF biomarkers beta-amyloid protein of 42 amino acids (Abeta(1-42)), total tau protein (T-tau), and tau phosphorylated at threonine 181 (P-tau(181P)) are well validated. A combined analysis of these biomarkers is of help to discriminate AD from non-AD dementias (including VaD), reaching sensitivity and specificity levels that exceed 80%. Moreover, the added value of CSF biomarkers could lie within those cases in which the clinical diagnostic work-up is not able to discriminate between AD or a non-AD dementia. In case of doubt between VaD or mixed AD-VaD pathology in dementia patients, the determination of CSF Abeta(1-42), T-tau and P-tau(181P) levels is of help to confirm or exclude the AD component in the pathophysiology of the dementia syndrome. PMID- 22947897 TI - WITHDRAWN: Increase in phosphorylation of PDK1 and cell survival after acute spinal cord injury. AB - The Publisher regrets that this article is an accidental duplication of an article that has already been published, doi:10.1016/j.jns.2012.06.003. The duplicate article has therefore been withdrawn. PMID- 22947900 TI - Mechanisms and implications of bone adipose tissue-mineral relationships. PMID- 22947901 TI - Mini nutritional assessment and 10-year mortality in free-living elderly women: a prospective cohort study with 10-year follow-up. AB - BACKGROUND/OBJECTIVES: Mini nutritional assessment (MNA) is the most frequently used screening test for malnutrition in elderly populations in continental Europe and Asia. Most studies on MNA's ability to predict mortality have only included persons admitted to hospital, living in nursing homes or at home with professional help with activities of daily living. The aim of this cohort study was to examine if MNA can predict 10-year mortality in the general elderly female population. SUBJECTS/METHODS: Of the 584 free-living elderly women invited, 351 agreed to participate and were tested with MNA between 1999 and 2000. A 10-year follow-up was conducted in 2010 with dates of death obtained from the Swedish death register. RESULTS: Participants whose MNA score was <= 23.5 points at inclusion had a significantly higher age-adjusted 10-year mortality risk than participants with a MNA score of >23.5 points. The hazard ratio was 2.36 (95% confidence interval 1.25-4.46), P <0.01. CONCLUSIONS: Participants with a MNA score, indicating an increased risk for malnutrition, were more than twice as likely to die during the 10-year follow-up as participants whose MNA score indicated normal nutritional status. Hence, MNA can predict mortality in a general, free-living, elderly female population. PMID- 22947902 TI - The value of identifying major T cell epitopes of clinically important allergens. PMID- 22947903 TI - Effects of neonatal alcohol dose and exposure window on long delay and trace eyeblink conditioning in juvenile rats. AB - Classical eyeblink conditioning has been used to assess learning and memory impairments in both humans and animal model studies of fetal alcohol spectrum disorders (FASD). Gestational exposure to alcohol in humans and its equivalent in rats severely impairs various eyeblink conditioning tasks, but less is known about how these effects are influenced by variables, such as the timing and dose of alcohol exposure. In a series of four experiments, we systematically examine how varying the timing and dose of alcohol exposure impact long delay and trace eyeblink conditioning in juvenile rats, tasks that both depend on a brainstem cerebellar circuit but differ in that trace conditioning additionally recruits the hippocampus and prefrontal cortex. Using a "third-trimester-equivalent" alcohol exposure model, rats were exposed to a high binge dose of alcohol at one of two alcohol doses over postnatal days (PD) 4-9 or PD 7-9, windows of exposure thought to differentially target the cerebellum and hippocampus. Sham-intubated and untreated rats served as controls. As juveniles, rats from each treatment condition were trained in either a long delay or trace eyeblink conditioning task. Alcohol-exposed rats demonstrated general conditioning impairments compared to controls during long delay conditioning, with more robust impairments in rats exposed to the higher alcohol dose (5.25 g/kg/day) than those that received the lower dose (4.66 g/kg/day). Alcohol-exposed rats showed trace conditioning impairments compared to controls only when the high dose of alcohol was administered over PD 4-9 or PD 7-9. These findings indicate significant learning and memory impairments following neonatal alcohol exposure at both PD 4-9 and PD 7-9. The pattern of impairments across delay and trace conditioning suggest that alcohol disrupts processes that are common to both tasks. These findings are consistent with studies of delay and trace eyeblink conditioning in children with FASD. Future studies of the mechanisms underlying these deficits will further our understanding of brain injury and memory impairments resulting from developmental alcohol exposure. PMID- 22947904 TI - Individual phenotype predicts nicotine-haloperidol interaction in catalepsy: possible implication for the therapeutic efficacy of nicotine in Tourette's syndrome. AB - In individuals with Tourette's syndrome, the therapeutic efficacy of haloperidol can be augmented by nicotine. In laboratory rats, the dopamine antagonist haloperidol produces catalepsy and nicotine can potentiate it, although this effect is variable and not always observed. Our aim was to understand this variability. In rats, the locomotor response to a novel environment predicts the magnitude of the locomotor response to nicotine. Since the psychostimulant effect of nicotine might counter catalepsy, we hypothesized that rats with a high locomotor response to novelty would show reduced vulnerability to nicotine potentiation of haloperidol catalepsy. First, we administered haloperidol (0, 0.1 or 0.3mg/kg, ip) and found stronger catalepsy in rats with low reactivity to novelty. Second, we administered haloperidol (0.3mg/kg) or haloperidol plus nicotine (0.1mg/kg, ip) and found that nicotine indeed potentiated haloperidol catalepsy but only in rats with low reactivity to novelty. Nicotine did not induce catalepsy on its own. Thus, previously reported inconsistencies in the catalepsy potentiating effect of nicotine may have been due to differential vulnerability to its stimulant actions. As previously observed, the potentiation of haloperidol catalepsy was greatest 4h after injection. Given the short half life of nicotine, the mechanism(s) underlying the delayed expression of its pro cataleptic capacity remains obscure. PMID- 22947905 TI - The immunopathogenic role of reactive oxygen species in Alzheimer disease. AB - Reactive oxygen species (ROS) are produced in many normal and abnormal processes in humans, including atheroma, asthma, joint diseases, cancer, and aging. Basal levels of ROS production in cells could be related to several physiological functions including cell proliferation, apoptosis and homeostasis. However, excessive ROS production above basal levels would impair and oxidize DNA, lipids, sugars and proteins and consequently result in dysfunction of these molecules within cells and finally cell death. A leading theory of the cause of aging indicates that free radical damage and oxidative stress play a major role in the pathogenesis of Alzheimer disease (AD). Because the brain utilizes 20% more oxygen than other tissues that also undergo mitochondrial respiration, the potential for ROS exposure increases. In fact, AD has been demonstrated to be highly associated with cellular oxidative stress, including augmentation of protein oxidation, protein nitration, glycoloxidation and lipid peroxidation as well as accumulation of Amyloid beta (Abeta). The treatment with anti-oxidant compounds can provide protection against oxidative stress and Abeta toxicity. In this review, our aim was to clarify the role of ROS in pathogenesis of AD and will discuss therapeutic efficacy of some antioxidants studies in recent years in this disease. PMID- 22947906 TI - The in vitro effect of oxidized LDL and PHA on proliferation and gene expression of regulatory T cells in patients with atherosclerosis. AB - Atherosclerosis is a chronic inflammatory condition that affects the arterial wall. Oxidized low-density lipoprotein (ox-LDL) seems to have an important role in atherosclerotic plaque formation.This study was performed to investigate the effects of ox-LDL as well as PHA on proliferation and gene expression of peripheral blood mononuclear cells (PBMCs) in patients with atherosclerosis compared to healthy controls. Proliferation of PBMCs was assessed by BrdU assay, while gene expression was assessed by real-time PCR. Both PHA and ox-LDL significantly induced proliferation of PBMCs of patients and controls. PBMCs from controls showed significantly higher proliferation when stimulated with ox-LDL compared to patients. Expression of TGF-beta was significantly lower in PBMCs from patients compared to healthy controls (p<0.001). Following simulation with PHA, TGF-beta and Foxp3 gene expression levels in patients and controls were significantly decreased (p<0.001). Expression of Foxp3 in PBMCs treated with ox LDL was significantly decreased in patients and controls.Decreased expression of TGF-beta and Foxp3 genes after ox-LDL stimulation may be due to more sensitivity of Treg cells than effector T cells to ox-LDL. Presence of ox-LDL within atheroma could be associated with the diminished population of Treg cells in the atherosclerotic patients. PMID- 22947907 TI - Association of single nucleotide polymorphisms in the human tumor necrosis factor alpha and interleukin 1-beta genes in patients with pre-eclampsia. AB - Pre-eclampsia is a pregnancy-specific syndrome that may be dangerous especially to the fetus. Different cytokines have been found to be elevated in women with pre-eclampsia and may have possible roles in the development of this disorder. Alleles of the interleukin-l-beta (IL-lbeta) and tumor necrosis factor alpha (TNF alpha) genes are associated with pr-eeclampsia in several studies in different populations. The aim of the present study was to investigate the relationship between IL-lbeta (C+3954T) and TNF-alpha (G-308A) gene polymorphisms with pre eclampsia in north east of Iran (Khorasan province).This study included 54 diagnosed patients with pre-eclampsia and 50 normal pregnant women as control group. DNA was extracted from peripheral blood and the polymorphisms were determined by PCR-RFLP method. Data was analyzed using chi-square and Fisher's exact tests.There was significant association between TNF-alpha (G-308A) genotype and pre-eclampsia (p=0.001) but we did not find any significant association between IL-lbeta (C+3954T) genotype and pre-eclampsia (p=0.39).The present study might suggest a role for TNF-alpha in the development of pre-eclampsia; however, IL-lbeta (C+3954T) polymorphism could not be considered as a marker of susceptibility to preeclampsia in our population. PMID- 22947908 TI - Fish consumption, fish atopy and related heavy metals in childhood eczema. AB - Due to increasing worldwide water pollution, fish might be a source of excessive zinc, mercury, arsenic or manganese intake. The aim of this study was to evaluate if fish atopy/sensitization and fish consumption behavior are associated with eczema severity and blood levels of the 4 heavy metals.One-hundred and nineteen patients with eczema and 43 patients with miscellaneous non-eczema skin diseases were studied. There were no differences in average weekly fish consumption and blood levels of the 4 heavy metals between eczema and non-eczema groups. Blood levels of these metals were generally within the upper limits of local reference ranges in all these patients. In eczema patients, freshwater fish consumption behavior in days-per-week was correlated with blood arsenic and mercury levels (rho=0.17, p<0.01 for both metals), but not with zinc or manganese. Levels of arsenic and mercury were also correlated with days of seawater fish consumption per week (arsenic: 0.38, mercury: 0.24, p <0.05).Fish sensitization was present in 25% of patients with eczema. Nevertheless, there was no difference in terms of fish consumption behavior, eczema severity, quality of life, and heavy metal levels between eczema patients with or without fish sensitization. We conclude that without exceeding local normal reference ranges, blood arsenic and mercury levels correlated with fish consumption behavior. There is no evidence to suggest that fish sensitization is associated with more severe eczema (bad for eczema), or that patients have milder eczema with more days of fish consumption (good for eczema). PMID- 22947909 TI - Efficacy of atorvastatin and antihistamines in comparison with antihistamines plus placebo in the treatment of chronic idiopathic urticaria: a controlled clinical trial. AB - Chronic idiopathic urticaria is defined as recurrent hives occurring for at least 6 weeks. In the majority of cases, there is no identifiable underlying etiology despite extensive evaluation. A subset of these patients is classified as having autoimmune urticaria defined by the presence of a functional IgG antibody to the alpha subunit of the high-affinity IgE receptor (FceRIa) or to IgE. The aim of this study was to evaluate the effects of the drug atorvastatin in patients with chronic urticaria compared to the placebo.In this single-blind study, 50 patients suffering from chronic urticaria (15-45 years old) were selected and divided into two groups by simple randomization method. The first group was treated with atorvastatin and antihistamines and the second group (control group) was treated with placebo and antihistamines for 3 months. Urticaria severity was measured by score index, before and after the treatment course: ASST (autologous serum skin test) was performed for all patients and sera were collected to measure cytokines. In cases, IL-5 decreased and IL-10 increased after treatment compared to the time point before treatment (p<0.05). All patients with severe utricaria according our scoring, had positive ASST.The patients with severe urticaria identified by urticaria score and ASST positivity had chronic idiopathic urticaria. By prescribing the atorvastatin plus antihistamines in severe and resistant forms of urticaria, the use of more toxic medications like cytotoxic drugs may be avoided. PMID- 22947910 TI - Association between anti-thyroid peroxidase antibody and asthma in women. AB - About 8% of the general population suffers from autoimmune diseases, from which 78% are women. One of the most important causes of thyroid diseases is autoimmunity in origin, and it seems that people with thyroid diseases present more signs of asthma. This study was therefore designed to investigate the frequency of autoimmune thyroid diseases in women suffering from bronchial asthma.In a cross-sectional study, 100 women with asthma and 100 women as control group were tested for thyroid function and anti-thyroid peroxidase antibody (anti TPO Ab) measurements. The asthmatic patients were selected based on having chronic cough, dyspnea, wheezing and clinical examination of the chest. The diagnosis was confirmed by pulmonary function tests. Blood tests were done by electrochemiluminescence immunoassay method.No hyperthyroid patient was found in either group. Serum TSH and Total T4 levels were not statistically different between the two groups, but serum anti-TPO Ab levels in women with asthma (74+/ 13.6 IU/ml) was significantly higher than control group (45.24+/-10.56 IU/ml). After adjusting the effect of age and BMI, the relationship between asthma and anti-TPO Ab (>50 IU/ml) was statistically significant (OR=3.3, P<0.01). Positive anti-TPO Ab in asthmatic patients may show presence of a hidden autoimmune thyroiditis in these patients. We suggested checking asthmatic patients for thyroid diseases. PMID- 22947911 TI - The achilles heel in melatonin: asthma. AB - Asthma is a clinical syndrome characterized by chronic airway inflammation, airway responsiveness, and expiratory airflow limitation. Nocturnal symptoms and decreases in lung function are common aspects of the asthma clinical syndrome. Nocturnal symptoms also appear to be associated with asthma-related mortality. In addition to its importance to the regulation of human circadian rhythms, an accumulating body of evidence also suggests that melatonin is also involved in the regulation of smooth muscle tone. For this reason, this study aimed to evaluate contraction and relaxation responses in tracheal smooth muscle rings obtained from rats treated with melatonin. Following administration of melatonin (50mg/kg/day) at the same time every day for 6 weeks, in vitro organ bath experiments were performed with rat tracheal preparations exposed to contractile (acetycholine and serotonin) and relaxant (theophylline and papaverine) agents. Melatonin treatment strengthened contraction responses, but did not affect relaxation responses in rat tracheal preparations. We think that melatonin might play a role in the pathogenesis of nocturnal asthma. Therefore, clinicians should be aware of the importance of melatonin to nocturnal exacerbation of asthma symptoms and alert asthmatic patients that use exogenous melatonin supplementation of its potential negative effects. PMID- 22947913 TI - Exercise induced changes in spirometry and impulse oscillometry measurements in persistent allergic rhinitis. AB - The link between allergic rhinitis and asthma is well known. Bronchial hyperreactivity (BHR) may be present in rhinitis. The present study was aimed to compare airway responses in patients with rhinitis symptoms alone following exercise challenge, and to determine relationship of two different respiratory function tests.98 subjects with rhinitis were investigated by spirometry and impulse oscillometry before and after exercise challenge. No significant difference was detected between spirometry and impulse oscillometry measurements before and after exercise challenge in subjects with rhinitis alone. No correlation between spirometry and impulse oscillometry indices was found in pre and post-exercise stages.We therefore conclude that exercise challenge is not an appropriate test to determine airway hyperresponsive in subjects with rhinitis symptoms alone and findings of spirometry and impulse oscillometry are not interrelated. PMID- 22947912 TI - Assessment of sensitization to insect aeroallergens among patients with allergic rhinitis in Yazd City, Iran. AB - The frequency of allergic diseases such as allergic rhinitis is considerable in general population. Insect aeroallergens are important allergens which can induce airway inflammation. The aim of this study was to determine the prevalence of sensitization to insect aeroallergens in allergic rhinitis patients in Yazd as a desert city in Iran.A cross-sectional study was undertaken on 95 allergic rhinitis patients who were referred to allergy clinic of Yazd city. Skin prick tests (SPT) by standard extracts of three insect aeroallergens including Mosquito, Corn moth, Cockroach and two species of mites as common aeroallergens in allergic rhinitis (Dermatophagoid Farina, Dermatophagoid Peteronysinus) were done.SPT results showed that the most common insect aeroallergens were: mosquito (32.6%) followed by corn moth (26.3%) and cockroach (13.7%).The prevalence of SPT positive response to Dermatophagoid Peteronysinus, Dermatophagoid Farina were 8.4% and 7.4%, respectively. These results demonstrated that sensitization to insect aeroallergens was significantly more common compared to mites in patients with allergic rhinitis in Yazd city, a city surrounded by deserts. High prevalence of skin reactivity to mosquito and corn moth as insect aeroallergens in Yazd city with hot and dry climate in contrast to humid regions such as north of Iran, where mites are more frequent, indicates differences in the prevalence of aeroallergen reactivity in various areas with different climates. Our study could highlight the importance of insect aeroallergens for clinicians for better diagnosis and management of patients with allergic rhinitis. PMID- 22947914 TI - A tragic case of atopic eczema: malnutrition and infections despite multivitamins and supplements. AB - Eczema is a common childhood atopic condition and treatment is with emollients, topical corticosteroids and avoidance of possible triggers. S. aurues colonization is a common complication. During exacerbation, intensification of treatment is needed to relieve the child from the miserable symptoms of pruritus and sleep disturbance. Systemic antibiotics against S. aureus may be required. We report an infant with eczema who presented with a generalised rash, cardiac arrest and septic shock. Kwashiorkor-like protein energy malnutrition was noted presumably due to deviated dietary practice. Childhood eczema is an eminently treatable atopic disease. Extreme alternative therapy seems not to be efficacious and may even be associated with grave sequelae. PMID- 22947915 TI - Bitter taste receptor research comes of age: from characterization to modulation of TAS2Rs. AB - The recognition of potentially harmful food components by the gustatory system is important for survival and well-being of vertebrates. The plethora of structurally diverse bitter substances present in nature is recognized by multiple bitter taste receptors belonging to the taste receptor 2 family (TAS2R) of heptahelical receptors resulting in a highly complex mechanism of bitterness perception. In particular, research on human bitter taste receptors allowed the characterization of the receptive range of most of the 25 TAS2Rs, which was a prerequisite for detailed experiments to elucidate the structure-function relationships of TAS2Rs and for the discovery of the first reasonably specific TAS2R antagonists. These new findings will be the focus of the present review. PMID- 22947916 TI - Modulation of sweet responses of taste receptor cells. AB - Taste receptor cells play a major role in detection of chemical compounds in the oral cavity. Information derived from taste receptor cells, such as sweet, bitter, salty, sour and umami is important for evaluating the quality of food components. Among five basic taste qualities, sweet taste is very attractive for animals and influences food intake. Recent studies have demonstrated that sweet taste sensitivity in taste receptor cells would be affected by leptin and endocannabinoids. Leptin is an anorexigenic mediator that reduces food intake by acting on leptin receptor Ob-Rb in the hypothalamus. Endocannabinoids such as anandamide [N-arachidonoylethanolamine (AEA)] and 2-arachidonoyl glycerol (2-AG) are known as orexigenic mediators that act via cannabinoid receptor 1 (CB1) in the hypothalamus and limbic forebrain to induce appetite and stimulate food intake. At the peripheral gustatory organs, leptin selectively suppresses and endocannabinoids selectively enhance sweet taste sensitivity via Ob-Rb and CB1 expressed in sweet sensitive taste cells. Thus leptin and endocannabinoids not only regulate food intake via central nervous systems but also modulate palatability of foods by altering peripheral sweet taste responses. Such reciprocal modulation of leptin and endocannabinoids on peripheral sweet sensitivity may play an important role in regulating energy homeostasis. PMID- 22947917 TI - Cisplatin GG-crosslinks within single-stranded DNA: origin of the preference for left-handed helicity. AB - Molecular dynamics (MD) simulations of the single-stranded DNA trinucleotide TG*G*, with the G* guanines crosslinked by the antitumor drug cisplatin, were performed with explicit representation of the water as solvent. The purpose of the simulations was to explain previous NMR observations indicating that in single-stranded cisplatin-DNA adducts, the crosslinked guanines adopt a left handed helical orientation, whereas in duplexes, the orientation is right-handed. The analysis of the MD trajectory of TG*G* has ascribed a crucial role to hydrogen-bonding (direct or through-water) interactions of the 5'-oriented NH(3) ligand of platinum with acceptor groups at the 5'-side of the crosslink, namely the TpG* phosphate and the terminal 5'-OH group. These interactions bring about some strain into the trinucleotide which is slightly but significantly (1-1.5 kcal.mol(-1)) higher for the right-handed orientation than for the left-handed one. During the unconstrained, 3 ns long MD simulation, left-handed conformations were ~15 times more abundant than the right-handed ones. This sampling difference agrees roughly with the calculated energy difference in strain energy. Overall, these results show that the Pt-GG crosslink within single-stranded DNA is malleable and can access different conformations at a moderate energy cost. This malleability could be of importance in interactions between the platinated DNA and cellular proteins, in which the DNA is locally unwound. PMID- 22947918 TI - Semiconducting allotrope of graphene. AB - From first-principles calculations, we predict a planar stable graphene allotrope composed of a periodic array of tetragonal and octagonal (4, 8) carbon rings. The stability of this sheet is predicted from the room-temperature molecular dynamics study and the electronic structure is studied using state-of-the-art calculations such as the hybrid density functional and the GW approach. Moreover, the mechanical properties of (4, 8) carbon sheet are evaluated from the Young's modulus and intrinsic strength calculations. We find this is a stable planar semiconducting carbon sheet with a bandgap between 0.43 and 1.01 eV and whose mechanical properties are as good as graphene's. PMID- 22947919 TI - Clinical features of Pittsburgh compound-B-negative dementia. AB - BACKGROUND/AIMS: We previously found that some cases of clinically diagnosed Alzheimer's disease (AD) were rated as Pittsburgh compound B (PiB) negative by amyloid imaging (i.e. cases of PiB-negative dementia). The present study was designed to analyze the clinical features of PiB-negative dementia patients in detail. METHODS: Of the 64 cases of clinically diagnosed AD, 14 were rated PiB negative. Eleven of these were further analyzed using CSF biomarker levels and findings from MRI, FDG-PET, (123)I-MIBG myocardial scintigraphy and voxel-based morphometry (VBM). RESULTS: When examined by (123)I-MIBG myocardial scintigraphy, the heart/mediastinum ratio was significantly higher in the PiB-negative dementia group than in the dementia with Lewy bodies (DLB) group. Analyses of CSF biomarkers and MRI and FDG-PET findings suggested argyrophilic grain disease (AGD) in 3 cases, frontotemporal lobar degeneration (FTLD) in 3 cases, neurofibrillary tangle-predominant dementia (NFTD) in 1 case, and AD in 2 cases. In the VBM data analysis, the PiB-positive AD group showed significant atrophy of both hippocampi compared with the healthy control group, while the PiB-negative dementia group presented with significant atrophy of the left precuneus. CONCLUSION: PiB-negative dementia is unlikely to include DLB, while it most likely includes diseases of tauopathy, such as FTLD, AGD and NFTD. A better understanding of PiB-negative dementia is expected to further improve the accuracy of the clinical AD diagnosis. PMID- 22947920 TI - Renal and cardiac effects of DPP4 inhibitors--from preclinical development to clinical research. AB - Inhibitors of type 4 dipeptidyl peptidase (DDP-4) were developed and approved for the oral treatment of type 2 diabetes. Its mode of action is to inhibit the degradation of incretins, such as type 1 glucagon like peptide (GLP-1), and GIP. GLP-1 stimulates glucose-dependent insulin secretion from pancreatic beta-cells and suppresses glucagon release from alpha-cells, thereby improving glucose control. Besides its action on the pancreas type 1 glucagon like peptide has direct effects on the heart, vessels and kidney mainly via the type 1 glucagon like peptide receptor (GLP-1R). Moreover, there are substrates of DPP-4 beyond incretins that have proven renal and cardiovascular effects such as BNP/ANP, NPY, PYY or SDF-1 alpha. Preclinical evidence suggests that DPP-4 inhibitors may be effective in acute and chronic renal failure as well as in cardiac diseases like myocardial infarction and heart failure. Interestingly, large cardiovascular meta analyses of combined phase II/III clinical trials with DPP-4 inhibitors point all in the same direction: a potential reduction of cardiovascular events in patients treated with these agents. A pooled analysis of pivotal phase III, placebo controlled, registration studies of linagliptin further showed a significant reduction of urinary albumin excretion after 24 weeks of treatment. The observation suggests direct renoprotective effects of DPP-4 inhibition that may go beyond its glucose-lowering potential. Type 4 dipeptidyl peptidase inhibitors have been shown to be very well tolerated in general, but for those excreted via the kidney dose adjustments according to renal function are needed to avoid side effects. In conclusion, the direct cardiac and renal effects seen in preclinical studies as well as meta-analysis of clinical trials may offer additional potentials - beyond improvement of glycemic control - for this newer class of drugs, such as acute kidney failure, chronic kidney failure as well as acute myocardial infarction and heart failure. PMID- 22947921 TI - Potential of treating age-related depression and cognitive decline with nutraceutical approaches: a mini-review. AB - A variety of consumable plant-derived phytochemicals exhibit nutraceutical properties because they produce physiological benefits and combat disease processes. Emerging evidence suggests that widely accessible and safe organic polyphenolic phytochemicals, in particular, treat depression at much lower concentrations than clinical doses of classical drugs. Structurally similar polyphenolics such as curcumin, resveratrol, and proanthocyanidins exhibit antioxidant and immunomodulatory properties and recent research suggests that they also modulate hypothalamic-pituitary-adrenal (HPA) axis activity, serotonergic transmission and hippocampal neurogenesis (perhaps via their effects on serotonin and HPA activity). These data tempt speculation that polyphenolic compounds could also combat age-related cognitive decline, which is often accompanied by depression and potentially by reduced levels of hippocampal neurogenesis. Here we review the relationships between dysregulation of these systems and age-related cognitive decline. We then suggest that this group of structurally similar polyphenolic compounds may be particularly promising therapeutic leads for age-related cognitive decline and depression because they modulate these processes. PMID- 22947922 TI - Asymmetric free-standing film with multifunctional anti-bacterial and self cleaning properties. AB - A superhydrophobic/hydrophilic asymmetric free-standing film has been created using layer-by-layer assembly technique. Poly(ethylene-imine)-Ag(+) complex (PEI Ag(+)) at pH 9.0 was assembled with poly(acrylic acid) (PAA) at pH 3.2 on a Teflon substrate to yield a micronanostructured surface that can be turned to be superhydrophobic after being coated with a low surface energy compound. Silver nanoparticle loaded free-standing film with one surface being superhydrophobic while the other surface is hydrophilic was then obtained after detachment from the substrate. The superhydrophobicity enabled the upper surface with anti adhesion and self-cleaning properties and the hydrophilic bottom surface can release silver ions as antibiotic agent. The broad-spectrum antimicrobial capability of silver ions released from the bottom surface coupled with superhydrophobic barrier protection of the upper surface may make the free standing film a new therapy for open wound. PMID- 22947923 TI - Experimental and numerical tribological studies of a boundary lubricant functionalized poro-viscoelastic PVA hydrogel in normal contact and sliding. AB - Hydrogels are a cross-linked network of polymers swollen with liquid and have the potential to be used as a synthetic replacement for local defects in load bearing tissues such as articular cartilage. Hydrogels display viscoelastic time dependent behavior, therefore experimental analysis of stresses at the surface and within the gel is difficult to perform. A three-dimensional model of a hydrogel was developed in the commercial finite element software ABAQUSTM, implementing a poro-viscoelastic constitutive model along with a contact dependent flow state and friction conditions. Water content measurements, sliding, and indentation experiments were performed on neat polyvinyl alcohol (PVA), and on low friction boundary lubricant functionalized (BLF-PVA) hydrogels, both manufactured by freeze-thaw processes. Modulus results from the indentation experiments and coefficient of friction values from the sliding experiments were used as material property inputs to the model, while water content was used to calculate initial flow conditions. Tangential force and normal displacement data from a three-dimensional simulation of sliding were compared with the experiments. The tangential force patterns indicated important similarities with the fabricated hydrogels that included an initially high force value due to time dependent deformation followed by a decrease in a stabile value. A similar trend was observed with the normal displacement. These comparisons rendered the model suitable as a representation and were used to analyze the development and propagation of stresses in the immediate surface region. The results showed that in a three-dimensional stress field during sliding, the maximum stress shifted to the surface and rotated closer to the leading edge of contact. This occurred because the stress field becomes dominated by an amplified compressive stress at the leading edge due to the biphasic viscoelastic response of the material during sliding. Also, the complex multi-axial contact stress field was reduced to focus predominately on stress in the contact surface region in the direction of sliding. The results showed that during biphasic viscoelastic frictional sliding, the maximum tensile stress develops at the trailing edge of contact and a compressive stress develops at the leading edge in the direction of motion. The BLF-PVA hydrogels displayed a decrease in this tensile and compressive stress as compared to the standard PVA. The diminishment of these stresses would be expected to give the BLF-PVA hydrogels lower material wear with greater life expectancy as a synthetic articular cartilage implant. PMID- 22947924 TI - Dynamics of the primary cilium in shear flow. AB - In this work, the equilibrium shape and dynamics of a primary cilium under flow are investigated by using both theoretical modeling and experiment. The cilium is modeled as an elastic beam that may undergo large deflection due to the hydrodynamic load. Equilibrium results show that the anchoring effects of the basal body on the cilium axoneme behave as a nonlinear rotational spring. Details of the rotational spring are elucidated by coupling the elastic beam with an elastic shell. We further study the dynamics of cilium under shear flow with the cilium base angle determined from the nonlinear rotational spring, and obtain good agreement in cilium bending and relaxing dynamics when comparing between modeling and experimental results. These results potentially shed light on the physics underlying the mechanosensitive ion channel transport through the ciliary membrane. PMID- 22947925 TI - Decoupling substrate stiffness, spread area, and micropost density: a close spatial relationship between traction forces and focal adhesions. AB - Mechanical cues can influence the manner in which cells generate traction forces and form focal adhesions. The stiffness of a cell's substrate and the available area on which it can spread can influence its generation of traction forces, but to what extent these factors are intertwined is unclear. In this study, we used microcontact printing and micropost arrays to control cell spreading, substrate stiffness, and post density to assess their effect on traction forces and focal adhesions. We find that both the spread area and the substrate stiffness influence traction forces in an independent manner, but these factors have opposite effects: cells on stiffer substrates produce higher average forces, whereas cells with larger spread areas generate lower average forces. We show that post density influences the generation of traction forces in a manner that is more dominant than the effect of spread area. Additionally, we observe that focal adhesions respond to spread area, substrate stiffness, and post density in a manner that closely matches the trends seen for traction forces. This work supports the notion that traction forces and focal adhesions have a close relationship in their response to mechanical cues. PMID- 22947926 TI - Single-molecule force spectroscopy of the Aplysia cell adhesion molecule reveals two homophilic bonds. AB - Aplysia californica neurons comprise a powerful model system for quantitative analysis of cellular and biophysical properties that are essential for neuronal development and function. The Aplysia cell adhesion molecule (apCAM), a member of the immunoglobulin superfamily of cell adhesion molecules, is present in the growth cone plasma membrane and involved in neurite growth, synapse formation, and synaptic plasticity. apCAM has been considered to be the Aplysia homolog of the vertebrate neural cell adhesion molecule (NCAM); however, whether apCAM exhibits similar binding properties and neuronal functions has not been fully established because of the lack of detailed binding data for the extracellular portion of apCAM. In this work, we used the atomic force microscope to perform single-molecule force spectroscopy of the extracellular region of apCAM and show for the first time (to our knowledge) that apCAM, like NCAM, is indeed a homophilic cell adhesion molecule. Furthermore, like NCAM, apCAM exhibits two distinct bonds in the trans configuration, although the kinetic and structural parameters of the apCAM bonds are quite different from those of NCAM. In summary, these single-molecule analyses further indicate that apCAM and NCAM are species homologs likely performing similar functions. PMID- 22947927 TI - A kinetic model for type I and II IP3R accounting for mode changes. AB - Based upon an extensive single-channel data set, a Markov model for types I and II inositol trisphosphate receptors (IP(3)R) is developed. The model aims to represent accurately the kinetics of both receptor types of IP(3)R depending on the concentrations of inositol trisphosphate (IP(3)), adenosine trisphosphate (ATP), and intracellular calcium (Ca(2+)). In particular, the model takes into account that for some combinations of ligands the IP(3)R switches between extended periods of inactivity alternating with intervals of bursting activity (mode changes). In a first step, the inactive and active modes are modeled separately. It is found that, within modes, both receptor types are ligand independent. In a second step, the submodels are connected by transition rates. Ligand-dependent regulation of the channel activity is achieved by modulating these transitions between active and inactive modes. As a result, a compact representation of the IP(3)R is obtained that accurately captures stochastic single-channel dynamics including mode changes in a model with six states and 10 rate constants, only two of which are ligand-dependent. PMID- 22947928 TI - Transfer of Kv3.1 voltage sensor features to the isolated Ci-VSP voltage-sensing domain. AB - Membrane proteins that respond to changes in transmembrane voltage are critical in regulating the function of living cells. The voltage-sensing domains (VSDs) of voltage-gated ion channels are extensively studied to elucidate voltage-sensing mechanisms, and yet many aspects of their structure-function relationship remain elusive. Here, we transplanted homologous amino acid motifs from the tetrameric voltage-activated potassium channel Kv3.1 to the monomeric VSD of Ciona intestinalis voltage-sensitive phosphatase (Ci-VSP) to explore which portions of Kv3.1 subunits depend on the tetrameric structure of Kv channels and which properties of Kv3.1 can be transferred to the monomeric Ci-VSP scaffold. By attaching fluorescent proteins to these chimeric VSDs, we obtained an optical readout to establish membrane trafficking and kinetics of voltage-dependent structural rearrangements. We found that motifs extending from 10 to roughly 100 amino acids can be readily transplanted from Kv3.1 into Ci-VSP to form engineered VSDs that efficiently incorporate into the plasma membrane and sense voltage. Some of the functional features of these engineered VSDs are reminiscent of Kv3.1 channels, indicating that these properties do not require interactions between Kv subunits or between the voltage sensing and the pore domains of Kv channels. PMID- 22947930 TI - Evolution of the hemifused intermediate on the pathway to membrane fusion. AB - The pathway to membrane fusion in synthetic and biological systems is thought to pass through hemifusion, in which the outer leaflets are fused while the inner leaflets engage in a hemifusion diaphragm (HD). Fusion has been proposed to be completed by lysis of the expanded HD that matures from a localized stalklike initial connection. However, the process that establishes the expanded HD is poorly understood. Here we mathematically modeled hemifusion of synthetic vesicles, where hemifusion and fusion are most commonly driven by calcium and membrane tension. The model shows that evolution of the hemifused state is driven by these agents and resisted by interleaflet frictional and tensile stresses. Predicted HD growth rates depend on tension and salt concentration, and agree quantitatively with experimental measurements. For typical conditions, we predict that HDs expand at ~30 MUm(2)/s, reaching a final equilibrium area ~7% of the vesicle area. Key model outputs are the evolving HD tension and area during the growth transient, properties that may determine whether HD lysis occurs. Applying the model to numerous published experimental studies that reported fusion, our results are consistent with a final fusion step in which the HD ruptures due to super-lysis HD membrane tensions. PMID- 22947929 TI - Kinetic comparisons of heart and kidney Na+,K(+)-ATPases. AB - Most kinetic measurements of the partial reactions of Na(+),K(+)-ATPase have been conducted on enzyme from mammalian kidney. Here we present a kinetic model that is based on the available equilibrium and kinetic parameters of purified kidney enzyme, and allows predictions of its steady-state turnover and pump current in intact cells as a function of ion and ATP concentrations and the membrane voltage. Using this model, we calculated the expected dependence of the pump current on voltage and extracellular Na(+) concentration. The simulations indicate a lower voltage dependence at negative potentials of the kidney enzyme in comparison with heart muscle Na(+),K(+)-ATPase, in agreement with experimental results. The voltage dependence is enhanced at high extracellular Na(+) concentrations. This effect can be explained by a voltage-dependent depopulation of extracellular K(+) ion binding sites on the E2P state and an increase in the proportion of enzyme in the E1P(Na(+))(3) state in the steady state. This causes a decrease in the effective rate constant for occlusion of K(+) by the E2P state and hence a drop in turnover. Around a membrane potential of zero, negligible voltage dependence is observed because the voltage-independent E2(K(+))(2) -> E1 + 2K(+) transition is the major rate-determining step. PMID- 22947931 TI - Two-step mechanism of membrane disruption by Abeta through membrane fragmentation and pore formation. AB - Disruption of cell membranes by Abeta is believed to be one of the key components of Abeta toxicity. However, the mechanism by which this occurs is not fully understood. Here, we demonstrate that membrane disruption by Abeta occurs by a two-step process, with the initial formation of ion-selective pores followed by nonspecific fragmentation of the lipid membrane during amyloid fiber formation. Immediately after the addition of freshly dissolved Abeta(1-40), defects form on the membrane that share many of the properties of Abeta channels originally reported from single-channel electrical recording, such as cation selectivity and the ability to be blockaded by zinc. By contrast, subsequent amyloid fiber formation on the surface of the membrane fragments the membrane in a way that is not cation selective and cannot be stopped by zinc ions. Moreover, we observed that the presence of ganglioside enhances both the initial pore formation and the fiber-dependent membrane fragmentation process. Whereas pore formation by freshly dissolved Abeta(1-40) is weakly observed in the absence of gangliosides, fiber dependent membrane fragmentation can only be observed in their presence. These results provide insights into the toxicity of Abeta and may aid in the design of specific compounds to alleviate the neurodegeneration of Alzheimer's disease. PMID- 22947932 TI - Velocity-dependent actomyosin ATPase cycle revealed by in vitro motility assay with kinetic analysis. AB - The actomyosin interaction plays a key role in a number of cellular functions. Single-molecule measurement techniques have been developed to study the mechanism of the actomyosin contractile system. However, the behavior of isolated single molecules does not always reflect that of molecules in a complex system such as a muscle fiber. Here, we developed a simple method for studying the kinetic parameters of the actomyosin interaction using small numbers of molecules. This approach does not require the specialized equipment needed for single-molecule measurements, and permits us to observe behavior that is more similar to that of a complex system. Using an in vitro motility assay, we examined the duration of continuous sliding of actin filaments on a sparsely distributed heavy meromyosin coated surface. To estimate the association rate constant of the actomyosin motile system, we compared the distribution of experimentally obtained duration times with a computationally simulated distribution. We found that the association rate constant depends on the sliding velocity of the actin filaments. This technique may be used to reveal new aspects of the kinetics of various motor proteins in complex systems. PMID- 22947933 TI - A mechanochemical model of actin filaments. AB - In eukaryotic cells, actin filaments are involved in important processes such as motility, division, cell shape regulation, contractility, and mechanosensation. Actin filaments are polymerized chains of monomers, which themselves undergo a range of chemical events such as ATP hydrolysis, polymerization, and depolymerization. When forces are applied to F-actin, in addition to filament mechanical deformations, the applied force must also influence chemical events in the filament. We develop an intermediate-scale model of actin filaments that combines actin chemistry with filament-level deformations. The model is able to compute mechanical responses of F-actin during bending and stretching. The model also describes the interplay between ATP hydrolysis and filament deformations, including possible force-induced chemical state changes of actin monomers in the filament. The model can also be used to model the action of several actin associated proteins, and for large-scale simulation of F-actin networks. All together, our model shows that mechanics and chemistry must be considered together to understand cytoskeletal dynamics in living cells. PMID- 22947934 TI - A branched kinetic scheme describes the mechanochemical coupling of Myosin Va processivity in response to substrate. AB - Myosin Va is a double-headed cargo-carrying molecular motor that moves processively along cellular actin filaments. Long processive runs are achieved through mechanical coordination between the two heads of myosin Va, which keeps their ATPase cycles out of phase, preventing both heads detaching from actin simultaneously. The biochemical kinetics underlying processivity are still uncertain. Here we attempt to define the biochemical pathways populated by myosin Va by examining the velocity, processive run-length, and individual steps of a Qdot-labeled myosin Va in various substrate conditions (i.e., changes in ATP, ADP, and P(i)) under zero load in the single-molecule total internal reflection fluorescence microscopy assay. These data were used to globally constrain a branched kinetic scheme that was necessary to fit the dependences of velocity and run-length on substrate conditions. Based on this model, myosin Va can be biased along a given pathway by changes in substrate concentrations. This has uncovered states not normally sampled by the motor, and suggests that every transition involving substrate binding and release may be strain-dependent. PMID- 22947935 TI - The interconversion between a flexible beta-sheet and a fibril beta-arrangement constitutes the main conformational event during misfolding of PSD95-PDZ3 domain. AB - The temperature-induced misfolding pathway of PDZ3, the third PDZ domain of the PSD95 neuronal protein, is populated by a trimeric beta-sheet-rich intermediate state that leads to a stepwise and reversible formation of supramacromolecular structures. Using FTIR, we have found that misfolding of this pathway is not due to different ensembles of a variety of precursors, but comes mainly from the interconversion of a flexible beta-sheet of the domain to wormlike fibrils. The appearance of the wormlike fibril FTIR component is also accompanied by a slight decrease of the band that corresponds to loops in the native state, whereas the rest of the regular elements of secondary structure are fairly well maintained upon misfolding. Transmission electron microscope micrographs have confirmed the presence of wormlike fibrils upon heating at 60 degrees C, where the trimeric intermediate is maximally populated. Toxicity assays in the human neuroblastoma cell line SH-SY5Y show that cytotoxicity increases as the aggregation pathway proceeds. NMR analysis of chemical shifts as a function of temperature has revealed, as one of the main conformational aspects of such an interconversion at the residue level, that the beta-sheet arrangement around strand beta3 promotes the change that drives misfolding of the PDZ3 domain. PMID- 22947936 TI - Identification of minimally interacting modules in an intrinsically disordered protein. AB - The conformational characterization of intrinsically disordered proteins (IDPs) is complicated by their conformational heterogeneity and flexibility. If an IDP could somehow be divided into smaller fragments and reconstructed later, theoretical and spectroscopic studies could probe its conformational variability in detail. Here, we used replica molecular-dynamics simulations and network theory to explore whether such a divide-and-conquer strategy is feasible for alpha-synuclein, a prototypical IDP. We characterized the conformational variability of alpha-synuclein by conducting >100 unbiased all-atom molecular dynamics simulations, for a total of >10 MUs of trajectories. In these simulations, alpha-synuclein formed a heterogeneous ensemble of collapsed coil states in an aqueous environment. These states were stabilized by heterogeneous contacts between sequentially distant regions. We find that alpha-synuclein contains residual secondary structures in the collapsed states, and the heterogeneity in the collapsed state makes it feasible to split alpha-synuclein into sequentially contiguous minimally interacting fragments. This study reveals previously unknown characteristics of alpha-synuclein and provides a new (to our knowledge) approach for studying other IDPs. PMID- 22947937 TI - Nonlinear Poisson equation for heterogeneous media. AB - The Poisson equation is a widely accepted model for electrostatic analysis. However, the Poisson equation is derived based on electric polarizations in a linear, isotropic, and homogeneous dielectric medium. This article introduces a nonlinear Poisson equation to take into consideration of hyperpolarization effects due to intensive charges and possible nonlinear, anisotropic, and heterogeneous media. Variational principle is utilized to derive the nonlinear Poisson model from an electrostatic energy functional. To apply the proposed nonlinear Poisson equation for the solvation analysis, we also construct a nonpolar solvation energy functional based on the nonlinear Poisson equation by using the geometric measure theory. At a fixed temperature, the proposed nonlinear Poisson theory is extensively validated by the electrostatic analysis of the Kirkwood model and a set of 20 proteins, and the solvation analysis of a set of 17 small molecules whose experimental measurements are also available for a comparison. Moreover, the nonlinear Poisson equation is further applied to the solvation analysis of 21 compounds at different temperatures. Numerical results are compared to theoretical prediction, experimental measurements, and those obtained from other theoretical methods in the literature. A good agreement between our results and experimental data as well as theoretical results suggests that the proposed nonlinear Poisson model is a potentially useful model for electrostatic analysis involving hyperpolarization effects. PMID- 22947938 TI - Hybrid dynamics simulation engine for metalloproteins. AB - Quality computational description of metalloproteins is a great challenge due to the vast span of time- and lengthscales characteristic of their existence. We present an efficient new method that allows for robust characterization of metalloproteins. It combines quantum mechanical (QM) description of the metal containing active site, and extensive dynamics of the protein captured by discrete molecular dynamics (DMD) (QM/DMD). DMD samples the entire protein, including the backbone, and most of the active site, except for the immediate coordination region of the metal. QM operates on the part of the protein of electronic and chemical significance, which may include tens to hundreds of atoms. The breathing quantum-classical boundary provides a continuous mutual feedback between the two machineries. We test QM/DMD using the Fe-containing electron transporter protein, rubredoxin, and its three mutants as a model. QM/DMD can provide a reliable balanced description of metalloproteins' structure, dynamics, and electronic structure in a reasonable amount of time. As an illustration of QM/DMD capabilities, we then predict the structure of the Ca(2+) form of the enzyme catechol O-methyl transferase, which, unlike the native Mg(2+) form, is catalytically inactive. The Mg(2+) site is ochtahedral, but the Ca(2+) is 7-coordinate and features the misalignment of the reacting parts of the system. The change is facilitated by the backbone adjustment. QM/DMD is ideal and fast for providing this level of structural insight. PMID- 22947939 TI - Tyrosine replacement of PSGL-1 reduces association kinetics with P- and L selectin on the cell membrane. AB - Binding of selectins to P-selectin glycoprotein ligand-1 (PSGL-1) mediates tethering and rolling of leukocytes on the endothelium during inflammation. Previous measurements obtained with a flow-chamber assay have shown that mutations of three tyrosines at the PSGL-1 N-terminus (Y46, Y48, and Y51) increase the reverse rates and their sensitivity to the force of bonds with P- and L-selectin. However, the effects of these mutations on the binding affinities and forward rates have not been studied. We quantified these effects by using an adhesion frequency assay to measure two-dimensional affinity and kinetic rates at zero force. Wild-type PSGL-1 has 2.2- to 8.5-fold higher binding affinities for P and L-selectin than PSGL-1 mutants with two of three tyrosines substituted by phenylalanines, and 9.6- to 49-fold higher affinities than the PSGL-1 mutant with all three tyrosines replaced. In descending order, the affinity decreased from wild-type to Y48/51F, Y46/51F, Y46/48F, and Y46/48/51F. The affinity differences were attributed to major changes in the forward rate and minor changes in the reverse rate, suggesting that these tyrosines regulate the accessibility of PSGL 1 to P- and L-selectin via electrostatic interactions, which is supported by molecular-dynamics simulations. Our results provide insights into the structure function relationship of receptor-ligand binding at a single-residue level. PMID- 22947940 TI - Partial least-squares functional mode analysis: application to the membrane proteins AQP1, Aqy1, and CLC-ec1. AB - We introduce an approach based on the recently introduced functional mode analysis to identify collective modes of internal dynamics that maximally correlate to an external order parameter of functional interest. Input structural data can be either experimentally determined structure ensembles or simulated ensembles, such as molecular dynamics trajectories. Partial least-squares regression is shown to yield a robust solution to the multidimensional optimization problem, with a minimal and controllable risk of overfitting, as shown by extensive cross-validation. Several examples illustrate that the partial least-squares-based functional mode analysis successfully reveals the collective dynamics underlying the fluctuations in selected functional order parameters. Applications to T4 lysozyme, the Trp-cage, the aquaporin channels Aqy1 and hAQP1, and the CLC-ec1 chloride antiporter are presented in which the active site geometry, the hydrophobic solvent-accessible surface, channel gating dynamics, water permeability (p(f)), and a dihedral angle are defined as functional order parameters. The Aqy1 case reveals a gating mechanism that connects the inner channel gating residues with the protein surface, thereby providing an explanation of how the membrane may affect the channel. hAQP1 shows how the p(f) correlates with structural changes around the aromatic/arginine region of the pore. The CLC-ec1 application shows how local motions of the gating Glu(148) couple to a collective motion that affects ion affinity in the pore. PMID- 22947941 TI - Solvent-induced tuning of internal structure in a protein amyloid protofibril. AB - An important goal in studies of protein aggregation is to obtain an understanding of the structural diversity that is characteristic of amyloid fibril and protofibril structures at the molecular level. In this study, what to our knowledge are novel assays based on time-resolved fluorescence anisotropy decay and dynamic quenching measurements of a fluorophore placed at different specific locations in the primary structure of a small protein, barstar, have been used to determine the extent to which the protein sequence participates in the structural core of protofibrils. The fluorescence measurements reveal the structural basis of how modulating solvent polarity results in the tuning of the protofibril conformation from a pair of parallel beta-sheets in heat-induced protofibrils to a single parallel beta-sheet in trifluorethanol-induced protofibrils. In trifluorethanol-induced protofibrils, the single beta-sheet is shown to be built up from in-register beta-strands formed by nearly the entire protein sequence, while in heat-induced protofibrils, the pair of beta-sheets motif is built up from beta-strands formed by only the last two-third of the protein sequence. PMID- 22947942 TI - Engineered bi-histidine metal chelation sites map the structure of the mechanical unfolding transition state of an elastomeric protein domain GB1. AB - Determining the structure of the transition state is critical for elucidating the mechanism behind how proteins fold and unfold. Due to its high free energy, however, the transition state generally cannot be trapped and studied directly using traditional structural biology methods. Thus, characterizing the structure of the transition state that occurs as proteins fold and unfold remains a major challenge. Here, we report a novel (to our knowledge) method that uses engineered bi-histidine (bi-His) metal-binding sites to directly map the structure of the mechanical unfolding transition state of proteins. This method is adapted from the traditional psi-value analysis, which uses engineered bi-His metal chelation sites to probe chemical (un)folding transition-state structure. The phi(M2+)(U) value is defined as DeltaDeltaG(?-N)/DeltaDeltaG(U-N), which is the energetic effects of metal chelation by the bi-His site on the unfolding energy barrier (DeltaG(?-N)) relative to its thermodynamic stability (DeltaG(U-N)) and can be used to obtain information about the transition state in the mutational site. As a proof of principle, we used the small protein GB1 as a model system and set out to map its mechanical unfolding transition-state structure. Using single-molecule atomic force microscopy and spectrofluorimetry, we directly quantified the effect of divalent metal ion binding on the mechanical unfolding free energy and thermodynamic stability of GB1, which allowed us to quantify phi(M2+)(U)-values for different sites in GB1. Our results enabled us to map the structure of the mechanical unfolding transition state of GB1. Within GB1's mechanical unfolding transition state, the interface between force-bearing beta-strands 1 and 4 is largely disrupted, and the first beta-hairpin is partially disordered while the second beta-hairpin and the alpha-helix remain structured. Our results demonstrate the unique application of psi-value analysis in elucidating the structure of the transition state that occurs during the mechanical unfolding process, offering a potentially powerful new method for investigating the design of novel elastomeric proteins. PMID- 22947943 TI - Comparison of fragments comprising the first two helices of the human Y4 and the yeast Ste2p G-protein-coupled receptors. AB - Solution NMR techniques are used to determine the structure and the topology of micelle integration of a large fragment of the Y4 receptor, a human G-protein coupled receptor, that contains the entire N-terminal domain plus the first two transmembrane (TM) segments. The structure calculations reveal that the putative TM helices are indeed helical to a large extent, but that interruptions of secondary structure occur close to internal polar or charged residues. This view is supported by (15)N relaxation data, amide-water exchange rates, and attenuations from micelle-integrating spin labels. No contacts between different helices are observed. This is in contrast to a similar TM1-TM2 fragment from the yeast Ste2p receptor for which locations of the secondary and the tertiary structure agreed well with the predictions from a homology model. The difference in structure is discussed in terms of principal biophysical properties of residues within central regions of the putative TM helices. Overall, using the biophysical scale of Wimley and White the TM regions of Ste2p display much more favorable free energies for membrane integration. Accordingly, the full secondary structure and the tertiary structure in TM1-TM2 of the Y4 receptor is likely to be formed only when tertiary contacts with other TM segments are created during folding of the receptor. PMID- 22947944 TI - Ion-mediated RNA structural collapse: effect of spatial confinement. AB - RNAs are negatively charged molecules that reside in cellular environments with macromolecular crowding. Macromolecular confinement can influence the ion effects in RNA folding. In this work, using the recently developed tightly bound ion model for ion fluctuation and correlation, we investigate the effect of confinement on ion-mediated RNA structural collapse for a simple model system. We find that for both Na(+) and Mg(2+), the ion efficiencies in mediating structural collapse/folding are significantly enhanced by the structural confinement. This enhancement of ion efficiency is attributed to the decreased electrostatic free energy difference between the compact conformation ensemble and the (restricted) extended conformation ensemble due to the spatial restriction. PMID- 22947946 TI - Nanoscale electrostatic domains in cholesterol-laden lipid membranes create a target for amyloid binding. AB - Amyloid fibrils are associated with multiple neurodegenerative disorders, such as Alzheimer's disease. Although biological membranes are involved in fibril plaque formation, the role of lipid membrane composition in fibril formation and toxicity is not well understood. We investigated the effect of cholesterol on the interaction of model lipid membranes with amyloid-beta peptide (Abeta). With atomic force microscopy we demonstrated that binding of Abeta (1-42) to DOPC bilayer, enriched with 20% cholesterol, resulted in an intriguing formation of small nonuniform islands loaded with Abeta. We attribute this effect to the presence of nanoscale electrostatic domains induced by cholesterol in DOPC bilayers. Using frequency-modulated Kelvin probe force microscopy we were able to resolve these nanoscale electrostatic domains in DOPC monolayers. These findings directly affect our understanding of how the presence of cholesterol may induce targeted binding of amyloid deposits to biomembranes. We postulate that this nonhomogeneous electrostatic effect of cholesterol has a fundamental nature and may be present in other lipid membranes and monolayers. PMID- 22947947 TI - Virucidal activity of chemical biocides against mimivirus, a putative pneumonia agent. AB - BACKGROUND: Acanthamoeba polyphaga mimivirus (APMV), the largest known virus, has been studied as a putative pneumonia agent, especially in hospital environments. Despite the repercussions of the discovery of APMV, there has been no study related to the control of APMV and the susceptibility of this virus to disinfectants. OBJECTIVES: This work investigated the virucidal activity against mimivirus of chemical biocides commonly used in clinical practice for the disinfection of hospital equipment and rooms. STUDY DESIGN: APMV was dried on sterilized steel coupons, exposed to different concentrations of alcohols (ethanol, 1-propanol and 2-propanol) and commercial disinfectants (active chlorine, glutaraldehyde and benzalkonium chloride) and titrated in amoebas using the TCID50 value. The stability of APMV on an inanimate surface was also tested in the presence and absence of organic matter for 30 days. RESULTS: APMV showed a high level of resistance to chemical biocides, especially alcohols. Only active chlorine and glutaraldehyde were able to decrease the APMV titers to undetectable levels. Dried APMV showed long-lasting stability on an inanimate surface (30 days), even in the absence of organic matter. CONCLUSIONS: The data presented herein may help health and laboratory workers plan the best strategy to control this putative pneumonia agent from surfaces and devices. PMID- 22947945 TI - Coarse-grained simulations of protein-protein association: an energy landscape perspective. AB - Understanding protein-protein association is crucial in revealing the molecular basis of many biological processes. Here, we describe a theoretical simulation pipeline to study protein-protein association from an energy landscape perspective. First, a coarse-grained model is implemented and its applications are demonstrated via molecular dynamics simulations for several protein complexes. Second, an enhanced search method is used to efficiently sample a broad range of protein conformations. Third, multiple conformations are identified and clustered from simulation data and further projected on a three dimensional globe specifying protein orientations and interacting energies. Results from several complexes indicate that the crystal-like conformation is favorable on the energy landscape even if the landscape is relatively rugged with metastable conformations. A closer examination on molecular forces shows that the formation of associated protein complexes can be primarily electrostatics-driven, hydrophobics-driven, or a combination of both in stabilizing specific binding interfaces. Taken together, these results suggest that the coarse-grained simulations and analyses provide an alternative toolset to study protein-protein association occurring in functional biomolecular complexes. PMID- 22947949 TI - Grandparental child care in Europe: evidence for preferential investment in more certain kin. AB - Theories of kin selection and parental investment predict stronger investment in children and grandchildren by women and maternal kin. Due to paternity uncertainty, parental and grandparental investments along paternal lineages are based on less certain genetic relatedness with the children and grandchildren. Additionally, the hypothesis of preferential investment (Laham, Gonsalkorale, and von Hippel, 2005) predicts investment to vary according to available investment options. Two previous studies have tested this hypothesis with small samples and conflicting results. Using the second wave of the large and multinational Survey of Health, Ageing and Retirement in Europe (SHARE), collected in 2006-07, we study the preferential investment hypothesis in contemporary Europe based on self reported grandparental provision of child care. We predict that 1) maternal grandmothers provide most care for their grandchildren, followed by maternal grandfathers, paternal grandmothers and last by paternal grandfathers; 2) maternal grandfathers and paternal grandmothers provide equal amounts of care when the latter do not have grandchildren via a daughter; 3) women who have grandchildren via both a daughter and a son will look after the children of the daughter more; and 4) men who have grandchildren via both a daughter and a son will look after the children of the daughter more. Results support all four hypotheses and provide evidence for the continuing effects of paternity uncertainty in contemporary kin behavior. PMID- 22947951 TI - Relationships of smiling and flirtation to aggression and 2D:4D, a prenatal androgen index. AB - Smiling has been reported to be a signal of submission/lower status, or a sign of cooperation. In the present study, use of smiling and flirtation to "make people receptive to my ideas" was conceptualized as mild aggression, since it is mildly manipulative of the perception of others as to one's internal emotional status. For 91 participants (55 female, 36 male), use of smiling and flirtation to make others receptive to one's ideas were associated with relational aggression and a more male-typical (smaller) right 2D:4D finger length ratio. The only significant relationship in the male sample alone was the relationship between smiling and relational aggression. In the female sample alone, use of smiling and flirtation to "make people receptive to my ideas" was associated with a more male-typical 2D:4D finger length ratio pattern, and there was a trend for flirtation to be associated with greater physical aggression. Both 2D:4D and physical aggression have been associated with higher prenatal androgen level. It is concluded that deliberate smiling and flirtation are mild forms of relational aggression, and are related to prenatal androgenic activity in a manner similar to physical aggression. These findings are discussed in terms of the different evolutionary strategies of men and women to control their social environments. PMID- 22947954 TI - Recognition of novel faces after single exposure is enhanced during pregnancy. AB - Protective mechanisms in pregnancy include Nausea and Vomiting in Pregnancy (NVP) (Fessler, 2002; Flaxman and Sherman, 2000), increased sensitivity to health cues (Jones et al., 2005), and increased vigilance to out-group members (Navarette, Fessler, and Eng, 2007). While common perception suggests that pregnancy results in decreased cognitive function, an adaptationist perspective might predict that some aspects of cognition would be enhanced during pregnancy if they help to protect the reproductive investment. We propose that a reallocation of cognitive resources from nonessential to critical areas engenders the cognitive decline observed in some studies. Here, we used a recognition task disguised as a health rating to determine whether pregnancy facilitates face recognition. We found that pregnant women were significantly better at recognizing faces and that this effect was particularly pronounced for own-race male faces. In human evolutionary history, and today, males present a significant threat to females. Thus, enhanced recognition of faces, and especially male faces, during pregnancy may serve a protective function. PMID- 22947956 TI - Voice pitch influences perceptions of sexual infidelity. AB - Sexual infidelity can be costly to members of both the extra-pair and the paired couple. Thus, detecting infidelity risk is potentially adaptive if it aids in avoiding cuckoldry or loss of parental and relationship investment. Among men, testosterone is inversely related to voice pitch, relationship and offspring investment, and is positively related to the pursuit of short-term relationships, including extra-pair sex. Among women, estrogen is positively related to voice pitch, attractiveness, and the likelihood of extra-pair involvement. Although prior work has demonstrated a positive relationship between men's testosterone levels and infidelity, this study is the first to investigate attributions of infidelity as a function of sexual dimorphism in male and female voices. We found that men attributed high infidelity risk to feminized women's voices, but not significantly more often than did women. Women attributed high infidelity risk to masculinized men's voices at significantly higher rates than did men. These data suggest that voice pitch is used as an indicator of sexual strategy in addition to underlying mate value. The aforementioned attributions may be adaptive if they prevent cuckoldry and/or loss of parental and relationship investment via avoidance of partners who may be more likely to be unfaithful. PMID- 22947957 TI - The effect of attractiveness on food sharing preferences in human mating markets. AB - The current study explored how physical attractiveness affects food sharing by studying payment preferences for hypothetical romantic dinner dates (a hypothetical mating market). We analyzed payment preferences, self-rated attractiveness, and rated attractiveness for hypothetical dates in 416 participants. We hypothesized that (1) men would be more likely to prefer to pay than would women, (2) attractive individuals of both sexes would be less willing to pay, and (3) preferences to enter an exchange would be influenced by the attractiveness of prospective partners such that (3a) men would prefer to pay for attractive women, and (3b) women would prefer to be paid for by attractive men. All hypotheses were supported by our results. Individuals with higher self-rated attractiveness were more likely to prefer that their date would pay for the meal, and we found clear sex differences in how the attractiveness of potential dates affected payment preferences. Male participants preferred to pay for dates that had higher facial attractiveness, while female participants preferred that attractive men would pay. Individuals show condition dependent financial preferences consistent with the provisioning hypothesis in this mating market that are adaptive to evaluations of their own quality and that of prospective partners. PMID- 22947958 TI - Questioning the integrity of the John Templeton Foundation. PMID- 22947959 TI - Jealousy reconsidered: a reply to DeSteno (2010). AB - In a recent commentary, DeSteno (2010) critiqued the work of Levy and Kelley (2010) which investigated the relationship of attachment style to the sex difference in jealousy. This commentary addresses the concerns raised by DeSteno; I briefly review some of the literature that was not addressed by DeSteno's commentary and discuss directions that future research may take. PMID- 22947960 TI - To defer or to stand up? How offender formidability affects third party moral outrage. AB - According to models of animal behavior, the relative formidability of conspecifics determines the utility of deferring versus aggressing in situations of conflict. Here we apply and extend these models by investigating how the formidability of exploiters shapes third party moral outrage in humans. Deciding whether to defer to or stand up against a formidable exploiter is a complicated decision as there is both much to lose (formidable individuals are able and prone to retaliate) and much to gain (formidable individuals pose a great future threat). An optimally designed outrage system should, therefore, be sensitive to these cost- benefit trade-offs. To test this argument, participants read scenarios containing exploitative acts (trivial vs. serious) and were presented with head-shot photos of the apparent exploiters (formidable vs. non-formidable). As predicted, results showed that, compared to the non- formidable exploiter, the formidable exploiter activated significantly more outrage in male participants when the exploitative act was serious. Conversely, when it was trivial, the formidable exploiter activated significantly less outrage in male participants. However, these findings were conditioned by the exploiters' perceived trustworthiness. Among female participants, the results showed that moral outrage was not modulated by exploiter formidability. PMID- 22947961 TI - Preliminary evidence that the limbal ring influences facial attractiveness. AB - The limbal ring of the eye appears as a dark annulus where the iris meets the sclera. Both width and opacity of the limbal ring are influenced by iris pigmentation and optical properties of the region. With age the limbal ring becomes less prominent, making it a probabilistic indicator of youth and health. This raises the question: Are judgments of facial attractiveness sensitive to this signal in a potentially adaptive way? Here we show that the answer is yes. For male and female observers, both male and female faces with a dark and distinct limbal ring are rated as more attractive than otherwise identical faces with no limbal ring. This result is observed not just for upright faces but also for inverted faces, suggesting that the limbal ring is processed primarily as a local feature rather than as a configural feature in the analysis of facial beauty. We also discuss directions for future research that can clarify the role of the limbal ring in the visual perception of facial attractiveness. PMID- 22947962 TI - An implicit theory of self-esteem: the consequences of perceived self-esteem for romantic desirability. AB - The provision of information appears to be an important property of self-esteem as evidenced by previous research concerning the status-tracking and status signaling models of self-esteem. The present studies examine whether there is an implicit theory of self-esteem that leads individuals to assume targets with higher levels of self-esteem possess more desirable characteristics than those with lower levels of self-esteem. Across 6 studies, targets with ostensibly higher levels of self-esteem were generally rated as more attractive and as more desirable relationship partners than those with lower levels of self- esteem. It is important to note, however, that this general trend did not consistently emerge for female targets. Rather, female targets with high self-esteem were often evaluated less positively than those with more moderate levels of self esteem. The present findings are discussed in the context of an extended informational model of self-esteem consisting of both the status-tracking and status-signaling properties of self-esteem. PMID- 22947966 TI - Surveillance cues enhance moral condemnation. AB - Humans pay close attention to the reputational consequences of their actions. Recent experiments indicate that even very subtle cues that one is being observed can affect cooperative behaviors. Expressing our opinions about the morality of certain acts is a key means of advertising our cooperative dispositions. Here, we investigated how subtle cues of being watched would affect moral judgments. We predicted that participants exposed to such cues would affirm their endorsement of prevailing moral norms by expressing greater disapproval of moral transgressions. Participants read brief accounts of two moral violations and rated the moral acceptability of each violation. Violations were more strongly condemned in a condition where participants were exposed to surveillance cues (an image of eyes interposed between the description of the violation and the associated rating scale) than in a control condition (in which the interposed image was of flowers). We discuss the role that public declarations play in the interpersonal evaluation of cooperative dispositions. PMID- 22947969 TI - Conceptualizing the autism spectrum in terms of natural selection and behavioral ecology: the solitary forager hypothesis. AB - This article reviews etiological and comparative evidence supporting the hypothesis that some genes associated with the autism spectrum were naturally selected and represent the adaptive benefits of being cognitively suited for solitary foraging. People on the autism spectrum are conceptualized here as ecologically competent individuals that could have been adept at learning and implementing hunting and gathering skills in the ancestral environment. Upon independence from their mothers, individuals on the autism spectrum may have been psychologically predisposed toward a different life-history strategy, common among mammals and even some primates, to hunt and gather primarily on their own. Many of the behavioral and cognitive tendencies that autistic individuals exhibit are viewed here as adaptations that would have complemented a solitary lifestyle. For example, the obsessive, repetitive and systemizing tendencies in autism, which can be mistakenly applied toward activities such as block stacking today, may have been focused by hunger and thirst toward successful food procurement in the ancestral past. Both solitary mammals and autistic individuals are low on measures of gregariousness, socialization, direct gazing, eye contact, facial expression, facial recognition, emotional engagement, affiliative need and other social behaviors. The evolution of the neurological tendencies in solitary species that predispose them toward being introverted and reclusive may hold important clues for the evolution of the autism spectrum and the natural selection of autism genes. Solitary animals are thought to eschew unnecessary social contact as part of a foraging strategy often due to scarcity and wide dispersal of food in their native environments. It is thought that the human ancestral environment was often nutritionally sparse as well, and this may have driven human parties to periodically disband. Inconsistencies in group size must have led to inconsistencies in the manner in which natural selection fashioned the social minds of humans, which in turn may well be responsible for the large variation in social abilities seen in human populations. This article emphasizes that individuals on the autism spectrum may have only been partially solitary, that natural selection may have only favored subclinical autistic traits and that the most severe cases of autism may be due to assortative mating. PMID- 22947971 TI - Is the social brain theory applicable to human individual differences? Relationship between sociability personality dimension and brain size. AB - Our study intends to examine whether the social brain theory is applicable to human individual differences. According to the social brain theory primates have larger brains as it could be expected from their body sizes due to the adaptation to a more complex social life. Regarding humans there were few studies about the relationship between theory of mind and frontal and temporal brain lobes. We hypothesized that these brain lobes, as well as the whole cerebrum and neocortex are in connection with the Sociability personality dimension that is associated with individuals' social lives. Our findings support this hypothesis as Sociability correlated positively with the examined brain structures if we control the effects of body size differences and age. These results suggest that the social brain theory can be extended to human interindividual differences and they have some implications to personality psychology too. PMID- 22947972 TI - Children's risky play from an evolutionary perspective: the anti-phobic effects of thrilling experiences. AB - This theoretical article views children's risky play from an evolutionary perspective, addressing specific evolutionary functions and especially the anti phobic effects of risky play. According to the non-associative theory, a contemporary approach to the etiology of anxiety, children develop fears of certain stimuli (e.g., heights and strangers) that protect them from situations they are not mature enough to cope with, naturally through infancy. Risky play is a set of motivated behaviors that both provide the child with an exhilarating positive emotion and expose the child to the stimuli they previously have feared. As the child's coping skills improve, these situations and stimuli may be mastered and no longer be feared. Thus fear caused by maturational and age relevant natural inhibition is reduced as the child experiences a motivating thrilling activation, while learning to master age adequate challenges. It is concluded that risky play may have evolved due to this anti-phobic effect in normal child development, and it is suggested that we may observe an increased neuroticism or psychopathology in society if children are hindered from partaking in age adequate risky play. PMID- 22947973 TI - Is there a sensitive period in human incest avoidance? AB - Many studies support the proposition that early cosocialization with opposite-sex children has the effect of inhibiting later mutual sexual attraction, but the existence of a period in the life cycle in which individuals are sensitive to the effect of early cosocialization has been a matter of controversy. Drawing on earlier traditional psychological research, and on more recent work guided by parental investment theory, we hypothesized that only for maternal perinatal association (MPA)-absent males a less-than- around-three-years age difference with the sister can predict stronger aversion to sibling incest. The results corroborated the hypothesis. The results can be interpreted as support for the existence of a sensitive period as well as for the potent role of MPA. Cross cultural comparative studies were called on to further test the hypothesis. PMID- 22947977 TI - Age-related changes in the signal value of tears. AB - Emotional tears may be uniquely human and are an effective signal of distress in adults. The present study explored whether tears signal distress in younger criers and whether the effect of tears on observers is similar in magnitude across the life span. Participants rated photographs of crying infants, young children, and adults, with tears digitally removed or added. The effectiveness of tears in conveying sadness and eliciting sympathy was greatest for images of adults, intermediate for images of children, and least potent for images of infants. These findings suggest that the signal value of tears varies with the age of the crier. The results may shed light on the functional significance of crying at different stages of human development. PMID- 22947979 TI - Physical cues of ovulatory status: a failure to replicate enhanced facial attractiveness and reduced waist-to-hip ratio at high fertility. AB - We investigated women's facial attractiveness and body shape as a function of menstrual cycle phase, with the expectation from previous research that both would be enhanced during the high fertile phase. To control for the effects of women's daily behaviors on their appearance and waistline, we visited 37 normally cycling women twice in their dorm, where we photographed and measured them at low and high fertile days of their cycle immediately upon their waking. Seventy-four judges from a separate institution chose, for each woman, the picture they thought was more attractive. We analyzed a subset of 20 women who, by forward counting, had a High Fertility visit between Days 10-13 and a Low Fertility visit between Days 20-23; and we also analyzed a subsample of 17 women who, by reverse counting, had a High Fertility visit on the days leading to ovulation and a Low Fertility visit one week after ovulation. In neither set of analyses were women's waist- to-hip ratios lower nearer ovulation, and in neither set were women's high fertile pictures chosen at an above-chance rate by either male or female judges. We did not find evidence that facial attractiveness and waist-to-hip ratio are reliable physical cues of ovulatory status. PMID- 22947980 TI - Left-handedness and male-male competition: insights from fighting and hormonal data. AB - Male-male competition can shape some behavioral or morphological traits of males. Here we investigate if this competition could play a role in the persistence of the polymorphism of handedness in human populations. A negative frequency dependent selection mechanism has been hypothesized, based on the fact that left handed men may benefit from a "surprise" advantage during fighting interactions because they are rare in human populations. This advantage may thereby enhance the probability of survival of left- handed men and/or their reproductive success through an increase in social status. In this study, we first explored the association between hand preference and lifetime fighting behavior in a population of 1,161 French men. No effect of hand preference on the probability of fighting was detected, suggesting that the innate propensity to fight does not differ between left- and right-handers. However, among men who had been involved in at least one fight during their lifetime, left-handers reported significantly more fights than right-handers. To explore the biological basis of this behavior, we also investigated the testosterone concentration in saliva samples from 64 French university students. Consistent with frequencies of fights, we found a significantly higher average testosterone concentration in left-handers than in right-handers. We suggest that these behavioral and hormonal differences may be acquired throughout life due to previous experiences in a social context and may favor the persistence of left-handers in humans. PMID- 22947981 TI - Predicting preferences for sex acts: which traits matter most, and why? AB - Several dispositional traits have been examined in mating contexts by evolutionary psychologists. Such traits include life history strategy, sociosexuality, and the Big Five. Recently, scholars have examined the validity and predictive utility of mating intelligence, a new construct designed to capture the cognitive processes that underlie mating psychology. The current research employed a battery of dispositional traits that include all these constructs in an effort to predict preferences for different kinds of sex acts. Sexual acts vary wildly, and the ability to predict this variability may well hold an important key to underlying sexual strategies. A sample of 607 young adults (144 males and 463 females) completed measures of each of these traits as well as a measure of preference for specific sex acts (along with providing information on their sexual orientation). The traits predicted variability in preference for sex acts - with mating intelligence being the most predictive (for instance, mating intelligence was positively related to preference for vaginal intercourse across the sexes). Sex differences emerged (e.g., males show a stronger preference for anal sex than do females). Discussion focuses on (a) sex differences in preference for sex acts along with (b) why the trait variables predicted preferences in sex acts. PMID- 22947982 TI - Songs as a medium for embedded reproductive messages. AB - Research shows that sensational news stories as well as popular romance novels often feature themes related to important topics in evolutionary psychology. In the first of four studies described in this paper we examined the song lyrics from three Billboard charts: Country, Pop, and R&B. A content analysis of the lyrics revealed 18 reproductive themes that read like an outline for a course in evolutionary psychology. Approximately 92% of the 174 songs that made it into the Top Ten in 2009 contained one or more reproductive messages, with an average of 10.49 reproductive phrases per song. Although differences in the frequency of different themes between charts were found, further analyses showed that the most popular/bestselling songs contained significantly more reproductive messages. An analysis of the lyrics of opera arias and art songs also revealed evidence for many of the same embedded reproductive messages extending back more than 400 years. PMID- 22947983 TI - Spatial distance regulates sex-specific feelings to suspected sexual and emotional infidelity. AB - The present study investigates the hitherto neglected influence of the spatial distance between the jealous person, the partner, and a potential rival as a proximate contextual factor regulating emotion intensity. The study tested four predictions. (1) The jealousy mechanism responds with mild negative feelings at most as long as the partner is close to the jealous person. (2) The negative feelings increase when the partner is far from the jealous person but the rival is close. (3) The most uncomfortable feelings result when the partner and the rival are close together and both far from the jealous person. (4) Based on the evolutionary psychological considerations, men report stronger negative feelings than women when suspecting sexual infidelity. Conversely, women report stronger negative feelings than men when suspecting emotional infidelity. The results confirmed predictions 1 and 4. Reversing predictions 2 and 3, the close rival consistently elicited the most uncomfortable feelings. Implications and limitations of the present study are discussed and suggestions for future research are provided. PMID- 22947987 TI - The affective quality of human-natural environment relationships. AB - Using a psychometric methodology the present study explored the associations between natural environments and experiential feeling states. The effects of the frequency of participants' (N = 90) experience of the natural environment and of the location of their childhood upbringing were also investigated. Ten natural environments mapped on to an orthogonal two-component experiential structure labeled Eudemonia (ostensibly positive feelings) and Apprehension (ostensibly negative feelings). Generally, the more natural environments tended to be associated with higher eudemonia and higher apprehension, the less natural environments with both lower eudemonia and lower apprehension. In line with expectations, participants from rural childhood locations, compared with urban participants, reported less Apprehension and participants with greater experience of the natural environment, compared with participants with less experience, reported greater Eudemonia and less Apprehension. Results are discussed in relation to environmental experiences and affective psychological wellbeing. PMID- 22947988 TI - Parent-offspring conflict over mating: testing the tradeoffs hypothesis. AB - The difference in genetic relatedness between parents and offspring results into traits such as beauty being more beneficial in a spouse than in an in-law. As a consequence, mate and in-law preferences do not overlap, and each party tends to prefer more the traits that give it more benefits. This paper tests the hypothesis that this divergence in preferences interacts with the tradeoffs nature of mating to give rise to parent-offspring conflict over mating. In particular, using a design where mate choice is constrained by a budget, three hypotheses are tested: First, asymmetries between in-law and mate preferences result in asymmetrical compromises in the choice of an in-law and a spouse. Second, the hypothesis is tested that when choice is constrained, disagreement spreads to traits where there is no divergence between in-law and mate preferences. Finally, it is hypothesized that there is a negative relationship between mate value and parent-offspring conflict over mating. Evidence from two independent studies in two different countries provides support for all three hypotheses. PMID- 22947989 TI - Prenatal influences on sexual orientation: digit ratio (2D:4D) and number of older siblings. AB - Prenatal androgen levels are suggested to influence sexual orientation in both sexes. The 2D:4D digit ratio has been found to associate with sexual orientation, but published findings have often been contradictory, which may partly be due to the large ethnic diversity between and within studied populations. In men, number of older brothers has been found to correlate positively with homosexuality. This phenomenon has been explained with a maternal immune reaction, which is provoked only by male fetuses and which gets stronger after each pregnancy. Here we assessed the relationship of sexual orientation to 2D:4D ratios and number of older siblings in Finland, where the population is found to be genetically relatively homogeneous. As in many previous studies, heterosexual men had lower 2D:4D than non-heterosexual men, which supports the notion that non- heterosexual men experience higher androgen levels in utero than population norms. Contrary to previous reports, non-heterosexual women had higher 2D:4D than heterosexual women. Non-heterosexual men had more older brothers and older sisters than heterosexual men. The greater number of older sisters in non-heterosexual men indicates that there are other factors that contribute to the higher birth order of homosexual men than the maternal immunization. PMID- 22947990 TI - Competitive disadvantage makes attitudes towards rape less negative. AB - Evolutionary theorists have argued that perceived competitive disadvantage may lead to more positive evaluation of, and greater likelihood of engaging in, risky and antisocial behavior. However, experimental studies have not yet examined the effects of competitive disadvantage on perceptions of rape. In the current study, we created a manipulation of perceived competitive status to test its effects on beliefs about rape. In one condition, participants were made to feel disadvantaged relative to male peers in terms of financial, physical, and intellectual power, whereas in the other condition they were made to feel advantaged. Participants were 120 heterosexual male undergraduate students. The manipulation was effective; compared to participants in the advantage condition, those in the disadvantage condition rated themselves as significantly worse off financially, shorter, in worse physical shape, and as having lower course marks than the average male student at the university. Compared to perceived competitive advantage, perceived disadvantage led to less negative attitudes towards rape. However, perceived competitive status did not significantly affect justifications and excuses for rape. Future studies using similar experimental manipulations can complement correlational studies and may contribute to greater clarity, precision, and sophistication of research and theory on the role of competitive disadvantage in rape. PMID- 22947993 TI - Acute stress eliminates female advantage in detection of ambiguous negative affect. AB - The human stress response evolved to maximize an individual's probability of survival when threatened. The present study addressed whether physical danger modulates perception of an unrelated ambiguous threat and, if so, to what extent this response is sex- specific. The authors utilized a first-time tandem skydive as a stressor, which had been previously validated as producing a highly controlled, genuinely stressful environment. In a counter-balanced within subjects design, participants wore a virtual reality helmet to complete an emotion-identification task during the plane's ascent (stress condition) and in the laboratory (control condition). Participants were presented static male faces morphed between 20-80% aggression, which gradually emerged from degraded images. Using a binary forced-choice design, participants identified each ambiguous face as aggressive or neutral. Results showed that participants characterized emotion more rapidly under stress versus control conditions. Unexpectedly, the results also show that while women were more sensitive to affect ambiguity than men under control conditions, they exhibited a marked decrease in sensitivity equivalent to men while under stress. PMID- 22947994 TI - Friends with benefits: the evolved psychology of same- and opposite-sex friendship. AB - During human evolution, men and women faced distinct adaptive problems, including pregnancy, hunting, childcare, and warfare. Due to these sex-linked adaptive problems, natural selection would have favored psychological mechanisms that oriented men and women toward forming friendships with individuals possessing characteristics valuable for solving these problems. The current study explored sex-differentiated friend preferences and the psychological design features of same- and opposite-sex friendship in two tasks. In Task 1, participants (N = 121) categorized their same-sex friends (SSFs) and opposite-sex friends (OSFs) according to the functions these friends serve in their lives. In Task 2, participants designed their ideal SSFs and OSFs using limited budgets that forced them to make trade-offs between the characteristics they desire in their friends. In Task 1, men, more than women, reported maintaining SSFs for functions related to athleticism and status enhancement and OSFs for mating opportunities. In Task 2, both sexes prioritized agreeableness and dependability in their ideal SSFs, but men prioritized physical attractiveness in their OSFs, whereas women prioritized economic resources and physical prowess. These findings suggest that friend preferences may have evolved to solve ancestrally sex-linked adaptive problems, and that opposite-sex friendship may directly or indirectly serve mating functions. PMID- 22947995 TI - Human sexual conflict from molecules to culture. AB - Coevolutionary arms races between males and females have equipped both sexes with mutually manipulative and defensive adaptations. These adaptations function to benefit individual reproductive interests at the cost of the reproductive interests of opposite-sex mates, and arise from evolutionary dynamics such as parental investment (unequal reproductive costs between the sexes) and sexual selection (unequal access to opposite-sex mates). Individuals use these adaptations to hijack others' reproductive systems, psychological states, and behaviors--essentially using other individuals as extended phenotypes of themselves. Such extended phenotypic manipulation of sexual rivals and opposite sex mates is enacted by humans with the aid of hormones, pheromones, neurotransmitters, emotions, language, mind-altering substances, social institutions, technologies, and ideologies. Furthermore, sexual conflict may be experienced at an individual level when maternal genes and paternal genes are in conflict within an organism. Sexual conflict may be physically and emotionally destructive, but may also be exciting and constructive for relationships. By extending the biological concept of sexual conflict into social and cultural domains, scholars may successfully bridge many of the interdisciplinary gaps that separate the sciences from the humanities. PMID- 22947996 TI - The effect of individual differences and manipulated life expectancies on the willingness to engage in sexual coercion. AB - The role of the individual difference variables of mate value, short-term and long-term mating preferences, and life history strategy along with the manipulated variable of life expectancy were used to predict differences in the willingness to engage in sexually coercive behaviors. Short-term preferences and long-term preferences were correlated with the willingness to engage in sexual coercion at all life expectancies. Life history strategy was correlated with the willingness to engage in sexual coercion at only the shortest and longest life expectancies. Most importantly short-term and long-term mating preferences interacted with life expectancy to predict the willingness to engage in sexually coercive behaviors. Short life expectancies increased willingness in individuals with high short-term and low long-term preferences. The results are discussed in terms of the varying theories of sexual coercion with emphasis put on a life history approach. PMID- 22947997 TI - More men run relatively fast in U.S. road races, 1981-2006: a stable sex difference in non-elite runners. AB - Recent studies indicate that more men than women run fast relative to sex- specific world records and that this sex difference has been historically stable in elite U.S. runners. These findings have been hypothesized to reflect an evolved male predisposition for enduring competitiveness in "show-off" domains. The current study tests this hypothesis in non-elite runners by analyzing 342 road races that occurred from 1981-2006, most in or near Buffalo, NY. Both absolutely and as a percentage of same-sex finishers, more men ran relatively fast in most races. During the 1980s, as female participation surged, the difference in the absolute number of relatively fast men and women decreased. However, this difference was stable for races that occurred after 1993. Since then, in any given race, about three to four times as many men as women ran relatively fast. The stable sex difference in relative performance shown here for non-elites constitutes new support for the hypothesis of an evolved male predisposition for enduring competitiveness. PMID- 22947998 TI - Plantar pressure and daily cumulative stress in persons affected by leprosy with current, previous and no previous foot ulceration. AB - Not only plantar pressure but also weight-bearing activity affects accumulated mechanical stress to the foot and may be related to foot ulceration. To date, activity has not been accounted for in leprosy. The purpose was to compare barefoot pressure, in-shoe pressure and daily cumulative stress between persons affected by leprosy with and without previous or current foot ulceration. Nine persons with current plantar ulceration were compared to 15 with previous and 15 without previous ulceration. Barefoot peak pressure (EMED-X), in-shoe peak pressure (Pedar-X) and daily cumulative stress (in-shoe forefoot pressure time integral*mean daily strides (StepwatchTM Activity Monitor)) were measured. Barefoot peak pressure was increased in persons with current and previous compared to no previous foot ulceration (mean+/-SD=888+/-222 and 763+/-335 vs 465+/-262kPa, p<0.05). In-shoe peak pressure was only increased in persons with current compared to without previous ulceration (mean+/-SD=412+/-145 vs 269+/ 70kPa, p<0.05). Daily cumulative stress was not different between groups, although persons with current and previous foot ulceration were less active. Although barefoot peak pressure was increased in people with current and previous plantar ulceration, it did not discriminate between these groups. While in-shoe peak pressure was increased in persons with current ulceration, they were less active, resulting in no difference in daily cumulative stress. Increased in-shoe peak pressure suggests insufficient pressure reducing footwear in persons with current ulceration, highlighting the importance of pressure reducing qualities of footwear. PMID- 22948000 TI - Physiological measurement of the small airways. AB - Noninvasive physiological measurements are reviewed that have been reported in the literature with the specific aim being to study the small airways in lung disease. This has mostly involved at-the-mouth noninvasive measurement of flow, pressure or inert gas concentration, with the intent of deriving one or more indices that are representative of small airway structure and function. While these measurements have remained relatively low-tech, the effort and sophistication increasingly reside with the interpretation of such indices. When aspiring to derive information at the mouth about structural and mechanical processes occurring several airway generations away in a complex cyclically changing cul-de-sac structure, conceptual or semi-quantitative lung models can be valuable. Two assumptions that are central to small airway structure-function measurement are that of an average airway change at a given peripheral lung generation and of a parallel heterogeneity in airway changes. While these are complementary pieces of information, they can affect certain small airways tests in confounding ways. We critically analyzed the various small airway tests under review, while contending that negative outcomes of these tests are probably a true reflection of the fact that no change occurred in the small airways. Utmost care has been taken to not favor one technique over another, given that most current small airways tests still have room for improvement in terms of rendering their content more specific to the small airways. One way to achieve this could consist of the coupling of signals collected at the mouth to spatial information gathered from imaging in the same patient. PMID- 22947999 TI - The effects of muscle fatigue on dynamic standing balance in people with and without patellofemoral pain syndrome. AB - The aim was to examine the effects of muscle fatigue of knee extensor and hip abductor muscles on dynamic standing balance of patients with patellofemoral pain syndrome (PFPS) compared to their healthy matched controls. Thirty participants (15 with PFPS, 15 controls) were recruited. Isolated muscle fatigue of two muscles was induced isokinetically in three separate sessions (one practice and two testing sessions) with a rest interval of at least 72h. In each testing session, fatigue protocol of only one muscle group was performed for the both legs with a rest time of 30min. After determining peak torque, participants were encouraged to perform continuous maximal concentric-eccentric contraction of the target muscle until the torque output dropped below 50% of peak value for 3 consecutive repetitions. Immediately after the completion of the fatigue protocol, balance testing of participants was undertaken during single leg standing using the Biodex stability system. Balance stability measures included the overall, anteroposterior and mediolateral stability indices (OSI, APSI and MLSI, respectively). Patients exhibited decreased balance stability in the sagittal plane (higher APSI) when compared to controls. Isolated muscle fatigue of the knee extensors and hip abductors reduced balance stability in both study groups. Fatigue of hip abductors was associated with greater balance instability (higher OSI and APSI) than fatigue of knee extensors. PMID- 22948001 TI - Recent developments in basophil research: do basophils initiate and perpetuate type 2 T-helper cell responses?. AB - Basophils account for only 0.1-1% of all peripheral blood leukocytes. They were considered to be a redundant cell type for a long time. However, several findings show a non-redundant role for basophils in type 2 T-helper cell (Th2) immune responses in helminth infections, allergy and autoimmunity. Both immunoglobulin-E dependent and -independent pathways have been described to contribute to basophil activation. In addition, several recent studies reported that basophils can function as antigen-presenting cells and are important in the initiation of Th2 immune responses. However, there are also conflicting studies that do not corroborate the importance of basophils in Th2 immune responses. This review discusses the role of basophils in Th2 immune responses in view of these recent findings. PMID- 22948002 TI - Abnormal functioning of the semantic network in schizophrenia patients with thought disorganization. An exemplar production task. AB - Numerous studies have indicated that thought disorganization in schizophrenia is associated with an enhanced semantic priming effect. This suggests abnormal functioning of the semantic network in these patients, with disinhibited spreading of semantic activation. We investigated whether thought disorganization is also associated with atypical responses in the production of semantic category exemplars. An exemplar production task was administered to 43 patients with schizophrenia and 24 healthy controls. The names of 16 semantic categories were provided, and the participants were requested to produce an exemplar for each category. The typicality of the response was rated according to norms. Higher ratings of thought disorganization were associated with the production of more atypical exemplars. In addition, the patients with high thought disorganization scores were significantly more atypical in their responses than were the healthy controls. In contrast, the patients with low thought disorganization scores were equivalent to the healthy controls. Higher ratings of affective flattening were associated with the production of less atypical exemplars. The results corroborate, within a different paradigm than semantic priming, the theory that thought disorganization is associated with faster and more distant connections within the semantic network. This effect is counteracted by affective flattening. PMID- 22948003 TI - The design and testing of a caring teaching model based on the theoretical framework of caring in the Chinese Context: a mixed-method study. AB - AIM: This paper aims to report the design and test the effectiveness of an innovative caring teaching model based on the theoretical framework of caring in the Chinese context. BACKGROUND: Since the 1970's, caring has been a core value in nursing education. In a previous study, a theoretical framework of caring in the Chinese context is explored employing a grounded theory study, considered beneficial for caring education. METHODS: A caring teaching model was designed theoretically and a one group pre- and post-test quasi-experimental study was administered to test its effectiveness. From Oct, 2009 to Jul, 2010, a cohort of grade-2 undergraduate nursing students (n=64) in a Chinese medical school was recruited to participate in the study. Data were gathered through quantitative and qualitative methods to evaluate the effectiveness of the caring teaching model. RESULTS: The caring teaching model created an esthetic situation and experiential learning style for teaching caring that was integrated within the curricula. Quantitative data from the quasi-experimental study showed that the post-test scores of each item were higher than those on the pre-test (p<0.01). Thematic analysis of 1220 narratives from students' caring journals and reports of participant class observation revealed two main thematic categories, which reflected, from the students' points of view, the development of student caring character and the impact that the caring teaching model had on this regard. CONCLUSIONS: The model could be used as an integrated approach to teach caring in nursing curricula. It would also be beneficial for nursing administrators in cultivating caring nurse practitioners. PMID- 22948004 TI - A response to: Gardner (2012) From Novice to Expert: Benner's legacy for nurse education Nurse Education Today 32 (4) 339-340. PMID- 22948005 TI - Does ursodeoxycholic acid exert a protective effect on liver grafts in orthotopic liver transplantation? PMID- 22948006 TI - Large-scale homogeneously distributed Ag-NPs with sub-10 nm gaps assembled on a two-layered honeycomb-like TiO2 film as sensitive and reproducible SERS substrates. AB - We present a surface-enhanced Raman scattering (SERS) substrate featured by large scale homogeneously distributed Ag nanoparticles (Ag-NPs) with sub-10 nm gaps assembled on a two-layered honeycomb-like TiO(2) film. The two-layered honeycomb like TiO(2) film was achieved by a two-step anodization of pure Ti foil, with its upper layer consisting of hexagonally arranged shallow nano-bowls of 160 nm in diameter, and the lower layer consisting of arrays of about fifty vertically aligned sub-20 nm diameter nanopores. The shallow nano-bowls in the upper layer divide the whole TiO(2) film into regularly arranged arrays of uniform hexagonal nano-cells, leading to a similar distribution pattern for the ion-sputtered Ag NPs in each nano-cell. The lower layer with sub-20 nm diameter nanopores prevents the aggregation of the sputtered Ag-NPs, so that the Ag-NPs can get much closer with gaps in the sub-10 nm range. Therefore, large-scale high-density and quasi ordered sub-10 nm gaps between the adjacent Ag-NPs were achieved, which ensures homogeneously distributed 'hot spots' over a large area for the SERS effect. Moreover, the honeycomb-like structure can also facilitate the capture of target analyte molecules. As expected, the SERS substrate exhibits an excellent SERS effect with high sensitivity and reproducibility. As an example, the SERS substrate was utilized to detect polychlorinated biphenyls (PCBs, a kind of persistent organic pollutants as global environmental hazard) such as 3,3',4,4' pentachlorobiphenyl (PCB-77) with concentrations down to 10(-9) M. Therefore the large-scale Ag-NPs with sub-10 nm gaps assembled on the two-layered honeycomb like TiO (2) film have potentials in SERS-based rapid trace detection of PCBs. PMID- 22948007 TI - Predicting genes involved in human cancer using network contextual information. AB - Protein-Protein Interaction (PPI) networks have been widely used for the task of predicting proteins involved in cancer. Previous research has shown that functional information about the protein for which a prediction is made, proximity to specific other proteins in the PPI network, as well as local network structure are informative features in this respect. In this work, we introduce two new types of input features, reflecting additional information: (1) Functional Context: the functions of proteins interacting with the target protein (rather than the protein itself); and (2) Structural Context: the relative position of the target protein with respect to specific other proteins selected according to a novel ANOVA (analysis of variance) based measure. We also introduce a selection strategy to pinpoint the most informative features. Results show that the proposed feature types and feature selection strategy yield informative features. A standard machine learning method (Naive Bayes) that uses the features proposed here outperforms the current state-of-the-art methods by more than 5% with respect to F-measure. In addition, manual inspection confirms the biological relevance of the top-ranked features. PMID- 22948008 TI - Imprinting localized plasmons for enhanced solar cells. AB - Imprinted silver nanovoid arrays are investigated via angle-resolved reflectometry to demonstrate their suitability for plasmonic light trapping. Both wavelength- and subwavelength-scale nanovoids are imprinted into standard solar cell architectures to achieve nanostructured metallic electrodes which provide enhanced absorption for improving solar cell performance. The technique is versatile, low-cost and scalable and can be applied to a wide range of organic semiconductors. Absorption features which are independent of incident polarization and weakly dependent on incident angle reveal localized plasmonic modes at the structured interface. Metallic nanostructure-PCPDTBT:PCBM samples demonstrate absorption enhancements of up to 40%. The structured interface provides light trapping, which boosts absorption at wavelengths where the semiconductors absorb poorly. PMID- 22948009 TI - Abstraction of core measure data: creating a process for interrater reliability. AB - Health care facilities are challenged with an ever-increasing demand for producing accurate quality data to be used for guiding internal improvement initiatives as well as for reimbursement. It is essential that data abstraction be reliable and valid. In this article, we describe an interrater reliability process of data abstraction using the Centers for Medicare and Medicaid Services core measures that successfully reduced variability between abstractors and produced higher quality data. PMID- 22948010 TI - The postpartum endometrial inflammatory response: a normal physiological event with potential implications for bovine fertility. AB - After calving, the bovine endometrium undergoes marked morphological and functional changes that are necessary for subsequent re-breeding. Regulation and integration of these key events are largely uncharacterised. Here, endometrial swabs and biopsies were taken at 15, 30 and 60 days postpartum (DPP) from 13 healthy primiparous cows, 10 of which subsequently conceived, with a view to characterising innate and inflammatory gene expression profiles. Endometrial biopsies exhibited severe inflammation (>75 leukocytes per high-power field) at 15 DPP, which had begun to resolve by 30 DPP and had completely resolved by 60 DPP. The severe inflammation at 15 DPP coincided with uterine infection in all cows and a significant increase (P < 0.05) in the expression of all of 16 genes investigated, including CD45, IL8, IL6, IL1, TNF, TAP, SAA3 and HP at 15 DPP, relative to 60 DPP. All of these parameters had begun to return to normal physiological levels at 30 DPP. Systemically, serum protein concentrations of IL 8 were elevated at 15 DPP compared with 60 DPP (78 pgmL(-1)vs 48 pgmL(-1); P = 0.02). These results indicate that endometrial inflammation, leukocyte infiltration and increased expression of pro-inflammatory, antimicrobial and acute-phase protein genes are expected features of the postpartum period, critical to bacterial clearance and uterine involution. PMID- 22948011 TI - Engineering of L-tyrosine oxidation in Escherichia coli and microbial production of hydroxytyrosol. AB - The hydroxylation of tyrosine is an important reaction in the biosynthesis of many natural products. The use of bacteria for this reaction has not been very successful due to either the over-oxidation to ortho-quinone when using tyrosinases from bacteria or plants, or the lack of the native cofactor, tetrahydrobiopterin (BH4), needed for the activity of tyrosine hydroxylases (TH). Here, we demonstrate that an Escherichia coli cofactor, tetrahydromonapterin (MH4), can be used as an alternative cofactor for TH in presence of the BH4 regeneration pathway, and tyrosine hydroxylation is performed without over oxidation. We used this platform for biosynthesis of one of the most powerful antioxidants, hydroxytyrosol. An endogenous aromatic aldehyde oxidase was identified and knocked out to prevent formation of the side product, and this resulted in nearly exclusive production of hydroxytyrosol in engineered E. coli. Finally, hydroxytyrosol production from a simple sugar as a sole carbon source was demonstrated. PMID- 22948013 TI - Highly selective and sensitive recognition of cobalt(II) ions directly in aqueous solution using carboxyl-functionalized CdS quantum dots as a naked eye colorimetric probe: applications to environmental analysis. AB - Quantum dots (QDs) are usually used as fluorescent probe, and they are difficult to use in colorimetric detection. However, in this report carboxyl-functionalized CdS (COF-CdS) QDs were synthesized in aqueous solution for colorimetric detection following a classic method. On the basis of inducing the aggregation of COF-CdS QDs, a simple naked eye colorimetric method with high sensitivity and selectivity was developed for the sensing of Co(2+) ions in aqueous solutions. The Co(2+) ions induced COF-CdS QDs results in a marked enhancement of the UV-vis absorption spectra at 360 nm, and the process was accompanied by a visible color change from colorless to yellowish brown within 5 min, which proves a sensitive detection of Co(2+) ions. The sensing of Co(2+) ions can therefore be easily achieved by a UV vis spectrophotometer or even by the naked eye. Under the optimized circumstances, this method yields excellent sensitivity (LOD = 0.23 MUg mL(-1)) and selectivity toward Co(2+) ions. The calibration plot of (A - A(0)) at 360 nm against concentration of Co(2+) ions was linear over the range from 0.5 to 14 MUg mL(-1) with a correlation coefficient of 0.9996. The accuracy and reliability of the method were further ascertained by recovery studies via standard addition method with percent recoveries in the range of 99.63-102.46%. The plausible mechanism for the color change reaction has also been discussed. Our attempt may provide a cost-effective, rapid, and simple solution for the inspection of Co(2+) ions in the presence of a complex matrix from environmental aqueous samples. PMID- 22948012 TI - Impact of physical fitness and daily energy expenditure on sleep efficiency in young and older humans. AB - BACKGROUND: Physical activity is known to influence sleep efficiency. Relatively little is known about the relationship between physical activity and sleep efficiency in young and older humans and the impact of exercise training on sleep efficiency in healthy older individuals. OBJECTIVES: To determine the relationship between physical fitness and daily energy expenditure with sleep efficiency in young and older subjects, and assess the effect of 12-month exercise training on sleep efficiency in healthy older participants. METHODS: The relationship between physical fitness (maximal cycling test) and daily energy expenditure (accelerometry) with sleep efficiency (accelerometry) was examined cross-sectionally in 12 healthy young adults (27 +/- 5 years) and 21 healthy older participants (69 +/- 3 years). Subsequently, the effect of 12-month exercise training (n = 11) or control period (n = 10) on sleep efficiency in older participants was examined using a randomized controlled trial. RESULTS: Daily energy expenditure and sleep efficiency did not differ between young and older subjects. A significant correlation was found between energy expenditure and sleep efficiency (r = 0.627, p = 0.029) in young adults, but not in older participants (r = -0.158, p = 0.49). Physical fitness did not correlate with sleep efficiency in either group. Exercise training significantly improved physical fitness (15.0%, p < 0.001), but failed to alter sleep characteristics such as sleep efficiency, sleep onset latency and awakenings. CONCLUSIONS: We found that young adults with higher daily energy expenditure have greater sleep efficiency, whilst this relationship is diminished with advanced age. In contrast, we found no correlation between physical fitness and sleep characteristics in healthy young or older participants, which may explain the lack of improvement in sleep characteristics in older participants with 12-month exercise training. Exercise training may be more successful in subjects with existing sleep disturbances to improve sleep characteristics rather than in healthy older subjects. PMID- 22948016 TI - Joint Bayesian analysis of forensic mixtures. AB - Evaluation of series of PCR experiments referring to the same evidence is not infrequent in a forensic casework. This situation is met when 'series of results in mixture' (EPGs produced by reiterating PCR experiments over the same DNA mixture extract) have to be interpreted or when 'potentially related traces' (mixtures that can have contributors in common) require a combined interpretation. In these cases, there can be uncertainty on the genotype assignment, since: (a) more than one genotype combination fall under the same peak profile; (b) PCR preferential amplification alters pre-PCR allelic proportions; (c) other, more unpredictable technical problems (dropouts/dropins, etc.) take place. The uncertainty in the genotype assignment is in most cases addressed by empirical methods (selection of just one particular profile; extraction of consensual or composite profiles) that disregard part of the evidence. Genotype assignment should conversely take advantage from a joint Bayesian analysis (JBA) of all STRs peak areas generated at each experiment. This is the typical case of Bayesian analysis in which adoption of object-oriented Bayesian networks (OOBNs) could be highly helpful. Starting from experimentally designed mixtures, we created typical examples of 'series of results in mixture' of 'potentially related traces'. JBA was some administered to the whole peak area evidence, by specifically tailored OOBNs models, which enabled genotype assignment reflecting all the available evidence. Examples of a residual ambiguity in the genotype assignment came to light at assumed genotypes with partially overlapping alleles (for example: AB+AC->ABC). In the 'series of results in mixture', this uncertainty was in part refractory to the joint evaluation. Ambiguity was conversely dissipated at the 'potentially related' trace example, where the ABC allelic scheme at the first trace was interpreted together with other unambiguous combinations (ABCD; AB) at the related trace. We emphasize the need to carry out extensive, blind sensitivity tests specifically addressing the residual ambiguity that arises from overlapping results mixed at various quantitative ratios. PMID- 22948014 TI - Effect of chenodeoxycholic acid on fibrosis, inflammation and oxidative stress in kidney in high-fructose-fed Wistar rats. AB - BACKGROUND: Recent studies indicate farnesoid X receptor (FXR) plays an important role in regulating lipid metabolism in kidney disease. The purpose of the present study is to investigate the effect of chenodeoxycholic acid (CDCA), a FXR agonist, on fibrosis, inflammation and oxidative stress in kidney in rats fed on high fructose. METHODS: Twenty-four healthy male Wistar rats were randomly divided into three groups (n=8): normal control group, high fructose group and chenodeoxycholic acid group. Rats were sacrificed by the end of 16 weeks after feeding. Blood urea nitrogen, serum creatinine, fast glucose, lipid concentration were observed, spot urine samples were obtained to measure the albumin and creatinine levels. Triglyceride of renal cortices was detected. The mRNA level and protein contents of the fibrosis-inducing growth factor transforming growth factor beta1 (TGF-beta1) and plasminogen activator inhibitor (PAI-I), inflammatory cytokines tumor necrosis factor alpha (TNF-alpha) and interleukin 6 (IL-6), oxidative stress index NADPH oxidase 2 (Nox2) and p22phox in kidney were examined. The pathological changes of kidney were examined by PAS staining and immunohistochemical staining. Electron microscope sections were made to measure glomerular basement membrane (GBM) width. RESULTS: Renal injuries including mesangial expansion, GBM thickness and podocyte foot process effacement were found in fructose-fed Wistar rats, FXR agonist CDCA modulates renal lipid metabolism, decreases proteinuria and improves renal fibrosis, inflammation and oxidation stress. High-fructose-feeding may cause lipid nephrotoxicity through down-regulated farnesoid X receptor and increases expression of profibrotic growth factors, proinflammatory cytokines, and oxidative stress in Wistar rats. CONCLUSION: FXR activation by chenodeoxycholic acid can prevent the injury in kidney induced by high fructose feeding. PMID- 22948017 TI - Ultrasound protocols to measure carotid intima-media thickness: one size does not fit all. PMID- 22948018 TI - Stem cells: hierarchy in the population. PMID- 22948019 TI - DNA damage response: restricting repair.